Documents

IN THE HIGH COURT OF DELHI AT NEW DELHI
(Original Commercial Jurisdiction – IP Division)
CS (Comm.) No. 660 of 2022
In the matter of:

Bayer Health Care LLC. …Plaintiff
versus
MSN Laboratories Private Limited …Defendant
LIST OF DOCUMENTS FILED ON BEHALF OF

DEFENDANT
MASTER INDEX
VOL-1
S. Particulars Details of Wheth Mode of Issuanc Line of Page
No. of the the parties er Execution e of Custody No.
Document to the docum Receipt
document ent in
possess
ion/po
wer/co
ntrol/c
ustody
is
origina
l/office
copy/p
hotoco
py
1. E Register of Indian Patent Copy Executed by Availab From
IN 240207 Office and IPO le on Defenda 1-3
Bayer IPO nt to its
Healthcare website Counsel
LLC
(Publicly
Available)
2. Form 1 of IN Indian Patent Copy Executed by Availab From 4-6
240207 Office and Bayer le on Defenda
Bayer Pharmaceuti IPO nt to its
Healthcare cals website Counsel
LLC Corporation
(Publicly
Available)
3. Form 3s of IN Indian Patent Copy Executed by Availab From
240207 Office and Bayer le on Defenda 7-17
LLC Corporation
(Publicly
Available)
4. First Indian Patent Copy Executed by Availab From
Examination Office and IPO le on Defenda
Report of IN Bayer IPO nt to its 18-
240207 Healthcare website Counsel 19
LLC
(Publicly
Available)
5. Response to Indian Patent Copy Executed by Availab From
First Office and Bayer le on Defenda
Examination Bayer Pharmaceuti IPO nt to its 20-
Report to IN Healthcare cals website Counsel 23
240207 LLC Corporation
(Publicly
Available)
6. Claims (as Indian Patent Copy Executed by Availab From
filed) of IN Office and Bayer le on Defenda
240207 Bayer Pharmaceuti IPO nt to its 24-
Healthcare cals website Counsel 34
LLC Corporation
(Publicly
Available)
granted) of Office and IPO le on Defenda 35-
IN 240207 Bayer IPO nt to its 36
LLC
(Publicly
Available)
8. Copy of World Copy Executed by Availab From
WO/2005/00 Intellectual WIPO le on Defenda
9961 Property WIPO nt to its 37-
Organization website Counsel 104
and Bayer
Pharmaceuti
cals
Corporation
(Publicly
Available)
9. Copy of US United Copy Executed by Availab From
8,637,553 States USPTO le on Defenda
Patents and USPTO nt to its 105-
Trademark website Counsel 146
Office and
Bayer Health
Care LLC
(Publicly
Available)
10. Copy of Indian Patent Copy Executed by Availab From
1628/DELNP Office and Bayer le on Defenda
/2009 Bayer Schering IPO nt to its 147-
Schering Pharma website Counsel 148
Pharma AG Aktiengesel
(Publicly lschaft
Available) (Bayer AG)
11. Form 1 of Indian Patent Copy Executed by Availab From
(Publicly lschaft
12. Form 3s of Indian Patent Copy Executed by Availab From
Pharma website Counsel 238
Schering Aktiengesel
Pharma AG lschaft
(Publicly (Bayer AG)
Available)
(Publicly
Available)
filed) of Office and Bayer le on Defenda
1628/DELNP Bayer Schering IPO nt to its 239-
/2009 Schering Pharma website Counsel 240
(Publicly lschaft
(Publicly
Available)
Examination Office and Indian le on Defenda
Report of Bayer Patent IPO nt to its 241-
1628/DELNP Schering Office website Counsel 243
/2009 Pharma AG
(Publicly
Available)
(Publicly
Available)
15. Reply to FER Indian Patent Copy Executed by Availab From
of Office and Bayer le on Defenda
(Publicly lschaft
(Publicly
Available)
16. Copy of European Copy Executed by Availab From
objection Patent Office European le on Defenda
from and Bayer Patent EPO nt to its 251-
European Schering Office website Counsel 253
Patent Office Pharma AG
on (Publicly
EP2097381 Available)
17. Reply to European Copy Executed by Availab From
objection Patent Office Bayer le on Defenda
from and Bayer Schering EPO nt to its 254-
European Schering Pharma website Counsel 255
Patent Office Pharma AG Aktiengesel
on (Publicly lschaft
EP2097381 Available) (Bayer AG)
VOL-2
18. Australia Department Copy Executed by Availab From
regulatory of Health, Department le on Defenda
approval for Australian of Health, TGA nt to its 256-
Stivarga Government Australian website Counsel 315
and Bayer Government
Australia
Limited
(Publicly
Available)
19. USFDA USFDA and Copy Executed by Availab From
regulatory Bayer USFDA le on Defenda
approval for HealthCare USFDA nt to its 316-
Stivarga Pharmaceuti website Counsel 333
cals Inc.
(Publicly
Available)
20. Europe European Copy Executed by Availab From
regulatory Medicines European le on Defenda
approval for Agency and Medicines Europea nt to its 334-
Stivarga Bayer Agency n Counsel 424
Pharma AG Medicin
(Publicly es
Available) Agency
IN 215758 Office and IPO le on Defenda
Bayer IPO nt to its 425-
Corporation website Counsel 427
(Publicly
Available)
22. Form 1 of IN Indian Patent Copy Executed by Availab From
215758 Office and Bayer le on Defenda 428
Bayer Corporation IPO nt to its
Corporation website Counsel
(Publicly
Available)
23. Complete Indian Patent Copy Executed by Availab From
Specification Office and IPO le on Defenda 429-
(as granted) Bayer IPO nt to its 531
of IN 215758 Corporation website Counsel
(Publicly
Available)
VOL-3
filed) of IN Office and Bayer le on Defenda 532-
215758 Bayer Corporation IPO nt to its 556
(Publicly
Available)
(Publicly
Available)
and Bayer
Corporation
(Publicly
Available)
Office and
Bayer
Pharmaceuti
cals
Corporation
(Publicly
Available)
VOL-4
28. Copy of the United Copy Executed by Availab From
patent term States Bayer le at Defenda
extension Patents and Pharmaceuti USPTO nt to its 745-
application of Trademark cals website Counsel 826
US 7,351,834 Office and Corporation
Bayer
Healthcare
LLC
(Publicly
Available)
29. Copy of the United Copy Executed by Availab From
patent term States USPTO le at Defenda
extension Patents and USPTO nt to its 827-
certificate of Trademark website Counsel 828
US 7,351,834 Office and
Bayer
Healthcare
LLC
(Publicly
Available)
30. Copy of the Onyx Copy Executed by Availab From
complaint Pharmaceuti Onyx le Defenda
filed by Onyx cals and Pharmaceuti through nt to its 829-
Pharmaceutic Bayer cals Internet. Counsel 844
als against Corporation
Bayer & Bayer
Corporation AG.
& Bayer AG. (Publicly
at the United Available)
States District
Court,
Northern
District of
California
reply filed by Pharmaceuti Bayer le Defenda
Bayer cals and Corporation through nt to its 845-
Corporation Bayer & Bayer Internet. Counsel 870
& Bayer AG Corporation AG
against the & Bayer
complaint AG.
filed by Onyx (Publicly
Pharmaceutic Available)
als at the
United States
District
Court,
Northern
District of
California
VOL-5
32. Copy of the Bayer Copy Executed by Availab From
settlement Healthcare Bayer le on Defenda
agreement LLC & Healthcare www.se nt to its 871-
between Onyx LLC & c.gov Counsel 929
Bayer Pharmaceuti Onyx
Healthcare cals, INC Pharmaceuti
LLC & Onyx (Publicly cals, INC
Pharmaceutic Available)
als, INC filed
with SEC
order passed Pharmaceuti United le Defenda 930-
by United cals and States through nt to its 955
States District Bayer District Internet Counsel
Court, Corporation Court,
Northern & Bayer Northern
District of AG. District of
California in (Publicly California
Onyx Available)
Pharmaceutic
als Vs. Bayer
Corporation
& Bayer AG
1633/MUMN Office and IPO le at Defenda 956-
P/2007 Bayer IPO nt to its 957
(Publicly
Available)
1633/MUMN Office and Bayer le at Defenda 958-
P/2007 Bayer Corporation IPO nt to its 965
(Publicly
Available)
VOL-6
(Publicly
Available)
37. Claims as Indian Patent Copy Executed by Availab From
filed in Office and Bayer le at Defenda 1006
1633/MUMN Bayer Corporation IPO nt to its -
P/2007 Corporation website Counsel 1029
(Publicly
Available)
38. Claim Indian Patent Copy Executed by Availab From
amendments Office and Bayer le at Defenda 1030
in Bayer Corporation IPO nt to its -
1633/MUMN Corporation website Counsel 1046
P/2007 (Publicly
Available)
Examination Office and IPO le at Defenda 1047
Report of Bayer IPO nt to its -
1633/MUMN (Publicly
P/2007 Available)
of Office and Bayer le at Defenda 1050
(Publicly
Available)
refusal order Office and IPO le at Defenda 1060
for grant of Bayer IPO nt to its -
P/2007 as (Publicly
divisional Available)
Patent
European Patent Office EPO le at Defenda
Application and Bayer EPO nt to its 1066
EP 1793824 Healthcare website Counsel -
LLC 1068
(Publicly
Available)
43. Copy of EP Bayer Copy Executed by Availab From
Appeal Board Healthcare EP Appeal le at EP Defenda 1069
Decision - T LLC & Ter Board Appeal nt to its -
18 0377 Meer Board Counsel 1096
Steinmeister website
& Partner
Patentanwale
te mbB
(Publicly
Available)
VOL-7
44. Copy of US USPTO and Copy Executed by Availab From
7235576 Bayer USPTO le at Defenda 1097
Pharmaceuti USPTO nt to its -
cals website Counsel 1163
Corporation
(Publicly
Available)
45. Copy of Columbian Copy Executed by Availab From
Patent Status Patent Columbian le at Defenda 1164
CO28604 Office, Patent ESPAC nt to its -
(equivalent of Bayer Office ENET Counsel 1174
WO’012) Corporation
and Bayer
Healthcare
LLC
(Publicly
Available)
CO06005884 Patent Office Columbian le at Defenda
(equivalent to & Bayer Patent ESPAC nt to its 1175
suit patent in Pharmaceuti Office ENET Counsel -
Columbia) cal 1179
Corporation
(Publicly
Available)
refusal order Patent Office Columbian le at Defenda
of & Bayer Patent ESPAC nt to its 1180
CO06005884 Corporation Office ENET Counsel -
(equivalent to (Publicly 1189
suit patent in Available)
Columbia)
48. Copy of Argentina Copy Executed by Availab From
Argentina Patent Office Argentina le at Defenda
Patent (AR and Bayer Patent Argenti nt to its 1190
035310B1) Corporation Office na Counsel -
(WO’012 (Publicly Patent 1194
equivalent) Available) Office
Website
Argentina Patent Office Argentina le at Defenda 1195
Application and Bayer Patent Argenti nt to its -
(AR Healthcare Office na Counsel 1196
048741A1) LLC Patent
(equivalent to
(Publicly Office
suit patent)
Available) Website
50. Copy of WIPO and Copy Executed by Availab From 1197
WO2000/041 Bayer WIPO le at Defenda -
698 Corporation WIPO nt to its 1344
(Publicly website Counsel
Available)
51. Copy of WIPO and Copy Executed by Availab From
WO2004/078 Bayer WIPO le at Defenda 1345
746 Pharmaceuti WIPO nt to its -
cals website Counsel 1430
Corporation
(Publicly
Available)
52. PROOF OF SERVICE 1431
Through
Place: Noida (NCR)
y-
Date: 03.10.2022
Counsel for the Defendant
Guruswamy Nataraj
LCGN Advocates & IP Attorneys
A-6, 2nd Floor, Sector 7
NOIDA 201 307, NCR
Phone: 9811808373
Email: litigation@gnataraj.com
IN THE HIGH COURT OF DELHI AT NEW
DELHI
CS (Comm.) No. 660 of 2022
In the matter of:

versus

DEFENDANT
MASTER INDEX
VOL-1
document ent in
possess
ion/po
wer/co
ntrol/c
ustody
is
origina
l/office
copy/p
hotoco
py
IN 240207 Office and IPO le on Defenda 1-3
Bayer IPO nt to its
LLC
(Publicly
Available)
2. Form 1 of IN Indian Patent Copy Executed by Availab From 4-6
240207 Office and Bayer le on Defenda
LLC Corporation
(Publicly
Available)
3. Form 3s of IN Indian Patent Copy Executed by Availab From
240207 Office and Bayer le on Defenda 7-17
LLC Corporation
(Publicly
Available)
Examination Office and Bayer le on Defenda
Report of IN Bayer Pharmaceuti IPO nt to its 18-
240207 Healthcare cals website Counsel 19
LLC Corporation
(Publicly
Available)
5. Response to Indian Patent Copy Executed by Availab From
First Office and Bayer le on Defenda
Examination Bayer Pharmaceuti IPO nt to its 20-
Report to IN Healthcare cals website Counsel 23
240207 LLC Corporation
(Publicly
Available)
filed) of IN Office and Bayer le on Defenda
240207 Bayer Pharmaceuti IPO nt to its 24-
Healthcare cals website Counsel 34
LLC Corporation
(Publicly
Available)
granted) ofOffice and IPO le on Defenda 35-
LLC
(Publicly
Available)
and Bayer
Pharmaceuti
cals
Corporation
(Publicly
Available)
Office and
Bayer Health
Care LLC
(Publicly
Available)
(Publicly lschaft
Pharma website Counsel 159
Schering Aktiengesel
Pharma AG lschaft
(Publicly (Bayer AG)
Available)
12. Form 3s of Indian Patent Copy Executed by Availab From
(Publicly lschaft
(Publicly
Available)
filed) of Office and Bayer le on Defenda
(Publicly lschaft
(Publicly
Available)
Examination Office and Indian le on Defenda
Report of Bayer Patent IPO nt to its 241-
1628/DELNP Schering Office website Counsel 243
/2009 Pharma AG
(Publicly
Available)
(Publicly
Available)
of Office and Bayer le on Defenda
(Publicly lschaft
(Publicly
Available)
objection Patent Office European le on Defenda
from and Bayer Patent EPO nt to its 251-
European Schering Office website Counsel 253
Patent Office Pharma AG
on (Publicly
EP2097381 Available)
17. Reply to European Copy Executed by Availab From
objection Patent Office Bayer le on Defenda
from and Bayer Schering EPO nt to its 254-
European Schering Pharma website Counsel 255
Patent Office Pharma AG Aktiengesel
on (Publicly lschaft
EP2097381 Available) (Bayer AG)
Through
Place: Noida (NCR)
Date: 03.10.2022
Guruswamy Nataraj
NOIDA 201 307, NCR
Phone: 9811808373
Email:litigation@gnataraj.com
I
Office of the Controller General of Patents, Designs & Trade Marks
Department of Industrial Policy & Promotion,
Ministry of Commerce & Industry,
Government of India
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(http://ipindia.nic.in/index.htm)
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PROPERTYINDIA
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Legal Status : Inforce
Due date of next renewal : 22/07/2023
Patent Number : 240207 Date of Patent : 22/07/2004
Application Number : 402/DELNP/2006 Date of Grant : 29/04/2010
Type of Application : PCT NATIONAL PHASE APPLICATION Date of Recordal : 29/04/2010
Parent Application : --- Appropriate Office : DELHI

Number
PCT International : PCT/US2004/023500 PCT International Filing Date : 22/07/2004

Application Number
Grant Title : "A FLUORO SUBSTITUTED OMEGA-CARBOXYARYL DIPHENYL UREA COMPOUND OR

A SALT, AN ISOLATED STEREOISOMER THEREOF
SlNo
SI No Name
Nameof
ofGrantee
Grantee Grantee Addn!$$
GrantieeAddress
1 BAYER HEALTHCARE LLC 555 WHITE PLAINS ROAD,TARRYTOWN,NEW YORK 10591,USA
SlNo
SI No Name
Nameof
of Patentee
Patentee Address of
Addres.sof Patentee
Patentee
1 BAYER HEALTHCARE LLC 100, Bayer Boulevard, Whippany, New Jersey, 07981, United States of America.
Address : ANAND AND ANAND ADVOCATES, B-41, Nizamuddin East, New Delhi – 110013, Phone No: 0091-
of Service 11-24355076, 24358078, +91-120-4059300 , Fax No: 0091-11-24354243, 91-120-4243056,-058 E-
mail: email@anandandanand.com; archana@anandandanand.com
Additional :
Address
of Service
Priority : 23/07/2003
Date
Year Due
Year Duedates
datesfor
for Renewal
Renewal CBR
CBR CBR Date
CBR Date Renewal
Renaval Renewal
Renaval Date
Da1IIof
of Renewal
RenaralPeriod:
Peflad:
No
No Amount
Amount Certificate Renewal
Cenllk:ateRenaral
No
No
[fu~JE coi>v]!
Normal Due Date From To
Due Date with
Extension
3rd 29/07/2010 29/01/2011 6417 29/07/2010 2000 6541 29/07/2010 22/07/2006 22/07/2007
year
4th 29/07/2010 29/01/2011 6417 29/07/2010 2000 6541 29/07/2010 22/07/2007 22/07/2008
year
5th 29/07/2010 29/01/2011 6417 29/07/2010 2000 6541 29/07/2010 22/07/2008 22/07/2009
year
6th 29/07/2010 29/01/2011 6417 29/07/2010 2000 6541 29/07/2010 22/07/2009 22/07/2010
year
7th 29/07/2010 29/01/2011 6417 29/07/2010 6000 6541 29/07/2010 22/07/2010 22/07/2011
year
8th 22/07/2011 22/01/2012 6245 11/07/2011 6000 6997 11/07/2011 22/07/2011 22/07/2012
year
9th 22/07/2012 22/01/2013 6609 18/07/2012 6000 6869 18/07/2012 22/07/2012 22/07/2013
year
10th 22/07/2013 22/01/2014 5713 07/06/2013 6000 5286 07/06/2013 22/07/2013 22/07/2014
year
11th 22/07/2014 22/01/2015 10586 02/06/2014 24000 10122 02/06/2014 22/07/2014 22/07/2015
year
12th 22/07/2015 22/01/2016 12391 11/06/2015 24000 11686 11/06/2015 22/07/2015 22/07/2016
year
13th 22/07/2016 22/01/2017 13641 07/06/2016 24000 11578 07/06/2016 22/07/2016 22/07/2017
year
14th 22/07/2017 22/01/2018 21606 22/06/2017 24000 25724 22/06/2017 22/07/2017 22/07/2018
year
15th 22/07/2018 22/01/2019 15982 21/06/2018 24000 27138 21/06/2018 22/07/2018 22/07/2019
year
16th 22/07/2019 22/01/2020 19648 21/06/2019 40000 31053 21/06/2019 22/07/2019 22/07/2020
year
17th 22/07/2020 22/01/2021 20457 24/06/2020 40000 38859 24/06/2020 22/07/2020 22/07/2021
year
18th 22/07/2021 22/01/2022 22006 23/06/2021 40000 43937 23/06/2021 22/07/2021 22/07/2022
year
19th 22/07/2022 22/01/2023 24750 29/06/2022 40000 47893 29/06/2022 22/07/2022 22/07/2023
year
20th -- -- -- -- -- -- -- -- --
year
Sl DII•
SI Date of
of Particulars/Remarks
Pl111Clllal'IIIWnallis
No &try
NG Entry
1 23/03/2021 Entry u/s 67 Rule 88: ORIGINAL APPLICATION No.: ORA/9/2020/PT/DEL/ filed before IPAB For
the Revocation of Patent No. IN240207. By Order: Joint Controller of Patents and Designs
PATENT OFFICE DELHI-(Entry Made by User: drsssingh)
2 06/11/2018 Entry for Alteration u/r 94…..… In Pursuance of the three request received u/r 94(1) dated
05/08/2016 17/02/2012 & 28/03/2014 (E-25/259/2016/DEL E-25/92/2012-DEL & E-25/48/2014-
DEL) for alteration of change of address of the patentee from 555 White Plains Road
Tarrytown New York 10591 United States of America" to "100 Bayer Boulevard Whippany
New Jersey 07981 United States of America"" and further change of address for services of
the patentee as ANAND AND ANAND ADVOCATES B-41 Nizamuddin East New Delhi –
110013 Phone No: 0091-11-24355076 24358078 +91-120-4059300 Fax No: 0091-11-
24354243 91-120-4243056 -058 E-mail: email@anandandanand.com;
archana@anandandanand.com” is hereby allowed and thus entries in the register of patents
to this effect be made and altered accordingly. By Order: Deputy Controller of Patents &
Designs PATENT OFFICE DELHI. User : maneedev
Information u/s 146 (Working of Patents)
Sl No
SINo Patent Number
,_Number Year
1 240207 2013-2014 View Document
2 240207 2014-2015 View Document
3 240207 2015-2016 View Document
4 240207 2016-2017 No Document
5 240207 2017-2018 View Document
6 240207 2018-2019 View Document
7 240207 2019-2020 View Document
I View Documents
Ap~OcJloQ '~/ I ? 0 06
DELNP
Filing date:
Amount of Fee paid: 2 3 JAN
2006
CBRNo.
Signature:
FORM 1
THE PATENTS ACT, 1970
[39 OF 1970)
&
THE PATENTS RULES, 2003
APPLICATION FOR GRANT OF PATENT
[See Sections 7, 135 and rule 20 (1)]
1. We, BAYER PHARMACEUTICALS CORPORATION, a corporation

organised under the laws of the State of Delaware, United States of
America, of 400 Morgan Lane, West Haven, CT 06516-4175, United
States of America,
2. JACQUES DUMAS, a French citizen of 98 Farmview Road,

Bethany, CT 06524, USA; STEPHEN BOYER, a German citizen of
Mittelstrasse 55, 40721 Hilden, Germany; BERND RIEDL, a
German citizen of Vin-der-Golz Strasse 7, 42329, Wuppertal,
Germany and SCOTI WILHELM, a US citizen of 255 Midland
Drive, Orange, CT 06477, USA,
3. "FLUORO SUBSTITUTED OMEGA-CARBOXYARYL DIPHENYL

UREA FOR THE TREATMENT AND PREVENTION OF DISEASE"
4. That our address for service in India is:

REMFRY & SAGAR
Attorneys-at-Law
Remfry House.
Millennium Plaza
Sector 27, Gurgaon 122 002,
India. - Telephone No. 91-124-280-6100
Telefax No. 91-124-280 6101
5.
[a] U.S.A. and U.S.A.
[b) 60/489,102 and 60/54(},326
[c] 23.7.2003 AND 2.2.2004
2----
[d) JACQUES DUMAS, STEPHEN BOYER, BERND RIEDL AND SCOTI
WILHELM I
[e] "FLUORO SUBSTITUTED OMEGA-CARBOXYARYL DIPHENYL

6. Particulars for filing National phase application
I PCT/US04/023500 I 22.7.2004
IITRUE COPYjl
Declaration by the applicant(s) in the convention country
I/We, JACQUES DUMAS, a French citizen of 98 Farmview Road,
Mittelstrasse 55, 40721 Hilden, Germany; BERND RIEDL, a German
citizen of Vin-der-Golz Strasse 7, 42329, Wuppertal, Germany and
SCOTT WILHELM, a US citizen of 255 Midland Drive, Orange, CT 06477,
USA, the applicant(s) in the convention country declare that the applicant(s)
herein is/are my/our assignee or legal representative.
JACQUES DUMAS STEPHEN BOYER
BERND RIEDL SCOTT WILHELM
Declaration by the applicant(s):
I/We, the applicant(s) hereby declare(s) that:-

I am/we are in possession of the above-mentioned invention
The complete specification relating to the invention is filed
with this application.
There is no lawful ground of objection to the grant of the
Patent to me/us.
The application or each of the applications, particulars of
which are given in Para 5 was the first application in
convention country/ countries in respect of my/ our
invention.
I/we claim the priority from the above mentioned
application(s) filed in convention country /countries and
state that no application for protection in respect of the
invention had been made in a convention country before that
date by me/us or by any person from which I/we derive the
title.
My/ our application in India is based on International
application under Patent Cooperation Treaty (PCT) as
mentioned in Para-6.
Following are the attachment with the application:
(a) Complete specification in conformation with the Jnternatiorn=i1
application/as amended before the International Preliminary \
Examination Authority (IPEA), as applicable (2 copies), No. of pages
68 No. of claims 54.
[b] Statement and undertaking on Form 3
[c] Declaration of inventorship on Form 5
[d] Fee Rs. 58400 /- by cheque
IiTRUE COPYjl
I/We hereby declare that to the best of my /our knowledge, information
and belief the fact and matters stated herein are correct and I/we
request that a patent may be granted to me/us for the said invention.
Dated this 23/1/2006
BAYER PHARMACEUTICALS CORPORATION,
~
B. KOMBI
OF REMFRY & SAGAR
ATIORNEY FOR THE APPLICANT[S]
THE CONTROLLER OF PATENTS,

THE PATENT OFFICE, DELHI
IITRUE COPYjl
Ap~OcJloQ '~/ I ? 0 06
DELNP
Filing date:
Amount of Fee paid: 2 3 JAN
2006
CBRNo.
Signature:
FORM 1
[39 OF 1970)
&
APPLICATION FOR GRANT OF PATENT
[See Sections 7, 135 and rule 20 (1)]
1. We, BAYER PHARMACEUTICALS CORPORATION, a corporation

States of America,
2. JACQUES DUMAS, a French citizen of 98 Farmview Road,

Germany and SCOTI WILHELM, a US citizen of 255 Midland
Drive, Orange, CT 06477, USA,
3. "FLUORO SUBSTITUTED OMEGA-CARBOXYARYL DIPHENYL

4. That our address for service in India is:

REMFRY & SAGAR
Attorneys-at-Law
Remfry House.
Millennium Plaza
Telefax No. 91-124-280 6101
5.
[a] U.S.A. and U.S.A.
[b) 60/489,102 and 60/54(},326
[c] 23.7.2003 AND 2.2.2004
2----
[d) JACQUES DUMAS, STEPHEN BOYER, BERND RIEDL AND SCOTI
WILHELM I
[e] "FLUORO SUBSTITUTED OMEGA-CARBOXYARYL DIPHENYL

6. Particulars for filing National phase application
I PCT/US04/023500 I 22.7.2004
IITRUE COPYjl
Declaration by the applicant(s) in the convention country
I/We, JACQUES DUMAS, a French citizen of 98 Farmview Road,
Mittelstrasse 55, 40721 Hilden, Germany; BERND RIEDL, a German
citizen of Vin-der-Golz Strasse 7, 42329, Wuppertal, Germany and
SCOTT WILHELM, a US citizen of 255 Midland Drive, Orange, CT 064 77,
USA, the applicant(s) in the convention country declare that the applicant(s)
herein is/are my/our assignee or legal representative.
JACQUES DUMAS STEPHEN BOYER
BERND RIEDL SCOTT WILHELM
Declaration by the applicant(s):

The complete specification relating to the invention is filed
with this application.
There is no lawful ground of objection to the grant of the
Patent to me/us.
The application or each of the applications, particulars of
which are given in Para 5 was the first application in
convention country/countries in respect of my/our
invention.
I/we claim the priority from the above mentioned
application(s) filed in convention country/countries and
state that no application for protection in respect of the
invention had been made in a convention country before that
date by me/us or by any person from which I/we derive the
title.
My/ our application in India is based on International
application under Patent Cooperation Treaty (PCT) as
mentioned in Para-6.
(a) Complete specificatjon in conformation with the International
application/ as amended before the International Preliminary \
Examination Authority (IPEA), as applicable (2 copies), No. of pages
68 No. of claims 54.
[c] Declaration of inventorship on Form 5
[d] Fee Rs. 58400/- by cheque
[ITRUE COPYII
I/We hereby declare that to the best of my /our knowledge, information
and belief the fact and matters stated herein are correct and I/we
request that a patent may be granted to me/us for the said invention.
BAYER PHARMACEUTICALS CORPORATION,
~
B. KOMBI
OF REMFRY & SAGAR
ATIORNEY FOR THE APPLICANT[S]

IITRUE COPYjl
FORM3
PATENTS ACT, 1970
[39 OF 1970]
&
THE PATENTS (AMENDMENT) RULES, 2006
STATEMENT & UNDERTAKING UNDER SECTION 8
[See Section 8 and Rule 12]
We, BAYER HEALTHCARE LLC., a corporation organized under the laws of Delaware,
USA with address at 555 White Plains Road, Tarrytown, New York 10591, United States of
America,
hereby declare:-
[i] We JACQUES DUMAS, a French citizen, of 98 Fannview Road, Bethany, CT

06524, USA; STEPHEN BOYER, a German citizen, of Mittelstrasse 55, 40721
Hilden, Germany, BERND RIEDL, a German citizen, of Vin-der-Golz Strasse 7,
42329, Wuppertal, Germany, and SCOTT WILHELM, a US citizen, of 255 Midland
Drive, Orange, CT 06477, USA, have made this application No. 402/DELNP/2006
dated 23/10/2006 jointly made for the <same/substantially> same invention
application[s] for patent in the USA, the particulars of which is given below:
Country Filing date Application no. Status Publicati Grant Patent

on date date no.
USA 11/09/2003 10/659,639 Abandoned - - -
USA 22/07/2004 10/895,985 Allowed - - -
[ii] that the rights in the aforementioned application have been assigned to BAYER
HEALTHCARE LLC.
[iii] that we have made this application No: 402/DELNP/2006 dated: 23/01/2006 jointly
made for the <same/substantially> same invention application[s] for patent in the
other countries the particulars of which are given below:
See Annexure
iv] that the rights in the application[s] have been assigned to: BAYER HEALTHCARE
LLC.
that we undertake that up to the date of grant of the patent, by the Controller, I/we
would keep him informed in writing the details regarding corresponding applications
for patents filed outside India within six months from the date of filing of such
application.
Dated this 5th day of January, 2010.

N~S1lJv~
(NEHASRIV ASTAVA)
OF REMFRY & SAGAR
ATTORNEY FOR THE APPLICANT[S]
To
THE PATENT OFFICE, DELID
IITRUE COPYjl
ANNEXURE
Application No.: 402/DELNP/2006
Application#/ Patent#/
Country FUingDate Issue Date Status
Armenia 200600317 010485

2J26l2006 10l3CY2008
Nelher1ands tnactive
Anliles
Argentina P040102614 Pending
7123/2003
Australia 20042597f,() Pending
7/22J2004
Aruba lnadive
Azeftlc$!n 200600317 010485 Gralted

2J26l2006 10f.3Cll2008
Brazil PI0412219-4 Pending
1/20l2006
Ba-.arra 1761 Pending
Islands 1/5/2005
Belarus 200600317 010485 Granted
2J26l2006 10l3CY2008
2~ Pending
1117/2006
Olie 1834-2004 Pending
7/23fJfJ03
Ctina 200480021091.1 ~ished

1/20l2006
cco,ua 06-5884 ~ished
1/23/2006
CooTua ~ished
8111/2006
costaRica 8212 2673
112312006 fN'29J2008
costaRica 01093 Pending
5'2t2008
2006-0013 Pending
1/23/2006
Neh_.3:::.S
<l.tvM~"-f?
zE--
IITRUE COPYII
Dominican P-2004/21 /07/02 Pending
Rep. 7/21/2004
Algeria 06<m2 Pending
2/2212006
Euasia"I 200600317 010485 Glarted
Paer1t 2/26/2006 1Ol30l'2008
Ecuador SP-06-6302 ~ished
1/23/2006
Egypt PCTl5&'2{)ffi PendllQ
1/19/2006
Etrnpeat Inactive
PatentOffice
GulfCoast Inactive
Commes
Pl--2004-0140 5303
7/21f2004 6l'22/2009
HongKong 07100236.7 ~ished
1/8/2007
Pl/0E2004254 4692.19511X
7/231'J003
Croatia P-2fD50073A ~ished
2l20l2006
Hali Pending
W-00200600196 Gralted
1/23/2006 11/14/2008
173256 Pending
1/19/2006
Iran
Jamaica 18/1/4339 3663

1/4/2005 10/4/2006
Jorda\ 22/2006 Pending
1/23/2006
Japan ~1221 Pending
7/22J2004
Kyrgyzstan 200600317 010485 Gra1ted
2/26/2006 10/30/2008
IITRUE COPYjl
Korea.south 10-2006-7001558 Pending
1/23/2006
762/2008 Pending
11/6/2008
200600317 010485
2/26/2006 10/30f2008
Lebanal delete
Morocoo 28799 27946

2113'2006 6/1!2006
2CD:i00317 010485
2/26/2006 1000/2008
~lfeliego P-383/08 Pending
10/17/2008
Mexico 2000000860 261954
1f23l2006 11/6'2008
Malaysia Pl20042941 Pending
7!22J2004
Nigeria 0712006 RP16640 Gfa1ted
1f23l2006 111'l212(D;,
Nicaagua 2006-CXXXJ16 1949 Glalted
1/20'2006 9117/2009
2CD50070 Pending
m2l20Clo
NewZeaaro 544920 Pending
7!22J2004
IITRUE COPYjl
FORM3 °R,G/NAl
THE PATENTS ACT, 1970 'i
[39 OF 1970]
&
THE PATENT RULES, 2003
As amended by
THE PATENTS (AMENDEMNET) RULES, 2006
We, BAYER PHARMACEUTICALS CORPORATION, a corporation organized under the laws

of the State of Delaware, United States of America, of 400 Morgan Lane, West Haven, CT
06516-4175, United States of America,
hereby declare:
[i] That we have made this application No. 402/DELNP/2006 Dated 23/01/2006
<alone/jointly> made for the <same/substantially> same invention application[s] for
patent in the other countries, the particulars of which are given below:
See Annexure
[ii] That the rights in the application[s] has/have been assigned to: No one
iii] that <I/we> undertake that up to the date of grant of the patent, by the Controller, I/we
would keep him informed in writing the details regarding corresponding applications for patents
filed outside India within six months from the date of filing of such application.
Dated this day of August, 2009.
N~;il v~Va
[NEHA SRIVASTAVA]
OF REMFRY & SAGAR
To
THE PATENT OFFICE,
DELID
IITRUE COPYjl
Annexure
Application No. 402/DELNP/2006
COUNTRY APPLICATION FILING PATENT GRANT

NO. DATE NO. DATE
ALGERIA 060082 22/02/2006
ARGENTINA P040102614 23/07/2003
AUSTRALIA 2004259760 22/07/2004
BRAZIL PI0412219-4 20/01/2006
BAHAMA 1761 05/01/2005
ISLANDS
CANADA 2532865 17/01/2006
CHILE 1834-2004 23/07/2003
CHINA 200480021091.1 20/01/2006
COLOMBIA 06-5884 23/01/2006
COSTA RICA 8212 23/01/2006 2673 29/05/2008
CUBA 2006-0013 23/01/2006
DOMINICAN P-2004/21/07 /02 21/07/2004
REP.
EURASIAN 200600317 26/02/2006
PATENT
ECUADOR SP-06-6302 23/01/2006
EGYPT PCT/58/2006 19/01/2006
GUATEMALA PI-2004-0140 21/07/2004
HONGKONG 07100236.7 08/01/2007
HONDURAS PIIDE2004254 23/07/2003 4692/95/IX
CROATIA P-20060073A 20/02/2006
INDONESIA W-00200600196 23/01/2006 14/11/2008
ISRAEL 173256 19/01/2006
JAMAICA 18/1/4339 04/01/2005 3663 04/10/2006
JORDAN 22/2006 23/01/2006
JAPAN 2006-521221 22/07/2004
SOUTH 10-2006-7001558 230/1/2006
KOREA
MOROCCO 28799 13/02/2006 27946 06/01/2006
MONTENEGRO P-383/08 13/02/2006
MEXICO 2006/000860 23/01/2006 261954 6/11/2008
MALAYSIA PI20042941 22/07/2004
NIGERIA 07/2006 23/01/2006 RP16640 22/11/2006
NICARAGUA 2006-000016 20/01/2006
NORWAY 20060870 22/02/2006
NEW 544920 22/07/2004
ZEALAND
PERU 000709-2004 23/07/2004
PHILIPPINES 1-2006-500171 20/01/2006
PAKISTAN 139016 14/07/2004 139016 14/11/2006
SINGAPORE 200600441-0 13/01/2006 119040 30/05/2007
EI SALVADOR E-2776-04 23/07/2004
THAILAND 092472 23/07/2003
'""'nIf\ ,,.,.nnr,
TUNISIA 06020 &--
1
IITRUE COPYjl
TAIWAN 093122197 23/07/2003
UKRAINE 2006 00766 27/01/2006 84156 25/09/2008
URGUAY 28.428 23/07/2003
VENEZUELA 2004-002064 23/07/2004
SERBIA P-37/2006 23/01/2006
SOUTH 2006/00609 23/01/2006 2006/00609 30/05/2007
AFRICA
USA 10/895,985 22/07/2004
IITRUE COPYjl
THE PAiE~~~ A~A~J'· , 2 , oaNP, r;no.6
[39 OF 1970]
&
THE PATENTS RULES, 2003 '
2006
2 3 JAN
We, BAYER PHARMACEUTICALS CORPORATION, a corporation

States of America,
hereby declare:
(i) That JACQUES DUMAS, a French citizen of 98 Farmview Road,
Germany and SCOTT WILHELM, a US citizen of 255 Midland
Drive, Orange, CT 06477, USA, who have made this application No.
dated 23/1/2006 for the same/substantially same invention,
application (s) for patent in the other countries, the particulars of
which are given below:
COUNTRY APPLICATION NO. FILING DATE
U.S.A. 60/489,102 23.7.2003

U.S.A. 60/540,326 2.2.2004
PCT PCT/US2004/023500 22.7.2004
iii] that the rights in the application[s] have been assigned to : No

One
that <I/we> undertake that up to the date of grant of the patent, by

the Controller, I/we would keep him informed in writing the details
regarding corresponding applications for patents filed outside India
within three months from the date of filing of such application.
Dated this 23 / 1/ 2006 v-----i__

B. KOMBI ,
OF REMFRY & SAGAR '
THE PATENT OFFICE,
DELHI
IITRUE COPYjl
(:)l!ta Tel no.(091)(11)(25300200)
■Ii' Fax No. 28034301,02
INTELLECTUAL E-mail: delhi-patent.nic.in
PROPERTYINDIA Web Site: www.ipindia.gov.in
GOVERNMENT OF INDIA
PATENT OFFICE
INTELLECTUAL PROPERTY BUILDING
Plot No. 32 Sector 14, Dwarka, New Delhi-110078
Date : 09/01/2009
To,
REMFRY & SAGAR
ATTORNEYS-AT-LAW,
REMFRY HOUSE MILLENNIUMPLAZA,
SECTOR 27 GURGAON-122 002 INDIA
SUB : Examination Report

APPLICATION NUMBER : 402/DELNP/2006
DATE OF FILING : 23/01/2006
DATE OF REQUEST FOR EXAMINATION : 28/07/2006
DATE OF PUBLICATION : 24/08/2007
a. With reference to request no.6362/RQ-DEL/2006 dt.28/07/2006 by you for examination, the above
quoted application has been examined under section 12 of the Patent Act,1970 as amended and the
First Examination Report containing a statement of objection is forwarded herewith for compliance
thereof.
The documents enclosed shall be resubmitted within 12(Twelve) months from the date of issue of
the said report together with your observation if any, in connection with the compliance of the
requirements of this First Examination Report.
The application referred to will be deemed to have been abandoned under section 21(1) unless all the
requirements imposed by the said Act and the rules there under are complied with within the above
said prescribed period.
The pages of the complete specification should be freshly typed wherever corrections of
interpolation are made. The typed pages in duplicate should be on white pages in order that clear
photocopies of the specification can be prepared.The original pages in that case should be returned to
this office duly cancelled.
It is in the interest of the applicant to comply with the requirements at the earliest.
( Dr.A.P.Singh )
a. Encl:
1. Form-1-Application for Grant of Patent
2. Form-2-Provisional/Complete Specification
NOTE : All Communications to be sent to the Controller of Patents at the above address.
a. Observations:
1. Subject matter of claims 1-54 does not constitute an invention-Inventive step/obvious u/s
2(1)(j) of patent act in view of documents cited herein ,(1) CA 2549558 AA (2) WO 02070008
(3) WO 00 42012 (4) WO 03047523 (5) WO 2004 078746
2. Claims 12-48 fall within the scope of such clause (i) of section 3 patent act .
3. Claims 1-11 and 49-52 fall within the scope of sub clause (d) of section 3 of patent act .
4. Details regarding application for Patents which may be filed outside India from time to time
for the same or substantially the same invention should be furnished within Six months from
the date of filing of the said application under clause(b) of sub section(1) of secton 8 and rule
12(1) of Indian Patent Act.
5. Details regarding the search and/or examination report including claims of the application
allowed, as referred to in Rule 12(3) of the Patent Rule, 2003, in respect of same or
substantially the same invention filed in all the major Patent offices such as USPTO,EPO and
JPO etc., along with appropriate translation where applicable, should be submitted within a
period of Six months from the date of receipt of this communication as provided under section
8(2) of the Indian Patents Act.
6. Superseded application form should be cancelled and refiled in prescribed manner .
7. Pages of the specification should be renumbered.
8. Extraneous matter from the specification should be deleted.
9. Abstract should be filed with a title and concise summary of the invention within 150 words in
accordance with rules 13(7)(a) of Patent Rules, 2003.
ESTABLISHED 1827
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Tel: 91-124-2806100 Fax: 91-124-280 6101 & 257 2123 E-Mail: remfry-sagar@remfry.com http://www.remfry.com
NEH/saa/IP: 402/DELNP/2006
January 06, 2010
THE CONTROLLER OF PATENTS

THE PATENT OFFICE
DELID
URGENT
EXAMINER: DR. A.P. SINGH
FINAL DATE: JANUARY 09. 2010
Dear Sirs,
Re: BAYER HEALTHCARE LLC

Indian Patent Application No. 402/DELNP/2006
Filing date: 23/01/2006
With reference to the official letter dated January 09, 2009, we resubmit the under mentioned
documents and present the following reply:
Regarding paragraph 1, the Applicant respectfully resists the learned Controller's objection and
submits that the subject matter of the claims of the present application is novel and inventive
over the cited prior art documents (1) CA 2549558 (2) WO 02070008 (3) WO 00 42012 (4) WO
03047523 (5) WO 2004 078746. In this regard the Applicant humbly submits the following:
The International Searching Authority (ISA) found that claims 1 to 33 and 37 to 54 met the
requirements of novelty and inventive step over the prior art documents WO 2002/07008, WO
2000/42012, WO 2003/047523 and WO 2004/078741. Since the disclosure of Canadian patent
CA 2549558 is equivalent to WO 2000/42012, the Applicant submits the International Searching
Authority would have found that claims 1 to 33 and 37 to 54 satisfy the requirements of novelty
and inventive step in view of Canadian patent CA 2549558. Nevertheless, a detailed explanation
in this regard is humbly submitted.
CA 2549558 and WO 2000/42012
These references disclose urea compounds which are shown to inhibit raf kinase. The urea
compound of formula I and the derivatives thereof defined in claims 1 to 33 and 37 to 54 are
novel in view of the disclosure within CA 2549558 and WO 2000/42012. The fluorine
substituent distinguishes the compound from compound 42 and compound 49 exemplified in the
tables of these references. As indicated in the report of the International Search Authority,
claims 1 to 33 and 37 to 54 satisfy the criteri • ventive step based on the activity illustrated
in the specification. Obtaining such activity was not obvious in view of the prior art disclosures.
The reference WO 2000/42012 was designated under category "A" by the International Search
Authority, relevant for defining only a general state of the art with no particular relevance to the
subject matter claimed. Therefore, the disclosure in Canadian Patent CA 2549558 is also of no
particular relevance to the subject matter claimed.
WO 2002/07008
This reference was designated as category "X" with respect to claims 34 to 36 by the
International Search Authority. These claims define methods of treatment which are not limited
to the use of compounds of formula I. A combination of agents is used in claims 34 to 36 which
are defined by their function and not their structure. These claims have been duly cancelled
from the subject application. The reference WO 2002/07008 discloses the use of a number of
EGFR antagonists on pages 13 to 16 and VEGF receptor antagonists (antibodies and small
molecules) on pages 19 to 21. No mention is made of ureas consistent with the structure of
formula I such that the disclosure within WO 2002/070008 has no relevance with regard to the
novelty and inventive step of claims 1 to 33 and 37 to 54. It is humbly submitted that the
International Searching Authority did not cite this reference against claims 1 to 33 and 37 to 54.
WO 2003/047523
This reference discloses the use of Bay 43-9006 as a RAF-MEK-ERK pathway inhibitor in
treating cancer such as chronic myelogenous leukemia. The compound Bay 43-9006 has a
distinct structure from that of the compound of formula I herein (no fluorine substituent on a
ring structure) and its derivatives such that the subject matter of claims 1 to 33 and 37 to 54 is
novel in view of the disclosure within WO 2003/047523. The subject matter of claims 1 to 33
and 37 to 54 also satisfies inventive step in that the RAF-MEK-ERK pathway inhibition
disclosed in WO 2003/047523 does not suggest the activity obtained from the compound of
formula I and its derivatives. The reference WO 2003/047523 was designated as category "A"
citation by the International Searching Authority, and was found to be relevant only or defining
the general state of the art.
WO 2004/0787 46
International application WO 2004/078746 was filed on March 1, 2004 and claims priority to
US provisional application 60/450323, filed on February 28, 2003, copy of which is attached.
Information was added to the priority document when WO 2004/078746 was filed such that not
all subject matter contained therein is entitled to a priority date of February 28, 2003.
International application WO 2004/078746 was filed after the priority date (July 23 2003) for
this application such that not all subject matter contained therein is prior art to claims 1 to 33
and 37 to 54.
Examples 2 to 4 of WO 2004/078746 were added to the disclosure when International

application WO 2004/078746 was filed on March 1, 2004. Although examples 2 to 4 of WO
2004/078746 disclose compounds (prodrugs) which can form the compound of formula I of
claims 1 to 33 and 37 to 54 when metabolized, they are not prior art to these claims.
IITRUE COPYjl
The general and specific disclosure of WO 2004/078746 supported by provisional application
60/450323 is entitled to a February 28, 2003 priority date. However the disclosure within
provisional application 60/450323 is similar to that of WO 2000/42012 and does not anticipate
or render obvious the subject matter of claims 1 to 33 and 37 to 54.
Since WO 2004/078746 was published after the subject application was filed, it was designated
an "E" reference relevant only with regard to novelty. Since, WO 2004/078746 does not disclose
the compound of Formula I herein, it is novel over the published disclosure of WO
2004/078746. The International Searching Authority did not need to determine the effective
priority date of the disclosure within WO 2004/078746 to dismiss it as a reference.
The present invention is therefore novel and inventive over the prior arts cited by the learned
Controller. Accordingly, the Applicant humbly requests the learned Controller to kindly waive
the said objection.
Regarding paragraph 2, the Applicant humbly submits that the objected claims 12 to 48 have
been duly deleted to meet the objection raised by the learned Controller. Accordingly, the
Applicant humbly requests the learned Controller to kindly review the amended claims and
waive the said objection.
Additionally, the Applicant submits that the claims of the present application have been
thoroughly revised. and amended to meet the other objections raised by the learned Controller. In
this regard, the Applicant humbly submits that the name of the compound has been incorporated
in claim 1 and the claims have been made in line with the claims granted in the corresponding
EP patent.
Regarding paragraph 3, with respect to the learned Controller's objection against the claims on
the ground of falling under the prohibition of Section 3(d), the Applicant respectfully resist and
submits that the claimed compound is a novel compound as explained in the preceding
paragraphs. Further, the Applicant submits that generally the nature of the activity (VEGF
inhibition) has been found to be sufficient to demonstrate inventive step and substantial
improvement in activity. Accordingly, the claimed compound cannot be considered as a mere
new form of a known substance and thus do not fall under the prohibition of Section 3(d).
In view of the aforesaid, the Applicant humbly requests the learned Controller to kindly waive
the said objection.
The amendments carried out in the specification have necessitated retyping of pages 1 and 57 to
67 as fresh pages 2 and 58 to 60. The retyped pages are submitted in duplicate along with former
pages which have been cancelled. The remaining pages of the specification have been
renumbered.
Regarding paragraph 4, we have the honor to submit the updated details of the corresponding
foreign applications filed in other countries in a further statement and undertaking on Form 3.
Regarding paragraph 5, we have the honor to submit the copy of corresponding granted EP
Patent (EP 1663 978) and copy of corresponding US provisional application to meet the
statutory requirement under Section 8(2) of the Act.
IITRUE COPYjl
Regarding paragraph 9, we have the honor to submit an abstract of the invention (in duplicate).
We have the honor to submit Substitute Power of Authority in favor of our Attorneys.
All the remaining requirements have been complied with.
Grant of this application within the final period expiring on January 09, 2010 is respectfully
requested.
In any event, before taking any adverse decision on this case, the Controller is respectfully
requested to give an opportunity to the Applicants to be officially heard in this matter.
Yours faithfully,
N~1..,'v~~
[NEHA SRIVASTAVA]
OF REMFRY & SAGAR
Enclosure(s ):
Application Form 1 (as received);
Revised Application Form 1 (in duplicate);
Substitute power of authority;
Updated Form 3 (in duplicate);
Revised Form 2 (in duplicate);
Complete specification (as received);
Abstract (in duplicate);
Retyped pages (in duplicate);
Cancelled pages;
Copy of granted EP patent; and
Copy of provisional application US 60/450323
IITRUE COPYjl
Claims
L A compound of Formula (I) or a salt, or a prodmg or a metabolite or an

isolated steredisomerthereof
(I)
2. A pharmaceutically acceptable salt of a compound of Formula I of claim 1

•which is
a) a basic salt of an organic acid or inorganic acid which is hydrochloric

acid, hydrobrornic acid, sulfuric acid, phosphoric acid, methanesulfonic acid,
acid, benzenesulfonicacid, p-toluene sulfonicacid (tosylate
trifluoromethanesulfonic
salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid,
trifluoroaceticacid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid,
succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic
acid, or mandelicacid; or
b) an acid salt of an organic or inorganic base containing an alkali metal

cation, an alkaline earth metal cation, an ammonium cation, an aliphatic substituted
ammoniumcation or an aromatic substituted ammonium cation.
3. A compound which is 4 {4-[3-(4--chloro-3-tiifluo:rometbylphenyl)-ureido

J-3-
fluorophenoxy}-pyridine-2-carboxylic acid methylamide,or a salt thereof.
4. • A pharmaceutically acceptable salt of a compound of claim 3 which is a basic

salt of an organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid,
phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid,
benzenesulfonic acid, p-toluene sulfonic acid (tosylate salt), 1-napthalene sulfonic
57
IITRUE _COPY!I
WO 2005/009961 PCT/US2004/023500
acid, 2-napthalenesulfonicacid, acetic acid, trifluoroaceticacid,malic acid, tartaric

acid, citric acid, lactic acid, oxalic acid, succinicacid, fumaricacid, maleic acid,
benzoicacid, salicylic acid, phenylaceticacid, or mandelicacid.
5. A compound which is which is a hydro chloride, benzenesulfonate,or

methanesulfonate salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'
-2-fluoro-(4-(2-
(N-methylcarbamoyl)-4-pyridyloxy)phenyl)
urea.
6. A pharmaceutical composition comprising a compound of claim 1 and a

physiologically acceptable carrier.

8. A pharmaceutical composition for the treatment of a disease in a human or

other mammal regulated by a protein kinase, associated with an aberration in the
protein kinase signal transductionpathway comprising a compound of claim 1 and a
• 9. A pharmaceutical compositiomfor the treatment of a hyper-proliferative

disorder comprising a compound of claim 1 and a physiologically acceptable carrier.
10. A pharmaceutical composition for the treatment of a cancerous cell growth

comprising a compound of claim 1 and a physiologically acceptable carrier.
11. A pharmaceutical composition which comprises a pharmaceutically acceptable

salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'
-2-fluoro-(4-(2-(N-
✓
methylcarbamoyl)-4-pyridyloxy)phenyl)urea and a physiologically .acceptable

carrier.
58
IITRUE COPYII
12. A method for regulating tyrosine kinase signal transduction comprising
administering to a human or other mammal a compound of claim!.
13. A method for treating or preventing a disease in a human or other mammal

which is regulated by tyrosine kinase and associated with an aberration in the tyrosine
kinase signal transduction pathway, said method comprising administering to a human
or other mammal a compound of claim I.
14. A method for treating or preventing a disease in a human and/or other

mammal which is a mediated disorder, said method comprising
administering to a human or other mammal a compound of claim

mammal which is a PDGFR mediated disorder, said method comprising administering
to a human or other mammal a compound of claim 1.

which is a raf-mediated disorder, said method comprising administering to a human or
other mammal a compound of claim 1.

which is a p38-mediateddisorder, said method comprising administering to a human
or other mammal a compound of claim 1.

1
which is a VEGF-mediateddisorder, said method comprising administering to a

human or other mammal a compound of claim 1.

which is a hyper-proliferative,inflammatory and/or angiogenesis disorder which
comprises administering to a human or other mammala compound of claim
59
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which is a hyper-proliferativedisorder which comprises administering.to a human or
other mammal a compound of claim
21. A method as in claim 20, whereinthe hyper-proliferativedisorder is cancer.
22. A method as in claim 21, wherein said method comprises administering to a

human or other mammal a compound of claim 1 in combination with one or several
additional anti-cancer agents.

characterized by abnormal angiogenesis or hyperperrniabilityprocesses comprising
administering to a human or other mammal a compound of claim
24. A method as in claim 23, for treating1orpreventing a disease in a human or

other mammal characterized by abnormal angiogenesis or hyperpermeability
processes, comprising administering to a human or other mammal, a compound of
claim 1 simultaneously with another anti-angiogenesisagent, either in the same
.formulationor in separate formulations.
25. A method for treating or preventing one or more of the following conditions in
humans and/or other mammals:
tumor growth, retinopathy, ischemic retinal-vein occlusion, retinopathy of
prematurity, age related macular degeneration; rheumatoid arthritis, psoriasis, a
bullous disorder associated with subepidermal blister formation, including bullous
pemphigoid, erythema multifonne, or dermatitis herpetiformis, rheumatoid arthritis,
osteoarthritis,septic arthritis, tumor metastasis, periodontaldisease, carnal ulceration,
proteinuria and coronary thrombosis from atherosclerotic plaque, aneurismalaortic,
birth control, dystrophobic epidermolysis bullosa, degenerative cartilage loss
following traumatic joint injury, oste_openiasmediated by MMP activity, tempero
mandibularjoint disease or dernyelatingdisease of the nervous system,
said method comprising administering to a human or other mammal, a
compound of.claim1.
60
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humans other mammals: tumor growth, retinopathy, ischemic retinal-vein
occlusion, retinopathy of prematurity, age related macular degeneration; rheumatoid
arthritis, psoriasis, a bullous disorder associated with subep.rdennalblister formation,
including bullous pemphigoid,erythema multiforme,or dermatitis herpetifonnfa;
in combination with another condition selected from the group consisting of:
rheumatic fever, bone resorption, postmenopausalosteoporosis, sepsis, gram

negative sepsis, septic shock, endotoxic shock, toxic shock syndrome, systemic
inflammatory response syndrome, inflammatory bowel disease (Krohn's disease and
ulcerative colitis), Jarisch-Herxheimerreaction, asthma, adult respiratory distress
syndrome, acute pulmonary fibrotic disease, pulmonary sarcoidosis, allergic
respiratory disease, silicosis, coal worker's pneumoconiosis,alveolar i~ury,, hepatic
•failure, liver disease during acute inflammation, severe alcoholic hepatitis, malaria
(Plasmodium falciparum malaria and cerebral malaria), non-insulin-dependent
diabetes mellitus (NIDDM),congestive heart failure, damage following heart disease,
atherosclerosis, Alzheimer's disease, acute encephalitis,.brain injury, multiple
sclerosis (demyelation and oligiodendrocyte loss . in multiple sclerosis), advanced
cancer, lymphoid malignancy, pancreatitis, impaired wound healing in infection,
inflammation and cancer, myelodysplasticsyndromes, systemic lupus erythematosus,
biliary cirrhosis, bowel necrosis, radiation injury/ toxicityfollowing administration of
monoclonal antibodies, host-versus-graftreaction (ischemia reperfusion injury and
allograft rejections of .kidney, liver, heart, and· skin), lung allograft rejection
(obliterativebronchitis) and complications due to total hip replacement,•
said method comprising administering to a human or other mammal a

compound of claim 1.
humans and/or other mammals: tumor growth, retinopathy, diabetic retinopathy,
ischemic retinal-vein occlusion, retinopathy of prematurity, age related macular
degeneration; rheumatoid arthritis, psoriasis, bullous disorder associated with
subepidermal blister formation, bullous pemphigoid, erythema multiforme, and
dermatitis herpetiformis,
61
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in combination with an infectious disease selected from the group consisting
of:
tuberculosis, Helicobacter pylori infection during peptic ulcer disease, Chaga's

disease resulting from Trypanosoma cruzi infection, effects • of Shiga-like toxin
resulting from E. coli infection, effects of enterotoxin A resulting from
Staphylococcus infection, meningococcal infection, and infections from Borrelia
burgdorferi, Treponema pallidum, cytomegalovirus, influenza vims, Theiler's
virus, and the human immunodeficiencyvirus (HIV); .
enc_ephalomyelitis

28. A method as in claim 22 wherein the additional anti-cancer agent is selected

from the group consisting of asparaginase, bleomycin, carboplatin, carmustine,
ch1orambucil, cisp1atin, colaspase, cyc1ophosphamide, cytarabine, dacarbazine,
dac~omycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-
fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin,
lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C,
mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen,_ streptozocin,
tamoxifen, thioguanine, .topotecan, vinblastine, vincristine, vindesine,
aminoglutet~mide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan,
diethylstilbestrol, 2',2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyl
adenine, ethinyl estradiol, 5-fluorodeoxyuridine,. 5-fluorodeoxyuridine
monophosphate, .fludarabine phosphate, fluoxymesterone, flutamide,
hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogester~ne acetate,
megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N-phosphonoacetyl-L-
aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate,
th.'iotepa, trimethylmelamine, uridine, and vinorelbine, oxaliplatin, gemcitabine,
capecitabine, epothilone and its natural or synthetic derivatives, tositumomab,
trabedectin, and temozolom1de. trastuzumab, cetuximab, bevacizumab, pertuzumab,
ZD-1839 (Iressa), Os1.:774 (Tarceva), CI-1033, GW-2016, CP-724,714, HKI-27i,
EKB-569, STI-571 (Gleevec), PTK-787, SU-11248, ZD-6474, AG-13736, KRN-951,
CP-547,632,. CP-673,451, CHIR-258, MLN-518, AZD-2171, PD-325901, ARRY-
62
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142886, suberoylanilidehydroxamic acid (SAHA),LAQ-824,LBH-589, MS-275,
FR-901228,bortezomib,and CCJ-779.
29. A method as in claim 22 wherein the additional anti-cancer agent 'is a

cytotoxic agent selected from the group consisting of DNA topoisomeraseI and II
inhibitors, DNA intercalators,alk-ylatingagents,anti-metabolites, cell-cycle blockers,
microtubuledisruptors,and·Eg5inhibitors.

from the group consisting of inhibitors of growth factor receptor signaling, histone
deacetylase inhibitors, inhibitors of the PKB pathway, inhibitors of the
pathway, inhibitors of the mTOR
Rat7MEK/ERK pathway, and proteasomeinhibitors.
A method for treating or preventing one or more of the following conditions in

rheumatic fever, bone resorption, postmenopausalosteoporosis, sepsis, gram
inflammatory response syndrome, inflammatory bowel disease (Krohn's disease and
ulcerative colitis), J arisch-Herxheimerreaction, asthma, adult respiratory distress
respiratory disease, silicosis, coal worker's pneumoconiosis, alveolar injury, hepatic
failure, liver disease during acute inflammation, severe alcoholic hepatitis, malaria '
(Plasmodium falciparum malaria and cerebral malaria), non-insulin-dependent
diabetes mellitus (NIDDM),congestive heart failure, damage following heart disease,
atherosclerosis, Alzheimer's disease, acute encephalitis, brain injury, multiple
sclerosis (demyelation and oligiodendrbcyteloss in multiple sclerosis), advanced
can.;er, lyrnphoiclmalignancy, pancrcatitis, impaired wound healing in infection,
'-
inflammation and cancer, myelodysplastic syndromes, systemic lupus erythematosus,
biliary cirrhosis, bowel necrosis, psoriasis, radiation injury/ toxicity following
administration of monoclonal antibodies, h9st-versus-graft reaction (ischemia
. reperfusioninjury and allograft rejections of kidney, liver, heart, and lung
. allogra:ft rejection (obliterative bronchitis) or complications due to total hip
replacement,
63
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said method comprising administeringto a human or other mammal, a
humans and/orother mammals:
tuberculosis, Helicobacterpylori infection during peptic ulcer disease, Chaga's
disease resulting from Trypanosoma cruzi infection, effects of Shig'a-liketoxin
Staphylococcris. infection, meningococcal infection, and infections from Borrelia
burgdorferi, Treponema pallidum, cytomegalovims, influenza virus, Theiler's
virus, and the human immunodeficiency virus (HIV),
encephalomyelitis
33. A method for treating or preventing osteoporosis, inflammation, and angiogenesis

disorders, with the exclusion of cancer, in a human and/or other mammal by
administering an effective amount of a compound of claim 1 to said mammal.
34. A method for treating or preventing cancer in a human or other mammal which
comprises administering to a human or other mammal a single active principle
combining inhibition of tumor cell proliferation mediated by the raf / MEK / ERK
pathway, and inhibition of angiogenesis mediated by PDGF and VEGF.
35. A method of claim 34 where said inhibition of tumor cell proliferation is caused
by inhibition of r'af kinase, and said inhibition oi angiogenesis is caused by dual
inhibition qf PDGFR-beta and VEGFR-2 lonases.
\
36. A method for.treatingor preventing cancer in a human or other mammal which
comprises administering to • a human. or other mammal a single active principle
combining inhibition of tumor cell proliferation mediated by the raf pathway, and
inhibition of angiogenesis mediated by PDGF or VEGF.·
64
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37. A method of treating and/or
preventing a disease condition in a subject in
and/or
need thereof, comprising administering an effective amount of a compound of claim 1
or2.
38. A method of claim 37, wherein said method comprises causing tumor regression
in a subject or cells therefrom.
39. A method of claim 37, wherein said method comprises inhibiting

lymphangiogenesis.
40. A method of claim 37,wherein said method comprises inhibiting

angiogenesis.

lymphangiogenesis and angiogenesis.
42. A method of claim 37, wherein said method comprises stimulating the
proliferation of hematopoietic progenitor cells.
43. A method of claim 37, wherein said method comprises treating a disorder in a
mammalian subject mediated by raf, VEGFR-3, PDGFR-beta, p38 and/or
flt-3.
44. A method of claim 37, wherein said method comprises determining whether a
condition.can be modulated by said compound, comprising measuring the expression
or activity ofraf, VEGFR-2, VEGFR-3, PDGFR-beta, p38 ~d/or flt-3, in a sample

comprising cells or a cell extract, wherein said ample is obtained from a subject or
cell having said condition, whereby said condition can be modulated by said
compound when said expression or activity is different in said condition as compared
to a normalcontrol.
45. A method of claim•44, further comprising comparing the expression in said

sample to said normal control.
65
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46. A method of claim 37, wherein said method comprises assessing the efficacy of
said compound disorder, comprising administering said compound, measuring the
expression or activity of raf, VEGFR-2, VEGFR-3, PDGFR-beta, p38, and/or flt-3,
and determining the effect of said compound on said expression or activity. •
47. A method of claim 37, wherein said method comprises determining the
presence of raf, VEGFR-2,VEGFR-3, PDGFR-beta, p38 and/or flt-3 in a sample of a
biological material, contacting said sample with said compound, and determining
whether said compound binds to said material.
48. A method of claim 37, wherein said method comprises treating a tumor in a
subject in need thereof, comprising administering an effective amount of said
compound wherein said amount is effective to inhibit tumor cell 'proliferationand
neovascularization.
49. A compound which is a naturally occurring metabolite of the compound of

claim 3.
50. A compound of claim 49 where the metabolism site is either one of the two
urea nitrogen atoms, or the pyridine nitrogen atom, or the methylarnidefunctionality,
or any combination of the above.
51. A compound of claim 49 where either urea nitrogen atom carries a hydroxyl
group, and/orthe pyridine nitrogen atom is oxidized, and/orthe amide functionality is
de-methylated.
52. A c0mpotmd of claim 49 which if\ selected from:

' \
4 {4-[3-(4-cbloro-3-trifluoromethylphenyl)-ureido
]-3-fluorophenoxy}-pyridine-2-
carbqxylicacid amide,
~-
4 {4-(3-(4-chloro-3-trifluorome~ylphenyl)-ureido
]-3-fluorophenoxy}-l-hydroxy-
pyridine-2-carboxylicacid methylamide, or
4 {4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido
]-3-fluorophenoxy}-1-hydroxy-
pyridine-2-carboxylicacid amide.
66
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53. A method as in claim 19, where the inflammatory disorder is selected from
rheumatoid arthritis, COPD, Crohn's disease and proriasis.
54. A method for treatirlg or preventing a disease in a human or other mammal

which is a flt-3 mediated disorder, said method comprising administering to a human
or other mammal a compound of claim 1. .

(B. KOMBI)
OF REMFRY & SAGAR
ATTORNEY FOR THE APPLICANTS.
67
IITRUE COPYII
WfECLAIM:
1. A fluoro substituted omega-carboxyaryl diphenyl urea compound of Formula (I) or a

salt, or an isolated stereoisomer thereof:
,..CH3
N
H
(I)
2. A compound as claimed in claim 1 which is:
a) a basic salt of an organic acid or inorganic acid which is hydrochloric acid, hydrobromic acid,
sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid,
benzenesulfonic acid, p-toluene sulfonic acid (tosylate salt}, 1-napthalene sulfonic acid, 2-
napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid,
lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid,
phenylacetic acid, or mandelic acid; or
b} an acid salt of an organic or inorganic base containing an alkali metal cation, an alkaline earth
metal cation, an ammonium cation, an aliphatic substituted ammonium cation or an aromatic
substituted ammonium cation.
3. A compound as claimed in claim l which is 4{4-[3~(4-chloro-3-trifluoromethylphenyl)-

ureido]-3-fluorophenoxy}•pyridine-2-carboxylicacid methylamide, or a salt thereof.
4. A compound as claimed in claim 3 which is a basic salt of an organic acid such as

hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid,
tri.tluoromethanesulfonicacid, benzenesulfonic acid, p-toluene sulfonic acid (tosylate salt), 1-
napthalene sulfonic acid, 2~napthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid,
tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic
acid, salicylic acid, phenylacetic acid, or mandelic acid.
5. A compound as claimed in claim 1 which is a hydrochloride, benzenesulfonate, or
(ITRlJE COPYII
fethanesulfonate salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N' -2-fluoro-(4-(2-(N-
methylcarbamoyl)-4-pyridyloxy)phenyl)urea.
6. A compound of Formula (I) as claimed in claim 1 wherein one or more of the urea
nitrogens and/or the methylamide group of the compound are substituted with a hydroxy group
and/or the pyridine nitrogen atom of the compound is in the N- oxide fonn.
7. A compound of Fonnula (I) as claimed in claim l wherein the methylamide group of the
compound is de-methylated and/or one or more of the urea nitrogens of the compound are
substituted with a hydroxy group and/or the pyridine nitrogen atom of the compound is in the N-
oxide form.
8. A compound as claimed in any of claims 6 or 7 which is selected from:
4{4-[3-(4-chloro-3-trifluoromethylphenyl-ureido-3-fiuorophenoxy)-pyridine-2-carboxylic acid
amide,
4{4-[3(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fiuorophenoxy}-1-hydroxy-pyridine-2-
carboxylic acid methylamide. or
4 {4-[3·( 4-chloro-3-trifluoromethylphenyl)-ureido-3-fluorophenoxy}-l-hydroxy-pyridine-2-
carboxylic acid amide.
9. The compounds or pharmaceutically acceptable salts thereof as claimed in any of the

preceding claims as and when used in the preparation of a pharmaceutical composition.
Dated this 23rd day of January, 2006.
f\\~1--1\JaAktv <'.t..
[NEHA SRN ASTAVA]
OF REMFRY& SAGAR
11TRUE COPYjl
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(19) World Intellectual Property

Organization
International Bureau 1111111111111111
IIIIIIIIIII1111111111111111111111111111111111111111
IIIIIIIIIIIIIIIIIIIIIIIIIIII
(43) International Publication Date (10) International Publication Number

3 February 2005 (03.02.2005) PCT WO 2005/009961 A2
(51) International Patent Classification 7: C07D213/00 (81) Designated States (unless otherwise indicated, for every
kind of national protection available): AE, AG, AL, AM,
(21) International Application Number: AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
PCT/US2004/023500 CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, Fl,
(22) International Filing Date: 22 July 2004 (22.07.2004) GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD,
(25) Filing Language: English MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG,
PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM,
(26) Publication Language: English
TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM,
(30) Priority Data: zw.
60/489,102 23 July 2003 (23.07.2003) US
60/540,326 2 February 2004 (02.02.2004) US (84) Designated States (unless otherwise indicated, for every
kind of regional protection available): ARIPO (BW, GH,
(71) Applicant (for all designated States except US): BAYER
PHARMACEUTICALS CORPORATION [US/US]; GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
400 Morgan Lane, West Haven, CT 06516-4175 (US). ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, Fl,
(72) Inventors; and FR, GB, GR, HU, IE, IT, LU, MC, NL, PL, PT, RO, SE, SI,
---
iiiiiiii
(75) Inventors/Applicants (for US only): DUMAS, Jacques
[FR/US]; 98 Farmview Road, Bethany, CT 06524 (US).
BOYER, Stephen [US/DE]; Mittelstrasse 55, 40721
SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
GW, ML, MR, NE, SN, TD, TG).
iiiiiiii Hilden (DE). RIEDL, Bernd [DE/DE]; Von-der-Golz Published:

--
iiiiiiii
Strasse 7, 42329 Wuppertal (DE). WILHELM, Scott
[US/US]; 255 Midland Drive, Orange, CT 06477 (US).
without international search report and to be republished
upon receipt of that report
-- (74) Agents: TRAVERSO, Richard, J. et al.; Millen, White,

Zelano & Branigan, P.C., Suite 1400, Arlington Courthouse For two-letter codes and other abbreviations, refer to the "Guid-
- Plaza 1, 2200 Clarendon Boulevard, Arlington, VA 22201

(US).
ance Notes on Codes and Abbreviations" appearing at the begin-
ning of each regular issue of the PCT Gazette.
iiiiiiii
-
-
iiiiiiii
iiiiiiii
---------------------------------------------
- (54) Title: FLUORO SUBSTITUTED OMEGA-CARBOXYARYL DIPHENYL UREA FOR THE TREATMENT AND PREVEN-
TION OF DISEASES AND CONDITIONS
M
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0 (57) Abstract: A compound of Formula (I): (I) salts thereof, prodrugs thereof, metabolites thereof, pharmaceutical compositions
:, containing such a compound, and use of such compound and compositions to treat diseases mediated by raf, VEGFR, PDGFR, p38
;;, and flt-3.
IITRUE COPYII
WO 2005/009961 PCT/0S2004/023500
Fluoro substituted Omega~Carboxyarvl Diphenvl Urea

for the Treatment and Prevention of Diseases and Conditions
Field of the Invention

This invention relates to novel compo1mds, pharmaceutical compositions
containing such compounds and the use of those compounds or compositions for
treating diseases and conditions mediated by abnormal VEGFR, PDGFR, raf, p38,
and/or flt-3 kinase signaling, either alone or in combination with anti-cancer agents.
Background.of the Invention

Activation of the ras signal transduction pathway indicates a cascade of events
that have . a profound impact on • cellular proliferation, differentiation, and
transformation. Raf kinase, a downstream effector of· ras, is recognized as a key
mediator of these signals from cell surface receptors to the cell nucleus (Lowy, D. R. ;-
. Willumsen, B. M.-Ann. Rev. Biochem. 1993, 62, 851; Bos, J. L. Cancer Res. 1989, 49,_
4682). It has been shown that inhibiting the effect of active ras by inhibiting the raf
kinase signaling pathway by administration of deactivating antibodies to raf kinase or
by co-expression of dominant negative raf kinase or dominant negative MEK, the
substrate of raf kinase, leads to the reversion of transformed cells to the normal
growth phenotype (see: Daum et al. Trends Biochem. Sci. 1994, 19, 474-80; Fridman
•et-·al·.J _Biol. Che_m. 1994, 269, 30105-8. Kolch et al. (Nature 1991, 349, 426-28)
have further indicated that inhibition of raf expression by antisense _RNAbloclcs cell
proliferation in membrane-associated oncogenes. Similarly, inhibition of raf kinase
(by antisense oligodeoxynucleotides) has been correlated in vitro and in vivo with
inhibition of the growth of a variety of human h1mor types (Mania et al., Nat. }I.led.
1996, 2, 668-75).
To support progressive tumor growth beyond th(_;size of 1-2 mm3 , it is
recognized that tumor cells require a functional stroma, a support strncture consisting
of fibroblast, smooth muscle cells, endothelial cells, extracellular matrix proteins, and
soluble factors (Pollan.an, J., Semin. Oneal. 2002. 29(6 Suppl 16), 15-8). Tumors
induce the formation of stromal tissues through the secretion of soluble growth factors
such as PDGF and transforming growth factor-beta (TGF-beta), which in tum
IITRUE COPYjl
WO 2005/009961 PCT /US2004/023500
stimulate the secretion of complimentary factors by host cells such as fibroblast

growth factor (FGF), epidermal growth factor (EGF), and vascular endothelial growth
factor (VEGF). These stimulatory factors induce the formation of new blood vessels,
or angiogenesis, which brings oxygen and nutrients to the tumor and allows it to grow
and provides a route for metastasis. It is believed some therapies directed at inhibiting
stroma formation will inh~bit the growth of epithelial· tumors from a wide variety of
histological types. (George, D. Semin. Oneal. 2001. 28(5 Suppl 17), 27-33; Shaheen,
R.M., et al., Cancer Res. 2001, 61(4), 1464-8; Shaheen, RM., et al. Cancer Res.
1999, 59(21), 5412-6). However, because of the complex nature and the multiple
growth f~ctors involved in angiogenesis process and tumor progression; an agent
targeting a single pathway may have limited efficacy. It is desirable to provide
treatment against a number of key signaling pathways utilized by tumors to induce
angiogenesis in the host stroma. These include PDGF, a potent stimulator· of stroma
formation (Ostman, A. and C.H. Heldin, Adv. Cancer Res. 2001, 80, 1-38), FGF, a
chemo-attractant and mitogen for fibroblasts and endothelial cells, and VEGF, a
potent regulator of vascularization.
PDGF is a key regulator of stromal formation, which is secreted by many
h1mors in a paracrine fashion and is believed to promote the growth of fibroblasts,
smooth muscle and endothelial cells, promoting stroma formation and angiogenesis.
PDGF was originally identified as the v-sis oncogene product of the simian sarcoma
virus (Heldin, C.H., et al.,J Cell. Sci. Suppl. 1985, 3, 65-76). The growth factor is
made -up of two peptide chains, referred to as A or B chains which share 60%
homology in their primary amino acid sequence. The chains are disulfide cross linked
to form the 30 kDa mature protein composed of either AA, BB or AB homo- or
heterodimmers. PDGF is found at high levels in platelets, and _is expressed by
endothelial cells and vascular smooth muscle cells. In addition, the production of
PDGF is up regulated under low oxygen conditions such as those found in poorly
vascularized tumor tissue (Kourembanas, S., et al., Kidney Int. 1997, 51(2), 438-43)..
PDGF binds with high affinity to the J>DGFreceptor, a 1106 amino acid 124 k.Da
transmembrane tyrosine kinase receptor (Beldin, C.H., A. Ostman, and L.
Ronnstrand, Biochim. Biophys. Acta 1998, 1378(1), 79-113). PDGFR is found as
homo- or heterodimer chains which have 30% homology overall in their amino acid
sequence· and 64% homology betvveen their kinase domains (Heldin, C.H., et al..
Embo J 1988, 7(5), 1387-93). PDGFR is a member of a family of tyrosine kinase
IITRUE COPYjl
WO 2005/009961 PCT /US2004/023500
receptors with split kinase domains that includes VEGFR-2 (I<DR), VEGFR-3 (flt-4),
c-kit, and flt-3. The PDGF receptor is expressed primarily on fibroblasts, smooth
muscle cells, and pericytes and to a lesser extent on neurons, kidney mesangial,
Leydig, and Schwann cells of the central nervous system. Upon binding to the
receptor, PDGF induces receptor dimerization and undergoes auto- and trans-
phosphorylation of tyrosine residues which increase the receptors' kinase activity and
promotes the recruitment of downstream effectors through the activation of SH2
protein binding domains. A number of signaling molecules form complexes with
activated PDGFR including PI-3-kinase, phospholipase C-gamma, src and GAP
(GTPase activating protein for p21-ras) (Soskic, V., et al. Biochemistry 1999, 38(6),
1757-64). Through the activation of PI-3-kinase, PDGF activates the Rho signaling
pathway inducing cell. motility and migration, and through the activation of GAP,
induces mitogenesis through the activation of p2 l-ras and the MAPK signaling
pathway.
In adults, it is believed the major function of PDGF is to facilitate and increase
the rate of wound healing and to maintain blood vessel homeostasis (Baker, E.A. and
D.J. Leaper, Wound Repair 1?..egen.2000, 8(5), 392-8, and Yu, J., A. Moon, and H.R.
Kim, Biochem. Biophys. Res. Commun. 2001, 282(3), 697-700). PDGF is found at
high concentrations in platelets and is a potent chemoattractant for fibroblast, smooth
muscle cells, neutrophils and macrophages. In addition to its role in wound healing
PDGF is known to help maintain vascular homeostasis. During the development of
new blood vessels, PDGF recmits pericytes and smooth muscle cells that are needed
for the stmctural integrity of the vessels. PDGF is thought to play a similar role during
hunor neovascularization. As part of its role in angiogenesis PDGF controls
!
interstitial fluid pressure, regulating the permeability of vessels through ·its regulation
of the interaction between connective tissue cells and the extracellular matrix.
Inhibiting PDGFR activity can lower interstitial pressure and facilitate the influx o·f
cytotoxics into tumors improving the anti-tumor efficacy of these agents (Pietras, K.,
et al. Cancer Res. 2002, 62(19), 5476-84; Pietras, K., et al. Cancer Res. 2001, 61(7),
2929-34).
PDGF can promote hunor growth through either the paracrine or autocrine
stimulation of PDGFR receptors on stromal cells or tumor cells directly, or through
the amplification of the receptor or activation of the receptor by recombination. Over
expressed PDGF can transform human melanoma cells and keratinocytes (Forsberg,
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K., et al. Proc. Natl. Acad. Sci. US A. 1993, 90(2), 393-7; Skobe, M. and N.E.
Fusenig, Proc. Natl. Acad. Sci. US A. 1998, 95(3), 1050-5), two cell types that do not
express PDGF receptors, presumably by the direct effect of PDGF on stroma
formation and induction of angiogenesis. This paracrine stimulation of tumor stroma
is also observed in carcinomas of the colon, lung, breast, and prostate (Bhardwaj, B.,
et al. Clin. Cancer Res. 1996, 2(4), 773-82; Nakanishi, K., et al. lvfod. Pathol. 1997,
10(4), 341-7; Sundberg, C., et al. Am. J Pathol. 1997, 151(2), 479-92; Lindmark, G.,
et al. Lab. Invest. 1993, 69(6), 682-9; Vignaud, J.M., et al, Cancer Res. 1994, 54(20),
5455-63) where the tumors express PDGF, but not the receptor. The autoc1ine
stimulation of tumor cell growth, where a large faction of tumors analyzed express
both the ligand PDGF and the receptor, has ,been reported in glioblastomas (Fleming,
T.P., et al. Cancer Res. 1992, 52(16), 4550-3), soft tissue sarcomas (Wang, J., M.D.
Coltrera, and AM. Gown, Cancer Res. 1994, 54(2), 560-4) and cancers of the ovary
(Henriksen, R., et al. Cancer Res. 1993, 53(19), 4550-4), prostate (Fudge, K., C.Y.
• Wang, and M.E. Stearns, Mod. Pathol. 1994, 7(5), 549-54), pancreas (Puna, K., et al.
Cancer Res. 1990, 50(3), 748-53) and lung (Antoniades, H.N., et al., Proc. Natl.
Acad. Sci. US A 1992, 89(9), 3942-6). Ligand independent activation -of the receptor
is found to a lesser extent but has been reported ill' chronic myelomonocytic leukemia
(CMML) where the- a chromosomal translocation event forms a fusion protein
between the Ets-like transcription factor TEL and the PDGF receptor. In addition,
activating mutations in PDGFR have been found in gastrointestinal stromal tumors in
which c-kit activation is not involved (Heinrich, M.C., et al., Science 2003, 9, 9).
Another major regulator of angiogenesis and vasculogenesis in both
embryonic development . and some angiogenic-dependent diseases is vascular
endothelial growth factor (VEGF; also called vascular permeability factor, VPF).
VEGF represents a family of isoforms of mito gens existing in homodimeric forms due
to alternative RNA splicing. The VEGF isoforms are highly specific for vascular
endothelial cells (for reviews, see: Farrara et al: Endocr. Rev. 1992, 13, 18; Neu:field
et al. FASEB J. 1999, 13, 9).
VEGF expression is induced by hypoxia (Shweiki et al. Nature 1992, 359,
843), as well as by a variety of cytokines and growth facto~s, such as interleukin- I,
interleukin-6, epidermal growth factor and transforming growth factor. To ct.ate,
VEGF and the VEGF family members have been repqrted to bind to one or more of
three transmembrane 1'eceptor tyrosine kinases (Mustonen et al. J Cell Biol. 1995,
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129, 895), VEGF receptor-I (also known as flt-1 (fins-like tyrosine kinase-I)),
VEGFR-2 (also known as kinase insert domain containing receptor (KDR); the
murine analogue ofVEGFR-2 is known as fetal liver kinase-I (flk-1)), and VEGFR-3
(also known as flt-4). VEGFR-2 and flt-1 have been shown to have different signal
transduction properties (Waltenberger et al. J. Biol. Chem. 1994, 269, 26988); Park et
al. Oncogene 1995, 10, 135). Thus, VEGFR-2 tmdergoes strong ligand-dependant
tyrosine phosphorylation in intact cells, whereas flt-1 displays a weak response.
Thus, binding to VEGFR-2 is believed to be a critical requirement for induction of the
full spectmm of VEGF-mediated biological responses.
In vivo, VEGF plays a central role in vasculogenesis, and induces
angiogenesis and permeabilization of blood vessels. Deregulated VEGF expressimi
contributes to the development of a number of diseases that are characterized by
abnormal angiogenesis and/or hyperpermeability processes. It is believed that
regulation of the VEGF-mediated signal transduction cascade by some agents can
provide a usefol control of abnormal angiogenesis and/or hyperpermeability
processes. Tumorigenic cells within hypoxic regions of tumors respond by stimulation •
of VEGF production, which triggers activation of quiescent endothelial cells to
stimulate new blood vessel formation. (Shweiki et al. Proc. Nat'l. Acad. Sci. 1995, 92,
768). In addition, VEGF production in tumor regions where there is no angiogenesis
may proceed through the ras signal transduction pathway (Gmgel et al. J. Biol. Chem.
1995, 270, 25915; Rak et al. Cancer Res. 1995, 55, 4575). In situ hybridization
studies have demonstrated VEGF mRNA is strongly upregulated in a wide variety of
human tumors, including lung (Mattern et al. Br. J. Cancer 1996, 73, 931), thyroid
(Viglietto et al. Oncogene 1995, 11, 1569), breast (Brown et al. Human Pathol. 1995,
26, 86), gastrointestinal tract (Brown et al. Cancer Res. 1993, 53, 4727; Suzuki et al.
Cancer Res·. 1996, 56, 3004), kidney and bladder (Brown et al. Am. J. Pathol. 1993,
1431, 1255), ovary (Olson et al. Cancer Res. 1994, 54, 1255), and cervical (Guidi et
al. J. Nat'l Cancer Inst. 1995, 87, 12137) carcinomas, as well as angiosarcoma
(Hashimoto et al. Lab. Invest. 1995, 73, 859) and several intracranial tumors (Plate et
al. Nature 1992, 359, 845; Phillips et al. Int. J. Oneal. 1993, 2, 913; Berkman et al. J.
Clin. Invest. 1993, 91, 153). Neutralizing monoclonal antibodies to VEGFR-2 have
been shown to be efficacious in blocking tumor angiogenesis (Kim et al. Nature 1993,
362, 841; Rockwell et al. lvfol. Cell. Differ. 1995, 3,315).
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Overexpression of VEGF, for example under conditions of extreme hypoxia,

can lead to intraocular angiogenesis, resulting in hyperproliferation of blood vessels,
leading eventually to blindness. Such a cascade of events has been observed for a
number of retinopathies, including diabetic retinopathy, ischemic retinal-vein
occlusion, and retinopathy of prematurity (Aiello et al. New Engl. J. Nied. 1994, 331,
1480; Peer et al. Lab. Invest. 1995, 72, 638), and age-related macular degeneration
(AMD; see, Lopez et al. Invest. Opththalmol. V{s. Sci. 1996, 37, 855).
In rheumatoid arthritis (RA), the in-growth of vascular pannus may be
mediated by production of angiogenic factors. Levels of immunoreactive VEGF are
high in the synovial fluid of RA patients, while VEGF levels were low in the synovial
fluid of patients with other fom1s of arthritis of with degenerative joint disease (Koch
et al:J. Immunol. 1994, 152, 4149). The angiogenesis inhibitor AGM-170 has been
shown to prevent neovascularization of the joint in the rat collagen arthritis model
(Peacock et al. J. Exper. Med. 1992, 175, 1135).
Increased VEGF expression has also been shown in l?soriatic skin, as well as
bullous disorders associated with subepidermal blister formation, such as bullous
pemphigoid, erythema multiforme, and dermatitis herpetiformis (Brown et al. J.
Invest. Dermatol. 1995, 104, 744).
The vascular endothelial growth factors (VEGF, VEGF-C, VEGF-D) and their
receptors (VEGFR-2, VEGFR-3) are not only key regulators of tumor angiogenesis,
but also lymphangiogenesis. VEGF, VEGF-C and VEGF-D are expressed in most
tumors, primarily during periods of tumor growth and, often at substantially increased
levels. VEGF expression is stimulated by hypoxia, cytokines, oncogenes such as ras,
or by inactivation of tumor suppressor genes (McMahon, G. Oncologist 2000,
5(Suppl. 1), 3-10; McDonald, N.Q.; Hendrickson, W.A. Cell 1993, 73, 421-424)
The biological activities of the VEGFs are mediated through binding to their
receptors. VEGFR-3 (also called flt-4) is predominantiy expressed on lymphatic
endothelium in normal adult tissues. VEGFR-3 function is needed for new lymphatic
vessel formation, _butnot for maintenance of the pre-existing lymphatics. VEGFR-3
is also upregulated on blood vessel endothelium in tumors. Recently VEGF-C and
VEGF-D, ligands for VEGFR-3, have been identified as regulators of
lymphangiogenesis in mammals. Lymphangiogenesis induced by tumor-associated
lymphangiogenic factors could promote the growth o{ new vessels into the tumor,
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providing tumor cells access to systemic circulation. Cells that invade the lymphatics
could find their way into the bloodstream via the thoracic duct. Tumor expression
studies have allowed a direct comparison of VEGF-C, VEGF-D and VEGFR-3
expression with clinicopathological factors that relate directly to the ability of primary
tumors to spread (e.g., lymph node involvement, lymphatic invasion, secondary
metastases, and disease-free survival). In many instances, these studies demonstrate a
statistical correlation between the expression of lymphangiogenic factors and the
ability of a primary solid tumor to metastasize (Skobe, M. et al. Nature Med. 2001,
7(2), 192-198; Stacker, S.A. et al.. Nature Nfed. 2001, 7(2), 186-191; Makinen, T. et
al. Nature Med. 2001, 7(2), 199-205; Mand1iota, S.J. et al. EMBO J 2001, 20(4), 672-
82; Karpanen, T. et al. Cancer Res. 2001, 61(5), 1786-90; Kubo, H. et al. Blood
2000, 96(2), 546-53).
Hypoxia appears to be an important stimulus for VEGF production in

malignant cells. Activation of p38 MAP kinase is required for VEGF induction by
tumor cells in response to hypoxia (Blaschke, F. et al. Biochem. Biophy$. Res.
Commun. 2002, 296, 890-896; Shemirani, B. et al. Oral Oncology 2002, 38, 251-
257). In addition to its involvement in angiogenesis through regulation of VEGF
secretion, p3 8 MAP kinase promotes malignant cell invasion, and migration of
different tumor types through regulation of collagenase activity and urokinase
plasminogen activator expression (Laferriere, J. et al. J Biol. Chem. 2001, 276,
33762-33772; Westermarck, J. et al. Cancer Res. 2000, 60, 7156-7162; Huang, S. et
al. J Biol. Che~n.2000, 275, 12266,-.-1'2272;
Simon, C. et al. Exp. Cell Res. 2001, 271,
344-355).
Inhibition of the mito gen-activated protein· kinase (MAPK.) p3 8 hJs been
shown to inhibit both cytokine production (e.g., TNF, IL-:1, IL-6, IL-8) and
proteolytic enzyme production (e.g., MMP-1, MMP-3) in vitro and/or in vivo. The
mitogen activated protein (MAP) kinase p38 is involved in IL-1 and TNF signaling
pathways (Lee, J. C.; Layden, J. T.; McDonnell, P. C.; Gallagher, T. F.; Kumar, S.;
Green, D.; McNulty, D.; Blumenthal, M. J.; Heys, J. R.; Landvatter, S. W.; Stricker, J.
E.; McLaughlin, M. M.; Siemens, I. R.; Fisher, S. M.; Livi, G. P.; White, J. R.;
Adams, J. L.; Yound, P.R. Nature 1994, 372, 739).
Clinical sh1dies have linked tumor necrosis factor (TNF) production and/or
signaling to a number of diseases including rheumatoid arthritis (Maini. J Royal .Coll.
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Physicians London 1996, 30, 344). In addition, excessive levels of TNF have been
implicated in a wide variety of inflammatory and/or immunomodulatory diseases,
including acute rheumatic fever (Yegin et al. Lancet 1997, 349, 170), bone resorption
(Pacifici et al. J. Clin. Endocrinol. Nfetabol. 1997, 82, 29), postmenopausal
osteoporosis (Pacifici et al. J Bone Nfineral Res. 1996, 11, 1043), sepsis (Blackwell
et al. Br. J. Anaesth. 1996, 77, 110), gram negative sepsis (Debets et al. Prag. Clin.
Biol. Res. 1989, 308, 463), septic shock (Tracey et al. Nature 1987, 330, 662;
Girardin et al. New England J. Med. 1988, 319, 397), endotoxic shock (Beutler et al.
Science 1985, 229, 869; Ashkenasi et al. Proc. Nat'!. Acad. Sci. USA 1991, 88,
10535), toxic shock syndrome, (Saha et al. J. Immunol. 1996, 157, 3869; Lina et al.
FEMS Immunol. Med. Microbial. 1996, 13, 81), systemic inflammatory response
syndrome (Anon. Crit. Care Med. 1992, 20, ~64), inflammatory bowel diseases
(Stokkers et al. J. Inflamm. 1995-6, 47, 97) including Crohn's disease (van Deventer
et al. Aliment. Pharmacol. •Therapeu. 1996, 10 (Suppl. 2), 107; van Dullemen et al.
Gastroenterology 1995, 109, 129) and ulcerative colitis (Masuda et al. J. Clin. Lab.
Immunol. 1995, 46, 111), Jarisch-Herxheimer reactions (Fekade et al. New England J.
Med. -1996, 335, 311), asthma (Amrani et al. Rev. Malad. Respir. 1996, 13, 539),.
adult respiratory distress syndrome (Roten et al. Am. ~ev. Respir. Dis. 1991, 143,
590; Suter et al. Arn. Rev. Respir. Dis. 1992, 145, 1016), acute pulmonary fibrotic
diseases (Pan et al. Path.al. Int. 1996, 46, 91), pulmonary sarcoidosis (Ishioka ~t al.
Sarcoidosis Vasculitis Dijfusk Lung Dis. 1996, 13, 139), allergic_respiratory diseases
(Casale et al: Am . .J Respir. Cell }.;fol.Biol. 1996, 15, 35), silicosis (Gossart et al. J
Immunol. 1996, 156, 1540; Vanhee et al. Eur. Respir. J. 1995, 8, 834), coal worker's
pneumoconiosis (Bormet al. Am. Rev. Respir. Dis. 1988, 138, 1589), alveolar injury
(Horinouchi et al. Am. J. Respir. Cell Mol. -Biol. 1996, 14, 1044), hepatic failure
(Gantner et al. J. Pharmacol. Exp. Therap. 1997, 280, 53), liver disease during acute
inflammation (Kim et al. J Biol. Chem. 1997, 272, 1402), severe alcoholic hepatitis
(Bird et al. Ann. Intern. Med. 1990, 112, 917), malaria (Grau et al. Immunol. Rev.
1989, 112, 49; Taveme et al. Parasitol. Today 1996, 12, 290) including Plasmodium
falciparnm malaria (Perlrnann et al. Infect. Immunit. 1997, 65, 116) and cerebral
malaria (Rudin et al. Am. J. Pathol. 1997, 150, 257), non-insulin-dependent diabetes
mellitus (NIDDM; Stephens et al. J Biol. Chem. 1997,. 272, 971; Ofei et al. Diabetes
1996, 45, 881), congestive heart failure (Doyama et al. Int. J Cardiol. 1996, 54,217;
McMurray et al. Br. Heart J 1991, 66, 356), damage following heart disease (Malkiel
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et al. Mo!. Jvled. Today 1996, 2, 336), atherosclerosis (Panuns et al. J Pathol. 1996,
179, A46), Alzheimer's disease (Fagarasan et al. Brain Res. 1996, 723,231; Aisen et
al. Gerontology 1997, 43, 143), acute encephalitis (Ichiyama et al. J Neural. 1996,
243, 457), brain injury (Cannon et al. Crit. Care Med. 1992, 20, 1414; Hansbrough et
al. Surg. Clin. N Am. 1987, 67, 69; Marano et al. Surg. Gynecol. Obstetr. 1990, 170,
32), multiple sclerosis (M.S.; Coyle. Adv. Neuroimmunol. 1996, 6, 143; Matusevicius
et al. J. Neuroimmunol. 1996, 66, 115) including demyelation and oligiodendrocyte
loss in multiple sclerosis (Brosnan et al. Brain Pathol. 1996, 6, 243), advanced cancer
(MucWierzgon et al. J Biol. Regulators Homeostatic Agents 1996, 10, 25), lymphoid
malignancies (Levy et al. Crit. Rev. Immunol. 1996, 16, 31), pancreatitis (Exley et al.
Gut 1992, 33, 1126) including systemic complications in acute pancreatitis (McKay
et al. Br. J Surg. 1996, 83, 919), impaired wound healing in infection inflammation
and cancer (Buck et al. Am. J. Pathol. 1996, 149, 195), myelodysplastic syndromes
(Raza et al. Int. J. Hematol. 1996, 63, 265), systemic lupus erythematosus (Maury et
al. Arthritis Rheum. 1989, 32, 146), biliary cirrhosis (Miller et al. Am. ·J
Gasteroenterolog. 1992, 87, 465), bowel necrosis (Sun et al. J Clin. Invest. 1988, 81,
1328), psoriasis (Christophers. Austr. J Dermatol. 1996, 37, S4), radiation injury
(Redlich et al. J Immunol. 1996, 157, 1705), and toxicity following administration of
monoclonal antibodies such as OKT3 (Brod et al. Neurology 1996, 46, 1633). TNF
levels have also been related to host-versus-graft reactions (Piguet et al. Immunol.
Ser. 1992, 56, 409) including ischemia reperfusion injury (Colletti et al. J Clin.
Invest. 1989, 85, 1333) and allograft rejections including those of the kidney (Maury
et al. J Exp. Med. 1987, 166, 1132), liver (Imagawa et al. Transplantation 1990, 50,
219), heart (Bolling et al. Transplantation 1992, 53, 283), and skin (Stevens et al.
Transplant. Proc. 1990, 22, 1924), lung allograft rejection (Grossman et al. Immunol.
Allergy Clin. N Am. 1989, 9, 153) including chronic lung allograft rejection
(obliterative bronchitis; LoCicero et al. J Thorac. Cardiovasc. Surg. 1990, 99, 1059),
as well as complicatio_nsdue to total hip replacement (Cirino et al. Life Sci. 1996, 59,
86). TNF has also been linked to infectious diseases (review: Beutler et al. Crit. Care
Med. 1993, 21, 5423; Degre. Biotherapy 1996, 8,219) including tuberculosis (Rook
et al. Med. Malad. Infect. 1996, 26, 904), Helicobacter pylori infection during peptic •
ulcer disease (Beales et al. Gastroenterology 1997, 112, 136), Chaga's disease
resulting from Trypanosoma crnzi infection (Chandrasekar et al. Biochem. Biophys.
Res. Commun. 1996, 223, 365), effects of Shiga-like toxin resulting from E. coli
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infection (Harel et al. J Clin. Invest. 1992, 56, 40), the effects of enterotoxin A
resulting from Staphylococcus infection (Fischer et al. J Immunol. 1990, 144, 4663),
meningococcal infection (Waage et al. Lancet 1987, 355; Ossege et al. J Neurolog.
Sci. 1996, 144, l ), and infections from Borrelia burgdorferi (Brandt et al. Infect.
Immunol. 1990, 58, 983), Treponema pallidum (Chamberlin et al. Infect, Immunol.
1989, 57, 2872), cytomegalovims (CMV; Geist et al. Am. J Respir._Cell Mal. Biol.
1997, 16, 31), influenza vims (Beutler et al. Clin. Res. 1986, 34, 491a), Sendai virus
(Goldfield et al. Proc. Nat'!. Acad. Sci. USA 1989, 87, 1490), Theiler's
encephalomyelitis virus (Sierra et al. Immunology 1993, 78, 399), and the human
immunodeficiency virus (RN; _Poli. Proc. Nat'!. Acad. Sci. USA 1990, 87, 782;
Vyakaram et al. AIDS 1990, 4, 21; Badley et al. J Exp. Med. 1997, 185, 55).
A number of diseases are thought to be mediated .by' excess or undesired
matrix-destroying metalloprotease (MMP) activity or by an imbalance in the ratio of
the MMPs to the tissue inhibitors of metalloproteinases (TIMPs). These include
.osteoarthritis (Woessner et al. J Biol. Chem. 1984, 259, 3633), rheumatoid arthritis
(Mullins et al. Biochim. f!iophys. Acta 1983, 695, 117; Woolley et al. Arthritis
Rheum. 1977, 20, 1231; Gravallese et al. Arthritis Rheum. 1991, 34, •1076), septic
arthritis (Williams· et al. Arthritis Rheum. 1990, 33, 533), tumor metastasis (Reich et
al. Cancer Res. 1988, 48, 3307; Matrisian et al. Proc. Nat'!. Acad. Sci., USA 1986, 83,
9413), periodontal diseases (Overall et al. J Periodontal Res. 1987, 22, 81), corneal
ulceration (Bums et al. Invest. Opthalmol. Vis. Sci. 1989, 30, 1569), proteinuria
(Baiicos et al. Biocheni. J 1988, 254, 609), coronary thrombosis from atherosclerotic
plaque rupture (Henney et al. Proc. Nat'l. Acad. Sci., USA 1991, 88, 8154),
aneurysmal aortic disease (Vine et al. Clin. Sci. 1991, 81, 233), birth control
(Woessner et al. Steroids 1989, 54, 491),· dystrophobic epidermolysis bullosa
(Kronberger et al. J Invest. Dermatol. 1982, 79, 208), degenerative cartilage loss
following traumatic joint injury, osteopenias mediated by MMP activity, tempera
mandibular joint disease, and demyelating diseases of the nervous system (Chantry et
_al.J Neurochem. i988, 50, 688).
Because inhibition of p38 l~ads to inhibition of TNF production and MMP
production, it is believed inhibition of mitogen activated protein (MAP). kinase p38
enzyme can provide an approach to the treatment of the above listed diseases
including osteoporosis and inflammatory disorders such as rheumatoid arthritis and
10
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COPD (Badger, A. M.; Bradbeer, J. N.; Votta, B.; Lee, J.C.; Adams, J. L.; Griswold,
D. E. J Phann. Exper. Ther. 1996, 279, 1453).
Hypoxia appears to be an important stimulus for VEGF production in
malignant cells. Activation of p38 kinase is required for VEGF induction by tumor
cells in response to hypoxia (Blaschke, F. et al. Biochem. Biophys. Res. Commun.
2002, 296, 890-896; Shemirani, B. et al. Oral Oncology 2002, 38, 251'."257). In
addition to its involvement in angio.genesis through regulation of VEGF secretion,
p38 kinase promotes malignant cell invasion, and migration of different tumor types
through regulation of collagenase activity and urokinase plasminogen activator
expression (Laferriere, J. et_al. J Biol. Chem. 2001, 276, 33762-33772; Westermarck,
I
J. et al. Cancer Res. 2000, 60, 7156-7162; Huang; S. et al. J Biol. Chem. 2000, 275,
12266-12272; Simon, C. et al. Exp. Cell Res. 2001, 271, 344-355).- Therefore,
inhibition of p38 kinase is also expected to impact tumor growth by interfering with'
signaling cascades associated with both angiogenesis and malignant cell invasion.
Certain ureas have been described as having activity as serine-threonine kinase

and/or as tyrosine kinase inhibitors. In particular, the utility of certain ureas as an
active ingredient in pharmaceutical compositions for the treatment of cancer,
angiogenesis disorders, inflammatory disorders, has been demonstrated.
For cancer and angiogenesis, see:
Smith et al., Bioorg. M~d. Chem. Lett. 2001, 11, 2775-2778.
Lowinger et al., (Jin. Cancer Res. iOOO,6(suppl.), 335.
Lyons et al., Endocr.-Relat. Cancer 2001, 8, 219-225.
RiJdl et al., Book of Abstracts, 92nd AACR Meeting, New Orleans, LA, USA, abstract
4956.
Khire et al., Book of Abstracts, 93rdAACR Meeting, San Francisco, CA, USA,.
abstract 4211.
Lowinger et al., Curr. Pharm. Design 2002, 8, 99-110.
Carter et al., Book of Abstracts, 92ndAACR Meeting, New Orleans, LA, USA,
abstract 4954.
Vincent et al., Book of Abstracts, 38th ASCO Meeting, Orlando, FL, USA, abstract
1900.
Hilger et al., Book ·of Abstracts, 38 th ASCO Meeting, Orlando, FL, USA, abstract
19i6.
11
~
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WO 2005/009961 PCT/US2004/023500
th
Moore et al., Book of Abstracts, 38 ASCO Meeting, Orlando, FL, USA, abstract
1816.
th
Stmmberg et al., Book of Abstracts, 38 ASCO Meeting, Orlando, FL, USA, abstract
121.
For p38 mediated diseases, including inflammatory disorders, see:

Redman et al., Bioorg. Jvfed. Chem. Lett. 2001, 11, 9-12.
Dumas et al., Bioorg. Med. Chem. Lett. 2000, JO, 2047-2050.
Dumas et al., Bioorg. Med. Chem. Lett. 2000, JO, 2051-2054.
Ranges et al., Book of Abstracts, 220th ACS Nationai Meeting, Washington, DC,
USA, MEDI 149.
Dtm1as et al., Bioorg. Med. Chem. Lett. 2002, 12, 1559-1562.
Regan et al., J Med. Chem. 2002, 45, 2994-3008.
Pargellis et al., Nature Struct. Biol. 2002, 9(4), 268-272. •
Madwed J. B., Book of Abstracts, Protein Kinases: Novel Target Identification and
Validation for Therapeutic Development, San Diego, CA, USA, March 2002.
Pargellis C. et al., Curr. Opin. Invest. Drugs 2003, 4, 566-571.
Branger J. et al., J lmmunol. 2002, 168, 4070-4077.
Branger J. et al., Blood 2003, 1 OJ, 4446-4448.
Omega-Carboxyaryl diphenyl ureas are disclosed in WO00/42012, published:

July 20, 2000, WO00/41698, published: July 20, 2000, the following published U.S.
applications:
US2002-0165394-Al, published November 7, 2002,
US2001-003447-Al, published October 25, 2001,
US2001-0016659-Al, published August 23, 2001,
US2002-013774-Al, published September 26, 2002,
and copending U.S. applications:
09/758,547, filed January 12, 2001,
09/889,227, filed July 12, 2001,
09/993,647, filed November 27, 2001,
10/042,203, filed January 11, 2002 and
10/071,248, filed Febmary 11, 2002,
12
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PCT /US2004/023500
Description of the Invention

. It has been discovered that the omega-carboxyaryl diphenyl urea of Formula I
below, which has a 2-fluoro-4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenylene
group bound to urea is a potent inhibitor raf kinase, VEGFR kinase, p38 kinase, and
•PDGFR kinase, which an~ all molecular targets of interest for the treatment and
prevention of osteoporosis, inflammatory disorders, hyper-proliferatrive disorders,
and angiogenesis disorders, including cancer.
The present invention provides, e.g.,
(i) a novel compound of Formula (I), salts, prodrugs, and metabolites thereof,
(ii) pharmaceutical compositions.containing such compound, and
(ili) use of this compound or compositions for 'treating_diseases and. conditions
mediated by raf, VEGFR, PDGFR, flt-3, and p38, either as a sole agent or in
combination with cytotoxic therapies.
The compound of the Formula I below, salts, prodmgs and metabolites thereof
is collectively referred to as the "compounds of the invention". Formula I is as
follows:
The metabolites of the compound of this invention include oxidized

derivatives of Formula I wherein one or -more of t~e urea nitrogens are substituted
with a hydroxy group. The metabolites of the compound of this invention also include
analogs where the methylamide group of the compound of Formula I is hydroxylated
then de-methylated by metabolic degradation. The metabolites of the compound of
this invention furth~r include oxidized derivatives where the pyridine nitrogen atom is
in the N-oxide form (e.g. carries a hydroxy substituent) leading to those ·strnctures
referred to in the art as 1-oxo-pyridine and I-hydroxy-pyridine.
13
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WO 2005/009961 PCT /US2004/023500
Where the plural form of the word compounds, salts, and the like; is used
herein, this is taken to mean also a single compound, salt, or the like.
The use of pharmaceutically acceptable salts of the compounds of Formula I is
also within the scope of this invention. The term "phannaceutically acceptable salt"
refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound
of the present invention. For example, see S. M. Berge, et al. "Pharmaceutical Salts,"
J Pharm. Sci. 1977, 66, 1-19.
Representative salts of the compound of this invention include the

conventional non-toxic salts, for example, from inorganic or organic acids by means
well known in the art. For example, such acid addition salts include acetate, adipate, .
alginate, ascorbate, aspartate, benzoate, benzenesulfonate; bisulfate, butyrate, citrate,
camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate,
dodecylsulfate,. ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, .
hemisulfate, heptanoate;•hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-
hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfmiate, 2-
naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-
. phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate,
thiocyanate, tosylate, and undecanoate.
The salts or prodrugs of the compounds of Formula I may contain one or more
asymmetric centers. Asymmetric carbon atoms may be present in the .(R) or (S)
configuration or (R,S) configuration. Substituents on a ring may also be present in
either cis or trans form. It is intended that all such configurations •(including
enantiomers and diastereomers), are included within .the· scope of the present
invention. Preferred isomers are those with the configuration which produces the
• : .
more desirable biological activity. Separated, pure or partially purified isomers or
racemic mixtures of the compounds of this invention are also included within the
scope of the present invention. The purification of said isomers and the separation of
said isomeric mixtures can be accomplished by standard techniques lmown in the art.
The particular process to be utilized in the· preparation of the co~pound used

in this embodiment of the .invention is described in Example 1. Salt forms of tl1.e
compound of Formula (I) are described in Examples 2, 3, and 4.
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Methods of use
The present invention provides compounds which are capable of modulating

one or more signal transduction pathways involving raf, VEGFR, PDGFR, p38,
and/or flt-3 kinases. Raf is an important signaling molecule involved in the regulation
of a number of key cellular processes, including cell growth, cell survival and
invasion. It is a member of the Ras/raf/MEK/ERK pathway. This pathway is present
in most tumor cells. VEGFR, PDGFR, and flt-3 are transmembrane receptor
molecules which, when stimulated by an_ appropriate ligand, trigger ,the
I
Ras/raf/MEK/ERK cell signaling pathway, leading to a cascade of cellular events.

Each of these receptor molecules have tyrosine kinase activity.
The VEGFR receptors are stimulated by vascular endothelial growth factors
(VEGF), and are important control points in the regulation of endothelial cell
development and function. The PDGF-beta receptor regulates cell proliferation and
survival in a number _ofcell types, including mesenchymal cells. Flt-3 is a receptor
for the FL ligand. It is structurally similar to c-kit, and modulates the growth of
pluripotent haemopoietic cells, influencing the development of T-cells, B-cells, and
. .
dendritic cells.
Any gene or isoform of raf, VEGFR, PDGFR, p38, and/or flt-3_ can be
modulated in ac9ordance with present invention, including both wild-type and mutant
forms. Raf or raf-1 _kinaseis a family of serine/threonine kinases "".'hichcomprise at
l~ast three family members, a-raf, b-raf, and c-raf or raf-1. See, e.g., Dhillon and
Kolch, Arch. Biochem. Biophys. 2002, 404, 3-9. C-raf and b-raf are preferred targets
for compounds of the present invention. Activating b-raf mutations (e.g., V599E
• mutant) have been identified in various cancers, including melanoma, and the
compounds described herein can be utilized to inhibit their activity.
By the term 11~odulate 11, it is meant that the functional activity of the .pathway
(or a component of it) 1s changed in comparison to its normal activity in the absence
of the compound. This effect includes any quality or degree of modulation, including,
increasing, agonizing, augmenting, enhancing, facilitating, stimulating, decreasing,
blocking, inhibiting, reducing, diminishing, antagonizing, etc.
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The compounds of the present invention can also modulate one or more of the
following processes, including, but not limited to, e.g., cell growth (including, e.g.,
differentiation, cell survival, and/or proliferation), tumor cell growth (including, e.g.,
differentiation, cell survival, and/or proliferation), tumor regression, endoth,elial cell
growth (including, e.g., differentiation, cell survival, and/or proliferation),
angiogenesis (blood "'.".essel
growth), lymphangi9genesis (lymphatic vessel growth),
and/or hematopoiesis (e.g., T- and B-cell development,_dendritic .cell development,
etc.).·
While not wishing· to be bound by any theory or mechanism- of action, it has
been found that compounds of the present invention possess the ability to modulate
kinase activity. Th_emethods of the present invention, however, are not limited to any
particular mechanism or how the compounds achieve their therapeutic effect. By the •
term "kinase activity", ·it is meant a catalytic activity in which a gamma~phosphate
from adenosine triphosphate (ATP) is transferred to an amino. acid residue (e.g.'.
serine,· threonine, or tyrosine) in a protein substrate. A ·compound can modulate
kinase activity, e.g., inhibiting it by directly competing with A.TP for the ATP-binding
pocket of the kinase, by producing a conformational change in the enzyme's· stmcture
that affects :fts activity (e.g., by dismpting the biologically~active three-dimensional
structure), etc.
Kinase activity can be determined routinely using conventional assay methods.
, Kinase assays typically comprise the •kinase enzyme, substrates, buffers, and
components of a detection system. A typical kinase assay involves the reaction of a
32
protein-kinase with a peptide substrate and an ATP, such as P-ATP, to produce a
phosphorylated end-product (for instance, a phosphoprotein when a peptide substrate
is used). The resulting end-product can be detected using any suitable method. When
radioactive ATP is utilized,. a radioactively labeled· phosphoprotein can be separated
from the unreacted ·ga.mina-32P-ATP using an affinity membrane or gel
electrophoresis, and then visualized on the gel using autoradiography or detec.tedwith
a scintillation counter. Non-radioactive methods can- also be used. Methods can
utilize an antibody which recognizes. the phosphorylated substrate, e.g., an anti-
phosphotyrosine antibody. For instance, kinase enzyme can incubated with a
• substrate in the presence of ATP and kinase buffer under conditions which are
effective for the enzyme to phosphorylate the substrate. The reaction mixhlfe can be
separated, e.g., electrophoretically, and then phosphorylation of the substrate can be
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measured, e.g., by Western blotting using an anti-phosphotyrosine antibody. The

antibody can be labeled with a detectable label, e.g., an enzyme, such as HRP, avidin
or biotin, chemiluminescent reagents, etc. Other methods can utilize ELISA formats,
affinity membrane separation, fluorescence polarization assays, luminescent assays,
etc.
An alternative to a radioactive format is time-resolved fluorescence resonance
energy transfer (TR-FRET). This method follows the standard kinase reaction, where
a substrate, e.g., biotinylated poly(GluTyr), is phosphoryJated by a protein kinase in
.the presence of ATP. The end-product can then detected with a europium chelate
·phosphospecific antibody (anti-phosphotyrosine or phosphoserine/threonine), and
•streptavidin-APC, which binds the biotinylated substrate. These two components are
brought together spatially upon binding, and energy transfer from the phosphospecific
antibody to the acceptor (SA-APC) produces fluorescent readout in the homogeneous
format.
The compounds of th~ present invention can be used to treat and/or prevent .
any disease or condition mediated by one or more cellular signal transduction
pathways involving raf, VEGFR, PDGFR, p38, and/or flt-3 kinases. The term
"treating" is used conventionally, e.g., _themanagement or-care of a subject for the
. purpose of combating, alleviating, reducing, relieving, improving the condition of,
etc., of a disease or disorder. The compounds can also be destribed as be~g used to
prevent and/or treat diseases and/or condition mediated by the signaling molecules.
The term "mediated" indicates, e.g., that the signaling mo_lec~leis part of the pathway
which is aberrant or disturbed in the disease and/or condition.
Diseases and conditions that can be treated include· any of those mentioned
above and below, as well as:
Raf associated diseases include, e.g., cell-proliferation disorders, cancer,
. tumors, etc.;
VEGFR-2 associated diseases include, e.g., cancer, h1mor growth,
'inflammatory disease, rheumatoid arthritis, retinopathy, psoriasis, glomemlonephritis,
asthma, chronic bronchitis, atherosclerosis, transpiant rejection, conditions in~olving
angiogenesis, etc.;
VEGFR-3 associated diseases include, e.g., cancer, corneal disease, inflamed
cornea (e.g., Hamrah, Am. J Path. 2003, 163, • 57-68), • corneal transplantation·
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(Cursiefen et al., Cornea 2003, 22, 273-81), lymphatic hyperplasia, conditions

involving lymphangiogenesis, etc.;
PDGFR-beta associated diseases include, e.g., diseases or c_onditions
characterized by cell proliferation, cell matrix production, cell movement, and/or
extracellular matrix production. Specific ·examples, include, e.g., tumors,
malignancies, cancer, metastasis, chronic myeloid leukemia, inflammation, renal
disease, diabetic nephropathy, mesangial proliferative glomemlonephritis, fibrotic
conditions, atherosclerosis; restenosis, hypertension-related a:rteriosclerosis, venous
bypass graft arteriosclerosis, scleroderma, interstitial pulmonary diseas.es,.synovial
disorders, arthritis, leukemias, lymphomas, etc;
Flt-3 associated diseases include, e.g., immune-related disorders, blood cell.
disorders, conditions involving hematopoietic cell development (e.g., T-cells, B-cells,
· dendritic cells, cancer, anemia, HIV, acquired hnmune deficiency syndrome, etc.
p3 8 ass~ciated diseases include inflammatory disorders, immunomodulatory
disorders, and other disorders that have been linked to abnormal cytokine production,
especi;llly TNF-alpha; or abnormal MMP activity. These dis_ordersinclude, but are not_
limited to, rheumatoid arthritis, COPD, osteoporosis, C~ohn'sdisease and psoriasis.
In addition, compounds of the present invention can be.used to treat conditions
and disorders disclosed in ·u.s.Pat.. No. 6,316,479, e.g., -glomerular sclerosis,
interstitial nephritis, interstitial P,Ulmonaryfibrosis,· atherosclerosis,. wound scarring
and scleroderma.
The compounds of this in~ention also have a broad therap_euticactivity to treat
or prevent the progression of a broad array of diseases, such as inflammatory ·
conditions, coronary restenosis, • tumor-associated angiogenesis, atherosclerosis,
autoimmune diseases, inflammation, certain kidney diseases associ~ted with
proliferation of glom~mlar or mesangial cells, and ocular diseases associated with
reti~1al vess·e1 proliferation. psoriasis, hepatic ·cirrhosis, diabetes, atherosclerosis,
restenosis, vascular graft restenosis, in-stent stenosis, angiogenesis, ocurlar diseases,
pulmonary fibrosis, obliterative bronchiolitis, glomerular nephritis, rheumatoid
arthritis.
The present invention also provides for treating, preventing, modulating, etc.,
one or more of the following conditions in humans and/or _other mammals:
retinopathy, including diabetic retinopathy, ischemic retinal-vein occlusion,
retinopathy of prematurity and age related macular degeneration; rheumatoid arthritis,
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psoriasis, or bullous disorder associated with subepidennal blister formation,

including bullous pemphigoid, erythema multiforme, or dermatitis herpetifonnis,
rheumatic fever, bone resorption, postmenopausal osteoperosis, sepsis, gram negative
sepsis, septic shock, endotoxic shock, toxic shock syndrome, systemic inflammatory
response syndrome, inflammatory bowel disease (Crohn's disease and ulcerative
colitis), Jarisch-Herxheimer reaction, asthma, adult respiratory distress syndrome,
acute pulmonary fibrotic disease, pulmonary sarcoidosis, allergic respiratory disease,
sil~cosis, coal worker's pneumoconiosis, alveolar injury, hepatic failure, liver disease
during acute inflammation, severe alcoholic hepatitis, malaria (Plasmodium
falciparum malaria and cerebral malaria), non-insulin-dependent diabetes mellitus
(NIDDM), congestive heart failure, damage following heart disease, _atherosclerosis;
Alzheimer's disease, acute encephalitis, brain injury, multiple sclerosis (demyelation
and oligiodendrocyte loss in multiple sclerosis), . adva1iced cancer, lymphoid
. .
malignancy, · pancreati.tis, impaired wound healing in infection, inflammation and

cancer, :i:nyelodysplasticsyndromes, systemic lupus erythematosus, biliary. cirrhosis,
bowel necrosis, radiation injury/ toxicity following admi_nistration of ·monoclonal
anti~odies, host-versus-graft reaction (ischemia reper:fusion injury and allograft
rejections of kidney, liver, heart, and skin), lung allograft rejection (obliterative
bronchitis), or complications due to total hip replacement, ad an infectious disease
selected from tuberculosis, Helicobacter pylori infection during peptic ulcer disease,
Chaga's disease resulting frorh Trypanosoma cmzi infection, effects of Shiga-like
toxin resulting from E. • coli infection, effects of enterotoxin A resulting from
·burgdorferi, Treponema pallid um, cytomegalovirus, influenza virus, Theiler's
encephalomyelitis virus, and the human immunodeficiency virus (HIV), papilloma,
blastoglioma, •Kaposi's sarcoma, melanoma, hmg cancer, ovarian cancer, prostate
cancer, squamous cell carcinoma, astrocytoma, head cancer, neck cancer, bladder
cancer, breast cancer, colorectal cancer, thyroid. cancer, pancreatic cancer, gastric
cancer, hepatocellular carcinoma, leukemia, lymphoma, Hodgkin's disease, Burkitt's .•
disease, arthritis, rheumatoid arthritis, diabetic retinopathy, angiogenesis, restenosis,
in-stent _resten~sis, vascular graft restenosis, pulll!onary fibrosis, _hepatic cirrhosis,
atherosclerosis, glomerulonophritis, diabetic nephropathy, thrombic micoangiopathy
syndromes, transplant rejection, psoriasis, diabetes, wound healing, inflammation, and
neurodegenerative diseases. hyperimmune disorders, hemangioma, myocardial
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angiogenesis, coronary and cerebral collateral vascularization, ischemia, corneal

disease, rnbeosis, neovascular glaucoma, macular degeneration retinopathy of
prematurity, wound healing, ulcer Helicobacter related diseases, fractures,
endometriosis, a diabetic condition, cat scratch fever, thyroid hyperplasia, asthma or
edema following burns, trauma, chronic lung disease, stroke, polyps, cysts, synovitis,
chronic and allergic inflammation, ovarian hyperstimulation syndrome, pulmonary
' .
and cerebral edema, keloid, fibrosis, cirrhosis, carpal tunnel syndrome, adult
respiratory distress syndrome, ascites, an -'ocularcondition, a cardiov_ascuiarcondition,
Crow-Fukase (POEMS) disease, Crolm's disease, glomernfonophritis, osteoarthritis,
multiple sclerosis, graft rejection, Lyme disease, sepsis, von Rippel Lindau disease,
pemphigoid, Paget's disease, polycystic kidney disease, sarcoidosis, throiditis,
hyperviscosity syndrome, Osler-Weber-Rendlf disease, chronic qccl~sive pulmonary
disease, radiation, hypoxia, preeclampsia, menometrorrhagia, endometriosis, infection
by Herpes simplex, ischemic retinopathy, corneal angiogenesis, Herpes Zoster, human
immunodeficiency virus, parapoxvirus, protozoa, toxoplasmosis, and h1mor-
associated effusions and edema.
The compounds of this invention can possess more than one of th~ mentioned
activities, and therefore can target a plurality of signal transduction pathways. Thus,
these compounds can achieve therapeutic and prophylactic effects which normally are
only obtained when using a combination of different compounds. For instance, the
ability to inhibit both new vessel formation (e._g.,associated with VEGFR-2 and
VEGFR-3 function) (e.g., blood and/or lymph) and cell-proliferation (e.g., associated
with raf and PDGFR-beta function) using a single compound is especially beneficial
1
in the treatrµent of cancer, and other cell-proliferation. disorders that are facilitated by
neo-vasctilarization. Thus, the present invention relates specifically to compounds
which possess at least anti-cell proliferation and anti-angiogenic (i.e., inhibits
angiogenesis) activity. Any disorder or condition that would benefit from inhibiting
vessel growth and cell proliferation can be treated in accordance with the present
inventio_n. Using a single compound is also advantageous because its range of
activities tan be more precisely defined.
As indicated_above, the pi:esent invention relates to methods of treating and/or
preventing diseases and conditions; and/or modulating one or more of the pathways,
polypeptides, genes, diseases, conditions, etc., associated with raf, VEGFR, PDGFR,
p38, and/or flt-3. These methods generally involve administering effective amounts of
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compounds of the present invention, where an effective amount is the quantity of the
compound which is useful to achieve the desired result. Compounds can be
administered in any effective form by any effective route, as discussed in more detail
below.
Methods. inciude·modulating tu~or eel~proliferation, including inhibiting cell
proliferation. The latter indicates that the growth and/or differentiation of tumor cells .
is reduced, decreased, diminished, slowed, etc. The term "proliferation" includes any
process which relates to cell growth and division, and includes differentiation and
apoptosis. As discussed above, raf kinases play a key role in the activation of the
cytoplasmic signaling cascade involved . in cell proliferation, differentiation, and
apoptosis. For example, studies have found that inhibiting c-raf by anti-sense
oligonucleotides can block cell proliferation (see above). Any amount of inhibition is
considered therapeutic..
Included in the methods of the present invention is a method for using the
compound described above (Compound of Formula I), including salts, prodrngs,
metabolites (oxidized
. .
derivatives) and compositions
.
thereof, to treat mammalian
hyper-proliferative. disorders comprising administering to· a mammal, including a
human in need thereof, an amount of a compound of this invention, pharmaceutically·
acceptable salt, prodrug,· metabolite (oxidized derivative), and composition thereof,
which is effective to treat the disor&:r. Hyper-proliferative disorders include btit are
not limited to solid tumors, such as cancers of the breast, :respiratory tract, brain,·
reproductive: otgans, digestive tract, urinary tract, eye, liver, skin, head and neck,
thyroid, parathyroid and their distant metastases. Those disorders also include
lyrp.phomas,.sarcomas,and leukemias.
Any tumor or cancer can be treated, including, but not limited to,' cancers
having one or more mutations in rat ras, and/or flt-3; as well as any upstream or
downstream member of the si~aling pathways of which they are a part. As discussed
earlier, a cancer can be .treated with a compound of the pr~sent invention irrespective
of the mechanism which is responsible for it. Cancers of any organ can be treated,
including cancers of, but are not limited to, e.g., colon, pancreas, breast, prostate,
bone, liver, kidney, lung, testes, skin, pancreas, stomach, colorectal cancer, renal cell
carcinoma, hepatocellular carcinoma, melanoma, etc.
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Examples of breast cancer include, but are not limited to, invasive ductal
carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular
carcinoma in situ.
Examples of cancers of the respiratory tract include, _butare not limited to,
small-cell and non-small-cell lung carcinoma, as wen· as bronchial adenoma and
pleuropulmonary blastoma.
Examples of brain cancers include, but are not limited to, brain stem and
hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma,
ependymoma, as well as neuroectodermal and pineal tumor.
Tumors of the male reproductive organs include,· but are not limited to,
prostate and testicular cancer. Tumors of the female reproductive organs inclt1de,but
_are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well •
as sarcoma of the uterus.
Tumors of the digestive tract. include, but are not limited to, anal, colon,
colorectal, esophageal, .gallbladder, gastric, pancreatic, rectal, small-intestine, and
salivary gland cancers.
Tumors of the urinary tract include, but are not limited to, bladder, penile,
kidne~, renal pelvis, ureter, and urethral cancers.
Eye cancers include, but are not limited- to, intraocular melanoma . and
retinoblastoma.
Examples of liver cancers include, but are not . limited to, hepatocellular
carcinoma (liver cell · carcmomas with or without fibrolamellar variant), -
cholangiocarcinonia (intrahepatic ·bile duct carcinoma), and mixed hepatocellular
·cholangiocarcinoma.
Skin cancers include, but are not limited to, squamous cell carcinoma,
Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer,.and non-melanoma
-skin cancer.
Head-and-neck. cancers include, but are not limited • to, laryngeal,
hypopharyngeal, nasopharyngeal, and/or oropharyngeal cancers, and lip and oral
cavity cancer.
Lymphomas include, but are not limited to, AIDS-related lymphoma, non-
Hodgkin's • lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and
lymphoma of the central nervous system.
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Sarcomas include, but are not limited to, sarcoma of the soft tissue,
osteosarcoma, malignant fibrous histiocytoma, lyrnphosarcoma, and
rhabdomyosarcoma.
Leukemias include, but are not limited to, acute myeloid leukemia, acute
lymphoblastic leukemia,_ chronic lymphocytic leukemia, chronic myelogenous
leukemia, and hairy cell leukemia.
In addition to inhibiting the proliferation of tumor cells, compounds of the
present invention can also cause tumor regression, e.g., a decreas_e in the size of a
tumor, or in the extent of cancer in the body.·
The pres~nt invention also relates to methods of modulating angiogenesis
and/or lymphangiogenesis in a system comprising cells, comprising administering to
the system an effective amount of a compound described herein: _A system
comprising cells can be an in vivo system, such as a tumor in a patient, isolated
organs, tissues, or cells, in vitro assays systems (CAM, BCE, etc), animal models
(e.g., in vivo', subcutaneous, cancer m~dels), hosts in need of treatment (e.g., hosts
suffering from diseases having angiogenic and/or lymphangiogenic component, such
as cancer), etc.
Inappropriate and ectopic expression of angiogenesis can be deleterious to an
organism. A number of pathological conditions are associated with the growth of
extraneous blood vessels. These include, e.g., diabetic retinopathy, neov~scular
glaucoma, psoriasis; retrolental fibroplasias, angiofibroma, inflammation, etc. In
addition, the increased blood supply associated with cancerous and neoplastic tissue,
encourages growth, leading to rapid t-i.nnore_nlargement and metastasis. Moreover,
the growth of new blood an4 lyinph vessels in a tumor provides an escape route for
renegade cellsi.encouraging metastasis and the consequence spread of the cancer.
• I Useful systems for measuring angiogenesis and/or lymphangiogenesis, and
inhibit1on thereof, include, e.g., neovascularization of tumor explants (e.g., U.S. Pat.
Nos. 5,192,744; ·6,024,688), chicken chorioallantoic ~embrane (CAM) assay (~.g.,
Taylor and Folkman, Nature 1982, 297, 307-'.?12; Eliceiri et al., J Cell _Biol.1998,
140, 1255-1263),·bovine capillary endothelial (BCE) cell assay (e.g., U.S. Pat. No.
6,0~4,688; Polverini, P. J. et al., Method$-Enzymol. 1991, 198, 440-450), migration
assays, and HUVEC (human umbilical cord vascular endothelial cell) growth
inhibi~ion assay (e.g., U.S. Pat. No. '6,060,449), and use of the rabbit ear model (e.g.,
Szuba et al., FASEB J 2002, 16(14), 1985-7).
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Modulation of angiogenesis can be determined by any other method. For

example, the degree of tissue vascularity is typically determined by assessing the
number and density of vessels present in a given sample. For example, microvessel
density (MVD) can be estimated by counting the number of endothelial clusters in a
high-power microscopic field, or detecting a marker specific for microvascular
endothelium or other markers of growing or established blood vess·els; such as CD31
(also known as platelet-endothelial cell adhesion molecule or PECAM). A CD31
antibody can be employed in conventional immunohistological methods to
imm.uriostaintissue sections as described._by,e.g., U.S. Pat. No. 6,017,949; Dellas et
al., Gyn.. Oncol. 1997, 67, 27-3.3; an4 others. Other markers for angiogenesis, incl\1de;
e.g., Vezfl (e.g., Xiang et al., Dev. Bio. 1999, 206, 123-141), angiopoietin, Tie-I, and
' . . .
Tie-2 (e.g., Sato et al., Nature 1995, 376, 70-74) ..
Additionally, the present invention relates to methods of screening patients to
determine their sensitivity to compounds of the present invention. For example, the
invention relates to methods of determining whether a condition can be.modulated by
a compound disclosed herein, comprising measuring the expression or activity of raf,
. . \ . . •
VEGFR-2, VEGFR-3, PDGFR-beta, p38, and/or flt-3 in a sample comprising-cells or

a cell extract, wherein said sample has been obtained :from a cell or subject having
said condition. When the results of the determination indicate that one or more of the
mentioned genes (and/or polypeptides which they encode) differ from the normal
state, this identifies the condition as being treatable with a compound of the present •
invention, i.e., whereby said disorder or.condition can be modulated by the compound
when said expression or· activity is inc~eased in said condition as compared to a •
normal control. The method can further comprise a step of comparing the expression
in a sample with a normal control, or expression.in a sample obtained from normal or
• unaffected tissue. Comparing can be done manually, against a standard, in an
electronic form (e.g., against a database), etc. The normal control can be a standard
sample that is provided with the assay; it. can be obtained from adjacent, but
unaffected, tissue from the_same patient; ot, it can be pre~deterrnined values, etc.
Gene expression, protein expression (e.g., abundance in a eel~),protein activity (e.g.,
kinase activity), etc., can b~ determined.
For instance, a biopsy from a cancer patient can be assayed for the presence,
quantity, and/or activity cifraf, VEGFR-2, VEGFR-3, PDGFR-beta, p38, and/or flt-3.
Increased expression or activity of one· or more of these can indicate that the cancer
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can be targeted for treatment by a compound of the present invention. For example,
as described in the examples below, raf activity can be monitored by its ability to
initiate the cascade leading to ERK phosphoryl_ation(i.e., raf/MEK/ERK), resulting in
phospho-ERK. Increased phospho-ERK levels in a cancer specimen shows that its raf
activity is elevated, suggesting the use of compounds of the present invention to treat
it.
Measuring expression includes determining or detecting the amount of the
polypeptide present in a cell or shed by it, as well as measuring the underlying
mRNA, where the quantity of mRNA present .is considered to ·reflect the quantity of
polypeptide manufactured by the cell. Furthermore, the genes for raf, VEGFR-2,
VEGFR-3, PDGFR-beta, p38, and/or Flt-3 _can be analyzed to determine whether
there is a gene d.ef~ctresponsible for aberrant expression or polypep,tide activity.
Polypeptide detection can be carried out by any available method, e.g., by
Western blots, ELISA, dot blot, nnmunoprecipitation, RIA, immunohistoche~istry,
etc. For instance, a tissue section can be prepared and labeled with a specific
antibody (indirect or direct and visualized with a microscope. Amount of a
polypeptide can be quantitated without visualization, e.g., by preparing lysate of _a
c:1-
sample of interest, and then determining by _ELISA or 'Western the ·amount of

polypeptide per quantity of tissue. Antibodies and other specific binding agents can
be used. There is no limitation on how detection is performed.
Assays can be utilized which permit quantification and/or presence/absence
detection pf a·targ.et nucleic acid (e.g., genes, mRNA, etc., for raf, VEGFR, PDGFR,
r .
p38, and/or flt-3) in a sample. Assays can be performed at the single-cell level, or in a
sample comprisin·g many cells, where the -assay is "averaging" expression over the
entire collection of cells and tissue present in the sample. Any suitable assay format
can be used, 'including, but not limited to, e.g., Southern blot analysis, Northern blot
analysis, polymerase chain reaction ("PCR") (e.g., Saiki.et al., Science 1988, 241, 53;
·u.s.Pat. Nos. 4,683,195, 4,683,202, and 6,040,166; PCR Protocols: A Guide to
Methods and Applications, Innis et al., eds., Academic Press, New York, ·1990),
reverse transcriptase polymerase chain reaction ("RT~PCR"), anchored PCR, rapid
amplification of cDNA ends ("RACE") (e.g., Schaefer in Gene Cloning and Analysis:
Current Innovations, Pages 99-115, 1997), ligase ch~in reaction ("LCR") (EP 320
308), one-sided PCR (Ohara et al., .Proc. Natl. Acad. Sci. 1989, 86, 5673-5677),
indexing methods (e:g., U.S. Pat. No. 5,508,169), in situ hybridization, ·differential
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display (e.g., Liang et al., Nucl. Acid. Res. 1993, 21, 3269 3275; U.S. Pat. Nos.
5,262,311, 5,599,672 and 5,965,409; WO97/18454; Prashar and Weissman, Proc.
Natl. Acad. Sci., 93:659-663, and U.S. Pat Nos. 6,010,850 and 5,712,126; Welsh et
al., Nucleic Acid Res., 20:4965-4970, 1992, and U.S. Pat. No. 5,487,985) and other
RNA fingerprint~ng techniques, nucleic acid sequence based amplification
("NASBA") and other transcription based amplification systems (e.g., U.S. Pat. Nos.
5,409,818 and 5,554,527; WO 88/10315), polynucleotide arrays (e.g., U.S. Pat. Nos.
5,143,854, 5,424,186; 5,700,637, 5,.874,219,.and 6,054,270; PCT WO 92/10092; PCT
WO 90/15070), Qbeta Replicase (PCT/US87/00880), Strand Displacement
Amplification ("SDA"), Repair Chain Reaction ("RCR"), _nucleaseprotection assays,
subtraction-based methods, Rapid-Scan, etc. Additional useful methods include, but
. .
are not limited to, e.g., template-based amplification methods, competitive PCR (e.g.,
U.S .•Pat No. 5,747,251), redox-based assays (e.g., U.S. Pat. No. 5,871,918)~Taqman-
based assays (e.g., Holland et al., Proc. Natl. Acad, Sci. 1991, 88, 7276-7280; U.S.
Pat. Nos. 5,210,015 and 5,994,063), real-time fluorescence-based monitot1ng (e.g.,
U.S. Pat. 5,928,907), molecular energy transfer labels (e.g., U.S. Pat. Nos. 5,348,853,
5,532,129·, 5,565,322, 6,030,787, and 6,117,635; Tyagi and Kramer, Nature Biotech.,
14:303-309, 1996). Any method suitable for single cell analysis of gene or protein
expression can be used, including in situ hybridization, immunocytochemistry,
. • r
MACS, FACS, flow cytometry, etc. For single cell assays, expression products can
·be measured using antibodies, PCR, or ~ther types of nucleic acid amplification (e.g.,
Brady et al., Methods Mol. '& Cell. Biol. 1990, ~' 17-25; Eberwine et al.,. Proc. Natl .
• ··' '
Acad. Sci. 1992, 89, 3010-3014; U.S. Pat. No. 5,723,290). These and other methods
- .
can be carried out conventionally, e.g., as described in the mentioned publications.

Activity of raf, VEGFR-2, VEGFR-3,· PDGFR-beta, p38, and/or flt-3 can be
assessed routinely, e.g., as described in the examples below, or using standard assays
for kinase activity.
The present invention also pr(?vides methods of assessing the efficacy of a
compound of the present invention in treating a disorder, comprising one or more of
the following steps in any effective order, e.g., administering· an amount of a
compotmd, measuring the expression or activity of raf, VEG1'.R-2,' VEGFR-3,
PDGFR-beta, p3-8, and/or flt-3 (see above), determining the effect of said compound
on said expression: or activity. For instance, biopsy samples can be removed from
patients who have been treated with a compound of the present invention, and t];ien
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assayed for the presence and/or activity of the mentioned signaling molecules.
Similarly, as discussed above, decreases in the levels of phospho-ERK in the cancer
tissue (e.g., compared to normal tissue or before treatment) indicate that the
compound is exerting in vivo efficacy and a therapeutic effect. The method can be
used to detem1ine appropriate dosages and dosing regimens, e.g., how much
compound to administer and at what frequency to administer it. By monitoring its
effect . on the signaling molecules in the tissue, the clinician can determine the
appropriate treatment protocol and whether it is achieving the desired effect, e.g., on
modulating or inhibiting the signal transduction pathway.
Compounds of the present invention also can be used as markers todetermine
the presence and quantity of ra[, VEGFR-2, VEGFR-3, PDGFR-beta, p38, and/or flt-
3, in a sample comprising a•biological material. This comprises one or more of the
following steps in any effective order: (i) contacting said sample comprising a
biological .material with a compound of the present invention, and (ii) determining
whether said compound binds to said material. The compound can be labeled, or it
•can be used as a competitor to a labeled compound, such as labeled-ATP.
The invention also provides methods for treating, preventing, modulating, etc.,
diseases and conditions in rp.ammals comprising administering a compound of this
invention with another modulator of the signal transduction pathway comprising, but
not limited to raf, VEGFR, PDGFR, p38, and/or flt-3. These can be present in the
same composition or in· separate· formulations or dosage units. Administration can be.
•the same or different routes, and can be simultaneous or sequential.
The following publications relate to VEGFR~3 modulation and are

incorporated herein for their description of disease states mediated by VEGFR-3 and
• assays to determine such activity.
WO95/33772 Alitalo, et. al.

WO95/33650 Charnock-Jones, et. al..
WO96/39421 Hu, et. al.
WO02/060950 · Alitalo, et. al.
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WO02/081520 Boesen, et. al.
The following publications relate to VEGFR-2 modulation and are

incorporated herein for their description of disease states mediated by VEGFR-2 and
ass~ys to determine such activity.
EP0882799 Hanai, et. al.

EP1167384 Ferraram, et, al.
EP1086705 Sato; et. al.
EPl 1300032 Tesar, et. al.
EP1166798 Haberey, et. al.
EP1166799 • H~berey, et. al.
EP1170017 Maini, et. al.
EP1203827 Smith
WO02/083850 Rosen, et. al.
The following p1+blicationsrelate to flt-3 modulation and are incorporated.

herein for thejr description of disease· states mediated by flt-3 and assays to determine
such activity.
2002/0034517 Brasel, et. al.

2002/0107365 Lyman, et. al.
2002/0111475 Graddis, et. al.
EP0627487 Beckermann, et. al.
WO9846750 Bauer, et. al.
WO9818923 McWherter, et. al.
WO9428391 Beckermann, et al.
WO9426891 Birnbaum, et. al.
The following paterits and publication relate to PDGF/PDGFR modulation and

are incorporated herein for their d_escriptionof the disease states mediated by PDGFR-
beta and assays to determine such activity.
5,094,941 Hart, et. al.
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5,371,205 Kelly, et. al.

5,418,135 Pang
5,444,15J Vassbotn, et. al.
5,468,468 LaRochelle, et. al.
5,567,584 Sledziewski, et. al.
5,618,678 Kelly, et. al.
5,620,687 Hart, et. al.
5,648,076 Ross, et. al.
5,668,264 J anjic, et. al.
5,686,572 Wolf, et. al.
5,817,310 Ramakrishnan, et. al.
5,833,986 •. . LaRochelle, et. al.
l.
5,863,739 LaRochelle, et. at

5,872,218 Wolf, et. al.
5,882,644 Chang, et. al.
5,891,652 Wolf, et. al.
5,976,534 Hart, e(al.
5,990,141 Hirth; et. al.
6,022,854 Shuman
6,043,211 Williams, et. al.
6,110,737 Escobedo, et. al.
6,207,816Bl Gold, et. al.
6,228,600B 1 •Matsui, et. al.
6,229,002Bl J anjic, et. al.
.6,316,60313] McTigue, et. al.
6,372,438Bl Williams, et. al.
6,403,769Bl La Rochelle, et. al.
6,440,445B 1 Nowak, et. al.
6,475,782Bl . Escobedo, et. al.
WO02/081520 Boesen, et. ·al.
WO02/079498 Thomas, et. al.
WO02/070008 • Rockwell, et. al.
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WO09959636 Sato, et. al.

WO09946364 Cao, et. al.
WO09940118 Hanai, et. al.
WO9931238 Y abana, et. al.
WO9929861 Klagsbrun, et. al.
WO9858053 Kendall, et. al.
WO9851344 Maini, et.· al.
WO9833917 Alitalo, et: al.
WO9831794 Matsumoto, et. al.
WO9816551 Ferrara, et. aL
WO9813071. Kendall, et al.
WO9811223 Martiny-Baron, et. al.
WO9744453 Chen, et. al.
WO9723510 Plouet, et. al.
W09715662 Stinchcomb, et. al.
WO9708313. Ferrara, et. al.
WO9639515 Cao, et. al.
WO9623065 Smith, et. al.
WO9606641 • Fleurbaaij, et. al.
WO9822316 Kyowa
WO9521868 Rockwell, et. al.
WO02/060489 Xia, et. al.
PDGFR-beta.
EP0869177 Matsui, et. al.

WO09010013 Matsui, et. al.
PDGFR-alpha
EP1000617 Lammers, et. al.

EP0869177 .Matsui, et. al.
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EP0811685 Escobedo, et. al.
Pharmaceutical compositions based on the compounds of the present invention
This invention also relates to pharmaceutical compositions containing a

compound of the present invention and pharmaceutically acceptable salts thereof.
These compositions can be utilized to achieve the desired pharmacological effect by
administration to a patient in need thereof. A patient, for the purpose of this
invention, is a mammal, including a human, in need of treatment for the particular
•condition or disease. . Therefore, the present invention includes pharmaceutical
compositions which are comprised of a pharmaceutically acceptable carrier and a
pharmaceutically effective amount of a compound, or salt thereof, of the present
invention. Th_eterm "pharmaceutically accep.table carrier". is meant as any carrier
which is relatively non-toxic and· innocuous to a patient at co_ncentrat!onsconsistent
with effective activity of the active ingredient so that any side effects ascribable to the
carrier do not vitiate the beneficial effects of the active ingredient.A phannaceutically
effective amount of compounq is that amount which produces a result or exerts an
influence on the particular condition being treated. The compound of the present
invention can be administered with pharmaceutically-acceptable carriers well known
in the art using any effective conventional dosage unit forms, including immediate,
slow and timed release preparations, orally, parenterally, topically,. nasally,
ophthalrnically, optically, sublingually, rectally, vaginally, and the like.
For oral administration, the compound can be formulated into solid or liquid
preparations such as capsules, pills, tablets, troches, • lozenges, melts, powders,
solutions, suspensions, or emulsions, and may be prepared according to methods
known to the art for the manufacture of pharmaceutical compo·sitions. The solid unit
dosage forms can be a capsule which can be of the ordinary hard- or soft-shelled
gelatin type containing, for example, surfactants, lubricants, and inert fillers such. as
lactose, sucrose, calcium phosphate, and com starch.
In another embodiment, the compounds of this invention may be tableted with
conventional tablet bases such as lactose, sucrose and cornstarch in combination w1th
binders such as acacia, com starch or gelatin, disintegrating agents intended to assist
the break-up and dissolution of the tablet following administration such as potato
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starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants
intended to improve the flow of tablet granulation and to prevent the adhesion of
tablet material to the surfaces of the tablet dies and punches, for example talc, stearic
acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and flavoring
agents such as peppermint, oil of wintergreen, or cherry flavoring, intended to
enhance the aesthetic qualities of the tablets and make them more acceptable to the
patient. Suitable excipients for use in oral liquid dosage forms include dicalcium
phosphate and diluents such as water and al.cohols, for example, ethanol, benzyl
alcohol, and polyethylene alcohols, either with or without the addition of a
pharmaceuticaU-x acceptable surfactant, su~pending agent or emulsifying agent.
Various other _materials may be pr~sent as coatings or to otherwise modify the
physical form of the dosage unit. For instance tablets, pills or capsules may be coated
with shellac, sugar or both.
Dispersible powders and granules are suitable •for the preparation of an
aqueous suspension. They provide the active ingredient in admixture with a dispersing
or wetting agent, a suspending agent and one or more preservatives. Suitable
dispersing or wetting agents and suspending agents are exemplified by those already
mentioned above. Additional excipients, for example those sweetening, flavoring and
coloring agents described above, may also be present.
The pharmaceutical compo~itions of this invention may also be in the form of
•oil-in-water emulsions. _Theoily·phase may be a vegetable oil such as liquid paraffin
or a mixture of vegetable oils. Suitable emulsifying agents may be (1) naturally
occurring gums such as gum acacia. and gum tragacanth, (2) naturally .occurring
phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form
fatty acids and hexitol anhydrides, for example, sorbitan monooleate, .•(4)
condensation products of said partial esters with ethylene oxide, for example,
, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening
and flavoring agents.
Oily suspensions may be formulated by su&pendingthe active ingredient in a
vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or
in ·a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening
agent such as, for example, beeswax, hard paraffin, or cetyl al.cohol.The suspensions
may also contain ope or more preservatives, for example, ethyl or n-propyl p-
hydroxybenzoate; one or more coloring agents; ·one or more flavoring agents; and one
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or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, for
example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also
contain a demulcent, and preservative, such as methyl and propyl parabens and
flavoring and coloring agents.
The compounds of this invention may also be administered parenterally, that
is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or
interperitoneally, as injectable dosages of the compound in a physiologically
acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or
mixture of-liquids such as water, saline, aqueous
(
dextrose and
•
related sugar solutions,
an ·alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as
propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-di!_!lethyl-l,l-
dioxolane-4-methanol, ethers such as poly( ethylene glycol) 400,"an oil,· a fatty acid, a
fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or
without the addition of a pharmaceutically acceptable surfactant such as a soap or a
detergent, suspending agent such as pectin, carbomers, • methycellulose,.
hydroxypropylmethylcellulose, or carboxymethylcellulose, oi emulsifying agent and
other pharmaceutical adjuvants.
Illustr~tive of oils which can be used in the parenteral. formulations of this
invention are those of petroleum, animal, vegetable, or synthetic origin, for example,
peanut oil, soyb~an oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and
mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and
myristic. acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl
myristate. Suitable soaps include fatty acid alkali metal, ammonium, and
triethanolamine salts and suitable detergents include cationic detergents, for example
dimethyl dialkyl ·ammonium halides, alkyl pyridinium halides, and alkylamine
acetates; anionic detergents, for example, alkyl', aryl, and olefin sulfonates, alkyl,
olefin, ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents,
for example, fatty amine oxides, fatty acid alkanolamides; and poly( oxyethylene-
oxypropylene)s or ethylene oxide or propylene oxide copolymers; and amphoteric
detergents, for example, alkyl-beta-aminopropionates, •and 2-alkylimidazoline
quartemary ammonium salts, as well as mixtures.
The parenteral compositions of this invention will typically contain from about
0.5% to about 25% by weight of the active ingredient in solution. Preservatives and
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buffers may also be used advantageously. In order to minimize or eliminate irritation

at the site of injection, such compositions may contain a non-ionic surfactant having a
hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of
surfactant in such formulation ranges from about 5% to about 15% by weight. The
surfactant can be a single component having the above HLB or can be a mixture of
two or more components having the desired HLB.
Illustrative of surfactants used in parenteral formulations are the class of
•polyethylene sorbitan fatty acid esters, for example, sorbitan monoole_ateand the high
molecular weight adducts of ethylene oxide with a hydrophobic. base, fom1ed by the
. condensation of propylene oxide with propylene glycol.
The pharmaceutical compositions may be in the form of sterile injectable
aqueous suspensions. Such suspensions may be formulated according to known
methods· using suitable dispersing or wetting agents and s.uspending agents such as,
for example, sodium carboxymethylcellulos,e,'methylcelldlose, hydroxypropylmethyl-
cellulose, .sodium alginate, gum tragacanth and gum acacia;, dispersing or wetting
agents which may be a naturally occurring phosphatide. such as lecithin, a
condensation product of an alkylene oxide with a fatty acid, for example,
•polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain
aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product
of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as
polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide
with a partial ester derived from a fatty. acid and a hexitol anhydride, for_example
polyoxyethylene sorbitan monooleate.
The sterile injectable preparation may also be a sterile injectable solution or
suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and
, solvents that may be employed are, for example, water, Ringer's so_lution,isotonic
sodium chloride solutions and isotonic glucose solutions. In addition, sterile fixed oils
are conventionally employed as solvents or suspending media. For this purpose, any
bland, fixed oil may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid can be used in the preparation of injectables.
A composition of the invention may also be administered in the form of
suppositories. fo: rectal administration. of the drug. These compositions ·can. be
prepared by mixing the drug with a suitable non-irritation excipient which is solid at
ordinary temperatures but liquid at the rectal temperature and will therefore melt in
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the rectum to release the drug. Such material 1s, for example, cocoa butter and
polyethylene glycol.
Another formulation employed in the methods of the present invention
employs transdermal delivery devices ("patches"). Such transdermal patches may be
used to provide continuous or discontinuous infusion of the compounds of the present
invention in controlled amounts. The construction and use of transdermal patches-for
\_
the delivery or°phannaceutical agents is. well known in the art (see, e.g., US Patent
No. 5,023,252, issued June 11, 1991, incorporated herein by reference). Such patches
may be constructed for continuous, pulsatile, or on demand_ delivery of
pharmaceutical agents.
Controlled release formulations for parenteral· administration include
liposomal, pol~eric microsphere and polymeric gel formulations which are known
in the art.
It may be desirable or:necessary to introduce the pharmaceutical composition
to the patient via a mechanical delivery device. The construction and use of
mechanical delivery devices for the delivery of pharmaceutical agents is well known
in the art. Direct techniques for, for example, administering a drug directly to the
brain usually involve placement of a drng delivery catheter into the patient's
ventricular system ·to bypass the blood-brain barrier. One such implantable delivery
system, used for the transport of agents to specific anatomical regions of the body, is
described in US Patent No. 5,011,472, issued April 30,. 1991.
_The compositions of the invention can also contain other conventional .
pharmaceutically ac.ceptable compounding ingredients, generally referred to as
carriers or diluents, as necessary or desired. Conventional procedures for preparing
such compositions in appropriate dosage forms can be util_ized.•Such ingredients· arid
procedures include those described in the following references, each of which is
incorporated herein by reference: Powell, M.F. et-al,·_"Compendium of Excipients for
Parenteral Formulations" PDA Journal of Pharmaceutical Science & Technology
1998, 52(5), 238-311; Strickley, R.G "Parenteral Formulations of Small Molecule
Therapeutics Marketed in the United States (1999)-Part.:1" PDA Journal of
Pharmaceutical Science & Technology 1999, 53(6),- 324-349; and Nema, S. et al,
"Excipients and Their Use in Injectable Products" PDA Journal of Pharmaceutical
Science & Technology 1997, 51(4), 166-17(
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Commonly used pharmaceutical ingredients which can be used as appropriate

to formulate the composition for its intended route of administration include:
• acidifying agents (examples include but are not limited to acetic acid, citric acid,
fumaric ·acid, hydrochloric acid, nitric acid);
• alkalinizing agents (examples include but are not limited to ammonia solution,
ammonium carbonate, diethanolamine, moE.oethanolamine, potassium hydroxide,
sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine );
• adsorbents (examples include but are not limited to powdered cellulose and
activated charcoal);
• aerosol propellants (examples include but are not limited to carbon dioxide,
CChF 2, F2ClC-CClF2 and CClF3)
• air displacement agents (examples include but are not limited to nitrogen and
argon);
• antifungal preservatives (examples. include but are not limited· to benzoic acid,
butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate);
• antimicrobial preservatives (examples include but are not limited to benzalk:onium
chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride,
chlorobutanol, phenol, .phenylethyl alcohol, phenylmercuric nitrate ·and
thimerosal); .
• antioxidants (examples include but are not limited to ascorbic acid, ascorbyl
palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus
• acid, monothi()glycerol, propyl gallate, so_dium ascorbate, sodium bisulfite,
sodium formaldehyde sulfoxylate, sodium metabisulfite );
• binding materials (examples include but are not ·limited to block polymers, natural
and synthetic rubber, polyacrylates, polyurethanes, silicones, polysiloxanes ·and
styrene-bu,tadiene copolymers);
• buffering agents (examples i:r:iclude but are not limited to potassium
metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydrous
and sodium citrate dihydrate)
• carrying agents (examples include but are. not limited· to acacia syrup, aromatic
syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, com oil,
mineral oil, peanut oil, sesame oil, bacteriostatic. sodium chloride injection and
bacteriostatic water for injection)
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• chelating agents (examples include but are not limited to edetate disodium and
edetic acid)
• colorants (examples include but are not limited to FD&C Red No. 3, FD&C Red
No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C
Orange No. 5, D&C Red No. 8, caramel and ferric oxide red);
• clarifying agents (examples include but are not limited to bentonite);
• emulsifying agents (examples include but are not limited to acacia, cetomacrogol,
cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate,
polyoxyethylene 50 monostearate);
• enc.apsulating agents (examples include but are not limited to gelatin and cellulose
acetate phthalate)
• flavorants (examples include but are not limited to anise oil, cinnamon oil, cocoa,
menthol, orange oil, peppermint oil and vanillin);
• • humectants (examples include but are not limited to glycerol, propylene glycol .
and sorbito!);
• levigating agents ( examples include but are not limited to mineral oil and
glycerin);
• oils (examples include but are not limited to arachis oil, mineral oil, olive oil,
peanut oil, sesame oil and vegetable oil);
• ointment bases (ex_amples include but are not limited to lanolin, hydrophilic
ointment, polyethylene glycol ointment, petrolah1m, hydrophilic petrolatum, white
ointment, yellow ointment, and.rose water ointment);
• penetration enhancers (transdermal delivery)·(examples include but are not limited
to monohydroxy or-polyhydroxy alcohols, mono-or polyva1ent alcohols, saturated
.or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or
unsaturated d~carboxylic acids, essential oils, phosphatidyl derivatives, cephalin,
terpenes, amides, ethers, ketones and ureas)
• plasticizers (examples include but are not limited to diethyl phthalate and
glycerol);
• solvents (examples include but are not limited to ethanol, com oil, cottonseed oil,
glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for
injection, sterile water for injection and sterile water for irrigation);
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• stiffening agents (examples include but are not limited to cetyl alcohol, cetyl
esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow
wax);
• suppository bases (examples include but are not limited to cocoa butter and
polyethylene glycols (mixtures));
• surfactants (examples include but are not limited to benzalkonium chloride,
nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan
mono-palmitate);
• suspending agents (examples include but are not limited to agar, bentonite,
carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose,
tragacanth and veegum);
• sweetening agents (examples include but are not limited to aspartame, dextrose,
glycerol, mannitol, propylene glycol, saccharin sodimn, sorbitol and sucrose);
• tablet anti-adherents (examples include but are not limited to. magnesium stearate
and talc);
• tablet binders (examples include but are not limited to acacia, alginic acid,
carboxymethylcelhilose sodium, compressible sugar, ethylcellulose, gelatin, liquid
glucose, methylcellulose, and pregelatinized starch);
• tablet and capsule· diluents (examples include but are not limited to dibasic
calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered
cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate,
sorbitol and starch);
• tablet coating agents (examples include but are not limited to liquid glucose,
hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
methylcellulose, ethylcellulose, cellulose acetate phthalate a:ndshellac);
• tablet direct •compression excipients (examples include but are not limited to
dibasic calcium phosphate);
• tablet disintegrants (examples include but are not limited •to alginic acid,
carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium,
sodium alginate, sodium starch glycollate and starch);.
• • tablet _glidants(examples include but are not limited to colloidal silica, com starch
and talc);
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• tablet lubricants (examples include but are not limited to calcium stearate,
magnesium stearate, mineral oil, stearic acid and zinc stearate);
• tablet/capsule opaquants (examples include but are not limited to titanium
dioxide);
• tablet polishing agents (examples include but are not limited to carnauba wax and
white wax);
• thickening agent~ (examples include but are not limited to beeswax, cetyl alcohol
and paraffin);
• tonicity agents (examples include but are not limited to dextrose and 'sodium
chloride);
• , viscosity inc~easing ,agents (examples inclµde but are not limited to alginic acid,
bentonite, carbomers, carboxymethylcellulose sodium, methylcellulose, sodium
alginate and tragacanth); and
• wetting agents (examples include but are not limit<::dto heptadecaethylene
oxycetanoI; lecithin, sorbitol monooleate, polyoxyethylene sorbitol monooleate,
and polyoxyethylene stearate).
Pharmaceutical compositions according to the present invention can be illustrated as

follows:
Sterile N Solution: a 5 mg/mL solution of the desired compound of this invention-is

made using sterile, injectable water, and the pH is ~djusted if necessary. The solution
is diluted for administration to 1 - 2 mg(mL with sterile 5% dextrose and is
administered as an IV infusion over 60 minutes.
Lyophilized powder for IV administration: A sterile preparation can be prepared with

(i) 100 - 1000 mg of the desired compound of this invent-ionas a lypholized powder,
(ii) 32- 327 mg/mL sodium citrate, and (iii). 300 - 3000 mg Dextran 40. The
formulation is reconstituted· with steril~, injectable saline or dextrose 5% to a
concentration of 1-0to 20 mg/mL, which is further diluted with saline or dextrose 5%
to 0.2 - 0.4 mg/mL, and is administered either IV bolus or by N infusion over 15 -
60 minutes.
Intramuscular suspension: The following solution or suspension can be prepared, for

. intramuscular injection:
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50 mg/mL of the desired, water-insoluble compound of this invention

5 mg/mL sodium carboxyrnethylcellulose
4 mg/mL Tween 80
9 mg/mL sodium chloride
9 mg/mL benzyl alcohol
Hard Shell Capsules: A large number of unit capsules are prepared by filling standard
two-piece hard galantine capsules each with 100 mg of powdered active ingredient,
150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
Soft Gelatin Capsules: A mixture of active ingredient in a digestible oil such as

soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive
displacement pump into molten gelatin to form soft gelatin capsules containing 100
mg of the active ingredient. The capsules are washed and dried. • The active
ingredient can be dissolved in a mixture of polyethylene glycol, glycerin. and sorbitol
to prepare a water miscible medicine mix.
Tablets: A large number of tablets ate prepared by conventional procedures so that

the dosage unit was 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5
mg ofmagnesiuni stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and
98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to
increase palatability, improve elegance and stability or delay absorption.
hnmediate Release Tablets/Capsules: These are solid 'Oral dosage forms made by
conventional and novel processes. These units are taken orally without water for
immediate dissolution and dehvery of the medication. The active ingredient is mixed
in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These •
liquids. are solidified into solid tablets or caplets by freeze drying and solid state
extraction techniques .. The drug compounds may be compressed with viscoelastic and .
thermoelastic sugars and polymers . or effervescent components to produce porous
matrices intended for immediate release, without the need of water.
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Dosage of the pharmaceutical compositions of the present invention
Based upon standard laboratory teclmiques known to evaluate compounds useful for
the treatment of any of the aforementioned disorders, by standard toxicity tests and by
standard pharmacological assays for the determination of treatment of the conditions
identified above in mammals, and by comparison of these results with the results of
known medicaments that are used to treat these conditions, the effective dosage ofthe
compounds of this invention can readily be determined for treatment of each desired
indication. The amount of the active ingr~dient to be administered in the treatment of
one of these conditions can vary widely according to such considerations as the
particular _compound and dosage u~it employed, the mode of administration, the
period of treatment, the age and sex of the p~tient treated, and the nature and extent of
the conditiol:),treated.
The total amount of the active ingredient to be administered can range from
about 0.001 mg/kg-to about 200 mg/kg, and preferably from about 0.1 mg/kg to about
50 mg/kg body weight per day. A unit dosage may preferably contain from about 5
mg to about 4000 mg of active ingredient, and can be administered one or more times
per day. The daily dosage for oral administration will preferably be from 0.1 to 50
mg/kg of. total body weight. The d;;tily dosage for administration by injection,
including. intr~venous, intramuscular, subcutaneous and parenteral injections, and use
of infusion techniques will preferably be from 0.1 to 10 mg/kg of total body weight.
The daily rectal dosage regimen will preferably be from 0.1 to 50 mg/kg of total body
weight. The ·daily vaginal dosage regimen will preferably be from 0.1 to 50 mg/kg of
total body weight. The daily topical dosage regimen will preferably be from 0.1 to 10
mg/kg administered between one to four times daily. The transdermal concentration
will preferably be that required to mai~tain a daily dose of from 0.1 to 10 mg/kg. The
daily inhalation dosage regimen will preferably be from 0.1 to 10 mg/kg of total body
weight. Other dosages and amounts can be selected routinely.
The specific initial and continuing dosage regimen for each patient will vary
according to the nah1re and severity of the condition as determined by the attending
diagnostician, the activity of the specific compound employed, the age and general
condition of the patient, time of administration, route of administration, rate of
excretion of the drug, drug combinations, and the like. The desired mode·of treatment
and number of doses of a compound of the present invention or a pharmaceutically
IITRUE COPYII
WO 2005/009961 PCT /0S2004/023500
acceptable salt or ester or composition thereof can be ascertained by those skilled in

the art using conventional treatment tests.
Combination of the compounds and compositions of the present invention with

additional active ingredients
Compounds of this invention can be administered as the sole pharmaceutical

agent or in combination with one or more other pharmaceutical agents where the
combination causes no unacceptable adverse effects. This may be of particular
relevance for the treatment of hyper-proliferative diseases such as cancer. In. this
instance, the compound of this invention can be combined with' known cytotoxic
agents, signal transduction inhibitors, or with other anti-cancer agents, as well as with
admixtures and combinations thereof.
In one embodiment, the compounds of the present invention can be combined
with cytotoxic anti-cancer agents. Examples of such agents can be found in the 11th
Edition of the Merck Index (1996). These agents include, by no way of limitation,
asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase,
cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin
(adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine,
hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-
mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone,
prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thioguanine, topotecan,
vinblastine, vincristine, and vindesine.
Other ·cytotoxic drugs suitable for use with the compounds of the invention
include, but are ·not limited to, those compounds acknowledged to be used in the
treatment of neoplastic diseases in Goodman and Gilman 's The Pharmacological
Basis of Therapeutics (Ninth Edition, 1996, McGraw-Hill). These agents include, by
no way of limitation, aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine
cladribine, busulfan, diethylstilbestrol, 2', 2'-difluorodeoxycytidine, docetaxel,
erythrohydroX:ynonyladenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5-
fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone,
flutamide, hydroxyprogesterone caproate, . idarubicin, interferon,
medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel,
pentostatin, N-phosphonoacetyl-L-aspartate (PALA), piicamycin, semustine,
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teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and

vinorelbine.
Other cytotoxic anti-cancer agents suitable for use in combination with the
compounds of the invention also include newly discovered cytotoxic principles such
as oxaliplatin, gemcitabine, capecitabine, epothilone and its natural or synthetic
derivatives, temozolomide (Quinn et al., J Clin. Oncology 2003, 21(4), 646-651),
tositumomab (Bexxar), trabedectin (Vidal et al., Proceedings of the American Society
for Clinical -Oncology 2004, 2 3, abstract 3181), and the inhibitors of the kinesin
spindle protein Eg5 (Wood et al., Curr. Opin. Pharmacol. 2001, 1, 370-377).
In another embodiment, the compounds of the present invention can be

combined with other signal transduction inhibitors. Of particular interest' are signal
transduction inhibitors which target the EGF:R family, such as EGFR, HER-2, and
HER-4 (Raymond et al., Drugs 2000, 60 _(Suppl.l), 15-23; Harari et al., Oncogene
2000, 19 ·(53), 6102.:6114), and their respective ligands. Examples of such agents
- I -
include, by no way of limitation, antibody therapies such as Herceptin (trastuzumab),

, ,
Erbitux (cetuximab), and pertuzumab._Examples of such therapies also include, by no

way of limitation, small-molecule kinase inhibitors such _asZD-1839 / Iressa (Baselga
et al., Drugs 2000, 60 (Suppl. 1), 33-40), OSI-774 / Tarceva (Pollack et aL J Pharm. -
Exp. Ther. 1999, 291(2), 739-748), CI-1033 (Bridges, Curr. Med. Chem. 1999, 6,
nd
825-843), GW-2016 (Lackey et al., 92 MCR Meeting, New Orleans, March 24-28,
2001, abstract 4582), CP-724,714 (Jani et al., Proceedings of the American Society
for Clinical Oncology 2004, 23, abstract 3122), HKI-272 (Rabindran et al., Cancer
Res. 2004, 64, 3958-3965), and EKR-569 (Greenberger et al., 1th NCI-EORTC-
AACR Symposium on New Drugs in Cancer 'Therapy, Amsterdam, November 7-10,
• 2000, abstract 388).
In another •embodiment, the compounds of the present invention can be
combined with other signal transduction inhibitors targeting receptor kinases of the
split-kinase domain families (VEGFR, FGFR, PDGFR, flt-3, c-kit, c-frns, and the
like), and their respective ligands. These agents include, by no way of limitation,
..antibodies such as Avastin (bevacizumab). These agents also include, by no way of
limitation, small-molecule inhibitors such as STI-571 / Gleevec (Zvelebil, Curr.
Opin. Oneal., Endocr. Metab. Invest. Drugs 2000, 2(1), 74-82), PTK-787 (Wood et •
al., Cancer Res. 2000, 60(8), 2178-2189), SU-11248 (Demetri et al., Proceedings of
, 43
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WO 2005/009961 PCT/0S2004/023500
the American Society for Clinical Oncology 2004, 23, abstract 3001), ZD-6474
(Hennequin et al., 92nd AACR Meeting, New Orleans, March 24-28,. 2001, abstract
3152), AG-13736 (Herbst et al., Clin, Cancer Res. 2003, 9, 16 (suppl 1), abstract
C253), KRN-951 (Taguchi et al., 95 th AACR lvfeeting, Orlando, FL, 2004, abstract
2575), CP-547,632 (Beebe et al., Cancer Res. 2003, 63, 7301-7309), G:P-673,451
(Roberts et al., Proceedings of the American Association of Cancer Research_2004,
45, abstract 3989), CHIR-258 (Lee et al., Proceedings of the American Association of
Cancer Research 2004, 45, abstract 2130), MLN-518 (Shen et al., Blood 2003, 102,
11, abstract 476), and .Az:D-2171 (Hennequin et al., Proceedi11gs of the American
Association of Cancer Research 2004, 45, abstract 4539).
In another embodiment, the compounds of the present invention can be •
•combined with inhibitors of the Raf/MEK/ERK transduction pathway (Avruch et al.,
Recent Prag. Horm._Res. 2001, 56, 127-155), or the PKB (akt) pathway (Lawlor et
al., J. Cell Sci. 2001, 114, 2903-2910). These include, by no way of limitation, PD-
325901 (Sebolt-Leopold et al., Proceedings of the American Association of Cancer
Research 2004, 45, abstract 4003), and ARRY-142886 (Wallace et al., Proceedings
of the American Association of Cancer Research 2004, 45, abstract 3891).
In another embodiment, the compounds ·of the present invention can be
combined with inhibitors of histone deacetylase. Examples of such agents include, by
no way of limitation, suberoylanilide hydroxamic acid (SAHA), LAQ-824 (Otttnann
et al., Proceedings of the American Society for Clinical Oncology 2004, 23, abstract
3024), LBH-589 (Beck et al., Proceedings of _the American Society for Clinical
Oncology 2004, 23, abstract 3025), MS-275 (Ryan et al., Proceedings of the
I
American Association of Cancer Research 2004, 45, abstract 2452), and FR-901228
(Piekarz et al., Proceedings of the American Society for Clinical Oncology 2004, 23, •
abstract 3028).
In another embodiment, •the compounds of the present invention can be
combined with other anti-cancer agents such as proteasome inhibitors, and n;i-TOR
inhibitors. These include, by no way of li~itation, bortezomib (Mackay et al.,
Proceedings of the American Society for Clinical Oncology 2004, 23, Abstract 3109),
-and CCI-779 (Wu et al., Proceedings of the American Association of Cancer
Research 2004, 45, abstract 3849).
44
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Generally, the use of cytotoxic and/or cytostatic anti-cancer agent in

combination with a compound or composition of the present invention for the
treatment of cancer will serve to:
(1) yield better efficacy in reducing the growth of a h1mor or even eliminate
the tumor as compared to administration of either agent alone,
(2) provide for the administration of lesser. amounts of the administered
chemotherapeutic agents,
(3) provide for a chemotherapeutic treatment that is well tolerated in the
patient with fewer deleterious phannacological complications than observed with
single agent chemotherapies and certain other combined therapies,
(4) provide for treating a broader spectrum of different cancer types m
mammals_,-especially humans,
(5) provide for a higher response rate among treated patients,
(6) provide for a longer survival time among treated patients compared to
standard chemotherapy treatments,
(7) provide a longer time for tumor progression, and/or
(8) yield efficacy and tolerability results_at least as good as t~ose of the agents
_used alone,: compared to known instances where other cancer ,agent combinations
produce antagonistic effects.
Examples·
Abbreviations used in this specifi<::ationare·as follows:
HPLC high pressure liquid chromatography
MS mass spectrometry
ES electrospray
DMSO dimethylsulfoxide
MP melting point
NMR nuclear resonance spectroscopy
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TLC thin layer chromatography
rt room femperature
Preparation of 4-amino-3-fluorophenol
To a dry flask purged with Argon was added 10% Pd/C (80 mg) followed by 3-fluoro-
4-nitrophenol (1.2 g, 7.64 rnrnol) as a solution in ethyl acetate (40 mL). The mixture
•was stirred lmder an H 2 atmosphere for 4 h. The mixture was filtered through a pad of
Celite and the solvent was evaporated under reduced pressure to afford the desired
. . 1
product as a tan solid (940 mg, 7.39 rnrnol; 97 % yield); H-NMR (DMSO-d 6) 4.38 (s,
2H), 6.29-6.35 (m, lH), 6.41 (dd, J:=2.5, 12.7, lH), 6.52-6.62 (m, lH), 8.76 (s, lH).
Preparation of 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamide
·o~~>
H2 N
Y F
~~.
A solution of 4-amino-3-fluorophenol (500 mg, 3.9 rnrnol) in N,N-dimethylacetarnide

(6 mL) ~ooled to O °C was treated with potassium tert-butoxide (441 mg, 3.9 rnrnol),
. and the brown solution was allowed to stir at O °C for 25 min. To the mixture was
added 4-chloro-N-methyl-2-pyridinecarboxarnide (516.mg, 3.0 rnrnol) as a solution in
dimethylacetamide (4 mL). The reaction was heated at 100 °C for 16 h. The mixture
~
v:,,ascooled to room temperature, quenched with H2O (20 mL), and extracted with
ehtylacetate (4 x 40 mL). The combined organics were washed withH2O (2 x 30 mL),
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1
dried (MgSO4), and evaporated to afford a red-brown oil. H-NMR indicated the
presence of residual dimethylacetamide, thus the oil was taken up in diethylether (50
mL) and was further washed with brine (5 x 30 mL). The organic layer was dried
(MgSO4) and concentrated to give 950 mg of the desired product as a red-brown solid,
which was used in the next step without purification.
A method of preparing 4-chloro-N-methyl-2-pyridinecarboxamide is described m

Bankston et al., Org. Proc. Res. Dev. 2002, 6(6), 777-781.
Example 1: Preparation of 4 {4-[3-( 4-chloro-3-trifluoromethylphenyl)-ureido ]-3-

fluorophenoxy}-pyridine-2-carboxylic acid methylamide
To a solution of 4-( 4-arrtino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamide

I
(177 mg, 0.68 mmol) in toluene (3 mL) was added 4-chloro-3-(trifluoromethyl)phenyl

isocyanate (150.mg, 0.68 mmol). The mixture was stirred at rt for 72 h. The reaction
was concentrated under reduced pressure and the residue was triturated with
diethylether. The resulting solid was collected by filtration and dried in vacuo for 4 h
- . to afford the title compound (155 mg,. 0.32 mmol; 47% yield); 1H-NMR (DMSO-d6)
2.78 (d, J=4.9, 3H), 7.03-7.08 (m, lH), 7.16 (dd, J=2.6, 5.6, IH), 7.32 (dd, J=2.7, 11.6,
IH), 7.39 (d, J=2.5, lH), 7.60 (s, 2H), 8.07-8.18 (m, 2H), 8.50 (d, J=5.7, lH), 8.72 (s,
lH), 8.74-8.80 (m, lH), 9.50 (s, lH); MS (HPLC/ES) 483.06 m/z = (M + 1).
·,
Example 2: Preparation • of 4 {4-[3,-(4-chloro-3-trifluoromethylphenyl)-ureido ]-3-
fluorophenoxy}-pyridine-2-carboxylic acid methylamide hydrochloride
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The compound of example 1 as a free base (2.0 g) was dissolved in anhydrous
tetrahydrofuran (15 mL) and a 4M HCl/dioxane was added (excess). The solution
was then concentrated in vacuo to afford 2.32 grams of off-white solids. The crude
salt was dissolved in hot ethanol (125 mL), activated carbon was added and the
mixture heated at reflux for 15 minutes. The hot suspensiOn was filtered through a
pad of Celite 521 and allowed to cool to room temperature. The flask was placed in a
freezer overnight. The crystalline solids were collected by suction .filtration, washed
with ethanol, then hexane and air-dried. The mother liquors were concentrated down
and crystallization (in freezer) allowed taking place overnight. A second crop of
solids was collected and combined with the first crop. The colorless salt was dried in a
vacuum oven at 60 °C over two days. Yield of hydrochloride salt obtained 1.72 g
(79%).
Melting point: 215 °C
Elemental analysis:
Calcd. Found
C 48.57 48.68
H 3.11 2.76
N 10.79 10.60
Cl 13.65 13.63
F 14.63 14.88
Example _~3:: Preparation of 4 {4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido J-3-

fluorophenoxy }-pyridine-2-carboxylic acid methylamide mesylate
The compound of example 1 as a free base (2.25 g) was dissolved in ethanol (100
mL) and a stock solution of methanesulfonic acid (excess) was added. The solution
was then concentrated in vacuo to afford a yellow oil. Ethanol was added and
concentration repeated, affording 2.41 g of off-white solids. The crude salt was
dissolved in hot ethanol (~125 mL) and then cooled slowly to crystallize. After
reaching room temperature, the flask was placed in a freezer overnight. The colorless
crystalline material was collected by suction filtration; the filter cake was washed with
ethanol, then hexane and air-dried, to afford 2.05 g of material, which was_dried in a
vacuum oven at 60 °C overnight.
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Elemental analysis:
Calcd. Found
C 45.64 45.34
H 3.31 3.08
N 9.68 9.44
Cl 6.12 6.08
F 13.13 13.42
s 5.54 5.59
Example 4: Preparation of 4 {4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido ]-3-

·fluorophenoxy}-pyridine-2-carboxylic acid methylamide phenylsul~onate
The compound of example 1 as a free base (2.25 g) was suspended 1n ethanol (50 mL)
and benzensulfonic acid (0.737 g) in ethanol (50 mL) was added. The mixture was
heated with vigorou~ stirring. All solid material dissolved to give a reddish solution.
The solution was allowed to cool .to room temperature and the flask scratched.
Crystal formation was difficult to ach1eve, some seeds were fotmd, added to solution
and placed in freezer overnight. Grayish-tan solids had formed in the flask; the
material was broken up & collected by suction filtration. The solids were washed
' I
with ethanol, then hexane and air-dried. --Weighedproduct: 2.05 g, 69% yield.
Elemental Analysis:
·calcd. Found
·C 50.59 50.24
H 3.30 3.50
N 8.74 8.54
F 11.86 11.79
Cl 5.53 5.63
s 5.00 5.16
Example 5: c-raf (raf-1) Biochemical Assay
The c-raf biochemical assay was perfon;ned with a c-raf enzyme that was
activated (phosphorylated) by Lek kinase. Lek-activated c-raf (Lck/c-raf) was
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produced in Sf9 insect cells by co-infecting cells with baculoviruses expressing, under
the control of the po lyhedrin promoter, GST-c-raf (from amino acid 302 to amino acid
648) and Lek (full-length). Both baculoviruses were used at the multiplicity of
infection of 2.5 and the cells were harvested 48 h post infection.
MEK-1 protein was produced in Sf9 insect cells by infecting cells with the
baculovirus expressing GST-MEK-1 (full-length) fusion protein at the multiplicity of
infection of 5 and harvesting the cells 48 hours post infection. Similar purification
procedure was used for GST-c-raf 302-648 and GST-MEK-1.
Transfected cells were suspended at 100 mg of wet cell biomass per mL in a buffer
containing 10 mM sodium phosphate, 140 mM sodium chloride pH 7.3, 0.5% Triton
X-100 and· the protease inhibitor cocktail. The cells were disrupted with Polytron
homogenizer and centrifuged 30,000g for 30 minutes. The 30,000g supernatant was
applied onto GSH-Sepharose. The resin was washed with a buffer containing 50 mM
Tris, pH 8.0, 150 mM NaCl and 0.01% Triton X-100.' The GST-tagged proteins were
eluted with a solution containing 100 mM Glutathione, 50 mM Tris, pH 8.0, 150 mM
NaCl and 0.01% Triton X-100. The purified proteins were dialyzed into a buffer
containing 20 mM Tris, pH 7.5, 150 mM NaCl and 20% Glycerol.
Test compounds were serially diluted in DMSO using three-fold dilutions to
stock concentrations ranging typically from 50 µM to 20 nM (final concentrations in
the assay range from 1 µM to 0.4 nM). The c-Raf biochemical assay was performed
as a radioactive filtermat assay in 96-well Costar polypropylene plates (Costar 3365).
The plates were loaded with 75 µL solution containing 50 mM HEPES pH 7.5, 70
mM NaCl, 80 ng of Lck/c-raf and 1 µg MEK-1. Subsequently, 2 µL of the serially
diluted individual compounds were added to the reaction, prior to the addition of
ATP. The ~-eactionwas initiated with 25 µL ATP solution containing SµM ATP and
0.3. µCi [33P]-ATP. The plates were sealed and incubated at· 32 °C for 1 h. The
reaction was quenched with the addition of 50 µL of 4 % Phosphoric Acid and
harvested onto P30 filtermats (PerkinElmer) using a Wallac Tomtec Harvester.
Filtermats were washed with 1 % -PhosphoricAcid first and deinonized H2 0 second.
The filters. were dried in a microwave, soaked in scintillation fluid ·and read in a
Wallac 1205 Betapfate Counter (Wallac Inc., Atlanta, GA, U.S.A.). The results were
expressed as percent inhibition.
% Inhibition = [100-(Tib/Ti)]x 100 where
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Tib= (counts per minute with inhibitor)-(background)

Ti = (counts per minute without inhibitor)-(background)
The compound of the present invention shows potent inhibition of raf kinase in this
assay.
Example 6: p38 kinase in vitro assay

Purified and His-tagged p3 8 a2 (expressed in E. Coli) was activated in vitro
by MMK-6 to a high specific_activity. Using a microtiter format, all reactions were
conducted in 100 µL volumes with reagents diluted to yield 0.05 µg/well of activated.
p38 a2 and 10 µg/well of myelin basic protein in assay buffer (25 mM HEPES 7.4, 20
mM MgCiz, 150 mM NaCl). Test' compounds (5 µL of a 10% DMSO solution in
water) were prepared and diluted into the assay to cover a final concentration range
from 5 nM to 2.5 µM. The kinase assay was initiated by addition of 25 µL of an ATP
cocktail to give_a final concentration of 10 µM cold ATP .and 0.2 µCi [gamma-33P]
ATP per well (200-400 dpm/pmol of ATP). The plate was incubated at 32 °C for 35
min., and the reaction quenched with 7 µL of a I N aq HCl solution. The samples
were harvested onto a P30 Filtermat (Wallac, Inc.) using a TomTec 1295 Harvester
(Walfac, Inc.), and counted in a LKB 1205 Betaplate Liquid Scintillation Counter
(Wallac, Inc.). Negative controls included substrate plus ATP alone. SW1353 cellular
assay: SW1353 cells (human chondro-sarcoma) are seeded (1000 cells/100 µL
DMEM l 0% FCS/well) into 96-well plates and incubated overnight. After medium
replacement, cells are exposed to test compounds for I h at 37 °C, •at which time
human IL-I (1 ng/mL, Endogen, Woburn, WA) and recombinant human TNFalpha
(10 ng/mL) are·added. Cultures are incubated for 48 hat 37 °C, then supernatant IL-6
values are detel'!l1inedby ELISA. The compound of this invention shows significant
inhibition of p38 kinase.
Example 7: Bio~PlexPhospho-ERK ½ immunoassa)'.

A 96 well pERK immunoassay, using laser flow cytometry (Bio-Rad) platform has
been established to measure inhibition of basal pERK. in breast cancer cell line.
MDA-MB-231 cells were plated at 50,000 ce.lls per well in 96 well microtitre plates
• in complete growth media. For effects of test compounds on basal pERKI/2
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inhibition, the next day after plating, MDA-MB-231 cells were transferred to DMEM
with 0.1%_ BSA and incubated with test compounds diluted· 1:3 to a final
concentration_of 3 µM to 12 nM in 0.1% DMSO. Cells were incubated with test
compounds for 2 h, washed, and lysed in Bio-Plex whole cell lysis buffer A. Samples
are diluted with buffer B 1:1 (v/v) and directly transferred to assay plate or frozen at
-80 C degrees until processed. 50 µL of diluted MDA-MB-231 cell lysates were
incubated with about 2000 of 5 micron Bio-Plex beads conjugated with an anti-
ERK.1/2 antibody overnight on a shaker at room temperature. The next day,
biotinylated phospho-ERK.1/2 sandwich immunoassay was performed, beads are
washed 3 times during each incubation and then 50 µL of PE-strepavidin was used as
a developing reagent. The relative fluorescence units of pERK.1/2 were detected by
counting 25 beads with Bio-Plex flow cell (probe) at hig}].sensitivity. The IC50 was
calculated by taking untreated cells as maximum and no cells (beads only) as
background using in an Excel spreadsheet based program.
The compound of this invention shows significant inhibition in this assay.
Example 8: Flk-1 (murine VEGFR-2) Biochemical Assay

This assay was performed in 96-well opaque plates (Costar 3915) in the TR-FRET
format. Reaction conditions are as follows: 10 µM ATP , 25 nM poly GT-biotin , 2
nM Eu-labelled phospho-Tyr Ab, 10 nM APC, 7 nM Flk-1 (kinase domain), 1%
DMSO, 50 mM HEPES pH 7.5, 10 mM MgCb, 0.1 mM EDTA, 0.015% BRIJ, 0.1
mg/mL BSA, 0.1% mercapto-ethanol). Reaction is-initiated upon addition ofenzyme.
Final"reaction volume in each well is 100 µL. Plates are read at both 615 and 665 nM
on a Perkin Elmer Victor V Multilabel counter at about 1.5- 2.0 hours after reaction
. initiation. Signal is calculated as a ratio: (665 nm/ 615 nm) * 10000 for each well.
The compound of this invention shows significant inhibition ofVEGFR2 kinase.
Example 9·:Murine PDGFR FRET biochemical assay

This assay was formatted in a 96-well black plate (Costar 3915). The following
reagents are used: Europium-labeled anti-phosphotyrosine antibody pY20 (Perand
streptavidin-APC; poly GT-biotin from, and mouse PDGFR. The reaction conditions
are as follows: 1 nM mouse PDGFR is combined with 20 µM ATP, 7 nM poly GT-
biotin, 1 nM pY20 antibody, 5 nM streptavidin-APC, and 1% DMSO in assay buffer
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(50 mM HEPES pH 7.5, 10 mM MgClz, 0.1 mM EDTA, 0.015% BRIJ 35, 0.1 mg/mL
BSA, 0.1% mercaptoethanol). Reaction is initiated upon addition of enzyme. Final
reaction volume in each well is 100 µL. After 90 minutes, the reaction i~ stopped by
addition of 10 µL/well of 5 µM staurosporine. Plates are read at both 615 and 665 nm
on a Perkin Elmer VictorV Multilabel counter at about 1 hour after the reaction is
stopped. Signal is calculated as a ratio: (665 nm/ 615 nm) * 10000 for each well.
The compound of this invention shows significant inhibition of PDGFR kinase.
For IC50 generation for both PDGFR and Flk-1, compounds were added p1ior to the
enzyme initiation. A SO-fold stock plate was made with compounds serially diluted
1:3 in a 50% DMSO/50% d.H2O solution. A 2 µL addition of the stock to the assay
gave final compound concentrations ranging from 10 µM - 4.56 nM in 1% DMSO.
The data were expressed as percent inhibition: % inhibition = 100-((Signal with
inhibitor-background)/(Signal without inhibitor - background))* 100
Example 10: MDA-MB231 proliferation assay

Human breast carcinoma cells (MDA MB-231, NCI) were cultured in standard
growth medium (DMEM) supplemented with 10% heat-inactivated FBS at 37°C in
5% CO2 (vol/ vol) in a humidified incubator. Cells were plated at a density of 3000
cells per well in 90 µL. growth medium· in a 96 well culture dish. In order to
determine TOh CTG values, 24 hours after plating, 100 µL of CellTiter-Glo
Luminescent Reagent (Promega) was added to each well and incubated at room
temperature for 30 minutes. Luminescence was recorded on a Wallac_Vfotor II
instrument. The CellTiter-Glo reagent results in cell lysis and generation of a
luminescent signal proportional to the amount of ATP present, which, in turn is
directly proportional to the number of cells present.
Test compounds are dissolved in 100% DMSO to prepare 10 mM stocks.
Stocks were further diluted 1:400 in growth medium to yield working stocks of 25 µM
test compound in 0.25% DMSO. Test compounds were serially diluted in growth
medium containing 0.25% DMSO to maintain constant DMSO concentrations for all
wells. 60 µL of diluted test compound were added to each culture well to give a final
volume of 180 µL. The cells with and without individual test compounds were
incubated for 72 hours at which time ATP dependent luminescence was measured, as
described previously, to yield Tm values. Optionally, the IC50 values can be
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determined with a least squares analysis program using compound concentration

versus percent inhibition.
% Inhibition= [l-(Tnhtes1-Toh)/(Tn11ctr1-Toh)]
x 100, where
Tnh test= ATP dependent luminescence at 72 hours in the presence oftest compound
Tm ctr!= ATP dependent luminescence at 72 hours in the absence oftest compound
Toh= ATP dependent luminescence at Time Zero
' The compound of this invention shows significant inhibition of proliferation using
this assay.
Example 11: pPDGFR-beta sandwich ELISA in AoSMC cells

100K P3-P6 Aortic SMC were plated in each weH of _12-wellcluster in 1000
µL volume/ well of SGM-2 using standard cell culture techniques. Next day, cells
were rinsed with l 000 µL D-PBS once, then sernm starved in 500 µL SBM (smooth
muscle cell basal media) with 0.1% BSA overnight. Compounds were diluted at a
dose range from (10 µM to 1 nM in IO-fold dilution steps in DMSO. Final DMSO
concentration 0.1 %). Remove old media by inversion into the sink quickly then add
100 µL of each dilution to corresponding well of ceils_for 1 h at 37-0c. Cells were
then stimulated with 10 ng/mL PDGF-BB ligand for 7 min at 37 °c. The media is
decanted and 150 µL of isotonic lysis buffer with protea-seinhibitor tablet (Complete;
EDTA-free) and 0.2 mM Na vanadate is added. Cells are lysed for 15 min at 4 °con
shaker in cold room. Lysates are put in eppendorf tubes to which 15 µL of agarose-
conjugated anti-PDGFR-beta antibody is added and incubated at 4 °c overnight. Next
-day, beads are rinsed in 50-volumes_ofPBS three times and boiled in lx LDS sample
buffer for 5 minutes. Samples were run on 3-8% gradient Tris-Acetate gels and
transferred onto Nitrocellulose. Membranes were blocked in 1% BSA/TBS-T for 1
hr. before incubation in anti-phospho-PDGFR-b (Tyr-857) antibody in blocking
buffer ( 1:1000 dilution) for 1 h. After three washes in TBS-T, membranes were
incubated in Goat anti-rabbit HRP IgG (1:25000 dilution) for 1 hr. Three more washes
followed before addition of ECL substrate. Membranes were exposed to Hyperfilm-
ECL. Subsequently, membranes were stripped and reprobed with anti-PDGFR-beta
antibody for total PDGFR-beta.
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Table 1 illustrates the results of in vitro kinase biochemical assays for p38 kinase,
PDGFR kinase and VEGFR2 kinase. These three kinase targets are all involved in
stroma activation and endothelial cell proliferation, leading to angiogenesis, and
providing blood supply to the tumor tissue.
Table 1
mPDGFR mVEGFR2 p38

IC50,nM IC50, nM -IC50,nM
Example 1 83 5.5 24
Table 2 illustqites the results of two cellular a$says for raf kinase activity, which are
(i) inhibition of pERK in MDA-MB231 cells, a mechanistic readout of raf kinase
activity, and (ii) a proliferation assay of MDA-MB231 cells, a functional assay ofraf
kinase . activity. In addition, Table 2 illustrates· the results of PDGFR driven
phosphorylation of PDGFR-beta in aortic smooth muscle cells, which is a mechanistic
readout of PDGFR kinase inhibition.
Table 2
pERK in cells· Proliferation . ·pPDGFR

(MDA-MB- (MDA-MB-231) (AoSMC)
231) IC50, nM IC50, nM
IC50, nM
Example 1 22 600 43.6
Overall, compounds of the present invention provide a unique combination of

inhibition of angiogenesis and tumor cell proliferation. They also possess an improved
inhibition profile against several key kinase targets such as raf, p38, PDGFR, and
VEGFR-2, which are all molecular targets of interest for the treatment of
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osteoporosis, inflanunatory diseases, and hyper-proliferative diseases, including

cancer.
It is believed that one skilled in the art, using the preceding information and
information available in the art, can utilize the present invention to its fullest extent. It
should be apparent to one of ordinary skill in the art that changes and modifications
can be made to this invention without departing from the spirit or scope of the
invention as it is set forth herein. All publications, applications and patents cited
above and below are incorporated herein by reference.
The topic headirtgs set forth above and below are meant as guidance where
certain information can be found in the application, but are not intended to be the only
source in the application where information on such topic can be found.
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Claims
1. A compound of Formula (I) or a salt, or a prodrng or a metabolite or an

_isolatedstereoisomer thereof
2. A pharmaceutically acceptable salt of a compound of Formula I of claim 1

-whichis

acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid,
trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid (tosylate
trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid,
acid, or mandelic •acid; or

ammonium cation or an aromatic substituted ammonium cation.
3. A compound which is 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-

fluorophenoxy}-pyridine-2-c~rboxylic acid methylamide, or a salt thereof
4. - A phannaceutically acceptable salt of a compound of claim 3 which is a basic

salt of an organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid,
phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid,
benzenesulfonic acid, p-toluene sulfonic acid (tosylate salt), 1-napthalene sulfonic
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acid, 2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric
acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid,
benzoic acid, salicylic acid, phenylacetic acid, or mandelic acid.
5. A compotmd which is which is a hydrochloride, benzenesulfonate, or

methanesulfonate salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N' -2-fluoro-(4-(2-
(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea.
6. A pharmaceutical composition c.omprising a compound of claim 1 and a


8. A pharmaceutical composition for the treatment of a disease in a human or

other mammal regulated by a protein kinase, associated with an aberration in the
protein kinase signal transduction pathway comprising a compound of claim 1 and a
•9. A _pharmaceutical compositiolil for the treatment of a hyper-proliferative

disorder comprising a compound of claim 1 and a physiologically acceptable carrier.
10. A pharmaceutical composition for the treatment of a cancerous cell growth

comprising a compound of claim 1 and a physiologically acceptable carrier:·
11. A pharmaceutical composition which comprises a pharmaceutically acceptable •

salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N' -2-fluoro-(4-(2-(N-
methylcarbamoyl)-4-pyridyloxy)phenyl) urea and a physiologically .acceptable
carrier.
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12. A method for regulating tyrosine kinase signal transduction comprising

administering to a human or other mammal a compound of claiml.

which is regulated by tyrosine kinase and associated with an aberration in the tyrosine
kinase signal transduction pathway, said method comprising administering to a human
14. A method for treating or preventing a· disease in a human and/or other

mammal which is a VEGFR-2 mediated disorder, said method comprising
administering to a human or other mammal a compound .of claim 1.

mammal which i; a PDGFR mediatetl disorder, said method comprising administering
to a human or other mammal a compound of claim 1.

which is a raf-mediated disorder, said method comprising administering to a human _or

which is a p3 8-mediated disorder, said method comprising administering to a human

I
which is a VEGF-mediated disorder, said method comprising administering to a

hum.an or other mammal a compound of claim 1.

which is a hyper-proliferative, inflammatory and/or angiogenesis disorder which
comprises administering to a human or other mammal a comp0tmd of claim 1.
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which is a hyper-proliferative disorder which comprises administering.to a human or
21. A method as in claim 20, wherein the hyper-proliferative disorder is cancer.
22. A method as in claim 21, wherein said method comprises administering to a

human or other mammal a compound of claim 1 in combination with one or several
additional anti-cancer agents.
23. A method for treating or preventing a disease in ·a human or other mammal

characterized by abnormal angiogenesis or hyperpermiability processes comprising
administering to a human or other mammal a compound of claim 1.
24. A method as in claim 23, for treating ,or preventing a disease in a human or
other mammal characterized by abnormal angiogenesis or hyperpermeability
processes, comprising administering to a human or other mammal, a compound of
claim 1 simultaneously with another anti-angiogenesis agent, either m the same
.formulation or in separate formulations.
25. A method for tr.eatingor preventing one or more of the following conditions in
tumor growth, retinopathy, ischemic retinal-vein occlusion, retinopathy of
prematurity, age related macular degeneration; rheumatoid arthritis, psoriasis, a
bullous disorder associated with subepidermal blister formation, including bullous
pemphigoid, erythema multiforme, or dermatitis herpetiformis, rheumatoid arthritis,
osteoarthritis, septic arthritis, tumor metastasis, periodontal disease, carnal ulceration,
proteinuria and coronary thrombosis from atherosclerotic plaque, aneurismal aortic,
mandibular joint disease or demyelating disease of the nervous system,
compound of.claim 1.
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humans and/or other mammals: tumor growth, retinopathy, ischemic retinal-vein
occlusion, retinopathy of prematurity, age relat~d macular degeneration; rheumatoid
arthritis, psoriasis, a bullous disorder associated with subepidermal blister formation,
including bullous pemphigoid, erythema multiforme, or dermatitis herpetifonnis;
in combination with another condition selected from the group consisting of:
rheumatic fever, bone resorption, postmenopausal osteoporosis, sepsis, gram

inflammatory response syndrome, inflammatory bowel disease (Krohn' s disease and
ulcerative colitis), Jarisch-Herxheimer reaction, asthma, adult respiratory distress
failure, liver disease during acute inflammation, severe alcoholic hepatitis, malaria
(Plasmodium falciparnm malaria and cerebral malaria), non-insulin-dependent
diabetes mellitus (NIDDM), congestive heart failure, damage following heart disease,
sclerosis (demyelation and oligiodendrocyte loss in multiple sclerosis), advanced
biliary cirrhosis, bowel necrosis, radiation injury/ toxicity following administration of
monoclonal antibodies, host-versus-graft reaction (ischemia reperfusion injury and
allograft • rejections of kidney, liver, heart, and skin), lung allograft rejection
(obliterative bronchitis) and complications due to total hip replacement,·
said method comprising ad~inistering to a human or other mammal a

humans and/or other mammals: tumor growth, retinopathy, diabetic retinopathy,
ischemic retinal-vein occlusion, retinopathy_ of prematurity, age related macular
degeneration; rheumatoid arthritis, psoriasis, bullous disorder associated with
subepidermal blister formation, bullous pemphigoid, erythema multiforme, and
de~atitis herpetiformis,
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in combination with an infectious disease selected from the group consisting
of:

disease resulting from Trypanosoma cruzi infection, effects of Shiga-like toxin
burgdorferi, Treponema pallidum, cytomegalovirns, influenza virus, Theiler's
enc_ephalomyelitisvirus, and the human immunodeficiency virus (HN); .


from the group consisting of asparaginase, bleomycin, carboplatin, carmustine,
chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine,
dactinomycin, daunorubicin, doxornbicin (adriamycine), epirubicin, etoposide, 5-
fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin,
lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C,
mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen,_ streptozocin,
tamoxifen, thioguanine, .topotecan, • vinblastine, vincristine, vindesine,
aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan,
'
diethylstilbestrol, 2',2'-difluorodeoxycytidine, docetaxe1, erythrohydroxynonyl
adenine, ethinyl estradfol, 5-fluorodeoxyuridine, . 5-fluorodeoxyuridine
monophosphate, fludarabine phosphate, fluoxymesterone, flutamide,
hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate,
megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N-phosphonoacetyl-L-
aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate,
thiotepa, trimethylmelamine, uridine, and vinorelbine, oxaliplatin, gemcitabine,
capecitabine, epothilone and its nah1ral or synthetic derivatives, tositumomab,
trabedectin, and temozolom1de. trastuzumab, cetuximab, bevaciz~imab, pertuzumab,
ZD-1839 (Iressa), OSI-774 (Tarceva), CI-1033, GW-2016, CP-724,714, HKI-272,
EKB-569, STI-571 (Gleevec), PTK-787, SU-11248, ZD-6474, AG-13736, KRN-951,
CP-547,632,. CP-673,451, CHIR-258, MLN-518, AZD-2171, PD-325901, ARRY-
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142886, suberoylanilide hydroxamic acid (SAHA), LAQ-824, LBH-589, MS-275,
FR-901228, bortezomib, and CCI-779.
29. A method as in claim 22 wherein the additional anti-cancer agent is a

cytotoxic agent selected from the group consisting of DNA topoisomerase I and II
inhibitors, DNA intercalators, alkylating agents, anti-metabolites, cell-cycle blockers,
microtubule disruptors, and Eg5 inhibitors.
30. A method as in claim 22 where_inthe additional anti-cancer agent is selected

from the group consisting of inhibitors of growth factor receptor signaling, histone
deacetylase inhibitors, inhibitors of the PKB pathway, inhibitors of the
Ra£'MEK/ERK pathway, inhibitors of the mTOR pathway, and proteasome inhibitors.
31. A method for treating or preventing one or more of the fol_Iowingconditions in

rheumatic fever, bone resorption, postmenopausal osteoporosis, sepsis, gram
inflammatory response syndrome, inflammatory bowel disease (Krohn' s disease and
ulcerative colitis), Jarisch-Herx~eimer reaction, asthma, adult respiratory distress
respiratory_disease, silicosis, coal worker's pneumoconiosis, alveolar injury, hepatic
failure, liver disease during acute inflammation, severe alcoholic hepatitis, malaria •
(Plasmodium falciparum malaria and cerebral malaria), non-insulin-:dependent
sclerosis (demyelation and oligiodendrbcyte loss in multiple sclerosis), advanced
biliary cirrhosis, bowel necrosis, psoriasis, radiation injury/ toxicity following
administration of monoclonal antibodies, host-versus-graft reaction (ischemia
reperfusion injury and allograft rejections . of kidney, liver, heart, and ·skin), lung
.
allograft rejection (obliterative bronchitis) or complications due to total hip

replacement,
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disease resulting from Trypanosoma cruzi infection, effects of Shig;1a-liketoxin
Staphylococcus .infection, meningococcal infection, and infections from Borrelia
burgdorferi, Treponema pallidum, cytomegalovirus, influenza virus, Theiler's
encephalomyelitis virus, and the human immunodeficiency virus (HN) ,
33. A method for treating or preventing osteoporosis, inflammation, and angiogenesis

disorders, with the exclusion of cancer, in a human and/or other mammal by
administering an effective c1;mount
of a compound of claim 1 to said mammal.
34. A method for treating or preventing cancer in a human or other mammal which
comprises administering to a human or other mammal a single active principle
combining inhibit.ion of tumor cell proliferation mediated by the raf / MEK I ERK
pathway, and inhibition of angiogenesis mediated by PDGF and VEGF.
35. A method of claim 34 where said inhibition of _tumorceff proliferation is caused

by inhibition of raf kinase, and said inhibition oJ angiogenesis is caused by dual
inhibition of PDGFR-beta and VEGFR-2 lcinases.
36. A method for.treating or preventing cancer in a human or other mammal which

comprises administering to· a human. or other mammal a single active principle
combining inhibition of tumor cell proliferation mediated by the raf pathway, and
inhibition of angiogenesis mediated by PDGF or VEGF.
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37. A method of treating and/or preventing a disease and/or condition in a subject in

need thereof, comprising administering an effective amount of a compound of claim 1
or 2.
38. A method of claim 37, wherein said method coi:n-prisescausing tumor regression
in a subject or cells therefrom.

lymphangiogenesis.
40. A method of claim 37, wherein said method comprises inhibiting angiogenesis.
4L A method of claim 37, wherein said method comprises inhibiting

lymphangiogenesis and angiogenesis.
42. A method of claim 37, wherein said method comprises stimulating the
proliferation of hematopoietic progenitor cells.
43. A method of claim 37, wherein said method comprises treating a disorder in a
mammalian subject mediated by raf, VEGFR-2, VEGFR-3, PDGFR-beta, p38 and/or
flt-3.
44. A method of claim 37, wherein said method comprises determining whether a
•' . .
condition can be modulated by said compound, comprisi~g measuring the expression
or activity of raf, VEGFR-2, VEGFR-3, PDGFR-beta, p38 and/or flt-3, in a sample
comprising cells or a cell extract, wherein said ample is obtained from a subject or
cell having said condition, whereby said condition can be modulated by said
compound when said expression or activity is different in said condition as compared
to a norm\11control.
45. A method of claim 44, further comprising comparing the expression in said
sa,mpleto said normal control.
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46. A method of claim 37, wherein said method comprises assessing the efficacy of
said compound disorder, comprising administering said compound, measuring the
expression or activitJ'. of raf, VEGFR-2, VEGFR-3, PDGFR-beta, p38, and/or flt-3,
and determining the effect of said compound on said expression or activity.
47. A method of claim 37, wherein said method comprises determining the
presence of raf, VEGFR-2, VEGFR-3, PDGFR-beta, p38 and/or flt-3 in a sample of a
biological material, contacting said sample with said compound, and determining
whether said compound binds to said material.
48. A method of claim 37, wherein said method comprises treating a tumor in a
subject in need thereof, comprising administering an effective amount of said
compound wherein said amount is effective to inhibit tumor cell :proliferation and
neovascularization.
49. A compound which is a naturally occurring metabolite of the compound of

claim 3.
50. A compound of claim 49 where the metabolism site is either one of the two
urea nitrogen atoms, or the pyridine nitrogen atom, or the methylamide functionality,
or any combination of the above .
. 51. A compound of claim 49 where either urea nitrogen atom carries a hydroxyl
group, and/or the pyridine nitrogen atom is oxidized, and/or the amide functionality is
de-methylated.
52. A compound of claim 49 which is selected from:

4 {4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido ]-3-fluorophenoxy}-pyridine-2-
carboxylic acid amide,
4 {4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido ]-3-fluorophenoxy }-1-hydroxy-
pyridine-2-carboxylic acid methylamide, or
4 {4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido ]-3-fluorophenoxy }-1-hydroxy-
pyridine-2-carboxylic acid amide.
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53. A method as in claim 19, where the inflammatory disorder is selected from
rheumatoid arthritis, COPD, Crohn's disease and proriasis.

which is a flt-3 mediated disorder, said method comprising administering to a human
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11111
1111111111
111111111111111
1111111111111111
IIII IIIIIIII
US008637553B2
c12) United States Patent (IO) Patent No.: US 8,637,553 B2

Boyer et al. (45) Date of Patent: Jan.28,2014
(54) FLUORO SUBSTITUTED 3,689,550 A 9/1972 Schellenbaum et al.

OMEGA-CARBOXYARYL DIPHENYL UREA 3,743,498 A 7/ 1973 Brantley
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(75) Inventors: Stephen Boyer, Hilden (DE); Jacques 3,990,879 A 11/1976 Soper
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(Continued)
Related U.S. Application Data
OTHER PUBLICATIONS
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USPC ........................................... 514/350; 546/298 Abstract ofEP 0 202 538 Al, "Growth Promoting Agents," Nov. 26,
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USPC ........................................... 546/298; 514/350 (Continued)
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(56) References Cited Primary Examiner - Kamal Saeed

Assistant Examiner - Janet L Coppins
U.S. PATENT DOCUMENTS (74) Attorney, Agent, or Firm -Millen, White, Zelano &
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1214-1220 (May 2001). Deposition Transcript ofT. Lowinger (Ex Bayer employee), Dec. 13,
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Treated Metastatic Breast Cancer" www.cancer.gov website (1998). Aug. 26, 2010.
National Cancer Institute, Clinical Trials (PDQ), "Phase II Random- Deposition transcript ofB. Riedl (Applicant/Bayer employee), Nov.
2010.
ized Study of ISIS 5132 or ISIS 3521 for Locally Advanced or
Deposition transcript of J. Dumas (Applicant/Ex-Bayer employee),
Metastatic Colorectal Cancer" www.cancer.gov website (1998).
Sep. 20, 2010.
National Cancer Institute, Clinical Trials (PDQ), "Phase II Random- Deposition transcript ofL. Adnane (Bayer employee), Jun. 24, 2010.
ized Study of ISIS 5132 or ISIS 3521 in Patients with Hormone Med Chem. Plans Slide (1998).
Refractory Prostate Cancer" www.cancer.gov website ( 1998). Med. Chem. Plans Slides, BAY00015872 at 879, BAY-A00299697 at
National Cancer Institute, Clinical Trials (PDQ), "Phase II Random- 703, BAY-A00484291 at 298, BAY-A00484328 at 335, BAY-
ized Study of ISIS 5132 in Patients with Advanced Pancreatic Can- A004844359 at 366, BAY-A0551200 at 207, BAY-A00484291 at
cer" www.cancer.gov website (Aug. 1999). 298, ONYX00316991 at 992 (Sep. 1998).
Salvatore et al, "BRAF Is a Therapeutic Target in Aggressive Thyroid Redacted Expert report of Bhagwat, Shripad (Onyx), Jan. 10, 2011.
Carcinoma" Clin Cancer Res 1623;12(5) (Mar. 1, 2006). Supplemental Information for Expert report of Bhagwat, (Onyx),
Keller et al, "The Role of Raf Kinase inhibitor protein (RKIP) in Mar. 7, 2011.
health and disease" Biochemical Pharmacology 68; 1049-1053 Redacted Ecpert report of Lipinski, Christopher (Bayer), Feb. 7,
(2004). 2011.
Robinson et al, "Enhanced Radiosensitization with Gemcitabine in Supplemental Information for Expert report of Lipinski (Bayer), Apr.
Mismatch Repair-Deficient HCT116 Cells" Cancer Research 63, 1, 2011.
6935-6941 (Oct. 15, 2003). Bayer Deposition Exhibit 318, Memo from Riedl to Lyons w/slides
Devlin et al, "Gatt and Discovery: Signigicant changes in US Patent attached (Sep. 17, 1998), John Lyons, pp. 121-126, 140-146, and
Law" vol. 3, No. 4 (Dec. 1995). 199-203.
Onyx Deposition Exhibit 163, Memo from Riedl to Lyons
Hanna et al, "Second-Line treatment of non-small cell lung cancer:
w/slides+notes attached (Sep. 17, 1998), C. Lipinski pp. 156-177;
Big targets, Small progress; Small Targets, Big progress?" Journal of
Bernd Riedl, pp. 151-179 and 187.
Thoracic Oncology vol. 1, No. 9, (Nov. 2006). Bayer Deposition Exhibit 59, ROC presentation (Sep. 18, 1998),
Valentino et al, "Prodrugs as therapeutics" Expert Opinion of Thera- Scott Wilhelm pp. 59-68, Bernd Riedl, pp. 173-174, Jacques Dumas,
peutic Patents 14(3): 277-280 (2004). pp. 136-159, 168-173, 244-247 and 350-252.
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Gollob, J. A. et al., "Sorafenib: scientific rationales for single-agent Bayer Deposition Exhibits 14, 319 and 341, Agenda JRDC Meeting
and combination therapy in clear-cell renal cell carcinoma," Clin w/slides attached (Sep. 28, 1998), Bernd Riedl, pp. 175-178; John
Genitourin Cancer, Dec. 2005, vol. 4, No. 3, pp. 167-174. Lyons, pp. 156-173; Shripad Bhagwat, pp. 146-153; and 193-201.
Hahn, 0. et al., "Sorafenib," Current Opinion Oncol, 2006, vol. 18, Bayer Deposition Exhibit 32, Raf Kinase Project (1998); Bernd
pp. 615-621. Riedl, pp. 186-193.
Lemoine et al., "Overview ofras oncogenes and their clinical poten- Bayer Deposition Exhibit 34, Research Report No. MRC-00984
tial," Chapter 10, In: Mutant Oncogenes: Targets for Therapy ( eds. (Oct. 11, 1999); Jacques Dumas, pp. 160-164, Shripad Bhagwat, p.
Lemoine NR & Epenetos A), Chapman & Hall, London. pp. 85-91; 259.
1992. Redacted Bayer Deposition Exhibit 35, Jennifer Burke Notebook
Naumann, U. et al., "Raf protein serine/threonine kinases" Chapter 7, records (2002); Jacques Dumas, pp. 225-228.
1996, pp. 203-236. Redacted Bayer Deposition Exhibit 39, Strategic Project Plan 2nd
Reddy et al., "Sorafenib: recent update on activity as a single agent Generation Raf Kinase Inhibitor report (Nov. 14, 2002); S. Wilhelm
and in combination with interferon-alpha2 in patients with advanced- pp. 164-224, B. Riedl, pp. 237-245.
stage renal cell carcinoma." Clin Genitourin Cancer, Mar. 2006, vol. Redacted Bayer Deposition Exhibit 63, Strategic Project Plan 2nd
4, No. 4, pp. 246-248. Generation Raf Kinase Inhibitor report (Nov. 25, 2002); S. Wilhelm,
Song, H. D. et al., "Cross-host evolution of severe acute respiratory pp. 224-227, J. Dumas, pp. 239-253, Bernd Riedl, pp. 247-249, Lila
syndrome coronavirus in palm civet and human." Proceedings of the Adnane, pp. 84-91.
National Academy of Science, Feb. 15, 2005, vol. 102, No. 7., pp. Redacted Bayer Deposition Exhibit 67, BRC-2002 Goals vs.
2430-2435. Achievements Status slides (Feb. 2003); Scott Wilhelm pp. 244-266.
Storm et al., "raf Oncogenes in Carcinogenesis" Critical Reviews in Bayer Deposition Exhibit 66. Second Generation Raf Kinase Inhibi-
Oncogenesis, vol. 2, Issue 1, pp. 1-8, 1990. tor Meeting slides (Jul. 22, 2003); Scott Wilhelm pp. 227-244.
Tang et al., "Inhaled nitric oxide attenuates pulmonary hypertension Redacted Bayer Deposition Exhibit 49, DPI Document, BAY
and improves lung growth in infant rats after neonatal treatment with 73-4506 slides, (Sep. 30, 2003); Scott Wilhelm pp. 227-266, B. Riedl,
a VEGF receptor inhibitor," Am J Physiol Lung Cell Mo! Physiol pp. 245-247, J. Dumas, pp. 196-214.
287: L344-L351, 2004. Redacted Bayer Deposition Exhibit 71, BAY 73-4506 GPT slides,
Wermuth, C.G. et al., "Designing Prodrugs and Bioprecursors II: (Jul. 12, 2007); Scott Wilhelm pp. 292-294.
Bioprecursor Prodrugs," The Practice of Medicinal Chemistry, 1996, Wilhelm Dep. at 234-237, 254-262 (Aug. 26, 2010).
Academic Press Ltd., pp. 697-715. Development Options meeting Slide, BAY-AO1164130 at 134, (Mar.
Yu et al., The role of Mcl-1 downregulation in the proapoptotic 28, 2008).
activity of the multikinase inhibitor BAY 43-9006, Oncogene, 2005, Redacted DAST Strategic Imperative Slides, BAY-A00131813,
vol. 24, pp. 6861-6869. (Dec. 7, 2007).
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2003).
OTHER PUBLICATIONS Unpublished paper, Riedl et al., Discovery of Nexavar, BAY-
A00498289, date created unknown, cited (Jan. 10, 2011).
Redacted Business and Positioning Strategy 2009 slides, Patani, George A., et al., "Bioisosterism: A Rational Approach in
BAY00289234, (Apr. 29, 2010). Drug Design," 96 Chem. Rev. 3147 (1996).
Redacted DPI Presentation Slides, BAY-A00565 l 79, (Nov. 18, 2003. Burger, Alfred, Burger's Medicinal Chemistry and Drug Discovery,
Onyx Exhibit-98, US Patent 7,351,834, Apr. 1, 2008, at pp. 8-11 of vol. 1, Principles and Practice (Manfred E. Wolff., 5th ed. 1995).
opinion. Patrick, Graham L., An Introduction to Medicinal Chemistry (Oxford
Onyx Exhibit-99, U.S. Appl. No. 60/115,877, field Jan. 13, 1999; at University Press, 1995).
p. 11 of opinion. Hanahan, Douglas & Weinberg, Robert A., The Hallmark of Cancer,
Bayer Deposition Exhibit 334, Chemical Structures Slide, atp. 110 of 40 Cell 57 (2000).
deposition, (Jun. 1998). Smith, Roger A., et al., "Recent Advances in the Research and Devel-
Bayer Deposition Exhibit 336, HIR Assay, (Jun. 19, 1998) at pp. opment of RAF Kinase Inhibitors," 6 Current Topics in Medicinal
112-114 of deposition. Chemistry 1071 (2006).
Med. Chem. Plans Slides, BAY000 15872 at 879, BAY-A00299697 at Smart, Bruce E., "Organofluorine Chemistry: Principles and Com-
703, BAY-A00484291 at 298, BAY-A00484328 at 335, BAY- mercial Application," 66-67 (Plenum Press 1994).
A004844359 at 366, BAY-A00551200 at 207, BAY-A00484291 at Chambers, Richard D., Fluorine in Organic Chemistry (CRC Press
298, ONYX0031699 l at 922 (Sep. 1998). 2004).
Med. Chem. Plans Slide, ONYX00020538 at 538, 539, (Sep. 1998). Bayer's Brief in support of Summary Judgment Motion (SJM) (Mar.
Kinase Profile Slide BAY-A00230103 at 107, BAY 00177850 at 853, 21, 2011).
BAY00037799 at 818, BAY-A0013813 at 28, (May 19, 2003, Dec. Joint Statement of Facts (Apr. 13, 2011).
17, 2007). Onyx's Response to Bayer's SJM (Apr. 12, 2011).
Summary of Sorafenib Evaluation InVitro/In Vivo, BAY-A00297658 Onyx's Objections to Bayer's Evidence in Support of SJM (Apr. 19,
at 669, after (2004). 2011).
Table of Raf Kinase Assay Results, BAY-A00564638 at 731, after Onyx's Second Response to SJM (Apr. 13, 2011).
(Jun. 2003). McCormick Declaration in Support of Onyx's Opposition to SJM
Tables of prepared Compounds, including BAY 734506, and assay (Apr. 15, 2011).
results, BAY-A00564638, 649, 670, 671, 836, after (Jun. 2003). Swanson Supplemental Declaration in Support of SJM (Mar. 15,
Chemical Synthesis BAY 734506 Slide, BAY00044106 at 132, (Jul. 2011).
22,2003) Swanson Supplemental Declaration in Support of SJM (Mar. 30,
RAF Kinase Project Slides, BAY0015744-770, 771, 777, (Oct. 2011).
1998). Schenker Declaration in Support of Onyx's Opposition to SJM (Mar.
Slide SummaryofRKI-2 Status, BAY-A00230119 at 121, (Feb.-Mar. 30, 2011).
2003). Bhagwat Declaration in Support of Onyx's Opposition to SJM (Mar.
Jennifer Burke Notebook Records, BAY00000036 at 036-038, (Dec. 31, 2011).
12, 2002). Memo and Order re Summary Judgment (May 5, 2011).
Jennifer Burke Notebook Records, BAY 00017043 at 077-078, 080, Exhibit 13 of Swanson declaration in support of Summary Judgment,
(Dec. 12, 2002). Deposition testimony ofW. Scott, pp. 1, 18, 19, 24, 67, 68, 110 NS
Med. Chem. Results Slides, BAY0015872 at 876, BAY-A00484291 111, (May 6, 2010).
at 293; BAY-A00551200 at 202, BAY00205344 at 350, Exhibit 16 of Swanson declaration in support of Summary Judgment,
ONYX00155950 at 963, ONYX00534085 at 091, (Sep. 18, 1998). Deposition testimonyofB. Riedl, pp. 1, 18-22 and 227, (Nov. 2010).
Screening Cascade Slides, BAY00015915 at 926, BAY-A00568497 Exhibit 20 of Swanson declaration in support of Summary Judgment,
at 497, BAY-A00572163, BAY-A00908144 at 150, BAY-01006731 at Notebook page (Reina Natero ), BAY00039916, (1998).
731, BAY-A00641601 at 628, ONYX00010785 at 807, Exhibit 22 of Swanson declaration in support of Summary Judgment,
ONYX00010847 at 850 and ONYX00207530 at 530, (Jun. 10, Report RAF Kinase Inhibition, BAY 43-9006 (Jan. 25, 1999).
1998). Exhibit 23 of Swanson declaration in support of Summary Judgment,
WHO correspondence re Non-proprietary name, BAY-A00608975, Deposition testimony of S. Wilhelm, pp. 1, 76 and 77, (Aug. 26,
(2007). 2010).
WHO Letter re Non-proprietary name, BAY00381873, (2008). Exhibit 25 of Swanson declaration in support of Summary Judge-
WHO Status Letter re Non-proprietary name, BAY00504872, ment, Notebook pp. (2) (Jennifer Burke), BAY000l 7080, (2002).
(2008). Exhibit 26 of Swanson declaration in support of Summary Judgment,
WHO Emails re Non-proprietary name, BAY-A00206034, (2008). Notebook page (Gloria Hofilena), BAYOO18315, (2002).
Research Report re Variation of Proximal Phenyl Group. Exhibit 27 of Swanson declaration in support of Summary Judgment,
BAY00012572 at 582,610, (Oct. 11, 1999). Deposition testimony of L. Adnane, pp. 1, 9-11, 73-76, (Jun. 24,
Summary page of SAR of RAF Kinase Inhibitor Lead, BAY- 2010).
A00908144 at 151, (Jan. 25, 1999). Exhibit 52 of Swanson declaration in support of Summary Judgment,
Slide ofSARofBiphenyl Ureas, BAY00015744 at 765, (Oct. 1998). Deposition testimony of J. Dumas, pp. 1, 199-200, (Sep. 20, 2010).
pp. 4-5 ofLowinger Publication, BAY-A00722597 at 510 and 511, Exhibit 106 of Schenker declaration in support of opposition, Depo-
published (2002). sition testimony of J. Dumas, pp. 1, 3, 199, 200, 221, 237 and 238,
2 nd Generation RKI Strategic Project Plan, pp. 21-22, BAY- (Sep. 20, 2010).
A00565114 at 135-136, (Nov. 14, 2002). Exhibit 111 of Schenker declaration in support of opposition, Depo-
RKI2 Actions Points e-mail, BAY-A00230173 (Aug. 1, 2003). sition testimony ofC. Lipinski pp. 1, 5, 214-216 (Feb. 18, 2011).
Table of Prepared Compounds and Assay Results, BAY-A00564638, Exhibit 112 of Schenker declaration in support of opposition, Depo-
after (Jun. 2003). sition testimonyofT. Lowinger, pp. 1, 3, 4, 26, 27, 32, 53, 71-73 and
Redacted Raf Kinase Project, Effects of Substitution on First Ring, 79, (Dec. 13, 2010).
BAY00015798 at 810, date created unknown, cited(Jan. 10, 2011). Exhibit 113 of Schenker declaration in support of opposition, Depo-
Raf Kinase Project Slides, BAY0015744, (Nov. 1998). sition testimony of J. Lyons, pp. 1, 5, 142-144, 150, 151,200,201 and
Redacted-2 nd Generation RAF Kinase Slides, BAY00221648, 205 (Mar. 4, 2011 ).
(Sep.-Oct. 2002). Exhibit 117 of Schenker declaration in support of opposition, Depo-
BAY 73-4506 DAST Inhibitor-Present Slides, BAY00l 79838, sition testimonyofB. Riedl, pp. 1, 5, 13, 14, 18, 21-24, 26, 27, 31, 32,
(May 7, 2008). 57-63, 91, 95,103, 118-120 and 204, (Nov. 2010).
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(56) References Cited Exhibit FF of Bhagwat declaration in support of opposition, Agenda

JRDC Meeting, (Jun. 10, 1998).
OTHER PUBLICATIONS (Cumulative to SJl 1-X) Exhibit G ofBhagwat declaration in support
of opposition, Article by Lowinger, et al., Design and Discovery of
Corrected Exhibit 121 of Schenker declaration in support of opposi- Small Molecules Targeting RAF-1, Current Pharmaceutical Design,
tion, Deposition testimony ofW. Scott, pp. 1, 5, 10, 11, 43, 44, 46, 47 2002, 8, 99-110.
and 112-114, (May 6, 2010). Exhibit H of Bhagwat declaration in support of opposition, Slides,
Exhibit 122 of Schenker declaration in support of opposition, Depo- "Lead Structure Check List," BAY0035386 date created unknown
sition testimony of S. Wilhelm, pp. 1, 6, 54 and 66-68 (Aug. 26, (Mar. 31, 2011).
2010). Exhibit I of Bhagwat declaration in support of opposition, RAF
Exhibit 123 of Schenker declaration in support of opposition, Depo- Kinase Project Slides, (Oct. 1998).
sition testimony of L. Adnane, pp. 1, 5, 11 and 69-73 (Jun. 24, 2010). Exhibit J ofBhagwat declaration in support of opposition, Report No.
Exhibit 127 of Schenker declaration in support of opposition, Note- MRC-00984 Research Report Slides, (Oct. 11, 1999).
book records of Jennifer Burke, pp. 56, 57, 58, 59, 62 and 63. (Dec. (Cumulative to L35) Exhibit K ofBhagwat declaration in support of
12, 2002). opposition, US Patent 7351834, (Apr. 1, 2008).
Exhibit 143 of Schenker declaration in support of opposition, Web (Cumulative to L36) Exhibit L ofBhagwat declaration in support of
page Clinica!Trials.gov, Regorafenib+FolFiri verses opposition, Onyx Exhibit-99, U.S. Appl. No. 60/115,877, filed Jan.
Placebo+FolFiri-Colorectal Cancer, 7 pages, (Feb. 16, 2011). 13, 1999.
(Cumulative to Ll 7) Exhibit 150 of Schenker declaration in support Exhibit M of Bhagwat declaration in support of opposition, Article,
of opposition, Memo from Riedl to J. Lyons with Slides, (Sep. 17, Discovery and Developmentof Sorafenib: A Multikinase for Treating
1998). Cancer, Nature Reviews, Drug Discovery, vol. 5, (Oct. 2006), 835-
Exhibit 152 of Schenker declaration in support of opposition, Memo 844.
to Bollag with Slides, (Oct. 15, 1998). (Cumulative to L60A-E) Exhibit N ofBhagwat declaration in support
Exhibit 154 of Schenker declaration in support of opposition, Agenda of opposition, List of Compounds Synthesized, BAY-A00564638,
JRDC meeting with Slides, (Sep. 28, 1998). after (Jun. 2003).
Exhibit 155 of Schenker declaration in support of opposition, E-mail (Cumulative to Ll6, SJll-K and SJll-P) Exhibit O ofBhagwat
with HIR data attached, (Jun. 24, 1998). declaration in support of opposition, Memo from B. Riedl to J. Lyons
Exhibit 156 of Schenker declaration in support of opposition, Min- with Slides, (Sep. 17, 1998).
utes for Meeting between Bayer/Miles and Onyx, (Sep. 24, 1993). (Cumulative to SJ8-D) Exhibit P ofBhagwat declaration in support of
(Cumulative to Ll 7 and SJl 1-K) Exhibit 157 of Schenker declaration opposition, Report "RAF Kinase Inhibitor BAY 43-9006", (Jan. 25,
in support of opposition, Memo from B. Riedl to L. Lyons with 1999).
Slides, (Sep. 17, 1998). Exhibit Q ofBhagwat declaration in support of opposition, Tables of
Exhibit 158 of Schenker declaration in support of opposition, Assay Results/solubility for Bayer compounds, BAY A0056473 l.
Redacted Slide of Analogs of BAY 43-9006, (Sep. 17, 1998). (Cumulative to L2 l) Exhibit R of Bhagwat declaration in support of
Exhibit 166 of Schenker declaration in support of opposition, Article, opposition, Slide, "RAF Kinase Project," (Sep. 1998).
Defauw, et al., J. Med. Chem., (1996), 39, 5215-5227. (Cumulative to Ll 7) Exhibit S of Bhagwat declaration in support of
Exhibit 168 of Schenker declaration in support of opposition, JRDC opposition, Memo to J. Lyons with Slides, Onyx Deposition Exhibit
Meeting Minutes, (Jun. 5, 1995). 163, (Sep. 17, 1998).
Exhibit 169 of Schenker declaration in support of opposition, JRDC (Cumulative to SJ 11-L) Exhibit U of Bhagwat declaration in support
Meeting Minutes, (Mar. 29, 1996). of opposition, Memo to G. Bollag with Slides, (Oct. 15, 1998).
Exhibit 170 of Schenker declaration in support of opposition, RAF (Cumulative to L20 and SJl 1-M) Exhibit W of Bhagwat declaration
Kinase Project Slides, (Apr. 8, 1997). in support of opposition, Agenda JRDC Meeting with Slides, (Sep.
Exhibit 171 of Schenker declaration in support of opposition, Memo 28, 1998).
re Onyx visit, (Apr. 30, 1993). Exhibit X of Bhagwat declaration in support of opposition, Text,
Exhibit 172 of Schenker declaration in support of opposition, Report Burgers Medicinal Chemsitry and Drug Discovery, Chapter 19,
No. MRC-00984, Research Report, (Oct. 11, 1999). (1995).
Exhibit 173 of Schenker declaration in support of opposition, Article (Cumulative to Al 7) Exhibit Y of Bhagwat declaration in support of
by Lowinger et al., Design and Discovery of Small Molecules Tar- opposition, Article, Bioisosterism: A Rational Approach in Drug
geting RAF-1, Current Pharmaceutical Design, 2002, 8, 99-110. Design, 96, Chem Rev 3147 (1996).
Exhibit 175 of Schenker declaration in support of opposition, Agenda Trial testimony of John Lyons, pp. 619-687, (Oct. 5, 2011).
JRDC meeting with Slides, (Sep. 23, 1998). Trial testimonyofJohn Lyons and ShripadBhagwat, 688-894 (Oct. 6,
Exhibit 187 of Schenker declaration in support of opposition, Fax to 2011).
G. Giotta re Collaboration, (Sep. 6, 2001 ). (Cumulative with Ll 7, SJl 1-K, SJl 1-P, SJ15-s) Trial Exhibit 3,
Exhibit 186.1 of Schenker declaration in support of opposition, Bayer Deposition Exhibit 318, Memo from B. Riedl to J. Lyons with
E-mail re DAST RCC ASCO Abstract (Dec. 19, 2003). Slides, (Sep. 17, 1998).
Corrected Exhibit 186.2 of Schenker declaration in support of oppo- (Cumulative with L22, SJll-W and SJ15-J) Trial Exhibit 5, Bayer
sition, E-mail re DAST RCC ASCO Abstract (Dec. 19, 2003). Deposition Exhibit 34, Report No. MRC-00984, Research Report,
Exhibit 188 of Schenker declaration in support of opposition, E-mail Oct. 11, 1999).
re G. Giotta re patent applications, (Jun. 22, 2003). (Cumulative with SJ8-D and SJ15-P) Trial Exhibit 6, Deposition
Exhibit A of Bhagwat declaration in support of opposition, Com- Exhibit 60, Report RAF Kinase Inhibitor BAY 43-9006, (Jan. 25,
pound list, "Key Compounds in the DiscoveryofDAST," date created 1999).
unknown, date cited: (Mar. 31, 2022). Redacted Trial Exhibit 61, Bayer Deposition Exhibit 273, Report,
Exhibit B of Bhagwat declaration in support of opposition, Table of "Cancer Exploratory Research, Inhibition of the RAS Pathway, First
Assay Results for Bayer Compounds, BAY 00207465, (Apr. 26, Quarter 1995," (May 26, 1995).
2010). Trial Exhibit 65, Bayer Deposition Exhibit 95, JRDC Agenda, (Dec.
Exhibit C of Bhagwat declaration in support of opposition, "High- 4, 1995).
lights" (Curriculum Vitae) of Shripad Bhagwat (Jan. 10, 2011). (Cumulative with SJll-T) Trial Exhibit 66, JRDC Minutes (Mar. 29,
Exhibit CC of Bhagwat declaration in support of opposition, Sum- 1996).
mary of HIR assay, (Jun. 10, 1998). (Cumulative with SJll-U) Trial Exhibit 71, RAF Kinase Project
Exhibit EE of Bhagwat declaration in support of opposition, RAF Slides, (Apr. 8, 1997).
Kinase Project Slides, (Oct. 1998). (Cumulative with SJ15-F) Trial Exhibit 84, JRDC Agenda Minutes,
Exhibit F of Bhagwat declaration in support of opposition, JRDC Slides, (Jun. 10, 1998).
Meeting Minutes, (Jun. 5, 1995). Trial Exhibit 90, RAF Kinase Project Slides, (Sep. 1998).
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(56) References Cited Application No. 13/3401272; Claims, Feb. 21, 2012.
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Trial Exhibit 131, Deposition Exhibit 63, Redacted Strategic Project U.S.Appl. No. 11/845,595; Claims andOfficeAction,Aug. 27, 2007.
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(Cumulative to L50) Trial Exhibit 277, Correspondence with WHO U.S. Appl. No. 10/361,858; Claims and Office Action, Feb. 11, 2003.
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Trial Exhibit 300, Correspondence with WHO re: International Non- U.S. Appl. No. 10/042,203; Claims and Office Action, Jan. 11, 2002.
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(Cumulative to L34) Redacted Trial Exhibit 551, DPI Presentation, U.S. Appl. No. 13/208,010; Claims, Aug. 11, 2011.
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Trial Exhibit 795, "Highlights" Curriculum Vitae of Shripad U.S. Appl. No. 13/189,945; Claims, Jul. 25, 2011.
Bhagwat, Expert for Onyx, (Jan. 10, 2011). U.S. Appl. No. 10/361,859; Claims and Office Action, Feb. 11, 2003.
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with Slides, (Sep. 28, 1998). U.S. Appl. No. 10/789,446; Claims and Office Action, Mar. 1, 2004.
Trial Exhibit 1108, Onyx Web Page (2011 ). U.S. Appl. No. 12/628,735; Claims, Dec. 1, 2009.
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Trial Exhibit 1375, Meeting Minutes FDA-Bayer/Onyx re: U.S. Appl. No. 10/571,100; Claims and Office Action, Jul. 28, 2006.
Sorafenib, (Sep. 10, 2010). U.S. Appl. No. 10/848,567; Claims and Office Action, May 19, 2004.
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Jennifer Burke, pp. 1-100 (Microfiche), (Nov. 15, 2002-Jan. 16, U.S.Appl. No. 11/212,109; Claims andOfficeAction,Aug. 26, 2005.
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Trial Exhibit 1916, Article, 4-Amino-5-Aryl-6-arylethynyl U.S.Appl. No. 12/093,515; ClaimsandOfficeAction, May 13, 2008.
pyrimidine Structure Activity Relationship of Non-Nucleoside U.S.Appl. No. 11/754,082; Claims and Office Action, May 25, 2007.
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Trial Exhibit 140, Onyx Press Release, (Jun. 11, 2003). U.S. Appl. No. 12/093,719; Claims, May 15, 2008.
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Redacted Trial Exhibit 2, Amendment to proposed Collaboration U.S. Appl. No. 12/523,667; Claims and Office Action, Jul. 17, 2009.
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Ll56 Trial Exhibit 948, Slide Presentation, Key Message Platform U.S. Appl. No. 12/090,408; Claims and Office Action, Jul. 14, 2008.
for Bay 43-9006, date created unknown, prior to (Nov. 7, 2003). U.S. Appl. No. 11/579,093; Claims and Office Action, Jan. 15, 2008.
Ll57 Trial Exhibit 950, Slide presentation, Targeting Cancer with U.S. Appl. No. 12/941,841; Claims and Office Action, Nov. 8, 2010.
Therapeutic Innovation at Bayer Schering Pharma, date created U.S. Appl. No. 12/095,611; Claims, May 30, 2008.
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Co-pending U.S. Appl. No. 09/776,936, filed Dec. 22, 1998. U.S. Appl. No. 12/520,609; Claims and Office Action, Jun. 22, 2009.
Co-pending U.S. Appl. No. 13/401,272, filed Feb. 21, 2012. U.S. Appl. No. 12/294,979; Claims, Sep. 29, 2009.
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1 2
FLUORO SUBSTITUTED induce angiogenesis in the host stroma. These include PDGF,
OMEGA-CARBOXYARYL DIPHENYL UREA a potent stimulator of stroma formation (Ostman, A. and C.H.
FOR THE TREATMENT AND PREVENTION Heldin, Adv. Cancer Res. 2001, 80, 1-38), FGF, a chemo-
OF DISEASES AND CONDITIONS attractant and mitogen for fibroblasts and endothelial cells,
5 and VEGF, a potent regulator ofvascularization.
This application claims the benefit of the filing date ofU.S. PDGF is a key regulator of stromal formation, which is
Provisional Application Ser. No. 60/489,102 filed Jul. 23, secreted by many tumors in a paracrine fashion and is
2003 and U.S. Provisional Application Ser. No. 60/540,326 believed to promote the growth of fibroblasts, smooth muscle
filed Feb. 2, 2004. and endothelial cells, promoting stroma formation and angio-
10 genesis. PDGF was originally identified as the v-sis oncogene
FIELD OF THE INVENTION product of the simian sarcoma virus (Heldin, C.H., et al., J.
Cell. Sci. Suppl. 1985, 3, 65-76). The growthfactorismadeup
This invention relates to novel compounds, pharmaceutical of two peptide chains, referred to as A or B chains which share
compositions containing such compounds and the use of 60% homology in their primary amino acid sequence. The
those compounds or compositions for treating diseases and 15 chains are disulfide cross linked to form the 30 kDa mature
conditions mediated by abnormal VEGFR, PDGFR, raf, p38, protein composed of either AA, BB or AB homo- or het-
and/or flt-3 kinase signaling, either alone or in combination erodimmers. PDGF is found at high levels in platelets, and is
with anti-cancer agents. expressed by endothelial cells and vascular smooth muscle
cells. In addition, the production of PDGF is up regulated
BACKGROUND OF THE INVENTION 20 under low oxygen conditions such as those found in poorly
vascularized tumor tissue (Kourembanas, S., et al., Kidney
Activation of the ras signal transduction pathway indicates Int. 1997, 51(2), 438-43). PDGF binds with high affinity to
a cascade of events that have a profound impact on cellular the PDGF receptor, a 1106 amino acid 124 kDa transmem-
proliferation, differentiation, and transformation. Rafkinase, brane tyrosine kinase receptor (Heldin, C. H., A. Ostman, and
a downstream effector of ras, is recognized as a key mediator 25 L. Ronnstrand, Biochim. Biophys. Acta 1998, 1378(1),
of these signals from cell surface receptors to the cell nucleus 79-113). PDGFR is found as homo- or heterodimer chains
(Lowy, D.R.; Willumsen, B. M.Ann. Rev. Biochem.1993, 62, which have 30% homology overall in their amino acid
851; Bos, J. L. Cancer Res. 1989, 49, 4682). It has been sequence and 64% homology between their kinase domains
shown that inhibiting the effect of active ras by inhibiting the (Heldin, C.H., et al., Embo J. 1988, 7(5), 1387-93). PDGFR
rafkinase signaling pathway by administration of deactivat- 30 is a member of a family of tyrosine kinase receptors with split
ing antibodies to rafkinase or by co-expression of dominant kinase domains that includes VEGFR-2 (KDR), VEGFR-3
negative rafkinase or dominant negative MEK, the substrate (flt-4), c-kit, and flt-3. The PDGF receptor is expressed pri-
of rafkinase, leads to the reversion of transformed cells to the marily on fibroblasts, smooth muscle cells, and pericytes and
normal growth phenotype (see: Daum et al. Trends Biochem. to a lesser extent on neurons, kidney mesangial, Leydig, and
Sci.1994, 19,474-80;Fridmanetal.J.Biol. Chem.1994,269, 35 Schwarm cells of the central nervous system. Upon binding to
30105-8. Kolchet al. (Nature 1991, 349, 426-28) have further the receptor, PDGF induces receptor dimerization and under-
indicated that inhibition of raf expression by antisense RNA goes auto- and trans-phosphorylation of tyrosine residues
blocks cell proliferation in membrane-associated oncogenes. which increase the receptors' kinase activity and promotes
Similarly, inhibition ofrafkinase (by antisense oligodeoxy- the recruitment of downstream effectors through the activa-
nucleotides) has been correlated in vitro and in vivo with 40 tion of SH2 protein binding domains. A number of signaling
inhibition of the growth of a variety of human tumor types molecules form complexes with activated PDGFR including
(Mania et al., Nat. Med. 1996, 2, 668-75). PI-3-kinase, phospholipase C-gamma, src and GAP (GTPase
To support progressive tumor growth beyond the size of activating protein for p21-ras) (Soskic, V., et al. Biochemistry
1-2 mm 3 , it is recognized that tumor cells require a functional 1999, 38(6), 1757-64). Through the activation of PI-3-kinase,
stroma, a support structure consisting of fibroblast, smooth 45 PDGF activates the Rho signaling pathway inducing cell
muscle cells, endothelial cells, extracellular matrix proteins, motility and migration, and through the activation of GAP,
and soluble factors (Folkman, J., Semin. Oneal. 2002. 29(6 induces mi to genesis through the activation of p2 l-ras and the
Suppl 16), 15-8). Tumors induce the formation of stromal MAPK signaling pathway.
tissues through the secretion of soluble growth factors such as In adults, it is believed the major function of PDGF is to
PDGF and transforming growth factor-beta (TGF-beta), 50 facilitate and increase the rate of wound healing and to main-
which in tum stimulate the secretion of complimentary fac- tain blood vessel homeostasis (Baker, E. A. and D. J. Leaper,
tors by host cells such as fibroblast growth factor (FGF), Wound Repair Regen. 2000, 8(5), 392-8, and Yu, J., A. Moon,
epidermal growth factor (EGF), and vascular endothelial and H. R. Kim, Biochem. Biophys. Res. Commun. 2001, 282
growth factor (VEGF). These stimulatory factors induce the (3), 697-700). PDGF is found at high concentrations in plate-
formation of new blood vessels, or angiogenesis, which 55 lets and is a potent chemoattractant for fibroblast, smooth
brings oxygen and nutrients to the tumor and allows it to grow muscle cells, neutrophils and macrophages. In addition to its
and provides a route for metastasis. It is believed some thera- role in wound healing PDGF is known to help maintain vas-
pies directed at inhibiting stroma formation will inhibit the cular homeostasis. During the development of new blood
growth of epithelial tumors from a wide variety of histologi- vessels, PDGF recruits pericytes and smooth muscle cells that
cal types. (George, D. Semin. Oneal. 2001. 28(5 Suppl 17), 60 are needed for the structural integrity of the vessels. PDGF is
27-33; Shaheen, R. M., eta!., Cancer Res. 2001, 61(4), 1464- thought to play a similar role during tumor neovasculariza-
8; Shaheen, R. M., et al. Cancer Res. 1999, 59(21), 5412-6). tion. As part of its role in angiogenesis PDGF controls inter-
However, because of the complex nature and the multiple stitial fluid pressure, regulating the permeability of vessels
growth factors involved in angiogenesis process and tumor through its regulation of the interaction between connective
progression, an agent targeting a single pathway may have 65 tissue cells and the extracellular matrix. Inhibiting PDGFR
limited efficacy. It is desirable to provide treatment against a activity can lower interstitial pressure and facilitate the influx
number of key signaling pathways utilized by tumors to of cytotoxics into tumors improving the anti-tumor efficacy
IITRUE COPY!I
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of these agents (Pietras, K., et al. Cancer Res. 2002, 62(19), to be a critical requirement for induction of the full spectrum
5476-84; Pietras, K., et al. Cancer Res. 2001, 61(7), 2929- ofVEGF-mediated biological responses.
34). In vivo, VEGF plays a central role in vasculogenesis, and
PDGF can promote tumor growth through either the para- induces angiogenesis and permeabilization of blood vessels.
crine or autocrine stimulation of PDGFR receptors on stromal 5 Deregulated VEGF expression contributes to the develop-
cells or tumor cells directly, or through the amplification of ment of a number of diseases that are characterized by abnor-
the receptor or activation of the receptor by recombination. mal angiogenesis and/or hyperpermeability processes. It is
Over expressed PDGF can transform human melanoma cells believed that regulation of the VEGF-mediated signal trans-
and keratinocytes (Forsberg, K., et al. Proc. Natl. A cad Sci. U duction cascade by some agents can provide a useful control
10 of abnormal angiogenesis and/or hyperpermeability pro-
SA. 1993, 90(2), 393-7; Skobe, M. and N. E. Fusenig, Proc.
cesses. Tumorigenic cells within hypoxic regions of tumors
Natl. Acad. Sci. US A. 1998, 95(3), 1050-5), two cell types
respond by stimulation ofVEGF production, which triggers
that do not express PDGF receptors, presumably by the direct
activation of quiescent endothelial cells to stimulate new
effect of PDGF on stroma formation and induction of angio- blood vessel formation. (Shweiki et al. Proc. Nat'!. Acad Sci.
genesis. This paracrine stimulation of tumor stroma is also 15 1995, 92, 768). In addition, VEGF production in tumor
observed in carcinomas of the colon, lung, breast, and pros- regions where there is no angiogenesis may proceed through
tate (Bhardwaj, B., et al. Clin. Cancer Res. 1996, 2(4), 773- the ras signal transduction pathway (Grugel et al. J. Biol.
82; Nakanishi, K., et al. Mod. Pathol. 1997, 10(4), 341-7; Chem. 1995, 270, 25915; Rak et al. Cancer Res. 1995, 55,
Sundberg, C., et al. Am. J. Pathol. 1997, 151(2), 479-92; 457 5). In situ hybridization studies have demonstrated VEGF
Lindmark, G., et al. Lab. Invest. 1993, 69(6), 682-9; Vignaud, 20 mRNA is strongly upregulated in a wide variety of human
J. M., et al, Cancer Res. 1994, 54(20), 5455-63) where the tumors, including lung (Mattern et al. Br. J. Cancer 1996, 73,
tumors express PDGF, but not the receptor. The autocrine 931), thyroid (Viglietto et al. Oncogene 1995, 11, 1569),
stimulation of tumor cell growth, where a large faction of breast (Brown et al. Human Pathol. 1995, 26, 86), gastrointes-
tumors analyzed express both the ligand PDGF and the recep- tinal tract (Brown et al. Cancer Res. 1993, 53, 4727; Suzuki et
tor, has been reported in glioblastomas (Fleming, T. P., et al. 25 al. Cancer Res. 1996, 56, 3004), kidney and bladder (Brown
Cancer Res. 1992, 52(16), 4550-3), soft tissue sarcomas et al. Am. J. Pathol. 1993, 1431, 1255), ovary (Olson et al.
(Wang, J., M. D. Coltrera, and A. M. Gown, Cancer Res. Cancer Res. 1994, 54, 1255), and cervical (Guidi et al. J.
1994, 54(2), 560-4) and cancers of the ovary (Henriksen, R., Nat'! Cancer Inst. 1995, 87, 12137) carcinomas, as well as
et al. Cancer Res. 1993, 53(19), 4550-4), prostate (Fudge, K., angiosarcoma (Hashimoto et al. Lab. Invest. 1995, 73, 859)
C. Y. Wang, and M. E. Stearns, Mod. Pathol. 1994, 7(5), 30 and several intracranial tumors (Plate et al. Nature 1992, 359,
549-54), pancreas (Puna, K., et al. Cancer Res. 1990, 50(3), 845; Phillips et al. Int. J. Oneal. 1993, 2, 913; Berkman et al.
748-53) and lung (Antoniades, H. N., et al., Proc. Natl. Acad. J. Clin. Invest. 1993, 91,153). Neutralizing monoclonal anti-
Sci. US A l 992, 89(9), 3942-6). Ligand independent activa- bodies to VEGFR-2 have been shown to be efficacious in
tion of the receptor is found to a lesser extent but has been blocking tumor angiogenesis (Kim et al. Nature 1993, 362,
reported in chronic myelomonocytic leukemia (CMML) 35 841; Rockwell et al. Mal. Cell. Differ. 1995, 3,315).
where the a chromosomal translocation event forms a fusion Overexpression ofVEGF, for example under conditions of
protein between the Ets-like transcription factor TEL and the extreme hypoxia, can lead to intraocular angiogenesis, result-
PDGF receptor. In addition, activating mutations in PDGFR ing in hyperproliferation of blood vessels, leading eventually
have been found in gastrointestinal stromal tumors in which to blindness. Such a cascade of events has been observed for
c-kit activation is not involved (Heinrich, M. C., et al., Science 40 a number of retinopathies, including diabetic retinopathy,
2003, 9, 9). ischemic retinal-vein occlusion, and retinopathy of prematu-
Another major regulator of angiogenesis and vasculogen- rity (Aiello et al. New Engl. J. Med. 1994, 331, 1480; Peer et
esis in both embryonic development and some angiogenic- al. Lab. Invest. 1995, 72, 638), and age-related macular
dependent diseases is vascular endothelial growth factor degeneration (AMD; see, Lopez et al. Invest. Opththalmol.
(VEGF; also called vascular permeability factor, VPF). 45 Vis. Sci. 1996, 37, 855).
VEGF represents a family ofisoforms of mi to gens existing in In rheumatoid arthritis (RA), the in-growth of vascular
homodimeric forms due to alternative RNA splicing. The parnms may be mediated by production of angiogenic factors.
VEGF isoforms are highly specific for vascular endothelial Levels of immunoreactive VEGF are high in the synovial
cells (for reviews, see: Farrara et al. Endocr. Rev. 1992, 13, fluid of RA patients, while VEGF levels were low in the
18; Neufield et al. FASEB J. 1999, 13, 9). 50 synovial fluid of patients with other forms of arthritis of with
VEGF expression is induced by hypoxia (Shweiki et al. degenerative joint disease (Koch et al. J. Immunol. 1994, 152,
Nature 1992, 359, 843), as well as by a variety of cytokines 4149). The angiogenesis inhibitor AGM-170 has been shown
and growth factors, such as interleukin-I, interleukin-6, epi- to prevent neovascularization of the joint in the rat collagen
dermal growth factor and transforming growth factor. To date, arthritis model (Peacock et al. J. Exper. Med. 1992, 175,
VEGF and the VEGF family members have been reported to 55 1135).
bind to one or more of three transmembrane receptor tyrosine Increased VEGF expression has also been shown in psori-
kinases (Mustonen et al. J. Cell Biol. 1995, 129, 895), VEGF atic skin, as well as bullous disorders associated with subepi-
receptor-I (also known as flt-1 (fms-like tyrosine kinase-I)), dermal blister formation, such as bullous pemphigoid,
VEGFR-2 (also known as kinase insert domain containing erythema multiforme, and dermatitis herpetiformis (Brown et
receptor (KDR); the murine analogue ofVEGFR-2 is known 60 al. J. Invest. Dermatol. 1995, 104, 744).
as fetal liver kinase-I (flk-1)), and VEGFR-3 (also known as The vascular endothelial growth factors (VEGF, VEGF-C,
flt-4). VEGFR-2 and flt-1 have been shown to have different VEGF-D) and their receptors (VEGFR-2, VEGFR-3) are not
signal transduction properties (Waltenberger et al. J. Biol. only key regulators of tumor angiogenesis, but also lymphan-
Chem. 1994, 269, 26988); Park et al. Oncogene 1995, 10, giogenesis. VEGF, VEGF-C and VEGF-D are expressed in
135). Thus, VEGFR-2 undergoes strong ligand-dependant 65 most tumors, primarily during periods of tumor growth and,
tyrosine phosphorylation in intact cells, whereas flt-1 dis- often at substantially increased levels. VEGF expression is
plays a weak response. Thus, binding to VEGFR-2 is believed stimulated by hypoxia, cytokines, oncogenes such as ras, or
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by inactivation of tumor suppressor genes (McMahon, G. 1987, 330, 662; Girardin et al. New England J. Med 1988,
Oncologist 2000, 5(Suppl. 1), 3-10; McDonald, N. Q.; Hen- 319,397), endotoxic shock (Beutler et al. Science 1985, 229,
drickson, W. A. Cell 1993, 73, 421-424) 869; Ashkenasi et al. Proc. Nat'!. Acad. Sci. USA 1991, 88,
The biological activities of the VEGFs are mediated 10535), toxic shock syndrome, (Saha et al. J. Immunol. 1996,
through binding to their receptors. VEGFR-3 (also called 5 157, 3869; Lina et al. FEMS Immunol. Med. Micro biol. 1996,
flt-4) is predominantly expressed on lymphatic endothelium 13, 81), systemic inflammatory response syndrome (Anon.
in normal adult tissues. VEGFR-3 function is needed for new Crit. Care Med. 1992, 20, 864), inflammatory bowel diseases
lymphatic vessel formation, but not for maintenance of the (Stokkers et al. J. Inflamm. 1995-6, 47, 97) including Crohn's
pre-existing lymphatics. VEGFR-3 is also upregulated on disease (van Deventer et al. Aliment. Pharmacol. Therapeu.
blood vessel endothelium in tumors. Recently VEGF-C and 10 1996, 10 (Suppl. 2), 107; van Dullemen et al. Gastroenterol-
VEGF-D, ligands forVEGFR-3, have been identified as regu- ogy 1995, 109, 129) and ulcerative colitis (Masuda et al. J.
lators of lymphangiogenesis in mammals. Lymphangiogen- Clin. Lab. Immunol. 1995, 46, 111), Jarisch-Herxheimer
esis induced by tumor-associated lymphangiogenic factors reactions (Fekadeetal.New England.!. Med. 1996, 335,311),
could promote the growth of new vessels into the tumor, asthma (Amrani et al. Rev. Malad Respir. 1996, 13, 539),
providing tumor cells access to systemic circulation. Cells 15 adult respiratory distress syndrome (Roten et al. Am. Rev.
that invade the lymphatics could find their way into the blood- Respir. Dis. 1991, 143,590; Suter et al.Am. Rev. Respir. Dis.
stream via the thoracic duct. Tumor expression studies have 1992, 145, 1016), acute pulmonary fibrotic diseases (Pan et
allowed a direct comparison of VEGF-C, VEGF-D and al. Pathol. Int. 1996, 46, 91), pulmonary sarcoidosis (Ishioka
VEGFR-3 expression with clinicopathological factors that et al. Sarcoidosis Vasculitis Diffuse Lung Dis. 1996, 13, 139),
relate directly to the ability of primary tumors to spread (e.g., 20 allergic respiratory diseases (Casale et al. Am. J. Respir. Cell
lymph node involvement, lymphatic invasion, secondary Mal. Biol. 1996, 15, 35), silicosis (Gossart et al. J. Immunol.
metastases, and disease-free survival). In many instances, 1996, 156, 1540; Vanhee et al. Eur. Respir. J. 1995, 8, 834),
these studies demonstrate a statistical correlation between the coal worker's pneumoconiosis (Bonn et al. Am. Rev. Respir.
expression of lymphangiogenic factors and the ability of a Dis. 1988, 138, 1589), alveolar injury (Horinouchi et al. Am.
primary solid tumor to metastasize (Skobe, M. et al. Nature 25 J. Respir. Cell Mal. Biol. 1996, 14, 1044), hepatic failure
Med. 2001, 7(2), 192-198; Stacker, S. A. et al., Nature Med. (Gantner et al. J. Pharmacol. Exp. Therap. 1997, 280, 53),
2001, 7(2), 186-191; Makinen, T. et al. Nature Med. 2001, liver disease during acute inflanmiation (Kim et al. J. Biol.
7(2), 199-205; Mandriota, S. J. et al. EMBOJ. 2001, 20(4), Chem. 1997, 272, 1402), severe alcoholic hepatitis (Bird et al.
672-82; Karpanen, T. eta!. Cancer Res. 2001, 61(5), 1786-90; Ann. Intern. Med. 1990, 112, 917), malaria (Grau et al. Immu-
Kubo, H. et al. Blood 2000, 96(2), 546-53). 30 nol. Rev. 1989, 112, 49; Taveme et al. Parasitol. Today 1996,
Hypoxia appears to be an important stimulus for VEGF 12, 290) including Plasmodium falciparum malaria (Per-
production in malignant cells. Activation of p38 MAP kinase lmann et al. Infect. Immunit. 1997, 65, 116) and cerebral
is required for VEGF induction by tumor cells in response to malaria (Rudin et al. Am. J. Pathol. 1997, 150, 257), non-
hypoxia (Blaschke, F. et al. Biochem. Biophys. Res. Commun. insulin-dependent diabetes mellitus (NIDDM; Stephens et al.
2002, 296, 890-896; Shemirani, B. et al. Oral Oncology 2002, 35 J. Biol. Chem. 1997, 272, 971; Ofei et al. Diabetes 1996, 45,
38, 251-257). In addition to its involvement in angiogenesis 881), congestive heart failure (Doyama et al. Int. J. Cardiol.
through regulation ofVEGF secretion, p38 MAP kinase pro- 1996, 54, 217; McMurray et al. Br. Heart J. 1991, 66, 356),
motes malignant cell invasion, and migration of different damage following heart disease (Malkiel et al. Mal. Med.
tumor types through regulation of collagenase activity and Today 1996, 2, 336), atherosclerosis (Parums et al. J. Pathol.
urokinase plasminogen activator expression (Laferriere, J. et 40 1996, 179, A46), Alzheimer's disease (Fagarasan et al. Brain
al.J. Biol. Chem. 2001, 276, 33762-33772; Westermarck, J. et Res. 1996, 723,231; Aisen et al. Gerontology 1997, 43, 143),
al. Cancer Res. 2000, 60, 7156-7162; Huang, S. et al. J. Biol. acute encephalitis (Ichiyama et al. J Neural. 1996, 243, 457),
Chem. 2000, 275, 12266-12272; Simon, C. et al. Exp. Cell brain injury (Cannon et al. Crit. Care Med. 1992, 20, 1414;
Res. 2001, 271, 344-355). Hansbrough et al. Surg. Clin. N. Am. 1987, 67, 69; Marano et
Inhibition of the mitogen-activated protein kinase 45 al. Surg. Gynecol. Obstetr. 1990, 170, 32), multiple sclerosis
(MAPK) p38 has been shown to inhibit both cytokine pro- (M. S.; Coyle. Adv. Neuroimmunol. 1996, 6, 143; Matusevi-
duction (e.g., TNF, IL-1, IL-6, IL-8) and proteolytic enzyme cius et al. J. Neuroimmunol. 1996, 66, 115) including demy-
production (e.g., MMP-1, MMP-3) in vitro and/or in vivo. elation and oligiodendrocyte loss in multiple sclerosis (Bro-
The mitogen activated protein (MAP) kinase p38 is involved snan et al. Brain Pathol. 1996, 6, 243), advanced cancer
in IL-1 and TNF signaling pathways (Lee, J.C.; Laydon, J. T.; 50 (Muc Wierzgon et al. J. Biol. Regulators Homeostatic Agents
McDonnell, P. C.; Gallagher, T. F.; Kumar, S.; Green, D.; 1996, 10, 25), lymphoid malignancies (Levy et al. Crit. Rev.
McNulty, D.; Blumenthal, M. J.; Heys, J. R.; Landvatter, S. Immunol. 1996, 16, 31), pancreatitis (Exley et al. Gut 1992,
W.; Stricker, J.E.; McLaughlin, M. M.; Siemens, I. R.; Fisher, 33, 1126) including systemic complications in acute pancre-
S. M.; Livi, G. P.; White, J. R.; Adams, J. L.; Yound, P.R. atitis (McKay et al. Br. J. Surg. 1996, 83, 919), impaired
Nature 1994, 372, 739). 55 wound healing in infection inflammation and cancer (Buck et
Clinical studies have linked tumor necrosis factor (TNF) al. Am. J. Pathol. 1996, 149, 195), myelodysplastic syn-
production and/or signaling to a numberof diseases including dromes (Raza et al. Int. J. Hematol. 1996, 63, 265), systemic
rheumatoid arthritis (Maini. J. Royal Coll. Physicians Lon- lupus erythematosus (Maury et al. Arthritis Rheum. 1989, 32,
don 1996, 30, 344 ). In addition, excessive levels ofTNF have 146), biliary cirrhosis (Miller et al. Am. J. Gasteroenterolog.
been implicated in a wide variety of inflammatory and/or 60 1992, 87,465), bowel necrosis (Sunetal.J. Clin. Invest.1988,
immunomodulatory diseases, including acute rheumatic 81, 1328), psoriasis (Christophers. Austr. J. Dermatol. 1996,
fever (Yegin et al. Lancet 1997, 349, 170), bone resorption 37, S4), radiation injury (Redlichetal. J. Immunol. 1996, 157,
(Pacifici et al. J. Clin. Endocrinol. Metabol. 1997, 82, 29), 1705), and toxicity following administration of monoclonal
postmenopausal osteoporosis (Pacifici et al. J. Bone Mineral antibodies such as OKT3 (Brod et al. Neurology 1996, 46,
Res. 1996, 11, 1043), sepsis (Blackwell et al. Br. J. Anaesth. 65 1633). TNF levels have also been related to host-versus-graft
1996, 77, 110), gram negative sepsis (Debets et al. Prag. Clin. reactions (Piguet et al. Immunol. Ser. 1992, 56, 409) includ-
Biol. Res. 1989, 308,463), septic shock (Tracey et al. Nature ing ischemia reperfusion injury (Colletti et al. J Clin. Invest.
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1989, 85, 1333) and allograft rejections including those of the required for VEGF induction by tumor cells in response to
kidney (Maury et al. J Exp. Med. 1987, 166, 1132), liver hypoxia (Blaschke, F. et al. Biochem. Biophys. Res. Commun.
(Imagawa et al. Transplantation 1990, 50, 219), heart (Bol- 2002, 296, 890-896; Shemirani, B. et al. Oral Oncology 2002,
ling et al. Transplantation 1992, 53,283), and skin (Stevens et 38, 251-257). In addition to its involvement in angiogenesis
al. Transplant. Proc. 1990, 22, 1924), lung allograft rejection 5 through regulation ofVEGF secretion, p38 kinase promotes
(Grossman et al. Immunol. Allergy Clin. N. Am. 1989, 9, 153) malignant cell invasion, and migration of different tumor
including chronic lung allograft rejection (obliterative bron- types through regulation of collagenase activity and uroki-
chitis; LoCicero et al. J. Thorac. Cardiovasc. Surg. 1990, 99, nase plasminogen activator expression (Laferriere, J. et al. J.
1059), as well as complications due to total hip replacement Biol. Chem. 2001, 276, 33762-33772; Westermarck, J. et al.
(Cirino et al. Life Sci. 1996, 59, 86). TNF has also been linked 10
Cancer Res. 2000, 60, 7156-7162; Huang, S. et al. J. Biol.
to infectious diseases (review: Beutler et al. Crit. Care Med.
Chem. 2000, 275, 12266-12272; Simon, C. et al. Exp. Cell
1993, 21, 5423; Degre. Biotherapy 1996, 8, 219) including
Res. 2001, 271, 344-355). Therefore, inhibition of p38 kinase
tuberculosis (Rook et al. Med. Malad. Infect. 1996, 26, 904),
Helicobacter pylori infection during peptic ulcer disease is also expected to impact tumor growth by interfering with
(Beales et al. Gastroenterology 1997, 112, 136), Chaga's 15
signaling cascades associated with both angiogenesis and
disease resulting from Trypanosoma cruzi infection (Chan- malignant cell invasion.
drasekar et al. Biochem. Biophys. Res. Commun. 1996, 223, Certain ureas have been described as having activity as
365), effects of Shiga-like toxin resulting from E. coli infec- serine-threonine kinase and/or as tyrosine kinase inhibitors.
tion (Hare! et al. J. Clin. Invest. 1992, 56, 40), the effects of In particular, the utility of certain ureas as an active ingredient
enterotoxin A resulting from Staphylococcus infection (Fis- 20 in pharmaceutical compositions for the treatment of cancer,
cher et al. J. Immunol. 1990, 144, 4663), meningococcal angiogenesis disorders, inflannnatory disorders, has been
infection (Waage et al. Lancet 1987, 355; Ossege et al. J. demonstrated.
Neurolog. Sci. 1996, 144, 1), and infections from Borrelia For cancer and angiogenesis, see:
burgdorferi (Brandt et al. Infect. ImmunoL. 1990, 58, 983), Smith et al., Bioorg. Med Chem. Lett. 2001, 11, 2775-2778.
Treponema pallidum (Chamberlin et al. Infect. Immunol. 25 Lowinger et al., Clin. Cancer Res. 2000, 6(suppl.), 335.
1989, 57, 2872), cytomegalovirus (CMV; Geist et al. Am. J. Lyons et al., Endocr.-Relat. Cancer 2001, 8, 219-225.
Respir. Cell Mal. Biol. 1997, 16, 31 ), influenza virus (Beutler Riedl et al., Book of Abstracts, 92nd AACR Meeting, New
et al. Clin. Res. 1986, 34, 491a), Sendai virus (Goldfield et al. Orleans, La., USA, abstract 4956.
Proc. Nat'!. Acad. Sci. USA 1989, 87, 1490), Theiler's Khire et al., Book of Abstracts, 93 rd AACR Meeting, San
encephalomyelitis virus (Sierra et al. Immunology 1993, 78, 30 Francisco, Calif., USA, abstract 4211.
399), and the human immunodeficiency virus (HIV; Poli. Lowinger et al., Curr. Pharm. Design 2002, 8, 99-110.
Proc. Nat'!. Acad. Sci. USA 1990, 87, 782; Vyakaram et al. Carter et al., Book of Abstracts, 92nd AACR Meeting, New
AIDS 1990, 4, 21; Badley et al. J. Exp. Med. 1997, 185, 55). Orleans, La., USA, abstract 4954.
A number of diseases are thought to be mediated by excess Vincent et al., Book of Abstracts, 38 th ASCO Meeting,
or undesired matrix-destroying metalloprotease (MMP) 35 Orlando, Fla. USA, abstract 1900.
activity or by an imbalance in the ratio of the MMPs to the Hilger et al., Book of Abstracts, 38 th ASCO Meeting,
tissue inhibitors of metalloproteinases (TIMPs ). These Orlando, Fla., USA, abstract 1916.
include osteoarthritis (Woessner et al. J. Biol. Chem. 1984, Moore et al., Book of Abstracts, 38 th ASCO Meeting,
259, 3633), rheumatoid arthritis (Mullins et al. Biochim. Bio- Orlando, Fla., USA, abstract 1816.
phys. Acta 1983, 695, 117; Woolley et al. Arthritis Rheum. 40 Strumberg et al., Book of Abstracts, 38 th ASCO Meeting,
1977, 20, 1231; Gravallese et al. Arthritis Rheum. 1991, 34, Orlando, Fla., USA, abstract 121.
1076), septic arthritis (Williams et al. Arthritis Rheum. 1990, For p38 mediated diseases, including inflammatory disor-
33, 533), tumor metastasis (Reich et al. Cancer Res. 1988, 48, ders, see:
3307; Matrisian et al. Proc. Nat'!. Acad. Sci., USA 1986, 83, Redman et al., Bioorg Med. Chem. Lett. 2001, 11, 9-12.
9413), periodontal diseases (Overall et al. J. Periodontal Res. 45 Dumas et al., Bioorg Med. Chem. Lett. 2000, 10, 2047-2050.
1987, 22, 81), corneal ulceration (Bums et al. Invest. Opthal- Dumas et al., Bioorg. Med. Chem. Lett. 2000, 10, 2051-2054.
mol. Vis. Sci. 1989, 30, 1569), proteinuria (Baricos et al. Ranges et al., Book of Abstracts, 220thACS National Meet-
Biochem. J. 1988, 254, 609), coronary thrombosis from ath- ing, Washington, D.C.,
erosclerotic plaque rupture (Henney et al. Proc. Nat 'l. A cad. USA, MEDI 149.
Sci., USA 1991, 88, 8154), aneurysmal aortic disease (Vine et 50 Dumas et al., Bioorg. Med. Chem. Lett. 2002, 12, 1559-1562.
al. Clin. Sci. 1991, 81, 233), birth control (Woessner et al. Regan et al., J. Med. Chem. 2002, 45, 2994-3008.
Steroids 1989, 54, 491), dystrophobic epidermolysis bullosa Pargellis et al., Nature Struct. Biol. 2002, 9(4), 268-272.
(Kronberger et al. J. Invest. Dermatol. 1982, 79, 208), degen- Madwed J. B., Book of Abstracts, Protein Kinases: Novel
erative cartilage loss following traumatic joint injury, Target Identification and
osteopenias mediated by MMP activity, tempera mandibular 55 Validation for Therapeutic Development, San Diego, Calif.,
joint disease, and demyelating diseases of the nervous system USA, March 2002.
(Chantry et al. J. Neurochem. 1988, 50, 688). Pargellis C. et al., Curr. Opin. Invest. Drugs 2003, 4, 566-571.
Because inhibition of p38 leads to inhibition ofTNF pro- Branger J. et al., J. Immunol. 2002, 168, 4070-4077.
duction and MMP production, it is believed inhibition of Branger J. et al., Blood 2003, 101, 4446-4448.
mitogen activated protein (MAP) kinase p38 enzyme can 60 Omega-Carboxyaryl diphenyl ureas are disclosed in
provide an approach to the treatment of the above listed WO00/42012, published: Jul. 20, 2000, WO00/41698, pub-
diseases including osteoporosis and inflannnatory disorders lished: Jul. 20, 2000, the following published U.S. applica-
such as rheumatoid arthritis and CO PD (Badger, A. M.; Brad- tions:
beer, J. N.; Votta, B.; Lee, J. C.;Adams, J. L.; Griswold, D. E. US2002-0165394-Al, published Nov. 7, 2002,
J. Pharm. Exper. Ther. 1996, 279, 1453). 65 US2001-003447-Al, published Oct. 25, 2001,
Hypoxia appears to be an important stimulus for VEGF US2001-0016659-Al, published Aug. 23, 2001,
production in malignant cells. Activation of p38 kinase is US2002-013774-Al, published Sep. 26, 2002,
IITRUE COPY!I
US 8,637,553 B2
9 10
and copending U.S. applications: bisulfate, butyrate, citrate, camphorate, camphorsulfonate,
Ser. No. 09/758,547, filed Jan. 12, 2001, cinnamate, cyclopentanepropionate, digluconate, dodecyl-
Ser. No. 09/889,227, filed Jul. 12, 2001, sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycero-
Ser. No. 09/993,647, filed Nov. 27, 2001, phosphate, hemisulfate, heptanoate, hexanoate, hydrochlo-
Ser. No. 10/042,203, filed Jan. 11, 2002 and ride, hydro bromide, hydroiodide, 2-hydroxyethanesulfonate,
itaconate, lactate, maleate, mandelate, methanesulfonate,
Ser. No. 10/071,248, filed Feb. 11, 2002,
2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate,
pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,
DESCRIPTION OF THE INVENTION propionate, succinate, sulfonate, tartrate, thiocyanate, tosy-
10 late, and undecanoate.
It has been discovered that the omega-carboxyaryl diphe- The salts or prodrugs of the compounds of Formula I may
nyl urea of Formula I below, which has a 2-fluoro-4-(2-(N- contain one or more asymmetric centers. Asymmetric carbon
methylcarbamoyl)-4-pyridyloxy)phenylene group bound to atoms may be present in the (R) or (S) configuration or (R,S)
urea is a potent inhibitor raf kinase, VEGFR kinase, p38 configuration. Substituents on a ring may also be present in
kinase, and PDGFR kinase, which are all molecular targets of either cis or trans form. It is intended that all such configura-
15 tions (including enantiomers and diastereomers), are
interest for the treatment and prevention of osteoporosis,
inflammatory disorders, hyper-proliferatrive disorders, and included within the scope of the present invention. Preferred
isomers are those with the configuration which produces the
angiogenesis disorders, including cancer.
more desirable biological activity. Separated, pure or par-
The present invention provides, e.g., tially purified isomers or racemic mixtures of the compounds
(i) a novel compound of Formula (I), salts, prodrugs, and 20 of this invention are also included within the scope of the
metabolites thereof, present invention. The purification of said isomers and the
(ii) pharmaceutical compositions containing such compound, separation of said isomeric mixtures can be accomplished by
and standard techniques known in the art.
(iii) use of this compound or compositions for treating dis- The particular process to be utilized in the preparation of
eases and conditions mediated by raf, VEGFR, PDGFR, 25 the compound used in this embodiment of the invention is
flt-3, and p38, either as a sole agent or in combination with described in Example 1. Salt forms of the compound of For-
cytotoxic therapies. mula (I) are described in Examples 2, 3, and 4.
The compound of the Formula I below, salts, prodrugs and Methods of Use
metabolites thereof is collectively referred to as the "com- The present invention provides compounds which are
pounds of the invention". Formula I is as follows: 30 capable of modulating one or more signal transduction path-
ways involving raf, VEGFR, PDGFR, p38, and/or flt-3
kinases. Raf is an important signaling molecule involved in
(I)
the regulation of a number of key cellular processes, includ-
ing cell growth, cell survival and invasion. It is a member of
35 the Ras/raf/MEK/ERK pathway. This pathway is present in
most tumor cells. VEGFR, PDGFR, and flt-3 are transmem-
brane receptor molecules which, when stimulated by an
appropriate ligand, trigger the Ras/raf/MEK/ERK cell signal-
ing pathway, leading to a cascade of cellular events. Each of
40 these receptor molecules have tyrosine kinase activity.
The VEG FR receptors are stimulated by vascular endothe-
The metabolites of the compound of this invention include lial growth factors (VEGF), and are important control points
oxidized derivatives of Formula I wherein one or more of the in the regulation of endothelial cell development and func-
urea nitrogens are substituted with a hydroxy group. The tion. The PDGF-beta receptor regulates cell proliferation and
metabolites of the compound of this invention also include 45 survival in a number of cell types, including mesenchymal
analogs where the methylamide group of the compound of cells. Flt-3 is a receptor for the FL ligand. It is structurally
Formula I is hydroxylated then de-methylated by metabolic similar to c-kit, and modulates the growth of pluripotent
degradation. The metabolites of the compound of this inven- haemopoietic cells, influencing the development of T-cells,
tion further include oxidized derivatives where the pyridine B-cells, and dendritic cells.
nitrogen atom is in the N-oxide form (e.g. carries a hydroxy 50 Any gene or isoform of raf, VEG FR, PDGFR, p38, and/or
substituent) leading to those structures referred to in the art as flt-3 can be modulated in accordance with present invention,
1-oxo-pyridine and I-hydroxy-pyridine. including both wild-type and mutant forms. Raf or raf-1
Where the plural form of the word compounds, salts, and kinase is a family of serine/threonine kinases which comprise
the like, is used herein, this is taken to mean also a single at least three family members, a-raf, b-raf, and c-raf or raf-1.
compound, salt, or the like. 55 See, e.g., Dhillon and Kolch, Arch. Biochem. Biophys. 2002,
The use of pharmaceutically acceptable salts of the com- 404, 3-9. C-rafand b-rafare preferred targets for compounds
pounds of Formula I is also within the scope of this invention. of the present invention. Activating b-raf mutations (e.g.,
The term "pharmaceutically acceptable salt" refers to a rela- V599E mutant) have been identified in various cancers,
tively non-toxic, inorganic or organic acid addition salt of a including melanoma, and the compounds described herein
compound of the present invention. For example, see S. M. 60 can be utilized to inhibit their activity.
Berge, et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, By the term "modulate", it is meant that the functional
1-19. activity of the pathway (or a component of it) is changed in
Representative salts of the compound of this invention comparison to its normal activity in the absence of the com-
include the conventional non-toxic salts, for example, from pound. This effect includes any quality or degree of modula-
inorganic or organic acids by means well known in the art. For 65 tion, including, increasing, agonizing, augmenting, enhanc-
example, such acid addition salts include acetate, adipate, ing, facilitating, stimulating, decreasing, blocking,
alginate, ascorbate, aspartate, benzoate, benzenesulfonate, inhibiting, reducing, diminishing, antagonizing, etc.
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The compounds of the present invention can also modulate ing" is used conventionally, e.g., the management or care of a
one or more of the following processes, including, but not subject for the purpose of combating, alleviating, reducing,
limited to, e.g., cell growth (including, e.g., differentiation, relieving, improving the condition of, etc., of a disease or
cell survival, and/or proliferation), tumor cell growth (includ- disorder. The compounds can also be described as being used
ing, e.g., differentiation, cell survival, and/or proliferation), to prevent and/or treat diseases and/or condition mediated by
tumor regression, endothelial cell growth (including, e.g., the signaling molecules. The term "mediated" indicates, e.g.,
differentiation, cell survival, and/or proliferation), angiogen- that the signaling molecule is part of the pathway which is
esis (blood vessel growth), lymphangiogenesis (lymphatic aberrant or disturbed in the disease and/or condition.
vessel growth), and/or hematopoiesis (e.g., T- and B-cell Diseases and conditions that can be treated include any of
development, dendritic cell development, etc.). 10 those mentioned above and below, as well as:
While not wishing to be bound by any theory or mechanism Raf associated diseases include, e.g., cell-proliferation dis-
of action, it has been found that compounds of the present orders, cancer, tumors, etc.;
invention possess the ability to modulate kinase activity. The VEGFR-2 associated diseases include, e.g., cancer, tumor
methods of the present invention, however, are not limited to growth, inflammatory disease, rheumatoid arthritis, retinopa-
any particular mechanism or how the compounds achieve 15 thy, psoriasis, glomerulonephritis, asthma, chronic bronchi-
their therapeutic effect. By the term "kinase activity", it is tis, atherosclerosis, transplant rejection, conditions involving
meant a catalytic activity in which a gamma-phosphate from angiogenesis, etc.;
adenosine triphosphate (ATP) is transferred to an amino acid VEGFR-3 associated diseases include, e.g., cancer, cor-
residue (e.g., serine, threonine, or tyrosine) in a protein sub- neal disease, inflamed cornea (e.g., Hamrah, Am. J. Path.
strate. A compound can modulate kinase activity, e.g., inhib- 20 2003, 163, 57-68), corneal transplantation (Cursiefen et al.,
iting it by directly competing with ATP for the ATP-binding Cornea 2003, 22, 273-81 ), lymphatic hyperplasia, conditions
pocket of the kinase, by producing a conformational change involving lymphangiogenesis, etc.;
in the enzyme's structure that affects its activity (e.g., by PDGFR-beta associated diseases include, e.g., diseases or
disrupting the biologically-active three-dimensional struc- conditions characterized by cell proliferation, cell matrix pro-
ture), etc. 25 duction, cell movement, and/or extracellular matrix produc-
Kinase activity can be determined routinely using convention. Specific examples, include, e.g., tumors, malignancies,
tional assay methods. Kinase assays typically comprise the cancer, metastasis, chronic myeloid leukemia, inflammation,
kinase enzyme, substrates, buffers, and components of a renal disease, diabetic nephropathy, mesangial proliferative
detection system. A typical kinase assay involves the reaction glomerulonephritis, fibrotic conditions, atherosclerosis, res-
of a protein kinase with a peptide substrate and an ATP, such 30 tenosis, hypertension-related arteriosclerosis, venous bypass
as 32 P-ATP, to produce a phosphorylated end-product (for graft arteriosclerosis, scleroderma, interstitial pulmonary dis-
instance, a phosphoprotein when a peptide substrate is used). eases, synovial disorders, arthritis, leukemias, lymphomas,
The resulting end-product can be detected using any suitable etc;
method. When radioactive ATP is utilized, a radioactively Flt-3 associated diseases include, e.g., immune-related dis-
labeled phosphoprotein can be separated from the unreacted 35 orders, blood cell disorders, conditions involving hematopoi-
ganima- 32 P-ATP using an affinity membrane or gel electro- etic cell development (e.g., T-cells, B-cells, dendritic cells,
phoresis, and then visualized on the gel using autoradiogra- cancer, anemia, HIV, acquired immune deficiency syndrome,
phy or detected with a scintillation counter. Non-radioactive etc.
methods can also be used. Methods can utilize an antibody p38 associated diseases include inflammatory disorders,
which recognizes the phosphorylated substrate, e.g., an anti- 40 immunomodulatory disorders, and other disorders that have
phosphotyrosine antibody. For instance, kinase enzyme can been linked to abnormal cytokine production, especially
incubated with a substrate in the presence of ATP and kinase TNF-alpha, or abnormal MMP activity. These disorders
buffer under conditions which are effective for the enzyme to include, but are not limited to, rheumatoid arthritis, COPD,
phosphorylate the substrate. The reaction mixture can be osteoporosis, Crohn's disease and psoriasis.
separated, e.g., electrophoretically, and then phosphorylation 45 In addition, compounds of the present invention can be
of the substrate can be measured, e.g., by Western blotting used to treat conditions and disorders disclosed in U.S. Pat.
using an anti-phosphotyrosine antibody. The antibody can be No. 6,316,479, e.g., glomerular sclerosis, interstitial nephri-
labeled with a detectable label, e.g., an enzyme, such as HRP, tis, interstitial pulmonary fibrosis, atherosclerosis, wound
avidin or biotin, chemiluminescent reagents, etc. Other meth- scarring and scleroderma.
ods can utilize ELISA formats, affinity membrane separation, 50 The compounds of this invention also have a broad thera-
fluorescence polarization assays, luminescent assays, etc. peutic activity to treat or prevent the progression of a broad
An alternative to a radioactive format is time-resolved fluo- array of diseases, such as inflammatory conditions, coronary
rescence resonance energy transfer (TR-FRET). This method restenosis, tumor-associated angiogenesis, atherosclerosis,
follows the standard kinase reaction, where a substrate, e.g., autoimmune diseases, inflanimation, certain kidney diseases
biotinylated poly(GluTyr), is phosphorylated by a protein 55 associated with proliferation of glomerular or mesangial
kinase in the presence of ATP. The end-product can then cells, and ocular diseases associated with retinal vessel pro-
detected with a europium chelate phosphospecific antibody liferation. psoriasis, hepatic cirrhosis, diabetes, atherosclero-
(anti-phosphotyrosine or phosphoserine/threonine ), and sis, restenosis, vascular graft restenosis, in-stent stenosis,
streptavidin-APC, which binds the biotinylated substrate. angiogenesis, ocurlar diseases, pulmonary fibrosis, oblitera-
These two components are brought together spatially upon 60 tive bronchiolitis, glomerular nephritis, rheumatoid arthritis.
binding, and energy transfer from the phosphospecific anti- The present invention also provides for treating, prevent-
body to the acceptor (SA-APC) produces fluorescent readout ing, modulating, etc., one or more of the following conditions
in the homogeneous format. in humans and/or other mammals: retinopathy, including dia-
The compounds of the present invention can be used to betic retinopathy, ischemic retinal-vein occlusion, retinopa-
treat and/or prevent any disease or condition mediated by one 65 thy of prematurity and age related macular degeneration;
or more cellular signal transduction pathways involving raf, rheumatoid arthritis, psoriasis, or bullous disorder associated
VEGFR, PDGFR, p38, and/or flt-3 kinases. The term "treat- with subepidermal blister formation, including bullous pem-
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phigoid, erythema multiforme, or dermatitis herpetiformis, nodeficiency virus, parapoxvirus, protozoa, toxoplasmosis,
rheumatic fever, bone resorption, postmenopausal osteopero- and tumor-associated effusions and edema.
sis, sepsis, gram negative sepsis, septic shock, endotoxic The compounds of this invention can possess more than
shock, toxic shock syndrome, systemic inflammatory one of the mentioned activities, and therefore can target a
response syndrome, inflammatory bowel disease (Crohn's plurality of signal transduction pathways. Thus, these com-
disease and ulcerative colitis), Jarisch-Herxheimer reaction, pounds can achieve therapeutic and prophylactic effects
asthma, adult respiratory distress syndrome, acute pulmonary which normally are only obtained when using a combination
fibrotic disease, pulmonary sarcoidosis, allergic respiratory of different compounds. For instance, the ability to inhibit
disease, silicosis, coal worker's pneumoconiosis, alveolar both new vessel formation (e.g., associated with VEGFR-2
10 and VEGFR-3 function) (e.g., blood and/or lymph) and cell-
injury, hepatic failure, liver disease during acute inflamma-
proliferation (e.g., associated with raf and PDGFR-beta func-
tion, severe alcoholic hepatitis, malaria (Plasmodium falci-
tion) using a single compound is especially beneficial in the
parum malaria and cerebral malaria), non-insulin-dependent
treatment of cancer, and other cell-proliferation disorders that
diabetes mellitus (NIDDM), congestive heart failure, damage are facilitated by neo-vascularization. Thus, the present
following heart disease, atherosclerosis, Alzheimer's disease, 15 invention relates specifically to compounds which possess at
acute encephalitis, brain injury, multiple sclerosis (demyela- least anti-cell proliferation and anti-angiogenic (i.e., inhibits
tion and oligiodendrocyte loss in multiple sclerosis), angiogenesis) activity. Any disorder or condition that would
advanced cancer, lymphoid malignancy, pancreat1t1s, benefit from inhibiting vessel growth and cell proliferation
impaired wound healing in infection, inflammation and can- can be treated in accordance with the present invention. Using
cer, myelodysplastic syndromes, systemic lupus erythemato- 20 a single compound is also advantageous because its range of
sus, biliary cirrhosis, bowel necrosis, radiation injury/toxicity activities can be more precisely defined.
following administration of monoclonal antibodies, host-ver- As indicated above, the present invention relates to meth-
sus-graft reaction (ischemia reperfusion injury and allograft ods of treating and/or preventing diseases and conditions;
rejections of kidney, liver, heart, and skin), lung allograft and/or modulating one or more of the pathways, polypep-
rejection (obliterative bronchitis), or complications due to 25 tides, genes, diseases, conditions, etc., associated with raf,
total hip replacement, ad an infectious disease selected from VEG FR, PDGFR, p38, and/or flt-3. These methods generally
tuberculosis, Helicobacter pylori infection during peptic involve administering effective amounts of compounds of the
ulcer disease, Chaga's disease resulting from Trypanosoma present invention, where an effective amount is the quantity
cruzi infection, effects of Shiga-like toxin resulting from E. of the compound which is useful to achieve the desired result.
coli infection, effects of enterotoxinA resulting from Staphy- 30 Compounds can be administered in any effective form by any
lococcus infection, meningococcal infection, and infections effective route, as discussed in more detail below.
from Borrelia Burgdorferi, Treponema pallidum, cytomega- Methods include modulating tumor cell proliferation,
lovirus, influenza virus, Theiler's encephalomyelitis virus, including inhibiting cell proliferation. The latter indicates
and the human immunodeficiency virus (HIV), papilloma, that the growth and/or differentiation of tumor cells is
blastoglioma, Kaposi's sarcoma, melanoma, lung cancer, 35 reduced, decreased, diminished, slowed, etc. The term "pro-
ovarian cancer, prostate cancer, squamous cell carcinoma, liferation" includes any process which relates to cell growth
astrocytoma, head cancer, neck cancer, bladder cancer, breast and division, and includes differentiation and apoptosis. As
cancer, colorectal cancer, thyroid cancer, pancreatic cancer, discussed above, rafkinases play a key role in the activation
gastric cancer, hepatocellular carcinoma, leukemia, lym- of the cytoplasmic signaling cascade involved in cell prolif-
phoma, Hodgkin's disease, Burkitt's disease, arthritis, rheu- 40 eration, differentiation, and apoptosis. For example, studies
matoid arthritis, diabetic retinopathy, angiogenesis, resteno- have found that inhibiting c-raf by anti-sense oligonucle-
sis, in-stent restenosis, vascular graft restenosis, pulmonary otides can block cell proliferation (see above). Any amount of
fibrosis, hepatic cirrhosis, atherosclerosis, glomerulonophri- inhibition is considered therapeutic.
tis, diabetic nephropathy, thrombic micoangiopathy syn- Included in the methods of the present invention is a
dromes, transplant rejection, psoriasis, diabetes, wound heal- 45 method for using the compound described above (Compound
ing, inflammation, and neurodegenerative diseases. of Formula I), including salts, prodrugs, metabolites (oxi-
hyperimmune disorders, hemangioma, myocardial angiogen- dized derivatives) and compositions thereof, to treat mamma-
esis, coronary and cerebral collateral vascularization, lian hyper-proliferative disorders comprising administering
ischemia, corneal disease, rubeosis, neovascular glaucoma, to a mammal, including a human in need thereof, an amount
macular degeneration retinopathy of prematurity, wound 50 of a compound of this invention, pharmaceutically acceptable
healing, ulcer Helicobacter related diseases, fractures, salt, prodrug, metabolite (oxidized derivative), and composi-
endometriosis, a diabetic condition, cat scratch fever, thyroid tion thereof, which is effective to treat the disorder. Hyper-
hyperplasia, asthma or edema following burns, trauma, proliferative disorders include but are not limited to solid
chronic lung disease, stroke, polyps, cysts, synovitis, chronic tumors, such as cancers of the breast, respiratory tract, brain,
and allergic inflammation, ovarian hyperstimulation syn- 55 reproductive organs, digestive tract, urinary tract, eye, liver,
drome, pulmonary and cerebral edema, keloid, fibrosis, cir- skin, head and neck, thyroid, parathyroid and their distant
rhosis, carpal tunnel syndrome, adult respiratory distress syn- metastases. Those disorders also include lymphomas, sarco-
drome, ascites, an ocular condition, a cardiovascular mas, and leukemias.
condition, Crow-Fukase (POEMS) disease, Crohn's disease, Any tumor or cancer can be treated, including, but not
glomerulonophritis, osteoarthritis, multiple sclerosis, graft 60 limited to, cancers having one or more mutations in raf, ras,
rejection, Lyme disease, sepsis, von Hippe! Lindau disease, and/or flt-3, as well as any upstream or downstream member
pemphigoid, Paget's disease, polycystic kidney disease, sar- of the signaling pathways of which they are a part. As dis-
coidosis, throiditis, hyperviscosity syndrome, Osler-Weber- cussed earlier, a cancer can be treated with a compound of the
Rendu disease, chronic occlusive pulmonary disease, radia- present invention irrespective of the mechanism which is
tion, hypoxia, preeclampsia, menometrorrhagia, 65 responsible for it. Cancers of any organ can be treated, includ-
endometriosis, infection by Herpes simplex, ischemic retin- ing cancers of, but are not limited to, e.g., colon, pancreas,
opathy, corneal angiogenesis, Herpes Zoster, human immu- breast, prostate, bone, liver, kidney, lung, testes, skin, pan-
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creas, stomach, colorectal cancer, renal cell carcinoma, hepa- inflammation, etc. In addition, the increased blood supply
tocellular carcinoma, melanoma, etc. associated with cancerous and neoplastic tissue, encourages
Examples of breast cancer include, but are not limited to, growth, leading to rapid tumor enlargement and metastasis.
invasive ductal carcinoma, invasive lobular carcinoma, ductal Moreover, the growth of new blood and lymph vessels in a
carcinoma in situ, and lobular carcinoma in situ. tumor provides an escape route for renegade cells, encourag-
Examples of cancers of the respiratory tract include, but are ing metastasis and the consequence spread of the cancer.
not limited to, small-cell and non-small-cell lung carcinoma, Useful systems for measuring angiogenesis and/or lym-
as well as bronchial adenoma and pleuropulmonary blas- phangiogenesis, and inhibition thereof, include, e.g., neovas-
toma. cularization of tumor explants (e.g., U.S. Pat. Nos. 5,192,744;
Examples of brain cancers include, but are not limited to, 10 6,024,688), chicken chorioallantoic membrane (CAM) assay
brain stem and hypophtalmic glioma, cerebellar and cerebral (e.g., Taylor and Folkman, Nature 1982, 297, 307-312; Eli-
astrocytoma, medulloblastoma, ependymoma, as well as neu- ceiri et al., J. Cell Biol. 1998, 140, 1255-1263), bovine cap-
roectodermal and pineal tumor. illary endothelial (BCE) cell assay (e.g., U.S. Pat. No. 6,024,
Tumors of the male reproductive organs include, but are 688; Polverini, P. J. et al., Methods Enzymol. 1991, 198,
not limited to, prostate and testicular cancer. Tumors of the 15 440-450), migration assays, and HUVEC (human umbilical
female reproductive organs include, but are not limited to, cord vascular endothelial cell) growth inhibition assay (e.g.,
endometrial, cervical, ovarian, vaginal, and vulvar cancer, as U.S. Pat. No. 6,060,449), and use of the rabbit ear model (e.g.,
well as sarcoma of the uterus. Szuba et al., FASEB J. 2002, 16(14), 1985-7).
Tumors of the digestive tract include, but are not limited to, Modulation of angiogenesis can be determined by any
anal, colon, colorectal, esophageal, gallbladder, gastric, pan- 20 other method. For example, the degree of tissue vascularity is
creatic, rectal, small-intestine, and salivary gland cancers. typically determined by assessing the number and density of
Tumors of the urinary tract include, but are not limited to, vessels present in a given sample. For example, microvessel
bladder, penile, kidney, renal pelvis, ureter, and urethral can- density (MVD) can be estimated by counting the number of
cers. endothelial clusters in a high-power microscopic field, or
Eye cancers include, but are not limited to, intraocular 25 detecting a marker specific for microvascular endothelium or
melanoma and retinoblastoma. other markers of growing or established blood vessels, such
Examples of liver cancers include, but are not limited to, as CD31 (also known as platelet-endothelial cell adhesion
hepatocellular carcinoma (liver cell carcinomas with or with- molecule or PECAM). A CD31 antibody can be employed in
out fibrolamellar variant), cholangiocarcinoma (intrahepatic conventional immunohistological methods to immunostain
bile duct carcinoma), and mixed hepatocellular cholangiocar- 30 tissue sections as described by, e.g., U.S. Pat. No. 6,017,949;
cinoma. Dellas et al., Gyn. Oneal. 1997, 67, 27-33; and others. Other
Skin cancers include, but are not limited to, squamous cell markers for angiogenesis, include, e.g., Vezfl (e.g., Xiang et
carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel al., Dev. Bio. 1999, 206, 123-141), angiopoietin, Tie-1, and
cell skin cancer, and non-melanoma skin cancer. Tie-2 (e.g., Sato et al., Nature 1995, 376, 70-74).
Head-and-neck cancers include, but are not limited to, 35 Additionally, the present invention relates to methods of
laryngeal, hypopharyngeal, nasopharyngeal, and/or oropha- screening patients to determine their sensitivity to com-
ryngeal cancers, and lip and oral cavity cancer. pounds of the present invention. For example, the invention
Lymphomas include, but are not limited to, AIDS-related relates to methods of determining whether a condition can be
lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell modulated by a compound disclosed herein, comprising mea-
lymphoma, Hodgkin's disease, and lymphoma of the central 40 suring the expression or activity ofraf, VEGFR-2, VEGFR-3,
nervous system. PDGFR-beta, p38, and/or flt-3 in a sample comprising cells
Sarcomas include, but are not limited to, sarcoma of the or a cell extract, wherein said sample has been obtained from
soft tissue, osteosarcoma, malignant fibrous histiocytoma, a cell or subject having said condition. When the results of the
lymphosarcoma, and rhabdomyosarcoma. determination indicate that one or more of the mentioned
Leukemias include, but are not limited to, acute myeloid 45 genes (and/or polypeptides which they encode) differ from
leukemia, acute lymphoblastic leukemia, chronic lympho- the normal state, this identifies the condition as being treat-
cytic leukemia, chronic myelogenous leukemia, and hairy able with a compound of the present invention, i.e., whereby
cell leukemia. said disorder or condition can be modulated by the compound
In addition to inhibiting the proliferation of tumor cells, when said expression or activity is increased in said condition
compounds of the present invention can also cause tumor 50 as compared to a normal control. The method can further
regression, e.g., a decrease in the size of a tumor, or in the comprise a step of comparing the expression in a sample with
extent of cancer in the body. a normal control, or expression in a sample obtained from
The present invention also relates to methods of modulat- normal or unaffected tissue. Comparing can be done manu-
ing angiogenesis and/or lymphangiogenesis in a system com- ally, against a standard, in an electronic form (e.g., against a
prising cells, comprising administering to the system an 55 database), etc. The normal control can be a standard sample
effective amount of a compound described herein. A system that is provided with the assay; it can be obtained from adja-
comprising cells can be an in vivo system, such as a tumor in cent, but unaffected, tissue from the same patient; or, it can be
a patient, isolated organs, tissues, or cells, in vitro assays pre-determined values, etc. Gene expression, protein expres-
systems (CAM, BCE, etc), animal models (e.g., in vivo, sub- sion (e.g., abundance in a cell), protein activity (e.g., kinase
cutaneous, cancer models), hosts in need of treatment (e.g., 60 activity), etc., can be determined.
hosts suffering from diseases having angiogenic and/or lym- For instance, a biopsy from a cancer patient can be assayed
phangiogenic component, such as cancer), etc. for the presence, quantity, and/or activity of raf, VEGFR-2,
Inappropriate and ectopic expression of angiogenesis can VEGFR-3, PDGFR-beta, p38, and/or flt-3. Increased expres-
be deleterious to an organism. A number of pathological sion or activity of one or more of these can indicate that the
conditions are associated with the growth of extraneous blood 65 cancer can be targeted for treatment by a compound of the
vessels. These include, e.g., diabetic retinopathy, neovascular present invention. For example, as described in the examples
glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, below, raf activity can be monitored by its ability to initiate
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the cascade leading to ERK phosphorylation (i.e., raf/MEK/ Tyagi and Kramer, Nature Biotech., 14:303-309, 1996). Any
ERK), resulting in phospho-ERK. Increased phospho-ERK method suitable for single cell analysis of gene or protein
levels in a cancer specimen shows that its raf activity is expression can be used, including in situ hybridization,
elevated, suggesting the use of compounds of the present immunocytochemistry, MACS, FACS, flow cytometry, etc.
invention to treat it. 5 For single cell assays, expression products can be measured
Measuring expression includes determining or detecting using antibodies, PCR, or other types of nucleic acid ampli-
the amount of the polypeptide present in a cell or shed by it, fication (e.g., Brady et al., Methods Mal. & Cell. Biol. 1990,
as well as measuring the underlying mRNA, where the quan- 2, 17-25; Eberwine et al., Proc. Natl. Acad. Sci. 1992, 89,
tity of mRNA present is considered to reflect the quantity of 3010-3014; U.S. Pat. No. 5,723,290). These and other meth-
polypeptide manufactured by the cell. Furthermore, the genes 10 ods can be carried out conventionally, e.g., as described in the
forraf, VEGFR-2, VEGFR-3, PDGFR-beta,p38, and/orFlt-3 mentioned publications.
can be analyzed to determine whether there is a gene defect Activity of raf, VEGFR-2, VEGFR-3, PDGFR-beta, p38,
responsible for aberrant expression or polypeptide activity. and/or flt-3 can be assessed routinely, e.g., as described in the
Polypeptide detection can be carried out by any available examples below, or using standard assays for kinase activity.
method, e.g., by Western blots, ELISA, dot blot, immunopre- 15 The present invention also provides methods of assessing
cipitation, RIA, immunohistochemistry, etc. For instance, a the efficacy of a compound of the present invention in treating
tissue section can be prepared and labeled with a specific a disorder, comprising one or more of the following steps in
antibody (indirect or direct and visualized with a microscope. any effective order, e.g., administering an amount of a com-
Amount of a polypeptide can be quantitated without visual- pound, measuring the expression or activity of raf, VEGFR-2,
ization, e.g., by preparing a lysate of a sample ofinterest, and 20 VEGFR-3, PDGFR-beta, p38, and/or flt-3 (see above), deter-
then determining by ELISA or Western the amount of mining the effect of said compound on said expression or
polypeptide per quantity of tissue. Antibodies and other spe- activity. For instance, biopsy samples can be removed from
cific binding agents can be used. There is no limitation on how patients who have been treated with a compound of the
detection is performed. present invention, and then assayed for the presence and/or
Assays can be utilized which permit quantification and/or 25 activity of the mentioned signaling molecules. Similarly, as
presence/absence detection of a target nucleic acid (e.g., discussed above, decreases in the levels of phospho-ERK in
genes, mRNA, etc., for raf, VEGFR, PDGFR, p38, and/or the cancer tissue (e.g., compared to normal tissue or before
flt-3) in a sample. Assays can be performed at the single-cell treatment) indicate that the compound is exerting in vivo
level, or in a sample comprising many cells, where the assay efficacy and a therapeutic effect. The method can be used to
is "averaging" expression over the entire collection of cells 30 determine appropriate dosages and dosing regimens, e.g.,
and tissue present in the sample. Any suitable assay format how much compound to administer and at what frequency to
can be used, including, but not limited to, e.g., Southern blot administer it. By monitoring its effect on the signaling mol-
analysis, Northern blot analysis, polymerase chain reaction ecules in the tissue, the clinician can determine the appropri-
("PCR") (e.g., Saiki et al., Science 1988, 241, 53; U.S. Pat. ate treatment protocol and whether it is achieving the desired
Nos. 4,683,195, 4,683,202, and 6,040,166; PCR Protocols: A 35 effect, e.g., on modulating or inhibiting the signal transduc-
Guide to Methods and Applications, Innis et al., eds., Aca- tion pathway.
demic Press, New York, 1990), reverse transcriptase poly- Compounds of the present invention also can be used as
merase chain reaction ("RT-PCR"), anchored PCR, rapid markers to determine the presence and quantity of raf,
amplification of cDNA ends ("RACE") (e.g., Schaefer in VEGFR-2, VEGFR-3, PDGFR-beta, p38, and/or flt-3, in a
Gene Cloning and Analysis: Current Innovations, Pages 40 sample comprising a biological material. This comprises one
99-115, 1997), ligase chain reaction ("LCR") (EP 320 308), or more of the following steps in any effective order: (i)
one-sided PCR (Ohara et al., Proc. Natl. Acad Sci. 1989, 86, contacting said sample comprising a biological material with
5673-5677), indexing methods (e.g., U.S. Pat. No. 5,508, a compound of the present invention, and (ii) determining
169), in situ hybridization, differential display (e.g., Liang et whether said compound binds to said material. The com-
al., Nucl. Acid. Res. 1993, 21, 3269 3275; U.S. Pat. Nos. 45 pound can be labeled, or it can be used as a competitor to a
5,262,311, 5,599,672 and 5,965,409; WO97 /18454; Prashar labeled compound, such as labeled-ATP.
and Weissman, Proc. Natl. Acad. Sci., 93:659-663, and U.S. The invention also provides methods for treating, prevent-
Pat. Nos. 6,010,850 and 5,712,126; Welsh et al., Nucleic Acid ing, modulating, etc., diseases and conditions in manmials
Res., 20:4965-4970, 1992, and U.S. Pat. No. 5,487,985) and comprising administering a compound of this invention with
other RNA fingerprinting techniques, nucleic acid sequence 50 another modulator of the signal transduction pathway com-
based amplification ("NASBA") and other transcription prising, but not limited to raf, VEGFR, PDGFR, p38, and/or
based amplification systems (e.g., U.S. Pat. Nos. 5,409,818 flt-3. These can be present in the same composition or in
and 5,554,527; WO 88/10315), polynucleotide arrays (e.g., separate formulations or dosage units. Administration can be
U.S. Pat. Nos. 5,143,854, 5,424,186; 5,700,637, 5,874,219, the same or different routes, and can be simultaneous or
and 6,054,270; PCT WO 92/10092; PCT WO 90/15070), 55 sequential.
Qbeta Replicase (PCT/US87/00880), Strand Displacement The following publications relate to VEGFR-3 modulation
Amplification ("SDA"), Repair Chain Reaction ("RCR"), and are incorporated herein for their description of disease
nuclease protection assays, subtraction-based methods, states mediated by VEGFR-3 and assays to determine such
Rapid-Scan, etc. Additional useful methods include, but are activity.
not limited to, e.g., template-based amplification methods, 60
competitive PCR (e.g., U.S. Pat. No. 5,747,251), redox-based
assays (e.g., U.S. Pat. No. 5,871,918), Taqman-based assays
(e.g., Holland et al., Proc. Natl. Acad, Sci. 1991, 88, 7276- WO95/33772 Alitalo, et. al.
WO95/33050 Charnock-Jones, et. al..
7280; U.S. Pat. Nos. 5,210,015 and 5,994,063), real-time WO96/39421 Hu, et. al.
fluorescence-based monitoring (e.g., U.S. Pat. No. 5,928, 65 WO98/33917 Alitalo, et. al.
907), molecular energy transfer labels (e.g., U.S. Pat. Nos. WO02/057299 Alitalo, et. al.
5,348,853, 5,532,129, 5,565,322, 6,030,787, and 6,117,635;
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-continued -continued
WO02/060950 Alitalo, et. al. WO02/083704 Rosen, et. al.
WO02/081520 Boesen, et. al. WO02/081520 Boesen, et. al.
WO02/079498 Thomas, et. al.
WO02/070008 Rockwell, et. al.
The following publications relate to VEGFR-2 modulation WO09959636 Sato, et. al.
and are incorporated herein for their description of disease WO09946364 Cao, et. al.
WO09940118 Hanai, et. al.
states mediated by VEGFR-2 and assays to determine such WO9931238 Yabana, et. al.
activity. WO9929861 Klagsbrun, et. al.
10 WO9858053 Kendall, et. al.
WO9851344 Maini, et. al.
WO9833917 Alitalo, et. al.
WO9831794 Matswnoto, et. al.
EP0882799 Hanai, et. al.
WO9816551 Ferrara, et. al.
EP1167384 Ferrararn, et, al.
WO9813071 Kendall, et al.
EP1086705 Sato, et. al.
WO9811223 Martiny-Baron, et. al.
EP11300032 Tesar, et. al. 15
WO9744453 Chen, et. al.
WO9723510 Plouet, et. al.
WO9715662 Stinchcomb, et. al.
EPll 70017 Maini, et. al.
WO9708313 Ferrara, et. al.
EP1203827 Smitb
WO9623065 Smith, et. al.
20 WO9606641 Fleurbaaij, et. al.
The following publications relate to flt-3 modulation and WO9822316 Kyowa
are incorporated herein for their description of disease states WO9521868 Rockwell, et. al.
mediated by flt-3 and assays to determine such activity. WO02/060489 Xia, et. al.
PDGFR-beta
25
EP0869177 Matsui, et. al.
2002/0034517 Brasel, et. al. WO9737029 Matsui, et. al.
2002/0107365 Lyman, et. al. PDGFR-alpha
2002/0111475 Graddis, et. al.
EP0627487 Beckermann, et. al. EP1000617 Lammers, et. al.
30
WO9846750 Bauer, et. al. EP0869177 Matsui, et. al.
WO9818923 McWherter, et. al. EP0811685 Escobedo, et. al.
WO9428391 Beckermann, et al.
WO9426891 Birnbaum, et. al.
Pharmaceutical Compositions Based on the Compounds of
The following patents and publication relate to PDGF/ 35 the Present Invention
PDGFR modulation and are incorporated herein for their This invention also relates to pharmaceutical compositions
description of the disease states mediated by PDGFR-beta containing a compound of the present invention and pharma-
and assays to determine such activity. ceutically acceptable salts thereof. These compositions can
be utilized to achieve the desired pharmacological effect by
40 administration to a patient in need thereof. A patient, for the
purpose of this invention, is a mammal, including a human, in
5,094,941 Hart, et. al. need of treatment for the particular condition or disease.
5,371,205 Kelly, et. al. Therefore, the present invention includes pharmaceutical
5,418,135 Pang
5,444,151 Vassbotn, et. al.
compositions which are comprised of a pharmaceutically
5,468,468 LaRochelle, et. al. 45 acceptable carrier and a pharmaceutically effective amount of
5,567,584 Sledziewski, et. al. a compound, or salt thereof, of the present invention. The term
5,618,678 Kelly, et. al. "pharmaceutically acceptable carrier" is meant as any carrier
5,620,687 Hart, et. al.
5,648,076 Ross, et. al.
which is relatively non-toxic and innocuous to a patient at
5,668,264 Janjic, et. al. concentrations consistent with effective activity of the active
5,686,572 Wolf, et. al. 50 ingredient so that any side effects ascribable to the carrier do
5,817,310 Ramakrishnan, et. al. not vitiate the beneficial effects of the active ingredient. A
pharmaceutically effective amount of compound is that
5,872,218 Wolf, et. al. amount which produces a result or exerts an influence on the
5,882,644 Chang, et. al. particular condition being treated. The compound of the
5,891,652 Wolf, et. al. 55 present invention can be administered with pharmaceutically-
5,976,534 Hart, et. al.
5,990,141 Hirth, et. al.
acceptable carriers well known in the art using any effective
6,022,854 Shuman conventional dosage unit forms, including immediate, slow
6,043,211 Williams, et. al. and timed release preparations, orally, parenterally, topically,
6,110,737 Escobedo, et. al. nasally, ophthalmically, optically, sublingually, rectally, vagi-
6,207,816Bl Gold, et. al.
6,228,600Bl Matsui, et. al.
60 nally, and the like.
6,229,002Bl Janjic, et. al. For oral administration, the compound can be formulated
6,316,603Bl McTigue, et. al. into solid or liquid preparations such as capsules, pills, tab-
6,372,438Bl Williams, et. al. lets, troches, lozenges, melts, powders, solutions, suspen-
6,403,769Bl La Rochelle, et. al.
6,440,445Bl Nowak, et. al.
sions, or emulsions, and may be prepared according to meth-
6,475,782Bl Escobedo, et. al. 65 ods known to the art for the manufacture of pharmaceutical
WO02/083849 Rosen, et. al. compositions. The solid unit dosage forms can be a capsule
which can be of the ordinary hard- or soft-shelled gelatin type
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containing, for example, surfactants, lubricants, and inert fill- aqueous dextrose and related sugar solutions, an alcohol such
ers such as lactose, sucrose, calcium phosphate, and corn as ethanol, isopropanol, or hexadecyl alcohol, glycols such as
starch. propylene glycol or polyethylene glycol, glycerol ketals such
In another embodiment, the compounds of this invention as 2,2-dimethyl-1,1-dioxolane-4-methanol, ethers such as
may be tableted with conventional tablet bases such as lac- poly( ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester
tose, sucrose and cornstarch in combination with binders such or, a fatty acid glyceride, or an acetylated fatty acid glyceride,
as acacia, corn starch or gelatin, disintegrating agents with or without the addition of a pharmaceutically acceptable
intended to assist the break-up and dissolution of the tablet surfactant such as a soap or a detergent, suspending agent
following administration such as potato starch, alginic acid, such as pectin, carbomers, methycellulose, hydroxypropylm-
corn starch, and guar gum, gum tragacanth, acacia, lubricants 10 ethylcellulose, or carboxymethylcellulose, or emulsifying
intended to improve the flow of tablet granulation and to agent and other pharmaceutical adjuvants.
prevent the adhesion of tablet material to the surfaces of the Illustrative of oils which can be used in the parenteral
tablet dies and punches, for example talc, stearic acid, or formulations of this invention are those of petroleum, animal,
magnesium, calcium or zinc stearate, dyes, coloring agents, vegetable, or synthetic origin, for example, peanut oil, soy-
and flavoring agents such as peppermint, oil of wintergreen, 15 bean oil, sesame oil, cottonseed oil, corn oil, olive oil, petro-
or cherry flavoring, intended to enhance the aesthetic quali- latum and mineral oil. Suitable fatty acids include oleic acid,
ties of the tablets and make them more acceptable to the stearic acid, isostearic acid and myristic acid. Suitable fatty
patient. Suitable excipients for use in oral liquid dosage forms acid esters are, for example, ethyl oleate and isopropyl
include dicalcium phosphate and diluents such as water and myristate. Suitable soaps include fatty acid alkali metal,
alcohols, for example, ethanol, benzyl alcohol, and polyeth- 20 ammonium, and triethanolamine salts and suitable detergents
ylene alcohols, either with or without the addition of a phar- include cationic detergents, for example dimethyl dialkyl
maceutically acceptable surfactant, suspending agent or ammonium halides, alkyl pyridinium halides, and alkylamine
emulsifying agent. Various other materials may be present as acetates; anionic detergents, for example, alkyl, aryl, and
coatings or to otherwise modify the physical form of the olefin sulfonates, alkyl, olefin, ether, and mono glyceride sul-
dosage unit. For instance tablets, pills or capsules may be 25 fates, and sulfosuccinates; non-ionic detergents, for example,
coated with shellac, sugar or both. fatty amine oxides, fatty acid alkanolamides, and poly(oxy-
Dispersible powders and granules are suitable for the ethylene-oxypropylene)s or ethylene oxide or propylene
preparation of an aqueous suspension. They provide the oxide copolymers; and amphoteric detergents, for example,
active ingredient in admixture with a dispersing or wetting alkyl-beta-aminopropionates, and 2-alkylimidazoline quar-
agent, a suspending agent and one or more preservatives. 30 ternary ammonium salts, as well as mixtures.
Suitable dispersing or wetting agents and suspending agents The parenteral compositions of this invention will typically
are exemplified by those already mentioned above. Addi- contain from about 0.5% to about 25% by weight of the active
tional excipients, for example those sweetening, flavoring ingredient in solution. Preservatives and buffers may also be
and coloring agents described above, may also be present. used advantageously. In order to minimize or eliminate irri-
The pharmaceutical compositions of this invention may 35 tation at the site of injection, such compositions may contain
also be in the form of oil-in-water emulsions. The oily phase a non-ionic surfactant having a hydrophile-lipophile balance
may be a vegetable oil such as liquid paraffin or a mixture of (HLB) of from about 12 to about 17. The quantity of surfac-
vegetable oils. Suitable emulsifying agents may be (1) natu- tant in such formulation ranges from about 5% to about 15%
rally occurring gums such as gum acacia and gum tragacanth, by weight. The surfactant can be a single component having
(2) naturally occurring phosphatides such as soy bean and 40 the above HLB or can be a mixture of two or more compo-
lecithin, (3) esters or partial esters derived form fatty acids nents having the desired HLB.
and hexitol anhydrides, for example, sorbitanmonooleate, (4) Illustrative of surfactants used in parenteral formulations
condensation products of said partial esters with ethylene are the class of polyethylene sorbitan fatty acid esters, for
oxide, for example, polyoxyethylene sorbitan monooleate. example, sorbitan monooleate and the high molecular weight
The emulsions may also contain sweetening and flavoring 45 adducts of ethylene oxide with a hydrophobic base, formed
agents. by the condensation of propylene oxide with propylene gly-
Oily suspensions may be formulated by suspending the col.
active ingredient in a vegetable oil such as, for example, The pharmaceutical compositions may be in the form of
arachis oil, olive oil, sesame oil or coconut oil, or in a mineral sterile injectable aqueous suspensions. Such suspensions
oil such as liquid paraffin. The oily suspensions may contain 50 may be formulated according to known methods using suit-
a thickening agent such as, for example, beeswax, hard par- able dispersing or wetting agents and suspending agents such
affin, or cetyl alcohol. The suspensions may also contain one as, for example, sodium carboxymethylcellulose, methylcel-
or more preservatives, for example, ethyl or n-propyl p-hy- lulose, hydroxypropylmethyl-cellulose, sodium alginate,
droxybenzoate; one or more coloring agents; one or more gum tragacanth and gum acacia; dispersing or wetting agents
flavoring agents; and one or more sweetening agents such as 55 which may be a naturally occurring phosphatide such as
sucrose or saccharin. lecithin, a condensation product of an alkylene oxide with a
Syrups and elixirs may be formulated with sweetening fatty acid, for example, polyoxyethylene stearate, a conden-
agents such as, for example, glycerol, propylene glycol, sor- sation product of ethylene oxide with a long chain aliphatic
bitol or sucrose. Such formulations may also contain a demul- alcohol, for example, heptadeca-ethyleneoxycetanol, a con-
cent, and preservative, such as methyl and propyl parabens 60 densation product of ethylene oxide with a partial ester
and flavoring and coloring agents. derived form a fatty acid and a hexitol such as polyoxyethyl-
The compounds of this invention may also be administered ene sorbitol monooleate, or a condensation product of an
parenterally, that is, subcutaneously, intravenously, intraocu- ethylene oxide with a partial ester derived from a fatty acid
larly, intrasynovially, intramuscularly, or interperitoneally, as and a hexitol anhydride, for example polyoxyethylene sorbi-
injectable dosages of the compound in a physiologically 65 tan monooleate.
acceptable diluent with a pharmaceutical carrier which can be The sterile injectable preparation may also be a sterile
a sterile liquid or mixture of liquids such as water, saline, injectable solution or suspension in a non-toxic parenterally
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acceptable diluent or solvent. Diluents and solvents that may adsorbents (examples include but are not limited to pow-
be employed are, for example, water, Ringer's solution, iso- dered cellulose and activated charcoal);
tonic sodium chloride solutions and isotonic glucose solu- aerosol propellants (examples include but are not limited to
tions. In addition, sterile fixed oils are conventionally carbon dioxide, CCl F F CIC-CCIF and CCIF
2 2
,
2 2 3
)
employed as solvents or suspending media. For this purpose, air displacement agents (examples include but are not lim-
any bland, fixed oil may be employed including synthetic ited to nitrogen and argon);
mono- or diglycerides. In addition, fatty acids such as oleic antifungal preservatives (examples include but are not lim-
acid can be used in the preparation of injectables. ited to benzoic acid, butylparaben, ethylparaben, meth-
A composition of the invention may also be administered ylparaben, propylparaben, sodium benzoate);
10
in the form of suppositories for rectal administration of the antimicrobial preservatives (examples include but are not
drug. These compositions can be prepared by mixing the drug limited to benzalkonium chloride, benzethonium chlo-
with a suitable non-irritation excipient which is solid at ordi- ride, benzyl alcohol, cetylpyridinium chloride, chlo-
nary temperatures but liquid at the rectal temperature and will robutanol, phenol, phenylethyl alcohol, phenylmercuric
therefore melt in the rectum to release the drug. Such material 15
nitrate and thimerosal);
is, for example, cocoa butter and polyethylene glycol. antioxidants (examples include but are not limited to ascor-
Another formulation employed in the methods of the bic acid, ascorbyl palmitate, butylated hydroxyanisole,
present invention employs transdermal delivery devices butylatedhydroxytoluene, hypophosphorus acid, mono-
("patches"). Such transdermal patches may be used to pro- thioglycerol, propyl gallate, sodium ascorbate, sodium
vide continuous or discontinuous infusion of the compounds 20 bisulfite, sodium formaldehyde sulfoxylate, sodium
of the present invention in controlled amounts. The construc- meta bi sulfite);
tion and use of transdermal patches for the delivery of phar- binding materials (examples include but are not limited to
maceutical agents is well known in the art (see, e.g., U.S. Pat. block polymers, natural and synthetic rubber, polyacry-
No. 5,023,252, issued Jun. 11, 1991, incorporated herein by lates, polyurethanes, silicones, polysiloxanes and sty-
reference). Such patches may be constructed for continuous, 25 rene-butadiene copolymers);
pulsatile, or on demand delivery of pharmaceutical agents. buffering agents (examples include but are not limited to
Controlled release formulations for parenteral administra- potassium metaphosphate, dipotassium phosphate,
tion include liposomal, polymeric microsphere and poly- sodium acetate, sodium citrate anhydrous and sodium
meric gel formulations which are known in the art. citrate dihydrate)
It may be desirable or necessary to introduce the pharma- 30 carrying agents (examples include but are not limited to
ceutical composition to the patient via a mechanical delivery acacia syrup, aromatic syrup, aromatic elixir, cherry
device. The construction and use of mechanical delivery syrup, cocoa syrup, orange syrup, syrup, com oil, min-
devices for the delivery of pharmaceutical agents is well eral oil, peanut oil, sesame oil, bacteriostatic sodium
known in the art. Direct techniques for, for example, admin- chloride injection and bacteriostatic water for injection)
istering a drug directly to the brain usually involve placement 35 chelating agents (examples include but are not limited to
of a drug delivery catheter into the patient's ventricular sys- edetate disodium and edetic acid)
tem to bypass the blood-brain barrier. One such implantable colorants (examples include but are not limited to FD&C
delivery system, used for the transport of agents to specific Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6,
anatomical regions of the body, is described in U.S. Pat. No. FD&C Blue No. 2, D&C Green No. 5, D&C Orange No.
5,011,472, issuedApr. 30, 1991. 40 5, D&C Red No. 8, caramel and ferric oxide red);
The compositions of the invention can also contain other clarifying agents (examples include but are not limited to
conventional pharmaceutically acceptable compounding bentonite);
ingredients, generally referred to as carriers or diluents, as emulsifying agents (examples include but are not limited to
necessary or desired. Conventional procedures for preparing acacia, cetomacrogol, cetyl alcohol, glyceryl
such compositions in appropriate dosage forms can be uti- 45 monostearate, lecithin, sorbitan monooleate, polyoxy-
lized. Such ingredients and procedures include those ethylene 50 monostearate);
described in the following references, each of which is incor- encapsulating agents (examples include but are not limited
porated herein by reference: Powell, M. F. et al, "Compen- to gelatin and cellulose acetate phthalate)
dium ofExcipients for Parenteral Formulations" PDA Jour- flavorants (examples include but are not limited to anise
nal of Pharmaceutical Science & Technology 1998, 52(5), 50 oil, cinnamon oil, cocoa, menthol, orange oil, pepper-
238-311; Strickley, R. G "Parenteral Formulations of Small mint oil and vanillin);
Molecule Therapeutics Marketed in the United States (1999)- humectants (examples include but are not limited to glyc-
Part-1 "PDA Journal of Pharmaceutical Science & Technol- erol, propylene glycol and sorbitol);
ogy 1999, 53(6), 324-349; andNema, S. eta!, "Excipients and levigating agents (examples include but are not limited to
Their Use in Injectable Products" PDA Journal of Pharma- 55 mineral oil and glycerin);
ceutical Science & Technology 1997, 51(4), 166-171. oils (examples include but are not limited to arachis oil,
Commonly used pharmaceutical ingredients which can be mineral oil, olive oil, peanut oil, sesame oil and veg-
used as appropriate to formulate the composition for its etable oil);
intended route of administration include: ointment bases (examples include but are not limited to
acidifying agents (examples include but are not limited to 60 lanolin, hydrophilic ointment, polyethylene glycol oint-
acetic acid, citric acid, fumaric acid, hydrochloric acid, ment, petrolatum, hydrophilic petrolatum, white oint-
nitric acid); ment, yellow ointment, and rose water ointment);
alkalinizing agents (examples include but are not limited to penetration enhancers (transdermal delivery) (examples
ammonia solution, ammonium carbonate, diethanola- include but are not limited to monohydroxy or polyhy-
mine, monoethanolamine, potassium hydroxide, 65 droxy alcohols, mono-or polyvalent alcohols, saturated
sodium borate, sodium carbonate, sodium hydroxide, or unsaturated fatty alcohols, saturated or unsaturated
triethanolamine, trolamine ); fatty esters, saturated or unsaturated dicarboxylic acids,
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essential oils, phosphatidyl derivatives, cephalin, terpe- wetting agents (examples include but are not limited to
nes, amides, ethers, ketones and ureas) heptadecaethylene oxycetanol, lecithin, sorbitol
plasticizers (examples include but are not limited to diethyl monooleate, polyoxyethylene sorbitol monooleate, and
phthalate and glycerol); polyoxyethylene stearate ).
solvents (examples include but are not limited to ethanol, Pharmaceutical compositions according to the present
corn oil, cottonseed oil, glycerol, isopropanol, mineral invention can be illustrated as follows:
oil, oleic acid, peanut oil, purified water, water for injec- Sterile IV Solution: a 5 mg/mL solution of the desired com-
tion, sterile water for injection and sterile water for irri- pound of this invention is made using sterile, injectable water,
gation); and the pH is adjusted if necessary. The solution is diluted for
10 administration to 1-2 mg/mL with sterile 5% dextrose and is
stiffening agents (examples include but are not limited to
administered as an IV infusion over 60 minutes.
cetyl alcohol, cetyl esters wax, microcrystalline wax,
Lyophilized powder for IV administration: A sterile prepara-
paraffin, stearyl alcohol, white wax and yellow wax);
tion can be prepared with (i) 100-1000 mg of the desired
suppository bases (examples include but are not limited to compound of this invention as a lypholized powder, (ii)
cocoa butter and polyethylene glycols (mixtures)); 15 32-327 mg/mL sodium citrate, and (iii) 300-3000 mg Dextran
surfactants (examples include but are not limited to benza- 40. The formulation is reconstituted with sterile, injectable
lkonium chloride, nonoxynol 10, oxtoxynol 9, polysor- saline or dextrose 5% to a concentration of 10 to 20 mg/mL,
bate 80, sodium lauryl sulfate and sorbitan mono-palmi- which is further diluted with saline or dextrose 5% to 0.2-0.4
tate ); mg/mL, and is administered either IV bolus or by IV infusion
suspending agents (examples include but are not limited to 20 over 15-60 minutes.
agar, bentonite, carbomers, carboxymethylcellulose Intramuscular suspension: The following solution or suspen-
sodium, hydroxyethyl cellulose, hydroxypropyl cellu- sion can be prepared, for intramuscular injection:
lose, hydroxypropyl methylcellulose, kaolin, methylcel- 50 mg/mL of the desired, water-insoluble compound of
lulose, tragacanth and veegum); this invention
sweetening agents (examples include but are not limited to 25 5 mg/mL sodium carboxymethylcellulose
aspartame, dextrose, glycerol, mannitol, propylene gly- 4 mg/mL Tween 80
col, saccharin sodium, sorbitol and sucrose); 9 mg/mL sodium chloride
tablet anti-adherents (examples include but are not limited 9 mg/mL benzyl alcohol
to magnesium stearate and talc); Hard Shell Capsules: A large number of unit capsules are
tablet binders (examples include but are not limited to 30 prepared by filling standard two-piece hard galantine cap-
sules each with 100 mg of powdered active ingredient, 150
acacia, alginic acid, carboxymethylcellulose sodium,
mg of lactose, 50 mg of cellulose and 6 mg of magnesium
compressible sugar, ethylcellulose, gelatin, liquid glu-
stearate.
cose, methylcellulose, and pregelatinized starch);
Soft Gelatin Capsules: A mixture of active ingredient in a
tablet and capsule diluents (examples include but are not 35 digestible oil such as soybean oil, cottonseed oil or olive oil is
limited to dibasic calcium phosphate, kaolin, lactose, prepared and injected by means of a positive displacement
mannitol, microcrystalline cellulose, powdered cellu- pump into molten gelatin to form soft gelatin capsules con-
lose, precipitated calcium carbonate, sodium carbonate, taining 100 mg of the active ingredient. The capsules are
sodium phosphate, sorbitol and starch); washed and dried. The active ingredient can be dissolved in a
tablet coating agents (examples include but are not limited 40 mixture of polyethylene glycol, glycerin and sorbitol to pre-
to liquid glucose, hydroxyethyl cellulose, hydroxypro- pare a water miscible medicine mix.
pyl cellulose, hydroxypropyl methylcellulose, methyl- Tablets: A large number of tablets are prepared by conven-
cellulose, ethylcellulose, cellulose acetate phthalate and tional procedures so that the dosage unit was 100 mg of active
shellac); ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of mag-
tablet direct compression excipients (examples include but 45 nesium stearate, 275 mg of microcrystalline cellulose, 11 mg
are not limited to dibasic calcium phosphate); of starch, and 98.8 mg of lactose. Appropriate aqueous and
tablet disintegrants (examples include but are not limited to non-aqueous coatings may be applied to increase palatability,
alginic acid, carboxymethylcellulose calcium, microc- improve elegance and stability or delay absorption.
rystalline cellulose, polacrillin potassium, sodium algi- Immediate Release Tablets/Capsules: These are solid oral
nate, sodium starch glycollate and starch); 50 dosage forms made by conventional and novel processes.
tablet glidants (examples include but are not limited to These units are taken orally without water for immediate
colloidal silica, corn starch and talc); dissolution and delivery of the medication. The active ingre-
tablet lubricants (examples include but are not limited to dient is mixed in a liquid containing ingredient such as sugar,
calcium stearate, magnesium stearate, mineral oil, gelatin, pectin and sweeteners. These liquids are solidified
stearic acid and zinc stearate ); 55 into solid tablets or caplets by freeze drying and solid state
tablet/capsule opaquants (examples include but are not extraction techniques. The drug compounds may be com-
limited to titanium dioxide); pressed with viscoelastic and thermoelastic sugars and poly-
tablet polishing agents (examples include but are not lim- mers or effervescent components to produce porous matrices
ited to carnauba wax and white wax); intended for immediate release, without the need of water.
thickening agents (examples include but are not limited to 60 Dosage of the Pharmaceutical Compositions of the Present
beeswax, cetyl alcohol and paraffin); Invention
tonicity agents (examples include but are not limited to Based upon standard laboratory techniques known to
dextrose and sodium chloride); evaluate compounds useful for the treatment of any of the
viscosity increasing agents (examples include but are not aforementioned disorders, by standard toxicity tests and by
limited to alginic acid, bentonite, carbomers, carboxym- 65 standard pharmacological assays for the determination of
ethylcellulose sodium, methylcellulose, sodium algi- treatment of the conditions identified above in mammals, and
nate and tragacanth); and by comparison of these results with the results of known
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27 28
medicaments that are used to treat these conditions, the effec- Other cytotoxic drugs suitable for use with the compounds
tive dosage of the compounds of this invention can readily be of the invention include, but are not limited to, those com-
determined for treatment of each desired indication. The pounds acknowledged to be used in the treatment of neoplas-
amount of the active ingredient to be administered in the tic diseases in Goodman and Gilman 's The Pharmacological
treatment of one of these conditions can vary widely accord- 5 Basis of Therapeutics (Ninth Edition, 1996, McGraw-Hill).
ing to such considerations as the particular compound and These agents include, by no way of limitation, aminoglute-
dosage unit employed, the mode of administration, the period thimide, L-asparaginase, azathioprine, 5-azacytidine cladrib-
of treatment, the age and sex of the patient treated, and the ine, busulfan, diethylstilbestrol, 2', 2'-difluorodeoxycytidine,
nature and extent of the condition treated. docetaxel, erythrohydroxynonyladenine, ethinyl estradiol,
10 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophos-
The total amount of the active ingredient to be adminis-
phate, fludarabine phosphate, fluoxymesterone, flutamide,
tered can range from about 0.001 mg/kg to about 200 mg/kg,
hydroxyprogesterone caproate, idarubicin, interferon,
and preferably from about 0.1 mg/kg to about 50 mg/kg body
medroxyprogesterone acetate, megestrol acetate, melphalan,
weight per day. A unit dosage may preferably contain from mitotane, paclitaxel, pentostatin, N-phosphonoacetyl-L-as-
about 5 mg to about 4000 mg of active ingredient, and can be 15 partate (PALA), plicamycin, semustine, teniposide, testoster-
administered one or more times per day. The daily dosage for one propionate, thiotepa, trimethylmelamine, uridine, and
oral administration will preferably be from 0.1 to 50 mg/kg of vinorelbine.
total body weight. The daily dosage for administration by Other cytotoxic anti-cancer agents suitable for use in com-
injection, including intravenous, intramuscular, subcutane- bination with the compounds of the invention also include
ous and parenteral injections, and use of infusion techniques 20 newly discovered cytotoxic principles such as oxaliplatin,
will preferably be from 0.1 to 10 mg/kg of total body weight. gemcitabine, capecitabine, epothilone and its natural or syn-
The daily rectal dosage regimen will preferably be from 0.1 to thetic derivatives, temozolomide (Quinn et al., J. Clin. Oncol-
50 mg/kg of total body weight. The daily vaginal dosage ogy 2003, 21(4), 646-651), tositumomab (Bexxar), trabedec-
regimen will preferably be from 0.1 to 50 mg/kg of total body tin (Vidal et al., Proceedings of the American Society for
weight. The daily topical dosage regimen will preferably be 25 Clinical Oncology 2004, 23, abstract 3181 ), and the inhibitors
from 0.1 to 10 mg/kg administered between one to four times of the kinesin spindle protein Eg5 (Wood et al., Curr. Opin.
daily. The transdermal concentration will preferably be that Pharmacol. 2001, 1, 370-377).
required to maintain a daily dose of from O.1 to 10 mg/kg. The In another embodiment, the compounds of the present
daily inhalation dosage regimen will preferably be from 0.1 to invention can be combined with other signal transduction
10 mg/kg of total body weight. Other dosages and amounts 30 inhibitors. Of particular interest are signal transduction
can be selected routinely. inhibitors which target the EGFR family, such as EGFR,
The specific initial and continuing dosage regimen for each HER-2, and HER-4 (Raymond et al., Drugs 2000, 60
patient will vary according to the nature and severity of the (Suppl.1), 15-23; Harari et al., Oncogene 2000, 19 (53), 6102-
condition as determined by the attending diagnostician, the 6114), and their respective ligands. Examples of such agents
activity of the specific compound employed, the age and 35 include, by no way of limitation, antibody therapies such as
general condition of the patient, time of administration, route Herceptin (trastuzumab ), Erbitux (cetuximab ), and pertu-
of administration, rate of excretion of the drug, drug combi- zumab. Examples of such therapies also include, by no way of
nations, and the like. The desired mode of treatment and limitation, small-molecule kinase inhibitors such as
number of doses of a compound of the present invention or a ZD-1839/Iressa (Baselga et al., Drugs 2000, 60 (Suppl. 1),
pharmaceutically acceptable salt or ester or composition 40 33-40), OSI-774/Tarceva (Pollack et al. J. Pharm. Exp. Ther.
thereof can be ascertained by those skilled in the art using 1999, 291(2), 739-748), CI-1033 (Bridges, Curr. Med. Chem.
conventional treatment tests. 1999, 6, 825-843), GW-2016 (Lackey eta!., 92nd AACRMeet-
Combination of the Compounds and Compositions of the ing, New Orleans, Mar. 24-28, 2001, abstract 4582), CP-724,
Present Invention with Additional Active Ingredients 714 (Jani et al., Proceedings of the American Society for
Compounds of this invention can be administered as the 45 Clinical Oncology 2004, 23, abstract 3122), HKI-272
sole pharmaceutical agent or in combination with one or more (Rabindran et al., Cancer Res. 2004, 64, 3958-3965), and
other pharmaceutical agents where the combination causes EKB-569 (Greenberger et al., 11th NCI-EORTC-AACR Sym-
no unacceptable adverse effects. This may be of particular posium on New Drugs in Cancer Therapy, Amsterdam,
relevance for the treatment of hyper-proliferative diseases November 7-10, 2000, abstract 388).
such as cancer. In this instance, the compound of this inven- 50 In another embodiment, the compounds of the present
tion can be combined with known cytotoxic agents, signal invention can be combined with other signal transduction
transduction inhibitors, or with other anti-cancer agents, as inhibitors targeting receptor kinases of the split-kinase
well as with admixtures and combinations thereof. domain families (VEGFR, FGFR, PDGFR, flt-3, c-kit, c-fms,
In one embodiment, the compounds of the present inven- and the like), and their respective ligands. These agents
tion can be combined with cytotoxic anti-cancer agents. 55 include, by no way of limitation, antibodies such as Avastin
Examples of such agents can be found in the 11th Edition of (bevacizumab ). These agents also include, by no way oflimi-
the Merck Index (1996). These agents include, by no way of tation, small-molecule inhibitors such as STI-571/Gleevec
limitation, asparaginase, bleomycin, carboplatin, carmustine, (Zvelebil, Curr. Opin. Oneal., Endocr. Metab. Invest. Drugs
chlorambucil, cisplatin, colaspase, cyclophosphamide, cyt- 2000, 2(1), 74-82), PTK-787 (Wood et al., Cancer Res. 2000,
arabine, dacarbazine, dactinomycin, daunorubicin, doxoru- 60 60(8), 2178-2189), SU-11248 (Demetri et al., Proceedings of
bicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, the American Society for Clinical Oncology 2004, 23,
hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, abstract 3001 ), ZD-64 74 (Hennequin et al., 92nd AACR Meet-
leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, ing, New Orleans, Mar. 24-28, 2001, abstract 3152),
mesna, methotrexate, mitomycin C, mitoxantrone, predniso- AG-13736 (Herbst et al., Clin. Cancer Res. 2003, 9, 16 (suppl
lone, prednisone, procarbazine, raloxifen, streptozocin, 65 1), abstract C253), KRN-951 (Taguchi et al., 95th AACR
tamoxifen, thioguanine, topotecan, vinblastine, vincristine, Meeting, Orlando, Fla., 2004, abstract 2575), CP-547,632
and vindesine. (Beebe et al., Cancer Res. 2003, 63, 7301-7309), CP-673,451
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(Roberts et al., Proceedings of the American Association of
Cancer Research 2004, 45, abstract 3989), CHIR-258 (Lee et
al., Proceedings of the American Association of Cancer HPLC high pressure liquid chromatography
Research 2004, 45, abstract 2130), MLN-518 (Shen et al.,
MS mass spectrometry
Blood 2003, 102, 11, abstract476), andAZD-2171 (Henne- 5
quin et al., Proceedings of the American Association of Can- ES electrospray
cer Research 2004, 45, abstract 4539). DMSO dimethylsulfoxide

In another embodiment, the compounds of the present MP melting point
invention can be combined with inhibitors of the Raf/MEK/ NMR nuclear resonance spectroscopy
10
ERK transduction pathway (Avruch et al., Recent Prag. TLC thin layer chromatography
Harm. Res. 2001, 56, 127-155), or the PKB (akt) pathway rt room temperature
(Lawlor et al., J. Cell Sci. 2001, 114, 2903-2910). These
include, by no way of limitation, PD-325901 (Sebolt-Le-
opold et al., Proceedings of the American Association of 15 Preparation of 4-amino-3-fluorophenol
Cancer Research 2004, 45, abstract 4003), and ARRY-
142886 (Wallace et al., Proceedings of the American Asso-
ciation of Cancer Research 2004, 45, abstract 3891).
In another embodiment, the compounds of the present
invention can be combined with inhibitors ofhistone deacety- 20
lase. Examples of such agents include, by no way of limita-
tion, suberoylanilide hydroxamic acid (SAHA), LAQ-824
(Ottmann et al., Proceedings of the American Society for
Clinical Oncology 2004, 23, abstract 3024), LBH-589 (Beck
et al., Proceedings of the American Society for Clinical 25
Oncology 2004, 23, abstract 3025), MS-275 (Ryan et al.,
Proceedings of the American Association of Cancer Research To a dry flask purged with Argon was added 10% Pd/C (80
2004, 45, abstract 2452), and FR-901228 (Piekarz et al., mg) followed by 3-fluoro-4-nitrophenol (1.2 g, 7.64 mmol) as
Proceedings of the American Society for Clinical Oncology a solution in ethyl acetate (40 mL). The mixture was stirred
30
2004, 23, abstract 3028). under an H2 atmosphere for 4 h. The mixture was filtered
In another embodiment, the compounds of the present through a pad of Celite and the solvent was evaporated under
invention can be combined with other anti-cancer agents such reduced pressure to afford the desired product as a tan solid
as proteasome inhibitors, and m-TOR inhibitors. These (940 mg, 7.39 mmol; 97% yield); 1 H-NMR (DMSO-d 6 ) 4.38
include, by no way oflimitation, bortezomib (Mackay et al., 35 (s, 2H), 6.29-6.35 (m, lH), 6.41 (dd, J=2.5, 12.7, lH), 6.52-
Proceedings of the American Society for Clinical Oncology 6.62 (m, lH), 8.76 (s, lH).
2004, 23, Abstract 3109), and CCI-779 (Wu et al., Proceed- Preparation of 4-( 4-amino-3-fluorophenoxy)pyridine-2-car-
ings of the American Association of Cancer Research 2004, boxylic acid methylamide
45, abstract 3849).
Generally, the use of cytotoxic and/or cytostatic anti-can- 40
cer agent in combination with a compound or composition of
the present invention for the treatment of cancer will serve to:
(1) yield better efficacy in reducing the growth of a tumor
or even eliminate the tumor as compared to administration of
either agent alone, 45
(2) provide for the administration oflesser amounts of the
administered chemotherapeutic agents,
(3) provide for a chemotherapeutic treatment that is well
tolerated in the patient with fewer deleterious pharmacologi-
50 A solution of 4-amino-3-fluorophenol (500 mg, 3.9 mmol)
cal complications than observed with single agent chemo-
therapies and certain other combined therapies, in N,N-dimethylacetamide (6 mL) cooled to 0° C. was treated
(4) provide for treating a broader spectrum of different with potassium tert-butoxide (441 mg, 3.9 mmol), and the
cancer types in mammals, especially humans, brown solution was allowed to stir at 0° C. for 25 min. To the
(5) provide for a higher response rate among treated mixture was added 4-chloro-N-methy 1-2-pyridinecarboxam-
55
patients, ide (516 mg, 3.0 mmol) as a solution in dimethylacetamide (4
(6) provide for a longer survival time among treated mL ). The reaction was heated at 100° C. for 16 h. The mixture
patients compared to standard chemotherapy treatments, was cooled to room temperature, quenched with H2 O (20
(7) provide a longer time for tumor progression, and/or mL), and extracted with ehtylacetate (4x40 mL). The com-
(8) yield efficacy and tolerability results at least as good as 60
bined organics were washed with H2 O (2x30 mL), dried
those of the agents used alone, compared to known instances (MgSO 4 ), and evaporated to afford a red-brown oil. 1H-NMR
where other cancer agent combinations produce antagonistic indicated the presence of residual dimethylacetamide, thus
effects. the oil was taken up in diethylether (50 mL) and was further
washed with brine (5x30 mL). The organic layer was dried
EXAMPLES 65 (MgSO 4) and concentrated to give 950 mg of the desired
product as a red-brown solid, which was used in the next step
Abbreviations used in this specification are as follows: without purification.
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A method of preparing 4-chloro-N-methyl-2-pyridinecar- Example 3
boxamide is described in Bankston et al., Org. Proc. Res. Dev.
2002, 6(6), 777-781. Preparation of 4{ 4-[3-( 4-chloro-3-trifluorometh-
y !phenyl )-ureido ]-3-fluorophenoxy }-pyridine-2-
Example 1 carboxylic acid methylamide mesylate
Preparation of 4{ 4-[3-( 4-chloro-3-trifluorometh- The compound of example 1 as a free base (2.25 g) was
dissolved in ethanol (100 mL) and a stock solution ofmeth-
y !phenyl )-ureido ]-3-fluorophenoxy }-pyridine-2- anesulfonic acid (excess) was added. The solution was then
carboxy lic acid methylamide concentrated in vacuo to afford a yellow oil. Ethanol was
10
added and concentration repeated, affording 2.41 g of off-
white solids. The crude salt was dissolved in hot ethanol
(-125 mL) and then cooled slowly to crystallize. After reach-
ing room temperature, the flask was placed in a freezer over-
night. The colorless crystalline material was collected by
15 suction filtration; the filter cake was washed with ethanol,
then hexane and air-dried, to afford 2.05 g of material, which
was dried in a vacuum oven at 60° C. overnight.
Melting point: 231 ° C.
Elemental analysis:
20
To a solution of 4-(4-amino-3-fluorophenoxy)pyridine-2-
carboxylic acidmethylamide (177 mg, 0.68 mmol) in toluene Calcd. Found
(3 mL) was added 4-chloro-3-(trifluoromethyl)phenyl isocy-
C 45.64 45.34
anate (150 mg, 0.68 mmol). The mixture was stirred at rt for 25 3.31 3.08
H
72 h. The reaction was concentrated under reduced pressure N 9.68 9.44
and the residue was triturated with diethylether. The resulting Cl 6.12 6.08
solid was collected by filtration and dried in vacuo for 4 h to F 13.13 13.42
afford the title compound (155 mg, 0.32 mmol; 47% yield);
s 5.54 5.59
1
H-NMR (DMSO-d 6 ) 2.78 (d, J=4.9, 3H), 7.03-7.08 (m, lH), 30
7.16 (dd, J=2.6, 5.6, lH), 7.32 (dd, J=2.7, 11.6, lH), 7.39 (d,
J=2.5, lH), 7.60 (s, 2H), 8.07-8.18 (m, 2H), 8.50 (d, J=5.7, Example 4
lH), 8.72 (s, lH), 8.74-8.80 (m, lH), 9.50 (s, lH); MS
(HPLC/ES) 483.06 m/z=(M+l). Preparation of 4{ 4-[3-( 4-chloro-3-trifluorometh-
y !phenyl )-ureido ]-3-fluorophenoxy }-pyridine-2-
35
Example 2 carboxy lic acid methylamide phenylsulfonate
Preparation of 4{ 4-[3-( 4-chloro-3-trifluorometh- The compound of example 1 as a free base (2.25 g) was
y !phenyl )-ureido ]-3-fluorophenoxy }-pyridine-2- suspended in ethanol (50 mL) and benzensulfonic acid (0.737
carboxy lic acid methylamide hydrochloride g) in ethanol (50 mL) was added. The mixture was heated
40
with vigorous stirring. All solid material dissolved to give a
The compound of example 1 as a free base (2.0 g) was reddish solution. The solution was allowed to cool to room
dissolved in anhydrous tetrahydrofuran (15 mL) and a 4M temperature and the flask scratched. Crystal formation was
HCl/dioxane was added (excess). The solution was then con- difficult to achieve, some seeds were found, added to solution
centrated in vacuo to afford 2.32 grams of off-white solids. and placed in freezer overnight. Grayish-tan solids had
45
The crude salt was dissolved in hot ethanol (125 mL), acti- formed in the flask; the material was broken up & collected by
vated carbon was added and the mixture heated at reflux for suction filtration. The solids were washed with ethanol, then
15 minutes. The hot suspension was filtered through a pad of hexane and air-dried. Weighed product: 2.05 g, 69% yield.
Celite 521 and allowed to cool to room temperature. The flask Melting point: 213° C.
was placed in a freezer overnight. The crystalline solids were Elemental Analysis:
50
collected by suction filtration, washed with ethanol, then
hexane and air-dried. The mother liquors were concentrated
down and crystallization (in freezer) allowed taking place
Calcd. Found
overnight. A second crop of solids was collected and com-
bined with the first crop. The colorless salt was dried in a 55
C 50.59 50.24
vacuum oven at 60° C. over two days. Yield of hydrochloride H 3.30 3.50
salt obtained 1.72 g (79%). N 8.74 8.54
F 11.86 11.79
Melting point: 215° C. Cl 5.53 5.63
Elemental analysis: s 5.00 5.16
60
Calcd. Found
C 48.57 48.68 Example 5

H 3.11 2.76
N 10.79 10.60
Cl 13.65 13.63
c-raf (raf-1) Biochemical Assay
F 14.63 14.88 65
The c-raf biochemical assay was performed with a c-raf
enzyme that was activated (phosphorylated) by Lek kinase.
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Lek-activated c-raf (Lck/c-raf) was produced in Sf9 insect concentration range from 5 nM to 2.5 µM. The kinase assay
cells by co-infecting cells with baculoviruses expressing, was initiated by addition of 25 µL of an ATP cocktail to give
under the control of the polyhedrin promoter, GST-c-raf a final concentration of 10 µM cold ATP and 0.2 µCi [gamma-
(from amino acid 302 to amino acid 648) and Lek (full- 33
P] ATP per well (200-400 dpm/pmol of ATP). The plate was
length). Both baculoviruses were used at the multiplicity of 5 incubated at 32° C. for 35 min., and the reaction quenched
infection of 2.5 and the cells were harvested 48 h post infec- with 7 µL of a 1 N aq HCl solution. The samples were
tion. harvested onto a P30 Filtermat (Wallac, Inc.) using a TomTee
MEK-1 protein was produced in Sf9 insect cells by infect- 1295 Harvester (Wallac, Inc.), and counted in a LKB 1205
ing cells with the baculovirus expressing GST-MEK-1 (full- Betaplate Liquid Scintillation Counter (Wallac, Inc.). Nega-
length) fusion protein at the multiplicity of infection of 5 and 10
tive controls included substrate plus ATP alone. SW1353
harvesting the cells 48 hours post infection. Similar purifica-
cellular assay: SW1353 cells (human chondro-sarcoma) are
tion procedure was used for GST-c-raf 302-648 and GST-
seeded (1000 cells/100 µL DMEM 10% PCS/well) into
MEK-1. Transfected cells were suspended at 100 mg of wet
cell biomass per mL in a buffer containing 10 mM sodium 96-well plates and incubated overnight. After medium
phosphate, 140 mM sodium chloride pH 7.3, 0.5% Triton 15
replacement, cells are exposed to test compounds for 1 h at
X-100 and the protease inhibitor cocktail. The cells were 37° C., at which time human IL-1 (1 ng/mL, Endogen,
disrupted with Polytron homogenizer and centrifuged 30,000 Woburn, Wash.) and recombinant human TNFalpha (10
g for 30 minutes. The 30,000 g supernatant was applied onto ng/mL) are added. Cultures are incubated for 48 hat 37° C.,
GSH-Sepharose. The resin was washed with a buffer contain- then supernatant IL-6 values are determined by ELISA. The
ing 50 mM Tris, pH 8.0, 150 mM NaCl and 0.01% Triton 20 compound of this invention shows significant inhibition of
X-100. The GST-tagged proteins were eluted with a solution p38 kinase.
containing 100 mM Glutathione, 50 mM Tris, pH 8.0, 150
mM NaCl and 0.01 % Triton X-100. The purified proteins Example 7
were dialyzed into a buffer containing 20 mM Tris, pH 7.5,
150 mM NaCl and 20% Glycerol. 25 Bio-Plex Phospho-ERK ½ immunoassay.
Test compounds were serially diluted in DMSO using
three-fold dilutions to stock concentrations ranging typically A 96 well pERK immunoassay, using laser flow cytometry
from 50 µM to 20 nM (final concentrations in the assay range (Bio-Rad) platform has been established to measure inhibi-
from 1 µM to 0.4 nM). The c-Raf biochemical assay was tion of basal pERK in breast cancer cell line. MDA-MB-231
performed as a radioactive filtermat assay in 96-well Costar 30 cells were plated at 50,000 cells per well in 96 well microtitre
polypropylene plates (Costar 3365). The plates were loaded plates in complete growth media. For effects of test com-
with 75 µL solution containing 50 mM HEPES pH 7.5, 70 pounds on basal pERK½ inhibition, the next day after plat-
mM NaCl, 80 ng ofLck/c-rafand 1 µg MEK-1. Subsequently, ing, MDA-MB-231 cells were transferred to DMEM with
2 µL of the serially diluted individual compounds were added 0.1 % BSA and incubated with test compounds diluted 1:3 to
to the reaction, prior to the addition of ATP. The reaction was 35 a final concentration of3 µM to 12 nM in 0.1 % DMSO. Cells
initiated with 25 µL ATP solution containing 5 µM ATP and were incubated with test compounds for 2 h, washed, and
0.3 µCi [33P]-ATP. The plates were sealed and incubated at lysed in Bio-Plex whole cell lysis buffer A. Samples are
32° C. for 1 h. The reaction was quenched with the addition of diluted with buffer B 1:1 (v/v) and directly transferred to
50 µL of 4% Phosphoric Acid and harvested onto P30 filter- assay plate or frozen at -80 C. degrees until processed. 50 µL
mats (PerkinElmer) using a Wallac Tomtec Harvester. Filter- 40 of diluted MDA-MB-231 cell lysates were incubated with
mats were washed with 1% Phosphoric Acid first and dein- about 2000 of 5 micron Bio-Plex beads conjugated with an
onized H2 0 second. The filters were dried in a microwave, anti-ERK½ antibody overnight on a shaker at room tempera-
soaked in scintillation fluid and read in a Wallac 1205 Beta- ture. The next day, biotinylated phospho-ERK½ sandwich
plate Counter (Wallac Inc., Atlanta, Ga., U.S.A.). The results immunoassay was performed, beads are washed 3 times dur-
were expressed as percent inhibition. 45 ing each incubation and then 50 µL of PE-strepavidin was
used as a developing reagent. The relative fluorescence units
% Inhibition~[l00-(Ta/T,)]xl00 where
of pERK ½ were detected by counting 25 beads with Bio-Plex
flow cell (probe) at high sensitivity. The IC50 was calculated
T,b~(counts per minute with inhibitor)-(background)
by taking untreated cells as maximum and no cells (beads
50 only) as background using in an Excel spreadsheet based
r,~(counts per minute without inhibitor)-(back- program. The compound of this invention shows significant
ground)
inhibition in this assay.
The compound of the present invention shows potent inhi-
bition ofrafkinase in this assay. Example 8
55
Example 6 Flk-1 (murine VEGFR-2) Biochemical Assay
p38 kinase in vitro assay This assay was performed in 96-well opaque plates (Costar
3915) in the TR-FRET format. Reaction conditions are as
Purified and His-tagged p38 a2 (expressed in E. Coli) was 60 follows: 10 µMATP, 25 nM poly GT-biotin, 2 nM Eu-labelled
activated in vitro by MMK-6 to a high specific activity.Using phospho-Tyr Ab, 10 nMAPC, 7 nM Flk-1 (kinase domain),
a microtiter format, all reactions were conducted in 100 µL 1% DMSO, 50 mM HEPES pH 7.5, 10 mM MgC12 , 0.1 mM
volumes with reagents diluted to yield 0.05 µg/well of acti- EDTA, 0.015%BRIJ, 0.1 mg/mL BSA, 0.1 %mercapto-etha-
vated p38 a2 and 10 µg/well ofmyelin basic protein in assay nol). Reaction is initiated upon addition of enzyme. Final
buffer (25 mM HEPES 7.4, 20 mM MgC12 , 150 mM NaCl). 65 reaction volume in each well is 100 µL. Plates are read at both
Test compounds (5 µL of a 10% DMSO solution in water) 615 and 665 nM on a Perkin Elmer Victor V Multilabel
were prepared and diluted into the assay to cover a final counterat about 1.5-2.0 hours after reaction initiation. Signal
IITRUE COPY!I
US 8,637,553 B2
35 36
is calculated as a ratio: (665 nm/615 nm)*l0000 for each T 72h test=ATP dependent luminescence at 72 hours in
well. The compound of this invention shows significant inhi- the presence oftest compound
bition ofVEGFR2 kinase.
T 72h ctrFATP dependent luminescence at 72 hours in
Example 9 the absence of test compound
Murine PDGFR FRET biochemical assay

T Oh=ATP dependent luminescence at Time Zero
This assay was formatted in a 96-well black plate (Costar The compound of this invention shows significant inhibi-
3915). The following reagents are used: Europium-labeled 10 tion of proliferation using this assay.
anti-phosphotyrosine antibody pY20 (Perand streptavidin-
APC; poly GT-biotin from, and mouse PDGFR. The reaction
conditions are as follows: 1 nM mouse PDGFR is combined Example 11
with 20 µM ATP, 7 nM poly GT-biotin, 1 nM pY20 antibody,
5 nM streptavidin-APC, and 1% DMSO in assay buffer (50 15
mMHEPESpH7.5, 10mMMgC1 2 , 0.1 mMEDTA, 0.015% pPDGFR-beta sandwich ELISA inAoSMC cells
BRIJ 35, 0.1 mg/mL BSA, 0.1 % mercaptoethanol). Reaction
is initiated upon addition of enzyme. Final reaction volume in 100K P3-P6 Aortic SMC were plated in each well of
each well is 100 µL. After 90 minutes, the reaction is stopped 12-well cluster in 1000 µL volume/well of SGM-2 using
by addition of 10 µL/well of 5 µM staurosporine. Plates are 20 standard cell culture techniques. Next day, cells were rinsed
read at both 615 and 665 nm on a Perkin Elmer VictorV with 1000 µL D-PBS once, then serum starved in 500 µL
Multilabel counter at about 1 hour after the reaction is SBM (smooth muscle cell basal media) with 0.1% BSA over-
stopped. Signal is calculated as a ratio: (665 nm/615 night. Compounds were diluted at a dose range from (10 µM
nm)* 10000 for each well. The compound of this invention to 1 nM in 10-fold dilution steps in DMSO. Final DMSO
shows significant inhibition of PDGFR kinase. 25 concentration 0 .1%) . Remove old media by inversion into the
For IC50 generation for both PDGFR and Flk-1, com- sink quickly then add 100 µL of each dilution to correspond-
pounds were added prior to the enzyme initiation. A 50-fold ing well of cells for 1 hat 37° C. Cells were then stimulated
stock plate was made with compounds serially diluted 1:3 in with 10 ng/mL PDGF-BB ligand for 7 min at 37° C. The
a 50% DMSO/50% dH2O solution. A 2 µL addition of the media is decanted and 150 µL of isotonic lysis buffer with
stock to the assay gave final compound concentrations rang- 30 protease inhibitor tablet (Complete; EDTA-free) and 0.2 mM
ing from 10 µM-4.56 nM in 1% DMSO. The data were Na vanadate is added. Cells are lysed for 15 min at 4° C. on
expressed as percent inhibition: % inhibition=l00-((Signal shaker in cold room. Lysates are put in eppendorf tubes to
with inhibitor-background)/(Signal without inhibitor-back- which 15 µL of agarose-conjugated anti-PDGFR-beta anti-
ground))* 100 body is added and incubated at 4° C. overnight. Next day,
35 beads are rinsed in SO-volumes of PBS three times and boiled
Example 10 in lxLDS sample buffer for 5 minutes. Samples were run on
3-8% gradient Tris-Acetate gels and transferred onto Nitro-
MDA-MB231 proliferation assay cellulose. Membranes were blocked in 1% BSA/TBS-T for 1
hr. before incubation in anti-phospho-PDGFR-b (Tyr-857)
Human breast carcinoma cells (MDA MB-231, NCI) were 40 antibody in blocking buffer (1:1000 dilution) for 1 h. After
cultured in standard growth medium (DMEM) supplemented three washes in TBS-T, membranes were incubated in Goat
with 10% heat-inactivated FBS at 37° C. in 5% CO 2 (vol/vol) anti-rabbit HRP IgG (1 :25000 dilution) for 1 hr. Three more
in a humidified incubator. Cells were plated at a density of washes followed before addition of ECL substrate. Mem-
3000 cells per well in 90 µL growth medium in a 96 well branes were exposed to Hyperfilm-ECL. Subsequently, mem-
culture dish. In order to determine Toh CTG values, 24 hours 45 branes were stripped and reprobed with anti-PDGFR-beta
after plating, 100 µL of CellTiter-Glo Luminescent Reagent antibody for total PDGFR-beta.
(Promega) was added to each well and incubated at room
Table 1 illustrates the results of in vitro kinase biochemical
temperature for 30 minutes. Luminescence was recorded on a
assays for p38 kinase, PDGFR kinase and VEGFR2 kinase.
Wallac Victor II instrument. The CellTiter-Glo reagent results
These three kinase targets are all involved in stroma activation
in cell lysis and generation of a luminescent signal propor- 50 and endothelial cell proliferation, leading to angiogenesis,
tional to the amount of ATP present, which, in tum is directly
and providing blood supply to the tumor tissue.
proportional to the number of cells present.
Test compounds are dissolved in 100% DMSO to prepare
10 mM stocks. Stocks were further diluted 1:400 in growth TABLE 1
medium to yield working stocks of 25 µM test compound in 55 mPDGFR mVEGFR2 p38
0.25% DMSO. Test compounds were serially diluted in IC50,nM IC50,nM IC50,nM
growth medium containing 0.25% DMSO to maintain con-
Example 1 83 5.5 24
stant DMSO concentrations for all wells. 60 µL of diluted test
compound were added to each culture well to give a final
volume of 180 µL. The cells with and without individual test 60 Table 2 illustrates the results of two cellular assays for raf
compounds were incubated for 72 hours at which time ATP kinase activity, which are (i) inhibition of pERK in MDA-
dependent luminescence was measured, as described previ- MB231 cells, a mechanistic readout of rafkinase activity, and
ously, to yield Tnh values. Optionally, the IC 50 values can be (ii) a proliferation assay ofMDA-MB231 cells, a functional
determined with a least squares analysis program using com- assay of rafkinase activity. In addition, Table 2 illustrates the
pound concentration versus percent inhibition. 65 results of PDGFR driven phosphorylation of PDGFR-beta in
% lnhibition~[l-(T 72 h ,,,,-T 0h)/(Tnh curToh)]xl00, aortic smooth muscle cells, which is a mechanistic readout of
where PDGFR kinase inhibition.
IITRUE COPY!I
US 8,637,553 B2
37 38
TABLE2 2. A pharmaceutically acceptable salt of a compound of
Formula I
pERKin cells
(MDA-MB- Proliferation pPDGFR
231) (MDA-MB-231) (AoSMC)
IC50,nM IC50,nM IC50,nM (I)
Example 1 22 600 43.6
Overall, compounds of the present invention provide a

unique combination of inhibition of angiogenesis and tumor
cell proliferation. They also possess an improved inhibition
profile against several key kinase targets such as raf, p38,
PDGFR, and VEGFR-2, which are all molecular targets of
interest for the treatment of osteoporosis, inflammatory dis- which is a basic salt of an organic acid or inorganic acid which
eases, and hyper-proliferative diseases, including cancer. 15 is hydrochloric acid, hydrobromic acid, sulfuric acid, phos-
It is believed that one skilled in the art, using the preceding phoric acid, methanesulfonic acid, trifluoromethanesulfonic
information and information available in the art, can utilize acid, benzenesulfonic acid, p-toluene sulfonic acid (tosylate
the present invention to its fullest extent. It should be apparent salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid,
to one of ordinary skill in the art that changes and modifica- acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric
tions can be made to this invention without departing from the 20 acid, lactic acid, oxalic acid, succinic acid, fumaric acid,
spirit or scope of the invention as it is set forth herein. All maleic acid, benzoic acid, salicylic acid, phenylacetic acid, or
publications, applications and patents cited above and below mandelic acid.
are incorporated herein by reference. 3. A compound which is 4{4-[3-( 4-chloro-3-trifluorom-
The topic headings set forth above and below are meant as ethy !phenyl )-ureido ]-3-fluorophenoxy }-pyridine-2-car-
guidance where certain information can be found in the appli- 25 boxy lic acid methylamide, or a pharmaceutically acceptable
cation, but are not intended to be the only source in the salt thereof.
application where information on such topic can be found. 4. A pharmaceutically acceptable salt of a compound of
Without further elaboration, it is believed that one skilled claim 3 which is a basic salt of an organic acid or inorganic
in the art can, using the preceding description, utilize the acid which is hydrochloric acid, hydrobromic acid, sulfuric
present invention to its fullest extent. The preceding preferred 30 acid, phosphoric acid, methanesulfonic acid, trifluo-
specific embodiments are, therefore, to be construed as romethanesulfonic acid, benzenesulfonic acid, p-toluene sul-
merely illustrative, and not !imitative of the remainder of the fonic acid (tosylate salt), 1-napthalene sulfonic acid,
disclosure in any way whatsoever. 2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid,
In the foregoing and in the examples, all temperatures are malic acid, tartaric acid, citric acid, lactic acid, oxalic acid,
set forth uncorrected in degrees Celsius and, all parts and 35 succinic acid, fumaric acid, maleic acid, benzoic acid, sali-
percentages are by weight, unless otherwise indicated. cylic acid, phenylacetic acid, or mandelic acid.
The entire disclosures of all applications, patents and pub- 5. A compound which is a hydrochloride, benzene-
lications, cited herein and of corresponding U.S. Provisional sulfonate, or methanesulfonate salt ofN-( 4-chloro-3-(trifluo-
Application Ser. No. 60/489,102, filed Jul. 23, 2003 and U.S. romethyl )phenyl)- N'-2-fluoro-( 4-(2-(N-methylcarbamoy 1)-
Provisional Application Ser. No. 60/540,326 filed Feb. 2, 40 4-pyridyloxy )phenyl) urea.
2004 are incorporated by reference herein. 6. A pharmaceutical composition comprising a compound
The preceding examples can be repeated with similar suc- of claim 1 and a physiologically acceptable carrier.
cess by substituting the generically or specifically described 7. A pharmaceutical composition comprising a compound
reactants and/or operating conditions of this invention for of claim 2 and a physiologically acceptable carrier.
those used in the preceding examples. 45 8. A pharmaceutical composition comprising a compound
From the foregoing description, one skilled in the art can of claim 3 and a physiologically acceptable carrier.
easily ascertain the essential characteristics of this invention 9. A pharmaceutical composition which comprises a phar-
and, without departing from the spirit and scope thereof, can maceutically acceptable salt of N-(4-chloro-3-(trifluorom-
make various changes and modifications of the invention to ethyl)phenyl)-N'-2-fluoro-(4-(2-(N-methylcarbamoyl)-4-
adapt it to various usages and conditions. 50 pyridyloxy)phenyl) urea and a physiologically acceptable
carrier.
The invention claimed is: 10. A compound which is a metabolite of the compound of
1. A compound of Formula (I) or a pharmaceutically Formula (I) or a pharmaceutically acceptable salt thereof, or
acceptable salt thereof, or an isolated stereoisomer of a phar- an isolated stereoisomer of a pharmaceutically acceptable salt
maceutically acceptable salt thereof 55 thereof,
(I) (I)
IITRUE COPY!I
US 8,637,553 B2
39 40
where the metabolism site is either one of the two urea nitro- 4{4-[3-( 4-chloro-3-trifluoromethylphenyl)-ureido ]-3-
gen atoms, or the pyridine nitrogen atom, or the methylamide fluorophenoxy }-l-hydroxy-pyridine-2-carboxylic acid
functionality, or any combination of the above. amide.
11. A compound of which is a metabolite of the compound
of Formula (I), 13. A compound of Formula (I)
(I)
(I)
where 14. A pharmaceutical composition comprising the com-

a) either urea nitrogen atom carries a hydroxyl group, or pound of claim 13 and a physiologically acceptable carrier.
b) the pyridine nitrogen atom is oxidized, or
15. A salt of a compound of Formula (I)
c) the amide functionality is de-methylated, or 20
d) the pyridine nitrogen atom is oxidized and the amide
functionality is de-methylated, or
(I)
e) either urea nitrogen atom carries a hydroxyl group and
the pyridine nitrogen atom is oxidized, or
f) either urea nitrogen atom carries a hydroxyl group and 25
the amide functionality is de-methylated, or
g) either urea nitrogen atom carries a hydroxyl group and
the pyridine nitrogen atom is oxidized and the amide
functionality is de-methylated.
12. A compound which is: 30
4{4-[3-( 4-chloro-3-trifluoromethylphenyl)-ureido ]-3-
fluorophenoxy }-pyridine-2-carboxylic acid amide,
16. A pharmaceutical composition comprising a salt of
4{4-[3-( 4-chloro-3-trifluoromethylphenyl)-ureido ]-3-
fluorophenoxy }-l-hydroxy-pyridine-2-carboxylic acid claim 15 and a physiologically acceptable carrier.
methylamide, or * * * * *
IITRUE COPY!I
UNITED STATES PATENT AND TRADEMARK OFFICE
CERTIFICATE OF CORRECTION
PATENT NO. : 8,637,553 B2 Page 1 of 1
APPLICATION NO. : 10/895985
DATED : January 28, 2014
INVENTOR(S) : Boyer et al.
It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:
On the Title Page:
The first or sole Notice should read --
Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b)
by 2400 days.
Signed and Sealed this

Sixteenth Day of June, 2015
Michelle K. Lee
Director of the United States Patent and Trademark Office
IITRUE COPY!I
I~O!'la
Government of India
..
c)I!!:.
PROPERTY
•AN:HTSI
~
INOIA
OE$.tGNSl1'AAOt
MAAU
GlOGMPt-lC>J.
ltC>K:AIIOK$
Application Detalls
Application Details
APPLICATION NUMBER 1628/DELNP/2009
APPLICATION TYPE PCT NATIONAL PHASE APPLICATION
DATE OF FILING 12/03/2009
APPLICANT NAME BAYER HEALTHCARE

MYER HEALTHCARE LLC
L1C
TITLE OF INVENTION "4-[4-({ [4-CHLORO-3-(TRIFLUOROMETHYL)PHENYL)]CARBAMOYL}
AMINO)-3-FLUOROPHENOXY]-N-METHYLPYRIDINE-2-CARBOXAMIDE
MONOHYDRATE"
FIELD OF INVENTION PHARMACEUTICALS
E-MAIL (As Per Record)
ADDITIONAL-EMAIL (As Per Record) remfry-sagar@remfry.com
E-MAIL (UPDATED Online) mail@perfexiolegal.com
PCT INTERNATIONAL APPLICATION PCT/EP2007/008503

NUMBER
PCT INTERNATIONAL FILING DATE 29/09/2007
PRIORITY DATE 11/10/2006
REQUEST FOR EXAMINATION DATE 05/10/2010
PUBLICATION DATE (U/S 11A) 22/05/2009
REPLY TO FER DATE 19/01/2015
Application SU1US
ApphcaUon Status
APPLICATION STATUS Application in

Appllcatfon in Hearing
Hearlng
(filtJE c~l
[ View Examination Report(s) View Documents
.. ..
➨ Filed ➨ Published ➨ RQ Filed ➨ Under Examination
- ..
➨ Disposed ..
In case of any discrepancy in status, kindly contact ipo-helpdesk@nic.in
FORM 1 Application No:
THE PATENTS ACT, 1970 Filing date:
[39 OF 1970] Amount of Fee paid:
&
THE PATENTS (AMENDMENT)
CBR No.
Signature:
/½~--
RULES, 2006
APPLICATION FOR GRANT OF 12 MAR
2009
PATENT
[See Sections 7, 135 and rule
(qo2-
20 (1) l
t'l••AU
1. APPLICANT (S) )
I ~ 1-1n1, 2009
Name Nationality Address

BAYER SCHERING PHARMA a German of Mullerstrasse 178, 13353 Berlin,
AKTIENGESELLSCHAFT, company, Germany,
2. INVENTOR (S)

ALFONS GRUNENBERG, a German of Gneisenaustrasse 15, 41539
citizen, Dormagen, Germany,
JUERGEN STIEHL, a German of Rosenstrasse 28, 45549
citizen, Sprockhovel, Germany,
KATHARINA TENBIEG, a German of Busenbergstrasse 103, 44269
citizen, Dortmund, Germany,
BIRGIT KEIL, a German of Sudetenstrasse 36, 40231
citizen, Dusseldorf, Germany,
3. TITLE OF THE INVENTION
"4-[4-({ [4-CHLORO-3-(TRIFLUOROMETHYL)PHENYL)]CARBAMOYL} AMINO)-3-
FLUOROPHENOXY]-N-METHYLPYRIDINE-2-CARBOXAMIDE MONOHYDRATE"
4. ADDRESS FOR CORRESPONDENCE OF APPLICANT/
AUTHORISED PATENT AGENT IN INDIA
REMFRY & SAGAR

Attorneys-at-Law
Remfry House
Millennium Plaza
Telefax No. 91-124-280 6101
5. PRIORITY PARTICULARS OF THE APPLICATION (S) FILED IN

CONVENTION COUNTRY
-....J
~ountry Application Filing Date Name of the Title of the invention
Number applicant
EP 06021296.6 11.10.2006 BAYER "4-[4-({ [4-CHLORO-3-
SCHERING (TRIFLUOROMETHYL)PH
PHARMA ENYL)]CARBAMOYL}
AKTIENGESEL AMINO)-3-
LSCHAFT, FLUOROPHENOXY]-N-
METHYLPYRIDINE-2-
CARBOXAMIDE
IITRUE COPYjl
MONOHYDRATE"
6. PARTICULARS FOR FILING PATENT COOPERATION TREATY (PCT)
NATIONALPHASE APPLICATION
PCT/EP2007 /008503 29.09.2007
7. DECLARATIONS:
i) Declaration by the applicant(s):
1 am/we are in possession of the above-mentioned invention
The complete specification relating to the invention is filed with this
application.
There is no lawful ground of objection to the grant of the Patent to
me/us.
The application or each o the applications, particulars of which are
given in Para 5 was the first application in convention
country/ countries in respect of my/ our invention.
I/we claim the priority from the above mentioned application(s) filed
in convention country/ countries and state that no application for
protection in respect of the invention had been made in a convention
country before that date by me/us or by any person from which I/we
derive the title.
My/ our application in India is based on International application
under Patent Coo eration Trea PCT as mentioned in Para-6.
(a) Complete specification in conformation with the International
application/ as amended before the International Preliminary Examination
Authority (IPEA), as applicable (2 copies), No. of pages 41 No. of claims 17.
[b] Drawing(s) in conformation with the international application/ as amended
before the International Preliminary Examination Authority (IPEA), as
applicable (2 copies), No. of sheets (7).
[c] Statement and undertaking on Form 3
[d] Declaration of inventorship on Form 5
[e] Fee Rs. 14000 /- by cheque
I/We hereby declare that to the best of my/our knowledge, information and belief
the fact and matters stated herein are correct and I/we request that a patent may
be granted to me/us for the said invention.
BAYER SCHERING
DHURY)
& SAGAR
ICANT[S)

IITRUE COPYjl
ORIGINAL
FORMl
(FOR OFFICE USE ONLY)
THE PATENTS ACT, 1970 I
Application No.:
(39 of 1970)
& Filing Date:
THE PA TENTS RULES, 2003 Amount of Fee Paid:
APPLICATION FOR GRANT OF
CBRNo: \1\\\\\\\11\\\41\\1\
\11111
000004846
PATENT Signature:
[Seesections 7, 54 & 135 and rule 20(1)] i
1. APPLICANT(S)
NAME NATIONALITY ADDRESS
BAYER SCHERING PHARMA German of Miillerstrasse 178, 13353 Berlin,
AKTIENGESELLSCHAFT Germany,
2. XNVENTOR(S)

GRUNENBERG, Alfons German Gneisenaustrasse 15, 41539 Dormagen,
Germany
STIEHL, Juergen German Rosenstrasse 28, 45549 Sprockhovel,
Germany
TENBIEG, Katharina German Busenbergstrasse 103, 44269 Dortmund,
Germany
KEIL, Birgit German Sudetenstrasse 36, 40231 Otisseldorf,
Germany
3. TITLE OF THE INVENTION: "4-[4-({[4-CHLORO-3-
(TRIFLUOROMETHYL)PHENYL)]CARBAMOYL}AMINO)-3-FLUOROPHENOXY]-N-
METHYLPYRIDINE-2-CARBOXAMIDE MONOHYDRA TE"
4. ADDRESS FOR CORRESPONDENCE OF APPLICANT/AUTHORIZED PATENT AGENT
IN INDIA
PERFEXIO LEGAL
Attorneys-At-Law
9655, Sector-C, Pocket-9
VasantKunj
New Delhi- 110 070 India
.. Telephone No. +91-120-434-3600/ +91-11-41767656
l.Vj:obile
No.: +91-9810404749
Telefax No.: +91-120-434-3643
Email: mail@oerfexioleQ"al.com
5. PRIORITY PARTICULARS OF THE APPLICATION(S) FILED IN CONVENTION
COUNTRY:
Country Application Filing Date Name of the Title of the Invention
Number Applicant :
Europe 06021296.6 October 11, BAYER "4-[{-( {[4-CHLORO-3-

2006 PHARMA (TRIFLUOROMETHYL)PHEN .
.. . ., . .
IITRUE COPY!I
AKTIENGESELL YL)]CARBAMOYL}AMINO)-3-
SCHAFT FLUOROPHENOXY]-N-
(formerly known METHYLPYRIDINE-2-
as BAYER CARBOXAMIDE
SCHERING MONOHYDRATE"
PHARMA
AKTIENGESELL
SCHAFT)
6. PARTICULARS FOR FILING PATENT COOPERATION TREATY(PCT) NATIONAL
PHASE APPLICATION:
International Application No. International filing date as allotted by the receiving office
PCT/ EP2007/ 008503 September 29, 2007

7. PARTICULARS FOR FILING DIVISIONAL APPLICATION:
Original (first) application number Date of filing of Original (first) application

I
Not applicable
8. PARTICULARS FOR FILING PATENT OF ADDITION:
Main application/Patent Number Date of filing of main application

I
~
Not applicable
9. DECLARATIONS:
I
(i) Declaration by the true and first inventor(s):
1/-We, GRUNENBERG, Alfons, a German citizen, of Gneisenaustrasse 15, 41539 Dormagen,

Germany; STIEHL, Juergen, a German citizen, of Rosenstrasse 28, 45549 Sprockhovel, Germany;
TENBIEG, Katharina, a German citizen, of Busenbcrgstrasse 103, 44269 Dorhnund, Germany and
KEIL, Birgit, a German citizen, of Sudetenstrasse 36, 40231 Diisseldorf, Germany the above
named inventor(s) is-fare the true and first inventor(s) for this invention and declare that the
applicant BAYER SCHERING PHARMA AKTIENGESELLSCHAFT, a German company, of
Miillerstrasse 178, 13353 Berlin Germany, is our assignee.
Date: J.o)'i-Jl -,19

Signature: ~~~~P1/, ri)f~J
ltRUNENBERG9 AlionU STIEHL, Juergen
TENBIEG, Katharina KEIL, Birgit
-··.TPO flEEnI-c-cl~-9--"0:-:r:::=z:0-i"s=cc IS'~ 2"~:C---
IITRUE COPYII
(iii) Declaration by the applicantts)
the applicantts) hereby declare(s) that:-
"If-We,
!ZII--am-fWe are in possession of the above-mentioned invention.
!ZIThe complete specification relating to the invention is filed with this application.
IZIThere is no lawful ground of objection to the grant of patent to mefus.
IZIThe application or each of applications, particulars of which are given in Para. 5 was the
first application in the convention country / countries in respect of my/-our invention.
IZ!l--amf-We claim the priority from the above-mentioned applicationW filed in convention
country/countries and state that no application for protection in respect of the invention
had been made in a convention country before that date by mefus or by any person from
which If-we derive the title.
IZIMyf Our application is based on International application under Patent Cooperation Treaty
(PCT) as mentioned in Para-6.
10. FOLLOWING ARE THE ATTACHMENTS WITH THE APPLICATION:
a. Complete Specification (in conformation with the international application/as amended
before the IPEA), as applicable (2-copies); No of pages: 41; No of Claims: 17;
b. Drawings (in conformation with the international application /as amended before the
Il2EA), as applicable (2-copies); No of sheets: 7;
c. Form PCT/IB/304;
d. Statement and undertaking on Form-3(in duplicate);
e. Declaration as to inventorship on Form-5(in duplicate); and
f. Officialfee Rs. 14000/- by Cheque.
If-We hereby declare that to the best of my/-our knowledge, information and belief the fact and
matters stated herein are correct and If we request that a patent may be granted to mefus for the
said invention.
Dated this day 6f March, 2009
BAYER SCHERING PHARMA AKTIEN~FT
(SAi:J KUMAR)
ATENTAGENT
, F PERFEXIO LEGAL
ATTORNEYS FOR THE APPLICANT
To,
The Controller of Patents
The Patent Office at DELHI
==~:ir.m::r-;;o;-::
O:~~Rr;::'"'~ii~~e~/c:c:;eOZ!- S:;. rs: ·~ _;.l-:~:':-·' ••• •
&--
~ TRUE COPYII
'
?--~-'}
FORMl
Application No.:
(39 of 1970)
& Filing Date:
CBRNo:
PATENT Signature:
[See sections 7, 54 & 135 and rule 20(1)]
1. APPLICANT(S)
BAYER SCHERING PHARMA German of Miillerstrasse 178, 13353 Berlin,
2. INVENTOR(S)

Germany
Germany
Germany
KEIL, Birgit German Sudetenstrasse 36, 40231 Diisseldorf,
Germany
3. TITLE OF THE INVENTION: "4-[4-({[4-CHLOR0-3-
(TRIFLUOROMETHYL)PHENYL)]CARBAMOYL}AMIN0)-3-FLUOROPHENOXY]-N-
METHYLPYRIDINE-2-CARBOXAMIDE MONOHYDRATE"
IN INDIA
PF.RFf.XJOLEGAL
Attorneys-At-Law
VasantKunj
..../ .. Telephone No. +91-120-434-3600/+91-11-41767656
Mobile No.: +91-9810404749
Telefax No.: +91-120-434-3643
Email: mail@oerfexiole2:al.com
COUNTRY:
Number Applicant
Europe 06021296.6 October 11, BAYER "4-[4-({[4-CHLOR0-3-
2006 PHARMA (TRIFLUOROMETHYL)PHEN
-:r=po~-=DcoE"cnJ[-1. 9"=---"e=-r_:=---2-=-01c:5
1=5c:cc:-2·3-=·
-
:i/1{-
{}//if.! tcF/;11
IITRUE COPY!I
AKTIENGESELL YL)]CARBAMOYL}AMINO)-3-
PHARMA
AKTIENGESELL
SCHAFT)
PHASE APPLICATION:
PCT/ EP2007/ 008503 September 29, 2007


I
Not applicable

I
Not applicable
9. DECLARATIONS:
(i) Declaration by the true and first inventor(s):
If-We, GRUNENBERG, Alfons, a German citizen, of Gneisenaustrasse 15, 41539 Dormagen,

Germany; STIEHL, Juergen, a German citizen, of Rosenstrasse 28, 45549 Sprockhovel, Germany;
TENBIEG, Katharina, a German citizen, of BusP.nbergstrasse 103, 44269 Dortmund, Germany and
KEIL, Birgit, a German citizen, of Sudetenstrasse 36, 40231 Dtisseldorf, Germany the above
named inventor(s) isfare the true and first inventor(s) for this invention and declare that the
Mtillerstrasse 178, 13353 Berlin Germany, is our assignee.
Date:
Si~ature: ~:Af- ~\j

GRUNENBERG, Alfons ~TI.EHL, Juerf~n
3,<gfl;cL,{
IITRUE COPY!I
....----------------------------------- ----- --- - -- --
(iii) Declaration by the applicantts}

J/We, the applicantts} hereby declare(s) that:-
[gl I-am-fWe are in possession of the above-mentioned invention.
[gl The complete specification relating to the invention is filed with this application.
[gl There is no lawful ground of objection to the grant of patent to mef us.
[gl The application or each of applications, particulars of which are given in Para. 5 was the
first application in the convention country / cot¼fltriesin respect of myfour invention.
[gl !--amf-We claim the priority from the above-mentioned applicationts} filed in convention
country/cmm.tries and state that no application for protection in respect of the invention
had been made in a convention country before that date by mef us or by any person from
[gl Myf Our application is based on International application under Patent Cooperation Treaty
a. Complete Specification (in conformation with the international application/as amended
b. Drawings (in conformation with the international application /as amended before the
WEA), as applicable (2-copies); No of sheets: 7;
c. Form PCT/IB/304;
e. Declaration as to inventorship on Form-S(in duplicate); and
ff-We hereby declare that to the best of myfour knowledge, information and belief the fact and
matters stated herein are correct and 1/-we request that a patent may be granted to mef us for the
said invention.
Dated this 12th day of March, 2009
BAYER SCHERING PHARMA AKTIEN~ISCHAFT
(S AYKUMAR)
PATENT AGENT
OF PERFEXIO LEGAL
To,
IITRUE COP511
' .,
ORIGINAL
FORMl
THE PA TENTS ACT, 1970
Application No.:
(39 of 1970)
& Filing Date:
CBRNo:
PATENT Signature:
[Seesections 7, 54 & 135 and rule 20(1)]
1. APPLICANT(S)
BAYER SCHERING PHARMA German of M iillerstrasse 178, 13353 Berlin,
2. INVENTOR(S)

Germany
Germany
Germany
KEIL, Birgit German Sudetenstrasse 36, 40231 Diisseldorf,
Germany
3. TITLE· OF THE INVENTION: "4-[4-({[4-CHLORO-3-
(TRIFLUOROMETHYL)PHENYL)]CARBAMOYL}AMINO)-3-FLUOROPHENOXY]-N-
METHYLPYRIDINE-2-CARBOXAMIDE MONOHYDRA TE"
IN INDIA
PERFEXIO LEGAL
Attorneys-At-Law
VasantKunj
.. .,
Telephone No. +91-120-434-3600/+91-11-41767656
Mobile No.: +91-9810404749
Telefax No.: +91-120-434-3643
Email: mail@oerfexiole2:al.com
COUNTRY:
Number Applicant
Europe 06021296.6 . October 11, BAYER "4-[4-({[4-CHLORO-3-
2006 PHARMA (TRIFLUOROMETHYL)PHEN
[ITRUE COPYII
AKTIENGESELL YL)]C::ARBAMOYL}AMINO)-3-
I
PHARMA
AKTIENGESELL
I SCHAFT)
PHASE APPLICATION: '
PCT/ EP2007/ 008503 September 29, 2007


I
Not applicable

I
Not applicable
:
9. DECLARATIONS:
(i) Declaration by the true and first inventor(~):
1/-We, GRUNENBERG, Alfons, a German dtizen, of Gneisenaustrasse 15, 41539 Dormagen,

Germany; STIEHL, Juergen, a German citizen,: of Rosenstrasse 28, 45549 Sprockhbvel, Germany;
TENBIEG, Katharina, a German citizen, of Busenbergstrasse 103, 44269 Dortmund, Germany and
KEIL, Birgit, a German citizen, of Sudetenstrasse 36, 40231 Diisseldorf, Germany the above
named inventor(s) isfare the true and first inventor(s) for this invention and declare that the
Miillerstrasse 178, 13353 Berlin Germany, is our assignee.
Date:/~-)~ -~oAy
Signature:
GRUNENBERG, Alfons STIEHL, Juergen
TU~dt ()aJfti~~
rp··cl D iecFr:r-1~9~=- ~o-r::-2u:r~ri:;--::-2. ~
[ITRUE COPYII
(iii) Declaration by the applicant(s) •
IfWe, the applicant(s) hereby declare(s) that:- l
~ I--am-fWe are in possession of the above-mentioned invention.
~ The complete specification relating to the invention is filed with this application.
~ There is no lawful ground of objection to the grant of patent to mef-us.
~ The application or each of app1icatior1:s,particulars of which are given in Para. 5 was the
first application in the convention country / countries in respect of myf-our invention.
~ ±--a:mj-Weclaim the priority from the above-mentioned appliq:ation(s) filed in convention
country/col::1:Rtriesand state that no application for protection in respect of the invention
had been made in a convention country before that date by mef-us or by any person from
~ Myf Our application is based on International application under Patent Cooperation Treaty
a. Complete Specification (in conformation with the international application/as amer1:ded
b. Drawings (in conformation with the international application /as amer1:dedbefore the
WEA), as applicable (2-copies); No of sheets: 7;
c. Form PCT/IB/304;
e. Declaration as to inventorship on Form-S(in duplicate); and
If-We hereby declare that to the best of myf-our knowledge, information and belief the fact and
matters stated herein are correct and If we request that a patent may be granted to mef-us for the
said invention.
Dated this 12th day of March, 2009
BAYER SCHERING PHARMA AKTIENGESELLSCHAFT
'A.TENT AGENT
OF PERFEXIO LEGAL
To,
IITRUE COPYII
FORM 3
[39 OF 1970]
&
THE PATENTS (AMENDMENT} RULES, 2006
We, BAYER SCHERING PHARMA AKTIENGESELLSCHAFT, a Gem!2. MAR

2009
company, of Mullerstrasse 178, 13353 Berlin, Germany,
hereby declare:
(i} That we have made this application No. dated 12/03/2009

for the same/substantially same invention, application (s} for patent in the
other countries, the particulars of which are given below:
COUNTRY APPLICATION NO. FILING DATE

EP 06021296.6 11.10.2006
PCT PCT/EP2007/008503 29.09.2007
[iii] that the rights in the application[s] have been assigned to : No One
that <I/we> undertake that up to the date of grant of the patent, by the
Controller, I/we would keep him informed in writing the details regarding
corresponding applications for patents filed outside India within six months
from the date of filing of such application.
REMFRY AGAR
ATTORNEY F THE APPLI ANT(S]
THE PATENT OFFICE,
DELHI
IITRUE COPYjl
,_)RIGINAL
FORM3
[39 OF 1970]
&
We, BAYER SCHERING PHARMA AKTIENGESELLSCHAFT, a German company of

Mullerstrasse 178, 13353 Berlin, Germany
hereby declare:-
(i) that we have made this Application No. 1628/DELNP/2009 dated 12.03.2009 for the
<same/substantially> same invention application[s] for patent in the other countries, the
particulars of which are given below:
SEE ANNEXURE
(ii) that the rights in the application[s] has/have been assigned to: No one
(iii) that <we> undertake that up to the date of grant of the patent, by the Controller, we
would keep him informed in writing the details regarding corresponding applications for
patents filed outside India within six months from the date of filing of such application.
Dated this August 8, 2012
(SW~)
OF REMFRY & SAGAR
To
IITRUE _coP511
ANNEXURE: 1628/DELNP/2009
Patent Application Publication Issue

Country status date Aoolication no. date Publication no. date Patent no. Aoolication status
01 - patent applied
AE 04 - active 29/09/07 328-2009 for
01 - patent applied
AR 04 - active 20/09/07 070104168 for
01 - patent applied
AU 04 - active 29/09/07 2007306716 for
01 - patent applied
BR 04 - active 29/09/07 0719828-0 for
01 - patent applied
...., BS 04 - active 25/03/08 2042 for
7J 01 - patent applied
C BY 04 - active 29/09/07 20090677 for
..~I~
,-<:
CA 04 - active 29/09/07 2666170
01 - patent applied
for
01 - patent applied
CL 04 - active 11/10/07 2930-2007 for
0 I - patent applied
CN 04 - active 29/09/07 200780037680.2 30/09/09 101547903 for
01 - patent applied
co 04 - active 29/09/07 09025191 for
01 - patent applied
CR 04 - active 29/09/07 PCT/EP2007/008503 for
01 - patent applied ()
cu 04 - active 29/09/07 2009-0039 for
;o
DO 04 - active 29/09/07 2009-45
01 - patent applied
for -
·G)
z)>-
01 - patent applied
DZ 04 - active 29/09/07 090135 for
r-
01 - patent applied
EC 04 - active 29/09/07 2009-9185 for
01 - patent applied
EG 04 - active 29/09/07 488-2009 for
01 - patent applied
EP 04 - active 29/09/07 07818583.2 09/09/09 2097381 for
EP 03 - inactive 11/10/06 06021296.6 for
GT 04 - active 29/09/07 A2009-00057 for
01 - patent applied
HK 04 - active 24/03/10 10103082.1 25/06/10 1136287 for
01 - patent applied
HN 04 - active 29/09/07 2009-000499 for
~ 01 - patent applied
..;1~ for
ID 04 - active 29/09/07 00200900838 28/05/09 0491990
01 - patent applied
IL 04 - active 29/09/07 197369 for
01 - patent applied
-< JM 04 - active 10/04/08 18/1/4772 for
01 - patent applied
JO 04 - active 07/10/07 423-2007 for
01 - patent applied
JP 04 - active 29/09/07 2009-531733 25/02/10 2010-505888 for
01 - patent applied
KE 04 - active 29/09/07 KEIP /2009/00891 for
01 - patent applied
KR 04 - active 29/09/07 I 0-2009-7007422 for
01 - patent applied
KW 04 - active 10/10/07 150-2007 for
MA 04 - active 29/09/07 31857 02/11/09 30878 02 - patent granted
01 - patent applied
MX 04 - active 29/09/07 2009/002642 for
01 - patent applied
MY 04 - active 29/09/07 20091350 for
NZ 04 - active 29/09/07 576153 24/02/12 05/06/12 576153 02 - patent granted
01 - patent applied
OM 04 - active 29/09/07 39-2009 for
PA 04 - active 10/10/07 87503 13/07/09 87503 02 - patent granted
01 - patent applied
PE 04 - active 10/10/07 1368-2007 for
01 - patent applied
PH 04 - active 29/09/07 1-2009-500662 17/04/08 for
01 - patent applied
PK 04 - active 04/10/07 1159-2007 for
~ 01 - patent applied
..;1~
-<
RU
SA
04 - active
03 - inactive
29/09/07
03/10/07
2009117388
07280545
for
01 - patent applied
for
01 - patent applied
SG 04 - active 03/10/11 201107199-0 for
01 - patent applied
SG 04 - active 29/09/07 200901899-5 for
01 - patent applied
sv 04 - active 29/09/07 2009003187 for
01 - patent applied
TH 04 - active 04/10/07 0701005024 24/09/09 98396 for
TN 04 - active 29/09/07 0072-2009 22/10/10 20820 02 - patent granted
01 - patent applied
TT 04 - active 29/09/07 TT/A/2009/00076 for
01 - patent applied
TW 04 - active 09/10/07 96137745 for
UA 04 - active 29/09/07 200904623 26/09/11 95984 02 - patent granted
2010-0173953- 01 - patent applied
us 04 - active 29/09/07 12/444974 08/07/10 Al for
01 - patent applied
UY 04 - active 08/10/07 30633 for
01 - patent applied
VE 04 - active 11/03/08 2008-000467 29/09/11 for
01 - patent applied
VN 04 - active 29/09/07 1-2009-00698 for
01 - patent applied
WO 03 - inactive 29/09/07 PCT/EP2007/008503 17/04/08 2008/043446 for
2009-
ZA 04 - active 29/09/07 2009-02469 30/06/10 02469 02 - patent granted
~
ijl'~ Yo~
JI. (SWARUPKUMAR)
FORM3
THE PATENTSACT, 1970 ORIGINAL
(39OF 1970)
&
THE PATEN1S RULES,2003
STATEMENTAND UNDERTAKINGUNDER SECTION 8
I,/-We, BAYERPHARMA AKTIENGESELLSCHAFf,a German company of Mullerstrasse

178, 13353Berlin, Germany
hereby declare:-
[i) that If-we who have made this application No. 1628/DELNP /2009 dated March 12,
2009 alonefjoiftt:I.rmade for the same/substantially same invention, application [s]
for patent in the other countries the particulars of which are given below:
Please see the Annexure
[ii] that the rights in the application[s] ftaS{-havebeen assigned to: No one
[iii) that If-we undertake that upto the date of grant of the patent by the Controller, If we
would keep him informed in writing the details regarding corresponding
applications for patents filed outside India within six months from the date of filing
of such application.
Dated this 12th day of August, 2013. -4

~~UMAR)
E ENT AGENT
0 - ERFEXIO LEGAL
To,
The Controller of Patents,
The Patent Office,
DELHI.
IiTRUE _coPYjl
ANNEXURE TO FORM 3 DATED AUGUST 12, 2013
Application Number: 1628/DELNP/2009
STATUS OF PUBLICATI
NAME OF THE APPLICATION APPLICATION DATE OF DATE OF PATENT
THE ON
COUNTRY DATE NUMBER PUBLICATION GRANT NUMBER
APPLICATION NUMBER
AUSTRIA 29.09.2007 07818583.2 GRANTED - - 19.06.2013 EAT2097381
BELGIUM 29.09.2007 07818583.2 GRANTED - - 19.06.2013 EBE2097381
BULGARIA 29.09.2007 07818583.2 GRANTED - - 19.06.2013 EBG 2097381
SWITZERLAND 29.09.2007 07818583.2 GRANTED - - 19.06.2013 ECH2097381
CYPRUS 29.09.2007 07818583.2 GRANTED - - 19.06.2013 ECY2097381
i CZECH REPUBLIC 29.09.2007 07818583.2 GRANTED - - 19.06.2013 ECZ2097381
.n
0
"'O
-<
~ GERMANY
DENMARK
29.09.2007
29.09.2007
07818583.2
07818583.2
GRANTED
GRANTED
-
-
-
-
19.06.2013
19.06.2013
602007031165.9
EDK2097381
ESfONIA 29.09.2007 07818583.2 GRANTED - - 19.06.2013 EEE2097381
EUROPEAN 29.09.2007 07818583.2 GRANTED 09.09.2009 2097381 19.06.2013 2097381

PATENT OFFICE
SPAIN 29.09.2007 07818583.2 GRANTED - - 19.06.2013 EFS2097381
FINLAND 29.09.2007 07818583.2 GRANTED - - 19.06.2013 EFI 2097381
FRANCE 29.09.2007 07818583.2 GRANTED - - 19.06.2013 EFR2097381
~ L\UNITED KINGDOM 29.09.2007 07818583.2 GRANTED - - 19.06.2013 EGB2097381
,,..._) ''
Page 1 of 3
APPLICATION STATUS OF PUBLICATI

NAME OF THE APPLICATION DATE OF DATE OF PATENT
DATE THE ON
COUNTRY NUMBER PUBLICATION GRANT NUMBER
APPLICATION NUMBER
GREECE 29.09.2007 07818583.2 GRANTED - - 19.06.2013 EGR2097381
HUNGARY 29.09.2007 07818583.2 GRANTED - - 19.06.2013 EHU2097381
IRELAND 29.09.2007 07818583.2 GRANTED - - 19.06.2013 EIE 2097381
ICELAND 29.09.2007 07818583.2 GRANTED - - 19.06.2013 EIS2097381
ITALY 29.09.2007 07818583.2 GRANTED - - 19.06.2013 EIT 2097381

,...,
LITHUANIA 29.09.2007 07818583.2 GRANTED - - 19.06.2013 ELT2097381
~t1i LUXEMBOURG 29.09.2007 07818583.2 GRANTED - - 19.06.2013 ELU 2097381
n ·~
~ LATVIA 29.09.2007 07818583.2 GRANTED - - 19.06.2013 ELV2097381
~
MONACO 29.09.2007 07818583.2 GRANTED - - 19.06.2013 EMC2097381
MALTA 29.09.2007 07818583.2 GRANTED - - 19.06.2013 EMT2097381
NETHERLANDS 29.09.2007 07818583.2 GRANTED - - 19.06.2013 ENL2097381
POLAND 29.09.2007 07818583.2 GRANTED - - 19.06.2013 EPL2097381
PORTUGAL 29.09.2007 07818583.2 GRANTED - - 19.06.2013 EPT2097381
ROMANIA 29.09.2007 07818583.2 GRANTED - - 19.06.2013 ERO2097381
~~
SWEDEN 29.09.2007 07818583.2 GRANTED - - 19.06.2013 07818583.2
~~ Page 2 of 3
Application Number: 1628/DELNP/2.009
APPLICATION STATUS OF PUBLICATI

NAME OF THE APPLICATION DATE OF DATE OF PATENT
DATE THE ON
COUNTRY NUMBER PUBLICATION GRANT NUMBER
APPLICATION NUMBER
SLOVENIA 29.09.2007 07818583.2 GRANTED - - 19.06.2013 ESI 2097381
SLOVAKIA 29.09.2007 07818583.2 GRANTED - - 19.06.2013 ESK2097381

\.f",
I(\
.~~ TURKEY
29.09.2007 07818583.2 GRANTED - - 19.06.2013 ETR2097381
,~ ·" 'I.
!1~
~
Page 3 of 3
FORM3
(39 OF 1970)
ORIGINAL
&
STATEMENT AND UNDERTAKING UNDER SECTION 8
[See section 8 and rule 12]
2014
If-We, Bayer HealthCare LLC, of 100 Bayer Boulevard, Whippany, New Jersey 0798~, USA,
hereby declare:-
[i] that If-we who have made this application No. 1628/DELNP /2009 dated March 12,
2009 alone/joiRtly made for the same/substantially same invention, application [s]
for patent in the other countries the particulars of which are given below:
[ii] that the rights in the application[s] hasfhave been assigned to: No one
[iii] that If-we undertake that upto the date of grant of the patent by the Controller, If- we
Dated this 4th day of March, 2014.
MAR)
NT AGENT
OF P FEXIO LEGAL
TO
THE CONTROLLER OF PA TENTS,
THE PATENT OFFICE,
DELHI.
IITRUE COPYjl
ANNEXURE TO FORM 3 DATED MARCH 4, 2014
STATUS OF
NAME OF THE APPLICATION DATE OF PUBLICATION DATE OF
DATE OF THE PATENT NUMBER
COUNTRY NUMBER PUBLICATION NUMBER GRANT
APPLICATION APPLICATION
Australia 29/09/2007 2007306716 Granted - - 24/12/2013 2007306716

Brazil 29/09/2007 0719828-0 Published 04/02/2014 - - -
,...,
~ China 29/09/2007 200780037680.2 Granted 30/09/2009 101547903 15/01/2014 ZL200780037680.2
~
n
0
""O
f Colombia
Costa Rica
29/09/2009
29/09/2007
09025191
10663
Tobe
abandoned
Pending
-
-
-
-
-
-
-
-
Cuba 29/09/2007 2009-0039 Abandoned - - - -
Japan 29/09/2007 2009-531733 Granted 25/02/2010 2010-505888 23/08/2013 5346293
.
. l,0
I
Mexico 29/09/2007 2009/002642 Granted - - 19/04/2013 308874
~ !>
c::,
.....
?,:
:;c>-
:;;O
........,
~ Page 1 of 1
--
FORM3
THE PA TENTS ACT, 1970
(39 OF 1970)
ORIGINAL
&
If We, Bayer HealthCare LLC, of 100 Bayer Boulevard, Whippany, New Jersey 07981,
USA,
hereby declare:-
[i] that If-we who have made this application No. 1628/DELNP /2009 dated
March 12, 2009 alone/jointly made for the same/ substantially same
invention, application [s] for patent in the other countries the particulars of
[ii] that the rights in the application[s] hasfhave been assigned to: No one
[iii] that If-we undertake that upto the date of grant of the patent by the
Controller, If we would keep him informed in writing the details regarding
Dated this 12th day of August, 2014
(S AYKUMAR)
PATENT AGENT
OF PERFEXIO LEGAL
TO
THE PATENT OFFICE,
DELHI.
IITRUE COPYjl
STATUS OF
NAME OF THE APPLICATION DATE OF PUBLICATION DATE OF
DATE OF THE PATENT NUMBER
COUNTRY NUMBER PUBLICATION NUMBER GRANT
APPLICATION APPLICATION
---.--
December 16,
BAHAMAS March 25, 2008 2042 Granted - - 2042
2013
September 29,
ALGERIA
2007
090135 Granted - - March 9, 2011 6384
September 29,
~ GUATEMALA
2007
A2009-00057 Granted - - February 19, 2014 N/A
~
~ REPUBLIC OF September 29,
-
~
10-2009-7007422 Granted - July 4, 2014 10-1418623
KOREA 2007
n TAIWAN,
0
"'O PROVINCE OF October 9, 2007 96137745 Granted - - March 1, 2014 1428322
CHINA
UNITED STATES September 29,
12/444974 Granted July 8, 2010 2010-0173953-Al May 27, 2014 8735592
OF AMERICA 2007
UNITED STATES
OF AMERICA
May 14, 2014 14/277095 Pending - - - -
September 29,
~ VIETNAM 1-2009-00698 Granted - - February 13, 2014 12397
\(~ 2007
0
/ ~
c.P '"'~
~~
ct>
Page 1 of 1 ~~
~ \
~
FORM3
ORIGiNAL
(39 OF 1970)
&
THE PATENTS RULES, 2003 \\\\\\\\\\1
\\\\\I\\
II\\\\
0000048466
ff We, Bayer HealthCare LLC, of 100 Bayer Boulevard, Whippany, New Jersey 07981,
USA,
hereby declare:-
[i] that ffwe who have made this application No. 1628/DELNP /2009 dated
[ii] that the rights in the application[s] l=tasfhave been assigned to: No one
[iii] that Ifwe undertake that upto the date of grant of the patent by the
Controller, ff we would keep him informed in writing the details regarding
Dated this 19th day of January, 2015
AR)
ENT
FEXIOLEGAL
ATTORNEYS THE APPLICANT
TO
THE PA TENT OFFICE,
DELHI.
IITRUE COPY!I
H
~
0
ANNEXURE TO FORM 3 DATED JANUARY 19, 2015
Application Number: 1628/DELNP/2009 •
0 Date of Status of the
m Name of the country Application Number Date of Publication Date of Grant
r Application Application
~ UNITED ARAB
~ EMIRATES
September 29, 2007 328-2009 Pending - -
ARGENTINA September 20, 2007 070104168 Pending - -
H
w AUSTRIA September 29, 2007 07818583.2 Granted - June 19, 2013
1' AUSTRALIA September 29, 2007 2007306716 Granted - December 24, 2013
0 BELGIUM September 29, 2007 07818583.2 Granted - June 19, 2013
~
I
BULGARIA September 29, 2007 07818583.2 Granted - June 19, 2013
N BRAZIL September 29,_2007 0719828-0 Pending February 4, 2014 -
0 BAHAMAS March 25, 2008 2042 Granted - December 16, 2013
~ -
BELARUS September 29, 2007 20090677 Granted July 5, 2012
u,
,'
CANADA September 29, 2007 2666170 Pending - -
.,J SWITZERLAND September 29, 2007 07818583.2 Granted - June 19, 2013
U1 CHILE October 11, 2007 2930-2007 Granted - May 20, 2014
N
lN
CHINA
COLOMBIA
September 29, 2007
September 29, 2007
200780037680.2
09025191
Granted
·to be
abandoned
September 30, 2009
-
January 15, 2014
-
11 ~~
COSTA RICA September 29, 2007 10663 Pending - -
CUBA September 29, 2007 2009-0039 Abandoned - -
CYPRUS September 29, 2007 07818583.2 Granted - June 19, 2013
CZECH REPUBLIC September 29, 2007 07818583.2 Granted - June 19, 2013
GERMANY September 29, 2007 07818583.2 Granted - June 19, 2013
DENMARK
September 29, 2007 07818583.2 Granted - June 19, 2013
DOMINICAN
REPUBLIC
September 29, 2007 2009-45 Granted - May 15, 2013
ALGERIA September 29, 2007 090135 Granted - March 9, 2011
ECUADOR September 29, 2007 2009-9185 Pending - -
r\ ESTONIA September 29, 2007 07818583.2 Granted - June 19, 2013
~,~, ~
EGYPT September 29, 2007 488-2009 Pending - -
~
Page 1 of 4
H
-a
0
ANNEXURE TO FORM 3 DATED JANUARY 19, 2015 ._
C Date of Status of the
r EUROPEAN
Application Application
X September 29, 2007 07818583.2 Granted September 9, 2009 June 19, 2013
r1 PATENT OFFICE
SPAIN September 29, 2007 07818583.2 Granted - June 19, 2013
~
~
FINLAND · September 29, 2007 07818583.2 Granted - June 19, 2013
\ FRANCE September 29, 2007 07818583.2 Granted - June 19, 2013
0 UNITED KINGDOM September 29, 2007 07818583.2 Granted - June 19, 2013
F" GREECE September 29, 2007 07818583.2 Granted - June 19, 2013
GUATEMALA September 29, 2007 A2009-00057 Granted - February 20, 2014
N
0 THE HONG KONG
t,-.a SPECIAL
V, ADMINISTRATIVE
REGION March 24, ~010 10103082.1 Granted June 25, 2010 September 26, 2014 ~
~
OF THE PEOPLE'S
U1
f'.)
L~
l
REPUBLIC OF
CHINA
HONDURAS
HUNGARY
September 29, 2007
September 29, 2007
2009-000499
07818583.2
Pending
Granted
-
-
-
June 19, 2013
11 ~~
INDONESIA September 29, 2007 00200900838 Pending May 28, 2009 -
IRELAND September 29, 2007 07818583.2 Granted - June 19, 2013
ISRAEL September 29, 2007 197369 Pending - -
.ICELAND September 29, 2007 07818583.2 Granted - June 19, 2013
ITALY September 29, 2007 07818583.2 Granted - June 19, 2013
JAMAICA April 10, 2008 18/1/4772 Pending - -
I
JORDAN October 7, 2007 423-2007 Pending - -
I
1'1 JAPAN September 29, 2007 2009-531733 Granted February 25, 2010 August 23, 2013
KENYA September 29, 2007 . KE/P /2009/00891 Granted - September 13, 2012
REPUBLIC OF
September 29, 2007 10-2009-7007422 Granted - July 4, 2014
KOREA
\ iA= KUWAIT
~ LITHUANIA
October 10, 2007
September 29, 2007
150-2007
07818583.2
Pending
Granted
-
-
-
June 19, 2013
~
Page 2 of 4
H
"'O ANNEXURE TO FORM 3 DATED JANUARY 19, 2015
0
'-.
0 Status of the
m Name of the country
Date of
Application Number Application Date of Publication Date of Grant
r Application
;c
H LUXEMBOURG September 29, 2007 07818583.2 Granted - June 19, 2013
LATVIA September 29, 2007 07818583.2 Granted - June 19, 2013
~ MOROCCO September 29, 2007 31857 Granted - November 2, 2009
U)
I
MONACO September 29, 2007 07818583.2 Granted - June 19, 2013
0 MALTA September 29, 2007 07818583.2 Granted - June 19, 2013
H MEXICO September 29, 2007 2009/002642 Granted - April 19, 2013
MALAYSIA September 29, 2007 20091350 Pending - -
r•,;
0
NETHERLANDS September 29, 2007 07818583.2 Granted - June 19, 2013
I-Ji NEW ZEALAND September 29, 2007 576153 Granted February 24, 2012 June 5, 2012
u, OMAN September 29, 2007 39-2009 Pending - -
PANAMA October 10, 2007 87503 Granted - July 13, 2009 ~
H
V1
r-J
PERU
PHILIPPINES
October 10, 2007
September 29, 2007
1368-2007
1-2009-500662
to be
abandoned
Pending
-
April 17, 2008
-
-
11 !
l~~ PAKISTAN October 4, 2007 1159-2007 Pending - - ~~

POLAND September 29, 2007 07818583.2 Granted - June 19, 2013
PORTUGAL September 29, 2007 07818583.2 Granted - June 19, 2013
ROMANIA September 29, 2007 07818583.2 Granted - June 19, 2013
RUSSIAN
September 29, 2007 2009117388 Granted - November 20, 2012
FEDERATION
SAUDI ARABIA October 3, 2007 07280545 Abandoned - -
SWEDEN September 29, 2007 07818583.2 Granted - June 19, 2013
SINGAPORE September 29, 2007 200901899-5 Abandoned - -
SINGAPORE October 3, 2011 201107199-0 Pending - -
SLOVENIA September 29, 2007 07818583.2 Granted - June 19, 2013
SLOVAKIA September 29, 2007 07818583.2 Granted - June 19, 2013
EL SALVADOR September 29, 2007 2009003187 Pendj.ng - -
I'"'\ THAILAND October 4, 2007 0701005024 Pending September 24, 2009 -
-~
~ TUNISIA September 29, 2007 0072-2009 Granted - October 22, 2010
~
Page 3 of 4
~-~
~ ANNEXURE TO FORM 3 DATED JANUARY 19, 2015 ,_
Q Application Number: 1628/DELNP/2009
C Date of Status of the
r~, Application Application
~ TURKEY September 29, 2007 07818583.2 Granted - June 19, 2013
t~ TRINIDAD AND
TOBAGO
September 29, 2007 TT/ A/2q09/00076 Pending - -
~~
~ic, TAIWAN,
PROVINCE OF October 9, 2007 96137745 Granted - March 1, 2014
Q CHINA
~ September 29, 2007 200904623 Granted - September 26, 2011
UKRAINE
IP. I
~•JI'
UKRAINE - -
0 UNITED STATES OF
September 29, 2007 12/444974 Granted July 8, 2010 May 27, 2014
~ AMERICA
,.r, UNITED STATES OF
AMERICA
May 14, 2014 14/277095 Pending October 23, 2014 -
,~,)
tl"1 URUGUAY October 8, 2007 30633 Pending - -
11
I
~:~ VENEZUELA,
r·,) BOLIVARIAN March 11, 2008 2008-000467 Pending September 29, 2011 -
41 REPUBLIC OF
VIETNAM Sep.tember 29, 2007 1-2009-00698 Granted - February 13, 2014
~~
\~ ~ SOUTH AFRICA September 29, 2007 • 2009-02469 Granted - June 30, 2010
Page 4 of 4
FORM3
1111111111111111111
•
'''473195 THE PATENTS ACT, 1970 ORIGINAL
(39 OF 1970)
&
I/We, BAYER HealthCare LLC, of 100 Bayer Boulevard, Whippany, New Jersey 07981,
USA,
hereby declare-
[i] that Ifwe who have made this application no. 1628/DELNP /2009 dated
inventions, application [s] for patent in the other countries, the particulars of
[ii] that the rights in the application[s]--hasfhave been assigned to: No one
' \
[iii] that If we undertake that· upto the date of grant of the patent by the
Dated this 29th day of July, 2015
J
KUMAR)
P ENT AGENT
• OF RFEXIO LEGAL
To,
The Patent Office, .
NEWDELHI
-----
IITRUE COPY!I -----------
·1H
. ·:-u ANNEXURE TO FORM-3 DATED JULY.29, 2015
:-,o Application Number: 1628/DELNP/2009
q:,1
;1m Status of the
::r Name of the country Date of Application Application Number Date of Publication Date of Grant
.::c Application
'iH
UNITED ARAB
September 29, 2007 328-2009 PENDING - -
EMIRATES
I
ARGENTINA September 20, 2007 070104168 PENDING - -

.......
~ AUSTRIA September 29, 2007 07818583.2 GRANTED - June 19, 2013
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:r-.. AUSTRALIA September 29, 2007 2007306716 GRANTED - December 24, 2013
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=,r.J BAHAMAS March 25, 2008 2042 GRANTED December 16, 2013
BELARUS September 29, 2007 20090677 GRANTED - July 5, 2012
BELARUS -. - PENDING - -
CANADA September 29, 2007 2666170 PENDING - -
SWITZERLAND September 29, 2007 07818583.2 -GRANTED - June 19, 2013
CHILE October 11, 2007 2930-2007 GRANTED - May 20, 2014
CHINA September 29, 2007 200780037680.2 GRANTED September 30, 2009 January 15, 2014
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ABANDONED
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··11 ANNEXURE TO FORM 3 DATED JULY 29, 2015
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(~ GERMANY September 29, 2007 07818583.2 GRANTED - June 19, 2013
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:i-,c DENMARK September 29, 2007 07818583.2 GRANTED - June 19, 2013
:1.J! DOMINICAN REPUBLIC September 29, 2007 2009-45 GRANTED - May 15, 2013
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ESTONIA September 29, 2007 07818583.2 GRANTED - June 19, 2013
EGYPT September 29, 2007 488:-2009 PENDING - -
EUROPEAN PATENT
October 11, 2006 06021296.6 ABANDONED - -
OFFICE (EPO) •
EUROPEAN PATENT
September 29, 2007 07818583.2 GRANTED September9,2009 June 19, 2013
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OFFICE (EPO)
..
SPAIN September 29, 2007 07818583.2 GRANTED - June 19, 2013
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Name of the country Date of Application Application Number Date of Publication Date of Grant
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UNITED KINGDOM September 29, 2007 07818583.2 GRANTED - June 19, 2013
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J GUATEMALA September 29, 2007 A2009-00057 GRANTED - February 20, 2014
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HONDURAS September 29, 2007 2009-000499 GRANTED - February 28, 2013
HUNGARY September 29, 2007 . 07818583.2 GRANTED - June 19,.2013
INDONESIA September 29, 2007 00200900838 PUBLISHpD May 28, 2009 -
IRELAND September29,2007 07818583.2 GRANTED -· June 19, 2013
ISRAEL September 29, 2007 197369 PUBLISHED Jun~ 30, 2q15 -
ICELAND September 29, 2007 07818583.2 GRANTED - June 19, 2013
ITALY September 29, 2007 07818583.2 GRANTED - June 19, 2013
JAMAICA April 10, 2008 18/1/4772 PENDING - -
$:) JORDAN October 7, 2007 423-2007 PENDING - - :
Page 3 of 7
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,,o Application Number: 1628/DELNP/2009
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KUWAIT October 10, 2007 150-2007 PENDING - -
r-. LITHUANIA September29,2007 07818583.2 GRANTED - June 19, 2013
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f= LUXEMBOURG September 29, 2007 07818583.2 GRANTED - June 19, 2013
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MOROCCO September29,2007 31857 GRANTED - November 2, 2009
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MEXICO September 29, 2007 2009/002642 GRANTED - April 19, 2013
MALAYSIA September 29, 2007 20091350 GRANTED - October 31, 2014
NETHERLANDS September 29, 2007 07818583.2 GRANTED - June 19, 2013
NEW ZEALAND September 29, 2007 576153 GRANTED February 24, 2012 June 5, 2012
OMAN September 29, 2007 39-2009 PENDING - -

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RUSSIAN FEDERATION September 29, 2007 2009117388 GRANTED - November 20, 2012
SAUDI ARABIA October 3, 2007 07280545 ABANDONED - -
SWEDEN September 29, 2007 07818583.2 GRANTED - June 19, 2013
SINGAPORE September 29, 2007 200901899-5 ABANDONED - -
~;g_SINGAPORE October 3, 2011 201107199-0. GRANTED - • March 16, 2015
Page 5 of 7
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SLOVENIA September 29, 2007 07818583.2 GRANTED - June 19, 2013
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SLOVAKIA September29,2007 07818583.2 GRANTED - June 19, 2013
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EL SALVADOR September 29, 2007 2009003187 PENDING - -
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TAIWAN, PROVINCE OF
October 9, 2007 96137745 GRANTED - March 1, 2014
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UKRAINE September 29, 2007 200904623 GRANTED - September 26, 2011
UNITED STATES OF TOBE

•••• ·'T May 14, 2014 14/277095 October 23, 2014 -
AMERICA ABANDONED
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Page 7 of 7
ANAND &.ANAND
Due Date: N/ A
Our Ref: 17099A(P-32) 23 rd September 2016

The Patent Office
DELHI
Re: Indian patent application number 1628/DELNP/2009
Sir,
We write in respect of the above application and are enclosing herewith the
following documents:
1) Updated Form 3
Kindly take the said documents on record.
,~~-
Yours faithfully,
Archana Shanker
Encl: As stated above.
\\askFill\Patent Data\Sheetal\DELHI-Patent Office.docx
First Channel Building, Plot No. 17A, Sector 16A, Film City, Naida 201301 (UP) India +91-120-4059300 erna_il(g)ananclancJ?_r_}~
nd. cor_r_1
REGISTERED OFFICE: 8-41, Nizamuddin East, New Delhi 110 o· :!!!E-- • IOIDA NEW DELHI MUMBAI CHENNAI
IITRUE _COPYll
FORM 3
(39 of 1970)
&
The Patents Rules, 2003
(As amended)
(See Section 8, Rule 12)
I/We, BAYER HEALTHCARE LLC, a corporation organized and existing under the laws of USA,
of 100 Bayer Boulevard, Whippany, New Jersey 07981, USA.
Hereby declare:
(i) That I/We have not made any application for the same/substantially the same invention
outside India.
(ii) That I/We who have made this Application No. 1628/DELNP /2009 dated 29 th
September 2007 alone/jointly with made for the same/ substantially same invention,
application(s) for patent in the other countries, the particulars of which are given below:
Date of Status of I Date of I Date of

application I application publication grant
Please See Annexure
That the right in the application(s) has/have been assigned to.
I/We undertake that upto the date of grant of the patent, by the Controller, I/We would keep
him informed in writing the details regarding corresponding applications for patents filed outside
India within six months from the date of filing of such application.
Dated this 23 rd Day of September 2016
Archana Shanker
~~-
of Anand And Anand Advocates
Agents for the Applicants
To
The Patent Office, Delhi
* The data/information may include entries that relate to continuation applications, continuation-in-part applications, child continuity applications,
divisional applications and other similar applications. Though the applicant readily believes that said applications do not relate to the same or
substantially the same invention as the instant application, in the absence of any interpretation of the expression "same/substantially the same", said
data is being included only by way of abundant caution,
I[TRUE COPYjl
ANNEXURE to Form 3
IndianPatentAppiicationNo.l.~.~./!)E
Lt-,t/' /ol dlJ q
Count-v Patent Patent status Annlication date Aoolication no. Publication date Publication no. Date of Grant Patent no.
AR - Ar-Jentina 04 • active 2013-09-04 20130103145
BS - Baharras 04 • active 2013-09-03 2530
EP - E • Eurooean Patent 03 - inactive 2012-09-06 12183331.3
GC • GJlf Coooeration Council 04 - active 2013-09-04 2013-25296
JM - Jamaica 04 • active 2013-09-10 18/1/5449
,.
JO - Jordan 04 • active 2013-09-04 268/2013
KS· KOSOVC 03 • inactive 2013-09-02 KS/P/2013/62
AE - United Arab Emirates 04 - active 2013-09-05 291/2015
AP· ARIPO 04 - active 2013-09-05 AP/P/2015/008292
AU • ALStralia 04 • active 2013-09-05 2013312531
BR - Br3zil 04 - active 2013-09-05 1120150049362
rA • Canad3 04 • active 2013-09-05 2883767
:L - Chile 04 - active 2013-09-05 2015-00544 2015-08-21 NONE
:N - 0-ina 04 - active 2013-09-05 201380049461.1 2015-09-09 104902878
~II
IK • H-:,no Kono 04 • active 2016-03-01 16102327 .2 2016-07-22 121470A
:o - C:,lombia 04 • active 2013-09-05 15-050805 2015-06-30 528
~
:R - Ccsta Ri,:a 04 - active 2013-09-05 2015-0114
:u - Ci.ba 04 - active 2013-09-05 2015-0020
>O - DomiriC3n Reoublic 04 • active 2013-09-05 P2015·0049 2015-04-15 NONE
DZ - Alneria 04 - active 2013-09-05 150122
EA - Eurasia 04 - active 2013-09-05 201590520
BA· Bosnia and Herzeoo·✓ ina 04 - active 2013-09-05 PCT/US2013/058257
EC - EcJador 03 - inactive 2013-09-05 2015-8248
EG • Eov □ t 04 • active 2013-09-05 345/2015
ME • Monte7eoro 04 • active 2013-09-05 PCT/US2013/058257
EP - E - Eurooean Patent 04 • active 2013-09-05 13762967.1 2015-07-15 2892507
GT - G,.atemala 04 - active 2013-09-05 A2015-000053
HN - H:induras 04 - active 2013-09-05 2015-000469
ID - Jnjonesia 04 • active 2013-09-05 P00201502009
IL - Israel 04 - active 2013-09-05 237350
IN - Jnjia 04 • active 2013-09-05 1673/DELNP/2015 2015-07-03 N.A.
JP - Jaran 04 - active 2013-09-05 2015-531194 2015-09-17 2015-527395
KE • Kenva 03 - inactive 2013-09-05 PCT/US2013/058257
KR - Korea Reoublic of 04 - active 2013-09-05 10-2015-7008402
MA - Moroc,:c 04 • active 2013-09-05 37888
Page 1 of 2
MX - Mexico 04 - active 2013-09-05 MX/a/2015/002815
MY - Malavsia 04 - active 2013-09-05 Pl2015700672
NZ - New Zealand 04 - active 2013-09-05 705578
OM - Oman 04 - active 2013-09-05 OM/P/2015/00055
PA - Panamc 04 - active 2013-09-05 90580-01
PE - Peru 04 - active 2013-09-05 0289-2015/DIN 2015-06-27 NONE
PH - Philippires 04 - active 2013-09-05 1-2015-500460 2014-03-13
SA - Saudi Arabia 04 - active 2013-09-05 515360113
SG - Sinqapcre 04 - active 2013-09-05 11201501683W
SV - El Sal, a::lor 04 - active 2013-09-05 2015004929
TH - Thailand 04 - active 2013-09-05 1501001236
TN - Tunisia 04 - active 2013-09-05 TN2015/0078
TT - Trinidac and Tobaqo 04 - active 2013-09-05 TT/A/2015/00039
IA - Ukraine 04 - active 2013-09-05 a201502818
~ JS - United States 04 - active 2013-09-05 14/018516
~
1
N - Viet N3m 04 - active 2013-09-05 1201500787
8
~
:A - SoJth Africa
'K - Pakistan
W - Taiwa, Republic of China
JS - United States
04 - active
04 - active
04 - active
04 - active
2013-09-05
2013-08-26
2013-09-05
2013-09-05
2015/01394
566/2013
102131928
14/018516
2014-04-16 201414510
UY - Uruoua·, 04 - active 2013-09-04 35006 2014-03-31 174

VE - Venezuela 03 - inactive 2013-09-04 2013-001110
WO - PCT - Patent Cooperation Treaty 04 - active 2013-09-05 PCT/US2013/058257 2014-03-13 WO 2014/039677
//J
i ! .t - -,, ' . t~
~11', ..f-b~.Lt
Page 2 of 2
ANAND & ANAND
Our ref. 17099A/P-32 February 8, 2017

The Patent Office
Delhi
Re.: Indian patent application number 1628/DELNP/2009
Sir,
following document:
1) Updated form 3
Kindly take the said document on record.
Yours faithfully,
/1} ,Ld<Lh
~---
Archana Shanker
Of Anand And Anand Advocates
Encl.: as stated above
\\askfill\Patent Data\Siddharlh\2017\Delhi Oocumen1\January Delhi Paten! doc 2017.docx
First Channel Building, Plol No. 17A, Sec.;lo116A, Fih11City, Nui,J· .-.n<0n, 1110
'
1
····• 1;, +91-120-4059300 cmail@onandandanand.com
zE--
F,FCIST[IU'D OFF-:C:f• B-41, Nizamuddin East, New Delhi 11CII TRUE COPYjl NOIDA NEW DELHI MUMBAI CHENNAI
FORM 3
THE PATENT ACT, 1970
(39 OF 1970)
&
(As Amended)
(See section 8, rule 12)
I/We, BAVER HEALTHCARE LLC., a corporation organized and existing under the laws of USA, of
100 Bayer Boulevard, Whippany, New Jersey 07981, USA.
Hereby declare:
(i) That I/we have not made any application for the same/substantially the same invention outside
India.
(ii)That I/we, who have made this application No. 1628/DELNP/2009 dated September 29, 2007
alone/jointly with made for the same/ substantially same invention, application(s) for patent in the
Country! Appl~cition I Date of Status of the Publication No. and Date of I Date of
application I application I
publication grant
Kindly See Annexure
(iii)That the rights in the application(s) has/have been assigned to.
I/We undertake that upto the date of grant of the patent, by the Controller, I/We would keep him
informed in writing the details regarding corresponding applications for patents filed outside India
within six months from the date of filing of such application.
Dated this 8 th day of February 2017
,
,l,JJLLLk.L'h
--------·
Archana Shanker
To
The Patent Office, New Delhi
The annexed doto/information may include entries thnt relate to continuation applications, wntinuation-in-part applications, chilrl continuity applications, divisional
applications and other similar applications. Though the applicant readily believes that said applications do not relate to the same or substantially the same invention ass
the instant application, in the absence of any interpretation of the expression "same/substantially the same", said data is being included only by way of abundant caution.
IITRUE _COPYII
Annexure to Form 3
Country Patent Patent status Application date Application no. Publication date Publication no. Date of Grant Patent no.
AR - Argentina 04 - active 2007-09-20 070104168
BS- Bahamas 04 - active 2008-03-25 2042 2013-12-16 2042
CL- Chile 04 - active 2007-10-11 2930-2007 2014-05-20 50218
CL- Chile 04 - active 2007-10-11 2930-2007 2014-05-20 50218
EP- E - European Patent 03 - inactive 2006-10-11 06021296.6
JM -Jamaica 04 - active 2008-04-10 18/1/4772
JO -Jordan 04 - active 2007-10-07 423-2007 2016-09-05 2016-12-07 3021
KW- Kuwait 04 - active 2007-10-10 150-2007
PA- Panama 04- active 2007-10-10 87503 2009-07-13 87503
AE - United Arab Emirates 04 - active 2007-09-29 328-2009
AU - Australia 04 - active 2007-09-29 2007306716 2013-12-24 2007306716
AU - Australia 04 - active 2014-05-23 2007306716 2015-02-26 2007306716
BR - Brazil 04 - active 2007-09-29 0719828-0 2014-02-04
!1~
BY- Belarus/ White Russia 04 - active 2007-09-29 20090677 2012-07-05 16460
BY- Belarus/ White Russia 04 - active 2007-09-29 20090677 2015-09-28 16460
CA- Canada 04 - active 2007-09-29 2666170 2016-05-24 2666170
CN - China 04 - active 2007-09-29 200780037680.2 2009-09-30 101547903 2014-01-15 ZL200780037680.2
e< HK - Hong Kong 04 - active 2010-03-24 10103082.1 2010-06-25 1136287 2014-09-26 HK1136287
CO - Colombia 03 - inactive 2007-09-29 09025191
CR- Costa Rica 04 - active 2007-09-29 10663
CU - Cuba 03 - inactive 2007-09-29 2009-0039
DO - Dominican Republic 04 - active 2007-09-29 2009-45 2013-05-15 2009-0045
DZ-Algeria 04 - active 2007-09-29 090135 2011-03-09 6384
EC- Ecuador 03 - inactive 2007-09-29 2009-9185
EG - Egypt 03 - inactive 2007-09-29 488-2009
EP- E - European Patent 04 - active 2007-09-29 07818583.2 2009-09-09 2097381 2013-06-19 2097381
GT - Guatemala 04 - active 2007-09-29 A2009-00057 2014-02-20 5738
HN - Honduras 04 - active 2007-09-29 2009-000499 2013-02-28 5354
ID - Indonesia 04 - active 2007-09-29 00200900838 2009-05-28 0491990
IL - Israel 04 - active 2007-09-29 197369 2015-06-30 N.A. 2015-10-01 197369
IN - India 04 - active 2007-09-29 1628/DELNP/2009
JP - Japan 04 - active 2007-09-29 2009-531733 2010-02-25 2010-505888 2013-08-23 5346293
KE- Kenya 04 - active 2007-09-29 KE/P/2009/00891 2012-09-13 535
KR- Korea, Republic of 04 - active 2007-09-29 10-2009-7007422 2014-07-04 10-1418623
MA- Morocco 04 - active 2007-09-29 31857 2009-11-02 30878
~- I o..f_1
MX-Mexico 04 - active 2007-09-29 2009/002642 2013-04-19 308874
MY - Malaysia 04 - active 2007-09-29 20091350 2014-10-31 MY-152595-A
NZ - New Zealand 04- active 2007-09-29 576153 2012-02-24 2012-06-05 576153
OM-Oman 04 - active 2007-09-29 39-2009
PH - Philippines 04 - active 2007-09-29 1-2009-500662 2008-04-17 2013-09-02 1-2009-500662
RU - Russian Federation 04 - active 2007-09-29 2009117388 2012-11-20 2466992
RU - Russian Federation 04- active 2016-07-08 2009117388
SG - Singapore 03 - inactive 2007-09-29 200901899-5
SG - Singapore 04 - active 2011-10-03 201107199-0 2015-03-16 175584
SV - El Salvador 04- active 2007-09-29 2009003187
TN - Tunisia 04- active 2007-09-29 0072-2009 2010-10-22 20820
TT - Trinidad and Tobago 04 - active 2007-09-29 TT/A/2009/00076
UA- Ukraine 04 - active 2007-09-29 200904623 2011-09-26 95984
UA - Ukraine 04 - active 2007-09-29 200904623 2011-09-26 95984
!1~
US - United States 04 - active 2007-09-29 12/444974 2010-07-08 2010-0173953-Al
US - United States 03 - inactive 2014-05-14 14/277095 2014-10-23 2014-0315958
VN -Viet Nam 04 - active 2007-09-29 1-2009-00698 2014-02-13 12397
ZA - South Africa 04 - active 2007-09-29 2009-02469 2010-06-30 2009-02469
PE- Peru 03 - inactive 2007-10-10 1368-2007
e< AT - Austria 04 - active 2007-09-29 07818583.2 2013-06-19 EAT 2097381
BE- Belgium 04 - active 2007-09-29 07818583.2 2013-06-19 EBE2097381
BG - Bulgaria 04 - active 2007-09-29 07818583.2 2013-06-19 EBG2097381
CH - Switzerland 04 - active 2007-09-29 07818583.2 2013-06-19 ECH2097381
CY - Cyprus 04 - active 2007-09-29 07818583.2 2013-06-19 ECY2097381
CZ- Czech Republic 04 - active 2007-09-29 07818583.2 2013-06-19 ECZ2097381
DE-Germany 04 - active 2007-09-29 07818583.2 2013-06-19 602007031165.9
DK - Denmark 04 - active 2007-09-29 07818583.2 2013-06-19 EDK2097381
EE- Estonia 04 - active 2007-09-29 07818583.2 2013-06-19 EEE2097381
ES-Spain 04 - active 2007-09-29 07818583.2 2013-06-19 EE52097381
Fl - Finland 04 - active 2007-09-29 07818583.2 2013-06-19 EFl2097381
FR- France 04 - active 2007-09-29 07818583.2 2013-06-19 EFR2097381
GB - United Kingdom 04 - active 2007-09-29 07818583.2 2013-06-19 EGB2097381
GR- Greece 04 - active 2007-09-29 07818583.2 2013-06-19 EGR2097381
HU - Hungary 04 - active 2007-09-29 07818583.2 2013-06-19 EHU 2097381
IE - Ireland 04 - active 2007-09-29 07818583.2 2013-06-19 EIE 2097381
IS - Iceland 04 - active 2007-09-29 07818583.2 2013-06-19 EIS2097381
IT - Italy 04 - active 2007-09-29 07818583.2 2013-06-19 502013902189977
J- °T3
LT - Lithuania 04 - active 2007-09-29 07818583.2 2013-06-19 ELT2097381
LU - Luxembourg 04 - active 2007-09-29 07818583.2 2013-06-19 ELU 2097381
LV - Latvia 04 - active 2007-09-29 07818583.2 2013-06-19 ELV 2097381
MC- Monaco 04 - active 2007-09-29 07818583.2 2013-06-19 EMC 2097381
MT- Malta 04 - active 2007-09-29 07818583.2 2013-06-19 EMT2097381
NL - Netherlands 04 - active 2007-09-29 07818583.2 2013-06-19 ENL 2097381
PL - Poland 04 - active 2007-09-29 07818583.2 2013-06-19 EPL2097381
PT - Portugal 04- active 2007-09-29 07818583.2 2013-06-19 EPT2097381
RO- Romania 04 - active 2007-09-29 07818583.2 2013-06-19 ERO2097381
SE-Sweden 04 - active 2007-09-29 07818583.2 2013-06-19 07818583.2
SI - Slovenia 04 - active 2007-09-29 07818583.2 2013-06-19 ESl2097381
SK- Slovakia 04 - active 2007-09-29 07818583.2 2013-06-19 ESK2097381
TR - Turkey 04 - active 2007-09-29 07818583.2 2013-06-19 ETR2097381
....., PK- Pakistan 04 - active 2007-10-04 1159-2007 2016-06-17 142226
1,~
SA - Saudi Arabia 03 - inactive 2007-10-03 07280545
TH - Thailand 04 - active 2007-10-04 0701005024 2009-09-24 98396
TW - Taiwan, Republic of China 04 - active 2007-10-09 96137745 2014-03-01 1428322
TW - Taiwan, Republic of China 04- active 2015-11-09 96137745 2015-11-09 1428322
UY - Uruguay 04 - active 2007-10-08 30633
VE - Venezuela 04 - active 2008-03-11 2008-000467 2011-09-29
WO - PCT- Patent Cooperation Treaty 03 - inactive 2007-09-29 PCT/EP2007/008503 2008-04-17 2008/043446
Dated this 8 th day of February 2017
,.~
Archana Shanker
7>Gj 3
A
ANAND & ANAND
Our ref. 17099A/P-32 August 1, 2017

The Patent Office
Delhi
Sir,
following document:
1) Updated form 3
Yours faithfully,
Archana Shanker
\\askfill\Patent Data\Siddharth\2017\Delhi Document\August Delhi Patent doc 2017.docx
First Channel Building, Plot No. 17A, Sector 16A, Film City, Noida 201301 (UP) India +91-120-4059300 email@anandandanand.com
REGISTERED OFFICE: B-41, Nizamuddin East, New Delhi 110 013 NOIDA NEW DELHI MUMBAI CHENNAI
&---
IITRUE COPYII
FORM 3
(39 OF 1970)
&
I/We, BAYER HEALTHCARE LLC., a corporation organized and existing under the laws of USA, of 100
Bayer Boulevard, Whippany, New Jersey 07981, USA.
Hereby declare:
-(i)That I/we have not made any application for the same/substantially the same invention outside India.
alone/jointly with made for the same/ substantially same invention, application(s) for patent in the
Application Date of Status of the Date of Date of
I I
Country
No I application I application
Kindly See annexure
I publication I grant
I
informed in writing the details regarding corresponding applications for patents filed outside India within
six months from the date of filing of such application.
Dated this 1st day of August 2017
~.
Archana Shanker
To
The annexed data/information may include entries that relate to continuation applications, continuation-in-part applications, child continuity applications,
divisional applications and other similar applications. Though the applicant readily believes that said applications do not relate to the same or substantially the
same invention ass the instant application, in the absence of any interpretation of the expression “same/substantially the same”, said data is being included
only by way of abundant caution.
Annexure to Form 3
Application Publication Publication Application
File Country Patent Patent status date Application no. date no. Issue date Patent no. Status
01 - patent
BHC061143 AR AR - Argentina 04 - active 2007-09-20 070104168 applied for
02 - patent
BHC061143 BS BS - Bahamas 04 - active 2008-03-25 2042 2013-12-16 2042 granted
02 - patent
BHC061143 CL CL - Chile 04 - active 2007-10-11 2930-2007 2014-05-20 50218 granted
03 - patent
BHC061143 CL SPC CL - Chile 04 - active 2007-10-11 2930-2007 2014-05-20 50218 finally granted
EP - E - European 01 - patent
BHC061143 EP Patent 03 - inactive 2006-10-11 06021296.6 applied for
01 - patent
BHC061143 JM JM - Jamaica 04 - active 2008-04-10 18/1/4772 applied for
02 - patent
BHC061143 JO JO - Jordan 04 - active 2007-10-07 423-2007 2016-09-05 2016-12-07 3021 granted
01 - patent
BHC061143 KW KW - Kuwait 04 - active 2007-10-10 150-2007 applied for
02 - patent
BHC061143 PA PA - Panama 04 - active 2007-10-10 87503 2009-07-13 87503 granted
AE - United Arab 01 - patent
BHC061143 PCT-AE Emirates 04 - active 2007-09-29 328-2009 applied for
02 - patent
BHC061143 PCT-AU AU - Australia 04 - active 2007-09-29 2007306716 2013-12-24 2007306716 granted
BHC061143 PCT-AU 03 - patent
SPC AU - Australia 04 - active 2014-05-23 2007306716 2015-02-26 2007306716 finally granted
01 - patent
BHC061143 PCT-BR BR - Brazil 04 - active 2007-09-29 0719828-0 2014-02-04 applied for
BY - Belarus / 02 - patent
BHC061143 PCT-BY White Russia 04 - active 2007-09-29 20090677 2012-07-05 16460 granted
BHC061143 PCT-BY BY - Belarus / 03 - patent
SPC White Russia 04 - active 2007-09-29 20090677 2015-09-28 16460 finally granted
02 - patent
BHC061143 PCT-CA CA - Canada 04 - active 2007-09-29 2666170 2016-05-24 2666170 granted
02 - patent
BHC061143 PCT-CN CN - China 04 - active 2007-09-29 200780037680.2 2009-09-30 101547903 2014-01-15 ZL200780037680.2 granted
BHC061143 PCT- 02 - patent
CN-HK HK - Hong Kong 04 - active 2010-03-24 10103082.1 2010-06-25 1136287 2014-09-26 HK1136287 granted
01 - patent
BHC061143 PCT-CO CO - Colombia 03 - inactive 2007-09-29 09025191 applied for
01 - patent
BHC061143 PCT-CR CR - Costa Rica 04 - active 2007-09-29 10663 applied for
01 - patent
BHC061143 PCT-CU CU - Cuba 03 - inactive 2007-09-29 2009-0039 applied for
DO - Dominican 02 - patent
BHC061143 PCT-DO Republic 04 - active 2007-09-29 2009-45 2013-05-15 2009-0045 granted
02 - patent
BHC061143 PCT-DZ DZ - Algeria 04 - active 2007-09-29 090135 2011-03-09 6384 granted
01 - patent
BHC061143 PCT-EC EC - Ecuador 03 - inactive 2007-09-29 2009-9185 applied for
01 - patent
BHC061143 PCT-EG EG - Egypt 03 - inactive 2007-09-29 488-2009 applied for
BHC061143 PCT- EP - E - European 02 - patent
EP01 Patent 04 - active 2007-09-29 07818583.2 2009-09-09 2097381 2013-06-19 2097381 granted
02 - patent
BHC061143 PCT-GT GT - Guatemala 04 - active 2007-09-29 A2009-00057 2014-02-20 5738 granted
02 - patent
BHC061143 PCT-HN HN - Honduras 04 - active 2007-09-29 2009-000499 2013-02-28 5354 granted
02 - patent
BHC061143 PCT-ID ID - Indonesia 04 - active 2007-09-29 00200900838 2009-05-28 0491990 granted
02 - patent
BHC061143 PCT-IL IL - Israel 04 - active 2007-09-29 197369 2015-06-30 N.A. 2015-10-01 197369 granted
01 - patent
BHC061143 PCT-IN IN - India 04 - active 2007-09-29 1628/DELNP/2009 applied for
02 - patent
BHC061143 PCT-JP JP - Japan 04 - active 2007-09-29 2009-531733 2010-02-25 2010-505888 2013-08-23 5346293 granted
BHC061143 PCT-JP
SPC JP - Japan
02 - patent
BHC061143 PCT-KE KE - Kenya 04 - active 2007-09-29 KE/P/2009/00891 2012-09-13 535 granted
KR - Korea, 02 - patent
BHC061143 PCT-KR Republic of 04 - active 2007-09-29 10-2009-7007422 2014-07-04 10-1418623 granted
02 - patent
BHC061143 PCT-MA MA - Morocco 04 - active 2007-09-29 31857 2009-11-02 30878 granted
02 - patent
BHC061143 PCT-MX MX - Mexico 04 - active 2007-09-29 2009/002642 2013-04-19 308874 granted
02 - patent
BHC061143 PCT-MY MY - Malaysia 04 - active 2007-09-29 20091350 2014-10-31 MY-152595-A granted
NZ - New 02 - patent
BHC061143 PCT-NZ Zealand 04 - active 2007-09-29 576153 2012-02-24 2012-06-05 576153 granted
OM OM - Oman 04 - active 2007-09-29 39-2009 applied for
02 - patent
BHC061143 PCT-PH PH - Philippines 04 - active 2007-09-29 1-2009-500662 2008-04-17 2013-09-02 1-2009-500662 granted
RU - Russian 02 - patent
BHC061143 PCT-RU Federation 04 - active 2007-09-29 2009117388 2012-11-20 2466992 granted
BHC061143 PCT-RU RU - Russian 03 - patent
SPC Federation 04 - active 2016-07-08 2009117388 2016-11-01 2466992 finally granted
01 - patent
BHC061143 PCT-SG SG - Singapore 03 - inactive 2007-09-29 200901899-5 applied for
SG01 SG - Singapore 04 - active 2011-10-03 201107199-0 2015-03-16 175584 granted
02 - patent
BHC061143 PCT-TN TN - Tunisia 04 - active 2007-09-29 0072-2009 2010-10-22 20820 granted
TT - Trinidad 01 - patent
BHC061143 PCT-TT and Tobago 04 - active 2007-09-29 TT/A/2009/00076 applied for
02 - patent
BHC061143 PCT-UA UA - Ukraine 04 - active 2007-09-29 200904623 2011-09-26 95984 granted
BHC061143 PCT-UA 03 - patent
SPC UA - Ukraine 04 - active 2007-09-29 200904623 2011-09-26 95984 finally granted
US - United 2010- 01 - patent
BHC061143 PCT-US States 04 - active 2007-09-29 12/444974 2010-07-08 0173953-A1 applied for
BHC061143 PCT- US - United 2014- 01 - patent
US01 States 03 - inactive 2014-05-14 14/277095 2014-10-23 0315958 applied for
02 - patent
BHC061143 PCT-VN VN - Viet Nam 04 - active 2007-09-29 1-2009-00698 2014-02-13 12397 granted
02 - patent
BHC061143 PCT-ZA ZA - South Africa 04 - active 2007-09-29 2009-02469 2010-06-30 2009-02469 granted
01 - patent
BHC061143 PE PE - Peru 03 - inactive 2007-10-10 1368-2007 applied for
BHC061143 PEP- 02 - patent
AT01 AT - Austria 04 - active 2007-09-29 07818583.2 2013-06-19 EAT 2097381 granted
BE01 BE - Belgium 04 - active 2007-09-29 07818583.2 2013-06-19 EBE 2097381 granted
BG01 BG - Bulgaria 04 - active 2007-09-29 07818583.2 2013-06-19 EBG 2097381 granted
CH01 CH - Switzerland 04 - active 2007-09-29 07818583.2 2013-06-19 ECH 2097381 granted
CY01 CY - Cyprus 04 - active 2007-09-29 07818583.2 2013-06-19 ECY 2097381 granted
BHC061143 PEP- CZ - Czech 02 - patent
CZ01 Republic 04 - active 2007-09-29 07818583.2 2013-06-19 ECZ 2097381 granted
DE01 DE - Germany 04 - active 2007-09-29 07818583.2 2013-06-19 602007031165.9 granted
DK01 DK - Denmark 04 - active 2007-09-29 07818583.2 2013-06-19 EDK 2097381 granted
EE01 EE - Estonia 04 - active 2007-09-29 07818583.2 2013-06-19 EEE 2097381 granted
ES01 ES - Spain 04 - active 2007-09-29 07818583.2 2013-06-19 EES 2097381 granted
FI01 FI - Finland 04 - active 2007-09-29 07818583.2 2013-06-19 EFI 2097381 granted
FR01 FR - France 04 - active 2007-09-29 07818583.2 2013-06-19 EFR 2097381 granted
BHC061143 PEP- GB - United 02 - patent
GB01 Kingdom 04 - active 2007-09-29 07818583.2 2013-06-19 EGB 2097381 granted
GR01 GR - Greece 04 - active 2007-09-29 07818583.2 2013-06-19 3081679 granted
HU01 HU - Hungary 04 - active 2007-09-29 07818583.2 2013-06-19 EHU 2097381 granted
IE01 IE - Ireland 04 - active 2007-09-29 07818583.2 2013-06-19 EIE 2097381 granted
IS01 IS - Iceland 04 - active 2007-09-29 07818583.2 2013-06-19 EIS 2097381 granted
IT01 IT - Italy 04 - active 2007-09-29 07818583.2 2013-06-19 502013902189977 granted
LT01 LT - Lithuania 04 - active 2007-09-29 07818583.2 2013-06-19 ELT 2097381 granted
LU01 LU - Luxembourg 04 - active 2007-09-29 07818583.2 2013-06-19 ELU 2097381 granted
LV01 LV - Latvia 04 - active 2007-09-29 07818583.2 2013-06-19 ELV 2097381 granted
MC01 MC - Monaco 04 - active 2007-09-29 07818583.2 2013-06-19 EMC 2097381 granted
MT01 MT - Malta 04 - active 2007-09-29 07818583.2 2013-06-19 EMT 2097381 granted
NL01 NL - Netherlands 04 - active 2007-09-29 07818583.2 2013-06-19 ENL 2097381 granted
PL01 PL - Poland 04 - active 2007-09-29 07818583.2 2013-06-19 EPL 2097381 granted
PT01 PT - Portugal 04 - active 2007-09-29 07818583.2 2013-06-19 EPT 2097381 granted
RO01 RO - Romania 04 - active 2007-09-29 07818583.2 2013-06-19 ERO 2097381 granted
SE01 SE - Sweden 04 - active 2007-09-29 07818583.2 2013-06-19 07818583.2 granted
SI01 SI - Slovenia 04 - active 2007-09-29 07818583.2 2013-06-19 ESI 2097381 granted
SK01 SK - Slovakia 04 - active 2007-09-29 07818583.2 2013-06-19 ESK 2097381 granted
TR01 TR - Turkey 04 - active 2007-09-29 07818583.2 2013-06-19 ETR 2097381 granted
02 - patent
BHC061143 PK PK - Pakistan 04 - active 2007-10-04 1159-2007 2016-06-17 142226 granted
01 - patent
BHC061143 SA SA - Saudi Arabia 03 - inactive 2007-10-03 07280545 applied for
01 - patent
BHC061143 TH TH - Thailand 04 - active 2007-10-04 0701005024 2009-09-24 98396 applied for
TW - Taiwan,
Republic of 02 - patent
BHC061143 TW China 04 - active 2007-10-09 96137745 2014-03-01 I428322 granted
TW - Taiwan,
Republic of 03 - patent
BHC061143 TW SPC China 04 - active 2015-11-09 96137745 2015-11-09 I428322 finally granted
01 - patent
BHC061143 UY UY - Uruguay 04 - active 2007-10-08 30633 applied for
01 - patent
BHC061143 VE VE - Venezuela 04 - active 2008-03-11 2008-000467 2011-09-29 applied for
WO - PCT -
Patent
Cooperation 01 - patent
BHC061143 WO Treaty 03 - inactive 2007-09-29 PCT/EP2007/008503 2008-04-17 2008/043446 applied for
Dated this 1st day of August 2017
Archana Shanker
Our ref. 17099A/P-32
A
ANAND & ANAND
February 9, 2018

The Patent Office
Delhi
Sir,
We write in respect of the above application and are enclosing herewith the following
document:
1) Updated form 3
Yours faithfully,
Archana Shanker
\\askfill\Patent Data\Siddharth\2018\Delhi Document\Documents\17099a-p32_form 3.docx
[rnuF. co~'3I
FORM 3
(39 OF 1970)
&
(As Amended)
I/We, Bayer Healthcare LLC., a corporation organized and existing under the laws of USA, of 100
Bayer Boulevard, Whippany, New Jersey 07981, USA.
Hereby declare:
(i) That I/we have not made any application for the same/substantially the same invention outside India.
alone/jointly with made for the same/ substantially same invention, application(s) for patent in the other
countries, the particulars of which are given below:
Application Date of Status of the Publication No. and Date of Date of
I I
Country
No
I application
I application
Kindly See Annexure
I
publication
I grant
I
informed in writing the details regarding corresponding applications for patents filed outside India
within six months from the date of filing of such application.
Dated this 9th day of February 2018
~-
Archana Shanker
To
The annexed data/information may include entries that relate to continuation applications, continuation-in-part applications, child continuity applications, divisional
applications and other similar applications. Though the applicant readily believes that said applications do not relate to the same or substantially the same invention ass
the instant application, in the absence of any interpretation of the expression “same/substantially the same”, said data is being included only by way of abundant caution.
Annexure to Form 3
Publication
File Country Patent Patent status Application date Application no. Publication date no. Issue date Patent no. Application Status
BHC061143 AR AR - Argentina 03 - inactive 2007-09-20 070104168 01 - patent applied for
BHC061143 BS BS - Bahamas 04 - active 2008-03-25 2042 2013-12-16 2042 02 - patent granted
BHC061143 CL CL - Chile 04 - active 2007-10-11 2930-2007 2014-05-20 50218 02 - patent granted
BHC061143 CL SPC CL - Chile 04 - active 2007-10-11 2930-2007 2014-05-20 50218 03 - patent finally granted
-
BHC061143 EP EP - E - European Patent 03 - inactive 2006-10-11 06021296.6 01 - patent applied for
BHC061143 JM JM - Jamaica 04 - active 2008-04-10 18/1/4772 01 - patent applied for
BHC061143 JO JO - Jordan 04 - active 2007-10-07 423-2007 2016-09-05 2016-12-07 3021 02 - patent granted
BHC061143 KW KW - Kuwait 04 - active 2007-10-10 150-2007 01 - patent applied for
BHC061143 PA PA - Panama 04 - active 2007-10-10 87503 2009-07-13 87503 02 - patent granted
BHC061143 PCT-AE AE - United Arab Emirates 04 - active 2007-09-29 328-2009 01 - patent applied for
BHC061143 PCT-AU AU - Australia 04 - active 2007-09-29 2007306716 2013-12-24 2007306716 02 - patent granted
BHC061143 PCT-AU SPC AU - Australia 04 - active 2014-05-23 2007306716 2015-02-26 2007306716 03 - patent finally granted
BHC061143 PCT-BR BR - Brazil 04 - active 2007-09-29 0719828-0 2014-02-04 01 - patent applied for
BHC061143 PCT-BY BY - Belarus / White Russia 04 - active 2007-09-29 20090677 2012-07-05 16460 02 - patent granted
BHC061143 PCT-BY SPC BY - Belarus / White Russia 04 - active 2007-09-29 20090677 2015-09-28 16460 03 - patent finally granted
BHC061143 PCT-CA CA - Canada 04 - active 2007-09-29 2666170 2016-05-24 2666170 02 - patent granted
BHC061143 PCT-CN CN - China 04 - active 2007-09-29 200780037680.2 2009-09-30 101547903 2014-01-15 ZL200780037680.2 02 - patent granted
BHC061143 PCT-CN-HK HK - Hong Kong 04 - active 2010-03-24 10103082.1 2010-06-25 1136287 2014-09-26 HK1136287 02 - patent granted
BHC061143 PCT-CO CO - Colombia 03 - inactive 2007-09-29 09025191 01 - patent applied for
BHC061143 PCT-CR CR - Costa Rica 04 - active 2007-09-29 10663 01 - patent applied for
BHC061143 PCT-CU CU - Cuba 03 - inactive 2007-09-29 2009-0039 01 - patent applied for
BHC061143 PCT-DO DO - Dominican Republic 04 - active 2007-09-29 2009-45 2013-05-15 2009-0045 02 - patent granted
BHC061143 PCT-DZ DZ - Algeria 04 - active 2007-09-29 090135 2011-03-09 6384 02 - patent granted
BHC061143 PCT-EC EC - Ecuador 03 - inactive 2007-09-29 2009-9185 01 - patent applied for
BHC061143 PCT-EG EG - Egypt 03 - inactive 2007-09-29 488-2009 01 - patent applied for
BHC061143 PCT-EP01 EP - E - European Patent 04 - active 2007-09-29 07818583.2 2009-09-09 2097381 2013-06-19 2097381 02 - patent granted
BHC061143 PCT-GT GT - Guatemala 04 - active 2007-09-29 A2009-00057 2014-02-20 5738 02 - patent granted
BHC061143 PCT-HN HN - Honduras 04 - active 2007-09-29 2009-000499 2013-02-28 5354 02 - patent granted
BHC061143 PCT-ID ID - Indonesia 04 - active 2007-09-29 W00200900838 2009-05-28 0491990 2017-04-18 IDP000045505 02 - patent granted
BHC061143 PCT-IL IL - Israel 04 - active 2007-09-29 197369 2015-06-30 N.A. 2015-10-01 197369 02 - patent granted
BHC061143 PCT-IN IN - India 04 - active 2007-09-29 1628/DELNP/2009 01 - patent applied for
BHC061143 PCT-JP JP - Japan 04 - active 2007-09-29 2009-531733 2010-02-25 2010-505888 2013-08-23 5346293 02 - patent granted
BHC061143 PCT-JP SPC JP - Japan 04 - active 2017-09-25 2017-700182 2017-12-18 2017-700182 03 - patent finally granted
BHC061143 PCT-KE KE - Kenya 04 - active 2007-09-29 KE/P/2009/00891 2012-09-13 535 02 - patent granted
BHC061143 PCT-KR KR - Korea, Republic of 04 - active 2007-09-29 10-2009-7007422 2014-07-04 10-1418623 02 - patent granted
BHC061143 PCT-MA MA - Morocco 04 - active 2007-09-29 31857 2009-11-02 30878 02 - patent granted
BHC061143 PCT-MX MX - Mexico 04 - active 2007-09-29 2009/002642 2013-04-19 308874 02 - patent granted
BHC061143 PCT-MY MY - Malaysia 04 - active 2007-09-29 20091350 2014-10-31 MY-152595-A 02 - patent granted
BHC061143 PCT-NZ NZ - New Zealand 04 - active 2007-09-29 576153 2012-02-24 2012-06-05 576153 02 - patent granted
BHC061143 PCT-OM OM - Oman 04 - active 2007-09-29 39-2009 01 - patent applied for
BHC061143 PCT-PH PH - Philippines 04 - active 2007-09-29 1-2009-500662 2008-04-17 2013-09-02 1-2009-500662 02 - patent granted
BHC061143 PCT-RU RU - Russian Federation 04 - active 2007-09-29 2009117388 2012-11-20 2466992 02 - patent granted
BHC061143 PCT-RU SPC RU - Russian Federation 04 - active 2016-07-08 2009117388 2016-11-01 2466992 03 - patent finally granted
BHC061143 PCT-SG SG - Singapore 03 - inactive 2007-09-29 200901899-5 01 - patent applied for
BHC061143 PCT-SG01 SG - Singapore 04 - active 2011-10-03 201107199-0 2015-03-16 175584 02 - patent granted
BHC061143 PCT-SV SV - El Salvador 04 - active 2007-09-29 2009003187 01 - patent applied for
BHC061143 PCT-TN TN - Tunisia 04 - active 2007-09-29 0072-2009 2010-10-22 20820 02 - patent granted
BHC061143 PCT-TT TT - Trinidad and Tobago 04 - active 2007-09-29 TT/A/2009/00076 01 - patent applied for
BHC061143 PCT-UA UA - Ukraine 04 - active 2007-09-29 200904623 2011-09-26 95984 02 - patent granted
BHC061143 PCT-UA SPC UA - Ukraine 04 - active 2007-09-29 200904623 2011-09-26 95984 03 - patent finally granted
2010-
BHC061143 PCT-US US - United States 04 - active 2007-09-29 12/444974 2010-07-08 0173953-A1 01 - patent applied for
BHC061143 PCT-US01 US - United States 03 - inactive 2014-05-14 14/277095 2014-10-23 2014-0315958 01 - patent applied for
BHC061143 PCT-VN VN - Viet Nam 04 - active 2007-09-29 1-2009-00698 2014-02-13 12397 02 - patent granted
BHC061143 PCT-ZA ZA - South Africa 04 - active 2007-09-29 2009-02469 2010-06-30 2009-02469 02 - patent granted
BHC061143 PE PE - Peru 03 - inactive 2007-10-10 1368-2007 01 - patent applied for
BHC061143 PEP-AT01 AT - Austria 04 - active 2007-09-29 07818583.2 2013-06-19 EAT 2097381 02 - patent granted
BHC061143 PEP-BE01 BE - Belgium 04 - active 2007-09-29 07818583.2 2013-06-19 EBE 2097381 02 - patent granted
BHC061143 PEP-BG01 BG - Bulgaria 04 - active 2007-09-29 07818583.2 2013-06-19 EBG 2097381 02 - patent granted
BHC061143 PEP-CH01 CH - Switzerland 04 - active 2007-09-29 07818583.2 2013-06-19 ECH 2097381 02 - patent granted
BHC061143 PEP-CY01 CY - Cyprus 04 - active 2007-09-29 07818583.2 2013-06-19 ECY 2097381 02 - patent granted
BHC061143 PEP-CZ01 CZ - Czech Republic 04 - active 2007-09-29 07818583.2 2013-06-19 ECZ 2097381 02 - patent granted
_l:OPYI
BHC061143 PEP-DE01 DE - Germany 04 - active 2007-09-29 07818583.2 2013-06-19 602007031165.9 02 - patent granted
BHC061143 PEP-DK01 DK - Denmark 04 - active 2007-09-29 07818583.2 2013-06-19 EDK 2097381 02 - patent granted
[!_:1uJJ::
BHC061143 PEP-EE01 EE - Estonia 04 - active 2007-09-29 07818583.2 2013-06-19 EEE 2097381 02 - patent granted
:;._:E_
BHC061143 PEP-ES01 ES - Spain 04 - active 2007-09-29 07818583.2 2013-06-19 EES 2097381 02 - patent granted
-
BHC061143 PEP-FI01 FI - Finland 04 - active 2007-09-29 07818583.2 2013-06-19 EFI 2097381 02 - patent granted
BHC061143 PEP-FR01 FR - France 04 - active 2007-09-29 07818583.2 2013-06-19 EFR 2097381 02 - patent granted
BHC061143 PEP-GB01 GB - United Kingdom 04 - active 2007-09-29 07818583.2 2013-06-19 EGB 2097381 02 - patent granted
BHC061143 PEP-GR01 GR - Greece 04 - active 2007-09-29 07818583.2 2013-06-19 3081679 02 - patent granted
BHC061143 PEP-HU01 HU - Hungary 04 - active 2007-09-29 07818583.2 2013-06-19 EHU 2097381 02 - patent granted
BHC061143 PEP-IE01 IE - Ireland 04 - active 2007-09-29 07818583.2 2013-06-19 EIE 2097381 02 - patent granted
BHC061143 PEP-IS01 IS - Iceland 04 - active 2007-09-29 07818583.2 2013-06-19 EIS 2097381 02 - patent granted
BHC061143 PEP-IT01 IT - Italy 04 - active 2007-09-29 07818583.2 2013-06-19 502013902189977 02 - patent granted
BHC061143 PEP-LT01 LT - Lithuania 04 - active 2007-09-29 07818583.2 2013-06-19 ELT 2097381 02 - patent granted
BHC061143 PEP-LU01 LU - Luxembourg 04 - active 2007-09-29 07818583.2 2013-06-19 ELU 2097381 02 - patent granted
BHC061143 PEP-LV01 LV - Latvia 04 - active 2007-09-29 07818583.2 2013-06-19 ELV 2097381 02 - patent granted
BHC061143 PEP-MC01 MC - Monaco 04 - active 2007-09-29 07818583.2 2013-06-19 EMC 2097381 02 - patent granted
BHC061143 PEP-MT01 MT - Malta 04 - active 2007-09-29 07818583.2 2013-06-19 EMT 2097381 02 - patent granted
BHC061143 PEP-NL01 NL - Netherlands 04 - active 2007-09-29 07818583.2 2013-06-19 ENL 2097381 02 - patent granted
BHC061143 PEP-PL01 PL - Poland 04 - active 2007-09-29 07818583.2 2013-06-19 EPL 2097381 02 - patent granted
BHC061143 PEP-PT01 PT - Portugal 04 - active 2007-09-29 07818583.2 2013-06-19 EPT 2097381 02 - patent granted
BHC061143 PEP-RO01 RO - Romania 04 - active 2007-09-29 07818583.2 2013-06-19 ERO 2097381 02 - patent granted
BHC061143 PEP-SE01 SE - Sweden 04 - active 2007-09-29 07818583.2 2013-06-19 07818583.2 02 - patent granted
BHC061143 PEP-SI01 SI - Slovenia 04 - active 2007-09-29 07818583.2 2013-06-19 ESI 2097381 02 - patent granted
BHC061143 PEP-SK01 SK - Slovakia 04 - active 2007-09-29 07818583.2 2013-06-19 ESK 2097381 02 - patent granted
BHC061143 PEP-TR01 TR - Turkey 04 - active 2007-09-29 07818583.2 2013-06-19 ETR 2097381 02 - patent granted
BHC061143 PK PK - Pakistan 04 - active 2007-10-04 1159-2007 2016-06-17 142226 02 - patent granted
BHC061143 SA SA - Saudi Arabia 03 - inactive 2007-10-03 07280545 01 - patent applied for
BHC061143 TH TH - Thailand 04 - active 2007-10-04 0701005024 2009-09-24 98396 01 - patent applied for
TW - Taiwan, Republic of
BHC061143 TW China 04 - active 2007-10-09 96137745 2014-03-01 I428322 02 - patent granted
BHC061143 TW SPC China 04 - active 2015-11-09 96137745 2015-11-09 I428322 03 - patent finally granted
BHC061143 UY UY - Uruguay 04 - active 2007-10-08 30633 01 - patent applied for
BHC061143 VE VE - Venezuela 04 - active 2008-03-11 2008-000467 2011-09-29 01 - patent applied for
WO - PCT - Patent Cooperation
BHC061143 WO Treaty 03 - inactive 2007-09-29 PCT/EP2007/008503 2008-04-17 2008/043446 01 - patent applied for
Archana Shanker
ANAND & ANAND
DELHI
Our ref: 17099A/P-32 July 31, 2018

The Patent Office
DELHI
Re.: Indian patent application number: 1628/DELNP/2009

Applicant: Bayer Healthcare LLC.,
Type of Application: National Phase
Sir / Madam,
We write in respect of the above application and are enclosing herewith the following
document:
1. Updated Form-3
The Controller is requested to kindly take said documents on record.
Yours faithfully,
Archana Shanker
IN PA # 149
\\askfill\Patent Data\Siddharth\2018\Delhi Document\17099A-p32_form 3.docx
&--
IITRUE COPYII
FORM 3
(39 OF 1970)
&
(As Amended)
I/We, Bayer Healthcare LLC., a corporation organized and existing under the laws of USA, of 100 Bayer
Boulevard, Whippany, New Jersey 07981, USA.
Hereby declare:
(i) That I/we have not made any application for the same/substantially the same invention outside India.
alone/jointly with made for the same/ substantially same invention, application(s) for patent in the other
Application Date of Status of the Publication No. and Date of Date of

Country
I No I application I application
Kindly See Annexure
I
publication I grant
I I
I/We undertake that upto the date of grant of the patent, by the Controller, I/We would keep him informed
in writing the details regarding corresponding applications for patents filed outside India within six months
Dated this 31st day of July 2018
~·
Archana Shanker
IN PA # 149
To
The annexed data/information may include entries that relate to continuation applications, continuation-in-part applications, child continuity applications, divisional applications and
other similar applications. Though the applicant readily believes that said applications do not relate to the same or substantially the same invention ass the instant application, in the
absence of any interpretation of the expression “same/substantially the same”, said data is being included only by way of abundant caution.
&--.
IITRUE COPYII
Annexure to Form 3
Patent Application Publication Publication
File Country Patent status date Application no. date no. Issue date Patent no. Application Status
03 -
BHC061143 AR AR - Argentina inactive 2007-09-20 070104168 01 - patent applied for
BHC061143 PCT-AU 03 - patent finally
SPC AU - Australia 04 - active 2014-05-23 2007306716 2015-02-26 2007306716 granted
_l:OPYII
[!_:1uJJ::
:;._:E_
-
BHC061143 PCT-BY BY - Belarus / White Russia 04 - active 2007-09-29 20090677 2012-07-05 16460 02 - patent granted
BHC061143 PCT-BY 03 - patent finally
SPC BY - Belarus / White Russia 04 - active 2007-09-29 20090677 2015-09-28 16460 granted
BHC061143 PEP-CH01
SPC CH - Switzerland
03 - patent finally
BHC061143 CL SPC CL - Chile 04 - active 2007-10-11 2930-2007 2014-05-20 50218 granted
BHC061143 PCT-CN CN - China 04 - active 2007-09-29 200780037680.2 2009-09-30 101547903 2014-01-15 ZL200780037680.2 02 - patent granted
03 -
BHC061143 PCT-CO CO - Colombia inactive 2007-09-29 09025191 01 - patent applied for
03 -
BHC061143 PCT-CU CU - Cuba inactive 2007-09-29 2009-0039 01 - patent applied for
BHC061143 PCT-DO DO - Dominican Republic 04 - active 2007-09-29 2009-45 2013-05-15 2009-0045 02 - patent granted
03 -
BHC061143 PCT-EC EC - Ecuador inactive 2007-09-29 2009-9185 01 - patent applied for
03 -
BHC061143 PCT-EG EG - Egypt inactive 2007-09-29 488-2009 01 - patent applied for
03 -
BHC061143 EP EP - E - European Patent inactive 2006-10-11 06021296.6 01 - patent applied for
BHC061143 PCT-EP01 EP - E - European Patent 04 - active 2007-09-29 07818583.2 2009-09-09 2097381 2013-06-19 2097381 02 - patent granted
_l:OPYII
[!_:1uJJ::
:;._:E_
-
BHC061143 PCT-CN-
HK HK - Hong Kong 04 - active 2010-03-24 10103082.1 2010-06-25 1136287 2014-09-26 HK1136287 02 - patent granted
BHC061143 PCT-ID ID - Indonesia 04 - active 2007-09-29 W00200900838 2009-05-28 0491990 2017-04-18 IDP000045505 02 - patent granted
BHC061143 PCT-IL IL - Israel 04 - active 2007-09-29 197369 2015-06-30 N.A. 2015-10-01 197369 02 - patent granted
BHC061143 JO JO - Jordan 04 - active 2007-10-07 423-2007 2016-09-05 2016-12-07 3021 02 - patent granted
BHC061143 PCT-JP 03 - patent finally
SPC JP - Japan 04 - active 2017-09-25 2017-700182 2017-12-18 2017-700182 granted
BHC061143 PCT-KR KR - Korea, Republic of 04 - active 2007-09-29 10-2009-7007422 2014-07-04 10-1418623 02 - patent granted
BHC061143 PCT-MX MX - Mexico 04 - active 2007-09-29 2009/002642 2013-04-19 308874 02 - patent granted
BHC061143 PCT-NZ NZ - New Zealand 04 - active 2007-09-29 576153 2012-02-24 2012-06-05 576153 02 - patent granted
03 -
BHC061143 PE PE - Peru inactive 2007-10-10 1368-2007 01 - patent applied for
BHC061143 PK PK - Pakistan 04 - active 2007-10-04 1159-2007 2016-06-17 142226 02 - patent granted
_l:OPYII
BHC061143 PCT-RU RU - Russian Federation 04 - active 2007-09-29 2009117388 2012-11-20 2466992 02 - patent granted
BHC061143 PCT-RU 03 - patent finally
[!_:1uJJ::
SPC RU - Russian Federation 04 - active 2016-07-08 2009117388 2016-11-01 2466992 granted
:;._:E_
03 -
-
BHC061143 SA SA - Saudi Arabia inactive 2007-10-03 07280545 01 - patent applied for
03 -
BHC061143 PCT-SG SG - Singapore inactive 2007-09-29 200901899-5 01 - patent applied for
BHC061143 PCT-SG01 SG - Singapore 04 - active 2011-10-03 201107199-0 2015-03-16 175584 02 - patent granted
BHC061143 TW China 04 - active 2007-10-09 96137745 2014-03-01 I428322 02 - patent granted
TW - Taiwan, Republic of 03 - patent finally
BHC061143 TW SPC China 04 - active 2015-11-09 96137745 2015-11-09 I428322 granted
BHC061143 PCT-UA UA - Ukraine 04 - active 2007-09-29 200904623 2011-09-26 95984 02 - patent granted
BHC061143 PCT-UA 03 - patent finally
SPC UA - Ukraine 04 - active 2007-09-29 200904623 2011-09-26 95984 granted
2010-0173953-
BHC061143 PCT-US US - United States 04 - active 2007-09-29 12/444974 2010-07-08 A1 2018-05-01 9957232 02 - patent granted
03 -
BHC061143 PCT-US01 US - United States inactive 2014-05-14 14/277095 2014-10-23 2014-0315958 01 - patent applied for
BHC061143 PCT-US02 US - United States 04 - active 2018-01-30 15/884103 01 - patent applied for
BHC061143 VE VE - Venezuela 04 - active 2008-03-11 2008-000467 2011-09-29 01 - patent applied for
03 -
BHC061143 WO WO - PCT inactive 2007-09-29 PCT/EP2007/008503 2008-04-17 2008/043446 01 - patent applied for
Dated this 31st day of July 2018
Archana Shanker
IN PA # 149
IITRUE CQP)ll
zE--'
ANAND & ANAND
Our Ref: 17099A/P-32 29th January 2019

The Patent Office
DELHI

Applicant: Bayer Healthcare LLC
Sir,
We write in respect of the above-mentioned patent and are enclosing herewith the
following document:
1) Updated Form 3
Yours faithfully,
Archana Shanker
\\askfill\Patent Data\Sheetal\DELHI-Patent Office.docx
IITRUE COPYII
FORM 3
(39 of 1970)
&
(As amended)
Hereby declare:
outside India.
(ii) That I/We who have made this Application No. 1628/DELNP/2009 dated 29th
Country Application Date of Status of Date of Date of

I No I application I application I publication I grant
Please See Annexure
Dated this 29th Day of January 2019
~-
Archana Shanker
To
* The data/information may include entries that relate to continuation applications, continuation‐in‐part applications, child continuity applications,
substantially the same invention as the instant application, in the absence of any interpretation of the expression “same/substantially the same”, said
data is being included only by way of abundant caution.
z!E---
11TRUE COPYjl
ANNEXURE TO FORM 3
File Patent status Application date Application no. Publication date Publication no. Issue date Patent no. Application Status Decision of Grant
BHC061143 AR 03 - inactive 2007-09-20 070104168 01 - patent applied for
BHC061143 BS 04 - active 2008-03-25 2042 2013-12-16 2042 02 - patent granted
BHC061143 CL 04 - active 2007-10-11 2930-2007 2014-05-20 50218 02 - patent granted
BHC061143 CL SPC 04 - active 2007-10-11 2930-2007 2014-05-20 50218 03 - patent finally granted
BHC061143 EP 03 - inactive 2006-10-11 06021296.6 01 - patent applied for
BHC061143 JM 04 - active 2008-04-10 18/1/4772 01 - patent applied for
BHC061143 JO 04 - active 2007-10-07 423-2007 2016-09-05 2016-12-07 3021 02 - patent granted 2016-12-07
BHC061143 KW 04 - active 2007-10-10 150-2007 01 - patent applied for
BHC061143 PA 04 - active 2007-10-10 87503 2009-07-13 87503 02 - patent granted
BHC061143 PCT-AE 04 - active 2007-09-29 328-2009 01 - patent applied for
BHC061143 PCT-AU 04 - active 2007-09-29 2007306716 2013-12-24 2007306716 02 - patent granted
BHC061143 PCT-AU SPC 04 - active 2014-05-23 2007306716 2015-02-26 2007306716 03 - patent finally granted
BHC061143 PCT-BR 04 - active 2007-09-29 0719828-0 2014-02-04 01 - patent applied for
BHC061143 PCT-BY 04 - active 2007-09-29 20090677 2012-07-05 16460 02 - patent granted 2012-05-28
BHC061143 PCT-BY SPC 04 - active 2007-09-29 20090677 2015-09-28 16460 03 - patent finally granted
_l:OPYI
BHC061143 PCT-CA 04 - active 2007-09-29 2666170 2016-05-24 2666170 02 - patent granted
[!_:1uJJ::
BHC061143 PCT-CN 04 - active 2007-09-29 200780037680.2 2009-09-30 101547903 2014-01-15 ZL200780037680.2 02 - patent granted 2013-09-27
:;._:E_
-
BHC061143 PCT-CN-HK 04 - active 2010-03-24 10103082.1 2010-06-25 1136287 2014-09-26 HK1136287 02 - patent granted
BHC061143 PCT-CO 03 - inactive 2007-09-29 09025191 01 - patent applied for
BHC061143 PCT-CR 04 - active 2007-09-29 10663 01 - patent applied for
BHC061143 PCT-CU 03 - inactive 2007-09-29 2009-0039 01 - patent applied for
BHC061143 PCT-DO 04 - active 2007-09-29 2009-45 2013-05-15 2009-0045 02 - patent granted
BHC061143 PCT-DZ 04 - active 2007-09-29 090135 2011-03-09 6384 02 - patent granted
BHC061143 PCT-EC 03 - inactive 2007-09-29 2009-9185 01 - patent applied for
BHC061143 PCT-EG 03 - inactive 2007-09-29 488-2009 01 - patent applied for
BHC061143 PCT-EP01 04 - active 2007-09-29 07818583.2 2009-09-09 2097381 2013-06-19 2097381 02 - patent granted
BHC061143 PCT-GT 04 - active 2007-09-29 A2009-00057 2014-02-20 5738 02 - patent granted
BHC061143 PCT-HN 04 - active 2007-09-29 2009-000499 2013-02-28 5354 02 - patent granted
BHC061143 PCT-ID 04 - active 2007-09-29 W00200900838 2009-05-28 0491990 2017-04-18 IDP000045505 02 - patent granted 2017-04-18
BHC061143 PCT-IL 04 - active 2007-09-29 197369 2015-06-30 N.A. 2015-10-01 197369 02 - patent granted 2015-10-01
BHC061143 PCT-IN 04 - active 2007-09-29 1628/DELNP/2009 01 - patent applied for
BHC061143 PCT-JP 04 - active 2007-09-29 2009-531733 2010-02-25 2010-505888 2013-08-23 5346293 02 - patent granted
BHC061143 PCT-JP SPC 04 - active 2017-09-25 2017-700182 2017-12-18 2017-700182 03 - patent finally granted
BHC061143 PCT-KE 04 - active 2007-09-29 KE/P/2009/00891 2012-09-13 535 02 - patent granted
BHC061143 PCT-KR 04 - active 2007-09-29 10-2009-7007422 2014-07-04 10-1418623 02 - patent granted
BHC061143 PCT-MA 04 - active 2007-09-29 31857 2009-11-02 30878 02 - patent granted
BHC061143 PCT-MX 04 - active 2007-09-29 2009/002642 2013-04-19 308874 02 - patent granted 2013-02-22
BHC061143 PCT-MY 04 - active 2007-09-29 20091350 2014-10-31 MY-152595-A 02 - patent granted
BHC061143 PCT-NZ 04 - active 2007-09-29 576153 2012-02-24 2012-06-05 576153 02 - patent granted 2012-06-05
BHC061143 PCT-OM 04 - active 2007-09-29 39-2009 01 - patent applied for
BHC061143 PCT-PH 04 - active 2007-09-29 1-2009-500662 2008-04-17 2013-09-02 1-2009-500662 02 - patent granted
BHC061143 PCT-RU 04 - active 2007-09-29 2009117388 2012-11-20 2466992 02 - patent granted 2012-07-22
BHC061143 PCT-RU SPC 04 - active 2016-07-08 2009117388 2016-11-01 2466992 03 - patent finally granted
BHC061143 PCT-SG 03 - inactive 2007-09-29 200901899-5 01 - patent applied for
BHC061143 PCT-SG01 04 - active 2011-10-03 201107199-0 2015-03-16 175584 02 - patent granted 2015-03-16
BHC061143 PCT-SV 04 - active 2007-09-29 2009003187 01 - patent applied for
BHC061143 PCT-TN 04 - active 2007-09-29 0072-2009 2010-10-22 20820 02 - patent granted
BHC061143 PCT-TT 04 - active 2007-09-29 TT/A/2009/00076 01 - patent applied for
BHC061143 PCT-UA 04 - active 2007-09-29 200904623 2011-09-26 95984 02 - patent granted 2011-08-23
BHC061143 PCT-UA SPC 04 - active 2007-09-29 200904623 2011-09-26 95984 03 - patent finally granted
BHC061143 PCT-US 04 - active 2007-09-29 12/444974 2010-07-08 2010-0173953-A1 2018-05-01 9957232 02 - patent granted
BHC061143 PCT-US01 03 - inactive 2014-05-14 14/277095 2014-10-23 2014-0315958 01 - patent applied for
BHC061143 PCT-US02 04 - active 2018-01-30 15/884103 2018-07-12 US-2018-0194730-A1 01 - patent applied for
BHC061143 PCT-VN 04 - active 2007-09-29 1-2009-00698 2014-02-13 12397 02 - patent granted
_l:OPYI
BHC061143 PCT-ZA 04 - active 2007-09-29 2009-02469 2010-06-30 2009-02469 02 - patent granted
[!_:1uJJ::
BHC061143 PE 03 - inactive 2007-10-10 1368-2007 01 - patent applied for
:;._:E_
BHC061143 PEP-AT01 04 - active 2007-09-29 07818583.2 2013-06-19 EAT 2097381 02 - patent granted
-
BHC061143 PEP-BE01 04 - active 2007-09-29 07818583.2 2013-06-19 EBE 2097381 02 - patent granted
BHC061143 PEP-BG01 04 - active 2007-09-29 07818583.2 2013-06-19 EBG 2097381 02 - patent granted
BHC061143 PEP-CH01 04 - active 2007-09-29 07818583.2 2013-06-19 ECH 2097381 02 - patent granted
BHC061143 PEP-CH01 SPC 04 - active 2018-08-03 C02097381/01 01 - patent applied for
BHC061143 PEP-CY01 04 - active 2007-09-29 07818583.2 2013-06-19 ECY 2097381 02 - patent granted
BHC061143 PEP-CZ01 04 - active 2007-09-29 07818583.2 2013-06-19 ECZ 2097381 02 - patent granted
BHC061143 PEP-DE01 04 - active 2007-09-29 07818583.2 2013-06-19 602007031165.9 02 - patent granted
BHC061143 PEP-DK01 04 - active 2007-09-29 07818583.2 2013-06-19 EDK 2097381 02 - patent granted
BHC061143 PEP-EE01 04 - active 2007-09-29 07818583.2 2013-06-19 EEE 2097381 02 - patent granted
BHC061143 PEP-ES01 04 - active 2007-09-29 07818583.2 2013-06-19 EES 2097381 02 - patent granted
BHC061143 PEP-FI01 04 - active 2007-09-29 07818583.2 2013-06-19 EFI 2097381 02 - patent granted
BHC061143 PEP-FR01 04 - active 2007-09-29 07818583.2 2013-06-19 EFR 2097381 02 - patent granted
BHC061143 PEP-GB01 04 - active 2007-09-29 07818583.2 2013-06-19 EGB 2097381 02 - patent granted
BHC061143 PEP-GR01 04 - active 2007-09-29 07818583.2 2013-06-19 3081679 02 - patent granted
BHC061143 PEP-HU01 04 - active 2007-09-29 07818583.2 2013-06-19 EHU 2097381 02 - patent granted
BHC061143 PEP-IE01 04 - active 2007-09-29 07818583.2 2013-06-19 EIE 2097381 02 - patent granted
BHC061143 PEP-IS01 04 - active 2007-09-29 07818583.2 2013-06-19 EIS 2097381 02 - patent granted
BHC061143 PEP-IT01 04 - active 2007-09-29 07818583.2 2013-06-19 502013902189977 02 - patent granted
BHC061143 PEP-LT01 04 - active 2007-09-29 07818583.2 2013-06-19 ELT 2097381 02 - patent granted
BHC061143 PEP-LU01 04 - active 2007-09-29 07818583.2 2013-06-19 ELU 2097381 02 - patent granted
BHC061143 PEP-LV01 04 - active 2007-09-29 07818583.2 2013-06-19 ELV 2097381 02 - patent granted
BHC061143 PEP-MC01 04 - active 2007-09-29 07818583.2 2013-06-19 EMC 2097381 02 - patent granted
BHC061143 PEP-MT01 04 - active 2007-09-29 07818583.2 2013-06-19 EMT 2097381 02 - patent granted
BHC061143 PEP-NL01 04 - active 2007-09-29 07818583.2 2013-06-19 ENL 2097381 02 - patent granted
BHC061143 PEP-PL01 04 - active 2007-09-29 07818583.2 2013-06-19 EPL 2097381 02 - patent granted
BHC061143 PEP-PT01 04 - active 2007-09-29 07818583.2 2013-06-19 EPT 2097381 02 - patent granted
BHC061143 PEP-RO01 04 - active 2007-09-29 07818583.2 2013-06-19 ERO 2097381 02 - patent granted
BHC061143 PEP-SE01 04 - active 2007-09-29 07818583.2 2013-06-19 07818583.2 02 - patent granted
BHC061143 PEP-SI01 04 - active 2007-09-29 07818583.2 2013-06-19 ESI 2097381 02 - patent granted
BHC061143 PEP-SK01 04 - active 2007-09-29 07818583.2 2013-06-19 ESK 2097381 02 - patent granted
BHC061143 PEP-TR01 04 - active 2007-09-29 07818583.2 2013-06-19 ETR 2097381 02 - patent granted
BHC061143 PK 04 - active 2007-10-04 1159-2007 2016-06-17 142226 02 - patent granted 2015-12-31
BHC061143 SA 03 - inactive 2007-10-03 07280545 01 - patent applied for
BHC061143 TH 04 - active 2007-10-04 0701005024 2009-09-24 98396 01 - patent applied for
BHC061143 TW 04 - active 2007-10-09 96137745 2014-03-01 I428322 02 - patent granted
BHC061143 TW SPC 04 - active 2015-11-09 96137745 2015-11-09 I428322 03 - patent finally granted
BHC061143 UY 04 - active 2007-10-08 30633 01 - patent applied for
BHC061143 VE 04 - active 2008-03-11 2008-000467 2011-09-29 01 - patent applied for
BHC061143 WO 03 - inactive 2007-09-29 PCT/EP2007/008503 2008-04-17 2008/043446 01 - patent applied for
A c ana an e
o Anand And Anand Ad ocate
A ent o t e Applicant
ANAND & ANAND
Our Ref: 17099A/P-32 29th July 2019

The Patent Office
DELHI

Sir,
following document:
1) Updated Form 3
Yours faithfully,
(Archana Shanker)
of Anand and Anand Advocates
Agents for the Applicant
Patent Agent: IN/PA-149
IITRUE COPYII
FORM 3
(39 of 1970)
&
(As amended)
Hereby declare:
outside India.
(ii) That I/We who have made this Application No. 1628/DELNP/2009 dated 29th

Please See Annexure
Dated this 29th Day of July 2019
~-
Archana Shanker
To
:&--
IITRUE COPY!I
ANNEXURE TO FORM 3
Indian patent application number 1628/DELNP/2009
File Country Patent Patent status Application Application no. Publication Publication no. Issue date Patent no. Application Status Decision
date date of Grant
BHC061143 AR AR - Argentina 03 - inactive 2007-09-20 070104168 01 - patent applied for
BHC061143 PCT-AU SPC AU - Australia 04 - active 2014-05-23 2007306716 2015-02-26 2007306716 03 - patent finally granted
BHC061143 PCT-BY BY - Belarus / White Russia 04 - active 2007-09-29 20090677 2012-07-05 16460 02 - patent granted 2012-05-28
BHC061143 PCT-BY SPC BY - Belarus / White Russia 04 - active 2007-09-29 20090677 2015-09-28 16460 03 - patent finally granted
BHC061143 PEP-CH01 SPC CH - Switzerland 04 - active 2018-08-03 C02097381/01 01 - patent applied for
_l:OPYII
BHC061143 CL SPC CL - Chile 04 - active 2007-10-11 2930-2007 2014-05-20 50218 03 - patent finally granted
BHC061143 PCT-CN CN - China 04 - active 2007-09-29 200780037680.2 2009-09-30 101547903 2014-01-15 ZL200780037680.2 02 - patent granted 2013-09-27
[!_:1uJJ::
BHC061143 PCT-CO CO - Colombia 03 - inactive 2007-09-29 09025191 01 - patent applied for
:;._:E_
-
BHC061143 PCT-CU CU - Cuba 03 - inactive 2007-09-29 2009-0039 01 - patent applied for
BHC061143 PCT-DO DO - Dominican Rep. 04 - active 2007-09-29 2009-45 2013-05-15 2009-0045 02 - patent granted
BHC061143 PCT-EC EC - Ecuador 03 - inactive 2007-09-29 2009-9185 01 - patent applied for
BHC061143 PCT-EG EG - Egypt 03 - inactive 2007-09-29 488-2009 01 - patent applied for
BHC061143 EP EP - European Patent 03 - inactive 2006-10-11 06021296.6 01 - patent applied for
BHC061143 PCT-EP01 EP - European Patent 04 - active 2007-09-29 07818583.2 2009-09-09 2097381 2013-06-19 2097381 02 - patent granted
BHC061143 PCT-CN-HK HK - Hong Kong 04 - active 2010-03-24 10103082.1 2010-06-25 1136287 2014-09-26 HK1136287 02 - patent granted
Page 1 of 3 - July 24, 2019
date date of Grant
BHC061143 PCT-ID ID - Indonesia 04 - active 2007-09-29 W00200900838 2009-05-28 0491990 2017-04-18 IDP000045505 02 - patent granted 2017-04-18
BHC061143 PCT-IL IL - Israel 04 - active 2007-09-29 197369 2015-06-30 N.A. 2015-10-01 197369 02 - patent granted 2015-10-01
BHC061143 JO JO - Jordan 04 - active 2007-10-07 423-2007 2016-09-05 2016-12-07 3021 02 - patent granted 2016-12-07
BHC061143 PCT-JP SPC JP - Japan 04 - active 2017-09-25 2017-700182 2017-12-18 2017-700182 03 - patent finally granted
BHC061143 PCT-KR KR - Korea 04 - active 2007-09-29 10-2009-7007422 2014-07-04 10-1418623 02 - patent granted
_l:OPYII
[!_:1uJJ::
:;._:E_
-
BHC061143 PCT-MX MX - Mexico 04 - active 2007-09-29 2009/002642 2013-04-19 308874 02 - patent granted 2013-02-22
BHC061143 PCT-NZ NZ - New Zealand 04 - active 2007-09-29 576153 2012-02-24 2012-06-05 576153 02 - patent granted 2012-06-05
BHC061143 PE PE - Peru 03 - inactive 2007-10-10 1368-2007 01 - patent applied for
BHC061143 PK PK - Pakistan 04 - active 2007-10-04 1159-2007 2016-06-17 142226 02 - patent granted 2015-12-31
BHC061143 PCT-RU RU - Russian Federation 04 - active 2007-09-29 2009117388 2012-11-20 2466992 02 - patent granted 2012-07-22
BHC061143 PCT-RU SPC RU - Russian Federation 04 - active 2016-07-08 2009117388 2016-11-01 2466992 03 - patent finally granted
BHC061143 SA SA - Saudi Arabia 03 - inactive 2007-10-03 07280545 01 - patent applied for
BHC061143 PCT-SG SG - Singapore 03 - inactive 2007-09-29 200901899-5 01 - patent applied for
BHC061143 PCT-SG01 SG - Singapore 04 - active 2011-10-03 201107199-0 2015-03-16 175584 02 - patent granted 2015-03-16
Page 2 of 3 - July 24, 2019
date date of Grant
BHC061143 TW TW - Taiwan, Rep. of China 04 - active 2007-10-09 96137745 2014-03-01 I428322 02 - patent granted
BHC061143 TW SPC TW - Taiwan, Rep. of China 04 - active 2015-11-09 96137745 2015-11-09 I428322 03 - patent finally granted
BHC061143 PCT-UA UA - Ukraine 04 - active 2007-09-29 200904623 2011-09-26 95984 02 - patent granted 2011-08-23
BHC061143 PCT-UA SPC UA - Ukraine 04 - active 2007-09-29 200904623 2011-09-26 95984 03 - patent finally granted
BHC061143 PCT-US US - United States 04 - active 2007-09-29 12/444974 2010-07-08 2010- 2018-05-01 9957232 02 - patent granted
0173953-A1
BHC061143 PCT-US01 US - United States 03 - inactive 2014-05-14 14/277095 2014-10-23 2014- 01 - patent applied for
0315958
BHC061143 PCT-US02 US - United States 04 - active 2018-01-30 15/884103 2018-07-12 US-2018- 01 - patent applied for
0194730-A1
COPY!I
BHC061143 VE VE - Venezuela 03 - inactive 2008-03-11 2008-000467 2011-09-29 01 - patent applied for
BHC061143 WO WO - PCT 03 - inactive 2007-09-29 PCT/EP2007/008503 2008-04-17 2008/043446 01 - patent applied for
IITRUE
r
Arc ana an er
o Anand and Anand Ad ocate
Patent A ent IN/PA 1 9
Page 3 of 3 - July 24, 2019
ANAND & ANAND
Our Ref: 17099A/P-32 31st March 2020

The Patent Office
DELHI

Sir,
following document:
1) Updated Form 3
We request the Learned Controller to kindly take the said document on record.
Yours faithfully,
(Archana Shanker)
of Anand and Anand Advocates
IITRUE COPY!I
FORM 3
(39 of 1970)
&
(As amended)
Hereby declare:
outside India.
(ii) That I/We who have made this Application No. 1628/DELNP/2009 dated 29th September
2007 alone/jointly with made for the same/ substantially same invention, application(s) for patent
in the other countries, the particulars of which are given below:

Please See Annexure
(iii) That the right in the application(s) has/have been assigned to us.
Dated this 31st Day of March 2020
~-
Archana Shanker
To
:&--
IITRUE COPY!I
ANNEXURE TO FORM 3
Indian patent application number 1628/DELNP/2009
Country Application Date Application No. Publication Date Publication No. Grant Date Grant No. Status
AR 2007‐09‐20 0704168 withdrawn
BS 2008‐03‐25 2042 2042 granted
CL 2007‐10‐11 2930‐2007 50218 granted
CL 2007‐10‐11 2930‐2007 50218 granted
EP 2006‐10‐11 06021296.6 withdrawn
JM 2008‐04‐10 18/1/4772 pending
JO 2007‐10‐07 423‐2007 26‐09‐05 3021 granted
KW 2007‐10‐10 150‐2007 pending
PA 2007‐10‐10 87503 87503 granted
AE 2007‐09‐29 328‐2009 pending
AU 2007‐09‐29 2007306716 2007306716 granted
AU 24‐05‐23 2007306716 2007306716 granted
BR 2007‐09‐29 0719828‐0 24‐02‐04 published
BY 2007‐09‐29 20090677 16460 granted
BY 2007‐09‐29 20090677 16460 granted
CA 2007‐09‐29 2666170 2666170 granted
CN 2007‐09‐29 200780037680.2 2009‐09‐30 1547903 ZL200780037680.2 granted
CN‐HK 20‐03‐24 103082.1 20‐06‐25 1136287 HK1136287 granted
CO 2007‐09‐29 09025191 withdrawn
CR 2007‐09‐29 10663 pending
CU 2007‐09‐29 2009‐0039 withdrawn
DO 2007‐09‐29 2009‐45 2009‐0045 granted
DZ 2007‐09‐29 0935 6384 granted
EC 2007‐09‐29 2009‐9185 withdrawn
EG 2007‐09‐29 488‐2009 withdrawn
EP 2007‐09‐29 07818583.2 2009‐09‐09 2097381 2097381 granted
GT 2007‐09‐29 A2009‐00057 5738 granted
HN 2007‐09‐29 2009‐000499 5354 granted
ID 2007‐09‐29 W00200900838 2009‐05‐28 0491990 IDP000045505 granted
IL 2007‐09‐29 197369 25‐06‐30 N.A. 197369 granted
IN 2007‐09‐29 1628/DELNP/2009 pending
1
JP 2007‐09‐29 2009‐531733 20‐02‐25 20‐505888 5346293 granted
JP 27‐09‐25 27‐7082 27‐7082 granted
KE 2007‐09‐29 KE/P/2009/00891 535 granted
KR 2007‐09‐29 10‐2009‐7007422 10‐1418623 granted
MA 2007‐09‐29 31857 30878 granted
MX 2007‐09‐29 2009/002642 308874 granted
MY 2007‐09‐29 20091350 MY‐152595‐A granted
NZ 2007‐09‐29 576153 22‐02‐24 576153 granted
OM 2007‐09‐29 39‐2009 pending
PH 2007‐09‐29 1‐2009‐500662 2008‐04‐17 1‐2009‐500662 granted
RU 2007‐09‐29 2009117388 2466992 granted
RU 26‐07‐08 2009117388 2466992 granted
SG 2007‐09‐29 2009899‐5 withdrawn
SG 21‐10‐03 2107199‐0 175584 granted
SV 2007‐09‐29 2009003187 pending
TN 2007‐09‐29 0072‐2009 20820 granted
TT 2007‐09‐29 TT/A/2009/00076 pending
UA 2007‐09‐29 200904623 95984 granted
UA 2007‐09‐29 200904623 95984 granted
US 2007‐09‐29 12/444974 20‐07‐08 20‐73953‐A1 9957232 granted
US 24‐05‐14 14/277095 24‐10‐23 24‐0315958 withdrawn
US 28‐‐30 15/884103 28‐07‐12 US‐28‐94730‐A1 published
VN 2007‐09‐29 1‐2009‐00698 12397 granted
ZA 2007‐09‐29 2009‐02469 2009‐02469 granted
PE 2007‐10‐10 1368‐2007 withdrawn
AT 2007‐09‐29 07818583.2 EAT 2097381 granted
BE 2007‐09‐29 07818583.2 EBE 2097381 granted
BG 2007‐09‐29 07818583.2 EBG 2097381 granted
CH 2007‐09‐29 07818583.2 ECH 2097381 granted
CH 28‐08‐03 C02097381/ pending
CY 2007‐09‐29 07818583.2 ECY 2097381 granted
CZ 2007‐09‐29 07818583.2 ECZ 2097381 granted
DE 2007‐09‐29 07818583.2 602007031165.9 granted
DK 2007‐09‐29 07818583.2 EDK 2097381 granted
EE 2007‐09‐29 07818583.2 EEE 2097381 granted
2
ES 2007‐09‐29 07818583.2 EES 2097381 granted
FI 2007‐09‐29 07818583.2 EFI 2097381 granted
FR 2007‐09‐29 07818583.2 EFR 2097381 granted
GB 2007‐09‐29 07818583.2 EGB 2097381 granted
GR 2007‐09‐29 07818583.2 3081679 granted
HU 2007‐09‐29 07818583.2 EHU 2097381 granted
IE 2007‐09‐29 07818583.2 EIE 2097381 granted
IS 2007‐09‐29 07818583.2 EIS 2097381 granted
IT 2007‐09‐29 07818583.2 5023902189977 granted
LT 2007‐09‐29 07818583.2 ELT 2097381 granted
LU 2007‐09‐29 07818583.2 ELU 2097381 granted
LV 2007‐09‐29 07818583.2 ELV 2097381 granted
MC 2007‐09‐29 07818583.2 EMC 2097381 granted
MT 2007‐09‐29 07818583.2 EMT 2097381 granted
NL 2007‐09‐29 07818583.2 ENL 2097381 granted
PL 2007‐09‐29 07818583.2 EPL 2097381 granted
PT 2007‐09‐29 07818583.2 EPT 2097381 granted
RO 2007‐09‐29 07818583.2 ERO 2097381 granted
SE 2007‐09‐29 07818583.2 07818583.2 granted
SI 2007‐09‐29 07818583.2 ESI 2097381 granted
SK 2007‐09‐29 07818583.2 ESK 2097381 granted
TR 2007‐09‐29 07818583.2 ETR 2097381 granted
PK 2007‐10‐04 1159‐2007 142226 granted
SA 2007‐10‐03 07280545 withdrawn
TH 2007‐10‐04 07005024 2009‐09‐24 98396 published
IITRUE COPYII
TW 2007‐10‐09 96137745 I428322 granted
TW SPC 25‐11‐09 96137745 I428322 granted
UY 2007‐10‐08 30633 pending
VE 2008‐03‐11 2008‐000467 21‐09‐29 withdrawn
WO 2007‐09‐29 PCT/EP2007/008503 2008‐04‐17 2008/043446 withdrawn
Dated: 31st March 2020
Archana Shanker
3
ANAND & ANAND
Our Ref: 17099A/P-32 July 24, 2020

The Patent Office
Delhi

Applicant: BAYER HEALTHCARE LLC
Respected Sir/Madam,
We write in respect of the above application and are enclosing herewith the following document:
1) Updated Form 3
The Learned Controller is requested to take the aforesaid document on record.
Yours faithfully
Saibal Ghosh
IN/PA 524
Of Anand and Anand Advocates
\\askfill\Patent Data\MD Noor Hasan\S. Malik Sir\17099A-P31\Section 8.1
First Channel Building, Plot No. 17 A, Sector 16 A, Film City, ~ +91-120-4059300 email@anandandanand.com
REGISTEREDOFFICE: B-41, Nizamuddin East, New Delhi 110 II TRUE COPYII NOIDA I NEW DELHI I MUMBAI I CHENNAI
FORM 3
(39 of 1970)
&
(As amended)
I/We, Bayer Healthcare LLC., a corporation organized and existing under the laws of USA, of 100 Bayer Boulevard,
Whippany, New Jersey 07981, USA.
Hereby declare:
(i) That I/We have not made any application for the same/substantially the same invention outside India.
(ii) That I/We who have made this Application No 1628/DELNP/2009 dated September 29, 2007 alone/jointly with
made for the same/ substantially same invention, application(s) for patent in the other countries, the particulars of which
are given below:
Status of the
Country Application No Date of application Patent No. Date of grant
application
KINDLY SEE ANNEXURE
I/We undertake that upto the date of grant of the patent, by the Controller, I/We would keep him informed in writing the
details regarding corresponding applications for patents filed outside India within six months from the date of filing of
such application.
Dated this 24th day of July, 2020
:fp_,Q,/-N'
-·
Saibal Ghosh
IN/PA 524
To
The Patent Office,
Delhi
IITRUE COPYII
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Filenumber Application Date Application No Publication Date Publication No Grant Date Grant No Status
BHC061143 AR 2007-09-20 070104168 inactive
BHC061143 BS 2008-03-25 2042 2013-12-16 2042 granted
BHC061143 CL 2007-10-11 2930-2007 2014-05-20 50218 granted
BHC061143 CL SPC 2007-10-11 2930-2007 2014-05-20 50218 granted
BHC061143 EP 2006-10-11 06021296.6 inactive
BHC061143 JM 2008-04-10 18/1/4772 pending
BHC061143 JO 2007-10-07 423-2007 2016-09-05 2016-12-07 3021 granted
BHC061143 KW 2007-10-10 150-2007 pending
BHC061143 PA 2007-10-10 87503 2009-07-13 87503 granted
BHC061143 PCT-AE 2007-09-29 328-2009 pending
BHC061143 PCT-AU 2007-09-29 2007306716 2013-12-24 2007306716 granted
BHC061143 PCT-AU SPC 2014-05-23 2007306716 2015-02-26 2007306716 granted
BHC061143 PCT-BR 2007-09-29 0719828-0 2014-02-04 published
BHC061143 PCT-BY 2007-09-29 20090677 2012-07-05 16460 granted
BHC061143 PCT-BY SPC 2007-09-29 20090677 2015-09-28 16460 granted
BHC061143 PCT-CA 2007-09-29 2666170 2016-05-24 2666170 granted
BHC061143 PCT-CN 2007-09-29 200780037680.2 2009-09-30 101547903 2014-01-15 ZL200780037680.2 granted
BHC061143 PCT-CN-HK 2010-03-24 10103082.1 2010-06-25 1136287 2014-09-26 HK1136287 granted
BHC061143 PCT-CO 2007-09-29 09025191 inactive
BHC061143 PCT-CR 2007-09-29 10663 pending
BHC061143 PCT-CU 2007-09-29 2009-0039 inactive
BHC061143 PCT-DO 2007-09-29 2009-45 2013-05-15 2009-0045 granted
BHC061143 PCT-DZ 2007-09-29 090135 2011-03-09 6384 granted
BHC061143 PCT-EC 2007-09-29 2009-9185 inactive
BHC061143 PCT-EG 2007-09-29 488-2009 inactive
BHC061143 PCT-EP01 2007-09-29 07818583.2 2009-09-09 2097381 2013-06-19 2097381 granted
BHC061143 PCT-GT 2007-09-29 A2009-00057 2014-02-20 5738 granted
BHC061143 PCT-HN 2007-09-29 2009-000499 2013-02-28 5354 granted
BHC061143 PCT-ID 2007-09-29 W00200900838 2009-05-28 0491990 2017-04-18 IDP000045505 granted
BHC061143 PCT-IL 2007-09-29 197369 2015-06-30 N.A. 2015-10-01 197369 granted
BHC061143 PCT-IN 2007-09-29 1628/DELNP/2009 pending
BHC061143 PCT-JP 2007-09-29 2009-531733 2010-02-25 2010-505888 2013-08-23 5346293 granted
BHC061143 PCT-JP SPC 2017-09-25 2017-700182 2017-12-18 2017-700182 granted
BHC061143 PCT-KE 2007-09-29 KE/P/2009/00891 2012-09-13 535 granted
BHC061143 PCT-KR 2007-09-29 10-2009-7007422 2014-07-04 10-1418623 granted
BHC061143 PCT-MA 2007-09-29 31857 2009-11-02 30878 granted
BHC061143 PCT-MX 2007-09-29 2009/002642 2013-04-19 308874 granted
BHC061143 PCT-MY 2007-09-29 20091350 2014-10-31 MY-152595-A granted
BHC061143 PCT-NZ 2007-09-29 576153 2012-02-24 2012-06-05 576153 granted
BHC061143 PCT-OM 2007-09-29 39-2009 pending
BHC061143 PCT-PH 2007-09-29 1-2009-500662 2008-04-17 2013-09-02 1-2009-500662 granted
BHC061143 PCT-RU 2007-09-29 2009117388 2012-11-20 2466992 granted
BHC061143 PCT-RU SPC 2016-07-08 2009117388 2016-11-01 2466992 granted
BHC061143 PCT-SG 2007-09-29 200901899-5 inactive
BHC061143 PCT-SG01 2011-10-03 201107199-0 2015-03-16 175584 granted
BHC061143 PCT-SV 2007-09-29 2009003187 pending
BHC061143 PCT-TN 2007-09-29 0072-2009 2010-10-22 20820 granted
BHC061143 PCT-TT 2007-09-29 TT/A/2009/00076 pending
BHC061143 PCT-UA 2007-09-29 200904623 2011-09-26 95984 granted
BHC061143 PCT-UA SPC 2007-09-29 200904623 2011-09-26 95984 granted
BHC061143 PCT-US 2007-09-29 12/444974 2010-07-08 2010-0173953-A1 2018-05-01 9957232 granted
BHC061143 PCT-US01 2014-05-14 14/277095 2014-10-23 2014-0315958 inactive
BHC061143 PCT-US02 2018-01-30 15/884103 2018-07-12 US-2018-0194730-A1 inactive
BHC061143 PCT-VN 2007-09-29 1-2009-00698 2014-02-13 12397 granted
BHC061143 PCT-ZA 2007-09-29 2009-02469 2010-06-30 2009-02469 granted
BHC061143 PE 2007-10-10 1368-2007 inactive
BHC061143 PEP-AT01 2007-09-29 07818583.2 2013-06-19 EAT 2097381 granted
BHC061143 PEP-BE01 2007-09-29 07818583.2 2013-06-19 EBE 2097381 granted
BHC061143 PEP-BG01 2007-09-29 07818583.2 2013-06-19 EBG 2097381 granted
BHC061143 PEP-CH01 2007-09-29 07818583.2 2013-06-19 ECH 2097381 granted
BHC061143 PEP-CH01 SPC 2018-08-03 C02097381/01 pending
BHC061143 PEP-CY01 2007-09-29 07818583.2 2013-06-19 ECY 2097381 granted
BHC061143 PEP-CZ01 2007-09-29 07818583.2 2013-06-19 ECZ 2097381 granted
BHC061143 PEP-DE01 2007-09-29 07818583.2 2013-06-19 602007031165.9 granted
BHC061143 PEP-DK01 2007-09-29 07818583.2 2013-06-19 EDK 2097381 granted
BHC061143 PEP-EE01 2007-09-29 07818583.2 2013-06-19 EEE 2097381 granted
BHC061143 PEP-ES01 2007-09-29 07818583.2 2013-06-19 EES 2097381 granted
BHC061143 PEP-FI01 2007-09-29 07818583.2 2013-06-19 EFI 2097381 granted
BHC061143 PEP-FR01 2007-09-29 07818583.2 2013-06-19 EFR 2097381 granted
BHC061143 PEP-GB01 2007-09-29 07818583.2 2013-06-19 EGB 2097381 granted
BHC061143 PEP-GR01 2007-09-29 07818583.2 2013-06-19 3081679 granted
BHC061143 PEP-HU01 2007-09-29 07818583.2 2013-06-19 EHU 2097381 granted
BHC061143 PEP-IE01 2007-09-29 07818583.2 2013-06-19 EIE 2097381 granted
BHC061143 PEP-IS01 2007-09-29 07818583.2 2013-06-19 EIS 2097381 granted
BHC061143 PEP-IT01 2007-09-29 07818583.2 2013-06-19 502013902189977 granted
BHC061143 PEP-LT01 2007-09-29 07818583.2 2013-06-19 ELT 2097381 granted
BHC061143 PEP-LU01 2007-09-29 07818583.2 2013-06-19 ELU 2097381 granted
BHC061143 PEP-LV01 2007-09-29 07818583.2 2013-06-19 ELV 2097381 granted
...., BHC061143 PEP-MC01 2007-09-29 07818583.2 2013-06-19 EMC 2097381 granted
BHC061143 PEP-MT01 2007-09-29 07818583.2 2013-06-19 EMT 2097381 granted
BHC061143 PEP-NL01 2007-09-29 07818583.2 2013-06-19 ENL 2097381 granted
:1~ BHC061143 PEP-PL01

BHC061143 PEP-PT01
BHC061143 PEP-RO01
BHC061143 PEP-SE01
2007-09-29
2007-09-29
2007-09-29
2007-09-29
07818583.2
07818583.2
07818583.2
07818583.2
2013-06-19
2013-06-19
2013-06-19
2013-06-19
EPL 2097381
EPT 2097381
ERO 2097381
07818583.2
granted
granted
granted
granted
BHC061143 PEP-SI01 2007-09-29 07818583.2 2013-06-19 ESI 2097381 granted
BHC061143 PEP-SK01 2007-09-29 07818583.2 2013-06-19 ESK 2097381 granted
BHC061143 PEP-TR01 2007-09-29 07818583.2 2013-06-19 ETR 2097381 granted
BHC061143 PK 2007-10-04 1159-2007 2016-06-17 142226 granted
BHC061143 SA 2007-10-03 07280545 inactive
BHC061143 TH 2007-10-04 0701005024 2009-09-24 98396 published
BHC061143 TW 2007-10-09 96137745 2014-03-01 I428322 granted
BHC061143 TW SPC 2015-11-09 96137745 2015-11-09 I428322 granted
BHC061143 UY 2007-10-08 30633 pending
BHC061143 VE 2008-03-11 2008-000467 2011-09-29 inactive
BHC061143 WO 2007-09-29 PCT/EP2007/008503 2008-04-17 2008/043446 inactive
pated this 24• day of July, 2020 s..Q::-.

Saibal Ghosh
INIPA524
Aeents for the Applicant
ANAND & ANAND
Our Ref: 17099A/P-32 August 08, 2022

The Patent Office
Delhi

Applicant: BAYER HEALTHCARE LLC
Respected Sir/Madam,
We write in respect of the above application and are enclosing herewith the following document:
1) Updated Form 3
The Learned Controller is requested to take the aforesaid document on record.
Yours faithfully
Saibal Ghosh
IN/PA 524
\\askfill\Patent Data\MD Noor Hasan\S. Malik Sir\17099A-P32\Section 8.1 dated 08.08.2022
First Channel Building, Plot No. 17 A, Sector 16 A, Film City, &-- +91-120-4059300 ■ email@anandandanand.com
REGISTEREDOFFICE B-41, Nizamuddin East, New Delhi 110 IITRUE COPYII NOIDA I NEW DELHI I MUMBAI I CHENNAI
FORM 3
(39 of 1970)
&
(As amended)
I/We, Bayer Healthcare LLC., a corporation organized and existing under the laws of USA, of 100 Bayer Boulevard,
Whippany, New Jersey 07981, USA.
Hereby declare:
(i) That I/We have not made any application for the same/substantially the same invention outside India.
(ii) That I/We who have made this Application No 1628/DELNP/2009 dated September 29, 2007 alone/jointly with
made for the same/ substantially same invention, application(s) for patent in the other countries, the particulars of which
are given below:
Status of the
Country Application No Date of application Patent No. Date of grant
application
KINDLY SEE ANNEXURE
That the right in the application(s) has/have been assigned to us.
I/We undertake that upto the date of grant of the patent, by the Controller, I/We would keep him informed in writing the
details regarding corresponding applications for patents filed outside India within six months from the date of filing of
such application.
:fp_,Q,/-N'
-·
Saibal Ghosh
IN/PA 524
To
The Patent Office,
Delhi
* The annexed data/information may include entries that relate to continuation applications,
continuation-in-part applications, child continuity applications, divisional applications and other similar
applications. Though the applicant readily believes that said applications do not relate to the same or
substantially the same invention as the instant application, in the absence of any interpretation of the
expression “same/substantially the same”, said data is being included only by way of abundant caution.
IITRUE COPYII
Annexure to Form-3
Indian Patent Application No.
Application Internal Publication Date of
Filenumber Application Status Date Application No Status Date Publication No Grant Patent No
BHC061143 AR 01 - patent applied for 2007-09-20 070104168 03 - inactive
BHC061143 BS 02 - patent granted 2008-03-25 2042 04 - active 2013-12-16 2042
BHC061143 CL 02 - patent granted 2007-10-11 2930-2007 04 - active 2014-05-20 50218
03 - patent finally
BHC061143 CL SPC granted 2007-10-11 2930-2007 04 - active 2014-05-20 50218
BHC061143 EP 01 - patent applied for 2006-10-11 06021296.6 03 - inactive
BHC061143 JM 01 - patent applied for 2008-04-10 18/1/4772 04 - active
_l:OPYII
BHC061143 JO 02 - patent granted 2007-10-07 423-2007 04 - active 2016-09-05 2016-12-07 3021
BHC061143 KW 01 - patent applied for 2007-10-10 150-2007 04 - active
[!_:1uJJ::
BHC061143 PA 02 - patent granted 2007-10-10 87503 04 - active 2009-07-13 87503
:;._:E_
-
BHC061143 PCT-AE 02 - patent granted 2007-09-29 328-2009 04 - active 2020-05-13 2082
BHC061143 PCT-AU 02 - patent granted 2007-09-29 2007306716 04 - active 2013-12-24 2007306716
BHC061143 PCT-AU 03 - patent finally
SPC granted 2014-05-23 2007306716 04 - active 2015-02-26 2007306716
BHC061143 PCT-BR 02 - patent granted 2007-09-29 0719828-0 04 - active 2014-02-04 2022-05-17 PI0719828-0
BHC061143 PCT-BY 02 - patent granted 2007-09-29 20090677 04 - active 2012-07-05 16460
BHC061143 PCT-BY 03 - patent finally
BHC061143 PCT-CA 02 - patent granted 2007-09-29 2666170 04 - active 2016-05-24 2666170
BHC061143 PCT-CN 02 - patent granted 2007-09-29 200780037680.2 04 - active 2009-09-30 101547903 2014-01-15 ZL200780037680.2
BHC061143 PCT-CN-
HK 02 - patent granted 2010-03-24 10103082.1 04 - active 2010-06-25 1136287 2014-09-26 HK1136287
BHC061143 PCT-CO 01 - patent applied for 2007-09-29 09025191 03 - inactive
BHC061143 PCT-CR 01 - patent applied for 2007-09-29 10663 03 - inactive
BHC061143 PCT-CU 01 - patent applied for 2007-09-29 2009-0039 03 - inactive
BHC061143 PCT-DO 02 - patent granted 2007-09-29 2009-45 04 - active 2013-05-15 2009-0045
BHC061143 PCT-DZ 02 - patent granted 2007-09-29 090135 04 - active 2011-03-09 6384
BHC061143 PCT-EC 01 - patent applied for 2007-09-29 2009-9185 03 - inactive
BHC061143 PCT-EG 01 - patent applied for 2007-09-29 488-2009 03 - inactive
BHC061143 PCT-EP01 02 - patent granted 2007-09-29 07818583.2 04 - active 2009-09-09 2097381 2013-06-19 2097381
BHC061143 PCT-GT 02 - patent granted 2007-09-29 A2009-00057 04 - active 2014-02-20 5738
BHC061143 PCT-HN 02 - patent granted 2007-09-29 2009-000499 04 - active 2013-02-28 5354
BHC061143 PCT-ID 02 - patent granted 2007-09-29 W00200900838 04 - active 2009-05-28 0491990 2017-04-18 IDP000045505
BHC061143 PCT-IL 02 - patent granted 2007-09-29 197369 04 - active 2015-06-30 N.A. 2015-10-01 197369
1628/DELNP/200
BHC061143 PCT-IN 01 - patent applied for 2007-09-29 9 04 - active
BHC061143 PCT-JP 02 - patent granted 2007-09-29 2009-531733 04 - active 2010-02-25 2010-505888 2013-08-23 5346293
03 - patent finally
BHC061143 PCT-JP SPC granted 2017-09-25 2017-700182 04 - active 2017-12-18 2017-700182
BHC061143 PCT-KE 02 - patent granted 2007-09-29 KE/P/2009/00891 04 - active 2012-09-13 535
_l:OPYI
BHC061143 PCT-KR 02 - patent granted 2007-09-29 10-2009-7007422 04 - active 2014-07-04 10-1418623
[!_:1uJJ::
BHC061143 PCT-MA 02 - patent granted 2007-09-29 31857 04 - active 2009-11-02 30878
:;._:E_
-
BHC061143 PCT-MX 02 - patent granted 2007-09-29 2009/002642 04 - active 2013-04-19 308874
BHC061143 PCT-MY 02 - patent granted 2007-09-29 20091350 04 - active 2014-10-31 MY-152595-A
BHC061143 PCT-NZ 02 - patent granted 2007-09-29 576153 04 - active 2012-02-24 2012-06-05 576153
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00107/00006/215-
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BHC061143 PCT-US01 01 - patent applied for 2014-05-14 14/277095 03 - inactive 2014-10-23 2014-0315958
US-2018-0194730-
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BHC061143 PEP-CH01 03 - patent finally
SPC granted 2018-08-03 C02097381/01 04 - active 2021-02-26 C02097381/01
_l:OPYI
BHC061143 PEP-CY01 02 - patent granted 2007-09-29 07818583.2 04 - active 2013-06-19 ECY 2097381
[!_:1uJJ::
BHC061143 PEP-CZ01 02 - patent granted 2007-09-29 07818583.2 04 - active 2013-06-19 ECZ 2097381
:;._:E_
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BHC061143 PEP-DE01 02 - patent granted 2007-09-29 07818583.2 04 - active 2013-06-19 602007031165.9
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-,, TRUE COPYII

BHC061143 TW 02 - patent granted 2007-10-09 96137745 04 - active 2014-03-01 I428322
03 - patent finally
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PCT/EP2007/0085
BHC061143 WO 01 - patent applied for 2007-09-29 03 03 - inactive 2008-04-17 2008/043446
Saibal Ghosh
IN/PA 524
- 32 -
What is claimed is:
1. A compound of the formuJa (II)
(Il)
2. The compound of claim I which shows in the X-ray diffractometry a peak maximum of
the 2 Theta angel of21.2.
3. The compound of claim 1 which shows in the FIR spectrum a peak maximum of 353
cm·1•
4. A process for the preparation of the compound of the fonnula {Il) of any of claims 1 to
3 which comprises dissolution of 4-[4-({[4-chloro-3-
(trifluoromethyl)phenylJcarbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-
carboxamide and adding water until precipitation.
5. The preparation of the compound of the formula (Il) of any of claims l to 3 which
comprises suspension of 4-[4-( {[4-chloro-3-
(trifluoromethyl)phenyl]carbamoyl}amino}-3-fluorophenoxy]-N-melhylpyridine-2-
carboxamide in an aqueous solvent and then stirring or shaking until conversion to the
compound of the fonnula (II).
6. A compound of the formula (ll) of any of claims 1 to 3 for the treatment of hyper-
proliferative disorders.
7. A compound of the formula (II) of any of claims 1 to 3 for the treatment of solid tumors,
lymphomas, sarcomas, leukemias, cancers of the breast, respiratory tract, brain,
reproductiv~ organs, digestive tract, urinary tract, eye, liver, skin, head and neck.
thyroid and/or parathyroid.
8. A use of the compound of the formula (II) of any of claims 1 to 3 for the preparation of a
pharmaceutical composition for the treabnent of hyper-proliferative disorders.
11TRUE COPYjl
-33 -
9. The use of claim 8 for the treabnent of solid twnors, lymphomas, sarcomas, leukemias,
cancers of the breast, respiratory tract, brain. reproductive organs, digestive tract,
urinary tract, eye, liver, skin, head and neclc,thyroid and/or parathyroid.
10. A pharmaceutical composition comprising the compound of the formula (II) of any of
claims 1 to 3 mainly, no significant fractions of another form of 4-(4-( {[4-chloro-3-
(trifluoromethyl)phenyl]carbamoyl} amino )-3-fluorophenoxy]-N-methylpyridine-2-
carboxamide and one or more inert, nontoxic, pharmaceuticallysuitable excipients.
11. The phannaceutical composition of claim 10 containing more than 90 percent by weight
of the comp01mdof the formula (Il) of any of claims 1 to 3 related to the total amount of
the compoundof the formula (D)present in the composition.
12. The pharmaceuticalcomposition of any of claims IOor 11 for the treatment of disorders.
13. A method for treating hyper-proliferative disorders using an effective amount of the
compol.Dldof the fonnula (Il) of any of claims l to 3 or of a pharmaceuticalcomposition
as defined in one of claims 10 to J 2.
14. A combinationcomprisingthe compoundof the formuJa(Il) of any of claims1 to 3 and

one or more other pharmaceutical agents.
15. The combination of claim 14 wherein the one or more other phannaceutical agents are
cytoto,dc agents, signal transduction inhibitors, anti--canceragents, or anticmctics.
16. The phannaceutical composition of any of claims IO to 12 comprising one or more other
phannaceutical agents.
17. The pharmaceutical composition of claim 16 wherein the one or more other
phannaceuticaJ agents are anti-hyper-proliferative agents, cytotoxic agents, signal
transduction inhibitors, anti-canceragents and/or antiemetics.
ATTORNEY FO
IITRUE _COPYII
GOVERNMENT OF INDIA Tel No. (091)(011) 28034304-
t:)l!!l. PATENT OFFICE 06,22
■ 1• INTELLECTUAL PROPERTY BUILDING Fax No. 011
INTELLECTUAL Plot No. 32, Sector-14,Dwarka 28034301,28034302
PROPERTY INDIA New Delhi - 110 078 E-mail : delhi-patent@nic.in
Web Site : www.ipindia.nic.in
Letter No.: CHEM/2022 Date : 13/08/2014
SUB : First Examination Report
APPLICATION NUMBER : 1628/DELNP/2009
Applicant Name : BAYER

BAYER PHARMA AKTIENGESELISCHAFT
PHARMAAKTIENGESELISCHAFT
Description :
1. With reference to the RQ No. 7519/RQ-DEL/2010 Dated 05/10/2010 in the above mentioned application
for Grant of Patent , Examination has been conducted under Section 12 and 13 of the Patents Act 1970 ,
The following objections are hereby communicated
2. You are requested to comply with the objections by filing your reply by way of explanation and/or
amendments within 12 months from the date of issue of FER failing which you application will be
treated as "Deemed to have been abandoned" under section 21(1) of the Act. The last Date is
13/08/2015.
3. You are advised to file your reply at the earliest so that the office can further proceed with application
and complete the process within the prescribed period.
Objections :
1. Novelty Under Section 2(1) (j) of Patents Act, 1970.
The present application does not meet the requirement of section 2(1) (j) of patents Act, 1970 because
the subject-matter of claim-1 and their dependent claims is not new over following cited documents.
D1: WO2006/026500
D1 dicloses regorafenib hydrate including the monohydrate forms of formula-II. It further discloses the
pharmaceutical composition and combination with other pharmaceutical agents (see page-1, 4 Para 30-
31, 82). Hence the present application lacks novelty and fails to meet the requirement of section 2(1) (j)
of the Patents Act, 1970.
Inventive Step Under Section 2(1) (j)------
----------- (a) of Patent Act, 1970.
Subject-matter of claims 1-17 does not involve an inventive step as it does not appear to involve any
technical advancement or economic significance over the D1-D7
D2: WO 2005/009961
D3: Stephen Byrn et. al "Pharmaceutical solid: A strategic approach to regulatory considerations"
IITRUE COPYjl
"published in Pharmaceutical Research, vol. 12, No.7, 1995
D4: Rong Liu "Water insoluble drug Formation (2000)" Chapter 15" -Alteration of the solid state of drug
substance: Polymorphs, solvates, and Amorphous Forms
D5:WO2005/077845 entitled "Process for preparing 2-aminothiazole-5-aromatic carboxamide as kinase
inhibitor" published in August 25, 2005
D6: Rober et. al " Assay of 855 test chemicals in ten tester strains using a new modification of Ames test
for bacterial mutagens" published in Cancer Res 1979; 39:682-693
D7: US 4,223,153 entitled "Crystalline forms of N-2-(6-methoxy)benzothiazolyl-N"phenyl urea" published
on September 16, 1980.
D2 discloses Regorafenib of formula-1 or salts, prodrugs or metabolites thereof. It further discloses
pharmaceutical compositions comprising Regorafenib and the use of the compound of formula-1.
D3 discloses a drug molecule can be obtained in the form of polymorphs, hydrates, desolvated solvates,
and amorphous forms.
D4 discloses a method to study a solid state drug during pre-formulation screening and its importance.
It further discloses that water should be included during the crystallisation experiments.
D5 discloses monohydrate form of dasatinib its purity as well as production process.
D6 discloses type of a genotoxic impurity that is commonly found in N, N diaryl urea compounds.
D7 discloses a process for the reduction of genotoxic impurity in anN, N-diaryl urea derivative,
Frentizole.
Therefore it would appear that the combination of the technical teaching as disclosed in D1-D7 is
suggested to the skilled person in order to provide additional compounds used for the same purpose.
Hence, in view of the above cited documents the alleged invention lacks inventive step & fails to meet
the requirement of section 2(1) (j)(a) of the Patents Act, 1970.
2. As worded the subject matter of the claims 8-9 do not constitute an invention under section 2(1) (j) of
the Patents Act, 1970 because neither process nor product has been defined.
3. The alleged invention as claimed in claims 1-3 is not allowable u/s 3(d). The said claims relate to mere
derivative of known compound and fail to describe any significant improvement with respect to the
therapeutic effect.
The alleged invention as claimed in claims 4-5 is not allowable u/s 3(d). The said claims relate to known
process for making known compounds.
Claims 10-12 and 14-17 fall u/s 3(e) of Patents Act, 1970 because it is mere admixture of the
components and does not contain synergistic ratios of the constituents.
Claim 13 fall u/s 3(i) of Patents Act, 1970 because the subject matter of the said clam related to method
of treating disease on human beings.
4. Recitations, and/or, in claims is vague and unclear and make the scope of the claims indefinite for which
protection is sought.
5. (a)The claim part of the complete specification should commence with phrase; I/We claim.
(b)The expression "of claim" as used in claims should be replaced "as claimed in”.
6. Claim-1 lacks clarity because of “x H2O”. The “x” implies a range of water molecules with the exact
number not defined.
7. Form-3 filed by the applicant dated on 12/08/2013 and 04/03/2014 may not be taken on the record as
the information regarding the filing of application in Austria, Belgium, Bulgaria, et.c has not been filed
within Prescribed time limit as per the section 8(1) and rule 12 of Patents Act, 1970.
8. The form-1 is to be filed in the prescribed manner as per rule 20(7) of the Patents Act 1970. The column
which is not applicable,only struck-out not to be deleted.
9. The applicant fails to meet the requirement of section 7(2) because Endorsement by or assignment
from inventor or applicant in convention country has not filed as per Rule 10 of the Patents Act, 1970.
10. English translation of the priority documents is to file as per the rule 21(2) of Patents Act, 1970.
11. The applicant fails to meet the requirement of rule 15 of Indian Patents Act 1970 in respect of drawing.
The same is to be filed in sequentially or systematically numbering, name of the applicant, signature of
the applicant or agent etc.
12. The applicant fails to meet the requirement of rule 13(7) of Indian Patents Act 1970 because the
abstract is to be filed with title of the invention.
13. Details regarding the search and/or examination report including claims of the application allowed, as
referred to in Rule 12(3) of the Patent Rule, 2003, in respect of same or substantially the same invention
filed in all the major Patent offices along with appropriate translation where applicable, should be
submitted within a period of Six months from the date of receipt of this communication as provided
under section 8(2) of the Indian Patents Act.
14. Details regarding application for Patents which may be filed outside India from time to time for the
same or substantially the same invention should be furnished within Six months from the date of filing
of the said application under clause(b) of sub section(1) of secton 8 and rule 12(1) of Indian Patent Act.
( Dr. Ajay Thakur )

Asst. Controller of Patents & Designs
NOTE : All Communications to be sent to the Controller of Patents at INTELLECTUAL PROPERTY BUILDING
Plot No. 32, Sector-14,Dwarka New Delhi - 110 078.
-~---------------------------------------~-- -7
PERfE~O LEGAL
Attorneys-At-Law
9655, Sector- C, Pocket- 9
Vasant Kunj
New Delhi 110070 India
Tel. : +91 11 4176 7656
Email : mail@perfexiolegal.com
Video Conf IP: 182.71.72.195
Website: www.perfexiolegal.com
I
Our Ref: SKR/VRN/IP 1628/DELNP /2009
Monday, January 19, 2015
lllllIIIIIII III IIIII
IIll
THE CONTROLLER OF PATENTS 0000048462
- THE PATENT OFFICE
DELHI
Kind attention: Dr. Ajay Thakur
Assistant Controller of Patents
FINAL DEADLINE: August 1.3,2015
Dear Sirs,
Re: BAYER HEALTHCARE LLC

Indian Patent Application No. 1628/DELNP /2009
Dated: March 12, 2009
Priority date: October 11, 2006
With reference to the official letter dated August 13, 2014, we submit herewith the
under-mentioned documents and present the following reply:
The first objection of the Learned Controller is respectfully resisted. It is submitted

that the present invention is novel and involves an inventive step. The Learned
Controller has cited the following prior art documents -
► Dl: ,t\7O2006/026500;
► D2: WO 2005/009961;
► D3: Stephen Byrn et.al "Pharmaceutical solid: A strategic approach to
regulatory considerations", published in Pharmaceutical Research, vol. 12,
No. 7, 1995;
► 04: Rong Liu "Water insoluble drug Formation (2000)" Chapter 15" -
Alteration of the solid state of drug substance: Polymorphs, solvates, and
Amorphous Forms;
► D5: WO2005/077945 (erroneously referred to as WO2005/077~45 by the
Controller) entitled "Process for preparing 2-aminothiazole-5-aromatic
carboxamide as kinase inhibitor" published. on August 25, 2005;
► 06: Robert et. al" Assay of 855 test chemicals in ten tester strains using a new
modification of Ames test for bacterial mutagens" published in Cancer Res
1979; 39:682-693; and -- -
9 or"-~z-cJrs=-1 s :-2: 3- --•
-neLHI 1 - - •-
--· Pa el of7
Advant Navis Business Park, Tower B,.B-203, 2nd Floor, Plot No. 7, Sector 142, Expressway, Noida - 201 305"In~
Tel.: +91 120 4343 (M' '"' ~"' '"'0 ··: +91 120 4343 643
IiTRUE COPYjl
► D7: US 4,223,153 entitled "Crystalline forms of N-2-(6-
methoxy)benzothiazolyl-N"phenyl urea" published on September 16, 1980;
It is submitted that none of the above documents, read alone or in combination,

anticipates or make the present invention obvious for the reasons mentioned
hereinbelow:
RE NOVELTY:
It is submitted that D1 discloses regorafenib (which is the compound of formula (II),·
• page 1, paragraph [0031] and its hydrates. However, it is pertinent to note that D1
clearly mentions hydrates in the plural form and not in the singular form. Therefore
the monohydrate of regorafenib (which is the compound of formula (II) as claimed
in the present claim 1) is not specifically disclosed by bl and therefore, regorafenib
monohydrate is not anticipated by D1.
In view of the above, the prior art document D1 cited by the Learned Controller does
not disclose or anticipate regorafenib monohydrate and therefore, the present claim
1 is novel. It is submitted that .the dependent claims of claim 1 are novel at least by
virtue of novel claim 1.
RE INVENTIVE STEP:
It is submitted that none of the prior art documents cited by the Learned Controller,
either read alone or in combination, would make the present invention obvious to a
person skilled in the art for the reasons submitted hereinbelow:
It is submitted that while prior art document D1 describes regorafenib hydrates,
however, it does not describe the specific monohydrate. The closest prior art can be
found in D1, where the difference to the present claim 1 is the type or form of
hydrate which ,is the provision of the monohydrate form. The problem to be solved
was the provision of a form of regorafenib with high stability and high purity. The
problem is solved by the monohydrate of regorafenib which surprisingly shows a
higher stability and higher purity than the water-free regorafenib.
It is further submitted that D1 does not teach or suggest which regorafenib form, in
particular, which hydrate form of regorafenib shows said improved properties.
Starting from D1 there are several forms of regorafenib available like the water-free
form in different polymorphic forms; salts, solvates or hydrates. It is further
submitted that D1 does not disclose that the monohydrate form is the form of
regorafenib having improved properties regarding stability and purity. During the
storage of regorafenib, a side product is formed caused by hydrolyses which is 4-(4-
amino-3-fl u?rophenoxy)pyridine-2-carboxy lie acid methy lamide (AFP-PMA ).
Surprisingly, the monohydrate of regorafenib which contains water in an amount of
3.6% by weight is more stable during storage than the water-free regorafenib known
from the prior art. This is the more surprising because the side product is caused by
hydrolysis of regorafenib. The skilled person would refrain from an
election/ selection of a hydrate form when he would know that regorafenib is
15: 23
Page 2 of 7
~ TRUE COPYII
sensitive over hydrolysis. Therefore, it is very surprising that it is the monohydrate,
which is the more stable form.
In respect to D2, it is submitted that D2 only discloses the water-free regorafenib but
not the monohydrate. It is further submitted that the skilled person recejves from D2
no indication at all of solvates, let alone of hydrates, and particularly not of the
monohydrate. It is submitted that there is a fundamental difference between
complexes, such as hydrate complexes, for example, and salts. For this reason
already, the skilled person receives no motivation at all from D2 to prepare hydrates,
let alone monohydrate.
D2 •is therefore, unsuitable as a prior art, since this document does not reveal any
indication of regorafenib hydrate to the skilled person nor motivates him or her to
prepare a monohydrate. ·consequently, the subject matter of claims on record is
inventive over D2.
Regarding D3, it is submitted that D3 is a review article on the identification of
solids, such as of po\ymorphs, hydrates, solvates and amorphous forms, for
example. D3 likewise provides the skilled person with no motivation to prepare
monohydrates in order to increase the product stability. •
This reflects the very complex situation at the beginning when looking for a stable
form. It can be seen'that there are many possibilities to end up and the hydrate form
is one of a plenty of possibilities. It is further submitted that D3 does not teach that
one has to elect the monohydrate form for regorafenib. D3 only describes a general
method how to characterize solids but it does not give any advice/ suggestion as to
which is to be elected/ selected.
It is further submitted that D4 is from a disclosure degree equivalent to D3. D4 deals
with the problem of water insoluble drugs and how to improve solubility. D4
describes that it is a huge effort to find the most soluble drug by looking into the
different forms of drugs like polymorphs, salts, solvates and hydrates. D4 prefers the
use of stable hydrates over the free base, since the free base on storage may convert
to the hydrate and, as a result, unwanted product inhomogeneities are likely. D4,
however, provides no indication of a smaller concentration of degradation products
in the monohydrate.
•There is no clear guidance which is the preferred form but D4 describes that it is a
drug-by-drug situation which means it is different for· each drug which is the most
stable and/ or most soluble form. It is submitted that this is exactly a very complex
problem as explained on page 541 of D4. It is further submitted that often the best
soluble form of a drug is the most unstable one. Therefore, the problem to be solved
is to find the balance between stability and solubility which is not a routine work
and the outcome thereof cannot be predicted.
Regarding D5, it is submitted that D5 is only about dasatinib which is a different
chemical compound as regorafenib and, therefore, is not relevant at all for
establishing inventive step or otherwise of invention covered by the patent
application.
DELHI Page 3 of 7
IITRUE COPY!I
It is submitted that D6 deals about the Ames test to determine the mutagenic activity
of inter alia, several amino aryl compounds. It is pertinent to note that D6 is silent
about regorafenib as well as about which compound form of regorafenib_ is
preferred. In view of the above, it is submitted that D6 is not relevant.
It is further submitted that D7 deals about the compound frentizole. Since frentizole
is not regorafenib, D7 is not relevant.
In view of what has been stated hereinabove, it is submitted that Dl, D2, D3, D4, D5,
D6, and D7, read alone or in combination would not make the subject matter of the
patent application, obvious to a person skilled in the art.
Regarding paragraph 2, it is submitted that claims 8 and 9 along with claims 6, 7 and
12 have been deleted. Waiver of the objection is respectfully requested.
The third objection of the Learned Controller that claims 1 to 3 fall within the scope
of Section 3(d) is respectfully resisted. It is submitted that the improved stability of
the monohydrate is demonstrated by the following stability test data:
Regorafenib monohydrate and regorafenib polymorph I (water free) was
stored at 60°C for 6 months in a brown bottle. The amount of AFP-PMA was
analyzed with the following HPLC method:
HPLC (trace analysis method for quantification of 4-(4-amino-3-
fluorophenoxy)-N-methylpyridine-2-carboxamide): stationary phase: X-
Bridge Shield C18 (150 mm length, 3.0 mm ID, 3.5 µm particle size); mobile
phase A: 1.5 g potassium dihydrogenphosphate + 0.5 g dipotassium
hydrogenphosphate 1 L water; mobile phase B: acetonitrile; UV detection at
228 nm; oven temperature: 50 °C, injection volume: 3 µl, flow: 1.0 mL / min;
linear gradient in 1 step: 8% B -> 80% B (15 min.), RT of 4-(4-amino-3-
fluorophenoxy)-N-methylpyridine-2-carboxamide: 7.0 min., quantification
against external standard of 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-
2-carboxamide.
Amount of AFP-PMA at start: regorafenib polymorph I (17.5 ppm),
regorafenib monohydrate (17 ppm)
Amount of AFP-PMA after 6 months: regorafenib polymorph I (40.5 ppm),
regorafenib monohydrate (29 ppm)
This means that the AFP-PMA amount increased by 131 % for regorafenib
polymorph I and only by 70 % for regorafenib monohydrate.
We also submit evidence in the form of a technical affidavit deposed by one, Dr.
Alfons Grunenberg marked as Annexure A for your consideration. The said affidavit
also forms part of evidence filed with reply statement filed in reply to representation
by way of Opposition to the grant of patent of the captioned application filed by the
law firm, S. Majumdar & Co., 5 Harish Mukherjee Road, Kolkata-700 025, State of
West Bengal, represented by Dr. Sanchita Ganguli. In view of above, it is submitted
that based on evidence in the form of technical affidavit submitted herewith, the
present.invention does not fall within the prohibition of Section 3(d) and also, clearly
involves technical advancement and economical significance over the prior arts:
__j;,o OELHI 19 Ol 201~· 1s:23 Page 4 of 7

2=----
IITRUE COPY!I
With regard to objection raised under Section 3(e) of the Patents Act, it is submitted
that claimed subject matter does not fall under Section 3(e) of the Patents Act, since
compound of formula (II) is novel and inventive over the prior art. Therefore, a
composition/ combination comprising the compound of formula (II) cannot be
regarded as a "mere admixture resulting only in aggregation of the properties" by
logical consequence,_since always more than "mere" admixing and more than "only"
aggregation of known properties is involved. It is also submitted that the
composition/ combination shows surprising effect when the inventive compound of
formula (II) is used in high purity with other components as indicated in the claims
and no significant fraction of another form of the compound of formula (I) is used. In
this regard, the Learned Controller's attention is invited to page 2, lines 5 to 13 of the
specification. In view of the above, it is submitted that claims 10 to 11 and 14 to 17
directed to pharmaceutical composition do not attract Section 3(e) of the Patents Act.
To meet the objection raised under Section 3(i) of the Patents Act, claim 13 has been
deleted. The Learned Controller is respectfully requested to reconsider and waive
the objection.
Regarding paragraphs 4 to 6, itis submitted that while the claims are clearly worded
and not vague, the preambles thereof have been suitably amended to meet the
requirement of Learned Controller.
The amendments carried out in the specification have necessitated retyping of pages
1, 32 to 33 as fresh pages 1, 33 to 34. The re-numbered pages are submitted herewith.
The superseded pages 1, 32 to 33 may be considered as cancelled.
Regarding paragraph 7, it is respectfully submitted that as the applications filed in

Austria, Belgium, Bulgaria anq. other countries· are National Phase Applications
under PCT, the details of these applications are deemed to have been disclosed once
the details of the PCT applications are disclosed at the time of filing of the National
Phase application and therefore, requirement under Rule 12 of the Patents Rules has
been met. Further statement and undertaking on Form 3 filed respectively on
August 12, 2013 and March 4, 2014 pertains to updated details of application filed
pursuant to their availability. However, if the Learned Controller is still of the view
that the objections have not been met, we have the honour to submit herewith a
petition under rule 137 along with the prescribed official fee, to take the aforesaid
details of corresponding foreign applications on Form 3 on record.
Regarding paragraphs 8 and 9, the Applicant has the honour to submit herewith the
duly executed application form 1 (in original) to meet the requirement of the
objections raised by the Learned Controller. The Learned Controller is therefore,
requested to withdraw these objections.
Regarding paragraph 10, it is submitted that the priority document was filed in
English. A copy of the priority document is submitted herewith for your ready
reference. The Learned Controller is respectfully requested to waive the objection.
Page 5 of 7
IITRUE COPYjl
Regarding paragraph 11, we have the honour to submit herewith the drawings (in
duplicate) to meet the present requirement. The Learned Controller is therefore,
requested to withdraw this objection.
Regarding paragraph 12, we have the honour to submit herewith abstract (in
duplicate) to meet the requirement of Learned Controller's objection. The Learned
Controller is r,espectfully requested to waive the objection.
Regarding paragraph 13, it is submitted that details of corresponding foreign
application have been submitted under cover of letters dated March 12, 2009, August
8, 2012, February 15, 2013, August 12, 2013, March 4, 2014 and August 12, 2014. in
addition to the above, we have the honour to submit herewith updated details of
corresponding foreign applications to meet the requirements of Section 8(1) of the
Patents Act. As and when further updates are available, we shall further submit the
same at the Patent Office. The Learned Controller is respectfully requested to waive
the present objection.
Regarding paragraph 14, it is respectfully submitted that we have the honour to
submit herewith the prosecution details of corresponding foreign application in USA
Europe, International Preliminary Report on Patentability, and Written Opinion of
the International Searching Authority to meet requirements of Section 8(2) of the
Patents Act. The Learned Controller is respectfully requested to waive the present
objecti_on.
As the Learned Controller requires details/ documents pertaining to the
corresponding foreign applications filed in major Patent Offices, we are submitting
herewith the documents in relation to the countries identified above. However, if the
Learned .Controller requires documents/ information in relation to any other
jurisdiction, the Learned_ Controller is requested to intimate the same.
i•
'
Grant of a Patent on this application within the final and inextensible period
expiring on August 13, 2015 is respectfully requested. Before taking any adverse
decision on this case, the Learned Controller is respectfully requested to give an
opportunity to the Applicant to be officially heard in this matter.
ydi:'
[~~KUMAR]
atent Agent
Of Perfexio Legal
Attorneys for the Applicant
Enclosure(s):
1. Duly executed Application Form l(in duplicate);
2. Petition under Rule 137 along with prescribed fee (in duplicate);
3. Form 3 (in duplicate);
4. Form 2 (in duplicate);
IPO DELHI 19::-·-~(f-'-1=2015---crs: 2. 3
~
IITRUE COPYII
5. Retyped pages (in duplicate);
6. Abstract (in duplicate); •
7. Drawings (in duplicate);
8. _Copy of affidavit of Dr. Alfons Grunenberg marked as Annexure A;
9. Copy of Priority Document;
10. Prosecution details of corresponding US and European applications,
International Preliminary Report on Patentability, and Written Opinion of the
International Searching Authority (in the form of a CD); and
11. Herewith Rs. 8800/- by Cheque No. ooo2f! o dated January 19, 2015.
-------~---------
~~v0c~o-1=!:'RI,H-coT-~213-rs rs-,-z-3 • ___
Page 7 of 7
~
IITRUE COPYII
Europaisches
Patentamt European Patent Office
European 80298 MUNICH
Patent Office GERMANY
Office europeen Tel: +49 89 2399 0
des brevets Fax: +49 89 2399 4465
7 Formalities Officer
Name: Lombart, Isabelle
Illllllllllllllllllllllllllllllllllll111111111111111111 Tel: +49 89 2399 - 8779

or call
+31 (0)70 340 45 00
Bayer Schering Pharma Aktiengesellschaft
LP-PL, Building 018 Substantive Examiner
51368 Leverkusen Name: Cortes, Jose
ALLEMAGNE Tel: +49 89 2399 - 8206
L _J
Application No. Ref. Date

07 818 583.2 - 2101 BHC061143 PCT 11.01.2010
I I
Applicant
Bayer Schering Pharma Aktiengesellschaft
Communication pursuant to Article 94(3) EPC
The examination of the above-identified application has revealed that it does not meet the requirements of the
European Patent Convention for the reasons enclosed herewith. If the deficiencies indicated are not rectified
the application may be refused pursuant to Article 97(2) EPC.
You are invited to file your observations and insofar as the deficiencies are such as to be rectifiable, to correct
the indicated deficiencies within a period
of 4 months
from the notification of this communication, this period being computed in accordance with Rules 126(2) and
131(2) and (4) EPC. One set of amendments to the description, claims and drawings is to be filed within the
said period on separate sheets (R. 50(1) EPC).
Failure to comply with this invitation in due time will result in the application being deemed to be
withdrawn (Art. 94(4) EPC).
Cortes, Jose
Primary Examiner
For the Examining Division
Enclosure(s): 2 page/s reasons (Form 2906)
Registered Letter
EPO Form2001 12.07CSX
I[TRUE COPYjl
Datum Blatt Anmelde-Nr.:
Date 11 . 0 1 . 2 0 1 0 Sheet 1 Application No.: 07 818 583.2
Date Feuille Demande n°:
The examination is being carried out on the following application documents:
Description, Pages
1-31 as published
Claims, Numbers
1-17 as published
Drawings, Sheets
1/7-7/7 as published
1. Methods of Treatment excluded by Article 53c) EPC
Claim 13 relates to a method of treatment which is excluded from patentability by

Article 53c) EPC.
2. Prior Art
The following documents have been cited in the International Search Report:
D1: WO 2006/026500 A (BAYER PHARMACEUTICAL CORP [US]) 9 March

2006 (2006-03-09)
D2: WO 2005/009961 A (BAYER PHARMACEUTICALS CORP [US) 3 February

2005 (2005-02-03), cited in the application
3. Inventive Step (Article 56 EPC)
D1 and D2 disclose the unsolvated free base of the title compound. D1

additionally discloses solvates and hydrates of the title compound in a generic
from. D1 could be regarded as the closest prior art. D2 additionally discloses three
salts of the title compound.
The problem of the invention was the provision of a new solid form of the title
compound.
This problem has been solved by the provision of the monohydrate of the title
compound.
EPA Form 2906 12.0?CSX
I[TRUE COPYjl
Datum Blatt Anmelde-Nr.:
Date 11 . 0 1 . 2 0 1 0 Sheet 2 Application No.: 07 818 583.2
Date Feuille Demande n°:
The preparation of the monohydrate from the unsolvated free base, which is
known from e.g. D1 or D2 is regarded as a routine task for a skilled person, which
does not require an inventive step; in particular in view of the fact that hydrates of
the title compound are mentioned in D1.
Therefore the claimed matter lacks an inventive step.
4. Description (Rule 42 EPC)
When filing amended claims the description has to be brought in line with the
amended claim set at the same time (Rule 42(1 )c) EPC).
Those parts of the application which then do not refer any more to the claimed
invention should be deleted.
The relevant prior art cited in the search reports and in EPO's communications
should be cited in the description (Rule 42(1 )b) EPC).
Those parts of the application referring to methods of treatment excluded from

patentability by article 53(c)EPC should be reformulated into an allowable form or
deleted.
Those parts of the application containing irrelevant or unnecessary expressions

within the meaning of Rule 48(1 )c) EPC, like e.g. "incorporated by reference" or
"They are for illustrative purposes only, and are not to be construed as limiting the
invention in any way" or "It should be apparent to one of ordinary skill in the art
that changes and modifications can be made to this invention without departing
from the spirit or scope of the invention as it is set forth herein" should be deleted.
It is recommended to file a hand-amended version wherein the amendments are

visible and a re-typed version as the Druckexemplar.
EPA Form 2906 12.0?CSX
I[TRUE COPYjl
Bayer HealthCare
Bayer Schering Pharma
EPO-Munich
73
15.Juli2010
•
Europaisches Patentamt
Erhardtstraf1e 27
80298 MCmchen
Europaische Patentanmeldung Nr. 07 818 583.2-2101 July 13, 2010

To the office communication of January 11, 2010 Dr. Albers/Ml
BHC 06 1143-EP
Claim 13 shall be deleted. Bayer Schering Pharma
Aktiengesellschaft
Patents and Licensing, Q 18
Regarding inventive step discussion the closest prior art is the water-free 51368 Leverkusen
base compound regorafenib (INN, compound of the formula I) disclosed in Germany
01 and 02. According to the present invention it was now found that the Tel. ++49-214-30-66484
monohydrate of regorafenib has a very high stability and is formed during the Fax ++49-214-30-9677717
markus.albers@
up-scaled manufacturing process with a very high preference over the water- bayerhealthcare.com
free compound. It means in the presence of water in the manufacturing pro- www.bayerhealthcare.com
cess the monohydrate is directly formed and it is very hard to obtain the wa- Board of Management:
ter-free product in such a process. This aspect is very important in the syn- Andreas Fibig
Chairman of the Board
thesis of regorafenib in an industrial scale because when up-scaling the pro- Andreas Busch
cess it is much easier to use standard solvents which can contain water and Ulrich Kostlin
Kemal Malik
to use aqueous work-up procedures. It is much more expensive and complex Bernd Metzner
to produce a water-free substance because all the solvents used in the pro-
Chairman of the
cess must be kept and handled under water exclusion. The monohydrate Supervisory Board:
allows now the use of standard solvents containing traces of water. Further-
more extraction steps with water can be conducted easily. This is not Registered Office:
possible in the synthesis of the water-free product; otherwise an expensive fi- Berlin, Deutschland
Local Court Charlottenburg
nal drying step is needed. Nothing in the prior art teaches or suggests that 93 HRB 283 B
the monohydrate can be obtained in a manufacturing process under stan-
dard conditions easier and better than the water-free product. Surprisingly
the monohydrate is preferred over the water-free product.
The grant of a patent on the basis of the present claims is further requested
and it is asked for the communication under Art. 71 (3) EPC.
IITRUE COPYII
Bayer HealthCare
page 2 (BHC 06 1 143-EP/July 13, 2010)
If the Examinig Devision cannot agree to grant, it is asked for a further office
action pursuant Article 94 (3) EPC or personal consultation. Otherwise oral
proceeding under Article 116 EPC is applied for.
Bayer Schering Pharma AG
~.udtl
(Dr. Albers)
Law and Patents
IITRUE COPYII
IN THE HIGH COURT OF DELHI AT NEW
DELHI
CS (Comm.) No. 660 of 2022
In the matter of:

versus

DEFENDANT
MASTER INDEX
VOL-2
document ent in
possess
ion/po
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ntrol/c
ustody
is
origina
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1. Australia Department Copy Executed by Availab From
regulatory of Health, Department le on Defenda
approval for Australian of Health, TGA nt to its 256-
Stivarga Government Australian website Counsel 315
(Regorafenib and Bayer Government
Tablets)
Australia
Limited
(Publicly
Available)
2. USFDA USFDA and Copy Executed by Availab From
regulatory Bayer USFDA le on Defenda
approval for HealthCare USFDA nt to its 316-
Stivarga Pharmaceuti website Counsel 333
(Regorafenib cals Inc.
Tablets) (Publicly
Available)
3. Europe European Copy Executed by Availab From
regulatory Medicines European le on Defenda
approval for Agency and Medicines Europea nt to its 334-
Stivarga Bayer Agency n Counsel 424
(Regorafenib Pharma AG Medicin
Tablets) (Publicly es
Available) Agency
IN 215758 Office and IPO le on Defenda
Bayer IPO nt to its 425-
(Publicly
Available)
5. Form 1 of IN Indian Patent Copy Executed by Availab From
215758 Office and Bayer le on Defenda 428
Bayer Corporation IPO nt to its
(Publicly
Available)
6. Complete Indian Patent Copy Executed by Availab From
Specification Office and IPO le on Defenda 429-
(as granted) Bayer IPO nt to its 531
of IN 215758 Corporation website Counsel
(Publicly
Available)
Through
Place: Noida (NCR)
Date: 03.10.2022
Guruswamy Nataraj
NOIDA 201 307, NCR
Phone: 9811808373
Email:litigation@gnataraj.com
Australian Public Assessment Report
for Regorafenib
Proprietary Product Name: Stivarga
Sponsor: Bayer Australia Ltd
February 2014
About the Therapeutic Goods Administration (TGA)
• The Therapeutic Goods Administration (TGA) is part of the Australian Government
Department of Health, and is responsible for regulating medicines and medical
devices.
• The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk
management approach designed to ensure therapeutic goods supplied in Australia
meet acceptable standards of quality, safety and efficacy (performance), when
necessary.
• The work of the TGA is based on applying scientific and clinical expertise to decision-
making, to ensure that the benefits to consumers outweigh any risks associated with
the use of medicines and medical devices.
• The TGA relies on the public, healthcare professionals and industry to report problems
with medicines or medical devices. TGA investigates reports received by it to
determine any necessary regulatory action.
• To report a problem with a medicine or medical device, please see the information on
the TGA website <http://www.tga.gov.au>.
About AusPARs
• An Australian Public Assessment Record (AusPAR) provides information about the
evaluation of a prescription medicine and the considerations that led the TGA to
approve or not approve a prescription medicine submission.
• AusPARs are prepared and published by the TGA.
• An AusPAR is prepared for submissions that relate to new chemical entities, generic
medicines, major variations, and extensions of indications.
• An AusPAR is a static document, in that it will provide information that relates to a
submission at a particular point in time.
• A new AusPAR will be developed to reflect changes to indications and/or major
variations to a prescription medicine subject to evaluation by the TGA.
Copyright
© Commonwealth of Australia 2014
This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal
use or, if you are part of an organisation, for internal use within your organisation, but only if you or your
organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all
disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or
allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any
part of this work in any way (electronic or otherwise) without first being given specific written permission from the
Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA
Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to
<tga.copyright@tga.gov.au>.
Contents
I. Introduction to product submission _____________________________________ 5
Submission details____________________________________________________________________ 5
Product background __________________________________________________________________ 5
Regulatory status _____________________________________________________________________ 6
Product Information__________________________________________________________________ 6
II. Quality findings _____________________________________________________________ 6
Drug substance (active ingredient) _________________________________________________ 6
Drug product __________________________________________________________________________ 7
Biopharmaceutics ____________________________________________________________________ 7
Advisory committee considerations ________________________________________________ 8
Quality summary and conclusions __________________________________________________ 8
III. Nonclinical findings _______________________________________________________ 8
Introduction___________________________________________________________________________ 8
Pharmacology _________________________________________________________________________ 9
Pharmacokinetics____________________________________________________________________13
Toxicology ____________________________________________________________________________19
Nonclinical summary and conclusions _____________________________________________29
IV. Clinical findings __________________________________________________________ 32
Introduction__________________________________________________________________________32
Pharmacokinetics and pharmacodynamics _______________________________________34
Dosage selection for the pivotal studies ___________________________________________37
Efficacy _______________________________________________________________________________37
Safety _________________________________________________________________________________41
First round benefit-risk assessment _______________________________________________44
Clinical questions ____________________________________________________________________45
Recommendation regarding authorisation ________________________________________45
V. Pharmacovigilance findings ____________________________________________ 45
Risk management plan ______________________________________________________________45
VI. Overall conclusion and risk/benefit assessment __________________ 47
Quality ________________________________________________________________________________48
Nonclinical ___________________________________________________________________________48
Clinical ________________________________________________________________________________48
Risk management plan ______________________________________________________________52
Risk-benefit analysis ________________________________________________________________53
Initial decision _______________________________________________________________________54
Review of initial decision ___________________________________________________________55
Final outcome ________________________________________________________________________58
Attachment 1. Product Information ____________________________________ 59
Attachment 2. Extract from the Clinical Evaluation Report __________ 59
I. Introduction to product submission
Submission details
Type of submission: New chemical entity
Decision: Initial decision: Rejected

Final decision: Approved
Date of decision: Date of initial decision: 25 June 2013;

Date of final decision: 26 November 2013
Active ingredient: Regorafenib
Product name: Stivarga
Sponsor’s name and address: Bayer Australia Limited

875 Pacific Highway
Pymble NSW 2073
Dose form: Tablet
Strength: 40 mg
Container: Bottle
Pack sizes: 28 and 3 x 28
Approved therapeutic use: Stivarga is indicated for the treatment of patients with
metastatic colorectal cancer (CRC) who have been previously
treated with fluoropyrimidine,- oxaliplatin- and irinotecan-
based chemotherapy, an anti-VEGF therapy, and, if KRAS wild
type, an anti-EGFR therapy. 1
Route of administration: Oral
Dosage (abbreviated): Four Stivarga (40 mg) tablets daily for three weeks on therapy
(21 days) followed by one week off therapy (7 days) to comprise
a cycle of four weeks (28 days).
ARTG Number: 200553
Product background
This AusPAR describes the application by Bayer Australia Ltd (the sponsor) to register
tablets containing 40 mg regorafenib (Stivarga) for the following indication:
Stivarga is indicated for the treatment of patients with metastatic colorectal cancer
(CRC) irrespective of KRAS mutational status who have been previously treated with,
1 Abbreviations: VEGF: vascular endothelial growth factor; KRAS: Kirsten rat sarcoma viral oncogene homolog
(protein), member of the RAS family of GTPases (guanosine triphosphate hydrolases); EGRF: epithelial
growth factor receptor.
or are not considered candidates for, fluoropyrimidine based chemotherapy, an anti-
VEGF therapy, and, if KRAS wild type, an anti EGFR therapy.
Regorafenib is an oral anti-tumour agent that inhibits a variety of kinases using
biochemical and cellular kinase phosphorylation. It blocks kinases associated with
the regulation of tumour vasculature (vascular endothelial growth factor receptors
(VEGFR) 1, 2 and 3, tyrosine kinase with immunoglobulin, and epidermal growth
factor (EGF) homology domain 2), oncogenesis by mutant kinases (KIT, RET, RAF1,
BRAF, and BRAFV600E), and tumour microenvironment (platelet-derived growth
factor receptor‐β (PDGFRB) and fibroblast growth factor receptor 1 (FGFR1))
(Wilhelm et al., 2011 2, Demetri et al., 2013).
Most colorectal cancers (CRCs) are adenocarcinomas. Carcinomas are the result of
sequential accumulation of mutations in various genes (oncogenes, tumour suppressor
genes and mismatch repair genes), that initially cause adenomatous polyps, some of which
then acquire additional mutations and become malignant. Differentiation may range from
tall, columnar cells resembling the adenomatous lesions (but invading the submucosa and
muscularis propria) to undifferentiated, anaplastic masses. The following stages can be
distinguished: normal mucosa, small adenoma, larger adenoma, invasive adenocarcinoma,
metastases.
Regulatory status
The product received initial registration on the Australian Register of Therapeutic Goods
(ARTG) on 29 November 2013.
At the time this application was considered by the TGA, a similar application was
approved in the USA, Canada and Switzerland and was under review in the European
Union (EU).
Product Information
The approved Product Information (PI) current at the time this AusPAR was prepared can
be found as Attachment 1.
II. Quality findings
Drug substance (active ingredient)

Regorafenib is a synthetic urea derivative. The structure (Figure 1) is not closely related to
registered drugs. Regorafenib is not chiral and does not show isomerism:
Figure 1. Structure of regorafenib monohydrate
F
0 F
Ck x·F O (/(0, /.::::: JN,CH,
u)l_~
~ ~ F
er H
x H20
2Wilhelm SM, Dumas J, Adnane L et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of
angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J
Cancer 2011:129(1);245–255.
fu~JE COPYI!
The molecular formula of regorafenib is C21H15ClF4N4O3.H2O and it has a molecular weight
of 500.83 (monohydrate) or 482.82 (free base).
The drug substance is regorafenib monohydrate. The water is lost during the formulation
process for the drug product so the active drug substance present in the tablets is
amorphous and anhydrous regorafenib.
Regorafenib is practically insoluble in water and only very slightly more soluble in acid.
The drug is very lipophilic. Particle size and polymorphism controls are not relevant
because the drug is dissolved in solvents during tablet manufacture.
Potential impurities in regorafenib monohydrate were investigated and are controlled in
the drug substance.
Drug product
Bayer proposes registration of 40 mg, unscored, film-coated tablets. These are light-pink
ovals (16 x 7 mm) marked “Bayer” and “40” on opposite sides. They are presented in an
high density polyethylene (HDPE) bottle, with a child-resistant cap, of 28 tablets as a pack
of 1 or 3 bottles (that is, 84 tablets). Bottles have a desiccant.
The tablets are stably formulated with amorphous drug, which enhances drug dissolution
in vivo. Excipients are otherwise conventional.
Solid solution tablets (20, 40 and 100 mg, all direct scales) have been used in clinical trials.
The 40 mg solid solution tablets were used in Phase III studies. The only notable change in
the solid solution tablet formulation during development was a change of the film coating.
This did not affect bioavailability (Study 12437).
Biopharmaceutics
No absolute bioavailability study has been done. Bayer argues that it is not feasible to
make an intravenous solution acceptable for human use.
Two bioavailability studies were reviewed:
• Study 14656: Food effect
Study 14656 was a 3-way, cross-over, single dose study comparing the effects of a high-fat
breakfast, a low-fat breakfast and fasting state on the bioavailability of 4 x 40 mg tablets
(formulation for registration) in healthy volunteers. Food increased both exposure (area
under the plasma concentration-time curve, AUC) and maximum plasma concentration
(Cmax) while slightly delaying the time of maximum plasma concentration (Tmax), with high
fat having the greatest effect. Point estimators (least-squares means) and two-sided 90%
confidence intervals (CIs) of selected PK parameters after administration of regorafenib
(in all subjects valid for PK (n = 24) are shown in Table 1.
Table 1. Point estimators for selected PK parameters
Estimated 90% confidence
Analyte Ratio Parameter
Ratio(%) interval (%)
BAY 73-4506 Low Fat/ Fasted AUC 136.05 (123.12; 150.33)
c.... 154.29 (137.88; 172.66)
High Fat / Fasted AUC 148.20 (134.12; 163 77)
Cmax 172.63 (154.26; 193.18)
High Fat/ Low Fat AUC 108.93 (98.58; 120.37]
Cmax 111.88 [99.98: 125.201
Interestingly, exposure to active metabolites (M-2 and M-5) is higher with the low fat meal
rather than the high fat meal (details not shown here). The PI recommends that doses are
taken after a light meal.
IITRUE COP)jl
• Study 12437: bioequivalence
Study 12437 was a two-way, single dose, crossover bioequivalence comparison of the
clinical trial solid solution tablets (1 x 100 mg + 3 x 20 mg) and the 40 mg solid solution
tablets as proposed for registration (4 x 40 mg). The study showed bioequivalence.
Advisory committee considerations

The application was considered at 151st (May 2013) meeting of the Pharmaceutical
Subcommittee (PSC) of the Advisory Committee on Prescription Medicines (ACPM). A
summary of the PSC advice is as follows:
1. The PSC endorsed all the issues raised by the TGA in relation to pharmaceutic and
biopharmaceutic aspects of the submission by Bayer Australia Ltd to register Stivarga
film coated tablet containing 40 mg of regorafenib. In particular, the PSC supported
the issues raised in relation to labelling and advised that these should be resolved in
line with best practice guidelines.
2. The PSC noted that no absolute bioavailability study had been undertaken. Such
studies are considered a fundamental part of the pharmacokinetic characterisation of
a drug. The PSC recommended that, if Stivarga was registered, this issue should be
reconsidered if the use of the drug changed significantly in the future.
3. The PSC advised that the product should be stored with a maximum recommended
temperature of 25°C.
There was no requirement for this submission to be reviewed again by the PSC before it is
presented for consideration by the ACPM.
Quality summary and conclusions

Matters relating to chemistry, quality control and bioavailability have been resolved.
Registration is recommended with respect to chemistry, quality control and bioavailability
aspects.
III. Nonclinical findings
Introduction
General comments
The overall quality of the submission was good. Appropriate studies were conducted and
pivotal studies were compliant with good laboratory practice (GLP). Toxicity studies were
well supported by toxicokinetic data. Additional studies were conducted on the two major
circulating metabolites in humans that were not adequately covered by the use of the rat
and dog as the primary nonclinical species. However, some primary pharmacology studies
that would appear to have been conducted by the sponsor but were not submitted.
Pharmacology
Primary pharmacology
Various growth factors and receptors are involved in the regulation of tumour growth.
These include vascular endothelial growth factor receptor (VEGFR) and tyrosine kinase
with immunoglobulin and epidermal growth factor homology domain 2 (TIE2), both of
which are receptor tyrosine kinases (RTKs) that control tumour angiogenesis (see review
by Yancopoulos et al., 2000 3). VEGFR includes various members, with VEGFR-2
(previously known as KDR or Flk-1) believed to mediate the major growth and
permeability actions of VEGF; other members of the family include VEGFR-1 (previously
known as Flt-1) and VEGFR-3 (previously known as Flt-3) (Yancopoulos et al., 2000).
Fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor
(PDGFR) are also involved in angiogenesis but have broader roles, such as regulation of
cell proliferation, differentiation, growth, survival and migration (Turner and Grose,
2010 4; Williams, 1989 5). The oncogenic RTKs, KIT (also known as stem/mast cell growth
factor), RET and BRAF are also targets for cancer therapy as they have been identified as
driving oncogenic events in certain tumour types (Lanzi et al., 2009 6; Fletcher and Rubin,
2007 7; Lo, 2012 8).
Regorafenib is a new chemical entity which inhibits multiple kinases that are involved in
tumour growth, as well as in a wide range of normal cellular functions. Regorafenib and its
two major circulating metabolites in humans, M-2 (N-oxide metabolite) and M-5 (N-oxide
and N-desmethyl metabolite), were tested in biochemical and in cellular assays for
inhibition of various kinases. In the biochemical assays, the kinases inhibited at the lowest
concentrations of regorafenib included RET/RET variants, KIT/KIT variants, PDGFR (α
and β/variants), VEGFR-1,-2, and -3, FGFR-1 and -2, TIE2 and BRAF/BRAF variants, as well
as DDR1 and 2, ZAK, HIPK4, LOK, CSF1R, ABL1-nonphosphorylated, ERK8, EPHA6, p38β,
FLT4, TIE1 and PTK5. In a number of in vitro biochemical assays investigating the
inhibitory effect of regorafenib on various kinases, half maximal inhibitory concentration
(IC50)/dissociation constant (Kd) values for VEGFR1, -2, and -3, TIE2, PDGFR, FGFR,
RET/RET variants, Kit/Kit variants, RAF-1 and BRAF/BRAF variants often fell within the
range 1 to 300 nM. It is, however, notable that there were some KIT, PDGFR and FGFR
variants with IC50/Kd values higher than this.
When tested against a number of kinases (including VEGFR, FGFR, PDGFR, Kit, Ret and
BRAF and/or their variants, but not TIE2), the M-2 and M-5 metabolites showed inhibitory
activity that was similar to, and sometimes higher than, the activity of regorafenib parent
drug (studies SAG103 and SAG161), with IC50/Kd values falling within a broadly similar
range to those for regorafenib (1 to 300 nM).
The mean plasma maximum concentration (Cmax) values of regorafenib, M-2 and M-5 at a
dose of 160 mg/day were about 3.5, 3.3 and 4.0 µg/mL, respectively, corresponding to
7.2 µM, 6.6 µM and 8.3 µM (Study 11650). These values are well above the 1-300 nM range
of the IC50/Kd values for some of the critical kinases. A correction for protein binding can
be made using a value of 0.488% for fraction unbound (fu) for regorafenib in pooled
human plasma (Report PH-34096, although other values for fu were also obtained),
3 Yancopoulos GD, Davis S, Gale NW et al. Vascular-specific growth factors and blood vessel formation. Nature
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4 Turner N and Grose R. Fibroblast growth factor signalling from development to cancer. Nat. Rev. Cancer
2010:10;116-129.
5 Williams LT. Signal transduction by the platelet-derived growth factor receptor. Science 1989: 243;1564-70.
6 Lanzi C, Cassinelli G, Nicolini V and Zunino F. Targeting RET for thyroid cancer therapy. Biochem Pharmacol
2009:77;297-309.
7 Fletcher JA and Rubin BP. KIT mutations in GIST. Curr Opin Genet Dev 2007:17;3-7.
8 Lo RS. Receptor tyrosine kinases in cancer escape from BRAF inhibitors. Cell Res 2012: 22;945-947.
0.188% for fu for M-2 and 0.053% for fu for M-5. Correcting for protein binding, the
concentrations of free regorafenib, M-2 and M-5 are about 35, 12 and 4.4 nM, respectively,
which are still within the IC50/Kd ranges, although towards the lower end. Thus, both these
metabolites are likely to contribute to the clinical antitumour efficacy of regorafenib.
Regorafenib also showed inhibitory activity against kinases in cellular assays: in Chinese
hamster ovary (CHO) cells transfected with human TIE2, in rat-1 cells transfected with
BRAF-V600E and in M07e megakaryoblastic leukaemia cell line expressing high levels of
cKIT. IC50 values for regorafenib in the cellular assays lay within the same range as those
in the biochemical assays (24-41 nM for inhibition of TIE2 in the CHO cells, 23 nM for
inhibition of KIT in M07e cells and 69 nM for inhibition of BRAF in rat-1 cells). As in the
biochemical assays, the metabolites M-2 and M-5 were pharmacologically active, with both
showing broadly similar activity to parent drug in all three test systems.
Regorafenib also inhibited the proliferation of various human colorectal and pancreatic
cell lines. However, half maximal effective concentration (EC50) values (in the range 2.7 to
9.7 µM for 23 of the 33 cell lines tested), while similar to the expected Cmax for total drug,
were considerably higher than the Cmax for free drug, and 6 of the 25 colorectal cell lines
tested had EC50 values >10 µM.
Orally administered regorafenib inhibited tumour growth in in vivo studies performed in
nude mice transplanted with human xenografts and in mice transplanted with murine
cancer cells. Activity was investigated against five human colorectal tumour xenografts
(including three oxaliplatin-resistant xenografts) and one human breast tumour xenograft
in nude mice, and against implanted H129 hepatoma and 4T1 breast cancer cells in
syngeneic mice. The primary endpoint was inhibition of tumour growth, except in the
hepatoma study in which it was survival. Toxicity was determined from mortality and
body weight changes, and was acceptable (1/8 mice given the high dose (HD) died in the
HT-29 colorectal xenograft study but there were no other deaths at the same dose in the
other studies; body weights remained within an acceptable range).
Regorafenib showed moderate anti-tumour activity in the HT-29 colorectal tumour model,
eliciting 34% and 67% reductions in tumour volume over the study at 3 and 10
mg/kg/day. The 10 mg/kg/day dose was comparable to (about 75% of) the maximum
recommended human dose (MRHD) based on area under the plasma concentration-time
curve from time of administration until 24 h post-dose (AUC0-24 h) (38.3 µg.h/mL after
multiple dosing (Report A55575) compared with 51.3 µg.h/mL in humans), while the 3
mg/kg/day dose gave an AUC only about 20% of that at the MRHD. Protein binding is
similar in mice and humans, so a correction is not required. In the oxaliplatin-resistant
Co8183 and Co8435 colorectal models, regorafenib also showed moderate efficacy,
eliciting respectively, 69% and 64% reductions in tumour volumes at 10 mg/kg/day.
While a combination of regorafenib and irinotecan was of superior efficacy to either drug
alone in both of these models tumour, inhibitory effects were less than additive. However,
regorafenib was not effective in all colorectal models, having minimal activity in the
oxaliplatin-resistant Co8434 and Co5896 models, while irinotecan was highly efficacious
in both models.
Although not relevant to the indication for the current submission, regorafenib also
demonstrated moderate efficacy in the MDA MB231 and 4T1 breast cancer models
(inhibition of tumour growth) and improved survival of mice bearing H129 hepatomas. It
significantly reduced lung metastases in the 4T1 breast cancer model.
Given that exposure (AUC) in nude mice was lower (75% at 10 mg/kg/day) than the
expected regorafenib clinical AUC, and given that moderate efficacy was observed in
several colorectal xenograft models, the primary pharmacology results are predictive of
efficacy in some, but not all, colorectal tumour types.
In the HT-29 and MDA MB231 models, M-2 and M-5 were also tested at the same two
doses (mg/kg/day basis) as regorafenib, and both metabolites showed similar activity to
parent drug in both models, which is consistent with in vitro data. Both metabolites
showed moderate efficacy at 10 mg/kg/day in the HT-29 model, a dose which achieved
exposures comparable to those expected at the MRHD (for M-2, an exposure of
51.9 µg.h/mL can be estimated based on data from multiple dosing in Report A55575
comparable to the expected clinical exposure of 49.8 µg.h/mL; for M-5, an exposure of
52.8 µg.h/mL can be estimated based on data from multiple dosing in Report A55575,
similar to the expected clinical exposure of 64.2 µg.h/mL). These data suggest that both
metabolites will make a contribution to efficacy in patients, although it is noted that a
correction for interspecies differences in protein binding for M-2 and M-5 would result in
the mouse M-2 AUC being about 5 fold the expected human value and the mouse M-5 AUC
being about 7 times the expected human value.
The antiangiogenic effects of orally administered regorafenib and M-2 were investigated
in female Fischer rats bearing implanted gliomas in studies using nuclear magnetic
resonance imaging (MRI) following Gadomer-17 injection to estimate tumour blood vessel
volume and total permeability surface area of tumour vessels. Decreased MRI signals in
tumours from rats treated with regorafenib and M-2 are indicative of in vivo
antiangiogenic activity of both compounds. Tumour growth inhibition (no growth for 4
days after the last dose) after multiple (4) daily oral doses of 10 mg/kg regorafenib
correlated with the antiangiogenic effect (significant reduction in MRI signal). At 10 mg/kg
regorafenib which elicited significant decreases in MRI signals after both single and
multiple doses, estimated AUC0-24 h values are 48.1 and 86.9 ng.h/mL, respectively (data
from the 2 week rat toxicity study in female Wistar rats; no adequate pharmacokinetic
(PK) data available for Fischer rats). These AUC values are comparable to and 1.7 fold the
expected clinical AUC for regorafenib, respectively, suggesting beneficial effects on tumour
angiogenesis at the MRHD, although as the fraction of regorafenib unbound in rat plasma
is slightly higher than in human plasma, a correction factor of 1.5 can be applied to this
calculation, giving exposures of about 1.4 and 2.5 times those expected clinically.
An in vivo experiment examining potential anti-VEGF activity of regorafenib and the M-2
and M-5 metabolites was conducted in male Wistar rats. At 1 mg/kg intravenously (IV),
regorafenib and both of its metabolites were able to block VEGF-induced hypotension.
Extrapolation of PK data from Report PH-34034 gives an AUC0-24 h of about 6.8 µg.h/mL
and plasma concentrations of about 1.2 μg/mL (when BP was measured) at this IV dose
which are below the AUC (51.3 μg.h/mL) and Cmax (3.5 μg/mL) expected at the MRHD. The
plasma regorafenib concentration (1.2 μg/mL) was also below the expected clinical Cmax.
The findings suggest that regorafenib will be exhibiting anti-VEGF activity at the
recommended clinical dose in patients.
Secondary pharmacodynamics and safety pharmacology
Secondary pharmacodynamic (PD) studies did not reveal analgesic activity or
pro-convulsive potential at oral doses of up to 50 mg/kg regorafenib in male Wistar rats.
This dose achieved a Cmax of 5.7 μg/mL (in the 2-week rat toxicity study), about 1.6 fold
(2.4 fold corrected) the expected clinical Cmax (AUC was 1.2 fold (1.8 fold corrected) the
expected clinical value). Blood glucose concentrations were reduced in both fed and fasted
rats after a single oral dose of 50 mg/kg regorafenib, and also in fasted rats at 2 and
10 mg/kg, but the magnitude of the reductions was small (<20%). No effects on plasma
glucose levels were observed in the repeat dose toxicity studies in any species, although
there were some reductions in liver glycogen levels in rodents.
Although drugs with antiangiogenic properties may suppress wound healing, this was not
investigated in any specific nonclinical or clinical study. However, the proposed PI
includes a statement relating to this issue and recommends interruption of treatment with
Stivarga in patients undergoing major surgical procedures.
Specialised safety pharmacology studies for regorafenib and its metabolites M-2 and M-5
covered the core systems (central nervous system (CNS), cardiovascular and respiratory),
although the in vitro cardiovascular safety studies on regorafenib were not GLP compliant.
Regorafenib was also tested in supplementary systems (renal and gastrointestinal). At
doses up to 50 mg/kg orally (PO) regorafenib or 20 mg/kg PO M-5, open field behaviour in
male Wistar rats was not affected, but some effects (most notably prone position and
stereotypic licking in 1/6 rats, and slightly elevated body temperature at 4 h post dose)
were observed at 20 mg/kg M-2. Cmax values at these doses were 1.6 fold, 2.3 (7.7/3.3) fold
and 70% (2.78/4.0) of the expected clinical Cmax for regorafenib, M-2 and M-5,
respectively, but correction for interspecies differences in protein binding would increase
these ratios by about 1.5, 3.6 and 5.4, respectively for regorafenib, M-2 and M-5. These
results suggest that CNS effects are unlikely in patients. CNS safety studies were backed up
by investigation of various CNS parameters in some of the repeat dose toxicity studies,
including a functional observation battery and motor activity assessment in the 13-week
rat study (which revealed a reduction in motor and locomotor activity in HD females (8
mg/kg/day, exposure ratio (ER) 1.3 or 2 after correction for protein binding)), and
measurement of body temperature in the 4-, 13- and 52-week dog studies, testing of
reflexes in the 13-week dog study, and testing of nervous system function in the 52-week
dog study (no effects of treatment were observed in any of these tests). These results give
further support to the conclusion that CNS effects are unlikely in patients.
Human Ether-à-go-go-Related Gene (hERG) current was reduced by regorafenib in
transfected HEK293 cells in protein free medium (up to 38% compared to predrug values
at 20 µM, significant at 10 and 20 µM; IC50 27 µM). This IC50 value is 3.8 fold the Cmax
expected in patients of 7.2 µM (total drug) and 1000 fold taking into account protein
binding (comparing free drug), so this inhibition is unlikely to be of clinical relevance.
Metabolites M-2 and M-5 were more potent inhibitors of hERG current than parent drug,
with IC50 values of 1.1 and 1.8 µM, respectively. These are below the Cmax values at the
MRHD, about 6.6 and 8.3 µM, respectively (17% and 22%, respectively of these Cmax
values). Although the comparison based on total drug suggests a risk associated with
reduction in hERG current due to the metabolites, if protein binding is taken into account,
there is no evidence of a risk. Using a mean value of 0.239% for the fu of M-2 in human
plasma (Report PH-34096) gives an expected Cmax for free M-2 in patients of 16 nM which
is well below the IC50 for hERG inhibition by M-2. Using the value of 0.053% for the fu of
M-5 in human plasma (Report PH-34096) gives an expected Cmax for free M-5 in patients of
4 nM which is well below the IC50 for hERG inhibition by M-5. Further, regorafenib elicited
a reduction rather than an increase in action potential duration (APD50 and APD90) values
in rabbit cardiac Purkinje fibres, which might be expected because of its weak hERG
blocking activity.
No effects of regorafenib at intraduodenal doses of up to 100 mg/kg were observed for
haemodynamic, electrocardiogram (ECG) or respiratory parameters in anaesthetised dogs.
However, plasma regorafenib concentrations were very low with this route of
administration (Cmax values were up to 0.141 µg/mL which is about 4% of the expected
regorafenib clinical Cmax (3.5 µg/mL)). Due to these low exposures, the study was repeated
using a 30-min IV infusion to achieve greater exposures (Cmax values were up to 4.63
µg/mL at the high dose of 2.25 mg/kg; this is about 1.3 fold the expected clinical Cmax (2.6
fold taking into account species differences in protein binding). Again, no effects of
treatment were observed, although the exposure margin achieved was still relatively low.
No effects on ECG/cardiovascular parameters were observed in the repeat dose toxicity
studies in which these investigations were conducted (4-, 13- and 52-week dog studies).
Findings of the animal studies were consistent with the results of a dedicated clinical
study on the QT interval 9 in cancer patients at 160 mg regorafenib, which did not reveal
any QTc prolonging effects. Heart rate and blood pressure were also measured in some of
the repeat dose toxicity studies (4-, 13- and 52-week dog studies) and no effects were
observed.
Since M-2 and M-5 were major circulating metabolites in humans, but were only produced
at low levels in plasma in dogs, separate but similar cardiovascular/respiratory studies
using the IV route were conducted with administration of these metabolites. No effects
were observed after administration of either M-2 or M-5. Achieved plasma M-2 Cmax values
were up to 5.63 µg/mL which is about 1.7 fold the expected M-2 clinical Cmax of 3.3 µg/mL.
Plasma M-5 Cmax values were up to 5.54 µg/mL which is 1.4 fold the expected M-5 clinical
Cmax of 4.0 µg/mL. However, differences in protein binding between humans and dogs
were quite high (a factor of 6.5 for M-2 and 7.8 for M-5), raising the exposure ratios for
free drug to 11 for both M-2 and M-5.
Even though not predicted by the nonclinical studies, an increased incidence of arterial
hypertension has been observed in patients treated with regorafenib and the proposed
product information recommends monitoring of BP, treating hypertension according to
standard medical practice and reducing the dose or interrupting or discontinuing
treatment with Stivarga, depending on severity of reaction.
Although the kidney was a target organ for toxicity upon repeated dosing in all species
investigated (including rats), there were no effects on renal function of single oral doses of
regorafenib up to 50 mg/kg in male rats, a dose which achieved an AUC of 1.2 fold the
expected clinical value (1.8 fold after correction for species differences in protein binding).
Regorafenib was also tested for effects on contractions/relaxation responses to
acetylcholine, barium chloride, serotonin (5-HT) and histamine in isolated guinea pig
ileum. No effects were observed but concentrations tested were relatively low (up to
1 µg/mL, that is, about 30% of the expected clinical Cmax of regorafenib). Regorafenib
reduced gastrointestinal transit of a barium sulfate meal in male Wistar rats, with a
significant effect at the lowest dose tested, 2 mg/kg, which would be expected to achieve a
Cmax of about 0.68 µg/mL (Report PH-3034) or about 20% (30% after protein binding
correction) of the expected clinical Cmax. This suggests that gastrointestinal transit might
be reduced at patients at the MRHD.
Pharmacokinetics
Absorption
The extent of absorption of a radioactive oral dose was estimated as 79% after a dose of
2 mg/kg in rats and 71% after a dose of 2.5 mg in dogs. Estimates of oral bioavailability
were similar to estimates of absorption in rats, and only slightly lower in dogs, suggesting
little first pass effect. Estimates in rats ranged from 77-89%, while in dogs, oral
bioavailability declined with increasing dose, from 67% at 1 mg/kg to 29% at 10 mg/kg,
suggesting saturation of absorption with increasing dose. Oral absorption was reasonably
rapid, with mean Tmax values in rats being 4-6 h (over the dose range 0.5-8 mg/kg) and in
dogs being 1.6-2.7 h (over the dose range 1-10 mg/kg), while in humans Tmax was 3-4 h at
the 160 mg dose. Oral absorption was also reasonably rapid in mice (Tmax 1-2 h over the
dose range 3-10 mg/kg) and rhesus monkeys (Tmax 2.6 h at a dose of 1 mg/kg), but extent
9 QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's
electrical cycle. A lengthened QT interval is a biomarker for ventricular tachyarrhythmias like torsades de
pointes and a risk factor for sudden death. QTc is QT interval corrected for heart rate.
of absorption and absolute bioavailability were not estimated in these species, nor in
humans.
Clearance was estimated to be 0.15 L/h/kg in rats, 0.21-0.27 L/h/kg in dogs, but was not
estimated in humans. Volume of distribution was moderate to high, being about 0.9 L/kg
in rats and about 1.8 L/kg in dogs, but was not estimated in humans. Mean half-life ranged
from 3.4 to 4.0 h in mice, 4.1 to 7.3 h rats, 5.3 to 8.1 h in dogs which was considerably
shorter than in rhesus monkeys (32.6 h) or humans (20-30 h).
In single dose studies, AUC was dose proportional over the dose range 3 to 10 mg/kg PO in
mice, 0.5 to 2 mg/kg IV in rats, 0.5 to 8 mg/kg PO in rats, but was less than dose
proportional over the dose range 1 to 10 mg/kg PO in dogs. In humans, regorafenib PKs
were generally linear up to a dose of 160 mg following a single dose, and up to 60 mg
following multiple doses. At higher doses, AUC increased in a less than dose proportional
manner, while Cmax remained relatively constant. Repeat dose studies did not reveal any
accumulation with multiple dosing in the mouse, but slight to moderate accumulation was
observed in the rat studies, while in the dog, exposures tended to decline with multiple
dosing. In humans, accumulation of regorafenib at steady-state was approximately 2-fold,
as expected given the mean elimination half life of 20-30 h. Plasma concentration data in
the repeat dose studies were pooled for both sexes to estimate PK parameters. This was
acceptable in mice and dogs as there was no evidence of sex differences in these species,
but in rats, exposures tended to be higher in females than males (for example in the 2-
week study T6073132).
In Caco-2 cells, apparent permeability Papp A-B and Papp B-A were 124 nm/s and 104 nm/s,
respectively, giving an efflux ratio of 0.835. Thus, regorafenib was considered to be highly
permeable according to FDA guidelines for the biopharmaceutical classification system
(BCS) and there was no evidence of involvement of an efflux transport protein for
regorafenib.
Distribution
Plasma protein binding was very high in all species, but there were some species
differences. Fraction unbound (mean values from several studies) was in the range 0.25-
0.49% in humans; in the nonclinical species, fu was 0.58% in mice, 0.72% in rats, 0.97% in
dogs, 1.68% in rabbits and 2.16% in rhesus monkeys. Human serum albumin and α-
globulin were identified as important binding components in human plasma. Regorafenib
was also bound extensively to the non-esterified fatty acids (oleic, palmitic and stearic).
Regorafenib did not show a propensity to distribute into erythrocytes, as plasma
concentrations of radioactivity were higher than those of blood or erythrocytes following
incubation of blood with radiolabelled (14C)-regorafenib and following administration of
14C-regorafenib to rats.
In tissue distribution studies in rats, radioactivity was rapidly and widely distributed to
the tissues. Consistent with the role of the liver in excretion of regofafenib in the rat, a high
concentration of radioactivity was observed in this organ (6.6 tissue:blood ratio at the Cmax
(Report PH-35209)). The adrenals (particularly the cortex), adipose tissue and Harderian
gland were also consistently highly labelled (tissue:blood ratios of 5.6 (6.3 for cortex), 2.8
and 3.6, respectively). The contents of the bile ducts and gastrointestinal tract were also
highly labelled (Report PH-33804; no data for these in Report PH-35209), consistent with
biliary excretion. Penetration across the blood/testes and placental barriers was low-
moderate (tissue:blood ratio of 0.37 for testes and fetal blood:maternal blood ratio of
0.51) and across the blood/brain barrier was low (tissue:blood ratio of 0.19). Seminal
vesicles also had a low concentration of radioactivity (tissue:blood ratio of 0.13), but other
reproductive tissues had moderate concentrations. There was no evidence of retention of
radioactivity in any organ/tissue, and in most tissues, the half life of radioactivity was
similar to that in blood. There was evidence of slight melanin binding as the eye-
wall:blood ratio for radioactivity was higher in pigmented Long Evans rats than in Wistar
albino rats (1.75 compared with 0.88 at 24 h post dose), but there were no differences in
skin:blood ratio of radioactivity between highly pigmented and less pigmented skin in the
Long Evans rats or between the skin of the two strains. An interesting feature of the tissue
distribution of regorafenib/metabolites was the heterogeneity of labelling within some
tissues, most notably the adrenals and kidneys (cortex>medulla in both organs).
Metabolism
Nine metabolites of regorafenib were identified in an in vitro study with rat, dog and
human hepatocytes, although metabolite M-1 was only observed in incubations with
human hepatocytes, and then only in trace amounts. The two glucuronidated metabolites
(M-7 and M-8) were also only observed in incubations with human hepatocytes while the
glutathione conjugate (M-9) was only observed in incubations with rat hepatocytes. An in
vitro study with liver microsomes from mice (two strains, CD-1 and NMRI), rats, dogs,
rabbits, rhesus monkeys and humans suggested that the metabolic profiles of regorafenib
in mice and rabbits were the most similar to the metabolic profile in humans, but this
study was limited by the fact that M-1/M-5 coeluted in the system used and combined
results for these metabolites were presented. There were no differences in metabolic
profile for the two mouse strains.
Results of investigation of the metabolic profile of regorafenib in vivo in mice, rats, dogs
and humans were consistent with the in vitro data, although M-2, which was formed in
significant amounts by mouse microsomes, was only observed as a minor circulating
metabolite in mice (there were no data in this species for metabolic profiles in other
matrices). The metabolism of regorafenib involves N-oxidation of the pyridine moiety
leading to M-2 (a major pathway in humans, minor in mice, minimal in rats and dogs), N-
methylhydroxylation leading to M-3 (major pathway in rats and dogs, minor in mice and
humans), N-demethylation leading to M-4 (a substantial pathway in rats, minor in mice,
dogs and humans), N-demethylation and hydrolysis leading to M-6 (major pathway in
dogs, minor in rats (not detected in plasma, but significant in bile/faeces) and humans
(not detected in plasma but significant in faeces)), N-glucuronidation (at the urea nitrogen
adjacent to the trifluoromethyl-chloro phenyl moiety) leading to M-7 (minor pathway in
humans (low levels in plasma, low to moderate levels in urine), not in rats or dogs)),
glutathione conjugation leading to M-9 (minor pathway in rats in vitro, not in mice, dogs
or humans) and combinations of these pathways leading to M-1, M-5 and M-8 (M-1 not
detected in vivo in humans, not in mice, rats or dogs (trace in humans in vitro)), M-5 being
a metabolite in humans, very minor in mice, rats and dogs, and M-8 being a minor
metabolite in humans (detected in urine, not plasma), not in mice, rats or dogs).
Whether there were any sex differences in metabolism is not clear as metabolism was only
investigated in male mice and rats, and in female dogs. There were no sex differences in
tissue distribution of regorafenib, and rats were the only species in which a difference
(relatively small) was observed in plasma concentrations of regorafenib.
In experiments using recombinant cytochrome P450 (CYP) isoforms and CYP isoform
selective inhibitors, CYP3A4 was identified as the main CYP isoform responsible for the
Phase I metabolism of regorafenib (pyridine N-oxidation leading to the formation of M-2,
N-methylhydroxylation leading to the formation of M-3 and N-demethylation leading to
the formation of M-4; other metabolites formed by Phase I reactions were the result of
combinations of these pathways). CYP3A4 was the only recombinant isoform (except for
slight activity of CYP3A5) producing M-2 and M-5, and this was confirmed in the case of M-
2, by the finding that ketoconazole and azamulin (CYP3A4 selective inhibitors) abolished
or almost abolished M-2 formation. Using recombinant isoforms, CYP2J2 was identified as
an isoform of secondary importance to CYP3A4 in the N-methylhydroxylation reaction
leading to M-3 (a metabolite detected in human faeces but not plasma). The finding that
ketoconazole and azamulin reduced M-3 formation to about 10-20% of control is
consistent with a major role of CYP3A4 in M-3 formation.
In humans, although M-7 (N-glucuronidated regorafenib) was not a major circulating
metabolite, about 18% of the dose was eliminated as M-7, while about 5% of the dose was
eliminated as M-8 (N-glucuronidated pyridine N-oxide metabolite). In experiments with
recombinant uracil diphosphate (UDP) glucuronosyltransferases (UGTs), UGT1A9 was
identified as the main UGT isoform responsible for the glucuronidation of regorafenib to
M-7 in human liver and kidney microsomes, with UGT1A7 forming trace amounts of M-7.
This major role of UGT1A9 was confirmed by the finding that niflumic acid (an inhibitor of
UGT1A9) reduced formation of M-7 by both liver and kidney microsomes by about 90%. In
experiments with recombinant UGTs, UGT1A9 was identified as the only UGT isoform
responsible for the glucuronidation of M-2 to M-8. The major role of UGT1A9 in this
conversion was confirmed by the finding that niflumic acid reduced formation of M-8 by
liver microsomes by 90%.
Unchanged drug was the dominant circulating moiety in all species investigated (mice,
rats, dogs and humans) representing ≥47% of plasma radioactivity AUC (and up to 86% in
mice). The dominant circulating metabolites in humans were M-2, followed by M-5 and M-
7. This contrasts with the dominant circulating metabolites in rats (M-3 and M-4) and in
dogs (M-3 and M-6, followed by M4). M-2, together with M-3 and M-4, were the major
circulating metabolites in mice, so in this species at least, the major circulating metabolite
in humans (M-2) was produced. However, metabolism was less extensive in mice than in
the other species, so the concentrations of M-2 in mouse plasma were relatively low. Thus,
even in the relatively short term (4 and 5 weeks) toxicity studies in mice, relatively low
exposure ratios for M-2 (AUC for M-2 mouse/AUC M-2 in humans) were achieved (up to
0.9 at 80 mg/kg/day, the HD in the 4-week study, and up to 0.4 at 20 mg/kg/day, the HD
in the 5 week study). M-5 was not measured in the 4 week study, but the exposure ratios
achieved for M-5 in the 5-week study were very low (0.03 at the HD). Since rats and dogs,
the two main species used in toxicity testing, produced little or none of the two major
human metabolites, M-2 and M-5, it was appropriate that the sponsor conducted
additional studies with these metabolites.
In faeces, parent drug, followed by M-6 were the major moieties in humans, while M-6 and
M-3, followed by M-4, were the major moieties in rats, and M-6 followed by M-3 were the
major moieties in dogs, after oral administration. Given the enterohepatic circulation
observed in humans, the parent drug found in faeces could be derived from intestinal
microbial breakdown of conjugated metabolites as well as (possibly) unabsorbed drug.
Parent drug was not detected in urine in rats, dogs or humans (except in trace amounts in
one IV study in rats). Renal excretion was minor in rats and dogs, but there was
substantial renal excretion in humans, with the glucuronides, M-7, followed by M-8, being
the major metabolites in human urine. In rat and dog urine, no identified metabolite was
detected, but relatively large numbers (8-17) of unidentified metabolites were present,
each representing a small fraction (generally <1%) of the dose.
Excretion
Faeces was the major route of excretion in rats and dogs, with 88.2% and 87.6% of an
administered oral dose excreted in faeces over 0-168 h in rats and dogs, respectively. It
was also the major route of excretion in humans, but faecal excretion over 0-288 h
represented only 71.2% of the dose in humans. As noted above, urine was a more
significant route of excretion in humans than in rats and dogs, representing 19.3% of the
dose, compared with 5.5% and 0.75% in rats and dogs, respectively. Given the relatively
low level of renal excretion, regorafenib exposures might not be expected to differ greatly
between patients with impaired and normal renal function. Regorafenib/metabolites
showed marked excretion in rat milk, with the ratio of radioactivity for milk:maternal
plasma being 6.8.
Faecal excretion after oral administration in the rat was due to biliary excretion, as no
radioactivity was detected in faeces in bile duct-cannulated rats. Consistent with this
conclusion is the finding of comparable proportions of the dose being excreted in faeces
after IV and oral administration in the rat, and the same was the case in dogs. In bile duct-
cannulated rats given 14C-regorafenib IV, 8.2% of the administered dose was excreted in
faeces, suggesting excretion of this proportion of the drug across the gut wall. In humans,
enterohepatic circulation was observed, with the main contributors being regorafenib and
M-2. The extent of enterohepatic recirculation in the nonclinical animal species was not
specifically investigated.
In summary, there were marked differences in the biotransformation of regorafenib in
humans compared with rats and dogs. M-2 formation was much more pronounced in
humans than M-3 formation which was a major pathway in rats and dogs. M-5 was a
significant metabolite in humans but was a very minor metabolite in mice, rats and dogs.
Glucuronidation was a significant biotransformation pathway in humans, but not in rats
and dogs, and this difference was reflected in a greater component of urinary excretion in
humans than in rats and dogs.
Pharmacokinetic drug interactions

The potential for PK drug interactions involving regorafenib via a variety of mechanisms
was investigated.
In an in vitro study (primary human hepatocyte cultures), regorafenib (up to 10 µg/mL
(approximately 3 fold the expected clinical Cmax for total drug and 580 fold the expected
clinical Cmax for free drug)) did not show any potential for induction of the major CYP
isoforms, CYP1A2, 2B6, 2C19 and 3A4. The study included cell viability tests and positive
controls. In vivo investigation of the potential for induction of liver enzymes was
conducted in the repeat dose toxicity studies (2- and 4-week rat and 4-week dog), with a
broader range of enzymes studied. A consistent effect was not observed, although there
was a trend for increases in the 4-week rat study.
In studies with human liver microsomes and recombinant isoforms, regorafenib was
demonstrated to inhibit some CYP isoforms at clinically relevant concentrations of total
drug (about 7.2 µM), but at concentrations well above the expected level of free
regorafenib (35 nM). Isoforms inhibited were CYP2C8 (IC50 1.7 µM, Ki 0.6 µM), 2C9 (IC50
2.7 µM, Ki 4.7 µM), 2B6 (IC50 8.1 µM, Ki 5.2 µM) and 3A4 (IC50 5.8/8.3/9.1/10.4 µM, Ki 11.1
µM), and possibly also 2C19 (Ki 16.4 µM), with similar results being obtained for the
isoforms that were investigated in both studies. However, in a clinical study, regorafenib
(160 mg for 14 days) when coadministered with a single dose of 4 mg rosiglitazone (a
CYP2C8 substrate), did not alter exposure to rosiglitazone or its CYP2C8-selective
metabolite. A preliminary clinical study in which the effect of regorafenib on the PKs of a
single dose of 10 mg warfarin (a substrate of CYP2C9) was investigated, also suggested a
lack of any inhibition by CYP2C9, but when a single oral dose of 2 mg midazolam (a
substrate of CYP3A4) was co-administered with regorafenib, there was a slight (24%)
increase in midazolam AUC, suggestive of weak CYP3A4 inhibition.
Metabolite M-2 showed a broadly similar CYP isoform inhibitory profile to the parent
drug, although it was more active against CYP2D6 and less active against CYP2B6. It
inhibited CYP2C8 and 2C9, and possibly also 3A4 and 2D6 at clinically relevant total drug
concentrations (about 6.6 µM) (IC50 values 2.4, 6.1, 9.5/12/21/22, and 13 µM,
respectively), while M-5 only inhibited CYP2C8 (IC50 2.5 µM) at clinically relevant
concentrations (about 8.3 µM). However, M-2 and M-5 were highly protein bound, even
more so than parent drug (fu = 0.188% and 0.053%, respectively), so the concentrations
at which M-2 and M-5 showed inhibitory activity would be well above plasma levels of the
free metabolites at the MRHD.
Regorafenib also inhibited two UDP-glucuronosyltransferases at clinically relevant total
drug concentrations: UGT1A9 (Ki 2.1 µM) and UGT1A1 (Ki 0.7/3.1 µM). At clinically
relevant concentrations, M-2 also inhibited UGT1A1 (IC50 1.6/1.9 µM) and UGT1A9 (IC50
8.3 µM), while M-5 inhibited UGT1A1 (IC50 1.8/2.0 µM). Again, the concentrations at which
inhibition was observed would be well above the expected clinical free concentrations of
regorafenib, M-2 and M-5.
Regorafenib (at concentrations up to 10 µM) was not found to be a substrate of Breast
Cancer Resistance Protein (BCRP) when tested in BCRP over expressing and wild type L-
MDCKII cells, as efflux ratios were 0.036 and 0.030 in these respective cells and
compounds are considered to be substrates if the efflux ratio is ≥2 in cells that express the
transporter (International Transporter Consortium). Similarly, regorafenib (up to 10 µM)
was not found to be a substrate of P-glycoprotein (P-gp) when tested in P-gp transfected
and wild type L-MDR1 cells, with efflux ratios again ≤2 (0.30 and 0.093, respectively). For
both transporters, this conclusion was supported by the lack of an increase in Papp A-B in the
presence of the relevant inhibitors.
Regorafenib was found to be an inhibitor of both BCRP and P-gp. Estimated IC50 values
were 44.8 and 67.7 nM (mean 56 nM) for BCRP. These values lie below the clinically
relevant range (about 7.2 µM) for regorafenib based on total drug concentrations and are
less than double the clinically relevant free concentration of regorafenib (35 nM). These
calculations suggest that regorafenib might show clinically relevant inhibitory potential
toward BCRP, increasing the plasma concentrations of concomitant medicines that are
BCRP substrates, such as methotrexate. Estimated IC50 values were in the range 0.78-3.4
µM (mean 2.2 µM) for P-gp. These values lie below the clinically relevant range for
regorafenib based on total drug concentrations but are about 60 fold above the clinically
relevant free concentration of regorafenib, suggesting a possible but not probable
interaction with P-gp substrates in vivo. Digoxin is a P-gp substrate with a narrow
therapeutic index for which a drug-drug interaction might be of significance. Regorafenib
may also have the potential to inhibit the intestinal absorption of a co-administered P-gp
substrate, since at a dose of 160 mg regorafenib, a duodenal concentration of 1.3 mM can
be estimated (based on an assumed duodenal volume of 250 mL), which is considerably
higher than the IC50 value for P-gp inhibition at 2.2 µM.
Regorafenib (up to 10 µM) was found to be neither a substrate nor an inhibitor of organic
anion transporter (OAT) OATP1B1 and was not a substrate of OATP1B3 when tested in
OATP1B1 and OATP1B3 transfected and control HEK cells. Regorafenib showed 23%
inhibition (non significant) of OAT1B3 transport at 5 µM. This is unlikely to be of clinical
relevance. Pravastatin was used as a substrate positive control for both transporters, but
there was no positive control inhibitor for either transporter. At concentrations up to
10 µM, regorafenib was also found not to be an inhibitor of OAT1, OAT3 or OCT2 in
transfected and control HEK cells, whereas positive controls showed the expected activity.
Investigation of the potential for 129 compounds (mainly other drugs from a variety of
drug classes) to increase exposure to regorafenib by reducing formation of M-2 via
inhibition of CYP3A4 revealed, as expected, inhibition by many of the typical CYP3A4
substrates. Drugs with IC50 values below 1 µM included clotrimazole, ritonavir and
ketoconazole, with IC50 values of 0.02, 0.10 and 0.11 µM, respectively. Ketoconazole was
tested for drug interactions in a clinical study. Co-administration of regorafenib (160 mg
on day 5) and ketoconazole (400 mg for 18 days) resulted in a 90% decrease in exposure
to M-2 (AUC and Cmax), but exposure to regorafenib was increased by only 30-40%
suggesting that glucuronidation represented an important alternative pathway. Given that
ketoconazole is one of the strongest inhibitors identified in this study, this increase in
exposure to regorafenib of 30-40% is likely to be the maximum extent of any interaction
by this mechanism.
The same drugs were also investigated for the potential to increase exposure to
regorafenib by reducing formation of M-7 via inhibition of UGT1A9. Several drugs
inhibited regorafenib glucuronidation with IC50 values below 20 µM. Considering the
therapeutic plasma concentrations of each of these, niflumic acid and possibly mefenamic
acid may affect glucuronidation of regorafenib in vivo.
5-Fluorouracil is an anticancer drug that might potentially be prescribed concomitantly
with regorafenib. Neither regorafenib nor its metabolites, M-2, M-4 and M-5, each at
concentrations up to 20 µM (well above expected clinical concentrations of total or free
regorafenib/metabolites) was found to inhibit dihydropyrimidine dehydrogenase, the
enzyme that is responsible for 85% of the metabolism of 5-fluorouracil.
As regorafenib is highly protein bound, it may interact with other highly protein bound
drugs via competition for protein binding sites. Such potential interactions were
addressed by examining the regorafenib fu when 14C-regorafenib was incubated with 11
other highly protein bound drugs at therapeutic and supratherapeutic (5 times)
concentrations. Although the concentration of regorafenib used in this study was
relatively low (0.2 µM), none of the drugs, when tested at therapeutic concentrations,
elicited an increase in the fu for regorafenib.
Inducers of CYP3A4 might be expected to reduce exposure to regorafenib, although this
may not reduce efficacy due to the comparable pharmacological activity of the main
human regorafenib metabolites and parent drug. This drug interaction was not specifically
investigated in nonclinical studies, but a clinical study with rifampicin (600 mg for 9 days,
a strong inducer of CYP3A4) was conducted in which the AUC of regorafenib (160 mg on
day 7) was reduced by about 50% and there was a 3-4 fold increase in exposure to M-5,
but no change in exposure to M-2. The proposed PI recommends the avoidance of strong
inducers of CYP3A4.
As regorafenib undergoes enterohepatic recirculation (at least in humans), co-
administration of regorafenib with antibiotics may alter regorafenib exposure by altering
the gut microbial flora, but no nonclinical or clinical studies were conducted to investigate
this effect.
Toxicology
Due to the poor solubility of regorafenib in water and other solvents, a 10% coprecipitate
formulation was developed in order to maximise systemic exposure. This formulation,
which was not described in detail, was used in the majority of the pivotal toxicity studies.
Acute toxicity
Single dose toxicity studies were limited to investigation of a single dose level
(250 mg/kg) given by the oral (clinical) route in mice and rats (females only). This dose
was the maximum possible dose achievable with the formulation used and was non-lethal
and did not elicit any clinical signs, and although there was no control group for
comparison, animals gained weight over the standard 14 day observation period. Thus,
regorafenib was of low acute toxicity by the clinical route. Although these studies were
very limited (no control group, females only, oral route only, non-rodent not investigated),
drugs from this class have generally been found to have low acute toxicity and further or
more detailed studies are unlikely to have provided additional information of relevance in
assessing the toxicity of regorafenib.
Repeat-dose toxicity
Studies of up to 5 weeks duration were conducted in mice, 6 months in rats and 12 months
in dogs. All studies used the oral (clinical) route, with daily dosing, as is proposed clinically
(although no ‘off period’ was included). Study designs, including species used, duration,
group sizes and investigated parameters were consistent with the requirements in
Guideline CPMP/SWP/1042/99, and toxicokinetic data were collected in all studies.
Primary pharmacology studies in mice and rats revealed these species to be
pharmacologically responsive to regorafenib, and judging by the toxic effects of
regorafenib in dogs, this species is also pharmacologically responsive to regorafenib.
Relative exposure
Exposure ratios have been calculated based on animal:human plasma AUC0–24 h. Human
reference values (regorafenib 51.3 μg.h/mL; M-2 49.8 μg/h/mL; M-5 64.2 μg/h/mL) are
from Clinical Study 11650 (mean values from 3 cohorts of patients including those with
CRC). As is typical for this class of drugs, exposure ratios were very low. Values have also
not been corrected for the 3 week on-one week off cycle in humans compared with
continuous dosing in the nonclinical species.
Table 2. Relative exposure in repeat-dose toxicity studies
Species; Study Analyte Dose AUC0–24 h Exposure

study duration (mg/kg/day) (µg∙h/mL) ratio#@
Mouse 5 15.5 0.3 (0.4)

(CD-1);
study Regorafenib 20 63.0 1.2 (1.5)
T3076262*
80 186 3.6 (4.4)
4 weeks
5 2.43 0.05
M-2 20 11.7 0.2
80 45.8 0.9
Mouse (CD- 1 3.13 0.1 (0.1)

1); study
T5079478* Regorafenib 5 18.4 0.4 (0.4)
20 84.0 1.6 (2.0)

5 weeks
5 2.97 0.1
M-2
20 17.8 0.4
M-5 20 2.02 0.03
Rat 10 60.5 1.2 (1.8)

(Wistar);
study 2 weeks Regorafenib 25 145 2.8 (4.2)
T6073132^
50 196 3.8 (6)
Rat 4 weeks Regorafenib 1 5.8 0.1 (0.2)

Species; Study Analyte Dose AUC0–24 h Exposure
study duration (mg/kg/day) (µg∙h/mL) ratio#@
(Wistar);
4 20.4 0.4 (0.6)
study
T107462^
16 81 1.6 (2.4)
Rat 0.5 3.14 0.1 (0.1)

(Wistar);
study Regorafenib 2 10.8 0.2 (0.3)
T4075651^ 13 weeks
8 68.6 1.3 (2.0)
M-2 8 0.431 0.01
Rat 0.1 0.511 0.01 (0.01)

(Wistar);
study Regorafenib 0.5 3.15 0.1 (0.1)
T2078241^ 26 weeks
2 12.5 0.2 (0.4)
M-5 2 0.130 0.002
Dog 5 12.9 0.3 (0.5)

(Beagle);
Regorafenib 20 32.2 0.6 (1.3)
studies
T2074704
and 80 71.8 1.4 (2.8)
4 weeks/13
T3076046*$ weeks
5 0.094 0.002
M-2 20 0.479 0.01
80 1.07 0.02
Dog 1 3.19 0.1 (0.1)

(Beagle);
Regorafenib 4 13.9 0.3 (0.5)
study
TXST20070
037* 16 38.2 0.7 (1.5)
52 weeks
4 0.235 0.005
M-2
16 0.923 0.02
M-5 16 <0.118 0.002
# = animal:human plasma AUC0–24 h (human AUC = 51.3 μg.h/mL); @ exposure ratios in parentheses are
values corrected for differences between humans and the nonclinical species in protein binding, using
correction factors of 1.2 for mice, 1.5 for rats and 2.0 for dogs; * AUC values are the mean of all sampling
times as there was no accumulation (mice) or a decrease in AUC with repeated dosing (dogs); ^ AUC
values are from the final sampling time as accumulation was evident; $ values for regorafenib are means
of data from the 4 and 13 week studies
Major toxicities
The toxicological profile of regorafenib was characterised by degenerative and
inflammatory changes in multiple tissues at exposures comparable to or less than those
expected clinically. This is not unexpected for this class of drugs. ERs refer to values
uncorrected for species differences in plasma protein binding.
Target organs were the liver, skin, kidney, teeth, bone/cartilage, heart, digestive system
(stomach, intestine, pancreas, salivary glands), male and female reproductive organs
(testes, epididymides, ovaries, uterus, vagina, cervix), haematopoietic/lymphoreticular
system (spleen, thymus, bone marrow, Peyer’s patches, and to a lesser extent, lymph
nodes) and endocrine system (adrenals, pituitary, thyroid). Some (possibly many) of these
target organ toxicities, most notably the skin changes in the dog and the dentine changes
in both rats and dogs, may be related to the primary pharmacological activity of the drug.
Gastrointestinal and skin effects are commonly observed with VEGF inhibition, and skin
effects with KIT inhibition.
There were no consistently observed major haematological changes or effects on blood
coagulation in any of the nonclinical species.
The liver was a target organ in mice, rats and dogs. In mice, changes were limited to a
reduction in weight (also seen in rats and dogs) and a reduction in glycogen (also seen in
rats). Some additional changes, seen in both rats and dogs, included bile duct proliferation,
increased pigment storage in Kupffer cells, cytoplasmic changes, mononuclear cell
infiltration and pigment deposition. Additionally, perihepatitis, increased
apoptoses/mitoses and rounded hepatocytes were seen in rats and centrilobular
hypertrophy and fat accumulation in dogs. In dogs, the gall bladder was also affected in the
52-week study (most notably, inspissation and epithelial hyperplasia). Most changes in the
rat were observed at ≥2 mg/kg/day (ER 0.2). In dogs, the majority of findings were at ≥ 20
mg/kg/day (ER 0.6). A number of serum clinical chemistry changes were consistent with
liver damage induced by regorafenib. These included increases in serum aspartate
transaminase (AST) and alanine transaminase (ALT) in all the repeat dose rat and dog
studies, with significant increases observed at ≥5 mg/kg/day in mice (ER 0.4), ≥ 0.5
mg/kg/day in rats (ER 0.1) and ≥ 16 mg/kg/day in dogs (ER 0.7). Lactate dehydrogenase
(LDH), creatinine kinase (CK) and glutamate dehydrogenase (GLDH) were also measured
in some studies and were increased. Increases were also observed in cholesterol (2-, 4-and
13-week rat studies) and bilirubin (2- and 4-week rat studies). Consistent with the
nonclinical data, hepatotoxicity has been identified as an important adverse drug reaction
in patients. It is appropriate that the proposed Product Information contains a statement
recommending that close monitoring of overall safety is conducted in patients with
moderate to severe hepatic impairment.
The skin was a major target organ in dogs, but no effects on the skin were observed in
mice, while in rats, the only finding in skin was in the 2-week study in which apoptosis of
hair follicles was observed in females mainly at ≥ 25 mg/kg/day (ER ≥2.8)(there were no
findings in skin in the longer term studies at doses up to 16 mg/kg/day (ER up to 1.6)).
Skin histological changes in the dog were characterised by folliculitis/perifolliculitis and
hair growth arrest after 13 weeks dosing (but not after 4 weeks dosing at the same doses),
and additionally, after 52 weeks, hyperkeratosis, follicular keratosis, hypergranulosis,
comedo, fibrosis, crusts, pigment clumping, inflammation and lymphoid cell infiltration.
These changes resulted in gross skin changes/clinical signs of alopecia or sparse coat after
13 weeks and additionally, skin reddening, thickening and swelling, formation of scabs,
papules, pustules, abscesses, wounds and eczema after 52 weeks. Skin changes were
observed at all doses in the 52-week dog study (ER ≥ 0.1). Consistent with the nonclinical
data, dermatological adverse reactions have been observed in patients, with hand-foot
skin reaction (HFSR)/plantar-plantar erythrodyesthesia syndrome being the most
frequently observed skin reaction. The tongue was also affected in rats and dogs, but
findings were inflammatory changes (52-week dog study), reductions in mast cells (4- and
13-week rat studies) and interstitial oedema (4-week rat study) (as well as changes to the
sublingual glands noted above), rather than epithelial changes.
The kidney was a target organ in mice, rats and dogs. Glomerulopathy and tubular dilation
were observed in all these species. Additional changes were observed in rats and dogs,
with many being common to both these species, including tubular degeneration (often
accompanied by regeneration), interstitial fibrosis, increased PAS positive staining and
casts. Additional findings in the 52 week dog study included glomerulosclerosis, Bowmans
capsule hypertrophy and cortical mineralisation. Kidney changes were observed in rats
mainly at ≥ 2 mg/kg/day (ER 0.2) and in dogs mainly at ≥ 4 mg/kg/day (ER 0.3). Kidney
lesions were associated with urinalysis findings in some studies.
The teeth were affected in all species, with histological changes including dentine
alterations (all species), and additionally in rodents, ameloblast and odontoblast
degeneration, and in rats only, angiectasis/oedema of the periodontal ligament and
inflammation/degeneration of the pulp. Grossly, discolouration was observed in rodents
and additionally, broken, missing and spit teeth were observed in rats. Changes to the
teeth were observed at doses ≥ 5 mg/kg/day in mice (ER ≥ 0.3), at ≥ 8 mg/kg/day in rats
(ER ≥ 1.3) and at ≥ 20 mg/kg/day in dogs (ER ≥.0.6). The findings in rodents may not be of
relevance in humans because rodent teeth are constantly growing, but dentine alteration
was also observed in dog teeth, in both the 4- and 13-week studies in which the dogs were
6-7 months or 7-8 months old at treatment initiation, that is, relatively mature.
Bone was a target organ in mice, rats and dogs. Thickened growth plate was observed in
all these species, and hypocellularity of the growth plate in rats, but these changes are
likely to only be of relevance to young patients. Chondrodystrophy (cartilage
maldevelopment) was also observed in all species, mainly at the higher doses in the
shorter term studies in rodents (in mice, mainly at 80 mg/kg/day (ER 3.6) and in rats at ≥
8 mg/kg/day (ER ≥ 1.3)), while in dogs, it was observed in the 2 week study, but
surprisingly not at the same doses in the 13 week study in similarly aged dogs. Again, this
is likely to be of relevance mainly to young patients.
Digestive system: Histological changes in the gastrointestinal tract were observed in mice,
rats and dogs. Stomach changes were mainly in the rodent forestomach
(hyperkeratosis/acanthosis) which does not have a counterpart in humans and therefore
is not considered relevant for risk assessment. However, cell hypertrophy in the pyloric
region of the glandular stomach was also observed in the 4- and 13-week rat studies
mainly at 8 mg/kg/day (ER 1.3), while at the higher doses used in the 2 week rat study,
changes included erosion/ulceration and mucosal degeneration (at ≥25 mg/kg/day, ER
2.8) and dys-/hyperkeratosis (at ≥10 mg/kg/day). In dogs, findings in the stomach
(mucosal mineralisation and hypertrophy of zymogenic cells) were only seen at the higher
doses used in the 4 week study (ER >0.6).
The duodenum was affected in rats, but not mice or dogs. The main findings were seen in
the 4- and 13-week studies and included hypertrophy of the mucosa, musculature and
blood vessels, as well as degeneration/regeneration and inflammatory cell infiltration at 8
mg/kg/day in the 13 week study (ER 1.3), with thickening observed grossly. The
choleduodenal junction was also affected (degeneration/regeneration, inflammation,
fibrosis and intraluminal debris) in the 13-week rat study. The ileum was only affected in
dogs, with degeneration of villi observed in the 13-week study at 80 mg/kg/day (ER 1.4.).
Findings in the colon, caecum and/or rectum were relatively minor (including submucosal
oedema in the 4-week rat study and inflammatory cell infiltrate in the 13-week dog study).
Gastrointestinal clinical signs (increased incidence of diarrhoea and vomiting, discoloured
faeces, mucus and/or blood in faeces) were observed in dogs at ≥ 1 mg/kg/day (ER 0.1).
Consistent with the nonclinical data, gastrointestinal adverse reactions were observed in
patients, including gastrointestinal perforation.
Atrophy (general and acinar cells) was the main finding in the pancreas and was observed
in mice, rats and dogs. It was associated with degeneration and apoptosis in rats and dogs
(and there was a compensatory increase in mitosis in rats), as well as inflammatory
interstitial oedema. Effects were observed at doses ≥ 20 mg/kg/day in mice (ER 1.2), ≥ 8
mg/kg/day in rats (ER 1.3) and mainly at 80 mg/kg/day in dogs (ER 1.4).
Salivary glands (parotid, submandibular and/or sublingual glands) were also affected
(atrophy or hypertrophy, generally of acinar cells) in the 4- and 13-week rat and dog
studies.
Reproductive organs: In males, testicular atrophic changes were observed. These were
restricted to reduced weights in the mouse (4 week study), but histological changes
(testicular atrophy, immaturity or tubular atrophy/degeneration) were observed in rats
(4-, 13- and 26-week studies) and dogs (4- and 13-week studies). Spermatid giant cells
were observed in both the 13- and 52-week dog studies. Rats were affected at doses ≥ 2
mg/kg/day (ER ≥ 0.2) and dogs at 20 mg/kg/day (ER 0.6). Some histological changes were
observed in the epididymides, most notably cellular debris in rats and dogs, and
additionally, aspermia, lymphocytic cell infiltration, tubular mineralisation and epithelial
vacuolar degeneration in dogs, but were not always clearly dose-related.
In females, histological changes were observed in the ovaries in mice, rats and dogs.
Reductions in ovary weight and/or atrophic changes were observed in rats and dogs,
while changes to the numbers of follicles (reduced developing follicles, atrophic, cystic or
degenerative) and/or corpora lutea (cystic or necrotic) were seen in all species. Some of
these changes are likely to be secondary to hormonal changes, although there was no
investigation of these. Findings in the ovaries were observed at doses ≥ 5 mg/kg/day (ER
0.4) in mice, mainly at ≥ 8 mg/kg/day (ER 1.3) in rats, and mainly at ≥ 4 mg/kg/day (ER
0.3) in dogs. The most notable change in the uterus was atrophy/juvenile appearance
accompanied by a reduction in organ weight in the 4- and 13- week rat studies (at ≥ 8
mg/kg/day (ER 1.3)), but other changes included stromal atrophy and oedema (in mice),
luminal dilatation (rats) and cystic glandular dilatation (dogs). Similarly, the most notable
changes in the vagina and cervix were atrophy/juvenile appearance in rats (in the 4- and
13-week studies at ≥ 8 mg/kg/day (ER 1.4)). There was also an increase in the proportion
of rats in prooestrus (decrease in proportion in met/dioestrus and in vaginal mucification)
in the 4-, 13- and 26-week studies. Other changes included vaginal keratinisation in mice,
epithelial exfoliation in rats and a mononuclear cell infiltrate and increased vaginal
discharge in dogs. Homogeneity of corpora lutea in rats suggested irregular oestrous
cycling.
Haematopoietic/lymphoreticular system: A reduction in spleen weight, reduced
haematopoiesis and marginal zone atrophy were observed in the spleen of mice and
reduced haematopoiesis in the spleen of rats, but largely at relatively high doses (the HD
in the 4-week studies in both species). Reduced thymus weights and thymic atrophy were
observed in mice, rats and dogs at doses of 80 mg/kg/day in mice (ER 3.6), ≥ 8 mg/kg/day
in rats (ER 1.3) and ≥ 16 mg/kg/day in dogs (ER 0.7). Lymphoid depletion (depletion of
follicular centres, single cell necrosis and/or atrophy/degeneration) was observed in
Peyer’s patches in rats (at ≥ 16 mg/kg/day (ER 1.6)) and dogs (at ≥ 20 mg/kg (ER 0.6)).
There were also changes in bone marrow, which included hyperaemia in rodents,
hypocellularity and/or increased fat in all species, and increased myelopoiesis/increased
ME ratio in mice and dogs, although these changes did not have a major impact on
peripheral blood cell numbers. Bone marrow changes were observed in mice at ≥ 20
mg/kg/day (ER 1.4), in rats at ≥ 10 mg/kg/day (ER 1.2) and in dogs at ≥ 1 mg/kg/day (ER
0.1).
Endocrine system: The most notable findings in the adrenals were degenerative changes
at relatively low incidences in rats (necrosis mainly at ≥ 8 mg/kg/day (ER 1.3) in the 4-
and 13-week studies; peliosis was observed at high incidence in females in the same
studies at ≥ 8 mg/kg/day) and in dogs (vacuolar degeneration of the cortex in the 52-week
study mainly at ≥ 4 mg/kg/day (ER 0.3)). Changes in the pituitary were relatively minor,
and were different in rats (increased pale cells in the 4- and 13-week studies) and dogs
(most notably, mononuclear cell infiltration in the pars nervosa in the 13- and 52-week
studies). The same was the case with the thyroid. In rats, a flattened epithelium was
observed in the 4-, 13- and 26-week studies (in the latter study, in HD males only) at
≥ 2 mg/kg/day (ER 0.2), and was associated with a reduction in thyroxine (T4) and an
increase in thyroid stimulating hormone (TSH) in the 4- and 13-week studies, and an
increase only in TSH in HD males in the 26-week study. Thyroid atrophy was observed in
dogs, but only in the 13-week study, while mineralisation was observed in the 52-week
study, but was not clearly dose-dependent. In dogs, some thyroid hormone changes were
seen (a small increase in TSH at the HD (male and female combined) in the 52 week study;
thyroid hormones were not measured in the other dog studies).
Some changes were observed in the heart of rats, most notably, perivascular oedema (4-
and 13-week studies at ≥8 mg/kg/day (ER 1.3)) and thickening of the atrioventricular
valves (26-week study at 2 mg/kg/day (ER 0.2)).
Ophthalmological examinations were conducted in the 13- and 26-week rat studies and
the 4-, 13- and 52-week dog studies and did not reveal an effect of treatment.
Recovery was examined following a 4 week recovery period in three of the repeat dose
toxicity studies: the 4- and 13-week rat studies and the 4-week dog study. In the 4-week
rat study, recovery was poor and mortality high in the treated group. In the dog study,
data interpretation was difficult due to the low animal numbers (3/sex/group in the
treatment period and 2/sex/group in the recovery period), however, with the exception of
dentine alterations in the teeth, there was evidence for recovery of many of the drug-
induced changes (including diarrhoea), although some histological changes still remained
in the liver (increased serum transaminases resolved), skin, testes and ovaries in the
recovery animals. The 13-week rat study provided good data on recovery and it was clear
that, with the exception of the teeth (and in particular, dentine alterations), partial or
complete recovery was observed for the majority of findings seen during/at the end of the
treatment period.
Since rats and dogs, the two main species used in toxicity testing, produced little or none
of the two major circulating human metabolites, M-2 and M-5, the sponsor conducted
repeat dose toxicity studies (4-week mouse) with these metabolites. M-2 and M-5 showed
lower toxicity than parent drug. The histological changes induced by M-2 and M-5 were
limited to incisor dentine alterations and, additionally for M-2, hepatic haematopoiesis,
and additionally for M-5, dilated bone marrow sinuses (indicative of hypocellularity).
Changes elicited by regorafenib were more extensive. The ER achieved for AUC0-24 h at the
HD of M-2 in the 4-week mouse study was 1.4 (69.4 (mean of day 1 and day 30
values)/49.8), although this would increase to 7 (1.4 x 4.7) if corrected for interspecies
differences in protein binding. The ER achieved for AUC0-24 h at the HD of M-5 in the 4-
week mouse study was 1.5 (98.5 (mean of day 1 and day 30 values)/64.2), although this
would increase to 12 (1.5 x 7.8) if corrected for interspecies differences in protein binding.
In conclusion, the nonclinical data suggest a substantial clinical risk of changes in the liver,
skin, kidneys, digestive system and male and female reproductive organs.
Genotoxicity
A standard set of genotoxicity studies was submitted: a bacterial reverse mutation study,
an in vitro chromosome aberration study in Chinese hamster V79 cells and an in vivo
mouse micronucleus test. All studies were GLP compliant, adequately conducted, used
appropriate concentrations/doses and included positive controls. Although
concentrations scored in the chromosome aberration study in the presence of S9 did not
elicit reductions in mitotic or survival indices of >50%, the reductions in survival indices
were substantial (>40%).
The bacterial reverse mutation study included Salmonella typhimurium strain TA102
which detects mutations at A-T sites and was conducted using both the standard plate
incorporation assay, as well as the preincubation assay. Males only were used in the
micronucleus test. This is acceptable ‘unless there are obvious differences in toxicity and
metabolism between male and female rodents’ (International Conference on
Harmonisation (ICH) Guideline 3B6a). Although the metabolism of regorafenib was only
investigated in male mice and rats, so no comparison of metabolism between the sexes
could be made, all repeat dose toxicity studies in both mice and rats included both sexes,
with no major sex differences evident. Although the toxicity studies were conducted in the
CD-1 strain of mice and the genotoxicity studies in the NMRI strain, metabolism in these
two strains was similar (Study PH-33760). Overall, the use of males only is considered
acceptable. The results of all genotoxicity studies were negative.
Given that rat hepatocytes produced minimal or no M-2 and M-5 (Study A57473), and that
the S9 mix used in the in vitro genotoxicity studies on regorafenib was from rat liver, it
was appropriate that specific genotoxicity studies (bacterial reverse mutation assays and
in vitro chromosome aberration studies) were conducted on M-2 and M-5. These studies
were also GLP compliant, adequately conducted, used appropriate concentrations
(although in the chromosomal aberration studies, a 50% reduction in mitotic
index/survival index was not achieved in all instances), and positive controls (in most
instances), and were conducted in the presence and absence of metabolic activation (rat
liver S9). Results were negative except for the chromosome aberration study with M-2 (4
h exposure) in which the percentage of abnormal metaphases was significantly increased
at the 30 h harvest (±S9) and at the highest concentration scored following the 18 h
harvest (+S9). For the 30 h harvest, the result in the absence of S9 (6.5%) fell within the
historical control range (0-8.5%), but the result in the presence of S9 fell considerably
outside the historical control range (17.5% compared with 0-5.5%). The result for the 18 h
harvest (+S9) fell only marginally outside the historical control range (10.5% compared
with 0-8.5%). While M-2 is the major circulating human metabolite of regorafenib and
represented nearly 30% of plasma radioactivity in study A59022, the positive
clastogenicity finding is not considered a major concern because it was only marked after
the later harvest in the presence of S9 and it is not known whether the metabolism of M-2
by rat liver S9 mix reflects the human metabolism of M-2. Further, the short lifespan of the
patient population needs to be taken into account.
Carcinogenicity
Carcinogenicity studies on regorafenib were not conducted and are not required for drugs
to be used for the treatment of advanced cancers where the predicted life expectancy of
the patients is short.
Reproductive toxicity
No fertility and early embryonic development or pre-/postnatal development studies
were submitted. This is acceptable given the proposed indication (see ICH S9). Given the
mode of action of regorafenib and the effects on the reproductive system in both males
(most notably, testicular atrophy or tubular atrophy/degeneration) and females (atrophic
changes in the ovaries, and degenerative or necrotic changes to follicles and/or corpora
lutea, and probably perturbations to oestrous cycling) seen in the repeat dose toxicity
studies, effects on fertility and on pre-/postnatal development might be expected.
Two embryofetal development studies were submitted: one in rats and one in rabbits,
both using oral administration. The rabbit study was a full GLP compliant study with 20
females/group and toxicokinetic assessment, but the rat study was a non-GLP pilot study,
with 7 females/group, and included 7 dose levels (and control). Both studies were
adequately conducted, with standard treatment periods and parameters investigated (in
the rat pilot study, fetal examination included visceral and skeletal examination, as well as
external examination). Dose selection was appropriate in the rabbit study, as was the dose
range covered in the rat pilot study. Pharmacokinetic studies in pregnant and lactating
rats showed that regorafenib/metabolites crossed the placenta (ratios of fetal/maternal
tissues ranging 0.1-1.6) and was excreted in milk (milk/plasma AUC ratio 6.8).
In the rat, teratogenic effects were observed at doses of ≥0.8 mg/kg/day, while fetal
weights were significantly decreased at 1.6 mg/kg/day and the number of viable
fetuses/litter was significantly reduced at 2 mg/kg/day. Although there were no
toxicokinetic data for this study, available toxicokinetic data from the repeat dose toxicity
studies in rats suggest that major reproductive toxicity occurred at exposures well below
those that might be expected at the MRHD (a dose of 2 mg/kg/day was associated with an
ER of 0.2).
In rabbits, at the high dose (1.6 mg/kg/day, ER 0.4 for regorafenib), there were significant
increases in postimplantation loss, decreases in number of live fetuses/litter and increases
in fetal and/or litter incidences of various malformations. The main malformations were
in the urinary system (rabbits only), the heart and major vessels, and the skeleton.
Relative exposure in the rabbit embryofetal development study
Exposure ratios have been calculated based on animal:human plasma AUC0–24 h. Exposure
ratios were very low (Table 3).
Table 3. Exposure in rabbit reproductive toxicity study
Species Analyte Dose AUC0–24 h Exposure

(mg/kg/day) (µg∙h/mL)^ ratio#
Rabbit Regorafenib 0.4 3.2 0.1

(NZW)
0.8 8.76 0.2
1.6 18.5 0.4
M-2 1.6 0.396 0.01
M-5 1.6 0.132 0.002
^ AUC values are from the final sampling time as accumulation was evident; # = animal:human plasma
AUC0-24 h (51.3 μg.h/mL from Clinical Study 11650).
Pregnancy classification
The sponsor has proposed Pregnancy Category D 10 which is appropriate and consistent
with the category for other kinase inhibitors.
10Use in pregnancy Category D is defined as: Drugs which have caused, are suspected to have caused or may be
expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may
also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
Local tolerance
Specific local tolerance studies were not conducted and are not required for a tablet
formulation. The toxic effects of regorafenib on the gastrointestinal tract have been noted
above, with some (in particular, the gastrointestinal clinical signs observed in dogs)
probably due to a local effect.
Immunotoxicity
Immunotoxicity assessment was incorporated into the 4- and 13-week repeat dose rat
studies and included splenic cell counts and FACScan analyses of splenic cell
subpopulations and determination of serum immunoglobulin (Ig) IgG, IgA and IgM titres.
Additionally, a plaque forming cell assay was conducted in the 13-week study. There were
no effects of regorafenib in the plaque forming cell assay and minor effects on splenic cell
counts. While there were effects on splenic cell subpopulations (most notably, decreases
in CD4total, CD45high and CD8total) and in serum antibody titres (most notably, increases in
IgM and decreases in IgG), mainly at the HD in both studies, these did not overtly affect the
susceptibility of the animals to infection and are not considered of major toxicological
significance.
Phototoxicity
Phototoxicity studies were required as regorafenib and its metabolites M-2 and M-5
absorb the ultraviolet/visible light at the wavelength range 290 -700 nm and are
distributed to the skin following systemic administration. Phototoxicity was initially
studied in the in vitro 3T3 NRU phototoxicity test, which has been validated by the
Organization for Economic Cooperation and Development (OECD) and is recommended in
the European Medicines Agency (EMA) photosafety testing guideline
(CPMP/SWP/398/01). The study was adequately conducted and included positive
controls which gave the expected responses. However, the results for regorafenib (3
assays) were variable, with photoirritation factor (PIF) values of 0.73, 1.8 and 6.12
obtained. PIF values of <2 are considered to predict no phototoxicity, values between 2
and 5 to predict probable phototoxicity and values >5 to predict phototoxicity. Thus, two
values predicted no phototoxicity while one predicted phototoxicity. This study was
therefore followed by an adequately conducted in vivo study. Based on toxicokinetic data
from the 4- and 5-week mouse studies, the highest dose used in the in vivo study would
have achieved an exposure above that expected clinically. Results of this study were
negative suggesting that regorafenib is unlikely to have phototoxic potential.
Metabolic activation was not used in the in vitro study (it is not recommended by the
OECD), but a separate 3T3 NRU phototoxicity study was conducted with metabolites, M-2
and M-5. The results for M-2 (PIF of 2.86) weakly predicted probable phototoxicity, while
the results for M-5 (PIF of 7.82) predicted phototoxicity. This study was therefore
followed by an in vivo study on M-5 which gave negative results suggesting that M-5 does
not have phototoxic potential. These studies, both in vitro and in vivo, were again
adequately conducted and used positive controls which gave the expected responses.
Based on toxicokinetic data from the 4-week mouse study with M-5, the highest dose used
in the in vivo study would have achieved an exposure above that expected clinically.
Impurities
Impurities/degradants in the drug substance/product are either below the ICH
qualification thresholds or can be considered adequately qualified.
Metabolites
Studies conducted on the two major metabolites in humans that were formed only in small
quantities in rats and dogs (the major species used in the repeat dose toxicity studies)
were quite extensive and included in vitro cardiovascular and in vivo CNS and
cardiovascular/respiratory safety studies, absorption studies in nude mice and rats,
plasma protein binding studies (range of species), CYP and UGT inhibition studies, in vitro
genotoxicity studies (bacterial reverse mutation and chromosome aberration studies) and
repeat dose oral toxicity studies (4 weeks in mice, supported by toxicokinetic data) and
phototoxicity studies (in vitro, and additionally, an in vivo study with M-5).
Paediatric use
Regorafenib is not proposed for paediatric use and no specific studies in juvenile animals
were submitted. The repeat dose toxicity studies revealed toxicities that would be of
concern if regorafenib was to be used in juveniles. These toxicities were to the teeth (most
notably dentine alterations, and ameloblast and odontoblast degeneration) and in bone
(most notably thickening of the growth plate and chondrodystrophy).
Comments on the safety specification of the risk management plan

Results and conclusions drawn from the nonclinical program for regorafenib detailed in
the sponsor’s draft Risk Management Plan are in general concordance with those of the
nonclinical evaluator. Some comments are made regarding proposed PI statements.
Details of these are beyond the scope of the AusPAR.
Nonclinical summary and conclusions

• The overall quality of the submission was good. Appropriate studies were conducted
and pivotal studies were GLP compliant.
• In biochemical assays, regorafenib inhibited multiple kinases that are involved in
tumour growth, most notably antiangiogenic (VEGFR-2 and TIE2), stromal (FGFR and
PDGFR) and oncogenic (KIT, RET and BRAF). IC50/Kd values for inhibition of many, but
not all, were in a clinically relevant range. In cellular assays, regorafenib inhibited
TIE2, cKIT and BRAF-V600E with clinically relevant IC50 values. However, EC50 values
for inhibition of proliferation of colorectal and pancreatic cell lines lay in a higher
range (clinically relevant for total but not free drug). In nude mice bearing human
colorectal xenografts, regorafenib showed moderate efficacy in 3 of 5 models at a
clinically relevant dose, while little efficacy was observed in 2 models. Antiangiogenic
activity was demonstrated in a rat tumour (glioma) model at a clinically relevant dose.
Regorafenib reduced lung metastases in a breast cancer model. The major circulating
metabolites in humans (M-2 (N-oxide) and M-5 (N-oxide and desmethyl)) showed
similar pharmacological activity to the parent drug and are likely to contribute to
pharmacological activity.
• Secondary pharmacology studies revealed no analgesic activity or pro-convulsive
activity, and little effect on blood glucose concentrations at exposures above those
expected clinically. Safety pharmacology studies revealed little potential for CNS or
respiratory effects of regorafenib, M-2 or M-5. Regorafenib did not show potential for
effects on renal function but showed potential to inhibit gastrointestinal motility that
may be clinically relevant. Regorafenib, M-2 and M-5 inhibited hERG current in in vitro
studies, with the metabolites showing greater potency than parent drug, but IC50
values were considerably higher than free fraction plasma concentrations in patients,
suggesting a low risk of QT interval prolongation. No findings (ECG findings/QT
prolongation) were observed in the in vivo safety studies or in the repeat dose dog
toxicity studies. No other cardiovascular risks were identified.
• The PKs of regorafenib in rats were characterised by rapid and extensive absorption,
high oral bioavailability, low first pass effect, moderate to high volume of distribution,
and extensive tissue distribution, with liver, adrenals and adipose tissue being
relatively highly labelled. There was no evidence of retention of
regorafenib/metabolites in any specific tissue, and only slight evidence of melanin
binding. Plasma protein binding was high in all species (but with some species
differences). Major metabolic pathways included N-oxidation, N-methylhydroxylation
and N-demethylation, but metabolism varied between species, with M-2 formation
being more pronounced in humans than M-3 (N-methylhydroxylated) formation which
was a major pathway in rats and dogs. M-5 was a significant metabolite in humans but
was a very minor metabolite in mice, rats and dogs. Glucuronidation was a significant
metabolic pathway in humans, but not in rats and dogs, and this difference was
reflected in a greater component of urinary excretion in humans than in rats and dogs,
although faecal excretion was the main route of excretion in all species. Marked
excretion of regorafenib/metabolites was seen in rat milk. In humans, CYP3A4 was the
main CYP isoform responsible for the oxidative metabolism of regorafenib, while
UGT1A9 was the main UGT isoform responsible for regorafenib glucuronidation.
• Regorafenib showed potential for drug interactions via inhibition of various CYP
isoforms (particularly CYP2C8, 2C9 and 2B6) and UGT1A1 and UGT1A9, as well as
inhibition of P-glycoprotein and BCRP. Regorafenib showed no inhibitory potential
towards OATP1B1, OATB1B3, OAT1, OAT3 and OCT2. No significant enzyme induction
was observed with regorafenib.
• Regorafenib did not show any acute toxicity following a single oral dose of 250 mg/kg
in mice and rats. Repeat dose toxicity studies of up to 5 weeks duration were
conducted in mice, 6 months in rats and 12 months in dogs. The toxicological profile of
regorafenib was characterised by degenerative and inflammatory changes in multiple
tissues at exposures (based on AUC) comparable to or less than those expected
clinically. The nonclinical data suggest a substantial clinical risk of changes in the liver,
skin, kidneys, gastrointestinal system and male and female reproductive systems.
Major target organs were the liver (increased serum transaminases and a range of
histological changes), skin (particularly hair growth arrest and folliculitis in dogs) and
kidney (particularly tubular degeneration and glomerulopathy) and major target
organ systems were the gastrointestinal system (stomach, intestine, pancreas and
salivary glands, with diarrhoea marked in dogs) and the male and female reproductive
systems (in particular, the testes, ovaries and uterus, (mainly atrophic changes), but
also epididymides, vagina and cervix)). The haematopoietic/lymphoreticular system
(spleen, thymus, bone marrow and Peyer’s patches) and endocrine system (adrenals,
pituitary and thyroid) were also affected. Teeth (particularly dentine alterations) and
bone/cartilage (particularly growth plate thickening and chondrodystrophy) were
target organs that would be of particular relevance to children/adolescents (the
current indication is for adults). Some changes were also observed in the heart.
Metabolites M-2 and M-5 showed lower toxicity than parent drug in 4-week studies in
mice.
• Regorafenib was negative in a standard set of genotoxicity studies (a bacterial reverse
mutation study, an in vitro chromosome aberration study in Chinese hamster V79 cells
and an in vivo mouse micronucleus test). M-2 and M-5 were also tested in the same in
vitro studies, with negative results except for M-2 in the chromosome aberration
study. An impurity, 4-amino-3-fluorophenoxy-picolinmethylamide (present at up to
0.01% in the active ingredient and 0.10% in the finished product) showed weak
genotoxic activity. These findings are considered of relatively minor concern given the
patient population. Carcinogenicity studies were not conducted and are not required.
• Embryofetal development studies in rats (pilot study) and rabbits (full study) revealed
embryofetal toxicity and teratogenicity at exposures (based on AUC) lower than those
expected clinically. The main malformations were in the urinary system (rabbits only),
the heart and major vessels, and the skeleton. Neither a fertility and early embryonic
development study nor a pre-/postnatal development study was conducted and this is
acceptable. Given the mode of action of regorafenib and the findings in the
reproductive systems in males and females in the repeat dose toxicity studies, effects
on fertility and pre-/postnatal development might be anticipated in patients.
• Regorafenib, M-2 and M-5 were considered to lack phototoxic potential given the
results of the in vivo phototoxicity studies, despite some positive results in the in vitro
studies for all three compounds.
Conclusions and recommendation

An acceptable package of nonclinical data was submitted, with no major deficiencies.
• The primary pharmacology studies demonstrated efficacy and support the use of
regorafenib for the proposed indication, although some limitations were evident, most
notably, antiproliferative effects on colorectal cell lines were only observed at
relatively high concentrations (about clinical Cmax for total drug) and in vivo, a clinically
relevant dose of regorafenib showed efficacy in only 3 out of 5 human colorectal
xenografts in nude mice.
• No clinically relevant hazards were identified by the secondary and safety
pharmacology studies.
• Several potential drug interactions were predicted and there are adequate statements
relating to these in the proposed Product Information.
• The toxicological profile of regorafenib was characterised by degenerative and
inflammatory changes in multiple tissues at exposures comparable to or less than
those expected clinically. This is not unexpected for this class of drugs, and rather than
establishing the safety of the drug, the focus is on identifying toxic effects and the
exposures at which these effects are observed. Identified target organs/organ systems
of particular clinical relevance were the liver, skin, kidney, gastrointestinal system and
male and female reproductive systems. Teeth and bone/cartilage were important
target organs of relevance to children/adolescents (not the currently proposed patient
population). The haematopoietic/lymphoreticular system, endocrine system and heart
were also identified as target organs/organ systems.
• Genotoxicity studies on regorafenib were negative and carcinogenicity studies were
not conducted. A major circulating metabolite (M-2) was identified as having
genotoxic potential, as was an impurity, but the risk associated with this is considered
low for this patient population.
• Fertility and pre-/postnatal development studies were not conducted but effects on
fertility and pre-/postnatal development might be anticipated given the mode of
action of regorafenib and the findings in the reproductive systems in males and
females in the repeat dose toxicity studies. In embryofetal development studies in both
rats and rabbits, regorafenib was found to be embryofetotoxic (decreases in live
fetuses/litter) and teratogenic at exposures lower than those expected clinically.
There are no nonclinical objections to registration of regorafenib for the proposed
indication.
Recommended revisions to nonclinical statements in the draft PI are beyond the scope of
the AusPAR.
IV. Clinical findings

A summary of the clinical findings is presented in this section. Further details of these
clinical findings can be found in Attachment 2.
Introduction
Regorafenib is for the proposed indication:
the treatment of patients with metastatic colo-rectal cancer irrespective of KRAS
mutational status who have been previously treated with, or are not considered
candidates for, fluoropyrimidine based chemotherapy, an anti-VEGF therapy, and, if
KRAS wild type, an anti EGFR therapy.
Regorafenib is provided in a 40 mg tablet formulation for oral administration. Proposed
administration is 160 mg regorafenib (4 tablets) taken orally once daily for 3 weeks (21
days, on therapy) followed by 1 week (7 days) off therapy to comprise a cycle of 4 weeks.
The dosage regimen is also referred to as intermittent dosing: 3 weeks on / 1 week off.
Clinical rationale
The clinical development of regorafenib as a single agent was initiated in 2005 for patients
with advanced solid tumours (Study 11650) and progressed to Phase III trials in patients
with advanced cancers including CRC. The first indication was for treatment of patients
with metastatic CRC irrespective of KRAS mutational status who have been previously
treated with, or are not considered candidates for, fluoropyrimidine chemotherapy, an
anti-VEGF therapy and, if KRAS wild type, an anti-EGFR therapy, which is the subject of
this application.
Contents of the clinical dossier

A total of 15 clinical trials are submitted including full reports and appropriate summaries
as summarised in Table 4.
Table 4. Overview of Phase I, II and III regorafenib studies.
Study no. Type of study Tumor type Dosing No. of Report no.
Countries atlents
Phase 1: Regorafenib in healthy volunteers
12435 Effect of NIA Regorafenib 80 and 160 mg 24 PH-36717,
USA ketoconazoleon PK single dose ModuleS.3.3.4
of regorsfenib (4 x 40 mg tablets)
Ketoconazole 400 mg
12436 PK, metabolism, NIA Single dose of 120 mg 4 PH,36734,
UK exetetion,mass regorafenib solution containing Module 5.3.3.1
balance approximately1.5 mg of 14C·
r&diolabeled regotafenib
12437 Relative NIA 2 -single doses of 160 rng 48 PH-36595,
USA bloavallability Module S.3.1.2
1 x 100 mg tablets+ 3 x 20 mg
tablets compaHtd to
4 x 40 mg tablets
146S6 Bioavailabitity, higfl.- NIA 3 s;ng!edosesof 160mg 24 PH,36S2S,
USA fat vs. low-fat {4 x 40 mg tablets) Module 5.3. 1.1
breakfastvs, fasting
st.ateeffect on PK
15524 Effect of rifampin NIA Regorafenib 160 mg single dose 24 PH-36716,

USA (rifamplcln)on PK of (4 x 4-0mg tablets) ModuleS.3.3.4
regorafenib
rifampin(rifampicin) dose 600 mg
Phase 1. Regorafenib as single agent in cancer patients

116S0 Dose escalation.PK. Advanoed solid Re!>O{ofenlb10 - 220 mg od 76 (of which PH-36733,
Germany PD, tvmor response, tumo,.. 39CRC Module 5.3.3.2
safety iinte,mittE~ntdosing s<::h&dule patients)
(3 weeks on 11 week off)
116S1 Dose escalation, Advanoed solid Reg,orafenib 20 - 140 mg od 84 PH,36741,
USA PK, safety tumo,s continuous dosing PH-36742,
ModuleS.3.3.2
12434 Ptobe subsltate. PK Advanced solki Regorafenlb 160 mg. od GroupA: 20 PH-36721,
Canada safety tumors (4 x 40 mg tablets) (planned} Module 5.3.3.4
intermitten1 dosing sd'le<lule 6 (actual) Preliminary PK
(3 w&eks on / 1 week off) rel)Ort
~:20
Group A; Warfarin 10 mg. (planned),
Omeprazole 40 mg, Midaz.olam
2mg 10 (actual)
Group B: RosigJitazone 4 mg
13172 PK, safe\y Advanced and R,e90<afenib 160 mg od 16 AS1164
Japan refractory solid (4 x 4-0mg tablets) Module 5.3.3.2
tumors
inte,.mittenl dosing sdledule
(3 weeks on / 1 week off)
14814 ca,dk>vascular Advancedsolid R-eg0<afenib160 mg od S4 PH-36720,
USA safety (QT/QTc. tumors (4 x 40 mg tablets) Module 5.3.4.2
LVEF),PK. safety
inte.rmittenl dosing $Che<lule Interim QTc report
(3 weeks on 11 week off) on 25 patients
·································-·························-·························································
[£RUE COPY]!
Table 4 continued. Overview of Phase I, II and III regorafenib studies.
Study no. Type of study Tumor type Dosing No. of Report no.
Countries atlents
14996 PK. safety Actvanc&dand Ragorafenlb 160 mg od 24 A51600,
China refractorysolid (4 x 40 mg tablets) Module5.3.3.2
tumors
lnte,mlttentdosing schedule
(3 week$ on/ 1 week off)
Phase 1: Regorafenibcombinedwith other medicinalprodCJclsin cancer patients

11656 PK. safety Metastatic CRC 1" Regorafenib 160 mg od 45 PH-36735,
Germany or 21\dline on days 4-10 and Module 5.3.3.2
1~24 of every 4 week cyde
Plus mFOLFOX6 or FOLFIRI
Phase 2: Regorafenib in cancer patients

11726 Uncontrolled, Metastaticor Regorafenib 160 mg od: 49 A46572.
USA. single-arm study, unresectable renal Module 5.3.5.2
France. efficacy.safety.PK ceUcancet (1 x 100 mg lablelS + 3 x 20 mg A55873.
Germany. (previouslyuntreated tablets or Module 5.3.5.2
Poland, UK, patients) 4 x 40 mg tablets)
Finland
intermittent dosing schedule
(3 weeks on/ 1 w&ek off)
14596 Uncontrolled, HepatoceUulst Regorafenib 160 mg od 36 A51601,
Germany. slngle-atm study. eancet (4 x 40 mg tablets) Module5.3.5.2
ttaly. Spain. safety.efficacy,PK
Ko«,a intermittent dosing schedule
(3 weeks on/ 1 week off)
Phase 3: Regorafenib in metastatic CRC patients

14387 Randomized. Metastatic CRC Regorafenib 160 mg od 760 A53306.
Norlh dout)le-blind. (progressed after (4 x 40 mg lablelS) Regorafenib: Module 5.3.5.1
America, placebo-controlled standard therapy} 505
Europe. study:re,gorafenlb
+ lnte,mittentdosing schedule
Israel, BSC VS, placebo, (3 weeks on/ 1 week off)
Auslralie, efficacy, safety, PK, Placebo:
Matching placebo 255
Asia• blomarka,s
• Countries: North America (Canada and USA). Europe (Belgium. Czech Republic, France, Germany. Hungary. Italy,
Switzerland, Spain, The Nethertands), IStael. Australia, and Asia {China and Japan)
AWeviatiorl$: SSC - best supportive care; CRC - oolorectal carcinoma; PD - pharmacodynamics;PK - pharmacokinetk;$;
UK - United Kingdom: USA - United States of America: mFOLFOX6 - FOUnic add/Fluoroura<:iVOXclliplatln (m = modifl&d.
the number 6 indicates this is the sixth variation of the regimen developed}; FOLFIRI - FOLinic acidfFluorouraci1/IRlnotecan
In addition, the sponsor provided a clinical overview, summary of clinical efficacy,

summary of clinical safety as well as literature references.
Paediatric data
Not applicable.
Good clinical practice

All aspects of good clinical practice were observed in the studies.
Pharmacokinetics and pharmacodynamics
Studies providing pharmacokinetic and pharmacodynamic data

Fifteen studies provide clinical pharmacological data for regorafenib as summarised in
Table 5. Studies were categorised as studies in cancer patient, studies in healthy
volunteers, dose escalation studies (which served as the basis for dose selection),
biopharmaceutical studies, metabolism (and interaction) studies, special population
studies and special studies (a cardiovascular study).
filuE co:_tiY!]
Table 5. Clinical pharmacology studies of regorafenib
Module no. DesignI Number of
(Protocol no.) RegorafenibDose Study patients Main outcomes/
Region Duration population Total CRC Reference
Phase 1 Studies in Cancer Patients

Dose Escalation Studies
PH-36733 Open-label;uncontrolled; Cancer patients 76 39 Safety profile; PK; PD'
(11650) Dose-escalation with advanced MTD; recommended
Germany (10-220 mg OD~ solidtumors Phase 2dose
Intermittentdosingschedule: 5.3.3.2.1, PH-36733
3 v,eekson/ 1 v,eekoff
PH-36741 Open-label;uncontrolled; Cancer patients 84 0 Safety profile; PK; MTD;

PH-36742 Dose-escalation with advanced recommendedPhase 2
(11651) (20-140 mg OD~ solidtumors dose
Continuousdosing 5.3.3.2.3, PH-36741,
USA
schedule. 5.3.3.2.2, PH-36742
Special Populations Studies

A51164 Open-label;uncontrolled; Cancer patients 16 0 Safety; PK
(13172) 160 mg OD; with advanced 5.3.3.2.4, A51164
Japan Intermittentdosingschedule: refradory solid
3 v,eekson/ 1 v,eekoff tumors
A51600 Open-label;uncontrolled; Cancer patients 12 8 Safety, PK

(14996) 160 mg OD; with advanced 5.3.3.2.5, A51600
Hong Kong Intermittentdosingschedule: refradory solid
Singapore 3 v,eekson/ 1 v,eekoff tumors
Drug Interaction Studies

PH-36735 Open label;uncontrolled Patientsv..ith 45 45 Safety, PK, PD of
(11656) 160 mg OD metastaticCRC regorafenibv..ilh
Germany On days 4-10 and 18-24 of mFOLFOX6 or FOLFlRI
every 4-v,eekcycle. 5.3.3.2.6, PH-36735
PH-36721 Open label, uncontrolled;, Cancer patients Grp.A Not PK of probesubstrate~
(12434) 160 mg OD; with advanced =6 Avail- Safety, PK, PD of
Canada Intermittentdosingschedule: solidtumors Grp B able regorafenib
3 v,eekson/ 1 v,eekoff = 10 5.3.3.4.3, PH-36721
Studyongoing;
preliminaryPK report
Special Studies
PH-36720 Open-label,uncontrolled; Cancer patients 54 Not Safety; PK, OT/OTC
(14814) 160 mg OD; with advanced Avail- intervaIs and LVE F.
USA Intermittentdosingschedule: solidtumors able 5.3.4.2.1, PH-36720
3 v,eekson/ 1 v,eekoff Studyongoing;interim
re ort
{Table oontinued)
[rRLTE COPY!!
Table 5 continued. Clinical pharmacology studies of regorafenib
Module no. Design/ Number of
(Protocol no.) RegorafenibDose Stu1dy patients Main outcomes/
Phase 1 Studies in Health~ Volunteers
Biopharmaceutics Studies
PH-36525 Open label,randomized Healthy 24 0 Bioavailability; high-fat
(14656) 3 singleoraldosesof 160 mg volunteers vs low-fatbreakfastvs
USA fastingstateeffecton
PK
5.3.1.1.1, PH-36525
PH-36595 Open-label,randomized; Healthy 0 Relativebioavailability
(12437) 160 mg; 2 singleoraldoses: volunteers 5. 3.1.2.1, P H-36595
USA 1 x 100 mg• 3x20 mg; and
4x 40 mg
Metabolism (Drug interaction) Studies
PH-36734 Open label,singlecenter, Healthymale 4 0 Metabolism,excretion,
(12436) Singleoraldose of120 mg volunteers mass balance,safety,
1
UK 'C-radiolabeledregorafenib tolerabilityand PK
5. 3.3.1.1, P H-36734
PH-36717 Open label Healthy 24 0 Effed of ketoconazole
(12435) Singleoraldose of160 mg volunteers on PK of regorafenib
5.3.3.4.1, PH-36717
PH-36716 Open label Healthy 24 0 Effed ofrifampinon PK
(15524) Singleoraldose of160 mg volunteers of regorafenib
USA 5.3.3.4.2, PH-36716
Phase 2/3 Studies With PK in Cancer Patients

A51601 Uncontrolled, Hepatocellular 36 0 E flicacy, safety, PK
(14596) single-armstudy cancer 5.3.5.2.1, A51601
Germany, Italy, 160 mg 00
Spain, Korea intennittent
dosingschedule
(3 v.eeks on/ 1 v.eek off)
A46572 Uncontrolled, Metastaticor 49 0 E flicacy, safety, Pk,
A55873 single-armstudy unresedable biomarker
(11726) 160 mg OD renalce'II 5.3.5.2.2, A46572
USA, France, intennittent
dosingschedule cancer 5.3.5.2.3, A55873
(3 v.eeks on/ 1 v.eek off) (previou;sly
Germany,
untreated
Poland, UK, patients)
Finland
A53306 Randomized,double-blind, Met&taticCRC 7e() 7e() EffiCSOJ.safety. PK.
(14387) placebo-controlled study; { i:,ogesse<I after Rega Rega biorrwter
regorafenib+ BSC vs. stands.rd afaiib: afaiib:
Europe, USA, therapy) 505 505
placebo 5.3.5.1.1, A53306
Canada,
160 mg OD
Australia, Asia
intennittent
dosingschedule
(table cx,nti~
(3 v.eekson/ 1 v.eeko~
CRC = colorectal cancer; MTD = maximum tolerated dose; FOLFOX = chemotherapy regimen consisting of
FOLinic acid/Fluorouracil/Oxaliplatin; FOLFORI = chemotherapy regimen consisting of FOLinic
acid/Fluorouracil/IRinotecan
Evaluator’s conclusion on pharmacodynamics and pharmacokinetics

The pharmacological data from these 15 studies has determined the PK and PD profile of
regorafenib. It clearly indicates that metabolism of regorafenib results in formation of two
major metabolites, M-2 and M-5, which have clinically significant activity. Furthermore
metabolism principally occurs in the liver and excretion occurs via the faeces.
There is no evidence from this data that various intrinsic factors play a role in influencing
the metabolism of regorafenib. There is however some evidence that strong CYP3A4
inducers may increase the metabolism of regorafenib. This only appears to be a modest
dose response to toxicity relationship which will need to be further evaluated.
There is no evidence of significant cardiovascular toxicity associated with regorafenib
from this data. The food effect evaluation clearly shows that dosing of regorafenib after a
low fat or light meal maximizes exposure to parent drug as well as to the active
metabolites.
Dosage selection for the pivotal studies

Two early Phase I studies were conducted in cancer patients to define the best dose and
dose regimen to be carried into Phase II–III clinical development. Study 11650, with a 3
week on / 1 week off schedule, and Study 11651, with a continuous dosing schedule, were
evaluated to compare the safety and tolerability, PK, anti-tumour activity and the various
potential advantages and disadvantages with respect to subsequent clinical use.
In Study 11650, the maximum tolerated dose (MTD) of regorafenib was 160 mg daily on a
treatment schedule of 3 weeks on 1 week off in repeated 28-day cycles.
In Study 11651, the MTD of regorafenib in the continuous dosing schedule was 100 mg
daily.
The regorafenib 160 mg once daily in the treatment schedule 3 week on / 1 week off in
repeating 28 day cycles was selected over the regorafenib 100 mg once daily in the
continuous dosing schedule due to a number of considerations, including safety and
tolerability.
Safety and tolerability at the MTD were similar when comparing the intermittent versus
continuous dosing regimen. However for approximately the same potential toxicity a 20%
higher total dose of regorafenib can be delivered using the intermittent schedule when
compared to the continuous schedule. This may translate into greater tumour activity.
The intermittent dosing schedule provided an opportunity for patients to recover at least
partially from toxicities such as skin and gastrointestinal effects. A potential down side of
the intermittent dosing schedule might be tumour flare up during the treatment break
period. However the relatively robust disease control rate in patients treated with 160 mg
of regorafenib with the intermittent dose schedule from Study 11650 suggests that this
may not be a disadvantage in actual clinical use.
In the intermittent dosage schedule patients could receive regorafenib 160 mg, as
compared to 100 mg in the continuous dosing schedule, and thus would be exposed to a
higher steady state AUC0-24 h and Cmax of regorafenib and its two pharmacologically active,
equally potent metabolites, M-2 and M-5. The higher exposure during the dosing days in
the 3 weeks on / 1 week off schedule may prove advantageous with respect to anti-
tumour activity for some tumours.
An intermittent dosing schedule may offer advantages in terms of combining with other
agents which are dosed intermittently and decrease the chances of any possible PK drug-
to-drug interactions.
Accordingly for the pivotal studies a dose schedule of 160 mg taken for 3 weeks and a 1
week break period on a 4 week schedule has been chosen.
Efficacy
Studies providing efficacy data

Two clinical trials are provided in this submission to support efficacy for regorafenib in
the proposed indication, as summarised in Table 6.
Table 6. Overview of clinical studies to demonstrate efficacy of regorafenib in metastatic CRC
Study no. Title Study Dosing Number of Main
(Report no.) population patients by outcomes
treatment
Regions/
group
countries
involved
Pivotal, randomized, controlled trial
14387 A randomized, double- Patients with 160 mg oral Total: 760 Primary: OS
(A53306) blind, placebo- metastatic
Intermittent: Regorafenib + Secondary:
controlled Phase 3 CRC
North 3 weeks on BSC: 505
study of regorafenib PFS, ORR,
America, /1 week off
plus BSC versus Placebo+ DCR
Europe, Israel,
placebo plus BSC in BSC: 255
Australia, Asia Tertiary:
patients with
metastatic CRC who DOR, DSD,
have progressed after PRO, PK.
standard therapy biomarkers
Safety
Clinical pharmacology trial
11650 Open label, Phase 1 Patients with 10-220 mg; Total 76 PK
(PH-36733) study to determine the advanced oral including
Germany
safety, tolerability, solid tumors Intermittent: 38 with CRC ~~!~~~:or
MTD, PK, and Metastatic 3 weeks on treated wi th DCR
biomarker status of CRC /1 week off .:5o mg
BAY 73 4506 in regorafenib od Biomarkers
patients with advanced expansion
malignancies cohort Safety
Abbreviations: SSC - best supportive care: DCR - disease control rate; DOR - duration of
response; DSD - duration of stable disease; CRC - colorectal carcinoma; no. - number; MTD -
maximum tolerated dose; ORR - objective response rate; OS - overall survival; PFS - progression
free survival; PK - pharmacokinetics PRO - patient reported outcomes; RECIST - Response
Evaluation Criteria in Solid Tumors.
Countries: North America (Canada and USA), Europe (Belgium, Czech Republic, France, Germany
Hungary, Italy, Switzerland, Spain, The Netherlands). Israel, Australia, and Asia (China and Japan)
The pivotal study was Study 14387, a randomised double blind, placebo controlled, Phase
III study involving a total of 760 male and female patients of at least 18 years of age with
metastatic CRC. Patients were randomly assigned on a 2 to 1 ratio to 1 of 2 treatment
groups: the experimental arm of regorafenib 160 mg once per day for 3 weeks on / 1 week
off together with best supportive care (BSC), and the comparator arm of matching placebo
plus BSC.
The primary objective variable for this study was overall survival (OS). The secondary
efficacy endpoints were progression free survival (PFS), objective response rate (ORR),
which was the percentage of patients with complete response (CR) or partial response
(PR), and overall disease control rate (DCR), which included the percentage of patients
whose best response was CR, PR or stable disease and excluded those patients with stable
disease less than 6 weeks from randomisation. Tertiary end points of the study included
duration of response (DOR), duration of stable disease (DUC), and health-related quality of
life assessed by patient reported outcomes. Evaluation of disease response was based on
the RECIST version 1.1 criteria 11.
The second study, Study 11650, was a supportive, Phase I, open label, single agent study
assessing efficacy, safety, PK, and MTD for regorafenib in patients with progressive solid
tumours. Secondary objectives were to evaluate biomarker status, PD parameters and
tumour response of patients treated with regorafenib. A dose escalation phase included
regorafenib doses from 10 to 220 mg once per day given on an intermittent dosage
schedule. At the end of the dose escalation phase an expansion cohort of 23 patients with
CRC was evaluated at a dose level of 160 mg per day regorafenib given on a 3 weeks on / 1
week off schedule.
11Response Evaluation Criteria for Solid Tumors (RECIST) is a voluntary, international standard using unified,
easily applicable criteria for measuring tumor response using X-ray, CT and MRI.
11TRUE COPx!I
Evaluator’s conclusions on efficacy
Study 14387
Summary data for the primary endpoint, OS, are shown for the intent to treat (ITT)
population in Table 7 and Figure 2.
Table 7. Overall survival in Study 14387 (primary analysis; ITT)
Placebo + BSC Regorafenib + BSC
(N = 255) (N = 505)
Number of patients(%) with event 157 (61.6) 275 (54.5)
Number of patients (%) censored 98 (38.4) 230 (45.5)
Median overall survival (days) 151 196
95% a for median 134, 177 178,222
Range (days, without censored values) 13-315 5-375
Range (days, including censored values) (5-401.. )
(1 .. -413.. )
Hazard ratio (regorafenib/placebo) 0.774
95% a for hazard ratio 0.636,0.942
One-sided p-value from log rank test 0.005178
.. = censoredobservation;a = confidence interval; ITT = intent-to-treat population
Note: Stratification based on CRF data. A hazard ratio < 1 indicates superiority of regorafenib over
placebo. The hazard ratio and its 95% Cl was based on Cox Regression Model, stratified by
prior treatment with VEGF drugs (yes/no), time from diagnosis of metastatic disease
(~18 months or <18 months) and geographical region 1 (North America, Western Europe, Israel
and Australia) versus region 2 (Asia) versus region 3 (Eastern Europe, South America, Turkey).
Figure 2. Kaplan-Meier curves of Overall survival in Study 14387 (ITT)

1.00
0.75
1
.
C
',I 0.50
i.•
0
j
~ 025
"'
ODO
0 50 100 150 200 250 300 350 400
Dey, From Randomization
STRATA: -- treatment=Plaoebo 0 0 <>Censored tregtment=Placebo

- - - tre1tment•R ego, ■ fenlb 1&0 mo 0 0 0 Censored tr11tment•Regoufenlb 180 mg
Summary data for the secondary end point PFS are shown for ITT population in Table 8
and Figure 3.
[i'RUE. COPYjl
Table 8. Progression-free survival in Study 14387 (ITT)
Placebo• BSC Regorafenlb • BSC
(N • 255) (N • !105)
Number or patients (%) with event 241 (94 5) 430(851)
Nur'l'lbe(of pall~ta (%) c•n10tll<I 14 (!>.!>) 75 (14.9)
Median PFS (doys) 52 59
95% Clrormed1811 (51, 53) (57, 65)
Range (day,. without cen,ored values) 6-277 5-333
Rllnge (dl'ys, lnclud1n9cenSOted1/l'IU&S) (1 "-277) (1"-336")
Ha.can!ratJO(rogoralenibfplacebo) 0.494
95% Cl for hazard ratio 0.419. 0.582
One-sided p-value from log rank test <0.000001
•• • ooMOredobJONetion. Cl "' oonfidenco interval; ITT '" intent 10treat: PFS " f)f0grtt$lon-free
SUMVAI
Note. PFS wH based on the invesbgator'sas~ssmenl.
Noto: Medio.nPFS and 95% Cls computed using Kaplan-Moler ostim:11cs.A haulrd r.illo < 1
lnd1Ca1H superlOfltyot regoraftnlt> 160 mg 01/tr PIICll>O, HIWltd nlllO anCI IIS95% Cl WIS
b3sed on Cox RegresSIOflModel. stratified by ptior lfe3tment wilh anb-VEGF drugs (yes/no).
time from diagnosis of metas1alicdisease {.t18 months or <18 months) and geographicalregion
1 (Noflh Amenca. Western EurOl)e.Imel and Au,1ral1<1) ven1n tllll!Ofl 2 (Asia) versus region 3
(Eutem Europe, South AmeriGA.Turtcey). StratiBeatlonwu based on CRF data.
Figure 3. Kaplan-Meier curves of progression-free survival in Study 14387 (ITT).

l.00
0 75
\
'
50 100 150 200 250 300 350
Day.t. From R.am2omi2c1tlo,i
STRATA: -- treatmerit.=Placebo 0 0 0 Cen!>ate~ lre.Rlment=Placeba

- - - t,eatment=Regorafenib 160 mg O O O Cenaor&O treetment=Regorafenib 160 mg
The data from this large, heavily pretreated population of patients with metastatic CRC has
shown a comprehensive benefit for regorafenib in terms of both OS and PFS. The primary
endpoint benefit for overall survival of 22.6% reduction in hazard is clinically meaningful
and a 29.2% improvement in overall survival is confirmation of this. Similarly, the PFS
data adds weight to the significant benefits for OS.
Further indication of the value of regorafenib is indicated by the fact that patients
irrespective of KRAS mutation status benefited, with the subgroup analyses confirming a
benefit.
Study 11650
Median PFS for the 38 patients who received at least 60 mg of regorafenib in this study
was 107 days with a range of 1 to 279 days. Data on PFS of CRC patients receiving at least
60 mg regorafenib including information about their tumour KRAS mutation status, and
Kaplan-Meier curves showed no clear difference in progression free survival between the
two KRAS groups.
The data from the Phase I trial presents very limited information regarding the degree of
modest efficacy for regorafenib in these heavily pretreated patients. This data cannot be
really considered strongly supportive of the pivotal study because of the small number of
patients and the nature of the Phase I trial together with the limited number of patients
receiving 160 mg of regorafenib therapy.
l[TRUE COPY\I
Safety
Studies providing evaluable safety data

Safety data for this evaluation is based on the safety data derived from various Phase I, II,
and III clinical studies as indicated in Table 9.
Table 9. Clinical development program: overview of clinical studies to demonstrate efficacy
and/or safety of regorafenib
study Report no. Design/ No. of treated
(Protocol no.) Regorafenib Dose study patients Main outcomes/
Pivotal Phase 3 study in Colorectal Cancer Patients
A53306(14387) Randomized;double-blind; Coloredal 753 (all CRC) Efficacy;safety,PK,
(Pool 3) placebo-controlled; cancerpatients bioma11<ers
(afterfailureof 253 placebo
Europe,North 160 mg; interrrittentdosing: Module5.3.5.1,
standard 500
Arrerica (incl USA), 3 weeks on/ 1 week off therapy) A53306
Israel,Australia, regorafenib
Asia ~apan,China)
Phase 2 Studies in Cancer Patients
A46572(11726) Uncontrolled;open-label; Renalcell 49 0 Efficacy,safety.
(Pool 1) cancerpatients
160 rrg; interrrittentdosing: with acllanced Module5.3.5.2,
USA,France, 3 weeks on/ 1 week off cancer A46572
Germany,Poland, (previously
UK, Finland untreated,
A55873 rretastaticor Module5.3.5.2,
(addenci.Jmfor unresectable) A55873
11726)
A51601(14596) Uncontrolled;open-label; Hepatocellular 36 0 Safetyprofile;
(Pool 1) cancerpatients efficacy
160 rrg; interrrittentdosing:
Germany,Italy, 3 weeks on/ 1 week off Module5.3.5.2,
Spain,Korea A51601
~ Stua1es
F'Fiase m CancerF'al1enls
PH-36733(11650) Uncontrolled,open-label; Ganeerpatients 76 39 Tumorresponse;
(Pool 1) multicenter; with acllanced Safetyprofile;PK:
solidtumors MTD; recomrrended
Germany Dose-escalation Phase2 dose
(10-220mg);
Module5.3.3.2.1,
I nterrnittentdosing: PH-36733
3 weeks on/ 1 week off
PH-36742(11551) Uncontrolled,open-label; Ganeerpatients 84 6 Safetyprofile;PK:
(Pool 2) multicenter; with acllanced MTD; recomrrended
solidtumors Phase2 dose
USA Dose-escalation
(20-140mg); Module5.3.3.2.2,
continuousdosing schedule. PH-36742
PH-36735(11656) Open label Patientswith 45 45 Safety,PK/ PD of
(not pooled) metastaticCRC regorafenibwith
160 rrg oncedaily days 4-1O mFOLFOX6or
Germany and 18-24of every 4-week FOLFIRI
cycle.
Module5.3.3.2.6,
PH-36735
A51164(13172) Uncontrolled;open-label; Ganeerpatients 16 0 Safetyprofile;PK
(Pool 1) with acllanced
160 rrg; interrrittentdosing: refractorysolid Module5.3.3.2.4,
Japan 3 weeks on/ 1 week off A51164
tumors
Table 9 continued. Clinical development program: overview of clinical studies to
demonstrate efficacy and/or safety of regorafenib
Stuc!yReport no. Design/ No. of treated
(Protocol no.) Regorafenib Dose Stuc1y patients Main outcomes I
A51600 (14996) Uncontrolled;open-label; Cancer 12 8 Safetyprofile; PK

(Pool 1) patientswith
160 rrg; intermittentdosing: Module5.3.3.2.5,
acllanced
Hong Kong 3 weeks on I 1 week off refractorysolid A51600
Singapore tumors
TOTAL Exposed to regorafenib Cancer 818 598
Exposed to placebo patients 253 253
Phase 1 Studies in Healthy Volunteers
PH-36595(12437) Twoway, randomized,open Healthy 48 0 Relative
label stuc!y; volunteers bioavailability
(not pooled)
160 rrg tablets Module5.3.1.2 1,
USA PH-36595
2 singleoral doses:
1 x 100mg + 3 x 20 mg; and
4X 40 mg
PH-36525(14656) Open label Healthy 24 0 Bioavailability;high-
volunteers fat VS low-fat
(not pooled) 3 singleoral doses of breakfastvs fasting
160 rrg
USA state effect on PK
Module5.3.1.1.1,
PH-36525
PH-36734(12436) Single center,open label Healthymale 4 0 Metabolism,
volunteers excretion,mass
(not pooled) Singleoral dose of 120 rrg balance,safety,
"C-radiolabeled regorafenib tolerabilityand PK
USA
Module5.3.3.1.1,
PH-36734
PH-36717(12435) Open label Healthy 24 0 Effect of
volunteers ketoconazoleon PK
(not pooled) Singleoral dose of 160 rrg of regorafenib
USA Module5.3.3.4.1,
PH-36717
PH-36716 (15524) Open label Healthy 24 0 Effect of rifampinon
volunteers PK of regorafenib
(not pooled) Singleoral dose of 160 rrg
Module5.3.3.4.2,
USA PH-36716
TOTAL Exposed to regorafenib Healthy 124 0
volunteers
TOTAL Exposed to regorafenib Cancer pis+ 942 598
Exposed to placebo healthy 253 253
volunteers
CRC = Colorectalcancer;MTD = rreximumtolerateddose; FOLFOX= chemotherapyregimenof FOLinic
acid/Fluorouracil/OXaliplatin;
FOLFIRI= chemotherapyregimenconsistingof FOLinicacio'Fluorouracil
/IRInotecan, PK= pharmacokinetics,UK= UnitedKingdom;USA = UnitedStatesof Arrerica
The main analyses are based on safety data pooled from completed company sponsored
monotherapy trials in patients with cancer. Data from the pivotal Study 14387 forms Pool
3; data from the Phase I Study 11651 of regorafenib administered continuously once daily
forms Pool 2; and pooled data from the Phase I and II studies in cancer patients with
intermittent dosing (3 weeks on / 1 week off) forms Pool 1. A total of approximately 1,145
cancer patients with all types of cancer have been treated with regorafenib, of whom 621
were CRC patients.
Adverse events (AEs) of pooled data were coded using the Medical Dictionary for
Regulatory Activities (MedDRA) recognised clinical dictionary and severity of AEs were
categorised by National Cancer Institute (NCI) criteria.
Extent of exposure
The extent of exposure in the various 3 pools is indicated in Table 10.
Table 10. Extent of exposure to regorafenib and placebo treatments in pools 1 to 3 (Safety
Analysis Set)
Pool 1 Pool2 Pool3
Regorafenib Regorafenib Regorafenib Placebo
N = 188 N = 84 N = 500 N = 255
Overall time under treatment
Mean ±SD (weeks) 25.79 ± 19.74 ± 29.99 12.08 ± 9.74 7.78 ± 5.19
33.47
Median 14.79 11.43 7.27 6.98
Range 0.1 -179.4 0.1 - 145.0 0.28 -47.01 0.57 -38.61
Actual time under treatment•

Mean ±SD (weeks) 18.86 ± 18.01 ± 27.14 8.85 ± 6.78 6.29 ± 3.79
24.38
Median (range) 9.64 9.93 5.98 5.98
Range 0.1 - 132.3 0.1-134.1 0.28-35.9 0.57 -29.92
Actual daily dose (mg)•

Mean ±SD 137.38 ± 39.41 88.82 ± 29.06 147.13 ± 18.64 159.25 ± 4.85
Median 160.00 100.0 160.00 160.00
Range 10 - 220 20.0 -140.0 85.7 -160.0 107.00 -160.0
Any dose modification, n (%) 112 (59.6%) 83 ( 98.8%) 378 ( 75.6%) 97 ( 38.3%)
Dose reduction per patient, n

(%)•
Any dose reduction 79 (42.0) 5 (6.0) 100 ( 20.0) 8 ( 3.2)
1 45 (23.9) 5 (6.0) 82 ( 16.4) 8 ( 3.2)
2 26 (13.8) 0 14 ( 2.8) 0
2:3 8 (4.2) 0 4 ( 0.8) 0
Dose interruptions per

patient, n (%)
Any dose interruption 148 (78.7) 83 ( 98.8) 352 ( 70.4) 95 ( 37.5)
1 70 (37.2) 22 ( 26.2) 178 ( 35.6) 70 ( 27.7)
2 27 (14.4) 32 ( 38.1) 94 ( 18.8) 19 ( 7.5)
.:3 51 (27 1) 29 (34.5) 80 (16.0) 6 ( 2.4)
Abbreviations: N - number of patients (in total); n - number of patients with the event; SAF - safety analysis set;
SD = standard deviation
• Including time off drug/interruptions
• Excluding time off drug/interruptions
<Dose reduction was re-calculated in Pool 2 and differs from that originally presented in the CSR for 11651. If a
subject had a dose interruption (a dose of O mg), the next non-zero dose was considered a 'reduction' in the
CSR, but in this summary it was counted as re-challenge at lower than protocol dose.
The percent of planned dose was calculated consistently for all studies (Pool 1 and 2) and consistently with
calculation rules in Pool 3 on the data mapped to the new CDISC standard.
Evaluator’s conclusions on safety

The data clearly indicates that there is a significant incidence of toxicities in association
with regorafenib administration. Adverse events were noted in 95% of all patients
receiving this therapy. Although the majority of AEs were mild to moderate in severity a
proportion was Grade 3 and higher. The most common AEs noted included palmar-plantar
erythrodysesthesia syndrome, diarrhoea, fatigue, dysphonia, decreased appetite,
hypertension and nausea. The most common Grade 3 events were hypertension, fatigue,
diarrhoea, palmar-plantar erythrodysesthesia syndrome, pain in the extremity, abdominal
pain hyperbilirubinemia, hypophosphatemia and increased transaminases.
In terms of significant toxicities, there was a definite risk associated with potential for
severe drug induced liver injury, haemorrhage, myocardial ischaemia/infarction, arterial
hypertension and hypertensive crisis, and palmar-plantar erythrodysesthesia syndrome.
Also to be assessed carefully is the potential for gastrointestinal perforation and fistula.
These AEs are in general terms consistent with the mechanism of action of regorafenib
and the AE profiles associated with other tyrosine kinase inhibitor. While requiring careful
monitoring, these AEs are in general terms managed adequately with early intervention
and in the appropriate circumstances with prophylactic treatment.
,~_COPY!I
First round benefit-risk assessment
First round assessment of benefits

Data from the pivotal Study 14387 is the principal determinant of evidence of benefit in
relation to regorafenib for the proposed indication. This study was a multi-national
randomised, placebo controlled, Phase III trial involving 760 patients who were
randomised on a 2 to 1 basis to regorafenib plus BSC versus placebo plus BSC.
The results showed a statistically significant benefit in OS for regorafenib over placebo.
The estimated hazard ratio (HR, risk of death with regorafenib + BSC versus placebo +
BSC) was 0.774 [0.636, 0.942] (one sided p-value = 0.005178). This represents an
improvement in OS of 29% for regorafenib treated patients, with a median increase of 6.4
months versus 5 months in the placebo group, corresponding to a 23% reduction in
hazard over placebo. This represents a clinically significant improvement in outcome for
patients who have otherwise failed all standard therapies as no evidence-based therapy
has been available up to the present time that has clearly demonstrated a prolongation of
overall survival as has occurred in this trial.
Progression free survival data were consistent with the OS results, with an estimated HR
of 0.494 (p-value < 0.000001) representing a 50.6% reduction in hazard with regorafenib
compared to placebo.
Sensitivity and subgroup analyses confirmed the benefit for regorafenib in this pivotal
trial, both in terms of OS and PFS.
First round assessment of risks

The data presented in the evaluation clearly demonstrates a quite high incidence of AEs
associated with regorafenib treatment. More than 95% of patients experienced at least
one treatment emergent AE. While the majority of these were Grade 1 and 2, nearly 50%
were Grade 3 or greater in severity. The most frequent of these included palmar-plantar
erythrodysesthesia, diarrhoea, fatigue, dysphonia, decreased appetite, hypertension and
nausea. The majority of these adverse events could be managed either prophylactically or
with adequate intervention.
Nevertheless results reveal a definite incidence of more severe complications requiring
careful monitoring, in particular those events related to hepatotoxicity, myocardial
ischaemia/infarction, gastrointestinal perforation and fistula. These require relevant
monitoring as well as early intervention.
While accepting the fact that there is a definite toxicity profile for regorafenib it is
commensurate with that observed with other tyrosine kinase inhibitors which are
generally adequately managed with appropriate monitoring and early intervention.
First round assessment of benefit/risk balance

The data from this evaluation has shown an impressive evidence of benefit from the
pivotal trial in relation to OS improvement and PFS improvement in this heavily pre-
treated patient population with metastatic colorectal carcinoma. Nevertheless this is off-
set to some extent by the significant toxicity profile associated with regorafenib, although
in general terms the vast majority of these AEs would be adequately managed in modern
oncology settings.
Accordingly, the clinical evaluator considered that the balance favours the benefit of
regorafenib for the treatment of patients with metastatic CRC irrespective of KRAS
mutational status who have previously been treated with and who are not considered
candidates for fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and, if with
KRAS wild type, an anti-EGFR therapy.
Clinical questions
None
Recommendation regarding authorisation

The evaluator considered that the benefit/risk balance favours approval of regorafenib for
the proposed indication, namely treatment of patients with metastatic colorectal cancer
irrespective of KRAS mutational status who have been previously treated with or are not
considered candidates for fluoropyrimidine-base chemotherapy, an anti-VEGF therapy and,
in KRAS wild type, an anti-EGFR therapy.
V. Pharmacovigilance findings
Risk management plan

The sponsor submitted a Risk Management Plan (Core Safety Risk Management Plan (in
EU-RMP format) Version 1.1 (dated 14/05/2011, DLP 31/12/2011)) which was reviewed
by the TGA’s Office of Product Review (OPR).
Safety specification
Subject to the evaluation of the non-clinical aspects of the Safety Specification (SS) by the
Toxicology area of the OSE and the clinical aspects of the SS by the OMA, the summary of
the Ongoing Safety Concerns as specified by the sponsor is as follows (Table 11):
Table 11. Summary of Ongoing Safety Concerns
hn1,0r1:ml idt>ulifit>d riSks • Se\'ett d.m~-induced lh·er Uljury
• Cardiac is.chemic e\·em.s.
• Hypimcnsion and h)'))C'rtcnsi\'ccrisis
• Hemorrhage
• Hand-foot .skinreaction (HFSR)
• Rct·cniblt _postc1iorJeuk«n«pl:lalopa1hyiYJldroruc(RPLS)
Imporrnm pottntlAI 11sks • Sle\·ens-Jolmsou-Syudrome (SJS) rroxic epidennal

11ecroly.s.is
(TEN")
• WOl,lJldhealing compliC<'lttOn~
• OJ pcrforaliou and fi$hili,
• hllcr...lilinllnng di.,cnsc
lmpoa·1ao1mis.singiurormafiou • QTc 1:,rotonia1ion
Notwithstanding the evaluation of the nonclinical and clinical aspects of the SS, some
safety concerns are missing. The sponsor should add the following as safety concerns:
• Interactions with substrates of CYP2C8, CYP2C9, CYP3A4 and CYP2C19.
• Important missing information: severe renal impairment, severe hepatic impairment.
Pharmacovigilance plan
The sponsor proposes routine pharmacovigilance activities for important identified and
potential risks and missing information (as stated above). Furthermore, an open-label
Phase IIIb study is planned for the risk of severe drug-induced liver injury (DILI) and a
cardiac safety study was planned for the risk of QTc prolongation.
Risk minimisation activities

The sponsor states that no additional risk minimisation activities are necessary. The
sponsor’s conclusion is acceptable.
Summary of round 1 recommendations

The OPR provides these recommendations in the context that the submitted RMP (Core
Safety Risk Management Plan (in EU-RMP format) Version 1.1 (dated 14/05/2011, DLP
31/12/2011)) is supportive to the application; the implementation of a RMP satisfactory
to the TGA is imposed as a condition of registration; the submitted EU-RMP is applicable
without modification in Australia unless so qualified; and the draft product information
and consumer medicine information documents should not be revised until the Delegates
Overview has been received:
Further safety considerations
1. Safety considerations may be raised by the nonclinical and clinical evaluators through
the consolidated section 31 request and/or the Nonclinical and Clinical Evaluation
Reports respectively. It is important to ensure that the information provided in
response to these includes a consideration of the relevance for the Risk Management
Plan, and any specific information needed to address this issue in the RMP. For any
safety considerations so raised, please provide information that is relevant and
necessary to address the issue in the RMP.
Unless the sponsor can provide compelling justification against any of the following
recommendations, the following should be considered:
Recommendations in regard to the proposed indication
2. The sponsor should define the criteria used to determine whether a patient is not a
candidate for fluoropyrimidine-based chemotherapy, an anti-VEGF therapy, and, if
KRAS wild type, an anti-EGFR therapy. The sponsor should provide a justification for
the proposed Australian indication that differs from the US indication, especially
given that the provided evidence does not seem to support it.
The FDA approved indication is as follows:
(CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and
irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-
EGFR therapy.
Recommendations in regard to safety concerns
3. The sponsor should add the following as safety concerns:
a. Interactions with substrates of CYP2C8, CYP2C9, CYP3A4 and CYP2C19.
b. Important missing information: severe renal impairment, severe hepatic
impairment.
Recommendations in regard to pharmacovigilance activities
4. The sponsor should consider relevant pharmacovigilance activities for the additional
safety concerns recommended above.
5. The sponsor should consider conducting a drug interaction study in regard to
substrates of CYP2C8, CYP2C9, CYP3A4 and CYP2C19. It is noted that the sponsor has
agreed to provide results of a similar study to the FDA by the end of 2012.
6. Given that the sponsor has identified several important potential risks, the sponsor
should provide a justification why no additional pharmacovigilance activities have
been planned to investigate these further. The sponsor should consider additional
pharmacovigilance activities for the identified potential risks to characterise them
further, or at least assign them to an existing study.
Recommendations in regard to risk minimisation activities
7. In regard to the proposed routine risk minimisation activities, revisions were
recommended to several statements in the draft PI. Details of these are beyond the
scope of the AusPAR.
Second round review

The RMP evaluator considered the sponsor’s response to the recommendations above
adequately addressed all of the issues identified in the RMP evaluation report, except for
some statements in the draft PI which were drawn to the attention of the Delegate.
In addition, the sponsor provided an updated RMP: EU-RMP Version 1.3 (dated
01/02/2013, DLP 31/12/2012) with Australian Specific Annex Version 1 (dated February
2013).
Final recommendation to the Delegate

Approval of this application should include the implementation of EU-RMP Version 1.3
(dated 01/02/2013, DLP 31/12/2012) with Australian Specific Annex Version 1 (dated
February 2013) and any future updates as a condition of registration. Usual conditions
regarding provision PSURs should also be imposed.
VI. Overall conclusion and risk/benefit assessment

The submission was summarised in the following Delegate’s overview and
recommendations:
Background
Regorafenib tablets (Stivarga) are proposed for the following:
(CRC) who have been previously treated with, or are not considered candidates for,
fluoropyrimidine-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type,
an anti-EGFR therapy.
Regorafenib inhibits multiple protein kinases including those involved in oncogenesis,
tumour angiogenesis and maintenance of the tumour microenvironment.
Current treatment options for patients with metastatic CRC include fluoropyrimidine-,
oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild
type, an anti-EGFR therapy.
A relevant European Guideline adopted by TGA is the Guideline on the Evaluation of
Anticancer Medicinal Products in Man (CPMP/EWP/205/95/Rev.3/Corr.2, 14 December
2005).
Quality
There were no objections to registration on the grounds of chemistry, quality control and
bioavailability aspects.
Nonclinical
• In vitro studies in human tissues showed that regorafenib is metabolised with CYP3A4
being the main enzyme involved in oxidative metabolism and UGT1A9 in
glucuronidation. There is potential for drug interactions. This is adequately covered in
the PI.
• In mice, rats and dogs, regorafenib was toxic in multiple organs at exposures (based on
AUC) similar to those expected clinically. Degenerative and inflammatory changes
were seen mostly in the liver, skin, kidneys, gastrointestinal system and male and
female reproductive systems. Regorafenib is expected to adversely affect fertility in
humans.
• In rats and rabbits, regorafenib was teratogenic at exposures (based on AUC) lower
than those expected clinically. There were malformations in the urinary system
(rabbits), the heart and major vessels and the skeleton and embryofetal deaths.
Pregnancy category D is recommended.
The evaluator supported registration.
Clinical
Pharmacokinetics
• Absorption of regorafenib after oral administration is relatively rapid (median Tmax 3-4
h) and about 70-80% complete. Regorafenib is predominantly eliminated through
metabolism with mean elimination half-life of 20-30 h. The main metabolites M-2 and
M-5 have similar pharmacological activity to regorafenib. M-5 is eliminated more
slowly (elimination half-life 60 h) than the parent drug and M-2. The plasma
concentrations of M-2 and M-5 are initially low; however, they accumulate non-
linearly so that at steady-state the plasma concentrations are similar to the parent
drug. Accumulation of drug and metabolites at steady-state is about 2-fold with dosing
from day 1 to day 21.The bioavailability of regorafenib and metabolites is increased
with low and high fat breakfasts. It is recommended that regorafenib be administered
with a low fat light meal to maximise exposure.
• Regorafenib, M-2 and M-5 exposure based on AUC is not increased to a clinically
significant extent in mild to moderate renal or hepatic impairment. Exposure has not
been studied in severe renal or hepatic impairment. Close monitoring is recommended
in hepatic impairment.
• Concomitant ketoconazole (a strong CYP3A4 inhibitor) increased regorafenib
exposure by a mean 33% and decreased M-2 and M-5 exposure by a mean 90%. It is
recommended that strong CYP3A4 inhibitors be avoided with regorafenib since the
impact on the efficacy and safety of regorafenib is unclear.
• Concomitant rifampicin (a strong CYP3A4 inducer) significantly decreased regorafenib
exposure by a mean 50% and increased exposure to M-5 by 3-4-fold. There was no
change in M-2 exposure. It is recommended that strong CYP3A4 inducers be avoided
with regorafenib since the impact on the efficacy and safety of regorafenib is unclear.
Pharmacodynamics
• Biomarker studies are ongoing.
• There was no evidence of a clinically significant prolongation of the QTcF interval in
advanced cancer patients.
• The maximum tolerated dose of regorafenib was 100 mg/day with continuous dosing
(Study 11651) and 160 mg/day with 3 weeks on, 1 week off dosing (Study 11650).
The latter dosing schedule was chosen for the pivotal trial. The dose-limiting toxicity
was hand-foot syndrome.
Efficacy
• Efficacy was assessed in a multinational, randomised, double-blind, placebo-controlled
Study 14387 (referred to as CORRECT, published in Lancet12). Subjects were randomly
assigned 2:1 to regorafenib 160 mg/day (3 weeks on / 1 week off) plus BSC or placebo
plus BSC and treated until disease progression or unacceptable toxicity.
• Subjects with metastatic CRC whose disease progressed during or within 3 months of
the last dose of standard therapy including fluoropyrimidine-, oxaliplatin- and
irinotecan-based chemotherapy, bevacizumab and cetuximab (if KRAS wild type) were
enrolled. The median age of subjects was 61 years, range 22-85. 60% of subjects were
male.
• The primary efficacy endpoint was overall survival. Based on the second preplanned
interim analysis, the data monitoring committee considered that the primary efficacy
endpoint had been met, so the study was unblinded and crossover from placebo to
regorafenib allowed.
• Regorafenib increased OS by a median of 1.4 months which was statistically significant
(Table 12). In subgroup analyses, the OS increase was statistically significant in
subjects with KRAS wild type but not KRAS mutant cancer. The increase in PFS was
smaller but also statistically significant. Few subjects achieved a tumour response;
however, regorafenib stabilised the disease based on better disease control rate than
placebo. Quality-of-life worsened to a similar extent in both groups.
Table 12. Pivotal trial results. Interim at 21 July 2011. Intent-to-Treat
Regorafenib Placebo Hazard Ratio1/
n=505 n=255 Difference
[95% CI]
log-rank p2
Duration of Treatment median
1.7 1.6 -
(range) months
(0.1-10.8) (0.1-8.9)
Overall Survival – median months 6.4 5.0 0.77

[0.64, 0.94]
p=0.0052
KRAS wild type (n=299) 7.2 4.9 0.65

[0.48, 0.90]
12 Grothey A, Van Cutsem E, Sobrero A et al. Regorafenib monotherapy for previously treated metastatic
colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial.

Lancet 2013; 381: 303–312.
Regorafenib Placebo Hazard Ratio1/
n=505 n=255 Difference
[95% CI]
log-rank p2
KRAS mutant (n=430) 6.1 5.1 0.87
[0.67, 1.12]
Progression-Free Survival3 – median 1.9 1.7 0.49

months
[0.42, 0.58]
p<0.0001
KRAS wild type (n=299) 1.9 1.7 0.48

[0.36, 0.62]
KRAS mutant (n=430) 1.9 1.7 0.53

[0.43, 0.65]
Overall Response Rate4 1.0% 0.4% 0.6%6

[-1.7, 0.5]
Disease Control Rate5 41.0% 14.9% -25.9%6

[-32.1, -19.8]
EORTC QLQ-C30 (0-100) QOL13 – -14.9 -16.1 +1.27

mean change from baseline
[?, ?]
1 Cox Regression Model stratified by prior VEGF treatment, time from diagnosis of metastatic disease and
geographical region. 2 Stratified one-sided log rank test – met O’Brien-Fleming boundary for the interim
analysis: p<0.0093. 3 Investigator assessment. 4 Complete response (CR) + partial response (PR)
according to Response Evaluation Criteria for Solid Tumors (RECIST) criteria. All are PR. 5 CR + PR +
maintenance of stable disease (SD). SD earlier than 6 weeks after randomisation not counted. 6 Cochran
Mantel-Haenszel Test adjusted for stratification factors. 7 Difference of 10 required for clinical
significance. EORTC: European Organization for Research and Treatment of Cancer; QLQ: quality of life
questionnaire.
Safety
• The safety data was presented in three pools. Pool 3 contained the pivotal CORRECT
trial only. Across all Pools, a total of 1,145 cancer patients received regorafenib of
whom 621 were CRC patients. The pattern of AEs was similar in the three Pools. The
focus is on Pool 3 in which 500 patients received regorafenib and 253 placebo. The
median regorafenib dose was 160 mg/day (range 86-160 mg) and the median time on
treatment 1.4 months (range 0.1-8.3 month) excluding interruptions. Of regorafenib
subjects, 76% had dose modifications, either dose reduction or interruption.
• Most subjects experienced AEs. The incidence of severe AEs (≥ Grade 3) was greater
with regorafenib (78%) than placebo (49%). The incidences of serious AEs and AEs
13 The EORTC quality of life questionnaire (QLQ) is an integrated system for assessing the health related
quality of life (QoL) of cancer patients participating in international clinical trials. The core questionnaire is
the QLQ-C30.
leading to drug discontinuation were similar in the two groups: 44% versus 40% and
18% versus 13% respectively.
• Common AEs with a notably higher incidence with regorafenib (> 10 percentage
points) included (regorafenib versus placebo): fatigue (63% versus 46%), decreased
appetite (47% versus 29%), palmar-plantar erythrodysaesthesia syndrome (47%
versus 8%, diarrhoea (43% versus 17%), decreased weight (32% versus 11%),
dysphonia (32% versus 6%), hypertension (30% versus 8%), mucositis (29% versus
5%), rash (29% versus 5%), pyrexia (28% versus 15%), infection (25% versus 14%),
haemorrhage (20% versus 7%), increased serum bilirubin (20% versus 10%),
stomatitis (17% versus 3%) and thrombocytopenia (16% versus 2%) (Table 13). An
increased incidence of hypophosphataemia with regorafenib of uncertain significance
was also noted (57% regorafenib versus 11% placebo).
Table 13. Incidence (%) of treatment-emergent adverse events (any grade) occurring in at
least 10% of the patients in any treatment group.
Event Placebo Regorafenib

(n = 253) (n = 500)
Any 96.8 99.6
Blood/bone marrow 14.6 30.0

Hemoglobin 11.9 14.4
Platelets 2.4 15.6
Cardiac general 11.5 33.0

Hypertension 7.9 30.4
Constitutional symptoms 62.8 84.6

Constitutional symptoms - NOS
13.0 10.6
Fatigue
46.2 63.4
Fever
15.4 28.4
Weight loss
11.1 32.0
Dermatology/skin 22.9 71.2

Dry skin 4.0 10.0
Hand-foot skin reaction 7.5 47.0
Rash/desquamation
5.1 29.0
Gastrointestinal 65.6 83.2

Anorexia 28.5 46.8
Constipation 19.0 23.8
Diarrhoea 17.0 42.8
Mucositis (symptomatic), oral 4.7 28.8
cavity
21.7 22.4
Nausea
16.2 16.0
Event Placebo Regorafenib
(n = 253) (n = 500)
Vomiting
Haemorrhage/bleeding 6.7 20.4
Infection 14.2 25.2
Lymphatics 7.1 12.2
Metabolic/laboratory 24.5 45.6

Bilirubin 9.5 20.0
(hyperbilirubinaemia)
Neurology 24.9 27.0

Neuropathy: sensory 9.9 10.0
Pain 53.0 65.6

Pain, abdomen NOS 18.6 24.4
Pain, back 10.3 15.0
Pain, head/headache 7.1 10.4
Pulmonary/upper respiratory 27.7 50.4

Cough 11.1 11.0
Dyspnoea (shortness of breath) 13.0 18.2
Voice changes 6.3 32.0
For patients experiencing the same adverse event several times, the adverse event has been counted
only once by the worst severity grade. NOS – not otherwise specified
• In relation to deaths assessed as being related to regorafenib, the PI states: The rate of
death due to adverse events not associated with disease progression was slightly higher
with regorafenib (1.6% vs 1.2%). Five deaths were considered to be regorafenib-related:
one case each of liver dysfunction; sudden death; cerebrovascular incident; pulmonary
haemorrhage, bronchus; haemorrhage, gastrointestinal, anus and haemorrhage,
genitourinary, vagina (the last two occurred in one patient).
• The PI has appropriate precautionary statements related to hepatic effects,
haemorrhage and cardiac ischaemia.
Clinical evaluator’s recommendation

The evaluator supported registration.
Risk management plan

The sponsor satisfactorily addressed issues raised by the RMP evaluator.
The evaluator recommended the RMP and PSURs as conditions of registration.
Risk-benefit analysis
Delegate considerations
In preclinical models, regorafenib inhibited protein kinases involved in oncogenesis,
tumour angiogenesis and maintenance of the tumour microenvironment. However,
further research is needed to define its exact mechanism of action.
In the pivotal CORRECT trial in subjects with metastatic CRC who received all currently
recognised treatments, regorafenib produced a statistically significant but small increase
in overall survival (median 1.4 months). Overall survival was the primary endpoint. Based
on this analysis, the trial data monitoring committee considered that the primary endpoint
had been met and allowed unblinding and crossover from placebo to regorafenib which
would confound any future analysis.
The Delegate did not agree with the clinical evaluator that the increase in OS is clinically
significant. The benefit was small and not supported by the recognised secondary
endpoints, PFS (median 0.2 months increase), tumour response rate (1.0%) and quality-
of-life (decreased). Some patients may benefit from regorafenib but it is not clear who
they might be. A biomarker study is underway which may clarify the optimal patient
population.
Regorafenib has significant toxicity including skin, gastrointestinal, hepatic,
cardiovascular, immunological and haematological adverse effects. There were deaths due
to hepatotoxicity, haemorrhage and cardiovascular events related to the pharmacology of
the drug. Close monitoring of patients would be required.
In view of the small survival benefit and significant toxicity, the benefit-risk balance of
regorafenib is negative in the trial population. In most patients, the small increase in
survival is likely to be accompanied by significant risk and discomfort due to adverse
reactions.
The sponsor seeks a broader indication than the trial population, treatment of patients
previously treated with or who are not considered candidates for fluoropyrimidine-based
chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy. Such an
indication would allow the use of regorafenib before oxaliplatin- and irinotecan-based
chemotherapy had been tried. The Delegate did not support this indication on the grounds
of negative benefit-risk in the trial population
Proposed actions
The Delegate proposed to reject this application for regorafenib (Stivarga) for treatment of
patients previously treated with or who are not considered candidates for fluoropyrimidine-
based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy, for
reasons stated above.
Request for ACPM advice

The Delegate proposed to seek general advice on this application from the ACPM and to
request the committee also advise on the following specific issues:
1. What is the committee’s opinion of the median 1.4 month increase in OS with
regorafenib?
2. Should the indication be restricted to last-line treatment?
3. What is the committee’s opinion of the benefit-risk balance of regorafenib in the
proposed indication?
The committee was also requested to provide advice on any other issues that it thinks may
be relevant to a decision on whether or not to approve this application.
Response from sponsor

The sponsor's response to matters raised in the Delegate's Overview has not been
included in this AusPAR.
Advisory committee considerations

The Advisory Committee on Prescription Medicines (ACPM), having considered the
evaluations and the Delegate’s overview, as well as the sponsor’s response to these
documents, advised the following:
The ACPM, taking into account the submitted evidence of pharmaceutical quality, safety
and efficacy agreed with the delegate that this product has an overall negative benefit-risk
profile for the proposed indication.
The ACPM advised that the evidence submitted demonstrated efficacy that was not
clinically significant while toxicities reported were severe.
Initial decision
Regarding the submission by Bayer Australia Ltd dated August 2012 to register Stivarga
(regorafenib) tablets 40 mg for the following indication:
(CRC) irrespective of KRAS mutational status who have been previously treated with,
or are not considered candidates for, fluoropyrimidine-based chemotherapy, an anti-
VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy.
which was subsequently amended in the Bayer Pre-ACPM Response dated May 2013 to:
STIVARGA is indicated for the treatment of patients with metastatic colorectal
cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-
and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type,
an anti-EGFR therapy.
Pursuant to section 25 of the Therapeutic Goods Act 1989 (“the Act”) the Delegate of the
Secretary notified the sponsor of the decision not to register Stivarga (regorafenib)
tablets 40 mg for this indication on the grounds that the efficacy and safety of the product
have not been satisfactorily established for the purposes for which it is to be used. The
summary of the reasons for this decision is as follows:
The efficacy of regorafenib in the indication was not satisfactorily established for the
following reasons:
• In the single efficacy trial (trial 14387), a placebo-controlled trial, regorafenib did not
increase overall survival by a clinically relevant amount. The median increase was 1.4
months. There was no clear separation of the Kaplan-Meier survival curves.
• Regorafenib did not provide clinically relevant increases in the recognised 14 secondary
endpoints of progression-free survival (median increase 0.2 months) and overall
tumour response rate (increase of 0.6 percentage points).
14 Guideline on the evaluation of anticancer medicinal products in man CPMP/EWP/205/95/Rev.3/Corr.2

London, 14 December (adopted by the TGA).
• Regorafenib did not improve quality-of-life, assessed by the EORTC LQ-C30 – quality-
of-life worsened to a similar extent in both regorafenib and placebo-treated patients.
The safety of regorafenib in the indication was not satisfactorily established for the
following reasons:
• Regorafenib had significant toxicity including skin, gastrointestinal, hepatic,
cardiovascular, immunological and haematological adverse effects.
• The incidence of severe adverse events (grade 3 or greater) was higher with
regorafenib (78%) than placebo (49%).
• There were deaths due to hepatotoxicity, haemorrhage and cardiovascular events
related to the pharmacology of regorafenib.
Review of initial decision

Following the initial decision described above, the sponsor (under cover of
correspondence dated 18 September 2013) sought a review of the decision under the
provisions of Section 60 of the Act.
The Delegate of the Minister for the review noted that section 9A of the Act, which deals
with the creation of the ARTG, and paragraph 25(1) of the Act, which requires the goods to
be evaluated with regard to whether the quality, safety and efficacy of the goods for the
purposes for which they are to be used have been satisfactorily established, are of
particular relevance.
Findings of fact
A summary of the Delegate of the Minister’s main findings of fact as a result of the review
is as follows:
There was one pivotal study, 14387 (CORRECT), which was a randomised, double-blind,
placebo controlled, Phase III trial where adult patients with metastatic CRC who had
disease progression during or within 3 months after administration of standard therapy
were enrolled and randomised on a 2:1 basis to receive either regorafenib plus best
supportive care or placebo plus best supportive care. The primary endpoint was overall
survival and the secondary endpoints were progression free survival, objective response
rate and disease control rate.
Regorafenib was administered as 4 x 40mg oral tablets at = 160mg once daily for three
weeks followed by one week off therapy with a four week period constituting a cycle. The
treatment was stopped for disease progression and unacceptable toxicity with dosage
reduction allowed for reintroduction after toxicity.
The design of the study was intended to detect a hazard ratio of 0.75 for overall survival
after 582 deaths using assumed median survival times of 6 months and 4.5 months for the
regorafenib and placebo treated arms respectively. There were two planned reviews, for
futility review after 174 deaths and an interim efficacy analysis and futility review at 408
deaths. The study was appropriately powered.
The study was stopped at the interim efficacy analysis. In the ITT group the hazard ratio
(regorafenib to placebo) at the cut off was 0.774 (CI 0.636, 0.942), one sided p-value from
log rank 0.005178. Updated at the time of crossover for placebo patients the hazard ratio
was 0.790 (CI 0.664, 0.939), p-value 0.003791.
Median Overall survival was 196 days in patients receiving regorafenib and 151 days in
patients receiving placebo with a difference of around 1.5 months.
Median progression free survival at cut off was 52 in the placebo group and 59 in the
regorafenib group with CI of 51, 53 and 57, 65 respectively. The range in days (without
censored values) was 6-277 and 5-333 respectively and at each of months 3, 6 and 9
progression free survival rate was greater in the regorafenib than the placebo group.
There was a retrospective analysis of 3 genetic biomarkers (KRAS, PIK3CA, BRAF) and 15
non-genetic biomarkers. The analysis of results by biomarker was unplanned and
exploratory only. However, the analysis did show some benefit in all subgroups and no
group to which activity of the drug could be limited.
There were no complete responses but 5 patients in the regorafenib group and 1 in the
placebo group had partial responses. The differences in objective response rates between
the two groups were not statistically significant.
In terms of disease progression, at cut off 85.1 percent of patients in the regorafenib group
and 94.5 percent of patients in the placebo group had experienced an event.
Quality of life was measured using two instruments, EORTC QLQ-C30 and EQ-5D, at
baseline, and on day 1 of alternate cycles form Cycle 2 onwards. There were no differences
between patients receiving regorafenib and those receiving placebo, despite the observed
toxicity from treatment with regorafenib (see below).
Whilst adverse events were experienced by the majority of patients in the pivotal trial on
either regorafenib or placebo and in the supporting studies on regorafenib, drug related
and serious adverse events were more common in patients on regorafenib than placebo
with the most frequent drug related adverse events including decreased appetite, palmar-
plantar erythrodysesthesia, diarrhoea, fatigue, decreased weight, hypertension, pyrexia,
asthenia, constipation and rash. Dose interruption due to adverse event occurred in 61%
of regorafenib and 38% of placebo recipients and discontinuations due to drug related
adverse events occurred in 8.2% of regorafenib and 1.2% of placebo recipients. The
incidence of Grade 3 (56% versus 26.5%) and Grade 4 (8.6% versus 7.9%) adverse events
were higher amongst those on regorafenib than on placebo. There were 138 deaths in
patients on regorafenib, the majority of which (111 were due to disease progression. The
most common causes of death other than disease progression were haemorrhage (4),
cardiac arrest (3) and pneumonia (3).
Reviewers in the USA, EU and Australia noted that the drug adverse reaction profile from
regorafenib is similar to that observed with other drugs approved for the treatment of
metastatic solid tumours.
In the USA, the summary review includes the assessment that;
‘The CORRECT trial demonstrated a statistically persuasive and clinically
meaningful increase in overall survival in patients for whom there is no FDA-
approved treatment. The effects were supported by consistent trends in improved
survival in relevant patient subgroups and evidence of a significant improvement
in progression-free survival. Specifically the benefits of regorafenib are longer
overall survival and longer progression-free survival. While both effects are
modest, judged in the context of the very short survival and progression-free
survival expected these improvements are clinically meaningful in this population
for which there are currently no FDA-approved treatments. Furthermore, the
clinical benefits re meaningful in light of the adverse drug reaction profile. The
adverse drug reaction profile of regorafenib is qualitatively similar to that
observed with drugs previously approved for the treatment of metastatic solid
tumours an which have been deemed acceptable by the patient and medical
community in light of the potential benefits.’
The EMA convened a Scientific Advisory Group (SAG) in Oncology in March 2013 to
consider the clinical benefit of regorafenib. The advice of that group is reported to include:
‘A statistically significant difference was observed in the primary analysis of OS in
study 14387 in the overall population. The difference in median OS between
regorafenib and placebo was modest (45) days. The clinical relevance of this
magnitude of treatment effect is considered to be minimal. The rapid onset of
progression in the majority of patients suggests that a favourable effect is limited
to a minority of patients.
Importantly, however, regorafenib was associated with significant toxicity in the
majority of patients.....
Due to the significant toxicity and the minimal efficacy the SAG was uncertain that
the balance of benefits and risks is positive.’
Following the advice of the SAG a second list of outstanding issues was provided to the
applicant who responded with material also included in this appeal, including on sub
group analysis and biomarker work. Following assessment of the company response the
CHMP issued a positive opinion for granting a Marketing Authorisation to Stivarga
(regorafenib).
In Australia the reviewers of the clinical, toxicological and risk management plan (RMP)
had supported approval but the Delegate, as is usual practice, sought the view of the
Advisory Committee on Prescription Medicines (ACPM). The Delegate brought the
following issues to the ACPM: the clinical significance of the overall survival benefit, the
appropriateness of the indication and the benefit-risk balance. ACPM was consulted on the
application for registration or regorafenib at its June 2013 meeting and issued the
following resolution:
The ACPM, taking into account the submitted evidence of pharmaceutical quality,
safety and efficacy agree with the delegate that this product has an overall
negative benefit-risk profile for the proposed indication.
The ACPM advised that the evidence submitted a demonstrated efficacy that was
not clinically significant while toxicities reported were severe.
At the time of the meeting neither the Delegate nor the committee had access to the final
European assessment report, the CHMP outcome, and the biomarker data that had been
submitted in Europe.
The biomarker data and sub group analyses are briefly summarised above. To repeat a
benefit in terms of overall survival was seen consistently in all subgroups.
Summary
Regorafenib has been shown to have a statistically significant and consistent, albeit
modest, benefit in terms of overall survival and progression free survival in heavily pre-
treated patients with metastatic CRC where there is no approved treatment alternative.
Significant toxicities occurred that were consistent with those seen in other similar drugs
approved for use in metastatic solid tumours. The effect of these toxicities can be
mitigated, but not eliminated, through skilled management of treatment cycles by expert
oncologists.
Materials on which the findings of fact were based

In conducting the review, the Delegate of the Minister considered the following
documents:
• Application by Bayer Australia Ltd for registration of Stivarga (the Application);
• TGA evaluation reports of the application;
• Delegate of the Secretary’s overview, recommendations and request for ACPM advice;
• Response from the sponsor to the Delegate of the Secretary’s overview,
recommendations and request for ACPM advice;
• Extract of Minutes of ACPM of 6-7 June 2013;
• Delegate of the Secretary’s initial decision letter dated 25 June 2013;
• Appeal against the initial decision by Bayer Australia Ltd, dated 18 September 2013,
and all attached documents (Volumes 1 to 5);
• FDA Summary review of Stivarga dated 20 September 2012, as published on FDA
website;
• EMA Assessment report dated 27 June 2013, as published on EMA website;
• CPMP/EWP/205/95/Rev.3/Corr. (Guideline on the Evaluation of Anticancer Medicinal
Products in Man); and
• EMEA/CHMP/EWP/27994/2008 (Methodological Considerations for Using
Progression-Free Survival (PFS) as Primary Endpoint in Confirmatory Trials for
Registration).
Reasons
The Delegate of the Minister considered the arguments of the applicant and information
on the evaluation of Stivarga (regorafenib) in Australia, by the EMA and US FDA and the
information on biomarkers and sub group analyses and expert opinions within the appeal
document.
There is evidence of statistically significant and consistent, albeit modest, benefit in terms
of overall survival and progression free survival in heavily pre-treated patients with
metastatic CRC where there is no approved treatment alternative.
Significant toxicities occurred that were consistent with those seen in other similar drugs
approved for use in metastatic solid tumours. The effect of these toxicities can be
mitigated, but not eliminated, through skilled management of treatment cycles by expert
oncologists.
In considering the reasons given by the initial decision maker for the decision not to
register Stivarga (regorafenib) there is evidence that there is a modest, statistically and
clinically relevant effect on overall survival and progression-free survival. There is no
improvement in quality of life measures, but also no deterioration despite treatment.
Significant toxicities were observed but these were similar to those seen with other drugs
approved for use in metastatic solid tumours which have been considered acceptable in
the light of the conditions to be treated and the potential benefit of treatment.
Conclusion
For the reasons referred to above, the Delegate of the Minister decided to revoke the
decision not to approve the registration of Stivarga (regorafenib) 40 mg tablets. The
section 60 Appeal’s Delegate replaced the "the initial decision" for Stivarga (regorafenib)
40 mg tablets under Section 60 (2) of the Act.
Final outcome
The Delegate was of the view that the requirements of efficacy and safety in the Act have
been met to include the Stivarga (regorafenib) 40 mg tablets in the ARTG. The reasons for
the Delegate’s decision and results of the reconsiderations of the initial decision are set
out above.
Accordingly, pursuant to Section 60 of the Act, the Delegate notified the sponsor of the
decision to approve the registration of Stivarga regorafenib 40 mg tablet bottle for the
indication:
(CRC) who have been previously treated with fluoropyrimidine,- oxaliplatin- and
irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an
anti-EGFR therapy.
This approval was based on the evaluation of the information and data provided with the
original letter of application and with any subsequent correspondence and submissions
relating to the application including additional information submitted with the sponsor’s
appeal of 18 September 2013.
Specific conditions of registration applying to these therapeutic goods

The Stivarga EU-RMP Version 1.3 (dated 01/02/2013, DLP 31/12/2012) with Australian
Specific Annex Version 1 (dated February 2013) and any future updates, as agreed with
the TGA will be implemented in Australia.
Attachment 1. Product Information

The Product Information approved at the time this AusPAR was published is at
Attachment 1. For the most recent Product Information please refer to the TGA website at
<http://www.tga.gov.au/hp/information-medicines-pi.htm>.
Attachment 2. Extract from the Clinical Evaluation

Report
HIGHLIGHTS OF PRESCRIBING INFORMATION • Dermatological toxicity: Interrupt and then reduce or discontinue Stivarga
These highlights do not include all the information needed to use depending on severity and persistence of dermatologic toxicity. (5.3)
STIVARGA safely and effectively. See full prescribing information for • Hypertension: Temporarily or permanently discontinue Stivarga for severe
STIVARGA. or uncontrolled hypertension. (5.4)
STIVARGA (regorafenib) tablets, oral • Cardiac ischemia and infarction: Withhold Stivarga for new or acute cardiac
Initial U.S. Approval: 2012 ischemia/infarction and resume only after resolution of acute ischemic events.
(5.5)
WARNING: HEPATOTOXICITY • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Discontinue
See full prescribing information for complete boxed warning. Stivarga. (5.6)
Severe and sometimes fatal hepatotoxicity has been observed in clinical • Gastrointestinal perforation or fistulae: Discontinue Stivarga. (5.7)
trials. Monitor hepatic function prior to and during treatment. Interrupt • Wound healing complications: Stop Stivarga before surgery. Discontinue in
and then reduce or discontinue Stivarga for hepatotoxicity as manifested patients with wound dehiscence. (5.8)
by elevated liver function tests or hepatocellular necrosis, depending upon • Embryofetal toxicity: Can cause fetal harm. Advise women of potential risk
severity and persistence. (2.2, 5.1) to a fetus. (5.9, 8.1)
------------------------------ ADVERSE REACTIONS -----------------------------

---------------------- INDICATIONS AND USAGE -------------------------------- The most common adverse reactions (≥30%) are asthenia/fatigue, decreased
Stivarga is a kinase inhibitor indicated for the treatment of patients with appetite and food intake, hand-foot skin reaction (HFSR) [palmar-plantar
metastatic colorectal cancer (CRC) who have been previously treated with erythrodysesthesia (PPE)], diarrhea, mucositis, weight loss, infection,
fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti- hypertension, and dysphonia. (6)
VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy. (1)
To report SUSPECTED ADVERSE REACTIONS, contact Bayer
---------------------- DOSAGE AND ADMINISTRATION ---------------------- HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-
• Recommended Dose: 160 mg orally, once daily for the first 21 days of each FDA-1088 or www.fda.gov/medwatch
28-day cycle. (2.1)
• Take Stivarga with food (a low-fat breakfast). (2.1, 12.3) ------------------------------ DRUG INTERACTIONS -----------------------------
• Strong CYP3A4 inducers: Avoid strong CYP3A4 inducers. (7.1)
--------------------- DOSAGE FORMS AND STRENGTHS -------------------- • Strong CYP3A4 inhibitors: Avoid strong CYP3A4 inhibitors. (7.2)
40 mg film-coated tablets (3)
----------------------- USE IN SPECIFIC POPULATIONS ----------------------
------------------------------ CONTRAINDICATIONS ----------------------------- Nursing Mothers: Discontinue drug or nursing, taking into consideration the
None. importance of the drug to the mother. (8.3)
----------------------- WARNINGS AND PRECAUTIONS ---------------------- See 17 for PATIENT COUNSELING INFORMATION and FDA-
• Hemorrhage: Permanently discontinue Stivarga for severe or life-threatening approved patient labeling.
hemorrhage. (5.2) Revised: 09/2012
FULL PRESCRIBING INFORMATION: CONTENTS*

8 USE IN SPECIFIC POPULATIONS
1 INDICATIONS AND USAGE 8.1 Pregnancy
2 DOSAGE AND ADMINISTRATION 8.3 Nursing Mothers
2.1 Recommended Dose 8.4 Pediatric Use
2.2 Dose Modifications 8.5 Geriatric Use
3 DOSAGE FORMS AND STRENGTHS 8.6 Hepatic Impairment
4 CONTRAINDICATIONS 8.7 Renal Impairment
5 WARNINGS AND PRECAUTIONS 8.8 Females and Males of Reproductive Potential
5.1 Hepatotoxicity 10 OVERDOSAGE
5.2 Hemorrhage 11 DESCRIPTION
5.3 Dermatological Toxicity 12 CLINICAL PHARMACOLOGY
5.4 Hypertension 12.1 Mechanism of Action
5.5 Cardiac Ischemia and Infarction 12.3 Pharmacokinetics
5.6 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) 13 NONCLINICAL TOXICOLOGY
5.7 Gastrointestinal Perforation or Fistula 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
5.8 Wound Healing Complications 13.2 Animal Toxicology and/or Pharmacology
5.9 Embryo-Fetal Toxicity 14 CLINICAL STUDIES
6 ADVERSE REACTIONS 16 HOW SUPPLIED/STORAGE AND HANDLING
6.1 Clinical Trials Experience 16.1 How Supplied
7 DRUG INTERACTIONS 16.2 Storage and Handling
7.1 Effect of Strong CYP3A4 Inducers on Regorafenib 17 PATIENT COUNSELING INFORMATION
7.2 Effect of Strong CYP3A4 Inhibitors on Regorafenib
*Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION
WARNING: HEPATOTOXICITY
Severe and sometimes fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function prior to
and during treatment. Interrupt and then reduce or discontinue Stivarga for hepatotoxicity as manifested by
elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence [see Dosage and
Administration (2.2), Warnings and Precautions (5.1)].
1 INDICATIONS AND USAGE

Stivarga® is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously
treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS
wild type, an anti-EGFR therapy.
2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose
The recommended dose is 160 mg regorafenib (four 40 mg tablets) taken orally once daily for the first 21 days of each 28-
day cycle. Continue treatment until disease progression or unacceptable toxicity.
Take Stivarga at the same time each day. Swallow tablet whole with a low-fat breakfast that contains less than 30% fat
[see Clinical Pharmacology (12.3)]. Examples of a low-fat breakfast include 2 slices of white toast with 1 tablespoon of
low-fat margarine and 1 tablespoon of jelly, and 8 ounces of skim milk (319 calories and 8.2 g fat); or 1 cup of cereal, 8
ounces of skim milk, 1 slice of toast with jam, apple juice, and 1 cup of coffee or tea (520 calories and 2 g fat). Do not
take two doses of Stivarga on the same day to make up for a missed dose from the previous day.
2.2 Dose Modifications
Interrupt Stivarga for the following:
• NCI CTCAE Version 3.0 (v3.0) Grade 2 hand-foot skin reaction (HFSR) [palmar-plantar erythrodysesthesia (PPE)]
that is recurrent or does not improve within 7 days despite dose reduction; interrupt therapy for a minimum of 7 days
for Grade 3 HFSR
• Symptomatic Grade 2 hypertension
• Any NCI CTCAE v3.0 Grade 3 or 4 adverse reaction
Reduce the dose of Stivarga to 120 mg:

• For the first occurrence of Grade 2 HFSR of any duration
• After recovery of any Grade 3 or 4 adverse reaction
• For Grade 3 aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) elevation; only resume if the potential
benefit outweighs the risk of hepatotoxicity
Reduce the dose of Stivarga to 80 mg:

• For re-occurrence of Grade 2 HFSR at the 120 mg dose
• After recovery of any Grade 3 or 4 adverse reaction at the 120 mg dose (except hepatotoxicity)
Discontinue Stivarga permanently for the following:

• Failure to tolerate 80 mg dose
• Any occurrence of AST or ALT more than 20 times the upper limit of normal (ULN)
• Any occurrence of AST or ALT more than 3 times ULN with concurrent bilirubin more than 2 times ULN
• Re-occurrence of AST or ALT more than 5 times ULN despite dose reduction to 120 mg
• For any Grade 4 adverse reaction; only resume if the potential benefit outweighs the risks
3 DOSAGE FORMS AND STRENGTHS

Stivarga is a 40 mg, light pink, oval shaped, film-coated tablet, debossed with ‘BAYER’ on one side and ‘40’ on the other
side.
4 CONTRAINDICATIONS
None
5 WARNINGS AND PRECAUTIONS

5.1 Hepatotoxicity
Severe drug induced liver injury with fatal outcome occurred in 0.3% of 1100 Stivarga-treated patients across all clinical
trials. Liver biopsy results, when available, showed hepatocyte necrosis with lymphocyte infiltration. In Study 1, fatal
hepatic failure occurred in 1.6% of patients in the regorafenib arm and 0.4% of patients in the placebo arm; all the patients
with hepatic failure had metastatic disease in the liver.
Obtain liver function tests (ALT, AST and bilirubin) before initiation of Stivarga and monitor at least every two weeks
during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor
liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the
ULN or baseline.
Temporarily hold and then reduce or permanently discontinue Stivarga depending on the severity and persistence of
hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis [see Dosage and Administration
(2.2)].
5.2 Hemorrhage
Stivarga caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 21% in Stivarga-treated
patients compared to 8% in placebo-treated patients in Study 1. Fatal hemorrhage occurred in 4 of 500 (0.8%) of Stivarga-
treated patients and involved the respiratory, gastrointestinal, or genitourinary tracts.
Permanently discontinue Stivarga in patients with severe or life-threatening hemorrhage. Monitor INR levels more
frequently in patients receiving warfarin [see Clinical Pharmacology (12.3)].
5.3 Dermatological Toxicity
Stivarga caused an increased incidence of hand-foot skin reaction (HFSR) also known as palmar-plantar
erythrodysesthesia (PPE) and rash frequently requiring dose modification. The overall incidence of HFSR (45% versus
7%) and the incidence of Grade 3 HFSR (17% versus 0) were increased in Stivarga-treated patients in Study 1. The
overall incidence of rash (26% versus 4%) and the incidence of Grade 3 rash (6% versus <1%) were higher in Stivarga-
treated patients in Study 1 [see Adverse Reactions (6.1)]. The onset of dermatologic toxicity occurred in the first cycle of
treatment in most patients.
Temporarily hold and then reduce or permanently discontinue Stivarga depending on the severity and persistence of
dermatologic toxicity [see Dosage and Administration (2.2)]. Institute supportive measures for symptomatic relief.
5.4 Hypertension
Stivarga caused an increased incidence of hypertension (30% of Stivarga-treated patients vs. 8% of placebo-treated
patients in Study 1) [see Adverse Reactions (6.1)]. Hypertensive crisis occurred in 0.18% of 1100 Stivarga-treated patients
across all clinical trials. The onset of hypertension occurred during the first cycle of treatment in most patients. Do not
initiate Stivarga until blood pressure is adequately controlled.
Monitor blood pressure weekly for the first 6 weeks of treatment and then every cycle, or more frequently, as clinically
indicated. Temporarily or permanently withhold Stivarga for severe or uncontrolled hypertension [see Dosage and
Administration (2.2)].
5.5 Cardiac Ischemia and Infarction

Stivarga increased the incidence of myocardial ischemia and infarction (1.2% for Stivarga-treated patients vs. 0.4% of
placebo-treated patients) [see Adverse Reactions (6.1)].
Withhold Stivarga in patients who develop new or acute onset cardiac ischemia or infarction. Resume Stivarga only after
resolution of acute cardiac ischemic events if the potential benefits outweigh the risks of further cardiac ischemia.
5.6 Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
RPLS (also known as posterior reversible encephalopathy syndrome) occurred in one of 1100 Stivarga-treated patients
across all clinical trials. Confirm the diagnosis of RPLS with MRI and discontinue Stivarga in patients who develop
RPLS.
5.7 Gastrointestinal Perforation or Fistula
Gastrointestinal perforation or fistula occurred in 0.6% of 1100 patients treated with Stivarga across clinical trials.
Permanently discontinue Stivarga in patients who develop gastrointestinal perforation or fistula.
5.8 Wound Healing Complications

No formal studies of the effect of regorafenib on wound healing have been conducted. Since vascular endothelial growth
factor receptor (VEGFR) inhibitors such as regorafenib can impair wound healing, treatment with regorafenib should be
stopped at least 2 weeks prior to scheduled surgery. The decision to resume regorafenib after surgery should be based on
clinical judgment of adequate wound healing. Regorafenib should be discontinued in patients with wound dehiscence.
5.9 Embryo-Fetal Toxicity

Stivarga can cause fetal harm when administered to a pregnant woman. Regorafenib was embryolethal and teratogenic in
rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of
cardiovascular, genitourinary, and skeletal malformations. If this drug is used during pregnancy, or if the patient becomes
pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific
Populations (8.1)].
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed elsewhere in the labeling:
• Hepatotoxicity [See Warnings and Precautions (5.1)]

• Hemorrhage [See Warnings and Precautions (5.2)]
• Dermatological Toxicity [See Warnings and Precautions (5.3)]
• Hypertension [See Warnings and Precautions (5.4)]
• Cardiac Ischemia and Infarction [See Warnings and Precautions (5.5)]
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [See Warnings and Precautions (5.6)]
• Gastrointestinal Perforation or Fistula [See Warnings and Precautions (5.7)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials
of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rate observed in
practice.
The safety data described below, except where noted, are derived from a randomized (2:1), double-blind, placebo-
controlled trial (Study 1) in which 500 patients (median age 61 years; 61% men) with previously treated metastatic
colorectal cancer received Stivarga as a single agent at the dose of 160 mg daily for the first 3 weeks of each 4 week
treatment cycle and 253 patients (median age 61 years; 60% men) received placebo. The mean duration of therapy was 12
weeks for patients receiving Stivarga and 8 weeks for patients receiving placebo. Due to adverse reactions, 61% of the
patients receiving Stivarga required a dose interruption and 38% of the patients had their dose reduced. Drug-related
adverse reactions that resulted in treatment discontinuation were reported in 8.2% of Stivarga-treated patients compared to
1.2% of patients who received placebo. Skin toxicity (HFSR/PPE or rash) was the most common cause of permanent drug
discontinuation.
The most frequently observed adverse drug reactions (≥30%) in patients receiving Stivarga are asthenia/fatigue, decreased
appetite and food intake, HFSR/PPE, diarrhea, mucositis, weight loss, infection, hypertension and dysphonia.
The most serious adverse drug reactions in patients receiving Stivarga are hepatotoxicity, hemorrhage, and gastrointestinal
perforation.
Table 1 compares the incidence of adverse reactions (≥10%) in patients receiving Stivarga and reported more commonly
than in patients receiving placebo (Study 1).
Table 1: Adverse drug reactions (≥10%) reported in patients treated with Stivarga and reported more commonly than in
patients receiving placebo
Stivarga Placebo
(n=500) (n=253)
Adverse Reactions
Grade Grade
All ≥3 All ≥3
% % % %
General disorders and
administration site conditions
Asthenia/fatigue 64 15 46 9
Pain 29 3 21 2
Fever 28 2 15 0
Metabolism and nutrition
disorders
Decreased appetite and food
intake 47 5 28 4
Skin and subcutaneous tissue
disorders
HFSR/PPE 45 17 7 0
Rash 26 6 4 <1
Gastrointestinal disorders
Diarrhea 43 8 17 2
Mucositis 33 4 5 0
Investigations
Weight loss 32 <1 10 0
Infections and infestations
Infection 31 9 17 6
Vascular disorders
Hypertension 30 8 8 <1
Hemorrhage* 21 2 8 <1
Respiratory, thoracic and
mediastinal disorders
Dysphonia 30 0 6 0
Nervous system disorders
Headache 10 <1 7 0
*
fatal outcomes observed
Other clinically important adverse reactions observed more commonly in less than 10% of Stivarga-treated patients and at
a higher incidence than in placebo-treated patients included the following: alopecia (7.6% vs. 1.6%), taste disorder (7.6%
vs. 2.4%), musculoskeletal stiffness (6.0% vs. 2.0%), dry mouth (4.8% vs. 2.0%), hypothyroidism (4.2% vs. 0.4%),
tremor (2.0% vs. 0.0), gastroesophageal reflux (1.4% vs. 0.0), and gastrointestinal fistula (0.8% vs. 0.4%).
Keratoacanthoma/squamous cell carcinoma of the skin occurred in 0.09% of 1100 Stivarga-treated patients across open-
label or placebo-controlled clinical trials.
Laboratory Abnormalities
Laboratory abnormalities observed in Study 1 are shown in Table 2.
Table 2: Laboratory test abnormalities reported in Study 1
Stivarga plus BSC Placebo plus BSC

(n=500*) (n=253*)
Laboratory Parameter Grade** Grade**
All 3 4 All 3 4
% % % % % %
Blood and lymphatic system
disorders
Anemia 79 5 1 66 3 0
Thrombocytopenia 41 2 <1 17 <1 0
Neutropenia 3 1 0 0 0 0
Lymphopenia 54 9 0 34 3 0
disorders
Hypocalcemia 59 1 <1 18 1 0
Hypokalemia 26 4 0 8 <1 0
Hyponatremia 30 7 1 22 4 0
Hypophosphatemia 57 31 1 11 4 0
Hepatobiliary disorders
Hyperbilirubinemia 45 10 3 17 5 3
Increased AST 65 5 1 46 4 1
Increased ALT 45 5 1 30 3 <1
Renal and urinary disorders
Proteinuria 60 <1 0 34 <1 0
Investigations
Increased INR *** 24 4 N/A 17 2 N/A
Increased Lipase 46 9 2 19 3 2
Increased Amylase 26 2 <1 17 2 <1
*
% based on number of patients with post-baseline samples which may be less than 500 (regorafenib) or 253 (placebo)
**
Common Terminology Criteria for Adverse Events (CTCAE), v3.0
***
International normalized ratio: No Grade 4 denoted in CTCAE, v3.0
7 DRUG INTERACTIONS
7.1 Effect of Strong CYP3A4 Inducers on Regorafenib
Co-administration of a strong CYP3A4 inducer (rifampin) with a single 160 mg dose of Stivarga decreased the mean
exposure of regorafenib, increased the mean exposure of the active metabolite M-5, and resulted in no change in the mean
exposure of the active metabolite M-2. Avoid concomitant use of strong CYP3A4 inducers (e.g. rifampin, phenytoin,
carbamazepine, phenobarbital, and St. John’s Wort) [see Clinical Pharmacology (12.3)].
7.2 Effect of Strong CYP3A4 Inhibitors on Regorafenib
Co-administration of a strong CYP3A4 inhibitor (ketoconazole) with a single 160 mg dose of Stivarga increased the mean
exposure of regorafenib and decreased the mean exposure of the active metabolites M-2 and M-5. Avoid concomitant use
of strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole,
telithromycin, and voriconazole) [see Clinical Pharmacology (12.3)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D [see Warnings and Precautions (5.9)]
Risk Summary
Based on its mechanism of action, Stivarga can cause fetal harm when administered to a pregnant woman. There are no
adequate and well-controlled studies with Stivarga in pregnant women. Regorafenib was embryolethal and teratogenic in
rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of
cardiovascular, genitourinary, and skeletal malformations. If this drug is used during pregnancy or if the patient becomes
pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
Animal Data
In embryo-fetal development studies, a total loss of pregnancy (100% resorption of litter) was observed in rats at doses as
low as 1 mg/kg (approximately 6% of the recommended human dose, based on body surface area) and in rabbits at doses
as low as 1.6 mg/kg (approximately 25% of the human exposure at the clinically recommended dose measured by AUC).
In a single dose distribution study in pregnant rats, there was increased penetration of regorafenib across the blood-brain
barrier in fetuses compared to dams. In a repeat dose study with daily administration of regorafenib to pregnant rats
during organogenesis, findings included delayed ossification in fetuses at doses > 0.8 mg/kg (approximately 5% of the
recommended human dose based on body surface area) with dose-dependent increases in skeletal malformations including
cleft palate and enlarged fontanelle at doses ≥ 1 mg/kg (approximately 10% of the clinical exposure based on AUC). At
doses ≥ 1.6 mg/kg (approximately 11% of the recommended human dose based on body surface area), there were dose-
dependent increases in the incidence of cardiovascular malformations, external abnormalities, diaphragmatic hernia, and
dilation of the renal pelvis.
In pregnant rabbits administered regorafenib daily during organogenesis, there were findings of ventricular septal defects
evident at the lowest tested dose of 0.4 mg/kg (approximately 7% of the AUC in patients at the recommended dose). At
doses of ≥ 0.8 mg/kg (approximately 15% of the human exposure at the recommended human dose based on AUC),
administration of regorafenib resulted in dose-dependent increases in the incidence of additional cardiovascular
malformations and skeletal anomalies as well as significant adverse effects on the urinary system including missing
kidney/ureter; small, deformed and malpositioned kidney; and hydronephrosis. The proportion of viable fetuses that were
male decreased with increasing dose in two rabbit embryo-fetal toxicity studies.
8.3 Nursing Mothers
It is unknown whether regorafenib or its metabolites are excreted in human milk. In rats, regorafenib and its metabolites
are excreted in milk. Because many drugs are excreted in human milk and because of the potential for serious adverse
reactions in nursing infants from Stivarga, a decision should be made whether to discontinue nursing or discontinue the
drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use

The safety and efficacy of Stivarga in pediatric patients less than18 years of age have not been established.
In 28-day repeat dose studies in rats there were dose-dependent findings of dentin alteration and angiectasis. These
findings were observed at regorafenib doses as low as 4 mg/kg (approximately 25% of the AUC in humans at the
recommended dose). In 13-week repeat dose studies in dogs there were similar findings of dentin alteration at doses as
low as 20 mg/kg (approximately 43% of the AUC in humans at the recommended dose). Administration of regorafenib in
these animals also led to persistent growth and thickening of the femoral epiphyseal growth plate.
8.5 Geriatric Use
Of the total number of subjects in clinical studies of Stivarga, 39% were 65 and over, while 8% were 75 and over. No
overall differences in safety or efficacy were observed between these patients and younger patients.
8.6 Hepatic Impairment
No clinically important differences in the mean exposure of regorafenib or the active metabolites M-2 and M-5 were
observed in patients with hepatocellular carcinoma and mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic
impairment compared to patients with normal hepatic function [see Clinical Pharmacology (12.3)]. No dose adjustment is
recommended in patients with mild or moderate hepatic impairment. Closely monitor patients with hepatic impairment for
adverse reactions [see Warnings and Precautions (5.1)].
Stivarga is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) as it has not been
studied in this population.
8.7 Renal Impairment
No clinically relevant differences in the mean exposure of regorafenib and the active metabolites M-2 and M-5 were
observed in patients with mild renal impairment (CLcr 60-89 mL/min/1.73m2) compared to patients with normal renal
function following regorafenib 160 mg daily for 21 days [see Clinical Pharmacology (12.3)]. No dose adjustment is
recommended for patients with mild renal impairment. Limited pharmacokinetic data are available from patients with
moderate renal impairment (CLcr 30-59 mL/min/1.73m2). Stivarga has not been studied in patients with severe renal
impairment or end-stage renal disease.
8.8 Females and Males of Reproductive Potential
Contraception
Use effective contraception during treatment and up to 2 months after completion of therapy.
Infertility
There are no data on the effect of Stivarga on human fertility. Results from animal studies indicate that regorafenib can
impair male and female fertility [see Nonclinical Toxicology (13.1)].
10 OVERDOSAGE
The highest dose of Stivarga studied clinically is 220 mg per day. The most frequently observed adverse drug reactions at
this dose were dermatological events, dysphonia, diarrhea, mucosal inflammation, dry mouth, decreased appetite,
hypertension, and fatigue.
There is no specific antidote for Stivarga overdose. In the event of suspected overdose, interrupt Stivarga, institute
supportive care, and observe until clinical stabilization.
11 DESCRIPTION
Stivarga (regorafenib) has the chemical name 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-
fluorophenoxy]-N-methylpyridine-2-carboxamide monohydrate. Regorafenib has the following structural formula:
F
F
Cl
Regorafenib is a monohydrate and it has a molecular formula C21H15ClF4N4O3 • H2O and a molecular weight of 500.83.
Regorafenib is practically insoluble in water, slightly soluble in acetonitrile, methanol, ethanol, and ethyl acetate and
sparingly soluble in acetone.
Stivarga tablets for oral administration are formulated as light pink oval shaped tablets debossed with "BAYER" on one
side and "40" on the other. Each tablet contains 40 mg of regorafenib in the anhydrous state, which corresponds to 41.49
mg of regorafenib monohydrate, and the following inactive ingredients: cellulose microcrystalline, croscarmellose
sodium, magnesium stearate, povidone, and colloidal silicon dioxide. The film-coating contains the following inactive
ingredients: ferric oxide red, ferric oxide yellow, lecithin (soy), polyethylene glycol 3350, polyvinyl alcohol, talc, and
titanium dioxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal
cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor
microenvironment. In in vitro biochemical or cellular assays, regorafenib or its major human active metabolites M-2 and
M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2,
TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, BRAFV600E , SAPK2, PTK5, and Abl at concentrations of regorafenib that
have been achieved clinically. In in vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model,
and inhibition of tumor growth as well as anti-metastatic activity in several mouse xenograft models including some for
human colorectal carcinoma.
12.3 Pharmacokinetics
Absorption
Following a single 160 mg dose of Stivarga in patients with advanced solid tumors, regorafenib reaches a geometric mean
peak plasma level (Cmax) of 2.5 µg/mL at a median time of 4 hours and a geometric mean area under the plasma
concentration vs. time curve (AUC) of 70.4 µg*h/mL. The AUC of regorafenib at steady-state increases less than dose
proportionally at doses greater than 60 mg. At steady-state, regorafenib reaches a geometric mean Cmax of 3.9 µg/mL and
a geometric mean AUC of 58.3 µg*h/mL. The coefficient of variation of AUC and Cmax is between 35% and 44%.
The mean relative bioavailability of tablets compared to an oral solution is 69% to 83%.
In a food-effect study, 24 healthy men received a single 160 mg dose of Stivarga on three separate occasions: under a
fasted state, with a high-fat meal and with a low-fat meal. A high-fat meal (945 calories and 54.6 g fat) increased the mean
[TRLTE COPY!!
AUC of regorafenib by 48% and decreased the mean AUC of the M-2 and M-5 metabolites by 20% and 51%,
respectively, as compared to the fasted state. A low-fat meal (319 calories and 8.2 g fat) increased the mean AUC of
regorafenib, M-2 and M-5 by 36%, 40% and 23%, respectively as compared to fasted conditions. Stivarga was
administered with a low-fat meal in Study 1 [see Dosage and Administration (2.1), Clinical Studies (14)].
Distribution
Regorafenib undergoes enterohepatic circulation with multiple plasma concentration peaks observed across the 24-hour
dosing interval. Regorafenib is highly bound (99.5%) to human plasma proteins.
Metabolism
Regorafenib is metabolized by CYP3A4 and UGT1A9. The main circulating metabolites of regorafenib measured at
steady-state in human plasma are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), both of them having similar in
vitro pharmacological activity and steady-state concentrations as regorafenib. M-2 and M-5 are highly protein bound
(99.8% and 99.95%, respectively).
Elimination
Following a single 160 mg oral dose of Stivarga, the geometric mean (range) elimination half-lives for regorafenib and the
M-2 metabolite in plasma are 28 hours (14 to 58 hours) and 25 hours (14 to 32 hours), respectively. M-5 has a longer
mean (range) elimination half-life of 51 hours (32 to 70 hours).
Approximately 71% of a radiolabeled dose was excreted in feces (47% as parent compound, 24% as metabolites) and 19%
of the dose was excreted in urine (17% as glucuronides) within 12 days after administration of a radiolabeled oral solution
at a dose of 120 mg.
Patients with hepatic impairment
The pharmacokinetics of regorafenib, M-2, and M-5 were evaluated in 14 patients with hepatocellular carcinoma (HCC)
and mild hepatic impairment (Child-Pugh A); 4 patients with HCC and moderate hepatic impairment (Child-Pugh B); and
10 patients with solid tumors and normal hepatic function after the administration of a single 100 mg dose of Stivarga. No
clinically important differences in the mean exposure of regorafenib, M-2, or M-5 were observed in patients with mild or
moderate hepatic impairment compared to the patients with normal hepatic function. The pharmacokinetics of regorafenib
has not been studied in patients with severe hepatic impairment (Child-Pugh C).
Patients with renal impairment
The pharmacokinetics of regorafenib, M-2, and M-5 were evaluated in 10 patients with mild renal impairment (CLcr 60-
89 mL/min/1.73m2) and 18 patients with normal renal function following the administration of Stivarga at a dose of 160
mg daily for 21 days. No differences in the mean steady-state exposure of regorafenib, M-2, or M-5 were observed in
patients with mild renal impairment compared to patients with normal renal function. Limited pharmacokinetic data are
available from patients with moderate renal impairment (CLcr 30-59 mL/min/1.73m2). The pharmacokinetics of
regorafenib has not been studied in patients with severe renal impairment or end-stage renal disease.
Drug-drug interactions
In vitro screening on cytochrome P450 enzymes: In vitro studies with human hepatic microsomes or recombinant
enzymes showed that regorafenib competitively inhibits CYP2C8, CYP2C9, CYP2B6, CYP3A4, and CYP2C19 with R1
values > 1.1; M-2 inhibits CYP2C9, CYP2C8, CYP3A4, and CYP2D6 with R1 values > 1.1 and M-5 inhibits CYP2C8
with a R1 value > 1.1. In vitro studies with primary human hepatocytes showed that regorafenib is not expected to induce
CYP1A2, CYP2B6, CYP2C19, and CYP3A4 enzyme activity.
In vitro screening on uridine diphosphate glucuronosyltransferases: In vitro studies with human hepatic microsomes
showed that regorafenib, M-2, and M-5 competitively inhibits UGT1A9 and UGT1A1 at therapeutically relevant
concentrations.
In vitro screening on transporters: In vitro data showed that regorafenib is an inhibitor of ABCG2 (Breast Cancer
Resistance Protein) and ABCB1 (P-glycoprotein).
Effect of CYP3A4 Strong Inducers on Regorafenib: Twenty-two healthy men received a single 160 mg dose of Stivarga
alone and then 7 days after starting rifampin. Rifampin, a strong CYP3A4 inducer, was administered at a dose of 600 mg
daily for 9 days. The mean AUC of regorafenib decreased by 50% and mean AUC of M-5 increased by 264%. No change
in the mean AUC of M-2 was observed [see Drug Interactions (7.1)].
Effect of CYP3A4 Strong Inhibitors on Regorafenib: Eighteen healthy men received a single 160 mg dose of Stivarga
alone and then 5 days after starting ketoconazole. Ketoconazole, a strong CYP3A4 inhibitor, was administered at a dose
of 400 mg daily for 18 days. The mean AUC of regorafenib increased by 33% and the mean AUC of M-2 and M-5 both
decreased by 93%.
Effect of regorafenib on a substrate of UGT1A1 substrates: Eleven patients received irinotecan-containing combination
chemotherapy with Stivarga at a dose of 160 mg. The mean AUC of irinotecan increased 28% and the mean AUC of SN-
38 increased by 44% when irinotecan was administered 5 days after the last of 7 daily doses of Stivarga.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies examining the carcinogenic potential of regorafenib have not been conducted. Regorafenib itself did not
demonstrate genotoxicity in in vitro or in vivo assays; however, a major human active metabolite of regorafenib, (M-2),
was positive for clastogenicity, causing chromosome aberration in Chinese hamster V79 cells.
Dedicated studies to examine the effects of regorafenib on fertility have not been conducted; however, there were
histological findings of tubular atrophy and degeneration in the testes, atrophy in the seminal vesicle, and cellular debris
and oligospermia in the epididymides in male rats at doses similar to those in human at the clinical recommended dose
based on AUC. In female rats, there were increased findings of necrotic corpora lutea in the ovaries at the same exposures.
There were similar findings in dogs of both sexes in repeat dose studies at exposures approximately 83% of the human
exposure at the recommended human dose based on AUC. These findings suggest that regorafenib may adversely affect
fertility in humans.
13.2 Animal Toxicology and/or Pharmacology
In a chronic 26 week repeat dose study in rats there was a dose-dependent increase in the finding of thickening of the
atrioventricular valve. At a dose that resulted in an exposure of approximately 12% of the human exposure at the
recommended dose, this finding was present in half of the examined animals.
14 CLINICAL STUDIES
The clinical efficacy and safety of Stivarga were evaluated in an international, multi-center, randomized (2:1), double-
blind, placebo-controlled trial (Study 1) in 760 patients with previously treated metastatic colorectal cancer. The major
efficacy outcome measure was overall survival (OS); supportive efficacy outcome measures included progression-free
survival (PFS) and objective tumor response rate.
Patients were randomized to receive 160 mg regorafenib orally once daily (n=505) plus Best Supportive Care (BSC) or
placebo (n=255) plus BSC for the first 21 days of each 28-day cycle. Stivarga was administered with a low-fat breakfast
that contains less than 30% fat [see Dose and Administration (2.1), Clinical Pharmacology (12.3)]. Treatment continued
until disease progression or unacceptable toxicity.
In the all-randomized population, median age was 61 years, 61% were men, 78% were White, and all patients had
baseline ECOG performance status of 0 or 1. The primary site of disease was colon (65%), rectum (29%), or both (6%).
History of KRAS evaluation was reported for 729 (96%) patients; 430 (59%) of these patients were reported to have
KRAS mutation. The median number of prior lines of therapy for metastatic disease was 3. All patients received prior
treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and with bevacizumab. All but one
patient with KRAS mutation-negative tumors received panitumumab or cetuximab.
The addition of Stivarga to BSC resulted in a statistically significant improvement in survival compared to placebo plus
BSC (see Table 3 and Figure 1).
Table 3: Efficacy Results from Study 1
Stivarga + BSC Placebo + BSC

(N=505) (N=255)
Overall Survival
Number of deaths, n (%) 275 (55%) 157 (62%)
Median Overall Survival (months) 6.4 5.0
95% CI (5.8, 7.3) (4.4, 5.8)
HR (95% CI) 0.77 (0.64, 0.94)
a,b
Stratified Log-Rank Test P-value 0.0102
Progression-free Survival
Number of Death or Progression, n (%) 417 (83%) 231 (91%)
Median Progression-free Survival (months) 2.0 1.7
95% CI (1.9, 2.3) (1.7, 1.8)
HR (95% CI) 0.49 (0.42, 0.58)
Stratified Log-Rank Test P-value a <0.0001
Overall Response Rate
Overall response, n (%) 5 (1%) 1 (0.4%)
95% CI 0.3%, 2.3% 0%, 2.2%
a
Stratified by geographic region and time from diagnosis of metastatic disease.
b
Crossed the O’Brien-Fleming boundary (two-sided p-value < 0.018) at second interim analysis.
Figure 1: Kaplan-Meier Curves of Overall Survival
--- snvarga + BSC (N=505)

- - - - Placebo+ BSC (N-255)
25
a 2 4 6 8 10 12 14
Monlhs From Randomization
Patients at Risk
Slivarga + BSC 452 352 187 93 33 7
Placebo + BSC 221 150 75 32 9 3
16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied
Stivarga tablets are supplied in packages containing three bottles, with each bottle containing 28 tablets, for a total of 84
tablets per package (NDC 50419-171-03).
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16.2 Storage and Handling
Store Stivarga at 25°C (77°F); excursions are permitted from 15 to 30°C (59 to 86°F) [See USP Controlled Room
Temperature].
Store tablets in the original bottle and do not remove the desiccant. Keep the bottle tightly closed after first opening.
Discard any unused tablets 28 days after opening the bottle. Dispose of unused tablets in accordance with local
requirements.
17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling (Patient Information).
Inform your patients of the following:
• Stivarga may cause severe or life-threatening liver damage. Inform patients that they will need to undergo monitoring
for liver damage and to immediately report any signs or symptoms of severe liver damage to their health care
provider.
• Stivarga can cause severe bleeding. Advise patients to contact their health care provider for any episode of bleeding.
• Stivarga can cause hand-foot skin reactions or rash elsewhere. Advise patients to contact their health care provider if
they experience skin changes associated with redness, pain, blisters, bleeding, or swelling.
• Stivarga can cause or exacerbate existing hypertension. Advise patients they will need to undergo blood pressure
monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension
occur including severe headache, lightheadedness, or neurologic symptoms.
• Stivarga increased the risk for myocardial ischemia and infarction. Advise patients to seek immediate emergency help
if they experience chest pain, shortness of breath, or feel dizzy or like passing out.
• Contact a healthcare provider immediately if they experience severe pains in their abdomen, persistent swelling of the
abdomen, high fever, chills, nausea, vomiting, severe diarrhea (frequent or loose bowel movements), or dehydration.
• Stivarga may complicate wound healing. Advise patients to inform their health care provider if they plan to undergo a
surgical procedure or had recent surgery.
• Inform patients that regorafenib can cause fetal harm. Advise women of reproductive potential and men of the need
for effective contraception during Stivarga treatment and for up to 2 months after completion of treatment. Instruct
women of reproductive potential to immediately contact her health care provider if pregnancy is suspected or
confirmed during or within 2 months of completing treatment with Stivarga.
• Advise nursing mothers that it is not known whether regorafenib is present in breast milk and discuss whether to
discontinue nursing or to discontinue regorafenib.
• Inform patients to take any missed dose on the same day, as soon as they remember, and that they must not take two
doses on the same day to make up for a dose missed on the previous day.
• Inform patients to store medicine in the original container. Do not place medication in daily or weekly pill boxes. Any
remaining tablets should be discarded 28 days after opening the bottle. Tightly close bottle after each opening and
keep the desiccant in the bottle.
Patient Information
Stivarga (sti-VAR-gah)
(regorafenib)
tablets
Read this Patient Information before you start taking Stivarga and each time you get a refill.
There may be new information. This information does not take the place of talking to your
healthcare provider about your medical condition or treatment.
What is the most important information I should know about Stivarga?
Stivarga can cause serious side effects, including:
Liver problems. Stivarga can cause liver problems which can be serious and sometimes lead to
death. Your healthcare provider will do blood tests to check your liver function before you start
taking Stivarga and during your treatment with Stivarga to check for liver problems. Tell your
healthcare provider right away if you get any of these symptoms of liver problems during
treatment:
• yellowing of your skin or the white part of your eyes (jaundice)
• nausea or vomiting
• dark “tea-colored” urine
• change in sleep pattern
What is Stivarga?
Stivarga is a prescription medicine used to treat people with colon or rectal cancer that has
spread to other parts of the body and for which they have received previous treatment with
certain chemotherapy medicines.
Stivarga has not been used to treat children less than 18 years of age.
What should I tell my healthcare provider before taking Stivarga?
Before you take Stivarga, tell your healthcare provider if you:
• have liver problems

• have bleeding problems
• have high blood pressure
• have heart problems or chest pain
• plan to have any surgical procedures
• have any other medical conditions
• are pregnant or plan to become pregnant. Stivarga can harm your unborn baby. Females
and males should use effective birth control during treatment with Stivarga and for 2
months after your last dose of Stivarga. Tell your healthcare provider right away if you or
your partner becomes pregnant either while taking Stivarga or within 2 months after your
last dose of Stivarga.
• are breastfeeding or plan to breastfeed. It is not known if Stivarga passes into your breast
milk. You and your healthcare provider should decide if you will take Stivarga or
breastfeed.
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins and herbal supplements. Stivarga may affect the way other
medicines work, and other medicines may affect how Stivarga works.
Know the medicines you take. Keep a list of your medicines and show it to your healthcare
provider and pharmacist when you get a new medicine.
How should I take Stivarga?

• Take Stivarga exactly as your healthcare provider tells you.
• You will usually take Stivarga 1 time a day for 21 days (3 weeks) and then stop for 7 days (1
week). This is 1 cycle of treatment. Repeat this cycle for as long as your healthcare provider
tells you to.
• Swallow Stivarga tablets whole.
• Take Stivarga at the same time each day with a low-fat breakfast.
Examples of a low-fat breakfast include:
• 2 slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon of jelly,
and 8 ounces of skim milk (319 calories and 8.2 grams fat), or
• 1 cup of cereal, 8 ounces of skim milk, 1 slice of toast with jelly, apple juice, and 1 cup
of coffee or tea (520 calories and 2 grams fat).
• Your healthcare provider may stop your treatment or change the dose of your treatment if
you get side effects.
• If you miss a dose, take it as soon as you remember on that day. Do not take two doses on
the same day to make up for a missed dose.
• If you take too much Stivarga call your healthcare provider or go to the nearest emergency
room right away.
What should I avoid while taking Stivarga?
• Avoid drinking grapefruit juice and taking St. John’s Wort while taking Stivarga. These can
affect the way Stivarga works.
What are the possible side effects of Stivarga?
Stivarga can cause serious side effects including:

• See “What is the most important information I should know about Stivarga?”
• severe bleeding. Stivarga can cause bleeding which can be serious and sometimes lead to
death. Tell your healthcare provider if you have any signs of bleeding while taking Stivarga
including:
• vomiting blood or if your vomit looks like coffee-grounds
• pink or brown urine
• red or black (looks like tar) stools
• coughing up blood or blood clots
• menstrual bleeding that is heavier than normal
• unusual vaginal bleeding
• nose bleeds that happen often
• a skin problem called hand-foot skin reaction and skin rash. Hand-foot skin reactions
can cause redness, pain, blisters, bleeding, or swelling on the palms of your hands or soles of
your feet. If you get this side effect or a skin rash, your healthcare provider may stop your
treatment for some time.
• high blood pressure. Your blood pressure should be checked every week for the first 6
weeks of starting Stivarga. Your blood pressure should be checked regularly and any high
blood pressure should be treated while you are receiving Stivarga. Tell your healthcare
provider if you have severe headaches, lightheadedness, or changes in your vision.
• decreased blood flow to the heart and heart attack. Get emergency help right away and
call your healthcare provider if you get symptoms such as chest pain, shortness of breath,
feel dizzy or feel like passing out.
• a condition called Reversible Posterior Leukoencephalopathy Syndrome (RPLS). Call
your healthcare provider right away if you get: severe headaches, seizure, confusion, or
change in vision.
• a tear in your stomach or intestinal wall (perforation). Tell your healthcare provider
right away if you get:
• severe pain in your stomach-area (abdomen)
• swelling of the abdomen
• high fever
• wound healing problems. If you need to have a surgical procedure, tell your healthcare
provider that you are taking Stivarga. You should stop taking Stivarga at least 2 weeks
before any planned surgery.
The most common side effects of Stivarga include:
• tiredness, weakness, fatigue
• loss of appetite
• frequent or loose bowel movements (diarrhea)
• swelling, pain and redness of the lining in your mouth, throat, stomach and bowel
(mucositis)
• weight loss
• infection
• voice changes or hoarseness
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
These are not all of the possible side effects of Stivarga. For more information, ask your
healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-
800-FDA-1088.
How do I store Stivarga?
• Store Stivarga tablets at room temperature between 68° F to 77° F (20° C to 25° C).
• Keep Stivarga in the bottle that it comes in. Do not put Stivarga tablets in a daily or weekly
pill box.
• The Stivarga bottle contains a desiccant to help keep your medicine dry. Keep the desiccant
in the bottle.
• Keep the bottle of Stivarga tightly closed.
• Safely throw away (discard) any unused Stivarga tablets after 28 days of opening the bottle.
Keep Stivarga and all medicines out of the reach of children.
General information about Stivarga.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information
leaflet. Do not use Stivarga for a condition for which it was not prescribed. Do not give Stivarga
to other people even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about Stivarga. If you would like more
information, talk with your healthcare provider. You can ask your healthcare provider or
pharmacist for information about Stivarga this is written for healthcare professionals.
For more information, go to www.STIVARGA-US.com or call 1-888-842-2937.
What are the ingredients in Stivarga?
Active ingredient: regorafenib
Inactive ingredients: cellulose microcrystalline, croscarmellose sodium, magnesium stearate,
povidone and colloidal silicon dioxide.
Film coat: ferric oxide red, ferric oxide yellow, lecithin (soy), polyethylene glycol 3350,
polyvinyl alcohol, talc and titanium dioxide.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Manufactured in Germany
Distributed and marketed by:
Bayer HealthCare Pharmaceuticals Inc.,
Wayne, NJ 07470
© 2012 Bayer HealthCare Pharmaceuticals Inc.

Issued: 09/2012
0
EUROPEANMEDICINESAGENCY
SCIENCE MEDICINES HEALTH
27 June 2013
EMA/CHMP/403683/2013
Committee for Medicinal Products for Human Use (CHMP)
Assessment report
Stivarga
International non-proprietary name: REGORAFENIB
Procedure No. EMEA/H/C/002573/0000
Note
Assessment report as adopted by the CHMP with all information of a commercially confidential
nature deleted.
11TRUE COPY]I
Table of contents
1. Background information on the procedure .............................................. 6

1.1. Submission of the dossier ...................................................................................... 6
1.2. Manufacturers ...................................................................................................... 7
1.3. Steps taken for the assessment of the product ......................................................... 7
2. Scientific discussion ................................................................................ 8

2.1. Introduction......................................................................................................... 8
2.2. Quality aspects .................................................................................................... 9
2.2.1. Introduction ...................................................................................................... 9
2.2.2. Active Substance ............................................................................................... 9
2.2.3. Finished Medicinal Product ................................................................................ 11
2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 14
2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 14
2.3. Non-clinical aspects ............................................................................................ 14
2.3.1. Introduction .................................................................................................... 14
2.3.2. Pharmacology ................................................................................................. 14
2.3.3. Pharmacokinetics............................................................................................. 16
2.3.4. Toxicology ...................................................................................................... 18
2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 22
2.3.6. Discussion on non-clinical aspects...................................................................... 24
2.3.7. Conclusion on the non-clinical aspects ................................................................ 28
2.4. Clinical aspects .................................................................................................. 28
2.4.1. Introduction .................................................................................................... 28
2.4.2. Pharmacokinetics............................................................................................. 29
2.4.3. Pharmacodynamics .......................................................................................... 35
2.4.4. Discussion on clinical pharmacology ................................................................... 36
2.4.5. Conclusions on clinical pharmacology ................................................................. 40
2.5. Clinical efficacy .................................................................................................. 41
2.5.1. Dose response studies...................................................................................... 41
2.5.2. Main study ...................................................................................................... 42
2.5.3. Discussion on clinical efficacy ............................................................................ 58
2.5.4. Conclusions on the clinical efficacy ..................................................................... 62
2.6. Clinical safety .................................................................................................... 63
2.6.1. Discussion on clinical safety .............................................................................. 76
2.6.2. Conclusions on the clinical safety ....................................................................... 80
2.7. Pharmacovigilance .............................................................................................. 80
2.8. Risk Management Plan ........................................................................................ 80
2.9. User consultation ............................................................................................... 85
3. Benefit-Risk Balance ............................................................................. 85
4. Recommendations................................................................................. 90
List of abbreviations
ADH alcohol dehydrogenase
ADR adverse drug reaction
AE adverse event
AESI adverse event of special interest
ALP alkaline phosphatase
ALT alanine aminotransferase
AST aspartate aminotransferase
AUC area under the curve
BCRP Breast Cancer Resistant Protein
BCS Biopharmaceutical Classification System
BRAF virus-induced Rapidly Accelerated Fibrosarcoma (v-raf) B1 homologue
BSC best supportive care
BUN blood urea nitrogen
BW body weight
CNS central nervous system
CI confidence interval
CR complete response
CTCAE common terminology criteria for adverse events
CAPIRI capecitabine, irinotecan
CAPOX capecitabine, oxaliplatin
CMH Cochran-Mantel-Haenszel
CRC colorectal cancer
CYP cytochrome P450
DCE-MRI Dynamic contrast enhanced MRI (magnetic resonance imaging)
DILI drug-induced liver injury
DPD dihydro-pyrimidine dehydrogenase
ECG electrocardiogram
ECOG Eastern Cooperative Oncology Group
EGFR epidermal growth factor receptor
FACS fluorescence activated cell sorter
FOLFIRI folinic acid (leucovorin), 5-fluorouracil, irinotecan
FOLFOX folinic acid (leucovorin), 5-fluorouracil, oxaliplatin
GGT gamma glutamyl transferase
HB haemoglobin
HCC hepatocellular carcinoma
HCT haematocrit
HFSR Hand-foot skin reaction
HPLC high performance liquid chromatography
HR hazard ratio
KRAS Kirsten rat sarcoma 2 viral oncogene homologue
LDH lactate dehydrogenase
LVEF left ventricular ejection fraction
MCH mean corpuscular haemoglobin
MCHC mean corpuscular haemoglobin concentration
mCRC metastatic colorectal cancer
MCV mean corpuscular volume
MRP multidrug resistance-associated protein
MTD maximum tolerated dose
NSCLC non-small cell lung cancer
NOAEL no observed adverse effect level
OATP Organic anion-transporting polypeptide
ORR objective response rate
OS overall survival
OVAT One Variable At a Time
PK pharmacokinetics
PFS progression free survival
PR partial response
RECIST response evaluation criteria in solid tumours
RPES Posterior reversible encephalopathy syndrome
SAE serious adverse event
SD stable disease
SJS Stevens-Johnson-Syndrome
TEN Toxic epidermal necrolysis
TG triglycerides
TKI tyrosine kinase inhibitor
TSH thyroid stimulating hormone
UGT Uridine 5'-diphospho-glucuronosyltransferase
ULN upper limit of normal
VEGF vascular endothelial growth factor
VEGFR vascular endothelial growth factor receptor
1. Background information on the procedure
1.1. Submission of the dossier
The applicant Bayer Pharma AG submitted on 3 May 2012 an application for Marketing
Authorisation to the European Medicines Agency (EMA) for Stivarga, through the centralised
procedure falling within the Article 3(1) and point 3 of Annex of Regulation (EC) No 726/2004.
The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 21 July 2011.
The applicant applied for the following indication: Stivarga is indicated for the treatment of adult
patients with metastatic colorectal cancer (CRC) who have been previously treated with, or are
not considered candidates for, available therapies. These include fluoropyrimidine-based
chemotherapy, an anti-VEGF therapy, and, in case of KRAS wild type CRC, an anti-EGFR therapy.
The legal basis for this application refers to:
Article 8.3 of Directive 2001/83/EC - complete and independent application
The application submitted is composed of administrative information, complete quality data,

non-clinical and clinical data based on applicants’ own tests and studies and/or bibliographic
literature substituting/supporting certain tests or studies.
Information on Paediatric requirements
Pursuant to Article 7 (EC) No 1901/2006, the application included an EMA Decision CW/1/2011
on the granting of a class waiver.
Information relating to orphan market exclusivity
Similarity
Pursuant to Article 8 of Regulation (EC) No. 141/2000 and Article 3 of Commission Regulation
(EC) No 847/2000, the applicant did not submit a critical report addressing the possible
similarity with authorised orphan medicinal products because there is no authorised orphan
medicinal product for a condition related to the proposed indication.
New active Substance status
The applicant requested the active substance regorafenib contained in the above medicinal
product to be considered as a new active substance in itself, as the applicant claims that it is
not a constituent of a product previously authorised within the Union.
Scientific Advice
The applicant did not seek Scientific Advice at the CHMP for the colorectal cancer indication.
Licensing status
The product was not licensed in any country at the time of submission of the application.
1.2. Manufacturers
Manufacturer responsible for batch release
Bayer Pharma AG
51368 Leverkusen
Germany
1.3. Steps taken for the assessment of the product
The Rapporteur and Co-Rapporteur appointed by the CHMP were:
Rapporteur: Barbara van Zwieten-Boot Co-Rapporteur: Daniela Melchiorri
• The application was received by the EMA on 3 May 2012.
• Accelerated Assessment procedure was agreed-upon by CHMP on 19 April 2012
• The procedure started on 23 May 2012.
• The Rapporteur's first Assessment Report was circulated to all CHMP members on 10
August 2012. The Co-Rapporteur's first Assessment Report was circulated to all CHMP
members on 10 August 2012
• During the meeting on 20 September 2012, the CHMP agreed on the consolidated List of
Questions to be sent to the applicant. The final consolidated List of Questions was sent to
the applicant on 20 September 2012
• The applicant submitted the responses to the CHMP consolidated List of Questions on
15 November 2012.
• The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the
List of Questions to all CHMP members on 19 December 2012
• During the PRAC meeting on 10 January 2013, the PRAC adopted an RMP Advice and
assessment overview
• During the CHMP meeting on 17 January 2013, the CHMP agreed on a list of outstanding
issues to be addressed in writing by the applicant
• The applicant submitted the responses to the CHMP List of Outstanding Issues on
18 February 2013.
• During the PRAC meeting on 7 March 2013, the PRAC adopted an RMP Advice and
assessment overview
• During a meeting of a SAG Oncology on 7 March 2013, experts were convened to address
questions raised by the CHMP
list of outstanding issues to all CHMP members on 13 March 2013 During the CHMP
meeting on 21 March 2013, the CHMP agreed on a 2nd list of outstanding issues to be
addressed in writing by the applicant
• The applicant submitted the responses to the CHMP List of Outstanding Issues on
27 May 2013.
2nd list of outstanding issues to all CHMP members on 7 June 2013
• During the PRAC meeting on 13 June 2013, the PRAC adopted an RMP Advice and
assessment overview
• The Rapporteurs circulated an updated Joint Assessment Report on the applicant’s

responses to the 2nd list of outstanding issues to all CHMP members on 21 June 2013
• During the meeting on 27 June 2013, the CHMP, in the light of the overall data submitted
and the scientific discussion within the Committee, issued a positive opinion for granting a
Marketing Authorisation to Stivarga.
2. Scientific discussion
2.1. Introduction
Colorectal cancer (CRC) is the third most common cancer in men and the second most common
cancer in women worldwide. In Europe, CRC is the most frequently diagnosed cancer and the
second leading cause of cancer death (Ferlay J, Parkin DM, Steliarova-Foucher E (2010).
‘Estimates of cancer incidence and mortality in Europe in 2008’ Eur J Cancer; 46(4):765-81). The
stage of disease at the time of diagnosis represents the most relevant prognostic factor. Five-
year survival rates range from 93% for stage I disease to less than 10% for stage IV. In
approximately 60% of cases the initial diagnosis is carried out at late stages of disease which are
characterised by poor prognosis.
Surgery, followed by adjuvant chemotherapy in certain cases, represents the standard

therapeutic approach for patients with loco-regional disease. However, around 25% of patients
will subsequently develop distant metastases. Besides this, approximately 25% of patients
present with metastatic disease at initial diagnosis.
At present, there is no curative treatment for patients with metastatic CRC (mCRC). When left
untreated, these patients have a poor prognosis, with a median survival of about 6 months. With
the exception of few selected patients where resection of metastases is indicated, the standard
treatment for patients with metastatic disease is represented by systemic chemotherapy, which
has demonstrated to significantly improve overall survival to an average of 20 months. The
currently available systemic chemotherapeutic options for patients with mCRC consist essentially
of fluoropyrimidine-based regimens alone or in combination with oxaliplatin (FOLFOX, CAPOX) or
irinotecan (FOLFIRI, CAPIRI). Fluoropyrimidine-based regimens have demonstrated similar
activity when given as first or second line therapy (Tournigand C, André T, Achille E, Lledo G,
Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C,
de Gramont A (2004). ‘FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced
colorectal cancer: a randomized GERCOR study’ J Clin Oncol; 22(2):229-37). Addition of the
anti-VEGF monoclonal antibody bevacizumab to the above mentioned first or second line
chemotherapies has demonstrated to modestly improve survival and delay disease progression.
In patients carrying tumours with a wild type form of the Kirsten rat sarcoma (KRAS) gene, the
anti-epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab or panitumumab
can also be administered as monotherapy or in combination with fluoropyrimidine-based
regimens. Finally, the anti-VEGF fusion protein aflibercept has recently been approved in
combination with FOLFIRI as second line treatment of patients with mCRC.
Regorafenib is low molecular weight, orally available, inhibitor of multiple protein kinases,
including kinases involved in tumour angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT,
RET, RAF-1, BRAF, BRAFV600E), and the tumour microenvironment (PDGFR, FGFR). In preclinical
studies regorafenib has demonstrated antitumour activity in a broad spectrum of tumour models
including colorectal tumour models which is mediated both by its antiangiogenic and
antiproliferative effects. Major human metabolites (M-2 and M-5) exhibited similar efficacies
compared to regorafenib both in vitro and in vivo models.
The indication sought for regorafenib is the following: Stivarga is indicated for the treatment of
adult patients with metastatic colorectal cancer (CRC) who have been previously treated with, or
are not considered candidates for, available therapies. These include fluoropyrimidine-based
chemotherapy, an anti-VEGF therapy, and, in case of KRAS wild type CRC, an anti-EGFR therapy.
The finally approved indication is the following: Stivarga is indicated for the treatment of adult
not considered candidates for, available therapies. These include fluoropyrimidine-based
chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy.
The recommended dose is 160 mg once daily (four 40 mg tablets OD) for 3 weeks on therapy
followed by 1 week off therapy to comprise a cycle of 4 weeks. Regorafenib should be taken at
the same time each day after a light meal.
2.2. Quality aspects
2.2.1. Introduction
The finished product is presented as film-coated tablets containing 40 mg of regorafenib as the

active substance. The excipients used in the formulation of Stivarga are povidone, croscarmellose
sodium, microcrystalline cellulose, silica colloidal anhydrous and magnesium stearate.
The product is available in white opaque HDPE bottle closed with a PP/PP screw cap with sealing
insert and a molecular sieve desiccant. Each bottle contains 28 film-coated tablets.
2.2.2. Active Substance
Regorafenib monohydrate is a white to slightly pink or slightly brownish solid substance,

practically insoluble in water, dilute alkaline solution, dilute acid solution, n-heptane, glycerine
and toluene. It is slightly soluble in acetonitrile, dichloromethane, propylene glycol, methanol, 2-
propanol, ethanol and ethyl acetate. It is sparingly soluble in acetone and soluble in PEG 400
(macrogol). Regorafenib is not hygroscopic.
The chemical name is 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl} amino)-3-

fluorophenoxy]-Nmethylpyridine-2-carboxamide (monohydrate) and has the following structural
formula:
Figure 1: chemical structure of regorafenib
Regorafenib crystallizes in three modifications with melting points at 206 °C (Mod. I), at 181 °C
(Mod. II,) and at 141 °C (Mod. III). In addition, one pseudo-polymorph has been found, a
monohydrate (water content of 3.6 %). Solid state form characterisation has been performed by
XRD, IR, Raman, NIR, FIR, 13C-solid state-NMR, DSC and TGA. Regorafenib monohydrate was
selected as stable active substance which can be manufactured reproducibly and is used in
crystalline, non-micronized form for the production of Regorafenib tablets.
The structure of regorafenib monohydrate has been elucidated using IR and Raman
spectroscopy, UV-VIS, NMR (1H and 13C), MS, elemental analysis and X-Ray structural analysis.
The analysis was performed on one batch of the active substance.
Manufacture
Regorafenib is synthesized in three main steps using well defined starting materials with
acceptable specification.
Adequate in-process controls are applied during the synthesis. The specifications and control
methods for intermediate products, starting materials and reagents have been presented.
The manufacturing process has been developed using elements of Quality by Design such as risk-
assessment, OVAT (One Variable At a Time) experiments, design of experiments and spiking
experiments. The results of these studies were used to define proven acceptable ranges for the
different steps of the regorafenib manufacturing process. For each stage of the synthesis an
experimental model was established taking potential scale effects into consideration. The models
used were shown to be scientifically justified and therefore enable a prediction of quality. This
supports the extrapolation of operating conditions and amounts of reacting materials across
multiple scales and equipment.
The characterisation of the active substance and its impurities are in accordance with the EU
guideline on chemistry of new active substances. Potential and actual impurities were well
discussed with regards to their origin and characterised.
Impurities present at higher than the qualification threshold according to ICH Q3A were qualified
by toxicological and clinical studies and appropriate specifications have been set.
Batch analysis data is provided on three commercial scale batches produced with the proposed
synthetic route, and the batch analysis data show that the active ingredient can be manufactured
reproducibly.
The active substance is packed in polypropylene or polyethylene bags. The secondary packaging
is a closed container for mechanical protection.
Specification
The active substance specification includes tests for: appearance (visual examination), identity
(IR, HPLC), assay (HPLC) impurities (HPLC), residual solvents (GC) and water content (Karl
Fisher).
The analytical methods used have been adequately described and (non-compendial methods)
appropriately validated in accordance with the ICH guidelines.
Batch analysis data on three production scale batches of the active substance are provided. The
results are within the specifications and consistent from batch to batch.
Stability
Three pilot scale batches of the active substance packed in the intended commercial package
from the proposed manufacturer were put on stability testing as per ICH conditions: under long
term (25°C/60%RH) for up 24 months, and accelerated (40°C/75%RH) for up 12 months.
Results on stress conditions (thermal, oxidative, and hydrolytic stress) show that regorafenib is
chemically extremely stable to thermal stress, has good stability towards hydrolytic stress and is
quite stable to oxidative stress. Photostability studies were also performed on one batch. The
results showed that in the solid state regorafenib is not sensitive to light, when irradiated
according to ICH Q1B.
The following parameters were tested: appearance, organic impurities, assay and water. The
stability results justify the proposed retest period in the proposed container.
2.2.3. Finished Medicinal Product
Pharmaceutical Development
The objective of the pharmaceutical development was to provide an immediate release solid
dosage form of regorafenib with high oral bioavailability and high patient compliance.
A solid solution (co-precipitate) tablet formulation was selected as dosage form, in order to
transfer the active substance, which is characterized by an extremely low solubility in aqueous
media, into the amorphous form. Upon contact with the dissolution medium the tablets
disintegrate and the solid solution dissolves forming a supersaturated solution with a significantly
higher concentration of regorafenib in solution than expected based on the solubility of the
crystalline active substance. Consequently, higher oral bioavailability is achieved when
administering regorafenib as a solid solution tablet compared to a conventional tablet comprising
the active substance in crystalline micronized form.
The excipients used in the formulation of regorafenib tablets are common ingredients for a solid
oral dosage form. The excipients have been chosen based on preliminary formulation
development experience and compatibility studies. Regorafenib tablets are film-coated in order
to provide a homogeneous appearance, to add a colour for product identification, to reduce
dusting during handling of the tablets and to facilitate swallowing. The coating system comprises
PVA, ferric oxide red, ferric oxide yellow and titanium dioxide, lecithin, macrogol and talc.
The pharmaceutical development of the finished product contains QbD elements.
A comprehensive risk analysis was performed using the failure mode effect analysis (FMEA)
method in order to define critical process steps and process parameters that may have an
influence on specified finished product attributes. The risk identification was based on the prior
knowledge of products with similar formulations and manufacturing processes as well as on the
experience from formulation development, process design and scale-up studies with regorafenib
tablets. The critical process parameters were monitored carefully during validation and the
critical quality attributes were evaluated intensively during process validation and stability tests.
In addition, further studies were conducted to define adequate operating ranges for these
process parameters to ensure a robust and reproducible manufacturing process. Furthermore,
development studies enabled the identification of appropriate in-process controls and product
specifications to ensure the intended quality, safety, efficacy and performance of the product
through traditional final product release testing.
The dissolution method has been adequately developed and its discriminating capability
demonstrated. The use of surfactant and the dissolution medium was justified. Sink conditions
were confirmed. The dissolution test was shown to be sufficiently discriminative in detecting
relevant changes to the solid solution granules.
The formulation used during clinical studies is the same as that used for marketing.
The primary packaging proposed is white opaque HDPE bottle closed with a PP/PP screw cap with
sealing insert and a molecular sieve desiccant. The material complies with Ph.Eur. requirements
and it is adequate to support the stability and use of the product.
Adventitious agents
No excipients derived from animal or human origin have been used.
Manufacture of the product
The manufacture of the finished product involves conventional processes including (1) mixing,
(2) granulation, (3) roller compaction, (4) blending, (5) post-blending, (6) tableting, (7) coating
and (8) drying. The process is considered to be a standard manufacturing process.
The manufacturing process has been validated by a number of studies for the major steps of the
manufacturing process and has been demonstrated to be capable to reproducibly produce
finished product of the intended quality. The in process controls are adequate for this film coated
tablet preparation.
The batch analysis data on five full scale batches shows that the tablets can be manufactured
reproducibly according to the agreed finished product specification, which is suitable for control
of this oral preparation.
Product specification
The finished product release specifications include appropriate tests for appearance (visual
examination), identity (HPLC and TLC or NIR), uniformity of dosage units (Ph.Eur.), degradation
products (HPLC), assay (HPLC), dissolution (Ph.Eur.), absence of crystalline regorafenib (XRPD),
water content (Karl Fisher), residual solvents (GC) and microbiological contamination (Ph.Eur).
Batch analysis results of five production scale batches confirm consistency and uniformity of
manufacture and indicate that the process is capable and under control.
The specification is acceptable, ensures batch-to-batch consistency and provides an adequate

control of the solid state form. The analytical methods have been adequately described and
validated.
Stability of the product
Stability data on three pilot scale batches stored under long term conditions for 36 months at
25ºC/60%RH and at 30°C/76% RH, and for up to 6 months under accelerated conditions at
40ºC/75%RH according to ICH guidelines were provided. The batches of regorafenib film-coated
tablets are identical to those proposed for marketing and were packed in the primary packaging
proposed for marketing.
Samples were tested for appearance, dissolution, degradation products, assay, water content,
breaking load, disintegration and microbial purity. The analytical procedures used were stability
indicating.
Photostability testing as defined in the ICH Guideline on Photostability Testing of New Drug
Substances and Products was performed. No significant differences were seen and no light
storage restrictions are needed.
Stability data has been provided demonstrating that the product remains stable following first
opening of the container, when stored at 30°C/75% RH. The in-use stability data provided justify
the claimed maximum in-use shelf-life of 7 weeks.
The finished product is sensitive to moisture. For this reason the tablets are packed and stored in
tightly closed HDPE bottles with a desiccant capsule inside.
Based on available stability data, the proposed shelf-life and storage conditions as stated in the
SmPC are acceptable.
2.2.4. Discussion on chemical, pharmaceutical and biological aspects
Information on development, manufacture and control of the active substance and finished
product has been presented in a satisfactory manner. The finished product is formulated as an
amorphous solid solution dosage form, in the presence of a precipitation inhibitor. This leads to
an increase in solubility of the active substance. The presence of the precipitation inhibitor helps
maintain supersaturation levels, thereby improving bioavailability. Quality by Design principles
have been used in this application during the pharmaceutical development but a Design Space
was not claimed for the manufacturing process of the active substance neither for the finished
product. Risk assessment was performed to optimise the manufacturing conditions of the active
substance. For the finished product, the Quality by Design approach was used for the
development of the manufacturing process. The control strategy and process validation follow
the traditional approach. The results of tests carried out indicate consistency and uniformity of
important product quality characteristics, and these in turn lead to the conclusion that the
product should have a satisfactory and uniform performance in the clinic.
2.2.5. Conclusions on the chemical, pharmaceutical and biological

aspects
The quality of this product is considered to be acceptable when used in accordance with the
conditions defined in the SmPC. Physicochemical and biological aspects relevant to the uniform
clinical performance of the product have been investigated and are controlled in a satisfactory
way.
2.3. Non-clinical aspects
2.3.1. Introduction
In vivo studies were performed in mouse, rat, rabbit, dog and monkey. All pivotal toxicological
studies were conducted in accordance with current regulatory requirements and in compliance
with the principles of Good Laboratory Practice (GLP). Safety pharmacology studies were
conducted under GLP regulations as requested by ICH S7A and B with the exception of a study
investigating the effect of regorafenib on hERG K+ currents.
2.3.2. Pharmacology
Primary pharmacodynamic studies
The kinase activity of regorafenib was tested in biochemical assays by either measuring enzyme
inhibition or by a competitive binding assay. Regorafenib inhibited a distinct set of kinases,
including the angiogenic and stromal receptor tyrosine Kinases (RTKs) VEGFR1-3, TIE2, FGFR1
and PDGFRβ with IC50 values ranging from 4 to 311 nM, and the oncogenic RTKs KIT and RET,
along with the intracellular signalling kinases C-RAF/RAF-1 and wild-type and mutant B-RAF with
IC50 values in the range of ~ 2 to 30 nM. M-2 and M-5, the two pharmacologically active
metabolites of regorafenib, showed kinase selectivity profiles similar but different from
regorafenib. Inhibition of kinase phosphorylation was analysed in cells expressing relevant target
kinases. Regorafenib inhibited phosphorylation of VEGFR2, VEGFR3, TIE2, PDGFRβ, KIT (wild-
type and mutant), mutant RET and FGFR with IC50 ranging from ~ 3-200 nM; persistent
inhibition of VEGFR2 autophosphorylation was observed for 24h after removal of regorafenib
from NIH-3t3/VEGFR2 cells. The antiproliferative activity of regorafenib was evaluated in a panel
of tumour cell lines of different origin and on VEGF stimulated proliferation of HUVECs. Inhibition
of proliferation was seen for most cell lines, although the IC50s were in the lower µM range and
IC50 values could not be determined for a number of cell lines (highest concentration tested was
10 µM).
Xenografts of cancer specimens derived from patients were injected in immunodeficient mice to
test the in vivo antitumour effect of regorafenib, orally administered at a daily dose of 10 mg/kg
for 22 days. The drug, either alone or in combination with irinotecan, induced a significant
growth delay in patient derived-CRC xenografts. However, in only 2 of 4 patient derived-CRC
xenografts a significant growth inhibition was observed for regorafenib treated animals, and in
only 1 of these 4 this response was better than oxaliplatin (a substance stated to have only
limited anti-colorectal tumour effect). Potent tumour growth inhibition was seen in 8 patient-
derived gastric cancer (GC) xenograft models. Dose dependent tumour growth inhibition was
seen in mice for regorafenib and, with lower potency, for the two active metabolites M-2 and M-
5, at oral doses of 3 or 10 mg/kg for 27 days. No correlation was observed between antitumour
activity and the mutation status of either KRAS or BRAF in the injected cell lines. Regorafenib
also inhibited syngeneic orthotopic or intramuscularly growing liver, breast, and brain tumours,
significantly improving for example the survival of mice transplanted with a syngeneic hepatoma.
The mechanistic data showed reduced vascularisation and increased apoptosis in tumour tissue.
Secondary pharmacodynamic studies
An in vivo assay based on the transient hypotensive effect of VEGF in anaesthetised rats was
used to characterise the acute effect of regorafenib and its metabolites M-2 and M-5 after
intravenous administration. Intravenous administration of 0.1 mg/kg regorafenib (10 minutes
prior to VEGF injection) attenuated while injection of 1 mg/kg completely prevented the
hypotensive response to VEGF. Also M-2 and M-5 inhibited the transient hypotensive effect
induced by VEGF injection.
Safety pharmacology programme
In vitro data from the whole-cell voltage-clamp technique on HEK293 cells stably transfected
with the HERG K+ channel indicated that regorafenib as well as M-2 and M-5 can inhibit the
hERG K+ current in a concentration-dependent manner. However, exposure of rabbit cardiac
Purkinje fibers to regorafenib did not induce changes of resting membrane potential, action
potential amplitude, maximal depolarization velocity and action potential duration at 20 %
repolarization at all concentrations tested with the exception of the highest one which was close
to the limit of solubility.
For the cardiovascular and respiratory systems, four GLP-compliant studies in anesthetised dogs
were submitted. A single intraduodenal administration of regorafenib as suspension at doses of
10, 30 and 100 mg/kg or a cumulative intravenous infusion of regorafenib, M-2 and M-5, at dose
steps of 0.25, 0.75 and 2.25 mg/kg (30 minutes per dose step) had no effects on cardiovascular
function, ECG, lung mechanics, acid/base-status, haematocrit and plasma electrolytes.
Four GLP-compliant studies in conscious male rats were conducted in order to investigate
potential effects of regorafenib and its metabolites M-2 and M-5 on parameters of CNS function.
Single oral doses of regorafenib (2, 10, and 50 mg/kg), M-2 (1, 5 and 20 mg/kg,) or M5 (1, 5
and 20 mg/kg) did not elicit substantial adverse CNS (behavioural, locomotor activity, body
temperature) effects. No effect on nocifensive reflex responses to acute heart exposure,
hexobarbital sleep and chemoconvulsion threshold dose were seen following single oral doses of
regorafenib (2, 10 and 50 mg/kg).
In another GLP-compliant study, treatment with regorafenib inhibited the intestinal barium
transport in rats in a statistically significant and dose-related manner.
Finally, after a single oral dose of regorafenib, a significant decrease in blood glucose
concentration was seen in rats.
Pharmacodynamic drug interactions
Regorafenib was tested in an in vivo tumour xenograft study in combination with irinotecan and
in another study with an investigational MEK inhibitor, without observing additional toxicity in
either case. Regarding synergism, a beneficial effect from the addition of regorafenib to
irinotecan was only observed in the most regorafenib-sensitive tumour.
2.3.3. Pharmacokinetics
The in vivo pharmacokinetics of regorafenib and its metabolites M-2 and M-5 was investigated in
mouse, rat, rabbit, dog and monkey. Additionally, in vitro studies were performed to investigate
plasma protein binding, blood cell/plasma partitioning, drug-drug interaction potential,
metabolism and transport.
The permeability of regorafenib was determined in Caco-2 cells; a comparison with 22 reference
compounds revealed that regorafenib is highly permeable.
Single IV and/or PO administration studies were performed in rats, dogs and monkey. The oral
bioavailability of regorafenib was high in rats and independent of dose (~80%). In contrast, the
absolute bioavailability in dogs decreased with increasing dose (from ~70 to 29%). Cmax was
reached after 4 to 6 h in rat and after 1.6 to 2.7 h in dogs and monkeys. The volume of
distribution was lower in rats than in dogs (0.9 versus 1.8 L/kg). In mice, the AUC and Cmax
increased slightly more than dose proportional with increasing dose at the 1 to 20 mg/kg and a
slightly less than dose proportional increase at 20 to 80 mg/kg. In rats, the AUC was dose
proportional and the Cmax increased slightly less than dose proportional. In dogs, AUC and
Cmax increased dose proportionally from 1 to 2.5 mg/kg and less than dose proportional from
2.5 to 10 mg/kg.
After repeated dosing, a slight to moderate increase in AUC and Cmax was observed in rat and
rabbit. In contrast, AUC and Cmax decreased slightly to moderately in mice and dogs. In mice,
the AUC and Cmax increased slightly more than dose proportional with increasing dose at the low
to medium dose and a slightly less than dose proportional increase at the medium to high dose.
The binding of regorafenib to plasma proteins of mice, rats, rabbits, monkeys, dogs and human,
investigated in vivo, was high (>98%) and species dependent. The main binding protein was
serum albumin. The in vitro blood-to-plasma ratio of regorafenib (1-45 µg/L) was investigated in
blood from rat, dog and human. Regorafenib was mainly distributed into plasma with a blood-to-
plasma ratio of 0.63 to 0.72.
Regorafenib radioactivity was thoroughly distributed to almost all organs and tissues and there
was no evidence of irreversible binding or retention of radioactivity. In terms of AUC, exposure
was highest for the kidney, liver, adrenal gland, Harderian gland, submandibular gland and
cardiac muscle. After 168 h, radioactivity was still present in several tissues, including thyroid,
hypophysis, bone marrow, liver and kidney. After a single oral dose of [14C]-regorafenib (3
mg/kg) to pregnant albino rats a moderate penetration across the placental barrier was
observed.
In vitro metabolite profiles revealed two primary phase I reactions: N oxidation at the pyridine to
give M-2 and hydroxylation of the N-methyl group to give M-3. Based on comparison of
metabolite profiles, humans, mice, rabbits and monkeys favour M-2 over M-3 formation. In
contrast, rat and dog favour the formation of M-3 and only small amounts of metabolite M-2
were found. Incubations of regorafenib with hepatocytes showed the same species dependence.
Furthermore, an important interspecies difference was the presence of two glucuronides (M-7
and M-8) in human hepatocyte incubations. Rat and dog hepatocytes were not capable of
forming these conjugates.
CYP3A4 catalysed the formation of the metabolites M-2 and M-3. CYP2J2 only catalysed the
formation of M-3. The formation of M-4 and M-6 were catalysed by alcohol dehydrogenase
(ADH). UGT1A9 is the major enzyme involved in the glucuronidation of regorafenib and M-2
(metabolite M-7 and M-8) and UGT1A7 to a lesser extent.
The in vivo biotransformation of regorafenib was studied in mice, rats, dogs, and humans.
Following a single oral administration of regorafenib, the parent compound was the major
component in mouse, rat, dog, and human plasma. Metabolite M-2 was the main metabolite in
human plasma, but was only found in small amounts in mouse plasma and not in rat and dog
plasma. Furthermore, the metabolites M-5 (amide pyridine N-oxide) and M-7 (urea N-
glucuronide) were only found in human plasma as minor metabolites and could not be detected
in plasma of all other species. In rat and dog plasma methylhydroxylated metabolite M-3 was a
major. Metabolite M-4 was found in plasma of all species, but as trace in humans and as major
metabolite in rats. Metabolite M-6 was only present in considerable amounts in dog plasma, but
could only be detected in traces in plasma of rats and not at all in plasma of humans and mice.
The excretion of radioactivity was mainly via the biliary/faecal route and to a minor extent via
urine. However, the contribution of urine to the overall excretion played a more important role in
humans than in the other species. Furthermore, regorafenib or its radioactive metabolites were
secreted into the milk. No metabolite profile was identified in milk.
Regorafenib was not displaced from its plasma protein binding by any tested highly protein
bound compound at clinically relevant concentrations. Regorafenib, M-2 and M-5 were inhibitors
of P-glycoprotein and BCRP. Regorafenib, M-2 and M-5 are not substrates of MRP2 at clinically
relevant concentrations. Regorafenib was not a substrate for P-glycoprotein, BCRP, OATP1B1,
and OATP1B3. Regorafenib and metabolites M-2 and M-5 are inhibitors of P-glycoprotein and
BCRP and therefore interaction may occur via these transporters. Regorafenib, M-2 and M-5 are
not inhibitors of DPD, which is important in the metabolism of 5 fluorouracil. Regorafenib was not
an inducer of CYP1A2, CYP2B6 and CYP3A4. However, regorafenib, M-2 and M-5 were inhibitors
of CYP2C8, CYP2B6, CYP2C9, CYP2D6, UGT1A1 and UGT1A9 at clinically relevant concentrations.
2.3.4. Toxicology
Single dose toxicity
Single dose toxicity was tested in mice and rats, up to the technically maximum feasible doses
(250 mg/kg orally); no signs of toxicity were observed.
Repeat dose toxicity
Repeat dose toxicity studies are summarised in the following Table 1.
Table 1: Repeat-dose toxicity studies with regorafenib

Study ID Species/Sex/ Dose/Route Duration NOEL/ NOAEL
Number/Group
PH-34500 Mouse 0, 5, 20, 80 mg/kg/day 4 weeks ND
GLP 10/sex/dose Oral gavage
9/sex/dose for TK
Major findings
≥5: 2 mortalities, AST and ALT (F), heart weight (F), dentin alterations, hyperkeratosis of forestomach,
glycogen content in liver
≥20: 2 mortalities, emaciation (F), BW, ALT (M), glomerulopathy (F), amelioblast degeneration,
interstitial oedema of tongue, deposition of iron in spleen, thickened growth plate, corpora lutea, stomal
atrophy of uterus, eosinophilia of zona fasciculate of adrenal glands, atrophy of exocrine pancreas
=80: 11 mortalities, hindleg dragging, labored breathing, HB and HCT (M), MHC and MCHC, leukocytes,
AST (M), chol and albumin (F), plasma protein, spleen weight, thymus and testes weight (M),
atrophy of sublingual gland, dilation of gall bladder, haematopoiesis in spleen, foam cells in mesenteric
lymph nodes, blood content in bone marrow, hypertrophy of lacrimal glands
Number/Group
PH-35918 Mouse 0, 1, 5, 20 mg/kg/day 5 weeks 1 mg/kg/day
18/sex/dose for TK
Major findings
≥5: food intake (F), HB, HCT (M), bilirubin (M), liver weight, hyperkeratosis of forestomach (F),
hyperkeratosis of esophagus, dentin alteration, corpora lutea, oedema in uterus
=20: BW, LYM, AST and ALT, chol (F), bilirubin (F), plasma protein, hyperkeratosis of forestomach
(M), hypocellularity of bone marrow, width of epiphyseal plate (F), ameloblast and ondotoblast
degeneration, keratinization in vagina
Number/Group
PH-33468 Rat 0, 10, 25, 50 mg/kg/day 2 weeks ND
Non-GLP 5/sex/dose Oral gavage
3/sex/dose for TK
Major findings
≥10: BW (M), HB and HCT (M), neutrophils (M), ALT and AST, other clinical chemistry changes,
p450 enzymes in liver, liver weight, lung weight (F), histopathology findings in the kidney, ovary, bone
marrow, growth plate, adrenals, pancreas, liver, teeth, hair follicles
≥25: Ery (M), MCHC (F), reticulocytes and thrombocytes, ovary weight, histopathology findings in
stomach
=50: BW (F), neutrophils (F)
Number/Group
PH-34206 Rat 0, 1, 4, 16 mg/kg/day 4 weeks ND
GLP 10/sex/dose Oral gavage + 4 weeks
5/sex for recovery recovery
9/sex/dose for TK
Major findings
≥1: Ery and HB (M), leucocytes (M), ALT, degenerative changes in kidney (M)
≥4: ungroomed coat, HCT (M), AST, Bilirubin, B cells, CD4 and CD8 cells (F), glomerulopathy,
degeneration of dentin, haematopoiesis in spleen, hypocellularity of bone marrow, chondrodystrophy
=16: pallor, BW, FC and WI, Ery, HB and HCT (F), chol, plasma protein, T4, TSH, urine volume,
urine protein, CD4, CD45 and CD8 cells (M), IgM and IgG, adrenal and kidney weight, thymus,
heart (M) and uterus (F) weight, atrophy lymph nodes, mast cells in tongue, bile duct proliferation, adrenal
changes, flattened follicular epithelial of thyroid, myocardial oedema, atrophy of ovaries, corpora lutea
Recovery (no clinical lab data):
=16: 5 mortalities, apathy, emaciation, tooth changes, BW, FC and WI, kidney changes, teeth changes,
bone marrow, spleen, thymus and lymph node changes, glycogen, adrenal and thyroid changes,
chondrodystrophy, irregular estrous cycle
Number/Group
PH-34484 Rat 0, 0.5, 2, 8 mg/kg/day 13 weeks ND
GLP 10/sex/dose Oral gavage + 4 weeks
10/sex/dose for recovery
recovery
6/sex/dose for TK
Major findings
≥0.5: BW (M), WI, AST, ALT, urine crea (M), tubular degeneration and dilation, liver: decreased
glycogen, Kupffer cell activation (M)
≥2: FC, GGT (F), liver, epididymides weight (M), kidney discoloration, glomerulopathy, liver:
cytoplasmatic basophilia (M), flattened follicular epithelium of thyroid gland, haematopoiesis in spleen
=8: 2 mortalities, teeth changes (dentin, periodontal ligaments, degeneration), BW (F), ungroomed coat,
ery, Hb, HCT, MCHC (F), MCV, MCH, reticulocytes, thrombocytes (F), neutrophils, hQuick, alb, T4,
Glu (M), chol, TG, BUN, TSH, crea (M), urine pH (F), urine crea (F), kidney, spleen weight,
thymus, testes, prostate weight, liver: cytoplasmatic basophilia, focal perihepatitis/peritonititis (F), pancreas;
atrophy, inflammation, vasculitis, atrophy and vacuolation of tongue, hyperkeratosis and hypertrophy of
stomach, hypertrophy and inflammation of duodenum, peliosis and necrosis of adrenal gland, heart edema,
thymus atrophy, thickening of growth plate, chondrodystrophy (femur and sternum), atrophy of uterus,
ovaries, vagina, lacrimal glands
Recovery:
≥2: ungroomed coat, teeth changes, uterus weight, ), kidney discoloration
=8: 2 mortalities, , BW, MCV, MCH, neutrophils, chol, TG, BUN crea (M), alb, liver, spleen,
kidney weight, pigment deposition in adrenal gland, femur and sternum changes, atrophy of ovaries, stomach
and duodenum changes
Number/Group
PH-35874 Rat 0, 0.1, 0.5, 2 mg/kg/day 26 weeks 0.1 mg/kg/day
Major findings
≥0.1: initial in leucocytes count
≥0.5: slight Ery, Hb, HCT (F), ALT, liver weight
=2: ungroomed coat, very slight lymphocyte changes, TSH (M), kidney weight (F), Liver: pigment
storage in Kupffer cells (F), periportal cytoplasmic basophilia, kidney: tubular degeneration (M),
glomerulopathy, mesenteric lymph nodes: increased number of mast cells, activated germinal centres,
flattened follicular epithelium of thyroid gland, valvular thickening in heart
Number/Group
PH-34182 Beagle dog 0, 5, 20, 80 mg/kg/day 4 weeks+ 4 weeks N.D.
GLP 3/sex/dose Oral gavage recovery
2/sex/dose for
recovery
Major findings
≥5: mushy\liquid faeces, dentin alterations (M)
≥20: slight BW gain, atypical leukocytes, AST, dentin alterations (F), hepatocellular hypertrophy (F),
haematopoiesis in spleen, follicle necrosis of tonsils, cortical atrophy of thymus (F), chondrodystrophy
(sternum)
=80: vomiting, bleeding gums, ALT, GLDH, hypertrophy of zymogenic cells in stomach, hepatocellular
hypertrophy (M), acinar atrophy, cortical atrophy of thymus, hypocellularity and thickening of growth plate
(femur)
Recovery:
bile duct proliferations, thickening of growth plate (femur), dentin alterations

Number/Group
PH-34580 Beagle dog 0, 5, 20, 80 mg/kg/day 13 weeks N.D.
4/sex/dose for TK
Major findings
≥5: BW gain, FC, white mucus and bloody particles in faeces, alopecia, kidney weight, sparse haircoat
≥20: vomiting, gums bleeding/anaemic, swollen eyelids, ALP, thymus, ovary weight, kidney: tubular
degen/regeneration, glomerulopathy, atrophy of thymus, tonsil, larynx, cecum, peyers patches, pancreas,
thyroid gland, adrenal gland and sublingual gland, follicular degeneration of mesenteric lymph node, liver:
bile duct proliferation, centrilobular fat accumulation, centrilobular hypertrophy, cytoplasmic change,
increased fatty replacement in sternum and femur, persistent growth plate (femur), dentin alterations,
lymphangiectasia in duodenum
=80: slight atypical cells, thrombocytes, ALT, GLDH, slightly AST, haematopoiesis, blood in spleen
(M), degeneration of duodenum, perivascular mononuclear cell infiltration in pituitary gland
Number/Group
A45739 Beagle dog 0, 1, 4, 16 mg/kg/day 52 weeks N.D
4/sex/dose for TK
Major findings
≥1: Shaking of body, scratching, thinning of fur, scab formation, wounds, papules, itching, hematomas,
diarrhoea and vomiting, Relative beta-globulin (F), pancreas weight (F), inspissation in gal bladder,
hyaline casts, alveolar/foamy macrophages, vacuolar degener in adrenal cortex (F), spermat. giant cells, hair
growth arrest, hyperkeratosis, number of myeloid cells in sternum
≥4: monocytes (M), glu, , Relative beta-globulin (M), Relative gamma-globulin, ALP (M), kidney,
pancreas weight (M), mononuclear infiltration in liver, epithelial hyperplasia in gall bladder, glomerulosclerosis
(M), hyperplasia in Bowmanns Capsule and cortical mineralization (F), tub degen/regen, glomerulopathy,
foll. Degener, cystic gld. dilatation, pigment clumping in skin, haematopoiesis and pigment deposit in spleen
=16: articular muscle atrophy, stomatitis, pustules, monocytes (F), Relative alb, Alb/globulin quotient,
ALP (F), AST, initially ALT, GLDH, TSH and fibrinogen, urine GGT, kidney, pancreas weight (F),
mandibular gland weight, thymus weight, glomerulosclerosis (F), hyperplasia in Bowmanns Capsule and
cortical mineralization (M), interstit. Fibrosis, vacuolar degener in adrenal cortex (M), cystic Corpora Lutea,
follicular cyst, devel. Follicles, peri-/folliculitis (skin), lymphoid hyperplasia in spleen, mineralization of
tonsils
alb: albumin, ALT: alanine aminotransferase, ALP: alkaline phosphatase AST: aspartate aminotransferase,
BUN: blood urea nitrogen, BW: body weight, chol: cholesterol, crea: creatinine, Ery: erythrocytes, FC:
food consumption, GLDH: glutamate lactate dehydrogenase, Glu: glucose, HB: haemoglobin, HCT:
haematocrit, hQuick: hepato Quick test, LYM: lymphocytes, MCH: mean corpuscular haemoglobin, MCHC:
mean corpuscular haemoglobin concentration, ND: not determined, T4: Thyroxine, TG: triglycerides, TSH:
thyroid stimulating hormone, WI: water intake
Genotoxicity
Regorafenib was tested in vitro in the Salmonella/microsome assay and a mammalian

chromosome aberration assay and in vivo in the bone marrow micronucleus test. None of these
assays indicated genotoxic potential of regorafenib.
Carcinogenicity
No studies were submitted (see discussion on non-clinical aspects).
Reproduction Toxicity
No fertility and early embryonic development studies were submitted (see discussion on Non-
clinical aspects).
The influence of regorafenib on embryo-foetal development was investigated in pilot studies in

rats and rabbits and in a pivotal GLP study in rabbits.
In the rabbit pivotal study, signs of maternal toxicity were observed at the dose of 1.6
mg/kg/day including a marginal to slight body weight loss, total resumptions and thus a
decreased gestation rate. Post-implantation loss was severely increased at this dose level.
Therefore, based on the results of this study a NOAEL of 0.8 mg/kg/day could be derived for
systemic maternal toxicity. A treatment related effect on malformations was clearly observed at
1.6 mg/kg/day (mainly findings of the urinary system, the heart, and the axial skeleton) and at
0.8 mg/kg/day (mainly malposition of forelimb(s) or hind limb(s), findings of the heart and major
vessels, urinary system, and skeleton [skull bones, caudal vertebral bodies]). A treatment
related effect on external and visceral deviations is assumed for findings of the urinary system at
1.6 mg/kg/day and 0.8 mg/kg/day. Foetal examinations for skeletal retardations and variations
revealed increased incidence of fused sternebrae and 7th cervical ribs at 0.8 mg/kg/day and 1.6
mg/kg/day. The applicant stated that, based on these results, a NOAEL of 0.4 mg/kg/day for
embryo-foetal development could be derived in this study.
No pre- and post-natal development or juvenile toxicity studies were submitted (see discussion
on non-clinical aspects).
Toxicokinetic data
In mice, the AUC and Cmax increased slightly more than dose proportionally with increasing dose
at the 1 to 20 mg/kg dose range and a slightly less than dose proportional increase was
observed at 20 to 80 mg/kg. In rats, the AUC was dose proportional and the Cmax increased
slightly less than dose proportionally. In rabbits, the AUC and Cmax increased dose-proportionally
from 0.4 to 0.8 mg/kg and moderately more than dose proportionally from 0.8 to 1.6 mg/kg. In
dogs, AUC and Cmax increased dose proportionally from 1 to 2.5 mg/kg and less than dose
proportionally from 2.5 to 10 mg/kg.
Major interspecies differences in metabolite pattern were observed. In humans, N-oxidation of

the pyridine to form metabolite M-2 was much more pronounced than N-methylhydroxylation to
form metabolite M-3, which was predominantly found in rats and dogs. Additionally,
glucuronidation only played an important role in the biotransformation of regorafenib in humans.
Four human specific metabolites were identified, namely M-2, M-5, M-7 and M-8. The human
specific metabolites M-2 and M-5 are pharmacologically active. The applicant investigated the
kinetics of the human specific metabolites M-2 and M-5 and not of the glucuronide metabolites
M-7 and M-8.
The excretion of regorafenib and its metabolites was mainly via the faeces. However, the
contribution of urine to the overall excretion was larger in humans than in the animal species. In
humans, a pronounced enterohepatic circulation was observed. This can be explained by hepatic
formation of primary metabolites M-2 and M-7 and their secretion into gut followed by reduction
of M-2 and deconjugation of M-7 each to parent drug by microbial flora and subsequent intestinal
reabsorption. This was not observed in the animal species.
Local Tolerance
No dedicated local tolerance studies have been conducted. However, various morphological
changes were noted in the gastrointestinal tract of animals treated orally by gavage with the
10% coprecipitate formulation of regorafenib. Signs of degenerative and regenerative processes
were seen in particular in the stomach and duodenum of mice and rats. Morphological changes in
dogs were less pronounced although clinical signs of gastrointestinal intolerance were observed
(bloody diarrhoea, emesis).
Other toxicity studies
No antigenicity or dependence studies were submitted.
Immunotoxicity endpoints were evaluated in the 13-week rat study. No immunotoxic potential
for regorafenib was observed.
Evaluation of the systemic toxicity of the main human metabolites M-2 and M-5 in 4-week mouse
repeat-dose studies with daily oral administration provided evidence that both metabolites induce
less toxicity than the parent compound.
Several batches of regorafenib with a spectrum of the relevant impurities were used in the
nonclinical toxicology program. All impurities were qualified in the toxicological studies at the
individual levels specified. In addition, the genotoxic potential of four impurities that could be
expected in the drug substance/product was experimentally evaluated in genotoxicity assays. For
one of them a mutagenic potential was shown in the Ames test. Moreover, a weak mutagenic
potential for the same impurity was also shown in the Comet assay (data not shown, see
discussion on Non-clinical aspects).
An in vitro phototoxic study suggested that regorafenib is a probable phototoxic compound but
this was not confirmed in the in vivo study conducted in mice.
2.3.5. Ecotoxicity/environmental risk assessment
Table 2: Summary of main study results
Substance (INN/Invented Name): regorafenib

CAS-number (if available): 755037-03-7 (free base); 1019206-88-2 (monohydrate)
PBT screening Result Conclusion
Bioaccumulation potential- log OECD117 3.9 see below
K ow
PBT-assessment
Parameter I Result relevant I I Conclusion
for conclusion
Bioaccumulation log K ow 3.9 (HPLC determined)
BCF 2018 L/kg B
3241 L/kg
Persistence ready not readily biodegradable
biodegradability
DT50 water <1d vP
DT50 system >> 100 d at 22-24°C
DT50 soil 181 d at 20±2°C
Toxicity NOEC algae PM potentially T
NOEC Daphnia PM
NOEC fish PM
CMR not fully investigated
PBT-statement : PM
Phase I
Calculation Value Unit Conclusion
PEC surfacewater 0.6 µg/L > 0.01 threshold
PEC surfacewater , redefined with 0.112 µg/L
published incidence data (EU-
27)
Other concerns (e.g. chemical antineoplastic
class)
Phase II Physical-chemical properties and fate
Study type Test protocol Results Remarks
Adsorption-Desorption OECD 121 PM
Ready Biodegradability Test OECD 301 not readily biodegradable
Aerobic and Anaerobic OECD 308 DT 50, water = < 1 d T=22-24°C
Transformation in Aquatic DT 50, sediment = >> 100 d
Sediment systems DT 50, whole system = >> 100
d
% shifting to sediment =
68-81% at day 2
Phase IIa Effect studies
Study type Test protocol Endpoint value Unit Remarks
Algae, Growth Inhibition OECD 201 NOEC PM µg/L growth rate
Test/Species EC10
EC50
Daphnia sp. Reproduction OECD 211 NOEC PM µg/L PM
Test
Fish, Early Life Stage Toxicity OECD 210 NOEC PM µg/L PM
Test/Species
Activated Sludge, Respiration OECD 209 EC10 >S w a µg/L S w < 56 µg/L
Inhibition Test EC50 >S w a µg/L
Phase IIb Studies
Bioaccumulation in fish OECD 305 BCF 2018 L/kg normalised to 5%
L. macrochirus 3241 L/kg lipids
Aerobic and anaerobic OECD 307 DT50 181 d extrapolated
transformation in soil %CO 2 1.1 % DT50;
one soil tested
Soil Microorganisms: Nitrogen OECD 216 %effect 8.9 % at 1250 mg/kg dw .
Transformation Test Not significant
acc. to OECD 216
criteria
Terrestrial Plants, Growth OECD 208 NOEC ≥197 mg/ emergence and
Test / kg growth,
P.sativum, R. sativus, Z. normalised to 2%
mays o.c.
Earthworm, Acute Toxicity OECD 207 LC50 >40 mg/ normalised to 2%
Tests kg o.c.
Collembola, Reproduction OECD 232 NOEC >40 mg/ reproduction and
Test kg mortality,
F. candida normalised to 2%
o.c.
Sediment dwelling organism / OECD 218 EC10= 2.7 mg/ total nr or midges
C. riparius NOEC kg and mortality
a
Since the water solubility (S w ) was not determined (reported as a < value), the result of the study cannot
be displayed correctly. Since no effect was observed at the highest tested concentration, the result is
displayed as >S w for practical reasons.
Regorafenib is potentially PBT (persistent, bioaccumulative and toxic). The criterion can only be
concluded after evaluation of the additionally requested aquatic studies. The substance is very
persistent (vP). It is also bioaccumulative, but not very bioaccumulative (vB).
The revised PECsurface water was calculated at 0.112 µg/L. The Koc will have to be determined
using an OECD 106 study. PECsoil and PECsediment can only be (re)calculated after the results
of this study are available. A risk to the STP (Sewage Treatment Plants) is considered unlikely.
Apart from the OECD 106 study, the dossier was complete. However the chronic studies with
algae, Daphnia and fish are considered unreliable, the results cannot be used in the risk
assessment. In conclusion, the risk assessment for the surface water, groundwater, soil and
sediment compartment cannot be completed.
In view of the nature of the molecule and in the light of the recommended further studies, the
CHMP is of the Opinion that a precautionary approach regarding the disposal of the medicine into
the environment needs to be adopted. The SmPC and PL have been updated accordingly.
In the context of the obligation of the MAH to take due account of technical and scientific
progress, the CHMP recommends the following points to be addressed:
– An adsorption/desorption study with 3 soils and 2 sludges (OECD 106)
– A toxicity study with a green algal species (OECD 201)
– A chronic toxicity study with Daphnia magna (OECD 211)
– A chronic toxicity study with fish; early life stage toxicity test (OECD 210).
2.3.6. Discussion on non-clinical aspects
Data from the in vitro and in vivo primary pharmacology studies indicate that regorafenib has
broad anti-tumour activity; however, it appears that there is significant variation in the response
of colon tumours to regorafenib treatment.
The pharmacological activity of regorafenib in animal species besides immunodeficient mice has
not been reported. It is assumed that regorafenib has the same activity in animals when
compared to humans. This assumption is supported by amino acid sequence homology and the
observed effects in animals. It is however not clear if the potency of regorafenib to inhibit the
different RTKs is similar across species. However, as treatment-related adverse effects were seen
in animals at exposures equal to or below the clinical exposure level, further studies on this issue
were not considered necessary.
Findings in the secondary pharmacology studies may indicate inhibition of VEGF-mediated signal
transduction which could be expected based on the tyrosine kinase inhibition profile. Additional
secondary activity studies were not submitted. However, as findings in the safety pharmacology
studies are considered to be consistent with the pharmacological activity of regorafenib, no
further studies were considered necessary.
Regarding the safety pharmacology, the in vitro concentrations of M2 and M5 at which significant
hERG K+ inhibition was observed were lower than the maximum concentration in plasma at
steady state for M2 (~6.7 µM) and M5 (~6.0 µM). However, due to the high protein binding, the
concentrations of unbound substance are much lower for both (M2: ~13 nM, M5: ~3.2nM) and
well below the concentration at which hERG K+ blockade can be expected. Moreover, no effects
on ECG parameters were seen in isolated rabbit cardiac Purkinje fibers exposed to regorafenib
and in four GLP-compliant studies in anaesthetised dogs.
In in vivo studies, no substantial adverse effects were seen on cardiovascular, respiratory, and
CNS function.
The kinetics of regorafenib was sufficiently investigated in mouse, rat, rabbit, dog and monkey.
The major animal species studied were rat and dog. Large interspecies differences were observed
making the extrapolation of the pre-clinical data to humans difficult.
Repeat dose toxicity with daily administration by oral gavage of regorafenib was evaluated in
mice (up to 5 weeks), rats (up to 26 weeks) and dogs (up to 52 weeks).
Studies in these species revealed a comparable toxicological profile characterised by

degenerative changes, frequently accompanied by regenerative and inflammatory processes in
multiple tissues in the range of or below the anticipated clinical exposure. Target organs are
largely consistent with those seen with other tyrosine kinase inhibitors and most effects are
considered to be of clinical relevance, as they occurred at systemic exposures in the range of or
below the anticipated human exposure (based on AUC comparison). After repeated dosing to
mice, rats and dogs, adverse effects were observed in a number of organs, primarily in the
kidneys, liver, digestive tract, thyroid gland, lympho /haematopoietic system, endocrine system,
reproductive system and skin.
Compared to dogs, rats and mice appear to be more sensitive regarding effects particularly on
kidneys, gastrointestinal tract, and teeth, but less sensitive regarding effects particularly on skin
and liver.
Prominent clinical signs in rats after repeated dosing consisted of changes in the teeth structure
with markedly increased growth. Histologically, dentin and amenoblast degeneration were
observed.
Alterations with regard to increased growth of teeth (histologically associated with dentin and
amenoblast degeneration) and bones (thickening of growth plate, chondrodystrophy) are related
to the pharmacological mode of action of regorafenib but are considered not to present a
potential risk for adult humans, because in adults these organs are not subject to growth.
However, they do indicate a potential risk for children and adolescents.
Furthermore, in the 6-month rat study, an increased incidence of thickening of the

atrioventricular valves of the heart was observed at 2 mg/kg. This effect was not observed in the
4 and 13 week study in rats using higher doses and it might be an accelerated age-related
physiological process. Monitoring of cardiovascular parameters including QT interval in the dog
repeat-dose studies revealed no adverse effects attributed to regorafenib.
Interstitial oedema and atrophy of the tongue were seen in mice and rats, respectively, and is of
unknown relevance. However, due to mucolytic activity of the compound, patients experiencing
pain in the mouth are suspended from treatment and an effect like atrophy is not expected.
Indeed, there were no reports of tongue atrophy or atrophic glossitis in the clinical trial program.
Clinical relevance of this finding is therefore unlikely.
Dogs developed bloody diarrhoea, emesis, alopecia, stomatitis and occasionally bleeding
gums/anaemia and swelling of eyelids. Hair growth arrest was observed together with other skin
alterations such as epidermal and follicular hyperkeratosis, parakeratosis, comedo formation,
acanthosis, hypergranulosis, pigment clumping, peri-folliculitis, crusts, fibrosis, lymphoid cell
infiltration and retention of sebaceous. In the 12-month study, female dogs showed additionally
signs of an effect on the hormone balance (increased incidence of vulva swelling, decreased
incidence of mammary complex swelling).
The severity and extent of adverse effects in the repeat dose toxicity studies were dependent on
dose and duration of exposure. The MTD declined with the prolongation of treatment in rats and
dogs.
Findings in serum chemistry, analysis of liver tissue, and urinalysis in the repeat-dose toxicity
studies with administration of regorafenib comprised changes indicating an influence on liver
function (increased serum transaminase and glutamate dehydrogenase (GLDH) activities,
increased bilirubin), kidneys (increased serum creatinin, proteinuria) and thyroid (increased
thyroid stimulating hormone [TSH], reduced T4). Haematology findings indicated slight but
inconsistent changes in red and white blood cell parameters (reduced erythrocyte counts,
haemoglobin, haematocrit; increased neutrophil counts; atypical leucocytes) and blood
coagulation (reduced or increased platelet counts; reduced clotting time).
Regorafenib was tested in a battery of genotoxicity tests, and was shown to have no genotoxic
potential. No carcinogenicity studies have been performed with regorafenib. This is in line with
ICH S9 guideline (Nonclinical Evaluation for Anticancer Pharmaceuticals,
EMEA/CHMP/ICH/646107/2008) and considered acceptable taking into account the intended
indication as well as the short life-expectancy of patients for which regorafenib is currently
intended.
Specific studies with regorafenib on fertility and early embryonic development were not
submitted. However, an impact of regorafenib can be expected based on the pharmacological
mode of action and findings in the general repeat-dose toxicity studies, i.e. morphological
changes in the testes, ovaries, and the uterus observed after repeated dosing in rats and dogs at
exposures below the anticipated human exposure (based on AUC comparison). The observed
changes were only partially reversible. Pilot embryo-foetal toxicity studies have been performed
in two species, rats and rabbits, whereas the main study was only performed in rabbits. This is
acceptable, since it was shown that regorafenib is embryolethal and teratogenic in rabbits, and
therefore confirmation in a second species is not considered necessary. Of note, teratogenicity
was also seen in the rat pilot study.
There are no data on the effect of Stivarga on human fertility. Women of childbearing potential
must be informed that regorafenib may cause foetal harm. Effective contraception in men and
women should be ensured during treatment and up to 8 weeks after completion of therapy.
There are no data on the use of regorafenib in pregnant women. Stivarga should not be used
during pregnancy unless clearly necessary and after careful consideration of the benefits for the
mother and the risk to the foetus. Finally, it is unknown whether regorafenib or its metabolites
are excreted in human milk. In rats, regorafenib or its metabolites are excreted in milk. A risk to
the breast fed child cannot be excluded. Breast feeding must be discontinued during treatment
with Stivarga.
No pre- and postnatal development or juvenile toxicity studies were performed with regorafenib
in line with the ICH S9 guideline which was considered acceptable.
Special investigations on the immunotoxic potential of regorafenib performed in the frame of the
13-week rat study (splenic cell count, FACS analysis, total anti-body titre, plaque forming cell
assay after immunisation) revealed no indication for a toxicologically relevant effect.
Regorafenib was found to be probably phototoxic in vitro. As there is no appropriate animal

model for in vivo studies, no further studies were deemed necessary. Of note, no relevant signals
emerged from the clinical studies.
One impurity tested positive in the Ames test and Comet assay, but negative in the Micronucleus
test. Since these tests evaluate different endpoints, a negative Micronucleus test does not
overrule the Ames test, and the impurity may be considered as possibly mutagenic. Because the
indication of regorafenib does allow for higher limits of impurities, and the results of the
genotoxicity tests also indicate only a weak genotoxic potential with unlikely relevance for
humans, the proposed specification limit is acceptable.
In terms of local tolerance, various morphological changes (in particular signs of degenerative
and regenerative processes in the stomach and duodenum in mice and rats) and clinical signs of
gastrointestinal intolerance (bloody diarrhoea and emesis in dogs) were noted in the
gastrointestinal tract of animals treated orally by gavage. The observed effects are most likely
due to the expected mechanism-related impact of regorafenib on rapidly dividing cells.
Regorafenib is potentially PBT (persistent, bioaccumulative and toxic). The criterion can only be
concluded after evaluation of the additionally requested aquatic studies. The substance is very
persistent (vP). It is also bioaccumulative, but not very bioaccumulative (vB).
The revised PEC surface water was calculated at 0.112 µg/L. The K oc will have to be determined using
an OECD 106 study. PEC soil and PEC sediment can only be (re)calculated after the results of this
study are available. A risk to the STP (Sewage Treatment Plants) is considered unlikely. Apart
from the OECD 106 study, the dossier was complete. However the chronic studies with algae,
Daphnia and fish are considered unreliable, the results cannot be used in the risk assessment. In
conclusion, the risk assessment for the surface water, groundwater, soil and sediment
compartment cannot be completed. In the light of this outcome, the CHMP agreed that
precautionary statements in the product information regarding the disposal of the medicine into
the environment have to be adopted and the SmPC and PL were updated in accordance.
2.3.7. Conclusion on the non-clinical aspects
From the non-clinical standpoint, there are no major objections against authorisation, however
additional data is needed for completion of the environmental risk assessment.
2.4. Clinical aspects
2.4.1. Introduction
Regorafenib is indicated for the treatment of patients with metastatic colorectal cancer (CRC)
who have been previously treated with, or are not considered candidates for, fluoropyrimidine-
based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy.
The recommended dosing regimen is an intermittent dosing schedule: 160 mg qd for 3 weeks
followed by 1 week without regorafenib medication (3/1 week(s) on/off).
GCP
The Clinical trials were performed in accordance with GCP as claimed by the applicant.
The applicant has provided a statement to the effect that clinical trials conducted outside the
community were carried out in accordance with the ethical standards of Directive 2001/20/EC.
• Tabular overview of clinical studies
Table 3: Overview of clinical studies with regorafenib
Study no. Type of study Tumour type Dosing No. of patients

Phase 1: Regorafenib in healthy volunteers
12435 Effect of ketoconazole on PK of N/A Regorafenib 80 and 160 mg single dose 24
regorafenib (4 x 40 mg tablets)
Ketoconazole 400 mg
12436 PK, metabolism, excretion, N/A Single dose of 120 mg regorafenib 4
mass balance solution containing approximately 1.5 mg
of 14C-radiolabeled regorafenib
12437 Relative bioavailability N/A 2 single doses of 160 mg 48
1 x 100 mg tablets + 3 x 20 mg tablets
compared to
4 x 40 mg tablets#
14656 Bioavailability, high-fat vs. low- N/A 3 single doses of 160 mg 24
fat breakfast vs. fasting state (4 x 40 mg tablets)
effect on PK
15524 Effect of rifampin (rifampicin) on N/A Regorafenib 160 mg single dose 24
PK of regorafenib (4 x 40 mg tablets)
Rifampin (rifampicin) dose 600 mg
Phase 1: Regorafenib as single agent in cancer patients

11650 Dose escalation, PK, PD, Advanced solid Regorafenib 10 – 220 mg od 76 (of which 39
tumour response, safety tumours CRC patients)
(3 weeks on / 1 week off)#
11651 Dose escalation, Advanced solid Regorafenib 20 – 140 mg od 84
Study no. Type of study Tumour type Dosing No. of patients
PK, safety tumours continuous dosing#
12434 Probe substrate, PK, safety Advanced solid Regorafenib 160 mg, od Group A: 20
tumours (4 x 40 mg tablets) (planned)
intermittent dosing schedule 6 (actual)
Group B: 20
Group A: Warfarin 10 mg, Omeprazole (planned),
40 mg, Midazolam 2 mg
10 (actual)
Group B: Rosiglitazone 4 mg
13172 PK, safety Advanced and Regorafenib 160 mg od(4 x 40 mg 16
refractory solid tablets)#
tumours
(3 weeks on / 1 week off)#
14814 Cardiovascular safety (QT/QTc, Advanced solid Regorafenib 160 mg od 54
LVEF), PK, safety tumours (4 x 40 mg tablets)
14996 PK, safety Advanced and Regorafenib 160 mg od 24
refractory solid (4 x 40 mg tablets)
tumours
Phase 1: Regorafenib combined with other medicinal products in cancer patients

11656 PK, safety Metastatic CRC 1st Regorafenib 160 mg od# 45
or 2nd line on days 4–10 and
18–24 of every 4 week cycle
Plus mFOLFOX6 or FOLFIRI
Phase 2: Regorafenib in cancer patients

11726 Uncontrolled, Metastatic or Regorafenib 160 mg od: 49
single-arm study, efficacy, unresectable renal
safety, PK cell cancer (1 x 100 mg tablets + 3 x 20 mg tablets
(previously untreated or
patients) 4 x 40 mg tablets)#
14596 Uncontrolled, Hepatocellular Regorafenib 160 mg od 36
single-arm study, safety, cancer (4 x 40 mg tablets)
efficacy, PK
Phase 3: Regorafenib in metastatic CRC patients

14387 Randomized, double-blind, Metastatic CRC Regorafenib 160 mg od 760
placebo-controlled study; (progressed after (4 x 40 mg tablets) Regorafenib: 505
regorafenib + BSC vs. placebo, standard therapy)
efficacy, safety, PK, biomarkers intermittent dosing schedule
(3 weeks on / 1 week off) Placebo:
255
Matching placebo
2.4.2. Pharmacokinetics
Regorafenib pharmacokinetics was evaluated following oral administration of single doses to

healthy volunteers and single or multiple doses to cancer patients. In the evaluation of the
pharmacokinetics of regorafenib, consideration needs to be given to the fact that two metabolites
of regorafenib, M-2 and M-5, have demonstrated in vitro pharmacologic activity similar to that of
unchanged regorafenib. Therefore, the evaluation of metabolite PK for M-2 and M-5 was included
in all PK studies.
Overall, 11 Phase 1 trials have been conducted with regorafenib as a single-agent: 5 in healthy
volunteers and 6 in advanced cancer patients. The healthy volunteer studies were conducted
using single doses of regorafenib and included a total of 124 subjects in Europe and the USA
addressing the relative bioavailability of the final tablet formulation (study 12437), food effect
(study 14656), mass balance and metabolite profile (study 12436), and the interaction of
regorafenib with ketoconazole and rifampin (studies 12435 and 15524, respectively).
Two of the Phase 1 studies in patients with advanced solid tumours were dose escalation studies
to define the maximum tolerated dose of two different dosing schedules: intermittent dosing - 3
weeks on / 1 week off treatment (study 11650) and continuous dosing (study 11651). The
recommended Phase 2 dose of 160 mg in the intermittent dosing schedule was applied in the two
Asian trials (14996 and 13172, both in patients with advanced solid tumours). Finally, a cocktail
drug drug interaction study (12434), and a study (14814) to evaluate cardiovascular safety were
conducted.
Adequately validated methods were used to analyse regorafenib and metabolites M-2 and M-5 in
plasma and urine.
Absorption
Following oral administration of a single 160 mg dose with tablets, regorafenib is absorbed with a
median t max ranging from approximately 3 to 4 hours with a mean maximum concentration
(C max ) of 2.5 mg/L. The plasma concentration time curve was characterised by multiple peaks
and slow elimination of regorafenib. After a single dose of 160 mg, plasma concentrations of the
two active metabolites M-2 and M-5 were below those of parent compound. However, after
multiple dosing at Day 21, due to the nonlinear accumulation of metabolites, plasma
concentrations were similar for parent drug and metabolites.
Due to the insolubility of the drug substance in aqueous media without surfactant, no i.v.
solution (for human use) was developed to conduct an absolute bioavailability (BA) study.
Following single dose administration of 60 and 100 mg doses, the relative bioavailability of the
final solid solution formulation of regorafenib tablets was approximately 70% -83% of the 2%
w/v oral solution. Comparative bioavailability of conventional immediate release tablets was
<10% of the oral solution, therefore conventional immediate release tablets were not used in the
clinical studies. All studies were conducted with solid solution tablets or in some phase 1 studies
as 2% w/v solution. Based on results in mass balance study 12436, showing 19% of radioactivity
excreted in urine and 24% excreted in faeces in the form of metabolites following single dose
administration of 120 mg oral solution, it can be estimated that at least 30-35% of regorafenib is
being absorbed following administration of solid solution tablets.
In vitro investigations using a validated Caco-2 assay showed that regorafenib belongs to the
class of highly permeable substances. Regorafenib therefore classifies as a Class II drug
according to the criteria of the Biopharmaceutical Classification System (BCS).
Relative bioavailability and bioequivalence of different regorafenib formulations employed in the
course of clinical development was demonstrated (data not shown).
Bioavailability (AUC) of regorafenib was increased by approximately 48% and 36% when
administered with a high-fat and low-fat breakfast, respectively, compared with dosing under
fasting conditions (study 14656). Corresponding increases in C max were 73% (high fat) and 54%
(low-fat). AUC and Cmax of the metabolites M-2 and M-5 were higher when regorafenib was
given with a low fat breakfast compared to fasting conditions and lower when given with high fat
meal compared to fasting conditions. The highest cumulative exposure of regorafenib and its
metabolites was achieved when administered following a low fat breakfast.
Distribution
From Study 11650 the reported geometric mean volume of distribution for the 120 mg and
160 mg tablet doses was 99 L (range 87-137L) and 93 L (range 37-178 L), respectively. In
human blood, regorafenib was mainly distributed into plasma with a concentration ratio
(plasma/blood) (Cp/Cb) of 1.59 in the concentration range 1.49 to 40.7 mg/L.
Regorafenib, M-2 and M-5 are highly bound to plasma proteins > 99% over a therapeutically
relevant concentration range. In vitro binding experiments showed that regorafenib was not
displaced from the binding site by warfarin, taxol, salicylic acid, gefitinib, ibuprofen, digitoxin,
cisplatin, furosemide, nifedipine, propranolol, and docetaxel at clinically relevant concentrations.
Quantitative tissue distribution studies in rats involving oral or intravenous administration of

[14C] regorafenib revealed that radioactivity was thoroughly distributed to almost all organs and
tissues. Blood concentrations of radioactivity were similar to the concentrations found in most
organs and tissues. Blood-brain barrier penetration was low.
Elimination
Regorafenib was eliminated from plasma with a half-life of 20 to 40 hours following a single oral
dose in healthy volunteers and in cancer patients. A similar range of half-life estimates (20 – 30
hours) was found for metabolite M-2. The elimination half-life of M-5 was slower, averaging
approximately 60 hours, with individual values ranging from 40 to 100 hours.
In study 12436, it was shown that regorafenib was excreted in urine and faeces as unchanged
drug and metabolites after oral administration of 120 mg [14C]regorafenib solution to four
healthy volunteers. Renal elimination of total radioactivity accounted for approximately 19% of
dose, while approximately 71% of the dose was recovered in faeces as both unchanged drug
(47%) and metabolites (24%). Urinary excretion of radioactivity was almost complete by
72 hours post-dose, whereas excretion via faeces continued until 144 hours post-dose, after
which the rate of excretion exhibited a near plateau. While M-2 and M-5 are the metabolites
circulating in plasma, M-7 and M-8 (glucuronides of regorafenib and M-2, respectively) are
excreted in urine. In faeces, regorafenib was the most predominant metabolite followed by M-6
and M-7.
In another study (11650), following administration of a 120 mg tablet at steady state (Day 21),
a mean of 8.4% of the dose was recovered in urine over 24 hours as either M-8 (1.6%) or M-7
(6.8%). The corresponding excretion for the 160 mg tablet dose was lower, 0.5% as M-8 and
1.9% as M-7.
Regorafenib undergoes extensive and complex metabolism, including oxidation and

glucuronidation. In man, CYP3A4 is the major CYP isoform for phase I (oxidative) metabolism of
regorafenib to form M-2 and M-3. M-2 and M-3 are further metabolised to M-5. Glucuronidation
of regorafenib was catalysed by human liver and kidney microsomes fortified with UGPGA. UDP-
glucuronosyltransferase (UGT) 1A9 was identified to be responsible for conjugation of
regorafenib with glucuronic acid, to form M-7. M-5 is not further metabolised but reduction to
M-4 may take place by microflora in the gut. Also the metabolites M-7, M-8 and M-2 may be
reduced and/or cleaved in the intestinal milieu to form regorafenib resulting in enterohepatic
cycling in vivo.
Dose proportionality and time dependencies
The pharmacokinetics of regorafenib at different doses from oral solution and tablet dosage form
was investigated in studies 11650 (doses 10-220 mg, intermittent schedule) and 11651 (20-
140 mg, continuous administration). Following single dose administration, AUC and Cmax of
regorafenib increased with increasing dose, though not in proportion to dose. Administration of a
solution (10-120 mg) resulted in dose-dependent increases in systemic exposure up to the 100
mg dose while a linear increase in exposure was not achieved when escalating to 120 mg
solution. Regorafenib was administered as solid solution tablets at doses of 60, 100, 120, 160,
and 220 mg to separate cohorts of cancer patients. AUC(0-tlast), and Cmax values were
consistent with dose proportionality over the dose range of 60 to 160 mg after a single dose.
Plasma concentrations of the two major metabolites M-2 and M-5 were measured along with
parent drug. At low doses (below 60 mg), the plasma concentrations of both metabolites after a
single dose of regorafenib were lower than those of regorafenib. A sharp increase in metabolite
exposure was seen when the dose was increased from 30 to 60 mg. A more gradual increase up
to 220 mg dose was observed.
Following multiple dose administration, regorafenib exposure at steady-state seemed not to

increase significantly at doses ≥ 60 mg. At doses < 60 mg, the plasma concentrations of both
metabolites was relatively low but increased at doses ≥ 60 mg. Pharmacokinetics of regorafenib,
M-2 and M-5 is not dose proportional after multiple dosing.
Time dependent pharmacokinetics was assessed by comparing pharmacokinetics of regorafenib,

M-2 and M-5 at day 21 with single dose administration of 160 mg regorafenib in study 11650.
Mean steady-state Cmax,ss and AUC(0-24)ss values following dosing with 160 mg were 3.9 mg/L
and 58.0 mg*hr/L, respectively. The accumulation of regorafenib at steady-state was
approximately 2-fold as expected considering the mean elimination half-life of 20 – 40 hours.
Plasma concentrations of both metabolites were below those of parent compound following single
dose administration but by Day 21, plasma concentrations were similar for parent drug and
metabolites due to the nonlinear accumulation of metabolites. Accumulation was greater for M-2
(5-fold) and M-5 (up to 67-fold) than for regorafenib itself.
Special populations
In study 11650, PK analyses were performed on subgroups of patients based on renal function.
No consistent differences in AUC or Cmax were found between patients with mild renal
impairment and those with normal renal function. When pooling phase 1/2 studies, the mean
AUC(0-24)ss of 38 mgh/L for the normal renal function group was considerably lower than the
value of 50 – 60 mgh/L seen in healthy volunteers with normal renal function. No trends were
observed for M-2 and M-5.
The effect of hepatic impairment on pharmacokinetics of regorafenib, M-2 and M-5 was studied in
hepatocellular carcinoma patients in study 11651 and in study 14596. Mild and moderate hepatic
impairment did not affect regorafenib, M-2 and M-5 pharmacokinetics following single dose
administration. PK of regorafenib, M-2 and M-5 at steady-state has been estimated by
population-based PK modelling. The effect of hepatic impairment on the PK was estimated. It
was estimated that exposure to regorafenib increased 2.2-fold in patients with moderate hepatic
impairment.
Pharmacokinetics of regorafenib was similar in males and females.
Analysis of ethnic differences in PK focused on Asians and Caucasians. Separate studies were
conducted in Japanese (Study 13172), Chinese (Study 14996), and Korean (Study 14596)
cancer patients in which regorafenib was administered at a dose of 160 mg daily and PK data
were collected. The exposure of regorafenib in various Asian populations (Chinese, Japanese,
Korean) is within the same range as seen in Caucasians.
Analysis of pooled Phase 1/2 data showed a trend toward increased exposure at higher body
weights.
The PK of regorafenib was not dependent on age. Mean steady-state AUC(0-24) and Cmax values
of regorafenib for patients 65 years were similar to those for patents < 65 years. Although
mean values suggested a higher exposure of M-2 and M-5 in patients > 65 years, there was no
obvious trend.
Pharmacokinetic interaction studies
Study 12435 was a single-centre, non-randomised, open-label 2-period cross-over study

evaluating the effect of 400 mg ketoconazole, a strong CYP3A4 inhibitor, on the
pharmacokinetics of 80 mg and 160 mg regorafenib single doses. Each subject received two
single oral doses of regorafenib with an 18-day washout period between administrations.
There was a 33% increase in mean regorafenib AUC and a 40% increase in mean Cmax following
a 160 mg dose of regorafenib when given with ketoconazole. Following administration of 160 mg
regorafenib, there was a 94% decrease in mean M-2 AUC and a 97% decrease in mean Cmax
upon concomitant administration with ketoconazole. Similar to M-2, the mean M-5 AUC
decreased 93% and the mean Cmax decreased 93% following administration of 160 mg
regorafenib with ketoconazole. A similar pattern of inhibition was seen for regorafenib as well as
M-2 and M-5 for the 80 mg dose of regorafenib.
Study 15524 was a single-centre, non-randomised, open-label 2-period cross-over study
evaluating the effect of 600 mg rifampicin on the pharmacokinetics of 160 mg regorafenib single
dose. Each subject received two single oral doses of regorafenib with a 14-day washout period
between administrations.
There was a statistically significant decrease in both AUC and Cmax (approximately 50% and
20% in mean, respectively) of regorafenib, when administered concomitantly with rifampicin.
There was no significant change in metabolite M-2 AUC as the 90% confidence interval included
100%, although there was a significant increase in Cmax (58%) when regorafenib was
administered concomitantly with rifampicin. There was a greater than 3-fold increase in
metabolite M-5 AUC and greater than 4-fold increase in Cmax when regorafenib was administered
concomitantly with rifampicin.
A probe substrate study was performed (Study 12434) to evaluate the effect of regorafenib on
the pharmacokinetics of probe substrates of CYP2C8 (rosiglitazone), CYP2C9 (s-warfarin),
CYP2C19 (omeprazole) and CYP3A4 (midazolam). No meaningful effects on the PK of
rosiglitazone, S-warfarin, omeprazole and midazolam were observed.
A drug-drug interaction study was performed (Study 11656) evaluating the combination of
regorafenib with mFOLFOX6 (oxaliplatin/folinic acid/5-FU) or FOLFIRI (irinotecan/folinic acid/5-
FU). On Days 4 - 10 and 18 - 24, patients received 160 mg regorafenib once daily for Cycles 1-6.
For Cycle 7 onward, regorafenib was administered in a 21 days on / 7 days off schedule. A cycle
was defined as 28 days. Both irinotecan and SN-38, its active metabolite, had significantly higher
AUCs in Cycle 2 compared to Cycle 1, i.e. they were higher when given 5 days after regorafenib
treatment compared with administration without preceding regorafenib administration. For
irinotecan, the AUC in the presence of regorafenib was increased 28% with a 90% confidence
interval of 107 to 154%; and for SN-38, the AUC in the presence of regorafenib was increased
44% with a 90% confidence interval of 112 to 185%. There were no significant differences with
respect to Cmax.
Pharmacokinetics using human biomaterials
Regorafenib exhibited no inductive potential on major CYP isoforms (e.g. CYP1A2 and 3A4).
Regorafenib potently inhibited CYP2C8 (Ki = 0.6 µM), and also considerably inhibited CYP2C9
(Ki = 4.7 µM) and CYP2B6 (Ki = 5.2 µM). The inhibitory potency towards CYP3A4 (Ki = 11.1 µM)
and CYP2C19 (Ki = 16.4 µM) was less pronounced. Regorafenib is an inhibitor of Pgp and BRCP.
M-2 potently inhibited CYP2C8 (Ki = 1.0 µM) and CYP2C9 (Ki = 0.8 µM with diclofenac as
substrate) and also considerably affected CYP3A4 (Ki = 4.0 µM, testosterone as substrate) as
well as CYP2D6 (K = 7.8 µM). Weak to moderate inhibitory potency was observed for M-2
towards CYP2B6 (IC50 = 20 µM), and CYP3A4 (IC50 = 22 µM with midazolam as substrate).
M-5 potently inhibited CYP2C8 (Ki = 1.3 μM), whereas CYP2B6 was weakly inhibited (IC50 = 47
µM). M-5 did not alter the activities of CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1,
and CYP3A4. Additionally, no significant time-dependent inhibition on CYP3A4 following 30 min
pre-incubation of M-5 with NADPH-supplemented human liver microsomes was observed.
2.4.3. Pharmacodynamics
Mechanism of action
No clinical studies addressing the mechanism of action were submitted.
Primary and Secondary pharmacology
Biomarkers evaluation in the clinical studies included KRAS mutational status (dose finding study
11650 and pivotal phase 3 study 14387-CORRECT) and plasma protein levels VEGF and VEGFR2
in studies 11650 and 11726 in RCC patients and dynamic contrast-enhanced MRI (DCE-MRI) in
study 11650. Additionally, in the pivotal study, genetic biomarker analyses were performed: the
mutational status of three proto-oncogenes commonly associated with CRC (KRAS, PIK3CA and
BRAF) was evaluated. Plasma protein biomarkers evaluated included those associated with
angiogenesis (ANG-2, IL-6, IL-8, PlGF, VEGFR-1, TIE-1, VEGF-A, VEGF-C, VEGF-D, VEGFA- 121),
as well others with known or hypothesised roles in CRC pathogenesis (BMP-7, VWF, M-CSF, SDF-
1 and TIMP-2).
KRAS mutational status was evaluated in two studies: the dose finding study 11650 and the
pivotal phase 3 study 14387 (CORRECT). In Study 11650 (Phase 1 mCRC), KRAS mutational
status was evaluated using plasma DNA. Plasma samples from 54% (20/37) of the evaluable
patients were found to be KRAS mutant and 46% (17/37) were found to be KRAS wild type. The
median PFS was 84 days for KRAS mutant patients and 161 days for KRAS wild type patients. In
Study 14387 (pivotal Phase 3 mCRC), historical (pre-existing) KRAS mutational data was
available from 96% (729/760) of all randomised patients, of which 59% (430/729) were
reported as KRAS mutant and 41% (299/729) as KRAS wild type. Subgroup analyses evaluating
PFS by KRAS mutational status showed trends in favour of regorafenib-treated patients in both
KRAS wild type and KRAS mutant subgroups [KRAS wild type: HR of 0.475 (95% CI: 0.362,
0.623); KRAS mutant: HR of 0.525 (95% CI: 0.425, 0.649)]. Correlative analysis also indicated
a trend towards a survival benefit for regorafenib as compared to placebo in the KRAS wild type
subgroup (regorafenib/placebo HR: 0.653 [95% CI: 0.476, 0.895]) as well as in the KRAS
mutant subgroup (regorafenib/placebo HR: 0.867 [95% CI: 0.670, 1.123]).
PIK3CA mutational status was available from 66% of all randomised patients, of which 17% were
PIK3A mutant and 83% were PIK3CA wild type. Correlative analysis for OS indicated trends in
favour of regorafenib in both PIK3CA wild type (regorafenib/placebo HR: 0.75 [95% CI: 0.57,
0.99]) and PIK3CA mutant (regorafenib/placebo HR: 0.84 [95% CI: 0.47, 1.50]) subgroups. The
interaction p-value among these subgroups was 0.723, indicating no significant difference in
regorafenib clinical efficacy (vs. placebo) related to PIK3CA mutational status. BRAF mutational
status was determined from 66% of all randomised patients, of which 3.4% were BRAF mutant
and 96.6% were BRAF wild type. Due to the small number of BRAF mutant patients, a correlative
analysis was not conducted based on BRAF mutational status.
Data from study 11650 and study 11726 revealed biological effects of regorafenib treatment that
were in line with the activity of this compound at inhibiting VEGF signalling, i.e. increased levels
of VEGF and decreased levels of VEGFR2 with regorafenib treatment. In study 11650, increased
levels of VEGF and decreased levels of VEGFR2 with regorafenib treatment were observed with
regorafenib doses ≥ 60 mg. A DCE-MRI was performed at baseline, on Day 2 of Cycle 1, Day 21
of Cycles 1 - 4 and afterwards every second cycle, as well as at the final visit to assess tumour
blood flow / tumour vessel permeability in a subgroup of patients. A decrease in the iAUC60 for
the gadolinium curve as measured by DCE-MRI was observed at regorafenib doses ≥ 120 mg.
In study 11726, levels of VEGF increased and VEGFR2 decreased with regorafenib treatment. The
consistency of the change in VEGFR2 is exemplified by the finding that each of the 28 patients
evaluated exhibited a decrease in plasma VEGFR2 levels with regorafenib treatment. Other
plasma proteins were found to be altered with regorafenib treatment. Some of these proteins
have been linked to angiogenesis (TIE1, ANG2), where others represent kinase receptors
inhibited by regorafenib (c-KIT) or proteins released following apoptotic cell death (CK18M30).
A dedicated cardiovascular study of advanced cancer patients (Study 14814) was conducted to
evaluate cardiovascular safety for the 160 mg once daily dosing with regorafenib. Fifty-four (54)
patients were enrolled in this cardiovascular safety study and all patients received at least one
dose of 160 mg once daily regorafenib in this clinical evaluation of potential changes in QT/QTc
on ECG and in LVEF. The primary variable with regard to QT/QTc was the change in QTcF from
the tmax of regorafenib on Cycle 1 or 2, Day 21 to the average of the baseline QT intervals from
the ECGs collected over 24 hours on Cycle 1, Day -1, and corrected using Fridericia's method for
heart rate correction; Bazett’s correction was also calculated. In addition, left ventricular ejection
fraction (LVEF) was to be assessed by MUGA (multi gated acquisition) scan at baseline and at
least once under on-going regorafenib treatment, typically after a minimum 2 cycles of
regorafenib treatment.
The range of AUC and Cmax values in this study fall within the full range of that seen in previous
studies, and the median tmax (3 hours) is also similar to that seen in other studies. At the tmax
of regorafenib, the mean changes from baseline in QTcB and QTcF were -1 and 2 msec,
respectively and in both cases, the 90% confidence interval did not include the value 10 msec.
Additionally, a secondary analysis of the QT/QTc variables evaluated the maximal change from
baseline in QTcB and QTcF over the 24-hour measurement period on Day 21. Results for the
QTcB and QTcF maximal median change from baseline were 7 and 9 msec, respectively. No
patient had a QTcB or QTcF value > 500 msec during the post-treatment Holter monitoring visits
(at Cycle 1 or 2, Day 21).
2.4.4. Discussion on clinical pharmacology
Regorafenib reaches mean peak plasma levels of about 2.5 mg/l at about 3 to 4 hours after a
single oral dose of 160 mg given as 4 tablets each containing 40 mg. Following single doses of
60 mg or 100 mg, the average relative bioavailability of tablets compared to an oral solution was
69% and 83%, respectively.
Two metabolites of regorafenib, M-2 and M-5, have demonstrated in vitro pharmacologic activity
similar to that of unchanged regorafenib. Although regorafenib, M-2 and M-5 have shown similar
activity in vitro, the contribution of each moiety to clinical efficacy and toxicity is not known.
Systemic exposure of regorafenib at steady state increases dose proportionally up to 60 mg and
less than proportionally at doses greater than 60 mg. Accumulation of regorafenib at steady
state results in about a 2 fold increase in plasma concentrations, which is consistent with the
elimination half-life and dosing frequency. At steady state, regorafenib reaches mean peak
plasma levels of about 3.9 mg/L (8.1 micromolar) after oral administration of 160 mg
regorafenib and the peak to trough ratio of mean plasma concentrations is less than 2. On the
other hand, both metabolites, M 2 and M 5, exhibit non-linear accumulation, which might be
caused by entero-hepatic recycling or saturation of the UGT1A9 pathway discussed below.
This supports the dose selection for which maximal exposure to all three active moieties was
taken into consideration. The increase in total exposure to the 3 active moieties may also
support the 3/1 on/off schedule over the continuous schedule because higher plasma
concentrations of combination regorafenib, M-2 and M-5 can be achieved with the 160 mg dose
compared to the 100 mg dose and also a higher cumulative exposure of regorafenib and its
metabolites can be obtained with the 160 mg 3/1 on/off schedule. Finally, whereas plasma
concentrations of M 2 and M 5 after a single dose of regorafenib are much lower than those of
parent compound, steady state plasma concentrations of M 2 and M 5 are comparable to those of
regorafenib.
The concentrations of regorafenib and its major pharmacologically active metabolites (M-2 and
M-5) were highest when given after a low fat (light) breakfast as compared to either a high fat
breakfast or fasting condition. The exposure for regorafenib was increased by 48% when
administered with a high fat breakfast, and 36% when administered with a low fat breakfast,
compared to fasting. The exposure of metabolites M-2 (N oxide) and M-5 (N oxide and
N desmethyl) is higher when regorafenib is given with a low fat breakfast as compared to fasting
condition and lower when given with a high fat meal as compared to fasting condition.
The increase in exposure of regorafenib following intake of food is in line with the poor solubility
characteristics of regorafenib. Alternatively, food constituents may enhance absorption of
regorafenib. To maximize exposure to parent drug as well as to the active metabolites it is
recommended for regorafenib to be dosed after a low-fat (light) meal. This was consistently
recommended in the clinical studies.
Plasma concentration-time profiles for regorafenib as well as for the major circulating
metabolites showed multiple peaks across the 24-hour dosing interval, which are attributed to
enterohepatic circulation. In vitro protein binding of regorafenib to human plasma proteins is
high (99.5%).In vitro protein binding of M-2 and M-5 is higher (99.8% and 99.95%,
respectively) than that of regorafenib.
Metabolites M-2 and M-5 are weak substrates of P-gp. Metabolite M-5 is a weak BCRP-substrate.
Regorafenib is metabolised primarily in the liver by oxidative metabolism mediated by CYP3A4,

as well as by glucuronidation mediated by UGT1A9. Two major and six minor metabolites of
regorafenib have been identified in plasma. The main circulating metabolites of regorafenib in
human plasma are M-2 (N oxide) and M-5 (N oxide and N desmethyl), which are
pharmacologically active and have similar concentrations as regorafenib at steady state. M-2 is
further metabolised by oxidative metabolism mediated by CYP3A4, as well as by glucuronidation
mediated by UGT1A9. Metabolites may be reduced or hydrolysed in the gastrointestinal tract by
microbial flora, allowing reabsorption of the unconjugated active substance and metabolites
(enterohepatic circulation). Co administration of antibiotics that affect the flora of the
gastrointestinal tract may interfere with the enterohepatic circulation of regorafenib and may
result in a decreased regorafenib exposure. The clinical significance of these potential
interactions is unknown, but may result in a decreased efficacy of regorafenib.
Moreover, bile salt-sequestering agents such as cholestyramine and cholestagel may interact
with regorafenib by forming insoluble complexes which may impact absorption (or reabsorption),
thus resulting in potentially decreased exposure. The clinical significance of these potential
interactions is unknown, but may result in a decreased efficacy of regorafenib.
Administration of ketoconazole (400 mg for 18 days), a strong CYP3A4 inhibitor, with a single
dose of regorafenib (160 mg on day 5) resulted in an increase in mean exposure (AUC) of
regorafenib of approximately 33%, and a decrease in mean exposure of the active metabolites,
M 2 (N oxide) and M 5 (N oxide and N desmethyl), of approximately 90%. It is recommended to
avoid concomitant use of strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit
juice, itraconazole, ketoconazole, posaconazole, telithromycin and voriconazole) as their
influence on the steady state exposure of regorafenib and its metabolites has not been studied.
Co-administration of a strong UGT1A9 inhibitor (e.g. mefenamic acid, diflunisal, and niflumic
acid) during regorafenib treatment should be avoided, as their influence on the steady-state
exposure of regorafenib and its metabolites has not been studied.
Administration of rifampicin (600 mg for 9 days), a strong CYP3A4 inducer, with a single dose of
regorafenib (160 mg on day 7) resulted in a reduction in AUC of regorafenib of approximately
50%, a 3 to 4 fold increase in mean exposure of the active metabolite M 5, and no change in
exposure of active metabolite M 2. Other strong CYP3A4 inducers (e.g. phenytoin,
carbamazepine, phenobarbital, St. John’s wort) may also increase metabolism of regorafenib.
Strong inducers of CYP3A4 should be avoided, or selection of an alternate concomitant medicinal
product, with no or minimal potential to induce CYP3A4 should be considered.
In vitro data indicate that regorafenib as well as its active metabolite M 2 inhibit glucuronidation
mediated by UGT1A1 and UGT1A9 whereas M 5 only inhibits UGT1A1 at concentrations which are
achieved in vivo at steady state. Administration of regorafenib with a 5 day break prior to
administration of irinotecan resulted in an increase of approximately 44% in AUC of SN 38, a
substrate of UGT1A1 and an active metabolite of irinotecan. An increase in AUC of irinotecan of
approximately 28% was also observed. This indicates that co administration of regorafenib may
increase systemic exposure to UGT1A1 and UGT1A9 substrates.
Following oral administration, mean elimination half-life for regorafenib and its metabolite M 2 in
plasma ranged from 20 to 30 hours in different studies. The mean elimination half-life for the
metabolite M 5 is approximately 60 hours (range from 40 to 100 hours).
Approximately 90% of the radioactive dose was recovered within 12 days after administration,
with about 71% of the dose excreted in faeces (47% as parent compound, 24% as metabolites),
and about 19% of the dose excreted in urine as glucuronides. Urinary excretion of glucuronides
decreased below 10% under steady state conditions. Parent compound found in faeces could be
derived from intestinal degradation of glucuronides or reduction of metabolite M 2 (N oxide), as
well as unabsorbed regorafenib.
The inter- and intra-individual variability in exposure to regorafenib, M-2 and M-5 is rather high.
A pop PK analysis was used to evaluate covariate effects in study 14387 and to derive exposure
parameters which can be used for exposure-response analysis of this study. Intrinsic factors
identified during the covariate analysis of the population PK evaluation were baseline bilirubin for
regorafenib, baseline bilirubin and body weight for M-2, as well as baseline bilirubin, body weight
and sex for M-5. Bilirubin and weight increased exposure to regorafenib and M-2 by 20%. M-5
exposure was 77% higher in females than males but overall, the covariates did reduce the
variability only modestly.
Overall, age did not affect the regorafenib pharmacokinetics over the studied age range (29 – 85
years). The pharmacokinetics of regorafenib is not influenced by gender. The exposure of
regorafenib in various Asian populations (Chinese, Japanese, Korean) is within the same range as
seen in Caucasians.
No major difference in pharmacokinetics in mild and moderate hepatic impairment following

single dose administration of 100 mg regorafenib was observed. No data were available for
pharmacokinetics in hepatic impairment following multiple dose administration because most
patients had dose interruptions or needed a dose reduction during the first cycle. PK of
regorafenib, M-2 and M-5 at steady-state has been estimated by popPK modelling. The effect of
hepatic impairment on the PK was estimated. It was estimated that exposure to regorafenib
increased 2.2-fold in patients with moderate hepatic impairment. Considering the aggregated of
total (bound and unbound) of regorafenib, M-2 and M-5 together, the increase 1.3-fold in
exposure in moderate hepatic impairment is modest. It is considered that these data are not
enough for dose recommendations in moderate hepatic impairment. There are no data for
patients with severe hepatic impairment. Regorafenib is mainly eliminated via the liver, and
exposure might be increased in this patient population.
No dedicated study was conducted to study pharmacokinetics in patients with renal impairment.
This is acceptable as excretion in urine of unchanged regorafenib was low (<1%) and excretion
of the metabolites M-7 and M-8 in urine was <10% at steady-state. Available clinical data and
physiology based pharmacokinetic modelling indicate similar steady state exposure of
regorafenib and its metabolites M 2 and M 5 in patients with mild and moderate renal impairment
compared to patients with normal renal function.
The pharmacokinetics of regorafenib has not been studied in patients with severe renal
impairment or end stage renal disease. However, physiology based pharmacokinetic modelling
does not predict any relevant change in exposure in these patients.
Available clinical data and physiology based pharmacokinetic modelling indicate similar steady
state exposure of regorafenib and its metabolites M 2 and M 5 in patients with mild and
moderate renal impairment compared to patients with normal renal function.
The pharmacokinetics of regorafenib has not been studied in patients with severe renal
impairment or end stage renal disease. However, physiology based pharmacokinetic modelling
does not predict any relevant change in exposure in these patients.
In vitro data indicate that regorafenib is an inhibitor of BCRP (IC50 values about 40 70
nanomolar) and P glycoprotein (IC50 value of about 2 micromolar). Co administration of
regorafenib may increase the plasma concentrations of concomitant BCRP substrates, such as
methotrexate, or P glycoprotein substrates, such as digoxin.
In vitro data indicate that regorafenib is a competitive inhibitor of the cytochromes CYP2C8 (Ki
value of 0.6 micromolar), CYP2C9 (Ki value of 4.7 micromolar), CYP2B6 (Ki value of 5.2
micromolar) at concentrations which are achieved in vivo at steady state (peak plasma
concentration of 8.1 micromolar). The in vitro inhibitory potency towards CYP3A4 (Ki value of
11.1 micromolar) and CYP2C19 (Ki value of 16.4 micromolar) was less pronounced.
A clinical probe substrate study was performed to evaluate the effect of 14 days of dosing with
160 mg regorafenib on the pharmacokinetics of probe substrates of CYP2C8 (rosiglitazone)
CYP2C9 (S warfarin), CYP 2C19 (omeprazole) and CYP3A4 (midazolam).
Pharmacokinetic data indicate that regorafenib may be given concomitantly with substrates of
CYP2C8, CYP2C9, CYP3A4, and CYP2C19 without a clinically meaningful drug interaction (see
also section 4.4).
Regorafenib is an oral anti-tumour agent that can inhibit multiple protein kinases, including
kinases involved in tumour angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1,
BRAF, BRAFV600E), and the tumour microenvironment (PDGFR, FGFR). In the supportive study
11650, an effect on VEGF signalling was observed at regorafenib doses ≥ 60 mg but no clear
exposure effect relation was apparent. In the extension cohort, VEGFR2 was decreased compared
to baseline in all mCRC patients. Similar findings have been previously described for other agents
that inhibit VEGFR/VEGFR2 signalling and in fact are considered to be a ‘class effect’ for these
types of agents.
Genetic biomarker analysis has been conducted for KRAS, PIK3CA and BRAF. Plasma protein
biomarkers evaluated include those associated with angiogenesis (ANG-2, IL-6, IL-8, PlGF,
VEGFR-1, TIE-1, VEGF-A, VEGF-C, VEGF-D, VEGFA- 121), as well others with known or
hypothesised roles in CRC pathogenesis (BMP-7, VWF, M-CSF, SDF-1 and TIMP-2). None of the
biomarkers analysed appear to be conclusively predictive of regorafenib clinical activity but some
concerns over the provided biomarker analysis have been raised due to the limited number of
tumour tissues available, the absence of fresh biopsies performed at study entry and concerns
regarding the validity of genetic measurements performed on DNA isolated from fresh plasma.
Moreover, based on the historical KRAS data capturing the majority (97%) of patients enrolled in
the pivotal study, both KRAS subgroups appear to do better on regorafenib treatment than on
placebo, with the KRAS wild type subgroup exhibiting a stronger positive effect (see also
discussion on clinical efficacy).
The results from the cardiovascular safety study are in-line with the pre-clinical safety
pharmacology data indicating no relevant effect on cardiac repolarisation in vivo. The observed
effects of regorafenib in humans at tmax on the QTc intervals of the ECG were minimal; the
maximal median change was modest and unlikely to be of clinical significance in the setting of
cancer treatment.
2.4.5. Conclusions on clinical pharmacology
The pharmacokinetics of regorafenib, M-2 and M-5 have been investigated sufficiently.
Information regarding interactions has been reflected in the SmPC and remaining uncertainties
regarding interactions have been addressed in the RMP.
Genetic biomarker analyses have been submitted. None of the biomarkers analysed appear to
be predictive of regorafenib clinical activity.
2.5. Clinical efficacy
Support for the efficacy of regorafenib in the treatment of patients with metastatic colorectal
cancer (mCRC) who have been previously treated with, or are not considered candidates for,
fluoropyrimidine-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-
EGFR therapy comes from one pivotal phase III (CORRECT, 14387) trial. The results of the
expansion cohort of the phase I 11650 study enrolling pre-treated patients with mCRC have been
submitted as supportive, as well.
Table 4: Clinical efficacy studies of regorafenib in mCRC
Number of patients
Study Phase Dosages Regorafenib Control Endpoints
14387 III 160 mg OD 500 253 1°: OS
(CORRECT) 3W on/1W off 2°: PFS, ORR, DCR

and Safety
3°: duration of
response and SD,
QoL, PK and
biomarkers
11650 I 160 mg OD 23 - 1°: BORR
(expansion 3W on/1W off 2º: PFS, PK, Safety

cohort)
Total 523 253
2.5.1. Dose response studies
The proposed regorafenib dosing regimen of 160 mg orally once daily on a 3 weeks on/1 week
off schedule in patients with metastatic CRC has been selected on the basis of nonclinical data
and clinical efficacy and safety observed in the phase I dose escalation 11650 study. Data of
another phase I study 11651 conducted with regorafenib administered orally once daily in a
continuous regimen are also of relevance.
In the phase I 11650 dose escalation study conducted in patients with advanced solid tumours
(76 patients), with one expansion cohort in patients with metastatic CRC (23 patients), doses
ranging from 10 mg once daily to 220 mg once daily as oral solution (10, 30, 60, 120 mg) or
tablets (120, 160, 220 mg) were administered according to a 3 weeks on/1 week off schedule in
repeated cycles of 4 weeks. The Maximum Tolerated Dose (MTD) of regorafenib was 160 mg
once daily (as co-precipitate tablets; with DLTs of grade 3 hand-foot skin reaction and
hypertension). Pharmacokinetic analysis revealed a similar exposure at steady state for the
parent compound regorafenib and the two pharmacologically active metabolites M-2 and M-5 at
the MTD. Overall, 58% of all patients experienced disease control (PR+SD); 3 patients (RCC;
CRC; osteosarcoma) achieved PR.
In the phase I study 11651, where regorafenib was administered orally once daily in a
continuous regimen, a total of 84 patients were included, 38 patients in the dose escalation
cohort, and 20 and 26 patients in two dose expansion cohorts in hepatocellular carcinoma (HCC)
and non-small cell lung cancer (NSCLC), respectively. The MTD of regorafenib on the continuous
dosing schedule was 100 mg once daily (with DLTs of grade 3 hand-foot skin reaction and
hypertension). Overall, 37% of all patients experienced disease control (PR+SD); 4 patients (2
HCC, 1 neuro-endocrine carcinoma and 1 squamous cell carcinoma of the preorbit) achieved PR.
2.5.2. Main study
Study 14387 (CORRECT)
Methods
Study 14387 (CORRECT) was a pivotal multi-centre (114 study centres in 16 countries),
randomised, double-blind, placebo-controlled phase III study comparing regorafenib plus best
supportive care (BSC) versus placebo plus BSC in patients with mCRC who have progressed after
standard therapy which had to include all of the following: fluoropyrimidine, oxaliplatin,
irinotecan, bevacizumab and cetuximab or panitumumab (if KRAS wild type).
Participants
The CORRECT study population included patients with histologically or cytological confirmed
metastatic CRC (Stage IV, adenocarcinoma), who experienced disease progression during or
within 3 months following the last administration of approved standard therapies which had to
include fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab and cetuximab or panitumumab (if
KRAS wild type), unless contraindicated or stopped before disease progression due to
unacceptable toxicity or not registered in the country where the study was performed. Patients
treated with oxaliplatin in an adjuvant setting were to have progressed during or within 6 months
of completion of adjuvant therapy. Patients who had progressed more than 6 months after
completion of oxaliplatin-containing adjuvant treatment were to be retreated with oxaliplatin-
based therapy to be eligible. Patients with unknown KRAS status at screening were to have
received prior anti-EGFR treatment. According to the inclusion criteria, patients were required to
have an ECOG Performance Status score of 0-1, age ≥ 18 years, measurable or not measurable
disease but evaluable by RECIST (version 1.1) and adequate bone marrow, renal and hepatic
functions.
Patients with any CNS metastases were excluded as well as patients that received prior
radiotherapy 2 or 4 weeks (depending on the extension of the field irradiated). Other main
exclusion criteria were presence of uncontrolled hypertension, unstable angina pectoris or new
onset of angina within 3 months, myocardial infarction within 6 months, congestive heart failure
≥ New York Heart Association class 2, cardiac arrhythmias requiring anti-arrhythmic therapy
(except beta blockers or digoxin), any bleeding diathesis or haemorrhage or bleeding ≥ CTCAE
grade 3 within 4 weeks, healing wound, ulcer or bone fracture, persistent proteinuria of CTCAE
grade≥3 and arterial or venous thrombotic or embolic events within 6 months prior to study
entry.
Treatments
Patients were randomised (2:1) to receive either regorafenib or matching placebo 160 mg (4 x
40 mg tablets) once daily orally for 3 weeks followed by 1 week off therapy (cycle of 4 weeks)
plus BSC. Patients were treated until disease progression according to RECIST 1.1, clinical
progression, unacceptable toxicity, and/or consent withdrawal. Regorafenib (film-coated, not
divisible, gray-orange-red, oval, length 16 mm tablets) or placebo had to be taken in the
morning with approximately 240 ml of water after a low-fat breakfast. Up to two regorafenib
dose-reductions due to toxicity were allowed (from 160 mg to 120 mg to 80 mg). After
implementation of a dose reduction, dose re-escalation was permitted provided that toxicities
were resolved to baseline.
After the primary study endpoint (OS) was met at the second pre-planned interim analysis
according to the DMC, study protocol was amended (amendment 3) and patients on placebo
treatment who had not yet progressed were offered to cross over to regorafenib in open label
treatment.
BSC included any concomitant medications or treatments: antibiotics, analgesics, radiation

therapy for pain control (limited to bone metastases), corticosteroids, transfusions,
psychotherapy, growth factors, palliative surgery, or any other symptomatic therapy necessary
to provide BSC, except other investigational anti-tumour agents or anti-neoplastic
chemo/hormonal/immuno-therapy.
During treatment, caution was required in case of concomitant treatment with agents interfering
with CYP enzymes or glucuronsyl transferases UGT1A1 and 1A9, due to possible drug-drug
interactions with regorafenib. Use of bisphosphonates or erythropoietin in patients under chronic
treatment was allowed. Concomitant radiotherapy was allowed if target lesion(s) were not
included within the radiation field and no more than 10% of the bone marrow was irradiated.
Objectives
The primary objective of the CORRECT trial was to show superiority of regorafenib plus BSC
versus placebo plus BSC in terms of efficacy. Secondary objectives included comparisons in
terms of safety and pharmacokinetics. A biomarker analysis was also included as exploratory.
Outcomes/endpoints
The primary study endpoint was overall survival (OS), defined as the time (days) from
randomisation to death due to any cause. Patients alive at the time of analysis were censored at
the last date known to be alive. Patients lost to follow-up were censored at day 1.
Secondary endpoints included progression-free survival (PFS, defined as the time [days] from
randomisation to first observed disease progression [radiological or clinical, as assessed by
investigators] or death due to any cause, if death occurred before disease progression was
documented), Objective response rate (ORR, defined as the percentage of patients with complete
response [CR] or partial response [PR] according to RECIST 1.1), and disease control rate (DCR,
defined as the percentage of patients with CR, PR or stable disease [SD]).
Regarding PFS, if progression occurred after 2 consecutive missed or non-evaluable assessments
(progression later than date of last evaluable scan + 16 weeks + 1 week), PFS was censored at
the date of last evaluable scan. Death without progression was a PFS event only if it occurred
within the 16+1 weeks of the last evaluable tumour assessment. If it occurred later, PFS was
censored at the date of last evaluable tumour assessment. For patients who discontinued or
withdrew treatment before progression, PFS was censored on the date of the last evaluable
tumour assessment unless the patients died within 16+1 weeks after the last evaluable
assessment. In this case, death was considered a PFS event. For patients who changed
anticancer therapy before progression, PFS was censored at the date of last scan performed prior
to the change of therapy.
Tumor assessments were performed at screening and then every 8 weeks during the treatment
period until progression was documented, and also at the end of treatment visit, if applicable.
Upon discontinuation of study drug patients were followed up for survival, approximately every
month (telephone follow-up was acceptable), with the exception of patients who specifically
withdrew consent. Patients were followed for AEs (adverse events) up to 30 days after the last
dose of study drug.
Tertiary endpoints were duration of response (i.e., time from the first documented objective
response of CR of PR, whichever was noted earlier, to disease progression or death [if death
occurred before progression], in patients achieving CR or PR), duration of stable disease (i.e.,
time from randomisation to disease progression or death, calculated only in patients who failed
to achieve CR or PR), and evaluation of patient reported outcomes (PROs). PROs included
evaluation of Health Related Quality of life (according to EORTC QLQ-C30 and EQ-5D
questionnaires).
In approximately 150 patients from selected sites, blood samples were collected for
pharmacokinetic analyses of regorafenib and its metabolites at steady state.
Finally, a biomarker analysis was also included as exploratory. Biomarker analyses were
performed on whole blood and plasma samples as well as archived diagnostic tumour biopsies
(voluntary patients with a separate consent). Biomarker analysis included evaluation of mutation
of genes of interest (e.g., BRAF, KRAS, PI3KCA), expression of several genes (eg, VEGFR,
PDGFR, FGFR, c-KIT, TIE2) on archival tumour biopsies and/or blood/plasma samples.
Sample size
The study was designed to have 90% power to detect a 33.3% increase in median OS (i.e., a HR
of 0.75, regorafenib over placebo). Assuming one-sided overall alpha of 0.025, power of 90%, a
randomisation ratio of 2:1 between regorafenib and placebo and 2 formal interim analyses of OS
during this study using an O’Brien-Fleming-type error spending function, a total of 582 death
events for the final OS analysis were estimated to be required.
Randomisation
Patients were randomised to receive regorafenib or placebo with a ratio of 2:1 and they were
planned to start study treatment within 7 days of randomisation. Randomisation was stratified
by:
1- Prior treatment with VEGF targeting drugs (yes/no)
2- Time from diagnosis of metastatic disease (≥18 months versus <18 months)
3- Geographic region 1 (North America, Western Europe, Israel, and Australia), versus region 2
(Asia), versus region 3 (South America, Turkey and Eastern Europe)
In order to maintain a balanced representation of each region, not more than 250 patients from
Asia were planned to be randomised.
Blinding (masking)
The study was double-blind.
Statistical methods
The primary population for the efficacy analysis was the ITT population, which was defined as all
randomised patients, independently on whether they received or not study medication. The
population for safety analysis comprised all patients who received at least 1 dose of study
medication.
OS and PFS were compared using a log-rank test stratified by the same stratification factors as
used for randomisation. In addition, the HR (regorafenib plus BSC group/placebo plus BSC
group) for OS and its 95% confidence interval were calculated using the Cox model, stratified by
the same stratification factors as above. Kaplan-Meier (KM) estimates for OS and KM survival
curves were also presented for each treatment group.
ORR and DCR were compared between treatment groups using the Cochran-Mantel-Haenszel
(CMH) test adjusting for the same stratification factors as for the primary endpoint. Estimates
and 95% confidence intervals were computed for each treatment group. The differences in ORR
between the regorafenib and placebo group and the corresponding 95% confidence intervals
were also calculated.
Two formal interim analyses were planned during the study. The first interim analysis (i.e., at
approximately 30% (175 deaths) of the planned total number of events) served as a futility
analysis only, and the second interim analysis (i.e., at approximately 70% (408 deaths) of the
planned total number of events) was to evaluate both efficacy and futility. Stopping boundaries
were calculated for the interim analyses based on the actual number of events observed up to
the database cut-off date used for the interim analyses. A Lan-Demets alpha spending function
determined the monitoring boundary for early stopping for efficacy so that the overall false
positive rate, alpha, was less than or equal to 0.025 (one-sided). The alpha spending function
was the O’Brien-Fleming-type boundary specified. Futility boundaries were calculated separately
for the interim analyses, too. The futility boundaries were based on ruling out a true hazard ratio
(HR) of 0.7502 or lower (corresponding to approximately the targeted 33.3% or more increase in
median overall survival over placebo). As the efficacy and futility boundaries were independent of
each other, non-adherence to the futility boundaries would not inflate the overall false positive
rate, alpha, to over 0.025 (one-sided).
Results
Participant flow
Excluded (n=292)
Assessed for Eligibility
Screening failure
Enrolment
(n=1052)
Randomised (n=760)
l
1 1
Allocated to regorafenib + BSC (n=505) Allocated to placebo + BSC (n=255)
Allocation
Received regorafenib (n=500) Received placebo (n=253)

Did not receive regorafenib (n=5): Did not receive placebo (n=2):
[Disease Progression (n=2), Deterioration of [Disease progression (n=2)]
ECOG PS (n=1), Withdrawal of consent (n=1)
Adverse events not associated with disease
progression (n=1)]
l 1
Discontinued therapy (n=448): Discontinued therapy (n=244):
Follow-up
[Progression (radiological, n=315), [Progression (radiological, n=192),

Progression (clinical, n= 20), Adverse Progression (clinical, n= 13), Adverse
events (n=85), Death (n=7), Refused events (n=30), Death (n=4), Refused
therapy (n=16), Other (n=3), Protocol therapy (n=5)]
violation (n=2)]
Still on therapy (n=52) Still on therapy (n=9)
1 1
Analysis
Analysed for Efficacy (ITT) (n=505): Analysed for Efficacy (ITT) (n=255):
- with death event (n=275) - with death event (n=157)
- with PFS event (n=430) - with PFS event (n=241)
Analysed for Safety (n=500) Analysed for Safety (n=253)
In total, 540 patients (71.1%) entered post-treatment survival follow-up: 353 (69.9%) from the
regorafenib + BSC group and 187 (73.3 %) from the placebo + BSC group.
Recruitment
Patients were enrolled between 30 April 2010 and 22 March 2011. 52 patients in the regorafenib
arm and 9 patients in the placebo arm were still on the study at the time of the clinical data cut-
off (21 July 2011, second interim analysis).
Conduct of the study
A total of 432 death events (56.8%) were included at the second interim analysis (cut-off
21 July 2011), 275 (54.5%) events in the regorafenib arm and 157 events (61.6%) in the
placebo arm. As the pre-specified O’Brien-Fleming-type efficacy boundary (one-sided alpha
0.009279) was crossed and the DMC proclaimed the study as positive, this interim analysis was
presented as the final analysis. An updated OS analysis was performed using a later database
cut-off date (13 November 2011, the day before the first placebo randomised patient crossed-
over), when 97% (566) of the total planned events had occurred.
According to the Applicant, major protocol deviation/violations were reported in 7 patients who
did not receive study drug and have been excluded from the ‘per-protocol’ population.
The most common (≥10% patients) minor deviations by term were ‘Procedures, tests or
measurements for this patient were not performed when scheduled’ (60.6% vs 54.1% in the
regorafenib and placebo groups, respectively), ‘Scheduled procedures, tests or measurements for
this patient were not performed within the allowed time windows’ (28.5% vs 21.2%,
respectively), and ‘Study medication not taken or administered according to protocol’ (15.6% vs
11.6%). Moreover, 13.3% of patients in each treatment group were randomized despite not
meeting all inclusion/exclusion criteria, essentially consisting of presence of uncontrolled
hypertension (8.3% vs 7.5%, respectively), and “INR/PTT greater than 1.5 x ULN (1.6% in both
arms).
A total of 33 patients (15 in the placebo + BSC group and 18 patients in the regorafenib + BSC
group) had inaccurate stratification information entered into IVRS. Two of the 33 total patients
were mis-stratified for more than 1 factor. In light of the mis-stratification, sensitivity analyses
on OS and PFS were also specified to be performed as unstratified analyses.
The original study protocol dated 10 February 2010 was subsequently amended 3 times, twice
after the data cut-off for the second pre-planned interim analysis (considered as the final
analysis).
Amendment 1 (dated 28 September 2010) essentially clarified inclusion/exclusion criteria, dose

modification/delay, permitted (or not) concomitant medications, study procedures/assessments,
pharmacokinetics sampling. Moreover, adverse events of special interest were updated and
several minor textual changes of the study protocol were implemented.
Amendment 2 (dated 03 August 2011) essentially included recommendations for dose

modification for AST, ALT and bilirubin increases related to study drug, introduction of weekly
evaluation of ALT, AST and bilirubin during the first two cycles of treatment, introduction of
guidance for patients developing diarrhoea, mucositis, anorexia or other events predisposing to
fluid loss or inadequate fluid intake.
Amendment 3 (dated 01 November 2011) was implemented after the second interim analysis in
order to allow patients on placebo treatment to receive regorafenib through open label
treatment.
Baseline data
Baseline demographic and disease characteristics are summarised in the following Table 5.
Table 5: Baseline demographic and disease characteristics, 14387 (CORRECT) study
Regorafenlb Placebo
n=SDS n=255
54 n c%1
Female 194 (38.4) 102 (40)
Hale 311 '6t.6\ 153 '60\
Race n r%1
White 392 77.6) 201 78.8l
Black or African American 6, 1.2 8 3.1)
Asian 76 15 35 13.7\
American Jndlan or Alaska nattve 1 0.2 1 0.4\
Not re rted/multlole 30 5.9 10 3.9)
Aae at ra.ndomlzatkm ears\
Mean r ranae J 60.7 (22-82) 60.1 (25-85)
Median 61 61
< 65 "ears 309 '61.2\ 166 '65.1'
:!: 65 vears 196 (38.8) 89 (34.9)
G ,. lcR Ion, n l%\
Nonh America, Westem Eur" , lsrael, AJJstralla 420 83.2) 212 83.1)
Asia 69 13.7) 35 13.7\
South America Turke" Eastern EtJron.e 16 3.2\ 8 3.1 \
ECOG Performa.nce Status n [%1
0 265 (52.5) 146 (57.3)
I 240 (47.5) 109 (42.71
Hlstolo n l%\
Ad enocarclnoma 495 /98\ 248 97.2\
Mudnous cardnoma C>50% coUOld s (1) 4 1.6
Adeno uamous carcinoma 1 l0.2\ I 0.4
Und,fferentlated cardnoma 0 I 0.4
cardnoma NOS 4 {0.8\ 1 0.4
Prima site of disease n '%'
Colon 323 {64 172 67.4
Rectum
Colon and rectum
Mission
ISi 29.9)
30 S.91
I 0.2\
,.
69 27.1
0
5.5)
Prior VEGF tar tln,. dru,.s n'%'

Yes sos '100) 255 (100\
No 0 0
Tin'le sl.nce metastatic dlaanosts. weeks
Mean , raone, 152 l 18-837\ 150 (10~553)
Median 133.1 128.5
< 18 months n % 91 (18) 49 (19.2\
:!: 18 months n % 414 {82\ 97 (80.8\
Tin'le sl.nce last resslon .. weeks
Mean , raone, 6.46 (0.1-50) 6.2 (0.3-52\
Median 4.99 4.56
Mission 30 (5.9) 9 f3.Sl
KRAS mutation, n l%\
No 205 40.6) 94 36.9)
Yes 273 54.1' 157 61.6)
Unknown 27 5.3 4 1.6
BRAF mutat&on n f%\
No 205 40.6) 94 36.9\
Yes 273 54.ll 157 61.5)
Unknown 27 S.3l 4 1.6)
Previous anticancer theranles ft t%l
Fluoro r1mkllne 5051505 100 2551255 100
eevaclzumab 505/505 100 255/255 100
Oxallclatln 505/505 100 255/255 100
lrlnotecan 505/505 100 255/255 100
Panltumumab,cetux:lmab
Al natients 2641505 52.3 121MSS (47.Sl
KRASVIT 204'205 99.S 94,94 '100\
KRAS mutated 33/273 12.1 23/157 (14.6)
KRAS unknown 27/27 I 100) 4/4 l100)
Numbers analysed
All 760 randomised patients were included in the intent-to-treat (ITT) population, the primary
efficacy population. Of them, the 753 patients who received at least one dose of study drug were
included in the safety (SAF) population.
Outcomes and estimation
Primary objective: Overall Survival (OS)
Results are summarised in the following Table 6 and Figures 2 and 3.
Table 6: Overall Survival, 14387 (CORRECT) study, ITT population

(N = 255) (N = 505)
Number of patients(%) censored 98 (38.4) 230 (45.5)
Median overall survival (days) 151 196
95% Cl for median 134, 177 178,222
Range (days, without censored values) 13-315 5-375
Range (days, including censored values) (1**-413**) (5 - 401 **)
Overall survival rate at
Month 3 (95% Cl) 0.727 (0.672, 0.782) 0.803 (0.768, 0.838)
Month 6 (95% Cl) 0.435 (0.371, 0.498) 0.525 (0.479, 0.571)
Month 9 (95% Cl) 0.308 (0 238, 0.378) 0.382 (0 329, 0.435)
Month 12 (95% Cl) 0.240 (0.151, 0.330) 0.243 (0.155, 0.331)
Hazard ratio (regorafenib/placebo )• 0.774

95% Cl for hazard ratio 0.636, 0.942
One-sided p-value from log rank test 0.005178
Abbreviations: •• - censored observation; Cl - confidence interval; ITT - intent to treat
a. A Hazard ratio < 1 indicates superiority of regorafenib over placebo.
Note: Stratification based on CRF data. The hazard ratio and its 95% Cl was based on Cox Regression
Model, stratified by prior treatment with anti-VEGF drugs (yes/no), time from diagnosis of metastatic
disease (;,:18 months vs <18 months) and geographical region 1 (North America, Western Europe, Israel
and Australia) versus region 2 (Asia) versus region 3 (South America, Turkey and Eastern Europe).
Figure 2: Kaplan-Meier Plot of OS, 14387 (CORRECT) study, ITT population
1.00
0.75
0.50
0.25
-<lB -<ID
0.00 '--,----~---~--~---~---~---~--~---~----.---'
0 50 100 150 200 250 300 350 400 450
Days From Randomization
STRATA: -- treatment:Placebo o o o Censored treatment;::;Placebo

- ~ ~ treatment=Regorafenib 160 mg o o o Censored treatment=Regorafenib 160 mg
IITRUE COPYII
Figure 3: Forest plot for OS by subgroups, 14387 (CORRECT) study, ITT population
Race,
Subgroup
14:WHITE
sex.
ASIAII
N·A.I
-
RG-9i-0n (CRI=): NorthAmG-fieG,
Ago
W ,a lorn EU, l;roQI

Group, H:<66yr~
;.=o,
onC Au)troli:,
yr> ---
South Ami=:1ico, Turh,y <0-nd Ea)te111 EU
Time 1,1 Oi-09. oi MD lo Rond,,
Prior Trt. with

mth,(C
VEGI= Tor9ei
RI=):<
Drug)
18 month)
;,,: 13 montl'ls
(CA.l=):Y --
FIU0100)1f,, OX8111)131,, lrll'IOtec .. 8eveclz..
Nu m bor of P,iot l1oottl'lont
No. or Prior rn line$ on or 8ft Meta DI;: ~=i

Anll•EGFR.
Lino): <=l - -
,,
KRAS Uul8tlon 81 StuCIY Entry: fl
P,imory
Go,cline ECOC
Site oi Oheo)c:
Score:
Colon
Roctum
y
0
--.-
Colon :and R oc1um
0.0
'
o.s 1.0
'
1.5
'
2.0
'
2.S
'
>.O
Hazard Ra1,o (Reg/Pia) and 95% Cl
Results from the updated OS analysis (cut-off date 13 November 2011, the day before the first
placebo randomised patient crossed-over) are summarised in the following Table 7.
Table 7: Updated Overall survival analysis (cut-off 13 November 2011), 14387

(CORRECT) study, ITT population
Placebo Regorafenib Total

(N=255) (N=505) (N=760)
N 255 505 760
Number(%) of 197 ( 77.3%) 369(73.1%) 566 ( 74.5%)
subjects with event
Number(%) of 58 ( 22.7%) 136 ( 26.9%) 194 ( 25.5%)
subjects censored
Hazard ratio (Reg/Pia) [95% Cl]• 0.790 (0.664,0.939)
One-sided p.-value from log rank Stratified (CRF data) 0.003791
test
Median (95% Cl) Days 152 194 179
( 134, 178) (177,214) ( 167, 197)
Overall Survival rate at Month 3 [95% Cl) 0.727 0.803 0.778
(0.672,0.782) (0.768,0.838) (0.748,0.807)
Month 6 [95% Cl) 0.431 0.522 0.492
(0.369,0.492) (0.479,0.566) (0.456,0.527)
Month 9 [95% Cl) 0.269 0.349 0.323
(0.212,0.325) (0.307,0.392) (0.289,0.357)
Month 12 [95% Cl) 0.170 0.241 0.218
(0.114,0.226) (0.198,0.283) (0.184,0.252)
.. censored observation.
Median, percentile and other 95% Cls computed using Kaplan.Meier estimates.
Secondary endpoint: Progression Free Survival (PFS)
The analysis of PFS, conducted at the time of the second interim analysis, was based on 671
(88%) PFS events: 430 (85.1%) in the regorafenib group and 241 (94.5%) in the placebo group.
Results are summarised in the following Table 8 and Figures 4 and 5.
Table 8: PFS (investigator assessment), 14387 (CORRECT) study

(N = 255) (N = 505)
Number of patients(%) censored 14 (5.5) 75 (14.9)
Median PFS (days) 52 59
95% Cl for median (51, 53) (57, 65)
Range (without censored values) 6-277 5-333
Range (days, including censored values) (1**-277) ( 1** -336**)
PFS rate at
Month 3 (95% Cl) 0.135 (0.093, 0.177) 0.420 (0.376, 0.464)
Month 6 (95% Cl) 0.021 (0.000, 0.044) 0.130 (0.098, 0.163)
Month 9 (95% Cl) 0.010 (0.000, 0.029) 0.051 (0.025, 0.076)
Month 12 (95% Cl) 0.000 (0.000, 1.000) A (0.000, 1.000)
Hazard ratio (regorafenib/placebo) • 0.494

95% CI for hazard ratio 0.419, 0.582
One-sided p-value from log rank test <0.000001
Abbreviations: •• - censored observation; Cl - confidence interval; ITT - intent to treat; PFS - progression-
free survival; A - value cannot be estimated due to censored data
a. A Hazard ratio< 1 indicates superiority of Regorafenib 160 mg (experimental) over Placebo (control)
Note: Median PFS and 95% Cls computed using Kaplan-Meier estimates. Hazard ratio and its 95% Cl was
based on Cox Regression Model, stratified by prior treatment with anti-VEGF drugs (yes/no), time from
diagnosis of metastatic disease (2:18 months vs <18 months) and geographical region 1 (North America,
Western Europe, Israel and Australia) versus region 2 (Asia) versus region 3 (South America, Turkey and
Eastern Europe). Stratification based on CRF data.
Figure 4: Kaplan–Meier Plot of PFS, 14387 (CORRECT) study

1.00
0.75
6
:g
C
::,
u.
C
.Q 0.50
:i
.0
·;::
U>
0
~
-~ 0.25
(/) ---,
C)-€)19 - - - - ~
=-""""---~-e-e-,_ ______ -o-.'.::._-:o~-:_-=-=-:-ci:>-
_ -€0-- __ -o- ,o
0.00 '----T-----,-------.---------,-------,-------,-----r--------r--'
0 50 100 150 200 250 300 350
Days From Randomization
STRATA: -- treatment=Placebo o o o Censored treatment=Placebo

- - - treatment=Regorafenlb 160 mg o o o Censored treatment=Regorafenib 160 mg
IITRUE COPYII
Figure 5: Forest plot for OS by subgroups, 14387 (CORRECT) study, ITT population
SubCHOUD
R;,cca, ti:WMITE.
ASIA I~ -
-
s~x.N:M
F
Aic G,oup, ti: <&5 yr~
-
>=0!) yrs
R c9 ion (CR I=): No rU, ,...,m:ric,, VI :~tc rn iaU, l~r~ cl ¢.ld Au ~tnli,
A~i;,
SoutlAm:rJc:1. Tuo:eyau Eas1e,n EU
-
Titr1c l~t Oi;,g. oi MO to R ;,nd .. m th~(CR I=):< 11 month;
>= ta montn~
----
-.--
P ,ior Trt. • itll V EGI= T, rge t Drug~ (C RI=): Y
----
P r101 i::-.n1~cancer a rug o rou p. rt· Fluo ,opyr . O l(a11p!e, .. m,io 1ec.. a ev.ac1z.
i: k.ooro pyr .. O:u lipt,t., lrinote ❖ .. Sc V¢ ci:: .. A nt~"iaG i:-R
Nu,nbcarofPric,rTro;attr1ont Lilo~·<=i
--+--
--
>3
No.ofPriorTrtLinc~ono1 ,ft lolet"Di~: <•3 -.-
>l
KRAS M ut~tii>n '°!Study Enlly.1~
--------
Baseline ECOG
Primary Sl!e or Disease. Coli>n

Score: O
Rc ❖ h.rm
y
--
Co loll:= r.d Roeh1m
o.,
00 '.0
'' 2.0
Hazard Ratio (Reg/Pio) and 95% Cl
Secondary objective: Overall Response Rate (ORR) and Disease Control Rate (DCR)
Overall response rate (ORR=CR + PR, per RECIST 1.1, as assessed by investigator) was not
statistically significant different between the two treatment arms: 1% (0+5 patients) with
regorafenib +BSC versus 0.4% (0+1 pt) with placebo plus BSC.
Disease Control Rate (DCR: CR+ PR+ SD) was significantly higher with regorafenib (41%, [207
patients]) compared with placebo (14.9%, [38 patients]), essentially due to a higher rate of
patients with disease stabilisation.
Tertiary objective: Duration of response and Duration of stable disease
Only 6 patients (5 treated with regorafenib and 1 with placebo) achieved tumour response. For
the 5 patients treated with regorafenib median duration of response could not be evaluated due
to small number of patients (range without censored values 59-64 days), whereas it was 68 days
in the patient treated in the placebo group.
Duration of stable disease was not significantly different between the two treatment arms (60
days with regorafenib vs 52 days with placebo).
Tertiary endpoint: Patient-Reported Outcomes: EORTC QLQ-C30 and EQ-5D
EORTC QLQ-C30 and EQ-5D questionnaires were administered at baseline, on Day 1 of Cycles 2-
4, and every other cycle thereafter and at end of treatment visit. Higher scores of the EORTC
QLQ-C30 (range 0-100) and EQ-5D represent a higher level of functioning and better HRQoL.
Change of ≥10 points in EORTC QLQ-C30 or, 0.07 to 0.12 points on the EQ-5D index or of 7-12
points on the visual analogue scale (VAS) are considered as clinically meaningful.
The EORTC QLQ-C30 was completed by 697 (92%) patients at baseline, 604 (79%) patients at
cycle 2, and 557 (73%) patients at cycle 3. The mean EORTC QLQ-C30 score at baseline was
62.64 and 64.65 in the regorafenib and placebo groups, respectively. The mean score at the End
11TRUE COPY!I
of Treatment (EOT) visit was 48.94 and 51.85, respectively. The deterioration in global score was
not significantly different between the two treatment arms. The least square (LS) mean
regarding time-adjusted AUC was slightly but not statistically significantly higher with placebo
compared with regorafenib (58.13 vs 56.93, respectively).
The EQ-5D questionnaire was completed by 705 (93%) patients at baseline, 637 (84%) patients
at cycle 2, and 601 (79%) patients at cycle 3. The mean EQ-5D index score (general health
status) was 0.727 and 0.738 in the regorafenib and placebo groups, respectively at baseline, and
0.593 and 0.591, respectively, at the EOT visit. The mean EQ-5D VAS score was 65.4 and 65.8
in the regorafenib and placebo groups, respectively, at baseline and 55.5 and 57.3, respectively,
at the EOT visit. Mean changes in scores from baseline for EQ-5D index and VAS were, overall,
similar between the regorafenib + BSC and placebo + BSC groups, suggesting similar
deterioration in both arms.
Exploratory endpoint: biomarkers
Subgroup analyses of OS and PFS by KRAS tumour status based on historical data prior to study
enrolment are presented in Figure 6 .
Figure 6: OS and PFS by historical KRAS tumour status, 14387 study, ITT population
, __
-....'
110
WT, HR 0.653 (0.476-0.895) "' Mutant, HR 0.867 (0.670-1.123)
- 75 ' .....
9
N=299
- n N=430
228 events
~ 204 events
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J. lS J. !5
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lfullrls fr•n Ro•do•i11I •••
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- "' -.'\ WT, HR 0.475 (0.362-0.623) - '" Mutant, HR 0.525 (0.425-0.649)
i,. ,, ii
,. N=299 ii
,£ " N=430
261 events 385 events
!
j
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so
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" " 10 11
A retrospective analysis of 3 genetic biomarkers (KRAS, PIK3CA, BRAF) and 15 non-genetic

biomarkers considered relevant for CRC (ANG-2, IL-6, IL-8, VEGFR-1, TIE-1, VEGF-A, VEGF-C,
VEGF-D, VEGF-A-121, BMP-7, VWF, M-CSF, SDF-1 and TIMP-2), based on DNA isolated from
fresh baseline plasma and archival tumour tissue specimens, was submitted.
Plasma KRAS data was generated for 66% (503) of all randomised patients, of which 69% were
KRAS mutant, compared to 59% from the archival tumour tissue, and 31% were KRAS wild type.
Correlative analysis for OS indicated trends in favour of regorafenib in both KRAS wild type
(regorafenib/placebo HR: 0.67 [95% CI: 0.41, 1.08]) and KRAS mutant (regorafenib/placebo
HR: 0.81 [95% CI: 0.61, 1.09]) subgroups. The interaction p-value comparing the HRs of the de
novo plasma KRAS subgroups was 0.561, indicating no significant difference in regorafenib
IITRUE COPYjl
clinical efficacy (vs. placebo) related to KRAS mutational status. Likewise, interaction p-values
for subgroups in which KRAS status was determined via BEAMing of DNA isolated from archival
tumour tissue were not significant. Pre-existing/historical KRAS data were available from 96% of
all randomized patients, of which 59% were KRAS mutant and 41% were KRAS wild type.
Correlative analysis indicated a trend towards a survival benefit for regorafenib as compared to
placebo in the KRAS wild type subgroup (regorafenib/placebo HR: 0.653 [95% CI: 0.476,
0.895]) as well as in the KRAS mutant subgroup (regorafenib/placebo HR: 0.867 [95% CI:
0.670, 1.123]).
PIK3CA mutation data were available from 66% of all randomised patients, of which 17% were
PIK3CA mutant and 83% were PIK3CA wild type. Correlative analysis for OS indicated trends in
favour of regorafenib in both PIK3CA wild type (regorafenib/placebo HR: 0.75 [95% CI: 0.57,
0.99]) and PIK3CA mutant (regorafenib/placebo HR: 0.84 [95% CI: 0.47, 1.50]) subgroups. The
interaction p-value among these subgroups was 0.723, indicating no significant difference in
regorafenib clinical efficacy (vs. placebo) related to PIK3CA mutational status. Likewise,
interaction p-values for subgroups in which PIK3CA status was determined via BEAMing of DNA
isolated from archival tumour tissue were not significant.
Since KRAS and PIK3CA mutations may co-exist in the same tumour, subgroup analyses were
also conducted based on various combinations of KRAS and PIK3CA mutations, with mutational
status determined via BEAMing of DNA isolated from fresh plasma. In the KRAS mutant +
PIK3CA mutant subgroup the regorafenib/placebo HR was 0.71 (95% CI: 0.37, 1.35), in the
KRAS mutant + PIK3CA wild type subgroup the regorafenib/placebo HR was 0.84 (95% CI: 0.61,
1.16) and in the KRAS wild type + PIK3CAwild type subgroup the regorafenib/placebo HR was
0.57 (95% CI: 0.34, 0.96). There were too few patients in the KRAS wild type + PIK3CA mutant
subgroup to permit a meaningful correlative analysis.
BRAF mutational status using DNA isolated from fresh plasma was determined from 66% of all
randomized patients, of which 3.4% were BRAF mutant and 96.6% were BRAF wild type. Due to
the small number of BRAF mutant patients, a correlative analysis was not conducted based on
BRAF mutational status.
The non-genetic biomarker analysis in the pivotal study involved the quantification of 15 different
plasma proteins at baseline, many associated with angiogenesis (ANG-2, TIE-1, VEGF-A, VEGFA-
121, VEGF-C, VEGF-D, PlGF, VEGFR1, IL-6, IL-8), as well as others with known or hypothesised
roles in CRC pathogenesis (SDF-1, BMP-7, M-CSF, TIMP-2 and von Willebrand Factor [VWF]).
number of these proteins are either directly inhibited by regorafenib or directly interact with
proteins or pathways inhibited by regorafenib (VEGFR1, VEGF-A, VEGFA-121, VEGF-C, VEGF-D,
PlGF, TIE-1). Correlative analyses of OS comparing subgroups with high or low protein levels
defined based on median values demonstrated that none of these proteins were predictive of
regorafenib clinical activity vs placebo (i.e., no interaction p-value reached p<0.05). One plasma
protein, TIE-1, appeared to be predictive for regorafenib clinical activity, although both ‘high’ and
‘low’ TIE-1 subgroups showed a trend towards benefitting from regorafenib. High TIE-1 levels
correlated with greater regorafenib benefit than low TIE- 1 levels (regorafenib/placebo HR for OS
in patients with low TIE-1: 0.87 [95% CI: 0.64, 1.20]; and in patients with high TIE-1: 0.56
[95% CI: 0.41, 0.77]; interaction p-value: 0.035). A similar analysis of plasma biomarkers vs
PFS demonstrated that levels of VWF appeared to be predictive for regorafenib clinical activity.
Low VWF levels correlated with greater regorafenib benefit than high VWF levels
(regorafenib/placebo HR for PFS in patients with low VWF of 0.39 [95% CI: 0.30, 0.51] and in
patients with high VWF of 0.60 [95% CI: 0.46, 0.78]; interaction p-value: 0.020). Notably, in the
PFS analyses TIE-1 did not correlate with regorafenib benefit; and conversely, in the OS
analyses, VWF did not correlate with benefit.
Ancillary analyses
The results of the primary OS analysis were consistent with the results of an unstratified OS
analysis (unstratified HR=0.773, 95% CI 0.634-0.942, p=0.005255), and with an OS analysis
using stratification information from the IVRS instead of the CRF (HR=0.767, 95% CI 0.630-
0.933, p=0.003905), performed due to observed mis-stratification of some patients.
Similarly, the results of the primary PFS analysis were consistent with the results of an
unstratified PFS analysis (unstratified HR=0.501, 95% CI 0.425-0.590, p<0.000001), and with a
PFS analysis using stratification information from the IVRS instead of the CRF (HR=0.479, 95%
CI 0.405-0.565, p=0.000001), performed due to observed misstratification of some patients.
For PFS stratified per randomisation based on CRF data, new treatment initiation date in follow-
up period considered as event date for patients who discontinued prior to progression, results
(HR 0.497, 95% CI 0.422-0.586, p<0.000001, median PFS 59 days vs 52 days with regorafenib
and placebo, respectively) were consistent with the primary PFS analysis.
For PFS stratified per randomisation based on CRF data, considering all available tumour
assessment data from follow-up period, results (HR 0.497, 95% CI 0.422-0.586, p<0.000001,
median PFS 59 days vs 52 days with regorafenib and placebo, respectively) were consistent with
the primary PFS analysis.
For Time to Progression (TTP) stratified per randomisation based on CRF data, median was 60
days and 52 days with regorafenib and placebo, respectively, HR 0.469 (95% CI 0.396-0.556),
p<0.000001. Results were similar in the analysis stratified per randomisation based on IVRS
data.
Summary of main study
The following tables summarise the efficacy results from the main studies supporting the present
application. These summaries should be read in conjunction with the discussion on clinical
efficacy as well as the benefit risk assessment (see later sections).
Table 9: Summary of Efficacy for study 14387
Title: A randomized, double-blind, placebo-controlled phase III study of regorafenib plus BSC versus
placebo plus BSC in patients with metastatic colorectal cancer (CRC) who have progressed after
standard therapy
Study identifier 14387, CORRECT
Design Randomised, double-blind, multicenter, phase 3 study.
Duration of main phase: until disease progression or unacceptable
toxicity or patient consent withdrawal or
physician’s decision or non-compliance with
protocol
Duration of Run-in phase: not applicable
Duration of Extension phase: not applicable
Hypothesis Superiority
Treatments groups regorafenib + BSC Regorafenib 160 mg od once daily, for 21
days every 4 weeks (3 weeks on, 1 week off),
505 patients randomised
placebo + BSC Matching placebo od once daily, for 21 days
every 4 weeks (3 weeks on, 1 week off),
255 patients randomised
Endpoints and Primary OS time from randomization to death due to any
definitions endpoint cause
Secondary PFS Time from randomization to first observed PD
endpoint (radiological or clinical) or death due to any
cause
Secondary ORR Percentage of patients with CR or PR as best
endpoint overall response
Secondary DCR Percentage of patients whose best response
endpoint was not PD (i.e. CR, PR or SD)
Database lock 21 July 2011
Results and Analysis

Analysis description Primary Analysis
Analysis population ITT population: 760
and time point
description
Descriptive statistics Treatment group regorafenib+BSC placebo+BSC
and estimate
Number of 505 255
variability
patients
median OS 196 151
(days)
95% CI for 178, 222 134, 177
median
median PFS 59 52
(days)
95% CI for 57, 65 51, 53
median
ORR 5 (1.0%) 1 (0.4%)
n (%)
95% CI 0.3, 2.3 0.0, 2.2
DCR 207 (41.0%) 38 (14.9%)
n (%)
95% CI 36.7, 45.4 10.8, 19.9
Effect estimate per Primary endpoint Comparison groups regorafenib vs placebo
comparison (OS)
Hazard Ratio 0.774
(95% CI) 0.636 – 0.942
P-value 0.005178
Secondary Comparison groups regorafenib vs placebo
endpoint
Hazard Ratio 0.494
(PFS) (95% CI) 0.419 – 0.582
P-value <0.000001
endpoint
P-value 0.188432
(ORR)
endpoint
P-value <0.000001
(DCR)
Analysis performed across trials (pooled analyses and meta-analysis)
Not applicable
Clinical studies in special populations
No studies in special populations have been submitted (see discussion on clinical pharmacology
and discussion on clinical safety).
Supportive study
The Applicant has submitted one phase I (Study 11650) trial, the expansion cohort of which
included 23 patients with mCRC.
Study 11650
Study 11650 was a single-centre, open-label, non-randomised, single-agent, dose escalation

study to determine the safety, tolerability and maximum tolerated dose (MTD), recommended-
phase-2-dose pharmacokinetics and to evaluate biomarkers in 76 patients with advanced solid
tumours. After a dose escalation phase including doses 10 mg once daily to 220 mg once daily,
an expansion cohort in patients with CRC was conducted at dose level 160 mg once daily
regorafenib on an intermittent dosing schedule. Tumour response and progression were
evaluated based on RECIST, v. 1.0. All patients with CRC treated at doses of ≥60 mg once daily
(in the dose escalation or dose expansion part of the study) were included in a subgroup
analysis. Overall, 39 patients with metastatic CRC refractory to standard treatment were enrolled
in Study 11650 with intermittent dosing schedule of regorafenib, of which 23 patients were
enrolled in the expansion cohort of the study. First signs of clinical activity were observed at dose
levels ≥ 60 mg, which were received by 38 patients with mCRC treated. Of the 38 patients, 20
(54%) had positive KRAS mutation status, whereas 17 patients (46%) were KRAS wild type. In
one case the KRAS mutation analysis was not successful.
A total of 27 patients (out of 38 patients treated at dose ≥60 mg once daily) were evaluable for
response according to RECIST (v. 1.0). Best responses included a confirmed partial response
(PR) in 1 patient (4%) and stable disease (SD) in 19 patients (70%), resulting in a DCR of 74%
in evaluable patients. Seven patients (26%) had progressive disease. The median PFS was
107 days (95% CI 66-161; range of 1-279 days).
2.5.3. Discussion on clinical efficacy
Design and conduct of clinical studies
The applicant submitted one single pivotal study and this is acceptable by EMA. Nevertheless, the
study has to be particularly compelling with respect to internal and external validity, critical
relevance, statistical significance, data quality and internal consistency. Study 14387 was the
pivotal, phase III, multicentre, multinational, randomised, double blind, placebo-controlled study.
A total of 760 patients with mCRC previously treated with, or not considered candidates for,
fluoropyrimidine-based chemotherapy, anti-VEGF therapy, and, if KRAS wild type, anti-EGFR
therapy, were randomised (2:1) to receive oral regorafenib 160 mg OD (3 weeks on/1 week off)
plus BSC or matching placebo plus BSC.
The two arm design of the study with placebo plus BSC as comparator is considered acceptable,
as patients enrolled in the trial had received all the standard treatment options currently
available in EU Countries. The use of superiority design is endorsed. The selection of OS as
primary endpoint corresponds to the accepted standards of clinical cancer research and is in
accordance with EMA guidelines, in view of the lack of further active therapeutic options for the
target population and the poor life expectancy of these patients. PFS as secondary endpoint is
considered acceptable.
Randomisation, in agreement with EMA guidelines, was stratified according to geographical

region and other factors (time from diagnosis of metastatic disease, prior treatment with anti-
VEGF drugs) that represent well-recognised prognostic covariates in the target population.
Major protocol modifications were introduced with the implementation of protocol amendment 3,
in order to allow cross-over to regorafenib for patients treated with placebo. However, as the
amendment was implemented after the cut-off date for the secondary interim OS analysis
(presented as final), it is not expected to impact interpretation of the data.
The population enrolled in the pivotal study reflects the target population as mentioned by the
wording of the proposed indication. The study population was similar to the general patient
population with mCRC in several aspects. The great majority of patients were males (60.8%),
white (78.2%), with a median age of 61 years (range, 22-85 yr), an ECOG PS 0 (54.9%) and a
median time since metastatic diagnosis of 130 weeks (128 weeks with regorafenib and 133
weeks with placebo). Primary site of disease was colon in the majority of patients in both groups
(67.5% and 64%). All patients had metastatic disease and were pre-treated with a VEGF
inhibitor, fluoropyrimifine, oxaliplatin and irinotecan. Moreover, 99.5% of patients with KRAS
wildtype or unknown status had received panitumumab and/or cetuximab.
Demographic and baseline characteristics appeared to be comparable between the two study
arms. Baseline information on KRAS mutations in the tumours (historical data) was available in
478 (94.7%) patients in the regorafenib group vs 251 (98.4%) patients in the placebo group.
Baseline information on BRAF mutations in the tumours (historical data) was available in 45
(8.9%) vs 27 (10.6%) patients in the regorafenib and placebo groups, respectively, and was
positive in 0.8% of patients in each treatment group. Unfortunately, no distribution of tumour
characteristics able to discriminate patients with slowly or rapidly progressive disease has been
identified.
No significant differences in concomitant medications or in medical history between treatment
arms was observed, although patients in the placebo group consistently appeared to have a
slightly higher number of co-morbidities and were more pre-treated with radiotherapy (30.6% vs
26.7%).
With regard to post-study treatments, slightly more patients in the placebo received systemic
anti-cancer therapy during follow-up compared with patients in the regorafenib group (29.8% vs
25.9%). Post-study treatments essentially consisted of pyrimidine analogues (20.4% vs 18.6%,
respectively), other cytotoxic antibiotics (11.4% vs 7.5%), monoclonal antibodies (8.6% 7.7%),
folic acid and derivatives (8.2% vs 5.5%), and platinum compounds (5.5% vs 6.9%).
The overview on systemic anticancer therapy during follow-up has been updated for the later
13 November 2011 database cut-off. Overall, the percentage of patients receiving post-study
systemic anticancer therapy was comparable to the numbers reported at the second, pre-
planned, formal interim analysis.
Efficacy data and additional analyses
The proposed regorafenib oral daily dose of 160 mg OD administered according to a 3 weeks
on/one week off schema, which was used in the pivotal study, was supported by a phase I dose-
finding study (11650). However, it should be noted that clinical data directly comparing the
continuous dosing regimen with the 3 weeks on/1week off schedule are lacking. The evidence of
efficacy of regorafenib in patients with mCRC is based on the results of one pivotal study (14387
or CORRECT), supported by the data of the expansion cohort of the phase I 11650 study,
enrolling patients with mCRC.
The present submission for MAA is based upon the results of the second interim OS analysis
presented as final performed after 432 death events (56.8%, 275 in the regorafenib arm and
157 in the placebo arm, cut-off 21 July 2011). At this analysis, the pre-specified O’Brien-
Fleming-type efficacy boundary (one-sided alpha 0.009279) was crossed and the DMC assessed
the results as positive. Therefore, this interim analysis was presented as the final analysis.
The results show a statistically significant improvement in OS for regorafenib compared to

placebo (HR 0.77, 95% CI 0.636-0.942, p=0.005178), with a gain in median OS of 1.5 months
in favour of regorafenib (median OS 196 days vs 151 days, respectively). The OS effect
appeared to be consistent in the updated analysis performed with a cut-off of
13 November 2011, after 97% of death events occurred and before cross-over was allowed
(median OS:194 vs 152 days, HR 0.790, 95% CI 0.664, 0.393, p=0.003791). The observed OS
benefit is considered limited and its clinical relevance needs to be considered taking into account
both the treatment effect on symptom control as well as drug tolerability.
The effect on OS was observed in several subgroups of the population, with the exception of
patients with rectum as primary tumour localisation (220 patients, 109 events, HR 0.953, CI
0.633, 1.436). The small sample size could potentially explain the lack of effect in this subgroup.
The effect on OS in patients with KRAS mutated tumours was inferior (430 patients, 228 events,
HR 0.867, CI 0.670, 1.123). As mentioned previously, no imbalance in post-study therapies
between the two study arms was observed from the data provided. However, the trend towards
a smaller observed benefit in the KRAS mutant subgroup might be at least partly explained by a
higher rate of subsequent anti-cancer therapy in the KRAS-mutated placebo subgroup compared
to the KRAS-mutated regorafenib subgroup (33.1% vs. 24.9%, respectively). Additionally, the
difference could be due to imbalances in baseline characteristics of the patients included in these
subgroups and for these non-randomised comparisons.
The OS results appear to be supported by the investigator-assessed PFS data. A statistically

significant increase in PFS was observed with regorafenib compared with placebo (HR 0.494,
95% CI 0.419-0.582, p<0.00000). However, the difference in median PFS between the two
study arms was only one week (median PFS 59 days with regorafenib vs 52 days with placebo).
This could be related to the timing of protocol-specified assessment, as at the time of the first
radiological evaluation (8 weeks) more than 50% of patients in both study arms had experienced
disease progression already. The high rate of patients not responding to treatment in the
regorafenib arm could suggest activity of the drug limited to a subgroup of the population (58%
of patients were progressive after 3 months).
The treatment effect on PFS for regorafenib was consistent across different subgroups regardless
of age, ECOG PS, gender, geographical region, previous treatment with a VEGF and EGFR
targeting drug, primary site of disease and KRAS mutation status.
The results of a correlative analysis including 3 genetic biomarkers (KRAS, PIK3CA, BRAF) and 15
non-genetic biomarkers (ANG-2, IL-6, IL-8, P1GF, VEGFR-1, TIE1, VEGF-A, VEGF-C, VEGF-D,
VEGF-A-121, BMP-7, VWF, M-CSF, SDF-1 and TIMP-2) measured in plasma and/or tumour tissue
have been provided, but no specific biomarker was identified that can be used for patient
selection and to predict regorafenib clinical activity. Methodological concerns over the provided
biomarkers analyses have been raised due to the limited number of tumour tissues available, the
absence of fresh biopsies performed at study entry and concerns regarding the validity of genetic
measurements performed on DNA isolated from fresh plasma.
ORR (CR+PR) was very low and similar between the two treatment arms (1% with regorafenib
and 0.4% with placebo). The claimed improvement in OS and PFS appears to be essentially
driven by patients experiencing disease stabilisation under treatment. No remarkable difference
between the two study arms was observed in the evaluation of Quality of life. However, a
numerical trend towards lower scores (and therefore worse quality of life) for patients treated
with regorafenib is consistently observed overtime by evaluation of single domains. Other patient
reported outcomes able to indirectly assess clinical benefit for patients (e.g. use of analgesics,
pain control, other specific disease related symptoms) have not been evaluated.
Additional expert consultation
The CHMP convened a Scientific Advisory Group in Oncology (SAG-O) to address questions
related to efficacy. The SAG-O advice was the following:
1. Does the SAG consider the clinical benefit of regorafenib adequately demonstrated
in the population as a whole enrolled in the pivotal study 14387, although PFS
results suggest a benefit limited only to a subgroup of the mCRC population
treated (>50% of patients experiencing disease progression at the time of first
radiological evaluation)?
A statistically significant difference was observed in the primary analysis of OS in study 14387 in
the overall population. The difference in median OS between regorafenib and placebo was
modest (45 days). The clinical relevance of this magnitude of treatment effect is considered to be
minimal.. The rapid onset of progression in the majority of patients suggests that a favourable
effect is limited to a minority of patients.
Importantly, however, regorafenib was associated with significant toxicity in the majority of
patients. The most-frequent drug-related adverse event was hand-foot syndrome, which was
observed (any Grade) in 44.6% vs 7.1% of patients for regorafenib and placebo, respectively.
The most common Grade 3 adverse events with higher frequency in the regorafenib, compared
to the placebo arm in study 14387, were hand-foot syndrome (16.6% vs 0.4%), fatigue (15.0%
vs 8.3%), diarrhoea (8.2% vs 2.0%), hypertension (7.6% vs 0.8%), rash/desquamation (5.8%
vs 0.4%), reduced platelet counts (3.4% vs 0.4%), reduced haemoglobin (5.4% vs 3.2%),
mucositis (3.2% vs 0%), hyperbilirubinaemia (6.8% vs 4.3%), AST increase (2.4% vs 1.2%),
and (abdominal) pain (9.8% vs 5.7%). In the great majority of cases these events were
considered drug-related. Overall, severe, life-threatening or fatal (Grade 3-5) adverse drug
reactions were observed in 55.0% vs 13.8% of patients for regorafenib and placebo, respectively
(page 56-58, Rapporteurs’ Joint Assessment Report).
Due to the significant toxicity and the minimal efficacy the SAG was uncertain that the balance of
benefits and risks is positive.
In view of the toxicity profile of regorafenib, should this product be widely available to the
oncology community, appropriate educational material and risk minimisation measures should be
in place to ensure appropriate monitoring and follow-up of toxicity with this oral agent.
2. Whereas 50% or more of the patients in the experimental treatment arm have
already progressed by Week 8, and few patients experienced a tumour response,
the Kaplan-Meier curves for Overall Survival appear to separate already at 50 days,
after only a minority of patients in both groups have died. Could the SAG offer an
opinion on the internal consistency of the pattern of results observed and
comment on the clinical relevance of the differences in OS for the assessment of
efficacy of the product?
The lack of a clear effect in terms of PFS may be due to a number of reasons, including the
scheduled frequency of the assessment. In and of itself, the apparent discordance between PFS
and OS is not considered of concern and does not necessarily suggest lack of internal
consistency.
3. Does the SAG consider the provided analyses exploring biomarkers and other
clinical and tumour parameters of patients enrolled in the pivotal study 14387
adequate and compelling in order to eventually identify parameters for proper
patient selection for treatment with regorafenib?
Unfortunately, the trial was not adequately designed to ensure availability of tumour and tissue
collection to maximise the likelihood of identifying important biomarkers associated with a
response to treatment. Even for established biomarkers such as KRAS, the data for analysis were
missing in a high proportion of patients.
Furthermore, notwithstanding the reduced data set available for biomarker analysis, the
biological and statistical analyses presented were inadequate and far from compelling
methodologically in ruling out identification of important biomarkers. Exhaustive explorative
analyses were not conducted and even standard statistics (Kaplan-Meier estimates) have not
been presented systematically to allow at least informal evaluation.
Undue importance was given by the applicant company to the risk of chance findings. However,
in this context, where it is clear that a majority of patients receives no benefit from the drug
whilst being exposed to significant toxicity, it is essential to conduct a systematic and in-depth
exploratory analysis of all potential clinical and biological factors that may help patient selection
or, at least, to generate hypotheses to be validated on independent data sets.
4. Does the SAG foresee additional analyses to be performed with the available data
and/or in future studies in order to identify patients who may benefit from
treatment with regorafenib?
It is essential to conduct a systematic and exhaustive exploratory analysis on the available data
(including data from compassionate use programmes, where appropriate) of all potential factors
that may help patient selection or, at least, to generate hypotheses to be validated on
independent data sets.
Tabular and graphical presentations of particular statistics (Kaplan-Meier estimates, etc.), should
be systematically produced. An in-depth univariate and multivariate analysis of factors
associated with treatment effect should be conducted and presented.
The association between KRAS mutation and lack of response to treatment should be clarified as
a matter of priority (based on the available data, if possible). Furthermore, factors associated
with a treatment effect in patients with longer PFS (using different landmarks, e.g., 4, 6, 8
months) should be explored.
Additional biomarkers could be derived from exploration of the role of standard tumour biological
parameters (e.g., mitotic index, Ki-67, tumour grade). In addition analysis of specific biological
(intracellular) pathways known to be affected by the drug should be conducted.
Furthermore, as a non-hypothesis driven approach in a research setting, next-generation

sequencing, number of circulating tumour cells, endothelial cells and endothelial progenitor cells
may help to identify biomarkers for future patient selection.
Similarly, further analysis of factors associated with individual differences in drug metabolism
may help to clarify the dose-response relationship and help to identify a sub-population for whom
regorafenib is likely to have a better risk-benefit balance.
2.5.4. Conclusions on the clinical efficacy
This single pivotal trial demonstrated a statistically significant benefit for regorafenib in
metastatic colorectal cancer patients pre-treated or unsuitable for all approved standard
therapies.
Although the benefit in terms of both OS and PFS is undisputable from a statistical perspective,
the magnitude of the effect is limited, no improvement has been reported on symptoms and the
median duration of stable disease is very short in the overall population. It seems that the
benefit is driven by a subset of patients, considering that half of the treated population progress
or die very early (58% at 3 months). Unfortunately, none of the biomarkers explored to date
appears to be predictive of regorafenib clinical activity.
The CHMP considers the following measures necessary to address issues related to efficacy:
- To submit pre-specified, exploratory wild-type and mutant KRAS subgroup analyses from
study 15808 (CONCUR - randomised, double-blind, placebo-controlled phase III study of
regorafenib plus best supportive care (BSC) versus placebo plus BSC in Asian subjects with
metastatic colorectal cancer (CRC) who have progressed after standard therapy)
To submit NRAS and BRAF biomarker analyses from the same study, subject to sample
availability and confirmation of appropriate informed consent
A proposal for additional biomarkers assessment should be submitted to the CHMP within two
months of the marketing authorisation.
- To submit pre-specified, exploratory genetic (including NRAS, KRAS, BRAF and PIK3CA) and
non-genetic (ANG-2, IL-6, IL-8, P1GF, VEGFR-1, TIE1, VEGF-A, VEGF-C, VEGF-D, VEGF-A-121,
BMP-7, VWF, M-CSF, SDF-1) appropriate biomarker analyses from study 15983 (randomised,
double-blind, placebo-controlled phase-III study of adjuvant regorafenib versus placebo for
patients with stage IV colorectal cancer after curative treatment of liver metastases). Genetic
and non-genetic biomarker analysis should be implemented as mandatory for all enrolled
patients.
Prospective serial measurement should be planned and assessed for biomarkers. The proposed
protocol for biomarkers assessment should be submitted to the CHMP within two months of the
marketing authorisation.
2.6. Clinical safety
Patient exposure
Overall approximately 1145 patients with cancer, including 621 patients with CRC and 124
healthy volunteers have been exposed to regorafenib in applicant-sponsored trials up to
31 December 2011.The safety database of regorafenib has been presented in 3 different
populations:
- Pool 1: 188 patients enrolled in Phase 1 and Phase 2 uncontrolled studies conducted with
single agent regorafenib administered on an intermittent dosing schedule (3 weeks on/ 1 week
off): studies 11650, 13172, 14996, 11726, and 14596. The dose of regorafenib was 160 mg od
in these studies, with the exception of the dose escalation study 11650, in which regorafenib
doses from 20 to 220 mg od were administered.
- Pool 2: 84 patients enrolled in uncontrolled Phase 1 study 11651 performed with single-agent
regorafenib administered continuously once daily at doses ranging from 10 to 140 mg in patients
with metastatic and/or unresectable solid tumours.
- Pool 3: 753 patients in the safety population from the pivotal Phase 3 study 14387 in mCRC
(500 patients having received single agent regorafenib vs 253 patients having received placebo).
Moreover, deaths and SAEs as observed in other studies performed with regorafenib
administered in combination with chemotherapy or as monotherapy with other dose schedules or
in other indications than mCRC were reported.
However, the safety analysis below is focused on the data available from the phase 3 pivotal
study, where regorafenib was compared with placebo in the target population. In this study and
as of the clinical cut-off date, the median actual daily dose was 160 mg in both study arms,
which corresponded to the protocol target daily dose of 160 mg/day. The median duration of
treatment was similar between regorafenib and placebo (7.27 vs 6.98 weeks, respectively, with
overlapping ranges), whereas the mean was 12.08 (±9.74) and 7.78 (±5.19) weeks,
respectively.
Exposure to regorafenib in the different safety populations is summarised in the following Table 10.
Table 10: Extent of exposure to regorafenib and placebo in Pools 1 to 3, safety

population
Pool 1 Pool2 Pool3
N = 188 N=84 N = 500 N =255
Overall time under treatment
•
Mean ±SD (weeks) 25.79 ± 19.74 ± 29.99 12.08 ± 9.74 7.78 ± 5.19
33-47
Median 14.79 11.43 7.27 6.98
Range 0.1 -179.4 0.1 -145.0 0.28 -4701 0.57 -38.61
Actual time under treatment b

Mean ±SD (weeks) 18.86 ± 18.01 ± 27.14 8.85 ± 6.78 6.29 ± 3.79
24.38
Median (range) 9.64 9.93 5.98 5.98
Range 0.1 -132.3 0.1-134.1 0.28-35.9 0.57 -29.92
Actual daily dose (mg) b

Mean ±SD 137.38 ± 39.41 88.82 ± 29.06 147.13±18.64 159.25 ± 4.85
Median 160.00 100.0 160.00 160.00
Range 10 - 220 20.0 -140.0 85.7 -160.0 107.00 -160.0
Any dose modification, n (%) 112 (59.6%) 83 ( 98.8%) 378 ( 75.6%) 97 ( 38.3%)
Dose reduction per patient, n

(%) C
An~ Jose reduction 79 (42.0) 5 (6.0) 100 ( 20.0) 8 ( 3.2)
1 45 (23.9) 5 (6.0) 82( 16.4) 8 ( 3.2)
2 26 (13.8) 0 14 ( 2.8) 0
,!3 8 (4.2) 0 4 ( 0.8) 0
Dose interruptions per

patient, n (%)
Any dose interruption 148 (78.7) 83 ( 98.8) 352 ( 70.4) 95 ( 37.5)
1 70 (37.2) 22 ( 26.2) 178 ( 35.6) 70 ( 27.7)
2 27 (14.4) 32 ( 38.1) 94 ( 18.8) 19 ( 7.5)
>3 51 (27.1\ 29 (34 5) 80 (16 0) 6 p.4l
Abbreviations: N - number of patients (in total); n - number of patients with the event; SAF - safety analysis set;
SD = standard deviation
lfil!JE coill
Adverse events
An overview of adverse events in the different safety populations is presented in Table 11.
Table 11: Overview of Adverse Events in Pools 1 to 3 (SAF)
IP00I1 PooI2 Pool3

Characteristic N = 188 N =84 N = 500 N = 253
Number of patients (%) with:
AnyAE 187 (99.5) 81 (96.4) 498 (99.6) 245 (96.8)
Worst grade
Grade 3 108 (57.4) 47 (56.0) 280 (56.0) 67 (26.5)
Grade 4 23 (12.2) 7 (8.3) 43 (8.6) 20 (7.9)
Grade 5 22 (11.7) 7 (8.3) 67 (13.4) 37 (14.6)
SAE 102 (54.3) 40 (47.6) 219 (43.8) 100 (39.5)
Leading to permanent discontinuation •60 (31.9) 25 (29.8) 88 (17.6) 32 (12.6)
of study drug
Leading to dose modification 114 (60.6) 35 (41.7) 333 (66.6) 57 (22.5)
Any drug-related AE 170 (90.4) 73 (86.9) 465 (93.0) 154 (60.9)

Worst grade
Grade 3 100 (53.2) 37 (44.0) 253 (50.6) 31 (12.3)
Grade 4 9 ( 4.8) 1 (1.2) 17(3.4) 4 (1.6)
Grade 5 • 5 ( 2.7) 0 5 (1) 0
SAE 47 (25.0) 4 (4.8) 59(11.8) 9 (3.6)
Leading to permanent discontinuation 34 ( 18.1) 5 (6.0) 41 (8.2) 3 (1.2)
of study drug
Leading to dose modification 97 ( 51.6) 32 (38.1) 278 (55.6) 23 (9.1)
Abbreviations: AE - adverse event; N - number of patients; SAF - safety analysis set; SAE = serious adverse
event
• Although there are 5 patients in the regorafenib group with drug-related grade 5 events included in this table,
there were in actuality 4 patients (not 5) with grade 5 events in the regorafenib group (and none in the placebo
group) assessed by the investigator as drug related. For 1 patient in the regorafenib group, a hepatic failure
was incorrectly recorded as related to regorafenib; this has been corrected post dinical database locK.
Abbreviations: AE - adverse event; SAE - serious adverse event; SAF - safety population
In the pivotal 14387 (CORRECT) study, adverse events (AEs) were coded using MedDRA 14.0
and graded using the National Cancer Institute Common Toxicity Criteria (version 3.0). An
overview of the most common AEs in the different safety populations is presented in Table 12.
In the pivotal study, AEs (any grade, by CTCAE term) notably more frequently observed (≥10%
difference) with regorafenib compared with placebo were fatigue (63.4% vs 46.2%), hand-foot
syndrome (47.0% vs 7.5%), anorexia (46.8% vs 28.5%), diarrhoea (42.8% vs 17.0%), weight
loss (32.0% vs 11.1%), voice changes/dysphonia (32.0% vs 6.3%), hypertension (30.4% vs
7.9%), rash/desquamation (29.0% vs 5.1%), mucositis (functional/ symptomatic), oral cavity
(28.8% vs 4.7%), fever (28.4% vs 15.4%), hyperbilirubinemia (20.0% vs 9.5%), platelet counts
abnormalities (15.6% vs 2.4%), haemorrhage (20.4% vs 6.7%) and infections (25.2% vs
14.2%). The difference was mainly due to a higher incidence of grade 1-3 events. These AEs
were also most frequently reported as drug-related events.
The most common Grade 3 AEs (by CTCAE term) with higher frequency in the regorafenib,
compared to the placebo arm, were hand-foot syndrome (16.6% vs 0.4%), fatigue (15.0% vs
8.3%), diarrhoea (8.2% vs 2.0%]), hypertension (7.6% vs 0.8%), rash/desquamation (5.8% vs
0.4%), platelet counts abnormalities (3.4% vs 0.4%) haemoglobin abnormalities (5.4% vs
3.2%), mucositis (3.2% vs 0%), hyperbilirubinemia (6.8% vs 4.3%), AST increase (2.4% vs
1.2%), and (abdominal) pain (9.8% vs 5.7%). In the great majority of cases these events were
considered drug related.
The incidence of the most common (≥ 1% patients in either treatment group) grade 4 AEs was
similar between the two treatment arms. They were (regorafenib vs placebo) infections (1.6% vs
0.4%), lipase abnormalities (1.2% vs 0.4%), constitutional symptoms (1.0% vs 1.2%),
hyperbilirubinemia (0.8% vs 2.0%) and fatigue (0.4% vs 2.0%).
The observed regorafenib AE profile was comparable between the Pool 1-3 populations. Overall,
the most frequently reported AEs in patients treated with regorafenib were decreased appetite,
palmar-plantar erythrodysesthesia syndrome, diarrhoea, fatigue, weight decreased,
hypertension, dysphonia, pyrexia, asthenia, constipation, nausea, rash and pain (in the
extremity, abdominal back).
Table 12: Most Common (>10 % overall in regorafenib group) AEs by MedDRA
preferred term (Pool 3, study 14387, SAF)
Pool1 Pool2 Pool3

Regorafenib Regorafenib Regorafenib Placebo a
N = 188 N = 84 N = 500 N = 253
AnyAE n (%) 187 (99.5) 81 (96.4) 498 (99.6) 245 (96.8)
Decreased appetite 69 (36.7) 25 (29.8) 234 (46.8) 72 (28.5)
Palmar-plantar erythrodys- 103 (54.8) 21 (25.0) 225 (45.0) 18 (7.1)
aesthesia syndrome
Diarrhoea 91 (48.4) 24 (28.6) 214 (42.8) 43 (17.0)
Fatigue 87 (46.3) 41 (48.8) 201 (40.2) 74 (29.2)
Weight decreased 54 (28.7) 4 (4.8) 161 (32.2) 26 (10.3)
Hypertension 65 (34.6) 24 (28.6) 152 (30.4) 20 (7.9)
Dysphonia 73 (38.8) 19 (22.6) 150 (30.0) 16 (6.3)
Pyrexia 52 (27.7) 14 (16.7) 140 (28.0) 37 (14.6)
Asthenia 9 (4.8) 4 (4.8) 132 (26.4) 45 (17.8)
Constipation 51 (27.1) 21 (25.0) 119 (23.8) 48 (19.0)
Nausea 57 (30.3) 26 (31.0) 112 (22.4) 55 (21.7)
Rash 30 (16.0) 20 (23.8) 110 (22.0) 8 (3.2)
Abdominal pain 40 (21.3) 19 (22.6) 98 (19.6) 41 (16.2)
Dyspnoea 39 (20.7) 18 (21.4) 85 (17.0) 32 (12.6)
Stomatitis 25 (13.3) 3 (3.6) 85 (17.0) 8 ( 3.2)
Mucosal inflammation 31 (16.5) 11 (13.1) 82 (16.4) 4 ( 1.6)
Vomiting 43 (22.9) 18 (21.4) 80 (16.0) 41 (16.2)
Hyperbilirubinaemia 7 (3.7) 11 (13.1) 65 (13.0) 17 (6.7)
Back pain 31 (16.5) 18(21.4) 63 (12.6) 25 (9.9)
Anaemia 12 (6.4) 7 (8.3) 55 (11.0) 21 (8.3)
Cough 31 (16.5) 14 (16.7) 53 (10.6) 27 (10.7)
Headache 41121.8l 12 p4.3l 51 110.2i 11 (6.7l
Abbreviations: AE - adverse event; N - number of patients (in total); n - number of patients with the event;
SAF - safety analysis set
A patient may have had more than one AE (may appear more than once in this table)
Events are listed in decreasing frequency in the regorafenib total group
a Placebo group of study 14387 to be compared to Pool 3 regorafenib arm of the same study
Adverse Drug Reactions (ADRs)
From all clinical experience to date, the most frequently observed adverse drug reactions
(≥30%) in patients receiving Stivarga were asthenia/fatigue, decreased appetite and food intake,
hand foot skin reaction, diarrhoea, weight loss, infection, hypertension and dysphonia. The most
serious adverse drug reactions in patients receiving Stivarga were severe liver injury,
haemorrhage and gastrointestinal perforation. ADRs of Stivarga are summarised in the following
Table 13.
IITRUE COPYII
Table 13: Adverse drug reactions (ADRs) reported in clinical trials in patients treated
with Stivarga
System Organ
Class Very common Common Uncommon Rare
(MedDRA)
Infections and Infection
infestations
Neoplasms benign, Keratoacanthoma/
malignant and Squamous cell
unspecified carcinoma of the
(including cysts and skin
polyps)
Blood and lymphatic Thrombocytopenia Leucopenia
system disorders Anaemia
Endocrine disorders Hypothyroidism
Metabolism and Decreased appetite Hypokalaemia

nutrition disorders and food intake Hypophosphataemia
Hypocalcaemia
Hyponatraemia
Hypomagnesaemia
Hyperuricaemia
Nervous system Headache Tremor Posterior

disorders reversible
encephalopathy
syndrome (PRES)
Cardiac disorders Myocardial
infarction
Myocardial
ischaemia
Vascular disorders Haemorrhage* Hypertensive
Hypertension crisis
Respiratory, thoracic Dysphonia
and mediastinal
disorders
Gastrointestinal Diarrhoea Taste disorders Gastrointestinal
disorders Stomatitis Dry mouth perforation*
Gastro-oesophageal Gastrointestinal
reflux fistula
Gastroenteritis
Hepatobiliary Hyperbilirubinaemia Increase in Severe liver
disorders transaminases injury*#
Skin and Hand-foot skin Dry skin Erythema Stevens-Johnson
subcutaneous tissue reaction** Alopecia multiforme syndrome
disorders Rash Nail disorder Toxic epidermal
Exfoliative rash necrolysis
Musculoskeletal and Musculoskeletal
connective tissue stiffness
disorders
Renal and urinary Proteinuria
disorders
General disorders Asthenia/fatigue
and administration Pain
site conditions Fever
Mucosal inflammation
Investigations Weight loss Increase in amylase
Increase in lipase
Abnormal
International
normalised ratio
* fatal cases have been reported
** palmar-plantar erythrodysesthesia syndrome in MedDRA terminology
#
according to drug-induced liver injury (DILI) criteria of the international DILI expert working group
Adverse Events of special interest (AESI)
AEs of special interest (AESI) included hypertension, hand-foot skin reaction, rash, diarrhoea,
myocardial ischemia, bleeding, gastrointestinal perforationhepatobiliary events, proteinuria and
renal failure, impaired wound healing and thromboembolic events.
Hypertension was reported in approximately 30% of patients treated with regorafenib in all
studies performed. Generally hypertension was mild or moderate in severity (grade 3 events
reported in 7.6%, no grade 4 or 5) and appears to be manageable with anti-hypertensive drugs.
Within the all regorafenib safety database one event of hypertensive crisis associated with
development of reversible posterior leukoencephalopathy syndrome (RPLS) was observed.
Hand-foot syndrome (HFS) was observed in 47% of patients treated with regorafenib. Most
events were of grade 1 or 2 severity, grade 3 events were observed in 16.6% of patients,
whereas no grade 4 was reported. HFS AEs could usually be managed by dose reductions or
interruptions. HFS led to permanent discontinuation, dose reduction and interruption in 7
(1.4%), 92 (18.4%) and 96 (19.2%) regorafenib treated patients, respectively.
Rash was experienced in around 47% of regorafenib-treated, with time to first onset within the
first 8 weeks of therapy. Events were generally mild or moderate in severity and led to dose
modifications in a low percentage of patients (2.8%). Data on skin toxicity and recommended
dose modifications for management of HFS and rash are reflected in the SPC.
Gastrointestinal toxicity was also frequently observed (especially diarrhoea [42.8%] and
mucositis/stomatitis [28.8%]) but events were generally of mild and moderate severity and
considered manageable. In toxicology studies atrophy of the tongue has been observed in mice
and rats, but no information regarding reporting of such AE in clinical studies has been provided
by the Applicant.
Cardiac events have been observed in 8-26% of patients treated with regorafenib in different
studies. An increased frequency of myocardial ischemia and infarction has been associated with
treatment with regorafenib (1.2% vs 0.4% with regorafenib vs placebo, respectively) in the
pivotal study, with a slightly increased risk in patients with cardiovascular risk factors. The
incidence of other thromboembolic events did not appear to be significantly influenced by
treatment with regorafenib. More patients treated with regorafenib compared with placebo (9.8%
vs 7.1%) in the pivotal study experienced congestive heart failure and related symptoms, but as
the difference was primarily due to peripheral oedema and no routine evaluation of LVEF was
performed, the clinical relevance of such findings is unclear. By analysis of study 14814,
evaluating the effect of regorafenib on LVEF and QT prolongation, regorafenib does not appear to
significantly affect LVEF% and QTc interval. In the pivotal trial the incidence of atrial fibrillation
was higher in the regorafenib arm. The reason of this increased incidence could be that there
were more patients with supraventricular arrhythmias history in regorafenib group at baseline
(5.0% of patients with a baseline history of supraventricular arrhythmias in the regorafenib
group compared to 2.5% of patients in the placebo group).
Haemorrhage/bleeding events were reported in 20.4% of regorafenib-treated patients versus

6.7% of placebo-treated patients in the pivotal study, with most of events being either grade 1
(17.0% vs 4.7%) or grade 2 (1.4% vs 1.2%) and very few grade 3/4 events (1.4% vs 0.8%).
The most common bleeding AE (any grade) in both treatment groups was haemorrhage
pulmonary/nose (8.8% vs 2.4%), followed by haemorrhage anus (3.2% vs 0.4%), urinary (2.2%
vs 1.2%), rectum (1.2% vs 0%), and others (2% vs 0%). A total of 4 patients (0.8%) in the
regorafenib arm vs no patient in the placebo arm experienced fatal bleedings, 3 of them
considered as drug-related. A clear relation between haemorrhages and thrombocytopenia
and/or alteration of coagulation parameters observed in regorafenib treated patients could not be
made. In Pool 3, all reported respiratory tract haemorrhage (haemoptysis in 1 placebo patient,
pulmonary haemorrhage in 2 regorafenib patients, 1 of which fatal) occurred in patients with
baseline or lung metastases.
Similar to other inhibitors of the VEGFR pathway, a slightly increased incidence of

gastrointestinal perforation or fistula was observed with regorafenib (0.8 vs 0.4%, respectively),
although analysis is hampered by confounding factors related to underlying disease. By
cumulative review of all regorafenib treated patients in the safety database, 7 cases, 4 of which
fatal, were considered by the investigators as possibly related to regorafenib. No specific
population was identified to be at higher risk.
Hyperbilirubinemia (probably related to impaired glucuronidation through UGT1A1 inhibition) and

liver enzyme (AST/ALT) abnormalities were commonly observed with regorafenib (13%, 45%
and 65%, respectively), and with higher incidence compared with placebo (hyperbilirubinemia:
6.7%). Most of events were grade 1 or 2 in severity. Two cases meeting Hy’s Law criteria and 3
cases of severe drug-induced liver injury (DILI) events were described.
The most common hepatobiliary disorders in the pivotal study were hyperbilirubinemia, hepatic
function abnormal, hepatic pain, and hepatic failure. Serious hepatobiliary disorders (including
fatal events) were reported in 5.4% of patients treated with regorafenib, and more frequently
than in placebo patients. There were 11 deaths due to hepatobiliary disorders, 3 (1.2%) in the
placebo group and 8 (1.6%) in the regorafenib group. Hepatobiliary events resulting in death
included one event of cholestasis (placebo group); 7 events of hepatic failure (placebo, 1;
regorafenib, 6); and 3 events of hepatic function abnormal (placebo, 1; regorafenib, 2).
Proteinuria was more frequently reported in the regorafenib group compared with the placebo
group of the pivotal study (8% vs 2.4) with 7% and 1.6%, respectively, considered related to
study drug. Most events were grade 1 or 2. Grade 3 proteinuria was reported in 8 (1.6%) and 1
(0.4%) patient in the regorafenib and placebo arm, respectively. No grade 4 or 5, neither SAE of
proteinuria was reported. No cases of proteinuria resulting in acute renal failure were observed.
Proteinuria AEs were usually observed within the first 2 cycles of therapy and could usually be
managed by dose reductions or interruptions. Proteinuria led to permanent discontinuation, dose
reduction and interruption in 2 (0.4%), 3 (0.6%) and 6 (1.2%) regorafenib treated patients,
respectively. Asian patients treated with regorafenib had a higher incidence of proteinuria
compared with White patients (27/74, 36.5% vs 10/389, 2.6%). The rate of protenuria events,
mainly Grade 1 and 2, was consistent between the pivotal trial (8.6%) and the pooled
monotherapy safety set (8.2%). In 17 of the 43 patients in the pivotal trial (39.5%) and in 22 of
the 63 patients in the pooled safety set (34.9%) the proteinuria event was registered as not
recovered/not resolved. Considering that in one third of patients proteinuria does not recovered
and renal failure cases, mainly secondary to dehydration due to diarrhoea/vomiting, have been
reported from Eudravigilance, the Applicant should add information on cases with not recovery of
proteinuria in Section 4.8 of the SmPC.
Renal failure was reported in <5% of patients treated with regorafenib in the studies performed
and in the pivotal study the incidence of renal failure was slightly but not significantly higher in
the regorafenib arm compared with the placebo arm (2.2% vs 1.6%). Most of events were grade
3 (1.8% vs 1.2% of cases), no grade 4 events and one grade 5 event were observed in the
regorafenib arm. Increase in creatinine laboratory data was similar in both arms (15%).
No cases of impaired wound healing were observed in the pivotal study, whereas according to a
cumulative review of all patients treated with regorafenib up to 31 December 2011 a total of 6
cases were reported (5 serious and 1 non-serious), one of which treated with placebo.
Information over this AE has been added to the SPC.
No cases of interstitial lung disease have been reported in patients treated with regorafenib. In
the pivotal study the most common respiratory AEs were dysphonia (30% vs 6.3%), dyspnoea
(17% vs 12.6%), and cough (10.6% vs 10.7%) with overall a similar incidence of serious
respiratory, thoracic and mediastinal events.
In all 3 pools, the frequency of pulmonary embolism events in regorafenib-treated patients (Pool
3: 0.8%; Pool 2: 2.4%; Pool 1: 1.1%) and other venous thromboembolic events (Pool 3: 1.2%;
Pool 2: 2.4%; Pool 1: 0.5%) was relatively low, and, in Pool 3 it was similar to the placebo group
(1.2% and 0.8%, respectively).
In in vitro assays a potential for phototoxicity was identified for regorafenib and its active
metabolites M2 and M5, but it was not confirmed in pre-clinical models and only 0.5% of patients
in the pivotal study reported phototoxicity related events, all of grade 1 severity.
The effect of regorafenib on QT interval was evaluated in Study 14814, conducted in patients
with advanced solid tumours, where ECGs are collected by Holter monitoring over 24 hours at
baseline and after at least one 21 day cycle of treatment. Overall, the effect of regorafenib at
tmax on the QTc intervals of the ECG was very limited, and even with the most conservative
evaluation, the maximal median change was modest and unlikely to be of clinical significance in
the setting of cancer treatment. In the ECG assessment related to the pivotal 14387 study, a
12-lead ECG was performed on Day 1 of each cycle for the first 6 cycles (and at subsequent
cycles at the investigator’s discretion). A similar percentage of patients in either treatment group
(regorafenib and placebo) had a QTcB or QTcF increase > 60 ms from baseline at end of
treatment evaluation (QTcB: 3.2% vs 3.4%; QTcF: 2.2% vs 2.7%). For both QTcB and QTcF, a
higher percentage of regorafenib-treated patients than placebo-treated patients had a QTcB or
QTcF increase > 30 - < 60 ms from baseline (QTcB: 12.9% vs 5.5%, respectively; QTcF: 7.2%
vs 2.7%, respectively). For patients in both groups, the QTcF and QTcB remained relatively
constant for the duration of the study. In an analysis of AEs which could be potentially related to
QT prolongation observed in patients enrolled in Study 14814 and the pivotal study 14387, no
safety signals suggesting a correlation between QT prolongation and such events could be
identified.
Serious adverse event/deaths/other significant events
Serious Adverse Events (SAEs)
Common SAEs in 1-3 Pools included general physical health deterioration, pyrexia, abdominal
pain, pneumonia, dyspnoea, fatigue, urinary tract infection, diarrhoea, decreased appetite and
infection.
In Pool 3 (pivotal 14387 study), incidence of SAEs was slightly higher with regorafenib compared
with placebo (43.8% vs 39.5%). SAEs were mostly related to general physical health
deterioration (7.2% vs 9.5%) and not considered related to study drug. In the regorafenib arm,
there was a higher incidence of the SAEs pyrexia (2.8% vs 0.4%), abdominal pain (2.4% vs.
0.8%), diarrhoea (1.6% vs 0%), hepatic failure (1.4% vs. 0.8%), haemorrhages (1% vs 0%),
and jaundice (0.4% vs 0%), whereas incidence of pneumonia (2.0% vs 1.6%) and dyspnoea
(2.0% vs 1.2%) was similar between the two arms.
In Pool 2 the most frequently reported SAEs were fatigue (4.8%), chest pain (3.6%), pneumonia
(3.6%), urinary tract infection (3.6%) and dyspnoea (3.6%). Two haemorrhage SAEs (3.6%)
and 1 hypertensive crisis were also reported.
In Pool 1 the most frequently reported SAEs were similar to Pool 2 and 3 and consisted of
infection (4.3%), fatigue (3.7%), abdominal pain (3.2%), diarrhoea (3.2%), and physical
deterioration (2.7%). One case of cerebral haemorrhage SAE and 4 cases of hypertension SAE
(2.1%) were also seen.
Deaths
Across patients enrolled in Pool 1-3, a total of 138 death events occurred during treatment and
up to 30 days after treatment discontinuation, the majority (111 deaths) of which were
associated with disease progression. Across all pools, the most common cause of death other
than disease progression in regorafenib-treated patients was haemorrhage (4 patients:
gastrointestinal, vaginal, pulmonary, and intracranial haemorrhages, respectively), cardiac arrest
(3 patients), and pneumonia (3 patients).
In Pool 3, there were 110 total deaths reported, with a slightly higher frequency in the placebo
group (13.6% with regorafenib vs 16.2% with placebo). Deaths not associated with disease
progression represented a minority of the events and, in the regorafenib group, included
3 patients with haemorrhage (1 gastrointestinal, 1 vaginal, and 1 pulmonary haemorrhages),
2 patients with death due to pneumonia, 1 patient with cardiac arrest, 1 patient with general
physical health deterioration, 1 intestinal obstruction, 1 cerebrovascular accident, 1 sudden death
and 1 death unknown. Deaths not associated with disease progression in the placebo group
included 2 sudden deaths, 2 pneumonias, 1 cardiac arrest and 1other death not further specified.
In Pool 1, there were 21 deaths, 12 associated with disease progression. Deaths not associated
with disease progression included 2 cardiac arrest, 1 pulmonary embolism, 1 pneumonia, 1
haemoptysis, 1 haematoma, 1 intracranial haemorrhage; 1 intestinal obstruction; and 1 ascites.
In Pool 2, of the 7 deaths observed, 6 were associated with disease progression and one was
classified as ‘other’.
Laboratory findings
The most common haematological and biochemical abnormalities in the pivotal 14387 study are
summarised in the following Table 14.
Table 14: Laboratory test abnormalities, study 14387, safety population
Stivarga plus BSC§ Placebo plus BSC§

Laboratory parameter (N=500) (N=253)
(in % of samples
investigated) All Grade Grade All Grade Grade
Grades* 3* 4* Grades* 3* 4*
Blood and lymphatic

system disorders
Haemoglobin decreased 78.5 4.7 0.6 66.3 2.8 0
Platelet count decreased 40.5 2.4 0.4 16.8 0.4 0
Neutrophil count decreased 2.8 0.6 0 0 0 0
Lymphocyte count 54.1 9.3 0 34.4 3.2 0
decreased
disorders
Calcium decreased 59.3 1.0 0.2 18.3 1.2 0
Potassium decreased 25.7 4.3 0 8.3 0.4 0
Phosphate decreased 57.4 30.5 0.6 11.1 3.6 0
Hepatobiliary disorders
Bilirubin increased 44.6 9.6 2.6 17.1 5.2 3.2
AST increased 65.0 5.3 0.6 45.6 4.4 0.8
ALT increased 45.2 4.9 0.6 29.8 2.8 0.4
Renal and urinary
disorders
Proteinuria 59.7 0.4 0 34.1 0.4 0
Investigations
INR increased** 23.7 4.2 -# 16.6 1.6 -#
Lipase increased 46.0 9.4 2.0 18.7 2.8 1.6
Amylase increased 25.5 2.2 0.4 16.7 2.0 0.4
§
Best Supportive Care
* Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0
** International normalized ratio
#
No Grade 4 denoted in CTCAE, Version 3.0
Regarding thyroid function tests (TSH, fT3 and fT4) as observed in the pivotal study, a higher
mean increase of TSH (thyroid stimulating hormone, thyrotropin) and decrease of fT3
(triiodothyronine) from baseline was reported in patients treated with regorafenib compared with
placebo. In general, mean and median values of thyroid function tests were similar between
baseline and end of treatment with the exception of TSH in the regorafenib arm where mean and
median values at end of treatment were approximately twice the values at baseline.
Safety in special populations
A population PK analysis of the pivotal study in order to evaluate the influence of intrinsic factors
(age, gender, body weight, ethnicity, renal and hepatic functions) on PK was submitted.
No safety data of regorafenib in paediatric patients are available, as there is no relevant use of
Stivarga in paediatric patients in the colorectal cancer indication. Important safety information
regarding the elderly population is in presented in the following Table 15.
Table 15: Overview of adverse events by age group, study 14387, safety population
Placebo Regorafenib 60-160 mg

Age <65 Age 65-74 Age 75-84 Age <65 Age 65-74 Age 75-84
N=164 N=71 N=17 N=307 N=155 N=38
(100%) (100%) (100%) (100%) (100%) (100%)
Adverse Events
Any event 157 ( 95.7%) 71 (100.0%) 16 ( 94.1%) 305 ( 99.3%) 155 (100.0%) 38 (100.0%)
Serious Adverse Events - Total 64 ( 39.0%) 32 ( 451%) 4 ( 235%) 137 ( 44.6%) 68 (439%) 14 ( 36.8%)
- Fatal 30 ( 183%) 12 ( 169%) 2 ( 118%) 42 ( 13.7%) 24 ( 155%) 8 ( 21.1%)
- Hospitalization/prolong existing 57 ( 34.8%) 28 ( 39.4%) 3 ( 17.6%) 120 ( 39.1%) 59 ( 38 1%) 12 ( 31.6%)
hospitalization
- Life-threatening 6 ( 37%) 7 ( 99%) 0 18 ( 5.9%) 8 ( 5.2%) 2 ( 5.3%)
- Disability/incapacity 4 ( 2.4%) 0 1 ( 59%) 3 ( 1.0%) 4 ( 26%) 0
- Other (medically significant) 4 ( 2.4%) 2 ( 2 8%) 0 10 ( 33%) 7 ( 45%) 1 ( 26%)
AE leading to drop-out 18 ( 11.0%) 10 ( 14.1%) 4 ( 235%) 54 ( 17.6%) 26 ( 16 8%) 8 ( 21.1%)
Psychiatric disorders (SOC) 21 ( 12.8%) 12 ( 16.9%) 1 ( 59%) 40 ( 13.0%) 26 ( 168%) 6 ( 15.8%)
Nervous system disorders (SOC) 17 ( 10.4%) 5 ( 70%) 1 ( 59%) 69 ( 22.5%) 36 (232%) 9 ( 237%)
Accidents and injuries (SMQ) 2 ( 1.2%) 3 ( 4.2%) 0 11 ( 3.6%) 2 ( 1 3%) 0
Cardiac disorders (SOC) 12 ( 7.3%) 2 ( 28%) 0 26 ( 8.5%) 12 ( 7 7%) 4 ( 10.5%)
Vascular disorders (SOC) 15 ( 9 1%) 14 ( 19 7%) 3 ( 176%) 100 ( 32.6%) 56 ( 36 1%) 16 ( 42.1%)
Cerebrovascular disorders (SMQ) 0 2 ( 2.8%) 1 ( 59%) 2 ( 0.7%) 4 ( 26%) 1 ( 2.6%)
Infections and infestations (SOC) 30 ( 183%) 1 'I ( 155%) 2 ( 118%) 91 ( 29.6%) 53 ( 342%) 10 ( 26 3%)
Quality of life decreased (PT) 0 0 0 0 0 0
Drug-related Adverse Events
Any event 94 ( 57.3%) 49 ( 69.0%) 10 ( 58.8%) 288 ( 93.8%) 142 ( 91.6%) 35 ( 92.1%)
Serious Adverse Events - Total 7 ( 4.3%) 2 ( 2.8%) 0 30 ( 9.8%) 24 ( 155%) 5 ( 13.2%)
- Fatal 0 0 0 5 ( 1.6%) 2 ( 1 3%) 1 ( 2.6%)
- Hospitalization/prolong existing 5 ( 3.0%) 1 ( 1.4%) 0 25 ( 8.1%) 22 ( 142%) 5 ( 13.2%)
hospitalization
- Life-threatening 0 0 0 6 ( 2.0%) 3 ( 1.9%) 1 ( 2.6%)
- other (medically significant) 2 ( 12%) 1 ( 1.4%) 0 5 ( 1.6%) 4 ( 26%) 1 ( 2 6%)
AE leading to drop-out 2 ( 12%) 1 ( 1.4%) 0 27 ( 8.8%) 11 ( 7 1%) 3 ( 7.9%)
Psychiatric disorders (SOC) 3 ( 1.8%) 1 ( 1.4%) 0 5 ( 1.6%) 4 ( 26%) 1 ( 2.6%)
Nervous system disorders (SOC) 6 ( 3.7%) 1 ( 1.4%) 0 42 ( 13.7%) 21 ( 13 5%) 6 ( 15.8%)
Cardiac disorders (SOC) 3 ( 1.8%) 0 0 10 ( 3.3%) 5 ( 3.2%) 1 ( 2.6%)
Vascular disorders (SOC) 8 ( 4.9%) 10 ( 14 1%) 2 ( 11.8%) 87 ( 28.3%) 49 ( 316%) 11 ( 28.9%)
Cerebrovascular disorders (SMQ) 0 0 0 0 2 ( 1.3%) 1 ( 2.6%)
Infections and infestations (SOC) 5 ( 3.0%) 0 0 27 ( 8.8%) 15 ( 9.7%) 2 ( 5.3%)
Quality of life decreased (PT) 0 0 0 0 0 0
The incidence of AEs was similar for female patients and male patients overall (98.3% females vs
98.9% males), in the regorafenib group (100% vs 99.3%) and in the placebo group (95.0% vs
98.0%) of the pivotal study.
~ TRUE COPYJI
In the pivotal 14387 study, the overall incidence of any AE and the incidence of most of the
common AEs was similar among race groups. In the regorafenib group, compared with
Caucasians, there was a higher incidence in Asians of palmar-plantar erythrodysaesthesia
syndrome (78.4% vs 38%), rash (40.5% vs 19.3%), and hypertension (54.1% vs 16.5%); and a
lower incidence of asthenia (1.4% vs 28.8%), abdominal pain (4.1% vs 22.4%), mucosal
inflammation (4.1% vs 18.3%), dyspnoea (8.1% vs 18%), hyperbilirubinemia (8.1% vs 14.7%),
diarrhoea (28.4% vs 45.8%), weight decrease (20.3% vs 33.9%), and anaemia (1.4% vs
12.9%). However, overall the same AEs were seen in all groups. Moreover, as the majority of
patients treated were Whites, no firm conclusion can be made regarding other ethnic groups, in
particular Blacks and Other.
No studies specifically in patients with hepatic impairment have been conducted. All patients
included in the studies performed with regorafenib to date were required to have bilirubin ≤ 1.5x
ULN and AST/ALT ≤ 2.5 or 5x ULN in case of liver metastases. No relevant safety data is
available for patients with moderate or severe hepatic impairment.
An analysis has been provided where AEs observed in the pivotal 14387 study were reported
according to three categories of AST and ALT at baseline: a) ≤ 1.5 x ULN (666 patients, 440
patients treated with regorafenib and 226 treated with placebo); b) > 1.5 xULN and ≤ 3xULN (67
patients, 44 patients treated with regorafenib and 23 treated with placebo); c) <3 xULN (7
patients, 2 patients treated with regorafenib and 5 treated with placebo). Very few patients were
enrolled in the third category to draw any meaningful conclusion. In the second category, more
patients treated with regorafenib experienced AEs of stomatitis (25.0%, vs. 17.0% overall),
dyspnoea (34.1% vs. 17.0% overall), hyperbilirubinemia (22.7% vs. 13.0% overall), general
physical health deterioration (25.0% vs. 9.2%), and peripheral oedema (22.7% vs 9.2%
overall). For patients with normal hepatic function at baseline (first category), the incidence of
SAEs was similar between treatment groups (42.8% with regorafenib and 38.5% with placebo);
in the second category, the incidence of SAEs was higher in the regorafenib group (52.3%) and
similar to the normal hepatic function group in the placebo arm (39.1%).
No studies in patients with renal impairment have been conducted. All patients included in the
studies performed with regorafenib to date were required to have serum creatinin ≤ 1.5x ULN
and estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73 m2 according to the MDRD
(modified diet in renal disease) abbreviated formula. Renal function was considered normal when
eGFR was ≥ 60 mL/min/1.73 m², and moderately impaired when eGFR was <60 mL/min/1.73
m². No relevant pharmacokinetics and safety data is available for patients with severe renal
impairment.
In the pivotal 14387 study (Pool 3), 30 patients had moderate renal impairment at baseline (21
treated with regorafenib and 9 with placebo). The incidence of most common AEs was similar
between normal and moderately renally impaired patients. In the regorafenib +BSC group,
patients with impaired renal function had a higher incidence (>10%) of reported AEs of
decreased appetite (57.1% vs 46.8% overall), diarrhoea (52.4% vs 42.8% overall), dysphonia
(47.6% vs. 30.0% overall), rash (33.3% vs. 22.0% overall), anaemia (28.6% vs. 11.0%
overall), and peripheral oedema (19.0% vs. 9.2% overall).
In the phase 1 dose escalating 11650 study, a pharmacokinetic analysis performed on patients
grouped according to renal function (according to MDRD equation) showed no differences in
regorafenib AUC or Cmax between patients with mild renal impairment and those with normal
renal function.
In conclusion, very few patients with impaired renal function (eGFR <60 mL/min/1.73 m2) have
been treated with regorafenib in the pivotal trial. A higher rate of drug-related SAEs has been
reported in patients with moderately impaired kidney function vs normal/mildly impaired kidney
function (28.6% vs 11.1%).
Safety related to drug-drug interactions and other interactions
Please refer to pharmacokinetic drug interactions and the discussion on clinical pharmacology.
Discontinuation due to adverse events
Fewer regorafenib-treated patients discontinued in Pool 3 (17.6%) than in Pool 2 (29.8%) or Pool
1 (31.9%). In Pool 3 treatment discontinuation occurred more frequently with regorafenib
(17.6%) compared with placebo (12.6%). The most frequent AEs causing regorafenib
discontinuation were general physical health deterioration (3.6%), palmar-plantar
erythrodysaesthesia syndrome (1.4%) and hepatic failure (0.8%) in Pool 3, chest pain (2.4%),
fatigue (2.4%), hyperbilirubinemia (2.4%), and small intestinal obstruction (2.4%) in Pool 2, and
fatigue (3.7%), palmar-plantar erythrodysaesthesia syndrome (1.6%), renal failure (1.6%), and
thrombocytopenia (1.6%) in Pool 1.
Dose reductions were reported in 37.6% of regorafenib-treated patients in Pool 3, 39.4% in Pool
1 and 22.6% in Pool 2. In Pool 3 (pivotal 14387 study) dose reductions occurred more frequently
with regorafenib (37.6%) compared with placebo (3.2%). The most frequent AEs causing
regorafenib dose reductions in Pool 3 and 1 were palmar-plantar erythrodysaesthesia syndrome
(18.2% in Pool 3 and 17.6% in Pool 1) and diarrhoea (3.8% and 4.8%, respectively), which were
also the most common regorafenib-related AEs in both Pools. In Pool 2, the most common AEs
causing dose reduction were palmar-plantar erythrodysaesthesia syndrome (6%), blister (4.8%),
skin exfoliation (3.6%), and pain in extremity (3.6%). In Pool 3, other reasons for regorafenib
dose reductions were hypertension (3.2%), fatigue (2%), rash (2%) and mucosal inflammation
(1.2%). These were observed also in Pool 1 and 2 with similar frequencies.
Regarding AEs leading to dose interruptions, there was a higher incidence of dose interruptions in
regorafenib treated patients in Pool 3 (60.8%) than in Pool 2 (39.3%) or Pool 1 (51.1%), and
within Pool 3, in regorafenib (60.8%) compared to placebo (21.7%) arm. The most common AEs
causing dose interruption in Pool 3 and Pool 1 were palmar-plantar erythrodysaesthesia
syndrome (18.8% and 11.2%, respectively) and diarrhoea (6.2% and 6.4%), followed by, in Pool
3, pyrexia (4.6%), fatigue (4%), rash (3.6%), hyperbilirubinaemia (3.6%), hypertension (2.6%).
Similar incidences were reported in Pool 1 and 2.
Post marketing experience
Not applicable
2.6.1. Discussion on clinical safety
Overall, the safety profile of regorafenib (Stivarga) was consistent across studies and is typical
for a small molecule with targeted inhibition of the VEGFR and other tyrosine kinase-mediated
pathways: hypertension, skin (hand-foot syndrome, rash) and gastrointestinal toxicities
(diarrhoea, mucositis) were prominent, whereas haematologic toxicities were limited.
The analysis of the safety profile of the drug is hampered by the limited safety follow-up.
Moreover, in all the phase I-III studies performed to date patients with regorafenib history of
hepatic or renal impairment or with on-going or recent cardiovascular diseases were excluded.
In the pivotal 14387 study, AEs more frequently observed (≥10% difference) with regorafenib
compared with placebo were fatigue (63.4% vs 46.2%), hand-foot syndrome (47.0% vs 7.5%),
anorexia (46.8% vs 28.5%), diarrhoea (42.8% vs 17.0%), weight loss (32.0% vs 11.1%),
dysphonia (32.0% vs 6.3%), hypertension (30.4% vs 7.9%), rash/desquamation (29.0% vs
5.1%), mucositis/stomatitis (28.8% vs 4.7%), fever (28.4% vs 15.4%), hyperbilirubinemia
(20.0% vs 9.5%), platelet counts abnormalities (15.6% vs 2.4%), haemorrhage (20.4% vs
6.7%) and infections (25.2% vs 14.2%). The difference was mainly due to a higher incidence of
grade 1-3 events.
In the pivotal trial, the overall incidence of hypertension was 30.4% in patients treated with
Stivarga and 7.9% in patients receiving placebo. Most cases of hypertension in patients treated
with Stivarga appeared during the first cycle of treatment and were mild to moderate in severity
(Grades 1 and 2: 22.8%). The incidence of Grade 3 hypertension was 7.6%.
Blood pressure should be controlled prior to initiation of treatment with Stivarga. It is

recommended to monitor blood pressure and to treat hypertension in accordance with standard
medical practice. In cases of severe or persistent hypertension despite adequate medical
management, treatment should be temporarily interrupted and/or the dose reduced at the
discretion of the physician. In case of hypertensive crisis, treatment should be discontinued.
Posterior reversible encephalopathy syndrome (PRES) has been reported in association with
Stivarga treatment. Signs and symptoms of PRES include seizures, headache, altered mental
status, visual disturbance or cortical blindness, with or without associated hypertension. A
diagnosis of PRES requires confirmation by brain imaging. In patients developing PRES,
discontinuation of Stivarga, along with control of hypertension and supportive medical
management of other symptoms is recommended.
In the placebo controlled phase III trial in patients with metastatic CRC the overall incidence of
hand foot skin reactions was 45.2% in patients treated with Stivarga as compared to 7.1% in
patients receiving placebo. Most cases of hand foot skin reactions were mild to moderate in
severity (Grades 1 and 2: 28.6%) and most appeared during the first cycle of treatment with
Stivarga.
Rash was experienced in around 47% of regorafenib-treated patients in the pivotal and other
studies, with time to first onset within the first 8 weeks of therapy. Events were generally mild or
moderate in severity and led to dose modifications in a low percentage of patients (2.8%).
Hand-foot skin reaction (HFSR) or palmar-plantar erythrodysesthesia syndrome and rash

represent the most frequently observed dermatological adverse reactions with Stivarga.
Measures for the prevention of HFSR include control of calluses and use of shoe cushions and
gloves to prevent pressure stress to soles and palms. Management of HFSR may include the use
of keratolytic creams (e.g. urea-, salicylic acid-, or alpha hydroxyl acid-based creams applied
sparingly only on affected areas) and moisturizing creams (applied liberally) for symptomatic
relief. Dose reduction and/or temporary interruption of Stivarga, or in severe or persistent cases,
permanent discontinuation of Stivarga should be considered.
Gastrointestinal toxicity was also very commonly observed (especially diarrhoea [42.8%] and
mucositis/stomatitis [28.8%]) but events were generally of mild and moderate severity and
considered manageable. In toxicology studies, atrophy of the tongue has been observed in mice
and rats, but has not been reported in patients.
Stivarga has been associated with an increased incidence of myocardial ischaemia and infarction.
Patients with unstable angina or new onset angina (within 3 months of starting Stivarga
therapy), recent myocardial infarction (within 6 months of starting Stivarga therapy) and those
with cardiac failure New York Heart Association (NYHA) Classification 2 or higher were excluded
from the clinical studies.
Patients with a history of ischaemic heart disease should be monitored for clinical signs and
symptoms of myocardial ischaemia. In patients who develop cardiac ischaemia and/or infarction,
interruption of Stivarga is recommended until resolution. The decision to re start Stivarga
therapy should be based on careful consideration of the potential benefits and risks of the
individual patient. Stivarga should be permanently discontinued if there is no resolution.
Stivarga has been associated with an increased incidence of haemorrhagic events, some of which
were fatal. In the pivotal trial, the overall incidence of haemorrhage was 21.4% in patients
treated with Stivarga as compared to 7.5% in patients receiving placebo. Most cases of bleeding
events in patients treated with Stivarga were mild to moderate in severity (Grades 1 and 2:
19.2%), most notably epistaxis (8.8%). Fatal events in patients treated with Stivarga were
uncommon (0.8%), and involved the respiratory, gastrointestinal and genitourinary tracts. Blood
counts and coagulation parameters should be monitored in patients with conditions predisposing
to bleeding, and in those treated with anticoagulants (e.g. warfarin and phenprocoumon) or
other concomitant medicinal products that increase the risk of bleeding. In the event of severe
bleeding necessitating urgent medical intervention, permanent discontinuation of Stivarga should
be considered.
Gastrointestinal perforation and fistulae have been reported in patients treated with Stivarga.
These events are also known to be common disease related complications in patients with intra-
abdominal malignancies. Discontinuation of Stivarga is recommended in patients developing
gastrointestinal perforation or fistula.
Abnormalities of liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase

[AST] and bilirubin) have been frequently observed in patients treated with Stivarga. Severe liver
function test abnormalities (Grade 3 to 4) and hepatic dysfunction with clinical manifestations
(including fatal outcomes) have been reported in 3 out of more than 1,100 Stivarga treated
patients across all clinical trials (0.3%). Two of the patients had liver metastases. Liver
dysfunction in these patients had an onset within the first 2 months of therapy, and was
characterised by a hepatocellular pattern of injury with transaminase elevations >20xULN,
followed by bilirubin increase. Liver biopsies in 2 patients revealed hepatocellular necrosis with
inflammatory cell infiltration.
It is recommended to perform liver function tests (ALT, AST and bilirubin) before initiation of
treatment with Stivarga and monitor closely (at least every two weeks) during the first 2 months
of treatment. Thereafter, periodic monitoring should be continued at least monthly and as
clinically indicated.
Regorafenib is a uridine diphosphate glucuronosyl transferase (UGT) 1A1 inhibitor. Mild, indirect
(unconjugated) hyperbilirubinaemia may occur in patients with Gilbert’s syndrome.
For patients with observed worsening of liver function tests considered related to treatment with
Stivarga (i.e. where no alternative cause is evident, such as post hepatic cholestasis or disease
progression), the dose modification and monitoring advice in Table 2 should be followed.
Regorafenib is eliminated mainly via the hepatic route. Close monitoring of the overall safety is
recommended in patients with mild or moderate hepatic impairment (see also sections 4.2 and
5.2). Stivarga is not recommended for use in patients with severe hepatic impairment (Child
Pugh C) as Stivarga has not been studied in this population and exposure might be increased in
these patients.Proteinuria was more frequently reported in regorafenib-treated compared with
placebo-treated patients in the pivotal study (8% vs 2.4%, grade 3: 1.6% vs 0.4%) with most
events considered related to study drug.
In the pivotal trial, the overall incidence of treatment emergent proteinuria was 7.4% in patients
treated with Stivarga as compared to 2.4% in patients receiving placebo . Of these events,
40.5% in the Stivarga arm and 66.7% in the placebo arm have been reported as not recovered /
not resolved. No grade 4 or 5, neither proteinuria SAE nor proteinuria resulting in acute renal
failure was observed. Proteinuria AEs were usually observed within the first 2 cycles of therapy
and could usually be managed by dose reductions (0.6%) or interruptions (1.2%). Permanent
discontinuation due to proteinuria was reported in 0.4% of patients. Renal failure was reported in
<5% of patients treated with regorafenib in the studies performed and in the pivotal study the
incidence of renal failure was slightly but not significantly higher in the regorafenib arm
compared with the placebo arm (2.2% vs 1.6%). Most of events were grade 3 (1.8% vs 1.2% of
cases). Renal failure and proteinuria was observed in patients as a result of treatment with
regorafenib. Although proteinuria is a known class effect of TKI, the overall number of patients
with renal failure is limited.
No cases of impaired wound healing were observed in the pivotal study, whereas according to a
cumulative review of all patients treated with regorafenib up to 31 December 2011 a total of 6
cases were reported (5 serious and 1 non-serious), one of which treated with placebo. As
medicinal products with anti angiogenic properties may suppress or interfere with wound healing,
temporary interruption of Stivarga is recommended for precautionary reasons in patients
undergoing major surgical procedures. The decision to resume treatment with Stivarga following
major surgical intervention should be based on clinical judgment of adequate wound healing.
Each daily dose of 160 mg of Stivarga contains 2.427 mmol (or 55.8 mg) of sodium which should
be taken into consideration by patients on a controlled sodium diet. Moreover, each daily dose of
160 mg contains 1.68 mg of lecithin (derived from soya).
In the pivotal trial, infections were more often observed in patients treated with Stivarga as
compared to patients receiving placebo (all grades: 30.8% vs. 17.0%). Most infections in
patients treated with Stivarga were mild to moderate in severity (Grades 1 and 2: 22.0%), and
included urinary tract infections (7.2%) as well as mucocutaneous and systemic fungal infections
(6.6%). No difference in fatal outcomes associated with infection between treatment groups was
observed (0.6%, Stivarga arm vs. 0.8%, placebo arm).
No cases of interstitial lung disease have been reported in patients treated with regorafenib.
In in vitro assays as potential read-out for phototoxicity was identified for regorafenib and its
active metabolites M2 and M5. Furthermore, reporting in the SmPC of ADRs observed with low
frequency to date but considered of clinical relevance for the population treated (e.g. Steven
Johnson syndrome) is considered important, in view also of the relatively short safety follow-up
available.
Stivarga has been associated with an increased incidence of electrolyte abnormalities (including
hypophosphatemia, hypocalcaemia, hyponatraemia and hypokalaemia) and metabolic
abnormalities (including increases in thyroid stimulating hormone, lipase and amylase). The
abnormalities are generally of mild to moderate severity, not associated with clinical
manifestations, and do not usually require dose interruptions or reductions. It is recommended to
monitor biochemical and metabolic parameters during Stivarga treatment and to institute
appropriate replacement therapy according to standard clinical practice if required. Dose
interruption or reduction, or permanent discontinuation of Stivarga should be considered in case
of persistent or recurrent significant abnormalities (see section 4.2).
Overall, tests on thyroid stimulating hormone (TSH) showed post baseline >ULN in 23.1% in the
regorafenib and 13.3% in the placebo arm. TSH post baseline >4 times ULN was reported in
4.0% in the regorafenib arm and in no patients in the placebo arm. Concentration of free
triiodothyronine (FT3) post baseline below lower limit of normal (< LLN) was reported in 20.8%
in the regorafenib arm and 15.7% in the placebo arm. Concentration of free thyroxin (FT4) post
baseline <LLN was reported in 8.5% in regorafenib arm and 7.2% in the placebo arm.
Regarding the elderly, the overall incidence of any AE and the incidence of most of the common
AEs across clinical studies was similar between age groups (<65 years, ≥65 years). The
incidence of AEs and SAEs (42.5 vs 44.6%) was similar between the two age groups.
Hypertension (28% vs 34.2%), anorexia (42.7% vs 53.4%) and headache (8.5% vs 13%) were
more frequently reported in ≥65 years old patients treated with regorafenib compared with <65
years old, whereas HFS (48.5% vs 39.4%), hyperbilirubinemia (15% vs 9.8%) and back pain
(15% vs 8.8%) were more frequent in the younger (<65 years) subgroup of the population. With
the exception of decreased appetite and headache, similar trends were seen in the placebo
group. The rate of drug-related serious adverse events was higher in patients older than 65
years (9.8% in aged <65; 15.5% in aged 65-74; 13.2% in aged 75-84), even if no difference
was reported in terms of fatal cases. Moreover, based on the rate of dose modification across
age group no differences can be highlighted, even if the limited number (53) of patients older
than 75 years could have hampered the safety assessment in this subgroup.
The highest dose of Stivarga studied clinically was 220 mg per day. The most frequently
observed adverse drug reactions at this dose were dermatological events, dysphonia, diarrhoea,
mucosal inflammation, dry mouth, decreased appetite, hypertension, and fatigue. There is no
specific antidote for Stivarga overdose. In the event of suspected overdose, Stivarga should be
discontinued immediately, with best supportive care initiated by a medical professional, and the
patient should be observed until clinical stabilisation.
From the safety database all the adverse reactions reported in clinical trials have been included
in the Summary of Product Characteristics.
2.6.2. Conclusions on the clinical safety
The safety profile of regorafenib shows consistency across studies and is similar to the profile of
other anti-angiogenic and multi-kinase inhibitors. Hypertension, skin (hand-foot syndrome,
rash) and gastrointestinal toxicities (diarrhoea, mucositis) were prominent, whereas
hematologic toxicities were limited. Hyperbilirubinaemia and liver enzymes aberrations were
frequently observed with regorafenib, especially in patients with liver metastases.
Haemorrhages, with fatal outcome in few cases, as well as myocardial ischemia and infarction
have been reported with regorafenib.
Overall the toxicity related to regorafenib treatment appears to be manageable, but not
negligible. In any case toxicity of regorafenib does not seem to be out of balance when
compared to other anti-angiogenic and multiple tyrosine kinase inhibitors, like sorafenib.
The full evaluation of the safety profile of the drug is limited by the paucity of a long-term
safety database.
2.7. Pharmacovigilance
Detailed description of the pharmacovigilance system
The CHMP considered that the Pharmacovigilance system as described by the applicant fulfils
the legislative requirements.
2.8. Risk Management Plan
The CHMP received the following PRAC Advice on the submitted Risk Management Plan:
PRAC Advice
Based on the PRAC review of the Risk Management Plan version 1.4, the PRAC considers by
consensus that the risk management system for regorafenib (Stivarga) in the treatment of
not considered candidates for fluoropyrimidine-based chemotherapy, an anti-VEGF therapy, and,
if KRAS wild type, an anti-EGFR therapy is acceptable.
The following minor revision is recommended for the next RMP update:
• The MAH should provide clear milestones for 14814 (An open-label, nonrandomized Phase I
study of regorafenib (BAY 73-4506) to evaluate cardiovascular safety, tolerability,
pharmacokinetics and anti-tumour activity in patients with advanced solid tumours: Long-
term LVEF data) as the term ‘approximately 12 months after last patient last visit’ is not a
traceable date.
Following the PRAC advice, the applicant has submitted two subsequent RMP updates to address
CHMP recommendations for inclusion of activity in KRAS mutant tumours as additional
information to be provided (v 1.5) and for commitment to investigate additional biomarkers in
future studies following the Oral Explanation (v 1.6).
The finally agreed content of the Risk Management Plan was the following:
Safety concerns
Table 16: Summary of the Safety Concerns
Main identified risks • Severe drug-induced liver injury

• Cardiac ischemic events
• Hypertension and hypertensive crisis
• Hemorrhage
• Hand-foot skin reaction (HFSR)
• Posterior reversible encephalopathy syndrome
(RPES)
• GI perforation and fistulae
• Stevens-Johnson-Syndrome (SJS)/Toxic
epidermal necrolysis (TEN)
Main potential risks • Wound healing complications
• Interstitial Lung Disease (ILD)
• Atrial fibrillation
• Reproductive and developmental toxicity
• Renal failure
• Phototoxicity
Additional information to be • Safety in severe hepatic impairment
provided
• Safety in children
• Safety in patients with a cardiac history
• Safety in severe renal impairment
• Interaction with antibiotics
• Interaction with BCRP substrates
• Activity in KRAS mutated tumours or other
biomarker-defined tumour subtypes
Pharmacovigilance plans
Planned
date for Planned date for
Protocol Protocol
Study submission submission of
version status
of final data
interim data
Planned
Protocol Protocol
version status
of final data
interim data
15967
An open-label phase IIIb
Final
study of regorafenib in
protocol
patients with metastatic
available.
colorectal cancer (CRC) who
Version 2.0,
have progressed after Not applicable September 2014
3 August 2012 CTA
standard therapy.
applications
currently
Eudra CT No.: 2011-
ongoing.
005836-25
To submit final results

and pre-specified,
exploratory wild-type
and mutant KRAS
subgroup analyses:
15808 31/08/2014
A randomized, double-blind,
placebo-controlled phase III In addition an annual
study of regorafenib plus report will be submitted
best supportive care (BSC)
versus placebo plus BSC in Final A proposal for
Version 1.0
Asian subjects with protocol Not applicable additional biomarkers
14 Feb 2012
metastatic colorectal cancer available assessment should be
(CRC) who have progressed submitted to the CHMP
after standard therapy within two months of
(CONCUR) the marketing
authorization:
Eudra CT No.: NA 31/10/2013
To submit additional
genetic (NRAS, BRAF)
biomarker analyses:
31/08/2015
Effect of antibiotic
pretreatment on the Not yet
Not drafted Not applicable Q2/2015
pharmacokinetics of available
regorafenib in healthy
volunteers
Effect of multiple-dose
regorafenib on the Not yet
Not drafted Not applicable Q4/2015
pharmacokinetics of a BCRP available
substrate in cancer
patients.
14814
An open-label, non-
randomized Phase I study
Addendum to the CSR
of Regorafenib (BAY 73-
including longer term
4506) to evaluate
Final LVEF results will be
cardiovascular safety Version 2.0,
protocol Not applicable generated and provided
parameters, tolerability, 4 August 2011
available approximately 12
pharmacokinetics, and anti-
months after last
tumor activity in patients
patient last visit
with advanced solid tumors
Eudra CT No.: NA (US
study)
15983 An interim Planned for 31/12/2020
Not yet
A Randomized, Double- Not drafted analysis for
available
blind, futility Submission of results of
Planned
Protocol Protocol
version status
of final data
interim data
Placebo-controlled Phase- will be genetic (including
III Study of Adjuvant conducted NRAS, KRAS, BRAF and
Regorafenib Versus Placebo when PIK3CA) and non-
for Patients with Stage IV approximately genetic (ANG-2, IL-6,
Colorectal Cancer After 95 IL-8, P1GF, VEGFR-1,
Curative Treatment of Liver DFS events, TIE1, VEGF-A, VEGF-C,
Metastases which VEGF-D, VEGF-A-121,
is 30% of the BMP-7, VWF, M-CSF,
targeted final SDF-1) appropriate
DFS biomarker analyses:
events, have 31/12/2020
been
observed. The proposed protocol
for biomarkers
assessment should be
submitted to the CHMP
within two months of
the marketing
authorization:
31/10/2013
In addition an annual
report will be submitted
Moreover, additional biomarkers will be explored in studies 15808, 15983 and other future
studies, guided by the scientific literature and with the intention of improving patient selection.
Annual updates will be submitted for regulatory review.
Risk minimisation measures
Safety concern Routine risk minimisation Additional risk minimisation

measures measures
Main Identified Risks

Severe DILI SmPC Section 4.2 ‘Dose and None
method of administration’, sub-
section ‘Dose modification’;
section 4.4. ‘Warnings and
precautions for use’ and section
4.8 ‘Undesirable effects’
Cardiac ischemic events SmPC Section 4.4. ‘Warnings and None
Hypertension and SmPC Section 4.4. ‘Warnings and None
hypertensive crisis precautions for use’ and section
Hemorrhage SmPC Section 4.4. ‘Warnings and None
Hand-foot skin reaction SmPC Section 4.2 ‘Dose and None
(HFSR) method of administration’, sub-
section ‘Dose modification’;
section 4.4. ‘Warnings and
Safety concern Routine risk minimisation Additional risk minimisation
measures measures
Posterior reversible SmPC Section 4.4. ‘Warnings and None

encephalopathy precautions for use’ and section
syndrome (PRES) 4.8 ‘Undesirable effects’
GI perforation and SmPC Section 4.4. ‘ Warnings and None
fistulae precautions for use’ and section
Stevens-Johnson- SmPC Section 4.8 ‘Undesirable None
Syndrome (SJS) /Toxic effects’
epidermal necrolysis
(TEN)
Main potential risks
Wound healing SmPC Section 4.4. ‘Warnings and None
complications precautions for use’
Interstitial Lung Disease None None

(ILD)
Atrial fibrillation None None
Reproductive and SmPC Section 4.6. ‘Fertility, None

developmental toxicity pregnancy and lactation’
Renal failure None None
Phototoxicity None None
Additional Information to be provided

Safety in severe hepatic SmPC Section 4.2 ‘Posology and None
impairment method of administration’, 4.4
‘Warnings and Precautions’ and
5.2 ‘Pharmacokinetic Properties’
Safety in children SmPC Section 4.2 ‘Posology and None
method of administration’
Safety in patients with a SmPC Section 4.4 ‘Warnings and None
cardiac history precautions for use’
Safety in severe renal SmPC Section4.2 ‘Posology and None
impairment method of administration’
Interaction with SmPC Section 4.5 ‘Interaction None
antibiotics with other medicinal products and
other forms of interaction’
Interaction with BCRP SmPC Section 4.5 ‘Interaction None
substrates with other medicinal products and
other forms of interaction’
Activity in KRAS mutant SmPC Section 4.4. ‘Warnings and None
tumours or other precautions for use’
biomarker-defined SmPC section 5.1
tumour subtypes ‘Pharmacodynamic properties’
The CHMP endorsed the PRAC advice with changes.
These changes concerned the following elements of the Risk Management Plan:
- activity in KRAS mutant tumours
- identification of biomarkers to further aid definition of the target population
The CHMP justified these changes as follows:
In the pivotal study, the results of secondary endpoints reporting the majority of patients
experiencing early disease progression at the time of the first radiological evaluation suggest a
benefit limited to a subgroup of the population treated. In view of the substantial, although
manageable, toxicity of the drug, identification of patient/tumour characteristics for proper
patient selection is important, in order to avoid (unnecessary) exposure of patients in the last
weeks of their life to a toxic drug. Biomarker analyses from two prospective studies (15808
[CONCUR] and 15983) could provide some further insights into the potentially differential activity
of regorafenib in patients with wild-type or mutant KRAS tumours. Moreover, additional
biomarkers will be explored in studies 15808, 15983 and other future studies, guided by the
scientific literature and with the intention of improving patient selection. Annual updates will be
submitted for regulatory review.
2.9. User consultation
The results of the user consultation with target patient groups on the package leaflet submitted
by the applicant show that the package leaflet meets the criteria for readability as set out in the
Guideline on the readability of the label and package leaflet of medicinal products for human
use.
3. Benefit-Risk Balance
Benefits
Beneficial effects
The results of the pivotal study, based on the second interim analysis performed after 432
(56.8%) death events, showed a statistically significant improvement in the primary endpoint of
OS for regorafenib plus BSC compared with placebo plus BSC (HR 0.77, 95% CI 0.636-0.942,
p=0.005178), with a gain in median OS of 1.5 months in favour of regorafenib (median OS 196
days vs 151 days, respectively). The results were consistent at an updated OS analysis
performed with later cut-off, when 97% (566) of the planned death events occurred and before
cross over was allowed (median OS 194 vs 152 days, HR 0.79, 95% CI 0.664, 0.939,
p=0.003791). The effect on OS was observed in several subgroups of the population. Of
particular interest, the OS effect appears to be maintained also despite previous treatment with
other VEGF inhibitors (i.e., bevacizumab). No imbalance in post-study therapies between the two
study arms was observed from the data provided in both analyses.
The OS results appeared to be supported by the investigator-assessed PFS data (secondary

study endpoint). A statistically significant increase in PFS was observed with regorafenib
compared with placebo (HR 0.494, 95% CI 0.419-0.582, p<0.000001. Median PFS was formally
59 vs 52 days with regorafenib and placebo, respectively. PFS improvement was observed in all
the subgroups explored according to Cox regression model.
Overall response rate (ORR: CR+PR) was very low and similar between the two treatment arms
(1% with regorafenib and 0.4% with placebo). Disease control rate was significantly higher in the
regorafenib arm compared with the placebo arm (41% vs 14.9%, respectively). However,
duration of disease stabilisation was very similar between the two study arms (60 vs 52 days,
respectively).
Considering the sought indication in a late stage of disease, the oral formulation of regorafenib
could be perceived by patients as an advantage allowing the home-based care treatment.
Uncertainty in the knowledge about the beneficial effects
The clinical relevance of the observed difference in PFS is unclear, as the gain in median PFS
associated with regorafenib was only 1 week (59 vs 52 days, respectively). However, the
analysis was confounded by the timing of the radiological evaluation. Indeed, at the time of the
first PFS assessment (8 weeks) 58% of regorafenib treated patients had experienced disease
progression already.
Moreover, the reliability of the PFS results could be questioned, as an investigator-driven bias
cannot be ruled out completely considering that obvious differences in treatment induced
toxicities between study arms might potentially have compromised the double-blind nature of the
trial.
The very high rate of patients not responding to treatment with regorafenib could suggest
activity of the drug limited to a subgroup of the population. Unfortunately, from the analyses
submitted, no specific biomarkers or other patient/tumour parameters were identified that could
be used for patient selection. In patients enrolled in the CORRECT study, KRAS status seemed to
poorly predict the PFS outcome with a statistically significant improvement being observed in
patients with both mutated and wild type tumours. However, mutated KRAS status appeared to
be associated with a worse PFS outcome regardless of treatment arm and in a multivariate
analysis, KRAS mutation was consistently identified as potentially prognostic parameter in terms
of OS and PFS. On the other hand, a differential activity of regorafenib was observed according
to KRAS mutation status by Kaplan-Meier analysis, HRs and median values. Compared to the
overall study population, an inferior difference was observed between the two study arms in
terms of OS in patients with mutant KRAS tumours (HR 0.87, 95% CI 0.67-1.12), whereas the
difference in OS was not adversely affected in the smaller subgroup of patients with wild type
KRAS tumours (HR 0.66, 95% CI 0.48-0.80, p=0.007). However, there was no evidence of
heterogeneity in treatment effect (non-significant interaction test) and the analyses by KRAS
tumour status were non-randomised comparisons. The exploratory nature of the subgroup
analyses presented does not allow any firm conclusion over this issue.
No significant difference between the two study arms was observed in the evaluation of Quality
of life.
Risks
Unfavourable effects
Overall, the safety profile of regorafenib was consistent across studies and was typical for an
angiogenetic and multi-tyrosine kinase inhibitor: hypertension, skin (hand-foot syndrome, rash)
and gastrointestinal toxicities (diarrhoea, mucositis) were prominent, whereas hematologic
toxicities were limited.
In the pivotal 14387 study, Adverse Events (AEs) more frequently observed (≥10% difference)
with regorafenib compared with placebo were fatigue (63% vs 46.%, respectively), hand-foot
syndrome (47.0% vs 7.5%), anorexia (47% vs 28%), diarrhoea (43% vs 17%), weight loss
(32% vs 11%), dysphonia (32% vs 6%), hypertension (30% vs 8%), rash/desquamation (29%
vs 5%), mucositis/stomatitis (29% vs 5%), fever (28% vs 15%), hyperbilirubinemia (20% vs
9%), platelet counts abnormalities (16% vs 2%), haemorrhages (20% vs 7%) and infections
(25% vs 14%). The difference was mainly due to a higher incidence of grade 1-3 events.
Hand-foot syndrome (HFS) was observed in 47% of patients treated with regorafenib. Most
events were of grade 1 or 2 severity, grade 3 events were observed in 17% of patients, whereas
no grade 4 was reported. HFS AEs could usually be managed by dose reductions or interruptions.
HFS led to permanent discontinuation, dose reduction and interruption in 7 (1.4%), 92 (18%)
and 96 (19%) regorafenib treated patients, respectively.
Cardiac events have been observed in 8-26% of patients treated with regorafenib in different
studies. An increased frequency of myocardial ischemia and infarction has been associated with
treatment with regorafenib (1.2% vs 0.4% with regorafenib vs placebo, respectively) in the
pivotal study, with a slightly increased risk in patients with cardiovascular risk factors.
Arrhythmias (especially atrial fibrillation) were reported with higher incidence in the regorafenib
arm. The incidence of other thromboembolic events did not appear to be significantly influenced
by treatment with regorafenib.
The most common bleeding AE (any grade) in both treatment groups was haemorrhage
pulmonary/nose (9% vs 2.4%) followed by haemorrhage anus (3% vs 0.4%), urinary (2.2% vs
1.2%), rectum (1.2% vs 0%), and others (2% vs 0%). A total of 4 pts (0.8%) in the regorafenib
arm vs no patient in the placebo arm experienced fatal bleedings, 3 of them considered as drug-
related. Patients experiencing bleeding events appeared to have often additional causative
factors (e.g., anticoagulant use, liver cirrhosis, etc.), but a clear relation could not be made with
thrombocytopenia and alteration of coagulation parameters observed in regorafenib treated
patients.
Similar to other inhibitors of the VEGFR pathway, a slightly increased incidence of

gastrointestinal perforation or fistula was observed with regorafenib.
Impaired wound healing was rarely reported (< 1%).
Hyperbilirubinemia (probably related to impaired glucuronidation through UGT1A1 inhibition) and

liver enzyme (AST/ALT) abnormalities were commonly observed with regorafenib (13%, 45%
and 65%, respectively), and with higher incidence compared with placebo. Most of events were
grade 1 or 2 in severity. Two cases meeting Hy’s Law criteria and 3 cases of severe drug-induced
liver injury event were described.
Renal failure was reported in <5% of patients treated with regorafenib in all the studies
performed and in the pivotal study the incidence of renal failure was slightly but not significantly
higher in the regorafenib arm compared with the placebo arm (2.2% vs 1.6). Most of events
were grade 3 (1.8% vs 1.2% of cases).
One event of hypertensive crisis associated with development of reversible posterior

leukoencephalopathy syndrome (RPLS) has been reported.
One case of serious and potentially life-threatening Steven-Johnson syndrome event has been
observed.
In the pivotal trial, the rate of study treatment discontinuation due to TEAE was higher in the
regorafenib arm in comparison to placebo (17.6% versus 12.6%). Moreover, a dose modification
was required in regorafenib patients almost twice as much as it was needed in placebo patients
(regorafenib 75.6% vs placebo 38.3%), with a rate of dose reductions of 20% vs 3.2% in the
regorafenib and placebo arm, respectively.
Uncertainty in the knowledge about the unfavourable effects
Long term safety data are lacking.
In all clinical studies performed to date, patients with history of moderate or severe hepatic
dysfunction (including hyperbilirubinemia > 1.5 ULN or AST/ALT increase > 5 ULN) or severe
renal impairment, with ECOG PS >1 or with ongoing or recent cardiovascular diseases were
excluded. Limited information is available in patients with moderate hepatic impairment (Child-
Pugh B) and no data are available in patients with severe hepatic impairment (Child-Pugh C).
Very few patients with impaired renal function have been treated with regorafenib in the pivotal
trial.
The tolerability of the drug in patients with ECOG PS>1 is uncertain, as such patients were
excluded from the pivotal phase III study. This is considered relevant as a worst performance
status is not uncommon in patients treated in clinical practice.
Benefit-risk balance
Importance of favourable and unfavourable effects
Regorafenib is a new tyrosine kinase inhibitor proposed for the treatment of patients with mCRC
that have exhausted, or are not candidate for, all the currently available standard anticancer
treatment options. Therefore an unmet medical need for such population is readily
acknowledged.
In this context the results of the pivotal 14387 study are considered of potential clinical
relevance. A statistically significant improvement in OS associated with treatment with
regorafenib compared with placebo, and supported by a statistically significant improvement in
PFS was observed. However, the absolute gain in median OS (1.5 months) is rather modest,
whereas the median improvement in PFS consists of few weeks at best (formally the difference in
median PFS between treatment arms was only 1 week). The clinical relevance of these results is
modest, considering also that ORR is negligible and that there is no clear indication of a positive
effect of the treatment on disease symptoms or QoL.
This modest clinical benefit has to weighed against the toxicity of regorafenib, which is, although
manageable, substantial. Fatigue, hand-foot syndrome, anorexia, diarrhoea, weight loss,
hypertension, rash, mucositis, fever, hyperbilirubinaemia, platelet count abnormalities,
haemorrhage and infections were observed very commonly in patients treated with regorafenib,
with a significantly higher incidence compared with placebo-treated patients. In particular, the
incidence of AEs of special interest associated with regorafenib was very high (>30%), and
appears to significantly increase overtime.
Benefit-risk balance
The efficacy results of the pivotal 14387 study show a statistically significant OS improvement
associated with treatment with regorafenib (median OS gain of 1.5 months), supported by a
statistically significant improvement in delay in disease progression. Moreover, a low rate of
tumour shrinkage was reported (1%) and evaluation of quality of life did not show any significant
difference between the two treatment arms in the pivotal study. In other words, the modest
prolongation in survival appears to be essentially related to disease stabilisation for a few weeks
at best.
Whether this could translate in a clinically relevant benefit for the patients treated needs to be
critically weighed with the observed/expected drug-related toxicity. The safety profile of
regorafenib was consistent across studies and was typical for an angiogenesis and multi-tyrosine
kinase inhibitor: hypertension, skin (hand-foot syndrome, rash) and gastrointestinal toxicities
(diarrhoea, mucositis) were prominent, whereas haematologic toxicities were limited. Several
adverse events able to affect patient’s quality of life, like (abdominal) pain, fatigue, anorexia,
rash, diarrhoea, mucositis, hand-foot syndrome and hypertension were significantly more
frequently reported in patients treated with regorafenib compared with placebo.
All together, the clinical relevance of the results appears to be modest. However, in the intended
population of patients with metastatic colorectal cancer having exhausted all currently available
therapeutic options, the benefits of regorafenib are considered to outweigh the risks associated
with its use.
Discussion on the benefit-risk balance
A statistically significant improvement in OS (median OS gain of 1.5 month) has been associated
with treatment with regorafenib compared with placebo in the mCRC population enrolled in the
pivotal Study 14387. However, the results of secondary endpoints reporting the majority of
patients experiencing early disease progression at the time of the first radiological evaluation
suggest a benefit limited to a subgroup of the population treated. In view of the substantial,
although manageable, toxicity of the drug, identification of patient/tumour characteristics for
proper patient selection is important, in order to avoid (unnecessary) exposure of patients in the
last weeks of their life to a toxic drug.
Nevertheless, the available data do not currently support a restriction of the indication in any
subpopulation of patients with metastatic colorectal cancer having exhausted all available
therapeutic options. A differential activity of regorafenib was observed according to KRAS
mutation status by Kaplan-Meier analysis, HRs and median values. However, there was no
evidence of heterogeneity in treatment effect (non-significant interaction test) and the trend
towards a smaller observed benefit in the KRAS mutant subgroup might be at least partly
explained by a higher rate of subsequent anti-cancer therapy in the KRAS-mutated placebo
subgroup compared to the KRAS-mutated regorafenib subgroup. Additionally, the difference
could be due to imbalances in baseline characteristics of the patients included in these subgroups
and for these non-randomised comparisons. Overall, the exploratory nature of the subgroup
analyses presented does not allow any firm conclusion over this issue.
Biomarker analyses from two prospective studies (15808 [CONCUR] and 15983) could provide
some further insights into the potentially differential activity of regorafenib in patients with wild-
type or mutant KRAS tumours.
4. Recommendations
Outcome
Based on the CHMP review of data on quality, safety and efficacy, the CHMP considers by
consensus that the risk-benefit balance of Stivarga in the treatment of adult patients with
metastatic colorectal cancer (CRC) who have been previously treated with, or are not
considered candidates for, available therapies; these include fluoropyrimidine-based
chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy, is favourable and therefore
recommends the granting of the marketing authorisation subject to the following conditions:
Conditions or restrictions regarding supply and use
Medicinal products subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
Conditions and requirements of the Marketing Authorisation
• Periodic Safety Update Reports
The marketing authorisation holder shall submit the first periodic safety update report for this
product within 6 months following authorisation. Subsequently, the marketing authorisation
holder shall submit periodic safety update reports for this product in accordance with the
requirements set out in the list of Union reference dates (EURD list) provided for under Article
107c(7) of Directive 2001/83/EC and published on the European medicines web-portal.
Conditions or restrictions with regard to the safe and effective use of

the medicinal product
• Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed
subsequent updates of the RMP.
In addition, an updated RMP should be submitted:
At the request of the European Medicines Agency;
Whenever the risk management system is modified, especially as the result of new information
being received that may lead to a significant change to the benefit/risk profile or as the result of
an important (pharmacovigilance or risk minimisation) milestone being reached.
If the submission of a PSUR and the update of a RMP coincide, they can be submitted at the
same time.
• Obligation to conduct post-authorisation measures
The MAH shall complete, within the stated timeframe, the below measures:
Description Due date

To submit pre-specified, exploratory wild-type and mutant KRAS subgroup analyses 31/08/2014
from study 15808 (CONCUR - randomised, double-blind, placebo-controlled phase
III study of regorafenib plus best supportive care (BSC) versus placebo plus BSC in
Asian subjects with metastatic colorectal cancer (CRC) who have progressed after
standard therapy)
To submit NRAS and BRAF biomarker analyses from the same study, subject to 31/08/2015
sample availability and confirmation of appropriate informed consent.
A proposal for additional biomarkers assessment should be submitted to the CHMP 31/10/2013
within two months of the marketing authorisation.
To submit pre-specified, exploratory genetic (including NRAS, KRAS, BRAF and 31/12/2020
PIK3CA) and non-genetic (ANG-2, IL-6, IL-8, P1GF, VEGFR-1, TIE1, VEGF-A, VEGF-
C, VEGF-D, VEGF-A-121, BMP-7, VWF, M-CSF, SDF-1) appropriate biomarker
analyses from study 15983 (randomised, double-blind, placebo-controlled phase-III
study of adjuvant regorafenib versus placebo for patients with stage IV colorectal
cancer after curative treatment of liver metastases). Genetic and non-genetic
biomarker analysis should be implemented as mandatory for all enrolled patients.
Prospective serial measurement should be planned and assessed for biomarkers. 31/10/2013
The proposed protocol for biomarkers assessment should be submitted to the CHMP
within two months of the marketing authorisation.
New Active Substance Status
Based on the CHMP review of data on the quality properties of the active substance, the CHMP
considers that regorafenib is qualified as a new active substance.
I
Government of India
~0!1@
..
c)l!!i:.
~
PROPERTYINDIA
,>Jtt-lT$10($,tQ,t,,1$1ff.A.l)(
MAAr..S
GlOGMPt-lC>J.
lt-C>tC.AIIOK$
Legal Status : Term Expired
Date of Expiry : 12/01/2020
Patent Number : 215758 Date of Patent : 12/01/2000
Application Number : IN/PCT/2001/00799/MUM Date of Grant : 03/03/2008
Type of Application : PCT NATIONAL PHASE Date of Recordal : 27/03/2008

APPLICATION
Parent Application Number : --- Appropriate Office : MUMBAI
PCT International Application : PCT/US00/00648 PCT International Filing : 12/01/2000

Number Date
Grant Title : CARBOXYARYL SUBSTITUTED DIPHENYL UREAS
SlNo
SI No Nameof
Name ofGrantee
Grantee Grantee Addn!$$
Grantee Address
1 BAYER CORPORATION 100 BAYER ROAD, PITTSBURGH, PENNSYLVANIA, 15205.
SlNo
SI No Nameof
Name of PatA!ntee
Patentee Address of
Addres.sof Patentee
Patentee
1 BAYER CORPORATION 100 BAYER ROAD, PITTSBURGH, PENNSYLVANIA, 15205, U.S.A.
Address of Service : PERFEXIO LEGAL ATTORNEYS-AT-LAW 9655, SECTOR-C, POCKET-9 VASANT-KUNJ, NEW
DELHI – 110 070, INDIA.
Additional Address of :
Service
Priority Date : 13/01/1999
Year Due
Year Duedates
datesfor
for Renewal
Renewal CBR
CBR CBR Date
CBR Date Renewal Renewal
Rener.rtalDate
Rener.rtal of
of
Datlll Renewal Period:
P«lod:
Rener.rial
No
No Amount Certificate
Amount O!lr1llkate Renewal
Rener.rial
No
No
Normal Due Date From To
Due Date with
Extension
[fu~JE coi>v]!
3rd 27/06/2008 27/12/2008 5729 26/06/2008 2000 3455 26/06/2008 12/01/2002 12/01/2003
year
4th 27/06/2008 27/12/2008 5729 26/06/2008 2000 3455 26/06/2008 12/01/2003 12/01/2004
year
5th 27/06/2008 27/12/2008 5729 26/06/2008 2000 3455 26/06/2008 12/01/2004 12/01/2005
year
6th 27/06/2008 27/12/2008 5729 26/06/2008 2000 3455 26/06/2008 12/01/2005 12/01/2006
year
7th 27/06/2008 27/12/2008 5729 26/06/2008 6000 3455 26/06/2008 12/01/2006 12/01/2007
year
8th 27/06/2008 27/12/2008 5729 26/06/2008 6000 3455 26/06/2008 12/01/2007 12/01/2008
year
9th 27/06/2008 27/12/2008 5729 26/06/2008 6000 3455 26/06/2008 12/01/2008 12/01/2009
year
10th 12/01/2009 12/07/2009 67 02/01/2009 6000 49 02/01/2009 12/01/2009 12/01/2010

year
11th 12/01/2010 12/07/2010 11848 14/12/2009 12000 6540 14/12/2009 12/01/2010 12/01/2011
year
12th 12/01/2011 12/07/2011 15906 13/12/2010 12000 6443 13/12/2010 12/01/2011 12/01/2012
year
13th 12/01/2012 12/07/2012 14585 09/12/2011 12000 6331 09/12/2011 12/01/2012 12/01/2013
year
14th 12/01/2013 12/07/2013 16263 05/12/2012 12000 6443 05/12/2012 12/01/2013 12/01/2014
year
15th 12/01/2014 12/07/2014 18339 12/12/2013 12000 6505 12/12/2013 12/01/2014 12/01/2015
year
16th 12/01/2015 12/07/2015 18209 05/12/2014 40000 9971 05/12/2014 12/01/2015 12/01/2016
year
17th 12/01/2016 12/07/2016 18869 09/12/2015 40000 10017 09/12/2015 12/01/2016 12/01/2017
year
18th 12/01/2017 12/07/2017 1923 27/01/2017 40000 764 27/01/2017 12/01/2017 12/01/2018
year
19th 12/01/2018 12/07/2018 23768 21/12/2017 40000 13563 21/12/2017 12/01/2018 12/01/2019
year
20th 12/01/2019 12/07/2019 27341 20/12/2018 40000 16221 20/12/2018 12/01/2019 12/01/2020
year
Sl llalaof
SI Date of Particulars/Remarks
Pardait.af'IIRwa•ks
No Entry
Nol:my
1 05/12/2019 In pursuance of Form 16 received on the 07/10/2019, made by NATCO PHARMA LIMITED of
‘NATCO HOUSE’, Road No. 2, Banjara Hills, Hyderabad- 500034 registered as licensee by way of
“compulsory license” granted on date 09/03/2012 made between “BAYER CORPORATION” as
the one part and “NATCO PHARMA LIMITED” as the other part.
2 05/04/2016 In pursuance of a request made under Rule 94 (1) on 30/09/2011 the address for service of
Patentee has been altered to PERFEXIO LEGAL ATTORNEYS-AT-LAW 9655 SECTOR-C POCKET-9
VASANT-KUNJ NEW DELHI – 110 070 INDIA.
3 27/04/2011 The address for service has been changed to :- Lakshmi Kumaran & Sridharan Attorneys B-
6/10 Safdarjung Enclave New Delhi - 110 029.
Information u/s 146 (Working of Patents)
Sl No
SI No Patent Number
Paent Number Year
1 215758 2013-2014 View Document
2 215758 2014-2015 View Document
3 215758 2015-2016 View Document
4 215758 2016-2017 No Document
5 215758 2017-2018 View Document
6 215758 2018-2019 View Document
7 215758 2019-2020 View Document
8 215758 2019-2020 View Document
I View Documents
FORM 1
[39 OF 1970]
APPLICATION FOR GRANT OF A PATENT
[See Sections 5(2), 7 and 135]
We, BAYER CORPORATION, 100 Bayer Road, Pittsburgh, Pennsylvania, 15205,

U.S.A.,
hereby declare-
[a] that we are in possession of an invention titled: "CARBOXYARYL
SUBSTITUTED DIPHENYL UREAS"
[b] that the complete specification relating to this invention is filed with this
application;
[c] that there is no lawful ground of objection to the grant of a patent to us;
further declare that the inventor[s] for the said invention BEREND RIEDL, of Von
Der Goltz Strasse 7, 42329 Wuppertal, Germany; JACQUES DUMAS, of 821
Beechwood Road, Orange, Connecticut 06477, USA; UDAY KHIRE, of 101
Tanglewood Drive, Hamden, Connecticut 06518, USA; TIMOTHYB. LOWINGER, of
#203, 5- 7 Chitose-Cho, Nishingomiya City, Hyogo, 662-0046, Japan; WILLIAM J.
SCOTT, of 210 Saddle Hill Drive, Guilford, Connecticut 06437, USA; ROGER A.
SMITH, of 65 Winterhill Road, Madison, Connecticut 06443, USA; JILL E. WOOD, of
72 Pickwick Road, Hamden, Connecticut 06517, USA; MARY-KATHERINE
MONAHAN, of 134 Park Avenue, Hamden, Connecticut 06517, USA; REINA
NATERO, of 113 Edgecomb Street, Hamden, Connecticut 06518, USA; JOEL
RENICK, of 11 Wall Street, #4, Milford, Connecticut 06460, USA; ROBERT N.
SIBLEY, of 1187 Mt. Carmel Avenue, North Haven, Connecticut 06473, USA,
We, claim the priority from the application[s] filed in convention country[ies],
particulars of which are as follows :
[a] U.S.A.
[b] 60/115,877; 09/257,266; 09/425, 228
[c] 13/01/1999, 25/02/1999 and 2/10/1999
[d) BEREND RIEDL, JACQUES DUMAS, UDAY KHIRE, TIMOTHY B.
LOWINGER, WILLIAMJ. SCOTT, ROGER A. SMITH, JILL E. WOOD, MARY-
KATHERINE MONAHAN, REINA NATERO, JOEL RENICK and ROBERT N.
SIBLEY
[e] "@-CARBOXYARYLSUBSTITUTED DIPHENYL UREAS AS RAF KINASE
INHIBITORS"
and declare that above application or each of the above applications was the first
application[s] in a convention country/countries in respect of my/our invention.
That our address for service in India is:
REMFRY & SAGAR,

Attorneys-at-Law
79, Nariman Bhavan, 7 th Floor
227, Backbay Reclamation
Nariman Point,
MUMBAI 400 021, INDIA
011'grMt I / ,qqE{:,~:
Tel & Fax: 91-22-2285 3633
remf~emfry.com
-:fn/ p.£11iooI
IiTRUE COPYII C!3) 2 7 SEP2007
cQ.i5t58
cP8 Io.3{
J(fJ 8
FORM2
THE PATENTS ACT 1970
[39 OF 1970]
&
COMPLETE SPECIFICATION
(See Section 10; rule 13]
"CARBOXY ARYL SUBSTITUTED DIPHENYL UREAS"
BAYER CORPORATION, 100 Bayer Road, Pittsburgh, Pennsylvania,

15205, U.S.A.,
The following specification particularly describes the invention and the

manner in which it is to be performed:
C/lfr/1/T(fJ>
mi tj , NI I
~~ff? c_7/~oo I /7<:(tl,( ~~w ~
1
.2 7 SEPi.U
----az
.,,
0 if o?lafl'll ...IITRUE COPYII
oo~Carboxyaryl.substitnted dipl>enylJJreas as raf kim1seinhibitors

. .
This inventionrelatesto the use of a groupof carboxyarylsub~11tuted
diphe..yl ureas
eRH-ii1 frea~ing
Pr=yl rafmediateddiseases~and phannaceuticalcompositions for use in
suchtherupy.
Backgroundof the Inyention

111
Thep21 s oncogene.is a majorcontributorto the development_
and progressionof human
solidcaiit:ersand is mutatedin30% of ~I humancancers_
(Bolton et al. Ann. Rep. Med
Chem. .1994, 29: 165-74;Bos.Cancer Res.1989, 49, 4682-9). ln its normal, unmutated
form, the ras protein is a key elementof the signal transductioncascade dirc:ctedby
growthfactorreceptorsin almostall tissues(Avrucb:,*t
al. TrendsBiochem.Sci. 1994, 19,
•.w-1
279~83). Biochernically, ras is a guaninenucleot~_?f}indingprotein, and cycling between ,

a GTP-b,>und activated and a.GDP-bound
•
res_p)igfoim
/·s_,.,
. .-
is strictly contro)Ied by ras'
endogenc1us Jn the ras mutants in cancer
GTPaseactivityand other.regulatocy,;proteins.
• . ;! r
eells. the endogenous GTPase activity is alleviated and, th~fote. the protein delivers
constitutive growth signals to downstreameffectors such as the enzyme raf kinase. This
leadsto rhe cancerousgrowthof the cells which carrythese mutants(Magnusonet al.
Sem;n. Cancer Biol. 1994. 5, 247-53). It has been shown that inhibiting the effect of
active nu. by inhibiting the rafkinase signaling pathwayby administration of deactivating
antibodies to raf kinase or by co~expression
of dominant negativeraf kinaseor dominant
9-- # •
IITRUE COPY!I
negative MEK,the substrate of raf kinase. leads to the reversionof transformedcells to
the normhlgrowthphenotype(.see:Daum et al. Trend.sB;ochem.Sci. 1994. 19, 474-80;
F'ridmant:t al. J. Biol. Chem.1994,269, -30105-8.Kolchet al. (Nature 1991. 349, 426-,
28) h&vefurtherindicatedthat inhibitionof raf expressionby antisenseRNA blocks cell
~roliferationin membrane-associated
oncogenes. Similarly.inhibitionof raf kinase (by
.llltisenseoligodeoxynucleotides)
has been correlatedin vitro and in vivo with inhibition
of the gwwth of a variety of humantumor types (Moniaet a)., Nat. Med. 1996, 2, 668-
75).
Summaryof the Inveoti,>n

--~ r ~
The prestnt inventfonprovidescompoundswhichare inhibitorsof the enzymeraf kinase.

Since tht· enzyme is a downstream effector of p21ra\ the inhibitors are useful in
pharmaceuticalcomposition$for human or veterinaryuse where inhibition of the raf
icinasepai:hwayis indicated,e.g., in the treatment of tumorsand/or cancerouscell growth
mediated •by ra.f kinase. In panicular, the compounds are useful in the treatw.ent of
humanor animalsolid cancers,e.g.,murinecancer,s~ce tho progressionof these cancers
is dependentuponthe ras proteinsignaltransductioncascadeand thereforesusceptible to
•'..•J
treatmentby interruptionof the cascade, i.e., by inhlll!;tingr~kinase. Accordingly,the
,t·._,,. -
compoundsof the inventionare usefulin treatingcfi.Ii.ters,

includingsolid cancers, such
as, for example, carcinomas(e.g., of the JungsJ'C;-~creas,
thyroid. bladd~ror coJon),
•; • ~; .I
myeloiddisorders(e.g., myeJoidleukemia)or aden(:)J'rtas

(e.g.. viJJouscolonadenoma).
The pres..:nt.irwentiontherefore provides compoundsgenerallydescn'bed as aryl ureas,

• including both aryl and heteroarylanalogues, which inhibit the raf kinase pathway . ..!fhe
ie.,,·eneau alse pFO''l'idesa ntethofl fer treatiR-g a raf mediated disease ~*tt*C?
in humaus
e11 mftffl1ftftls. Thus,the inventionis directedto compoundswhichinhibit the enzymeraf
kinase Md also compounds and compositions&nd methods for the treatment of
cancerou~cell growth mediatedby raf kinase whereina compound of the invention
li'eFERHIA I-i& admini~eFed 8F can be in the form of a pharmaceutically acceptable
salt--theR~
A compCJundof the ·invention is selected from the group consisting of
IITRUE COPYjl
the 4-chI,,ro-3-(trifluoromethyl)phcnyJ
ureas:
ErrorJBo,>kmark
not defined.
N-( 4.-chloro-3-(trifluoromcthyl)phenyl)-N'-{3-l.2-carbamoyl-4-pyridylo:xy)phenyl)
nrea,
N-{4-cbloro--3-Ctrifluoromethyl)phenyl}-N'-C3-£2:fN-.mtthylcarbamovll:4-
PYridyloiy)phenyl} urea,
. .
:<4-l2-carba~ovJ-4w·
N-<4-cbloro-3-(trifluoromethyDphenvD-N,
• pyridylo,.,y)phcnyl)urea
N-( 4-chloro-3:{trjfluoromethyl}phenyl)-N'
-(4..,1-(N-.methylcarbamoylH-
py~idyloxy)phenyn urea and
N :;(4-tblc,ro-3-ftriflu.oromcthyl)pbenyl)-N'-(2--chloro...4-(2-(N-methylcarbarnoyl)-4-
pyridyloxy)phenyl) urea.
Error! BQokmarknot denned.
the 4-bromo-3-(trifluoromethyl)phenyf ureas:

N--f4-broino-3-(trifluoromethyl}J2henyll--N'
:f3:G:(N-0Jetbylcarbamoyl)-4~
.. ~
"di )h n-
pyn y ov p eny urea, .,/ ..
.:.
.·/::'
N-(4-bromo-3-(trifluoromethyl)phenyl}-N'-(4-;[2:(N-methylcarbainoyl}--4-
/··.~-> .'
pyridylo.cy)phenyl) urea, Y -';~
N-(4-bromo-3::(trilluorometlryf)phcayJ)-.N'-(3-12-{N-methyfcarbamoylH::
pyridyltliio)phenyl) urea.
N-{4-bromo-J{tritluoromcthyl}pheitYO:N'-{2.-.;hforo-4-{2-(N-mcthylcarbantoy0(4-
pyridylo'(y))pbcnyl) urea and
N-(4-bromo-3-(trifluoromethyl)pbenyl}:N'-(3-chloro-4-(2-(N-n1ethylcarbamoy!){4-
PYtidyloJy))phcnyl) urea; a,id
the 2-methoxy-4-chloro-S-(trifluoromothyl)phenyl 1n-eu:

•N-{2-mcthoxy-4-cbloro-5-(trifluorometbyl)phenvl}:N'..(4-(2..(N-mcthylcarbamoyl}-4-
pyridylo 9:)phenyQ urea and
IITRUE COPY!I
Nf2~metho_xy-4...ehloro--5-(trifluoro~ethyllpllenyll-N"-(b!hlor.o-4-{2-{N-
methvlcatbamoyD(4-pyrldyloxy))pbenyQ urea or a phannaceutlcally acceptable salt
thon,c>f'
:Examplesof phannaccnticaJlv acceptable 1dts includethose of
N{4-chloro-3:Ctrifluoromethv0 pbenyll~N'-(4..(2..carbamoyl-4-pyridvloxyl
pbenyD urea of the formula: •
. c~ o
--------- c1~
~vN
-l~Ood~
I
N
I
H H and
N-(~chloro-3-(trift~orometbyQ. phcoyl):N~:(f:{2:(N-methylcarbarm,tl}--4-
whic;hcan be in tlae
00
In feranttlaI, D 15 NH C:(O}NII ,
},.,·is a•aa111er the feF1Rula:L EM

a suhatiluted meietyof up te 40 e11Fbo11
L-1-➔'I , 'R'heFeL is a § or 6 membeFed e,relie st. u..tare ha~nd diFeetlr te D, L;J.
eompFis«:S-ft--Mlb-stituted
eyelie melef)• hiwi11gat least ! moml,en, M is a bFidgmg
g-i-eup ha1vingat lmM eee Hell1, 11is an in:tege.,.ef fFOlll 1 ~; and eaeh. eyelie
swem Fo-el-l:ran4-1/ eeetains O 4 memheFSef the g~0up eonsitting or 11itNtgee,
e~en and sulfuF, and
Bs a subsetut:ed er ansuhstitlded, 11p te wleyeli11 a-,1 or lleteFaaeyl

• meie-ty ef 1111
t9 aO eaFheu ll1'9Rl8 1\cfi:h •t least 9d& fi memheF ~s~ie 5H=Re'8Fl8b~ead .
IITRUE COPYII
r-
. ' •
. dire~ly • - g
·.... '· '9 :g ••eent IHllRg 4 • • • . ef Ritf:9gee e~gett •
: .. membePSef_the gtieup eonaisti&g
and 911lf'u.r; · • • • • ' •
'- __ . __,,w.i,•l~+
. . 19su7s~te
b titu d hy at le_ast,
• one• sahl!lth$:t_ aeleeted
• fffm the gNup
: esnsf!tm.g qt SO~ C(O}ll.·1tit~ C~~ •
. . ~ is lty,lroge,, ilF " .. ~.,. based Rteietj' el"ap le .21 eaFbee IIIH15 opt;e11ally
.~e 9 Ieeted .a-rem
. eenta1111eg-:ltet,cFeal:e1Rs ir. • •
N, S B:ntl-0 •
and • -· •
eptioilally •• • -
haleHhstitsmd, •
11p
to per hal&t •
_ ...••~ ;.~.,;-~•~• OMii;;

h~~-;~1df
ofBPte u•~fhDll
..~;...apt1011aru,
~-sand
; ·.•,fQR,~iR"1g_ll~&F01te~s.·11elee-.~d.from Q and,·. if alh;' b,. :· ' , • ,
Hii~io' ..,;. id( .. ·. · :· ., ··/ • ··' ·, • • ,· •· "I' !'8.·, .. olihlNd.t,y
>•g- •t".">r and, ~,:h<!!I
~-••h1!botff.itet1II,
ef op iM>
11 earh~IIateins,..:i,;eh
~ f,8mN, 8 ud O .,.d _. eptie~
.[ ·•~J •"'!lltttHIhft!OI'~...,. •.
.... od~
'/al,!11; .. .• •• • •• •
~.... .IHI
-It~ 18~- a:, MU4.wheR ..lf4,~~ -~ •
a) iadepeodendy
llfdr_e:en, _·fl • . .-
. . _ . . _.~
, a GIINOB tiased
> ,~et •M)"O' up ,t~ "varben' , : e&lltaicing
atam11Ofjtie~ellf
ill!,,.oa!"
Ii d · 1119· sele!!!ed fFem · N, .Ii ·..8Bd0
· ··-,//!eptifl11alt;111bllll$dl>y
-·.. - •. • . _ h a Io,:en,
y re~ &IMH!&l'bo_n
-. .
based substiments of~~
_ ._ . · . , ..
eam
_
:u·
-~••••• .•••• • ••• • • •. , •
en a. ems, wb1ell optie~
eonta1n laete~atoms _~rom seleet d fl N S ar1dfO and are
7 • • eptieilally_
•• • suhsffluteEI
• • i,,,
Lalogen, ff
Q~i(RJ.;~hel'e R. i:ali)idAgen er· a earhaa llased meiety of up ~ a4

ea.tthea
_n utems epfie•I~- eo t ~n
i inget-et=eatems
h seleeted frem N, S 11ado a..ct
epttanally substituted lly haleeen, llyd11eqrand enrhoe haa~-EI
subffitae11fs et tip to
24 ee.Ph6~ atems_ ,pwhieh oati o&aIIy eaat11:tn
-! lletereatetM ,eleeted ffiem N, S allfl-G
end P:ff aptiQoally substituted 13)·halogeeJ OP
h) R. and Ri,tegedler feAH a S 1 member heteree, eNe sl'flletHFe alt 3

.n BF a. 11.-Mtitllt-ed
IJef:eroatams seleeted fff 9N s anu...v,
~ _m • S 7 ~emlJef' heteFOefelie
• :n"iFQHUPd
·"-·· - :sf,:1a lletetrt>atema
· ..s~leete
· · If.em ·,N :.B~d
_ •
O .. 'IJit:~- : ., ••••
• ,·- ·_;
• •• ••.•
,- _1,yd.,,"'Yer • • .. • ·• -~ c-· -••L.,ffltled~al<ol:M•
earbaa btied~SHllstitumti.ef_flfLlP __ 24 _e11r~~II.
~to.m.s..1-,,·~ o1nie~llll,·
IITRUE COPYII
11~qlw· tf et: tin Je AJa!~HIJh1&tfft~o~u.J u puu ',i:llfOOtttN
::.(ff•u~p.t.19-'m1ofa
-'-t;lffl(ffiD:tlfN •~tfttiN-:t'ttS \lfO 'to.M ·'tfftti:N:k>);:, ':tl:f(O)O ~t~fle)
'NO J9 ~H!=f.SJSUoadmw= aw we.uPaJiJafH hf)HafJY3dapu!&f z qaua peu f 0:1o Sf
JU 'fllz •'tt pe:JR~Pfq.i11'f1uuo!4de
Q!e.1al(N.. Mlpat,O;J!Jsqes
1nu, 'e1u11:1adOJ dR •ea:le1u11
.\lfUll&!fdo- 8! qafll,lil. '=.iRJfRS puu ueiM:e '119~9.lJ!tl JB Su~moa ll~'IJ WO.If
p.JJ33f,l6 Sal81f81abl t 6 !JU!U!UIJll9't HR$!fllJ.)S: ap8W9..IU JQEf1H3W 9 olO S U Sf .iV
s:1.Jt puu 'f 1 _ m a.11:nf,\\

puu fua~e1111
LW{~lf3N puu lll{?ffa-) s ' r.XO ' .xIIiJ Dt('lD➔o I 4~('lfC>➔ C-S"'{Zffe»
~~'R:,3 ' ' s ' o st e, u1;ucn1A\

mo)uo ' {wa ' "'rto) ' <tH>N:.
'ea:IGfbil -"q patntM:fi'tlUI
,CJ1v11efldo
p1111 pua o s 'N 111:0.rJ~aps SlR1tJ18data't
=~!GtBJllOO Aff11U9~d~ 5sm.e:p, aoq;J1r~\Z ~ dn .JO ~!OIH • peAq •lioq,aa u JO H
*
•ieeJJ p~a1a1 ~apuad~pe1 t . ,;~... ~ff61r-f;l~~B'-B~iflfll~•tHO(O)OtHN·-
-. -'ttf{t))[)alf.N "oN . ~t't:'4l1N:
--~is 'tlIO 't~lfN(t})a 41iHfo)r) -\tf'Eee>
'MO Je =~5!1119~ du~ elf:l paJ~as .~uapuadep11J· q,ae~ uew Jo_

•. eae MlMllffllHfRB£t1uueftde.puu ~ pua s '.'1~oiJJp~aa1asmoJ.Bo•a-J3'1 a.,!~u_oo
Aftl98ffd8 'SHIQlU ~Oq.lH JIZbJd11J8 ~pa10111 pe&aqU9t\llU9 p■u 'alV l) ' tiEo)::>.H:ht .
. . . ·• . .•...• ' •• . . . ·. .•· . .. • . • • . .• } ·. : :
. . ;
1
tRttfNfEo➔a Jt;~
1
. --1 ,l.l6~)0tll:N'. 'ttitlf.N , t~tll0. :{o)a ..ON \U , .. :
. . . ·. . . . . . .. .·,·. .. .. · ·..
. . . · . . . ··.. . > I
• 'NO)8 3U!;J~sueaElll&.1:l alff. WOJJp~aa1as.4ffilapuadapu1 SJ It\.qau; li!N9111A •••• : _:'J,~!
•• ff. 6 S! II·;y311.w;
1H2\t+:
'·' . ~
a1ad;ea dn 'ue3ef~ JU 9u.!W!Seeadno a:a1p WNJ pet9e19S~.1uSlQ"?H~~qas
ps~ ••1•11
a• 'pa•ff~ns Afl~~~•~~~-•J t.'I ,e piJ:ld:Jf:l"fRS Sf 'l 'fielanisqos5! fl 01Ye1rM .•.
. •• ·---,-----,•-c··:---··-····-- ---· . .• . ----:-------.;._
iuaff9'f1n1
.CqP9tRt!J$(fR!il 1\.19 _pauO PIBJ$ 'N lilBdJ pa:)1)3faR
,~1111epdo GUIQJ90d3:laq •
YflflUOO Aft8Y9!J,dO lf9jlfA4. isWOJB UO~.HJa ~r;8.f. dRJO,~naqn, paS'Bq

B~CJ.183. pa9 .
4,(ff.lp.Cq•aa:Je1uqJe !h!!'f!IIIN d~~ aiff: WO:IJ pa:J~er_ae

iMB da~ Bil3fAJlfH f.HofU:t!cfff
~ fO piltDJ!:JSqasaqJJU cs.aaqwamj )SU31 JV.'fJ?,Vz a.1e.tan:.lfg
st•BBJl:)$flDS31p: UJ3:l9q,ltl,.
->!P'-'e
a HYO;J 9:J 'I &J3!DW aqJ9:) paneq dno133Pi1fMf~ :)H8f8r..fP 5(t-~
• 1' JG dae:13BQ~~ff1' .JUilfB"JP.·S;) ts B ' {6)() 5! ~ .18 "fl J0 ,ue (a
. Je hmlefUtf
Ml l'&.l~"fllS AftUUOpEle
lllU pas O PH s ~:KWOdJ pat90fa8 UW9lJ:U&.Ja~11UfD,tll~a
IITRUE COPYII
e1Jptffmieghetefoatoms selaateEIA=omN, S aad O anil optiemlly 1ubstit11t- b:f ene
selectedfnm t-he~ep
or mere_,;u-hsr:iinents consistingof CH, (?O.tRil,COR-1,-
C~O)NR;1R;t~!7,sR 11
, NOi, •NR;i;t,--NR:,:CfO)B.', and NR;tC(O)OR;t, witll g-1....,.
• defined plfftve.
In ~FmUla l 1 suitable hetafo/1 groups i~elude, h.-t _&Fe net limited. to, S 1.2
earhoe atom nramatie rings OFrieg systeAlS eantaiBing13 ·Fmgs, at least aae of
"'.'hi~ is are1r1etie, in ,,•hieh &HeOF more, e.g., l 4 eafben: atoms in one Of more 9:f
:- :. the Fings ean he FeplaeQd by o~~~~-;-~~-;;~;~; •;,~m~-. Eneh Piegc,,-iea11y
1
• )~i;-~ 7 at&m~r.ex.t~{e.,.Jl ~~~,h~.2 OF3 rn.,,1, 2 •e,3 tllienyl,l eF 4 triMiliyl; •

·; r ').
...
·',2 Bf:~-
' '.. .
I i i, ., ·8~ s imidsa:~iyl,1 , 3. ' ., .8F 5.py.-Olyl, ~ , 4
P,'FFGl;)rl,
~' ' '
8F s.
, , ~~ljii, ~ oP S ifleI112e~rI, 2' , f er S thiuei,•~ ii , 4 e• S iset:JJmei,r.J,
l ,J e-·1
~--JiYda.r•t
;s·,:4 ·s '8F..' pytimid~...,~., 1/l;J t~ies~ 1 .•• 4.. er ••5 yl,· l,l,4 .tFi~ol
I 1' 3
•er S ,ii~-l ••ittt S-teWH~lyl, 1,2,3,8:Jettiazol •. or.S yl, 1,2,, H&diH_. l er S yl,
l~,4 t=h
...di•el 2 or S yl 1 l,2 74 (t:,qdiazol 3 or S yl, 1~~4tlwuliaMill er § yl,
l,3,1 thiPdifti)el .3 OF S )'I, 1,2,3 thiadiuel 4,rf'f' S yl, 2 , 3., 4 , S ~fl 6 2H
.. thiep;•l'81i)1I, 2 '3 8F 4 4H thiop:r-..ebfl, a Of .i=idft!l!m,1, pyMinyl, 2 '3 '4 , s '
6 or
l ,2, 1
a=~::::·~
Ir~
, :t.';;:·
1
:::::::
1tl
6 ••4
1 , 3 , ~, . 1-
•'
.
S; • ::;
e e ;tr: . el; 2 , 4 . , .
r::
benzeNft!l',(11)•1, J , 4 , i 6 611 7 ben!Zibo:musotyI; 1., 3 , 4 , 5 , 6 er 7 henMthiaelylJ? ,
4 , s , 6- oF 7 be1u5aomieolyj, 2 , 4 , s , , er 7 bea2 l;;, o:r;atlipol,•~ 2 , 3 , 4 ,.5 , 6 ,
7 BF 8 qttinolinyl, l , J , 1 , S , 6 , 7 , S MOEJainelilty-l,
1 , l , 3 , 4. sr 9 e&t"ffll:ffly~I
,J , a, 4, 5 , 6 , 7 , 8 er 9 aeFidiPyl, 8F 2, 1, a, , , 7 OF 8 tt11inuelisyl, 011
sdEli-tia.-ully aptienally suhstimteEI phenyl, 2 o.- 3 thie11;¥1,l,];4 tlliadieoly), 3

pyFryl, ~ pym!lolyl, :2dliaR:olylor S thiHei, 11, em. Fo-r a.11:111ple, .8 eae-be 4 medt,<J
pheH:YI, S me~·I 2 thieRyl, 4 methyl 2 tbien-yl, 1 methyl 3 11,FFJ'I, I 1t1etB) 1 l
~rrazel) 1~ethy-l 2 thitu;elyl er S mefltyl 1,2,4 fhiallieHI 2 yl
Saitftble alli:yl gre11ps asfl alley:( pomeM ef gre11p,, e.g.,. allia~, er:e.
1 ~1'8pyl, lrutyl, et:e,, h1eb1diagall swaight ehaie and
tltr=eYgl¼uetinelaEle met~i. etl.1:::)1
. .
-bP&nelted ~~ .
isemel"S,ueh as isoprepy4 1 isobu.tyl, f;ee h.ut,rl, .'.m.f'tJl.Vb~l,
IITRUE COPYII
&rlttdde aryl greeps whioo Elanet contaiP hetereet:ems inelude, :fer elEample,•
pµ:enyl ft1tdl RRIJ2-n,phthyl.
ll!l,e ieF111"cyelealk!rl", as useti he.-ei~ Fefen te eyeli_eetmetqFes w-itll a.-
. . w
withiJut &lfiy-1
suhstituents et1ekmat, far ei;ample, "G., eyeloalkyJ"fqeludes mefftyl
sulistitutt.:d eyelepre_pylgroaps ti •:well ~ ~rele_hu"rlg.Feeps. The term
. ~'cyeloalllyl",as 1Medlterein a.Isaineludes se:turatedheteroeyelie g,-e:aps.,
.Sttitable &alegen greeps ineh1de .t; CIJ Br, ae'dhr l, fFom one ta per
sa~stimtion (i.e. all II· am~s en a group Feplaeerlhy a halogen atom) lleieg possible
a.a alkyl group is in!'hatitoted_lty halegea, m:ix:e4
.W_he~e ..suhstitutien of halagen atom
.·t:yp~, b~ing.pffllsi~le meiet,~.
otHt1:kreli
ltte-in¥eneonalsorelate11
to eempoundsper se;ofl'emmla--1.-
~' The •p~ent invention is also directed .to phanna_ceutically:.1:1Cceptable

salts of .!
i
• compound of;the invention fef'flliilaI. Suitableph~aceutieally accepable ·salts_are
well known·to those skilledin the art a.ndinclude basic salts of inorganicand .organic
acids, su.:::has hydrochloricacid; hydrobromic acid, sulfuric acid, phosphoric acid)
methanesolphonic acid, trifluoromethanesulfo' acid. benzenesulfonic acid, p-
t~ILJene~lfo~ic acid. 1-~apht~alenes~foni~ ac~d,,,~phthal~ne~lfonfo~id, _acetic~~'
_·trrtluoroacenc,:acld, mahc acJd,tartaric ac1d,.~ac1~ lacti.cac1~ oxahc ac1d1succm1c
a.cid, fumaric acid, ma.ltic &eid, benzoic aci~/'salicylic acid, pbenylacetic acid, and
mandelic acid. ln addition, pharmaceutically·acceptable salts include acid salts of
inorganic bases, such as salts containingalkalinecations (e.g., Lr1"Na+ or K1, alkaline
earth cations (e.g.. Mg+ Ca+ or Ba+ the ammoniumcation, as well as acid salts of
2
,
2 2
),
organic t.ases,including aliphaticartd aromaticStJbstitutedammonium~

and quaternary
ammonium cations. such as those arising from protonation or pera.lkylationof
triethylamine, N,N-diethylarn.ine.N.N-dicyclohexylamine,lysine. pyridine~ N,N-
dimethylaminopyridine (OMAP). 1,+diazabiclo[2.2.2Joctane (DABCO), 1,5-
diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
A numbc-rof the compounds~ possessasymmetriccarbonsand can therefor

• • . I
exist in racemicand opticallyactive fonns.

• Methodsofsepa.tation~ofenantiomerioand_
# •
IITRUE COPYII
dia.stereoineric
mixturesare well knownto one skilledin the art. _Thepresentinvention•
any isolatedracemi~ot opticallyactive fonn of the compounds of the
encompas-ses
acceptable salts thereof dt$eFih~ in Fomu~la I
invention or ·pbarmaceuticaJJy
-.. which po~sessrafinhihitoryactivity.
Gcnef~I PreparativeMeth_ods
The com1)0unds of FoFHuda•I the. invention may be prepared·by the use of known
chemical reactions·
and procedures,some fromstartingmaterialswhichare commercially
r available~N;~rthele~;~,-g~;;;i~-~~pir~tlve.method$are provided 'belowto aid one •
' sltjlledin·the an in synthesizingthese compounds,with more detailedexamplesbeing
I
'II . . . .
i • proviped~n.theExperimental sectionwhichfollows.
• Substitutt~anilines m~y be generatedusing standardmethods (March. Advanced

Chemistry,3rd Ed,; John Wlley:NewYork (J.985). Larock. Comprehensive
0rg(111;c
OrganicI'ransformatior,s;
VCH Publishers:New "(dirk(1989)). As showninScheme I.
aryl aminesare commonlys;rnthesizedby redu~•-:-f,
·: of nitr0~ls usinga metalcatalyst,
- such asNl Pd. or Pt, andH2 or a hydride~ ' ~ suchi,s ;fur:mate;
cyclohexadierie,
•or a bornhydride(Rylander.Hydrogenatiolfii~hoi;; A,~mic Pre.ss: Lon.don, UK
(1985)). Nitroarylsmay also be directlyreducedusinga stronghydride source.such as
h.eductiOn9by the A/wrr,;no-and Borohydride.sin Organic
LiAIH.t(Seyden-Penne.-
Synrhesis;VCHPublishers:New York(1991)),or U$inga :zerovalent metal,such as Fe,
Sn or a:~.often in acidic media. Many methods exist for the synthesis of nitroaryls
(March. AdvancedOrganicChemistry,3rd Ed.; John 'Wiley:New York (1985). Larock.
ComprehensiveOrgwtieTransformations;
VCHPublishers:New York(1989)).
~~
..---{e9.fe, ~- ...._.
IITRUE COPYII
SchemeI Reductionof Nitroarylsto Aryl Amines
- Nitroaryl~are commonlyformedby electrophilicaromaticnitrationusing HNO3,ot an

altemativoNO/ source. Nitroarylsmay be furtherelaborated prior to reduction. Thus,
"-... _nitroarylssubstitutedwith
potential leavinggroups (e.g. F>Cl. Br. etc.) may undergosubstitutionreactions on -

~--~atment-with-nueloophi_les.-~such-.as~-thiolate_.(exemplifled JI) or phenoxide.
_in,Scheme
. Nitroary.h.
mayalso undergoUllman;.type
couplingreru:tions(Sch;mell);
ArSH
_02N>~sH~ 2
R/-=.T CuOI base {f
3 Ji!
£<,tlt
:it•·~~- . •
tf Scheme JI Select~ NucleophilicArom~,~,bstitatio~usin, Nitt-oaryls _

1
-Nitroaryl:imay also. widergotransitionmetal iediated cross coupling"reactions.- For
example,nitroarylelectrophiles.such as nitroarylbromides,iodidesor trl:flates.l.llldergo
palladiummediatedcrosscouplingreactionswith aryl nQCleophiles,
such as arylboronic
acids (Suzuki reactions, exemplifiedbelow), aryltins (Stille reactions) or arylzincs
(Negishireaction)to affordthe biaryl(S).
Ar8(0f{')2
Pd(O)
..
Either nitroaryls or anilinesmay be convertedInto the corresporiding_ ~~stll:fony1
:ehlorjde:wrcfL;
··,
0
acid, ·Reacti~11-0¥tii~--~ulfunyl
chloride(7) oit treatmentwltlfchlorosa1fonic
IiTRUE _coPYjl
a fluoride source~such-asKF then affordssulfonylfluoride(8). Reactionof sulfonyl
fluoride8.with trim~thylsilyl in the presenceof a fluoridesource,such
trifluoromethane
.... as .tris(dirnethylamino)sulfonium
ditluorotrimethylsiliconate
•(TA~F) leads to the .
correspondingtrifluoromethylsulfone(9). Alternatively.S1.4lfonyJ
chloride 7 may be
~uce~ tt, the arenethiol(10). for examplewith zinc amaJgum.Reactionof thiol 10 with
the presenceof base gives the difluoromethyl
••CHClF2i'r1: mere:aptam(11)~which may be·
oxidized to the sulfone(12) with any of a variety of oxidants~ including CfOJ-acetic
-anhydride_
(Sedovaet ai __ 1~7~.
"~:._C!J'g:"_~j_llJ...6,_(~~~)..
i,
...
0-
6
R
SH:
G --RI
10
tse
• '·CH.CIF2
J _coi
S~CHF2
6 R 12
Scheme III Selected Methods ofFluorinateti Aryl Sulfone Synthesis
As shown
.
in Scheme IV, non-symm_c;trjc;;aj
urea
.
formation may involvesreact.ion9fan aryJ
. ..... •••• -,,,,,:,~·-·"··· ·····------.•·····•'""" ...... ··•~ ......... ~-·-··' ···:"•··•• ....... -
. isocyanace
. .
(14) witb. an~nyl~~m;_(l~).:' ..··•---··-·--
The···-····
•• •
heteroaryl isocyanate may
····-······~-··- ·--~--.•·--·--··· .........
be, .. synthesized
·.. -· : -·
••
IITRUE COPYII
from a heteroaryl~mine_bytreatmentwith phosgeneor a phosgeneequivalent. suoh as
trichlor~methyl chlorofonnate (diphosgene), bis(trichloromethyl) carbonate
(triphosgene),
or .N,N'..carbonyldHmidazole
(CDI)._Theisocyanatemayalso be derived
from a· he-terocyoiic
•carboxyJicacid derivative,such as an ester, an acid.
' .
halide or an •
anhydrideby a Curtius..typerearrangement.ThUs,reaction of acid derivative16 wi'fu..an
aride source, followed by reammgementaffords _.theisocyanate. The corresponding
carboxylh: acid (17) may also be subjected to Curtius-type· rearrangements using
diphenylpho~phoryl
azide (DPPA)or a similarTr?agent.
1
...Ar -NH
--·-···---2 13
.i•
coc~
H2N-~ 0
1
Ar -NCO • Ar1,NJlN~Af2.
14 H H.
15
N•/ \OPPA
~~~,
·!8
·10 17 , : ;,f
JJ:SchemeJV . Selected Methods ofN011~~~";,', ·cal Urea Formation •
I , , , •• ::;• , •
,.• Finally, ureas rnay be furtber manipulatedusi~,thtethodsfamiliarto thogeskiUedin the

art.
The inve-ntionalso includes phanna.ceuticalcompositions including a coJnpound of

tJic invention, or a pharmaceuticallyac~eptable salt thereof, and a
Fe-r-RHtla-1.
physiologicalJyacceptablecarrier.
The compounds may be administeredorally, topically, parentera.Hy,by inhalation or

spray or rectally in dosage unit formulations.The tenn 'administrationby injection'
includes intravenous,intramuscular.subcutaneousand parenteralinjections,as well as
4se of infusiontechniques. One or more compoundsmay be presentin associati?n with
IITRUE COPYII
one pr m1>re
non~toxicpharmaceuticallyacceptableearners and if desiredother active.•
ingredients.
Compositionsi~tendedfor oral ~ may be preparedaccordingfo any suitable method i • •

...........
• known to the. art •for the. manuf~ture of phannaceutical compositions~ Such
agents selectedfrom·the group cousistingof ·
compositionsmay .c.ontainone or .more.
.
diluertts.:-i~eetening
agt::nts,flavoringagents,cc;,loring
agents and•preservingagents in
order to ·providepalatable preparations. Tablets contain •the active in~ient in
. admixtU~with no1rtoxicpharmaceutically
acceptableexcipientswhich are suitablefor
tbe\ffi~Ufa.Ctu~oftablets. Theseexcipi6ntsmay°t>~,-forexample~·fnefr-diluei,ts;
such as
calci!lri'icarbonate. s~di1.1m
carbonate,lactose,calciumphosphateor sodiumpho5Phate;
com .starch,or.aigini~ acid;.and .•
• • : ~ulating Jl_ncldi$integratingagentsj for .eX8I11ple.
; ~i'ndi~g·ager~. f9r exainpJe~agnesium~~ate, St~atjc~id or t~lc. •••Thef:abl~tS!11,ay
be
~ .('urtcQaied
..or:t_h~y.may be 'CO~ted by known teclmiqu_es
to cl~]ay·di~egratio~ and
: adsorptio1~· tract and thereby ~rovidea sustainedacti~ii .over ~
in-th~ gastroi,ntestinal
longer pc-~lod.For example,.~time delay material such as gl~cc:~Imonostearateor
gly~ryl tlistearatemay be'
employed. Theseco~~ds. may alsobe_preparedin solid, •
rapidlyreleased fonn. · • • if · ·
. . ~l7
. . . . iii .
;;".i . · • $l!iffe
.\: · • ·· •
:ffFormulations_
for oral us~ may also be pres~~j' as hard gelatincapsules.whereinthe
•is mixed with an inert solidlcrf
• active ingredien~ 1uent,for example.calciumcarbonate, •
calcium phosphateor kaolin,or as son gelatin capsuleswhereinthe activeingredientis
mixedwithwateror an oil medium,for ex.amplepeanutoil, liquidparaffinor olive oil.
Aqueoussuspensionscontainthe active materialsin admix~ .with exdpient.s.suitable

for the manufacture of aqtJeous suspensions. Such exclpients are suspending agents, for
example sodium carboxymethylcellulose, methylce)h.tlose. hydroxypropyJ
methylcellulase,sodiumalginate,polyviny1pyrro1idone,
gum tragacanthand gum aca.cia;
dispersing or wetting agents may be a ~turally occurring phosphatide, for example,
lecithin, or condensation products or an alkylene oxide .with fatty acids> for example.
poJyoxyf·thy}i:ne stearat", or contJe~inJon prothlcts of ethyJene ox)oc with)ong chain_.....
. ........ ''. •·, . . -•····'"'' ______ ~·-- '-~- ·-·····•-·---···:-.,_., ·•··-··-··-··~-·------
IITRUE COPYII
&lcohols,for ~ample· heptadecaethyleneoxycetanol,or condensationproducts.
aliph_atic_
of ethylcue oxide with _partial esters derived from fatty acids .and hexitol such as
'sorbitolmonooleate,or condensationproduct'lof ethyleneoxide.with ,Ii
polyo~'Yethyl~ne
~ partial est~rs.derivedfrom fatty acids and hexitolanhydrides,for examplepolyethylene
..
•sorbitan monooleate. The aqueous suspensions may also contaia one or rnorc
preservati\feS,for exampleethyl, or n-propylp-hydrOxybenzoate,one or more coloring
or moretla~orlng'agents,and oneor moresweetening.agents,such as sucrose
aients~one-'
. or sat~atin.
_ _._._..,..,._ __ ..,.:...........;.... 1/ -·----···---- ··-~·······-
i Dispersiblepowde~ and granulessuitablefor pzeparatlonof an .aqueollSsuspensionby ·

•I /th~~qi~~-R
o.f ~ter·provide'the active ingredient.in admixture. with.a tiispersi1:1g,or •
j"we.tti~g,~ge.pt.
:Sl:Jspendi~g
agent and one or more prese~atives.. Suita!JJedi~g or .
.. ;, ~':/rweti.~~~ ~~b~ts'andsuspe11di11g by ~osealre~dy m~ntj9n~ -~()Ve •
a.gents,a~ exemplifie:d
I
for example,sweetening,flavoringand 'coloringagents,may also
•.•••/tAtlditi9i)al-e.~ipi¢nts, . •
.; be presem~
. may.BISO
The.compol11!<1, .be.Inthe form of boolwus liquid formulatious,e.g., oily
.·.suspen~ions_whichmaybe formulatedby S\lSpe~! the.active ingrediei:rt5
in a vegetable
;tt:oil. for e>JUnple
,.
a.rachis.
oil, oliveoil, sesame
•
tfll;j
~
peanutoili or in a mineraloil such as
..-.~ -t> . • • • .
• liquid paraffin. The oily suspensions may tohtain

a thickening agent,_for examf)lc ••
beeswax,hard paraffinor cetyl aicohol. Sweeteningagents such as those set fQrthabove. •
and flavoring agents may be added to provide palatable oral preparations. These
compositionsmaybe preservedby the additionof an anti-oxidantsuch as ascorbic acid.
•..
Pharmact:uticalcompositionsof the inventionmay also be in the forn1 of oil-in-water
emulsions. The oily phase may be a vegetableoil, for example olive oil or araohis oil, or
a mineral oil, for exampleliquid paraffin or mixtures of these. SuitableemuJsifying
a.gentsmay be naturally-occurringgums, for example gum acacia or gum tragacanth,
. -naturally-occurring phosphatides, fot example soy bean,, lecithin,· and esters or partial
~ esters derived from fatty acids and hexitol anhydrides. for ~~le Sel~bimnrrionqct~.~~>..:::
said partiaieswrs·-with.ethylene·oxide, for-·.e:x'sMple'-c'-
••and conclensationpro-~i"ucts·-~(the
IITRUE COPYII
sorbital:J
•polyoxyetl1ylene ·monooleate:The emulsionsmay also containsweeteningand.
flavoring ,tgents.
.· Syrups and_eli~rs •~ay be formulatedwith,sweet.eningagents,.for exampleglycerql,'

'-
' propyleneglycol.sorbitoJor sucrose.·Suchfortnulationsmay alsocontaina d~mulcent,a
preservativea:i1dflavoringand coloringagents..
The .:;om
pounds may also be administeredin the .form of suppositori~ for rectal
of the drug,,Thesecompositionscan be preparedby mixingthe drug.with
; administn1tion
,excipientwhichis solidai-~rdinary
.-:a suitablenoil-irritatirig tcn{~ranireil>utliquid at the
l "rectaltemperaturearid\vili thereforemelt in the' re~tumto releasethe drug~ -Such-
[materiaJs''iriclude'
cocoab)rtt:~rahdpqlyethyleneglycols ..
of .u~edisclosedhereiri
,.,:;:For ~1j:::re·ginien~ 'for comppiiodsdf' ~8t,11Ul1t
.lt,he inventionor ••·
!_'- ' ' ' '.· ·_. ,' ' ,,"__ ' ' .' ' ' ' ,· : ,, ' '•, '' .' ' '·' ' ' ' ,· '
t pbe.nnateikncaity_.acceptabJe. salts ihc~f , •the''. cw~ -tios~_ge ·regimen ••will •

'. preferablybe from: O.Oltc>290 mg/Kg of total body. weight. :The.daily- dosage for •
•·admirustrati~nby injecti-on,includingfrrtravem;~f~.
iri~usci.llar, subcutaneousand
parentera~injections,an~ use of in~i~n t.echni. wil~ptefe~bly be from-0.0l to 200
t/ mg/Kg or total bodyweight. Thedaily ~ctal ~ge regirn~,~II. pre~rably_·be
from 0.01
~;?,to 200 mg/Kgof total b~: weight: The d1}pical, ~osage ~~me wilJ :re:era.bly.be
from 0, 1 to 200 mg administeredbetweenone to four umes daiJy. The daily mhalation
dosage n:gimo will preferably be from 0.01 to 10 mg/Kg of total body weight.
It will be appreci&t.ed by those skilled in the an that the particular method of

administration wm depend on a variety offactors 1 all of whicb-areconsidered routinely
when adinlnistcringtherapeutics. It will also be appreciated by one skilled in the art that
the specific dose level for a given patient depends on a variety of factors, including
specific1etivityof the compoundadministered,ag~,bodyweight,health,sex, diet, time
md rout!! of administration, rate of excretion, etc, It will be further appreciated by one
• skilied in the an that the optimal courseof treatment, ie., the modeof treatmentand the
' '
;~r. a
., daily number of doses of a compound of Ft,m1uft(I ~-of ~~~-=.!!l!~#~o!_
IITRUE COPYII
pharm~ceutically acceptable -salt thereof given for a defined number of days~ can be
ascertained by those skilled in the art using conventional treatment tests..
-JtwilJbe ,mderstood>
however,that the specificdose levelfor any particularpatientwill
depend upon a variety of factors, includingthe· activity of the specific.compound
. .
employed.the age, body weight. generalhealth~sex. diet.time of administration,roLJte
of
adminisiration. and rate of excretion, drug combination and the severfty•oftbe conditjon •
undergoing therapy.
The entb·eenelesYR ef an 9:f'plieatiee11

patentsnfldpublieatie111i-.ei~~-
abo,reand.
: •bdow 11:ru
i1eFeby
in¢e~e•~~(} by PC~Feeee,inel~din: p-=a,visienal
appli~atiens~rial
;_Ho~:so.'HS.Siii.
filed.hnuaey 13, 1999 and aen previsienll~applieati~n geFialN.e.
~ · 0~~~'1,lf.G 2i-,1999.
Riedl2ebA1QFJ'. •. • • • • ••
The compoQndscan be producedfrom knowncompounds (or from startingmaterials

• which, h, rum, can be producedfrom knowncompounds), e.g.. through the general 0
preparative methods -shown below. The activiJ/of a given compound to inhibit raf
•kinase et1nbe routinely as~ayed.e.g., accoi'di,pl1o procedures disclosed below. .The
if.•followingexamplesare for iUustrativep . •,
·,i: ~ ·!/t;
~-itmlyand are not i~ded,
,1
nor should
they be c.:>nstruedto limit the inventionin anf~y.
EXAMPLES
All react ions were performed in flame~driedor oven-dried glassware under a positive
pressure of dry argon or dry nitrogen. and were stirred magnetically unless otllel"Wise
indicated. Sensitive liquids and solutions were transferredviasyringe or cannul~ and
introduced into reaction vessels through rubber septa. Unless otherwise stated, the term
cconcentration under reducedpressure' refers to use of a Buchi rotary evaporator at
approximately 15 mmHg, Unless otherwise state~ the term 'lJI'.l.der
high vacuum' refers
to a vacrn1mof0.4- 1.0 mmHg.
IITRUE COPY!I
All temperatures are- reported uncorrected in degrees Celsius (°C). Unless otherwise .
• iicated, all parts and percentages.are by weight.
Commercial grade reagents and solvents were used without further purification. N-
cyc lohexyl-N'-{methylpolystyrene)carbodiimide• was purchased from Calbioch~rn-
Novabiochem Corp. 3-tert-Butylaniline, 5-tert-butyl-2-methoxyaniline, 4-bromo-3-
(trifluoromethyl)aniline, 4-chloro-3-{trifluoromethyl)aniiine 2-methoxy-5-
(trifluorornethyl)aniline, 4-tert-butyl-2-nitroaniline, 3-amino-2-naphthol, ethyl 4-
isocyanatobenzoate, N-acetyl-4-chloro-2-methoxy-5-(trifluoromethyl)aniline and 4-chloro-3-
(trifluoromethyl)phenyl isocy~ate were purchased and used without. further purification.
I
Synth~es of 3-amino-2-methoxyquinoline (E. Cho et al. WO, 98/00402; A. Cordi et al. EP
542,609; IBID Bioorg. Med. Chem.. 3, 1995, 129), 4-(3-carbamoylphenoxy)-1-nitrobenzene
(K. Ikawa Yakugaku Z,asshi 79, 1959, 160; Chem. Abstr. 53, 1959, 12761b), 3-tert-
butylphenyl isocyanate (0. Rohr et al. DE 2,436,108) and 2-methoxy-5-
(trifluoromethyl)phenyl isocyanate (K. Inukai et al. JP •42,025,067; IBID Kogyo Kagaku
Zasshi 70, J967, 491) have previously been desc1ib~d.
tJ
Thin-layer chromatography (TLC) was performed using w~/~manx: pre-coated glass-backed
silica !,!el60A F-254 250 µm plates. Visualization of plat~{was effected by one or more of
thl! lo~lowing tcchniq.ues: {a) ultraviolet illumination. \~;);'exposure to iodine \'aper. (C)
IITRUE COPYII
¥.immersion of the plate _ina 10% solution of phosphomolybdic acid in ethanol followed by
heating, (d) immersion of the plate in a cerium sulfate solution followed by heating, and/or
(e) immersion of the plate in an acidic ethanol solution of 2,4-dinitrophenylhydrazmc:
followed by heating. Column chromatography (flash chromatography) was performed using
230-400 mesh EM Science®silica gel.
Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or a
Mettler FP66 automated melting paint apparatus and are uncorrected. Fourier transforr.1
infrared spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer.
Proton ( 1H) nuclear magnetic resonance (NMR) spectra were measured with a General
1 Electric GN-Omega 300 (300 MHz) spectrometer with either Me4Si (8 0.00) or residual
3
protonated solvent (CHC\3 8 7.26; MeOH 8 3.30; DMSO 8 2.49) as standard. Carbon ( C)
NMR spectra were measured witr. 1 Geni:>ralElectric GN-Onega 300 (75 i'.v1Hz)
spectromet;::,
with solvent (CDCl3 8 77.0; MeOD-d3;8 49.0; DMSO-d6 8 39.5) as standard. Low resolut10n
mass spectra (MS) and high resolution mass spectra (HRMS) were either obtained as electron
impact (EI) mass spectra or as fast atom bombardment (FAB) mass spectra. Electron impac:
mass spectra (El-MS) were obtained with a Hewlett Packard 5989A mass spectrometer
equipped with a Vacumetrics Desorption Chemical Ionization Probe for sample introduction.
The ion source was maintained at 250 °C. Electron impact ionization was performed with
electron energy of 70 eV and a trap current of 300 µA. Liquid-cesium secondary ion mass
spectra (FAB-MS), an updated version of fast atom bombardment were obtained using a
Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained
using a Hewlett Packard MS-Engine (5989A) with methane or ammonia as the reagent gas
( 1x l 0-4 torr to 2.5x I 0-4torr). The direct insertion desorption chemical ionization (DCI) probe
(Vaccumetrics, Inc.) was ramped from 0-1.5 amps in l O sec and held at l O amps until all
traces of the sample disappeared ( ~ l-2 min). Spectra were scanned from 50-800 amu at 2
sec per scan. HPLC - electrospray mass spectra (HPLC ES-MS) were obtained using a
Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength
detector. a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with clcctrospra:
ionization. Spectra were scanned from l 20-800 amu using a variable ion t1m12 Jt:c1.wJ111~t,,
the number of ions in the source. Gas chromatography• ion selective mass spectra tCC-\ISi
IITRUE COPY!I
t were obtained with a Hewlett Packard 5890 gas chromatograph equipped with an HP· I
methyl silicone column (0..33 mM coating; 25 m x 0.2 mm) and a Hewlett Packard 5971
Mass Selective Detector (ionization energy 70 eV). Elemental analyses are conducted by
Robertson Microlit Labs, Madison NJ.
All compounds displayed NMR spectra, LR.t\1Sand either elemental analysis or HR.i.\11S
consistent with assigned structures.
List of Abbreviations and Acronyms:

AcOH acetic acid
anh anhydrous
atrn atrnosphere(s)
BOC rerr-butoxycarbonyI
CDI 1,1'-carbonyl diimidazole

cone concentrated
d day(s)
dee decomposition
DMAC N,N-dimethylacetamide
DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone
DMF N.N-dimethylfonnamide
DPPA diphenylphosphoryl azide
EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
EtOAc ethyl acetate
5 EtOH ethanol ( l 00%)
Et2O diethyl ether
Et3N triethylamine
h hour(s)
HOBT 1-hydroxybenzotriazole
111-CPBA 3-chloroperoxybenzoic acid
.vfeOH methanol
pct. ether petroleum ether (boiling range 30-60 °()
IITRUE COPYII
temn. temperature
• TH~ tetrahydrofuran
TFA trifluoroAcOH
Tf .
tri fluoromethanesulfonvl'
A. General Methods for Synthesis of Substituted Anilines

Al. General Method for Aryl Amine Formation via Ether Formation
Followed by Ester Saponification, Curtius Rearrangement, and
Carbamate Deprotection. Synthesis of 2-Amino-3-methoxynaphthaleoe.
~co 2Me
OMe
Step l. Methyl 3-methoxy-2-naphthoate

A slurry of methyl 3-hydroxy-2-naphthoate (10.l g, 50.l mmol) and K2CO 3 (7.96 g, 57.6
mmol) in DMF (200 mL) was stirred at room temp. for 15 min., then treated with
iodomethane (3.43 mL, 55.l mmol). The mixture was allowed to stir at room temp.
overnight, then was treated with water (200 mL). The resulting mixture was extracted with
EtOAc (2 x 200 mL). The combined organic layers were washed with a saturated NaCl
solution ( 100 mL), dried (MgSO 4), concentrated under reduced pressure (approximately 0.4
m.mHg overnight) to give methyl 3-methoxy-2-naphthoate as an amber oil ( 10.30 g): 1H-
NMR (DMSO-d6) 8 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, 1=8.09 Hz, IH), 7.44 (s, lH), 7.53
(app t, J=8.09 Hz, lH), 7.84 (d, J=8.09 Hz, lH), 7.90 (s, lH), 8.21 (s, lH).
~co,H
OMe
Step 2. 3-Metboxy-2-naphthoic acid

A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29. l O mmol) and water (IO ml) in
MeOH ( I 00 ml) at room temp. was treated with a I N NaOH solution (33.4 ml. 3]-+ 111mol
l.
The mixture was heated at the reflux temp. for J h, cooled to room temp.. anJ 111JJ1.· J(1d1(
with a I0% citric acid solution. The resulting solution was extracted with Et0.-\L" ( 2 , I1111
-1-r-
IITRUE COPY!I
mL). The combined organic layers were washed with a saturated NaCl solution, dried
1,, (MgSO.i) and concentrated under reduced pressure. The residue was triturated with hexane
then washed several times with hexane to give 3-methoxy-2-naphthoic acid as a white solid
(5.40 g, 92%): 1H-NMR (DMSO-d6) 8 3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, lH),
7.83 (d,J=8.09Hz, lH), 7.91 (d,1=8.09 Hz, lH), 8.19(s, lH), 12.83 (brs, lH).
Qo
x.-~)vu
Step 3. 2-(N-(Carbobenzyloxy)amino-3-methoxynapbthalene
A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and EtJN (2.59 ml, 18.6
mmol) in anh toluene (70 mL) was stirred at room temp. for 15 min., then treated with a
solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 mL) via pipette. The resulting mixture
was heated at 80 °C for 2 h. After cooling the mixture to room temp., benzyl alcohol (2.06
mL, 20 mrnol)was added via syringe. The mixture was then warmed to 80 °C overnight. The
resulting mixture was cooled to room temp., quenched with a 10% citric acid solution, and
extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a
saturated NaCl solution, dried (MgSO4) and concentrated under reduced pressure. The
residue was purified by column chromatography (14% EtOAc/86% hexane) to give 2-(N-
(carbobenzyloxy)amino-3-methoxynaphthalene as a pale yellow oil (5.1 g, 100%): 1H-NN!R
(DMSO-d6 ) 8 3.89 (s, 3H), 5.17 (s, 2H), 7.27-:-7.44(m, 8H), 7.72-7.75 (m, 2H), 8.20 (s, lH),
8.76(s, lH).
~NH,
OMe
Step 4. 2-Amino-3-metboxynaphthalene
A slurry of 2-(N-(carbobenzyloxy)amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and 10%
Pd/C (0.5 g) in EtOAc (70 mL) was maintained under a H2 atm (balloon) at room temp.
overnight. The resulting mixture was filtered through Celitet- and concentrated under
reduced pressure to gi\e 2-amino-3-methoxynaphthalene as a pale pink powdt!r ( 2 .io g..
IITRUE COPY!I
1
.5%): H-N1vfR (DMSO-do) 8 3.86 (s, 3H), 6.86 (s, 2H), 7.04-7.16 (m, 2H), 7.43 (d, J=8.0
Hz, lH), 7.56 (d, 1=8.0 Hz, IH); EI-MS mlz I 73 (l'vt).
A2. Synthesis of w-Carbamyl Anilines via Formation of a Carbamylpyridine
Followed by Nucleophilic Coupling with an Aryl Amine. Synthesis of 4-

(2-N-Methylcarbamyl-4-pyridyloxy)aniline
0
Cl~NHMe
~~
Step la. Synthesis of 4-chloro-N-metbyl-2-pyridinecarboxamide via the Menisci
reaction
Caution: this is a highly hazardous, potentially explosive reaction. To a stirring solution of
4-chloropyridine ( I 0.0 g) in N-methylformamide (250 mL) at room temp. was added cone.
H2SO4 (3.55 mL) to generate an exotherm. To this mixture was added H2O2 (30% wt in H 2O,
17 mL) followed by FeSO4•7H 2O (0.56 g) to generate another exotherm. The resulting
mixture was stirred in the dark at room temp. for I h, then warmed slowly over 4 h to 45 °C.
When bubbling had subsided, the reaction was heated at 60 °C for 16 h. The resulting
opaque brown solution was diluted with H2O (700 mL) followed by a 10% NaOH solution
(250 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The organic
phases were washed separately with a saturated NaCl solution (3 x -150 mL), then they were
combined, dried (MgSO 4 ) and filtered through a pad of silica gel with the aid of EtOAc. The
resulting brown oil was purified by column chromatography (gradient from 50% EtOAc/50%
hexane to 80% EtOAc/20% hexane). The resulting yellow oil crystallized at O °Cover 72 h to
give 4-chloro-N-methyl-2-pyridinecarboxamide (0.61 g, 5.3%): TLC (50% EtOAc/50¾
hexane) R1 0.50; 1H NMR (CDCh) 8 3.04 (d, 1=5.1 Hz, 3H), 7.43 (dd, 1=5.4, 2.4 Hz, l H),
7.96 (br s, lH), 8.21 (s, lH), 8.44 (d, 1=5.1 Hz, l H); CI-MS mlz 171 ((M+Hf).
Cl~CI
~N HCI
Step 1b. Synthesis of 4-chloropyridine-2-carbonyl chloride HCI salt via picolinic

acid
IITRUE COPYII
,t ,\nhydrous DMF (6.0 mL) was slowly added to SOCl 2 ( 180 mL) between 40° and 50 °(.
The solution was stirred in that temperature range for 10 min. then picolinic acid (60.0 g, 487
mmol) was added in portions over 30 min. The resulting solution was heated at 72 °C
(vigorous SO2 evolution) for 16 h to generate a yellow solid precipitate. The resulting
mixture was cooled to room temp., diluted with toluene (500 mL) and concentrated to 200
mL. The toluene addition/concentration process was repeated twice. The resulting nearly
dry residue was filtered and the solids were washed with toluene (2 x 200 mL) and dried
under high vacuum for 4 h to afford 4-chloropyridine-2-carbonyl chloride HCI salt as a
yellow-orange solid (92.0 g, 89%).
0
Cl~ ---::: OMe

I /, N HCI
Step 2. Synthesis of methyl 4-cbloropyridine-2-carboxylate HCIsalt

Anh DMF (10.0 mL) was slowly added to SOC!i (300 mL) at 40-48 °C. The solution was
stirred at that temp. range for 10 min., then picolinic acid ( 100 g, 812 mmol) was added over
30 min. The resulting solution was heated at 72 °C (vigorous SO2 evolution) for 16 h to
generate a yellow solid. The resulting mixture was cooled to room temp., diluted with
toluene (500 mL) and concentrated to 200 mL. The toluene addition/concentration process
was repeated twice. The resulting nearly dry residue was filtered, and the solids were washed
with toluene (50 mL) and dried under high vacuum for 4 hours to afford 4-chloropyridine-2-
carbonyl chloride HCl salt as an off-white solid (27.2 g, 16%). This material was set aside.
The red filtrate was added to MeOH (200 mL) at a rate which kept the internal temperature
below 55 °C. The contents were stirred at room temp. for 45 min., cooled to 5 °C and treated
with Et20 (200 mL) dropwise. The resulting solids were filtered, washed with Et20 (200
ml) and dried under reduced pressure at 35 °C to provide methyl 4-chloropyridine-2-
carboxylate HCI salt as a white solid ( 110 g, 65%): mp l 08-112 °C; 1H-N?v1R(DMSO-d0 ) 8
3.88 (s, 3H); 7.82 (dd, J=5.5, 2.2 Hz, lH); 8.08 (d, J=2.2 Hz, lH); 8.68 (d, 1=5.5 Hz. I H);
I 0.68 (br s, I H); HPLC ES-MS ml:: 172 ((M+Hf).
IITRUE COPY!I
0
Cl~NHMe
~~
Step 3a. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from methyl 4-
c h lo ropyridine-2-carboxylate
A suspension of methyl 4-chloropyridine-2-carboxylate HCI salt (89.0 g, 428 mmol) in
MeOH (75 rnL) at 0 °C was treated with a 2.0 M methyiamine solution in THF ( l L) at a rate
which kept the internal temp. below 5 °C. The resulting mixture was stored at 3 °C for 5 h,
then concentrated under reduced pressure. The resulting solids were suspended in EtOAc ( 1
L) and filtered. The filtrate was washed with a saturated NaCl solution (500 mL), dried
(Na 2 S0 4 ) and concentrated under reduced pressure to afford 4-chloro-N-methyl-2-
pyridinecarboxamide as pale-yellow crystals (71.2 g, 97%): mp 41-43 °C; 1H-NMR (DMSO-
d6 ) o 2.81 (s, 3H), 7.74 (dd, 1=5.1, 2.2 Hz, IH), 8.00 (d, J:a:2.2, IH), 8.61 (d, J,;5.1 Hz, IH),
8.85 (br d, IH); Cl-MS m/z 171 ((M+Hf).
Cl~O
I --.::::: NHMe
✓, N
Step 3b. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from 4-

chloropyridine-2-carbooyl chloride
4-Chloropyridine-2-carbonyl chloride HCl salt (7.0 g, 32.95 mmol) was added in portions to
a mixture of a 2.0 M methylamine solution in THF (100 mL) and MeOH (20 mL) at O 0 C.
The resulting mixture was stored at 3 °C for 4 h, then concentrated under reduced pressure.
The resulting nearly dry solids were suspended in EtOAc ( 100 mL) and filtered. The filtrate
was washed with a saturated NaCl solution (2 x 100 mL), dried (Na 2SO4) and concentrated
under reduced pressure to provide 4-chloro-N-methyl-2-pyridinecarboxamide as a yellow,
crystalline solid (4.95 g, 88%): mp 37-40 °C.
0
oO'CrNHMe
H2N
Seep 4. Synthesis of 4-(2-(N-methykarbamoyl)-4-pyridyloxy)aniline

A ~elution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. DMF ( 150 ml) was treated \\ 1th
potassium tert-butoxide (10.19 g, 91 .7 mmol), and the reddish-brown mixture was stirred at
IiTRUE COPYII
room temp. for 2 h. The contents were treated with 4-chloro-N-methyl-2-
pyridinecarboxamide (15.0 g, 87.9 mmol) and KzCO3 (6.50 g, 47.0 mrnol) and then heated ar
80 °C for 8 h. The mixture was cooled to room temp. and separated between EtOAc (500
mL) and a saturated NaCl solution (500 rnL). The aqueous phase was back-extracted with
EtOAc (300 ml). The combined organic layers were washed with a saturated NaCl solution
(4 x 1000 mL), dried (Na 2SO4) and concentrated under reduced pressure. The resulting solids
were dried under reduced pressure at 35 °C for 3 h to afford 4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)aniline as a light-brown solid 17.9 g, 84%): 1H-NNfR (DMSO-d 6) 8 2.77 (d, J:;;:4_8
Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (AA'BB' quartet, 1=8.4 Hz, 4H), 7.06 (dd, 1=5.5, 2.5 Hz.
lH), 7.33 (d, J=,;2.5Hz, lH), 8.44 (d, Jc,,;5.5Hz, lH), 8.73 (br d, lH); HPLC ES-MS m/:::244
({M+Hf).
A3. General Method for the Synthesis of Anilines by Nucleopbilic Aromatic
Addition Followed by Nitroarene Reduction. Synthesis of 5-(4-
Aminophenoxy)isoindoline-l,3-dione
Step 1. Synthesis of 5-hydroxyisoiodoline-1,3-dione

To a mixture of ammonium carbonate (5.2~ g, 54.9 mmol) in cone. AcOH (25 mL) was
slowly added 4-hydroxyphthalic acid (5.0 g, 27 .45 mmol). The resulting mixture was heared
at 120 °C for 45 min., then the clear, bright yellow mixture was heated at 160 °C for 2 h. The
resulting mixture was maintained at 160 °C and was concentrated to approximately 15 mL,
then was cooled to room temp. and adjusted pH IO with a IN NaOH solution. This mixture
was cooled to O °C and slowly acidified to pH 5 using a 1N HCl solution. The resultant
precipitate was collected by filtration and dried under reduced pressure to yield 5-
1
hydroxyisoindoline-1,3-dione as a pale yellow powder as product (3.24 g, 72%): H NMR
(DMSO-d 6 ) 8 7.00-7.03 (m, 2H), 7.56 (d, J=9.3Hz, l H).
IITRUE _coPYjl
Step 2. Synthesis of 5-(4-nitrophenoxy)isoindoline-1,3-diooe
To a stirring sluny of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) at 0 °C was added a solution
of 5-hydroxyisoindoline-1,3-dione (3.2 g, 19.6 mmol) in DMF (40 mL) dropwise. The bright
yellow-green mixture was allowed to return to room temp. and was stirred for 1 h, then l-
fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added via syringe in 3-4 portions. The
resulting mixture was heated at 70 °C overnight, then cooled to room temp. and diluted
slowly with water (150 mL), and extracted with EtOAc (2 x 100 mL). The combined organic
layers were dried (MgSQ4) and concentrated under reduced pressure to give 5-(4-
nitrophenoxy)isoindoline-l,3-dione as a yellow solid (3.3 g, 62%): TLC (30% EtOAc/70%
hexane) R1 0.28; lH NMP. (DMSO-d6) 8 7.3~ (d, 1=12 Hz, 2H). 7.52-7.57 (m, 2H;, 7.89(d,
J=7.8 Hz, lH), 8.29 (d, 1=9 Hz, 2H), 11.43 (br s, lH); CI-MS mlz 285 ((M+H/, 100%).
Step 3. Synthesis of 5-(4-aminophenoxy)isoindoline-1,3-dione

A solution of 5-(4-nitrophenoxy)isoindoline-1,3-dione (0.6 g, 2.11 mmol) in cone. AcOH ( 12
mL) and water (0.1 mL) was stirred under stream of argon while iron powder (0.59 g, 55.9
mmol) was added slowly. This mixture stirred at room temp. for 72 h, then was diluted with
water (25 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were
dried (MgSO 4) and concentrated under reduced pressure to give 5-(4-
aminophenoxy)isoindoline-l,3-dione as a brownish solid (0.4 g, 75%): TLC (50%
1
EtOAc/50% hexane) Rt 0.27; H NMR (DMSO-d 6 ) 8 5.14 (br s, 2H), 6.62 (d, J=8. 7 Hz, 2H),
6.84 (d, 1=8.7 Hz, 2H), 7.03 (d, J=2.l Hz, lH), 7.23 (dd, lH), 7.75 (d, J=8.4 Hz, IH), l 1.02
(s, l H); HPLC ES-MS mlz 255 ((M+H/, 100%).
A4. General Method for the Synthesis of Pyrrolylanilines. Synthesis of 5-tert-

Butyl-2-(2,5-dimethylpyrrolyl)aniline
I[TRUE COPYjl
Step 1. Synthesis of l-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole
To a stirring solution of 2-nitro-4-tert-butylaniline (0.5 g, 2.5 7 rrunol) in cyclohexane (IO
mL) was added AcOH (0. lmL) and acetonylacetone (0.299 g, 2.63 mmol) via syringe. The
reaction mixture was heated at 120 °C for 72 h with azeotropic removal of volatiles. The
reaction mixture was cooled to room temp., diluted with CH 2 Ch (IO mL) and sequentially
·washed with a lN HCI solution (15 mL), a IN NaOH solution (15 mL) and a saturated NaCl
solution ( 1SmL), dried ( MgSQ4) and concentrated under reduced pressure. The resulting
orange-brown solids were purified via column chromatography (60 g SiO 2; gradient fror:1 6°"o
EtOAc/94% hexane to 25% EtOAc/75% hexane) to give 1-( 4-tert-butyl-2-nitrophenyl)-2,5-
dimethylpyrrole as an orange-yellow solid (0.34 g, 49%): TLC (15% EtOAc/85% hexane) Rr
0.67; 1H N1v[R(CDCb) d l.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 (m, lH), 7.62
(dd, I H), 7.88 (d, J=2.4 Hz, lH); CI-MS mlz 273 ((M+H)\ 50%).
Step 2.
--u N
Synthesis of 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline
A slurry of l-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole (0.341 g, 1.25 mmol),
I 0¾Pd/C (0.056 g) and EtOAc (50 ml) under an H 2 atmosphere (balloon) was stirred for 72
h, then filtered through a pad of Celite®. The filtrate was concentrated under reduced
pressure to give 5-tert--butyl-2-(2,5-dimethylpyrrolyl)aniline as yellowish solids (0.30 g,
1
99%): TLC (10% EtOAc/90% he;ane) Rr0.43; H NMR (CDCh) 8 1.28 (s, 9H), l.87-1.91
(m. 8H). 5.85 {br s, 2H), 6. 73-6.96 (m, 3H), 7.28 (br s, I H).
IITRUE COPYII
General Method for the Syntb.esis of Anilines from Anilines by
Nucleophilic Aromatic Substitution. Synthesis of 4-(2-(N-
Methylcarbamoyl)-4-pyridyloxy}-2-metbylaniline HCI Salt
0
HN
2
q Me
·o~NHMe
~~
HCI
A solution of 4-amino-3-methylphenol (5.45 g, 44.25 mmol) in dry dimethylacetamide (7 5
mL) was treated with potassium cerr-butoxide (10.86 g, 96.77 mmol) and the black mixture
was stirred at room temp. until the flask had reached room temp. The contents were then
treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step Jb; 7.52 g, 44.2
mmol) and heated at 110 °C for 8 h. The mixture was cooled to room temp. and diluted with
water (7 5 mL). The organic layer was extracted with EtOAc (5 x 100 mL). The combined
organic layers were washed with a saturated NaCl solution (200 mL), dried (MgSOJ) and
concentrated under reduced pressure. The residual black oil was treated with Et 2O (50 ml)
and sonicated. The solution was then treated with HCI (1 M in Et 2O; l 00 mL) and stirred at
room temp. for 5 min. The resulting dark pink solid (7 .04 g, 24.1 mmol) was removed by
filtration from solution and stored under anaerobic conditions at O °C prior to use: 1H N1v1R
(DMSO-d 6) 8 2.41 (s, 3H), 2.78 (d, J=4.4 Hz, 3H), 4.93 (hrs, 2H), 7.19 (dd, J=8.S. 2.6 Hz.
IH), 7.23 (dd, 1=5.5, 2.6 Hz, lH), 7.26 (d, J=2.6 Hz, IH), 7.55 (d, J=2.6 Hz, IH), 7.64 (d,
1=8.8 Hz, lH), 8.55 (d, 1=5.9Hz, IH), 8.99 (q, J=4.8 Hz, IH).
A6. General Method for the Synthesis of Anilines from Hydroxyanilines·by N-

Protection, Nucleophilic Aromatric Substitution and Deprotection.
Syo thesis of 4-(2-(N-Meth ylcarbamoyl)-4-pyridyloxy)-2-chloroan ilin e
0 NOH
F3C)lNY
H Cl
Step I: Syn thesis of 3-Ch loro"'.4-(2,2,2-trifluoroacetylamino )phenol

!ron (3.24 g, 58.00 mmol) was added to stirring TFA (200 ml). To this slurry was added>
chloro- ➔ -nitrophenol ( I 0.0 g, 58.0 mmol) and trifluoroacetic anhydride (20 ml). Tim '.;;fJ:
slurry was stirred al room temp. for 6 d. The iron was filtered from solution :111J th1.'
2L
£- r
IITRUE COPYjl
remaining material was concentrated under reduced pressure. The resulting gray solid was
•dissolved in water (20 mL). To the resulting yellow solution was added a saturated NaHCO 3
solution (50 mL). The solid which precipitated from solution was removed. The filtrate was
slowly quenched with the sodium bicarbonate solution until the product visibly separated
from solution (determined-was using a mini work-up vial). The slightly cloudy yellow
solution was extracted with EtOAc (3 x 125 mL). The combined organic layers were washed
with a saturated NaCl solution (125 mL), dried (Mg$O4) and concentrated under reduced
I
pressure. The H NMR (DMSO-d 6 ) indicated a l: 1 ratio of the nitrophenol starting material
and the intended product 3-chloro-4-(2,2,2-trifluoroacetylamino )phenol. The crude material
was taken on to the next step without further purification.
0
o No~NHMe
F3C)lNy ~~
H Cl
Step 2: Synthesis of 4-(2-(N-Methykarbamoyl)-4-pyridyloxy)-2-chJoropbeayl

(222-trifluoro)acetamide
A solution of crude 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol (5.62 g, 23.46 mmol) in
dry dimethylacetamide (50 mL) was treated with potassium tert-butoxide (5.16 g, 45.98
mmol) and the brownish black mixture was stirred at room temp. until the flask had cooled to
room temp. The resulting mixture was treated with 4-chloro-N-methyl-2-
pyridinecarboxamide (Method A2, Step 3b; 1.99 g, 11.7 mmol) and heated at 100 °( under
argon for 4 d. The black reaction mixture was cooled to room temp. and then poured into
cold water (100 mL). The mixture was extracted with EtOAc (3 x 75 rnL) and the combined
organic layers were concentrated under reduced pressure. The residual brown oil was
purified by column chromatography (gradient from 20% EtOAc/pet. ether to 40% EtOAc/pet.
ether) to yield 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-
tritluoro)acetamide as a yellow solid (8.59 g, 23.0 mmol).
0
O
('¾y' ~NHMe
H2N~CI ~~
Step 3. Synthes is of 4-(2-(/V-!\lethyka rbamoyl)-4-pyridyloxy)-2-ch loroaniline
IITRUE COPYjl
~\ solution of crude 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222 •
trifluoro)acetamide (8.59 g, 23.0 mmol) in dry 4-dioxane (20 mL) was treated with a 1N
NaOH solution (20 mL). This brown solution was allowed to stir for 8 h. To this solution
was added EtOAc (40 mL). The green organic layer was extracted with EtOAc (3 x 40 mL)
and the solvent was concentrated to yield 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-
1
chloroaniline as a green oil that solidified upon standing (2.86 g, 10.30 mmol): H NMR
(DMSO-d 6) 8 2.77 (d, J=4.8 Hz, 3H), 5.51 (s, 2H), 6.60 (dd, J=8.5, 2.6 Hz, IH), 6.76 (d,
1=2.6 Hz, lH), 7.03 (d, J=S.5 Hz, IH), 7.07 (dd, J=S.5, 2.6, Hz, lH), 7.27 (d. J=2.6 Hz, IH).
8.46 (d. J=S.5 Hz, lH), 8.75 (q, J=4.8, lH).
A7. General Method for the Deprotection of an Acylated Aniline. Synthesis of

4-Cbloro-2-methoxy-5-(trifluorometbyl)aniline
CF3
CIY)
VNH2
OMe
A suspension of 3-chloro-6-(N-acetyl)-4-(trifluoromethyl)anisole (4.00 g, 14.95

mmol) in a 6M HCI solution (24 mL) was heated at the reflux temp. for I h. The
resulting solution was allowed to cool to room temp. during which time it solidified
slightly. The resulting mixture was diluted with water (20 mL) then treated with a
combination of solid NaOH and a saturated NaHCO 3 solution until the solution was
basic. The organic layer was extracted with CH 2Ch (3 x 50 mL). The combined
organics were dried (MgSQ4) and concentrated under reduced pressure to yield 4-
1
chloro-2-methoxy-5-(trifluoromethyl)aniline as a brown oil (3.20 g, 14.2 mmol): H
m-1R (DMSO-d6) 8 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).
AS. General Method for Synthesis of ro-Alkoxy-ro-carboxyphenyl Anilines.

Synthesis of 4-(3-(N-Metbylcarbamoly)-4-metboxypbenoxy)aniline.
0
oO'(XOMe
02N OMe
Step I. 4-( 3-1\1eth ox yea rbon y 1-4-meth oxyph enoxy)-1-n itrobenzen e:
I[TRUE COPYjl
p To a solution of 4-(3-carboxy-4-hydroxyphenoxy)-1-nitrobenzene (prepared from 2,5-
dihydroxybenzoic acid in a manner analogous to that described in Method A 13. Step 1, 12
mmol) in acetone (50 mL) was added K2CO3 (5 g) and dimethyl sulfate (3.5 mL). The
resulting mixture was heated at the reflux temp. overnight, then cooled to room temp. and
filtered through a pad of Celite®. The resulting solution was concentrated under reduced
pressure, absorbed onto Si0 2, and purified by column chromatography (50% EtOAc i 50%
hexane) to give 4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene as a yelJow
powder (3 g): mp 115-118 °C.
0
OO~OH
02N OMe
Step 2. 4-(3-Carboxy-4-meth oxyphen oxy)-1-nitrobenzene:

A mixture of 4-(3-methoxycarbonyl-4-methoxyphenoxy)-l-nitrobenzene (I .2 g), KOH (0.33
g) and water (5 mL) in MeOH (45 mL) was stirred at room temp. overnight and then heated
at the reflux temp. for 4 h. The resulting mixture was cooled to room temp. and concentrated
under reduced pressure. The residue was dissolved in water (50 mL), and the aqueous
mixture was made acidic with a IN HCl solution. The resulting mixture was extracted with
EtOAc (50 mL). The organic layer was dried (MgSO4 ) and concentrated under reduced
pressure to give 4-(3-carboxy-4-methoxyphenoxy)-l-nitrobenzene ( 1.04 g).
0
~o~NHMe
0 2N}v llAOMe
Step 3. 4-(3-(N-Methylcarbamoly)-4-methoxyphenoxy)-1-nitrobenzene:
To a solution of 4-(3-carboxy-4-methoxyphenoxy)-l-nitrobenzene (0.50 g, 1.75 mmol) in
CH2Ch ( 12 mL) was added SOCI2 (0.64 mL, 8.77 mmol) in portions. The resulting solution
was heated at the reflux temp. for 18 h, cooled to room temp., and concentrated under
reduced pressure. The resulting yellow solids were dissolved in CH2Ch (3 mL) then the
resulting solution was treated with a methylamine solution (2.0 M in THF, 3.5 ml, 7.02
mmol) in portions (CAUTION: gas evolution), and stirred at room temp. for 4 h. The
resulting mixture was treated with a 1N NaOH solution, then extracted with CH1Cl2 (25 ml)
....2i---
~
nTRUE COPYI1
The organic layer was dried (Na2SO4) and concentrated under reduced pressure to give 4-(3-
.(N-methylcarbamoly)-4-methoxyphenoxy)-l-nitrobenzene as a yellow solid (0.50 g, 95%).
0
oO'CX:NHMe
H2N OMe
Step 4. 4-(3-(N-Methylcarbamoly)-4-methoxyphenoxy)aniline:
A slurry of 4-(3-(N-methylcarbamoly)-4-methoxyphenoxy)-l-nitrobenzene (0. 78 g, 2.60
mmol) and 10% Pd/C (0.20 g) in EtOH (55 mL) was stirred under l atm of H2 (balloon) for
2.5 d, then was filtered through a pad of Celite®. The resulting solution was concentrated
under reduced pressure to afford 4-(3-(N-methylcarbamoly)-4-methoxyphenoxy)aniline as an
off-white solid (0.68 g, 96%): TLC (0.1% Et3N/99.9% EtOAc) R1 0.36.
A9. Genera\ M.ethod for Preparation of (l)-J\lky\phtba\imide-containing

Anilines. Synthesis of 5-(4-Aminophenoxy)-2-methylisoindoline-l,3-dione
0
r""Y ~-Me
02N)v v½ 0
Step I. Synthesis of 5-(4-Nitropheooxy)-2-metbylisoindoline-1,3-dione:
A slurry of 5-( 4-nitrophenoxy)isoindoline-1,3-dione (A3 Step 2; 1.0 g, 3 .52 mmol) and NaH
(0.13 g, 5.27 mmol) in DMF (15 mL) was stirred at room temp. for 1 h, then treated with
methyl iodide (0.3 mL, 4.57 mmol). The :resulting mixture was stirred at room temp.
overnight, then was cooled to °C and treated with water (10 mL). The resulting solids were
. collected and dried under reduced pressure to give 5-(4-nitrophenoxy)-2-methylisoindoline-
1,3-dione as a bright yellow solid (0.87 g, 83%): TLC (35% EtOAc/65% hexane) Rr0.61.
0
r""Y '(~-{-Me
H2NA_)J v½ 0
II TRUE COPYII
.. ep 2. Synthesis of S-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione:
A sluny of nitrophenoxy)-2-methylisoindoline-l,3-dione (0.87 g, 2.78 mmol) and 10% Pd/C
(0.10 g) in MeOH was stirred under l atm of H2 (balloon) overnight. The resulting mixture
was filtered through a pad of Celite® and concentrated under reduced pressure. The resulting
yellow solids were dissolved in EtOAc (3 mL) and filtered through a plug of Si0 2 (60%
EtOAc/40% hexane) to afford 5-( 4-aminophenoxy)-2-methylisoindoline-1,3-dione as a
yellow solid (0.67 g, 86%): TLC (40% EtOAc/60% hexane) R10.27.
Al 0. General Method for Synthesis of w-Carbamoylaryl Anilines Through

Reaction of w-Alkoxycarboaylaryl Precursors with Amines. Synthesis of
4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline
0
CkcrN-,~Co
Step 1. Synthesis of 4-Cbloro-2-(N-(2-morpbolin-4-ylethyl)carbamoyl)pyridine

To a solution of methyl 4-chloropyridine-2-carboxylate HCl salt (Method A2, Step 2; 1.01 g,
4.86 mmol) in THF (20 mL) was added 4-(2-aminoethyl)morpholine (2.55 mL, 19.4 mmol)
dropwise and the resulting solution was heated at the reflux temp. for 20 h, cooled to room
temp., and treated with water (50 mL). The resulting mixture was extracted with EtOAc (50
mL). The organic layer was dried (MgSO4)-·and concentrated under reduced pressure to
afford 4-chloro-2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine as a yellow oil ( 1.25 g,
95%): TLC (10% MeOH/90% EtOAc) RrO.SO.
1.A-
~
IITRUE COPY!I
~tep 2. Synthesis of 4;.(2-(N-(2-Morpbolin-4-
ylethyl)carbamoyl)pyridyloxy)aniline.
' g, 4. 75
A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium tert-butoxide (0.53
mol) in DMF (8 mL) was stirred at room temp. for 2 h, then was sequentially treated with 4-
chloro-2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine (1.22 g, 4.52 mmol) and Kz(O3
(0.31 g, 2.26 mmol). The resulting mixture was heated at 75 °C overnight, cooled to room
temp., and separated between EtOAc (25 mL) and a saturated NaCl solution (25 mL). The
aqueous layer was back extracted with EtOAc (25 mL). The combined organic layers were
washed with a saturated NaCl solution (3 x 25 mL) and concentrated under reduced pressure.
The resulting brown solids were purified by column chromatography (58 g; gradient from
100% EtOAc to 25% MeOH/75% EtOAc) to afford 4-(2-(N-(2-morpholin-4-
ylethyl)carbamoyl)pyridyloxy)aniline (1.0 g, 65%): TLC (10% MeOH/90% EtOAc) Rr0.32.
Al 1. General Method for the Reduction of Nitroarenes to Arylamines.

Synthesis of 4-(3-Carboxypheooxy)aniline.
0
ood'OH
H2N
A slurry of 4-(3-carboxyphenoxy)-l-nitrobenzene (5.38 g, 20.7 mmol) and 10% Pd/C (0.50

g) in MeOH (120 mL) was stirred under an H 2 atmosphere (balloon) for 2 d. The resulting
mixture was filtered through a pad of Celite®, then concentrated under reduced pressure to
afford 4-(3-carboxyphenoxy)aniline as a brown solid (2.26 g, 48%): TLC (10% MeOH/90%
CH2Cli) Rr 0.44 (streaking).
Al 2. General Method for the Synthesis of lsoindolinone-Containing Anilines.

Synthesis of 4-(1-0xoisoindolin~S-yloxy)anilioe.
HO~ I NH
:::c-.._
I[TRUE COPYII
Step 1. Synthesis of 5-bydroxyisoindolin-1-one
~o a solution of 5-hydroxyphthalimide (19.8 g, 121 rnmol) in AcOH (500 ml) was slowly
added zinc dust (4 7 .6 g, 729 mmol) in portions, then the mixture was heated at the reflux
cemp. for 40 min., filtered hot, and concentrated under reduced pressure. The reaction was
repeated on the same scale and the combined oily residue was purified by column
chromatography (I. I Kg Si0 2; gradient from 60% EtOAc/40% hexane to 25% MeOH/75%
EtOAc) to give 5-hydroxyisoindolin-l-one (3.77 g): TLC (100% EtOAc) R10.17; HPLC ES-
MS mlz 150 ((M+Hf).
Step 2. S yo thesis of 4-(1-isoindolinon-5:-Yloxy)-l-nitrobenzeoe

To a slurry of NaH (0.39 g, 16.I mmol) in DMF at O °C was added 5-hydroxyisoindolin- l-
one (~.O g, 13.4 r.::nol) ir. portions. The resulting slurry 'VJ.S albwed to warn to room temp
and was stirred for 45 min., then 4-fluoro-1-nitrobenzene was added and then mixture was
heated at 70 °C for 3 h. The mixture was cooled to O °C and treated with water dropwise
until a precipitate fonned. The resulting solids were collected to give 4-(l-isoindolinon-5-
yloxy)-l-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC ( 100% EtOAc) R1 0.35.
£fo'(rNH
H2N ~
0
Step 3. Synthesis of 4-(1-oxoisoindolin-S•yloxy)aniline

A slurry of 4-(l-isoindolinon-5-yloxy)-l-nitrobenzene (2.12 g, 7.8 mmol) and 10% Pd/C
(0.20 g) in EtOH (50 mL) was stirred under an Hz atmosphere (balloon) for 4 h, then filtered
through a pad of Celite®. The filtrate _was concentrated under reduced pressure to afford 4-( l -
oxoisoindolin-5-yloxy)aniline as a dark yellow solid: TLC (100% EtOAc} R;0.15.
Al 3. General Method for the Synthesis or ro-Carbamoyl Anilines via EDCI-

Mediated Amide Formation Followed by Nitroarene Reduction.
Synthesis of 4-(J-N-Metbylcarbamoylpbenoxy)aniline.
IITRUE _COPYII
012
0 2N ~v
~O~OEt
Step 1. Synthesis of 4-(3-ethoxycarbooylphenoxy)-1-aitrobenzene

A mixture of 4-tluoro-1-nitrobenzene ( 16 rnL, 150 mmol), ethyl 3-hydroxybenzoate 25 g,
150 mmol) and K2C0 3 (41 g, 300 mrnol) in DMF (125 rnL) was heated at the reflux temp.
overnight, cooled to room temp. and treated with water (250 mL). The resulting mixture was
extracted with EtOAc (3 x 150 mL). The combined organic phases were sequentially washed
with water (3 x I 00 mL) and a saturated NaCl solution (2 x I 00 mL), dried (Na 2S0 4) and
concentrated under reduced pressure. The residue was purified by column chromatography
( l 0% EtOAc/90% hexane) to afford 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene as an oil
(38 g).
Step 2. Synthesis of 4-(3-carboxyphenoxy)-1-nitrobenzene

To a vigorously stirred mixture of 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene (5 .14 g, 17.9
mmol) in a 3: l THF/water solution (75 mL). was added a solution LiOH•H 2 0 ( 1.50 g, 35.8
mmol) in water (36 mL). The resulting mixture was heated at 50 °C overnight, then cooled to
room temp., concentrated under reduced pressure, and adjusted to pH 2 with a l M HCl
solution. The resulting bright yellow solids were removed by filtration and washed with
hexane to give 4-(3-carboxyphenoxy)-l-nitrobenzene (4.40 g, 95%).
0
~o~NHMe
02N~ V
IITRUE COPYII
'Step 3. Synthesis of 4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene
A mixture of 4-(3-carboxyphenoxy)-l-nitrobenzene (3.72 g, 14.4 mmol), EDCI·HCI (3.63 g,
18.6 mmol), N-methylmorpholine (1.6 mL, 14.5 mmol) and methylarnine (2.0 M in THF; 8
mL, 16 mmol) in CH 2C!2 (45 mL) was stirred at room temp. for 3 d, then concentrated under
reduced pressure. The residue was dissolved in EtOAc (50 mL) and the resulting mixture
was extracted with a IM HCl solution (50 mL). The aqueous layer was back-extracted with
EtOAc (2 x 50 mL). The combined organic phases were washed with a saturated NaCl
solution (50 mL), dried (Na 2S04), and concentrated under reduced pressure to give 4-(3-(N-
rnethylcarbarnoyl)phenoxy)- l-nitrobenzene as an oil (1.89 g).
0
~o~NHMe
H2N~ V
Step 4. Synthesis of 4-(3-(N-metbylcarbamoyl)pheooxy)aniline
A slurry of 4-(3-(N-methylcarbamoyl)phenoxy)-l-nitrobenzene (1.89 g, 6.95 mmol) and 5%
Pd/C (0.24 g) in EtOAc (20 mL) was stirred under an H 2 atm (balloon) overnight. The
resulting mixture was filtered through a pad of Celite® and concentrated under reduced
pressure. The residue was purified by column chromatography (5% MeOH/95% CH 2Cb).
The resulting oil solidified under vacuwn overnight to give 4-(3-(N-
methylcarbamoyl)phenoxy)aniline as a yellow solid (0.95 g, 56%).
Al4. General Method for the Synthesis of ro-Carbamoyl Anilines via EDCI-
Synthesis of 4-3-(5-Methylcarbamoyl)pyridyloxy)aniline
0 2N
o 0
lfaMe
N
0
Step 1. Syn thesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-oitrobenzene

To a slurry of NaH (0.63 g, 26.1 mmol) in DMF (20 ml) was added a solution of methyl 5-
hydroxynicorinate (2.0 g, I 3.1 mn;iol) in DMF (IO ml). The resulting mixture was added 10 a
14
11TRUE COPYII
.solution of 4-fluoronitrobenzene (l.4 mL, 13.l mmol) in DMF (10 mL) and the resulting
mixture was heated at 70 °C overnight, cooled to room temp., and treated with MeOH ( 5 ml)
followed by water (50 mL). The resulting mixture was extracted with EtOAc (100 mL). The
organic phase was concentrated under reduced pressure. The residue was purified by column
chromatography (30% EtOAc/70% hexane) to afford 4-(3-(5-methoxycarbonyl)pyridyloxy)-
l -nitrobenzene (0.60 g).
0
o-odOMe
H2N N
Step 2. Synthesis of 4-(3-(5-methoxycarbooyl)pyridyloxy)aniline

A slurry of 4-(3-(5-methoxycarbonyl)pyridyloxy)-l-nitrobenzene (0.60 g, 2.20 mmo l) and
10% Pd/C in MeOH/EtOAc was stirred under an Hz atmosphere (balloon} for 72 h. The
resulting ,rixture was filtered and the filtrate wa~ concentrated unde, reduced pressure. ·1he
residue was purified by column chromatography (gradient from l 0% EtOAc/90% hexane to
30% EtOAc/70% hexane to 50% EtOAc/50% hexane) to afford 4-(3-(5-
methoxycarbonyl)pyridyloxy)aniline(0.28 g, 60%): 1H NMR (CDCl3) o 3.92 (s, 3H), 6. 71 (d,
2H), 6.89 (d, 2H), 7.73 (, lH), 8.51 (d, lH), 8.87 (d, lH).
IITRUE COPYII
.15. Synthesis of an Aniline via Electrophilic Nitration Followed by Reduction.
Synthesis of 4-(3-Metbylsulfamoylphenoxy)aniline.
Step 1. Synthesis of N-methyl-3-bromobenzeoesulfonamide

To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, I 1.2 mmol) in THF ( 15 mL) at 0
°C was added methylamine (2.0 M in THF; 28 mL, 56 mmol). The resulting solution was
allowed to warm to room temp. and was stirred at room temp. overnight. The resulting
mixture was separated between EtOAc (25 mL) and a l M HCI solution (25 mL). The
aqueous phase was back-extracted with EtOAc (2 x 25 mL). The combined organic phases
were sequentially washed with water (2 x 25 mL) and a saturated NaCl solution (25 mL),
dried (MgS.0;.\ aud ccm.ce.nti:a.tedu.n.de:c reduced 9ces.is.uce.ta ?:,1.'le N-metl;,.~:1._
;_
bromobcnzenesulfonamide as a white solid (2.8 g, 99%).
er'O o
0, ,,0
's"
'NHMe
Step 2. Synthesis of 4-(3-(N-methylsulfamoyl)pheJlYloxy)benzene

To a slurry of phenol ( 1.9 g, 20 mmol), K2CO 3 (6.0 g, 40 rnmol), and Cul (4 g, 20 mmol) in
DMF (25 mL) was added N-methyl-3-bromobenzenesulfonamide (2.5 g, 10mmol), and the
resulting mixture was stirred at the reflux temp. overnight, cooled to room temp., and
separated between EtOAc (50 mL) and a 1 N-HCI solution (50 mL). The aqueous layer was
back-extracted with EtOAc (2 x 50 mL). The combined organic phases were sequentially
washed with water (2 x 50 mL) and a saturated NaCl solution (50 mL), dried (MgSO 4), and
c:.oncen.r..rateduuder reduced ?te:~~ure. 1'he re~\du.i.~ Q,i.J, 'N?S 1p\0,fre.i ~'J c:.c1,•.1mr,
chromatography (30% EtOAc/70% hexane) to give 4-(3-(N-
methylsulfamoyl)phenyloxy)benzene (0.30 g).
IITRUE COPY!I
.. Step 3. Synthesis of 4-(3-(N-methylsu}famoyl)phenyloxy)-1-nitrobenzene
To a solution of 4-(3-(N-methylsulfamoyl)phenyloxy)benzene (0.30 g, 1.14 mmol) in TFA (6
mL) at -10°C was added NaNO 1 (0.097 g, 1.14 mmol) in portions over 5 min. The resulting
solution was stirred at -10 °C for l h, then was allowed to wann to room temp., and was
;-; concentrated under reduced pressure. The residue was separated between EtOAc (IO mL)
and water (10 mL). The organic phase was sequentially washed with water (10 ml) and a
saturated NaCl solution (10 mL), dried (MgS0 4) and concentrated under reduced pressure to
give 4-(3-(N-methylsulfamoyl)phenyloxy)-l-nitrobenzene (0.20 g). This material carried on
to the next step without further purification.
Step 4. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)aniline

A slurry of 4-(3-(N-methylsulfamoyl)phenyloxy)- l-nitrobenzene (0.30 g) and l 0% Pd/C
(0.030 g) in EtOAc (20 mL) was stirred under an H 2 atmosphere (balloon) overnight. The
resulting mixture was filtered through a pad of Celite®. The filtrate was concentrated under
reduced pressure. The residue was purified by column chromatography (30% EtOAc/70%
hexane) to give 4-(3-(N-rnethylsulfamoyl)phenyloxy)aniline (0.070 g).
Al 6. Modification of ro-ketones. Synthesis of 4~(4-(1-(N-

methoxy)iininoethyl)phenoxy~niline HCl salt.
,o....._
H,N~CI ~
~A)0
To a slurry of 4-( 4-acetylphenoxy)aniline HC! salt (prepared m a manner analogous to
Method Al3, step 4; 1.0 g, 3.89 mmol) in a mixture ofEtOH (10 mL) and pyridine ( ! .0 ml)
was added O-methylhydroxylamine HCl salt (0.65 g, 7.78 mmol, 2.0 equiv.). The resulting
solution was heated at the reflux temperature for 30 min, cooled to room temperature and
concentrated under reduced pressure. The resulting solids were triturated with water ( l O ml)
and \,·ashed with water to give 4-(4-( 1-(N-methoxy)iminoethyl) phenoxyaniline HCI salt JS J
IITRUE COPY!I
1
~ellow solid (0.85 g): TLC (50% EtOAc/50% pet. ether) R10.78; H NMR (Dtv1SO-d6) 8 3.90
(s, 3H), 5.70 (s, 3H); HPLC-MS mlz 257 ((M+Hf).
Al 7. Synthesis of N-(w-Silyloxyalkyl)amides. Synthesis of 4-(4-(2-(N-(2-
Triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline.
Step 1. 4-Chloro-N-{2-triisopropylsilyloxy)etbylpyridine-2-carboxamide
To a solution of 4-chloro-N-(2-hydroxyethyl)pyridine-2-carboxamide (prepared in a manner
analogous to Method Al, Step 3b; 1.5 g, 7.4 mmol) in anh DMF (7 mL) was added
triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv.) and imidazole (1.12 g, 16.4 mmol,
2.2 equiv.). The resulting yellow solution was stirred for 3 h at room temp, then was
concentrated under reduced pressure. The residue was separated between water (10 mL) and
EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3 x IO mL). The combined
organic phases were dried (MgSQ4), and concentrated under reduced pressure to afford 4-
chloro-2-(N-(2-triisopropylsilyloxy)ethyl)pyridinecarboxamide as an orange oil (2.32 g,
88%). This material was used in the next step without further purification.
0 )--
O O
(Y ~N~ 'Si
H2N~ ~·~ H ~ \
Step 2. 4-(4-(2-(N-(2-Triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline
To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in anh DMF (8 mL) was added
potassium tert-butoxide (0.67 g, 6.0 mrnol, 1.0 equiv.) in one portion causing an exothenn.
When this mixture had cooled to room temperature, a solution of 4-chloro-2-(N-(2-
triisopropylsilyloxy)ethyl)pyridinecarboxamide (2.32 g, 6 mmol, l equiv.) in DMF (4 mL)
was added followed by K2CO3 (0.42 g, 3.0 mmol, 0.50 equiv.). The resulting mixture was
heated at 80 °C overnight. An additional portion of potassium rerr-butoxide (0.34 g, 3 mmol,
0.5 equiv.) was then added and the mixture was stirred at 80 °C an additional 4 h. The
mi;,;.ture,, as cooled to 0 °C with an ice/,vater bath. then water (approx. \ ml) was slo\\,:\y
;iJded Jropwise. The organic layer was extracted with EtOAc (3 x IO ml). The combinl!d
~
l t ,)
-
IITRUE COPY!I
*rganic layers were washed with a saturated NaCl solution (20 ml), dried (MgSQ4) and
concentrated under reduced pressure. The brown oily residue was purified by column
chromatography (SiO2; 30% EtOAc/ 70% pet ether) to afford 4-(4-(2-(N-(2·
triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline as a clear light brown oil (0.99 g,
38%).
A18. Synthesis of 2-Pryidinecarboxylate Esters via Oxidation of 2-

Methylpyridines. Synthesis of 4-(5-(2-
methoxycarbonyl)pyridyloxy)aniline .
. (Yo~
02N~ ~N;l____
Step 1. 4-( 5-(2-Metbyl)pyridyloxy)-1-nitrobenzene.

A mixtu~ of 5-hydroxy-2-rr.ethylpyridine (10.') g, 91.6 mrnol), : Daorc-4-nitroben~cne (9.S
ml, 91.6 mrnol, 1.0 equiv.), K2C03 (25 g, 183 mrnol, 2.0 equiv.) in DMF (100 mL) was
heated at the reflux temperature overnight. The resulting mixture was cooled to room
temperature, treated with water (200 mL), and extracted with EtOAc (3 x 100 mL). The
combined organic layers were sequentially washed with water (2 x 100 mL) and a saturated
NaCl solution ((100 mL), dried (MgSQ4) and concentrated under reduced pressure to give 4-
(5-(2-methyl)pyridyloxy)-1-nitrobenzene as a brown solid (12.3 g).
0 2N
~o½
~_.~I
N
OMe
Step 2. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)-l-nitrobenzene.

A mixture of 4-(5-(2-methyl)pyridyloxy)-I-nitrobenzene (1.70 g, 7.39 mmol) and selenium
dioxide (2.50 g, 22.2 mmol, 3.0 equiv.) in pyridine (20 mL) was heated at the reflux
temperature for 5 h, then cooled to room temperature. The resulting slurry was filtered , then
concentrated under reduced pressure. The residue was dissolved in MeOH ( 100 mL). The
solution was treated with a cone HCI solution (7 ml), then heated at the reflux temperature
for 3 h. cooled to room temperature and concentrated under reduced pressure. The residue
was separated between EtOAc (50 ml) and a IN NaOH solution (50 ml). The aqueous layer
was extracted with EtOAc (2 x 50 ml). The combined organic layers were sequentially
I[TRUE COPY!I
.ashed with water (2 x 50 mL) and a saturated NaCl solution (50 mL), dried (MgSOJ) and
(SiO 2 ; 50% EtOAc/50% hexane) to afford 4-(5-{2-methoxycarbonyl)pyridyloxy)-l-
nitrobenzene (0. 70 g).
H,NOO½OMe
0
Step 3. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)aniline.
A slurry of 4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.50 g) and 10% Pd/C
(0.050 g) in a mixture of EtOAc (20 mL) and MeOH (5 mL) was placed under a H 2
atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celite\
and the filtrate was concentrated under reduced pressure. The residue was purified by
column chromatography (SiO2; 70% EtOAc/30% hexane) to give 4-(5-\2-
methoxycarbonyl)pyridyloxy)aniline (0.40 g).
A19. Synthesis of co-Sulfonylpbenyl Anilines. Synthesis of 4-{4-
Methylsulfonylphenyoxy)aniline.
ONOOUS,Me
2 a''o
Step I. 4-(4-Metbylsulfonylpbenoxy)-l-,nitrobeozene: To a solution of 4-(4-
rnethylthiophenoxy)-l-nitrobenzene (2.0 g, 7.7 mmol) in CH 2Ch (75 mL) at 0 °C was slowly
added m-CPBA (57-86%, 4.0 g), and the reaction mixture was stirred at room temperature for
5 h. The reaction mixture was treated with a l N NaOH solution (25 mL). The organic layer
was sequentially washed with a l N NaOH solution (25 mL), water (25 mL) and a saturated
NaCl solution (25 mL), dried (MgSO4), and concentrated under reduced pressure to give 4.
(4-methylsul fonylphenoxy)-1-nitrobenzene as a solid (2.1 g).
Step 2. 4-(4-Methylsulfonylphenoxy)-1-aniline: 4-(4-Methylsulfonylphenoxy)-I-

nitrobenzene was reduced to the aniline in a manner analogous to that described 1n \,1ethod
:\ 13. step 3
~(JLf
IITRUE COPYII
Svnthesis of l;rea Precursors
• \
Bl. General Method for the Synthesis of Isocyanates from Anilines Using
\
CDI. Synthesis of 4-Bromo-3-(trifluorometbyl)phenyl Isocyanate.
Br'O
NH2•HCI
Step 1. Synthesis of 4-bromo-3-(trifluoromethyl)aniline HCl salt

To a solution of 4-bromo-3-(trifluoromethyl)aniline (64 g, 267 mmol) in Et2O (500 ml) was
added an HCI solution (I Min Et2O; 300 mL) dropwise and the resulting mixture was stirred
at room temp. for 16 h. The resulting pink-white precipitate was removed by filtration and
washed with Et2O (50 mL) and to afford 4-bromo-3-(trifluoromethyl)aniline HC! salt (73 g ,
98%).
Step 2. Synthesis of 4-bromo-3-(trifluoromethyl)phenyl isocyanate

A suspension of 4-bromo-3-(trifluoromethyl)aniline HCI salt (36.8 g, 133 mmol) in toluene
(278 mL) was treated with trichloromethyl chloroformate dropwise and the resulting mixture
was heated at the reflux temp. for 18 h. The resulting mixture was concentrated under
reduced pressure. The residue was treated wilh toluene (500 mL), then concentrated under
reduced pressure. The residue was treated with CH 2Cl 2 (500 mL), then concentrated under
reduced pressure. The CH 2Cl 2 treatment/concentration protocol was repeated and resulting
amber oil was stored at -20 °C for 16 h, to afford 4-brorno-3-(trifluoromethy\)pheny\
isocyanate as a tan solid (35.1 g, 86%): GC-MS mlz 265 (M\
C. Methods of Urea Formation

Cla. General Method for the Synthesis of Ureas by Reaction of an Isocyanate
with an Aniline. Synthesis of N-(4-Chloro-3-{trifluoromethyl)pbenyl)-N'-
(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)pheoyl) Urea
IITRUE COPY!I
CF3 0
Clti I O 00~ I II I NHMe

:::::-.. )l :::::-., vN
N N
H H
A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (14.60 g, 65.90 mmol) in CH2Cl2

(35 mL) was added dropwise to a suspension of 4-(2-(N-methy!carbamoyl)-4-
pyridyloxy)aniline (Method A2, Step 4; 16.0 g, 65.77 mmol) in CH 2Ch (35 mL) at 0 0 C. The
resulting mixture was stirred ·at room temp. for 22 h. The resulting yellow solids were
removed by filtration, then washed with CH2Clz (2 x 30 mL) and dried under reduced
pressure (approximately 1 mmHg) to afford N-( 4-chloro-3-(trifluoromethyl)phenyl)-N '-(4-( 2-
(N-methylcarbarnoyl)-4-pyridyloxy)phenyl) urea as an off-white solid (28.5 g, 93%): mp
207-209 °C; 1H-NMR (DMSO-d6) 8 2.77 (d, 1=4.8 Hz, 3H), 7. I 6 (m, 3H), 7.37 {d, 1==2.5
Hz,
IH), 7.62 (m, 4H), 8.11 (d, 1==2.5
Hz, lH), 8.49 (d, 1=5.5 Hz, lH), 8.77 (br d, IH), 8.99 (s,
lH), 9.21 (s, lH); HPLC ES-MS m/z 465 ({M+Hf).
Clb. General Method for the Synthesis of Ureas by Reaction of an Isocyanate

with an Aniline. Synthesis of N-(4-Bromo-3-(trifluoromethyl)phenyl)-N'-
{4-(2-(N-metbylcarbamoyl)-4-pyridyloxy)phenyl) Urea
CF3 0
Br~ 0 ~o~NHMe
UNJlN,V ~~
H H
A solution of 4-bromo-3-(trifluoromethyl)phenyl isocyanate (Method B 1, Step 2; 8.0 g, 30. l

mmol) in CH 2Cl 2 (80 ml) was added dropwise to a solution of 4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)aniline (Method A2, Step 4; 7.0 g, 28.8 mmol) in CH 2Ch (40 mL) at 0 0 C. The
resulting mixture was stirred at room temp. for 16 h. The resulting yellow solids were
removed by filtration, then washed with CH2Cl2 (2 x 50 mL) and dried under reduced
pressure (approximately l mmHg) at 40 °C to afford N-(4~bromo-3-(trifluoromethyl)phenyl)-
N ·-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a pale-yellow solid ( I 3.2 g.
1
90%): mp 203-205 °C; H-NMR(DMSO-d6) 8 2.77 (d, 1=4.8 Hz, 3H}, 7.16 (m, 3H), 7.37 (d.
1=2.5 Hz, IH}, 7.58 (m, JH), 7.77 (d, 1=8.8 Hz, !H), 8.11 (d, 1=2.5 Hz. IH). 8. ➔ 9 (J. J=5 5
Hz, IH).8.77(brd, IH),8.99(s, IH),9.21 (s. lH); HPLC ES-MS m/:509((\1-Hl.J.
~ I •. ,.
~ :,
I[TRUE COPY!I
General Method for the Synthesis of Ureas by Reaction of an Isocyanate
with an Aniline. Synthesis of N-(4-Chloro-3-(trifluoromethyl)phenyl)-N'-
(2-metbyl-4-(2-(N-methylcarbamoyl)( 4-pyridyloxy))phenyl) Urea
CF3 0
CIU· o qodNHMe
I /2
II
N,,>'--..N''
" I I N
oh
H H Me
A solution of 2-methyl-4-(2-(N-methylcarbamoyl)( 4-pyridyloxy))aniline (Method A5; 0.11 g,

0.45 mmol) in CH 2Cl2 (1 mL) was treated with Et 3N (0.16 mL) and 4-chloro-3-
(trifluorornethyl)phenyl isocyanate (0.10 g, 0.45 rnmol). The resulting brown solution was
stirred at room temp. for 6 d, then was treated with water (5 mL). The aqueous layer was
back-extracted with EtOAc (3 x 5 rnL). The combined organic layers were dried (MgSO4)
and concentrated under reduced pressure to yield N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-
(2-:r1ethy!-4-(2-(N-mc::hylcarbamoyl)(4-p~Tidyloxy))phenyl) :1~eaas a brown oii :0.11 g, 0.22
1
rnmol): H ~'MR (DMSO-d 6 ) 8 2.27 (s, 3H), ~.77 (d, J=4.8 Hz, 3H), 7.03 (dd, J=8.5, 2.6 Hz,
lH), 7.11 (d, J=2.9 Hz, IH), 7.15 (dd, J,;;:5.5,
2.6, Hz, IH), 7.38 (d, J=2.6 Hz, lH), 7.62 (app
d, J=2.6 Hz, 2H), 7.84 (d, 1=8.8 Hz, lH), 8.12 (s, lH), 8.17 (s, lH); 8.50 (d, 1=5.5 Hz, lH),
8.78 (q, 1=5.2, lH), 9.52 (s, lH); HPLC ES-MS m/z 479 ((M+Hf).
Cld. General Method for the Synthesis of Ureas by Reaction of an Isocyanate

with an Aniline. Synthesis of N-(4-Chloro-3-(trifluoromethyl)phenyl)-N'-
(4-aminophenyl) Urea
CF3
Cl'Y.¾ O ~NH2
UA~N N
H H
To a solution of 4-chloro-3-(trifluorornethyl)phenyl isocyanate (2.27 g, l 0.3 mmol) in
CH 2Cl 2 (308 rnL) was added p-phenylenediamine (3.32 g, 30.7 mmol) in one part. The
resulting mixture was stirred at room temp. for l h, treated with CH 2Cli ( l 00 mL), and
concentrated under reduced pressure. The resulting pink solids were dissolved in a mixture
of EtOAc (II 0 ml) and MeOH ( I 5ml), and the clear solution was washed with a 0.05 I\;
HCI solution. The organic layer was concentrated under reduced pressure to afford impure
~LAl-
nTRUE COPYI1
•I-( 4-chloro-3-(trifluoromethyl)phenyl)-N'-( 4-aminophenyl) urea (3.3 g): TLC ( l 00°,o
EtOAc) R10.72.
Cle. General Method for the Synthesis of Ureas by Reaction of an Isocyanate

with an Aniline. Synthesis of N-(4-Chloro-3-(trifluoromethyl)pbenyl)-N'-
(4-ethoxycarbonylphenyl) Urea
CF 3 0
Cl+
u 0
N )l_ N
H H
AJ
~OEt
To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CH 2Ch (30 ml) was
added 4-chloro-3-(trifluoromethyl)aniline (3.21 g, 16.4 mmol), and the solution was stirred at
room temp. overnight. The resulting slurry was diluted with CH 2Cb (50 mL) and filtered to
afford N-( 4-chloro-3-(trifluoromethyl)phenyl)-N '-(4-ethoxycarbonylphenyl) urea as a white
solid (5.93 g, 97%): TLC (40% EtOAc/60% hexane) R10.44.
Clf. General Method for the Synthesis of Ureas by Reaction of an Isocyanate

with an Aniline. Synthesis of N-(4-Chloro-3-(trifluorometbyl)pbenyl)-N'-
(3-carboxypbenyl) Urea
CF3 0
Cl+ 0 ~O~OH
~N)l_N~
H H
V
To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (1.21g, 5.46 mmol) in CH2Ch
(8 mL) was added 4-(3-carboxyphenoxy)aniline (Method All; 0.81 g, 5.76 mmol) and the
resulting mixture was stirred at room temp. overnight, then treated with MeOH (8 mL), and
stirred an additional 2 h. The resulting mixture was concentrated under reduced pressure.
The resulting brown solids were triturated with a 1: I EtOAclbexane solution to give 1\/-(4-
chloro-3-(trifluoromethyl)phenyl)-N '-(3-carboxyphenyl) urea as an off-white solid ( 1.21 g,
76%).
C2a. General Method for Urea Synthesis by Reaction of an Aniline with .V,.V'-
Carbonyl Diimidazole Followed by Addition of a Second Aniline.
~ (
I[TRUE COPYjl
Synthesis of N-(2-Methoxy-5-{trifluoromethyl)pbeoyl)-.N'-(4-(2-{N-
methylcarbamoyl)-4-pyridyloxy)pbenyl) Urea
<i)vOo'Cf NHMe
OMe H H
To a solution of2-methoxy-5-(trifluoromethyl)aniline (0.15 g) in anh CH2Cl2 (15 mL) at O°C

was added CDI (0.13 g). The resulting solution was allowed to warm to room temp. over 1 h,
was stirred at room temp. for 16 h, then was treated with 4-(2-(N-methylcarbamoyl)-4-
pyridy\oxy)aniline (0.18 g). The resulting yellow solution was stirred at room temp. for 72 h,
then was treated with H20 ( 125 mL). The resulting aqueous mixture was extracted with
EtOAc (2 x 150 mL). The combined organics were washed with a saturated NaCl solution
(100 mL), dried (Mg$Q4) and concentrated under reduced pressure. The residu~ w:i.s
triturated (90% EtOAc/10% hexane). The resulting white solids were collected by filtration
and washed with EtOAc. The filtrate was concentrated under reduced pressure and the
residual oil purified by column chromatography (gradient from 33% EtOAc/67% hexane to
50% EtOAc/50% hexane to 100% EtOAc) to give N-(2-methoxy-5-(trifluoromethyl)phenyl)-
N '-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a light tan solid (0.098 g, 30%):
TLC (100% EtOAc) Rj 0.62; 1H NMR (DMSO-C¼)cS2.76 (d, J=4.8 Hz, 3H), 3.96 (s, 3H),
7.1-7.6 and 8.4-8.6 (m, llH), 8.75 (d, J=4.8 Hz, IH), 9.55 (s, l H); FAB-MS mlz 461
((M+Hf').
C2b. General Method for Urea Synthesis by Reaction of an Aniline with N,N'-
Symmetrical Urea's as Side Products of a N,N'-Carbonyl Diimidazole
Reaction Procedure. Synthesis of Bis(4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)phenyl) Urea
0 0
MeHN~
~~
O
Y)
~ N )l
0
V
0°'C(-..::::
✓,N
NHMe
N
H H
IITRUE COPYII
j.o a stirring solution of3-amino-2-methoxyquinoline (0.14 g) in anhydrous CH2Cli (15 mL)
·at 0 C was added CDI (0.13 g). The resulting solution was allowed to warm to room temp .
.
over 1 h then was stirred at room temp. for 16 h. The resulting mixture was treated with 4-(2 •
(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.18 g). The resulting yellow solution stirred at
room temp. for 72 h, then was treated with water (125 ml). The resulting aqueous mixture
was extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with a
sacurared NaCl solution (WO ml), dried (MgSQ4) and concentrated under reduced pressure.
The residue was triturated (90% EtOAc/10% hexane). The resulting white solids were
collected by filtration and washed with EtOAc to give bis( 4-(2-(N-methylcarbamoyl)-4-
1
pyridyloxy)phenyl) urea (0.081 g, 44%): TLC (100% EtOAc) R10,50; H NMR (DMSO-d6) o
2.76 (d, J=S.I Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, J=5.4 Hz, lH), 8.75 (d, J=:4.8 Hz, 2H),.
8.86 (s, 2H); HPLC ES-MS mlz 513 ((M+Hf).
C2c. General Method for the Synthesis of Ureas by Reaction of an Isocyanate

with an Aniline. Synthesis of N-(2-Methoxy-S-(trifluorometbyl)pheoyJ-N'-
(4-(1,3-dioxoisoindolin-5-yloxy)phenyl) Urea
A JOO~:
YN
OMe H
N
H NH
0
To a stirring solution of2-methoxy-5-(trifluotomethyl)phenyl isocyanate (0.10 g, 0.47 mmol)

in CH2Ch (1.5 mL) was added 5-( 4-aminophenoxy)isoindoline-1,3-dione (Method A3, Step
3; 0.12 g, 0.47 mrnol) in one portion. The resulting mixture was stirred for 12 h, then was
treated with CH2Ch (10 mL) and MeOH {5 mL). The resulting mixture was sequentially
washed with a lN HCI solution (15 mL) and a saturated NaCl solution (15 mL), dried
(MgSO4) and concentrated under reduced pressure to afford N-(2-methoxy-5-
(tritluoromethyl)phenyl-N'-(4-( l ,3-dioxoisoindolin-5-yloxy)phenyl) urea as a white solid (0.2
1
g, 96%): TLC (70% EtOAc/30% hexane) R10.50; H NMR (DMSO-d 6) 8 3.95 (s, 3H), 7.31-
7.l 0 (m, 6H), 7.57 (d, J=9.3Hz, 2H), 7.80 (d, J=8.7 Hz, 1H), 8.53 (br s, 2H), 9.57 (s, l H).
l 1.27 (br s. ! H); HPLC ES-MS 472.0 ((M+Hf. 100%).
~-
&---- •)
IITRUE COPY!I
General Method for Urea Synthesis by Reaction of an Aniline with lV,1V'-
Synthesis of N-(S-(tert-Butyl)-2-(2,5-dirnethylpyrrolyl)pbenyl)-N'-(4-(2-
(N-methylcarbamoyl)-4-pyridyloxy)pbenyl) Urea
To a stirring solution of CDI (0.21g, 1.30 mmol) in CH 2Cl2 (2 mL) was added 5-(tert-butyl)-
2-(2,5-dimethylpyrrolyl)aniline (Method A4, Step 2; 0.30 g, 1.24 mmol) in one portion. The
resulting mixture was stirred at room temp. for 4 h, then 4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)anilinc (0.065 g, 0,267rrtr10I) was then adced in one portion The resulting
mixture was heated at 36 °C overnight, then cooled to room temp. and diluted with EtOAc (5
mL). The resulting mixture was sequentially washed with water (15 mL) and a IN HCI
solution ( 15ml), dried (MgSQ4), and filtered through a pad of silica gel (50 g) to afford N·{S-
( tert-buty 1)-2-(2 ,5-d imethylpyrroly l)phenyl)-N •-( 4-(2-(N-methylcarbamoyl )-4-
pyridylox y)phenyl) urea as a yellowish solid (0.033 g, 24%): TLC (40% EtOAc/60% hexane)
R10.24; 1H NMR (acetone-d6) & 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, J=4.8Hz. 3H), 5.83 (s,
2H), 6.87-7.20 (m, 6H), 7.17 (dd, lH), 7.51~7.58 (m, 3H), 8.43 (d, J=5.4Hz, lH), 8.57 (d,
J=2.1Hz, IH), 8.80 (br s, lH); HPLC ES-MS 512 ((M+H)\ 100%).
C3. Combinatorial Method for the Synthesis of Diphenyl Ureas Using

Triphosgene
One of the anilines to be coupled was dissolved in dichloroethane (0.1 O M). This so lutron
was added to a 8 mL vial (0.5 rnL) _containing dichloroethane (1 mL). To this was added a
bis(trichloromethyl) carbonate solution (0.12 M in dichloroethane, 0.2 mL, 0.4 equiv.},
followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The vial
was capped and heat at 80 °C for 5 h, then allowed to cool to room temp for approx1ma1ely
IO h. The second aniline was aeided (0.10 M in dichloroethane, 0.5 mL. 1.0 equi\'. ). folio\\ i:J
by u1isopropylethylamine (0.35 M in dichloroethane. 0.2 ml. 1.2 equi\·.). The result1n~
IITRUE COPY!I
l,lixture was heated at 80 °C for 4 h, cooled to room temperature and treated with MeOH (0.5
mL). The resulting mixture was concentrated under reduced pressure and the products were
purified by reverse phase HPLC.
C4. General Method for Urea Synthesis by Reaction of an Aniline with Phosgene
Followed by Addition of a Second Aniline. Synthesis of N•(2•Methoxy•5-
(triflu orometbyl)pbenyl)-N'-{ 4--(2-(N-methykarbamoyl)-4-pyridyloxy)pbenyl) Urea
0
¢t)~No
OMe H H
1f NHMe
To a stirring solution of phosgene (1.9 M in toluene; 2.07 mL0.2lg, 1.30 mmol) in CH 2Cl~
(20 mL) at 0 °C ~as added anh pyridine (0.32 mL) followed by 2-methoxy-5-
(trifluoromethyl)aniline (0.75 g). The yellow solution was allowed to warm to room temp
during which a precipitate formed. The yellow mixture was stirred for 1 h, then concentrated
under reduced pressure. The res1,1ltingsolids were treated with anh toluene (20 mL) followed
by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (prepared as described in Method .A...2;
0.30 g) and the resulting suspension was heated at 80 °C for 20 h, then allowed to cool to
room temp. The resulting mixture was diluted with water (100 mL), then was made basic
with a saturated NaHCO 3 solution (2-3 mL). The basic solution was extracted with EtOAc (2
x 250 mL). The organic layers were separately washed with a saturated NaCl solution,
combined, dried (MgSO 4), and concentrated under reduced pressure. The resulting pink-
brown residue was dissolved in MeOH and absorbed onto SiO 2 (100 g). Column
chromatography (300 g SiO2 ; gradient from 1% Et3N/33% EtOAc/66% hexane to l %
Et3N/99% EtOAc to 1% Et3N/20% MeOH/79% EtOAc) followed by concentration under
reduced pressure at 45 °C gave a wann concentrated EtOAc solution, which was treated with
hexane ( 10 mL) to slowly fonn crystals of N-(2-methoxy-5-(trifluoromethyl)phenyl)-N '-(4-
(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea (0.44 g): TLC (I% Et3N/99% EtOAc) Ri
0.40.
~ r-;-"'2-
IITRUE COPYII
Interconversion of Ureas
j;
Dla. Conversion of w-Aminophenyl Ureas into w-(Aroylamino)phenyl Ureas.
Synthesis of N-(4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-
methoxycarbonylpheny))carboxyamiuopbenyl) Urea
CF3 HAI
Cl~ O ~N ~ OMe
UN.ANN O 0
H H
To a solution of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-aminophenyl) urea (Method

Cld; 0.050 g, 1.52 mmol), mono-methyl isophthalate (0.25 g, 1.38 rnrnol), HOBT•H 2O (0.41
g, 3.03 mmol) and N-methylmorpholine (0.33 mL, 3.03 mmol) in DMF (8 mL) was added
EDCI •HCI (0.29 g, 1.52 mmol). The resulting mixture was stirred at room temp. overnight,
diluted with EtOAc (25 mL) and sequentially washed with water (25 mL) and a saturated
NaHCO 3 solution (25 mL). The organic layer was dried (Na 2SC 4 ) and concentraiec unde,
reduced pressure. The resu]ting solids were triturated with an EtOAc solution (80%
EtOAc/20% hexane) to give N-( 4-chloro-3-((trifluoromethyl)phenyl)-N"-( 4-(J-
methoxycarbonylphenyl)carboxyaminophenyl) urea (0.27 g, 43%): mp 121-122; TLC (80%
EtOAc/20% hexane) R1 0.75.
D1b. Conversion of ffi-Carboxyphenyl Ureas into w-(Atylcarbamoyl)phenyl

Ureas. Synthesis of N-(4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-
methylcarbamoylphenyl)carbamoylphenyl) Urea
CF 3 0 ()
Cl~ O ~N~NHMe
VAAJ N N
H 0
H H
To a solution of N-(4-chloro-3-( (trifluoromethyl)phenyl)-N '-(4-(3-methylcarbamoylphenyl)

carboxyaminophenyl) urea (0.14 g, 0.48 mmol), 3-methylcarbamoylaniline (0.080 g, 0.53
mmol), HOBT•H2O (0.14 g, 1.07 mmol), and N-methylmorpholine (0.5ml, 1.07 mmol) in
DMF (3 mL) at O°C was added EDCI·HCl (0.10 g, 0.53 mmol). The resulting mixture was
allowed to warm co room remp. and was stirred overnight. The resulting mixture was creaced
with water ( I 0ml), and extracted with EtOAc (25 ml). The organic phase was concentrated
IITRUE COPY!I
under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 mL) then
'ri1tered through a pad of silica gel (17 g, gradient from 70% EtOAc/30% hexane to l 0%
MeOH/90% EtOAc) to give N-(4-chloro-3-( (trifluoromethyl)phenyl)-N '-(4-(3-
-methylcarbamoylphenyl)carbamoylphenyl) urea as a white solid (0.097 g, 41 %): mp 225-
229; TLC (100% EtOAc) R10.23.
Dlc. Combinatorial Approach to the Conversion of ro-Carboxyphenyl Ureas

into ro-(Arylcarbamoyl)phenylUreas. Synthesis of N-(4-Chloro-3-
((trifluoromethyl)pbenyl)-N'-(4-(N-(3-(N-(3-
pyridyl)carbamoyl)phenyl)carbamoyl)phenyl) Urea
Cl~
CF3
0 ~N
0 ½l
~
H
N~N
UNANA} H O V
H H
A mixture of N•(4-chloro-3-((trifluoromethyl)phenyl)-N'-(3-carboxyphenyl) urea (Method
Clf; 0.030 g, 0.067 mmol) and N-cyclohexyl-N'-(methylpolystyrene)carbodiimide (55 mg) in
l ,2-dichloroethane ( l mL) was treated with a solution of 3-aminopyridine in CH 2Cb ( l M;
0.074 mL, 0.074 mmol). (In cases of insolubility or turbidity, a small amount of DMSO was
also added.) The resulting mixture was heated at 36 °C overnight. Turbid reactions were then
treated with THF (1 mL) and heating was continued for 18 h. The resulting mixtures were
treatad with poly(4•(isocyanatomethyl)styrene) (0.040 g) and the resulting mixture was
stirred at 36 °C for 72 h, then cooled ·to room temp. and filtered. The resulting solution was
filtered through a plug of silica gel (1 g). Concentration under reduced pressure afforded N-
(4-chloro-3•( (trifluoromethyl)phenyl)-N '-(4-(N-(3-(N-(3-
pyridyl )carbamoyl)phenyl)carbamoyl)phenyl) urea (0.024 g, 59%): TLC (70% EtOAc/30%
hexane) Ri0.12.
D2. Conversion of ro-CarboalkoxyarylUreas into ro-CarbamoylarylUreas.

Synthesis of N-(4-Ch loro-3-((trifluoromethyl)pbenyl)-N '-(4-(3-
merhylcarbamoylphenyl)carboxyaminophenyl) Urea
IITRUE COPYII
CF3 HAI
Cl~ O ~N ~ NHMe
UNAN~ 0 0
H H
To a sample of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-carbomethoxyphenyl)
carboxyaminophenyl) urea (0.17 g, 0.34 mmol) was added methylamine (2 M in THF; I mL,
l .? mmal) and the. re~ulti.n.i mi.x.tu.i:e at mQm t.f'....w.1.
was 'iti.:r:ced. Q.'<f!W..i.gl;.v.,
tJ;im. ~W~l!r.i.tr.V.f'Ji
, under reduced pressure to give N-( 4-chloro-3-((trifluoromethyl)phenyl)-N '-(4-(3-

methylcarbamoylphenyl)carboxyaminophenyl) urea as a white solid: mp 24 7; TLC ( 100%
EtOAc) R10.35.
D3. Conversion of w-Carboalkoxyaryl Ureas into w-Carboxyaryl Ureas.

Synthesis of N-(4,Ch}oro-3-((trifiuorometbyl)phenyl)-N'-(4-
carboxyphenyl) Vrea
CF3 0
Cl~ 0 ~OH
UA~N N
H H
To a slurry of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-ethoxycarbonylphenyl) urea

(Method Cle; 5.93 g, 15.3 mmol) in MeOH (75 mL) was added an aqueous KOH solution
{2.5 N, 10 mL, 23 mmol). Toe resulting mixture was heated at the reflux temp. for 12 h,
cooled to room temp., and concentrated under reduced pressure. The residue was diluted
with water (50 mL), then treated with a 1 N HCl solution to adjust the pH to 2 to 3. The
resulting solids were collected and dried under reduced pressure to give N-( 4-chloro-3-
((trifluoromethyl)phenyl)-N '-(4-carboxyphenyl) urea as a white solid (5.05 g, 92%).
D4. General Method for the Conversion of w-Alkoxy Esters into w-Alkyl Amides.
Synthesis of N-(4-Chloro-3-((trifluoromethyl)pbenyl)-N'~((4-(3-(5-(2-
dimethylaminoethyl)carbamoyl)pyridyl)oxypbenyl) Urea
Cf3 0
Cl~I O ~O~.OH
~ N
Jl N ~ l ..JJ
N
H H
IiTRUE _coPYjl
atep I. Synthesis of N-(4-Cbloro-3-(trifluoromethyl)pbenyl)-.V'-((4-(3-(5-
carboxypyridyl) oxypbenyl) Urea
N-( 4-Chloro-3-(tri fluoromethyl)phen yl )-N '-((4-( 3-( 5-methoxycarbonylpyrid yl )oxyphenyl)
urea was synthesized from 4-chloro-3-(trifluoromethyl)phenyl isocyanate and 4-(3-(5-
methoxycarbonylpyridyl) oxyaniline (Method A 14, Step 2) in a manner analogous to Method
Cla. A suspension of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-
methoxycarbonylpyridyl)oxyphenyl) urea (0.26 g, 0.56 mmol) in MeOH ( l 0 mL) was treated
with a solution of KOH (0.14 g, 2.5 mmol) in water (I mL) and was stirred at room temp. for
I h. The resulting mixture was adjusted to pH 5 with a I N HCI solution. The resulting
precipitate was removed by filtration and washed with water. The resulting solids were
dissolved in EtOH (10 mL) and the resulting solution was concentrated under reduced
pressure. The EtOH/concentration procedure was repeated twice to give N-( 4-chloro-3-
\ uifluoromethyl)phc:·nyl)-.N'-((4-(3-(5-cr:)oXY?yridyl) oxyphenyl) urea (0.18 f, 71 %).
CF3 0 I
()'Olf ~~N,
UNH1H
Cl~
N~ N
Step 2. Synthesis of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-(2-

dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) urea
A mixture of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-
carboxypyridyl)oxyphenyl) urea (0.050 g, 0,011 mrnol), N,N-dimethylethylenediamine (0.22
mg, 0.17 mmol), HOBT (0.028 g, 0. I 7 mmol), N-methylmorpholine (0.035 g, 0.28 mmol),
and EDCI•HCI (0.032 g, 0.17 mmol) in DMF (2.5 mL) was stirred at room temp. overnight.
The resulting solution was separated between EtOAc (50 mL) and water (50 mL). The
organic phase was washed with water (35 mL), dried (MgSO4 ) and concentrated under
reduced pressure. The residue was dissolved in a minimal amount of CH 2Ci 2 (approximately
2 mL). The resulting solution was treated with Et 2O dropwise to give N-( 4-chloro-3-
(trifluoromethyl)phenyl)-N'-((4-(3-(5-(2-dimethylaminoethyl)carbarnoyl)pyridy!)oxyphenyl)
1
urea as a white precipitate (0.48 g, 84%: H NMR (DMSO-d 6 ) 8 2.10 s, 6H), 3.26 {s, H ), 7.03
(d, 2H), 7.52 (d, 2H), 7.60 (m, 3H), 8.05 (s, IH), 8.43 (s, IH), 8.58 (t, IH), 8.69 (s. 1H). 8.90
{s, 1H), 9.14 (s, IH); HPLC ES-MS ml: 512 {(M+H)'").
l!TRUE COPYII
General Method for the Deprotection of N-(w-Silyloxyalkyl)amides.
Synthesis of N-(4-Chloro-3-( (trifluoromethyl)phenyl)-N'-( 4-( 4-(2-(N-(2-
bydroxy)ethylcarbamoyl)pyridyloxypbenyl) Urea.
CF3 0 >--
Cl~ 0 r0ro~N~O-si
UNAN~ ~~ H --< \
H H
To a solution of N-( 4-chloro-3-((trifluoromethyl)phenyl)-N '-(4-( 4-(2-(N-(2-
triisopropylsilyloxy) ethylcarbamoyl)pyridyloxyphenyl) urea (prepared in a manner
analogous to Method Cla; 0.25 g, 0.37 mmol) in anh THF (2 mL) was tetrabutylammonium
fluoride (1.0 Min THF; 2 mL). The mixture was stirred at room temperature for 5 min, then
was treated with water (IO mL). The aqueous mixture was extracted with EtOAc (3 x 10
mL). The combined organic layers were dried (MgSO 4) and concentrated under reduced
pres..,ure. The residue was pu:ified by cobmn chromatograp\ 1 (SiO 2; gradient from 100%
hexane to 40% EtOAc/60% hexane) to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-
(4-(2-(N-(2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl) urea as a white solid (0.019 g, 10%).
Listed below are compounds listed in the Tables below which have been synthesized
according to the Detailed Experimental Procedures given above:
Syntheses of Exemplified Compounds

(see Tables for compound characterization)
Entry l: 4-(3-N-Methylcarbamoylphenoxy)aniline was prepared according to Method AlJ.

According to Method C3, 3-tert-butylaniline was reacted with bis(trichloromethyl)carbonate
followed by 4-(3-N-Methylcarbamoylphenoxy)aniline to afford the urea.
Entry 2: 4-Fluoro- 1-nitrobenzene and p-hydroxyacetophenone were reacted according to

Method A 13, Step 1 to afford the 4-( 4-acetylphenoxy)-1-nitrobenzene. 4-( 4-AcetylphenoKy)-
l -nitrobenzene was reduced according to Method Al3, Step 4 to afford 4-(4-
acetylphenoxy)aniline. According to Method C3, 3-tert-butylaniline was reacted with
bis(trichloromethyl) carbonate followed by 4-(4-acetylphenoxy)aniline to afford the urea.
~~q-
i!TRUE _coPYjl
,Entry 3: According to Method C2d, 3-tert-butylaniline was treated with. CDI, followed by 4-
(3-N-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared according to
Method A8, to afford the urea.
Entry 4: 5-tert-Butyl-2-methoxyaniline was converted to 5-tert-butyl-2-methoxyphenyl

isocyanate according to Method BI. 4-(3-N-Methylcarbamoylphenoxy)aniline, prepared
according to Method A13, was reacted with the isocyanate according to Method CI a to
afford the urea.
Entry 5: According to Method C2d, 5-tert-butyl-2-methoxyaniline was reacted with CD[

followed by 4-(3-N-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared
according to Method A8, to afford the urea.
Entry 6: 5-(4-Aminophenoxy)isoindoline-1,3-dione was prepared according to Method A3.

According to Method 2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI followed by 5-
(4-aminophenoxy)isoindoline- l ,3-dione to afford the urea.
Entry 7: 4-(1-0xoisoindolin-5-yloxy)aniline was synthesized according to Method All.

( l-oxoisoindolin-5-yloxy)aniline to afford the urea.
Entry 8: 4-(3-N-Methylcarbarnoylphenoxy)aniline was synthesized according to Method

Al 3. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with CDI
followed by 4-(3-N-methylcarbamoylphenoxy)aniline to afford the urea.
Entry 9: 4-Hydroxyacetophenone was reacted with 2-chloro-5-nitropyridine to give 4-(4-

acetylphenoxy)-5-nitropyridine according to Method AJ, Step 2. According to Method A8,
Step 4, 4-( 4-acetylphenoxy)-5-nitropyridine was reduced to 4-( 4-acetylphenoxy)-5-
aminopyridine. 2-Methoxy-5-(trifluoromethyl)aniline was convened to 2-methoxy-5-
(tri fluoromethyl )phenyl isocyanate according to Method B 1. The isocyanate was reacted
,vith 4-( 4-acetylphenoxy)-5-aminopyridine according to Method CI a to afford the urea.
IiTRUE COPYII
~ntry l 0: 4-Fluoro-l -nitrobenzene and p-hydroxyacetophenone were reacted according to
Method AlJ, Step 1 to afford the 4-(4-acetylphenoxy)-l-nitrobenzene. 4-(4-Acetylphenoxy)-
l-nitrobenzene was reduced according to Method A 13, Step 4 to afford • 4-( 4-
acetylphenoxy)aniline. According to Method C3, 5-(trifluoromethyl)-2-methoxybutylaniline
was reacted with bis(trichloromethyl) carbonate followed by 4-(4-acetylphenoxy)aniline to
afford the urea.
Entry 11: 4-Chloro-N-methyl-2-pyridinecarboxamide,which was synthesized according to

Method A.2,Step 3a, was reacted with 3-aminophenol according to Method A1, Step 4 using
DMAC in place of DMF to give 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline.According
to Method C4, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by
3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)anilineto afford the urea.
Entry 12: 4-Chloropyridine-2-carbonyl chloride HCI salt was reacted with ammonia
according to Method A1, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-
pyridinecarboxamidewas reacted with 3-aminophenol according to Method A1, Step 4 using
DMAC in place of DMF to give 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method
C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 3-(2-
carbamoyl-4-pyridyloxy)anilineto afford the urea.
Entry I 3: 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized according to Method

A2, Step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamide was reacted with 4-aminophenol
according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-(N-
methylcarbamoyl)-4-pyridylox.y)aniline. According to Method C2a, 2-methoxy-5-
(trifluoromethyl)aniline was reacted with CDI followed by 4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)anilineto afford the urea.
according to Method A2, Step 3b to form 4-chloro-2-pytidinecarboxamide. 4-Chloro-2-
pyridinecarboxamide was reacted with 4-aminophenol according to Method Al. Step 4 usin~
DMAC in place of DMF to give 4-(2-carbamoyl-4-pyridyloxy)aniline. According tu \kthoJ
~..-1
IITRUE COPYII
~4, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 4-(2-
carbamoyl-4-pyridyloxy)aniline to afford the urea.
Entry 15: According to Method C2d, 5-(triflouromethyl)-2-methoxyaniline was reacted with

CDI followed by 4-(3-N-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been
prepared according to Method AS, to afford the urea.
Entry 16: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was synthesized

according to Method AS. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. The isocyanate was
reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-methylaniline according to Method
C l c to afford the urea.
Entry 17: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized

according to Method A6. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5-
(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-
4-pyridyloxy)-2-chloroaniline according to Method Cla to afford the urea.
Entry 18: According to Method .A1, Step 4, 5-amino-2-methylphenol was reacted with 4-
chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method
Al, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. 5-
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl
isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was
C 1~ to afford the urea.
Entry 19: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to

Method A2, Step Jb. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted
with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-
pyridyloxy)aniline. 5-(Tritluoromethyl)-2-methoxyaniline was converted into 5-
( rrifluoromethyl )-2-merhoxyphenyl isocyanate according to Method Bl. 5-(Tri tluoromethyl )-
11TRUE COPYII
tf •~ethoxyphenyl isocyanate was reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline
according to Method Cl a to afford the urea.
Entry 20: According to Method Al, Step 4, 4-amino-2-chlorophenol was reacted with 4-
A2, Step 3b, to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 5-
isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was
reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline according to Method
C 1a to afford the urea.
Entry 21: 4-( 4-Methylthiophenoxy)-1-nitrobenzene was oxidized according to Method A 19.

Step 1 to give 4-( 4-methylsulfonylphenoxy)-1-nitrobenzene. The nitrobenzen~ was r~duced
according to Method Al9, Step 2 to give 4-(4-methylsulfonylphenoxy)-l-aniline. According
to Method Cla, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4-
methylsulfonylphenoxy)-l-aniline to afford the urea.
Entry 22: 4-(3-carbamoylphenoxy)- 1-nitrobenzene was reduced to 4-( 3-

carbamoylphenoxy)aniline according to Method Al 5, Step 4. According to Method C 1a, 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-
carbamoylphenoxy)aniline to afford the urea. :
Entry 23: 5-( 4-Aminophenoxy)isoindoline-1,3-dione was synthesized according to Method

AJ. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl
isocyanate was reacted with 5-( 4-aminophenoxy)isoindoline-1,3-dione according to Method
CI a to afford the urea.
Entry 24: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according

to Method A2, Step 3b. The resulting 4-chloro-N.N-dimethyl-2-pyridinecarboxam1de \\ as
reacted \\ith 4-aminophenol according to Method A2, Step 4 to gi,-c -H 2-l .\ . .\"-
d imethylcarbamoyl )-4-pyridyloxy)ani Iine. 5-(Tri fluoromethyl )-2-methox yanll I ni: \\ as
IITRUE COPYII
convened into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-
.• (Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N.N-
dimethylcarbamoyl)-4-pyridyloxy)aniline according to Method Cla to afford the urea.
p Entry 25: 4-(1-0xoisoindolin-5-yloxy)aniline was synthesized according to Method A 12. 5-

(Trifluoromethyl)-2-methoxyaniline was treated with CDI, followed by 4-( l-oxoisoindolin-5-
yloxy)aniline according to Method C2d to afford the urea.
Entry 26: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to

Method Al3, Step 1 to give .4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was
reduced according to Method A 13, Step 4 to afford 4-( 4-acetylphenoxy)aniline, which was
convened to the 4-( 4-( 1-(N-methoxy)iminoethyl)phenoxyaniline HCl salt according to
Method Al6. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trif1uoromethyl)-
2-me_:hoxyphenyl isocya;1ate ac..cordingto Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl
isocyanate was reacted with 4-( 4-( 1-(N-methoxy)iminoethyl)phenoxyaniline HCI salt to
Method C 1a to afford the urea.
Entry 27: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Method

A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method
A2, Step 4 to give 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. 5-(Trifluoromethyl)-2-
methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate
according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with
4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline according to Method Cla to afford the urea.
Entry 28: 5-(4-Aminophenoxy)-2-methylisoindoline-l,3-dione was synthesized according to

Method A9. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl
isocyanate was reacted with 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione according to
Method Cl a to afford the urea.
Entry 29: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in \-1cthoJ

A2. Step Jb. The chloropyridine was reacted with J-aminothiophenol according to \-kthoJ
IITRUE COPY!I
ft-....2,Step 4 to give 3-(4-(2-(N-methylcarbamoyl)phenylthio )aniline. 5-(Trifluoromethy I)-2-
3-(4-(2-(N-methylcarbamoyl)phenylthio )aniline according to Method Cl a to afford the urea.
Entry 30: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine according

to Method Al, Step 3b. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxamide was
reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(.N-
isopropylcarbamoyl)-4-pyridyloxy)aniline. 5-(Trifiuoromethyl)-2-methoxyaniline was
converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method BI. 5-
(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N-
isopropylcarbamoyl)-4-pyridyloxy)aniline according to Method Cla to afford the urea.
Entry 31: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method

A 14. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to
Method C 1a to afford the urea. N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N'-( 4-(3-(5•
methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step l,
and the corresponding acid was coupled with 4-(2-aminoethyl)morpholine to afford the
amide according to Method D4, Step 2.

Al4. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
Method CI a to afford the urea. N-{5-{Trifluoromerhyl)-2-methoxyphenyl)-N'-{4-(3-(5-
methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1,
and the corresponding acid was coupled with methylamine according to Method D4, Step 2
to afford the amide.
IITRUE COPYjl
'-1try 33: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method
A14. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyi
Method Cla to afford the urea. N-(5-(Trifluoromethyl)-2-rnethoxyphenyl)-N'-(4-(3-(5-
and the corresponding acid was coupled with N,N-dimethylethylenediamine according to
Method D4, Step 2 to afford the amide.
Entry 34: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al 1. 5-

isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-
(~rifluoromethyl)-2-methoxypher.yl isocyanate according to Method Clf tu afford ,V-~5-
(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with 3-
aminopyridine according to Method DI c.

isocyanate according to Method BI. 4-(3-Carboxyphenoxy)aniline was reacted with 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-(5-
(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with N-
(4-fluorophenyl)piperazine according-to Method Dlc.
Entry 36: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A 11. 5-

( trifluoromethyl)-2-methoxyphenyl isocyanate according to Method CI f to afford N-(5-
(tritluoromethyl)-2-rnethoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with 4-
fluoroaniline according to Method D le.

:EE-- ' .(
IITRUE COPYII
4' (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-(5-
(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled ,vnh ...:,_
(dimethylamino)aniline according to Method Dlc.
Entry 38: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A 11 :--

(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxypheny!
isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford 1V-(5-
amino-2-methoxypyridine according to Method D l c.
Entry 39: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A 1 l 5-

(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-rnethoxyphenyl
isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-( 5-
morpholinoaniline according to Method Dlc.

( trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-{5-
(2-pyridyi)piperazine according to Method DI c.
Entry 41: 4-(3-(N-Methylcarbamoyl)phenoxy)aniline was synthesized according to Method

A I 3. According to Method CJ, 4-chloro-3-(trifluoromethyl)aniline was converted to the
isocyanate, then reacted with 4-(3-(N-Methyicarbamoyl)phenoxy}aniline to afford the urea.
IITRUE COPYII
Entry 42: 4-(2-N-Methylcarbamyl-4-pyridyloxy)aniline was synthesized according to
'1ethod A2. 4-Chloro-3-(trif1uoromethyl)phenyl isocyanate was reacted with 4-(2-i'v·-

methylcarbamyl-4-pyridyloxy)aniline according to Method C 1a to afford the urea.
~ Entry 43: 4-Chloropyridine-2-carbonyl chloride HCI salt was reacted with ammonia
pyridinecarboxamide was reacted with 4-arninophenol according to Method A2, Step 4 to
fonn 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-3-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-carbamoyl-4-pyridyloxy)aniline to
afford the urea.
according to Method A2, Step 3b to fonn 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-
pyridinecarboxamide was reacted with 3-arninophenol according to Method A2, Step 4 to
form 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method Cl a. 4-chloro-3-
(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-carbarnoyl-4-pyridyloxy)aniline to
afford the urea.
Entry 45: 4-Chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to

Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to
fonn 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-
3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-(N-methylcarbamoyl)-4-
pyridyloxy)aniline to afford the urea.
Entry 46: 5-(4-Arninophenoxy)isoindoline-l ,3-dione was synthesized according to Method

AJ. According to Method CI a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted
with 5-(4-aminophenoxy)isoindoline-1,3-dione to afford the urea.

according to Method AS. According to Method Cle, 4-chloro-3-(trifluoromethyl)pheny!
isocyanate was reacted with 5-( 4-ammophenoxy)isoindoline-1,J-dione to afford the urea.
IITRUE COPYjl
tatry 48: 4-(3-N-Methylsulfamoy!)phenyloxy)aniline was synthesized according to Method
Al5. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted
with 4-(3-N-methylsulfamoyl)phenyloxy)aniline to afford the urea.

according to Method A6. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl
isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline to
afford the urea.
Entry 50: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-
A2, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. According to
Method C la, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-f.\"-
methylcarbamoyl)-4-pyridyloxy)-4-rnethylaniline to afford the urea.

Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted
pyridyloxy)aniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl
isocyanate was reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 52: According to Method Al, Step 4, 4-amino-2-chlorophenol was reacted with 4-
A2, Step 3b, to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. According to
Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-
methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.
Entry 53: 4-(4-Methylthiophenoxy)-l-nitrobenzene was oxidized according to Method A 19.

Step I to give 4-( 4-methylsulfonylphenoxy)-1-nitrobenzene. The nitrobenzene was reduced
according to Method A 19, Step 2 to give 4-( 4-methylsulfonylphenoxy)-l-aniline. According
to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted \\1th -H-1-
IITRUE COPY!I
•□try 54: 4-Bromobenzenesulfonyl chloride was reacted with methylamine according to
Method A 15, Step 1 to afford N-methyl-4-bromobenzenesulfonamide. N-Methyl-4-
bromobenzenesulfonamide was coupled with phenol according to Method Al 5, Step 2 to
afford 4-( 4-(N-methylsulfamoyl)phenoxy)benzene. 4-( 4-(N-
Methylsulfamoyl)phenoxy)benzene was converted into 4-( 4-(N-methylsulfamoyl)phenoxy)-
l-nitrobenzene according to Method A 15, Step 3. 4-( 4-{N-Methylsulfamoyl)phenoxy)- l -
nitrobenzene was reduced to 4-(4-N-methylsuifamoyl)phenyloxy)aniline according to
Method Al5, Step 4. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl
isocyanate was reacted with 4-(3-N-methylsulfamoyl)phenyloxy)aniline to afford the urea.
Entry 55: 5-Hydroxy-2-methylpyridine was coupled with l-fluoro-4-nitrobenzene according

to Method A 18, Step 1 to give 4-(5-(2-Methyl)pyridyloxy)-l-nitrobenzene. The
methylpyridine was oxidized according to the carbox:(ic acid, then esterificd according to
Method Al 8, Step 2 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene. The
nitrobenzene was reduced according the Method Al8, Step 3 to give 4-(5-(2-
methoxycarbonyl)pyridyloxy)aniline. The aniline was reacted with 4-chloro-3-
(trifluoromethyl)phenyl isocyanate according to Method Cl a to afford the urea.
Entry 56: 5-Hydroxy-2-methylpyridine was coupled with 1-fluoro-4-nitrobenzene according

to Method Al8, Step 1 to give 4-(5-(2-Methyl)pyridyloxy)-1-nitrobenzene. The
methylpyridine was oxidized according to the carboxylic acid, then esterified according to
Method Al8, Step 2 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene. The
nitrobenzene was reduced according the Method Al8, Step 3 to give 4-(5-(2-
(tri fluoromethyl)phenyl isocyanate according to Method C 1a to give N-(4-chloro-3-
(tri fluoromethy l)pheny 1)-N '-(4~(2-(methoxycarbonyl)-5-pyridyloxy)phenyl) urea. The
methyl ester was reacted with methylamine according to Method D2 to afford N-(4-chloro-3-
(tri fluoromethyl )pheny I)-N '-(4-(2-(N-methylcarbamoy 1)-5-pyridyloxy)phenyl) urea.
Entry 5 7: N-( 4-Ch loro-3-(tri fluoromethyl)phenyl-N ··( 4-aminophenyl) urea was prepared
according 10 Method CI d. N-(4-Chloro-3-(tri tluoromethyl)phenyl-N'-( 4-aminophenyl) urea
was coupled with mono-methyl isophthalate according to Method D 1a to afford the urea.
IITRUE COPYII
Entry 58: N-( 4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) urea was prepared
according to Method Cld. N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-arninophenyl)urea
was coupled with mono-methyl isophthalate according to Method D 1a to afford N-(4-chloro-
3-(trifluoromethyl)phenyl-N'-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl) urea.
According to Method D2, N-(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(3-
methoxycarbonylphenyl)carboxyaminophenyl) urea was reacted with methylamine to afford
the corresponding methyl amide.
Entry 59: 4-Chloropyridine-2-carbonyl chloride was reacted '-Vithdimethylamine according

to Method A2, Step 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecarboxamidewas
reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N.N-
c!imethylcarbamoyl)-4-pyri<lyloxy)anilin
~- According to iv!ethod C l.:l. 4-chloro-3-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N.N-dimethylcarbarnoyl)-4-

Method A 13, Step 1 to give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was
reduced according to Method 13, Step 4 to afford 4-(4-acetylphenoxy)aniline, which was
convened to the 4-(4-(1-(N-methoxy)iminoethyl) phenoxyaniline HCI salt according to
Method A 16. According to Method C 1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was
reacted with 4-(4-acetylphenoxy)aniline to afford the urea.
Entry 61: 4-(J-Carboxyphenoxy}-1-nilrobenzene was synthesized according to Mechod A l3,

Step 2. 4-(3-Carboxyphenoxy)-l-nitrobenzene was . coupled with 4-(2-
aminoethyl)morpholine according to Method Al3, Step 3 to give 4-(3-(N-{2-
morpholinylethyl)carbamoyl)phenoxy)-l-nitrobenzene. According to Method A 13 Step 4, 4-
(3-(N-(2-morpholinylethyl)carbarnoyl)phenoxy)-l-nitrobenzene was reduced to 4-(3-(N-(2-
morpholinylethyl)carbamoyl)phenoxy)aniline. According to Method CI a. 4-chloro-3-
(tri fluoromethyl)phenyl isocyanate was reacted with 4-(J-(N-(2-
morpholinylethyl)carbarnoyl)phenoxy)aniline to afford the urea.
~-i
IITRUE _COPYII
Sntry 62: 4-(3-Carboxyphenoxy)-l-nitrobenzene was synthesized accorcling to Method AIJ,
4\cep 2. 4-(3-Carboxyphenoxy)- l-nitrobenzene was coupled with 1-(2-aminoethyl)piperidine
according to Method A 13, Step 3 to give 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)- I-
nitrobenzene. According to Method AIJ Step 4, 4-(3-(N-(2-
1 piperidylethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-(2-
piperidylethyl)carbamoyl)phenoxy)aniline. According to Method Cl a, 4-chloro-3-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(2-
piperidylethyl)carbamoyl)phenoxy)aniline to afford the urea.
Entry 63: 4-(3-Carboxyphenoxy)-l-nitrobenzene was synthesized according to Method A 13,

Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with tetrahydrofurfurylamine
according to Method Al3, Step 3 to give 4-(3-(1'./-
(tetrahydrofurylmethyl)carbamoyl)phenoxy)-l-nitrobenzene. According to Method A 13 Step
4, 4-(3-(N·(tetrahydrofurylmethyl)carbamoyl)phenoxy)-l-nitrobenzene was reduced to 4-(3·
(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline. According to Method Cl a, 4-chloro-
3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-
(tetrahydrofurylmethyl)carbamoyl) phenoxy)aniline to afford the urea.
Entry 64: 4-(3-Carboxyphenoxy)-l-nitrobenzene was synthesized according to Method Al 3,

Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with 2-aminomethyl-l •
ethylpyrrolidine according to Method. Al3, Step 3 to give 4-(3-(N•(( l -
methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A 13
Step 4, 4-(3-(N-(( 1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene was
reduced to 4-(3-(N-(( 1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline. According to
Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(( 1-
methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline to afford the urea.

A2. Step 4 to give 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. According to Method
Cla. 4-chloro-3-(trilluoromethyl)phenyl isocyanate was reacted with -H-H2-(.\-
methylcarbamoyl)phenylthio)aniline to afford the urea .
.....-Afr--
z!E----
I[TRUE COPYjl
to Method A2, Step 3b. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxamide was
reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-
=J isopropylcarbamoyl)-4-pyridyloxy)ani\ine. According to Method Cl a, 4-chloro-3-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-isopropylcarbamoyi)-4-
Entry 67: N-(4-Chloro-3-(trifluoromethyl)phenyl-N '-(4-ethoxycarbonylphenyl) urea was

synthesized according to Method Cle. N-( 4-Chloro-3-(trifluoromethyl)phenyl-N '-(4-
ethoxycarbonylphenyl) urea was saponified according to Method D3 to give N-(4-chloro-3-
( trifluoromethyl)phenyl-N '-(4-carboxypheny I) urea. N-( 4-Chloro-3-( trifluoromethyl)phen y 1-
N '-(4-carboxyphenyl) urea was coupled with 3-methylcarbamoylaniline according tc ~fethod
DI b to give N-( 4-chloro-3-(trifluoromethyl)phenyl-N'-( 4-(3-
methylcarbamoylphenyl)carbamoylphenyl) urea.
Entry 68: 5-(4-Aminophenoxy)-2-methylisoindoline-l,3-dione was synthesized according to

Method A9. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was
reacted with 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione to afford the urea.

Al, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to Method
A2, Step 4 to give 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. According to Method
Cl a, 4-ch!oro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(4-(2-(N-
methylcarbamoyl)phenylthio )aniline to afford the urea.
Entry 70: 4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was synthesized

according to Method AlO. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl
isocyanate was reacted with 4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline to
afford the urea.
~ \
l[TRUE COPYII
.ntry 71: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method
Al4. 4-Chloro-3-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-
methoxycarbonyl)pyridyloxy)aniline according to Method C 1a to afford the urea. .1'/-(J.._
Chloro-3-(trifluoromethyl)phenyl)-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea
was saponified according to Method D4, Step 1, and the corresponding acid was coupled with
4-(2-aminoethyl)morpholine to afford the amide.

Al4. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5-
methoxycarbonyl)pyridyloxy)aniline according to Method Cl a to afford the urea. N-( 5-
(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea
was saponified according to Method D4, Step I, and the corresponding acid was coupled with
n:ethylarnine2.ccordingto Method D4, Step 2 to affo-d the 'lmide.
Entry 73: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to l\,lethod

Al4. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5-
methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea. N-(5-
(Trifluoromethyl)-2-methoxyphenyl)-N •-(4-(3-(5-methoxycarbonylpyrid y1)oxy)phenyI) urea
N,N-dimethylethylenediamine according to Method D4, Step 2 to afford the amide.
Emry 74: 4-Chloropyridine-2-carbonyl chloride HCI salt was reacted with 2-

hydroxyethylamine according to Method A2, Step 3b to fonn 4-chloro-N-(2-
triisopropylsilyloxy)ethylpyridine-2-carboxamide. 4-Chloro-N-(2-
triisopropylsilyloxy)ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride,
followed by 4-aminophenol according to Method Al 7 to form 4-(4-(2-(N-(2-
triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline. According to Method CI a. 4-chloro-
3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(N-(2-
triisopropylsilyloxy)ethylcarbamoyl) pyridyloxyaniline to afford N-(4-chloro-3-
((trif1uoromethyl)phenyl)-N'-(4-(4-(2-(N-(2-triisopropylsilyloxy)
ethylcarbamoyl)pyridyloxyphenyl) urea.
~-2
IITRUE COPYII
41'1try75: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A 11. 4-
Chloro-3-(tritluoromethyl)phenyl isocyanate was reacted with 4-(3-(5-
rnethoxycarbonyl)pyridyloxy)aniline according to Method C 1f to afford the urea, which was
coupled with 3-aminopyridine according to Method Dlc.
Emry 76: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al 1. 4-

Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline
according to Method Cl f to afford the urea, which was coupled with N-( 4-
acetylphenyl)piperazine according to Method D l c.

according to Method Clf to afford the urea, which was coupled witr. 4-fluoroaniline
according to Method Ole.
Entry 78: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-

according to Method Clf to afford the urea, which was coupled with 4-
(dimethylamino )aniline according to Method D 1c.

according to Method Clf to afford the urea, which was coupled with N-
phenylethylenediamine according to Method D 1c.

according to Method Cl f to afford the urea, which was coupled with 2-methoxyethylamine
according to Method Ole.

Chloro-J-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-·carboxyphenoxy)aniline
~-
~ ~
IITRUE COPYII
.fccording to Method C 1f to afford the urea, whic:h was coupled with 5-amino-2 •
methoxypyridine according to Method D l c.
Entry 82: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A 11. 4.

according to Method Cl f to afford the urea, which was coupled with 4-morpholinoaniline
according to Method Dlc.
Entry 83: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A 1 1. 4.

according to Method Cl f to afford the urea, which was coupled with N-(2-pyridyl)piperazine
accordingto Method Dlc.
Entry 84: 4-Chloropyridine-2-carbonyl chloride HCI salt was reacted with 2-

hydroxyethylamine according to Method A2, Step Jb to form 4-chloro-N-(2-
triisopropylsilyloxy)ethylpyridine-2-carboxamide. 4-Chloro-N-(2 •
triisopropylsilyloxy)ethylcarbarnoyl)pyridyloxyaniline. According to Method C 1a, 4-chloro-
3-(trifluoromethyl)phenyl isocyanate . was reacted with 4-(4-(2-(N-(2-
triisopropylsilyloxy)ethylcarbarnoyl)pyridyloxyaniline to give N_-(
4-chloro-3-
(( tri fluoromethyl)phenyl)-N '-(4-( 4-(2-(N-(2-
triisopropylsilyloxy)ethylcarbamoyl)pyridyloxypheny l) urea. The urea was deprotected
according to Method D5 to afford N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N-(2-
hydrox.y)ethylcarbarnoy l)pyridyloxyphenyl) urea.
Entry 85: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to

Method A2. 4-Bromo-3-(trifluoromethyl)aniline was converted to 4-bromo-3-
(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method Cl a. 4-
bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4•
• pyridyloxy)aniline to afford the urea.
IiTRUE COPY!I
4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized
according to Method A6. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-
(tritluoromethyl)phenyl isocyanate according to Method BI. According to Method C 1a, 4-
bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-
5 pyridyloxy)-2-chloroaniline to afford the urea.
Entry 87: According to Method A2, Step 4, 4-arnino-2-chlorophenol was reacted with 4-
Al, Step 3b, to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-Bromo-3-
(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate
according to Method Bl. According to Method Cl a, 4-bromo-3-(trifluoromethyl)phenyl
afforci the urea.

with 4-aminophenol according to Method Al, Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-
pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-
(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method CI a, 4-
bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-ethylcarbamoyl)-4-

Method Al, Step 3a, was reacted with 3-arninophenol according to Method A2, Step 4 to
form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-(trifluoromethy\)ani line
was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method 81.
According to Method CI a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with J-
(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 90: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted ,, 11h -+-
chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according 10 \,kthoJ
A2. Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylanilinc. -4-Bromo-~-
IITRUE COPY!I
,frifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate
according to Method Bl. According to Method Cl a, 4-bromo-3-(trifluoromethyl)phenyl
isocyanate was reacted with 3-(2-(N-methylcarbarnoyl)-4-pyridyloxy)-4-methylaniline to
afford the urea.

to Method A2, Step 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecarboxamide was
reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N.N-
I
dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Brorno-3-(trifluoromethyl)aniline was
converted into 4-bromo-J-(trifluoromethyl)phenyl isocyanate according to Method B 1.
According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-
(2-(N.N-dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

Al, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method
Al, Step 4 to give 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. 4-Bromo-3-
(trif1uoromethyl)aniline was converted into 4-bromo~3-(trifluoromethyl)phenyl isocyanate
according to Method Bl. According to Method Cla, 4-bromo-3-(trifluorornethyl)phenyl
isocyanate was reacted with 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline to afford the
urea.

A.2, Step 4 to give 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. 4-Bromo-3-
(trifluoromethyl)aniline was converted into 4-brorno-3-(trifluoromethyl)phenyl isocyanate
acc_ording to Method Bl. According to Method Cl a, 4-bromo-3-(trifluorornethyl)phenyl
isocyanate was reacted with 3-( 4-(2-(N-methylcarbamoyl)phenylthio )aniline to afford the
urea.

according to Method A I 0. 4-Bromo-3-(tritluoromethyl)aniline was converted into 4-bromo-
3-(triOuoromethyl)phenyl isocyanate according to Method 81. According to Method CI a, 4-
IITRUE COPY!I
bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-(2-Morpholin-4-
'l,1ethy\)carbamoyl)pyridyloxy)aniline to afford the urea.
Entry 95: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)anilinewas synthesized according to

Method A2. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to
Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)anilinewas converted into 4-chloro-2-
methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to
Method C 1a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenylisocyanate was reacted with 4-
(2-(N-methylcarbamoyl)-4-pyridyloxy)anilineto afford the urea.

according to Method A6. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized
according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into
4-chloro-2-mcthoxy-5-(trifluoron:ethyl)phenyl isocyanate according to Method Bi.
According to Method Cla, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was
reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroanilineafford the urea.
Entry 97: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-
:hloro-N-methyl-2-pyridinecarboxamide,which had been synthesized according to Method
Al, Step 3b, to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-Chloro-2-
methoxy-5-(trifluoromethyl)anilinewas synthesized according to Method A7. 4-Chloro-2-
methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-
[trifluoromethyl)phenylisocyanate according to Method B 1. According to Method CI a, 4-
::hloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(1V-
methylcarbamoyl)-4-pyridyloxy)-3-chloroanilineto afford the urea.
Entry 98: 4-Chloro-N-methyl-2-pyridinecarboxamide,which was synthesized according to

Method Al, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to
fonn 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxy-5-
'.trifluoromethyl)aniline was synthesized according to Method A 7. 4-Chloro-2-metho.xy-5-
'.trifluoromethyl)aniiine was converted into 4-chloro-2-methoxy-5-( tri fluoromcthyl)phcn: I
,socyanate according to Method Bl. According to Method Cla, 4-chloro-2-mctho,y-5-
IITRUE COPY!I
\ifluoromethyl)phenyl isocyanate as was reacted with 3-(-2-(N-merhylcarbamoyl)-4-
Entry 99: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylarnine according to

with 4-arninophenol according to Method A2, Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-
pyridyloxy )aniline. 4-Chloro- 2-methoxy-5-( trifluoromethyl)aniline was synthesized
4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B 1.
According to Method C 1a, 4-chloro-2-methoxy-5-{trifluoromethyl)phenyl isocyanate was
reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

to Method Al, Step 3b. The resulting 4-chloro-N.N-dimethyl-2-pyridinecarboxamide was
reacted with 4-aminophenol according to Method Al, Step 4 to give 4-(2-(N,N-
dimethy lcarbamoy 1)-4-pyridyloxy)aniline. 4-Chloro-2-methoxy-5-( tri fluoromethyl )aniline
was synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline
was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to
Method Bl. According to Method Cla, 4-chloro-2-rnethoxy-5-(trifluoromethyl)phenyl
isocyanate was reacted with 4-(2-(N,N-dirnethylcarbamoyl)-4-pyridyloxy)aniline to afford the
urea.
Entry 101: 4-Chloro-N-rnethyl-2-pyridinecarboxamide, which was synthesized according to

Method A2, Step 3a, was reacted with 3-aminophenol according to Method Al., Step 4 to
form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. 2-Arnino-3-methoxynaphthalene was
synthesized as described Method Al. According to Method C3, 2-arnino-3-
methoxynaphthalene was reacted with bis(trichloromethyl) carbonate followed by 3-(-2-(N-
methylcarbamoyl)-4-pyridyloxy)aniline to form the urea.
Entry I 02: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to

Method Al. 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline was synthesized according to
_4LL___
IITRUE COPYII
ti'fethod A4. 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline was reacted with CDI followed by
4-(2-{N-methylcarbamoyl)-4-pyridyloxy)aniline according to Method C2d to afford the urea.
Entry 103: 4~Chloro-N-methyl-2-pyridinecarboxarnide was synthesized according to Method

methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2b, reaction of 3-amino-2-
methoxyquinoline with CDI followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline
afforded bis( 4-(2-(N-methylcarbamoyl)-4-pyridlyoxy )phenyl)urea.
Listed in the Tables below are compounds which have been synthesized according to
tr.e Detailed Experirr.ental Procedures given above:
Tables
The compounds listed in Tables 1-6 below were synthesized according to the general
methods shown above, and the more detailed exemplary procedures are in the entry listings
above and characterizations are indicated in the tables.
IITRUE COPY!I
3-tert-Butylphenyl Ureas
0~
R,N)lND
H H
TLC Mass
mp HPLC TLC Solvent Spec. Synth.
Entrv R (OC) (min.) Rr System rsourcel Method
I 0 0.22 50% 418 Al3 C3
rN.H EtOAc (M+H)+
Me I 50% (HPLC
2
-0--0 0 \\ /J
o 0.58
hexane
50%
ES-MS)
403 AJ3 C3
-0-~ 0 \\ II Me
EtOAc
/ 50%
hexane
(M+H)+
(HPLC
ES-MS)
-0-o ◊o~:
O
3 133- 0.68 100% 448 A8 C2d
NH 135 EtOAc (M+H)+
(FAB)
1 Table 2. 5-tert-Butyl-2-methoxyphenyl Ureas
TLC Mass
mp HPLC TLC Solvent Spec. Synlh.
Entrv R (OC) (min.) R, Svstem rSourcel Method
4 5.93 448 Al3
O NH
.
-O
(M+H)+ Bl
Me (HPLC Cla
5
-0- 0
0 120- 0.67 100%

ES-MS)
478 A8
◊o~:
NH 122 EtOAc (M+H}+ C2d
(FAB)
-0-
-
o
6
-0- 0~
\\ /2
0
NH
0.40 50¾
EtOAc
I 50%
hexane
460
(M~H)~
(HPLC
ES-\15)
A3
(2d
~ref)
IITRUE COPY!I
~- 7
-0-o-Q!li 0
NH
0.79 50%
EtOAc
I 50%
hexane
446
(M+H)+
(HPLC
ES-MS)
Al2
C2d
Table 3. S-(Trifluorometbyl)-2-methoxypbeoyl Ureas .
R.N.Jl)l(
H
0
H
A OMe
TLC Mass
mp HPLC TLC Solvent • Spec. Synth.
Entrv R (DC) (min.) Rr Svstem rsourcel Method
8 250 460 A13
O NH
-O
{dee) (M+H)+ C2a
Me (FAB)
9
-0- 0
o 206- 0.54 10% 446 A3 step
--0-~~N O /J Me
208 MeOH
/90%
CH2CI
(M+H)+
(HPLC
ES-MS)
2,
A8 step
4,
2 Bl,
Cla
10 o 0.33 50% 445 AlJ C3
-0-~ ~ 0 II Me
EtOAc (M+H)+
I 50% (HPLC
pet ES-MS)
ether
-Q-d:
11 0.20 2% 461 A2
O N_H Et3N/ (M+H)+ C4
- Me 98% (HPLC
Et0Ac ES-MS)
0 ~ /JN
12 0.27 1% 447 A2
Et3N/ (M+H)+ C4
-G-QO NH2 99% (HPLC
EtOAc ES-MS)
0 ~ ;,N
13 0 0.62 100% 461 A2 C2a
-O
NH EtOAc (M+H)+
Me (FAB)
14
-0- 0
114- 0.40 1% 447 A2

O
-0- -d:
NH 117 Et3N/ (M+H)+ C4
2
99% (FAB)
0 EtOAc
-
IITRUE COPY!I
0.54 100% 490 AS C2d
-Q-o◊ o~:
O
232·
1115 NH 235 EtOAc (M+H)+
(FAB)
_
16 210- 0.29 5% 475 AS
213 MeOH (M+H)+ Bl Cle
Me -OO NH
Me
-0-
I 45% (HPLC
EtOAc ES-MS)
0 ~ ;,N
I 50%
pct
ether
17
Cl
-0- _ 0
-OO
~ I, N
NH
Me
187-
188
0.17 50¾ 495
EtOAc (M+H)+
150% {HPLC
pet
ether
ES-MS)
A6
BI C!a
18
-Q-~e O NH2
0.48 100% 475
EtOAc (M+H)+
(HPLC
ES-MS)
Al step
4,
Bl Cla
0 ~ 1,N
19 0 194- 0.31 5% 475 Al

NH 196 McOH (M+H)+ Bl Cla
Et /45% (HPLC
-0- 0
-O
EtOAc
/50%
pct
ES-MS)
ether
20
-0- _Cl
0
-OO
~ ;,N
NH
Me
214-
216
0.2S 5%
MeOH
/45%
EtOAc
/50%
495
(M+H)+
(HPLC
ES-MS)
A2 Cla
pet
ether
21 208-- 0.30 50% 481 Al9 C2a
-Q-a--Q-~~~ 210 EtOAc
/ 50%
(M+H)+
(HPLC
hexane ES-MS)
22 0 188- 0.30 70% 447 Al 5.
-O
NH2 190 EtOAc (M+H)+ step 4.
I 50% (HPLC C!a
23
-0-o 0.50
hexane
70%
ES-MS)
472
-0- 0 A3
~ ii EtOAc (M+H)+ Bl Cla
0~ NH / 30% (FAB)
hexane
0
24 0 Me 203- 0.13 100% 479 Al Bl
205 EtOAc (M-'-H)· Cla
{HPLC
-0- 0-o~Me
' ~ I,
ES-MS)
~
~~-" --
IITRUE COPYII
25
~ -O-o-Qfi° 0
NH
0.09 75% 458
EtOAc (M+H)+
125%
hexane
(HPLC
ES-MS)
Al2
C2d
26 MeO\ 169- 0.67 50% 474 A13

171 EtOAc (M+H)+ step I,
-0- 0~N
~ o Me
/50%
pct
ether
(HPLC
ES-MS)
Ai3 step
4,
Al 6,
Bl
Cla
27 218- 0.40 50% 477 A2 step
-d:
O NH 219 EtOAc (M+H)+ 3b,
Me /50% (HPLC A2 step
-0-
-
s pet
ether
ES-MS) 4,
Bl,
Cla
212· 0.30 40% A9
28
-Q-o-Q;t,
0 o
NMe
214 EtOAc
160%
Bl Cia
hexane
0
19 0.33 50% 474 A2 step
O N_H EtOAc (M+Hi+ 3b,
-Q-d: S
-
~ ;,N
Me /50%
pct
ether
(HPLC
ES-MS)
A2 step
4,
Bl,
Cla
30 210- A2
-d:
O NH 211 Bl
Pr-i Cla
31
-0- 0
210- 0.43 10% Al4

O NH
-0- -O c'j
204 MeOH Bl
0
s N
I
CH2Cl
Cla
D4
2
N
32 247- 0.57 10% Al4

O NH
--0- -O
249 Me0H Bl
Me I Cla
0 CH2Cl D4
N 2
33 217- 0.07 I 00/o Al4
NH
-0- -O
O 219 Me0H Bl
I Cla
0 :N-ME CH2CI D4
N Me 2
IITRUE _COPYII
• 34
-0-o -Ob
O NH
0.1 I 70%
EtOAc
/ 30%
hexane
Al 1
Bl
Clf
Die
All
QN)
35 0.38 70%
EtOAc Bl
/ 30% Clf
hexane Die
\_N
-Q-o-Oo
36 0.77 70% Al 1
F-0-NH EtOAc Bl
/30% Clf
-Q-o-Oo hexane Die
37
-0-
Me
M)~ 1/-0~ NH 0
0.58 70%
EtOAc
/30%
All
Bl
Clf
hexane Dlc
38
-0- 0 ~ /J
0.58 70% All
Me0-0-NH EtOAc Bl
/30% Clf
-Q-o-Oo hexane Dlc
39 0.17 70% All

rN-o-~ NH EtOAc Bl
/30% Clf
-0-o
\__/ -00
~-II
hexane: Die
40 0.21 70% All

EtOAc Bl
o-N:}-0-NH O I 30% Clf
hexane Die
-O-o-0
Table 4. 3-(Trifluorometbyl}-4-cbloropheoyl Ureas
0 FiF Cl
R.N)lNJ;r
H H
IITRUE _COPYII
..
Entrv R (OC) (min.) R,
TLC
mp HPLC TLC Solvent
Svstem
Mass
Spec.
rsource1
Synth.
Method
41 163- 0.08 50% 464 A13
O NH
-O
165 EtOAc/ (M+H)+ C3
Me 50% pet (HPLC
-0- 0 ether ES-MS)
42
O NH
Me
215 0.06 50%
EtOAc/
50% pet
465
(M+H)+
(HPLC
A2
Cla
-0-
- -d: 0 ether ES-MS)
43
O NH2
0.10 50%
EtOAc/
50% pet
451
(M+H)+
(HPLC
A2
Cla
-0-
- -d: 0 ether ES-MS)
44
-G-C,O0 ~ 1,N
NH2
0.25 30%
EtOAc/
70% pet
ether
451
(M+H)+
(HPLC
ES-MS)
A2
Cla
45
O N_H
0.31 30%
EtOAc/
465
(M+H)+
A2
Cla
-Q-d: 0
-
~ ;,N
Me 70% pet
ether
(HPLC
ES-MS)
46
-0- 0~0 ~ /J
NH
176-
179
0.23 40%
EtOAc/
60%
hexane
476
(M+H}+
(FAB)
A3
Cla
0
47
Me -d:o
- NH
0.29 5%
MeOH/
478
(M+H)+
AS
Cle
-0- 0 ~
/2
N
_Me 45%
EtOAc/
50% pet
ether
(HPLC
ES-MS)
48 0 ,o 206- AI5
~S~NH 209 Cla
-0- o-O
Me
~ /;
49
Cl -d:O
- NH
147-
151
0.22 50%
EtOAc/
499
(M+H)+
A6
Cla
50
-0- 0 ~
O
I, N
Me
0.54
50% pet
ether
100%
(HPLC
ES-MS)
479 A2
e N_H EtOAc (M..-H)• Cla
-Q~ 0 ~
-\
1,N
Me (HPLC
ES-\1S)
I
~r-c:;-
11TRUE COPY!I
,tit 51 0 187- 0.33 5% 479 A2
-d:
NH 189 MeOH/ (M+H)+ C!a
Et 45% (HPLC
-0-
-
0 EtOAc/
50% pet
ether
ES-MS)
219 0.18 5% 499 A2
-
52
MeOH/ (M+H)+ Cla
Cl -d:O NH
-0- Me 45% (HPLC

0 ~
EtOAc/ ES-MS)
/, N 50% pet
ether
53 246- 0.30 50% 485 Al 9, Cla
-0- o-OOs::::O
~ /;
•
.Me 248 EtOAc/
50%
hexane
(M+H)+
(HPLC
ES-MS)
54 196- 0.30 70% 502 Al5
-0- o-O~::::O
~ /J
Me'
'NH
200 EtOAc/
30%
hexane)
(M+H)+
(HPLC
ES-MS)
Cla
55 0 228- 0.30 30% 466

~o 230 EtOAc' {M+H)+
·Me 70% (HPLC
56
-0--0 0 ~ I, N
238-
CH2Cl2 ES-MS)
-0- o<MN
/J
M£f
0
NH
245
57 221- 0.75 80% 492 Cid

0 222 EtOAc/ (M+H)+ Dia
HlQo Me 20% (FAB)
58
-0- N ~ /J
247 0.35
hexane
100% Cld
O NH EtOAc Ola
H Me D2
59
-0- N
lQ
.
198- 0.09 100% 479 A2

0 ~: 200 EtOAc (M+H)+ Cla
(HPLC
60
-0--6 0 ~ I,
N
MeO. 158- 0.64 50%

ES-MS)
160 EtOAc/
.61
-0- 0~N
~ 11 Me
195- 0.39
50% pet
ether
10% AlJ
O NH
-O
197 MeOH/ Cla
~
CH2Cl
I/ '---\ 2
-0-o (_)
0
~M'.'E;
IITRUE COPYII
,. 170- 0.52 10% Al3
62
O NH
-O Q
172 McOH/ Cla
~ ~
CH2Cl
-0-o
I/ 2
63 168- 0.39 10% Al3
-0- -O~
O NH 0 171 MeOH/ Cla
CR.lC\
0 2
-
64 0 Et, 176- 0.35 10% Al3
177
-0- -0 ~
NH N MeOH/ Cla
CH2CI
0 2
-
65 130- 487 Al
O NH
-0- -d:
133 (M+H)+ Bl
Me (HPLC Cla
s ES-MS)
66 155 A2
O NH
-0- -d:
Cla
·Pr-i
0
'
67 225- 0.23 100% Cle
NH
aj
O 229 EtOAc D3
H Me Dlb
-0- N
234- 0.29 40%
-0-
68 A9
236 EtOAc/ Cla
0~0 ~ /;
NMe 60%
hexane
0
69 0.48 50% 481
O N_H
-0-d:
EtOAc/ (M+H)+
- Me 50% pet (HPLC
ether ES-MS)
S ~ /,N
70 0.46 5% 564 AIO
-O
O NH MeOH/ (M+H)+ Cia
~
-0-o
I/~
N)
\_o
95¾
CH 2Cl2
(H PLC
ES-MS)
zE=--r":"1-:r-
liTRUE COPYII
1
199-
201
I I 0.50 I 10%
McOH/
l l Al4
Cla 7
CH2Cl D4
2
72 235- 0.55 10% Al4

J-NH 237 McOH/ Cla
CH2Cl D4
-0-o-CJ Me 2
73 N 200- 0.21 50% Al4

201 McOH/ Cla
CH2C1 D4
12
74 145-
o NH
-d
148
--0-
~
1/' 0
N
'-'.
OSi(Pr-i)J
75 0.12 70% 527 All

EtOAd (M+H)+ Clf
30% (HPLC Dlc
hexane ES-MS)
76 0.18 70% Al I
EtOAc/ Clf
30% •01c
hexane
77 0.74 70% All

EtOAc/ Clf
JO% Die
hexane
L
78 0.58 70% All
EtOAc/ Clf
30% Die
hexane
I I
-
~ _,,~
IITRUE COPYII ~
•I 79
O NH
0.47 70% 569 Al I
-Od
EtOAc/ (M+H)+ Clf
30% (HPLC Ole
-0- 0 ~NH hexane ES-MS)
/J
80 0.18 70% 508 Al I
o NH
-d
EtOAc/ (M+H)+ Clf
30% (HPLC Die
-Q-o ~Me hexane ES-MS}
81 0.58 70% 557 Al I

Me0-0-NH EtOAc/ (M+H}+ Clf
30% (HPLC Die
-Q-o-Oo hexane ES-MS)
82
rN-o-~ NH
0.37 70%
EtOAc/
30%
611
(M+H)+
(HPLC
All
Clf
Die
\._J -00 hexane ES-MS)
83
-0- 0
~
-
/;
0.19 70% Al I
EtOAc/ Clf
~N
30% Ole
N) hexane
\_N
-Q-o-do
84 179- A2
O NH
-O
183 Al7
Cla
-0- 0 ~H .
D5
Table 5. 3-(Trifluorometbyl)-4-bromopbeoyl Ureas
0 FtF Br
R_N)l_No
H H
TLC Mass
mp HPLC TLC Solvent Spec. Synch.
EntrY R (OC) (min.) R, System fSourcel Method
85 l86- 0.l3 SO¾ 509 AZ
O NH l87 EtOAc/ (M+H)+ Bl
Me 50% pet (HPLC ES- Cta
%6
-0-
-
0
-O
\SO- O.}l
ether
50%
MS)
545 1-.6
Cl
-b- - 0
-OO
~ I, N
NH
Me
152 EtOAc/
50% pet
ether
(M+H)+ Bl
(HPLC ES- Cla
MS)
_
87 217- 0.l6 50% 545 A2
219 EtOAc/ (M+H}+ Bl
Cl -OO NH
---6- Me 50% pet (HPLC ES- Cla

ether MS)
0 ~ I, N
88 183- 0.31 50% 525 A2
O NH
-O
184 EtOAc/ (M+H)+ Bl
Et 50% pet tHPLC ES- Cia
89
-0-
- 0
0.21
ether
50%
MS)
511 AZ
0 N_H
-0-0
EtOAd (M+H)+ Bl
- Me - 50%pet (HPLC ES- Cla
ether MS)
0 ~ ;,N
90 0.28 50% 525 A2
e O N_H EtOAc/ (M+H)+ Bl
-Q-~ 0 ~
_
1,N
Me 50% pet
ether
(HPLC ES- Cla
MS)
91 214- 0.28 50% 522 AZ

0 { 216 EtOAc/ (M+H)+ Bl
-0--0
S0%pct (HPLC ES- Cla
ether MS)
0 ~ I, N
92 0.47 50% 527 A2 Step
O NH
-0- -O
EtOAcl (M+H)+ 3b.
Me 50% pet (HPLC ES- A2 step
s ether MS) 4,
.
Bl,
Cla
93 0.46 50% 527 A2 step
0 N_H EtOAc/ (M+H)+
-0-0
3b.
- Me 50% pct (HPLC ES- A2 step
ether MS) 4.
S ~ /.N BI.
C1 a
IITRUE COPYII
r
94 145- 0.41 5% AJO

O NH 150 MeOH/ Bl
• '--\ 95% Cla
-0- 0
-O
\_0
N)
CH2Cl2
Table 6. 5-(Trifluorometbyl)-4-cbloro-2-metboxyphenyJ Ureas
O tCI
R,N)l_Ny
H H OMe
TLC Mass
EntrY R (aC) (min.) R, Svstcm rsourcc, Method
95 140- 0.29 5% 495 A2
-o
o_ NH 144 MeOH/ (M+H)+ A7
Me 45% (HPLC Bl
-0- 0 EtOAd
50% pet
ether
ES-MS) Cla
96 244- 0.39 5% 529 A6

Cl
-b- - 0
-OO
~ ;,N
NH
Me
245 MeOH/
45%
EtOAc/
50%pet
(M+H)+
(HPLC
ES-MS)
A7
Bl
Cla
ether
97 220- 0.25 5% 529 A2
221 McOH/ (M+H)+ A7
Cl -OO NH
- Me 45% (HPLC Bl
EtOAc/ ES-MS) Cla
0 ~ ;,N
-6- S0¾pet
ether
-Q-O
98 0.27 5% 495 A2
O N_H MeOH/ (M+H)+ A7
- Me 45% (HPLC Bl
EtOAd ES-MS) Cla
0 ~ /,N
50% pct
ether
"99 180- 0.52 5% 509 A2
O NH
-0- -O
181 ·McOH/ (M+H)+ A7
Et 45% (HPLC Bl
0 EtOAc/ ES-MS) Cla
- 50% pct
ether
100 0 162· A2
NH 165 A7
Pr-i 81
-0-
- 0
-O
Cla
IITRUE COPYII
Table 7. Additional Ureas
••
TLC Mass
Entry R (OC) (min.) Rr System rsource] Method
IOI 162- Al
% N
OMeH
0
)l_
N
H
o,od--:::
::::... .&
o~H
Me
165
0.10 442
A2
C3
~
102 50% A2
0 EtOAc/ (M+H)+ A4
0 9' O -..;::, NH 50% (HPLC C2d
N)l_N,0- -ct/,,, hexane ES-MS)
H H
Me--(yMe
103 0 125- 0.24 40% 512 Al.

130 EtOAc/ (M+H)+ C2b
p
HN)l_NH
60% (FAB)
Q hexane
op
0 0
qo
NH-Me Me-NH
The preceding examples can be repeated with similar success by substituting the generically
or specifically described reactants and/or operating conditions of this invention for those used
in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential
characteristics of this invention and, without departing from the spirit and scope thereof, can
make various changes and modifications of the invention to adapt it to various usages and
conditions.
11TRUE COPYII
WE CLAIM:
1.. A compound selected from the group consisting of

the 4-chloro-3-(trifluoromethyl)phenyl ureas:
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-
pyridyloxy)phenyl)urea,
N-(4-chloro-3-(trifluoromethyl)phenyl)-N' -(3-(2-(N-methylcarbamoyl)-4-
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl)-4-
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)phenyl)urea and
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-N-
methylcarbamoyl)(4-pyridyloxy)phenyl)urea,
the 4-bromo-3(trifluoromethyl)phenyl ureas:
N-(4-bromo-3-(trifluoromethyl)pheny)-N' -(3-(2-(N-methylcarbamoyl)-4-
N-(4-bromo-3-(trifluoromethyl)phenyl)-N' -(4-(2-(N-methylcarbamoyl)-4-
N-(4-bromo-3-(trifluoromethyl)phenyl)-N' -(3-(2-(N-methylcarbamoyl)-4-
pyridylthio)phenyl)urea,
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-2-(N-
methylcarbamoyl)(4-pyridyloxy))phenyl)urea, and
N-(4-bromo-3-(trifluoromethyl) )phenyl)-N'-(3-chloro-4-2-(N-
methylcarbamoy1)(4-pyridyloxy)phenyl)urea.
the 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl ureas:
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-2-(N-
IITRUE COPY!I
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N' -(2-chloro-4-(2-(N-
methylcarbamoyl) (4-pyridyloxy) )phenyl)urea .
•
or a pharmaceutically acceptable salt thereof.
2. A compound as claimed in claim 1, wherein a pharmaceutically

acceptable salt thereof selected from the group consisting of:
a) basic salts of organic acids and inorganic acids selected from the
group consisting of hydrochloric acid hydrobromic acid, sulphuric acid,
phophoric acid, methanesulphonic acid, trifluorosulphonic acid,
benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt), 1-napthalene
sulfonic acid, 2-napthalne sulfonic acid, acetic
"-t:'
acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic ~d,
oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic
acid, phenylacetic acid, and mandelic acid; and
b) acid salts of organic and inorganic bases containing cations selected
from the group consisting of alkaline cations, alkaline earth cations, the
ammonium cation, aliphatic substituted ammonium cations and aromatic
substituted ammonium cations.
3. A pharmaceutical composition comprising a compound as claimed in

claim 1 or a pharmaceutically acceptable salt thereof and a physiologically
acceptable carrier.
4. A compound as claimed in claim 1 selected from the group consisting

of:
N:-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl-
pyridyloxy)phenyl) urea,
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyll
(4-pyridyloxy))phenyl) urea,
IITRUE COPY!I
N-{4-bromo-3-(trifluoromethyl)phenyl)-N'-( 4-(2-(N-methylcarbamoyl)-4-
pyridyloxy) phenyl) urea,
N~-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-
methylcarbamoyl)-4-pyridyloxy)phenyl) urea,
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-
methylcarbamoyl) (4-pyridyloxy)) phenyl) urea,
5. A compound as claimed in claim 4 which is a pharmaceutically

a) basic salts of organic adds and inorganic acids selected from the
group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid,
phosphoric acid, methanesulphonic acid, trifluorosulphonic acid,
sulfonic acid, 2-napthalene sulfonic acid, acetic
acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid,
acid,
phenylacetic acid, and mandelic acid; and

acceptable carrier.

of:
IITRUE COPY!I
p~dyloxy)phenyl) urea,
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)4-
pyridyloxy) phenyl) urea and
N-(4-chloro-3-(trifluoromethyl)phenyl)- N-(2-chloro-4-(2-(N-
methylcarbamoyl) (4-pyridyloxy) )phenyl) urea,
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl}-4-
pyridyloxy) phenyl urea.
N-(4-bromo-3-(trrifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-
pyridylthio) phenyl) urea,
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-
methylcarbamoyl)(4-pyridyloxy))phenyl) urea and
methylcarbamoyl)(4-pyridyloxy) )phenyl) urea;
N-(2-methoxy-4-chloro-5-(trifluoromethylphenyl)-N'-(4-(2-(N-
N-(2-methoxy- 4-chloro-5-(trifluoromethyl) phenyl)-N' -(2-chloro-4-(2-(N-
methylcarbamoyl) (4-pyridyloxy)) phenyl) urea
or a pharmaceutically acceptable salt thereof for the manufacture of a

medicament for the treatment of a cancerous cell growth mediated by raf
kinase.
IITRUE COPY!I
of4t
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbarnoyl-4-
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbarnoyl-4-
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-( 4-(2-(N-methylcarbamoyl)-4-
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-
N-(4-bromo-3-(trifluoromethyl)phenyl)-N' -(3-(2-(N-methylcarbamoyl)4-
pyridyloxy) phenyl urea,
N-(4-bromo-3-(trifluoromethyl)phenyl)-N' -(3-chloro-4-(2-(N-
methylcarbamoyl) (4-pyridyloxy) )phenyl) urea;
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N' -(4-(2-(N-
IITRUE COPYII
N-(2-methoxy-4-chloro-5-(trifluoromethyl) phenyl)-N'-(2-chloro-4-(2-(N-
•
medicament for the treatment of:
i) carcinoma of the lungs, pancreas, thyroid, bladder, colon,

ii) myeloid leukemia or
iii) villous colon adenoma.
of:
the 4-chloro-3-(trifluoromethyl)phonyl ureas:
N-{4-chloro-3-(trifluoromethyl)phenyl)-N'-( 4-(2-carbamoyl-4-
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-( 4-(2-(N-methylcarbamoyl)-4-
methylcarbamoyl)(4-pyridyloxy) )phenyl) urea,
N-(4-bromo-3-(trifluoromethyl)phenyl)-N' -(3-(2-(N-methylcarbamoyl)4-
N-(4-bromo-3-(trifluoromethyl)phenyl)-N-(3-(2-(N-methylcarbamoyl)-4-
methylcarbamoyl)(4-pyridyloxy) )phenyl) urea· and
zE--
IiTRUE COPY!I
N-(4-bromo-3-(trifluoromethyl)phenyl)-N' -(3-chloro-4-(2-(N-
methylcarbamoyl)(4-pyridyloxy) )phenyl) urea;
•
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-( 4-(2-(N-
methylcarbamoyl)(4-pyridyloxy)phenyl) urea,

medicament for the treatment of tumors.

of:
N~(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-N-methylcarbamoyl)-4-
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-( 4-(2-carbamoyl-4-
N-(4-chloro-3-(trifluoromethyl)phenyl)-N' -(2-chloro-4-(2-(N-
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N' -(4-(2-(N-
methylcarbamoyl) (4-pyridyloxy))phenyl) urea.
or a pharmaceutically acceptable salt hereof for the manufacture of a

kinase.
IITRUE COPYII
0.
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-N-methylcarbamoyl)-4-
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)
phenyl) urea,
N-(4-chloro-3-(trifluoromethyl)phanyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)
N-(4-bromo-3-(trifluoromethyl)phenyl)-N' -(4-(2-(N-methylcarbamoyl)~4
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-

i) carcinoma of the lungs, panaeas, thyroid, bladder, colon,


of:
N-(4 ..chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-N-methylcarbamoyl)-4-
N-(4-chloro-3-(trifluoromethyl)phenyl)-N '-(2-chloro-4-(2-(N-
methylcarbamoyl) (4-pyridyloxy))phenyl) urea,
IiTRUE COPY!I
N-(4-bromo-3-(trifluoromethyl)phenyl)-N' -(4-(2-(N-methylcarbamoyl)-4
N-5-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N' -(4-(2-(N-
methylcarbamoyl)-4-pyridyloxy)phenyl)urea,
methylcarbamoyl)(4-pyridyloxy))phenyl) urea

13. A compound as claimed in claim 1 which is N-(4-chloro-3-

(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl) urea.

(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)
urea
15. A pharmaceutical composition comprising N-(4-chloro-3-

(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl) urea or a
pharmaceutically acceptable salt thereof and a physiologically acceptable
carrier.

(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl)
urea or a pharmaceutically acceptable salt thereof and a physiologically
acceptable carrier.
17. N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-
kinase.
18. N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-
£--
IITRUE COPYII
pyridyloxy)phenyl) urea or a pharmaceutical acceptable salt thereof for the
manufacture of a medicament for the treatment of a cancerous cell growth
m9:iated by raf kinase.
19. A pharmaceutically acceptable salt of a compound which is:
pyridyloxy)phenyl) urea of the formula:
or
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-( 4-(2-(N-methylcarbamoyl-4-
20. A pharmaceutically acceptable salt as claimed in claim 19 which is a

basic salt of an organic acid or an inorganic acid which is hydrochloric acid,
hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid,
trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid
(tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic
acid, phenylacetic acid, or mandelic acid.
21. A pharmaceutically acceptable salt which is the tosylate salt of:
IITRUE COPY!I
phenyl) urea of the formula:
• CF 0
Clu::~~ o ~O~NH,
~~)l~
N N
~~
I I
H H or
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-N-methylcarbamoyl-4-
Cl'(;c
c1=
IS
I .,/.
O
II
N_.A..._N ''
00
~ I
'if
I
~
~N
o
NH/
CH
3
I I
H H
22. A pharmaceutical composition comprising a pharmaceutically

acceptable salt of claim 19, 20 or 21 and pharmaceutically acceptable
carrier.
Dated this 5th day of July, 2001.
(RAN A MEHTA-DUTIJ
OF REMFRY & SAGAR
ATIORNEY FOR THE APPLICANT(S)
IITRUE COPYII
CS (Comm.) No. 660 of 2022
In the matter of:

versus
LIST OF DOCUMENTS FILED ON BEHALF OF DEFENDANT
MASTER INDEX
VOL-3
document ent in
possess
ion/po
wer/co
ntrol/c
ustody
is
origina
l/office
copy/p
hotoco
py
filed) of IN Office and Bayer le on Defenda 532-
215758 Bayer Corporation IPO nt to its 556
(Publicly
Available)
(Publicly
Available)
and Bayer
Corporation
(Publicly
Available)
Office and
Bayer
Pharmaceuti
cals
Corporation
(Publicly
Available)
Through
Place: Noida (NCR)
Date: 03.10.2022
Guruswamy Nataraj
NOIDA 201 307, NCR
Phone: 9811808373
WO 00/42012 PCT/US00/00648
WHAT IS CLAJMED IS:
1. A compound of Formula I:
A-D-B (I)
5 or a pharmaceutically acceptable salt thereof, wherein
D is -NH-C(O)-NH-,
1
A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L )q ,
where L is a 5 or 6 membered cyclic structure bound directly to D, L 1 comprises a
substituted cyclic moiety having at least 5 members, M is a bridging group having at least
10 one atom, q is an integer of from 1-3; and each cyclic structure of Land L 1 contains 0-4
members of the group consisting of nitrogen, oxygen and sulfur, and
B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to

30 carbon atoms with at least one 6-member cyclic structure bound directly to D containing
0-4 members of the group consisting of nitrogen, oxygen and sulfur,
1
!5 wherein L is substituted by at least one substituent selected from the group consisting
of -SO2R~. -C(O)Rx and -C(NRy) Rz,
Ry is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally

containing heteroatorns selected from N, S <l:Tld
O and optionally halosubstituted, up to per
halo,
20 R 2 is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally

containing heteroatoms selected from N, S and O and optionally substituted by halogen,
hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain
heteroatoms selected from N, S and O and are optionally substituted by halogen;
25 a) independently hydrogen,
a carbon based moiety of up to 30 carbon atoms optionally containing

hetcroatoms selected from N. S and O and optionally substituted by halogen. hydroxy and
89
~
IITRUE COPYII
WO 00/41012
PCT/US00/00648
carbon based substituents of up to 24 carbon atoms, which optionally Contain heteroatoms

·selected from N, S and O and are optionally substituted by halogen, or
-OSi(Rc)J where Rr is hydrogen or a carbon based moiety of up to 24 carbon

atoms optionally containing heteroatoms selected from N, S and O and optionally substituted
5 by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which
optionally contain heteroatoms selected from N, S and O and are optionally substituted by
halogen; or
b) Ra and Rb together form a 5-7 member heterocyclic structure of 1-3

heteroatoms selected from N, Sand 0, or a substituted 5-7 member heterocyclic structure of
1o 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based
substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N,
S and O and are optionally substituted by halogen; or
c) one of Ra or Rb is -C(O)-, a C,-Cs divalent alkylene group or a substituted C 1-

C5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5
15 members, wherein the substituents of the substituted C 1-C 5 divalent alkylene group are-
selected from the group consisting of halogen, hydroxy, and carbon based_substituems of up
to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are
optionally substituted by halogen;
I
where B is substituted, L 1s substituted or L is additionally substituted, the
20 substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where
n is 0-3;
wherein each W is independently selected from the group consisting of -CN, -CO2 R',
-C(O)NR R7. -C(O)-R7, ~NO2, -OR -SR7, -NR R', -NR C(O)OR -NR C(O)R -Q-Ar, and
7 7 7 7
7 7 7
, , ,
carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected

25 from N, S and O and optionally substituted by one or more substituents independently
selected from the group consisting of -CN, -CO R -C(O)R7, -C(O)NR R7, -OR -SR\ -
7 7 7
, ,
2
7 7
NR.7R7, -NO 2, -NR 7C(O)R7, -NR C(O)OR and halogen up to per-halo; with each R;
independently selected from Hor a carbon based moiety of up to 24 carbon atoms, optionally
containing heteroatorns selected from N. Sand O and optionally substituted by halogen.
90
[TRUE COPYjl
WO 00/42012 PCT/US00/00648
wherein Q is -0-, -S-, -N(R;)-, -(CH2)m·, -C(O)-, -CH(OH)-, -(CH2)mO·, -(CH2)mS-,

7 2
-{CH2)mN(R )·, -O(CH2)m· CHX -, -CX'z-, -S-(CH2)m· and -N(R')(CH 2 )m·, where m::::; 1-3,
and x• is halogen; and
AI is a 5- or 6-member aromatic structure containing 0-2 members selected from the

5 group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen,
up w per-halo, and optionally substituted by Zn1, wherein nl is 0 to J and each Z is
7 7
independently selected from the group consisting of -CN, -C0 2 R , -C(O)R;, -C(O)NR R 7 , -
7 7 7 7 7
NO 2 , -OR , - SR -NR R7, -NR C(O)OR\ -NR C(O)R\ and a carbon based moiety of up to
24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally
10 substituted by one or more substituents selected from the group consisting of -CN, -CO 2R 7 , -
7 7 7 7 7 7 7
COR\ -C(O)1'-rR R7, -OR7, -SR , -NO,, -NR R , -NR C(O)R7. and -NR C(O)OR7, with R as
defined above.
2. A compound as in claim I wherein:
I5 Ry is hydrogen, C1.10 alkyl, C1.10 alkoxy, C1.10 cycloalkyl having 0-3 heteroatoms, C 2 .
10 alkenyl, C1.1o alkenoyl, C6-l2 aryl, (3.12 hetaryl having l-3 heteroatoms selected from N, S
and 0, C 7. 24 aralkyl, C1.z4 alkaryl, substituted C1.10 alkyl, substituted C 1. 10 alkoxy, substituted
C 3. 10 cycloalkyl having 0-3 heteroatoms selected from N, S a.I].d0, substituted Co -C14 aryl,
substituted C 3. 12 hetaryl having 1-3 heteroatoms selected from N, S and 0, substituted C1. 24
20 alkaryl or substituted C1~C24 aralkyl, where Ry is a substituted group, it is substituted by
ha\ogen up to per haio,
Rz is hydrogen, C1.10 alkyl, C1.10 alkoxy, (3.10 cycloalkyl having 0-3 heteroatom, C2 .1 0
alkenyl, C 1. 10 alkenoyl, C6-12 aryl, C1 -C 12 hetaryl having 1-3 heteroatoms selected from, S, N
25 and 0, C 7. 24 alkaryl, C1.24 aralkyl, substituted C1.10 alkyl, substituted Ci. I0 alkoxy, substituted
C,-C 1* aryl, substituted CJ -C10 cycloalkyl having 0-3 heteroatoms selected from S, N and 0,
substituted C 3. 12 hetaryl having 1-3 heteroatorns selected from S, N and 0, substituted C ,.:~
alkaryl or substituted CrC2~ aralkyl where Rz is a substituted group, it is subs1i1uted by
halogen up to per halo, hydroxy, C1.10 alkyl, CJ-12 cycloalkyl having 0-3 he1eroatoms selected
:O fron1 0. S and N. C_1-
1~ he1ary! having 1-3 heteroatoms selected from N, S and 0. C1.;11
91
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WO 00/42012 PCT /US00/00648
alkoxy, ( 6.12 aryl, C1-6 halo substituted alkyl up to per halo alkyl, C 6 -C 12 halo substituted aryl
up to per halo aryl, C 3 -C 12 halo substituted cycloalkyl up to per halo cycloalkyl having 0-3
heteroatoms selected from N, S and 0, halo substituted C 3-C 12 hetaryl up to per halo hetaryl
having 1-3 heteroatoms selected from 0, N and S, halo substituted CrC 24 aralkyl up to per
5 halo aralkyl, halo substituted C,-C24 alkaryl up to per halo alkaryl, and -C(O)Rg,
a) independently hydrogen,
a carbon based moiety selected from te group consisting of C 1 -C 10 alkyl, C 1 -

10 C 10 alkoxy, C,.10 cycloalkyl, C2.10 alkenyl, C1.10 alkenoy!, C6.12 aryl, C 3.j 2 hetaryl having 1-3
heteroatoms selected from 0, N and S, (3.12 cycloalkyl having 0-3 heteroatoms selected from
N, S and 0, C,.24 aralkyl, CrCc'1 a!karyl, substituted C1.1o alkyl, substituted C 1. 10 alkoxy,
substituted C3.1o cycloalk.-yl, having 0-3 heteroatoms selected from N, S and 0, substituted C6_
12 aryl, substituted (3.12 hetaryl having 1-3 heteroatoms selected from N, Sand 0, substituted
15 C;.24 aralkyl, substituted C1.24 alkaryl, where Ra and Rb are a substituted group, they are
substituted by halogen up to per halo, hydroxy, C 1. 10 alkyl, C 3. 12 cycloalkyl having 0-3
heteroatoms selected from 0, Sand N, C3.12 hetaryl having 1-3 heteroatoms selected from N,
Sand 0, C1.10 alkoxy, C6-12 aryl, C1-o halo substituted alkyl up to per halo alkyl, C 6 -C 12 halo
substituted aryl up to per halo aryl, C3-C 12 halo substituted cycloalkyl having 0-3 heteroatoms
20 selected from N, Sand 0, up to per halo cycloalkyl, halo substituted C 3 -C 12 hetaryl up to per
halo heteraryl, halo substituted C1-C24 aralkyl up to per halo aralkyl, halo substituted C1-C24
alkaryl up to per halo alkaryl, and -C(O)R 8 ; or
-OSi(Rfh where Rr is hydrogen, C1-10 alkyl, C 1. 10 alkoxy, C 3-C 10 cycloalkyl

having 0-3 heteroatoms selected from 0, S and N, C 6. 12 aryl, C 3-C 12 hetaryl having 1~3
25 het~roatoms selected from 0, S and N, C1.2,; aralkyl, substituted C 1. 10 alkyl, substituted C 1-
C 10 alkoxy, substituted C3-C12 cycloalkyl having 0-3 heteroatoms selected from 0, S and N,
substituted C;-C 12 heteraryl having 1-3 heteroatoms selected from 0, S, and N, substituted
C6 . 12 aryl, and substituted (7-24 alkaryl, where Rr is a substituted group it is substituted
halogen up to per halo, hydroxy, C1.1o alkyl, (3.12 cycloalkyl having 0-3 heteroatoms selected
~o from 0, S and N. C_i.12 hetaryl having 1-3 heteroatoms selected from N. S and 0. C1.w
alkoxy. C,.12 ary!. C1 -C2~ alkaryl, C1 -Cz~ aralky!, C1. 6 halo substituted alkyl up to per halo
92
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alkyl, C 6 -C l2 halo substituted aryl up to per halo aryl, C;-C 12 halo substituted cycloalkyl
having 0-J heteroatoms selected from N, S and 0, up to per halo cycloa'lkyi. halo substituted
C 3-C 12 hetaryl up to per halo heteraryl, halo substituted (p(i 4 aralkyl up to per halo aralkyl.
halo substituted C,-C24 alkar1l up to per halo alkaryl, and -C(O)R 8 ,
5 or
b) Ra and Ri, together form a 5-7 member heterocyclic strncture of 1-3

heteroatoms selected from N, S and 0, or a substituted 5-7 member heterocyclic structure of
1-3 heteroatoms selected from N, S and O with substituents selected from the gro~p
consisting of halogen up to per halo, hydroxy, C1.10 alkyl, C3. 12 cycloalkyl having 0-3
10 heteroatorns selected from 0, Sand N, C3.12 hetaryl having 1-3 heteroatoms selected from N,
Sand 0, C;.10 alkoxy, C6.12 aryl, C1 -C24 alkaryl, C1 -C24 aralkyl, halo substituted C 1. 6 alkyl
up 10 per halo alkyl, halo substituted C6-Cr2 aryl up to per halo aryl, halo substituted C 3-C 12
cycloalkyl having 0-3 heteroatoms selected from N, S and 0, up to per halo cycloalkyl, halo
substituted C3-C12 hetaryl up to per halo heteraryl, haio substiruted C 7 -C 24 aralkyl up to per
15 halo aralkyl, halo substituted CrC 24 alkaryl up to per halo alkaryl, and -C(O)Rg,
or
c) one of R. or Rb is -C(O)-, a C ,-Cs divalent alkylene group or a substituted C 1-

C 5 divalent alkylene group bound to the moiety L to fonn a cyclic structure with at least 5
20 members,
wherein the substituents of the substituted C1-C5 divalent alkylene group are selected from
the group consisting of halogen, hydroxy, C1.10 alkyl, C3.12 cycloalkyl having 0-3 heteroatoms
selected from 0, S and N, C3. 12 hetaryl having 1-3 heteroatoms selected from N, S and 0, C 1-
io alkoxy, C6-12 aryl, C1 -C24 alkaryl, C1 -C24 aralkyl, C1-6 halo substituted alkyl up to per halo
25 alkyl, C 6 -C11 halo substituted aryl up to per halo aryl, C 3-C 12 halo substituted cycloalkyl
having 0-3 heteroatoms selected from N, S and 0, up to per halo cycloalkyl, halo substituted
C 3-C 12 hetaryl up to per halo heteraryl, halo substituted C1-C24 aralkyl up to per halo aralkyl,
halo substituted C1-C 24 alkaryl up to per halo alkaryl, and -C(O)Rg,
where Rg is ( 1. 10 alkyl; -CN, -CO2Ri, -ORJ, -SRJ, -NO2, -C(O) R:. -'-:R,rR,. •
;o NR.i C(O)OR.., and -Nl<,JC(O)R..,. and R;J and R.:are independently selected from the ~roup
93
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WO 00/42012 PCT/US00/00648
consisting of hydrogen, C 1. 10, alkyl, C1-10 alkoxy, CJ.JO cycioalkyl having 0-3 heteroaroms
selected from 0, N and S, C6 . 12 aryl, C3- C,2 hetaryl with 1-3 heteroatoms selected from 0, N
and S and C1 -C 24 aralkyl, C 7 -C 24 alkaryl, up to per halo substituted C 1-C 10 alk-y\, up to per
halo substituted C3 -C 10 cycloalkyl having 0-3 heteroatoms selected from 0, N and S, up to
s per halo substituted C 6 -C I 4 aryl, up to per halo substituted C 3 -C I2 hetaryl having 1-J
heteroatoms selected from 0, N, and S, halo substituted (7-( 24 alkaryl up to per halo alkaryl,
and up to per halo substituted CrC 24 aralkyl,
Wis independently selected from the group consisting of -CN, -CO R -C(O)NR R
7 7 7
, ,
2
7 7 7 7
10 -C(O)-R7, -NO 2 , -OR , -SR7, -l'•iRiR7, -NR C(O)OR7, -NR C(O)R , C 1-C 10 alkyl, C,-C1o
alkoxy, Ci-Cio alkenyl, C 1-C 10 alkenoyl, C3-C10 cycloalkyl having 0-3 heteroatoms selected
from 0, S and N, C6-C I J aryl, C1-C24 alkaryl, C, -C24 aralkyl, C3-C 12 heteroaryl having 1-3
het~rnatmns selected from 0, N and S, C.-C21 alk.heteroaryl having 1-3 heteroatoms selected
from 0, N and $, substituted C1-C10 alkyl, substituted C1-C10 alkoxy, substituted C2-C10
15 alkenyl, substituted C 1 -C 10 alkenoyl, subst1tuted C3-C1o cycloalkyl,having 0-3 heteroatoms

selected from 0, N and S, substituted C6-C 12 aryl, substituted C 3-C 12 hetaryl having 1-3
heteroatoms selected from 0, N and S, substituted C7-C24 aralkyl, substituted C;-C 24 alkaryl,
substituted C4-C23 alkheteroaryl having 1-3 heteroatoms selected from 0, N and S, and -Q-
Ar;
20
7
R is independently selected from H, C,-C10 alkyl, C 1-C 10 alkoxy, C2-C 1o alkenyl, C1-
C 1o alkenoyl, C 3-C, 0 cycloalkyl having 0-3 heteroatoms selected from 0, S and N. C6-C14
aryl, C -C
3 13
hetaryl having 1-3 heteroatoms selected from 0, N and S, C,-C 1
4 alkaryl, C1 -C24
aralkyl, CrC 23 alkheteroaryl having 1-3 heteroatoms selected from 0, N and S, up to per-
25 halosubstituted C 1-C 10 alkyl, up to per-halosubstituted C 3-C 1o cycloalkyl having 0-3
heteroatoms selected from 0, N and S, up to per-halosubstituted C6 -C 14 aryl, up to per-
halosubstituted CrCn hetary\ having l-3 heteroatoms selected from 0, N and S, up to per-
halosubstituted C1-C24 aralkyl, up to per-halosubstituted CrC24 alkaryl, and up to per-
halosubstituted C-C 2_, alkheteroaryl; and
JO
IITRUE COPYII
WO 00/42012 PCT /US00i00648
each Z is independently selected from the group consisting of -CN, -CO 2 R7, -C(O)R 7 ,
- • -NO2, - OR 7 , - SR; - NR' R,7 -NR 7 C(O)OR,7 ~N"R'C(O)R
-C(O)NR'R', - -1
, C -Crn alh.--yl,
C 1-C10
1
alkoxy, C 2-C10 alkenyl, C1-C10 alkenoyl, C3-C10 cycloalkyt having 0-3 heteroatoms selected
frorn 0, N and S, C6-Cl4 aryl, C3-(13 hetaryl having l-3 h~teroatoms selected from 0, N and
5 S, CrC 24 alkaryl, C, -(24 aralkyl, (4-(23 alkheteroaryl having 1-3 heteroatoms selected from
O, N and S, substituted C1-C10 alkyl, substituted C1-C10 alkoxy, substituted CrC 10alkenyl,
substituted C 1-Cw alkenoyl, substituted (3-C10 cycloalkyl having 0-3 heteroatorns selected
from 0, N and S, substituted C6-C12 aryl, substituted C::rC,4 alkaryl, substituted CrC24
aralkyl and substituted C4-(23 alkheteroaryl having 1-3 heteroatoms selected from 0, N
1D and S; wherein if Z is a substituted group, the one or more substiruents are selected from the
7
group consisting of -CN, -CO2R , -COR7, -C(O)NR;:tz7, -OR7, -SR 7 , -NO 2 , -NR'R 7
,
7 7
-NR C(O)R7, and -I'•rR'C(O)OR .
3. A compound as in claim I wherein M is on(: or more bridging groups selected

7
15 from the group consisting of -0-, -S-, -N(R )-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)mO-, -
1
(CH2)mS-, -{CH2)mN(R )-, -O(CH2)m· CHX•-, -CXar, -S-(CH 2):n- and -N(R 1)(CH 2)m-, where
7
m==1-3, x• is halogen and R is as defined in claim 1.
4. A compound as in claim I wherein the cyclic structures of B and L bound

directly to D are not substituted in the ortho position by-OB:.
20 5. A compound as in claim l wherein the cyclic structures of B and L bound

directly to D are not substituted in the ortho position by a moiety having an ionizable
hydrogen and a pKa of 10 or less.
6. A compound of claim l wherein B of Formula I is a substituted or

unsubstituted six member azyJ moiety or six member h{:taryl moiety, said hetary1 moiety
25 having l to 4 members selected from the group of heta.ryl atoms consisting of nitrogen,
oxygen and sulfur with the balance of the hetaryl moiety being carbon.
7. A compound of claim 1 wherein B of Formula I is an unsubstituted phenyl

group, an unsubstituted pyridyl group, an unsubstitut~d pyrimidinyl, a phenyl group
substituted by a substituent selected from the group consisting of halogen and Wn wherein W
30 and n are as defined in claim I, a pyrimidinyl group substituted by a substituem selected from
95
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PCT /US00/00648
the group constituting of halogen and \Vn, whereas W and n are as defined in Claim 1, or a
substituted pyridyl group substituted by a substituent selected from the group consisting of
halogen and Wn wherein W and n are as defined in claim 1.
8. A compound of claim 6 wherein B of Formula I is a substituted phenyl group.

5 a substituted pyrimidinyl group, or substituted pyrridyl group substituted 1 to 3 times by I or
more substituents selected from the group consisting of -CN, halogen, C1-C 10 alkyl, C 1-C 10
alkoxy, -OH, up to per halo substituted C 1-Cio alkyl, up to per halo substituted C 1-C 10 alkoxy
or phenyl substituted by halogen up to per halo.
9. A compound of claim 1, wherein L, the six member cyclic structure bound

10 directly to D, is a substituted or unsubstituted 6 member aryl moiety or a substicuted or
unsubstituted 6 member hetaryl moiety, wherein said hetaryl moiety has 1 to 4 members
selected from the group of heteroatoms consisting of nitrogen, oxygen and sulfur with the
balance of said hetaryl moiety being carbon, wherein the one or more substituems are
selected from the group consisting of halogen and Wn wherein W and n are as defined in
15 claim 1.
10. A compound of claim 8, wherein L, the 6 member cyclic structure bound

directly to D, is a substituted phenyl, unsubstituted phenyl, substituted pyrimidinyl,
unsubstituted pyrimidinyl, substituted pyridyl or unsubstituted pyridyl group.
I
11. A compound of claim 1, wherein said substituted cyclic moiety L comprises a
20 5 to 6 membered aryl moiety or hetaryl moiety, wherein said heteraryl moiety comprises 1 to
4 members selected from the group of heteroatoms consisting of nitrogen, oxygen and sulfur.
12. A compound of claim 1, wherein said substituted cyclic moiety L I is phenyl,

pyridinyl or pyrimidinyl.
1
13. A compound of claim 3, wherein said substituted cyclic moiety L is phenyl.
25 pyridinyl or pyrimidinyl.
I
14. A compound of c!aim 6, wherein said substituted cyclic moiety L is phenyl,
I
15. A compound of claim 8. wherein said substituted cyclic moiety L is phenyl.
Q(i
&--
IITRUE COPYjl
WO 00/42012 PCT/US00/00648
l 6. A compound of claim 9, wherein said substituted cyclic moiety L 1 is phenyl,

17. A compound of claim 10, wherein said substituted cyclic moiety L 1 is phenyl,
5 18. A compound of claim 14, wherein Mis one or more bridging groups selected
7
from the group consisting of -0-, -S-, -N(R )-, -(CH2)m·, -C(O)-, ~CH(OH)-, -(CH 2)rnO·, -
7 7
(CH2)mS·, -(CH2)mN(R )-. -O(CH2)m· CHXa-, -CXa2-, -S-(CH2)m· and -N(R )(CH2)m·, where
7
m= 1-3, Xa is halogen and R is hydrogen or a carbon based moiety of up to 24 carbon atoms,
optionally containing heteroatoms selected from N, S and O and optionally substituted by
10 halogen up to per hal<?.
19.A compound of claim I 5, wherein M is one or more bridging groups selected

7
from the group consisting of -0-, -S-, -N(R )-, -(CH2)m·, -C(O)-, -CH(OH)-, -(CH2)rnO-, -
7
-CXa2-, -S-(CH2)m· and -N(R 7)(CH2)m·, where
3
(CH2)mS·, -(CH2)mN(R )-, -O(CH2)m· CHX -,
7
m:a: 1-3, Xa is halogen and R is hydrogen or a carbon based moiety of up to 24 carbon atoms,
15 optionally containing heteroatoms selected from N, S and O and optionally substituted by
halogen up to per halo.
20. A compound of claim l 6, wherein M is one or more bridging groups selected

7
from the group consisting of -0-, -S-, -N(R )-, -(CH2)m·, -C(0)-, -CH(OH)-, -(CH 2)mO-, -
7 3 7
(CH2)mS·, -(CH2)mN(R )-, -O(CH2)m· CHX ·, -CXar, -S-(CH2)m· ~d -N(R )(CH2)m·, where
20 m= 1-3, x· is halogen 7
and R is hydrogen or a:carbon based moiety ofup to 24 carbon atoms,
2 l.
A compound of claim 17, wherein M is one or more bridging groups selected
7
from the group consisting of -0-, -S-, -N(R )-, -(CH 2)m·, -C(O)-, -CH(OH)-, -(CH 2)mO-, -
(CJ:I2)mS-, -(CH2)mN(R7 )-, -O(CH2)m· CHXa-, -CX -S-{CH2)m· and -N(R 7)(CH2)m·, where
3
25 2-,
m= l-3, x• is halogen 7
and R is hydrogen or a carbon based moiety of up to 24 carbon atoms,
1
22. A compound of claim I wherein L is additionally substituted I to 3 times by
)0 one or more substituents selected from the group consisting of C 1-C 10 alkyl, up to per halo
97
~
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WO 00/4201: PCT/US00/00648
substituted C 1-C10 alkyl, -CN, -OH, halogen, C,-C10 alkoxy and up to per halo substituted C 1-
C1o alkoxy.
I
23. A compound of claim 13 wherein L is additionally substituted l to 3 times by
one or more subs ti tuents selected from the group consisting of C 1-C 10 alkyl, up to per halo
5 substituted C,-C10 al~--yl,-CN, -OH, halogen, C1-C10 alkoxy and up to per halo substituted C1-
Cio alkoxy.
I
24. A compound of claim 18 wherein L is additionally substituted 1 to 3 times by
one or more substituents selected from the group consisting of C 1-Cto alkyl, up to per halo
substituted C 1-Cio alkyl, -CN, -OH, halogen, C1-C10 alkoxy and up to per halo substituted ( 1-
10 Cio alkoxy.
25. A compound of claim 19 wherein L I is additionally substituted 1 to 3 times by

one or more substituents selected from the group consisting of C 1-C 10 alkyl, up to per halo
substituted Ci-C!o alkyl, -CN, -OH, halogen, C,-Cio alkoxy and up to per halo substituted C 1,.-
C,o alkoxy.
15 26. A compound of claim 20 wherein L 1 is additionally substituted 1 to 3 times by

one or more substituents selected from the group consisting of C 1-C 10 alkyl, up to per halo
substituted C 1-C10 alkyl, -CN, -OH, halogen, C1-C10 alkoxy and up to per halo substituted C 1-
Cio alkoxy.
1
20 one or more substituents selected from the group consisting of C 1-C 10 alkyl, up to per halo
substituted C 1-C10 alkyl, -CN, -OH, halogen, C1-C10 alkoxy and up to per halo substituted C1-
C10 alkoxy.
1
28. A compound of claim I wherein L is substituted by -C(O)R~.
I
29. A compound of claim 1 wherein L is substituted by -SO 2 Rx .
1
25 30. A compound of claim l wherein L is substituted only by -C(O)R,.
1
3 l. A compound of claim I wherein L is substituted only by -SO 2 R, .
I
32. A compound of claim I wherein L is substituted by -C(O)R~ or -SO~R,,
wherein R, is NRa~-
98
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WO 00/42012 PCT/US00/00648
I
33. A compound of claim 13 wherein L is substituted by -C(O)R, or -SO~R,,
whe:-ein Rx is NRaR.o•and R. and R 0 are
a cir'oon based moiety of up to 30 carbon atoms optionally containing

5 heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and
carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms
selected from N, S and O and are optionally substituted by halogen, or
-OSi(Rr)3 where Rr is hydrogen or a carbon based moiety of up to 24 carbon

halogen; or
b) R. and Rb together form a 5-7 member heterocyclic strucrure of 1-3

heteroatoms selected from N, S and O. or a substituted 5-7 member heterocyclic structure of
1s l -3 heteroatoms selected from N. S and O substituted by halogen, hydroxy or carbon based
c) one of Ra or~ is -C(O)-, a C1-Cs divalent alkylene group or a substituted C 1-

20 members, wherein the substituents of the substituted C 1-~ 5 divalent alky\ene group are
sdected from the group consisting of halogen, hydroxy, and carbon based substituems of up
optionally substituted by halogen.
1
34. A compound of claim 18 wherein L is substituted by -C(O)R( or -SO 2R.,,,
25 wherein R" is NR,Ro and Ra and Rb are independently hydrogen or a carbon based moiety
of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and
optionally s,ubstituted by halogen, hydroxy and carbon based substituents of up to 24 carbon
atoms, which optionally contain heteroatoms selected from N, S and O and are optionally
substituted by halogen.
99
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WO 00/42012 PCT/US00/00648
1
35. A compound of claim 19 wherein L is substituted by-C{O)R,, wherein R, is
NRaRb and Ra and R:, are independently hydrogen or a carbon based moiety of up to 30
carbon atoms option·ally containing heteroatoms selected from N, S and O and optionally
substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms,
5 which optionally contain heteroatoms selected from N, S and O and are optionally
36. A compound of claim 20 wherein L I is substituted by -C(O)R~ or -S0 2Rx,

wherein Rx is NRaRb and Ra and Rb are independently hydrogen or a carbon based moiety
iO optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon
substi ruted by halogen.
1
37. A compound of claim 2i wh::rein 1., is substituted by -C(O)Rx or -SO 2R.1(,
wherein R,_ is NR~~ and Ra and ~ are independently hydrogen or a carbon based moiety
15 of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and
optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon
atoms, which optionally contain heteroatorns selected from N, S and O and are optionally
20 38. A compound of Formula I:
A-D-8 (I)
or a pharmaceutically acceptable salt thereof, wherein
D is ·'NH-C(O)-N1i-,
1
A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L )q ,
25 where L is a 6 membered aryl moiety or a 6 membered hetaryl moiety bound directly to D,
L1 comprises a substituted cyclic moiety having at least 5 members, M is a bridging group
1
having at least one atom, q is an integer of from 1-3; and each cyclic structure of Land L
contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and
100
~
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WO 00/4::!012 PCT'1JS00i00648

30 carbon atoms with at least one 6-rnember cyclic structure bound directly to D containing
I
whe:-ein L is substituted by at least one substituent selected from the group consisting
5 of -SO2Rx, -C(O)Rx and -C(NR:,-)R:,

containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per
halo,
Rz is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally

1o containing heteroatoms selected from N, S and O and optionally substituted by halogen,
hydroxy a.11dcarbon based substituents of up to 24 carbon atoms, which optionally contain
heteroatoms se\ected from N, Sand O and are optiona\\y substituted by ha\ogen~
R, is Rz or NRaRii where R. and R, are
15 a carbon based moiety of up to 30 carbon atoms optionally containing

heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and
carbon based substituents of up to 24 carbon atoms, which optional1y contain heteroatoms
-OSi(Rrh where Rr is hydrogen or a carbon based moiety of up to 24 carbon

20 atoms optionally containing heteroatoms selected from N, S and O and optionally substituted
by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms. which
halogen; or
b} Ra and Rb together form a 5- 7 member heterocyclic structure of 1-3

25 heteroatoms selected from N, S and 0, or a substituted 5- 7 member heterocyclic structure of
1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based
.substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N.
cl one of R, or Rb is -C(O)-. a C1-C 5 divalent alkylene group or a substitut~J C-

~o C divalent a\ky\ene group bound to the moiety L to form a cyclic structure: with at kast 5
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WO 00/4201::: PCT/liS00/006~~
members, wherein the substituents of the substituted C 1-C 5 divalent alkylene group are
selected from the grOLIP consisting of halogen, hydroxy, and carbon based substituents of up
ro 24 carbon atoms, ,vhich optionally contain heteroatoms selected from N, S and O and are
o-p\,mya\\'jsubs',\\U\.ed by \\,.\~'?,~\\;
1
5 where 8 is 5ubstituted, L is substituted or L is additionally substituted, the
substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where.
n is 0-3;
wherein each W is independently selected from the group consisting of -CN, -CO 2R7,
7 7 7 7 7 7
-C(O)NR 7R7, -C(O)-R , -NO2, -OR , -SR , -NR R1, -NR C(O)OR7, -NR C(O)R7, -Q-Ar, and
1o carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected
from N, S and O and optionally substituted by one or more substituents independently
selected from the group consisting of -CN, -CO2R -C(O)R -C(O)NR R -OR', -SR
7 7 7 7 7
, , , , -
7 7 7 7 7
~'R 7R 7, -N0 1 , -NR C(O)R , -1'fR.C(O)OR and halogen· up to per-halo; with each /,
independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally
15 containing heteroatoms selected from N, S and O and optionally substituted by halogen,
7
wherein Q is -0-, -S-. -N(R. )-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)mO-, -(CH2)mS-,
3 7
-(CH2)mN(R7 )-, -O(CfUm- CHX -, -CXa2-, -S-(CH2)m- and -N(R )(CH2)m-, where m= 1-3,
and Xa is halogen;
AI is a 5- or 6-member aromatic structure containing 0-2 members selected from the

20 group consisting of nitrogen, oxygen and su~for, which is optionally substituted by halogen,
up to per-halo, and optionaiiy suostitutea by 2n 1, wnerein n) 'is D to 3 ana each 2 'is
7 7
independently selected from the group consisting of -CN, -CO 2R , -C(O)R7. -C(O)NR R1, -
7 7 7 7
NO 2, -OR7, - SR; -NR R , -NR C(O)OR7, -NR C(O)R7, and a carbon based moiety of up to
substituted by one or more substituents are selected from the group consisting of -CN, •
7 7 7 7 7 7
Ca°2 R7 , -COR 7 , -C(O)NR R7. -OR.7, -SR , -NO2, -NR R , -NR. C(O)R7, and -NR C(O)OR7,
with R; as defined above; and
wherein M is one or more bridging groups selected from the group consisting of -0-, -S-. -
N(R 7)-, -(CH~)m-, -C(O)-, -CH(OH)-, -(CH2)mO-, -(CH2)mS-. -(CH2)mN(Ri)-, -O(CH~)m·
7
30 CHX"-. -CX,~-. -S-(CH1)m- and -N(R )(CH2)m-, where m=-=1-3. X' is halogen.
IITRUE COPYII
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A-D-B (1)
D is -NH-C(O)-NH-,
A is a substituted moiety of up to 40 carbon atoms of the formula: -L-{M-L 1 )q,

where L is a substicuted or unsubstituted phenyl or peritoneal moiety bound directly to D, L 1
comprises a substituted phenyl, peritoneal or pyrimidinyt moiety, M is a bridging group
1o having at least one atom, q is an integer of from 1-3; and
B is .a substituted or unsubstituted phenyl or pyridine group bound directly to D.

1
wherein L is su!Jstituted by 2: least one substitucnt ~elected from ih~ grou;:i consisting

15 containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per
halo, and;
Rz is hydrogen .or a carbon based moiety of up to 30 carbon atoms optionally

comaining heteroatoms selected from N, S and O and ·optionally substituted by halogen,
20 heteroatoms selected from N, S and O and are optionally s1.1bstitutedby halogen;
RJI;is Rz or NR.Ri, where Ri and Rt, are

25 carbon based substituents of up to 24 carbon atoms, whic::h optionally contain heteroatoms
-OSi(Rrh where Rt' is hydrogen or a carbon based moiety of up to 24 carbon

atoms optionally containing heteroatoms selected from N, Sand O and op1ionally subs111uti:J
by halogen, hydroxy and carbon based substituents of up to 24 carbon illoms. \\ hich
103
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halogen; or
b) Ra and R 0 together form a 5-7 member heterocyclic structure of 1-3

heteroatoms selected from N, Sand 0, or a substituied 5-7 member heterocyciic structure of
5 1-J heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based
substituents of up to 24 carbon atoms, •,vhich optionally contain heteroatoms selected from N,
c) one of Ra or R is -C(O)-, a Ci-Cs divalent alkylene group or a substituted C

0 1
-
C 5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5
lO members, wherein the substituents of the substituted Ci-Cs divalent alkylene group are
se!ected from the group consisting of halogen, hydroxy, and carbon based substituents of up
to 24 carbon atoms, \vhich optionally contain heteroatoms selected from N, S and O and are
I
where B is substituted, L 1s substituted or L is additionally substituted, the
n is 0-3;
7
wherein each W is independently selected from the group consisting of -CN, -CO 2 R ,
-C(O)NR R -C(O)-R -NO2, -OR -SR -NR R -NR;C(O)OR -NR C(O)R -Q-Ar, and
7 7 7 7 7 7 7 7
7 7
, , , , , , ,

selected from the group consisting of -CN, -CO R -C(O)R7, -C(O)NR R7, -OR\ -SR
7 7 7
, , -
2
7 7 7 7 7
NR 7R , -NO 2 , -NR C(O)R7, -NR C(O)OR and halogen up to per-halo; with each R
7
25 wherein Q is -0-, -S-, -N(R )-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)mO-, -{CH2)mS-,
7
-(CH~)mN(R )-, -O(CH2)m· CHX 3 -, -CX 3 z-, -S-{CH2)m· and -N(R 7)(CH2)m-, where m= 1-3,
and Xa is halogen;
Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the

group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen.
JO up 10 per-halo. and optionally substituted by Zn1, wherein n l is O to J and each Z is
104
&-
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WO 00/42012 PCT/US00/00648
independently selected from the group consisting of -CN, -CO 2R\ -C(O)R7, -C(O)NR;R\ -
7 7 7 7 7 7 7
N0 2 , -OR , - SR -NR R7, -1'-i"RC(O)OR , -NR C(O)R , and a carbon based moiety of up to
24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optional-ly
7
substituted by one or more substituents selected from the group consisting of -CN, -C0 2R , -
- 77 - 7 -- 7 - - 7
5 COR', -C(O)NR R, -OR', -SR, -NO2, -NR'R', -'NR C(O)R', and-NR'C(O)OR ; and
wherein M is one or more bridging groups selected from the group consisting of -0-, -5-, -
7
N(R )-, -(CH2)m-, -C(O)-,· -CH(OH)-, -(CH2)mO-, -{CH2)mS-, -{CH2)mN(Ri)-, -O(CH2)m-
3 7
CHX 3 -, -CX i-, -S-(CH 2)m- and -N(R )(CH2)m-, where m= 1-3, Xa is halogen.
40. A compound as in claim 38 wherein the cyclic structures of B and L bound

IO directly to D are not substituted in the ortho position by-OH.

directly to D are not substituted in the ortho position by a moi.ety havi.ng an loniz.able
hydrogen and a pKa of l O or less.

15 directly to Dare not substituted in the ortho position by-OH.

44. A compound as in claim 38 wherein substituents for B and L and additional •

20 substituents for • L 1, are selected from the group consisting of C 1-C 10 alkyl up to per halo
substituted C1-C10 alkyl, CN, OH, halogen, C1-CJOalkoxy and up to per halo substituted C1-
C10 alkoxy.
45. A compound as in claim 39 wherein substituents for B and L and additional

substituents for L 1, are selected from the group consisting of C 1-C 10 alkyl up to per halo
25 substituted C 1-C 10 alkyl, CN, OH, halogen, C1-C 10alkoxy and up to per halo substituted C,-
C,o alkoxy.
1
46. A compound of claim 38 wherein L is substituted by C(O)R._or S0 2 R_,.
I
4 7. A compound of claim 39 wherein L is substituted by C(O)R, or SO:iR,.
48. A compound of claim 46 wherein R., is NRaRb and Ra and R0 are

JO independently hydrogen and a carbon based moiety of up to 30 carbon atoms optionally
105
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WO 00/4~01:? PCT /US00/00648

heteroatoms selected from N, S and O and are optionally substituted by halogen ..
49. A compound of claim 4 7 wherein R,. is NRaRo and Ra and R0 are

s independently hydrogen and a carbon based moiety of up to 30 carbon atoms optionally
containing heteroatoins selected from N, S and O and optionally substituted by halogen,
heteroatoms selected from N, S and O and are optionally substituted by halogen.
50. A compound of claim l which _is a pharmaceutically acceptable salt of a

10 compound of formula I selected from the group consisting of
a) basic salts of organic acids and inorganic acids selected from the group
consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,
methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic
acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid,
15 trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid.
fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid;
and
b) acid salts of organic and inorganic bases containing cations selected from the
group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic
20 substituted ammonium cations and aromatic substituted ammonium cations.
51. A compound of claim 2 which is a pharmaceutically acceptable salt of a

compound of formula I selected from the group consisting of
consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid.
25 methanesulphonic acid, tri fluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic
tri fluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid.
fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid:
and
106
~
I[TRUE COPYII
WO 00/42011 PCT /US00/00648
substituted ammonium cations and aromatic substituted ammonium cations.
52. A compound of claim 33 which is a phannaceutically acceptable salt of a

methanesu !phonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic
10 trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid,
and
t5 substituted ammonium cations and aromatic substituted ammonium cations.

20 methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic
acid (tosylate salt), · 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid,
trifluoroacetic acid, rnalic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid,
and
25 b) acid salts of organic and inorganic bases containing cations selected from the
12rouo consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic
54. A compound of claim 39 which is a phannaceutically acceptable salt of a compound

-
of formula I selected from the group consisting of
107
&--
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a) basic salts of organic acids and inorganic ,acids select_ed from the group

acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid.
5 trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic _acid,
furnaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid;
and
55. A pharmaceutical composition comprising a compound of claim 1 or a

pharmaceutically acceptable salt of a compound of formula I , and a physiologically
acceptable canier.
56. A pharmaceutical composition comprising a compound of claim 2 consistent

15 with fonnula I or a phannaceutically acceptable salt thereof, and a physiologically
acceptable carrier.
57. A pharmacd1tical composition comprising a compound of claim 33 consistent

with formula I or a pharmaceutically acceptable salt thereof, and a physiologically
acceptable carrier.
20 58. A pharmaceutical composition comprising a compound of claim 38 consistent

acceptable carrier.

with formula I or a pharmaceutically acceptable salt thereof and a physiologically
25 acceptable carrier.
60. A compound selected from the group consisting of
3-tert butyl phenyl ureas of Table I above;
5-tert butyl-2-methoxyphenyl ureas of Table 2 above;
108
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5-(trif1uoromethyl)-2 phenyl ureas of Table 3 above;
3-(trifluoromethyl) -4 chiorophenyl ureas of Table 4 above;
3-(trifluoromethyl)-4-bromophenyl ureas of Table 5 above;
5-(trifluoromethyl)-4-chloro-2 methoxyphenyl ureas of Table 6 above; and
5 ureas 101-103 in Table 7 above.
the 3-tert butyl phenyl ureas:

N-(3-tert-butylphenyl)-N '-(4-(3-(N-methylcarbamoyl)phenoxy)phenyl urea and
N-(3-cert-butylphenyl)-N'-( 4-( 4-acetylphenoxy)phenyl urea;
10
the 5-tert-butyl-2-methoxyphenyl ureas:

N-( 5-tert-butyl-2-methoxyphenyl)-N' -(4-( 1,3-dioxoisoindolin-5 ~ y loxy)phenyl) urea,
N-(5-tert-butyl-2-methoxyphenyl)-N'-( 4-( l -oxoisoindolin-5,yloxy)phenyl) urea,
N-( 5-tert-butyl-2-methoxyphenyl)-N '-{4-( 4-methoxy-3-(N-
l5 mechylcarbamoyl)phenoxy)phenyl) urea and
N-( 5-terr-butyl-2-methoxyphenyl)-N'-( 4-(3-(N-methylcarbarnoy l)phenoxy)phenyl) urea;
the 2-methoxy-5-tri fluoromethyl)phenyl ureas:

N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyJ-4-pyridyloxy)phenyl) urea,
20 N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(3-(2-{N-methylcarbamoyl)-4-
N-(2-methoxy-5-( tri fluoromethyl)phenyl)-N'-( 4-(2-carbamoyt-4-pyridyloxy)phenyl) urea,
N-(2-methoxy-5-( tri tluoromethyl)phenyl)-N '-( 4-(2-(N-methylcarbamoyl)-4-
25 N-(2-methoxy-5-( tri fluoromethyl)phenyl)-N '-( 4-(2-(N-rnethylcarbamoyl)-4-
pyridy lthio )pheny I) urea,
N-( 2-methoxy-5-(tri fluoromethyl)phenyl)-N '-(2-chloro-4-(2-{N-methylcarbamoyl)( 4-
pyridylox y))phenyl) urea and
109
z!E_---
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N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-
pyridyloxy))phenyl) urea;

5 N-( 4-chloro-3-{trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxy)phenyl) urea,
N-( 4-chloro-3-( trifluoromethy l)phenyl)-N '-( 3-(2-(N-rnethylcarbarnoy l)-4-pyridylox y )phenyl)
urea,
N-( 4-chloro-3-(trifluoromethyl)phenyl)-N '-( 4-(2-carbamoyl-4-pyridyloxy)phenyl) urea and
N-( 4-chloro-3-(trifluoromethyl)phenyl)-N'-( 4-(2-(.N-methylcarbarnoyl)-4-pyridyloxy)phenyl)
10 urea.
the 4-romo-3-(trifluoromethyl)phenyl ureas:

N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phen~·I)
urea,
15 N-(4-bromo-3-{trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)
urea,
·N-( 4-bromo-3-(trifluorornethyl)phenyl)-N '-(3-(2-(N-methylcarbarnoyl)-4-pyridylthio )pheny I)
urea,
N-( 4-bromo-3-(trifluoromethyl)phenyl)-N '-(2-chloro-4-(2-(N-methylcarbamoyl)( 4-
20 pyridy1oxy))phenyl) urea and

N-(4-brom0-3-( tri fluoromethy l)phen y 1)-N'-( 3-chloro-4-(2-(N-meth y lcarbamoy I)(4-
pyrid y lo xy) )phenyl) urea; and
the 2-methoxy-4-chloro-S-( trifluoromethyl)phenyl ureas:

25 N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-
N-(2-methoxy-4-chloro-5-( trifl uoromethy l)pheny 1)-N'-(4-(2-(N-meth y lcarbamoy I)-4-
pyrid y lox y )phenyl) urea,
N-(2-methoxy-4-chloro-5-(tri fluoromethy I)phenyl)-N •-(2-chloro-4-(2-(N-
30 methylcarbarnoyl)(4-pyridyloxy))phenyl) urea and
N-( 2 -methox y-4-ch loro-5-( tri f1uoromethyl )phenyl )-N '-(3-chloro-4-{ 2-( N-
meth y lcarbamoy I)(4-pyridyloxy))phenyl) urea.
110
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62. A method for the treatment of a cancerous cell growth mediated by raf kinase.
comprising administering a compound of Formula I of claim 1.
63. A method for the treatment of a cancerous cell growth mediated by raf kinase,
5 comprising administering a compound of Formula I of claim 33.
comprising administering a compound offonnula I of claim 38.
lO 66. A method for the treatment of a cancerous cell growth mediated by raf kinase,
comprising administrating a compound selected from the group consisting of
3-tert butyl phenyl ureas of Tao le I above;
5-(trifluoromethyl)-2 phenyl ureas of Table 3 above;
15 3-(trifluoromethyl)-4 chlorophenyl ureas of Table 4 above;
5-(trifluorornethyl)-4-chloro-2 methoxyphenyl _ureas of Table 6 above; and
ureas 101-103 in Table 7 above.
20 comprising administrating a compound selected from the group consisting of
N-(3-tert-butylphenyl)-N'-( 4-(3-(N-methy1carbamoyl)phenoxy)phenyl urea and
N-(3-tert-butyiphenyl)-N '-(4-( 4-acetylphenoxy)phenyl urea;
25 the 5-ren-buty!-2-methoxyphenyl ureas:

.V-( 5-terr-butyl-2-methoxyphen yl)-N '-(4-( 1,3-dioxoisoindo lin-5-yloxy)pheny I) urea.
N-( 5-terr-butyl-2-methoxyphenyl)-N '-(4-( l-oxoisoindolin-5-yloxy)phenyl) urea.
111
-&.--
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N-( 5-rert-butyl-2-methoxyphenyl)-N '-(4-( 4-methoxy-3-(N-

methylcarbamoyl)phenoxy)phenyl) urea and
N-( 5-rert-butyl-2-methoxyphenyl)-N '-(4-(3-(N-methylcarbarnoyl )phenoxy )phenyl) urea;
5 the 2-methoxy-5-trif1uoromethyl)phenyl ureas:

N-(2-methox y-5-( trifluoromethy l)phenyl )-N •-(3-(2-carbamoy l-4-pyridy loxy)phenyl) urea,
N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-
pyridyloxy)phenyl) t,lrea,
N-( 2-methoxy-5-( tri tluoromethy I)pheny I)-N '-(4-(2-carbamoy 1-4-pyrid ylox y)phen y 1) urea,
1o N-(2-methoxy-5-(trifluoromethyl)phenyl)-N '-(4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)phenyl) l)rea,
N-(2-methoxy-5-(tritluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-
pyridylthio)phenyl) 1.1rea,
15 N-(2-methoxy-5~(trifluorornethyl)phenyl)-N '-(2-chloro-4-(2-(N-methylcarbamoyl)( 4-
pyridyloxy))phenyl) urea and

N-(2-methoxy-5~(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)( 4-
20 the 4-chloro-3-(trifluoromethyl)phenyl ureas:

N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3:(2-carbamoyl-4-pyridyloxy)phenyl) urea,
N-( 4-ch1oro-3-( tri fluoromethy1)phen y1)-N'-l3-(2-l N-methyk arbamoy 1)-4-pyridyloxy )phenyl)
urea,
N-( 4-chloro-3-(trifluoromethyl)phenyl)-N'-( 4-(2-carbamoyl-4-pyridyloxy)phenyl) urea and
25 N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)pheny!)
urea;

N-(4-bromo-3-( tri f!uoromethyl)pheny 1)-N'-(3-( 2-(N-methylcarbamoy l)-4-pyridylox y)pheny 1)
30 urea .
.V-( -+-bromo-3-( tri nuoromethyl)pheny!)-N '-(4-( 2-(N-rnethylcarbamoyl)-4-pyridyloxy}phenyl)
urea,
112
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N-( 4-bromo-3-( trifl uoromethy l)phenyl)-N '-(3-(2-(N-methylcarbamoyl)-4-pyridylthio )phenyl)
urea,
/./-(4-bromo-3-( tri fluoromethyl)pheny 1)-N'-(2-chloro-4-(2-(N-methy lcarbamoyl)( 4-
pyridy loxy) )phenyl) urea and
s N-( 4-bromo-3-(tri f1uoromethyl)phenyl)-N '-{3-chioro-4-(2-(N-methylcarbamoyl)( 4-
pyridyloxy))phenyl) urea; and

/v'-(2-methoxy-4-chloro-5-(uifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-
10 pyridyioxy)phenyl) urea,
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-
N-(2-metho"Ky-4-chlmo-5-(tri fluornmethy l)pheny 1)-N•-\2-~hlorn-4-(2-(N-
methylcarbamoy l)( 4-pyridyloxy))phenyl) urea and
15 N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N '-(3-chloro-4-(2-(N-
methylcarbamoyl)( 4-pyridyloxy))phenyl) urea.
113
liTRUE COPYII
WE CLAIM:
1-11 A compound selected from the group consisting of

pyridyloxy)phenyl)urea, \..,-
pyridyloxy)phenyl)urea, ....,,,,,-
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl)-4-
pyridyloxy)phenyl)urea, L--
pyridyloxy)phenyl)urea and ~
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-N-
methylcarbamoyl)(4-pyridyloxy)phenyl)urea, ~
N-(4-bromo-3-(trifluoromethyl)pheny)-N'-(3-(2-(N-methylcarbamoyl)-4-
pyridyl thio) phenyl)urea,
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-2-(N-
methylcarbamoyl)( 4-pyridyloxy))phenyl)urea, and
N-(4-bromo-3-(trifluoromethyl))phenyl)-N'-(3-chloro-4-2-(N-
methylcarbamoyl)(4-pyridyloxy)phenyl)urea.
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-2-(N-
IITRUE corYJI
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N '-(2-chloro-4-(2-(N-
methylcarbamoyl)( 4-pyridyloxy))phenyl)urea.
2. A compound as claimed in claim 1, wherein a pharmaceutically

group consisting of hydrochloric acid hydrobromic acid, sulphuric acid,
phophoric acid, methanesulphonic acid, trifluorosulphonic acid,
sulfonic acid, 2-napthalne sulfonic acid, acetic
0--<--\'--d
acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic .add,
acid, phenylacetic acid, and mandelic acid; and

acceptable carrier.

of:
N:-{4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl-
-1,
pyridyloxy)phenyl) urea, .;
N-( 4-chloro-3-(trifluoromethyl)phenyl)-N '-(2-chloro-4-(2-(N-methylcarbamoyl)
IITRUE corYJI
N4'2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-( 4-(2-(N-
methylcarbamoyl) (4-pyridyloxy)) phenyl) urea,
5. A compound as claimed in claim 4 which is a pharmaceutically

a) basic salts of organic adds and inorganic acids selected from the
phosphoric acid, methanesulphonic acid, trifluorosulphonic acid,
sulfonic acid, 2-napthalene sulfonic acid, acetic
acid,
I
c/6. A pharmaceutical composition comprising a compound as claimed in
acceptable carrier.

of:
~)
IITRUE corYJI
pJ4dyloxy)phenyl) urea,
I-\Tidyloxy) phenyl) urea,
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)4-
N-(4-chloro-3-(trifluoromethyl)phenyl)-N-(2-chloro-4-(2-(N-
methylcarbamoyl)(4-pyridyloxy))phenyl) urea,
pyridyloxy) phenyl urea.
N-(4-bromo-3-(trrifluoromethyl)phenyl)-N'-(3-(2-(N-inethylcarbamoyl)-4-
N-(4:.bromo-3-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-
methylcarbamoyl) (4-pyridyloxy) )phenyl) urea;
the 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl u.reas:
N-(2-methoxy-4-chloro-5-(trifluoromethylphenyl)-N'-(4-(2-(N-
N-(2-methoxy- 4-chloro-5-(trifluoromethyl) phenyl)-N' -(2-chloro-4-(2-(N-

kinase.
IITRUE COPYII
of♦
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)4-
N-(4-bromo-3-{trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-
methylcarbamoyl)(4-pyridyloxy))phenyl) urea;
,...,,..,
&---
IITRUE corYJI
N-(2-methoxy-4-chloro-5-(trifluoromethyl) phenyl)-N' -(2-chloro-4-(2-(N-
-
or a pharmaceutically
medicament
acceptable
for the treatment of:
salt thereof for the manufacture of a
i) carcinoma of the lungs, pancreas, thyroid, bladder, colon,

of:
the 4-chloro-3-(trifluoromethyl)phonyl ureas:
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)4-
N-(4-bromo-3-(trifluoromethyl)phenyl)-N-(3-(2-(N-methylcarbamoyl)-4-
methylcarbamoyl) (4-pyridyloxy) )phenyl) urea· and
no
:&---
IiTRUE COPY!I
methylcarbamoyl) (4-pyridyloxy) )phenyl} urea;
methylcarbamoyl)-4-pyridyloxy}phenyl) urea,
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N' -(2-chloro-4-(2-(N-
methylcarbamoyl) (4-pyridyloxy)phenyl} urea,


of:
N-( 4-chloro-3-{ trifluoromethyl) phenyl)- N'-(4-(2- N-methylcarbamoy 1)-4-

N-{4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-
N-(4-bromo-3-(trifluoromethyl}phenyl)-N'-( 4-(2-(N-methylcarbamoyl)-4
N-(2-methoxy-4-chloro-5-( trifl uoromethyl) phenyl)- N'-(2-chloro-4-(2-(N-
methylcarbamoyl) (4-pyridyloxy))phenyl) urea.

kinase.
IITRUE COPYjl
c4
N-(4-chloro-3-(trifluoromethyl)phenyl)-N' -(4-(2-N-methylcarbamoyl)-4-
phenyl) urea,
N-(4-chloro-3-(trifluoromethyl)phanyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)
N-(4-bromo-3-(trifluoromethyl)phenyl)-N' -(4-(2-(N-methylcarbamoyl)~4

i) carcinoma of the lungs, panaeas, thyroid, bladder, colon,


of:
N-(4~chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-N-methylcarbamoyl)-4-
N-(4-chloro-3-( trifluoromethy !)phenyl)- N'-(4-(2-carbamoyl-4-
1 r.r.
&---
IiTRUE COPYjl
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4
N•-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-
methylcarbamoyl)-4-pyridyloxy)phenyl)urea,
methylcarbamoyl)(4-pyridyloxy))phenyl) urea


~~fluoromethyl)phenyl)-N' -(4-(2-carbamoyl-4-pyridyloxy)phenyl) urea.
14. A compound as claimed in claim 1 which i_s N-(4-chloro-3-

(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)
urea•✓

i:- (trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl) urea or a
pharmaceutically acceptable salt thereof and a physiologically acceptable
carrier.

ftrifluoromethyl)phenyl)-N' -(4-(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl)
urea or a pharmaceutically acceptable salt thereof and a physiologically
acceptable carrier.
17. N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-
kinase.
18. N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-
IiTRUE COPY!I
pyridyloxy)phenyl) urea or a pharmaceutical acceptable salt thereof for the
manufacture of a medicament for the treatment of a cancerous cell growth
rr•ated by raf kinase.
or
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl-4-
20. A pharmaceutically acceptable salt as claimed in claim 19 which is a

basic salt of an organic acid or an inorganic acid which is hydrochloric acid,
trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid
(tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic
acid, phenylacetic acid, or mandelic acid.
21. A pharmaceutically acceptable salt which is the tosylate salt of:
1 r'lf"\
&---
IITRUE COPYjl
--
or
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-N-methylcarbamoyl-4-
,0 ! od
o= o
Cl'(t
13
I ., ~
O
II
N~N
'"
~
I
---:::::
hN
NH/
CH
3
I I
H H
22. A pharmaceutical composition compnsmg a pharmaceutically

acceptable salt of claim 19, 20 or 21 and pharmaceutically acceptable •
earner.
Dated this 5 th day of July, 2001.
[RANJ A MEHTA-DUTT]
OF REMFRY & SAGAR
ATTORNEY FOR THE APPLICANT(S)
IITRUE COPYjl
PCT WORLD INTELLECTUALPROPERTYORGANIZATION
InternationalBureau
INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(51) International Patent Classification 7 : (11) International Publication Number: WO 00/42012
C07D 211178, 211172, A61K 31/33, Al
31/54, 31/535, 31/17, C07C 275/20, (43) International Publication Date: 20 July 2000 (20.07.00)
27 5/22, 27 5/24, 27 5/28
(21) International Application Number: PCT/US00/00648 (72) Inventors; and

(75) Inventors/Applicants (for US only): RIEDL, Bernd [DE/DE];
(22) International Filing Date: 12 January 2000 (12.01.00) Von-der-Glotz-Strasse 7, D-42329 Wuppertal (DE). DU-
MAS, Jacques [FR/US]; 821 Beechwood Road, Orange,
CT 06477 (US). KHIRE, Uday [IN/US]; 101 Tanglewood
(30) Priority Data: Drive, Hamden, CT 06518 (US). LOWINGER, Timothy,
60/115,877 13 January 1999 (13.01.99) us B. [CNJP]; # 203, 5-7, Chitose-Cho, Nishinomiya City,
09/257,266 25 February 1999 (25.02.99) us Hyogo 662-0046 (JP). SCOTT, William, J. [US/US]; 210
09/425,228 22 October 1999 (22.10.99) us Saddle Hill Drive, Guilford, CT 06437 (US). SMITH, Roger,
A. [CNUS]; 65 Winterhill Road, Madison, CT 06443 (US).
WOOD, Jill, E. [US/US]; 72 Pickwick Road, Hamden,
(63) Related by Continuation (CON) or Continuation-in-Part CT 06517 (US). MONAHAN, Mary-Katherine [US/US];
(CIP) to Earlier Applications 134 Park Avenue, Hamden, CT 06517 (US). NATERO,
us 60/115,877 (CIP) Reina [US/US]; 113 Edgecomb Street, Hamden, CT 06518
(US). RENICK, Joel [US/US]; 11 Wall Street #4, Milford,
Filed on 13 January 1999 (13.01.99)
us 09/257,266 (CIP) CT 06460 (US). SIBLEY, Robert, N. [US/US]; 1187 Mt.
Carmel Avenue, North Haven, CT 06473 (US).
Filed on 25 February 1999 (25.02.99)
us 09/425,228 (CIP)
(74) Agents: TRAVERSO, Richard, J. et al.; Millen, White, Zelano
Filed on 22 October 1999 (22.10.99)
& Branigan, P.C., Arlington Courthouse Plaza 1, Suite 1400,
2200 Clarendon Boulevard, Arlington, VA 22201 (US).
CORPORATION [US/US]; 100 Bayer Road, Pittsburgh, PA
15205 (US). (81) Designated States: AE, AL, AM, AT, AU, AZ, BA, BB, BG,
n.B~c~c~rn.cr,cuc~D~D~D~~
ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP,
KE,KG,KP,KR,KZ,LC,LK,LR,LS,LT,LU,LV,MA,
MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU,
SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG,
US, UZ, VN, YU, ZA, ZW, ARIPO patent (GH, GM, KE,
LS, MW, SD, SL, SZ, TZ, UG, ZW), Eurasian patent (AM,
AZ, BY, KG, KZ, MD, RU, TJ, TM), European patent (AT,
BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU,
MC, NL, PT, SE), OAPI patent (BF, BJ, CF, CG, CI, CM,
GA, GN, GW, ML, MR, NE, SN, TD, TG).
Published
With international search report.
Before the expiration of the time limit for amending the
claims and to be republished in the event of the receipt of
amendments.
(54) Title: w-CARBOXY ARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS
(57) Abstract
This invention relates to the use of a group of aryl ureas in treating raf mediated diseases, and pharmaceutical compositions for use
in such therapy.
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FOR THE PURPOSESOF INFORMATIONONLY
Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
AL Albania ES Spain LS Lesotho SI Slovenia

AM Armenia Fl Finland LT Lithuania SK Slovakia
AT Austria FR France LU Luxembourg SN Senegal
AU Australia GA Gabon LV Latvia sz Swaziland
AZ Azerbaijan GB United Kingdom MC Monaco TD Chad
BA Bosnia and Herzegovina GE Georgia MD Republic of Moldova TG Togo
BB Barbados GH Ghana MG Madagascar TJ Tajikistan
BE Belgium GN Guinea MK The former Yugoslav TM Turkmenistan
BF Burkina Faso GR Greece Republic of Macedonia TR Turkey
BG Bulgaria HU Hungary ML Mali TI Trinidad and Tobago
BJ Benin IE Ireland MN Mongolia UA Ukraine
BR Brazil IL Israel MR Mauritania UG Uganda
BY Belarus IS Iceland MW Malawi us United States of America
CA Canada IT Italy MX Mexico uz Uzbekistan
CF Central African Republic JP Japan NE Niger VN Viel Nam
CG Congo KE Kenya NL Netherlands YU Yugoslavia
CH Switzerland KG Kyrgyzstan NO Norway zw Zimbabwe
CI Cote d'Ivoire KP DemocraticPeople's NZ New Zealand
CM Cameroon Republic of Korea PL Poland
CN China KR Republic of Korea PT Portugal
cu Cuba KZ Kazakstan RO Romania
CZ Czech Republic LC Saini Lucia RU Russian Federation
DE Germany LI Liechtenstein SD Sudan
DK Denmark LK Sri Lanka SE Sweden
EE Estonia LR Liberia SG Singapore
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WO 00/42012 PCT /US00/00648
ro-Carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
10 Cross-Reference to Related Applications

This is a continuation-in-part of Serial No. 09/257,266. filed February 25, 1999 and a
continuation-in-part of Serial No. 60/115,877 filed January 13, 1999.

15 This invention relates to the use of a group of aryl ureas in treating raf mediated diseases, and
phannaceutical compositions for use in such therapy.
Background of the Invention

The p21ras oncogene is a major contributor to the development· and progression of human
20 solid cancers and is mutated in 30% of all human cancers (Bolton et al. Ann. Rep. Med.
Chem. 1994, 29, 165-74; Bos. Cancer Res. 1989, 49, 4682-9). In its nonnal, unmutated form,
the ras protein is a key element of the signal transduction cascade directed by growth factor
receptors in almost all tissues (Avruch et al. Trends Biochem. Sci. 1994, 19, 279-83).
Biochemically, ras is a guanine nucleotide binding protein, and cycling between a GTP-
25 bound activated and a GDP-bound resting fonn is strictly controlled by ras' endogenous
GTPase activity and other regulatory proteins. In the ras mutants in cancer cells, the
endogenous GTPase activity is alleviated and, therefore, the protein delivers constitutive
growth signals to downstream effectors such as the enzyme raf kinase. This leads to the
cancerous growth of the cells which carry these mutants (Magnuson et al. Semin. Cancer
30 Biol. 1994. 5, 247-53). It has been shown that inhibiting the effect of active ras by inhibiting
tht: rar kinase signaling path\vay by administration of deactivating antibodies to raf kinase or
by co-expression of dominant negative raf kinase or dominant negative MEK. the substrate of
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WO 00/42012 PCT /US00/00648
raf kinase, leads to the reversion of transformed cells to the normal growth phenotype (see:
Daum et al. Trends Biochem. Sci. 1994, 19, 474-80; Fridman et al. J. Biol. Chem. 1994, 269,
30105-8. Kolch et al. (Nature 1991, 349, 426-28) have further indicated that inhibition ofraf
expression by antisense RNA blocks cell proliferation in membrane-associated oncogenes.
5 Similarly, inhibition ofrafkinase (by antisense oligodeoxynucleotides) has been correlated in
vitro and in vivo with inhibition of the growth of a variety of human tumor types (Monia et
al., Nat. Med. 1996, 2, 668-75).
Summary of the Invention

10 The present invention provides compounds which are inhibitors of the enzyme raf kinase.
Since the enzyme is a downstream effector of p21 ras, the inhibitors are useful in
pharmaceutical compositions for human or veterinary use where inhibition of the raf kinase
pathway is indicated, e.g., in the treatment of tumors and/or cancerous cell growth mediated
by raf kinase. In particular, the compounds are useful in the treatment of human or animal
15 solid cancers, e.g., murine cancer, since the progression of these cancers is dependent upon
the ras protein signal transduction cascade and therefore susceptible to treatment by
interruption of the cascade, i.e., by inhibiting raf kinase. Accordingly, the compounds of the
invention are useful in treating cancers, including solid cancers, such as, for example,
carcinomas (e.g., of the lungs, pancreas, thyroid, bladder or colon), myeloid disorders (e.g.,
20 myeloid leukemia) or adenomas (e.g., villous colon adenoma).
The present invention therefore provides compounds generally described as aryl ureas,
including both aryl and heteroaryl analogues, which inhibit the raf kinase pathway. The
invention also provides a method for treating a raf mediated disease state in humans or
25 mammals. Thus, the invention is directed to compounds which inhibit the enzyme raf kinase
and also compounds, compositions and methods for the treatment of cancerous cell growth
mediated by raf kinase wherein a compound of Formula I is administered or pharmaceutically
acceptable salt thereof.
A-D-B (I)
30 In fom1UlaL Dis -NH-C(O)-NH-.
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WO 00/42012 PCT/US00/00648
A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L 1 )q , .

where L is a 5 or 6 membered cyclic structure bound directly to D, L I comprises a
substituted cyclic moiety havtng at least 5 members, M is a bridging group having at least
one atom, q is an integer of from 1-3; and each cyclic structure of L and L I contains 0-4
5 members of the group consisting of nitrogen, oxygen and sulfur, and

I
wherein L is substituted by at least one .substituent selected from the group consisting
10 of -SO2Rx, -C(O)Rx and -C(NRy) R2 ,

halo,
R2 is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally


heteroatoms selected from N, S and O ·and optionally substituted by halogen, hydroxy and

by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which
halogen; or
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WO 00/42012 PCT /US00/00648

5 S and O and are optionally substituted by halogen; or
c) one of Ra or Rb is -C(O)-, a C1-C5 divalent alkylene group or a substituted C 1-

members, wherein the substituents of the substituted C 1-C5 divalent alkylene group are
selected from the group consisting of halogen, hydroxy, and carbon based substituents of up
10 to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are
where B is substituted, L is substituted or L 1 is additionally substituted, the

substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where
n is 0-3;
15 wherein each W is independently selected from the group consisting of -CN, -CO2R7,
-C(O)NR 7R7 , -C(O)-R 7 , -NO 2, -OR 7 , -SR 7 , -NR 7R7, -NR 7C(O)OR 7 , -NR7 C(O)R 7, -Q-Ar, and
7
selected from the group consisting of -CN, -CO 2R , -C(O)R 7, -C(O)NR 7R 7 , -OR 7 , -SR 7 , -
7
20 NR 7R7, -NO2, -NR 7C(O)R 7, -NR 7C(O)OR and halogen up to per-halo; with each R7
containing heteroatoms selected from N, Sand O and optionally substituted by halogen,
7
wherein Q is -0-, -S:, -N(R )-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)mO-, -(CH2)mS-,
-(CH2)mN(R7)-, -O(CH2)m- CHXa-, -CXa2-, -S-(CH2)m- and -N(R 7)(CH2)m-, where m= 1-3,
25 and Xa is halogen; and

group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen,
up to per-halo, and optionally substituted by Zn1, wherein nl is O to 3 and each Z is
independently selected from the group consisting of -CN, -CO 2R7• -C(O)R~. -C(O)NR _R__-
7 7
30 NO2 • -OR~. - SR 7 -NR 7 R7 • -NR C(O)OR7, -NR C(O)R7. and a carbon based moiety of up to
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WO 00/42012 PCT /US00/00648
substituted by one or more substituents selected from the group consisting of -CN, -C0 2 R7 , -
7 7 7
COR7 , -C(O)NR 7 R7 , -OR7, -SR7, -N02, -NR R , -NR C(O)R7, and -NR 7 C(O)OR 7 , with R7 as
defined above.
In formula I, suitable hetaryl groups include, but are not limited to, 5-12 carbon-atom
aromatic rings or ring systems containing 1-3 rings, at least one of which is aromatic, in
which one or more, e.g., 1-4 carbon atoms in one or more of the rings can be replaced by
oxygen, nitrogen or sulfur atoms. Each ring typically has 3-7 atoms. For example, B can be
10 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl,
1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-,
4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 1,2,3-triazol- l-, -4- or -5-
yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-
oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-
15 thiadiazol-2- or -5-yl, 1,3,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5-
or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-,
6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-,
4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl,
3-, 4-, 5- 6- or 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-
20 benzisothiazolyl, 2-, 4-, 5-, 6- or 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-:-,7- or 8-quinolinyl,
1-, 3-, 4-, 5-, 6-, 7-, 8- isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-. 8-
or 9-acridinyl, or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, or additionally optionally substituted
phenyl, 2- or 3-thienyl, 1,3,4-thiadiazolyl, 3-pyrryl, 3-pyrazolyl, 2-thiazolyl or 5-thiazolyl.
etc. For example, B can be 4-methyl-phenyl, 5-methyl-2-thienyl, 4-methyl-2-thienyl, 1-
25 methyl-3-pyrryl, l-methyl-3-pyrazolyl, 5-methyl-2-thiazolyl or 5-methyl-1,2,4-thiadiazol-2-
yl.
Suitable alkyl groups and alkyl portions of groups, e.g., alkoxy, etc. throughout
include methyl, ethyl, propyl, butyl, etc., including all straight-chain and branched isomers
such as isopropyl, isobutyl, sec-butyl, tert-butyl, etc.
_10 Suitable aryl groups \vhich do not contain heteroatoms include, for example. phl?nyl
anJ 1- anJ 2-naphthyl.
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WO 00/42012 PCT /US00/00648
The term "cycloalkyl", as used herein, refers to cyclic structures with or without alkyl
substituents such that, for example, "C 4 cycloalkyl" includes methyl substituted cyclopropyl
groups as well as cyclobutyl groups. The term "cycloalkyl", as used herein also includes
saturated heterocyclic groups.
5 Suitable halogen groups include F, Cl, Br, and/or I, from one to per-substitution (i.e.
all H atoms on a group replaced by a halogen atom) being possible where an alkyl group is
substituted by halogen, mixed substitution of halogen atom types also being possible on a
given moiety.
The invention also relates to compounds per se, of formula I.
10
The present invention is also directed to pharmaceutically acceptable salts of formula I.

Suitable pharmaceutically acceptable salts are well known to those skilled in the art and
include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic
acid, sulfuric acid, phosphoric acid, -methanesulphonic acid, trifluoromethanesulfonic acid,
15 benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-
naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid,
lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid,
phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts include
acid salts of inorganic bases, such as salts containing alkaline cations (e.g., Lt Na+ or K+),
20 alkaline earth cations (e.g., Mg+ 2
, Ca+ or Ba+
2 2
), the ammonium cation, as well as acid salts

of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary
ammonium cations, such as those arising from protonation or peralkylation of triethylamine,
N,N-diethylamine, N,N-dicyclohexylamine, lysine, pyridine, N,N-dimethylaminopyridine
(DMAP), 1,4-diazabiclo(2.2.2]octane (DABCO), 1,5-diazabicyclo[ 4.3 .0]non-5-ene (DBN)
25 and 1,8-diazabicyclo[S.4.0]undec-7-ene (DBU).
A number of the compounds of Formula I possess asymmetric carbons and can therefor exist
in racemic and optically active forms. Methods of separation of enantiomeric and
diastereomeric mixtures are well known to one skilled in the art. The present invention
>0 encompasses any isolated racemic or optically active form of compounds described in
Formula I which possess raf inhibitory activity.
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General Preparative Methods
The compounds of Formula I may be prepared by the use of known chemical reactions and
procedures, some from starting materials which are commercially available. Nevertheless,
general preparative methods are provided below to aid one skilled in the art in synthesizing
5 these compounds, with more detailed examples being provided in the Experimental section
which follows.
Substituted anilines may be generated using standard methods (March. Advanced Organic
Chemistry, 3rd Ed.; John Wiley: New York (1985). Larock. Comprehensive Organic
10 Transformations; VCH Publishers: New York (1989)). As shown in Scheme I, aryl amines
are commonly synthesized by reduction of nitroaryls using a metal catalyst, such as Ni, Pd, or
Pt, and H2 or a hydride transfer agent, such as formate, cyclohexadiene, or a borohydride
(Rylander. Hydrogenation Methods; Academic Press: London, UK (1985)). Nitroaryls may
also be directly reduced using a strong hydride source, such as LiAIH4 (Seyden-Penne.
15 Reductions by the Alumina- and Borohydrides in Organic Synthesis; VCH Publishers: New
York (1991) ), or using a zero valent metal, such as Fe, Sn or Ca, often in acidic media. Many
methods exist for the synthesis of nitroaryls (March. Advanced Organic Chemistry, 3rd Ed.;
John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH
Publishers: New York (1989)).
H2 / catalyst
~ [H"]
~
20 (eg. Fe, Sn, Ca)
Scheme I Reduction of Nitroaryls to Ary) Amines
Nitroaryls are commonly formed by electrophilic aromatic nitration using HN01, or an

alternative NO~- source. Nitroaryls may be further elaborated prior to reduction. Thus.
nitroaryls substituted with
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WO 00/42012 PCT /US00/00648
Ar-H
potential leaving groups (e.g. F, Cl, Br, etc.) may undergo substitution reactions on treatment
with nucleophiles, such as thiolate (exemplified in Scheme II) or phenoxide. Nitroaryls may
also undergo Ullman-type coupling reactions (Scheme II).
02N ~
'---;(D-" Br-Ar
(' ' SH
R./\- CuO / base
5 3
Scheme II Selected Nucleophilic Aromatic Substitution using Nitroaryls
Nitroaryls may also undergo transition metal mediated cross coupling reactions. For
example, nitroaryl electrophiles, such as nitroaryl bromides, iodides or triflates, undergo
palladium mediated cross coupling reactions with aryl nucleophiles, such as arylboronic acids
10 (Suzuki reactions, exemplified below), aryltins (Stille reactions) or arylzincs (Negishi
reaction) to afford the biaryl (5).
ArB(OR')2
Pd(O)
Either nitroaryls or anilines may be converted into the corresponding arenesulfonyl chloride
(7) on treatment with chlorosulfonic acid. Reaction of the sulfonyl chloride with a fluoride
15 source, such as KF then affords sulfonyl fluoride (8). Reaction of sulfonyl fluoride 8 with
trimethylsi lyl trifluoromethane in the presence of a fluoride source, such as
tris( dimethylamino )sulfonium difluorotrimethylsiliconate (T ASF) leads to the corresponding
trifluoromethylsulfone (9). Alternatively, sulfonyl chloride 7 may be reduced to the
arenethiol (10). for example with zinc amalgum. Reaction of thiol 10 with CHCIF~ in the
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presence of base gives the difluoromethyl mercaptarn (11), which may be oxidized to the •
sulfone (12) with any of a variety of oxidants, including Cr03-acetic anhydride (Sedova et al.
Zh. Org. Khim. 1910, 6, (568).
0-R
6
10
l f~~IF2
(§HF:
9 11
~ [0]
5 Scheme III Selected Methods of Fluorinated Aryl Sulfone Synthesis
As shown in Scheme IV, non-symmetrical urea fonnation may involve reaction of an aryl
isocyanate (14) with an aryl amine (13). The heteroaryl isocyanate may be synthesized from
a heteroaryl amine by treatment with phosgene or a phosgene equivalent, such as
trichloromethyl chlorofonnate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), or
10 N,N'-carbonyldiimidazole (CDI). The isocyanate may also be derived from a heterocyclic
carboxylic acid derivative, such as an ester, an acid halide or an anhydride by a Curtius-type
rearrangement. Thus, reaction of acid derivative J6 with an azide source. followed by
rearrangement affords the isocyanate. The corresponding carboxylic acid ( t 7) may also be
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WO 00/42012 PCT /US00/00648
subjected to Curtius-type rearrangements using diphenylphosphoryl azide (DPP A) or a

similar reagent.
Ar1-NH2 13
i coc,,
H2 N-Ar2
Ar 1-NCO )Ill
14
N,1 \DPPA
0 0
Ar 1)lX Ar 1)lOH
16 17
Scheme IV Selected Methods of Non-Symmetrical Urea Formation
s Finally, ureas may be further manipulated using methods familiar to those skilled in the an.
The invention also includes pharmaceutical compositions including a compound of Formula

I, and a physiologically acceptable carrier.
10 The compounds may be administered orally, topically, parenterally, by inhalation or spray or

rectally in dosage unit formulations. The term 'administration by injection' includes
intravenous, intramuscular, subcutaneous and parenteral injections, as well as use of infusion
techniques. One or. more compounds may be present in association with one or more non-
toxic pharmaceutically acceptable carriers and if desired other active ingredients.
15
Compositions intended for oral use may be prepared according to any suitable method known
to the art for the manufacture of pharmaceutical compositions. Such compositions may
contain one or more agents selected from the group consisting of diluents, sweetening agents.
navoring agents. coloring agents and preserving agents in order to provide palatable
~o preparations. Tablets contain the active ingredient in admixture with non-toxic
phamiaceutically acceptable excipients which are suitable for the manufacture of tahkts.
These c:xcipients may be. for e:xample, inert diluents, such as calcium carbonate. sotlium
10
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carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating

agents, for example, com starch, or alginic acid; and binding agents, for example magnesium
stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known
techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby
5 provide a sustained action over a longer period. For example, a time delay material such as
glyceryl monostearate or glyceryl distearate may be employed. These compounds may also
be prepared in solid, rapidly released form.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active
10 ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with
water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for
15 the manufacture of aqueous suspensions. Such excipients are suspending agents, for example
sodium carboxyrnethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium
alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents
may be a naturally occurring phosphatide, for example, lecithin, or condensation products or
an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation
20 products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene
oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty
acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of
ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for
example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one
25 or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more
coloring agents, one or more flavoring agents, and one or more sweetening agents, such as
sucrose or saccharin.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the
_,o addition of water provide the active ingredient in admixture with a dispersing or wetting
agent. suspending agent and one or more preservatives. Suitable dispersing or wetting agents
11
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WO 00/42012 PCT /US00/00648
and suspending agents are exemplified by those already mentioned above. Additional •
excipients, for example, sweetening, flavoring and coloring agents, may also be present.
The compounds may also be in the form of non-aqueous liquid formulations, e.g., oily
5 suspensions which may be formulated by suspending the active ingredients in a vegetable oil,
for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard
paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring
agents may be added to provide palatable oral preparations. These compositions may be
Io preserved by the addition of an anti-oxidant such as ascorbic acid.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water

emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a
mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents
15 may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-
occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation
products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan
monooleate. The emulsions may also contain sweetening and flavoring agents.
20
Syrups and elixirs may be formulated with sweetening agents, for example glycerol,
propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a
preservative and flavoring and coloring agents.
25 The compounds may also be administered in the form of suppositories for rectal
administration of the drug. Thes·e compositions can be prepared by mixing the drug with a
suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal
temperature and will therefore melt in the rectum to release the drug. Such materials include
cocoa butter and polyethylene glycols.
For all regimens of use disclosed herein for compounds of Formula L the daily oral Josagl.?
regimen will preferably be from 0.0 I to 200 mg/Kg of total body weight. The Jail;-, Josagl.?
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for administration by injection, including intravenous, intramuscular, subcutaneous and·

parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200
mg/Kg of total body weight. The daily rectal dosage regime will preferably be from 0.01 to
200 mg/Kg of total body weight. The daily topical dosage regime will preferably be from 0.1
5 to 200 mg administered between one to four times daily. The daily inhalation dosage regime
will preferably be from 0.01 to 10 mg/Kg of total body weight.
It will be appreciated by those skilled in the art that the particular method of administration
will depend on a variety of factors, all of which are considered routinely when administering
10 therapeutics. It will also be appreciated by one skilled in the art that the specific dose level
for a given patient depends on a variety of factors, including specific activity of the
compound administered, age, body weight, health, sex, diet, time and route of administration,
rate of excretion, etc. It will be further appreciated by one skilled in the art that the optimal
course of treatment, ie., the mode of treatment and the daily number of doses of a compound
15 of Formula I or a pharmaceutically acceptable salt thereof given for a defined number of
days, can be ascertained by those skilled in the art using conventional treatment tests.
It will be understood, however, that the specific dose level for any particular patient will
depend upon a variety of factors, including the activity of the specffic compound employed,
20 the age, body weight, general health, sex, diet, time of administration, route of administration,
and rate of excretion, drug combination and the severity of the condition undergoing therapy.
The entire enclosure of all applications, patents and publications cited above and below are
hereby incorporated by reference, including provisional application Serial No. 60/1 I 5,877,
25 filed January 13, 1999 and non-provisional application Serial No. 09/257,266 filed February
25, 1999.
The compounds can be produced from known compounds (or from starting materials which,
in tum, can be produced from known compounds), e.g., through the general preparative
:,o methods shown below. The activity of a given compound to inhibit raf kinase can be
routinely assayed. e.g .. according to procedures disclosed below. The following examples
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are for illustrative purposes only and are not intended, nor should they be construed to limit •
the invention in any way.
EXAMPLES
5 All reactions were performed m flame-dried or oven-dried glassware under a pos1t1ve
pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise
indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and
introduced into reaction vessels through rubber septa. Unless otherwise stated, the term
'concentration under reduced pressure' refers to use of a Buchi rotary evaporator at
10 approximately 15 mmHg. Unless otherwise stated, the term 'under high vacuum' refers to a
vacuum of 0.4 - 1.0 mmHg.
All temperatures are- reported uncorrected in degrees Celsius (0 C). Unless otherwise
indicated, all parts and percentages are by weight.
15
Commercial grade reagents and solvents were used without further purification. N-
cyclohexyl-N'-(methylpolystyrene )carbodiimide was purchased from Calbiochem-
(trifluoromethyl)aniline, 4-chloro-3-( trifluoromethy l)aniline 2-methox y-5-
20 (trifluoromethyl)aniline, 4-tert-butyl-2-nitroaniline, 3-amino-2-naphthol, ethyl 4-
isocyanatobenzoate, N-acetyl-4-chloro-2-methoxy-5-(trifluoromethyl)aniline and 4-chloro-3-
(trifluoromethyl)phenyl isocyanate were purchased and used without further purification.
i
Syntheses of 3-amino-2-methoxyquinoline (E. Cho et al. WO 98/00402; A. Cordi et al. EP
542,609; IBID Bioorg. Med. Chem.. 3, 1995, 129), 4-(3-carbamoylphenoxy)-1-nitrobenzene
25 (K. Ikawa Yakugaku Zasshi 79, 1959, 760; Chem. Abstr. 53, 1959, 12761b), 3-tert-
butylphenyl isocyanate (0. Rohr et al. DE 2,436,108) and 2-methoxy-5-
(trifluoromethyl)phenyl isocyanate (K. Inukai et al. JP 42,025,067; IBID Kogyo Kagaku
Zasshi 70, 1967, 491) have previously been described.
30 Thin-layer chromatography (TLC) was performed using Whatman! pre-coated glass-backed

silica gel 60A F-254 250 µm plates. Visualization of plates was effected by one or more or
the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor. (c)
14
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immersion of the plate in a I 0% solution of phosphomolybdic acid in ethanol followed by

heating, (d) immersion of the plate in a cerium sulfate solution followed by heating, and/or
(e) immersion of the plate in an acidic ethanol solution of 2,4.:dinitrophenylhydrazine
followed by heating. Column chromatography (flash chromatography) was performed using
5 230-400 mesh EM Science® silica gel.
Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or a
Mettler FP66 automated melting point apparatus and are uncorrected. Fourier transfonn
infrared spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer.
10 Proton (1H) nuclear magnetic resonance (NMR) spectra were measured with a General
Electric GN-Omega 300 (300 MHz) spectrometer with either Me 4 Si (8 0.00) or residual
protonated solvent (CHC13 8 7.26; MeOH 8 3.30; DMSO 8 2.49) as standard. Carbon ( 13C)
NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer
with solvent (CDCl3 8 77.0; MeOD-d3; 8 49.0; DMSO-d6 8 39.5) as standard. Low resolution
15 mass spectra (MS) and high resolution mass spectra (HRMS) were either obtained as electron
impact (EI) mass spectra or as fast atom bombardment (F AB) mass spectra. Electron impact
mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer
equipped with a Vacumetrics Desorption Chemical Ionization Probe for sample introduction.
The ion source was maintained at 250 °C. Electron impact ionization was performed with
20 electron energy of 70 eV and a trap current of 300 µA. Liquid-cesium secondary ion mass
spectra (FAB-MS), an updated version of fast atom bombardment were obtained using a
Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained
using a Hewlett Packard MS-Engine (5989A) with methane or ammonia as the reagent gas
( 1x10-4 torr to 2.5x 10-4torr). The direct insertion desorption chemical ionization (DCI) probe
25 (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at 10 amps until all
traces of the sample disappeared ( ~ 1-2 min). Spectra were scanned from 50-800 amu at 2
sec per scan. HPLC - electrospray mass spectra (HPLC ES-MS) were obtained using a
Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength
detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with elcctrospray
30 ionization. Spectra were scanned from 120-800 amu using a variable ion time accorJin~ to
the number of ions in the source. Gas chromatography - ion selective mass spectra (GC-\lS1
15
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were obtained with a Hewlett Packard 5890 gas chromatograph equipped with an HP-1
methyl silicone column (0.33 mM coating; 25 m x 0.2 mm) and a Hewlett Packard 5971
Mass Selective Detector (ionization energy 70 eV). Elemental analyses are conducted by
5
All compounds displayed NMR spectra, LRMS and either elemental analysis or HRMS
consistent with assigned structures.

10 AcOH acetic acid
anh anhydrous
atm atmosphere(s)
BOC tert-butoxycarbonyl
15 cone concentrated
d day(s)
dee decomposition
DMPU 1,3-dimethy 1-3,4,5 ,6-tetrahydro-2( I H)-pyrimidinone
20 DMF N,N-dimethylformamide
EDCI 1-(3-dimethylaminopropy l)-3-ethylcarbodiimide
EtOAc ethyl acetate
25 EtOH ethanol (100%)
Et2O diethyl ether
Et3N triethylamine
h hour(s)
30 111-CPBA 3-chloroperoxybenzoic acid
MeOH methanol
pet. ether petroleum ether (boiling range 30-60 °C)
16
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temp. temperature
THF tetrahydrofuran
TF A trifluoroAcOH
Tf trifluoromethanesulfonyt
5

Carbamate Deprotection. Synthesis of 2-Amino-3-metboxynaphtbalene.
~co,Me
OMe
Step 1. Methyl 3-methoxy-2-naphthoate

A slurry of methyl 3-hydroxy-2-naphthoate (I 0.1 g, 50.1 mmol) and K2CO 3 (7.96 g, 57.6
mmol) in DMF (200 mL) was stirred at room temp. for 15 min., then treated with
iodomethane (3.43 n'lL, 55.1 mmol). The mixture was allowed to stir at room temp.
15 overnight, then was treated with water (200 mL). The resulting mixture was extracted with
EtOAc (2 x 200 mL). The combined organic layers were washed with a saturated NaCl
solution (100 mL), dried (MgSO4), concentrated under reduced pressure (approximately 0.4
mmHg overnight) to give methyl 3-methoxy-2-naphthoate as an amber oil (10.30 g): 1H-
NMR (DMSO-d 6) 8 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, J=8.09 Hz, lH), 7.44 (s, 1H), 7.53
20 (app t, 1=8.09 Hz, lH), 7.84 (d, 1=8.09 Hz, lH), 7.90 (s, lH), 8.21 {s, lH).
~co,H
OMe
Step 2. 3-Methoxy-2-naphthoic acid

A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 ml) in
MeOH ( 100 mL) at room temp. was treated with a I N NaOH solution (33.4 ml. 33.-l mmol ).
25 The mixture was heated at the reflux temp. for 3 h, cooled to room temp .. and maJ~ ac1d1C
\Vith a I 0% citric acid solution. The resulting solution was extracted with EtO ..\c (2 , 11111
17
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mL). The combined organic layers were washed with a saturated NaCl solution, dried .
(MgSO4 ) and concentrated under reduced pressure. The residue was triturated with hexane
then washed several times with hexane to give 3-methoxy-2-naphthoic acid as a white solid
(5.40 g, 92%): 1H-NMR (DMSO-d6) o 3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, lH),
s 7.83 (d, 1=8.09 Hz, lH), 7.91 (d, J=8.09 Hz, IH), 8.19 (s, lH), 12.83 (br s, lH).
Step 3. 2-(N-(Carbobenzyloxy)amino-3-methoxynaphthalene
A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and Et3N (2.59 mL, 18.6
mmol) in anh toluene·(70 mL) was stirred at room temp. for 15 min., then treated with a
IO solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 mL) via pipette. The resulting mixture
was heated at 80 °C for 2 h. After cooling the mixture to room temp., benzyl alcohol (2.06
mL, 20 mmol)was added via syringe. The mixture was then warmed to 80 °C overnight. The
resulting mixture was cooled to room temp., quenched with a 10% citric acid solution, and
extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a
15 saturated NaCl solution, dried (MgSO4) and concentrated under reduced pressure. The
residue was purified by column chromatography (14% EtOAc/86% hexane) to give 2-(N-
(carbobenzyloxy)amino-3-methoxynaphthalene as a pale yellow oil (5.1 g, 100%): 1H-NMR
(DMSO-d6) o3.89 (s, 3H), 5.17 (s, 2H), 7.27-7.44 (m, 8H), 7.72-7.75 (m, 2H), 8.20 (s, lH),
8.76 (s, lH).
~NH,
20 OMe
Step 4. 2-Amino-3-methoxynaphthalene
A slurry of 2-(N-( carbobenzyloxy)amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and I 0%
Pd/C (0.5 g) in EtOAc (70 mL) was maintained under a H2 atm (balloon) at room temp.
overnight. The resulting mixture was filtered through Celite:& and concentrated under
25 reduced pressure to gi,·e 2-amino-3-methoxynaphthalene as a pale pink powder (2.40 g.
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1
85%): H-NMR (DMSO-d6) o 3.86 (s, 3H), 6.86 (s, 2H), 7.04-7.16 (m, 2H), 7.43 (d, J=8.0
Hz, lH), 7.56 (d, J=8.0 Hz, lH); EI-MS mlz 173 (M+).
A2. Synthesis of co-Carbamyl Anilines via Formation of a Carbamylpyridine

5 Followed by Nucleophilic Coupling with an Aryl Amine. Synthesis of 4-
(2-N-Methylcarbamyl-4-pyridyloxy)aniline
0
Cl~NHMe
~~
Step la. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide via the Menisci
reaction
10 Caution: this is a highly hazardous, potentially explosive reaction. To a stirring solution of
4-chloropyridine (10.0 g) in N-methylformamide (250 mL) at room temp. was added cone.
H2SO4 (3.55 mL) to generate an exotherm. To this mixture was added H2O2 (30% wt in H2O,
17 mL) followed by FeSO4 •7H2O (0.56 g) to generate another exotherm. The resulting
mixture was stirred in the dark at room temp. for 1 h, then warmed slowly over 4 h to 45 °C.
15 When bubbling had subsided, the reaction was heated at 60 °C for 16 h. The resulting
opaque brown solution was diluted with H2O (700 mL) followed by a 10% NaOH solution
(250 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The organic
phases were washed separately with a saturated NaCl solution (3 x-150 mL), then they were
combined, dried (MgSO4) and filtered through a pad of silica gel with the aid of EtOAc. The
20 resulting brown oil was purified by column chromatography (gradient from 50% EtOAc/50%
hexan~ to 80% EtOAc/20% hexane). The resulting yellow oil crystallized at O °C over 72 h to
give 4-chloro-N-methyl-2-pyridinecarboxamide (0.61 g, 5.3%): TLC (50% EtOAc/50%
hexane) R1 0.50; 1H NMR (CDCb) o 3.04 (d, J=5.l Hz, 3H), 7.43 (dd, 1=5.4, 2.4 Hz, lH),
7.96 (br s, lH), 8.21 (s, lH), 8.44 (d, J=5. I Hz, 1 H); CI-MS mlz 171 ((M+Hf).
25
0
Cl~CI
~~ HCI
Step 1b. Synthesis of 4-chloropyridine-2-carbonyl chloride HCI salt via picolinic

acid
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Anhydrous DMF (6.0 mL) was slowly added to SOCh (180 mL) between 40° and 50 °C.
The solution was stirred in that temperature range for 10 min. then picolinic acid (60.0 g, 487
mmol) was added in portions over 30 min. The resulting solution was heated at 72 °C
(vigorous SO2 evolution) for 16 h to generate a yellow solid precipitate. The resulting
5 mixture was cooled to room temp., diluted with toluene (500 mL) and concentrated to 200
mL. The toluene addition/concentration process was repeated twice. The resulting nearly
dry residue was filtered and the solids were washed with toluene (2 x 200 mL) and dried
under high vacuum for 4 h to afford 4-chloropyridine-2-carbonyl chloride HCl salt as a
yellow-orange solid (92.0 g, 89%).
Clti:O
I~ OMe
/4 N HCI
Step 2. Synthesis of methyl 4-chloropyridine-2-carboxylate HCI salt

Anh DMF (10.0 mL) was slowly added to SOCli (300 mL) at 40-48 °C. The solution was
stirred at that temp. range for 10 min., then picolinic acid (100 g, 812 mmol) was added over
30 min. The resulting solution was heated at 72 °C (vigorous SO2 evolution) for 16 h to
15 generate a yellow solid. The resulting mixture was cooled to room temp., diluted with
toluene (500 mL) and concentrated to 200 mL. The toluene addition/concentration process
was repeated twice. The resulting nearly dry residue was filtered, and the solids were washed
with toluene (50 mL) and dried under high vacuum for 4 hours to afford 4-chloropyridine-2-
carbonyl chloride HCl salt as an off-white solid (27.2 g, 16%). This material was set aside.
20
The red filtrate was added to MeOH (200 mL) at a rate which kept the internal temperature
below 55 °C. The contents were stirred at room temp. for 45 min., cooled to 5 °C and treated
with Et2O (200 mL) dropwise. The resulting solids were filtered, washed with Et2O (200
mL) and dried under reduced pressure at 35 °C to provide methyl 4-chloropyridine-2-
25 carboxylate HCI salt as a white solid (110 g, 65%): mp 108-112 °C; 1H-NMR (DMSO-d6) 8
3.88 (s, 3H); 7.82 (dd, 1=5.5, 2.2 Hz, lH); 8.08 (d, 1=2.2 Hz, lH); 8.68 (d, 1=5.5 Hz, I H);
I0.68 (br s, 1H); HPLC ES-MS mlz 172 ((M+Ht).
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c,yvNHMe
~~
Step 3a. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from methyl 4-
cbloropyridine-2-carboxylate
A suspension of methyl 4-chloropyridine-2-carboxylate HCl salt (89.0 g, 428 mmol) in
5 MeOH (75 mL) at O °C was treated with a 2.0 M methylamine solution in THF (1 L) at a rate
which kept the internal temp. below 5 °C. The resulting mixture was stored at 3 °C for 5 h,
then concentrated under reduced pressure. The resulting solids were suspended in EtOAc ( 1
L) and filtered. The filtrate was washed with a saturated NaCl solution (500 mL), dried
(Na2SO4 ) and concentrated under reduced pressure to afford 4-chloro-N-methyl-2-
10 pyridinecarboxamide as pale-yellow crystals (71.2 g, 97%): mp 41-43 °C; 1H-NMR (DMSO-
d6 ) 8 2.81 (s, 3H), 7.74 (dd, J=5.l, 2.2 Hz, lH), 8.00 (d, J=2.2, lH), 8.61 (d, J=5.1 Hz, lH),
8.85 (br d, IH); CI-MS m/z 171 ((M+Ht).
Citro
I ~ NHMe
✓-:
N

15 chloropyridine-2-carbonyl chloride
4-Chloropyridine-2-carbonyl chloride HCl salt (7.0 g, 32.95 mmol) was added in portions to
a mixture of a 2.0 M methylamine solution in THF (100 mL) and MeOH (20 mL) at O 0 C.
The resulting mixture was stored at 3 °C for 4 h, then concentrated under reduced pressure.
The resulting nearly dry solids were suspended in EtOAc (100 mL) and filtered. The filtrate
20 was washed with a saturated NaCl solution (2 x 100 mL), dried (Na 2 SO4 ) and concentrated
under reduced pressure to provide 4-chloro-N-methyl-2-pyridinecarboxamide as a yellow,
crystalline solid (4.95 g, 88%): mp 37-40 °C.
Step 4. Synthesis of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline

25 A ~olution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. DMF ( 150 ml) was treated with
potassium tert-butoxide ( 10.29 g, 9 I. 7 mmol), and the reddish-brown mixture was stirred at
21
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room temp. for 2 h. The contents were treated with 4-chloro-N-methyl-2-

pyridinecarboxamide (15.0 g, 87.9 mmol) and K2CO3(6.50 g, 47.0 mmol) and then heated at
80 °C for 8 h. The mixture was cooled to room temp. and separated between EtOAc (500
mL) and a saturated NaCl solution (500 mL). The aqueous phase was back-extracted with
5 EtOAc (300 mL). The combined organic layers were washed with a saturated NaCl solution
(4 x 1000 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting solids
were dried under reduced pressure at 35 °C for 3 h to afford 4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)aniline as a light-brown solid 17.9 g, 84%): 1H-NMR (DMSO-d 6) 8 2.77 (d, 1=4.8
Hz, 3H), 5.17 (hrs, 2H), 6.64, 6.86 (AA'BB' quartet, 1=8.4 Hz, 4H), 7.06 (dd, 1=5.5, 2.5 Hz,
10 IH), 7.33 (d, 1=2.5 Hz, lH), 8.44 (d, 1=5.5 Hz, IH), 8.73 (hr d, lH); HPLC ES-MS mlz 244
((M+Hf).
A3. General Method for the Synthesis of Anilines by Nucleophilic Aromatic
Addition Followed by Nitroarene Reduction. Synthesis of 5-(4-
Aminophenoxy)isoindoline-1,3-dione
15
HO~NH
0
Step 1. Synthesis of 5-hydroxyisoindoline-1,3-dione
To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in cone. AcOH (25 mL) was
slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated
20 at 120 °C for 45 min., then the clear, bright yellow mixture was heated at 160 °C for 2 h. The
resulting mixture was maintained at 160 °C and was concentrated to approximately 15 mL,
then was cooled to room temp. and adjusted pH 10 with a IN NaOH solution. This mixture
was cooled to O °C and slowly acidified to pH 5 using a IN HCl solution. The resultant
precipitate was collected by filtration and dried under reduced pressure to yield 5-
1
25 hydroxyisoindoline-1,3-dione as a pale yellow powder as product (3.24 g, 72%): H NMR
(DMSO-d6) 8 7.00-7.03 (m, 2H), 7.56 (d,J=9.3Hz, lH).
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Step 2. Synthesis of 5-(4-nitrophenoxy)isoindoline-l,3-dione

To a stirring slurry ofNaH (1. 1 g, 44.9 mmol) in DMF (40 mL) at O°C was added a solution
of 5-hydroxyisoindoline-1,3-dione (3.2 g, 19.6 mmol) in DMF (40 mL) dropwise. The bright
5 yellow-green mixture was allowed to return to room temp. and was stirred for 1 h, then 1-
fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added via syringe in 3-4 portions. The
resulting mixture was heated at 70 °C overnight, then cooled to room temp. and diluted
slowly with water (150 mL), and extracted with EtOAc (2 x 100 mL). The combined organic
layers were dried (MgSO4) and concentrated under reduced pressure to give 5-(4-
10 nitrophenoxy)isoindoline-1,3-dione as a yellow solid (3.3 g, 62%): TLC (30% EtOAc/70%
hexane) R10.28; IH NMR (DMSO-d6) o 7.32 (d, J=12 Hz, 2H), 7.52-7.57 (m, 2H), 7.89(d,
1=7.8 Hz, lH), 8.29 (d, J=9 Hz, 2H), 11.43 (br s, lH); CI-MS mlz 285 ((M+H)\ 100%).
H,NOOU 0
J-t
0

15 A solution of 5-(4-nitrophenoxy)isoindoline-1,3-dione (0.6 g, 2.11 mmol) in cone. AcOH ( 12
mL) and water (0.1 mL) was stirred under stream of argon while iron powder (0.59 g, 55.9
mmol) was added slowly. This mixture stirred at room temp. for 72 h, then was diluted with
water (25 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were
dried (MgSO4) and concentrated under reduced pressure to give 5-(4-
20 aminophenoxy)isoindoline-1,3-dione as a brownish solid (0.4 g, 75%): TLC (50%
EtOAc/50% hexane) R1 0.27; 1H NMR (DMSO-d6) 8 5.14 (br s, 2H), 6.62 (d, J=8.7 Hz, 2H),
6.84 (d, J=8.7 Hz, 2H), 7.03 (d, J=2.1 Hz, lH), 7.23 (dd, lH), 7.75 (d, J=8.4 Hz, lH), 11.02
(s, 1H); HPLC ES-MS mlz 255 ((M+H(, 100%).
15 A4. General Method for the Synthesis of Pyrrolylanilines. Synthesis of 5-tert-

Butyl-2-(2,5-dimethylpyrrolyl)aniline
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--u N
Step I. Synthesis of 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole

To a stirring solution of 2-nitro-4-tert-butylaniline (0.5 g, 2.57 mmol) in cyclohexane (10
mL) was added AcOH (O.lmL) and acetonylacetone (0.299 g, 2.63 mmol) via syringe. The
5 reaction mixture was heated at 120 °C for 72 h with azeotropic removal of volatiles. The
reaction mixture was cooled to room temp., diluted with CH2Ch (10 mL) and sequentially
washed with a lN HCl solution (15 mL), a lN NaOH solution (15 mL) and a saturated NaCl
solution (15mL), dried ( MgSQ4) and concentrated under reduced pressure. The resulting
orange-brown solids were purified via column chromatography (60 g SiO2; gradient from 6%
10 EtOAc/94% hexane to 25% EtOAc/75% hexane) to give l-(4-tert-butyl-2-nitrophenyl)-2,5-
dimethylpyrrole as an orange-yellow solid (0.34 g, 49%): TLC (15% EtOAc/85% hexane) R1
0.67; 1H NMR (CDCh) d 1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 (m, lH), 7.62
(dd, lH), 7.88 (d, J=2.4 Hz, lH); CI-MS mlz 273 ((M+H)\ 50%).
15 Step 2.
--u N
Synthesis of 5-tert--Butyl-2-(2,5-dimethylpyrrolyl)aniline
A slurry of l-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole (0.341 g, 1.25 mmol),
10%Pd/C (0.056 g) and EtOAc (50 mL) under an H2 atmosphere (balloon) was stirred for 72
h, then filtered through a pad of Celite®. The filtrate was concentrated under reduced
pressure to give 5-tert--butyl-2-(2,5-dimethylpyrrolyl)aniline as yellowish solids (0.30 g,
20 99%): TLC (10% EtOAc/90% he~ane) R10.43; 1H NMR (CDCl3) 8 1.28 (s, 9H), 1.87-1.91
(rn. 8H), 5.85 (br s, 2H), 6. 73-6.96 (rn, 3H), 7.28 (br s, l H).
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AS. General Method for the Synthesis of Anilines from Anilines by

Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline HCI Salt
0
0
('y trNHMe
H2 NY HCI
Me
5 A solution of 4-amino-3-methylphenol (5.45 g, 44.25 mmol) in dry dimethylacetamide (75

mL) was treated with potassium tert-butoxide (10.86 g, 96.77 mmol) and the black mixture
was stirred at room temp. until the flask had reached room temp. The contents were then
treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 7.52 g, 44.2
mmol) and heated at 110 °C for 8 h. The mixture was cooled to room temp. and diluted with
10 water (75 mL). The organic layer was extracted with EtOAc (5 x 100 mL). The combined
organic layers were washed with a saturated NaCl solution (200 mL), dried (MgSO 4 ) and
concentrated under reduced pressure. The residual black oil was treated with Et2O (50 mL)
and sonicated. The solution was then treated with HCl (1 M in EtiO; 100 mL) and stirred at
room temp. for 5 min. The resulting dark pink solid (7.04 g, 24.1 mmol) was removed by
15 filtration from solution and stored under anaerobic conditions at O °C prior to use: 1H NMR
(DMSO-d6) & 2.41 (s, 3H), 2.78 (d, J=4.4 Hz, 3H), 4.93 (br s, 2H), 7.19 (dd, J=8.5, 2.6 Hz,
lH), 7.23 (dd, J=5.5, 2.6 Hz, lH), 7.26 (d, J=2.6 Hz, lH), 7.55 (d, J=2.6 Hz, lH), 7.64 (d,
J=8.8 Hz, lH), 8.55 (d, J-=5.9Hz, lH), 8.99 (q, J=4.8 Hz, lH).
20 A6. General Method for the Synthesis of Anilines from Hydroxyanilines by N-

Protection, Nucleophilic Aromatric Substitution and Deprotection.
Synthesis of 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline
0 NOH
F3Cj(Ny
• H Cl
Step 1: Synthesis of 3-Chloro-4-(2,2,2-trifluoroacetylamino)phenol

25 Iron (3.24 g, 58.00 mmol) was added to stirring TFA (200 mL). To this slurry was added 2-
chloro--i-nilrophenol ( I 0.0 g, 58.0 mmol) and trifluoroacetic anhydride (20 ml). This gray
slurry was stirred at room temp. for 6 d. The iron was filtered from solution and th~
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remaining material was concentrated under reduced pressure. The resulting gray solid was
dissolved in water (20 mL). To the resulting yellow solution was added a saturated NaHCO 3
solution (50 mL). The solid which precipitated from solution was removed. The filtrate was
slowly quenched with the sodium bicarbonate solution until the product visibly separated
5 from solution (determined-was using a mini work-up vial). The slightly cloudy yellow
solution was extracted with EtOAc (3 x 125 mL). The combined organic layers were washed
with a saturated NaCl solution (125 mL), dried (MgSO4) and concentrated under reduced
pressure. The I H NMR (DMSO-d6) indicated a 1:1 ratio of the nitrophenol starting material
and the intended product 3-chloro-4-(2,2,2-trifluoroacetylamino )phenol. The crude material
10 was taken on to the next step without further purification.
0
O (YoyvNHMe
F3C)lNy ~~ .
H Cl
Step 2: Synthesis of 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl

(222-trifluoro )acetamide
A solution of crude 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol (5.62 g, 23.46 mmol) in
15 dry dimethylacetamide (50 mL) was treated with potassium tert-butoxide (5.16 g, 45.98
mmol) and the brownish black mixture was stirred at room temp. until the flask had cooled to
room temp. The resulting mixture was treated with 4-chloro-N-methyl-2-
pyridinecarboxamide (Method A2, Step 3b; 1.99 g, 11.7 mmol) and heated at 100 °C under
argon for 4 d. The black reaction mixture was cooled to room temp. and then poured into
20 cold water (100 mL). The mixture was extracted with EtOAc (3 x 75 mL) and the combined
organic layers were concentrated under reduced pressure. The residual brown oil was
purified by column chromatography (gradient from 20% EtOAc/pet. ether to 40% EtOAc/pet.
ether) to yield 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-
trifluoro)acetamide as a yellow solid (8.59 g, 23.0 mmol).
0
H2N~CI
<; O
~NHMe
~~
25
Step 3. Synthesis of 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline
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A solution of crude 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-

trifluoro)acetamide (8.59 g, 23.0 mmol) in dry 4-dioxane (20 mL) was treated with a IN
NaOH solution (20 mL). This brown solution was allowed to stir for 8 h. To this solution
was added EtOAc (40 mL). The green organic layer was extracted with EtOAc (3 x 40 mL)
5 and the solvent was concentrated to yield 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-
1
chloroaniline as a green oil that solidified upon standing (2.86 g, 10.30 mmol): H NMR
(DMSO-d6) 8 2.77 (d, J=4.8 Hz, 3H), 5.51 (s, 2H), 6.60 (dd, J=8.5, 2.6 Hz, IH), 6.76 (d,
J=2.6 Hz, IH), 7.03 (d, J=8.5 Hz, lH), 7.07 (dd, J=5.5, 2.6, Hz, lH), 7.27 (d, J=2.6 Hz, lH),
8.46 (d, J=5.5 Hz, lH), 8.75 (q, J=4.8, lH).
10
A7. General Method for the Deprotection of an Acylated Aniline. Synthesis of

4-Chloro-2-methoxy-5-(trifluoromethyl)aniline
Cl~
YNH2
OMe
A suspension of 3-chloro-6-(N-acetyl)-4-(trifluoromethyl)anisole (4.00 g, 14.95

15 rnmol) in a 6M HCl solution (24 mL) was heated at the reflux temp. for 1 h. The
resulting solution was allowed to cool to room temp. during which time it solidified
slightly. The resulting mixture was diluted with water (20 mL) then treated with a
combination of solid NaOH and a saturated NaHCO 3 solution until the solution was
basic. The organic layer was extracted with CH2Ch (3 x 50 mL). The combined
20 organics were dried (MgSQ4) and concentrated under reduced pressure to yield 4-
1
chloro-2-methoxy-5-(trifluoromethyl)aniline as a brown oil (3.20 g, 14.2 mmol): H
NMR (DMSO-d 6) 8 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).
AS. General Method for Synthesis of ro-Alkoxy-ro-carboxyphenyl Anilines.

25 Synthesis of 4-(3-(N-Methylcarbamoly)-4-methoxyphenoxy)aniline.
0
o,Noo~M~Me
Step 1. 4-(3-Methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene:
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To a solution of 4-(3-carboxy-4-hydroxyphenoxy)-1-nitrobenzene (prepared from 2,5- .

dihydroxybenzoic acid in a manner analogous to that described in Method A13, Step 1, 12
mmol) in acetone (50 mL) was added K2CO3 (5 g) and dimethyl sulfate (3.5 mL). The
resulting mixture was heated at the reflux temp. overnight, then cooled to room temp. and
5 filtered through a pad of Celite®. The resulting solution was concentrated under reduced
pressure, absorbed onto SiO2, and purified by column chromatography (50% EtOAc I 50%
hexane) to give 4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene as a yellow
powder (3 g): mp 115-11$ °C.
O
(-"';( ~oH
02N~ ~OMe
10 Step 2. 4-(3-Carboxy-4-methoxyphenoxy)-l-nitrobenzene:
A mixture of 4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene (1.2 g), KOH (0.33
g) and water (5 mL) in MeOH (45 mL) was stirred at room temp. overnight and then heated
at the reflux temp. for 4 h. The resulting mixture was cooled to room temp. and concentrated
under reduced pressure. The residue was dissolved in water (50 mL), and the aqueous
15 mixture was made acidic with a IN HCl solution. The resulting mixture was extracted with
EtOAc (50 mL). The organic layer was,dried (MgSO 4) and concentrated under reduced
pressure to give 4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (1.04 g).
0
,0°)X:NHMe
02N • OMe
Step 3. 4-(3-(N-Methylcarbamoly)-4-methoxyphenoxy)-1-nitrobenzene:
20 To a solution of 4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (0.50 g, 1.75 mmol) in
CH2Ch (12 mL) was added SOCh (0.64 mL, 8.77 mmol) in portions. The resulting solution
was heated at the reflux temp. for 18 h, cooled to room temp., and concentrated under
reduced pressure. The resulting yellow solids were dissolved in CH2Ch (3 mL) then the
resulting solution was treated with a methylamine solution (2.0 M in THF, 3.5 mL, 7.02
25 mmol) in portions (CAUTION: gas evolution), and stirred at room temp. for 4 h. The
resulting mixture was treated with a l N NaOH solution, then extracted with CH 2Cl 2 (25 ml).
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The organic layer was dried (Na2SO4) and concentrated under reduced pressure to give 4-(3-
(N-methylcarbamoly)-4-methoxyphenoxy)-l-nitrobenzene as a yellow solid (0.50 g, 95% ).
0
OO~NHMe
H2N · OMe
5 A slurry of 4-(3-(N-methylcarbamoly)-4-methoxyphenoxy)-l-nitrobenzene (0. 78 g, 2.60
mmol) and 10% Pd/C (0.20 g) in EtOH (55 mL) was stirred under 1 atm of H'.
2 (balloon) for
2.5 d, then was filtered through a pad of Celite®. The resulting solution was concentrated
under reduced pressure to afford 4-(3-(N-methylcarbamoly)-4-methoxyphenoxy)aniline as an
off-white solid (0.68 g, 96%): TLC (0.1% Et3N/99.9% EtOAc) R1 0.36.
A9. General Method for Preparation of co-Alkylphthalimide-containing

Anilines. Synthesis of 5-(4-AminopheiJ.oxy)-2-methylisoindoline-1,3-dione
0
~o~N-Me
02NA)J
•
~0
Step 1. Synthesis of 5-(4-Nitrophenoxy)-2-methylisoindoline-1,3-dione:
• 15 A slurry of 5-(4-nitrophenoxy)isoindoline-1,3-dione (A3 Step 2; 1.0 g, 3.52 mmol) and NaH
(0.13 g, 5.27 mmol) in DMF (15 mL) was stirred at room temp. for 1 h, then treated with
methyl iodide (0.3 mL, 4.57 mmol). The resulting mixture was stirred at room temp.
overnight, then was cooled to °C and treated with water (10 mL). The resulting solids were
. collected and dried under reduced pressure to give 5-(4-nitrophenoxy)-2-methylisoindoline-
20 1,3-dione as a bright yellow solid (0.87 g, 83%): TLC (35% EtOAc/65% hexane) ly0.61.
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Step 2. Synthesis of 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione:

A sluny of nitrophenoxy)-2-methylisoindoline-1,3-dione (0.87 g, 2. 78 mmol) and 10% Pd/C
(0.10 g) in MeOH was stirred under 1 atm of H2 (balloon) overnight.· The resulting mixture
was filtered through a pad of Celite® and concentrated under reduced pressure. The resulting
5 yellow solids were dissolved in EtOAc (3 mL) and filtered through a plug of SiO2 (60%
EtOAc/40% hexane) to afford 5-(4-aminophenoxy)-2-methylisoindoline-l,3-dione as a
yellow solid (0.67 g, 86%): TLC (40% EtOAc/60% hexane) R10,27.
AlO. General Method for Synthesis of ro-Carbamoylaryl Anilines Through

Reaction of ro-Alkoxycarbonylaryl Precursors with Amines. Synthesis of
4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline
0
Cl~ /'
~N N~N'-_l
Step 1. Synthesis of 4-Chloro-2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine

15 To a solution of methyl 4-chloropyridine-2-carboxylate HCl salt (Method A2, Step 2; 1.01 g,
4.86 mmol) in THF (20 mL) was added 4-(2-aminoethyl)morpholine (2.55 mL, 19.4 mmol)
dropwise and the resulting solution was heated at the reflux temp. for 20 h, cooled to room
temp., and treated with water (50 mL). The resulting mixture was extracted with EtOAc (50
mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to
20 afford 4-chloro-2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine as a yellow oil ( 1.25 g,
95%): TLC (10% MeOH/90% EtOAc) Rr0.50.
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Step 2. Synthesis of 4-(2-(N-(2-Morpholin-4~

I
A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium tert-butoxide (0.53 g, 4. 75

mol) in DMF (8 mL) was stirred at room temp. for 2 h, then was sequentially treated with 4-
5 chloro-2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine (1.22 g, 4.52 mmol) and K2CO3
(0.31 g, 2.26 mmol). The resulting mixture was heated at 75 °C overnight, cooled to room
temp., and separated between EtOAc (25 mL) and a saturated NaCl solution (25 mL). The
aqueous layer was back extracted with EtOAc (25 mL). The combined organic layers were
washed with a saturated NaCl solution (3 x 25 mL) and concentrated under reduced pressure.
10 The resulting brown solids were purified by column chromatography (58 g; gradient from
100% EtOAc to 25% MeOH/75% EtOAc) to afford 4-(2-(N-(2-morpholin-4-
ylethyl)carbamoyl)pyridyloxy)aniline (1.0 g, 65%): TLC (10% MeOH/90% EtOAc) R1 0.32.
All. General Method for the Reduction of Nitroarenes to Arylamines.

15 Synthesis of 4-(3-Carboxyphenoxy)aniline.
0
~O~OH
H2N~ V
A slurry of 4-(3-carboxyphenoxy)-1-nitrobenzene (5.38 g, 20.7 mmol) and 10% Pd/C (0.50
g) in MeOH (120 mL) was stirred under an H2 atmosphere (balloon) for 2 d. The resulting
mixture was filtered through a pad of Celite®, then concentrated under reduced pressure to
20 afford 4-(3-carboxyphenoxy)aniline as a brown solid (2.26 g, 48%): TLC (10% MeOH/90%
CH2Cl2)Rr 0.44 (streaking).
Al 2. General Method for the Synthesis of Isoindolinone-Containing Anilines.

Synthesis of 4-(1-0xoisoindolin-5-yloxy)aniline.
HO~ I NH
::::,..._
25 0
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Step 1. Synthesis of 5-hydroxyisoindolin-1-one

To a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 mL) was slowly
added zinc dust (47.6 g, 729 mmol) in portions, then the mixture was heated at the reflux
temp. for 40 min., filtered hot, and concentrated under reduced pressure. The reaction was
s repeated on the same scale and the combined oily residue was purified by column
chromatography (1.1 Kg SiO2; gradient from 60% EtOAc/40% hexane to 25% MeOH/75%
EtOAc) to give 5-hydroxyisoindolin-1-one (3.77 g): TLC (100% EtOAc) R10.I7; HPLC ES-
MS mlz 150 ((M+Hf).
0
10 Step 2. Synthesis of 4-(1-isoindolinon-5".'yloxy)-l-nitrobenzene
To a slurry of NaH (0.39 g, I 6.1 mmol) in DMF at O °C was added 5-hydroxyisoindolin-1-
one (2.0 g, 13.4 mmol) in portions. The resulting slurry was allowed to warm to room temp.
and was stirred for 45 min., then 4-fluoro-1-nitrobenzene was added and then mixture was
heated at 70 °C for 3 h. The mixture was cooled to O °C and treated with water dropwise
I5 until a precipitate formed. The resulting solids were collected to give 4-( 1-isoindolinon-5-
yloxy)-1-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) Ri0.35.
r(YO~NH
H2N¼J ~
0
Step 3. Synthesis of 4-(1-oxoisoindolin-5-yloxy)aniline
A slurry of 4-( l-isoindolinon-5-yloxy)-1-nitrobenzene (2.12 g, 7 .8 mmol) and 10% Pd/C
20 (0.20 g) in EtOH (50 mL) was stirred under an H2 atmosphere (balloon) for 4 h, then filtered
through a pad of Celite®. The filtrate ,was concentrated under reduced pressure to afford 4-( l-
oxoisoindolin-5-yloxy)aniline as a dark yellow solid: TLC ( 100% EtOAc) R10.15.
A13. General Method for the Synthesis of ro-Carbamoyl Anilines via EDCI-
25 Mediated Amide Formation Followed by Nitroarene Reduction.
Synthesis of 4-(3-N-Methylcarbamoylphenoxy)aniline.
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Step 1. Synthesis of 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene

A mixture of 4-fluoro-1-nitrobenzene (16 mL, 150 mmol), ethyl 3-hydroxybenzoate 25 g,
s 150 mmol) and K2CO 3 (41 g, 300 mmol) in DMF (125 mL) was heated at the reflux temp.
overnight, cooled to room temp. and treated with water (250 mL). The resulting mixture was
extracted with EtOAc (3 x 150 mL). The combined organic phases were sequentially washed
with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (Na2 S0 4 ) and
10 (10% EtOAc/90% hexane) to afford 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene as an oil
(38 g).
15 Step 2. Synthesis of 4-(3-carboxyphenoxy)-l-nitrobenzene

To a vigorously stirred mixture of 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene (5.14 g, 17.9
mmol) in a 3:1 THF/water solution (75 mL) was added a solution LiOH•H2O (1.50 g, 35.8
mmol) in water (36 mL). The resulting mixture was heated at 50 °C overnight, then cooled to
room temp., concentrated under reduced pressure, and adjusted to pH 2 with a IM HCI
20 solution. The resulting bright yellow solids were removed by filtration and washed with
hexane to give 4-(3-carboxyphenoxy)-1-nitrobenzene (4.40 g, 95%).
0
~o~NHMe
02N~ V
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Step 3. Synthesis of 4-(3-(N-methylcarbamoyl)phenoxy)-l-nitrobenzene

A mixture of 4-(3-carboxyphenoxy)-l-nitrobenzene (3.72 g, 14.4 mmol), EDCI•HCl (3.63 g,
18.6 mmol), N-methylmorpholine (1.6 mL, 14.5 mmol) and methylamine (2.0 M in THF; 8
mL, 16 mmol) in CH2Ch (45 mL) was stirred at room temp. for 3 d, then concentrated under
5 reduced pressure. The residue was dissolved in EtOAc (50 mL) and the resulting mixture
was extracted with a lM HCI solution (50 mL). The aqueous layer was back-extracted with
EtOAc (2 x 50 mL). The combined organic phases were washed with a saturated NaCl
solution (50 mL), dried (Na2SO4), and concentrated under reduced pressure to give 4-(3-(N-
methylcarbamoyl)phenoxy)-1-nitrobenzene as an oil (1.89 g).
0
0
r(Y vyNHMe
10
H2N~ V
Step 4. Synthesis of 4-(3-(N-methylcarbamoyl)phenoxy)aniline
A slurry of 4-(3-(N-methylcarbamoyl)phenoxy)-l-nitrobenzene (1.89 g, 6.95 mmol) and 5%
Pd/C (0.24 g) in EtOAc (20 mL) was stirred under an H2 atm (balloon) overnight. The
15 resulting mixture was filtered through a pad of Celite® and concentrated under reduced
pressure. The residue was purified by column chromatography (5% MeOH/95% CH2Ch).
The resulting oil solidified under vacuum overnight to give 4-(3-(N-
methylcarbamoyl)phenoxy)aniline as a yellow solid (0.95 g, 56%).
20 A14. General Method for the Synthesis of ro-Carbamoyl Anilines via EDCI-
02N
o 0
lfoMe
N
0
25 Step 1. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene

To a slurry of NaH (0.63 g, 26.1 mmol) in DMF (20 ml) was added a solution of methyl 5-
hydroxynicotinate (2.0 g, 13.l mmol) in DMF ( 10 ml). The resulting mixture was added to a
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solution of 4-fluoronitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 mL) and the resulting
mixture was heated at 70 °C overnight, cooled to room temp., and treated with MeOH (5 mL)
followed by water (50 mL). The resulting mixture was extracted with EtOAc (100 mL). The
organic phase was concentrated under reduced pressure. The residue was purified by column
5 chromatography (30% EtOAc/70% hexane) to afford 4-(3-(5-methoxycarbonyl)pyridyloxy)-
l-nitrobenzene (0.60 g).
H2N
o 0
lfoMe
N
0
Step 2. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline

A slurry of 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.60 g, 2.20 mmol) and
10 10% Pd/C in MeOH/EtOAc was stirred under an H2 atmosphere (balloon) for 72 h. The
resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The
residue was purified by column chromatography (gradient from 10% EtOAc/90% hexane to
30% EtOAc/70% hexane to 50% EtOAc/50% hexane) to afford 4-(3-(5-
methoxycarbonyl)pyridyloxy)aniline (0.28 g, 60%): 1H NMR (CDCh) 8 3.92 (s, 3H), 6.71 (d,
15 2H), 6.89 (d, 2H), 7.73 (, lH), 8.51 (d, lH), 8.87 (d, lH).
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Al5. Synthesis of an Aniline via Electrophilic Nitration Followed by Reduction. .

Synthesis of 4-(3-Methylsulfamoylphenoxy)aniline.
o,,❖o
BrVS'NHMe
Step 1. Synthesis of N-methyl-3-bromobenzenesulfonamide

s To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 mL) at 0
°C was added methylamine (2.0 M in THF; 28 mL, 56 mmol). The resulting solution was
allowed to warm to room temp. and was stirred at room temp. overnight. The resulting
mixture was separated between EtOAc (25 mL) and a 1 M HCl solution (25 mL). The
aqueous phase was back-extracted with EtOAc (2 x 25 mL). The combined organic phases
10 were sequentially washed with water (2 x 25 mL) and a saturated NaCl solution (25 mL),
dried (MgSO4 ) and concentrated under reduced pressure to give N-methyl-3-
bromobenzenesulfonamide as a white solid (2.8 g, 99%).
o,, /,P
UOUS'NHMe
Step 2. Synthesis of 4-(3-(N-metbylsulfamoyl)phenyloxy)benzene

15 To a slurry of phenol (1.9 g, 20 mmol), K2CO3 (6.0 g, 40 mmol), and Cul (4 g, 20 mmol) in
DMF (25 mL) was added N-methyl-3-bromobenzenesulfonamide (2.5 g, 10mmol), and the
resulting mixture was stirred at the reflux temp. overnight, cooled to room temp., and
separated between EtOAc (50 mL) and a 1 N HCl solution (50 mL). The aqueous layer was
back-extracted with EtOAc (2 x 50 mL). The combined organic phases were sequentially
20 washed with water (2 x 50 mL) and a saturated NaCl solution (50 mL), dried (MgSO 4 ), and
concentrated under reduced pressure. The residual oil was purified by column
methylsulfamoyl)phenyloxy)benzene (0.30 g).
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Step 3. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)-l-nitrobenzene

To a solution of 4-(3-(N-methylsulfamoyl)phenyloxy)benzene (0.30 g, 1.14 mmol) in TF A (6
mL) at -10°C was added NaNO 2 (0.097 g, 1.14 mmol) in portions over 5 min. The resulting
solution was stirred at -10 °C for 1 h, then was allowed to warm to room temp., and was
5 concentrated under reduced pressure. The residue was separated between EtOAc (10 mL)
and water (10 mL). The organic phase was sequentially washed with water (IO mL) and a
saturated NaCl solution (10 mL), dried (MgSO4) and concentrated under reduced pressure to
give 4-(3-(N-methylsulfamoyl)phenyloxy)-l-nitrobenzene (0.20 g). This material carried on
to the next step without further purification.
0, /0
(Yo~s:NHMe
10
H2N~ V
A slurry of 4-(3-(N-methylsulfamoyl)phenyloxy)- l-nitrobenzene (0.30 g) and 10% Pd/C
(0.030 g) in EtOAc (20 mL) was stirred under an H2 atmosphere (balloon) overnight. The
resulting mixture was filtered through a pad of Celite®. The filtrate was concentrated under
15 reduced pressure. The residue was purified by column chromatography (30% EtOAc/70%
hexane) to give 4-(3-(N-methylsulfamoyl)phenyloxy)aniline (0.070 g).
A16. Modification of ro-ketones. Synthesis of 4-(4-(1-(N-

methoxy)iminoethyl)phenoxyaniline HCI salt.
,..o,
H2NY)HCI«~
20 ~0 ~'
To a slurry of 4-(4-acetylphenoxy)aniline HCl salt (prepared in a manner analogous to
Method A13, step 4; 1.0 g, 3.89 mmol) in a mixture of EtOH (10 mL) and pyridine ( 1.0 ml)
was added O-methylhydroxylamine HCI salt (0.65 g, 7.78 mmol, 2.0 equiv.). The resulting
solution was heated at the reflux temperature for 30 min, cooled to rootn temperature and
25 concentrated under reduced pressure. The resulting solids were triturated with water (IO ml)
and \\'ashed with water to give 4-(4-( 1-(N-methoxy)iminoethyl) phenoxyaniline HCI salt as a
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yellow solid (0.85 g): TLC (50% EtOAc/50% pet. ether) R_r0.78;1H NMR (DMSO-d6) o3.90
(s, 3H), 5.70 (s, 3H); HPLC-MS mlz 257 ((M+Ht).
Al 7. Synthesis of N-(ro-Silyloxyalkyl)amides. Synthesis of 4-(4-(2-(N-(2-

5 Triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline.
CI'C( 0
~o
>--
..5 •I
I N
~NH -<\
Step 1. 4-Chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide
To a solution of 4-chloro-N-{2-hydroxyethyl)pyridine-2-carboxamide (prepared in a manner
analogous to Method A2, Step 3b; 1.5 g, 7.4 mmol) in anh DMF (7 mL) was added
IO triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv.) and imidazole (1.12 g, 16.4 mmol,
2.2 equiv.). The resulting yellow solution was stirred for 3 h at room temp, then was
concentrated under reduced pressure. The residue was separated between water (10 mL) and
EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined
organic phases were dried (MgSO4), and concentrated under reduced pressure to afford 4-
15 chloro-2-(N-(2-triisopropylsilyloxy)ethyl)pyridinecarboxamide as an orange oil (2.32 g,
88%). This material was used in the next step without further purification.
0 >--
H2N
oo'Cr~~~l\ - \
Step 2. 4-(4-(2-(N-(2-Triisopropylsilyloxy )etbylcarbamoyl)pyridyloxyaniline

20 potassium tert-butoxide (0.67 g, 6.0 mmol, 1.0 equiv.) in one portion causing an exotherm.
When this mixture had cooled to room temperature, a solution of 4-chloro-2-(N-(2-
triisopropylsilyloxy)ethyl)pyridinecarboxamide (2.32 g, 6 mmol, 1 equiv.) in DMF (4 mL)
was added followed by K2 CO3 (0.42 g, 3.0 mmol, 0.50 equiv.). The resulting mixture was
heated at 80 °C overnight. An additional portion of potassium tert-butoxide (0.34 g, 3 mmol,
25 0.5 equiv.) was then added and the mixture was stirred at 80 °C an additional 4 h. The
mixture was cooled to O °C with an ice/v,·ater bath, then water (approx. l ml) was slowly
added Jropwise. The organic layer was extracted with EtOAc (3 x 10 ml). The.combined
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organic layers were washed with a saturated NaCl solution (20 mL), dried (MgSO4 ) and
concentrated under reduced pressure. The brown oily residue was purified by column
chromatography (SiO2; 30% EtOAc/ 70% pet ether) to afford 4-(4-(2-(N-(2-
triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline as a clear light brown oil (0.99 g,
5 38%).
A18. Synthesis of 2-Pryidinecarboxylate Esters via Oxidation of 2-

methoxycarbonyl)pyridyloxy)aniline .
• ~o~
02N~ ~N~
Step 1. 4-(5-(2-Methyl)pyridyloxy)-1-nitrobenzene.
A mixture of 5-hydroxy-2-methylpyridine (10.0 g, 91.6 mmol), 1-fluoro-4-nitrobenzene (9.8
mL, 91.6 mmol, 1.0 equiv.), K2CO3 (25 g, 183 mmol, 2.0 equiv.) in DMF (100 mL) was
heated at the reflux temperature overnight. The resulting mixture was cooled to room
15 temperature, treated with water (200 mL), and extracted with EtOAc (3 x 100 mL). The
combined organic layers were sequentially washed with water (2 x 100 mL) and a saturated
NaCl solution ((100 mL), dried (MgSO 4) and concentrated under reduced pressure to give 4-
(5-(2-methyl)pyridyloxy)-1-nitrobenzene as a brown solid (12.3 g).
o,N0°Vy0Me
0
20 Step 2. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)-1-nitrobenzene.
A mixture of 4-(5-(2-methyl)pyridyloxy)-l-nitrobenzene (1.70 g, 7.39 mmol) and selenium
dioxide (2.50 g, 22.2 minol, 3.0 equiv.) in pyridine (20 mL) was heated at the reflux
temperature for 5 h, then cooled to room temperature. The resulting slurry was filtered , then
concentrated under reduced pressure. The residue was dissolved in MeOH (100 mL). The
25 solution was treated with a cone HCl solution (7 mL), then heated at the reflux temperature
for 3 h, cooled to room temperature and concentrated under reduced pressure. The residue
was separated between EtOAc (50 ml) and a IN NaOH solution (50 ml). The aqueous layer
was extracted with EtOAc (2 x 50 ml). The combined organic layers were sequentially
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washed with water (2 x 50 mL) and a saturated NaCl solution (50 mL), dried (MgSO 4) and
(SiO2 ; 50% EtOAc/50% hexane) to afford 4-(5-(2-methoxycarbonyl)pyridyloxy)-l-
nitrobenzene (0. 70 g).
H,NOoVyoMe
5 0
A slurry of 4-(5-(2-methoxycarbonyl)pyridyloxy)-l-nitrobenzene (0.50 g) and 10% Pd/C
(0.050 g) in a mixture of EtOAc (20 mL) and MeOH (5 mL) was placed under a H2
atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celite·'ID,
and the filtrate was concentrated under reduced pressure. The residue was purified by
column chromatography (SiO2 ; 70% EtOAc/30% hexane) to give 4-(5-(2-
methoxycarbonyl)pyridyloxy)aniline (0.40 g).
Al9. Synthesis of ro-Sulfonylphenyl Anilines. Synthesis of 4-(4-

15 Methylsulfonylphenyoxy)aniline.
ONOo'Qs_Me
2 // ,,
0 0
Step 1. 4-(4-Methylsulfonylphenoxy)-1-nitrobenzene: To a solution of 4-(4-
methylthiophenoxy)-1-nitrobenzene (2.0 g, 7.7 mmol) in CH2 Ch (75 mL) at O °C was slowly
added m-CPBA (57-86%, 4.0 g), and the reaction mixture was stirred at room temperature for
20 5 h. The reaction mixture was treated with a lN NaOH solution (25 mL). The organic layer
was sequentially washed with a lN NaOH solution (25 mL), water (25 mL) and a saturated
NaCl solution (25 mL), dried (MgSQ4), and concentrated under reduced pressure to give 4-
(4-methylsulfonylphenoxy)-1-nitrobenzene as a solid (2.1 g).
25 Step 2. 4-(4-Methylsulfonylphenoxy)-1-aniline: 4-(4-Methylsulfonylphenoxy)-l-

nitrobenzene was reduced to the aniline in a manner analogous to that described in \1ethod
:\ 18. st~p 3.
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B. Synthesis of Urea Precursors

Bl. General Method for the Synthesis of Isocyanates from Anilines Using
CDI. Synthesis of 4-Bromo-3-(trifluoromethyl)phenyl Isocyanate.
Br~
I ~ NH2•HCI
5 Step 1. Synthesis of 4-bromo-3-(trifluoromethyl)aniline HCI salt

To a solution of 4-bromo-3-(trifluoromethyl)aniline (64 g, 267 mmol) in Et20 (500 mL) was
added an HCl solution (1 Min Et20; 300 mL) dropwise and the resulting mixture was stirred
at room temp. for 16 h. The resulting pink-white precipitate was removed by filtration and
washed with Et20 (50 mL) and to afford 4-bromo-3-(trifluoromethyl)aniline HCl salt (73 g ,
IO 98%).
Br~
UNCO
A suspension of 4-bromo-3-(trifluoromethyl)aniline HCl salt (36.8 g, 133 mmol) in toluene
15 (278 mL) was treated with trichloromethyl chloroformate dropwise and the resulting mixture
was heated at the reflux temp. for 18 h. The resulting mixture was concentrated under
reduced pressure. The residue was treated with toluene (500 mL), then concentrated under
reduced pressure. The residue was treated with CH2Ch (500 mL), then concentrated under
reduced pressure. The CH2Ch treatment/concentration protocol was repeated and resulting
20 amber oil was stored at -20 °C for 16 h, to afford 4-bromo-3-(trifluoromethyl)phenyl
isocyanate as a tan solid (35.1 g, 86%): GC-MS mlz 265 (M+).

Cla. General Method for the Synthesis of Ureas by Reaction of an Isocyanate
25 with an Aniline. Synthesis of N-(4-Chloro-3-(trifluoromethyl)phenyl)-N'-
(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) Urea
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c~ o
Cl~ 0 ~o~NHMe
UN)l_N~ ~~
H H
A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (14.60 g, 65.90 mmol) in CH2Clz
(35 mL) was added dropwise to a suspension of 4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)aniline (Method A2, Step 4; 16.0 g, 65.77 mmol) in CH2Ch (35 mL) at O 0 C. The
5 resulting mixture was stirred ·at room temp. for 22 h. The resulting yellow solids were
removed by filtration, then washed with CH2Clz (2 x 30 mL) and dried under reduced
pressure (approximately 1 mmHg) to afford N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-
(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as an off-white solid (28.5 g, 93%): mp
207-209 °C; 1H-NMR (DMSO-d 6 ) o2.77 (d, J=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J=2.5 Hz,
10 lH), 7.62 (m, 4H), 8.11 (d, J=2.5 Hz, lH), 8.49 (d, J=5.5 Hz, lH), 8.77 (br d, lH), 8.99 (s,
lH), 9.21 (s, lH); HPLC ES-MS mlz 465 ((M+Ht).
Clb. General Method for the Synthesis of Ureas by Reaction of an Isocyanate

with an Aniline. Synthesis of N-(4-Bromo-3-(trifluoromethyl)phenyl)-N'-
15 (4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) Urea
c~ o
Br~ O ~o~NHMe
UN)l_N~ ~~
H H
A solution of 4-bromo-3-(trifluoromethyl)phenyl isocyanate (Method B 1, Step 2; 8.0 g, 30. l
mmol) in CH2Ch (80 mL) was added dropwise to a solution of 4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)aniline (Method A2, Step 4; 7.0 g, 28.8 mmol) in CH2Ch (40 mL) at O 0 C. The
20 resulting mixture was stirred at room temp. for 16 h. The resulting yellow solids were
removed by filtration, then washed with CH2Ch (2 x 50 mL) and dried under reduced
pressure (approximately l mmHg) at 40 °C to afford N-(4-bromo-3-(trifluoromethyl)phenyl)-
N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a pale-yellow solid ( 13.2 g.
90%): mp 203-205 °C; 1H-NMR (DMSO-d6) o2.77 (d, J=4.8 Hz, 3H), 7.16 (m. 3H ). 7.37 (d.
25 J=2.5 Hz, IH), 7.58 (m, 3H), 7.77 (d, J=8.8 Hz, lH), 8.11 (d, J=2.5 Hz, lH). 8.49 (d . ./=5.5
Hz. IH). 8.77 (br d, lH), 8.99 (s, lH), 9.21 (s. lH); HPLC ES-MS m/: 509 ((;v1---H).).
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with an Aniline. Synthesis of N-(4-Chloro-3-(trifluorometbyl)phenyl)-N'-
(2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))pbenyl) Urea
c~ o
Clu---:::::. O qOtrNHMe
I ,,,,.,, ~ I
/ N,,,.>'--....N
II I ~N
H H Me
5 A solution of 2-methyl-4-(2-(N-methylcarbamoyl)( 4-pyridyloxy))aniline (Method AS; 0.11 g,

0.45 mmol) in CH2Ch (1 mL) was treated with Et3N (0.16 mL) and 4-chloro-3-
(trifluoromethyl)phenyl isocyanate (0.10 g, 0.45 mmol). The resulting brown solution was
stirred at room temp. for 6 d, then was treated with water (5 mL). The aqueous layer was
back-extracted with EtOAc (3 x 5 mL). The combined organic layers were dried (MgSO 4 )
10 and concentrated under reduced pressure to yield N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-
(2-methyl-4-(2-(N-methylcarbamoyl)( 4-pyridyloxy))phenyl) urea as a brown oil (0.11 g, 0.22
mmol): 1H NMR (DMSO-d6) 8 2.27 (s, 3H), i.77 (d, J=4.8 Hz, 3H), 7.03 (dd, J=8.5, 2.6 Hz,
lH), 7.11 (d, J=2.9 Hz, lH), 7.15 (dd, J=S.5, 2.6, Hz, lH), 7.38 (d, J=2.6 Hz, lH), 7.62 (app
d, J=2.6 Hz, 2H), 7.84 (d, 1=8.8 Hz, lH), 8.12 (s, lH), 8J7 (s, lH); 8.50 (d, 1=5.5 Hz, JH),
15 8.78 (q, 1=5.2, lH), 9.52 (s, lH); HPLC ES-MS m/z 479 ((M+Ht).
Cld. General Method for the Synthesis of Ureas by Reaction of an Isocyanate

with an Aniline. Synthesis of N-(4-Cbloro-3-(trifluorometbyl)phenyl)-N'-
(4-aminophenyl) Urea
CF3
CIY.¾ O r7'YNH2
~A~
N N
20 H H
To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (2.27 g, 10.3 mmol) in
CH2Ch (308 mL) was added p-phenylenediamine (3.32 g, 30.7 mmol) in one part. The
resulting mixture was stirred at room temp. for 1 h, treated with CH2Ch (100 mL ), and
concentrated under reduced pressure. The resulting pink solids were dissolved in a mixture
25 of EtOAc (110 mL) and MeOH (15ml), and the clear solution was washed with a 0.05 ~
HCl solution. The organic layer was concentrated under reduced pressure to afford impure
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N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-( 4-aminophenyl) urea (3.3 g): TLC ( 100%

EtOAc) R10.72.

(4-ethoxycarbonylphenyl) Urea
CF3 0
Cl+ 0 ~OEt
~NAN,v
H H
To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CH2Ch (30 mL) was
added 4-chloro-3-(trifluoromethyl)aniline (3.21 g, 16.4 mmol), and the solution was stirred at
10 room temp. overnight. The resulting slurry was diluted with CH2Ch (50 mL) and filtered to
afford N-( 4-chloro-3-(trifluoromethyl)phenyl)-N'-( 4-ethoxycarbonylphenyl) urea as a white
solid (5.93 g, 97%): TLC (40% EtOAc/60% hexane) R10.44.
Clf. General Method for the Synthesis of Ureas by Reaction of an Isocyanate

(3-carboxyphenyl) Urea
c~ o
Cl+
~NAN~
H
0
H
~O~OH
u
To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (1.21g, 5.46 mmol) in CH2Ch
(8 mL) was added 4-(3-carboxyphenoxy)aniline (Method All; 0.81 g, 5.76 mmol) and the
20 resulting mixture was stirred at room temp. overnight, then treated with MeOH (8 mL), and
stirred an additional 2 h. The resulting mixture was concentrated under reduced pressure.
The resulting brown solids were triturated with a 1:1 EtOAc/hexane solution to give N-( 4-
chloro-3-(trifluoromethyl)phenyl)-N '-(3-carboxyphenyl) urea as an off-white solid (1.21 g,
76%).
25
C2a. General Method for Urea Synthesis by Reaction of an Aniline ·with N,N'-
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Synthesis of N-(2-Metboxy-5-(trifluorometbyl)pbenyl)-N'-(4-(2-(N-
metbylcarbamoyl)-4-pyridyloxy)phenyl) Urea
c~ o
A o 0°~NHMe
YN)lN~ lL~
OMe H H
To a solution of 2-methoxy-5-(trifluoromethyl)aniline (0.15 g) in anh CH 2Ch (15 mL) at O°C

5 was added CDI (0.13 g). The resulting solution was allowed to warm to room temp. over I h,
was stirred at room temp. for 16 h, then was treated with 4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)aniline (0.18 g). The resulting yellow solution was stirred at room temp. for 72 h,
then was treated with H2O (125 mL). The resulting aqueous mixture was extracted with
EtOAc (2 x 150 mL). The combined organics were washed with a saturated NaCl solution
10 (100 mL), dried (MgSO 4) and concentrated under reduced pressure. The residue was
triturated (90% EtOAc/10% hexane). The resulting white solids were collected by filtration
and washed with EtOAc. The filtrate was concentrated under reduced pressure and the
residual oil purified by column chromatography (gradient from 33% EtOAc/67% hexane to
50% EtOAc/50% hexane to 100% EtOAc) to give N-(2-methoxy-5-(trifluoromethyl)phenyl)-
15 N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a light tan solid (0.098 g, 30%):
TLC (100% EtOAc) R1 0.62; 1H NMR (DMSO-C¾)8 2.76 (d, J=4.8 Hz, 3H), 3.96 (s, 3H),
7.1-7.6 and 8.4-8.6 (m, llH), 8.75 (d, J=4.8 Hz, lH), 9.55 (s, 1 H); FAB-MS m/z 461
((M+Hf).
20 C2b. General Method for Urea Synthesis by Reaction of an Aniline with N,N'-
Symmetrical Urea's as Side Products of a N,N'-Carbonyl Diimidazole
Reaction Procedure. Synthesis of Bis( 4-(2-(N-methylcarbamoyl)-4-
0 0
0
MeHN~ Y) 0 0°~NHMe
~~ ~N)l_N~ ~~
25 H H
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To a stirring solution of 3-amino-2-methoxyquinoline (0.14 g) in anhydrous CH2Ch (15 mL)

at O C was added CDI (0.13 g). The resulting solution was allowed to warm to room temp.
-
over 1 h then was stirred at room temp. for 16 h. The resulting mixture was treated with 4-(2-
(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.18 g). The resulting yellow solution stirred at
5 room temp. for 72 h, then was treated with water (125 mL). The resulting aqueous mixture
was extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with a
saturated NaCl solution (100 ml), dried (MgSO 4) and concentrated under reduced pressure.
The residue was triturated (90% EtOAc/10% hexane). The resulting white solids were
collected by filtration and washed with EtOAc to give bis(4-(2-(N-methylcarbamoyl)-4-
IO pyridyloxy)phenyl) urea (0.081 g, 44%): TLC (100% EtOAc) R1 0.50; 1H NMR (DMSO-d6 ) 8
2.76 (d, J=5.l Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, J=5.4 Hz, lH), 8.75 (d, J=4.8 Hz, 2H),.
8.86 (s, 2H); HPLC ES-MS mlz 513 ((M+H/).
C2c. General Method for the Synthesis of Ureas by Reaction of an Isocyanate

15 with an Aniline. Synthesis of N-(2-Methoxy-5-(trifluoromethyl)phenyl-N'-
(4-(1,3-dioxoisoindolin-5-yloxy)phenyl) Urea
~ o <YOU
~~)l~~ J_;ro
0
To a stirring solution of 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.47 mmol)
in CH2 Ch (1.5 mL) was added 5-(4-aminophenoxy)isoindoline-l ,3-dione (Method A3, Step
20 3; 0.12 g, 0.47 mmol) in one portion. The resulting mixture was stirred for 12 h, then was
treated with CH2Cli (10 mL) and MeOH (5 mL). The resulting mixture was sequentially
washed with a IN HCl solution (15 mL) and a saturated NaCl solution (15 mL), dried
(MgSO4 ) and concentrated under reduced pressure to afford N-(2-methoxy-5-
(trifluoromethyl)phenyl-N '-(4-( l ,3-dioxoisoindolin-5-yloxy)phenyl) urea as a white solid (0.2
25 g, 96%): TLC (70% EtOAc/30% hexane) R1 0.50; 1H NMR (DMSO-d 6) 8 3.95 (s, 3H), 7.31-
7.10 (m, 6H), 7.57 (d, J=9.3Hz, 2H), 7.80 (d, J=8.7 Hz, lH), 8.53 (br s, 2H), 9.57 (s, lH),
11.27 (br s, I H); HPLC ES-MS 472.0 ((M+Hf, 100%).
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C2d. General Method for Urea Synthesis by Reaction of an Aniline with N,N'-
Synthesis of N-(5-(tert-Butyl)-2-(2,5-dimethylpyrrolyl)phenyl)-N'-(4-(2-
(N-methylcarbamoyl)-4-pyridyloxy)phenyl) Urea
5
To a stirring solution of CDI (0.2 lg, 1.30 mmol) in CH2Clz (2 mL) was added 5-(tert-butyl)-
2-(2,5-dimethylpyrrolyl)aniline (Method A4, Step 2; 0.30 g, 1.24 mmol) in one portion. The
resulting mixture was stirred at room temp. for 4 h, then 4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)aniline (0.065 g, 0.267mmol) was then added in one portion. The resulting
10 mixture was heated at 36 °C overnight, then cooled to room temp. and diluted with EtOAc (5
mL). The resulting mixture was sequentially washed with water (15 mL) and a lN HCl
solution (l 5mL), dried (MgSO4), and filtered through a pad of silica gel (50 g) to afford N-(5-
(tert-butyl)-2-(2,5-dimethylpyrrolyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)phenyl) urea as a yellowish solid (0.033 g, 24%): TLC (40% EtOAc/60% hexane)
15 R10.24; 1H NMR (acetone-d6) 8 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, J=4.8Hz, 3H), 5.83 (s,
2H), 6.87-7.20 (m, 6H), 7.17 (dd, lH), 7.51-7.58 (m, 3H), 8.43 (d, J=5.4Hz, lH), 8.57 (d,
1=2. IHz, lH), 8.80 (br s, lH); HPLC ES-MS 512 ((M+H)\ 100%).
CJ. Combinatorial Method for the Synthesis of Diphenyl Ureas Using

20 Triphosgene
One of the anilines to be coupled was dissolved in dichloroethane (0.10 M). This solution
was added to a 8 mL vial (0.5 mL) containing dichloroethane (1 mL). To this was added a
bis(trichloromethyl) carbonate solution (0.12 M in dichloroethane, 0.2 mL, 0.4 equiv.),
followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The vial
25 was capped and heat at 80 °C for 5 h, then allowed to cool to room temp for approximately
10 h. The second aniline was added (0.10 Min dichloroethane, 0.5 mL, 1.0 equiv.). followed
by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The resulting
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mixture was heated at 80 °C for 4 h, cooled to room temperature and treated with MeOH (0.5
mL). The resulting mixture was concentrated under reduced pressure and the products were
purified by reverse phase HPLC.
5 C4. General Method for Urea Synthesis by Reaction of an Aniline with Phosgene
Followed by Addition of a Second Aniline. Synthesis of N-(2-Methoxy-5-
(trifluorometbyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) Urea
¢lNtNoodNHMe
OMe H H
To a stirring solution of phosgene (1.9 Min toluene; 2.07 mL0.21g, 1.30 mrnol) in CH2Ch
10 (20 mL) at O °C was added anh pyridine (0.32 mL) followed by 2-methoxy-5-
(trifluoromethyl)aniline (0.75 g). The yellow solution was allowed to warm to room temp
during which a precipitate formed. The yellow mixture was stirred for 1 h, then concentrated
under reduced pressure. The resulting solids were treated with anh toluene (20 mL) followed
by 4-(2-{N-methylcarbamoyl)-4-pyridyloxy)aniline (prepared as described in Method A2;
15 0.30 g) and the resulting suspension was heated at 80 °C for 20 h, then allowed to cool to
room temp. The resulting mixture was diluted with water (100 mL), then was made basic
with a saturated NaHCO 3 solution (2-3 mL). The basic solution was extracted with EtOAc (2
x 250 mL). The organic layers were separately washed with a saturated NaCl solution,
combined, dried (MgSO4), and concentrated under reduced pressure. The resulting pink-
20 brown residue was dissolved in MeOH and absorbed onto SiO2 (100 g). Column
chromatography (300 g SiO2 ; gradient from 1% Et3N/33% EtOAc/66% hexane to 1%
Et3N/99% EtOAc to 1% Et3N/20% MeOH/79% EtOAc) followed by concentration under
reduced pressure at 45 °C gave a warm concentrated EtOAc solution, which was treated with
hexane (10 mL) to slowly form crystals of N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-
25 (2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea (0.44 g): TLC (1% Et3N/99% EtOAc) R1
0.40.
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D. Interconversion of Ureas
Dla. Conversion of ro-Aminophenyl Ureas into ro-(Aroylamino)phenyl Ureas.
Synthesis of N-(4-Chloro-3-( (trifluoromethyl)phenyl)-N'-( 4-(3-
methoxycarbonylphenyl)carboxyaminophenyl) Urea
CF3 H ~
Cl~ O ~N~OMe
llA)l}0J
N N
o o
5 H H
To a solution of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-aminophenyl) urea (Method
Cld; 0.050 g, 1.52 rnmol), mono-methyl isophthalate (0.25 g, 1.38 rnmol), HOBT•H 2O (0.41
g, 3.03 rnmol) and N-methylmorpholine (0.33 mL, 3.03 mmol) in DMF (8 mL) was added
EDCI •HCl (0.29 g, 1.52 mmol). The resulting mixture was stirred at room temp. overnight,
10 diluted with EtOAc (25 mL) and sequentially washed with water (25 mL) and a saturated
NaHCO3 solution (25 mL). The organic layer was dried (Na2 SO4 ) and concentrated under
reduced pressure. The resulting solids were triturated with an EtOAc solution (80%
EtOAc/20% hexane) to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-
methoxycarbonylphenyl)carboxyaminophenyl) urea (0.27 g, 43%): mp 121-122; TLC (80%
15 EtOAc/20% hexane) Ri0.75.
Dlb. Conversion of ro-Carboxyphenyl Ureas into ro-(Arylcarbamoyl)phenyl

Ureas. Synthesis of N-(4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-
CF3 0 ~
Cl'O O • ~N~NHMe
I~
N
)l,V
N
H O
20 H H
To a solution of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-( 4-(3-methylcarbamoylphenyl)
carboxyaminophenyl) urea (0.14 g, 0.48 mmol), 3-methylcarbamoylaniline (0.080 g, 0.53
mmol), HOBT•H2O (0.14 g, 1.07 mmol), and N-methylmorpholine (0.5mL, 1.07 mmol) in
DMF (3 mL) at O °C was added EDCl•HCl (0.10 g, 0.53 mmol). The resulting mixture was
25 allowed to warm to room temp. and was stirred overnight. The resulting mixture was treated
with water (10ml), and extracted with EtOAc (25 mL). The organic phase was concentrated
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under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 mL) then
filtered through a pad of silica gel (17 g, gradient from 70% EtOAc/30% hexane to 10%
MeOH/90% EtOAc) to give N-( 4-chloro-3-((trifluorom.:ethyl)phenyl)-N'-(4-(3-
,methylcarbamoylphenyl)carbamoylphenyl) urea as a white solid (0.097 g, 41%): mp 225-
5 229; TLC (100% EtOAc) R10,23.
Ole. Combinatorial Approach to the Conversion of ro-Carboxyphenyl Ureas

into ro-(Arylcarbamoyl)phenyl Ureas. Synthesis of N-{4-Chloro-3-
((trifluoromethyl)phenyl)-N'-( 4-(N-(3-(N-(3-
IO pyridyl)carbamoyl)phenyl)carbamoyl)phenyl) Urea
CF3 0 ½H
Cl'Cl)lNd~ ~ 0 NC
H H
A mixture of N-( 4-chloro-3-((trifluoromethyl)phenyl)-N'-(3-carboxyphenyl) urea (Method
Clf; 0.030 g, 0.067 mmol) and N-cyclohexyl-N'-(methylpolystyrene)carbodiimide (55 mg) in
15 1,2-dichloroethane (1 mL) was treated with a solution of 3-aminopyridine in CH2Ch (1 M;
0.074 mL, 0.074 mmol). (In cases of insolubility or turbidity, a small amount of DMSO was
also added.) The resulting mixture was heated at 36 °C overnight. Turbid reactions were then
treated with THF (1 mL) and heating was continued for 18 h. The resulting mixtures were
treated with poly(4-(isocyanatomethyl)styrene) (0.040 g) and the resulting· mixture was
20 stirred at 36 °C for 72 h, then cooled to room temp. and filtered. The resulting solution was
filtered through a plug of silica gel ( 1 g). Concentration under reduced pressure afforded N-
(4-chloro-3-( (trifluoromethyl)phenyl)-N '-(4-(N-(3-(N-(3-
pyridyl)carbamoyl)phenyl)carbamoyl)phenyl) urea (0.024 g, 59%): TLC (70% EtOAc/30%
hexane) Ri0.12.
25
D2. Conversion of ro-Carboalkoxyaryl Ureas into ro-Carbamoylaryl Ureas.

Synthesis of N-(4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-
methylcarbamoylphenyl)carboxyaminophenyl) Urea
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CF3 H r)
Cl~ O ~N~NHMe
lAN)lN~ 0 0
H H
To a sample of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-carbomethoxyphenyl)
carboxyaminophenyl) urea (0.17 g, 0.34 mmol) was added methylamine (2 M in THF; 1 mL,
1.7 mmol) and the resulting mixture was stirred at room temp. overnight, then concentrated
5 under reduced pressure to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-
methylcarbamoylphenyl)carboxyaminophenyl) urea as a white solid: mp 247; TLC (100%
EtOAc) R10.35.
D3. Conversion of ro-Carboalkoxyaryl Ureas into ro-Carboxyaryl Ureas.

10 Synthesis of N-:(4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-
carboxyphenyl) Urea
CF3 0
Cl~ 0 ~OH
lA
N
Jl,V
N
H H
To a slurry of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-ethoxycarbonylphenyl) urea
(Method Cle; 5.93 g, 15.3 mmol) in MeOH (75 mL) was added an aqueous KOH solution
15 (2.5 N, 10 mL, 23 mmol). The resulting mixture was heated at the reflux temp. for 12 h,
cooled to room temp., and concentrated under reduced pressure. The residue was diluted
with water (50 mL), then treated with a 1 N HCl solution to adjust the pH to 2 to 3. The
resulting solids were collected and dried under reduced pressure to give N-(4-chloro-3-
((trifluoromethyl)phenyl)-N '-(4-carboxyphenyl) urea as a white solid (5.05 g, 92%).
20
D4. General Method for the Conversion of ro-Alkoxy Esters into ro-Alkyl Amides.
Synthesis of N-(4-Chloro-3-((trifluoromethyl)phenyl)-N'-((4-(3-(5-(2-
dimetbylaminoethyl)carbamoyl)pyridyl)oxyphenyl) Urea
CF3 0
Cl~ 0 00~0H
UN)lN~ lNJ
H H
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Step 1. Synthesis of N-(4-Chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-

carboxypyridyl) oxyphenyl) Urea
N-(4-Chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-methoxycarbonylpyridyl)oxyphenyl)
urea was synthesized from 4-chloro-3-(trifluoromethyl)phenyl isocyanate and 4-(3-(5-
5 methoxycarbonylpyridyl) oxyaniline (Method Al 4, Step 2) in a manner analogous to Method
Cla. A suspension of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-
methoxycarbonylpyridyl)oxyphenyl) urea (0.26 g, 0.56 mmol) in MeOH (10 mL) was treated
with a solution of KOH (0.14 g, 2.5 mmol) in water (1 mL) and was stirred at room temp. for
1 h. The resulting mixture was adjusted to pH 5 with a 1 N HCl solution. The resulting
10 precipitate was removed by filtration and washed with water. The resulting solids were
dissolved in EtOH (10 mL) and the resulting solution was concentrated under reduced
pressure. The EtOH/concentration procedure was repeated twice to give N-(4-chloro-3-
(trifluoromethyl)phenyl)-N'-(( 4-(3-(5-carboxypyridyl) oxyphenyl) urea (0.18 g, 71%).
c~ o I
Clti Jl oO«~~N,
N N N
H H
15 Step 2. Synthesis of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-(2-
dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) urea
A mixture of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-
carboxypyridyl)oxyphenyl) urea (0.050 g, 0.011 mmol), N,N-dimethylethylenediamine (0.22
mg, 0.17 mmol), ROBT (0.028 g, 0.17 mmol), N-methylmorpholine (0.035 g, 0.28 mmol),
20 and EDCI•HCI (0.032 g, 0.17 mmol) in DMF (2.5 mL) was stirred at room temp. overnight.
The resulting solution was separated between EtOAc (50 mL) and water (50 mL). The
organic phase was washed with water (35 mL), dried (MgSO 4 ) and concentrated under
reduced pressure. The residue was dissolved in a minimal amount of CH2Ch (approximately
2 mL). The resulting solution was treated with Et2O dropwise to give N-(4-chloro-3-
25 ( trifluorometh yl)phenyl)-N '-((4-(3-( 5-(2-dimethylaminoethy 1)carbamoyl )pyridy 1)oxypheny I)
urea as a white precipitate (0.48 g, 84%: 1H NMR (DMSO-d 6) & 2.10 s, 6H), 3.26 (s, H), 7.03
(d, 2H), 7.52 (d, 2H), 7.60 (m, 3H), 8.05 (s, IH), 8.43 (s, IH), 8.58 (t, IH). 8.69 (s, I H). 8.90
(s, IH), 9.14 (s, IH); HPLC ES-MS mlz 522 ((M+Ht).
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D5. General Method for the Deprotection of N-(co-Silyloxyalkyl)amides.

Synthesis of N-( 4-Chloro-3-( (trifluoromethyl)phenyl)-N'-( 4-( 4-(2-(N-(2-
bydroxy )etbylcarbamoyl)pyridyloxyphenyl) Urea.
CF3 0 >--
Cl'O O ~O~N/'-...../O'Si
~ I Jl N~
N
~~ H __/ \
~ \
H H
5 To a solution of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N-(2-
analogous to Method Cla; 0.25 g, 0.37 mmol) in anh THF (2 mL) was tetrabutylammonium
fluoride (1.0 Min THF; 2 mL). The mixture was stirred at room temperature for 5 min, then
was treated with water (10 mL). The aqueous mixture was extracted with EtOAc (3 x 10
10 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced
pressure. The residue was purified by column chromatography (SiO2 ; gradient from 100%
hexane to 40% EtOAc/60% hexane) to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-
(4-(2-(N-(2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl) urea as a white solid (0.019 g, 10%).
15 Listed below are compounds listed in the Tables below which have been synthesized
according to the Detailed Experimental Procedures given above:

(see Tables for compound characterization)
20
Entry 1: 4-(3-N-Methylcarbamoylphenoxy)aniline was prepared according to Method A13.

According to Method C3, 3-tert-butylaniline was reacted with bis(trichloromethyl)carbonate
followed by 4-(3-N-Methylcarbamoylphenoxy)aniline to afford the urea.
25 Entry 2: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to

Method A 13, Step 1 to afford the 4-( 4-acetylphenoxy)-1-nitrobenzene. 4-(4-Acetylphenoxy)-
1-nitrobenzene was reduced according to Method Al3, Step 4 to afford 4-(4-
acetylphenoxy)aniline. According to Method C3, 3-tert-butylaniline was reacted with
bis(trichloromethyl) carbonate followed by 4-(4-acetylphenoxy)aniline to afford the urea .
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Entry 3: According to Method C2d, 3-tert-butylaniline was treated with CDI, followed by 4-
(3-N-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared according to
Method A8, to afford the urea.
5 Entry 4: 5-tert-Butyl-2-methoxyaniline was converted to 5-tert-butyl-2-methoxyphenyl

isocyanate according to Method B 1. 4-(3-N-Methylcarbamoylphenoxy)aniline, prepared
according to Method Al3, was reacted with the isocyanate according to Method Cla to
afford the urea.
10 Entry 5: According to Method C2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI

followed by 4-(3-N-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared
according to Method A8, to afford the urea.
Entry 6: 5-(4-Aminophenoxy)isoindoline-1,3-dione was prepared according to Method A3.

15 According to Method 2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI followed by 5-
(4-aminophenoxy)isoindoline-1,3-dione to afford the urea.
Entry 7: 4-(1-0xoisoindolin-5-yloxy)aniline was synthesized according to Method Al2.

20 ( 1-oxoisoindolin-5-yloxy)aniline to afford the urea.
Entry 8: 4-(3-N-Methylcarbamoylphenoxy)aniline was synthesized· according to Method

A13. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with CDI
followed by 4-(3-N-methylcarbamoylphenoxy)aniline to afford the urea.
25
Entry 9: 4-Hydroxyacetophenone was reacted with 2-chloro-5-nitropyridine to give 4-(4-

acetylphenoxy)-5-nitropyridine according to Method A3, Step 2. According to Method A8,
Step 4, 4-(4-acetylphenoxy)-5-nitropyridine was reduced to 4-(4-acetylphenoxy)-5-
aminopyridine. 2-Methoxy-5-(trifluoromethyl)aniline was converted to 2-methoxy-5-
30 (trifluoromethyl)phenyl isocyanate according to Method B 1. The isocyanate was reacted
with 4-(4-acetylphenoxy)-5-aminopyridine according to Method CI a to afford the urea.
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Entry 10: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to

Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-l-nitrobenzene. 4-(4-Acetylphenoxy)-
l-nitrobenzene was reduced according to Method Al3, Step 4 to afford • 4-(4-
acetylphenoxy)aniline. According to Method C3, 5-(trifluoromethyl)-2-methoxybutylaniline
5 was reacted with bis(trichloromethyl) carbonate followed by 4-(4-acetylphenoxy)aniline to
afford the urea.

Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 using
10 DMAC in place ofDMF to give 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According
to Method C4, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by
3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 12: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia
15 according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-
pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 using
DMAC in place of DMF to give 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method
C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 3-(2-
20
Entry 13: 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized according to Method

methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2a, 2-methoxy-5-
25 (trifluoromethyl)aniline was reacted with CDI followed by 4-(2-(N-methylcarbamoyl)-4-
Entry 14: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammoma
30 pyridinecarboxamide was reacted with 4-aminophenol according to Method A2. Step 4 using
DMAC in place of DMF to give 4-(2-carbamoyl-4-pyridyloxy)aniline. According to \lethoJ
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C4, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 4-(2- •

Entry 15: According to Method C2d, 5-(triflouromethyl)-2-methoxyaniline was reacted with

5 CDI followed by 4-(3-N-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been
prepared according to Method A8, to afford the urea.

according to Method A5. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-
1o (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. The isocyanate was
C 1c to afford the urea.

15 according to Method A6. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-
(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-
4-pyridyloxy)-2-chloroaniline according to Method Cla to afford the urea.
20 Entry 18: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-
A2, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. 5-
isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was
25 reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline according to Method
C 1ll to afford the urea.

30 with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-
pyridyloxy)aniline. 5-(Tritluoromethyl)-2-methoxyaniline was converted into 5-
(tritluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Tritluoromethyl)-
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2-methoxyphenyl isocyanate was reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline

according to Method Cla to afford the urea.
5 chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method
A2, Step 3b, to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 5-
isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was
reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline according to Method
1o C 1a to afford the urea.
Entry 21: 4-(4-Methylthiophenoxy)-1-nitrobenzene was oxidized according to Method A19,

Step 1 to give 4-(4-methylsulfonylphenoxy)-1-nitrobenzene. The nitrobenzene was reduced
according to Method Al 9, Step 2 to give 4-(4-methylsulfonylphenoxy)-1-aniline. According
15 to Method Cla, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4-
methylsulfonylphenoxy)-1-aniline to afford the urea.
Entry 22: 4-(3-carbamoylphenoxy)-1-nitrobenzene was reduced to 4-(3-

carbamoylphenoxy)aniline according to Method Al5, Step 4. According to Method Cla, 5-
20 (trifluoroinethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-
carbamoylphenoxy)aniline to afford the urea.
Entry 23: 5-(4-Aminophenoxy)isoindoline-1,3-dione was synthesized according to Method

25 methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl
isocyanate was reacted with 5-(4-aminophenoxy)isoindoline-1,3-dione according to Method
Cl a to afford the urea.

30 to Method A2, Step 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecarboxamide was
reacted with 4-aminophenol according to Method A2, Step 4 to gi,·c -H 2-( .\". .\"-
dimethylcarbamoyl)-4-pyridyloxy)aniline. s~(Trifluoromethyl)-2-methoxyanilinc ,, as
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converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5-

(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N,N-
dimethylcarbamoyl)-4-pyridyloxy)aniline according to Method Cla to afford the urea.
5 Entry 25: 4-(1-0xoisoindolin-5-yloxy)aniline was synthesized according to Method Al2. 5-

(Trifluoromethyl)-2-methoxyaniline was treated with CDI, followed by 4-( 1-oxoisoindolin-5-
yloxy)aniline according to Method C2d to afford the urea.

10 Method A13, Step 1 to give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was
reduced according to Method A13, Step 4 to afford 4-(4-acetylphenoxy)aniline, which was
converted to the 4-( 4-( 1-(N-methoxy)iminoethyl)phenoxyaniline HCl salt according to
Method A 16. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-
. 2-m~thoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl
15 isocyanate was reacted with 4-(4-(1-(N-methoxy)iminoethyl)phenoxyaniline HCl salt to
Method Cla to afford the urea.

20 A2, Step 4 to give 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. 5-(Trifluoromethyl)-2-
4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline according to Method Cla to afford the urea.
25 Entry 28: 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione was synthesized according to

Method A9. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
isocyanate was reacted with 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione according to
Method C 1a to afford the urea.
30
Entry 29: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in \1cthod

A2. Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to :'vkthod
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A2, Step 4 to give 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. 5-(Trifluoromethyl)-2-

3-(4-(2-(N-methylcarbamoyl)phenylthio )aniline according to Method C 1a to afford the urea.
5

isopropylcarbamoyl)-4-pyridyloxy)aniline. 5-(Trifluoromethyl)-2-methoxyaniline was
Io converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5-
isopropylcarbamoyl)-4-pyridyloxy)aniline according to Method Cla to afford the urea.

15 A14. 5-{Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
Method Cla to afford the urea. N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5-
20 and the corresponding acid was coupled with 4-(2-aminoethyl)morpholine to afford the
amide according to Method D4, Step 2.

Al4. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
25 methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl
Method Cla to afford the urea. N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5-
and the corresponding acid was coupled with methylamine according to Method D4, Step 2
30 to afford the amide.
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methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl
5 Method Cla to afford the urea. N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5-
and the corresponding acid was coupled with N,N-dimethylethylenediamine according to
10 Entry 34: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al 1. 5-

15 aminopyridine according to Method D 1c.

20 (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-(5-
(4-:fluorophenyl)piperazine accordingto Method Dlc.

25 (Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl
fluoroaniline according to Method Dlc.
30
Entry 37: 4-(3-Carboxyphenoxy)aniline \Vas synthesize? according to Method A 11. 5-
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isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted with 5- •

5
10 (trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with 5-
amino-2-methoxypyridine according to Method Dlc.
Entry 39: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-

15 isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-
morpholinoaniline according to Method Dlc.
20 Entry 40: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A 11. 5-

25 (2-pyridyl)piperazine according to Method Dlc.
Entry 41: 4-(3-(N-Methylcarbamoyl)phenoxy)aniline was synthesized according to Method

A 13. According to Method C3, 4-chloro-3-(trifluoromethyl)aniline was converted to the
isocyanate, then reacted with 4-(3-(N-Methylcarbamoyl)phenoxy)aniline to afford the urea.
30
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Entry 42: 4-(2-N-Methylcarbamyl-4-pyridyloxy)aniline was synthesized according to

Method A2. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-N-
methylcarbamyl-4-pyridyloxy)aniline according to Method Cla to afford the urea.
5 Entry 43: 4-Chloropyridine-2-carbonyl chloride HCI salt was reacted with ammonia
. according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-
pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to
form 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-3-
Io afford the urea.
pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 to
15 form 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-3-
afford the urea.

20 Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to
form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C 1a, 4-chloro-
3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-(N-methylcarbamoyl)-4-
25 Entry 46: 5-(4-Aminophenoxy)isoindoline-1,3-dione was synthesized according to Method

A3. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted
with 5-(4-aminophenoxy)isoindoline-1,3-dione to afford the urea.

30 according to Method AS. According to Method Cle, 4-chloro-3-(trifluoromethyl)phenyl
isocyanate was reacted with 5-(4-arninophenoxy)isoindoline-1,3-dione to afford the urea.
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Entry 48: 4-(3-N-Methylsulfamoyl)phenyloxy)aniline was synthesized according to Method

A15. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted
with 4-(3-N-methylsulfamoyl)phenyloxy)aniline to afford the urea.
5 Entry 49: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized

according to Method A6. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl
afford the urea.
A2, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. According to
Method C 1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-(N-
methylcarbamoyl)-4-pyridyloxy)-4-methylaniline to afford the urea.
15

Method A2, Step 3b. The resulting 4-chloio-N-ethyl-:2-pyridinecarboxamide was reacted
pyridyloxy)aniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl
20 isocyanate was reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
A2, Step 3b, to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. According to
25 Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-
Entry 53: 4-(4-Methylthiophenoxy)-1-nitrobenzene was oxidized according to Method A 19,

Step 1 to give 4-( 4-methylsulfonylphenoxy)-1-nitrobenzene. The nitrobenzene was reduced
30 according to Method A 19, Step 2 to give 4-( 4-methylsulfonylphenoxy)-1-aniline. According
to Method Cla, 4-chloro-3-(tritluoromethyl)phenyl isocyanate was reacted with ➔ -(4-
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Entry 54: . 4-Bromobep.zenesulfonyl chloride was reacted with methylamine according to

Method A15, Step 1 to afford N-methyl-4-bromobenzenesulfonamide. N-Methyl-4-
bromobenzenesulfonamide was coupled with phenol according to Method A15, Step 2 to
afford 4-( 4-(N-methylsulfamoyl)phenoxy)benzene. 4-( 4-(N-
5 Methylsulfamoyl)phenoxy)benzene was converted into 4-(4-(N-methylsulfamoyl)phenoxy)-
1-nitrobenzene according to Method Al5, Step 3. 4-(4-(N-Methylsulfamoyl)phenoxy)-l-
nitrobenzene was reduced to 4-(4-N-methylsulfamoyl)phenyloxy)aniline according to
Method A15, Step 4. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl
isocyanate was reacted with 4-(3-N-methylsulfamoyl)phenyloxy)aniline to afford the urea.
Entry 55: 5-Hydroxy-2-methylpyridine was coupled with 1-fluoro-4-nitrobenzene according

to Method A 18, Step 1 to give 4-(5-(2-Methyl)pyridyloxy)-l-nitrobenzene. The
Method A18, Step 2 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)-l-nitrobenzene. The
15 nitrobenzene was reduced according the Method Al8, Step 3 to give 4-(5-(2-
(trifluoromethyl)phenyl isocyanate according to Method Cla to afford the urea.
Entry 56: 5-Hydroxy-2-methylpyridine was coupled with l-fluoro-4-nitrobenzene according

20 to Method A18, Step 1 to give 4-(5-(2-Methyl)pyridyloxy)-1-nitrobenzene. The
Method Al8, Step 2 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)-l-nitrobenzene. The
nitrobenzene was reduced according the Method A18, Step 3 to give 4-(5-(2-
25 (trifluoromethyl)phenyl isocyanate according to Method Cla to give N-(4-chloro-3-
(trifluoromethyl)phenyl)-N'-(4-(2-(methoxycarbonyl)-5-pyridyloxy)phenyl) urea. The
methyl ester was reacted with methylamine according to Method D2 to afford N-(4-chloro-3-
(tri fluoromethy 1)phenyl )-N '-(4-(2-(N-methy lcarbamoy 1)-5-pyridy loxy )pheny I) urea.
:;o Entry 57: N-( 4-Ch loro-3-( tri fluoromethyl)phenyl-N '-(4-aminophenyl) urea was prepared
according to Method CI d. N-( 4-Chloro-3-(tri fluoromethyl)phenyl-N '-(4-aminophenyl) urea

was coupled with 1110110-methyl
isophthalate according to Method D la to afford the urea.
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Entry 58: N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) urea was prepared

according to Method Cld. N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) urea
was coupled with mono-methyl isophthalate according to Method Dla to afford N-(4-chloro-
5 3-(tri fluoromethyl )phenyl-N '-(4-(3-methoxycarbonylphenyl)carboxyaminopheny I) urea.
According to Method D2, N-( 4-chloro-3-(trifluoromethyl)phenyl-N '-(4-(3-
methoxycarbonylphenyl)carboxyaminophenyl) urea was reacted with methylamine to afford
the corresponding methyl amide.
10 Entry 59: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according

reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N,N-
dimethylcarbamoyl)-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-3-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N,N-dimethylcarbamoyl)-4-
15 pyridyloxy)aniline to afford the urea.

Method Al3, Step I to give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was
reduced according to Method 13, Step 4 to afford 4-(4-acetylphenoxy)aniline, which was
20 converted to the 4-(4-(1-(N-methoxy)iminoethyl) phenoxyaniline HCl salt according to
Method Al6. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was
reacted with 4-( 4-acetylphenoxy)aniline to afford the urea.
Entry 61: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method Al3,

25 Step 2. 4-(3-Carboxyphenoxy)-l-nitrobenzene was . coupled with 4-(2-
aminoethyl)morpholine according to Method A13, Step 3 to give 4-(3-(N-(2-
morpholinylethyl)carbamoyl)phenoxy)-l-nitrobenzene. According to Method A13 Step 4, 4-
(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)-l-nitrobenzene was reduced to 4-(3-(N-(2-
morpholinylethyl)carbamoyl)phenoxy)aniline. According to Method C 1a. 4-chloro-3-
30 (trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(2-
morpholinylethyl)carbamoyl)phenoxy)aniline to afford the urea.
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Entry 62: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method Al3,

Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with 1-(2-aminoethyl)piperidine
according to Method A13, Step 3 to give 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)-l-
nitrobenzene. According to Method A13 Step 4, 4-(3-(N-(2-
5 piperidylethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-(2-
piperidylethyl)carbamoyl)phenoxy)aniline. According to Method Cla, 4-chloro-3-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(2-
10 Entry 63: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method Al3,

Step 2. 4-(3-Carboxyphenoxy)-l-nitrobenzene was coupled with tetrahydrofurfurylamine
according to Method A13, Step 3 to give 4-(3-(N-
(tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A 13 Step
4, 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-
15 (N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline. According to Method Cla, 4-chloro-
3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-
(tetrahydrofurylmethyl)carbamoyl) phenoxy)aniline to afford the urea.
Entry 64: 4-(3-Carboxyphenoxy)-l-nitrobenzene was synthesized according to Method A 13,

20 Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with 2-aminomethyl-1-
ethylpyrrolidine according to Method Al3, Step 3 to give 4-(3-(N-((l-
methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A 13
Step 4, 4-(3-(N-(( 1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene was
reduced to 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline. According to
25 Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(( 1-

30 A2, Step 4 to give 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. According to Method
CI a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-( 4-( 2-(\"-
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5 isopropylcarbamoyl)-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-3-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-isopropylcarbamoyl)-4-
Entry 67: N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-ethoxycarbonylphenyl) urea was

10 synthesized according to Method Cle. N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-
ethoxycarbonylphenyl) urea was saponified according to Method D3 to give N-(4-chloro-3-
(trifluoromethyl)phenyl-N '-(4-carboxyphenyl) urea. N-( 4-Chloro-3-(trifluoromethyl)phenyl-
N '-(4-carboxyphenyl) urea was coupled with 3-methylcarbamoylaniline according to Method
Dlb to give N-(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(3-
15 methylcarbamoylphenyl)carbamoylphenyl) urea.
Entry 68: 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione was synthesized according to

Method A9. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was
reacted with 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione to afford the urea.
20

A2, Step 4 to give 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. According to Method
Cl a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(4-(2-(N-
25 methylcarbamoyl)phenylthio )aniline to afford the urea.

according to Method AlO. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl
isocyanate was reacted with 4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline to
30 afford the urea.
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Al4. 4-Chloro-3-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-
methoxycarbonyl)pyridyloxy)aniline according to Method Cl a to afford the urea. N-( 4-
Chloro-3-(trifluoromethyl)phenyl)-N'-( 4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea

5 was saponified according to Method D4, Step 1, and the corresponding acid was coupled with
4-(2-aminoethyl)morpholine to afford the amide.

A14. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5-
10 methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea. N-(5-
(Trifluoromethyl )-2-methoxyphenyl)-N '-(4-(3-( 5-methoxycarbonylpyridyl)oxy )phenyl) urea
methylamine according to Method D4, Step 2 to afford the amide.
15 Entry 73: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method

A14. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3~(5-
methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea. N-(5-
(Trifluoromethyl )-2-methoxyphenyl)-N '-(4-(3-( 5-methoxycarbonylpyridy I)oxy )pheny 1) urea
20 N,N-dimethylethylenediamine according to Method D4, Step 2 to afford the amide.
Entry 74: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with 2-

hydroxyethylamine according to Method A2, Step 3b to form 4-chloro-N-(2-
triisopropylsilyloxy )ethylpyridine-2-carboxamide. 4-Chloro-N-( 2-
25 triisopropylsilyloxy)ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride,
triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline. According to Method CI a, 4-chloro-
3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(N-(2-
triisopropylsilyloxy)ethylcarbamoyl) pyridyloxyaniline to afford N-( 4-ch loro-3-
30 ((trifluoromethyl)phenyl)-N '-(4-(4-(2-(N-(2-triisopropylsilyloxy)
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Entry 75: 4-(3-Carboxyphenoxy )aniline was synthesized according to Method A 11. 4-

Chloio-3-( trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5-
methoxycarbonyl)pyridyloxy)aniline according to Method Cl f to afford the urea, which was
coupled with 3-aminopyridine according to Method Dlc.
5

according to Method Clf to afford the urea, which was coupled with N-(4-
acetylphenyl)piperazine according to Method Dlc.
10

according to Method Clf to afford the urea, which was coupled with 4-fluoroaniline
15

according to Method Clf to afford the urea, which was coupled with 4-
20

according to Method Clf to afford the urea, which was coupled with N-
phenylethylenediamine according to Method Dlc.
25

according to Method C 1f to afford the urea, which was coupled with 2-methoxyethylamine
30

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according to Method Clf to afford the urea, which was coupled with 5-amino-2-
methoxypyridine according to Method Dlc.

5 Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline
according to Method Clf to afford the urea, which was coupled with 4-morpholinoaniline
according to Method D le.
Entry 83: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method ·A11. 4-

10 Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline
according to Method Clf to afford the urea, which was coupled with N-(2-pyridyl)piperazine
according to Method D le.
Entry 84: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with 2-

15 hydroxyethylamine according to Method A2, Step 3b to form •4-chloro-N-(2-
triisopropylsilyloxy)ethylpyridine-2-carboxamide. 4-Chloro-N-{2-
triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline. According to Method C 1a, 4-chloro-
20 3-(trifluoromethyl)phenyl isocyanate . was reacted. with 4-(4-(2-(N-(2-
triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline to give N-(4-chloro-3-
((trifluoromethyl)phenyl)-N '-(4-(4-(2-(N-(2-
triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyphenyl) urea. The urea was deprotected
according to Method D5 to afford N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-( 4-(4-(2-(N-(2-
25 hydroxy)ethylcarbamoyl)pyridyloxyphenyl) urea.

Method A2. 4-Bromo-3-(trifluoromethyl)aniline was converted to 4-bromo-3-
(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method C 1a, 4-
30· bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-
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according to Method A6. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-
(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4-
bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-
5 pyridyloxy)-2-chloroaniline to afford the urea.
A2, Step 3b, to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-Bromo-3-
10 (trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate
according to Method Bl. According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl
afford the urea.
15 Entry 88: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to

pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-
(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method CI a, 4-
20 bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-ethylcarbamoyl)-4-

Method A2, Step 3a, was reacted with 3-aminoph~nol according to Method A2, Step 4 to
25 form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-( trifluoromethyl )aniline
was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1.
According to Method C 1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-
(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to .\kthoJ
A2. Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylanilinc. 4-Brom?-~-
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according to Method B 1. According to Method C 1a, 4-bromo-3-(trifluoromethyl)phenyl
isocyanate was reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline to
afford the urea.
5
reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N,N-
dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline was
10 converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1.
According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-
(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

15 A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method
A2, Step 4 to give 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. 4-Bromo-3-
according to Method B 1. According to Method C 1a, 4-bromo-3-(trifluoromethyl)phenyl
isocyanate was reacted with 4-(4-(2-(N-methylcarbamoyl)phenylthio )aniline to afford the
20 urea.

A2, Step 4 to give 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. 4-Bromo-3-
25 (trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate
acc_ordingto Method B 1. According to Method C 1a, 4-bromo-3-(trifluoromethyl)phenyl
isocyanate was reacted with 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline to afford the
urea.
30 Entry 94: 4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was synthesized

according to Method A 10. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-
3-(tri fluoromethyl)phenyl isocyanate according to Method BI. According to Method CI a, 4-
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bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-(2-Morpholin-4-

ylethyl)carbamoyl)pyridyloxy)aniline to afford the urea.

5 Method A2. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to
Method A 7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-
methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to
Method C 1a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-
(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
10

according to Method A6. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized
4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B 1.
15 According to Method Cla, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was
reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline afford the urea.
20 A2, Step 3b, to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-Chloro-2-
methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A 7. 4-Chloro-2-
methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-
(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4-
chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-
25 methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.

form 3-(-2-(N-methy lcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methox y-5-
30 (trifluoromethyl)aniline was synthesized according to Method A 7. 4-Chloro-2-methoxy-5-
(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(tri fluoromcthyl )phenyl
isocyanate according to Method Bl. According to Method C 1a, 4-chloro-2-mcthoxy-5-
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(trifluoromethyl)phenyl isocyanate as was reacted with 3-(-2-(N-methylcarbamoyl)-4-


5 Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted
pyridyloxy)aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized
according to Method A 7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into
4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate .according to Method B 1.
10 According to Method Cla, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was
reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

15 reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N,N-
dimethy lcarbamoy 1)-4-pyridyloxy)aniline. 4-Chloro-2-methoxy-5-( tri fluoromethyl )aniline
was synthesized according to Method A 7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline
was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to
Method Bl. According to Method Cla, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl
20 isocyanate was reacted with 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the
urea.

25 form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. 2-Amino-3-methoxynaphthalene was
synthesized as described Method Al. According to Method C3, 2-amino-3-
methoxynaphthalene was reacted with bis(trichloromethyl) carbonate followed by 3-(-2-(N-
methylcarbamoyl)-4-pyridyloxy)aniline to form the urea.
30 Entry 102: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to

Method A2. 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline was synthesized according to
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Method A4. 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline was reacted with CDI followed by

4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline according to Method C2d to afford the urea.
Entry 103: 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized according to Method

5 A2, Step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamide was reacted with 4-aminophenol
methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2b, reaction of 3-amino-2-
methoxyquinoline with CDI followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline
afforded bis(4-(2-(N-methylcarbamoyl)-4-pyridlyoxy)phenyl)urea.
Listed in the Tables below are compounds which have been synthesized according to
the Detailed Experimental Procedures given above:
15
Tables
20 The compounds listed in Tables 1-6 below were synthesized according to the general
methods shown above, and the more detailed exemplary procedures are in the entry listings
above and characterizations are indicated in the tables.
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Table 1. 3-tert-Butylphenyl Ureas
0~
R,N)lND
H H
TLC Mass
Entrv R (OC) (min.) Rr System fSourcel Method
I 0.22 50% 418 A13 C3
-O
O NH EtOAc (M+H)+
Me I 50% (HPLC
-0- 0 hexane ES-MS)
2
. ~o
-0- ~ O /J Me
0.58 50%
EtOAc
403
(M+H)+
A13 C3
I 50% (HPLC
hexane ES-MS)
3 133- 0.68 100% 448 A8 C2d
-6o~:
0 NH 135 EtOAc (M+H)+
-0-o (FAB)
5 Table 2. 5-tert-Butyl-2-methoxyphenyl Ureas
TLC Mass
Entrv R (OC) (min.) Rr System fSourcel Method
4 5.93 448 Al3
-O
O NH (M+H)+ Bl
Me (HPLC Cla
5
-0- 0
120- 0.67 100%
ES-MS)
478 A8
0 NH
-6
122 EtOAc (M+H)+ C2d
-0-o o~: (FAB)
6 0.40 50% 460 A3

-0-o~/;. 0
NH
EtOAc
I 50%
hexane
(M.,.H)+
(HPLC
ES-\1S)
C2d
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7 0 0.79 50% 446 Al2

EtOAc (M+H)+ C2d
-Q-o-Qj/J I 50% (HPLC
NH
hexane ES-MS)
Table 3. 5-(Trifluoromethyl)-2-methoxyphenyl Ureas
H
0
R,NJlNY
H
A OMe
TLC Mass
Entry R (OC) (min.) Rr System rsourcel Method
8 250 460 Al3
o NH
-d
(dee) (M+H)+ C2a
Me (FAB)
9
-0- 0
206- 0.54 10% 446 A3 step
-0- N
0~/J 0
Me
208 MeOH
/90%
CH2Cl
(M+H)+
(HPLC
ES-MS)
2,
A8 step
4,
2 Bl,
Cla
10 0.33 50% 445 Al3 C3
-Q-o-Q-( EtOAc
I 50%
(M+H)+
(HPLC
pet ES-MS)
ether
11 0.20 2% 461 A2
O N_H Et3N/ (M+H)+ C4
- Me 98% (HPLC
EtOAc ES-MS)
-Q-d: O ~ ;,N
12 0.27 1% 447 A2
Et3N/ (M+H)+ C4
-Q-d:O NH2 99% (HPLC
EtOAc ES-MS)
0 ~ ;,N
13 0.62 100% 461 A2 C2a
O NH
-d:
EtOAc (M+H)+
Me (FAB)
14
-0- 0
114- 0.40 1% 447 A2
-0- -d:
O ~H2 117 Et3N/ (M+H)+ C4
99% (FAB)
0 EtOAc
-
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0.54
◊o~:
O
15 232- 100% 490 A8 C2d
NH 235 EtOAc (M+H)+
(FAB)
-Q-o
16 0 210- 0.29 5% 475 A5
Me
-b- - 0
-ONH
~ ;,N
Me
213 MeOH
I 45%
EtOAc
I 50%
(M+H)+
(HPLC
ES-MS)
Bl Cle
pet
ether
-
17 187- 0.17 50% 495 A6
Cl -OO NH 188 EtOAc (M+H)+ Bl Cla
18
-0 0 ~ I,
N
Me
0.48
I 50%
pet
ether
100%
(HPLC
ES-MS)
475 A2 step
EtOAc (M+H)+ 4,
--Q-~e O NH2 (HPLC Bl Cla
ES-MS)
0 ~ ;,N
19 194- 0.31 5% 475 A2
O NH
-d:
196 MeOH (M+H)+ Bl Cla
Et 145% (HPLC
-0- 0 EtOAc
I 50%
pet
ES-MS)
ether
214- 0.25 5% 495
-
20 A2 Cla
Cl -OO NH 216 MeOH (M+H)+
--0- 0 ~ ;,N
Me 145%
EtOAc
I 50%
pet
ether
(HPLC
ES-MS)
21 208- 0.30 50% 481 A19 C2a
-Q-o-0-\~ 210 EtOAc

I 50%
hexane
(M+H)+
(HPLC
ES-MS)
22
o NH
188- 0.30 70% 447 Al 5.
-d
2 190 EtOAc (M+H)+ step 4,
I 50% (HPLC Cla
-Q-o hexane ES-MS)
23 0.50 70% 472 A3

-Q-o-qt/J 0
NH
EtOAc (M+H)+
I 30% (FAB)
Bl Cla
hexane
0
24
-0-
0-00N
~ I,
~c 203-
205
0.13 100% 479
EtOAc (M+H)+
(HPLC
ES-MS)
A2
Cla
Bl
78.
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PCT /US00/00648
25
-0-o~J NH
o 0.09 75%
EtOAc
/25%
458
(M+H)+
(HPLC
A12
C2d
hexane ES-MS)
26 Meq 169- 0.67 50% 474 A13
171 EtOAc (M+H)+ step 1,
-0-o-Q-{ I 50%
pet
(HPLC
ES-MS)
A13 step
4,
ether A16,
Bl
Cla
27 218- 0.40 50% 477 A2 step
O NH
-O
219 EtOAc {M+H)+ 3b,
Me I 50% (HPLC A2 step
-0- s pet
ether
ES-MS) 4,
Bl,
Cla
28
-0-o-Q;!Jo NMe
212-
214
0.30 40%
EtOAc
/60%
A9
Bl Cla
hexane
0
-Q-O
29 0.33 50% 474 A2 step
O N_H EtOAc (M+H)+ 3b,
- Me I 50% (HPLC A2 step
pet ES-MS) 4,
S ~ /,N
ether Bl,
Cla
30
·-oo NH
Pr-1
210-
211
A2
Bl
Cla
31
-0- 0
210- 0.43 10% A14
-O (J
O NH 204 MeOH Bl
~ I Cla
-0-o N
CH2Cl
2
D4
32 247- 0.57 10% A14

O NH
-0- -O
249 MeOH Bl
Me I Cla
0 CH2Cl D4
N 2
33 217- 0.07 10% A14
-0- -O
O NH 219 MeOH Bl
I Cla
0 '---\N-ME CH2Cl D4
N Me1 2
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34 0.11 70% All

O NH
-O()
EtOAe Bl
I 30% Clf
-Q-o hexane Dle
35
Q N)
0.38 70%
EtOAe
/30%
hexane
All
Bl
Clf
Dlc
\__N
-Q-a-do
36 0.77 70% Al 1
F-0-NH EtOAe Bl
/30% Clf
-Q-a-Oo hexane Die
37
MeN I/ -0- ~ NH
0.58 70%
EtOAe
I 30%
Al I
Bl
Clf
hexane
-0-a-Oo Die
38 0.58 70% Al 1
Me0--0-NH EtOAe Bl
/30% Clf
-Q-a-Oo hexane Dlc
39 0.17 70% Al I
rN-o-·~ NH EtOAe Bl
\.__/-00 I 30%
hexane
Clf
-Q-o ~-/; Die
40 0.21 70% All

EtOAe Bl
0-CN-0-NHO
/ 30% Clf
hexane Die
-Q-a-0
Table 4. 3-(Trifluoromethyl)-4-cbloropbenyl Ureas
F F F
O Cl
R_N)lN
H H
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TLC Mass
Entry R (OC) (min.) R, Svstem fSourcel Method
41
o NH
163- 0.08 50% 464 Al3
-d
165 EtOAc/ (M+H)+ C3
Me 50% pet (HPLC
42
-0- 0
215 0.06
ether
50%
ES-MS)
465 A2
O NH EtOAc/ (M+H)+ Cla
Me 50% pet (HPLC
43
-0- 0
-O
0.10
ether
50%
ES-MS)
451 A2
O NH2 EtOAc/ (M+H)+ Cla
50% pet (HPLC
-Q-o -O
ether ES-MS)
44 0.25 30% 451 A2

EtOAc/ (M+H)+ Cla
--0-QO NH2 70% pet (HPLC
ether ES-MS)
0 ~ /,N
45 0.31 30% 465 A2
0 N_H EtOAc/ (M+H)+ Cla
- Me 70%pet (HPLC
ether ES-MS)
--0-0 0 ~ /,N
46 0 176- 0.23 40% 476 A3
-Q-o-Q;tj NH
179 EtOAc/
60%
(M+H)+
(FAB)
Cla
hexane
0
47 0.29 5% 478
- .
A5
MeOH/ (M+H)+ Cle
Me -OO NH
-0- 0 ~ ;,N
Me 45%
EtOAc/
50% pet
ether
(HPLC
ES-MS)
48
0 ,0 206- Al5
~S~NH 209 Cla
Me
-Q-o-{J
49
Cl
-0- _ 0
-OO
~ ;,N
NH
Me
147-
151
0.22 50%
EtOAc/
50% pet
ether
499
(M+H)+
(HPLC
ES-MS)
A6
Cla
50 0.54 100% 479 A2

e O N.H EtOAc (M-t-H)+ Cla
-Q-~ 0 ~
-
;,N
Me (HPLC
ES-\.1S)
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51
O NH
Et
187-
189
0.33 5%
MeOH/
45%
479
(M+H)+
(HPLC
A2
Cla
-0-
- -d: 0 EtOAc/
50% pet
ether
ES-MS)
52
-d:O
- Cl NH
219 0.18 5%
MeOH/
499
(M+H)+
A2
Cla
--0-- Me 45% (HPLC

EtOAc/ ES-MS)
0 ~ ;,N
50% pet
ether
53 246- 0.30 50% 485 Al 9, Cla
248 EtOAc/ (M+H)+
-0-o-Q-~~~ 50% (HPLC
hexane ES-MS)
54 196- 0.30 70% 502 A15
o-OOs::::O 200 EtOAc/ · (M+H)+ Cla
-0- ~ /; 'NH 30% (HPLC
: /
hexane) ES-MS)
Me
55
O OM<,
228-
230
0.30 30%
EtOAc/
70%
466
(M+H)+
(HPLC
56
-0--d: 0 ~ I,
N
o 238-
CH2Cl2 ES-MS)
-0-~ ~ II 0
M~
NH
245
57 221- 0.75 80% 492 Cld

OQ 222 EtOAc/ (M+H)+ Ola
H Me 20% (FAB)
N hexane
-0- ~
58 247 0.35 100% Cid
• ~O NH EtOAc Ola
H O - Me 02
N ~ /;
-0-
59 198- 0.09 100% 479 A2
200 EtOAc (M+H)+ Cla
o ~:: (HPLC
60
-0--d: 0 ~ /,N
MeQ 158- 0.64 50%
ES-MS)
-o-
160 EtOAc/
o-07N 50% pet
~ 11 Me ether
61 195- 0.39 10% Al3
O NH
-O
197 MeOH/ Cla
y1 ~ ~ CH2Cl
2
-Q-o (_)
0
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62 170- 0.52 10% Al3

O NH
-O Q
172 MeOH/ Cla
I/ ~ ~ CH2Cl
-Q-o 2
63 168- 0.39 10% Al3

171 MeOH/ Cla
0-00 N~ CH2Cl
64
-0- ~ /;
0 Et 176- 0.35
2
10% Al3
N
-O~
NH 177 MeOH/ Cla
CH2Cl
65
-0-
-
0
130-
2
487 A2
-O
O NH 133 {M+H)+ Bl
Me (HPLC Cla
66
-0- s
155
ES-MS)
A2
-0- -O
O NH Cla
0
Pr-i
0
67 225- 0.23 100% Cle
O NH 229 EtOAc D3
H Me Dlb
-0- N
~
234- 0.29 40%
-0-
68 A9
o-Q;to
~ /; 236 EtOAc/
60%
Cla
NMe
hexane
0
69 0.48 50% 481
O N_H EtOAc/ (M+H)+
-Q-O S
-
~ ;,N
Me 50% pet
ether
(HPLC
ES-MS)
70 0.46 5% 564 AI0
-O
O NH MeOH/ (M+H)+ Cla
~
95% (HPLC
-0-o
I/~
N) CH2Cl2 ES-MS)
\_o
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,
71 199- I To.5o 10% A14
O NH
-O
201 MeOH/ Cla
~ CH2Cl D4
-0-o
I/
.
N
'---\
• \_o
N)
2
72 235- 0.55 10% Al4

O NH
-0- -O
237 MeOH/ Cla
Me CH2Cl D4
0 2
.
N
73 200- 0.21 50% A14
NH
-0-o-O
O 201 MeOH/ Cla
I/ ~ '---\ N-Me
CH2Cl
2
D4
N Me'
74 145-
O NH
-O
148
-0-o
~
I/
N
'---\
OSi(Pr-i)J
75 0.12 70% 527 All

0-NH EtOAc/ {M+H)+ Clf
30% (HPLC Dlc
-O-o-Oo hexane ES-MS)
76 0 0.18 70% All

EtOAc/ Clf
Meo 30% Dlc
hexane
N)
\_N
-O-o-Oo
77 0.74 70% All
F-0-NH EtOAc/ Clf
30% Dlc
-Q-o-Oo he xane
78 Me 0.58 70% Al 1
:N-0-NH EtOAc/ Clf
30% Die
~
-0-o-Oo hex ane
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79 0.47 70% 569 Al 1
-Od
O NH EtOAe/ (M+H)+ Clf
30% (HPLC Ole
-0- 0 ~H hexane ES-MS)
/J
80 0.18 70% 508 Al 1
-Q-o -O
O NH EtOAe/ (M+H)+ Clf
30% (HPLC Ole
~Me hexane ES-MS)
81 0.58 70% 557 Al I

Me0-0-NH EtOAe/ (M+H)+ Clf
30% (HPLC Ole
-O-o-Oo hexane ES-MS)
82 0.37 70% 611 Al I

rN-o-~ NH EtOAe/ (M+H)+ Clf
30% (HPLC Ole
\_j -00 hexane
-Q-o ~-/J
ES-MS)
83 0.19 70% Al I
QN) EtOAe/
30%
hexane
Clf
Ole
\_N
-O-o-Oo
84 179- A2
O NH
-O
183 Al7
Cla
-0-o ~H 05
Table 5. 3-(Trifluoromethyl)-4-bromophenyl Ureas
0 Ft Br
R,N)lND
H H
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TLC Mass
Entrv R (OC) (min.) Rr System [Sourcel Method
85 186- 0.13 50% 509 A2
O NH 187 EtOAc/ (M+H)+ Bl
Me 50% pet (HPLC ES- Cla
-0- -
0
-b
ether
50%
MS)
545 A6
-
86 150- 0.31
Cl -bO NH
-0- Me 50% pet (HPLC ES- Cla

ether MS)
0 ~ /,N
217- 0.16 50% 545 A2
-
87
Cl -bO NH
-0- Me 50% pet (HPLC ES- Cla

ether MS)
. 0 ~ ;,N
88 183- 0.31 50% 525 A2
O NH 184 EtOAc/ (M+H)+ Bl
Et 50% pet (HPLC ES- Cla
89
-0- -
0
-b
0.21
ether
50%
MS)
511 A2
O N_H EtOAc/ (M+H)+ Bl
-Q-b 0
-
~ /,N
Me 50%pet
ether
(HPLC ES- Cla
MS)
90 0.28 50% 525 A2

e O N_H EtOAc/ (M+H}+ Bl
-Q-~ 0
-
~ ;,N
Me 50% pet
ether
(HPLC ES- Cla
MS)
91 214- 0.28 50% 522 A2

0 ~::
50% pet (HPLC ES- Cla
92
-0--6 0 ~ /,N
0.47
ether
50%
MS)
527 A2 step
O NH EtOAc/ {M+H}+ 3b.
Me 50%pet (HPLC ES- A2 step
-0- -
s
-b
ether MS)
Bl,
Cla
4,
93 0.46 50% 527 A2 step

O N_H EtOAc/ (M+H)+ 3b.
-Q-b S
-
~ ;,N
Me 50% pet (HPLC ES- A2 step
ether MS) 4.
Bl.
Cla
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94 145- 0.41 5% AIO

O NH 150 MeOH/ Bl
• ~ 95% Cla
-0- 0 -O N>
\_ 0
CH2Cl2
Table 6. 5-(Trifluorometbyl)-4-chloro-2-methoxypbenyl Ureas
o tCI
R,N)lNY
H H 0Me
TLC Mass
Entry R (OC) (min.) Rr System fSourcel Method
95 140- 0.29 5% 495 A2
O NH 144 MeOH/ (M+H)+ A7
Me 45% (HPLC Bl
-0- 0
-O
EtOAc/
50% pet
ether
ES-MS) Cla
244- 0.39 5% 529 A6
-
96
245 MeOH/ (M+H)+ A7
Cl -OO NH
-0- 0 ~ /,N
Me 45%
EtOAc/
50%pet
ether
(HPLC
ES-MS)
Bl
Cla
97 220- 0.25 5% 529 A2
-0- - Cl
0
-OO
~ ;,N
NH
Me
221 MeOH/
45%
EtOAc/
50% pet
(M+H)+
(HPLC
ES-MS)
A7
Bl
Cla
ether
98 0.27 5% 495 A2
O N_H MeOH/ (M+H)+ A7
- Me 45% (HPLC Bl
-Q-O EtOAc/ ES-MS) Cla
0 ~ /,N
50% pet
ether
'99 180- 0.52 5% 509 A2
O NH 181 'MeOH/ (M+H)+ A7
Et 45% (HPLC Bl
-0- 0
-O
EtOAc/
50% pet
ether
ES-MS) Cla
100 162- A2
-d:
O NH 165 A7
Pr-1 Bl
-0- 0 Cla
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TLC Mass
Entry R (OC) (min.) R, System fSourcel Method
~
101 0 162- Al
165 A2
o 01 od'--:: ~H C3
N)l_N~ h Me
OMe H H
~
102 0.10 50% 442 A2
0 EtOAc/ (M+H)+ A4
~
0
N)lNO
H H
'C( Me
I O I ---::: NH 50%
hexane
(HPLC
ES-MS)
C2d
MevN Me
~ I.
103 0 125- 0.24 40% 512 A2
130 EtOAc/ (M+H)+ C2b
HN)lNH
60% (FAB)
0
0 Q 0
hexane
OF 9=0
NH-Me Me-NH
The preceding examples can be repeated with similar success by substituting the generically
or specifically described reactants and/or operating conditions of this invention for those used
in the preceding examples.
10 From the foregoing description, one skilled in the art can easily ascertain the essential
characteristics of this invention and, without departing from the spirit and scope thereof, can
make various changes and modifications of the invention to adapt it to various usages and
conditions.
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l!TRUE COPYII
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WHAT IS CLAIMED IS:
A-D-B (I)
D is -NH-C(O)-NH-,
A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L 1 )q ,

where L is a 5 or 6 membered cyclic structure bound directly to D, L I comprises a
substituted cyclic moiety having at least 5 members, M is a bridging group having at least
10 one atom, q is an integer of from 1-3; and each cyclic structure of L and L 1 contains 0-4

15 wherein L 1 is substituted by at least one substituent selected from the group consisting
of -SO2Rx, -C(O)Rx and -C(NRy) Rz,

halo,
20 R2 is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally

Rx is Rz or NRaRbwhere Ra and Rb are
25 a) independently hydrogen,

89
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halogen; or

Io 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based
c) one of Ra or Rb is -C(O)-, a C 1-Cs divalent alkylene group or a substituted C 1-

15 members, wherein the substituents of the substituted C1-C5 divalent alkylene group are
where B is substituted, L is substituted or L I is additionally substituted, the

n is 0-3;
wherein each W is independently selected from the group consisting of -CN, -CO2R7,
-C(O)NR 7R7 , -C(O)-R 7 , .;NO2,-OR 7 , -SR7 , -NR 7R7 , -NR7 C(O)OR 7 , -NR 7C(O)R7, -Q-Ar, and
selected from the group consisting of -CN, -CO2R7, -C(O)R 7 , -C(O)NR 7R7 , -OR7 , -SR7, -
7
NR7R7, -NO2, -NR 7C(O)R 7 , -NR 7C(O)OR 7 and halogen up to per-halo; with each R
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wherein Q is -0-, -S-, -N(R 7)-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)mO-, -(CH2)mS-,
-(CH2)mN(R7)-, -O(CH2)m- CHXa-, -CXa2-, -S-(CH2)m- and -N(R 7)(CH2)m-, where m= 1-3,
and Xa is halogen; and

up to per-halo, and optionally substituted by Z01 , wherein nl is 0 to 3 and each Z is
independently selected from the group consisting of -CN, -CO 2R 7 , -C(O)R 7 , -C(O)NR 7R 7 , -
NO 2, -OR SR -NR R -NR C(O)OR -NR C(O)R and a carbon based moiety of up to
7 7 7 7 7 7 7
7
, - , , ,
10 substituted by one or more substituents selected from the group consisting of -CN, -CO 2R7, -
7 7 7
COR 7 , -C(O)NR 7R 7 , -OR 7 , -SR 7, -NO 2 , -NR R , -NR C(O)R 7 , and -NR 7C(O)OR7, with R 7 as
defined above.
2. A compound as in claim 1 wherein:
15 Ry is hydrogen, C 1. 1o alkyl, C1.10alkoxy, C3.10cycloalkyl having 0-3 heteroatoms, C2.

10alkenyl, C 1.1oalkenoyl, C6-12aryl, C3.12hetaryl having 1-3 heteroatoms selected from N, S
and 0, C1.24aralkyl, C1.24alkaryl, substituted C1.10alkyl, substituted C1.10alkoxy, substituted
C3. 10cycloalkyl having 0-3 heteroatoms selected from N, S and 0, substituted C6 -C 14aryl,
substituted C3. 12hetaryl having 1-3 heteroatoms selected from N, S and 0, substituted C1. 24
20 alkaryl or substituted C 7~C24 aralkyl, where Ry is a substituted group, it is substituted by

halogen up to per halo,
R 2 is hydrogen, C 1. 1o alkyl, C1.10alkoxy, C3.10cycloalkyl having 0-3 heteroatom, C2 .,o

alkenyl, C 1. 10alkenoyl, C 12aryl, C3 -C12hetaryl having 1-3 heteroatoms selected from, S, N
6
.
25 and 0, C 7. 24 alkaryl, C 7. 24 aralkyl, substituted C1.10alkyl, substituted C 1. 1o alkoxy, substituted

C6 -C 14aryl, substituted C3 -C10cycloalkyl having 0-3 heteroatoms selecred from S, N and 0,
substituted C 12hetaryl having 1-3 heteroatoms selected from S, N and 0, substituted
3
. c~.2 ➔
alkaryl or substituted C 7-C24 aralkyl where R2 is a substituted group, it is substituted by

halogen up to per halo, hydroxy, C 1. 10alkyl, C 12cycloalkyl having 0-3 heteroatoms selected
3
.
:0 from 0. S and N, C;. 12 hetaryl having 1-3 heteroatoms selected from N, S and 0. C1.111
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IITRUE COPYjl
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alkoxy, C 6_12 aryl, C 1. 6 halo substituted alkyl up to per halo alkyl, C6-C12 halo substituted aryl
up to per halo aryl, C 3-C 12 halo substituted cycloalkyl up to per halo cycloalkyl having 0-3
heteroatoms selected from N, S and 0, halo substituted C3-C12 hetaryl up to per halo hetaryl
having 1-3 heteroatoms selected from 0, N and S, halo substituted C1-C2 4 aralkyl up to per
5 halo aralkyl, halo substituted C7-C 24 alkaryl up to per halo alkaryl, and -C(O)R 8 ,
Ra and Rb are,
a carbon based moiety selected from te group consisting of C 1 -C 10 alkyl, C I -
10 C 10 alkoxy, C3.10 cycloalkyl, C2.10 alkenyl, C1.10 alkenoyl, C6-12 aryl, C3.12 hetaryl having 1-3
heteroatoms selected from 0, N and S, C3.12 cycloalkyl having 0-3 heteroatoms selected from
N, S and 0, C1.24 aralkyl, CrC24 alkaryl, substituted C1.10 alkyl, substituted C 1. 10 alkoxy,
substituted C3. 10 cycloalkyl, having 0-3 heteroatoms selected from N, Sand 0, substituted C6.
12 aryl, substituted C3. 12 hetaryl having 1-3 heteroatoms selected from N, Sand 0, substituted
15 C7. 24 aralkyl, substituted C1.24 alkaryl, where Ra and Rb are a substituted group, they are
substituted by halogen up to per halo, hydroxy, C1.10 alkyl, C3.12 cycloalkyl having 0-3
heteroatoms selected from 0, Sand N, C3. 12 hetaryl having 1-3 heteroatoms selected from N,
S and 0, C 1. 1o alkoxy, C6-12 aryl, C1-6 halo substituted alkyl up to per halo alkyl, C6-C 12 halo
substituted aryl up to per halo aryl, C3-C 12 halo substituted cycloalkyl having 0-3 heteroatoms
20 selected from N, S and 0, up to per halo cycloalkyl, halo substituted C3-C12 hetaryl up to per
halo heteraryl, halo substituted C 7-C2 4 aralkyl up to per halo aralkyl, halo substituted C1-C 24
alkaryl up to per halo alkaryl, and -C(O)R 8 ; or
-OSi(Rrh where Rr is hydrogen, C1.10 alkyl, C1.10 alkoxy, C3-C 10 cycloalkyl

having 0-3 heteroatoms selected from 0, S and N, C6.12 aryl, C3-C 12 hetaryl having 1-3
25 het~roatoms selected from 0, S and N, C1.24 aralkyl, substituted C 1-10 alkyl, substituted C1-
C 10 alkoxy, substituted C3-C12 cycloalkyl having 0-3 heteroatoms selected from 0, S and N,
substituted C3-C 12 heteraryl having 1-3 heteroatoms selected from 0, S, and N, substituted
C6. 12 aryl, and substituted C7. 24 alkaryl, where Rr is a substituted group it is substituted
halogen up to per halo, hydroxy, C 1. 10 alkyl, C3.12 cycloalkyl having 0-3 heteroatoms selected
30 from 0, S and N, C 3. 12 hetaryl having 1-3 heteroatoms selected from N, S and 0, C1.10
alkoxy. C,.12 aryl. C1 -C2.i alkaryl, C1 -C 2.i aralkyl, C1.6 halo substituted alkyl up to per halo
92
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alkyl, C 6-C 12 halo substituted aryl up to per halo aryl, C 3-C12 halo substituted cycloalkyl
C 3-C 12 hetaryl up to per halo heteraryl, halo substituted CrC24 aralkyl up to per halo aralkyl,
halo substituted CrC24 alkaryl up to per halo alkaryl, and -C(O)R 8 ,
5 or

1-3 heteroatoms selected from N, S and O with substituents selected from the group
consisting of halogen up to per halo, hydroxy, C1.10 alkyl, C3.12 cycloalkyl having 0-3
10 heteroatoms selected from 0, Sand N, C3.12 hetaryl having 1-3 heteroatoms selected from N,
S and 0, C1.10 alkoxy, C6-12 aryl, C1 -C24 alkaryl, C1 -C24 aralkyl, halo substituted C1-6 alkyl
up to per halo alkyl, halo substituted C6-C12 aryl up to per halo aryl, halo substituted C 3-C 12
cycloalkyl having 0-3 heteroatoms selected from N, S and 0, up to per halo cycloalkyl, halo
substituted C3-C 12 hetaryl up to per halo heteraryl, halo substituted C 7-C 24 aralkyl up to per
15 halo aralkyl, halo substituted CrC24 alkaryl up to per halo alkaryl, and -C(O)Rg,
or
c) one of Ra or Rb is -C(O)-, a C 1-C5 divalent alkylene group or a substituted C 1-

20 members,
wherein the substituents of the substituted C,-Cs divalent alkylene group are selected from
the group consisting of halogen, hydroxy, C1.10 alkyl, C3.12 cycloalkyl having 0-3 heteroatoms
selected from 0, Sand N, C3. 12 hetaryl having 1-3 heteroatoms selected from N, Sand 0, C 1.
10 alkoxy, C6.12 aryl, C1 -C24 alkaryl, C1 -C24 aralkyl, C1-6 halo substituted alkyl up to per halo
25 alkyl, C 6-C 12 halo substituted aryl up to per halo aryl, C3-C12 halo substituted cycloalkyl
C3-C 12 hetaryl up to per halo heteraryl, halo substituted C1-C24aralkyl up to per halo aralkyl,
where Rg is C 1. 10 alkyl; -CN, -CO2Ri, -ORI, -SRI, -NO2, -C(O) R._., -,R.iR, .. •
30 NRi C(O)ORe and -NRJ C(O)Re, and Ri and R: are independently selected from the group
93
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consisting of hydrogen, C 1_10, alkyl, C1-10 alkoxy, C3-10 cycloalkyl having 0-3 heteroatoms
selected from 0, N and S, C 6. 12 aryl, CJ- C12 hetaryl with 1-Jheteroatoms selected from 0, N
and S and C1 -C24 aralkyl, C 7 -C24 alkaryl, up to per halo substituted C 1-C 1o alkyl, up to per
halo substituted C3 -C 10 cycloalkyl having 0-3 heteroatoms selected from 0, N and S, up to
5 per halo substituted C 6 -C 14 aryl, up to per halo substituted C 3 -C 12 hetaryl having 1-3
heteroatoms selected from 0, N, and S, halo substituted C1-C 24 alkaryl up to per halo alkaryl,
and up to per halo substituted C7-C24 aralkyl,
Wis independently selected from the group consisting of -CN, -C0 2R 7, -C(O)NR 7R7 ,
10 -C(O)-R7, -N0 2, -OR 7 , -SR7, -NR7R7 , -NR7 C(O)OR7 , -NR.7C(O)R7, C1-C 10 alkyl, C1-C10
alkoxy, C 2-C 1o alkenyl, C 1-C 1o alkenoyl, C3-C10 cycloalkyl having 0-3 heteroatoms selected
from 0, S and N, C6-C14 aryl, CrC24 alkaryl, C1 -C24 aralkyl, C3-C12 heteroaryl having 1-3
heteroatoms selected from 0, N and S, C4-C23 alkheteroaryl having 1-3 heteroatoms selected
from 0, N and S, substituted C1-C10 alkyl, substituted C1-C10 alkoxy, substituted C 2-C 10
15 alkenyl, substituted C 1-C 1o alkenoyl, substituted C3-C 10 cycloalkyl having 0-3 heteroatoms
selected from 0, N and S, substituted C6-C12 aryl, substituted C3-C 12 hetaryl having 1-3
heteroatoms selected from 0, N and S, substituted C1-C24 aralkyl, substituted C 7-C 24 alkaryl,
substituted C4 -C23 alkheteroaryl having 1-3 heteroatoms selected from 0, N and S, and -Q-
Ar;
20
R7 is independently selected from H, C1-C10 alkyl, C1-C10 alkoxy, C 2 -C 1o alkenyl, C 1-
C 10 alkenoyl, C3-C10 cycloalkyl having 0-3 heteroatoms selected from 0, S and N, C 6-C 14
aryl, C3-C13 hetaryl having 1-3 heteroatoms selected from 0, N and S, C1-C14 alkaryl, C1 -C24
aralkyl, C4-C23 alkheteroaryl having 1-3 heteroatoms selected from 0, N and S, up to per-
25 halosubstituted C 1-C 10 alkyl, up to per-halosubstituted C 3-C10 cycloalkyl having 0-3
heteroatoms selected from 0, N and S, up to per-halosubstituted C6-C 14 aryl, up to per-
halosubstituted C3-C 13 hetaryl having 1-3 heteroatoms selected from 0, N and S, up to per-
halosubstituted CrC 24 aralkyl, up to per-halosubstituted C1-C24 alkaryl, and up to per-
halosubstituted C.i-C23 alkheteroaryl; and
30
94
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each Z is independently selected from the group consisting of -CN, -CO 2R7, -C(O)R7,
7 7 7 7
-C(O)NR 7R7, -NO2, -OR , - SR -NR R7, -NR 7C(O)OR 7 , -NR C(O)R7, C1-C10alkyl, C1-C10
alkoxy, C2-C 10alkenyl, C1-C10alkenoyl, C3-C10cycloalkyl having 0-3 heteroatoms selected
from O, N and S, C6-C14aryl, C3-C13hetaryl having 1-3 heteroatoms selected from 0, N and
5 S, C7-C24alkaryl, C1 -C24aralkyl, C4-C23alkheteroaryl having 1-3 heteroatoms selected from
O, N and S, substituted C1-C10alkyl, substituted C1-C10alkoxy, substituted C2-C1o alkenyl,
substituted C1-C10alkenoyl, substituted C3-C10cycloalkyl having 0-3 heteroatoms selected
from 0, N and S, substituted C6-C12 aryl, substituted C1-C24alkaryl, substituted C1-C24
aralkyl and substituted C4-C23 alkheteroaryl having 1-3 heteroatoms selected from 0, N
10 and S; wherein if Z is a substituted group, the one or more substituents are selected from the
group consisting of -CN, -CO2R7, -COR 7, -C(O)NR 7R 7, -OR7 , -SR7 , -NO2, -NR 7R7 ,
-NR 7C(O)R 7 , and -NR 7C(O)OR 7 .
3. A compound as in claim 1 wherein Mis one or more bridging groups selected

15 from the group consisting of -0-, -S-, -N(R 7)-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH 2)mO-, -
(CH2)mS-,-(CH2)mN(R7)-, -O(CH2)m-CHXa-, -CXa2-, -S-(CH2)m-and -N(R 7)(CH2)m-,where
m= 1-3, xa is halogen and R 7is as defined in claim 1.

directly to D are not substituted in the ortho position by-OH.
20 5. A compound as in claim 1 wherein the cyclic structures of B and L bound

directly to D are not substituted in the ortho position by a moiety having an fonizable
6. A compound of claim 1 wherein B of Formula I is a substituted or

unsubstituted six member aryl moiety or six member hetaryl moiety, said hetaryl moiety
25 having 1 to 4 members selected from the group of hetaryl atoms consisting of nitrogen,
7. A compound of claim l wherein B of Formula I is an unsubstituted phenyl

group, an unsubstituted pyridyl group, an unsubstituted pyrimidinyl, a phenyl group
30 and n are as defined in claim 1, a pyrimidinyl group substituted by a substituent selected from
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PCT /US00/00648
the group constituting of halogen and Wn, whereas W and n are as defined in Claim 1, or a
halogen and Wn wherein W and n are as defined in claim 1.
8. A compound of claim 6 wherein B of Formula I is a substituted phenyl group,

5 a substituted pyrimidinyl group, or substituted pyrridyl group substituted 1 to 3 times by 1 or
more substituents selected from the group consisting of -CN, halogen, C1-C10alkyl, C 1-C 10
alkoxy, -OH, up to per halo substituted C 1-C 10 alkyl, up to per halo substituted C 1-C 10alkoxy
9. A compound of claim 1, wherein L, the six member cyclic structure bound

10 directly to D, is a substituted or unsubstituted 6 member aryl moiety or a substituted or
unsubstituted 6 member hetaryl moiety, wherein said hetaryl moiety has 1 to 4 members
balance of said hetaryl moiety being carbon, wherein the one or more substituents are
selected from the group consisting of halogen and Wn wherein W and n are as defined in
15 claim 1.
10. A compound of claim 8, wherein L, the 6 member cyclic structure bound

directly to D, is a substituted phenyl, unsubstituted phenyl, substituted pyrimidinyl,
unsubstituted pyrimidinyl, substituted pyridyl or unsubstituted pyridyl group.
11. A compound of claim 1, wherein said substituted cyclic moiety L I comprises a

20 5 to 6 membered aryl moiety or hetaryl moiety, wherein said heteraryl moiety comprises 1 to
4 members selected from the group of heteroatoms consisting of nitrogen, oxygen and sulfur.


25 pyridinyl or pyrimidinyl.
I
14. A compound of claim 6, wherein said substituted cyclic moiety L is phenyl,
I
15. A compound of claim 8, wherein said substituted cyclic moiety.L is phenyl.
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16. A compound of claim 9, wherein said substituted cyclic moiety L 1 is pheny 1,

17. A compound of claim 10, wherein said substituted cyclic moiety L 1 is phenyl,
5 18. A compound of claim 14, wherein M is one or more bridging groups selected
7
from the group consisting of -0-, -S-, -N(R )-, -(CH2)m-, -C(O)-, ~CH(OH)-, -(CH 2)mO-, -
(CH2)mS-, -(CH2)mN(R7)-, -O(CH2)m- CHXa-, -CXa2-, -S-(CH2)m- and -N(R 7)(CH2)m-, where
m= 1-3, X3 is halogen and R7 is hydrogen or a carbon based moiety of up to 24 carbon atoms,
Io halogen up to per hal~-
19. A compound of claim 15, wherein Mis one or more bridging groups selected
from the group consisting of -0-, -S-, -N(R 7)-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH 2)mO-, -
7
(CH2)mS-, -(CH2)mN(R )-, -O(CH2)m- CHXa-, -CXa2-, -S-(CH2)m- and -N(R 7)(CH2)m-, where
m= 1-3, X3 is halogen and R7 is hydrogen or a carbon based moiety of up to 24 carbon atoms,
15 optionally containing heteroatoms selected from N, S and O and optionally substituted by
20. A compound of claim 16, wherein M is one or more bridging groups selected
from the group consisting of -0-, -S-, -N(R 7)-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH 2)mO-, -
7 7
(CH2)mS-, -(CH2)mN{R )-, -O(CH2)m- CHXa-, -CXa2-, -S-(CH2)m· ~d -N(R )(CH2)m·, where
20 m= 1-3, Xa is halogen and R7 is hydrogen or a carbon based moiety of up to 24 carbon atoms,
21. A compound of claim 17, wherein M is one or more bridging groups selected
from the group consisting of -0-, -S-, -N(R 7)-, -(CH2)m·, -C(O)-, -CH(OH)-, -(CH2)mO-, -
7 7
25 (CJ:I2)mS-,-(CH2)mN(R )-, -O(CH2)m- CHXa-, -CXa2-, -S-(CH2)m· and -N(R )(CH2)m·, where
m= 1-3, Xa is halogen and R 7 is hydrogen or a carbon based moiety of up to 24 carbon atoms,
22. A compound of claim l wherein L 1 is additionally substituted l to 3 times by

30 one or more substituents selected from the group consisting of C1-C10 alkyl, up to per halo
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substituted C 1-Cw alkyl, -CN, -OH, halogen, C1-C10alkoxy and up to per halo substituted C,-
Cw alkoxy.
23. A compound of claim 13 wherein L 1 is additionally substituted 1 to 3 times by
one or more substituents selected from the group consisting of C1-C1o alkyl, up to per halo
5 substituted C 1-C 10alkyl, -CN, -OH, halogen, C1-C10alkoxy and up to per halo substituted C 1-
Cw alkoxy.
substituted C 1-C 10alkyl, -CN, -OH, halogen, C1-C10alkoxy and up to per halo substituted C 1-
10 C10 alkoxy.

C10 alkoxy.
15 26. A compound of claim 20 wherein L 1 is additionally substituted 1 to 3 times by

one or more substituents selected from the group consisting of C 1-C 10alkyl, up to per halo
substituted C1-C10alkyl, -CN, -OH, halogen, C1-C10alkoxy and up to per halo substituted C 1-
C10 alkoxy.

20 one or more substituents selected from the group consisting of C 1-C 10alkyl, up to per halo
C10 alkoxy.
28. A compound of claim 1 wherein L 1 is substituted by -C(O)Rx .
29. A compound of claim 1 wherein L I is substituted by -SO 2Rx .
25 30. A compound of claim 1 wherein L I is substituted only by -C(O)Rx .
31. A compound of claim I wherein L I is substituted only by -SO 2 Rl( .
32. A compound of claim I wherein L 1 is substituted by -C(O)Rx or -SO~R,,

wherein Rx is NRaRb.
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33. A compound of claim 13 wherein L 1 is substituted by -C(O)Rx or -SO 2Rx,

wherein Rx is NRaR.ii,and Ra and Rb are

5 heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and
selected from N, Sand O and are optionally substituted by halogen, or

halogen; or

15 1-3 heteroatoms selected from N, Sand O substituted by halogen, hydroxy or carbon based
substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected fromN,
c) one of Ra or Rb is -C(O)-, a C 1-C 5 divalent alkylene group or a substituted C 1-

20 members, wherein the substituents of the substituted C 1-C5 divalent alkylene group are
to 24 carbon atoms, which optionally contain heteroatoms selected from N, Sand O and are
optionally substituted by halogen.
34. A compound of claim 18 wherein L 1 is substituted by -C(O)Rx or -SO2Rx,

25 wherein Rx is NRaRb and Ra and Rb are independently hydrogen or a carbon based moiety
optionally sµbstituted by halogen, hydroxy and carbon based substituents of up to 24 carbon
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35. A compound of claim 19 wherein L I is substituted by -C(O)Rx, wherein Rx is

NRaRb and Ra and ~ are independently hydrogen or a carbon based moiety of up to 30
carbon atoms optionally containing heteroatoms selected from N, S and O and optionally
substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms,
5 which optionally contain heteroatoms selected from N, S and O and are optionally
36. A compound of claim 20 wherein L 1 is substituted by -C(O)Rx or -SO 2Rx,

IO optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon
atoms, which option.ally contain heteroatoms selected from N, S and O and are optionally
37. A compound of claim 21 wherein L 1 is substituted by -C(O)Rx or -SO2Rx,

15 of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and
optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon
20 38. A compound of Formula I:
A-D-B (I)
D is -NH-C(O)-NH-,
A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L 1 )q ,

25 where L is a 6 membered aryl moiety or a 6 membered hetaryl moiety bound directly to D,
L I comprises a substituted cyclic moiety having at least 5 members, M is a bridging group
having at least one atom, q is an integer of from 1-3; and each cyclic structure of Land L 1
IITRUE COPYII
WO 00/42012 PCT/US00/00648

wherein L I is substituted by at least one substituent selected from the group consisting
5 of -SO2Rx, -C(O)Rx and -C{NRy) R2 ,

halo,

heteroatoms selected from N, Sand O and are optionally substituted by halogen;
Rx is Rz or NRaR.i,where Ra and Rb are


halogen; or

25 heteroatoms selected from N, S and 0, or a substituted 5-7 member heterocyclic structure of
l-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based
c) one of Ra or Rb is -C(O)-, a C1-C5 divalent alkylene group or a substituted C-

30 C5 divalent alkylene group bound to the moiety L to form a cyclic structure with at kast 5
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members, wherein the substituents of the substituted C 1-Cs divalent alkylene group are
5 where B is substituted, L is substituted or L I is additionally substituted, the

n is 0-3;
wherein each W is independently selected from the group consisting of -CN, -CO 2R7,
-C(O)NR7R7 , -C(O)-R 7, -NO2, -OR7, -SR7, -NR7R7, -NR7C(O)OR7, -NR 7C(O)R7, -Q-Ar, and
10 carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected
selected from the group consisting of -CN, -CO2R7, -C(O)R 7, -C(O)NR 7R7, -OR7 , -SR 7, -
7 7 7 7 7 7
NR R7, -NO2, -NR C(O)R , -NR C(O)OR and halogen up to per-halo; with each R
15 containing heteroatoms selected from N, Sand O and optionally substituted by halogen,
7
wherein Q is -0-, -S-, -N(R )-, -(CH2)m-,-C(O)-, -CH(OH)-, -(CH2)mO-,-(CH2)niS-,
-(CH2)mN(R7)-, -O(CH2)m- CHX2 -, -CX2 2-, -S-(CH2)m-and -N(R7)(CH2)m-, where m= 1-3,
and Xa is halogen;

up to per-halo, and optionally substituted by Zn1, wherein nl is 0 to 3 and each Z is
independently selected from the group consisting of -CN, -CO 2R7, -C(O)R 7, -C(O)NR 7R 7, -
NO2, -OR 7 , - SR7 -NR 7R7 , -NR7C(O)OR7, -NR7C(O)R7, and a carbon based moiety of up to
25 substituted by one or more substituents are selected from the group consisting of -CN, -
CO~R7 , -COR\ -C(O)NR 7R7, -OR7, -SR7, -NO2, -NR 7R 7 , -NR 7 C(O)R7, and -NR7C(O)OR7,
with R 7 as defined above; and
wherein M is one or more bridging groups selected from the group consisting of -0-, -S-, -
N(R7)-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)mO-, -(CH2)mS-, -(CH2)mN(R7)-, -O(CH2)m-
30 CHXa-. -CX3 2-. -S-(CH 2)m-and -N(R7)(CH2)m-,where m= 1-3, Xa is halogen.
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A-D-B (I)
D is -NH-C(O)-NH-,
A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L 1 )q,

where L is a substituted or unsubstituted phenyl or peritoneal moiety bound directly to D, L 1
comprises a substituted phenyl, peritoneal or pyrimidinyl moiety, M is a bridging group
10 having at least one atom, q is an integer of from 1-3; and
Bis a substituted or unsubstituted phenyl or pyridine group bound directly to D,
wherein L 1 is substituted by at least one substituent selected from the group consisting
of -SO2Rx, -C(O)Rx and -C(NRy) Rz,

15 containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per
halo, and;
R2 is hydrogen .or a carbon based moiety of up to 30 carbon atoms optionally

20 heteroatoms selected from N, Sand O and are optionally substituted by halogen;
Rx is R2 or NRaR.iiwhere Ra and Rb are

25 carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms
-OSi(Rrh where Rr is hydrogen or a carbon based moiety of up to 24 carbon

atoms optionally containing heteroatoms selected from N, S an·d O and optionally substituted
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halogen; or

5 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based
c) one of Ra or Rb is -C(O)-, a C1-Cs divalent alkylene group or a substituted C 1-

10 members, wherein the substituents of the substituted C 1-C5 divalent alkylene group are
to 24 carbon atoms, which optionally contain heteroatoms selected from N, Sand O and are

n is 0-3;
wherein each W is independently selected from the group consisting of -CN, -CO2R 7,
-C(O)NR 7R7, -C(O)-R 7, -NO2, -OR 7, -SR 7, -NR 7R 7, -NR7C(O)OR7, -NR 7C(O)R 7, -Q-Ar, and
selected from the group consisting of -CN, -CO 2R 7, -C(O)R 7, -C(O)NR 7R 7 , -OR 7, -SR 7, -
NR 7R7, -NO2, -NR 7C(O)R7, -NR 7C(O)OR 7 and halogen up to per-halo; with each R 7
25 wherein Q is -0-, -S-, -N(R7)-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)mO-, -(CH2)mS-,

-(CH2)mN(R7)-, -O(CH2)m-CHX -CX3 2-, -S-(CH2)m-and -N(R 7)(CH2)m-, where m= 1-3,
3
-,
and Xa is halogen;

30 up to per-halo, and optionally substituted by Z0 1, wherein nl is O to 3 and each Z is
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independently selected from the group consisting of -CN, -CO2R 7, -C(O)R7, -C(O)NR 7R7, -
NO2, -OR7, - SR -NR R -NR C(O)OR -NR C(O)R
7 7 7
,
7 7
,
7 7
, and a carbon based moiety of up to

substituted by one or more substituents selected from the group consisting of -CN, -CO2R7, -
5 COR 7 , -C(O)NR R -OR -SR -NO 2, -NR R7,-NR C(O)R7, and -NR 7C(O)OR
7 7
,
7
,
7
,
7 7 7
; and
7
N(R )-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)mO-, -(CH2)mS-, -(CH2)mN(R7)-, -O(CH2)m-
CHX 2 -, -CX2 2-, -S-(CH2)m-and -N(R 7)(CH2)m-,where m= 1-3, Xa is halogen.

10 directly to Dare not substituted in the ortho position by-OH.


15 directly to D are not substituted in the ortho position by-OH.

44.
A compound as in claim 38 wherein substituents for B and L and additional •
20 substituents for -L 1, are selected from the group consisting of C 1-C 10alkyl up to per halo
substituted C,-C,o alkyl, CN, OH, halogen, C1-C10alkoxy and up to per halo substituted C 1-
C10alkoxy.
45. A compound as in claim 39 wherein substituents for B and L and additional

substituents for L1, are selected from the group consisting of C 1-C 10alkyl up to per halo
25 substituted C1-C10alkyl, CN, OH, halogen, C1-C,o alkoxy and up to per halo substituted C 1-
C10 alkoxy.
46. A compound of claim 38 wherein L 1 is substituted by C(O)Rx or SO2Rx.
47. A compound of claim 39 wherein L 1 is substituted by C(O)Rx or SO1R,.
48. A compound of claim 46 wherein R, is NRaRb and Ra and Rb are

30 independently hydrogen and a carbon based moiety of up to 30 carbon atoms optionally
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heteroatoms selected from N, S and O and are optionally substituted by halogen ..
49. A compound of claim 47 wherein Rx is NRaRb and Ra and Rb are

5 independently hydrogen and a carbon based moiety of up to 30 carbon atoms optionally

acid (tosylate salt), 1-napthalene su_lfonic acid, 2-napthalene sulfonic acid, acetic acid,
and

trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid,
and
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and

and
25 b) acid salts of organic and inorganic bases containing cations selected from the
54. A compound of claim 39 which is a pharmaceutically acceptable salt of a compound

107
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and
IO substituted ammonium cations and aromatic substituted ammonium cations.
55. A pharmaceutical composition comprising a compound of claim 1 or a

pharmaceutically acceptable salt of a compound of formula I , and a physiologically
acceptable carrier.

15 with fQrmula I or a pharmaceutically acceptable salt thereof, and a physiologically
acceptable carrier.

acceptable carrier.
20 58. A pharmaceutical composition comprising a compound of claim 38 consistent

acceptable carrier.

25 acceptable carrier.
3-tert butyl phenyl ureas of Table 1 above;
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3-(trifluoromethyl) -4 chlorophenyl ureas of Table 4 above;
5 ureas 101-103 in Table 7 above.

N-(3-tert-butylphenyl)-N '-( 4-(3-(N-methylcarbamoyl)phenoxy)phenyl urea and
N-(3-tert-butyiphenyI)-N'-( 4-( 4-acetylphenoxy)phenyl urea;

N-(5-tert-butyl-2-methoxyphenyl)-N '-(4-( 1,3-dioxoisoindolin-5-y loxy )phenyl) urea,
N-(5-tert-butyl-2-methoxyphenyl)-N'-(4-(1-oxoisoindolin-5-yloxy)phenyl) urea,
N-( 5-tert-butyl-2-methoxyphenyl)-N '-(4-( 4-methoxy-3-(N-
15 methylcarbamoyl)phenoxy)phenyl) urea and
N-(5-tert-butyl-2-methoxyphenyl)-N'-(4-(3-(N-methylcarbamoyl)phenoxy)phenyl) urea;
the 2-methoxy-5-trifluoromethyl)phenyl ureas:

N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxy)phenyl) urea,
20 . N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-
N-(2-methoxy-5-( trifluoromethyl)phenyl)-N '-(4-(2-carbamoy 1-4-pyridyloxy )phenyl) urea,
25 N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-
pyridylthio )phenyl) urea,
N-( 2-methoxy-5-( tri fluoromethyl )phenyl )-N '-(2-chloro-4-(2-(N-methy lcarbamoy 1)(4-
109
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WO 00/42012 PCT /US00/00648
N-{2-methoxy-5-( trifluoromethyl)pheny I)-N '-(3-chloro-4-(2-(N-methylcarbamoyl)( 4-

pyridyloxy) )phenyl) urea;

s N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxy)phenyl) urea,
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)
urea,
N-( 4-chloro-3-(trifluoromethyl)phenyl)-N'-( 4-(2-carbamoyl-4-pyridyloxy)phenyl) urea and
N-( 4-chloro-3-( trifluoromethyl)pheny 1)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridy loxy )phenyl)
10 urea.

N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)
urea,
15 N--(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)
urea,
·N-( 4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridylthio )phenyl)
urea,
N-( 4-bromo-3-( trifluoromethy l)pheny 1)-N'-(2-chloro-4-(2-(N-methy lcarbamoyl)( 4-
20 pyridyloxy))phenyl) urea and
N-( 4-bromo-3-( trifluoromethyl)phenyl)-N '-(3-chloro-4-(2-(N-methylcarbamoy 1)(4-
pyridyloxy) )phenyl) urea; and

25 N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-
N-(2-methoxy-4-chloro-5-( trifluoromethyl)phenyl)-N '-(4-(2-(N-methylcarbamoy 1)-4-
pyridy loxy )phenyl) urea,
N-( 2-methoxy-4-chloro-5-( tri fluoromethy I)pheny I)-N '-(2-chloro-4-(2-( N-
30 methylcarbamoyl)(4-pyridyloxy))phenyl) urea and

110
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WO 00/42012 PCT/US00/00648
5 comprising administering a compound of Formula I of claim 33.
10 66. A method for the treatment of a cancerous cell growth mediated by raf kinase,
comprising administrating a compound selected from the group consisting of
3-tert butyl phenyl ureas of Table 1 above;
15 3-(trifluoromethyl)-4 chlorophenyl ureas of Table 4 above;
ureas 101-103 in Table 7 above.
20 comprising administrating a compound selected from the group consisting of
N-( 3-tert-butylpheny 1)-N'-(4-(3-(N-methylcarbamoyl)phenoxy )phenyl urea and
N-(3-tert-butylphenyl)-N'-( 4-(4-acetylphenoxy)phenyl urea;
25 the 5-tert-butyl-2-methoxyphenyl ureas:

;\'-(5-tert-butyl-2-methoxyphenyl)-N '-(4-( 1,3-dioxoisoindolin-5-yloxy)phenyl) urea,
N-(5-tert-butyl-2-methoxyphenyl)-N '-(4-( l-oxoisoindolin-5-yloxy)phenyl) urea,
111
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WO 00/42012 PCT /US00/00648
N-( 5-tert-butyl-2-methoxyphenyl)-N '-(4-( 4-methoxy-3-(N-

N-(5-tert-butyl-2-methoxyphenyl)-N'-(4-(3-(N-methylcarbamoyl)phenoxy)phenyl) urea;
5 the 2-methoxy-5-trifluoromethyl)phenyl ureas:

N-(2-methoxy-5-( trifluoromethyl)phenyl)-N '-(3-(2-carbamoyl-4-pyridy loxy )phenyl) urea,
N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl) urea,
1o N-(2-methoxy-5-( trifluoromethyl)phenyl)-N '-(4-(2-(N-methylcarbamoyl)-4-
pyridyloxy )phenyl) urea,
N-(2-methoxy-5-( trifluoromethyl)phenyl)-N '-(4-(2-(N-methylcarbamoy I)-4-
15 N-(2-methoxy-5-( trifluoromethy 1)phenyl)-N '-(2-chloro-4-(2-(N-methylcarbamoy I)(4-

pyridyloxy) )phenyl) urea and
N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)( 4-
20 the 4-chloro-3-(trifluoromethyl)phenyl ureas:

N-( 4-chloro-3-( trifluoromethyl)phenyl )-N '-(3-(2-carbamoy 1-4-pyridyloxy)pheny I) urea,
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)
urea,
N-( 4-chloro-3-(trifluoromethyl)phenyl)-N '-(4-(2-carbamoyl-4-pyridyloxy)phenyl) urea and
25 N-( 4-chloro-3-( trifluoromethyl)phenyl)-N •-(4-(2-(N-methylcarbamoy 1)-4-pyridyloxy)phenyl)
urea;

N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)
30 urea,
1\/-(4-bromo-3-( trifluoromethyl )phenyl )-N '-(4-( 2-(N-methy lcarbamoyl )-4-pyridyloxy )phenyl)
urea,
112
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WO 00/42012 PCT /US00/00648
N-( 4-bromo-3-( trifluoromethyl )phenyl )-N '-(3-(2-(N-methylcarbamoyl )-4-pyridylthio )pheny 1)
urea,
N-( 4-bromo-3-( trifl uoromethy l)phenyl)-N '-(2-chloro-4-(2-(N-methy lcarbamoy I)(4-

5 N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-

IO pyridyloxy)phenyl) urea,
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-( 4-(2-(N-methylcarbamoyl)-4-
N-(2-methoxy-4-chloro-5-( trifluoromethyl)phenyl)-N '-(2-chloro-4-(2-(N-
methy lcarbamoy l)(4-pyridyloxy) )phenyl) urea and
15 N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-
113
l!TRUE COPYII
INTERNATIONAL SEARCH REPORT International application No.
PCT /US00/00648
A. CLASSIFICATION OF SUBJECT MATTER

IPC(7) :Please See Extra Sheet.
US CL :Please See Extra Sheet.
According to International Patent Classification (!PC) or to both national classification and !PC
B. FIELDS SEARCHED
Minimum documentation searched (cla~,;ification system followed by classification symbols)
U.S. : 546/288, 289,291,300; 514/183, 222.2, 228.8, 588,595,597,598; 564/49, 50, 52,
Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)
CAS ONLINE, REGISTRY, HCAPLUS
search terms : cancer, raf kinase
C. DOCUMENTS CONSIDERED TO BE RELEVANT
Category• Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.
y WO 98/52558 Al (BAYER CORPORATION) 26 November 1998, 1-67

(26.11.98) especially Tables 1-4, pages 65-76.
y WO 98/52559 Al (BAYER CORPORATIONl) 26 November 1998 1-67

(26.11.98), especially Tables 1-4, pages 15-17.
Y,P Database HCAPLUS, DN 131:87909, DUMAS et al. 'Inhibition of 1-67

P38 kinase activity using substituted heterocyclic ureas.' Abstract,
WO 99/32111, 01 July 1999, see entire document.
Y,P Database HCAPLUS, DN 131:73649, DUMAS et al. 'Preparation of 1-67

pyrazolyl aryl ureas and related compounds as P38 kinase
inhibitors. ' Abstract, WO 99/32110, 01 July 1999, see entire
document.
~ Further documents are listed in the continuation of Box C.

□ See patent family annex.
. Special categories of cited documencs: 'T' lacer documenl published after che in1ema1ionalfiling dace or priority
date and nol in conflict with the application but cited to understandche
"A" documencdefining the general slate.of lhe art which is nol considered principle or cheoryunderlying :he invencion
10 be of particular relevance
"X" documenc of particular relevance: che claimed invencion cannot be
"E" earlier documencpublished on or after che incemacionalfiling date considered novel or cannot be considered to involve an inventive step
"L" documenc which may lhrow doubts on priority claim(s) or which is when che documenl is caken alone
ciced 10 escablish lhe publicacion dace of anocher ci1a1ionor ocher
special reason (as specified) "Y" documenl of particular relevance: the claimed invention cannoc b.e
considered to involve an inventive step when the document 1s
"O" document referring to an oral disclosure, use, exhibition or other means combined with one or more other such documents. such combination
being obvious 10 a person skilled in che art
"'P"' documenl published prior to che in1ema1ionalfiling dace buc lacerchan
lhe prioricydace claimed "&"" documenl member of che same palent family
Date of the actual completion of the international search Date of mailing of the international search report
22 MAY 2000 29 JUN200(1

Authorized officer J'G\
1~~ fn'
Name and mailing address of the ISA/US
Commissioner of Patents and Trademarks CJ\)· l'l 1
Box PCT
Washington, D.C. 20231
RITA DESAI ( (
Facsimile No. (703) 305-3230 Telephone No. (703) 308-1235

Form PCT/ISA/210 (second sheet) (July 1998)*
I!TRUE COPYII
PCT/US00/00648
C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT
Category• Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.
X Database HCAPLUS, DN 127:293717, KURIK M.V. et al. 1-48,60 and 61

'Optical properties of segmented oligourethane with azomethine
terminal fragments.' Abstract, Vysokomol. Soedin. 1996, Vol. 38,
No. 12, pages 2038-2041, especially RN# 197149-54-5.
X Database HCAPLUS, DN 127:34137, KUBO et al. 'Preparation of 1-67

quinoline and quinazoline derivatives inhibiting platelet-derived
growth factor receptor autophosphorylation.' Abstract, WO
97/17329. 15 May 1997, see entire document, especially RN #
190726-87-5, 190726-88-6, 190727-39-0, 190727-43-6.
X Database HCAPLUS, DN 126:166148, WINKLER et al. 'Inhibitors 1-67

of coenzyme A-independent transacylase induce apoptosis in
human HL-60 cells.' Journal of Pharmacol. 1996, Vol. 279, No. 2,
pages 956-966, see entire document, especially RN# 162793-63-7
and 187173-03-1.
X Database HCAPLUS, DN 98:78152, CHUGAI 1-67

PHARMACEUTICAL CO. LTD., JAPAN. 'Antitumor
benzophenone derivatives.' Abstract, JP 57185219. 15 November
1982, see entire document, especially RN# 3086-71-4.
A Database HCAPLUS, DN 72:79046, HIRT et al. 'Tuberculostatic 1-67

and cancerstatic polybasic ureas.' Abstract, CH 479557. 15 October
1969, see entire document, especially RN# 5262-16-8.
X,P Database HCAPLUS, DN 131:58658, MILLER et al. 'Inhibition of 1-67

raf kinase using symmetrical and unsymmetrical substituted
diphenyl ureas.' Abstract, WO 99/32436. 01 July I 999, see entire
document, especially RN# 228399-32-4.
X Database HCAPLUS, DN 127:273945, DEARDEN et al. 1-48, 50 and 61

'Quantitative structure-biodegradability studies: an investigation of
the MITI aromatic compound database.' Nato ASI Srv. 1996, Vol.
23, pages 93-104, see entire document, especially RN# 24019-05-4.
X Database HCAPLUS, ON 125:245169, BONWICK et al. 1-67

'Production of murine monoclonal antibodies against sulcofuron
and flucofuran by in-vitro immunization.' Journal of
Immunological Methods. 1996, Vol. I 96, No. 2, pages 163-173.
See entire document, especially RN# 240 I 9-05-04.
Form PCT/ISA/210 (continuation of second sheet) (July 1998)*
\!TRUE coPYJI
PCT/US00/00648
Box I Observations where certain claims were found unsearchable (Continuation of item 1 of first sheet)
This international report has not been established in respect of certain claims under Article l 7(2)(a) for the following reasons:
I. D Claims Nos.:
because they relate to subject matter not required to be searched by this Authority, namely:
2. □ Claims Nos.:
because they relate to parts of the international application that do not comply with the prescribed requirements to such
an extent that no meaningful international search can be carried out, specifically:
3. □ Claims Nos.:
because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).
Box II Observations where unity of invention is lacking (Continuation of item 2 of first sheet)
This International Searching Authority found multiple inventions in this international application, as follows:
Please See Extra Sheet.
I. ~ As all required additional search fees were timely paid by the applicant, this international search report covers all searchable
claims.
2. □ As all searchable claims could be searched without effort justifying an additional fee, this Authority did not invite payment
of any additional fee.
3. □ As only some of the required additional search fees were timely paid by the applicant. this international search report covers
only those claims for which fees were paid, specifically claims Nos.:
4. □ No required additional search fees were timely paid by the applicant. Consequently. this international search report is
restricted to the invention first mentioned in the claims; it is covered by claims Nos.:
Remark on Protest [2 The additional search fees were accompanied by the applicant's protest.
D No protest accompanied the payment of additional search fees.
Form PCT/ISA/2 IO (continuation of first sheet( I)) (July 1998)*
l!TRUE COPYII
PCT /US00/00648
A. CLASSIFICATION OF SUBJECT MATTER:

IPC (7):
com 211/78, 211/72; A61 K 31/33, 31/54, 31/535. 31/17; C07C 275/20, 275/22, 275/24, 275/28
A. CLASS IFICA TIOJ\I OF SUBJECT MATTER:

US CL :
546/288, 289,291,300; 514/183, 222.2, 228.8, 588,595,597.598; 564/49, 50, 52,
BOX II. OBSERVATIONS WHERE UNITY OF INVENTION WAS LACKING

This ISA found multiple inventions as follows:
This application contains the following inventions or groups of inventions which are not so linked as to form a single
inventive concept under PCT Rule 13.1. In order for all inventions to be searched, the appropriate additional search fees
must be paid.
Group I, claims 1-37,50-58 and 60-67 in part, drawn to compounds pharmaceutical compositions and method of using
these, wherein D is -NH-C(O)-NH-, B is a 3-tert butylphenyl or 5 tert butyl or trifluoromethyl (methoxy and / or
chloro substituted) phenyl, and r is a non-hetero biaryl linked via an Oxygen atom.
Group II, claims 1-37, 50-58, 60-67 in part , drawn to compounds compositions and methods of using these, wherein D
is -NH-C(O)-NH-, B is a 3-tert butylphenyl or a 5 tert butyl or trifluoromethyl (methoxy and/or chloro substituted)
phenyl, and R is a biaryl, in which one of them is a pyridine group linked via an Oxygen atom.
Group III, claims 1-37 50-58, 60-67 in part , drawn to compounds pharmaceutical compositions and methods of using
these, wherein D is -NH-C(O)-NH-, B is a 3-tert butylphenyl or a 5 tert butyl or trifluoromethyl (methoxy and /or chloro
substituted) phenyl , and R is a biaryl, in which one of them is a pyrimidnyl linked via an Oxygen atom.
Group IV , claims 1-37, 50-58,60-67 in part , drawn to compounds , pharmaceutical compositions and method of using
these, wherein D is -NH-C(O)-NH-, B is a 3-tert butylphenyl or a 5 tert butyl or trifluoromethyl (methoxy and /or chloro
substituted ) phenyl, and R is another hetero group linked via an Oxygen atom (may be subject to further restriction).
Group V, claims 1-37, 50-58,60-67 in part, drawn to compounds, pharmaceutical compositions and a method of using
these wherein R is a biaryl or an hetero group linked via an Nitrogen/amide/urea linkage anJ which may be subject to
further restriction depending on the selected hetero group.
Group VI , claims 39, 42,43,45,47,49,59 in part , drawn to a different scope of compounds and compositions , subject
to further restriction.
Group VII. claims 38,40,41,44,46,48,49,50 in part , drawn to a different scope of compounds of formula I , subject to
further restriction.
Group VIII, claims 50-54 , drawn to various salts of compounds and their compositions , may be subject to further
restriction.
They form an improper Markush Grouping and do not have a common core.
I. The inventions listed as Groups I, 11, and III do not relate to a single general inventive concept under PCT
Rule 13.1 because, under PCT Rule 13.2, they lack the same or corresponding special technical features for the
following reasons:
(t) "Markush Practice." The situation involving the so-called "Markush practice" wherein a single claim defines
alternatives (chemical or non-chemical) is also governed by Rule 13.2. In this special situation, the requirement of a
technical interrelationship and the same or corresponding special technical features as defined in Rule 13.2, shall be
considered to be met when the altenatives arc of a similiar nature.
(i) When the Markush grouping is for alternatives of chemical compounds, they shall be regarded as being of a
similiar nature where the following criteria are fulfilled:
(A) all alternatives have a common property or activity, and
(8)( I) a common structure is present, i.e., a significant structural element is shared by all of the alternatives, or
(8)(2) in cases where th.: common structure cannot be the unifying criteria, all alternatives belong to a recognized
class of chemical compounds in the art to which the invention pertains.
(ii) In paragraph (f)(i)(B)( I), above , the words "significant structural element is shared by all of the alternatives" refer
to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or
in case the compounds have in common only a small portion of their structures, the commonly shared structure
constitutes a structurally distinctive portion in view of the existing prior art. The structural element may be a single
component or a combination of individual components linked to-gether.
The different A and D along with the L's. R's and M substituents have so many variables with the heterocyclic and
non-hetero groupings , they have different bonding and properties , and have achieved a different status in the art , and
Form PCT/ISA/210 (extra sheet) (July 1998)*
\!TRUE coPYJI
PCT/US00/00648
is burdensome to search and hence are objected to as being drawn to an improper Markush group on the grounds of
lack of a common nucleus. The terms A, B,L's, R's and M are so broad in scope that a prior art reference anticipating
the claims with respect to one member
under 35 USC 102(b) would not render obvious the same claims under 35 USC 103a with respec. :o another member.
The improper Markush group rejection finds basis in case law, compare In re Swenson 56 USPQ 180; In re Ruzicka, 66
USPQ 226; In re Winnek, 73 USPQ 225: In re Harnisch, 206 USPQ 300, 305 (CCPA 1980).In view of the foregoing,
restriction is required.
Form PCT/ISA/210 (extra sheet) (July 1998)*
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I 1111111111111111
11111
1111111111
111111111111111
lllll 111111111111111
11111111
US007351834Bl
c12) United States Patent (10) Patent No.: US 7,351,834 Bl

Riedl et al. (45) Date of Patent: *Apr. 1, 2008
(54) w-CARBOXYARYL SUBSTITUTED 2,745,874 A 5/1956 Schetty et al.

DIPHENYL UREAS AS RAF KINASE 2,781,330 A 2/1957 Downey
INHIBITORS 2,797,214 A 6/1957 Werner Bossard
2,867,659 A 1/1959 Model et al.
(75) Inventors: Bernd Riedl, Wuppertal (DE); Jacques 2,877,268 A 3/1959 Applegate et al.
Dumas, Orange, CT (US); Uday Khire, 2,960,488 A 11/1960 Tamblyn et al.
Hamden, CT (US); Timothy Lowinger, 2,973,386 A 2/1961 Weldon
Hyogo (JP); William Scott, Guilford, 3,151,023 A 9/1964 Martin
CT (US); Roger A. Smith, Madison, 3,200,035 A 8/1965 Martin et al.
CT (US); Jill E. Wood, Hamden, CT
3,230,141 A 1/1966 Frick et al.
(US); Mary-Katherine Monahan,
3,284,433 A 11/1966 Becker et al.
Hamden, CT (US); Reina Natero,
Hamden, CT (US); Joel Renick, 3,424,760 A 1/1969 Helsley et al.
Milford, CT (US); Robert Sibley, 3,424,761 A 1/1969 Helsley et al.
North Haven, CT (US) 3,424,762 A 1/1969 Helsley et al.
3,547,940 A 12/1970 Brantley
(73) Assignee: Bayer Pharmaceuticals Corporation, 3,646,059 A 2/1972 Brantley
West Haven, CT (US) 3,689,550 A 9/1972 Schellenbaum et al.
3,743,498 A 7/1973 Brantley
( *) Notice: Subject to any disclaimer, the term of this
patent is extended or adjusted under 35 3,754,887 A 8/1973 Brantley
U.S.C. 154(b) by O days. 3,823,161 A 7/1974 Lesser
3,828,001 A 8/1974 Broad et al.
This patent is subject to a terminal dis- 3,860,645 A 1/1975 Nikawitz
claimer. 3,990,879 A 11/1976 Soper
4,001,256 A 1/1977 Callahan et al.
(21) Appl. No.: 09/889,227 4,009,847 A 3/1977 Aldrich et al.
4,042,372 A 8/1977 Harper
(22) PCT Filed: Jan. 12, 2000
4,062,861 A 12/1977 Yukinaga et al.
(86) PCT No.: PCT /US00/00648 4,071,524 A 1/1978 Banitt
4,111,680 A 9/1978 Yukinaga et al.
§ 371 (c)(l),
(2), (4) Date: Jan. 8, 2002
(87) PCT Pub. No.: WO00/42012 (Continued)

PCT Pub. Date: Jul. 20, 2000 FOREIGN PATENT DOCUMENTS
Related U.S. Application Data CA 2146707 10/1995
(60) Provisional application No. 60/115,877, filed on Jan.

13, 1999.
(Continued)
(51) Int. Cl.
C07D 213130 (2006.01) OTHER PUBLICATIONS
A61K 31144 (2006.01)
Caplus 113:106314, Abstract of JP 2022650, Silver Halide color
(52) U.S. Cl. ....................................... 546/290; 514/247 photographic material containing a cyan coupler of 2-ureido-phenol
(58) Field of Classification Search ................ 546/290, type to improve dye developability and remove lecuo cyan dye,
546/300, 329, 346; 544/242, 298, 309, 329, Noboru Mizukura et al. Jan. 25, 1990.
544/358; 564/48, 52, 53, 55, 63; 514/256,
514/345,351,357,482,588,596,247,277 (Continued)
Primary Examiner-Rita Desai
(56) References Cited (74) Attorney, Agent, or Firm-Millen, White, Zelano &
Branigan, P.C.
U.S. PATENT DOCUMENTS
(57) ABSTRACT
502,504 A 8/1893 Thoms
1,742,156 A 12/1929 Fritzky
2,046,375 A 7/1936 Goldstein et al.
2,093,265 A 9/1937 Coffey et al. This invention relates to the use of a group of aryl ureas in
2,288,422 A 6/1942 Rohm treating raf mediated diseases, and pharmaceutical compo-
2,649,476 A 8/1953 Martin sitions for use in such therapy.
2,683,082 A 7/1954 Hill et al.
2,722,544 A 11/1955 Martin 41 Claims, No Drawings
IITRUE COPY!I
US 7,351,834 Bl
Page 2
U.S. PATENT DOCUMENTS 6,133,319 A 10/2000 Widdowson

6,143,764 A 11/2000 Kubo et al.
4,111,683 A 9/1978 Singer 6,147,116 A 11/2000 Barbachyn et al.
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4,173,638 A 11/1979 Nishiyama et al. 6,178,399 Bl 1/2001 Takebayashi et al.
4,183,854 A 1/1980 Crossley 6,180,675 Bl 1/2001 Widdowson et al.
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4,468,380 A 8/1984 O'Doherty et al. 6,297,381 Bl 10/2001 Cirillo et al.
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4,546,191 A 10/1985 Nishiyama et al. 6,344,476 Bl 2/2002 Ranges et al.
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4,808,588 A 2/1989 King 6,492,393 Bl 12/2002 Breitfelder et al.
4,820,871 A 4/1989 Kissener et al. 6,500,863 Bl 12/2002 Qi et al.
4,863,924 A 9/1989 Haga et al. 6,525,046 Bl 2/2003 Cirillo et al.
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Forbes, Ian T., "N-(l-Methyl-5-indolyl)-N -(3-methyl-5- of variously substituted carboxamides of the central nervous ststem"
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pp. 226-228. * cited by examiner
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w-CARBOXYARYL SUBSTITUTED including solid cancers, such as, for example, carcinomas
DIPHENYL UREAS AS RAF KINASE (e.g., of the lungs, pancreas, thyroid, bladder or colon),
INHIBITORS myeloid disorders (e.g., myeloid leukemia) or adenomas
(e.g., villous colon adenoma).
CROSS-REFERENCE TO RELATED The present invention therefore provides compounds gen-
APPLICATIONS erally described as aryl ureas, including both aryl and
heteroaryl analogues, which inhibit the raf kinase pathway.
This application is a 371 of PCT/US00/00648 filed Jan. 8, The invention also provides a method for treating a raf
2000, which claims the benefit of provisional application mediated disease state in humans or mammals. Thus, the
Ser. No. 60/115,877, filed Jan. 13, 1999. 10 invention is directed to compounds which inhibit the
enzyme raf kinase and also compounds, compositions and
FIELD OF THE INVENTION methods for the treatment of cancerous cell growth mediated
by raf kinase wherein a compound of Formula I is admin-
This invention relates to the use of a group of aryl ureas istered or pharmaceutically acceptable salt thereof.
in treating raf mediated diseases, and pharmaceutical com- 15
A-D-B (I)
positions for use in such therapy.
In formula I, D is -NH-C(O)-NH-,
BACKGROUND OF THE INVENTION A is a substituted moiety of up to 40 carbon atoms of the
1
formula: -L-(M-L )q, where L is a 5 or 6 membered
The p21ras oncogene is a major contributor to the <level- 20 cyclic structure bound directly to D, L1comprises a substi-
opment and progression of human solid cancers and is tuted cyclic moiety having at least 5 members, M is a
mutated in 30% of all human cancers (Bolton et al. Ann. Rep. bridging group having at least one atom, q is an integer of
Med. Chem. 1994, 29, 165-74; Bos. Cancer Res. 1989, 49, from 1-3; and each cyclic structure ofL and L1contains 0-4
4682-9). In its normal, unmutated form, the ras protein is a members of the group consisting of nitrogen, oxygen and
key element of the signal transduction cascade directed by 25 sulfur, and
growth factor receptors in almost all tissues (Avruch et al. B is a substituted or unsubstituted, up to tricyclic aryl or
Trends Biochem. Sci. 1994, 19, 279-83). Biochemically, ras heteroaryl moiety ofup to 30 carbon atoms with at least one
is a guanine nucleotide binding protein, and cycling between 6-member cyclic structure bound directly to D containing
a GTP-bound activated and a GDP-bound resting form is 0-4 members of the group consisting of nitrogen, oxygen
strictly controlled by ras' endogenous GTPase activity and 30 and sulfur,
other regulatory proteins. In the ras mutants in cancer cells, wherein L 1 is substituted by at least one substituent
the endogenous GTPase activity is alleviated and, therefore, selected from the group consisting of -SO 2 Rx, ----C(O)Rx,
the protein delivers constitutive growth signals to down- and -C(NRy)R 2 ,
stream effectors such as the enzyme rafkinase. This leads to RY is hydrogen or a carbon based moiety of up to 24
the cancerous growth of the cells which carry these mutants 35 carbon atoms optionally containing heteroatoms selected
(Magnuson et al. Semin. Cancer Biol. 1994, 5, 247-53). It from N, S and O and optionally halosubstituted, up to per
has been shown that inhibiting the effect of active ras by halo,
inhibiting the rafkinase signaling pathway by administration R2 is hydrogen or a carbon based moiety of up to 30
of deactivating antibodies to raf kinase or by co-expression carbon atoms optionally containing heteroatoms selected
of dominant negative rafkinase or dominant negative MEK, 40 from N, S and O and optionally substituted by halogen,
the substrate of raf kinase, leads to the reversion of trans- hydroxy and carbon based substituents of up to 24 carbon
formed cells to the normal growth phenotype (see: Daum et atoms, which optionally contain heteroatoms selected from
al. Trends Biochem. Sci. 1994, 19, 474-80; Fridman et al. J. N, S and O and are optionally substituted by halogen;
Biol. Chem. 1994, 269, 30105-8. Kolch et al. (Nature 1991, Rx is R2 , or NRaRb where Ra and Rb are
349, 426-28) have further indicated that inhibition of raf 45 a) independently hydrogen,
expression by antisense RNA blocks cell proliferation in a carbon based moiety of up to 30 carbon atoms optionally
membrane-associated oncogenes. Similarly, inhibition of raf containing heteroatoms selected from N, S and O and
kinase (by anti sense oligodeoxynucleotides) has been cor- optionally substituted by halogen, hydroxy and carbon
related in vitro and in vivo with inhibition of the growth of based substituents of up to 24 carbon atoms, which
a variety of human tumor types (Mania et al., Nat. Med. 50 optionally contain heteroatoms selected from N, S and
1996, 2, 668-75). 0 and are optionally substituted by halogen, or
-OSi(Rf) 3 where Rf is hydrogen or a carbon based
SUMMARY OF THE INVENTION moiety of up to 24 carbon atoms optionally containing
heteroatoms selected from N, S and O and optionally
The present invention provides compounds which are 55 substituted by halogen, hydroxy and carbon based
inhibitors of the enzyme raf kinase. Since the enzyme is a substituents ofup to 24 carbon atoms, which optionally
downstream effector of p21ras, the inhibitors are useful in contain heteroatoms selected from N, S and O and are
pharmaceutical compositions for human or veterinary use optionally substituted by halogen; or
where inhibition of the rafkinase pathway is indicated, e.g., b) Ra and Rb together form a 5-7 member heterocyclic
in the treatment of tumors and/or cancerous cell growth 60 structure of 1-3 heteroatoms selected from N, Sand 0, or a
mediated by raf kinase. In particular, the compounds are substituted 5-7 member heterocyclic structure of 1-3 het-
useful in the treatment of human or animal solid cancers, eroatoms selected from N, S and O substituted by halogen,
e.g., murine cancer, since the progression of these cancers is hydroxy or carbon based substituents of up to 24 carbon
dependent upon the ras protein signal transduction cascade atoms, which optionally contain heteroatoms selected from
and therefore susceptible to treatment by interruption of the 65 N, S and O and are optionally substituted by halogen; or
cascade, i.e., by inhibiting raf kinase. Accordingly, the c) one of Ra or Rb is -C(O)-, a C 1 -C5 divalent alkylene
compounds of the invention are useful in treating cancers, group or a substituted C 1-C5 divalent alkylene group bound
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US 7,351,834 Bl
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to the moiety L to form a cyclic structure with at least 5 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl,
members, wherein the substituents of the substituted C 1 -C5 or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, or additionally option-
divalent alkylene group are selected from the group con- ally substituted phenyl, 2- or 3-thienyl, 1,3,4-thiadiazolyl,
sisting of halogen, hydroxy, and carbon based substituents of 3-pyrryl, 3-pyrazolyl, 2-thiazolyl or 5-thiazolyl, etc. For
up to 24 carbon atoms, which optionally contain heteroat- 5 example, B can be 4-methyl-phenyl, 5-methyl-2-thienyl,
oms selected from N, S and O and are optionally substituted 4-methyl-2-thienyl, l-methyl-3-pyrryl, l-methyl-3-pyra-
by halogen; zolyl, 5-methyl-2-thiazolyl or 5-methyl-1,2,4-thiadiazol-2-
where B is substituted, Lis substituted or L 1 is addition- yl.
ally substituted, the substituents are selected from the group Suitable alkyl groups and alkyl portions of groups, e.g.,
consisting of halogen, up to per-halo, and Wn, where n is 10 alkoxy, etc. throughout include methyl, ethyl, propyl, butyl,
0-3; etc., including all straight-chain and branched isomers such
wherein each Wis independently selected from the group as isopropyl, isobutyl, sec-butyl, tert-butyl, etc.
consisting of ----CN, -CO 2R7 , -C(O)NR 7 R7 , -C(O)- Suitable aryl groups which do not contain heteroatoms
R7 , -NO 2, ---OR 7 , -SR 7 , -NR 7 R7 , -NR 7 C(O)OR 7 , include, for example, phenyl and 1- and 2-naphthyl.
-NR 7 C(O)R 7 , ---Q-Ar, and carbon based moieties ofup 15 The term "cycloalkyl", as used herein, refers to cyclic
to 24 carbon atoms, optionally containing heteroatoms structures with or without alkyl substituents such that, for
selected from N, S and O and optionally substituted by one example, "C 4 cycloalkyl" includes methyl substituted cyclo-
or more substituents independently selected from the group propyl groups as well as cyclobutyl groups. The term
consisting of -CN, -CO 2R7 , -C(O)R 7 , -C(O)NR 7 R17 , "cycloalkyl", as used herein also includes saturated hetero-
-OR 7 , -SR 7 , -NR 7 R7 , -NO 2, -NR 7 C(O)R 7 , -NR C 20 cyclic groups.
(O)OR 7 and halogen up to per-halo; with each R7 indepen- Suitable halogen groups include F, Cl, Br, and/or I, from
dently selected from Hor a carbon based moiety ofup to 24 one to per-substitution (i.e. all H atoms on a group replaced
carbon atoms, optionally containing heteroatoms selected by a halogen atom) being possible where an alkyl group is
from N, S and O and optionally substituted by halogen, substituted by halogen, mixed substitution of halogen atom
wherein Q is ---0-, -S-, -N(R 7 )-, -(CH 2)m-, 25 types also being possible on a given moiety.
-C(O)-, ----CH(OH)-, -(CH2)mO, -(CH2)mS-, The invention also relates to compounds per se, of for-
-(CH2)mN(R 7 )-, ---O(CH2)m-, ----CHXa-, ----CXa2-, mula I.
7
-S-(CH 2)m-, and-N(R )(CH 2)m-, where m=l-3, and The present invention is also directed to pharmaceutically
xa is halogen; and acceptable salts of formula I. Suitable pharmaceutically
Ar is a 5- or 6-member aromatic structure containing 0-2 30 acceptable salts are well known to those skilled in the art and
members selected from the group consisting of nitrogen, include basic salts of inorganic and organic acids, such as
oxygen and sulfur, which is optionally substituted by halo- hydrochloric acid, hydrobromic acid, sulfuric acid, phos-
gen, up to per-halo, and optionally substituted by Zn 1 , phoric acid, methanesulfonic acid, trifluoromethanesulfonic
wherein nl is O to 3 and each Z is independently selected acid, benzenesulfonic acid, p-toluenesulfonic acid, 1-naph-
from the group consisting of -CN, ----CO2R7 , ----C(O)R7 , 35 thalenesulfonic acid, 2-naphthalenesulfonic acid, acetic
-C(O)NR_R_, -NO 2, ---OR 7 , -SR 7 -NR 7 R7 , -NR 7 C acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid,
(O)OR 7 , -NR 7 C(O)R 7 , and a carbon based moiety ofup to lactic acid, oxalic acid, succinic acid, fumaric acid, maleic
24 carbon atoms, optionally containing heteroatoms selected acid, benzoic acid, salicylic acid, phenylacetic acid, and
from N, S and O and optionally substituted by one or more mandelic acid. In addition, pharmaceutically acceptable
substituents selected from the group consisting of ----CN, 40 salts include acid salts of inorganic bases, such as salts
-CO 2R7 , -COR 7 , ----C(O)NR7 R7 , ---OR 7 , -SR 7 , -NO 2, containing alkaline cations (e.g., Li+ Na+ or K+), alkaline
-NR 7 R7 , -NR 7 C(O)R 7 , and -NR 7 C(O)OR 7 , with R7 as earth cations (e.g., Mg+2, ca+ 2 or Ba+2), the ammonium
defined above. cation, as well as acid salts of organic bases, including
In formula I, suitable hetaryl groups include, but are not aliphatic and aromatic substituted ammonium, and quater-
limited to, 5-12 carbon-atom aromatic rings or ring systems 45 nary ammonium cations, such as those arising from proto-
containing 1-3 rings, at least one of which is aromatic, in nation or peralkylation oftriethylamine, N,N-diethylamine,
which one or more, e.g., 1-4 carbon atoms in one or more of N,N-dicyclohexylamine, lysine, pyridine, N,N-dimethy-
the rings can be replaced by oxygen, nitrogen or sulfur laminopyridine (DMAP), 1,4-diazabiclo[2.2.2]octane
atoms. Each ring typically has 3-7 atoms. For example, B (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and
can be 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 1-, 2- 50 1,8-diazabicyclo[5.4.0]undec- 7-ene (DBU).
or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 11-, 3-, 4- or A number of the compounds of Formula I possess asym-
5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, metric carbons and can therefor exist in racemic and opti-
4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, cally active forms. Methods of separation of enantiomeric
2-, 4-, 5- or 6-pyrimidinyl, 1,2,3-triazol-1-, -4- or -5-yl, and diastereomeric mixtures are well known to one skilled
1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxa- 55 in the art. The present invention encompasses any isolated
diazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadia- racemic or optically active form of compounds described in
zol-2- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol- Formula I which possess raf inhibitory activity.
2- or -5-yl, 1,3,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4-
or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H- General Preparative Methods
thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- 60
or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, The compounds of Formula I may be prepared by the use
4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, of known chemical reactions and procedures, some from
4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzox- starting materials which are commercially available. Nev-
azolyl, 3-, 4-, 5- 6- or 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- or ertheless, general preparative methods are provided below to
7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 2-, 4-, 65 aid one skilled in the art in synthesizing these compounds,
5-, 6- or 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or with more detailed examples being provided in the Experi-
8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, 1-, 2-, 3-, mental section which follows.
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Substituted anilines may be generated using standard
methods (March. Advanced Organic Chemistry, 3rd Ed.;
John Wiley: New York (1985). Larock. Comprehensive
ArB(OR'h
Organic Transformations; VCH Publishers: New York
Pd(0)
(1989)). As shown in Scheme I, aryl amines are commonly 5
synthesized by reduction of nitroaryls using a metal catalyst,
such as Ni, Pd, or Pt, and H2 or a hydride transfer agent, such
as formate, cyclohexadiene, or a borohydride (Rylander.
Hydrogenation Methods; Academic Press: London, UK Either nitroaryls or anilines may be converted into the
(1985)). Nitroaryls may also be directly reduced using a 10 corresponding arenesulfonyl chloride (7) on treatment with
strong hydride source, such as LiAIH4 (Seyden-Penne. chlorosulfonic acid. Reaction of the sulfonyl chloride with a
Reductions by the Alumina- and Borohydrides in Organic fluoride source, such as KF then affords sulfonyl fluoride (8).
Synthesis; VCH Publishers: New York (1991)), or using a Reaction of sulfonyl fluoride 8 with trimethylsilyl trifluo-
zero valent metal, such as Fe, Sn or Ca, often in acidic romethane in the presence of a fluoride source, such as
media. Many methods exist for the synthesis of nitroaryls 15 tris( dimethylamino )sulfonium difluorotrimethylsiliconate
(March. Advanced Organic Chemistry, 3rd Ed.; John Wiley (TASF) leads to the corresponding trifluoromethylsulfone
New York (1985). Larock. Comprehensive Organic Trans- (9). Alternatively, sulfonyl chloride 7 may be reduced to the
formations; VCH Publishers: New York (1989)). arenethiol (10), for example with zinc amalgum. Reaction of
thiol 10 with CHCIF 2 in the presence of base gives the
20 difluoromethyl mercaptam (11), which may be oxidized to
H2/catalyst the sulfone (12) with any of a variety of oxidants, including
/ (eg. Ni, Pd, Pt)\ Cr0 3 -acetic anhydride (Sedova et al. Zh. Org. Khim. 1970,
ArNO2 [ff] 6, (568).
\ M(0) / 25
(eg. Fe, Sn, Ca)
Scheme I Reduction of Nitroaryls to Ary! Amines

Nitroaryls are commonly formed by electrophilic aro-
matic nitration using HNO 3 , or an alternative NO 2 - source.
Nitroaryls may be further elaborated prior to reduction.
30
0 -R
I
Thus, nitroaryls substituted with

SH
O 6-rn
35 SO,C RS
HNO3
Ar-H ArNO2
I
potential leaving groups (e.g. F, Cl, Br, etc.) may undergo CHClF2
40 (Me2N)3S Me3SiF2!
substitution reactions on treatment with nucleophiles, such Me3SiCF3 base
as thiolate (exemplified in Scheme II) or phenoxide. Nitroar- !
yls may also undergo Ullman-type coupling reactions SCHF2
6 6-"'
(Scheme II). SO,CC;R S
45
I
RX_
f
02N');(~'
F
ArSH
~
![OJ
f
02N');(~'
S-Ar
50
SO2CHF2
RX_
f
02N');(~'
RX_
SH
Br-Ar
CuO/base
/ 2
55 6-RU
Scheme III Selected Methods of Fluorinated Ary! Sulfone
Scheme II Selected Nucleophilic Aromatic Substitution Synthesis
using Nitroaryls 60 As shown in Scheme IV, non-symmetrical urea formation
Nitroaryls may also undergo transition metal mediated may involve reaction of an aryl isocyanate (14) with an aryl
cross coupling reactions. For example, nitroaryl electro- amine (13). The heteroaryl isocyanate may be synthesized
philes, such as nitroaryl bromides, iodides or triflates, from a heteroaryl amine by treatment with phosgene or a
undergo palladium mediated cross coupling reactions with phosgene equivalent, such as trichloromethyl chloroformate
aryl nucleophiles, such as arylboronic acids (Suzuki reac- 65 ( diphosgene ), bis(trichloromethyl) carbonate (triphosgene ),
tions, exemplified below), aryltins (Stille reactions) or arylz- or N,N'-carbonyldiimidazole (CDI). The isocyanate may
incs (Negishi reaction) to afford the biaryl (5). also be derived from a heterocyclic carboxylic acid deriva-
IITRUE COPY!I
US 7,351,834 Bl
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tive, such as an ester, an acid halide or an anhydride by a an inert solid diluent, for example, calcium carbonate,
Curtius-type rearrangement. Thus, reaction of acid deriva- calcium phosphate or kaolin, or as soft gelatin capsules
tive 16 with an azide source, followed by rearrangement wherein the active ingredient is mixed with water or an oil
affords the isocyanate. The corresponding carboxylic acid medium, for example peanut oil, liquid paraffin or olive oil.
(17) may also be subjected to Curtius-type rearrangements Aqueous suspensions contain the active materials in
using diphenylphosphoryl azide (DPPA) or a similar admixture with excipients suitable for the manufacture of
reagent. aqueous suspensions. Such excipients are suspending
agents, for example sodium carboxymethylcellulose, meth-
ylcellulose, hydroxypropyl methylcellulose, sodium algi-
10 nate, polyvinylpyrrolidone, gum tragacanth and gum acacia;
dispersing or wetting agents may be a naturally occurring
phosphatide, for example, lecithin, or condensation products
or an alkylene oxide with fatty acids, for example polyoxy-
0 ethylene stearate, or condensation products of ethylene
1
Ar ,
N
~ N ,,,,.Ar2 15 oxide with long chain aliphatic alcohols, for example hep-
tadecaethylene oxycetanol, or condensation products of eth-
H H ylene oxide with partial esters derived from fatty acids and
15 hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters
N3/ \DPPA 20 derived from fatty acids and hexitol anhydrides, for example
polyethylene sorbitan monooleate. The aqueous suspensions
0 0
may also contain one or more preservatives, for example
ethyl, or n-propyl p-hydroxybenzoate, one or more coloring
agents, one or more flavoring agents, and one or more
Ar1Ax Ar 1)lOH 25 sweetening agents, such as sucrose or saccharin.
16 17 Dispersible powders and granules suitable for preparation
of an aqueous suspension by the addition of water provide
the active ingredient in admixture with a dispersing or
Scheme IV Selected Methods of Non-Symmetrical Urea wetting agent, suspending agent and one or more preserva-
30 tives. Suitable dispersing or wetting agents and suspending
Formation
Finally, ureas may be further manipulated using methods agents are exemplified by those already mentioned above.
familiar to those skilled in the art. Additional excipients, for example, sweetening, flavoring
The invention also includes pharmaceutical compositions and coloring agents, may also be present.
including a compound of Formula I, and a physiologically The compounds may also be in the form of non-aqueous
35
acceptable carrier. liquid formulations, e.g., oily suspensions which may be
The compounds may be administered orally, topically, formulated by suspending the active ingredients in a veg-
parenterally, by inhalation or spray or rectally in dosage unit etable oil, for example arachis oil, olive oil, sesame oil or
formulations. The term 'administration by injection' peanut oil, or in a mineral oil such as liquid paraffin. The oily
includes intravenous, intramuscular, subcutaneous and suspensions may contain a thickening agent, for example
40
parenteral injections, as well as use of infusion techniques. beeswax, hard paraffin or cetyl alcohol. Sweetening agents
One or more compounds may be present in association with such as those set forth above, and flavoring agents may be
one or more non-toxic pharmaceutically acceptable carriers added to provide palatable oral preparations. These compo-
and if desired other active ingredients. sitions may be preserved by the addition of an anti-oxidant
Compositions intended for oral use may be prepared such as ascorbic acid.
45
according to any suitable method known to the art for the Pharmaceutical compositions of the invention may also be
manufacture of pharmaceutical compositions. Such compo- in the form of oil-in-water emulsions. The oily phase may be
sitions ma contain one or more agents selected from the a vegetable oil, for example olive oil or arachis oil, or a
group consisting of diluents, sweetening agents, flavoring mineral oil, for example liquid paraffin or mixtures of these.
agents, coloring agents and preserving agents in order to 50
Suitable emulsifying agents may be naturally-occurring
provide palatable preparations. Tablets contain the active gums, for example gum acacia or gum tragacanth, naturally-
ingredient in admixture with non-toxic pharmaceutically occurring phosphatides, for example soy bean, lecithin, and
acceptable excipients which are suitable for the manufacture esters or partial esters derived from fatty acids and hexitol
of tablets. These excipients may be, for example, inert anhydrides, for example sorbitan monooleate, and conden-
diluents, such as calcium carbonate, sodium carbonate, 55
sation products of the said partial esters with ethylene oxide,
lactose, calcium phosphate or sodium phosphate; granulat- for example polyoxyethylene sorbitan monooleate. The
ing and disintegrating agents, for example, com starch, or emulsions may also contain sweetening and flavoring
alginic acid; and binding agents, for example magnesium agents.
stearate, stearic acid or talc. The tablets may be uncoated or Syrups and elixirs may be formulated with sweetening
they may be coated by known techniques to delay disinte- 60 agents, for example glycerol, propylene glycol, sorbitol or
gration and adsorption in the gastrointestinal tract and sucrose. Such formulations may also contain a demulcent, a
thereby provide a sustained action over a longer period. For preservative and flavoring and coloring agents.
example, a time delay material such as glyceryl monostear- The compounds may also be administered in the form of
ate or glyceryl distearate may be employed. These com- suppositories for rectal administration of the drug. These
pounds may also be prepared in solid, rapidly released form. 65 compositions can be prepared by mixing the drug with a
Formulations for oral use may also be presented as hard suitable non-irritating excipient which is solid at ordinary
gelatin capsules wherein the active ingredient is mixed with temperatures but liquid at the rectal temperature and will
IITRUE COPY!I
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therefore melt in the rectum to release the drug. Such biochem Corp. 3-tert-Butylaniline, 5-tert-butyl-2-
materials include cocoa butter and polyethylene glycols. methoxyaniline, 4-bromo-3-( trifluoromethy 1)aniline,
For all regimens of use disclosed herein for compounds of 4-chloro-3-(trifluoromethyl)aniline 2-methoxy-5-(trifluo-
Formula I, the daily oral dosage regimen will preferably be romethyl)aniline, 4-tert-butyl-2-nitroaniline, 3-amino-2-
from 0.01 to 200 mg/Kg of total body weight. The daily 5 naphthol, ethyl 4-isocyanatobenzoate, N-acetyl-4-chloro-2-
dosage for administration by injection, including intrave- methoxy-5-(trifluoromethyl)aniline and 4-chloro-3-
nous, intramuscular, subcutaneous and parenteral injections, (trifluoromethyl)phenyl isocyanate were purchased and used
and use of infusion techniques will preferably be from 0.01 without further purification. Syntheses of 3-amino-2-meth-
to 200 mg/Kg of total body weight. The daily rectal dosage oxyquinoline (E. Cho et al. WO 98/00402; A. Cordi et al. EP
regime will preferably be from 0.01 to 200 mg/Kg of total 10 542,609; IBID Bioorg. Med. Chem. 3, 1995, 129), 4-(3-
body weight. The daily topical dosage regime will prefer- carbamoylphenoxy)-1-nitrobenzene (K. Ikawa Yakugaku
ably be from 0.1 to 200 mg administered between one to four Zasshi 79, 1959, 760; Chem. Abstr. 53, 1959, 12761b),
times daily. The daily inhalation dosage regime will prefer- 3-tert-butylphenyl isocyanate (0. Rohr et al. DE 2,436,108)
ably be from 0.01 to 10 mg/Kg of total body weight. and 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (K.
It will be appreciated by those skilled in the art that the 15 Inukai et al. JP 42,025,067; IBID Kogyo Kagaku Zasshi 70,
particular method of administration will depend on a variety 1967, 491) have previously been described.
of factors, all of which are considered routinely when Thin-layer chromatography (TLC) was performed using
administering therapeutics. It will also be appreciated by one Whatman® pre-coated glass-backed silica gel 60A F-254
skilled in the art that the specific dose level for a given 250 µm plates. Visualization of plates was effected by one or
patient depends on a variety of factors, including specific 20 more of the following techniques: (a) ultraviolet illumina-
activity of the compound administered, age, body weight, tion, (b) exposure to iodine vapor, (c) immersion of the plate
health, sex, diet, time and route of administration, rate of in a 10% solution of phosphomolybdic acid in ethanol
excretion, etc. It will be further appreciated by one skilled in followed by heating, (d) immersion of the plate in a cerium
the art that the optimal course of treatment, i.e., the mode of sulfate solution followed by heating, and/or (e) immersion
treatment and the daily number of doses of a compound of 25 of the plate in an acidic ethanol solution of 2,4-dinitrophe-
Formula I or a pharmaceutically acceptable salt thereof nylhydrazine followed by heating. Colunm chromatography
given for a defined number of days, can be ascertained by (flash chromatography) was performed using 230-400 mesh
those skilled in the art using conventional treatment tests. EM Science® silica gel.
It will be understood, however, that the specific dose level Melting points (mp) were determined using a Thomas-
for any particular patient will depend upon a variety of 30 Hoover melting point apparatus or a Mettler FP66 auto-
factors, including the activity of the specific compound mated melting point apparatus and are uncorrected. Fourier
employed, the age, body weight, general health, sex, diet, transform infrared spectra were obtained using a Mattson
time of administration, route of administration, and rate of 4020 Galaxy Series spectrophotometer. Proton (1H) nuclear
excretion, drug combination and the severity of the condi- magnetic resonance (NMR) spectra were measured with a
tion undergoing therapy. 35 General Electric GN-Omega 300 (300 MHz) spectrometer
The entire disclosure of all applications, patents and with either Me4 Si (Ii 0.00) or residual protonated solvent
publications cited above and below are hereby incorporated (CHC13 Ii 7.26; MeOH Ii 3.30; DMSO Ii 2.49) as standard.
by reference, including provisional application Ser. No. Carbon (13 C) NMR spectra were measured with a General
60/115,877, filed Jan. 13, 1999. Electric GN-Omega 300 (75 MHz) spectrometer with sol-
The compounds can be produced from known compounds 40 vent (CDC13 ll 77.0; MeOD-d 3 ; ll 49.0; DMSO-d 6 ll 39.5) as
(or from starting materials which, in tum, can be produced standard. Low resolution mass spectra (MS) and high reso-
from known compounds), e.g., through the general prepara- lution mass spectra (HRMS) were either obtained as electron
tive methods shown below. The activity of a given com- impact (EI) mass spectra or as fast atom bombardment
pound to inhibit raf kinase can be routinely assayed, e.g., (FAB) mass spectra. Electron impact mass spectra (EI-MS)
according to procedures disclosed below. The following 45 were obtained with a Hewlett Packard 5989A mass spec-
examples are for illustrative purposes only and are not trometer equipped with a Vacumetrics Desorption Chemical
intended, nor should they be construed to limit the invention Ionization Probe for sample introduction. The ion source
in any way. was maintained at 250° C. Electron impact ionization was
performed with electron energy of 70 eV and a trap current
EXAMPLES 50 of300 µA. Liquid-cesium secondary ion mass spectra (FAB-
MS), an updated version of fast atom bombardment were
All reactions were performed in flame-dried or oven-dried obtained using a Kratos Concept 1-H spectrometer. Chemi-
glassware under a positive pressure of dry argon or dry cal ionization mass spectra (CI-MS) were obtained using a
nitrogen, and were stirred magnetically unless otherwise Hewlett Packard MS-Engine (5989A) with methane or
indicated. Sensitive liquids and solutions were transferred 55 ammonia as the reagent gas (lxl0- 4 torr to 2.5xl0- 4 torr).
via syringe or cannula, and introduced into reaction vessels The direct insertion desorption chemical ionization (DCI)
through rubber septa. Unless otherwise stated, the term probe (Vacuumetrics, Inc.) was ramped from 0-1.5 amps in
'concentration under reduced pressure' refers to use of a 10 sec and held at 10 amps until all traces of the sample
Buchi rotary evaporator at approximately 15 mmHg. Unless disappeared (-1-2 min). Spectra were scanned from 50-800
otherwise stated, the term 'under high vacuum' refers to a 60 amu at 2 sec per scan. HPLC---electrospray mass spectra
vacuum of 0.4-1.0 mmHg. (HPLC ES-MS) were obtained using a Hewlett-Packard
All temperatures are reported uncorrected in degrees 1100 HPLC equipped with a quaternary pump, a variable
Celsius (° C.). Unless otherwise indicated, all parts and wavelength detector, a C-18 colunm, and a Finnigan LCQ
percentages are by weight. ion trap mass spectrometer with electrospray ionization.
Commercial grade reagents and solvents were used with- 65 Spectra were scanned from 120-800 amu using a variable
out further purification. N-cyclohexyl-N'-(methylpolysty- ion time according to the number of ions in the source. Gas
rene)carbodiimide was purchased from Calbiochem-Nova- chromatography-ion selective mass spectra ((GC-MS)
IITRUE COPY!I
US 7,351,834 Bl
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were obtained with a Hewlett Packard 5890 gas chromato- with water (200 mL). The resulting mixture was extracted
graph equipped with an HP-1 methyl silicone colunm (0.33 with EtOAc (2x200 mL). The combined organic layers were
mM coating; 25 mx0.2 mm) and a Hewlett Packard 5971 washed with a saturated NaCl solution (100 mL), dried
Mass Selective Detector (ionization energy 70 eV). Elemen- (MgSO 4), concentrated under reduced pressure (approxi-
tal analyses are conducted by Robertson Microlit Labs, 5 mately 0.4 mmHg overnight) to give methyl 3-methoxy-2-
Madison N.J. naphthoate as an amber oil (10.30 g): 1 H-NMR (DMSO-d 6 )
All compounds displayed NMR spectra, LRMS and either Ii 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, J=8.09 Hz, lH), 7.44
elemental analysis or HRMS consistent with assigned struc- (s, lH), 7.53 (app t, J=8.09 Hz, lH), 7.84 (d, J=8.09 Hz, lH),
tures. 7.90 (s, lH), 8.21 (s, lH).
10
AcOH acetic acid

anh anhydrous 15
atm atmosphere(s)
BOC tert-butoxycarbonyl
cone concentrated
d day(s) OMe
dee decomposition 20
DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
DMF N,N-dimethylformamide Step 2. 3-Methoxy-2-naphthoic acid
1-(3-dimethylaminopropyl )-3-ethylcarbodiimide
A solution of methyl 3-methoxy-2-naphthoate (6.28 g,
EDCI
EtOAc ethy 1 acetate 25 29.10 mmol) and water (10 mL) in MeOH (100 mL) at room
EtOH ethanol (100%) temp. was treated with a 1 N NaOH solution (33.4 mL, 33.4
Et2 0 diethyl ether mmol). The mixture % vas heated at the reflux temp. for 3
Et 3 N triethylamine
h, cooled to room temp., and made acidic with a 10% citric
h hour(s)
HOBT 1-hydroxybenzotriazole acid solution. The resulting solution was extracted with
m-CPBA 3-chloroperoxybenzoic acid 30 EtOAc (2x100 mL). The combined organic layers were
MeOH methanol washed with a saturated NaCl solution, dried (MgSO 4) and
pet. ether petroleum ether (boiling range 30-60° C.)
concentrated under reduced pressure. The residue was tritu-
temp. temperature
THF tetrahydrofuran rated with hexane then washed several times with hexane to
TFA trifluoroAcOH give 3-methoxy-2-naphthoic acid as a white solid (5.40 g,
Tf trifluoromethanesulfonyl 35 92%): 1 H-NMR (DMSO-d 6 ) Ii 3.88 (s, 3H), 7.34-7.41 (m,
2H), 7.49-7.54 (m, lH), 7.83 (d, J=8.09 Hz, lH), 7.91 (d,
J=8.09 Hz, lH), 8.19 (s, lH), 12.83 (br s, lH).
A. General Methods for Synthesis of Substituted
Anilines 40
Al. General Method for Ary! Amine Formation Via

Ether Formation Followed by Ester Saponification,
Curtius Rearrangement, and Carbamate
Deprotection
45
Synthesis of 2-Amino-3-methoxynaphthalene
50
Step 3. 2-(N-(Carbobenzyloxy)amino-3-methox-
ynaphthalene
A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6

55 mmol) and Et3 N (2.59 mL, 18.6 mmol) in anh toluene (70
mL) was stirred at room temp. for 15 min., then treated with
a solution ofDPPA (5.12 g, 18.6 mmol) in toluene (10 mL)
OMe
via pipette. The resulting mixture was heated at 80° C. for
2 h. After cooling the mixture to room temp., benzyl alcohol
60 (2.06 mL, 20 mmol) was added via syringe. The mixture was
Step 1. Methyl 3-methoxy-2-naphthoate then warmed to 80° C. overnight. The resulting mixture was
cooled to room temp., quenched with a 10% citric acid
A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 solution, and extracted with EtOAc (2x100 mL). The com-
mmol) and K2 CO 3 (7.96 g, 57.6 mmol) in DMF (200 mL) bined organic layers were washed with a saturated NaCl
was stirred at room temp. for 15 min., then treated with 65 solution, dried (MgSO 4) and concentrated under reduced
iodomethane (3.43 mL, 55.1 mmol). The mixture was pressure. The residue was purified by colunm chromatog-
allowed to stir at room temp. overnight, then was treated raphy (14% EtOAc/86% hexane) to give 2-(N-(carboben-
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zyloxy)amino-3-methoxynaphthalene as a pale yellow oil lized at 0° C. over 72 h to give 4-chloro-N-methyl-2-
(5.1 g, 100%): 1 H-NMR (DMSO-d 6 ) Ii 3.89 (s, 3H), 5.17 (s, pyridinecarboxamide (0.61 g, 5.3%): TLC (50% EtOAc/
2H), 7.27-7.44 (m, SH), 7.72-7.75 (m, 2H), 8.20 (s, lH), 50% hexane) Rf0.50; 1 H NMR (CDCl 3 ) ll 3.04 (d, J=5.1 Hz,
8.76 (s, lH). 3H), 7.43 (dd, J=5.4, 2.4 Hz, lH), 7.96 (br s, lH), 8.21 (s,
5 lH), 8.44 (d, J=5.1 Hz, lH); CI-MS m/z 171 ((M+Hr).
10 Cl~O
----: Cl
I ✓,::;N HCl
OMe
15
Step 1b. Synthesis of 4-chloropyridine-2-carbonyl
chloride HCI salt via picolinic acid
Anhydrous DMF (6.0 mL) was slowly added to SOCl 2
A slurry of 2-(N-(carbobenzyloxy)amino-3-methox- (180 mL) between 40° and 50° C. The solution was stirred
ynaphthalene (5.0 g, 16.3 mmol) and 10% Pd/C (0.5 g) in 20
in that temperature range for 10 min. then picolinic acid
EtOAc (70 mL) was maintained under a H2 atm (balloon) at (60.0 g, 487 mmol) was added in portions over 30 min. The
room temp. overnight. The resulting mixture was filtered resulting solution was heated at 72° C. (vigorous SO2
through Celite® and concentrated under reduced pressure to evolution) for 16 h to generate a yellow solid precipitate.
give 2-amino-3-methoxynaphthalene as a pale pink powder The resulting mixture was cooled to room temp., diluted
(2.40 g, 85%): 1 H-NMR (DMSO-d 6 ) ll 3.86 (s, 3H), 6.86 (s, 25
with toluene (500 mL) and concentrated to 200 mL. The
2H), 7.04-7.16 (m, 2H), 7.43 (d, J=S.0 Hz, lH), 7.56 (d, toluene addition/concentration process was repeated twice.
J=S.0 Hz, lH); EI-MS m/z 173 (M+). The resulting nearly dry residue was filtered and the solids
were washed with toluene (2x200 mL) and dried under high
A2. Synthesis of w-Carbamyl Anilines Via vacuum for 4 h to afford 4-chloropyridine-2-carbonyl chlo-
Formation of a Carbamylpyridine Followed by 30
ride HCI salt as a yellow-orange solid (92.0 g, 89%).
Nucleophilic Coupling with an Ary! Amine
Synthesis of
4-(2-N-Methylcarbamyl-4-pyridyloxy)aniline
35
Cl~O
~ OMe
1
✓,::;N HCl
0
40
Clv ~ NHMe
Step 2. Synthesis of methyl
1 4-chloropyridine-2-carboxylate HCI salt
✓,::;N
Anh DMF (10.0 mL) was slowly added to SOCl 2 (300

45 mL) at 40-48° C. The solution was stirred at that temp. range
Step la. Synthesis of for l0min., thenpicolinic acid (100 g, 812 mmol) was added
4-chloro-N-methyl-2-pyridinecarboxamide via the over 30 min. The resulting solution was heated at 72° C.
Menisci reaction (vigorous SO2 evolution) for 16 h to generate a yellow solid.
The resulting mixture was cooled to room temp., diluted
Caution: this is a highly hazardous, potentially explosive 50 with toluene (500 mL) and concentrated to 200 mL. The
reaction. To a stirring solution of 4-chloropyridine (10.0 g) toluene addition/concentration process was repeated twice.
in N-methylformamide (250 mL) at room temp. was added The resulting nearly dry residue was filtered, and the solids
cone. H2 SO4 (3.55 mL) to generate an exotherm. To this were washed with toluene (50 mL) and dried under high
mixture was added H2 O2 (30% wt in H2 O, 17 mL) followed vacuum for 4 hours to afford 4-chloropyridine-2-carbonyl
by FeSO 4 .7H2 O (0.56 g) to generate another exotherm. The 55 chloride HCI salt as an off-white solid (27.2 g, 16%). This
resulting mixture was stirred in the dark at room temp. for material was set aside.
1 h, then warmed slowly over 4 h to 45° C. When bubbling The red filtrate was added to MeOH (200 mL) at a rate
had subsided, the reaction was heated at 60° C. for 16 h. The which kept the internal temperature below 55° C. The
resulting opaque brown solution was diluted with H2 O (700 contents were stirred at room temp. for 45 min., cooled to 5°
mL) followed by a 10% NaOH solution (250 mL). The 60 C. and treated with Et 2 O (200 mL) dropwise. The resulting
resulting mixture was extracted with EtOAc (3x500 mL). solids were filtered, washed with Et2 O (200 mL) and dried
The organic phases were washed separately with a saturated under reduced pressure at 35° C. to provide methyl 4-chlo-
NaCl solution (3x-150 mL), then they were combined, dried ropyridine-2-carboxylate HCI salt as a white solid (110 g,
(MgSO 4) and filtered through a pad of silica gel with the aid 65%): mp 108-112° C.; 1 H-NMR (DMSO-d 6 ) ll 3.88 (s, 3H);
of EtOAc. The resulting brown oil was purified by column 65 7.82 (dd, J=5.5, 2.2 Hz, lH); 8.08 (d, J=2.2 Hz, lH); 8.68 (d,
chromatography (gradient from 50% EtOAc/50% hexane to 1=5.5 Hz, lH); 10.68 (br s, lH); HPLC ES-MS m/z 172
80% EtOAc/20% hexane). The resulting yellow oil crystal- ((M+Hr).
IITRUE COPY!I
US 7,351,834 Bl
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(10.29 g, 91.7 mmol), and the reddish-brown mixture was
stirred at room temp. for 2 h. The contents were treated with
4-chloro-N-methyl-2-pyridinecarboxamide (15.0 g, 87.9
mmol) and K2 CO 3 (6.50 g, 47.0 mmol) and then heated at
ClvO 80° C. for 8 h. The mixture was cooled to room temp. and
~ NHMe 5
separated between EtOAc (500 mL) and a saturated NaCl
1
.,&'N solution (500 mL). The aqueous phase was back-extracted
with EtOAc (300 mL). The combined organic layers were
washed with a saturated NaCl solution (4x1000 mL), dried
10 (Na2 SO4 ) and concentrated under reduced pressure. The
Step 3a. Synthesis of
resulting solids were dried under reduced pressure at 35° C.
4-chloro- N-methy 1-2-pyridinecarboxamide from
for 3 h to afford 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)
methy I 4-chloropyridine-2-carboxy late
aniline as a light-brown solid 17.9 g, 84%): 1H-NMR
(DMSO-d 6) Ii 2.77 (d, J=4.8 Hz, 3H), 5.17 (br s, 2H), 6.64,
A suspension of methyl 4-chloropyridine-2-carboxylate 15 6.86 (AA'BB' quartet, J=8.4 Hz, 4H), 7.06 (dd, J=5.5, 2.5
HCI salt (89.0 g, 428 mmol) in MeOH (75 mL) at 0° C. was Hz, lH), 7.33 (d, J=2.5 Hz, lH), 8.44 (d, J=5.5 Hz, lH), 8.73
treated with a 2.0 M methylamine solution in THF (1 L) at (br d, lH); HPLC ES-MS m/z 244 ((M+Hr).
a rate which kept the internal temp. below 5° C. The
resulting mixture was stored at 3° C. for 5 h, then concen- A3. General Method for the Synthesis of Anilines
trated under reduced pressure. The resulting solids were by Nucleophilic Aromatic Addition Followed by
20
suspended in EtOAc (I L) and filtered. The filtrate was Nitroarene Reduction
washed with a saturated NaCl solution (500 mL), dried
(Na2 SO4 ) and concentrated under reduced pressure to afford Synthesis of
4-chloro-N-methyl-2-pyridinecarboxamide as pale-yellow 5-(4-Aminophenoxy )isoindoline-1,3-dione
crystals (71.2 g, 97%): mp 41-43° C.; 1 H-NMR (DMSO-d 6 )
25
Ii 2.81 (s, 3H), 7.74 (dd, J=5.1, 2.2 Hz, lH), 8.00 (d, J=2.2,
~:
lH), 8.61 (d, J=5.1 Hz, lH), 8.85 (br d, lH); CI-MS m/z 171
((M+Hr).
30
HO~
0
35
Step 3b. Synthesis of To a mixture of ammonium carbonate (5.28 g, 54.9 mmol)

4-chloro- N-methy 1-2-pyridinecarboxamide from in cone. AcOH (25 mL) was slowly added 4-hydroxyph-
4-chloropyridine-2-carbonyl chloride 40 thalic acid (5.0 g, 27.45 mmol). The resulting mixture was
heated at 120° C. for 45 min., then the clear, bright yellow
4-Chloropyridine-2-carbonyl chloride HCI salt (7.0 g, mixture was heated at 160° C. for 2 h. The resulting mixture
32.95 mmol) was added in portions to a mixture of a 2.0 M was maintained at 160° C. and was concentrated to approxi-
methylamine solution in THF (100 mL) and MeOH (20 mL) mately 15 mL, then was cooled to room temp. and adjusted
at 0° C. The resulting mixture was stored at 3° C. for 4 h, 45 pH 10 with a IN NaOH solution. This mixture was cooled
then concentrated under reduced pressure. The resulting to 0° C. and slowly acidified to pH 5 using a IN HCI
nearly dry solids were suspended in EtOAc (100 mL) and solution. The resultant precipitate was collected by filtration
filtered. The filtrate was washed with a saturated NaCl and dried under reduced pressure to yield 5-hydroxyisoin-
solution (2x100 mL), dried (Na2 SO4 ) and concentrated doline-1,3-dione as a pale yellow powder as product (3.24 g,
under reduced pressure to provide 4-chloro-N-methyl-2- 50 72%): 1 H NMR (DMSO-d 6 ) Ii 7.00-7.03 (m, 2H), 7.56 (d,
pyridinecarboxamide as a yellow, crystalline solid (4.95 g, J=9.3 Hz, lH).
88%): mp 37-40° C.
55
o,NVoD o
60
-)-~
0
Step 4. Synthesis of Step 2. Synthesis of

4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline 5-(4-nitrophenoxy)isoindoline-1,3-dione
65
A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. To a stirring slurry ofNaH (1.1 g, 44.9 mmol) in DMF (40
DMF (150 mL) was treated with potassium tert-butoxide mL) at 0° C. was added a solution of 5-hydroxyisoindoline-
IITRUE COPY!I
US 7,351,834 Bl
17 18
1,3-dione (3.2 g, 19.6 nnnol) inDMF (40mL) dropwise. The mL) and acetonylacetone (0.299 g, 2.63 nnnol) via syringe.
bright yellow-green mixture was allowed to return to room The reaction mixture was heated at 120° C. for 72 h with
temp. and was stirred for 1 h, then l-fluoro-4-nitrobenzene azeotropic removal of volatiles. The reaction mixture was
(2.67 g, 18.7 nnnol) was added via syringe in 3-4 portions. cooled to room temp., diluted with CH 2 Cl2 (10 mL) and
The resulting mixture was heated at 70° C. overnight, then 5 sequentially washed with a IN HCl solution (15 mL), a IN
cooled to room temp. and diluted slowly with water (150 NaOH solution (15 mL) and a saturated NaCl solution (15
mL), and extracted with EtOAc (2x100 mL). The combined mL), dried (MgSO 4) and concentrated under reduced pres-
organic layers were dried (MgSO 4) and concentrated under sure. The resulting orange-brown solids were purified via
reduced pressure to give 5-(4-nitrophenoxy)isoindoline-l,3- column chromatography (60 g SiO2 ; gradient from 6%
EtOAc/94% hexane to 25% EtOAc/75% hexane) to give
dione as a yellow solid (3.3 g, 62%): TLC (30% EtOAc/70% 10
1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole as an
hexane) Rf0.28; 1 H NMR (DMSO-d 6 ) Ii 7.32 (d, J=12 Hz,
orange-yellow solid (0.34 g, 49%): TLC (15% EtOAc/85%
2H), 7.52-7.57 (m, 2H), 7.89 (d, J=7.8 Hz, lH), 8.29 (d, J=9 1
hexane) Rf0.67; H NMR (CDC13 ) Ii 1.34 (s, 9H), 1.89 (s,
Hz, 2H), 11.43 (br s, lH); CI-MS m/z 285 ((M+Ht, 100%). 6H), 5.84 (s, 2H), 7.19-7.24 (m, lH), 7.62 (dd, lH), 7.88 (d,
1=2.4 Hz, lH); CI-MS m/z 273 ((M+Ht, 50%).
15
20
Step 3. Synthesis of 25 N
5-(4-aminophenoxy )isoindoline-1,3-dione
A solution of 5-(4-nitrophenoxy)isoindoline-l,3-dione
~
(0.6 g, 2.11 nnnol) in cone. AcOH (12 mL) and water (0.1
mL) was stirred under a stream of argon while iron powder 30 Step 2. Synthesis of
(0.59 g, 55.9 nnnol) was added slowly. This mixture stirred 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline
at room temp. for 72 h, then was diluted with water (25 mL)
and extracted with EtOAc (3x50 mL). The combined A slurry of l-(4-tert-butyl-2-nitrophenyl)-2,5-dimeth-
organic layers were dried (MgSO 4) and concentrated under ylpyrrole (0.341 g, 1.25 nnnol), 10% Pd/C (0.056 g) and
reduced pressure to give 5-(4-aminophenoxy)isoindoline-l, 35
EtOAc (50 mL) under an H2 atmosphere (balloon) was
3-dione as a brownish solid (0.4 g, 75%): TLC (50% stirred for 72 h, then filtered through a pad of Celite®. The
EtOAc/50% hexane) Rf0.27; 1 H NMR (DMSO-d 6 ) D5.14
filtrate was concentrated under reduced pressure to give
(br s, 2H), 6.62 (d, J=S.7 Hz, 2H), 6.84 (d, J=S.7 Hz, 2H), 5-tert-butyl-2-(2,5-dimethylpyrrolyl)aniline as yellowish
7.03 (d, J=2.1 Hz, lH), 7.23 (dd, lH), 7.75 (d, J=S.4 Hz,
solids (0.30 g, 99%): TLC (10% EtOAc/90% hexane) Rf
lH), 11.02 (s, lH); HPLC ES-MS m/z 255 ((M+Ht, 100%). 40
1
0.43; H NMR (CDC13 ) Ii 1.28 (s, 9H), 1.87-1.91 (m, SH),
5.85 (br s, 2H), 6.73-6.96 (m, 3H), 7.28 (br s, lH).
A4. General Method for the Synthesis of
Pyrrolylanilines AS. General Method for the Synthesis of Anilines
from Anilines by Nucleophilic Aromatic
Synthesis of 45 Substitution
5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline
Synthesis of 4-(2-(N-Methylcarbamoyl)-4-pyridy-
loxy)-2-methylaniline HCl Salt
50
N
55
H2N
q o~M™,
~~ HCl
~
Me
60
A solution of 4-amino-3-methylphenol (5.45 g, 44.25
nnnol) in dry dimethylacetamide (75 mL) was treated with
potassium tert-butoxide (10.86 g, 96.77 nnnol) and the black
Step 1. Synthesis of mixture was stirred at room temp. until the flask had reached
1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole room temp. The contents were then treated with 4-chloro-
65 N-methyl-2-pyridinecarboxamide (Method A2, Step 3b;
To a stirring solution of 2-nitro-4-tert-butylaniline (0.5 g, 7.52 g, 44.2 nnnol) and heated at 110° C. for 8 h. The
2.57 nnnol) in cyclohexane (10 mL) was added AcOH (0.1 mixture was cooled to room temp. and diluted with water
IITRUE COPY!I
US 7,351,834 Bl
19 20
(75 mL). The organic layer was extracted with EtOAc Step 2: Synthesis of 4-(2-(N-Methylcarbamoyl)-4-
(5x100 mL). The combined organic layers were washed pyridyloxy)-2-chlorophenyl (222-trifluoro )acetamide
with a saturated NaCl solution (200 mL), dried (MgSO 4) and
concentrated under reduced pressure. The residual black oil A solution of crude 3-chloro-4-(2,2,2-trifluoroacety-
was treated with Et2 O (50 mL) and sonicated. The solution 5 lamino )phenol (5.62 g, 23.46 mmol) in dry dimethylaceta-
was then treated with HCl (1 Min Et2 O; 100 mL) and stirred mide (50 mL) was treated with potassium tert-butoxide
at room temp. for 5 min. The resulting dark pink solid (7.04 (5.16 g, 45.98 mmol) and the brownish black mixture was
g, 24.1 mmol) was removed by filtration from solution and stirred at room temp. until the flask had cooled to room
stored under anaerobic conditions at 0° C. prior to use: 1H temp. The resulting mixture was treated with 4-chloro-N-
NMR (DMSO-d 6 ) Ii 2.41 (s, 3H), 2.78 (d, J=4.4 Hz, 3H), 10 methyl-2-pyridinecarboxamide (Method A2, Step 3b; 1.99
4.93 (br s, 2H), 7.19 (dd, J=8.5, 2.6 Hz, lH), 7.23 (dd, J=5.5, g, 11.7 mmol) and heated at 100° C. under argon for 4 d. The
2.6 Hz, lH), 7.26 (d, J=2.6 Hz, lH), 7.55 (d, J=2.6 Hz, lH), black reaction mixture was cooled to room temp. and then
7.64 (d, J=8.8 Hz, lH), 8.55 (d, J=5.9 Hz, lH), 8.99 (q, J=4.8 poured into cold water (100 mL ). The mixture was extracted
Hz, lH). with EtOAc (3x75 mL) and the combined organic layers
15
were concentrated under reduced pressure. The residual
brown oil was purified by colunm chromatography (gradient
A6. General Method for the Synthesis of Anilines from 20% EtOAc/pet. ether to 40% EtOAc/pet. ether) to
from Hydroxyanilines by N-Protection, yield 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chlo-
Nucleophilic Aromatic Substitution and rophenyl (222-trifluoro )acetamide as a yellow solid (8.59 g,
Deprotection 23.0 mmol).
20
loxy )-2-chloroaniline
q
25
OH
0
FCAN
3 H
30
Cl Step 3. Synthesis of 4-(2-(N-Methylcarbamoyl)-4-
pyridy loxy )-2-chloroaniline
A solution of crude 4-(2-(N-Methylcarbamoyl)-4-pyridy-

Step 1: Synthesis of
35
loxy)-2-chlorophenyl (222-trifluoro)acetamide (8.59 g, 23.0
3-Chloro-4-(2,2,2-trifluoroacetylamino )phenol
mmol) in dry 4-dioxane (20 mL) was treated with a IN
NaOH solution (20 mL). This brown solution was allowed
Iron (3.24 g, 58.00 mmol) was added to stirring TFA (200 to stir for 8 h. To this solution was added EtOAc (40 mL).
mL). To this slurry was added 2-chloro-4-nitrophenol (10.0 The green organic layer was extracted with EtOAc (3x40
g 58.0 mmol) and trifluoroacetic anhydride (20 mL). This mL) and the solvent was concentrated to yield 4-(2-(N-
gray slurry was stirred at room temp. for 6 d. The iron was 40
Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline as a green
filtered from solution and the remaining material was con- oil that solidified upon standing (2.86 g, 10.30 mmol): 1H
centrated under reduced pressure. The resulting gray solid NMR (DMSO-d 6 ) Ii 2.77 (d, J=4.8 Hz, 3H), 5.51 (s, 2H),
was dissolved in water (20 mL). To the resulting yellow 6.60 (dd, J=8.5, 2.6 Hz, lH), 6.76 (d, J=2.6 Hz, lH), 7.03 (d,
solution was added a saturated NaHCO 3 solution (50 mL). J=8.5 Hz, lH), 7.07 (dd, J=5.5, 2.6, Hz, lH), 7.27 (d, J=2.6
The solid which precipitated from solution was removed. 45 Hz, lH), 8.46 (d, J=5.5 Hz, lH), 8.75 (q, J=4.8, lH).
The filtrate was slowly quenched with the sodium bicarbon-
ate solution until the product visibly separated from solution A 7. General Method for the Deprotection of an
(determined was using a mini work-up vial). The slightly Acylated Aniline
cloudy yellow solution was extracted with EtOAc (3x125
mL). The combined organic layers were washed with a 50 Synthesis of
saturated NaCl solution (125 mL), dried (MgSO 4) and
4-Chloro-2-methoxy-5-(trifluoromethyl)aniline
concentrated under reduced pressure. The 1H NMR
(DMSO-d 6 ) indicated a 1: 1 ratio of the nitrophenol starting
material and the intended product 3-chloro-4-(2,2,2-trifluo-
roacetylamino )phenol. The crude material was taken on to
55
the next step without further purification.
60
A suspension of 3-chloro-6-(N-acetyl)-4-(trifluorom-
65 ethyl)anisole (4.00 g, 14.95 mmol) in a 6M HCl solution (24
mL) was heated at the reflux temp. for 1 h. The resulting
solution was allowed to cool to room temp. during which
IITRUE COPY!I
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time it solidified slightly. The resulting mixture was diluted
with water (20 mL) then treated with a combination of solid
NaOH and a saturated NaHCO 3 solution until the solution
was basic. The organic layer was extracted with CH 2 Cl 2
(3x50 mL ). The combined organics were dried (MgSO 4) and 5
concentrated under reduced pressure to yield 4-chloro-2-
methoxy-5-(trifluoromethyl)aniline as a brown oil (3.20 g,
14.2 mmol): 1 H NMR (DMSO-d 6 ) Ii 3.84 (s, 3H), 5.30 (s,
2H), 7.01 (s, 2H).
10
AS. General Method for Synthesis of Step 3. 4-(3-(N-Methylcarbamoyl)-4-methoxyphe-

w-Alkoxy-w-carboxyphenyl Anilines noxy )-1-nitro benzene
Synthesis of To a solution of 4-(3-carboxy-4-methoxyphenoxy)-1-ni-

15
4-(3-(N- Methylcarbamoyl )-4-methoxyphenoxy )aniline trobenzene (0.50 g, 1.75 mmol) in CH 2 Cl 2 (12 mL) was
added SOC12 (0.64 mL, 8.77 mmol) in portions. The result-
ing solution was heated at the reflux temp. for 18 h, cooled
to room temp., and concentrated under reduced pressure.
The resulting yellow solids were dissolved in CH 2 Cl2 (3
20
mL) then the resulting solution was treated with a methy-
lamine solution (2.0 M in THF, 3.5 mL, 7.02 mmol) in
portions (CAUTION: gas evolution), and stirred at room
temp. for 4 h. The resulting mixture was treated with a IN
NaOH solution, then extracted with CH 2 Cl2 (25 mL). The
25
organic layer was dried (Na2 SO4 ) and concentrated) under
reduced pressure to give 4-(3-(N-methylcarbamoyl)-4-
methoxyphenoxy)-1-nitrobenzene as a yellow solid (0.50 g,
Step 1. 4-(3-Methoxylcarbonyl-4-methoxyphe- 95%).
noxy )-1-nitro benzene
30
To a solution of 4-(3-carboxy-4-hydroxyphenoxy)-1-ni-
trobenzene (prepared from 2,5-dihydroxybenzoic acid in a
manner analogous to that described in MethodA13, Step 1,
12 mmol) in acetone (50 mL) was added K2 CO 3 (5 g) and
35
dimethyl sulfate (3.5 mL). The resulting mixture was heated
at the reflux temp. overnight, then cooled to room temp. and
filtered through a pad of Celite®. The resulting solution was
concentrated under reduced pressure, absorbed onto SiO2 ,
and purified by colunm chromatography (50% EtOAc/50% Step 4.
40
hexane) to give 4-(3-methoxycarbonyl-4-methoxyphe- 4-(3-(N- Methylcarbamoy 1)-4-methoxyphenoxy )aniline
noxy)-1-nitrobenzene as a yellow powder (3 g): mp 115-
118° C.
A slurry of 4-(3-(N-methylcarbamoly)-4-methoxyphe-
noxy)-1-nitrobenzene (0.78 g, 2.60 mmol) and 10% Pd/C
45 (0.20 g) in EtOH (55 mL) was stirred under 1 atm of H2
(balloon) for 2.5 d, then was filtered through a pad of
Celite®. The resulting solution was concentrated under
reduced pressure to afford 4-(3-(N-methylcarbamoly)-4-
methoxyphenoxy)aniline as an off-white solid (0.68 g,
50 96%): TLC (0.1% Et3 N/99.9% EtOAc) Rf0.36.
A9. General Method for Preparation of

w-Alkylphthalimide-containing Anilines
Step 2.
4-(3-Carboxy-4-methoxyphenoxy )-1-nitrobenzene 55 Synthesis of
5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione
A mixture of 4-(3-methoxycarbonyl-4-methoxyphenoxy)-
l-nitrobenzene (1.2 g), KOH (0.33 g) and water (5 mL) in
MeOH (45 mL) was stirred at room temp. overnight and
then heated at the reflux temp. for 4 h. The resulting mixture 60
was cooled to room temp. and concentrated under reduced
pressure. The residue was dissolved in water (50 mL), and
the aqueous mixture was made acidic with a IN HCl
solution. The resulting mixture was extracted with EtOAc
(50 mL). The organic layer was dried (MgSO 4) and con- 65
centrated under reduced pressure to give 4-(3-carboxy-4-
methoxyphenoxy)- 1-nitrobenzene (1.04 g).
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Step 1. Synthesis of
5-(4-Nitrophenoxy )-2-methylisoindoline-1,3-dione
A slurry of 5-(4-nitrophenoxy)isoindoline-l,3-dione (A3

Step 2; 1.0 g, 3.52 mmol) and NaH (0.13 g, 5.27 mmol) in 5
DMF (15 mL) was stirred at room temp. for 1 h, then treated
with methyl iodide (0.3 mL, 4.57 mmol). The resulting
mixture was stirred at room temp. overnight, then was
cooled to° C. and treated with water (10 mL). The resulting
solids were collected and dried under reduced pressure to 10
give 5-(4-nitrophenoxy)-2-methylisoindoline-1,3-dione as a Step 2. Synthesis of 4-(2-(N-(2-Morpholin-4-yl-
bright yellow solid (0.87 g, 83%): TLC (35% EtOAc/65% ethyl )carbamoy l)pyridyloxy )aniline
hexane) Rf0.61.
A solution of 4-aminophenol (0.49 g, 4.52 mmol) and
15
potassium tert-butoxide (0.53 g, 4.75 mo!) in DMF (8 mL)
was stirred at room temp. for 2 h, then was sequentially
treated with 4-chloro-2-(N-(2-morpholin-4-ylethyl)carbam-
oyl)pyridine (1.22 g, 4.52 mmol) and K2 CO 3 (0.31 g, 2.26
mmol). The resulting mixture was heated at 75° C. over-
20
night, cooled to room temp., and separated between EtOAc
(25 mL) and a saturated NaCl solution (25 mL). The aqueous
layer was back extracted with EtOAc (25 mL). The com-
bined organic layers were washed with a saturated NaCl
solution (3x25 mL) and concentrated under reduced pres-
Step 2. Synthesis of 25
sure. The resulting brown solids were purified by colurmi
5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione chromatography (58 g; gradient from 100% EtOAc to 25%
MeOH/75% EtOAc) to afford 4-(2-(N-(2-morpholin-4-yl-
A slurry of nitrophenoxy)-2-methylisoindoline-1,3-dione ethyl)carbamoyl)pyridyloxy)aniline (1.0 g, 65%): TLC
(0.87 g, 2.78 mmol) and 10% Pd/C (0.10 g) in MeOH was (10% MeOH/90% EtOAc) Rf0.32.
stirred under 1 atm of H2 (balloon) overnight. The resulting 30
mixture was filtered through a pad of Celite® and concen- Al 1. General Method for the Reduction of
trated under reduced pressure. The resulting yellow solids Nitroarenes to Arylamines
were dissolved in EtOAc (3 mL) and filtered through a plug
ofSiO 2 (60% EtOAc/40% hexane) to afford 5-(4-aminophe- Synthesis of 4-(3-Carboxyphenoxy)aniline
noxy)-2-methylisoindoline-l,3-dione as a yellow solid (0.67 35
g, 86%): TLC (40% EtOAc/60% hexane) Rf0.27.
AlO. General Method for Synthesis of

w-Carbamoylaryl Anilines Through Reaction of
co-Alkoxycarbonylaryl Precursors with Amines 40
Synthesis of 4-(2-(N-(2-morpholin-4-ylethyl)car-
bamoyl )pyridy loxy )aniline
45
A slurry of 4-(3-carboxyphenoxy)-1-nitrobenzene (5.38 g,
20.7 mmol) and 10% Pd/C (0.50 g) in MeOH (120 mL) was
stirred under an H2 atmosphere (balloon) for 2 d. The
resulting mixture was filtered through a pad of Celite®, then
50 concentrated under reduced pressure to afford 4-(3-carbox-
yphenoxy)aniline as a brown solid (2.26 g, 48%): TLC (10%
MeOH/90% CH 2 Cl2 ) Rf0.44 (streaking).

Step 1. Synthesis of 4-Chloro-2-(N-(2-morpholin-4- 55 Isoindolinone-Containing Anilines
ylethyl)carbamoyl)pyridine
Synthesis of 4-(1-Oxoisoindolin-5-yloxy)aniline
To a solution of methyl 4-chloropyridine-2-carboxylate
HCI salt (MethodA2, Step 2; 1.01 g, 4.86 mmol) in THF (20
mL) was added 4-(2-aminoethyl)morpholine (2.55 mL, 19.4 60
mmol) dropwise and the resulting solution was heated at the
reflux temp. for 20 h, cooled to room temp., and treated with
water (50 mL). The resulting mixture was extracted with
HO~
I NH
EtOAc (50 mL). The organic layer was dried (MgSO 4) and ~
concentrated under reduced pressure to afford 4-chloro-2- 65 0
(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine as a yellow
oil (1.25 g, 95%): TLC (10% MeOH/90% EtOAc) Rf0.50.
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Step 1. Synthesis of 5-hydroxyisoindolin-1-one Step 1. Synthesis of
4-(3-ethoxycarbonylphenoxy )-1-nitrobenzene
To a solution of 5-hydroxyphthalimide (19.8 g, 121
mmol) inAcOH (500 mL) was slowly added zinc dust (47.6 A mixture of 4-fluoro-1-nitrobenzene (16 mL, 150 mmol),
g, 729 mmol) in portions, then the mixture was heated at the 5
ethyl 3-hydroxybenzoate 25 g, 150 mmol) and K2 CO 3 (41 g,
reflux temp. for 40 min., filtered hot, and concentrated under 300 mmol) in DMF (125 mL) was heated at the reflux temp.
reduced pressure. The reaction was repeated on the same
overnight, cooled to room temp. and treated with water (250
scale and the combined oily residue was purified by column
chromatography (1.1 Kg SiO 2 ; gradient from 60% EtOAc/ mL). The resulting mixture was extracted with EtOAc
40% hexane to 25% MeOH/75% EtOAc) to give 5-hydroxy- 10 (3x150 mL). The combined organic phases were sequen-
isoindolin-1-one (3.77 g): TLC (100% EtOAc) Rf 0.17; tially washed with water (3x100 mL) and a saturated NaCl
HPLC ES-MS m/z 150 ((M+Hr). solution (2x100 mL), dried (Na2 SO4 ) and concentrated
under reduced pressure. The residue was purified by colurmi
chromatography (10% EtOAc/90% hexane) to afford 4-(3-
15 ethoxycarbonylphenoxy)-1-nitrobenzene as an oil (38 g).
20
4-(1-isoindolinon-5-yloxy )-1-nitrobenzene
To a slurry ofNaH (0.39 g, 16.1 mmol) in DMF at 0° C.

25
was added 5-hydroxyisoindolin-1-one (2.0 g, 13.4 mmol) in
portions. The resulting slurry was allowed to warm to room Step 2. Synthesis of
temp. and was stirred for 45 min., then 4-fluoro-1-nitroben- 4-(1-isoindolinon-5-yloxy )-1-nitrobenzene
zene was added and then mixture was heated at 70° C. for
3 h. The mixture was cooled to 0° C. and treated with water
dropwise until a precipitate formed. The resulting solids 30 To a slurry ofNaH (0.39 g, 16.1 mmol) in DMF at 0° C.
were collected to give 4-(1-isoindolinon-5-yloxy)-1-ni- was added 5-hydroxyisoindolin-1-one (2.0 g, 13.4 mmol) in
trobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% portions. The resulting slurry was allowed to warm to room
EtOAc) Rf0.35. temp. and was stirred for 45 min., then 4-fluoro-1-nitroben-
zene was added and then the mixture was heated at 70° C.
35
for 3 h. The mixture was cooled to 0° C. and treated with
water dropwise until a precipitate formed. The resulting
solids were collected to give 4-(1-isoindolinon-5-yloxy)-1-
nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC
40 (100% EtOAc) Rf0.35.
4-(1-oxoisoindolin-5-yloxy )aniline
45
A slurry of 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene
(2.12 g, 7.8 mmol) and 10% Pd/C (0.20 g) in EtOH (50 mL)
was stirred under an H2 atmosphere (balloon) for 4 h, then
filtered through a pad of Celite®. The filtrate was concen-
trated under reduced pressure to afford 4-(1-oxoisoindolin-
5-yloxy)aniline as a dark yellow solid: TLC (100% EtOAc) 50
Rf0.15. Step 3. Synthesis of
4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene
w-Carbamoyl Anilines via EDCI-Mediated Amide
55 A mixture of 4-(3-carboxyphenoxy)-1-nitrobenzene (3.72
Formation Followed by Nitroarene Reduction
g, 14.4 mmol), EDCI.HCI (3.63, 18.6 mmol), N-methylmor-
Synthesis of pholine (1.6 mL, 14.5 mmol) and methylamine (2.0 M in
4-(3-N- Methylcarbamoylphenoxy )aniline THF; 8 mL, 16 mmol) in CH 2 Cl2 (45 mL) was stirred at
room temp. for 3 d, then concentrated under reduced pres-
60
sure. The residue was dissolved in EtOAc (50 mL) and the
resulting mixture was extracted with a IM HCI solution (50
mL). The aqueous layer was back-extracted with EtOAc
(2x50 mL). The combined organic phases were washed with
65 a saturated NaCl solution (50 mL), dried (Na2 SO4 ), and
concentrated under reduced pressure to give 4-(3-(N-meth-
ylcarbamoyl)phenoxy)-l-nitrobenzene as an oil (1.89 g).
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4-(3-( 5-methoxycarbonyl )pyridy loxy )aniline
A slurry of 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-ni-
5 trobenzene (0.60 g, 2.20 mmol) and 10% Pd/C in MeOH/
EtOAc was stirred under an H2 atmosphere (balloon) for 72
h. The resulting mixture was filtered and the filtrate was
concentrated under reduced pressure. The residue was puri-
fied by colunm chromatography (gradient from 10% EtOAc/
10 90% hexane to 30% EtOAc/70% hexane to 50% EtOAc/
Step 4. Synthesis of 50% hexane) to afford 4-(3-(5-methoxycarbonyl)
4-(3-(N-methylcarbamoyl )phenoxy )aniline pyridyloxy)aniline (0.28 g, 60%): 1 H NMR (CDC13 ) Ii 3.92
(s, 3H), 6.71 (d, 2H), 6.89 (d, 2H), 7.73 (, lH), 8.51 (d, lH),
8.87 (d, lH).
A slurry of 4-(3-(N-methylcarbamoyl)phenoxy)-1-ni- 15
trobenzene (1.89 g, 6.95 mmol) and 5% Pd/C (0.24 g) in A15. Synthesis of an Aniline Via Electrophilic
EtOAc (20 mL) was stirred under an H2 atm (balloon) Nitration Followed by Reduction
overnight. The 1-5 resulting mixture was filtered through a
pad of Celite® and concentrated under reduced pressure. Synthesis of 4-(3-Methylsulfamoylphenoxy)aniline
The residue was purified by colunm chromatography (5% 20
MeOH/95% CH 2 Cl 2 ). The resulting oil solidified under
vacuum overnight to give 4-(3-(N-methylcarbamoyl)phe-
noxy)aniline as a yellow solid (0.95 g, 56%). 0 0

w-Carbamoyl Anilines via EDCI-Mediated Amide
25
V
Bryy\(
NHMe
Synthesis of
30
4-3-( 5-Methylcarbamoyl )pyridy loxy )aniline Step 1. Synthesis of
N-methy 1-3-bromobenzenesulfonamide
To a solution of3-bromobenzenesulfonyl chloride (2.5 g,

11.2 mmol) in THF (15 mL) at 0° C. was addedmethylamine
35
(2.0 Min THF; 28 mL, 56 mmol). The resulting solution was
allowed to warm to room temp. and was stirred at room
temp. overnight. The resulting mixture was separated
between EtOAc (25 mL) and a 1 M HCl solution (25 mL).
The aqueous phase was back-extracted with EtOAc (2x25
40
mL). The combined organic phases were sequentially
washed with water (2x25 mL) and a saturated NaCl solution
Step 1. Synthesis of (25 mL), dried (MgSO 4) and concentrated under reduced
4-(3-(5-methoxycarbonyl)pyridyloxy )-1-nitrobenzene pressure to give N-methyl-3-bromobenzenesulfonamide as a
white solid (2.8 g, 99%).
45
To a slurry ofNaH (0.63 g, 26.1 mmol) in DMF (20 mL)
was added a solution of methyl 5-hydroxynicotinate (2.0 g,
13.1 mmol) in DMF (10 mL). The resulting mixture was
added to a solution of 4-fluoronitrobenzene (1.4 mL, 13.1
mmol) in DMF (10 mL) and the resulting mixture was 50
heated at 70° C. overnight, cooled to room temp., and treated
with MeOH (5 mL) followed by water (50 mL). The
resulting mixture was extracted with EtOAc (100 mL). The
organic phase was concentrated under reduced pressure. The
residue was purified by colunm chromatography (30% 55 Step 2. Synthesis of
EtOAc/70% hexane) to afford 4-(3-(5-methoxycarbonyl) 4-(3-(N-methylsulfamoyl)phenyloxy)benzene
pyridyloxy)-1-nitrobenzene (0.60 g).
To a slurry of phenol (1.9 g, 20 mmol), K2 CO 3 (6.0 g, 40
mmol), and Cul (4 g, 20 mmol) in DMF (25 mL) was added
60 N-methyl-3-bromobenzenesulfonamide (2.5 g, 10 mmol),
and the resulting mixture was stirred at the reflux temp.
overnight, cooled to room temp., and separated between
EtOAc (50 mL) and a 1 N HCl solution (50 mL). The
aqueous layer was back-extracted with EtOAc (2x50 mL).
65 The combined organic phases were sequentially washed
with water (2x50 mL) and a saturated NaCl solution (50
mL), dried (MgSO 4), and concentrated under reduced pres-
IITRUE COPY!I
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sure. The residual oil was purified by column chromatog- 3.89 mmol) in a mixture ofEtOH (10 mL) and pyridine (1.0
raphy (30% EtOAc/70% hexane) to give 4-(3-(N-methyl- mL) was added O-methylhydroxylamine HCl salt (0.65 g,
sulfamoyl)phenyloxy)benzene (0.30 g). 7.78 mmol, 2.0 equiv.). The resulting solution was heated at
the reflux temperature for 30 min, cooled to room tempera-
ture and concentrated under reduced pressure. The resulting
solids were triturated with water (10 mL) and washed with
water to give 4-(4-(1-(N-methoxy)iminoethyl)phenoxya-
niline HCl salt as a yellow solid (0.85 g): TLC (50%
10 EtOAc/50% pet. ether) Rf0.78; 1 H NMR (DMSO-d 6 ) Ii 3.90
(s, 3H), 5.70 (s, 3H); HPLC-MS m/z 257 ((M+Hr).
Al 7. Synthesis of N-(w-Silyloxyalkyl)amides
4-(3-(N-methylsulfamoyl)phenyloxy )-1-nitrobenzene 15 Synthesis of 4-( 4-(2-(N-(2-Triisopropylsilyloxy)
To a solution of 4-(3-(N-methylsulfamoyl)phenyloxy) ethylcarbamoyl)pyridyloxyaniline
benzene (0.30 g, 1.14 mmol) in TFA (6 mL) at -10° C. was
added NaNO 2 (0.097 g, 1.14 mmol) in portions over 5 min.
The resulting solution was stirred at -10° C. for 1 h, then 20
was allowed to warm to room temp., and was concentrated
under reduced pressure. The residue was separated between
EtOAc (10 mL) and water (10 mL). The organic phase was
sequentially washed with water (10 mL) and a saturated
NaCl solution (10 mL), dried (MgSO 4) and concentrated 25
under reduced pressure to give 4-(3-(N-methylsulfamoyl)
phenyloxy)-1-nitrobenzene (0.20 g). This material carried
on to the next step without further purification.
Step 1. 4-Chloro-N-(2-triisopropylsilyloxy)ethylpy-
30
ridine-2-carboxamide
To a solution of 4-chloro-N-(2-hydroxyethyl)pyridine-2-
carboxamide (prepared in a manner analogous to Method
35 A2, Step 3b; 1.5 g, 7.4 mmol) in anh DMF (7 mL) was added
triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv.) and
imidazole (1.12 g, 16.4 mmol, 2.2 equiv.). The resulting
Step 4. Synthesis of yellow solution was stirred for 3 h at room temp, then was
4-(3-(N-methy lsulfamoy l)pheny loxy )aniline concentrated under reduced pressure. The residue was sepa-
40
rated between water (10 mL) and EtOAc (10 mL). The
A slurry of 4-(3-(N-methylsulfamoyl)phenyloxy)-1-ni- aqueous layer was extracted with EtOAc (3x10 mL). The
trobenzene (0.30 g) and 10% Pd/C (0.030 g) in EtOAc (20 combined organic phases were dried (MgSO 4), and concen-
mL) was stirred under an H2 atmosphere (balloon) over- trated under reduced pressure to afford 4-chloro-2-(N-(2-
night. The resulting mixture was filtered through a pad of triisopropylsilyloxy)ethyl)pyridinecarboxamide as an
45
Celite®. The filtrate was concentrated under reduced pres- orange oil (2.32 g, 88%). This material was used in the next
sure. The residue was purified by column chromatography step without further purification.
(30% EtOAc/70% hexane) to give 4-(3-(N-methylsulfa-
moyl)phenyloxy)aniline (0.070 g).
A16. Modification of w-Ketones
Synthesis of
4-( 4-(1-(N-methoxy )iminoethyl)phenoxyaniline HCl
salt
Step 2. 4-( 4-(2-(N-(2-Triisopropylsilyloxy)ethylcar-

bamoyl)pyridyloxyaniline
60
To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in

anh DMF (8 mL) was added potassium tert-butoxide (0.67
g, 6.0 mmol, 1.0 equiv.) in one portion causing an exotherm.
65 When this mixture had cooled to room temperature, a
To a slurry of 4-(4-acetylphenoxy)aniline HCl salt (pre- solution of 4-chloro-2-(N-(2-triisopropylsilyloxy)ethyl)py-
pared in a manner analogous to Method Al3, step 4; 1.0 g, ridinecarboxamide (2.32 g, 6 mmol, 1 equiv.) in DMF (4
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mL) was added followed by K2 CO 3 (0.42 g, 3.0 mmol, 0.50 mL), then heated at the reflux temperature for 3 h, cooled to
equiv.). The resulting mixture was heated at 80° C. over- room temperature and concentrated under reduced pressure.
night. An additional portion of potassium tert-butoxide (0.34 The residue was separated between EtOAc (50 mL) and a 1
g, 3 mmol, 0.5 equiv.) was then added and the mixture was
stirred at 80° C. an additional 4 h. The mixture was cooled 5
N NaOH solution (50 mL). The aqueous layer was extracted
to 0° C. with an ice/water bath, then water (approx. 1 mL) with EtOAc (2x50 mL). The combined organic layers were
was slowly added dropwise. The organic layer was extracted sequentially washed with water (2x50 mL) and a saturated
with EtOAc (3x10 mL). The combined organic layers were NaCl solution (50 mL), dried (MgSO 4) and concentrated
washed with a saturated NaCl solution (20 mL), dried under reduced pressure. The residue was purified by column
(MgSO 4) and concentrated under reduced pressure. The 10
brown oily residue was purified by colunm chromatography chromatography (SiO2 ; 50% EtOAc/50% hexane) to afford
(SiO 2 ; 30% EtOAc/70% pet ether) to afford 4-(4-(2-(N-(2- 4-( 5-(2-methoxycarbonyl)pyridyloxy )-1-nitrobenzene (0.70
triisopropylsily loxy )ethylcarbamoy 1)pyridy loxyaniline as a g).
clear light brown oil (0.99 g, 38%).
15
A18. Synthesis of 2-Pryidinecarboxylate Esters via
Oxidation of 2-Methylpyridines
Synthesis of
4-( 5-(2-methoxycarbonyl )pyridy loxy )aniline 20
25
4-( 5-(2-Methoxycarbonyl )pyridy loxy )aniline
A slurry of 4-(5-(2-methoxycarbonyl)pyridyloxy)-1-ni-
30 trobenzene (0.50 g) and 10% Pd/C (0.050 g) in a mixture of
Step 1. 4-(5-(2-Methyl)pyridyloxy)-1-nitrobenzene EtOAc (20 mL) and MeOH (5 mL) was placed under a H2
atmosphere (balloon) overnight. The resulting mixture was
A mixture of 5-hydroxy-2-methylpyridine (10.0 g, 91.6 filtered through a pad of Celite®, and the filtrate was
mmol), l-fluoro-4-nitrobenzene (9.8 mL, 91.6 mmol, 1.0 35 concentrated under reduced pressure. The residue was puri-
equiv.), K2 CO 3 (25 g, 183 mmol, 2.0 equiv.) in DMF (100 fied by column chromatography (SiO2 ; 70% EtOAc/30%
mL) was heated at the reflux temperature overnight. The hexane) to give 4-(5-(2-methoxycarbonyl)pyridyloxy)
resulting mixture was cooled to room temperature, treated
aniline (0.40 g).
with water (200 mL), and extracted with EtOAc (3x100
40
mL). The combined organic layers were sequentially washed
A19. Synthesis of w-Sulfonylphenyl Anilines
with water (2x100 mL) and a saturated NaCl solution ((100
mL), dried (MgSO 4) and concentrated under reduced pres- Synthesis of 4-(4-Methylsulfonylphenoxy)aniline
sure to give 4-(5-(2-methyl)pyridyloxy)-1-nitrobenzene as a
brown solid (12.3 g). 45
50
55
Step 1. 4-(4-Methylsulfonylphenoxy)-1-nitrobenzene: To
a solution of 4-(4-methylthiophenoxy)-1-nitrobenzene (2.0
g, 7.7 mmol) in CH 2 Cl2 (75 mL) at 0° C. was slowly added
4-( 5-(2-Methoxycarbonyl)pyridyloxy )-1-nitrobenzene
m-CPBA (57-86%, 4.0 g), and the reaction mixture was
A mixture of 4-(5-(2-methyl)pyridyloxy)-1-nitrobenzene 60 stirred at room temperature for 5 h. The reaction mixture was
(1.70 g, 7.39 mmol) and selenium dioxide (2.50 g, 22.2 treated with a lNNaOH solution (25 mL). The organic layer
mmol, 3.0 equiv.) in pyridine (20 mL) was heated at the was sequentially washed with a IN NaOH solution (25 mL),
reflux temperature for 5 h, then cooled to room temperature. water (25 mL) and a saturated NaCl solution (25 mL), dried
The resulting slurry was filtered, then concentrated under 65 (MgSO 4), and concentrated under reduced pressure to give
reduced pressure. The residue was dissolved in MeOH (100 4-( 4-methylsulfonylphenoxy)-1-nitrobenzene as a solid (2.1
mL). The solution was treated with a cone HCl solution (7 g).
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Step 2. 4-(4-Methylsulfonylphenoxy)-1-aniline: 4-( 4-Me- C. Methods of Urea Formation
thy lsulfony lphenoxy )-1-nitro benzene was reduced to the
aniline in a manner analogous to that described in Method Cla. General Method for the Synthesis of Ureas by
A18. step 3. Reaction of an Isocyanate with an Aniline
Synthesis of N-( 4-Chloro-3-(trifluoromethyl)phe-

B. Synthesis of Urea Precursors nyl)-N'-( 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)
phenyl)Urea
Bl. General Method for the Synthesis of
Isocyanates from Anilines Using CDI 10
Synthesis of 4-Bromo-3-(trifluoromethyl)phenyl
Isocyanate
"c,~ 0 ~oy-lM™,
UN)lN~
H H
~h
A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyan-
20
ate (14.60 g, 65.90 mmol) in CH 2 Cl2 (35 mL) was added
dropwise to a suspension of 4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)aniline (MethodA2, Step 4; 16.0 g, 65.77 mmol)
in CH 2 Cl 2 (35 mL) at 0° C. The resulting mixture was stirred
at room temp. for 22 h. The resulting yellow solids were
25
removed by filtration, then washed with CH 2 Cl2 (2x30 mL)
and dried under reduced pressure (approximately 1 mmHg)
Step 1. Synthesis of to afford N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-
4-bromo-3-(trinfluoromethyl)aniline HCl salt (N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea as an off-
white solid (28.5 g, 93%): mp 207-209° C.; 1 H-NMR
30
(DMSO-d 6) Ii 2.77 (d, 1=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d,
To a solution of 4-bromo-3-(trifluoromethyl)aniline (64 g, 1=2.5 Hz, lH), 7.62 (m, 4H), 8.11 (d, 1=2.5 Hz, lH), 8.49 (d,
267 mmol) in Et2 0 (500 mL) was added an HCl solution (1 1=5.5 Hz, lH), 8.77 (br d, lH), 8.99 (s, lH), 9.21 (s, lH);
Min Et2 0; 300 mL) dropwise and the resulting mixture was HPLC ES-MS m/z 465 ((M+Hr).
stirred at room temp. for 16 h. The resulting pink-white 35
precipitate was removed by filtration and washed with Et2 0 Clb. General Method for the Synthesis of Ureas by
(50 mL) and to afford 4-bromo-3-(trifluoromethyl)aniline Reaction of an Isocyanate with an Aniline
HCl salt (73 g, 98% ).
Synthesis of N-( 4-Bromo-3-(trifluoromethyl)phe-
40
nyl)-N'-( 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)
phenyl)Urea
Br~
" lli~ 0 ~oy-l=,

UNCO
UN)lN~
H H
~h
50
Step 2. Synthesis of A solution of 4-bromo-3-(trifluoromethyl)phenyl isocy-

4-bromo-3-(trifluoromethyl)phenyl isocyanate anate (Method Bl, Step 2; 8.0 g, 30.1 mmol) in CH 2 Cl2 (80
mL) was added dropwise to a solution of 4-(2-(N-methyl-
A suspension of 4-bromo-3-(trifluoromethyl)aniline HCl 55 carbamoyl)-4-pyridyloxy)aniline (MethodA2, Step 4; 7.0 g,
salt (36.8 g, 133 mmol) in toluene (278 mL) was treated with 28.8 mmol) in CH 2 Cl2 (40 mL) at 0° C. The resulting
trichloromethyl chloroformate dropwise and the resulting mixture was stirred at room temp. for 16 h. The resulting
mixture was heated at the reflux temp. for 18 h. The resulting yellow solids were removed by filtration, then washed with
mixture was concentrated under reduced pressure. The resi- CH 2 Cl 2 (2x50 mL) and dried under reduced pressure (ap-
due was treated with toluene (500 mL), then concentrated 60 proximately 1 mmHg) at 40° C. to afford N-( 4-bromo-3-
(trifluoromethy l)pheny 1)-N'-(4-(2-(N-methy lcarbamoy 1)-4-
under reduced pressure. The residue was treated with
pyridy loxy )pheny l)urea as a pale-yellow solid (13.2 g,
CH 2 Cl2 (500 mL), then concentrated under reduced pres- 90%): mp 203-205° C.; 1 H-NMR (DMSO-d 6 ) Ii 2.77 (d,
sure. The CH 2 Cl2 treatment/concentration protocol was 1=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, 1=2.5 Hz, lH), 7.58
repeated and resulting amber oil was stored at -20° C. for 16 65 (m, 3H), 7.77 (d, 1=8.8 Hz, lH), 8.11 (d, 1=2.5 Hz, lH), 8.49
h, to afford 4-bromo-3-(trifluoromethyl)phenyl isocyanate (d, 1=5 Hz, lH), 8.77 (br d, lH), 8.99 (s, lH), 9.21 (s, lH);
as a tan solid (35.1 g, 86%): GC-MS m/z 265 (M+). HPLC ES-MS m/z 509 ((M+Ht).
IITRUE COPY!I
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Cle. General Method for the Synthesis of Ureas by Cle. General Method for the Synthesis of Ureas by
Reaction of an Isocyanate with an Aniline Reaction of an Isocyanate with an Aniline
Synthesis of N-( 4-Chloro-3-(trifluoromethyl)phe- Synthesis of N-( 4-Chloro-3-(trifluoromethyl)phe-

nyl )-N'-( 4-ethoxycarbony lpheny I)Urea
ny l)-N'-(2-methy 1-4-(2-(N-methylcarbamoy I)(4-
pyridy loxy) )phenyl) Urea
CF3 0
10
c,+ 0 ~Ofa
UN)lNA) H H
To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4

mmol) in CH 2 Cl 2 (30 mL) was added 4-chloro-3-(trifluo-
romethyl)aniline (3.21 g, 16.4 mmol), and the solution was
A solution of 2-methyl-4-(2-(N-methylcarbamoyl)(4-py- stirred at room temp. overnight. The resulting slurry was
20
ridyloxy))aniline (MethodA5; 0.11 g, 0.45 mmol) in CH Cl 2 diluted with CH 2 Cl2 (50 mL) and filtered to afford N-(4-
(1 mL) was treated with Et3 N (0.16 mL) and 4-chlor~-3- chloro-3-( trifluoromethy l)pheny I)-N'-( 4-ethoxycarbon-
(trifluoromethyl)phenyl isocyanate (0.10 g, 0.45 mmol). The y lpheny l)urea as a white solid (5.93 g, 97%): TLC (40%
resulting brown solution was stirred at room temp. for 6 d, EtOAc/60% hexane) Rf0.44.
then was treated with water (5 mL). The aqueous layer was 25 Clf. General Method for the Synthesis of Ureas by
back-extracted with EtOAc (3x5 mL). The combined Reaction of an Isocyanate with an Aniline
organic layers were dried (MgSO 4) and concentrated under
reduced pressure to yield N-(4-chloro-3-(trifluoromethyl) Synthesis of N-( 4-Chloro-3-(trifluoromethyl)phe-
pheny 1)-N'-(2-methyl-4-(2-(N-methylcarbamoyl )(4-pyridy- nyl)-N'-(3-carboxyphenyl)Urea
30
loxy) )pheny l)urea as a brown oil (0.11 g, 0.22 mmol): 1H
NMR (DMSO-d 6 ) Ii 2.27 (s, 3H), 2.77 (d, J=4.8 Hz, 3H),
7.03 (dd, J=8.5, 2.6 Hz, lH), 7.11 (d, J=2.9 Hz, lH), 7.15
(dd, J=5.5, 2.6, Hz, lH), 7.38 (d, J=2.6 Hz, lH), 7.62 (app
d, J=2.6 Hz, 2H), 7.84 (d, J=8.8 Hz, lH), 8.12 (s, lH), 8.17 35
(s, lH); 8.50 (d, J=5.5 Hz, lH), 8.78 (q, J=5.2, lH), 9.52 (s,
lH); HPLC ES-MS rn/z 479 ((M+Hr).
Cid. General Method for the Synthesis of Ureas by To a solution of 4-chloro-3-(trifluoromethyl)phenyl iso-
40 cyanate (1.21 g, 5.46 mmol) in CH 2 Cl 2 (8 mL) was added
Reaction of an Isocyanate with an Aniline
4-(3-carboxyphenoxy)aniline (Method All; 0.81 g, 5.76
mmol) and the resulting mixture was stirred at room temp.
Synthesis of N-( 4-Chloro-3-(trifluoromethyl)phe- overnight, then treated with MeOH (8 mL), and stirred an
nyl)-N'-( 4-aminophenyl)Urea additional 2 h. The resulting mixture was concentrated under
45 reduced pressure. The resulting brown solids were triturated
with a 1:1 EtOAc/hexane solution to give N-( 4-chloro-3-
(trifluoromethy l)pheny l)-N'-(3-carboxypheny !)urea as an
off-white solid (1.21 g, 76%).
C2a. General Method for Urea Synthesis by
50 Reaction of an Aniline with N,N'-Carbonyl
Diimidazole Followed by Addition of a Second
Aniline
Synthesis of N-(2-Methoxy-5-(trifluoromethyl)phe-
55 nyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)
To a solution of 4-chloro-3-(trifluoromethyl)phenyl iso- phenyl)Urea
cyanate (2.27 g, 10.3 mmol) in CH 2 Cl 2 (308 mL) was added
p-phenylenediamine (3.32 g, 30.7 mmol) in one part. The
A
resulting mixture was stirred at room temp. for 1 h, treated
with CH 2 Cl2 (100 mL), and concentrated under reduced
pressure. The resulting pink solids were dissolved in a 00 N~Noo~-,
mixture of EtOAc (110 mL) and MeOH (15 mL), and the
clear solution was washed with a 0.05 N HCI solution. The
YH H
organic layer was concentrated under reduced pressure to 65 OMe
afford impure N-( 4-chloro-3-( trifluoromethy l)pheny 1)-N'-
(4-aminopheny l)urea (3.3 g): TLC (100% EtOAc) Rf0.72.
IITRUE COPY!I
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To a solution of 2-methoxy-5-(trifluoromethyl)aniline C2c. General Method for the Synthesis of Ureas by
(0.15 g) in anh CH 2 Cl2 (15 mL) at 0° C. was added CDI Reaction of an Isocyanate with an Aniline
(0.13 g). The resulting solution was allowed to warm to
room temp. over 1 h, was stirred at room temp. for 16 h, then Synthesis of N-(2-Methoxy-5-(trifluoromethyl)phe-
was treated with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy) 5
nyl-N'-( 4-(1,3-dioxoisoindolin-5-yloxy )phenyl)Urea
aniline (0.18 g). The resulting yellow solution was stirred at
room temp. for 72 h, then was treated with H2 O (125 mL).
The resulting aqueous mixture was extracted with EtOAc
(2x150 mL). The combined organics were washed with a
saturated NaCl solution (100 mL), dried (MgSO 4) and 10
CC; 0 (YO~~
rated (90% EtOAc/10% hexane). The resulting white solids
were collected by filtration and washed with EtOAc. The
filtrate was concentrated under reduced pressure and the N)lNA/
H H
# 0
residual oil purified by colunm chromatography (gradient 15
from 33% EtOAc/67% hexane to 50% EtOAc/50% hexane OMe NH
to 100% EtOAc) to give N-(2-methoxy-5-(trifluoromethyl) 0
pheny 1)-N'-( 4-(2-(N-methy lcarbamoy 1)-4-pyridyloxy )phe-
ny l)urea as a light tan solid (0.098 g, 30%): TLC (100%
EtOAc) Rf0.62; 1 H NMR (DMSO-d 6 ) Ii 2.76 (d, J=4.8 Hz, 20
To a stirring solution of 2-methoxy-5-(trifluoromethyl)
3H), 3.96 (s, 3H), 7.1-7.6 and 8.4-8.6 (m, lH), 8.75 (d, J=4.8 phenyl isocyanate (0.10 g, 0.47 mmol) in CH 2 Cl2 (1.5 mL)
Hz, lH), 9.55 (s, lH); FAB-MS m/z 461 ((M+Hr). was added 5-(4-aminophenoxy )isoindoline-1,3-dione
(MethodA3, Step 3; 0.12 g, 0.47 mmol) in one portion. The
resulting mixture was stirred for 12 h, then was treated with
C2b. General Method for Urea Synthesis by 25 CH 2 Cl 2 (10 mL) and MeOH (5 mL). The resulting mixture
Reaction of an Aniline with N,N'-Carbonyl was sequentially washed with a IN HCI solution (15 mL)
Diimidazole Followed by Addition of a Second and a saturated NaCl solution (15 mL), dried (MgSO 4) and
Aniline concentrated under reduced pressure to afford N-(2-meth-
oxy-5-( trifluoromethyl )pheny 1-N'-( 4-( l ,3-dioxoisoindolin-
Symmetrical Urea's as Side Products of a 30 5-yloxy)phenyl)urea as a white solid (0.2 g, 96%): TLC
N,N'-Carbonyl Diimidazole Reaction Procedure (70% EtOAc/30% hexane) Rf0.50; 1 H NMR (DMSO-d 6 ) Ii
3.95 (s, 3H), 7.31-7.10 (m, 6H), 7.57 (d, J=9.3 Hz, 2H), 7.80
Synthesis of Bis( 4-(2-(N-methylcarbamoyl)-4-py- (d, J=8.7 Hz, lH), 8.53 (br s, 2H), 9.57 (s, lH), 11.27 (br s,
ridyloxy)phenyl)Urea lH); HPLC ES-MS 472.0 ((M+Ht, 100%).
To a st1rnng solution of 3-amino-2-methoxyquinoline C2d. General Method for Urea Synthesis by

(0.14 g) in anhydrous CH 2 Cl2 (15 mL) at O C was added CDI Reaction of an Aniline with N,N'-Carbonyl
(0.13 g). The resulting solution was allowed to warm to Diimidazole Followed by Addition of a Second
50 Aniline
room temp. over 1 h then was stirred at room temp. for 16
h. The resulting mixture was treated with 4-(2-(N-methyl- Synthesis of N-(5-(tert-Butyl)-2-(2,5-dimethylpyrro-
carbamoyl)-4-pyridyloxy)aniline (0.18 g). The resulting yel- ly!)phenyl)-N'-( 4-(2-(N-methy lcarbamoy 1)-4-pyridy-
low solution stirred at room temp. for 72 h, then was treated loxy )phenyl )Urea
55
with water (125 mL). The resulting aqueous mixture was
extracted with EtOAc (2x150 mL). The combined organic
phases were washed with a saturated NaCl solution (100
ml), dried (MgSO 4) and concentrated under reduced pres-
sure. The residue was triturated (90% EtOAc/10% hexane). 60
The resulting white solids were collected by filtration and
washed with EtOAc to give bis( 4-(2-(N-methylcarbamoyl)-
4-pyridyloxy)phenyl)urea (0.081 g, 44%): TLC (100%
N
EtOAc) Rf0.50; 1 H NMR (DMSO-d 6 ) Ii 2.76 (d, J=5.1 Hz,
6H), 7.1-7.6 (m, 12H), 8.48 (d, J=5.4 Hz, lH), 8.75 (d, J=4.8
65
"(Y
Hz, 2H), 8.86 (s, 2H); HPLC ES-MS m/z 513 ((M+Hr).
IITRUE COPY!I
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To a stirring solution of CDI (0.21 g, 1.30 mmol) in room temp. The resulting mixture was diluted with water
CH Cl 2 (2 mL) was added 5-(tert-butyl)-2-(2,5-dimethylpyr- (100 mL), then was made basic with a saturated NaHCO 3
rolyl)aniline (MethodA4, Step 2; 0.30 g, 1.24 mmol) in one solution (2-3 mL). The basic solution was extracted with
portion. The resulting mixture was stirred at room temp. for EtOAc (2x250 mL). The organic layers were separately
4 h, then 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline 5 washed with a saturated NaCl solution, combined, dried
(0.065 g, 0.267 mmol) was then added in one portion. The (MgSO 4), and concentrated under reduced pressure. The
resulting mixture was heated at 36° C. overnight, then resulting pink-brown residue was dissolved in MeOH and
cooled to room temp. and diluted with EtOAc (5 mL). The absorbed onto SiO 2 (100 g). Colunm chromatography (300
resulting mixture was sequentially washed with water (15 g SiO2 ; gradient from 1% Et3 N/33% EtOAc/66% hexane to
mL) and a IN HCI solution (15 mL), dried (MgSO 4), and 1% Et3 N/99% EtOAc to 1% Et 3 N/20% MeOH/79% EtOAc)
10
filtered through a pad of silica gel (50 g) to afford N-(5- followed by concentration under reduced pressure at 45° C.
(tert-butyl )-2-(2,5-dimethylpyrroly l)pheny I)-N-( 4-(2-(N- gave a warm concentrated EtOAc solution, which was
methy lcarbamoy l)-4-pyridy loxy )phenyl )urea as a yellowish treated with hexane (10 mL) to slowly form crystals of
solid (0.033 g, 24%): TLC (40% EtOAc/60% hexane) R N-(2-methoxy-5-( trifluoromethyl )pheny 1)-N'-( 4-(2-(N-me-
0.24; 1 H NMR (acetone-d 6 ) Ii 1.37 (s, 9H), 1.89 (s, 6H), 2.89 thy lcarbamoy l)-4-pyridy loxy )phenyl )urea (0.44 g): TLC
(d, J=4.8 Hz, 3H), 5.83 (s, 2H), 6.87-7.20 (m, 6H), 7.17 (dd, 15 (1% Et3 N/99% EtOAc) Rf 0.40.
lH), 7.51-7.58 (m, 3H), 8.43 (d, J=5.4 Hz, lH), 8.57 (d,
J=2.1 Hz, lH), 8.80 (br s, lH); HPLC ES-MS 512 ((M+H)+, D. Interconversion of Ureas
100%).
Dia. Conversion of w-Aminophenyl Ureas into
C3. Combinatorial Method for the Synthesis of 20 w-Arylamino )phenyl Ureas
Diphenyl Ureas Using Triphosgene
Synthesis of N-( 4-Chloro-3-((trifluoromethyl)phe-
One of the anilines to be coupled was dissolved in ny 1)-N'-(4-(3-methoxycarbony lpheny l)carboxyami-
dichloroethane (0.10 M). This solution was added to a 8 mL nopheny l)Urea
vial (0.5 mL) containing dichloroethane (1 mL). To this was 25
added a bis(trichloromethyl) carbonate solution (0.12 Min
dichloroethane, 0.2 mL, 0.4 equiv.), followed by diisopro-
pylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2
equiv.). The vial was capped and heated at 80° C. for 5 h,
then allowed to cool to room temp for approximately 10 h.
The second aniline was added (0.10 Min dichloroethane, 0.5
30
Cl'&
CF3
O o~~OMe
n
mL, 1.0 equiv.), followed by diisopropylethylamine (0.35 M l~)l~IN a a
in dichloroethane, 0.2 mL, 1.2 equiv.). The resulting mixture N
H H
was heated at 80° C. for 4 h, cooled to room temperature and
treated with MeOH (0.5 mL). The resulting mixture was 35
concentrated under reduced pressure and the products were To a solution ofN-(4-chloro-3-((trifluoromethyl)phenyl)-
purified by reverse phase HPLC. N'-( 4-aminophenyl)urea (Method Cid; 0.050 g, 1.52 mmol),
mono-methyl isophthalate (0.25 g, 1.38 mmol), HOBT-H 2 O
C4. General Method for Urea Synthesis by (0.41 g, 3.03 mmol) and N-methylmorpholine (0.33 mL,
Reaction of an Aniline with Phosgene Followed by 3.03 mmol) in DMF (8 mL) was added EDCI.HCI (0.29 g,
40
Addition of a Second Aniline 1.52 mmol). The resulting mixture was stirred at room temp.
overnight, diluted with EtOAc (25 mL) and sequentially
Synthesis of N-(2-Methoxy-5-(trifluoromethyl)phe- washed with water (25 mL) and a saturated NaHCO 3
nyl )-N'-( 4-(2-(N-methy lcarbamoyl )-4-pyridy loxy) solution (25 mL). The organic layer was dried (Na2 SO4 ) and
concentrated under reduced pressure. The resulting solids
phenyl)Urea
45 were triturated with an EtOAc solution (80% EtOAc/20%
hexane) to give N-( 4-chloro-3-((trifluoromethyl)phenyl)-N'-
(4-(3-methoxycarbonylphenyl)carboxyaminophenyl)urea
(0.27 g, 43%): mp 121-122; TLC (80% EtOAc/20% hexane)
Rf0.75.
Dlb. Conversion of w-Carboxyphenyl Ureas into

w-(Arylcarbamoyl)phenyl Ureas

55 ny 1)-N'-(4-(3-methylcarbamoylpheny I)carbam-
To a stirring solution of phosgene (1.9 Min toluene; 2.07

mL 0.21 g, 1.30 mmol) in CH 2 Cl2 (20 mL) at 0° C. was
added anh pyridine (0.32 mL) followed by 2-methoxy-5- 60 Cl~
CF3
0
oylpheny l)Urea
~N~NHMe
0 n
(trifluoromethyl)aniline (0.75 g). The yellow solution was
allowed to warm to room temp during which a precipitate
formed. The yellow mixture was stirred for 1 h, then
UJlN N
H
N
H
H O

were treated with anh toluene (20 mL) followed by 4-(2-
(N-methylcarbamoyl)-4-pyridyloxy)aniline (prepared as 65 To a solution ofN-(4-chloro-3-((trifluoromethyl)phenyl)-
described in Method A2; 0.30 g) and the resulting suspen- N'-( 4-(3-methy lcarbamoy lpheny I) carboxyaminophenyl)
sion was heated at 80° C. for 20 h, then allowed to cool to urea (0.14 g, 0.48 mmol), 3-methylcarbamoylaniline (0.080
IITRUE COPY!I
US 7,351,834 Bl
41 42
g, 0.53 mmol), HOBT-H 2 0 (0.14 g, 1.07 mmol), and N-me- (0.17 g, 0.34 mmol) was added methylamine (2 Min THF;
thylmorpholine (0.5 mL, 1.07 mmol) in DMF (3 mL) at 0° 1 mL, 1.7 mmol) and the resulting mixture was stirred at
C. was added EDCI.HCI (0.10 g, 0.53 mmol). The resulting room temp. overnight, then concentrated under reduced
mixture was allowed to warm to room temp. and was stirred pressure to give N-(4-chloro-3-((trifluoromethyl)phenyl)-
overnight. The resulting mixture was treated with water (10 5 N'-( 4-(3-methy lcarbamoy lpheny l)carboxyaminopheny I)
mL), and extracted with EtOAc (25 mL). The organic phase urea as a white solid: mp 247; TLC (100% EtOAc) Rf0.35.
was concentrated under reduced pressure. The resulting
yellow solids were dissolved in EtOAc (3 mL) then filtered D3. Conversion of w-Carboalkoxyaryl Ureas into
through a pad of silica gel (17 g, gradient from 70% w-Carboxyaryl Ureas
EtOAc/30% hexane to 10% MeOH/90% EtOAc) to give 10
N-( 4-chloro-3-( (trifluoromethyl)phenyl)-N'-( 4-(3-methyl- Synthesis of N-( 4-Chloro-3-((trifluoromethyl)phe-
carbamoylphenyl)carbamoylphenyl)urea as a white solid nyl)-N'-( 4-carboxyphenyl)Urea
(0.097 g, 41%): mp 225-229; TLC (100% EtOAc) Rf0.23.
Die. Combinatorial Approach to the Conversion of 15

w-Carboxyphenyl Ureas into CF3 0

c,+ o ~OH
nyl)-N'-( 4-(N-(3-(N-(3-pyridyl)carbamoyl)phenyl)
carbamoyl)phenyl)Urea
20
UNJlNN H H
To a slurry ofN-( 4-chloro-3-((trifluoromethyl)phenyl)-N-

(4-ethoxycarbonylphenyl)urea (Method Cle; 5.93 g, 15.3
25
mmol) in MeOH (75 mL) was added an aqueous KOH
solution (2.5 N, 10 mL, 23 mmol). The resulting mixture
was heated at the reflux temp. for 12 h, cooled to room
temp., and concentrated under reduced pressure. The residue
30
was diluted with water (50 mL), then treated with a 1 N HCI
solution to adjust the pH to 2 to 3. The resulting solids were
A mixture ofN-(4-chloro-3-((trifluoromethyl)phenyl)-N'- collected and dried under reduced pressure to give N-(4-
(3-carboxyphenyl)urea (Method Clf; 0.030 g, 0.067 mmol) chloro-3-( (trifluoromethyl )pheny 1)-N'-( 4-carboxypheny I)
and N-cyclohexy 1-N'-(methy !polystyrene )carbodiimide (55 urea as a white solid (5.05 g, 92%).
mg) in 1,2-dichloroethane (1 mL) was treated with a solution 35
of 3-aminopyridine in CH 2 Cl2 (1 M; 0.074 mL, 0.074 D4. General Method for the Conversion of
mmol). (In cases of insolubility or turbidity, a small amount w-Alkoxy Esters into w-Alkyl Amides
ofDMSO was also added.) The resulting mixture was heated
at 36° C. overnight. Turbid reactions were then treated with Synthesis of N-( 4-Chloro-3-((trifluoromethyl)phe-
THF (1 mL) and heating was continued for 18 h. The 40
nyl )-N'-( (4-(3-( 5-(2-dimethy laminoethy l)carbamoyl)
resulting mixtures were treated with poly(4-(isocyanatom- pyridyl)oxyphenyl)Urea
ethyl)styrene) (0.040 g) and the resulting mixture was stirred
at 36° C. for 72 h, then cooled to room temp. and filtered.
The resulting solution was filtered through a plug of silica
gel (1 g). Concentration under reduced pressure afforded 45
N-( 4-chloro-3-( (trifluoromethyl)phenyl)-N'-( 4-(N-(3-(N-(3-
pyridy l)carbamoy I)phenyl )carbamoy l)pheny I)urea (0.024 g,
59%): TLC (70% EtOAc/30% hexane) Rf0.12.
D2. Conversion of w-Carboalkoxyaryl Ureas into 50

w-Carbamoylaryl Ureas
Synthesis of N-( 4-Chloro-3-((trifluoromethyl)phe- Step 1. Synthesis of N-( 4-Chloro-3-(trifluorom-

ny 1)-N'-(4-(3-methylcarbamoy lpheny l)carboxyami- ethy l)pheny I)-N'-( (4-(3-( 5-carboxypyridyl )oxyphe-
nopheny l)Urea 55 ny l)Urea
N-( 4-Chloro-3-(trifluoromethyl)phenyl)-N'-(( 4-(3-( 5-

methoxycarbonylpyridyl)oxyphenyl)urea was synthesized
D~
from 4-chloro-3-(trifluoromethyl)phenyl isocyanate and
Cl'&
CF
3
Al~ NHMe
60 4-(3-(5-methoxycarbonylpyridyl)oxyaniline (Method A14,
Step 2) in a manner analogous to Method Cla. A suspension
0
I# N
)l N
~I O a of N-( 4-chloro-3-(trifluoromethyl)phenyl)-N'-(( 4-(3-(5-
methoxycarbonylpyridyl)oxyphenyl)urea (0.26 g, 0.56
H H mmol) in MeOH (10 mL) was treated with a solution of
65 KOH (0.14 g, 2.5 mmol) in water (1 mL) and was stirred at
To a sample of N-(4-chloro-3-((trifluoromethyl)phenyl)- room temp. for 1 h. The resulting mixture was adjusted to
N'-( 4-(3-carbomethoxypheny I) carboxyaminopheny !)urea pH 5 with a 1 N HCl solution. The resulting precipitate was
IITRUE COPY!I
US 7,351,834 Bl
43 44
removed by filtration and washed with water. The resulting raphy (SiO2 ; gradient from 100% hexane to 40% EtOAc/
solids were dissolved in EtOH (10 mL) and the resulting 60% hexane) to give N-(4-chloro-3-((trifluoromethyl)phe-
solution was concentrated under reduced pressure. The nyl)-N'-( 4-( 4-(2-(N-(2-hydroxy )ethylcarbamoyl)
EtOH/concentration procedure was repeated twice to give pyridyloxyphenyl)urea as a white solid (0.019 g, 10%).
N-( 4-chloro-3-(trifluoromethyl)phenyl)-N'-(( 4-(3-(5-car- Listed below are compounds listed in the Tables below
boxypyridyl)oxyphenyl)urea (0.18 g, 71%). which have been synthesized according to the Detailed
Experimental Procedures given above:
See Tables for Compound Characterization
Entry 1: 4-(3-N-Methylcarbamoylphenoxy)aniline was

prepared according to Method A13. According to Method
15 C3,3-tert-butylaniline was reacted with bis(trichloromethyl)
Step 2. Synthesis of N-( 4-chloro-3-(trifluoromethyl) carbonate followed by 4-(3-N-Methylcarbamoylphenoxy)
phenyl)- N'-( (4-(3-( 5-(2-dimethy laminoethy l)carbam- aniline to afford the urea.
oy l)pyridyl )oxypheny l)urea Entry 2: 4-Fluoro-1-nitrobenzene and p-hydroxyac-
etophenone were reacted according to Method A13, Step 1
A mixture of N-( 4-chloro-3-(trifluoromethyl)phenyl)-N'- 20 to afford the 4-(4-acetylphenoxy)-1-nitrobenzene. 4-(4-
((4-(3-(5-carboxypyridyl)oxyphenyl)urea (0.050 g, 0.011 Acetylphenoxy)-1-nitrobenzene was reduced according to
mmol), N,N-dimethylethylenediamine (0.22 mg, 0.17 Method A13, Step 4 to afford 4-(4-acetylphenoxy)aniline.
mmol), HOBT (0.028 g, 0.17 mmol), N-methylmorpholine According to Method C3,3-tert-butylaniline was reacted
(0.035 g, 0.28 mmol), and EDCI.HCI (0.032 g, 0.17 mmol) with bis(trichloromethyl) carbonate followed by 4-(4-
in DMF (2.5 mL) was stirred at room temp. overnight. The 25 acetylphenoxy)aniline to afford the urea.
Entry 3: According to Method C2d, 3-tert-butylaniline
resulting solution was separated between EtOAc (50 mL)
was treated with CDI, followed by 4-(3-N-methylcarbam-
and water (50 mL). The organic phase was washed with oyl)-4-methoxyphenoxy)aniline, which had been prepared
water (35 mL), dried (MgSO 4) and concentrated under according to Method AS, to afford the urea.
reduced pressure. The residue was dissolved in a minimal 30 Entry 4: 5-tert-Butyl-2-methoxyaniline was converted to
amount of CH 2 Cl2 (approximately 2 mL). The resulting 5-tert-butyl-2-methoxyphenyl isocyanate according to
solution was treated with Et 2 O dropwise to give N-(4- Method Bl. 4-(3-N-Methylcarbamoylphenoxy)aniline, pre-
chloro-3-( trifluoromethy !)phenyl)-N'-( (4-(3-( 5-(2-dimethy- pared according to Method A13, was reacted with the
laminoethyl )carbamoy l)pyridyl )oxypheny l)urea as a white isocyanate according to Method Cla to afford the urea.
35 Entry 5: According to Method C2d, 5-tert-butyl-2-meth-
precipitate (0.48 g, 84%: 1 H NMR (DMSO-d 6 ) Ii 2.10 s,
6H), 3.26 (s, H), 7.03 (d, 2H), 7.52 (d, 2H), 7.60 (m, 3H), oxyaniline was reacted with CDI followed by 4-(3-N-me-
8.05 (s, lH), 8.43 (s, lH), 8.58 (t, lH), 8.69 (s, lH), 8.90 (s, thylcarbamoyl)-4-methoxyphenoxy)aniline, which had been
lH), 9.14 (s, lH); HPLC ES-MS m/z 522 ((M+Hr).
Entry 6: 5-(4-Aminophenoxy)isoindoline-l,3-dione was
D5. General Method for the Deprotection of 40 prepared according to Method A3. According to Method 2d,
N-( w-Silyloxyalkyl)amides 5-tert-butyl-2-methoxyaniline was reacted with CDI fol-
lowed by 5-(4-aminophenoxy)isoindoline-l,3-dione to
Synthesis of N-( 4-Chloro-3-((trifluoromethyl)phe- afford the urea.
nyl)-N'-( 4-(4-(2-(N-(2-hydroxy)ethylcarbamoyl) Entry 7: 4-(1-Oxoisoindolin-5-yloxy)aniline was synthe-
pyridyloxyphenyl)Urea sized according to Method A12. According to Method 2d,
To a solution ofN-(4-chloro-3-((trifluoromethyl)phenyl)- 5-tert-butyl-2-methoxyaniline was reacted with CDI fol-

N'-( 4-(4-(2-(N-(2-triisopropylsilyloxy )ethylcarbamoyl)py- lowed by 4-(1-oxoisoindolin-5-yloxy)aniline to afford the
ridyloxyphenyl)urea (prepared in a manner analogous to 60
urea.
Method Cla; 0.25 g, 0.37 mmol) in anh THF (2 mL) was Entry 8: 4-(3-N-Methylcarbamoylphenoxy)aniline was
tetrabutylammonium fluoride (1.0 M in THF; 2 mL). The synthesized according to Method Al 3. According to Method
mixture was stirred at room temperature for 5 min, then was C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with
treated with water (10 mL). The aqueous mixture was CDI followed by 4-(3-N-methylcarbamoylphenoxy)aniline
extracted with EtOAc (3x10 mL). The combined organic 65 to afford the urea.
layers were dried (MgSO 4) and concentrated under reduced Entry 9: 4-Hydroxyacetophenone was reacted with
pressure. The residue was purified by column chromatog- 2-chloro-5-nitropyridine to give 4-(4-acetylphenoxy)-5-ni-
IITRUE COPY!I
US 7,351,834 Bl
45 46
tropyridine according to Method A3, Step 2. According to to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocy-
Method AS, Step 4,4-( 4-acetylphenoxy)-5-nitropyridine was anate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridy-
reduced to 4-( 4-acetylphenoxy)-5-aminopyridine. 2-Meth- loxy)-2-chloroaniline according to Method Cla to afford the
oxy-5-(trifluoromethyl)aniline was converted to 2-methoxy- urea.
5-(trifluoromethyl)phenyl isocyanate according to Method 5 Entry 18: According to Method A2, Step 4,5-amino-2-
Bl. The isocyanate was reacted with 4-(4-acetylphenoxy)- methylphenol was reacted with 4-chloro-N-methyl-2-pyridi-
5-aminopyridine according to Method Cla to afford the necarboxamide, which had been synthesized according to
urea. Method A2, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-
Entry 10: 4-Fluoro-1-nitrobenzene and p-hydroxyac- pyridyloxy)-4-methylaniline. 5-(Trifluoromethyl)-2-meth-
etophenone were reacted according to Method A13, Step 1 10 oxyaniline was converted into 5-(trifluoromethyl)-2-meth-
to afford the 4-(4-acetylphenoxy)-1-nitrobenzene. 4-(4- oxyphenyl isocyanate according to Method Bl.
Acetylphenoxy)-1-nitrobenzene was reduced according to 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was
Method A13, Step 4 to afford 4-(4-acetylphenoxy)aniline. reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-
According to Method C3,5-(trifluoromethyl)-2-methoxybu- methylaniline according to Method Cla to afford the urea.
tylaniline was reacted with bis(trichloromethyl) carbonate 15 Entry 19: 4-Chloropyridine-2-carbonyl chloride was
followed by 4-(4-acetylphenoxy)aniline to afford the urea. reacted with ethylamine according to Method A2, Step 3b.
Entry 11: 4-Chloro-N-methyl-2-pyridinecarboxamide, The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was
which was synthesized according to Method A2, Step 3a, reacted with 4-aminophenol according to Method A2, Step
was reacted with 3-aminophenol according to Method A2, 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline.
Step 4 using DMAC in place of DMF to give 3-(-2-(N- 20 5-(Trifluoromethyl)-2-methoxyaniline was converted into
methylcarbamoyl)-4-pyridyloxy)aniline. According to 5-(trifluoromethy 1)-2-methoxypheny I isocyanate according
Method C4,2-methoxy-5-(trifluoromethyl)aniline was to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocy-
reacted with phosgene followed by 3-(-2-(N-methylcarbam- anate was reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridy-
oyl)-4-pyridyloxy)aniline to afford the urea. loxy)aniline according to Method Cla to afford the urea.
Entry 12: 4-Chloropyridine-2-carbonyl chloride HCI salt 25 Entry 20: According to Method A2, Step 4,4-amino-2-
was reacted with ammonia according to MethodA2, Step 3b chlorophenol was reacted with 4-chloro-N-methyl-2-pyridi-
to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-py- necarboxamide, which had been synthesized according to
ridinecarboxamide was reacted with 3-aminophenol accord- Method A2, Step 3b, to give 4-(2-(N-methylcarbamoyl)-4-
ing to Method A2, Step 4 using DMAC in place of DMF to pyridy loxy )-3-chloroaniline. 5-(Trifluoromethyl )-2-meth-
give 3-(2-carbamoyl-4-pyridyloxy)aniline. According to 30 oxyaniline was converted into 5-(trifluoromethyl)-2-meth-
Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was oxyphenyl isocyanate according to Method Bl.
reacted with phosgene followed by 3-(2-carbamoyl-4-py- 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was
ridyloxy)aniline to afford the urea. reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-
Entry 13: 4-Chloro-N-methyl-2-pyridinecarboxamide chloroaniline according to Method Cla to afford the urea.
was synthesized according to Method A2, Step 3b. 35 Entry 21: 4-( 4-Methylthiophenoxy)-1-nitrobenzene was
4-Chloro- N-methy 1-2-pyridinecarboxamide was reacted oxidized according to Method Al 9, Step 1 to give 4-( 4-
with 4-aminophenol according to Method A2, Step 4 using methylsulfonylphenoxy)-1-nitrobenzene. The nitrobenzene
DMAC in place ofDMF to give 4-(2-(N-methylcarbamoyl)- was reduced according to Method A19, Step 2 to give
4-pyridyloxy)aniline. According to Method C2a, 2-meth- 4-( 4-methylsulfonylphenoxy)-1-aniline. According to
oxy-5-(trifluoromethyl)aniline was reacted with CDI fol- 40 Method Cla, 5-(trifluoromethyl)-2-methoxyphenyl isocyan-
lowed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline ate was reacted with 4-( 4-methylsulfonylphenoxy)-1-aniline
to afford the urea. to afford the urea.
Entry 14: 4-Chloropyridine-2-carbonyl chloride HCI salt Entry 22: 4-(3-carbamoylphenoxy)-1-nitrobenzene was
was reacted with ammonia according to MethodA2, Step 3b reduced to 4-(3-carbamoylphenoxy)aniline according to
to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-py- 45 Method Al 5, Step 4. According to Method Cla, 5-(trifluo-
ridinecarboxamide was reacted with 4-aminophenol accord- romethyl)-2-methoxyphenyl isocyanate was reacted with
ing to Method A2. Step 4 using DMAC in place of DMF to 4-(3-carbamoylphenoxy)aniline to afford the urea.
give 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Entry 23: 5-(4-Aminophenoxy)isoindoline-l,3-dione was
Method C4,2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A3. 5-(Trifluoromethyl)-
reacted with phosgene followed by 4-(2-carbamoyl-4-py- 50 2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
ridyloxy)aniline to afford the urea. methoxyphenyl isocyanate according to Method B 1. 5-(Tri-
Entry 15: According to Method C2d, 5-(trifluoromethyl)- fluoromethyl)-2-methoxyphenyl isocyanate was reacted
2-methoxyaniline was reacted with CDI followed by 4-(3- with 5-(4-aminophenoxy )isoindoline-1,3-dione according to
N-methy lcarbamoy 1)-4-methoxyphenoxy )aniline, which Method Cla to afford the urea.
had been prepared according to Method AS, to afford the 55 Entry 24: 4-Chloropyridine-2-carbonyl chloride was
urea. reacted with dimethylamine according to Method A2, Step
Entry 16: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2- 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecar-
methylaniline was synthesized according to Method AS. boxamide was reacted with 4-aminophenol according to
5-(Trifluoromethyl)-2-methoxyaniline was converted into Method A2, Step 4 to give 4-(2-(N,N-dimethylcarbamoyl)-
5-(trifluoromethy 1)-2-methoxypheny I isocyanate according 60 4-pyridyloxy)aniline. 5-(Trifluoromethyl)-2-methoxyaniline
to Method Bl. The isocyanate was reacted with 4-(2-(N- was converted into 5-(trifluoromethyl)-2-methoxyphenyl
methy lcarbamoy 1)-4-pyridyloxy )-2-methy !aniline accord- isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-
ing to Method Cle to afford the urea. methoxyphenyl isocyanate was reacted with 4-(2-(N N-dim-
Entry 17: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2- ethylcarbamoyl)-4-pyridyloxy)aniline according to Method
chloroaniline was synthesized according to Method A6. 65 Cla to afford the urea.
5-(Trifluoromethyl)-2-methoxyaniline was converted into Entry 25: 4-(1-Oxoisoindolin-5-yloxy)aniline was syn-
5-(trifluoromethy 1)-2-methoxypheny I isocyanate according thesized according to Method Al 2. 5-(Trifluoromethyl)-2-
IITRUE COPY!I
US 7,351,834 Bl
47 48
methoxyaniline was treated with CDI, followed by 4-(1- ethyl)-2-methoxyaniline was converted into 5-(trifluorom-
oxoisoindolin-5-yloxy )aniline according to Method C2d to ethyl)-2-methoxyphenyl isocyanate according to Method
afford the urea. Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was
Entry 26: 4-Hydroxyacetophenone was reacted with reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline
4-fluoronitrobenzene according to Method A13, Step 1 to 5 according to Method Cla to afford the urea. N-(5-(Trifluo-
give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene romethy 1)-2-methoxypheny 1)-N'-( 4-(3-( 5-methoxycarbon-
was reduced according to Method A13, Step 4 to afford y lpyridy l)oxy )pheny l)urea was saponified according to
4-( 4-acetylphenoxy)aniline, which was converted to the Method D4, Step 1, and the corresponding acid was coupled
4-( 4-(1-(N-methoxy)iminoethyl)phenoxyaniline HCI salt with methylamine according to Method D4, Step 2 to afford
according to Method Al 6. 5-(Trifluoromethyl)-2-methoxya- 10 the amide.
niline was converted into 5-(trifluoromethyl)-2-methox- Entry 33: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline
yphenyl isocyanate according to Method Bl. 5-(Trifluorom- was synthesized according to Method A14. 5-(Trifluorom-
ethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4- ethyl)-2-methoxyaniline was converted into 5-(trifluorom-
(1-(N-methoxy)iminoethyl)phenoxyaniline HCI salt to ethyl)-2-methoxyphenyl isocyanate according to Method
Method Cla to afford the urea. 15 Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was
Entry 27: 4-Chloro-N-methylpyridinecarboxamide was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline
synthesized as described in Method A2, Step 3b. The chlo- according to Method Cla to afford the urea. N-(5-(Trifluo-
ropyridine was reacted with 4-aminothiophenol according to romethy 1)-2-methoxypheny 1)-N'-( 4-(3-( 5-methoxycarbon-
Method A2, Step 4 to give 4-(4-(2-(N-methylcarbamoyl) y lpyridy l)oxy )pheny l)urea was saponified according to
pheny lthio )aniline. 5-(Trifluoromethy 1)-2-methoxyaniline 20 Method D4, Step 1, and the corresponding acid was coupled
was converted into 5-(trifluoromethyl)-2-methoxyphenyl with N,N-dimethylethylenediamine according to Method
isocyanate according to Method Bl. 5-(Trifluoromethyl)-2- D4, Step 2 to afford the amide.
methoxyphenyl isocyanate was reacted with 4-( 4-(2-(N- Entry 34: 4-(3-Carboxyphenoxy)aniline was synthesized
methylcarbamoyl)phenylthio )aniline according to Method according to Method Al 1. 5-(Trifluoromethyl)-2-methoxya-
Cla to afford the urea. 25 niline was converted into 5-(trifluoromethyl)-2-methox-
Entry 28: 5-(4-Aminophenoxy)-2-methylisoindoline-1,3- yphenyl isocyanate according to Method Bl. 4-(3-Carbox-
dione was synthesized according to Method A9. 5-(Trifluo- yphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-
romethyl)-2-methoxyaniline was converted into 5-(trifluo- methoxyphenyl isocyanate according to Method Clf to
romethyl)-2-methoxyphenyl isocyanate according to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-car-
Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyan- 30 boxyphenyl)urea, which was coupled with 3-aminopyridine
ate was reacted with 5-(4-aminophenoxy)-2-methylisoindo- according to Method Die.
line-l,3-dione according to Method Cla to afford the urea. Entry 35: 4-(3-Carboxyphenoxy)aniline was synthesized
Entry 29: 4-Chloro-N-methylpyridinecarboxamide was according to Method Al 1. 5-(Trifluoromethyl)-2-methoxya-
synthesized as described in Method A2. Step 3b. The chlo- niline was converted into 5-(trifluoromethyl)-2-methox-
ropyridine was reacted with 3-aminothiophenol according to 35 yphenyl isocyanate according to Method Bl. 4-(3-Carbox-
Method A2, Step 4 to give 3-(4-(2-(N-methylcarbamoyl) yphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-
pheny lthio )aniline. 5-(Trifluoromethy 1)-2-methoxyaniline methoxyphenyl isocyanate according to Method Clf to
was converted into 5-(trifluoromethyl)-2-methoxyphenyl afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-car-
isocyanate according to Method Bl. 5-(Trifluoromethyl)-2- boxyphenyl)urea, which was coupled with N-(4-fluorophe-
methoxyphenyl isocyanate was reacted with 3-( 4-(2-(N- 40 nyl)piperazine according to Method Die.
methylcarbamoyl)phenylthio )aniline according to Method Entry 36: 4-(3-Carboxyphenoxy)aniline was synthesized
Cla to afford the urea. according to Method Al 1. 5-(Trifluoromethyl)-2-methoxya-
Entry 30: 4-Chloropyridine-2-carbonyl chloride was niline was converted into 5-(trifluoromethyl)-2-methox-
reacted with isopropylamine according to Method A2, Step yphenyl isocyanate according to Method Bl. 4-(3-Carbox-
3b. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxa- 45 yphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-
mide was reacted with 4-aminophenol according to Method methoxyphenyl isocyanate according to Method Clf to
A2, Step 4 to give 4-(2-(N-isopropylcarbamoyl)-4-pyridy- afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-car-
loxy)aniline. 5-(Trifluoromethyl)-2-methoxyaniline was boxyphenyl)urea, which was coupled with 4-fluoroaniline
converted into 5-(trifluoromethyl)-2-methoxyphenyl isocy- according to Method Die.
anate according to Method Bl. 5-(Trifluoromethyl)-2-meth- 50 Entry 37: 4-(3-Carboxyphenoxy)aniline was synthesized
oxyphenyl isocyanate was reacted with 4-(2-(N-isopropyl- according to Method Al 1. 5-(Trifluoromethyl)-2-methoxya-
carbamoyl)-4-pyridyloxy)aniline according to Method Cla niline was converted into 5-(trifluoromethyl)-2-methox-
to afford the urea. yphenyl isocyanate according to Method Bl. 4-(3-Carbox-
Entry 31: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline yphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-
was synthesized according to Method A14. 5-(Trifluorom- 55 methoxyphenyl isocyanate according to Method Clf to
ethyl)-2-methoxyaniline was converted into 5-(trifluorom- afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-car-
ethyl)-2-methoxyphenyl isocyanate according to Method boxyphenyl)urea, which was coupled with 4-(dimethy-
Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was lamino)aniline according to Method Die.
reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline Entry 38: 4-(3-Carboxyphenoxy)aniline was synthesized
according to Method Cla to afford the urea. N-(5-(Trifluo- 60 according to Method Al 1. 5-(Trifluoromethyl)-2-methoxya-
romethy 1)-2-methoxypheny 1)-N'-(4-(3-( 5-methoxycarbon- niline was converted into 5-(trifluoromethyl)-2-methox-
y lpyridy l)oxy )pheny l)urea was saponified according to yphenyl isocyanate according to Method Bl. 4-(3-Carbox-
Method D4, Step 1, and the corresponding acid was coupled yphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-
with 4-(2-aminoethyl)morpholine to afford the amide methoxyphenyl isocyanate according to Method Clf to
according to Method D4, Step 2. 65 afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-car-
Entry 32: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline boxyphenyl)urea, which was coupled with 5-amino-2-meth-
was synthesized according to Method Al 4. 5-(Trifluorom- oxypyridine according to Method Die.
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49 50
Entry 39: 4-(3-Carboxyphenoxy)aniline was synthesized Entry 49: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-
according to Method Al 1. 5-(Trifluoromethyl)-2-methoxya- chloroaniline was synthesized according to Method A6.
niline was converted into 5-(trifluoromethyl)-2-methox- According to Method Cla, 4-chloro-3-(trifluoromethyl)phe-
yphenyl isocyanate according to Method Bl. 4-(3-Carbox- nyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-
yphenoxy)aniline was reacted with 5-(trifluoromethyl)-2- 5 4-pyridyloxy)-2-chloroaniline to afford the urea.
methoxyphenyl isocyanate according to Method Clf to Entry 50: According to Method A2, Step 4,5-amino-2-
afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-car- methylphenol was reacted with 4-chloro-N-methyl-2-pyridi-
boxyphenyl)urea, which was coupled with 4-morpholinoa- necarboxamide, which had been synthesized according to
niline according to Method Dlc. Method A2, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-
Entry 40: 4-(3-Carboxyphenoxy)aniline was synthesized 10 pyridyloxy)-4-methylaniline. According to Method Cla,
according to Method Al 1. 5-(Trifluoromethyl)-2-methoxya- 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted
niline was converted into 5-(trifluoromethyl)-2-methox- with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy )-4-methyla-
yphenyl isocyanate according to Method Bl. 4-(3-Carbox- niline to afford the urea.
yphenoxy)aniline was reacted with 5-(trifluoromethyl)-2- Entry 51: 4-Chloropyridine-2-carbonyl chloride was
methoxyphenyl isocyanate according to Method Clf to 15 reacted with ethylamine according to Method A2, Step 3b.
afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-car- The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was
boxyphenyl)urea, which was coupled with N-(2-pyridyl) reacted with 4-aminophenol according to Method A2, Step
piperazine according to Method Dlc. 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline.
Entry 41: 4-(3-(N-Methylcarbamoyl)phenoxy)aniline was According to Method Cla, 4-chloro-3-(trifluoromethyl)phe-
synthesized according to Method Al 3. According to Method 20 nyl isocyanate was reacted with 4-(2-(N-ethylcarbamoyl)-
C3,4-chloro-3-(trifluoromethyl)aniline was converted to the 4-pyridyloxy)aniline to afford the urea.
isocyanate, then reacted with 4-(3-(N-Methylcarbamoyl) Entry 52: According to Method A2, Step 4,4-amino-2-
phenoxy )aniline to afford the urea. chlorophenol was reacted with 4-chloro-N-methyl-2-pyridi-
Entry 42: 4-(2-N- Methy lcarbamy 1-4-pyridyloxy )aniline necarboxamide, which had been synthesized according to
was synthesized according to Method A2. 4-Chloro-3-(trif- 25 Method A2, Step 3b, to give 4-(2-(N-methylcarbamoyl)-4-
luoromethyl)phenyl isocyanate was reacted with 4-(2-N- pyridyloxy)-3-chloroaniline. According to Method Cla,
methy lcarbamy 1-4-pyridyloxy )aniline according to Method 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted
Cla to afford the urea. with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroa-
Entry 43: 4-Chloropyridine-2-carbonyl chloride HCI salt niline to afford the urea.
was reacted with ammonia according to MethodA2, Step 3b 30 Entry 53: 4-( 4-Methylthiophenoxy)-1-nitrobenzene was
to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-py- oxidized according to Method Al 9, Step 1 to give 4-( 4-
ridinecarboxamide was reacted with 4-aminophenol accord- methylsulfonylphenoxy)-1-nitrobenzene. The nitrobenzene
ing to Method A2, Step 4 to form 4-(2-carbamoyl-4-pyridy- was reduced according to Method A19, Step 2 to give
loxy)aniline. According to Method Cla, 4-chloro-3- 4-( 4-methylsulfonylphenoxy)-1-aniline. According to
(trifluoromethyl)phenyl isocyanate was reacted with 4-(2- 35 Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate
carbamoyl-4-pyridyloxy)aniline to afford the urea. was reacted with 4-(4-methylsulfonylphenoxy)-1-aniline to
afford the urea.
Entry 44: 4-Chloropyridine-2-carbonyl chloride HCI salt
Entry 54: 4-Bromobenzenesulfonyl chloride was reacted
was reacted with ammonia according to MethodA2, Step 3b
with methy !amine according to Method Al 5, Step 1 to afford
to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-py-
40 N-methy 1-4-bromobenzenesulfonamide. N-Methy 1-4-bro-
ridinecarboxamide was reacted with 3-aminophenol accord-
mo benzenesulfonamide was coupled with phenol according
ing to Method A2, Step 4 to form 3-(2-carbamoyl-4-pyridy-
to Method A15, Step 2 to afford 4-(4-(N-methylsulfamoyl)
loxy)aniline. According to Method Cla, 4-chloro-3-
phenoxy )benzene. 4-( 4-(N-Methylsulfamoyl)phenoxy)ben-
(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-
zene was converted into 4-( 4-(N-methylsulfamoyl)phe-
45 noxy)-1-nitrobenzene according to Method A15, Step 3.
Entry 45: 4-Chloro-N-methyl-2-pyridinecarboxamide, 4-( 4-(N-Methylsulfamoyl)phenoxy )-1-nitrobenzene was
which was synthesized according to Method A2, Step 3a, reduced to 4-(4-N-methylsulfamoyl)phenyloxy)aniline
was reacted with 3-aminophenol according to Method A2, according to Method Al 5, Step 4.Accordingto Method Cl a,
Step 4 to form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy) 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted
aniline. According to Method Cla, 4-chloro-3-(trifluorom- 50 with 4-(3-N-methylsulfamoyl)phenyloxy)aniline to afford
ethyl)phenyl isocyanate was reacted with 3-(2-(N-methyl- the urea.
carbamoyl)-4-pyridyloxy)aniline to afford the urea. Entry 55: 5-Hydroxy-2-methylpyridine was coupled with
Entry 46: 5-(4-Aminophenoxy)isoindoline-l,3-dione was l-fluoro-4-nitrobenzene according to MethodA18, Step 1 to
synthesized according to Method A3. According to Method give 4-(5-(2-Methyl)pyridyloxy)-1-nitrobenzene. The meth-
Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was 55 ylpyridine was oxidized according to the carboxylic acid,
reacted with 5-(4-aminophenoxy)isoindoline-1,3-dione to then esterified according to Method A18, Step 2 to give
afford the urea. 4-( 5-(2-methoxycarbonyl)pyridyloxy )-1-nitrobenzene. The
Entry 47: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2- nitrobenzene was reduced according the Method Al 8, Step
methylaniline was synthesized according to Method AS. 3 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline. The
According to Method Cle, 4-chloro-3-(trifluoromethyl)phe- 60 aniline was reacted with 4-chloro-3-(trifluoromethyl)phenyl
nyl isocyanate was reacted with 5-(4-aminophenoxy)isoin- isocyanate according to Method Cla to afford the urea.
doline-l,3-dione to afford the urea. Entry 56: 5-Hydroxy-2-methylpyridine was coupled with
Entry 48: 4-(3-N- Methy lsulfamoy I)pheny loxy )aniline l-fluoro-4-nitrobenzene according to MethodA18, Step 1 to
was synthesized according to Method A15. According to give 4-(5-(2-Methyl)pyridyloxy)-1-nitrobenzene. The meth-
Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate 65 ylpyridine was oxidized according to the carboxylic acid,
was reacted with 4-(3-N-methylsulfamoyl)phenyloxy) then esterified according to Method A18, Step 2 to give
aniline to afford the urea. 4-(5-(2-methoxycarbonyl)pyridyloxy)- l-nitrobenzene. The
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51 52
nitrobenzene was reduced according the Method Al 8, Step yphenoxy)-1-nitrobenzene was coupled with tetrahydrofur-
3 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline. The furylamine according to Method A13, Step 3 to give 4-(3-
aniline was reacted with 4-chloro-3-(trifluoromethyl)phenyl (N-(tetrahydrofurylmethyl)carbamoyl)phenoxy )-1-
isocyanate according to Method Cla to give N-(4-chloro- nitrobenzene. According to Method A13 Step 4,4-(3-(N-
3-(trifluoromethy !)phenyl)-N'-( 4-(2-(methoxycarbony 1)-5- 5 ( tetrahydrofury !methyl )carbamoy l)phenoxy )-1-
pyridy loxy )phenyl )urea. The methyl ester was reacted with nitro benzene was reduced to 4-(3-(N-
methylamine according to Method D2 to afford N-( 4-chloro- (tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline.
3-(trifluoromethy !)phenyl)-N'-( 4-(2-(N-methylcarbamoyl )- According to Method Cla, 4-chloro-3-(trifluoromethyl)phe-
5-pyridy loxy )phenyl )urea. nyl isocyanate was reacted with 4-(3-(N-(tetrahydrofurylm-
Entry 57: N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4- 10 ethyl)carbamoyl)phenoxy)aniline to afford the urea.
aminophenyl)urea was prepared according to Method Cld. Entry 64: 4-(3-Carboxyphenoxy)-1-nitrobenzene was
N-( 4-Chloro-3-(trifluoromethyl)phenyl-N'-( 4-aminophenyl) synthesized according to MethodA13, Step 2. 4-(3-Carbox-
urea was coupled with mono-methyl isophthalate according yphenoxy)-1-nitrobenzene was coupled with 2-aminom-
to Method Dla to afford the urea. ethyl-1-ethylpyrrolidine according to Method A13, Step 3 to
Entry 58: N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4- 15 give 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)
aminophenyl)urea was prepared according to Method Cld. phenoxy)-1-nitrobenzene. According to Method A13 Step
N-( 4-Chloro-3-(trifluoromethyl)phenyl-N'-( 4-aminophenyl) 4,4-(3-(N-( ( 1-methylpyrrolidiny I)methy l)carbamoy l)phe-
urea was coupled with mono-methyl isophthalate according noxy )-1-nitro benzene was reduced to 4-(3-(N-((1-meth-
to Method Dla to afford N-(4-chloro-3-(trifluoromethyl) y lpyrrolidinyl )methy l)carbamoyl )phenoxy )aniline. Accord-
pheny 1-N'-(4-(3-methoxycarbonylpheny I)carboxyami- 20 ing to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl
nopheny l)urea. According to Method D2, N-( 4-chloro-3- isocyanate was reacted with 4-(3-(N-((1-methylpyrrolidi-
(trifluoromethy l)pheny 1-N'-( 4-(3-methoxycarbony lpheny I) nyl)methyl)carbamoyl)phenoxy)aniline to afford the urea.
carboxyaminophenyl)urea was reacted with methylamine to Entry 65: 4-Chloro-N-methylpyridinecarboxamide was
afford the corresponding methyl amide. synthesized as described in Method A2, Step 3b. The chlo-
Entry 59: 4-Chloropyridine-2-carbonyl chloride was 25 ropyridine was reacted with 4-aminothiophenol according to
reacted with dimethylamine according to Method A2, Step Method A2. Step 4 to give 4-(4-(2-(N-methylcarbamoyl)
3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecar- phenylthio )aniline. According to Method C 1a. 4-chloro-3-
boxamide was reacted with 4-aminophenol according to (trifluoromethyl)phenyl isocyanate was reacted with 4-(4-
Method A2, Step 4 to give 4-(2-(N,N-dimethylcarbamoyl)- (2-(N-methylcarbamoyl)phenylthio )aniline to afford the
4-pyridyloxy)aniline. According to Method Cla, 4-chloro- 30 urea.
3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2- Entry 66: 4-Chloropyridine-2-carbonyl chloride was
(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline to afford reacted with isopropylamine according to Method A2, Step
the urea. 3b. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxa-
Entry 60: 4-Hydroxyacetophenone was reacted with mide was reacted with 4-aminophenol according to Method
4-fluoronitrobenzene according to Method A13, Step 1 to 35
A2, Step 4 to give 4-(2-(N-isopropylcarbamoyl)-4-pyridy-
give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene loxy)aniline. According to Method Cla, 4-chloro-3-(trifluo-
was reduced according to Method 13, Step 4 to afford romethyl)phenyl isocyanate was reacted with 4-(2-(N-iso-
4-( 4-acetylphenoxy)aniline, which was converted to the propylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
4-( 4-(1-(N-methoxy)iminoethyl)phenoxyaniline HCI salt
according to Method A16. According to Method Cla, Entry 67: N-( 4-Chloro-3-(trifluoromethyl)phenyl-N'-( 4-
40
ethoxycarbonylphenyl)urea was synthesized according to
4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted
Method Cle. N-( 4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-
with 4-( 4-acetylphenoxy)aniline to afford the urea.
ethoxycarbonylphenyl)urea was saponified according to
Entry 61: 4-(3-Carboxyphenoxy)-1-nitrobenzene was
Method D3 to give N-(4-chloro-3-(trifluoromethyl)phenyl-
synthesized according to MethodA13, Step 2. 4-(3-Carbox-
N'-( 4-carboxyphenyl)urea. N-( 4-Chloro-3-(trifluoromethyl)
yphenoxy)-1-nitrobenzene was coupled with 4-(2-aminoet- 45
phenyl-N'-(4-carboxyphenyl)urea was coupled with 3-me-
hyl)morpholine according to Method A13, Step 3 to give
thylcarbamoylaniline according to Method Dlb to give
4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy )-1-ni-
N-( 4-chloro-3-(trifluoromethyl)phenyl-N'-( 4-(3-methylcar-
trobenzene. According to Method A13 Step 4,4-(3-(N-(2-
bamoy lpheny l)carbamoy lpheny !)urea.
morpholinylethyl)carbamoyl)phenoxy )-1-nitrobenzene was
reduced to 4-(3-(N-(2-morpholinylethyl)carbamoyl)phe- 50 Entry 68: 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-
noxy)aniline. According to Method Cla, 4-chloro-3-(trifluo- dione was synthesized according to Method A9. According
romethyl)phenyl isocyanate was reacted with 4-(3-(N-(2- to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocy-
morpholinylethyl)carbamoyl)phenoxy)aniline to afford the anate was reacted with 5-(4-aminophenoxy)-2-methylisoin-
urea. doline-l,3-dione to afford the urea.
Entry 62: 4-(3-Carboxyphenoxy)-1-nitrobenzene was 55 Entry 69: 4-Chloro-N-methylpyridinecarboxamide was
synthesized according to MethodA13, Step 2. 4-(3-Carbox- synthesized as described in Method A2, Step 3b. The chlo-
yphenoxy)-1-nitrobenzene was coupled with 1-(2-aminoet- ropyridine was reacted with 3-aminothiophenol according to
hyl)piperidine according to Method A13, Step 3 to give Method A2, Step 4 to give 3-(4-(2-(N-methylcarbamoyl)
4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy )-1-nitroben- phenylthio )aniline. According to Method C 1a, 4-chloro-3-
zene. According to Method A13 Step 4,4-(3-(N-(2-pip- 60 (trifluoromethyl)phenyl isocyanate was reacted with 3-(4-
eridylethyl)carbamoyl)phenoxy )-1-nitrobenzene was (2-(N-methylcarbamoyl)phenylthio )aniline to afford the
reduced to 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy) urea.
aniline. According to Method Cla, 4-chloro-3-(trifluorom- Entry 70: 4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl)py-
ethyl)phenyl isocyanate was reacted with 4-(3-(N-(2-pip- ridyloxy)aniline was synthesized according to Method Al 0.
eridylethyl)carbamoyl)phenoxy)aniline to afford the urea. 65 According to Method Cla, 4-chloro-3-(trifluoromethyl)phe-
Entry 63: 4-(3-Carboxyphenoxy)-1-nitrobenzene was nyl isocyanate was reacted with 4-(2-(N-(2-morpholin-4-
synthesized according to MethodA13, Step 2. 4-(3-Carbox- ylethyl)carbamoyl)pyridyloxy)aniline to afford the urea.
IITRUE COPY!I
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53 54
Entry 71: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline aniline according to Method Clf to afford the urea, which
was synthesized according to Method A14. 4-Chloro-3- was coupled with N-phenylethylenediamine according to
(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted Method Die.
with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline accord- Entry 80: 4-(3-Carboxyphenoxy)aniline was synthesized
ing to Method Cla to afford the urea. N-( 4-Chloro-3- 5 according to Method Al 1. 4-Chloro-3-(trifluoromethyl)phe-
(trifluoromethy l)pheny 1)-N'-(4-(3-( 5-methoxycarbony lpy- nyl isocyanate was reacted with 4-(3-carboxyphenoxy)
ridyl )oxy )phenyl )urea was saponified according to Method aniline according to Method Clf to afford the urea, which
D4, Step 1, and the corresponding acid was coupled with was coupled with 2-methoxyethylamine according to
4-(2-aminoethyl)morpholine to afford the amide. Method Die.
Entry 72: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline 10 Entry 81: 4-(3-Carboxyphenoxy)aniline was synthesized
was synthesized according to Method A14. 4-Chloro-3- according to Method Al 1. 4-Chloro-3-(trifluoromethyl)phe-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(3- nyl isocyanate was reacted with 4-(3-carboxyphenoxy)
(5-methoxycarbonyl)pyridyloxy)aniline according to aniline according to Method Clf to afford the urea, which
Method Cla to afford the urea. N-(5-(Trifluoromethyl)-2- was coupled with 5-amino-2-methoxypyridine according to
methoxyphenyl)-N'-( 4-(3-( 5-methoxycarbonylpyridyl)oxy) 15 Method Die.
phenyl)urea was saponified according to Method D4, Step 1, Entry 82: 4-(3-Carboxyphenoxy)aniline was synthesized
and the corresponding acid was coupled with methylamine according to Method Al 1. 4-Chloro-3-(trifluoromethyl)phe-
according to Method D4, Step 2 to afford the amide. nyl isocyanate was reacted with 4-(3-carboxyphenoxy)
was synthesized according to Method A14. 4-Chloro-3- 20 was coupled with 4-morpholinoaniline according to Method
(trifluoromethyl)phenyl isocyanate was reacted with 4-(3- Die.
(5-methoxycarbonyl)pyridyloxy)aniline according to Entry 83: 4-(3-Carboxyphenoxy)aniline was synthesized
Method Cla to afford the urea. N-(5-(Trifluoromethyl)-2- according to Method Al 1. 4-Chloro-3-(trifluoromethyl)phe-
methoxypheny 1)-N'-( 4-(3-( 5-methoxycarbonylpyridy l)oxy) nyl isocyanate was reacted with 4-(3-carboxyphenoxy)
phenyl)urea was saponified according to Method D4, Step 1, 25
aniline according to Method Clf to afford the urea, which
and the corresponding acid was coupled with N,N-dimeth- was coupled with N-(2-pyridyl)piperazine according to
ylethylenediamine according to Method D4, Step 2 to afford Method Die.
the amide.
was reacted with 2-hydroxyethylamine according to Method
was reacted with 2-hydroxyethylamine according to Method 30
A2, Step 3b to form 4-chloro-N-(2-triisopropylsilyloxy)
A2, Step 3b to form 4-chloro-N-(2-triisopropylsilyloxy)
ethylpyridine-2-carboxamide. 4-Chloro-N-(2-triisopropylsi-
ethylpyridine-2-carboxamide. 4-Chloro-N-(2-triisopropylsi-
lyloxy )ethylpyridine-2-carboxamide was reacted with triiso-
lyloxy)ethylpyridine-2-carboxamide was reacted with triiso-
propylsilyl chloride, followed by 4-aminophenol according
propylsilyl chloride, followed by 4-aminophenol according
to Method Al 7 to form 4-(4-(2-(N-(2-triisopropylsilyloxy) to Method Al 7 to form 4-(4-(2-(N-(2-triisopropylsilyloxy)
35
ethylcarbamoyl)pyridyloxyaniline. According to Method
ethylcarbamoyl)pyridyloxyaniline. According to Method
Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was
Cla 4-chloro-3-(trifluoromethyl)phenyl isocyanate was
reacted with 4-( 4-(2-(N-(2-triisopropylsilyloxy )ethylcar-
reacted with 4-( 4-(2-(N-(-2-triisopropylsilyloxy)ethylcar-
bamoyl)pyridyloxyaniline to give N-(4-chloro-3-((trifluo-
bamoyl)pyridyloxyaniline to afford N-(4-chloro-3-((trifluo-
romethy l)pheny I)-N'-( 4-( 4-(2-(N-(2-triisopropylsily loxy) 40
romethyl)phenyl)-N'-( 4-( 4-(2-(N-(2-triisopropylsilyloxy)
ethylcarbamoyl)pyridyloxyphenyl)urea. The urea was
ethy lcarbamoyl )pyridy loxypheny !)urea.
Entry 75: 4-(3-Carboxyphenoxy)aniline was synthesized deprotected according to Method D5 to afford N-( 4-chloro-
3-( (trifluoromethyl)phenyl)-N'-( 4-(4-(2-(N-(2-hydroxy)eth-
according to Method Al 1. 4-Chloro-3-(trifluoromethyl)phe-
y lcarbamoy l)pyridy loxypheny I)urea.
nyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)
pyridyloxy)aniline according to Method Clf to afford the 45 Entry 85: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)
urea, which was coupled with 3-aminopyridine according to aniline was synthesized according to MethodA2. 4-Bromo-
Method Die. 3-(trifluoromethyl)aniline was converted to 4-bromo-3-(tri-
Entry 76: 4-(3-Carboxyphenoxy)aniline was synthesized fluoromethyl)phenyl isocyanate according to Method Bl.
according to Method Al 1. 4-Chloro-3-(trifluoromethyl)phe- According to Method Cla, 4-bromo-3-(trifluoromethyl)phe-
nyl isocyanate was reacted with 4-(3-carboxyphenoxy) 50 nyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-
aniline according to Method Clf to afford the urea, which 4-pyridyloxy)aniline to afford the urea.
was coupled with N-( 4-acetylphenyl)piperazine according Entry 86: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-
to Method Die. chloroaniline was synthesized according to Method A6.
Entry 77: 4-(3-Carboxyphenoxy)aniline was synthesized 4-Bromo-3-(trifluoromethyl)aniline was converted into
according to Method Al 1. 4-Chloro-3-(trifluoromethyl)phe- 55 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to
nyl isocyanate was reacted with 4-(3-carboxyphenoxy) Method Bl. According to Method Cla, 4-bromo-3-(trifluo-
aniline according to Method Clf to afford the urea, which romethyl)phenyl isocyanate was reacted with 4-(2-(N-me-
was coupled with 4-fluoroaniline according to Method Die. thylcarbamoyl)-4-pyridyloxy)-2-chloroaniline to afford the
Entry 78: 4-(3-Carboxyphenoxy)aniline was synthesized urea.
according to Method Al 1. 4-Chloro-3-(trifluoromethyl)phe- 60 Entry 87: According to Method A2, Step 4,4-amino-2-
nyl isocyanate was reacted with 4-(3-carboxyphenoxy) chlorophenol was reacted with 4-chloro-N-methyl-2-pyridi-
aniline according to Method Clf to afford the urea, which necarboxamide, which had been synthesized according to
was coupled with 4-(dimethylamino)aniline according to Method A2, Step 3b, to give 4-(2-(N-methylcarbamoyl)-4-
Method Die. pyridyloxy)-3-chloroaniline. 4-Bromo-3-(trifluoromethyl)
Entry 79: 4-(3-Carboxyphenoxy)aniline was synthesized 65 aniline was converted into 4-bromo-3-(trifluoromethyl)phe-
according to Method Al 1. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to
nyl isocyanate was reacted with 4-(3-carboxyphenoxy) Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate
IITRUE COPY!I
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55 56
was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)- Method Bl. According to Method Cla, 4-bromo-3-(trifluo-
3-chloroaniline to afford the urea. romethyl)phenyl isocyanate was reacted with 4-(2-(N-(2-
Entry 88: 4-Chloropyridine-2-carbonyl chloride was Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline to
reacted with ethylamine according to Method A2, Step 3b. afford the urea.
The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was 5 Entry 95: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)
reacted with 4-aminophenol according to Method A2, Step aniline was synthesized according to Method A2. 4-Chloro-
4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline. 2-methoxy-5-(trifluoromethyl)aniline was synthesized
4-Bromo-3-(trifluoromethyl)aniline was converted into according to Method A7. 4-Chloro-2-methoxy-5-(trifluo-
4-bromo-3-(trifluoromethyl)phenyl isocyanate according to romethyl)aniline was converted into 4-chloro-2-methoxy-5-
Method Bl. According to Method Cla, 4-bromo-3-(trifluo- 10 (trifluoromethyl)phenyl isocyanate according to Method Bl.
romethyl)phenyl isocyanate was reacted with 4-(2-(N-eth- According to Method Cla, 4-chloro-2-methoxy-5-(trifluo-
ylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. romethyl)phenyl isocyanate was reacted with 4-(2-(N-me-
Entry 89: 4-Chloro-N-methyl-2-pyridinecarboxamide, thylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
which was synthesized according to Method A2, Step 3a, Entry 96: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-
was reacted with 3-aminophenol according to Method A2, 15 chloroaniline was synthesized according to Method A6.
Step 4 to form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy) 4-Chloro-2-methoxy-5-( trifluoromethy !)aniline was synthe-
aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted sized according to Method A7. 4-Chloro-2-methoxy-5-(tri-
into 4-bromo-3-(trifluoromethyl)phenyl isocyanate accord- fluoromethyl)aniline was converted into 4-chloro-2-meth-
ing to Method Bl. According to Method Cla, 4-bromo-3- oxy-5-(trifluoromethyl)phenyl isocyanate according to
(trifluoromethyl)phenyl isocyanate was reacted with 3-(-2- 20 Method Bl. According to Method Cla, 4-chloro-2-meth-
(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the oxy-5-(trifluoromethyl)phenyl isocyanate was reacted with
urea. 4-(2-(N-methylcarbamoy I)-4-pyridyloxy )-2-chloroaniline
Entry 90: According to Method A2, Step 4,5-amino-2- afford the urea.
methylphenol was reacted with 4-chloro-N-methyl-2-pyridi- Entry 97: According to Method A2, Step 4,4-amino-2-
necarboxamide, which had been synthesized according to 25 chlorophenol was reacted with 4-chloro-N-methyl-2-pyridi-
Method A2. Step 3b, to give 3-(2-(N-methylcarbamoyl)-4- necarboxamide, which had been synthesized according to
pyridyloxy)-4-methylaniline. 4-Bromo-3-(trifluoromethyl) Method A2, Step 3b, to give 4-(2-(N-methylcarbamoyl)-4-
aniline was converted into 4-bromo-3-(trifluoromethyl)phe- pyridyloxy)-3-chloroaniline. 4-Chloro-2-methoxy-5-(trif-
nyl isocyanate according to Method Bl. According to luoromethyl)aniline was synthesized according to Method
Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate 30 A 7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was
was reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)- converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phe-
4-methylaniline to afford the urea. nyl isocyanate according to Method Bl. According to
Entry 91: 4-Chloropyridine-2-carbonyl chloride was Method C 1a, 4-chloro-2-methoxy-5-( trifluoromethy !)phe-
reacted with dimethylamine according to Method A2, Step nyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-
3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecar- 35 4-pyridyloxy)-3-chloroaniline to afford the urea.
boxamide was reacted with 4-aminophenol according to Entry 98: 4-Chloro- N-methy 1-2-pyridinecarboxamide,
Method A2, Step 4 to give 4-(2-(N,N-dimethylcarbamoyl)- which was synthesized according to Method A2, Step 3a,
4-pyridy loxy )aniline. 4-Bromo-3-( trifluoromethy !)aniline was reacted with 3-aminophenol according to Method A2,
was converted into 4-bromo-3-(trifluoromethyl)phenyl iso- Step 4 to form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)
cyanate according to Method Bl. According to Method Cla, 40 aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was
4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted synthesized according to Method A7. 4-Chloro-2-methoxy-
with 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline 5-(trifluoromethyl)aniline was converted into 4-chloro-2-
to afford the urea. methoxy-5-(trifluoromethyl)phenyl isocyanate according to
Entry 92: 4-Chloro-N-methylpyridinecarboxamide was Method Bl. According to Method Cla, 4-chloro-2-meth-
synthesized as described in Method A2, Step 3b. The chlo- 45 oxy-5-(trifluoromethyl)phenyl isocyanate as was reacted
ropyridine was reacted with 4-aminothiophenol according to with 3-(-2-(N-methy lcarbamoy 1)-4-pyridyloxy )aniline to
Method A2, Step 4 to give 4-(4-(2-(N-methylcarbamoyl) afford the urea.
phenylthio )aniline. 4-Bromo-3-(trifluoromethyl)aniline was Entry 99: 4-Chloropyridine-2-carbonyl chloride was
converted into 4-bromo-3-(trifluoromethyl)phenyl isocyan- reacted with ethylamine according to Method A2, Step 3b.
ate according to Method Bl. According to Method Cla, 50 The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was
4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted reacted with 4-aminophenol according to Method A2, Step
with 4-( 4-(2-(N-methylcarbamoyl)phenylthio )aniline to 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline.
afford the urea. 4-Chloro-2-methoxy-5-( trifluoromethy !)aniline was synthe-
Entry 93: 4-Chloro-N-methylpyridinecarboxamide was sized according to Method A7. 4-Chloro-2-methoxy-5-(tri-
synthesized as described in Method A2, Step 3b. The chlo- 55 fluoromethyl)aniline was converted into 4-chloro-2-meth-
ropyridine was reacted with 3-aminothiophenol according to oxy-5-(trifluoromethyl)phenyl isocyanate according to
Method A2, Step 4 to give 3-(4-(2-(N-methylcarbamoyl) Method Bl. According to Method Cla, 4-chloro-2-meth-
phenylthio )aniline. 4-Bromo-3-(trifluoromethyl)aniline was oxy-5-(trifluoromethyl)phenyl isocyanate was reacted with
converted into 4-bromo-3-(trifluoromethyl)phenyl isocyan- 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the
ate according to Method Bl. According to Method Cla, 60 urea.
4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted Entry 100: 4-Chloropyridine-2-carbonyl chloride was
with 3-( 4-(2-(N-methylcarbamoyl)phenylthio )aniline to reacted with dimethylamine according to Method A2, Step
afford the urea. 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecar-
Entry 94: 4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl)py- boxamide was reacted with 4-aminophenol according to
ridyloxy)aniline was synthesized according to Method AlO. 65 Method A2, Step 4 to give 4-(2-(N,N-dimethylcarbamoyl)-
4-Bromo-3-(trifluoromethyl)aniline was converted into 4-pyridy loxy )aniline. 4-Chloro-2-methoxy-5-( trifluorom-
4-bromo-3-(trifluoromethyl)phenyl isocyanate according to ethyl )aniline was synthesized according to Method A7.
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4-Chloro-2-methoxy-5-( trifluoromethy !)aniline was con- Entry 103: 4-Chloro-N-methyl-2-pyridinecarboxamide
verted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl was synthesized according to Method A2, Step 3b.
isocyanate according to Method B 1. According to Method 4-Chloro-N-methyl-2-pyridinecarboxamide was reacted
C 1a, 4-chloro-2-methoxy-5-( trifluoromethy l)pheny I isocy-
anate was reacted with 4-(2-(N,N-dimethylcarbamoyl)-4- 5
with 4-aminophenol according to Method A2, Step 4 using
pyridyloxy)aniline to afford the urea. DMAC in place ofDMF to give 4-(2-(N-methylcarbamoyl)-
Entry 101: 4-Chloro-N-methyl-2-pyridinecarboxamide, 4-pyridyloxy)aniline. According to Method C2b, reaction of
which was synthesized according to Method A2, Step 3a, 3-amino-2-methoxyquinoline with CDI followed by 4-(2-
was reacted with 3-aminophenol according to Method A2, (N-methylcarbamoyl)-4-pyridyloxy)aniline afforded bis( 4-
Step 4 to form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy) 10
(2-(N-methylcarbamoyl)-4-pyridlyoxy)phenyl)urea.
aniline. 2-Amino-3-methoxynaphthalene was synthesized as
Listed in the Tables below are compounds which have
described Method Al. According to Method C3,2-amino-3-
been synthesized according to the Detailed Experimental
methoxynaphthalene was reacted with bis(trichloromethyl)
Procedures given above:
carbonate followed by 3-(-2-(N-methylcarbamoyl)-4-py- 15
ridyloxy)aniline to form the urea.
TABLES
Entry 102: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)
aniline was synthesized according to Method A2. 5-tert-
Butyl-2-(2,5-dimethylpyrrolyl)aniline was synthesized The compounds listed in Tables 1-6 below were synthe-
according to Method A4. 5-tert-Butyl-2-(2,5-dimethylpyr- 20 sized according to the general methods shown above, and
rolyl)aniline was reacted with CDI followed by 4-(2-(N- the more detailed exemplar procedures are in the entry
methylcarbamoyl)-4-pyridyloxy)aniline according to listings above and characterizations are indicated in the
Method C2d to afford the urea. tables.
TABLE 1
R....._N)lN
H H
TLC Mass
Entry R (" C.) (min.) Rf System [Source] Method
0.22 50% 418 A13 C3

EtOAc/ (M+ H) +
50% hexane (HPLC
ES-MS)
0 \,,
2
-0--0 0 \ ;)
0.58 50% 403 A13 C3

EtOAc/ (M+ H) +
50% hexane (HPLC
ES-MS)
-O-o--0---(
133-135 0.68 100% 448 AS C2d
EtOAc (M+ H) +
(FAB)
0
-0-o ◊ o:,
NH
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TABLE 2
5-tert-Butyl- 2-meth oxyphenyl Ureas
OMe
TLC Mass
4 5.93 448 A13

(M + H) + Bl
(HPLC Cla
ES-MS)
0 _)-N\,,
--0- --0
120-122 0.67 100% 478 AS
EtOAc (M + H) + C2d
(FAB)
-d=
O NH
--0-o
f \ kie
OMe
0.40 50% 460 A3

EtOAc/ (M + H) + C2d
50% (HPLC
hexane ES-MS)
--0- 0~0 \ j
NH
0.79 50% 446 A12

50% (HPLC
hexane ES-MS)
--0--Q{
0 ~
~ j
NH
0
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TABLE 3
5-(Trifluoromethyl)-2-methoxyphenyl Ureas
F
F
R,
N
)l N
H H
OMe
TLC Mass
Entry R (" c.) (min.) Rf System [Source] Method
0 \,, 250
(dee)
460 A13
(M + H) + C2a
(FAB)
-0--0 0 \_ j
9 o 206-208 0.54 10% 446 A3 step
--0- ~ N
O \_ j
Me
MeOH/
90%
CH2Cl2
(M + H) + 2,
(HPLC
ES-MS)
AS step
4,
Bl,
Cla
10 o 0.33 50% 445 A13 C3
-0-~ 0 \_ j
Me
EtOAc/
50%
pet ether
(M+ H) +
(HPLC
ES-MS)
11 0.20 2% 461 A2
--Q-00\,, Et3N/
98%
EtOAc
(M+H)+
(HPLC
ES-MS)
C4
0 \_ 1/
12 0.27 1% 447 A2
Et3N/ (M+H)+ C4
99% (HPLC
--Q-OO NH2 EtOAc Es-MS)
0 \_ ,/
13
0 \,, 0.62 100%

EtOAc
461
(M+ H) +
(FAB)
A2 C2a
14
-0--0 0 \_
Ii
N
114-117 0.40 1% 447 A2

0
Et3N/ (M+H)+ C4
99% (FAB)
EtOAc
-o-0-0NH,
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63 64
TABLE 3-continued
OMe
TLC Mass
15 232-235 0.54 100% 490 AS C2d

EtOAc (M+ H) +
o \,, (FAB)
16
-0--d= O \_ ,f OMe
210-213 0.29 5% 475 AS

MeOH/ (M+ H) + Bl Cle
45% (HPLC
--0-
Me -CO\,, EtOAc/ ES-MS)
50%
pet ether
0 \_ N
j
17 187-188 0.17 50% 495 A6

EtOAc/ (M+ H) + Bl Cla
-CO\,, 50% (HPLC
--0-
Cl pet ether ES-MS)
0 \_ N
j
18 0 0.48 100% 475 A2 step
--Q- EtOAc (M + H) + 4,
-O
NH2 (HPLC Bl Cla
ES-MS)
19 194-196 0.31 5% 475 A2

MeOH/ (M+ H) + Bl Cla
o \, 45% (HPLC
EtOAc/ ES-MS)
-0--c
50%
pet ether
0 \_ N
#
20 214-216 0.25 5% 495 A2 Cla
MeOH/ (M+ H) +
Cl -CO NH
45% (HPLC
-0-
EtOAc/ ES-MS)
-- k1e 50%
pet ether
0 \_ N
j
-o-o-o-TI~
21 208-210 0.30 50% 481 A19 C2a
0 EtOAc/ (M+ H) +
50% (HPLC
\_ j \ hexane ES-MS)
Me
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65 66
TABLE 3-continued
F
F
R......_NAN
H H
OMe
TLC Mass
22 0 188-190 0.30 70% 447 A15,

EtOAc/ (M+ H) + step 4,
50% (HPLC Cla
hexane ES-MS)
-o-0-0NH,
23 0.50 70% 472 A3

0 EtOAc/ (M+ H) + Bl Cla
-0- -Q;!
0 30% (FAB)
hexane
24 203-205 0.13 100% 479 A2 Bl

EtOAc (M+ H) + Cla
0 (
(HPLC
ES-MS)
-0--0 0 \
j N
-0-o-Q{
25 0.09 75% 458 A12
EtOAc/ (M+ H) + C2d
25% (HPLC
hexane ES-MS)
26 MeO 169-171 0.67 50% 474 A13

\ EtOAc/ (M+ H) + step!,
-0-o-0--( 50%
pet ether
(HPLC
ES-MS)
A13 step
4,A16,
Bl
Cla
27 0 218-219 0.40 50% 477 A2 step

EtOAc/ (M+ H) + 3b,
50% (HPLC A2 step
N:e pet ether ES-MS) 4, Bl,
-0--0
Cla
S \ N
j
28 212-214 0.30 40% A9
-0-o-Q;!: EtOAc/
60%
hexane
Bl Cla
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67 68
TABLE 3-continued
F
F
R,N)lN
H H
OMe
TLC Mass
29 0.33 50% 474 A2 step
--Q-Co
\,, EtOAc/
50%
pet ether
(M + H) + 3b,
(HPLC
ES-MS)
A2 step
4, Bl,
Cla
s \ it
30 210-211 A2
Bl
-C
O NH
Cla
\r-i
--0-
-
0
31 210-204 0.43 10% A14

MeOH/ Bl
--o-0-d-(;
CH2Cl2 Cla
D4
32 0 247-249 0.57 10% A14

MeOH/ Bl
CH2Cl2 Cla
N:e D4
--0--0 0 \ /J
N
33 217-219 0.07 10% A14
-O
O NH MeOH/ Bl
CH2Cl2 Cla
D4
--0- 0
N
~-Me
Ml
34 0.11 70% All

EtOAc/ Bl
--o-0-db
30% Clf
hexane Dlc
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TABLE 3-continued
5-(Trifluoromethyl)-2-methoxYJ2henyl Ureas
F
F
R,N)lN
H H
OMe
TLC Mass
35 0.38 70% All
QN)
F
EtOAc/ Bl
30% Clf
hexane Dlc
\_N
-o-0-00
36 0.77 70% All
EtOAc/ Bl
F-0-NH O 30% Clf
hexane Dlc
37
-o-0-0 0.58 70% All
EtOAc/ Bl
Me\-0-NH
30% Clf
-0-0-00
hexane Dlc
38 0.58 70% All

EtOAc/ Bl
M,0-0-NH O 30% Clf
hexane Dlc
39
-o-0-0 0.17 70% All
EtOAc/ Bl
r"N-0-NH 30% Clf
-0-0-00
hexane Dlc
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TABLE 3-continued
F
F
R...__N)lN
H H
OMe
TLC Mass
40 0.21 70% All
0-CN-0-NH 0
EtOAc/
30%
hexane
Bl
Clf
Dlc
-o-0-0
TABLE 4
3-(Trifluoromethyl)-4-chloro12henyl Ureas
R...__N)lN
H
0
H
◊ Cl
TLC Mass
41 163-165 0.08 50% 464 A13

EtOAc/ (M+ H) + C3
0 \,, 50% (HPLC
pet ether ES-MS)
42
-0--0 0 \ ;}
215 0.06 50% 465 A2

EtOAc/ (M+ H) + Cla
0 \,, 50% (HPLC
pet ether ES-MS)
43
-0--0 0 \
;}N
0 0.10 50% 451 A2

EtOAc/ (M+ H) + Cla
50% (HPLC
pet ether ES-MS)
-o-0-0NH,
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TABLE 4-continued
3-(Trifluoromethyl)-4-chlorophenyl Ureas
TLC Mass
44 0.25 30% 451 A2

EtOAc/ (M + H) + Cla
70% (HPLC
pet ether ES-MS)
45 0.31 30% 465 A2

70% (HPLC
pet ether ES-MS)
46 176-179 0.23 40% 476 A3

60% (FAB)
hexane
47 0.29 5% 478 AS
MeOH/ (M + H) + Cle
45% (HPLC
EtOAc/ ES-MS)
50%
pet ether
48 206-209 A15
Cla
49 147-151 0.22 50% 499 A6

50% (HPLC
pet ether ES-MS)
50 0.54 100% 479 A2

EtOAc (M + H) + Cla
(HPLC
ES-MS)
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TABLE 4-continued
R,N,l
H 1i
E Cl
TLC Mass
51 187-189 0.33 5% 479 A2

MeOH/ (M+ H) + Cla
-c
45% (HPLC
o""" EtOAc/ ES-MS)
-0-
50%
pet ether
0 \_ N
ll
52 219 0.18 5% 499 A2
MeOH/ (M+ H) + Cla
-CO\,, 45% (HPLC
---0-
Cl EtOAc/ ES-MS)
50%
pet ether
0 \_ N
ll
53 246-248 0.30 50% 485 A19,
-0-
EtOAc/ (M+ H) + Cla
0 -o-~~o
\_ ;j \
50%
hexane
(HPLC
ES-MS)
Me
54 196-200 0.30 70% 502 A15
-0-
EtOAc/ (M+ H )+ Cla
0 -o-~~o
\_ ;j \
30%
hexane)
(HPLC
ES-MS)
NH
Ml
55 228-230 0.30 30% 466

EtOAc/ (M+ H) +
70% (HPLC
O \M, CH2Cl2 ES-MS)
-0--C 0 \_
ll
N
56 o 238-245
-0-~ 0 \_ ;j
Ml
NH
57 221-222 0.75 80% 492 Cld

o o EtOAc/ (M+ H) + Dla
20% (FAB)
hexane
-0-
H \e
N
~
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TABLE 4-continued
3-(Trifluoromethyl)-4- chl orophenyl Ureas
TLC Mass
58 247 0.35 100% Cld

EtOAc Dla
D2
59 198-200 0.09 100% 479 A2

EtOAc (M + H) + Cla
(HPLC
ES-MS)
60 MeO 158-160 0.64 50%

EtOAc/
50%
61
-0- 0~\
\_ ;j
Me
195-197
pet ether
0.39 10% A13
~
MeOH/ Cla
CH2Cl2
-0- 0-00
\_ ;j N
\_) 0
62 170-172 0.52 10% A13

MeOH/ Cla
CH2Cl2
-o-0-d~
- \_;j 0
63 168-171 0.39 10% A13
MeOH/ Cla
-0- 0-00
\_ ;j
'----0 CH2Cl2
64 176-177 0.35 10% A13

MeOH/ Cla
-o-o-d'--0
CH2Cl2
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79 80
TABLE 4-continued
R......_N~N
H
0
H
J Cl
TLC Mass
65
0 \,, 130-133 487
(HPLC
ES-MS)
A2
(M + H) + Bl
Cla
66
-0--0 S \
0
j N
155 A2
Cla
-O
NH
\r-i
67
-
-0- 0
225-229 0.23 100% Cle
_tJ-
O NH EtOAc D3
Dlb
\
-0-
H Me
N
68 234-236 0.29 40% A9
-0-o~:
EtOAc/ Cla
60%
hexane
69 0.48 50% 481
--Q-00\,,
S \ #N
EtOAc/
50%
pet ether
(M+ H) +
(HPLC
ES-MS)
70 0.46 5% 564 Al0

MeOH/ (M + H) + Cla
95% (HPLC
CH2Cl2 ES-MS)
-o-0-d(; 0
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81 82
TABLE 4-continued
TLC Mass
71 199-201 0.50 10% A14

MeOH/ Cla
CH2Cl2 D4
72 235-237 0.55 10% A14

MeOH/ Cla
CH2Cl2 D4
5-1,
-0-
0
--C) N
73 200-201 0.21 50% A14
-O
O NH MeOH/ Cla
CH2Cl2 D4
-0-
f ' 0 ~ N-Me
N Ml
74 145-148
75 0.12 70% 527 All

EtOAc/ (M + H) + Clf
30% (HPLC Dlc
Jo
0-NH
hexane ES-MS)
od
-0- -0
IITRUE COPY!I
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83 84
TABLE 4-continued
TLC Mass
76 0.18 70% All

EtOAc/ Clf
30% Dlc
hexane
77 0.74 70% All

EtOAc/ Dlf
30% Dlc
hexane
78 0.58 70% All

EtOAc/ Clf
30% Dlc
hexane
79 0.47 70% 569 All

30% (HPLC Dlc
hexane ES-MS)
80 0.18 70% 508 All

30% (HPLC Dlc
hexane ES-MS)
IITRUE COPY!I
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85 86
TABLE 4-continued
TLC Mass
81 0.58 70% 557 All

Meo--{)- NH 0 30% (HPLC Dlc
hexane ES-MS)
-o-0-0
82 0.37 70% 611 All
r"N-0-NH 30% (HPLC Dlc
-0-0-00
hexane ES-MS)
QN)
83 0.19 70% All
EtOAc/ Clf
30% Dlc
hexane
\_N
-o-0-00
84 179-183 A2
A17
Cla
D5
-o-0-d~H
IITRUE COPY!I
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87 88
TABLE 5
3-(Trifluoromethyl)-4-b romophenyl Ureas
TLC Mass
85 186-187 0.13 50% 509 A2

EtOAc/ (M+ H )+ Bl
50% (HPLC Cla
pet ether ES-MS)
86 150-152 0.31 50% 545 A6

EtOAc/ (M + H) + Bl
50% (HPLC Cla
pet ether ES-MS)
87 217-219 0.16 50% 545 A2

EtOAc/ (M + H) + Bl
50% (HPLC Cla
pet ether ES-MS)
88 183-184 0.31 50% 525 A2

EtOAc/ (M + H) + Bl
50% (HPLC Cla
pet ether ES-MS)
89 0.21 50% 511 A2

EtOAc/ (M + H) + Bl
50% (HPLC Cla
pet ether ES-MS)
90 0.28 50% 525 A2

EtOAc/ (M + H) + Bl
50% (HPLC Cla
pet ether ES-MS)
91 214-216 0.28 50% 522 A2

EtOAc/ (M + H) + Bl
50% (HPLC Cla
pet ether ES-MS)
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89 90
TABLE 5-continued
3-(Trifluoromethyl)-4-bromophenyl Ureas
TLC Mass
mp HPLC TLC Solvent Spec. Syn th.
Entry R (0 C.) (min.) Rf System [Source] Method
5-NH
92 0.47 50% 527 A2 step
EtOAc/ (M + H) + 3b,
50% (HPLC A2 step
--0-s---c) \,,
pet ether ES-MS) 4, Bl,
Cla
93 0.46 50% 527 A2 step

50% (HPLC A2 step
pet ether ES-MS) 4, Bl,
Cla
145-150 0.41 5% AlO

MeOH/ Bl
95% Cla
CH2Cl2
TABLE 6
5-(Trifluoromethyl)-4-chloro-2-methoxyphenyl Ureas
Cl
0
R....._N~N
H H
OMe
TLC Mass
Entry R ( 0 C.) (min.) Rf System [Source] Method
95 140-144 0.29 5% 495 A2

MeOH/ (M + H) + A7
45% (HPLC Bl
EtOAc/ ES-MS) Cla
50%
pet ether
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TABLE 6-continued
5-(Trifluoromethyl) -4 -chl oro-2-methoxyphenyl Ureas
F
F F
Cl
0
R,
N
)l N
H H
OMe
TLC Mass
96 244-245 0.39 5% 529 A6

MeOH/ (M + H) + A7
45% (HPLC Bl
-0-
Cl -CO \fo EtOAc/ ES-MS) Cla
50%
pet ether
0 ~ N
~ j
97 220-221 0.25 5% 529 A2

MeOH/ (M + H) + A7
Cl -OO NH 45% (HPLC Bl
---0-
EtOAc/ ES-MS) Cla
- ~e 50%
pet ether
0 ~ N
~ j
98 0.27 5% 495 A2
MeOH/ (M + H) + A7
45% (HPLC Bl
EtOAc/ ES-MS) Cla
50%
pet ether
99 180-181 0.52 5% 509 A2

MeOH/ (M +H) + A7
0 \, 45% (HPLC Bl
EtOAc/ ES-MS) Cla
-0--0
50%
pet ether
0 ~ N
~ j
100 162-165 A2
-C
O NH A7
Bl
Cla
\r-i
-0- -
0
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93 94
TABLE 7
Additional Ureas
TLC Mass
Entry R (° C.) (min.) Rf System [Source] Method
101
0 162-165 Al
A2
C3
10,010V~t
~ )l # Me
N N
H H
OMe
102 0.10 50% 442 A2

EtOAc/ (M + H) + A4
0 50% (HPLC C2d
°'Cr~
hexane ES-MS)
O
I )l
,01
~ ✓,::;N t
Me
N N
H H
103 0 125-130 0.24 40% 512 A2

EtOAc/ (M + H) + C2b
60% (FAB)
HN)lNH hexane
PQ
of NH-Me
~o
Me-NH
Biological Examples resolved by electrophoresis on 7 .5% Laemmli gels. Gels

were fixed, dried and exposed to an imaging plate (Fuji).
In Vitro raf Kinase Assay Phosphorylation was analyzed using a Fujix Bio-Imaging
50 Analyzer System.
In an in vitro kinase assay, raf was incubated with MEK All compounds exemplified displayed IC50 s of between 1
in 20 mM Tris-HCl, pH 8.2 containing 2 mM 2-mercapto- nM and 10 µM.
ethanol and 100 mM NaCl. This protein solution (20 µL)
was mixed with water (5 µL) or with compounds diluted Cellular Assay:
with distilled water from 10 mM stock solutions of com- 55 For in vitro growth assay, human tumor cell lines, includ-
pounds dissolved in DMSO. The kinase reaction was initi- ing but not limited to HCT116 and DLD-1, containing
ated by adding 25 µL [A-33 P]ATP (1000-3000 dpm/pmol) in mutated K-ras genes were used in standard proliferation
80 mM Tris-HCl, pH 7.5, 120 mM NaCl, 1.6 mM DTT, 16 assays for anchorage dependent growth on plastic or anchor-
mM MgC12 . The reaction mixtures were incubated at 32° C., age independent growth in soft agar. Human tumor cell lines
usually for 22 min. Incorporation of 33 P into protein was 60 were obtained from ATCC (Rockville Md.) and maintained
assayed by harvesting the reaction onto phosphocellulose in RPMI with 10% heat inactivated fetal bovine serum and
mats, washing away free counts with a 1% phosphoric acid 200 mM glutamine. Cell culture media and additives were
solution and quantitating phosphorylation by liquid scintil- obtained from Gibco/BRL (Gaithersburg, Md.) except for
lation counting. For high throughput screening, 10 µM ATP fetal bovine serum (JRH Biosciences, Lenexa, Kans.). In a
and 0.4 µM MEK was used. In some experiments, the kinase 65 standard proliferation assay for anchorage dependent
reaction was stopped by adding an equal amount ofLaemmli growth, 3xl0 3 cells were seeded into 96-well tissue culture
sample buffer. Samples were boiled 3 min and the proteins plates and allowed to attach overnight at 37° C. in a 5% CO 2
IITRUE COPY!I
US 7,351,834 Bl
95 96
incubator. Compounds were titrated in media in dilution A) independently
series and added to 96-well cell cultures. Cells were allowed a) hydrogen,
to grow 5 days typically with a feeding of fresh compound b) cl -ClO alkyl,
containing media on day three. Proliferation was monitored c) C 6 aryl,
by measuring metabolic activity with standard XTT colori- 5 d) pyridinyl
metric assay (Boehringer Mannheim) measured by standard e) substituted C 1 _10 alkyl,
ELISA plate reader at OD 490/560, or by measuring 3 H-thy- f) substituted C 6 aryl,
midine incorporation into DNA following an 8 h culture g) substituted pyridinyl
with 1 µCu 3 H-thymidine, harvesting the cells onto glass h) -phenylpiperazine(pyridinyl),
fiber mats using a cell harvester and measuring 3 H-thymi- 10 i) -phenylmorpholinyl,
dine incorporation by liquid scintillant counting. j) -ethylmorpholinyl,
For anchorage independent cell growth, cells were plated k) -ethylpiperidyl,
at lxl0 3 to 3xl0 3 in 0.4% Seaplaque agarose in RPMI 1) -methyl pyrrolidinyl,
complete media, overlaying a bottom layer containing only m) -methyl tetrahydrofuryl,
0.64% agar in RPMI complete media in 24-well tissue 15 or
culture plates. Complete media plus dilution series of com- n) -C 2 H4 NH(phenyl);
pounds were added to wells and incubated at 37° C. in a 5% where when Ra and Rb are a substituted group, they are
CO 2 incubator for 10-14 days with repeated feedings of substituted by
fresh media containing compound at 3-4 day intervals. a) halogen up to per halo,
Colony formation was monitored and total cell mass, aver- 20 b) hydroxy,
age colony size and number of colonies were quantitated c) -N(CH 3 ) 2 ,
using image capture technology and image analysis software d) cl -ClO alkyl,
(Image Pro Plus, media Cybernetics). e) C 1 -C 10 alkoxy,
In Vivo Assay: f) halosubstituted C 1 _6 alkyl, or
An in vivo assay of the inhibitory effect of the compounds 25 g) -OSi(Pr-i) 3 ; or
on tumors (e.g., solid cancers) mediated by rafkinase can be B) Ra and Rb together form piperazine or a substituted
performed as follows: piperazine with substituents selected from the group
CDI nu/nu mice (6-8 weeks old) are injected subcutane- consisting of
ously into the flank at lxl0 6 cells with human colon adeno- a) halogen,
carcinoma cell line. The mice are dosed i.p., i.v. orp.o. at 10, 30 b) hydroxy,
30, 100, or 300 mg/Kg beginning on approximately day 10, c) cl-10 alkyl,
when tumor size is between 50-100 mg. Animals are dosed d) pyridinyl
for 14 consecutive days once a day; tumor size was moni- e) cl-10 alkoxy,
tored with calipers twice a week. f) C 6 aryl,
The inhibitory effect of the compounds on raf kinase and 35 g) halo substituted C 6 aryl, and
therefore on tumors (e.g., solid cancers) mediated by raf h) N-(4-acetylphenyl);
kinase can further be demonstrated in vivo according to the M is selected from the group consisting of oxygen and
technique of Mania et al. (Nat. Med. 1996, 2, 668-75). sulfur;
The preceding examples can be repeated with similar and
success by substituting the generically or specifically 40
Bis
described reactants and/or operating conditions of this
invention for those used in the preceding examples. phenyl, substituted with 1-3 substituents independently
selected from the group consisting of halogen and
From the foregoing description, one skilled in the art can R7,
easily ascertain the essential characteristics of this invention
and, without departing from the spirit and scope thereof, can 45
and R7 is
make various changes and modifications of the invention to (a) C 1 -C 6 linear or branched alkyl, optionally substituted
adapt it to various usages and conditions. with 1-3 halogen substituents; or
(b) C 1 -C 6 linear or branched alkoxy.
What is claimed is:
2. A compound as in claim 1 wherein M is oxygen.
50 3. A compound as in claim 1 wherein the cyclic structures
A-D-B (I) of B and L bound directly to D are substituted in the ortho
or a pharmaceutically acceptable salt thereof, wherein position by hydrogen.
D is -NH-C(O)-NH-, 4. A compound of claim 1 wherein B of Formula I is
A is a substituted moiety of the formula: phenyl, substituted with 1-3 substituents independently
1
55 selected from the group consisting of chlorine, C 1 -C 6 alkoxy
-L-M-L ,
or up to per halo substituted C 1 -C6 alkyl.
wherein Lis phenyl, optionally substituted by halogen, 5. A compound of claim 2 wherein B of Formula I is
up to per-halo, and Wn, where n is 0-3; phenyl, substituted with 1-3 substituents independently
wherein each W is independently selected from the selected from the group consisting of chlorine, C 1 -C 6
group consisting of C 1 -Cs linear or branched alkyl, 60 alkoxy, or substituted C 1 -C 6 alkyl, substituted by one or
C 1 -Cs linear or branched haloalkyl up to perha- more halogen substituents.
loalkyl and C 1 -C3 alkoxy L 1 is selected from pyridi- 6. A compound of claim 3 wherein B of Formula I is
nyl substituted by -C(O)Rx, and phenyl, substituted 1 to 3 times by 1 or more substituents
optionally substituted with 1-3 additional substituents selected from the group consisting of chlorine, C 1 -C 6 alkoxy
independently selected from the group consisting of 65 or up to per halo substituted C 1 -C6 alkyl.
R7 and halogen; 7. A compound of claim 1, wherein Lis phenyl, optionally
wherein R, is NRaRb and Ra and Rb are substituted by halogen up to perhalo.
IITRUE COPY!I
US 7,351,834 Bl
97 98
8. A compound of claim 1, wherein Lis phenyl, optionally M is selected from the group consisting of oxygen and
substituted with 1-3 substituents independently selected sulfur
from the group consisting of halogen and C 1 -C3 alkoxy. and
9. A compound of claim 3, wherein Mis ---0-. Bis phenyl, substituted with 1-3 substituents indepen-
10. A compound of claim 6 wherein M is ---0-. dently selected from the group consisting of R7 and
11. A compound of claim 7 wherein Mis ---0-. halogen;
and R7 is
12. A compound of claim 8 wherein M is ---0-. (a) C 1 -C 6 linear or branched alkyl, optionally substi-
13. A compound of claim 1 wherein L 1 is additionally tuted with 1-3 halogen substituents; or
substituted 1 to 3 times by one or more substituents selected 10 (b) C 1 -C6 linear or branched alkoxy.
from the group consisting of C 1 -C 6 alkyl, halogen and C 1 -C 6 25. A compound of Formula I:
alkoxy.
A-D-B (I)
14. A compound of claim 2 wherein L 1 is additionally
substituted 1 to 3 times by one or more substituents selected or a pharmaceutically acceptable salt thereof, wherein
from the group consisting of C 1 -C 6 alkyl, halogen and C 1 -C 6 15 D is -NH-C(O)-NH-,
alkoxy. A is of the formula: -L-M-L1,
15. A compound of claim 9 wherein L 1 is additionally Lis phenyl,
substituted 1 to 3 times by one or more substituents selected Mis ---0-,
from the group consisting of C 1 -C 6 alkyl, halogen and C 1 -C 6 L 1 is pyridinyl substituted by -C(O)Rx,
alkoxy. 20 wherein Rx is NRaRb and Ra and Rb are independently
16. A compound of claim 10 wherein L 1 is additionally hydrogen,
substituted 1 to 3 times by one or more substituents selected cl -ClO alkyl,
from the group consisting of C 1 -C 6 alkyl, halogen and C 1 -C 6 C 6 aryl,

alkoxy. pyridinyl,
25 substituted C 1 _ 10 alkyl,
17. A compound of claim 11 wherein L1 is additionally
substituted 1 to 3 times by one or more substituents selected substituted C 6 aryl, or
from the group consisting of C 1 -C 6 alkyl, halogen and C 1 -C 6 substituted pyridinyl
alkoxy. where Ra and Rb are a substituted group, they are substi-
18. A compound of claim 12 wherein L 1 is additionally tuted by halogen up to per halo,
30
substituted 1 to 3 times by one or more substituents selected and
from the group consisting of C 1 -C 6 alkyl, halogen and C 1 -C 6 B is a phenyl group substituted by trifluoromethyl or
alkoxy. tert-butyl, and optionally additional substituents
19. A compound of claim 2 wherein Ra and Rb are selected from the group consisting of halogen up to
independently hydrogen or C 1 -C 6 alkyl. per halo, and Wn where n is 0-3, and each W is
35
20. A compound of claim 9 wherein Ra and Rb are independently selected from the group consisting of
cl -ClO alkyl,
independently hydrogen or C 1 -C 6 alkyl.
cl -ClO alkoxy,
21. A compound of claim 10 wherein Ra and Rb are
independently hydrogen or C 1 -C 6 alkyl. C 6 aryl,
22. A compound of claim 11 wherein Ra and Rb are 40
pyridinyl,
independently hydrogen or C 1 -C 6 alkyl. and substituted C 1 -C 10 alkyl, substituted by one or
more substituents independently selected from the
23. A compound of claim 12 wherein Ra and Rb are group consisting of halogen up to per halo.
independently hydrogen or C 1 -C 6 alkyl.
26. A compound as in claim 24 wherein the cyclic
24. A compound of Formula I: structures of B and L bound directly to D are substituted in
45
A-D-B (I) the ortho position by hydrogen.
or a pharmaceutically acceptable salt thereof, wherein structures of B and L bound directly to D are substituted in
D is -NH-C(O)-NH-, the ortho position by hydrogen.
1 28. A compound as in claim 24 wherein substituents for
A is of the formula: -L-M-L , wherein 50
Lis phenyl, optionally substituted with 1-3 substituents B, are selected from the group consisting of up to per halo
independently selected from the group consisting of substituted C 1 -C 6 alkyl and halogen.
C -Cs linear or branched alkyl, C 1 -Cs linear or 29. A compound as in claim 25 wherein the optional
b)anched haloalkyl up to perhalo, C 1 -C3 alkoxy and substituents for B are selected from the group consisting of
halogen; 55 up to per halo substituted C 1 -C6 alkyl and halogen.
30. A pharmaceutically acceptable salt of a compound of
L 1 is pyridinyl, substituted by ----C(O)Rx;
formula I of claim 1 which is
wherein Rx is NRaRb and Ra and Rb are independently a) a basic salt of an organic acid or inorganic acid which
hydrogen, is hydrochloric acid, hydrobromic acid, sulfuric acid,
cl -ClO alkyl, 60 phosphoric acid, methanesulfonic acid, trifluo-
C6 aryl, romethanesulfonic acid, benzenesulfonic acid, p-tolu-
pyridinyl, substituted C 1 _10 alkyl, ene sulfonic acid (tosylate salt), 1-napthalene sulfonic
acid, 2-napthalene sulfonic acid, acetic acid, trifluoro-
substituted C 6 aryl, or acetic acid, malic acid, tartaric acid, citric acid, lactic
substituted pyridinyl, 65 acid, oxalic acid, succinic acid, fumaric acid, maleic
where Ra and Rb are a substituted group, they are substi- acid, benzoic acid, salicylic acid, phenylacetic acid, or
tuted by halogen up to per halo; and mandelic acid; or
IITRUE COPY!I
US 7,351,834 Bl
99 100
b) an acid salt of an organic or inorganic base containing L 1 is pyridinyl, substituted with-C(O)NRaRb;
an alkali metal cation, an alkaline earth metal cation, an wherein Ra and Rb independently are
ammonium cation, an aliphatic substituted ammonium a) hydrogen
cation or an aromatic substituted ammonium cation. b) methyl;
31. A pharmaceutically acceptable salt of a compound of 5 c) ethyl; or
claim 24 which is d) propyl
a) a basic salt of an organic acid or inorganic acid which Bis phenyl, substituted by tert-butyl or trifluoromethyl
is hydrochloric acid, hydrobromic acid, sulfuric acid, and optionally substituted with additional substitu-
phosphoric acid, methanesulfonic acid, trifluo- ents independently selected from the group consist-
romethanesulfonic acid, benzenesulfonic acid, p-tolu- 10 ing of
ene sulfonic acid (tosylate salt), 1-napthalene sulfonic a) halogen, or
acid, 2-napthalene sulfonic acid, acetic acid, trifluoro- b) methoxy.
acetic acid, malic acid, tartaric acid, citric acid, lactic 36. A compound of claim 35 where L has no optional
acid, oxalic acid, succinic acid, fumaric acid, maleic substituents.
acid, benzoic acid, salicylic acid, phenylacetic acid, or 15 37. A compound of claim 35 where Ra is hydrogen and Rb
mandelic acid; or is methyl.
b) an acid salt of an organic or inorganic base containing 38. A compound of claim 35 where B is substituted by
an alkali metal cation, an alkaline earth metal cation, an trifluoromethyl and chlorine or bromine.
ammonium cation, an aliphatic substituted ammonium 39. A compound which is N-( 4-chloro-3-(trifluoromethyl)
cation or an aromatic substituted ammonium cation. 20 phenyl)-N'-( 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phe-
32. A pharmaceutically acceptable salt of a compound of nyl)urea of the formula X
claim 25 which is
a) a basic salt of an organic acid or inorganic acid which
is hydrochloric acid, hydrobromic acid, sulfuric acid, (X)
phosphoric acid, methanesulfonic acid, trifluo- 25
romethanesulfonic acid, benzenesulfonic acid, p-tolu-
ene sulfonic acid (tosylate salt), 1-napthalene sulfonic
acetic acid, malic acid, tartaric acid, citric acid, lactic
acid, oxalic acid, succinic acid, fumaric acid, maleic 30
acid, benzoic acid, salicylic acid, phenylacetic acid, or
mandelic acid; or
b) an acid salt of an organic or inorganic base containing or a pharmaceutically acceptable salt thereof.
an alkali metal cation, an alkaline earth metal cation, an 40. A compound of claim 39 which is a pharmaceutically
ammonium cation, an aliphatic substituted ammonium 35 acceptable salt of N-( 4-chloro-3-(trifluoromethyl)phenyl)-
cation or an aromatic substituted ammonium cation. N'-( 4-(2-(N-methy lcarbamoy 1)-4-pyridyloxy )phenyl )urea
33. A compound of claim 1 wherein the optional substitu- that is a basic salt of an organic acid or an inorganic acid
ents on L 1 are selected from the group consisting of methyl, which is hydrochloric acid, hydrobromic acid, sulfuric acid,
trifluoromethyl, methoxy, Cl and F. phosphoric acid, methanesulfonic acid, trifluoromethane-
34. A compound of claim 1 wherein the substituents of B 40 sulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid
and L are independently selected from the group consisting (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sul-
of methyl, trifluoromethyl, tert-butyl, methoxy, Cl, and F. fonic acid, acetic acid, trifluoroacetic acid, malic acid,
35. A compound of Formula I: tartaric acid, citric acid, lactic acid, oxalic acid, succinic
A-D-B (I) acid, fumaric acid, maleic acid, benzoic acid, salicylic acid,
45 phenylacetic acid, or mandelic acid.
41. A compound of claim 39 which is a tosylate salt of
D is -NH-C(O)-NH-,
1 N-( 4-chloro-3-(trifluoromethyl)phenyl)-N'-( 4-(2-(N-meth-
A is a substituted moiety of the formula: -L-M-L ,
y lcarbamoy 1)-4-pyridyloxy )phenyl )urea.
wherein L is phenyl, optionally substituted with chlorine
or methyl substituents; * * * * *
IITRUE COPY!I
CS (Comm.) No. 660 of 2022
In the matter of:

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IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
In re Patent No.: 7,351,834 Inventors: Bernd Riedl;

Jacques Dumas;
Uday Khire;
Issued: April l, 2008 Timothy Lowinger;
William Scott;
Roger A. Smith;
Assignee: Bayer HealthCare LLC Jill E. Wood;
Mary-Katherine Monahan;
Reina Natero;
Title: OMEGA-CARBOXY ARYL Joel Renick; and
SUBSTITUTED DIPHENYL UREAS AS Robert Sibley
RAF KINASE INHIBITORS
APPLICATION FOR EXTENSION OF PATENT TERM UNDER 35 U.S.C. § 156
Commissioner for Patents

P.O. Box 1450
Alexandria, VA 22313-1450
Dear Sir:
Applicant, Bayer HealthCare LLC, represents that it is the owner of the entire right
and interest in and to United States Patent No. 7,351,834 issued to Bernd Riedl; Jacques Dumas;
Uday Khire; Timothy Lowinger; William Scott; Roger A. Smith; Jill E. Wood; Mary-Katherine
Monahan; Reina Natero; Joel Renick; and Robert Sibley on April 1, 2008, for "Omega-
carboxyaryl Substituted Diphenyl Ureas as Raf Kinase Inhibitors." An assignment by the
inventors was executed in the name of Bayer Corporation and recorded January 8, 2002 in the
U.S. Patent and Trademark Office at Reel 012476/Frame 0140; an assignment by Bayer
Corporation to Bayer Pharmaceuticals Corporation was· recorded June 9, 2003 at Reel
014125/Frame 0545; and an assignment from Bayer Pharmaceuticals Corporation to Bayer
HealthCare LLC was recorded November 26, 2008 at Reel 021893/Frame 0485.
11/27/2812NBLAMCO
UOOD
133372 7351834
l>Of.108024
01 FC:1457 1120.00DA
IITRUE COPYjl
Patent No. 7,351,834 2
Application for Extension of Patent Term wider 35 U.S.C. § 156 dated November 23, 2012
Applicant hereby submits this application for extension of patent tenn under 35
U.S.C. § 156, which includes the following information in accordance with 35 U.S.C. § 156(d)
and 37 C.F.R. § 1.740, following the format set forth in 37 C.F.R. § l.740(a):
(1) A complete identification of the approved product as by appropriate chemical and

generic name, physical structure or characteristics; [37 C.F.R. § 1.740(a)(l)]
The approved product is STIVARGA® (generic name: regorafenib) tablets, 40 mg,

for oral administration. It is indicated for the treatment of patients with metastatic colorectal
cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and
irinotecan-based chemotherapy, an anti-VGEF therapy, and, if KRAS wild type, an anti-EGFR
therapy.
Regorafenib has the chemical name 4-[4-( {[4-chloro-3-(trifluoromethyl) phenyl]

carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide monohydrate and the
following structural formula:
Regorafenib has a molecular formula C21H 15ClF 4N4O3 • H20 and a molecular weight
of 500.83. Regorafenib is practically insoluble in water, slightly soluble in acetonitrile,
methanol, ethanol, and ethyl acetate and sparingly soluble in acetone.
(2) A complete identification of the Federal statute including the applicable provision of
law under which the regulatory review occurred; [37 C.F.R. § 1.740(a)(2)]
Bayer HealthCare Pharmaceuticals Inc. submitted New Drug Application (NDA)

203,085 for STIVARGA® on April 27, 2012, under section 505(b) of the Federal Food, Drug,
and Cosmetic Act (FDCA) (21 U.S.C. § 355(b)). Regulatory review occurred under section 505
of the FDCA.
IITRUE COPYII
PatentNo. 7,351,834 3
Application for Extension of Patent Term under 35 U.S.C. § 156 dated November 23, 2012
(3) An identification of the date on which the product received permission for
commercial marketing or use under the provision of law under which the applicable
regulatory review period occurred; [37 C.F.R. § 1.740(a)(3)]
Bayer HealthCare Phannaceuticals Inc. received approval of NDA 203,085 under

section 505 of the FDCA for commercial marketing of STIVARGA® on September 27, 2012.
(4) In the case of a drug product, an identification of each active ingredient in the
product and as to each active ingredient, a statement that it bas not been previously
approved for commercial marketing or use under the Federal Food, Drug, and
Cosmetic Act, the Public Health Service Act, or the Virus-Serum-Toxin Act, or a
statement of when the active ingredient was approved for commercial marketing or
use (either alone or in combination with other active ingredients), the use for which
it was approved, and the provision of law under which it was approved; [37 C.F.R.
§ 1.740(a)(4)]
The only active ingredient in STIVARGA® is regorafenib. Regorafenib has not been
previously approved for commercial marketing or use under the Federal Food, Drug, and
Cosmetic Act, the Public Health Service Act, or the Virus-Serum-Toxin Act, prior to the
approval of NDA 203,085.
(5) A statement that the application is being submitted within the sixty day period
permitted for submission pursuant to§ 1.720(f) and an identification of the date of
the last day on which the application could be submitted; [37 C.F.R. § 1.740(a)(5)]
This application is being submitted within the sixty day period beginning on the date
STIVARGA ® first received approval for commercial marketing or use, which period is believed
to expire on November 25, 2012. Because the last day of this period falls on a Sunday, the
application would still be considered timely if submitted the next succeeding business day, i.e.,
November 26, 2012.
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Patent No. 7,351,834 4
Application for Extension of Patent Tenn under 35 U.S.C. § 156 dated November 23, 2012
(6) A complete identification of the patent for which an extension is being sought by the
name of the inventor, the patent number, the date of issue, and the date of
expiration; (37 C.F.R. § 1.740(a)(6)]
Inventors: Bernd Riedl; Jacques Dumas; Uday Khire; Timothy Lowinger; William
Scott; Roger A. Smith; Jill E. Wood; Mary-Katherine Monahan; Reina Natero; Joel
Renick; and Robert Sibley
U.S Patent No.: 7,351,834
Issue Date: April 1, 2008
Expiration Date: January 12, 2020
(7) A copy of the patent for which an extension is being sought, including the entire
specification (including claims) and drawings; [37 C.F.R. § 1.740(a)(7)]
A copy of U.S. Patent No. 7,351,834 is attached as Exhibit A.
(8) A copy of any disclaimer, certificate of correction, receipt of maintenance fee

payment, or reexamination certificate issued in the patent; [37 C.F.R. § 1.740(a)(8)]
Terminal disclaimers submitted July 23, 2007 and August 28, 2007 are attached as
Exhibit B. A Maintenance Fee Statement showing timely payment of the maintenance fee due at
the 4th year is attached as Exhibit C. No certificate of correction or reexamination certificate has
been issued for U.S. Patent No. 7,351,834.
(9) A statement that the patent claims the approved product, or a method of using or
manufacturing the approved product, and a showing which lists each applicable
patent claim and demonstrates the manner in which at least one such patent claim
reads on:
(i) The approved product, if the listed claims include any claim to the approved
product;
(ii) The method of using the approved product, if the listed claims include any claim
to the method of using the approved product; and
IITRUE COPY!I
Patent No. 7,351,834 5
(iii) The method of manufacturing the approved product, if the listed claims include
any claim to the method of manufacturing the approved product; [37 C.F.R. §
1.740(a)(9)]
U.S. Patent No. 7,351,834 claims the approved product STIVARGA® and the active
ingredient thereof. Specifically, the active ingredient regorafenib is covered by claims 1-12, 19-
29, and 34, which are reproduced below:
A-D-B
Dis -NH-C(O)-NH-,
A is a substituted moiety of the formula:

I
-L-M-L,
wherein L is phenyl, optionally substituted by halogen, up to per-halo, and Wn, where n

is 0-3;
wherein each W is independently selected from the group consisting of C 1-C5 linear or
branched alkyl, C 1-C 5 linear or branched haloalkyl up to perhaloalkyl and C1-C3
alkoxy L I is selected from pyridinyl substituted by -C(O)Rx, and
optionally substituted with 1-3 additional substituents independently selected from the
group consisting of R 7 and halogen;
wherein Rx is NRal¼,and Raand I¼,are
A) independently
a) hydrogen,
b) C1-C10 alkyl,
c) C6 aryl,
d) pyridinyl
e) substituted C 1_10 alkyl,
f) substituted C6 aryl,
g) substituted pyridinyl
h) -phenylpiperazine(pyridinyl),
i) -phenylmorpholinyl,
j) -ethylmorpholinyl,
IITRUE COPYII
Patent No. 7,351,834 6
k) -ethylpiperidyl,
1)-methyl pyrrolidinyl,
m) -methyl tetrahydrofuryl,
or
n) --C 2~NH(phenyl);
where when Raand Roare a substituted group, they are substituted by

a) halogen up to per halo,
b) hydroxy,
c)-N(CH3)2,
d) C1-C10 alkyl,
e) C1-C10 alkoxy,
f) halosubstituted C 1-6 alkyl, or
g) --OSi(Pr-i)J; or
B) Raand Rotogether form piperazine or a substituted piperazine with substituents

selected from the group consisting of
a) halogen,
b) hydroxy,
c) C1-10 alkyl,
d) pyridinyl
e) C1-10 alkoxy,
f) C6 aryl,
g) halo substituted C6 aryl, and
h) N-(4-acetylphenyl);
M is selected from the group consisting of oxygen and sulfur; and
B is phenyl, substituted with 1-3 substituents independently selected from the group consisting
of halogen and R7,
and R7 is
(a) C 1-C6 linear or branched alkyl, optionally substituted with 1-3 halogen substituents;
or
(b) C 1-C6 linear or branched alkoxy.
2. A compound as in claim l wherein M is oxygen.
4. A compound of claim l wherein B of Formula I is phenyl, substituted with 1-3 substituents

independently selected from the group consisting of chlorine, C 1-C6 alkoxy or up to per halo
substituted C1-C6alkyl.
5. A compound of claim 2 wherein B of Formula I is phenyl, substituted with 1-3 substituents

independently selected from the group consisting of chlorine, C1-C 6 alkoxy, or substituted C 1-C 6
alkyl, substituted by one or more halogen substituents.
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Patent No. 7,351,834 7
Applicationfor Extensionof Patent Term under 35 U.S.C. § 156datedNovember 23, 2012
7. A compound of claim 1, wherein L is phenyl, optionally substituted by halogen up to perhalo.
8. A compound of claim I, wherein L is phenyl, optionally substituted with 1-3 substituents

independently selected from the group consisting of halogen and C 1-C3 alkoxy.
11. A compound of claim 7 wherein M is -0-.
19. A compound of claim 2 wherein R, and Reare independently hydrogen or C 1-C6 alkyl.
22. A compound of claim I I wherein R, and 14are independently hydrogen or C 1-C6 alkyl.
23. A compound of claim 12 wherein R, and 14are independently hydrogen or C 1-C6 alkyl.
A-D-B
D is -NH-C(O}-NH-,
1
A is of the formula:-L-M-L , wherein
L is phenyl, optionally substituted with 1-3 substituents independently selected from the group
consisting of C 1-C5 linear or branched alkyl, C 1-C5 linear or branched haloalkyl up to
perhalo, C1-C3 alkoxy and halogen;
L 1 is pyridinyl, substituted by-C(O)Rx;
wherein Rx is NR,14and R, and 14 are independently

hydrogen,
C1-C10alkyl,
C6 aryl,
pyridinyl, substituted C1-10 alkyl,
substituted C6 aryl, or
substituted pyridinyl,
where R, and 14 are a substituted group, they are substituted by halogen up to per
halo; and
M is selected from the group consisting of oxygen and sulfur
and
IITRUE COPYII
Patent No. 7,351,834 8
Applicationfor Extensionof Patent Tenn under 35 U.S.C. § 156dated November 23, 2012
B is phenyl, substituted with 1-3 substituents independently selected from the group consisting
ofR 7 and halogen;
and R7 is
(a) C 1-C6 linear or branched alkyl, optionally substituted with 1-3 halogen substituents;
or
28. A compound as in claim 24 wherein substituents for B, are selected from the group
consisting ofup to per halo substituted C1-C6alkyl and halogen.
34. A compound of claim 1 wherein the substituents ofB and Lare independently selected from
the group consisting of methyl, trifluoromethyl, tert-butyl, methoxy, Cl, and F.
Demonstration of the manner in which at least one claim reads on the approved product
The approved product STIVARGA® contains the active ingredient regorafenib,

which has the following structural formula:
F F
0
3
Cl O qO'CrN_,CH
N
Jl N ~ I I
/4
N H
H H ·HP
F
Claim I reads on the approved product because regorafenib is a compound of the

formula A-D--B, where
D is -NH--C(O}--NH-;
1
A is a substituted moiety of the formula: -L-M-L , where
L is phenyl substituted by one halogen (specifically, fluorine) and Wn, in which n is

0,
L I is pyridinyl substituted by -C(O)R.x, where
Rx is NRaRt,, in which Raand Rt, are
independently hydrogen and C1-C1o alkyl (specifically, methyl);
IITRUE COPYjl
Patent No. 7,351,834 9
M is oxygen; and
B is phenyl, substituted with one halogen (specifically, chlorine) and one R7, where
R7 is C 1-C6 linear alkyl (specifically, methyl) substituted with 3 halogen substituents

(specifically, fluorine).
IITRUE COPYjl
Patent No. 7,351,834 10
(10) A statement beginning on a new page of the relevant dates and information
pursuant to 35 U.S.C. 156(g) in order to enable the Secretary of Health and Human
Services or the Secretary of Agriculture, as appropriate, to determine the applicable
regulatory review period as follows:
(i) For a patent claiming a human drug, antibiotic, or human biological product:
(A) The effective date of the investigational new drug (IND) application and the
IND number;
(B) The date on which a new drug application (NDA) or a Product License
Application (PLA) was initially submitted and the NDA or PLA number; and
(C) The date on which the NDA was approved or the Product License issued;
[37 C.F.R. § 1.740(a)(10)]
The relevant dates and information pursuant to 35 U.S.C. § I 56(g) to enable the
Secretary of Health and Human Services to determine the applicable regulatory review period
are as follows:
(A) ·Investigational New Drug (IND) Application 75,642 was filed with the
Food and Drug Administration (FDA) on July 19, 2006. IND 75,642
became effective August 18, 2006.
(B) NOA 203,085 for STIVARGA® was submitted to the FDA on April 27,
2012.
(C) NOA 203,085 for STIVARGA® was approved by the FDA on September
2t2012.
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Patent No. 7,351,834 ll
(11) A brief description beginning on a new page of the significant activities

undertaken by the marketing applicant during the applicable regulatory review
period with respect to the approved product and the significant dates applicable to
such activities; [37 C.F.R. § 1.740(a)(ll)]
A brief description of the significant activities undertaken by Bayer HealthCare

Pharmaceuticals Inc. during the regulatory review period of STIVARGA® and the dates
applicable to such activities are attached as Exhibit D.
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Patent No. 7,351,834 12
(12) A statement beginning on a new page that in the opinion of the applicant the
patent is eligible for the extension and a statement as to the length of extension
claimed, including bow the length of extension was determined; [37 C.F.R. §
1.740(a)(l2))
In the opinion of the Applicant, U.S. Patent No. 7,351,834 is eligible for an extension
of patent term under 35 U.S.C. § 156 because each of the following requirements is satisfied:
35 U .S.C. § I 56(a)
U.S. Patent No. 7,351,834 claims STIVARGA®, a drug product as defined by 35
u.s.c.§ 156(f).
35 u.s.c.§ 156(a)(l)
The term of said patent has not expired prior to the submission of this application.
35 U.S.C. § 156(a)(2)
The term of said patent has not previously been extended under 35 U.S.C. §
156(e)(l).
35 U.S.C. § 156(a)(3)
This application is submitted by the owner of record of said patent within the 60-day
period beginning on the date NDA 203,085 for STIVARGA ® was approved and in accordance
with the requirements of paragraphs (1) through (4) of35 U.S.C. § 156(d).
35 U.S.C. § 156(a)(4)
STIVARGA ® has been subject to a regulatory review period as defined by 35 U.S.C.

§ 156(g) before its commercial marketing or use.
35 U.S.C. § l 56(a)(5)(A)
The approval of NDA 203,085 was the first permitted commercial marketing or use
ofSTIVARGA®(regorafenib) under section 505 ofthe FDCA.
IITRUE COPYjl
PatentNo. 7,351,834 13
Application for Extension of Patent Term under 35 U.S.C. § 156dated November 23, 2012
35 U.S.C. § l 56(c)(4}
The term of no other patent has been extended for the approval of NOA 203,085.
Further, in the opinion of the Applicant, U.S. Patent No. 7,351,834 is eligible for an
extension of 898 days. The length of extension was determined in accordance with 35 U.S.C. §
l56(c) and 37 C.F.R. § 1.775 as follows:
Length of the Regulatory Review Period

Under 37 C.F.R. § l.775(c), the length of the Regulatory Review Period is the sum
of:
{A) the Testing Phase, which began on the date IND 75,642 became effective
(i.e., August 18, 2006) and ended on the date NDA 203,085 was submitted
to the FDA (i.e., April 27, 2012), which period is equal to 2080 days; and
(B) the Approval Phase, which began on the date NOA 203,085 was submitted
to the FDA (i.e., April 27, 2012) and ended on the date NOA 203,085 was
approved by the FDA (i.e., September 27, 2012), which period is equal to
154 days.
Therefore, the length of the Regulatory Review Period is 2080 + 154, or 2234 days.
Determination of the Length of Extension
Under 37 C.F.R. § l.775(d), the length of extension is determined by
(1) subtracting from the Regulatory Review Period:
(a) the number of days which were on or before the date U.S. Patent No.
7,351,834 issued (i.e., April 1, 2008), which is equal to 593 days;
(b) the number of days during which the Applicant did not exercise due
diligence, which is equal to 0 days; and
(c) one-half the number of days of the Testing Phase after subtracting the
number of-days from the preceding two subparagraphs, which is
½(2080 - 593 - 0) or 743.5 days,
IITRUE COPYII
PatentNo. 7,351,834 14
Application for Extensionof Patent Term under 35 U.S.C. § 156 dated November 23, 2012
for the purposes of the subtraction half days are ignored, resulting in a
calculation of2234- 593 -0- 743, or 898 days;
(2) adding the number of days calculated in the preceding subparagraph to the
original patent term as shortened by any terminal disclaimer (i.e., January
12, 2020), resulting in a date of June 28, 2022;
(3) adding 14 years to the date NDA 203,085 was approved by the FDA (i.e.,
September 27, 2012), resulting in a date of September 27, 2026;
(4) selecting the earlier date of the two preceding subparagraphs, which is June
28,2022;and
(5) selecting the earlier of the date of the preceding subparagraph and the date
that is 5 years added to the original expiration date of U.S. Patent No.
7,351,834 (i.e., January 12, 2025), resulting in a date of June 28, 2022.
Therefore, U.S. Patent No. 7,351,834 is eligible for an extension of 898 days, i.e., to June 28,
2022.
(13) A statement that applicant acknowledges a duty to disclose to the Director of the
United States Patent and Trademark Office and the Secretary of Health and
Human Services or the Secretary of Agriculture any information which is material
to the determination of entitlement to the extension sought (see§ 1.765 ); [37 C.F.R.
§ 1.740(a)(l3)]
Applicant acknowledges a duty to disclose to the Director of the United States Patent
and Trademark Office and the Secretary of Health and Human Services any information which is
material to the determination of entitlement to the extension of the term of U.S. Patent No.
7,351,834.
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PatentNo. 7,351,834 15
Applicationfor Extensionof Patent Tenn under 35 U.S.C. § 156dated November23, 2012
(14) The prescribed fee for receiving and acting upon the application for extension (see
§ 1.20(j) ); and [37 C.F.R. § 1.740(a)(l4)]
Please charge the prescribed fee of $1, 120 pursuant to 37 C.F .R. § 1.200) to Deposit
Account No. 13-3372. Should additional fees be necessary in connection with this application,
the Director is hereby authorized to charge Deposit Account No. 13-3372 for any such fee.
(15) The name, address, and telephone number of the person to whom inquiries and
correspondence relating to the application for patent term extension are to be
directed. [37 C.F.R. § 1.740(a)(l5)]
Please direct all inquiries and correspondence relating to this application to:
Barbara A. Shimei
Bayer HealthCare LLC
Patents and Licensing - Pharmaceuticals
555 White Plains Road
Tarrytown, New York 1091
(914) 333-6945
Pursuant to 37 C.F.R. § l.740(b), this application is accompanied by two additional

copies.
Dated: November 23, 2012 Respectfully submitted,
han R. Harris
Registration No.: 60,473

Patents & Licensing - Pharmaceuticals
555 White Plains Road - 3rd Floor
Tarrytown, New York 10591
(914) 333-6168
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PatentNo. 7,351,834
Exhibit A
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I1m1191111111
HIiiHillm111111111111
m1111111111111111111111111
US007351834Bl
c12) United States Patent (IO) Patent No.: US 7,351,834 Bl

Riedl et al. (45) Date of Patent: *Apr. 1, 2008
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DIPHENYL UREAS AS RAF KINASE 2,781,330 A 2/1957 Downey
INHffilTORS 2,797,214 A 6/1957 Werner Bossard
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(.)
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Notice: Subject to any disclaimer, the term of this
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(22)
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§ 371 (c)(I),
(2), (4) Date: Jan. 8, 2002
(87) PCT Pub. No.: WO00/42012 (Continued)
PCf Pub. Date: Jul. 20, 2000 FOREIGN PATENT DOCUMENTS
Related U.S. Application Data CA 2146707 10/1995
(60) Provisional application No. 60/ll 5,877, filed on Jan.

13, 1999.
(Continued)
(SI) Int. Cl.
com 211110 (2006.0I) OTHER PUBLICATIONS
A61K 31/44 (2006.01)
Caplus 113:106314, Abstract of JP 2022650, Silver Halide color
(52) U.S. Cl. ....................................... S46/290; 514/247
photographic material containing a cyan coupler of 2-ureido-phenol
(58) Field of Classification Search ................ 546/290, type lo improve dye developabilityand remove lecuo cyan dye,
546/300, 329, 346; 544/242, 298, 309, 329, Noboru Mizukuraet al. Jan. 25, 1990.
544/358; 564/48, 52, 53, 55, 63; 514/256,
5]4/345,35),357,482, 588,596,247,277 (Continued)
Primary Examiner-Rita Desai
(56) References Cited (74) Anorney, Agent, or Firm-Millen, White, Zelano &
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U.S. PATENT DOCUMENTS
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2,683,082 A 7/1954 Hill et al.
IITRUE COPYII
US 7,351,834 Bl
Page 2
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pp. 226-228. • cited by examiner
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w-CARBOXYARYL SUBSTITUTED including solid cancers, such as, for example, carcinomas
DIPHENYL UREAS AS RAF KINASE (e.g., of the lungs, pancreas, thyroid, bladder or colon),
INHIBITORS myeloid disorders (e.g., myeloid leukemia) or adenomas
(e.g., villous colon adenoma).
CROSS-REFERENCE TO RELATED The present invention therefore provides compounds gen-
APPLICATIONS erally described as aryl ureas, including both aryl and
heteroaryl analogues, which inhibit the raf kinase pathway.
This application is a 371 of PCT/US00/00648 filed Jan. 8, The invention also provides a method for treating a raf
2000, which claims the benefit of provisional application mediated disease state in humans or mammals. Thus. the
Ser. No. 60/115,877, filed Jan. 13, 1999. 10 invention is directed to compounds which inhibit. the
enzyme raf kinase and also compounds, compositions and
FIELD OF THE INVENTION methods for the treatment of cancerous cell growth mediated
This invention relates to the use of a group of aryl ureas istered or pharmaceutically acceptable salt thereof.
in treating raf mediated diseases, and pharmaceutical com- 15 A-D-B (I)
In formula I, D is -NH-C(O)--NH-,
1
formula: -L-{M-L )q, where Lis a 5 or 6 membered
1
The p21,as oncogene is a major contributor to the devel- 20 cyclic structure bound directly to D, L comprises a substi-
opment and progression of human solid cancers and is tuted cyclic moiety having at least 5 members, M is a
mutated in 30% of all human cancers (Bolton et aJ.Ann. Rep. bridging group having at least one atom, q is an integer of
Med. Chem. 1994, 29, 165-74; Bos. Cancer Res. 1989, 49, from 1-3; and each cyclic structure of L and L1contains 0-4
4682-9). In its normal, umnutated form, the ras protein is a members of the group consisting of nitrogen, oxygen and
key element of the signal transduction cascade directed by 25 sulfur, and
growth factor receptors in almost all tissues (Avruch et al. B is a substituted or unsubstituted, up to tricyclic aryl or
Trends Biochem. Sci. 1994, 19, 279-83). Biochemically, ras heteroaryl moiety ofup to 30 carbon atoms with at least one
is a guanine nucleotide binding protein, and cycling between 6-member cyclic structure bound directly to D containing
a GTP-bound activated and a GDP-bound resting form is 0-4 members of the group consisting of nitrogen, oxygen
strictly controlled by ras' endogenous GTPase activity and 30 and sulfur,
other regulatory proteins. In the ras mutants in cancer cells, wherein L 1 is substituted by at least one substituent
the endogenous GTPase activity is alleviated and, therefore, selected from the group consisting of -S0 2 R,.,-C(O)R.,
the protein delivers constitutive growth signals to down- and -C(NR_y)I½,
stream effectors such as the enzyme raf kinase. This leads to ~ is hydrogen or a carbon based moiety of up to 24
the cancerous growth of the cells which carry these mutants 35 carbon atoms optionally containing heteroatoms selected
(Magnuson et al. Semin. Cancer Biol. 1994, 5, 247-53). It from N, S and O and optionally halosubstituted, up to per
has been shown that inhibiting the effect of active ras by halo,
inhibiting the rafkinase signaling pathway by administration R., is hydrogen or a carbon based moiety of up to 30
of deactivating antibodies to raf kinase or by co-expression carbon atoms optionally containing heteroatoms selected
of dominant negative rafkinase or dominant negative MEK, 40 from N, S and O and optionally substituted by halogen,
the substrate of raf kinase, leads to the reversion of trans- hydroxy and carbon based substituents of up to 24 carbon
formed cells to the normal growth phenotype (see: Daum et atoms, which optionally contain heteroatoms selected from
al. Trends Biochem. Sci. 1994, 19, 474-80; Fridman et al. J. N, S and O and are optionally substituted by halogen;
Biol. Chem. 1994, 269, 30105-8. Kotch et al. (Nature 1991, R.is R.,,or NRaRb where Ra and Rb are
349, 426-28) have further indicated that inhibition of raf 45 a) independently hydrogen,
expression by antisense RNA blocks cell proliferation in a carbon based moiety of up to 30 carbon atoms optionally
membrane-associated oncogenes. Similarly, inhibition of raf containing heteroatoms selected from N, S and O and
kinase (by antisense oligodeoxynucleotides) has been cor- optionally substituted by halogen, hydroxy and carbon
related in vitro and in vivo with inhibition of the growth of based substituents of up to 24 carbon atoms, which
a variety of human tumor types (Mania et al., Nat. Med. so optionally contain heteroatoms selected from N, S and
1996, 2, 668-75). 0 and are optionally substituted by halogen, or
--0Si(Rf) 3 where Rf is hydrogen or a carbon based
SUMMARY OF THE INVENTION moiety of up to 24 carbon atoms optionally containing
heteroatoms selected from N, S and O and optionally
The present invention provides compounds which are 55 substituted by halogen, hydroxy and carbon based
inhibitors of the enzyme raf kinase. Since the enzyme is a substituents of up to 24 carbon atoms, which optionally
downstream effector of p21=, the inhibitors are useful in contain heteroatoms selected from N, S and O and are
pharmaceutical compositions for human or veterinary use optionally substituted by halogen; or
where inhibition of the raf kinase pathway is indicated, e.g., b) R0 and Rb together form a 5-7 member heterocyclic
in the treatment of tumors and/or cancerous cell growth 60 structure of 1-3 heteroatoms selected from N, S and 0, or a
mediated by raf kinase. In particular, the compounds are substituted 5-7 member heterocyclic structure of 1-3 het-
useful in the treatment of human or animal solid cancers, eroatoms selected from N, Sand O substituted by halogen,
e.g., murine cancer, since the progression of these cancers is hydroxy or carbon based substituents of up to 24 carbon
dependent upon the ras protein signal transduction cascade atoms, which optionally contain heteroatoms selected from
and therefore susceptible to treatment by interruption of the 65 N, S and O and are optionally substituted by halogen; or
cascade, i.e., by inhibiting raf kinase. Accordingly, the c) one of R.,or Rb is -C(O)-, a C 1 -Cs divalent alkylene
compounds of the invention are useful in treating cancers, group or a substituted C 1 -Cs divaJent alkylene group bound
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US 7,351,834 Bl
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to the moiety L to form a cyclic structure with at least 5 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl,
members, wherein the substituents of the substituted C 1-C5 or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, or additionally option-
divalent alkylene group are selected from the group con- ally substituted phenyl, 2- or 3-thienyl, 1,3,4-thiadiazolyl,
sisting of halogen, hydroxy, and carbon based substituents of 3-pynyl, 3-pyrazolyl, 2-thiarolyl or 5-thiazolyl, etc. For
up to 24 carbon atoms, which optionally contain heteroat- 5 example, B can be 4-methyl-phenyl, 5-methyl-2-thienyl,
oms selected from N, Sand O and are optionally substituted 4-methyl-2-thienyl, 1-methyl-3-pyrryl, l-methyl-3-pyra-
by halogen; zolyl, 5-methyl-2-thiazolyl or 5-methyl-1,2,4-thiadiazol-2-
where B is substituted, L is substituted or L 1 is addition- yl.
ally substituted, the substituents are selected from the group Suitable alkyl groups and alkyl portions of groups, e.g.,
consisting of halogen, up to per-halo, and Wn, where n is 10 alkoxy, etc. throughout include methyl, ethyl, propyl, butyl,
0-3; etc., including all straight-chain and branched isomers such
wherein each Wis independently selected from the group as isopropyl, isobutyl, sec-butyl, tert-butyl, etc.
consisting of --CN, -CO 2 R7, -C(O)NR 7 R7 , -C(O)-- Suitable aryl groups which do not contain heteroatoms
R7 , ---NO 2 , -OR 7 , --SR 7 , -NR 7 R7 , -NR 7 C(O)OR7 , include, for example, phenyl and I- and 2-naphthyl.
-NR 7 C(O)R 7 , -Q-Ar, and carbon based moieties ofup 15 The term "cycloalkyl", as used herein, refers to cyclic
to 24 carbon atoms, optionally containing heteroatoms structures with or without alkyl substituents such that, for
Selected from N, Sand O and optionally substituted by one example, "C4 cycloalkyl" includes methyl substituted cyclo-
or more substituents independently selected from the group propyl groups as well as cyclobutyl groups. The term
consisting of -CN, -CO 2 R7, -C(O)R 7 , -C(O)NR 7 R77 , "cycloalkyl", as used herein also includes saturated hetero-
-OR 7 , --SR 7 , -NR 7 R7 , -NO 2 , -NR 7 C(O)R 7 , -NR C 20 cyclic groups.
(O)OR 7 and halogen up to per-halo; with each R7 indepen- Suitable halogen groups include F, Cl, Br, and/or I, from
dently selected from H or a carbon based moiety of up to 24 one to per-substitution (i.e. all H atoms on a group replaced
carbon atoms, optionally containing heteroatoms selected by a halogen atom) being possible where an alkyl group is
from N, S and O and optionally substituted by halogen, substituted by halogen, mixed substitution of halogen atom
wherein Q is -0-, -S-, -N(R 7)--, -{CH 2)m-, 25 types also being possible on a given moiety.
-C(O)--, -CH(OH)--, -{CH 2 )mO, -{CHJ.,S-, The invention also relates to compounds per se, of for-
-{CHJmN(R 7)--, -O(CHJ,..-, -CHXa-, -CXa 2-, mula I.
-S-{CHJ,..-, and-N(R 7 XCHi),..-, where m=l-3, and The present invention is also directed to pharmaceutically
Xa is halogen; and acceptable salts of formula I. Suitable pharmaceutically
Ar is a 5- or 6-member aromatic structure containing 0-2 30 acceptable salts are well known to those skilled in the art and
members selected from the group consisting of nitrogen, include basic salts of inorganic and organic acids, such as
oxygen and sulfur, which is optionally substituted by halo- hydrochloric acid, hydrobromic acid, sulfuric acid, phos-
gen, up to per-halo, and optionally substituted by Z,.1 , phoric acid, methanesulfonic acid, trifluoromethanesulfonic
wherein nl is 0 to 3 and each Z is independently selected acid, benzenesulfonic acid, p-toluenesulfonic acid, 1-naph-
from the group consisting of --CN, -CO 2 R7 , -C(O)R 7 , 35 thalenesulfonic acid, 2-naphthalenesulfonic acid, acetic
-C(O)NR_R_, -NO 2 , -OR 7 , --SR 7-NR 7 R7 , -NR 7C acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid,
(O)OR 7 , -NR 7 C(O)R7 , and a carbon based moiety ofup to lactic acid, oxalic acid, succinic acid, fumaric acid, maleic
24 carbon atoms, optionally containing heteroatoms selected acid, benzoic acid, salicylic acid, phenylacetic acid, and
from N, Sand O and optionally substituted by one or more mandelic acid. In addition, pharmaceutically acceptable
substituents selected from the group consisting of --CN, 40 salts include acid salts of inorganic bases, such as salts
-CO 2 R7 ,-COR 7 , -C(O)NR 7 R7 , -OR 7 , -SR 7 , -NO 2 , containing alkaline cations (e.g., Li+ Na+ or K+), alkaline
-NR 7 R7 , -NR 7 C(O)R7, and -NR 7 C(O)OR 7 , with R 7 as earth cations (e.g., Mg+2 , ea+ 2
or Ba+2 ), the ammonium
defined above. cation, as well as acid salts of organic bases, including
limited to, 5-12 carbon-atom aromatic rings or ring systems 45 nary ammonium cations, such as those arising from proto-
containing 1-3 rings, at least one of which is aromatic, in nation or peralkylation of triethylamine, N,N-diethylamine,
which one or more, e.g., 1-4 carbon atoms in one or more of N,N-dicyclohexylamine, lysine, pyridine, N,N-dimethy-
the rings can be replaced by oxygen, nitrogen or sulfur laminopyridine {DMAP), 1,4-diazabiclo[2.2.2]octane
atoms. Each ring typically has 3-7 atoms. For example, B (DABCO), 1,5-diazabicyclo(4.3 .0]non-5-ene (DBN) and
can be 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 1-, 2- 50 l ,8-diazabicyclo[5.4.0]undec-7-ene {DBU).
or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 11-, 3-, 4- or A number of the compounds of Formula I possess asym-
5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, metric carbons and can therefor exist in racemic and opti-
2-, 4-, 5- or 6-pyrimidinyl, 1,2,3-triazol-l-, -4- or -5-yl, and diastereomeric mixtures are well known to one skilled
1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxa- 55 in the art. The present invention encompasses any isolated
diazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadia- racemic or optically active form of compounds described in
zol-2- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol- Formula I which possess raf inhll>itoryactivity.
2- or -5-yl, 1,3,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4-
or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H- General Preparative Methods
thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- 60
or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, The compounds of Formula I may be prepared by the use
4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, of known chemical reactions and procedures, some from
4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzox- starting materials which are commercially available. Nev-
azolyl, 3-, 4-, 5- 6- or 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- or ertheless, general preparative methods are provided below to
7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 2-, 4-, 65 aid one skilled in the art in synthesizing these compounds,
5-, 6- or 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or with more detailed examples being provided in the Experi-
8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, 1-, 2-, 3-, mental section which follows.
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methods (March. Advanced Organic Chemistry, 3nt Ed.;
John Wiley: New York (1985). Larock. Comprehensive ArB(OR')i
Organic Transformations; VCH Publishers: New York
Pd(O)
(1989)). As shown in Scheme l, aryl amines are commonly 5
such as Ni, Pd, or Pt, and H2 or a hydride transfer agent, such
as formate, cyclohexadiene, or a borohydride (Rylander.
Hydrogenation Methods; Academic Press: London, UK Either nitroaryls or anilines may be converted into the
(1985)). Nitroaryls may also be directly reduced using a 10 corresponding arenesulfonyl chloride (7) on treatment with
strong hydride source, such as LlAIH4 (Seyden-Penne. chlorosulfonic acid. Reaction of the sulfonyl chloride with a
Reductions by the Alumina- and Borohydrides in Organic fluoride source, such as KF then affords sulfonyl fluoride (8).
Synthesis; VCH Publishers: New York (1991)), or using a Reaction of sulfonyl fluoride 8 with trimethylsilyl trifluo-
zero valent metal, such as Fe, Sn or Ca, often in acidic romethane in the presence of a fluoride source, such as
media. Many methods exist for the synthesis of nitroaryls 1s tris(dimethylamino)sulfonium difluorotrimethylsiliconate
(March. Advanced Organic Chemistry, 3"' Ed.; John Wiley (fASF) leads to the corresponding trifluoromethylsulfone
New York (1985). Larock. Comprehensive Organic Trans- (9). Alternatively, sulfonyl chloride 7 may be reduced to the
formations; VCH Publishers: New York (1989)). arenethiol ( l 0), for example with zinc amalgum. Reaction of
thiol 10 with CHCIF2 in the presence of base gives the
20 difluoromethyl mercaptam (11), which may be oxidized to
H2/catalyst the sulfone (12) with any of a variety of oxidants, including
/ (eg. Ni, Pd, Pt)\ Ci0 3 -acetic anhydride (Sedova et al. Zh. Org. Khim. 1970,
ArNOJ [H·J ArNH2
6, (568).
\ M(0) / 25
(cg. Fe, Sn, Ca)
Scheme I Reduction of Nitroaryls to Ary! Amines

matic nitration using HNO3 , or an alternative NO2 - source.
Nitroaryls may be further elaborated prior to reduction.
30
O 6
I
R
-
CISO)H
6 6
SH
35 00,S R 8
HN0 3
Ar-H - ArN02
I Rm
potential leaving groups (e.g. F, Cl, Br, etc.) may undergo CHCIF2
40
substitution reactions on treatment with nucleophiles, such
as thiolate (exemplified in Scheme II) or phenoxide. Nitroar-
yls may also undergo Ullman-type coupling reactions
1 base
SCHF2
6RU
(Scheme II).
45
ArSH
~
1101
50
6
SO2CHF2
Br-Ar /
CuO/base
RU
55
Scheme III Selected Methods of Fluorinated Aryl Sulfone

Scheme Il Selected Nucleophilic Aromatic Substitution Synthesis
using Nitroaryls 60 As shown in Scheme IV, non-symmetrical urea formation
Nitroaryls may also undergo transition metal mediated may involve reaction of an aryl isocyanate (14) with an aryl
cross coupling reactions. For example, nitroaryl electro- amine (13). The heteroaryl isocyanate may be synthesized
philes, such as nitroaryl bromides, iodides or triflates, from a heteroaryl amine by treatment with phosgene or a
undergo palladium mediated cross coupling reactions with phosgene equivalent, such as trichloromethyl chloroformate
aryl nucleophiles, such as arylboronic acids (Suzuki reac- 65 (diphosgene), bis(trichloromethyl) carbonate (triphosgene),
tions, exemplified below), aryltins (Stille reactions) or arylz- or N,N'-carbonyldiimidazole (CDI). The isocyanate may
incs (Negishi reaction) to afford the biaryl (5). also be derived from a heterocyclic carboxylic acid deriva-
IITRUE COPYII
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tive, such as an ester, an acid halide or an anhydride by a an inert solid diluent, for example, calcium carbonate,
Curtius-type rearrangement. Thus, reaction of acid deriva- calcium phosphate or kaolin, or as soft gelatin capsules
tive 16 with an azide source, followed by rearrangement wherein the active ingredient is mixed with water or an oil
affords the isocyanate. The corresponding carboxylic acid medium, for example peanut oil, liquid paraffin or olive oil.
(17) may also be subjected to Curtius-type rearrangements Aqueous suspensions contain the active materials in
using diphenylphosphoryl azide (DPPA) or a similar admixture with excipients suitable for the manufacture of
reagent. aqueous suspensions. Such excipients are suspenwng
agents, for example sowum carboxymethylcellulose, meth-
ylcellulose, hydroxypropyl methylcellulose, sodium algi-
10 nate, polyvinylpyrrolidone, gum tragacanth and gum acacia;
dispersing or wetting agents may be a naturally occurring
phosphatide, for example, lecithin, or condensation products
or an alkylene oxide with fatty acids, for example polyoxy-
ethylene stearate, or condensation products of ethylene
15 oxide with long chain aliphatic alcohols, for example hep-
Ar -Nco
1
tadecaethylene oxycetanol, or condensation products of eth-
14
ylene oxide with partial esters derived from fatty acids and
15 hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters
\orrA 20 derived from fatty acids and hexitol anhydrides, for example
polyethylene sorbitan monooleate. The aqueous suspensions
may also contain one or more preservatives, for example
ethyl, or n-propyl p-hydroxybenz.oate,one or more coloring
agents, one or more flavoring agents, and one or more
25 sweetening agents, such as sucrose or saccharin.
16 Dispersible powders and granules suitable for preparation
of an aqueous suspension by the addition of water provide
the active ingredient in admixture with a dispersing or
Scheme JV Selected Methods of Non-Symmetrical Urea wetting agent, suspending agent and one or more preserva-
3o tives. Suitable dispersing or wetting agents and suspending
Formation
Finally, ureas may be further manipulated using methods agents are exemplified by those already mentioned above.
familiar to those skilled in the art. Additional excipients, for example, sweetening, flavoring
The invention also includes pharmaceutical compositions and coloring agents, may also be present.
including a compound of Formula I, and a physiologically 35 The compounds may also be in the form of non-aqueous
acceptable carrier. liquid formulations, e.g., oily suspensions which may be
The compounds may be administered orally, topica1Jy, formulated by suspending the active ingredients in a veg-
parenterally, by inhalation or spray or rectally in dosage unit etable oil, for example arachis oil, olive oil, sesame oil or
formulations. The term 'administration by injection' peanut oil, or in a mineral oil such as liquid paraffin. The oily
includes intravenous, intramuscular, subcutaneous and 40 suspensions may contain a thickening agent, for example
one or more non-toxic pharmaceutically acceptable carriers added to provide palatable oral preparations. These compo-
Compositions intended for oral use may be prepared 45 such as ascorbic acid.
sitions ma contain one or more agents selected from the a vegetable oil, for example olive oil or arachis oil, or a
agents, coloring agents and preserving agents in order to 50 Suitable emulsifying agents may be naturally-occurring
ingredient in admixture with non-toxic pharmaceutica1Jy occurring phosphatides, for example soy bean, lecithin, and
acceptable excipients which are suitable for the manufacture esters or partial esters derived from fatty acids and hexitol
wluents, such as calcium carbonate, sodium carbonate, 55 sation products of the said partial esters with ethylene oxide,
alginic acid; and binding agents, for example magnesium agents.
they may be coated by known techniques to delay wsinte- 60 agents, for example glycerol, propylene glycol, sorbitol or
gration and adsorption in the gastrointestinal tract and sucrose. Such formulations may also contain a demulcent, a
example, a time delay material such as glyceryl monostear- The compounds may also be administered in the form of
ate or g)yceryl distearate may be employed. These com- suppositories for rectal administration of the drug. These
pounds may also be prepared in solid, rapidly released form. 65 compositions can be prepared by mixing the drug with a
Formulations for oral use may also be presented as hard suitable non-irritating excipient which is solid at ordinary
gelatin capsules wherein the active ingredient is mixed with temperatures but liquid at the rectal temperature and will
IITRUE COPYII
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therefore melt in the rectum to release the drug. Such biochem Corp. 3-tert-Butylaniline, 5-tert-butyl-2-
materials include cocoa butter and polyethylene glycols. methoxyaniline, 4-bromo-3-(trifluoromethyl)aniline,
For all regimens of use disclosed herein for compounds of 4-<:hloro-3-(trifluoromethyl)aniline 2-methoxy-5-(trifluo-
Formula I, the daily oral dosage regimen will preferably be romethyl)aniline, 4-tert-butyl-2-nitroaniline, 3-amino-2-
from 0.01 to 200 mlefK.gof total body weight. The daily 5 naphthol, ethyl 4-isocyanatobenzoate, N-acetyl-4-chloro-2-
dosage for administration by injection, including intrave- methoxy-5-(trifluoromethyl)aniline and 4-<:hloro-3-
nous, intramuscular, subcutaneous and parenteral injections, (trifluoromethyl)phenyl isocyanate were purchased and used
and use of infusion techniques will preferably be from 0.Ql without further purification. Syntheses of 3-amino-2-meth-
to 200 mlefK.gof total body weight. The daily rectal dosage oxyquinoline (E. Cho et al. WO 98/00402; A. Cordi et al. EP
regime will preferably be from 0.Ql to 200 mg/Kg of total 10 542,609; IBID Bioorg. Med. Chem. 3, 1995, 129), 4-(3-
body weight. The daily topical dosage regime will prefer- carbamoylphenoxy)-1-nitrobenzene (K. Ikawa Yakugaku
ably be from 0.1 to 200 mg administered between one to four Zasshi 79, 1959, 760; Chem. Abstr. 53, 1959, 12761b),
times daily. The daily inhalation dosage regime will prefer- 3-tert-butylphenyl isocyanate (0. Rohr et al. DE 2,436,108)
ably be from 0.01 to 10 mg/Kg of total body weight. and 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (K.
It will be appreciated by those skilled in the art that the 15 Inukai et al. JP 42,025,067; IBID Kogyo Kagaku Zasshi 70,
particular method of administration will depend on a variety 1967, 491) have previously been described.
of factors, all of which are considered routinely when Thin-layer chromatography (TLC) was performed using
administering therapeutics. It will also be appreciated by one Whatman® pre-coated glass-backed silica gel 60A F-254
skilled in the art that the specific dose level for a given 250 µm plates. Visualization of plates was effected by one or
patient depends on a variety of factors, including specific 20 more of the following techniques: (a) ultraviolet illumina-
activity of the compound administered, age, body weight, tion, (b) exposure to iodine vapor, (c) immersion of the plate
health, sex, diet, time and route of administration, rate of in a 10% solution of phosphomolybdic acid in ethanol
excretion, etc. It will be further appreciated by one skilled in followed by heating, (d) immersion of the plate in a cerium
the art that the optimal course of treatment, i.e., the mode of sulfate solution followed by heating, and/or (e) immersion
treatment and the daily number of doses of a compound of 25 of the plate in an acidic ethanol solution of 2,4-dinitrophe-
Formula I or a pharmaceutically acceptable salt thereof nylhydrazine followed by heating. Column chromatography
given for a defined number of days, can be ascertained by (flash chromatography) was performed using 230-400 mesh
those skilled in the art using conventional treatment tests. EM Science® silica gel.
It will be understood, however, that the specific dose level Melting points (mp) were determined using a Thomas-
for any particular patient will depend upon a variety of 30 Hoover melting point apparatus or a Mettler FP66 auto-
factors, including the activity of the specific compound mated melting point apparatus and are uncorrected. Fourier
employed, the age, body weight, general health, sex, diet, transform infrared spectra were obtained using a Mattson
time of administration, route of administration, and rate of 4020 Galaxy Series spectrophotometer. Proton (1H)nuclear
excretion, drug combination and the severity of the condi- magnetic resonance (NMR) spectra were measured with a
tion undergoing therapy. 35 General Electric GN-Omega 300 (300 MHz) spectrometer
The entire disclosure of all applications, patents and with either Me4 Si (I', 0.00) or residual protonated solvent
publications cited above and below are hereby incorporated (CHCl3 117.26; MeOH 113.30; DMSO 112.49) as standard.
by reference, including provisional application Ser. No. Carbon {13C) NMR spectra were measured with a General
60/115,877, filed Jan. 13, 1999. Electric GN-Omega 300 (75 MHz) spectrometer with sol-
The compounds can be produced from known compounds 40 vent (CDC13 l'l77.0; Me0D-d 3 ; 6 49.0; DMSO-d 6 l'l39.5) as
(or from starting materials which, in turn, can be produced standard. Low resolution mass spectra (MS) and high reso-
according to procedures disclosed below. The following 45 were obtained with a Hewlett Packard 5989A mass spec-
examples are for illustrative purposes only and are not trometer equipped with a Vacumetrics Desorption Chemical
performed with electron energy of70 eV and a trap current
EXAMPLES 50 of300 µA. Liquid-cesium secondary ion mass spectra (FAB-
MS), an updated version of fast atom bombardment were
All reactions were performed in flame-dried or oven-dried obtained using a Kratos Concept 1-H spectrometer. Chemi-
glassware under a positive pressure of dry argon or dry cal ioni1.ationmass spectra (0-MS) were obtained using a
nitrogen, and were stirred magnetically unless otherwise Hewlett Packard MS-Engine (5989A) with methane or
indicated. Sensitive liquids and solutions were transferred 55 ammonia as the reagent gas (lxlo-4 torr to 2.5xl0-4 torr).
via syringe or cannula, and introduced into reaction vessels The direct insertion desorption chemical ionization (DCI)
through rubber septa. Unless otherwise stated, the term probe (Vacuumetrics, Inc.) was ramped from 0-1.5 amps in
'concentration under reduced pressw-e' refers to use of a l O sec and held at 10 amps until all traces of the sample
Buehl rotary evaporator at approximately 15 mmHg. Unless disappeared (-1-2 min). Spectra were scanned from 50-800
otherwise stated, the term 'under high vacuum' refers to a 60 amu at 2 sec per scan. HPLC---electrospray mass spectra
vacuum of 0.4-1.0 mmHg. (HPLC ES-MS) were obtained using a Hewlett-Packard
All temperatures are reported uncorrected in degrees 1100 HPLC equipped with a quaternary pump, a variable
Celsius (0 C.). Unless otherwise indicated, all parts and wavelength detector, a C-18 column, and a Finnigan LCQ
percentages are by weight. ion trap mass spectrometer with electrospray ionization.
Commercial grade reag-entsand solvents were used with- 65 Spectra were scanned from 120-800 amu using a variable
out further purification. N-cyclohexyl-N'-(methylpolysty- ion time according to the number of ions in the source. Gas
rene)carbodiimide was purchased from Ca)biochem-Nova- chromatography-ion selective mass spectra ((GC-MS)
IITRUE _COPYII
US 7,351,834 Bl
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were obtained with a Hewlett Packard 5890 gas chromato- with water (200 mL). The resulting mixture was extracted
graph equipped with an HP-1 methyl silicone column (0.33 with EtOAc (2x200 mL). The combined organic layers were
mM coating; 25 mx0.2 mm) and a Hewlett Packard 5971 washed with a saturated NaCl solution (100 mL), dried
Mass Selective Detector (ionization energy 70 eV). Elemen- (MgSO4), concentrated under reduced pressure (approxi-
tal analyses are conducted by Robertson Microlit Labs, mately 0.4 mmHg overnight) to give methyl 3-methoxy-2-
Madison N .1. naphthoate as an amber oil (10.30 g): 1 H-NMR (DMSO-d6 )
All compounds displayed NMR spectra, LRMS and either {>2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, J=8.09 Hz, IH), 7.44
elemental analysis or HRMS consistent with assigned struc- (s, lH), 7.53 (app t, 1=8.09 Hz, lH), 7.84 (d, 1=8.09 Hz, lH),
tures. 7.90 (s, IH), 8.21 (s, lH).
10
AcOH a.cetic acid

anh anhydrous 15
a.an a.anosphcre(s)
BOC tcrt-butoxycarbonyl
CDI I, l '-arl>onyl diimidazole
cone concentrated
d day(s) OMe
dee decomposition 20
DMPU 1,3-dimethyl-3 ,4,5,6-tctrahydro-2(1 H)-pyrimidinone
DMF N ,N-dimcthylfonnamide Step 2. 3-Methoxy-2-naphthoic acid •
DMSO dimethylsulfoltide
DPPA diphenylphosphoryl azide A solution of methyl 3-methoxy-2-naphthoate (6.28 g,
EDCI 1-(3-dimelhylaminopropyl)-3-ethylcarbodiimide
EtOAc ethyl ace181e 25 29.10 mmol)and water (l0mL) inMeOH (lOOmL) at room
EtOH ethanol (100%) temp. was treated with a 1 N NaOH solution (33.4 mL, 33.4
Et2 O diethyl ether mmol). The mixture % vas heated at the reflux temp. for 3
Et3N triethylamine h, cooled to room temp., and made acidic with a 100/ocitric
h hour(s)
HOBT 1-hydroxybenzotriazole acid solution. The resulting solution was extracted with
m-CPBA 3-cbloroperoxybcnzoic acid 30 EtOAc (2x100 mL). The combined organic layers were
MeOH methanol washed with a saturated NaCl solution, dried (MgSO4) and
temp. temperature
THF tetrahydrofumn rated with hexane then washed several times with hexane to
TFA trifluoroAcOH give 3-methoxy-2-naphthoic acid as a white solid (5.40 g,
Tf trifluoromethanesulfonyl 35 92"/o): 'H-NMR (DMSO-d 6) {> 3.88 (s, 3H), 7.34-7.41 (m,
--------------------- 2H), 7.49-7.54 (m, lH), 7.83 (cl, 1=8.09 Hz, lH), 7.91 (cl,
1=8.09 Hz, lH), 8.19 (s, lH), 12.83 (br s, IH).
A. General Methods for Synthesis of Substituted
Anilines 40
Al. General Method for Ary) Amine Formation Via

Ether Formation Followed by Ester Saponification,
Curtius Rearrangement, and Carbamate
Deprotection 45
Synthesis of 2-Amino-3-methoxynaphthalene
50
Step 3. 2-(N-(Carbobenzyloxy)amino-3-methox-
ynaphthalene

55 mmol) and Et3 N (2.59 mL, 18.6 mmol) in anh toluene (70
COiMe mL) was stirred at room temp. for 15 min., then treated with
OMe
Step 1. Methyl 3-methoxy-2-naphthoate then warmed to 80° C. overnight. The resulting mixture was
cooled to room temp., quenched with a 10% citric acid
A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 solution, and extracted with EtOAc (2xl00 mL). The com-
mmol) and K2CO3 (7.96 g, 57.6 mmol) in DMF (200 mL) bined organic layers were washed with a saturated NaCl
was stirred at room temp. for 15 min., then treated with 65 solution, dried (MgSO4 ) and concentrated under reduced
iodomethane (3.43 mL, 55.1 mmol). The mixture was pressure. The residue was purified by column chromatog-
allowed to stir at room temp. overnight, then was treated raphy (14% EtOAc/86% hexane) to give 2-(N-(carl>oben-
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zyloxy)amino-3-methoxynaphthalerie as a pale yellow oil lized at 0° C. over 72 h to give 4-chloro-N-methyl-2-
(5.1 g, 100%): 1 H-NMR (DMSO-dJ 6 3.89 (s, 3H), 5.17 (s, pyridinecarboxamide (0.61 g, 5.3%): TLC (50% EtOAc/
2H), 7.27-7.44 (m, 8H), 7.72-7.75 (m, 2H), 8.20 (s, IH), 50"/ohexane) R._r0.50;H NMR (COCl 6 3.04 (d, J=5.l Hz,
1
3
)
8.76 (s, IH). 3H), 7.43 (dd, 1=5.4, 2.4 Hz, IH), 7.96 (br s, IH), 8.21 (s,
s lH), 8.44 (d, J=5.I Hz, IH); CI-MS m/z 171 ((M+Hr).
Cl'd:O
~ Cl
I .-,::::N HCI
OMe
15
Step lb. Synthesis of 4-chloropyridine-2-carbonyl
chloride HCI salt via picolinic acid
Anhydrous DMF (6.0 mL) was slowly added to SOCl2
A slurry of 2-(N-(carbobenzyloxy)amino-3-methox- (180 mL) betw 40° d 50° c Th I ti0 sf eel
Ynaphthalene (5.0 g, 16.3 mmol) and 10% Pd/C (0.5 g) in 20 •
m that temperature an fior 1 •mm.
een range
0
. e sothu ':1w1~-
en pico llT_d
IIllC ac1
EtOAc (70 mL) was maintained under a H2 atm (balloon) at (60.0 g, 487 mmol) was added in portions over 30 min. The
room temp. overnight. The resulting mixture was filtered resulting solution was heated at 72° C. (vigorous SO2
through Celite® and concentrated under reduced pressure to evolution) for 16 h to generate a yellow solid precipitate.
give 2-amino-3-methoxynaphthalene as a pale pink powder The resulting mixture was cooled to room temp., diluted
1 25
(2.40 g, 85%): H-NMR (DMSO-dJ 6 3.86 (s, 3H), 6.86 (s, with toluene (500 mL) and concentrated to 200 mL. The
2H), 7.04-7.16 (m, 2H), 7.43 (d, J=8.0 Hz, lH), 7.56 (d, toluene addition/concentration process was repeated twice.
J=8.0 Hz, IH); El-MS m/z 173 (M+). The resulting nearly dry residue was filtered and the solids
were washed with toluene (2x200 mL) and dried under high
A2. Synthesis of w-Carbamyl Anilines Via
Formation of a Carbamylpyridine Followed by
Nucleophilic Coupling with an Ary! Amine
30 ~~:u:ct~:I~ ! t; :~:w~~;;~;f~~~~~~;. chlo-
Svnthesis of
4-(2-N-Methylcarbamyl-4-pyridyloxy)aniline
35 Cl~O
~ OMe
1 .-,::::N HCI
Cl'd'O 40
~ NHMe
Step 2. Synthesis of methyl
1 oN 4-chloropyridine-2-carl>oxylateHCl salt
Anh DMF (10.0 mL) was slowly added to SOCl2 (300

45 mL) at 40-48° C. The solution was stirred at that temp. range
Step la. Synthesis of for IO min., then picolinic acid (JOOg, 812 mmol) was added
4-chloro-N-methyl-2-pyridinecarboxamide via the over 30 min. The resulting solution was heated at 72° C.
Menisci reaction (vigorous SO2 evolution) for 16 h to generate a yellow solid.
Caution: this is a highly hazardous, potentially explosive 50 with toluene (500 mL) and concentrated to 200 mL. The
reaction. To a stirring solution of 4-chloropyridine (10.0 g) toluene addition/concentration process was repeated twice.
in N-methylformamide (250 mL) at room temp. was added The resulting nearly dry residue was filtered, and the solids
cone. H2 SO4 (3.55 mL) to generate an exotherm. To this were washed with toluene (50 mL) and dried under high
mixture was added H2 O2 (30"/owt in H2 O, 17 mL) followed vacuum for 4 hours to afford 4-chloropyridine-2-carbonyl
by FeSO4 .7H2 O (0.56 g) to generate another exotherm. The 55 chloride HCl salt as an off-white solid (27.2 g, 16%). This
resulting mixture was stirred in the dark at room temp. for material was set aside.
I h, then warmed slowly over 4 h to 45° C. When bubbling The red filtrate was added to MeOH (200 mL) at a rate
had subsided, the reaction was heated at 60° C. for 16 h. The which kept the internal temperature below 55° C. The
resulting opaque brown solution was diluted with H2 O (700 contents were stirred at room temp. for 45 min., cooled to 5°
mL) followed by a 10% NaOH solution (250 mL). The 60 C. and treated with Et2O (200 mL) dropwise. The resulting
resulting mixture was extracted with EtOAc (3x500 mL). solids were filtered, washed with Et2O (200 mL) and dried
The organic phases were washed separately with a saturated under reduced pressure at 35° C. to provide methyl 4-chlo-
NaCI solution (3x-150 mL), then they were combined, dried ropyridine-2-carboxylate HO salt as a white solid (110 g,
(MgSO and filtered through a pad of silica gel with the aid
4
) 65%): mp 108-112°C.; H-NMR (DMSO-d fl 3.88 (s, 3H);
1
6
)
of EtOAc. The resulting brown oil was purified by column 65 7.82 (dd, J=5.5, 2.2 Hz, IH); 8.08 (d, J=2.2 Hz, IH); 8.68 (d,
chromatography (gradient from 50% EtOAc/50% hexane to J=5.5 Hz, IH); 10.68 (hr s, IH); HPLC F.s-MS m/z 172
80% EtOAc/20"/ohexane). The resulting yellow oil ciystal- ((M+Ht).
IITRUE COPYII
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(10.29 g, 91.7 mmol), and the reddish-brown mixture was
stirred at room temp. for 2 h. The contents were treated with
4-chloro-N-methyl-2-pyridinecarboxamide (15.0 g, 87.9
mmol) and K2 CO3 (6.50 g, 47.0 mmol) and then heated at
Cl~O
~ NHMe 5 80" C. for 8 h. The mixture was cooled to room temp. and
separated between EtOAc (500 mL) and a saturnted NaCl
1 solution (500 mL). Toe aqueous phase was back~xtracted
.&l N
with EtOAc (300 mL). Toe combined organic layers were
washed with a saturated NaO solution (4xl000 mL), dried
10 (Na2S0 4 ) and concentrated under reduced pressure. Toe
Step 3a. Synthesis of resulting solids were dried under reduced pressure at 35° C.
4-chJoro-N-methyl-2-pyridinecarboxamide from for 3 h to afford 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)
methy I 4-chloropyridine-2-carboxylate aniline as a light-brown solid 17.9 g, 84%): 'H-NMR
(DMSO-d6) b 2.77 (cl, 1=4.8 Hz, 3H), 5.17 (br s, 2H), 6.64,
A suspension of methyl 4-chloropyridine-2-carboxylate IS 6.86 (AA'BB' quartet, 1=8.4 Hz, 4H), 7.06 (dd, 1=5.5, 2.5
HCI salt (89.0 g, 428 mmol) in MeOH (75 mL) at 0° C. was Hz, lH), 7.33 (d, 1=2.5Hz, IH), 8.44 (d, 1=5.5Hz, lH), 8.73
treated with a 2.0 M methylamine solution in THF (I L) at (br d, IH); HPLC ES-MS m/z 244 ((M+H)"'}
a rate which kept the internal temp. below 5~ C. The
resulting mixture was stored at 3° C. for 5 h, then concen- A3. General Method for the Synthesis of Anilines
trated under reduced pressure. Toe resulting solids were 20 by Nucleophilic Aromatic Addition Followed by
suspended in EtOAc (I L) and filtered. Toe filtrate was Nitroarene Reduction
(Na2 SO4 ) and concentrated under reduced pressure to afford Synthesis of
4-chloro-N-methyl-2-pyridinecarboxamide as pale-yellow 5-(4-Aminophenoxy)isoindoline-l,3-dione
1
crystals (71.2 g, 97%): mp 41-43° C.; H-NMR (DMSO-d6 ) 25
b 2.81 (s, 3H), 7.74 (dd, 1=5.1, 2.2 Hz, IH), 8.00 (d, 1=2.2,
IH), 8.61 (d, J=5.l Hz, IH), 8.85 (br d, IH); CI-MS m/z 171
((M+Hr).
~o
30
HO~NH
Cl~O
~ NHMe 0
1 ,&lN
35
Step 3b. Synthesis of To a mixture of ammonium carbonate (5.28 g, 54.9 mmol)

4-chloro-N-methyl-2-pyridinecarboxamide from in cone. AcOH (25 mL) was slowly added 4-hydroxyph-
4-chloropyridine-2-carbonyl chloride 40 thalic acid (5.0 g, 27.45 mmol). Toe resulting mixture was
heated at 120° C. for 45 min., then the clear, bright yellow
4-Chloropyridine-2-carbonyl chloride HCI salt (7.0 g, mixture was heated at 160° C. for 2 h. Toe resulting mixture
32.95 mmol) was added in portions to a mixture of a 2.0 M was maintained at 160° C. and was concentrated to approxi-
methylamine solution in THF (100 mL) and MeOH (20 mL) mately 15 mL, then was cooled to room temp. and adjusted
at 0° C. Toe resulting mixture was stored at 3° C. for 4 h, 45 pH 10 with a IN NaOH solution. This mixture was cooled
then concentrated under reduced pressure. The resulting to 0° C. and slowly acidified to pH 5 using a IN HCI
nearly dry solids were suspended in EtOAc (JOOmL) and solution. Toe resultant precipitate was collected by filtration
filtered. Toe filtrate was washed with a saturnted NaCl and dried under reduced pressure to yield 5-hydroxyisoin-
solution (2xl00 mL), dried (Na2 SO4 ) and concentrated doline-1,3-dione as a pale yellow powder as product (3.24 g,
under reduced pressure to provide 4-chJoro-N-methyl-2- 50 72%): 1 H NMR (DMSO-<4) 5 7.00-7.03 (m, 2H), 7.56 (cl,
pyridinecarboxamide as a yellow, crystalline solid (4.95 g, 1=9.3 Hz, 1H).
88%): mp 37-40° C.
55
60
Step 4. Synthesis of Step 2. Synthesis of

4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline 5-(4-nitrophenoxy)isoindoline-1,3-dione
65
A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. To a stirring slurry ofNaH (1.1 g, 44.9 mmol) in DMF (40
DMF (150 mL) was treated with potassium tert-butoxide mL) at 0° C. was added a solution of 5-hydroxyisoindoline-
IITRUE COPYII
US 7,351,834 Bl
17 18
1,3-dione (3.2 g, 19.6 mmol) in DMF (40 mL) dropwise. The mL) and acetonylacetone (0.299 g, 2.63 mmol) via syringe.
bright yellow-green mixture was allowed to return to room The reaction mixture was heated at 120° C. for 72 h with
temp. and was stirred for 1 h, then l-fluoro-4-nitrobenzene 37.eOtropicremoval of volatiles. The reaction mixture was
(2.67 g, 18.7 mmol) was added via syringe in 3-4 portions. cooled to room temp., diluted with CH2 Cl2 (IO mL) and
The resulting mixture was heated at 70° C. overnight, then s sequentially washed with a IN HCI solution (15 mL), a IN
cooled to room temp. and diluted slowly with water (150 NaOH solution (15 rnL) and a saturated NaCl solution (15
mL), and extracted with EtOAc (2xl00 mL). The combined mL), dried (MgSO4) and concentrated under reduced pres-
organic layers were dried (MgS0 4) and concentrated under sure. The resulting orange-brown solids were purified via
reduced pressure to give 5-(4-nitrophenoxy)isoindoline-1,3- column chromatography (60 g SiO2 ; gradient from 6%
dione as a yellow solid(3.3 g, 62%): TLC (30"/oEtOAd70% 10
EtOAc/94% hexane to 25% Et0Ad75% hexane) to give
1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole as an
hexane) Rf0.28; 1H NMR (DMS0-'4) & 7.32 (d, J=l2 Hz, orange-yellow solid (0.34 g, 49%): TLC (15% Et0Ad85%
2H), 7.52-7.57 (m, 2H), 7.89 (d, J=7.8 Hz, 1H), 8.29 (d, J=9 hexane) R._r0.67;1 H NMR (COCl3 ) & 1.34 (s, 9H), 1.89 (s,
Hz, 2H), 11.43 (br s, IH); CI-MS m/z 285 ((M+H)+, 100%). 6H), 5.84 (s, 2H), 7.19-7.24 (m, IH), 7.62 (dd, IH), 7.88 (d,
J=2.4 Hz, lH); CI-MS m/z 273 ((M+H)+, 50"/o).
15
I~
0'2r
H 2N # NH 0
20
Step 3. Synthesis of 25
5-(4-aminophenoxy )isoindoline-1,3-dione
A solution of 5-(4-nitrophenoxy)isoindoline-l,3-dione
(0.6 g, 2.11 mmol) in cone. AcOH (12 mL) and water (0.1
mL) was stirred under a stream of argon while iron powder 30 Step 2. Synthesis of
(0.59 g, 55.9 mmol) was added slowly. This mixture stirred 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline
at room temp. for 72 h, then was diluted with water (25 mL)
and extracted with EtOAc (3x50 mL). The combined A slurry of 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimeth-
organic layers were dried (MgSO4) and concentrated under ylpyrrole (0.341 g, 1.25 mmol), 10"/oPd/C (0.056 g) and
reduced pressure to give 5-(4-aminophenoxy)isoindoline-l, 35 EtOAc (50 mL) under an H2 atmosphere (balloon) was
3-dione as a brownish solid (0.4 g, 75%): TLC (50% stirred for 72 h, then filtered through a pad of Celite®. The
EtOAc/50% hexane) R 0.27; 1H NMR (DMSO-d6 ) 05.14 filtrate was concentrated under reduced pressure to give
(br s, 2H), 6.62 (cl, J=l_ 7 Hz, 2H), 6.84 (cl, J=8.7 Hz, 2H), 5-tert-butyl-2-(2,5-dimethylpyrrolyl)aniline as yellowish
7.03 (d, J=2.l Hz, lH), 7.23 (dd, lH), 7.75 (d, J=8.4 Hz, solids (0.30 g, 99%): TLC (10% EtOAc/90"/o hexane) Rf
lH), 11.02 (s, lH); HPLC ES-MSm/z255 ((M+H)+, 100"/o). 40 0.43; 'H NMR (COCl3 ) & 1.28 (s, 9H), 1.87-1.91 (m, SH),
5.85 (br s, 2H), 6.73-6.96 (m, 3H), 7.28 (br s, IH).
Pyrrolylanilines AS. General Methodfor the Synthesis of Anilines
from Anilines by Nucleophilic Aromatic
Synthesis of 45 Substitution
5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline
loxy)-2-methylaniline HCI Salt
so
55
NOi
N
'(Y 60
mmol) in dry dimethylacetamide (75 mL) was treated with
potassium tert-butoxide (10.86 g, 96.77 mmol) and the black
Step I. Synthesis of mixture was stirred at room temp. until the flask had reached
1-(4-tert-butyl-2-nitrophenyl)-2, 5-dimethylpyrrole room temp. The contents were then treated with 4-chloro-
65 N-methyl-2-pyridinecarboxamide (Method A2, Step 3b;
To a stirring solution of 2-nitro-4-tert-butylaniline (0.5 g, 7.52 g, 44.2 mmol) and heated at 110° C. for 8 h. The
2.57 mmol) in cyclohexane (10 mL) was added AcOH (0.1 mixture was cooled to room temp. and diluted with water
IITRUE COPYjl
US 7,351,834 Bl
19 20
(75 mL). The organic layer was extracted with EtOAc Step 2: Synthesis of 4-(2-(N-Methylcarbamoyl)-4-
(5xl00 mL). The combined organic layers were washed pyridyloxy)-2-chlorophenyl (222-trifluoro)acetamide
with a saturated NaCl solution (200 mL), dried (MgSO4) and
concentrated under reduced pressure. The residual black oil A solution of crude 3-chloro-4-(2,2,2-trifluoroacety-
was treated with Et2 O (50 mL) and sonicated. The solution s lamino)phenol (5.62 g, 23.46 mmol) in dry dimethylaceta-
was then treated with HCI ( I M in Et2 O; 100 mL) and stirred mide (50 mL) was treated with potassium tert-butoxide
at room temp. for 5 min. The resulting darlc pink solid (7 .04 (5.16 g, 45.98 mmol) and the brownish black mixture was
g, 24.l mmol) was removed by filtration from solution and stirred at room temp. until the flask had cooled to room
1
stored under anaerobic conditions at 0° C. prior to use: H temp. The resulting mixture was treated with 4-chloro-N-
NMR (DMSO-d6) b 2.41 (s, 3H), 2.78 (d, J=4.4 Hz, 3H), 10 methyl-2-pyridinecarboxamide (Method A2, Step 3b; 1.99
4.93 (br s, 2H), 7.19 (dd, J=8.5, 2.6 Hz, lH), 7.23 (dd, 1=5.5, g, 11.7 mmol) and heated at 100° C. under argon for 4 d. The
2.6 Hz, IH), 7.26 (d, J=2.6 Hz, lH), 7.55 (d, J=2.6 Hz, lH), black reaction mixture was cooled to room temp. and then
7.64 (cl,J=8.8 Hz, lH), 8.55 (d, J=5.9 Hz, I H), 8.99 (q, J=4.8 poured into cold water (100 mL). The mixture was extracted
Hz, IH). with EtOAc (3x75 mL) and the combined organic layers
15
were concentrated under reduced pressure. The residual
brown oil was purified by column chromatography (gradient
A6. General Method for the Synthesis of Anilines from 20"/o EtOAc/pet. ether to 40% EtOAc/pet. ether) to
from Hydroxyanilines by N-Protection, yield 4-{2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chlo-
Nucleophilic Aromatic Substitution and rophenyl (222-trifluoro)acetamide as a yellow solid (8.59 g,
Deprotection 23.0 mmol).
20
loxy)-2-chloroaniline
0
25 nY y-lNHM,
H2N~CI ~J.
30
Step 3. Synthesis of 4-(2-(N-Methylcarbamoyl)-4-
pyridyloxy)-2-chloroaniline
A solution of crude 4-(2-(N-Methylcarbamoyl)-4-pyridy-

Step I: Synthesis of
35 loxy)-2-chlorophenyl (222-trifluoro)acetamide (8.59 g, 23.0
3-Chloro-4-(2,2,2-trifluoroacetylamino)phenol
mmol) in dry 4-dioxane (20 mL) was treated with a IN
NaOH solution (20 mL). This brown solution was allowed
Iron (3.24 g, 58.00 mmol) was added to stirring TFA (200 to stir for 8 h. To this solution was added EtOAc (40 mL).
mL). To this slurry was added 2-chloro-4-nitrophenol (10.0 The green organic layer was extracted with EtOAc (3x40
g 58.0 mmol) and trifluoroacetic anhydride (20 mL). This mL) and the solvent was concentrated to yield 4-(2-(N-
gray slurry was stirred at room temp. for 6 cl. The iron was 40 Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline as a green
filtered from solution and the remaining material was con- oil that solidified upon standing (2.86 g, 10.30 mmol): 1 H
centrated under reduced pressure. The resulting gray solid NMR (DMSO-d6) fl 2.77 (cl, J=4.8 Hz, 3H), 5.51 (s, 2H),
was dissolved in water (20 mL). To the resulting yellow 6.60 (dd, J=8.5, 2.6 Hz, IH), 6.76 (cl,J=2.6 Hz, lH), 7.03 (d,
solution was added a saturated NaHCO3 solution (50 mL). J=8.5 Hz, IH), 7.07 (dd, J=5.5, 2.6, Hz, IH), 7.27 (cl, J=2.6
The solid which precipitated from solution was removed. 45 Hz, IH), 8.46 (cl, J=5.5 Hz, IH), 8.75 (q, J=4.8, JH).
The filtrate was slowly quenched with the sodium bicarbon-
ate solution until the product visibly separated from solution A7. General Method for the Deprotection of an
(determined was using a mini work-up vial). The slightly Acylated Aniline
cloudy yellow solution was extracted with EtOAc (3x125
mL). The combined organic layers were washed with a 50 Synthesis of
saturated NaCl solution (125 mL), dried (MgSO4 ) and
concentrated under reduced pressure. The 1 H NMR 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline
(DMSO-dJ indicated a I: I ratio of the nitrophenol starting
material and the intended product 3-chloro-4-(2,2,2-trifluo-
roacetylamino)phenol. The crude material was taken on to
55
60
A suspension of 3-chloro-6-(N-acetyl)-4-(trifluorom-
65 ethyl)anisole (4.00 g, 14.95 mmol) in a 6M HCl solution (24
mL) was heated at the reflux temp. for I h. The resulting
solution was allowed to cool to room temp. during which
IITRUE COPYII
US 7,351,834 Bl
21 22
time it solidified slightly. The resulting mixture was diluted
with water (20 mL) then treated with a combination of solid
NaOH and a sanuated NaHCO3 solution until the solution
was basic. The organic layer was extracted with CH2Cl2
(3x50 mL). The combined organics were dried (MgSO4 ) and 5
concentrated under reduced pressure to yield 4-chloro-2-
methoxy-5-(trifluoromethyl)aniline as a brown oil (3.20 g,
~oy-l~
OiN~ lAOMe
14.2 mmol): 1 H NMR (DMSO-d6 ) 6 3.84 (s, 3H), 5.30 (s,
2H), 7.01 (s, 2H).
10
AS. General Method for Synthesis of Step 3. 4-(3-(N-Methylcarbamoyl)-4-methoxyphe-

w-Alkoxy-w-carboxyphenyl Anilines noxy)-l-nitrobenz.ene
Synthesis of To a solution of 4-(3-carboxy-4-methoxyphenoxy)-1-ni-

15
4-(3-(N-Methylcarbamoyl)-4-methoxyphenoxy)aniline trobenzene (0.50 g, 1.75 mmol) in CH2 Cl 2 (12 mL) was
added SOCl2 (0.64 mL, 8.77 mmol) in portions. The result-
ing solution was heated at the reflux temp. for 18 h, cooled
to room temp., and concentrated under reduced pressure.
The resulting yellow solids were dissolved in CH2 CI~ (3
20
mL) then the resulting solution was treated with a methy-
lamine solution (2.0 M in THF, 3.5 mL, 7.02 mmol) in
portions (CAUTION: gas evolution), and stirred at room
temp. for 4 h. The resulting mixture was treated with a IN
NaOH solution, then extracted with CH2 Cl2 (25 mL). The
25
organic layer was dried (Na2 SO4 ) and concentrated) under
reduced pressure to give 4-(3-(N-methylcarbamoyl)-4-
methoxyphenoxy)-1-nitrobenzene as a yellow solid (0.50 g,
Step 1. 4-(3-Methoxylcarbonyl-4-methoxyphe- 95%).
noxy)-1-nitrobenzene
30
To a solution of 4-(3-carboxy-4-hydroxyphenoxy)-1-ni-
trobenz.ene (prepared from 2,5-dihydroxybenwic acid in a
manner analogous to that described in Method AB, Step 1,
12 mmol) in acetone (50 mL) was added K2 C0 3 (5 g) and
35
dimethy I sulfate (3.5 mL). The resulting mixture was heated
at the reflux temp. overnight, then cooled to room temp. and
and purified by column chromatography (50% EtOAc/50% Step 4.
40
hexane) to give 4-(3-methoxycarbonyl-4-methoxyphe- 4-(3-(N-Methylcarbamoyl)-4-methoxyphenoxy)aniline
noxy)-1-nitrobenzene as a yellow powder (3 g): mp 115-
118° C. A sluny of 4-(3-(N-methylcarbamoly)-4-methoxyphe-
noxy)-1-nitrobenzene (0.78 g, 2.60 mmol) and 10% Pd/C
45 (0.20 g) in EtOH (55 mL) was stirred under 1 atm of H2
(balloon) for 2.5 d, then was filtered through a pad of
Celite®. The resulting solution was concentrated under
O I ~
O'CCO
OH reduced pressure to afford 4-(3-(N-methylcarbamoly)-4-
methoxyphenoxy)aniline as an off-white solid (0.68 g,
OiN # OMe 50 96%): TLC (0.1% Et3N/99.9% EtOAc) 8t-0.36.
A9. General Method for Preparation of

w-Alkylphthalimide-containing Anilines
Step 2.
4-(3-Carboxy-4-methoxyphenoxy)-1-nitrobenzene 55 Synthesis of
5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione
then heated at the reflux temp. for 4 h. The resulting mixture 60
was cooled to room temp. and concentrated under reduced
pressure. Toe residue was dissolved in water (50 mL), and
the aqueous mixture was made acidic with a lN HCI
solution. The resulting mixture was extracted with EtOAc
(50 mL). The organic layer was dried (MgSO4) and con-
centrated under reduced pressure to give 4-(3-carboxy-4-
65
OiN 0 0~0
I
#
N-Me
methoxyphenoxy)-l-nitrobenzene (1.04 g).
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23 24
Step I. Synthesis of
5-(4-Nitrophenoxy )-2-methylisoindoline-1,3-dione
A slurry of 5-(4-nitrophenoxy)isoindoline-1,3-dione (A3

Step 2; 1.0 g, 3.52 mmol) and NaH (0.13 g, 5.27 mmol) in 5
DMF (15 mL) was stirred at room temp. for I h, then treated
with methyl iodide (0.3 mL, 4.57 mmol). The resulting
mixture was stirred at room temp. overnight, then was
cooled to° C. and treated with water (10 mL). The resulting
solids were collected and dried under reduced pressure to lO
give 5-(4-nitrophenoxy)-2-methylisoindoline-1,3-<iioneas a Step 2. Synthesis of 4-(2-(N-(2-Morpholin-4-yl-
bright yellow solid (0.87 g, 83%): TLC (35% EtOAc/65% ethyl)carbamoyl)pyridyloxy)aniline
hexane) Rf0.61.
15 potassium tert-butoxide (0.53 g, 4.75 mol) in DMF (8 mL)
was stinecl at room temp. for 2 h, then was sequentially
treated with 4-chloro-2-(N-(2-morpholin-4-ylethyl)carbam-
D
H2N
o~o
I .# N-Me
0
oyl)pyridine (1.22 g, 4.52 mmol) and K2 CO3 (0.31 g, 2.26
mmol). The resulting mixture was heated at 75° C. over-
20 night, cooled to room temp., and separated between EtOAc
(25 mL) and a saturated NaCl solution (25 mL). The aqueous
layer was back extracted with EtOAc (25 mL). The com-
Step 2. Synthesis of 25 sure. The resulting brown solids were purified by column
5-(4-Aminophenoxy)-2-methylisoindoline-1,3-<iione chromatography (58 g; grawent from 100°/oEtOAc to 25%
MeOH/75% EtOAc) to afford 4-(2-(N-(2-morpholin-4-yl-
A slurry of nitrophenoxy)-2-methylisoindoline-1,3-<iione ethyl)carbamoyl)pyridyloxy)aniline (1.0 g, 65%): TLC
(0.87 g, 2.78 mmol) and 10% Pd/C (0.10 g) in MeOH was (10% MeOH/90% EtOAc) R_,-0.32.
stirred under I atm of H2 (balloon) overnight. The resulting 30
mixture was filtered through a pad of Celite® and concen- A 11. General Method for the Reduction of
trated under reduced pressure. The resulting yellow solids Nitroarenes to Arylamines
were dissolved in EtOAc (3 mL) and filtered through a plug
ofSiO 2 (60% EtOAc/40% hexane) to afford 5-(4-aminophe- Synthesis of 4-(3-Carboxyphenoxy)aniline
noxy)-2-methylisoindoline-l,3-<iione as a yellow solid (0.67 35
g, 86%): TLC (40% EtOAc/60% hexane) Rf0.27.
AIO. General Method for Synthesis of

w-Carbamoylaryl Anilines Through Reaction of
co-Alkoxycarbonylaryl Precursors with Amines 40
Synthesis of 4-(2-(N-(2-morpholin-4-ylethyl)car-
bamoyl)pyridyloxy)aniline
45
A slurry of 4-(3-carboxyphenoxy)- 1-nitrobenzene (5.38 g,
stirred under an H2 atmosphere (balloon) for 2 d. The
resulting mixture was filtered through a pad ofCelite®, then
50 concentrated under reduced pressure to afford 4-(3-carbox-
yphenoxy)aniline as a brown solid (2.26 g, 48%): TLC (10%
MeOH/90% CH2 Cl2 ) Rf0.44 (streaking).
Al 2. General Method for the Synthesis of

Step I. Synthesis of 4-Chloro-2-(N-(2-morpholin-4- 55 Isoindolinone-Containing Anilines
Synthesis of 4-(1-0xoisoindolin-5-yloxy)aniline
To a solution of methyl 4-chloropyridine-2-carl>oxylate
HCI salt (MethodA2, Step 2; 1.01 g, 4.86 mmol) in THF (20
mL) was added 4-(2-aminoethyl)morpholine (2.55 mL, 19.4 60
mmol) dropwise and the resulting solution was heated at the
reflux temp. for 20 h, cooled to room temp., and treated with
water (50 mL). The resulting mixture was extracted with
HO'CQ
~
I NH
EtOAc (50 mL). The organic layer was dried (MgS0 4 ) and
concentrated under reduced pressure to afford 4-chloro-2- 65 0
(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine as a yellow
oil (1.25 g, 95%): TLC (10% MeOH/90% EtOAc) R_r0.50.
IITRUE COPYjl
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25 26
Step 1. Synthesis of 5-hydroxyisoindolin-1-one Step 1. Synthesis of
4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene
To a solution of 5-hydroxyphthalimide (19.8 g, 121
mmol) in AcOH (500 mL) was slowly added zinc dust (47.6 A mixture of 4-fluoro-l-nitrobenzene (I 6 mL, 150 mmol),
g, 729 mmol) in portions, then the mixture was heated at the 5
ethyl 3-hydroxybenmate 25 g, 150 mmol) and K2CO3 (41 g,
reflux temp. for 40 min., filtered hot, and concentrated under 300 mmol) in DMF (125 mL) was heated at the reflux temp.
reduced pressure. The reaction was repeated on the same overnight, cooled to room temp. and treated with water (250
scale and the combined oily residue was purified by column
chromatography (I .l Kg SiO2 ; gradient from 60%, EtOAc/ mL). The resulting mixture was extracted with EtOAc
40% hexane to 25% MeOH/75% EtOAc) to give 5-hydroxy- 10 (3xl50 mL). The combined organic phases were sequen-
isoindolin-1-one (3.77 g): TLC (100% EtOAc) R_,.0.17; tially washed with water (3xl00 mL) and a saturated NaCl
HPLC ES-MS m/z 150 ((M+Ht}. solution (2xl00 mL), dried (Na2 SO4 } and concentrated
under reduced pressure. The residue was purified by column
chromatography (10% Et0Ad90"/o hexane) to afford 4-(3-
15 ethoxycarbonylphenoxy)-1-nitrobenzene as an oil (38 g).
20
4-(l-isoindolinon-5-yloxy)- l-nitrobenzene
To a sluny ofNaH (0.39 g, 16.l mmol) in DMF at 0° C.

25
was added 5-hydroxyisoindolin-1-one (2.0 g, 13.4 mmol) in
portions. The resulting sluny was allowed to warm to room Step 2. Synthesis of
temp. and was stirred for 45 min., then 4-fluoro-1-nitroben- 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene
zene was added and then mixture was heated at 70° C. for
3 h. The mixture was cooled to 0° C. and treated with water
dropwise until a precipitate formed. The resulting solids 30 To a slurry ofNaH (0.39 g, 16.1 mmol) in DMF at 0° C.
were collected to give 4-(1-isoindolinon-5-yloxy)-1-ni- was added 5-hydroxyisoindolin-1-one (2.0 g, 13.4 mmol) in
trobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% portions. The resulting sluny was allowed to warm to room
EtOAc) R_,.0.35. temp. and was stirred for 45 min., then 4-fluoro-1-nitroben-
zene was added and then the mixture was heated at 70° C.
35
for 3 h. The mixture was cooled to 0° C. and treated with
water dropwise until a precipitate formed. The resulting
solids were collected to give 4-(1-isoindolinon-5-yloxy)-l-
nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC
40 (100% EtOAc) R_,.0.35.
4-(1-oxoisoindolin-5-yloxy)aniline
45
A sluny of 4-(1-isoindolinon-5-yloxy)-l-nitrobenzene
(2.12 g, 7.8 mmol) and 10"/oPd/C (0.20 g) in EtOH (50 mL)
5-yloxy)aniline as a dark yellow solid: TLC (100% EtOAc) so
R_,.0.15. • Step 3. Synthesis of
4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene
Al3. General Method for the Synthesis of
oo-CarbamoylAnilines via EDCI-Mediated Amide
55 A mixture of 4-(3-carboxyphenoxy)-l-nitrobenzene (3.72
g, 14.4 mmol), EDCI.HCI (3.63, 18.6 mmol}, N-methylmor-
Svnthesis of pholine (1.6 mL, 14.5 mmol) and methylamine (2.0 M in
4-(3-N-Methyl~bamoylphenoxy)aniline THF; 8 mL, 16 mmol) in CH2 Cl2 (45 mL) was stirred at
room temp. for 3 d, then concentrated under reduced pres-
60 sure. The residue was dissolved inEtOAc (50 mL) and the
resulting mixture was extracted with a IM HCI solution (50
mL). The aqueous layer was back-extracted with EtOAc
(2x50 mL). The combined organic phases were washed with
65 a saturated NaCl solution (50 mL), dried (Na2 SO4 ), and
concentrated under reduced pressure to give 4-(3-(N-meth-
ylcarbamoyl)phenoxy)-l-nitrobenzene as an oil (1.89 g).
IITRUE COPY!I
US 7,351,834 Bl
27 28
4-(3-(5-methoxycarbonyl)pyridyloxy)aniline
A slUJTYof 4-(3-(5-methoxycarbonyl)pyridyloxy)-l-ni-
5 trobenz.ene (0.60 g, 2.20 mmol) and 10% Pd/C in MeOH/
EtOAc was stirred under an H2 atmosphere (balloon) for 72
h. The resulting mixture was filtered and the filtrate was
concentrated under reduced pressure. The residue was puri-
fied by column chromatography (gradient from 10% EtOAc/
10 90% hexane to 30% EtOAc/70% hexane to 50% EtOAd
Step 4. Synthesis of 50"/o hexane) to afford 4-(3-(5-methoxycarbonyl)
4-(3-(N-methylcarbamoyl)phenoxy)aniline pyridyloxy)aniline (0.28 g, 60%): 1 H NMR (CDCl3 ) Ii 3.92
(s, 3H), 6.71 (d, 2H), 6.89 (d, 2H), 7.73 (, lH), 8.51 (d, IH),
8.87 (d, IH).
A slUJTYof 4-(3-(N-methylcarbamoyl)phenoxy)-l-ni- 15
trobenz.ene (1.89 g, 6.95 mmol) and 5% Pd/C (0.24 g) in Al5. Synthesis of an Aniline Via Electrophilic
EtOAc (20 mL) was stirred under an H2 atm (balloon) Nitration Followed by Reduction
overnight. The 1-5 resulting mixture was filtered through a
pad of Celite® and concentrated under reduced pressure. Synthesis of 4-(3-Methylsulfamoylphenoxy)aniline
The residue was purified by column chromatography (5% 20
MeOH/95% CH2 Cl~. The resulting oil solidified under
vacuum overnight to give 4-(3-(N-methylcarbamoyl)phe-
noxy)aniline as a yellow solid (0.95 g, 56%).
\II°
Al 4. General Method for the Synthesis of 25 Brus...._ NHMe
w-Carbamoyl Anilines via EDCI-Mediated Amide 1
~
Synthesis of
30
4-3-(5-Methylcarbamoyl)pyridyloxy)aniline Step l. Synthesis of
N-methyl-3-bromobenz.enesulfonamide
To a solution of3-bromobenzenesulfonyl chloride (2.5 g,

11.2 mmol) in THF ( 15 mL) at 0° C. was added methylamine
35 (2.0 Min THF; 28 mL, 56 mmol). The resulting solution was
allowed to warm to room temp. and was stirred at room
temp. overnight. The resulting mixture was separated
between EtOAc (25 mL) and a 1 M HCI solution (25 mL).
The aqueous phase was back-extracted with EtOAc (2x25
40
mL). The combined organic phases were sequentially
washed with water (2x25 mL) and a saturated NaCl solution
Step I. Synthesis of (25 mL), dried (MgSO4) and concentrated under reduced
4-(3-(5-methoxycarbonyl)pyridyloxy}-1-nitrobenz.ene pressure to give N-methyl-3-bromobenzenesulfonamide as a
white solid (2.8 g, 99%).
45
To a slUJTYofNaH (0.63 g, 26.1 mmol) in DMF (20 mL)
was added a solution of methyl 5-hydroxynicotinate (2.0 g,
13.l mmol) in DMF (10 mL). The resulting mixture was
added to a solution of 4-fluoronitrobenzene (1.4 mL, 13.1
mmol) in DMF (IO mL) and the resulting mixture was so
heated at 70° C. overnight, cooled to room temp., and treated
with MeOH (5 mL) followed by water (50 mL). The
resulting mixture was extracted with EtOAc (100 mL). The
residue was purified by column chromatography (30% 55 Step 2. Synthesis of
EtOAc/70% hexane) to afford 4-(3-(5-methoxycarbonyl) 4-(3-(N-methylsulfamoyl)phenyloxy)benz.ene
To a slUJTYof phenol (1.9 g, 20 mmol), K2CO3 (6.0 g, 40
mmol), and Cul (4 g, 20 mmol) in DMF (25 mL) was added
60 N-methyl-3-bromobenz.enesulfonamide (2.5 g, to mmol),
and the resulting mixture was stirred at the reflux temp.
overnight, cooled to room temp., and separated between
EtOAc (50 mL) and a I N HCI solution (50 mL). The
65 The combined organic phases were sequentially washed
with water (2x50 mL) and a saturated NaCl solution (50
mL), dried (MgS0 4), and concentrated under reduced pres-
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sure. The residual oil was purified by column chromatog- 3.89 mmol) in a mixture of EtOH (10 mL) and pyridine (1.0
raphy (30% EtOAc/70% hexane) to give 4-(3-(N-methyl- mL) was added O-methylhydroxylamine HCl salt (0.65 g,
sulfamoyl)phenyloxy)benz.ene (0.30 g). 7.78 mmol, 2.0 equiv.). The resulting solution was heated at
the reflux temperature for 30 min, cooled to room tempera-
s ture and concentrated under reduced pressure. The resulting
solids were triturated with water (10 mL) and washed with
water to give 4-(4-(1-(N-methoxy)iminoethyl)phenoxya-
niline HCI salt as a yellow solid (0.85 g): TLC (50%
10 EtOAc/50"/opet. ether) R_r0.78; 1H NMR (DMSO-d6 ) b 3.90
(s, 3H), 5.70 (s, 3H); HPLC-MS m/z 257 ((M+Hr).
Al 7. Synthesis of N-(c.o-Silyloxyalkyl)amides
4-(3-(N-methylsulfamoyl)phenyloxy)-l-nitrobenzene 15 Synthesis of 4-(4-(2-(N-(2-Triisopropylsilyloxy)
To a solution of 4-(3-(N-methylsulfamoyl)phenyloxy) ethylcarbamoyl)pyridyloxyaniline
benzene (0.30 g, 1.14 mmol) in TFA (6 mL) at-10" C. was
added NaNO2 (0.097 g, 1.14 mmol) in portions over 5 min.
The resulting solution was stirred at -10° C. for 1 h, then 20
was allowed to warm to room temp., and was concentrated
under reduced pressure. The residue was separated between
sequentially washed with water (10 mL) and a saturated
NaCl solution (10 mL), dried (MgSO4 ) and concentrated 25
under reduced pressure to give 4-(3-(N-methylsulfamoyl)
phenyloxy)-1-nitrobenz.ene (0.20 g). This material carried
Step 1. 4-Chloro-N-(2-triisopropylsilyloxy)ethylpy-
30
ridine-2-carboxamide
To a solution of 4-chloro-N-(2-hydroxyethyl)pyridine-2-
carboxamide (prepared in a manner analogous to Method
35 A2, Step 3b; 1.5 g, 7.4 mmol) inanhDMF (7 mL) was added
triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv.) and
imidazole (1.12 g, 16.4 mmol, 2.2 equiv.). The resulting
Step 4. Synthesis of yellow solution was stirred for 3 h at room temp, then was
4-(3-(N-methylsulfamoyl)phenyloxy)aniline concentrated under reduced pressure. The residue was sepa-
40
A slurry of 4-(3-(N-methylsulfamoyl)phenyloxy)-l-ni- aqueous layer was extracted with EtOAc (3xl0 mL). The
trobenzene (0.30 g) and 10% Pd/C (0.030 g) in EtOAc (20 combined organic phases were dried (MgSO4), and concen-
mL) was stirred under an H2 atmosphere (balloon) over- trated under reduced pressure to afford 4<hloro-2-(N-(2-
night. The resulting mixture was filtered through a pad of
45 triisopropylsilyloxy)ethyl)pyridinecarboxamide as an
Celite®. The filtrate was concentrated under reduced pres- orange oil (2.32 g, 88%). This material was used in the next
sure. The residue was purified by column chromatography step without further purification.
(30% EtOAc/70% hexane) to give 4-(3-(N-methylsulfa-
moyl)phenyloxy)aniline (0.o70 g).
Al 6. Modification of c.o-Ketones
Synthesis of
4-(4-(1-(N-methoxy)iminoethyl)phenoxyaniline HCI
salt
Step 2. 4-(4-(2-(N-(2-Triisopropylsilyloxy)ethylcar-
bamoyl)pyridyloxyaniline
60

To a slurry of 4-(4-acetylphenoxy)aniline HCl salt (pre- solution of 4<hloro-2-(N-(2-triisopropylsilyloxy)ethyl)py-
pared in a manner analogous to Method Al 3, step 4; 1.0 g, ridinecarboxamide (2.32 g, 6 mmol, l equiv.) in DMF (4
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mL) was added followed by K2CO3 (0.42 g, 3.0 mmol, 0.50 mL), then heated at the reflux temperature for 3 h, cooled to
equiv.). The resulting mixture was heated at 80° C. over- room temperature and concentrated under reduced pressure.
night. An additional portion of potassium tert-butoxide (0.34 The residue was separated between EtOAc (50 mL) and a 1
N NaOH solution (50 mL). The aqueous layer was extracted
stirred at 80° C. an additional 4 h. The mixture was cooled 5
to 0° C. with an ice/water bath, then water (approx. 1 mL) with EtOAc (2x50 mL). The combined organic layers were
was slowly added dropwise. The organic layer was extracted sequentially washed with water (2x50 mL) and a saturated
with EtOAc (3xl0 mL). The combined organic layers were NaCl solution (50 mL), dried (MgSO4) and concentrated
washed with a saturated NaCl solution (20 mL), dried under reduced pressure. The residue was purified by column
(MgSO4) and concentrated under reduced pressure. The 10
chromatography (SiO2; 50%, EtOAc/50%, hexane) to afford
brown oily residue was purified by column chromatography
(SiO2 ; 30% EtOAc/70%, pet ether) to afford 4-(4-(2-(N-(2- 4-(5-(2-methoxycarbonyl)pyridyloxy)- l-nitrobenz.ene (0.70
triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline as a g).
clear light brown oil (0.99 g, 38%).
15
Al 8. Synthesis of 2-Pryidinecarboxylate Esters via
Oxidation of 2-Methylpyridines
Synthesis of
4-(5-(2-methoxycarbonyl)pyridyloxy)aniline 20
25
4-(5-(2-Methoxycarbonyl)pyridyloxy)aniline
A slurry of 4-(5-(2-methoxycarbonyl)pyridyloxy)-l-ni-
30 trobenzene (0.50 g) and 10% Pd/C (0.050 g) in a mixture of
Step 1. 4-(5-(2-Methyl)pyridyloxy)-l-nitrobenz.ene EtOAc (20 mL) and MeOH (5 mL) was placed under a H2
atmosphere (balloon) overnight. The resulting mixture was
A mixture of 5-hydroxy-2-methylpyridine (10.0 g, 91.6 filtered through a pad of Celite®, and the filtrate was
mmol), I-fluoro-4-nitrobenzene (9.8 mL, 91.6 mmol, LO 35 concentrated under reduced pressure. The residue was puri-
equiv.), K2CO 3 (25 g, 183 mmol, 2.0 equiv.) in DMF (JOO fied by column chromatography (SiO2 ; 70% EtOAc/30%
mL) was heated at the reflux temperature overnight. The hexane) to give 4-(5-(2-methoxycarbonyl)pyridyloxy)
resulting mixture was cooled to room temperature, treated aniline (0.40 g).
with water (200 mL), and extracted with EtOAc (3xl00
40
mL ). The combined organic layers were sequentially washed
Al 9. Synthesis of w-Sulfonylphenyl Anilines
with water (2xl00 mL) and a saturated NaCl solution ((100
mL), dried (MgSO4) and concentrated under reduced pres- Synthesis of 4-(4-Methylsulfonylphenoxy)aniline
sure to give 4-(5-(2-methyl)pyridyloxy)-l-nitrobenzene as a
brown solid (12.3 g). • 45
50
55 Step I. 4-(4-Methylsulfonylphenoxy)-l-nitrobenz.ene: To
a solution of 4-(4-methylthiophenoxy)-1-nitrobenz.ene (2.0
g, 7.7 mmol) in CH 2 Cl 2 (75 mL) at 0° C. was slowly added
4-( 5-(2-Methoxycarbonyl)pyridyloxy )-1-nitrobenzene
m-CPBA (57-86%, 4.0 g), and the reaction mixture was
A mixture of 4-(5-(2-methyl)pyridyloxy)-1-nitrobenzene 60 stirred at room temperature for 5 h. The reaction mixture was
(1.70 g, 7.39 mmol) and selenium dioxide (2.50 g, 22.2 treated with a IN NaOH solution (25 mL). The organic layer
mmol, 3.0 equiv.) in pyridine (20 mL) was heated at the was sequentially washed with a IN NaOH solution (25 mL),
reflux temperature for 5 h, then cooled to room temperature. water (25 mL) and a saturated NaCl solution (25 mL), dried
The resulting slurry was filtered, then concentrated under 65
(MgSO4), and concentrated under reduced pressure to give
reduced pressure. The residue was dissolved in MeOH (100 4-(4-methylsulfonylphenoxy)-1-nitrobenzene as a solid (2.1
mL). The solution was treated with a cone HCI solution (7 g).
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Step 2. 4-(4-Metbylsulfonylphenoxy)-l-aniline: 4-(4-Me- C. Methods of Urea Formation
thylsulfonylphenoxy)-l-nitrobenzene was reduced to the
aniline in a manner analogous to that described in Method Cla. General Method for the Synthesis of Ureas by
Al8. step 3. Reaction of an Isocyanate with an Aniline
Synthesis of N-(4-Chloro-3-(trifluoromethyl)phe-
B. Synthesis of Urea Precursors nyl}-N'-(4-(2-(N-methylcarbamoyl}-4-pyridyloxy)
phenyl)Urea
Bl. General Method for the Synthesis of
lsocyanates from Anilines Using CDI 10
Synthesis of 4-Bromo-3-(trifluoromethyl)phenyl • ~ 0
Isocyanate
15 Cl~ 0 ~o~NHMe
UNAN~ H H
~!
A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyan-
20
ate (14.60 g, 65.90 mmol) in CH2 Cl2 (35 m.L) was added
dropwise to a suspension of 4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)aniline (MethodA2, Step 4; 16.0 g, 65.77 mmol)
in CH 2 Cl2 (35 mL) at 0° C. The resulting mixture was stirred
at room temp. for 22 h. The resulting yellow solids were
25
removed by filtration, then washed with CH2Cl2 (2x30 mL)
and dried under reduced pressure (approximately I mmHg)
Step l. Synthesis of to afford N-(4-chloro-3-(trifluorometbyl)phenyl)-N'-(4-(2-
4-bromo-3-(trinfluoromethyl)aniline HCI salt (N-methylcarbamoyl)-4-pyridy loxy)phenyl)urea as an off-
white solid (28.5 g, 93%): mp 207-209° C.; 1 H-NMR
3
o (DMSO-d 6) 6 2.77 (d, J=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d,
To a solution of 4-bromo-3-(trifluoromethyl)aniline (64 g, 1=2.5Hz., IH), 7.62 (m, 4H), 8.11 (d, 1=2.5Hz, IH), 8.49 (d,
267 mmol) in E'2O (500 mL) was added an HCI solution (I 1=5.5 Hz, IH), 8.77 (hr d, IH), 8.99 (s, IH), 9.21 (s, HI);
Min Et2O; 300 mL) dropwise and the resulting mixture was HPLC ES-MS m/z 465 ((M+Ht).
stirred at room temp. for 16 h. The resulting pink-white 35
precipitate was removed by filtration and washed with Et2O Clb. General Method for the Synthesis of Ureas by
(50 mL) and to afford 4-bromo-3-(trifluoromethyl)aniline Reaction of an Isocyanate with an Aniline
HCl salt (73 g, 98%).
Synthesis of N-(4-Bromo-3-(trifluoromethyl)phe-
40
nyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)
phenyl)Urea
~ ~ 0
Br~ 0 ~O~NHMe
UNAN~ H H
~t
50
Step 2. Synthesis of A solution of 4-bromo-3-(trifluoromethyl)phenyl isocy-

4-bromo-3-(trifluoromethyl)phenyl isocyanate anate (Method Bl, Step 2; 8.0 g, 30.1 mmol) in CH2 Cl2 (80
mL) was added dropwise to a solution of 4-(2-(N-methyl-
A suspension of 4-bromo-3-(trifluorometbyl)aniline HCI 55 carbamoyl)-4-pyridyloxy)aniline (Method A2, Step 4; 7.0 g,
salt (36.8 g, 133 mmol) in toluene (278 mL) was treated with 28.8 mmol) in CH2 CJ2 (40 mL) at 00 C. The resulting
trichloromethyl chloroformate dropwise and the resulting mixture was stirred at room temp. for 16 h. The resulting
mixture was heated at the reflux temp. for 18 h. The resulting yellow solids were removed by filtration, then washed with
mixture was concentrated under reduced pressure. The resi- CH 2Cl 2 (2x50 mL) and dried under reduced pressure (ap-
due was treated with toluene (500 mL), then concentrated 60 proximately 1 mmHg) at 400 C. to afford N-{4-bromo-3-
(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-
under reduced pressure. The residue was treated with
pyridyloxy)phenyl)urea as a pale-yellow solid (13.2 g,
CH2 Cl2 (500 mL), then concentrated under reduced pres- 90%): mp 203-205° C.; 'H-NMR (DMSO-d6 ) 6 2.77 (d,
sure. The CH 2 Cl2 treatment/concentration protocol was J=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, 1=2.5 Hz, IH), 7.58
repeated and resulting amber oil was stored at -20° C. for 16 65 (m, 3H), 7.77 (cl,J=8.8 Hz, lH), 8.11 (d, 1=2.5Hz, 1H), 8.49
h, to afford 4-bromo-3-(trifluoromethyl)phenyl isocyanate (d, 1=5 Hz, IH), 8.77 (hr d, lH), 8.99 (s, lH), 9.21 {s, lH);
as a tan solid (35.l g, 86%): GC-MS m/z 265 (M+). HPLC ES-MS m/z 509 ((M+H)-).
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Cle. General Method for the Synthesis of Ureas by Cle. General Method for the Synthesis of Ureas by
Reaction of an Isocyanate with an Aniline Reaction of an Isocyanate with an Aniline
Synthesis of N-(4-Chloro-3-(trifluoromethyl)phe- Synthesis of N-(4-Chloro-3-(trifluoromethyl)phe-

nyl)-N'-(4-ethoxycarbonylphenyl)Urea
ny 1)-N'-(2-methyl-4-(2-(N-methylcarbamoyl)(4-
pyridyloxy))phenyl)Urea
10
To a solution of ethyl 4-isocyanatohenzoate (3.14 g, 16.4
~=;H:~:·c~;e!f 1
mmol) in CH2 Cl2 (30 mL) was added 4-chloro-3-(trifluo-
romethyl)aniline (3.21 g, 16.4 mmol), and the solution was
A solution of 2-methyl-4-(2-(N-methylcarbamoyl)(4-py-
ridyloxy))aniline (MethodA5; 0.11 g, 0.45 mmol) in CH2CJ2
20
:i; 0
~J11~t= ~:~;~~N~:~
chloro-3-(trifluoromethyl)phenyl)-N'-(4-ethoxycarbon-
(1 mL) was treated with Et3 N (0.16 mL) and 4-chloro-3-
(trifluoromethyl)phenyl isocyanate (0.10 g, 0.45 mrnol). The ylphenyl)urea as a white solid (5.93 g, 97%): TLC (40%
resulting brown solution was stirred at room temp. for 6 d, EtOAc/60% hexane) Rf0.44.
then was treated with water (5 mL). The aqueous layer was 25 Clf. General Method for the Synthesis of Ureas by
back-extracted with EtOAc (3x5 mL). The combined Reaction of an Isocyanate with an Aniline
organic layers were dried (MgSO4 ) and concentrated under
reduced pressure to yield N-(4-chloro-3-(trifluoromethyl) Synthesis of N-(4-Chloro-3-(trifluoromethyl)phe-
phenyl)-N'-(2-methyl-4-(2-(N-methylcarbamoylX4-pyridy- nyl)-N'-(3-carboxyphenyl)Urea
30
loxy))phenyl)urea as a brown oil (0.11 g, 0.22 mmol): 1 H
NMR (DMSO-d6 ) 6 2.27 (s, 3H), 2.77 (d, 1=4.8 Hz, 3H),
7.03 (dd, 1=8.5, 2.6 Hz, IH), 7.11 (d, 1=2.9 Hz, lH), 7.15
(dd, 1=5.5, 2.6, Hz, IH), 7.38 (d, 1=2.6 Hz, IH), 7.62 (app
d, 1=2.6 Hz, 2H), 7.84 (d, J=8.8 Hz, IH), 8.12 (s, lH), 8.17 35
(s, lH); 8.50 (d, 1=5.5Hz, lH), 8.78 (q, J=5.2, lH), 9.52 (s,
lH); HPLC ES-MS m/z 479 ((M+Ht).
Cid. General Method for the Synthesis of Ureas by To a solution of 4-chloro-3-(trifluoromethyl)phenyl iso-
40 cyanate (1.21 g, 5.46 mmol) in CH2 Cl2 (8 mL) was added
Reaction of an Isocyanate with an Aniline 4-(3-carboxyphenoxy)aniline (Method All; 0.81 g, 5.76
mmol) and the resulting mixture was stirred at room temp.
Synthesis of N-( 4-Chloro-3-(trifluoromethyl)phe- overnight, then treated with MeOH (8 mL), and stirred an
nyl)-N'-(4-aminophenyl)Urea additional 2 h. The resulting mixture was concentrated under
45 reduced pressure. The resulting brown solids were triturated
with a I: 1 EtOAc/hexane solution to give N-(4-chloro-3-
(trifluoromethyl)phenyl)-N'-(3-carboxyphenyl)urea as an
off-white solid (1.21 g, 76%).
C2a. General Method for Urea Synthesis by
50 Reaction of an Aniline with N,N'-Carbonyl
Diiniidazole Followed by Addition of a Second
Aniline
Synthesis of N-(2-Methoxy-5-(trifluoromethyl)phe-
55 nyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)
To a solution of 4-chloro-3-(trifluoromethyl)phenyl iso- phenyl)Urea
cyanate (2.27 g, 103 mmol) in CH2 Cl2 (308 mL) was added
00
with CH 2 0 2 (100 mL), and concentrated under reduced
pressure. The resulting pink solids were dissolved in a
mixture ofEtOAc (ll0 mL) and MeOH (15 mL), and the
clear solution was washed with a 0.05 N HCI solution. The
organic layer was concentrated under reduced pressure to 65
afford impure N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-
(4-aminophenyl)urea (3.3 g): TLC (100% EtOAc) Rf0.72.
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To a solution of 2-methoxy-5-(triftuoromethyl)aniline C2c. General Method for the Synthesis of Ureas by
(0.15 g) in anh CH2 Cl2 (15 mL) at 0° C. was added CDI Reaction of an Isocyanate with an Aniline
(0.13 g). The resulting solution was allowed to wann to
room temp. over I h, was stirred at room temp. for 16 h, then Synthesis of N-(2-Methoxy-5-(triftuoromethyl)phe-
was treated with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy) 5
nyl-N'-(4-(1,3-0ioxoisoindolin-5-yloxy)phenyl)Urea
aniline (0.18 g). The resulting yellow solution was stirred at
The resulting aqueous mixture was extracted with EtOAc
(2xl50 mL). The combined organics were washed with a
saturated NaCl solution (100 mL), dried (MgSO4) and 10
rated (90% EtOAc/10% hexane). The resulting white solids
were collected bv filtration and washed with EtOAc. The
filtrate was conc"entrated under reduced pressure and the
residual oil purified by column chromatography (gradient 15
from 33% EtOAc/67% hexane to 50% EtOAc/50% hexane
to 100% EtOAc) to give N-(2-methoxy-5-(triftuoromethyl)
phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phe-
nyl)urea as a light tan solid (0.098 g, 30%): TLC (100%
EtOAc) Rf0.62; 1H NMR (DMSO-d6) Ii 2.76 (d, J=4.8 Hz, 20 To a stirring solution of 2-methoxy-5-(trifluoromethyl)
3H), 3.96 (s, 3H), 7.1-7.6 and 8.4-8.6 (m, lH), 8.75 (d, J=4.8 phenyl isocyanate (0.10 g, 0.47 mmol) in CH2 Cl 2 (1.5 mL)
Hz, lH), 9.55 (s, lH); FAB-MS m/z 461 ((M+H)•). was added 5-(4-aminophenoxy)isoindoline-l,3-0ione
(MethodA3, Step 3; 0.12 g, 0.47 mmol) in one portion. The
resulting mixture was stirred for 12 h, then was treated with
C2b. General Method for Urea Synthesis by 25 CH2 Cl2 (10 mL) and MeOH (5 mL). The resulting mixture
Reaction of an Aniline with N,N'-Crubonyl was sequentially washed with a l N HCJ solution (15 mL)
Diimidazole Followed by Addition of a Second and a saturated NaCl solution (15 mL), dried (MgSO4) and
Aniline concentrated under reduced pressure to afford N-(2-meth-
oxy-5-(trifluoromethyl)phenyl-N'-(4-(1,3-dioxoisoindolin-
Symmetrical Urea's as Side Products of a 30 5-yloxy)phenyl)urea as a white solid (0.2 g, 96%): TLC
N,N'-Crubonyl Diimidazole Reaction Procedure (70% EtOAc/30% hexane) Iy0.50; 'H NMR (DMSO~) Ii
3.95 (s, 3H), 7.31-7.lO(m, 6H), 7.57 (d,J=9.3 Hz, 2H), 7.80
Synthesis of Bis(4-(2-(N-methylcarbamoyl)-4-py- (d, J=8.7 Hz, IH), 8.53 (br s, 2H), 9.57 (s, lH), 11.27 (br s,
ridyloxy)phenyl)Urea lH); HPLC ES-MS 472.0 ((M+H)+, 100%).
To a stunng solution of 3-amino-2-methoxyquinoline C2d. General Method for Urea Synthesis by

(0. l 4 g) in anhydrous CH2 CI2 ( 15 mL) at O C was added CDI Reaction of an Aniline with N,N'-Carbonyl
(0. 13 g). The resulting solution was allowed to warm to Diimidazole Followed by Addition of a Second
50 Aniline
room temp. over 1 h then was stirred at room temp. for 16
h. The resulting mixture was treated with 4-(2-(N-methyl- Synthesis of N-(5-(tert-Butyl)-2-(2,5-dimethylpyrro-
carbamoyl)-4-pyridyloxy)aniline (0.18 g). The resulting yel- lyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridy-
low solution stirred at room temp. for 72 h, then was treated loxy)phenyl)Urea
55
with water (125 mL). The resulting aqueous mixture was
phases were washed with a saturated NaCl solution (100
ml), dried (MgSO4 ) and concentrated under reduced pres-
sure. The residue was triturated (900/oEtOAc/10% hexane). 60
The resulting white solids were collected by filtration and
washed with EtOAc to give bis(4-(2-(N-methylcarbamoyl)-
4-pyridyloxy)phenyl)urea (0.081 g, 44%): TLC (100%
EtOAc) Iy0.50; 'H NMR (DMSO-dJ Ii 2.76 (d, 1=5.1 Hz, 65
6H), 7.1-7.6 (m, 12H), 8.48 (cl,J=5.4 Hz, lH), 8.75 (cl,J=4.8
Hz, 2H), 8.86 (s, 2H); HPLC ES-MS m/z 513 ((M+Hr).
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To a stirring solution of CDI (0.21 g, 1.30 mmol) in room temp. The resulting mixture was diluted with water
CH Cl 2 (2 mL) was added 5-(tert-butyl}-2-(2,5-dimethylpyr- (100 mL), then was made basic with a saturated NaHCO3
rolyl)aniline (Method A4, Step 2; 0.30 g, 1.24 mmol) in one solution (2-3 mL). The basic solution was extracted with
portion. The resulting mixture was stirred at room temp. for EtOAc (2x250 mL). The organic layers were separately
4 h, then 4-(2-(N-methylcarbamoyl}-4-pyridyloxy)aniline 5 washed with a saturated NaCl solution, combined, dried
(0.065 g, 0.267 mmol) was then added in one portion. The (MgSO4 ), and concentrated under reduced pressure. The
resulting mixture was heated at 36° C. overnight, then resulting pink-brown residue was dissolved in MeOH and
cooled to room temp. and diluted with EtOAc (5 mL). The absorbed onto SiO2 (100 g). Column chromatography (300
resulting mixture was sequentially washed with water (15 g SiO2 ; gradient from 1% Et3 N/33% EtOAc/66% hexane to
mL) and a IN HCI solution (15 mL), dried (MgSO4 ), and 1% Et3 N/99% EtOAc to 1% Et3 N/20% MeOH/79% EtOAc)
10
filtered through a pad of silica gel (50 g) to afford N-(5- followed by concentration under reduced pressure at 45° C.
(tert-butyl}-2-(2,5-dimethylpyrrolyl)phenyl}-N-(4-(2-(N- gave a warm concentrated EtOAc solution, which was
methylcarbamoyl}-4-pyridyloxy)phenyl)urea as a yellowish treated with hexane (10 mL) to slowly form crystals of
solid (0.033 g, 24%): TLC (40"/o EtOAc/60% hexane) R1 N-(2-methoxy-5-(trifluoromethyl)phenyl}-N'-(4-(2-(N-me-
0.24; 1 H NMR(aceton~) a 1.37 (s, 9H), 1.89 (s, 6H), 2.89 thylcarbamoyl)-4-pyridyloxy)phenyl)urea (0.44 g): TLC
(d, J=4.8 Hz, 3H), 5.83 (s, 2H), 6.87-7.20 (m, 6H), 7.17 (dd, 15 (1% Et3 N/99% EtOAc) ~0.40.
lH), 7.51-7.58 (m, 3H), 8.43 (d, J=5.4 Hz, lH), 8.57 (d,
J=2.l Hz, IH), 8.80 (br s, IH); HPLC ES-MS 512 ((M+H)"., D. Interconversion of Ureas
100"/o).
Dia. Conversion of w-Aruinophenyl Ureas into
C3. Combinatorial Method for the Synthesis of 20 w-Arylamino)phenyl Ureas
Diphenyl Ureas Using Triphosgene
Synthesis of N-(4-Chloro-3-((trifluorornethyl)phe-
One of the anilines to be coupled was dissolved in nyl)-N'-(4-(3-methoxycarbonylphenyl)carboxyami-
dichloroethane (0.10 M). This solution was added to a 8 mL nopheoyl)Urea
vial (0.5 mL) containing dichloroethane (1 mL). To this was 25
equiv.). The vial was capped and heated at 80° C. for 5 h, CF3 (')
then allowed to cool to room temp for approximately 10 h. 30
The second aniline was added (0.10 M in dichloroethane, 0.5 CID- O o¾~OMe
mL, 1.0 equiv.), followed by diisopropylethylamine (0.35 M l#)l~IN o o
in dichloroethane, 0.2 mL, 1.2 equiv.). The resulting mixture N
H H
was heated at 80° C. for 4 h, cooled to room temperature and
treated with MeOH (0.5 mL). The resulting mixture was 35
concentrated under reduced pressure and the products were To a solution ofN-(4-chloro-3-((trifluoromethyl)phenyl)-
purified by reverse phase HPLC. N'-(4-aminopheoyl)urea (Method Cid; 0.050 g, 1.52 mmol),
mono-methyl isophthalate (0.25 g, 1.38 mmol), HOBT-H2 O
C4. General Method for Urea Synthesis by (0.41 g, 3.03 mmol) and N-methylmorpholine (0.33 mL,
Reaction of an Aniline with Phosgene Followed by 3.03 mmol) in DMF (8 mL) was added EDCI.HCI (0.29 g,
40 1.52 mmol). The resulting mixture was stirred at room temp.
Addition of a Second Aniline
overnight, diluted with EtOAc (25 mL) and sequentially
Synthesis of N-(2-Methoxy-5-(trifiuoromethyl)phe- washed with water (25 mL) and a saturated NaHCO3
nyl)-N'-(4-(2-(N-methylcarbamoyl}-4-pyridyloxy) solution (25 mL). The organic layer was dried (Na2 SO4 ) and
phenyl)Urea 45 were triturated with an EtOAc solution (80% EtOAc/20%
hexane) to give N-(4-chloro-3-((trifluoromethyl)pheoyl)-N'-
(4-(3-methoxycarbonylphenyl)carboxyaminophenyl)urea
(0.27 g, 43%): mp 121-122; TLC (80"/oEtOAc/20"/ohexane)
A
~0.75.
Yu)lu.A,,)
~yvl-,'"
O
l_,,,!
Dlb. Conversion of w-Carboxyphenyl Ureas into
Synthesis of N-(4-Chloro-3-((trifluoromethyl)phe-
OMc 55 nyl)-N'-(4-(3-methylcarbamoylphenyl)carbam-
oylpheoyl)Urea
To a stirring solution of phosgene (1.9 M in toluene; 2.07
mL 0.21 g, 1.30 mmol) in CH2 CI2 (20 mL) at 00 C. was
added anh pyridine (0.32 mL) followed by 2-methoxy-5-
(trifluoromethyl)aniline (0.75 g). The yellow solution was 60
(N-methylcarbamoyl}-4-pyridyloxy)aniline (prepared as 65 To a solution ofN-(4-chloro-3-((trifluoromethyl)pheoyl)-
described in Method A2; 0.30 g) and the resulting suspen- N'-(4-(3-methylcarbamoylpheoyI) carboxyaminophenyl)
sion was heated at 800 C. for 20 h, then allowed to cool to urea (0.14 g, 0.48 mmol), 3-methylcarbarnoylaniline (0.080
IITRUE COPY!I
US 7,351,834 Bl
41 42
g, 0.53 mmol), HOBT-H2O (0.14 g, 1.07 mmol), and N-me- (0.17 g, 0.34 mmol) was added methylamine (2 M in THF;
thylmorpboline (0.5 mL, 1.07 mmol) in DMF (3 mL) at 0° I mL, 1.7 mmol) and the resulting mixture was stirred at
C. was added EDCJ.HCl (0.10 g, 0.53 mmol). The resulting room temp. overnight, then concentrated under reduced
mixture was allowed to warm to room temp. and was stirred pressure to give N-( 4-chloro-3-((trifiuoromethyl)phenyl)-
overnight. The resulting mixture was treated with water (10 s N'-(4-(3-methylcarbamoylphenyl)carboxyaminophenyl)
mL), and extracted with EtOAc (25 mL). The organic phase urea as a white solid: mp 247; TLC (100"/oEtOAc) R1 0.35.
was concentrated under reduced pressure. The resulting
yellow solids were dissolved in EtOAc (3 mL) then filtered D3. Conversion of ro-Carboalkoxyaryl Ureas into
through a pad of silica gel (I 7 g, gradient from 70% (1)-CarboxyarylUreas
EtOAc/30% hexane to 10% MeOH/90% EtOAc) to give to
N-(4-chloro-3-((trifiuoromethyl)phenyl)-N'-( 4-(3-methyl - Synthesis of N-(4-Chloro-3-((trifluoromethyl)phe-
carbamoylphenyl)carbamoylphenyl)urea as a white solid nyl)-N'-(4-carboxyphenyl)Urea
(0.097 g, 41%): mp 225-229; TLC (100% EtOAc) Rf0.23.
Dlc. Combinatorial Approach to the Conversion of 15

(1)-CarboxyphenylUreas into
(1)-(Arylcarbamoyl)phenylUreas
Synthesis of N-(4-Chloro-3-((trifluoromethyl)pbe-
nyl)-N'-(4-(N-(3-(N-(3-pyridyl)carbamoyt)phenyl) 20
carbamoyl)phenyl)Urea
To a slWT)'ofN-( 4-chloro-3-((trifluoromethyl)phenyl)-N-
(4-ethoxycarbonylphenyl)urea (Method Cle; 5.93 g, 15.3
25
mmol) in MeOH (75 mL) was added an aqueous KOH
was heated at the reflux temp. for 12 b, cooled to room
was diluted with water (50 mL), then treated with a 1 N HCl
30
solution to adjust the pH to 2 to 3. The resulting solids were
A mixture ofN-(4-chloro-3-((lrifiuoromethyl)pbenyl)-N'- collected and dried under reduced pressure to give N-(4-
(3-carboxyphenyl)urea (Method Clf; 0.030 g, 0.067 mmol) cbloro-3-((trifluoromethyl)phenyl)-N'-( 4-carboxyphenyl)
and N-cyclohexyl-N'-(methylpolystyrene )carbodiimide (55 urea as a white solid (5.05 g, 92%).
mg) in 1,2-dichloroethane (I mL) was treated with a solution 35
of 3-aminopyridine in CH2 Cl2 (I M; 0.074 rnL, 0.074 D4. General Method for the Conversion of
mmol). (In cases of insolubility or turbidity, a small amount ro-AJkoxy Esters into ro-Alkyl Amides
of DMSO was also added.) The resulting mixrure was heated
at 36° C. overnight. Turbid reactions were then treated with Synthesis of N-(4-Chloro-3-((trifluorometbyl)pbe-
THF (I mL) and beating was continued for 18 h. The nyl)-N'-((4-(3-(5-(2-dimethylaminoethyl)carbamoyl)
40
resulting mixtures were treated with poly(4-(isocyanatom- pyridyl)oxyphenyl)Urea
ethyl)styrene) (0.040 g) and the resulting mixture was stirred
at 36° C. for 72 h, then cooled to room temp. and filtered.
The resulting solution was filtered through a plug of silica
gel (I g). Concentration under reduced pressure afforded CF3 0
45
N-(4-chloro-3-((lrifluoromethyl)pbenyl)-N'-( 4-(N-(3-(N-(3- 0
pyridyl)carba.moyl)phenyl)carbamoyl)phenyl)urea (0.024 g, ~ 0
('Yo~oH
59%): TLC (70"/oEtOAc/30"/ohexane) Rf0.12.
02. Conversion of ro-Carboalkoxyaryl Ureas into

UNANA/ H H
lNJ
50
ro-Carbamoylaryl Ureas
Synthesis of N-(4-Chloro-3-((trifluoromethyl)phe- Step 1. Synthesis of N-( 4-Chloro-3-(trifluorom•

nyl)-N'-(4-(3-methylcarbamoylphenyl)carboxyami- ethyl)pbenyl)-N'-((4-(3-( 5-carboxypyridyl)oxypbe-
nopbenyl)Urea 55 nyl)Urea
N-(4-Chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-
CF3 ~ from 4-chloro-3-(trifluoromethyl)phenyl isocyanate and
60 4-(3-(5-methoxycarbonylpyridyl)oxyaniline (Method Al4,
Cl'Cl O Dij~NHMc Step 2) in a manner analogous to Method Cla. A suspension
I# )l ~I a a of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5•
u ~
methoxycarbonylpyridyl)oxyphenyl)urea (0.26 g, 0.56
mmol) in MeOH (10 mL) was treated with a solution of
65 KOH (0.14 g, 2.5 mmol) in water (1 mL) and was stirred at
To a sample of N-(4-chloro-3-((trifluoromethyl)pbenyl)- room temp. for I h. The resuhing mixture was adjusted to
N'-(4-(3-carbomethoxyphenyl) carboxyaminophenyl)urea pH 5 with a I N HCI solution. The resulting precipitate was
IITRUE COPY!I
US 7,351,834 Bl
43 44
removed by filtration and washed with water. The resulting raphy (SiO2 ; gradient from 100% hexane to 40"/o EtOAc/
solids were dissolved in EtOH (10 mL) and the resulting 60% hexane) to give N-(4-chloro-3-((trifluoromethyl)pbe-
solution was concentrated under reduced pressure. The nyl)-N'-(4-(4-(2-(N-(2-bydroxy)etbylcarbamoyl)
EtOH/concentration procedure was repeated twice to give pyridyloxyphe:nyl)ureaas a white solid (0.019 g, 10%).
N-(4-chloro-3-(trifluorometbyl)phenyl)-N'-((4-(3-(5-car- s Listed below are compounds listed in the Tables below
boxypyridyl)oxyphenyl)urea (0.18 g, 71%). which have been synthesized according to the Detailed
~ o I Syntheses of Exemplified Compounds

CID O oo~N.,,,..______,,,N, 10
'- I )l
tl ~
I l ..J
N
H
See Tables for Compound Characterization
Entry I: 4-(3-N-Methylcarbamoylphenoxy)aniline was

prepared according to Method Al3. According to Method
15 C3,3-tert-butylaniline was reacted with bis(trichloromethyl)
Step 2. Synthesis of N-(4-cbloro-3-(trifluoromethyl) carbonate foJlowed by 4-(3-N-Methylcarbamoylphenoxy)
phenyl)-N'-(( 4-(3-(5-(2-dimethylaminoetbyJ)carbam- aniline to afford the urea.
oyl)pyridyl)oxyphenyl)urea Entry 2: 4-Fluoro-1-nitrobenzene and p-bydroxyac-
etophenone were reacted according to Method Al3, Step I
A mixture of N-(4-cbloro-3-(trifluoromethyl)phenyl)-N'- 20 to afford the 4-(4-acetylphenoxy}-l-nitrobenzene. 4-(4-
((4-(3-(5-carboxypyridyl)oxyphenyl)urea (0.050 g, 0.011 Acetylphenoxy}-l-nitrobenzene was reduced according to
mmol), N,N-dimethylethylenediamine (0.22 mg, 0.17 Method Al3, Step 4 to afford 4-(4-acetylphenoxy)aniline.
mmol), HOBT (0.028 g, 0.17 mmol), N-methylmorpholine According to Method C3,3-tert-butylaniline was reacted
(0.035 g, 0.28 mmol), and EOCI.HCI (0.032 g, 0.17 mmol) with bis(trichloromethyl) carbonate foJlowed by 4-(4-
in DMF (2.5 mL) was stirred at room temp. overnight. The 25 acetylphenoxy)aniline to afford the urea.
resulting solution was separated between EtOAc (50 m.L) Entry 3: According to Method C2d, 3-tert-butylaniline
was treated with CDI, foJlowed by 4-(3-N-methylcarbam-
and water (50 m.L). The organic phase was washed with oyl)-4-methoxyphenoxy)aniline, which had been prepared
water (35 mL), dried (MgSO4 ) and concentrated under according to Method AS, to afford the urea.
reduced pressure. The residue was dissolved in a minimal 30 Entry 4: 5-tert-Butyl-2-methoxyaniline was converted to
amount of CH 2 Cl2 (approximately 2 m.L). The resulting 5-tert-butyl-2-methoxyphenyl isocyanate according to
solution was treated with Et2 O dropwise to give N-(4- Method Bl. 4-(3-N-Metbylcarbamoylphenoxy)aniline, pre-
cbloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-(2-dimethy- pared according to Method Al3, was reacted with the
Jaminoethyl)carbamoyl)pyridyl)oxyphenyl)urea as a white isocyanate according to Method Cla to afford the urea.
precipitate (0.48 g, 84%: 1H NMR (DMSO-d6 ) I\ 2.10 s, 35 Entry 5: According to Method C2d, 5-tert-butyl-2-meth-
6H), 3.26 (s, H), 7.03 (d, 2H), 7.52 (d, 2H), 7.60 (m, 3H), oxyaniline was reacted with CDI foJlowed by 4-(3-N-me-
8.05 (s, lH), 8.43 (s, IH), 8.58 (t, JH), 8.69 (s, IH), 8.90 (s, thylcarbamoyl)-4-methoxyphenoxy)aniline, which had been
IH), 9.14 (s, JH); HPLC ES-MS m/z 522 ((M+H)•).
Entry 6: 5-(4-Aruinophenoxy)isoindoline-l,3-dione was
D5. General Method for the Deprotection of 40 prepared according to MethodA3. According to Method 2d,
N-(w-Silyloxyalkyl)amides 5-tert-butyl-2-methoxyaniline was reacted with CDI fol-
lowed by 5-(4-aminophenoxy)isoindoline-l,3-dione to
Synthesis of N-(4-Cbloro-3-((trifluoromethyl)phe- afford the urea.
nyl)-N'-( 4-(4-(2-(N-(2-hydroxy)ethylcarbamoyl) Entry 7: 4-(1-0xoisoindolin-5-yloxy)aniline was synthe-
pyridyloxypbenyl)Urea sized according to Method A 12. According to Method 2d,
To a solution ofN-(4-chloro-3-((trifluoromethyl)phenyl)- 5-tert-butyl-2-methoxyaniline was reacted with CDI fol-

N'-(4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)py- lowed by 4-(1-0xoisoindolin-S-yloxy)aniline to afford the
ridyloxyphenyl)urea (prepared in a manner analogous to (,() urea.
Method Cla; 0.25 g, 0.37 mmol) in anh TIIF (2 mL) was Entry 8: 4-(3-N-Metbylcarbamoylphenoxy)aniline was
tetrabutylammonium fluoride (1.0 M in TIIF; 2 mL). The synthesized according to Method Al3. According to Method
mixture was stirred at room temperature for 5 min, then was C2a, 2-methoxy-5-(trifluorometbyl)aniline was reacted with
treated with water (10 m.L). The aqueous mixture was CDI followed by 4-(3-N-methylcarbamoylphenoxy)aniline
extracted with EtOAc (3xl0 m.L). The combined organic 65 to afford the urea.
layers were dried (MgSO4) and concentrated under reduced Entry 9: 4-Hydroxyacetophenone was reacted with
pressure. The residue was purified by column chromatog- 2<hloro-5-nitropyridine to give 4-(4-acetylphenoxy)-5-ni-
IITRUE COPY!I
US 7,351,834 Bl
45 46
tropyridine according to Method A3, Step 2. According to to Method Bl. 5-(frifluoromethyl)-2-metboxyphenyl isocy-
Method AS, Step 4,4-( 4-acetylphenoxy)-5-nitropyridine was anate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridy-
reduced to 4-( 4-acetylphenoxy)-5-aminopyridine. 2-Meth- loxy)-2-chloroaniline according to Method Cla to afford the
oxy-5-(triftuoromethyl)aniline was converted to 2-methoxy- urea.
5-(trifluoromethyl)phenyl isocyanate according to Method 5 Entry 18: According to Method A2, Step 4,5-amino-2-
Bl. The isocyanate was reacted with 4-(4-acetylphenoxy)- methylpbenol was reacted with 4-chloro-N-methyl-2-pyridi-
5-aminopyridine according to Method Cla to afford the necarboxamide, which had been synthesized according to
urea. Method A2, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-
Entry IO: 4-Fluoro-l-nitrobenzene and p-hydroxyac- pyridyloxy)-4-methylaniline. 5-(f riftuoromethyl)-2-meth-
etophenone were reacted according to Method Al3, Step 1 lO oxyaniline was converted into 5-(trifluoromethyl)-2-meth-
to afford the 4-(4-acetylphenoxy)-l-nitrobenzene. 4-(4- oxyphenyl isocyanate according to Method Bl.
Acetylphenoxy)-1-nitrobenzene was reduced according to 5-(f rifluoromethyl)-2-methoxypbenyl isocyanate was
Method Al3, Step 4 to afford 4-(4-acetylphenoxy)aniline. reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-
According to Method C3,5-(trifluoromethyl)-2-methoxybu- methylaniline according to Method Cla to afford the urea.
tylaniline was reacted with bis(trichloromethyl) carbonate 15 Entry 19: 4-Chloropyridine-2-carbonyl chloride was
followed by 4-(4-acetylphenoxy)aniline to afford the urea. reacted with ethylamine according to Method A2, Step 3b.
Entry 11: 4-Chloro-N-methyl-2-pyridinecarboxamide, The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was
which was synthesized according to Method A2, Step 3a, reacted with 4-aminophenol according to Method A2, Step
was reacted with 3-aminophenol according to Method A2, 4 to give 4-(2-(N-ethylcarbamoyl)-4•pyridyloxy)aniline.
Step 4 using DMAC in place of DMF to give 3-(-2-(N- 20 5-(frifluoromethyl)-2-methoxyaniline was converted into
methylcarbamoyl)-4-pyridyloxy)aniline. According to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according
Method C4,2-methoxy-5-(trifluoromethyl)aniline was to Method Bl. 5-(frifluoromethyl)-2-metboxyphenyl isocy-
reacted with phosgene followed by 3-(-2-(N-methylcarbam- anate was reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridy-
oyl)-4-pyridyloxy)aniline to afford the urea. loxy)aniline according to Method Cla to afford the urea.
Entry 12: 4-Chloropyridine-2-carbonyl chloride HCI salt 25 Entry 20: According to Method A2, Step 4,4-amino-2-
was reacted with ammonia according to Method A2, Step 3b chlorophenol was reacted with 4-chloro-N-methyl-2-pyridi-
to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-py- necarboxamide, which had been synthesized according to
ridinecarboxamide was reacted with 3-aminophenol accord- Method A2, Step 3b, to give 4-(2-(N-methylcarbamoyl)-4-
ing to Method A2, Step 4 using DMAC in place of DMF to pyridyloxy)-3-chloroaniline. 5-(frifluoromethyl)-2-meth-
give 3-(2-carbamoyl-4-pyridyloxy)aniline. According to 30 oxyaniline was converted into 5-(trifluoromethyl)-2-meth-
Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was oxyphenyl isocyanate according to Method Bl.
reacted with phosgene followed by 3-(2-carbamoyl-4-py- 5-(frifluoromethyl)-2-metboxyphenyl isocyanate was
ridyloxy)aniline to afford the urea. reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-
Entry 13: 4-Chloro-N-methyl-2-pyridinecarboxamide chloroaniline according to Method Cla to afford the urea.
was synthesized according to Method A2, Step 3b. 35 Entry 21: 4-(4-Methylthiophenoxy)-l-nitrobenzene was
4-Chloro-N-methyl-2-pyridinecarboxamide was reacted oxidized according to Method Al9, Step I to give 4-(4-
with 4-aminophenol according to Method A2, Step 4 using methylsulfonylphenoxy)-l-nitrobeozeoe. The nitrobenzene
DMAC in place of DMF to give 4-(2-(N-methylcarbamoyl)- was reduced according to Method Al9, Step 2 to give
4-pyridyloxy)aniline. According to Method C2a, 2-meth- 4-(4-methylsulfonylphenoxy )-I -aniline. According to
oxy-5-(triftuoromethyl)aniline was reacted with CDI fol- 40 Method Cla, 5-(trifluoromethyl)-2-methoxyphenyl isocyan-
lowed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline ate was reacted with 4-( 4-methylsulfonylphenoxy)-1-aniline
to afford the urea. to afford the urea.
Entry 14: 4-Chloropyridine-2-carbonyl chloride HCl salt Entry 22: 4-(3-carbamoylphenoxy)-l-nitrobenzene was
was reacted with ammonia according to Method A2, Step 3b reduced to 4-(3-carbamoylphenoxy)aniline according to
to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-py- 45 Method Al 5, Step 4. According to Method Cla, 5-(trifluo-
ridinecarboxamide was reacted with 4-aminophenol accord- romethyl)-2-methoxyphenyl isocyanate was reacted with
ing to Method A2. Step 4 using DMAC in place of DMF to 4-(3-carbamoylpbenoxy)aniline to afford the urea.
give 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Entry 23: 5-(4-Aruinophenoxy)isoindoline-l,3-dione was
Method C4,2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A3. 5-(Trifluoromethyl)-
reacted with phosgene followed by 4-(2-carbamoyl-4-py- 50 2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
ridyloxy)aniline to afford the urea. methoxyphenyl isocyanate acc!)rding to Method Bl. 5-(fri-
Entry 15: According to Method C2d, 5-(trifluorometliyl)- fluoromethyl)-2-methoxyphenyl isocyanate was reacted
2-methoxyaniline was reacted with CDI followed by 4-(3- with 5-(4-aminophenoxy)isoindoline-l ,3-dione according to
N-methylcarbamoyl)-4-methoxyphenoxy)aniline, which Method Cla to afford the urea.
had been prepared according to Method AS, to afford the 55 Entry 24: 4-Chloropyridine-2-carbonyl chloride was
urea. reacted with dimethylamine according to Method A2, Step
Entry 16: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2- 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecar-
methylaniline was synthesized according to Method A5. boxamide was reacted with 4-aminopbenol according to
5-(f rifluoromethyl)-2-methoxyaniline was converted into Method A2, Step 4 to give 4-(2-(N,N-dimethylcarbamoyl)-
5-(trifluoromethyl)-2-methoxyphenyl isocyanate according 60 4-pyridyloxy)aniline. 5-(f rifluorometbyl)-2-methoxyaniline
to Method Bl. The isocyanate was reacted with 4-(2-(N- was converted into 5-(trifluoromethyl)-2-methoxyphenyl
methylcarbamoyl)-4-pyridyloxy)-2-methylaniline accord- isocyanate according to Method Bl. 5-(friftuoromethyl)-2-
ing to Method Cle to afford the urea. methoxyphenyl isocyanate was reacted with 4-(2-(N N-dim-
Entry 17: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2- ethylcarbamoyl)-4-pyridyloxy)aniline according to Method
chloroaniline was synthesized according to Method A6. 65 Cla to afford the urea.
5-(f rifluoromethyl)-2-methoxyaniline was converted into Entry 25: 4-(1-0xoisoindolin-5-yloxy)aniline was syn•
5-(trifluoromethyl)-2-methoxypbenyl isocyanate according thesized according to Method A12. 5-(frifluoromethyl)-2-
IITRUE COPYjl
US 7,351,834 Bl
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methoxyaniline was treated with CDJ, followed by 4-(1- ethyl)-2-methoxyaniline was converted into 5-(trifluorom-
oxoisoindolin-5-yloxy)aniline according to Method C2d to ethyl)-2-methoxyphenyl isocyanate according to Method
afford the urea. Bl. 5-(frifluoromethyl)-2-methoxyphenyl isocyanate was
Entry 26: 4-Hydroxyacetophenone was reacted with reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline
4-fluoronitrobenzene according to Method Al3, Step I to s according to Method CJ a to afford the urea. N-(5-(Trifluo-
give 4-(4-acetylpheooxy)oitrobenzene. The nitrobenzene romethyl)-2-methoxyphenyl)-N'-(4-(3-(5-methoxycarbon-
was reduced according to Method Al3, Step 4 to afford ylpyridyl)oxy)phenyl)urea was saponified according to
4-(4-acetylphenoxy)aniline, which was converted to the Method D4, Step 1, and the corresponding acid was coupled
4-(4-(1-(N-methoxy)iminoethyl)phenoxyaniline HCI salt with methylamine according to Method D4, Step 2 to afford
according to Method Al 6. 5-(Trifluoromethyl)-2-methoxya- 10 the amide.
oiline was converted into 5-(trifluoromethyl)-2-methox- Entry 33: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline
yphenyl isocyanate according to Method Bl. 5-(frifluorom- was synthesized according to Method Al4. 5-(Trifluorom-
ethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4- ethyl)-2-methoxyaniline was converted into 5-(trifluorom-
(l-(N-methoxy)iminoethyl)phenoxyaniline HCI salt to ethyl)-2-methoxyphenyl isocyanate according to Method
Method Cla to afford the urea. 1s Bl. 5-(frifluoromethyl)-2-methoxyphenyl isocyanate was
Entry 27: 4-Chloro-N-methylpyridinecarboxamide was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline
synthesized as described in Method A2, Step 3b. The chJo- according to Method Cla to afford the urea. N-(5-(frifluo-
ropyridine was reacted with 4-aminothiophenol according to romethyl)-2-methoxyphenyl)-N'-(4-(3-(5-methoxycarbon-
Method A2, Step 4 to give 4-(4-(2-(N-methylcarbamoyl) ylpyridyl)oxy)phenyl)urea was saponified according to
phenylthio)aniline. 5-(frifluoromethyl)-2-methoxyaniline 20 Method D4, Step 1, and the corresponding acid was coupled
was converted into 5-(trifluoromethyl)-2-methoxyphenyl with N,N-dimethylethylenediamine according to Method
isocyanate according to Method 81. 5-(Trifluoromethyl)-2- D4, Step 2 to afford the amide.
methoxyphenyl isocyanate was reacted with 4-(4-(2-(N- Entry 34: 4-(3-Carboxyphenoxy)aniline was synthesized
methylcarbamoyl)phenylthio)aniline according to Method according to Method Al 1. 5-(frifluoromethyl)-2-methoxya-
Cla to afford the urea. 25 niline was converted into 5-(trifluoromethyl)-2-methox-
Entry 28: 5-(4-Aminophenoxy)-2-methylisoindoline-l,3- yphenyl isocyanate according to Method 81. 4-(3-Carbox-
dione was synthesized according to Method A9. 5-(Trifluo- yphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-
romethyl)-2-methoxyaniline was converted into 5-(trifluo- methoxyphenyl isocyanate according to Method Clf to
romethyl)-2-methoxyphenyl isocyanate according to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-{3-car-
Method 81. 5-(Trifluoromethyl)-2-methoxyphenyl isocyan- 30 boxyphenyl)urea, which was coupled with 3-aminopyridine
ate was reacted with 5-(4-aminophenoxy)-2-methylisoindo- according to Method DJc.
line-1,3-dione according to Method Cla to afford the urea. Entry 35: 4-(3-Carboxyphenoxy)aniline was synthesized
Entry 29: 4-Chloro-N-methylpyridinecarboxamide was according to Method Al 1. 5-(frifluoromethyl)-2-methoxya-
synthesized as described in Method A2. Step 3b. The chlo- oiline was converted into 5-(trifluoromethyl)-2-methox-
ropyridine was reacted with 3-aminothiophenol according to 3S yphenyl isocyanate according to Method 81. 4-(3-Carbox-
Method A2, Step 4 to give 3-(4-(2-(N-methylcarbamoyl) yphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-
phenylthio)aniline. 5-(frifluoromethyl)-2-methoxyaniline methoxyphenyl isocyanate according to Method Clf to
was converted into 5-(trifluoromethyl)-2-methoxyphenyl afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-car-
isocyanate according to Method Bl. 5-(Trifluoromethyl)-2- boxyphenyl)urea, which was coupled with N-(4-fluorophe-
methoxyphenyl isocyanate was reacted with 3-(4-(2-(N- 40 nyl)piperazine according to Method Die.
methylcarbamoyl)phenylthio)aniline according to Method Entry 36: 4-(3-Carboxyphenoxy)aniline was synthesized
Cla to afford the urea. according to Method All. 5-(frifluoromethyl)-2-methoxya-
Entry 30: 4-Chloropyridine-2-carbonyl chloride was oilioe was converted into 5-(trifluoromethyl)-2-methox-
reacted with isopropylamine according to Method A2, Step yphenyl isocyanate according to Method Bl. 4-(3-Carbox-
3b. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxa- 45 yphenoxy)anilioe was reacted with 5-(trifluoromethyl)-2-
mide was reacted with 4-aminophenol according to Method methoxyphenyl isocyanate according to Method Clf to
A2, Step 4 to give 4-(2-(N-isopropylcarbamoyl)-4-pyridy- afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-car-
loxy)anilioe. 5-(frifluoromethyl)-2-methoxyaniline was boxyphenyl)urea, which was coupled with 4-fluoroaniline
converted into 5-(trifluoromethyl)-2-methoxyphenyl isocy- according to Method Dlc.
anate according to Method Bl. 5-(Trifluoromethyl)-2-meth- 50 Entry 37: 4-(3-Carboxyphenoxy)aniline was synthesized
oxyphenyl isocyanate was reacted with 4-(2-(N-isopropyl- according to Method All. 5-(Trifluoromethyl)-2-methoxya-
carbamoyl)-4-pyridyloxy)anilioe according to Method Cla nilioe was converted into 5-(trifluoromethyl)-2-methox-
to afford the urea. yphenyl isocyanate according to Method 81. 4-(3-Carbox-
Entry 31: 4-(3-(5-Methoxycarlxmyl)pyridyloxy)aniline yphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-
was synthesized according to Method Al 4. 5-(Trifluorom- ss methoxyphenyl isocyanate according to Method Clf to
ethyl)-2-methoxyaniline was converted into 5-(trifluorom- afford N-{5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-car-
ethyl)-2-methoxyphenyl isocyanate according to Method boxyphenyl)urea, which was coupled with 4-(dimethy-
81. 5-(frifluoromethyl)-2-methoxyphenyl isocyanate was Jamino)anilioe according to Method Die.
reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline Entry 38: 4-(3-Carboxyphenoxy)aniline was synthesized
according to Method Cla to afford the urea. N-(5-(f rifluo- 60 according to Method Al 1. 5-(frifluoromethyl)-2-methoxya-
romethyl)-2-methoxyphenyl)-N'-(4-(3-(5-methoxycarbon- oilioe was converted into 5-(trifluoromethy))-2-methox-
ylpyridyl)oxy)phenyl)urea was saponified according to yphenyl isocyanate according to Method 81. 4-(3-Carbox-
Method D4, Step I, and the corresponding acid was coupled yphenoxy)anilioe was reacted with 5-(trifluoromethyl)-2-
with 4-(2-aminoethyl)morpholine to afford the amide methoxyphenyl isocyanate according to Method Clf to
according to Method D4, Step 2. 65 afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-car-
Entry 32: 4-(3-(5-Methoxycarl>onyl)pyridyloxy)aniline boxyphenyl)urea, which was coupled with 5-amino-2-meth-
was synthesized according to Method Al 4. 5-(frifluorom- oxypyridine according to Method Die.
IITRUE COPYII
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49 50
Entry 39: 4-(3-Carboxyphenoxy)aniline was synthesized Entry 49: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-
according to Method Al I. 5-(frifluoromethyl)-2-methoxya- chloroaniline was synthesized according to Method A6.
niline was converted into 5-(trifluoromethyl)-2-methox- According to Method Cla, 4-chloro-3-(trifluoromethyl)phe-
yphenyl isocyanate according to Method Bl. 4-(3-Carbox- nyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-
yphenoxy)aniline was reacted with 5-(trifluoromethyl)-2- 5 4-pyridyloxy)-2-chloroaniline to afford the urea.
methoxyphenyl isocyanate according to Method Clf to Entry 50: According to Method A2, Step 4,5-amino-2-
afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-car- methylphenol was reacted with 4-chloro-N-methyl-2-pyridi-
boxyphenyl)urea, which was coupled with 4-morpholinoa- necarboxamide, which had been synthesized according to
niline according to Method Ole. Method A2, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-
Entry 40: 4-(3-Carboxyphenoxy)aniline was synthesized 10 pyridyloxy)-4-methylaniline. According to Method Cla,
according to Method Al 1. 5-(f rifluoromethyl)-2-methoxya- 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted
niline was converted into 5-(trifluoromethyl)-2-methox- with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methyla-
yphenyl isocyanate according to Method Bl. 4-(3-Carbox- niline to afford the urea.
yphenoxy)aniline was reacted with 5-(trifluoromethyl)-2- Entry 51: 4-Chloropyridine-2-carbonyl chloride was
methoxyphenyl isocyanate according to Method Clf to ts reacted with ethylamine according to Method A2, Step 3b.
afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-car- The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was
boxyphenyl)urea, which was coupled with N-(2-pyridyl) reacted with 4-aminophenol according to Method A2, Step
piperazine according to Method Die. 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline.
Entry 41: 4-(3-(N-Methylcarbamoyl)phenoxy)aniline was According to Method Cla, 4-chloro-3-(trifluoromethyl)phe-
synthesized according to Method A 13.According to Method 20 nyl isocyanate was reacted with 4-(2-(N-ethylcarbamoyl)-
C3,4-chloro-3-(trifluoromethyl)aniline was converted to the 4-pyridyloxy)aniline to afford the urea.
isocyanate, then reacted with 4-(3-(N-Methylcarbamoyl) Entry 52: According to Method A2, Step 4,4-amino-2-
phenoxy)aniline to afford the urea. chlorophenol was reacted with 4-chloro-N-methyl-2-pyridi-
Entry 42: 4-(2-N-Methylcarbamyl-4-pyridyloxy)aniline necarboxamide, which had been synthesized according to
was synthesized according to Method A2. 4-Chloro-3-(trif- 25 Method A2, Step 3b, to give 4-(2-(N-methylcarbamoyl)-4-
luoromethyl)phenyl isocyanate was reacted with 4-(2-N- pyridyloxy)-3-chloroaniline. According to Method Cla,
methylcarbamyl-4-pyridyloxy)aniline according to Method 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted
Cla to afford the urea. with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroa-
Entry 43: 4-Chloropyridine-2-carbonyl chloride HCI salt niline to afford the urea.
was reacted with ammonia according to Method A2, Step 3b 30 Entry 53: 4-(4-Methyllhiophenoxy)-1-nitrobenzene was
to form 4-chloro-2-pyridinecarboxamide. 4-ChJoro-2-py- oxidized according to Method A19, Step 1 to give 4-(4-
ridinecarboxamide was reacted with 4-aminophenol accord- methylsulfonylphenoxy)-l-nitrobenzene. The nitrobenzene
ing to Method A2, Step 4 to form 4-(2-carbamoyl-4-pyridy- was reduced according to Method Al 9, Step 2 to give
loxy)aniline. According to Method Cla, 4-chloro-3- 4-( 4-methylsulfonylphenoxy)-1-aniline. According to
(trifluoromethyl)phenyl isocyanate was reacted with 4-(2- 35 Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate
carbamoyl-4-pyridyloxy)aniline to afford the urea. was reacted with 4-(4-methylsulfonylphenoxy)-1-aniline to
afford the urea.
Entry 54: 4-Bromobenzenesulfonyl chloride was reacted
was reacted with ammonia according to Method A2, Step 3b
withmethylamine according to Method Al 5, Step 1 to afford
to form 4-chloro-2-pyridinecarboxamide. 4-ChJoro-2-py-
40 N-methyl-4-bromobenzenesulfonamide. N-Methyl-4-bro-
ridinecarboxamide was reacted with 3-aminophenol accord-
mobenzenesulfonamide was coupled with phenol according
ing to Method A2, Step 4 to form 3-(2-carbamoyl-4-pyridy-
to Method Al5, Step 2 to afford 4-(4-(N-methylsulfamoyl)
loxy)aniline. According to Method Cla, 4-chloro-3-
phenoxy )benzene. 4-(4-(N-Methylsulfamoyl)phenoxy)ben-
zene was converted into 4-(4-(N-methylsulfamoyl)phe-
45 noxy)-1-nitrobenzene according to Method Al5, Step 3.
Entry 45: 4-Chloro-N-methyl-2-pyridinecarboxamide, 4-(4-(N-Methylsulfamoyl)phenoxy)-1-nitrobenzene was
which was synthesized according to Method A2, Step 3a, reduced to 4-(4-N-methylsulfamoyl)phenyloxy)aniline
was reacted with 3-aminophenol according to Method A2, according to Method A 15, Step 4. According to Method Cla,
Step 4 to form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy) 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted
aniline. According to Method Cla, 4-chloro-3-(trifluorom- with 4-(3-N-methylsulfamoyl)phenyloxy)aniline to afford
50
ethyl)phenyl isocyanate was reacted with 3-(2-(N-methyl-
the urea.
carbamoyl)-4-pyridyloxy)aniline to afford the urea. Entry 55: 5-Hydroxy-2-methylpyridine was coupled with
Entry 46: 5-(4-Aminophenoxy)isoindoline-l,3-dione was 1-fluoro-4-nitrobenzene according to Method A18, Step 1 to
synthesized according to Method A3. According to Method give 4-(5-(2-Methyl)pyridyloxy)-1-nitrobenzene. The meth-
Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was 55 ylpyridine was oxidized according to the carboxylic acid,
reacted with 5-(4-aminophenoxy)isoindoline-1,3-dione to then esrerified according to Method Al8, Step 2 to give
afford the urea. 4-( 5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene. The
Entry 47: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2- nitrobenzene was reduced according the Method Al 8, Step
methylaniline was synthesized according to Method AS. 3 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline. The
According to Method Cle, 4-chloro-3-(trifluoromethyl)phe- 60 aniline was reacted with 4-chloro-3-(trifluoromethyl)phenyl
nyl isocyanate was reacted with 5-(4-aminophenoxy)isoin- isocyanate according to Method Cla to afford the urea.
doline-1,3-dione to afford the urea. Entry 56: 5-Hydroxy-2-methylpyridine was coupled with
Entry 48: 4-(3-N-Methylsulfamoyl)phenyloxy)aniline l-fluoro-4-nitrobenzene according to Method Al 8, Step I to
was synthesized according to Method A15. According to give 4-(5-(2-Methyl)pyridyloxy)-l-nitrobenzene. The meth-
Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate 65 ylpyridine was oxidized according to the carboxylic acid,
was reacted with 4-(3-N-methylsulfamoyl)phenyloxy) then esterified according to Method Al8, Step 2 to give
aniline to afford the urea. 4-(5-(2-methoxycarbonyl)pyridyloxy)- l-nitrobenzene. The
IITRUE COPY!I
US 7,351,834 Bl
51 52
nitrobenzene was reduced according the Method Al 8, Step yphenoxy)-l-nitroben7.ene was coupled with tetrahydrofur-
3 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline. The furylamine according to Method A 13, Step 3 to give 4-(3-
aniline was reacted with 4-chloro-3-(trifluoromethyl)phenyl (N-(tetrahydrofurylmethyl)carbamoyl)pbenoxy)-1-
isocyanate according to MethodCla to give N-(4-chloro- nitrobenzene. According to Method Al3 Step 4,4-(3-(N-
3-(trifluoromethyl)phenyl)-N'-(4-(2-(methoxycarbonyl)-5- 5 (tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-
pyridyloxy)phenyl)urea. The methyl ester was reacted with nitrobenzene was reduced to 4-(3-(N-
methylamine according to Method D2 to afford N-(4-chloro- (tetrahydrofurylmethyl)carbamoyl)pbenoxy)a.niline.
3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)- According to Method Cla, 4-cbloro-3-(trifluoromethyl)pbe-
5-pyridyloxy)phenyl)urea. nyl isocyanate was reacted with 4-(3-(N-(tetrahydrofurylm-
Entry 57: N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4- lO ethyl)carbamoyl)phenoxy)aniline to afford the urea.
aminophenyl)urea was prepared according to Method Cid. Entry 64: 4-(3-Carboxyphenoxy)-l-nitrobenzene was
N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) synthesized according to Method A13, Step 2. 4-(3-Carbox-
urea was coupled with mono-methyl isophthalate according yphenoxy)-l-nitrobenzene was coupled with 2-aminom-
to Method Dia to afford the urea. ethyl-1-ethylpyrrolidine according to MethodA13, Step 3 to
Entry 58: N-(4-Chloro-3-(trifluoromethyl)pbenyl-N'-(4- 15 give 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)
aminopbenyl)urea was prepared according to Method Cid. pbenoxy)-l-nitroben7.ene. According to Method Al3 Step
N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) 4,4-(3-(N-(( l -methylpyrrolidinyl)methyl)carbamoyl)phe-
urea was coupled with mono-methyl isophthalate according noxy)-1-nitrobenzene was reduced to 4-(3-(N-((1-meth-
to Method Dia to afford N-(4-chloro-3-(trifluoromethyl) ylpyrrolidinyl)metbyl)carbamoyl)phenoxy)aniline. Accord-
phenyl-N'-(4-(3-methoxycarbonylpbenyl)carboxyami- 20 ing to Method Cla, 4-chloro-3-(trifluoromethyl)pbenyl
nophenyl)urea. According to Method D2, N-(4-chloro-3- isocyanate was reacted with 4-(3-(N-((l-methylpyrrolidi-
(trifluoromethyl)pbenyl-N'-(4-(3-methoxycarbonylpbenyl) nyl)methyl)carbamoyl)pbenoxy)aniline to afford the urea.
carboxyaminopbenyl)urea was reacted with methylamine to Entry 65: 4-Chloro-N-methylpyridinecarboxamide was
afford the corresponding methyl amide. synthesized as described in Method A2, Step 3b. The chlo-
Entry 59: 4-Chloropyridine-2-carbonyl chloride was 25 ropyridine was reacted with 4-aminothiophenol according to
reacted with dimethylamine according to Method A2, Step Method A2. Step 4 to give 4-(4-(2-(N-methylcarbamoyl)
3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecar- pbenylthio)aniline. According to Method C 1a. 4-chloro-3-
boxamide was reacted with 4-aminophenol according to (trifluoromethyl)phenyl isocyanate was reacted with 4-(4-
Method A2, Step 4 to give 4-(2-(N,N-dimethylcarbamoyl)- (2-(N-methylcarbamoyl)pbenylthio)aniline to afford the
4-pyridyloxy)aniline. According to Method Cla, 4-chloro- 30 urea.
3-(trifluoromethyl)pbenyl isocyanate was reacted with 4-(2- Entry 66: 4-Chloropyridine-2-carbonyl chloride was
(N,N-dimethylcarbamoy 1)-4-pyridyloxy)aniline to afford reacted with isopropylamine according to Method A2, Step
the urea. 3b. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxa-
Entry 60: 4-Hydroxyacetopbenone was reacted with mide was reacted with 4-aminophenol according to Method
4-fluoronitrobenzene according to Method Al3, Step I to 35 A2, Step 4 to give 4-(2-(N-isopropylcarbamoyl)-4-pyridy-
give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene loxy)aniline. According to Method Cla, 4-chloro-3-(trifluo-
was reduced according to Method 13, Step 4 to afford romethyl)phenyl isocyanate was reacted with 4-(2-(N-iso-
4-(4-acetylphenoxy)aniline, which was converted to the propylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
4-(4-(1-(N-metboxy)im.inoethyl)phenoxyaniline HCI salt
Entry 67: N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-
according to Method Al6. According to Method Cla, 40
ethoxycarbonylphenyl)urea was synthesized according to
4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted
Method Cle. N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-
with 4-(4-acetylphenoxy)aniline to afford the urea.
ethoxycarbonylphenyl)urea was saponified according to
Entry 61: 4-(3-Carboxypbenoxy )-1-nitrobenzene was
Method D3 to give N-(4-chloro-3-(trifluoromethyl)phenyl-
synthesized according to Method Al 3, Step 2. 4-(3-Carbox-
N'-(4-carboxyphenyl)urea. N-(4-Chloro-3-(trifluoromethyl)
yphenoxy)-l-nitrobenzene was coupled with 4-(2-aminoet- 45
phenyl-N'-(4-carboxyphenyl)urea was coupled with 3-me-
byl)morpboline according to Method Al3, Step 3 to give
thylcarbamoylaniline according to Method Dlb to give
4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy )-1-ni-
N-(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(3-methylcar-
trobenzene. According to Method Al3 Step 4,4-(3-(N-(2-
bamoylphenyl)carbamoylphenyl)urea.
morpbolinylethyl)carbamoyl)pbenoxy)-1-nitroben7.ene was
reduced to 4-(3-(N-(2-morpholinylethyl)carbamoyl)pbe- 50 Entry 68: 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-
noxy)aniline. According to Method Cla, 4-chloro-3-(trifluo- dione was synthesized according to Method A9. According
romethyl)phenyl isocyanate was reacted with 4-(3-(N-(2- to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocy-
morpholinylethyl)carbamoyl)phenoxy)aniline to afford the anate was reacted with 5-(4-aminophenoxy)-2-methylisoin-
urea. doline-l ,3-dione to afford the urea.
Entry 62: 4-(3-Carboxyphenoxy)-l-nitrobenzene was 55 Entry 69: 4-Chloro-N-methylpyridinecarboxamide was
synthesized according to Method Al3, Step 2. 4-(3-Carbox- synthesized as described in Method A2, Step 3b. The chlo-
yphenoxy)-1-nitrobenzene was coupled with 1-(2-aminoet- ropyridine was reacted with 3-aminothiophenol according to
byl)piperidine according to Method A13, Step 3 to give Method A2, Step 4 to give 3-(4-(2-(N-methylcarbamoyl)
4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)- l -nitroben- phenylthio)aniline. According to Method C 1a, 4-cbloro-3-
zene. According to Method Al3 Step 4,4-(3-(N-(2-pip- 60 (trifluoromethyl)phenyl isocyanate was reacted with 3-(4-
eridylethyl)carbamoyl)phenoxy)- l-nitrobenzene was (2-(N-methylcarbamoyl)phenylthio)aniline to afford the
reduced to 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy) urea.
aniline. According to Method Cla, 4-chloro-3-(trifluorom- Entry 70: 4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl)py-
ethyl)phenyl isocyanate was reacted with 4-(3-(N-(2-pip- ridyloxy)aniline was synthesized according to MethodAIO.
eridylethyl)carbamoyl)phenoxy)aniline to afford the urea. 65 According to Method Cla, 4-chloro-3-(trifluoromethyl)phe-
Entry 63: 4-(3-Carboxyphenoxy)-l-nitrobenzene was nyl isocyanate was reacted with 4-(2-(N-(2-morpholin-4-
synthesized according to Method Al3, Step 2. 4-(3-Carbox- ylethyl)carbamoyl)pyridyloxy)aniline to afford the urea.
IITRUE COPYII
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53 54
Entry 71: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline aniline according to Method CI f to afford the urea, which
was synthesi7.ed according to Method A14. 4-Chloro-3- was coupled with N-phenylethylenediamine according to
(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted Method Die.
with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline accord- Entry 80: 4-(3-Carboxyphenoxy)aniline was synthesized
ing to Method Cla to afford the urea. N-(4-Chloro-3- s according to Method All. 4-Chloro-3-(trifluoromethyl)phe-
(trifluoromethyl)phenyl)-N'-(4-(3-(5-methoxycarbonylpy- nyl isocyanate was reacted with 4-(3-carboxyphenoxy)
ridyl)oxy)phenyl)urea was saponified according to Method aniline according to Method Clf to afford the urea, which
D4, Step I, and the corresponding acid was coupled with was coupled with 2-methoxyethylamine according to
4-(2-aminoethyl)morpholine to afford the amide. Method Ole.
Entry 72: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline 10 Entry 81: 4-(3-Carboxyphenoxy)aniline was synthesized
was synthesized according to Method Al4. 4-Chloro-3- according to Method All. 4-Chloro-3-(trifluoromethyl)phe-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(3- nyl • isocyanate was reacted with 4-(3-carboxyphenoxy)
(5-methoxycarbonyl)pyridyloxy)aniline according to aniline according to Method Clf to afford the urea, which
Method Cla to afford the urea. N-(5-(Trifluoromethyl)-2- was coupled with 5-amino-2-methoxypyridine according to
methoxyphenyl)-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy) 15 Method Dlc.
phenyl)urea was saponified according to Method D4, Step 1, Entry 82: 4-(3-Carboxyphenoxy)aniline was synthesized
and the corresponding acid was coupled with methylamine according to MethodAll. 4-Chloro-3-(trifluoromethyl)phe- .
according to Method 04, Step 2 to afford the amide. nyl isocyanate was reacted with 4-(3-carboxyphenoxy)
was synthesized according to Method Al4. 4-Chloro-3- 20 was coupled with 4-morpholinoaniline according to Method
(trifluoromethyl)phenyl isocyanate was reacted with 4-(3- Ole.
(5-methoxycarbonyl)pyridyloxy)aniline according to Entry 83: 4-(3-Carboxyphenoxy)aniline was synthesized
Method Cla to afford the urea. N-(5-(Trifluoromethyl)-2- according to Method Al 1. 4-Chloro-3-(trifluoromethyl)phe-
methoxyphenyl)-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy) nyl isocyanate was reacted with 4-(3-carboxyphenoxy)
phenyl)urea was saponified according to Method D4, Step 1, 25 aniline according to Method Cl f to afford the urea, which
and the corresponding acid was coupled with N,N-dimeth- was coupled with N-(2-pyridyl)piperazine according to
ylethylenediamine according to Method D4, Step 2 to afford Method Dlc.
the amide.
Entry 74: 4-Chloropyridine-2-carbonyl chloride HCl salt Entry 84: 4-Chloropyridine-2-carbonyl chloride HO salt
was reacted with 2-hydroxyethylamine according to Method 30 was reacted with 2-hydroxyethylamine according to Method
A1., Step 3b to form 4-chloro-N-(2-triisopropylsilyloxy) A1., Step 3b to form 4-chloro-N-(2-triisopropylsilyloxy)
ethylpyridine-2-carboxamide. 4-Chloro-N-(2-triisopropylsi- ethylpyridine-2-carboxamide. 4-Chloro-N-(2-triisopropylsi-
propylsilyl chloride, followed by 4-aminophenol according propylsilyl chloride, followed by 4-aminophenol according
to Method Al 7 to form 4-(4-(2-(N-(2-triisopropylsilyloxy) 35 to Method Al 7 to form 4-(4-(2-(N-(2-triisopropylsilyloxy)
ethylcarbamoyl)pyridyloxyaniline. According to Method ethylcarbamoyl)pyridyloxyaniline. According to Method
Cla 4-chloro-3-(trifluoromethyl)phenyl isocyanate was Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was
reacted with 4-(4-(2-(N-(-2-triisopropylsilyloxy)ethylcar- reacted with 4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcar-
bamoyl)pyridyloxyaniline to afford N-(4-chloro-3-((trifluo- bamoyl)pyridyloxyaniline to give N-(4-chloro-3-((trifluo-
romethyl)phenyl)-N'-(4-(4-(2-(N-(2-triisopropylsilyloxy) 40
romethyl)phenyl)-N'-(4-(4-(2-(N-(2-triisopropylsilyloxy)
ethylcarbamoyl)pyridyloxyphenyl)urea. ethylcarbamoyl)pyridyloxyphenyl)urea. The urea was
Entry 75: 4-(3-Carboxyphenoxy)aniline was synthesized deprotected according to Method 05 to afford N-(4-chloro-
according to Method Al 1. 4-Chloro-3-(trifluoromethyl)phe- 3-((trifluoromethyl)pheny 1)-N'-(4-(4-(2-(N-(2-hydroxy)eth-
ylcarbamoyl)pyridyloxyphenyl)urea.
nyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)
pyridyloxy)aniline according to Method Clf to afford the 45 Entry 85: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)
urea, which was coupled with 3-aminopyridine according to aniline was synthesized according to Method A1.. 4-Bromo-
Method Ole. 3-(trifluoromethyl)aniline was converted to 4-bromo-3-(tri-
Entry 76: 4-(3-Carboxyphenoxy)aniline was synthesized fluoromethyl)phenyl isocyanate according to Method Bl.
according to Method Al 1. 4-Chloro-3-{trifluoromethyl)phe- According to MethodCla, 4-bromo-3-(trifluoromethyl)phe-
nyl isocyanate was reacted with 4-(3-carboxyphenoxy) 50 nyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-
aniline according to Method Clf to afford the urea, which 4-pyridyloxy)aniline to afford the urea.
was coupled with N-(4-acetylphenyl)piperazine according Entry 86: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-
to Method Ole. chloroaniline was synthesized according to Method A6.
Entry 77: 4-(3-Carboxyphenoxy)aniline was synthesized 4-Bromo-3-(trifluoromethyl)aniline was converted into
according to Method Al 1. 4-Chloro-3-{trifluoromethyl)phe- 55 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to
nyl isocyanate was reacted with 4-(3-carboxyphenoxy) Method Bl. According to Method Cla, 4-bromo-3-(trifluo-
aniline according to Method CI f to afford the urea, which romethyl)phenyl isocyanate was reacted with 4-(2-(N-me-
was coupled with 4-fluoroaniline according to Method Ole. thylcarbamoyl)-4-pyridyloxy)-2-chloroaniline to afford the
Entry 78: 4-(3-Carboxyphenoxy)aniline was synthesized urea.
according to MethodAl 1. 4-Chloro-3-(trifluoromethyl)phe- 60 Entry 87: According to MethodA1., Step 4,4-amino-2-
nyl isocyanate was reacted with 4-(3-carboxyphenoxy) chlorophenol was reacted with 4-chloro-N-methyl-2-pyridi-
aniline according to Method Clf to afford the urea, which necarboxamide, which had been synthesized according to
was coupled with 4-(dimethylamino)aniline according to Method A1., Step 3b, to give 4-(2-(N-methylcarbamoyl)-4-
Method Ole. pyridyloxy)-3-chloroaniline. 4-Bromo-3-(trifluoromethyl)
Entry 79: 4-(3-Carboxyphenoxy)aniline was synthesized 65 aniline was_converted into 4-bromo-3-(trifluoromethyl)phe-
according to Method Al 1. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to
nyl isocyanate was reacted with 4-(3-carboxyphenoxy) Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate
IITRUE COPY!I
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55 56
was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)- Method Bl. According to Method Cla, 4-bromo-3-(trifluo-
3-chloroaniline to afford the urea. romethyl)phenyl isocyanate was reacted with 4-(2-(N-(2·
Entry 88: 4-Chloropyridine-2-carbonyl chloride was Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline to
reacted with ethylamine according to Method A2, Step 3b. afford the urea.
The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was 5 Entry 95: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)
reacted with 4-aminophenol according to Method A2, Step aniline was synthesized according to Method A2. 4-Chloro-
4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline. 2-methoxy-5-(trifluoromethyl)aniline was synthesized
4-Bromo-3-(trifluoromethyl)aniline was converted into according to Method A7. 4-Chloro-2-methoxy-5-(trifluo-
4-bromo-3-(trifluoromethyl)phenyl isocyanate according to romethyl)aniline was converted into 4-<:hloro-2-methoxy-5-
Method Bl. According to Method Cla, 4-bromo-3-(trifluo- 10 (trifluoromethyl)phenyl isocyanate according to Method Bl.
romethyl)phenyl isocyanate was reacted with 4-(2-(N-eth- According to Method Cla, 4-chloro-2-methoxy-5-(trifluo-
ylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. romethyl)phenyl isocyanate was reacted with 4-(2-(N-me-
Entry 89: 4-Chloro-N-methyl-2-pyridinecarboxamide, thylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
which was synthesized according to Method A2, Step 3a, Entry 96: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2·
was reacted with 3-aminopbenol according to Method A2, 15 chloroaniline was synthesized according to Method A6.
Step 4 to form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy) 4-Chloro-2-methoxy-5-(trifluorometbyl)aniline was synthe-
aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted sized according to Method A7. 4-Chloro-2-methoxy-5-(tri-
into 4-bromo-3-(trifluoromethyl)phenyl isocyanate accord- fluoromethyl)aniline was converted into 4-chloro-2-meth-
ing to Method Bl. According to Method Cla, 4-bromo-3- oxy-5-(trifluoromethyl)phenyl isocyanate according to
(trifluoromethyl)phenyl isocyanate was reacted with 3-(-2- 20 Method Bl. According to Method Cla, 4-chloro-2-meth-
(N-methylcarhamoyl)-4-pyridyloxy)aniline to afford the oxy-5-(trifluoromethyl)phenyl isocyanate was reacted with
urea. 4-(2-(N-metbylcarbamoyl)-4-pyridyloxy)-2-chloroaniline
Entry 90: According to Method A2, Step 4,5-amino-2- afford the urea.
methylphenol was reacted with 4-chloro-N-methyl-2-pyridi- Entry 97: According to Method A2, Step 4,4-amino-2-
necarboxamide, which had been synthesized according to 25 chlorophenol was reacted with 4-<:hloro-N-methyl-2-pyridi-
Method A2. Step 3b, to give 3-(2-(N-methylcarbamoyl)-4- necarboxamide, which had been synthesized according to
pyridyloxy)-4-methylaniline. 4-Bromo-3-(trifluoromethyl) Method A2, Step 3b, to give 4-(2-(N-methylcarbamoyl)-4-
aniline was converted into 4-bromo-3-(trifluoromethyl)phe- pyridyloxy)-3-<:hloroaniline. 4-Chloro-2-methoxy-5-(trif-
nyl isocyanate according to Method Bl. According to luoromethyl)aniline was synthesized according to Method
Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate 30 A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was
was reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)- converted into 4-chloro-2-methoxy-5-(trifiuoromethyl)phe-
4-methylaniline to afford the urea. nyl isocyanate according to Method Bl. According to
Entry 91: 4-Chloropyridine-2-<:arbonyl chloride was Method Cla, 4-chloro-2-methoxy-5-(trifluoromethyl)phe-
reacted with dimethylamine according to Method A2, Step nyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-
3b. The resulting 4-chloro-N,N-climethyl-2-pyridinecar- 35 4-pyridyloxy)-3-<:hloroanilineto afford the urea.
boxamide was reacted with 4-aminophenol according to Entry 98: 4-Chloro-N-methyl-2-pyridinecarboxamide,
Method A2, Step 4 to give 4-(2-(N,N-dimethylcarbamoyl)- which was synthesized according to Method A2, Step 3a,
4-pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline was reacted with 3-aminophenol according to Method A2,
was converted into 4-bromo-3-(trifluoromethyl)phenyl iso- Step 4 to form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)
cyanate according to Method Bl. According to Method Cla, 40 aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was
4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted synthesized according to Method A7. 4-Chloro-2-methoxy-
with 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline 5-(trifluoromethyl)aniline was converted into 4-<:hloro-2-
to afford the urea. methoxy-5-(trifluoromethyl)phenyl isocyanate according to
Entry 92: 4-Chloro-N-methylpyridinecarboxamide was Method Bl. According to Method Cla, 4-chloro-2-metb-
synthesized as described in Method A2, Step 3b. The chlo- 45 oxy-5-(trifluoromethyl)phenyl isocyanate as was reacted
ropyridine was reacted with 4-aminothiophenol according to with 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to
Method A2, Step 4 to give 4-(4-(2-(N-methylcarbamoyl) afford the urea.
phenylthio)aniline. 4-Bromo-3-(trifluoromethyl)aniline was Entry 99: 4-Chloropyridine-2-<:arbonyl chloride was
converted into 4-bromo-3-(trifluoromethyl)phenyl isocyan- reacted with ethylamine according to Method A2, Step 3b.
ate according to Method Bl. According to Method Cla, 50 The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was
4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted reacted with 4-aminophenol according to Method A2, Step
with 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline to 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline.
afford the urea. 4-Chloro-2-metboxy-5-(trifluoromethyl)aniline was synthe-
Entry 93: 4-Chloro-N-methylpyridinecarboxamide was sized according to Method A7. 4-Chloro-2-methoxy-5-(tri-
synthesized as described in Method A2, Step 3b. The chlo- 55 fluoromethyl)aniline was converted into 4-chloro-2-meth-
ropyridine was reacted with 3-aminothiophenol according to oxy-5-(trifluoromethyl)phenyl isocyanate according to
Method A2, Step 4 to give 3-(4-(2-(N-methylcarbamoyl) Method Bl. According to Method Cla, 4-chloro-2-meth-
phenylthio)aniline. 4-Bromo-3-(trifluoromethyl)aniline was oxy-5-(trifluoromethyl)phenyl isocyanate was reacted with
converted into 4-bromo-3-(trifluoromethyl)phenyl isocyan- 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the
ate according to Method Bl. According to Method Cla, 60 urea.
4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted Entry 100: 4-Chloropyridine-2-<:arbonyl chloride was
with 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline to reacted with climethylamine according to Method A2, Step
afford the urea. 3b. The resulting 4-<:hloro-N,N-dimethyl-2-pyridinecar-
Entry 94: 4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl)py- boxamide was reacted with 4-aminophenol according to
ridyloxy)aniline was synthesized according to Method AlO. 65 Method A2, Step 4 to give 4-(2-(N,N-dimethylcarbamoyl)-
4-Bromo-3-(trifluoromethyl)aniline was converted into 4-pyridyloxy)aniline. 4-Chloro-2-methoxy-5-(trifluorom-
4-bromo-3-(trifluoromethyl)phenyl isocyanate according to ethyl)aniline was synthesized according to Method A7.
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4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was con- Entry 103: 4-Chloro-N-methyl-2-pyridinecarboxamide
vened into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl was synthesized according to Method A2, Step 3b.
isocyanate according to Method Bl. According to Method 4-Chloro-N-methyl-2-pyridinecarboxamide was reacted
Cla, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocy-
anate was reacted with 4-(2-(N,N-dimethylcarbamoyl)-4- 5 with 4-aminophenol according to Method A2, Step 4 using
pyridyloxy)aniline to afford the urea. DMAC in place ofDMF to give 4-(2-(N-methylcarbamoyl)-
Entry 101: 4-Chloro-N-methyl-2-pyridinecarboxamide, 4-pyridyloxy)aniline. According to Method C2b, reaction of
which was synthesized according to Method A2, Step 3a, 3-amino-2-methoxyquinoline with CDI followed by 4-(2-
was reacted with 3-aminophenol according to Method A2, (N-methylcarbamoyl)-4-pyridyloxy)aniline afforded bis(4-
Step 4 to form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy) 10 (2-(N-methylcarbamoyl)-4-pyridlyoxy)phenyl)urea.
aniline. 2-Amino-3-methoxynaphthalene was synthesized as
Listed in the Tables below are compounds which have
described Method Al. According to Method C3,2-amino-3-
been synthesized according to the Detailed Experimental
methoxynaphthalene was reacted with bis(trichloromethyl)
Procedures given above:
carbonate followed by 3-(-2-(N-methylcarbamoyl)-4-py- 15
ridyloxy)aniline to form the urea.
TABLES
Entry 102: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)
aniline was synthesized according to Method A2. 5-tert-
Butyl-2-(2,5-dimethylpyrrolyl)aniline was synthesized The compounds listed in Tables 1-6 below were synthe-
according to Method A4. 5-tert-Butyl-2-(2,5~dimethylpyr- 20 sized according to the general methods shown above, and
rolyl)aniline was reacted with CDI followed by 4-(2-(N- the more detailed exemplar procedures are in the entry
methylcarbamoyl)-4-pyridyloxy)aniline according to listings above and characterizations are indicated in the
Method C2d to afford the urea. tables.
TABLE 1
TLC Mass
Entry R (° C.) (min.) R, System (Source I Method
0.22 50% 418 Al3 C3

EtOAc/ (M + H) +
0t 50% hexane (HPLC

ES-MS)
2
-0--0 0 " ti
0.58 50% 403 Al3 CJ
EtOAc/ (M + H) +
50% hexane (HPLC
ES-MS)
-Q-o--0---{
3 133-135 0.68 100% 448 AB C2d
EtOAc (M+H)+
(FAB)
0
-o-0-d=!,
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TABLE 2
OMe
nc Mass
Spec. Synth.
EntJy R [Somu) Method
4 448 A13
(M + H) + Bl
(HPLC Cl 8
ES-MS)
0 _)-\._
-0- -0
120-122 0.67 100% 478 AS
EtOAc (M+H)+ C2d
(FAB)
0 NH
- \te
-0-~
O \_j OMe
6 0.40 50% 460 A3

EtOAc/ (M+H)+ C2d
50"/4 (HPLC
hexane ES-MS)
0.79 50% 446 A12

50% (HPLC
hexane ES-MS)
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TABLE 3
5-(Triftuoromcthyl)-2-methoxyphenyl Ureas
F
F
R._,_~)ltt
I
OMe
TLC Mass
Entry R (" c.J (min.) R, System [Source] Method
8 250 460 A13

0 \., (dee) (M+H)+
(FAB)
C2a
9
-0--0 0 \ J
206-208 0.54 10%, 446 A3 step
V--0--{ MeOH/
90%,
CH2Cl2
(M + H) + 2,
(HPLC
ES-MS)
AS step
4,
Bl,
Cla
10 0.33 50% 445 Al3 CJ
--0-a-O--{ EtOAc/
50"/4
pet ether
(M+H)+
(HPLC
ES-MS)
-Q-<jo\.,
II 0.20 2% 461 A2
Et3N/ (M+H)+ C4
98% (HPLC
EtOAc ES-MS)
0 \ 1/
12
-Q-<jo NH2
0.27 1%
Et3N/
99%
EtOAc
447
(M+H)+
(HPLC
Es-MS)
A2
C4
0 \ 1/
13 0 0.62 100% 461 A2 C2a
EtOAc (M+H)+
(FAB)
-o-0--0\.,
14 0 114-117 0.40 1% 447 A2
Et3N/ (M+H)+C4
99% (FAB)
EtOAc
-o-0--d:NH,
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TABLE 3-continued
S-(Trifluoromethyl)-2-mcthoXYJ)henylUreas
OMe
TLC Mass
mp HPLC TLC Solvenl Spec. Synth.
Entry R ("C.) (min.) R, System [Sowa:] Method
IS 232-235 0.54 JOO% 490 AS C2d

EtOAc (M + H) +
o \,, (FAD)
16
-0--d=
'\_J O OMe
210-213 0.29 5% 475 AS

MeOW (M + H) + Bl Cle
Me -do\,, 45% (HPLC
-0-
EtOAc/ ES-MS)
50o/o
pet ether
0 '\_ N
J
17 187-188 0.17 50% 495 A6
EIOAc/ (M + H) + Bl Cla
a -do\,, 50"A, (HPLC
-0-
pet ether ES-MS)
0 '\_ N
J
18 0.48 JOO% 475 A2 step
EIOAc (M + H) + 4,
2 (HPLC Bl C!a
-Q--Oe O NH ES-MS)
0 \ DN
•
19 194-196 0.31 5% 475 A2
MeOW (M + H) + Bl Cla
-do "('B 45%
EtOAc/
(HPLC
ES-MS)
-0-
50%
pet ether
0 '\_ N
J
20 214-216 0.25 5% 495 A2 Cla
MeOW (M+H)+
CI -do NH
45% (HPLC
---0-
EtOAc/ ES-MS)
- ~e SO%
pet ether
0 '\_ N
J
21 208-210 0.30 SO% 481 Al9C2a
-0- 0 -0-tt?o
\ J \ Me
EtOAc/
50%
hexane
(M + H) +
(HPLC
ES-MS)
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TABLE 3-continued
5-(Trifluorometh:z:1)-2-meth~ben:z:l Ureas
F
F
R..__u)l~
I
OMe
nc Mass
mp HPLC TLC Solvent Sp= Synth.
Entry R ("C.) (min.) It, System [Source] Method
22 0 188-190 0.30 70% 447 A15,

EtOAc/ (M + H) + step 4,
50% (HPLC Cla
hexane ES-MS)
-o-0-DNH,
23 0.50 70% 472 A3
-0-o-Q;C EtOAc/
30%
hexane
(M + H) + Bl Cla
(FAB)
24 203-205 0.13 100% 419 A2B1

EtOAc (M+ H) + Cla
0 {
(HPLC
ES-MS)
-0--0 0 \
#
N
---<=r-Q(
25 0.09 75% 458 Al2
EtOAc/ (M+ H) + C2d
25% (HPLC
hexane ES-MS)
26 MeO 169-171 0.67 50% 474 AJ3

\ EtOAc/ (M + H) + step!,
-0-o-O--{ 50%
pet ether
(HPLC
ES-MS)
Al3 step
4,Al6,
Bl
Cla
27 218-219 0.40 50% 477 A2 step
0 "t ElOAc/
50%
pet ether
(M + H)+
(HPLC
ES-MS)
Jb,
A2 step
4, Bl,
-0--0
Cla
s \ DN
28 212-214 0.30 40%, A9
-0-o-Q;=f: ElOAc/
60%
hexane
Bl Cla
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TABLE 3~o
~ nmued
1·
S-(frifluoromcmyt)-i- methoxyphcnyl u~as
OMe
n.c Mass
Entty R ("C.) (min.) Rt System (Source) Method
29 0.33 50% 474 A2

ElOAc/ (M + H) + 3b step
50% (HPLC Ai
pct ether ES-MS) 4,
Cla
e"::'
30 210-211 A2
Bl
o "\'.,_; Cla
-0-~ 0 ~
~ J
N
31 210-204 0.43 10"/o A14

McOH/ Bl
CH2Cl2 Cla
D4
-0-
.
o-do"
" D
N
N
\_)
0
32 247-249 0.57 10"/o A14

McOH/ Bl
CH2Cl2 Cla
D4
33 217-219 0.07 10"/o A14

McOH/ Bl
CH2Cl2 Cla
D4
34 0.11 70% All

EtOAc/ Bl
30% Clf
hc:x.ane Die
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TABLE 3-continued
5:!!rifluorom!a!!l'.ll:2-metho!n!henxl Ureas
F
F
R,~)ltt
I
OMe
nc Mass
mp HPLC UC Solvcn1 Spa:. Synth.
Enll'y R (" C.) (min.) R, System [Soo=) Method
35 F 0.38 70% All
Q
EtOAc/ Bl
30% Clf
h=c Die
N)
\_N
-0-o-Oo
36 0.77 70"/o All
EtOAc/ Bl
F-0-NH O 30% Clf
bCJCAIIC Die
37
-o-0-0 0.58 70% All
Mc -0- EIOAc/ Bl
\ f " NH 30% Clf
-0-0-00
hexane Die
0
38 0.58 70% All
EtOAc/ Bl
M«>--0-NH 30% Clf
hexane Die
39
-o-0-0 0.17 70% All
,-\-0-NH EIOAc/ Bl
30"/o Clf
◊-00
hexane Die
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TABLE 3-continued
5-(Trifluoromcthyl)-2-methoxypbenyl Ureas
F
F
R.___~)l~
OMe
1LC Mass
mp HPLC 1LC Solvent Spec. Synth.
Entry R ('C.) (min.) R1 System [So=] Method
40 0.21 70% All
0-(~)-0-NH 0 EtOAc/
300/4
hexane
Bl
Clf
Die
-o-0:C
TABLE 4
3Qrifluorometh:tl}±chloroEhcn:tl Ureas
R,~)l~
0
i mp
Cl
HPLC
1LC
1LC Solvent
Mass
Spec. Synth.
Entry R ("C.) (min.) R, $)-stem [So=) Method
41
0 \. 163-165 0.08 500/o

EtOAc/
500/4
pet Clhcr
464
(M+H)+C3
(HPLC
ES-MS)
Al3
42
-0--0 0 \. J
215 0.06 500/4 465 A2
EtOAc/ (M+ H) + Cla
o \. 500/4 (HPLC
pet ether ES-MS)
43
-0--c- 0 \_
J
0
N
0.10 50% 451 A2

SO% (HPLC
pet ether ES-MS)
-o-0-C-NH'
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u\BLE 4-continued
3-(!:rilluorom!:!:!!r:l)-4-chlo~n;j'.l Ur=
R.__ti)l_ti
0
£ mp
Cl
HPLC UC
11..C
Solvent
Mass
Spec. Synth.
Entry R (°C.) (min.) R, System [Source] Method
44 0.25 30"/4 451 A2

70% (HPLC
-Q-bO NH2 pet ether ES-MS)
0 \ 1/
45 0.31 30% 465 A2
EtOAc/ (M+ H) + Cla
70"/o (HPLC
-Q-b" 't pet ether ES-MS)
0 \ #N
46 176-179 0.23 40% 476 A3
-0- 0~
\ ;)
NH
0 EtOAc/
60"/4
hexane
(M+ H) + Cla
(FAB)
47
-bo"\., 0.29 5%
MeOW
45%
478 A5
(M+ H)+ Cle
(HPLC
-0-
Me EtOAc/ ES-MS)
50%
pet ether
0 \
JN
48 0 0 206-209 Al5
V NH
Cla
~
-0--0 0 \ ;)
49
-bO't 147-151 0.22 S0"/4

EtOAc/
50"/4.
499 A6
(M + H) + Cla
(HPLC
---0-
Cl pet ether ES-MS)
0 \
JN
50 054 100% 479 A2
--Q-=c·'t
0 \
0
#N
EtOAc (M + H) + Cla
(HPLC
ES-MS)
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TABLE 4-continued
3-(Triflnoromelhyl)-4-chloropheJ!yl Ureas
TLC MAss
Entry R (" C.) (min.) R1 System [Souroe] Method
51 187-189 0.33 5% 419 Al

MeOH/ (M + H) + Cla
45% (HPLC
EtOAd ES-MS)
SO%
pet ether
52 219 0.18 5% 499 Al

MeOH/ (M + H) + Cla
45% (HPLC
EtOAd ES-MS)
SO"A,
pet ether
53 246-248 0.30 50% 485 Al 9,

EtOAd (M + H) + Cl•
S0"/4 (HPLC
hexane ES-MS)
54 196-200 0.30 70"/4 502 AIS

EtOAd (M+ H )+ Cla
30"/o (HPLC
hexane) ES-MS)
55 228-230 0.30 30"/o 466

EtOAd (M + H) +
70% (HPLC
CH2Cl2 ES-MS)
56 238-245
57 221-222 0.75 80% 492 Cid

EtOAd (M + H) + Dia
20% (FAB)
hexane
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TABLE 4-continued
3:{Trifluoromcthyl)± chlomphenyl Ureas
TI.C Mass
mp HPLC UC Solvent Spec. Synth.
Enuy R (" C.) (min.) R, System [Soun:e] Method
58 247 0.35 100% Cid
EtOAc Dia
D2
~~o \.
59
-0- \ I
198-200 0.09 100% 479 A2
0 ( EtOAc (M + H) + Cla
(HPLC
ES-MS)
60
-0--0 '0 \ N
158-160 0.64 50%

EtOAc/
50%
pet ether
61 195-197 0.39 10% Al3

McOH/ Cla
CH2Cl2
62 0.52 10% Al3

McOH/ Cla
CH2Cl2
63 0.39 10% Al3

McOH/ Cla
CH2Cl2
64 0.35 10% Al3

McOH/ Cla
CH2Cl2
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TABLE 4-continued
3-{Trifluommethyl)-4-chlorophcoyl Ureas
•yl~ ~ Cl
TLC Mass
Entry R ("C.) (min.) ~ System (Sowa:] Method
65 130-133 487 A2
(M + H) + Bl
0 \,. (HPLC Cla
ES-MS)
66
-0--0 s \. bN
155 A2
Cla
0 "e~-i
67
-0- -0 0 \_ bN
225-229 0.23 100% Cle
. \.. O NH EtOAc 03
Dlb
68
-0- ~
~
234-236 0.29 40¾ A9
-0-o~:
EtOAc/ Cla
60¾
hexane
69 0.48 50% 481

EtOAc/ (M+H)+
50% (HPLC
pet ether ES-MS)
~-OON \,.
\. J
70 0.46 5% 564 AIO

MeOW (M + H) + Cia
95% (HPLC
-o-~(;
CH2Cl2 ES-MS)
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TABLE4-conu·nued
3-{Trifluoromethyl)-4-chloropbenyl Ureas
TLC Mass
mp HPLC nc Solvent Spec. Synth.
Entry R ("C.) (min.) R1 System [Sou=) Method
71 0 199-201 0.50 10"/4 Al4

MeOH/ Cla
-o-0-D~
CH2Cl2 D4
N \_)
0
235-237 0.55 10"/o AJ4

MeOH/ Cla
CH2Cl2 D4
200-201 0.21 50"/4 Al4

MeOH/ Cla
CH2Cl2 D4
74 145-148
75 0.12 70"/4 527 All

30"/4 (HPLC Ole
hexane ES-MS)
IITRUE COPY!I
US 7,351,834 Bl
83 84
TABLE 4-continued
3-{Trifluoromethy1};4-chlorophenyl Ureas
TLC Mass
mp HPLC nc Solvent Spec. Synth.
Entry R (" C.) (min.) Rr System [Source) Method
76 0.18 70"A, All-

EtOAc/ Clf
30"/o Die
hexane
77 0.74 70% All

EtOAc/ Dlf
30"/o Die
hexane
78 0.58 70% All

EtOAc/ Clf
30"/4 Die
hexane
79 0.47 70"/4 569 All

30% (HPLC Die
hexane ES-MS)
80 0.18 70"/4 508 All

EtOAc/ (M + H)+ Clf
30"/4 (HPLC Die
hexane ES-MS)
IITRUE COPYII
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TABLE 4-continued
3-(Triftuoromethyl)-4-chlorophenyl Ureas
R,NAN
H
0
H
£ Cl
n.c Mass
mp HPLC TI..C Solvent Spec. Synth.
Entry R (" C.) (min.) R, System [Sowce] Method
81 0.58 70% 551 All

EtOAc/ (M+ H)+ Clf
Me0-0-NH 30% (HPLC Die
-o-0-00
hexane ES-MS)
82 0.37 70"/o 611 All
r\-o-NH EtOAc/
30"/o
(M + H) + Clf
(HPLC Die
-0-0-00
hexane ES-MS)
83
QN 0.19 70"/o
EtOAc/
30%
hexane
All
Clf
Die
N)
\_N
-o-o-c>o
84 0 179-183 A2
Al7
-o-0-o~.
Cla
DS
IITRUE COPY!I
US 7,351,834 Bl
87 88
TABLE5
3 -ITrifluaromcthyl}-4-
--:-- bromophcnYIUreas
TLC Mass
mp HPLC TLC SolvCllt Spec. Synth.
Entry R {°C.) (min.) R, System [Sow=] Method
85 186-187 0.13 500/o 509 A2

EtOAc/ (M + H }i- Bl
500/o (HPLC Cla
pet ether ES-MS)
86 150-152 031 500/o 545 A6

ElOAc/ (M + H) + Bl
500/4 (HPLC Cla
pct ether ES-MS)
87 217-219 0.16 500/o 545 A2

EtOAc/ (M+ H)+ Bl
500/o (HPLC Cla
pet ether ES-MS)
88 183-184 031 50% 525 A2

EtOAc/ (M+ H) + Bl
50% (HPLC Cla
pet ether ES-MS)
89 0.21 500/o 511 A2

EtOAc/ (M + H) + Bl
500/o (HPLC Cla
pct ether ES-MS)
90 0.28 500/4 525 A2

ElOAc/ (M + H) + Bl
50% (HPLC Cl 8
pet ether ES-MS)
91 214-216 0.28 50% 522 A2

o { EtOAc/ (M + H) + Bl
-0--d:
50% (HPLC Cia
pct ether ES-MS)
0
' ~
~
N
IITRUE COPY!I
US 7,351,834 Bl
89 90
TABLE 5-continued
3-(Trifluoromethyl)-4-bromopbenyl Uress
TLC Mass
mp HPLC TLC Solvem Spec. Syntb.
Entry R (" C.) (min.) R, System (Source] Method
92
0 \. 0.47 50%
EtOAc/
50%
pet ether
527
(HPLC
ES-MS)
A2 step
(M + H) + 3b,
A2 step
4,BI,
-0--0
Cla
S \_ N
#
93 0.46 50"/o 527 A2 step
-Q-00 \,,S \_ #N
EtOAc/
50"/o
pet ether
(M + H) +
(HPLC
ES-MS)
3b,
A2 step
4,Bl,
Cla
94 145-150 0.41 5% AlO

McOW Bl
95% Cla
CH2Cl2
-o-0-Jc
TABLE 6
5-/Trifluoromethyl}-4-cbloro-2-metboxyphenyl Ureas
Cl
OMe
TLC Mass
mp HPLC TLC Solvent Spec. Symh.
Entry R (o C.) (min.) R, Symm (Source] Method
95
0 '\.. 140-144 0.29 5%

Mc:OH/
45%
EtOAc/
495
(HPLC
ES-MS)
A2
(M + H) + A7
Bl
Cla
-0--0
0 \_ #N
50%
pct ether
IITRUE COP)jl
US 7,351,834 Bl
91 92
TABLE 6-<:ontinued
5-(Trifluorom•""•I'-"~••
-, ,-.--.....oro- 2-methoxyphenyl Ureas
Cl
OMe
1LC Mass
mp HPLC TI.C Solvent Spec. Synth.
Entry R (° C.) (min.) R, System (Soun:e] Method
-
96 244-245 0.39 5% 529 A6
MeOH/ (M+H)+ A7
45% (HPLC Bl
Cl -OO
--b-
F.tOAc/ ES-MS) Cla
1e 50%
pet ether
0 \
/) N
97 220-221 0.25 5% 529 A2

MeOH/ (M+H)+ A7
45% (HPLC Bl
CI -OO NH
-0-
F.tOAc/ ES-MS) Cla
- ~e 50%
pet ether
\ /)N
-Q-{)o\,.
98 0.27 5% 495 A2
MeOH/ (M+H)+ A7
45% (HPLC Bl
F.tOAc/ ES-MS) Cla
50%
pet ether
0 \ /)N
99 180-181 0.52 5% 509 A2

MeOH/ (M + H) + A7
0 ~& 45% (HPLC Bl
F.tOAc/ ES-MS) Cla
-0--0
50",!,
pet ether
0 \
/) N
100 162-165 A2
A7
Bl
0 '\.;
Cla
-0--0 0 \
/) N
IITRUE COPY!I
US 7,351,834 Bl
93 94
TABLE 7
Additional Ureas
TLC Mass
mp HPLC TLC Solvent Spec. Symh.
Entry R (° C.) (min.) R, System [Source] Method
101 162-165 Al
0 A2
CJ
)l
0 010~~
~ #
i
Me
ii ii
OMe
102 0.10 50"/4 442 A2

EtOAc/ (M+H)+ A4
0 50% (HPLC C2d
hexane ES-MS)
I )l
0
~
010~~
uN
i
Me
N N
H H
Me'(yMe
103 0 125-130 0.24 40"/4 512 A2

EtOAc/ (M + H) + C2b
60"/4 (FAB)
HN)l_NH hexane
9
0
Q
0
op NH-Me
~o
Me-NH
Biological Examples resolved by electrophoresis on 7 .5% Laemmli gels. Gels

were fixed, dried and exposed to an imaging plate (Fuji).
In Vitro raf Kinase Assay Phosphorylation was analyzed using a Fujix Bio-Imaging
50 Analyzer System.
In an in vitro kinase assay, raf was incubated with MEK All compounds exemplified displayed IC50 s of between 1
in 20 mM Tris-HCI, pH 8.2 containing 2 mM 2-mercapto- nM and 10 µM.
ethanol and 100 mM NaCl. This protein solution (20 µL)
was mixed with water (5 µL) or with compounds diluted Cellular Assay:
with distilled water from 10 mM stock solutions of com- 55 For in vitro growth assay, human tumor cell lines, includ-
pounds dissolved in DMSO. The kinase reaction was initi- ing but not limited to HCT116 and DLD-1, containing
ated by adding 25 µL (A-33P]ATP (1000-3000 dpm/pmol) in mutated K-ras genes were used in standard proliferation
80 mM Tris-HCI, pH 7.5, 120 mM NaCl, 1.6 mM DTT, 16 assays for anchorage dependent growth on plastic or anchor-
mM MgCl2 . The reaction mixtures were incubated at 32° C., age independent growth in soft agar. Human tumor cell lines
usually for 22 min. Incorporation of 33P into protein was 60 were obtained from ATCC (Rockville Md.) and maintained
assayed by harvesting the reaction onto phosphocellulose in RPMI with 10% heat inactivated fetal bovine serum and
mats, washing away free counts with a 1% phosphoric acid 200 mM glutamine. Cell culture media and additives were
solution and quantitating phosphorylation by liquid scintil- obtained from Gibco/BRL (Gaithersburg, Md.) except for
lation counting. For high throughput screening, 10 µM ATP fetal bovine serum (JRH Biosciences, Lenexa, Kans.). In a
and 0.4 µM MEK was used. In some experiments, the kinase 65 standard proliferation assay for anchorage dependent
reaction was stopped by adding an equal amount ofLaemmli growth, 3xlQ3 cells were seeded into 96-well tissue culture
sample buffer. Samples were boiled 3 min and the proteins plates and allowed to attach overnight at 37° C. in a 5% CO2
IITRUE COPYII
US 7,351,834 Bl
95 96
incubator. Compounds were titrated in media in dilution A) independently
series and added to 96-well cell cultures. Cells were allowed a) hydrogen,
to grow 5 days typically with a feeding of fresh compound b) C 1-C 10 alkyl,
containing media on day three. Proliferation was monitored c) C6 aryl,
by measuring metabolic activity with standard XTI colori- s d) pyridinyl
metric assay (Boehringer Mannheim) measured by standard e) substituted C 1 _10 alkyl,
ELISA plate reader at OD 490/560, or by measuring 3 H-thy- f) substituted C 6 aryl,
midine incorporation into DNA following an 8 h culture g) substituted pyridinyl
with 1 µCu 3 H-thymidine, harvesting the cells onto glass h) -phenylpiperazine(pyridinyl),
fiber mats using a cell harvester and measuring 3 H-thymi- 10 i) -phenylmorpholinyl,
dine incorporation by liquid scintillant counting. j) -ethylmorpholinyl,
For anchorage independent cell growth, cells were plated k) -ethylpiperidyl,
at lxlW to 3xlW in 0.4% Seaplaque agarose in RPM! 1) -methyl pyrrolidinyl,
complete media, overlaying a bottom layer containing only m) -methyl tetrahydrofuryl,
0.64% agar in RPMJ complete media in 24-well tissue 15 or
culture plates. Complete media plus dilution series of com- n) --C 2 H4 NH(phenyl);
pounds were added to wells and incubated at 37° C. in a 5% where when Ra and Rb are a substituted group, they are
CO2 incubator for 10-14 days with repeated feedings of substituted by
fresh media containing compound at 3-4 day intervals. a) halogen up to per halo,
Colony formation was monitored and total cell mass, aver- 20 b) hydroxy,
age colony size and number of colonies were quantitated c) -N(CH 3 ) 2 ,
using image capture technology and image analysis software d) C 1 -C 10 alkyl,
(Image Pro Plus, media Cybernetics). e) C 1-C 10 alkoxy,
In Vivo Assay: f) halosubstituted C 1_6 alkyl, or
An in vivo assay of the inhibitory effect of the compounds 25 g) -0Si(Pr-i) 3 ; or
on tumors (e.g., solid cancers) mediated by rafkinase can be B) Ra and Rb together form piperazine or a substituted
performed as follows: piperazine with substituents selected from the group
CDI nu/nu mice (6-8 weeks old) are injected subcutane- consisting of
ously into the flank at lx10 6 cells with human colon adeno- a) halogen,
carcinoma cell line. The mice are dosed i.p., i.v. or p.o. at 10, 30 b) hydroxy,
30, 100, or 300 mg/Kg beginning on approximately day I 0, c) C 1_10 alkyl,
when tumor size is between 50-100 mg. Animals are dosed d) pyridinyl
for 14 consecutive days once a day; tumor size was moni- e) C 1_10 alkoxy,
tored with calipers twice a week. f) C 6 aryl,
The inhibitory effect of the compounds on raf kinase and 35 g) halo substituted C 6 aryl, and
therefore on tumors (e.g., solid cancers) mediated by raf h) N-(4-acetylphenyl);
kinase can further be demonstrated in vivo according to the M is selected from the group consisting of oxygen and
technique of Monia et al. (Nat. Med. 1996, 2, 668-75). sulfur;
The preceding examples can be repeated with similar and
success by substituting the generically or specifically 40
Bis
described reactants and/or operating conditions of this
invention for those used in the preceding examples. phenyl, substituted with 1-3 substituents independently
selected from the group consisting of halogen and
From the foregoing description, one skilled in the art can
R7,
and, without departing from the spirit and scope thereof, can 45 and R7 is
make various changes and modifications of the invention to (a) C 1-C6 linear or branched alkyl, optionally substituted
adapt it to various usages and conditions. with 1-3 halogen substituents; or
What is claimed is:
2. A compound as in claim 1 wherein M is oxygen.
50 3. A compound as in claim 1 wherein the cyclic structures
A-D-8 (I) of B and L bound directly to D are substituted in the ortho
or a pharmaceutically acceptable salt thereof, wherein position by hydrogen.
D is -NH--C(O}-NH-, 4. A compound of claim 1 wherein B of Formula I is
A is a substituted moiety of the formula: phenyl, substituted with 1-3 substituents independently
55 selected from the group consisting of chlorine, C 1-C6 alkoxy
-L-M--L',
or up to per halo substituted C 1-C6 alkyl.
wherein L is phenyl, optionally substituted by halogen, 5. A compound of claim 2 wherein B of Formula 1 is
up to per-halo, and Wn, where n is 0-3; phenyl, substituted with 1-3 substituents independently
wherein each W is independently selected from the selected from the group consisting of chlorine, C 1-C6
group consisting of C 1-C5 linear or branched alkyl, 60 alkoxy, or substituted C 1-C6 alkyl, substituted by one or
C 1 -C5 linear or branched haloalkyl up to perha- more halogen substituents.
loalkyl and C 1-C3 alkoxy L 1 is selected from pyridi- 6. A compound of claim 3 wherein B of Formula I is
nyl substituted by --C(O)R,., and phenyl, substituted 1 to 3 times by 1 or more substituents
optionally substituted with 1-3 additional substituents selected from the group consisting of chlorine, C 1 -C6 alkoxy
independently selected from the group consisting of 65 or up to per halo substituted C 1-C6 alkyl.
R7 and halogen; 7. A compound of claim 1, wherein Lis phenyl, optionally
wherein Rxis NRJ¼ and R0 and Rb are substituted by halogen up to perhalo.
IITRUE COPY!I
US 7,351,834 Bl
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8. A compound of claim 1, wherein Lis phenyl, optionally M is selected from the group consisting of oxygen and
substituted with 1-3 substituents independently selected sulfur
from the group consisting of halogen and C 1 -C3 allroxy. and
9. A compound of claim 3, wherein M is -0-. B is phenyl, substituted with 1-3 substituents indepen-
10. A compound of claim 6 wherein M is -0-. 5 dently selected from the group consisting of R7 and
halogen;
and R7 is
12. A compound of claim 8 wherein M is -0-. (a) C 1 -C6 linear or branched alkyl, optionally substi-
13. A compound of claim 1 wherein L 1 is additionally tuted with 1-3 halogen substituents; or
substituted I to 3 times by one or more substituents selected 10 (b) C 1 -C6 linear or branched alkoxy.
from the group consisting of C 1 -C6 alkyl, halogen and C 1 -C6 2S. A compound of Formula I:
alkoxy.
A-D-B (I)
14. A compound of claim 2 wherein L 1 is additionally
substituted I to 3 times by one or more substituents selected or a pharmaceutically acceptable salt thereof, wherein
from the group consisting ofC 1-C 6 alkyl, halogen and C 1 -C6 1s D is -NH--C(O)---NH-,
1
alkoxy. A is of the formula: -L-M-L ,
1
1S. A compound of claim 9 wherein L is additionally Lis phenyl,
substituted 1 to 3 times by one or more substituents selected Mis-0-,
from the group consisting of C 1-C6 alkyl, halogen and C 1-C6 L 1 is pyridinyl substituted by --C(O)R,.,
alkoxy. 20 wherein ~ is NRaRb and Ra and Rb are independently
16. A compound of claim 10 wherein L1 is additionally hydrogen,
substituted I to 3 times by one or more substituents selected C 1 -C10 alkyl,
from the group consisting of C 1-C6 alkyl, halogen and C 1-C6 C 6 aryl,
alkoxy. pyridinyl,
17. A compound of claim 11 wherein L1 is additionally 25 substituted C 1 _ 10 alkyl,
substituted I to 3 times by one or more substituents selected substituted C6 aryl, or
from the group consisting of C 1-C6 alkyl, halogen and C 1-C6 substituted pyridinyl
alkoxy. where Ra and Rb are a substituted group, they are substi-
18. A compound of claim 12 wherein L1 is additionally tuted by halogen up to per halo,
30
substituted I to 3 times by one or more substituents selected and
from the group consisting of C 1-C6 alkyl, halogen and C 1-C6 B is a phenyl group substituted by trifluoromethyl or
alkoxy. tert-butyl, and optionally additional substituents
19. A compound of claim 2 wherein Ra and Rb are selected from the group consisting of halogen up to
independently hydrogen or C 1-C6 alkyl. per halo, and Wn where n is 0-3, and each Wis
35
20. A compound of claim 9 wherein Ra and Rb are independently selected from the group consisting of
independently hydrogen or C 1-C6 alkyl. C 1-C 10 alkyl,
C 1-C 10 alkoxy,
21. A compound of claim 10 wherein Ra and Rb are
independently hydrogen or C 1-C6 alkyl. C6 aryl,
22. A compound of claim 11 wherein Ra and Rb are 40 pyridinyl,
independently hydrogen or C 1-C6 alkyl. and substituted C 1 -C 10 alkyl, substituted by one or
more substituents independently selected from the
23. A compound of claim 12 wherein Ra and Rb are group consisting of halogen up to per halo.
independently hydrogen or C 1-C6 alkyl.
45 structures of B and L bound directly to D are substituted in
A-D-B (I) the ortho position by hydrogen.
or a pharmaceutically acceptable salt thereof, wherein structures of B and L bound directly to D are substituted in
D is -NH--C(O)---NH-, the ortho position i,y hydrogen.
A is of the formula: -L-M-L 1
, wherein so 28. A compound as in claim 24 wherein substituents for
L is phenyl, optionally substituted with 1-3 substituents B, are selected from the group consisting of up to per halo
independently selected from the group consisting of substituted C 1 -C6 alkyl and halogen.
C 1-C5 linear or branched alkyl, C 1-C5 linear or 29. A compound as in claim 2S wherein the optional
branched haloalkyl up to perhalo, C 1 ~ alkoxy and substituents for B are selected from the group consisting of
halogen; S5 up to per halo substituted C 1 -C6 alkyl and halogen.
1 30. A pharmaceutically acceptable salt of a compound of
L is pyridinyl, substituted by --C(O)~;
formula I of claim 1 which is
wherein ~ is NR 0~ and Ra and Rb are independently a) a basic salt of an organic acid or inorganic acid which
hydrogen, is hydrochloric acid, hydrobrom.ic acid, sulfuric acid,
C 1 -C 10 alkyl, 60 phosphoric acid, methanesulfonic acid, trifluo-
C6 aryl, romethanesulfonic acid, benzenesulfonic acid, p-tolu-
pyridinyl, substituted C 1 . 10 alkyl, ene sulfonic acid (tosylate salt), 1-napthalene sulfonic
substituted C6 aryl, or acetic acid, malic acid, tartaric acid, citric acid, lactic
substituted pyridinyl, 65 acid, oxalic acid, succinic acid, fumaric acid, maleic
where Ra and Rb are a substituted group, they are substi- acid, benzoic acid, salicylic acid, phenylacetic acid, or
tuted by halogen up to per halo; and mandelic acid; or
IITRUE COPY!I
US 7,351,834 Bl
99 100
b) an acid salt of an organic or inorganic base containing L 1 is pyridinyl, substituted with-C(O)NR"Rb;
an alkali metal cation, an alkaline earth metal cation, an wherein Ra and Rb independently are
ammonium cation, an aliphatic substituted ammonium a) hydrogen
cation or an aromatic substituted ammonium cation. b) methyl;
31. A pharmaceutically acceptable salt of a compound of 5 c) ethyl; or
claim 24 which is • d) propyl
a) a basic salt of an organic acid or inorganic acid which B is phenyl, substituted by tert-butyl or trifluoromethyl
is hydrochloric acid, hydrobromic acid, sulfuric acid, and optionally substituted with additional substitu-
phosphoric acid, methanesulfonic acid, trifluo- ents independently selected from the group consist-
romethanesulfonic acid, benzenesulfonic acid, p-tolu- 10 ing of
ene sulfonic acid (tosylate salt), 1-napthalene sulfonic a) halogen, or
acid, 2-napthalene sulfonic acid, acetic acid, trifluoro- b) methoxy.
acetic acid, malic acid, tartaric acid, citric acid, lactic 36. A compound of claim 35 where L has no optional
acid, oxalic acid, succinic acid, fumaric acid, maleic substituents.
acid, benzoic acid, salicylic acid, phenylacetic acid, or 15 37.Acompound of claim 35 where Ra is hydrogen and Rb
mandelic acid; or is methyl.
b) an acid salt of an organic or inorganic base containing 38. A compound of claim JS where B is substituted by
an alkali metal cation, an alkaline earth metal cation, an trifluoromethyl and chlorine or bromine.
ammonium cation, an aliphatic substituted ammonium 39. A compound which is N-(4-chloro-3-(trifluoromethyl)
cation or an aromatic substituted ammonium cation. 20 phenyl)-N'-( 4-(2-(N-methylcarbamoyl}-4-pyridyloxy)phe-
32. A pharmaceutically acceptable salt of a compound of nyl)urea of the formula X
claim 25 which is
a) a basic salt of an organic acid or inorganic acid which
is hydrochloric acid, hydrobromic acid, sulfuric acid, (X)
phosphoric acid, methanesulfonic acid, trifluo- 25
romethanesulfonic acid, benzenesulfonic acid, p-tolu-
ene sulfonic acid (tosylate salt), 1-napthalene sulfonic
acetic acid, malic acid, tartaric acid, citric acid, lactic
acid, oxalic acid, succinic acid, fumaric acid, maleic 30
acid, benzoic acid, salicylic acid, phenylacetic acid, or
mandelic acid; or
b) an acid salt of an organic or inorganic base containing or a pharmaceutically acceptable salt thereof.
an alkali metal cation, an alkaline earth metal cation, an 40. A compound of claim 39 which is a pharmaceutically
ammonium cation, an aliphatic substituted ammonium 35 acceptable salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-
cation or an aromatic substituted ammonium cation. N'-( 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea
33. A compound of claim 1 wherein the optional substitu- that is a basic salt of an organic acid or an inorganic acid
ents on L 1 are selected from the group consisting of methyl, which is hydrochloric acid, hydrobromic acid, sulfuric acid,
trifluoromethyl, methoxy, Cl and F. phosphoric acid, methanesulfonic acid, trifluoromethane-
34. A compound of claim 1 wherein the substituents of B 40 sulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid
and L are independently selected from the group consisting (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sul-
of methyl, trifluoromethyl, tert-butyl, methoxy, Cl, and F. fonic acid, acetic acid, trifluoroacetic acid, malic acid,
35. A compound of Formula I: tartaric acid, citric acid, lactic acid, oxalic acid, succinic
A-D-B en45 acid, fumaric acid, maleic acid, benzoic acid, salicylic acid,
phenylacetic acid, or mandelic acid.
41. A compound of claim 39 which is a tosylate salt of
D is -NH-C(O)-NH-, N-( 4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-meth-
1
A is a substituted moiety of the formula: -L-M-L ,
ylcarbamoyl)-4-pyridyloxy)phenyl)urea.
wherein L is phenyl, optionally substituted with chlorine
or methyl substituents; • • • • •
IITRUE COPY!I
Patent No. 7,351,834
Exhibit B
IITRUE COPYII
PTO/SB/26 (09-04)
Approved for use through 07/31/2006. 0MB 065Hl031
U.S. Palen! and Trademarl<Office; U.S. DEPARTMENT OF COMMERCE
Underthe l':menMlrk Redudion Pd. d 1995,no""""""' are remnredIDrasrnnd to a oollectionof informationunless a<fisnl,n,,a va6d0MB controlnurrt>er
Docket Number (Optional)

TERMINAL DISCLAIMER TO OBVIATE A DOUBLE PATENTING
BAYER-0015-A
REJECTION OVER A PRIOR APPLICATION AND PATENT
In re Application of: RIEDL, Bernd et al.

Application No. 09/889,227
Filed: 1/08/2002
For:co-CARBOXY ARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS

The·owner",Baver Pharmaceutical Corporation of 100 percent interest by virtue of an assignment document recorded on
June 9, 2003 (Reel 014125/Frame 0545), in the instant application hereby disclaims, except as provided below, the
terminal part of the statutory term of any patent granted on the instant application, which would extend beyond the
expiration date of the full statutory term defined in 35 U.S.C. 154 to 156 and 173 as shortened by any terminal disclaimer
filed prior to the grant of any patent granted on pending second Application Number 09/993,647, filed on November 27,
2001. The owner hereby agrees that any patent so granted on the instant application shall be enforceable only for and
during such period that it and any patent granted on the second application are commonly owned. This agreement runs
with any patent granted on the instant application and is binding upon the grantee, its successors or assigns.
In making the above disclaimer, the owner does not disclaim the terminal part of any patent granted on the instant
application that would extend to the expiration date of the full staMory term as defined in 35 U.S.C. 154 to 156 and 173
of any patent granted on the second application, as shortened by any terminal disclaimer filed prior to the patent grant,
in the event that any such granted patent: expires for failure to pay a maintenance fee, is held unenforceable, is found
invalid by a court of competent jurisdiction, is statutorily disclaimed in whole or terminally disclaimed under 37 CFR
1.321, has all claims cancelled by a reexamination certificate, is reissued, or is in any manner terminated prior to the
expiration of its lull statutory term as shortened by any terminal disclaimer filed prior to its grant.
The owner*,Bayer Pharmaceutical Corporation of 100 percent interest in the instant application hereby disclaims, except
as provided below, the terminal part of the staMory term of any patent granted on the instant application which would
extend beyond the expiration date of the full statutory term prior patent No. 7,235,576 B1, which issued from application
no. 10/042,203, as the term of said prior patent is defined in 35 U.S.C. 154 and 173, and as the term of said prior
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In making the above disclaimer, the owner does not disclaim the terminal part of any ~ent granted on the instant
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prior patent, ·as the term of said prior patent is presently shortened by any terminal disclaimer; in the event that said
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expires for failure to pay a maintenance fee; is held unenforceable is found invalid by a court of
competent jurisdiction; is statutorily disclaimed in whole or terminally disclaimed under 37 CFR 1.321;
has all claims cancelled by a reexamination certificate; is reissued; or is in any manner terminated
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be included on this form. Provide credit card information end authorization on PT0-2038.
• Sta!emen1under 37 CFR 3.73{b) is required~ terrrinal disclaimer is signed by the assignee (owner).
Form PTO/SB/96 may be used for making this certification. See MPEP § 324.
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PTCVSB/26(!9-04)
Approved for use through 07/31/2006. 0MB 0651--0031
U.S. Patent and Trademark Office; U.S. DEPARTMENTOF COMMERCE
l.k1der
the.,,,,__ Reduction Pd al 1995 no""""""' an, mauired ID...,,.,.... to a cotlection of inlormation unlesstt cfJSDlavs a valid Olvll ccn1rol rurt>er
Docket Number (Optional)

TERMINAL DISCLAIMER TO OBVIATE A DOUBLE PATENTING
BAYER-0015-A
REJECTION OVER PENDING APPLICATIONS
In re Application of: RIEDL, Bernd et al.

Application No. 09/889,227
Filed: 1/08/2002
For: ro-CARBOXY ARYL SUBSTITUTED DIPHENYL UREAS AS RAF KIN ASE INHIBITORS
The owner".Bayer Pharmaceutical Corporation of 100 percent interest by virtue of an assignment document recorded on
June 9, 2003 (Reel 014125/Frame 0545), in the instant application hereby disclaims, except as provided below, the
terminal part of the statutory term of any patent granted on the instant application, which would extend beyond the
expiration date of the full statutory term defined in 35 U.S.C. 154 to 156 and 173 as shortened by any terminal disclaimer
filed prior to the grant of any patent granted on pending second Application Number 10/071248, filed on FEBRUARY
11, 2002 .. The owner hereby agrees that any patent so granted on the instant application shall be enforceable only for
and during such period that It and any patent granted on the second application are commonly owned. This agreement
runs with any patent granted on the instant application and is binding upon the grantee, its successors or assigns.
In making the above disclaimer, the owner does not disclaim the terminal part of any patent granted on the instant
application that would extend to the expiration date of the full staMory term as defined in 35 U.S. C. 154 to 156 and 173
of any patent granted on the second application, as shortened by any terminal disclaimer filed prior 10 the patent grant,
in the event that any such granted patent expires for failure to pay a maintenance fee, is held unenforceable, is found
invalid by a court of competent jurisdiction, Is statutorily disclaimed in whole or terminally disclaimed under 37 CFR
1.321, has all claims cancelled by a reexamination certificate, is reissued, or is in any manner terminated prior to the
expiration of its full statutory term as shortened by any terminal disclaimer filed prior to its grant.
Check either box 1 or 2 below, if appropriate.
1. D For submissions on behalf of a business/organization (e.g., corporation, partnership, university, govemmen1

agency, etc.), the undersigned is empowered to act on behalf of the business/organization.
I hereby declare that all statements made herein of my own knowledge are true and that all statements made on
information and belief are believed to be true; and further that these statements were made with the knowledge lha1
willful false statements and the like so made are punishable by fine or imprisonment, or both, under Section 1001 of Title
18 of the United States Code and that such willful false statements may jeopardize the validity of the application or any
patent issued thereon.
2.181 The undersigned is an attorney or agent of record. Reg. No. 30,595
/Richard J. Traverso/ 08-28-2007

Signature Date
Richard J. Traverso 30 595

Typed or Printed Name
Telephone Number
181
Terminal disclaimer fee under 37 CFR 1.20(d) is included.
WARNING: Information on this form may become public. Credit card information should not
be included on this form. Provide credit card information and authorization on PT0-2038.
• Sta!emen1under 37 CFR 3.73(b) is required~ terrrinal disdaimer is signed by the assignee (owner).
Form PTO/SB/96 may be used for mal<ingthis certification. See MPEP § 324.
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Exhibit C
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__ UNITED STATES PATENT AND TRADEMARK OFFICE
United States Patent and Trademark Office
P.O. Box 1450
Alexandria, VA 223 I 3-1450
www.uspto.gov
Customer No 000000000 ISTMT DATE PRINTED

11/23/2012
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.

2200 CLARENDON BL VD.
SUITE 1400
ARLINGTON VA 22201
MAINTENANCE FEE STATEMENT

According to the records of the U.S.Patent and Trademark Office (USPTO), the maintenance fee and any necessary surcharge
have been timely paid for the patent listed below. The "PYMT DATE" column indicates the payment date (i.e., the date the
payment was filed).
The payment shown below is subject to actual collection. If the payment is refused or charged back by a financial institution, the
payment will be void and the maintenance fee and any necessary surcharge unpaid.
Direct any questions about this statement to: Mail Stop M Correspondence, Director of the USPTO, P.O.Box 1450, Alexandria,
VA 22313-1450.
U.S. PATENT APPL.

PATENT SUR PYMT APPLICATION ISSUE FILING PAYMENT ENTITY ATIYDKT
NUMBER FEE AMT CHARGE DATE NUMBER DATE DATE YEAR STATUS NUMBER
7351834 $980.00 $0.00 09/07/11 09889227 04/01/08 01/08/02 04 LARGE BAYER-0015-A
PTOIAJ9 (Rrv. 09~
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Exhibit D
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Regulatory milestones in clinical development of regorafenib (IND 75,642)
Country/ Regulatory milestone Date Outcome

Region
us IND Filed 19 JUL 2006 IND Filed with FDA
us IND May Proceed Letter 18AUG 2006 FDA allows Bayer to proceed with
clinical study
us FDA Granting of IND 13 OCT 2006 FDA detennines it is reasonably safe
to proceed with clinical study
us Non-Clinical Amendment Filed 23 OCT 2006 Non-clinical study reports to IND

us Non-Clinical Amendment Filed 16 MAR 2007 Non-clinical study reports to IND
us Non-Clinical Amendment Filed 16 AUG 2007 Non-clinical study report to IND
us IND Annual Report Filed 17 SEP 2007 IND Annual Report
us CMC Amendment Filed 12 OCT 2007 CMC Amendment to IND
us CMC Amendment Filed 29JAN 2008 CMC Amendment to IND
us New Protocol 11726 Filed 15APR 2008 New Protocol to IND
us CMC Amendment Filed 12 MAY 2008 CMC Amendment to IND
us Revised Protocol 11726 Filed 16 JUL 2008 Protocol Amendment to IND
us Non-Clinical Amendment Filed 5AUG 2008 Non-clinical study report to IND
us Revised Protocol 11651 Filed 9 SEP 2008 Protocol Amendment to IND
us IND Annual Report Filed 16 OCT2008 IND Annual Report
us CMC Amendment Filed 3 FEB 2009 CMC Amendment to IND
us Revised Protocol 11726 Filed 13APR 2009 Protocol Amendment to IND
us CMC Amendment Filed 30 JUN 2009 CMC Amendment to IND
us New Protocol 12437 Filed 7 AUG 2009 New Protocol to IND
us End of Phase 2 meeting 03 SEP 2009 Advice for Phase 3 study design
{CRC)
us FDA End-of Phase 2 Minutes 2 OCT2009 FDA End-of 0 Phase 2 meeting minutes
received
us CMC Amendment Filed 9 OCT 2009 CMC Amendment to IND
us Special Protocol Assessment for New 8 DEC 2009 Special Protocol Assessment
Protocol 14387 Requested
us Special Protocol Assessment - No 22 JAN 2010 Advice for Phase 3 study design
Agreement Letter from FDA {CRC)
us CMC Amendment Filed 26 MAR 2010 CMC Amendment to IND
us Response to Type A meeting 09 APR 2010 Agreement on Phase 3 study design
questions - FDA {CRC)
us Special Protocol Assessment for New 14 APR 2010 Revised Special Protocol Assessment
Protocol 14387 Requested
us Withdrawal of Special Protocol 3 MAY 2010 Withdrawal of SPA request
Assessment for Protocol 14387
us CMC Amendment Filed 3MAY2010 CMC Amendment to IND
us New Protocol 14387 Filed 18 MAY 2010 New Protocol to IND
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us Type B Meeting Request for GIST 28 MAY 2010 Submission of Meeting Request to
FDA to Discuss GIST Development
Program
us New Protocol 14458 Filed 23 JUN 2010 New Protocol to IND
us Type B Meeting for GIST 25 AUG 2010 Meeting between FDA and Bayer to
Discuss GIST Development
us New Protocol 14874 Filed 13 OCT 2010 New Protocol to IND
us Revised Protocol 11726 Filed 15 OCT 2010 Protocol Amendment to IND
us IND Annual Report Filed 18 OCT 2010 IND Annual Report to IND
us Revised Protocol 14387 Filed 25OCT 2010 Protocol Amendment to IND
us New Protocol 14814 Filed 19 NOV 2010 New Protocol to IND
us Orphan Drug Designation Request for 2 DEC 2010 Orphan Drug Designation Request
GIST
us New Protocols 12434 and 12435 21 JAN 2011 New Protocols to IND
us Orphan Drug Request Granted by 25 JAN 2011 Orphan Drug Designation Granted
FDA
us Revised Protocol 14874 18 FEB 2011 Protocol Amendment to IND
us Fast Track Designation Requested for 28 FEB 2011 Fast Track Designation Request to
GIST IND
us New Protocol 15524 Filed 29 MAR 2011 New Protocol to IND
us Revised Protocol 15524 Filed 31 MAR 2011 Protocol Amendment to IND
us CMC Amendment (Stability) Filed 12 APR 2011 CMC Amendment to IND
us Fast Track Designation Requested for 15 APR 2011 Fast Track Designation Requested
CRC
us Revised Protocol 12435 Filed 19 APR 2011 Protocol Amendment to IND
us Fast Tract Designation Approved for 21 APR 2011 Fast Tract Designation
GIST
us Fast Track Designation Approved for 10 JUN 2011 Fast track designation granted (CRC)
CRC
us Revised Protocol 14874 15 AUG 2011 Protocol Amendment to IND
us Pre-NDA meeting FDA 23AUG 2011 Pre-submission guidance, agreement
on format and content of NDA (CRC)
us Revised Protocol 11726 8 SEP 2011 Protocol Amendment to IND
us Pre-NDA Meeting Minutes from FDA 20 SEP 2011 FDA Meeting Minutes
us Proprietary Name Review Request 30 SEP 2011 Proprietary Name Review Request
us Revised Protocol 14874 12 OCT 2011 Protocol Amendment to IND
us IND Annual Report 18 OCT 2011 IND Annual Report
us Revised Protocol 14387 4 NOV 2011 Protocol Amendment to IND
us New Protocol 15967 19 JAN 2012 New Protocol to IND
us Split of IND into CRC (IND 75,642) 7 FEB 2012 IND Split
and GIST (IND 113,896}, Submission
of Statistical Analysis Plan for 14387
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us May Proceed Letter for New Protocol 15 FEB 2012 FDA May Proceed Letter for New
15967 Protocol 15967
us CMC Amendment Filed 15 MAR 2012 CMC Amendment to IND
us Notification to FDA that Bayer will 22 MAR 2012 DSUR Letter to IND
submit DSUR in lieu of IND Annual
Report
us FDA Comments on Study 14387 30 MAR 2012 FDA Comments on SAP
Statistical Analysis Plan
us Teleconference with FDA to discuss 3APR 2012 FDA Teleconference
Clinical Pharmacology Program
us OSI Request from FDA 6 APR 2012 OSI Request
us FDA Granted Bayer's Request for 19APR 2012 FDA Approval of DSURs
DSUR in lieu of IND Annual Reports
us Bayer Response to Statistical Analysis 23APR 2012 Bayer Response on SAP
Plan Comments for 14387
us NOA 203,085 Filed for CRC 27 APR 2012 NOA Filing for CRC Indication
us NOA 203,085 Approved for CRC 27 SEP 2012 NOA Approval for CRC Indication
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.,
I
UNITED STATESPATENTAND TRADEMARKOFFICE

United States Patent and Trademark Office
P.O. Box 1450
Alexandria, VA 22314-1450
www.uspto.gov
Bayer HealthCare LLC (PH) In Re: Patent Term Extension
attn: Aseem V. Mehta Application for
Vice-President, Chief Patent Counsel U.S. Patent No. 7,351,834
100 Bayer Boulevard
P.O. Box 915
Whippany, NJ 17981-0915
APR
...4 2017
Dear Mr. Mehta:
A certificate under 35 U.S.C. § 156 is enclosed extending the term of U.S. Patent
No. 7,351,834 for a period of 898 days. While a courtesy copy of this letter is being forwarded
to the Food and Drug Administration (FDA), you should directly correspond with the FDA
regarding any required changes to the patent expiration dates set forth in the Patent and
Exclusivity Data Appendix of the Orange Book (Approved Drug Products with Therapeutic
Equivalence Evaluations) or in the Patent Information set forth in the Green Book (FDA
Approved Animal Drug Products). Effective August 18, 2003, patent submissions for
publication in the Orange Book and Docket *95S-0117 need to be submitted on form FDA-3542
which may be downloaded from FDA's Electronic Forms Download Website:
http://www. fda.gov/ opacorn/morechoices/f daforms/ default.html
(http://www.fda.gov/opacom/morechoices/fdaforms/FDA-3542.pdf).
Inquiries regarding this communication should be directed to the undersigned by telephone at

(571) 272-7755, or by e-mail at mary.till@uspto.gov.
Senior Legal Advisor

Office of Patent Legal Administration
Office of the Deputy Commissioner
for Patent Examination Policy
cc: Food and Drug Administration RE: STIV ARGA®

CDER, Office of Regulatory Policy (regorafenib)
10903 New Hampshire Avenue, Docket No.: FDA-2014-E-0307
Bldg. 51 Room 6250
Silver Spring MD 20993-0002
Attention: Beverly Friedman
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(12) CERTIFICATE EXTENDING PATENT TERM

UNDER 35 U.S.C. § 156
(68) PATENT NO. 7,351,834
(45) ISSUED April 1, 2008
(75) INVENTOR Bernd Riedl et al.
(73) PATENT OWNER Bayer HealthCare LLC
(95) PRODUCT ·sTIVARGA® (regorafenib)
This is to certify that an application under 35 U.S.C. § 156 has been filed in the United States
Patent and Trademark Office, requesting extension of the term of U.S. Patent No. 7,351,834
based upon the regulatory review of the product STIVARGA® (regorafenib) by the Food and
Drug Administration. Since it appe·ars that the requirements of the law have been met, this
certificate extends the term of the patent for the period of
(94) 898 days
from January 12, 2020, the original expiration date of the patent, subject to the payment of
maintenance fees as provided by law, with all rights pertaining thereto as provided by 35
u.s.c. § 156.
I have caused the seal of the United States Patent and

Trademark Office to be affixed this 30th day of March 2017.
Michelle K. Lee
Under Secretary of Commerce for Intellectual Property
and Director of the United States Patent and TrademarkOffice
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Case 3:09-cv-021{)MHP Document1
1 COOLEY GODWARD KRONISH LLP

THOMAS J. FRIEL, JR. (80065) (tfriel@cooley.com)
2 MARTINS. SCHENKER (109828) (mschenker@cooley.com)
101 California Street, 5th Aoor
3 San Francisco, CA 94111-5800
Telephone: (415) 693-2000
4 Facsimile: (415) 693-2222
5 COOLEY GODWARD KRONISH LLP

MICHELLE S. RHYU, PH.D.(212922)(rhyums@cooley.com)
6 BRADLEY A. WAUGH (220964) (bwaugh@cooley.com)
Five Palo Alto Square
7 3000 El Camino Real
Palo Alto, CA 94306-2155
8 Telephone: (650) 843-5000
Facsimile: (650) 857-0663
9
10 Attorneys for Plaintiff

ONYX PHARMACEUTICALS, INC.
11
12 UNITED STATES DISTRICT COURT
13
NORTHERNm@VT °IJ9IFORNIA 2 14 5
14
Case No. ______ _
15 . ONYX PHARMACEUTICALS, INC.,
16 Plaintiff, COMPLAINT FOR:
• 17 v. (1) BREACH OF CONTRACT;

(2) BREACH OF THE IMPLIED
18 BAYER CORPORATION and BAYER AG, COVENANT OF GOOD FAITH AND
FAIR DEALING;
19 Defendants. (3) BREACH OF FIDUCIARY DUTY; AND
(4) DECLARATORY RELIEF
20
DEMANDFORJURYTRIAL
21
22
23 INTRODUCTION
24 Onyx Pharmaceuticals, Inc. ("Onyx") ·allegesas follows:

25 1. Onyx files this lawsuit to stop Bayer Corporation ("Bayer") from seizing for itself
26 what the parties agreed to share - the proceeds from a potentially lifesaving and lucrative cancer
27 drug discovered through the parties' longstanding scientific collaboration.

28
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Case 3:09-cv-02145-MHP Document 1 Filed 05/15/2009
~~
Page 2 of 16
1 2. That collaboration, first formalized in a 1994 Collaboration Agreement, merged

2 Onyx's expertise regarding a biochemical process associated with the growth of cancer cells (and
3 potential therapies for preventing growth of those cells) with Bayer's experience with small
4 molecule pharmaceutical compounds. Following years of investigation and analysis, the parties
5 identified a compound, known as sorafenib, as a promising candidate, and agreed to move
6 forward with development activities, including clinical trials. Under the Collaboration
7 Agreement, the parties equally shared the costs of development. For Bayer, the American arm of
8 a multinational pharmaceutical giant, the costs were modest. But for Onyx, a start-up company
9 with few assets beyond the human capital of its scientists, the investment in sorafenib literally
10 was a •'bet the company" proposition. To finance its share of the cost, Onyx was forced to
11 sacrifice all activities not essential to the development of sorafenib: the company shut down all
12 of its discovery efforts on other compounds, laid off its entire drug discovery team, and
13 terminated an unrelated clinical program.
14 3. Ultimately, Onyx's gamble paid off. Sorafenib (marketed as "Nexavar®")
15 received regulatory approvals worldwide for the treatment of advanced kidney cancer and liver
16 cancer, and has generated sales to date of more than a billion dollars, as well as substantial
17 profits, which the parties have shared. From Onyx's perspective, the Collaboration Agreement
18 has been an overwhelming success.
19 4. Bayer, as it turns out, held a different view. Now that Onyx had taught Bayer how
20 to identify effective targeted cancer therapies and introduced Bayer to a class of compounds with
21 potent anti-cancer properties, Bayer was no longer satisfied with the division of sorafenib's
22 profits. Bayer therefore devised a plan in an effort to bypass the Collaboration Agreement's
23 profit-sharing formula and appropriate for itself a substantially greater share of the joint venture's
24 blockbuster discovery. Bayer embarked on a secret program to develop a compound that the
25 parties first identified early in their collaboration. This compound, known as fluoro-sorafenib, is
26 identical to sorafenib, except for the substitution of a single fluorine atom in the place of a
27 hydrogen atom. Bayer, together with its parent company, Bayer AG, and their affiliates, then
28 moved forward to develop the compound outside the Collaboration Agreement, surreptitiously
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Case 3:09-cv-02145-MHP Document 1 Filed 05/15/2009 Page 3 of ,16
l •filing patent applications and initiating clinical trials. When Onyx recently discovered Bayer's
2 scheme and confronted Bayer, Bayer refused to concede Onyx's rights in fluoro-sorafenib and
3 refused to allow Onyx to join in bringing the compound to market.
4 5. Onyx brings this suit to establish its rights to fluoro-sorafenib and to recover the
5 damages caused by Bayer and Bayer AG's actions.
6 THEPARTIES
7 6. . Plaintiff, Onyx Pharmaceuticals, Inc., is a small but innovative biopharmaceutical
8 company based in Emeryville, California. Onyx was founded in 1992 by a team of scientists
9 internationally recognized for their understanding of the biochemical mechanisms of cancer cells.
10 In particular, the Onyx scientists had a specialized understanding of an intracellular pathway,
11 known as the Ras Pathway, associated with the uncontrolled growth of cancer cells. Onyx's
12 highly specialized knowledge of the Ras Pathway enabled it to identify targets for pharmaceutical
13 compounds that would inhibit cancer cell proliferation and to devise laboratory tests or "assays"
14 to assess a compound's efficacy in doing so. Onyx also possessed a "library," or collection, of
15 chemical compounds to test once the assays were developed. Onyx was thus ·uniquely positioned
16 with the talent and know-how to search for and identify novel drugs for treating cancer.
17 A number of large pharmaceutical companies recognized Onyx's unique capabilities and sought
18 research partnerships to tap into Onyx's expertise.
-
19 7. Onyx's commitment to translating its knowledge of cellular processes into
20 effective cancer treatments has proved successful. Its lead cancer drug, sorafenib, is approved in
21 over 70 countries for the treatment of patients with advanced kidney cancer and/or liver cancer.
22 Sorafenib also is being evaluated for treatment of patients with lung cancer, breast cancer, and
23 other cancers.
24 8. Onyx is a corporation organized and existing under the laws of the State of
25 Delaware, with ~tsprincipal place of business located in Emeryville, California.
26 9. Bayer Corporation is, and at all relevant times was, a corporation organized and
27 existing under the laws of the State of Indiana, with its principal place of business located in
28 Pittsburgh, Pennsylvania. Before approximately March 28, 1995, Bayer Corporation operated
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Case 3:09-cv-02145-MHP Document 1 Filed 05/15/2009 Page 4 of 16
1 under the name Miles Inc.
2 10. Bayer Corporation is part of Bayer AG, a German holding company with over
3 100,000 employees, operations in nearly every country in the world, and sales in 2008 exceeding
4 32 billion Euros. Bayer AG is a German corporation organized and existing under the laws of
5 Germany, with its principal place of business located in Leverkusen, Germany.
6 JURISDICTIONAND VENUE
-
7 11. This Court has original jurisdiction pursuant to 28 U.S.C. § 1332(a), in that this is
8 a civil action between citizens of different states in which the matter in controversy exceeds,
9 exclusive of costs and interest, seventy-five thousand dollars ($75,000.00).
10 12. This Court has jurisdiction over the defendants because they are corporations
11 actively doing business in California and have sufficient minimum contacts in California, or
12 otherwise intentionally availed themselves of the benefits of conducting business in California to
13 be subject to the court's jurisdiction. In particular, the Collaboration Agreement was negotiated
14 within the jurisdiction of this Court, and the parties understood that Onyx's obligations under the
15 Agreement would be performed within this Court's jurisdiction. The Collaboration Agreement
16 and the Letter Agreement (described below) expressly provide that they are governed by
17 California law.
18 13. Venue is proper in this district pursuant to 28 U.S.C. § 139l(a) and (c):
19 A substantial part of the events underlying this action occurred within this district. This Court
20 also has personal jurisdiction over the defendant corporations and, accordingly venue is proper.
21 INTRADISTRICTAsSIGNMENT
22 14. The appropriate lntradistrict Assignment for this case is the San Francisco
23 Division or the Oakland Division, pursuant to Civ. L.R. 3-2(c) and (d). A substantial part of the
24 events underlying this action occurred within Alameda County and Contra Costa County.
25 COMMONALLEGATIONS
26 The Collaboration Agreement
27 15. In the early 1990s, Bayer AG established the goal of exploiting new business
28 opportunities in the market for targeted cancer therapies. Bayer AG and its affiliates, however,
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1 lacked the scientific expertise to research and develop these therapies independently. Bayer AG
2 recognized the expertise of Onyx's scientists in the Ras Pathway, and understood that identifying
3 compounds that inhibit proteins in the Ras Pathway could be the key to success in targeted cancer
4 research. Bayer AG therefore approached Onyx and sought to gain access to the company's
5 technology, know-how, and library of chemical compounds that could have effects on the Ras
6 Pathway.
- 7
8
9
10
16. Bayer AG and Onyx engaged in· extensive negotiations over the terms of the
proposed collaboration to develop cancer drugs. Late in the negotiations, Bayer AG informed
Onyx that Bayer (then known as Miles Inc.), not Bayer AG, would be the party that would sign a
contract with Onyx. Shortly thereafter, on April 22, 1994, Onyx and Bayer entered into a
11 •Collaboration Agreement. Under the Collaboration Agreement and its 1996 and 1999
12 amendments, the parties committed to work together to discover, develop and market chemical
13 compounds having activity against proteins in the Ras Pathway.
14 17. Onyx recognized that other companies within the Bayer AG family of companies
15 might assist Bayer in performing under the Collaboration Agreement, and was concerned by
16 Bayer AG's late substitution of Bayer as the contracting party. Accordingly, "as an inducement
17 to Onyx to execute the Agreement," Bayer AG entered into an agreement (the "Letter
18 Agreement") with Bayer, contemporaneous with the signing of the Collaboration Agreement,
19 confirming that, to the extent Bayer AG or any of its "Affiliates" conducted research,
20 development, or marketing or otherwise undertook Bayer's obligations under the Collaboration
21 Agreement, the Affiliates would "do so in accordance with the provisions of the Agreement."
22 "Affiliate" was defined in the Collaboration Agreement and the Letter Agreement as any entity
23 that directly or indirectly, is under common ownership with Bayer. The Letter Agreement
24 between Bayer and Bayer AG expressly recognized Onyx as a third-party beneficiary.

25 18. The Collaboration Agreement defined two categories of compounds, referred to as
26 "Collaboration Compounds" and "Post-Collaboration Compounds," that are the subject of joint
27 development. Collaboration Compounds generally cover compounds that, before January 31,
28 2000, were "discovered, identified or synthesized" by Onyx or Bayer and "recognized" as
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1 satisfying the standard for cancer inhibiting activity set forth in Exhibit D to the Collaboration
2 Agreement. Post-Collaboration Compounds generally cover those compounds (a) whose
3 chemical genus both covers a Collaboration Compound and is claimed in an Onyx or Bayer
4 patent and (b) that were "synthesized, identified or discovered" and recognized before a later
5 cutoff date as satisfying the standard in Exhibit D.
6 19. The Collaboration Agreement. specifies the requirements for developing
7 Collaboration Compounds and Post-Collaboration Compounds into marketable, FDA-approved
8 products. The Collaboration Agreement requires the parties to work together in such
9 development and allows one party to pursue independent pre-clinical research of a Collaboration
10 Compound only if the other party is first given the opportunity for joint pre-clinical research and
11 declines to participate. Even then, however, the party pursuing independent pre-clinical research
12 must offer the other party the opportunity to collaborate in development if the research looks
13 promising.
14 20. The Collaboration Agreement established a Joint Research and Development
15 Committee (JRDC), populated by representatives of Bayer and Onyx, to govern the collaboration.
16 The role of the JRDC was to manage and make decisions regarding the collaboration. The JRDC,
17 later renamed the Joint Development Committee, still exists and continues to meet.
18 21. So that those decisions could be well informed, the Collaboration Agreement
-
19 established numerous obligations for information disclosure and good faith between .the parties.
20 Article 10.1 of the Collaboration Agreement, for example, requires full disclosure to the other
21 party of "the Information and all other significant information, data, and results known or
22 developed by each party as of the Effective Date and during the Research Term" (defined to end
23 on January 31, 1999) "as soon as practicable" after the information is obtained or its significance
24 is appreciated.
25 22. Article 10.2 of the Collaboration Agreement extends the obligation to make
26 quarterly reports to the JRDC beyond the Research Term, such ·that, if a party continues work on
27 Collaboration Compounds not yet in development as of the end of the Research Term, it must
28 provide sufficient disclosure to enable the other party to assess whether or not to pursue joint
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1 • funding of pre-clinical research and/or development.
2 23. Article 20.2 addresses patent disclosures, obligating a party to disclose to the other
3 party patentable inventions arising in the course of the collaboration. This section also requires a
4 party to furnish the other party with drafts of any patent application that discloses a Collaboration
5 Compound, allowing adequate time for review and comment before filing.
6 24. Article 26.2 of the Collaboration Agreement recognizes (similar to the Bayer AG
- 10
7
8
9
Letter Agreement) that Bayer may perform its obligations through Affiliates and provides that, in
such cases, Bayer "shall remain responsible and be guarantor" of the Affiliates' compliance with
the provisions of the Collaboration Agreement.

25. In the course of negotiations, the parties emphasized the importance of a
11 collaborative relationship built on principles of trust and good faith. To embody this model, the
12 parties included in Article 3.6 of the Collaboration Agreement an express covenant of good faith:
13 In all matters related to the collaboration established by this Agreement, the

14 Parties shall be guided by standards of reasonableness in economic terms and
fairness to each of the Parties, striving to balance as best they can the legitimate
15 interests and concerns of the Parties and to realize the economic potential of the
Products. In conducting research, development, and commercialization activities
16 under this Agreement neither Party shall prejudice the value of a Product by
reason of such Party's activities outside of the Field.
17
26. The Collaboration Agreement also sought to ensure that Onyx and Bayer shared in
18
the risks as well as the rewards of drug discovery. For example, the parties were to share equally
19
in the costs of co-developing Collaboration Compounds and Post-Collaboration compounds for
20
the marketplace, which might entail expensive and lengthy clinical trials for which approval
21
would be far from assured. If successful, however, the parties would share in the rewards. For
22
any co-developed Collaboration Compound sold in the marketplace, the reward was to be an
23
equal share of the profits. For any Post-Collaboration Compound, the reward was to be a royalty
24
paid by the seller.
25
Steps in the Collaboration
26
27. Early in the collaboration, the parties agreed that one Ras Pathway protein, raf
27
kinase, would be a good target for investigation. Raf kinase was understood to be involved in
28
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1 processes leading to cell division and proliferation. The parties hypothesized that raf kinase
2 inhibitors, or chemical compounds that inhibit raf kinase, would prove effective in controlling
3 cancer cell growth. Using their expert knowledge of the Ras Pathway, Onyx scientists created a
4 unique assay, exclusive to the collaboration, that could test the raf-inhibitory activity of any
5 compound.
6 28. With the assay in hand and its own library of small molecule compounds in house,
- 7
9
10
Onyx began searching for a Ras Pathway inhibitor. This effort succeeded, and Onyx identified an
inhibitor, dubbed N34213. Although N34213 was too weak an inhibitor to develop as a cancer
treatment, the basic chemical structure of that compound provided the key information that Bayer
and Onyx used to create thousands of synthetic compounds for further evaluation. As the number
11 of synthesized compounds increased over the course of the collaboration, the parties decided that
12 Bayer would conduct initial tests on the synthesized compounds, using the assay created by
13 Onyx. Onyx thus conveyed the assay protocol to Bayer, along with various purified reagents
14 necessary to carry out the assay.
15 29. Bayer synthesized and ran initial tests on compounds. They discussed some of
16 these results with Onyx, and transferred some of these compounds to Onyx for further evaluation.
17 Following discussions with Onyx, Bayer also synthesized additional compounds that were
18 structural analogs of compounds that showed promising activity.
- 20
21
22
19 Sorafeniband Its Analogs
30. This collaborative process ultimately led the parties to their pioneering cancer drug
sorafenib. Sorafenib was so effective at inhibiting raf kinase, in fact, that it satisfied the specified
standard for inhibitory activity set forth in Exhibit D by a factor of more than 1000. Eventually,
23 the parties learned that sorafenib inhibited other biological targets as well, rendering it a "multi-
24 kinase" inhibitor.
25 31. Sorafenib was not the only compound discovered and recognized to have
26 inhibitory activity under the collaboration. Bayer filed a patent application on January 13, 1999
27 (during the Research Term) that illustrates over 100 compounds (including sorafenib) that have
28 raf-kinase inhibitory activity satisfying the standard specified in Exhibit D.
COOLEY GoOIVARD
KRONISHLLP
COMPLAINT
ATTORNF.'1-'S AT LAW
SAN FRANCISCO
IITRUE COPYII
1 32. The January 13, 1999 patent application also shows that a sorafenib molecule can
2 be modified at one particular location with minimal effect on its raf-kinase inhibitory activity.
3 The chemical formula for sorafenib is illustrated below in Figure 1, with an arrow pointing to the
4 position "2" on the central ring structure of the molecule. In sorafenib, that position has a
5 hydrogen atom attached to the ring (per standard chemical drawing practice, the hydrogen is not
6 shown). The January 13, 1999 application explicitly shows two substitutions at this position.
7 In one case, a chlorine atom (Cl) replaces the hydrogen. In another case, a much larger, methyl
8 group (CH3), replaces the hydrogen. In both cases, the compounds were confirmed to have raf
9 kinase inhibitory activity well within the specified standard in Exhibit D to the Collaboration
10 Agreement.
11
0
12
Cl /CHa
13
14
0~I N
H
15
~)l")v
16 Figure 1: Sorafenib Jndicating position "2")
17 33. The illustrated compounds are not the only ones discussed and described in the
18 January 13, 1999 application. In text, the patent application explains that "halogens," a class of
19 elements to which both fluorine and chlorine belong, can be substituted for one another in the
20 compound. The patent that ultimately issued from this application as United States Patent
21 No. 7,351,834 claims the chemical structures of sorafenib and its halogenated brethren, and
22 reports the raf kinase-inhibiting properties of the entire family. Accordingly, the raf kinase-
23 inhibiting properties of sorafenib, chloro-sorafenib and fluoro-sorafenib were recognized well
24 before the cutoff date for the recognition of Collaboration Compounds, January 31, 2000.
25 34. The chemical formulas for sorafenib and the fraternal twins chloro- and fluoro-
26 sorafenib, are illustrated below in Figures 2, 3 and 4, respectively.
27
28
CooLEYGOOWARD
KRONISHLLP
COMPLAINT
A TI'OR.NEYS AT LAW
SAN FaANC:l!-iCO
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1
0
2
Cl /CH3
3
010 N
H
.A. ~
0
4
H H
5
Figure 2: Sorafenib
6
0
7
8 Cl 0 /CH3
0 N
H
10
9
.A.
H H
11
12 Figure 3: Fluoro-Sorafenib
13
14
Cl /CH3
15 N
H
16
17
18
- 19
20
21
22
35.
Figure 4: Chloro-Sorafenib
The parties fully understood, well before the cutoff date for the recognition _of
Collaboration Compounds, January 31, 2000, that sorafenib and its halogenated twins would
exhibit raf kinase-inhibitory activity well within the specified standard. This is no surprise given
23 that sorafenib and its halogenated brethren are, chemically speaking, nearly identical.
24 36. Ultimately, the parties chose to develop sorafenib and began clinical trials in late
25 2000. In accordance with the Collaboration Agreement, the parties co-funded the clinical trials,
26 and Onyx made substantial payments to Bayer, which otherwise funded and managed the trials.
27 The trials ultimately proved successful, leading to FDA approval in 2005 and 2007 for the
28 marketing of sorafenib for treating patients with kidney and liver cancer, respectively.
COOLEYGOOWIIRO
Kl!ONISHLLP
COMPLAINT
A TTORN•:vs AT LAW
SAN FRANCISCO
IITRUE COPYII
1 Bayer's Secret Scheme to Develop Fluoro-Sorafenib
2 37. Meanwhile, as the jointly-funded clinical trials progres~ed and Bayer began to
3 realize that sorafenib was destined for success, defendants secretly launched a plan to displace it.
4 In or around 2003, Bayer, along with other subsidiaries of Bayer AG, surreptitiously began filing
5 patent applications directed to fluoro-sorafenib. Fluoro-sorafenib was not a compound that Bayer
6 had recently discovered or, indeed, that involved any new discovery effort by Bayer following the
7 end of the Research Term in early 1999. On the contrary, Onyx and Bayer had explicitly
8 identified fluoro-sorafenib in 1998. Nonetheless, neither Bayer nor its Affiliates disclosed the
9 patent filings for fluoro-sorafenib to Onyx, which remained unaware of these actions. Then, in or
10 around 2005, Bayer and its Affiliates announced clinical trials on a cancer drug they referred to as
11 DAST. But Bayer withheld the chemical formula for DAST, leaving Onyx unaware that DAST
12 was a code name for fluoro-sorafenib. Nor did Bayer notify the Joint Development Committee
13 that it was beginning clinical trials on a compound that arose from the collaboration. Bayer has
14 given Onyx no chance to review and comment on the clinical trial submissions, much less to
15 participate in the trials.
16 38. In or around April 2007, Bayer made a presentation to Onyx of various cancer
17 compounds it was then investigating. But despite the fact that clinical trials for fluoro-sorafenib
18 had been initiated in 2005 and were ongoing, the Bayer executives and employees attending the
-
19 April 2007 meeting failed to disclose to Onyx that Bayer was developing fluoro-sorafenib.
20 39. Bayer Affiliates then began publishing their research and discovery efforts ~ith
21 DAST. In June 2007, Bayer HealthCare AG and Bayer Schering Pharma AG announced DAST
22 as being one of their development candidates for cancer therapy (again without revealing that it
23 was fluoro-sorafenib).
24 40. In early 2009, as the details of the DAST clinical trials became better known,
25 Onyx asked Bayer to reveal the chemical structure of DAST. Initially, Bayer denied that DAST
26 was a Collaboration Compound, but refused to reveal more. Finally, on March 31, 2009, an
27 executive of Bayer HealthCare Pharmaceuticals, Inc. (an Affiliate of Bayer), admitted that the
28 chemical structure of DAST was, indeed, fluoro-sorafenib. According to the executive, because
COOLEYGoDWARD
l<RONISH LLP
ATTc.HtNOS AT LAW
COMPLAINT
SAN fRANl'l~CO
IITRUE COPYII
1 Bayer had postponed testing of fluoro-sorafenib until after January 31, 2002, Bayer had not
2 "recognized" that the compound satisfied the specified standard for ras inhibitory activity by that
3 date. Accordingly, Bayer declared, it is entitled to develop and market fluoro-sorafenib
4 "unrestrained" by Onyx.
5 41. On April 15, 2009, Onyx wrote to Bayer proposing a meeting of executives to
6 negotiate in good faith toward a resolution of the parties' dispute regarding whether fluoro-
7 sorafenib is covered under the Agreement. The executives met, but the parties were unable to
8 resolve the dispute.
9 42. In May 2009, Bayer HealthCare Pharmaceuticals, Inc., which is responsible for a
10 clinical trial of fluoro-sorafenib in the U.S., is expected to report, by way of its clinical trial
11 investigators, on the results of a phase II trial in kidney cancer. Onyx is informed and believes
12 that if fluoro-sorafenib secures FDA approval, Bayer and its Affiliates intend to market Onyx and
13 Bayer's joint discovery-(1.uoro-sorafenib-as a direct competitor to the parties' joint product,
14 sorafenib, thereby reaping all of the benefits of the parties' collaboration without sharing the
15 rewards.
16 43. • Onyx is informed and believes, and based thereon alleges, that its damages exceed
17 the amount of seventy-five thousand dollars ($75,000), exclusive of costs and interest.
18 FIRST CLAIMFORRELIEF.
19 (BREACHOF CONTRACT)
20 44. Onyx re-alleges and incorporates by reference paragraphs 1-43, inclusive, as

21 though fully set forth herein.
22 45. Onyx performed all of the terms and conditions of the parties' Collaboration
23 Agreement, as amended.
24 46. Defendants breached the Collaboration Agreement by, among other things:
25 (a) failing to disclose their research and development plans for fluoro-
26 sorafenib;
27 (b) failing to treat fluoro-sorafenib as a Collaboration Compound; and
COOI.ErGooWARD
28
, ,,,'
__
~~~2.
KROl.!ISH lLP
COMPLAINT
ATlllJ:HE'!I!- AT LAW
SAN f'.aANCl!-C(I
IITRUE COPY\I
1 (c) undermining the value of sorafenib through their development of fluoro-
2 sorafenib.
3 47. Defendants further breached their obligations under the Collaboration Agreement
4 and the Letter Agreement to cause their Affiliates to comply with the provisions of the
5 Collaboration Agreement.
6 48. Alternatively, in the event a compound must be tested to be recognized under the
7 Collaboration Agreement as a Collaboration Compound, defendants breached the Collaboration
8 Agreement if (as Bayer claims) they deferred testing of fluoro-sorafenib until after January 31,
9 2000.
10 49. As a proximate result of defendants' breach of the Collaboration Agreement and
11 the Letter Agreement, Onyx has sustained, continues to sustain, and will sustain damages,
12 including, but not limited to lost sales, damage to goodwill, and the inability to profit from sales
13 of fluoro-sorafenib. In addition, defendants were, are, and will be unjustly enriched through their
14 appropriation for themselves of the entire value of fluoro-sorafenib.
15 SECOND CLAIM FOR RELIEF
16 (BREACH OF IMPLIED COVENANT OF Goon FAITH AND FAIR DEALING)
17 SO. Onyx re-alleges and incorporates by reference paragraphs 1-43, inclusive, as
-
19 51. A covenant to deal fairly and act in good faith is implied in the Onyx/Bayer
20 Collaboration Agreement and later amendments.
21 52. Defendants breached these covenants by, among other things:
23 sorafenib;

26 sorafenib.
27 53. Defendants further breached these covenants by failing to satisfy their obligations
28 under the Collaboration Agreement and the Letter Agreement to cause their Affiliates to comply
COOLEYGODWARD
KRONISHLLP
ATTORNEY:,: AT LAW
COMPLAINT
SAN fRANCl!'CO
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~(11 l
1 with the provisions of the Collaboration Agreement.
2 54. Alternatively, in the event a compound must betested to be recognized under the
3 Collaboration Agreement as a Collaboration Compound, Bayer breached these covenants if (as
4 Bayer claims) it deferred testing until after January 31, 2000.
10 • THIRD CLAIM FOR RELIEF
11 (BREACH OF FIDUCIARY DUTY)
12 56. Onyx re-alleges and incorporates by reference paragraphs 1-43, inclusive, as

14 57. • The Collaboration Agreement created a legal joint venture. As collaborators and
15 joint venturers, defendants owed Onyx the highest degree of fiduciary duty, including but not
16 limited to the duty of loyalty and honesty.

17 58. Defendants breached their fiduciary duty to Onyx by, among other things:
-
19 sorafenib;

22 sorafenib.
24 Collaboration Agreement as a Collaboration Compound, Bayer Corporation breached its fiduciary
25 duty if (as Bayer claims) it deferred testing until after January 31, 2000.
COOLEVGoDIVARD
KRON!SHLLP
ATTOKNEVS AT LAW
COMPLAINT
SAN fRAN<.:IS<.:O
IITRUE COPYII
3 61. Defendants' conduct in breaching their fiduciary duties was malicious, oppressive,
4 fraudulent, and otherwise entitles Onyx to an award of exemplary and punitive damages.
5 CLAIM FORRELIEF
FOURTH
6 (DECLARATORY
RELIEF)
7 62. •Onyx re-alleges and incorporates by reference paragraphs 1-43, inclusive, as

9 63. Onyx desires a declaration regarding its rights to fluoro-sorafenib.
10 64. An actual controversy exists between Onyx and the defendants relating to their
11 respective rights to fluoro-sorafenib. In particular, there is a dispute regarding whether fluoro-
12 sorafenib is a Collaboration Compound. Defendants contend that it is not, and that they therefore
13 may independently develop fluoro-sorafenib and eventually sell it without sharing profits with
14 Onyx. Onyx contends that fluoro-sorafenib is a Collaboration Compound, entitling Onyx to
15 participate equally in co-development and to share equally in the profits from any future sales.
16 65. In order to resolve this dispute, Onyx requests that the Court declare the rights and
17 obligations of Onyx and Bayer regarding fluoro-sorafenib. Specifically, Onyx requests a
18 declaration that fluoro-sorafenib is a Collaboration Compound, that Onyx is entitled to participate
19 equally in co-development, and that Onyx should receive a 50% share in the profits (as defined in
20 the Collaboration Agreement) from any future sales of fluoro-sorafenib.
21 WHEREFORE,
Onyx prays for the following relief:
•22 1. That this Court award compensatory damages to Onyx in an amount to be proven
23 at trial;
24 2. That this Court award punitive damages to Onyx in amount to be determined at
25 trial;
3. That this Court award to Onyx the benefits and profits enjoyed by defendants as a
27 result of their unjust enrichment as determined at trial;
28 4. That this Court declare fluoro-sorafenib to be a Collaboration Compound as
CooLEYGoDWARD
KRONISHLLP
ATTOJl:NE'r'S AT LAW
COMPLAINT
SAN FRANCISCO
IITRUE COPY\I
1 defined under the parties• Collaboration Agreement;
2 5. That this Court order defendants to allow Onyx to participate in co-development of
3 fluoro-sorafenib under the parties' Collaboration Agreement;
4 6. That this Court declare that Onyx is entitled to a 50% share in the profits from any
5 future sales of fluoro-sorafenib by defendants, as defined in the Collaboration Agreement;
6 7. That this Court enjoin defendants from developing fluoro-sorafenib without
7 Onyx's participation;
8 8. That this Court award Onyx its costs, including attorneys' fees to the extent
9 allowable; and
10 9. That this Court grant Onyx such additional relief as it deems just and proper.
11 Dated: May 15, 2009 COOLEY GODWARD KRONISH LLP

MARTINS. SCHENKER (109828)
12
13
14 Martin S. Schenker (109828)
Attorneys for Plaintiff
15 ONYX PHARMACEUTICALS, INC.
16
17
18
-
19 1133353v I/SF
20
21
22
23
24
25
26
27
28
CclOLEYGoDWARD
l<RONISHLLP COil!PLAINT
ATT<J5':NllYS AT LAW
SAN FRANCISCO
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Case3:09-cv-02145-MHP Document35 Filed08/12/09 Page1 of 26
1 LAWRENCER. KATZIN (CA SBN 142885)

LK.atzin@mofo.com
2 NATALIE THINGELSTAD (CA SBN 255400)
NThingelstad@mofo.com
3 AMY C. DACHTLER (CA SBN 248589)
ADachtler@mofo.com
4 MORRISON & FOERSTER LLP
425 Market Street
5 San Francisco, California 94105-2482
Telephone: (415) 268-7000
6 Facsimile: (415) 268-7522
7 MARK L. LEVINE (admitted pro hac vice)

mark.levine@bartlit-beck.com
8 JASON L. PELTZ (admitted pro hac vice)
jason.peltz@bartlit-beck.com
9 BRIAN C. SWANSON (admitted pro hac vice)
brian.swanson@bartlit-beck.com
10 J. SCOTT MCBRIDE (admitted pro hac vice)
scott.mcbride@bartlit-beck.com
11 BARTLITBECKHERMANPALENCHAR & SCOTTLLP
54 West Hubbard St., Suite 300
12 Chicago, IL 60654
Telephone: (312) 494-4400
13 Facsimile: (312) 494-4440
14 Attorneys for Defendants

BAYERCORPORATION, BAYERHEALTHCARELLC,
BAYERAGAND
15 BAYERSCHERING PHARMA AG
16
UNITED STATES DISTRICT COURT
17
NORTHERN DISTRICT OF CALIFORNIA
18
SAN FRANCISCO DMSION
19
ONYX PHARMACEUTICALS, INC., Case No. CV 09 2145 MHP
20
Plaintiff,
21 ANSWER AND AFFIRMATIVE
v. DEFENSES OF BAYER AG AND
22 BAYER SCHERING PHARMA AG
BAYER CORPORATION, et al., TO ONYX PHARMACEUTICALS,
23 INC.'S FIRST AMENDED
Defendants. COMPLAINT
24
DEMAND FOR JURY TRIAL
25
26
Bayer AG and Bayer Schering Pharma AG (collectively, the "German Bayer Entities")
27
respond to the First Amended Complaint of Onyx Pharmaceuticals, Inc. ("Onyx") as follows:
. 28
::;$
ANSWER AND AfFIRMATNE DEFENSES OF BA YER AG AND BA YER
SCHERING PHARMAAG To ONYXPHARMACEUTICALS,
INc. 's FlRST V•
- c,.,, No. CV 092145 MIIP
COMN.AfNT, &---- ~,
IITRUE COPYII
Case3:09-cv-02145-MHP Document35 Filed08/12/09 Page2 of 26
1 1. Onyx files this lawsuit to stop Bayer Corporation ("Bayer") from seizing for itself
what the parties agreed to share - the proceeds from a potentially lifesaving and lucrative
2 cancer drug discovered through the parties' longstanding scientific collaboration.
3 ANSWER: The German Bayer Entities admit that Onyx has filed a lawsuit. The
4 German Bayer Entities deny any remaining allegations not expressly admitted herein.
5 2. That collaboration, first formalized in a 1994 Collaboration Agreement, merged
6 Onyx's expertise regarding a biochemical process associated with the growth of cancer cells
(and potential therapies for preventing growth of those cells) with Bayer's experience with
7 small molecule pharmaceutical compounds. Following years of investigation and analysis, the
parties identified a compound, known as sorafenib, as a promising candidate, and agreed to
8 move forward with development activities, including clinical trials. Under the Collaboration
Agreement, the parties equally shared the costs of development. For Bayer, the American arm
9
of a multinational pharmaceutical giant, the costs were modest. But for Onyx, a start-up
10 company with few assets beyond the human capital of its scientists, the investment in sorafenib
literally was a "bet the company" proposition. To finance its share of the cost, Onyx was
11 forced to sacrifice all activities not essential to the development of sorafenib: the company shut
down all of its discovery efforts on other compounds, laid off its entire drug discovery team,
12 and terminated an unrelated clinical program.
13 ANSWER: The German Bayer Entities admit (1) that under. a 1994 Collaboration
14 Agreement (together with its two amendments, the· "Collaboration Agreement"), Bayer identified
15 and the parties developed the anti-cancer compound sorafenib, and (2) that the Collaboration
16 Agreement outlined how the parties would allocate costs as well as profits from the development
17 of compounds covered by the Collaboration Agreement. The German Bayer Entities are without
18 knowledge or information sufficient to form a belief as to the truth of the allegations relating to
19 the burden on Onyx of the development of sorafenib, and therefore denies those allegations. The
21 3. Ultimately, Onyx's gamble paid off. Sorafenib (marketed as "Nexavar®") received
22 regulatory approvals worldwide for the treatment of advanced kidney cancer and liver cancer,
and has generated sales to date of more than a billion dollars, as well as substantial profits,
23 which the parties have shared. From Onyx's perspective, the Collaboration Agreement has
been an overwhelming success.
24
ANSWER: The German Bayer Entities admit (1) that sorafenib has received regulatory
25
approval in over 70 countries for.treatment of kidney and liver cancer under the brand name
26
Nexavar®, and (2) that Nexavar® has generated total sales to date of more than a billion dollars.
27
The German Bayer Entities are without knowledge or information sufficient to form a belief as
28
ANSWER AND AFFIRMATIVE DEFENSES OF BAYER

SCHERING PHARMA AG TO ONYX
AMmm~COM=,CAs,No.CV092145MHP
AG ANDBA YER
PHARMACEUTICALS, INC. 's
FIRST
~
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(\_ ¼'
IITRUE COPYII
Case3:09-cv-02145-MHP Document35 Filed0B/12/09 Page3 of 26
1 to the truth of the allegation relating to Onyx's perspective on the success of the Collaboration
2 Agreement, and therefore deny that allegation. The German Bayer Entities deny any remaining
3 allegations not expressly admitted herein.
4 4. Bayer, as it turns out, held a different view. Now that Onyx had taught Bayer how
to identify effective targeted cancer therapies and introduced Bayer to a class of compounds
5 with potent anti-cancer properties, Bayer was no longer satisfied with the division of
sorafenib's profits. Bayer therefore devised a plan in an effort to bypass the Collaboration
6
Agreement's profit-sharing formula and appropriate for itself a substantially greater share of
7 the joint venture's blockbuster discovery. Bayer embarked on a secret program to develop a
compound that the parties first identified early in their collaboration. This compound, known
8 as fluoro-sorafenib, is identical to sorafenib, except for the substitution of a single fluorine
atom in the place of a hydrogen atom. Bayer, together with its parent company, Bayer AG,
9 and its affiliates, including Bayer HealthCare LLC ("Bayer HealthCare") and Bayer Schering
Pharma AG ("Bayer Schering Pharma"), then moved forward to develop the compound outside
10
the Collaboration Agreement, surreptitiously filing patent applications and initiating clinical
11 trials. When Onyx recently discovered this scheme and confronted defendants, they refused to
concede Onyx's rights in fluoro-sorafenib and refused to allow Onyx to join in bringing the
12 compound to market.
13 ANSWER: The German Bayer Entities admit that Bayer HealthCare LLC, a subsidiary
14 of Bayer Corp., is developing a new anti-cancer compound, known internally as DAST and
15 known publicly under the official International Nonproprietary Name of regorafenib, in which
16 Onyx has no rights. The German Bayer Entities deny that this development was part of a
17 "scheme" or "secret program" done in an "effort to bypass the Collaboration Agreement" or that
18 it was "surreptitiously" undertaken. The German Bayer Entities further deny that regorafenib is
19 "known as fluoro-sorafenib." The German Bayer Entities deny any remaining allegations not
20 expressly admitted herein.
21 5. Onyx brings this suit to establish its rights to fluoro-sorafenib and to recover the
damages caused by defendants' actions.
22
23 ANSWER: The German Bayer Entities deny (1) that Onyx has rights to regorafenib,
24 (2) that any Bayer entity has caused Onyx any damage alleged in this lawsuit, and (3) that there
25 is a compound known as "fluoro-sorafenib." The German Bayer Entities are without knowledge
26 or information sufficient to form a belief as to the truth of the remaining allegations in this
27 paragraph, and therefore deny them.
28
=~2:r,~~;~=~~
13):i
IITRUE COPYII
1 The Parties
2 6. Plaintiff, Onyx Pharmaceuticals, Inc., is a small but innovative biopharmaceutical

company based in Emeryville, California. Onyx was founded in 1992 by a team of scientists
3 internationally recognized for their understanding of the biochemical mechanisms of cancer
4 cells. In particular, the Onyx scientists had a specialized understanding of an intracellular
pathway, known as the Ras Pathway, associated with the uncontrolled growth of cancer cells.
5 Onyx's highly specialized knowledge of the Ras Pathway enabled it to identify targets for
pharmaceutical compounds that would inhibit cancer cell proliferation and to devise laboratory
6 tests or "assays" to assess a compound's efficacy in doing so. Onyx also possessed a "library,"
or collection, of chemical compounds to test once the assays were developed. Onyx was thus
-
7 uniquely positioned with the talent and know-how to search for and identify novel drugs for
8 treating cancer. A number oflarge pharmaceutical companies recognized Onyx's unique
capabilities and sought research partnerships to tap into Onyx's expertise.
9
ANSWER: The German Bayer Entities admit (1) that Onyx is based in Emeryville,
10
California, (2) that Onyx had an understanding of the Ras Pathway, (3) that Onyx developed
11
"assays" to identify compounds that inhibited the Ras Pathway, and (4) that Onyx possessed a
12
small "library" of compounds available to test for inhibition of the Ras Pathway. The German
13
Bayer Entities are without knowledge or information sufficient to form a belief as to the truth of
14
the allegations relating to the founding of Onyx, and therefore deny them. The German Bayer
15
Entities deny any remaining allegations not expressly admitted herein.
16
7. Onyx's commitment to translating its knowledge of cellular processes into effective
17 cancer treatments has proved successful. Its lead cancer drug, sorafenib, is approved in over
70 countries for the treatment of patients with advanced kidney cancer and/or liver cancer.
18 Sorafenib also is being evaluated for treatment of patients with lung cancer, breast cancer, and
other cancers. •
19
20 ANSWER: The German Bayer Entities admit that Bayer's compound Nexavar® has
21 been approved in over 70 countries for treatment of kidney and liver cancer, and that-Bayer
22 HealthCare LLC is evaluating Nexavar® for certain types of treatment of patients with lung
23 cancer, breast cancer, and other cancers. The German Bayer Entities are without knowledge or
24 information sufficient to form a belief as to the remaining allegations in this paragraph, and
25 therefore deny them.

26 8. Onyx is a corporation organized and existing under the laws of the State of
Delaware, with its principal place of business located in Emeryville, California.
27
ANSWER: Admitted.
28
ANSWER AND AFFIRMATIVE DEFENSES OF BA YER AG AND BA YER
SCHERING PHARMA AG TO ONYX PHARMACEUTICALS, INC. 's FIRST
AMENDED COMPLAINT, CASE No. CV 09 2145 MHP
IITRUE COPYII
1 9. Bayer Corporation is, and at all relevant times was, a corporation organized and
existing under the laws of the State of Indiana, with its principal place of business located in
2 Pittsburgh, Pennsylvania. Before approximately March 28, 1995, Bayer Corporation operated
under the name Miles Inc.
3
4 ANSWER: Admitted.
5 10. Onyx is informed and believes, and on that basis alleges, that Bayer HealthCare is a
limited liability company whose sole owner and member is Bayer Corporation. Onyx is
6 further informed and believes, and on that basis alleges, that in 2007, the right, title, and
interest in and to the Collaboration Agreement were assigned to Bayer HealthCare LLC.
7
ANSWER: A,dmitted.
8
11. Bayer Schering Pharma is a corporation organized and existing under the laws of
9' Germany, with its principal place of business located in Berlin, Germany.
10
ANSWER: Admitted.
11 12. Bayer Corporation, Bayer HealthCare and Bayer Schering Pharma are part of Bayer
12 AG, a German holding company with over 100,000 employees, operations in nearly every
country in the world, and sales in 2008 exceeding 32 billion Euros. Bayer AG is a corporation
13 organized and existing under the laws of Germany, with its principal place of business located
in Leverkusen, Germany.
14
•ANSWER: The German Bayer Entities admit (1) that Bayer AG is a German
15
corporation with its principal place of business in Leverkusen, Germany, (2) that Bayer
16
Corporation and Bayer Schering Pharma AG are wholly-owned subsidiaries of Bayer AG and
17
(3) that Bayer HealthCare LLC is a subsidiary of Bayer Corp. The German Bayer Entities deny
18
any remaining allegations not expressly admitted herein.
19
Jurisdiction And Venue
20
13. This Court has original jurisdiction pursuant to 28 U.S.C. § 1332(a), in that this is a
21 civil action between citizens of different states in which the matter in controversy exceeds,
22 exclusive of costs and interest, seventy-five thousand dollars ($75,000.00).
23 ANSWER: The German Bayer Entities admit that this action is styled on its face as a
24 diversity action under 28 U.S.C. § 1332(a), for which Onyx is claiming the matter in controversy
25 exceeds, exclusive of costs and interest, seventy-five thousand dollars ($75,000.00). The
27 14. This Court has jurisdiction over the defendants because they actively do business in
California and have sufficient minimum contacts in California, or otherwise intentionally
28 availed themselves of the benefits of conducting business in California to be subject to the
ANSWER AND AFFIRMATIVE DEFENSES OF BAYER AG AND BAYER -5-
SCHERING PHARMA AG TO ONYXPHARMACEUTICALS, INC. 'S FIRST
Case3:09-cy-.02145-MHP Document35 Filed0B/12/09 • Page6 of 26
1 court's jurisdiction. In particular, the Collaboration Agreement was negotiated within the
jurisdiction of this Court, and the parties understood that Onyx's obligations under the
2 Agreement would be performed within this Court's jurisdiction. The Collaboration Agreement
and the Letter Agreement (described below) expressly provide that they are governed by
3
California law.
4
ANSWER: The German Bayer Entities admit that the Court has specific personal
5
jurisdiction over Bayer AG and Bayer_Schering Pharma AG in this matter. The German Bayer
6
Entities deny that the Court has general jurisdiction over Bayer AG and Bayer Schering Pharma
7
AG. The German Bayer Entities deny any remaining allegations not expressly admitted herein.
8
15. Venue is proper in this district pursuant to 28 U.S.C. § 1391(a) and (c). A
9 substantial part of the events underlying this action occurred within this district. This Court
also has personal jurisdiction over defendants and, accordingly venue is proper.
10
ANSWER: The German Bayer Entities admit that venue is proper in this district.
11
Intradistrict Assignment
12
16. The appropriate Intradistrict Assignment for this case is the San Francisco Division -
13 or the Oakland Division, pursuant to Civ. L.R. 3-2(c) and (d). A substantial part of the events
14 underlying this action occurred within Alameda County and Contra Costa County.
15 ANSWER: The 'German Bayer Entities admit that the San ·Francisco or Oakland
16 Division is an appropriate Intradistrict Assignment for this case. The German Bayer Entities
17 deny any remaining allegations not expressly admitted herein.
18 Common Allegations
-
19 17. In the early 1990s, Bayer AG established the goal of exploiting new business
opportunities in the market for targeted cancer therapies. Bayer AG and its affiliates, however,
20 lacked the scientific expertise to research and develop these therapies independently. Bayer
AG recognized the expertise of Onyx's scientists in the Ras Pathway, and understood that
21
identifying compounds that inhibit proteins in the Ras Pathway could be the key tq success in
22 targeted cancer research. Bayer AG therefore approached Onyx and sought to gain access to
the company's technology, know-how, and library of chemical compounds that could have
23 effects on the Ras Pathway.
24 ANSWER: The German Bayer Entities admit (1) that in the early 1990's Bayer entities
25 sought opportunities in the field of targeted cancer therapies, and (2) that Bayer AG and Onyx
26 engaged in discussions about technology relating to the Ras Pathway. The German Bayer
27 Entities deny that Bayer AG and its affiliates lacked the scientifip expertise to research and
28
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~
Case3:09-cv-02145-MHP Document35 Filed08/12/09 Page? of 26
1 develop these therapies independently .. The German Bayer Entities deny any remaining
3 18. Bayer AG and Onyx engaged in extensive negotiations over the terms of the
proposed collaboration to develop cancer drugs. · Late in the negotiations, Bayer AG informed
4 Onyx that Bayer (then known as Miles Inc.), not Bayer AG, would be the party that would sign
a contract with Onyx. Shortly thereafter, on April 22, 1994, Onyx and Bayer entered into a
5
Collaboration Agreement. Under the Collaboration Agreement and its 1996 and 1999
6 amendments, the parties committed to work together to discover, develop and market chemical
compounds having activity against proteins in the Ras Pathway.
-
7
ANSWER: The German Bayer Entities adniit that Onyx and Bayer AG negotiated
8
, various terms of the 1994 Collaboration Agreement, and ultimately Onyx and Miles (corporate
9
predecessor to Bayer Corporation) entered into th~ 1994 Collaboration Agreement on April 22,
10
1994, under which Miles and Onyx agreed to certain specific obligations relating to the research,
11
development, and marketing of certain specificall:x-defined compounds having activity inhibiting
12
Ras Function. The German Bayer Entities deny any remaining allegations not expressly
13.
admitted herein.
14
19. Onyx recognized that other companies within the Bayer AG family of companies
15 might assist Bayer in performing under the Collaboration Agreement, and was concerned by
Bayer AG's late substitution of Bayer as the contracting party. Accordingly, "as an
. 16 inducement to Onyx to execute the Agreement," Bayer AG entered into an agreement (the .
17 "Letter Agreement") with Bayer, contemporaneous with the signing of the Collaboration
Agreement, confirming that, to the extent Bayer AG or any of its "Affiliates" conducted
18 research, development, or marketing or otherwise undertook Bayer's obligations under the
Collaboration Agreement, the Affiliates would "do so in accordance with the provisions of the
19 Agreement." "Affiliate"was defined in the Collaboration Agreement and the Letter Agreement
as any entity that, directly or indirectly, is under common ownership with Bayer. The Letter
20
Agreement between Bayer and Bayer AG expressly recognized Onyx as a third-party
21 beneficiary. Onyx recently was informed by Bayer, and on that basis alleges, that the Letter
Agreement was transferred to Bayer Schering Pharma. Pursuant to such transfer, Bayer
22 Schering Pharma now holds (jointly with BayerAG) Bayer AG's rights and obligations there-
under.
23
ANSWER: The German Bayer Entities admit that Bayer AG signed an April 22, 1994
24
letter to Miles Inc. (corporate predecessor to Bayer Corporation). The April 22, 1994 letter
25
speaks for itself and the German Bayer Entities deny Onyx's characterization of that letter. The
26
German Bayer Entities further admit (1) that the Collaboration Agreement defined "Affiliate" as
27
"any entity that directly or indirectly Owns, is Owned by, or is under common Ownership" with
28
ANSWER AND AFFIRMATIVE DEFENSES OF BA YER AG AND BAYER : _ 7-
SCHERING PHARMA AG TOONYXPHARMACEUTICALS, INC. 'S FIRsT . 0 ~
""'""'°"°"""""•
c,.,,;No. CV 092145 MHP &-- (\ /~
IITRUE COPYII
1 Miles, (2) that on March 11, 2003, Bayer AG and Bayer HealthCare AG executed a "Hive-Down
2 and Transfer Agreement" between them that transferred to Bayer HealthCare AG all contracts
3 exclusively or primarily allocated to the health care business, and (3) that this transfer would
4 necessarily include the April 22, 1994 letter to the extent it is found to be a contract. On
5 December 30, 2008, Bayer HealthCare AG merged into Bayer Schering Pharma AG and, per the
6 relevant German law regulating the transformation of companies, Bayer HealthCare AG ceased
7 to exist and all assets and liabilities of Bayer HealthCare AG (including any rights and/or
8 obligations that may exist as a result of the April 22, 1994 letter) were transferred to Bayer
9 Schering Pharma AG. The German Bayer Entities deny any remaining allegations not expressly
10 admitted herein.
11 20. The Collaboration Agreement defined two categories of compounds, referred to as

"Collaboration Compounds" arid "Post-Collaboration Compounds," that are the subject of joint
12 development. Collaboration Compounds generally cover compounds that, before January 31,
2000, were "discovered, identified or synthesized" by Onyx or Bayer and "recognized" as
13
satisfying the standard for cancer inhibiting activity set forth in Exhibit D to the Collaboration
14 Agreement. Post-Collaboration Compounds generally cover those compounds (a) whose
chemical genus both covers a Collaboration Compound and is claimed in an Onyx or Bayer
15 patent and (b) that were "synthesized, identified or discovered" and recognized before a later
cutoff date as satisfying the standard in Exhibit D.
16
ANSWER: The German Bayer Entities admit that the Collaboration Agreement defines
17
"Collaboration Compounds" and "Post-Collaboration Compounds" in sections 1.9 and 1.39,
18
respectively, as amended, which speak for themselves. The German Bayer Entities deny the
19
factual allegations in this paragraph to the extent they purport to summarize the definitions of
20
Collaboration Compounds and Post-Collaboration Compounds in a manner inconsistent with the
21
explicit language of sections 1.9 and 1.39 of the Collaboration Agreement. The German Bayer
22
Entities deny any remaining allegations not expressly admitted herein.
23
21. The Collaboration Agreement specifies the requirements for developing
24 Collaboration Compounds and Post-Collaboration Compounds into marketable, FDA-approved
25 products. The Collaboration Agreement requires the parties to work together in such
development and allows one party to pursue independent pre-clinical research of a
26 Collaboration Compound only if the other party is first given the opportunity for joint pre-
clinical research and declines to participate. Even then, however, the party pursuing
27 independent pre-clinical research must offer the other party the opportunity to collaborate in
development if the research looks promising.
28
ANSWER AND AFFIRMATIVEDEFENSES OF BAYER AG AND BA ".ER -8-

SCHERINGPHARMA AG TO ONYX PHARMACEUTICALS,INC. 'S FIRST
AMENDEDCOMPLAINT,
CASENo. CV 09 2145 MHP
=-"'-~
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1 ANSWER: The German Bayer Entities admit that the Collaboration Agreement's
2 various sections define the requirements and exceptions that existed during the Research Term
3 that were associated with co-development of Collaboration Compounds and Post-Collaboration
4 Compounds into FDA-approved products, as well as the requirements for either party to pursue
5 independent research and development. The German Bayer Entities deny the remaining factual
6 allegations in this paragraph to the extent they purport to summarize the detailed requirements of
7 the Collaboration Agreement's relevant sections in a manner inconsistent with the language of
8 the Collaboration Agreement. The German Bayer Entities deny any remaining allegations not
9 expressly admitted herein.
10 22. The Collaboration Agreement established a Joint Research and Development

Committee (JRDC), populated by representatives of Bayer and Onyx, to govern the
11 collaboration. The role of the JRDC was to manage and make decisions regarding the
collaboration. The JRDC, later renamed the Joint Development Committee, still exists and
12
continues to meet.
13
ANSWER: The German Bayer Entities admit that the Collaboration Agreement
14
established a Joint Research and Development Committee (JRDC), populated by representatives
15
of Bayer and Onyx, and that the role of the JRDC is set forth in section 3 of the Collaboration
16
Agreement. The German Bayer Entities deny that the JRDC was "later renamed the Joint
17
Development Committee." The German Bayer Entities admit that there currently is a "Joint
18
Development Committee" that was established as a subcommittee of the "Executive
19
Committee," which is the successor to the JRDC created after the end of the Research Term.
20
The German Bayer Entities deny any remaining allegations not expressly admitted herein.
21
23. So that those decisions could be well informed, the Collaboration Agreement
22 established numerous obligations for information disclosure and good faith between the
parties. Article 10.1 of the Collaboration Agreement, for example, requires full disclosure to
23 the other party of "the Information and all other significant information, data, and results
known or developed by each party as of the Effective Date and during the Research Term"
24 (defined to end on January 31, 1999) "as soon as practicable" after the information is obtained
25 or its significance is appreciated.
26 ANSWER: The German Bayer Entities admit that the Collaboration Agreement
27 established and defined the limits of the parties' collaboration obligations, including any
28 obligations for information disclosure during the "Research Term." The German Bayer Entities
ANSWER AND AFFIRMATIVE DEFENSES OF BAYER AG AND BAYER -9-

AMENDEDCOMPLAINT,
£~
IITRUE COPY!I
1 further admit that there is a section 10.1 of the Collaboration Agreement, and it states that "Onyx
2 and Miles shall make available and disclose to each other the Information and all other
3 significant information, data, and results known or developed by each party as of the Effective
4 Date and during the Research Term, relating to the Field and the Field of Collaborative
5 Research," "with significant discoveries or advances [in the Field and the Field of Collaborative
6 Research] being communicated as soon as practicable after such information is obtained or its
7 significance is appreciated." The German Bayer Entities deny the factual allegations in this
8 paragraph to the extent they purport to summarize section 10.1 in a manner inconsistent with its
9 express language, and. specifically deny that the Collaboration Agreement defines an express
10 contractual obligation of "good faith" between the parties. The German Bayer Entities deny any
11 remaining allegations not expressly admitted herein.

i
12 24. Article 10.2 of the Collaboration Agreement extends the obligation to make
quarterly reports to the JRDC beyond the Research Term, such that, if a party continues work
13 on Collaboration Compounds not yet in development as of the end of the Research Term, it
must provide sufficient disclosure to enable the other party to assess whether or not to pursue
14
joint funding of pre-clinical research and/or development.
15
ANSWER: The German Bayer Entities admit that section 10.2 of the Collaboration
16
Agreement states that parties shall submit quarterly reports to the JRDC beyond the Research
17
Term "regarding all work being done by such Party with respect to Collaboration Compounds
18
not yet in Development and other compounds under active investigation in the Research as of the
19
end of the Research Term, at a level of detail sufficient to enable the other Party to understand
20
the progress being made and to evaluate whether to participate in funding such preclinical work
21
under Section 9.6." The German Bayer Entities deny any remaining allegations not expressly
22
admitted herein.
23
25. Article 20.2 addresses patent disclosures, obligating a party to disclose to the other
24 party patentable inventions arising in the course of the collaboration. This section also requires
a party to furnish the other party with drafts of any patent application that discloses a
25 Collaboration Compound, allowing adequate time for review and comment before filing.
26 ANSWER: The German Bayer Entities admit that section 20.2 addresses "Disclosure of
27 Patentable Inventions," the language of which speaks for itself. The German Bayer Entities deny
'i.·
28 the factual allegations in this paragraph to the extent they purport to summarize section 20.2 in a
.4
ANSWER AND AFFIRMATIVE DEFENSES OF BA YER AG AND BA YER -10-
SCHERING PHARMA AG TOONYXPHARMACEUTICALS, INC. 's FmsT
AMmm>DCoM,~, CM, No. CV 09 2145 MHP 2(.✓
zE----
11TRUE COPYII
1 manner inconsistent with that section's explicit language. ~e German Bayer· Entities deny any
3 26. Article 26.2 of the Collaboration Agreement recognizes (similar to the Bayer AG
Letter Agreement) that Bayer may perform its obligations through Affiliates and provides that,
4 in such cases, Bayer "shall remain responsible and be guarantor" of the Affiliates' compliance
with the provisions of the Collaboration Agreement.
5
6 ANSWER: The German Bayer Entities admit that section 26.2 of the Collaboration
7 agreement recognizes that either party ,may perform some or all of its obligations through
8 Affiliates and provides that, in such:cases, each party "shall remain responsible and be guarantor
9 of the performance by such Affiliates and shall cause such Affiliates to comply with the
10 provisions of this [Collaboration] Agreement in connection with such performance." The
12 27. Article 28.1 of the Collaboration Agreement provides that any assignment of rights
or obligations under the Agreement by Bayer to any Affiliate shall not relieve Bayer of its
13 responsibilities for performance of its obligations under the Agreement.
14 ANSWER: The German Bayer Entities admit that section 28.1 of the Collaboration
15 Agreement addresses "Assignment," and allows in subsection (a) that "[e]ither Party may assign
16 any of its rights or ob~igations under the Agreement in any country to any Affiliates; provided,
17 however, that such assignment shall not relieve th.e assigning Party of its responsibilities for
18 performance of its obligations under this Agreement." The German Bayer Entities deny any

20 28. In the course of negotiations, the parties emphasized the importance of a
collaborative relationship built on principles of trust and good faith. To embody this model,
21 the parties included in Article 3.6 of the Collaboration Agreement an express covenant of good
faith:
22
. . - .
23 In all matters related to the collaboration established by this Agreement, the

Parties shall be guided by standards of reasonableness in economic terms and
24 fairness to each of the Parties, striving to balance as best they can the legitimate
interests and concerns of the Parties and to realize the economic potential of the
25 Products. fu conducting research, development, and commercialization ·activities
under this Agreement neither Party shall prejudice the value of a Product by
26
reason of such Party's activities outside of the Field.
27
28
ANSWER AND AFFIRMATIVE DEFENSES OF BAYER AG AND BAYER
-11- ,.
SCHERING PHARMA AG TO ONYX PHARMACEUTICALS, INC. 'S FIRST -
AMmmm>"°""-'""• CAo;No. CV 09 2145MHP ~ t(''#
IITRUE COPYII
1 ANSWER: The German Bayer Entities admit that the above excerpted paragraph
2 accurately quotes section 3 .6 of the Collaboration Agreement. The German Bayer Entities deny
3 any remaining allegations not expressly admitted herein.
4 29. The Collaboration Agreement also sought to ensure that Onyx and Bayer shared in
the risks as well as the rewards of drug discovery. For example, the parties were to share
5 equally in the costs of co-developing Collaboration Compounds and Post-Collaboration
compounds for the marketplace, which might entail expensive and lengthy clinical trials for
6
which approval would be far from assured .. If successful, however, the parties would share in
7 the rewards. For any co-developed Collaboration Compound sold in the marketplace, the
•
reward was to be an equal share of the profits. For any Post-Collaboration Compound, the
8 reward was to be a royalty paid by the seller.
9 ANSWER: The German Bayer Entities state that the language of the Collaboration
,10 Agreement speaks for itself, and deny the allegations of this paragraph ·to the extent they purport
11 to summarize the detailed requirements of the Collaboration Agreement's relevant se~tions in a

12 manner inconsistent with the language of the Collaboration Agreement. The German Bayer
13 Entities admit that the Collaboration Agreement outlined how the parties would allocate costs as
14 well as profits from the research and development of compounds covered by the Collaboration
15 Agreement. The German Bayer Entities deny any remaining allegations not expressly admitted
16 herein.
17 30. Early in the collaboration, the parties agreed that one Ras Pathway protein, raf
kinase, would be a good target for investigation. Raf kinase was understood to be involved in
18 processes leading to cell division and proliferation. The part1es hypothesized that raf kinase
'19 inhibitors, or chemical compounds that inhibit raf kinase, would prove effective in controlling
cancer cell growth. Using their expert knowledge of the Ras Pathway, Onyx scientists created
20 a unique assay, exclusive to the collaboration, that could test the raf-inhibitory activity of any
compound.
,21'
ANSWER: The German Bayer Entities admit (1) that Bayer and Onyx identified several
22
targets for investigation, one of which was rafkinase, (2) that rafkinase was understood to be
23
involved in cell division and proliferation processes, (3) that Bayer and Onyx hypothesized that
24
compounds inhibiting raf kinase could prove effective in inhibiting cancer cell growth, and
25
(4) that one of the many parts of the research, testing, and development of potential targeted
26
cancer therapies was a cell-based assay for testing raf-inhibitory activity that Onyx provided.
27
The German Bayer Entities are without knowledge or information sufficient to form a belief as
28
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1 to the truth of the allegation that Onyx "created" the assay it provided or that the assay was
2 "unique," and therefore deny that allegation. The tjerman Bayer Entities deny any remaining
I
i
4 31. With the assay in hand and its own library of small molecule compounds in house,
Onyx began searching for a Ras Pathway inhibitor. This effort succeeded, and Onyx identified
5 an inhibitor, dubbed N34213. Although N34213 was too weak an inhibitor to develop as a
cancer treatment, the basic chemical structure of that compound provided the key information
6
that Bayer and Onyx used to create thousands of ~ynthetic compounds for further evaluation.
7 As the number of synthesized compounds increased over the course of the collaboration, the
parties decided that Bayer would conduct initial tests on the synthesized compounds, using the
8 assay created by Onyx. Onyx thus conveyed the assay protocol to Bayer, along with various
purified reagents necessary to carry out the assay.!
9
ANSWER: The German Bayer Entities adrpit (1) that Onyx conveyed an assay protocol
10
to Bayer for testing raf-inhibitory activity, (2) that 9nyx identified a raf-inhibitor molecule that
11
'
lacked sufficient inhibitory activity to be a potential cancer therapy, and (3) that subsequently
12
Bayer synthesized thousands of different compounds in multiple research phases. From its
13
- . synthesis of additional compounds, Bayer identified additional unique raf-inhibitor compounds.
14 i
Through further Bayer research and optimization e~forts on these new and unique Bayer-
15
identified compounds, Bayer eventually discovered, and synthesized the compound that became
16
Nexavar®. The German Bayer Entities deny that the ''basic chemical structure of that [Onyx
17
I
inhibitor] compound provided the key information": for Bayer's subsequent research efforts. The
18
German Bayer Entities deny any remaining allegations not expressly admitted herein.
19
32. Bayer synthesized and ran initial tests on compounds. They discussed some of
20
these results with Onyx, and transferred some of these compounds to Onyx for further
21 evaluation. Following discussions with Onyx, Bdyer also synthesized additional compounds
that were structural analogs of compounds that sh.owedpromising activity.
22
ANSWER: The German Bayer Entities ad~it (1) that Bayer synthesized compounds in
23 i
multiple phases and ran tests on those compounds for raf-inhibitory activity, (2) that, as part of
I
24
its research plan, Bayer synthesized some structural analogs to compounds that showed
25
promising activity, and (3) that Bayer reported and ~iscussed its research plans and results with
26
Onyx. The German Bayer Entities deny any remaitling allegations not expressly admitted
27 I -
I
herein. 1
28
ANSWER AND AFFIRMATIVE DEFENSES OF BAYER AG AND BA YER

-13- -
SCHERING PHARMA AG TO ONYX PHARMACEUTICALS, INC. 'S FIRST
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Case3:09-cv-02145-MHP Document35 Filed0S/12/09 Page14 of 26
1 33. This collaborative process ultimately led the parties to their pioneering cancer drug
sorafenib. Sorafenib was so effective at inhibiting rafkinase, in fact, that it satisfied the
2 specified standard for inhibitory activity set forth in Exhibit D by a factor of more than 1000.
Eventually, the parties learned that sorafenib inhibited other biological targets as well,
3
rendering it a "multi-kinase" inhibitor.
4
ANSWER: The German Bayer Entities admit (1) that Bayer's research efforts led to
5
sorafenib, (2) that sorafenib satisfies the standards jn Exhibit D of the Collaboration Agreement
6
by a factor of more than 1000, and (3) that sorafenib is a multi-kinase inhibitor. The German
-
7
Bayer Entities deny Onyx's reference to sorafenib as "their pioneering cancer drug" to the extent
8
this implies that Onyx jointly owns sorafenib. The German Bayer Entities deny any remaining
9
allegations not expressly admitted herein.
10
34. Sorafenib was not the only compound discovered and recognized to have inhibitory
11 activity under the collaboration. Bayer filed a p~tent application on January 13, 1999 (during
the Research Term) that illustrates over 100 compounds (including sorafenib) that have raf-
12 kinase inhibitory activity satisfying the standard specified in Exhibit D.
13 ANSWER: The <Jerman Bayer Entities a~mit that Bayer filed a provisional patent
14 applicatiop. on January 13, 1999 that disclosed specific examples, including sorafenib and a
15 variety of possible analogues. Regorafenib was not one of the example compounds disclosed in
16 the January 13, 1999 application; and the January 13, 1999 application does not disclose
17 regorafenib's rafkinase inhibitory activity. The German Bayer Entities further admit that the
18 January 13, 1999 application states that the "compounds exemplified displayed IC50s of between
19 1 nm and l0µm." The German Bayer Entities deny any remaining allegations not expressly
20 admitted herein.
21 35. The January 13, 1999 patent application also shows that a sorafenib molecule can
be modified at one particular location with minimal effect on its raf-kinase inhibitory activity.
22
The chemical formula for sorafenib is illustrated below in Figure 1, with an arrow pointing to
23 the position "2" on the central ring structure of the molecule. In sorafenib, that position has a
hydrogen atom attached to the ring (per standard chemical drawing practice, the hydrogen is
24 not shown). The January 13, 1999 application explicitly shows two substitutions at this
position .. In one case, a chlorine atom (Cl) replaces the hydrogen. In another case, a much
25 larger, methyl group (CH 3), replaces the hydrogen. In both cases, the compounds were
confirmed to have rafkinase inhibitory activity well within the specified standard in Exhibit D
26
to.the Collaboration Agreement. •
27 '~~
:
28
ANSW
SCHEI
AMEN
1 ANSWER: The German Bayer Entities admit (1) that figure 1 is the chemical formula
2 for sorafenib, (2) that the arrow in figure 1 points to a position on sorafenib where a hydrogen
3 atom is attached, and that standard chemical drawing practice omits displaying hydrogen atoms,
4 (3) that two of the compounds disclosed as specific examples in the January 13, 1999 patent
5 application are compounds that substitute a methyl group and a chlorine atom, respectively, at
6 the position indicated by the arrow in Figure 1, and (4) that the January 13, 1999 application
7 states that the "compounds exemplified displayed ICsos of between 1 nm and lOµm" The
8 German Bayer Entitie.s deny (1) that the January 13, 1999 patent application discloses as an
9 example any compound that substitutes a fluorine atom at the position indicated by the arrow in
10 Figure 1, and (2) that the January 13, 1999 application shows that modification at the position
11 "2" indicated in Figure 1 could occur "with minimal effect on its raf-kinase inhibitory activity."
12 The German Bayer Entities deny any remaining allegations not expressly admitted herein.
13 36. The illustrated compounds are not the only ones discussed and described in the
January 13, 1999 application. In text, the patent application explains that "halogens," a class
14 of elements to which both fluorine and chlorine belong, can be substituted for one another in
the compound. The patent that ultimately issued from this application as Unites States Patent
15
No. 7,351,834 claims the chemical structures of sorafenib and its halogenated brethren, and
16 reports the rafkinase-inhibiting properties of the entire family. Accordingly, the rafkinase-
inhibiting properties of sorafenib, chloro-sorafenib and fluoro-sorafenib were recognized well
17 before the cutoff date for the recognition of Collaboration Compounds, January 31, 2000.
18 ANSWER: The German Bayer Entities admit that the January 13, 1999 patent
19 application and the issued patent U.S. Pat. No. 7,351,834 state (at column 4:21-25), "Suitable
20 halogen groups include F, Cl, Br, and/or I, from one to per-substitution (i.e. all H atoms on a
21 group replaced by a halogen atom) being possible where an alkyl group is substituted by a
22 halogen, mixed substitution of halogen atom types also being possible on a given moiety." The
23 German Bayer Entities further admit that certain generic claims of the '834 patent could be read
24 to cover a variety of compound structures including the structure of sorafenib and regorafenib.
25 The German Bayer Entities deny (1) that the January 13, 1999 application "reports the raf
26 kinase-inhibiting properties of the entire family," (2) that the regorafenib molecule was disclosed
27 in the January 13, 1999 application, (3) that regorafenib was synthesized or tested prior to
28 January 31, 2000, (4) that the raf-kinase inhibiting properties ofregorafenib were "recognized"
AMENDED COMPLAINT, CASE NO. CV 09 2145 MHP
IITRUE COPYII
1 before January 31, 2000, and (5) that there are any compounds known as "chloro-sorafenib" or
2 "fluoro-sorafenib." The German Bayer Entities deny any remaining allegations not expressly
3 admitted herein.
4 37. The chemical formulas for sorafenib and the fraternal twins chloro- and fluoro-
sorafenib,'are illustrated below in Figures 2, 3 and 4, respectively.
5
-
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
ANSWER: The German Bayer Entities deny that there are compounds known as
23
"chloro-sorafenib" or "fluoro-sorafenib." The German Bayer Entities admit (1) that Figure 2 is
24
the chemical formula for sorafenib, (2) that Figure 3 is the chemical structure of regorafenib,
25
and (3) that figure 4 is a chemical formula of a chlorine-substituted compound corresponding to
26
example number 49 disclosed in the '834 patent at column 73-74. The German Bayer Entities
27
deny any remaining allegations not expressly admitted herein.
28
ANSWER AND AFFlRMA TIVE DEFENSES OF BA YER AG AND BA YER
SCHERING PHARMA AG TOONYX PHARMACElITICALS, INC. 'S FCRST
IITRUE COPYII
1 38. The-parties fully understood, well before the cutoff date for the recognition of
Collaboratidn Compounds, January 31, 2000, that sorafenib and its halogenated twins would
2 exhibit rafkinase-inhibitory activity well within: the specified standard. This is no surprise
given that sorafenib and its halogenated brethren are, chemically speaking, nearly identical.
3
4 ANSWER: The German Bayer Entities admit (1) that sorafenib satisfied Exhibit D's
5 inhibitory activity standard for the primary assay prior to January 31, 2000, (2) that the chlorine-
6 substituted compound in Figure 4 was disclosed as a specific example in the January 13, 1999
7 patent application, and (3) that the January 13, 1999 application states that the "compounds
- 8
10
exemplified displayed IC50s of between 1 nm and l0µm." .The German Bayer Entities deny
(1) that regorafenib was synthesized ortested prior to January-31, 2000, (2) that the raf-kinase
inhibiting properties ofregorafenib were "recognized" before January 31, 2000,.and (3) that the
11 compounds in figures 2-4 are "chemically speaking, nearly identicaL" The German Bayer
12 Entities deny any remaining allegations not expressly admitted herein.
13 39. Ultimately, the parties chose to develop sorafenib and began clinical trials in late
2000. •In accordance with the Collaboration Agreement, the parties co-funded the clinical
14 trials, and Onyx made substantial payments to Bayer, which otherwise funded and managed
the trials. The trials ultimately proved successful, 'leading to FDA approval in 2005 and 2007
15 for the marketing of sorafenib for treating patients with kidney and liver cancer, respectively.
16 ANSWER: The German Bayer Entities admit (1) that the parties ultimately decided to
17 focus development efforts on sorafenib and (2) that the parties co-funded the clinical trials of
18 sonifenib. •The German Bayer Entities deny that Bayer "otherwise funded and managed the
19 trials." The German Bayer Entities further admit that Bayer managed trials relating to kidney
20 and liver cancer, which ultimately resulted in FDA approval, but states that Onyx managed
21 clinical trials relating to melanoma, which failed to secure FDA approval. The German Bayer
22 Entities deny any remaining allegations not expressly admitted herein.
23 40. Meanwhile, as the jointly-funded clinical trials progressed and Bayer began to
realize that sorafenib was destined for success,·defendants secretly launched a plan to displace
24
it. In or around 2003, Bayer, along with other subsidiaries of Bayer AG, surreptitiously began
25 filing patent applications directed to fluoro-sorafenib. Fluoro-sorafenib was not a compound
that Bayer had recently discovered or, indeed, that involved any new discovery effort by Bayer
26 or its Affiliates following the end of the Research Term in early 1999. On the contrary, Onyx
and Bayer had explicitly identified ffuoro-sorafenib in 1998. Nonetheless, neither Bayer nor
27 its Affiliates disclosed the patent filing~ for fluoro-sorafenib to Onyx, which remained unaware
28 of these actions. Then, in or around 2005, Bayer and its Affiliates announced clinical trials on
-j.t"
i-
a cancer drug they referred to as DAST. But the announcement omitted the chemical formula
ANSWER AND Af'FIRMATIVEDEFENSES OF BAYER AG AND BA YER 17
SCHERING PHARMA AG TO ONYX PHARMACEUTICALS,INC.'s-FIRST -
AM>NmID"'™"-"""'•
C•" No. cv 092145 MHP i\ .
z£-- .
IITRUE COPYII
1 for DAST, leaving Onyx unaware that DAST was a code name for fluoro-sorafenib. Nor did
defendants ever notify the Joint Development Committee that they were beginning clinical
2 trials on a compound that arose from the collaboration. Defendants have given Onyx no
chance to review and comment on the clinical trial submissions, much less to participate in the
3
trials.
4
ANSWER: The German Bayer Entities deny that there is a compound known as "fluoro-
5
sorafenib." The German Bayer Entities deny that Bayer "secretly launched a plan to displace"
6
sorafenib. The German Bayer Entities admit (1) that Bayer filed patent applications relating to
7
regorafenib beginning in the summer of 2003, (2) that Bayer did not disclose such patent
8
applications to Onyx, as it was not required to do so, (3) that Bayer announced its regorafenib
9
clinical trials in or around 2005, and, per standard procedure, did not at that time disclose the
10
chemical formula of regorafenib in these announcements, and (4) that Bayer did not, nor was it
11
required to, notify the JRDC of its clinical trials on regorafenib, nor ask Onyx or the JRDC to
12
comment on, or participate in, the clinical trials on regorafenib. The German Bayer Entities deny
13
any remaining allegations not expressly admitted herein.
14
41. In or around April 2007, Bayer Affiliates made a presentation to Onyx of various
15 cancer compounds they were investigating. Butdespite the fact that clinical trials for fluoro-
sorafenib had been initiated i.p_2005 and were ongoing, the executives and employees attending
16 the April 2007 meeting failed to disclose to Onyx that Bayer Affiliates were developing fluoro-
sorafenib. •
17
18
sorafenib." The German Bayer Entities admit (1) that beginning in around April 2007, Bayer
19
HealthCare, LLC began discussions ~ith Onyx about potential business arrangements relating to
20
various new, Bayer-developed compounds: including regorafenib and (2) that Bayer HealthCare,
21
LLC did not, at that time, specifically disclose the _chemicalstructure of any of its newly
22
developed products, including regorafenib. The German Bayer Entities deny any remaining
23
allegations not expressly admitted herein.
24
42. Bayer Affiliates then began publishing their research and discovery efforts with
25
DAST. In June 2007, Bayer HealthCare AG and Bayer Schering Pharma announced DAST as
26 being one of their development candidates for cancer therapy (again without revealing that it
was fluoro-sorafenib ).
27
28
ANSWER AND AFFIRMATIVE DEFENSES OF BAYER AG AND BA YER
SCHERING PHARMA AG TO ONYX PHARMACEUTICALS,INC. 'S FIRST
AMENDEDCOMPLAINT,
CASENO. CV 09 2145 MHP
IITRUE COPYII
1 ANSWER: The German Bayer Entities deny that there is a compound known as "fluoro-
2 sorafenib." The German Bayer Entities admit that Bayer HealthCare, LLC or one of its
3 predecessors began publishing articles relating to regorafenib, and that in and around
4 approximately June 2007 it announced regorafenib as a development candidate for targeted
5 cancer therapy. The German Bayer Entities deny any remaining allegations not expressly
6 admitted herein.
7 43. In early 2009, as the details of the DAST clinical trials became better known, Onyx
asked Bayer Affiliates to reveal the chemical structure ofDAST. Initially, they denied that
8 DAST was a Collaboration Compound, but refused to reveal more. Finally,'on March 31,
2009, an executive of Bayer HealthCare Pharmaceuticals, Inc. (an Affiliate of Bayer),
9
admitted that the chemical structure ofDAST was, indeed, fluoro-sorafenib. According to the
10 executive, because Bayer had postponed testing of fluoro-sorafenib until after January 31,
2002, Bayer had not "recognized" that the compound satisfied the specified standard for ras
11 inhibitory activity by that date. Accordingly, the executive declared, Bayer and its Affiliates
are entitled to develop and market fluoro-sorafenib ''unrestrained" by Onyx.
12
13
sorafenib." The German Bayer Entities admit that on March 20, 2009, Onyx wrote a letter to
14
Bayer HealthCare LLC asking it to confirm that regorafenib had the chemical formula listed
15
above in figure 3 and demanding that Bayer acknowledge regorafenib as a "Collaboration
16
Compound" or "Post-Collaboration Compound" under the Collaboration Agreement. The
17
German Bayer Entities further admit that Bayer H~althCare, LLC confirmed the chemical
18
structure of regorafenib, informed Onyx that regorafenib is not a "Collaboration Compound" or
-
19
"Post-Collaboration Compound," and informed Onyx that Onyx has no rights in regorafenib
20
under the Collaboration Agreement. The German Bayer Entities deny any remaining allegations
21
not expressly admitted herein .
. 22
44. On April 15, 2009, Onyx proposed a meeting of executives to negotiate in good
23
faith toward a resolution of the parties' dispute regarding whether fluoro-sorafenib is covered
24 under the Agreement. The executives met, but the parties were unable to resolve the dispute.
25 ANSWER: The German Bayer Entities deny that there is a compound known as "fluoro-
26 sorafenib." The German Bayer Entities admit (1) that on April 15, 2009, Onyx sent Bayer
27 HealthCare, LLC a letter as formal notice that Onyx was invoking the dispute resolution
28 provisions under the Collaboration Agreement relating to Onyx's position on regorafenib, and
ANSWER AND AFFIRMATIVE DEFENSES OF BAYER AG AND BAYER

AMENDED COMPLAINT, CASE NO. CV 09 2145 MHP
IiTRUE COPY!I
Ca~e3:09-cv-02145-MHP Document35 Filed0B/12/09 Page20 of 26
1 (2) that Bayer HealthCare, LLC and Onyx executives met, but Were unable to resolve the
2 situation. The German Bayer Entities deny any remaining allegations not expressly admitted
3 herein.·
4 45. In May 2009, Bayer HealthCare Pharmaceuticals, Inc., which is responsible for a
clinical trial offluoro-sorafenib in the U.S., reported on the results of a phase II trial in kidney
5 cancer and announced its intention to move forward with a phase III trial. Onyx is informed
and believes that if fluoro-sorafenib secures FDA approval, Bayer and its Affiliates intend to
6
market Onyx and Bayer's joint discovery-fluoro-sorafenib-as a direct competitor to the
7 parties' joint product, sorafenib, thereby reaping all of the benefits of the parties' collaboration
without sharing the rewards.
8
ANSWER: The German Bayer Entities deny that there is a compound known as ":tl.uoro-
9
sorafenib." The German Bayer Entities admit that Bayer HealthCare Pharmaceuticals Inc.
10
supported a phase II trial for regorafenib in kidney cancer, the results of which were reported in
11
May 2009 at an industry conference; The German Bayer Entities deny any remaining allegations
12
not expressly admitted herein.
13
46. Onyx is informed and believes, and based thereon alleges, that its.damages exceed
14 the amount of seventy-five·thousand dollars ($75,000), exclusive of costs and interest.
15 ANSWER: Denied.
16 First Claim For Relief
(Breach Of Contract)
17
47. Onyx re-alleges and incorporates by reference paragraphs 1-46, inclusive, as though
18 fully set forth herein.
19
•
ANSWER: The German Bayer Entities refer to and incorporates herein by reference
20
their answers to all the foregoing allegations of paragraphs 1-46 inclusive as if fully set forth
21
herein.
22
48. Onyx performed all of the terms and conditions of the parties' Collaboration
23 Agreement, as amended.
24 ANSWER: The German Bayer Entities are without knowledge or information sufficient
25 to form a belief as to the truth of the allegations in this paragraph and therefore deny that
26 allegation.
27 49. Defendants breached the Collaboration Agreement by, among other things:
28
ANSWER AND AFFIRMATIVEDEFENSES OF BAYER AG AND BA YER
-20- ,
1INC. 's FIRST
SCHERINGPHARMAAG TO ONYX PHARMACEUTICALS
AMENDEDCOMPLAINT,
~/2
IiTRUE COPYII
sorafenib;
(c) undermining the value of sorafenib through their development of
3 fluoro-sorafenib. •
4
ANSWER: Denied.
5
50. Defendants further breached their obligations under the Collaboration Agreement
6 and the Letter Agreement to cause their Affiliates to comply with the provisions of the
Collaboration Agreement.
7
ANSWER: Denied.
8
51. Alternatively, in the event a compound must be tested to be recognized under the-
9 Collaboration Agreement as a Collaboration Compound, defendants breached the
Collaboration Agreement if (as Bayer claims) they deferred testing of fluoro-sorafenib until
10
after January 31, 2000.
11
ANSWER: Denied.
12
52. As a proximate result of defendants' breach of the Collaboration Agreement and the
13 Letter Agreement, Onyx has sustained, continues to sustain, and will sustain damages,
including, but not limited to lost sales, damage to goodwill, and the inability to profit from
14 sales of fluoro-sorafenib. In addition, defendants were, are, and will be unjustly enriched
through their appropriation for themselves of the entire value of fluoro-sorafenib.
15
16 ANSWER: Denied.
17 Second Claim For Relief

(Breach Of Implied Covenant Of Good Faith And Fair Dealing)
18
19 fully set forth herein.
20 ANSWER: The German Bayer Entities refer to and incorporates herein by reference
21 their answers to all the foregoing allegations of paragraphs 1-52 inclusive as if fully set forth
22 herein.
23 54. A covenant to deal fairly and act in good faith is implied in the Onyx/Bayer
Collaboration Agreement and later amendments.
24
ANSWER: Denied.
25
55. Defendants breached these covenants by, among other things:
26
27 (a) failing to disclose their research and development plans for fluoro- •
sorafenib;

SCHERING PHARMA AG TO ONYX PHARMACEUTICALS, INC. 'S FIRsT
AMENDED COMPLAINT, CASE NO. CV 09 2145 MHl'
IITRUE COPY!I
1 (c) undermining the value of sorafenib through their development of

fluoro-sorafenib.
2
ANSWER: Denied.
3
56. Defendants further breached these covenants by failing to satisfy their obligations
4 under the Collaboration Agreement and the Letter Agreement to cause their Affiliates to
comply with the provisions of the Collaboration Agreement.
5
6 ANSWER: Denied.
-
Collaboration Agreement as a Collaboration Compound, Bayer breached these covenants if (as
8 Bayer claims) it deferred testing until after January 31, 2000.
9 ANSWER: Denied.
10 58. As a proximate result of defendants' breach of the Collaboration Agreement and the
Letter Agreement, Onyx has sustained, continues to sustain, and will sustain damages,
11 including, but not limited to lost sales, damage to goodwill, and the inability to profit from
12 sales offluoro-sorafenib. In addition, defendants were, are, and will be unjustly enriched
13
ANSWER: Denied.
14
Third Claim For Relief
15 (Breach of Fiduciary Duty)
16 59. Onyx re-alleges and incorporates by reference paragraphs 1-46, inclusive, as though
fully set forth herein.
17 l)
18
19
herein.·
20
60. The Collaboration Agreement created a legal joint venture. As collaborators and
21 joint venturers, defendants owed Onyx the highest degree of fiduciary duty, including but not
limited to the duty ofloyalty and honesty.
22
23 ANSWER: Denied.
24 61. Defendants breached their fiduciary duty to Onyx by, among other things:
sorafenib;
(c) undermining the value of sorafenib through their development of fluoro-
27 sorafenib.
28
ANSWER: Denied.
.AMENDED
COMPLAINT,
IITRUE COPY!I
Collaboration Agreement as a Collaboration Compound, Bayer Corporation breached its
2 fiduciary duty if(as Bayer claims) it deferred testing until after January 31, 2000.
3 ANSWER: Denied.
4 63. As a proximate result of defendants' breach of the Collaboration Agreement and the
5 Letter Agreement, Onyx has sustained, continues to sustain, and will sustain damages,
including, but not limited to lost sales, damage to goodwill, and the inability to profit from
6 sales of fluoro-sorafenib. In addition, defendants were, are, and will be unjustly enriched
7
ANSWER: Denied.
8
64. Defendants' conduct in breaching their fiduciary duties was malicious, oppressive,
9 fraudulent, and otherwise entitles Onyx to an award of exemplary and punitive damages.
10
ANSWER: Denied.
11 Fourth Claim For Relief
(Declaratory Relief)
12
13
fuliy set forth herein.
14
15
16
herein.
17
66. Onyx desires a declaration regarding its rights to fluoro-sorafenib.
18
ANSWER: The German Bayer Entities deny that there is a compound lmown as "fluoro-
19
sorafenib." The German Bayer Entities are without lmowledge or information sufficient to form
20
a belief as to the truth of the remaining allegations in this paragraph and therefore deny that
21
allegation.
22
67. An actual controversy exists between Onyx and the defendants relating to their
23 respective rights to fluoro-sorafenib. In particular, there is a dispute regarding whether fluoro-
sorafenib is a Collaboration Compound. Defendants contend that it is not, and that they
24 therefore may independently develop fluoro-sorafenib and eventually sell it without sharing
25 profits with Onyx. Onyx contends that fluoro-sorafenib is a Collaboration Compound,
entitling Onyx to participate equally in co-development and to share equally in the profits from
26 any future sales.
27 ANSWER: The German Bayer Entities deny that there is a compound lmown as "fluoro-
28 sorafenib." The German Bayer Entities admit that this First Amended Complaint describes an
ANSWER AND AFFIRMATIVEDEFENSES OF BAYER AG AND BA YER
SCHERINGPHARMAAG TO ONYX PHARMACEUTICALS,INC. 's FIRST
IITRUE COPY!I
1 actual controversy between Onyx and Bayer with respect to regorafenib in the manner alleged in
2 this paragraph. The German Bayer Entities deny any remaining allegations not expressly
3 admitted herein.
4 68. In order to resolve this dispute, Onyx requests that the Court declare the rights and
obligations of Onyx and Bayer regarding fluoro-sorafenib. Specifically, Onyx requests a
5 declaration that fluoro-sorafenib is a Collaboration Compound, that Onyx is entitled to
participate equally in co-development, and that Onyx should receive a 50% share in the profits
6
(as defined in the Collaboration Agreement) from any future sales offluoro-sorafenib.
7
ANSWER: Denied.
8
RESPONSE TO PLAINTIFF'S PRAYER FOR RELIEF
9
The German Bayer Entities deny that Onyx is entitled to the judgment it seeks in
10
paragraphs 1-9 of its Prayer For Relief. Onyx's First Amended Complaint should be dismissed,
11
and its prayer for relief should be denied in its entirety, with prejudice.
12
AFFIRMATIVE DEFENSES
13
Further answering the First Amended Complaint and as additional defenses thereto, the
14
German Bayer Entities assert the following affirmative defenses, without assuming any burden
15
of proof it would not otherwise bear under applicable law.
16
FAILURE
T0STATEACLAIM
17
1. The First Amended Complaint fails to state a claim upon which relief can be
18
granted.
19
STATUTE
OFLIMITATIONS
20
2. Onyx's claims are barred in whole or in part by relevant statutes oflimitations.
21
EST0PPEL,
WAIVER,
AND/ORLACHES
22
3. Onyx's claims are barred in whole or in part by the doctrines ofEstoppel, Waiver,
23
and/or Laches.
24
AGREEMENT,
RATIFICATION,
ANDACQUIESCENCE
25
4. Onyx's claims are barred in whole or in part by its agreement to, ratification of,
26
and/or acquiescence to, the acts and omissions about which it now complains.
27
28
ANSWER AND AFFIRMATNE DEFENSES OF BA YER AG AND BA YER
SCHERING PHARMA AG TOONYX PHARMACEUTICALS, INC. 'S FIRST
AMENDEDCOMPLAINT,
CASENO. CV09 2145MHP
IITRUE COPYII
1 FAILURE OF CONDITIONS PRECEDENT
2 5. Onyx's claims are barred in whole or in part by the failure of conditions precedent
3 to Bayer's performance.
4 UNCLEAN HANDS
5 6. Onyx's claims are barred in whole or in part by the doctrine of unclean hands.
6 RESERVATION OF RIGHTS
-
7 7. The German Bayer Entities reserve the right to assert any and all additional
8 affirmative defenses that may be determined duringthe course of discovery.

9 JURYDEMAND
10 The German Bayer Entities respectfully request that a jury try the issues in this matter.
11
12 Dated: August 12,2009 LAWRENCE R. KATZIN

NATALIE THINGELSTAD
13 AMY C. DACHTLER
14 MORRISON& FOERSTER
LLP
15 MARK L. LEVINE
JASON L. PELTZ
16 BRIAN C. SWANSON
J. SCOTT MCBRIDE
17
BARTLITBECKHER.MAN
PALENCHAR & SCOITLLP
18
19 By: Isl Lawrence R. Katzin
LAWRENCE R. KATZIN
20
Attorneys for Defendants
21
BAYERCORPORATION, BAYER
22 HEALTHCARE LLC, BAYERAG AND BAYER
SCHERING PHARMA AG
23
24
25
26
27
28
.ANSWERANDAfFIRMATIVEDEFENSESOFBAYERAGANDB~AYER
SCHERINGPHARMAAG TO ONYX PHARMACElITICALS,INC. 'S FIRST
-2.5-~ nr
• \../
Ji•
AMENDED
COMPLAINT,
IITRUE COPYII
1 CERTIFICATE OF SERVICE
2 The undersigned certifies that the foregoing document was filed electronically. As such,
3 this document was served on all counsel who are deemed to have consented to electronic service.
4 Pursuant to Fed. R. Civ. P. 5(d) all other counsel of record not deemed to have consented to
5 electronic service were served with a true and correct copy of the foregoing by email and/or fax,
6 on this 12th day of August, 2009.
-
7 BY: /s/LAWRENCER.KATZIN
8 LAWRENCE R. KATZIN
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
ANSWER AND AfFIRMATIVE DEFENSES OF BA YER AG AND BA YER
SCHERING PHARMA AG TO ONYXPIIARMACEUTICALS, INC.'S FIRsT
AMENDEDCOMPLAINT,
CASENO. CV 09 2145 MHP
IITRUE COPYII
CS (Comm.) No. 660 of 2022
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EX-10.1(VI) 4 d265452dex101vi.htm AGREEMENT REGARDING REGORAFENIB
[ * ] = Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately
with the Securities and Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of 1934, as amended.
EXHIBIT 10.1(vi)
AGREEMENT REGARDING REGORAFENIB
between
BAYER HEALTHCARE LLC
and
Dated as of October 11, 2011

AGREEMENT REGARDING REGORAFENIB
This AGREEMENT REGARDING REGORAFENIB (this “Agreement”) is entered into as of this 11th day of October, 2011
(the “Effective Date”) between BAYER HEALTHCARE LLC, a Delaware limited liability company (“Bayer”) and ONYX
PHARMACEUTICALS, INC., a Delaware corporation (“Onyx”). Bayer and Onyx are sometimes referred to herein individually as a
“Party” and collectively as the “Parties.”
RECITALS
WHEREAS, Bayer’s predecessor, Miles Inc., and Onyx entered into a Collaboration Agreement dated April 22, 1994, as
amended on April 4, 1996 and February 1, 1999 and as further amended by that certain U.S. Co-Promotion Agreement between the
Parties dated March 6, 2006 (the “2006 Co-Promotion Agreement”) and by the Fourth Amendment to the Collaboration Agreement
dated of even date herewith (the “Fourth Amendment”) (collectively, as amended, the “Collaboration Agreement”);
WHEREAS, pursuant to the Collaboration Agreement, the Parties conducted a collaborative research program and jointly
developed a pharmaceutical product now marketed under the trade name Nexavar®;
WHEREAS, Bayer is engaged in clinical development of a multikinase inhibitor known as regorafenib, and in 2009 Onyx
commenced litigation regarding rights in regorafenib under the Collaboration Agreement (Onyx v. Bayer, Case No. C09-02145 EMC
pending in U.S. District Court for the Northern District of California, the “Litigation”); and
WHEREAS, the Parties have agreed to resolve the Litigation pursuant to a Settlement Agreement of even date herewith,
pursuant to which the Parties have agreed, among other things, that (i) Onyx will agree that regorafenib is not a Collaboration
Compound under the Collaboration Agreement, and (ii) Bayer will grant Onyx certain rights related to the development and
promotion of regorafenib, and pay Onyx royalties based on the sales of regorafenib together with fees for co-promotion services, all as
set forth herein.
NOW, THEREFORE, in consideration of the mutual covenants and agreements set forth in this Agreement, and for other good
and valuable consideration, the Parties hereto agree as follows, with the intent to be legally bound:
AGREEMENT
ARTICLE 1
DEFINITIONS
Capitalized terms used in this Agreement (other than the headings of the Sections or Articles) have the meanings set forth in this
Article 1 or, if not listed in this Article 1, the meanings as designated in the text of this Agreement.
1
[ * ] = Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the
Securities and Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of 1934, as amended.
In addition, unless the context otherwise clearly requires, whenever used in this Agreement: (i) the words “include”, “includes”
or “including” shall be construed as incorporating also the phrase “but not limited to” or “without limitation” and shall mean
including, without limiting the generality of any description preceding such words; (ii) the word “day” or “year” or “quarter” shall
mean a calendar day or calendar year or calendar quarter, unless otherwise specified; (iii) the words “hereof,” “herein,” “hereby” and
derivative or similar words refer to this Agreement (including any Exhibits); (iv) words of any gender include the other gender; and
(v) words using the singular or plural number also include the plural or singular number, respectively.
1.1 “ACCME Standards” means the standards set forth by the Accreditation Council for Continuing Medical Education
relating to educating the medical community in the United States.
1.2 “Act” means the United States Federal Food, Drug and Cosmetic Act, as it may be amended from time to time.
1.3 “Affiliate” means, with respect to a Party, any entity that directly or indirectly Owns, is Owned by, or is under common
Ownership with such Party. As used in this Section 1.3, “Owns” or “Ownership” means direct or indirect possession of at least 50% of
the outstanding voting securities of a corporation or a comparable equity interest in any other type of entity, or, where the laws of the
jurisdiction in which such entity operates prohibits the ownership by a Party of 50%, such ownership shall be at the maximum level of
ownership allowed by such jurisdiction.
1.4 “Agreement” has the meaning set forth in the Preamble and shall include all appendices, exhibits and schedules referenced
herein or attached hereto, and as the same may be amended or supplemented from time to time hereafter pursuant to the provisions
hereof.
1.5 “Alliance Steering Committee” or “ASC” means that committee described and set forth in the Fourth Amendment.
1.6 “Applicable Laws” means, with respect to a given country, the applicable laws, rules and regulations that may be in effect
from time to time in such country and that relate to a Party’s activities under this Agreement, including any rules, regulations,
guidelines, or other requirements of the Governmental or Regulatory Authorities of such country.
1.7 “Bayer” has the meaning set forth in the Preamble.
1.8 “Bayer Indemnified Party” has the meaning set forth in Section 8.1.1.
1.9 “Bayer Patents” means all Patents that are Controlled by Bayer or any of its Affiliates at any time during the Term that
claim the Compound or a Product or the manufacture or use of the Compound or a Product.
1.10 “Breaching Party” has the meaning set forth in Section 6.2.
2
1.11 “Change of Control” means, with respect to a particular Party: (a) the sale to one or more Third Parties of all or
substantially all of such Party’s assets; (b) a merger, reorganization or consolidation involving such Party and one or more Third
Parties in which the voting securities of such Party outstanding immediately prior thereto cease to represent at least fifty percent
(50%) of the combined voting power of the surviving entity immediately after such merger, reorganization or consolidation; or (c) the
acquisition by one or more Third Parties acting in concert or under common control of more than fifty percent (50%) of the voting
equity securities of such Party.
1.12 “CIA” means the Corporate Integrity Agreement between the Office of Inspector General of the Department of Health and
Human Services and Bayer Corporation dated November 25, 2008.
1.13 “Claims” means any and all claims, suits, proceedings or causes of action brought against a Party.
1.14 “CMC Information” means Information related to the chemistry, manufacturing and controls of the Product for a
particular Separate Indication, as specified by the FDA or EMA.
1.15 “Code of Conduct” means the Healthcare Fraud and Abuse Code of Conduct of Bayer.
1.16 “Collaboration Agreement” has the meaning set forth in the Recitals.
1.17 “Collaboration Compound” has the meaning set forth in the Collaboration Agreement
1.18 “Collaboration Product” has the meaning set forth in the Collaboration Agreement.
1.19 “Combination Product” means a product containing both a Product and one or more other active ingredients in addition to
such Product where the other active ingredients have independent prophylactic or therapeutic effect when used to treat the disease or
indication for which the Combination Product is labeled, where such Product and the other active ingredients are together in a
physical mixture or packaged and priced together as a single product.
1.20 “Commercially Reasonable Efforts” means the level of efforts and resources (including the promptness with which such
efforts and resources would be applied) commonly used [ * ] with respect to a product of commercial potential [ * ] to the Product at a
[ * ], taking into consideration its [ * ] and all other relevant factors.
1.21 “[ * ] Product” means any [ * ] product having the [ * ] as the Product and that is intended as a [ * ] for, and [ * ] for, the
Product, [ * ].
1.22 “Compound” means the compound designated as regorafenib (also referred to as BAY 73-4506), together with (i) [ * ]
thereof or (ii) any other modification which [ * ].
3
1.23 “Confidential Information” means, with respect to a Party, all Information of such Party that is disclosed to the other Party
under this Agreement, except for that portion of such Information that the receiving Party can demonstrate:
(i) was already known to the receiving Party or its Affiliate, other than under an obligation of confidentiality, at the time of
disclosure by the other Party;
(ii) was generally available to the public or otherwise part of the public domain at the time of its disclosure to the receiving
Party;
(iii) became generally available to the public or otherwise part of the public domain after its disclosure and other than
through any act or omission of the receiving Party in breach of this Agreement;
(iv) is subsequently disclosed to the receiving Party or its Affiliate by a Third Party without obligations of confidentiality
with respect thereto; or
(v) is independently discovered or developed by the receiving Party or its Affiliate without the aid, application, or use of
Confidential Information of the disclosing Party.
1.24 “Control” means, with respect to any material, Information, or intellectual property right, that a Party (a) owns such
material, Information, or intellectual property right, or (b) has a license or right to use such material, Information, or intellectual
property right, in each case with the ability to grant to the other Party access, a right to use, a license, or a sublicense (as applicable) to
such material, Information, or intellectual property right on the terms and conditions set forth herein, without violating the terms of
any agreement or other arrangement with any Third Party.
1.25 “Co-Promote” or “Co-Promotion” means the joint Promotion of the Product through Bayer, Onyx and their respective
sales forces under a single Product trademark in the United States.
1.26 “Co-Promotion Effective Date” means the date of First Commercial Sale of the first Product in the United States.
1.27 “Co-Promotion Expiration Date” has the meaning set forth in Section 2.8 of Exhibit A.
1.28 “Co-Promotion Plan” has the meaning set forth in Section 2.2(a) of Exhibit A.
1.29 “Co-Promotion Program” means, collectively, the Sales Program and the Medical Affairs Program.
1.30 “Co-Promotion Term” has the meaning set forth in Section 2.8 of Exhibit A.
1.31 “Cost of Goods” means, with respect to a Compound or Product,
4
(a) if such Compound or Product is manufactured by a Third Party manufacturer, [ * ]; and
(b) if such Compound or Product is manufactured by Bayer, [ * ]. For clarity, such [ * ] cost shall be calculated (i) [ * ] and
(ii) in accordance with generally accepted accounting practices consistently applied by Bayer and based upon all similar activities
conducted by Bayer (i.e., not to disproportionately allocate costs to manufacturing of Compounds or Products when compared to
similar costs for other manufacturing activities of Bayer). Costs that [ * ], shall not be included in the determination of Cost of Goods.
For clarity, Cost of Goods does not include any margin or mark-up relating to inter-company supply between Bayer and its Affiliates
(or among such Affiliates).
1.32 “CRM System” means a customer relationship management system utilized in connection with the tracking of sales
activity relating to the Product in the United States.
1.33 “Detail” or “Detailing” has the meaning set forth in Exhibit A.
1.34 “Detail Fee” has the meaning set forth in Exhibit A.
1.35 “Detailing Plan” has the meaning set forth in Exhibit A.
1.36 “Dispute” has the meaning set forth in Article 11.
1.37 “Dollars” or “$”means United States Dollars.
1.38 “Drug Approval” means, with respect to a Product in a country or regulatory jurisdiction, any and all approvals, licenses,
registrations, or authorizations of any Governmental or Regulatory Authority necessary to commercially market and sell such Product
in such country or jurisdiction, including any and all marketing authorizations granted in the European Union, but excluding Price
Approval.
1.39 “Drug Approval Application” means an NDA, MAA or any corresponding foreign application, including all additions,
supplements, extensions and modifications thereto.
1.40 “Effective Date” means the date specified in the Preamble above.
1.41 “EMA” means the European Medicines Agency and any successor agency thereto.
1.42 “European Union” or “EU” means the economic, scientific and political organization of European member states, as its
membership may be altered from time to time, and any successor thereto, and which, as of the Effective Date, consists of Austria,
Belgium, Bulgaria, Cyprus, the Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy,
Latvia, Lithuania, Luxembourg, Malta, the Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, and the
United Kingdom.
5
1.43 “Executive Committee” or “EC” means that committee described and set forth in the Collaboration Agreement, which was
originally organized as the JRDC under the Collaboration Agreement and was renamed the Executive Committee.
1.44 “FDA” means the United States Food and Drug Administration or any successor entity thereto.
1.45 “First Commercial Sale” means, with respect to a Product and country, the first sale to a Third Party of such Product in
such country after Drug Approval has been obtained in such country.
1.46 “Force Majeure Event” has the meaning set forth in Section 12.10.
1.47 “Fourth Amendment” has the meaning set forth in the Recitals.
1.48 “Generic Product” means, with respect to a Product, any pharmaceutical product in a particular regulatory jurisdiction
that: (i) contains [ * ]; (ii) is approved [ * ]; (iii) has [ * ]; (iv) is [ * ]; and (v) is sold in such jurisdiction by a Third Party that (a) is not
a licensee or sublicensee of Bayer or its Affiliates or any of their licensees or sublicensees, (b) has not obtained such product from a
chain of distribution including Bayer, its Affiliates or any of their licensees or sublicensees, and (c) is not otherwise authorized by
Bayer or any of its Affiliates, licensees, sublicensees or distributors to sell such product.
1.49 “Good Manufacturing Practices” or “GMPs” means the standards relating to the then-current Good Manufacturing
Practices for fine chemicals, active pharmaceutical ingredients, intermediates, bulk products or finished pharmaceutical products set
forth (i) in 21 U.S.C. 351(a)(2)(B), in U.S. FDA regulations at 21 C.F.R. Parts 210 and 211 and in The Rules Governing Medicinal
Products in the European Community, Volume IV, Good Manufacturing Practice for Medicinal Products, each as may be amended
from time to time or (ii) in guidelines promulgated by the International Conference on Harmonization with respect to the manufacture
of active pharmaceutical ingredients and finished pharmaceuticals, as may be amended from time to time.
1.50 “Governmental or Regulatory Authority” means any supra-national, federal, national, state, regional, local, municipal,
provincial or other governmental authority of any nature (including any governmental division, prefecture, subdivision, department,
agency, bureau, branch, office, commission, council, court, arbitral body or other tribunal), including the FDA and the EMA.
1.51 “Information” means any data, results, and information of any type whatsoever, in any tangible or intangible form,
including know-how, trade secrets, practices, techniques, methods, processes, inventions, developments, specifications, formulations,
formulae, materials or compositions of matter of any type or kind (patentable or otherwise), software, algorithms, marketing reports,
clinical and non-clinical study reports, regulatory submission summaries and regulatory submission documents, expertise, technology,
test data including pharmacological, biological, chemical, biochemical, toxicological, and clinical test data, analytical and quality
control data, stability data, studies and procedures.
6
1.52 “Initial Indication” means the indication for the Product for either of the following two diseases: (i) [ * ]; or (ii) [ * ].
“Initial Indications” means both [ * ] indications for the Product.
1.53 “Indemnifiable Losses” means liabilities, losses, damages or other amounts payable to a Third Party claimant, as well as
any reasonable attorneys’ fees and costs of litigation incurred by either the Bayer Indemnified Party or the Onyx Indemnified Party, as
the case may be, in connection with any Claim.
1.54 “Listed Commercial Information” means with respect to the Product, the following categories of information: (a) market
insights including primary research studies and findings, competitive assessments, secondary data sources and syndicated reports by
tumor type; (b) medical information including medical information letters, summaries of unsolicited requests and appropriate reports,
publication plans, posters, data and slides generated by a Party; (c) ongoing and tracking of IIS/IST information; (d) managed care and
payer strategy plans; (e) marketing and brand plans by key markets, (f) sales targeting and data management including sales training
materials, detailing information for the United States, sales reports by region and comparison with plan and targeting; (g) execution
including metrics of and key execution/annual goals of key promotional activities (e.g. Speaker programs, Congress plans); and
(h) health economics and value dossiers.
1.55 “LMR” means Bayer’s Legal Medical Regulatory review team.
1.56 “MAA” means a Marketing Authorization Application filed with the EMA pursuant to the European Union centralized
approval procedure or with the applicable Regulatory Authority of a country in the European Union with respect to the mutual
recognition or any other national approval procedure (and including all additions, supplements, extensions, and modifications thereto).
1.57 “Marketing Materials” has the meaning set forth in Section 2.12(a) of Exhibit A.
1.58 “Material Breach” has the meaning set forth in Section 6.3.1.
1.59 “Medical Affairs Program” means the program conducted by the Parties under Article 3 designed to ensure or improve
appropriate medical use of, conduct medical education of, or further research regarding, a Product sold in the United States, including
by way of example: (i) activities of MSLs; (ii) implementation of continuing medical education, symposia, or Third Party research
related to a Product; (iii) the publication and dissemination of medical and scientific publications relating to a Product that are in
compliance with ICMJE standards, as well as medical information services provided in response to inquiries communicated via sales
representatives or received by letter, phone call, email or other means of communication; and (iv) the conduct of advisory board
meetings, meetings with key opinion leaders or other programs, in each case the purpose of which is to obtain advice and feedback
related to the development of, or medical activities concerning, a Product.
7
1.60 “MMA” has the meaning set forth in Section 4.4(c) of Exhibit A.
1.61 “MSL FTE” means a full-time equivalent (based on a full-time equivalent year of [ * ]) field-based MSL who conducts
Medical Affairs Program activities with respect to a Product in the United States during the Co-Promotion Term, together with MSL
regional management and an allowance for national management. In the case of MSL regional managers who supervise MSLs with
responsibility for multiple products, the time of such managers shall be allocated to the Product in a reasonable manner based on the
relative effort of the MSLs they supervise (as between the Products and other products). In the event that either Party desires to utilize
MSL FTEs for one or more additional products (including Collaboration Products), the Parties shall reasonably agree and determine a
standard method of measurement to allocate such FTE efforts in an equitable and consistent manner.
1.62 “MSL FTE Costs” means, with respect to any calendar quarter, the Onyx MSL FTE Rate multiplied by the number of
Onyx MSL FTEs who performed or supported Medical Affairs Program activities in the United States during such calendar quarter in
accordance with the Medical Affairs Program.
1.63 “MSLs” means the medical science liaisons to be appointed by each Party.
1.64 “NDA” means a New Drug Application as defined in the Act and the regulations promulgated thereunder (including all
additions, supplements, extensions, and modifications thereto).
1.65 “Net Sales” means gross receipts and any other consideration received by Bayer, its Affiliates, licensee or sublicensees on
account of sales of Products, less deductions of the following items:
(i) trade, quantity and cash discounts or rebates, actually allowed and taken,
(ii) credits or allowances given for rejection or return of previously sold Product or outdated Product,
(iii) any tax or other governmental charge (including without limitation custom surcharges) borne by the selling Party other
than income tax levied on the sale, transportation or delivery of Product, and
(iv) any charges for packing, handling, freight, insurance, transportation and duty.
In the event a Product is sold in the form of a Combination Product, Net Sales for such Combination Product will be determined
by multiplying Net Sales of such Combination Product by the fraction A/(A + B), where A is the average prior year’s annual invoice
price of the
8
Product, if sold separately, and B is the average prior year’s annual invoice price of any other active component or components in the
combination, if sold separately, in each case in the same country and in the same dosage as in the Combination Product. If, on a
country-by-country basis, the other active component or components in the combination are not sold separately in such country, Net
Sales shall be calculated by multiplying actual Net Sales of such Combination Product by the fraction A/C where A is the average
prior year’s annual invoice price of the Product if sold separately, and C is the average prior year’s annual invoice price of the
Combination Product, in each case in the same country and in the same dosage as in the Combination Product. If, on a country-by-
country basis, the Product component of the Combination Product is not sold separately in such country, but the other active
component or components are sold separately, Net Sales shall be calculated by multiplying Net Sales of such Combination Product by
the fraction (C-B)/C where B is the average prior year’s invoice price of the other active component or components, if sold separately,
and C is the average prior year’s invoice price of the Combination Product, in each case in the same country and in the same dosage as
in the Combination Product. If, on a country-by-country basis, neither the Product nor the other active component or components of
the Combination Product is sold separately in such country, Net Sales for such Combination Product shall be determined by the
Parties in good faith. If there are no prior year’s invoices, the Parties may use an estimate of future invoice prices.
1.66 “Non-Publishing Party” has the meaning set forth in Section 7.3.
1.67 “Notice of Termination of Co-Promotion Program” has the meaning set forth in Section 6.3.3.
1.68 “Notifying Party” has the meaning set forth in Section 6.2.
1.69 “OIG” means the Office of the Inspector General.
1.70 “Onyx” has the meaning set forth in the Preamble of this Agreement.
1.71 “Onyx Indemnified Party” has the meaning set forth in Section 8.2.1.
1.72 “Onyx MSL FTE Rate” means [ * ], increased or decreased on January 1 of each calendar year, beginning [ * ], to reflect
any year-to-year percentage increase or decrease (as the case may be) in the Consumer Price Index for the US City Average (all items)
(CPI) (based on a cumulative index of CPI numbers starting on January of the immediately prior year (or with respect to the
adjustment made with respect to [ * ], the Effective Date) to the date of the calculation of such MSL FTE Rate).
1.73 “Patents” means (a) patent applications, issued patents, utility models and design patents; (b) reissues, substitutions,
confirmations, registrations, validations, re-examinations, additions, continuations, continued prosecution applications, continuations-
in-part, or divisions of or to any of the foregoing; (c) any other patent application claiming priority to any of the foregoing anywhere
in the world; and (d) extension, renewal or restoration of any of the foregoing by existing or future extension, renewal or restoration
mechanisms, including supplementary protection certificates or the equivalent thereof.
9
1.74 “PDMA” means the Prescription Drug Marketing Act of 1987, Title 21 of the U.S. Code of Federal Regulations, Parts 203
and 205, as amended, and any final regulations or guidances promulgated thereunder from time-to-time.
1.75 “Person” means an individual, corporation, partnership, limited liability company, trust, business trust, association, joint
stock company, joint venture, pool, syndicate, sole proprietorship, unincorporated organization, governmental authority, or any other
form of entity not specifically listed herein.
1.76 “Pharmacovigilance Agreement” has the meaning set forth in Article 5.
1.77 “PhRMA Code” means the Pharmaceutical Research and Manufacturers of America Code on Interactions with Healthcare
Professionals, as hereafter amended from time to time.
1.78 “Price Approval” means any and all governmental approvals, agreements, determinations or decisions establishing prices
that can be charged and/or reimbursed for the Product in a regulatory jurisdiction where a Governmental or Regulatory Authority
approves or determines the price and/or reimbursement of pharmaceutical products.
1.79 “Product” means any pharmaceutical form or dosage of, or diagnostic product based upon, the Compound, including a
Combination Product.
1.80 “Product Training Materials” has the meaning set forth in Section 2.11(a) of Exhibit A.
1.81 “Promotion” means Detailing, marketing and those other activities normally undertaken by a pharmaceutical company’s
sales force, and its supervisors and managers, to implement marketing plans and strategies aimed at encouraging the appropriate use
of a particular prescription pharmaceutical product. When used as a verb, “Promote” means to engage in such activities.
1.82 “Publishing Party” has the meaning set forth in Section 7.3.
1.83 “Royalty Term” has the meaning set forth in Section 4.1.2.
1.84 “Sales Program” means the program of Promoting (including Detailing) the Product in the United States, including all
supervision, management and training with respect thereto, conducted by the Parties under Exhibit A.
1.85 “SEC” means the United States Securities and Exchange Commission.
1.86 “Separate Development Costs” means, with respect to a particular Separate Indication, the actual and direct costs and
expenses reasonably incurred by Onyx and its
10
Affiliates or for its account , as calculated in accordance with United States generally accepted accounting principles consistently
applied, that are specifically identifiable or reasonably and consistently allocable to the development of the Product for such Separate
Indication, that are directed to obtaining Drug Approval from the FDA or EMA of the Approved Product for such Separate Indication
and that are reasonably commensurate in scope with the Separate Development Program undertaken by Onyx. The Separate
Development Costs shall include amounts, without mark-up, that Onyx pays to Third Parties involved in the conduct of the applicable
Separate Development Program, and the internal costs incurred by Onyx and costs of Bayer for services requested by Onyx in
connection with such Separate Development Program. Separate Development Costs include: (a) pre-clinical costs, such as costs for
toxicology, pharmacokinetics, pharmacological studies specifically directed to the Separate Indication; (b) costs of clinical trials of the
Product for the Separate Indication, including ethics committee fees, investigators’ fees, investigators’ meeting costs, hospital fees,
fees for clinical research organizations’ services; (c) costs of manufacturing or procuring the Product, comparators and placebos, as
applicable, for use in development activities directed toward the Separate Indication, as well as the direct costs and expenses of
disposal of drugs and other supplies used in such Separate Development Program; (d) regulatory expenses, including FDA and EMA
filing fees, relating to development activities for the purpose of obtaining Drug Approval by the FDA or EMA of the Product for the
Separate Indication; and (e) other costs and expenses that meet the criteria set forth above. Separate Development Costs shall
specifically exclude (i) [ * ] and (ii) [ * ]. In calculating the Separate Development Costs, Onyx’s FTE efforts shall be calculated based
upon Onyx’s actual costs for such FTEs.
1.87 “Separate Development Program” has the meaning set forth in Section 2.4.
1.88 “Separate Indication” means the combination of tumor-type, line of therapy and co-therapies (if any) to which a particular
Separate Development Program is directed.
1.89 “Target Healthcare Professionals” means physicians who are cancer specialists or other prescribers of oncology
therapeutics, including persons lawfully influencing (or in a position to lawfully influence) the opinions of such persons, in each case
who are authorized by Applicable Laws to prescribe the Product. If the Product is approved for use outside of oncology, Target
Healthcare Professionals shall also include prescribers, and persons lawfully influencing the opinions of such persons, who practice in
the area of the expanded indication.
1.90 “Term” has the meaning set forth in Section 6.1.
1.91 “Third Party” means any person or entity other than Bayer or Onyx, or an Affiliate of either of them.
1.92 “United States” shall mean the United States of America, its territories and possessions.
1.93 “Valid Claim” means a claim of an issued and unexpired patent, which has not been held invalid or unenforceable by a
patent office, court or other governmental agency of competent jurisdiction, which holding is unappealable or unappealed within the
time allowed for appeal, and which has not been admitted to be invalid by the owner through disclaimer or otherwise.
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ARTICLE 2
PRODUCT DEVELOPMENT AND COMMERCIALIZATION
2.1 Contract Status of Regorafenib. The Parties agree that the Compound is not a Collaboration Compound under the
Collaboration Agreement, and further that Onyx shall have the rights related to the Compound and Products set forth in this
Agreement. This resolution by the Parties regarding the Compound shall not be deemed to modify the definition of Collaboration
Compound or constitute an interpretation of such term. Neither this Agreement nor the terms hereof may be introduced by either Party
or any of its Affiliates in a legal proceeding in which the definition of Collaboration Compound is at issue.
2.2 Product Development Generally. Except as set forth in Section 2.4, Bayer shall be responsible, at its sole cost and expense,
for the development of the Product worldwide. Bayer shall conduct all Product development activities in compliance with Applicable
Laws under the oversight of the EC, and subject to strategic direction from the Alliance Steering Committee; provided, however, that,
except with respect to the Initial Indications Plans and any amendments thereto (which shall be governed by Section 2.3), Bayer shall
have the final decision-making authority regarding development of Product, including development of Product for any indications
other than the Initial Indications, subject to the rights of Onyx to conduct Separate Development Programs as provided in Section 2.4.
For the avoidance of doubt, except for the Initial Indications Plans (and material amendments thereto) and any plans for development
of Product pursuant to a Separate Development Program, all development plans with respect to Product shall be prepared by Bayer for
review and approval by the EC and, to the extent the EC cannot agree on any aspect of such plans, Bayer shall have the final decision-
making authority with respect to the same. Bayer shall keep Onyx appropriately informed, through the EC or otherwise (including via
the electronic collaboration space), of the status and results of any Product development work performed by or on behalf of Bayer,
including by providing on [ * ] basis (or more frequently to coincide with more frequent meetings of the EC, if applicable) a written
progress report describing the development activities conducted by or on behalf of Bayer, any difficulties and unexpected
circumstances encountered, summarized relevant data and results obtained, and any other relevant matters, in each case since the last
such progress report. Upon reasonable prior written notice, Onyx shall have the right to inspect any records, notebooks, documents
and other Information in the possession or under the control of Bayer reflecting Product development work done and results achieved
by or on behalf of Bayer. The Parties hereby adopt and agree to implement, with respect to development of Product, the Guiding
Principles set forth in Section 2.7.1. Notwithstanding anything to the contrary set forth herein, Onyx’s ability to develop the Product
pursuant to a Separate Development [ * ].
12
2.3 Initial Indications Development. Bayer shall use Commercially Reasonable Efforts to continue development of the Product
for the Initial Indications in accordance with the development plans delivered to the General Counsel of Onyx by letter of even date
herewith (the “Initial Indications Plans”), including the Phase 3 clinical trials of the Product for the Initial Indications as listed in the
Initial Indications Plans (the “Listed Trials”). The Initial Indications Plans may not be materially amended or modified except upon
the mutual written agreement of both Parties (by their representatives on the Executive Committee or otherwise).
2.4 Separate Development Activities. The Parties shall attempt, through the Executive Committee, to agree on any Product
development activities or programs beyond the scope of the work set forth in the Initial Indications Plans (as the same may be
amended by mutual written agreement of the Parties). In the event that Onyx proposes additional Product development activities that
are not already set forth in the Initial Indications Plans (as the same may be amended by mutual written agreement of the Parties) or
Bayer proposes to discontinue any ongoing development activities of the Product, including any Phase 3 clinical trials of the Product
for the Initial Indications other than the Listed Trials or any development of the Product for indications other than the Initial
Indications, and if the Parties do not reach agreement for Bayer to conduct such additional Product development activities at its sole
cost (such additional or continued activities, a “Separate Development Program”), Onyx shall have the right to conduct the Separate
Development Program, in its sole discretion and at its sole cost as provided below (and subject to Section 4.2).
2.4.1 Onyx Notice Requirement. Following the determination that Bayer will not conduct such Separate Development
Program as set forth above, and prior to the commencement of a Separate Development Program, Onyx shall give written notice to the
Bayer representatives on the EC of the content of the proposed Separate Development Program (a “Notice of Proposed
Development”). Bayer shall have a period of [ * ] following receipt of the Notice of Proposed Development within which to either
commit to carry out the clinical trials requested by Onyx at Bayer’s sole expense, or to otherwise reach agreement with Onyx
regarding modifications to the then-current Product development program. If the Parties do not reach agreement within such [ * ]
period, Onyx shall have the right to commence the Separate Development Program as set forth below in this Section 2.4 and otherwise
pursuant to this Agreement. In addition, Onyx may have the right to commence any Product development activities proposed to be
discontinued by Bayer promptly following notice thereof by Bayer and in accordance with a reasonable transition plan. If Bayer
believes, based upon reasonable medical or scientific grounds, that such Separate Development Program [ * ], it shall bring this
concern to the attention of Onyx within the [ * ] period described above and the Parties shall discuss through the EC before Onyx
commences such Separate Development Program. If Bayer still believes after such discussion that, based upon reasonable medical or
scientific grounds, such Separate Development Program [ * ], then Onyx may only proceed with such Separate Development Program
if [ * ]; under such circumstance, [ * ]. If Onyx commences a Separate Development Program, it may modify such development
program from time to time without the approval of Bayer or the EC, except that Onyx shall discuss at the EC any proposed
modification to any of the following: [ * ] (each such modification, a “Material Modification”) and, prior to implementation of such
modification, shall submit to Bayer a new Notice of Proposed
13
Development for such modified Separate Development Program (which would constitute termination of the original Separate
Development Program and the commencement of a new Separate Development Program). If Bayer decides to assume responsibility
for the Separate Development Program following such proposed Material Modification, then Bayer shall reimburse Onyx for [ * ] of
the Separate Development Costs already incurred by or on behalf of Onyx for such Separate Development Program, the Parties will
decide upon a reasonable plan for transitioning on-going development activities to Bayer while minimizing disruption and delay,
Bayer shall be responsible for future costs of such Separate Development Program, including those incurred by or on behalf of Onyx
prior to the completion of such transition. In the case of any Separate Development Program resulting from the discontinuance of
activities by Bayer, Bayer shall be responsible for the costs incurred by Bayer, and Onyx shall bear the responsibility for the costs to
transition the development activities from Bayer to Onyx, subject to reimbursement of such costs as Separate Development Costs
under this Agreement. Onyx may commence [ * ] for [ * ].
2.4.2 Bayer Obligations. If Onyx elects to conduct a Separate Development Program for a particular Separate Indication,
Bayer shall have the following obligations with respect to Onyx’s development of, and procurement of Drug Approval for, such
Separate Indication:
(i) As set forth in greater detail in this Section 2.4.2(i), Bayer shall supply primary packed unlabeled clinical trial material
of Product to Onyx, pursuant to purchase orders placed by Onyx and accepted by Bayer, at Bayer’s Cost of Goods for such Product.
Onyx shall provide Bayer with a [ * ] rolling forecast of its anticipated requirements for Product for the Separate Development
Program and shall provide Bayer with an updated forecast once per [ * ]. Provided that Onyx’s purchase order for Product does not
exceed its forecast for the applicable month by more than [ * ] or require delivery less than [ * ] after the date of such purchase order,
Bayer shall be deemed to have accepted such purchase order. All other Onyx purchase orders shall be deemed accepted by Bayer if
Bayer does not reject such purchase order within [ * ] after the date of such purchase order. Bayer shall deliver to Onyx, FCA
(Incoterms 2010) its storage facility nearest to Onyx, on the delivery date specified in the applicable accepted purchase order, the
quantity Product set forth in such purchase order, together with a Certificate of Analysis for such Product. Onyx will arrange for and
be responsible for the cost of all freight, insurance charges, taxes, import and export duties, inspection fees and other charges
applicable to the transport of Product delivered by Bayer hereunder. Bayer will provide Onyx with Bayer’s then-existing packaging
configurations and shelf life/re-test dates for the Product, or a copy of Bayer’s most recent IMPD or IND if available. Bayer
represents, warrants and covenants to Onyx that the Product delivered to Onyx pursuant to this Section 2.4.2(i); (A) will, at the time of
delivery, conform to the specifications for the Product and have a minimum shelf-life of [ * ]; (B) will remain in compliance with the
Product specifications throughout its shelf-life, provided that it is stored in strict compliance with the applicable long-term storage
conditions, and it is not tampered with, damaged, modified, mishandled or used in a manner other than as intended; and (C) will have
been manufactured in conformity with GMPs and will not be adulterated or misbranded within the meaning of the Act or comparable
state laws. If Bayer breaches the representation, warranty and covenant set forth in the previous sentence (the “Product
14
Warranty”) with respect to any quantity of Product, then Onyx shall not be obligated to pay for such quantity of Product and Bayer
shall, at Onyx’s request, promptly replace (at no additional cost to Onyx if Onyx paid Bayer’s invoice with respect to the non-
conforming Product) such quantity of non-conforming Product with the same quantity of Product that does conform with the Product
Warranty. [ * ] Bayer shall provide Onyx, no earlier than the applicable delivery date for such Product, with an invoice for Product
delivered by Bayer pursuant to this Section 2.4.2(i) and, provided that the Product conforms to the Product Warranty, Onyx shall pay
such invoice within [ * ]. Promptly after the Effective Date, the Parties shall negotiate in good faith and enter into a mutually agreed
quality agreement with respect to Bayer’s supply of Product pursuant to this Section 2.4.2(i). Such quality agreement shall contain
standard, commercially reasonable terms and conditions for agreements of such type, including rights for Onyx to review Bayer’s
manufacturing records for Product. Bayer shall supply to Onyx placebo matched to the Product pursuant to terms and conditions
similar to the terms and conditions set forth in this Section.
(ii) At the request and sole cost and expense of Onyx, Bayer shall facilitate Onyx’s performance of the Separate
Development Program and Onyx’s preparation of a Drug Approval Application(s) with respect to such Separate Indication, as
reasonably necessary to materially facilitate Onyx’s performance and preparation. Such facilitation shall include providing Onyx with
access to Bayer’s regulatory filings and approvals of Product on a worldwide basis. Bayer shall also provide Onyx with timely,
complete and accurate CMC Information for inclusion in such Drug Approval Application(s) and any other regulatory filings with the
FDA or EMA that require manufacturing-related information. At Onyx’s sole cost and expense, Bayer shall apply for and take, as
Onyx’s agent, all legal actions requested by Onyx that are necessary to materially facilitate conducting the Separate Development
Program and for obtaining approval of the Drug Approval Application for the Product in the applicable Separate Indication. Except
with respect to materials that, as between the Parties, only Bayer can prepare, Onyx shall prepare for submission by Bayer all
materials to be provided to an applicable Governmental or Regulatory Authority and such materials shall comply with the legal
requirements of such applicable Governmental or Regulatory Authority, and in the case of any filing for territories other than the U.S.
and the European Union, with Bayer’s written guidelines provided reasonably in advance of the commencement of such Separate
Development Program with respect to such territory. At Onyx’s request, and at Onyx’s sole cost and expense, Bayer shall prepare and
submit to the applicable Governmental or Regulatory Authority all other materials necessary to obtain approval of such Drug
Approval Application. Bayer shall own, and hold for the benefit of Onyx, such Drug Approval Application. Bayer will keep Onyx
fully informed regarding the status of such Drug Approval Application, including by providing Onyx with copies of all documents
filed with, and documents, correspondence and other communications received from, the applicable Governmental or Regulatory
Authority with respect thereto. Bayer shall provide Onyx with prompt notice of any meeting, teleconference or other interaction with
the applicable Governmental or Regulatory Authority with respect thereto and shall facilitate Onyx’s participation in such meetings,
teleconferences and interactions.
(iii) At Onyx’s request, and at Onyx’s sole cost and expense, Bayer shall (A) provide Onyx with access, through the shared
database established pursuant to Section 2.8,
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to Information in Bayer’s Control that is necessary for Onyx to develop the Product for such Separate Indication and to prepare Drug
Approval Application(s) with respect to such Separate Indication, (B) use good faith and Commercially Reasonable Efforts to provide
Onyx with Information in Bayer’s Control that would materially facilitate Onyx’s development of the Product for such Separate
Indication, including Information about preferred formulations, and preparation of Drug Approval Application(s) with respect to such
Separate Indication, including copies of correspondence with the FDA, EMA and other regulatory authorities and (C) introduce Onyx
to, and materially facilitate Onyx’s interactions with, key opinion leaders, potential clinical trial principal investigators, representatives
of patient advocacy groups, vendors of development services, and persons responsible for granting pricing approvals or making
reimbursement or formulary decisions, in each case only for external contacts with whom Bayer has a relationship with respect to the
Product. The foregoing Information delivery obligations shall include making appropriate Bayer personnel reasonably available
during normal business hours for reasonable time periods for consultation by Onyx either by telephone or email or at Bayer’s facilities
with reasonable advance notice (and without a travel obligation on the part of Bayer).
(iv) Onyx shall be responsible for reimbursing the costs of Bayer as Separate Development Costs in providing services
requested by Onyx under this Agreement to the extent such costs are reasonably incurred and reasonably commensurate in scope with
the services provided. Bayer will provide Onyx with reasonable documentation of such costs and Onyx will have the audit rights
described in Section 4.7 with respect to such amounts.
2.4.3 Information Sharing. If Onyx elects to conduct a Separate Development Program, Onyx shall keep Bayer
appropriately informed, through the JDC and Executive Committee or otherwise, of the status and results of work performed by or on
behalf of Onyx in the course of conducting such Separate Development Program, including by providing on a calendar quarterly basis
(or more frequently to coincide with more frequent meetings of the Executive Committee, if applicable) a written progress report
describing the Separate Development Program activities conducted by or on behalf of Onyx, any difficulties and unexpected
circumstances encountered, summarized relevant data and results obtained, and any other relevant matters, in each case since the last
such progress report. Upon reasonable prior written notice, Bayer shall have the right to inspect any records, notebooks, documents
and other Information in the possession or under the control of Onyx reflecting work done and results achieved by or on behalf of
Onyx in the course of conducting such Separate Development Program. Notwithstanding anything to the contrary herein, Bayer shall
have the right to use for internal purposes only (which, for clarity, shall exclude any public disclosure or publication thereof or use in
any materials provided to a Third Party) any Information disclosed by Onyx with respect to such Separate Development Program or
Separate Indication internally; provided, however, that Bayer may file required safety information with the applicable regulatory
authorities in accordance with Article 5 and the Pharmacovigilance Agreement. In addition, Bayer covenants that it shall not seek
regulatory approval for (except at the instruction of Onyx) or commercialize the Product for Separate Indication until such time as it
pays Onyx the amounts set forth under Section 2.4.7.
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2.4.4 Intellectual Property. Onyx shall own the entire, right, title and interest in and to any Information (including data),
whether or not patentable, that is generated, discovered, developed, identified, made or conceived by or on behalf of Onyx or its
Affiliates or their respective employees, agents or contractors in the course of conducting any Separate Development Programs,
together with all Patents, trademarks, copyrights and other intellectual property rights therein (collectively, “Onyx Developed IP”).
Onyx shall have the right to use, transfer, sell, license, pledge and otherwise exploit the Onyx Developed IP for any purpose subject to
the license granted in Section 2.4.8. For purposes of this Section 2.4, “Product-Specific Invention” means any invention within the
Onyx Developed IP, the practice of which necessarily includes the Product, including composition of matter or method of treatment
claims.
2.4.5 Patent Prosecution. Onyx shall disclose to the Joint IP subcommittee established by the Parties pursuant to the
Collaboration Agreement (the “IP Subcommittee”) all Onyx Developed IP that Onyx believes to be patentable. The IP Subcommittee
shall discuss the most advantageous procedures for obtaining patent protection for each such Onyx Developed IP. The Parties shall
comply with all such procedures agreed upon by the IP Subcommittee. In the event that the IP Subcommittee does not agree upon
such procedures within 30 days after Onyx’s disclosure of a particular Onyx Developed IP, Onyx have the first right, to prepare, file,
prosecute (including any reissues, re-examinations, post-grant proceedings, requests for patent term extensions, supplementary
protection certificates, interferences, and defense of oppositions) and maintain any Patent directed to such Onyx Developed IP
worldwide, at its own expense. If Onyx determines that it will not file in any country a Patent directed to a Product-Specific Invention,
it shall notify Bayer in writing sufficiently in advance so Bayer may, at its cost, assume the responsibility for the filing, in Bayer’s
name, prosecution or maintenance of Patents directed to such Product-Specific Invention in one or more countries as it elects. At
Bayer’s request and cost, Onyx will execute any documents necessary to effectuate transfer of title to the Patents directed to such
Product-Specific Invention, and will promptly transfer to Bayer all documents and information necessary to file, prosecute, maintain,
and enforce such Patent(s) and patent application(s). Bayer hereby grants to Onyx, effective upon such transfer of title, a non-
exclusive, fully paid, perpetual, irrevocable, non-transferrable (except for any permitted assignment under Section 12.1) worldwide
license to practice such transferred Product-Specific Invention. If Onyx declines to continue to prosecute a Patent in a particular
country directed to a Product-Specific Invention for which Onyx is pursing patent protection in one or more other countries, it shall
notify Bayer in writing sufficiently in advance so Bayer may, at its cost, assume the responsibility for the filing, in Onyx’s name,
prosecution or maintenance of Patents directed to such Product-Specific Invention. In the case of other inventions within the Onyx
Developed IP (that are not Product-Specific Inventions), Onyx will disclose the invention to the IP committee, as discussed above, but
Bayer will have no right to file, prosecute or obtain assignment of any Patent to any such inventions.
2.4.6 Patent Enforcement. If either party learns of potential infringement of any Onyx Developed IP, where such
infringement involves the use of the Product, it shall notify the other party. If a Third Party is infringing, or either Party reasonably
believes a Third Party may be infringing, any Patent within the Onyx Developed IP by reason of (i) the manufacture, import, use, offer
for sale or sale of a product competitive with the Product or (ii) the filing of an
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abbreviated new drug application (ANDA) pursuant to 21 U.S.C. §355(j) or a new drug application pursuant to 21 U.S.C. §355(b)(2)
of a product competitive with the Product by such Third Party (“Product-Specific Infringement”), [ * ] shall have the first right, but
not the obligation, to institute, prosecute, control, and settle any action or proceeding with respect to such infringement by counsel of
its own selection, at its expense. [ * ] shall provide [ * ] updates, via the IP Subcommittee, to [ * ] regarding the strategy and status of
any such proceeding, and shall provide [ * ] an opportunity to comment. If [ * ] fails to bring or settle such an action or proceeding
within [ * ] after receiving or giving written notice thereof (or, for actions brought under the Drug Price Competition and Patent Term
Restoration Act of 1984, as amended, [ * ]), then [ * ] shall have the right, but not the obligation, to bring and control any such action
by counsel of its own selection, at its expense. For all other Third Party infringement that is not a Product-Specific Infringement, the
IP Committee shall discuss options for pursuing the infringer. Unless [ * ] agrees otherwise, [ * ] shall have the first right but not the
obligation, to institute, prosecute, control, and settle any action or proceeding with respect to such infringement by counsel of its own
selection, at its expense. [ * ] shall provide [ * ] updates, via the IP Subcommittee, to [ * ] regarding the strategy and status of any such
proceeding, and shall provide [ * ] an opportunity to comment. The costs and expenses (including reasonable attorneys’ fees) of any
action against an infringer brought in accordance with this Section shall be borne by the Party controlling the infringement action.
Any monetary recovery in connection with such infringement action shall first be applied to reimburse the Party controlling the
infringement action for its out-of-pocket expenses (including reasonable attorneys’ fees) in taking such infringement action, and next
to reimburse the other Party for its out-of-pocket expenses (including reasonable attorneys’ fees) in assisting in such infringement
action. Once the Parties have been reimbursed for such expenses then the remainder will be apportioned as follows: For Product-
Specific Infringement (i) [ * ]; and (ii) [ * ]. For any other infringement, [ * ]. In any proceeding, the other Party will agree to be
joined as a party plaintiff (to the extent required by applicable law) and provide the prosecuting party with reasonable assistance, at
the requesting Party’s expense, to bring and prosecute such action or proceeding. Bayer shall not settle any action prosecuted under
this Section 2.4.6 that would adversely limit the scope of any Patent within the Onyx Developed IP without the prior written consent
of Onyx.
2.4.7 Drug Approval and Price Approval. In the event that Onyx conducts a Separate Development Program that results
in Bayer obtaining Drug Approval of Product from the FDA or the EMA with respect to the applicable Separate Indication, Bayer
shall promptly inform Onyx of such Drug Approval(s). Upon such Drug Approval and Price Approval (if any), Bayer shall pay Onyx
the Separate Development Costs as provided in Section 4.2 (with such amounts subject to Bayer’s right to audit as provided in
Section 4.7) and Bayer shall commercialize and promptly launch the Product for such Separate Indication as if the Separate Indication
had been developed internally by Bayer (and not pursuant to a Separate Development Program). Without limiting the generality of the
foregoing, Bayer shall use Commercially Reasonable Efforts to (i) obtain Drug Approval and Price Approval (if any) of the Product
for such Separate Indication in the United States, the major markets of the EU, [ * ] within [ * ] after first receipt of Drug Approval of
the Product in the United States or the European Union (as the case may be) with respect to such Separate Indication, and (ii) launch
the Product for such Separate Indication in all markets in which Drug Approval is obtained within a time period that
18
is consistent with similar product approvals (including Price Approval) and launches in such markets. In the event Onyx disputes
whether Bayer has exercised Commercially Reasonable Efforts to obtain Price Approval in a given territory, Onyx may refer such
dispute to arbitration in accordance with Section 12.3.
2.4.8 Licenses. Subject to the terms and conditions of this Agreement, Bayer hereby grants to Onyx a non-exclusive,
royalty-free, worldwide license (with the right to grant sublicenses with Bayer’s consent) under Information and Patents Controlled by
Bayer and its Affiliates to use, have used, develop and have developed Compound and Product pursuant to Separate Development
Programs and to otherwise conduct Separate Development Programs, including to perform regulatory activities to prepare Drug
Approval Applications with respect to Separate Indications in the United States and/or the European Union. Subject to the terms and
conditions of this Agreement, Onyx hereby grants to Bayer, effective upon Bayer’s payment pursuant to Section 4.2 of [ * ] of the
Separate Development Costs for a particular Separate Indication, an exclusive, royalty-bearing (to the extent of the royalties payable
under this Agreement), worldwide license (with the right to grant sublicenses) under the Onyx Developed IP developed pursuant to
the Separate Development Program which resulted in the approval for such Separate Indication to make, have made, use, have used,
sell, have sold, offer for sale, have offered for sale, import and have imported, the Product for all indications.
2.5 Commercialization Generally. Bayer shall be responsible, at its sole cost and expense, for commercialization of the Product
in all countries in the world, and Bayer shall conduct such commercialization in compliance with Applicable Laws under the oversight
of the EC, and subject to strategic direction from the Alliance Steering Committee; provided, however, that Bayer shall have the final
decision-making authority regarding Product Commercialization matters, subject to Onyx’s Co-Promotion rights and Section 2.4.7.
The commercialization of Product in the United States shall be governed by the terms of Article 3. Bayer shall keep Onyx
appropriately informed, through the EC or otherwise, of the Product commercialization activities performed by Bayer outside the
United States, including by providing on a semi-annual basis a written report summarizing such commercialization activities
conducted by or on behalf of Bayer since the last such report and including reasonable data from reports created by Bayer for its
internal management purposes including year-to-date Product gross sales, net sales, manufacturer selling price, commercial costs and
margins; final forecast of such metrics for the current year; and Product market analyses for each of the ten (10) largest countries (as
measured by Net Sales), including overall plan, challenges & opportunities. The Parties hereby adopt and agree to implement, with
respect to commercialization of Product both within and outside the United States, the Guiding Principles set forth in Section 2.7.1.
2.6 Information Delivery. In addition to any other information provided under this Agreement, Bayer shall provide to Onyx, in
October of each calendar year commencing in the first year of commercial sales of Product, its then-current forecast of global sales of
Product in the forthcoming calendar year, set forth on a calendar quarterly basis; Bayer shall provide Onyx updates to such forecast on
at least a semi-annual basis. At least once every 12 months, and subject to Article 7, Bayer shall provide Onyx with a list of all Drug
Approvals and Drug Approval Applications that cover the Product, and each Party shall provide the other Party with a list of all
Patents Controlled by such Party that cover the Product or its manufacture or use; such list shall include the filing date and priority
date of each such patent or patent application.
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2.7 Reconstitution of Executive Committee and its Subcommittees.
2.7.1 Guiding Principles. The Parties hereby agree to use diligent, good faith efforts to establish and maintain, throughout
the Term, a productive working relationship between the Parties, through the ASC, EC and the subcommittees of the EC, where each
of the Parties (i) provide each other with complete, accurate and timely information, regarding their activities and plans pursuant to
this Agreement and regarding activities and plans of, and communications with, Third Parties (including key opinion leaders,
principal investigators of investigator-sponsored studies or trials, and advisors) regarding the Product, (ii) promptly respond to all
reasonable inquiries of the other Party for additional information with respect thereto, (iii) fully discuss all concerns of the other Party
with respect thereto, and (iv) make and implement decisions subject to the decision making processes that facilitate, and if possible
optimize, the continued development and commercialization of the Product (collectively the “Guiding Principles”). Without limiting
the foregoing, each Party agrees to diligently pursue the goal of providing the other Party with the information described in (i) above
promptly after it is generated or becomes known to such Party and not materially later than such information is first provided to
employees of such Party with responsibility for the development or commercialization (as applicable) of the Product. For clarity, a
Party’s failure to comply with the Guiding Principles shall not, by itself, be considered a breach of this Agreement for which the other
Party may obtain damages or other remedy pursuant to Section 12.3, but such failure shall be brought to the attention of the ASC and
the ASC shall be responsible for devising mechanisms for monitoring and ensuring such Party’s compliance with the Guiding
Principles.
2.7.2 Executive Committee and Sub-Committees. The Parties agree the EC and subcommittees established under the
Collaboration Agreement, as amended, will be used to facilitate the Parties’ activities under this Agreement as described herein. All
references herein to the terms “EC” and “ASC” shall have the meanings provided in the Collaboration Agreement.
2.7.3 Powers of the Executive Committee. The collaboration between Bayer, Onyx, and their respective Affiliates under
this Agreement shall be managed by the Executive Committee in a manner that is consistent with the Guiding Principles and strategic
direction provided by the Alliance Steering Committee. The EC shall have responsibility for the matters described in this Agreement
together with responsibility for reviewing the Parties’ progress (including with respect to filings for Regulatory Approval and
supplements thereto) and comparing it with the applicable plan; responsibility for discussing new data and competitive threats;
responsibility for reviewing (but not approving) the annual development and marketing plan (including the budget therefor) and
lifecycle plan for developing and commercializing the Products; provided that the Bayer representative to the EC shall have the
deciding vote at the EC to resolve any dispute within the EC’s authority to the extent relating to the Product. Promptly following
Bayer’s submission of an annual development or marketing plan to its senior management, Bayer will present each such plan to the
EC in a level of detail suitable for Onyx to understand and provide comments upon the global plan for the Product. Bayer will provide
the
20
EC with the following information for the Product for top markets and the regions to the extent reasonable and extractable from
standard systems and templates and within Bayer’s Control and any additional information reasonably requested by Onyx’s EC
representatives for the purpose of evaluating any marketing plan:
(i) Actual year-to-date gross sales and Net Sales, commercial costs and margin, both globally and by top markets in Euros;
(ii) Final forecast for current year sales, commercial costs and margin;
(iii) Estimated ex-US sales, commercial costs and commercial margin plan figures;
(iv) manufacturer selling price (MSP) by country in preceding year;
(v) marketing costs (internal and external) and advertising & promotion costs for top markets and regions;
(vi) available market research data on patient penetration, duration of therapy, and market share in comparison with other
products in the same therapeutic space;
(vii) overall strategy for global business for the Product; and
(viii) analyses of the top markets, including overall plan, challenges, opportunities, and competitive landscape from both
commercial and clinical development perspectives.
For the purpose of this Section, “top markets” means the top 10 markets for the Product. For the purpose of clarification, this Section
shall not require Bayer to provide the EC any bidding or discount information or future pricing information with respect to the
Product.
2.7.4 Alliance Steering Committee. Commencing on the Effective Date, the strategic direction of the collaboration
between the Parties under this Agreement shall be managed by, and all disputes arising under this Agreement shall be submitted for
attempted resolution to the ASC. The ASC shall meet and attempt in good faith to promptly resolve all disputes arising under this
Agreement as described in Article 11. In addition to such meetings, the ASC shall meet at least once per Contract Year in late June or
early July to discuss and agree upon the strategic direction and priorities of the Parties’ efforts pursuant to this Agreement. The ASC
shall operate by consensus and pursuant to the procedures described in the Collaboration Agreement.
2.8 Product Information Exchange. Bayer and Onyx will disclose and make available to each other, to the extent permitted by
applicable law, preclinical, clinical, regulatory, commercial and other information known by Bayer or Onyx or their respective
Affiliates concerning the Product at any time during the term of this Agreement. All significant information and data will be disclosed
to the other Party promptly after it is learned or created.
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Promptly following the Effective Date, each Party will appoint a designee to facilitate the information exchange as described in this
Section 2.8 and be responsible for completing the following objectives: (i) convene an initial data exchange meeting for the Products
not later than sixty (60) days from the Effective Date; and (ii) establish a shared electronic collaboration space for the Parties to share
information, data, reports and updates regarding the Product not later than one hundred and twenty (120) days from the Effective
Date, in each case as described in this Section 2.8.
2.8.1 Within sixty (60) days after the Effective Date, the Parties agree to hold a meeting of the Parties’ respective key
technical and scientific personnel relating to the Product, including the designees of the EC and any relevant subcommittee members
for the purpose of providing an update and exchange of information and data regarding the Product. The Parties will mutually and
reasonably agree on the date, scope and agenda for such meeting, with specific areas of information exchange to be discussed in
advance of such meeting. The overall goal of the meeting is to provide Onyx with Product information and data that is reasonably
comparable in scope to that information disclosed to equivalent Bayer internal resources. In advance of such meeting, Onyx shall have
the right to specifically request Product information and data and request the participation by certain designated individuals. Bayer
shall use reasonable efforts to comply with Onyx’s request and provide information and data in the form and format currently existing
and used for Bayer’s own internal purposes.
2.8.2 Within one hundred and twenty (120) days after the Effective Date, Bayer, with the cooperation of Onyx, will
establish a shared electronic collaboration space that enables each Party (through representatives reasonably designated by such Party)
to access and provide access to the information and documents described in this Section, including presentations, data and reports
regarding the Product, correspondence with regulatory authorities with respect to the Product and Listed Commercial Information.
Each Party shall post non-public data from the ongoing development and commercialization (including safety monitoring) of the
Product to such electronic collaboration space on a regular and continuing basis; provided, that (a) the frequency of such posting may
be adjusted by consent of the EC, and (b) in the absence of any such consent, each Party shall post such data at the same time and in
the same format as made available to such Party’s internal project leadership team.
2.8.3 In the event that the Parties are unable for whatever reason to establish the information sharing activities within the
timeframes provided above, the designee of each Party established under this Section 2.8 shall provide a weekly, written report to the
ASC summarizing the scope of any delay, the reasons and the corrective actions being undertaken and the anticipated schedule to
achieve the objectives of this Section 2.8. Any failure to comply with the obligations set forth in this Section or agree on the scope of
the data to be included in such exchange shall be referred the EC and, if not remedied within 10 days of such referral, referred to the
ASC and not subject to arbitration under Section 12.3.
2.9 Collaboration Team Meeting. The Parties agree to hold promptly after the Effective Date, a meeting of the Parties’
respective key personnel, committee designees and senior management with the objective of establishing a collaborative and positive
framework for
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the Parties’ collaboration under this Agreement and the Collaboration Agreement. The overall goals for such meeting will be to:
(i) establish clear and open lines of communications between the Parties; (ii) provide joint guidance from the Parties on the strategic
and tactical implementation of this Agreement and the Collaboration Agreement; and (iii) the broad strategic objectives for the
collaboration between the Parties under this Agreement and the Collaboration Agreement. Each Party will promptly identify after the
Effective Date a designee to establish and coordinate the schedule, location and agenda for such meeting, which shall be reasonably
acceptable to each Party and selected to facilitate the broadest participation possible of key constituents within a reasonable time
period after the Effective Date (it being expected that the meeting should be conducted by [ * ] if reasonably possible).
ARTICLE 3
UNITED STATES CO-PROMOTION AND MEDICAL AFFAIRS PROGRAM
3.1 Generally. Bayer hereby agrees to retain Onyx on a co-exclusive basis with Bayer, to Co-Promote the Product, according to
the Detailing Plan and the other terms and conditions set forth on Exhibit A attached hereto and incorporated by reference as legally
binding terms.
3.2 Change of Control of Onyx. Onyx shall provide Bayer written notice of the occurrence of a Change of Control of Onyx
within [ * ] after the closing of the transaction which effected such Change of Control. Bayer may, at any time within [ * ] following
receipt of such notice, terminate Onyx’s rights of co-promotion under this Article 3 by delivery of written notice to Onyx. In the event
Bayer provides such notice of termination, the Co-Promotion Expiration Date shall be [ * ] following the date of Bayer’s notice of
termination. In such event, Bayer shall promptly modify the Co-Promotion Plan to provide for an orderly wind-down and transition of
Onyx’s activities under this Article 3, and Onyx shall withdraw its sales force and MSLs from such Co-Promotion Program activities
in a professional manner. During such period, Bayer shall remain responsible for payments as provided in Section 4.3. For clarity,
Bayer’s right to terminate Onyx’s rights of co-promotion under this Agreement in the event of a Change of Control of Onyx shall have
no effect on the Collaboration Agreement or Onyx’s rights of co-promotion with respect to Collaboration Products (as defined in such
agreement), including Nexavar.
3.3 Non-Solicitation of Employees. The Parties hereby agree that, throughout the Co-Promotion Term and for a period of [ * ]
immediately thereafter, neither will, directly or indirectly, solicit for employment any employee of the other Party (or of the other
Party’s Affiliates); provided, however, that the hiring of employees who respond to general advertisements for employment (not
targeted to employees of the other Party or their Affiliates) shall not be deemed to violate the foregoing provision.
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ARTICLE 4
FINANCIAL TERMS
4.1 Royalties.
4.1.1 Royalty. Bayer shall pay to Onyx non-refundable, non-creditable royalties equal to twenty percent (20%) of Net
Sales of all Products worldwide in human oncology during the Royalty Term. Bayer acknowledges that these payments are made
pursuant to settlement of the Litigation and do not depend on the existence or applicability of Onyx intellectual property. In countries
where a Product is approved for use only in human oncology, all Net Sales shall be royalty-bearing. In countries where a Product is
approved for use in both human oncology and non-oncology (whether human or otherwise), the Parties shall agree on a mechanism to
allocate sales between human oncology and non-oncology uses and, in the absence of agreement, may refer such issue to dispute
resolution in accordance with Article 11.
4.1.2 Royalty Term. Royalties shall be paid under this Section 4.1 on a country-by-country and Product-by-Product basis
during the period (the “Royalty Term”) from the First Commercial Sale of such Product in such country until the later of (a) [ * ], or
(b) [ * ]. Notwithstanding the foregoing, Bayer’s obligation to pay royalties pursuant to Section 4.1.1 shall [ * ] and the Royalty Term
shall [ * ] if [ * ], or if [ * ].
4.1.3 Royalty Reports and Payments. Within [ * ] following the end of each calendar quarter, commencing with the
calendar quarter in which the First Commercial Sale of Product is made anywhere in the world, Bayer shall provide Onyx a report
estimating Net Sales of the Product for such calendar quarter. Within [ * ] following the end of each calendar quarter, commencing
with the calendar quarter in which the First Commercial Sale of the Product is made anywhere in the world, Bayer shall provide Onyx
with a report containing the following information for such calendar quarter, on a country-by-country basis: (i) the amount of gross
sales of Product in such country, (ii) an itemized calculation of Net Sales showing deductions provided for in the definition of “Net
Sales,” (iii) the conversion of such Net Sales from the currency of sale into Dollars, and (iv) the calculation of the royalty payment
due on such sales pursuant to Section 4.1.1. Bayer shall pay to Onyx in Dollars all amounts due to Onyx pursuant to this Section 4.1
with respect to Net Sales by Bayer, its Affiliates and their respective licensees and sublicensees within [ * ] following the end of each
calendar quarter in which royalties are due under Section 4.1.1.
4.1.4 Books and Records. Bayer shall, and shall cause its Affiliates, licensees and sublicensees to, keep complete and
accurate books and records that disclose, on country-by-country basis, the total sales and Net Sales of Product, the number of units of
Product sold, and all matters relating to those sales that are relevant for the purposes of determining the royalties due Onyx hereunder.
Bayer shall, and shall cause its Affiliates to, (i) maintain such books and records in sufficient detail to calculate all amounts payable
hereunder and to verify compliance with Bayer’s obligations under this Agreement and (ii) retain such books and records until the
later of (a) [ * ] after the end of the period to which such books and records pertain, and (b) the expiration of the applicable tax statute
of limitations (or any extensions thereof), or for such longer period as may be required by Applicable Laws.
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4.1.5 Blocked Currency. In any country in which the local currency is blocked and cannot be removed from the country,
royalties accrued on Net Sales in such country shall be paid to Onyx in the equivalent amount in Dollars.
4.2 Payment of Separate Development Costs. If Onyx conducts one or more Separate Development Programs and Bayer
obtains Drug Approval of the Product from the FDA or EMA with respect to one or more Separate Indications based upon data
generated pursuant to a Separate Development Program, Bayer shall pay to Onyx [ * ] of the Separate Development Costs (or such
greater amount as set forth below) with respect to each and every such Separate Indication (with such amounts subject to Bayer’s right
to audit as provided in Section 4.7). Following Drug Approval of Product for each such Separate Indication, Onyx shall provide Bayer
with an invoice setting forth, in Dollars, [ * ] of the Separate Development Costs incurred with respect to such Separate Indication,
together with reasonable supporting documentation of such Separate Development Costs, provided that if such first approval was
obtained in the United States, the amount of such invoice shall be [ * ] of the Separate Development Costs unless, at the time of the
first dosing of a patient in the first clinical trial for such Separate Indication, the United States regulatory regime had changed to
require Price Approval prior to the commercial launch of a human pharmaceutical in a new indication (it being agreed that Price
Approval is not required in the United States as of the Effective Date). If such first approval was either (i) obtained with the EMA or
(ii) obtained in the United States and the United States regulatory regime had changed prior to the first dosing of a patient in the first
clinical trial for such Separate Indication to require Price Approval, then Bayer shall pay to Onyx an additional [ * ] of the Separate
Development Costs with respect to the Product upon the earlier of (X) Price Approval is obtained in the jurisdiction (European Union
or U.S. as the case may be) where the first Drug Approval was obtained or (Y) approval, including Price Approval if required, has
been obtained in the other jurisdiction (e.g., if the first approval is obtained with the EMA and, prior to Price Approval in the
European Union, approval is obtained in the United States and no Price Approval is then required in the United States). In all cases in
which a payment is conditioned upon Price Approval, if Price Approval is required in the European Union, Bayer’s obligation to pay [
* ] of the Separate Development Costs shall be conditioned upon Price Approval being granted in [ * ] major countries of the
European Union. In the event Onyx disputes whether Bayer has exercised Commercially Reasonable Efforts to obtain Price Approval
in a given territory pursuant to Section 2.4.7, Onyx may refer such dispute to arbitration in accordance with Section 12.3 and, in the
event it is determined that Bayer failed to use Commercially Reasonable Efforts to obtain Price Approval, Onyx shall be entitled to
receive the additional payment as if Price Approval had been obtained. Bayer’s obligation to pay Onyx the Separate Development
Costs shall, in the case of costs for services provided by Bayer, be [ * ] of the costs representing services provided by Bayer to Onyx.
Bayer shall pay to Onyx, in Dollars, the amount invoiced within [ * ] after the receipt of the invoice (or each invoice, in the case of
multiple payments). Onyx shall, and shall cause its Affiliates to, keep complete and accurate books and records pertaining to its and
their Separate Development Costs, in sufficient detail to calculate all amounts payable by Bayer under this Section 4.2. Onyx shall
retain such books and records until
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the later of (i) [ * ] after the end of the period to which such books and records pertain, and (ii) the expiration of the applicable tax
statute of limitations (or any extensions thereof), or for such longer period as may be required by Applicable Laws.
4.3 Co-Promotion Program Payments. In addition to all other amounts payable by Bayer to Onyx hereunder, Bayer shall pay
to Onyx its Detail Fees, MSL Expenses and Additional Expenses in accordance with Article III of Exhibit A. Onyx shall keep
complete and accurate books and records pertaining to its Detail Fees, MSL Expenses and Additional Expenses, in sufficient detail to
calculate all amounts payable by Bayer under this Section 4.3. Onyx shall retain such books and records until the later of (i) [ * ] after
the end of the period to which such books and records pertain, and (ii) the expiration of the applicable tax statute of limitations (or any
extensions thereof), or for such longer period as may be required by Applicable Laws.
4.4 Mode of Payment. All payments under this Agreement shall be made by deposit of Dollars in the requisite amount to such
bank account as Onyx may from time to time designate by notice to Bayer. For the purpose of calculating any sums due under, or
otherwise reimbursable pursuant to, this Agreement (including the calculation of Net Sales expressed in currencies other than
Dollars), a Party shall convert any amount expressed in a foreign currency into Dollar equivalents using its standard conversion
methodology consistent with United States generally accepted accounting principles consistently applied or international financial
reporting standards consistently applied, as applicable. Such standard conversion methodology shall be based upon the arithmetic
average of the daily exchange rates (obtained from the Reuters Daily Rate Report or The Wall Street Journal, Eastern U.S. Edition, or,
if not so available, as furnished by a Party’s local Affiliates) during the period from (a) the 25th day of the preceding month (or, if
such 25th day is not a Business Day, the immediately preceding Business Day) through (b) the 24th day of the current month (or, if
such 24th day is not a Business Day, the immediately preceding Business Day).
4.5 Taxes. The amounts payable by Bayer to Onyx pursuant to this Agreement (each a “Payment”) shall not be reduced on
account of any taxes unless required by Applicable Laws. If any Payment is subject to a deduction or withholding of tax, the Parties
shall use commercially reasonable efforts to perform all acts (including by executing all appropriate documents) so as to enable Onyx
to take advantage of any applicable double taxation agreement or treaty. In the event there is no applicable double taxation agreement
or treaty, or if an applicable double taxation agreement or treaty reduces but does not eliminate such tax, Bayer shall pay the
applicable tax to the appropriate Governmental or Regulatory Authority, shall deduct the amount paid from the Payment due Onyx,
and shall provide to Onyx evidence of such payment within [ * ] following such payment.
4.6 Interest on Late Payments. If any payment due under this Agreement is not paid when due, then such payment shall bear
interest at a rate equal to the lesser of: (a) [ * ] the United States prime rate as published by Citibank, N.A., New York, New York, or
any successor thereto, at 12:01 a.m. on the first day of each calendar quarter in which such payment is overdue or (b) the maximum
rate permitted by Applicable Law; in each case calculated on the number of days such payment is delinquent, compounded monthly.
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4.7 Audit. At the request of the other Party, each Party shall, and shall cause its Affiliates to, permit an independent auditor
designated by the auditing Party and reasonably acceptable to the audited Party, at reasonable times and upon reasonable notice, to
audit the books and records maintained pursuant to this Article 4 (subject to obligations of confidentiality to such audited Party) to
ensure the accuracy of all reports and payments made hereunder, but only as to any period ending not more than [ * ] prior to the date
of such request, and not more frequently than [ * ]. Except as provided below, the cost of this audit shall be borne by the auditing
Party, unless the audit reveals a variance of more than five percent (5%) from the reported amounts, in which case the audited Party
shall bear the cost of the audit. Unless disputed pursuant to Section 4.8 below, if such audit concludes that (a) additional amounts were
owed by the audited Party, the audited Party shall pay the additional amounts, with interest from the date originally due as provided in
Section 4.6 or (b) excess payments were made by the audited Party, the auditing Party shall reimburse such excess payments, in either
case ((a) or (b)), within thirty (30) days after the date on which such audit is completed by the auditing Party.
4.8 Audit Dispute. In the event of a dispute with respect to any audit under Section 4.7, the Parties shall work in good faith to
resolve the disagreement. If the Parties are unable to reach a mutually acceptable resolution of any such dispute within [ * ], the
dispute shall be submitted for resolution to a certified public accounting firm jointly selected by each Party’s certified public
accountants or to such other Person as the Parties shall mutually agree (the “Financial Expert”). The decision of the Financial Expert
shall be final and the costs of the Financial Expert as well as the initial audit shall be [ * ]. Not later than [ * ] after the decision of the
Financial Expert and in accordance with such decision, the audited Party shall pay the additional amounts, with interest from the date
originally due as provided in Section 4.6, or the auditing Party shall reimburse such excess payments, as applicable.
4.9 Confidentiality. The receiving Party shall treat all information subject to review under this Article 4 in accordance with the
confidentiality provisions of Article 7 and the Parties shall cause the independent auditor and the Financial Expert to enter into
reasonably acceptable confidentiality agreements with the audited Party obligating such firms to retain all such financial information
in confidence pursuant to such confidentiality agreements.
ARTICLE 5
PHARMACOVIGILANCE
The Parties will cooperate with each other in order to fulfill all regulatory requirements concerning drug safety surveillance and
product complaint reporting in the United States and in all countries in which Onyx is conducting any Separate Development
Program. For such purpose, as soon as reasonably practicable after the Effective Date, the Parties shall enter into a separate agreement
setting forth the pharmacovigilance responsibilities of the Parties and the procedures for safety information exchange to be carried out
by the Parties with respect to the
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Product (the “Pharmacovigilance Agreement”). In this regard, the Parties currently have in effect an agreement entitled Procedures
for Exchange of Pharmacovigilance Data Regarding Sorafenib dated June 21, 2005, as amended from time to time thereafter (the
“Existing Pharmacovigilance Agreement”). The Pharmacovigilance Agreement shall contain terms similar to those of the Existing
Pharmacovigilance Agreement.
ARTICLE 6
TERM AND TERMINATION
6.1 Term of Agreement. This Agreement shall become effective on the Effective Date and shall remain in effect on a Product-
by-Product and country-by-country basis until the expiration of the Royalty Term for such Product in such country (the “Term”).
Notwithstanding the foregoing, the Parties’ rights and obligations relating to the Co-Promotion Program in the United States, as set
forth in Article 3 and Section 4.3, shall terminate on the Co-Promotion Expiration Date.
6.2 Breaches. If either Party (the “Breaching Party”) shall have committed a breach of this Agreement, the other Party (the
“Notifying Party”) shall provide written notice of such breach to the Breaching Party. Upon receipt of a notice of breach other than a
Material Breach, the alleged Breaching Party shall have [ * ] (or [ * ] with respect to payment breaches) within which to cure such
breach following receipt of such notice; provided, however, for breaches other than payment, if the breach is capable of being cured
but cannot be reasonably cured in such [ * ] period, then the alleged Breaching Party shall have such additional time as necessary to
cure the breach if the alleged Breaching Party (i) during such [ * ] period has submitted a plan that, if successfully carried out, would
be effective in curing such breach, and has commenced its execution of such plan, and (ii) diligently pursues such plan thereafter. If
the matter is not resolved to the satisfaction of the Notifying Party during the foregoing cure period, then the Notifying Party may, at
its discretion, resort to the dispute resolution mechanisms of Article 11 with respect to claims for damages, attorneys’ fees and court
costs, requests for equitable relief and other available remedies in law or equity, provided that the Notifying Party shall have no right
to terminate this Agreement for such breach.
6.3 Termination of Co-Promotion Program for Material Breach. The Parties agree that, except for Onyx’s Co-Promotion
Program rights and obligations, this Agreement shall not be terminated under any circumstances. If Onyx shall have committed a
Material Breach (defined below), Bayer may terminate all of Onyx’s rights and obligations relating to the Co-Promotion Program in
the United States (as set forth in Article 3 and Section 4.3) as provided in this Section 6.3.
6.3.1 Material Breach. For purposes of this Agreement, a “Material Breach” means a breach of this Agreement that is [ *
] (provided, that without limiting the foregoing, [ * ].
6.3.2 Notice and Cure. If a Party believes that a Material Breach has occurred (or will occur in the event such breach is
determined to exist), it shall give written notice to the
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Breaching Party of the nature of the breach and the reason the Notifying Party believes it is a Material Breach. The alleged Breaching
Party shall then have a period of [ * ] following receipt of such notice in which to cure the breach; provided, however, if the Material
Breach is capable of being cured but cannot be reasonably cured in such [ * ] period, then the alleged Breaching Party shall have such
additional time as necessary to cure the breach if the alleged Breaching Party (i) during such [ * ]-period has submitted a plan that, if
successfully carried out, would be effective in curing such Material Breach, and has commenced its execution of such plan, and
(ii) diligently pursues such plan thereafter. Any such notice of alleged Material Breach by the Notifying Party shall include a
reasonably detailed description of all relevant facts and circumstances demonstrating, supporting and/or relating to each such alleged
Material Breach by the Breaching Party. In the event there is a dispute as to whether a Material Breach has occurred, this Agreement
shall survive pending a determination pursuant to Section 11 below that a Material Breach has occurred.
6.3.3 Termination of Co-Promotion Program. If an alleged Material Breach by Onyx is not cured within the cure period
specified in Section 6.3.2, Bayer may give notice of termination of the Co-Promotion Program (“Notice of Termination of Co-
Promotion Program”). If Onyx agrees that a Material Breach has occurred and was not cured within the cure period, then Bayer may
proceed to terminate the Co-Promotion Program and all of Onyx’s rights and obligations thereunder (including all rights and
obligations under Article 3 and Section 4.3). If Onyx does not agree that a Material Breach has occurred and was not cured within the
cure period, then the Co-Promotion Program shall survive, and the Parties shall continue to perform their obligations under this
Agreement with respect thereto, until the issue of whether there has been an uncured Material Breach by Onyx is resolved in
accordance with Article 11. Either Party may elect to arbitrate under Article 11 for an advance declaration that a breach, if found,
would constitute a Material Breach hereunder. If Bayer gives Notice of Termination of Co-Promotion Program, and it is later
determined by a court pursuant to Article 11 that in fact there has not been an uncured Material Breach by Onyx, then the Co-
Promotion Program, and all of the Parties’ rights and obligations under this Agreement with respect thereto, shall continue in full
force and effect. Notwithstanding the giving of any notice of termination pursuant to this Section 6.3.3, each Party shall continue to
fulfill its obligations under the Co-Promotion Program at all times until the effective date of any such termination.
6.4 Effects of Termination. Neither termination of the Co-Promotion Program nor expiration of this Agreement shall
release or operate to discharge either Party from any liability or obligation that may have accrued prior to such termination or
expiration. Except as provided in the preceding sentence, upon the Co-Promotion Expiration Date, neither Party shall have any further
rights or obligations under Article 3 or Exhibit A or otherwise with respect to the Co-Promotion Program. Onyx and Bayer shall
reasonably cooperate to transition to Bayer Onyx’s Co-Promotion Program activities so as to minimize disruption to Product sales and
Promotion activity, and Onyx shall withdraw its sales force from such Co-Promotion Program activities and its MSLs from the
Medical Support Program in a professional manner. Notwithstanding termination of the Co-Promotion Program, all other provisions
of this Agreement shall remain in full force and effect, including Bayer’s obligation to pay royalties pursuant to Section 4.1. Any
termination of the Co-Promotion Program as provided herein shall not be an exclusive remedy but shall be in addition to any remedies
whatsoever that may be available to the terminating Party pursuant to Article 11.
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6.5 Survival. The representations, warranties, covenants and agreements of the Parties in [ * ], and all provisions relating to
Confidential Information shall survive any expiration or termination of this Agreement. In addition, any provision of this Agreement
that, either from the express language or the context thereof, is intended to survive any termination or expiration of this Agreement
shall survive any such expiration or termination.
ARTICLE 7
CONFIDENTIALITY
7.1 Confidentiality. Except to the extent expressly authorized by this Agreement or otherwise agreed in writing by the Parties,
each Party agrees that, during the Term and for the [ * ] period following the expiration or termination of this Agreement, it shall keep
confidential and shall not publish or otherwise disclose and shall not use for any purpose other than as provided for in this Agreement
(which includes the exercise of any rights or the performance of any obligations hereunder) any Confidential Information furnished to
it by the other Party pursuant to this Agreement.
7.2 Authorized Disclosure. Each Party may disclose Confidential Information belonging to the other Party to the extent such
disclosure is reasonably necessary in the following situations:
(i) filing or prosecuting Patents;
(ii) regulatory filings and other filings with Governmental or Regulatory Authorities, including filings with the SEC, FDA
or EMA;
(iii) prosecuting or defending litigation;
(iv) complying with Applicable Laws, including regulations promulgated by securities exchanges;
(v) disclosure to its Affiliates, employees, agents, and independent contractors, and any sublicensees, in each case only on a
need-to-know basis and solely in connection with the performance of this Agreement, provided that each disclosee must be bound by
obligations of confidentiality and non-use at least as equivalent in scope as those set forth in this Article 7 prior to any such disclosure;
and
(vi) disclosure of the material terms of this Agreement to any bona fide potential or actual investor, investment banker,
acquirer, merger partner, or other potential or actual financial partner, with the prior written consent of the other Party not to be
unreasonably withheld, and provided that in connection with such disclosure, each disclosee must be bound by obligations of
confidentiality and non-use at least equivalent in scope to those set forth in this Article 7 prior to any such disclosure.
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Notwithstanding the foregoing, in the event a Party is required to make a disclosure of the other Party’s Confidential Information
pursuant to Sections 7.2(i), 7.2(ii), 7.2(iii) or 7.2(iv), it will, except where impracticable, give reasonable advance notice to the other
Party of such disclosure and use reasonable efforts to secure confidential treatment of such information. In any event, the Parties agree
to take all reasonable action to avoid disclosure of Confidential Information hereunder.
7.3 Public Announcements; Publications. During the Term, each Party (the “Publishing Party”) shall submit to the other
Party (the “Non-Publishing Party”) for review and approval all proposed press releases, public filings with the SEC, academic,
scientific and medical publications and public presentations that disclose previously undisclosed technical information regarding the
Product, provided that each Party shall have the right to make disclosures which in its judgment are required by law, regulation, or the
rules of any nationally-recognized securities exchange. Such review and approval shall be conducted for the purposes of preserving
intellectual property protection and the confidentiality of trade secrets and determining whether any portion of the proposed
publication or presentation containing the Confidential Information of the Non-Publishing Party should be modified or deleted.
Written copies of such proposed publications and presentations (other than press releases or SEC or securities exchange filings) shall
be submitted to the Non-Publishing Party as soon as reasonably practicable before submission for publication or presentation. In the
case of proposed SEC filings or other securities law filings containing non-technical information regarding the Product or this
Agreement, the Parties shall follow the procedures and agreements they have in place with respect to disclosures under the
Collaboration Agreement, provided that each Party shall have the right to make disclosures which in its judgment are required by law,
regulation, or the rules of any nationally-recognized securities exchange. Onyx and Bayer will each comply with standard academic
practice regarding authorship of scientific publications and recognition of contribution of other Parties in any publications.
ARTICLE 8
INDEMNIFICATION AND INSURANCE; LIMITATION OF LIABILITY
8.1 Indemnification by Onyx.
8.1.1 Indemnification. Onyx shall defend, indemnify and hold harmless Bayer and its Affiliates and each of their officers,
directors, shareholders, employees, successors and assigns (each a “Bayer Indemnified Party”) from and against all Claims of Third
Parties, and all associated Indemnifiable Losses, incurred or suffered by any of them to the extent resulting from or arising out of:
(i) the breach by Onyx or any of its Affiliates of any of its representations, warranties or covenants in this Agreement;
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(ii) the negligent acts or negligent omissions or willful misconduct by Onyx or any of its Affiliates in the performance of
any of its obligations under this Agreement; or
(iii) personal injury or death resulting from any human clinical trial included within a Separate Development Program
conducted by Onyx or any of its Affiliates.
Notwithstanding the foregoing, no Bayer Indemnified Party shall be entitled to any indemnification pursuant to this
Section 8.1, to the extent the Indemnifiable Loss for which indemnification is being sought is indemnifiable by Bayer pursuant to
Section 8.2, as to which Indemnifiable Loss each Party shall indemnify the other to the extent of their respective liability.
8.1.2 Procedure. Bayer shall give Onyx prompt written notice of any Claim for which it seeks to be indemnified under this
Section 8.1, but the omission of such notice shall not relieve Onyx from its obligations under this Section 8.1, except to the extent
Onyx can establish actual prejudice and direct damages as a result thereof. Onyx shall have no obligation under this Section 8.1 with
respect to any Claim unless Onyx is granted full authority and control over the defense, including, without limitation, settlement, of
such Claim, and Bayer cooperates fully with Onyx and its agents in defense of such Claim. Bayer shall have the right to participate in
the defense of any such Claim utilizing attorneys of its choice, at its own expense. Subject to the remainder of this subsection, Onyx
shall have full authority and control to handle the Claim for which Bayer seeks indemnification under this Section 8.1. Any settlement
of the Claim that would admit liability on the part of any Bayer Indemnified Party, or that would involve any relief (including the
payment of money damages), shall be subject to Bayer’s prior written approval, such approval not to be unreasonably withheld or
delayed.
8.2 Indemnification by Bayer.
8.2.1 Indemnification. Bayer shall defend, indemnify and hold harmless Onyx and its Affiliates and each of their officers,
directors, shareholders, employees, successors and assigns (each an “Onyx Indemnified Party”) from and against all Claims of Third
Parties, and all associated Indemnifiable Losses, incurred or suffered by any of them to the extent resulting from or arising out of:
(i) the breach by Bayer or any of its Affiliates of any of its representations, warranties or covenants in this Agreement;
(ii) the negligent acts or negligent omissions or willful misconduct by Bayer or any of its Affiliates in the performance of
any of its obligations under this Agreement;
(iii) the supply of Products to Onyx under this Agreement; or
(iv) the development, manufacture, commercialization, use, storage, import/export, or distribution of Products by or on
behalf of Bayer or any of its Affiliates including Claims based upon product liability.
32
(v) any claim that the development, manufacture, commercialization, use, storage, import/export, or distribution of
Products infringe(s) or misappropriate(s) any Third Party intellectual property rights except to the extent arising from the use of the
Product to conduct a Separate Development Program (and not otherwise attributable to the composition of matter or other uses of the
Product) by Onyx or any of its Affiliates.
Notwithstanding the foregoing, no Onyx Indemnified Party shall be entitled to any indemnification pursuant to this
Section 8.2 to the extent the Indemnifiable Loss for which indemnification is being sought is indemnifiable by Onyx pursuant to
Section 8.1, as to which Indemnifiable Loss each Party shall indemnify the other to the extent of their respective liability.
8.2.2 Procedure. Onyx shall give Bayer prompt written notice of any Claim for which it seeks to be indemnified under this
Section 8.2 but the omission of such notice shall not relieve Bayer from its obligations under this Section 8.2, except to the extent
Bayer can establish actual prejudice and direct damages as a result thereof. Bayer shall have no obligation under this Section 8.2 with
respect to any Claim unless Bayer is granted full authority and control over the defense, including, without limitation, settlement, of
such Claim, and Onyx cooperates fully with Bayer and its agents in defense of such Claim. Onyx shall have the right to participate in
the defense of any such Claim utilizing attorneys of its choice, at its own expense. Subject to the remainder of this subsection, Bayer
shall have full authority and control to handle the Claim for which Onyx seeks indemnification under this Section 8.2. Any settlement
of the Claim that would admit liability on the part of any Onyx Indemnified Party, or that would involve any relief (including the
payment of money damages), shall be subject to Onyx’s prior written approval, such approval not to be unreasonably withheld or
delayed.
8.3 Insurance. From and after the Effective Date and for a period of [ * ] after the expiration of this Agreement, Bayer and Onyx
shall each obtain and/or maintain, respectively, at its sole cost and expense, clinical trial insurance and product liability insurance
(including any self-insured arrangements) in amounts, respectively, which are reasonable and customary in the pharmaceutical
industry in the United States for companies of comparable size and activities at the respective place of business of such Party. Such
product liability insurance or self-insured arrangements shall insure against all liability, including, without limitation, personal injury,
physical injury, or property damage arising out of its clinical trials, or the manufacture, sale, distribution, or marketing of the Products.
Each Party shall provide to the other, upon request of the other Party, a certificate of insurance verifying the existence of such
insurance.
8.4 Limitation of Liability. NOTWITHSTANDING ANY OTHER PROVISION CONTAINED HEREIN, UNLESS
RESULTING FROM A PARTY’S FRAUDULENT BEHAVIOR, IN NO EVENT SHALL BAYER, ON THE ONE HAND, OR
ONYX, ON THE OTHER HAND, BE LIABLE TO THE OTHER OR ANY OF THE OTHER PARTY’S AFFILIATES FOR ANY
PUNITIVE OR EXEMPLARY DAMAGES SUFFERED OR INCURRED BY SUCH OTHER PARTY OR ITS AFFILIATES IN
CONNECTION WITH A BREACH OR ALLEGED BREACH OF THIS AGREEMENT. IT IS UNDERSTOOD THAT THE
FOREGOING SENTENCE SHALL NOT LIMIT THE OBLIGATIONS OF BAYER, ON THE ONE HAND, OR ONYX, ON THE
OTHER HAND, TO INDEMNIFY THE OTHER FROM AND AGAINST THIRD PARTY CLAIMS UNDER THIS ARTICLE 8.
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ARTICLE 9
REPRESENTATIONS, WARRANTIES AND COVENANTS
9.1 Representations by Onyx. Onyx represents and warrants to Bayer as of the Effective Date that:
(i) this Agreement has been duly authorized and executed by it and is legally binding upon it, enforceable in accordance
with its terms, and the execution, delivery and performance of this Agreement by Onyx does not conflict with, or constitute a breach
of or under, any order, judgment, agreement or instrument to which Onyx is a party;
(ii) the execution, delivery and performance of this Agreement by Onyx does not require the consent of any Person or the
authorization of (by notice or otherwise) any Governmental or Regulatory Authority; and
(iii) it has not and has never been, nor have any of its employees, agents or subcontractors who may provide services under
this Agreement ever been debarred or, to the best of its knowledge, (i) convicted of a crime for which a person or entity can be
debarred under Section 306(a) or 306(b) of the United States Generic Drug Enforcement Act of 1992 or under 42 U.S.C. Sections
1320-7; or (ii) sanctioned by, or suspended, excluded or otherwise ineligible to participate in any federal health care program,
including Medicare and Medicaid or in Federal Procurement or non-procurement programs.
9.2 Representations by Bayer. Bayer represents and warrants to Onyx as of the Effective Date that:
(i) this Agreement has been duly authorized and executed by it and is legally binding upon it, enforceable in accordance
with its terms, and the execution, delivery and performance of this Agreement by Bayer does not conflict with, or constitute a breach
of or under, any order, judgment, agreement or instrument to which Bayer is a party;
(ii) the execution, delivery and performance of this Agreement by Bayer does not require the consent of any Person or the
authorization of (by notice or otherwise) any Governmental or Regulatory Authority; and
(iii) it has not and has never been, nor have any of its employees, agents or subcontractors who may provide services under
this Agreement ever been debarred or, to the best of its knowledge, (i) convicted of a crime for which a person or entity can be
debarred under Section 306(a) or 306(b) of the United States Generic Drug Enforcement Act of 1992 or under 42 U.S.C. Sections
1320-7; or (ii) sanctioned by, or suspended, excluded or otherwise ineligible to participate in any federal health care program,
including Medicare and Medicaid or in Federal Procurement or non-procurement programs.
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9.3 Disclaimer Of Warranties. EXCEPT FOR THE EXPRESS REPRESENTATIONS AND WARRANTIES SET FORTH IN
SECTIONS 9.1 AND 9.2, NEITHER PARTY MAKES ANY REPRESENTATION OR GRANTS ANY WARRANTY, EXPRESS OR
IMPLIED, EITHER IN FACT OR BY OPERATION OF LAW, BY STATUTE OR OTHERWISE, AND EACH PARTY
SPECIFICALLY DISCLAIMS ANY OTHER WARRANTIES, WHETHER WRITTEN OR ORAL, OR EXPRESS OR IMPLIED,
INCLUDING ANY WARRANTY OF QUALITY, MERCHANTABILITY, OR FITNESS FOR A PARTICULAR USE OR
PURPOSE OR ANY WARRANTY AS TO THE VALIDITY OF ANY PATENTS OR THE NON-INFRINGEMENT OF ANY
INTELLECTUAL PROPERTY RIGHTS OF THIRD PARTIES.
9.4 Covenants.
9.4.1 No Debarment. Each Party covenants that, during the Term (i) it shall not use in any capacity, in connection with the
performance of the activities contemplated by this Agreement, any Person who has been debarred pursuant to Section 306 of the
FFDCA, or who is the subject of a conviction described in such section and (ii) it shall inform the other Party in writing immediately
if it or any Person who is performing activities hereunder on its behalf is debarred or is the subject of a conviction described in
Section 306, or if any action, suit, claim, investigation, or legal or administrative proceeding is pending or, to the best of its
knowledge, is threatened, relating to the debarment or conviction of it or any Person performing services hereunder on its behalf.
9.4.2 No Violation. Each Party covenants that, during the Term, neither it nor any of its Affiliates will enter into or
otherwise have any obligation to any Person, contractual or otherwise, that is in violation of the terms of this Agreement, inconsistent
with the rights and licenses granted to the other Party hereunder, or that would impede the fulfillment of such Party’s obligations
hereunder.
9.4.3 Training. Each Party covenants that, during the Co-Promotion Term, all of its employees who are involved in the
contracting for, or Promoting, selling or reporting the price of Products that are reimbursed by Medicare, Medicaid and all other
federal healthcare programs (as defined in 42 U.S.C. Section 1320(a)7(b)(f)) will, prior to deployment, receive appropriate training on
proper marketing and sales techniques consistent with the obligations of Bayer pursuant to the CIA and as directed by the Executive
Committee.
9.4.4 Product Trademarks. Bayer covenants that it holds, or will hold, all right, title and interest to all Product trademarks,
such trademarks shall be in full force as of the Co-Promotion Effective Date, and Bayer will use its Commercially Reasonable Efforts
to maintain such trademarks in full force during the Co-Promotion Term.
9.4.5 Product Supply. Bayer covenants that the Product to be supplied to Onyx for use in any Separate Development
Program during the Term shall meet the Product Warranty, and the Product to be distributed by Bayer in the United States during the
Co-Promotion Term will, at the time of shipment by or on behalf of Bayer, have been manufactured in conformity with GMPs and
will not be adulterated or misbranded within the meaning of the Act or comparable state laws.
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9.4.6 IP Matters. In connection with any proposed Separate Development Program, the Parties agree to cooperate and
share information regarding the existence of potential Third Party intellectual property rights relating to such activities. Each Party
agrees to disclose any information, of which it is aware, where the development activities proposed to be conducted under the
Separate Development Plan may be covered by any Third Party intellectual property rights; provided that neither Party shall be
required to investigate whether there are any intellectual property rights of Third Parties that may impact Onyx’s ability to conduct a
Separate Development Program.
ARTICLE 10
NOTICES
Except as otherwise specifically provided herein, any notice or other document to be given under this Agreement shall be in
writing and shall be deemed to have been duly given if sent by nationally recognized overnight courier or confirmed facsimile
transmission to a Party (followed by hard copy by mail) or delivered in person to a Party at the address or facsimile number set out
below for such Party or such other address as the Party may from time to time designate by written notice to the other in accordance
with this Article 10:
If to Bayer:
555 White Plains Road
Tarrytown, NY 10591
Attention: Sr. VP and General Counsel
Facsimile: (914) 366-1784
With a copy to:

Bayer HealthCare Pharmaceuticals Inc.
340 Changebridge Road
Montville, NJ
Attention: Global Head of Oncology
Facsimile: (973) 487-2929
If to Onyx:
Onyx Pharmaceuticals, Inc.
249 E. Grand Avenue
South San Francisco, CA 94080
Attention: Chief Executive Officer
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Telephone: (650) 266-0000
Facsimile: (650) 266-0100
With a copy to:

Cooley LLP
3175 Hanover Street
Palo Alto, CA 94304
Attention: Robert L. Jones, Esq.
Telephone: (650) 843-5000
Facsimile: (650) 849-7400
Any such notice or other document shall be deemed to have been received by the addressee simultaneously with the transmission
or delivery thereof.
ARTICLE 11
DISPUTE RESOLUTION
The Parties recognize that disputes under this Agreement (other than matters for which decisions or approvals are reserved to
Bayer under this Agreement) (“Dispute(s)”) may arise from time to time. It is the objective of the Parties to establish procedures to
facilitate the resolution of Disputes in an expedient manner by mutual cooperation and without resort to litigation. To accomplish this
objective, the Parties shall follow the procedures set forth in this Article 11 if and when a Dispute arises under this Agreement. Any
Disputes between the Parties that cannot be resolved by good faith negotiation shall be referred, by written notice from either Party to
the other, to the EC. The EC shall meet as soon as possible, and not more than thirty (30) days after such notice is received, and shall
make diligent, good faith efforts to resolve such Dispute in a manner that is consistent with the terms of this Agreement and the
principles underlying such terms and that balances the legitimate interests of both Parties. In the event that the members of the EC are
not able to resolve such Dispute during such meeting, the EC shall refer such Dispute to the ASC in writing. The ASC shall meet as
soon as possible, and not more than thirty (30) days after such notice is received, and if the ASC has not resolved such dispute by the
end of such 30-day period (or any mutually agreed extension thereof), either Party may submit such Dispute to arbitration as set forth
in Section 12.3.
ARTICLE 12
MISCELLANEOUS PROVISIONS
12.1 Assignment. Neither Party may assign or transfer this Agreement or any rights or obligations hereunder without the prior
written consent of the other, except that a Party may make such an assignment without the other Party’s consent to Affiliates or to a
successor to all or substantially all of the business of such Party, whether in a merger, sale of stock, sale of assets or other transaction.
Any permitted successor or assignee of rights and/or obligations hereunder
37
shall, in a writing to the other Party, expressly assume performance of such rights and/or obligations (and in any event, any Party
assigning this Agreement to an Affiliate shall remain bound by the terms and conditions hereof).
12.2 Royalty Transferability. Bayer recognizes that Onyx may desire to sell, to one or more Third Parties, Onyx’s rights to
receive royalties under this Agreement from the sale of Products. To facilitate such sale, the Parties hereby agree, notwithstanding
anything in this Agreement to the contrary, that (a) Onyx may, without Bayer’s consent, assign, sell, pledge, contribute or otherwise
transfer, in whole or in part, its rights to (i) receive royalties pursuant to Section 4.1, (ii) receive reports pursuant to Section 4.1 with
respect to Net Sales of the Product and other information relating to calculation of the royalty payments owed pursuant to Section 4.1,
(iii) receive copies of reports and/or results of any audit conducted pursuant to Section 4.7 with regard to the correctness of payments
made and reports provided pursuant to Section 4.1, and (iv) further assign, sell, pledge, contribute or otherwise transfer such rights to
receive, and ownership interests in, the royalties described in clause (a)(i), and the related reports and information described in clauses
(a)(ii) and (a)(iii), (b) the reports and information described in clauses (a)(ii) and (a)(iii) shall not be considered “Confidential
Information” under the Collaboration Agreement so long as (A) any proposed or actual assignee, purchaser, pledgee, contribution
recipient or other transferee is bound, prior to receiving such reports and information, to written or professional confidentiality and
non-use obligations no less stringent than those contained in the Collaboration Agreement (giving effect to this clause (b)), and (c) the
agreements contained in clauses (a) and (b) shall be binding on each of them and their respective successors and assigns, and (B) such
assignment, sale, pledge, contribution or other transfer creates no additional liabilities of Bayer, or rights in favor of the proposed or
actual assignee, purchaser, pledgee, contribution recipient or other transferee, in addition to the rights and liabilities of the Parties set
forth in this Agreement. In the event that Onyx transfers to a Third Party the right to receive [ * ] the royalty payments to which Onyx
is entitled to receive for Products under this Agreement, then, [ * ] and [ * ] shall [ * ].
12.3 Governing Law; Disputes.
12.3.1 This Agreement shall be deemed to have been entered into and shall be construed and enforced in accordance with
the laws of the State of California as applied to contracts made and to be performed entirely within the State of California without
giving effect to any choice or conflict of law provisions.
12.3.2 The Parties agree that all disputes arising out of or in connection with this Agreement (including whether a dispute is
subject to arbitration) shall be solely and exclusively resolved through arbitration in San Francisco, California before a panel of three
(3) neutral arbitrators, which shall be selected as follows within thirty (30) days from the request for arbitration: Bayer shall select one
arbitrator, Onyx shall select one arbitrator, and Bayer and Onyx shall seek to agree on the selection of the third arbitrator; provided
that if Bayer and Onyx fail to agree on such third arbitrator within such thirty (30)-day period, then the arbitrators designated by Onyx
and Bayer shall select the third arbitrator within fifteen (15) days. Judgment on the award may be entered in any court having
jurisdiction. The arbitration shall be
38
administered by JAMS pursuant to its Comprehensive Arbitration Rules & Procedures, except that the Parties expressly agree that any
arbitration pursuant to this Section 12.3.2 shall be a “baseball-style” arbitration governed by Rule 33 of the JAMS Comprehensive
Arbitration Rules & Procedures (effective October 1, 2010). Each Party shall bear its own costs and expenses in connection with a
dispute brought under this Section 12.3.2, provided that Bayer and Onyx shall share equally in the costs of the arbitration panel and
any fee imposed by JAMS. Notwithstanding any Rule to the contrary, the Parties expressly agree to the following discovery
procedures for any arbitration initiated pursuant to this Section 12.3.2: the Parties shall be entitled to take discovery within the scope
provided for in the JAMS Comprehensive Arbitration Rules & Procedures. With respect to limits on the type and amount of discovery,
each Party shall be entitled to [ * ]. The arbitration panel may allow discovery beyond these limits upon a showing a good cause.
12.3.3 Without modifying the agreement set forth in Section 12.3.2, the Parties intend that in the event of an operational
dispute under this Agreement, the Parties shall seek to resolve their differences through an expedited determination by a neutral expert
who has no affiliation whatsoever with either Party. The exact process and scope of such expert determination shall be determined by
the Parties at that time (or from time to time in the event of multiple referrals to such an expert). In the absence of mutual agreement
to pursue such an expedited expert determination, the rules of Section 12.3.2 shall apply. No written statement of reasons shall
accompany the arbitration decision unless both Parties agree that such a statement is necessary. To the extent non-monetary relief is an
issue in the arbitration, each Party shall submit its proposal regarding non-monetary relief, and the arbitration panel shall choose
between the Parties’ proposals.
12.4 Waiver. Except as specifically provided for herein, the waiver from time to time by either of the Parties of any of their
rights or their failure to exercise any remedy shall not operate or be construed as a continuing waiver of same or of any other of such
Party’s rights or remedies provided in this Agreement. No course of conduct or dealing between the Parties shall act as a modification
or waiver of any provisions of this Agreement.
12.5 Entire Agreement; Amendment. This Agreement and any and all documents or agreements referenced herein or Exhibits
hereto, including the Collaboration Agreement to the extent referenced herein, contain all of the terms agreed to by the Parties
regarding the subject matter of this Agreement and supersede any prior oral or written agreements, understandings or arrangements
between the Parties as to the subject matter hereof. This Agreement may not be amended, modified, altered or supplemented except by
means of a written agreement or other instrument executed by both of the Parties hereto.
12.6 Severability. If any term, covenant or condition of this Agreement or the application thereof to any Party or circumstance
shall, to any extent, be held to be invalid or unenforceable, then (i) the remainder of this Agreement, or the application of such term,
covenant or condition to the Parties or circumstances other than those as to which it is held invalid or unenforceable, shall not be
affected thereby and each term, covenant or condition of this Agreement shall be valid and be enforced to the fullest extent permitted
by law; and (ii) the
39
Parties covenant and agree to renegotiate any such term, covenant or application thereof in good faith in order to provide a reasonably
acceptable alternative to the term, covenant or condition of this Agreement or the application thereof that is invalid or unenforceable,
it being the intent of the Parties that the basic purposes of this Agreement are to be effectuated.
12.7 Relationship of the Parties. The Parties hereto are acting and performing as independent contractors, and nothing in this
Agreement creates the relationship of partnership, joint venture, sales agency or principal and agent. Neither Party is the agent of the
other, and neither Party may hold itself out as such to any other Person.
12.8 No Implied Licenses. Each of the Parties hereby acknowledges and agrees that, except as otherwise explicitly provided in
this Agreement, such Party shall not by entering into this Agreement have, assert or acquire any right, title or interest in or to any
intellectual property or other proprietary rights of the other Party.
12.9 Counterparts; Electronic Execution. This Agreement may be executed in one (1) or more counterparts, each of which
shall be deemed an original, but both of which together shall constitute one and the same instrument. Each Party may execute this
Agreement by facsimile transmission or in Adobe™ Portable Document Format (PDF) sent by electronic mail. Facsimile or PDF
signatures of authorized signatories of the Parties will be deemed to be original signatures, will be valid and binding upon the Parties,
and, upon delivery, will constitute due execution of this Agreement.
12.10 Force Majeure. Neither Party shall be liable or responsible to the other Party for loss or damages, nor shall it have any
right to terminate this Agreement for any default or delay attributable to any event beyond its reasonable control and without its fault
or negligence, including but not limited to acts of God, acts of government (including injunctions), fire, flood, earthquake, strike,
lockout, labor dispute, breakdown of plant, shortage of critical equipment, loss or unavailability of manufacturing facilities or
material, casualty or accident, civil commotion, acts of public enemies, acts or terrorism or threat of terrorist acts, blockage or
embargo and the like (a “Force Majeure Event”); provided, however, that in each such case the Party affected shall use
Commercially Reasonable Efforts to avoid such occurrence and to remedy it promptly. The Party affected shall give prompt notice of
any such cause to the other Party. The Party giving such notice shall thereupon be excused from such of its obligations hereunder as it
is thereby disabled from performing for so long as it is so disabled and the Party receiving notice shall be similarly excused from its
respective obligations which it is thereby disabled from performing; provided, however, that such affected Party commences and
continues to take reasonable and diligent actions to cure such cause.
12.11 Headings. The headings contained in this Agreement are for reference purposes only and shall not affect in any way the
meaning or interpretation of this Agreement.
12.12 Not An Amendment of The Collaboration Agreement. Although this contract addresses matters arising from the
Collaboration Agreement, it is a separate contract and shall not be considered an amendment of the Collaboration Agreement.
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REMAINDER OF PAGE INTENTIONALLY LEFT BLANK
41
IN WITNESS WHEREOF, the Parties have duly executed this Agreement as of the Effective Date.
BAYER HEALTHCARE LLC
By: /s/ R. Scott Meece
Title: General Counsel + Sr. Vice President
By: /s/ N. Anthony Coles
Title: President & CEO
SIGNATURE PAGE TO AGREEMENT REGARDING REGORAFENIB
1
Exhibit A
Provisions Regarding Co-Promotion
“Detail” shall mean a one-on-one in-person contact (which may include E-detailing performed by a human representative if included
by Bayer in the Co-Promotion Plan) in which an Onyx sales representative or E-detailing representative makes a presentation,
including, without limitation, selling message and features and benefits of the Product to a member of the Target Healthcare
Professionals, and during which [ * ]. Except as provided otherwise herein, [ * ] and [ * ] shall [ * ]. [ * ] and [ * ] shall [ * ]. [ * ] or [
* ] shall only be considered [ * ]; except that [ * ] shall constitute [ * ] that [ * ] and [ * ]. For the avoidance of doubt, [ * ] if [ * ].
When used as a verb, Detail shall mean to engage in the activities set forth herein.
“Detail Fee” means [ * ], increased or decreased on January 1 of each calendar year, beginning [ * ], to reflect any year-to-year
percentage increase or decrease (as the case may be) in the Consumer Price Index for the US City Average (all items) (CPI) (based on
a cumulative index of CPI numbers from the index most recently available at the date of the prior calculation to the index available as
of the date of the calculation of such Detail Fee); provided that the Detail Fee for E-details shall be reasonably agreed by the Parties in
the Co-Promotion Plan subject to escalation under Section 12.3 of the Agreement.
“Detailing Plan” shall mean the written plan included as part of the Co-Promotion Plan that describes the specific objectives and
obligations of the Parties with respect to Detailing of the Product to the Target Healthcare Professionals. The Detailing Plan shall be
consistent with this Agreement and may include such items as (i) identification and prioritization of Target Healthcare Professionals
by deciles, (ii) allocation of Target Healthcare Professionals between the Bayer and Onyx sales forces, including by geographic
territory, (iii) reach and frequency requirements for the Target Healthcare Professionals during each calendar quarter covered by the
Detailing Plan, (iv) sample requirements, if applicable, by deciles, and (v) Product tactics, selling message and strategies therefor.
ARTICLE I
GOVERNANCE OF CO-PROMOTION
1.1 Governance. The Parties agree to establish a committee (the “Working Group”) to discuss and resolve issues with the
development of the Detailing Plan and the development of the Medical Affairs Program.
1.2 Composition. The Working Group will be comprised of six members, three from Bayer and three from Onyx, including the
Onyx and Bayer Marketing Contacts. Either Party may substitute in its sole discretion members of the Working Group from time to
time provided, however that the described functionality is retained and bearing in mind that a key objective with respect to
membership in the Working Group shall be preserving continuity. At least [ * ] prior to the anticipated delivery date of the Co-
Promotion Plan, Bayer shall notify Onyx, and the Parties shall reasonably promptly appoint their representatives to the Working
Group and establish a charter outlining the general functions and matters to be discussed and referred to the Working Group.
1
1.3 Meetings. Meetings of the Working Group shall be held at least quarterly, unless both Bayer and Onyx determine, no later
than thirty (30) days in advance of any meeting following the initial meeting, that a meeting is unnecessary. In such instance, the next
meeting will be scheduled for the following calendar quarter. Unless otherwise agreed to by the Working Group the location of the
Working Group meetings shall alternate between the office of Onyx and Bayer. Meetings shall be face-to-face and in person except
that, upon the prior agreement of the Parties, meetings may be via other methods of communication such as teleconferences and/or
videoconferences. Each Party shall bear its own costs associated with its participation on the Working Group, including all travel and
living expenses.
1.4 Decision Making. The Working Group shall be chaired by a representative of Bayer. The Parties will strive to make decisions
within the Working Group by consensus, provided that Bayer shall have final decision-making authority on any matter that is within
the authority of the Working Group.
ARTICLE II
CO-PROMOTION AND MEDICAL AFFAIRS PROGRAM
2.1 Engagement. Bayer hereby agrees to engage Onyx during the Co-Promotion Term (defined below) to conduct the Co-
Promotion Program in the United States, upon and subject to the terms and conditions set forth in this Agreement, and hereby agrees
to engage Onyx to provide services under the Medical Affairs Program in those territories served by Onyx under the Co-Promotion
Program. Bayer hereby grants Onyx during the Co-Promotion Term a royalty-free co-exclusive license under Product trademarks and
copyrights Controlled by Bayer, to use and display such Product trademarks and copyrights solely in connection with the conduct of
the Co-Promotion Program and the Medical Affairs Program in the United States pursuant to this Agreement.
2.2 Co-Promotion Plan.
(a) Plan and Amendments. At least [ * ] in advance of the anticipated Co-Promotion Effective Date (defined below), and by
[ * ] of each succeeding year during the Co-Promotion Term, Bayer shall prepare and submit to the Working Group for review and
comment, but not approval, a written plan prepared by Bayer consistent with the terms of this Agreement that sets forth the strategy
and objectives of the Parties with respect to the Sales Program and the Medical Affairs Program covering a period of at least [ * ]
following First Commercial Sale of the Product (the “Co-Promotion Plan”). Each Party will cooperate with the other Party in the
establishment of the initial Co-Promotion Plan based upon Onyx’s election under Section 2.2(b) of this Exhibit A and the
implementation of such election by Bayer into the Co-Promotion Plan along with any resulting Detail Plan and Target Call List. Bayer
shall prepare and submit to the
2
Working Group for review and comment, but not approval, amendments and updates to the Co-Promotion Plan not less than [ * ],
sufficiently in advance of each Party’s sales direction meeting, which will occur generally at the same time, or more frequently as
needed to take into account changed circumstances or completion, commencement or cessation of the Co-Promotion Program
activities not contemplated by the then-current Co-Promotion Plan, subject to Section 2.1(b) of this Exhibit A. The Co-Promotion Plan
shall set forth the manner in which the Sales Program and the Medical Affairs Program are to be implemented in the United States
during the period to which the Co-Promotion Plan relates and shall address consistent with Section 2.2(c) of this Exhibit A:
(i) aggregate number of annual Details to be provided by the Parties, the geographic allocation and specific physician targets of such
Details and such other specific allocation of resources as to be included in a Detailing Plan; (ii) Product positioning and strategy;
(iii) training programs to be conducted; (iv) the allocation and list of Target Healthcare Professionals to be targeted for Detailing,
including allocation by geographic territory; (v) any information to be specifically included in the CRM System; (vii) administration
and logistics of the patient assistance program; (viii) market research; and (ix) such other information and projects relating to the Sales
Program as are deemed advisable by the Parties. Bayer will provide the following additional information relative to the Product to
Onyx when available to Bayer management: quarterly Details; Product tactics; professional and trade relations activities;
specifications for the development of Marketing Materials; and advertising. Bayer shall also deliver to the Working Group (if it has
not already received it) such information regarding the sales program for Collaboration Compounds (including the topics listed in
items (i) through (viii) above and the preceding sentence) as would be relevant to the development of the Co-Promotion Plan for the
Product. The purpose of the foregoing exchange and discussion of materials shall be to enable Onyx personnel to understand and
contribute to the marketing and sales of Product, and to seek to coordinate such activities with activities related to Collaboration
Compounds and the Parties allocation of rights and obligations under the Collaboration Agreement, while preserving the right of
Bayer to make final decisions related to the marketing and sales of Product. Bayer will promptly provide Onyx with any updated
projections for such First Commercial Sale and anticipated delays.
(b) Onyx Resource Commitment. Onyx shall have the right during the Co-Promotion Term to deploy up to [ * ] of the
aggregate Details set forth in the then-current Co-Promotion Plan. No later than [ * ] in advance of the anticipated Co-Promotion
Effective Date as part of the draft Co-Promotion Plan, Bayer shall provide Onyx with the total number of Details to be deployed in the
United States during the calendar year in which Product is expected to first be sold in the United States, and the first calendar year
thereafter. Thereafter, no later than [ * ] of the first full calendar year of Product sales in the United States, and [ * ] of each calendar
year thereafter during the Co-Promotion Term, Bayer shall provide Onyx with the total number of Details to be deployed in the United
States for the upcoming calendar year. Within [ * ] after Onyx’s receipt from Bayer of each of these amounts, Onyx shall determine in
its discretion, and shall inform Bayer of, the percentage of Details (not to exceed [ * ] of the aggregate) that Onyx shall deploy during
the upcoming calendar year (such percentage, the “Yearly Detail Percentage Election”). Bayer shall promptly notify Onyx of any
increase or decrease in the aggregate number of planned Details for the Product. In the event Bayer decreases the number of Details
from the level set forth in the then-current Co-Promotion Plan by more than [ * ],
3
Onyx shall have [ * ] to implement such decrease. In the event that Bayer increases the number of Details by more than [ * ] from the
level set forth in the then-current Co-Promotion Plan, it shall give Onyx at least [ * ] to implement any such increase. In connection
with any such proposed increase or decrease, Bayer shall amend the annual Co-Promotion Plan accordingly.
(c) Consistency with the Promotion of Collaboration Products. In furtherance of the Parties’ rights and obligations under
the Collaboration Agreement with respect to Collaboration Products and this Agreement, Bayer agrees that it shall use Commercially
Reasonable Efforts to plan, develop and implement Onyx’s participation in the Co-Promotion Program in a manner that is consistent
with the commercial activities allocated to the Parties under the Collaboration Agreement. Without limiting the generality of the
foregoing, Bayer shall use Commercially Reasonable Efforts to (i) allocate Onyx’s activities under the Co-Promotion Plan, Detailing
Plan and Target Call List in a manner that is consistent with Onyx’s commercial activities with Collaboration Compounds where
applicable; and (ii) provide that the allocation of Onyx’s sales representatives by geography for the Product is consistent with those
territories allocated to Onyx for Collaboration Products. In addition, each Party agrees not to take any action under this Agreement
that would contravene the other Party’s decision making and other rights under the Collaboration Agreement with respect to
Collaboration Products.
(d) Bayer Obligations. Bayer shall use Commercially Reasonable Efforts to perform its commercial activities for the
Product and obligations under this Agreement (including development and implementation of the Co-Promotion Plan, Detailing Plan
and Call List) in a manner reasonably designed to facilitate Onyx’s compliance with its obligations under this Agreement and
consistent with the performance provided to comparable Bayer resources, including the timely availability of Marketing Materials and
Product Training Materials. Onyx shall not be responsible for any delay or breach of this Agreement to the extent directly caused by
Bayer’s failure to perform its obligations under this Agreement.
(e) Onyx Sales Force. Onyx shall perform its obligations under the Detailing Plan through representatives under the direct
and exclusive authority, supervision and control of Onyx at all times during the Co-Promotion Term. Onyx shall supervise and
maintain such competent and qualified sales representatives as may be required to Promote the Product in the United States as
provided herein and in the Detailing Plan. Onyx shall not [ * ] without the prior approval of Bayer, except for [ * ] as part of the Co-
Promotion Plan. Subject to the immediately preceding sentence, Onyx sales representatives shall (i) be full-time employees on the
payroll of Onyx, (ii) of a quality at least equivalent to that provided by Onyx to product lines it is promoting at the time of its Co-
Promotion hereunder and (iii) not be Debarred by the FDA. At least [ * ] of Onyx sales representatives providing in-person Detailing
of the Product shall have a minimum of [ * ] of pharmaceutical sales experience, including at least [ * ] of oncology sales experience.
(f) Compensation Programs for Onyx Sales Representatives. Onyx shall be solely responsible for any compensation that is
payable to the Onyx sales representatives. Onyx represents and warrants to Bayer that its compensation programs for the Onyx sales
representatives do not, and will not, provide financial incentives that, to its knowledge, facilitate
4
the promotion, sales, and marketing of the Product in violation of applicable Laws. Onyx agrees to include the Product in its Onyx
sales representatives bonus compensation programs. Onyx further agrees that for its sales representatives no less than [ * ] of any
bonus payable to its sales representatives shall be tied to the Product.
2.3 Target Healthcare Professionals; Field Assignments.
(a) At least [ * ] in advance of the anticipated Co-Promotion Effective Date, and no later than [ * ] of each succeeding year,
the Working Group shall discuss prospective accounts, segmentation, targeting and other promotional benchmarks and, based on such
benchmarks as may be mutually agreed upon by the Parties, Bayer shall establish an annual Detailing and targeting plan consistent
with the terms of this Agreement, including Section 2.2(c) of this Exhibit A (“Target Call List”). Both Parties shall have full access
to the Target Call List and modifications thereto. Bayer shall seek Onyx’s input on the formulation of the Target Call List and the
determination of the number of Details, and will give due consideration to all such input provided by Onyx.
(b) Based on such consultation with Onyx and the Working Group, Bayer shall assign responsibility for Detailing by each
Party’s sales representatives to Target Healthcare Professionals identified on the Target Call List and shall assign responsibility for
medical education activities by each Party’s MSL FTEs consistent with the terms of this Agreement, including Section 2.2(c) of this
Exhibit A. Bayer shall equitably allocate such assignments so that each Party’s sales representatives will be assigned valuable
accounts and an equitable share of responsibility for desirable Target Healthcare Professionals, including high decile prescribers and
practices. Each Party’s MSLs will be assigned responsibility for an equitable share of medical education activities and all key opinion
leaders.
2.4 Detail Reports. Onyx, within thirty (30) calendar days after the end of each calendar quarter during the Co-Promotion Term,
will provide to Bayer on an electronic medium a record of its Detailing activity by account and healthcare professional, including
Details and reflecting the relevant territory, district and regional configuration (a “Detail Report”). This Detail Report will provide
information on all Details to Target Healthcare Professionals allocated to Onyx. Once submitted to Bayer, such Detail Report may not
be revised except to correct any error.
2.5 Medical Affairs Program.
(a) Program and Amendments. At least [ * ] in advance of the anticipated Co-Promotion Effective Date, and by [ * ] of each
succeeding year during the Co-Promotion Term, Bayer shall prepare and submit to the Working Group for review and comment, but
not approval, a written plan prepared by Bayer consistent with the terms of this Agreement that sets forth the strategy and objectives
of the Parties with respect to the Medical Affairs Program covering a period of at least [ * ] following First Commercial Sale of the
Product. Each Party will cooperate with the other Party in the establishment of the initial Medical Affairs Program plan based upon
Onyx’s selection under Section 2.5(b) of this Exhibit A and the implementation of such election by Bayer into the Medical Affairs
Program. Bayer shall prepare and submit to the Working
5
Group for review and comment, but not approval, amendments and updates to the Medical Affairs Program plan not less than [ * ] or
more frequently as needed to take into account changed circumstances or completion, commencement or cessation of Medical Affairs
Program activities. The Medical Affairs Program plan shall set forth the manner in which the MSL activities are to be implemented in
the United States during the period to which the Medical Affairs Program plan relates and shall address, at a minimum: (i) training
programs to be conducted; (ii) medical and educational programs to be conducted, (iii) professional and trade relations activities, and
(iv) such other information and projects relating to the Medical Affairs Program as are deemed advisable by the Parties. Bayer shall
also deliver to the Working Group (if it has not already received it) such information regarding the Medical Affairs Program for
Collaboration Products (including the topics listed in items (i) and (iv) of the preceding sentence) as would be relevant to the
development of the Medical Affairs Program for the Product. The purpose of the foregoing exchange and discussion of materials shall
be to enable Onyx personnel to understand and contribute to the Medical Affairs Program for the Product, and to seek to coordinate
such activities with activities related to Collaboration Compounds and the Parties allocation of rights and obligations under the
Collaboration Agreement, while preserving the right of Bayer to make final decisions related to the Medical Affairs Program for the
Product. No later than [ * ] before expected launch, Bayer will provide to the Working Group the Medical Affairs Program for the
period from the initial launch to [ * ] of the launch year, and each Party’s MSLs will be assigned responsibility for an equitable share
of medical education activities and all key opinion leaders. Thereafter the Working Group will meet no later than [ * ] of each year
during the Co-Promotion Term to review the existing plan and to prepare the plan for the upcoming year.
(b) Onyx Resource Commitment. Onyx shall have the right during the Co-Promotion Term to deploy up to [ * ] of the
aggregate MSL FTEs set forth in the then-current Medical Affairs Program. No later than [ * ] in advance of the anticipated Co-
Promotion Effective Date as part of the draft Medical Affairs Program, Bayer shall provide Onyx with the total number of MSL FTEs
to be deployed in the United States during the calendar year in which Product is expected to first be sold in the United States, and the
first calendar year thereafter, or such other period as Bayer may reasonably specify. Thereafter, no later than [ * ] of the first full
calendar year of Product sales in the United States, and [ * ] of each calendar year thereafter during the Co-Promotion Term, Bayer
shall provide Onyx with the total number of MSL FTEs to be deployed in the United States for the upcoming calendar year. Within [ *
] after Onyx’s receipt from Bayer of this amount, Onyx shall determine in its discretion, and shall inform Bayer of, the percentages of
MSL FTEs (not to exceed [ * ] of the aggregate) that Onyx shall deploy during the upcoming calendar year (such percentage, the
“Yearly MSL Percentage Election”). Bayer shall promptly notify Onyx of any increase or decrease in the number of planned MSL
FTEs for the Product. In the event Bayer decreases the number of MSL FTEs from the level set forth the then-current Medical Affairs
Program plan by more than [ * ], Onyx shall have [ * ] to implement such decrease. In the event that Bayer increases the aggregate
number of MSL FTEs by more than [ * ] from the level set forth in the then-current Medical Affairs Program plan, it shall give Onyx
at least [ * ] to implement any such increase. In connection with any such proposed increase or decrease, Bayer shall amend the annual
Medical Affairs Program plan accordingly.
6
(c) Consistency with the Provision of the Medical Affairs Program. In furtherance of the Parties’ rights and obligations
under the Collaboration Agreement with respect to Collaboration Products and this Agreement, Bayer agrees that it shall use
Commercially Reasonable Efforts to plan, develop and implement Onyx’s participation in the Medical Affairs Program in a manner
that is consistent with the MSL activities allocated to the Parties under the Collaboration Agreement. Without limiting the generality
of the foregoing, Bayer shall use Commercially Reasonable Efforts to (i) allocate Onyx’s activities under the Medical Affairs Program
in a manner that is consistent with Onyx’s activities with Collaboration Compounds where applicable; and (ii) provide that the
allocation of Onyx’s MSL FTEs by geography for the Product is consistent with those territories allocated to Onyx for Products. In
addition, each Party agrees not to take any action under this Agreement that would be contravene the other Party’s decision making
and other rights under the Collaboration Agreement with respect to Collaboration Products.
(d) Reports. Onyx, within [ * ] after the end of each calendar quarter during the Co-Promotion Term, will provide to Bayer
on an electronic medium a record of its Medical Affairs Program activity by territory. This report will provide information on all MSL
contacts with Physicians in Onyx’s territories. Once submitted to Bayer, such report may not be revised.
2.6 Compliance Audits; Audits. In addition to the access and audit rights of Bayer and Onyx provided for in Section 4.7 of the
Agreement, upon reasonable prior notice from Bayer and no more than once during any calendar year during the Co-Promotion Term,
Onyx shall afford to Bayer reasonable access during normal business hours (and at such other times as the Parties may mutually
agree) to inspect and audit the relevant books, records and other information of Onyx in order to monitor Onyx’s compliance with its
Detail Report and other relevant Co-Promotion Program obligations under the Detailing Plan and its activities under the Medical
Affairs Program, and for the purposes of determining compliance with Applicable Laws and the terms of this Agreement, but only as
to any period ending not more than [ * ] prior to the date of such request, and not more frequently than [ * ]. Any inspection conducted
by Bayer pursuant to this Section shall be at the sole cost and expense of Bayer. For clarity, the Parties agree that the audit rights
specified in Section 4.7 of the Agreement shall apply to books and records to be maintained by the Parties under this Agreement,
including the payment amounts specified in Article III.
2.7 Commercially Reasonable Efforts. Onyx shall use its Commercially Reasonable Efforts to Promote the Product to Target
Healthcare Professionals in the United States, and otherwise perform its obligations under the Co-Promotion Program, and conduct
the Medical Affairs Program in accordance with the then-current Co-Promotion Plan. If for any calendar quarter during the the Co-
Promotion Term, Onyx fails to meet the Detailing requirements or obligations under the Medical Affairs Program or anticipates that it
will not meet its Detailing requirements or obligations under the Medical Affairs Program, Bayer and Onyx shall meet to discuss the
causes for such failure and discuss what can be done to correct Onyx’s failure or anticipated failure.
7
(a) Performance Obligation.
(i) Onyx shall provide a minimum of not less than [ * ] of the Details assigned to Onyx in the then-current Detailing Plan
for any given calendar quarter and not less than [ * ] of the Details assigned to Onyx in the then-current Detailing Plan for any given
calendar year. In the event that Onyx provides less than [ * ] of the Details assigned to Onyx in a any given calendar quarter or less
than [ * ] of the Details assigned to Onyx in any given calendar year, in each case commencing with the first full calendar year after
the Co-Promotion Effective Date, then Onyx shall incur a [ * ] calculated as follows:
(A) For each Onyx Detail shortfall relative to the [ * ] standard for the calendar quarter, Onyx shall pay Bayer [ * ] for
each Onyx Detail shortfall.
(B) In the event Onyx fails to meet the [ * ] standard for a given calendar year, Onyx shall pay Bayer the amount, if
any, by which (i) [ * ] for any annual shortfall relative to the [ * ] standard exceeds (ii) the aggregate amounts payable under
subsection (A) above for all quarterly shortfalls in such calendar year.
(C) Any [ * ] due and payable under this Section will be due to Bayer no later than [ * ] following the expiration of the
calendar quarter or calendar year, as applicable, that gave rise to the [ * ]. In the event that the Parties disagree whether
Onyx has satisfied its obligation to provide the requisite percentage in a given period, the matter shall be reviewed by the
Working Group for up to [ * ] in an attempt to resolve the matter. In the event the Working Group cannot resolve the issue
within such time period, either Party shall be entitled to submit the issue for resolution pursuant to Article 11 of the
Agreement.
(D) Notwithstanding, the above [ * ] shall not apply during the [ * ] period following any increase in aggregate Details
by Bayer by more than [ * ] from the level set forth in the then-current Co-Promotion Plan.
(ii) Medical Affairs Program. Onyx shall provide a minimum of not less than [ * ] of the MSL FTEs assigned to Onyx in
the then-current Medical Affairs Program plan in any given calendar quarter and not less than [ * ] of the MSL FTEs assigned to Onyx
in the then-current Medical Affairs Program plan in any given calendar year. In the event that Onyx provides less than [ * ] of the
MSL FTEs assigned to Onyx for any given calendar quarter or less than [ * ] of the MSL FTEs assigned to Onyx in any given
calendar year, in each case commencing with the first full calendar year after the Co-Promotion Effective Date, then Onyx shall incur
a [ * ] calculated as follows:
(A) For each Onyx MSL FTE shortfall relative to the [ * ] standard for the calendar quarter, Onyx shall pay Bayer [ * ]
for each Onyx MSL FTE shortfall.
8
(B) In the event Onyx fails to meet the [ * ] standard for a given calendar year, Onyx shall pay Bayer the amount, if
any, by which (i) [ * ] for any annual shortfall relative to the [ * ] standard exceeds (ii) the aggregate amounts payable under
subsection (A) above for all quarterly shortfalls in such calendar year.
(C) Any [ * ] due and payable under this Section will be due to Bayer no later than [ * ] following the expiration of the
calendar quarter or calendar year, as applicable, that gave rise to the [ * ]. In the event that the Parties disagree whether
Onyx has satisfied its obligation to provide the requisite percentage for the given period, the matter shall be reviewed by
the Working Group for up to [ * ] in an attempt to resolve the matter. In the event the Working Group cannot resolve the
issue within such time period, either Party shall be entitled to submit the issue for resolution pursuant to Article 11 of the
Agreement.
(D) Notwithstanding, the above [ * ] shall not apply during the [ * ] period following any increase in aggregate MSL
FTEs by Bayer by more than [ * ] from the then-current Medical Affairs Program plan.
2.8 Co-Promotion Term. The Parties’ activities under this Agreement relating to the Co-Promotion Program in the United States
shall commence on the date that Bayer gives Onyx notice of the anticipated commencement of Co-Promotion (at least [ * ] in advance
of the anticipated First Commercial Sale of a Product in the United States) and shall remain in effect until the first to occur of the
following (the “Co-Promotion Expiration Date”): (i) the date that Products are no longer sold in the United States due to a
permanent Product withdrawal or recall, (ii) the mutual written agreement of both Parties to abandon the Co-Promotion Program in
the United States, (iii) early termination of the Co-Promotion Program pursuant to Section 3.2 thereto (Change of Control) or
Section 6.3 of the Agreement (for Material Breach), or (iv) termination of Onyx’s participation in the Co-Promotion Program, at
Onyx’s option and in its discretion, upon not less than [ * ] prior written notice to Bayer (the “Co-Promotion Term”).
2.9 Compliance. In performing its duties hereunder, Onyx shall, and shall cause its employees to: (i) Promote the Product in
conformity with the approved labeling for the Product; (ii) use only marketing and sales materials reviewed and approved under
Bayer’s LMR process, and (iii) comply with all Applicable Laws, including the FDA’s regulations and guidelines concerning the
advertising of prescription drug products, the Office of Inspector General’s Compliance Guidance Program, the American Medical
Association’s Guidelines on Gifts to Physicians, the PhRMA Code and the ACCME Standards, which may be applicable to the
services to be provided by Onyx hereunder. No employee of Onyx shall make any promotional representation, statement, warranty or
guaranty with respect to the Product that is not consistent with current labeling of the Product or Marketing Materials developed in
conformity with Section 2.11(a) hereof, that is deceptive or misleading or that disparages the Products or the good name, goodwill and
reputation of Bayer. Onyx shall use Commercially Reasonable Efforts to ensure that its Co-Promotion Program services delivered
pursuant to this Agreement will be provided in a professional, ethical and competent manner and shall have the right and discretion to
take any appropriate action to correct any deficiency.
9
2.10 Sales/Prescriber Data. Each Party shall be responsible for collecting and providing information about Product promotion, as
agreed by the Working Group in support of the Detailing Plan, which may include (for example) sales call activity and account
profiling information. Each Party may use a Customer Relationship Management system of its choice, or by other means provide the
information required to meet its obligations under this Section. Each Party shall provide the other Party with electronic access to such
Party’s sales/prescriber database for the Product, if any, in a manner reasonably to be agreed by the Parties. Each Party shall treat such
data as the Confidential Information of the other Party and shall use such data only for internal purposes directly related to the
performance of the Co-Promotion Program under this Agreement.
2.11 Training.
(a) Product Training Materials. Bayer, at its discretion in accordance with Bayer’s standard practices used for the Product
and sole expense, will create, develop, produce or obtain, continually update and provide materials to be used to train the Parties’ sales
representative with respect to Promoting the Product and to train the Parties’ MSL FTEs with respect to Medical Affairs Programs
activities relating to the Product (collectively, “Product Training Materials”). Bayer shall submit all proposed Product Training
Materials to Bayer’s LMR or Compliance Group, and to Onyx’s designee in its LMR function for approval. Bayer shall own all
copyright and other right, title and interest in and to all Product Training Materials; provided, that Bayer hereby grants to Onyx a non-
exclusive, royalty-free license under all copyrights in Product Training Materials solely for the purpose of copying, displaying, using
and distributing such Product Training Materials to the extent permitted under this Agreement. This license shall automatically and
immediately terminate upon the Co-Promotion Expiration Date and shall be non-transferable (except in connection with any permitted
assignment or transfer of the Agreement under Section 12.1 thereto) and non-sublicensable.
(b) Product-Specific Training. Each of the Parties agrees to make its sales representatives and MSLs available for Product
training. Bayer, at its sole expense (except as set forth below), shall conduct initial Product training of Onyx’s sales representatives
and MSLs in connection with and at the time of the launch of the Product in the United States for each of the first indication and any
subsequent indications, including the provision of Product Training Materials to Onyx sales representatives and other materials made
available to Bayer sales representatives. Thereafter, each Party, at its sole expense, shall conduct such training of its own sales force
and of its own MSLs; provided, that Bayer shall provide, at no cost to Onyx, all Product Training Materials in sufficient quantities for
Onyx to provide to its sales representatives for any such Product training. On an as-needed basis, Bayer shall provide ongoing Product
training for Onyx sales force trainers who will train any additional or replacement Onyx sales representatives, to the same standard as
the initial Onyx sales representatives trained by Bayer. Bayer shall reimburse Onyx for the costs of transportation, lodging and meals
for Onyx’s personnel to attend any Product training conducted prior to the initial launch of the Product or
10
the launch of the Product in any new indication. Except as provided above, each Party shall bear its own costs of transportation,
lodging and meals for such Party’s personnel to attend Product-specific training.
(c) Compliance Training. Each of Bayer and Onyx agrees to provide regular healthcare compliance training to its
employees involved in the sales, marketing, Promotion of, or price reporting for, the Product as appropriate and necessary. Such
compliance training shall meet the training requirements and standards established by the Working Group, and will, at a minimum,
cover the content and frequency of the training required by the CIA, Applicable Laws and all industry standards (including PhRMA
Code and OIG guidance).
2.12 Marketing Materials, Communications.
(a) Marketing Materials. Bayer, at its discretion in accordance with Bayer’s standard practices used for the Product and sole
expense, will create, develop, produce or obtain, and provide all sales, Promotion and advertising materials, regardless of form,
relating to the Product (“Marketing Materials”) to be used by the Parties’ sales representatives in Promoting the Product in quantities
sufficient for Onyx to perform its obligations under the Sales Program. Bayer shall submit all proposed Marketing Materials to
Bayer’s LMR for approval and to Onyx’s Compliance Group for review. Bayer shall own all copyright and other right, title and
interest in and to all Marketing Materials; provided, that Bayer hereby grants to Onyx a non-exclusive, royalty-free license under all
copyrights in Marketing Materials solely for the purpose of copying, displaying, using and distributing such Marketing Materials to
the extent permitted under this Agreement. This license shall automatically and immediately terminate upon the Co-Promotion
Expiration Date and shall be non-transferable (except in connection with any permitted assignment or transfer of the Agreement under
Section 12.1 thereto) and non-sublicensable. Whenever Marketing Materials are presented and described to the medical community
(including, for example, the physician, pharmacy, governmental, reimbursement and hospital sectors), the Parties will be presented
and described as joining in the Promotion of the Product in the United States.
(b) Communications. Following the initial Product launch, Onyx marketing and sales leaders shall be primarily responsible
for communicating to the Onyx sales representative and MSL FTEs the ongoing Product marketing strategy as approved by Bayer,
and delivering the Marketing Materials.
(c) No Modification. Each Party will ensure that its sales representatives and MSLs: (i) do not modify, alter, amend, adjust
or mask any portion of the Marketing Materials in any way, and (ii) do not use or distribute any marketing materials other than the
Marketing Materials approved for use in connection with the Promotion of the Product hereunder. Each Party will promptly notify the
other Party and take all necessary corrective action in the event a Party learns that any such modification, alteration, amendment,
adjustment or masking, or any such use or distribution of unapproved marketing materials has taken place. In addition, each Party
reserves the right to [ * ] who cause such Party to [ * ] of this Agreement, including without limitation [ * ].
11
2.13 Onyx Marketing Contact and Bayer Marketing Contact. Onyx shall designate one of its own full-time employees to serve as
Onyx’s primary contact with Bayer with respect to the Onyx Sales Force (the “Onyx Marketing Contact”). Bayer shall designate one
of its own full-time employees to serve as Bayer’s primary contact with Onyx with respect to the terms of this Agreement (the “Bayer
Marketing Contact”).
2.14 Onyx Attendance at Ongoing Meetings. The Parties agree that the Onyx sales representatives may, by prior agreement of
the Parties on a per meeting basis, attend national sales meetings, plan of action meetings, teleconferences, conventions and Bayer
sponsored sales representative events related to the Product. Each Party shall bear all costs and expenses associated with its
employees’ attendance at such national sales meetings, plan of action meetings, teleconferences and conventions, subject to
Section 2.11. In addition, Bayer shall notify Onyx through the Working Group of planned investigator or other meetings contemplated
as part of the Medical Affairs Program. Onyx MSL FTEs or other personnel shall have the right to attend such meetings at Onyx’s
expense.
ARTICLE III
FEES
3.1 Fees.
(a) Detailing Fees. As consideration for the Detailing to be undertaken by Onyx with respect to the Product, Bayer shall pay
Onyx the Detail Fee times the number of Details performed by Onyx (the “Detail Payment”) as reflected on the Detail Report;
provided that Bayer shall not be obligated to reimburse in excess of [ * ] of the number of Details specified in Detail Plan covering an
applicable calendar quarter. The Detail Payment shall begin accruing on the date Onyx begins to Detail the Product and shall be paid
as described in Section 3.1(e).
(b) MSL Expenses. Bayer shall pay Onyx for its MSL FTEs at the Onyx MSL FTE Rate. Within thirty (30) days following
the end of each calendar quarter during the Co-Promotion Term, Onyx will provide an invoice to Bayer of the aggregate amount of
any Onyx MSL FTE Costs, together with reasonable supporting documentation of such expenses, which shall include without
limitation a description of hours worked by Onyx’s MSLs as part of the Medical Affairs Program. Bayer shall pay the total amount
payable on such invoice within thirty (30) days following receipt thereof.
(c) Additional Expenses. In the event that Bayer delays the Co-Promotion Effective Date from the date originally proposed
by Bayer in Section 2.2(a) of this Exhibit A for the first indication for the Product [ * ], Bayer will reimburse Onyx for its or any
Affiliate’s internal and out-of-pocket expenses [ * ] directly associated with such delay as and to the extent directly allocable to the
Product (and not Collaboration Compounds or other products) (collectively, the “Additional Expenses”). Onyx shall use
Commercially Reasonable Efforts to mitigate such Additional Expenses and shall provide Bayer with an invoice setting forth, in
Dollars, such amounts, together with reasonable supporting documentation of such Additional Expenses. Bayer shall pay to Onyx, in
Dollars, the amount invoiced within [ * ] after the receipt of the invoice.
12
(d) Total Compensation. The amounts set forth in this Article 3 above represent all of the monetary compensation that
Onyx shall be entitled to receive under this Agreement for the Details and MSL FTEs, and Bayer shall not be required to compensate
Onyx or any member of the Onyx sales force for any direct or indirect costs incurred by Onyx or its Affiliates in connection with
Onyx’s Detail activities under this Agreement and MSL FTEs, including, without limitation, costs and expenses associated with
hiring, orientation, training, wages, benefits, incentive payments, taxes, or any automobiles or computer hardware or software
provided to the Onyx sales representatives.
(e) Reports. In addition to the information specified in Section 2.4 of this Exhibit A, the Detail Report shall, for an
applicable calendar quarter, contain: (1) the total number of Details performed by Onyx for such calendar quarter and (2) the total
amount of the Detail Payment due and payable by Bayer for such calendar quarter for the Onyx Details for the previous calendar
quarter. Bayer shall pay the total amount payable on the Detail Report within [ * ] following receipt thereof, unless it indicates to
Onyx, in writing, within such [ * ] period, the basis for any non-payment as well as Bayer’s calculations relating to any non-payment.
Bayer shall only withhold the Detail Payment (or portion thereof) for which it has supplied a written good faith basis for non-
payment. The Parties agree to promptly discuss the basis for any non-payment and shall use all reasonable efforts to reconcile any
differences subject to Section 3.3 of this Exhibit A.
3.2 Currencies. All payments under this Agreement shall be made in United States Dollars.
3.3 Interest on Late Payments. If any payment due under this Agreement is not paid when due, then such payment shall bear
interest at a rate equal to the lesser of: (a) [ * ] the United States prime rate as published by Citibank, N.A., New York, New York, or
any successor thereto, at 12:01 a.m. on the first day of each calendar quarter in which such payment is overdue or (b) the maximum
rate permitted by applicable law; in each case calculated on the number of days such payment is delinquent, compounded monthly.
ARTICLE IV
SALE OF PRODUCTS AND OTHER ACTIVITIES
4.1 Manufacture, Shipment, Booking, Invoicing, etc. of the Product.
(a) Bayer (and/or its Affiliates) shall have the sole responsibility, at its sole cost and expense (subject to Section 2.4.2 of the
Agreement) for the manufacture, shipment, distribution, warehousing, sale, invoicing, order entry and acknowledgement with regard
to sales of the Product in the United States and for the collection of receivables resulting from sales of the Product in the United
States. If for any reason Onyx receives orders for Products, Onyx shall promptly forward such orders to Bayer (or, if so directed by
Bayer, to Bayer’s wholesalers) as soon as practicable.
13
(b) Bayer shall manufacture and supply all Product for the United States in accordance with Good Manufacturing Practices
and any other applicable regulatory or legal requirements. All Products supplied by Bayer shall conform to all then-applicable
specifications set forth in the United States Drug Approval for the Products.
(c) Bayer shall have the sole, exclusive and final authority to determine the price of the Product in the United States during
the Co-Promotion Term, including price increases and decreases and the timing thereof. Bayer shall notify Onyx of all proposed
Product price increase or decreases with at least [ * ] notice (or such longer period as Bayer may provide to its sales representatives),
including Bayer’s assessment of the implications of net price, best price and average sales price.
4.2 Promotion of Competing Products. During the Co-Promotion Term, the Parties’ respective sales representatives responsible
for Promoting the Product shall not market a Competing Product without the prior written consent of the other Party. The Parties agree
that the promotion of Product under this Agreement is not a breach of the Collaboration Agreement.
4.3 United States Regulatory Matters.
(a) Authorizations. Each Party hereto shall, at its sole cost and expense, maintain in full force and effect all necessary
licenses, permits and other authorizations required by Applicable Laws to carry out its Co-Promotion Program duties and obligations
under this Agreement.
(b) Labeling and Packaging. No Product labeling, package inserts, monographs, packaging for the Product may be used or
distributed by the Parties unless such labeling, package inserts, monographs, packaging for the Products have been approved in
advance by Bayer’s LMR. Bayer’s LMR will be solely responsible for submitting, recording and storing all FDA 2253 submissions.
(c) Efficacy and Safety Information. Bayer shall furnish Onyx with efficacy and safety information reasonably requested by
Onyx to assist Onyx in Promoting the Product to Target Healthcare Professionals in the United States, including relevant clinical and
safety data included in the NDA for the Product and additional information, if any, related to the efficacy and safety profile of the
Product.
4.4 Regulatory Compliance. Each of the Parties shall comply with the following with respect to their Co-Promotion Program
activities in the United States:
(a) Each of Onyx and Bayer shall reasonably cooperate with the other Party in its efforts toward ensuring that all
government price and transfers of value reporting, sales, marketing and promotional practices in respect of the Product in the United
States meet the standards required by Applicable Laws, including state and federal laws and regulations, as well as applicable
guidelines concerning the advertising of prescription drug products, the Office of the Inspector General’s (“OIG”) Compliance
Guidance Program, the American Medical Association (the “AMA”) Guidelines on Gifts to Physicians, the PhRMA Code, and the
ACCME Standards.
14
(b) Each of Onyx and Bayer shall provide its employees and its contract sales force, if any, involved in sales, marketing,
Promotion, or price or transfers of value reporting for the Product in the United States appropriate training on proper marketing and
sales techniques. Such training will include, among other topics, FDA requirements and other state and federal regulations and
guidelines concerning the advertising of prescription drug products, the OIG Compliance Guidance Program, the AMA Guidelines on
Gifts to Physicians, the PhRMA Code, and the ACCME Standards. If requested by the other Party during the Co-Promotion Term,
each of Onyx and Bayer shall provide a written description of the training to the other Party no less frequently than on an annual basis.
(c) Each of Onyx and Bayer shall reasonably cooperate with the other Party to provide the other Party access to any and all
information, data and reports required by the other in order to comply with the relevant provisions of the Medicare Modernization Act
(“MMA”) and any other Applicable Laws, including reporting requirements, in a timely and appropriate manner. Bayer shall ensure
that its reporting to the Centers for Medicare and Medicaid Services and other federal and state healthcare programs related to the
Products is true, complete and correct in all respects; provided however, that Bayer shall not be held responsible for submitting
erroneous reports if such deficiencies result from information provided by Onyx which itself was not true, complete and correct.
(d) Onyx shall endeavor to prepare and provide to Bayer any data or other information covered by this Section in
accordance with methodologies specified by Bayer, and shall advise Bayer if there is any respect in which it has been unable to do so.
If Onyx has a question about whether a specific transaction or other event needs to be reported to Bayer pursuant to this Section,
Onyx’s obligation shall be satisfied by delivery of a true, complete and correct report of such transaction or other event, without a
determination as to the proper reporting or legal characterization of such matter.
(e) Onyx shall confer with Bayer on a regular basis to discuss its procedures and methodologies relating to Onyx’s
compliance to any Applicable Laws or fulfillment of any other obligation contained in this Section. In the event that the Parties have
different understandings or interpretations of this Section or of the applicability of or standards required by any Applicable Law, then
the Parties shall confer and seek to reach common agreement on such matters. In establishing standards required by any Applicable
Law (e.g., as to the permitted content or presentation of Marketing Materials or engagement with independent investigators), the
Parties shall apply to the promotion of Product the standards consistently applied and determined by Bayer (with reasonable prior
notification to Onyx) for a comparable activity performed by Bayer for the Product and other similar oncology products.
(f) For clarity, information disclosed by a Party to the other Party under this Exhibit A shall be subject to Article 7 of the
Agreement, including the prior notice specified in such Article.
15
4.5 Grants, CME and Other Activities. Any requests made to Onyx or any of the Onyx sales representatives or Onyx MSLs for
funding for a non-promotional program for the Product, such as an educational or CME event, an investigator initiated clinical trial,
any non-interventional study or registry or for a charitable cause, shall be referred by Onyx to Bayer; provided that any such request
that is applicable to the Product and Collaboration Products or to MSL activities shall be considered under the Parties’ obligations
under the Collaboration Agreement and Bayer shall approach funding such external requests in an equitable manner across Onyx and
Bayer territories. In no event shall Onyx, the Onyx sales representatives or Onyx MSLs commit or have the authority to commit Bayer
funding to any such request for the Product.
16
Onyx Pharmaceuticals, Inc. v. Bayer Corp., 863 F.Supp.2d 894 (2011)
863 F.Supp.2d 894

United States District Court,
N.D. California.
ONYX PHARMACEUTICALS, INC., Plaintiff,

v.
BAYERCORPORATION, et al., Defendants.
No. C-09-2145 EMC.

I
Sept. 21, 2011.
- Synopsis
Background:Biopharmaceutical company brought action alleging that competitor breached parties' collaboration
agreement, breached implied covenant of.good faith and fair dealing, and breached its fiduciary duties by failing to share
proceeds from cancer drug. Competitor filed motions in limine.
Holdings:The District Court, Edward M. Chen, J., held that:
evidence of negotiators' unexpressed intent was admissible;
evidence of competitor's allegedly improper conduct in course of developing drug in other indications was admissible;
documents related to competitor's discussions about its potential acquisition of company were admissible; and
damages expert's testimony was sufficiently certain to warrant its admission.
Motions denied.
AttorneysandLaw Finns
*895 Bradley Allen Waugh, Intel Litigation Group, Santa Clara, CA, Martin S. Schenker, Thomas J. Friel. Jr., Jeffrey
Gutkin, Cooley LLP, San Francisco, CA, Michelle S. Rhyu. Daniel Jedediah Knauss, Cooley Godward Kronish LLP,
Palo Alto, CA, for Plaintiff.
Alison Margaret Tucher, Amy Christine Dachtler, Morrison & Foerster LLP, San Francisco, CA, Brian Charles
Swanson, Georgia N. Alexakis, J. Scott McBride, James Breckinridge Heaton, III. Jason Lloyd Peltz, Mark Leslie
Levine, Philip Scott Beck, Bartlit Beck Herman Palenchar & Scott LLP, Chicago, IL, for Defendants.
FINAL PRETRIALCONFERENCEORDER
EDWARD M. CHEN, District Judge.
WE.SlL.AW © 2019 Thomson Reuters. No claim to original U.S. Government Works.

A Final Pretrial Conference was held in this matter on September 20, 2011. Pursuant to Federal Rule of Civil Procedure
16(e). this order memorializes the Court's rulings and/or the parties' stipulations. Also attached are the Court's standing
Guidelines for Trial.
I. TRIAL DATE & LENGTH OF TRIAL
The trial shall begin on October 3, 2011, Courtroom 5, 17th Floor. There shall be a total of twelve court days.
Trial shall be conducted from 8:30 a.m. to 2:00 p.m. (or slightly longer to finish a witness), with one 15-minute break and
one 40-minute lunch break. Parties must arrive by 8:00 a.m. or earlier as needed for any matters to be heard out of the
.Presence of the jury. The jury will be called at 8:30 a.m. The trial week is Monday through Thursday, excluding holidays.
Fridays are dark. Ifthere are matters that need to be discussed (e.g., objections to exhibits or witnesses), counsel should
- be prepared to meet with the Court at 8:00 a.m.
Plaintiff shall have 22 hours to present her evidence, and Defendant 22 hours. This includes direct examination by one
side of its witnesses, cross-examination by that side of the opposing party's ,vitnesses, and any rebuttal. This does not
include jury selection, jury instructions, opening statements, or closing arguments. The Court may impose separate time
limits for openings and closings.
IT.MOTIONS IN LIMINE
A. Defendant's Motion in Limine ( Docket No. 140)

Bayer's Motion in Limine requests that the Court exclude four categories of evidence. *896 For the reasons set forth
below, the Court DENIES the motion without prejudice.
I. Evidence of Negotiators' Unexpressed Intent

Bayer seeks to prevent Onyx from introducing evidence as to the unexpressed intent and understanding of Onyx's
negotiators to the Collaboration Agreement. Mot. in Limine, Docket No. 140 ("Mot."), at I. These witnesses are Frank
McCormick, Bob Jones, and Hollings Renton. Bayer contends that their testimony as to the meaning of the contract
is inadmissible under Rule 402 and 403 because they merely testify as to their own subjective, which is irrelevant under
California law. Mot. at 2. Bayer asks the Court to restrict the testimony of these witnesses to objective, expressed intent
rather than subjective, understood intent. Onyx counters that these witnesses will testify not as to their subjective intent,
but rather the parties' mutual intent and understanding of the contract terms. It argues that the witnesses are permitted
to testify as to expressed and unexpressed representations during the course of negotiations. Opp. at I.
Bayer overstates California law's restrictions on witness testimony as to a contract's meaning under the objective
theory of contracts. Bayer seeks to exclude these witnesses' testimony based on their admissions at some point in their
depositions that they did not recall "specific discussions" during the course of negotiations as to the meaning of certain
specific words in the contract. See Mot. at 2-3 (citing portions of Renton depo.); id. at 4 (citing portions of McCormick
depo.); id. (citing portions of Jones depo.). However, contrary to Bayer's implication, these admissions do not amount
to any broad concession that these witnesses remember nothing from the negotiations that would inform their memory
of and testimony as to the parties' expressed intent. A lack of specific recollection does not change the nature of the
testimony, only its weight. None of the cases to which Bayer cites require witnesses to quote from negotiations or provide
a detailed account of "specific discussions" in order to testify as to their memory of those negotiations. For example,
Bayer cites to Founding Members of Newport Beach Country Club v. Newport Beach Country Club, Inc., 109 Cal.App.4th
944 960, 135 Cal.Rptr.2d 505 (2003). However, Founding Members does not stand for the broad proposition that all
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/\ ~l,,/x·
zE--
IITRUE COPYII
testimony as to a negotiator's understanding of contract terms is inadmissible. Rather, Founding Members merely holds
that conversations between members of the same side in a negotiation, conversations between those persons and a sales
assistant, conversations with undisclosed third parties; and undisclosed statements of individual intent are not relevant
under the "objective theory of contracts." Id Other cases on which Bayer relies for support similarly do not discuss or
require the specificity it requests that this Court impose. See Winet v. Price 4 Cal.App.4th 1159, 1166, 6 Cal.Rptr.2d 554
(1992) (disregarding "testimony as to what [the witness] subjectively understood and intended the release to encompass");
Habitat Trust for Wildlife, Inc. v. City o(Rancho Cucamonga, 175 Cal.App.4th 1306, 1339, 96 Cal.Rptr.3d 813 (2009)
(affirming exclusion of self-described subjective statement: "I on behalf of Sage Council and Habitat Trust contemplated
that the contract purpose of the Settlement Release Agreement (Exhibit 41) was to ...," where the witness "does not
indicate that she expressed her asserted intention to anyone before or at the time of contracting" and "her prior language,
acts and conduct evidence a contrary intention").
*897 In contrast to these cases and others cited by Bayer, here Onyx's witnesses were present at the negotiations and
• contend their understanding of the meaning of contra:t te~s is based on the course of th~se negotiations. S:e: e.g.,
- Schenker Deel., Exh. 1 at 98 (excerpt of Renton depo. m which he states that he recalls talking about the defirution of
a collaboration compound with Bayer and that the "intent" to which he refers is based on "the assurances that Bayer
gave us"); id, Exh. 26 at 5 (McCormick's declaration explaining the course of the negotiations in which he participated
and his understanding of the contract based on those negotiations); id, Exh. 27 at 2--4 (Jones's declaration explaining
the parties' notes and negotiations as to what would constitute a Collaboration Compound). This kind of extrinsic
evidence is permitted, and indeed required, under California law ..See Dept. oflndus. Relations v. UI Video Stores, Inc..
55 Cal.App.4th 1084. 1094. 64 Cal.Rptr.2d 457 (1997) ("[T]he circumstances surrounding the execution of the contract
may be considered in determining the meaning of the language used therein.") (citing Cal.Code Civ. Proc.,§ 1860): Pac.
Gas & Elec. Co. v. G. W. Thomas Drayage and Rigging Co.. Inc., 69 Cal.2d 33, 39--40, 69 Cal.Rptr. 561. 442 P.2d 641
(1968) ( "[R]ational interpretation requires at least a preliminary consideration of all credible evidence offered to prove
the intention of the parties.").
Moreover, while Bayer is correct that courts have excluded evidence of the unexpressed intent of the parties, other courts
applying California law have allowed witnesses to testify about their understandingof a contract when that understanding
is not simply a private interpretation, but rather is founded in personal knowledge of the negotiations and the parties'
expressed intent. See First Nat'/ Mortg. Co. v. Fed Realty Inv. Trust. 631 F.3d 1058, 1068 {9th Cir.2011) (witness testified
as to "his understanding of the 'subject only to approval' clause"); Mickey Bearman Co. v. John Morrell & Co. No.
CV-00-05616 CAS {MCX), 2001 WL 36097432, at *3, 2001 U.S. Dist. LEXIS 26233, at *6--7(C.D.Cal. Oct. 29, 2001)
(attorney "who participated in the negotiations of the [contract], is entitled to testify as to what he, as a representative of
[Defendant], thought the ambiguous terms meant."); ASP Properties Group v. Fard Inc., 133 Cal.App.4th 1257, 1271.
35 Cal.Rptr.3d 343 (2005) ("When [Defendant's negotiator] was asked whether he understood at the time of negotiating
the Amendment [that] Tenant would be required to improve the Premises, he answered, 'Absolutely not.' "); Pacific Gas
& Elec. Co. v. G. W. Thomas Drayage & Rigging Co. 69 Cal.2d 33, 39, 69 Cal.Rptr. 561. 442 P.2d 641 (1968) (offering,
as example of circumstance warranting extrinsic evidence, situations in which "the parties' understanding of the words
used may have differed from the judge's understanding" and requiring the court to consider evidence that would place
it "in the same situation in which the parties found themselves at the time of contracting"); Wolf v. Superior Court. 114
Cal.App.4th 1343, 1359-60, 8 Cal.Rptr.3d 649 (2004) (finding triable issue of fact and lamenting the fact that "neither
side presented any direct or objective evidence regarding the negotiating parties' understanding of the term 'gross receipts'
at the time the parties entered into the contract.'') .
. The Court cannot discern any requirement that testimony must be supported by specific quotations of the words stated
in negotiation: Rather, California case law merely stands for the proposition that a negotiator's testimony as to contract
terms must be grounded in some foundation of personal knowledge as to the parties' expressed intent and understanding
during the course of negotiations, rather than *898 simply the witness's own subjective interpretation of the contract
or intent as to what the contract should mean. See, e.g., Hoopes v. Dolan. 168 Cal.App.4th 146 151. 85 Cal.Rptr.3d
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337 (2008) ("The real estate agent said she conducted the lease negotiations with Hoopes, and that the issue of parking
'never came up' during those negotiations."). While Bayer is certainly free to impeach the memory and credibility of these
witnesses with their own deposition statements that they lacked specific recall of what was stated in the negotiations as
to various contract terms, these weaknesses in their testimony are not sufficient to render them inadmissible.
Accordingly, Bayer's motion is DENIED as to this point, without prejudice to Bayer's objections at trial if certain
portions of the witnesses' testimony are in fact based solely on their subjective, unexpressed intent.
2. Evidence of Bayer's Allegedly Improper Conduct Beyond CRC~KRAS & Breast AI

Bayer seeks to preclude Onyx from introducing testimony with regard to Bayer's other allegedly improper conduct in the
course of developing Nexavar in indications beyond CRC-KRAS and Breast AI, as Onyx has not claimed compensatory
damages with respect to that conduct. See Mot. at 1. Bayer argues that such evidence is irrelevant under Rule 402,
• prejudicial under Rule 403, and inadmissible character evidence under Rule 404(b).
At oral argument, Onyx agreed to drop four of the five indications and trials at issue-pulmonary arterial hypertension
("P AH"); gastrointestinal stromal tumor ("GIST"); thyroid cancer; and breast cancer in combination with the
chemotherapy agent capecitabine ("Breast Cape"). Thus, the Court only considers the parties' arguments regarding 1st
line colorectal cancer ("CRC").
With respect to relevance, Bayer contends that evidence of Bayer's alleged efforts to block Nexavar's development in
CRC is irrelevant because Onyx does not claim any damages from this conduct, and the fact of damages is a necessary
component of Onyx's claims for breach of contract and breach of fiduciary duty. See Mot. at 6. But as the Court pointed
out at the hearing, the alleged conduct as to 1st line CRC, if proven to be part of a larger campaign to promote DAST
and undermine Nexavar, is probative to Bayer's motive and conduct vis-a-vis the blocking ofNexavar trials for which
damages are sought. As Onyx noted, both provisions of§ 3.6 arguably import (at least the jury may so find) motive as an
element of the breach claims. Section 3.6 makes Bayer's motive for blocking Nexavar relevant to whether it has breached
the contract because if Bayer blocked Nexavar for legitimate business reasons and in good faith, there is no violation
of§ 3.6. These documents are also relevant not just to show Bayer's "motive" to breach, but as direct evidence of its
alleged bad faith generally in violation of the implied covenant of good faith and fair dealing. See Universal Sales Corp.
v. California Press Mfg. Co., 20 Cal.2d 751, 772, 128 P.2d 665 (1942) ("In every contract there is an implied covenant that
neither party shall do anything which will have the effect of destroying or injuring the right of the other party to receive
the fruits of the contract."). In addition, as discussed above, Bayer's argument against offering evidence of motive is, at
the least, inapplicable to Onyx's tort-based claims.
Even assuming Bayer is correct that this conduct would be irrelevant for Onyx's damages claims, Bayer neglects to
address Onyx's remaining claims, including a claim for declaratory relief in the form of "a declaration that Bayer cannot
allow its products outside the Collaboration to prejudice *899 the development ofNexavar." Joint Pretrial Statement,
Docket No. 142, at 7. While Bayer seems to argue in reply that declaratory relief requires proof of damages as well,
see Reply at 8, such an argument runs directly counter to the provisions of both the California and federal declaratory
judgment statutes. See Cal.Code Civ. Pro.§ 1060 ("[T]he court may make a binding declaration of these rights or duties,
whether or not further relief is or could be claimed at the time .... The declaration may be had before there has been any
breach of the obligation in respect to which said declaration is sought."); 28 U.S.C. § 220Ha) ("[A]ny court of the United
States, upon the filing of an appropriate pleading, may declare the rights and other legal relations of any interested party .
seeking such declaration, whether or not further relief is or could be sought."). l
l Indeed, the cases Bayer cites in support of such a proposition do not even discuss declaratory relief.
In addition, because Onyx will seek to show that Bayer's conduct is sufficiently outrageous to warrant punitive damages,
evidence of the scope of Bayer's allegedly wrongful conduct is relevant to such a claim. Bayer points to the general and
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undisputed requirement that punitive damages must bear some relationship to compensatory damages as support for
its position that evidence of Bayer's other alleged wrongdoing cannot support punitive damages. See Reply at 9 (citing
O'Neil v. Spillane. 45 Cal.App.3d 147, 161, 119 Cal.Rptr. 245 (1975)); BMW ofN. Am., Inc. v. Gore 517 U.S. 559, 580,
116 S.Ct. 1589, 134 L.Ed.2d 809 (1996): Bains LLC v. Arco Prods. Co.. 405 F.3d 764, 776-77 (9th Cir.2005): Lew Wenzel
& Co. ofS. Cal., Inc. v. London Litho Supply Co.. 563 F.2d 1367, 1368 (9th Cir.1977). However, these cases do not stand
for the broad proposition that only evidence which is attached to a specific compensatory damages claim is relevant
to a claim for punitive damages. Rather, these cases merely discuss the difficulty of awarding punitive damages when
the plaintiff has suffered no compensable harm whatsoever, or when the amount of damages is out of proportion to
the amount of compensatory damages. This does not answer the question of whether evidence for which the plaintiff
does not claim damages may nonetheless inform a jury's determination of whether the defendant's conduct is worthy
of punitive damages.
Indeed, on this question, BMW indicates that evidence that does not go directly to compensatory damages is nonetheless
- relevant -~d admissible. In BMW, the Supreme Court explicit!! noted that conduct_which could not form the basis
- of a pumt1ve damages award-BMW's out-of-state conduct which was not unlawful m those states-was nonetheless
relevant. See BMW, 517 U.S. at 574 n. 21, 116 S.Ct. 1589("Of course, the fact that the Alabama Supreme Court correctly
concluded that it was error for the jury to use the number of sales in other States as a multiplier in computing the amount
of its punitive sanction does not mean that evidence describing out-of-state transactions is irrelevant in a case of this kind.
To the contrary, as we stated in TXO Production Corp. v. Alliance Resources Corp.. 509 U.S. 443,462, n. 28, 113 S.Ct.
271 I, 125 L.Ed.2d 366 0993), such evidence may be relevant to the determination of the degree of reprehensibility of the
defendant's conduct."). The Court also considered evidence of potential harm. Id at 575, 581-82, 116 S.Ct. 1589. Bayer
can thus point to no case that suggests that each specific example of wrongdoing must be attached to a compensable
damages claim in order to be relevant to its claim that Bayer breached its *900 fiduciary duties and should pay punitive
damages for its conduct. 2
Bayer's analysis of Bradbury originally cited by Onyx, is similarly flawed. See Reply at 9 (citing Bradbury v. Phillips Petroleum
Co.. 815 F.2d 1356, 1364 (10th Cir.1987}). Bayer seeks to distinguish Bradbury based on the fact that the prior conduct at
issue in that case-which the court found admissible to show the absence of mistake or accident-had resulted in compensable
damages. Yet Bradbury'sanalysis does not turn on the fact that the defendant had paid damages to past complainants. Indeed,
such a claim is nonsensical because the current plaintiff was not asserting any right to, or harm from, those previous acts.
Thus, such conduct was admissible despite the fact that it did not directly support any damage claim or independent cause
of action by the plaintiff. Rather, the key to the dispute was that the defendant had engaged in other, relevant bad acts,
regardless of whether each of those acts were legally cognizable claims, that indicated a pattern of bad conduct sufficient to
justify punitive damages.
e Accordingly, Bayer has failed to demonstrate that this evidence is irrelevant. See Fed.R.Evid. 401 (defining relevant
evidence broadly to include any testimony "having any tendency to make the existence of any fact that is of consequence
to the determination of the action more probable or less probable than it would be without the evidence").
Bayer also contends that this evidence would be prejudicial under Rule 403, and should be excluded on that basis.
However, given its relevance as noted above, Bayer has failed to demonstrate that the prejudicial result from its
introduction would substantially outweigh its probative value. Fed.R.Evid. 403. Bayer asserts that this evidence would
distract and mislead the jury, and lead to a series of mini-trials. However, Onyx has alleviated most of these concerns
by eliminating most of the indications at issue. In addition, the fact that Bayer will need to put on additional witnesses
to explain and defend its conduct with respect to _thesame plaintiff, under the same contract, does not lead to the kind
of prejudice or potential confusion that substantially outweighs the probative value of this evidence. Cf Tennison v.
Circus CircusEnterprises Inc. 244 F.3d 684, 690 (9th Cir.2001) (in sexual harassment case, finding that the exclusion of
evidence regarding complaints by other, non-plaintiff employees years prior to the conduct at issue in that action was
not an abuse of discretion). The _evidenceis admissible under 403.
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Finally, Bayer argues that this evidence is inadmissible character evidence under Rule404(b), which prohibits "[e]vidence
of other crimes, wrongs, or acts ... to prove the character of a person in order to show action in conformity therewith."
The Court is not persuaded. As with its arguments discussed above, here Bayer ignores Onyx's non-damages claims,
for which evidence of Bayer's alleged blocking ofNexavar in other indications is not "other crimes, wrongs, or acts,"
but rather is part of the same conduct Onyx challenges here and against which it seeks declaratory and punitive relief.
Moreover, Rule 404(b) allows for such character evidence where it may show "proof of motive, opportunity, intent,
preparation, plan, knowledge, identity, or absence of mistake or accident." While Bayer is correct that motive is not
relevant in an action seeking contract damages, see Applied Equip. Corp. v. Litton Saudi Arabia Ltd. 7 Cal.4th 503. 516,
28 Cal.Rptr.2d 475, 869 P.2d 454 (1994). Onyx has asserted tort claims as well as contract claims in this action, and as
explained at the hearing, Bayer's motive is relevant to a claim sounding in tort. J.
In its reply, Bayer makes the cursory argument-that all of Onyx's claims actually sound in contract, and that therefore its tort
claims are not viable. See Reply at 11 and n. 4. However, Bayer has not moved for, nor has the Court granted, dismissal or
summary judgment on this basis. Thus, the fact is that Onyx's tort claims remain in the litigation; Bayer's cursory challenge
to their viability at this late hour is unpersuasive. Similarly, Bayer appears to suggest that because the parties dispute whether
a fiduciary duty exists, Onyx should be precluded from introducing evidence that might tend to show breach of such a duty.
See Reply at 11 n. 4. This argument is meritless because it presumes Bayer will prevail on a disputed issue.
*901 Accordingly, the Court DENIES without prejudice Bayer's motion to exclude evidence of its alleged efforts to
block Nexavar's development in trials other than Breast AI and CRC-KRAS.
3. Evidence Relating to Othello

Bayer seeks to exclude any documents related to Project Othello, its internal codename for discussions about its potential
acquisi~ion of Onyx in 2009. Mot. at 8. Bayer argues that these documents are irrelevant because Bayer never acquired
Onyx, and prejudicial under Rule 403.
Given the content of these documents-which include admissions that Onyx may use to seek to rebut numerous
positions Bayer is taking in this litigation-Bayer has failed to demonstrate that they are irrelevant or substantially more
prejudicial than probative. As Onyx points out, see Opp. at 16-17, the fact that Bayer never acquired Onyx does not
negate the relevance of its discussions to this litigation, as those discussions concerned the relationship and acknowledged
potential conflicts between DAST and Nexavar, Bayer's obligations under the contract, and Bayer's ongoing relationship
with Onyx. See, e.g., Trial Exh. 384 at -082-83, (indicating that the "[c]ommercial value ofDAST is limited by Onyx
partnership" and that DAST is in "direct competition with Nexavar" and has "very similar molecular structure"); Trial
Exh. 397 (evaluating economic effects of developing DAST for certain indications instead ofNexavar); Trial Exh. 416
(discussing options for switching certain Nexavar trials to DAST); Trial Exh. 440 (discussing benefits of developing
DAST over Nexavar in certain indications). This evidence is probative of Bayer's knowledge and thus its potential
motives irrespective of the fact that it ultimately did not acquire Onyx.
Finally, as with the evidence discussed above in the second motion in limine, here Bayer has failed to demonstrate
prejudice that would substantially outweigh the probative value of these documents as a whole. Again, Bayer assumes
that this litigation solely involves a claim for breach of contract. See Reply at 14. Though the Court need not determine
whether this evidence would be admissible if only contract claims were asserted, because bad faith and breach of fiduciary
duty are at issue here, this evidence is sufficiently probative-notwithstanding its potential damaging effect on Bayer-
to bring it outside the confines of 403.
Bayer's motion to exclude these documents is DENIED without prejudice to more tailored objections on a case-by-case
basis.
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4. Evidence of Damages
Bayer seeks to exclude any testimony from Onyx's damages expert, Iain Cockburn, as to Onyx's claimed damages from
lost profits due to Bayer's alleged blocking of Nexavar's development in Breast AI and CRC-KRAS indications. Mot.
at 11. Bayer argues that Cockburn's testimony cannot establish that Onyx suffered damages with reasonable certainty,
as is required under California law. See Vestar Development IL LLC v. General Dynamics Corp.. 249 F.3d 958, 961 (9th
Cir.2001) ("It has long been settled in California that 'the proof must establish with reasonable certainty and probability
that damages will result in the future to the person *902 wronged.' ") (quoting Caminetti v. Manierre, 23 Cal.2d 94.
101. 142 P.2d 741. 745 (1943) (in bank)).
Bayer's arguments are nearly identical to those it raised in its motion for summary judgment, which Judge Patel denied.
Indeed, much of Bayer's motion appears to have been cut and pasted from its earlier summary judgment motion. In
her order, Judge Patel rejected Bayer's assertion that a 57% percent chance of FDA approval is insufficient to qualify
- as "reasonably certain." See Memorandum & Order, Docket No. 143, at 20. She found that "Onyx has raised at least
· an issue of fact as to the propriety of its requested damages." Id Bayer has not requested leave to file a motion for
reconsideration of that ruling. See Civ. L.R. 7-9.
Moreover, viewed independently, this Court agrees with Judge Patel's conclusion. Bayer argues that a 57-62% chance
of FDA approval is insufficient as a matter of law to create a "reasonable certainty." Mot. at 13. In addition, Bayer
contends that Onyx should not be permitted to present evidence of"risk-adjusted damages," which it claims demonstrate
that Onyx's damages claims are speculative. See Mot. at 15-16. As Onyx has agreed at oral argument not to introduce
any evidence of risk-adjusted damages, the Court considers only the reasonable certainty argument.
Bayer can point to no case, nor has Judge Patel or this Court uncovered such a case, in which California courts have
mandated a percentage of certainty above 57% in order to constitute "reasonable certainty." See Memorandum & Order,
Docket No. 143, at 20. Rather, most cases addressing reasonable certainty adhere to a qualitative approach, and the
cases Bayer cites do not support the kind of wholesale rejection of evidence that Bayer requests from this Court. For
example, as Judge Patel found, the principal case on which Bayer relies for its assertion that recovering damages for
lost profits in pharmaceutical products is "exceedingly difficult," see AlphaMed Pharm. Corp. v. Arriva Pharm. Inc. 432
. F.Supp.2d 1319 (S.D.Fla.2006), affd, 294 Fed.Appx. 501 (I 1th Cir.2008). is distinguishable on numerous grounds from
the instant case. See Memorandum & Order at 19 (emphasizing that AlphaMed unlike this case, involved a product
that had never been tested, might have been illegal to distribute, and for which it was uncertain whether there was a
sufficient research and development budget, among other differences). In another case on which Bayer relies, Matthews
v. Atchison Topeka & Santa Fe Railway Co.. 54 Cal.App.2d 549, 560, 129 P.2d 435 (1942), the court was referring to a
- case in which the court reduced, rather than eliminated, damages to account for their lack of certainty.
Under California law, damages evidence found to be too speculative faced more uncertainty than is present in this case,
in which Nexavar has already been approved for two cancer indications and the parties have experience successfully
promoting its sale. See, e.g., Kids' Universe v. In2Labs 95 Cal.App.4th 870, 887-888, 116 Cal.Rptr.2d 158 (2002) (finding
expert testimony insufficient to demonstrate lost profits where a small toy store claimed that flood damage to the store
caused by defendant led to $50 million in lost profits because Plaintiffs new website would have allowed it to compete
in the Internet toy marketing business); Vestar Dev. IL LLC v. Gen. Dynamics Corp., 249 F.3d 958, 962 (9th Cir.2001)
(finding lost profits claim too speculative for breach of agreement to negotiate where plaintiff sought "future profits that
it hoped to earn from the shopping center it had planned to build on the parcel it was attempting to buy"); Eisenmayer
v. Leonardt. 148 Cal. 596, 601, 84 P. 43 (1906) (affirming exclusion of testimony as *903 to value of unissued stock
for company never formed because there were "no facts stated-either real or hypothetical-as a basis for an intelligent
opinion"); Greenwich S.F.. LLC v. Wong. 190 Cal.App.4th 739, 766, 118 Cal.Rptr.3d 531 (2010) 1 (finding lost profits
claim too speculative where the plaintiff assumed, rather than proved, the reasonable certainty offuture predicate events
upon which the damages depended); Fisher v. Hampton 44 Cal.App.3d 741, 749, 118 Cal.Rptr. 811 (1975) (finding lost
profits evidence too speculative where "there was no testimony that any oil could be recovered at a profit from the drilling
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of one well, and there was no testimony as to the extent of possible profits from the one initial well."); Boyer v. Wells. No.
B205345, 2008 WL 3984342, at *8 (Cal.Ct.App. Aug. 29 2008) ("Blaha's testimony that there are generally unforeseen
rebuilding costs was too speculative to require the court to infer that there would be such costs in this case."). In contrast
to these cases, courts allow for projections oflost profits for unestablished businesses when those projections are rooted
in sound factual and statistical analysis, even though such testimony does not lend itself to absolute certainties with
respect to future damages. See Kids' Universe v. In2Labs 95 Cal.App.4th 870,884, 116 Cal.Rptr.2d 158 (2002) ("[l]fthe
business is a new one or ifit is a speculative one ..., damages may be established with reasonable certainty with the aid of
expert testimony, economic and financial data, market surveys and analyses, business records of similar enterprises, and
the like."); Parlour Enterprises Inc. v. Kirin Group, Inc. 152 Cal.App.4th 281,288, 61 Cal.Rptr.3d 243 (2007) ("[E]xpert
testimony alone is a sufficient basis for an award of lost profits in the new business context when the expert opinion
is supported by tangible evidence with a 'substantial and sufficient factual basis' rather than by mere 'speculation and
hypothetical situations.'") (quoting Kids' Universe. 95 Cal.App.4th at 885, 116 Cal.Rptr.2d 158): l A & M Produce v.
FMC Corp., 135 Cal.App.3d 473. 494, 186 Cal.Rptr. 114 (1982) (finding lost profits from destroyed tomato crop, which
- plaintiff had never grown before, proven to reasonable certainty where plaintiff"! provide[d] evidence regarding the size
. -- of the crop and general market price for that type of tomato, the fact that he was an experienced farmer, the condition
of the tomatoes pre-harvest, and the fact that there was no indication anything else would have ruined the crop had the
machine functioned properly"); see also Lightning Lube Inc. v. Witco Corp., 4 F.3d 1153, 1176 (3d Cir.1993) <finding
lost profits from franchisees that never opened proven to reasonable certainty despite the fact that the witness "did
not offer any documentary evidence comparing his operation to those of his competitors, did not discuss the market
conditions for quick-lube centers generally, did not assess the impact of the stock market crash of 1987 on the likelihood
of whether Lightning Lube would have gone public, and did not consider the impact of the 1990-91 recession on lube
sales generally").
Those cases that do attach some mathematical component to the reasonable certainty analysis further support Onyx's
view that a probability of greater than 50% is sufficient to create a "reasonable certainty." See Wagner v. Apex Marine
Ship Mgmt. Corp., 83 Cal.App.4th 1444. 1452, 100 Cal.Rptr.2d 533 (2000) (discussing the need for a more flexible
construction of the statute of limitations in latent disease cases because otherwise "most plaintiffs will be unable to
prove that the likelihood of the future illness is "reasonably certain," i.e., greater than 50 percent, as courts generally
require [for damages].") (quoting Wilson v. Johns-Manville Sales Corp. 684 F.2d 111 119 <D.C.Cir.1982) ("Recovery
of damages for speculative or conjectural future consequences *904 is not permitted. ·To meet the "reasonably certain"
standard, courts have generally required plaintiffs to prove that it is more likely than not (a greater than 50% chance) that
the projected consequence will occur.")); see also Henderson v. Sheahan, 196 F.3d 839, 850 (7th Cir.1999) ("Although
the Illinois courts have yet to squarely define the meaning of "reasonable certainty," other jurisdictions have construed
it to require a showing that it was more likely than not (i.e., greater than fifty percent probability) that the plaintiff
would develop the serious injury in the future [to recover damages].") (citing cases from the Fifth and Sixth Circuits);
Weeks Dredging & Contracting Inc. v. B. Turecamo Towing Corp.. 482 F.Supp. 1053, 1058 ffi.D.N.Y.1980) (describing
reasonably certain lost profits as "what profits more probably than not would have been earned had the incident not
transpired"). Bayer contends that Wagner is inapposite because it concerns latent disease in a tort action. However,
though not dispositive of the question, Wagner. like the instant case, involved analysis of a contingent event that affected
the availability of future damages. In Wagner. it was latent asbestos-related disease, whereas here, it is FDA approval.
Moreover, as Onyx points out, courts have treated tort and contract cases as analogous for purposes of establishing
future damages. See Kids' Universe. 95 Cal.App.4th at 883. 116 Cal.Rptr.2d 158.
At the least, then, California law provides no indication that an estimated 57% likelihood of FDA approval cannot
satisfy the reasonable certainty requirement. Moreover, as Judge Patel noted, Onyx has pointed out that 57% is a low
bar in this case, as it estimates an 80% likelihood that at least one of the indications will succeed. 1 See Memorandum
& Order *905 at 20 (citing Onyx Opp. to MSJ, Docket No. 96, at 24). Accordingly, the Court cannot conclude that
Onyx's expert testimony is insufficient as a matter of law to demonstrate damages with reasonable certainty. Bayer's
motion is denied.
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1 In its summary judgment briefing, Bayer argued that Onyx had to prove each source of damages-the Breast AI and the
CRC-separately, and therefore that it could not use the combined 80% probability of one indication receiving approval to
establish reasonable certainty. See Reply ISO MSJ, Docket No. 106, at 13 n.11. However, California law is clear that a party
must only prove thefact of damages to a reasonable certainty; it does not mandate that a party prove each individual source of
damages separately, as long as all of those sources stem from the defendant. Israel v. Campbell 163 Cal.App.2d 806 816 330
P.2d 83 (Cal.App.1958) (discussing difficulty of awarding damages when some damages may have been caused by defendant
and others may not be defendant's responsibility, but finding that problem did not apply where "[r]espondent's damages came
from only one source, namely, appellant's default"); see also Guntert & Zimmerman Const. Div. Inc. v. S. G.M.E. Usine Moser
S.A. No. C-88-3866 1992 WL 12602677,at *4 <N.D.Cal. June 3, 1992) ("Although certainty as to the fact of damages must
exist, a more liberal rule is applied in determining the amount of the damages."). Thus, if Onyx is able to present evidence at
trial sufficient to demonstrate with reasonable certainty that one of the indications would succeed, whether it can prove that
both would succeed goes more to the amount, rather than the existence, of damages. For those determinations, California uses
a liberal evidentiary rule. Grupe v. Glick 26 Cal.2d 680 691-93 160 P.2d 832 (Cal.1945); California Lettuce Growers v. Union
Sugar Co. 45 Cal.2d 474 486-87, 289 P.2d 785 <1955)("[W]hen it clearly appears that a party has suffered damage a liberal
rule should be applied in allowing a court or jury to determine the amount, and that, given proof of damage, uncertainty
as to the exact amount is no reason for denying all recovery.") (quotation omitted); Hiozt Foods Inc. v. Phillips 248 F.2d
23 33 (9th Cir.1957) (restating California rule); Dillingham-Ray Wilson v. City o[Los An"eles 182 Cal.App.4th 1396 1406
106 Cal.Rptr.3d 691 (2010) (same); see also Macken v. Martinez 214 Cal.App.2d 784. 790, 29 Cal.Rptr. 867 (1963) ("As
defendant's wrongful conduct made the exact ascertainment of damages difficult, he cannot complain because the court must
make an estimate of the damage and not an exact computation, provided, of course, that the estimate is a reasonable one.");
McConnell v. Corona City Water Co. 149 Cal. 60 66 85 P. 929 (Cal.1906) ("It is no objection to ... recovery that [damages]
cannot be directly and absolutely proved."). "It is within the sound discretion of the trier of fact to select the formula most
appropriate to compensate the injured party." MarSll B. V. v. Walt Disney Co. 185 F.3d 932 938 939 (9th Cir.1999) (finding
that the court had exercised its discretion appropriately by "considering several possible theories for determining damages"
and "declining to award compensation where it felt calculations were impermissibly speculative") (citing United States Liab.
Ins. Co. v. Haidinger-Hayes Inc. I Cal.3d 586 599 83 Cal.Rptr. 418 463 P.2d 770 '1970)).
m. WITNESSES
A witness or exhibit not listed in a party's pretrial conference statement may not be called or used without good cause.
This rule does not apply to true rebuttal witnesses (other than experts). Defense witnesses are normally considered case-
in-chief witnesses, not "rebuttal" witnesses.
•
The parties shall file their final witness lists by noon, September 30, 2011.
IV. EXPERT REPORTS
The parties shall lodge all expert reports, including their. supplemental expert reports, with the Court no later than
Wednesday, September 28, 2011.
V.EXHIBITS
Attached to this order as Exhibit A, the Court provides its rulings on Onyx's representative exhibits to which Bayer
objects. Attached as Exhibit B, the Court provides its rulings on Bayer's representative exhibits to which Onyx objects. At
the pretrial conference herein, the Court explained the principles it employs in adjudicating relevance and admissibility.
The parties are directed to meet and confer and resolve any remaining differences on objections. The parties shall submit
a revised narrowed list of exhibits and any remaining objections by September 28, 2011.
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VI. DEPOSITION DESIGNATIONS
The Court has considered the parties' representative deposition designations and objections, Docket No. 202. With
respect to Bayer's designation number 5, Robert Jones 22:23-23:1, the Court reserves this question for trial as to whether
Bayer has laid a sufficient foundation for the necessity of impeachment. With respect to Bayer's designation number 6,
Robert Jones 113:25-114:22, the Court reserves the question for trial as it is keyed to Exhibit 1077, for which the Court
has tentatively overruled Onyx's hearsay objection subject to a proper foundation at trial. See Exhibit B. With respect
to all other representative deposition designations, the Court overrules the objections. As with the exhibits, the parties
shall meet and confer and resolve objections. The parties shall submit a revised (narrowed) list by September 28, 2011.
VII. VOIR DIRE
Based on the parties' submissions and the Court's general practice, the Court intends to ask the following voir dire
questions during jury selection. Counsel. will be allowed a brief (20 minutes) follow-up voir dire after the Court's
questioning.
1. Name
2. City of residence
3. Occupational Status
4. Organizations
5. Hobbies
6. Marital Status
7. Spouse's occupation
8. Children (including ages).
*906 9. If a juror on another case
10. If ever a grand juror
11. If ever in the military:
12. Who is (or was) your employer?
a. How long have you worked (or did you work) for that employer?
13. Please describe your educational background, including where you went to school, your major areas of study, and
any degrees you have received.
14. The companies involved in this dispute are Bayer Corporation, Bayer AG, Bayer Healthcare LLC, Bayer Schering
Pharma AG, Bayer HealthCare Pharmaceuticals, Inc., Bayer HealthCare Pharmaceuticals LLC (collectively
referred to here as "Bayer") and Onyx Pharmaceuticals, Inc. (referred to here as "Onyx").
a. Other than in reference to the product Bayer Aspirin, have you ever heard of Bayer?
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b. Have you ever heard of Onyx?
c. Have you, any member of your family, or any of your close friends ever worked for Bayer or Onyx or had mir
business relationship with Bayer or Onyx? Identify the person and explain.
d. Have you or any member of your immediate family ever owned any stock.,bond, or ever had any financial in~
in Bayer or Onyx?
15. The law firms representing the parties involved in this dispute are Cooley LLP (formerly known as Cooley God~
and Cooley Godward Kronish), Morrison & Foerster LLP and Bartlit Beck Herman Palenchar & Scott LLP. Some
of the specific attorneys involved are:
From the law firm of Bartlit Beck Herman Palenchar & ScotfLLP:
Phil Beck
Mark Levine Brian Swanson
Scott McBride
From the law firm of Morrison & Foerster:
Alison Tucher From Bayer:
Scott Meece
From the law firm of Cooley LLP:
Stephen C. Neal
Martin S. Schenker
Michelle S. Rhyu
Benjamin Kleine
From Onyx:
• Suzanne Sberna
16. Do you have any college education, training, experience, or current or past employment in the follcnving areas?
(1) Pharmaceuticals
(2) Medicine or healthcare
(3) Biotechnology
(4) Drug Discovery or Development
(5) Chemistry including Medicinal Chemistry and Chemical Engineering
(6) Biology
17. The products that will be discussed in this case are cancer-fighting drugs ..
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(A) Have you, a family member or a close friend ever had cancer?
(B) Have you, a family member or a close friend ever taken the medication Nexavar®?
18. Do you have any personal experience or training specifically involving the drafting or review of contracts, Of"
dealing with a dispute over the terms of a contract, either in connection with your job or as part of your personal life?
19. Have you or an immediate family member ever started a business?
20. Do you have any personal knowledge of this case, or have you read about or heard it discussed, or have an opiniora
regarding it?
*907 21. Have you or any member of your immediate family ever been a party to a lawsuit? Please describe.
- a. Were you the plaintiff or defendant?
b. How was the case resolved?
c. Will your experiences from that lawsuit impact your ability to decide this case in a fair and impartial waf!
22. Are you or any member of your family an attorney or law student?
23. The following is a list of individuals who might appear as a witness in this case. Are you related to or personally
acquainted with any of these individuals?
1. Lila Adnane
2. Shripad Bhagwat
3. Hans Bishop
4. Klaus Brandau
5. Gideon Bollag
6. Laura Brege
7. Iain Cockburn
8. N. Anthony Coles, Jr.
9.JacquesDumas
10. Axel Eble
11. Henry (Hank) Fuchs
12. Mark Gelder
13. Greg Giotta
14. Arthur Higgins
15. Bob Jones
16. Juergen Lasowski
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17. Christopher Lipinski
18. Nathalie Lokker
19. Ted Love
20. Tim Lowinger
21. John Lyons
22. Kemal Malik
23. Bob Mass
• 24. Frank McCormick
25. Joerg Moeller
26. Chris Peetz
27. Wolfgang Plischke
28. Len Post
29. Paolo Pucci
30. Mohan Rao
31. Hollings Renton
32. Bernd Riedl
33. Rob Rosen
34. Eric Rowinsky
35. Peter Sandor
36. Bill Scott
37. Scott Wilhelm
38. Todd Yancey
24. Do you have any other experience, opinion, or matter which you believe should be called to the Court's or the
parties' attention that might have some bearing on your qualifications or ability to sit as a juror on this case, or
which you think may prevent you from rendering a fair and impartial verdict based solely upon the evidence and
the Judge's instructions as to the law?
25. Have you ever been involved in a serious business dispute? Briefly describe the nature of the dispute and how it
. .
was resolved.
VIIl. JURY INSTRUCTIONS & VERDICT FORM
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The Court shall address the verdict form at a subsequent date.
Regarding instructions, as the Court noted at the pretrial conference, the parties are directed to m and confer and try
to reach an agreement on the instructions. The parties shall file with the Court no later than noon F day, September 23,
2011, a set of agreed upon instructions and the parties' respective positions and proposed language here they disagree.
In addition to the above, the parties shall provide the Court with any stipulated facts to be read to the jury, to be filed
on *908 September 23, 2011, along with the jury instructions.
IT IS SO ORDERED .
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GUIDELINES FOR TRIAL IN CIVIL CASES ( JURY AND BENCH)
PRETRIAL ARRANGEMENTS
1. Should a daily transcript and/or real-time reporting be desired, the parties shall make arrangements with the Supervisor
of the Court Reporting Services at (415) 522-2079, at least ten calendar days prior to the trial date.
2. During trial, parties may wish to use, e.g., overhead projectors, laserdisk/computer graphics, poster blow-ups, models,
or specimens of devices. The *924 United States Marshal requires a court order to allow equipment into the Courthouse.
Parties should be prepared to fix any equipment, if necessary.
SCHEDULING
1. Trial will normally be conducted from 8:30 a.m. to 2:00 p.m. (or slightly longer to finish a witness), with one 15-
minute break and one 40-minute lunch break. Parties must arrive by 8:00 a.m. or, in a jury trial, earlier as needed for
any matters to be heard out of the presence of the jury. The jury will be called at 8:30 a.m. The trial week is Monday
through Thursday, excluding holidays. Fridays are dark.
JURY SELECTION
1. In civiljury cases, there are no alternate jurors, and the jury is typically selected as follows. At the outset, 18 potential
jurors are called and seated in the jury box and front courtroom bench in the order their names are drawn from the
drum. This placement will determine their order in the selection process. The Court will first conduct its voir dire of
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the entire panel (not just the seated 18) to determine hardships. Jurors excused from the seated 18 will be replaced from
those drawn from the panel. The Court will then voir dire the seated 18 for cause. Afterwards, the parties will be allowed
a brief follow-up voir dire (15 minutes). Once all voir dire is completed, the Court will address all challenges for cause
and excuse those potentialjurors who have been successfully challenged. After a short recess, each side may exercise its
allotment of peremptory challenges. The plaintiff has the first challenge, the defendant the next two, the plaintiff the next
two, and so forth. The default number of peremptory challenges per party or side is three. Any party that passes will be
deemed to have used a challenge. The eight (or such other size as will constitute the jury) surviving the challenge process
with the lowest numbers become the final jury. Once the jury selection is completed, the jurors' names will be read again,
and they will be seated in the jury box and sworn in. The Court may alter the above procedure in its discretion.
2. Jurors may take notes. Note pads will be distributed at the beginning of each trial. The pads will remain in the jury room
at the end of each day. Jurors will be instructed on the use of notes both in the preliminary and final jury instructions.
TIME LIMITS
I. Ordinarily, the Court shall set fixed time limits for the presentation of evidence by each side at the final pretrial
conference. The time limit includes all examination time (whether direct, cross, re-direct, or re-cross) for each witness
regardless of which party called the witness. Opening and closing time limits shall be separately considered.
OPENING STATEMENTS
1. Each side may be subject to a predetermined time limit for its opening statement.
2. Parties must cooperate and meet and confer to exchange any visuals, graphics, or exhibits to be used in the opening
statements, allowing for time to work out objections and any reasonable revisions one court day in advance of trial.
3. In a jury case, parties should be prepared to give opening statements as soon as the jury is sworn.
WITNESSES
I. At the close of each trial day (at 2:00 p.m.), parties shall exchange a list of witnesses for the next full court day and
the exhibits that will be used on direct and cross-examination (other than for impeachment of an adverse witness). By
4:00 p.m. *925 that same day, opposing parties shall provide any objections to such exhibits and further shall provide
a list of all exhibits to be used with the same witnesses on cross-examination (other than for impeachment). The Court
will address objections before 8:30 a.m. on the following day. The first notice of objection shall be provided one court
day prior to the first day of trial. All notices should be provided in writing and filed with the Court, and a courtesy copy
should be given to chambers immediately.
2. Parties should always have their next witness ready and in the Courthouse. Failure to have the next witness ready
may constitute resting.
3. Parties are expected to cooperate with each other in the scheduling and production of witnesses. Witnesses may be
taken out of order if necessary. Every effort shall be made to avoid calling a witness twice (as an adverse witness and
later as a party's witness).
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4. If a witness is testifying at the time of a recess or adjournment and has not been excused, the witness shall be seated
back on the stand when court reconvenes. If a new witness is to be called immediately following recess or adjournment.
the witness should be seated in the front row, ready to be sworn.
5. Immediately before each new witness takes the stand, counsel calling the witness shall place on the witness stand a
clearly marked copy of each exhibit that counsel expects to have the witness refer to during his or her direct examination.
Immediately before beginning cross-examination, counsel conducting cross-examination shall do the same with any
additional exhibits to be referenced on cross.
6. If counsel intends to have the witness draw diagrams or put markings on visual exhibits or diagrams prepared by the
party calling the witness, the witness shall do so before taking the stand. Once on the stand, the witness shall adopt the
diagrams and/or markings and explain what they represent. If the diagram or visual exhibit is prepared by the opposing.
party, the witness shall not make any markings on the diagram or visual exhibit without leave of the Court.
r,, 7. A witness or exhibit not listed in the joint pretrial conference statement may not be called or used without good cause.
This rule does not apply to true rebuttal witnesses (other than experts). Defense witnesses are normally considered case--
in-chief witnesses, not "rebuttal" witnesses.
USE OF DEPOSITIONS TO IMPEACH OR SHORT READ-INS
l. Depositions used at trial for impeachment shall comply with the following procedure:
a. On the first day of trial, bring the original and clean copies of any deposition(s) intended to be used. A sealed original
copy shall be provided to the Judge.
b. The first time a deposition is read, counsel should state the deponent's name, the date of the deposition, and the
name of the lawyer asking the question. If the deposition was a Rule 30(b)(6) deposition, counsel should so state.
c. When counsel reads a passage into the record, counsel should simply say, for example, "I wish to read in page __ ,
lines __ to __ from the witness's deposition." A brief pause will be allowed for any objection.
d. Counsel should then proceed by stating "question" and·reading the question exactly, then stating "answer" and
reading the answer exactly. Stating "question" and "answer" is necessary so that the court reporter, the Court, and
the jury (in a jury trial) can follow who was talking at the deposition.
e. Rather than reading a passage, counsel is free to play a videotaped version *926 of the passage, but counsel must
have a system for immediate display of the precise passage.
DEPOSITION DESIGNATIONS
1. The following procedure applies only to witnesses who appear by deposition. It does not apply to live witnesses whose
depositions are read in while they are on the stand. To prepare designated deposition testimony, counsel shall photocopy
the cover page, the page where the witness is sworn, and each page from which any testimony is proffered, including
pages containing a counter-designation made by opposing counsel. Counsel should redact objections or colloquy unl~
needed to understand the question. In addition, counsel should redact any testimony that has not been designated or any
testimony to which an objection has been made and sustained by the Court. Any corrections must be interlineated and
references to exhibit numbers must conform to the trial numbers. The finished packet should then be the actual script
and should smoothly present the identification and swearing of the witness and testimony desired.
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2. Counsel is free to play a videotaped version of any deposition testimony, but counsel must have a system for immediate
display of the precise testimony omitting any properly redacted passages.
EXHIBITS
1. Use numbers only, not letters, for exhibits, preferably the same numbers as were used in depositions. Blocks of numbers
should be assigned to fit the need of the case (e.g., Plaintiff has 1 to 100, Defendant A has 101 to 200, Defendant B has
201 to 300, etc.). A single exhibit should be marked only once. If the plaintiff has marked an exhibit, then the defendant
should not re-mark it. Different versions of the same document, e.g., a copy with additional handwriting, must be treated
as different exhibits. To avoid any party claiming "ownership" of an exhibit, all exhibits shall be marked and referred
, to as "Trial Exhibit No. __ ," not as "Plaintiffs Exhibit" or "Defendant's Exhibit." If an exhibit number differs from
• that used in a deposition transcript, however, then the latter must be conformed to the new trial number if and when the
deposition testimony is read (so as to avoid confusion over exhibit numbers).
2. Exhibits are not to be filed but rather shall be submitted to chambers (two sets). Exhibits must be premarked. In addition,
one set of exhibits must be tagged. Exhibits shall be three-hole punched and shall be submitted in binders. Sample tags
may be obtained from the Courtroom Deputy and are attached as Exhibit A hereto.
3. Parties must consult with each other and with the Courtroom Deputy at the end of each trial date and compare notes
as to which exhibits are in evidence and any limitations thereon. If there are any differences, parties should bring them
promptly to the Court's attention.
4. In a jury trial, before the case goes to the jury, parties must confer with the Courtroom Deputy to make sure th.e
exhibits going to the jury room are all in evidence and 111 good order. Parties may, but are not required to,jointly provide
a revised list of all exhibits actually in evidence (and no others) stating the exhibit number and a brief, non-argumentative
description (e.g., letter from A to B, dated August 17, 1999). This list may go into the jury room to help the jury sort
through exhibits. In a bench trial, parties may follow a similar procedure to help the Court sort through exhibits.
OBJECTIONS
I. Counsel shall stand when making objections and briefly state the basis of the objection.
*927 2. Counsel shall not make speaking objections.
3. There can be only one lawyer per witness per party for all purposes, including objections.
4. In a jury trial, sidebar conferences are discouraged. The procedures outlined in these guidelines should eliminate the
need for most sidebars.
5. In a jury trial, to maximize jury time, parties must alert the Court in advance of any problems that will require
discussion outside the presence of the jury so that the conference can be held before court begins or after the jury leaves
for the day.
SETTLEMENTS AND CONTINUANCES
WE.STLAW© 2019 Thomson Reuters. No claim to original ~-S~vernment Works. 25
J(' ✓U/y
~·
IITRUE COPYII
I. Shortly before trial or a final pretrial conference, parties occasionally wish jointly to advise the Courtroom Deputy
that a settlement has been reached and seek to take the matter off calendar, but it turns out later that there was only a
settlement "in principle" and disputes remain. Cases, however, cannot be taken off calendar in this manner. Unless and
until a legally binding settlement is reached, all parties must be prepared to proceed with the final pretrial conference as
scheduled and to proceed to trial on the trial date, or face dismissal of the case for lack of prosecution or entry of default
judgment. To facilitate settlement, the Court is available to place the material terms of a settlement on the record. Only
an advance continuance expressly approved by the Court will release parties from their obligation to proceed to trial
If parties expect that a settlement will be final by the time of trial or the final pretrial conference, they should notify
the Court immediately in writing or, if it occurs over the weekend before the trial or conference, by voicemail to the
Courtroom Deputy. The Court will attempt to confer with the parties as promptly as circumstances permit to determine
Y
(.. if a continuance will be in order or if it can assist the parties in putting the settlement on the record. Pending such a
conference, however, parties must prepare and make all filings and be prepared to proceed with trial.
2. Civil Local Rule 40-1 provides that jury costs may be assessed as sanctions for failure to provide the Court with timely
written notice of a settlement. Please be aware that any settlement reached on the day of trial, during trial, or at any time:
after the jury or potential jurors have been summoned will normally require the parties to pay juror costs.
*928
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863 F.Supp.2d 894
End of Document © 2019 Thomsou Reuters. No claim to 01iginalU.S. Government Works.
WESTLAW© 2019 Thomson Reuters. No claim to or:n:~7

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Application Detalls
Appllcatfon Details
APPLICATION NUMBER 1633/MUMNP/2007
APPLICATION TYPE DIVISIONAL PCT NATIONAL PHASE APPLICATION
DATE OF FILING 05/10/2007
APPLICANT NAME BAYER CORPORATION

BAVER CORPORATION
TITLE OF INVENTION ω - CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE

INHIBITORS
FIELD OF INVENTION CHEMICAL
E-MAIL (As Per Record)
ADDITIONAL-EMAIL (As Per Record) remfry-sagar@remfry.com
E-MAIL (UPDATED Online) mail@perfexiolegal.com
PCT INTERNATIONAL APPLICATION PCT/US00/00648

NUMBER
PCT INTERNATIONAL FILING DATE 12/01/2001
PARENT APPLICATION NUMBER IN/PCT/2001/00799/MUM
PARENT APPLICATION FILING DATE 05/07/2001
PRIORITY DATE 13/01/1999
REQUEST FOR EXAMINATION DATE 04/04/2008
PUBLICATION DATE (U/S 11A) 14/12/2007
REPLY TO FER DATE 12/10/2012

Application Stlillls
Appllcldon Status
APPLICATION STATUS Application Refused

Application RefusedU/S
UIS15
1S
______ _,I._I
___ _,I __
1__ _,
View Examination Report(s) Order(s)/Decision(s) View Documents
- - -
➨ Filed ➨ Published ➨ RQ Filed ➨ Under Examination -
➨ Disposed -
In case of any discrepancy in status, kindly contact ipo-helpdesk@nic.in
PCT CONVENTION APPLICATION
\QJ,4
\C3'3/fY\~•rrNl'f
c--lJD\Q()O/
FORM 1 Application 'No:
THE PATENTS ACT, 1970 Filing date:
[39 OF 1970] Amount of Fee paid:
& CBR No.
THE PATENTS (AMENDMENT) Signature:
RULES,2006
PATENT
[See Sections 7, 135 and Rule 20
( 1)]
1. APPLICANT (S)
Name Nationality - . , Address~O) ,J
BAYER CORPORATION, A US corporation 100 Bayer Road, Pittsburgh,

Pennsylvania, 15205, U.S.A.,
2. INVENTOR (S)
BERND RIEDL, of Von Der Goltz Strasse 7, 42329

Wuppertal, Germany
JACQUES DUMAS, of 821 Beechwood Road, Orange,

Connecticut 06477, USA
UDAY KHIRE, of 101 Tanglewood Drive, Hamden,

Connecticut 06518, USA
TIMOTHY B. LOWINGER, of #203, 5- 7 Chitose-Cho,

Nishingomiya City, Hyogo, 662-0046,
Japan;
WILLIAM J. SCOTT of 210 Saddle Hill Drive, Guilford,

Connecticut 06437, USA;
ROGER A. SMITH, of 65 Winterhill Road, Madison,

JILL E. WOOD, of 72 Pickwick Road, Hamden,

MARY-KATHERINE of 134 Park Avenue, Hamden,

MONAHAN, Connecticut 06517, USA;
REINA NATERO, of 113 Edgecomb Street, Hamden,

JOEL RENICK, of 11 Wall Street, #4, Milford,

IITRUE COPYII
ROBERT N. SIBLEY, of 1187 Mt. Carmel Avenue, North
Haven, Connecticut 064 73, USA,
3. TITLE OF THE INVENTION: "u1-CARBOXYARYL SUBSTITUTED DIPHENYL

UREAS AS RAF KINASE INHIBITORS"
4. ADDRESS FOR CORRESPONDENCE OF APPLICANT/

AUTHORISED PATENT AGENT IN INDIA
REMFRY & SAGAR,

Attorneys-at-Law
79, Nariman Bhavan, 7 th Floor
227, Backbay Reclamation
Nariman Point,
MUMBAI 400 021
Tel & Fax: 91-22-2285 3633
5. PRIORITY PARTICULARS OF THE APPLICATION (S) FILED IN

CONVENTION COUNTRY
Country Application Filing Date Name of the Title of the invention
Number Applicant/Inv
entor
U.S.A. 60/ 115, 877; 13/01/1999, BEREND "u1-CARBOXYARYL
RIEDL, SUBSTITUTED
09/257, 266; 25/02/1999 JACQUES DIPHENYL UREAS
DUMAS, AS RAF KINASE
and and UDAY KHIRE, INHIBITORS"
TIMOTHY B.
09/425,228 22/10/1999 LOWIN
GER,
WILLIAM J.
SCOTT,
ROGER A.
SMITH,
JILL E.
WOOD,
MARY-
KATHERINE
MONAHAN,
REINA
NATERO,
JOEL
RENICK
and
ROBERT N.
IITRUE _COPY!I
I I SIBLEY I
6. PARTICULARS FOR FILING PATENT COOPERATION TREATY (PCT)

NATIONAL PHASE APPLICATION:
International Application No. International filing date as allotted
by the receiving office:
PCT/US00/00648 12/01/2001
7. PARTICULARS FOR FILING DIVISIONAL APPLICATION
IN/PCT/2001, 00799/MUM I 05/07/2001
8. DECLARATIONS:
i) i) Declaration by the applicant(s) in the convention country
BERND RIEDL, of Von Der Goltz Strasse 7, 42329 Wuppertal, Germany; JACQUES
DUMAS, of 821 Beechwood Road, Orange, Connecticut 064 77, USA; UDAY KHIRE,
of 101 Tanglewood Drive, Hamden, Connecticut 06518, USA; TIMOTHY B.
LOWINGER, of #203, 5-7 Chitose-Cho, Nishingomiya City, Hyogo, 662-0046, Japan;
WILLIAM J. SCOTT, of 210 Saddle Hill Drive, Guilford, Connecticut 06437, USA;
ROGER A. SMITH, of 65 Winterhill Road, Madison, Connecticut 06443, USA; JILL
E. WOOD, of 72 Pickwick Road, Hamden, Connecticut 06517, USA; MARY-
KATHERINE MONAHAN, of 134 Park Avenue, Hamden, Connecticut 06517, USA;
REINA NATERO, of 113 Edgecomb Street, Hamden, Connecticut 06518, USA; JOEL
RENICK, of 11 Wall Street, #4, Milford, Connecticut 06460, USA; ROBERT N.
SIBLEY, of 1187 Mt. Carmel Avenue, North Haven, Connecticut 06473, USA, the
applicant(s) in the convention country declare that the applicant(s) herein is/are
my/ our assignee or legal representative.
BERND RIEDL, JACQUES DUMAS,
UDAYKHIRE, TIMOTHY B. LOWINGER,
WILLIAM J. SCOTT, ROGER A. SMITH,
JILL E. WOOD, MARY-KATHERINE MONAHAN,
REINA NATERO, JOEL RENICK,
~ TRUE COPYII
ROBERT N. SIBLEY,
ii) Declaration by the applicant(s):

The complete specification relating to the invention is filed with this
application.
There is no lawful ground of objection to the grant of the Patent to me/us.
The application or each of the applications, particulars of which are given in
Para 5 was the first application in convention country/ countries in respect of
my/ our invention.
I/we claim the priority from the above mentioned application(s) filed in
convention country/ countries and state that no application for protection in respect
of the invention had been made in a convention country before that date by me/us
or by any person from which I/we derive the title.
My/ our application in India is based on International application under
Patent Cooperation Treaty (PCT) as mentioned in Para-6.
The application is divided out of my/ our application particulars of which are
given in para 7 and pray that this application may be treated as deemed to have
been filed on Jul 05, 2001 under Section 16 of the Act.
(a) Complete specification (in duplicate)

[c] Declaration as to inventorship on Form 5
[d] Fee Rs. 80,400/- by cheque
I/We hereby declare that to the best of my/our knowledge, information and belief
the fact and matters stated herein are correct and I/we request that a patent may
be granted to me/us for the said invention.
Dated this 4 th day of October, 2007.
BAY CORPORATION,
[RANJ A MEHTA-DUTI]
OF REMFRY & SAGAR

THE PATENT OFFICE,
MUMBAI
IITRUE COPYII
FORMl
--- (FOR OFFICE USE ONLY)
Application No:
THE PATENTS ACT, 1970 (39 of 1970)
& Filing Date:
The Patents (Amendment) Rules, 2006 Amount of Fees Paid:
APPLICATION FOR GRANT OF PATENT CBRNo:
[Seesection7, 135 and rule 20(1)) Signature:
1. APPLICANT(S)
BAYER CORPORATION A US Corporation 100 Bayer Road, Pittsburgh, Pennsylvania,
15205, U.S.A.,
2. INVENTOR(S)
BERENDRIEDL, a German citizen of Von Der Goltz Strasse 7, 42329
Wuppertal, Germany;
JACQUES DUMAS a French citizen of 821 Beechwood Road, Orange,

UDAYKHIRE an Indian citizen of 101 Tanglewood Drive, Hamden,

TIMOTHY B. LOWINGER ·a Canadian citizen of #203, 5-7 Chitose-cho, Nishingomiya

City, Hyogo, 662-0046,Japan;
WILLIAM J.SCOTT a US citizen of 210 Saddle Hill Drive, Guilford,

ROGER A. SMITH a Canadian citizen of 65 Winterhill Road, Madison,

JILLE.WOOD a US citizen of 72 Pickwick Road, Hamden,

MARY-KATHERINE a US citizen of 134 Park Avenue, Hamden

MONAHAN Connecticut 06517, USA;
REINA NATERO a US citizen of 113 Edgecomb Street, Harnden,

JOEL RENICK, a US citizen of 11 Wall Street, #4, Milford, Connecticut

06460, USA; and
11TRUE COPY~
ROBERT N. SIBLEY a US citizen of 1187 Mt. Carmel Avenue, North
Haven, Connecticut 064733, USA
3. TITLE OF THE INVENTION:
"w-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS"
4. ADDRESS FOR CORRESPONDENCE OF APPLICANT/ AUTHORIZED PATENT AGENT IN INDIA
PERFEXIOLEGAL Tel: +91-120-245-9858

Attorneys-At-Law Direct +91-120-245-9859
9655, Sector-C, Pocket-9 Fax: +91-120-245-9860
Vasant Kunj, Email: sanjay.kumar@12erfexiolegal.com
New Delhi- 110 070
INDIA
5. PRIORITY PARTICULARS OF THE APPLICATION(S) FILED IN CONVENTION COUNTRY:
Country Application Filing Date Name of Applicant Title of Invention
No
U.S.A. 60/115,877; 13/01/999 BEREND RIEDL; "w-CARBOXYARYL
09/ 257,266; 25/02/1999 and JACQUES DUMAS; SUBSTITUTED
and 22/10/1999 UDAY KHIRE; DIPHENYL UREAS AS
09/425,228 RAF KINASE
TIMOTHY B. LOWINGER;
INHIBITORS"
WILLIAM J.SCOTT;
ROGER A SMITH;
JILL E.WOOD;
MARY-KA THERINE
MONAHAN;
REINA NATERO;
JOEL RENICK; and
ROBERT N. SIBLEY
6. PARTICULARS FOR FILING PATENT COOPERATION TREATY(PCT) NATIONAL PHASE
APPLICATION:
International filing date as allotted by the receiving
International Application No.
office
PCT/ USOO/ 00648 12/01/2000
7. PARTICULARS FOR FILING DIVISIONAL AP PUCA TION
Original (First) Application No. Date of filing of Original (First) Application
IN/PCT/2001, 00799/MUM 05/07/2001
8. PARTICULARS FOR FILING PATENT OF ADDITION
Main Application/Patent No. Date of filing of Main Application
Nil Nil
1 2ocrzom
IiTRUE COPYII
9. DECLARATIONS
(i) Declaration by the Applicant(s) in the convention country
I/We, BEREND RIEDL, a German citizen, of Von Der Goltz Strasse 7, 42329 Wuppertal, Germany;
JACQUES DUMAS, a French citizen, of 821 Beechwood Road, Orange, Connecticut 06477, USA;
UDAY KHIRE, a Indian citizen, of 101 Tanglewood Drive, Hamden, Connecticut 06518, USA;
TIMOTHY B. LOWINGER, a Canadian citizen of #203, 5-7 Chitose-cho, Nishingomiya City,
Hyogo, 662-0046, Japan, WILLIAM J. SCOTT, a US citizen, of 210 Saddle Hill Drive, Guilford,
Connecticut 06437, USA; ROGER A. SMITI-I,a Canadian citizen, of 65 Winterhill Road, Madison,
Connecticut 06443, USA; JILL E.WOOD, a US citizen, of 72 Pickwick Road, Hamden, Connecticut
06517, USA; MARY-KATHERINE MONAHAN, a US citizen, of 134 Park Avenue, Hamden
Connecticut 06517, USA; REINA NATERO, a US citizen, of 113 Edgecomb Street, Hamden,
Connecticut 06158, USA; JOEL RENICK, a US citizen, of 11 Wall Street, #4, Milford, Connecticut
06460, USA; ROBERT N. SIBLEY, a US citizen, of 1187 Mt. Carmel Avenue, North Haven,
Connecticut 064733, USA, the Applicant(s) in the convention country declare that the applicant (d) herein
is/ are my/ our assignee or legal representative.
BEREND RIEDL JACQUES DUMAS UDAYKHIRE
TIMOTI-IYB. LOWINGER WILLIAM J. SCOTT ROGER A. SMITI-I
JILLE.WOOD MARY-KATHERINE MONAHAN
REINA NATERO JOEL RENICK ROBERT N. SIBLEY
(ii) Declaration by the Applicant(s)

I/We hereby declare(s) that
- I am /We are in possession of the above mentioned invention.
• The complete Specification relating to the invention is filed with this application.
- There is no lawful ground of objection to the grant of patent to me/us.
- The application or each of applications, particulars of which are given in para 5 was the first
application in convention country / countries in respect of my/ our invention.
- I/ We claim priority from the above mentioned application(s) filed in convention country/ countries
and state that no application for protection in respect of the invention has been made in a
convention country before that date by me/us or by any person from which I/we derive the title.
- My/ our application is based on International application under Patent Cooperation Treaty as
mentioned in para 6.
- The application is divided out of my/ our application particulars of which are given in para -7 and
pray that this application may be treated as deemed to have been filed on July 5, 2001 under section
16 of the Act.
IITRUE _coPYjl
I 10. Following are the attachments with the application:
a. Complete Specification (in duplicate)
b. Statement and undertaking on Form-3
c. Declaration as to lnventorship on Form 5
d. Fee Rs. 80,400/- by cheque
I/We declare that to the best of my/ our knowledge, information and belief the fact and matters stated
herein are correct and I/We request that a patent may be granted t<>me/us for the said invention.
Dated this 5th day of October 2007
S KUMAR]
PERFEXIOLEGAL
ATIORNEY FOR 1HE APPUCANT(S)
To,
The Patent Office at Mumbai
l!TRUE COPYjl
CS (Comm.) No. 660 of 2022
In the matter of:

versus
INDEX
VOL-6
document ent in
possess
ion/po
wer/co
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ustody
is
origina
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copy/p
hotoco
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(Publicly
Available)
2. Claims as Indian Patent Copy Executed by Availab From
filed in Office and Bayer le at Defenda 1006
(Publicly
Available)
3. Claim Indian Patent Copy Executed by Availab From
amendments Office and Bayer le at Defenda 1030
in Bayer Corporation IPO nt to its -
P/2007 (Publicly
Available)
Examination Office and IPO le at Defenda 1047
Report of Bayer IPO nt to its -
P/2007 (Publicly
Available)
of Office and Bayer le at Defenda 1050
(Publicly
Available)
refusal order Office and IPO le at Defenda 1060
for grant of Bayer IPO nt to its -
P/2007 as (Publicly
divisional Available)
Patent
European Patent Office EPO le at Defenda
Application and Bayer EPO nt to its 1066
EP 1793824 Healthcare website Counsel -
LLC 1068
(Publicly
Available)
8. Copy of EP Bayer Copy Executed by Availab From
Appeal Board Healthcare EP Appeal le at EP Defenda 1069
Decision - T LLC & Ter Board Appeal nt to its -
18 0377 Meer Board Counsel 1096
Steinmeister website
& Partner
Patentanwale
te mbB
(Publicly
Available)
Through
Place: Noida (NCR)
Date: 03.10.2022
Guruswamy Nataraj
NOIDA 201 307, NCR
Phone: 9811808373
FORM3
[39 OF 1970]
&
as amended by
THE PATENTS (AMENDEMNET) RULES, 2006
[See Section 8 and 12]
We, BAYER CORPORATION, 100 Bayer Road, Pittsburgh, Pennsylvania,

15205, U.S.A.,
hereby declare:
[i] that we, BEREND RIEDL, of Von Der Goltz Strasse 7, 42329
Wuppertal, Germany; JACQUES DUMAS, of 821 Beechwood Road,
Orange, Connecticut 06477, USA; UDAY KHIRE, of 101 Tanglewood
Drive, Hamden, Connecticut 06518, USA; TIMOTHY B. LOWINGER, of
#203, 5-7 Chitose-Cho, Nishingomiya City, Hyogo, 662-0046, Japan;
WILLIAM J. SCOTT, of 210 Saddle Hill Drive, Guilford, Connecticut
06437, USA; ROGER A. SMITH, of 65 Winterhill Road, Madison,
Connecticut 06443, USA; JILL E. WOOD, of 72 Pickwick Road, Hamden,
Connecticut 06517, USA; MARY-KATHERINE MONAHAN, of 134 Park
Avenue, Hamden, Connecticut 06517, USA; REINA NATERO, of 113
Edgecomb Street, Hamden, Connecticut 06518, USA; JOEL RENICK, of
11 Wall Street, #4, Milford, Connecticut 06460, USA; ROBERT N.
SIBLEY, of 1187 Mt. Carmel Avenue, North Haven, Connecticut 06473,
USA, who have made this application number dated
, alone/jointly made for the same/substantially same
invention application[s] dated for patent in the other countries, the
particulars of which are given below:
SEE ANNEXURE
ii] that the rights in the application[s] have been assigned to: No one
iii] that we undertake that up to the date of acceptance of

the complete specification by the Controller, we would keep the
Controller informed in writing the details regarding
corresponding applications for patents filed outside India within six
months from the date of filing of such application;
(RANJNA MEHTA-DUTT)
OF REMFRY & SAGAR
ATI'ORNEY FOR THE APPLICANT[S]
To
THE PATENT OFFICE,
MUMBAI
IITRUE COPYII
ANNEXURE
COUNTRY APPLICATION NO. FILING DATE PATENT NO. GRANT DATE
EUROPE 00903239.2 12/01/2000 1140840 22/03/2006
USA 10/042,203 11/01/2002 7235576 26/06/2007
U.S.A. 60/ 115,877 13/01/1999
U.S.A. 09/257,266 25/02/1999
U.S.A. 09/425,228 2/10/1999
PCT PCT/US00/00648 12/01/2000
IITRUE COPY!I
ORIGINAL
FORM3
[39 OF 1970]
&
We, BA YER CORPORATION, a U.S. corporation of 100 Bayer Road, Pittsburgh, Pennsylvania,
15205, U.S.A.,
hereby declare:
(i) That in USA, BEREND RIEDL, of Von Der Goltz Strasse 7, 42329 Wuppertal, Germany;
JACQUES DUMAS, of 821 Beechwood Road, Orange, Connecticut 06477, USA; UDAY
KHIRE, of 101 Tanglewood Drive, Hamden, Connecticut 06518, USA; TIMOTHY B.
LOWINGER, of #203, 5-7 Chitose-Cho, Nishingomiya City, Hyogo, 662-0046, Japan,
WILLIAM J. SCOTT, of 210 Saddle Hill Drive, Guilford, Connecticut 06437, USA; ROGER
A. SMITH, of 65 Winterhill Road, Madison, Connecticut 06443, USA; JILL E. WOOD, of 72
Pickwick Road, Hamden, Connecticut 06517, USA; MARY-KATHERINE MONAHAN, of
134 Park Avenue, Hamden, Connecticut 06517, USA; REINA NATERO, of 113 Edgecomb
Street, Hamden, Connecticut 06518, USA; JOEL RENICK, of 11 Wall Street, #4, Milford,
Connecticut 06460, USA; ROBERT N. SIBLEY, of 1187 Mt. Carmel Avenue, North Haven,
Connecticut 064733, USA, who have made this Application No. 1633/MUMNP/2007 dated
04.10.2007 <alone/jointly> made for the <same/substantially> same invention application[ s] for
patent in the other countries, the particulars of which are given below:
Country Application Application Status Publication Grant No. &
Number Date Date Grant Date
United States of America 60/115,877 13.01.1999 - - -
United States of America 09/257,266 25.02.1999 - - -
United States of America 09/425,228 22.10.1999
United States of America 10/042,203 11.01.2002 Granted - 7235576
26.06.2007
United States of America - 27.08.2007 Pending 02.08.2001
(ii) that the rights in the application[s] have been assigned to: BAYER CROPSCIENCE AG
(jii)that we who have made this Application No. 1633/MUMNP/2007 dated 04.10.2007
alone/jointly, made for the same/substantially invention, application(s) for patent in the other
SEE ANNEXURE
(iv)that <I/we> undertake that up to the date of grant of the patent, by the Controller, I/we would
keep him informed in writing the details regarding corresponding applications for patents filed
outside India within six months from the date of filing of such application. ~ .~ /
Dated this 25 th day of October, 2010. fot/

(SWATI PAHUJA)
OF REMFRY & SAGAR
THE PATENT OFFICE, MUMBAI
•2 6 · OCTlUlU-'
II TRUE COPYII
oR\G\NAL ANNEXURE
APPLICATION NUMBER: 1633/MUMNP/2007
Name of Country Application Number Filing Date Status Publication Patent Grant Date
Date Number
Albania 5028442.1 12.01.2000 Patented - 10.03.2010
Argentina 20100102601 15.07.2010 Patented 12.05.2004 -
Australia 2004200722 24.02.2004 Patented 01.08.2000 - 24.04.2008
Austria 5028442.1 23.12.2005 Patented 15.04.2006 - 10.03.2010
Belgium 5028442.l 23.12.2005 Patented - 10.03.2010
Brazil PlO0l 7535.8 22.10.2009 Patented 23.09.2003 -
Bulgaria 109688 26.09.2006 Patented 29.03.2002 - 08.03.2010
Canada 2549558 20.06.2006 Patented 20.07.2000 - 31.08.2010
"'
a,, China
Cyprus
200510089504.6
5028442.1
27.07.2005
23.12.2005
Patented
Patented
18.01.2006 -
-
05.08.2010
10.03.2010
~1
C Czech Republic PV 2006-706 11.11.2006 Patented 16.01.2002 -
r ~
~
Denmark 5028442.1 23.12.2005 Patented 31.07.2006 - 10.03.2010 Ir-'
c:. El Salvador 2536/2006 19.05.2006 Patented 10.01.2001 -

F European Patent Office 5028442.l 23.12.2005 Patented 05.12.2001 - 10.03.2010
Finland 5028442.1 23.12.2005 Patented - 10.03.2010
France 5028442.l 23.12.2005 Patented - 10.03.2010
Germany 5028442.1 23.12.2005 Patented 24.08.2006 - 10.03.2010
Greece 5028442.1 23.12.2005 Patented - 10.03.2010
Guatemala PI20000002 25.07.2006 Patented - 13.07.2009
Hong Kong 6107837.6 13.07.2006 Patented 07.04.2006 - 16.04.2010
Hungarv P060087l 24.11.2006 Pending 28.07.2003 -
Indonesia W-00200802549 04.08.2008 Published -
Ireland, Republic of 5028442.1 23.12.2005 Patented - 10.03.2010
Israel - - - 30.06.2010 -
Italy 5028442.l 23.12.2005 Patented - 10.03.2010
Japan 2006-190034 12.01.2000 Patented 09.09.2003 - 12.03.2010
South Korean 7002656/2007 01.02.2007 Pending 16.02.2007 -
Latvia 5028442. l 12.01.2000 Patented - 10.03.2010
Lithuania 5028442.1 12.01.2000 Patented - 10.03.2010
Luxembourg 5028442. l 23.12.2005 Patented 13.12.2006 - 10.03.2010
Macedonia 5028442. l 12.01.2000 Patented - 10.03.2010
Monaco 5028442.l 23.12.2005 Patented - 10.03.2010
Morocco 5028442.1 23.12.2005 - 01.04.2004 -
Netherlands 5028442.l 20.07.2004 Patented 01.12.2006 - 10.03.2010
New Zealand 534209 20.07.2004 Abandoned 28.11.2008 -
Norway 20055863 01.12.2005 Pending 05.02.2007 -
Poland 386517 06.11.2008 Pending 06.09.2004 -
-
~ ti
Protugal 5028442.1 23.12.2005 Patented 31.05.2006 10.03.2010
~ Romania 5028442.1 12.01.2000 Patented - 10.03.2010
at Serbia P-491/0 l 05.10.2010 Un.filed -
~
0 Slovakia pp 5096-2006 13.11.2006 Patented 04.04.2002 -
c-, Slovenia 5028442. l 12.01.2000 Patented 30.06.2006 - 10.03.2010
-f ,r
~
Spain 5028442.1 23.12.2005 Patented 16.07.2006 - 10.03.2010
g Sweden 5028442.1 23.12.2005 Patented - 10.03.2010
~ Switzerland 5028442.1 23.12.2005 Patented - 10.03.2010
United Kingdom 5028442.1 23.12.2005 Patented - 10.03.2010
Yours faithfully,
~
[SWATI PAHUJA]
FORM3
(39 OF 1970)
AND
[SeeSection 8; rule 12)
We, BAYER CORPORATION, a U.S. corporation of 100 Bayer Road, Pittsburgh,

hereby declare:-
(i) that We who have made this application No. 1633/MUMNP /2007 dated
05.10.2007 <alone/jointly > made for the same/ substantially same invention
application(s) for patent in other countries, the particulars of which are attached
herewith:
SEE ANNEXURE
(ii) that the rights in the application(s) have been assigned to: No one
that <I/we> undertake that up to the date of grant of the patent by the Controller,
I/ we would keep him informed in writing the details regarding corresponding
Dated 11th October, 2012
(
OF P EXIO LEGAL
ATTORNEY FOR THE APPLICANT
TO
IITRUE COPYjl
ANNEXURE TO FORM 3
Application Number: 1633/MUMNP/2007 {Divisional out of 215758)

I . . ; . , • -
Name of the Country Date of Application Status of the Date of Date of

application number application publication grant
United states of America 08.01.2002 09/889,227 Granted 01.04.2008
United states of America 10.09.2001 09/948, 915 Abandoned 11.04.2002 -

United states of America 13.12.2007 11/956, 111 Pending 26.06.2008 -
United states of America 07.02.2001 09/777,920 Granted 07.11.2002 19.04.2011
Brazil - PI 0007487-0 - 23.09.2003 -
Cuba 13.07.2001 2001-0168 - - -
China 12.01.2000 00802685.8 - 05.08.2009 -
Colombia 13.012000 00001451 - - -
Czech Republic - PV 2001-2489 Granted - -
Europe 12.01.2000 00 903239.2 Granted - 22.03.2006
Israel 27.06.2001 144030 - 30.06.2010 -
Malaysia 13.01.2000 PI20000102 Pending - -
New Zealand 27.07.2001 513079 - 31.08.2001 -
New Zealand 20.07.2007 556598 Granted 08.11.2008 -
Norway 12.07.2001 20013463 Granted - -
Philippines 12.01.2000 1-2000-00073 - - -
Pakistan - 28/2000 - - -
Poland - 360085 - - -
Russia 12.12.2000 2001122818/0 - - -
4 (024513)
Taiwan - 89100575 - - -
Uruguay 25.02.2000 N° 26038 - -~ -
IITRUE COPYII
FORM3
(39 OF 1970) E-
\0 If '5076/?-bf 'L
AND
THE PATENTS RULES,2003
[SeeSection 8; rule 12]
We, BAYER CORPORATION, a U.S. corporation of 100 Bayer Road, Pittsburgh,

hereby declare:-
(i) that We who have made this application No. 1633/MUMNP /2007 dated
05.10.2007 <alone/jointly > made for the same/ substantially same invention
application(s) for patent in other countries, the particulars of which are attached
herewith:
SEE ANNEXURE
(ii) that the rights in the application(s) have been assigned to: No one
that we undertake that up to the date of grant of the patent by the Controller, we
Dated 11th October, 2012
(SA_~_ KUMAR)
OF PERFEXIOLEGAL
ATTORNEYFOR THE APPLICANT
TO
IITRUE COPY!I
ANNEXURE TO FORM 3
Application Number: 1633/MUMNP/2007 (Divisional out of 215758)
Name of the Country Date of Application Status of the Patent Number Date of
application number application grant
United states of America 25.02.1999 09/257,266 Abandoned - -
United states of America 13.07.2001 09/889,227 Granted 7315834 01.04.2008
United states of America 13.12.2007 11/956, 111 Pending - -
Unitedstates of America 10.09.2001 09/948, 915 Abandoned - -
Unitedstates of America 27.08.2007 11/845,595 Allowed - -
Unitedstates of America 22.10.1999 09/425,228 Abandoned - -
Unitedstates of America 12.01.2000 09/758,548 Abandoned - -
Unitedstates of America 07.02.2001 09/777,920 Granted 7928239 19.04.2011
Unitedstates of America 11.02.2002 10/071,248 Granted 7528255 05.05.2009
i--l
Albania 12.01.2000 00903239.2 Granted AL/P /2006/1850 22.03.2006
~
8~
Albania 12.01.2000 05028442.1 Granted 1690853 10.03.2010 :
Argentina 13.01.2000 000100153 Granted AR005711Bl 23.11.2010
'"ti Argentina 15.07.2010 20100102601 Pending - -
Austria 12.01.2000 00903239.2 Granted 1140840 22.03.2006
-·
. Austria 23.12.2005 5028442.1 Granted 1690853 10.03.2010
~
Australia 12.01.2000 25016/00 Abandoned - -
0 Australia 24.02.2004 2004200722 Granted 2004200722 24.04.2008
("""> Belgium 12.01.2000 00903239.2 Granted 1140840 22.03.2006
--1 Belgium 23.12.2005 05028442.1 Granted 1690853 10.03.2010
~
Bulgaria 01.08.2001 105763 Granted 65158 29.01.2007 •
~ Bulgaria 26.09.2006 109688 Granted 65945 08.03.2010
Bolivia - SP-200012 Granted 119/2005 27.09.2005
Brazil 12.01.2000 PI 0007487.0 Pending - -
•) Brazil 22.10.2009 PI0017535.8 Pending - -
. Bahama Islands 25.02.2000 1213 Granted 1213 18.12.2002
Canada 12.07.2001 2359510 Granted 2359510 13.02.2007
1
ANNEXURE TO FORM 3
Canada 20.06.2006 2549558 Granted 2549558 31.08.2010 .

Switzerland 12.01.2000 00903239.2 Granted 1140840 22.03.2006
Switzerland 23.12.2005 5028442.1 Granted 1690853 10.03.2010
Chile 12.01.2000 71-2000 Pending - -
China 11.07.2001 00802685.8 Granted 1219764 21.09.2005
China 27.07.2005 200510089504.6 Granted 200510089504.6 05.08.2009
Colombia 13.012000 00001451 Granted 28604 29.07.2006
Cuba 13.07.2001 168/2001 Granted 2004-172 20.02.2008
Cyprus 12.01.2000 00903239.2 Granted 1140840 22.03.2006
Cyprus 23.12.2005 05028442.1 Granted 1690853 10.03.2010
Czech Republic 09.07.2001 PV 2001-2489 Granted 299125 19.03.2008
Czech Republic 11.11.2006 PV 2006-706 Granted 302846 14.12.2011
Germany 12.01.2000 00903239.2 Granted 60026822.5 22.03.2006
Germany 23.12.2005 5028442.1 Granted 1690853 10.03.2010
11~
-<
Denmark
Denmark
Dominican Rep.
12.01.2000
23.12.2005
12.01.2000
00903239.2
05028442.1
-
Granted
Granted
Granted
1140840
1690853
422
22.03.2006
10.03.2010
06.11.2002
-
~
0
Algeria
Ecuador
Estonia
Egypt
12.01.2000
12.01.2000
12.07.2001
15.01.2000
0006/2000
SP-200-3318
P200100368
39/2000
Granted
Pending
Granted
Granted
3004
-
04913
24407
27.03.2004 :
-
15.10.2007
20.05.2009
.
•
0
--1 European Patent Office 23.12.2005 5028442.1 Granted 1690853 10.03.2010
Spain 12.01.2000 00903239.2 Granted 1140840 22.03.2006 .
;
r'1
Spain
Finland
23.12.2005
12.01.2000
5028442.1
00903239.2
Granted
Granted
1690853
1140840
10.03.2010
22.03.2006
Finland 23.12.2005 5028442.1 Granted 1690853 10.03.2010
- France
France
United Kingdom
12.01.2000
23.12.2005
00903239.2
5028442.1
Granted
Granted
Granted
1140840
1690853
22.03.2006
10.03.2010
22.03.2006
·
•
'
23.12.2005 00903239.2 1140840
.J
2
ANNEXURE TO FORM 3
United kingdom 23.12.2005 5028442.1 Granted 1690853 10.03.2010

Greece 12.01.2000 00903239.2 Granted 1140840 22.03.2006
Greece 23.12.2005 5028442.1 Granted 1690853 10.03.2010
Guatemala 12.01.2000 PI2000 / 0002 Granted 5128 27.08.2007
Guatemala 25.07.2006 PI20000002 Granted 5247 13.07.2009
Hong Kong 20.09.2002 02106872.8 Granted HK1045504 07.04.2006
Hong Kong 13.07.2006 06107837.6 Granted HK1087689 16.04.2010
Honduras - PI/ US2000/ 07 Granted 3.844 15.08.2001
Croatia 12.01.2000 P20010580A Granted P20010580 07.07.2010
Haiti 10.05.2002 - Granted No. 285 Reg. 5 10.05.2004
Hungary 13.07.2001 P0300866 Granted 225780 30.07.2007
,...,, Hungary 24.11.2006 P0600871 Pending - -
Indonesia 12.01.2000 W-00200101747 Granted 1D0022302 14.11.2008
~\~
Indonesia 04.08.2008 W-00200802549 Allowed - -
Ireland, republic of 12.01.2000 00903239.2 Granted 1140840 22.03.2006
Ireland, republic of 23.12.2005 5028442.1 Granted 1690853 10.0.2010
~ Israel 12.01.2000 144030 Granted 144030 01.10.2010
Iran 13.01.2000 37810035 Granted 26555 17.07.2000
-I Italy 12.01.2000 00903239.2 Granted 1140840 22.03.2006
I..O Italy 23.12.2005 5028442.1 Granted 1690853 10.03.2010
0 Jamaica 13.01.2000 18/1/3974 Granted 3746 28.02.2008
("")
Jordon 13.01.2000 137/5 Granted 2373 22.10.2006
-I
~
Japan 10.07.2001 2000-593580 Granted 3845792 01.09.2006
c::> Japan 12.01.2000 2006-190034 Granted 4472669 12.03.2010 .
~ Korea, South 12.07.2001 7008847/ 2001 Granted 10-0719166 10.05.2007
Korea, South 01.02.2007 7002656/ 2007 Abandoned - -
X
...w
Korea, South
Kosovo
Kuwait
26.05.2011
18.11.2008
12.01.2000
10-2011-7012056
P-980/08
2PA/2000
Granted
Granted
Pending
10-1091101
527/2012
-
01.12.2011
18.04.2012
-
3
ANNEXURE TO FORM 3
Application Number: 1633/MUMNP/2007 {Divisional out of 215758)
Lebanon 12.01.2000 6124 Granted - -

Lithuania 12.01.2000 00903239.2 Granted 1140840 22.03.2006
Lithuania 12.01.2000 5028442.1 Granted 1690853 10.03.2010
Luxembourg 12.01.2000 00903239.2 Granted 1140840 22.03.2006
Luxembourg 23.12.2005 5028442.1 Granted 1690853 10.03.2010
Latvia 12.01.2000 00903239.2 Granted 1140840 22.03.2006
Latvia 12.01.2000 5028442.1 Granted 1690853 10.03.2010
Morocco 12.01.2000 2077 Abandoned - -
Morocco 12.01.2000 26289 Granted 26038 01.04.2004
Monaco 12.01.2000 00903239.2 Granted 1140840 22.03.2006
Monaco 23.12.2000 5028442.1 Granted 1690853 10.03.2010
"""3
Montenegro 17.10.2008 P-369/08 Allowed - -
Macedonia 12.01.2000 00903239.2 Granted MK/P /2006/72 22.03.2006
ii~
Macedonia 12.01.2000 5028442.1 Granted 1690853 10.03.2010
Mexico 12.07.2001 P AA2001007118 Granted 238942 26.07.2006
Malaysia 13.01.2000 PI20000102 Granted MY-138897-A 28.08.2009
-
-<
'-0
0
0
Nigeria
Nicaragua
Netherlands
Netherlands
13.01.2000
12.01.2000
12.01.2000
20.07.2004
03/2000
84897-1
00903239.2
5028442.1
Granted
Granted
Granted
Granted
13791
1442
1140840
1690853
13.01.2000
20.11.2001
22.03.2006
10.03.2010
-I Norway 12.07.2001 20013463 Granted 321059 06.03.2006
~
c::::::,
Norway 12.01.2005 20055863 Pending - -
~
New Zealand 12.01.2000 513079 Pending - -
New Zealand 20.07.2004 534209 Abandoned - -
New Zealand 18.07.2007 556598 Granted 556598 12.03.2009
New Zealand 16.07.2008 569864 Abandoned - -
-
~
Panama 12.01.2001 99/084897 Granted 84897-01
Peru 07289 Abandoned - -
\~ Philippines 12.01.2000 1-2000-00073 Published - -
-
4
ANNEXURE TO FORM 3
Pakistan 13.01.2000 28/2000 Pending

Poland 13.07.2001 P-360085 Granted 203687 21.10.2009
Poland 06.11.2008 P-386517 Pending - -
Portugal 12.01.2000 00903239.2 Granted 1140840 22.03.2006
Portugal 23.12.2005 5028442.1 Granted 1690853 10.03.2010
Paraguay - 6/2000 Published - -
Romania 12.01.2000 00903239.2 Granted 1140840 22.03.2006
Romania 12.01.2000 5028442.1 Granted 1690853 10.03.2010
Russia Federation 12.01.2000 2001122818 Granted 2319693 20.03.2008
Sweden 12.01.2000 00903239.2 Granted 1140840 22.03.2006
Sweden 23.12.2005 5028442.1 Granted 1690853 10.03.2010 .
Singapore 12.01.2000 200104237-3 Granted 82244 27.02.2004
~\~~
Slovenia 12.01.2000 00903239.2 Granted 1140840 22.03.2006
Slovenia 12.01.2000 5028442.1 Granted 1690853 10.03.2010
Slovakia 12.01.2000 PV0988-2001 Granted 285532 10.01.2007
Slovakia 13.11.2006 pp 5096-2006 Granted 287419 14.07.2010
El Salvador 12.01.2000 012000000004 Granted 00247 28.09.2006
~ El Salvador 19.05.2006 2536/2006 Pending - -
\...0 Thailand 11.01.2000 055106 Published - -
0 Tangier 12.01.2000 1836 Pending - -
n Tunisia 12.01.2000 SN.00.010 Granted 17404 17.02.2002
-I Turkey 12.07.2001 Granted TR200102020 23.01.2006
2001/02020
I'->
c:> Trinidad & Tobago 12.01.2000 TT/ A/2001/00124 Pending - -
~ Taiwan 13.01.2000 89100575 Granted 1269791 01.01.2007
Ukraine 30.07.2001 2001075426 Granted 73731 -
Uruguay 25.02.2000 26038 Granted 14.351 01.09.2010
Venezuela 12.01.2000 000107-2000 Published - -
I Vietnam 09.07.2001 1-2001-00644 Granted 7318 20.10.2008
1~\ Serbia 11.07.2001 P-491/01 Granted 51497 23.12.2010
5
~-,'3,\\ '-\~t\\\C)..o ,~1\
FORM3 ORIGINAL
(39 OF 1970)
&
ff-We, BAYER CORPORATION, a U.S. corporation of 100 Bayer Road, Pittsburgh,

Pennsylvania, 15205 U.S.A.,
hereby declare:-
[i] that Ifwe who have made this application No. 1633/MUMNP /2007 dated
October 05, 2007 alone/jointly made for the same/ substantially same
[ii] that the rights in the application[s] l½asfhave been assigned to: No one
Dated this 8th day of April, 2014.

~
UMAR)
P T AGENT
OF RFEXIO LEGAL
TO
THE PATENT OFFICE,
MUMBAI
IITRUE COPYII
F1S APR2014
ANNEXTURE TO FORM 3 DATED APRIL 8, 2014
Application Number: 1633/MUMNP/2007
Name of the Date of Application Status of the Date of Date of Patent Number
Country Application Number Application Publication Grant
Chile 12/01/2000 71-2000 Granted - - -
Ecuador 12/01/2000 SP-200-3318 Granted - - -
Denmark - 093239.2, SPC CA Granted - - -
2007 00002
Indonesia 04/08/2008 W-00200802549 Granted - - -
Nigeria - 36586 Granted - - -
New Zealand 16/07/2008 569864 Granted - - -
Philippines 12/01/2000 1-2000-00073 Granted - - -
~ Poland 06/11/2008 P-386517 Granted - - -
"'- N Paraguay - 36678 Pending - - -
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~-,'3,\\ '-\~t\\\C)..o ,~1\
FORM3 ORIGINAL
(39 OF 1970)
&
ff-We, BAYER CORPORATION, a U.S. corporation of 100 Bayer Road, Pittsburgh,

hereby declare:-
[ii] that the rights in the application[s] l½asfhave been assigned to: No one

~
UMAR)
P T AGENT
OF RFEXIO LEGAL
TO
THE PATENT OFFICE,
MUMBAI
IITRUE COPYII
F1S APR2014
Name of the Date of Application Status of the Date of Date of Patent Number
Country Application Number Application Publication Grant
Chile 12/01/2000 71-2000 Granted - - -
Ecuador 12/01/2000 SP-200-3318 Granted - - -
Denmark - 093239.2, SPC CA Granted - - -
2007 00002
Indonesia 04/08/2008 W-00200802549 Granted - - -
Nigeria - 36586 Granted - - -
New Zealand 16/07/2008 569864 Granted - - -
Philippines 12/01/2000 1-2000-00073 Granted - - -
~ Poland 06/11/2008 P-386517 Granted - - -
"'- N Paraguay - 36678 Pending - - -
,--J
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Page 1 of 1
FORM3
ORIGINAL
(39 OF 1970)
&
IfWe, BAYER CORPORATION, a U.S. corporation of 100 Bayer Road, Pittsburgh,

hereby declare:-
[ii] that the rights in the application[s] oosfhave been assigned to: No one
UMAR)
TENT AGENT
0 PERFEXIO LEGAL
TO
THE PATENT OFFICE,
MUMBAI
\1 7 APR2014
IITRUE COPY!I
Name of the Date of Application Status of the Date of I Date of Patent Number
Application Number Application Publication Grant
13/10/2006 91280 Granted 13/12/2006 91280
13Lo1;2000 6L2000 Pendin:
...,
~
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Page 1 of 1
FORM 3
(39 OF 1970)
&
I/We, BAYER CORPORATION, a US corporation of 100 Bayer Road, Pittsburgh,

Pennsylvania, 15205, United States of America,
hereby declare-
[i] that I/We who have made this application No. 1633/MUMNP/2007 dated
October 5, 2007 alone/jointly made for the same/substantially same invention,
application[s] for patent in the other countries, the particulars of which are given
below:
Name of the country Date of Application Status of the Date of Date of

application number application publication grant
BRAZIL October 22, PI0017535.8 PENDING - -
2009
HUNGARY November P0600871 PENDING - -

24, 2006
KUWAIT January 12, 2PA/2000 PENDING - -

2000
MONTENEGRO October 17, P-369/08 PENDING - -

2008
PAKISTAN January 13, 28/2000 PENDING - -

2000
PAKISTAN March 7, 155/2014 PENDING - -

2014
PARAGUAY January 13, 6/2000 PENDING - -

2000
EL SALVADOR August 14, 2014004787 PENDING - -

2014
TANGIER January 12, 1836 PENDING - -

2000
TRINIDAD AND January 12, TT/A/2001 PENDING - -

TOBAGO 2000 /00124
Page 1 of 11
UNITED STATES OF July 13, 2001 09/889,227 GRANTED - April 1,
AMERICA 2008
ALBANIA January 12, 05028442.1 GRANTED - March 10,

2000 2010
ALBANIA January 12, 00903239.2 GRANTED - -

2000
ARGENTINA January 13, 000100153 GRANTED - November

2000 23, 2010
AUSTRIA January 12, 00903239.2 GRANTED - March 22,

2000 2006
AUSTRIA December 23, 05028442.1 GRANTED - March 10,

2005 2010
AUSTRIA November SZ 35/2006 GRANTED - May 29,

10, 2006 2008
AUSTRALIA February 24, 2004200722 GRANTED - April 24,

2004 2008
BELGIUM January 12, 00903239.2 GRANTED - March 22,

2000 2006
BELGIUM December 23, 05028442.1 GRANTED - March 10,

2005 2010
BELGIUM December 6, 2006C/039 GRANTED - -

2006
BULGARIA August 1, 105763 GRANTED - January 29,

2001 2007
BULGARIA September 109688 GRANTED - March 8,

26, 2006 2010
BOLIVIA, - SP-200012 GRANTED - September

PLURINATIONAL 27, 2005
STATE OF
BRAZIL January 12, P10007487.0 GRANTED - July 7, 2015
2000
CANADA July 12, 2001 2359510 GRANTED - February

13, 2007
CANADA June 20, 2006 2549558 GRANTED - August 31,

2010
Page 2 of 11
SWITZERLAND January 12, 00903239.2 GRANTED - March 22,
2000 2006
SWITZERLAND December 23, 05028442.1 GRANTED - March 10,

2005 2010
SWITZERLAND August 25, C01140840/01 GRANTED - April 30,

2006 2008
CHILE January 13, 71-2000 GRANTED - April 19,

2000 2013
CHINA July 11, 2001 00802685.8 GRANTED - September

21, 2005
CHINA July 27, 2005 200510089 GRANTED - August 5,

504.6 2009
COLOMBIA January 13, 00001451 GRANTED - July 29,

2000 2006
CUBA July 13, 2001 2001-0168 GRANTED - February

20, 2008
CYPRUS January 12, 00903239.2 GRANTED - March 22,

2000 2006
CYPRUS December 23, 05028442.1 GRANTED - March 10,

2005 2010
CYPRUS January 18, 00903239.2 GRANTED - -

2007
CZECH REPUBLIC July 9, 2001 PV 2001-2489 GRANTED - March 19,

2008
CZECH REPUBLIC November PV2006-706 GRANTED - December

11, 2006 14, 2011
CZECH REPUBLIC - SPC GRANTED - March 15,

/CZ2008-126 2016
GERMANY January 12, 00903239.2 GRANTED - March 22,

2000 2006
GERMANY December 23, 05028442.1 GRANTED - March 10,

2005 2010
GERMANY November 9, 12200600 GRANTED - February

2006 0059.3 11, 2013
Page 3 of 11
DENMARK January 12, 00903239.2 GRANTED - March 22,
2000 2006
DENMARK December 23, 05028442.1 GRANTED - March 10,

2005 2010
DENMARK January 16, CA 2007 00002 GRANTED - June 16,

2007 2008
DOMINICAN January 12, - GRANTED - November

REPUBLIC 2000 6, 2002
ALGERIA January 12, 0006/2000 GRANTED - March 27,

2000 2004
ESTONIA July 12, 2001 P200100368 GRANTED - October 15,

2007
ESTONIA December 6, P200100368 GRANTED - April 18,

2007 2016
EGYPT January 15, 39/2000 GRANTED - May 20,

2000 2009
EUROPEAN January 12, 00903239.2 GRANTED - March 22,

PATENT OFFICE 2000 2006
(EPO)
EUROPEAN December 23, 05028442.1 GRANTED - March 10,
(EPO)
SPAIN January 12, 00903239.2 GRANTED - March 22,
2000 2006
SPAIN December 23, 05028442.1 GRANTED - March 10,

2005 2010
SPAIN January 16, C 200700001 GRANTED - -

2007
FINLAND January 12, 00903239.2 GRANTED - March 22,

2000 2006
FINLAND December 23, 05028442.1 GRANTED - March 10,

2005 2010
FINLAND December 19, L20060018 GRANTED - February

2006 22, 2011
FRANCE January 12, 00903239.2 GRANTED - March 22,

2000 2006
Page 4 of 11
FRANCE December 23, 05028442.1 GRANTED - March 10,
2005 2010
FRANCE October 27, 06C0034 GRANTED - -

2006
UNITED KINGDOM January 12, 00903239.2 GRANTED - March 22,

2000 2006
UNITED KINGDOM December 23, 05028442.1 GRANTED - March 10,

2005 2010
UNITED KINGDOM December 27, SPC/GB07 GRANTED - April 14,

2006 /004 2008
GREECE January 12, 00903239.2 GRANTED - March 22,

2000 2006
GREECE December 23, 05028442.1 GRANTED - March 10,

2005 2010
GREECE November 20060800029 GRANTED - -

15, 2006
GUATEMALA January 12, PI2000/0002 GRANTED - September

2000 10, 2014
GUATEMALA July 25, 2006 PI20000002 A GRANTED - July 13,

2009
THE HONG KONG September 02106872.8 GRANTED - April 7,

SPECIAL 20, 2002 2006
ADMINISTRATIVE
REGION OF THE
PEOPLE’S REPUBLIC
OF CHINA
THE HONG KONG July 13, 2006 06107837.6 GRANTED - April 16,
SPECIAL 2010
ADMINISTRATIVE
REGION OF THE
PEOPLE’S REPUBLIC
OF CHINA
HONDURAS - PI/US2000/07 GRANTED - August 15,
2001
CROATIA January 12, P20010580A GRANTED - July 7, 2010

2000
CROATIA January 12, P20010580A GRANTED - February 2,

2000 2016
Page 5 of 11
HAITI May 10, 2002 - GRANTED - May 10,
2004
HUNGARY July 13, 2001 P0300866 GRANTED - July 30,

2007
HUNGARY November S070007 GRANTED - October 10,

20, 2007 2008
INDONESIA January 12, W-00200 GRANTED - November

2000 101747 14, 2008
INDONESIA August 4, W-00200 GRANTED - September

2008 802549 7, 2012
IRELAND January 12, 00903239.2 GRANTED - March 22,

2000 2006
IRELAND December 23, 05028442.1 GRANTED - March 10,

2005 2010
IRELAND October 16, 2006/031 GRANTED - -

2006
ISRAEL January 12, 144030 GRANTED - October 1,

2000 2010
INDIA July 5, 2001 200100799 GRANTED - March 3,

2008
IRAN (ISLAMIC January 13, 37810035 GRANTED - July 17,

REPUBLIC OF) 2000 2000
ITALY January 12, 00903239.2 GRANTED - March 22,

2000 2006
ITALY December 23, 05028442.1 GRANTED - March 10,

2005 2010
ITALY January 16, UB2007CC GRANTED - May 30,

2007 P944 2007
JAMAICA January 13, 18/1/3974 GRANTED - February

2000 28, 2008
JORDAN January 13, 137/5 GRANTED - October 22,

2000 2006
JAPAN July 10, 2001 2000-593580 GRANTED - September

1, 2006
Page 6 of 11
JAPAN January 12, 2006-190034 GRANTED - March 12,
2000 2010
JAPAN September 2014-700173 GRANTED - August 5,

19, 2014 2015
REPUBLIC OF July 12, 2001 7008847/2001 GRANTED - May 10,

KOREA 2007
REPUBLIC OF May 26, 2011 10-2011- GRANTED - December

KOREA 7012056 1, 2011
KOSOVO November P-980/08 GRANTED - April 18,

18, 2008 2012
LEBANON January 12, 6124 GRANTED - -

2000
LITHUANIA January 12, 00903239.2 GRANTED - March 22,

2000 2006

2000 2010
LITHUANIA December 18, PA2006008 GRANTED - September

2006 25, 2007
LUXEMBOURG January 12, 00903239.2 GRANTED - March 22,

2000 2006
LUXEMBOURG December 23, 05028442.1 GRANTED - March 10,

2005 2010
LUXEMBOURG October 13, 91280 GRANTED - December

2006 13, 2006
LATVIA January 12, 00903239.2 GRANTED - March 22,

2000 2006

2000 2010
LATVIA October 24, 00903239.2 GRANTED - -

2006
MOROCCO January 12, 26289 GRANTED - April 1,

2000 2004
MONACO January 12, 00903239.2 GRANTED - March 22,

2000 2006
Page 7 of 11
MONACO December 23, 05028442.1 GRANTED - March 10,
2005 2010
THE FORMER January 12, 00903239.2 GRANTED - March 22,

YUGOSLAV 2000 2006
REPUBLIC OF
MACEDONIA
THE FORMER January 12, 05028442.1 GRANTED - March 10,
YUGOSLAV 2000 2010
REPUBLIC OF
MACEDONIA
MEXICO July 12, 2001 PAA200100 GRANTED - July 26,
7118 2006
MALAYSIA January 13, PI 20000102 GRANTED - August 28,

2000 2009
NIGERIA January 13, 03/2000 GRANTED - January 13,

2000 2000
NICARAGUA January 12, 84897-1 GRANTED - November

2000 20, 2001
NETHERLANDS January 12, 00903239.2 GRANTED - March 22,

2000 2006
NETHERLANDS December 23, 05028442.1 GRANTED - March 10,

2005 2010
NETHERLANDS October 12, 300242 GRANTED - -

2006
NORWAY July 12, 2001 20013463 GRANTED - March 6,

2006
NORWAY December 9, 20055863 GRANTED - March 7,

2005 2016
NORWAY January 5, 321059 GRANTED - -

2007
NEW ZEALAND July 18, 2007 556598 GRANTED - March 12,

2009
PANAMA January 12, 99/084897 GRANTED - -

2001
PHILIPPINES January 12, 1-2000-00073 GRANTED - June 30,

2001 2009
Page 8 of 11
POLAND July 13, 2001 P-360085 GRANTED - October 21,
2009
POLAND November 6, P-386517 GRANTED - October 24,

2008 2013
POLAND November 150/203687 GRANTED - June 6, 2012

19, 2009
PORTUGAL January 12, 00903239.2 GRANTED - March 22,

2000 2006
PORTUGAL December 23, 05028442.1 GRANTED - March 10,

2005 2010
PORTUGAL October 30, 241 GRANTED - -

2006
ROMANIA January 12, 00903239.2 GRANTED - March 22,

2000 2006

2000 2010
SERBIA July 11, 2001 P-491/2001 GRANTED - December

23, 2010
RUSSIAN January 12, 2001122818 GRANTED - March 20,

FEDERATION 2000 2008
SWEDEN January 12, 00903239.2 GRANTED - March 22,

2000 2006
SWEDEN December 23, 05028442.1 GRANTED - March 10,

2005 2010
SWEDEN January 16, 0790003-8 GRANTED - -

2007
SINGAPORE January 12, 200104237-3 GRANTED - February

2000 27, 2004
SLOVENIA January 12, 00903239.2 GRANTED - March 22,

2000 2006

2000 2010
SLOVENIA November P200030837 GRANTED - April 25,

21, 2006 2007
Page 9 of 11
SLOVAKIA January 12, PV0988-2001 GRANTED - January 10,
2000 2007
SLOVAKIA November PP 5096-2006 GRANTED - July 14,

13, 2006 2010
EL SALVADOR January 12, 012000000004 GRANTED - September

2000 28, 2006
EL SALVADOR May 19, 2006 2536/2006 GRANTED - December

15, 2015
TUNISIA January 12, SN.00.010 GRANTED - February

2000 17, 2002
TURKEY July 12, 2001 2001/02020 GRANTED - January 23,

2006
TAIWAN, April 7, 2000 89100575 GRANTED - January 1,

PROVINCE OF 2007
CHINA
UKRAINE July 30, 2001 2001075426 GRANTED - -
URUGUAY February 25, 26.038 GRANTED - September

2000 1, 2010
VIET NAM July 9, 2001 1-2001-00644 GRANTED - October 20,

2008
SOUTH AFRICA January 12, 2001/5751 GRANTED - September

2000 23, 2003
UNITED STATES OF December 13, 11/956,111 PUBLISHED - -

AMERICA 2007
ALBANIA January 12, 00903239.2 PUBLISHED - March 22,

2000 2006
THAILAND January 11, 0001000072 PUBLISHED -

2000
VENEZUELA, January 12, 000107-2000 PUBLISHED - -

BOLIVARIAN 2000
REPUBLIC OF
[ii] that the rights in the application[s] has/have been assigned to : No one
[iii] that I/we undertake that upto the date of grant of the patent by the Controller, I/ we
Page 10 of 11
Dated this 10th day of June, 2016
(SANJAY KUMAR)
PATENT AGENT NO. IN/PA-202
OF PERFEXIO LEGAL
To,
The Patent Office,
MUMBAI
Page 11 of 11
FORM3
(39 of 1970)
and
THE PA TENTS RULES, 2003
(See section 8; Rule 12)
1. Name of the applicant(s). If We, BAYER CORPORATION, a US corporation of 100

Bayer Road, Pittsburgh, Pennsylvania, 15205, United States
of America,
hereby declare:
2. Name, address and nationality of (i) lllat IfWe ha•re Rat maae aAy applie-t=iefl-fef--4Ae
the joint applicant. same/substantially the same inYeRtieAeutsiae lAEiia
Gf
(ii) that lfWe who have made this Application o.

1633/MUMNP /2007 dated October 5, 2007 alonefjei:Rtly
made for the same/ substantially same invention,
application[s] for patent in the other countries, the
particulars of which are given below: I
ame of the Date of Application Status of the Date of Date of
country application number application publication grant
I
BRAZIL October 22, PIO0l7535.8 PENDING - -
2009
HUNGARY November P0600871 PENDING - -

24,2006
KUWAIT January 12, 2PA/2000 PENDING - -

2000
MONTENEGRO October 17, P-369/08 PENDING - -

2008
PAKISfAN January 13, 28/2000 PENDI G - -

2000
PAKISTAN March 7, 155/2014 PENDING - -

2014
I!
PARAGUAY January 13, 6/2000 PENDING - -
2000
EL SALVADOR August 14, 2014004787 PENDING - -

2014
TANGIER January 12, 1836 PENDING - -

2000
Page 1 of 10
~
IITRUE COPYII
TRINIDAD AND January 12, TT/ A/2001 PENDING - -
TOBAGO 2000 /00124
UNITED STA TES July 13, 2001 09/889,227 GRANTED - April 1,

OFAMERICA 2008
ALBANIA January 12, 05028442.1 GRANTED - March 10,

2000 2010
ALBANIA January 12, 00903239.2 GRANTED - -

2000
ARGENTINA January 13, 000100153 GRANTED - November

2000 23, 2010
AUSTRIA January 12, 00903239.2 GRANTED - March 22,

2000 2006
AUSTRIA December 23, 05028442.1 GRANTED - March 10,

2005 2010
AUSTRIA November S235/2006 GRANTED - May 29,

10,2006 2008
AUSTRALIA February 24, 2004200722 GRANTED - April 24,

2004 2008
BELGIUM January 12, 00903239.2 GRANTED - March 22,

2000 2006
BELGIUM December 23, 05028442.1 GRANTED - March 10,

2005 2010
BELGIUM December 6, 2006C/039 GRANTED - -

2006
BULGARIA August 1, 105763 GRANTED - January

2001 29,2007
BULGARIA September 109688 GRANTED - March 8,

26,2006 2010
BOLIVIA, January 12, SP-200012 GRANTED - September

PLURINATIONA 2000 27,2005
LSTATEOF
BRAZIL January 12, P10007487.0 GRANTED - July 7,
2000 2015 I
CA ADA July 12, 2001 2359510 GRANTED - February
13,2007
CANADA June 20, 2006 2549558 GRANTED - August 31,

2010
Page 2 of 10
~
11TRUE COPYjl
SWITZERLAND January 12, 00903239.2 GRANTED - March 22,
2000 2006
SWITZERLAND December 23, 05028442.1 GRANTED - March 10,

2005 2010
SWITZERLAND August 25, C0l 140840/ 01 GRANTED - April 30,

2006 2008
CHILE January 13, 71-2000 GRANTED - April 19,

2000 2013
CHINA July 11, 2001 00802685.8 GRANTED - September

21, 2005
I
CHINA July 27, 2005 200510089 GRANTED - August 5,

504.6 2009
COLOMBIA January 13, 00001451 GRANTED - July 29,

2000 2006
CUBA July 13, 2001 2001-0168 GRANTED - February

20,2008
CYPRUS January 12, 00903239.2 GRANTED - March 22,

2000 2006
I
CYPRUS December 23, 05028442.1 GRANTED - March 10, I

2005 2010
I
CYPRUS January 18, 00903239.2 GRANTED - -
2007 I
I
CZECH July 9, 2001 PV 2001-2489 GRANTED - March 19, 1
REPUBLIC 2008
CZECH November PV2006-706 GRANTED - December

REPUBLIC 11,2006 14, 2011
CZECH July 21, SPC GRANTED - March 15,

REPUBLIC 2006 / CZ2008-126 2016
GERMANY January 12, 00903239.2 GRANTED - March 22, 1
2000 2006 I
GERMANY December 23, 05028442.1 GRANTED - March 10, I

2005 2010
GERMANY November 9, 12200600 GRANTED - February 1
2006 0059.3 11,2013

i
DENMARK January 12, 00903239.2 GRANTED - I March 22, '
2000 2006
i I
Page3 of 10
:E--
IITRUE COPYII
DENMARK December 23, 05028442.1 GRANTED - March 10,
2005 2010
DENMARK January 16, CA 2007 00002 GRANTED - June 16,

2007 2008
DOMINICAN January 12, - GRANTED - November

REPUBLIC 2000 6,2002
ALGERIA January 12, 0006/2000 GRANTED - March 27,

2000 2004
ESTONIA July 12, 2001 P200100368 GRANTED - October

15,2007
ESTONIA December 6, P200100368 GRANTED - April 18,

2007 2016
EGYPT January 15, 39/2000 GRANTED - May 20,

2000 2009
EUROPEAN January 12, 00903239.2 GRANTED - March 22,

(EPO)
EUROPEAN December 23, 05028442.1 GRANTED - March 10,
(EPO)
SPAIN January 12, 00903239.2 GRANTED - March 22, 1
2000 2006
I
SPAIN December 23, 05028442.1 GRANTED - March 10,
2005 2010
I
SPAIN January 16, C 200700001 GRANTED - -
2007 I
I
FINLAND January 12, 00903239.2 GRANTED - March 22, I

2000 2006
FINLAND December 23, 05028442.1 GRANTED - March 10,

2005 2010
FINLAND December 19, L20060018 GRANTED - February

2006 22,2011
I
FRANCE January 12, 00903239.2 GRANTED - March 22, 1
2000 2006
FRANCE December 23, 05028442.1 GRANTED - March 10,

2005 2010
FRANCE October 27, 06C0034 GRANTED - -

2006
I
> IITRUE
Page 4 of 10
&--
COPYII
UNITED January 12, 00903239.2 GRANTED - March 22,
KINGDOM 2000 2006
UNITED December 23, 05028442.1 GRANTED - March 10,

KINGDOM 2005 2010
UNITED December 27, SPC/GB07 GRANTED - April 14,

KINGDOM 2006 /004 2008
GREECE January 12, 00903239.2 GRANTED - March 22,

2000 2006
GREECE December 23, 05028442.1 GRANTED - March 10,

2005 2010
GREECE November 20060800029 GRANTED - -

15,2006
GUATEMALA January 12, Pl2000/0002 GRANTED - September

2000 10,2014
GUATEMALA July 25, 2006 PI20000002 A GRANTED - July 13,

2009
THE HONG September 02106872.8 GRANTED - April 7,

KONG SPECIAL 20,2002 2006
ADMINISfRATI
VE REGION OF
THE PEOPLE'S
REPUBLIC OF
CHINA
THE HONG July 13, 2006 06107837.6 GRANTED - April 16,
KONG SPECIAL 2010
ADMINISfRA TI
VE REGION OF
THE PEOPLE'S
REPUBLIC OF
CHINA
HONDURAS January 12, PI/US2000/07 GRANTED - August 15,
2000 2001
CROATIA January 12, P20010580A GRANTED - July 7,

2000 2010
CROATIA January 12, P20010580A GRANTED - February

2000 2,2016
I
HAITI May 10, 2002 09/257 266 GRANTED - May 10,
200-1
HUNGARY July 13, 2001 P0300866 GRANTED - July 30,

2007
Page 5 of 10
&--
IITRUE COPYII
HUNGARY November S070007 GRANTED - October
20,2007 10,2008
INDONESIA January 12, W-00200 GRANTED - November

2000 101747 14,2008
INDONESIA August 4, W-00200 GRANTED - September

2008 802549 7,2012
IRELAND January 12, 00903239.2 GRANTED - March 22,

2000 2006
IRELAND December 23, 05028442.1 GRANTED - March 10,

2005 2010
IRELAND October 16, 2006/031 GRANTED - .

2006
ISRAEL January 12, 144030 GRANTED . October 1,

2000 2010
IRAN (ISLAMIC January 13, 37810035 GRANTED - July 17,

REPUBLIC OF) 2000 2000
ITALY January 12, 00903239.2 GRANTED . March 22,

2000 2006
ITALY December 23, 05028442.1 GRANTED - March 10,

2005 2010
ITALY January 16, UB2007CC GRANTED - May 30,

2007 P944 2007
JAMAICA January 13, 18/1/3974 GRANTED - February

2000 28,2008
JORDAN January 13, 137/5 GRANTED - October I
2000 22, 2006

I
JAPAN July 10, 2001 2000-593580 GRANTED - September I
1,2006
JAPAN January 12, 2006-190034 GRANTED . March 12,

2000 2010
JAPAN September 2014-700173 GRANTED - August 5,

19,2014 2015
REPUBLIC OF July 12, 2001 7008847/2001 GRANTED . May 10,

KOREA 2007
REPUBLIC OF May 26, 2011 10-2011- GRANTED . December

KOREA 7012056 1, 2011 I
I
> Page 6 of 10
&--
IITRUE COPYII
KOSOVO November P-980/08 GRANTED - April 18,
18,2008 2012
LEBANON January 12, 6124 GRANTED - -

2000

2000 2006

2000 2010
LITHUANIA December 18, PA2006008 GRANTED - September

2006 25,2007
LUXEMBOURG January 12, 00903239.2 GRANTED - March 22,

2000 2006
LUXEMBOURG December 23, 05028442.1 GRANTED - March 10,

2005 2010
LUXEMBOURG October 13, 91280 GRANTED - December

2006 13,2006
I

2000 2006

2000 2010
LATVIA October 24, 00903239.2 GRANTED - -

2006
MOROCCO January 12, 26289 GRANTED - April 1,

2000 2004
MONACO January 12, 00903239.2 GRANTED - March 22,

2000 2006
MONACO December 23, 05028442.1 GRANTED - March 10,

2005 2010
THE FORMER January 12, 00903239.2 GRANTED - March 22, 1
YUGOSLAV 2000 2006

REPUBLIC OF
MACEDONIA
THE FORMER January 12, 05028442.1 GRANTED - March 10, 1
YUGOSLAV 2000 2010

REPUBLIC OF
MACEDONIA
MEXICO July 12, 2001 PAA200100 GRANTED - July 26,
7118 2006
Page 7 of 10
&--
IITRUE COPYjl
MALAYSIA January 13, PI 20000102 GRANTED - August 28,
2000 2009
NIGERIA January 13, 03/2000 GRANTED - January

2000 13,2000
NICARAGUA January 12, 84897-1 GRANTED - November

2000 20,2001
NETHERLANDS January 12, 00903239.2 GRANTED - March 22,

2000 2006
NETHERLANDS December 23, 05028442.1 GRANTED - March 10,

2005 2010
NETHERLANDS October 12, 300242 GRANTED - -

2006
NORWAY July 12, 2001 20013463 GRANTED - March 6,

2006
NORWAY December 9, 20055863 GRANTED - March 7,

2005 2016
NORWAY January 5, 321059 GRANTED - -

2007
EW ZEALAND July 18, 2007 556598 GRANTED - March 12,

2009
- -
PA AMA January 12,
2001
99/084897 GRANTED
I
PHILIPPINES January 12, 1-2000-00073 GRANTED - June 30,
2001 2009 I
I
POLAND July 13, 2001 P-360085 GRANTED - October
21, 2009 I
POLAND November 6, P-386517 GRANTED - October
2008 24, 2013
POLAND November 150/203687 GRANTED - June 6,

19,2009 2012 I
PORTUGAL January 12, 00903239.2 GRANTED - March 22,
2000 2006
I
PORTUGAL December 23, 05028442.1 GRANTED - March 10,

2005 2010
PORTUGAL October 30, 241 GRANTED - -

2006
Page 8 of 10
&--
IITRUE COPYjl
2000 2006

2000 2010
SERBIA July 11, 2001 P-491/2001 GRANTED - December

23,2010
RUSSIAN January 12, 2001122818 GRANTED - March 20,

FEDERATION 2000 2008
SWEDEN January 12, 00903239.2 GRANTED - March 22,

2000 2006
SWEDEN December 23, 05028442.1 GRANTED - March 10,

2005 2010
SWEDEN January 16, 0790003-8 GRANTED - -

2007
SINGAPORE January 12, 200104237-3 GRANTED - February

2000 27,2004

2000 2006

2000 2010
I
SLOVENIA ovember P200030837 GRANTED - April 25, I
21,2006 2007
I
I
SLOVAKIA January 12, PV0988-2001 GRANTED - January I

2000 10,2007
SLOVAKIA November pp 5096-2006 GRANTED - July 14,

13,2006 2010
EL SALVADOR January 12, 012000000004 GRANTED - September

2000 28,2006
EL SALVADOR May 19, 2006 2536/2006 GRANTED - December

15, 2015
TUNISIA January 12, SN.00.010 GRANTED - February

2000 17, 2002
I
TURKEY July 12, 2001 2001/02020 GRANTED - January I
23,2006
TAIWAN, April 7, 2000 89100575 GRANTED - January 1,

PROVINCE OF 2007
CHINA
Page 9 of 10
:E--
IITRUE COPYII
UKRAINE July 30, 2001 2001075426 GRANTED - -
URUGUAY February 25, 26.038 GRANTED - September
2000 1,2010
VIETNAM July 9, 2001 1-2001-00644 GRANTED - October

20,2008
SOUTH AFRICA January 12, 2001/5751 GRANTED - September

2000 23,2003
UNITED Sf ATES December 13, 11/956,111 PUBLISHED - -

OF AMERICA 2007
ALBANIA January 12, 00903239.2 PUBLISHED - March 22,

2000 2006
THAILAND January 11, 0001000072 PUBLISHED -

2000
VENEZUELA, January 12, 000107-2000 PUBLISHED - -

BOLIVARIAN 2000
REPUBLIC OF
3. Name and address of the assignee (iii) that the rights in the application(s) has/ have been
assigned to: None
that If-we undertake that upto the date of grant of the

patent by the Controller, If-we would keep him informed
in writing the details regarding corresponding applications
for patents filed outside India within six months from the
date of filing of such application.

/7
4. To be signed by the applicant or his Signature:
authorized registered patent agent.
~MAR)
PATENT AGENT . IN/PA-202
OE RFEXIO LEGAL
ATTORNEYS R THE APPLICANT
§. !>Jameef lfle Aal:tual 13eFseAwhe has (..........................
)
, .,, ..___
.... ~
To,
The Patent Office,
at Mumbai I
Page 10 of 10
:1!!E--
IITRUE COPYjl
WE CLAIM:
1. A compound of Fomula 1: A - D - B (I), or a pharmaceutically

acceptable salt thereof, wherein
Dis -NH-C(O)-NH-,
A is a substituied moiety of the formula: -L-M-L 1,
wherein
Lis phenyl, optionally substituted by halogen, up to per-halo, and Wn, where n is 0-3;
wherein and each W is independently selected from the group consisting of C1-Cs
linear or branched alkyl, C 1-C5 linear or branched haloalkyl up to perhaloalkyl and C1-
C3 alkoxy
L 1 is selected from pyridinyl substituted by -C(O)Rx, and optionally substituted with 1-

3 additional substituents independently selected from the group consisting of R 7 and
halogen; wherein R is NRaRband Ra and Rb are:
i) independently
a) hydrogen,
b) C 1-C 10alkyl,
c) C6aryl,
d) pyridinyl
e) substituted C1-10 alkyl,
f) substituted C6 ary],
k) -ethylpiperidyl,
1) -methyl pyrrolidinyl,
m) -methyl tetrahydrofuryl, or
I[TRUE COPY!I
where when Ra and Rb are a substituted group, they are substituted by

b) hydroxy,
c)-N(CH3)2,
d) C 1-Cioalkyl,
e) C 1-C1oalkoxy,
f) halosubstituted C 1-6 alkyl, or
g) OSi(Pr-i)3; or
ii) Ra and ~ together form piperazine or a substituted piperazine with substituents

selected from the group consisting of:
a}halogen,
b) hydroxy,
c) C 1-C,oalkyl,
d) pyridinyl
e) C1-C10alkoxy,
f) C6aryl,
M is selected from the group consisting of oxygen and sulfur; and
B is phenyl, subtituied with 1-3 substituents independently selected from the group
consisting of halogen and R7, and R7 is
(a) C1-C6 linear or branched alkyl, optionally substituted with 1-3 halogen
substituents or
(b) C1-C6linear or branched alkoxy.
2. A compound as claimed in claim 1 wherein M is oxygen.
I
I[TRUE COPY!I
3. A compound as claimed in claim 2, wherein B of Formula I is phenyl,
substituted with 1-3 substituents independently selected from the group consisting of
chlorine, C 1-C6 alkoxy or up to per halo substituted C1-C6alkyl.
4. A compound as claimed in claim 3 wherein Lis phenyl, optionally substituted

with 1-3 substituents independently selected from the group consisting of halogen and
C1-C3alkoxy.
5. A compound as claimed in claim 4 wherein the substituents of B and L are

independently selected from the group consisting of methyl, tritluoromethyl, tert-butyl,
methoxy, CI, and F.
6. A compound as claimed in claim 5, wherein Ra and Rb are independently

hydrogen or C1-C6alkyl.
7. A compound as claimed in claim 1, wherein Ra and Rb are independently

8. A compound as claimed in claim 1, wherein L 1 is additionally substituted 1 to 3

times by one or more substituents selected from the group consisting of C 1-C6 alkyl,
halogen find C 1-C6 alkoxy.
9. A compound as claimed in claim 8, wherein the additional substituents on L 1

are selected from the group consisting of methyl, triflueromethyl, methoxy, Cl and F.
10. A compound of Formula I: A - D - B (I), or a pharmaceutically acceptable salt

thereof,
wherein
Dis -NH-C(O -NH-,
A is of the formula; -LM-L', wherein
L is phenyl, optionally substituted with 1-3 substituents independently selected from
the group consisting of C 1-C5 linear or branched alkyl, C 1-C5 linear or branched
haloalkyl up to perhalo, C 1-C3 alkoxy and halogen;
I[TRUE COPY!I
L 1is pyridinyl, substituted by -C(O)Rx;
wherein Rx is NRaRb and Ra and Rb are independently
hydrogen,
C1-C10alkyl,
C1-C10aryl,
pyridinyl, substituted C1-C10alkyl,
where Ra and Rb are a substituted group, they are substituted by halogen up to per halo;
and
M is selected from the group consisting of oxygen and sulfur and
B is phenyl, substituted with 1-3 substituents independently selected from the group
consisting of:
R7 and halogen; and R1 is
(a) C1-C6 linear or branched alkyl, optionally substituted with 1-3 halogen
substituents;
or
(b) C l-C6 linear or branched alkoxy.
11. A compound of Formula I: A - D - B (I) or a pharmaceutically acceptable salt

thereof,
wherein
D is -NH-C(O)-NH-,
A is of the formula; -L-M-L',
Lis phenyl,
M is-O-,
IITRUE COPYII
L 1 is pyridinyl substituted by C(O)R wherein R 1s NRaRb and Ra and Rb are
independently
hydrogen.
C1-C10alkyl,
C6 aryl,
pyridinyl,
substituted C1-C10alkyl,
substituted pyridinyl
where Ra and Rb are a substituted group, they are substituted by halogen up to per halo,
and
B is a phenyl group substituted by trifluoromethyl or tert-butyl, and optionally

additional subsiituents selected from the group consisting of halogen upto per halo, and
W where n is 0-3, and each Wis independently selected from the group consisting of:
C1-C10alkyl,
C1-C10alkoxy,
C,, aryl,
pyridinyl, and
substituted C1-C10alkyl, substituted by one or more substituents independently selected

from the group consisting of halogen up to per halo.
12. A compound as claimed in claim 10 wherein the optional substituents for B, are
selected from the group consisting of up to per halo substituted C 1-C6 alkyl and
halogen.
13. A compound as claimed in claim 11 wherein the optional substituents for Bare
selected from the group consisting of up to per halo substituted C1-C6 alkyl and
halogen.
IITRUE COPY!I
It,\.· A compound of Formula L
A-D-B (I)
o.r a pharmaceutically acceptable salt the~eof, wherein
Dis -NH-C(O)-NH-,
A is •a substitl,lted moiety of up to 40 carbon atoms of the formula: -L-(M-L 1 )q ,

where L is a 5 or 6 membered cyclic . structure bbund directly to D,. L 1 comprises a
substituted cyclic moiety having at .least 5 _members, M is a bridging group having at least
one· atom, q is an int_eger of from 1-3; and each cyclic structure bf L and L 1•contains 0-4
., :.,.a.substituted or .unsubstituted, tip to tricyc:licaryl or he_teroarylmoiety of up to

~---~"·"'~--J3js
3 O c~bon atoms with at least one 6-member cyclic structure bound directly to ~ containing
0-4 m~mbers·of the group consisting ofhitt:ogen, oxygen and sulfur,
wherein L 1 is substituted by at least one substituent selected from the group consisting
· of.:so~Rx, •-C(O)Rx and -C(NRy) Rz,
Ry is hydrogen or a carbon based moiety_ oCup •to 24 carbon atoms optionally

containing heteroato_ms selected from N, S arid O and optionally halosubstituted, up to per .
halo,
R2 is hydrogen or a carbon based moiety of up to. 30 carbon atq:tnsoptionally

.containing heteroatoms selected from N, S and O and optionally substituted by halogen,
heteroatoms selei;:tedfrom N, S and O and are optionally substituted by halogen;

heteroc1toms selected from N, S and O and optionally substituted by halogen, hydroxy and
IITRUE COPYII
.carbon based substituents of up to 24 carbon atoms, which optionally contain heteroawms
-OSi(Rr) 3 where Re is hydrogen or a carbon based moiety of up to 24 carbon

atoms optionalJy containing heteroatoms selected from N, S.and O and optionally substituted
••optionally contain heteroatoms selected from N, S and O and are optionally substituted by
halogen; or
b) Ra and Rb together form a 5- 7 member heterocyclic structure of 1-3

--s ·and O and are optionally substituted by halogen; or
c) one of Ra or Rb is -C(O)-, a C,-Cs divalent alkylene group or a substituted C 1-

members, wherein the substituents of the substituted C 1-C 5 divalent alkyiene group are-
where B is substituted, L 1s substituted or L I is additionally su~stituted, the

n is 0-3;
wherein each W is independently selected from the group consisting of -CN, -CO 2R 7,
7 7 7 7 7 7
-C(O)NR R 7, -C(O)-R , .:NO2 , -OR , -SR , -NR R , -NR7 C(O)OR7, -NR 7 C(O)R7, -Q-Ar, and
carbon based moieties of up to 24 carbon atoms, optionally containing heteroatorns selected
selected from the group consisting of -CN, -CO R7, -C(O)R -C(O)NR R -OR -SR
7 7 7 7 7
, , , , -
2
7 7 7 7 7 7
NR R7, -NO 2 , -NR C(O)R , -J,m_C(O)OR and halogen up to per-halo; with each R
containing beteroatoms selected from N, Sand O and optionally substituted by halogen.
11TRUE COPYII
7
-(C.H2)mN(R )-, -O(CH2)m- CHXa-, -CXa2-, -S-(CH2)m- and -N(R 7 )(CH2)m-, where m= 1-3,
and Xa is halogen; and
' .
AI is a 5- or 6-rnember aromatic structure containing 0-2 members selected from the
. up to per-halo, and optionally substituted by Z 01, wherein n I_ is 0 to 3 and each Z is
independently selected from the group consisting of -CN, -CO R -C(O)R7, -C(O)NR .R
7 7 7
, , -
2
NO 2
, -OR7,~ SR -NR R -NR C(O)OR -NR C(O)R
7 7 7
,
7 7
,
7 7

24 carbon atorris, optionally containing heteroatoms selected from N, S and O and optionally
7
substituted by one. or more substituents selected from the group consisting of -CN, -CO 2R , -
7 7 7 7 7 7 7 7 7 7 7
COR 7, -C(O)NR R , -OR , -SR , -NO2, -NR R , -NR C(O)R , and -NR C(O)OR , with R as
··-ddirred ··above.
/5. A compound as in claim l wherein:
Ry is hydrogen, C 1.10 alkyl, C1-10 alkoxy, C3-10 cyc]oalkyl having 0-3 heteroatoms, C2.
10 alk~nyl, C 1. 10 alkenoyl, C6-I2aryl, C3-12 hetaryl having 1-3 heteroatoms selected from N, S
·and 0, C 7. 24 aralkyl, C7_24 alkaryl, substituted C 1. 10 alkyl, substituted C 1. 10 alkoxy, substituted
C3. 10 cycloalkyl having 0-3 heteroatorns selected from N, Sand 0, substituted C 6 -C14 aryl,
substituted C3_12 hetaryl having 1-3 heteroatorns selected from N, S and 0, substituted C1-2.4
alkaryl or substituted C ~C24 aralkyl, where Ry is a substituted group, it is substituted
7
by
halogen up to per h_alo,
Rz is hydrogen, Ci-10 alkyl, C1-10 alkoxy, CJ-IO cycloalkyl having 0-3 heteroatom, C2 -10
a!kenyl, C 1. 10 alkenoyl, C 6. 12 aryl, C 3 -C12 het3:1YIhaving 1-3 heteroatoms selected from, S, N

and 0, C1. 24 alkaryl, C7 . 24 aralkyl, substituted Ci-io alkyl, substituted C 1. 10 alkoxy, substituted
C6 -C 14 ary!, substituted C3 -C 10 cycloalkyl having 0-3 heteroatoms selecred from S, N and 0.
substituted C 3_11 hetaryl having 1-3 heteroatoms selected from S, N and 0, substituted C,.~.i
alkaryl or substituted C7-C24 aralky! where R2 is a substituted group, it is substituted by
halogen up to per halo, hydroxy, ( 1. 10 alkyl, ( 3. 12 cycloalkyl having 0-3 heteroatoms selected
rrom 0. S and N, C;. 12 hetaryl having 1-3 heteroatoms selected from N, S and 0. C1.;r,
IiTRUE COPYII
·alkoxy, C 6. 12 aryl, C 1. 6 halo substituted alkyl up to per halo alkyl, C6-C12 ·halo substituted aryl.
,,
up to per halo aryl, C 3-C 12 halo substituted cycloalkyl up to per halo cycloalkyl having 0-3
heteroatoms selected from N, S_and 0, halo substituted CrC 12 hetaryl up to per halo hetaryl
having 1-3 heteroatoms selected from 0, N and S, halo substituted C1-C24aralkyl up to per
halo aralkyl, halo substituted CrC 24 alkary[ up to per halo alkaryl, and -C(O)Rg,
Ra and Rb are,
a carbon based moiety selected from te group consisting of C 1 -C 10 alkyl, C 1 -

C 10 alkoxy, C3.to cycloalkyl, C2.to alkenyl, Ci-10 alkenoyl, C6-t2 aryl, C3.;2 hetaryl having 1-3
heteroatoms selected from 0, N and S,
• '"·-~••s· .. ···•-·•~---·---·--•-··"•·- •• •••• ····'·· ·-·•'"·' ·····~•·1··
C3.12
···
cycloalkyl having 0-3 heteroatoms selected from
··· ·- •···
N, S ~nd O,_ C 7. 24 aralkyl, CrC24 alkaryl, substituted C 1.10 alkyl, substituted C 1. 10 alkoxy,
. . . .
substituted C3. 10 cycloalkyl, having 0-3 heteroatoms selected from N, S and 0, substituted C6.
12 aryl, substituted C,3.i 2 l:ietarylhaving 1-3 heteroatoms selected from N, S and 0, substituted
C7. 2: aralkyl, substituted C1.24 alkaryl, where Ra and Rb are a substituted group, they are
substituted by halogen up to per halo, hydroxy, C 1. 10 alkyl,. C 3. 12 cycloalkyl having 0-3
heteroatoms selected from 0, Sand N, C 3.12 hetaryl having 1-3 heteroatoms selected from N,
S and 0, C 1. 10 alkoxy, C 6. 12 aryl, C 1.6 halo substituted alkyl up to per halo alkyl, C 6-.C1 2 halo
substituted aryl up to per halo aryl, C3-C12 halo substituted cycloalkyl having 0-3 heteroatoms
selected from N, S and 0, up to per halo cycloalkyl, hafo substituted C3-C 12 hetaryl up to per
halo heteraryl, halo substituted CrC 24 aralkyl up to per halo aral.kyl, halo substituted C1-C24
alkaryl up to per halo alkaryl, and -C(O)Rg ; or
-OSi(Rr)3 where Rr is hydrogen, C1.10 alkyl, C1. 1o alkoxy, C3-C 1o c:ycloalkyl

having 0-3 heteroatoms selected from 0, S •and N, C 6. 12 aryl, C3-C 12 hetaryl having 1-3
het~r<?atoms selected from 0, Sand N, C1.24 aralkyl, substituted C 1. 10 alkyl, substituted C 1-
C 10 alkoxy, substituted C 3-C 12 cycloalkyl having 0-3 heteroatoms selected from 0, S and N,
substituted C3-C 12 heteraryl having 1-3 heteroatoms selected from 0, S, and N, substituted
C6. 12 aryl, and substituted C1.24 alkaryl, where Rr is a substituted group it is substituted
halogen up to per halo, hydroxy, C 1. 10 alkyl, C3 .•12 cycloalkyl having 0-3 heteroatoms selected
from 0, S and N, C;. 12 hetaryl having 1~3 heteroatoms selectedfrom N, S and 0, C1.1o
all-:oxy. C,. 12 aryl. C1 -C 24 alkaryl, C1 -C 24 aralkyl, C,. 6 halo substituted alkyl up to per halo
IiTRUE COPYII
alkyl, C.q-C12 halo substituted aryl up to per halo aryl, CrC 12 halo substituted cycloalky!
having 0-3 heteroatoms selected from N, S and 0, up to per halo cycloa·lkyl, halo substituted
C 3-C 12 hetaryl up to per halo heteraryl, halo substituted C1-C24 aralkyl up to per halo aralkyL
or
b) Ra and Rb together form a 5-7 member heterocyclic structure of l-3

heteroatorns selected from N, Sand 0, or a substituted 5-7 member heterocyc]ic structure of
1-3 heteroatoms selected from N, S and O with substituents selected from the group
consisting of haloge·n up to per halo, hydroxy, C,_ 10 alkyl, C 3. 12 cyc]oalkyl having 0-3
heteroatorns selected from 0, S and N, C3.12 hetaryl having 1-3 heteroatoms selected from N,
. S and 0, C 1. 10 alkoxy, C6-12 aryl, C1 -C24 alkaryl, C1 -C24 aralkyl, halo substituted C 1. 6 alkyl
up to per halo alkyl, halo substituted C6-C12 aryl up to per halo aryl, halo substituted C 3-C 12
cycloalkyl having 0-3 heteroatoms selected from N, S and 0, up to per halo cycloaJkyl, halo
su~stituted C3 -C 12 hetaryl up la per halo heteraryl, halo substituted CrC 24 aralkyl up to per
halo aralkyl, halo substituted Ci--C2~ alkaryl up to per halo alkaryl, and -C(O)Rg,
or
c) one of Ra or Rb is -C(O)-, a C1-Cs divalent alkylene group or a substituted ( 1- •
members,
wherein the substituents of the substituted C 1-C 5 divalent alkylene group are selected from
the group consisting of halogen, hydroxy, C1.10 alkyl, C 3. 12 cycloalkyl having 0-3 heteroatoms
selected from 0, Sand N, C3. 12 hetarylhaving 1--3heteroatoms selected from N, Sand 0, C 1.
10 alkoxy, C6-12 aryl, C1 -C24 alkaryl, C1 -C24 aralkyl, C 1. 6 halo substituted alkyl up to per halo
alkyl, C6 -C 12 halo substituted aryl up to per halo aryl, C~-C 12 halo substituted cycloalkyl
C3--C12 hetaryl up to per halo heterary!, halo s·ubstituted CrC 24 aralkyl up to per halo aralky!,
halo substituted C 7-C 24 a!karyl up to per halo alkaryl, and -C(O)R 8,
where Rg is C 1. 10 alkyl; -CN, -CO2Ri, --ORJ, --SR1, -NO2, -C(O) R_., .);RdR, .. -
NRi C(O)OR: arid -NR_i C(O)R:, and Ri and Re are independently selected from the group
IITRUE COPY!I
consisting, of hydrogen, C 1_10, alkyl, C1-10 alkoxy, CJ-ro cycloalkyl having 0-3 peteroatoms
selected from 0, N and S, C6_12aryl, C3- C12 hetaryl_with 1-3 heteroatoms selected from 0, N
and S and C1 -C24 aralkyl, C7 -C 24 alkaryl, up to per halo substituted C 1-C 10 alkyl, up to per
halo substituted CJ -·c10 cycloalkyl having 0-3 heteroatoms selected from 0, N and S, up to
per halo substituted C6 -C 14 aryl, up to per halo substituted C3 -C1.2hetaryl having 1-3
heteroatoms selected from 0, N, and S, halo substituted C 7 -C 24 alkaryl up to per halo alkaryl,
and up to per halo substituted C7-C 24 aralkyl,
7 7
Wis independently selected from the group consisting of -CN, -CO 2R , -C(O)NR R7,
-C(O)-R 7, -NO 2 , --OR , -SR
7 7
, -NR R
7 7
,
7
-NR C(O)OR
7
, -NR
7
C(O)R7, C 1-C 1o alkyl, C1-C10
alkoxy, C2-C ;··10 alkenyl,. C 1-C 10 alkenoyl, C3-C 10 cycloalkyl having 0-3 heteroatoms selected
~ ·······•·········•·····----
.J- ......... -·· •
from 0, Sand N, C6-Cl4 aryl, Crc;:24 alkaryl, C1 -C24aralkyl, C3-C 12 heteroaryl having 1-3
heteroatoms selected from 0, N and S, c4.:C23 alkheteroaryl having 1-3 heteroatoms :selected
from 0, N and S, substituted C1-C10 alkyl, substituted C 1-C 1o alkoxy, substituted Ci-C 1o
alkenyl,
~-
substituted C 1-CIO alkenoyl, substituted C3-C 10 cycloalkyl having 0-3 heteroatoms
.•
selected from 0, N and S, substituted C6-C 12 aryl, substituted C 3-C 12 hetaryl having 1-3
heteroatoms selected from 0, N and S, substituted CrC2 4 aralkyl, substituted CrC 24 alkaryl,
substituted C4-C23 a!kheteroaryl having 1-3 heteroatoms selected from 0, N and S, and -Q-
Ar;
7
R .is independently sei"ected from H, C1-C10alkyl, C 1-C10 alkoxy, C2-C10alkenyl, Ci-
. .
C 1o alkenoyl, C3-C10 cycloalkyl having 0-3 heteroatoms selected from 0, S and N, C6-C14
aryl, C3-C1}-hetaryl having 1-3 heteroatoms selected from 0, N and S, C7-C 14alkaryl, C1 -C24
aralkyl, C4-C23 alkheteroaryl having 1-3 heteroatoms •selec~ed from 0, N and S, up to per-
halosubstituted C 1-C10 alkyl, up to per-ha]osubstituted C 3-C 10 cycloalkyl having 0-3
heteroatoms selected from 0, N and S, up to per-halosubstituted C6~C14 aryl, up to per-
ha!osubstituted C3-C 13hetaryl having 1-3 heteroatoms selected from 0, N and S, up to per-
halosubstituted CrC 24 aralkyl, up to per-halosubstituted C 7-C 24 alkary!, and up to per-
ha!osubstituted Ci-C23 a!kheteroaryl; and
I[TRUE COPY!I
7 7
each Z is independently selected from the group consisting of -C~, -CO 2 R , -C(O)R ,
7 7 7 7 7 7 7 7
-C(O)NR 7R 7, -N02, -OR , - SR -NRR , -NR C(O)OR , -NR C(O)R , C1-Cl0 alkyl, C 1-C10
alkoxy, CrCio alkenyl, C1-C10 alkenoyl, C3-C 1o cycloalkyl having 0-3 heter·oatoms sele:ted
from O, N and S, C6-C 14aryl, C3-CJJ hetaryl having 1-3 heter?atoms selected from 0, N and
S, CrC 24
alkaryl, C1 -C24 aralkyl, C4-C23alkheteroaryl having 1-3 heteroatoms selected _from
O, N and S, sub~tituted C 1-C10 alkyl, substituted C 1-C 10 alkoxy, substituted CrCt0 alkenyl,
substituted C 1-C 10 alkenoyl, substituted C3 -CIO cycloalkyl having 0-:-3heteroatoms selected
from 0, N and S, substituted C6-C12aryl, substituted CrC24 alkaryl, substituted CrC24
aralkyl and substituted· C4-C 23 alkheteroaryl having 1-3 heteroatoms selected from 0, N
and S; wherein if Z is a substituted group, the one or more substituents are selected from the
group consisting of -CN, -CO2R -COR -C(O)NR R -OR -SR -NO 2, -NR R
7 7 7 7 7 7 7 7
, , , , , ,
-NR C(O)R and -NR ~(O)OR

7 7 7
7
, .
16. A compound as in claim !~wherein Mis one or more bridging groups selected
7
from the group consisting of -0-, -S-, -N(R )-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)mO-, -
7 7
(C~2)mS-, -(CH2)mN(R )-, -O(CH2)m- CHXa-, -CX\-, -S~(CH2)m-and -N(R )(CH2)m-, where
m= 1-3, Xa is halogen and R 7 is as defined in claim 1.
l1. A compound as in claim I~ wherein the cyclic structures of B and L bound

directly to Dare not substituted in the ortho position by-OH.
f 8,. A compound as in claim 1.4wherein the cyclic structures of B and L bound

)9. A compound of claim IL\wherein B of Formula I is a substituted or

unsubstituted six member aryl moiety or six member hetaryl moiety, said hetaryl moiety
having I to 4 members selected from the group of hetaryl atoms consisting of nitrogen,
2o. A compound of claim t4wherein B of Formula I is an' unsubstituted phenyl

group, an unsubstituted pyridyl group, an unsubstituted pyrimidinyl, a phenyl group
and n are as defined in claim I, a pyrimidinyl group substituted by a substituent selected from
IITRUE COPY!I
the group constituting of halogen and Wn, whe(eas W and n are_ as defined in Claim 1, or a
halogen and Wn whe.rein W and n are as defined in claim 1.
'2 l. A compound of claim rq~wherein B of Formula I is a substituted phenyl group,

. a substituted pyrimidinyl group, or substituted pyrridyl group substituted I to 3 times by 1 or
more substituents selected from the group consisting of -CN, halogen, C 1-C10 alkyl, C 1-C10
alkoxy, -OH, up to per halo substituted C1-C10 alkyl, up to per halo substituted C1-C10 alkoxy
2.2'- A compound of claim 1ijwherein L, the six member cyclic structure bound
.dire.f:Jly tp I), js a substituted or unsubstituted 6 member aryl moiety or a substituted or
unsubstituted 6 member hetaryl moiety, wherein said. hetaryl moiety has 1 to 4 members
balance of said hetaryl moiety being carbon, wher~in the one or .qi~re substituents are
seles::red from the group consisting of halogen and Wn wherein W and n are as defined in
claim I.
,9:::7/)'. A compound of claim 'l2. wherein L, the 6 member cyclic structure bound
directly to D, is a substituted phenyl, unsubstit.uted phenyl, substituted pyrimidinyl,
unsubstituted pyrimidinyl, substituted pyridyl or unsubstituted pyridyl group. •
2.1..,. A compound of claim 1, wherein said suhstituted cyclic moiety L 1 comprises a

5 to 6 membered aryl moi'ety or hetaryl moiety, wherein said heteraryl moiety comprises l to
4 members selected from the group of heteroatorns consisting ofnitr_ogen, oxygen and sulfur.
2-5 A compound of claim 1, wherein said substituted cyclic moiety L 1 is phenyl,

(
16 A compound of claim I 6, wherein said substituted cyclic moiety L I is phenyl,

21- A compound of claim 19.vherei:1 said substituted cyclic moiety L 1 is phenyl,

2 8. I
A compound of claim22,.,wherein said substituted cyclic moiety L is phenyl.
Jyridinyl or pyrimidinyl.
I~-
IITRUE COPYII
") ·, 1
2q. A compound of claim ~"";herein said substituted cyclic moiety L ,is phenyl,
pyndinyl •or pyrimidinyl.

•. ;?3 . . . . . I . ,
30, A compound of claim Ht, wherem said substituted c;ychc m01ety L 1s phenyl,
'.3/.A compound of claim 3', wherein M is one or more bridging groups selected
from th~ group consisting of -0-, -S-, ~N(R7)-, -(CH2)m-, -C(O)-,. -CH(OH)-, -(CHz)mO-,· -
7
(CI-h)mS-, -(CHz)mN(R7)-, -O(Cfh)m- CHXa-, -CXa2-, -S-(CH2)m- and -N(R )(CH2)m-, where
m= 1-3, Xa is halogen and R7 is hydrogen or a carbon based moiety ofup to 24 carbon atoms,
optionally containing heteroatoms selected from N, S and O and optionally _substituted by
halog~n up to per ha.Jo.
I
32. A cotnpound of claim 3_1w~erein L is additio~ally substituted I to 3 times by
one or more substituents selected from the group consisting of C1-C10 alk.-yl,up to per halo
substituted c;-c10• alkyl, -CN, -OH, halogen, C1-C10 alkoxy and up to per halo substit~ted C 1-
CJO alkoxy.
I
A compound of claim 14wherein L is substituted by C(O)R., or -SO~Rx, 0
wherein R_, is NRaRb.

3t]. , A compound of claim 31 -.vherein L I is substituted by -C(0)Rx or -SO 2 Rx,
•of up to 3 0 carbon atoms optionally containing heteroatoms selected from N, S and O and
optionally substituted by halogen, hydroxy and carbon bas~d •substi tuents of up to 24 carbon
atoms; which optionally contain heteroatoms selected from N, S and O and are optionally
3'5. A compound of Formula I:
A-D-B (J)
or a phamiaceutically acceptable salt thereof, wherein
Dis -NH-C(O)-NH-,
A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L 1 )9 ,
where L ~s a 6 membered aryl moiety or a 6 membered hetaryl moiety bound directly to D,

L I comprises a substituted cyclic moiety having at least 5 members, M is a bridging group
having at least one atom, q is an integer of from 1-3; and each cyclic structure of L and L 1
IITRUE COPYjl
Bis a substituted or unsubstituted, up to tricyclic aryl or heteroaryl ~oiety of up to
30 carbon ~toms with at least one 6-member cyclic structure bound directly to D containing
0-4 members of the group consist1ng of nitrogen, oxygen and sulfur,
wherein L1 is substituted by at least one substituent selected from the group consi-?ting
Ry is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally _

halo,
Rz is hydrogen, or a carbon based moiety of up to 30 carbon atoms optionally

·- ·conrn:ihirtg h·etetbatoms selected from N, S and O and optionally substituted by halogen,
Rx is R2 or NRaRii where Ra and Ri, are
a carbon based moiety of up to 30 carbon atoms optionally contarning

heteroatoms selected from N, S and O and optionally substituted by halogen, hydrox·y and
selected from N, Sand O and are optionally substituted by1 ha]ogen, or
-OSi(Rr) 3 where Rr is hydrog~n or a carbon based moiety of up to 24 carbon

' '
halogen; or
b) Ra and Rb together form a 5- 7 member heterocyc.lic structure of 1-3

1-3 heteroatoms selected from N, S and O substituted by halogen; hydroxy or carbon based
c) one of R, or Rb is -C(O)-, a C,-C divaJent alkylene group or a substituted r,-

- C divalent alkylene group bound to the moiety L to form a cyclic structure \Vith at k;:ist 5
IITRUE COPYjl
members, wherein the subsrituents of the substituted C 1-C 5 divalent ·alky!ene group are
to 24 c·arbon atoms, which optionally contain heteroatom:S selected from N, S and O and are
optionally substituted byhalogen;
where B is substituted, L is substituted or L 1 •is additionally substituted, the
n is 0-3;
wherein each W is independently selected from the group consisting of -CN, -CO 2R7.,
7
-C(O)NR 7R7, -C(O)-R 7 , -NO 2, -OR 7 , -SR 7, -NR 7R , -NR 7 C(O)OR7, -NR 7C(O)R7, -Q-Ar, and
selected f~om. !qe groupconsisting of -CN, -CO2R -C(O)R -C(O)NR R -OR -SR7,-
7 7 7 7 7
, , , ,
7 7 7 7 7
NR R7, -NO 2 , -r,m.7C(O)R , -NR C(O)OR and halogen up to per-halo; with each R
7
wherein Q is -0-, -S-, -N(R )-, -(CH2)rn-, -C(O)-, -CH(OH)-, -(CH2)mO-, -(CH2)mS-,
7 7
-(CH2)mN(R )-, -O(CH2)m- CHX\ -CXa2-, -S-(CH2)m- and -N(R )(CH2)m-, where m= 1-3,
and Xa is halogen;
Ar is a 5- or_6-member aromatic structure containing 0-2 members selected from the

group consisting of nitrogen, oxygen and sul:fur, which is optionally substituted by halogen,
up to per-halo, and optiona!ly substituted by Znr, wherein nl is 0 to 3 and each Z is
7 7
independently selected from the group consis,ting of -CN, -CO 2R 7, -C(O)R 7, -C(O)NR R , -
7 7 7 7 7 7 7
NO 2 , -OR 7, - SR -NR R , -NR C(O)OR , -NR C(O)R , and a carbon based moiety of up to
substituted by one or more substituents are selected from the group consisting of -CN, -
7 7 7 7 7
CO~R7, -COR\-C(O)NR R , -OR , -SR , -NO 2 , -NR 7R 7 , -NR 7C(O)R 7, and -NR 7C(O)OR ,
with R 7 as defined above; and
7 7
N(R )-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)mO·, -{CH2)mS-, -(CH2)mN(R )-, -O(CH2)m·
7
CHXJ-. -CXJ~-, -S-(CH 2 )m- and -N(R )(CH2)m-, where m= 1-3, Xa is halogen.
( ~
IITRUE _COPY!I
3f. A compound of Formula I:
A-D-B (I)
Dis -NH-C(O)-NH-,
• I
A is . a substjtuted moiety of up to 40 carbon atoms of the fonnula: -L-{M-L )q,
where Lis a substituted or unsubstituted phenyl or peritoneal moiety bound directly to D, L 1
comprises a substituted phenyl, peritoneal or pyr:imidinyl moiety, M is a bridging group
having at least one atom, q is an integer of from 1-3; and
. !:3_is__ .a substituted or unsubstituted phenyl or pyridine group bound directly to D,
wherein L 1 is substituted by at least one_substituent selecte_d from the group c;:onsis[in5

of ,.SO2Rx, -C(O)Rx and -C(NRy) Rz,
Ry is hydro~en or a carbon based moiety of up to 24 carbon atoms . optionally

containing heteroatoms selected from N, S and O and optionally ha]osubstituted, up to per
halo, and;
Rz is hydrogen .or a carbon based moiety of up to 30 carbon atoms optionally

containing heteroatoms selected from N, S and O and ·optionally substituted by halogen,
. heteroatoms .selected from N, S and O and are optionally . substituted
.
by halogen;
Rx is R2 or NRa~ where Ra and Rb are

heteroatoms selected from N, S and O and optionally substiruted by halogen, hydroxy and
-OSi(Rrh where Rr is_hydrogen or a carbon based moiety of up to 24 carbon·

atoms optionally containing heteroatoms selected from N, S an·d O and optionally substituteJ
In'::>
IITRUE COPYjl
optionally contain heteroatoms selected from N, S and O and are optionally substituted by· -
halogen; or

heteroatoms selected from N, S and 0, or·a substituted 5-7 member heterocyclic structure of
substituen~s of up to 24 carbon atoms, which optionally contain heteroatoms selected from N,
c) one of Ra or Rb is -C(O)-, a C 1-C 5 divalent alkylene group 9r a substituted C 1-

C5 divalent alkylene group bound to the moi~ty L to form a cyclic structure with at least 5
__members, .wben:in the st1l:Jstituentsof the substituted C 1-C 5 divalent alkylene group are
se[ected from the group consisting of halogen, hydroxy, and carbon based substituents of up
to 24 carbon atoms, which optionally contain h·eteroatoms selected from N, S and O and are
where B is substituted, L is substituted or L I is additionally" substituted, the

n is 0-3;
wherein each W is independently selected from the group consisting of -CN, -C02R 7,
-C(O)NR R -C(O)-R
7 7
,
7
, -NO -OR7, -SR7, -NR R -NR C(O)OR

2
,
7 7
,
7 7
, -NR C(O)R
7 7
, -Q-Ar, and
carbon based moieties of up to 24 carbon atoms, op~ionally containing heteroatoms selected
selected from the group consisting of -CN, -CO R -C(O)R -C(O)NR R -OR -SR
2
7
,
7
,
7 7
,
7
,
7
, -
NR 1R 1, -NO 2 , - NR1 C(O)R 1, -NR1C ( O)OR 1 and halogen up• to per-halo; with
• each R 1
independently selected from H or a carbon based moiety of up to 24 carbon atoms, optional_ly
7
wherein Q is -0-, -S-, -N(R )-, -(CH2)m-, -C(O)-, -CH(OH)-, --(CH2)mO-,-(CH2)mS-,
-(CH 2)rnN(R7)-, -O(CH 2 )m- CHX•-, -CXar, -S-(CH 2)rn- and -N(R 7)(CH 2)m-, where rn= 1-3,
and x• is halogen;
group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen.
up to per~halo, and op.tionalfy substituted by Zn1, wherein nl is O to 3 and each l, is
/uG
IITRUE COPY!I
• independently s·e]ected from the group _consistingof_-CN, -CO R7, -C(O)R -C(O)NR R 2
7
,
7 7
, -
NO -OR7, - SR -NR R -1'-l°R

2
, C(O)OR
7 7 7
,
7 7
, -NRC(O)R 7 7

24 carbon atoms, optionally containing heteroatoms selected from N, S and Q and· optionalJy
substituted by one or more substituents selected from the group consisting of -CN, -CO R 2
7
, -
COR -C(O)NR R7, -OR ,°~SR -NO2, -NR R -NR C(O)R and -NR C(O)OR and :
7 7 7 7 7 7
7 7 7 7
, , , , ;
wherein M is one or mo~e bridging 'groups selected from the group consisting of -0-, -S-, .-
N(R 7)-, -(CH2)rn-,-C(O)-,· -CH(OH)-, -(CH2)mO-, -(CH2)mS-, -(CH2)rnN(R7)-, -O(CH2)rn-
CHX 3 -, -CXa2-,-S.-{CH2)m-
and -N(R )(CH2)m·,where m= 1-3, xa· is halogen. 7
{ 3.-;;: A compou;:;f~ in daim 35, wherein substituents for B and L and additional •
~ . . ' • . .
'fsubst1tuen'ts-for 'L 1; ··areselected from·the group consisting of C 1-C 10 alkyl up to per halo
/ s~bstitiite~ C1-C10 alkyl, CN, OH, halogen; C1-C10a1koxyand up to per halo substituted C1-
J
I1 C1o·alkoxy.
I
I- _'f!~fs. A co~po~nd as in claim 39' wherein substi~ents for B and L and additional
I substituents for ·L1,
)
are selecteqJfrom the group c~~isting of C1-Ci'o alkyl up to per ·halo
' substituted C1-C 10 alkyl, CN, OH: halogen, c 1~c10 alkoxy and up to per halo substituted C 1-
C10alkoxy.
,3q, A compound of claim 35 wherein L1 is substituted by C(O)Rx or SO2R'<-
L..to A compo\lnd of claim 36.wherein L1 is substituted by_C(O)R'( or SO~R'(.
- /:;;/]. .A compound of claim ;3tj wherein R., is NRaRb and Ra and R are 0
independently hydrogen and a carbon based moiety of up to 30 carbon atoms optionally
IITRUE COP\jl
containing heteroatoms selected from N, S and ·o and optionally substituted by halogen,
heteroatoms selected from N, S and O and are optionally substituted by halogen:.
,,
42. A compound of claim 4C>wherein Rx is NRaR:i and Ra and Rb are

independently hydrogen and a carbon based moiety of up to 30 carbon atoms optio-~ally
containing heteroatoins selected from N, S and O and optionally substituted by halogen,
if3~ A compound of claim ILjwhkh is a pharmaceutically acceptable salt of a

consisting of hydrochloric acid, hydrobromic acid, sulphuric aci~, phosphoric acid,
acid (tosy1ate salt), 1-napthalene su_lfonic acid, 2-napthalene sulfonic acid, acetic acid,
trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxali_c acid, succinic acid,
fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid;·
and
44. A compound of claim 15which is a pharmaceutically acceptable salt of a

consisting of hydrochloric acid, hydrobroinic acid, sulphuric acid, phosphoric acid,
acid (tosylate salt), • 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid,
and
IITRUE _COPY!I
45, A compound of claim U which is a pharmaceutically acceptable salt of a

fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid,, and mandelic acid;
and
W6, A compound of claim 35 which is a pharmaceutical1y acceptable salt of a

compound of formula r'sdected from the group consisting of
acid (tosylate salt), · 1-napthalene sulfonic acid, 2-napthaJene sulfonic acid, acetic acid,
and
Lt/~ A compound of claim 36 which is a pharmaceutically acceptable salt of a compound

- IITRUE COPY!I
a) basic salts of organic acids and inorganic '.3-Cidsselect_ed from the group
consisting 9[ hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,
rnethanesulphonic acid, L.-rifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic
acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthaJene sulfonic acid, acetic acid,
and
48 A pharmaceutical composition comprising a compound bf clairi ILJor a

pharmaceutically acceptable salt of a compound of formula I, and a physiologically
acceptable carrier.
119. A pharmaceutical composition comprising a compound of claim I'Sconsistent

with fonnula I or a pharmaceutically acceptable salt thereof, and a physiologically
acceptable carrier.
50. A pharmaceutical composition comprising a compound of claim '26-

consistent
with formula I or a phannaceutically acceptable salt thereof, and a physiologically
acceptable carrier.
5L A pharmaceutical composition comprising a compound of claim 35.consisterit

with formula I or a phannaceutically acceptable salt thereof, and a physiologically
acceptable canier.
5'1 A pharmaceutical composition comprising a compound of claim 36 consistent

acceptable carrier.
J-tert butyl phenyl ureas of Table 1 above;
II zE---
IITRUE COPYII
-(trifluoromethyl)-2 phenyl ureas of Table 3 above;
-(trifluoromethyl) -4 chlorophenyl ureas of Table 4 above;
-(trifluoromethyJ)-4-bromophenyl ureas of Table 5 above;
(trifluorornethyl)-4-chloro-2 methoxyphenyl ureas of Table 6 above; and
reas 101-103 in Table 7 above_
SL-/. A compound selected from the group consisting of
~ 3-tert butyl phenyl ureas:

(3-tert-butylphenyl)-N '-(4-(3-(N-rnethylcarbamoyl)phenoxy)phenyl urea and
(3-tert-butylphenyl)-N'-( 4-( 4-acetylphenoxy)phenyl urea;
: 5-tert-butyl-2-methoxyphenyl ureas:
:5-tert-butyl-2-methoxyphenyl)-N'-( 4-( 1,3-dioxoisoindo lin-5...:yloxy)phenyl) urea,
:5-tert-butyl-2-methoxyphenyl)-N'-( 4-( l-oxoisoindolin-5-yloxy)phenyl) urea,
·s-terr-butyl-2-methoxyphenyl)-N '-(4-( 4-methoxy-3-(N-
thylcarbamoyl)phenoxy)phenyl) urea and
5-tert-butyl-2-methoxyphenyl)-N'-(4-(3-(N-methy!carbamoyl)phenoxy)phenyl) urea;
2-methoxy-5-trifluoromethyl)phenyl ureas:
2-methoxy-5-(trifluorornethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxy)phenyl) urea,
2-methoxy-5-( trifluoromethyl)phenyl)-N '-(3-(2-( N-methylcarbamoy 1)-4-
idy loxy )phenyl) urea,
2-methoxy-5-( trifl uoromethyl )phenyl)-N '-(4-(2-carbamoyl-4-pyridyloxy)phenyl) urea,
~-methoxy-5-(trifluorornethyl)phenyl)-N '-( 4-(2-(N-methy lcarbamoyl)-4-
d yloxy)phenyl) urea,
1-methoxy-5-( tri fl uorometh yl)phen y 1)-N'-(4-(2-(N-methy lcarbamoy 1)-4-
dy Ithio )phen y I) urea,
N-( 2-methoxy-5-(tri f1uoromethyl)phenyl)-N '-(2-chloro-4-(2-(N-methylcarbamoyl)( 4-
pyrid y lox y) )phenyl) urea and
I 11
£--
IITRUE ~OPYII
N-(2-methoxy-5-( trifluoromethy l)pheny I)-N '-(3-chloro-4-(2-(N-meth ylcarb amo y I)( 4-
pyridy loxy) )phen yI) urea;

N-(4-chloro-3-(trifluoromethyl)phenyl)-N '-(3-(2-carbamoy 1-4-pyridy loxy)pheny I) urea,
N-( 4-chloro-3-( trifluoromethyl)phenyl)-N '-(3-(2-(N-methylcarbamoy 1)-4-pyridylox y )pheny 1)
urea,
N-( 4-ch loro-3-(trifluoromethyl)phenyl)-N '-(4-(2-carbamoyl-4-pyridyloxy)phenyl) urea and

M-( 4-chloro-3-(trifluoromethyl)phenyl)-N '-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)
. urea.

N-( 4-bromo-3-(trifl uo ro methy l)pheny 1)-N '_(J-(2-(N-methy lcarba.TJ·10y!)-4-pyridy lo x.y)phenyl)
urea,
N"( 4-bromo-3-( trifl uoromethy l)pheny 1)-N '-(4-(2-(N-methy lcarbamoy I)-4-pyri d y loxy )phenyl)
urea,
-N-( 4~bromo-3-(trifl uoromethyl )phenyl)-N '-(3-(2-(N-methy lcarbamoyl)-4-pyri dylthio )phen y 1)
urea,
N-( 4-bromo-3-(trifl uoromethy l)phenyl)-N '-(2-chloro-4-(2-(N-methy lcarbamoyl )( 4-
pyridy Ioxy))phenyl) urea and
N-( 4-bromo-3-(trifl uoromethyl)phenyl)-,Y '-(J-chloro-4-(2-(N-methy lcarbamoyl)( 4-

N-(2-methoxy~4-chloro-5-(trifluorornethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-
N-(2-methoxy-4-chloro-5-( tri t1uorometh y I)phenyl )-N '-(2-chl oro-4-(2-(N-
methy lc arbamoy l)(4-p yridy lox y) )phen y I) urea and
N-(2-methoxy-4-chloro-5-( tri f1uorometh yl )phen yl)-N '-(3-chloro-4-(2-(N-
Dated this 4 th day of October, 2007.
[RANJNAMEHTA-DUTT]
OF REMFRY& SAGAR
ATTORNEYFORTHE APPLICANT(S)
IITRUE _COPYjl
Amen~ e clf3o{:fj
21~04-og
We claim:
A-D-B (I)
or a phannaceutically acceptable salt thereof, wherein
Dis -NH-C(O)~NH-,
-L-M-11,
wherein L is phenyl, optionally substituted by halogen, up to per-halo, and
Wn, where n is 0-3;
wherein each W is independently selected from the group consisting of C 1-C 5
linear or branched alkyl, C1-Cs linear or branched haloalkyl up to perhaioalkyl and
C 1-C3 alkoxy L 1 is selected from pyridinyl substituted by -C(O)Rx, and
optionally substituted with 1-3 additional substituents independently selected
from the group consisting of R 7 and halogen;
wherein Rx is NRa~ and Ra and Rt are
A) independently
a) hydrogen,
b) C1-C10 alkyl,
c) C6 aryl,
d) pyridinyl
e) substituted C 1.10 alkyl,
j) -cthylmorpholinyl,
k) -ethylpipertdyl,
I) -methyl pyrrolidinyl,
or
n) -C2H4NH(phenyl);

IITRUE COPYII
b) hydroxy,
c) -N(CH3)2,
d) C1-C10 alkyl,
e) C1-C10 alkoxy,
f) halosubstituted Ci-6 alkyl, or
g) -0Si(Pr-i)3; or
B) Ra and Rb together form p1perazme or a substituted p1perazme with

• substituents selected from the group consisting of •
a) halogen,
b) hydroxy,
c) Ct-IO alkyl,
d) pyridinyl
e) C1-10 alkoxy,
f) C6 aryl,
h) N-( 4-acetylphenyl);
M is selected from the group consisting of oxygen and sulfur;

and
Bis
phenyl, substituted with 1-3 substituents independently selected from the
group consisting of halogen and R7 ,
and R7 is
(a) C 1-C6 linear or branched alkyl, optionally substituted with 1-3 halogen
substituents; or
2. A compound as in claim 1 wherein M is oxygen .

directly to D are substituted in the ortho position by hydrogen.
4. A compound of claim 1 wherein B of Formula I is phenyl, substituted with 1-3
11TRUE. COPYjl
substituents independently selected from the group consisting of chlorine, C 1-C6
alkoxy or up to per halo substituted C 1-C6 alkyl.
5. A compound of claim 2 wherein B of Formula I is

phenyl, substituted with 1-3 substituents independently selected from the group
consisting of chlorine, C 1-C6 alkoxy, or substituted C1-C6 alkyl, substituted by one or
more halogen substituents.
6. A compound of claim 3 wherein B of Formula I is phenyl, substituted 1 to 3

times by 1 or more substituents selected from the group consisting of- -chlorine, C 1-C6
alkoxy or up to per halo substituted C1-C6alkyl.
7. A compound of claim I, wherein L is phenyl, optionally substituted by

halogen up to perhalo.
8. A compound of claim 1, wherein L is phenyl, optionally substiti.1tedwith 1-3

substituents independently selected from the group consisting of halogen and C 1-C3
alkoxy.
9. A compound of claim 3, wherein M is -0- .
10. A compound of claim 6 wherein Mis -0-.
12. A compound of claim 8 wherein M is -0- .
13. A compound of claim 1 wherein L I is additionally substituted l to 3 times by

one or more substituents selected from the group consisting of C 1-C6 alkyl, halogen
and C1-C6 alkoxy.

one or more substituents selected from the group consisting of Ct-C6 alkyl, halogen
and C 1-C5 alkoxy.
IITRUE COPYjj
15. A compound of claim 9 wherein L I is additionally substituted l to 3 times by
one or more substituents select~d from the group consisting of C 1-C6 alkyl, halogen
and C 1-C6alkoxy.
1
and C 1-C6 alkoxy.
1
and C 1-C6 alkoxy.

and C 1-C6 alkoxy.
19. A compound of claim 3 wherein Ra and Rb are independently hydrogen or C 1-

C6 alkyl.
20. A compound of claim 9 wherein Ra and Rb a.re independently hydrogen or C 1-

C6 alkyl.
21. A compound of claim l O wherein Ra and Rb are independently hydrogen or

C1-C6 alkyl.
22. A compound of claim 11 wherein Ra and Rb are independently hydrogen or

C1-C6alkyl.
23. A compound of claim 12 wherein Ra and Rb are independently hydrogen or

C1-C6 alkyl.
11TRUE _COPYII
A-D-B (I)
or a phannaceutically acceptable salt thereof, wherein
Dis -NH-C(O)-NH-,
A is of the formula: -L-M-L1, wherein
the group consisting of C 1-C5 linear or branched alkyl, C1-C 5 linear or branched
haloalkyl up toperhalo, C1-C3 alkoxy and halogen;
I.
L IS pyridinyl, substituted by -C(O)Rx; wherein
Rx is NRaRband Raand Rb are ip.dependently
hydrogen,
C1-C10 alkyl,
C6 aryl,
pyridinyl,
substituted C1. 1o alkyl,
substituted c6 aryl, OT
substituted pyridiny[,
where Ra and Rb are a substituted group, they are substituted by halogen up to per
halo; and
consisting of R7 and halogen; and
R7 is
(a) C 1-C6 linear or branched alkyl, optionally substituted with l-3 halogen
substituents; or
(I)
or a phannaceutica11y acceptablesalt thereof, wherein
Dis -NH-C(O)-NH-,
11TRUE _COPYII
A is of the formula: -L-M-1 1,
Lis phenyl,
Mis -0-,
L 1 is pyridinyl substituted by -C(O)Rx ,wherein
Rx is NRaRband Ra and Rb are independently
hydrogen,
C1-C10 alkyl,
C6 aryl,
pyridinyl,
substituted C1.10 alkyl,
substituted C 6 aryl, or
halo, and
B is a phenyl group substituted by trifluoromethyl or tert-buty1, and optionally
additional substituents selected from the group consisting of halogen up to per halo,
and Wn where n is 0-3, and each W is independently selected from the group
(.;On!>isling
of
C,-C, 0 alkyl,
C1-C10 alkoxy,
C6 aryl,
pyridinyl,
and substituted C 1-CJO alkyl, substituted by one or more substituents
independently selected from the group consisting of halogen up to per halo.

directly to Dare substituted in the ortho position by hydrogen.

directly to Dare substituted in the ortho position by hydrogen.
28. A compound as in claim 24 wherein substituents for B, are selected from the
group consisting of up to per ha1osubstituted C 1-C6 alkyl and halogen ..
l[TRUE COPYjl
29. A compound as in claim 25 wherein the· optional substituents for B are
selected from the group consisting of up to per halo substituted C 1-C6 alkyl and
halogen.
30. A pharmaceutically acceptable salt of a compound of formula I of claim 1

which is
trifl.uoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid,
acid, or mandelic acid; or
31. A pharmaceutically acceptable salt of a compound of claim 24 which is

a) a ~asic salt of an organic acid or inorganic acid which is hydrochloric
32. A pharmaceutically acceptable salt of a compound of claim 25 which is

IITRUE COPYjl
33. A compound of claim 1 wherein the optional substituents on L 1 are selected

from the group consisting of methyl, triflouromethyl, methoxy, Cl and F.
34. A compound of claim 1 wherein the substituents of B and L are independently

selected from the group consisting of methyl, triflouromethyl, tert-butyl, methoxy, Cl,
andF.

A-D-B (I)
Dis -NH-C(O)-NH-,
A is a substituted moiety of the formula: -L-M-L 1, wherein
L is phenyl, optionally substituted with chlorine or methyl substituents;
L 1 is pyridinyl, substituted with -C(O)NRaRbwherein
Ra and Rb independently are
a) hydrogen el'
b) methyl;
c) ethyl; or
d) propyl
B is phenyl, substituted by tert-butyl or trifluoromethy! and optionally substituted

with additional substituents independently selected from the group consisting of
a) halpgen, or
b) methoxy,
36. A compound of claim 35 where L has no optional substituents.
IITRUE _COPY!)
37. A compound of claim 35 where R 0 is hydrogen and Rb is methyl.
38. A compound of claim 35 where B is substituted by trifluoromethyl and

chlorine or bromine.
39. A compound which is N-(4-chloro-3-(trifluoromethyl) phenyl)-N'-(4-(2-(N-

methylcarbamoyl)-4-pyridyloxy) p·henyl) urea of the formula X
40. A compound of claim 39 which is a pharmaceutically acceptable salt of N-(4-

chloro-3-(trifluoromethyl) phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)
phenyl) urea that is a basic salt of an organic acid or an inorganic acid which is
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic
:-icid, 1rill11oronietha11esu!fonicacid, benzt::nesulfonic acid, p-!oluene sulfonic :1cid
(tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid,
acid, or mandelic acid.
41. A compound of claim 39 which is a tosylate salt of N-(4-chloro-3-

(trifluoromethyl) phenyl)-N '-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea.
Dated this 4 th day of October, 2007

~Q,~~1
(RICHA A DEY)
OF REMFRY & AGAR
ATTORNEY FOR THE APPLICANTS
11TRUE COPYII
The present invention relates to a compound of formula I and more
specifically to the use of a group of aryl ureas in treating raf mediated diseases, and
pharmaceutical compositions for use in such therapy.
Background of the invention
The p21rasoncogene is a major contributor to the development and progression of

human solid cancers and is mutated in 30% of all human cancers (Bolton et al. Ann.
Rep. Med. Chem. 1994, 29, 165-74; Bos. Cancer Res. 1989, 49, 4682-9). In its normal,
unmutated form, the ras protein is a key element of the signal transduction cascade
directed by growth factor receptors in almost all tissues (Avruch et al. Trends Biochem.
Sci. 1994, 19, 279-83). Biochemically, ras is a guanine nucleotide binding protein, and
cycling between a GIP-bound activated and a GDP-bound resting form is strictly
controlled by ras 1 endogenous GTPase activity and other regulatory proteins. In the
ras mutants in cancer cells, the endogenous GTPase activity is alleviated and,
therefore, the protein delivers constitutive growth signals to downstream effectors
such as the enzyme raf kinase. This leads to the cancerous growth of the cells vyhich
carry these mutants (Magnuson et al. Semin. Cancer Biol. 1994. 5, 247-53). It has been
shown that inhibiting the effect of active ras by inhibiting the raf kinase signaling
pathway by administrati9n or deactivating antibodies to raf kinase or by co-
expression of dominant negative raf kinase or dominant negative MEK. the substrate
of.---------------------------------====-
-,. 2 OCT20fZ
IITRUE COPYII
We claim:
A-D-B (I)
D is -NH-C(O)-NH-,
-L-M-L 1
'
wherein L is phenyl, optionally substituted by halogen, up to per-halo, and
Wn, where n is 0-3;
wherein each W is independently selected from the group consisting of C 1-C 5
linear or branched alkyl, C 1-C5 linear or branched haloalkyl up to perhaloalkyl and
C 1-C3 alkoxy L 1 is selected from pyridinyl substituted by -C(O)Rx, and
optionally substituted with 1-3 additional substituents independently selected
7
from the group consisting of R and halogen;
wherein Rx is NRaRband Ra and Rb are
A) independently
a) hydrogen,
b) C1-C10alkyl,
c) C6 aryl,
d) pyridinyl
e) substituted C1-10alkyl,
k) -ethylpiperidyl,
1) -methyl pyrrolidinyl,
or
n) -C2H4NH(phenyl);
90
~ -··
IITRUE COPY!I ~, 2 ocr201

b) hydroxy,
c) -N(CH3)2,
d) CJ-CJo alkyl,
e) CJ-CJo alkoxy,
f) halosubstituted CJ.6 alkyl, or
g) -OSi(Pr-i)3; or
B) Ra and Ri, together form piperazine or a substituted p1perazme with

substituents selected from the group consisting of
a) halogen,
b) hydroxy,
c) Ci.Jo alkyl,
d) pyridinyl
e) CJ.JOalkoxy,
f) C6 aryl,
h) N-( 4-acetylphenyl);
M is selected from the group consisting of oxygen and sulfur;

and
Bis
phenyl, substituted with 1-3 substituents independently selected from the
group consisting of halogen and R7,
and R7 is
substituents; or
2. A compound as claimed in claim 1, wherein M is oxygen.
3. A compound as claimed in claim 1, wherein the cyclic structures of B and L

bound directly to D are substituted in the ortho position by hydrogen.
91
zE-- -
IITRUE _COPY!I ~12 OCT201!
chlorine, C 1-C6 alkoxy or up to per halo substituted Cr-C6 alkyl.
5. A compound as claimed in claim 2, wherein B of Formula I is

phenyl, substituted with 1-3 substituents independently selected from the group
consisting of chlorine, C 1-C6 alkoxy, or substituted C 1-C6 alkyl, substituted by one or
more halogen substituents.

substituted 1 to 3 times by l or more substituents selected from the group consisting
of- chlorine, C1-C6alkoxy or up to per halo substituted C1-C6 alkyl.
7. A compound as claimed in claim I, wherein Lis phenyl, optionally substituted

by halogen up to perhalo. •
8. A compound as claimed in claim I, wherein L is phenyl, optionally substituted

with 1-3 substituents independently selected from the group consisting of halogen and
C1-C3alkoxy.
9. A.compound as claimed in claim 3 or 6 or 7 or 8, wherein Mis -0- .
10. A compound as claimed in claim I or 2 or 9, wherein L 1 is additionally

substituted l to 3 times by one or more substituents selected from the group consisting
of C1-C6alkyl, halogen and C1-C6 alkoxy.
11. A compound as claimed in claim 3 or 9, wherein Ra and Rb are independently


A-D-B (I)
92
2 OCT20ff
IiTRUE _COPYII p,1
Dis -NH-C(O)-NH-,
A is of the formula: -L-M-L I , wherein
the group consisting of C 1-C 5 linear or branched alkyl, C1-C5 linear or branched
haloalkyl up to perhalo, C 1-C3 alkoxy and halogen;
I.
L IS pyridinyl, substituted by -C(O)Rx; wherein
Rx is NRaRband Ra and Rb are independently
hydrogen,
C1-C10alkyl,
C6 aryl,
pyridinyl,
substituted C 1.10alkyl,
halo; and
consisting of R7 and halogen; and
R7 is
substituents; or
13. A compound of Formula i:
A-D-B (I)
Dis -NH-C(O)-NH-,
A is of the formula: -L-M-L 1,
Lis phenyl,
Mis -0-,
L 1 is pyridinyl substituted by -C(O)Rx ,wherein
93
&--
IITRUE COPY~ • ] 2 OCT201lt
Rx is NRaRband Ra and Rbare independently
hydrogen,
C1-C10alkyl,
C6 aryl,
pyridinyl,
substituted C1.10 alkyl,
halo, and
B is a phenyl group substituted by trifluoromethyl or tert-butyl, and optionally
additional substituents selected from the group consisting of halogen up to per halo,
and W 0 where n is 0-3, and each W is independently selected from the group
consisting of
C1-C10 alkyl,
C1-Crn alkoxy,
C6 aryl,
pyridinyl,
and substituted C 1-C 10 alkyl, substituted by one or more substituents
independently selected from the group consisting of halogen up to per halo.
14. A compound as claimed in claim 12 or 13, wherein the cyclic structures of B

and L bound directly to D are substituted in the ortho position by hydrogen.
15. A compound as claimed in claim 12, wherein substituents for B, are selected
from the group consisting of up to per halo substituted C 1-C6 alkyl and halogen.
16. A compound as claimed in claim 13, wherein the optional substituents for B
are selected from the group consisting of up to per halo substituted C 1-C6 alkyl and
halogen.
17. A pharmaceutically acceptable salt of a compound as claimed in claim 1 or 12

or 13, which is
94
~
IITRUE COPY\I ....2 orr.

20ft
18. A compound as claimed in claim I, wherein the optional substituents on L 1 are

selected from the group consisting of methyl, triflouromethyl, methoxy, Cl and F.
19. A compound as claimed in claim 1, wherein the substituents of B and L are

independently selected from the group consisting of methyl, triflouromethyl, tert-
butyl, methoxy, Cl, and F.

A-D-B (I)
Dis -NH-C(O)-NH-,
A is a substituted moiety of the formula: -L-M-L 1, wherein
L is phenyl, optionally substituted with chlorine or methyl substituents;
L1 is pyridinyl, substituted with -C(O)NRaRbwherein
Ra and Rb independently are
a) hydrogen;
b) methyl;
c) ethyl; or
d) propyl
B is phenyl, substituted by tert-butyl or trifluoromethyl and optionally substituted

with additional substituents independently selected from the group consisting of
a) halogen, or
b) methoxy
95
~
IITRUE COPYII
r12 OCT201'2'
21. A compound as claimed in claim 20, where L has no optional substituents.
22. A compound as claimed in claim 20, where Ra is hydrogen and Rb is methyl.
23. A compound as claimed in claim 20, where B is substituted by trifluoromethyl

and chlorine or bromine.
24. A compound which is N-(4-chloro-3-(trifluoromethyl) phenyl)-N'-(4-(2-(N-

methylcarbamoyl)-4-pyridyloxy) phenyl) urea of the formula X
25. A compound as claimed in claim 24, which is a pharmaceutically acceptable

salt of N-( 4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-(2-(N-methylcarbamoyl)-4-
pyridyloxy) phenyl) urea that is a basic salt of an organic acid or an inorganic acid
which is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,
methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluene
sulfonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid,
acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic
acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid,
phenylacetic acid, or mandelic acid.
26. A compound as claimed in claim 24, which is a tosylate salt of N-(4-chloro-3-

(trifluoromethyl) phenyl)-N '-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea.
Dated this 5th October, 2007

S KUMAR
OF PERFEXIO LEGAL
ATTORNERY FOR THE APPLICANT
96
&--- .
IITRUE COPYII rl:2 orT 20Jl;

GOVERNMENT OF INDIA Tel No. (091)(022) 24137701,
t:)l!!l. PATENT OFFICE 24141026, 24150381,
■ 1• INTELLECTUAL PROPERTY BUILDING 24148165, 24171457
INTELLECTUAL Near Antop Hill Post Office, Fax No. 022 24130387
PROPERTY INDIA S.M.Road,Antop Hill E-mail : mumbai-patent@nic.in
Mumbai - 400 037 Web Site : www.ipindia.nic.in
Letter No.: CHEM/2022 Date : 27/10/2011
SUB : First Examination Report
APPLICATION NUMBER : 1633/MUMNP/2007
Applicant Name : BAYER

BAYERCORPORATION
CORPORATION
Description :
1. With reference to the RQ No. 944/RQ-MUM/2008 Dated 04/04/2008 in the above mentioned application
for Grant of Patent , Examination has been conducted under Section 12 and 13 of the Patents Act 1970 ,
The following objections are hereby communicated
2. You are requested to comply with the objections by filing your reply by way of explanation and/or
amendments within 12 months from the date of issue of FER failing which you application will be
treated as "Deemed to have been abandoned" under section 21(1) of the Act. The last Date is
29/10/2012.
3. You are advised to file your reply at the earliest so that the office can further proceed with application
and complete the process within the prescribed period.
Objections :
1. D1;WO 99 20617
D1;WO99 20617((1999-04-29)
1999-04-29) Claims
Claimsabstract
abstract and
and particular
particular compounds
compoundsn,0,p
n,0,pand
and examples
examples1-17.
1-17.
D2;
D2; Raposo
RaposoCeser
CeserEt. Al 'Catalysis
Et. Al ‘Catalysis of
of nuclephilic
nuclephilic addition
addition of
of pyroolidine
pyroolidine to
to 2-(5H)-furanone
2-(5H)-furanonethrough
through chrommenone
chrommenone cleft-
cleft-
type receptors
type ‘Tetrahedron Lett.
receptors'Tetrahedron Lett. (( 1996)
1996)37
37 (( 38),
38),6947-6950, Abstract and
6947-6950,Abstract and Compound
Compound99 and
and 10,
10,
D3;
D3; US5447957
US5447957(( 1995-09-05) Abstract , column
1995-09-05)Abstract, column 1-5 and the
1-5 and the examples;
examples;in
in particular
particular,, the
the compounds
compoundsin
in column
column 7,
7, lines
lines 10-
10-
19,23-25, 29-32,36, and
19,23-25,29-32,36, and 37 and examples
37 and 2,4,5, and
examples2,4,5, and 6.
6.
IITRUE COPYjl
D4;US4973675 (1990-11-27) Abstract, column 1 and 2 and in table 1, the urea derivative AD 334;
D5;Database CA
l>S>Dabl- Chemical n
CA -online •, D•aal Abstract
ad -Service US, Vlfl
Columbus II.;,
.. _...., Yagi _...,
Toshihiko ET,AL,
El',AI.-‘Silver halide
hlllda photographic
.,,.,lllji.,,. ..
material
ro containing plwn.rc
I Ill _,..118 phenolic ~•
cyan -.,llr
coupler and
and i=I
colorless
I .,_,cyan 11111plr
coupler’ In
in particular
pwll lw a, compound
j rd "'1h with rn
m 129093-98-7,
1™7, in
In
abstract & JP 02023337
1btnctltJPhMI tiiif (( 1t90-Q1.JSJ
1990-01-25)
D6; D
Df. Database CA Chemical Al>llrl«Ser,b
tr ~AChdubl Abstract Service l'ollmal111
Mizukura N0bGru
Noboru ErEl'Sll'erhlldeailorpliOICIJapHc
ET El ‘Silver halide color photographic material
n-111 containing
ClOIUlnqiaa
~cyanCllqlltrof2-ln:lio
coupler of 2-ureido-phenol type to ill1jll'OW
phe!IOl~to improve .....
dye developability and IC,IM
'I.CJ)ll;>ll1Y1nd remove leuco
llu0i>cyan
C)'III dye
•'In ’ in particular
par1kla compound
C:C.il'w,!d
with m
""111 rn 129Ui
129093-98-7
• 7(1l(abstract) and JP02022650 ( 1990-01-25) .
b:rO.ldJP020?259>('ftO.Ot@.
D7; C
11'; Database
II CA ailna,
DI online , a.tmc1l:I
Chemical Abstract
id.- Service ClllurrioulJofti
Columbus Jeffocoat••. , A
A ftllllrt
robert ll!AI.
Et Al, '11,1
‘The metabolism
.-.tlboltm and
■ r-A toxicity
I I II)'of
af
thalogenated carbanilides Blll,Y
I $ >I "ltwilld• Biliary Mlllbol!M
metabolites of
of 3A4,0ICHDlll~nllilM
3,4,4,-trichlorocarbanilides -.I
and ~ld•
3-triflurocarbanilides inIn the
the rat’
llt' Drug
DftC
Metab.DI~
,._b. Dispos 1!197,
1997, 5
5 c;Q.
(2), 157-a
157-66.
Compounds with rn 63348-38-9 and 63348-30-1.

ComPN9""111m~1nd633413H.
D8; WO 99 32463 1 July 1999, Page 1-page 5, claims 1-21, tables 1-5.
D9;WO9533458 14 Dec:1995.
D!P:WDSS3M5114 Dec 1995. l'lp
Page 1,pqeS.
1-page 5, diiiml
claims 1-13.
1-13.
Fureter nflr
F1nt1r refer 1111
the documents
du, .. .-a US 5,/3
US 5773459,US4904668,
w9.P$WO US7351834
15H, USffi11134 ,, US APPLS
115 NPIS US2001011135,
usacot0111Sli,
US2001011136,US2001016659, US2001027202,US2001034447 , US2002137774, US2003105091,
USJQ010111»,US200101W, US20i"IQ27krt}IS'D'QSMt.7, 1'530)11'777~ IIS29QS105091, US2003181442
■ 6¥.S~l1"2. . So,
So.the
the
subject matter claimed in claims 1-41 is not satisfying
•ti•ct-dolnwdlndlhs14111111111 requirement
II r;,1.,......... of section 2 (1) (j) being anticipated
it.,_:Z(IJQlbel.,.rll by documents D1-
\ I l'.,daalm■ntsD1•
D8 , with reference
Dl,lllftl.,ar.aat..~ to relevant para mentioned above. Further your attention
... ntpe,.,r.clticaNd.bMt.r..tn.-,.....-ant..d-.mhl!MPER has drawn to the ISR/IPER generated
.. w. l",rfor
these claims.
111-dllmL
2. SIJ!dMI
Subject IN!llrd:i'l'Md
matter claimed in
in d:i'l'llln
claims are r.at,..-.:
not patentable
I I •u/s 3 (d) .r,-,11.4:
·11J(d) of Patents act;
3. 1"'1111!,bolli
Initially bothin
in partrt&-"'4111o."111
parent & instant divisional llll'la11on
application •me
same !let
set of
of dll11111
claims h.M
have bttn
been lled.Sut,Jta
filed.Subject mater claimed in
m■lt< dlli,ied inclaims
dMnl
are in
INI in ~lct'olllb
conflict with 1M
the P:lljett-
subject matter diiffl«I
claimed In
in dM!ll
claims ofU!e
of the PIA.llt
Parent al)lllmllan
application No IN/PCT/2001/0799/MUM, therefore
NoIN.'PCl'nool.l07MIYN, lh&al'ota
divisional
cMllon■I -. status of 111.p; .l .,.1an1on can nocbe lllclMII.RJntiW,1IHo,.::0:.:1 set
of the present application can not be allowed. Further, the narrower of claims
:satof with specific
dllms 'MIii i, adf.:
compounds which is fall within the scope of
Q.'..$ .andl¥itlcllisNiwlll'tnlhllGIPllofll~c.:; the compounds of formula claimed in the instant
idovffwmull diiinledlnlhl ir-appkll!OI\ application, have already
liMl ■n.t#
been granted in ther parent application.So, divisional status under section 16 of the Act to the present application can
bea111• I l111MrPftlitlA'k111onSo. "'' I ·- und..r--. 16af1MA<tCD1t..,a Wltll'l'llcloiflan
not be allowed.
nallNIIIGMcl.
4. Form 13 filed for technical amendments of claims can not be considered untill you file the highlighted
copy of the amendments carried on initially filed set of claims.
5. Power of attorney in your favor shall be filed.
6. Details regarding the search and/or examination report including claims of the application allowed, as
referred to in Rule 12(3) of the Patent Rule, 2003, in respect of same or substantially the same invention
filed in all the major Patent offices along with appropriate translation where applicable, should be
submitted within a period of Six months from the date of receipt of this communication as provided
under section 8(2) of the Indian Patents Act.
7. Details regarding application for Patents which may be filed outside India from time to time for the
same or substantially the same invention should be furnished within Six months from the date of filing
of the said application under clause(b) of sub section(1) of secton 8 and rule 12(1) of Indian Patent Act.
((ATl'Cll}
A T Patre )
Asst. Controller of Patents & Designs
NOTE : All Communications to be sent to the Controller of Patents at INTELLECTUAL PROPERTY BUILDING
S. M. Road, Antop Hill Mumbai-400 037.
AdvantNavisBusinessPark.TowerA
1108,l Ith Floor,PlotNo-7, Sector142
Expressway.Noida-20130:>India
Tel.: +91-120-2459858; 245 9859
Fax.:+91-120-2459860
Email:mail@pcrfexiolcgal.com
~ERfE~O LEGAL Website:www.pcrtcxiolcgal.com
Attorneys-At-Law
Our Ref: SKR/ ASY/SSL/rva/IP 1633/MUMNP/2007

Thursday, October 11, 2012.
EXTREMELYURGENT
FINAL DATE: October 2912012
THE CONTROLLER OF PA TENTS

THE PATENT OFFICE
MUMBAI
Kind attention: Mr. AT Patre
Assistant Controller of Patents
Dear Sirs,
Re: BAYER CORPORATION
Indian Patent Application No. 1633/MUMNP/2007
Dated: October 5, 2007
Divisional out of Indian Patent No. 215758
(formerly Indian Patent Application No. IN/PCT/2001, 00799/MUM)
Ante-Dated: January 12, 2000
Priority dates: January 13, 1999, February 25, 1999 and October 22, 1999
With reference to the official letter dated October 27, 2011, we submit the under -
mentioned documents and present the following reply:
Regarding the first paragraph of the office action, the Applicant respectfully submits
that the present invention is novel, has inventive step as well as industrial
application and corresponding US application has proceeded to grant with Patent
numbers US 7,235,576 and US 7,351,834 with the similar set of claims. It is also
submitted that none of the prior art documents cited by the Learned Controller
anticipates the invention. We present below the detailed analysis of the cited
documents:-
D1 WO 99/20617:
In addition to not having a remote pyridyl group with one of the required
substituents, the ureas defined in this publication require a 5-membered hetaryl aryl
group bound directly to the urea functional group and not a phenyl or pyridyl
group. Therefore, this reference is not relevant to the amended claims of the claimed
invention.
1 2 OCT2011·
Postal Address: 9655, Sector - C, Pocket-9, 'IITRUE COPYll)elhi- 110 070 India, Tel.: +91 11 41767656
D2 Raposo Cesar et al 'Catalysis of nucleophilic addition of pyrrolidine to 2-(5H)-
furanone through chromenone cleft type receptors' Tetrahedron Jett. (1996), 37 (38),
6947-6950.
The ureas disclosed in this publication have a bridging group with 10 member cyclic
structure bound directly to the urea group but the compound disclosed do not have
a remote pyridyl group with one of the required substituents SO2 NRaRb or
C(O)NRaRb.Therefore, this reference is not relevant to the amended claims.
D3 OS5447957(1995-09-05):
This patent discloses ureas having a bridged cyclic structure where ~ is H, R:3
C(O)R7, R7 is NR9R10,Rg is H and Rm is aryl. However, the compounds do not have
remote pyridyl group with or without one of the required substituents [C(O)NRaRb
or SO2NRaRbJ.
D4 OS4973675(1990-11-27):
This Patent discloses urea compounds having a bridged cyclic structure. However,
in addition to not having remote pyridyl group with one of the required
substituents, the cyclic structures bound directly to the urea group are not aromatic
(Please see compound 334) unlike the compound claimed herein.
D5 Database CA online, Chemical abstract service Columbus US, Yagi Toshihiko ET

AL, 'Silver halide photographic material containing phenolic cyan coupler and
colorless cyan coupler' in particular compound with rn 129093-97-7, in abstract &
JP02023337 (1990-01-25);and D6 Database CA Chemical abstract service Mizukura
Noboru ET EL "Silver halide color photographic material containing a cyan coupler
of 2-ureido-phenol type to improve dye developability and remove luco cyan dye' in
particular compound with rn 129093-98-7(Abstract) and JP 02022650 (1990-01-25):
These publications also disclose urea compounds with a bridged cyclic structure.
However, the remote cyclic structure is completely saturated (not pyridyl) and does
not have a substituent consistent with one of the required substituent of the present
invention.
D7 Database CA online, Chemical abstract service Columbus Jeffocoat, a Robert et

al, 'The metabolism and toxicity of halogenated carbanilides biliay metabolites of
3,4,4'-trichlorocarbanilides and 3-triflurocarbanilides in the rat' Drug Metab. Dispos
1997, 5(2), 157-66. Compounds with rn 63348-38-9and 63348-30-1.
This publication discloses a urea compound having a bridged cyclic structure with
the substituent CO2H on the terminal ring. The terminal ring is not pyridyl and the
substituent on this ring is not one of the required substituents.
&--- -1 20CT20111
IITRUE COPY~
D8 WO 99, 32463:
Ureas with bridged cyclic structure having a remote group substituted by

C(O)NRaRband phenyl bound directly to the other side of the urea function (moiety
B) are disclosed. However, these compounds do not have a pyridyl moiety as the
remote group which is substituted by SO2NRaRbor C(O)NRaRb..Those compounds
with a remote pyridyl groups have no substituents on the pyridyl group.
D9 WO 95, 33458:
This publication discloses urea compounds having a bridged cyclic structure,

however, the bridged cyclic structure does not have one of the required substituents
and does not have a pyridyl group as the remote cyclic structure.
US 5,773,459 and US 4,904,668
It is submitted these two references neither alone nor in combination disclose the
claimed compounds. US patent 4,904,668 discloses the pyridine ring bound to the
oxygen bridge at the 2-position.
When the teachings within US patent 5,773,459 and US patent 4,904,668 are
considered as a whole rather than the random hindsight selections thereof, there is
clearly no direction or motivation to arrive at the compounds claimed. There are
numerous distinctions in structure between the compounds claimed and those
disclosed in US patent 5,773,459 and US patent 4,904,668.
US patent 5,773,459 discloses urea and thiourea compounds for the treatment of cell
proliferative disorders such as cancer having the formula given at column 2, line 30:
R2-6
Or a pharmaceutically acceptable salts thereof wherein
Xis oxygen or sulfur,
R1is selected from the group .consisting of optionally substituted aryl, alkyaryl, and
heteroaryl and R2-6 are independently selected from the group consisting of
hydroxyl, hydrogen, alkyl, alkoxy, cyano, nitro, halo, trihalomethyl, amide,
carboxamide, sulfonyl, and sulfoxamide.
No definition of the optional substituents for R1 is given such that reference to
preferred substituents and exemplified compounds is necessary to determine the
scope of R1. At column 3, lines 49-51, US 5,773,459 discloses preferred substituents
for "aryl" groups as "halogen, trihalomethy 1, hydroxyl, SH, OH, NO2, amine,
thioether, cyano, alkoxy, alkyl and amino groups." Ethers are not included in this
definition and the thioethers, defined more specifically at column 4 line 7-8, are
unsubstituted. There is no mention, suggestion or support for a pyridyloxy group or
pyridylthio group, which is further substituted by carbamoyl or methylcarbomoyl.
The substituents for R2-6mentioned above also do not provide for a pyridyloxy
group or pyridylthio group, which is further substituted by carbamoyl or
methylcarbamoyl.
The broad teachings within US 5,773,459 do not support the features of a pyridyloxy
or pyridylthio group substituted by a carbamoyl or methylcarbamoyl group. There
is no mention, suggestion or support for a pyridyloxy group or pyridylthio group,
which is further substituted by carbamoyl or methylcarbamoyl. The substituents for
R1 and R2-6mentioned above do not provide for a pyridyloxy group or pyridylthio
group, which is further substituted by carbamoyl or methykarbamoyl.
Therefore, US 5,773,459 does not anticipate the compounds of the present invention
for the treatment of cancer.
The other reference, US 4,904,668 discloses benzoyl ureas as anti-tumour

compounds. The benzoylated ureas of US 4,904,668 are acylated ureas which are
completely different chemical substance class than ureas due to the benzoyl or acyl
substitution. Benzoyl or acyl ureas are made by a different synthesis route than ureas
and they have completely different chemical properties. For example, acyl ureas
have an acidic NH group whereas ureas do not. In view of the distinct structure,
synthesis and properties of these compounds, they provide no hint or suggestion of
the compounds claimed.
The benzoyl ureas disclosed by US 4,904,668are of the formula:
Q-coNHCONH
wherein Xis a halogen atom, a nitro group or a trifluoromethyl group, provided that
when Y is a nitro group, Xis a halogen atom or a nitro group, Y is a hydrogen atom,
a halogen atom, a nitro group or a trifluoromethyl group, Z1 is a hydrogen atom or a
halogen atom, Z2 is a hydrogen atom or a halogen atom, and A is a =CH- or a
nitrogen atom, or
benzoyl ureas disclosed by US 4,904,668 of the formula:
IITRUE COPY!I
X,-QCONHCONH ---Q-o----{1-z
X y
2
wherein each of X1 and X2 is a hydrogen atom, a halogen atom or a nitro group,

provided that when Y is a nitro group, X1 is a hydrogen atom, Z is a hydrogen atom,
Y is a hydrogen atom, a halogen atom, a nitro group or a trifluoromethyl group and
Z is a hydrogen atom, halogen atom or trifluoromethyl group.
These compounds have other structural distinctions from the compounds claimed.
In view of the submissions made hereinabove, US 5,773,459and US 4,904, 668 do not

teach or suggest the compounds claimed in the present invention and do not render
them anticipated.
US 7,351,834 and US 2003181442:
Applicant submits that US 7,351,834 pertains to the same priority date and
international application PCT/US00/00648 dated January 12, 2000. US2003181442
claims priority from a later date than the priority date of present application. Hence,
they are not considered as prior arts.
US2001011135, US2001011136, US2001016659, US2001027202, US2001034447,

US2002137774 and US2002042517: These abandoned applications claim priority
from the same priority application US 60/115, 877 dated January 13, 1999 and
therefore, are not considered as prior art. US2003105091corresponds to the same
priority date as of the present application and therefore, is not a prior art.
Following documents cited in ISR/IPER also does not anticipate the present
invention:
WO 98/52558 Al and WO 98/52559 Al
These publications do not disclose any ureas with a bridged cyclic structure.
Database HCAPLUS, DN 131:87909, Dumas et. al. and WO 99/32111
Ureas with raf kinase activity having a remote pyridyl group substituted by C(O)
NRaRbare described. However, these ureas are distinct from those claimed herein in
that they have a five membered hetaryl group bound directly to the other side of the
urea function (moiety B) instead of the phenyl or pyridyl groups as in the
compounds claimed herein.
..
IITRUE COPYjl
201f
~,2 OCT
Database HCAPLUS, DN 131:73649, Dumas et. al. and WO 99/32110
This publication does not disclose any ureas having a bridged cyclic structure on one
side of the urea group and a six membered cyclic structure on the opposite side of
the urea group.
Database HCAPLUS, DN 127:293717,Kurik M.V. et. al.
This publication discloses urea compounds having a bridged cyclic group; however
this bridged structure does not have one of the required substituents on the remote
cyclic structure.
Database l-lCAPLUS, DN 127:34137, Kubo et. al.
This publication does not disclose urea compounds which have one of the required
substituents on a remote pyridyl ring. The remote cyclic structure is a quinoline
group with two alkoxy subsituents.
Database HCAPLUS, DN 126:166148,Winkler et. al.
This publication discloses urea compounds having a bridged cyclic group; however,
the bridged structure does not have a remote pyridyl group as required of the
compounds claimed.
Database HCAPLUS, DN 98:78152, Chugai pharmaceutical Co. Ltd. and JP 57-

185219
Based on the English abstract, this publication discloses ureas having a bridged
cyclic structure. However, these urea compounds do not have the required
substituents on the remote cyclic structure; which is also not pyridyl.
Database HCAPLUS, DN 72:79046,Hirt et. al. and CH-479557
These compounds require two urea functional groups between cyclic moieties. None
of the compounds claimed herein have two urea groups such that the reference is
not relevant.
Database HCAPLUS, DN 131:58658,Miller et. al. and WO-9932436
This publication describes urea compounds having a bridged cyclic group

corresponding to L-M-L' as defined herein. However, there is no indication that any
of the required substituents is incorporated on the remote cyclic moiety
corresponding to L'.
IITRUE COPYII
1 2 OCT20ft
Database HCAPLUS, DN 127:273945,Dearden et. al.
This publication discloses urea compounds having a bridged cyclic strucutre.

However, this bridged cylic structure does not exhibit one of the required
substituents on the remote cyclic structure.
Database HCAPLUS, DN 125:245169, Bonwick et. al.
This publication described urea compounds having a bridged cyclic structure.

However, the bridged structure does not exhibit one of the required substituents on
the remote cyclic structure and does not have a remote pyridyl group.
In view of the submissions made hereinabove, it is submitted that the present

invention is not anticipated by the documents cited by the learned Controller.
Accordingly, the Applicant humbly requests the learned Controller to waive the said
objection.
Regarding paragraph 2, Applicant respectfully resists and submits that the claimed
compound of the present invention relates to a novel compound and therefore,
question of it falling under the prohibition of Section 3(d) does not arise. Hence, the
learned Controller is respectfully requested to withdraw this objection.
Regarding paragraphs 3 and 4, Applicant submits that while the divisional

application was filed with the claims of the parent application and subsequently
have been amended on April 11, 2008. Accordingly present claims on file do not
conflict with the claims granted on parent application.
However, claims have been further amended to delete the repetitious portion
therefrom.
The applicant submits herewith the highlighted version of claims to meet the learned
Controller's requirement.
The amendments carried out in the specification have necessitated retyping of pages
1 and 89 to 97 as fresh pages 2 and 90 to 96. The retyped pages are submitted
herewith (in duplicate). The superseded pages 1 and 89 to 97 may be considered as
cancelled.
With respect to paragraph 5, it is submitted that the power of authority has already
been filed on February 10, 2012. A copy of same is submitted herewith for your
ready reference. The Learned Controller is therefore, requested to withdraw this
objection.
IITRUE COPYII 1 2 OCT2012

Regarding paragraphs 6, we also have the honour to submit herewith the details of
the corresponding foreign applications in a further statement and undertaking on
Form 3. We also have the honour to submit herewith the petitions under Rules 137
and 138 alongwith the prescribed official fee for obviating the irregularity and
condoning the delay in conveying such details.
Regarding paragraph 7, we have the honour to submit herewith copies of

prosecution details of the corresponding applications outside India.
We also submit herewith the amended application form reflecting new address for
service.
Grant of a Patent on this application within the final and inextendible period
expiring on October 29, 2012 (October 27, 2012 and October 28, 2012 being weekend
holidays) is respectfully requested.
Before taking any adverse decision on this case, the Controller is respectfully
respected to give an opportunity to the applicant to be officially heard in this matter.
ly,
~
ay Kumar)
Patent Agent
Of Perfexio Legal
Attorney for the applicant
Enclosure( s):
Fresh retyped pages (in duplicate)

Copy of highlighted version of claims
Copy of our letter dated February 10, 2012 filing power of authority
Fresh Form 3 (in duplicate) alongwith Petitions under Rules 137 and 138 (in
duplicate)
Prosecution details (list enclosed)
Copy of granted US and EP patents
Fresh application form (in duplicate)
Herewith Rs. 8,000/- by Cheque No. 611845 dated October 11, 2012
IITRUE COP\jj ~, 2 OCT201!

.:\<hanlNal'is BusinessPark
T1wer ,\. Isl Floor.Plot:''fo-i,Seour 142.
Expressway.Nu,da-2013ll:i India
Tel.: +91-120-2459858; 245 98!)9
Fax.: +91-I20-24~9860
Em;1il:mail@perfexiulegal.corn
~RFE?<ZJO LEGAL Websile:w,,,w.perfexiolegal.coill
'Attorneys-At-Law
Our Ref: SKR/ASY/ IP: 1633/MUMNP/2007
Friday, February 10, 2012
BY HAND
The Patent Office
COPY
Mumbai
Dear Sir,
Re: Request for alteration of address of services in respect of Indian Patent
Application No. 1633/MUMNP /2007 in the name of Bayer Corporation
under Section 57 of The Patents Act, 1970
We write with respect to the captioned Indian patent application.
It is submitted that the applicant has appointed us the agent for the above-identified lndian
patent application in India. Accordingly, the applicant wishes to alter the address for
service in India in the records of the Patent Office as under:
PERFEXIOLEGAL
Attorneys-At-Law
Vasant Kunj
In this regard, we submit herewith a fresh power of authority duly executed by the
applicant along with a formal request for amendment on Form 13 for change of its address
for service. An official fee of Rs. 800 is also submitted herewith.
The Learned Controller is respectfully requested to record the change in the address for
service and send all future correspondence on this application to us.
ully,
•;
SANJ,. MAR
P t Agent
Of Perfexio Legal
Attorney for the Applicants
Enclosures:
Form 13 in duplicate;
Duly executed and starnped power of authority (in original) and
Herewith official fee of Rs. 800 by Cheque No. 566202 dated February 10, 2012
Drawn on HDFC Bank Ltd., Vasant Kunj, New Delhi.
··12 OCT2DfZ
IITRUE COPYll 70 India Tel.:
PostalAddress:C-9i%55, V;isam + 9l l ! '11767656
COPY
FORM13
(39 of 1970)
THE PATENTS (AMENDMENTS) RULES, 2006
APPLICATION FOR AMENDMENT OF THE APPLICATION FOR
PATENT COMPLETE SPECIFICATION UNDER SECTION 57
[See Section 57; rule 81 [1]
We, Bayer Corporation, an Indiana corporation having its principal place of

business at 100 Bayer Road, Pittsburgh, Pennsylvania 15205, United States of
America,
request leave --t_oamend the documents of Indian Patent Application No.

1633/MUMNP/2007 dated October 4, 2007.
"·
Our reason for making this amendment is as follows:
That the applicant has altered its address for service in India and wish to
amend the documents to reflect its new address for service indicated below:
PERFEXIO LEGAL
Attorneys-At-Law
Vasant Kunj
New Delhi-110 070 India
We declare that the facts and matters stated herein are true to the best of
our knowledge, information and belief.
Dated this 10th day of February, 2012
¾~
(SA~Yl<UMAR)
OF'PERFEXIO LEGAL
A TIORNEY FOR THE APPLICANTS
TO
THE CONTROLLER OF PA TENTS
THE PATENT OFFICE,
MUMBAI
llTRUE COPYjl
1 2 OCT20t!
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INTELLECTUAL
Governme
G
Patent Office,
O
nt of India
a
Boudhik Sampada
S Bhawa
an Email: mumbai-pa
atent@nic.in
PROPERTY INDIA M. Road, Near Po
S.M ost office,
PATENTSIDESIGNSITRADE MARKS
Web
bsite: www.ip
pindia.nic.in
Antop Hill,
H Mumba
ai – 400 03
37, India
GEOGRAPHICAL. INDICATIONS
on No. 1633/M
Applicatio MUMNP/200
07 19/05/202
22
To,
CTOR-C, POCK
9655, SEC KET-9, VASANT KUNJ, NEW
W DELHI-110 0070, INDIA
Sub; Orde
er under sectiion 15 for the
e Application for Patents N
No. 1633/MU MNP/2007
Please find enclosed an

n order under section 15 of
o Patents Actt;
SUHAS KULK KARNI

Asst .Co
ontroller of Paatents and Deesigns
Email, rem
mfry-sagar@rremfry.com
mail@perrfexiolegal.com
IITRUF, COPYjl
1.0 INTRODUCTION
Application Number ; 1633/MUMNP/2007

Date of filing ; 05/10/2007
Name of Applicant BAYER CORPORATION, 100 BAYER ROAD, PITTSBURGH,
PENNSYLVANIA, 15205.
Title of Application ;" CARBOXYARYL SUBSTITUTED DIPHENYL
UREAS AS RAF KINASE INHIBITORS”.
2.0 SUBEJCT MATTER CLAIMED IN CLAIMS
Subject matter claimed in claim 1 dated 12/09/2018 as listed below, instant application has total
10 claims , independent claim 1 as below,
2
1. A compound of Formula }:
------~- J\-D-Il _______ (!)~

or a pharmaceutically acceptable salt thereof, whcrcit)
___ Dis __ -NH-C(O)-NH-,
A is ___
a substitu!ied moiety of the formuJa:
1
-------~~~--- -L-\1-L '
._ ---~---""'herein
Lis phenyl, optionally substituted by halogen, up to per.halo, and Wn, where n is 0-3;
wherein l\1lcl-eachW is independently selected from the i,'troupconsisting of C 1-C5 linear
or bram:hed alkyl, C 1-Cs linear or branched haloalkyl up to perhaloalkyl and C,-C.1
alkoxy
J} is selected from pyridinyl substituted by -C(O)R~,and
___ optionally substituted with 1-3 additional subslinients independently selected
from the grl)up consisting of R,. and halogen;
__ wherein R~ is NRaRhand Ra and Rh are~
iA)_ independently
a) hydrogen,
b) C,-Cio_alkyl,
c) CG_aryl,
d} pyridinyl
e) substitutedC 1_rnalkyl,
I) substitutedc6 aryH,
g) subs1i1utedpyridinyl
h) ~phenylpiperazine(pyridinyl),
i) -phenylmorpholinyl.
j) -cthylmorpholinyl,
k) -ethyJpi peridy I,
I) -methyl pyrrolidinyl,
or
n) -C1l~NH(phenyl);
3
(ITRUE COPYII
where wh1:nR.iand Rb are a substituted group, they are sobstituted by
a) _halogen up 10 per halo,

b) hydroxy>
c) -N{CH3)2,
d) C1-C1o_alkyl,
e) C1-C1o_alkoxy)
f) HalosubslitutcdCi-6 alkyl, or
g) :OSi(Pr-i)3; or
iiH) -R 8 and Rb 1ogetherform piperazine or a ~uh~titutedpiperazinewith suhstituents

selected from the group consisting oJ~
a) _halogen,
b) hydroxy,
c) C1·.ir_l:
1+!alkyl1
d) pyridinyl
c) C,-1ll21rialkoxy,
f) C,;_aryL
g) halo substitutedC6 aryl, and
__ M is selected from the group conslsttng of oxygen and sulfur;

and
Bis
. ~phenyl, substitui1cdwith 1-3 subslitucnts independently selected from the group
consisting of halogen and Ri,
and R1 is
(a) C,-Cn linear or branched alkyt; optionally substituted with 1-3 hatogen
substituen1s~or
(b) C 1-Cr,linearor branched alkoxy.
&------
11TRUE COPY]I
3.0
0 Objections
1. Initiallyy both in parrent & instan
nt divisional application
a saame set of cclaims have b
been filed. Su
ubject
matter cllaimed in claaims are in conflict with
h the subjectt matter claimed in claims of the P
Parent
applicatio efore division al status of tthe present aapplication caannot
on No IN/PCTT/2001/0799//MUM, there
be allowe
ed. Further, th
he narrower set
s of claims with
w specific compounds w
which is fall w
within the sco
ope of
the comp
pounds of formula claimed
d in the instant applicatio n, have alreaady been granted in the p
parent
applicatio
on. So, divisio
onal status under
u section present application cannot be
n 16 of the Act to the p
allowed.
2. Form 13 filed for tecchnical amendments of claaims cannot bbe considered
d until you filee the highligh
hted
he amendmen
copy of th nts carried on
n initially filed
d set of claimss.
3. Subjectt-matter claim
med in claims 1-24 are in conflict
c with tthe claims of tthe granted cclaims of the
patent ap
pplication No. IN/PCT/2001
1/00799/MUM
M, therefore divisional staatus of the insstant applicattion
may not be
b allowed;
4..0 Analysis
Instant application iss divided out of the applicaation for Pateent No.IN/PCTT/2001/00799/MUM , insttant
applicaation claims a group of com
mpounds in which
w differs ffrom the pareent applicatio
on in the sensse ,
1. A compound of Formula l:
-----~-- J\-D-13 ___________ (I);

or a pharmaceutically acceptable salt thereof, whcrciJ\
___ Dis __ -NH-C(O)-NH-,
Definition
n of D wherein
n in D is As de
efined above,,
Documents as cited in the International Search Report
R of Par ent applicatio
on teaches,
Claims 1-2
27,29,81-88,4 48-5S,55-58 laack novelty uunder PCT Artticle ss (2) ass being anticipated
40,41,44,46,4
by Databaase HCaplus,
DEN J.C. et al.. "Quantitativve Structural Biodegradability studies: an investigation of
DN 127:27S945 DEARD
the MITI Aromatic
A com base" especiaally RN# 2401 9-05-4
mpound datab
RN # 240
019-05-4 read wherein B is a an 6-membered
ds on the compounds of the claimed invention w
substitute
ed aryl, Dis -NHC(O)-NH-, A is a substtituted moietty wherein L is a 6 memb
bered ring directly
linked to D and M is a bridging atom
m -0-, and L' iss phenyl ring substituted b
by S08H.
Claims 1-2
27,29,81-88,4 58,55-58 lack novelty und er PCT Article SS(2) as beeing anticipatted by
41,44,46,48-5
Database HCAPLUS,
[frRuEcoPYjl
DN 125:245169, BONWICK et al. "Production of Murine monoclonal antibodies against sulcofuron and
flucofuran by in-vitro immunization" Abstract, Journal of Immunological Methods, 1996, Vol. 196, No. 2,
pages 16S-17S. See entire document, especially RN # 24019-05-04.
RN # 24019-05-04 reads on the compounds of the claimed invention wherein B is a an 6-membered
substituted aryl , D is NH-C(O)-NH-, A is a substituted moiety wherein L is a 6 membered ring directly
linked to D and M is a bridging atom is-0-, and L' is a substituted phenyl group, substituted by "-S08H"
5.0 Conclusion
Therefore, subject matter claimed in claim 1 is not meeting requirement of section 2 (1) (j) and fall
within scope of section 3 (d) of Patents Act, application it is refused to proceed for grant,
SUHAS KULKARNI
Asst Controller of Patents
6
'"'•P""""
j Patent.amt
European
Patent Office
Office europeen
des brevets
Extract from the Register of European Patents
About this file: EP1793824
EP1793824 - NEW PHARMACEUTICAL COMPOSITIONS COMPRISING 4-(4-(3-(4-CHLORO-

--
3-TRIFLUOROMETHYL-PHENYL)-UREIDO)-3-FLUORO-PHENOXY)-PYRIDINE-2-
CARBOXYLIC ACID FOR THE TREATMENT OF HYPER-PROLIFERATIVE DISORDERS [Right-
click to bookmark this link]
Patent revoked
Status Status updated on 19.01.2022
Database last updated on 30.09.2022
published
Most recent event 21.01.2022
IRevocation of patent
Ion 23.02.2022 [2022/08]
For all designated states
Applicant(s) 100 Bayer Boulevard
Whippany, NJ 07981-0915 / US
[2014/47]
01 / DUMAS, Jacques
98 Farmview Road
Bethany, CT 06524 / US
02 / EHRLICH, Paul
Bockumer Straase 48
Inventor(s) 40489 Duesseldorf-Wittlaer / DE
03 / ZULEGER, Susanne
Klosterstrasse 92
50931 Koeln / DE
[2007/24]
Weickmann & Weickmann PartmbB
Postfach 860 820
Representative(s) 81635 München / DE
[N/P]
05792486.2 29.08.2005
Application number, filing date [2007/24]
WO2005US30541
US20040604752P 27.08.2004 Original published format: US 604752 P
Priority number, date
[2007/24]
Filing language EN
Procedural language EN
Type: A1 Application with search report
No.: WO2006026500
Date: 09.03.2006
Language: EN
[2006/10]
Type: A1 Application with search report
No.:
-
EP1793824
Date: 13.06.2007
Publication Language: EN
The application published by WIPO in one of the EPO official languages on 09.03.2006 takes the place of the
publication of the European patent application.
[2007/24]
-
Type: B1 Patent specification
No.: EP1793824
Date: 18.11.2015
Language: EN
[2015/47]
Search report(s) International search report - published on: EP 09.03.2006
A61K31/44, A61K31/4415, A61K9/14,
IPC: [2015/22]
A61K9/16, A61K9/20, A61P35/00
Classification
A61K31/44 (EP,KR,NO,US); A61K31/4415 (EP,US); A61K9/0053 (US);
CPC:
A61K9/14 (NO); A61K9/146 (EP,US); A61K9/16 (KR); (+)
:!!=-
l!TRUE COPYII_________ _
AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE, IS, IT, LI, LT, LU, LV,
Designated contracting states
MC, NL, PL, PT, RO, SE, SI, SK, TR [2015/47]
BA 27.03.2007
HR 27.03.2007
Extension states
MK 27.03.2007
YU 27.03.2007
NEUE PHARMAZEUTISCHE
ZUSAMMENSETZUNGEN MIT 4-(3-(4-
CHLORO-3-TRIFLUOROMETHYL-
PHENYL)-UREIDO)-3-FLUOR-PHENOXY)-
German: [2007/24]
PYRIDIN-2-CARBONSÄURE ZUR
BEHANDLUNG VON
HYPERPROLIFERATIVEN
ERKRANKUNGEN
NEW PHARMACEUTICAL COMPOSITIONS
COMPRISING 4-(4-(3-(4-CHLORO-3-
TRIFLUOROMETHYL-PHENYL)-
Title
English: UREIDO)-3-FLUORO-PHENOXY)- [2007/24]
PYRIDINE-2-CARBOXYLIC ACID FOR THE
TREATMENT OF HYPER-PROLIFERATIVE
DISORDERS
COMPOSITIONS PHARMACEUTIQUES
COMPORTANT DE L'ACIDE 4-(4-(3-(4-
CHLORO-3-TRIFLUOROMETHYL-
French: PHENYL)-UREIDO)-3-FLUORO- [2007/24]
PHENOXY)-PYRIDINE-2-CARBOXYLIQUE
POUR LE TRAITEMENT DE TROUBLES
HYPERPROLIFERATIFS
27.03.2007 National basic fee paid
Entry into regional phase 27.03.2007 Designation fee(s) paid
27.03.2007 Examination fee paid
Request for preliminary examination filed
27.06.2006
International Preliminary Examining Authority: US
27.03.2007 Examination requested [2007/24]
Despatch of a communication from the examining division (Time limit:
14.01.2011
M06)
20.07.2011 Reply to a communication from the examining division
14.12.2011
M06)
02.11.2012
M04)
Examination procedure Despatch of a communication from the examining division (Time limit:
25.03.2013
M02)
20.02.2014
M06)
26.05.2015 Communication of intention to grant the patent
Disapproval of the communication of intention to grant the patent by the
08.06.2015
applicant or resumption of examination proceedings by the EPO
14.07.2015 Communication of intention to grant the patent
08.10.2015 Fee for grant paid
08.10.2015 Fee for publishing/printing paid
08.10.2015 Receipt of the translation of the claim(s)
EP13151040.6 / EP2589384
Divisional application(s) The date of the Examining Division's first communication in respect of the earliest application for which a
communication has been issued is 14.01.2011
01 17.08.2016 23.08.2016 ADMISSIBLE
Ter Meer Steinmeister & Partner Patentanwälte mbB
Nymphenburger Strasse 4
80335 München / DE
Opponent(s) Opponent's representative
Opposition(s) Ter Meer Steinmeister & Partner
Patentanwälte mbB
Nymphenburger Straße 4
80335 München / DE
[2016/39]
deleted Deletion: Legal effect of rejection of opposition [ N /P ]
26.09.2016 Invitation to proprietor to file observations on the notice of opposition
16.01.2017 Reply of patent proprietor to notice(s) of opposition
20.10.2017 Date of oral proceedings
28.11.2017 Despatch of minutes of oral proceedings
28.11.2017 Date of despatch of rejection of opposition
07.09.2021 Legal effect of revocation of patent [2022/08]
:;._:E_
-
[!_:1uJJ::
_l:OPYII
17.12.2021 Despatch of communication that the patent will be revoked
08.02.2018 Appeal received No. T0377/18
06.04.2018 Statement of grounds filed
Appeal following opposition 07.09.2021 Result of appeal procedure: revocation of the patent
17.12.2021 Despatch of the decision of the Board of Appeal
07.09.2021 Date of oral proceedings
Renewal fee
31.08.2007 Renewal fee patent year 03
Fees paid
deleted
Lapses during opposition
[2016/27]
[DY]WO0042012 (BAYER AG [US], et al) [DY] 1-35 * page 4, line 12-
International search
14; compound 49 in table 4 *;
[Y]WO0041698 (BAYER AG [US], et al) [Y] 1-35 * page 8, line 10 -
page 11, line 6; compound 49 in table 4 *;
[Y]WO03068228 (BAYER AG [US], et al) [Y] 1-35 * page 4, line 1-
page, line 21; compound 49 on page 57 *;
[PX]WO2005009961 (BAYER PHARMACEUTICALS CORP [US], et al)
[PX] 1-35* examples 1-11 on pages 47-56 *;
[Y] - AHMAD TANYA ET AL, "Kinase inhibition with BAY 43-9006 in
renal cell carcinoma.", CLINICAL CANCER RESEARCH : AN
OFFICIAL JOURNAL OF THE AMERICAN ASSOCIATION FOR
CANCER RESEARCH. 15 SEP 2004, Presentation at First International
Cited in Conference on Innovations and Challenges in Renal Cancer,
Cambridge, Massachusetts, (20040319), vol. 10, no. 18 Pt 2, ISSN
1078-0432, pages 6388S - 92S, XP002362669 [Y] 1-35 * formula and
table on page 6389S *
DOI: http://dx.doi.org/10.1158/1078-0432.CCR-040028
[A] - LEUNER C ET AL, "Improving drug solubility for oral delivery
using solid dispersions", EUROPEAN JOURNAL OF
PHARMACEUTICS AND BIOPHARMACEUTICS, ELSEVIER SCIENCE
PUBLISHERS B.V., AMSTERDAM, NL, (20000703), vol. 50, no. 1,
ISSN 0939-6411, pages 47 - 60, XP004257179 [A] 1-35 * the whole
document *
DOI: http://dx.doi.org/10.1016/S0939-6411(00)00076-X
- WILHELM SCOTT M ET AL, "Regorafenib (BAY 73-4506): a new
oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor
Examination tyrosine kinases with potent preclinical antitumor activity",
INTERNATIONAL JOURNAL OF CANCER, (201107), vol. 129, no. 1,
ISSN 0020-7136(print), pages 245 - 255
- WILHELM SCOTT ET AL, "Discovery and development of sorafenib:
a multikinase inhibitor for treating cancer.", NATURE REVIEWS. DRUG
DISCOVERY OCT 2006 LNKD- PUBMED:17016424, (200610), vol. 5,
no. 10, ISSN 1474-1776, pages 835 - 844
- Bruno C Hancock ET AL, Pharmaceutical Research, (20000101), vol.
17, XP055102285
- European Medicines Agency Science Medicines Health,,
"Assessment report Stivarga International non-proprietary name:
other
REGORAFENIB", Assessment report EMA/467788/2017, (20170704),
pages 1 - 91, XP055714681
Opposition WO0042012
EP1350792
WO2005009961
- Excerpt from the DrugBank, page 1 and 4, URL:
http://www.drugbank.ca/drugs/DB08896
- C. LEUNER et al., "Improving drug solubility for oral delivery using
solid dispersions", Eur. J. Pharm. Biopharm., (20000000), vol. 50,
pages 47 - 60, XP004257179
DOI: http://dx.doi.org/10.1016/S0939-6411(00)00076-X
BESCHWERDEKAMMERN BOARDS OF APPEAL OF CHAMBRES DE RECOURS
DES EUROPÄISCHEN THE EUROPEAN PATENT DE L'OFFICE EUROPÉEN
PATENTAMTS OFFICE DES BREVETS
Internal distribution code:

(A) [- ] Publication in OJ
(B) [- ] To Chairmen and Members
(C) [- ] To Chairmen
(D) [X ] No distribution
Datasheet for the decision

of 7 September 2021
Case Number: T 0377/ 18 - 3.3.01
Application Number: 05792486.2
Publication Number: 1793824
IPC: A61K31/44, A61K31/4415,

A61K9/14, A61K9/16, A61K9/20,
A61P35/00
Language of the proceedings: EN
Title of invention:
NEW PHARMACEUTICAL COMPOSITIONS COMPRISING 4-(4-(3-(4-CHLORO-3-
TRIFLUOROMETHYL-PHENYL)-UREIDO)-3-FLUORO-PHENOXY)-PYRIDINE-2-
CARBOXYLIC ACID FOR THE TREATMENT OF HYPER-PROLIFERATIVE
DISORDERS
Patent Proprietor:
Opponent:
Ter Meer Steinmeister & Partner Patentanwälte mbB
Headword:
Regorafenib in solid dispersion/BAYER
Relevant legal provisions:

EPC Art. 56
RPBA 2020 Art. 13(2)
This datasheet is not part of the Decision.

EPA Form 3030 It can be changed at any time and without notice.
- 2 -
Keyword:
Inventive step - main request, auxiliary requests 1 to 5 (no)
Amendment after summons - taken into account - (no)
Admission of TIPA - (no)
This datasheet is not part of the Decision.

EPA Form 3030 It can be changed at any time and without notice.
fu1opih.cho Beschwerdekammern Boards of Appeal of the
European Patent Office
Patent amt
Richard-Reitzner-Allee 8
Boards of Appeal
tu,opol'I
P•ttnt Offi<t 85540 Haar
Office turopEcn
GERMANY
des b1tvtts Tel. +49 (0)89 2399-0
Chambres de recours Fax +49 (0)89 2399-4465
Case Number: T 0377/18 - 3.3.01
D E C I S I O N
of Technical Board of Appeal 3.3.01
of 7 September 2021
Appellant: Ter Meer Steinmeister & Partner Patentanwälte mbB

Nymphenburger Strasse 4
(Opponent)
80335 München (DE)
Representative: Ter Meer Steinmeister & Partner

Patentanwälte mbB
Nymphenburger Straße 4
80335 München (DE)
Respondent: Bayer HealthCare LLC

100 Bayer Boulevard
(Patent Proprietor)
Whippany, NJ 07981-0915 (US)
Representative: Weickmann & Weickmann PartmbB

Postfach 860 820
81635 München (DE)
Decision under appeal: Decision of the Opposition Division of the

European Patent Office posted on 28 November
2017 rejecting the opposition filed against
European patent No. 1793824 pursuant to Article
101(2) EPC.
Composition of the Board:

Chairwoman T. Sommerfeld
Members: M. Pregetter
L. Bühler
- 1 - T 0377/18
Summary of Facts and Submissions
I. European patent No. 1793824 is based on European patent

application No. 05792486.2, filed as an international
application published as WO2006/026500.
The patent as granted contains several independent

claims. Claim 1 as granted reads as follows:
"1. A composition comprising a solid dispersion

comprising at least 4{4-[3-(4-chloro-3-
trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-
pyridine-2-carboxylic acid methyl amide in
substantially amorphous form and a pharmaceutically
acceptable matrix."
II. The following documents, cited during the opposition

and appeal proceedings, are referred to below:
(2) WO2005/009961
(5) WO00/42012
(6) Leuner et al., Eur. J. Pharm. Biopharm., 2000, 50,

47-60
(14) "EMA approval on regorafenib for second-line

treatment of adult patients with hepatocellular
carcinoma (HCC), gastrointestinal stromal tumors (GIST)
and colorectal cancer", submitted on 19 September 2017,
47 pages
(15) "Test Protocol", 6 September 2017, 10 pages

- 2 - T 0377/18
(18) Lowinger et al., Curr. Pharm. Des., 2002, 8,

2269-78
(19) EMA Assessment Report on Stivarga, 4 July 2017, 91

pages
III. The patent was opposed under Article 100(a) and (b) EPC
on the grounds that the claimed subject-matter lacked
inventive step and was not disclosed in a manner
sufficiently clear and complete for it to be carried
out by a person skilled in the art.
In the course of the opposition proceedings, the patent

proprietor requested that the opposition be rejected,
and submitted auxiliary requests 1 to 4, all filed on
19 September 2017.
The opposition division rejected the opposition.
IV. The opponent (appellant) appealed against this

decision.
V. With its reply to the statement setting out the grounds

of appeal, dated 8 August 2018, the patent proprietor
(respondent) resubmitted auxiliary requests 1 to 4 and
submitted document (18).
Claim 1 of auxiliary request 1 differs from claim 1 as

granted by the additional definition
"wherein the matrix comprises a pharmaceutically

acceptable polymer, a sugar and/or sugar alcohol and/or
cyclodextrin."

granted by the definition that the matrix comprises a
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"pharmaceutically acceptable polymer."
Claim 1 of auxiliary request 3 further limits this

polymer to a polymer selected "from the group
consisting of polyvinylpyrrolidone, vinylpyrrolidone/
vinylacetate copolymer, polyalkylene glycol,
polyethylene glycol, hydroxyalkyl cellulose,
hydroxypropyl cellulose, hydroxyalkyl methyl cellulose,
hydroxypropyl methyl cellulose, carboxymethyl
cellulose, sodium carboxymethyl cellulose, ethyl
cellulose, polymethacrylates, polyvinyl alcohol,
polyvinyl acetate, vinyl alcohol/vinyl acetate
copolymer, polyglycolized glycerides, xanthan gum,
carrageenan, chitosan, chitin, polydextrin, dextrin,
starch and proteins."
Claim 1 of auxiliary request 4 provides a shorter list

of polymers, the polymers being selected "from the
group consisting of polyvinylpyrrolidone, hydroxypropyl
cellulose, hydroxypropyl methyl cellulose and
polyethylene glycole [sic]."
VI. On 7 February 2020 the board issued a summons to oral

proceedings, followed on 7 April 2020 by a
communication pursuant to Article 15(1) RPBA.
VII. On 24 June 2020 third-party observations including

document (19) were submitted.
VIII. With a letter dated 16 July 2020, the respondent

submitted auxiliary request 5.
Claim 1 of auxiliary request 5 is identical to claim 1

as granted.
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IX. Oral proceedings before the board took place on

7 September 2021. During the oral proceedings, the
respondent submitted auxiliary request 6.

granted in that the matrix is restricted to
polyvinylpyrrolidone.
X. The appellant's arguments, in so far as they are

relevant to the present decision, may be summarised as
follows:
Admission of third-party observations and document (19)
The third-party observations were to be admitted.

According to established case law relevance was one of
the criteria to consider. Furthermore, exceptional
circumstances existed in view of the respondent's
submission of document (18) and its claim of
superiority of regorafenib over sorafenib in its
submission of 8 August 2018. Document (19) was highly
relevant, since it rebutted the respondent's arguments
concerning superiority. As document (19) was published
one year after the opposition had been filed, it could
not have been submitted within the opposition period.
Inventive step
Document (5) represented the closest prior art. The

general class of compounds of document (5), i.e. diaryl
ureas, were known to be serine-threonine kinase
inhibitors as well as tyrosine kinase inhibitors
(paragraph [0002] of the patent in suit). Document (5)
described its compounds as raf kinase inhibitors. The
starting point for assessing inventive step was the
compound disclosed as entry 49. It was supported by
- 5 - T 0377/18
case law that an embodiment could serve as a starting

point. The difference between the subject-matter of
claim 1 of the patent as granted and entry 49 was the
fluorine substitution, instead of the chlorine
substitution in the same position, and the formulation
in amorphous form in a solid dispersion. Alternatively,
the compound of entry 42 (sorafenib) could be seen as
the starting point. The patent was silent on any
effects linked to differences in structure. It merely
referred to potential inhibitory actions of 4{4-[3-(4-
chloro-3-trifluoromethylphenyl)-ureido]-3-
fluorophenoxy}-pyridine-2-carboxylic acid methyl amide
(regorafenib), without providing any evidence thereof
(paragraph [0004]). Such inhibitory action could thus
not be acknowledged. Document (2), cited in
paragraph [0004], was post-published and, moreover, not
cited in the application as filed. As the patent was
focused on compositions and not on the activity of an
active compound, it contained no further relevant
information. Document (14) was post-published and could
not be taken into account in the absence of any initial
plausibility. Even if it were taken into account, it
could not show any superiority. The first partial
problem was thus the provision of an alternative
compound for the treatment of cancer. No effects had
been shown over the closest prior art concerning the
differences relating to the amorphous form and the
solid dispersion. The presence or absence of certain
molecular interactions that were possibly (not) present
in the closest prior art could thus not be assessed.
Moreover, the data in the patent in suit did not allow
an effect to be established over the whole scope. The
second partial problem was thus the provision of an
alternative formulation. The solution to both partial
problems was obvious. The structural aspects were
obvious from document (5) itself, since it contained
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"exemplified compounds" having either chlorine, methyl

or hydrogen in the same position, thus pointing to
substitutions in this position. As halogen
substitutions were taught by document (5), the
selection of a fluorine substitution in such a position
was obvious. Concerning the formulation as a solid
dispersion, this was obvious from document (6).
Document (6) gave an overview of various compounds and
thus showed the general applicability of solid
dispersions to increase solubility and bioavailability
of poorly soluble compounds. It also listed various
carriers. The document provided motivation for the
person skilled in the art to try solid dispersions for
compounds such as regorafenib and sorafenib.
The carriers defined in the respective claims 1 of

auxiliary requests 1 to 4 were taught by document (6).
Admission of auxiliary request 6
There were no exceptional circumstances justifying the

admission of auxiliary request 6, which had been
submitted at the latest possible stage.
XI. The respondent's arguments, in so far as they are

relevant to the present decision, may be summarised as
follows:
Admission of third-party observations and document (19)
The third-party observations should not be admitted.

Article 115 EPC could not serve to extend a third
party's rights beyond the rights of the parties to the
proceedings. Document (19) was not only late-filed but
furthermore post-published.
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Inventive step
Document (5), which represented the closest prior art,

disclosed a generic formula and 103 examples, none of
which was highlighted, including sorafenib and its
chlorine derivative. Various oral formulations of the
compounds as such or their salts were suggested,
including tablets, hard gelatin capsules, suspensions,
oily suspensions and so on, without however mentioning
solid dispersions. Document (2), cited in paragraph
[0004] of the patent, showed that regorafenib inhibited
the kinases mentioned in this paragraph. Document (2)
was from the same applicant and had been published
before the filing date of the patent. It thus proved
that the patent proprietor had been in possession of
the invention at the priority date. Document (14)
disclosed that regorafenib was even effective in
patients who showed insufficient response to the
treatment with sorafenib, which is mentioned in
document (5) as entry 42. It was thus clear that
regorafenib had a different activity from sorafenib.
With the reply to the statement setting out the grounds
of appeal, evidence was provided that regorafenib
showed an improved performance in inhibiting p38,
mPDGFR and mVEGFR2, inhibiting and preventing the
proliferation of MDA-MB231 cells, and was a more potent
inhibitor in the PDGFR cellular assay than entry 49 of
document (5) (Tables 1 and 2). The data in the patent
in suit showed the improved solubility and
bioavailability of regorafenib in solid dispersions
(Examples 18 to 20, supplemented by the data in
document (15)). The technical problem was thus the
provision of (I) an oral formulation having improved
solubility of (II) a carboxyaryl-substituted diphenyl
urea with improved kinase inhibition activity. It was
hindsight to arrive at regorafenib, after making
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several selections for various substituents, when

starting from document (5). There was no indication in
document (5) that regorafenib would be well-suited for
therapeutic use. Due to its fluorine substitution and
the aromatic rings, regorafenib was very insoluble.
Document (5) pointed to the use of salts, which is an
option the person skilled in the art would try first,
and disclosed galenic forms such as hard gelatin
capsules. From the disclosure of document (5) regarding
formulations, the person skilled in the art would not
have envisaged the use of solid dispersions. Again,
only hindsight would lead the person skilled in the art
to consider solid dispersions, as no information could
be found anywhere that regorafenib was a candidate for
solid dispersions. As already stressed in the abstract
of document (6), 40 years of research into solid
dispersions had resulted in only a few marketed
products, a trend that had not been broken even in
2021. Furthermore, document (6) did not disclose solid
dispersions with active agents that were structurally
or functionally related to regorafenib, and therefore
provided no hint to the person skilled in the art.
Moreover, document (6) raised certain concerns: it
indicated that solid dispersions might not work, that
formulations might be too large to be administered
orally and that there were issues with predictability
of results, in particular in vivo results (page 58,
left-hand column). In sum, document (6) could not raise
any expectation of success. Consequently, the person
skilled in the art would not have arrived at
regorafenib and would not have formulated it as a solid
dispersion.
There were no additional arguments for auxiliary

requests 1 to 5.
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Admission of auxiliary request 6
Auxiliary request 6 was to be admitted. It corresponded

to auxiliary request 4 limited to merely
polyvinylpyrrolidone. The reason for its late
submission was the surprising finding of the board
concerning inventive step for the higher-ranking
requests. This could not have been anticipated by the
respondent in view of the rejection of the opposition
by the opposition division and the lack of any
indication of problems relating to patentability in the
board's communication pursuant to Article 15(1) RPBA.
XII. The final requests of the parties were as follows:
The appellant requested that the decision under appeal

be set aside and the patent be revoked. It also
requested that the observations by a third party,
including document (19), be admitted into the appeal
proceedings, and that auxiliary request 6 not be
admitted.
The respondent requested that the appeal be dismissed.

Alternatively, it requested that the patent be
maintained based on the claims of any of auxiliary
requests 1 to 4 filed with the reply to the grounds of
appeal, or of auxiliary request 5 filed by the letter
dated 16 July 2020, or of auxiliary request 6 filed
during the oral proceedings on 7 September 2021. The
respondent further requested that the observations by a
third party not be admitted into the appeal
proceedings, and that auxiliary request 6 be admitted.
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Reasons for the Decision
1. The appeal is admissible.
2. Admission of the third-party observations and

document (19)
The third-party observations, including document (19),

were submitted on 24 June 2020, more than 2 months
after the board had issued a communication pursuant to
Article 15(1) RPBA 2020 and more than 4 months after
notification of the summons to oral proceedings, and
thus at a very late stage.
According to Article 13(2) RPBA 2020, any amendment to

a party's appeal case made after notification of a
summons to oral proceedings shall, in principle, not be
taken into account unless there are exceptional
circumstances, which have been justified with cogent
reasons by the party concerned.
The third party did not identify any exceptional

circumstances. The appellant identified the
respondent's line of argument in the reply to the
statement setting out the grounds of appeal and the
submission of document (18) as exceptional
circumstances. The board cannot accept this argument.
The third-party observations were submitted on
24 June 2020, almost two years after the reply to the
grounds of appeal, which was submitted on
8 August 2018. Consequently, the submission of the
third-party observations cannot be seen as a direct
reaction to this reply. The (potential) relevance of
- 11 - T 0377/18
the third-party observations or of document (19) does

not on its own constitute exceptional circumstances. In
addition, a third party is not an actual party to the
proceedings, and as such should not be accorded more
favourable treatment than an actual party.
Consequently, the third-party observations submitted on

24 June 2020 were not admitted into the proceedings.
3. Main request (patent as granted) - inventive step
3.1 The patent in suit relates to pharmaceutical

compositions and to their use for treating hyper-
proliferative disorders, such as cancer, either as a
sole agent or in combination with other therapies
(paragraph [0001]). To this end, a composition
comprising a solid dispersion comprising at least 4{4-
[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-
fluorophenoxy}-pyridine-2-carboxylic acid methyl amide
(regorafenib) in substantially amorphous form and a
pharmaceutically acceptable matrix is employed. The
description states that diaryl ureas are a class of
serine-threonine kinase inhibitors as well as tyrosine
kinase inhibitors and are used as active ingredients in
pharmaceutical compositions for the treatment of hyper-
proliferative diseases, such as cancer. Regorafenib, in
particular, has been discovered to be a potent
inhibitor of raf, VEGFR-2, p38 and PDGFR kinases. These
enzymes are said to be molecular targets of interest
for the treatment of hyper-proliferative diseases,
including cancer (paragraphs [0002] and [0004]). The
oral route of drug administration is advantageous, and
improved dissolution, superior absorption and increased
bioavailability result from the invention (paragraphs
[0005] to [0007]). Second-line treatments are not
- 12 - T 0377/18
mentioned.
3.2 It is common ground that document (5) represents the

closest prior art.
Document (5), cited as background art in the

application as filed on page 2, line 1, relates to the
use of a group of diaryl ureas in the treatment of raf-
mediated diseases (raf being a serine-threonine
kinase), such as cancer, and to pharmaceutical
compositions for use in such therapy. It was common
ground that regorafenib came under Formula I of
document (5). The compounds described under entries 42
and 49 differ from regorafenib only in a substitution
on one of the aryl rings (being hydrogen or chlorine
instead of fluorine). Information on the substitution
by halogens, including fluorine, chlorine, bromine and
iodine, can be found on page 4, lines 12 to 14 and page
6, lines 5 to 8. Concerning the formulation of these
actives, some general information is given on page 10,
line 10 to page 12, line 29. Solid dispersions are not
mentioned.
Concerning the precise starting point in document (5),

the following applies. The Markush formula denominated
"Formula (I)" describes the broadest teaching of this
document. Indications as to how the substituents may be
selected can be found in the specific compounds
described in the section "Synthesis of Exemplified
Compounds" (starting on page 53) and in Tables 1 to 6.
A total of 103 compounds are individualised. Their
depiction in Tables 1 to 6 clearly shows which
positions for substitution and which substituents are
particularly envisaged in order to obtain compounds for
the treatment of cancer. Consequently, either
Formula (I) or any of the 103 compounds, in particular
- 13 - T 0377/18
the closely-related compounds of entries 42 and 49, can

be taken as the starting point in the present case.
3.3 Starting from any point in document (5), the

differences are the structure of the active agent and
the formulation of the active agent in amorphous form
as a solid dispersion.
3.3.1 Firstly, it will be discussed whether any surprising

effect can be acknowledged to be linked to the
difference in structure.
The application as filed does not explicitly identify

any surprising effects linked to the structure of the
active agent.
The respondent pointed to paragraph [0004] of the

patent in suit, where four kinases, raf, VEGFR-2, p38
and PDGFR, are listed, and to the reference to
document (2) in that paragraph. According to the
respondent, the reference to document (2) showed that
regorafenib did indeed inhibit the listed kinases and
that this knowledge had been in the possession of the
patent proprietor at the filing date of the patent
application underlying the patent in suit. Furthermore,
it pointed to the data in the reply to the grounds of
appeal and to the disclosure of document (14). The four
kinases of paragraph [0004] are described as being
"molecular targets of interest for the treatment of
hyper-proliferative diseases, including cancer". The
first kinase listed, raf, is at the heart of the
disclosure of the closest prior art. No information is
provided as to whether regorafenib is capable of
inhibiting raf or any of the other three kinases in a
way different from the cited background art (including
document (5)) and/or whether such inhibition would lead
- 14 - T 0377/18
to any improvement in the treatment. In fact, the

application as filed contains no statement relating to
and no data confirming the extent of the inhibition or
indicating that this inhibition would lead to an
improvement in the treatment of any hyper-proliferative
disease. The appellant has furthermore pointed to the
fact that there was no evidence that regorafenib
inhibited these four kinases at all.
Document (2) was not cited or mentioned in any other

way in the application as filed. Its contents,
including the data presented, do not form part of the
disclosure of the application as filed (or of the
patent as granted). Consequently, document (2) is to be
treated in the same way as any other post-published
document. The fact that it has the same applicant as
the patent in suit is irrelevant in the context of the
present decision. When the disclosure of document (2)
is disregarded, there is indeed no evidence in the
application as filed that regorafenib inhibits raf,
VEGFR-2, p38 and PDGFR. The application as filed,
however, also includes a background section, in which
various publications, including document (5), are
discussed as disclosing diaryl ureas as serine-
threonine kinase inhibitors as well as as tyrosine
kinase inhibitors. Consequently, a person skilled in
the art would have considered it plausible that a
further diaryl urea, structurally closely resembling
the compounds exemplified in document (5), might have
similar activity. On the other hand, it cannot be
derived from the application as filed that regorafenib
had a pattern of inhibition different from these
structurally closely-related compounds. Such a pattern
of inhibition thus cannot represent a surprising
technical effect.
- 15 - T 0377/18
Document (14) does not bear a publication date. It

states on page 27 that the date of the first
[marketing] authorisation of Stivarga (regorafenib) was
26 August 2013. The respondent, in its letter dated
19 September 2017, states that EMA approval was issued
in August 2017. There is no information on file that
would lead to the conclusion that document (14) was
published before the effective date and none of the
parties has argued in this direction. Document (14) is
thus treated as a post-published document. According to
the respondent, this document shows that "regorafenib
was even effective in patients who showed insufficient
response to the treatment with sorafenib" (entry 42 of
document (5)). The appellant stated that document (14)
did not show superiority of regorafenib over sorafenib.
The board takes the statement made on page 2, point 4.1
of document (14), that one of the therapeutic
indications was a monotherapy for the treatment of
adult patients with "- hepatocellular carcinoma (HCC)
who have been previously treated with sorafenib", to
mean that regorafenib was indicated as a second-line
treatment when treatment with sorafenib was no longer
possible. However, in the absence of any indication in
the application as filed that regorafenib could be used
upon failure of treatment with other actives of the
same chemical class, i.e. diaryl ureas discussed in the
background section with reference to document (5), such
post-published evidence cannot be taken into account
for assessing inventive step.
In addition, in its reply to the grounds of appeal, the

respondent presented data which according to it
demonstrated the superiority in activity of regorafenib
as compared with compound 49 (Tables 1 and 2). Having
been submitted for the first time in the reply to the
grounds of appeal, the data are clearly post-published.
- 16 - T 0377/18
As they present data on an effect that cannot be

derived from the application as filed, despite document
(5) being discussed in the background section, the data
are to be disregarded.
Neither the information of documents (2) and (14), nor

the data contained in the reply to the grounds of
appeal, nor a statement summarising the results of
these sources of information and indicating their
relevance, was available before the effective date.
Furthermore, although document (5) is disclosed in the
description as background art, no advantageous effects
of the invention are discussed with regard to
document (5) and its raf kinase inhibitors (or in view
of any other document mentioned in the background
section).
The board thus comes to the conclusion that an

improvement over the compounds of document (5) was
neither foreshadowed, nor alleged, nor shown in the
application as filed. Document (5) is not merely a
document that could have been considered by the patent
proprietor (or the then applicant) when drafting the
application, but a document that actually was
considered as can be seen by its being cited in the
background section. Since, as a consequence, post-
published evidence cannot be taken into account, none
of the effects related to improved treatment (different
pattern of inhibition, second-line treatment, higher
levels of inhibition) can be considered when applying
the problem-solution approach.
3.3.2 Secondly, attention is paid to the effects linked to

the formulation of the amorphous active agent as a
solid dispersion.
- 17 - T 0377/18
The patent in suit provides data in example 18 showing

that solid dispersions of regorafenib in
polyvinylpyrrolidone (PVP) lead to better drug
dissolution in a particular aqueous medium than a
physical mixture of the two components. Similar data
for other excipients can be found in document (15).
Examples 19 and 20 show the corresponding improved
bioavailability for the drug from solid dispersions.
The data thus prove that solid dispersions comprising
regorafenib are suitable galenic forms capable of
delivering regorafenib to a patient.
The parties disagreed as to whether these data showed

an improved effect over the closest prior art.
In the situation at hand, it is as a matter of

principle not possible to provide a valid comparison
for the galenic component of the pharmaceutical
composition with the closest prior art. The reason for
this is that the compound under consideration has not
been individualised in the closest prior art and
galenic issues relate primarily to the compound and its
interaction (due to its physicochemical properties
which are determined by its molecular structure) with
its environment, be it with the excipients in the
pharmaceutical formulation or with the parts of the
patient's body during the absorption process. The data
of the patent and of document (15) show, however, that
not all galenic forms lead to the same solubility and
the same bioavailability and thus are not equally
suitable.
3.4 It follows that the technical problem is the provision

of a further active agent for use in the treatment of
hyper-proliferative diseases which is formulated in a
form which allows sufficient bioavailability.
- 18 - T 0377/18
The problem has been solved: this has not been

contested.
3.5 It remains to determine whether the solution is

obvious.
3.5.1 A galenic form can only be provided and tested for its
suitability once an active agent has been chosen.
Therefore the examination of obviousness will first
focus on the active agent.
It has been determined under point 3.3.1 above that no

surprising effect has been linked to the fluorine
substitution that distinguishes regorafenib from some
of the compounds exemplified in the closest prior art
document (5). It is furthermore common ground that
regorafenib comes under the Markush formula defined in
document (5). The person skilled in the art, starting
from document (5) and aiming at providing a further
active agent for the treatment of hyper-proliferative
diseases, would have considered any of the compounds,
and in particular compounds that are structurally
closely related to compounds exemplified in this
document. Consequently, the person skilled in the art
would have arrived at the claimed compound.
3.5.2 Having settled on one of the compounds which come under

the teaching of the closest prior art, the person
skilled in the art would have been faced with the need
to select a suitable galenic form.
Various galenic forms are known in the art: a person

skilled in the art would have chosen a particular one
based on their knowledge of the physicochemical
properties of the compound to be formulated and on the
- 19 - T 0377/18
desired route of administration. Further issues might

be a particular pattern of release (e.g. delayed or
sustained release). One of the crucial physicochemical
properties of a novel drug substance is its solubility.
Solubility is thus the property of a novel active agent
to which a person skilled in the art would have paid
particular attention and that would have been foremost
in their consideration for selecting an appropriate
galenic form.
It was common ground that a person skilled in the art

would have been aware that, due to their chemical
structure, which includes aromatic rings and halogen
substitution, the compounds of document (5) are poorly
soluble under physiological conditions. A person
skilled in the art would thus have started their
routine tests with galenic forms known to be
particularly suitable for poorly water-soluble active
agents.
A document dealing with the formulation of such poorly

water-soluble active agents is on file as document (6).
Document (6) is a review article, and thus an article
summarising the state of the art in relation to its
topic. It is entitled "Improving drug solubility for
oral delivery using solid dispersions". In its abstract
it stresses the challenging aspects in formulation
development caused by the solubility behaviour of
drugs. It goes on to state that the number of poorly
water-soluble compounds in this field has increased.
The purpose of the article is identified as giving an
overview of the historical background of various
systems and especially as providing information on
various aspects of solid dispersions. On page 47, it
identifies physical properties of the solid drug itself
(e.g. increase in available surface area, see Table 1)
- 20 - T 0377/18
but goes on to propagate that formulation approaches

are "the most attractive option for increasing the
release rate" (page 47, right-hand column, last
sentence of the full paragraph). In section 3.2
carriers for providing the matrix of the solid
dispersion of the drug are described. Various aspects
are discussed, such as molecular weight and solubility
in water and organic solvents. The link between release
rate from the solid dispersion and bioavailability is
addressed (e.g. page 53, left-hand column, first full
paragraph). Polyethylene glycol, polyvinylpyrrolidone,
cellulose derivatives such as hydroxypropyl methyl
cellulose and hydroxypropyl cellulose, and sugars,
polyols and their polymers (sections 3.2.1 to 3.2.7)
are discussed as possible carriers. The review article
ends with a summary, in which some concerns related to
solid dispersions are enumerated. Among these concerns
is the possibility that the amount of dispersion
required to administer the usual dose of the drug may
be too high to produce a tablet or a capsule that can
be easily swallowed, or that the correlation between in
vitro and in vivo release from the solid dispersion
might not be sufficient to lead to adequate
bioavailability (page 58, left-hand column, first
paragraph).
Document (6) thus clearly teaches that solid

dispersions are a galenic form worth exploring when
trying to provide a formulation of a poorly soluble
drug. It encompasses several concrete proposals for
carriers. The person skilled in the art would have
interpreted the concerns addressed in the final parts
of document (6) as meaning that there was no certainty
of success. However, these concerns would not have
deterred the person skilled in the art from seriously
considering a galenic form that has been described as
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advantageous for precisely such poorly soluble drugs as

regorafenib. Consequently, the person skilled in the
art would have seriously contemplated solid dispersions
in their routine tests to find a formulation for
regorafenib.
Furthermore, document (6) suggests trying to modify the

crystal habit of the active compound (Table 1). A
person skilled in the art would thus include variations
of the crystal habit, including the amorphous form, in
their routine tests without exercising inventive skill.
Finally, it must be stressed that in the case at hand

the issue to be decided on is merely which galenic
forms a person skilled in the art would have taken into
consideration when setting up their routine tests for
determining an appropriate galenic form. As no galenic
formulation for regorafenib had existed at the
effective date, the problem, as a matter of principle,
cannot be seen as providing an improved galenic
formulation.
The subject-matter of claim 1 of the main request

(patent as granted) does not involve an inventive step
(Article 56 EPC).
3.5.3 Further arguments
(a) The respondent argued that document (5) points to

salts, implying that solubility problems would
mainly be dealt with by providing more-soluble
forms of the active agents.
Salts are clearly one of the options a person

skilled in the art would consider, see Table 1 of
document (6). However, as can be seen from the
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patent in suit, see for example paragraphs [0010]

and [0011] and claims 7 and 8, active agents in the
form of salts and solid dispersions are not
mutually exclusive. The mere fact that several
options were at their disposal does not mean that
the skilled person would have restricted their
routine tests to one particular option and
disregarded other options.
(b) The respondent argued that in 2021 there were still

hardly any drugs marketed as solid dispersions.
Solid dispersions were complex to handle
("aufwändig") and a person skilled in the art would
only have considered using them in exceptional
circumstances ("Notfall").
The board follows the teaching of document (6) that

explicitly aims at providing formulations for
poorly water-soluble compounds and clearly refers
in its abstract to the "challenging" aspects of
solubility behaviour of drugs in formulation
development. The wording used in this abstract
clearly establishes that poorly water-soluble
compounds may need exceptional solutions with
regard to their formulation. Furthermore,
considerations extending up to 2021 cannot be taken
into account when assessing inventive step of a
patent with an effective date 15 years earlier.
(c) In addition, the respondent argued that

document (6) did not disclose solid dispersions
with active agents that were structurally or
functionally related to regorafenib.
The board draws attention to the abstract of

document (6), which identifies the solubility
- 23 - T 0377/18
behaviour as the determining factor. There is no

structural or functional discussion of the
compounds disclosed in document (6) in connection
with their suitability for being formulated in
solid dispersions. The exemplified drugs are varied
in structure and functionality (see statement
setting out the grounds of appeal, point 2.5).
4. Auxiliary requests 1 to 5 - inventive step
The subject-matter of claim 1 of auxiliary requests 1

to 4 differs from the subject-matter of claim 1 of the
patent as granted in the definition of the matrix. The
carriers forming the matrix and representing the
limitations applied in these claims are discussed in
detail in document (6) (see point 3.5.2 above).
Consequently, the line of reasoning given for claim 1
of the patent as granted applies mutatis mutandis to
the subject-matter of these claims.
The subject-matter of claim 1 of auxiliary request 5 is

the same as the subject-matter of claim 1 as granted.
The reasoning of point 3. applies.
The subject-matter of claim 1 of auxiliary requests 1

to 5 does not involve an inventive step
(Article 56 EPC).
5. Auxiliary request 6 - admission
Auxiliary request 6 was submitted at a very advanced

stage of the appeal proceedings, namely at the oral
proceedings before the board and after the discussion
of inventive step for the main request and for
auxiliary requests 1 to 5. The board does not consider
that a new situation had arisen during the oral
- 24 - T 0377/18
proceedings which might be considered as exceptional

circumstances justifying the filing of this request.
The fact that a board, on the basis of arguments
presented by a party, might take a different view from
the department whose decision is appealed cannot be
considered a surprising event as it is one of the two
possibilities. As the patent proprietor is the party
that is solely responsible for determining the text of
the patent (see Article 113(2) EPC), it is however
obliged to submit amendments or possible fall-back
positions. For reasons of procedural economy and
fairness to the other party this must be done at the
earliest possible opportunity, as reflected in the
RPBA.
As the appellant had failed to present exceptional

circumstances which justified the filing of amendments
during the oral proceedings and after the discussion of
inventive step, the board decided not to admit
auxiliary request 6 into the appeal proceedings
(Article 13(2) RPBA).
Order
For these reasons it is decided that:
1. The decision under appeal is set aside.
2. The patent is revoked.

- 25 - T 0377/18
The Registrar: The Chairwoman:
M. Schalow T. Sommerfeld
Decision electronically authenticated
IITRUE COPYII
CS (Comm.) No. 660 of 2022
In the matter of:

versus
INDEX
VOL-7
document ent in
possess
ion/po
wer/co
ntrol/c
ustody
is
origina
l/office
copy/p
hotoco
py
1. Copy of US USPTO and Copy Executed by Availab From
7235576 Bayer USPTO le at Defend 1097-
Pharmaceuti USPTO ant to 1163
cals website its
Corporation Counsel
(Publicly
Available)
Patent Status Patent Columbian le at Defend 1164-
CO28604 Office, Patent Office ESPAC ant to 1174
(equivalent Bayer ENET its
of WO’012) Corporation Counsel
and Bayer
Healthcare
LLC
(Publicly
Available)
CO0600588 Patent Office Columbian le at Defend
4 (equivalent & Bayer Patent Office ESPAC ant to 1175-
to suit patent Pharmaceuti ENET its 1179
in cal Counsel
Columbia) Corporation
(Publicly
Available)
refusal order Patent Office Columbian le at Defend
of & Bayer Patent Office ESPAC ant to 1180-
CO0600588 Corporation ENET its 1189
4 (equivalent (Publicly Counsel
to suit patent Available)
in
Columbia)
Argentina Patent Office Argentina le at Defend
Patent (AR and Bayer Patent Office Argenti ant to 1190-
035310B1) Corporation na its 1194
(WO’012 (Publicly Patent Counsel
equivalent) Available) Office
Website
Argentina Patent Office Argentina le at Defend 1195-
Application and Bayer Patent Office Argenti ant to 1196
(AR na
048741A1) Healthcare Patent its
(equivalentLLC Office Counsel
to suit (Publicly Website
patent) Available)
7. Copy of WIPO and Copy Executed by Availab From 1197-
WO2000/04 Bayer WIPO le at Defend 1344
1698 Corporation WIPO ant to
(Publicly website its
Available) Counsel
8. Copy of WIPO and Copy Executed by Availab From
WO2004/07 Bayer WIPO le at Defend 1345-
8746 Pharmaceuti WIPO ant to 1430
cals website its
Corporation Counsel
(Publicly
Available)
9. PROOF OF SERVICE I 1431
Through
Place: Noida (NCR)
Date: 03.10.2022
Guruswamy Nataraj
NOIDA 201 307, NCR
Phone: 9811808373
I 1111111111111111
11111
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US007235576Bl
c12) United States Patent (10) Patent No.: US 7,235,576 Bl

Riedl et al. (45) Date of Patent: Jun.26,2007
(54) OMEGA-CARBOXYARYL SUBSTITUTED 3,200,035 A 8/1965 Martin et al.

DIPHENYL UREAS AS RAF KINASE 3,230,141 A 1/1966 Frick et al.
INHIBITORS 3,424,760 A 1/1969 Helsley et al.
3,424,761 A 1/1969 Helsley et al.
3,424,762 A 1/1969 Helsley et al.
(75) Inventors: Bernd Riedl, Wuppertal (DE); Jacques
3,547,940 A 12/1970 Brantley
Dumas, Orange, CT (US); Uday Khire,
3,646,059 A 2/1972 Brantley
Hamden, CT (US); Timothy B. 3,689,550 A 9/1972 Schellenbaum et al.
Lowinger, Nishinomiya (JP); William 3,743,498 A 7/1973 Brantley
J. Scott, Guilford, CT (US); Roger A. 3,754,887 A 8/1973 Brantley
Smith, Madison, CT (US); Jill E. 3,823,161 A 7/1974 Lesser
Wood, Hamden, CT (US); 3,828,001 A 8/1974 Broad et al.
Mary-Katherine Monahan, Hamden, 3,860,645 A 1/1975 Nikawitz
CT (US); Reina Natero, Hamden, CT 3,990,879 A 11/1976 Soper
4,001,256 A 1/1977 Callahan et al.
(US); Joel Renick, Milford, CT (US);
4,009,847 A 3/1977 Aldrich et al.
Robert N. Sibley, North Haven, CT
4,042,372 A 8/1977 Harper
(US) 4,062,861 A 12/1977 Yukinaga et al.
4,071,524 A 1/1978 Banitt
(73) Assignee: Bayer Pharmaceuticals Corporation, 4,111,680 A 9/1978 Yukinaga et al.
West Haven, CT (US) 4,111,683 A 9/1978 Singer
4,116,671 A 9/1978 Yukinaga et al.
( *) Notice: Subject to any disclaimer, the term ofthis
4,173,637 A 11/1979 Nishiyama et al.
patent is extended or adjusted under 35 4,173,638 A 11/1979 Nishiyama et al.
U.S.C. 154(b) by O days. 4,183,854 A 1/1980 Crossley
4,212,981 A 7/1980 Yukinaga et al.
(21) Appl. No.: 10/042,203 4,240,820 A 12/1980 Dickore et al.
4,405,644 A 9/1983 Kabbe et al.
4,410,697 A 10/1983 Torok et al.
(22) Filed: Jan. 11, 2002 4,437,878 A 3/1984 Acker et al.
4,468,380 A 8/1984 O'Doherty et al.
4,473,579 A 9/1984 Devries et al.
Related U.S. Application Data
4,511,571 A 4/1985 Boger et al.
(60) Provisional application No. 60/367,380, filed on Jan. 12, 4,514,571 A 4/1985 Nakai et al.
2001.
4,526,997 A 7/1985 O'Doherty et al.
(51) Int. Cl. 4,623,662 A 11/1986 De Vries
A61K 31117 (2006.01) 4,643,849 A 2/1987 Hirai et al.
A61K 31144 (2006.01) (Continued)
C07D 213130 (2006.01)
C07C 275118 (2006.01) FOREIGN PATENT DOCUMENTS
C07C 275134 (2006.01)
CA 2146707 10/1995
DE 0 487 014 12/1929
(52) U.S. Cl. ....................... 514/388; 514/354; 514/358; DE 0 511 468 10/1930
514/597; 514/552; 546/329; 546/339; 564/54; DE 0 523 437 5/1931
564/55; 564/336 DE 2436179 C2 2/1975
(58) Field of Classification Search ................. 546/329,
546/339; 514/352, 354,358, 588, 597; 564/54, (Continued)
564/55, 336 OTHER PUBLICATIONS
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502,504 A 8/1893 Thoms
1,742,156 A 12/1929 Fritzky (Continued)
2,093,265 A 9/1937 Coflby et al. Primary Examiner-Alan L. Rotman
2,288,422 A 6/1942 Rohm Assistant Examiner-Rita Desai
2,649,476 A 8/1953 Martin
(74) Attorney, Agent, or Firm-Millen, White, Zelano &
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2,722,544 A 11/1955 Martin
Branigan, P.C.
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2,781,330 A 2/1957 Downey
2,797,214 A 6/1957 Bossard This invention relates to the use of a group of aryl ureas in
2,867,659 A 1/1959 Model et al. treating raf mediated diseases, and pharmaceutical compo-
2,877,268 A 3/1959 Applegate et al.
sitions for use in such therapy.
2,960,488 A 11/1960 Tamblyn et al.
2,973,386 A 2/1961 Weldon
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EP 0016371 Al 3/1980 WO 99/40673 8/1999
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1913, 143.
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al., May 2, 1983.
ate antisense oligodeopxynucleotide targeted against C-raf
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derivatives, Shionogi & Co., May 23, 1980. 668-675.
Chemical Abstract, vol. 116, No. 21, May 25, 1992, pp.
Lee, et al., Bicyclic Imidazoles as a Novel Class ofCytokine
741-742.
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Tarzia, G. et al., Whythesis and anit-inflammatory proper-
pp. 149-170.
ties of some pyrrolo(1H,3H) [3,4]pyrimidin-2---ones and
F. Lepage, et al., "New N-aryl isoxazolecarboxamides and
pyrrolo(1H,3H)[3,4-d]pyurimidin-2-ones and pyrrolo(lH,
N-isoxazolybenzamides as anticonvulsant agents," Eur. J.
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White, A. D., et al., "Heterocyclic Ureas: Inhibitors of Ridley, et al., "Actions ofIL-1 are Selectively Controlled by
Acyl-CoA:Cholesterol O-Acyltransferase as Hypocheles- p38 Mitogen-Activated Protein Kinase," The American
terolemic Agents," Jun. 6, 1996, pp. 4382-4395. Association of Immunologists, 1997, p. 3165-73.
Audia, James E., et al., "Potent, Selective N. S. Magnuson, et al., "The Raf-1 serine/threonine protein
Tetraphdro-~-carboline Antagonists of the Serotonin 2B kinase," Cancer Biology, vol. 5, 1994, pp. 247-253.
(5HTw) Contractile Receptor in the Rat Stomach Fundus," G. Daum, et al., The ins and outs ofRafKinases,: TIBS 19,
Jan. 22, 1996, pp. 2773-2780. Nov. 1994,pp. 474--480.
Forbes, Ian T., Grant, A.M. et al.: "Hypotensive thiadiazoles" J. Med.
"N-(l-Methyl-5-indolyl)-N-(3-methyl-5-isothiazolyl)urea: Chem. (1972), 15(10), 1082-4.
A Novel, High-Affinity 5-HT w Receptor Antagonist," Mar. Russo, F. et al. "Synthesis of 2, 6-substituted derivatives of
17, 1995, pp. 855-857. 5H-1,3,4-thiadiazolo'3,2-a!-s triazine-5,7---dione" FAR-
Boulton, A. J., et al., "Heterocyclic Rearrangements. Part MACO, ED.SCI. (1978), 33(12), 972-83.
X. 1 A Generalised Monocyclic Rearrangement," 1967, Joseph T. Bruder and Imre Kovesdi, Adenovirus Infection
2005-07. Stimulates the Raf/MAPK Signaling Pathway and Induces
W. Kolch, et al., "Raf-1 protein kinase is required for Interleukin-8 Expression, May 17, 1996, pp. 198-404.
growth of induced NIH/3T3 cells," Letters to Nature, vol. Foussard-Blanpin, Odette: "Comparative pharmacody-
349, Jan. 31, 1991, p. 226-228. namic study of variously substituted carboxamides of the
M. Fridman, et al., "The Minimal Fragments of c-Raf-1 and central nervous ststem" Ann. Phann. Fr. (1982), 40 (4),
NF! That Can Suppress v-Ha-Ras-Induced Malignant Phe- 339-50.
notype," The Journal of Biological Chemistry, vol. 269, No. Kubo, Hiroshi et al. "Herbicidal activity of 1,3,4-thiadiazole
48, Dec. 2, 1994, pp. 30105-30108. derivatives" J. Agr. Food Chem. (1970), 18(1), 60-5.
G. L. Bolton, et al., Chapter 17. Ras Oncogene Directed Avruch et al., "Raf meets Ras: completing the framework of
Approaches in Cancer Chemotherapy, Annual Reports In a signal transduction pathway", TIBS 19; Jul. 1994; pp.
Medicinal Chemistry, vol. 29, 1994, pp. 165-17 4. 279-2823.
J. L. Bos, "ras Oncogenes in Human Cancer: A Review,"
Cancer Research, vol. 49, Sep. 1, 1989, pp. 4682-4689. * cited by examiner
IITRUE COPY!I
US 7,235,576 Bl
1 2
OMEGA-CARBOXYARYL SUBSTITUTED heteroaryl analogues, which inhibit the raf kinase pathway.
DIPHENYL UREAS AS RAF KINASE The invention also provides a method for treating a raf
INHIBITORS mediated disease state in humans or mammals. Thus, the
invention is directed to compounds which inhibit the
Priority is claimed to provisional application Serial No. 5 enzyme raf kinase and also compounds, compositions and
60/367,380, filed on Jan. 12, 2001. methods for the treatment of cancerous cell growth mediated
FIELD OF THE INVENTION istered or pharmaceutically acceptable salt thereof.
This invention relates to the use of a group of aryl ureas A-D-B (I)
10
in treating raf mediated diseases, and pharmaceutical com-
In formula I, D is -NH-C(O)-NH-,
formula: -L-(M-L1)q, where Lis a 5 or 6 mem-
The p21ras oncogene is a major contributor to the <level- 15 bered cyclic structure bound directly to D, L 1 com-
opment and progression of human solid cancers and is
prises a substituted cyclic moiety having at least 5
mutated in 30% of all human cancers (Bolton et al. Ann. Rep.
members, M is a bridging group having at least one
Med. Chem. 1994, 29, 165-74; Bos. Cancer Res. 1989, 49,
atom, q is an integer of from 1-3; and each cyclic
4682-9). In its normal, unmutated form, the ras protein is a
structure of L and L1 contains 0---4members of the
key element of the signal transduction cascade directed by 20 group consisting of nitrogen, oxygen and sulfur, and
growth factor receptors in almost all tissues (Avruch et al.
Trends Biochem. Sci. 1994, 19, 279-83). Biochemically, ras B is a substituted or unsubstituted, up to tricyclic aryl or
is a guanine nucleotide binding protein, and cycling between heteroaryl moiety ofup to 30 carbon atoms with at least
a GTP-bound activated and a GDP-bound resting form is one 6-member cyclic structure bound directly to D
strictly controlled by ras' endogenous GTPase activity and containing 0---4members of the group consisting of
25 nitrogen, oxygen and sulfur,
other regulatory proteins. In the ras mutants in cancer cells,
the endogenous GTPase activity is alleviated and, therefore, wherein L 1 is substituted by at least one substituent
the protein delivers constitutive growth signals to down- selected from the group consisting of-SO 2 Rx, ----C(O)
stream effectors such as the enzyme rafkinase. This leads to Rx and ----C(NRy)R2 ,
the cancerous growth of the cells which carry these mutants 30 RY is hydrogen or a carbon based moiety of up to 24
(Magnuson et al. Semin. Cancer Biol. 1994, 5, 247-53). It carbon atoms optionally containing heteroatoms
has been shown that inhibiting the effect of active ras by selected from N, S and O and optionally
inhibiting the rafkinase signaling pathway by administration halosubstituted, up to per halo,
of deactivating antibodies to raf kinase or by co-expression R2 is hydrogen or a carbon based moiety of up to 30
of dominant negative rafkinase or dominant negative MEK, 35 carbon atoms optionally containing heteroatoms
the substrate of raf kinase, leads to the reversion of trans- selected from N, S and O and optionally substituted by
formed cells to the normal growth phenotype (see: Daum et halogen, hydroxy and carbon based substituents of up
al. Trends Biochem. Sci. 1994, 19, 474-80; Fridman et al. J. to 24 carbon atoms, which optionally contain heteroa-
Biol. Chem. 1994, 269, 30105-8. Kolch et al. (Nature 1991, toms selected from N, S and O and are optionally
349, 426-28) have further indicated that inhibition of raf 40 substituted by halogen;
expression by antisense RNA blocks cell proliferation in Rx is R2 or NRaRb where Ra and Rb are
membrane-associated oncogenes. Similarly, inhibition of raf a) independently hydrogen,
kinase (by anti sense oligodeoxynucleotides) has been cor- a carbon based moiety of up to 30 carbon atoms
related in vitro and in vivo with inhibition of the growth of optionally containing heteroatoms selected from
a variety of human tumor types (Mania et al., Nat. Med. 45 N, S and O and optionally substituted by halogen,
1996, 2, 668-75). hydroxy and carbon based substituents ofup to 24
SUMMARY OF THE INVENTION carbon atoms, which optionally contain heteroat-
oms selected from N, S and O and are optionally
The present invention provides compounds which are substituted by halogen, or
inhibitors of the enzyme raf kinase. Since the enzyme is a 50 -OSi(Rf) 3 where Rfis hydrogen or a carbon based
downstream effector of p21ras, the inhibitors are useful in moiety of up to 24 carbon atoms optionally con-
pharmaceutical compositions for human or veterinary use taining heteroatoms selected from N, S and O and
where inhibition of the rafkinase pathway is indicated, e.g., optionally substituted by halogen, hydroxy and
in the treatment of tumors and/or cancerous cell growth carbon based substituents of up to 24 carbon
mediated by raf kinase. In particular, the compounds are 55 atoms, which optionally contain heteroatoms
useful in the treatment of human or animal solid cancers, selected from N, S and O and are optionally
e.g., murine cancer, since the progression of these cancers is substituted by halogen; or
dependent upon the ras protein signal transduction cascade b) Ra and Rb together form a 5- 7 member heterocyclic
and therefore susceptible to treatment by interruption of the structure of 1-3 heteroatoms selected from N, Sand
cascade, i.e., by inhibiting raf kinase. Accordingly, the 60 0, or a substituted 5- 7 member heterocyclic struc-
compounds of the invention are useful in treating cancers, ture of 1-3 heteroatoms selected from N, S and 0
including solid cancers, such as, for example, carcinomas substituted by halogen, hydroxy or carbon based
(e.g., of the lungs, pancreas, thyroid, bladder or colon), substituents ofup to 24 carbon atoms, which option-
myeloid disorders (e.g., myeloid leukemia) or adenomas ally contain heteroatoms selected from N, S and 0
(e.g., villous colon adenoma). 65 and are optionally substituted by halogen; or
The present invention therefore provides compounds gen- c) one of Ra or Rb is ----C(O)-, a C 1-C 5 divalent
erally described as aryl ureas, including both aryl and alkylene group or a substituted C 1-C 5 divalent alky-
IITRUE COPY!I
US 7,235,576 Bl
3 4
lene group bound to the moiety L to form a cyclic 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or
structure with at least 5 members, wherein the sub- 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzothiazolyl, 2-,
stituents of the substituted C 1-C 5 divalent alkylene 4-, 5-, 6- or 7-benzisothiazolyl, 2-, 4-, 5-, 6- or 7-benz-1,3-
group are selected from the group consisting of oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-,
halogen, hydroxy, and carbon based substituents of 5 5-, 6-, 7-, 8-isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-,
up to 24 carbon atoms, which optionally contain 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, or 2-, 4-, 5-, 6-, 7- or
heteroatoms selected from N, S and O and are 8-quinazolinyl, or additionally optionally substituted
optionally substituted by halogen; phenyl, 2- or 3-thienyl, 1,3,4-thiadiazolyl, 3-pyrryl,
1
where B is substituted, Lis substituted or L is addition- 3-pyrazolyl, 2-thiazolyl or 5-thiazolyl, etc. For example, B
ally substituted, the substituents are selected from the 10 can be 4-methyl-phenyl, 5-methyl-2-thienyl, 4-methyl-2-
group consisting of halogen, up to per-halo, and Wn, thienyl, l-methyl-3-pyrryl, l-methyl-3-pyrazolyl, 5-methyl-
where n is 0-3; 2-thiazolyl or 5-methyl-1,2,4-thiadiazol-2-yl.
wherein each Wis independently selected from the group Suitable alkyl groups and alkyl portions of groups, e.g.,
7 7 7
consisting of -CN, -CO2R , -C(O)NR R , alkoxy, etc. throughout include methyl, ethyl, propyl, butyl,
7 7 7 7 7
-C(O)-R , -NO 2, -OR , -SR , -NR R , 15 etc., including all straight-chain and branched isomers such
7 7 7 7
-NR C(O)OR , -NR C(O)R , -Q-Ar, and carbon as isopropyl, isobutyl, sec-butyl, tert-butyl, etc.
based moieties of up to 24 carbon atoms, optionally Suitable aryl groups which do not contain heteroatoms
containing heteroatoms selected from N, Sand O and include, for example, phenyl and 1- and 2-naphthyl.
optionally substituted by one or more substituents The term "cycloalkyl", as used herein, refers to cyclic
independently selected from the group consisting of 20 structures with or without alkyl substituents such that, for
7 7 7 7 7
----CN, ----CO2R , -C(O)R , ----C(O)NR R , ---OR , example, "C 4 cycloalkyl" includes methyl substituted cyclo-
7 7 7 7 7 7
-SR , -NR R , -NO 2, -NR C(O)R , -NR C(O) propyl groups as well as cyclobutyl groups. The term
7 7
OR and halogen up to per-halo; with each R inde- "cycloalkyl", as used herein also includes saturated hetero-
pendently selected from H or a carbon based moiety of cyclic groups.
up to 24 carbon atoms, optionally containing heteroa- 25 Suitable halogen groups include F, Cl, Br, and/or I, from
toms selected from N,; S and O and optionally substi- one to per-substitution (i.e. all H atoms on a group replaced
tuted by halogen, by a halogen atom) being possible where an alkyl group is
wherein Q is ---0-, -S-, -N(R 7 )-, -(CH 2)m-, substituted by halogen, mixed substitution of halogen atom
-C(O)-, ----CH(OH)-, -(CH 2)mO-, -(CH 2)m types also being possible on a given moiety.
S-, -(CH 2)mN(R 7 )-, -O(CH 2 )m-CHXa-, 30 The invention also relates to compounds per se, of for-
7
----CXa2 -, -S-(CH 2)m- and -N(R )(CH 2)m-, mula I.
where m=l-3, and xa is halogen; and The present invention is also directed to pharmaceutically
Ar is a 5- or 6-member aromatic structure containing 0-2 acceptable salts of formula I. Suitable pharmaceutically
members selected from the group consisting of acceptable salts are well known to those skilled in the art and
nitrogen, oxygen and sulfur, which is optionally sub- 35 include basic salts of inorganic and organic acids, such as
stituted by halogen, up to per-halo, and optionally hydrochloric acid, hydrobromic acid, sulfuric acid, phos-
substituted by Znu wherein nl is Oto 3 and each Z is phoric acid, methanesulphonic acid, trifluoromethane-
independently selected from the group consisting of sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
----CN, ----CO2R7 , -C(O)R 7 , -C(O)NR 7 R7 , -NO 2, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid,
-OR 7 -SR 7 -NR 7 R7 -NR 7 C(O)OR 7 -NR 7 C 40 acetic acid, trifluoroacetic acid, malic acid, tartaric acid,
(O)R 7 , 'and a carbon bas~d moiety of up to' 24 carbon citric acid, lactic acid, oxalic acid, succinic acid, fumaric
atoms, optionally containing heteroatoms selected from acid, maleic acid, benzoic acid, salicylic acid, phenylacetic
N, S and O and optionally substituted by one or more acid, and mandelic acid. In addition, pharmaceutically
substituents selected from the group consisting of acceptable salts include acid salts of inorganic bases, such as
----CN, -CO 2R7 , -COR 7 , -C(O)NR 7 R7 , -OR 7 , 45 salts containing alkaline cations (e.g., Li+ Na+ or K+),
-SR 7 , -NO 2, -NR 7 R 7 , -NR 7 C(O)R 7 , and alkalineearthcations(e.g.,Mg+ 2,ca+ 2 orBa+ 2),theammo-
-NR 7 C(O)OR 7 , with R7 as defined above. nium cation, as well as acid salts of organic bases, including
limited to, 5-12 carbon-atom aromatic rings or ring systems nary ammonium cations, such as those arising from proto-
containing 1-3 rings, at least one of which is aromatic, in 50 nation or peralkylation of triethylamine, N,N-diethylamine,
which one or more, e.g., 1--4 carbon atoms in one or more N,N-dicyclohexylamine, lysine, pyridine, N,N-
of the rings can be replaced by oxygen, nitrogen or sulfur dimethylaminopyridine (DMAP), 1,4-diazabiclo[2.2.2]
atoms. Each ring typically has 3-7 atoms. For example, B octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)
can be 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 1-, 2- and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 55 A number of the compounds of Formula I possess asym-
5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4, or 5-isoxazolyl, 2-, metric carbons and can therefor exist in racemic and opti-
2-, 4-, 5- or 6-pyrimidinyl, 1,2,3-triazol-1-, -4- or -5-yl, and diastereomeric mixtures are well known to one skilled
1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3- in the art. The present invention encompasses any isolated
oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4- 60 racemic or optically active form of compounds described in
thiadiazol-2- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4- Formula I which possess raf inhibitory activity.
thiadiazol-2- or -5-yl, 1,3,4-thiadiazol-3- or -5-yl, 1,2,3-
thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, General Preparative Methods
3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, The compounds of Formula I may be prepared by the use
3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 65 of known chemical reactions and procedures, some from
7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or starting materials which are commercially available.
5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, Nevertheless, general preparative methods are provided
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below to aid one skilled in the art in synthesizing these aryl nucleophiles, such as arylboronic acids (Suzuki
compounds, with more detailed examples being provided in reactions, exemplified below), aryltins (Stille reactions) or
the Experimental section which follows. arylzincs (Negishi reaction) to afford the biaryl (5).
methods (March. Advanced Organic Chemistry, 3 rd Ed.; 5
ArB(OR')2
John Wiley: New York (1985). Larock. Comprehensive
Organic Transformations; VCH Publishers: New York Pd(0)
(1989)). As shown in Scheme I, aryl amines are commonly
such as Ni, Pd, or Pt, and H2 or a hydride transfer agent, such 10
as forinate, cyclohexadiene, or a borohydride (Rylander. Either nitroaryls or anilines may be converted into the
Hydrogenation Methods; Academic Press: London, UK corresponding arenesulfonyl chloride (7) on treatment with
(1985)). Nitroaryls may also be directly reduced using a chlorosulfonic acid. Reaction of the sulfonyl chloride with a
strong hydride source, such as LiIHA (Seyden-Penne. fluoride source, such as KF then affords sulfonyl fluoride (8).
Reductions by the Alumina- and Borohydrides in Organic Reaction of sulfonyl fluoride 8 with trimethylsilyl trifluo-
15
Synthesis; VCH Publishers: New York (1991)), or using a romethane in the presence of a fluoride source, such as
zero valent metal, such as Fe, Sn or Ca, often in acidic tris( dimethy !amino )sulfonium difluorotrimethy lsiliconate
media. Many methods exist for the synthesis of nitroaryls (TASF) leads to the corresponding trifluoromethylsulfone
(March. Advanced Organic Chemistry, b 3 rd Ed.; John (9). Alternatively, sulfonyl chloride 7 may be reduced to the
Wiley: New York (1985). Larock. Comprehensive Organic arenethiol (10), for example with zinc amalgum. Reaction of
20
Transformations; VCH Publishers: New York (1989)). thiol 10 with 5 CHCIF 2 in the presence of base gives the
difluoromethyl mercaptam (11), which may be oxidized to
Scheme I the sulfone (12) with any of a variety of oxidants, including
Reduction ofNitroaryls to Ary! Amines
Cr0 3 -acetic anhydride (Sedova et al. Zh. Org Khim. 1970, 6,
H2/catalyst 25 (568).
~ Scheme III
Selected Methods of Fluorinated Ary! Sulfone Synthesis
ArNO 2 ____ [H_*_l
__ __
\~_M_(O)~/ 30
0
(eg. Fe, Sn, Ca)
-R
I
matic nitration using HNO 3 , or an alternative NO 2 + source. 35
Nitroaryls may be further elaborated prior to reduction. ~(Hg)
potential leaving groups (e.g. F, Cl, Br, etc.) may undergo

substitution reactions on treatment with nucleophiles, such
as thiolate (exemplified in Scheme II) or phenoxide. Nitroar-
yls may also undergo Ullman-type coupling reactions
40
45 (Me2N)3S Me3SiF2!
6 SH-R
10
I
CHClF2
Me3SiCF3 Base
(Scheme II).
!
Scheme II
Selected Nucleophilic Aromatic Substitution using Nitroaryls
50
ArSH
~ 11
~
CuO I base 60
12
Nitroaryls may also undergo transition metal mediated

cross coupling. reactions. For example, nitroaryl 65 As shown in Scheme IV, non-symmetrical urea formation
electrophiles, such as nitroaryl bromides, iodides or triflates, may involve reaction of an aryl isocyanate (14) with an aryl
undergo palladium mediated cross coupling reactions with amine (13). The heteroaryl isocyanate may be synthesized
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US 7,235,576 Bl
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from a heteroaryl amine by treatment with phosgene or a Formulations for oral use may also be presented as hard
phosgene equivalent, such as trichloromethyl chloroformate gelatin capsules wherein the active ingredient is mixed with
(diphosgene ), bis(trichloromethyl)carbonate (triphosgene ), an inert solid diluent, for example, calcium carbonate,
or N,N'-carbonyldiimidazole (CDI). The isocyanate may calcium phosphate or kaolin, or as soft gelatin capsules
also be derived from a heterocyclic carboxylic acid wherein the active ingredient is mixed with water or an oil
derivative, such as an ester, an acid halide or an anhydride medium, for example peanut oil, liquid paraffin or olive oil.
by a Curtius-type rearrangement. Thus, reaction of acid Aqueous suspensions contain the active materials in
derivative 16 with an azide source, followed by rearrange- admixture with excipients suitable for the manufacture of
ment affords the isocyanate. The corresponding carboxylic aqueous suspensions. Such excipients are suspending
acid (17) may also be subjected to Curtius-type rearrange-
10 agents, for example sodium carboxymethylcellulose,
ments using diphenylphosphono azide (DPPA) or a similar
methylcellulose, hydroxypropyl methylcellulose, sodium
reagent.
alginate, polyvinylpyrrolidone, gum tragacanth and gum
Scheme IV
acacia; dispersing or wetting agents may be a naturally
Selected Methods of Non-Symmetrical Urea Formation occurring phosphatide, for example, lecithin, or condensa-
15 tion products or an alkylene oxide with fatty acids, for
example polyoxyethylene stearate, or condensation products
of ethylene oxide with long chain aliphatic alcohols, for
example heptadecaethylene oxycetanol, or condensation
products of ethylene oxide with partial esters derived from
20 fatty acids and hexitol such as polyoxyethylene sorbitol
0 monooleate, or condensation products of ethylene oxide
Ar1.....,_
N
)l N
_.,..M
with partial esters derived from fatty acids and hexitol
anhydrides, for example polyethylene sorbitan monooleate.
H H The aqueous suspensions may also contain one or more
14 15 25 preservatives, for example ethyl, or n-propyl
'f PPA
p-hydroxybenzoate, one or more coloring agents, one or
more flavoring agents, and one or more sweetening agents,
such as sucrose or saccharin.
0 0 Dispersible powders and granules suitable for preparation
30 of an aqueous suspension by the addition of water provide
Ar 1AX Ar 1)lOH the active ingredient in admixture with a dispersing or
16 17
wetting agent, suspending agent and one or more preserva-
tives. Suitable dispersing or wetting agents and suspending
agents are exemplified by those already mentioned above.
Finally, ureas may be further manipulated using methods 35 Additional excipients, for example, sweetening, flavoring
familiar to those skilled in the art. and coloring agents, may also be present.
The invention also includes pharmaceutical compositions The compounds may also be in the form of non-aqueous
including a compound b of Formula I, and a physiologically liquid formulations, e.g., oily suspensions which may be
acceptable carrier. formulated by suspending the active ingredients in a veg-
The compounds may be administered orally, topically, 40 etable oil, for example arachis oil, olive oil, sesame oil or
parenterally, by inhalation or spray or rectally in dosage unit
peanut oil, or in a mineral oil such as liquid paraffin. The oily
formulations. The term 'administration by injection'
suspensions may contain a thickening agent, for example
includes intravenous, intramuscular, subcutaneous and
one or more non-toxic pharmaceutically acceptable carriers 45 added to provide palatable oral preparations. These compo-
Compositions intended for oral use may be prepared such as ascorbic acid.
sitions may contain one or more agents selected from the 50 a vegetable oil, for example olive oil or arachis oil, or a
agents, coloring agents and preserving agents in order to Suitable emulsifying agents may be naturally-occurring
ingredient in admixture with non-toxic pharmaceutically occurring phosphatides, for example soy bean, lecithin, and
acceptable excipients which are suitable for the manufacture 55 esters or partial esters derived from fatty acids and hexitol
diluents, such as calcium carbonate, sodium carbonate, sation products of the said partial esters with ethylene oxide,
alginic acid; and binding agents, for example magnesium 60 agents.
they may be coated by known techniques to delay disinte- agents, for example glycerol, propylene glycol, sorbitol or
gration and adsorption in the gastrointestinal tract and sucrose, Such formulations may also contain a demulcent, a
example, a time delay material such as glyceryl monostear- 65 The compounds may also be administered in the form of
ate or glyceryl distearate may be employed. These com- suppositories for rectal administration of the drug. These
pounds may also be prepared in solid, rapidly released form. compositions can be prepared by mixing the drug with a
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US 7,235,576 Bl
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suitable non-irritating excipient which is solid at ordinary Commercial grade reagents and solvents were used with-
temperatures but liquid at the rectal temperature and will out further purification. N-cyclohexyl-N'-
therefore melt in the rectum to release the drug. Such (methylpolystyrene)carbodiimide was purchased from
materials include cocoa butter and polyethylene glycols. Calbiochem-Novabiochem Corp. 3-tert-Butylaniline, 5-tert-
For all regimens of use disclosed herein for compounds of 5 buty 1-2-methoxyaniline, 4- bromo-3-( trifluoromethy 1)
Formula I, the daily oral dosage regimen will preferably be aniline, 4-chloro-3-( trifluoromethy 1)aniline 2-methoxy-5-
from 0.01 to, 200 mg/Kg of total body weight. The. daily (tri fluo ro methyl )aniline, 4-tert-butyl-2-nitroaniline,
dosage for administration by injection, including 3-amino-2-naphthol, ethyl 4-isocyanatobenzoate, N-acetyl-
intravenous, intramuscular, subcutaneous and parenteral 4-chloro-2-methoxy-5-(trifluoromethy 1)aniline and
injections, and use of infusion techniques will preferably be 10 4-chloro-3-(trifluoromethyl)phenyl isocyanate were pur-
from 0.01 to 200 mg/Kg of total body weight. The daily chased and used without further purification. Syntheses of
rectal dosage regime will preferably be from 0.01 to 200 3-amino-2-methoxyquinoline (E. Cho et al. WO 98/00402;
mg/K of total body weight. The daily topical dosage regime A. Cordi et al. EP 542,609; IBID Bioorg. Med. Chem .. 3,
will preferably be from 0.1 to 200 mg administered between 1995, 129), 4-(3-carbamoylphenoxy)-1-nitrobenzene (K.
one to four times daily. The daily inhalation dosage regime 15 Ikawa Yakugaku Zasshi 79, 1959, 760; Chem. Abstr. 53,
will preferably be from 0.01 to 10 mg/Kg of total body 1959, 12761b), 3-tert-butylphenyl isocyanate (0. Rohr et al.
weight. DE 2,436,108) and 2-methoxy-5-(trifluoromethyl)phenyl
It will be appreciated by those skilled in the art that the isocyanate (K. Inukai et al. JP 42,025,067; IBID Kogyo
particular method of administration will depend on a variety Kagaku Zasshi 70, 1967, 491) have previously been
of factors, all of which are considered routinely when 20 described.
administering therapeutics. It will also be appreciated by one Thin-layer chromatography (TLC) was performed using
skilled in the art that the specific dose level for a given Whatman® pre-coated glass-backed silica gel 60A F-254
patient depends on a variety of factors, including specific 250 µm plates. Visualization of plates was effected by one or
activity of the compound administered, age, body weight, more of the following techniques: (a) ultraviolet
health, sex, diet, time and route of administration, rate of 25 illumination, (b) exposure to iodine vapor, (c) immersion of
excretion, etc. It will be further appreciated by one skilled in the plate in a 10% solution of phosphomolybdic acid in
the art that the optimal course of treatment, ie., the mode of ethanol followed by heating, (d) immersion of the plate in a
treatment and the daily number of doses of a compound of cerium sulfate solution followed by heating, and/or (e)
Formula I or a pharmaceutically acceptable salt thereof immersion of the plate in an acidic ethanol solution of
given for a defined number of days, can be ascertained by 30 2,4-dinitrophenylhydrazine followed by heating. Column
those skilled in the art using conventional treatment tests. chromatography (flash chromatography) was performed
It will be understood, however, that the specific dose level using 230--400 mesh EM Science® silica gel.
for any particular patient will depend upon a variety of Melting points (mp) were determined using a Thomas-
factors, including the activity of the specific compound Hoover melting point apparatus or a Mettler FP66 auto-
employed, the age, body weight, general health, sex, diet, 35 mated melting point apparatus and are uncorrected. Fourier
time of administration, route of administration, and rate of transform infrared spectra were obtained using a Mattson
excretion, drug combination and the severity of the condi- 4020 Galaxy Series spectrophotometer. Proton (1H) nuclear
tion undergoing therapy. magnetic resonance (NMR) spectra were measured with a
The entire enclosure of all applications, patents and General Electric GN-Omega 300 (300 MHz) spectrometer
publications cited above and below are hereby incorporated 40 with either Me4 Si (o0.00) or residual protonated solvent
by reference, including provisional application Serial No. (CHC13 07.26; MeOH 03.30; DMSO 02.49) as standard.
60/115,877, filed Jan. 13, 1999 and non-provisional appli- Carbon (13 C) NMR spectra were measured with a General
cation Ser. No. 09/257,266 filed Feb. 25, 1999. Electric GN-Omega 300 (75 MHz) spectrometer with sol-
The compounds can be produced from known compounds vent (CDC13 077.0; MeOD-d 3 ; M9.0; DMSO-d 6 039.5) as
(or from starting materials which, in tum, can be produced 45 standard. Low resolution mass spectra (MS) and high reso-
according to procedures disclosed below. The following were obtained with a Hewlett Packard 5989A mass spec-
examples are for illustrative purposes only and are not 50 trometer equipped with a Vacumetrics Desorption Chemical
performed with electron energy of 70 eV and a trap current
EXAMPLES of300 µA. Liquid-cesium secondary ion mass spectra (FAB-
All reactions were performed in flame-dried or oven-dried 55 MS), an updated version of fast atom bombardment were
glassware under a positive pressure of dry argon or dry obtained using a Kratos Concept 1-H spectrometer. Chemi-
nitrogen, and were stirred magnetically unless otherwise cal ionization mass spectra (CI-MS) were obtained using a
indicated. Sensitive liquids and solutions were transferred Hewlett Packard MS-Engine (5989A) with methane or
via syringe or cannula, and introduced into reaction vessels ammonia as the reagent gas (lxl0- 4 torr to 2.5x10- 4 torr).
through rubber septa. Unless otherwise stated, the term 60 The direct insertion desorption chemical ionization (DCI)
'concentration under reduced pressure' refers to use of a probe (Vaccumetrics, Inc.) was ramped from 0---1.5amps in
Buchi rotary evaporator at approximately 15 mmHg. Unless 10 sec and held at 10 amps until all traces of the sample
otherwise stated, the term 'under high vacuum' refers to a disappeared (-1-2 min). Spectra were scarmed from 50---800
vacuum of 0.4-1.0 mmHg. amu at 2 sec per scan. HPLC-electrospray mass spectra
All temperatures are reported uncorrected in degrees 65 (HPLC ES-MS).were obtained using a Hewlett-Packard
Celsius (° C.). Unless otherwise indicated, all parts and 1100 HPLC equipped with a quaternary pump, a variable
percentages are by weight. wavelength detector, a C-18 column, and a Finnigan LCQ
IITRUE COPY!I
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11 12
ion trap mass spectrometer with electrospray ionization. 3-methoxy-2-naphthoate as an amber oil (10.30 g):
1
Spectra were scanned from 120-800 amu using a variable H-NMR (DMSO-d 6 ) 02.70 (s, 3H), 2.85 (s, 3H), 7.38 (app
ion time according to the number of ions in the source. Gas t, 1=8.09 Hz, lH), 7.44 (s, lH), 7.53 (app t, 1=8.09 Hz, lH),
chromatography-ion selective mass spectra (GC-MS) were 7.84 (d, 1=8.09 Hz, lH), 7.90 (s, lH), 8.21 (s, lH).
obtained with a Hewlett Packard 5890 gas chromatograph 5
equipped with an HP-1 methyl silicone column (0.33 mM
coating; 25 mx0.2 mm) and a Hewlett Packard 5971 Mass
Selective Detector (ionization energy 70 eV). Elemental
analyses are conducted by Robertson Microlit Labs, Madi-
son N.l. 10
All compounds displayed NMR spectra, LRMS and either
elemental analysis or HRMS consistent with assigned struc-
tures. OMe
15

AcOH acetic acid A solution of methyl 3-methoxy-2-naphthoate (6.28 g,

anh anhydrous
29.10 mmol) and water (10 mL) in MeOH (100 mL) at room
atm atmosphere(s) 20
BOC tert-butoxycarbonyl temp. was treated with a 1 N NaOH solution (33.4 mL, 33.4
CDI 1,1'-carbonyl diimidazole mmol). The mixture was heated at the reflux temp. for 3 h,
cone concentrated
d day(s)
cooled to room temp., and made acidic with a 10% citric
dee decomposition acid solution. The resulting solution was extracted with
DMAC N,N-dimethylacetarnide 25 EtOAc (2x100 mL). The combined organic layers were
DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
DMF N,N-dimethylformarnide washed with a saturated NaCl solution, dried (MgSO 4) and
DMSO dimethylsulfoxide concentrated under reduced pressure. The residue was tritu-
rated with hexane then washed several times with. hexane to
EDCI 1-(3-dimethylaminopropyl )-3-ethylcarbodiimide
EtOAc ethy 1 acetate give 3-methoxy-2-naphthoic acid as a white solid (5.40 g,
30
EtOH ethanol (100%) 92%): 1 H-NMR (DMSO-d 6 ) 03.88 (s, 3H), 7.34-7.41 (m,
Et2 0 diethyl ether
Et 3 N triethylarnine
2H), 7.49-7.54 (m, lH), 7.83 (d, 1=8.09 Hz, lH), 7.91 (d,
h hour(s) 1=8.09 Hz, lH), 8.19 (s, lH), 12.83 (br s, lH).
m-CPBA 3-chloroperoxybenzoic acid
MeOH methanol 35
temp. temperature
THF tetrahydrofuran
TFA trifluoroAcOH
Tf trifluoromethanesulfonyl
40

Al. General Method for Ary! Amine Formation via Ether
Formation Followed by Ester Saponification, Curtius
Rearrangement, and Carbamate Deprotection. Synthesis 45
of 2-Amino-3-methoxynaphthalene Step 3. 2-(N-(Carbobenzyloxy)amino-3-
methoxynaphthalene

50
mmol) and Et3 N (2.59 mL, 18.6 mmol) in anh toluene (70
mL) was stirred at room temp. for 15 min., then treated with
OMe
then warmed to 80° C. overnight. The resulting mixture was
Step 1. Methyl 3-methoxy-2-naphthoate cooled to room temp., quenched with a 10% citric acid
A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 solution, and extracted with EtOAc (2x100 mL). The com-
mmol) and K2 CO 3 (7.96 g, 57.6 mmol) in DMF (200 mL)
was stirred at room temp. for 15 min., then treated with 60
iodomethane (3.43 mL, 55.1 mmol). The mixture was solution, dried (MgSO 4) and concentrated under reduced
allowed to stir at room temp. overnight, then was treated pressure. The residue was purified by column
with water (200 mL). The resulting mixture was extracted chromatography, (14% EtOAc/86% hexane) to give 2-(N-
with EtOAc (2x200 mL). The combined organic layers were (carbobenzyloxy)amino-3-methoxynaphthalene as a pale
washed with a saturated NaCl solution (100 mL), dried 65 yellow oil (5.1 g, 100%): 1 H-NMR (DMSO-d 6 ) 03.89 (s,
(MgSO 4), concentrated under reduced pressure 3H), 5.17 (s, 2H), 7.27-7.44 (m, SH), 7.72-7.75 (m, 2H),
(approximately 0.4 mmHg overnight) to give methyl 8.20 (s, lH), 8.76 (s, lH).
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Step 1b. Synthesis of 4-chloropyridine-2-carbonyl chloride
HCI salt via picolinic acid
Anhydrous DMF (6.0 mL) was slowly added to SOCl 2
(180 mL) between 40° and 50° C. The solution was stirred
5 in that temperature range for 10 min. then picolinic acid
(60.0 g, 487 mmol) was added in portions over 30 min. The
resulting solution was heated at 72° C. (vigorous SO2
evolution) for 16 h to generate a yellow solid precipitate.
OMe
with toluene (500 mL) and concentrated to 200 mL. The
10
toluene addition/concentration process was repeated twice.
Step 4. 2-Amino-3-methoxynaphthalene The resulting nearly dry residue was filtered and the solids
A slurry of 2-(N-(carbobenzyloxy)amino-3- were washed with toluene (2x200 mL) and dried under high
vacuum for 4 h to afford 4-chloropyridine-2-carbonyl chlo-
methoxynaphthalene (5.0 g, 16.3 mmol) and 10% Pd/C (0.5
ride HCI salt as a yellow-orange solid (92.0 g, 89%).
g) in EtOAc (70 mL) was maintained under a H2 atm 15
(balloon) at room temp. overnight. The resulting mixture
was filtered through Celite® and concentrated under
reduced pressure to give 2-amino-3-methoxynaphthalene as Cl~O
~ OMe
a pale pink powder (2.40 g, 85%): 1 H-NMR (DMSO-d 6 )
03.86 (s, 3H), 6.86 (s, 2H), 7.04-7.16 (m, 2H), 7.43 (d, 1=8.0 20 1
✓,:;N HCl
Hz, lH), 7.56 (d, 1=8.0 Hz, lH); EI-MS m/z 173 (M+).
A2. Synthesis of w-Carbamyl Anilines via Formation of a
Carbamylpyridine Followed by Nucleophilic Coupling Step 2. Synthesis of methyl 4-chloropyridine-2-carboxylate
with, an Ary! Amine. Synthesis of 4-(2-N- HCI salt
Methylcarbamyl-4-pyridyloxy)aniline 25 Anh DMF (10.0 mL) was slowly added to SOCl 2 (300
mL) at 40--48° C. The solution was stirred at that temp.
range for 10 min., then picolinic acid (100 g, 812 mmol) was
added over 30 min. The resulting solution was heated at 72°
Cl'CrO C. (vigorous SO2 evolution) for 16 h to generate a yellow
~ NHMe
30 solid. The resulting mixture was cooled to room temp.,
1 diluted with toluene (500 mL) and concentrated to 200 mL.
✓,::;N
The toluene addition/concentration process was repeated
twice. The resulting nearly dry residue was filtered, and the
Step la. Synthesis of 4-chloro-N-methyl-2- solids were washed with toluene (50 mL) and dried under
pyridinecarboxamide via the Menisci reaction 35 high vacuum for 4 hours to afford 4-chloropyridine-2-
carbonyl chloride HCI salt as an off-white solid (27.2 g,
Caution: this is a highly hazardous, potentially explosive 16%). This material was set aside.
reaction. To a stirring solution of 4-chloropyridine (10.0 g) The red filtrate was added to MeOH (200 mL) at a rate
in N-methylformamide (250 mL) at room temp. was added which kept the internal temperature below 55° C. The
cone. H2 SO4 (3.55 mL) to generate an exotherm. To this 40 contents were stirred at room temp. for 45 min., cooled to 5°
mixture was added H2 O2 (30% wt in H2 O, 17 mL) followed C. and treated with Et 2 O (200 mL) dropwise. The resulting
by FeSO 4 .7H2 O (0.56 g) to generate another exotherm. The solids were filtered, washed with Et2 O (200 mL) and dried
resulting mixture was stirred in the dark at room temp. for
under reduced pressure at 35° C. to provide methyl
1 h, then warmed slowly over 4 h to 45° C. When bubbling
4-chloropyridine-2-carboxylate HCI salt as a white solid
had subsided, the reaction was heated at 60° C. for 16 h. The
45 (110 g, 65%): mp 108-112° C.; 1 H-NMR (DMSO-d 6 ) 03.88
resulting opaque brown solution was diluted with H2 O (700
(s, 3H); 7.82 (dd, 1=5.5, 2.2 Hz, lH); 8.08 (d, 1=2.2 Hz, lH);
mL) followed by a 10% NaOH solution (250 mL). The 8.68 (d, 1=5.5 Hz, lH); 10.68 (br s, lH); HPLC ES-MS m/z
resulting mixture was extracted with EtOAc (3x500 mL).
172 ((M+Hr).
The organic phases were washed separately with a saturated
NaCl solution (3x150 mL), then they were combined, dried 50
(MgSO 4) and filtered through a pad of silica gel with the aid
of EtOAc. The resulting brown oil was purified by column ClvO
chromatography (gradient from 50% EtOAc/50% hexane to ~ NHMe
80% EtOAc/20% hexane). The resulting yellow oil crystal- 1
✓,::;N
lized at 0° C. over 72 h to give 4-chloro-N-methyl-2- 55
pyridinecarboxamide (0.61 g, 5.3%): TLC (50% EtOAc/
50% hexane) Rf0.50; 1 H NMR (CDCl 3 ) 03.04 (d, 1=5.1 Hz, Step 3a. Synthesis of 4-chloro-N-methyl-2-
3H), 7.43 (dd, 1=5.4, 2.4 Hz, lH), 7.96 (br s, lH), 8.21 (s, pyridinecarboxamide from methyl 4-chloropyridine-2-
lH), 8.44 (d, 1=5.1 Hz, lH); CI-MS m/z 171 ((M+Ht). carboxylate
60 A suspension of methyl 4-chloropyridine-2-carboxylate
HCI salt (89.0 g, 428 mmol) in MeOH (75 mL) at 0° C. was
treated with a 2.0 M methylamine solution in THF (1 L) at
Cl~O
-.;:: Cl a rate which kept the internal temp. below 5° C. The
I ✓,:;N HCl 65
resulting mixture was stored at 3° C. for 5 h, then concen-
trated under reduced pressure. The resulting solids were
suspended in EtOAc (1 L) and filtered. The filtrate was
IITRUE COPY!I
US 7,235,576 Bl
15 16
(Na2 SO4 ) and concentrated under reduced pressure to afford A3. General Method for the Synthesis of Anilines by
4-chloro-N-methyl-2-pyridinecarboxamide as pale-yellow Nucleophilic Aromatic Addition Followed by Nitroarene
crystals (71.2 g, 97%): mp 41-43° C.; 1H-NMR (DMSO-d 6 ) Reduction. Synthesis of 5-(4-Aminophenoxy)isoindoline-
1,3-dione
02.81 (s, 3H), 7.74 (dd, 1=5.1, 2.2 Hz, lH), 8.00 (d, 1=2.2,
lH), 8.61 (d, 1=5.1 Hz, lH), 8.85 (br d, lH); CI-MS m/z 171
((M+Hr).
('y{
10 HO~
Cl'CrO
~ NHMe
0
1
✓,:::N
To a mixture of ammonium carbonate (5.28 g, 54.9 mmol)
15
in cone. AcOH (25 mL) was slowly added
4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting
Step 3b. Synthesis of 4-chloro-N-methyl-2- mixture was heated at 120° C. for 45 min., then the clear,
pyridinecarboxamide from 4-chloropyridine-2-carbonyl bright yellow mixture was heated at 160° C. for 2 h. The
chloride resulting mixture was maintained at 160° C. and was con-
20
centrated to approximately 15 mL, then was cooled to room
temp. and adjusted pH 10 with a IN NaOH solution. This
4-Chloropyridine-2-carbonyl chloride HCI salt (7.0 g, mixture was cooled to 0° C. and slowly acidified to pH 5
32.95 mmol) was added in portions to a mixture of a 2.0 M using a IN HCI solution. The resultant precipitate was
methylamine solution in THF (100 mL) and MeOH (20 mL) collected by filtration and dried under reduced pressure to
at 0° C. The resulting mixture was stored at 3° C. for 4 h, 25
yield 5-hydroxyisoindoline-1,3-dione as a pale yellow pow-
then concentrated under reduced pressure. The resulting der as product (3.24 g, 72%): 1 H NMR (DMSO-d 6 )
nearly dry solids were suspended in EtOAc (100 mL) and 07.00-7.03 (m, 2H), 7.56 (d, 1=9.3 Hz, lH).
filtered. The filtrate was washed with a saturated NaCl
solution (2x100 mL), dried (Na2 SO4 ) and concentrated 30
under reduced pressure to provide 4-chloro-N-methyl-2-
pyridinecarboxamide as a yellow, crystalline solid (4.95 g,
88%): mp 37--40° C.
35
Step 2. Synthesis of 5-(4-nitrophenoxy)isoindoline-l,3-

dione
40 To a stirring slurry ofNaH (1.1 g, 44.9 mmol) in DMF (40
mL) at 0° C. was added a solution of 5-hydroxyisoindoline-
1,3-dione (3.2 g, 19.6 mmol) inDMF (40 mL) dropwise. The
bright yellow-green mixture was allowed to return to room
Step 4. Synthesis of 4-(2-(N-methylcarbamoyl)-4- temp. and was stirred for 1 h, then l-fluoro-4-nitrobenzene
pyridy loxy )aniline 45 (2.67 g, 18.7 mmol) was added via syringe in 3-4 portions.
The resulting mixture was heated at 70° C. overnight, then
cooled to room temp. and diluted slowly with water (150
A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. mL), and extracted with EtOAc (2x100 mL). The combined
DMF (150 mL) was treated with potassium tert-butoxide organic layers were dried (MgSO 4) and concentrated under
(10.29 g, 91.7 mmol), and the reddish-brown mixture was 50 reduced pressure to give 5-(4-nitrophenoxy)isoindoline-1,3-
stirred at room temp. for 2 h. The contents were treated with dione as a yellow solid (3.3 g, 62%): TLC (30% EtOAc/70%
hexane) Rf0.28; 1H NMR (DMSO-d 6) 07.32 (d, 1=12 Hz,
4chloro-N-methyl-2-pyridinecarboxamide (15.0 g, 87 .9
2H), 7.52-7.57 (m, 2H), 7.89(d, 1=7.8 Hz, lH), 8.29 (d, 1=9
mmol) and K2 CO 3 (6.50 g, 47.0 mmol) and then heated at Hz, 2H), 11.43 (br s, lH); CI-MS m/z 285 ((M+Ht, 100%).
80° C. for 8 h. The mixture was cooled to room temp. and
55
separated between EtOAc (500 mL) and a saturated NaCl
solution (500 mL). The aqueous phase was back-extracted
with EtOAc (300 mL). The combined organic layers were
washed with a saturated NaCl solution (4x1000 mL), dried
(Na2 SO4 ) and concentrated under reduced pressure. The 60
resulting solids were dried under reduced pressure at 35° C.
for 3 h to afford 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)
aniline as a light-brown solid 17.9 g, 84%): 1 H-NMR
(DMSO-d 6) 02.77 (d, 1=4.8 Hz, 3H), 5.17 (br s, 2H), 6.64, Step 3. Synthesis of 5-(4-aminophenoxy)isoindoline-l,3-
6.86 (AA'BB' quartet, 1=8.4 Hz, 4H), 7.06 (dd, 1=5.5, 2.5 65 dione
Hz, lH), 7.33 (d, 1=2.5 Hz, lH), 8.44 (d, 1=5.5 Hz; lH), 8.73 A solution of 5-(4-nitrophenoxy )isoindoline-1,3-dione
(br d, lH); HPLC ES-MS m/z 244 ((M+Hr). (0.6 g, 2.11 mmol) in cone. AcOH (12 mL) and water (0.1
IITRUE COPY!I
US 7,235,576 Bl
17 18
mL) was stirred under stream of argon while iron powder 0.43; 1 H NMR (CDCl 3 ) ol.28 (s, 9H), 1.87-1.91 (m, SH),
(0.59 g, 55.9 mmol) was added slowly. This mixture stirred 5.85 (br s, 2H), 6.73-6.96 (m, 3H), 7.28 (br s, lH).
at room temp. for 72 h, then was diluted with water (25 mL) AS. General Method for the Synthesis of Anilines from
and extracted with EtOAc (3x50 mL). The combined Anilines by Nucleophilic Aromatic Substitution. Synthe-
organic layers were dried (MgSO 4) and concentrated under 5 sis of 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-
reduced pressure to give 5-(4-aminophenoxy)isoindoline-l, methylaniline HCI Salt
3-dione as a brownish solid (0.4 g, 75%): TLC (50%
EtOAc/50% hexane) Rf 0.27; 1 H NMR (DMSO-d 6 ) 05.14
q
(br s, 2H), 6.62 (d, 1=8.7 Hz, 2H), 6.84 (d, 1=8.7 Hz, 2H),
7.03 (d, 1=2.1 Hz, lH), 7.23 (dd, lH), 7.75 (d, 1=8.4 Hz,
lH), 11.02 (s, lH); HPLC ES-MS m/z 255 ((M+Ht, 100%).
10 o~mw,
A4. General Method for the Synthesis of Pyrrolylanilines.
Synthesis of 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline H2N ~~ HCl
Me
15

mmol) in dry dimethylacetamide (75 mL) was treated with
potassium tert-butoxide (10.86 g, 96.77 mmol) and the black
mixture was stirred at room temp. until the flask had reached
20 room temp. The contents were then treated with 4-chloro-
N-methyl-2-pyridinecarboxamide (Method A2, Step 3b;
N 7.52 g, 44.2 mmol) and heated at 110° C. for 8 h. The
"(Y 25
mixture was cooled to room temp. and diluted with water
(75 mL). The organic layer was extracted with EtOAc
(5x100 mL). The combined organic layers were washed
with a saturated NaCl solution (200 mL), dried (MgSO 4) and
Step 1. Synthesis of 1-(4-tert-butyl-2-nitrophenyl)-2,5- concentrated under reduced pressure. The residual black oil
dimethylpyrrole was treated with Et2 O (50 mL) and sonicated. The solution
To a stirring solution of 2-nitro-4-tert-butylaniline (0.5 g, was then treated with HCI (1 Min Et2 O; 100 mL) and stirred
2.57 mmol) in cyclohexane (10 mL) was addedAcOH (0.1 30 at room temp. for 5 min. The resulting dark pink solid (7.04
mL) and acetonylacetone (0.299 g, 2.63 mmol) via syringe. g, 24.1 mmol) was removed by filtration from solution and
The reaction mixture was heated at 120° C. for 72 h with stored under anaerobic conditions at 0° C. prior to use: 1 H
azeotropic removal of volatiles. The reaction mixture was NMR (DMSO-d 6 ) 02.41 (s, 3H), 2.78 (d, 1=4.4 Hz, 3H),
cooled to room temp., diluted with CH 2 Cl2 (10 mL) and 4.93 (br s, 2H), 7.19 (dd, 1=8.5, 2.6 Hz, lH), 7.23 (dd, 1=5.5,
sequentially washed with a IN HCI solution (15 mL), a IN 35 2.6 Hz, lH), 7.26 (d, 1=2.6 Hz, lH), 7.55 (d, 1=2.6 Hz, lH),
NaOH solution (15 mL) and a saturated NaCl solution (15 7.64 (d, 1=8.8 Hz, lH), 8.55 (d, 1=5.9 Hz, lH), 8.99 (q, 1=4.8
mL), dried (MgSO 4) and concentrated under reduced pres- Hz, lH).
sure. The resulting orange-brown solids were purified via A6. General Method for the Synthesis of Anilines from
colunm chromatography (60 g SiO2 ; gradient from 6% Hydroxyanilines by N-Protection, Nucleophilic Aromat-
EtOAc/94% hexane to 25% EtOAc/75% hexane) to give 40 ric Substitution and Deprotection. Synthesis of 4-(2-(N-
1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole as an Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline
orange-yellow solid (0.34 g, 49%): TLC (15% EtOAc/85%
hexane) Rf0.67; 1 H NMR (CDCl 3 ) d 1.34 (s, 9H), 1.89 (s,
6H), 5.84 (s, 2H), 7.19-7.24 (m, lH), 7.62 (dd, lH), 7.88 (d,
1=2.4 Hz, lH); CI-MS m/z 273 ((M+H)+, 50%). 45
FC)lN
3
0
H
q Cl
OH
50 Step 1: Synthesis of 3-Chloro-4-(2,2,2-

trifluoroacety !amino)phenol
Iron (3.24 g, 58.00 mmol) was added to stirring TFA (200
mL). To this slurry was added 2-chloro-4-nitrophenol (10.0
N
g, 58.0 mmol) and trifluoroacetic anhydride (20 mL). This
"(Y 55 gray slurry was stirred at room temp. for 6 d. The iron was
filtered from solution and the remaining material was con-
centrated under reduced pressure. The resulting gray solid
was dissolved in water (20 mL). To the resulting yellow
Step 2. Synthesis of 5-tert-Butyl-2-(2,5-dimethylpyrrolyl) solution was added a saturated NaHCO 3 solution (50 mL).
aniline 60 The solid which precipitated from solution was removed.
A slurry of l-(4-tert-butyl-2-nitrophenyl)-2,5- The filtrate was slowly quenched with the sodium bicarbon-
dimethylpyrrole (0.341 g, 1.25 mmol), 10%Pd/C (0.056 g) ate solution until the product visibly separated from solution
and EtOAc (50 mL) under an H2 atmosphere (balloon) was (determined was using a mini work-up vial). The slightly
stirred for 72 h, then filtered through a pad of Celite®. The cloudy yellow solution was extracted with EtOAc (3x125
filtrate was concentrated under reduced pressure to give 65 mL). The combined organic layers were washed with a
5-tert--butyl-2-(2,5-dimethylpyrrolyl)aniline as yellowish saturated NaCl solution (125 mL), dried (MgSO 4) and
solids (0.30 g, 99%): TLC (10% EtOAc/90% hexane) Rf concentrated under reduced pressure. The 1 H NMR
IITRUE COPY!I
US 7,235,576 Bl
19 20
(DMSO-d 6 ) indicated a 1: 1 ratio of the nitrophenol starting A 7. General Method for the Deprotection of an Acy lated
material and the intended product 3-chloro-4-(2,2,2- Aniline. Synthesis of 4-Chloro-2-methoxy-5-
trifluoroacetylamino )phenol. The crude material was taken (trifluoromethy !)aniline
q~
0
0
0
~-, 10
FC)lN
3 H
# ~h
Cl
A suspension of 3-chloro-6-(N-acetyl)-4-
(trifluoromethyl)anisole (4.00 g, 14.95 mmol) in a 6M HCI
15
solution (24 mL) was heated at the reflux temp. for 1 h. The
resulting solution was allowed to cool to room temp. during
Step 2: Synthesis of 4-(2-(N-Methylcarbamoyl)-4- which time it solidified slightly. The resulting mixture was
pyridyloxy)-2-chlorophenyl (222-trifluoro )acetamide diluted with water (20 mL) then treated with a combination
of solid NaOH and a saturated NaHCO 3 solution until the
20
solution was basic. The organic layer was extracted with
A solution of crude 3-chloro-4-(2,2,2- CH 2 Cl 2 (3x50 mL). The combined organics were dried
trifluoroacetylamino )phenol (5.62 g, 23.46 mmol) in dry (MgSO 4) and concentrated under reduced pressure to yield
dimethylacetamide (50 mL) was treated with potassium 4-chloro-2-methoxy-5-(trifluoromethyl)aniline as a brown
tert-butoxide (5.16 g, 45.98 mmol) and the brownish black oil (3.20 g, 14.2 mmol): 1 H NMR (DMSO-d 6 ) 03.84 (s, 3H),
25
mixture was stirred at room temp. until the flask had cooled 5.30 (s, 2H), 7.01 (s, 2H).
to room temp. The resulting mixture was treated with AS. General Method for Synthesis of w-Alkoxy-w-
4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, carboxyphenyl Anilines. Synthesis of 4-(3-(N-
Step 3b; 1.99 g, 11.7 mmol) and heated at 100° C. under Methylcarbamoly)-4-methoxyphenoxy)aniline
argon for 4 d. The black reaction mixture was cooled to 30
room temp. and then poured into cold water (100 mL). The
mixture was extracted with EtOAc (3x75 mL) and the
combined organic layers were concentrated under reduced
pressure. The residual brown oil was purified by column
chromatography (gradient from 20% EtOAc/pet. ether. to 35
40% EtOAc/pet. ether) to yield 4-(2-(N-Methylcarbamoyl)-

4-pyridyloxy)-2-chlorophenyl (222-trifluoro )acetamide as a Step 1. 4-(3-Methoxycarbonyl-4-methoxyphenoxy)-1-
yellow solid (8.59 g, 23.0 mmol). nitro benzene:
40 To a solution of 4-(3-carboxy-4-hydroxyphenoxy)-1-
nitrobenzene (prepared from 2,5-dihydroxybenzoic acid in a
manner analogous to that described in Method Al 3, Step 1,
12 mmol) in acetone (50 mL) was added K2 CO 3 (5 g) and
dimethyl sulfate (3.5 mL). The resulting mixture was heated
45 at the reflux temp. overnight, then cooled to room temp. and
and purified by colunm chromatography (50% EtOAc/50%
hexane) to give 4-(3-methoxycarbonyl-4-
Step 3. Synthesis of 4-(2-(N-Methylcarbamoyl)-4- 50 methoxyphenoxy)-1-nitrobenzene as a yellow powder (3 g):
pyridy loxy )-2-chloroaniline mp 115-118° C.
A solution of crude 4-(2-(N-Methylcarbamoyl)-4-

pyridyloxy)-2-chlorophenyl (222-trifluoro )acetamide (8.59 55
g, 23.0 mmol) in dry 4-dioxane (20 mL) was treated with a
IN NaOH solution (20 mL). This brown solution was
allowed to stir for 8 h. To this solution was added EtOAc (40
mL). The green organic layer was extracted with EtOAc
(3x40 mL) and the solvent was concentrated to yield 4-(2- 60 Step 2. 4-(3-Carboxy-4-methoxyphenoxy)-1-nitrobenzene:
(N-Methy lcarbamoy I)-4-pyridy loxy )-2-chloroaniline as a
green oil that solidified upon standing (2.86 g, 10.30 mmol):
1
H NMR (DMSO-d 6 ) 02.77 (d, 1=4.8 Hz, 3H), 5.51 (s, 2H), then heated at the reflux temp. for 4 h. The resulting mixture
6.60 (dd, 1=8.5, 2.6 Hz, lH), 6.76 (d, 1=2.6 Hz, lH), 7.03 (d, 65 was cooled to room temp. and concentrated under reduced
1=8.5 Hz, lH), 7.07 (dd, 1=5.5, 2.6, Hz, lH), 7.27 (d, 1=2.6 pressure. The residue was dissolved in water (50 mL), and
Hz, lH), 8.46 (d, 1=5.5 Hz, lH), 8.75 (q, 1=4.8, lH). the aqueous mixture was made acidic with a IN HCI
IITRUE COPY!I
US 7,235,576 Bl
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solution. The resulting mixture was extracted with EtOAc solids were collected and dried under reduced pressure to
(50 mL). The organic layer was dried (MgSO 4) and con- give 5-(4-nitrophenoxy)-2-methylisoindoline-l,3-dione as a
centrated under reduced pressure to give 4-(3-carboxy-4- bright yellow solid (0.87 g, 83%): TLC (35% EtOAc/65%
methoxyphenoxy)-1-mitrobenzene (1.04 g). hexane) Rf0.61.
10
Step 3. 4-(3-(N-Methylcarbamoly)-4-methoxyphenoxy)-1-
Step 2. Synthesis of 5-(4-Aminophenoxy)-2-
nitro benzene:
To a solution of 4-(3-carboxy-4-methoxyphenoxy)-1- 15
methylisoindoline-l,3-dione:
nitrobenzene (0.50 g, 1.75 mmol) in CH 2 Cl 2 (12 mL) was A slurry of nitrophenoxy)-2-methylisoindoline-1,3-dione
added SOCl 2 (0.64 mL, 8.77 mmol) in portions. The result- (0.87 g, 2.78 mmol) and 10% Pd/C (0.10 g) in MeOH was
ing solution was heated at the reflux temp. for 18 h, cooled stirred under 1 atm of H2 (balloon) overnight. The resulting
to room temp., and concentrated under reduced pressure. mixture was filtered through a pad of Celite® and concen-
The resulting yellow solids were dissolved in CH 2 Cl2 (3 20
trated under reduced pressure. The resulting yellow solids
mL) then the resulting solution was treated with a methy- were dissolved in EtOAc (3 mL) and filtered through a plug
lamine solution (2.0 M in THF, 3.5 mL, 7.02 mmol) in of SiO 2 (60% EtOAc/40% hexane) to afford 5-(4-
portions (CAUTION: gas evolution), and stirred at room aminophenoxy)-2-methylisoindoline-l,3-dione as a yellow
temp. for 4 h. The resulting mixture was treated with a IN solid (0.67 g, 86%): TLC (40% EtOAc/60% hexane) Rf0.27.
NaOH solution, then extracted with CH 2 Cl2 (25 mL). The 25
AlO. General Method for Synthesis of w-Carbamoylaryl
organic layer was dried (Na2 SO4 ) and concentrated under Anilines Through Reaction of w-Alkoxycarbonylaryl Pre-
reduced pressure to give 4-(3-(N-methylcarbamoly)-4- cursors with Amines. Synthesis of 4-(2-(N-(2-morpholin-
methoxyphenoxy)-1-nitrobenzene as a yellow solid (0.50 g, 4-ylethyl)carbamoyl)pyridyloxy)aniline
95%).
30
35
Step 1. Synthesis of 4-Chloro-2-(N-(2-morpholin-4-ylethyl)
carbamoyl)pyridine
Step 4. 4-(3-(N-Methylcarbamoly)-4-methoxyphenoxy) To a solution of methyl 4-chloropyridine-2-carboxylate
aniline: HCI salt (MethodA2, Step 2; 1.01 g, 4.86 mmol) in THF (20
A slurry of 4-(3-(N-methylcarbamoly)-4- 40 mL) was added 4-(2-aminoethyl)morpholine (2.55 mL, 19.4
methoxyphenoxy)-1-nitrobenzene (0.78 g, 2.60 mmol) and mmol) dropwise and the resulting solution was heated at the
10% Pd/C (0.20 g) in EtOH (55 mL) was stirred under 1 atm reflux temp. for 20 h, cooled to room temp., and treated with
of H2 (balloon) for 2.5 d, then was filtered through a pad of water (50 mL). The resulting mixture was extracted with
Celite®. The resulting solution was concentrated under EtOAc (50 mL). The organic layer was dried (MgSO 4) and
reduced pressure to afford 4-(3-(N-methylcarbamoly)-4- 45 concentrated under reduced pressure to afford 4-chloro-2-
methoxyphenoxy)aniline as an off-white solid (0.68 g, (N-(2-morpholin-4-ylethyl)carbamoyl)pyridine as a yellow
96%): TLC (0.1% Et 3 N/99.9% EtOAc) Rf0.36. oil (1.25 g, 95%): TLC (10% MeOH/90% EtOAc) Rf0.50.
A9. General Method for Preparation of w-Alkylphthalimide-
containing Anilines. Synthesis of 5-(4-Aminophenoxy)-
2-methylisoindoline-l,3-dione 50
55
Step 2. Synthesis of 4-(2-(N-(2-Morpholin-4-ylethyl)
carbamoyl)pyridyloxy)aniline.
potassium tert-butoxide (0.53 g, 4.75 mo!) in DMF (8 mL)
Step 1. Synthesis of 5-(4-Nitrophenoxy)-2- 60 was stirred at room temp. for 2 h, then was sequentially
methy lisoindoline-1,3-dione: treated with 4-chloro-2-(N-(2-morpholin-4-ylethyl)
A slurry of 5-(4-nitrophenoxy)isoindoline-l,3-dione (A3 carbamoyl)pyridine (1.22 g, 4.52 mmol) and K2 CO 3 (0.31 g,
Step 2; 1.0 g, 3.52 mmol) and NaH (0.13 g, 5.27 mmol) in 2.26 mmol). The resulting mixture was heated at 75° C.
DMF (15 mL) was stirred at room temp. for 1 h, then treated overnight, cooled to room temp., and separated between
with methyl iodide (0.3 mL, 4.57 mmol). The resulting 65 EtOAc (25 mL) and a saturated NaCl solution (25 mL). The
mixture was stirred at room temp. overnight, then was aqueous layer was back extracted with EtOAc (25 mL). The
cooled to° C. and treated with water (10 mL). The resulting combined organic layers were washed with a saturated NaCl
IITRUE COPY!I
US 7,235,576 Bl
23 24
sure. The resulting brown solids were purified by column
chromatography (58 g; gradient from 100% EtOAc to 25%
MeOH/75% EtOAc) to afford 4-(2-(N-(2-morpholin-4-
ylethyl)carbamoyl)pyridyloxy)aniline (1.0 g, 65%): TLC 5
(10% MeOH/90% EtOAc) Rf 32.
Al 1. General Method for the Reduction of Nitroarenes to
Arylamines. Synthesis of 4-(3-Carboxyphenoxy)aniline.
10
A slurry of 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene
(2.12 g, 7.8 mmol).and 10% Pd/C (0.20 g) in EtOH (50 mL)
15
5-yloxy)aniline as a dark yellow solid: TLC (100% EtOAc)
A slurry of 4-(3-carboxyphenoxy )-1-nitro benzene (5 .38 g, Rf0.15.
A13. General Method for the Synthesis of w-Carbamoyl
stirred under an H2 atmosphere (balloon) for 2 d. The 20
Anilines via EDCI-MediatedAmide Formation Followed
resulting mixture was filtered through a pad of Celite®, then
by Nitroarene Reduction. Synthesis of 4-(3-N-
concentrated under reduced pressure to afford 4-(3-
Methy lcarbamoy lphenoxy )aniline
carboxyphenoxy)aniline as a brown solid (2.26 g, 48%):
TLC (10% MeOH/90% CH 2 Cl2 ) Rf0.44 (streaking).
A12. General Method for the Synthesis of Isoindolinone- 25
Containing Anilines. Synthesis of 4-(1-Oxoisoindolin-5-
yloxy)aniline
30
HO~
I NH
~
Step 1. Synthesis of 4-(3-ethoxycarbonylphenoxy)-1-
0 nitrobenzene
35
A mixture of 4-fluoro-1-nitrobenzene (16 mL, 150 mmol),
ethyl 3-hydroxybenzoate 25 g, 150 mmol) and K2 CO 3 (41 g,
To a solution of 5-hydroxyphthalimide (19.8 g, 121 300 mmol) in DMF (125 mL) was heated at the reflux temp.
mmol) inAcOH (500 mL) was slowly added zinc dust (47.6 overnight, cooled to room temp. and treated with water (250
g, 729 mmol) in portions, then the mixture was heated at the 40 mL). The resulting mixture was extracted with EtOAc
reflux temp. for 40 min., filtered hot, and concentrated under (3x150 mL). The combined organic phases were sequen-
reduced pressure. The reaction was repeated on the same tially washed with water (3x100 mL) and a saturated NaCl
scale and the combined oily residue was purified by column solution (2x100 mL), dried (Na2 SO4 ) and concentrated
chromatography (1.1 Kg SiO 2 ; gradient from 60% EtOAc/ under reduced pressure. The residue was purified by colurmi
40% hexane to 25% MeOH/75% EtOAc) to give 45 chromatography (10% EtOAc/90% hexane) to afford 4-(3-
5-hydroxyisoindolin-1-one (3.77 g): TLC (100% EtOAc) Rf ethoxycarbonylphenoxy)-1-nitrobenzene as an oil (38 g).
0.17; HPLC ES-MS m/z 150 ((M+Ht).
50
55
Step 2. Synthesis of 4-(1-isoindolinon-5-yloxy)-1- Step 2. Synthesis of 4-(3-carboxyphenoxy)-1-nitrobenzene
nitrobenzene
To a slurry ofNaH (0.39 g, 16.1 mmol) in DMF at 0° C. To a vigorously stirred mixture of 4-(3-
was added 5-hydroxyisoindolin-1-one (2.0 g, 13.4 mmol) in ethoxycarbonylphenoxy)-1-nitrobenzene (5.14 g, 17.9
portions. The resulting slurry was allowed to warm to room 60 mmol) in a 3:1 THF/water solution (75 mL) was added a
temp. and was stirred for 45 min., then 4-fluoro-1- solution LiOH.H 2 O (1.50 g, 35.8 mmol) in water (36 mL).
nitrobenzene was added and then mixture was heated at 70° The resulting mixture was heated at 50° C. overnight, then
C. for 3 h. The mixture was cooled to 0° C. and treated with cooled to room temp., concentrated under reduced pressure,
water dropwise until a precipitate formed. The resulting and adjusted to pH 2 with a IM HCl solution. The resulting
solids were collected to give 4-(1-isoindolinon-5-yloxy)-1- 65 bright yellow solids were removed by filtration and washed
nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC with hexane to give 4-(3-carboxyphenoxy)-1-nitrobenzene
(100% EtOAc) Rf0.35. (4.40 g, 95%).
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residue was purified by column chromatography (30%
EtOAc/70% hexane) to afford 4-(3-(5-methoxycarbonyl)
Step 3. Synthesis of 4-(3-(N-methylcarbamoyl)phenoxy)-1-

10
nitrobenzene
A mixture of 4-(3-carboxyphenoxy)-1-nitrobenzene (3.72
g, 14.4 mmol), EDCI.HCl (3.63 g, 18.6 mmol), Step 2. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)
aniline
N-methylmorpholine (1.6 mL, 14.5 mmol) and methylamine
A slurry of 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-
(2.0 Min THF; 8 mL, 16 mmol) in CH 2 Cl2 (45 mL) was 15 nitrobenzene (0.60 g, 2.20 mmol) and 10% Pd/C in MeOH/
stirred at room temp. for 3 d, then concentrated under EtOAc was stirred under an H2 atmosphere (balloon) for 72
reduced pressure. The residue was dissolved in EtOAc (50 h. The resulting mixture was filtered and the filtrate was
mL) and the resulting mixture was extracted with a IM HCl concentrated under reduced pressure. The residue was puri-
solution (50 mL). The aqueous layer was back-extracted fied by column chromatography (gradient from 10% EtOAc/
with EtOAc (2x50 mL). The combined organic phases were 20 90% hexane to 30% EtOAc/70% hexane to 50% EtOAc/
washed with a saturated NaCl solution (50 mL), dried 50% hexane) to afford 4-(3-(5-methoxycarbonyl)
(Na2 SO4 ), and concentrated under reduced pressure to give pyridyloxy)aniline (0.28 g, 60%): 1 H NMR (CDC13 ) 03.92
4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene as an (s, 3H), 6.71, (d, 2H), 6.89 (d, 2H), 7.73 (, lH), 8.51 (d, lH),
oil (1.89 g). 8.87 (d, lH).
A15. Synthesis of an Aniline via Electrophilic Nitration
25
Followed by Reduction. Synthesis of 4-(3-
Methy lsulfamoy lphenoxy )aniline
0 0
30 Bryy\(
V NHMe
Step 4. Synthesis of 4-(3-(N-methylcarbamoyl)phenoxy)

aniline
A slurry of 4-(3-(N-methylcarbamoyl)phenoxy)-1- 35 Step 1. Synthesis ofN-methyl-3-bromobenzenesulfonamide
nitrobenzene (1.89 g, 6.95 mmol) and 5% Pd/C (0.24 g) in To a solution of3-bromobenzenesulfonyl chloride (2.5 g,
EtOAc (20 mL) was stirred under an H2 atm (balloon) 11.2 mmol) in THF (15 mL) at 0° C. was addedmethylamine
overnight. The resulting mixture was filtered through a pad (2.0 Min THF; 28 mL, 56 mmol). The resulting solution was
of Celite® and concentrated under reduced pressure. The allowed to warm to room temp. and was stirred at room
residue was purified by column chromatography (5% 40 temp. overnight. The resulting mixture was separated
MeOH/95% CH 2 Cl 2 ). The resulting oil solidified under between EtOAc (25 mL) and a 1 M HCl solution (25 mL).
vacuum overnight to give 4-(3-(N-methylcarbamoyl) The aqueous phase was back-extracted with EtOAc (2x25
phenoxy)aniline as a yellow solid (0.95 g, 56%). mL). The combined organic phases were sequentially
A14. General Method for the Synthesis of w-Carbamoyl washed with water (2x25 mL) and a saturated NaCl solution
45 (25 mL), dried (MgSO 4) and concentrated under reduced
Anilines via EDCI-MediatedAmide Formation Followed
by Nitroarene Reduction. Synthesis of 4-3-(5- pressure to give N-methyl-3-bromobenzenesulfonamide as a
Methy lcarbamoy 1)pyridy loxy )aniline white solid (2.8 g, 99%).
50
55
Step 2. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)
Step 1. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)- benzene
l-nitrobenzene To a slurry of phenol (1.9 g, 20 mmol), K2 CO 3 (6.0 g, 40
To a slurry ofNaH (0.63 g, 26.1 mmol) in DMF (20 mL) mmol), and Cul (4 g, 20 mmol) in DMF (25 mL) was added
was added a solution of methyl 5-hydroxynicotinate (2.0 g, 60 N-methyl-3-bromobenzenesulfonamide (2.5 g, 10 mmol),
13.1 mmol) in DMF (10 mL). The resulting mixture was and the resulting mixture was stirred at the reflux temp.
added to a solution of 4-fluoronitrobenzene (1.4 mL, 13.1 overnight, cooled to room temp., and separated between
mmol) in DMF (10 mL) and the resulting mixture was EtOAc (50 mL) and a 1 N HCl solution (50 mL). The
heated at 70° C. overnight, cooled to room temp., and treated aqueous layer was back-extracted with EtOAc (2x50 mL).
with MeOH (5 mL) followed by water (50 mL). The 65 The combined organic phases were sequentially washed
resulting mixture was extracted with EtOAc (100 mL). The with water (2x50 mL) and a saturated NaCl solution (50
organic phase was concentrated under reduced pressure. The mL), dried (MgSO 4), and concentrated under reduced pres-
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sure. The residual oil was purified by column chromatog- Al 7. Synthesis of N-(w-Silyloxyalkyl)amides. Synthesis of
raphy (30% EtOAc/70% hexane) to give 4-(3-(N- 4-( 4-(2-(N-(2-Triisopropylsily loxy)ethylcarbamoy 1)
methylsulfamoyl)phenyloxy)benzene (0.30 g). pyridyloxyaniline
10
Step 3. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)-

l-nitrobenzene
To a solution of 4-(3-(N-methylsulfamoyl)phenyloxy) Step 1. 4-Chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-
15
benzene (0.30 g, 1.14 mmol) in TFA (6 mL) at -10° C. was carboxamide
added NaNO 2 (0.097 g, 1.14 mmol) in portions over 5 min.
The resulting solution was stirred at -10° C. for 1 h, then
was allowed to warm to room 5 temp., and was concentrated To a solution of 4-chloro-N-(2-hydroxyethyl)pyridine-2-
under reduced pressure. The residue was separated between carboxamide (prepared in a manner analogous to Method
20 A2, Step 3b; 1.5 g, 7.4 mmol) in anh DMF (7 mL) was added
sequentially washed with water (10 mL) and a saturated triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv.) and
NaCl solution (10 mL), dried (MgSO 4) and concentrated imidazole (1.12 g, 16.4 mmol, 2.2 equiv.). The resulting
under reduced pressure to give 4-(3-(N-methylsulfamoyl) yellow solution was stirred for 3 h at room temp, then was
phenyloxy)-1-nitrobenzene (0.20 g). This material carried concentrated under reduced pressure. The residue was sepa-
25
aqueous layer was extracted with EtOAc (3x10 mL). The
combined organic phases were dried (MgSO 4), and concen-
trated under reduced pressure to afford 4-chloro-2-(N-(2-
30 triisopropylsilyloxy)ethyl)pyridinecarboxamide as an
orange oil (2.32 g, 88%). This material was used in the next
step without further purification.
Step 4. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy) 35

aniline
A slurry of 4-(3-(N-methylsulfamoyl)phenyloxy)-1-
nitrobenzene (0.30 g) and 10% Pd/C (0.030 g) in EtOAc (20
mL) was stirred under an H2 atmosphere (balloon) over-
night. The resulting mixture was filtered through a pad of 40
Celite®. The filtrate was concentrated under reduced pres-
sure. The residue was purified by column chromatography
(30% EtOAc/70% hexane) to give 4-(3-(N-
Step 2. 4-( 4-(2-(N-(2-Triisopropylsilyloxy)ethylcarbamoyl)
methylsulfamoyl)phenyloxy)aniline (0.070 g).
pyridy loxyaniline
A16. Modification of w-ketones. Synthesis of 4-(4-(1-(N- 45
methoxy)iminoethyl)phenoxyaniline HCl salt.
solution of 4-chloro-2-(N-(2-triisopropylsilyloxy )ethyl)
pyridinecarboxamide (2.32 g, 6 mmol, 1 equiv.) in DME (4
mL) was added followed by K2 CO 3 (0.42 g, 3.0 mmol, 0.50
equiv.). The resulting mixture was heated at 80° C. over-
55
night. An additional portion of potassium tert-butoxide (0.34
To a slurry of 4-( 4-acetylphenoxy)aniline HCl salt
(prepared in a manner analogous to MethodA13, step 4; 1.0
stirred at 80° C. an additional 4 h. The mixture was cooled
g, 3.89 mmol) in a mixture ofEtOH (10 mL) and pyridine
(1.0 mL) was added O-methylhydroxylamine HCl salt (0.65 to 0° C. with an ice/water bath, then water (approx. 1 mL)
g, 7.78 mmol, 2.0 equiv.). The resulting solution was heated 60
was slowly added dropwise. The organic layer was extracted
at the reflux temperature for 30 min, cooled to room tem- with EtOAc (3x10 mL). The combined organic layers were
perature and concentrated under reduced pressure. The washed with a saturated NaCl solution (20 mL), dried
resulting solids were triturated with water (10 mL) and (MgSO 4) and concentrated under reduced pressure. The
washed with water to give 4-(4-(1-(N-methoxy)iminoethyl) brown oily residue was purified by column chromatography
phenoxyaniline HCl salt as a yellow solid (0.85 g): TLC 65 (SiO 2 ; 30% EtOAc/70% pet ether) to afford 4-( 4-(2-(N-(2-
(50% EtOAc/50% pet. ether) Rf0.78; 1 H NMR (DMSO-d 6 ) triisopropy lsily loxy )ethy lcarbamoy l)pyridy loxyaniline as a
03.90 (s, 3H), 5.70 (s, 3H); HPLC-MS m/z 257 ((M+Hr). clear light brown oil (0.99 g, 38%).
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A18. Synthesis of 2-Pryidinecarboxylate Esters via Oxida- hexane) to give 4-(5-(2-methoxycarbonyl)pyridyloxy)
tion of 2-Methylpyridines. Synthesis of 4-(5-(2- aniline (0.40 g).
methoxycarbony l)pyridy loxy )aniline A19. Synthesis of (w-Sulfonylphenyl Anilines. Synthesis of
4-( 4-Methy lsulfony lphenyoxy )aniline.
10
A mixture of 5-hydroxy-2-methylpyridine (10.0 g, 91.6
mmol), l-fluoro-4-nitrobenzene (9.8 mL, 91.6 mmol, 1.0 Step 1. 4-( 4-Methy lsulfony lphenoxy )-1-nitro benzene:
equiv.), K2 CO 3 (25 g, 183 mmol, 2.0 equiv.) in DMF (100 To a solution of 4-( 4-methylthiophenoxy)-1-nitrobenzene
mL) was heated at the reflux temperature overnight. The 15
(2.0 g, 7.7 mmol) in CH 2 Cl2 (75 nL) at 0° C. was slowly
resulting mixture was cooled to room temperature, treated added m-CPBA (57-86%, 4.0 g), and the reaction mixture
with water (200 mL), and extracted with EtOAc (3x100 was stirred at room temperature for 5 h. The reaction mixture
mL). The combined organic layers were sequentially washed was treated with a IN NaOH solution (25 mL). The organic
with water (2x100 mL) and a saturated NaCl solution ((100 layer was sequentially washed with a IN NaOH solution (25
mL), dried (MgSO 4) and concentrated under reduced pres- 20
mL), water (25 mL) and a saturated NaCl solution (25 mL),
sure to give 4-(5-(2-methyl)pyridyloxy)-1-nitrobenzene as a dried (MgSO 4), and concentrated under reduced pressure to
brown solid (12.3 g). give 4-(4-methylsulfonylphenoxy)-1-nitrobenzene as a solid
(2.1 g).
Step 2. 4-(4-Methylsulfonylphenoxy)-1-aniline
25
4-(4-Methylsulfonylphenoxy)-1-nitrobenzene was
reduced to the aniline in a manner analogous to that
described in Method A18, step 3.
B. Synthesis of Urea Precursors
B 1. General Method for the Synthesis of Isocyanates from
30
Anilines Using CDI. Synthesis of 4-Bromo-3-
Step 2. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)- (trifluoromethyl)phenyl Isocyanate
l-nitrobenzene.
A mixture of 4-(5-(2-methyl)pyridyloxy)-1-nitrobenzene
(1.70 g, 7.39 mmol) and selenium dioxide (2.50 g, 22.2
mmol, 3.0 equiv.) in pyridine (20 mL) was heated at the 35
reflux temperature for 5 h, then cooled to room temperature.
The resulting slurry was filtered, then concentrated under
reduced pressure. The residue was dissolved in MeOH (100
mL). The solution was treated with a cone HCl solution (7
mL), then heated at the reflux temperature for 3 h, cooled to 40 Step 1. Synthesis of 4-bromo-3-(trifluoromethyl)aniline HCl
room temperature and concentrated under reduced pressure. salt
The residue was separated between EtOAc (50 mL) and a To a solution of 4-bromo-3-(trifluoromethyl)aniline (64 g,
IN NaOH solution (50 mL). The aqueous layer was 267 mmol) in Et 2 O (500 mL) was added an HCl solution (1
extracted with EtOAc (2x50 mL). The combined organic Min Et2 O; 300 mL) dropwise and the resulting mixture was
layers were sequentially washed with water (2x50 mL) and 45 stirred at room temp. for 16 h. The resulting pink-white
a saturated NaCl solution (50 mL), dried (MgSO 4) and precipitate was removed by filtration and washed with Et 2 O
concentrated under reduced pressure. The residue was puri- (50 mL) and to afford 4-bromo-3-(trifluoromethyl)aniline
fied by column chromatography (SiO 2 ; 50% EtOAc/50% HCl salt (73 g, 98% ).
hexane) to afford 4-( 5-(2-methoxycarbony 1)pyridy loxy )-1-
nitro benzene (0.70 g). 50
Br~
UNCO
55
Step 2. Synthesis of 4-bromo-3-(trifluoromethyl)phenyl iso-

cyanate
Step 3. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy) A suspension of 4-bromo-3-(trifluoromethyl)aniline HCl
aniline. 60 salt (36.8 g, 133 mmol) in toluene (278 mL) was treated with
A slurry of 4-(5-(2-methoxycarbonyl)pyridyloxy)-1- trichloromethyl chloroformate dropwise and the resulting
nitrobenzene (0.50 g) and 1.0% Pd/C (0.050 g) in a mixture mixture was heated at the reflux temp. for 18 h. The resulting
ofEtOAc (20 mL) and MeOH (5 mL) was placed under a H2 mixture was concentrated under reduced pressure. The resi-
atmosphere (balloon) overnight. The resulting mixture was due was treated with toluene (500 mL), then concentrated
filtered through a pad of Celite®, and the filtrate was 65 under reduced pressure. The residue was treated with
concentrated under reduced pressure. The residue was puri- CH 2 Cl 2 (500 mL), then concentrated under reduced pres-
fied by column chromatography (SiO 2 ; 70% EtOAc/30% sure. The CH 2 Cl2 treatment/concentration protocol was
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repeated and resulting amber oil was stored at -20° C. for 16 Cle. General Method for the Synthesis of Ureas by Reaction
h, to afford 4-bromo-3-(trifluoromethyl)phenyl isocyanate of an Isocyanate with an Aniline. Synthesis of N-(4-
as a tan solid (35.1 g, 86%): GC-MS m/z 265 (M+). Chloro-3-(trifluoromethyl)phenyl)-N'-(2-methyl-4-(2-(N-
methylcarbamoyl)(4-pyridyloxy))phenyl)Urea
Cla. General Method for the Synthesis of Ureas by Reaction

of an Isocyanate with an Aniline. Synthesis of N-(4-
Chloro-3-(trifluoromethyl)phenyl)-N'-( 4-(2-(N-
methylcarbamoyl)-4-pyridyloxy)phenyl)Urea
CF3 0 A solution of 2-methyl-4-(2-(N-methylcarbamoyl)( 4-

pyridyloxy))aniline (Method AS; 0.11 g, 0.45 mmol) in
c,~ 0 !"'yoyJ-,rrru, 15
CH 2 Cl 2 (1 mL) was treated with Et3 N (0.16 mL) and
4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.45
UN)lN~
H H
~h mmol). The resulting brown solution was stirred at room
temp. for 6 d, then was treated with water (5 mL). The
20
The combined organic layers were dried (MgSO 4) and
A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyan- concentrated under reduced pressure to yield N-(4-chloro-
ate (14.60 g, 65.90 mmol) in CH 2 Cl2 (35 mL) was added 3-( trifluoromethy 1)pheny 1)-N' -(2-methy 1-4-(2-(N -
dropwise to a suspension of 4-(2-(N-methylcarbamoyl)-4- methylcarbamoyl)( 4-pyridyloxy))phenyl urea as a brown oil
pyridyloxy)aniline (MethodA2, Step 4; 16.0 g, 65.77 mmol) (0.11 g, 0.22 mmol): 1 H NMR (DMSO-d 6 ) 02.27 (s, 3H),
25 2.77 (d, 1=4.8 Hz, 3H), 7.03 (dd, 1=8.5, 2.6 Hz, lH), 7.11 (d,
in CH 2 Cl 2 (35 mL) at 0° C. The resulting mixture was stirred
1=2.9 Hz, lH), 7.15 (dd, 1=5.5, 2.6, Hz, lH), 7.38 (d, 1=2.6
at room temp. for 22 h. The resulting yellow solids were Hz, lH), 7.62 (app d, 1=2.6 Hz, 2H), 7.84 (d, 1=8.8 Hz, lH),
removed by filtration, then washed with CH 2 Cl 2 (2x30 mL) 8.12 (s, lH), 8.17 (s, lH); 8.50 (d, 1=5.5 Hz, lH), 8.78 (q,
and dried under reduced pressure (approximately 1 mmHg) 1=5.2, lH), 9.52 (s, lH); HPLC ES-MS m/z 479 ((M+Hr).
to afford N-( 4-chloro-3-(trifluoromethyl)phenyl)-N'-( 4-(2- 30 Cid. General Method for the Synthesis ofUreas by Reaction
(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea as an off- of an Isocyanate with an Aniline. Synthesis of N-(4-
white solid (28.5 g, 93%): mp 207-209° C. ; 1 H-NMR Chloro-3-( trifluoromethy 1)pheny 1)-N'-( 4-aminopheny 1)
Urea
(DMSO-d 6) 02.77 (d, 1=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d,
1=2.5 Hz, lH), 7.62 (m, 4H), 8.11 (d, 1=2.5 Hz, lH), 8.49 (d, 35
1=5.5 Hz, lH), 8.77 (br d, lH), 8.99 (s, lH), 9.21 (s, lH);
HPLC ES-MS m/z 465 ((M+Hr).
Cl b. General Method for the Synthesis of Ureas by Reaction
Bromo-3-(trifluoromethyl)phenyl)-N'-( 4-(2-(N - 40
methylcarbamoyl)-4-pyridyloxy)phenyl)Urea
To a solution of 4-chloro-3-(trifluoromethyl)phenyl iso-
cyanate (2.27 g, 10.3 mmol) in CH 2 Cl2 (308 mL) was added
R,-s O f"'YOyJ,rrru, 45
with CH 2 Cl2 (100 mL), and concentrated under reduced
UN)lN~
H H
~h pressure. The resulting pink solids were dissolved in a
mixture of EtOAc (110 mL) and MeOH (15 mL), and the
clear solution was washed with a 0.05 N HCl solution. The
50
organic layer was concentrated under reduced pressure to
A solution of 4-bromo-3-(trifluoromethyl)phenyl isocy-
afford impure N-( 4-chloro-3-(trifluoromethyl)phenyl)-N'-
anate (Method Bl, Step 2; 8.0 g, 30.1 mmol) in CH 2 Cl2 (80 (4-aminophenyl)urea (3.3 g): TLC (100% EtOAc) Rf0.72.
mL) was added dropwise to a solution of 4-(2-(N- Cle. General Method for the Synthesis of Ureas by Reaction
methylcarbamoyl)-4-pyridyloxy)aniline (Method A2, Step of an Isocyanate with an Aniline. Synthesis of N-(4-
4; 7.0 g, 28.8 mmol) in CH 2 Cl 2 (40 mL) at 0° C. The 55
Chl oro -3 -(tri fl uoromethyl )phenyl )-N' -( 4-
resulting mixture was stirred at room temp. for 16 h. The ethoxycarbony lpheny l)Urea
resulting yellow solids were removed by filtration, then
washed with CH 2 Cl2 (2x50 mL) and dried under reduced
pressure (approximately 1 mmHg) at 40° C. to afford 60
N-( 4-bromo-3-(trifluoromethyl)phenyl)-N'-( 4-(2-(N-
methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a pale-
yellow solid (13.2 g, 90%): mp 203-205° C.; 1 H-NMR
(DMSO-d 6) 02.77 (d, 1=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d,
1=2.5 Hz, lH), 7.58 (m, 3H), 7.77 (d, 1=8.8 Hz, lH), 8.11 (d, 65
1=2.5 Hz, lH), 8.49 (d, 1=5.5 Hz, lH), 8.77 (br d, lH), 8.99 To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4
(s, lH), 9.21 (s, lH); HPLC ES-MS m/z 509 ((M+Hr). mmol) in CH 2 Cl 2 (30 mL) was added 4-chloro-3-
IITRUE COPY!I
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(trifluoromethyl)aniline (3.21 g, 16.4 mmol), and the solu- were collected by filtration and washed with EtOAc. The
tion was stirred at room temp. overnight. The resulting slurry filtrate was concentrated under reduced pressure and the
was diluted with CH 2 Cl2 (50 mL) and filtered to afford residual oil purified by colunm chromatography (gradient
N -( 4-chl oro -3 -(trifl uoromethyl )phenyl )-N' -( 4-
ethoxycarbonylphenyl)urea as a white solid (5.93 g, 97%): 5
from 33% EtOAc/67% hexane to 50% EtOAc/50% hexane
TLC (40% EtOAc/60% hexane) Rf0.44. to 100% EtOAc) to give N-(2-methoxy-5-(trifluoromethyl)
Clf. General Method for the Synthesis of Ureas by Reaction pheny 1)-N'-( 4-(2-(N-methylcarbamoy 1)-4-pyridy loxy)
of an Isocyanate with an Aniline. Synthesis of N-(4- phenyl)urea as a light tan solid (0.098 g, 30%): TLC (100%
Chloro-3-( trifluoromethy I)pheny 1)-N'-(3-carboxypheny I) EtOAc) Rf0.62; 1 H NMR (DMSO-d 6 ) 02.76 (d, 1=4.8 Hz,
Urea 10
3H), 3.96 (s, 3H), 7.1-7.6 and 8.4-8.6 (m, llH), 8.75 (d,
1=4.8 Hz, lH), 9.55 (s, lH); FAB-MS m/z 461 ((M+Hr).
C2b. General Method for Urea Synthesis by Reaction of an
Aniline with N,N'-Carbonyl Diimidazole Followed by
Addition of a Second Aniline. Symmetrical Urea's as Side
Products of a N,N'-Carbonyl Diimidazole Reaction Pro-
cedure. Synthesis of Bis( 4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)phenyl)Urea
To a solution of 4-chloro-3-(trifluoromethyl)phenyl iso- 30 To a stJrnng solution of 3-amino-2-methoxyquinoline

cyanate (1.21 g, 5.46 mmol) in CH 2 Cl2 (8 mL) was added (0.14 g) in anhydrous CH 2 Cl2 (15 mL) at O C. was added
4-(3-carboxyphenoxy)aniline (Method All; 0.81 g, 5.76 CDI (0.13 g). The resulting solution was allowed to warm to
mmol) and the resulting mixture was stirred at room temp. room temp. over 1 h then was stirred at room temp. for 16
overnight, then treated with MeOH (8 mL), and stirred an h. The resulting mixture was treated with 4-(2-(N-
additional 2 h. The resulting mixture was concentrated under 35 methylcarbamoyl)-4-pyridyloxy)aniline (0.18 g). The result-
ing yellow solution stirred at room temp. for 72 h, then was
reduced pressure. The resulting brown solids were triturated treated with water (125 mL). The resulting aqueous mixture
with a 1:1 EtOAc/hexane solution to give N-(4-chloro-3- was extracted with EtOAc (2x150 mL). The combined
(trifluoromethy I)pheny I)-N'-(3-carboxypheny !)urea as an organic phases were washed with a saturated NaCl solution
off-white solid (1.21 g, 76%). (100 ml), dried (MgSO 4) and concentrated under reduced
40
C2a. General Method for Urea Synthesis by Reaction of an pressure. The residue was triturated (90% EtOAc/10%
Aniline with N,N'-Carbonyl Diimidazole Followed by hexane). The resulting white solids were collected by filtra-
Addition of a Second Aniline. Synthesis of N-(2- tion and washed with EtOAc to give bis(4-(2-(N-
Methoxy-5-( trifluoromethy I)pheny I)-N' -( 4-(2-(N- methylcarbamoyl)-4-pyridyloxy)phenyl)urea (0.081 g,
methylcarbamoyl)-4-pyridyloxy)phenyl)Urea 44%): TLC (100% EtOAc) Rf0.50; 1 H NMR (DMSO-d 6 )
45 02.76 (d, 1=5.1 Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, 1=5.4
Hz, lH), 8.75 (d, l=F4.8 Hz, 2H), 8.86 (s, 2H); HPLC
A
ES-MS m/z 513 ((M+Hr).
C2c. General Method for the Synthesis of Ureas by Reaction
N~Nood-· so Methoxy-5-(trifluoromethyl)phenyl-N'-( 4-( 1,3-
dioxoisoindolin-5-y loxy )pheny I)
YH H
OMe
To a solution of 2-methoxy-5-(trifluoromethyl)aniline 55 CC; 0 (YO~~

(0.15 g) in anh CH 2 Cl2 (15 mL) at 0° C. was added CDI
(0.13 g). The resulting solution was allowed to warm to
N)lN~ # 0
room temp. over 1 h, was stirred at room temp. for 16 h, then H H
was treated with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy) OMe NH
60
aniline (0.18 g). The resulting yellow solution was stirred at 0
The resulting aqueous mixture was extracted with EtOAc To a stirring solution of 2-methoxy-5-(trifluoromethyl)
(2x150 mL). The combined organics were washed with a phenyl isocyanate (0.10 g, 0.47 mmol) in CH 2 Cl2 (1.5 mL)
saturated NaCl solution (100 mL), dried (MgSO 4) and 65 was added 5-( 4-aminophenoxy )isoindoline-1,3-dione
concentrated under reduced pressure. The residue was tritu- (MethodA3, Step 3; 0.12 g, 0.47 mmol) in one portion. The
rated (90% EtOAc/10% hexane). The resulting white solids resulting mixture was stirred for 12 h, then was treated with
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CH 2 Cl2 (10 mL) and MeOH (5 mL). The resulting mixture C4. General Method for Urea Synthesis by Reaction of an
was sequentially washed with a IN HCl solution (15 mL) Aniline with Phosgene Followed by Addition of a Second
and a saturated NaCl solution (15 mL), dried (MgSO 4) and Aniline. Synthesis of N-(2-Methoxy-5-(trifluoromethyl)
pheny 1)-N'-( 4-(2-(N-methy lcarbamoyl )-4-pyridy loxy)
concentrated under reduced pressure to afford N-(2-
phenyl)Urea
methox y- 5 -( tri fl uoromethyl )phenyl-N' -( 4-( 1, 3 -
dioxoisoindolin-5-yloxy)phenyl)urea as a white solid (0.2 g,
96%): TLC (70% EtOAc/30% hexane) Rf 0.50; 1 H NMR
(DMSO-d 6 ) 03.95 (s,3H), 7.31-7.10 (m, 6H), 7.57 (d, 1=9.3
Hz, 2H), 7.80 (d, 1=8.7 Hz, lH), 8.53 (br s, 2H), 9.57 (s, lH), 10
11.27 (br s, lH); HPLC ES-MS 472.0 ((M+H)+, 100%).
C2d. General Method for Urea Synthesis by Reaction of an
Aniline with N,N'-Carbonyl Diimidazole Followed by
Addition of a Second Aniline. Synthesis of N-(5-(tert-
Butyl)-2-(2,5-dimethylpyrrolyl)pheny 1)-N'( 4-(2-(N- 15
To a stirring solution of phosgene (1.9 Min toluene; 2.07
methylcarbamoyl)-4-pyridyloxy)phenyl)Urea mL 0.21 g, 1.30 mmol) in CH 2 Cl2 (20 mL) at 0° C. was
added anh pyridine (0.32 mL) followed by 2-methoxy-5-
(trifluoromethyl)aniline (0.75 g). The yellow solution was
20
(N -methy lcarbamoy 1)-4-pyridy loxy )aniline (prepared as
described in Method A2; 0.30 g) and the resulting suspen-
25
sion was heated at 80° C. for 20 h, then allowed to cool to
room temp. The resulting mixture was diluted with water
(100 mL), then was made basic with a saturated NaHCO 3
solution (2-3 mL). The basic solution was extracted with
EtOAc (2x250 mL). The organic layers were separately
To a stirring solution of CDI (0.21 g, 1.30 mmol) in 30
washed with a saturated NaCl solution, combined, dried
CH 2 Cl 2 (2 mL) was added 5-(tert-butyl)-2-(2,5- (MgSO 4), and concentrated under reduced pressure. The
dimethylpyrrolyl)aniline (Method A4, Step 2; 0.30 g, 1.24 resulting pink-brown residue was dissolved in MeOH and
mmol) in one portion. The resulting mixture was stirred at absorbed onto SiO 2 (100 g). Colunm chromatography (300
room temp. for 4 h, then 4-(2-(N-methylcarbamoyl)-4- g SiO2 ; gradient from 1% Et3 N/33% EtOAc/66% hexane to
35
pyridyloxy)aniline (0.065 g, 0.267 mmol) was then added in 1% Et3 N/99% EtOAc to 1% Et 3 N/20% MeOH/79% EtOAc)
one portion. The resulting mixture was heated at 36° C. followed by concentration under reduced pressure at 45° C.
overnight, then cooled to room temp. and diluted with gave a warm concentrated EtOAc solution, which was
EtOAc (5 mL). The resulting mixture was sequentially treated with hexane (10 mL) to slowly form crystals of
washed with water (15 mL) and a 1N HCl solution (15 mL ), N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-( 4-(2-(N-
40
dried (MgSO 4), and filtered through a pad of silica gel (50 methylcarbamoyl)-4-pyridyloxy)phenyl)urea (0.44 g): TLC
g) to afford N-(5-(tert-butyl)-2-(2,5-dimethylpyrrolyl) (1% Et3 N/99% EtOAc) Rf 0.40.
pheny 1)-N'-( 4-(2-(N-methylcarbamoyl)-4-pyridy loxy) D. Interconversion of Ureas
Dia. Conversion of w-Aminophenyl Ureas into
phenyl)urea as a yellowish solid (0.033 g, 24%): TLC (40%
w-(Aroylamino )phenyl Ureas. Synthesis of N-( 4-Chloro-
EtOAc/60% hexane) Rf0.24; 1 H NMR (acetone-d 6 ) ol.37 45
3 - ( (trifluoromethyl)phenyl)-N' -( 4-(3-
(s, 9H), 1.89 (s, 6H), 2.89 (d, 1=4.8 Hz, 3H), 5.83 (s, 2H),
methoxycarbony lpheny l)carboxyaminopheny 1)Urea
6.87-7.20 (m, 6H), 7.17 (dd, lH), 7.51-7.58 (m, 3H), 8.43
(d, 1=5.4 Hz, lH), 8.57 (d, 1=2.1 Hz, lH), 8.80 (br s, lH);
HPLC EA-MS 512 ((M+H)+, 100%).
C3. Combinatorial Method for the Synthesis of Diphenyl
Ureas Using Triphosgene
One of the anilines to be coupled was dissolved in
50
Cl'&
CF
3
1.-?)l~I
O 0~ Al~ a a
OMe
dichloroethane (0.10 M). This solution was added to a 8 mL N N

H H
vial (0.5 mL) containing dichloroethane (1 mL). To this was
55
To a solution ofN-(4-chloro-3-((trifluoromethyl)phenyl)-
N'-( 4-aminophenyl)urea (Method Cid; 0.050 g, 1.52 mmol),
mono-methyl isophthalate-(0.25 g, 1.38 mmol), HOBT.H 2 O
equiv.). The vial was capped and heat at 80° C. for 5 h, then
(0.41 g, 3.03 mmol) and N-methylmorpholine (0.33 mL,
allowed to cool to room temp for approximately 10 h. The 60 3.03 mmol) in DMF (8 mL) was added EDCI.HCl (0.29 g,
second aniline was added (0.10 M in dichloroethane, 0.5 1.52 mmol). The resulting mixture was stirred at room temp.
mL, 1.0 equiv.), followed by diisopropylethylamine (0.35 M overnight, diluted with EtOAc (25 mL) and sequentially
in dichloroethane, 0.2 mL, 1.2 equiv.). The resulting mixture washed with water (25 mL) and a saturated NaHCO 3
was heated at 80° C. for 4 h, cooled to room temperature and solution (25 mL). The organic layer was dried (Na2 SO4 ) and
treated with MeOH (0.5 mL). The resulting mixture was 65 concentrated under reduced pressure. The resulting solids
concentrated under reduced pressure and the products were were triturated with an EtOAc solution (80% EtOAc/20%
purified by reverse phase HPLC. hexane) to give N-( 4-chloro-3-((trifluoromethyl)phenyl)-N'-
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(4-(3-methoxycarbony lpheny I)carboxyaminopheny I)urea THF (1 mL) and heating was continued for 18 h. The
(0.27 g, 43%): mp 121-122; TLC (80% EtOAc/20% resulting mixtures were treated with poly( 4-
hexane) Rf0.75. (isocyanatomethyl)styrene) (0.040 g) and the resulting mix-
Dl b. Conversion of w-Carboxyphenyl Ureas into
w-(Arylcarbamoyl)phenyl Ureas. Synthesis of N-( 4- 5
ture was stirred at 36° C. for 72 h, then cooled to room temp.
Chloro-3 -( (trifl uoromethyl )phenyl )-N' -( 4-(3- and filtered. The resulting solution was filtered through a
methy lcarbamoy lpheny l)carbamoylpheny I)Urea plug of silica gel (1 g). Concentration under reduced pres-
sure afforded N-( 4-chloro-3-( (trifluoromethy I)pheny 1)-N'-
(4-(N-(3-(N-(3-pyridy l)carbamoyl)pheny l)carbamoyl)
10
phenyl)urea (0.024 g, 59/o ): TLC (70% EtOAc/30% hexane)
CF 3 0 (')
Rf0.12.
Cl'& 0 dN~NHMe D2. Conversion of w-Carboalkoxyaryl Ureas into
I -v
A
N_,A..._N
II :,,..
....,_
I H O
15
w-Carbamoylaryl Ureas. Synthesis of N-(4-Chloro-3-
( (trifluoromethyl)phenyl)-N' -( 4-(3-
H H
methy lcarbamoy lpheny l)carboxyaminopheny I)Urea
20
To a solution ofN-(4-chloro-3-((trifluoromethyl)phenyl)- CF3 (')
N'-( 4-(3-methy lcarbamoy lpheny l)carboxyaminopheny I)
urea (0.14 g, 0.48 mmol), 3-methylcarbamoylaniline (0.080 Cl'& O o~~NHMe
g, 0.53 mmol), HOBT.H 2 0 (0.14 g, 1.07 mmol), and
N-methylmorpholine (0.5 mL, 1.07 mmol) in DMF (3 mL) 25
I# N
)l N
~I a a
H H
at 0° C. was added EDCI.HCI (0.10 g, 0.53 mmol). The
resulting mixture was allowed to warm to room temp. and
was stirred overnight. The resulting mixture was treated with
water (10 mL), and extracted with EtOAc (25 mL). The
30 To a sample of N-(4-chloro-3-((trifluoromethyl)phenyl)-
N'-( 4-(3-carbomethoxypheny I)carboxyaminopheny I)urea
resulting yellow solids were dissolved in EtOAc (3 mL) then
filtered through a pad of silica gel (17 g, gradient from 70% (0.17 g, 0.34 mmol) was added methylamine (2 Min THF;
EtOAc/30% hexane to 10% MeOH/90% EtOAc) to give 1 mL, 1.7 mmol) and the resulting mixture was stirred at
N-( 4-chloro-3-((trifluoromethyl)phenyl)-N'-( 4-(3- 35 room temp. overnight, then concentrated under reduced
methylcarbamoylphenyl)carbamoylphenyl)urea as a white pressure to give N-(4-chloro-3-((trifluoromethyl)phenyl)-
solid (0.097 g, 41%): mp 225-229; TLC (100% EtOAc) Rf N'-( 4-(3-methy lcarbamoy lpheny I)carboxyaminopheny I)
0.23. urea as a white solid: mp 247; TLC (100% EtOAc) Rf0.35.
Die. Combinatorial Approach to the Conversion of D3. Conversion of w-Carboalkoxyaryl Ureas into
40
w-Carboxyphenyl Ureas into w-(Arylcarbamoyl)phenyl
w-Carboxyaryl Ureas.
Ureas. Synthesis of N-( 4-Chloro-3-((trifluoromethyl)
pheny 1)-N'-( 4-(N-(3-(N-(3-pyridy l)carbamoy l)pheny I) Synthesis of N-( 4-Chloro-3-( (trifluoromethyl)phenyl)-N'-
carbamoyl)phenyl)Urea (4-carboxyphenyl)Urea
c,~
CF
3
O ~~
Dyi O
"',_
H
N'Y"'~
UN)lNJJ
H H
O V
A mixture ofN-(4-chloro-3-((trifluoromethyl)phenyl)-N'-
60 CF3 0
(3-carboxyphenyl)urea (Method Clf; 0.030 g, 0.067 mmol)
and N-cyclohexy 1-N'-(methy !polystyrene )carbodiimide (55
mg) in 1,2-dichloroethane (1 mL) was treated with a solution c,+ o ~OH
of 3-aminopyridine in CH 2 Cl2 (1 M; 0.074 mL, 0.074
mmol). (In cases of insolubility or turbidity, a small amount 65 UN)lNJJ
ofDMSO was also added.) The resulting mixture was heated H H
at 36° C. overnight. Turbid reactions were then treated with
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To a slurry of N-(4-chloro-3-((trifluoromethyl)phenyl)- Step 2. Synthesis of N-( 4-chloro-3-(trifluoromethyl)
N'-( 4-ethoxycarbonylphenyl)urea (Method Cle; 5.93 g, 15.3 pheny 1)-N'-( (4-(3-( 5-(2-dimethy laminoethy l)carbamoyl)
mmol) in MeOH (75 mL) was added an aqueous KOH pyridyl)oxyphenyl) urea
was heated at the reflux temp. for 12 h, cooled to room 5
A mixture of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-
was diluted with water (50 mL), then treated with a, 1 N HCI
solution to adjust the pH to 2 to 3. The resulting solids were ((4-(3-(5-carboxypyridyl)oxyphenyl)urea (0.050 g, 0.011
collected and dried under reduced pressure to give N-(4- mmol), N,N-dimethylethylenediamine (0.22 mg, 0.17
10
chloro-3-( (trifluoromethy I)pheny I)-N'-( 4-carboxypheny I) mmol), HOBT (0.028 g, 0.17 mmol), N-methylmorpholine
urea as a white solid (5.05 g, 92%). (0.035 g, 0.28 mmol), and EDCI.HCI (0.032 g, 0.17 mmol)
D4. General Method for the Conversion of w-Alkoxy Esters in DMF (2.5 mL) was stirred at room temp. overnight. The
into w-Alkyl Amides. Synthesis of N-(4-Chloro-3-
( (trifl uoromethyl )phenyl)-N' -( ( 4-(3 -( 5-(2- resulting solution was separated between EtOAc (50 mL)
15
dimethy laminoethy l)carbamoy l)pyridy l)oxypheny I)Urea and water (50 mL). The organic phase was washed with
water (35 mL), dried (MgSO 4) and concentrated under
reduced pressure. The residue was dissolved in a minimal
amount of CH 2 Cl 2 (approximately 2 mL) The resulting
20
solution was treated with Et 2 O dropwise to give N-(4-
chloro-3-(trifluoromethy I )pheny I )-N' -( ( 4-(3-( 5-(2-
dimethy laminoethy l)carbamoy l)pyridy I)oxypheny !)urea as
a white precipitate (0.48 g, 84%: 1 H NMR (DMSO-d 6 )
25
02.10 s, 6H), 3.26 (s, H), 7.03 (d, 2H), 7.52 (d, 2H), 7.60 (m,
3H), 8.05 (s, lH), 8.43 (s, lH), 8.58 (t, lH), 8.69 (s, lH),
Step 1. Synthesis of N-(4-Chloro-3-(trifluoromethyl)
phenyl)-N'-( (4-(3-(5-carboxypyridyl)oxyphenyl) Urea 8.90 (s, lH), 9.14 (s, lH); HPLC ES-MS m/z 522 ((M+Hr).
N-( 4-Chloro-3-(trifluoromethyl)phenyl)-N'-(( 4-(3-( 5-
30
from 4-chloro-3-(trifluoromethyl)phenyl isocyanate and D5. General Method for the Deprotection of N-(w-
4-(3-(5-methoxycarbonylpyridyl)oxyaniline (Method A14, Silyloxyalkyl)amides. Synthesis of N-( 4-Chloro-3-
Step 2) in a manner analogous to Method Cla. A suspension ( (trifluoromethyl)phenyl)-N-( 4-( 4-(2-(N-(2-hydroxy)
of N-( 4-chloro-3-(trifluoromethyl)phenyl)-N'-(( 4-(3-(5- ethylcarbamoyl)pyridyloxyphenyl)Urea.
methoxycarbonylpyridyl)oxyphenyl)urea (0.26 g, 0.56 To a solution ofN-(4-chloro-3-((trifluoromethyl)phenyl)-

mmol) in MeOH (10 mL) was treated with a solution of N'-( 4-( 4-(2-(N-(2-triisopropy lsilyloxy)ethylcarbamoyl)
pyridyloxyphenyl)urea (prepared in a manner analogous to
KOH (0.14 g, 2.5 mmol) in water (1 mL) and was stirred at 50 Method Cla; 0.25 g, 0.37 mmol) in anh THF (2 mL) was
room temp. for 1 h. The resulting mixture was adjusted to tetrabutylammonium fluoride (1.0 M in THF; 2 mL). The
pH 5 with a 1 N HCI solution. The resulting precipitate was mixture was stirred at room temperature for 5 min, then was
removed by filtration and washed with water. The resulting treated with water (10 mL). The aqueous mixture was
solids were dissolved in EtOH (10 mL) and the resulting layers were dried (MgSO 4) and concentrated under reduced
55
solution was concentrated under reduced pressure. The pressure. The residue was purified by column chromatog-
EtOH/concentration procedure was repeated twice to give raphy (SiO2 ; gradient from 100% hexane to 40% EtOAc/
N-( 4-chloro-3-(trifluoromethyl)phenyl)-N'-(( 4-(3-(5- 60% hexane) to give N-( 4-chloro-3-((trifluoromethyl)
phenyl)-N'-( 4-( 4-(2-(N-(2-hydroxy)ethylcarbamoyl)
carboxypyridyl)oxyphenyl)urea (0.18 g, 71 %).
pyridyloxyphenyl)urea as a white solid (0.019 g, 10%).
60 Listed below are compounds listed in the Tables below
CF3 0 I which have been synthesized according to the Detailed
Cl'& 0 OO~N~N'- Syntheses of Exemplified Compounds
~ I )l I# l_) H
N N N 65
(See Tables for Compound Characterization)
H H
Entry 1: 4-(3-N-Methylcarbamoylphenoxy)aniline was pre-
pared according to Method Al3. According to Method
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C3, 3-tert-butylaniline was reacted with bis Entry 12: 4-Chloropyridine-2-carbonyl chloride HCI salt
(trichloromethy I)carbonate followed by 4-(3-N- was reacted with anmionia according to Method A2, Step
Methylcarbamoylphenoxy)aniline to afford the urea. 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-
Entry 2: 4-Fluoro-1-nitrobenzene and pyridinecarboxamide was reacted with 3-aminophenol
p-hydroxyacetophenone were reacted according to 5 according to Method A2, Step 4 using DMAC in place of
Method A13, Step 1 to afford the 4-( 4-acetylphenoxy)-1- DMF to give 3-(2-carbamoyl-4-pyridyloxy)aniline.
nitrobenzene. 4-( 4-Acetylphenoxy)-1-nitrobenzene was According to Method C2a, 2-methoxy-5-
reduced according to Method A13, Step 4 to afford (trifluoromethyl)aniline was reacted with phosgene fol-
4-(4-acetylphenoxy)aniline. According to Method C3, lowed by 3-(2-carbamoyl-4-pyridyloxy)aniline to afford
3-tert-butylaniline was reacted with bis(trichloromethyl)
10 the urea.
carbonate followed by 4-(4-acetylphenoxy)aniline to
Entry 13: 4-Chloro-N-methyl-2-pyridinecarboxamide was
afford the urea.
Entry 3: According to Method C2d, 3-tert-butylaniline was synthesized according to Method A2, Step 3b. 4-Chloro-
treated with CDI, followed by 4-(3-N-methylcarbamoyl)- N-methyl-2-pyridinecarboxamide was reacted with
4-methoxyphenoxy)aniline, which had been prepared 4-aminophenol according to Method A2, Step 4 using
according to Method AS, to afford the urea. 15 DMAC in place of DMF to give 4-(2-(N-
Entry 4: 5-tert-Butyl-2-methoxyaniline was converted to methylcarbamoyl)-4-pyridyloxy)aniline. According to
5-tert-butyl-2-methoxyphenyl isocyanate according to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was
Method B 1. 4-(3-N-Methy lcarbamoy lphenoxy )aniline, reacted with CDI followed by 4-(2-(N-methylcarbamoyl)-
prepared according to Method A13, was reacted with the 4-pyridyloxy)aniline to afford the urea.
isocyanate according to Method Cla to afford the urea. 20 Entry 14: 4-Chloropyridine-2-carbonyl chloride HCl salt
Entry 5: According to Method C2d, 5-tert-butyl-2- was reacted with anmionia according to Method A2, Step
methoxyaniline was reacted with CDI followed by 4-(3- 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-
N-methylcarbamoyl)-4-methoxyphenoxy)aniline, which pyridinecarboxamide was reacted with 4-aminophenol
had been prepared according to Method AS, to afford the according to Method A2, Step 4 using DMAC in place of
urea. 25 DMF to give 4-(2-carbamoyl-4-pyridyloxy)aniline.
Entry 6: 5-(4-Aminophenoxy)isoindoline-1,3-dione was According to Method C4, 2-methoxy-5-(trifluoromethyl)
prepared according to Method A3. According to Method aniline was reacted with phosgene followed by 4-(2-
2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI carbamoyl-4-pyridyloxy )aniline to afford the urea.
followed by 5-(4-aminophenoxy)isoindoline-1,3-dione to
Entry 15: According to Method C2d, 5-(triflouromethyl)-2-
afford the urea.
30 methoxyaniline was reacted with CDI followed by 4-(3N-
Entry 7: 4-(1-Oxoisoindolin-5-yloxy)aniline was synthe-
sized according to Method Al 2. According to Method 2d, methy lcarbamoyl )-4-methoxyphenoxy )aniline, which
5-tert-butyl-2-methoxyaniline was reacted with CDI fol- had been prepared according to Method AS, to afford the
lowed by 4-(1-oxoisoindolin-5-yloxy)aniline to afford the urea.
urea. Entry 16: 4-(2-(A-Methy lcarbamoy I)-4-pyridy loxy )-2-
Entry 8: 4-(3-N-Methylcarbamoylphenoxy)aniline was syn- 35 methylaniline was synthesized according to Method AS.
thesized according to Method Al 3. According to Method 5-(Trifluoromethyl)-2-methoxyaniline was converted into
C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted 5-(trifluoromethy I)-2-methoxypheny I isocyanate accord-
with CDI followed by 4-(3-N-methylcarbamoylphenoxy) ing to Method Bl. The isocyanate was reacted with
aniline to afford the urea. 4-( 2-(N -methylc arbamoyl )-4-pyridyloxy )-2-
Entry 9: 4-Hydroxyacetophenone was reacted with 40 methylaniline according to Method Cle to afford the urea.
2-chloro-5-nitropyridine to give 4-( 4-acetylphenoxy)-5- Entry 17: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-
nitropyridine according to MethodA3, Step 2. According chloroaniline was synthesized according to Method A6.
to Method AS, Step 4, 4-(4-acetylphenoxy)-5- 5-(Trifluoromethyl)-2-methoxyaniline was converted into
nitropyridine was reduced to 4-( 4-acetylphenoxy)-5- 5-(trifluoromethy I)-2-methoxypheny I isocyanate accord-
aminopyridine. 2-Methoxy-5-(trifluoromethyl)aniline 45 ing to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl
was converted to 2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-
isocyanate according to Method Bl. The isocyanate was 4-pyridyloxy)-2-chloroaniline according to Method Cla
reacted with 4-( 4-acetylphenoxy)-5-aminopyridine to afford the urea.
according to Method Cla to afford the urea. Entry 18: According to Method A2, Step 4, 5-amino-2-
Entry 10: 4-Fluoro-1-nitrobenzene and 50 methylphenol was reacted with 4-chloro-N-methyl-2-
p-hydroxyacetophenone were reacted according to pyridinecarboxamide, which had been synthesized
Method A13, Step 1 to afford the 4-( 4-acetylphenoxy)-1- according to Method A2, Step 3b, to give 3-(2-(N-
nitrobenzene. 4-( 4-Acetylphenoxy)-1-nitrobenzene was methy lcarbarnoy I)-4-pyridy loxy )-4-methy !aniline.
reduced according to Method A13, Step 4 to afford 5-(Trifluoromethyl)-2-methoxyaniline was converted into
4-(4-acetylphenoxy)aniline. According to Method C3, 55 5-(trifluoromethy I)-2-methoxypheny I isocyanate accord-
5-(trifluoromethyl)-2-methoxybutylaniline was reacted ing to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl
with bis(trichloromethyl) carbonate followed by 4-(4- isocyanate was reacted with 3-(2-(N-methylcarbamoyl)-
acetylphenoxy)aniline to afford the urea. 4-pyridyloxy)-4-methylaniline according to Method Cla
Entry 11: 4-Chloro-N-methyl-2-pyridinecarboxamide, to afford the urea.
which was synthesized according to Method A2, Step 3a, 60 Entry 19: 4-Chloropyridine-2-carbonyl chloride was reacted
was reacted with 3-aminophenol according to MethodA2, with ethylamine according to Method A2, Step 3b. The
Step 4 using DMAC in place of DMF to give 3-(-2-(N- resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was
methy lcarbamoyl)-4-pyridy loxy )aniline. According to reacted with 4-aminophenol according to Method A2,
Method C4, 2-methoxy-5-(trifluoromethyl)aniline was Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)
reacted with phosgene followed by 3-(-2-(N- 65 aniline. 5-(Trifluoromethyl)-2-methoxyaniline was con-
methylcarbamoyl)-4-pyridyloxy)aniline to afford the verted into 5-(trifluoromethyl)-2methoxyphenyl isocyan-
urea. ate according to Method Bl. 5-(Trifluoromethyl)-2-
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methoxyphenyl isocyanate was reacted with 4-(2(N- ropyridine was reacted with 4-aminothiophenol according
ethylcarbamoyl)-4-pyridyloxy)aniline according to to Method A2, Step 4 to give 4-(4-(2-(N-
Method Cla to afford the urea. methyl c arb amoyl )pheny 1thi o) ani 1ine.
Entry 20: According to Method A2, Step 4, 4-amino-2- 5-(Trifluoromethyl)-2-methoxyaniline was converted into
chlorophenol was reacted with 4-chloro-N-methyl-2- 5 5-(trifluoromethy 1)-2-methoxypheny 1 isocyanate accord-
pyridinecarboxamide, which had been synthesized ing to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl
according to Method A2, Step 3b, to give 4-(2-(N- isocyanate was reacted with 4-(4-(2-(N-
methy lcarbamoy 1)-4-pyridy loxy )-3-chloro aniline. methylcarbamoyl)phenylthio )aniline according to
5-(Trifluoromethyl)-2-methoxyaniline was converted into Method Cla to afford the urea.
5-(trifluoromethyl)-2-methoxyphenyl isocyanate accord- 10 Entry 28: 5-(4-Aminophenoxy )-2-methy lisoindoline-1,3-
ing to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl dio ne was synthesized according to Method A9.
isocyanate was reacted with 4-(2-(N-methylcarbamoyl)- 5-(Trifluoromethyl)-2-methoxyaniline was converted
4-pyridyloxy)-3-chloroaniline according to Method Cla into, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate
to afford the urea. according to Method Bl. 5-(Trifluoromethyl)-2-
Entry 21: 4-(4-Methylthiophenoxy)-1-nitrobenzene was 15 methoxyphenyl isocyanate was reacted with 5-( 4-
oxidized according to Method A19, Step 1 to give 4-(4- aminophenoxy )-2-methylisoindoline-1,3-dione according
methylsulfonylphenoxy)-1-nitrobenzene. The nitroben- to Method Cla to afford the urea.
zene was reduced according to Method A19, Step 2 to Entry 29: 4-Chloro-N-methylpyridinecarboxamide was syn-
give 4-( 4-methylsulfonylphenoxy )- I-aniline. According thesized as described in Method A2, Step 3b. The chlo-
to Method Cla, 5-(trifluoromethyl)-2-methoxyphenyl iso- 20 ropyridine was reacted with 3-aminothiophenol according
cyanate was reacted with 4-( 4-methylsulfonylphenoxy)- to Method A2, Step 4 to give 3-(4-(2-(N-
1-aniline to afford the urea. methyl c arb amoyl )pheny 1thi o) ani 1ine.
Entry 22: 4-(3-carbamoylphenoxy)-1-nitrobenzene was 5-(Trifluoromethyl)-2-methoxyaniline was converted into
reduced to 4-(3-carbamoylphenoxy)aniline according to 5-(trifluoromethy 1)-2-methoxypheny 1 isocyanate accord-
Method A15, Step 4. According to Method Cla, 25 ing to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl
5-(trifluoromethyl)-2-methoxyphenyl isocyanate was isocyanate was reacted with 3-( 4-(2-(N-
reacted with 4-(3-carbamoylphenoxy)aniline to afford the methylcarbamoyl)phenylthio )aniline according to
urea. Method Cla to afford the urea.
Entry 23: 5-(4-Aminophenoxy)isoindoline-1,3-dione was Entry 30: 4-Chloropyridine-2-carbonyl chloride was reacted
synthesized according to Method A3. 30 with isopropylamine according to Method A2, Step 3b.
5-(Trifluoromethyl)-2-methoxyaniline was converted into The resulting 4-chloro-N-isopropyl-2-
5-(trifluoromethyl)-2-methoxyphenyl isocyanate accord- pyridinecarboxamide was reacted with 4-aminophenol
ing to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl according to Method A2, Step 4 to give 4-(2-(N-
isocyanate was reacted with 5-(4-aminophenoxy) i s opro pyl c arb amoy 1)-4-py ri dy lo xy) ani 1ine.
isoindoline-1,3-dione according to Method Cla to afford 35 5-(Trifluoromethyl)-2-methoxyaniline was converted into
the urea. 5-(trifluoromethy 1)-2-methoxypheny 1 isocyanate accord-
Entry 24: 4-Chloropyridine-2-carbonyl chloride was reacted ing to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl
with dimethylamine according to Method A2, Step 3b. isocyanate was reacted with 4-(2-(N-
The resulting 4-chloro-N,N-dimethyl-2- isopropylcarbamoyl)-4-pyridyloxy)aniline according to
pyridinecarboxamide was reacted with 4-aminophenol 40 Method Cla to afford the urea.
according to Method A2, Step 4 to give 4-(2-(N,N- Entry 31: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was
dimethy l c arb amoy l )-4 -p yri dyloxy)ani line. synthesized according to Method A14.
5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(Trifluoromethyl)-2-methoxyaniline was converted into
5-(trifluoromethyl)-2-methoxyphenyl isocyanate accord- 5-(trifluoromethy 1)-2-methoxypheny 1 isocyanate accord-
ing to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl 45 ing to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl
isocyanate was reacted with 4-(2-(N,N- isocyanate was reacted with 4-(3-(5-methoxycarbonyl)
dimethy lcarbamoy 1)-4-pyridy loxy )aniline according to pyridyloxy)aniline according to Method Cla to afford the
Method Cla to afford the urea. urea. N-( 5-(Trifluoromethyl)-2-methoxyphenyl)-N'-( 4-
Entry 25: 4-(1-Oxoisoindolin-5-yloxy)aniline was synthe- (3-( 5-methoxycarbony lpyridy 1)oxy )pheny 1)urea was
sized according to Method A12. 5-(Trifluoromethyl)-2- 50 saponified according to Method D4, Step 1, and the
methoxyaniline was treated with CDI, followed by 4-(1- corresponding acid was coupled with 4-(2-aminoethyl)
oxoisoindolin-5-yloxy)aniline according to Method C2d morpholine to afford the amide according to Method D4,
to afford the urea. Step 2.
Entry 26: 4-Hydroxyacetophenone was reacted with Entry 32: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was
4-fluoronitrobenzene according to MethodA13, Step 1 to 55 synthesized according to Method A14.
give 4-( 4-acetylphenoxy)nitrobenzene. The nitrobenzene 5-(Trifluoromethyl)-2-methoxyaniline was converted into
was reduced according to Method A13, Step 4 to afford 5-(trifluoromethy 1)-2-methoxypheny 1 isocyanate accord-
4-(4-acetylphenoxy)aniline, which was converted to the ing to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl
4-(4-(1-(N-methoxy)iminoethyl)phenoxyaniline HCl salt isocyanate was reacted with 4-(3-(5-methoxycarbonyl)
according to Method Al 6. 5-(Trifluoromethyl)-2- 60 pyridyloxy)aniline according to Method Cla to afford the
methoxyaniline was converted into 5-(trifluoromethyl)-2- urea. N-( 5-(Trifluoromethyl)-2-methoxyphenyl)-N'-( 4-
methoxyphenyl isocyanate according to Method Bl. (3-( 5-methoxycarbony lpyridy 1)oxy )pheny 1)urea was
5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was saponified according to Method D4, Step 1, and the
reacted with 4-( 4-( 1-(N-methoxy)iminoethyl) corresponding acid was coupled with methylamine
phenoxyaniline HCl salt to Method Cla to afford the urea. 65 according to Method D4, Step 2 to afford the amide.
Entry 27: 4-Chloro-N-methylpyridinecarboxamide was syn- Entry 33: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was
thesized as described in Method A2, Step 3b. The chlo- synthesized according to Method Al4.
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5-(Trifluoromethyl)-2-methoxyaniline was converted into Entry 40: 4-(3-Carboxyphenoxy)aniline was synthesized
5-(trifluoromethyl)-2-methoxyphenyl isocyanate accord- according to Method Al 1. 5-(Trifluoromethyl)-2-
ing to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl methoxyaniline was converted into 5-(trifluoromethyl)-2-
isocyanate was reacted with 4-(3-(5-methoxycarbonyl) methoxyphenyl isocyanate according to Method Bl. 4-(3-
pyridyloxy)aniline according to Method Cla to afford the 5 Carb oxyphenoxy )aniline was reacted with
urea. N-( 5-(Trifluoromethyl)-2-methoxyphenyl)-N'-( 4- 5-(trifluoromethy 1)-2-methoxypheny 1 isocyanate accord-
(3-( 5-methoxycarbony lpyridy 1)oxy )pheny 1)urea was ing to Method Clf to afford N-(5-(trifluoromethyl)-2-
saponified according to Method D4, Step 1, and the methoxyphenyl)-N'-(3-carboxyphenyl)urea, which was
corresponding acid was coupled with N,N- coupled with N-(2-pyridyl)piperazine according to
dimethylethylenediamine according to Method D4, Step 2
10 Method Die.
to afford the amide.
Entry 41: 4-(3-(N-Methylcarbamoyl)phenoxy)aniline was
Entry 34: 4-(3-Carboxyphenoxy)aniline was synthesized
according to Method Al 1. 5-(Trifluoromethyl)-2- synthesized according to Method A13. According to
methoxyaniline was converted into 5-(trifluoromethyl)-2- Method C3, 4-chloro-3-(trifluoromethyl)aniline was con-
methoxyphenyl isocyanate according to Method Bl. 4-(3- verted to the isocyanate, then reacted with 4-(3-(N-
Carb oxyphenoxy )aniline was reacted with 15 Methylcarbamoyl)phenoxy )aniline to afford the urea.
5-(trifluoromethyl)-2-methoxyphenyl isocyanate accord- Entry 42: 4-(2-N-Methylcarbamyl-4-pyridyloxy)aniline was
ing to Method Clf to afford N-(5-(trifluoromethyl)-2- synthesized according to Method A2. 4-Chloro-3-
methoxyphenyl)-N'-(3-carboxyphenyl)urea, which was (trifluoromethyl)phenyl isocyanate was reacted with 4-(2-
coupled with 3-aminopyridine according to Method Die. N-methylcarbamyl-4-pyridyloxy)aniline according to
Entry 35: 4-(3-Carboxyphenoxy)aniline was synthesized 20 Method Cla to afford the urea.
according to Method Al 1. 5-(Trifluoromethyl)-2- Entry 43: 4-Chloropyridine-2-carbonyl chloride HCl salt
methoxyaniline was converted into 5-(trifluoromethyl)-2- was reacted with annnonia according to Method A2, Step
methoxyphenyl isocyanate according to Method Bl. 4-(3- 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-
Carb oxyphenoxy )aniline was reacted with pyridinecarboxamide was reacted with 4-aminophenol
5-(trifluoromethyl)-2-methoxyphenyl isocyanate accord- 25 according to Method A2, Step 4 to form 4-(2-carbamoyl-
ing to Method Clf to afford N-(5-(trifluoromethyl)-2- 4-pyridy loxy )aniline. According to Method Cla,
methoxyphenyl)-N'-(3-carboxyphenyl)urea, which was 4-chloro-3-(trifluoromethyl)phenyl isocyanate was
coupled with N-( 4-fluorophenyl)piperazine according to reacted with 4-(2-carbamoyl-4-pyridyloxy)aniline to
Method Die.
afford the urea.
30 Entry 44: 4-Chloropyridine-2-carbonyl chloride HCl salt
according to Method Al 1. 5-(Trifluoromethyl)-2-
methoxyaniline was converted into 5-(trifluoromethyl)-2- was reacted with annnonia according to Method A2, Step
methoxyphenyl isocyanate according to Method Bl. 4-(3- 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-
Carb oxyphenoxy )aniline was reacted with pyridinecarboxamide was reacted with 3-aminophenol
5-(trifluoromethyl)-2-methoxyphenyl isocyanate accord- according to Method A2, Step 4 to form 3-(2-carbamoyl-
ing to Method Clf to afford N-(5-(trifluoromethyl)-2- 35 4-pyridyloxy)aniline. According to Method Cla,
methoxyphenyl)-N'-(3-carboxyphenyl)urea, which was 4-chloro-3-(trifluoromethyl)phenyl isocyanate was
coupled with 4-fluoroaniline according to Method Die. reacted with 3-(2-carbamoyl-4-pyridyloxy)aniline to
Entry 37: 4-(3-Carboxyphenoxy)aniline was synthesized afford the urea.
according to Method Al 1. 5-(Trifluoromethyl)-2- Entry 45: 4-Chloro-N-methyl-2-pyridinecarboxamide,
methoxyaniline was converted into 5-(trifluoromethyl)-2- 40 which was synthesized according to Method A2, Step 3a,
methoxyphenyl isocyanate according to Method Bl. 4-(3- was reacted with 3-aminophenol according to MethodA2,
Carb oxyphenoxy )aniline was reacted with Step 4 to form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)
5-(trifluoromethyl)-2-methoxyphenyl isocyanate accord- aniline. According to Method Cla; 4-chloro-3-
ing to Method Clf to afford N-(5-(trifluoromethyl)-2- (trifluoromethyl)phenyl isocyanate was reacted with 3-(2-
methoxyphenyl)-N'-(3-carboxyphenyl)urea, which was 45 (N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the
coupled with 4-( dimethylamino )aniline according to urea.
Method Die. Entry 46: 5-(4-Aminophenoxy)isoindoline-l,3-dione was
Entry 38: 4-(3-Carboxyphenoxy)aniline was synthesized synthesized according to Method A3. According to
according to Method Al 1. 5-(Trifluoromethyl)-2- Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyan-
methoxyaniline was converted into 5-(trifluoromethyl)-2- 50 ate was reacted with 5-(4-aminophenoxy)isoindoline-l,3-
methoxyphenyl isocyanate according to Method Bl. 4-(3- dione to afford the urea.
Carb oxyphenoxy )aniline was reacted with Entry 4 7: 4-(2-(N-Methy lcarbamoy 1)-4-pyridy loxy )-2-
5-(trifluoromethyl)-2-methoxyphenyl isocyanate accord- methylaniline was synthesized according to Method AS.
ing to Method Clf to afford N-(5-(trifluoromethyl)-2- According to Method Cle, 4-chloro-3-(trifluoromethyl)
methoxyphenyl)-N'-(3-carboxyphenyl)urea, which was 55 phenyl isocyanate was reacted with 5-(4-aminophenoxy)
coupled with 5-amino-2-methoxypyridine according to isoindoline-1,3-dione to afford the urea.
Method Die. Entry 48: 4-(3-N-Methylsulfamoyl)phenyloxy)aniline was
Entry 39: 4-(3-Carboxyphenoxy)aniline was synthesized synthesized according to Method A15. According to
according to Method Al 1. 5-(Trifluoromethyl)-2- Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyan-
methoxyaniline was converted into 5-(trifluoromethyl)-2- 60 ate was reacted with 4-(3-N-methylsulfamoyl)phenyloxy)
methoxyphenyl isocyanate according to Method Bl. 4-(3- aniline to afford the urea.
Carb oxyphenoxy )aniline was reacted with Entry 49: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-
5-(trifluoromethyl)-2-methoxyphenyl isocyanate accord- chloroaniline was synthesized according to Method A6.
ing to Method Clf to afford N-(5-(trifluoromethyl)-2- According to Method Cla, 4-chloro-3-(trifluoromethyl)
methoxyphenyl)-N'-(3-carboxyphenyl)urea, which was 65 phenyl isocyanate was reacted with 4-(2-(N-
coupled with 4-morpholinoaniline according to Method methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline to
Die. afford the urea.
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Entry 50: According to Method A2, Step 4, 5-amino-2- nitrobenzene. The nitrobenzene was reduced according
methylphenol was reacted with 4-chloro-N-methyl-2- the Method Al 8, Step 3 to give 4-(5-(2-methoxycarbonyl)
pyridinecarboxamide, which had been synthesized pyridyloxy)aniline. The aniline was reacted with
according to Method A2, Step 3b, to give 3-(2-(N- 4-chloro-3-(trifluoromethyl)phenyl isocyanate according
methy lcarbamoy 1)-4-pyridy loxy )-4-methy !aniline. 5 to Method Cla to give N-(4-chloro-3-(trifluoromethyl)
According to Method Cla, 4-chloro-3-(trifluoromethyl) pheny 1)-N'-( 4-(2-(methoxycarbony 1)-5-pyridy loxy)
phenyl isocyanate was reacted with 3-(2-(N- phenyl)urea. The methyl ester was reacted with methy-
methylcarbamoyl)-4-pyridyloxy)-4-methylaniline to lamine according to Method D2 to afford N-(4-chloro-3-
afford the urea. (trifluoromethy l)pheny I)-N'-( 4-(2-(N-methy lcarbamoy I)-
Entry 51: 4-Chloropyridine-2-carbonyl chloride was reacted 10 5-pyridyloxy )pheny l)urea.
with ethylamine according to Method A2, Step 3b. The Entry 57: N-( 4-Chloro-3-(trifluoromethyl)phenyl-N'-( 4-
resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was aminophenyl)urea was prepared according to Method
reacted with 4-aminophenol according to Method A2, C 1d. N-( 4-Chloro-3-(trifluoromethyl)phenyl-N'-( 4-
Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy) aminophenyl)urea was coupled with mono-methyl isoph-
aniline. According to Method Cla, 4-chloro-3- 15 thalate according to Method D 1a to afford the urea.
(trifluoromethyl)phenyl isocyanate was reacted with 4-(2- Entry 58: N-( 4-Chloro-3-(trifluoromethyl)phenyl-N'-( 4-
(N-methylcarbamoyl5-4-pyridyloxy)aniline to afford the aminophenyl)urea was prepared according to Method
urea. C 1d. N-( 4-Chloro-3-(trifluoromethyl)phenyl-N'-( 4-
Entry 52: According to Method A2, Step 4, 4-amino-2- aminophenyl)urea was coupled with mono-methyl isoph-
chlorophenol was reacted with 4-chloro-N-methyl-2- 20 thalate according to Method D 1a to afford N-( 4-chloro-
pyridinecarboxamide, which had been synthesized 3 -(tri fl uoromethyl)phenyl-N' -( 4-(3 -
according to Method A2, Step 3b, to give 4-(2-(N- methoxycarbony Ipheny I)carboxyaminopheny I)urea.
methy lcarbamoy I)-4-pyridy loxy )-3-chloro aniline. According to Method D2, N-(4-chloro-3-
According to Method Cla, 4-chloro-3-(trifluoromethyl) (tri fl uoromethyl )phenyl-N' -( 4-(3 -
phenyl isocyanate was reacted with 4-(2-(N- 25 methoxycarbony lpheny I)carboxyaminopheny !)urea was
methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to reacted with methylamine to afford the corresponding
afford the urea. methyl amide.
Entry 53: 4-( 4-Methylthiophenoxy )-1-nitro benzene was Entry 59: 4-Chloropyridine-2-carbonyl chloride was reacted
oxidized according to Method A19, Step 1 to give 4-(4- with dimethylamine according to Method A2, Step 3b.
methylsulfonylphenoxy)-1-nitrobenzene. The nitroben- 30 The resulting 4-chloro-N,N-dimethyl-2-
zene was reduced according to Method A19, Step 2 to pyridinecarboxamide was reacted with 4-aminophenol
give 4-( 4-methylsulfonylphenoxy )- I-aniline. According according to Method A2, Step 4 to give 4-(2-(N,N-
to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl iso- dimethylcarbamoyl)-4-pyridyloxy)aniline. According to
cyanate was reacted with 4-( 4-methylsulfonylphenoxy)- Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyan-
1-aniline to afford the urea. 35 ate was reacted with 4-(2-(N,N-dimethylcarbamoyl)-4-
Entry 54: 4-Bromobenzenesulfonyl chloride was reacted pyridyloxy)aniline to afford the urea.
with methylamine according to Method A15, Step 1 to Entry 60: 4-Hydroxyacetophenone was reacted with
afford N-methyl-4-bromo benzenesulfonamide. 4-fluoronitrobenzene according to MethodA13, Step 1 to
N-Methyl-4-bromobenzenesulfonamide was coupled give 4-( 4-acetylphenoxy)nitrobenzene. The nitrobenzene
with phenol according to Method Al 5, Step 2 to afford 40 was reduced according to Method 13, Step 4 to afford
4-( 4-(N-methylsulfamoyl)phenoxy)benzene. 4-( 4-(N- 4-(4-acetylphenoxy)aniline, which was converted to the
Methylsulfamoyl)phenoxy)benzene was converted into 4-(4-(1-(N-methoxy)iminoethyl) phenoxyaniline HCI salt
4-( 4-(N-methy lsulfamoyl )phenoxy )-1-nitro benzene according to Method A16. According to Method Cla,
according to Method A15, Step 3. 4-(4-(N- 4-chloro-3-(trifluoromethyl)phenyl isocyanate was
Methylsulfamoyl)phenoxy)-1-nitrobenzene was reduced 45 reacted with 4-(4-acetylphenoxy)aniline to afford the
to 4-(4-N-methylsulfamoyl)phenyloxy)aniline according urea.
to Method A15, Step 4. According to Method Cla, Entry 61: 4-(3-Carboxyphenoxy)-1-nitrobenzene was syn-
4-chloro-3-(trifluoromethyl)phenyl isocyanate was thesized according to Method A13, Step 2. 4-(3-
reacted with 4-(3-N-methylsulfamoyl)phenyloxy)aniline Carboxyphenoxy )-1-nitrobenzene was coupled with 4-(2-
to afford the urea. 50 aminoethyl)morpholine according to MethodA13, Step 3
Entry 55: 5-Hydroxy-2-methylpyridine was coupled with to give 4-(3-(N-(2-morpholinylethyl)carbamoyl)
l-fluoro-4-nitrobenzene according to Method Al 8, Step 1 phenoxy)-1-nitrobenzene. According to Method A13 Step
to give 4-(5-(2-Methyl)pyridyloxy)-1-nitrobenzene. The 4, 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy )-1-
methylpyridine was oxidized according to the carboxylic n it rob en z en e was reduced to 4-(3-(N-(2-
acid, then esterified according to Method Al 8, Step 2 to 55 morpholinylethyl)carbamoyl)phenoxy)aniline. According
give 4-( 5-(2-methoxycarbonyl)pyridyloxy )-1- to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl iso-
nitrobenzene. The nitrobenzene was reduced according cyanate was reacted with 4-(3-(N-(2-morpholinylethyl)
the Method Al 8, Step 3 to give 4-(5-(2-methoxycarbonyl) carbamoyl)phenoxy)aniline to afford the urea.
pyridyloxy)aniline. The aniline was reacted with Entry 62: 4-(3-Carboxyphenoxy)-1-nitrobenzene was syn-
4-chloro-3-(trifluoromethyl)phenyl isocyanate according 60 thesized according to Method A13, Step 2. 4-(3-
to Method Cla to afford the urea. Carboxyphenoxy )-1-nitrobenzene was coupled with 1-(2-
Entry 56: 5-Hydroxy-2-methylpyridine was coupled with aminoethyl)piperidine according to Method A13, Step 3
l-fluoro-4-nitrobenzene according to Method Al 8, Step 1 to give 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)-1-
to give 47(5-(2-Methyl)pyridyloxy)-1-nitrobenzene. The nitrobenzene. According to Method A13 Step 4, 4-(3-(N-
methylpyridine was oxidized according to the carboxylic 65 (2-piperidy !ethyl )carbamoy l)phenoxy )-1-nitro benzene
acid, then esterified according to Method Al 8, Step 2 to was reduced to 4-(3-(N-(2-piperidylethyl)carbamoyl)
give 4-( 5-(2-methoxycarbonyl)pyridyloxy )- I - phenoxy)aniline. According to Method Cla, 4-chloro-3-
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(trifluoromethyl)phenyl isocyanate was reacted with 4-(3- Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyan-
(N-(2-piperidylethyl)carbamoyl)phenoxy)aniline to ate was reacted with 3-(4-(2-(N-methylcarbamoyl)
afford the urea. phenylthio)aniline to afford the urea.
Entry 63: 4-(3-Carboxyphenoxy)-1-nitrobenzene was syn- Entry 70: 4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl)
thesized according to Method A13, Step 2. 4-(3- 5 pyridyloxy)aniline was synthesized according to Method
Carboxyphenoxy)-1-nitrobenzene was coupled with tet- AlO. According to Method Cla, 4-chloro-3-
rahydrofurfurylamine according to MethodA13, Step 3 to (trifluoromethyl)phenyl isocyanate was reacted with 4-(2-
give 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl) (N-(2-morpholin-4-y lethy l)carbamoyl )pyridy loxy )aniline
phenoxy)-1-nitrobenzene. According to Method A13 Step to afford the urea.
Entry 71: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was
4, 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)- 10
synthesized according to Method A14. 4-Chloro-3-
1-nitrobenzene was reduced to 4-(3-(N-
(trifluoromethyl)-2-methoxyphenyl isocyanate was
(tetrahydrofury lmethy I)carbamoy I)phenoxy )aniline. reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline
According to Method Cla, 4-chloro-3-(trifluoromethyl) according to Method Cla to afford the urea. N-( 4-Chloro-
phenyl isocyanate was reacted with 4(3-(N- 3 -(tri fl uoromethyl )phenyl )-N' -( 4-(3 -( 5 -
(tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline to 15 methoxycarbonylpyridyl)oxy)phenyl)urea was saponified
afford the urea. according to Method D4, Step 1, and the corresponding
Entry 64: 4-(3-Carboxyphenoxy)-1-nitrobenzene was syn- acid was coupled with 4-(2-aminoethyl)morpholine to
thesized according to Method A13, Step 2. 4-(3- afford the amide.
Carboxyphenoxy)-1-nitrobenzene was coupled with Entry 72: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was
2-aminomethyl-1-methylpyrrolidine according to Method 20 synthesized according to Method A14. 4-Chloro-3-
A13, Step 3 to give 4-(3-(N-((1-methylpyrrolidinyl) (trifluoromethyl)phenyl isocyanate was reacted with 4-(3-
methyl)carbamoyl)phenoxy )-1-nitrobenzene. According ( 5-methoxycarbonyl )pyridy loxy )aniline according to
to Method A13 Step 4, 4-(3-(N-((1-methylpyrrolidinyl) Method Cla to afford the urea. N-(5-(Trifluoromethyl)-
methyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced 2-methoxypheny I)-N'-( 4-(3-( 5-methoxycarbony lpyridy I)
to 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl) 25 oxy)phenyl) urea was saponified according to Method D4,
phenoxy)aniline. According to Method Cla, 4-chloro-3- Step 1, and the corresponding acid was coupled with
(trifluoromethyl)phenyl isocyanate was reacted with 4-(3- methylamine according to Method D4. Step 2 to afford the
(N-( ( 1-methy lpyrrolidiny I)methy I)carbamoy I)phenoxy) amide.
aniline to afford the urea. Entry 73: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was
Entry 65: 4-Chloro-N-methylpyridinecarboxamide was syn- 30 synthesized according to Method A14. 4-Chloro-3-
thesized as described in Method A2, Step 3b. The chlo- (trifluoromethyl)phenyl isocyanate was reacted with 4-(3-
ropyridine was reacted with 4-aminothiophenol according ( 5-methoxycarbonyl )pyridy loxy )aniline according to
to Method A2, Step 4 to give 4-(4-(2-(N- Method Cla to afford the urea. N-(5-(Trifluoromethyl)-
methylcarbamoyl)phenylthio )aniline. According to 2-methoxypheny I)-N'-( 4-(3-( 5-methoxycarbony lpyridy I)
Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyan- 35 oxy)phenyl) urea was saponified according to Method D4,
ate was reacted with 4-(4-(2-(N-methylcarbamoyl) Step 1, and the corresponding acid was coupled with
phenylthio )aniline to afford the urea. N,N-dimethylethylenediamine according to Method D4,
Entry 66: 4-Chloropyridine-2-carbonyl chloride was reacted Step 2 to afford the amide.
with isopropylamine according to Method A2, Step 3b. Entry 74: 4-Chloropyridine-2-carbonyl chloride HCI salt
The resulting 4-chloro-N-isopropyl-2- 40 was reacted with 2-hydroxyethylamine according to
pyridinecarboxamide was reacted with 4-aminophenol Method A2, Step 3b to form 4-chloro-N-(2-
according to Method A2, Step 4 to give 4-(2-(N- trii sopropy I sily loxy )ethy Ipyridine-2-carboxamide.
isopropylcarbamoyl )-4-pyridy loxy )aniline. According to 4-Chloro-N -(2-triisopropy lsily loxy )ethy lpyridine-2-
Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyan- carboxamide was reacted with triisopropylsilyl chloride,
ate was reacted with 4-(2-(N-isopropylcarbamoyl)-4- 45 followed by 4-aminophenol according to Method Al 7 to
pyridyloxy)aniline to afford the urea. form 4-( 4-(2-(N-(2-triisopropylsilyloxy )ethylcarbamoyl)
Entry 67: N-( 4-Chloro-3-(trifluoromethyl)phenyl-N'-( 4- pyridyloxyaniline. According to Method Cla, 4-chloro-
ethoxycarbonylphenyl)urea was synthesized according to 3-(trifluoromethyl)phenyl isocyanate was reacted with
Method C 1e. N-( 4-Chloro-3-( trifluoromethy l)phenyl-N'- 4-( 4-(2-(N-(2-triisopropylsilyloxy )ethy lcarbamoyl)
(4-ethoxycarbonylphenyl)urea was saponified according 50 pyridyloxyaniline to afford N-(4-chloro-3-
to Method D3 to give N-(4-chloro-3-(trifluoromethyl) ( (trifl uoromethyl )phenyl )-N' -( 4-( 4-( 2-(N -(2-
phenyl-N'-( 4-carboxyphenyl)urea. N-( 4-Chloro-3- triisopropy lsily loxy )ethy lcarbamoy I)pyridy loxypheny I)
(trifluoromethy I)pheny 1-N'-( 4-carboxypheny I)urea was urea.
coupled with 3-methylcarbamoylaniline according to Entry 75: 4-(3-Carboxyphenoxy)aniline was synthesized
Method Dlb to give N-(4-chloro-3-(trifluoromethyl) 55 according to Method Al 1. 4-Chloro-3(trifluoromethyl)
phenyl-N' -( 4-(3 -methyl c arb amoylphenyl) phenyl isocyanate was reacted with 4-(3-(5-
carbamoy lpheny !)urea. methoxycarbonyl)pyridyloxy)aniline according to
Entry 68: 5-( 4-Aminophenoxy)-2-methylisoindoline-1,3- Method Clf to afford the urea, which was coupled with
dione was synthesized according to Method A9. Accord- 3-aminopyridine according to Method Die.
ing to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl 60 Entry 76: 4-(3-Carboxyphenoxy)aniline was synthesized
isocyanate was reacted with 5-( 4-aminophenoxy)-2- according to Method All. 4-Chloro-3-(trifluoromethyl)
methylisoindoline-1,3-dione to afford the urea. phenyl isocyanate was reacted with 4-(3-
Entry 69: 4-Chloro-N-methylpyridinecarboxamide was syn- carboxyphenoxy)aniline according to Method Clf to
thesized as described in Method A2, Step 3b. The chlo- afford the urea, which was coupled with N-(4-
ropyridine was reacted with 3-aminothiophenol according 65 acetylphenyl)piperazine according to Method Die.
to Method A2, Step 4 to give 3-(4-(2-(N- Entry 77: 4-(3-Carboxyphenoxy)aniline was synthesized
methylcarbamoyl)phenylthio )aniline. According to according to Method All. 4-Chloro-3-(trifluoromethyl)
IITRUE COPY!I
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phenyl isocyanate was reacted with 4-(3- 4-Bromo-3-(trifluoromethyl)aniline was converted into
carboxyphenoxy )aniline according to Method C 1f to 4-bromo-3-( trifluoromethy l)pheny I isocyanate according
afford the urea, which was coupled with 4-fluoroaniline to Method Bl. According to Method Cla, 4-bromo-3-
according to Method Dlc. (trifluoromethyl)phenyl isocyanate was reacted with 4-(2-
Entry 78: 4-(3-Carboxyphenoxy)aniline was synthesized 5 (N-methylcarbamoyl)-4-pyridyloxy )-2-chloroaniline to
according to Method All. 4-Chloro-3-(trifluoromethyl) afford the urea.
phenyl isocyanate was reacted with 4-(3- Entry 87: According to Method A2, Step 4, 4-amino-2-
carboxyphenoxy )aniline according to Method C 1f to chlorophenol was reacted with 4-chloro-N-methyl-2-
afford the urea, which was coupled with pyridinecarboxamide, which had been synthesized
4-(dimethylamino)aniline according to Method Dlc.
10 according to Method A2, Step 3b, to give 4-(2-(N-
methy lcarbamoy I)-4-pyridy loxy )-3-chloroaniline.
according to Method All. 4-Chloro-3-(trifluoromethyl)
phenyl isocyanate was reacted with 4-(3- 4-Bromo-3-(trifluoromethyl)aniline was converted into
carboxyphenoxy )aniline according to Method C 1f to 4-bromo-3-( trifluoromethy l)pheny I isocyanate according
afford the urea, which was coupled with to Method Bl. According to Method Cla, 4-bromo-3-
N-phenylethylenediamine according to Method Dlc. 15 (trifluoromethyl)phenyl isocyanate was reacted with 4-(2-
Entry 80: 4-(3-Carboxyphenoxy)aniline was synthesized (N -methy lcarbamoy I)-4-pyridy loxy )-3-chloroaniline to
according to Method All. 4-Chloro-3-(trifluoromethyl) afford the urea.
phenyl isocyanate was reacted with 4-(3- Entry 88: 4-Chloropyridine-2-carbonyl chloride was reacted
carboxyphenoxy )aniline according to Method C 1f to with ethylamine according to Method A2, Step 3b. The
afford the urea, which was coupled with 20 resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was
2-methoxyethylamine according to Method Dlc. reacted with 4-aminophenol according to Method A2,
Entry 81: 4-(3-Carboxyphenoxy)aniline was synthesized Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)
according to Method All. 4-Chloro-3-(trifluoromethyl) aniline. 4-Bromo-3-(trifluoromethyl)aniline was con-
phenyl isocyanate was reacted with 4-(3- verted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate
carboxyphenoxy )aniline according to Method C 1f to 25 according to Method Bl. According to Method Cla,
afford the urea, which was coupled with 5-amino-2- 4-bromo-3-( trifluoromethy I)pheny I isocyanate was
methoxypyridine according to Method Dlc. reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)
Entry 82: 4-(3-Carboxyphenoxy)aniline was synthesized aniline to afford the urea.
according to Method All. 4-Chloro-3-(trifluoromethyl) Entry 89: 4-Chloro-N-methyl-2-pyridinecarboxamide,
phenyl isocyanate was reacted with 4-(3- 30 which was synthesized according to Method A2, Step 3a,
carboxyphenoxy )aniline according to Method C 1f to was reacted with 3-aminophenol according to MethodA2,
afford the urea, which was coupled with Step 4 to form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)
4-morpholinoaniline according to Method Dlc. aniline. 4-Bromo-3-(trifluoromethyl)aniline was con-
Entry 83: 4-(3-Carboxyphenoxy)aniline was synthesized verted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate
according to Method All. 4-Chloro-3-(trifluoromethyl) 35 according to Method Bl. According to Method Cla,
phenyl isocyanate was reacted with 4-(3- 4-bromo-3-( trifluoromethy I)pheny I isocyanate was
carboxyphenoxy )aniline according to Method C 1f to reacted with 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)
afford the urea, which was coupled with N-(2-pyridyl) aniline to afford the urea.
piperazine according to Method Dlc. Entry 90: According to Method A2, Step 4, 5-amino-2-
Entry 84: 4-Chloropyridine-2-carbonyl chloride HCI salt 40 methylphenol was reacted with 4-chloro-N-methyl-2-
was reacted with 2-hydroxyethylamine according to pyridinecarboxamide, which had been synthesized
Method A2, Step 3b to form 4-chloro-N-(2- according to Method A2, Step 3b, to give 3-(2-(N-
trii sopropy I sily loxy )ethy Ipyridine-2-carboxamide. methy lcarbamoy I)-4-pyridy loxy )-4-methy !aniline.
4-Chloro-N -(2-triisopropy lsily loxy )ethy lpyridine-2- 4-Bromo-3-(trifluoromethyl)aniline was converted into
carboxamide was reacted with triisopropylsilyl chloride, 45 4-bromo-3-( trifluoromethy l)pheny I isocyanate according
followed by 4-aminophenol according to Method Al 7 to to Method Bl. According to Method Cla, 4-bromo-3-
form 4-(4-(2-(N-(2-triisopropylsilyloxy )ethylcarbamoyl) (trifluoromethyl)phenyl isocyanate was reacted with 3-(2-
pyridyloxyaniline. According to Method Cla, 4-chloro- (N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline to
3-(trifluoromethyl)phenyl isocyanate was reacted with afford the urea.
4-( 4-(2-(N-(2-triisopropy lsily loxy )ethylcarbamoyl) 50 Entry 91: 4-Chloropyridine-2-carbonyl chloride was reacted
pyridyloxyaniline to give N-(4-chloro-3- with dimethylamine according to Method A2, Step 3b.
( (trifl uoromethyl )phenyl )-N' -( 4-( 4-(2-(N -(2- The resulting 4-chloro-N,N-dimethyl-2-
triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyphenyl) pyridinecarboxamide was reacted with 4-aminophenol
urea. The urea was deprotected according to Method D5 according to Method A2, Step 4 to give 4-(2-(N,N-
to afford N-( 4-chloro-3-((trifluoromethyl)phenyl)-N-( 4- 55 dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-
(4-(2-(N-(2-hydroxy )ethy lcarbamoy I)pyridy loxypheny I) (trifluoromethyl)aniline was converted into 4-bromo-3-
urea. (trifluoromethyl)phenyl isocyanate according to Method
Entry 85: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy )aniline Bl. According to Method Cla, 4-bromo-3-
was synthesized according to Method A2. 4-Bromo-3- (trifluoromethyl)phenyl isocyanate was reacted with 4-(2-
(trifluoromethyl)aniline was converted to 4-bromo-3- 60 (N,N-dimethylcarbamoyl)-4-pyridyloxy )aniline to afford
(trifluoromethyl)phenyl isocyanate according to Method the urea.
Bl. According to Method Cla, 4-bromo-3- Entry 92: 4-Chloro-N-methylpyridinecarboxamide was syn-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(2- thesized as described in Method A2, Step 3b. The chlo-
(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the ropyridine was reacted with 4-aminothiophenol according
urea. 65 to Method A2, Step 4 to give 4-(4-(2-(N-
Entry 86: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2- methy lcarbamoy I)pheny lthio )aniline. 4-Bromo-3-
chloroaniline was synthesized according to Method A6. (trifluoromethyl)aniline was converted into 4-bromo-3-
IITRUE COPY!I
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53 54
(trifluoromethyl)phenyl isocyanate according to Method ate as was reacted with 3-(-2-(N-methylcarbamoyl)-4-
Bl. According to Method Cla, 4-bromo-3- pyridyloxy)aniline to afford the urea.
(trifluoromethyl)phenyl isocyanate was reacted with 4-(4- Entry 99: 4-Chloropyridine-2-carbonyl chloride was reacted
(2-(N-methylcarbamoyl)phenylthio )aniline to afford the with ethylamine according to Method A2, Step 3b. The
urea. resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was
Entry 93: 4-Chloro-N-methylpyridinecarboxamide was syn- reacted with 4-aminophenol according to Method A2,
thesized as described in Method A2, Step 3b. The chlo- Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)
ropyridine was reacted with 3-aminothiophenol according aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline
to Method A2, Step 4 to give 3-(4-(2-(N- was synthesized according to Method A7. 4-Chloro-2-
methylcarbamoyl)phenylthio )aniline. 4-Bromo-3- 10
methoxy-5-(trifluoromethyl)aniline was converted into
(trifluoromethyl)aniline was converted into 4-bromo-3-
4-chloro-2-methoxy-5-( trifluoromethy 1)pheny 1 isocyan-
(trifluoromethyl)phenyl isocyanate according to Method
ate according to Method Bl. According to Method Cla,
Bl. According to Method Cla, 4-bromo-3-
(trifluoromethyl)phenyl isocyanate was reacted with 3-(4- 4-chloro-2-methoxy-5-( trifluoromethy 1)pheny 1 isocyan-
(2-(N-methylcarbamoyl)phenylthio )aniline to afford the 15
ate was reacted with 4-(2-(N-ethylcarbamoyl)-4-
urea. pyridyloxy)aniline to afford the urea.
Entry 94: 4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl) Entry 100: 4-Chloropyridine-2-carbonyl chloride was
pyridyloxy)aniline was synthesized according to Method reacted with dimethylamine according to Method A2,
AlO. 4-Bromo-3-(trifluoromethyl)aniline was converted Step 3b. The resulting 4-chloro-N,N-dimethyl-2-
into 4-bromo-3-(trifluoromethyl)phenyl isocyanate 20 pyridinecarboxamide was reacted with 4-aminophenol
according to Method Bl. According to Method Cla, according to Method A2, Step 4 to give 4-(2-(N,N-
4-bromo-3-(trifluoromethyl)phenyl isocyanate was dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-
reacted with 4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl) methoxy-5-(trifluoromethyl)aniline was synthesized
pyridyloxy)aniline to afford the urea. according to Method A7. 4-Chloro-2-methoxy-5-
Entry 95: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)aniline 25 (trifluoromethyl)aniline was converted into 4-chloro-2-
was synthesized according to Method A2. 4-Chloro-2- methoxy-5-(trifluoromethyl)phenyl isocyanate according
methoxy-5-(trifluoromethyl)aniline was synthesized to Method Bl. According to Method Cla, 4-chloro-2-
according to Method A7. 4-Chloro-2-methoxy-5- methoxy-5-(trifluoromethyl)phenyl isocyanate was
(trifluoromethyl)aniline was converted into 4-chloro-2- reacted with 4-(2-(N,N-dimethylcarbamoyl)-4-
methoxy-5-(trifluoromethyl)phenyl isocyanate according 30 pyridyloxy)aniline to afford the urea.
to Method Bl. According to Method Cla, 4-chloro-2- Entry 101: 4-Chloro-N-methyl-2-pyridinecarboxamide,
methoxy-5-(trifluoromethyl)phenyl isocyanate was which was synthesized according to Method A2, Step 3a,
reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy) was reacted with 3-aminophenol according to MethodA2,
aniline to afford the urea. Step 4 to form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)
Entry 96: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2- 35 aniline. 2-Amino-3-methoxynaphthalene was synthesized
chloroaniline was synthesized according to Method A6. as described Method Al. According to Method C3,
4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was syn- 2-amino-3-methoxynaphthalene was reacted with bis
thesized according to Method A7. 4-Chloro-2-methoxy- (trichloromethyl) carbonate followed by 3-(-2-(N-
5-(trifluoromethyl)aniline was converted into 4-chloro-2- methylcarbamoyl)-4-pyridyloxy)aniline to form the urea.
methoxy-5-( trifluoromethy l)pheny 1 isocyanate according 40 Entry 102: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)aniline
to Method Bl. According to Method Cla, 4-chloro-2- was synthesized according to Method A2. 5-tert-Butyl-2-
methoxy-5-(trifluoromethyl)phenyl isocyanate was (2,5-dimethylpyrrolyl)aniline was synthesized according
reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2- to Method A4. 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)
chloroaniline afford the urea. aniline was reacted with CDI followed by 4-(2-(N-
Entry 97: According to Method A2, Step 4, 4-amino-2- 45 methylcarbamoyl)-4-pyridyloxy)aniline according to
chlorophenol was reacted with 4-chloro-N-methyl-2- Method C2d to afford the urea.
pyridinecarboxamide, which had been synthesized Entry 103: 4-Chloro-N-methyl-2-pyridinecarboxamide was
according to Method A2, Step 3b, to give 4-(2-(N- synthesized according to Method A2, Step 3b. 4-Chloro-
methy lcarbamoy 1)-4-pyridy loxy )-3-chloro aniline. N-methyl-2-pyridinecarboxamide was reacted with
4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was syn- 50 4-aminophenol according to Method A2, Step 4 using
thesized according to Method A7. 4-Chloro-2-methoxy- DMAC in place of DMF to give 4-(2-(N-
5-(trifluoromethyl)aniline was converted into 4-chloro-2- methylcarbamoyl)-4-pyridyloxy)aniline. According to
methoxy-5-( trifluoromethy l)pheny 1 isocyanate according Method C2b, reaction of 3-amino-2-methoxyquinoline
to Method Bl. According to Method Cla, 4-chloro-2- with CDI followed by 4-(2-(N-methylcarbamoyl)-4-
methoxy-5-(trifluoromethyl)phenyl isocyanate was 55 pyri dyl oxy) aniline afforded bis(4-(2-(N-
reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3- methylcarbamoyl)-4-pyridyloxy)phenyl)urea.
chloroaniline to afford the urea. Listed in the Tables below are compounds which have
Entry 98: 4-Chloro-N-methyl-2-pyridinecarboxamide, been synthesized according to the Detailed Experimental
which was synthesized according to Method A2, Step 3a, Procedures given above:
was reacted with 3-aminophenol according to MethodA2, 60
Step 4 to form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy) Tables
aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline
was synthesized according to Method A7. 4-Chloro-2- The compounds listed in Tables 1-6 below were synthe-
methoxy-5-(trifluoromethyl)aniline was converted into sized according to the general methods shown above, and
4-chloro-2-methoxy-5-( trifluoromethy 1)pheny 1 isocyan- 65 the more detailed exemplary procedures are in the entry
ate according to Method Bl. According to Method Cla, listings above and characterizations are indicated in the
4-chloro- 2-methoxy- 5-(trifluoromethy 1)pheny 1 isocyan- tables.
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3-tert-Butylph eny l Ureas
TLC
HPLC TLC Solvent Synth.
(min.) R,- Method
418 A13
(M + H) + C3
(HPLC
hexane ES-MS)
0.58 50% 403 A13

EtOAc/ (M + H) + C3
50% (HPLC
hexane ES-MS)
0.68 100% 448 AS

EtOAc (M + H) + C2d
(FAB)
R,
N
)l N
H H
OMe
TLC Mass
Entry R (" c.) (min.) R,- System [Source] Method
4 5.93 448 A13

(M + H) + Bl
(HPLC Cla
--o-
ES-MS)
0-00 \,,
\ j
120- 0.67 100% 478 AS
-d=
O NH 122 EtOAc (M + H) + C2d
(FAB)
--0-o
f \ kie
OMe
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TABLE 2-continued
5-tert-Butyl-2-methoxyphenyl Ureas
R,
N
)l N
H H
OMe
TLC Mass
Entry R (" c.) (min.) R, System [Source] Method
0.40 50% 460 A3
-0-o-q~{ EtOAc/
50%
hexane
(M + H) +
(HPLC
ES-MS)
C2d
7 0.79 50% 446 A12
-0-o-Q{ EtOAc/
50%
hexane
(M + H) +
(HPLC
ES-MS)
C2d
TABLE 3
F
R,N)lN
H H
OMe
TLC Mass
Entry R (" C.) (min.) Rr System [Source] Method
250 460 A13
_}-\,, (dee) (M +H) +

(FAB)
C2a
-0- o--C)
206- 0.54 10% 446 A3 step
-O-o-0---( 208 MeOH/

90%
CH2Cl2
(M +H) +
(HPLC
ES-MS)
2,
AS step
4,
Bl,
Cla
10 0.33 50% 445 A13

EtOAc/ (M +H) + C3
50% pet (HPLC
ether ES-MS)
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59 60
TABLE 3-continued
5-(Trifluoromethyl) - 2-methoxyphenyl Ureas

F
OMe
TLC Mass
11 0.20 2% 461 A2
Et3N/ (M +H) + C4
98% (HPLC
EtOAc ES-MS)
12 0.27 1% 447 A2
Et3N/ (M +H) + C4
99% (HPLC
EtOAc ES-MS)
13 0.62 100% 461 A2

EtOAc (M +H) + C2a
0 \fo (FAB)
14
-0--0 0 ~
~ 11
N
114- 0.40 1% 447 A2

117 Et3N/ (M +H) + C4
99% (FAB)
EtOAc
15 232- 0.54 100% 490 AS
-d=
O NH 235 EtOAc (M +H) + C2d
(FAB)
f \ kie
-0-o OMe
16 210- 0.29 5% 475 AS

213 MeOH/ (M +H) + Bl
-CO\,, 45% (HPLC Cle
---0-
Me EtOAc/ ES-MS)
50% pet
ether
0 ~ N
~ 11
17 187- 0.17 50% 495 A6
188 EtOAc/ (M +H) + Bl
-CO\,, 50% pet (HPLC Cla
---0-
Cl ether ES-MS)
0 ~ N
~ 11
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61 62
TABLE 3-continued
F
F
R,
N
)l N
H H
OMe
TLC Mass
18 0.48 100% 475 A2 step

EtOAc (M +H) + 4,
2 (HPLC Bl
--Q-~e O NH ES-MS) Cla
0 \_ #N
19 194- 0.31 5% 475 A2

196 MeOH/ (M +H) + Bl
0 \, 45% (HPLC Cla
EtOAc/ ES-MS)
-0--0
50% pet
ether
0 \_ N
#
20 214- 0.25 5% 495 A2

216 MeOH/ (M +H) + Cla
45% (HPLC
---0-
Cl -CO \fo EtOAc/ ES-MS)
50% pet
ether
0 \_ N
#
21 208- 0.30 50% 481 A19
-0-
0
0 ---ry\~
\_ j \
210 EtOAc/
50%
hexane
(M +H) +
(HPLC
ES-MS)
C2a
Me
22 188- 0.30 70% 447 A15,

190 EtOAc/ (M +H) + step 4,
50% (HPLC Cla
0-CO NH2 hexane ES-MS)
-0- \_ j
23 0.50 70% 472 A3
-0- 0~
\_ j
NH
0 EtOAc/
30%
hexane
(M +H) +
(FAB)
Bl
Cla
24 203- 0.13 100% 479 A2

205 EtOAc (M +H) + Bl
0 {
(HPLC Cla
ES-MS)
-0--0 0 \_
#
N
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63 64
TABLE 3-continued
F
F
R......_N)lN
H H
OMe
TLC Mass
-0-o-Q{
25 0.09 75% 458 A12
EtOAc/ (M +H) + C2d
25% (HPLC
hexane ES-MS)
26 MeO 169- 0.67 50% 474 A13

\ 171 EtOAc/ (M +H) + step 1,
-0-o--0---( 50% pet

ether
(HPLC
ES-MS)
A13
step 4,
A16,
Bl
Cla
27
0 \,, 218-
219
0.40 50%
EtOAc/
50% pet
ether
477
(M +H) +
(HPLC
ES-MS)
A2 step
3b,
A2 step
4,
-0--0
Bl,
Cla
S \ #N
28 212- 0.30 40% A9
-0-o~:
214 EtOAc/ Bl
60% Cla
hexane
29 0.33 50% 474 A2 step
--Q-00\,,
S \ #N
EtOAc/
50% pet
ether
(M +H) +
(HPLC
ES-MS)
3b,
A2 step
4,
Bl,
Cla
30 210- A2
-C
O NH 211 Bl
Cla
-0-
\r-i
31 210- 0.43 10% A14

204 MeOH/ Bl
CH2Cl2 Cla
D4
-o-0-d-(; 0
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TABLE 3-continued
5-(Trifluoromethyl)- 2-methoxyphenyl Ureas

F
OMe
TLC Mass
32 247 0.57 10% A14

249 MeOH/ Bl
CH2Cl2 Cla
D4
33 217- 0.07 10% A14

219 MeOH/ Bl
CH2Cl2 Cla
D4
34 0.11 70% All

EtOAc/ Bl
30% Clf
hexane Dlc
0.38 70% All

EtOAc/ Bl
30% Clf
hexane Dlc
0.77 70% All

EtOAc/ Bl
30% Clf
hexane Dlc
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TABLE 3-continued
F
R,N)lN
H H
OMe
TLC Mass
37 0.58 70% All

EtOAc/ Bl
30% Clf
hexane Dlc
38 0.58 70% All

EtOAc/ Bl
30% Clf
M~-o-NH 0
hexane Dlc
--o-0-0
39 0.17 70% All
EtOAc/ Bl
0N-o-NH 30% Clf
-0-0-00
hexane Dlc
40 0.21 70% All

EtOAc/ Bl
30% Clf
hexane Dlc
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TABLE 4
' c,
R,
N
H
)l N
H
TLC Mass
Entry R (° C.) (min.) Rr System [Source] Method
41 163- 0.08 50% 464 Al 3

165 EtOAc/ (M + H) + C3
50% pet (HPLC
--0-o--O\,,
~NR ether ES-MS)
42 215 0.06 50% 465 A2

50% pet (HPLC
--0-o--O\,,
~NR ether ES-MS)
43 0.10 50% 451 A2

EtOAc/ (M +H) + Cla
50% pet (HPLC
ether ES-MS)
44 0.25 30% 451 A2

EtOAc/ (M +H) + Cla
70% pet (HPLC
ether ES-MS)
45 0.31 30% 465 A2

EtOAc/ (M +H) + Cla
70% pet (HPLC
ether ES-MS)
46 176- 0.23 40% 476 A3

179 EtOAc/ (M + H) + Cla
60% (FAB)
hexane
47 0.29 5% 478 AS
MeOH/ (M +H) + Cle
45% (HPLC
EtOAc/ ES-MS)
50% pet
ether
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TABLE 4-continued
' c,
R,
N
H
~ N
H
TLC Mass
48 206- A15
209 Cla
49 147- 0.22 50% 499 A6

50% pet (HPLC
ether ES-MS)
50 0.54 100% 479 A2

EtOAc (M + H) + Cla
(HPLC
ES-MS)
51 187- 0.33 5% 479 A2

189 MeOH/ (M + H) + Cla
45% (HPLC
EtOAc/ ES-MS)
50% pet
ether
52 219 0.18 5% 499 A2

MeOH/ (M + H) + Cla
45% (HPLC
EtOAc/ ES-MS)
50% pet
ether
53 246- 0.30 50% 485 A19,

50% (HPLC
hexane ES-MS)
54 196- 0.30 70% 502 A15

30% (HPLC
hexane ES-MS)
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TABLE 4-continued
TLC Mass
55 228 0.30 30% 466

230 EtOAc/ (M +H) +
0 \, 70% (HPLC
CH2Cl2 ES-MS)
56
-0--0 0 ~
\\ j
N
238-
o___j\_Jo
-0- -\_J--\
NH
M/
245
57 221- 0.75 80% 492 Cld

222 EtOAc/ (M +H) + Dla
20% (FAB)
hexane
ij O _}-\,
58
-0- ~
247 0.35 100% Cld
O NH EtOAc Dla
~ D2
-0-
~e
-
59 198- 0.09 100% 479 A2
200 EtOAc (M +H) + Cla
0 (
(HPLC
ES-MS)
60
-0--0 0 ~
~ j
N
158- 0.64 50%

160 EtOAc/
50% pet
ether
61 195- 0.39 10% A13

197 MeOH/ Cla
CH2Cl2
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TABLE 4-continued
TLC Mass
62 170 0.52 10% A13

172 MeOH/ Cla
CH2Cl2
-o-0-d~
- \ j 0
63 168- 0.39 10% A13
171 MeOH/ Cla
-0-
0-00
\ j
'----0 CH2Cl2
'--0
64 176- 0.35 10% A13
177 MeOH/ Cla
CH2Cl2
-0-
0-00
\ j
65 130- 487 A2
133 (M +H) + Bl
(HPLC Cla
0 \fo
ES-MS)
66
-0--0 S \
#N
155 A2
-O
O NH Cla
-0-
0 \r-i
67 225- 0.23 100% Cle
-0- ic>
O NH 229 EtOAc D3
~ kie
Dlb
68 234- 0.29 40% A9

236 EtOAc/ Cla
0 \ 0
-0-~ j 60%
hexane
NMe
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TABLE 4-continued
TLC Mass
69 0.48 50% 481

EtOAc/ (M +H) +
50% pet (HPLC
ether ES-MS)
70 0.46 5% 564 Al0

MeOH/ (M +H) + Cla
95% (HPLC
CH2Cl2 ES-MS)
71 199- 0.50 10% A14
-O~
O NH 201 MeOH/ Cla
CH2Cl2 D4
--0-0 f ' N\
N \_;
0
72 235- 0.55 10% A14

237 MeOH/ Cla
CH2Cl2 D4
73
--o- 0-00
\. ;}
N
\,,
200- 0.21 50% A14

201 MeOH/ Cla
-O
O NH
CH2Cl2 D4
--0-o N
~-M,
Ml
74 145-
O NH 148
--0-o- O N
~Si(Pr-i) 3
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TABLE 4-continued
't' .c,
Rvl)J"
H H
TLC Mass
75 0.12 70% 527 All

30% (HPLC Dlc
hexane ES-MS)
76 0.18 70% All

EtOAc/ Clf
30% Dlc
hexane
77 0.74 70% All

EtOAc/ Clf
30% Dlc
hexane
78 0.58 70% All

EtOAc/ Clf
30% Dlc
hexane
79 0.47 70% 569 All

30% (HPLC Dlc
hexane ES-MS)
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TABLE 4-continued
TLC Mass
80 0.18 70% 508 All

30% (HPLC Dlc
hexane ES-MS)
81 0.58 70% 557 All

30% (HPLC Dlc
hexane ES-MS)
82 0.37 70% 611 All

30% (HPLC Dlc
hexane ES-MS)
83 0.19 70% All

EtOAc/ Clf
30% Dlc
hexane
84 179- A2
183 A17
Cla
D5
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TABLE 5
F
O Br
R...__N)lN
H H
TLC Mass
85 186 0.13 50% 509 A2

187 EtOAc/ (M + H) + Bl
50% pet (HPLC Cla
o \fo
ether ES-MS)
86
-0-~ 0 ~
~ 11
N
150- 0.31 50% 545 A6

152 EtOAc/ (M + H) + Bl
5 0% pet (HPLC Cla
---0-
Cl ~O \,, ether ES-MS)
0 ~ N
\\ 11
87 217- 0.16 50% 545 A2
219 EtOAc/ (M + H) + Bl
Cl ~O NH 5 0% pet (HPLC Cla
---0-
ether ES-MS)
- ~e
0 ~ N
\\ 11
88 183- 0.31 50% 525 A2
184 EtOAc/ (M + H) + Bl
5 0% pet (HPLC Cla
ether ES-MS)
89 0.21 50% 511 A2

EtOAc/ (M + H) + Bl
5 0% pet (HPLC Cla
ether ES-MS)
90 0.28 50% 525 A2

EtOAc/ (M + H) + Bl
5 0% pet (HPLC Cla
ether ES-MS)
91 214- 0.28 50% 522 A2

216 EtOAc/ (M + H) + Bl
o ( 5 0% pet (HPLC Cla
ether ES-MS)
-0-~ 0 ~
~ 11
N
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TABLE 5-continued
TLC Mass
Entry R (" C.) (min.) R, System [Source] Method
92 0.47 50% 527 A2 step

o \,, 50% pet (HPLC A2 step
ether ES-MS) 4,
-0--c
Bl,
Cla
S \ N
11
93 0.46 50% 527 A2 step
--Q-Co
\,,
S \ /JN
50% pet (HPLC
ether ES-MS)
A2 step
4,
Bl,
Cla
94 145- 0.41 5% AlO

150 MeOH/ Bl
95% Cla
CH2Cl2
-o-0-d~j
TABLE 6
5-(Trifluoromethyl)-4-chloro-2-methoxyphenyl Ureas
F
Cl
0
R......_N)lN
H H
OMe
TLC Mass
Entry R (0 C.) (min.) Rr System [Source] Method
95 0.29 5% 495 A2
MeOH/ (M + H) + A7
45% (HPLC Bl
EtOAc/ ES-MS) Cla
50% pet
ether
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TABLE 6-continued
5-(Trifluoromethyl)-4-chloro-2-meth oxyp h enyl Ureas

F
Cl
OMe
TLC Mass
Entry R (" c.) (min.) Rr System [Source] Method
96 0.39 5% 529 A6
MeOH/ (M + H) + A7
45% (HPLC Bl
EtOAc/ ES-MS) Cla
50% pet
ether
97 0.25 5% 529 A2
MeOH/ (M + H) + A?
45% (HPLC Bl
EtOAc/ ES-MS) Cla
50% pet
ether
98 0.27 5% 495 A2
MeOH/ (M + H) + A?
45% (HPLC Bl
EtOAc/ ES-MS) Cla
50% pet
ether
99 180- 0.52 5% 509 A2
-0
181 MeOH/ (M + H) + A?
0 "Z',, 45%
EtOAc/
(HPLC
ES-MS)
Bl
Cla
-0-
50% pet
ether
0 ~ N
~ ll
100 A2
A7
Bl
Cla
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TABLE 7
Additional Ureas
TLC Mass
Entry R (0 C.) (min.) R, System [Source] Method
101 162- Al
0 165 A2
C3
l )l ,(Y1°'{Y'~t
~
0
# Me
N N
H H
OMe
102 0.10 50% 442 A2

EtOAc/ (M + H) + A4
0 50% (HPLC C2d
hexane ES-MS)
I o r"'yo~i
N
)l~ N
~k Me
H H
103 125- 0.24 40% 512 A2

130 EtOAc/ (M + H) + C2b
60% (FAB)
hexane
Biological Examples experiments, the kinase reaction was stopped by adding an

In Vitro raf Kinase Assay equal amount of Laemmli sample buffer. Samples were
In an in vitro kinase assay, raf was incubated with MEK boiled 3 min and the proteins resolved by electrophoresis on
in 20 mM Tris-HCl, pH 8.2 containing 2 mM 55
7 .5% Laemmli gels. Gels were fixed, dried and exposed to
2-mercaptoethanol and 100 mM NaCl. This protein solution an imaging plate (Fuji). Phosphorylation was analyzed using
(20 µL) was mixed with water (5 µL) or with compounds a Fujix Bio-Imaging Analyzer System.
diluted with distilled water from 10 mM stock solutions of All compounds exemplified displayed IC50 s of between 1
compounds dissolved in DMSO. The kinase reaction was nM and 10 µM.
initiated by adding 25 µL [A-33 P]ATP (1000-3000 dpm/ Cellular Assay
pmol) in 80 MM Tris-HCl, pH 7.5, 120 mM NaCl, 1.6 mM 6
° For in vitro growth assay, human tumor cell lines, includ-
DTT, 16 mM MgC12 . The reaction mixtures were incubated ing but not limited to HCT116 and DLD-1, containing
at 32° C., usually for 22 min. Incorporation of 33 P into mutated K-ras genes were used in standard proliferation
protein was assayed by harvesting the reaction onto phos- assays for anchorage dependent growth on plastic or anchor-
phocellulose mats, washing away free counts with a 1% age independent growth in soft agar. Human tumor cell lines
phosphoric acid solution and quantitating phosphorylation 65 were obtained from ATCC (Rockville Md.) and maintained
by liquid scintillation counting. For high throughput in RPMI with 10% heat inactivated fetal bovine serum and
screening, 10 µM ATP and 0.4 µM MEK was used. In some 200 mM glutamine. Cell culture media and additives were
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obtained from Gibco/BRL (Gaithersburg, Md.) except for 2. A pharmaceutically acceptable salt of the compound
fetal bovine serum (JRH Biosciences, Lenexa, Kans.). In a N-(5-tert-butyl-2-methoxy phenyl)-N'-( 4-( 4-methoxy-3-(N-
standard proliferation assay for anchorage dependent methy lcarbamoy l)phenoxy )phenyl )urea.
growth, 3xl cells were seeded into 96-well tissue culture 3. A pharmaceutically acceptable salt of claim 2 selected
plates and allowed to attach overnight at 37° C. in a 5% CO 2 5
from the group consisting of
incubator. Compounds were titrated in media in dilution
series and added to 96-well cell cultures. Cells were allowed a) basic salts of organic acids and inorganic acids selected
to grow 5 days typically with a feeding of fresh compound from the group consisting of hydrochloric acid, hydro-
containing media on day three. Proliferation was monitored bromic acid, sulpheric acid, phosphoric acid, methane-
by measuring metabolic activity with standard XTT colori- 10 sulphonic acid, triflurosulphonic acid, benzenesulfonic
metric assay (Boehringer Mannheim) measured by standard acid, p-tolune sulphonic acid(tosylate salt),
ELISA plate reader at OD 490/560, or by measuring 1-napthalene sulfonic acid, 2-napthalene sulfonic acid,
3
H-thymidine incorporation into DNA following an 8 h
acetic acid, trifluoroacetic acid, malic acid, tartaric
culture with 1 µCu 3 H-thymidine, harvesting the cells onto
glass fiber mats using a cell harvester and measuring 15
acid, citric acid, lactic acid, oxalic acid, succinic acid,
3
H-thymidine incorporation by liquid scintillant counting. fumaric acid, maleic acid, benzoic acid, salicyclic acid,
For anchorage independent cell growth, cells were plated phenylacetic acid, and mandelic acid; and
at lxl0 3 to 3xl0 3 in 0.4% Seaplaque agarose in RPMI b) acid salts of organic and inorganic bases containing
complete media, overlaying a bottom layer containing only cations selected from the group consisting of alkaline
0.64% agar in RPMI complete media in 24-well tissue 20
cations, alkaline earth cations, the ammonium cation,
culture plates. Complete media plus dilution series of com- aliphatic substituted ammonium cations and aromatic
pounds were added to wells and incubated at 37° C. in a 5%
CO 2 incubator for 10-14 days with repeated feedings of
fresh media containing compound at 3-4 day intervals. 4. A pharmaceutically acceptable salt of the compound
Colony formation was monitored and total cell mass, aver- 25 N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-( 4-(2-(N-
age colony size and number of colonies were quantitated methylcarbamoyl)-4-pyridyloxy)phenyl)urea.
using image capture technology and image analysis software 5. A pharmaceutically acceptable salt of a compound
(Image Pro Plus, media Cybernetics). which is:
In Vivo Assay
30 N-(2-methoxy-5-(trifluoromethyl) phenyl)-N' -(4(2-(N-
An in vivo assay of the inhibitory effect of the compounds
on tumors (e.g., solid cancers) mediated by rafkinase can be methylcarbamoyl)-4-pyridyloxy) phenyl) urea of the
performed as follows: formula:
CDI nu/nu mice (6-8 weeks old) are injected subcutane-
ously into the flank at lxl0 6 cells with human colon
35
adenocarcinoma cell line. The mice are dosed i.p., i.v. or p.o.
at 10, 30, 100, or 300 mg/Kg beginning on approximately
day 10, when tumor size is between 50-100 mg. Animals are
dosed for 14 consecutive days once a day; tumor size was
monitored with calipers twice a week.
40
The inhibitory effect of the compounds on raf kinase and
therefore on tumors (e.g., solid cancers) mediated by raf
kinase can further be demonstrated in vivo according to the
technique of Mania et al. (Nat. Med. 1996, 2, 668-75). N-( 4-chloro-3-(trifluoromethyl) phenyl)-N' -( 4(2-(N-
The preceding examples can be repeated with similar carbamoyl)-4-pyridyloxy) phenyl) urea of the formula:
45
success by substituting the generically or specifically
described reactants and/or operating conditions of this ~ 0
invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can c,+ o ~O~NH,
and, without departing from the spirit and scope thereof, can
50
UN~N~ ~h
make various changes and modifications of the invention to I I
adapt it to various usages and conditions. H H
What is claimed is:

1. A pharmaceutically acceptable salt of a compound 55
selected from the group consisting of: N-( 4-chloro-3-(trifluoromethyl) phenyl)-N' -( 4(2-(N-
N-(5-tert-butyl-2-methoxy phenyl)-N'-( 4-( 4-methoxy-3-(N- methylcarbamoyl)-4-pyridyloxy) phenyl) urea of the
methy lcarbamoy l)phenoxy )pheny !)urea,
N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-( 4-(2-(N-
0
formula:
ci'Q::D 0d
methylcarbamoyl)-4-pyridyloxy)phenyl)urea, 60
N -( 4-chloro-3-(trifluoromethyl)phenyl)-N'-( 4-(2- 3
carbamoy 1-4-pyridyloxy )phenyl )urea, 0 NH_,..CH
N-( 4-chloro-3-(trifluoromethyl)phenyl)-N'-( 4-(2-(N- I # N
)l
N ~
I I .,,::N
;or
methylcarbamoyl)-4-pyridyloxy)phenyl)urea;
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(3- 65 I I
H H
(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea and
their pharmaceutically acceptable salts.
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N-(2-methoxy-4-chloro-5-(trifloromethyl) phenyl)-N' -(3 N-(2-methoxy-4-chloro-5-(trifloromethyl) phenyl)-N' -(3
(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea of (2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea of
the formula: the formula:
10
15
8. A pharmaceutically acceptable salt of a compound
which is:
N-( 4-chloro-3-(trifluoromethyl) phenyl)-N' -( 4(2-(N-
6. A pharmaceutically acceptable salt of the compound
carbamoyl-4-pyridyloxy) phenyl) urea of the formula:
20
N-( 4-chloro-3-( triflouromethy l)pheny 1)-N'-(2carbamoy 1-4- ~ 0
pyridy loxy )pheny l)urea. -pyridyloxy)phenyl)urea.
7. A pharmaceutically acceptable salt which is the tosylate c,+ o ~O~NH,
salt of
25 UNANA/ ~k
N-(2-methoxy-5-(trifluoromethyl) phenyl)-N' -(4(2-(N- I I
H H
methylcarbamoyl)-4-pyridyloxy) phenyl) urea of the
formula:
N-( 4-chloro-3-(trifluoromethyl) phenyl)-N' -( 4(2-(N-
30 methylcarbamoyl)-4-pyridyloxy) phenyl) urea of the
formula:
40
N-( 4-chloro-3-(trifluoromethyl) phenyl)-N' -( 4(2-(N- N-(2-methoxy-4-chloro-5-(trifloromethyl) phenyl)-N' -(3
carbamoyl-4-pyridyloxy) phenyl) urea of the formula: (2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea of
the formula:
45
50
55
N-( 4-chloro-3-(trifluoromethyl) phenyl)-N' -( 4(2-(N- 9. A pharmaceutically acceptable salt of claim 8 selected
methylcarbamoyl)-4-pyridyloxy) phenyl) urea of the from the group consisting of
formula: a) basic salts of organic acids and inorganic acids selected
from the group consisting of hydrochloric acid, hydro-
60 bromic acid, sulphuric acid, phosphoric acid, methane-
sulphonic acid, trifluorosulphonic acid, benzene-
sulfonic acid, p-toluene sulphonic acid (tosylate salt),
1-napthalene sulfonic acid, 2-napthalene sulfonic acid,
acetic acid, trifluoroacetic acid, malic acid, tartaric
65 acid, citric acid, lactic acid, oxalic acid, succinic acid,
fumaric acid, maleic acid, benzoic acid, salicylic acid,
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b) acid salts of organic and inorganic bases containing N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-( 4-(2-(N-
cations selected from the group consisting of alkaline methy lcarbamoy 1)-4-pyridyloxy )phenyl )urea,
cations, alkaline earth cations, the ammonium cation, N -( 4-chloro-3-(trifluoromethyl)phenyl)-N'-( 4-(2-
aliphatic substituted ammonium cations and aromatic carbamoy 1-4-pyridyloxy )pheny !)urea,
substituted ammonium cations. 5 N-( 4-chloro-3-(trifluoromethyl)phenyl)-N'-( 4-(2-(N-
10. A pharmaceutically acceptable salt which is the tosy-
methylcarbamoyl)-4-pyridyloxy)phenyl)urea;
late salt of
N-( 4-chloro-3-(trifluoromethyl) phenyl)-N' -( 4(2-(N- N -(2-methoxy-4-chloro-5-( trifluoromethy I)pheny I)-N'-(3-
carbamoyl-4-pyridyloxy) phenyl) urea of the formula: (2-(N-methylcarbamoyl )4-pyridy loxy )pheny l)urea.
13. A method for the treatment of a cancerous cell growth
10
CF3 0 as in claim 12 mediated by RAF kinase comprising admin-
istering a pharmaceutically acceptable salt of
c,+ 0 ~o~NH, N-(5-tert-butyl-2-methoxy phenyl)-N'-( 4-( 4-methoxy-3-(N-
methy lcarbamoy l)phenoxy )phenyl )urea.
UN)lNA/ ~t 15
14. A method for the treatment of a cancerous cell growth
as in claim 12 mediated by RAF kinase comprising admin-
I I
H H istering a pharmaceutically acceptable salt of
N-( 4-chloro-3-(trifluoromethyl) phenyl)-N' -( 4(2-(N- methylcarbamoyl)-4-pyridyloxy)phenyl)urea.
methylcarbamoyl)-4-pyridyloxy) phenyl) urea of the 20 15. A method for the treatment of a cancerous cell growth
formula: as in claim 12 mediated by RAF kinase comprising admin-
od
0 N (4-chloro-3-( trifluoromethyl )phenyl)- N'-( 4-(2-carbamoy 1-
0 3 4-pyridyloxy )pheny l)urea.
Clu: O NH_,,..CH 25 16. A method for the treatment of a cancerous cell growth
I
# N
)l N "'=::,,.
I I
h'N
;or
as in claim 12 mediated by RAF kinase comprising admin-
I I
H H N-( 4-chloro-3-(trifluoromethyl)phenyl)-N'-( 4-(2-(N-
30
N-(2-methoxy-4-chloro-5-(trifloromethyl) phenyl)-N' -(3 17. A method for the treatment of a cancerous cell growth
(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea of as in claim 12 mediated by RAF kinase comprising admin-
the formula: istering a pharmaceutically acceptable salt of
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)N'-(3-(2-
35
(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea.
18. A method as in claim 12 for the treatment of solid
cancers.
19. A method as in claim 12 for the treatment of
carcinomas, myleoid disorders or adenomas.
40 20. A method as in claim 13 for the treatment of
45 carcinomas, myleoid disorders or adenomas.
11. A pharmaceutically acceptable salt of claim 10
selected from the group consisting of
a) basic salts of organic acids and inorganic acids selected
from the group consisting of hydrochloric acid, hydro-
bromic acid, sulphuric acid, phosphoric acid, methane- carcinomas, myleoid disorders or adenomas.
sulphonic acid, trifluorosulphonic acid, benzene- 50 25. A method as in claim 12 for the treatment of carci-
sulfonic acid, p-toluene sulphonic acid (tosylate salt), noma of the lung, pancreas, thyroid, bladder or colon.
1-napthalene sulfonic acid, 2-napthalene sulfonic acid, 26. A method as in claim 13 for the treatment of carci-
acetic acid, trifluoroacetic acid, malic acid, tartaric noma of the lung, pancreas, thyroid, bladder or colon.
acid, citric acid, lactic acid, oxalic acid, succinic acid, 27. A method as in claim 14 for the treatment of carci-
fumaric acid, maleic acid, benzoic acid, salicylic acid, 55 noma of the lung, pancreas, thyroid, bladder or colon.
phenylacetic acid, and mandelic acid; and 28. A method as in claim 15 for the treatment of carci-
b) acid salts of organic and inorganic bases containing noma of the lung, pancreas, thyroid, bladder or colon.
cations selected from the group consisting of alkaline 29. A method as in claim 16 for the treatment of carci-
cations, alkaline earth cations, the ammonium cation, noma of the lung, pancreas, thyroid, bladder or colon.
aliphatic substituted ammonium cations and aromatic 60 30. A method as in claim 17 for the treatment of carci-
substituted ammonium cations. noma of the lung, pancreas, thyroid, bladder or colon.
12. A method for the treatment of a cancerous cell growth 31. A method as in claim 12 for the treatment of myeloid
mediated by RAF kinase comprising administering a phar- leukemia or villous colon adenomas.
maceutically acceptable salt of a compound selected from 32. A method as in claim 13 for the treatment of myeloid
the group consisting of: 65 leukemia or villous colon adenomas.
N-(5-tert-butyl-2-methoxy phenyl)-N'-( 4-( 4-methoxy-3-(N- 33. A method as in claim 14 for the treatment of myeloid
methy lcarbamoy l)phenoxy )pheny !)urea, leukemia or villous colon adenomas.
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34. A method as in claim 15 for the treatment of myeloid 40. A method as in claim 15 where the pharmaceutical
leukemia or villous colon adenomas. acceptable salt administered is the tosylate salt of
35. A method as in claim 16 for the treatment of myeloid N-( 4-chloro-3-(trifluromethyl)phenyl)-N'-( 4-(2-(N-
leukemia or villous colon adenomas. methylcarbamoyl)-4-pyridyloxy)phenyl)urea.
36. A method as in claim 17 for the treatment of myeloid 5 41. A method as in claim 16 where the pharmaceutical
leukemia or villous colon adenomas. acceptable salt administered is the tosylate salt of
37. A method as in claim 12 wherein the pharmaceutically N-( 4-chloro-3-(trifluoromethyl)phenyl)-N'-( 4-(2-(N-
acceptable salt administered is selected from the group of methylcarbamoyl)-4-pyridyloxy)phenyl)urea.
42. A method as in claim 17 where the pharmaceutical
salts consisting of
10 acceptable salt administered is the tosylate salt of
a) basic salts of organic acids and inorganic acids selected N -(2-methoxy-4-chloro-5-( trifluoromethy I)pheny I)-N'-(3-
from the group consisting of hydrochloric acid, hydro- (2-(N-methylcarbamoyl )-4-pyridy loxy )pheny !)urea.
bromic acid, sulphuric acid, phosphoric acid, methane- 43. A pharmaceutical acceptable salt as in claim 2 which
sulphonic acid, trifluorosulphonic acid, benzene- is the tosylate salt of
sulfonic acid, p-toluene sulphonic acid (tosylate salt), 15 N-(5-tert-butyl-2-methoxy phenyl)-N'-( 4-( 4-methoxy-3-(N-
1-napthalene sulfonic acid, 2-napthalene sulfonic acid, methy lcarbamoy l)phenoxy )phenyl )urea.
acetic acid, trifluoroacetic acid, malic acid, tartaric 44. A pharmaceutical acceptable salt as in claim 4 which
acid, citric acid, lactic acid, oxalic acid, succinic acid, is the tosylate salt of
fumaric acid, maleic acid, benzoic acid, salicylic acid, N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-( 4-(2-(N-
phenylacetic acid, and mandelic acid; and 20 methylcarbamoyl)-4-pyridyloxy)phenyl)urea.
b) acid salts of organic and inorganic bases containing 45. A pharmaceutical acceptable salt as in claim 6 which
is the tosylate salt of
cations selected from the group consisting of alkaline
N -( 4-chloro-3-(trifluoromethyl)phenyl)-N'-( 4-(2-
cations, alkaline earth cations, the ammonium cation,
carbamoy 1-4-pyridyloxy )pheny !)urea.
aliphatic substituted ammonium cations and aromatic
25 46. A pharmaceutical acceptable salt as in claim 8 which
substituted ammonium cations. is the tosylate salt of
38. A method as in claim 13 where the pharmaceutical N-( 4-chloro-3-(trifluoromethyl)phenyl)-N'-( 4-(2-(N-
acceptable salt administered is the tosylate salt of methylcarbamoyl)-4-pyridyloxy)phenyl)urea.
N-(5-tert-butyl-2-methoxy phenyl)-N'-( 4-( 4-methoxy-3-(N- 47. A pharmaceutical acceptable salt as in claim 10 which
methy lcarbamoy l)phenoxy )pheny !)urea. 30 is the tosylate salt of
39. A method as in claim 14 where the pharmaceutical N -(2-methoxy-4-chloro-5-( trifluoromethy I)pheny I)-N'-(3-
acceptable salt administered is the tosylate salt of (2-(N-methylcarbamoyl )-4-pyridy loxy )pheny !)urea.
methy lcarbarmoyl )-4-pyridy loxy )pheny !)urea. * * * * *
IITRUE COPY!I
PATENT NO. : 7,235,576 Bl Page 1 of 2

DATED : June 26, 2007
INVENTOR(S) : Riedl et al.
It is certified that error appears in the above-identified patent and that said Letters Patent is
hereby corrected as shown below:
In column 3, line 31, reads "(CH 2)m-and", should read -- (CH2)m-,and--.
In column 4, line 31, reads "methanesulphonic," should read -- methanesulfonic --.
In column 9, line 27, reads "ie.," should read -- i.e., --.
In column 9, line 39, reads "enclosure", should read -- disclosure--.
In column 17, line 1, reads "under stream", should read -- under a stream--.
In column 18, lines 39 and 40, reads "Aromatric", should read -- Aromatic--.
In column 20, line 29, reads "Methylcarbamoly)", should read -- Methylcarbamoyl --.
In column 21, line 27, reads "(N-methylcarbamoly)", should read

-- (N-Methylcarbamoyl) --.

In column 23, line 62, reads "then mixture", should read -- then the mixture --.
In column 30, line 4, reads "( 4-(4-Methylsulfonylphenyoxy)", should read

-- (4-(4-Methylsulfonylphenoxy --.
In column 35, line 58, reads "heat", should read -- heated--.
In column 36, line 44, reads "m-(Aroylamino)phenyl", should read

-- m-(Arylamino)phenyl --.
IITRUE COPY!I

In column 42, line 29, reads "(triflouromethyl)", should read -- trifuoromethyl --.
Twenty-first Day of August, 2007
JONW.DUDAS
Director of the United States Patent and Trademark Office
IITRUE COPY!I

In column 3, line 31, reads "(CH 2)m-and", should read -- (CH2)m-,and--.
In column 4, line 31, reads "methanesulphonic," should read -- methanesulfonic --.
In column 9, line 27, reads "ie.," should read -- i.e., --.
In column 9, line 39, reads "enclosure", should read -- disclosure--.
In column 17, line 1, reads "under stream", should read -- under a stream--.
In column 18, lines 39 and 40, reads "Aromatric", should read -- Aromatic--.
In column 20, line 29, reads "Methylcarbamoly)", should read -- Methylcarbamoyl --.


In column 23, line 62, reads "then mixture", should read -- then the mixture --.
In column 30, line 4, reads "( 4-(4-Methylsulfonylphenyoxy)", should read

-- (4-(4-Methylsulfonylphenoxy --.
In column 35, line 58, reads "heat", should read -- heated--.
In column 36, line 44, reads "m-(Aroylamino)phenyl", should read

-- m-(Arylamino)phenyl --.
In column 42, line 29, reads "(triflouromethyl)", should read -- trifuoromethyl --.
IITRUE COPY!I

In columns 92-98, replace claims 2-4 7 with the claims 2-17 as follows:
2. A pharmaceutically acceptable salt of claim 1, which is

a) a basic salt of an organic acid or an inorganic acid which is hydrochloric acid,
salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, trifluoroacetic
acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric
acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, or mandelic acid; or
b) an acid salt of an organic or inorganic base containing an alkali metal cation,
an alkaline earth metal cation, an ammonium cation, an aliphatic substituted ammonium
cation or an aromatic substituted ammonium cation.
3. A pharmaceutically acceptable salt of claim 1 which is a basic salt of an

organic acid or an inorganic acid which is hydrochloric acid, hydrobromic acid, sulfuric
acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid,
benzenesulfonic acid, p-toluene sulfonic acid (tosylate salt), 1-napthalene sulfonic acid,
2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid,
citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic
IITRUE COPY!I

4. A pharmaceutically acceptable salt which is the tosylate salt of

N-( 5-tert-butyl-2-methoxy phenyl)-N'-( 4-( 4-methoxy-3-(N-methylcarbamoyl)
phenoxy) phenyl) urea,
N-(2-methoxy-5-(trifluoromethyl) phenyl)-N'-( 4-(2-(N-methylcarbamoyl)-4-
N-( 4-chloro-3-(trifluoromethyl) phenyl)-N'-( 4-(2-carbamoyl-4-pyridyloxy)
phenyl) urea,
N-( 4-chloro-3-(trifluoromethyl) phenyl)-N'-( 4-(2-(N-methylcarbamoyl)-4-
pyridyloxy) phenyl) urea; or
N-(2-methoxy-4-chloro-5-( trifluoromethyl) phenyl)-N'-(3-(2-(N-
methylcarbamoyl)-4-pyridyloxy) phenyl) urea.

pyridyloxy) phenyl) urea of the formula:
IITRUE COPY!I



3
Cl'QCF~ 0 oOtrO
7 ~ NH/ CH3
I,&' N~N
II ' I
,....._
I N
,-,:;
I I
H H ; or
N-(2-methoxy-4-chloro-5-(trifluoromethyl) phenyl)-N'-(3-(2-(N-
methylcarbamoyl)-4-pyridyloxy) phenyl) urea of the formula:
IITRUE COPY!I


citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid,
salicylic acid, phenylacetic acid, or mandelic acid.

od°
O NH/ CH
3
0 '::::
II I N
N/'-...N /4
l I
OMe H H

IITRUE COPY!I


; or
IITRUE COPY!I



c1UCF3
I~
~ 0
II
N.,A.__N
,0~ I o~o
I
~
~
N
NH/
CH 3
I I
H H
; or
IITRUE COPY!I




0
Cl
U 0
II
~dNH/
--- I
N.,-A-._N ,.......
I
H H
I
O
I
h
N
CH3
; or
IITRUE COPY!I

Cl
OMe

CF, o ,0odNH,......cH3
II
N_...).(,..._N
''
' I I /4
N
I I
OMe H H

, or
IITRUE COPY!I




IITRUE COPY!I


, or


or
IITRUE COPY!I


Clu~·
I ,O'
O
II
~od
"-
N...,A__N ''
I I /4
N
0
NH_,...,.CH3
I I
H H


or
IITRUE COPY!I


17. A pharmaceutical composition comprising a pharmaceutically acceptable salt

of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 and pharmaceutically
acceptable carrier.
This certificate supersedes the Certificate of Correction issued August 21, 2007.
Twenty-fourth Day of February, 2009
JOHN DOLL
Acting Director of the United States Patent and Trademark Office
IITRUE COPY!I
~ lndustria y Comcrcio ;'ffi'
~ ~ SUPERINTENDENCIA , GOBIERNO DE
COLOMBIA
H >
00001451 - National Patent - DIFENIL UREAS SUBSTITUIDAS CON W-
CARBOXIARILO Y SUS SALES FARMACEUTICAMENTE ACEPTABLES COMO
INHIBIDORES DE RAF QUINASA
Application Data
Submission
13 Jan 2000
Date
Patent
00001451
Number
Grant
28604 29 Jun 2006
Number Grant Date
Status Public Domain Expiry Date 13 Jan 2020
Journal Published
517 27 Jun 2002
Number Date
Contact
Agent
First
First
Id Last
Last Name
Name Address(es)
Name
Name
RODRÍGUEZ D Dirección Física : Carrera 11 Nª 93-43 of 404

41654882 DILIA
ÁLEMAN BOGOTÁ D.C. (CO)
Applicant(s)
First
Id
Id Last
Last Name
Name Address(es)
Name
Name
BAYER Dirección Física : SIN ESTABLECER PITTSBURG

32367
CORPORATION. PENNSYLVANIA (US)
Owner
First
First
Id
Id Last
Last Name
Name Address(es)
Name
Name
BAYER HEALTH Dirección Física : 100 Bayer Boulevard, WHIPPANY

160974
CARE LLC NEW JERSEY 07981 (US)
Application
Contact Post Address
Id Name Address Town Country
Code Type
Close
Close
11TRUE COPYII
41654882 DILIA RODRÍGUEZ Carrera 11 Nª 93- BOGOTÁ CO Physical
DÁLEMAN 43 of 404
Patent Information
Filing Date 13 Jan 2000
Patent type National Patent
Patent Date 13 Jan 2000
Technology Sub
Group Chemistry Technology Pharmaceuticals
Group
PPH D
Inventor(s)
First Last
Lut
Id Address(es)
Name Name
Nim•
Dirección Física : 98 FARMVIEW ROAD, BETHANY
174756 JACQUES DUMAS
NEW HAVEN CONNECTICUT 06524 (US)
186154 UDAY KHIRE
TIMOTHY Dirección Física : 5-7-203, Chitose-cho

227001 LOWINGER
B. NISHINOMIYA-SHI HYOGO 662-0046 (JP)
MARY-
191826 MONAHAN
KATHERI
SIBLEY Dirección Física : 1187 Mount Carmel Avenue NORTH

224512 N.
ROBERT HAVEN CONNECTICUT 06473 (US)
192382 REINA NATERO
196171 JOEL RENICK
Dirección Física : Claudiusweg 7, 42115 Wuppertal

196681 BERND RIEDL
WUPPERTAL RENANIA DEL NORTE-WESTFALIA (DE)
WILLIAM Dirección Física : 210 Saddle Hill Drive Guilford

1029736 SCOTT
JOHNSTON GUILFORD CONNECTICUT 06437 (US)
Dirección Física : 206, Bayberry Drive CHESTER

225658 ROGER A SMITH
SPRINGS PENNSYLVANIA PA 119425 (US)
GO 1 2 Items per page : 10
Notification
of
Entitlement
Title of
Invention DIFENIL UREAS SUBSTITUIDAS CON W-CARBOXIARILO Y SUS SALES FARMACEUTICAMENTE
ACEPTABLES COMO INHIBIDORES DE RAF QUINASA
Licensee
Contract
Number
Licensee
Contract from to
Period
Close
Priority
Priority
Country Prlor!IJ-
Priority Date Priority Numw
Pr!O~ Number
ESTADOS UNIDOS DE AMÉRICA 13 Jan 1999 60/115.887
ESTADOS UNIDOS DE AMÉRICA 25 Feb 1999 09/257.266
ESTADOS UNIDOS DE AMÉRICA 22 Oct 1999 09/425.228
Documents
Patent
Specification
Abstract 1.- Esta invención se relaciona con el uso de un grupo de arilo ureas en el tratamiento de
enfermedades medidas por raf, y composiciones farmacéuticas para el uso en tales
terapias de la fórmulaA-D-B en dondeD es -NH-C(O)-NHA es una unidad estructural
sustituída de la fórmula: -L-(M-L1)q,yB es una unidad estructural heteroarilo arilo tricíclico
sustituída ó no sustituída con al menos una estructura cíclica de 6 miembros enlazada
directamente a D que contiene 0-4 miembros del grupo que consiste en nitrógeno, oxígeno
y azufre.L es una estructura cíclica de 5-6 miembros enlazada directamente a D,L1
comprende una unidad estructural cíclica sustituída que tiene al menos 5 miembros.M es
un grupo enlazante que tiene al menos un átomo y q es un entero de 1-3.
Claims
Number of Recuerde usted que:
Claims
-el número de reivindicaciones diligenciado deberá estar coherente con el contenido del
documento anexo
-a partir de la undécima reivindicación, deberá presentar pago por cada una de ellas para
que éstas sean tenidas en cuenta durante el estudio de la solicitud_EN
10
Number of
0
Pages
Declarations DECLARACIÓN SOBRE USO DE RECURSOS GENÉTICOS O BIOLÓGICOS_EN
Declaro que el objeto de la presente solicitud de patente fue obtenido a partir de recursos
genéticos o biológicos de los que cualquiera de los países miembros de la Comunidad
Andina es país de origen._EN
0 Yes • No
Nota: En caso afirmativo deberá anexar copia del contrato de acceso de recursos genéticos
o productos derivados, o certificado o número de registro, expedido por la Autoridad
competente._EN
DECLARACION SOBRE USO DE CONOCIMIENTOS TRADICIONALES_EN

Declaro que el objeto de la presente solicitud de patente fue obtenido a partir de
conocimientos tradicionales de comunidades indígenas, afroamericanas o locales de países
miembros de la Comunidad Andina._EN
0 Yes • No
Nota: En caso afirmativo deberá anexar la licencia o autorización de uso de conocimiento

tradicional, o certificado, o número de registro expedido por la Autoridad competente._EN
DECLARACIÓN DE DOCUMENTOS DIVULGADOS DURANTE EL AÑO DE GRACIA_EN

Declaro que la invención fue divulgada por parte del inventor o causahabiente durante el
año anterior a la fecha de presentación y/o prioridad de la presente solicitud de acuerdo
con el Art. 17 de la Decisión 486._EN
Close
0 Yes • No
Nota: En caso afirmativo deberá anexar el documento que divulga el objeto de la invención
durante el año de gracia._EN
15 Application (s)
Application Application
,.,,,llc..uoft Application Submission Application
Link Type
Unk~ Owner
NumlHr
Number Type
1)pe TIiie
Title Date Status
Solicitado en
GR - PT Case
NC2019/0000888 Patente 29 Jan 2019 Validated N/A
Maintenance Maintenance
00001451
Solicitado en
GR - PT Case
00001451
Solicitado en
GR - PT Case
00001451
Solicitado en
00001451 GR - PT Case
Patente 30 Jan 2015 Validated N/A
012027 Maintenance Maintenance
00001451
Solicitado en
GR - PT Case
00001451 011026 Patente 31 Jan 2014 Validated N/A
00001451
Solicitado en
00001451 GR - PT Case
Patente 30 Jan 2013 Validated N/A
00001451
Solicitado en
00001451 GR - PT Case
Patente 26 Dec 2012 Refused N/A
00001451
Solicitado en
00001451 GR - PT Case
Patente 30 Mar 2012 Validated N/A
00001451
Solicitado en
00001451 GR - PT Case
Patente 26 Dec 2011 Validated N/A
00001451
Solicitado en
00001451 GR - PT Case
Patente 23 Dec 2010 Validated N/A
00001451
00
1 2 Items per page : 10 ...
18 History (ies)
History
H1ltlMy Creation
Qliidb1
Description Journal
Joumal Published
PubU1htd
Type
1)pe date
15 Jan
Caducidad. La solicitud Patent Caducó. 2020 15 Jan 2020
12:13:20 AM Close
Anualidad La Patente se renovó hasta 29 Jan 30 Jan 2019
de la 2019
patente. 03:20:22
PM
Inscripción
29 Jan
automática
La solicitud de anualidad ha sido radicada y 2019
de 30 Jan 2019
automáticamente inscrita. 03:20:21
anualidad
PM
de Patente
Edición 11 Sep 2018

Edición
Edlol6ft
10:36:50
The Inventor has been corrected to 1029736, WILLIAM
AM
J. SCOTT, 210 Saddle Hill Drive Guilford, Connecticut
06437, Estados Unidos de América, GUILFORD,
CONNECTICUT, US; 174756, JACQUES DUMAS, 98
FARMVIEW ROAD, BETHANY, NEW HAVEN,
CONNECTICUT 06524, US; 186154, UDAY KHIRE; 191826,
MARY-KATHERI MONAHAN; 192382, REINA NATERO;
196171, JOEL RENICK; 196681, BERND RIEDL,
Claudiusweg 7, 42115 Wuppertal, WUPPERTAL,
RENANIA DEL NORTE-WESTFALIA, DE; 224512, SIBLEY
ROBERT N.; 225658, ROGER A SMITH; 227001, TIMOTHY
B. LOWINGER; 228150, JILL E WOOD, 3007 RIDGE
ROAD CT 06473, NORTH HAVEN, CONNECTICUT, US.
(11)
(Número de
00001451
Patente)
DIFENIL UREAS SUBSTITUIDAS CON

(54)
W-CARBOXIARILO Y SUS SALES
(Título)
FARMACEUTICAMENTE ACEPTABLES
COMO INHIBIDORES DE RAF QUINASA
(22)
(Fecha de
13 Jan 2000
Presentación)
(71) BAYER CORPORATION., SIN

(Solicitante) ESTABLECER, PITTSBURG,
PENNSYLVANIA, US
(74) DILIA RODRIGUEZ DÁLEMAN, Carrera

(Contacto)
11 Nª 93-43 of 404, BOGOTÁ, D.C., CO
(72)
(Inventor(es))
Close
WILLIAM J. SCOTT, 210 Saddle Hill
Drive Guilford, Connecticut 06437,
Estados Unidos de América,
GUILFORD, CONNECTICUT, US
JACQUES DUMAS, 98 FARMVIEW
ROAD, BETHANY, NEW HAVEN,
CONNECTICUT 06524, US
UDAY KHIRE
MARY-KATHERI MONAHAN
REINA NATERO
JOEL RENICK
BERND RIEDL, Claudiusweg 7, 42115
Wuppertal, WUPPERTAL, RENANIA
DEL NORTE-WESTFALIA, DE
SIBLEY ROBERT N.
ROGER A SMITH
TIMOTHY B. LOWINGER
JILL E WOOD, 3007 RIDGE ROAD CT
06473, NORTH HAVEN, CONNECTICUT,
US
(51)
(Clasificación A61K 31/13
Internacional
A61K 31/19
de Patentes)
ESTADOS UNIDOS DE AMÉRICA 13

Jan 1999 60/115.887
(30)
(Prioridad)
Feb 1999 09/257.266
Oct 1999 09/425.228
Edición 04 Jul 2018

Edición
12:36:40
The Inventor has been corrected to 174756, JACQUES
PM
DUMAS, 98 FARMVIEW ROAD, BETHANY, CT 06524,
BETHANY, NOT DEFINED, US; 186154, UDAY KHIRE;
191826, MARY-KATHERI MONAHAN; 192382, REINA
NATERO; 196171, JOEL RENICK; 196681, BERND RIED,
RENANIA DEL NORTE-WESTFALIA, DE; 224512, SIBLEY
ROBERT N.; 225429, WILLIAM J SCOTT; 225658,
ROGER A SMITH; 227001, TIMOTHY B. LOWINGER;
228150, JILL E WOOD, 3007 RIDGE ROAD CT 06473,
NORTH HAVEN, CONNECTICUT, US.
(11)
(Número de
00001451
Patente)

(54)
(Título)
Close
(22) 13 Jan 2000
(Fecha de
Presentación)

PENNSYLVANIA, US

(Contacto)
11 Nª 93-43 of 404, BOGOTÁ, D.C., CO

ROAD, BETHANY, CT 06524, BETHANY,
NOT DEFINED, US
UDAY KHIRE
REINA NATERO
JOEL RENICK
(72) BERND RIED, Claudiusweg 7, 42115
(Inventor(es)) Wuppertal, WUPPERTAL, RENANIA
DEL NORTE-WESTFALIA, DE
SIBLEY ROBERT N.
WILLIAM J SCOTT
ROGER A SMITH
TIMOTHY B. LOWINGER
US
(51)
Internacional
A61K 31/19
de Patentes)

Jan 1999 60/115.887
(30)
(Prioridad)
Feb 1999 09/257.266
Oct 1999 09/425.228
29 Jan
Anualidad
2018
de la La Patente se renovó hasta 13 ene 2019 30 Jan 2018
10:59:30
patente.
AM
Inscripción
29 Jan
automática
La solicitud de anualidad ha sido radicada y 2018
de 30 Jan 2018
automáticamente inscrita. 10:59:30
anualidad
AM
de Patente
Edición 05 Jun
Edición
Edlcl6n 2017
The agent has been corrected to 41654882, DILIA
12:13:22 PM
RODRIGUEZ DÁLEMAN, Carrera 11 Nª 93-43 of 404,
BOGOTÁ, D.C., CO. The case contact has been
Close
corrected to 41654882, DILIA RODRIGUEZ DÁLEMAN,
Carrera 11 Nª 93-43 of 404, BOGOTÁ, D.C., CO.
(11)
(Número de
00001451
Patente)

(54)
(Título)
(22)
(Fecha de
13 Jan 2000
Presentación)

PENNSYLVANIA, US

(Contacto)
11 Nª 93-43 of 404, BOGOTÁ, D.C., CO

ROAD, BETHANY, CT 06524, BETHANY,
NOT DEFINED, US
UDAY KHIRE
REINA NATERO
JOEL RENICK
(72) BERND RIEDL, VON-DER-GOLZ
(Inventor(es)) STRASSE 7, 42329, WUPPERTAL, NOT
DEFINED, DE
SIBLEY ROBERT N.
WILLIAM J SCOTT
ROGER A SMITH
TIMOTHY B. LOWINGER
US
(51)
Internacional
A61K 31/19
de Patentes)

Jan 1999 60/115.887
(30)
(Prioridad)
Feb 1999 09/257.266
Oct 1999 09/425.228
Anualidad PATENTES 30 Jan 16 Feb 2015

de la TASA DE MANTENIMIENTO 2015 Close
patente. Expediente Nro : 00001451 04:33:16
Fecha Solicitud: 2015-01-30 16:33:16 PM
PATENTES DE INVENCION
Certificado : 28604
Vigencia : 2020-01-13
Solicitante : JERONIMO CASTILLO BONILLA
De : BOGOTA D.C. CUNDINAMARCA COLOMBIA
Direccion : CALLE 93 A NO. 14-17 OFICINA 311
Desde : 2016-01-13 Hasta : 2017-01-13
Estado Actual : APLICADA
Fecha Aplicación: 2015-02-16 09:18:53
PATENTES
TASA DE MANTENIMIENTO
Expediente Nro : 00001451
Fecha Solicitud: 2014-01-31 16:58:47
Anualidad Certificado : 28604 31 Jan 2014
de la Vigencia : 2020-01-13 04:58:47 06 Feb 2014
patente. Solicitante : JERONIMO CASTILLO BONILLA PM
Direccion : info@pcastillopineda.com
Desde : 2015-01-13 Hasta : 2016-01-13
PATENTES
Fecha Solicitud: 2013-01-30 16:30:51
30 Jan
Anualidad Certificado : 28604
2013
de la Vigencia : 2020-01-13 01 Feb 2013
04:30:51
patente. Solicitante : JERONIMO CASTILLO BONILLA
PM
Direccion : INFO@PCASTILLOPINEDA.COM
Desde : 2014-01-13 Hasta : 2015-01-13
PATENTES
Fecha Solicitud: 2012-03-30 18:05:40
30 Mar
2012
de la Vigencia : 2020-01-13 09 Apr 2012
06:05:40
patente. Solicitante : JERONIMO CASTILLO BONILLA
PM
Direccion : CALLE 93 A NO. 14-17 OFICINA 311
Desde : 2013-01-13 Hasta : 2014-01-13
Anualidad PATENTES 26 Dec 27 Jan 2012

de la TASA DE MANTENIMIENTO 2011
patente. Expediente Nro : 00001451 02:08:57
Close
Fecha Solicitud: 2011-12-26 14:08:57 PM
Vigencia : 2020-01-13
Solicitante : MARGARITA CASTELLANOS ABONDANO
Direccion : CALLE 94 A 7 A 09
Desde : 2012-01-13 Hasta : 2013-01-13
PATENTES
Fecha Solicitud: 2010-12-23 14:26:21
23 Dec
2010
de la Vigencia : 2020-01-13 27 Jan 2012
02:26:21
patente. Solicitante : MARGARITA CASTELLANOS ABONDANO
PM
Direccion : Calle 94 A No 7A- 09
Desde : 2011-01-13 Hasta : 2012-01-13
PATENTES
Fecha Solicitud: 2009-12-22 14:19:22
22 Dec
2009
02:19:22
PM
Desde : 2010-01-13 Hasta : 2011-01-13
PATENTES
Fecha Solicitud: 2008-12-23 14:31:57
23 Dec
2008
02:31:57
PM
Desde : 2009-01-13 Hasta : 2010-01-13
Anualidad PATENTES 14 Jan 16 May 2008

de la TASA DE MANTENIMIENTO 2008
patente. Expediente Nro : 00001451 04:17:31 PM
Fecha Solicitud: 2008-01-14 16:17:31
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Vigencia : 2020-01-13
Solicitante : SANDRA PATRICIA CASTILLO TORRES
Direccion : CRA 4 No.72-35 PISO 5
Desde : 2008-01-13 Hasta : 2009-01-13
PATENTES
Fecha Solicitud: 2007-01-31 17:01:26
31 Jan
2007
de la Vigencia : 2020-01-13 16 May 2008
05:01:26
patente. Solicitante : DILIA MARIA RODRIGUEZ D ALEMAN
PM
Direccion : CARRERA 11 No.86-53 PISO 6
Desde : 2007-01-13 Hasta : 2008-01-13
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06005884 - PCT Patent - OMEGA-CARBOXIARIL-DIFENIL-UREA CON
FLUOR PARA EL TRATAMIENTO Y LA PREVENCION DE ENFERMEDADES Y
AFECCIONES
Application Data Click to expand/collapse
Submission
23 Jan 2006
Date
Patent
06005884
Number
Status Denied
Journal Published
577 29 Jun 2007
Number Date
National
Phase Entry 23 Feb 2006
Date
Contact
Agent
Id
Id First Name
First Name Last
Last Name
Name Address(es)
80421942 MAURICIO JARAMILLO CAMPUZANO Calle 67 No. 7-35 Of 1204 (CO)
Applicant(s)
First
First
Id
Id Last
Last Name
Name Address(es)
Name
Name
BAYER PHARMACEUTICALS SIN ESTABLECER

156253
CORPORATION (US)
Application
Contact Post Address
Id Name Address Town Country
Code Type
MAURICIO
Calle 67 No.
80421942 JARAMILLO BOGOTÁ CO Physical
7-35 Of 1204
CAMPUZANO
0 We are the applicants for the PCT international application
0 We are the assignees of the applicant for the PCT application

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Patent Information
PCT
International
PCT/US2004/023500
Application
number
PCT
International
WO2005/009961
Publication
number
Filing Date 23 Jan 2006
Patent type PCT Patent
Chapter Chapter 2
PCT
International
22 Jul 2004
Application
Date
PCT
Publication 03 Feb 2005
date
Examination
Eligibility 23 Feb 2006
Date
Technology Sub
Group Chemistry Technology Pharmaceuticals
Group
PPH 0
Inventor(s)
Id
Id First Name
FhtNIIM Last Name Address(es)
729038 STEPHEN BOYER MITTELSTRASSE 55 (DE)
174756 JACQUES DUMAS 98 FARMVIEW ROAD, BETHANY (US)
196681 BERND RIEDL Claudiusweg 7, 42115 Wuppertal (DE)
729039 SCOTT M. WILHELM 255 Midland Drive (US)
Notification
of
Entitlement
Title of
Invention OMEGA-CARBOXIARIL-DIFENIL-UREA CON FLUOR PARA EL TRATAMIENTO Y LA
PREVENCION DE ENFERMEDADES Y AFECCIONES
Chemical
4-{4-[3-(4-cloro-3-trifluorometilfeni)l-ureido]-3-fluorofenoxi}-piridin-2-metilamida
Formula
Indication Cáncer
Priority
Priority
Country Priority Date Priority Number
Prlotlt,ylluMbtl-
Prlollli,,-
ESTADOS UNIDOS DE AMÉRICA 23 Jul 2003 60/489102
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ESTADOS UNIDOS DE AMÉRICA 02 Feb 2004 60/540326
Documents
Patent
Specification 1 Document (s)
1-
--
Document
FASE NACIONAL INCLUIDO CAPITULO I -

PRESENTACION
Type Col'lllld1mloUl;f
Confidentiality
Specifications Public
Abstract
Claims
Number of Recuerde usted que:
Claims
-el número de reivindicaciones diligenciado deberá estar coherente con el contenido del
documento anexo
-a partir de la undécima reivindicación, deberá presentar pago por cada una de ellas para
que éstas sean tenidas en cuenta durante el estudio de la solicitud_EN
0
Number of
0
Pages
Declarations DECLARACIÓN SOBRE USO DE RECURSOS GENÉTICOS O BIOLÓGICOS_EN
recursos genéticos o biológicos de los que cualquiera de los países miembros de la
Comunidad Andina es país de origen._EN
0 Yes • No
Nota: En caso afirmativo deberá anexar copia del contrato de acceso de recursos
genéticos o productos derivados, o certificado o número de registro, expedido por la
Autoridad competente._EN
DECLARACION SOBRE USO DE CONOCIMIENTOS TRADICIONALES_EN

conocimientos tradicionales de comunidades indígenas, afroamericanas o locales de
países miembros de la Comunidad Andina._EN
0 Yes • No
Nota: En caso afirmativo deberá anexar la licencia o autorización de uso de conocimiento

tradicional, o certificado, o número de registro expedido por la Autoridad
competente._EN
DECLARACIÓN DE DOCUMENTOS DIVULGADOS DURANTE EL AÑO DE GRACIA_EN

Declaro que la invención fue divulgada por parte del inventor o causahabiente durante el
año anterior a la fecha de presentación y/o prioridad de la presente solicitud de acuerdo
con el Art. 17 de la Decisión 486._EN
0 Yes • No
Nota: En caso afirmativo deberá anexar el documento que divulga el objeto de la

invención durante el año de gracia._EN
1 History (ies)
History Creation
Cl 27:ri
Description Journal
Joumll Published
Publi hid
Type date
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Edición Eil:lol6n 04 Jul 2018
Edición
12:37:40
The Inventor has been corrected to 174756, JACQUES
PM
DUMAS, 98 FARMVIEW ROAD, BETHANY, CT 06524,
BETHANY, NOT DEFINED, US; 196681, BERND RIED,
RENANIA DEL NORTE-WESTFALIA, DE; 729038,
STEPHEN BOYER, MITTELSTRASSE 55-40721, HILDEN,
NOT DEFINED, DE; 729039, SCOTT WILHELM, 255
MIDLAND DRIVE, ORENGE CT 06477, ORANGE,
CONNECTICUT, US.
(11)
(Número de
06005884
Patente)
OMEGA-CARBOXIARIL-DIFENIL-UREA
(54)
CON FLUOR PARA EL TRATAMIENTO
(Título)
Y LA PREVENCION DE
ENFERMEDADES Y AFECCIONES
(22)
(Fecha de
23 Jan 2006
Presentación)
(71) BAYER PHARMACEUTICALS

(Solicitante) CORPORATION, SIN ESTABLECER,
NEW CASTLE, PENNSYLVANIA, US
(74) MAURICIO JARAMILLO CAMPUZANO,

(Contacto) Calle 67 No. 7-35 Of 1204, BOGOTÁ,
D.C., CO

ROAD, BETHANY, CT 06524,
BETHANY, NOT DEFINED, US
BERND RIED, Claudiusweg 7, 42115
(72) Wuppertal, WUPPERTAL, RENANIA
(Inventor(es)) DEL NORTE-WESTFALIA, DE
STEPHEN BOYER, MITTELSTRASSE
55-40721, HILDEN, NOT DEFINED, DE
SCOTT WILHELM, 255 MIDLAND
DRIVE, ORENGE CT 06477, ORANGE,
CONNECTICUT, US
(51) C07D 213/81

Internacional A61P 35/00
de Patentes) A61K 31/17
A61K 31/85
(87)
(Número de
Publicación WO2005/009961
Internacional)
(30) ESTADOS UNIDOS DE AMÉRICA 23 Close

(Prioridad) Jul 2003 60/489102
Feb 2004 60/540326
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Industriay Comercio
SUPERINTENDENCIA
REPUBLICA DE COLOMBIA
SUPERINTENDENCIA DE INDUSTRIA Y COMERCIO
RESOLUCION N° No~. Q8 28
Por la cual se niega una patente de if'Kie'flc16n
Rad. N° PCT/06-005884
EL SUPERINTENDENTE DE INDUSTRIA Y COMERCIO

en ejercicio de sus facultades legales, en especial de las que se confirieron en el
articulo 4, numeral 5 del decreto 2153 de 1992, y
CONSIDERANDO
PRIMERO: Que mediante escrito radicado en esta Superintendencia el 23 de

enero de 2006, bajo el numero 06 - 005884, entr6 a fase nacional la solicitud de
patente de invenci6n titulada: "OMEGA-CARBOXIARIL-DIFENIL-UREA
SUSTITUIDA CON FLUOR PARA EL TRATAMIENTO Y LA PREVENCION DE
ENFERMEDADES Y AFECCIONES", que corresponde a la solicitud internacional
PCT/US2004/023500 del 22 de julio de 2004.
SEGUNDO: Que efectuado el examen de forma en cuanto a las requisites que

debe llenar la solicitud y cumplidas las exigencias legales, se orden6 publicar el
extracto sin que se hubieran presentado oposiciones por parte de terceros.
TERCERO: Que realizado el examen de patentabilidad se encontr6 que la

invenci6n no cumple con las requisites establecidos. En consecuencia, con
fundamento en lo dispuesto en el articulo 45 de la Decisi6n 486 de la Comisi6n de
la Comunidad Andina, se requiri6 al peticionario para que se pronunciara sobre las
objeciones efectuadas a la solicitud.
CUARTO: Que el solicitante mediante escrito radicado el 11 de agosto de 2008,

atendi6 oportunamente al requerimiento formulado y present6 aclaraciones. Con
esta respuesta se present6 divisional, la cual no se ajusta a las prescripciones
establecidas en el artfculo 36 de la Decision 486, por cuanto, ademas de que no
es clara, ni concisa, no realiza una division real de la materia, tal como se sustenta
en el punto 2 de esta resoluci6n.
QUINTO: Que segun lo dispuesto en el artfculo 14 de la Decision 486 expedida

por la Comisi6n de la Comunidad Andina se otorgaran patentes " ... para las
invenciones, sean de producto o de procedimiento, en todos los campos de la
tecnologia, siempre que sean nuevas, tengan nivel inventive y sean susceptibles
de aplicacion industrial."
SEXTO: Que las reivindicaciones 1 a 54 contenidas en las folios 168 a 180, no

son claras ni concisas. Asi mismo, las reivindicaciones 1 a 11 y 49 a 52 no
cumplen con los requisitos de novedad y nivel inventive; y, las reivindicaciones 12
a 48, 53 y 54 se tratan de un metodo de tratamiento. Lo anterior, de acuerdo con
las siguientes consideraciones:
Sede Centro: Carrera 13 No. 27-00 Pisos 2. 5, 7 y 10

Sede CAN: Tr. 40A No. 38-50 Conmutador: 3820840
Fax: 382 26 95. Linea 9800-910 165
Web: www.sic.gov.co e-mail: info@sic.gov.co
Bogot~ D.C .• Colombia
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Por la cual se niega una patente de invenci6n
Rad. N° PCT/06-005884
1. Objeto de la invenci6n
El objeto de la solicitud se refiere a un compuesto metilamida del acido 4{4(3-(4-

cloro-3-trifluorometilfenil)-ureido]-3-fluorofenoxi}-piridin-2-carboxilico y el uso de
dichos compuestos o composiciones para el tratamiento de enfermedades y
afecciones mediadas par una serializaci6n anormal de VEGFR, PDGFR, raf, p38
y/o flt-3 quinasa, ya sea·solo o en combinaci6n con agentes anticancerosos.
Segun la descripci6n, la activaci6n de la via de transducci6n de seriales ras inicia

una cascada de eventos que tienen un profundo impacto sabre la proliferaci6n,
diferenciaci6n y transformaci6n celular. La raf quinasa, un efector posterior en la
via de ras, es considerada coma uno de las mediadores clave de estas senales
entre los receptores de la superficie celular y el nucleo de la celula.
Concretamente, las reivindicaciones 1 a 5, 49 a 52 corresponden a un compuesto

de la formula (I) o una sal, o una prodroga o un metabolite o un estereois6mero
aislado del mismo.
Las reivindicaciones 6 a 11 se refieren a una composici6n farmaceutica, que

comprende un compuesto de la reivindicaci6n 1.
Las reivindicaciones 12 a 48, 53 y 54 consisten en un metodo para regular la

transducci6n de senales de tirosina quinasa.
Por su parte, el problema planteado en esta solicitud es la necesidad de un

tratamiento contra las numerosas vias de serializaci6n clave utilizadas par los
tumores para inducir angiogenesis en el estroma del huesped.
La soluci6n propuesta par la presente solicitud, consiste en el compuesto

metilamida del acido 4{4-(3-(4-cloro-3-trifluorometilfenil)-ureido)-3-fluorofenoxi}-
piridin-2 carboxilico, y su uso para el tratamiento de enfermedades y afecciones
mediadas par una senalizaci6n anormal de VEGFR, PDGFR, raf, p38 y/o flt-3
quinasa, ya sea solo o en combinaci6n con agentes anticancerosos.
2. Sobre la solicitud divisional
Seriala el articulo 36 de la Decision 486 lo siguiente: "El solicitante podra, en

cualquier momenta del tramite, dividir su solicitud en dos o mas fraccionarias, pero
ninguna de estas podra implicar una ampliaci6n de la protecci6n que corresponda
a la divulgaci6n contenida en la solicitud inicial. La oficina nacional competente
podra, en cualquier momenta del tramite, requerir al solicitante que divida la
solicitud si ella no cumpliera con el requisite de unidad de invenci6n ... "
Al respecto, es precise indicar que " ... en caso de division, las reivindicaciones de
Sede Centro: Carrera 13 No. 27-00 Pisos 2, 5. 7 y 10
2 Fax: 382 26 95. Linea 9800-910 165
Web: www.sic.gov.co e-mail: info@sic.qov.co
Bogota O.C. - Colombia
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la solicitud original o madre deben ser claramente delimitadas a una sola invenci6n
y las reivindicaciones de la solicitud fraccionaria, de forma clara y precisa, deben
ser delimitadas a materia no reclamada en la solicitud original. Si son varias
fraccionarias, cada una debe ajustarse a lo anterior y estar claramente delimitadas
a una sola invenci6n, de ser asi cada solicitud.fraccionaria se tramitara de manera
independiente.
"De acuerdo a lo anterior, la solicitud original y las fraccionarias no podran

reivindicar la misma materia, de tal manera que sus objetos deben ser clara y
precisamente distinguibles." 1
En efecto, las divisionales presentadas por el solicitante no son aceptadas, debido

a que el capitulo reivindicatorio de la segunda divisional (anexo 11,como lo ha
denominado el solicitante) no especifica en forma clara y concisa el derivado que
se desea proteger. Se suma a lo anterior, que en ambas divisionales se esta
solicitando protecci6n para un mismo compuesto, que corresponde a: metilamida
del acido 4{4-[3-(4-cloro-3trifluorometilfen il)-ureido]-3-fl uorofenoxi]-pirid in-2-
carboxflico. •
Por lo tanto, no se trata de un fraccionamiento de la solicitud inicialmente

presentada, en los terminos antes mencionados, de tal manera que se continuara
el estudio de patentabilidad sobre el capftulo reivindicatorio contenido en los folios
168 a 180.
3. No cumple con el articulo 30 de la Decision 486
El articulo 30 de la Decisi6n 486 senala que: "Las reivindicaciones definiran la

materia que se desea proteger mediante la patente. Deben ser claras y concisas y
estar enteramente sustentadas por la descripci6n." (Subrayados fuera de texto
original)
Cabe ser'ialar, que la claridad de un capitulo reivindicatorio es indispensable para

definir el objeto susceptible de protecci6n, necesario para la busqueda de posibles
antecedentes que puedan afectar la solicitud. Asf mismo es necesaria, teniendo en
cuenta que allf se delimita el objeto de protecci6n.
Al respecto ha serialado el Tribunal Andino de Justicia lo siguiente:
" ... las reivindicaciones constituyen, juridicamente hablando, el elemento de mayor

importancia dentro de una solicitud de patente, pues en ellas, el exarr:iinador
tecnico de patentes encontrara los elementos necesarios para determinar lo que
se pretende patentar, el alcance de la invenci6n y su definici6n para efectos de
entrar al analisis comparativo respecto del estado de la tecnica. Esto es para
1
de lndus\riay Comercio.Agosto21 de 2008.
Conceptosobreunidadde invenci6n.Superin\endencia
Sede Centro: Carrera 13 No. 27-00 Pisos 2, 5, 7 y 10
3 Fax: 382 26 95. Linea 9800-910 165
Bogota D.C. - Colombia
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SUPERINTENDENCIA
REPUBLICA OE COLOMBIA
SUPERINTENDENCIA OE INDUSTRIA Y COMERCIO
-
RESOLUCION N° Ng3 98 2 8
Por la cual se niega una patente de invencion
Rad. N° PCT/06-005884
reivindicar lo que se considera nuevo y con nivel inventivo. 2
"( ... ) las reivindicaciones constituyen parte esencial de la respectiva solicitud,

debido a que delimitan el campo de la patente y especifican la regla tecnica que se
desea patentar, razones par las cuales estas deben ser suficientemente claras y
concisas. Su fundamento radica pues en la descripci6n respectiva, de forma tal
que el alcance de la reivindicaci6n corresponda y se justifique con el contenido de
aquella". (Proceso 106-IP-2002, publicado en la G.O.A.C. N° 892, de 31 de enero
de 2003, patente: BATERIA CON CONTROLADOR INCORPORADO'')3
En el presente caso, el capitulo reivindicatorio contiene terminos que no son

concisos y/o que estan mal traducidos. Tai es el caso del termino "prodroga", el
cual esta mal traducido, y no se indica cual es el profarmaco; "metabolite", sobre
este termino cabe decir que nose indica cual es el metabolite, que clase es etc.,
entre otros.
Por su parte, sobre las reivindicaciones 49 a 52, que se refieren a "un compuesto
que es un metabolito natural del compuesto de la clausula 3", cabe serialar que no
es claro el termino metabolito natural", puesto que no se especifica cual es
exactamente.
Por los motivos anteriores, el pliego reivindicatorio no cumple con los requisites de
claridad y concision, exigidos por el articulo 30 de la Decision 486.
4. No es patentable
Seriala el artfculo 20 en su literal d), que no seran patentables "los metodos

terapeuticos o quirurgicos para el tratamiento humano o animal, asf como los
metodos de diagn6stico aplicados a los seres humanos o a animales".
En el presente caso, las reivindicaciones 12 a 48, 53 y 54, que se refieren a un

metodo para regular la transducci6n de senales de tirosina quinasa, no son
patentables, porque se tratan de un metodo de tratamiento, no protegido via
patente de invenci6n.
5. Determinacion del estado de la tecnica
5.1. Fecha determinante para el analisis comparativo.
Las fechas para determinar el estado de la tecnica son el 23 de julio de 2003 y el 2

de febrero de 2004, que corresponden a las fechas de prioridad invocadas
respecto de las solicitudes US No. 60/489, 102 y US 60/540326 respectivamente.
2 Proceso 156 IP 2006

Sede CAN: Tr. 40A No. 38·50 Conmutador. 3820840
4 Fax: 382 26 95. Linea 9800·910 165
Web: www.sic.gov.co e•mail: info@sic.gov.co
Bogota D.C.• Colombia
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Las prioridades fueron tenidas en cuenta para el examen de patentabilidad, segun

obra en el folio 317 del expediente en estudio.
5.2. Documentos del estado de la tecnica
Consultadas las bases de datos y los archives con que se cuenta, se encontr6 el
siguiente documento anterior a la fecha de la presentaci6n de la solicitud en
estudio y relacionado con la materia reclamada:
No. Documento Titulo Fecha de

publicaci6n
01 WO 00/42012 O°carboxyaryl substituted 2000-07-20
diphenyl ureas as fRAF
kinase inhibitors
6.Novedad
El articulo 16 de la Decision 486 seriala lo siguiente: "El estado de la tecnica

comprendera todo lo que haya sido accesible al publico por una descripci6n
escrita u oral, utilizaci6n, comercializaci6n o cualquier otro medio antes de la fecha
de presentaci6n de la solicitud de patente o, en su caso, de la prioridad
reconocida.".
Por su parte, el Tribunal Andino de Justicia, respecto al requisite de novedad ha

senalado lo siguiente:
"El requisite de novedad exige que la invenci6n no este comprendida en el estado de

la tecnica, el cual comprende el conjunto de conocimientos tecnol6gicos accesibles al
publico antes de la fecha de presentaci6n de la solicitud de patente o, en su caso, de
la prioridad reconocida.
"Para la aplicaci6n de este concepto, es importante que el estudio del estado de la

tecnica este basado en las caracteristicas o condiciones innovadoras del invento.
"En este sentido, el ·estado de la tecnica esta constituido por todo lo que antes de la
fecha de presentaci6n de la solicitud se ha hecho accesible al publico por una
descripci6n escrita u oral, por una utilizaci6n o por cualquier otro medio, en cualquier
lugar del mundo'. Todo ello, desde luego, considerando las excepciones previstas en
el artlculo 3 de la Decisi6n 344.
"En otras palabras, para que una invenci6n sea novedosa se requiere que no este
comprendida en el estado de la tecnica, es decir, que antes de la fecha de
presentaci6n de la solicitud de patente o de la prioridad reconocida, ni la innovaci6n ni
los conocimientos tecnicos que de ella se desprenden hayan sido accesibles al
publico, entendiendo que la difusi6n de la informaci6n que se menciona debe ser
detallada y suficiente para que una persona versada en la materia pueda utilizar esa

5 Fax: 382 26 95. Linea 9800-910 165
Bogota o.c.- Colombia
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4
informaci6n a fin de explotar la invenci6n."
Para el caso particular, comparando elemento por elemento. el objeto de esta

solicitud con lo ensenado en las anterioridades, tenemos que la presente solicitud
se refiere a un compuesto de la formula I o una sal, o una prodroga o un
metabolito o un estereois6mero asilado del mismo: metilamida del acido 4{4-[3-(4-
cloro-3trifl uorometilfen i I)-u reido ]-3-fluorofenoxi}-pirid in-2 -carboxilico:
Por su parte, la anterioridad WO 00/42012 (ver folios 202 a 208), se relaciona con
compuestos omega-carboxiaril-difenil-ureas sustituidos, y que son inhibidores de
RAF quinasa: A-D-B
Al hacer los reemplazos respectivos, se encuentra el compuesto:
Asi las cosas, dicho compuesto es identico al compuesto de la presente solicitud.
De tal suerte, el elemento caracteristico del compuesto omega-carboxiaril-difenil-

urea reivindicado, ya era conocido en el documento WO 00/42012; por lo cual, el
compuesto metilamida del acido 4{4-(3-(4-cloro-3-trifluorometilfenil)-ureido]-
3-fluorofenoxi}-pirid in-2 carboxilico y sus sales de las reivindicaciones 1 a 5, 49 a
52 (folios 168 y 169,179 y 180) nose consideran nuevos.
Teniendo en cuenta lo anterior, el documento D1 afecta la novedad de las

reivindicaciones mencionadas, al revelar el mismo compuesto, raz6n por la cual
incumple con lo dispuesto en el articulo 16 de la Decision 486.

6 Fax: 382 26 95. Linea 9800-910 165
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Par la cual se niega una patente de invenci6n
Rad. N° PCT/06-005884
7. Nivel inventivo
Segun lo dispuesto en el articulo 18 de la misma Decision 486, "Se considerara

que una invenci6n tiene nivel inventive, si para una persona del oficio
normalmente versada en la materia tecnica correspondiente, esa invenci6n no
hubiese resultado obvia ni se hubiese derivado de manera evidente del estado de
la tecnica."
El estado de la tecnica, al tenor de lo dispuesto en el articulo 16 de la misma

Decision, comprende "... todo lo que haya sido accesible al publico, par una
descripci6n escrita u oral, utilizaci6n, comercializaci6n o cualquier otro medio
antes de la fecha de presentaci6n de la solicitud de patente o, en su caso, de la
prioridad reconocida".
El Tribunal de Justicia de la Comunidad Andina recientemente ha dicho sabre

este requlsito, lo siguiente:
"'Con el requisite del nivel inventivo, lo que se pretende es dotar al examinador

tecnico de un elemento que le permita afirmar o no si a la invenci6n objeto de
estudio no se habrla podido llegar a partir de los conocimientos tecnicos que
existlan en ese memento dentro del estado de la tecnica... En este punto conviene
advertir que uno es el examen que realiza el tecnico media respecto de la novedad
y otro el que se efectua con respecto al nivel inventivo; si bien en uno y otro se
utiliza como parametro de referencia el 'estado de la tecnica', en el primero, se
coteja la invenci6n con las 'anterioridades' existentes dentro de aquella, cada uno
(sic} por separado, mientras que en el segundo (nivel inventive) se exige que el
tecnico medio que realiza el examen debe partir del conocimiento general que el
tiene sabre el estado de la tecnica y realizar el cotejo comparative con su
apreciaci6n de conjunto, determinando si con tales conocimientos tecnicos
existentes ha podido o no producirse tal invenci6n'".5
"Este requisite, ... presupone que la misma represente un salto cualitativo en relaci6n
con la tecnica existente y, ademas de no ser obvia para una persona del oficio
normalmente versada en la materia tecnica, debe ser siempre el resultado de una
actividad crealiva del hombre, lo que no impide que se alcance la regla tecnica
propuesta utilizando procedimientos o metodos comunes o ya conocidos en el area
tecnica correspondiente, aunque tampoco debe conslituir el resultado de
derivaciones evidentes o elementales de lo ya existente para un experto medio en
esa materia tecnica.
"'el estado de la tecnica puesto en consideraci6n para apreciar el nivel inventive es

normalmente un documento del estado de la tecnica que divulga un objeto
concebido en el mismo campo, o que esta dirigido a alcanzar el mismo objetivo de
la invenci6n reivindicada y que presenta, en lo esencial, caracterlsticas tecnicas
similares, o que remite poco a modificaciones de estructura. Cuando se trata de
escoger el estado de la tecnica mas pr6ximo, el hecho de que el problema tecnico a
ser resuelto sea identico es, de igual modo, un criteria a ser tornado en
5 (Proceso 192 IP 2005)

7· Fax: 382 26 95. Linea 9800-910 165
Web: www.s;c.gov.co e-mail: info@sic.gov.co
IITRUE COPYII
~
Industriay Comercio
SUPERINTENDENCIA
RESOLUCION N° N~3 98 2 8
Rad. N° PCT/06-005884
consideraci6n ( ... ). Las Camaras han precisado que, una vez fijado el estado de la
tecnica mas pr6ximo a la invenci6n reivindicada, conviene examinar si el experto en
la materia, sobre la base de toda la informaci6n disponible acerca del contexto
tecnico de aquella, habrla tenido suficientes razones para escoger ese estado de la
tecnica come punto de partida (Office europeen des brevets, op.cit.)( ... ). A fa vez, si
el objeto de la invenci6n reproduce, en lo sustancial, la funci6n, los medios y el
resultado de otro que forma parte del estado de la tecnica. aquel no tendra nivel
inventive. Tampoco lo tendra, dicen las Camaras, una nueva combinaci6n que
busque obtener un efecto conocido, sabre la base de procedimientos y/o materiales
y/o propiedades conocidos tambien, ya que, en ausencia de todo efecto inesperado,
no bastara la simple sustituci6n de un elemento por otro cuyas propiedades sean
conocidas come productoras de aquel efecto (Office europeen des brevets,
op.cit.)'" 6
En el presente caso, la solicitud reivindica un compuesto de la formula I o una sal,

o una prodroga o un metabolito o un estereois6mero asilado del mismo:
metilamida del acido 4{4-[3-(4-cloro-3-trifluorometilfen il)-ureido]-3-fluorofenoxi}-
piridin-2 -carboxilico.
Por su parte, la anterioridad D1 (folios 202 a 208) ensena compuestos omega-

carboxiaril-difenil-ureas sustituidos, inhibidores de RAF quinasa.
Estos compuestos, tienen una actividad igual a la del compuesto de la presente

solicitud y pertenecen al mismo sector tecnol6gico, raz6n por la cual, para una
persona normalmente versada en la materia seria obvio el empleo de uno de
dichos compuestos, incluido el compuesto reivindicado en la presente solicitud,
para tratar enfermedades y afecciones mediadas por una senalizaci6n anormal de
VEGFR, POGFR, raf, p38 y/o flt-3 quinasa, solo o en combinaci6n con otros
agentes anticancerosos.
El problema tecnico planteado en esta solicitud, que es la necesidad de un

tratamiento contra las numerosas vias de senalizaci6n clave utilizadas por los
tumores para inducir angiogenesis en el estroma del huesped, se habia resuelto
previamente mediante el compuesto metilamida del acido 4{4-[3-(4-cloro-3-
trifluorometilfenil)ureido]-3-fluorofenoxi}-piridin-2-carboxilico o sus sales
farmaceuticamente aceptables ya conocidos(as). Por esta raz6n se considera que
6 Proceso
11- IP-2007
Sede CAN: Tr. 40A No 38-50 Conmutador: 3820840
8 Fax: 382 26 95. Linea 9800-910 165
Web: www.sic.qov.co e-mail: info@sic.qov.co
IITRUE COPYII
fl
Industriay Comercio
SUPERINTENDENCIA
RESOLUCION N° N~ 3 98 2 8
Rad. N° PCT/06-005884
el compuesto derivado de omega-carboxiaril-difenil-urea reivindicado en la

presente solicitud es evidente para una persona medianamente versada en la
materia.
Respecto a las reivindicaciones 1 a 11 y 49 a 52 (folios 168 a 170, 179 y 180) de

esta solicitud, cabe indicar que no mencionan una caracterfstica que conceda un
efecto diferente o especial a los compuestos, que pueda considerarse un aporte a
la tecnica, siendo obvios para una persona versada en la materia.
Se suma a lo anterior, que 01 divulgaba previamente el compuesto especifico:

metilamida del acido 4{4-[3-(4-cloro-3-trifluorometilfenil)-ureido]-3-fluorofenoxi}-
piridin-2carboxilico (folios 202 a 208), asi que una persona medianamente
conocedora de la materia, motivada por tal sugerencia, lograria el objeto de esta
solicitud, es decir, el compuesto derivado de omega-carboxiaril-difenil-urea
reivindicado para el tratamiento de de enfermedades y afecciones mediadas par
una ser'\alizaci6n anormal de VEGFR, POGFR, raf, p38 y/o flt-3 quinasa.
De acuerdo a lo anterior, una persona del oficio normalmente versada en la

materia tecnica podria derivar de manera obvia el objeto de las reivindicaciones 1
a 11 y 49 a 52, del estado de la tecnica, por lo cual carecen de nivel inventive,
incumpliendo lo dispuesto por el artfculo 14 de la Decisi6n 486.
8. Sobre la respuesta del solicitante
Respecto a la solicitud divisional, y una vez revisada la misma se encontr6 que se

esta reclamando el mismo compuesto en ambas solicitudes, es decir, metilamida
del acido 4{4-[3-(4cloro-3-trifluorometilfenil)-ureido]-3-fluorofenoxi]-piridin-2-
carboxilico, por lo cual no hay division real de la materia. De otro lado, una de las
divisionales no especifica los derivados a los cuales se refieren, si bien mencionan
que: "en el derivado oxidado, uno o mas de los nitr6genos de la urea estan
substituidos con un grupo hidroxilo, y/o el atomo de nitr6geno de la piridina esta en
la forma de N-6xido y en el analogo, el grupo metilamida del compuesto esta
desmetilado y, opcionalmente, el atomo de nitr6geno de la piridina esta en la
forma de N-6xido" (ver folio 309), no es concise el derivado o los derivados al que
se estan refiriendo, y no se especifica en la estructura quimica, para una mejor
visualizaci6n. Por lo tanto, no se aceptaron las divisionales presentadas y se
continu6 con el estudio sobre el capitulo reivindicatorio contenido en los folios 168
a 180.
En cuanto a novedad, el solicitante afirma que: " ... no es clara dicha referenda
pues dicha anterioridad no revela el mismo compuesto ..." (Folio 219).
Al respecto, el documento WO 00/42012 citado como anterioridad, que afecta

tanto la novedad como el nivel Inventive del compuesto de la presente solicitud, si
Sede Centro: Carrera 13 No. 27-00 Pisos 2. 5, 7 y 10
9 Fax: 382 26 95. Linea 9800-910 165
Bogota D.C. • Colombia
IITRUE _COPYII
fl
lndustriay Comercio
SUPERINTENDENCIA
REP0BLICADECOLOMB~
RESOLUCION N° Ng 3 98 2 8
• Por la cual se niega una patente de invenci6n
Rad. N° PCT/06-005884
revela dicho compuesto, una vez se hacen los reemplazos de sustituyentes

correspondientes. En cuanto a la actividad farmacol6gica, en dicha anterioridad se
dice que los compuestos son inhibidores de RAF quinasa, por lo tanto, solucionan
el problema tecnico planteado en la presente solicitud.
Despues de lo anterior, se concluye que la solicitud no cumple las disposiciones

de los artfculos 14, 20 d), 16, 18 y 30 par las razones antes expuestas, ademas,
los alegatos y correcciones allegados no subsanan en forma alguna las objeciones
planteadas en ellos.
RESUELVE
ARTICULO PRIMERO: Negar el privilegio de patente de invenci6n a la creaci6n

denominada: "OMEGA-CARBOXIARIL-DIFENIL-UREA SUSTITUIDA CON
FLUOR PARA EL TRATAMIENTO Y LA PREVENCION DE ENFERMEDADES Y
AFECCIONES".
ARTICULO SEGUNDO: Notificar personalmente al doctor Mauricio Jaramillo

Campuzano, en su calidad de apoderado de la sociedad BAYER
PHARMACEUTICALS CORPORATION, o a quien haga sus veces, el contenido
de la presente resoluci6n, entregandole copia de la misma, advirtiendole que
contra ella precede el recurso de reposici6n ante el Superintendente de lndustria y
Comercio al momenta de notificarse o dentro de los 5 dias habiles siguientes.
NOTIFIQUESE Y CUMPLASE
Dada en Bogota D.C., a los 2 t OCT.
2008
EL SUPERINTENDENTE DE INDUSTRIA Y COM
Doctor
MAURICIO JARAMILLO CAMPUZANO
Calle 67 No. 7 - 35. Oficina 1204
_;::;iota
o.c.
202067

10 Fax: 382 26 95. Linea 9800-910 165
Web: www.sic.gov.co e-mail: info@sic.qov.co
IITRUE COPYII
7/9/2019 ON-LINE PROCEDURES
r Application Nro .: 20000100153 I

Digital File I
GENERAL DATA
PRESENTATION: 1/13/00 00:00:00
DIFFENILUREAS SUBSTITUTED WITH OMEGA CARBOXYARILO AS INHIBITORS OF
RAF QUINASA; ITS PHARMACEUTICAL COMPOSITIONS AND USE FOR THE
TITLE:
MANUFACTURE OF A MEDICINE FOR THE TREATMENT OF THE GROWTH OF CANCER
CELLS
MOTHER NUMBER 0
KIND PATENT OF INVENTION
CHARACTER INDEPENDENT
AGENT: 1102 -
HOME: LAVALLE 190 3RD FLOOR - CAPITAL CAPITAL FEDERAL
RESO.VIGENTE: DATE: 11/23/10 00:00:00 : AR035310B1
NOTIFICATION: 1/15/11 00:00:00 KIND: GRANTED
HEADLINE: BAYER CORPORATION
TECHNICAL: VIGO MARIA INES
PUBLICATION:
PUBLICATIONS: BULLETIN: 203 DATE: 05/12/04 00:00:00
AR035310A1
SUMMARY
W-CARBOXYRYL-SUBSTITUTED DIPHENYL-UREAS AS INHIBITORS OF RAF KINASE, OF FORMULA ADB OR A
PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, WHEREIN: D IS -NH-C (O) -NH-; A IS A GROUP SUBSTITUTED WITH 40
CARBON ATOMS AT MOST OF FORMULA: -L- (M-L1) Q, WHERE L IS A CYCLIC STRUCTURE OF 5 OR 6 MEMBERS DIRECTLY
ATTACHED TO D; L1 COMPRISES A SUBSTITUTED CYCLIC GROUP POSSESSING AT LEAST 5 MEMBERS; M IS A BRIDGE
GROUP THAT HAS AT LEAST ONE ATOM; Q IS AN INTEGER OF 1-3; EACH CYCLIC STRUCTURE OF L AND L1 CONTAINS 0-4
MEMBERS OF THE GROUP CONSISTING OF NITROGEN, OXYGEN AND SULFUR; AND B IS AN ARYL OR HETEROARYL GROUP
UP TO TRICYCLIC OF NOT MORE THAN 30 CARBON ATOMS, SUBSTITUTED OR UNSUBSTITUTED, WITH AT LEAST ONE 6-
MEMBERED CYCLIC STRUCTURE DIRECTLY LINKED TO D CONTAINING 0-4 MEMBERS OF THE GROUP CONSISTING OF
NITROGEN, OXYGEN AND SULFUR; WHERE L1 IS SUBSTITUTED WITH AT LEAST ONE SUBSTITUENT SELECTED FROM THE
GROUP CONSISTING OF -SO2RX, -C (O) RX AND -C (NRY) RZ; RY IS HYDROGEN OR A CARBON-BASED GROUP OF UP TO 24
CARBON ATOMS OPTIONALLY CONTAINING HETEROATOMS SELECTED FROM N, S AND O AND OPTIONALLY HALO-
SUBSTITUTED, UP TO PERHALO; RZ IS HYDROGEN OR A CARBON-BASED GROUP OF AT MOST 30 CARBON ATOMS, WHICH
OPTIONALLY CONTAINS HETEROATOMS SELECTED FROM N, S AND O AND IS OPTIONALLY SUBSTITUTED BY HALOGEN,
HYDROXY AND CARBON-BASED SUBSTITUENTS OF UP TO 24 CARBON ATOMS, OPTIONALLY CONTAINING HETEROATOMS
SELECTED FROM N, S AND O AND OPTIONALLY SUBSTITUTED BY HALOGEN; RX IS RZ OR NRARB, WHERE RA AND RB ARE
(A) INDEPENDENTLY HYDROGEN, A CARBON-BASED GROUP OF AT MOST 30 CARBON ATOMS, QUEOPTATIVAMENTE
CONTAINS HETEROATOMS SELECTED FROM N, S AND O AND IS OPTIONALLY SUBSTITUTED BY HALOGEN, HYDROXY AND
CARBON-BASED SUBSTITUENTS OF UP TO 24 CARBON ATOMS, WHICH OPTIONALLY CONTAIN HETEROATOMS SELECTED
FROM N, S AND O AND ARE OPTIONALLY SUBSTITUTED BY HALOGEN, OR -OSI (RF) 3, WHERE RF IS HYDROGEN OR A
CARBON-BASED GROUP OF UP TO 24 CARBON ATOMS, WHICH OPTIONALLY CONTAINS HETEROATOMS SELECTED FROM
N, S AND O AND IS OPTIONALLY SUBSTITUTED BY HALOGEN, HYDROXY AND CARBON-BASED SUBSTITUENTS OF UP TO 24
CARBON ATOMS. CARBON, OPTIONALLY CONTAINING HETEROATOMS SELECTED FROM N, S AND O AND OPTIONALLY
SUBSTITUTED BY HALOGEN; OR (B) RA AND RB FORM TOGETHER A HETEROCYCLIC STRUCTURE OF 5-7 MEMBERS, OF 1-3
HETEROATOMS SELECTED FROM N, S AND O, OR A SUBSTITUTED 5-7 MEMBERED HETEROCYCLIC STRUCTURE OF 1-3
https://consultas.inpi.gob.ar/Patentes_Resultado?Va=501614&Vb=Concedida&Vc=020000100153
HETEROATOMS SELECTED FROM N, S, AND O SUBSTITUTED BY HALOGEN, CARBON-BASED HYDROXY-SUBSTITUENTS OF1/5
UP TO 24 CARBON ATOMS, OPTIONALLY CONTAINING HETEROATOMS SELECTED FROM N, S, AND O; THEY ARE
OPTIONALLY SUBSTITUTED BY HALOGEN; OR (C) ONE OF RA OR RB IS -C (O) -, A C1-5 DIVALENT ALKYLENE GROUP OR A
SUBSTITUTED C1-5 DIVALENT ALKYLENE GROUP ATTACHED TO THE L PORTION TO FORM A CYCLIC STRUCTURE WITH AT
LEAST 5 MEMBERS, WHERE THE SUBSTITUENTS OF THE SUBSTITUTED C1-5 DIVALENT ALKYLENE GROUP ARE SELECTED
FROM THE GROUP CONSISTING OF HALOGEN, HYDROXY AND CARBON-BASED SUBSTITUENTS OF UP TO 24 CARBON
ATOMS, WHICH OPTIONALLY CONTAIN HETEROATOMS SELECTED FROM N, S AND O AND ARE OPTIONALLY SUBSTITUTED
BY HALOGEN; WHERE B IS SUBSTITUTED, L IS SUBSTITUTED OR L1 IS FURTHER SUBSTITUTED, THE SUBSTITUENTS ARE
SELECTED FROM THE GROUP CONSISTING OF HALOGEN, UP TO PERHALO AND WN, WHERE N IS 0-3; WHEREIN EACH W IS
INDEPENDENTLY SELECTED FROM THE GROUP CONSISTING OF -CN, -CO2R7, -C (O) NR7R7, -C (O) -R7, -NO2, -OR7, -SR7, -
NR7R7, -NR7C (O) OR7, -NR7C (O) R7, -Q-AR AND CARBON-BASED GROUPS OF UP TO 24 CARBON ATOMS, WHICH
OPTIONALLY CONTAIN HETEROATOMS SELECTED FROM N, S AND O AND ARE OPTIONALLY SUBSTITUTED BY ONE OR
MORE SUBSTITUENTS SELECTED INDEPENDENTLY FROM THE GROUP CONSISTING OF -CN , -CO2R7, -C (O) R7, -C (O)
NR7R7, -OR7, -SR7, -NR7R7, -NO2, NR7C (O) R7, -NR7C (O) OR7 AND HALO TO PERHALO; WHEREIN EACH R7 IS
INDEPENDENTLY SELECTED FROM H OR A CARBON-BASED GROUP OF UP TO 24 CARBON ATOMS, OPTIONALLY
CONTAINING HETEROATOMS SELECTED FROM N, S AND O AND OPTIONALLY SUBSTITUTED BY HALOGEN; WHERE Q IS -O-,
-S-, -N (R7) -, - (CH2) M-, -C (O) -, -CH (OH) -, - (CH2) MO-, - (CH2) MS-, - (CH2) MN (R7) -, -O (CH2) M -CHXA-, -CXA2-, -S- (CH2) M-
AND -N (R7) (CH2) M-, WHERE M = 1-3, AND XA IS HALOGEN; AND AR IS A 5 OR 6 MEMBER AROMATIC STRUCTURE
CONTAINING 0-2 MEMBERS SELECTED FROM THE GROUP CONSISTING OF NITROGEN, OXYGEN AND SULFUR, WHICH IS
OPTIONALLY SUBSTITUTED BY HALOGEN TO PERHALO, AND OPTIONALLY SUBSTITUTED BY ZN1, WHERE THE VALUE OF
N1 IS 0 AT 3 AND EACH Z IS INDEPENDENTLY SELECTED FROM THE GROUP CONSISTING OF -CN, -CO2R7, -C (O) R7, -C (O)
NR7R7, -NO2, -OR7, -SR7, -NR7R7, -NR7C (O) OR7 , -NR7C (O) R7 AND A CARBON-BASED GROUP OF UP TO 24 CARBON
ATOMS, OPTIONALLY CONTAINING HETEROATOMS SELECTED FROM N, S AND O AND IS OPTIONALLY SUBSTITUTED BY
ONE OR MORE SUBSTITUENTS SELECTED FROM THE GROUP CONSISTING OF -CN, CO2R7, -COR7, -C (O) NR7R7, -OR7, -SR7,
-NO2, -NR7R7, -NR7C (O) R7 AND -NR7C (O) OR7, WHERE R7 IS AS DEFINED ABOVE. THESE COMPOUNDS ARE INHIBITORS
OF THE RAF KINASE ENZYME. THE INHIBITORS ARE USEFUL IN PHARMACEUTICAL COMPOSITIONS FOR HUMAN AND
VETERINARY USE IN THE TREATMENT OF TUMORS AND / OR GROWTH OF CANCER CELLS MEDIATED BY RAF KINASE. IN
PARTICULAR, THESE COMPOUNDS ARE USEFUL IN THE TREATMENT OF CANCERS, INCLUDING SOLID CANCERS, SUCH AS,
FOR EXAMPLE, CARCINOMAS (E.G., LUNG, PANCREAS, THYROID, BLADDER, OR COLON), MYELOID DISORDERS (E.G.,
MYELOID LEUKEMIA), OR ADENOMAS (FOR EXAMPLE, VILLOUS ADENOMA OF THE COLON). -NR7C (O) R7 AND -NR7C (O)
OR7, WHERE R7 IS AS DEFINED ABOVE. THESE COMPOUNDS ARE INHIBITORS OF THE RAF KINASE ENZYME. THE
INHIBITORS ARE USEFUL IN PHARMACEUTICAL COMPOSITIONS FOR HUMAN AND VETERINARY USE IN THE TREATMENT OF
TUMORS AND / OR GROWTH OF CANCER CELLS MEDIATED BY RAF KINASE. IN PARTICULAR, THESE COMPOUNDS ARE
USEFUL IN THE TREATMENT OF CANCERS, INCLUDING SOLID CANCERS, SUCH AS, FOR EXAMPLE, CARCINOMAS (E.G.,
LUNG, PANCREAS, THYROID, BLADDER, OR COLON), MYELOID DISORDERS (E.G., MYELOID LEUKEMIA), OR ADENOMAS
(FOR EXAMPLE, VILLOUS ADENOMA OF THE COLON). -NR7C (O) R7 AND -NR7C (O) OR7, WHERE R7 IS AS DEFINED ABOVE.
THESE COMPOUNDS ARE INHIBITORS OF THE RAF KINASE ENZYME. THE INHIBITORS ARE USEFUL IN PHARMACEUTICAL
COMPOSITIONS FOR HUMAN AND VETERINARY USE IN THE TREATMENT OF TUMORS AND / OR GROWTH OF CANCER
CELLS MEDIATED BY RAF KINASE. IN PARTICULAR, THESE COMPOUNDS ARE USEFUL IN THE TREATMENT OF CANCERS,
INCLUDING SOLID CANCERS, SUCH AS, FOR EXAMPLE, CARCINOMAS (E.G., LUNG, PANCREAS, THYROID, BLADDER, OR
COLON), MYELOID DISORDERS (E.G., MYELOID LEUKEMIA), OR ADENOMAS (FOR EXAMPLE, VILLOUS ADENOMA OF THE
COLON). THE INHIBITORS ARE USEFUL IN PHARMACEUTICAL COMPOSITIONS FOR HUMAN AND VETERINARY USE IN THE
TREATMENT OF TUMORS AND / OR GROWTH OF CANCER CELLS MEDIATED BY RAF KINASE. IN PARTICULAR, THESE
COMPOUNDS ARE USEFUL IN THE TREATMENT OF CANCERS, INCLUDING SOLID CANCERS, SUCH AS, FOR EXAMPLE,
CARCINOMAS (E.G., LUNG, PANCREAS, THYROID, BLADDER, OR COLON), MYELOID DISORDERS (E.G., MYELOID LEUKEMIA),
OR ADENOMAS (FOR EXAMPLE, VILLOUS ADENOMA OF THE COLON). THE INHIBITORS ARE USEFUL IN PHARMACEUTICAL
COMPOSITIONS FOR HUMAN AND VETERINARY USE IN THE TREATMENT OF TUMORS AND / OR GROWTH OF CANCER
CELLS MEDIATED BY RAF KINASE. IN PARTICULAR, THESE COMPOUNDS ARE USEFUL IN THE TREATMENT OF CANCERS,
INCLUDING SOLID CANCERS, SUCH AS, FOR EXAMPLE, CARCINOMAS (E.G., LUNG, PANCREAS, THYROID, BLADDER, OR
COLON), MYELOID DISORDERS (E.G., MYELOID LEUKEMIA), OR ADENOMAS (FOR EXAMPLE, VILLOUS ADENOMA OF THE
https://consultas.inpi.gob.ar/Patentes_Resultado?Va=501614&Vb=Concedida&Vc=020000100153
COLON). 2/5
CLAIMS
N- (2-METHOXY-4-CHLORO-5- (TRIFLUOROMETHYL) PHENYL) -N- (4- (2- (N-METHYLCARBAMOYL) -4-PYRIDYLOXY) PHENYL)

UREA, AND N- (2-METHOXY) 4-CHLORO-5 - (/ TRIFLUOROMETHYL) PHENYL) -N- (2-CHLORO-4- (2- (N-METHYLCARBAMOYL)
(4-PYRIDYLOXY)) PHENYL) UREA. FOLLOW 17 CLAIMS N- (2-METHOXY-4-CHLORO-5- (TRIFLUOROMETHYL) PHENYL) -N- (4-
(2- (N-METHYLCARBAMOYL) -4-PYRIDYLOXY) PHENYL) UREA, AND N- (2-METHOXY) 4-CHLORO-5 - (/ TRIFLUOROMETHYL)
PHENYL) -N- (2-CHLORO-4- (2- (N-METHYLCARBAMOYL) (4-PYRIDYLOXY)) PHENYL) UREA. FOLLOW 17 CLAIMS
VIEWS
GENERATION DATE DATE ANSWER DATE NOTIFICATION DESCRIPTION
07/22/10 00:00:00 10/25/10 00:00:00 08/12/10 00:00:00 IRF 30
08/21/08 00:00:00 01/12/09 00:00:00 9/11/08 00:00:00 CLARIFICATION 90

01/01/00 00:00:00 06/03/02 00:00:00 12/05/01 00:00:00 PRELIMINARY EXAM
01/07/10 00:00:00 06/28/10 00:00:00 01/28/10 00:00:00 EXAMINATION OF FUND 60

PRIORITIES
DATE NUMBER COUNTRY
2/25/99 00:00:00 09/257266 US
10/22/99 00:00:00 09/425228 US
01/13/99 00:00:00 60/115877 US

WRITINGS
https://consultas.inpi.gob.ar/Patentes_Resultado?Va=501614&Vb=Concedida&Vc=020000100153 3/5
DATE NOTIF. LIFTING EXPIRATION KIND DETAIL

EXAMINATION OF THE
01/02/03 00:00:00
FUND
SPONTANEOUS
12/16/03 00:00:00
PRESENTATION
SPONTANEOUS
02/08/04 00:00:00
PRESENTATION
ANSWER RESOLUTION
01/31/05 00:00:00
P372 / 04
01/12/09 00:00:00 N / A CONTESTA VISTA
02/03/09 00:00:00 RATIFICA

08/05/10 00:00:00 MANIFESTA
06/01/11 00:00:00 TRANSFERS

2/8/11 00:00:00 TRANSFERS
REQUEST
03/30/15 00:00:00
PHOTOCOPIES
07/20/18 10:04:40 COPY OF DOCUMENT
EXCESS OF 10 PAGES,
9/21/18 09:47:39
BY PAGE
N / A REQUESTS
11/22/18 09:55:51
PHOTOCOPIES
EXCESS OF 10 PAGES,
1/23/19 10:49:21
BY PAGE
EXCESS OF TEN
03/20/19 14:31:38
PAGES, BY PAGES
EXTENSION OF CERT.
03/20/19 14:31:38
STATE OF PROCEDURE
AUTHENTICATED
03/20/19 14:31:38 PHOTOCOPY, UP TO 10
PAGES
04/15/19 8:08:40 EXCESS OF TEN

PM PAGES, BY PAGES
AUTHENTICATED
04/15/19 8:08:40
PHOTOCOPY, UP TO 10
PM
PAGES
05-15-19 19:49:30 COPY OF DOCUMENT
EXCESS OF 10 PAGES,
05-15-19 19:49:30
BY PAGE
ANNUITIES
VENC AMOUNT DATE 2ND

NO. PAY DAY AMOUNT AGENT STATE OBSERVATIONS
DATE 2ND VENC. VENC.
3 09/02/2011 200 1102 PAID

4 09/02/2011 500 1102 PAID
5 09/02/2011 500 1102 PAID

6 09/02/2011 500 1102 PAID
7 09/02/2011 1000 1102 PAID

8 09/02/2011 1000 1102 PAID
9 09/02/2011 1000 1102 PAID
10 09/02/2011 1000 1102 PAID
ELEVEN 09/02/2011 1000 1102 PAID

12 09/02/2011 1000 1102 PAID
13 09/02/2011 1000 1102 PAID
14 12/14/2012 1000 1056 PAID

FIFTEEN 01/06/2014 3000 1056 PAID
16 12/19/2014 3000 1056 PAID
17 12/28/2015 3800 1056 PAID
18 01/31/2017 7540 1056 PAID COD: 363700.
19 02/01/2018 7000 1056 PAID COD: 363000.
TWENTY 01/02/2019 7000 1056 PAID COD: 363000.
7/9/2019 TRAMITES ON-LINE
r Application Nro .: 20040102614 I

Digital File I
GENERAL DATA
PRESENTATION: 07/23/04 00:00:00
TITLE: DERIVATIVES OF OMEGA-CARBOXIARIL DIFENIL UREA REPLACED
MOTHER NUMBER 0
KIND PATENT OF INVENTION
CHARACTER INDEPENDENT
AGENT: 734 -
HOME: AV. DEL LIBERTADOR 5954 7TH FLOOR
RESO.VIGENTE: DATE: 08/24/16 00:00:00 : PN048741
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TECHNICAL: VIGO MARIA INES
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PUBLICATIONS: BULLETIN: 356 DATE: 05/24/06 00:00:00
AR048741A1
SUMMARY
A COMPOUND OF FORMULA (1), SALTS THEREOF, PRODRUGS THEREOF, METABOLITES THEREOF, PHARMACEUTICAL
COMPOSITIONS CONTAINING SAID COMPOUND, AND THE USE OF SAID COMPOUND AND COMPOSITIONS FOR TREATING
DISEASES MEDIATED BY RAF, VEGFR, PDGFR, P38, AND FLT -3.
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PCT WORLD INTELLECTUAL PROPERTY ORGANIZATION
International Bureau
INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(51) International Patent Classification 7 : (11) International Publication Number: WO 00/41698
A61K 31/535, 31/50, 31/445, 31/44, Al
31/40, 31/34, 31/17 (43) International Publication Date: 20 July 2000 (20.07.00)
(21) International Application Number: PCT/US00/00768 MAS, Jacques [FR/US]; 821 Beechwood Road, Orange,
CT 06477 (US). KHIRE,Uday [IN/US]; 101 Tanglewood
(22) International Filing Date: 13 January 2000 (13.01.00) Drive, Hamden, CT 06518 (US). LOWINGER, Timothy, B.
[CA/JP];# 203, 5-7 Chitose-cho, Nishinomiya City, Hyogo
662-0046 (JP). SCOTT, William, J. [US/US]; 210 Saddle
(30) Priority Data: Hill Drive, Guilford, CT 06437 (US). SMITH, Roger, A.
60/115,878 13 January 1999 (13.01.99) us [CA/US]; 65 Winterhill Road, Madison, CT 06443 (US).
WOOD, Jill, E. [US/US]; 72 Pickwick Road, Hamden,
09/257,265 25 February 1999 (25.02.99) us
09/425,229 22 October 1999 (22.10.99) us CT 06517 (US). MONAHAN, Mary-Katherine [US/US];
134 Park Avenue, Hamden, CT 06517 (US). NATERO,
Reina [US/US]; 113 Edgecomb Street, Hamden, CT 06518
(63) Related by Continuation (CON) or Continuation-in-Part (US). RENICK, Joel [US/US]; 11 Wall Street #4, Milford,
(CIP) to Earlier Applications CT 06460 (US). SIBLEY, Robert, N. [US/US]; 1187 Mt.
us 60/115,878 (CIP) Carmel Avenue, North Haven, CT 06473 (US).
Filed on 13 January 1999 (13.01.99)
us 09/257,265 (CIP) (74) Agents: TRAVERSO, Richard, J. et al.; Millen, White, Zelano
Filed on 25 February 1999 (25.02.99) & Branigan, P.C., Suite 1400, Arlington Courthouse Plaza
us 09/425,229 (CIP) I, 2200 Clarendon Boulevard, Arlington, VA 22201 (US).
Filed on 22 October 1999 (22.10.99)
(81) Designated States: AE, AL, AM, AT, AU, AZ, BA, BB, BG,
(71) Applicant (for all designated States except US): BAYER BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE,
CORPORATION [US/US]; 100 Bayer Road, Pittsburgh, PA ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP,
15205 (US). KE,KG,KP,KR,KZ,LC,LK,LR,LS,LT,LU,LV,MA,
MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU,
(72) Inventors; and SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG,
(75) Inventors/Applicants (for US only): RIEDL, Bernd [DE/DE]; US, UZ, VN, YU, ZA, ZW, ARIPO patent (GH, GM, KE,
Von Der Goltz Strasse 7, D-42329 Wuppertal (DE). DU- LS, MW, SD, SL, SZ, TZ, UG, ZW), Eurasian patent (AM,
AZ, BY, KG, KZ, MD, RU, TJ, TM), European patent (AT,
BE, CH, CY, DE, DK, ES, Fl, FR, GB, GR, IE, IT, LU,
MC, NL, PT, SE), OAPI patent (BF, BJ, CF, CG, CI, CM,
GA, GN, GW, ML, MR, NE, SN, TD, TG).
Published
With international search report.
Before the expiration of the time limit for amending the
claims and to be republished in the event of the receipt of
amendments.
(54) Title: w-CARBOXY ARYL SUBSTITUTED DIPHENYL UREAS AS p38 KINASE INHIBITORS
(57) Abstract
This invention relates to the use of a group of aryl ureas in treating p38 mediated diseases, and pharmaceutical compositions for use
in such therapy.
IITRUE COPYII
FOR THE PURPOSES OF INFORMATIONONLY
Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
AL Albania ES Spain LS Lesotho SI Slovenia

AM Armenia FI Finland LT Lithuania SK Slovakia
AT Austria FR France LU Luxembourg SN Senegal
AU Australia GA Gabon LV Latvia sz Swaziland
AZ Azerbaijan GB United Kingdom MC Monaco TD Chad
BA Bosnia and Herzegovina GE Georgia MD Republic of Moldova TG Togo
BB Barbados GH Ghana MG Madagascar TJ Tajikistan
BE Belgium GN Guinea MK The former Yugoslav TM Turkmenistan
BF Burkina Faso GR Greece Republic of Macedonia TR Turkey
BG Bulgaria HU Hungary ML Mali TT Trinidad and Tobago
BJ Benin IE Ireland MN Mongolia UA Ukraine
BR Brazil IL Israel MR Mauritania UG Uganda
BY Belarus IS Iceland MW Malawi us United States of America
CA Canada IT Italy MX Mexico uz Uzbekistan
CF Central African Republic JP Japan NE Niger VN Viet Nam
CG Congo KE Kenya NL Netherlands YU Yugoslavia
CH Switzerland KG Kyrgyzstan NO Norway zw Zimbabwe
CI COted'Ivoire KP DemocraticPeople's NZ New Zealand
CM Cameroon Republic of Korea PL Poland
CN China KR Republic of Korea PT Portugal
cu Cuba KZ Kazakstan RO Romania
CZ Czech Republic LC Saint Lucia RU Russian Federation
DE Germany LI Liechtenstein SD Sudan
DK Denmark LK Sri Lanka SE Sweden
EE Estonia LR Liberia SG Singapore
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WO 00/41698 PCT/US00/00768
10
co-CARBOXY ARYL SUBSTITUTED DIPHENYL UREAS AS

p38 KINASE INHIBITORS
15
Cross-Reference to Related Applications

This is a continuation-in-part of Serial No. 09/257,265 filed February 25,
1999 and a continuation-in-part of Serial No. 60/115,878 filed January 13, 1999.
20 This invention relates to the use of a group of aryl ureas in treating cytokine
mediated diseases and proteolytic enzyme mediated diseases, and pharmaceutical
compositions for use in such therapy.

25 Two classes of effector molecules which are critical for the progression of
rheumatoid arthritis are pro-inflammatory cytokines and tissue degrading proteases.
Recently, a family of kinases was described which is instrumental in controlling the
transcription and translation of the structural genes coding for these effector
molecules.
30 The mitogen-activated protein (MAP) kinase family is made up of a series of
structurally related proline-directed serine/threonine kinases which are activated
either by growth factors (such as EGF) and phorbol esters (ERK), or by IL-1, TNFa
or stress (p38, JNK). The MAP kinases are responsible for the activation of a wide
variety of transcription factors and proteins involved in transcriptional control of
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cytokine production. A pair of novel protein kinases involved in the regulation of

cytokine synthesis was recently described by a group from SmithKline Beecham
(Lee et al. Nature 1994, 372, 739). These enzymes were isolated based on their
affinity to bond to a class of compounds, named CSAIDSs (cytokine suppressive
5 anti-inflammatory drugs) by SKB. The CSAIDs, bicyclic pyridinyl imidazoles,
have been shown to have cytokine inhibitory activity both in vitro and in vivo. The
isolated enzymes, CSBP-1 and -2 (CSAID binding protein 1 and 2) have been
cloned and expressed. A murine homologue for CSBP-2, p38, has also been
reported (Han et al. Science 1994, 265, 808).
IO Early studies suggested that CSAIDs function by interfering with m-RNA
translational events during cytokine biosynthesis. Inhibition of p38 has been shown
to inhibit both cytokine production (eg., TNFa., IL-1, IL-6, IL-8) and proteolytic
enzyme production (eg., MMP-1, MMP-3) in vitro and/or in vivo.
Clinical studies have linked TNFa. production and/or signaling to a number
15 of diseases including rheumatoid arthritis (Maini. J. Royal Coll. Physicians London
1996, 30, 344). In addition, excessive levels of TNFa. have been implicated in a
wide variety of inflammatory and/or immunomodulatory diseases, including acute
rheumatic fever (Yegin et al. Lancet 1997, 349, 170), bone resorption (Pacifici et al.
J. Clin. Endocrinol. Metabol. 1997, 82, 29), postmenopausal osteoperosis (Pacifici
20 et al. J. Bone Mineral Res. 1996, I I, I 043), sepsis (Blackwell et al. Br. J. Anaesth.
1996, 77, 110), gram negative sepsis (Debets et al. Prog. Clin. Biol. Res. 1989, 308,
463), septic shock (Tracey et al. Nature 1987, 330, 662; Girardin et al. New
England J. Med. 1988, 319, 397), endotoxic shock (Beutler et al. Science 1985, 229,
869; Ashkenasi et al. Proc. Nat 'l. Acad. Sci. USA 1991, 88, 10535), toxic shock
25 syndrome, (Saha et al. J. Immunol. 1996, 157, 3869; Lina et al. FEMS Immunol.
Med. Microbial. 1996, 13, 81), systemic inflammatory response syndrome (Anon.
Crit. Care Med. 1992, 20, 864), inflammatory bowel diseases (Stokkers et al. J.
Inflamm. 1995-6, 47, 97) including Crohn's disease (van Deventer et al. Aliment.
Pharmacol. Therapeu. 1996, JO (Suppl. 2), 107; van Dullemen et al.
30 Gastroenterology 1995, 109, 129) and ulcerative colitis (Masuda et al. J. Clin. Lab.
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Immunol. 1995, 46, 111), Jarisch-Herxheimer reactions (Fekade et al. New England
J Med. 1996, 335, 311), asthma (Amrani et al. Rev. Malad. Respir. 1996, 13, 539),
adult respiratory distress syndrome (Roten et al. Am. Rev. Respir. Dis. 1991, 143,
590; Suter et al. Am. Rev. Respir. Dis. 1992, 145, 1016), acute pulmonary fibrotic
5 diseases (Pan et al. Pathol. Int. 1996, 46, 91), pulmonary sarcoidosis (lshioka et al.
Sarcoidosis Vasculitis Diffuse Lung Dis. 1996, 13, 139), allergic respiratory
diseases (Casale et al. Am. J Respir. Cell Mal. Biol. 1996, 15, 35), silicosis (Gossart
et al. J Jmmunol. 1996, 156, 1540; Vanhee et al. Eur. Respir. J 1995, 8, 834), coal
worker's pneumoconiosis (Borm et al. Am. Rev. Respir. Dis. 1988, 138, 1589),
IO alveolar injury (Horinouchi et al. Am. J. Respir. Cell Mo!. Biol. 1996, 14, 1044),
hepatic failure (Gantner et al. J Pharmacol. Exp. Therap. 1991, 280, 53), liver
disease during acute inflammation (Kim et al. J Biol. Chem. 1997, 272, 1402),
severe alcoholic hepatitis (Bird et al. Ann. Intern. Med. 1990, 112, 917), malaria
(Grau et al. Immunol. Rev. 1989, 112, 49; Taveme et al. Parasitol. Today 1996, 12,
15 290) including Plasmodium falciparum malaria (Perlmann et al. Infect. Immunit.
1997, 65, 116) and cerebral malaria (Rudin et al. Am. J Pathol. 1997, 150, 257),
non-insulin-dependent diabetes mellitus (NIDDM; Stephens et al. J Biol. Chem.
1997, 272, 971; Ofei et al. Diabetes 1996, 45, 881), congestive heart failure
(Doyama et al. Int. J Cardiol. 1996, 54, 217; McMurray et al. Br. Heart J 1991,
20 66, 356), damage following heart disease (Malkiel et al. Mol. Med. Today 1996, 2,
336), atherosclerosis (Parums et al. J. Pathol. 1996, 179, A46), Alzheimer's disease
(Fagarasan et al. Brain Res. 1996, 723, 231; Aisen et al. Gerontology 1997, 43,
143), acute encephalitis (Ichiyama et al. J Neural. 1996, 243, 457), brain injury
(Cannon et al. Crit. Care Med. 1992, 20, 1414; Hansbrough et al. Surg. Clin. N. Am.
25 1987, 67, 69; Marano et al. Surg. Gynecol. Obstetr. 1990, 170, 32), multiple
sclerosis (M.S.; Coyle. Adv. Neuroimmunol. 1996, 6, 143; Matusevicius et al. J
Neuroimmunol. 1996, 66, 115) including demyelation and oligiodendrocyte loss in
multiple sclerosis (Brosnan et al. Brain Pathol. 1996, 6, 243), advanced cancer
(MucWierzgon et al. J Biol. Regulators Homeostatic Agents 1996, JO, 25),
30 lymphoid malignancies (Levy et al. Crit. Rev. Immunol. 1996, 16, 31), pancreatitis
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(Exley et al. Gut 1992, 33, 1126) including systemic complications in acute
pancreatitis (McKay et al. Br. J Surg. 1996, 83, 919), impaired wound healing in
infection inflammation and cancer (Buck et al. Am. J Pathol. 1996, 149, 195),
myelodysplastic syndromes (Raza et al. Int. J. Hematol. 1996, 63, 265), systemic
5 lupus erythematosus (Maury et al. Arthritis Rheum. 1989, 32, 146), biliary cirrhosis
(Miller et al. Am. J. Gasteroenterolog. 1992, 87, 465), bowel necrosis (Sun et al. J.
Clin. Invest. 1988, 81, 1328), psoriasis (Christophers. Austr. J Dermatol. 1996, 37,
S4), radiation injury (Redlich et al. J. Jmmunol. 1996, 157, 1705), and toxicity
following administration of monoclonal antibodies such as OKT3 (Brod et al.
10 Neurology 1996, 46, 1633). TNFa levels have also been related to host-versus-
graft reactions (Piguet et al. Jmmunol. Ser. 1992, 56, 409) including ischemia
reperfusion injury (Colletti et al. J. Clin. Invest. 1989, 85, 1333) and allograft
rejections including those of the kidney (Maury et al. J. Exp. Med. 1987, 166,
1132), liver (lmagawa et al. Transplantation 1990, 50, 219), heart (Bolling et al.
15 Transplantation 1992, 53, 283), and skin (Stevens et al. Transplant. Proc. 1990, 22,
1924), lung allograft rejection (Grossman et al. Immunol. Allergy Clin. N. Am.
1989, 9, 153) including chronic lung allograft rejection (obliterative bronchitis;
LoCicero et al. J. Thorac. Cardiovasc. Surg. 1990, 99, 1059), as well as
complications due to total hip replacement (Cirino et al. Life Sci. 1996, 59, 86).
20 TNFa has also been linked to infectious diseases (review: Beutler et al. Crit. Care
Med. 1993, 21, 5423; Degre. Biotherapy 1996, 8, 219) including tuberculosis
(Rook et al. Med. Malad. Infect. 1996, 26, 904), Helicobacter pylori infection
during peptic ulcer disease (Beales et al. Gastroenterology 1997, 112, 136),
Chaga's disease resulting from Trypanosoma cruzi infection (Chandrasekar et al.
25 Biochem. Biophys. Res. Commun. 1996, 223, 365), effects of Shiga-like toxin
resulting from E. coli infection (Harel et al. J. Clin. Invest. 1992, 56, 40), the effects
of enterotoxin A resulting from Staphylococcus infection (Fischer et al. J. lmmunol.
1990, 144, 4663), meningococcal infection (Waage et al. Lancet 1987, 355; Ossege
et al. J. Neurolog. Sci. 1996, 144, I), and infections from Borrelia burgdorferi
30 (Brandt et al. Infect. Jmmunol. 1990, 58, 983), Treponema pallidum (Chamberlin et
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al. Infect. lmmunol. 1989, 57, 2872), cytomegalovirus (CMV; Geist et al. Am. J.
Respir. Cell Mo!. Biol. 1997, 16, 31), influenza virus (Beutler et al. Clin. Res. 1986,
34, 491a), Sendai virus (Goldfield et al. Proc. Nat'/. Acad. Sci. USA 1989, 87,
1490), Theiler's encephalomyelitis virus (Sierra et al. Immunology 1993, 78, 399),
5 and the human immunodeficiency virus (HIV; Poli. Proc. Nat 'l. Acad. Sci. USA
1990, 87, 782; Vyakaram et al. AIDS 1990, 4, 21; Badley et al. J. Exp. Med. 1997,
185, 55).
Because inhibition of p38 leads to inhibition of TNFa production, p38
inhibitors will be useful in treatment of the above listed diseases.
10 A number of diseases are thought to be mediated by excess or undesired
matrix-destroying metalloprotease (MMP) activity or by an imbalance in the ratio
of the MMPs to the tissue inhibitors of metalloproteinases (TIMPs). These include
osteoarthritis (Woessner et al. J. Biol. Chem. 1984, 259, 3633), rheumatoid arthritis
(Mullins et al. Biochim. Biophys. Acta 1983, 695, 117; Woolley et al. Arthritis
15 Rheum. 1977, 20, 1231; Gravallese et al. Arthritis Rheum. 1991, 34, 1076), septic
arthritis (Williams et al. Arthritis Rheum. 1990, 33, 533), tumor metastasis (Reich et
al. Cancer Res. 1988, 48, 3307; Matrisian et al. Proc. Nat'/. Acad. Sci., USA 1986,
83, 9413), periodontal diseases (Overall et al. J. Periodontal Res. 1987, 22, 81),
corneal ulceration (Burns et al. Invest. Opthalmol. Vis. Sci. 1989, 30, 1569),
20 proteinuria (Baricos et al. Biochem. J. 1988, 254, 609), coronary thrombosis from
atherosclerotic plaque rupture (Henney et al. Proc. Nat'!. Acad. Sci., USA 1991, 88,
8154), aneurysmal aortic disease (Vine et al. Clin. Sci. 1991, 81,233), birth control
(Woessner et al. Steroids 1989, 54, 491), dystrophobic epidermolysis bullosa
(Kronberger et al. J. Invest. Dermatol. 1982, 79, 208), degenerative cartilage loss
25 following traumatic joint injury, osteopenias mediated by MMP activity, tempero
mandibular joint disease, and demyelating diseases of the nervous system (Chantry
et al. J. Neurochem. 1988, 50, 688).
Because inhibition of p38 leads to inhibition of MMP production, p38
inhibitors will be useful in treatment of the above listed diseases.
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Inhibitors of p38 are active in animal models of TNFa production, including

a muime lipopolysaccharide (LPS) model of TNFa production. Inhibitors of p38
are active in a number of standard animal models of inflammatory diseases,
including carrageenan-induced edema in the rat paw, arachadonic acid-induced
5 edema in the rat paw, arachadonic acid-induced peritonitis in the mouse, fetal rat
long bone resorption, murine type II collagen-induced arthritis, and Fruend's
adjuvant-induced arthritis in the rat. Thus, inhibitors of p38 will be useful in
treating diseases mediated by one or more of the above-mentioned cytokines and/or
proteolytic enzymes.
IO The need for new therapies is especially important in the case of arthritic
diseases. The primary disabling effect of osteoarthritis, rheumatoid arthritis and
septic arthritis is the progressive loss of articular cartilage and thereby normal joint
function. No marketed pharmaceutical agent is able to prevent or slow this cartilage
loss, although nonsteroidal antiinflammatory drugs (NSAIDs) have been given to
15 control pain and swelling. The end result of these diseases is total loss of joint
function which is only treatable by joint replacement surgery. P38 inhibitors will
halt or reverse the progression of cartilage loss and obviate or delay surgical
intervention.
Several patents have appeared claiming polyarylimidazoles and/or
20 compounds containing polyarylimidazoles as inhibitors of p38 (for example, Lee et
al. WO 95/07922; Adams et al. WO 95/02591; Adams et al. WO 95/13067; Adams
et al. WO 95/31451). It has been reported that arylimidazoles complex to the ferric
form of cytochrome P450cam(Harris et al. Mal. Eng. 1995, 5, 143, and references
therein), causing concern that these compounds may display structure-related
25 toxicity (Howard-Martin et al. Toxicol. Pathol. 1987, 15, 369). Therefore, there
remains a need for improved p38 inhibitors.
Summary of the Invention

This invention provides compounds, generally described as aryl ureas,
30 including both aryl and heteroaryl analogues, which inhibit p38 mediated events and
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thus inhibit the production of cytokines (such as TNFa, IL-1 and IL-8) and
proteolytic enzymes (such as MMP-1 and MMP-3). The invention also provides a
method of treating a cytokine mediated disease state in humans or mammals,
wherein the cytokine is one whose production is affected by p38. Examples of such
5 cytokines include, but are not limited to TNFa, IL-1 and IL-8. The invention also
provides a method of treating a protease mediated disease state in humans or
mammals, wherein the protease is one whose production is affected by p38.
Examples of such proteases include, but are not limited to collagenase (MMP-1) and
stromelysin (MMP-3).
10 Accordingly, these compounds are useful therapeutic agents for such acute
and chronic inflammatory and/or immunomodulatory diseases as rheumatoid
arthritis, osteoarthritis, septic arthritis, rheumatic fever, bone resorption,
postmenopausal osteoperosis, sepsis, gram negative sepsis, septic shock, endotoxic
shock, toxic shock syndrome, systemic inflammatory response syndrome,
15 inflammatory bowel diseases including Crohn's disease and ulcerative colitis,
Jarisch-Herxheimer reactions, asthma, adult respiratory distress syndrome, acute
pulmonary fibrotic diseases, pulmonary sarcoidosis, allergic respiratory diseases,
silicosis, coal worker's pneumoconiosis, alveolar injury, hepatic failure, liver
disease during acute inflammation, severe alcoholic hepatitis, malaria including
20 Plasmodium falciparum malaria and cerebral malaria, non-insulin-dependent
diabetes mellitus (NIDDM), congestive heart failure, damage following heart
disease, atherosclerosis, Alzheimer's disease, acute encephalitis, brain injury,
multiple sclerosis including demyelation and oligiodendrocyte loss in multiple
sclerosis, advanced cancer, lymphoid malignancies, tumor metastasis, pancreatitis,
25 including systemic complications in acute pancreatitis, impaired wound healing in
infection, inflammation and cancer, periodontal diseases, corneal ulceration,
proteinuria, myelodysplastic syndromes, systemic lupus erythematosus, biliary
cirrhosis, bowel necrosis, psoriasis, radiation injury, toxicity following
administration of monoclonal antibodies such as OKT3, host-versus-graft reactions
30 including ischemia reperfusion injury and allograft rejections including kidney,
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liver, heart, and skin allograft rejections, lung allograft rejection including chronic
lung allograft rejection (obliterative bronchitis) as well as complications due to total
hip replacement, and infectious diseases including tuberculosis, Helicobacter pylori
infection during peptic ulcer disease, Chaga's disease resulting from Trypanosoma
5 cruzi infection, effects of Shiga-like toxin resulting from E. coli infection, effects of
enterotoxin A resulting from Staphylococcus infection, meningococcal infection,
and infections from Borrelia burgdorferi, Treponema pallidum, cytomegalovirus,
influenza virus, Theiler's encephalomyelitis virus, and the human
immunodeficiency virus (HIV).
10 The present invention, therefore, provides compounds generally described as
aryl ureas, including both aryi and heteroaryl analogues, which inhibit the p38
pathway. The invention also provides a method for treatment of p38-mediated
disease states in humans or mammals, e.g., disease states mediated by one or more
cytokines or proteolytic enzymes produced and/or activated by a p38 mediated
15 process. Thus, the invention is directed to compounds, compositions and methods
for the treatment of diseases mediated by p38 kinase wherein a compound of
Formula I is administered or a pharmaceutically acceptable salt thereof.
A- D - B (I)
20 In formula I, D is -NH-C(O)-NH-,
A is a substituted moiety ofup to 40 carbon atoms of the formula: -L-(M-
L 1 )q , where L is a 5 or 6 membered cyclic structure bound directly to D, L 1
comprises a substituted cyclic moiety having at least 5 members, M is a bridging
group having at least one atom, q is an integer of from 1-3; and each cyclic structure
25 of L and L I contains 0-4 members of the group consisting of nitrogen, oxygen and
sulfur, and
B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl

moiety of up to 30 carbon atoms with at least one 6-member cyclic structure bound
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WO 00/41698 PCT/US00/00768
directly to D containing 0-4 members of the group consisting of nitrogen, oxygen

and sulfur,
wherein L 1 is substituted by at least one substituent selected from the group

consisting of -SO2Rx, -C(O)Rx and -C(NRy) Rz,
5 Ry is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally

containing heteroatoms selected from N, S and O and optionally halosubstituted, up
to per halo,
R2 is hydrogen or a carbon based moiety ofup to 30 carbon atoms optionally

containing heteroatoms selected from N, S and O and optionally substituted by
10 halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which
optionally contain heteroatoms selected from N, S and O and are optionally
substituted by halogen;
Rx is R2 or NRaRbwhere Ra and Rb are
15 a carbon based moiety of up to 30 carbon atoms optionally

halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which
substituted by halogen, or
20 -OSi(Rr)3 where Rr is hydrogen or a carbon based moiety of up to

24 carbon atoms optionally containing heteroatoms selected from N, S and O and
optionally substituted by halogen, hydroxy and carbon based substituents of up to
24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0
and are optionally substituted by halogen; or
25 b) Ra and Rb together form a 5-7 member heterocyclic structure of 1-3

heteroatoms selected from N, S and 0, or a substituted 5-7 member heterocyclic
structure of 1-3 heteroatoms selected from N, S and O substituted by halogen,
IITRUE COPYII
WO 00/41698 PCT/US00/00768
hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally

contain heteroatoms selected from N, S and O and are optionally substituted by
halogen; or
c) one of Ra or Rb is -C(O)-, a C 1-Cs divalent alkylene group or a

5 substituted C 1-C 5 divalent alkylene group bound to the moiety L to form a cyclic
structure with at least 5 members, wherein the substituents of the substituted C1-Cs
divalent alkylene group are selected from the group consisting of halogen, hydroxy,
and carbon based substituents of up to 24 carbon atoms, which optionally contain
10 where B is substituted, L is substituted or L I is additionally substituted, the

substituents are selected from the group consisting of halogen, up to per-halo, and
Wn, where n is 0-3;
wherein each W is independently selected from the group consisting of -

7
CN, -CO2R7, -C(O)NR 7R 7, -C(O)-R , -NO2, -OR7, -SR7, -NR 7R 7, -NR 7C(O)OR7, -
15 NR 7C(O)R7, -Q-Ar, and carbon based moieties ofup to 24 carbon atoms, optionally
containing heteroatoms selected from N, S and O and optionally substituted by one
or more substituents independently selected from the group consisting of -CN, -
7 7 7 7 7
CO2R7, -C(O)R7, -C(O)NR 7R , -OR , -SR , -NR7R , -NO2, -NR 7C(O)R , -
NR7C(O)OR7 and halogen up to per-halo; with each R7 independently selected from

20 H or a carbon based moiety of up to 24 carbon atoms, optionally containing
heteroatoms selected from N, Sand O and optionally substituted by halogen,
wherein Q is -0-, -S-, -N(R 7)-, -(CH2)m-,-C(O)-, -CH(OH)-, -(CH2)mO-,-

(CH2)mS-, -(CH2)mN(R7)-, -O(CH2)m- CHXa-, -CXaz-, -S-(CH2)m- and -
7
N(R )(CH2)m-,where m= 1-3, and Xa is halogen; and
25 Ar is a 5- or 6-member aromatic structure containing 0-2 members selected

from the group consisting of nitrogen, oxygen and sulfur, which is optionally
substituted by halogen, up to per-halo, and optionally substituted by 2 01 , wherein nl
is O to 3 and each Z is independently selected from the group consisting of -CN, -
10
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WO 00/41698 PCT/US00/00768
CO2R7 , -C(O)R 7 , -C(O)NR7 R7 , -NO2 , -OR7 , -SR7 -NR7 R 7 , -NR7 C(O)OR7 , -
7 7
NR C(O)R , and a carbon based moiety of up to 24 carbon atoms, optionally
or more substituents selected from the group consisting of -CN, -CO2R 7 , -COR7 , -
7
5 C(O)NR 7 R 7 , -OR7 , -SR7 , -NO2 , -NR R7 , -NR7 C(O)R7 , and -NR7 C(O)OR 7 , with R7
as defined above.
In formula I, suitable hetaryl groups include, but are not limited to, 5-12
carbon-atom aromatic rings or ring systems containing 1-3 rings, at least one of
which is aromatic, in which one or more, e.g., 1-4 carbon atoms in one or more of
1o the rings can be replaced by oxygen, nitrogen or sulfur atoms. Each ring typically
has 3-7 atoms. For example, B can be 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl,
1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-
oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3-
or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-
15 1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or
-5-yl, 1,3,4-thiadiazol-2- or-5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or
-5-yl, 1,3,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-
2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-,
5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-
20 indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-,
5-, 6- or 7-benzoxazolyl, 3-, 4-, 5- 6- or 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- or 7-
benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 2-, 4-, 5-, 6- or 7-benz-1,3-
oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-
isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl,
25 or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, or additionally optionally substituted phenyl,
2- or 3-thienyl, 1,3,4-thiadiazolyl, 3-pyrryl, 3-pyrazolyl, 2-thiazolyl or 5-thiazolyl,
etc. For example, B can be 4-methyl-phenyl, 5-methyl-2-thienyl, 4-methyl-2-
thienyl, l-methyl-3-pyrryl, 1-methyl-3-pyrazolyl, 5-methyl-2-thiazolyl or 5-methyl-
1,2,4-thiadiazol-2-yl.
I1
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Suitable alkyl groups and alkyl portions of groups, e.g., alkoxy, etc.
throughout include methyl, ethyl, propyl, butyl, etc., including all straight-chain and
branched isomers such as isopropyl, isobutyl, sec-butyl, tert-butyl, etc.
Suitable aryl groups which do not contain heteroatoms include, for example,
•5 phenyl and 1- and 2-naphthyl.
The term "cycloalkyl", as used herein, refers to cyclic structures with or
without alkyl substituents such that, for example, "C 4 cycloakyl" includes methyl
substituted cyclopropyl groups as well as cyclobutyl groups. The term
"cycloalkyl", as used herein also includes saturated heterocyclic groups.
10 Suitable halogen groups include F, Cl, Br, and/or I, from one to per-
substitution (i.e. all H atoms on a group replaced by a halogen atom) being possible
where an alkyl group is substituted by halogen, mixed substitution of halogen atom
types also being possible on a given moiety.
The invention also relates to compounds per se, of formula I.
15 The present invention is also directed to pharmaceutically acceptable salts of
formula I. Suitable pharmaceutically acceptable salts are well known to those
skilled in the art and include basic salts of inorganic and organic acids, such as
hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,
methanesulphonic acid, trifluoromethanesulfonic acid, benzenesulphonic acid, p-
20 toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic
acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid,
acid, and mandelic acid. In addition, pharmaceutically acceptable salts include acid
salts of inorganic bases, such as salts containing alkaline cations (e.g., Li+ Na+ or
25 K+), alkaline earth cations (e.g., Mg+ 2
, Ca+ or Ba+
2 2
), the ammonium cation, as well

as acid salts of organic bases, including aliphatic and aromatic substituted
ammonium, and quaternary ammonium cations, such as those arising from
protonation or peralkylation of triethylamine, N,N-diethylamine, N,N-
dicyclohexylamine, lysine, pyridine, N,N-dimethylaminopyridine (DMAP), 1,4-
12
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diazabiclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and

1,8-diazabicyclo[ 5.4.0]undec-7-ene (DBU).
A number of the compounds of Formula I possess asymmetric carbons and
can therefore exist in racemic and optically active forms. Methods of separation of
5 enantiomeric and diastereomeric mixtures are well known to one skilled in the art.
The present invention encompasses any isolated racemic or optically active fonn of
compounds described in Formula I which possess p38 kinase inhibitory activity.

10 The compounds of Formula I may be prepared by use of known chemical
reactions and procedures, some from starting materials which are commercially
available. Nevertheless, the following general preparative methods are presented to
aid one of skill in the art in synthesizing these compounds, with more detailed
particular examples being presented in the experimental section describing the
15 working examples.
Substituted anilines may be generated using standard methods (March.

Advanced Organic Chemistry, 3rd Ed.; John Wiley: New York (1985). Larock.
Comprehensive Organic Transformations; VCH Publishers: New York (1989)). As
shown in Scheme I, aryl amines are commonly synthesized by reduction of
20 nitroaryls using a metal catalyst, such as Ni, Pd, or Pt, and H2 or a hydride transfer
agent, such as fonnate, cyclohexadiene, or a borohydride (Rylander. Hydrogenation
Methods; Academic Press: London, UK (1985)). Nitroaryls may also be directly
reduced using a strong hydride source, such as LiAlH4 (Seyden-Penne. Reductions
by the Alumina- and Borohydrides in Organic Synthesis; VCH Publishers: New
25 York (1991)), or using a zero valent metal, such as Fe, Sn or Ca, often in acidic
media. Many methods exist for the synthesis of nitroaryls (March. Advanced
Organic Chemistry, 3rd Ed.; John Wiley: New York (1985). Larock.
Comprehensive Organic Transformations; VCH Publishers: New York (1989)).
13
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Substituted anilines may be generated using standard methods (March. Advanced

Organic Chemislly, 3rd Ed.; John Wiley: New York (1985). Larock.
Comprehensive Organic Transformations; VCH Publishers: New York (1989)). As
shown in Scheme I, aryl amines are commonly synthesized by reduction of
5 nitroaryls using a metal catalyst, such as Ni, Pd, or Pt, and H2 or a hydride transfer
agent, such as formate, cyclohexadiene, or a borohydride (Rylander. Hydrogenation
Methods; Academic Press: London, UK (1985)). Nitroaryls may also be directly
reduced using a strong hydride source, such as LiAIH4 (Seyden-Penne. Reductions
by the Alumina- and Borohydrides in Organic Synthesis; VCH Publishers: New
IO York (1991)), or using a zero valent metal, such as Fe, Sn or Ca, often in acidic
media. Many methods exist for the synthesis of nitroaryls (March. Advanced
Organic Chemistry, 3rd Ed.; John Wiley: New York (1985). Larock.
Comprehensive Organic Transformations; VCH Publishers: New York (1989)).
H2 / catalyst
~ [H-]
~
15 (eg. Fe, Sn, Ca)
Scheme I Reduction of Nitroaryls to Aryl Amines
Nitroaryls are commonly formed by electrophilic aromatic nitration using HNO3, or

an alternative NO 2+ source. Nitroaryls may be further elaborated prior to reduction.
Ar-H
20
potential leaving groups (eg. F, Cl, Br, etc.) may undergo substitution reactions on
treatment with nucleophiles, such as thiolate (exemplified in Scheme II) or
14
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WO 00/41698 PCT /US00/00768
phenoxide. Nitroaryls may also undergo Ullman-type coupling reactions (Scheme

II).
Scheme II Selected Nucleophilic Aromatic Substitution using Nitroaryls
5 Nitroaryls may also undergo transition metal mediated cross coupling

reactions. For example, nitroaryl electrophiles, such as nitroaryl bromides, iodides
or triflates, undergo palladium mediated cross coupling reactions with aryl
nucleophiles, such as arylboronic acids (Suzuki reactions, exemplified below),
aryltins (Stille reactions) or arylzincs (Negishi reaction) to afford the biaryl (5).
10
ArB(OR'h
Pd(O)
Either nitroaryls or anilines may be converted into the corresponding

arenesulfonyl chloride (7) on treatment with chlorosulfonic acid. Reaction of the
15 sulfonyl chloride with a fluoride source, such as KF then affords sulfonyl fluoride
(8). Reaction of sulfonyl fluoride 8 with trimethylsilyl trifluoromethane in the
presence of a fluoride source, such as tris(dimethylamino)sulfonium
difluorotrimethylsiliconate (TASF) leads to the corresponding
trifluoromethylsulfone (9). Alternatively, sulfonyl chloride 7 may be reduced to the
15
IITRUE COPYII
WO 00/41698 PCT/US00/00768
arenethiol (10), for example with zinc amalgum. Reaction of thiol 10 with CHClF2
in the presence of base gives the difluoromethyl mercaptam (11), which may be
oxidized to the sulfone (12) with any of a variety of oxidants, including CrO3-acetic
anhydride (Sedova et al. Zh. Org. Khim. 1970, 6, 568).
G-R
6
10
ICHCIF2
• base
9 11
i [OJ
Scheme III Selected Methods of Fluorinated Aryl Sulfone Synthesis
As shown in Scheme IV, non-symmetrical urea formation may involve

reaction of an aryl isocyanate (14) with an aryl amine (13). The heteroaryl
10 isocyanate may be synthesized from a heteroaryl amine by treatment with phosgene
or a phosgene equivalent, such as trichloromethyl chloroformate (diphosgene),
bis(trichloromethyl) carbonate (triphosgene), or .N,N'-carbonyldiimidazole (CDI).
16
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The isocyanate may also be derived from a heterocyclic carboxylic acid derivative,
such as an ester, an acid halide or an anhydride by a Curtius-type rearrangement.
Thus, reaction of acid derivative 16 with an azide source, followed by
rearrangement affords the isocyanate. The corresponding carboxylic acid (17) may
5 also be subjected to Curtius-type rearrangements using diphenylphosphoryl azide
(DPP A) or a similar reagent.
Ar 1-NH2 13
~ coc1 2
H2 N-Ar2
Ar 1-NCO ►
14
N,; \DPPA
0 0
Ar1)lx Ar1)lOH
16 17
Scheme IV Selected Methods of Non-Symmetrical Urea Formation
Finally, ureas may be further manipulated using methods familiar to those

1o skilled in the art.
The invention also includes pharmaceutical compositions including a
compound of Formula I, and a physiologically acceptable carrier.
The compounds may be administered orally, topically, parenterally, by
inhalation or spray, vaginally, rectally or sublingually in dosage unit formulations.
15 The term 'administration by injection' includes intravenous, intramuscular,
subcutaneous and parenteral injections, as well as use of infusion techniques.
Dermal administration may include topical application or transdermal
administration. One or more compounds may be present in association with one or
17
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WO 00/41698 PCT/US00/00768
more non-toxic pharmaceutically acceptable carriers and if desired other active

ingredients.
Compositions intended for oral use may be prepared according to any
suitable method known to the art for the manufacture of phannaceutical
5 compositions. Such compositions may contain one or more agents selected from the
group consisting of diluents, sweetening agents, flavoring agents, coloring agents
and preserving agents in order to provide palatable preparations. Tablets contain the
active ingredient in admixture with non-toxic phannaceutically acceptable
excipients which are suitable for the manufacture of tablets. These excipients may
10 be, for example, inert diluents, such as calcium carbonate, sodium carbonate,
lactose, calcium phosphate or sodium phosphate; granulating and disintegrating
agents, for example, com starch, or alginic acid; and binding agents, for example
magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may
be coated by known teclmiques to delay disintegration and adsorption in the
15 gastrointestinal tract and thereby provide a sustained action over a longer period.
For example, a time delay material such as glyceryl monostearate or glyceryl
distearate may be employed. These compounds may also be prepared in solid,
rapidly released fonn.
Fonnulations for oral use may also be presented as hard gelatin capsules
20 wherein the active ingredient is mixed with an inert solid diluent, for example,
calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein
the active ingredient is mixed with water or an oil medium, for example peanut oil,
liquid paraffin or olive oil.
Aqueous suspensions containing the active materials in admixture with
25 excipients suitable for the manufacture of aqueous suspensions may also be used.
Such excipients are suspending agents, for example sodium carboxymethylcellulose,
methylcellulose, hydroxypropyl-methylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents
may be a naturally-occurring phosphatide, for example, lecithin, or condensation
30 products of an alkylene oxide with fatty acids, for example polyoxyethylene
18
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WO 00/41698 PCT /US00/00768
stearate, or condensation products of ethylene oxide with long chain aliphatic

alcohols, for example heptadecaethyleneoxycetanol, or condensation products of
ethylene oxide with partial esters derived from fatty acids and hexitol such as
polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide
5 with partial esters derived from fatty acids and hexitol anhydrides, for example
polyethylene sorbitan monooleate. The aqueous suspensions may also contain one
or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or
more coloring agents, one or more flavoring agents, and one or more sweetening
agents, such as sucrose or saccharin.
IO Dispersible powders and granules suitable for preparation of an aqueous
suspension by the addition of water provide the active ingredient in admixture with
a dispersing or wetting agent, suspending agent and one or more preservatives.
Suitable dispersing or wetting agents and suspending agents are exemplified by
those already mentioned above. Additional excipients, for example, sweetening,
15 flavoring and coloring agents, may also be present.
The compounds may also be in the form of non-aqueous liquid formulations,
e.g., oily suspensions which may be formulated by suspending the active ingredients
in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a
mineral oil such as liquid paraffin. The oily suspensions may contain a thickening
20 agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such
as those set forth above, and flavoring agents may be added to provide palatable oral
preparations. These compositions may be preserved by the addition of an anti-
oxidant such as ascorbic acid.
Compounds of the invention may also be administrated transdermally using
25 methods known to those skilled in the art (see, for example: Chien; "Transdermal
Controlled Systemic Medications"; Marcel Dekker, Inc.; 1987. Lipp et al.
WO94/04157 3Mar94). For example, a solution or suspension of a compound of
Formula I in a suitable volatile solvent optionally containing penetration enhancing
agents can be combined with additional additives known to those skilled in the art,
30 such as matrix materials and bacteriocides. After sterilization, the resulting mixture
19
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WO 00/41698 PCT /US00/00768
can be formulated following known procedures into dosage forms. In addition, on

treatment with emulsifying agents and water, a solution or suspension of a
compound of Formula I may be formulated into a lotion or salve.
Suitable solvents for processing transdermal delivery systems are known to
5 those skilled in the art, and include lower alcohols such as ethanol or isopropyl
alcohol, lower ketones such as acetone, lower carboxylic acid esters such as ethyl
acetate, polar ethers such as tetrahydrofuran, lower hydrocarbons such as hexane,
cyclohexane or benzene, or halogenated hydrocarbons such as dichloromethane,
chloroform, trichlorotrifluoroethane, or trichlorofluoroethane. Suitable solvents
10 may also include mixtures of one or more materials selected from lower alcohols,
lower ketones, lower carboxylic acid esters, polar ethers, lower hydrocarbons,
halogenated hydrocarbons.
Suitable penetration enhancing materials for transdermal delivery system are
known to those skilled in the art, and include, for example, monohydroxy or
15 polyhydroxy alcohols such as ethanol, propylene glycol or benzyl alcohol, saturated
or unsaturated C8-C 18 fatty alcohols such as lauryl alcohol or cetyl alcohol,
saturated or unsaturated C8-C 1s fatty acids such as stearic acid, saturated or
unsaturated fatty esters with up to 24 carbons such as methyl, ethyl, propyl,
isopropyl, n-butyl, sec-butyl isobutyl tertbutyl or monoglycerin esters of acetic acid,
20 capronic acid, lauric acid, myristinic acid, stearic acid, or palmitic acid, or diesters
of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons such
as diisopropyl adipate, diisobutyl adipate, diisopropyl sebacate, diisopropyl maleate,
or diisopropyl fumarate. Additional penetration enhancing materials include
phosphatidyl derivatives such as lecithin or cephalin, terpenes, amides, ketones,
25 ureas and their derivatives, and ethers such as dimethyl isosorbid and
diethyleneglycol monoethyl ether. Suitable penetration enhancing formulations
may also include mixtures of one or more materials selected from monohydroxy or
polyhydroxy alcohols, saturated or unsaturated Cs-C 1s fatty alcohols, saturated or
unsaturated C8-C 18 fatty acids, saturated or unsaturated fatty esters with up to 24
30 carbons, diesters of saturated or unsaturated discarboxylic acids with a total of up to
20
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24 carbons, phosphatidyl derivatives, terpenes, amides, ketones, ureas and their

derivatives, and ethers.
Suitable binding materials for transdermal delivery systems are known to
those skilled in the art and include polyacrylates, silicones, polyurethanes, block
5 polymers, styrenebutadiene coploymers, and natural and synthetic rubbers.
Cellulose ethers, derivatized polyethylenes, and silicates may also be used as matrix
components. Additional additives, such as viscous resins or oils may be added to
increase the viscosity of the matrix.
Pharmaceutical compositions of the invention may also be in the form of oil-
IO in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or
arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
Suitable emulsifying agents may be naturally-occurring gums, for example gum
acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean,
lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides,
15 for example sorbitan monooleate, and condensation products of the said partial
esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The
emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example
glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain
20 a demulcent, a preservative and flavoring and coloring agents.
The compounds may also be administered in the form of suppositories for
rectal administration of the drug. These compositions can be prepared by mixing
the drug with a suitable non-irritating excipient which is solid at ordinary
temperatures but liquid at the rectal or vaginal temperature and will therefore melt
25 in the rectum or vagina to release the drug. Such materials include cocoa butter and
polyethylene glycols.
For all regimens of use disclosed herein for compounds of Formula I, the
daily oral dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body
weight. The daily dosage for administration by injection, including intravenous,
30 intramuscular, subcutaneous and parenteral injections, and use of infusion
21
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techniques will preferably be from 0.01 to 200 mg/Kg of total body weight. The
daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total
body weight. The daily rectal dosage regimen will preferably be from 0.01 to 200
mg/Kg of total body weight. The transdermal concentration will preferably be that
5 required to maintain a daily dose of from 0.01 to 200 mg/Kg. The daily topical
dosage regimen will preferably be from 0.1 to 200 mg administered between one to
four times daily. The daily inhalation dosage regimen will preferably be from 0.01
to 10 mg/Kg of total body weight.
IO It will be appreciated by those skilled in the art that the particular method of
administration will depend on a variety of factors, all of which are considered
routinely when administering therapeutics. It will also be understood, however, that
the specific dose level for a given patient depends on a variety of factors, including
specific activity of the compound administered, the age of the patient, the body
15 weight of the patient, the general health of the patient, the gender of the patient, the
diet of the patient, time of administration, route of administration, rate of excretion,
drug combination, and the severity of the condition undergoing therapy, etc. It will
be further appreciated by one skilled in the art that the optimal course of treatment,
i.e., the mode of treatment and the daily number of doses of a compound of Formula
20 I or a pharmaceutically acceptable salt thereof given for a defined number of days,
can be ascertained by those skilled in the art using conventional course of treatment
tests.
The compounds of Figure I are producible from known compounds (or from starting
25 materials which, in tum, are producible from known compounds), e.g., through the
general preparative methods shown above. The activity of a given compound to
inhibit raf kinase can be routinely assayed, e.g., according to procedures disclosed
below. The following examples are for illustrative purposes only and are not
intended, nor should they be construed to limit the invention in any way.
30
22
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The entire disclosure of all applications, patents and publications cited above and
below are hereby incorporated by reference, including non-provisional application
Serial No. 09/257,265 filed February 25, 1999 and provisional application serial
number 60/115,878, filed on January 13, 1999.
5
The following examples are for illustrative purposes only and are not intended, nor
should they be construed to limit the invention in any way.
EXAMPLES
All reactions were performed in flame-dried or oven-dried glassware under a
10 positive pressure of dry argon or dry nitrogen, and were stirred magnetically unless
otherwise indicated. Sensitive liquids and solutions were transferred via syringe or
cannula, and introduced into reaction vessels through rubber septa. Unless otherwise
stated, the term 'concentration under reduced pressure' refers to use of a Buchi
rotary evaporator at approximately 15 mmHg. Unless otherwise stated, the term
15 'under high vacuum' refers to a vacuum of 0.4- 1.0 mmHg.
All temperatures are reported uncorrected in degrees Celsius (°C). Unless otherwise
indicated, all parts and percentages are by weight.
20 Commercial grade reagents and solvents were used without further purification. N-
cyclohexyl.:.N'-(methylpolystyrene)carbodiimide was purchased from Calbiochem-
(trifluoromethyl)aniline, 4-chloro-3-(trifluoromethyl)aniline 2-methoxy-5-
(trifluoromethyl)aniline, 4-tert-butyl-2-nitroaniline, 3-amino-2-naphthol, ethyl 4-
25 isocyanatobenzoate, N-acetyl-4-chloro-2-methoxy-5-(trifluoromethyl)aniline and 4-
chloro-3-(trifluoromethyl)phenyl isocyanate were purchased and used without
further purification. Syntheses of 3-amino-2-methoxyquinoline (E. Cho et al. WO
98/00402; A. Cordi et al. EP 542,609; IBID Bioorg. Med. Chem.. 3, 1995, 129), 4-
(3-carbamoylphenoxy)-1-nitrobenzene (K. Ikawa Yakugaku Zasshi 79, 1959, 760;
30 Chem. Abstr. 53, 1959, 12761b), 3-tert-butylphenyl isocyanate (0. Rohr et al. DE
23
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2,436,108) and 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (K. Inukai et al. JP

42,025,067; IBID Kogyo Kagaku Zasshi 70, 1967, 491) have previously been
described.
5 Thin-layer chromatography (TLC) was performed using Whatman® pre-coated

glass-backed silica gel 60A F-254 250 µm plates. Visualization of plates was
effected by one or more of the following techniques: (a) ultraviolet illumination, (b)
exposure to iodine vapor, (c) immersion of the plate in a 10% solution of
phosphomolybdic acid i11,i
ethanol followed by heating, (d) immersion of the plate in
IO a cerium sulfate solution followed by heating, and/or (e) immersion of the plate in
an acidic ethanol solution of 2,4-dinitrophenylhydrazine followed by heating.
Column chromatography (flash chromatography) was performed using 230-400
mesh EM Science®silica gel.
15 Melting points (mp) were determined using a Thomas-Hoover melting point

apparatus or a Mettler FP66 automated melting point apparatus and are uncorrected.
Fourier transform infrared spectra were obtained using a Mattson 4020 Galaxy
Series spectrophotometer. Proton ( 1H) nuclear magnetic resonance (NMR) spectra
were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer
20 with either Me4 Si (8 0.00) or residual protonated solvent (CHCh 8 7.26; MeOH 8
3.30; DMSO 8 2.49) as standard. Carbon (13C) NMR spectra were measured with a
General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDCh 8
77.0; MeOD-d3 ; 8 49.0; DMSO-d6 8 39.5) as standard. Low resolution mass spectra
(MS) and high resolution mass spectra (HRMS) were either obtained as electron
25 impact (EI) mass spectra or as fast atom bombardment (FAB) mass spectra.
Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A
mass spectrometer equipped with a Vacumetrics Desorption Chemical Ionization
Probe for sample introduction. The ion source was maintained at 250 °C. Electron
impact ionization was performed with electron energy of 70 eV and a trap current of
30 300 µA. Liquid-cesium secondary ion mass spectra (FAB-MS), an updated version
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of fast atom bombardment were obtained using a Kratos Concept 1-H spectrometer.
Chemical ionization mass spectra (CI-MS) were obtained using a Hewlett Packard
4
MS-Engine (5989A) with methane or ammonia as the reagent gas (lxl0- torr to
2.5x10-4 torr). The direct insertion desorption chemical ionization (DCI) probe
5 (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at 10 amps
until all traces of the sample disappeared ( ~ 1-2 min). Spectra were scanned from
50-800 amu at 2 sec per scan. HPLC - electrospray mass spectra (HPLC ES-MS)
were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary
pump, a variable wavelength detector, a C-18 column, and a Finnigan LCQ ion trap
10 mass spectrometer with electrospray ionization. Spectra were scanned from 120-
800 amu using a variable ion time according to the number of ions in the source.
Gas chromatography - ion selective mass spectra (GC-MS) were obtained with a
Hewlett Packard 5890 gas chromatograph equipped with an HP-1 methyl silicone
column (0.33 mM coating; 25 m x 0.2 mm) and a Hewlett Packard 5971 Mass
15 Selective Detector (ionization energy 70 eV). Elemental analyses are conducted by
All compounds displayed NMR spectra, LRMS and either elemental analysis or
HRMS consistent with assigned structures.
20

AcOH acetic acid
anh anhydrous
atm atmosphere( s)
25 BOC tert-butoxycarbonyl
cone concentrated
d day(s)
dee decomposition
30 DMAC N,N-dimethylacetamide
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DMPU l,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
DMF N,N-dimethylformamide
5 EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
EtOAc ethyl acetate
EtOH ethanol (100%)
Et2O diethyl ether
Et3N triethylamine
10 h hour(s)
m-CPBA 3-chloroperoxybenzoic acid
MeOH methanol
pet. ether petroleum ether (boiling range 30-60 °C)
15 temp. temperature
THF tetrahydrofuran
TFA trifluoroAcOH
Tf trifluoromethanesulfonyl
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Carbamate Deprotection. Synthesis of 2-Amino-3-
5 methoxynaphthalene.
~co 2 Me
OMe
Step 1. Methyl 3-methoxy-2-naphthoate

A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) and K2 CO3 (7.96 g,
57.6 mmol) in DMF (200 mL) was stirred at room temp. for 15 min., then treated
10 with iodomethane (3.43 mL, 55.1 mmol). The mixture was allowed to stir at room
temp. overnight, then was treated with water (200 mL). The resulting mixture was
extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with
a saturated NaCl solution (100 mL), dried (MgSO4), concentrated under reduced
pressure (approximately 0.4 mmHg overnight) to give methyl 3-methoxy-2-
15 naphthoate as an amber oil (10.30 g): 1H-NMR (DMSO-d 6) 8 2.70 (s, 3H), 2.85 (s,
3H), 7.38 (app t, J=8.09 Hz, lH), 7.44 (s, lH), 7.53 (app t, J=8.09 Hz, lH), 7.84 (d,
J=S.09 Hz, lH), 7.90 (s, lH), 8.21 (s, lH).
~co,H
OMe

20 A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10
mL) in MeOH (100 mL) at room temp. was treated with a 1 N NaOH solution (33.4
mL, 33.4 mmol). The mixture was heated at the reflux temp. for 3 h, cooled to room
temp., and made acidic with a 10% citric acid solution. The resulting solution was
extracted with EtOAc (2 x 100 mL). The combined organic layers were washed
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with a saturated NaCl solution, dried (MgSO4) and concentrated under reduced
pressure. The residue was triturated with hexane then washed several times with
hexane to give 3-methoxy-2-naphthoic acid as a white solid (5.40 g, 92%): 1H-NMR
(DMSO-d 6) 8 3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, lH), 7.83 (d, J=8.09
5 Hz, lH), 7.91 (d, J=8.09 Hz, lH), 8.19 (s, lH), 12.83 (br s, lH).
Step 3. 2-(N-(Carbobenzyloxy)amino-3-methoxynaphthalene
A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and Et 3N (2.59 mL,
18.6 mmol) in anh toluene (70 mL) was stirred at room temp. for 15 min., then
10 treated with a solution ofDPPA (5.12 g, 18.6 mmol) in toluene (10 mL) via pipette.
The resulting mixture was heated at 80 °C for 2 h. After cooling the mixture to room
temp., benzyl alcohol (2.06 mL, 20 mmol) was added via syringe. The mixture was
then warmed to 80 °C overnight. The resulting mixture was cooled to room temp.,
quenched with a 10% citric acid solution, and extracted with EtOAc (2 x 100 mL).
15 The combined organic layers were washed with a saturated NaCl solution, dried
(MgSO4) and concentrated under reduced pressure. The residue was purified by
column chromatography (14% EtOAc/86% hexane) to give 2-(N-
(carbobenzyloxy)amino-3-methoxynaphthalene as a pale yellow oil (5.1 g, 100%):
1
H-NMR (DMSO-d6) 8 3.89 (s, 3H), 5.17 (s, 2H), 7.27-7.44 (m, 8H), 7.72-7.75 (m,
20 2H), 8.20 (s, lH), 8.76 (s, lH).
~NH,
OMe
A slurry of 2-(N-(carbobenzyloxy)amino-3-methoxynaphthalene (5.0 g, 16.3 mmol)
and 10% Pd/C (0.5 g) in EtOAc (70 mL) was maintained under a H2 atm (balloon)
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at room temp. overnight. The resulting mixture was filtered through Celite® and
concentrated under reduced pressure to give 2-amino-3-methoxynaphthalene as a
pale pink powder (2.40 g, 85%): 1H-NMR (DMSO-d6) 8 3.86 (s, 3H), 6.86 (s, 2H),
7.04-7.16 (m, 2H), 7.43 (d, J=8.0 Hz, lH), 7.56 (d, J=8.0 Hz, IH); EI-MS m/z 173
s (M+).
A2. Synthesis of ro-Carbamyl Anilines via Formation of a

Carbamylpyridine Followed by Nucleophilic Coupling with an
Aryl Amine. Synthesis of 4-(2-N-Methylcarbamyl-4-
pyridyloxy)aniline
Cl~NHMe
~~
Step la. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide via the
15 Menisci reaction
Caution: this is a highly hazardous, potentially explosive reaction. To a stirring
solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) at room
temp. was added cone. H2SO4 (3.55 mL) to generate an exotherm. To this mixture
was added H2O2 (30% wt in H2 O, 17 mL) followed by FeSO 4 •7H2O (0.56 g) to
20 generate another exotherm. The resulting mixture was stirred in the dark at room
temp. for 1 h, then warmed slowly over 4 h to 45 °C. When bubbling had subsided,
the reaction was heated at 60 °C for 16 h. The resulting opaque brown solution was
diluted with H2O (700 mL) followed by a 10% NaOH solution (250 mL). The
resulting mixture was extracted with EtOAc (3 x 500 mL). The organic phases were
25 washed separately with a saturated NaCl solution (3 x 150 mL), then they were
combined, dried (MgSO4) and filtered through a pad of silica gel with the aid of
EtOAc. The resulting brown oil was purified by column chromatography (gradient
from 50% EtOAc/50% hexane to 80% EtOAc/20% hexane). The resulting yellow
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oil crystallized at O °C over 72 h to give 4-chloro-N-methyl-2-pyridinecarboxamide

(0.61 g, 5.3%): TLC (50% EtOAc/50% hexane) R10.50; 1H NMR (CDCh) o 3.04
(d, J=5.l Hz, 3H), 7.43 (dd, J=5.4, 2.4 Hz, lH), 7.96 (br s, lH), 8.21 (s, IH), 8.44
(d, J=5.l Hz, 1 H); CI-MS m/z 171 ((M+Ht).
5
0
Cl~CI
L~ HCI
Step lb. Synthesis of 4-chloropyridine-2-carbonyl chloride HCI salt via

picolinic acid
Anhydrous DMF (6.0 mL) was slowly added to SOCh (180 mL) between 40° and
lo 50 °C. The solution was stirred in that temperature range for 10 min. then picolinic
acid (60.0 g, 487 mmol) was added in portions over 30 min. The resulting solution
was heated at 72 °C (vigorous SO2 evolution) for 16 h to generate a yellow solid
precipitate. The resulting mixture was cooled to room temp., diluted with toluene
(500 mL) and concentrated to 200 mL. The toluene addition/concentration process
15 was repeated twice. The resulting nearly dry residue was filtered and the solids
were washed with toluene (2 x 200 mL) and dried under high vacuum for 4 h to
afford 4-chloropyridine-2-carbonyl chloride HCl salt as a yellow-orange solid (92.0
g, 89%).
0
Cl~OMe
L~ HCI
20 Step 2. Synthesis of methyl 4-chloropyridine-2-carboxylate HCI salt

Anh DMF (10.0 mL) was slowly added to SOCh (300 mL) at 40-48 °C. The
solution was stirred at that temp. range for 10 min., then picolinic acid (100 g, 812
mmol) was added over 30 min. The resulting solution was heated at 72 °C
(vigorous SO2 evolution) for 16 h to generate a yellow solid. The resulting mixture
25 was cooled to room temp., diluted with toluene (500 mL) and concentrated to 200
mL. The toluene addition/concentration process was repeated twice. The resulting
nearly dry residue was filtered, and the solids were washed with toluene (50 mL)
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and dried under high vacuum for 4 hours to afford 4-chloropyridine-2-carbonyl

chloride HCl salt as an off-white solid (27.2 g, 16%). This material was set aside.
The red filtrate was added to MeOH (200 mL) at a rate which kept the internal
5 temperature below 55 °C. The contents were stirred at room temp. for 45 min.,
cooled to 5 °C and treated with Et2O (200 mL) dropwise. The resulting solids were
filtered, washed with Et2O (200 mL) and dried under reduced pressure at 35 °C to
provide methyl 4-chloropyridine-2-carboxylate HCl salt as a white solid (110 g,
1
65%): mp 108-112 °C; H-NMR (DMSO-d6) 8 3.88 (s, 3H); 7.82 (dd, J=5.5, 2.2
IO Hz, lH); 8.08 (d, J=2.2 Hz, lH); 8.68 (d, J=5.5 Hz, lH); 10.68 (hrs, lH); HPLC
ES-MS mlz 172 ((M+H/).
Cl~NHMe
L~
Step 3a. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from
15 methyl 4-chloropyridine-2-carboxylate
A suspension of methyl 4-chloropyridine-2-carboxylate HCI salt (89.0 g, 428 mmol)
in MeOH (75 mL) at O °C was treated with a 2.0 M methylamine solution in THF (1
L) at a rate which kept the internal temp. below 5 °C. The resulting mixture was
stored at 3 °C for 5 h, then concentrated under reduced pressure. The resulting
20 solids were suspended in EtOAc (1 L) and filtered. The filtrate was washed with a
saturated NaCl solution (500 mL), dried (Na2SO4) and concentrated under reduced
pressure to afford 4-chloro-N-methyl-2-pyridinecarboxamide as pale-yellow crystals
(71.2 g, 97%): mp 41-43 °C; 1H-NMR (DMSO-d6) 8 2.81 (s, 3H), 7.74 (dd, J=5.l,
2.2 Hz, lH), 8.00 (d, J=2.2, lH), 8.61 (d, J=5.l Hz, lH), 8.85 (hr d, lH); CI-MS
25 mlz 171 ((M+H/).
Cl~O
I ~ NHMe
/4N
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chloropyridine-2-carbonyl chloride
4-Chloropyridine-2-carbonyl chloride HCl salt (7.0 g, 32.95 mmol) was added in
portions to a mixture of a 2.0 M methylamine solution in THF (100 mL) and MeOH
5 (20 mL) at O °C. The resulting mixture was stored at 3 °C for 4 h, then concentrated
under reduced pressure. The resulting nearly dry solids were suspended in EtOAc
(100 mL) and filtered. The filtrate was washed with a saturated NaCl solution (2 x
100 mL), dried (Na2SO4) and concentrated under reduced pressure to provide 4-
chloro-N-methyl-2-pyridinecarboxamide as a yellow, crystalline solid (4.95 g,
10 88%): mp 37-40 °C.
Step 4. Synthesis of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline

A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. DMF (150 mL) was
treated with potassium tert-butoxide (10.29 g, 91.7 mmol), and the reddish-brown
15 mixture was stirred at room temp. for 2 h. The contents were treated with 4-chloro-
N-methyl-2-pyridinecarboxamide (15.0 g, 87.9 mmol) and K2CO3 (6.50 g, 47.0
mmol) and then heated at 80 °C for 8 h. The mixture was cooled to room temp. and
separated between EtOAc (500 mL) and a saturated NaCl solution (500 mL). The
aqueous phase was back-extracted with EtOAc (300 mL). The combined organic
20 layers were washed with a saturated NaCl solution (4 x 1000 mL), dried (Na2SO4)
and concentrated under reduced pressure. The resulting solids were dried under
reduced pressure at 35 °C for 3 h to afford 4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)aniline as a light-brown solid 17.9 g, 84%): 1H-NMR (DMSO-d 6) o2.77
(d, J=4.8 Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (AA'BB' quartet, J=8.4 Hz, 4H), 7.06
25 (dd, J=5.5, 2.5 Hz, lH), 7.33 (d, J=2.5 Hz, lH), 8.44 (d, J=5.5 Hz, lH), 8.73 (br d,
lH); HPLC ES-MS mlz 244 ((M+Ht).
A3. General Method for the Synthesis of Anilines by Nucleophilic
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Aromatic Addition Followed by Nitroarene Reduction. Synthesis of 5-(4-

Aminophenoxy)isoindoline-1,3-dione
0
5 Step 1. Synthesis of 5-hydroxyisoindoline-1,3-dione
To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in cone. AcOH (25 mL)
was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting
mixture was heated at 120 °C for 45 min., then the clear, bright yellow mixture was
heated at 160 °C for 2 h. The resulting mixture was maintained at 160 °C and was
10 concentrated to approximately 15 mL, then was cooled to room temp. and adjusted
pH 10 with a lN NaOH solution. This mixture was cooled to O °C and slowly
acidified to pH 5 using a IN HCl solution. The resultant precipitate was collected
by filtration and dried under reduced pressure to yield 5-hydroxyisoindoline-1,3-
1
dione as a pale yellow powder as product (3.24 g, 72%): H NMR (DMSO-d6) i5
15 7.00-7.03 (m, 2H), 7.56 (d, J=9.3Hz, lH).
o,NOOLl 0
_}-t
0
Step 2. Synthesis of 5-(4-nitrophenoxy)isoindoline-1,3-dione
To a stirring slurry ofNaH (1.1 g, 44.9 mmol) in DMF (40 mL) at O °C was added
20 a solution of 5-hydroxyisoindoline-1,3-dione (3.2 g, 19.6 mmol) in DMF (40 mL)
dropwise. The bright yellow-green mixture was allowed to return to room temp.
and was stirred for 1 h, then 1-fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added
via syringe in 3-4 portions. The resulting mixture was heated at 70 °C overnight,
then cooled to room temp. and diluted slowly with water (150 mL), and extracted
25 with EtOAc (2 x 100 mL). The combined organic layers were dried (MgSO4) and
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concentrated under reduced pressure to give 5-(4-nitrophenoxy)isoindoline-1,3-

dione as a yellow solid (3.3 g, 62%): TLC (30% EtOAc/70% hexane) R1 0.28; lH
NMR (DMSO-d 6) 8 7.32 (d, 1=12 Hz, 2H), 7.52-7.57 (m, 2H), 7.89(d, 1=7.8 Hz,
lH), 8.29 (d, 1=9 Hz, 2H), 11.43 (br s, lH); CI-MS m/z 285 ((M+H)\ 100%).
5

• A solution of 5-(4-nitrophenoxy)isoindoline-1,3-dione (0.6 g, 2.11 mmol) in cone.
AcOH (12 mL) and water (0.1 mL) was stirred under stream of argon while iron
10 powder (0.59 g, 55.9 mmol) was added slowly. This mixture stirred at room temp.
for 72 h, then was diluted with water (25 mL) and extracted with EtOAc (3 x 50
mL). The combined organic layers were dried (MgSO4) and concentrated under
reduced pressure to give 5-(4-aminophenoxy)isoindoline-1,3-dione as a brownish
solid (0.4 g, 75%): TLC (50% EtOAc/50% hexane) R10.27; 1H NMR (DMSO-d6) 8
15 5.14 (br s, 2H), 6.62 (d, 1=8.7 Hz, 2H), 6.84 (d, 1=8.7 Hz, 2H), 7.03 (d, 1=2.1 Hz,
IH), 7.23 (dd, IH), 7.75 (d, 1=8.4 Hz, lH), 11.02 (s, lH); HPLC ES-MS m/z 255
((M+H)\ 100%).
A4. General Method for the Synthesis of Pyrrolylanilines. Synthesis

20 of 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline
Step 1.
--orN
Synthesis of 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole
To a stirring solution of 2-nitro-4-tert-butylaniline (0.5 g, 2.57 mmol) in
cyclohexane (10 mL) was added AcOH (0.lmL) and acetonylacetone (0.299 g, 2.63
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mmol) via syringe. The reaction mixture was heated at 120 °C for 72 h with
azeotropic removal of volatiles. The reaction mixture was cooled to room temp.,
diluted with CH2Cl2 (10 mL) and sequentially washed with a lN HCI solution (15
mL), a IN NaOH solution (15 mL) and a saturated NaCl solution (15mL), dried (
5 MgSO 4) and concentrated under reduced pressure. The resulting orange-brown
solids were purified via column chromatography (60 g SiO2 ; gradient from 6%
EtOAc/94% hexane to 25% EtOAc/75% hexane) to give l-(4-tert-butyl-2-
nitrophenyl)-2,5-dimethylpyrrole as an orange-yellow solid (0.34 g, 49%): TLC
(15% EtOAc/85% hexane) R10.67; 1H NMR (CDCh) d 1.34 (s, 9H), 1.89 (s, 6H),
10 5.84 (s, 2H), 7.19-7.24 (m, IH), 7.62 (dd, lH), 7.88 (d, J=2.4 Hz, lH); CI-MS m/z
273 ((M+H)\ 50%).
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N
--0--
Step 2. Synthesis of 5-tert--Butyl-2-(2,5-dimethylpyrrolyl)aniline
A slurry of 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole (0.341 g, 1.25 mmol),
5 10%Pd/C (0.056 g) and EtOAc (50 mL) under an H2 atmosphere (balloon) was
stirred for 72 h, then filtered through a pad of Celite®. The filtrate was concentrated
under reduced pressure to give 5-tert--butyl-2-(2,5-dimethylpyrrolyl)aniline as
yellowish solids (0.30 g, 99%): TLC (10% EtOAc/90% hexane) R1 0.43; 1H NMR
(CDCh) 8 1.28 (s, 9H), 1.87-1.91 (m, 8H), 5.85 (br s, 2H), 6.73-6.96 (m, 3H), 7.28
10 (br s, lH).
AS. General Method for the Synthesis of Anilines from Anilines by

Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline HCI Salt
0
0
('y '((NHMe
H2 NY HCI
15 Me
A solution of 4-amino-3-methylphenol (5.45 g, 44.25 mmol) in dry

dimethylacetamide (75 mL) was treated with potassium tert-butoxide (10.86 g,
96.77 mmol) and the black mixture was stirred at room temp. until the flask had
reached room temp. The contents were then treated with 4-chloro-N-methyl-2-
20 pyridinecarboxamide (Method A2, Step 3b; 7.52 g, 44.2 mmol) and heated at 110
°C for 8 h. The mixture was cooled to room temp. and diluted with water (75 mL).
The organic layer was extracted with EtOAc (5 x 100 mL). The combined organic
layers were washed with a saturated NaCl solution (200 mL), dried (MgSO4) and
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concentrated under reduced pressure. The residual black oil was treated with Et2O
(50 mL) and sonicated. The solution was then treated with HCl (1 Min Et2O; 100
mL) and stirred at room temp. for 5 min. The resulting dark pink solid (7.04 g, 24.1
mmol) was removed by filtration from solution and stored under anaerobic
5 conditions at O °C prior to use: 1H NMR (DMSO-d 6) 8 2.41 (s, 3H), 2.78 (d, J=4.4
Hz, 3H), 4.93 (br s, 2H), 7.19 (dd, J=8.5, 2.6 Hz, lH), 7.23 (dd, J=5.5, 2.6 Hz, lH),
7.26 (d, J=2.6 Hz, lH), 7.55 (d, J=2.6 Hz, lH), 7.64 (d, J=8.8 Hz, lH), 8.55 (d,
J=5.9 Hz, lH), 8.99 (q, J=4.8 Hz, lH).
10 A6. General Method for the Synthesis of Anilines from

Hydroxyanilines by N-Protection, Nucleophilic Aromatric Substitution and
Deprotection. Synthesis of 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-
chloroaniline
0 NOH
F3C)lNY
H Cl
15 Step 1: Synthesis of 3-Chloro-4-(2,2,2-trifluoroacetylamino )phenol

Iron (3.24 g, 58.00 mmol) was added to stirring TFA (200 mL). To this slurry was
added 2-chloro-4-nitrophenol (10.0 g, 58.0 mmol) and trifluoroacetic anhydride (20
mL). This gray slurry was stirred at room temp. for 6 d. The iron was filtered from
solution and the remaining material was concentrated under reduced pressure. The
20 resulting gray solid was dissolved in water (20 mL). To the resulting yellow
solution was added a saturated NaHCO3 solution (50 mL). The solid which
precipitated from solution was removed. The filtrate was slowly quenched with the
sodium bicarbonate solution until the product visibly separated from solution
(determined was using a mini work-up vial). The slightly cloudy yellow solution
25 was extracted with EtOAc (3 x 125 mL). The combined organic layers were
washed with a saturated NaCl solution (125 mL), dried (MgSO4) and concentrated
under reduced pressure. The 1H NMR (DMSO-d 6) indicated a 1:1 ratio of the
nitrophenol starting material and the intended product 3-chloro-4-(2,2,2-
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trifluoroacetylamino )phenol. The crude material was taken on to the next step
without further purification.
o No~NHMe
F3C)lNY ~~
H Cl
5 Step 2: Synthesis of 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-

chlorophenyl (222-trifluoro )acetamide
A solution of crude 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol (5.62 g, 23.46
mmol) in dry dimethylacetamide (50 mL) was treated with potassium tert-butoxide
(5.16 g, 45.98 mmol) and the brownish black mixture was stirred at room temp.
10 until the flask had cooled to room temp. The resulting mixture was treated with 4-
chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 1.99 g, 11.7 mmol)
and heated at 100 °C under argon for 4 d. The black reaction mixture was cooled to
room temp. and then poured into cold water (100 mL). The mixture was extracted
with EtOAc (3 x 75 mL) and the combined organic layers were concentrated under
15 reduced pressure. The residual brown oil was purified by column chromatography
(gradient from 20% EtOAc/pet. ether to 40% EtOAc/pet. ether) to yield 4-(2-(N-
Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-trifluoro )acetamide as a
yellow solid (8.59 g, 23.0 mmol).
0
O
('Y ~NHMe
H2N~CI ~~
20 Step 3. Synthesis of 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-
chloroaniline
A solution of crude 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-
trifluoro )acetamide (8.59 g, 23.0 mmol) in dry 4-dioxane (20 mL) was treated with a
IN NaOH solution (20 mL). This brown solution was allowed to stir for 8 h. To
25 this solution was added EtOAc (40 mL). The green organic layer was extracted
with EtOAc (3 x 40 mL) and the solvent was concentrated to yield 4-(2-(N-
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Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline as a green oil that solidified upon

standing (2.86 g, 10.30 mmol): 1H NMR (DMSO-d6) 6 2.77 (d, J=4.8 Hz, 3H), 5.51
(s, 2H), 6.60 (dd, J=8.5, 2.6 Hz, lH), 6.76 (d, J=2.6 Hz, IH), 7.03 (d, J=8.5 Hz,
lH), 7.07 (dd, J=5.5, 2.6, Hz, lH), 7.27 (d, J=2.6 Hz, lH), 8.46 (d, J=5.5 Hz, lH),
5 8.75 (q, J=4.8, lH).
A 7. General Method for the Deprotection of an Acylated Aniline.

Synthesis of 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline
Cl~
YNH2
OMe
10 A suspension of 3-chloro-6-(N-acetyl)-4-(trifluoromethyl)anisole (4.00 g,

14.95 mmol) in a 6M HCl solution (24 mL) was heated at the reflux temp.
for I h. The resulting solution was allowed to cool to room temp. during
which time it solidified slightly. The resulting mixture was diluted with
water (20 mL) then treated with a combination of solid NaOH and a
15 saturated NaHCO 3 solution until the solution was basic. The organic layer
was extracted with CH2Cli (3 x 50 mL). The combined organics were dried
(MgSO4) and concentrated under reduced pressure to yield 4-chloro-2-
methoxy-5-(trifluoromethyl)aniline as a brown oil (3.20 g, 14.2 mmol): 1H
NMR (DMSO-d6) 6 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).
20
AS. General Method for Synthesis of c.o-Alkoxy-c.o-carboxyphenyl

Anilines. Synthesis of 4-(3-(N-Methylcarbamoly)-4-
methoxyphenoxy)aniline.
0
oOO:OMe
02N OMe
25 Step 1. 4-(3-Methoxycarbonyl-4-methoxyph en oxy)-1-nitrobenzene:
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To a solution of 4-(3-carboxy-4-hydroxyphenoxy)-l-nitrobenzene (prepared from

2,5-dihydroxybenzoic acid in a manner analogous to that described in Method A13,
Step 1, 12 mmol) in acetone (50 mL) was added K2CO3 (5 g) and dimethyl sulfate
(3.5 mL). The resulting mixture was heated at the reflux temp. overnight, then
5 cooled to room temp. and filtered through a pad of Celite®. The resulting solution
was concentrated under reduced pressure, absorbed onto SiO2, and purified by
column chromatography (50% EtOAc / 50% hexane) to give 4-(3-methoxycarbonyl-
4-methoxyphenoxy)-1-nitrobenzene as a yellow powder (3 g): mp 115-118 °C.
0
~O~OH
0 2 N~ VOMe
10 Step 2. 4-(3-Carboxy-4-metboxyphenoxy)-1-nitrobenzene:
A mixture of 4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene (1.2 g),
KOH (0.33 g) and water (5 mL) in MeOH (45 mL) was stirred at room temp.
overnight and then heated at the reflux temp. for 4 h. The resulting mixture was
cooled to room temp. and concentrated under reduced pressure. The residue was
15 dissolved in water (50 mL), and the aqueous mixture was made acidic with a IN
HCl solution. The resulting mixture was extracted with EtOAc (50 mL). The
organic layer was dried (MgSO4) and concentrated under reduced pressure to give
4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene ( 1.04 g).
0
oodNHMe
02N OMe
20 Step 3. 4-(3-(N-Methylcarb amoly )-4-metboxyph en oxy )-1-nitrobenzene:

To a solution of 4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (0.50 g, 1.75
mmol) in CH2Ch (12 mL) was added SOCh (0.64 mL, 8.77 mmol) in portions. The
resulting solution was heated at the reflux temp. for 18 h, cooled to room temp., and
concentrated under reduced pressure. The resulting yellow solids were dissolved in
25 CH2Ch (3 mL) then the resulting solution was treated with a methylamine solution
(2.0 M in THF, 3.5 mL, 7.02 mmol) in portions (CAUTION: gas evolution), and
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stirred at room temp. for 4 h. The resulting mixture was treated with a lN NaOH
solution, then extracted with CH2Ch (25 mL). The organic layer was dried
(Na2 S0 4 ) and concentrated under reduced pressure to give 4-(3-(N-
methylcarbamoly)-4-methoxyphenoxy)-l-nitrobenzene as a yellow solid (0.50 g,
5 95%).
0
o01XNHMe
H2N OMe
A slurry of 4-(3-(N-methylcarbamoly)-4-methoxyphenoxy)-1-nitrobenzene (0.78 g,
2.60 mmol) and 10% Pd/C (0.20 g) in EtOH (55 mL) was stirred under 1 atm of H2
10 (balloon) for 2.5 d, then was filtered through a pad of Celite®. The resulting
solution was concentrated under reduced pressure to afford 4-(3-(N-
methylcarbamoly)-4-methoxyphenoxy)aniline as an off-white solid (0.68 g, 96%):
TLC (0.1% Et3N/99 .9% EtOAc) R10.36.
15 A9. General Method for Preparation of co-Alkylphthalimide-

containing Anilines. Synthesis of 5-(4-Aminophenoxy)-2-
methylisoindoline-1,3-dione
0
Step 1. Synthesis of 5-(4-Nitrophenoxy)-2-methylisoindoline-1,3-dione:
20 A slurry of 5-(4-nitrophenoxy)isoindoline-1,3-dione (A3 Step 2; 1.0 g, 3.52 mmol)
and NaH (0.13 g, 5.27 mmol) in DMF (15 mL) was stirred at room temp. for 1 h,
then treated with methyl iodide (0.3 mL, 4.57 mmol). The resulting mixture was
stirred at room temp. overnight, then was cooled to °C and treated with water (10
mL). The resulting solids were collected and dried under reduced pressure to give
25 5-(4-nitrophenoxy)-2-methylisoindoline-1,3-dione as a bright yellow solid (0.87 g,
83%): TLC (35% EtOAc/65% hexane) R10.6l.
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o«?
H2 NO I
~
0
N-Me
Step 2. Synthesis of 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione:

A slurry of nitrophenoxy)-2-methylisoindoline-1,3-dione (0.87 g, 2. 78 mmol) and
10% Pd/C (0.10 g) in MeOH was stirred under 1 atm ofH 2 (balloon) overnight. The
5 resulting mixture was filtered through a pad of Celite® and concentrated under
reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 mL) and
filtered through a plug of SiO2 (60% EtOAc/40% hexane) to afford 5-(4-
aminophenoxy)-2-methylisoindoline-l,3-dione as a yellow solid (0.67 g, 86%):
TLC (40% EtOAc/60% hexane) R10.27.
10
AlO. General Method for Synthesis of ro-Carbamoylaryl Anilines

Through Reaction of ro-Alkoxycarbonylaryl Precursors with
Amines. Synthesis of 4-(2-(N-(2-morpholin-4-
ylethyl)carbamoyl)pyridyloxy)aniline
0
Cl'CrN~cO
15
Step 1. Synthesis of 4-Chloro-2-(N-(2-morpholin-4-
To a solution of methyl 4-chloropyridine-2-carboxylate HCl salt (Method A2, Step
2; 1.01 g, 4.86 mmol) in THF (20 mL) was added 4-(2-aminoethyl)morpholine (2.55
20 mL, 19.4 mmol) dropwise and the resulting solution was heated at the reflux temp.
for 20 h, cooled to room temp., and treated with water (50 mL). The resulting
mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSO4)
and concentrated under reduced pressure to afford 4-chloro-2-(N-(2-morpholin-4-
ylethyl) carbamoyl)pyridine as a yellow oil (1.25 g, 95%): TLC (10% MeOH/90%
25 EtOAc) Rr 0.50.
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Step 2. Synthesis of 4-(2-(N-(2-Morpholin-4-

A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium tert-butoxide (0.53
5 g, 4.75 mol) in DMF (8 mL) was stirred at room temp. for 2 h, then was sequentially
treated with 4-chloro-2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine (1.22 g, 4.52
mmol) and K2CO3 (0.31 g, 2.26 mmol). The resulting mixture was heated at 75 °C
overnight, cooled to room temp., and separated between EtOAc (25 mL) and a
saturated NaCl solution (25 mL). The aqueous layer was back extracted with
10 EtOAc (25 mL). The combined organic layers were washed with a saturated NaCl
solution (3 x 25 mL) and concentrated under reduced pressure. The resulting brown
solids were purified by column chromatography (58 g; gradient from 100% EtOAc
to 25% MeOH/75% EtOAc) to afford 4-(2-(N-(2-morpholin-4-
ylethyl)carbamoyl)pyridyloxy)aniline (1.0 g, 65%): TLC (10% MeOH/90% EtOAc)
15 R10.32.
All. General Method for the Reduction of Nitroarenes to Arylamines.

Synthesis of 4-(3-Carboxyphenoxy)aniline.
0
H,N0°d H
20 A slurry of 4-(3-carboxyphenoxy)-1-nitrobenzene (5.38 g, 20.7 mmol) and 10%

Pd/C (0.50 g) in MeOH (120 mL) was stirred under an H2 atmosphere (balloon) for
2 d. The resulting mixture was filtered through a pad of Celite®, then concentrated
under reduced pressure to afford 4-(3-carboxyphenoxy)aniline as a brown solid
(2.26 g, 48%): TLC (10% MeOH/90% CH2Cli) Rr 0.44 (streaking).
25
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A12. General Method for the Synthesis of Isoindolinone-Containing

Anilines. Synthesis of 4-(1-0xoisoindolin-5-yloxy)aniline.
HO~NH
0
5 To a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 mL) was
slowly added zinc dust (47.6 g, 729 mmol) in portions, then the mixture was heated
at the reflux temp. for 40 min., filtered hot, and concentrated under reduced
pressure. The reaction was repeated on the same scale and the combined oily
residue was purified by column chromatography (1 .1 Kg SiO2 ; gradient from 60%
10 EtOAc/40% hexane to 25% MeOH/75% EtOAc) to give 5-hydroxyisoindolin-1-one
(3.77 g): TLC (100% EtOAc) R1 0.I 7; HPLC ES-MS mlz 150 ((M+H/).
0
Step 2. Synthesis of 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene
To a slurry of NaH (0.39 g, 16.1 mmol) in DMF at O °C was added 5-
15 hydroxyisoindolin-1-one (2.0 g, 13.4 mmol) in portions. The resulting slurry was
allowed to warm to room temp. and was stirred for 45 min., then 4-fluoro-1-
nitrobenzene was added and then mixture was heated at 70 °C for 3 h. The mixture
was cooled to O °C and treated with water dropwise until a precipitate formed. The
resulting solids were collected to give 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene as
20 a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) R1 0.35.
0
A slurry of 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene (2.12 g, 7.8 mmol) and 10%
Pd/C (0.20 g) in EtOH (50 mL) was stirred under an H2 atmosphere (balloon) for 4
25 h, then filtered through a pad of Celite®. The filtrate was concentrated under
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reduced pressure to afford 4-(1-oxoisoindolin-5-yloxy)aniline as a dark yellow

solid: TLC (100% EtOAc) R1 0.15.
A13. General Method for the Synthesis of ro-Carbamoyl Anilines via

5 EDCI-Mediated Amide Formation Followed by Nitroarene
Reduction. Synthesis of 4-(3-N-
Methylcarbamoylphenoxy)aniline.
0
0
r(Y ~0Et
02N¼1 V
Step 1. Synthesis of 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene
10 A mixture of 4-fluoro-1-nitrobenzene (16 mL, 150 mmol), ethyl 3-hydroxybenzoate
25 g, 150 mmol) and K2 CO3 (41 g, 300 mmol) in DMF (125 mL) was heated at the
reflux temp. overnight, cooled to room temp. and treated with water (250 mL). The
resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic
phases were sequentially washed with water (3 x 100 mL) and a saturated NaCl
15 solution (2 x 100 mL), dried (Na2SO4) and concentrated under reduced pressure.
The residue was purified by column chromatography (10% EtOAc/90% hexane) to
afford 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene as an oil (38 g).
Step 2.
o,No
0
d 0
H
Synthesis of 4-(3-carboxyphenoxy)-1-nitrobenzene
20 To a vigorously stirred mixture of 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene
(5.14 g, 17.9 mmol) in a 3:1 THF/water solution (75 mL) was added a solution
LiOH•H2 O (1.50 g, 35.8 mmol) in water (36 mL). The resulting mixture was heated
at 50 °C overnight, then cooled to room temp., concentrated under reduced pressure,
and adjusted to pH 2 with a IM HCl solution. The resulting bright yellow solids
25 were removed by filtration and washed with hexane to give 4-(3-carboxyphenoxy)-
1-nitrobenzene (4.40 g, 95%).
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oodNHMe
0 2N
Step 3. Synthesis of 4-(3-(N-methylcarbamoyl)phenoxy}-l-nitrobenzene

A mixture of 4-(3-carboxyphenoxy)-l-nitrobenzene (3.72 g, 14.4 mmol), EDCI•HCl
(3.63 g, 18.6 mmol), N-methylmorpholine (1.6 mL, 14.5 mmol) and methylamine
5 (2.0 Min THF; 8 mL, 16 mmol) in CH2Ch (45 mL) was stirred at room temp. for 3
d, then concentrated under reduced pressure. The residue was dissolved in EtOAc
(50 mL) and the resulting mixture was extracted with a lM HCl solution (50 mL).
The aqueous layer was back-extracted with EtOAc (2 x 50 mL). The combined
organic phases were washed with a saturated NaCl solution (50 mL), dried
10 (Na2SO4), and concentrated under reduced pressure to give 4-(3-(N-
methylcarbamoyl)phenoxy)-1-nitrobenzene as an oil (1.89 g).
oodNHMe
H2 N
15 Step 4. Synthesis of 4-(3-(N-methylcarbamoyl)phenoxy)aniline

A slurry of 4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene (1.89 g, 6.95 mmol)
and 5% Pd/C (0.24 g) in EtOAc (20 mL) was stirred under an H2 atm (balloon)
overnight. The resulting mixture was filtered through a pad of Celite® and
concentrated under reduced pressure. The residue was purified by column
20 chromatography (5% MeOH/95% CH2Clz). The resulting oil solidified under
vacuum overnight to give 4-(3-(N-methylcarbamoyl)phenoxy)aniline as a yellow
solid (0.95 g, 56%).
A14. General Method for the Synthesis of ro-Carbamoyl Anilines via

25 EDCI-Mediated Amide Formation Followed by Nitroarene Reduction.
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Step 1. Synthesis of 4-(3-(5-rnethoxycarbonyl)pyridyloxy)-1-

nitrobenzene
To a slurry of NaH (0.63 g, 26.1 mmol) in DMF (20 mL) was added a solution of
5 methyl 5-hydroxynicotinate (2.0 g, 13.1 mmol) in DMF (10 mL). The resulting
mixture was added to a solution of 4-fluoronitrobenzene (1 .4 mL, 13.1 mmol) in
DMF (10 mL) and the resulting mixture was heated at 70 °C overnight, cooled to
room temp., and treated with MeOH (5 mL) followed by water (50 mL). The
resulting mixture was extracted with EtOAc (100 mL). The organic phase was
10 concentrated under reduced pressure. The residue was purified by column
chromatography (30% EtOAc/70% hexane) to afford 4-(3-(5-
methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.60 g).
0
oOtrOMe
H2N N
Step 2. Synthesis of 4-(3-(5-rnethoxycarbonyl)pyridyloxy)aniline

15 A slurry of 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.60 g, 2.20
mmol) and 10% Pd/C in MeOH/EtOAc was stirred under an H2 atmosphere
(balloon) for 72 h. The resulting mixture was filtered and the filtrate was
chromatography (gradient from 10% EtOAc/90% hexane to 30% EtOAc/70%
20 hexane to 50% EtOAc/50% hexane) to afford 4-(3-(5-
1
methoxycarbonyl)pyridyloxy)aniline (0.28 g, 60%): H NMR (CDCh) 8 3.92 (s,
3H), 6.71 (d, 2H), 6.89 (d, 2H), 7.73 (, lH), 8.51 (d, lH), 8.87 (d, lH).
AlS. Synthesis of an Aniline via Electrophilic Nitration Followed by

25 Reduction. Synthesis of 4-(3-Methylsulfarnoylphenoxy)aniline.
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Step 1. Synthesis of N-methyl-3-bromobenzenesulfonamide

To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15
mL) at 0 °C was added methylamine (2.0 M in THF; 28 mL, 56 mmol). The
s resulting solution was allowed to warn1 to room temp. and was stirred at room temp.
overnight. The resulting mixture was separated between EtOAc (25 mL) and a 1 M
HCl solution (25 mL). The aqueous phase was back-extracted with EtOAc (2 x 25
mL). The combined organic phases were sequentially washed with water (2 x 25
mL) and a saturated NaCl solution (25 mL), dried (MgSO4) and concentrated under
10 reduced pressure to give N-methyl-3-bromobenzenesulfonamide as a white solid
(2.8 g, 99%).
av o
0, /0
's,,.
'NHMe
Step 2. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)benzene

To a slurry of phenol ( 1.9 g, 20 mmol), K2CO3 ( 6.0 g, 40 mmol), and Cul (4 g, 20
15 mmol) in DMF (25 mL) was added N-methyl-3-bromobenzenesulfonamide (2.5 g,
10mmol), and the resulting mixture was stirred at the reflux temp. overnight, cooled
to room temp., and separated between EtOAc (50 mL) and a 1 N HCl solution (50
mL). The aqueous layer was back-extracted with EtOAc (2 x 50 mL). The
combined organic phases were sequentially washed with water (2 x 50 mL) and a
20 saturated NaCl solution (50 mL), dried (MgSO4), and concentrated under reduced
pressure. The residual oil was purified by column chromatography (30%
EtOAc/70% hexane) to give 4-(3-(N-methylsulfamoyl)phenyloxy)benzene (0.30 g).
0, ,,.0
~oyYs:NHMe
02N~ V
Step 3. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)-1-nitrobenzene
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To a solution of 4-(3-(N-methylsulfamoyl)phenyloxy)benzene (0.30 g, 1.14 mmol)

in TFA (6 mL) at -10°C was added NaNO 2 (0.097 g, 1.14 mmol) in portions over 5
min. The resulting solution was stirred at -10 °C for I h, then was allowed to warm
to room temp., and was concentrated under reduced pressure. The residue was
5 separated between EtOAc (10 mL) and water (10 mL). The organic phase was
sequentially washed with water (10 mL) and a saturated NaCl solution (10 mL),
dried (MgSO 4) and concentrated under reduced pressure to give 4-(3-(N-
methylsulfamoyl)phenyloxy)-1-nitrobenzene (0.20 g). This material carried on to
0, ,,0
o 's"
r(y yY 'NHMe
10
H2N~ V
A slurry of 4-(3-(N-methylsulfamoyl)phenyloxy)-1-nitrobenzene (0.30 g) and 10%
Pd/C (0.030 g) in EtOAc (20 mL) was stirred under an H2 atmosphere (balloon)
overnight. The resulting mixture was filtered through a pad of Celite®. The filtrate
15 was concentrated under reduced pressure. The residue was purified by column
methylsulfamoyl)phenyloxy)aniline (0.070 g).
A16. Modification of co-ketones. Synthesis of 4-(4-(1-(N-

20 methoxy)iminoethyl)phenoxyaniline HCI salt.
,,o,
H2NUHClef~
~ I ~ I
0
To a slurry of 4-(4-acetylphenoxy)aniline HCl salt (prepared in a manner analogous

to Method A13, step 4; 1.0 g, 3.89 mrnol) in a mixture of EtOH (10 mL) and
pyridine (1.0 mL) was added O-methylhydroxylamine HCl salt (0.65 g, 7.78 mmol,
25 2.0 equiv.). The resulting solution was heated at the reflux temperature for 30 min,
cooled to room temperature and concentrated under reduced pressure. The resulting
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solids were triturated with water (10 mL) and washed with water to give 4-(4-(1-(N-
methoxy)iminoethyl) phenoxyaniline HCI salt as a yellow solid (0.85 g): TLC (50%
EtOAc/50% pet. ether) R1 0.78; 1H NMR (DMSO-d6) 8 3.90 (s, 3H), 5.70 (s, 3H);
HPLC-MS m/z 257 ((M+Ht).
5
Al 7. Synthesis of N-( ro-Silyloxyalkyl)amides. Synthesis of 4-(4-(2-(N-

(2-Triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline.
Step 1. 4-Chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide
10 To a solution of 4-chloro-N-(2-hydroxyethyl)pyridine-2-carboxamide (prepared in a
manner analogous to Method A2, Step 3b; 1.5 g, 7.4 mmol) in anh DMF (7 mL) was
added triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv.) and imidazole (1.12
g, 16.4 mmol, 2.2 equiv.). The resulting yellow solution was stirred for 3 hat room
temp, then was concentrated under reduced pressure. The residue was separated
15 between water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with
EtOAc (3 x 10 mL). The combined organic phases were dried (MgSO4), and
concentrated under reduced pressure to afford 4-chloro-2-(N-(2-
triisopropylsilyloxy)ethyl)pyridinecarboxamide as an orange oil (2.32 g, 88%). This
material was used in the next step without further purification.
20
Step 2. 4-(4-(2-(N-(2-
Triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline
potassium tert-butoxide (0.67 g, 6.0 mmol, 1.0 equiv.) in one portion causing an
25 exotherm. When this mixture had cooled to room temperature, a solution of 4-
chloro-2-(N-(2-triisopropylsilyloxy )ethyl)pyridinecarboxamide (2.32 g, 6 mmol, 1
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equiv.) in DMF (4 mL) was added followed by K2 CO3 (0.42 g, 3.0 mmol, 0.50
equiv.). The resulting mixture was heated at 80 °C overnight. An additional portion
of potassium tert-butoxide (0.34 g, 3 mmol, 0.5 equiv.) was then added and the
mixture was stirred at 80 °C an additional 4 h. The mixture was cooled to O °C with
5 an ice/water bath, then water (approx. 1 mL) was slowly added dropwise. The
organic layer was extracted with EtOAc (3 x 10 mL). The combined organic layers
were washed with a saturated NaCl solution (20 mL), dried (MgSO 4) and
concentrated under reduced pressure. The brown oily residue was purified by
column chromatography (SiO2 ; 30% EtOAc/ 70% pet ether) to afford 4-( 4-(2-(N-(2-
10 triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline as a clear light brown oil
(0.99 g, 38%).
Al8. Synthesis of 2-Pryidinecarboxylate Esters via Oxidation of 2-

15 methoxycarbonyl)pyridyloxy)aniline.
o,NOo'(:l
A mixture of 5-hydroxy-2-methylpyridine (10.0 g, 91.6 mmol), 1-fluoro-4-
nitrobenzene (9.8 mL, 91.6 mmol, 1.0 equiv.), K2CO3 (25 g, 183 mmol, 2.0 equiv.)
20 in DMF (100 mL) was heated at the reflux temperature overnight. The resulting
mixture was cooled to room temperature, treated with water (200 mL), and extracted
with EtOAc (3 x 100 mL). The combined organic layers were sequentially washed
with water (2 x 100 mL) and a saturated NaCl solution ((100 mL), dried (MgSO4)
and concentrated under reduced pressure to give 4-(5-(2-methyl)pyridyloxy)-1-
25 nitrobenzene as a brown solid (12.3 g).
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Step 2. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)-1-

nitrobenzene.
A mixture of 4-(5-(2-methyl)pyridyloxy)-1-nitrobenzene (1.70 g, 7.39 mmol) and
selenium dioxide (2.50 g, 22.2 mmol, 3.0 equiv.) in pyridine (20 mL) was heated at
5 the reflux temperature for 5 h, then cooled to room temperature. The resulting
slurry was filtered , then concentrated under reduced pressure. The residue was
dissolved in MeOH (100 mL). The solution was treated with a cone HCl solution (7
mL), then heated at the reflux temperature for 3 h, cooled to room temperature and
concentrated under reduced pressure. The residue was separated between EtOAc
10 (50 mL) and a IN NaOH solution (50 mL). The aqueous layer was extracted with
EtOAc (2 x 50 mL). The combined organic layers were sequentially washed with
water (2 x 50 mL) and a saturated NaCl solution (50 mL), dried (MgSO4) and
chromatography (SiO2; 50% EtOAc/50% hexane) to afford 4-(5-(2-
15 methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0. 70 g).
H,N0°'0y0Me
0

A slurry of 4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.50 g) and 10%
Pd/C (0.050 g) in a mixture ofEtOAc (20 mL) and MeOH (5 mL) was placed under
20 a H2 atmosphere (balloon) overnight. The resulting mixture was filtered through a
pad of Celite®, and the filtrate was concentrated under reduced pressure. The
residue was purified by column chromatography (SiO2; 70% EtOAc/30% hexane) to
give 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline (0.40 g).
25 A19. Synthesis of ro-Sulfonylphenyl Anilines. Synthesis of 4-(4-

Methylsulfonylphenyoxy)aniline.
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~0'0
0 2 N~ ~s~Me
~ ~
0 0
Step 1. 4-(4-Methylsulfonylphenoxy)-1-nitrobenzene: To a solution of 4-(4-
methylthiophenoxy)-1-nitrobenzene (2.0 g, 7.7 mmol) in CH2 Clz (75 mL) at O °C
was slowly added m-CPBA (57-86%, 4.0 g), and the reaction mixture was stirred at
5 room temperature for 5 h. The reaction mixture was treated with a IN NaOH
solution (25 mL). The organic layer was sequentially washed with a IN NaOH
solution (25 mL), water (25 mL) and a saturated NaCl solution (25 mL), dried
(MgSO 4), and concentrated under reduced pressure to give 4-(4-
methylsulfonylphenoxy)-1-nitrobenzene as a solid (2.1 g).
Step 2. 4-(4-Methylsulfonylphenoxy)-1-aniline: 4-(4-Methylsulfonylphenoxy)-1-

nitrobenzene was reduced to the aniline in a manner analogous to that described in
Method A18, step 3.
15 B. Synthesis of Urea Precursors

Bl. General Method for the Synthesis of Isocyanates from Anilines
Using CDI. Synthesis of 4-Bromo-3-(trifluoromethyl)phenyl
Isocyanate.
Br~
O
j NH2•HCI
20 Step 1. Synthesis of 4-bromo-3-(trifluoromethyl)aniline HCI salt

To a solution of 4-bromo-3-(trifluoromethyl)aniline (64 g, 267 mmol) in Et2O (500
mL) was added an HCl solution (1 Min Et2O; 300 mL) dropwise and the resulting
mixture was stirred at room temp. for 16 h. The resulting pink-white precipitate was
removed by filtration and washed with Et2O (50 mL) and to afford 4-bromo-3-
25 (trifluoromethyl)aniline HCl salt (73 g , 98%).
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A suspension of 4-bromo-3-(trifluoromethyl)aniline HCl salt (36.8 g, 133 mmol) in
toluene (278 mL) was treated with trichloromethyl chloroformate dropwise and the
5 resulting mixture was heated at the reflux temp. for 18 h. The resulting mixture was
concentrated under reduced pressure. The residue was treated with toluene (500
mL), then concentrated under reduced pressure. The residue was treated with
CH2Cli (500 mL), then concentrated under reduced pressure. The CH2Ch
treatment/concentration protocol was repeated and resulting amber oil was stored at
10 -20 °C for 16 h, to afford 4-bromo-3-(trifluoromethyl)phenyl isocyanate as a tan
solid (35.1 g, 86%): GC-MS 111/z265 (M+).

Cla. General Method for the Synthesis of Ureas by Reaction of an
15 Isocyanate with an Aniline. Synthesis of N-(4-Chloro-3-
(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-
CF3 0
Cl~ O ~o~NHMe
UN)lN~ ~~
H H
A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (14.60 g, 65.90 mmol)
20 in CH2Ch (35 mL) was added dropwise to a suspension of 4-(2-(N-
methylcarbamoyl)-4-pyridyloxy)aniline (Method A2, Step 4; 16.0 g, 65.77 mmol) in
CH2Ch (35 mL) at 0 0 C. The resulting mixture was stirred at room temp. for 22 h.
The resulting yellow solids were removed by filtration, then washed with CH2Ch (2
x 30 mL) and dried under reduced pressure (approximately 1 mmHg) to afford N-(4-
25 chloro-3-( tri fluoromethyl )phenyl)-N '-(4-(2-(N-meth ylcarbamoyl )-4-
pyridyloxy )phenyl) urea as an off-white solid (28.5 g, 93%): mp 207-209 °C; 1H-
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NMR (DMSO-d 6) 8 2.77 (d, J=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J=2.5 Hz, lH),
7.62 (m, 4H), 8.11 (d, J=2.5 Hz, lH), 8.49 (d, J=5.5 Hz, lH), 8.77 (br d, lH), 8.99
(s, lH), 9.21 (s, lH); HPLC ES-MS m/z 465 ((M+Ht).
5 Clb. General Method for the Synthesis of Ureas by Reaction of an

Isocyanate with an Aniline. Synthesis of N-(4-Bromo-3-
(triflu oromethyl)ph enyl)-N'-( 4-(2-(N-methylcarbamoyl)-4-
pyridy loxy)phenyl) Urea
CF3 0
Br~ O ~o~NHMe
UNJlN~ ~~
H H
10 A solution of 4-bromo-3-(trifluoromethyl)phenyl isocyanate (Method Bl, Step 2;
8.0 g, 30.1 mmol) in CH2Cb (80 mL) was added dropwise to a solution of 4-(2-(N-
methylcarbamoyl)-4-pyridyloxy)aniline (Method A2, Step 4; 7.0 g, 28.8 mmol) in
CH2Cli (40 mL) at O °C. The resulting mixture was stirred at room temp. for 16 h.
The resulting yellow solids were removed by filtration, then washed with CH2Cb (2
15 x 50 mL) and dried under reduced pressure (approximately 1 mmHg) at 40 °C to
afford N-( 4-bromo-3-(trifluoromethyl)phenyl)-N '-(4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)phenyl) urea as a pale-yellow solid (13.2 g, 90%): mp 203-205 °C; 1H-
NMR (DMSO-d6) 8 2.77 (d, J=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J=2.5 Hz, lH),
7.58 (m, 3H), 7.77 (d, J=8.8 Hz, lH), 8.11 (d, J=2.5 Hz, lH), 8.49 (d, J=5.5 Hz,
20 lH), 8.77 (br d, lH), 8.99 (s, lH), 9.21 (s, lH); HPLC ES-MS mlz 509 ((M+Ht).
Cle. General Method for the Synthesis of Ureas by Reaction of an

Isocyanate with an Aniline. Synthesis of N-(4-Chloro-3-
(trifluoromethyl)phenyl)-N'-(2-methyl-4-(2-(N-
25 methylcarbamoyl)(4-pyridyloxy))phenyl) Urea
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CF3 0
Cl'O O qodNHMe
I ,,,_,,,
/ N~NII ~ I I ~N
H H Me
A solution of 2-methyl-4-(2-(N-methylcarbamoyl)( 4-pyridyloxy))aniline (Method

A5; 0.11 g, 0.45 mmol) in CH2Clz (1 mL) was treated with Et3N (0.16 mL) and 4-
chloro-3-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.45 mmol). The resulting
5 brown solution was stirred at room temp. for 6 d, then was treated with water (5
mL). The aqueous layer was back-extracted with EtOAc (3 x 5 mL). The combined
organic layers were dried (MgSO4) and concentrated under reduced pressure to
yield N-( 4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-methyl-4-(2-(N-
methylcarbamoyl)( 4-pyridyloxy) )phenyl) urea as a brown oil (0.11 g, 0.22 mmol):
1
10 H NMR (DMSO-d 6) 8 2.27 (s, 3H), 2.77 (d, J=4.8 Hz, 3H), 7.03 (dd, J=8.5, 2.6 Hz,
lH), 7.11 (d, J=2.9 Hz, lH), 7.15 (dd, J=5.5, 2.6, Hz, lH), 7.38 (d, J=2.6 Hz, lH),
7.62 (app d, J=2.6 Hz, 2H), 7.84 (d, J=8.8 Hz, lH), 8.12 (s, lH), 8.17 (s, lH); 8.50
(d, J=5.5 Hz, lH), 8.78 (q, J=5.2, lH), 9.52 (s, lH); HPLC ES-MS mlz 479
((M+H)+).
15
Cld. General Method for the Synthesis of Ureas by Reaction of an

Isocyanate with an Aniline. Synthesis of N-(4-Chloro-3-
(trifluoromethyl)phenyl)-N'-( 4-aminophenyl) Urea
CF3
Cl~ O ~NH2
v~~
N N
H H
20 To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (2.27 g, 10.3 mmol)
in CH2Clz (308 mL) was added p-phenylenediamine (3.32 g, 30.7 mmol) in one
part. The resulting mixture was stirred at room temp. for 1 h, treated with CH2Ch
(100 mL), and concentrated under reduced pressure. The resulting pink solids were
dissolved in a mixture of EtOAc (110 mL) and MeOH (15mL), and the clear
25 solution was washed with a 0.05 N HCl solution. The organic layer was
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concentrated under reduced pressure to afford impure N-( 4-chloro-3-

(trifluoromethyl)phenyl)-N'-( 4-aminophenyl) urea (3.3 g): TLC (100% EtOAc) R1
0.72.
5 Cle. General Method for the Synthesis of Ureas by Reaction of an

Isocyanate with an Aniline. Synthesis of N-{4-Chloro-3-
(trifluoromethyl)phenyl)-N'-(4-ethoxycarbonylphenyl) Urea
CF3 0
Cl~ 0 ~OEt
VNANN
H H
To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CH2C}z(30 mL)
10 was added 4-chloro-3-(trifluoromethyl)aniline (3.21 g, 16.4 mmol), and the solution
was stirred at room temp. overnight. The resulting slurry was diluted with CH2Cli
(50 mL) and filtered to afford N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-{4-
ethoxycarbonylphenyl) urea as a white solid (5.93 g, 97%): TLC (40% EtOAc/60%
hexane) Ri0.44.
15 Clf. General Method for the Synthesis of Ureas by Reaction of an
Isocyanate with an Aniline. Synthesis of N-{4-Chloro-3-
(trifluoromethyl)phenyl)-N'-{3-carboxyphenyl) Urea
CF3 0
Cl~ 0 ~O~OH
VNAN~
H H
V
To a solution of 4-chloro-3-{trifluoromethyl)phenyl isocyanate (1.21g, 5.46 mmol)
20 in CH2 Ch (8 mL) was added 4-(3-carboxyphenoxy)aniline (Method All; 0.81 g,
5.76 mmol) and the resulting mixture was stirred at room temp. overnight, then
treated with MeOH (8 mL), and stirred an additional 2 h. The resulting mixture was
concentrated under reduced pressure. The resulting brown solids were triturated
with a 1:1 EtOAc/hexane solution to give N-( 4-chloro-3-(trifluoromethyl)phenyl)-
25 N'-(3-carboxyphenyl) urea as an off-white solid (1.21 g, 76%).
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C2a. General Method for Urea Synthesis by Reaction of an Aniline

with N,N'-Carbonyl Diimidazole Followed by Addition of a
Second Aniline. Synthesis of N-(2-Methoxy-5-
(triflu orometh yl)ph enyl)-N' -(4-(2-(N-methylcarbamoyl)-4-
5 pyridyloxy)phenyl) Urea
<i)vVodNHMe
OMe H H
To a solution of 2-methoxy-5-(trifluoromethyl)aniline (0.15 g) in anh CH2 Ch ( 15

mL) at O °C was added CDI (0.13 g). The resulting solution was allowed to warm
to room temp. over 1 h, was stirred at room temp. for 16 h, then was treated with 4-
10 (2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.18 g). The resulting yellow
solution was stirred at room temp. for 72 h, then was treated with H2 O (125 mL).
The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The
combined organics were washed with a saturated NaCl solution (100 mL), dried
(MgSO4 ) and concentrated under reduced pressure. The residue was triturated (90%
15 EtOAc/10% hexane). The resulting white solids were collected by filtration and
washed with EtOAc. The filtrate was concentrated under reduced pressure and the
residual oil purified by column chromatography (gradient from 33% EtOAc/67%
hexane to 50% EtOAc/50% hexane to 100% EtOAc) to give N-(2-methoxy-5-
(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoy1)-4-pyridyloxy)phenyl) urea
20 as a light tan solid (0.098 g, 30%): TLC (100% EtOAc) Rt 0.62; 1H NMR (DMSO-
d6) 8 2.76 (d, J=4.8 Hz, 3H), 3.96 (s, 3H), 7.1-7.6 and 8.4-8.6 (m, 1lH), 8.75 (d,
J=4.8 Hz, lH), 9.55 (s, 1 H); FAB-MS m/z 461 ((M+H)4).
C2b. General Method for Urea Synthesis by Reaction of an Aniline

25 with N,N'-Carbonyl Diimidazole Followed by Addition of a
Second Aniline. Symmetrical Urea's as Side Products of a N,N'-
Carbonyl Diimidazole Reaction Procedure. Synthesis of Bis(4-(2-
(N-methylcarbamoyl)-4-pyridy)oxy)phenyl) Urea
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0 0
MeHN~
~~
O
Y)
~N)lN)V
0 0r O
~NHMe
~~
H H
To a stirring solution of 3-amino-2-methoxyquinoline (0.14 g) in anhydrous CH2Cli
( 15 mL) at O C was added CDI (0.13 g). The resulting solution was allowed to warm
to room temp. over 1 h then was stirred at room temp. for 16 h. The resulting
5 mixture was treated with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.18 g).
The resulting yellow solution stirred at room temp. for 72 h, then was treated with
water (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150
mL). The combined organic phases were washed with a saturated NaCl solution
(100 ml), dried (MgSO4) and concentrated under reduced pressure. The residue was
Io triturated (90% EtOAc/10% hexane). The resulting white solids were collected by
filtration and washed with EtOAc to give bis(4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)phenyl) urea (0.081 g, 44%): TLC (100% EtOAc) R1 0.50; 1H NMR
(DMSO-d6) 8 2.76 (d, J=5.l Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, J=5.4 Hz, lH), 8.75
(d, J=4.8 Hz, 2H), 8.86 (s, 2H); HPLC ES-MS m/z 513 ((M+Ht).
15
C2c. General Method for the Synthesis of Ureas by Reaction of an

Isocyanate with an Aniline. Synthesis of N-(2-Methoxy-5-
(trifluoromethyl)phenyl-N'-(4-(1,3-dioxoisoindolin-5-
yloxy)phenyl) Urea
9')LN0°Ll o
20
OMe H H
0
_ii
To a stirring solution of 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (0.10 g,
0.47 mmol) in CH2Cli (1.5 mL) was added 5-(4-aminophenoxy)isoindoline-1,3-
dione (Method A3, Step 3; 0.12 g, 0.47 mmol) in one portion. The resulting mixture
was stirred for 12 h, then was treated with CH2Cli (10 mL) and MeOH (5 mL). The
25 resulting mixture was sequentially washed with a IN HCl solution (15 mL) and a
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saturated NaCl solution (15 mL ), dried (MgSO4) and concentrated under reduced
pressure to afford N-(2-methoxy-5-(trifluoromethyl)phenyl-N'-(4-(1,3-
dioxoisoindolin-5-yloxy)phenyl) urea as a white solid (0.2 g, 96%): TLC (70%
EtOAc/30% hexane) R1 0.50; 1H NMR (DMSO-d6) 8 3.95 (s, 3H), 7.31-7.10 (m,
5 6H), 7.57 (d, J=9.3Hz, 2H), 7.80 (d, J=8.7 Hz, lH), 8.53 (hr s, 2H), 9.57 (s, IH),
11.27 (br s, lH); HPLC ES-MS 472.0 ((M+H)\ 100%).
C2d. General Method for Urea Synthesis by Reaction of an Aniline

with N,N'-Carbonyl Diimidazole Followed by Addition of a
Second Aniline. Synthesis of N-(5-(tert-Butyl)-2-(2,5-
dimethylpyrrolyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-
To a stirring solution of CDI (0.2 lg, 1.30 mmol) in CH2Cli (2 mL) was added 5-
15 (tert-butyl)-2-(2,5-dimethylpyrrolyl)aniline (Method A4, Step 2; 0.30 g, 1.24 mmol)
in one portion. The resulting mixture was stirred at room temp. for 4 h, then 4-(2-
(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.065 g, 0.267mmol) was then added in
one portion. The resulting mixture was heated at 36 °C overnight, then cooled to
room temp. and diluted with EtOAc (5 mL). The resulting mixture was
20 sequentially washed with water (15 mL) and a lN HCl solution (15mL), dried
(MgSO4), and filtered through a pad of silica gel (50 g) to afford N-(5-(tert-butyl)-2-
(2,5-dimethylpyrrolyl)phenyl)-N'-( 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)
urea as a yellowish solid (0.033 g, 24%): TLC (40% EtOAc/60% hexane) R10.24;
I
H NMR (acetone-d6) 8 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, J=4.8Hz, 3H), 5.83 (s,
25 2H), 6.87-7.20 (m, 6H), 7.17 (dd, IH), 7.51-7.58 (m, 3H), 8.43 (d, J=5.4Hz, IH),
8.57 (d, J=2.1Hz, lH), 8.80 (br s, lH); HPLC ES-MS 512 ((M+H)\ 100%).
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C3. Combinatorial Method for the Synthesis of Diphenyl Ureas Using

Triphosgene
One of the anilines to be coupled was dissolved in dichloroethane (0.10 M). This
5 solution was added to a 8 mL vial (0.5 mL) containing dichloroethane (1 mL). To
this was added a bis(trichloromethyl) carbonate solution (0.12 M in dichloroethane,
0.2 mL, 0.4 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane,
0.2 mL, 1.2 equiv.). The vial was capped and heat at 80 °C for 5 h, then allowed to
cool to room temp for approximately 10 h. The second aniline was added (0.10 M
IO in dichloroethane, 0.5 mL, 1.0 equiv.), followed by diisopropylethylamine (0.35 M
in dichloroethane, 0.2 mL, 1.2 equiv.). The resulting mixture was heated at 80 °C
for 4 h, cooled to room temperature and treated with MeOH (0.5 mL). The resulting
mixture was concentrated under reduced pressure and the products were purified by
reverse phase HPLC.
15
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C4. General Method for Urea Synthesis by Reaction of an Aniline

with Phosgene Followed by Addition of a Second Aniline.
Synthesis of N-(2-Methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-
(N-methylcarbamoyl)-4-pyridyloxy)phenyl) Urea
9'),NOodNHMe
5 OMe H H
To a stirring solution of phosgene (1.9 M in toluene; 2.07 mL0.21 g, 1.30 mmol) in

CH2Ch (20 mL) at O °C was added anh pyridine (0.32 mL) followed by 2-methoxy-
5-(trifluoromethyl)aniline (0.75 g). The yellow solution was allowed to warm to
room temp during which a precipitate formed. The yellow mixture was stirred for 1
1o h, then concentrated under reduced pressure. The resulting solids were treated with
anh toluene (20 mL) followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline
(prepared as described in Method A2; 0.30 g) and the resulting suspension was
heated at 80 °C for 20 h, then allowed to cool to room temp. The resulting mixture
was diluted with water (100 mL), then was made basic with a saturated NaHCO3
15 solution (2-3 mL). The basic solution was extracted with EtOAc (2 x 250 mL). The
organic layers were separately washed with a saturated NaCl solution, combined,
dried (MgSO4), and concentrated under reduced pressure. The resulting pink-brown
residue was dissolved in MeOH and absorbed onto SiO2 (100 g). Column
chromatography (300 g SiO2; gradient from 1% Et3N/33% EtOAc/66% hexane to
20 1% Et3N/99% EtOAc to 1% Et3N/20% MeOH/79% EtOAc) followed by
concentration under reduced pressure at 45 °C gave a warm concentrated EtOAc
solution, which was treated with hexane (10 mL) to slowly form crystals of N-(2-
methoxy-5-(trifluoromethyl)phenyl)-N'-( 4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)phenyl) urea (0.44 g): TLC (1% Et3N/99% EtOAc) R10.40.
25
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D. Interconversion of Ureas
Dla. Conversion of w-Aminophenyl Ureas into w-(Aroylamino)phenyl
Ureas. Synthesis of N-(4-Chloro-3-((trifluoromethyl)phenyl)-N'-
(4-(3-methoxycarbonylphenyl)carboxyaminophenyl) Urea
CF3 HAI
c1'A O ~N ~ OMe
U)l
N N
✓ o o
5 H H
To a solution of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-aminophenyl) urea
(Method Cld; 0.050 g, 1.52 mmol), mono-methyl isophthalate (0.25 g, 1.38 mmol),
HOBT•H 2 O (0.41 g, 3.03 mmol) and N-methylmorpholine (0.33 mL, 3.03 mmol) in
DMF (8 mL) was added EDCI •HCI (0.29 g, 1.52 mmol). The resulting mixture
10 was stirred at room temp. overnight, diluted with EtOAc (25 mL) and sequentially
washed with water (25 mL) and a saturated NaHCO3 solution (25 mL). The organic
layer was dried (Na2SO4) and concentrated under reduced pressure. The resulting
solids were triturated with an EtOAc solution (80% EtOAc/20% hexane) to give N-
(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-
15 methoxycarbonylphenyl)carboxyaminophenyl) urea (0.27 g, 43%): mp 121-122;
TLC (80% EtOAc/20% hexane) R10.75.
Dlb. Conversion of w-Carboxyphenyl Ureas into w-

(Arylcarbamoyl)phenyl Ureas. Synthesis of N-(4-Chloro-3-
20 ((trifluoromethyl)phenyl)-N'-( 4-(3-
CF3 0 r)
c1'A O ~N~NHMe
U)lAJ N N
H 0
H H
To a solution of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-
methylcarbamoylphenyl) carboxyaminophenyl) urea (0.14 g, 0.48 mmol), 3-
25 methylcarbamoylaniline (0.080 g, 0.53 mmol), HOBT•H2O (0.14 g, 1.07 mmol),
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and N-methylmorpholine (0.5mL, 1.07 mmol) in DMF (3 mL) at 0 °C was added

EDCI•HCl (0.10 g, 0.53 mmol). The resulting mixture was allowed to warm to
room temp. and was stirred overnight. The resulting mixture was treated with water
(l0mL), and extracted with EtOAc (25 mL). The organic phase was concentrated
s under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3
mL) then filtered through a pad of silica gel (17 g, gradient from 70% EtOAc/30%
hexane to 10% MeOH/90% EtOAc) to give N-(4-chloro-3-
((trifluoromethyl)phenyl)-N'-(4-(3-methylcarbamoylphenyl) carbamoylphenyl) urea
as a white solid (0.097 g, 41%): mp 225-229; TLC (100% EtOAc) R1 0.23.
10
Dlc. Combinatorial Approach to the Conversion of ro-Carboxyphenyl

Ureas into ro-(Arykarbarnoyl}phenyl Ureas. Synthesis of N-(4-
Cbloro-3-((trifluoromethyl)phenyl)-N'-(4-(N-(3-(N-(3-
pyridyl)carbarnoyl)phenyl)carbamoyl)phenyl) Urea
15
Cl~
U)l)JN
0 ~N½~~~
V H O
N
H H
A mixture of N-(4-chloro-3-({trifluoromethyl)phenyl)-N'-(3-carboxyphenyl) urea
(Method Clf; 0.030 g, 0.067 mmol) and N-cyclohexyl-N'-
(methylpolystyrene)carbodiimide (55 mg) in 1,2-dichloroethane (1 mL) was treated
20 with a solution of 3-aminopyridine in CH2Ch (1 M; 0.074 mL, 0.074 mmol). (In
cases of insolubility or turbidity, a small amount of DMSO was also added.) The
resulting mixture was heated at 36 °C overnight. Turbid reactions were then treated
with THF (1 mL) and heating was continued for 18 h. The resulting mixtures were
treated with poly(4-(isocyanatomethyl)styrene) (0.040 g) and the resulting mixture
25 was stirred at 36 °C for 72 h, then cooled to room temp. and filtered. The resulting
solution was filtered through a plug of silica gel (1 g). Concentration under reduced
pressure afforded N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(N-(3-(N-(3-
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pyridyl)carbamoyl)phenyl)carbamoyl)phenyl) urea (0.024 g, 59%): TLC (70%

EtOAc/30% hexane) Ri0.12.
D2. Conversion of co-Carboalkoxyaryl Ureas into co-Carbamoylaryl

5 Ureas. Syn thesis of N-(4-Ch loro-3-( (trifluoromethyl)phenyl)-N'-
(4-(3-methylcarbamoylphenyl)carboxyaminophenyl) Urea
c1'A
CF3
O
H
~N~NHMe
n
lAJl~N N
a a
H H
To a sample of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-
carbomethoxyphenyl) carboxyaminophenyl) urea (0.17 g, 0.34 mmol) was added
10 methylamine (2 Min THF; 1 mL, 1.7 mmol) and the resulting mixture was stirred at
room temp. overnight, then concentrated under reduced pressure to give N-(4-
chloro-3-((trifluoromethyl)phenyl)-N '-(4-(3-
methylcarbamoylphenyl)carboxyaminophenyl) urea as a white solid: mp 247; TLC
(100% EtOAc) R10.35.
15
D3. Conversion of co-Carboalkoxyaryl Ureas into co-Carboxyaryl

Ureas. Synthesis of N-{4-Chloro-3-((trifluoromethyl)phenyl)-N'-
(4-carboxyphenyl) Urea
CF3 0
ciu O ,(roH
I ✓,:; )l ~I
N N
H H
20 To a slurry of N-( 4-chloro-3-((trifluoromethyl)phenyl)-N'-( 4-ethoxycarbonylphenyl)
urea (Method Cle; 5.93 g, 15.3 mmol) in MeOH (75 mL) was added an aqueous
KOH solution (2.5 N, 10 mL, 23 mmol). The resulting mixture was heated at the
reflux temp. for 12 h, cooled to room temp., and concentrated under reduced
pressure. The residue was diluted with water (50 mL), then treated with a 1 N HCl
25 solution to adjust the pH to 2 to 3. The resulting solids were collected and dried
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under reduced pressure to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-

carboxyphenyl) urea as a white solid (5.05 g, 92%).
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D4. General Method for the Conversion of c:o-AlkoxyEsters into c:o-

Alkyl Amides. Synthesis of N-(4-Chloro-3-
((trifluoromethyl)phenyl)-N'-((4-(3-(5-(2-
dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) Urea
CF3 0
Cl~ 0 00~0H
UNJlN~ lN)
5 H H
Step 1. Synthesis of N-( 4-Chloro-3-(trifluoromethyl)phenyl)-N'-(( 4-(3-(5-
carboxypyridyl) oxyphenyl) Urea
N-( 4-Chloro-3-( trifluorornethyl)phenyl)-N '-((4-(3-( 5-rnethoxycarbonylpyridyl)
oxyphenyl) urea was synthesized from 4-chloro-3-(trifluoromethyl)phenyl
10 isocyanate and 4-(3-(5-methoxycarbonylpyridyl) oxyaniline (Method Al4, Step 2)
in a manner analogous to Method Cla. A suspension of N-(4-chloro-3-
(trifluoromethyl)phenyl)-N '-((4-(3-( 5-methoxycarbonylpyridyl)oxyphenyl) urea
(0.26 g, 0.56 mmol) in MeOH (10 mL) was treated with a solution of KOH (0.14 g,
2.5 mmol) in water (1 mL) and was stirred at room temp. for 1 h. The resulting
15 mixture was adjusted to pH 5 with a 1 N HCl solution. The resulting precipitate
was removed by filtration and washed with water. The resulting solids were
dissolved in EtOH (10 mL) and the resulting solution was concentrated under
reduced pressure. The EtOH/concentration procedure was repeated twice to give N-
(4-chloro-3-(trifluoromethyl)phenyl)-N'-(( 4-(3-(5-carboxypyridyl) oxyphenyl) urea
20 (0.18 g, 71%).
CF3 0 j
Cl~
UN
H
1 N~
H
<;O«~~N,
N
Step 2. Synthesis of N-(4-chloro-3-( trifluoromethyl)phenyl)-N'-(( 4-(3-(5-

(2-dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) urea
A mixture of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-carboxypyridyl)
25 oxyphenyl) urea (0.050 g, 0.011 mmol), N,N-dirnethylethylenediamine (0.22 mg,
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0.17 mmol), HOBT (0.028 g, 0.17 mmol), N-methylmorpholine (0.035 g, 0.28

mmol), and EDCI•HCI (0.032 g, 0.17 mmol) in DMF (2.5 mL) was stirred at room
temp. overnight. The resulting solution was separated between EtOAc (50 mL) and
water (50 mL). The organic phase was washed with water (35 mL), dried (MgSO4)
5 and concentrated under reduced pressure. The residue was dissolved in a minimal
amount of CH2Ch (approximately 2 mL). The resulting solution was treated with
Et2O dropwise to give N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-(2-
dimethylaminoethyl)carbamoyl) pyridyl)oxyphenyl) urea as a white precipitate
(0.48 g, 84%: 1H NMR (DMSO-dG)8 2.10 s, 6H), 3.26 (s, H), 7.03 (d, 2H), 7.52 (d,
10 2H), 7.60 (m, 3H), 8.05 (s, lH), 8.43 (s, IH), 8.58 (t, lH), 8.69 (s, lH), 8.90 (s, lH),
9.14 (s, lH); HPLC ES-MS m/z 522 ((M+H/).
D5. General Method for the Deprotection of N-(ro-

Silyloxyalkyl)amides. Synthesis of N-(4-Chloro-3-
15 ((trifluoromethyl)phenyl)-N'-( 4-(4-(2-(N-(2-
hydroxy)ethylcarbamoyl)pyridyloxyphenyl) Urea.
CF3 • 0 >--
Cl~
u N
H
)l
0
N
H
JV
r(Yo~N~o,Si
~~ H _/
- \
\
To a solution of N-( 4-chloro-3-((trifluoromethyl)phenyl)-N '-(4-(4-(2-(N-(2-

20 analogous to Method Cla; 0.25 g, 0.37 mmol) in anh THF (2 mL) was
tetrabutylammonium fluoride (1.0 M in THF; 2 mL). The mixture was stirred at
room temperature for 5 min, then was treated with water (10 mL). The aqueous
mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were
dried (MgSO4) and concentrated under reduced pressure. The residue was purified
25 by column chromatography (SiO2 ; gradient from 100% hexane to 40% EtOAc/60%
hexane) to give N-( 4-chloro-3-( (trifluoromethyl)phenyl)-N'-( 4-(4-(2-(N-(2-
hydroxy)ethylcarbarnoyl) pyridyloxyphenyl) urea as a white solid (0.019 g, 10%).
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Listed below are compounds listed in the Tables below which have been
synthesized according to the Detailed Experimental Procedures given above:

5 (see Tables for compound characterization)
Entry 1: 4-(3-N-Methylcarbamoylphenoxy)aniline was prepared according to

Method A13. According to Method C3, 3-tert-butylaniline was reacted with
bis(trichloromethyl)carbonate followed by 4-(3-N-Methylcarbamoylphenoxy)aniline
1o to afford the urea.
Entry 2: 4-Fluoro-l-nitrobenzene and p-hydroxyacetophenone were reacted

according to Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-1-nitrobenzene.
4-(4-Acetylphenoxy)-1-nitrobenzene was reduced according to Method A13, Step 4
15 to afford 4-(4-acetylphenoxy)aniline. According to Method C3, 3-tert-butylaniline
was reacted with bis(trichloromethyl) carbonate followed by 4-(4-
acetylphenoxy)aniline to afford the urea.
Entry 3: According to Method C2d, 3-tert-butylaniline was treated with CDI,

20 followed by 4-(3-N-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been
prepared according to Method A8, to afford the urea.
Entry 4: 5-tert-Butyl-2-methoxyaniline was converted to 5-tert-butyl-2-

rnethoxyphenyl isocyanate according to Method B 1. 4-(3-N-
25 Methylcarbamoylphenoxy)aniline, prepared according to Method Al3, was reacted
with the isocyanate according to Method Cla to afford the urea.
Entry 5: According to Method C2d, 5-tert-butyl-2-rnethoxyaniline was reacted with

CDI followed by 4-(3-N-methylcarbamoyl)-4-rnethoxyphenoxy)aniline, which had
30 been prepared according to Method A8, to afford the urea.
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Entry 6: 5-(4-Aminophenoxy)isoindoline-1,3-dione was prepared according to

Method A3. According to Method 2d, 5-tert-butyl-2-methoxyaniline was reacted
with CDI followed by 5-(4-aminophenoxy)isoindoline-l ,3-dione to afford the urea.
5
Entry 7: 4-(1-Oxoisoindolin-5-yloxy)aniline was synthesized according to Method

Al 2. According to Method 2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI
followed by 4-(1-oxoisoindolin-5-yloxy)aniline to afford the urea.
10 Entry 8: 4-(3-N-Methylcarbamoylphenoxy)aniline was synthesized according to

Method Al3. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was
reacted with CDI followed by 4-(3-N-methylcarbamoylphenoxy)aniline to afford the
urea.
15 Entry 9: 4-Hydroxyacetophenone was reacted with 2-chloro-5-nitropyridine to give

4-(4-acetylphenoxy)-5-nitropyridine according to Method A3, Step 2. According to
Method A8, Step 4, 4-(4-acetylphenoxy)-5-nitropyridine was reduced to 4-(4-
acetylphenoxy)-5-aminopyridine. 2-Methoxy-5-(trifluoromethyl)aniline was
converted to 2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method
20 Bl. The isocyanate was reacted with 4-(4-acetylphenoxy)-5-aminopyridine
according to Method C 1a to afford the urea.
Entry 10: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted

according to Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-l-nitrobenzene.
25 4-(4-Acetylphenoxy)-1-nitrobenzene was reduced according to Method Al3, Step 4
to afford 4-(4-acetylphenoxy)aniline. According to Method C3, 5-(trifluoromethyl)-
2-methoxybutylaniline was reacted with bis(trichloromethyl) carbonate followed by
4-(4-acetylphenoxy)aniline to afford the urea.
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Entry 11: 4-Chloro-N-methyl-2-pyridinecarboxamide, which was synthesized

according to Method A2, Step 3a, was reacted with 3-aminophenol according to
Method A2, Step 4 using DMAC in place of DMF to give 3-(-2-(N-
methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C4, 2-methoxy-5-
5 (trifluoromethyl)aniline was reacted with phosgene followed by 3-(-2-(N-
methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-
10 Chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to
Method A2, Step 4 using DMAC in place of DMF to give 3-(2-carbamoyl-4-
pyridyloxy)aniline. According to Method C2a, 2-methoxy-5-
(trifluoromethyl)aniline was reacted with phosgene followed by 3-(2-carbamoyl-4-
15
Entry 13: 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized according to

Method A2, Step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamide was reacted with
4-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to
give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2a, 2-
20 methoxy-5-(trifluoromethyl)aniline was reacted with CDI followed by 4-(2-(N-
methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
25 Chloro-2-pyridinecarboxamide was reacted with 4-aminophenol according to
Method A2, Step 4 using DMAC in place of DMF to give 4-(2-carbamoyl-4-
pyridyloxy)aniline. According to Method C4, 2-methoxy-5-(trifluoromethyl)aniline
was reacted with phosgene followed by 4-(2-carbamoyl-4-pyridyloxy)aniline to
afford the urea.
30
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Entry 15: According to Method C2d, 5-(triflouromethyl)-2-methoxyaniline was

reacted with CDI followed by 4-(3-N-methylcarbamoyl)-4-
methoxyphenoxy)aniline, which had been prepared according to Method A8, to
afford the urea.
5
Entry 16: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was

synthesized according to Method A5. 5-(Trifluoromethyl)-2-methoxyaniline was
converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to
Method B 1. The isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-
10 pyridyloxy)-2-methylaniline according to Method Cle to afford the urea.
Entry 17: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was

synthesized according to Method A6. 5-(Trifluoromethyl)-2-methoxyaniline was
15 Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-
(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline according to Method Cla to
afford the urea.
Entry 18: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted

20 with 4-chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized
according to Method A2, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-
4-methylaniline. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-
25 methylcarbamoyl)-4-pyridyloxy)-4-methylaniline according to Method Cla to
afford the urea.
Entry 19: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine

according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-
30 pyridinecarboxamide was reacted with 4-aminophenol according to Method A2,
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Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline. 5-(Trifluoromethyl)-

2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl
isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl
isocyanate was reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline
5 according to Method Cla to afford the urea.
Entry 20: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted

with 4-chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized
IO 3-chloroaniline. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-
methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline according to Method Cla to afford
the urea.
15
Entry 21: 4-(4-Methylthiophenoxy)-1-nitrobenzene was oxidized according to

Method Al 9, Step 1 to give 4-(4-methylsulfonylphenoxy)-1-nitrobenzene. The
nitrobenzene was reduced according to Method Al9, Step 2 to give 4-(4-
methylsulfonylphenoxy)-1-aniline. According to Method Cla, 5-(trifluoromethyl)-
20 2-methoxyphenyl isocyanate was reacted with 4-(4-methylsulfonylphenoxy)-1-
aniline to afford the urea.
Entry 22: 4-(3-carbamoylphenoxy)-l-nitrobenzene was reduced to 4-(3-

carbamoylphenoxy)aniline according to Method A15, Step 4. According to Method
25 Cla, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-
carbamoylphenoxy)aniline to afford the urea.
Entry 23: 5-(4-Aminophenoxy)isoindoline-1,3-dione was synthesized according to

Method A3. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-
30 (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-
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(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 5-(4-

aminophenoxy)isoindoline-l,3-dione according to Method Cl a to afford the urea.
Entry 24: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine

5 according to Method A2, Step 3b. The resulting 4-chloro-N,N-dimethyl-2-
pyridinecarboxamide was reacted with 4-aminophenol according to Method A2,
Step 4 to give 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline. 5-
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-
10 methoxyphenyl isocyanate was reacted with 4-(2-(.N,N-dimethylcarbamoyl)-4-
pyridyloxy)aniline according to Method Cla to afford the urea.
Entry 25: 4-(1-0xoisoindolin-5-yloxy)aniline was synthesized according to Method

Al2. 5-(Trifluoromethyl)-2-methoxyaniline was treated with CDI, followed by 4-
15 (1-oxoisoindolin-5-yloxy)aniline according to Method C2d to afford the urea.
Entry 26: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene

according to Method A13, Step 1 to give 4-(4-acetylphenoxy)nitrobenzene. The
nitrobenzene was reduced according to Method A13, Step 4 to afford 4-(4-
20 acetylphenoxy)aniline, which was converted to the 4-(4-(1-(N-
methoxy)iminoethyl)phenoxyaniline HCl salt according to Method Al6. 5-
methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-
methoxyphenyl isocyanate was reacted with 4-(4-(l-(N-
25 methoxy)iminoethyl)phenoxyaniline HCl salt to Method Cla to afford the urea.
Entry 27: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in

Method A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol
according to Method A2, Step 4 to give 4-(4-(2-(N-
30 methylcarbamoyl)phenylthio)aniline. 5-(Trifluoromethyl)-2-methoxyaniline was
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Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-
(4-(2-(N-methylcarbamoyl)phenylthio )aniline according to Method Cl a to afford
the urea.
5
Entry 28: 5-(4-Aminophenoxy )-2-methylisoindoline-1,3-dione was synthesized

according to Method A9. 5-(Trifluoromethyl)-2-methoxyaniline was converted into
5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5-
(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 5-(4-
10 aminophenoxy)-2-methylisoindoline-l,3-dione according to Method Cla to afford
the urea.

15 according to Method A2, Step 4 to give 3-(4-(2-(N-
methylcarbamoyl)phenylthio )aniline. 5-(Trifluoromethyl)-2-methoxyaniline was
Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 3-
(4-(2-(N-methylcarbamoyl)phenylthio )aniline according to Method C 1a to afford
20 the urea.
Entry 30: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine

according to Method A2, Step 3b. The resulting 4-chloro-N-isopropyl-2-
25 Step 4 to give 4-(2-(N-isopropylcarbamoyl)-4-pyridyloxy)aniline. 5-
methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-
methoxyphenyl isocyanate was reacted with 4-(2-(N-isopropylcarbamoyl)-4-
pyridyloxy)aniline according to Method Cla to afford the urea.
30
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Entry 31: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according

to Method Al4. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-
(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-
5 methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea.
N-( 5-(Trifluoromethyl)-2-methoxyphenyl)-N '-(4-(3-( 5-
methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4,
Step 1, and the corresponding acid was coupled with 4-(2-aminoethyl)morpholine to
afford the amide according to Method D4, Step 2.

to Method A14. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-
N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N'-( 4-(3-(5-
Step 1, and the corresponding acid was coupled with methylamine according to
20

to Method A14. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-
N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N'-( 4-(3-(5-
Step 1, and the corresponding acid was coupled with N,N-dimethylethylenediamine
according to Method D4, Step 2 to afford the amide.
30
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Entry 34: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al 1.

5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline
was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to
5 Method Clf to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-
carboxyphenyl) urea, which was coupled with 3-aminopyridine according to
Method Dlc.
Entry 35: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.

10 . 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy )aniline

Method Clf to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-
carboxyphenyl) urea, which was coupled with N-(4-fluorophenyl)piperazine
15 according to Method Dlc.

methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline
20 was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to
Method C 1f to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-
carboxyphenyl) urea, which was coupled with 4-fluoroaniline according to Method
Dlc.
25 Entry 37: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.

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carboxyphenyl) urea, which was coupled with 4-(dimethylamino)aniline according

to Method D 1c.

5 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
carboxyphenyl) urea, which was coupled with 5-amino-2-methoxypyridine
Io according to Method D 1c.

methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline
15 was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to
carboxyphenyl) urea, which was coupled with 4-morpholinoaniline according to
MethodDlc.
20 Entry 40: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al 1.

25 carboxyphenyl) urea, which was coupled with N-(2-pyridyl)piperazine according to
MethodDlc.
Entry 41: 4-(3-(N-Methylcarbamoyl)phenoxy)aniline was synthesized according to

Method Al3. According to Method C3, 4-chloro-3-(trifluoromethyl)aniline was
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converted to the isocyanate, then reacted with 4-(3-(N-

Methylcarbamoyl)phenoxy)aniline to afford the urea.
Entry 42: 4-(2-N-Methylcarbamyl-4-pyridyloxy)aniline was synthesized according

5 to Method A2. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-
(2-N-methylcarbamyl-4-pyridyloxy)aniline according to Method Cla to afford the
urea.
to according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-
Chloro-2-pyridinecarboxamide was reacted with 4-aminophenol according to
Method A2, Step 4 to form 4-(2-carbamoyl-4-pyridyloxy)aniline. According to
Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-
15
Chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to
Method A2, Step 4 to form 3-(2-carbamoyl-4-pyridyloxy)aniline. According to
20 Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-

25 Method A2, Step 4 to form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline.
According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was
reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 46: 5-(4-Aminophenoxy)isoindoline-l,3-dione was synthesized according to

30 Method A3. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl
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isocyanate was reacted with 5-(4-aminophenoxy)isoindoline-1,3-dione to afford the

urea.
Entry 47: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was

5 synthesized according to Method AS. According to Method Cle, 4-chloro-3-
aminophenoxy)isoindoline-l,3-dione to afford the urea.
Entry 48: 4-(3-N-Methylsulfamoyl)phenyloxy)aniline was synthesized according to

10 Method Al5. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl
isocyanate was reacted with 4-(3-N-methylsulfamoyl)phenyloxy)aniline to afford
the urea.

15 synthesized according to Method A6. According to Method Cla, 4-chloro-3-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)-2-chloroaniline to afford the urea.

4-methylaniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl
isocyanate was reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-
methylaniline to afford the urea.
25
Entry 51: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine

Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline. According to Method
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Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-

ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

3-chloroaniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl
isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-
chloroaniline to afford the urea.
10
Entry 53: 4-(4-Methylthiophenoxy)-1-nitrobenzene was oxidized according to

Method A19, Step 1 to give 4-(4-methylsulfonylphenoxy)-1-nitrobenzene. The
nitrobenzene was reduced according to Method A19, Step 2 to give 4-(4-
methylsulfonylphenoxy)-1-aniline. According to Method Cla, 4-chloro-3-
15 (trifluoromethyl)phenyl isocyanate was reacted with 4-(4-methylsulfonylphenoxy)-
1-aniline to afford the urea.
Entry 54: 4-Bromobenzenesulfonyl chloride was reacted with methylamine

according to Method A15, Step 1 to afford N-methyl-4-bromobenzenesulfonamide.
20 N-Methyl-4-bromobenzenesulfonamide was coupled with phenol according to
Method A15, Step 2 to afford 4-(4-(N-methylsulfamoyl)phenoxy)benzene. 4-(4-(N-
Methylsulfamoyl)phenoxy)benzene was converted into 4-(4-(N-
methylsulfamoyl)phenoxy)-1-nitrobenzene according to Method A15, Step 3. 4-(4-
(N-Methylsulfamoyl)phenoxy)-l-nitrobenzene was reduced to 4-(4-N-
25 methylsulfamoyl)phenyloxy)aniline according to Method A15, Step 4. According
to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-
(3-N-methylsulfamoyl)phenyloxy)aniline to afford the urea.
Entry 55: 5-Hydroxy-2-methylpyridine was coupled with 1-fluoro-4-nitrobenzene

30 according to Method A18, Step 1 to give 4-(5-(2-Methyl)pyridyloxy)-1-
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nitrobenzene. The methylpyridine was oxidized according to the carboxylic acid,

then esterified according to Method Al 8, Step 2 to give 4-(5-(2-
methoxycarbonyl)pyridyloxy)-1-nitrobenzene. The nitrobenzene was reduced
according the Method Al 8, Step 3 to give 4-(5-(2-
5 methoxycarbonyl)pyridyloxy)aniline. The aniline was reacted with 4-chloro-3-
(trifluoromethyl)phenyl isocyanate according to Method Cla to afford the urea.
Entry 56: 5-Hydroxy-2-methylpyridine was coupled with 1-fluoro-4-nitrobenzene

according to Method A18, Step 1 to give 4-(5-(2-Methyl)pyridyloxy)-1-
10 nitrobenzene. The methylpyridine was oxidized according to the carboxylic acid,
then esterified according to Method Al 8, Step 2 to give 4-(5-(2-
methoxycarbonyl)pyridyloxy)-l-nitrobenzene. The nitrobenzene was reduced
according the Method Al 8, Step 3 to give 4-(5-(2-
15 (trifluoromethyl)phenyl isocyanate according to Method Cla to give N-(4-chloro-3-
(trifluoromethy 1)pheny 1)-N'-(4-(2-(methoxycarbonyl)-5-pyridyloxy )pheny I) urea.
The methyl ester was reacted with methylamine according to Method D2 to afford
pyridyloxy)phenyl) urea.
20
Entry 57: N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) urea was

prepared according to Method Cld. N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-
aminophenyl) urea was coupled with mono-methyl isophthalate according to
Method D 1a to afford the urea.
25
Entry 58: N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) urea was

prepared according to Method Cld. N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-
aminophenyl) urea was coupled with mono-methyl isophthalate according to
Method Dla to afford N-(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(3-
30 methoxycarbonylphenyl)carboxyaminophenyl) urea. According to Method D2, N-
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(4-chloro-3-(trifluoromethyl)phenyl-N '-(4-(3-
methoxycarbonylphenyl)carboxyaminophenyl) urea was reacted with methylamine
to afford the corresponding methyl amide.
5 Entry 59: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine

according to Method A2, Step 3b. The resulting 4-chloro-N,N-dimethyl-2-
Step 4 to give 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline. According to
10 (N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 60: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according

to Method A13, Step 1 to give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene
was reduced according to Method 13, Step 4 to afford 4-(4-acetylphenoxy)aniline,
15 which was converted to the 4-(4-(1-(N-methoxy)iminoethyl) phenoxyaniline HCl
salt according to Method Al6. According to Method Cla, 4-chloro-3-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-acetylphenoxy)aniline to
afford the urea.
20 Entry 61: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to

Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with 4-
(2-aminoethyl)morpholine according to Method Al3, Step 3 to give 4-(3-(N-(2-
morpholinylethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13
Step 4, 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)-1-nitrobenzene was
25 reduced to 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)aniline. According to
(N-(2-morpholinylethyl)carbamoyl)phenoxy)aniline to afford the urea.
Entry 62: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to

30 Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with 1-
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(2-aminoethyl)piperidine according to Method A13, Step 3 to give 4-(3-(N-(2-

piperidylethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13
Step 4, 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced
to 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)aniline. According to Method
5 Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(2-

Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with
10 tetrahydrofurfurylamine according to Method A13, Step 3 to give 4-(3-(N-
(tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method
A13 Step 4, 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene
was reduced to 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline.
According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was
15 reacted with 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl) phenoxy)aniline to afford
the urea.

Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with 2-
20 aminomethyl-1-ethylpyrrolidine according to Method A13, Step 3 to give 4-(3-(N-
((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene. According to
Method Al 3 Step 4, 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-
nitrobenzene was reduced to 4-(3-(N-((l-
methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline. According to Method C 1a,
25 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-((1-

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methylcarbamoyl)phenylthio )aniline. According to Method C 1a, 4-chloro-3-

(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(N-
5 Entry 66: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine

according to Method A2, Step 3b. The resulting 4-chloro-N-isopropyl-2-
Step 4 to give 4-(2-(N-isopropylcarbamoyl)-4-pyridyloxy)aniline. According to
Method C 1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-
10 (N-isopropylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 67: N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-ethoxycarbonylphenyl)

urea was synthesized according to Method Cle. N-(4-Chloro-3-
(trifluoromethyl)phenyl-N'-( 4-ethoxycarbonylphenyl) urea was saponified
15 according to Method D3 to give N-( 4-chloro-3-(trifluoromethyl)phenyl-N'-( 4-
carboxyphenyl) urea. N-( 4-Chloro-3-(trifluoromethyl)phenyl-N '-(4-carboxyphenyl)
urea was coupled with 3-methylcarbamoylaniline according to Method Dlb to give
N-(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(3-
methylcarbamoylphenyl)carbamoylphenyl) urea.
20
Entry 68: 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione was synthesized

according to Method A9. According to Method Cl a, 4-chloro-3-
(trifluoromethyl)phenyl isocyanate was reacted with 5-(4-aminophenoxy)-2-
methylisoindoline-1,3-dione to afford the urea.
25

methylcarbamoyl)phenylthio )aniline. According to Method Cl a, 4-chloro-3-
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(trifluoromethyl)phenyl isocyanate was reacted with 3-(4-(2-(N-

Entry 70: 4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was

5 synthesized according to Method AlO. According to Method Cla, 4-chloro-3-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-(2-morpholin-4-
ylethyl)carbamoyl)pyridyloxy)aniline to afford the urea.

10 to Method A14. 4-Chloro-3-(trifluoromethyl)-2-methoxyphenyl isocyanate was
reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method Cla
to afford the urea. N-(4-Chloro-3-(trifluoromethyl)phenyl)-N'-(4-(3-(5-
methoxycarbonylpyridyl) oxy)phenyl) urea was saponified according to Method D4,
Step 1, and the corresponding acid was coupled with 4-(2-aminoethyl)morpholine to
15 afford the amide.

to Method Al 4. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-
(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C 1a to afford the
20 urea. N-( 5-(Trifluoromethyl)-2-methoxyphenyl)-N'-( 4-(3-(5-
Step I, and the corresponding acid was coupled with methylamine according to
25 Entry 73: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according

to Method Al4. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-
(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the
urea. N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5-
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Step 1, and the corresponding acid was coupled with N,N-dimethylethylenediamine

according to Method D4, Step 2 to afford the amide.

5 hydroxyethylamine according to Method A2, Step 3b to form 4-chloro-N-(2-
triisopropylsilyloxy)ethylpyridine-2-carboxamide was reacted with triisopropylsilyl
chloride, followed by 4-aminophenol according to Method Al 7 to form 4-(4-(2-(N-
(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline. According to Method
IO Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(N-(2-
triisopropylsilyloxy)ethylcarbamoyl) pyridyloxyaniline to afford N-( 4-chloro-3-
((trifluoromethyl)phenyl)-N'-( 4-(4-(2-(N-(2-triisopropylsilyloxy)

4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5-
methoxycarbonyl)pyridyloxy)aniline according to Method Clf to afford the urea,
which was coupled with 3-aminopyridine according to Method Die.

4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-
carboxyphenoxy)aniline according to Method Clf to afford the urea, which was
coupled with N-( 4-acetylphenyl)piperazine according to Method D 1c.
25 Entry 77: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al I.

coupled with 4-fluoroaniline according to Method Die.
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coupled with 4-(dimethylamino)aniline according to Method Dlc.
5

coupled with N-phenylethylenediamine according to Method D le.
10

coupled with 2-methoxyethylamine according to Method Dlc.
15

coupled with 5-amino-2-methoxypyridine according to Method Dlc.
20

coupled with 4-morpholinoaniline according to Method Dlc.
25

coupled with N-(2-pyridyl)piperazine according to Method Dlc.
30
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hydroxyethylamine according to Method A2, Step 3b to fom1 4-chloro-N-(2-
triisopropylsilyloxy)ethylpyridine-2-carboxamide was reacted with triisopropylsilyl
5 chloride, followed by 4-aminophenol according to Method Al 7 to form 4-(4-(2-(N-
(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline. According to Method
Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(N-(2-
triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline to give N-( 4-chloro-3-
((trifluoromethyl)phenyl)-N'-( 4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)
10 pyridyloxyphenyl) urea. The urea was deprotected according to Method D5 to
afford N-( 4-chloro-3-( (trifluoromethy l)phenyl)-N '-(4-( 4-(2-(N-(2-
hydroxy )ethylcarbamoyl)pyridyloxyphenyl) urea.
Entry 85: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized

15 according to Method A2. 4-Bromo-3-(trifluoromethyl)aniline was converted to 4-
bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to
Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-
(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
20 Entry 86: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was

synthesized according to Method A6. 4-Bromo-3-(trifluoromethyl)aniline was
converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method
Bl. According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was
reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline to afford the
25 urea.

30 3-chloroaniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-
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(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method

Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-
s Entry 88: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine

Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-
(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl
10 isocyanate according to Method Bl. According to Method Cla, 4-bromo-3-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-ethylcarbamoyl)-4-

15 according to Method A2, Step 3a, was reacted with 3-aminophenol according to
Method A2, Step 4 to form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. 4-
Bromo-3-( trifluoromethy 1)aniline was converted into 4-bromo-3-
Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(-2-(N-
20 methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

25 4-methylaniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-
3-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to
Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-
(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline to afford the urea.
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Entry 91: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine

Step 4 to give 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-
5 (trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl
isocyanate according to Method B 1. According to Method C 1a, 4-bromo-3-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N,N-dimethylcarbamoyl)-
4-pyridyloxy)aniline to afford the urea.
10 Entry 92: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in

methylcarbamoyl)phenylthio )aniline. 4-Bromo-3-( trifluoromethyl)aniline was
15 Bl. According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was
reacted with 4-(4-(2-(N-methylcarbamoyl)phenylthio )aniline to afford the urea.

methylcarbamoyl)phenylthio )aniline. 4-Bromo-3-(trifluoromethyl)aniline was
Bl. According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was
reacted with 3-(4-(2-(N-methylcarbamoyl)phenylthio )aniline to afford the urea.
25
Entry 94: 4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was

synthesized according to Method AIO. 4-Bromo-3-(trifluoromethyl)aniline was
Bl. According to Method Cla, 4-bromo-3-(trifluorometliyl)phenyl isocyanate was
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reacted with 4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline to

afford the urea.

5 according to Method A2. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was
synthesized according to Method A7. 4-Chloro-2-methoxy-5-
(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-
(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method
Cla, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-
10 (2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

synthesized according to Method A6. 4-Chloro-2-methoxy-5-
(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-
15 methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-
(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method
(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline afford the urea.
20 Entry 97: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted

3-chloroaniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized
according to Method A 7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was
25 converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according
to Method Bl. According to Method Cla, 4-chloro-2-methoxy-5-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)-3-chloroaniline to afford the urea.
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Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method
5 A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-
methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B 1. According
to Method Cla, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate as was
reacted with 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
IO Entry 99: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine

Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxy-
5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-
15 methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-
(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
20 Entry 100: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine

Step 4 to give 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-
methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-
25 Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-
methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B 1. According
to Method Cla, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was
reacted with 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
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Amino-3-methoxynaphthalene was synthesized as described Method Al.
5 According to Method C3, 2-amino-3-methoxynaphthalene was reacted with
bis(trichloromethyl) carbonate followed by 3-(-2-(N-methylcarbamoyl)-4-
pyridyloxy)aniline to form the urea.

IO according to Method A2. 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline was
synthesized according to Method A4. 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline
was reacted with CDI followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline
according to Method C2d to afford the urea.
15 Entry 103: 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized according to

Method A2, Step 36. 4-Chloro-N-methyl-2-pyridinecarboxamide was reacted with
4-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to
give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2b,
reaction of 3-amino-2-methoxyquinoline with CDI followed by 4-(2-(N-
20 methylcarbamoyl)-4-pyridyloxy)aniline afforded bis( 4-(2-(N-methylcarbamoyl)-4-
pyridl yoxy)pheny 1)urea.
Tables
The compounds listed in Tables 1-6 below were synthesized according to the
25 general methods shown above, and the more detailed exemplary procedures are in
the entry listings above and characterizations are indicated in the tables.
Table 1. 3-tert-Butylphenyl Ureas
0~
R,N)lND
H H
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TLC Mass
Entry R (°C) (min.) R1 System [Source] Method
1 0.22 50% 418 A13
o NH
-d
EtOAc (M+H)+ C3
Me I 50% (HPLC
2
-0- 0
o 0.58
hexane
50%
ES-MS)
403 A13
-0-~ O ~ /J Me EtOAc
I 50%
(M+H)+ C3
(HPLC
hexane ES-MS)
◊
3
O NH
133-
135
0.68 100%
EtOAc
448 A8
(M+H)+ C2d
I/ Me (FAB)
-Q-o OMe
Table 2. 5-tert-Butyl-2-methoxyphenyl Ureas
10
TLC Mass
mp HPLC TL Solvent Spec. Synth.
Entry R (OC) (min.) CRr System [Source] Method
4 5.93 448 A13
O NH
-d
(M+H)+ Bl
Me
-0- 0
(HPLC
ES-MS)
Cla
◊
5
O NH
120-
122
0.67 100%
EtOAc
478
(M+H)+
A8
C2d
(FAB)
-Q-o o~:
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6
-0- -Q;!io
0 \ /;
NH
0.40 50%
EtOAc
I 50%
460
(M+H)+
(HPLC
A3
C2d
0 hexane ES-MS)
7
-0- -Qtio0 \ /;
NH
0.79 50%
EtOAc
I 50%
446
(M+H)+
(HPLC
Al2
C2d
hexane ES-MS)
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Table 3. 5-(Trifluoromethyl)-2-methoxyphenyl Ureas
Qt
R,NJlNY
H H OMe
TLC Mass
8 250 460 A13
o
-d
NH
(dee) (M+H)+ C2a
Me
9
-0- 0
o 206- 0.54 10%
(FAB)
446 A3 step
-0-~ N O ~ // Me
208 MeOH/ (M+H)+
90% (HPLC
2,
A8 step
CH2Cl2 ES-MS) 4,
Bl,
Cla
10 o 0.33 50% 445 A13
-0-~ · O ~ I/ Me
EtOAc/ (M+H)+ C3
50% pet (HPLC
ether ES-MS)
11 0.20 2% 461 A2
O N.H
--0-d: 0
-
~ ;,N
Me
Et3N/
98%
(M+H)+ C4
(HPLC
EtOAc ES-MS)
12 0.27 1% 447 A2
--o-c:O NH2 Et3N/ (M+H)+ C4
99% (HPLC
0 ~ ;,N EtOAc ES-MS)
13 0.62 100% 461 A2
O NH
14
-0- 0
-d: Me
114- 0.40
EtOAc
1%
(M+H)+ C2a
(FAB)
447 A2
-d:
O NH2
117 Et3N/ (M+H)+ C4
99% (FAB)
-Q-o EtOAc
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15 0 232- 0.54 100% 490 A8
◊
NH 235 EtOAc (M+H)+ C2d
(FAB)
-0-o o~:
16
Me -do
- NH
210-
213
0.29 5%
MeOH/
475 AS
(M+H)+ Bl
---0 0 \ ;,N
Me 45%
EtOAc/
50% pet
(HPLC Cle
ES-MS)
ether
-
17 187- 0.17 50% 495 A6
Cl -d:O NH 188 EtOAc/ (M+H)+ Bl
18
---0 0 \ I,
N
Me
0.48
50% pet
ether
100%
(HPLC Cla
ES-MS)
475 A2 step
--Q-~e O NH2 EtOAc (M+H)+ 4,
(HPLC Bl
O \ ;,N ES-MS) Cla
19 194- 0.31 5% 475 A2
O NH
196 MeOH/ (M+H)+ Bl
'Et
45% (HPLC Cla
0
-0- - -d: EtOAc/ ES-MS)
50% pet
ether
20
Cl -d:O
_ NH
214-
216
0.25 5%
MeOH/
495 A2
(M+H)+ Cla
-0-
Me
45% (HPLC
0 \ ;,N EtOAc/ ES-MS)
50% pet
ether
21 208- 0.30 50% 481 Al9
o-OOs:::O 210 EtOAc/ (M+H)+ C2a
-0- ~ 1; Me
50% (HPLC
hexane ES-MS)
22 188- 0.30 70% 447 A15,
O NH
-d
2 190 EtOAc/ (M+H)+ step 4,
50% (HPLC Cla
-0-o hexane ES~MS)
23 0 0.50 70% 472 A3
-0- ~ /; EtOAc/ (M+H)+ Bl
0~ NH 30% (FAB) Cla
0 hexane
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24
o N:: 203-
205
0.13 100%
EtOAc
479 A2
(M+H)+ Bl
-0--d: 0 ~ /,
N
(HPLC Cla
ES-MS)
25
-0- 0 -Q!oNH
~ /;
0.09 75%
EtOAc/
458 Al2
(M+H)+ C2d
25% (HPLC
hexane ES-MS)
26 Me0 \ 169- 0.67 50% 474 A13
171 EtOAc/ (M+H)+ stepl,
-Q-o--Q-( 50% pet (HPLC Al3
ether ES-MS) step 4,
Al6,
Bl
Cla
27 218- 0.40 50% 477 A2 step
-d:
O NH
219 EtOAc/ (M+H)+ 3b,
Me
-0- s
50% pet (HPLC A2 step
ether ES-MS) 4,
Bl,
Cla
28 0 212- 0.30 40% A9
-Q-o~J NMe
214 EtOAc/
60%
Bl
Cla
0 hexane
29 0.33 50% 474 A2 step
O N_H
EtOAc/ (M+H)+ 3b,
-Q-d: S
-
~ ;,N
Me 50% pet
ether
(HPLC
ES-MS)
A2 step
4,
Bl,
Cla
30 210- A2
-d:
O NH
211 Bl
Pr-1
31
-0- 0
210- 0.43 10%

Cla
Al4
o NH
-d
204 MeOH/ Bl
CH2Cl2 Cla
---0-o N 1-:>
D4
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32 0 247- 0.57 10% A14

NH 249 MeOH/ Bl
Me CH2Cl2 Cla
-0-o ~ N D4
33 217- 0.07 10% A14
O NH
219 MeOH/ Bl
-0- 0
~ N
~N-Me
Me1
CH2Cl2 Cla
D4
34 0.11 70% Al 1
O NH
EtOAc/ Bl
30% Clf
-Q-o () hexane Dlc
~
b
35 0.38 70% Al I
EtOAc/ Bl
30% Clf
hexane Dlc
N)
\_N
-Q-o-Oo
36 0.77 70% Al I
F-0-NH EtOAc/ Bl
30% Clf
-Q-o-Oo hexane Dlc
37 Me -0-
0.58 70% Al I
.M)~ 1/-0~ NH 0 EtOAc/
30%
Bl
Clf
38
-0- 0 ~ I)
0.58
hexane
70%
Die
All
Meo--Q-NH EtOAc/ Bl
30% Clf
-O-o-Oo hexane Dlc
39 0.17 70% All

rN-0-~ NH
EtOAc/ Bl
\.._/ -00 30% Clf
-Q-o ~-j hexane Dlc
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40
0- r-'
N~N -0- I/_~ NH 0
0.21 70%
EtOAc/
Al 1
Bl
30% Clf
--Q-o:;f hexane Die
Table 4. 3-(Trifluoromethyl)-4-chlorophenyl Ureas

F F F
Cl
0
R,N)lN
5 H H
TLC Mass
Entry R (OC) (min.) R1 System [Source] Method
41 0 163- 0.08 50% 464 A13
-O
NH 165 EtOAc/ (M+H)+ C3
Me 50% pet
42
-0- 0
215 0.06
ether
50%
(HPLC
ES-MS)
465 A2
O NH
43
-0- --d: 0
Me
0.10
EtOAc/
50% pet
ether
50%
(M+H)+
(HPLC
ES-MS)
451
Cla
A2
-Q-o -d:
O NH
2 EtOAc/ (M+H)+ Cla
50% pet (HPLC
ether ES-MS)
44 0.25 30% 451 A2
-o-30 NH2 EtOAc/ (M+H)+ Cla
70% pet (HPLC
0 ~ ;,N ether ES-MS)
-Q-d:
45 0.31 30% 465 A2
O N.H
EtOAc/ (M+H)+ Cla
- Me 70% pet (HPLC
46 176-
-0- 0~
~ j
NH
0
179
0.23 40%
EtOAc/
60%
476
(M+H)+
(FAB)
A3
Cla
0 hexane
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-
47 0.29 5% 478 A5
Me -d:NH MeOH/ (M+H)+ Cle
---0- 0 ~ I, N
Me 45%
EtOAc/
50% pet
(HPLC
ES-MS)
ether
48 0, It0 206- Al5
'S-NH 209 Cla
-0- o-{)
Me
~ /;
49
Cl-d:O
- NH
147-
151
0.22 50%
EtOAc/
499
(M+H)+
A6
Cla
50
---0- 0
e O
~ I, N
Me
N_H
0.54
50% pet
ether
100%
(HPLC
ES-MS)
479 A2
EtOAc (M+H)+ Cla
-Q-~ 0 ~
-
;,N
Me (HPLC
ES-MS)
51
O NH
Et
187-
189
0.33 5% 479
MeOH/ (M+H)+
A2
Cla
-0-
- -d: 0
45% (HPLC
EtOAc/ ES-MS)
50%pet
ether
52
-d:O
- Cl NH
219 0.18 5% 499
MeOH/ (M+H)+
A2
Cla
-0- 0 ~ I, N
Me 45% (HPLC
EtOAc/ ES-MS)
50% pet
ether
53
-o-o-Cf- ~ /J
0
s:::O
Me
246-
248
0.30 50% 485
EtOAc/ (M+H)+
50%
hexane
(HPLC
ES-MS)
A19,
Cla
54
-o-o-Cf- ~ /;
0
M~
s:::O
'NH
196-
200
0.30 70% 502
EtOAc/ (M+H)+
30% (HPLC
hexane) ES-MS)
Al5
Cla
55 228- 0.30 30% 466

o oMe 230 EtOAc/ (M+H)+
-0- -d: 0 ~ ;,N

70% (HPLC
CH2Cl2 ES-MS)
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56
-O-o--(MoNH
238-
245
MEf
57 221- 0.75 80% 492 Cld
222 EtOAc/ (M+H)+ Dla
20% (FAB)
hexane
58 247 0.35 100% Cld
EtOAc Dla
D2
59 198- 0.09 100% 479 A2

200 EtOAc (M+H)+ Cla
(HPLC
ES-MS)
60 158- 0.64 50%
160 EtOAc/
50% pet
ether
61 195- 0.39 10% A13
197 MeOH/ Cla
CH2Cl
2
62 170- 0.52 10% A13

172 MeOH/ Cla
CH2Cl
2
63 168- 0.39 10% A13

171 MeOH/ Cla
CH2Cl
2
64 176- 0.35 10% A13
177 MeOH/ Cla
CH2Cl
2
65 130- 487 A2
133 (M+H)+ Bl
(HPLC Cla
ES-MS)
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66 0 155 A2
-d:
NH Cla
Pr-1
67
-0-
-
0
225- 0.23 100% Cle

O NH
229 EtOAc D3
H Me Dlb
68
-0- N
~
234- 0.29 40% A9
-Q-o-Q;t11 ° NMe
236 EtOAc/
60%
Cla
0 hexane
69 0.48 50% 481
O N_H.
-Q-d: S
-
~ ;,N
Me
EtOAc/
50% pet
ether
(M+H)+
(HPLC
ES-MS)
70 0.46 5% 564 AlO
NH
-d:(j
O
MeOH/ (M+H)+ Cla
95% (HPLC
-Q-o CH2Cl2 ES-MS)
71 0 199- 0.50 10% A14

201 MeOH/ Cla
CH2Cl D4
-0-o-QN\J 2
72 235- 0.55 10% A14

O NH
-O
237 MeOH/ Cla
Me CH2Cl D4
73
-0- 0
N
200- 0.21
2
50% A14
-0- -O
O NH
201 MeOH/ Cla
CH2Cl D4
0 ~-Me
2
N Mi
74 145-
-Q-o -3
0 NH
148
N bsi(Pr-i>,
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75 0.12 70% 527 Al 1

0-NH EtOAc/ (M+H)+ Clf
30% (HPLC Dlc
76
-0- 0-00
0
~ /;
0.18
hexane
70%
ES-MS)
All
EtOAc/ Clf
Meo 30% Dlc
hexane
N)
\_N
-Q-0-60
77 0.74 70% Al 1
F-0-NH EtOAc/ Clf
30% Dlc
-Q-o-Oo hexane
78 Me~ -0-f
0.58 70% All
~ NH EtOAc/ Clf
30% Dlc
-cro-Oo hexane
79 0.47 70% 569 All

o NH
-dd EtOAc/ (M+H)+ Clf

1 ~ ~NH 30% (HPLC Dlc
-Q-o hexane ES-MS)
80 0.18 70% 508 All

o NH
-d
EtOAc/ (M+H)+ Clf
1 ~ ~OMe 30% (HPLC Dlc
-Q-o hexane ES-MS)
81 0.58 70% 557 All
Me0-0-NH EtOAc/ (M+H)+ Clf
30% (HPLC Dlc
-Q-o-Oo hexane ES-MS)
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82 0.37 70% 611 Al 1

r\N-o-~ NH
EtOAc/ (M+H)+ Clf
\_I ~o 30% (HPLC Dlc
-Q-o ~-/; hexane ES-MS)
83
GN 0.19 70%
EtOAc/
30%
Al 1
Clf
Dlc
N) hexane
\_N
-Q-o-Oo
84 179- A2
O NH
183 A17
-0-o -d:
~H
Cla
DS
5
Table 5. 3-(Trifluoromethyl)-4-bromophenyl Ureas
0 FtF Br
R,N)lNO
H H
TLC Mass
Entry R (OC) (min.) R1 System [Source] Method
85 186- 0.13 50% 509 A2
O NH
Me 50% pet (HPLC Cla
86
-0- 0
-d:
150-
ether ES-MS)
-
0.31 50% 545 A6
Cl -d:O NH 152 EtOAc/ (M+H)+ Bl
-0- 0 ~ ;,N
Me 50% pet
ether
(HPLC
ES-MS)
Cla
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87 0 217- 0.16 50% 545 A2

88
-6-a~ Cl -CNH
-
/,N
0
Me
183- 0.31
50% pet
ether
50%
(HPLC
ES-MS)
525
Cla
A2
NH 184 EtOAc/ (M+H)+ Bl
Et 50% pet (HPLC Cla
89
-0- 0
-C
0.21
ether
50%
ES-MS)
511 A2
O N.H
EtOAc/ (M+H)+ Bl
- Me 50% pet (HPLC Cla
-0-C 0 ~ ;,N ether ES-MS)
90 0.28 50% 525 A2
e O N.H
-Q~
EtOAc/ (M+H)+ Bl
- Me 50% pet (HPLC Cla
91 214- 0.28 50% 522 A2
o \: 216 EtOAc/ (M+H)+ Bl
92
-0--c 0 ~ ;,N
0.47
50% pet
ether
50%
(HPLC
ES-MS)
527
Cla
A2 step
O NH
EtOAc/ (M+H)+
3b,
Me 50% pet (HPLCA2 step
-0- s
-C ether 4,
ES-MS)
Bl,
Cla
93 0.46 50% 527 A2 step
O N.H
EtOAc/ (M+H)+ 3b,
- Me 50% pet (HPLC A2 step
-0-C S ~ ;,N ether ES-MS) 4,
Bl,
Cla
94 145- 0.41 5% AI0
O NH
150 MeOH/ Bl
-0-o -C (J 95%
CH2Cl2
Cla
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Table 6. 5-(Trifluoromethyl)-4-chloro-2-methoxyphenyl
Ureas
TLC Mass
95 140- 0.29 5% 495 A2
O NH
-O 144 MeOH/ (M+H)+ A7

Me 45% (HPLC Bl
-0- 0 EtOAc/
50% pet
ES-MS) Cla
ether
96
Cl
-0- _ 0
-OO
~ l,N
NH
Me
244-
245
0.39 5%
MeOH/
45%
EtOAc/
529
(M+H)+
(HPLC
ES-MS)
A6
A7
Bl
Cla
50% pet
ether
97 220- 0.25 5% 529 A2
-6- - Cl
0
-OO
~ l,N
NH
Me
221 MeOH/
45%
EtOAc/
(M+H)+
(HPLC
ES-MS)
A7
Bl
Cla
50% pet
ether
98 0.27 5% 495 A2
0 N_H
-0-0 0
-
~ 1,N
Me
MeOH/
45%
EtOAc/
50%pet
(M+H)+ A7
(HPLC Bl
ES-MS) Cla
ether
99 180- 0.52 5% 509 A2
O NH
181 MeOH/ (M+H)+ A7
Et 45% (HPLC Bl
-0- -
0
-O EtOAc/
50% pet
ES-MS) Cla
ether
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100 162- A2
O NH
-0- 0
-d: Pr-1
165 A7
Bl
Cla
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TLC Mass
Entry R (OC) (min.) R; System [Source] Method
~
101 q 162- Al
0
N)lN
{)1
~
OU."
._✓,;;
I, ~H
Me
165 A2
C3
OMe H H
~
102 0
0.10 50% 442 A2
I EtOAc/ (M+H)+ A4
0 7' O '-:: NH
50% (HPLC C2d
NJlNO~M, hexane ES-MS)
H H
MeuN Me
~ I.
103 0 125- 0.24 40% 512 A2
HN)lNH 130 EtOAc/ (M+H)+ C2b
0 Q
60% (FAB)
hexane
op
0 0
tto
NH-Me Me-NH
10
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BIOLOGICAL EXAMPLES
P38 Kinase Assay:
The in vitro inhibitory properties of compounds were determined using a
p38 kinase inhibition assay. P38 activity was detected using an in vitro kinase assay
5 run in 96-well microtiter plates. Recombinant human p38 (0.5 µg/mL) was mixed
with substrate (myelin basic protein, 5 µg/mL) in kinase buffer (25 mM Hepes, 20
33
mM MgC}z and 150 mM NaCl) and compound. One µCi/well of P-labeled ATP
(10 µM) was added to a final volume of 100 µL. The reaction was run at 32 °C for
30 min. and stopped with a IM HCl solution. The amount of radioactivity
10 incorporated into the substrate was determined by trapping the labeled substrate
onto negatively charged glass fiber filter paper using a 1% phosphoric acid solution
and read with a scintillation counter. Negative controls include substrate plus ATP
alone.
All compounds exemplified displayed p38 IC 50s of between 1 nM and 10
15 µM.
LPS Induced TNFa. Production in Mice:

The in vivo inhibitory properties of selected compounds were determined
usmg a murine LPS induced TNFa production in vivo model. BALB/c mice
20 (Charles River Breeding Laboratories; Kingston, NY) in groups of ten were treated
with either vehicle or compound by the route noted. After one hour, endotoxin (E.
coli lipopolysaccharide (LPS) 100 µg) was administered intraperitoneally (i.p.).
After 90 min, animals were euthanized by carbon dioxide asphyxiation and plasma
was obtained from individual animals by cardiac puncture into heparinized tubes.
25 The samples were clarified by centrifugation at 12,500 x g for 5 min at 4 °C. The
supernatants were decanted to new tubes, which were stored as needed at -20 °C.
TNFa levels in sera were measured using a commercial murine TNF ELISA kit
(Genzyme).
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The preceding examples can be repeated with similar success by substituting

the generically or specifically described reactants and/or operating conditions of this
invention for those used in the preceding examples.
5 From the foregoing discussion, one skilled in the art can easily ascertain the
essential characteristics of this invention and, without departing from the spirit and
scope thereof, can make various changes and modifications of the invention to adapt
it to various usages and conditions.
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WHAT IS CLAIMED IS:
1. A method of treating a disease mediated by p38 within a host, said method

comprising administering to said host a compound of Formula I:
A-D-B (I)
Dis -NH-C(O)-NH-,
A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-

1
L )q, where L is a 5 or 6 membered cyclic structure bound directly to D, L 1
group having at least one atom, q is an integer of from 1-3; and each cyclic
structure of L and L 1 contains 0-4 members of the group consisting of nitrogen,
oxygen and sulfur, and

and sulfur,
wherein L I is substituted by at least one substituent selected from the group

consisting of -SO2Rx, -C(O)Rx and -C(NRy) R2 ,

to per halo;

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a carbon based moiety of up to 30 carbon atoms optionally

-OSi(Rr)J where Rr is hydrogen or a carbon based moiety of up to


halogen; or
c) one of Ra or Rb is -C(O)-, a C1-C5 divalent alkylene group or a

substituted C 1-C5 divalent alkylene group bound to the moiety L to form a cyclic
structure with at least 5 members, wherein the substituents of the substituted C 1-C5
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Wn, where n is 0-3;

7
CN, -CO2R7, -C(O)NR 7R7, -C(O)-R , -NO2, -OR7, -SR 7, -NR 7R 7, -NR 7C(O)OR7, -
NR 7C(O)R 7, -Q-Ar, and carbon based moieties ofup to 24 carbon atoms, optionally
7 7 7
CO2R , -C(O)R 7, -C(O)NR 7R , -OR , -SR 7, -NR 7R 7, -NO2, -NR 7C(O)R7, -
7
NR C(O)OR 7 and halogen up to per-halo; with each R 7 independently selected from
H or a carbon based moiety of up to 24 carbon atoms, optionally containing
wherein Q is -0-, -S-, -N(R 7)-, -(CH2)m-,-C(O)-, -CH(OH)-, -(CH2)mO-, -

(CH2)mS-, -(CH2)mN(R7)-, -O(CH2)m- CHXa-, -CXa2-, -S-(CH2)m- and -
N(R 7)(CH 2)m-,where m= 1-3, and Xa is halogen; and
Ar is a 5- or 6-member aromatic structure containing 0-2 members selected

substituted by halogen, up to per-halo, and optionally substituted by Zn1, wherein nl
CO2R7 , -C(O)R 7, -C(O)NR 7R7, -NO2, -OR7, - SR7 -NR7R 7 , -NR7C(O)OR7, -
7
NR C(O)R7 , and a carbon based moiety of up to 24 carbon atoms, optionally
or more substituents selected from the group consisting of -CN, -CO 2R 7 , -COR7, -
7 7
C(O)NR 7R7, -OR7 , -SR7, -NO2, -NR R , -NR7C(O)R 7 , and -NR7C(O)OR 7, with R7
as defined above.
2. A method as in claim 1 for the treatment of a cancerous cell growth

mediated by p38 kinase.
3. A method as in claim 1 for the treatment of a disease other than
cancer.
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4. A method as in claim 1 wherein the condition within a host treated

by administering a compound of formula I is rheumatoid arthritis, osteoarthritis,
septic arthritis, tumor metastasis, periodontal disease, corneal ulceration,
proteinuria, coronary thrombosis from atherosclerotic plaque, aneurysmal aortic,
following traumatic joint injury, osteopenias mediated by MMP activity, tempero
mandibular joint disease or demyelating disease of the nervous system.
by administering a compound of formula I is rheumatic fever, bone resorption,
postmenopausal osteoperosis, sepsis, gram negative sepsis, septic shock, endotoxic
shock, toxic shock syndrome, systemic inflammatory response syndrome,
inflammatory bowel disease (Crohn's disease and ulcerative colitis), Jarisch-
Herxheimer reaction, asthma, adult respiratory distress syndrome, acute pulmonary
fibrotic disease, pulmonary sarcoidosis, allergic respiratory disease, silicosis, coal
worker's pneumoconiosis, alveolar injury, hepatic failure, liver disease during acute
inflammation, severe alcoholic hepatitis, malaria (Plasmodium falciparum malaria
and cerebral malaria), non-insulin-dependent diabetes mellitus (NIDDM),
congestive heart failure, damage following heart disease, atherosclerosis,
Alzheimer's disease, acute encephalitis, brain injury, multiple sclerosis
(demyelation and oligiodendrocyte loss in multiple sclerosis), advanced cancer,
lymphoid malignancy, pancreatitis, impaired wound healing in infection,
inflammation and cancer, myelodysplastic syndromes, systemic lupus
erythematosus, biliary cirrhosis, bowel necrosis, psoriasis, radiation injury/ toxicity
following administration of monoclonal antibodies, host-versus-graft reaction
(ischemia reperfusion injury and allograft rejections of kidney, liver, heart, and
skin), lung allograft rejection (obliterative bronchitis) or complications due to total
hip replacement.

by administering a compound of formula I is an an infectious disease selected from
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the group consisting of tuberculosis, Helicobacter pylori infection during peptic

ulcer disease, Chaga's disease resulting from Trypanosoma cruzi infection, effects
of Shiga-like toxin resulting from E. coli infection, effects of enterotoxin A
resulting from Staphylococcus infection, meningococcal infection, and infections
from Borrelia burgdorferi, Treponema pallidum, cytomegalovirus, influenza virus,
Theiler's encephalomyelitis virus, and the human immunodeficiency virus (HIV).
7. A method as in claim 1 wherein M is one or more bridging groups

selected from the group consisting of -0-, -S-, -N(R 7)-, -(CH2)m-,-C(O)-, -CH(OH)-
7
' -(CH2)mO-,-(CH2)mS-,-(CH2)mN(R)-, -O(CH2)m-CHX3 -, -CX 32-, -S-(CH2)m-and
-N(R 7)(CH2)m-,where m= 1-3, Xa is halogen and R7is as defined in claim 1.
8. A method as in claim 7, wherein said substituted cyclic moiety L 1 is

phenyl, pyridyl or pyrimidinyl.
9. A method of claim 1 wherein L 1 is substituted by -C(O)Rx or -SO2Rx,

wherein Rx is NRaRb.
10. A method of treating a disease mediated by p38 within a host, said

method comprising administering to said host a compound of Formula I:
A-D-B (I)
Dis -NH-C(O)-NH-,

1
L )q, where L is a 6 membered aryl moiety or a 6 membered hetaryl moiety bound
directly to D, L I comprises a substituted cyclic moiety having at least 5 members,
M is a bridging group having at least one atom, q is an integer of from 1-3; and
each cyclic structure of L and L 1 contains 0-4 members of the group consisting of
nitrogen, oxygen and sulfur, and
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Bis a substituted or unsubstituted, up to tricyclic aryl or heteroaryl

and sulfur,


to per halo;


-OSi(Rr)3 where Rr is hydrogen or a carbon based moiety of up to

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halogen; or
c) one of Ra or Rb is -C(O)-, a C1-Cs divalent alkylene group or a


Wn, where n is 0-3;
wherein each W is independently selected from the group consisting of -CN,

-CO2R7, -C(O)NR 7R7, -C(O)-R7, -NO2, -OR 7, -SR7, -NR7R7 , -NR 7C(O)OR7, -
7
NR C(O)R 7, -Q-Ar, and carbon based moieties ofup to 24 carbon atoms, optionally
containing heteroatoms selected from N, Sand O and optionally substituted by one
CO2R7, -C(O)R7 , -C(O)NR 7R7, -OR7, -SR7 , -NR7R7, -NO2, -NR 7C(O)R7, -
NR 7C(O)OR 7 and halogen up to per-halo; with each R7 independently selected from

7
wherein Q is -0-, -S-, -N(R )-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)mO-, -
N(R 7)(CH2)m-,where m= 1-3, and Xa is halogen;
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is 0 to 3 and each Z is independently selected from the group consisting of -CN, -
CO2R7, -C(O)R7 , -C(O)NR7R7, -NO2, -OR7, - SR7 -NR7R 7 , -NR7C(O)OR7, -
7
NR C(O)R7 , and a carbon based moiety of up to 24 carbon atoms, optionally
or more substituents selected from the group consisting of -CN, -CO2R 7, -COR7, -
C(O)NR 7R7, -OR7, -SR 7, -NO2, -NR7R7, -NR7C(O)R7, and -NR7C(O)OR 7 ; and
wherein M is one or more bridging groups selected from the group consisting of -0-
, -S-, -N(R7)-, -(CH2)m,-C(O)-, -CH(OH)-, -(CH2)mO-,-(CH2)mS-,-(CH2)mN(R7)-, -
O(CH2)m-CHXa-, -CXa2-, -S-(CH2)m-and -N(R7)(CH2)m-, where m= 1-3, Xa is
halogen and R 7 is as defined above.
11. A method of treating a disease mediated by p38 within a host, said

method comprising administering to said host a compound of Formula I:
A-D-B (I)
D is -NH-C(O)-NH-,

1
L )q, where L is a substituted or unsubstituted phenyl or pyridine moiety bound
directly to D, L I comprises a substituted phenyl, pyridine or pyrimidinyl moiety, M
is a bridging group having at least one atom, q is an integer of from 1-3; and
B is a substituted or unsubstituted phenyl or pyridine group bound

directly to D,

consisting of -SO2Rx, -C(O)Rx and -C(NRy) R2 ,
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to per halo;




halogen; or
c) one of Ra or Rb is -C(O)-, a C 1-C5 divalent alkylene group or a

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Wn, where n is 0-3;
wherein each Wis independently selected from the group consisting of -CN,
-CO 2R7, -C(O)NR 7R7, -C(O)-R 7, -NO2, -OR7, -SR 7, -NR 7R 7, -NR 7C(O)OR7, -
NR 7C(O)R 7 , -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally

CO2R7 , -C(O)R 7 , -C(O)NR 7R7, -OR7, -SR7, -NR7R7 , -NO2, -NR 7C(O)R7, -
7 7
NR C(O)OR 7 and halogen up to per-halo; with each R independently selected from
heteroatoms selected from N, S and O and optionally substituted by halogen,

N(R 7)(CH 2)m-,where m= 1-3, and Xa is halogen;

CO2R7 , -C(O)R7, -C(O)NR 7R7, -NO2, -OR7 , - SR7 -NR7R 7, -NR 7C(O)OR7, -
7
NR C(O)R 7, and a carbon based moiety of up to 24 carbon atoms, optionally
or more substituents selected from the group consisting of -CN, -CO 2R7 , -COR7, -
C(O)NR 7R 7, -OR7, -SR 7, -NO2, -NR7R7, -NR 7C(O)R 7, and -NR7C(O)OR 7 ; with R7
is as defined above; and
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7
, -S-, -N(R )-, -(CH2)m, -C(O)-, -CH(OH)-, -(CH2)mO-, -(CH2)mS-, -(CH2)mN(R 7)-, -
3 3 7
O(CH2)m- CHX -, -CX 2-, -S-(CH2)m- and -N(R )(CH2)m-, where m= 1-3, Xa is
halogen and R 7 is as defined above.
12. A method for the treatment of a disease mediated by p38 kinase other
than cancer which comprises administering a compound selected from the group
consisting of

N-(3-tert-butylphenyl)-N'-( 4-(3-(N-methylcarbamoyl)phenoxy)phenyl urea
and
N-(3-tert-butylphenyl)-N'-( 4-(4-acetylphenoxy)phenyl urea;

N-( 5-tert-butyl-2-methoxyphenyl)-N '-(4-( 1,3-dioxoisoindolin-5-
yloxy )phenyJ) urea,
N-(5-tert-butyl-2-methoxyphenyl)-N'-(4-(1-oxoisoindolin-5-yloxy)phenyl)
urea,
N-(5-tert-butyl-2-methoxyphenyl)-N'-(4-(4-methoxy-3-(N-
N-( 5:.tert-butyl-2-methoxyphenyl)-N '-(4-(3-(N-
methylcarbamoyl)phenoxy )phenyl) urea;

N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-
N-(2-methoxy-5-( trifluoromethy I)pheny 1)-N'-(4-(2-carbamoy 1-4-
pyridyloxy )phenyl) urea,
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N-(2-rnethoxy-5-( trifluororneth y I)pheny I)-N '-(4-(2-(N-rnethy lcarbarnoyl)-4-

pyri dy loxy )phenyl) urea,
N-(2-rnethoxy-5-( tri fl uorornethy I)pheny I)-N '-(4-(2-( N-rnethy lcarbarnoy 1)-4-
N-(2-rnethoxy-5-(trifluorornethyl)phenyl)-N'-(2-chloro-4-(2-(N-
rnethylcarbarnoyl)( 4-pyridyloxy))phenyl) urea and
N-(2-rnethoxy-5-(trifluorornethyl)phenyl)-N'-(3-chloro-4-(2-(N-
rnethylcarbarnoyl)( 4-pyridyloxy))phenyl) urea;
the 4-chloro-3-(trifluorornethyl)phenyl ureas:

N-( 4-chloro-3-( trifluorornethy I)phen y I)-N '-(3-(2-carbarnoyl-4-
pyrid yloxy )phenyl) urea,
N-(4-chloro-3-( trifluorornethy l)pheny I)-N '-(3-(2-(N-rnethy lcarbarnoyl)-4-
N-(4-chloro-3-( trifluorornethyl)phenyl)-N '-( 4-(2-carbarnoyl-4-
pyridyloxy )phenyl) urea and
N-(4-chloro-3-( tri fluorornethy l)phenyl)-N '-( 4-(2-(N-rnethy lcarbarnoyl)-4-
pyridy loxy )phenyl) urea;
the 4-brorno-3-(trifluorornethyl)phenyl ureas:

N-(4-brorno-3-( trifluorornethy })phenyl)-N '-(3-(2-(N-rnethy lcarbarnoyl)-4-
N-(4-brorno-3-( trifluorornethy I)phenyl)-N '-(4-(2-(N-rnethylcarbarnoy 1)-4-
N-(4-brorno-3-( trifluorornethy l)pheny 1)-N'-(3-(2-(N-rnethylcarbarnoyl)-4-
pyrid y lthio )phenyl) urea,
N-(4-brorno-3-( trifluorornethyl )phenyl)-N '-(2-chloro-4-(2-(N-
rnethy lcarbarnoy l)( 4-pyridyloxy))phenyl) urea and
N-(4-brorno-3-( trifluorornethy I)pheny 1)-N'-(3-chloro-4-(2-(N-
rnethy lcarbarnoy l)( 4-pyridyloxy))phenyl) urea; and
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N-(2-methoxy-4-chloro-5-( trifluoromethy l)pheny 1)-N '-(4-(2-( N-
methy lcarbamoy 1)-4-pyridy loxy)phenyl) urea,
13. A pharmaceutical composition for the treatment of a disease within a

host mediated by p38 comprising a compound of Formula I,
A-D-B (I)
or a pharmaceutically acceptable salt thereof, in an amount effective to treat a

disease mediated by p38 and a physiologically acceptable carrier:
wherein
Dis -NH-C(O)-NH-,

1
L )q, where L is a 5 or 6 membered cyclic structure bound directly to D, L 1
group having at least one atom, q is an integer of from 1-3; and each cyclic
1
structure of L and L contains 0-4 members of the group consisting of nitrogen,
oxygen and sulfur, and

and sulfur,
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Ry is hydrogen or a carbon based moiety ofup to 24 carbon atoms optionally

to per halo,




halogen; or
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I
where B is substituted, L is substituted or L is additionally substituted, the
Wn, where n is 0-3;

CN, -CO2R7, -C(O)NR 7R7, -C(O)-R 7, -NO2, -OR 7, -SR7 , -NR7R 7, -NR 7C(O)OR7, -
NR 7C(O)R 7, -Q-Ar, and carbon based moieties ofup to 24 carbon atoms, optionally
CO2R 7, -C(O)R 7, -C(O)NR 7R7, -OR7, -SR7, -NR7R7, -NO 2, -NR 7C(O)R7, -
7 7 7
NR C(O)OR and halogen up to per-halo; with each R independently selected from
wherein Q is -0-, -S-, -N(R 7)-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)mO-,-

(CH2)mS-, -(CH2)mN(R7)-, -O(CH2)m- CHXa-, -CXar, -S-(CH2)m- and -
N(R 7)(CH 2)m-,where m= 1-3, and Xa is halogen; and

CO2R7, -C(O)R7, -C(O)NR 7R 7, -NO2, -OR7, - SR7 -NR7R 7, -NR 7C(O)OR7, -
NR 7C(O)R 7, and a carbon based moiety of up to 24 carbon atoms, optionally

or more substituents selected from the group consisting of -CN, -CO 2R 7 , -COR7, -
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C(O)NR 7R 7, -OR 7 , -SR 7 , -NO 2, -NR 7R7, -NR 7C(O)R 7, and -NR 7 C(O)OR 7 , with R 7
as defined above.
14. A pharmaceutical composition as in claim 13 wherein:
Ry is hydrogen, C1-10 alkyl, C1-10 alkoxy, C3-10 cycloalkyl having 0-3

heteroatoms, C2_10 alkenyl, C1-10 alkenoyl, C6-12 aryl, C3-12 hetaryl having 1-3
heteroatoms selected from N, S and 0, C1-24 aralkyl, C1-24 alkaryl, substituted C1-10
alkyl, substituted Ci-,o alkoxy, substituted C3-10cycloalkyl having 0-3 heteroatoms
selected from N, S and 0, substituted C6 -C14 aryl, substituted C3_12hetaryl having
1-3 heteroatoms selected from N, S and 0, substituted C7_24 alkaryl or substituted
CrC 24aralkyl, where Ry is a substituted group, it is substituted by halogen up to per
halo,
Rz is hydrogen, C1-10 alkyl, C1-10 alkoxy, C3-10 cycloalkyl having 0-3

heteroatom, C2 -Jo alkenyl, C1-10alkenoyl, C6-12aryl, C3 -C12 hetaryl having 1-3
heteroatoms selected from, S, N and 0, C1-24 alkaryl, C1-24aralkyl, substituted C1-10
alkyl, substituted C1-io alkoxy, substituted C6-C14 aryl, substituted C3 -C10
cycloalkyl having 0-3 heteroatoms selected from S, N and 0, substituted C3_12
hetaryl having 1-3 heteroatoms selected from N, 0 and S, substituted C7_24 alkaryl
or substituted CrC 24 aralkyl where R2 is a substituted group, it is substituted by
halogen up to per halo, hydroxy, C1-10 alkyl, CJ-12 cycloalkyl having 0-3
heteroatoms selected from 0, Sand N, C3_12hetaryl having 1-3 heteroatoms selected
from N, S and 0, C 1_1o alkoxy, C6.J2aryl, C1-6halo substituted alkyl up to per halo
alkyl, C6-C12 halo substituted aryl up to per halo aryl, C3-C12 halo substituted
cycloalkyl up to per halo cycloalkyl having 0-3 heteroatoms selected from N, S and
0, halo substituted C3-C 12hetaryl up to per halo hetaryl having 1-3 heteroatoms
selected from N, S and 0, halo substituted CrC 24 aralkyl up to per halo aralkyl, halo
substituted CrC 24alkaryl up to per halo alkaryl, and -C(O)Rg,
Ra and Rb are,
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a carbon based moiety selected from te group consisting of C 1 -C 10

alkyl, C1 -C10 alkoxy, C3-10cycloalkyl, C2-10alkenyl, C1-10alkenoyl, C6-12aryl, C3-12
hetaryl having 1-3 heteroatoms selected from 0, N and S, C3_12 cycloalkyl having 0-
3 heteroatoms selected from N, S and 0, C7_24aralkyl, CrC2 4 alkaryl, substituted
C1-10 alkyl, substituted Ci-1o alkoxy, substituted C3-10 cycloalkyl, having 0-3
heteroatoms selected from N, S and 0, substituted C6-12aryl, substituted C3-12
hetaryl having 1-3 heteroatoms selected from N, S and 0, substituted C7_24 aralkyl,
substituted C7_24 alkaryl, where Ra and Rb are a substituted group, they are
substituted by halogen up to per halo, hydroxy, C 1_10alkyl, C3-12cycloalkyl having
0-3 heteroatoms selected from 0, S and N, C3_12 hetaryl having 1-3 heteroatoms
selected from N, S and 0, C1-10alkoxy, C6-12aryl, C 1_6 halo substituted alkyl up to
per halo alkyl, C6-C 12 halo substituted aryl up to per halo aryl, C3-C 12 halo
substituted cycloalkyl having 0-3 heteroatoms selected from N, S and 0, up to per
halo cycloalkyl, halo substituted C3-C12 hetaryl up to per halo heteraryl, halo
substituted C7-C 24 aralkyl up to per halo aralkyl, halo substituted CrC 24 alkaryl up
to per halo alkaryl, and -C(O)Rg ; or
-OSi(Rr) 3 where Rr is hydrogen, C1-10alkyl, C1-10alkoxy, C3-C10

cycloalkyl having 0-3 heteroatoms selected from 0, S and N, C6-12aryl, C3'-C12
hetaryl having 1-3 heteroatoms selected from 0, S and N, C7_24 aralkyl, substituted
C 1-10alkyl, substituted C 1-C 1o alkoxy, substituted C3-C12 cycloalkyl having 0-3
heteroatoms selected from 0, S and N, substituted C3-C12 heteraryl having 1-3
heteroatoms selected from 0, S, and N, substituted C6_12 aryl, and substituted C7_24
alkaryl, where Rr is a substituted group it is substituted halogen up to per halo,
hydroxy, C 1_10alkyl, C3_12cycloalkyl having 0-3 heteroatoms selected from 0, S and
N, C3-12hetaryl having 1-3 heteroatoms selected from N, S and 0, Ci-1o alkoxy, C6_
12 aryl, C7 -C24 alkaryl, C7 -C24 aralkyl, C1-6halo substituted alkyl up to per halo
alkyl, C6-C12 halo substituted aryl up to per halo aryl, C3-C12 halo substituted
cycloalkyl having 0-3 heteroatoms selected from N, S and 0, up to per halo
cycloalkyl, halo substituted C3-C12hetaryl up to per halo heteraryl, halo substituted
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CrC 24 aralkyl up to per halo aralkyl, halo substituted CrC 24 alkaryl up to per halo
alkaryl, and -C(O)Rg, or

structure of 1-3 heteroatoms selected from N, S and O with substituents selected
from the group consisting of halogen up to per halo, hydroxy, C 1_1o alkyl, C3_12
cycloalkyl having 0-3 heteroatoms selected from 0, S and N, C3_12hetaryl having 1-
3 heteroatoms selected from N, S and 0, C1-10alkoxy, C6-12aryl, C1 -C24 alkaryl, C7
-C 24 aralkyl, halo substituted C1-6alkyl up to per halo alkyl, halo substituted C6-C 12
aryl up to per halo aryl, halo substituted C3-C12cycloalkyl having 0-3 heteroatoms
selected from N, S and 0, up to per halo cycloalkyl, halo substituted C3-C 12hetaryl
up to per halo heteraryl, halo substituted CrC24 aralkyl up to per halo aralkyl, halo
substituted CrC 24alkaryl up to per halo alkaryl, and -C(O)Rg, or
c) one of Ra or Rb is -C(O)-, a C1-C5 divalent alkylene group or a

substituted C 1-C 5 divalent alkylene group bound to the moiety L to form a cyclic
C1-10alkyl, C3_12cycloalkyl having 0-3 heteroatoms selected from 0, S and N, C3_12
hetaryl having 1-3 heteroatoms selected from N, Sand 0, C1-ioalkoxy, C 6_12aryl, C7
-C24 alkaryl, C7 -C 24 aralkyl, C1-6halo substituted alkyl up to per halo alkyl, C6-C 12
halo substituted aryl up to per halo aryl, C3-C12halo substituted cycloalkyl having 0-
3 heteroatoms selected from N, S and 0, up to per halo cycloalkyl, halo substituted
C3-C12hetaryl up to per halo heteraryl, halo substituted CrC2 4 aralkyl up to per halo
aralkyl, halo substituted CrC 24 alkaryl up to per halo alkaryl, and -C(O)Rg,
where Rg is C1-10alkyl; -CN, -CO2Ro, -ORi, -SRi, -NO2, -C(O) Re, -NRoRe,-
NRoC(O)ORe and -NRi C(O)Re, and Ro and Re are independently selected from the
group consisting of hydrogen, C1-10,alkyl, C1-10alkoxy, C3-10cycloalkyl having 0-3
heteroatoms selected from 0, N and S, C6-12 aryl, C3- C 12 hetaryl with 1-3
heteroatoms selected from 0, N and S and C1 -C24aralkyl, C7 -C24alkaryl, up to per
halo substituted C 1-C 10alkyl, up to per halo substituted C 3 -C10cycloalkyl having 0-
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3 heteroatoms selected from 0, N and S, up to per halo substituted C6 -C 14 aryl, up

to per halo substituted C3 -C 12 hetaryl having 1-3 heteroatoms selected from 0, N,
and S, halo substituted CrC 24 alkaryl up to per halo alkaryl, and up to per halo
substituted CrC 24 aralkyl,
W is independently selected from the group consisting of -CN, -CO2R7, -
C(O)NR R -C(O)-R -NO2, -OR -SR -NR R -NR C(O)OR -NR C(O)R C 1-
7 7 7 7 7 7 7 7 7 7
7
, , , , , , ,
C10alkyl, C 1-C 10alkoxy, C2-C10alkenyl, C1-C10alkenoyl, C3-C10cycloalkyl having

0-3 heteroatoms selected from 0, S and N, C6-C14aryl, C1-C24 alkaryl, C7 -C24
aralkyl, C3-C 12 heteroaryl having 1-3 heteroatoms selected from 0, N and S, C4-C23
alkheteroaryl having 1-3 heteroatoms selected from 0, N and S, substituted C 1-C 10
alkyl, substituted C 1-C 10 alkoxy, substituted Ci-C10 alkenyl, substituted C 1-C 1o
alkenoyl, substituted C3-C10cycloalkyl having 0-3 heteroatoms selected from 0, N
and S, substituted C6-C 12 aryl, substituted C3-C12hetaryl having 1-3 heteroatoms
selected from 0, N and S, substituted CrC 24 aralkyl, substituted CrC 24 alkaryl,
substituted C4 -C23 alkheteroaryl having 1-3 heteroatoms selected from 0, N and S,
and -Q-Ar;
R is independently selected from H, C1-C10alkyl, C 1-C 10 alkoxy, C2-C10

7
alkenyl, C 1-C 10alkenoyl, C3-C10cycloalkyl having 0-3 heteroatoms selected from

0,
N and S, C6 -C 14aryl, C3 -C 13 hetaryl having 1-3 heteroatoms selected from 0, N and

S, C1-C14alkaryl, C -C24 aralkyl, C4-C23 alkheteroaryl having 1-3 heteroatoms
7
selected from 0, N and S, up to per-halosubstituted C -C 1 10

alkyl, up to per-
halosubstituted C3-C 10cycloalkyl having 0-3 heteroatoms selected from 0, N and S,
up to per-halosubstituted C6-C 14 aryl, up to per-halosubstituted C3 -C 13 hetaryl
having 1-3 heteroatoms selected from 0, N and S, up to per-halosubstituted CrC 24
aralkyl, up to per-halosubstituted CrC2 4 alkaryl, and up to per-halosubstituted C4-
C23alkheteroaryl; and
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each Z is independently selected from the group consisting of -CN, -CO2R7,

-C(O)R 7 , -C(O)NR 7R7 , -NO2, -OR7, - SR7 -NR 7R7, -NR 7C(O)OR 7, -NR 7C(O)R 7, C 1-
CIOalkyl, C 1-C 1o alkoxy, Cz-C10alkenyl, C1-C10alkenoyl, C3-C10cycloalkyl having
0-3 heteroatoms selected from 0, N and S, C6-C14aryl, C3-C13hetaryl having 1-3
heteroatoms selected from 0, N and S, CrC24 alkaryl, C1 -C24 aralkyl, C4-C23
alkheteroaryl having 1-3 heteroatoms selected from 0, N and S, substituted C 1-C 10
alkyl, substituted C 1-C10 alkoxy, substituted C2-C10 alkenyl, substituted C 1-C 10
alkenoyl, substituted C3-C 10 cycloalkyl having 0-3 heteroatoms selected from 0, N
and S, substituted C6-C12aryl, substituted CrC24 alkaryl, substituted CrC 24aralkyl
and substituted C4-C23 alkheteroaryl having 1-3 heteroatoms selected from 0, N
and S; wherein if Z is a substituted group, the one or more substituents are selected
from the group consisting of -CN, -CO2R7, -COR 7, -C(O)NR 7R 7, -OR7, -SR 7, -NO2,
-NR 7R7 , -NR7C(O)R 7, and -NR 7C(O)OR 7 .
15. A pharmaceutical composition as in claim 13 wherein M is one or

more bridging groups selected from the group consisting of -0-, -S-, -N(R7)-, -
(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)mO-, -(CH2)mS-, -(CH2)mN(R7)-, -O(CH2)m-
CHXa-, -CXa2-, -S-(CH 2)m- and -N(R7)(CH2)m-, where m= 1-3, Xa is halogen and
R7is as defined in claim 13.
16. A pharmaceutical composition as in claim 13 wherein the cyclic

structures of B and L bound directly to D are not substituted in the ortho position
by-OH.

structures of B and L bound directly to D are not substituted in the ortho position by
a moiety having an ionizable hydrogen and a pKa of 10 or less.
18. A pharmaceutical composition as in claim 13 wherein B of Formula I

is a substituted or unsubstituted six member aryl moiety or six member hetaryl
moiety, said hetaryl moiety having 1 to 4 members selected from the group of
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hetaryl atoms consisting of nitrogen, oxygen and sulphur with the balance of the
hetaryl moiety being carbon.
19. A pharmaceutical composition as in claim 13 wherein B of Formula I

is an unsubstituted phenyl group, an unsubstituted pyridyl group, an unsubstituted
pyrimidinyl group, a phenyl group substituted by a substituent selected from the
group consisting of halogen and Wn wherein W and n are as defined in claim 13, a
pyrimidinyl group substituted by a substituted selected from halogen and Wn,
wherein W and n are as defined in Claim 13, or a pyridyl group substituted by a
substituent selected from the group consisting of halogen and Wn wherein W and n
are as defined in claim 13.
20. A pharmaceutical composition as in claim 13, wherein L, the six

member cyclic structure bound directly to D, is a substituted or unsubstituted 6
member aryl moiety or a substituted or unsubstituted 6 member hetaryl moiety,
wherein said hetaryl moiety has 1 to 4 members selected from the group of
heteroatoms consisting of nitrogen, oxygen and sulphur with the balance of said
hetaryl moiety being carbon, wherein the one or more substituents are selected from
the group consisting of halogen and Wn, wherein Wand n are as defined in claim
13.
21. A pharmaceutical composition as m claim 13, wherein L, the 6

member cyclic structure bound directly to D, is a substituted phenyl, unsubstituted
phenyl, substituted pyridyl, unsubstituted pyridyl group, unsubstituted pryimidinyl
or substituted prymidinyl.
22. A pharmaceutical composition as m claim 13, wherein said

substituted cyclic moiety L I comprises a 5 to 6 membered aryl moiety or hetaryl
moiety, wherein said heteraryl moiety comprises 1 to 4 members selected from the
group ofheteroatoms consisting of nitrogen, oxygen and sulphur.
23. A pharmaceutical composition as in claim 13, wherein said

I
substituted cyclic moiety L is phenyl, pyridyl or pyrimidinyl and M is one or more
bridging groups selected from the group consisting of -0-, -S-, -N(R 7)-, -(CH2)m-, -
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C(O)-, -CH(OH)-, -(CH2)mO-, -(CH2)mS-, -(CH2)mN(R7)-, -O(CH2)m- CHX3 -, -
CX3 2-, -S-(CH2)m- and -N(R7)(CH2)111-, where m= 1-3, Xa is halogen and R7 is

hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing
heteroatoms selected from N, S and O and optionally substituted by halogen up to
pre halo.
24. A pharmaceutical composition as m claim 13 wherein L 1 is

additionally substituted 1 to 3 times by one or more substituents selected from the
group consisting of C1-C1o alkyl, up to per halo substituted C1-C10alkyl, -CN, -OH,
halogen, C 1-C 10 alkoxy and up to per halo substituted C 1-C 10alkoxy.
25. A pharmaceutical composition as in claim 13 wherein L 1 1s

substituted by -C(O)Rx .
26. A pharmaceutical composition as m claim 13 wherein L 1 1s

substituted by -C(O)Rx or -SO2Rx,wherein Rx is NRaRb.

host mediated by p38 comprising a compound of Formula I:
A-D-B (I)

disease mediated by p38 and a physiologically acceptable carrier, wherein
Dis -NH-C(O)-NH-,

1
L )q, where Lis a 6 membered aryl moiety or a 6 membered hetaryl moiety bound
directly to D, L 1 comprises a substituted cyclic moiety having at least 5 members,
M is a bridging group having at least one atom, q is an integer of from 1-3; and
each cyclic structure of L and L 1 contains 0-4 members of the group consisting of
nitrogen, oxygen and sulfur, and

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and sulfur,

Ry is hydrogen or a carbon based moiety ofup to 24 carbon atoms optionally

to per halo,




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halogen; or

substituted C 1-C 5 divalent alkylene group bound to the moiety L to form a cyclic
structure with at least 5 members, wherein the substituents of the substituted C1-C5

Wn, where n is 0-3;

CN, -CO2R7, -C(O)NR 7R7, -C(O)-R 7, -NO2, -OR 7, -SR 7 , -NR7R 7, -NR 7 C(O)OR 7, -
7 7
NR C(O)R , -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally
CO2R7, -C(O)R 7 , -C(O)NR 7R7, -OR 7, -SR7, -NR 7R7 , -NO2, -NR 7C(O)R7, -
NR 7C(O)OR 7 and halogen up to per-halo; with each R 7 independently selected from

7
wherein Q is -0-, -S-, -N(R )-, -(CH2)m-,-C(O)-, -CH(OH)-, -(CH2)mO-, -
(CH2)mS-, -(CH2)mN(R7)-, -O(CH2)m- CHXa-, -CXaz-, -S-(CH2)m- and -
N(R 7)(CH2)m-,where m= 1-3, and Xa is halogen;

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CO2R7, -C(O)R 7, -C(O)NR 7R 7, -NO 2, -OR 7 , - SR7 -NR 7R 7, -NR 7C(O)OR 7, -
NR.7C(O)R 7, and a carbon based moiety of up to 24 carbon atoms, optionally

or more substituents are selected from the group consisting of -CN, -CO 2R7 , -COR7,
-C(O)NR 7R 7 , -OR 7 , -SR 7 , -NO2, -NR 7R 7, -NR 7 C(O)R 7, and -NR 7C(O)OR 7 with R7
as defined above; and
, -S-, -N(R 7)-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)mO-, -(CH2)mS-, -(CH2)mN(R7)-,
-O(CH2)m- CHXa-, -CXa2-, -S-(CH2)m- and -N(R 7)(CH2)m-, where m= 1-3, Xa is
halogen and R7 is as defined above.
28. A pham1aceutical composition for the treatment of a disease within a

host mediated by p38 comprising a compound of Formula I:
A-D-B (I)

disease mediated by p38 and a physiologically acceptable carrier, wherein
D is -NH-C(O)-NH-,

L 1 )q, where L is a substituted or unsubstituted phenyl or pyridyl moiety bound
directly to D, L I comprises a substituted phenyl, pyridyl or pyrimidinyl moiety, M
is a bridging group having at least one atom, q is an integer of from 1-3; and
B is a substituted or unsubstituted phenyl or pyridine group bound

directly to D,

consisting of -SO2Rx, -C(O)Rx and -C(NR.y)Rz,

to per halo, and ;
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Rx is R2 or NRaRbwhere Ra and Rb are



halogen; or
c) one of Ra or Rb is -C(O)-, a C1-Cs divalent alkylene group or a

138
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WO 00/41698 PCT/US00/00768


Wn, where n is 0-3;

CN, -CO2R7, -C(O)NR 7R7, -C(O)-R 7, -NO2, -OR7 , -SR7, -NR7R 7, -NR 7C(O)OR7, -
NR 7C(O)R7, -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally
CO2R7 , -C(O)R 7 , -C(O)NR 7R7 , -OR7, -SR7 , -NR7R 7, -NO2, -NR 7C(O)R7 , -
NR 7C(O)OR 7 and halogen up to per-halo; with each R 7 independently selected from


(CH2)mS-, -(CH2)mN(R7)-, -O(CH2)m- CHX -, -CX2 2-, -S-(CH2)m- and -
3
N(R 7)(CH 2)m-,where m= 1-3, and X2 is halogen;

substituted by halogen, up to per-halo, and optionally substituted by Z 01 , wherein nl
CO2R7 , -C(O)R 7 , -C(O)NR 7R7, -NO2, -OR7, - SR7 -NR7R7 , -NR 7C(O)OR7, -
7
NR C(O)R7, and a carbon based moiety of up to 24 carbon atoms, optionally
or more substituents selected from the group consisting of -CN, -CO 2R 7, -COR7, -
C(O)NR 7R7 , -OR 7, -SR7, -NO2, -NR7R7, -NR 7C(O)R7 , and -NR7C(O)OR 7 with R7 as
defined above; and
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, -S-, -N(R7)-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)mO-,-(CH2)mS-, -(CH2)mN(R7)-,
-O(CH2)m- CHXa-, -CX 3 2-, -S-(CH2)m- and -N(R 7)(CH2)m-, where m= 1-3, Xa is
halogen and R7 is as defined above.

by-OH.
30. A pharmaceutical composition as in claim 27, wherein the cyclic

structures of B and L bound directly to D are not substituted in the ortho position by
31. A pharmaceutical composition as in claim 28, wherein the cyclic

by-OH.
32. A pharmaceutical composition as m claim 28 wherein the cyclic

structures of B and L bound directly to Dare not substituted in the ortho position by

substituted by C(O)Rx or SO2Rx, wherein Rx is NRaRb,

substituted by C(O)Rx or SO2Rx, wherein Rx is NRaRb,
35. A pharmaceutical composition as in claim 13 which comprises a

pharmaceutically acceptable salt of a compound of formula I selected from the
group consisting of
phosphoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic
acid, p-toluene sulphonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-
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napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid,
acid, salicylic acid, phenylacetic acid, and mandelic acid; and

from the group consisting of alkaline cations, alkaline earth cations, the ammonium
cation, aliphatic substituted ammonium cations and aromatic substituted ammonium
cations.

group consisting of

cations.

group consisting of
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WO 00/41698 PCT /US00/00768

cations.

host mediated by p38 comprising a compound selected from the group consisting of
N-(3-tert-butylphenyl)-N'-( 4-(3-(N-methylcarbamoyl)phenoxy)phenyl urea
and
N-(3-tert-buty lpheny 1)-N '-(4-(4-acety lphenoxy )pheny 1urea;

N-( 5-tert-butyl-2-methoxyphenyl)-N '-(4-( 1,3-dioxoisoindolin-5-
yloxy)phenyl) urea,
N-(5-tert-butyl-2-methoxyphenyl)-N'-(4-(1-oxoisoindolin-5-yloxy)phenyl)
urea,
N-( 5-tert-butyl-2-methoxyphenyl)-N'-( 4-( 4-methoxy-3-(N-
N-(5-tert-butyl-2-methoxyphenyl)-N'-(4-(3-(N-
methylcarbamoyl)phenoxy)phenyl) urea;

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N-(2-methoxy-5-( trifl uoromethy I)pheny 1)-N'-(4-(2-(N-methylcarbamoy 1)-4-
pyrid y loxy )phenyl) urea,
N-(2-methoxy-5-( trifluoromethyl )pheny I)-N '-( 4-(2-(N-methy lcarbamoyl)-4-
pyridy lthio )phenyl) urea,
N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-
methylcarbamoyl)( 4-pyridyloxy))phenyl) urea and
N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-
methylcarbamoyl)( 4-pyridyloxy))phenyl) urea;

N-( 4-chloro-3-( trifluoromethy I)phenyl)-N '-(3-(2-carbamoyl-4-

N-( 4-chloro-3-( tri fluorometh y I)phenyl)-N '-(3-(2-(N-methy lcarbamoyl)-4-
p yri dyloxy )phenyl) urea,

N-( 4-chloro-3-( trifluoromethyl)phenyl)-N '-(4-(2-carbamoyl-4-
pyridyloxy )phenyl) urea and

N-(4-chloro-3-( trifluoromethyl)phenyl)-N '-(4-(2-(N-methylcarbamoyl)-4-
pyridyloxy )phenyl) urea;
the 4-bromo-3-(trifluoromethyl)phenyl ureas:

N-( 4-bromo-3-( trifl uoromethy l)pheny I)-N '-(3-(2-(N-methy lcarbamoyl)-4-

N-( 4-bromo-3-( trifl uoromethy l)pheny 1)-N'-(4-(2-(N-methylcarbamoyl)-4-
pyri dy loxy )phenyl) urea,

N-( 4-bromo-3-( trifl uoromethyl)phenyl )-N '-(3-(2-(N-methy lcarbamoy 1)-4-
pyridy lthio )phenyl) urea,

N-( 4-bromo-3-( tri fluoromethy I)phenyl)-N '-(2-chloro-4-(2-(N-
meth ylcarbamoy l)(4-pyridyloxy) )phenyl) urea and
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N-( 4-bromo-3-( trifluoromethy I)phen y 1)-N '-(3-chloro-4-(2-(N-

methy lcarbamoy I)(4-pyridyloxy))phenyl) urea; and

N-(2-methoxy-4-chloro-5-( tri fluoromethy l)pheny 1)-N'-(4-(2-(N-
methy lcarbamoy l)-4-pyridy loxy )phenyl) urea,
methylcarbamoyl)( 4-pyridyloxy))phenyl) urea and
methylcarbamoyl)( 4-pyridyloxy))phenyl) urea, or a pharmaceutically
acceptable salt thereof.
144
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INTERNATIONAL SEARCH REPORT :national application No.
PCT /US00/00768
.-\. CL.-\SSIFIC..HIO~ OF SUB.JECT ,u TTER

IPC(7) A61K 31/535. 31/50, 31/445. 31/44. 31/40. 31/34. 31/17
US CL : Please See Extra Sheet.
According. to lmernational Patent Classification ([PC) or lo both national classification and IPC
B. FIELDS SEARCHED
Minimum documentation searched (classification system followed by classification symbols)
U.S. 514/235.5. 237.2. 252. 13. 253.01. 331. 345. 350, 416, 417. 428. 471. 596, 597. 598
Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
Electronic data base consulted during. the international search (name of data base and. where practicable. search tenns used)
Please See Extra Sheet.
C. DOCUMENTS CONSIDERED TO BE RELE\' ANT
Category* Citation of document. with indication. where appropriate, of the relevant passages Relevant to claim No.
X WO 95/33458Al (SMITHKLINEBEECHAMCORPORATION)14 1-38

December 1995 (14.12.95), see pages 1-11 and the claims.
□ Further documents are listed in the continuation of Box C. □ See patent family annex.
Special cati:goni:s of cited documents "T" later document published after the mtemattonal filing date or pnonty
date and not m con01ct wuh the apphcauon but cited to understand
"A" document defmmg the general state of the art which 1s not cons1dered the pnnc1ple or lheory underlymg lhe anvenllon
to be of parucular relevance
"E" earlier document pubhshed on or after the mtemauonal film~ date

·x· document of panicular relevance: the claimed mvcnuon cannot be
con:udercd novel or cannot be conS1deredto mvolve an mvcnuve step
"L" document which may throw doubts on pnorny clauntsl or which is when the document u taken alone
cited to cstabhsh the pubhcauon date of another c1tauon or other
special reason us specified) "Y" document of particular relevance: the claimed mvenuon cannot be
con:udered to mvolve an mvenuve step when the document 1s
·o· document refcrrm~ to an oral disclosure. use. cxh1b1tion or other combined with one or more other such documenu. such combmallon
means bcmg obvious to a person skilled in the an
•p• document published pnor to the mtcrnauonal filmg date but later than ·&· document member of the same patent family
the pnoruy date claimed
Date of the actual completion of the international search Date of mailing of the international search report
25 MARCH2000
16 MAY
ZOJ
0 r, "\ .
Name and mailing address of the ISA/US
~f~ r(;'[}u~~
Commissionerof Patents and Trademarks
Box PCT
Washington.0.C. 20231
Facsimile No. (703) 305-3230
Authorized officer
WILLIAM JARVIS
Telephone No.
1~,
(
(703) 308- 235
C
Fonn PCT/ISA/210 (second sheet) (July 1998) *
IITRUE COPYII
INTERNATIONAL SEARCH REPORT ... ernational application No.
PCT/US00/00768
A. CLASSIFICATION OF SUBJECT MATTER:

US CL :
514/235.5, 237.2, 252.13. 253.01. 331. 345, 350, 416, 417, 428. 471. 596, 597, 598
B. FIELDS SEARCHED
Electronic data bases consulted (Name of data base and where practicable terms used):
STN (REGISTRY (CHEMICAL STRUCTURE SEARCH), CAPLUS, USPATFUL)

search terms: cancer, tumor, neoplasm, antineoplastic. anticancer, anhritis, inflammation, antiinflammatory, mmp,
infection, autoimmune
Form PCT/ISA/210 (extra sheet) (July 1998)• z!!E.--

11TRUE COPYII
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(19) World Intellectual Property

Organization
International Bureau 1111111111111111
IIIIII
IIIII
11111111111111111111111111111111111111111111
IIIIIIIIIII
IIIIIIIIIIII
(43) International Publication Date (10) International Publication Number

16 September 2004 (16.09.2004) PCT WO 2004/078746 A2
(51) International Patent Classification 7: C07D 401/12, (74) Agents: TRAVERSO, Richard, J. et al.; Millen, White,
A61K 31/35, A61P 35/00 Zelano & Branigan, P.C., Arlington Courthouse Plaza 1,
2200 Clarendon Boulevard, Suite 1400, Arlington, VA
(21) International Application Number: 22201 (US).
PCT/US2004/006283
(81) Designated States (unless otherwise indicated, for every
(22) International Filing Date: 1 March 2004 (01.03.2004) kind of national protection available): AE, AG, AL, AM,
AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
(25) Filing Language: English CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, Fl,
GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD,
(26) Publication Language: English
MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG,
PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM,
(30) Priority Data: TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM,
60/450,323 28 February 2003 (28.02.2003) US zw.
---
iiiiiiii
PHARMACEUTICALS CORPORATION [US/US];
400 Morgan Lane, West Haven, CT 06516-4175 (US).
(84) Designated States (unless otherwise indicated, for every
kind of regional protection available): ARIPO (BW, GH,
GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), Euro-
iiiiiiii (72) Inventors; and
--
iiiiiiii
iiiiiiii
(75) Inventors/Applicants (for US only): BOYER, Stephen
[US/DE]; Mittelstrasse 55, 40721 Hilden (DE). DUMAS,
Jacques [FR/US]; 98 Farmview Road, Bethany, CT 06524
pean (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, Fl, FR,
GB, GR, HU, IE, IT, LU, MC, NL, PL, PT, RO, SE, SI, SK,
TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
ML, MR, NE, SN, TD, TG).
!!!!!!!!
(US). PHILLIPS,Barton [US/US]; 498 Whitney Avenue,
-
!!!!!!!!
Apt. 3D, New Haven, CT 06511 (US). SCOTT, William,
J. [US/US]; 210 Saddle Hill Drive, Guildford, CT 06437
(US). SMITH, Roger, A. [US/US]; 65 Winterhill Road,
Published:
without international search report and to be republished
Madison, CT 06443 (US). CHEN, Jianqing [CA/US]; 117 upon receipt of that report
Frederick Street, Apt. 2-L, New Haven, CT 06515 (US).
JAMES, Benjamin [US/US]; 37 Washington Ave. #3, For two-letter codes and other abbreviations, refer to the "Guid-
Hamden, CT 06518 (US). WANG, Gan [CN/US]; 5 Cas- ance Notes on Codes and Abbreviations" appearing at the begin-
sella Drive, Wallingford, CT 06492 (US). ning of each regular issue of the PCT Gazette.
-
-
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\0
~
r--...
Q0
r--...
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0
i -------------------------------------------
(54) Title: 2-OXO-1,3,5-PERHYDROTRIAZAPINE DERNATIVES USEFUL IN THE TREATMENT OF HYPER-PROLIFER-
0 ATIVE, ANGIOGENESIS, AND INFLAMMATRORY DISORDERS
M
0 (57) Abstract: This invention relates to novel diary! ureas, pharmaceutical compositions containing such compounds and the use of
:, those compounds or compositions for treating hyper-proliferative and angiogenesis disorders, as a sole agent or in combination with
;;, cytotoxic therapies.
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WO 2004/078746 PCT/US2004/006283
2-0xo-1,3,5-perhydrotriazapine Derivatives Useful

in the Treatment of Hyper-Proliferative, Angiogenesis, and Inflammatory
Disorders
s Field of the Invention

This invention relates to novel compounds,"' pharmaceutical compositions
containing such compounds and the use of those compounds or compositions for
treating hyper-proliferative and angiogenesis disorders, as a sole agent or in
combination with other active ingredients, e.g., cytotoxic therapies.

Activation of the ras signal transduction pathway indicates a cascade of
events that have a profound impact on cellular proliferation, differentiation, and
transformation. Raf kinase, a downstream effector of ras, is recognized as a key
1s mediator of these signals from cell surface receptors to the cell nucleus (Lowy, D. R.;
Willumsen, B. M. Ann. Rev. Biochem. 1993, 62, 851; Bos, J. L. Cancer Res. 1989,
49, 4682). It has been shown that inhibiting the effect of active ras by inhibiting the
raf kinase signaling pathway by administration of deactivating antibodies to raf kinase
or by co-expression of dominant negative raf kinase or dominant negative MEK, the
20 substrate of raf kinase, leads to the reversion of transformed cells to the normal
growth phenotype (see: Daum et aL Trends Biochem. Sci. 1994, 19, 474-80; Fridman
et al. J. Biol. Chem. 1994, 269, 30105-8. Kolch et al. (Nature 1991, 349, 426-28)
have further indicated that inhibition of raf expression by antisense RNA blocks cell
proliferation in membrane-associated oncogenes. Similarly, inhibition of raf kinase
25 (by antisense oligodeoxynucleotides) has been correlated in vitro and in vivo with
inhibition of the growth of a variety of human tumor types (Mania et al., Nat. Med.
1996, 2, 668-75). Some examples of small molecule inhibitors of Raf kinase activity
are important agents for the treatment of cancer. (Naumann, U.; Eisenmann-Tappe,
I.; Rapp, U. R. Recent Results Cancer Res. 1997, 143, 237; Mania, B. P.; Johnston,
30 J. F.; Geiger, T.; Muller, M.; Fabbro, D. Nature Medicine 1996, 2, 668).
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To support progressive tumor growth beyond the size of 1-2 mm3, it is

recognized that tumor cells require a functional stroma, a support structure consisting
of fibroblast, smooth muscle cells, endothelial cells, extracellular matrix proteins, and
soluble factors (Folkman, J., Semin Oneal, 2002. 29(6 Suppl 16), 15-8). Tumors
5 induce the formation of stromal tissues through the secretion of soluble growth
factors such as PDGF and transforming growth factor-beta (TGF-beta), which in turn
stimulate the secretion of complimentary factors by host cells such as fibroblast
growth factor (FGF), epidermal growth factor (EGF), and vascular endothelial growth
factor (VEGF). These stimulatory factors induce the formation of new blood vessels,
10 or angiogenesis, which brings oxygen and nutrients to the tumor and allows it to grow
and provides a route for metastasis. It is believed some therapies directed at
inhibiting stroma formation will inhibit the growth of epithelial tumors from a wide
variety of histological types. (George, D. Semin Oneal, 2001. 28(5 Suppl 17), 27-33;
Shaheen, R.M., et al., Cancer Res, 2001. 61(4), 1464-8; Shaheen, R.M., et al.
15 Cancer Res, 1999. 59(21), 5412-6). However, because of the complex nature and
the multiple growth factors involved in angiogenesis process and tumor progression,
an agent targeting a single pathway may have limited efficacy. It is desirable to
provide treatment against a number of key signaling pathways utilized by tumors to
induce angiogenesis in the host stroma. These include PDGF, a potent stimulator of
20 stroma formation (Ostman, A. and C.H. Heldin, Adv Cancer Res, 2001, 80, 1-38),
FGF, a chemo-attractant and mitogen for fibroblasts and endothelial cells, and
VEGF, a potent regulator of vascularization.
PDGF is another key regulator of stromal formation which is secreted by many

25 tumors in a paracrine fashion and is believed to promote the growth of fibroblasts,
smooth muscle and endothelial cells, promoting stroma formation and angiogenesis.
PDGF was originally identified as the v-sis oncogene product of the simian sarcoma
virus (Heldin, C.H., et al., J Cell Sci Suppl, 1985, 3, 65-76). The growth factor is
made up of two peptide chains, referred to as A or B chains which share 60%
30 homology in their primary amino acid sequence. The chains are disulfide cross linked
2
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to form the 30 kDa mature protein composed of either AA, BB or AB homo- or

heterodimmers. PDGF is found at high levels in platelets, and is expressed by
endothelial cells and vascular smooth muscle cells. In addition, the production of
PDGF is up regulated under low oxygen conditions such as those found in poorly
5 vascularized tumor tissue (Kourembanas, S., et al., Kidney Int, 1997, 51(2), 438-43).
PDGF binds with high affinity to the PDGF receptor, a 1106 amino acid 124 kDa
transmembrane tyrosine kinase receptor (Heldin, C.H., A. Ostman, and L.
Ronnstrand, Biochim Biophys Acta, 1998. 1378(1), 79-113). PDGFR is found as
homo- or heterodimer chains which have 30% homology overall in their amino acid
10 sequence and 64% homology between their kinase domains (Heldin, C.H., et al..
Embo J, 1988, 7(5), 1387-93). PDGFR is a member of a family of tyrosine kinase
receptors with split kinase domains that includes VEGFR2 (KOR), VEGFR3 (Flt4), c-
Kit, and FLT3. The PDGF receptor is expressed primarily on fibroblast, smooth
muscle cells, and pericytes and to a lesser extent on neurons, kidney mesangial,
15 Leydig, and Schwann cells of the central nervous system. Upon binding to the
receptor, PDGF induces receptor dimerization and undergoes auto- and trans-
phosphorylation of tyrosine residues which increase the receptors' kinase activity and
promotes the recruitment of downstream effectors through the activation of SH2
protein binding domains. A number of signaling molecules form complexes with
20 activated PDGFR including Pl-3-kinase, phospholipase C-gamma, src and GAP
(GTPase activating protein for p21-ras) (Soskic, V., et al. Biochemistry, 1999, 38(6),
1757-64). Through the activation of Pl-3-kinase, PDGF activates the Rho signaling
pathway inducing cell motility and migration, and through the activation of GAP,
induces mitogenesis through the activation of p21-ras and the MAPK signaling
25 pathway.
In adults, it is believed the major function of PDGF is to facilitate and increase

the rate of wound healing and to maintain blood vessel homeostasis (Baker, E.A. and
D.J. Leaper, Wound Repair Regen, 2000. 8(5), 392-8; Yu, J., A. Moon, and H.R.
30 Kim, Biochem Biophys Res Commun, 2001. 282(3), 697-700). PDGF is found at high
3
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WO 2004/078746 PCT/US2004/006283
concentrations in platelets and is a potent chemoattractant for fibroblast, smooth

muscle cells, neutrophils and macrophages. In addition to its role in wound healing
PDGF is known to help maintain vascular homeostasis. During the development of
new blood vessels, PDGF recruits pericytes and smooth muscle cells that are
5 needed for the structural integrity of the vessels. PDGF is thought to play a similar
role during tumor neovascularization. As part of its role in angiogenesis PDGF
controls interstitial fluid pressure, regulating the permeability of vessels through its
regulation of the interaction between connective tissue cells and the extracellular
matrix. Inhibiting PDGFR activity can lower interstitial pressure and facilitate the
10 influx of cytotoxics into tumors improving the anti-tumor efficacy of these agents
(Pietras, K., et al. Cancer Res, 2002. 62(19), 5476-84; Pietras, K., et al. Cancer Res,
2001. 61(7), 2929-34).
PDGF can promote tumor growth through either the paracrine or autocrine
15 stimulation of PDGFR receptors on stromal cells or tumor cells directly, or through
the amplification of the receptor or activation of the receptor by recombination. Over
expressed PDGF can transform human melanoma cells and keratinocytes (Forsberg,
I<., et al. Proc Natl Acad Sci US A., 1993. 90(2), 393-7; Skobe, M. and N.E. Fusenig,
Proc Natl Acad Sci US A, 1998. 95(3), 1050-5), two cell types that do not express
20 PDGF receptors, presumably by the direct effect of PDGF on stroma formation and
induction of angiogenesis. This paracrine stimulation of tumor stroma is also
observed in carcinomas of the colon, lung, breast, and prostate (Bhardwaj, B., et al.
Clin Cancer Res, 1996, 2(4), 773-82; Nakanishi, K., et al. Mod Pathol, 1997, 10(4),
341-7; Sundberg, C., et al. Am J Pathol, 1997, 151(2), 479-92; Lindmark, G., et al.
25 Lab Invest, 1993, 69(6), 682-9; Vignaud, J.M., et al, Cancer Res, 1994, 54(20), 5455-
63) where the tumors express PDGF, but not the receptor. The autocrine stimulation
of tumor cell growth, where a large faction of tumors analyzed express both the
ligand PDGF and the receptor, has been reported in glioblastomas (Fleming, T.P., et
al. Cancer Res, 1992, 52(16), 4550-3), soft tissue sarcomas (Wang, J., M.D.
30 Coltrera, and A.M. Gown, Cancer Res, 1994, 54(2), 560-4) and cancers of the ovary
4
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(Henriksen, R., et al. Cancer Res, 1993, 53(19), 4550-4), prostate (Fudge, K., C.Y.
Wang, and M.E. Stearns, Mod Pathol, 1994, 7(5), 549-54), pancreas (Funa, K., et al.
Cancer Res, 1990, 50(3), 748-53) and lung (Antoniades, H.N., et al., Proc Natl Acad
Sci U S A, 1992, 89(9), 3942-6). Ligand independent activation of the receptor is
s found to a lesser extent but has been reported in chronic myelomonocytic leukemia
(CMML) where the a chromosomal translocation event forms a fusion protein
between the Ets-like transcription factor TEL and the POGF receptor. In addition,
activating mutations in POGFR have been found in gastrointestinal stromal tumors in
which c-Kit activation is not involved (Heinrich, M.C., et al., Science, 2003, 9, 9).
10 Certain POGFR inhibitors will interfere with tumor stromal development and are
believed to inhibit tumor growth and metastasis.
Another major regulator of angiogenesis and vasculogenesis in both

embryonic development and some angiogenic-dependent diseases is vascular
15 endothelial growth factor (VEGF; also called vascular permeability factor, VPF).
VEGF represents a family of isoforms of mitogens existing in homodimeric forms due
to alternative RNA splicing. The VEGF isoforms are reported to be highly specific for
vascular endothelial cells (for reviews, see: Farrara et al. Endocr. Rev. 1992, 13, 18;
Neufield et al. FASEB J. 1999, 13, 9).
20
VEGF expression is reported to be induced by hypoxia (Shweiki et al. Nature

1992, 359, 843), as well as by a variety of cytokines and growth factors, such as
interleukin-1, interleukin-6, epidermal growth factor and transforming growth factor.
To date, VEGF and the VEGF family members have been reported to bind to one or
25 more of three transmembrane receptor tyrosine kinases (Mustonen et al. J. Cell Biol.,
1995, 129, 895), VEGF receptor-1 (also known as flt-1 (fms-like tyrosine kinase-1)),
VEGFR-2 (also known as kinase insert domain containing receptor (KOR); the
murine analogue of KOR is known as fetal liver kinase-1 (flk-1)), and VEGFR-3 (also
known as flt-4). KOR and flt-1 have been shown to have different signal transduction
30 properties (Waltenberger et al. J. Biol. Chem. 1994, 269, 26988); Park et al.
5
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Oncogene 1995, 10, 135). Thus, KOR undergoes strong ligand-dependant tyrosine
phosphorylation in intact cells, whereas flt-1 displays a weak response. Thus,
binding to KOR is believed to be a critical requirement for induction of the full
spectrum of VEGF-mediated biological responses.
5
In vivo, VEGF plays a central role in vasculogenesis, and induces
angiogenesis and permeabilization of blood vessels. Deregulated VEGF expression
contributes to the development of a number of diseases that are characterized by
abnormal angiogenesis and/or hyperpermeability processes. It is believed regulation
10 of the VEGF-mediated signal transduction cascade by some agents can provide a
useful mode for control of abnormal angiogenesis and/or hyperpermeability
processes.
Angiogenesis is regarded as an important prerequisite for growth of tumors

15 beyond about 1-2 mm. Oxygen and nutrients may be supplied to cells in tumor
smaller than this limit through diffusion. However, it is believed every tumor is
dependent on angiogenesis for continued growth after it has reached a certain size.
Tumorigenic cells within hypoxic regions of tumors respond by stimulation of VEGF
production, which triggers activation of quiescent endothelial cells to stimulate new
20 blood vessel formation. (Shweiki et al. Proc. Nat'/. Acad. Sci., 1995, 92, 768). In
addition, VEGF production in tumor regions where there is no angiogenesis may
proceed through the ras signal transduction pathway (Grugel et al. J. Biol. Chem.,
1995, 270, 25915; Rak et al. Cancer Res. 1995, 55, 4575). In situ hybridization
studies have demonstrated VEGF mRNA is strongly upregulated in a wide variety of
25 human tumors, including lung (Mattern et al. Br. J. Cancer 1996, 73, 931), thyroid
(Viglietto et al. Oncogene 1995, 11, 1569), and breast (Brown et al. Human Pathol.
1995, 26, 86), gastrointestinal tract (Brown et al. Cancer Res. 1993, 53, 4727; Suzuki
et al. Cancer Res. 1996, 56, 3004 ), kidney and bladder (Brown et al. Am. J. Pathol.
1993, 1431, 1255), ovary (Olson et al. Cancer Res. 1994, 54, 1255), and cervical
30 (Guidi et al. J. Nat'/ Cancer Inst. 1995, 87, 12137) carcinomas, as well as
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angiosacroma (Hashimoto et al. Lab. Invest. 1995, 73, 859) and several intracranial
tumors (Plate et al. Nature 1992, 359, 845; Phillips et al. Int. J. Oneal. 1993, 2, 913;
Berkman et al. J. C/in. Invest., 1993, 91, 153). Neutralizing monoclonal antibodies to
KOR have been shown to be efficacious in blocking tumor angiogenesis (Kim et al.
5 Nature 1993, 362,841; Rockwell et al. Mo/. Cell. Differ. 1995, 3, 315).
Over expression of VEGF, for example under conditions of extreme hypoxia,

can lead to intraocular angiogenesis, resulting in hyperproliferation of blood vessels,
leading eventually to blindness. Such a cascade of events has been observed for a
10 number of retinopathies, including diabetic retinopathy, ischemic retinal-vein
occlusion, and retinopathy of prematurity (Aiello et al. New Engl. J. Med. 1994, 331,
1480; Peer et al. Lab. Invest. 1995, 72, 638), and age-related macular degeneration
(AMO; see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855).
15 In rheumatoid arthritis (RA), the in-growth of vascular pannus may be

mediated by production of angiogenic factors. Levels of immunoreactive VEGF are
high in the synovial fluid of RA patients, while VEGF levels were low in the synovial
fluid of patients with other forms of arthritis of with degenerative joint disease (Koch
et al. J. lmmunol. 1994, 152, 4149). The angiogenesis inhibitor AGM-170 has been
20 shown to prevent neovascularization of the joint in the rat collagen arthritis model
(Peacock et al. J. Exper. Med. 1992, 175, 1135).
Increased VEGF expression has also been shown in psoriatic skin, as well as
bullous disorders associated with subepidermal blister formation, such as bullous
25 pemphigoid, erythema multiforme, and dermatitis herpetiformis (Brown et al. J.
Invest. Dermatol. 1995, 104, 744).
The vascular endothelial growth factors (VEGF, VEGF-C, VEGF-O) and their
receptors (VEGFR2, VEGFR3) are not only key regulators of tumor angiogenesis,
30 but also lymphangiogenesis. VEGF, VEGF-C and VEGF-O are expressed in most
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tumors, primarily during periods of tumor growth and, often at substantially increased
levels. VEGF expression is stimulated by hypoxia, cytokines, oncogenes such as ras,
or by inactivation of tumor suppressor genes (McMahon, G. Oncologist 2000,
5(Suppl. 1), 3-10; McDonald, N.Q.; Hendrickson, W.A. Ce// 1993, 73, 421-424).
5
The biological activities of the VEGFs are mediated through binding to their
receptors. VEGFR3 (also called Flt-4) is predominantly expressed on lymphatic
endothelium in normal adult tissues. VEGFR3 function is needed for new lymphatic
vessel formation, but not for maintenance of the pre-existing lymphatics. VEGFR3 is
10 also upregulated on blood vessel endothelium in tumors. Recently VEGF-C and
VEGF-D, ligands for VEGFR3, have been identified as regulators of
lymphangiogenesis in mammals. Lymphangiogenesis induced by tumor-associated
lymphangiogenic factors could promote the growth of new vessels into the tumor,
providing tumor cells access to systemic circulation. Cells that invade the lymphatics
15 could find their way into the bloodstream via the thoracic duct. Tumor expression
studies have allowed a direct comparison of VEGF-C, VEGF-D and VEGFR3
expression with clinicopathological factors that relate directly to the ability of primary
tumors to spread (e.g., lymph node involvement, lymphatic invasion, secondary
metastases, and disease-free survival). In many instances, these studies
20 demonstrate a statistical correlation between the expression of lymphangiogenic
factors and the ability of a primary solid tumor to metastasize (Skobe, M. et al.
Nature Med. 2001, 7(2), 192-198; Stacker, S.A. et al.. Nature Med. 2001, 7(2), 186-
191; Makinen, T. et al. Nature Med. 2001, 7(2), 199-205; Mandriota, S.J. et al. EMBO
J. 2001, 20(4), 672-82; Karpanen, T. et al. Cancer Res. 2001, 61(5), 1786-90; Kubo,
25 H. et al. Blood 2000, 96(2), 546-53).
Inhibition of the mitogen-activated protein kinase (MAPK) p38 has been

shown to inhibit both cytokine production (e.g., TNF, IL-1, IL-6, IL-8) and proteolytic
enzyme production (e.g., MMP-1, MMP-3) in vitro and/or in vivo. The mitogen
30 activated protein (MAP) kinase p38 is involved in IL-1 and TNF signaling pathways
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(Lee, J. C.; Laydon, J. T.; McDonnell, P. C.; Gallagher, T. F.; Kumar, S.; Green, D.;
McNulty, D.; Blumenthal, M. J.; Heys, J. R.; Landvatter, S. W.; Stricker, J. E.;
McLaughlin, M. M.; Siemens, I. R.; Fisher, S. M.; Livi, G. P.; White, J. R.; Adams, J.
L.; Yound, P. R. Nature 1994, 372, 739).
5
Clinical studies have linked tumor necrosis factor (TNF) production and/or
signaling to a number of diseases including rheumatoid arthritis (Maini. J. Royal Coll.
Physicians London 1996, 30, 344). In addition, excessive levels of TNF have been
implicated in a wide variety of inflammatory and/or immunomodulatory diseases,
10 including acute rheumatic fever (Yegin et al. Lancet 1997, 349, 170), bone resorption
(Pacifici et al. J. C/in. Endocrinol. Metabol. 1997, 82, 29), postmenopausal
osteoporosis (Pacifici et al. J. Bone Mineral Res. 1996, 11, 1043), sepsis (Blackwell
et al. Br. J. Anaesth. 1996, 77, 110), gram negative sepsis (Debets et al. Prog. Clin.
Biol. Res. 1989, 308, 463), septic shock (Tracey et al. Nature 1987, 330, 662;
15 Girardin et al. New England J. Med. 1988, 319, 397), endotoxic shock (Beutler et al.
Science '1985, 229, 869; Ashkenasi et al. Proc. Nat'/. Acad. Sci. USA 1991, 88,
10535), toxic shock syndrome, (Saha et al. J. lmmunol. 1996, 157, 3869; Lina et al.
FEMS lmmunol. Med. Microbial. 1996, 13, 81), systemic inflammatory response
syndrome (Anon. Grit. Care Med. 1992, 20, 864), inflammatory bowel diseases
20 (Stokkers et al. J. lnflamm. 1995-6, 47, 97) including Crohn's disease (van Deventer
et al. Aliment. Pharmacol. Therapeu. 1996, 10 (Suppl. 2), 107; van Dullemen et al.
Gastroenterology 1995, 109, 129) and ulcerative colitis (Masuda et al. J. Clin. Lab.
lmmuno/. 1995, 46, 111), Jarisch-Herxheimer reactions (Fekade et al. New England
J. Med. 1996, 335,311), asthma (Amrani et al. Rev. Malad. Respir. 1996, 13, 539),
25 adult respiratory distress syndrome (Roten et al. Am. Rev. Respir. Dis. 1991, 143,
590; Suter et al. Am. Rev. Respir. Dis. 1992, 145, 1016), acute pulmonary fibrotic
diseases (Pan et al. Pathol. Int. 1996, 46, 91), pulmonary sarcoidosis (lshioka et al.
Sarcoidosis Vasculitis Diffuse Lung Dis. 1996, 13, 139), allergic respiratory diseases
I
(Casale et al. Am. J. Respir. Cell Mo/. Biol. 1996, 15, 35), silicosis (Gossart et al. J.
30 lmmuno/. 1996, 156, 1540; Vanhee et al. Eur. Respir. J. 1995, 8, 834), coal worker's
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pneumoconiosis (Bormet al. Am. Rev. Respir. Dis. 1988, 138, 1589), alveolar injury
(Horinouchi et al. Am. J. Respir. Cell Mo/. Biol. 1996, 14, 1044), hepatic failure
(Gantner et al. J. Pharmacol. Exp. Therap. 1997, 280, 53), liver disease during acute.
inflammation (Kim et al. J. Biol. Chem. 1997, 272, 1402), severe alcoholic hepatitis
5 (Bird et al. Ann. Intern. Med. 1990, 112, 917), malaria (Grau et al. lmmunol. Rev.
1989, 112, 49; Taverne et al. Parasitol. Today 1996, 12, 290) including Plasmodium
falciparum malaria (Perlmann et al. Infect. lmmunit. 1997, 65, 116) and cerebral
malaria (Rudin et al. Am. J. Pathol. 1997, 150, 257), non-insulin-dependent diabetes
mellitus (NIDDM; Stephens et al. J. Biol. Chem. 1997, 272,971; Ofei et al. Diabetes
10 1996, 45, 881), congestive heart failure (Doyama et al. Int. J. Cardiol. 1996, 54, 217;
McMurray et al. Br. Heart J. 1991, 66, 356), damage following heart disease (Malkiel
et al. Mo/. Med. Today 1996, 2, 336), atherosclerosis (Parums et al. J. Pathol. 1996,
179, A46), Alzheimer's disease (Fagarasan et al. Brain Res. 1996, 723, 231; Aisen
et al. Gerontology 1997, 43, 143), acute encephalitis (lchiyama et al. J. Neural. 1996,
15 243, 457), brain injury (Cannon et al. Grit. Care Med. 1992, 20, 1414; Hansbrough et
al. Surg. Clin. N. Am. 1987, 67, 69; Marano et al. Surg. Gynecol. Obstetr. 1990, 170,
32), multiple sclerosis (M.S.; Coyle. Adv. Neuroimmunol. 1996, 6, 143; Matusevicius
et al. J. Neuroimmunol. 1996, 66, 115) including demyelation and oligiodendrocyte
loss in multiple sclerosis (Brosnan et al. Brain Pathol. 1996, 6, 243), advanced
20 cancer (MucWierzgon et al. J. Biol. Regulators Homeostatic Agents 1996, 10, 25),
lymphoid malignancies (Levy et al. Grit. Rev. lmmuno/. 1996, 16, 31), pancreatitis
(Exley et al. Gut 1992, 33, 1126) including systemic complications in acute
pancreatitis (McKay et al. Br. J. Surg. 1996, 83, 919), impaired wound healing in
infection inflammation and cancer (Buck et al. Am. J. Patho/. 1996, 149, 195),
25 myelodysplastic syndromes (Raza et al. Int. J. Hematol. 1996, 63, 265), systemic
lupus erythematosus (Maury et al. Arthritis Rheum. 1989, 32, 146), biliary cirrhosis
(Miller et al. Am. J. Gasteroenterolog. 1992, 87, 465), bowel necrosis (Sun et al. J.
Clin. Invest. 1988, 81, 1328), psoriasis (Christophers. Austr. J. Dermato/. 1996, 37,
S4), radiation injury (Redlich et al. J. /mmunol. 1996, 157, 1705), and toxicity
30 following administration of monoclonal antibodies such as OKT3 (Brod et al.
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Neurology 1996, 46, 1633). TNF levels have also been related to host-versus-graft
reactions (Piguet et al. lmmunol. Ser. 1992, 56, 409) including ischemia reperfusion
injury (Colletti et al. J. Clin. Invest. 1989, 85, 1333) and allografl rejections including
those of the kidney (Maury et al. J. Exp. Med.1987, 166, 1132), liver (lmagawa et al.
5 Transplantation 1990, 50, 219), heart (Bolling et al. Transplantation 1992, 53, 283),
and skin (Stevens et al. Transplant. Proc. 1990, 22, 1924), lung allografl rejection
(Grossman et al. lmmuno/. Allergy Clin. N. Am. 1989, 9, 153) including chronic lung
allografl rejection (obliterative bronchitis; LoCicero et al. J. Thorac. Cardiovasc. Surg.
1990, 99, 1059), as well as complications due to total hip replacement (Cirino et al.
10 Life Sci. 1996, 59, 86). TNF has also been linked to infectious diseases (review:
Beutler et al. Grit. Care Med. 1993, 21, 5423; Degre. Biotherapy 1996, 8, 219)
including tuberculosis (Rook et al. Med. Malad. Infect. 1996, 26, 904), Helicobacter
pylori infection during peptic ulcer disease (Beales et al. Gastroenterology 1997,
112, 136), Chaga's disease resulting from Trypanosoma cruzi infection
15 (Chandrasekar et al. Biochem. Biophys. Res. Commun. 1996, 223, 365), effects of
Shiga-like toxin resulting from E. coli infection (Harel et al. J. Clin. Invest. 1992, 56,
40), the effects of enterotoxin A resulting from Staphylococcus infection (Fischer et
al. J. lmmunol. 1990, 144, 4663), meningococcal infection (Waage et al. Lancet
1987, 355; Ossege et al. J. Neuro/og. Sci. 1996, 144, 1), and infections from Borrelia
20 burgdorferi (Brandt et al. Infect. lmmunol. 1990, 58, 983), Treponema pallidum
(Chamberlin et al. Infect. lmmuno/. 1989, 57, 2872), cytomegalovirus (CMV; Geist et
al. Am. J. Respir. Cell Mo/. Biol. 1997, 16, 31 ), influenza virus (Beutler et al. C/in.
Res. 1986, 34, 491a), Sendai virus (Goldfield et al. Proc. Nat'/. Acad. Sci. USA 1989,
87, 1490), Theiler's encephalomyelitis virus (Sierra et al. Immunology 1993, 78,
25 399), and the human immunodeficiency virus (HIV; Poli. Proc. Nat'/. Acad. Sci. USA
1990, 87, 782; Vyakaram et al. AIDS 1990, 4, 21; Badley et al. J. Exp. Med. 1997,
185, 55).
A number of diseases are thought to be mediated by excess or undesired

30 matrix-destroying metalloprotease (MMP) activity or by an imbalance in the ratio of
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the MMPs to the tissue inhibitors of metalloproteinases (TIMPs). These include

osteoarthritis (Woessner et al. J. Biol. Chem. 1984, 259, 3633), rheumatoid arthritis
(Mullins et al. Biochim. Biophys. Acta 1983, 695, 117; Woolley et al. Arthritis
Rheum. 1977, 20, 1231; Gravallese et al. Arthritis Rheum. 1991, 34, 1076), septic
5 arthritis (Williams et al. Arthritis Rheum. 1990, 33, 533), tumor metastasis (Reich et
al. Cancer Res. 1988, 48, 3307; Matrisian et al. Proc. Nat'/. Acad. Sci., USA 1986,
83, 9413), periodontal diseases (Overall et al. J. Periodontal Res. 1987, 22, 81 ),
corneal ulceration (Burns et al. Invest. Opthalmol. Vis. Sci. 1989, 30, 1569),
proteinuria (Baricos et al. Biochem. J. 1988, 254, 609), coronary thrombosis from
10 atherosclerotic plaque rupture (Henney et al. Proc. Nat'/. Acad. Sci., USA 1991, 88,
8154), aneurysmal aortic disease (Vine et al. Clin. Sci. 1991, 81,233), birth control
(Woessner et al. Steroids 1989, 54, 491 ), dystrophobic epidermolysis bullosa
(Kronberger et al. J. Invest. Dermatol. 1982, 79, 208), degenerative cartilage loss
15 mandibular joint disease, and demyelating diseases of the nervous system (Chantry
et al. J. Neurochem. 1988, 50, 688).
Because inhibition of p38 leads to inhibition of TNF production and MMP

production, it is believed inhibition of mitogen activated protein (MAP) kinase p38
20 enzyme can provide an approach to the treatment of the above listed diseases
including osteoporosis and inflammatory disorders such as rheumatoid arthritis and
COPD (Badger, A. M.; Bradbeer, J. N.; Votta, B.; Lee, J. C.; Adams, J. L.; Griswold,
D. E. J. Pharm. Exper. Ther. 1996, 279, 1453).
25 Hypoxia appears to be an important stimulus for VEGF production in

malignant cells. Activation of p38 MAP kinase is required for VEGF induction by
tumor cells in response to hypoxia (Blaschke, F. et al. Biochem. Biophys. Res.
Commun. 2002, 296, 890-896; Shemirani, B. et al. Oral Oncology 2002, 38, 251-
257). In addition to its involvement in angiogenesis through regulation of VEGF
30 secretion, p38 MAP kinase promotes malignant cell invasion, and migration of
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different tumor types through regulation of collagenase activity and urokinase

plasminogen activator expression (Laferriere, J. et al. J. Biol. Chem. 2001, 276,
33762-33772; Westermarck, J. et al. Cancer Res. 2000, 60, 7156-7162; Huang, S.
et al. J. Biol. Chem. 2000, 275, 12266-12272; Simon, C. et al. Exp. Cell Res. 2001,
5 271, 344-355). Therefore, inhibition of p38 kinase is also expected to impact tumor
growth by interfering with signaling cascades associated with both angiogenesis and
malignant cell invasion.
Some diarylureas have been described as having activity as serine-threonine

10 kinase and/or as tyrosine kinase inhibitors. The ultility of these diarylureas as an
active ingredient in pharmaceutical compositions for the treatment of cancer,
angiogenesis disorders, and inflammatory disorders has been demonstated. See
Redman et al., Bioorg. Med. Chem. Lett. 2001, 11, 9-12; Smith et al., Bioorg. Med.
Chem. Lett. 2001, 11, 2775-2778; Dumas et al., Bioorg. Med. Chem. Lett. 2000, 10,
15 2047-2050; Dumas et al., Bioorg. Med. Chem. Lett. 2000, 10, 2051-2054; Ranges
et al., Book of Abstracts, 22dh ACS National Meeting, Washington, DC, USA, MEDI
149; Dumas et al., Bioorg. Med. Chem. Lett. 2002, 12, 1559-1562; Lowinger et al.,
Clin. Cancer Res. 2000, 6(suppl.), 335; Lyons et al., Endocr.-Relat. Cancer 2001, 8,
219-225; Riedl et al., Book of Abstracts, 92nd AACR Meeting, New Orleans, LA, USA,
20 abstract 4956; Khire et al., Book of Abstracts, 93rdAACR Meeting, San Francisco,
CA, USA, abstract 4211; Lowinger et al., Curr. Pharm. Design 2002, 8, 99-11O;
Regan et al., J. Med. Chem. 2002, 45, 2994-3008; Pargellis et al., Nature Struct.
Biol. 2002, 9(4), 268-272; Carter et al., Book of Abstracts, 92ndAACR Meeting, New
Orleans, LA, USA, abstract 4954; Vincent et al., Book of Abstracts, 38th ASCO
25 Meeting, Orlando, FL, USA, abstract 1900; Hilger et al., Book of Abstracts, 38th
ASCO Meeting, Orlando, FL, USA, abstract 1916; Moore et al., Book of Abstracts,
38th ASCO Meeting, Orlando, FL, USA, abstract 1816; Strumberg et al., Book of
Abstracts, 38th ASCO Meeting, Orlando, FL, USA, abstract 121; Madwed JB: Book of
Abstracts, Protein Kinases: Novel Target Identification and Validation for Therapeutic
30 Development, San Diego, CA, USA, March 2002; Roberts et al., Book of Abstracts,
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38th ASCO Meeting, Orlando, FL, USA, abstract 473; Tolcher et al., Book of
Abstracts, 38th ASCO Meeting, Orlando, FL, USA, abstract 334; and Karp et al.,
Book of Abstracts, 38th AACR Meeting, San Francisco, CA, USA, abstract 2753.
s Despite the advancements in the art, there remains a need for improved
cancer treatments and t~eatments of inflammatory disorders. BAY 43-9006 and
BIRB 796 are two diarylureas of particular interest. BAY 43-9006 (N-(4-chloro-3-
(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea) has
been described in the art as an inhibitor of c-raf kinase, and shows activity in murine
10 tumor xenograft models (Carter et al., Book of Abstracts, 92ndAACR Meeting, New
Orleans, LA, USA, abstract 4954). BIRB 796 (1-(5-tert-butyl-2-(4-methyl-phenyl)-2H-
pyrazole-3-yl)-3-[4-(2-morpholinylethoxy)naphthalene-1-yl]urea) is a potent, orally
available inhibitor of p38 MAP kinase showing activity in a 5-week model of
established collagen-induced arthritis in mice (Regan et al., J. Med. Chem. 2002, 45,
15 2994).
Description of the Invention

The present invention pertains to:
20 (i) novel compounds and salts thereof, including diastereoisomeric forms,

(ii) pharmaceutical compositions containing such compounds, and
(iii) use of those compounds or compositions for treating diseases, e.g., hyper-
proliferative, angiogenesis, and inflammatory disorders, as a sole agent or in
combination with other active ingredients, e.g., cytotoxic therapies.
25
The compounds of formula I, and salts thereof, including diastereoisomeric

forms, (both isolated stereoisomers and mixtures of stereoisomers) are collectively
referred to herein as the "compounds of the invention".
Formula I is as follows:
30
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A ...____
N
)l / N
B...____
/ M
L:
~N)
Q
I
wherein A and Bare 5·10 membered cyclic moieties which are optionally substituted
with 1A substituents independently selected from the group consisting of R1, OR1,
s NR R S(O)pR1, SO2NR R2, C(O)NR R2, C(NR )R NR SO2R C(O)R1, C(O)OR1,
1 2
,
1 1 1 2
,
1 2
NR1C(O)R2, NR1C(O)OR 2, halogen, cyano, and nitro and A is additionally C3 to C5

linear or branched alkyl such as isopropyl.
A is preferably :
10 (i) phenyl, optionally substituted with 1-3 substituents independently selected from
the group consisting of R1, OR1, NR1R2 , S(O)pR1, SO2NR1R2 , NR1SO2 R2, C(O)R1,
C(O)OR1, C(O)NR 1R2, NR1C(O)R2, NR1C(O)OR2, halogen, cyano, and nitro;
(ii) naphthyl, optionally substituted with 1-3 substituents independently selected from
15 the group consisting of R1, OR1, NR R S(O)pR\ SO NR R NR SO R C(O)R1,
1 2
,
2
1 2
,
1
2
2
C(O)OR C(O)NR R2, NR C(O)R2, NR C(O)OR halogen, cyano, and nitro;

1
,
1 1 1 2
(iii) 5 and 6 membered monocyclic heteroaryl, having 1·3 heteroatoms independently

selected from the group consisting of 0, N and S, optionally substituted with 1-3
20 substituents independently selected from the group consisting of R1. OR1, NR R2, 1
S(O)pR1, SO2NR1R2, NR1SO2R2, C(O)R1, C(O)OR 1, C(O)NR 1R2, NR1C(O)R2,

NR1C(O)OR2, halogen, cyano, and nitro;
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(iv) 8 to 10 membered bicyclic heteroaryl, having 1-6 heteroatoms independently

1 2
substituents independently selected from the group consisting of R1, OR1, NR R ,
S(O)pR1, SO NR1R NR1SO2R C(O)R1, C(O)OR1, C(O)NR1R NR C(O)R 2 1 2
2 2
, , , ,
s NR1C(O)OR 2
, halogen, cyano, and nitro; or

(v) a group of the formula
optionally substituted with 1-4 substituents independently selected from the group
10 consisting of R1, OR1, NR1R S(O)pR1, SO NR1R NR1SO2R C(O)R1, C(O)OR1,
2
,
2
2
,
2
C(O)NR 1R NR C(O)R2, NR1C(O)OR halogen, cyano, and nitro.

2
,
1 2
B is preferably:
15 (i) phenyl or naphthyl, optionally substituted with 1-3 substituents independently

selected from the group consisting of C1-C5 linear or branched alkyl, C1-Cslinear or
branched haloalkyl up to perhalo, C1-C alkoxy, C1-C haloalkoxy up to per3 3
haloalkoxy, hydroxy, amino, C1-C alkylamino, C -C dialkylamino, halogen, cyano,

3 1 6
and nitro; or
20
(ii) 5-6 membered monocyclic heteroaryl groups, having 1-4 heteroatoms

independently selected from the group consisting of 0, N and S, optionally
C1-Cslinear or branched alkyl, C1-C5 linear or branched haloalkyl up to perhalo, C1-
2s C3 alkoxy, C1-C3 haloalkoxy up to per haloalkoxy, hydroxy, amino, C1-C3 alkylamino,
C -C dialkylamino, halogen, cyano, and nitro.
1 6
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B is most preferably phenyl, naphthyl, or pyridyl, optionally substituted with 1-4

substituents are, independently, C1-Cs linear or branched alkyl, C 1-C 5 linear or
branched haloalkyl, C1-C3 alkoxy, hydroxy, amino, CrC3 alkylamino, C1-C5
dialkylamino, halogen, cyano, or nitro.
5
L is a bridging group which is :
(a) -(CH2)m-O-(CH2)1-,
(b) -(CH2)m-(CH2)1-,
10 (c) -(CH2)m-C(O)-(CH2)1-,
3
(d) -(CH2)m-NR -(CH2)1-,
3
(e) -(CH2)m-NR C(O)-(CH2)1-,
(f) -(CH2)m-S-(CH2)1-,
(g) -(CH2)m-C(O)NR3 -(CH2)1-,
15 (h) -(CH2)m-CFr(CH2)1-,
(i) -(CH2)m-CCl2-(CH2)1-,
U) -(CH2)m-CHF-(CH2)1-,
(k) -(CH2)m-CH(OH)-(CH2)1-;
(I) -(CH2)m-C=C-(CH2)1-;or
20 (m) -(CH2)m-C=C-(CH2)1-;
m and I are integers independently selected from 0-4.
When Lis -(CH2)m-(CH2)1-,and m and I are 0, then Lis a single bond.

25
Mis:
(i) phenyl, optionally substituted with 1-3 substituents independently selected from
the group consisting of R4, OR4, NR4R5 , S(O)qR4, SO 2NR4R5, C(O)NR 4 R5 , C(NR 4 )R5,
30 NR4SO 2R5, C(O)R4, C(O)OR4, NR4C(O)R 5, NR4C(O)OR 5 , halogen, cyano, and nitro;
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4 4 5
the group consisting of R4, OR4, NR4 R5 , S(O)qR4, S0 2NR R5, C(O)NR 4 R5 , C(NR )R ,
4 5 4
NR4 S0 2R5 , C(O)R4, C(O)OR4, NR C(O)R , NR C(O)OR5, halogen, cyano, and nitro;
5 (iii) 5 and 6 membered monocyclic heteroaryl, having 1-3 heteroatoms

independently selected from the group consisting of 0, . N and S, optionally
substituted with 1-3 substituents independently selected from the group consisting
5 4 5 4 5
R4, OR4, NR4 R5, S(O)qR4, S0 2NR4 R5, C(O)NR 4 R , C(NR )R , NR S02R , C(O)R4,
C(O)OR4, NR4 C(O)R 5 , NR4 C(O)OR5, halogen, cyano, nitro and oxides (e.g. =O, -0-
10 or-OH);

substituents independently selected from the group consisting of R4. OR4, NR4 R5 ,
15 S(O)qR4, S0 2NR4 R5, C(O)NR 4 R5, C(NR 4 )R5, NR4 S02R5. C(O)R4, C(O)OR4,
NR4 C(O)R5. NR4C(O)OR 5 , halogen, cyano, nitro and oxides (e.g. =O, -o-or -OH);
(v) saturated and partially saturated C3-C 7 monocyclic carbocyclic moiety optionally
20 R4, OR4, NR4 R5 , S(O)qR4, S02NR 4 R5, C(O)NR 4 R5, C(NR 4 )R5 , NR4S0 2R5 , C(O)R4,
C(O)OR4, NR4 C(O)R5 , f\JR4C(O)OR5 , halogen, cyano, and nitro;
(vi) saturated and partially saturated C5-C 12 bicyclic carbocyclic moiety, optionally
25 R4, OR4, NR4 R5, S(O)qR4, S02NR 4 R5 , C(O)NR 4 R5, C(NR 4 )R5 , NR 4S0 2R5, C(O)R4,
C(O)OR4, NR4 C(O)R 5 , NR4C(O)OR 5 , halogen, cyano, and nitro;
(vii) saturated and partially saturated 5 to 7 membered monocyclic heterocyclic

moiety, having 1-3 heteroatoms independently selected from the group consisting of
30 0, N and S, optionally substituted with 1-3 substituents independently selected from
18
II TRUE _COPYII
WO 2004/078746 PCT /0S2004/006283
the group consisting of R4, OR4, NR4 R5, S(O)qR4,SO2 NR4 R5, C(O)NR4 R5, C(NR4 )R5,
NR4 SO2 R5 , C(O)R4, C(O)OR4, NR4C(O)R5, NR4 C(O)OR5, halogen, cyano, nitro and
oxides (e.g. =O, -o- or-OH); or
5 (viii) saturated and partially saturated 7 to 12 membered bicyclic heterocyclic moiety,

having 1-6 heteroatoms independently selected from the group consisting of 0, N
and S, optionally substituted with 1-3 substituents independently selected from the
group consisting of R4, OR4, NR4 R5, S(O)qR4, SO2 NR4 R5, C(O)NR4 R5, C(NR4 )R5,
NR4 SO R5, C(O)R4, C(O)OR4, NR4C(O)R5, NR4C(O)OR5, halogen, cyano, nitro and
2
10 oxides (e.g. =O, -0- or-OH).
M is preferably a nitrogen-containing, monocyclic or bicyclic, saturated,

partially saturated or aromatic group, such as preferably pyridine, quinoline,
morpholine, indazole, isoquinoline, pyrimidine, and benzimidazole, optionally
15 substituted as above, .
M is most preferably pyridine, optionally substituted as above.
Each R1, R2 , R3, R4, R5 and Q is independently selected from the group
20 consisting of:
(a) hydrogen,
(b) C1-C5linear, branched, or cyclic alkyl,
(c) C1-C5linear or branched hydroxy alkyl,
25 (d) C1-Cslinear or branched alkoxy substituted - C1-C5 linear or branched alkyl,
(e) phenyl,
(f) 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms selected from the
group consisting of 0, N and S or 8-10 membered bicyclic heteroaryl having 1-6
heteroatoms selected from the group consisting of 0, N and S,
30 (g) C1-C3alkyl-phenyl,
19
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WO 2004/078746 PCT /0S2004/006283
(h) C -C heteroaryl-alkyl having 1-4 heteroatoms selected from the group consisting
1 3
of 0, N and S, wherein said heteroaryl group is a 5-6 membered monocyclic

heteroaryl or a 8-10 membered bicyclic heteroaryl, and
(i) up to per-halo substituted C 1-C5 linear, branched or cyclic alkyl.
5
Each R1, R R3, R4, R and Q, when not hydrogen or perhalo substituted C
2
,
5
1
-
C5 linear or branched alkyl, is optionally substituted with 1-3 substituents

independently selected from the group consisting of C1-C5 linear or branched alkyl,
up to perhalo substituted C1-C linear or branched alkyl, C1-C alkoxy, hydroxy,
5 3
10 carboxy, amino, C -C alkylamino, C1-C dialkylamino, halogen, cyano, and nitro;

1 3 6
The variables p and q are integers independently selected from 0, 1, or 2.
In a group of compounds of interest,

15
A of formula I is phenyl, optionally substituted with 1-3 substituents independently

selected from the group consisting of R1, OR1, NR1R2, S(O)pR1, SO2NR1R2,
NR1SO2R2 , C(O)R1, C(O)OR1 , C(O)NR1R2 , NR1C(O)R2, NR1C(O)OR2, halogen,
cyano, and nitro;
20
B is phenyl, optionally substituted with 1-3 substituents independently selected

from the group consisting of C1-C5 linear or branched alkyl, C1-C5 linear or branched
haloalkyl up to perhalo, C1-C3 alkoxy, C1-C3 haloalkoxy up to per haloalkoxy,
hydroxy, amino, CrC3 alkylamino, C1-C dialkylamino, halogen, cyano, and nitro;
6
25
L is -0- or -S-,
M is phenyl, pyridine, quinoline, morpholine, indazole, isoquinoline, pyrimidine,

or benzimidazole, optionally substituted with 1-3 substituents independently selected
30 from the group consisting of R4, OR4, NR R5, S(O)qR4, SO2NR R4 4 5
, C(O)NR R
4 5
,
20
IITRUE COPYII
WO 2004/078746 PCT/US2004/006283
C(NR )R
4 5
, NR SO R
4
2
5
, C(O)R4, C(O)OR4, NR C(O)R5, NR C(O)OR

4
4 5
, halogen,
cyano, and nitro;
each R1, R2 , R4, R5 and Q is independently selected from the group consisting of:
5
(a) hydrogen,
(b) C1-C linear, branched, or cyclic alkyl,
5
(c) C1-C5 linear or branched hydroxy alkyl,

(d) C1-C linear or branched alkoxy substituted - C1-C linear or branched alkyl,
5 5
10 (e) phenyl,
(f) pyridinyl
(g) C1-C3alkyl-phenyl,
(h) C1-C3 alkyl-pyridinyl or
(i) up to per-halo substituted C1-C5 linear, branched or cyclic alkyl and
15 the variables p and q are integers independently selected from 0, 1, or 2.
Preferably, Mis phenyl or pyridine, and more preferably, Mis pyridine.
In another group of compounds of interest,

20 A of formula I is pyridinyl, optionally substituted with 1-3 substituents independently
selected from the group consisting of R1, OR1, NR1 R2 , S(O)pR1, SO2 NR1R2 ,
NR1SO R2 , C(O)R1, C(O)OR1, C(O)NR1R2 , NR1C(O)R2 , NR1C(O)OR2 , halogen,
2
cyano, and nitro;
25 B is phenyl, optionally substituted with 1-3 substituents independently selected

from the group consisting of C -C linear or branched alkyl, C1-C linear or branched
1 5 5

hydroxy, amino, C1-C3alkylamino, C1-C6 dialkylamino, halogen, cyano, and nitro;
30 L is -0- or -S-,
21
IITRUE COPYII
WO 2004/078746 PCT/US2004/006283

or benzimidazole, optionally substituted with 1-3 substituents which independently
are' R4, OR4, NR4 R5, S(O)qR4, SO NR4 R5, C(O)NR4 R5, C(NR4 )R5, NR4SO R5,
2 2
5 C(O)R4, C(O)OR4, NR4 C(O)R5, NR4C(O)OR5, halogen, cyano, or nitro;
each R1, R2, R4, R5 and Q is independently:
(a) hydrogen,
10 (b) C1-C5 linear, branched, or cyclic alkyl,
(d) C1-C5 linear or branched alkoxy substituted - C1-C5 linear or branched alkyl,
(e) phenyl,
(f) pyridinyl
15 (g) C1-C3 alkyl-phenyl,
the variables p and q are integers independently selected from 0, 1, or 2.
20 Preferably, M is phenyl or pyridine, and more preferably, M is pyridine.
In another group of compounds of interest,

A of formula I is pyrazole, optionally substituted with 1-3 substituents
independently selected from the group consisting of R1, OR1, NR1R2, S(O)pR1,
25 SO2NR1R2 , NR1SO2R2 , C(O)R1, C(O)OR1, C(O)NR1R2, NR1C(O)R2, NR1C(O)OR2,
halogen, cyano, and nitro;
B is phenyl or naphthyl, optionally substituted with 1-3 substituents

independently selected from the group consisting of C 1-C 5 linear or branched alkyl,
30 C1-C5linear or branched haloalkyl up to perhalo, C1-C3 alkoxy, C1-C3 haloalkoxy up
22
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WO 2004/078746 PCT /0S2004/006283
to per haloalkoxy, hydroxy, amino, C1-C3 alkylamino, C1-Cs dialkylamino, halogen,

cyano, and nitro;
L is -0- or -S-,
5

or benzimidazole, optionally substituted with 1-3 substituents which independently
are R4, OR4, NR4 R5, S(O)qR4, SO2 NR4 R5, C(O)NR4 R5, C(NR4 )R5, NR4 SO2 R5,
C(O)R4, C(O)OR4, NR4 C(O)R5, NR4 C(O)OR5, halogen, cyano, or nitro;
10
each R1, R2, R4, R5 and Q is independently:
(a) hydrogen,
15 (c) C1-C5linear or branched hydroxy alkyl,
(d) C1-C5linear or branched alkoxy substituted - C1-C5 linear or branched alkyl,
(e) phenyl,
(f) pyridinyl
20 (h) C1-C3alkyl-pyridinyl or
(i) up to per-halo substituted CrC 5 linear, branched or cyclic all<yland
Preferably, Mis pyridine or morpholine.

25
In another group of compounds of formula I of interest,

A is phenyl, optionally substituted with 1-3 substituents independently selected
from the group consisting of R1, OR 1 and halogen;
23
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WO 2004/078746 PCT/US2004/006283
B is phenyl, optionally substituted with 1-3 substituents independently selected

from the group consisting of C1-Cslinear or branched alkyl, C1-Cs linear or branched
hydroxy, amino, C1-C3 alkylamino, C1-C6 dialkylamino, halogen, cyano, and nitro;
5
L is -0- or -S-:
Mis pyridinyl, optionally with 1-3 substituents independently selected from the
group consisting R4, OR4, NR4 R5, S(O)qR4, SO2 NR4 R5 , C(O)NR4 R5 , C(NR4 )R5,
10 NR4SO2 R5, C(O)R4, C(O)OR4, NR4C(O)R5 , NR4 C(O)OR5 , halogen, cyano, nitro and
oxides;
each R4, R5 and Q is independently :
15 (a) hydrogen,
(b) CrC 5 linear, branched, or cyclic alkyl,
(e) phenyl,
20 (f) pyridinyl
(g) C1-C3 alkyl-phenyl,
25
In another group of compounds of formula I of interest,

A is of the formula X:
24
IITRUE COPYjl
WO 2004/078746 PCT /US2004/006283
A is optionally substituted with 1-4 substituents independently selected from

1 1 1
the group consisting of R1, OR 1, NR 1R 2
, S(O)pR , S0 NR R 2
2
, NR 1S0 R 2
2
, C(O)R ,
5 C(O)OR1, C(O)NR 1R NR 1C(O)R
2
,
2
, NR 1C(O)OR 2
, halogen, cyano, and nitro,
Bis phenyl, optionally substituted with 1-3 substituents independently selected

from the group consisting of C1-C5 linear or branched alkyl, C1-C5 linear or branched
haloalkyl up to perhalo, C 1-C 3 alkoxy, C 1-C 3 haloalkoxy up to per haloalkoxy,
10 hydroxy, amino, C1-C3 alkylamino, C 1-C6 dialkylamino, halogen, cyano, and nitro;
L is -0- or -S-:
Mis:
15
NR R5, S(O)qR4, S0 NR R5, C(O)NR R5, C(NR )R 5,
the group consisting of R4, OR 4
,
4
2
4 4 4
NR S0 R C(O)R4, C(O)OR4, NR C(O)R 5, NR C(O)OR halogen, cyano, and nitro;

4 5 4 4 5
2 , ,
or
20
(ii) pyridinyl optionally with 1-3 substituents independently selected from the group
consisting R4, OR4, NR R 4 5
, S(O)qR4, S0 NR R 2
4 5
, C(O)NR R5, C(NR )R5, NR S0 R5,
4 4 4
2
4 5 4
C(O)R4, C(O)OR4, NR C(O)R , NR C(O)OR5, halogen, cyano, nitro and oxides;
25 where R4, R5 and Q are independently :
25
IITRUE COPYjl
WO 2004/078746 PCT /0S2004/006283
a) hydrogen,
(b) CrC 5 linear, branched, or cyclic alkyl,
(d) C1-C5 linear or branched alkoxy substituted - C1-C51inearor branched alkyl,
5 (e) phenyl,
(f) pyridinyl
(h) CrC3 alkyl-pyridinyl or
(i) up to per-halo substituted C1-C5linear, branched or cyclic alkyl and
When any moiety is "substituted", it can have up to the highest number of

indicated substituents, and each substituent can be located at any available position
on the moiety and can be attached through any available atom on the substituent.
15 "Any available position" means any position on the moiety that is chemically
accessible through means known in the art or taught herein and that does not create
an unduly unstable molecule. When there are two or more substituents on any
moiety, each substituent is defined independently of any other substituent and can,
accordingly, be the same or different.
20
The term "optionally substituted" means that the moiety so modified may be
either unsubstituted, or substituted with the identified substituent(s).
It is understood that when M is pyridine, quinoline, or isoquinoline, the term

25 "oxide" includes those structures referred to in the art as 1-oxo-pyridine and 1-
hydroxy-pyridine. In contrast, when M is a partially saturated or saturated
carbocyclic moiety, the term "oxide" represents a keto group.
Where the plural form of the word compounds, salts, and the like, is used
30 herein, this is taken to mean also a single compound, salt, or the like.
26
llTRUE _COPYII
WO 2004/078746 PCT /0S2004/006283
The term C 1-Cs alkyl means straight or branched chain alkyl groups having
from one to five carbon atoms, which may be linear or branched with single or
multiple branching. Such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, terl-butyl, and the like.
5
The term haloC1-C5 alkyl means a saturated hydrocarbon radical having up to
five carbon atoms, which is substituted with a least one halogen atom, up to perhalo.
The radical may be linear or branched with single or multiple branching. The halo
substituent(s) include fluoro, chloro, bromo, or iodo. Fluoro, chloro and bromo are
10 preferred, and fluoro and chloro are more preferred. The halogen substituent(s) can
be located on any available carbon. When more than one halogen substituent is
present on this moiety, they may be the same or different. Examples of such
halogenated alkyl substituents include but are not limited to chloromethyl,
dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-
15 trifluoroethyl, and 1,1,2,2-tetrafluoroethyl, and the like.
The term C1-C3alkoxy means straight or branched chain alkoxy group having
from one to three saturated carbon atoms which may be linear or branched with
single or multiple branching, and includes such groups as methoxy, ethoxy, n-
20 propoxy, isopropoxy, and the like. It also includes halogenated groups such as 2,2-
dichloroethoxy, trifluoromethoxy, and the like.
Halo or halogen means fluoro, chloro, bromo, or iodo. Fluoro, chloro and
bromo are preferred, and fluoro and chloro are more preferred.
25
C1-C3 alkylamino means methylamino, ethylamino, propylamino or

isopropylamino.
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WO 2004/078746 PCT /0S2004/006283
Examples of C1-C5 dialkylamino group include but are not limited to

diethylamino, ethyl-isopropylamino, means methylamino, methyl-isobutylamino,
dihexylamino.
5 Monocyclic heteroaryl means an aromatic monocyclic ring having 5 to 6 ring

atoms, at least one of which is a hetero atom selected from N, 0 and S, the
remaining atoms being carbon. When· more than one hetero atom is present in the
moiety, they are selected independently from the other(s) so that they may be the
same or different. Monocyclic heteroaryl rings include, but are not limited to pyrrole,
10 furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole,
triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine,
and triazine.
Bicyclic heteroaryl means fused bicyclic moieties where one of the rings is
15 chosen from the monocyclic heteroaryl rings described above and the second ring is
either benzene or another monocyclic heteroaryl ring described above. When both
rings in the bicyclic moiety are heteroaryl rings, they may be the same or different, as
long as they are chemically accessible by means known in the art. Bicyclic
heteroaryl rings include synthetically accessible 5-5, 5-6, or 6-6 fused bicyclic
20 aromatic structures including, for example but not by way of limitation, benzoxazole
(fused phenyl and oxazole), quinoline (fused phenyl and pyridine), imidazopyrimidine
(fused imidazole and pyrimidine), and the like.
The term "saturated and partially saturated monocyclic and/or bicyclic

25 carbocyclic moiety" includes, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, decahydronapthalene, cyclopentenyl, cyclohexenyl, cyclohexadienyl,
tetrahydronaphthalene and the like.
The term "saturated or partially saturated monocyclic and/or bicyclic

30 heterocyclic moiety" includes, by no way of limitation, tetrahydropyranyl,
28
IITRUE _COPYII
WO 2004/078746 PCT /0S2004/006283
tetrahydrofuranyl, 1,3-dioxolane, 1,4-dioxanyl, morpholinyl, thiomorpholinyl,

piperazinyl, piperidinyl, piperidinonyl, tetrahydropyrimidonyl, pentamethylene sulfide,
tetramethylene sulfide dihydropyranyl, dihydrofuranyl, dihydrothienyl,
dihydropiperidinyl, dihydropyrimidonyl, and the like.
The term "C1-C3 phenyl-alkyl" includes, by no way of limitation, 3-phenyl-

propyl, 2-phenyl-1-methyl-ethyl. Substituted examples include 2-[2-
chlorophenyl]ethyl, 3,4-dimethylphenyl-methyl, and the like.
10 The term "CrC3 heteroaryl-alkyl" includes, by no way of limitation, 3-

imidazole-5-yl-propyl, 2-(2-pyridyl)-1-methyl-ethyl. Substituted examples include 2-[3-
chloropyridine-5-yl]ethyl, 3,4-dimethylthiophene-2-yl-methyl, and the like.
The compounds of Formula I may contain one or more asymmetric centers,

15 depending upon the location and nature of the various substituents desired.
Asymmetric carbon atoms may be present in the (R) or (SJ configuration or (R,S)
configuration. In certain instances, asymmetry may also be present due to restricted
rotation about a given bond, for example, the central bond adjoining two substituted
aromatic rings of the specified compounds. Substituents on a ring may also be
20 present in either cis or trans form. It is intended that all such configurations
(including enantiomers and diastereomers), are included within the scope of the
present invention. Preferred compounds are those with the absolute configuration of
the compound of Formula I which produces the more desirable biological activity.
Separated, pure or partially purified isomers or racemic mixtures of the compounds
25 of this invention are also included within the scope of the present invention. The
purification of said isomers and the separation of said isomeric mixtures can be
accomplished by standard techniques known in the art.
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WO 2004/078746 PCT /0S2004/006283
The use of pharmaceutically acceptable salts of the compounds of Formula I

are also within the scope of this invention. The term "pharmaceutically acceptable
salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a
compound of the present invention. For example, see S. M. Berge, et al.
5 "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.
Representative salts of the compounds of this invention include the

conventional non-toxic salts and the quaternary ammonium salts which are formed,
for example, from inorganic or organic acids or bases by means well known in the
10 art. For example, such acid addition salts include acetate, adipate, alginate,
ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate,
camphorate, carnphorsulfonate, cinnamate, cyclopentanepropionate, digluconate,
dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,
hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobrornide, hydroiodide, 2-
15 hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate,
2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate,
3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate,
thiocyanate, tosylate, and undecanoate.
Base salts include alkali metal salts such as potassium and sodium salts,
20 alkaline earth metal salts such as calcium and magnesium salts, and ammonium
salts with organic bases such as dicyclohexylamine and N-methyl-0-glucamine.
Additionally, basic nitrogen containing groups may be quaternized with such agents
as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides
and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl
25 sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides,
bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
Certain compounds of this invention can be further modified with labile

functional groups that are cleaved after in vivo administration to furnish an active
agent and the pharmacologically inactive derivatizing (functional) group. These
30 derivatives can be used, for example, to alter the physicochemical properties of the
30
IITRUE COPYjl
WO 2004/078746 PCT /0S2004/006283
active agent, to target the active agent to a specific tissue, to alter the
pharmacokinetic and pharmacodynamic properties of the active agent, and to reduce
undesirable side effects. The esters of appropriate compounds of this invention are
well-tolerated, pharmaceutically acceptable esters such as alkyl esters including
5 methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters. Additional esters
such as phenyl-C1-Csalkyl may be used, although methyl ester is preferred.
Methods for synthesizing prodrugs are described in the following reviews on

the subject, which are incorporated herein by reference for their description of these
methods:
10
• Higuchi, T.; Stella, V. eds. Prodrugs As Novel Drug Delivery Systems. ACS
Symposium Series. American Chemical Society: Washington, DC (1975).
• Roche, E. B. Design of Biopharmaceutical Properties through Prodrugs and
Analogs. American Pharmaceutical Association: Washington, DC (1977).
15 @ Sinkula, A. A.; Yalkowsky, S. H. J Pharm Sci. 1975, 64, 181-210.
® Stella, V. J.; Charman, W. N. Naringrekar, V. H. Drugs 1985, 29, 455-473.
• Bundgaard, H., ed. Design of Prodrugs. Elsevier: New York (1985).
• Stella, V. J.; Himmelstein, K. J. J. Med. Chem. 1980, 23, 1275-1282.
• Han, H-K; Amidon, G. L. AAPS Pharmsci 2000, 2, 1- 11.
20 o Denny, W. A. Eur. J. Med. Chem. 2001, 36, 577-595.
o Wermuth, C. G. in Wermuth, C. G. ed. The Practice of Medicinal Chemist,y
Academic Press: San Diego (1996), 697-715.
• Balant, L. P.; Doelker, E. in Wolff, M. E. ed. Burgers Medicinal Chemistry And
Drug Discovery John Wiley & Sons: New York (1997), 949-982.
25
The particular process to be utilized in the preparation of the compounds used

in this embodiment of the invention depends upon the specific compound desired.
Such factors as the selection of the specific substituents play a role in the path to be
31
IITRUE _COPYII
WO 2004/078746 PCT /0S2004/006283
followed in the preparation of the specific compounds of this invention. Those factors
are readily recognized by one of ordinary skill in the art.
The compounds of the invention may be prepared by use of known chemical

5 reaction~ and procedures. Nevertheless, the following general preparative methods
are presented to aid the reader in synthesizing the compounds of the present
invention, with more detailed particular examples being presented below in the
experimental section describing the working examples.
10 All variable groups of these methods are as described in the generic

description if they are not specifically defined below. When a variable group or
substituent with a given symbol is used more than once in a given structure, it is to
be understood that each of these groups or substituents may be independently
varied within the range of definitions for that symbol. It is recognized that compounds
15 of the invention with each claimed optional functional group cannot be prepared with
each of the below-listed methods. Within the scope of each method optional
substituents are used which are stable to the reaction conditions, or the functional
groups which may participate in the reactions are present in protected form where
necessary, and the removal of such protective groups is completed at appropriate
20 stages by methods well known to those skilled in the art.
The compounds of the invention can be made according to conventional

chemical methods, and/or as disclosed below, from starting materials which are
either commercially available or producible according to routine, conventional
25 chemical methods. General methods for the preparation of the compounds are given
below, and the preparation of representative compounds is specifically illustrated in
examples.
32
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WO 2004/078746 PCT /0S2004/006283
General Method
Q-NH2
A-NCO + H2N-B ►
•
II Ill IV
5 The compounds (I) can be synthesized according to the reaction sequence

shown in the General Method above. Thus, the compounds (IV) can be synthesized
by reacting amino compounds (Ill) with isocyante compounds (II). Reacting the urea
compounds (IV) with the amine H2 NQ and formaldehyde furnishes the compounds
(1).
10 The compounds (II) are commercially available or can be synthesized
according to methods commonly known to those skilled in the art [e.g. from treatment
of an amine with phosgene or a phosgene equivalent such as trichloromethyl
chloroformate (diphosgene), bis(trichloromethyl)carbonate (triphosgene), or N,N'-
carbonyldiimidazole (COi); or, alternatively by a Curtius-type rearrangement of an
15 amide, or a carboxylic acid derivative, such as an ester, an acid halide or an
anhydride]. The compounds (Ill) are commercially available or can be synthesized
according methods commonly known to those skilled in the art.
In addition, specific preparations of diaryl ureas of Formula (IV) are already

20 described in the patent literature, and can be adapted to the compounds of the
present invention. For example, Miller S. et al, "Inhibition of p38 Kinase using
Symmetrical and Unsymmetrical Diphenyl Ureas" PCT Int. Appl. WO 99 32463, Miller,
S et al. "Inhibition of raf Kinase using Symmetrical and Unsymmetrical Substituted
Diphenyl Ureas" PCT Int. Appl., WO 99 32436, Dumas, J. et al., "Inhibition of p38
25 Kinase Activity using Substituted Heterocyclic Ureas" PCT Int. Appl., WO 99 32111,
Dumas, J. et al., "Method for the Treatment of Neoplasm by Inhibition of raf Kinase
using N-Heteroaryl-N'-(hetero)arylureas" PCT Int. Appl., WO 99 32106, Dumas, J. et
33
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' al., "Inhibition of p38 Kinase Activity using Aryl- and Heteroaryl- Substituted
Heterocyclic Ureas" PCT Int. Appl., WO 99 32110, Dumas, J., et al., "Inhibition of raf
Kinase using Aryl- and Heteroaryl- Substituted Heterocyclic Ureas" PCT Int. Appl.,
WO 99 32455, Riedl, B., et al., "O-Carboxy Aryl Substituted Diphenyl Ureas as raf
5 Kinase Inhibitors" PCT Int. Appl., WO 00 42012, Riedl, B., et al., "O-Carboxy Aryl
Substituted Diphenyl Ureas as p38 Kinase Inhibitors" PCT Int. Appl., WO 00 41698,
Dumas, J. et al. "Heteroaryl ureas containing nitrogen hetero-atoms as p38 kinase
inhibitors" U.S. Pat. Appl. Pub/., US 20020065296, Dumas, J. et al. "Preparation of
N-aryl-N'-[(acylphenoxy) phenyl]ureas as raf kinase inhibitors" PCT Int. Appl., WO 02
10 62763, Dumas, J. et al. "Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl
ureas" PCT Int. Appl., WO 02 85857, Dumas, J. et al. "Preparation of quinolyl,
isoquinolyl or pyridyl-ureas as inhibitors of raf kinase for the treatment of tumors
and/or cancerous cell growth" U.S. Pat. Appl. Pub/., US 20020165394. All the
preceding patent applications are hereby incorporated by reference.
15
A specific preparation of BIRB 796 (1-(5-tert-butyl-2-(4-methyl-phenyl)-2H-

pyrazole-3-yl)-3-[4-(2-morpholinylethoxy)naphthalene-1-yl]urea) is described in the
literature (Regan et al., J. Med. Chem. 2002, 45, 2994; Zhang, L-H, et al., PCT Int.
Appl., WO 01 04115).
20
The reaction of the compounds (11)with (Ill) is carried out preferably in a

solvent. Suitable solvents comprise the customary organic solvents which are inert
under the reaction conditions. Non-limiting examples include ethers such as diethyl
ether, dioxane, tetrahydrofuran, 1,2-dimethoxy ethane; hydrocarbons such as
25 benzene, toluene, xylene, hexane, cyclohexane, mineral oil fractions; halogenated
hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride,
dichloroethane, trichloroethylene, chlorobenzene; alcohols such as methanol,
ethanol, n-propanol, isopropanol; esters such as ethyl acetate; ketones such as
acetone; nitriles such as acetonitrile; heteroaromatics such as pyridine; polar
30 solvents such as dimethyl formamide and hexamethyl phosphoric acid tris-amide;
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and mixtures of the above-mentioned solvents. Toluene, benzene, and

dichloromethane are preferred.
The compounds (Ill) are generally employed in an amount of from 1 to 3 mol

5 per mol of compounds (II); an equimolar amount or slight excess of compounds (Ill)
is preferred.
The reaction of the compounds (II) with (Ill) is generally carried out within a
relatively wide temperature range. In general, they are carried out in a range of from -
10 20 to 200°c, preferably from O to 100°C, and more preferably from 25 to 50°C. The
steps of this reaction are generally carried out under atmospheric pressure.
However, it is also possible to carry them out under superatmospheric pressure or
under reduced pressure (for example, in a range of from 0.5 to 5 bar). The reaction
time can generally be varied within a relatively wide range. In general, the reaction is
15 finished after a period of from 2 to 24 hours, preferably from 6 to 12 hours.
The amines QNH2 are commercially available or can be synthesized

according methods commonly known to those sl<illedin the art.
20 The reaction of the compounds (IV) with the amines QNH2 and formaldehyde
is described in l<napp, S.; Hale, J. J.; Bastos, M.; Gibson, F. S. Tetrahedron Lett.
1990, 31, 2109-2112; l<napp, S.; Hale, J. J.; Bastos, M.; Molina, A.; Chen K. Y. J.
Org. Chem. 1992, 57, 6239-6256. Kovalenko, A. L.; Serov, Yu. V.; Tselinskii, I. V.;
Nikonov, A. A Zhumal Organicheskoi Khimii, 1991, 27, 2388 - 2391. Nevertheless,
25 the following general preparative method is presented to aid the reader in
synthesizing the compounds of the present invention.
The reaction of the compounds (IV) with the amines QNH2 and formaldehyde
is carried out preferably in a solvent. Suitable solvents comprise water and the
30 customary organic solvents which are inert under the reaction conditions. Non-
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limiting examples include ethers such as diethyl ether, dioxane, tetrahydrofuran, 1,2-
dimethoxy ethane; hydrocarbons such as benzene, toluene, xylene, hexane,
cyclohexane, mineral oil fractions; halogenated hydrocarbons such as di-
chloromethane, trichloromethane, carbon tetrachloride, dichloroethane, trichloro-
5 ethylene, chlorobenzene; alcohols such as methanol, ethanol, n-propanol,
isopropanol; esters such as ethyl acetate; ketones such as acetone; nitriles such as
acetonitrile; heteroaromatics such as pyridine; polar solvents such as dimethyl
formamide and hexamethyl phosphoric acid tris-amide; and mixtures of the above-
mentioned solvents. Water, and a mixture of water and toluene are preferred.
10
The amines QNH2 are generally employed in an amount of from 1 to 5 mol

per mol of compounds (IV); a 2 mol excess of compounds (IV) is preferred.
The reaction of the compounds (IV) with the amines QNH2 and formaldehyde
15 is generally carried out within a relatively wide temperature range. In general, they
are carried out in a range of from -20 to 200°C, preferably from 0 to 120°C, and more
preferably from 50 to 120°C. The steps of this reaction are generally carried out
under atmospheric pressure. However, it is also possible to carry them out under
superatmospheric pressure or under reduced pressure (for example, in a range of
20 from 0.5 to 5 bar). The reaction time can generally be varied within a relatively wide
range. In general, the reaction is finished after a period of from 2 to 24 hours,
preferably from 6 to 12 hours.
Synthetic transformations that may be employed in the synthesis of

25 compounds of Formula I and in the synthesis of intermediates involved in the
synthesis of compounds of Formula I are known by or accessible to one skilled in the
art. Collections of synthetic transformations may be found in compilations, such as:
• J. March. Advanced Organic Chemistry, 4th ed.; John Wiley: New York (1992)
• R.C. Larock. Comprehensive Organic Transformations, 2nd ed.; Wiley-VCH: New
30 York (1999)
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• F.A. Carey; R.J. Sundberg. Advanced Organic Chemistry, 2nd ed.; Plenum
Press: New York (1984)
• T.W. Greene; P.G.M. Wuts. Protective Groups in Organic Synthesis, 3rd ed.;
John Wiley: New York (1999)
s • L.S. Hegedus. Transition Metals in the Synthesis of Complex Organic Molecules,
2nd ed.; University Science Books: Mill Valley, CA (1994)
• L.A. Paquette, Ed. The Encyclopedia of Reagents for Organic Synthesis; John
Wiley: New York (1994)
• A.R. Katritzky; 0. Meth-Cohn; C.W. Rees, Eds. Comprehensive Organic
10 Functional Group Transformations; Pergamon Press: Oxford, UK (1995)
• G. Wilkinson; F.G A. Stone; E.W. Abel, Eds. Comprehensive Organometallic
Chemistry; Pergamon Press: Oxford, UK (1982)
,• B.M. Trost; I. Fleming. Comprehensive Organic Synthesis; Pergamon Press:
Oxford, UK (1991)
15 • A.R. Katritzky; C.W. Rees Eds. Comprehensive Heterocylic Chemistry;
Pergamon Press: Oxford, UI-<(1984)
<JI AR. l<atritzl<y;C.W. Rees; E.F.V. Scriven, Eds. Comprehensive Heterocylic
Chemistry II; Pergamon Press: Oxford, UK (1996)
• C. Hansch; P.G. Samrnes; J.B. Taylor, Eds. Comprehensive Medicinal
20 Chemistry: Pergamon Press: Oxford, UK (1990).
In addition, recurring reviews of synthetic methodology and related topics

include Organic Reactions; John Wiley: New York; Organic Syntheses; John Wiley:
New York; Reagents for Organic Synthesis: John Wiley: New York; The Total
25 Synthesis of Natural Products; John Wiley: New York; The Organic Chemistry of
Drug Synthesis; John Wiley: New York; Annual Reports in Organic Synthesis;
Academic Press: San Diego CA; and Methoden der Organischen Chemie (Houben-
Wey!); Thieme: Stuttgart, Germany. Furthermore, databases of synthetic
transformations include Chemical Abstracts, which may be searched using either
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GAS Online or SciFinder, Handbuch der Organischen Chemie(Beilstein), which may

be searched using SpotFire, and REACCS.
Compositions of the compounds of this invention

5 This invention also relates to pharmaceutical compositions containing one or
more compounds of the present invention. These compositions can be utilized to
achieve the desired pharmacological effect by administration to a patient in need
thereof. A patient, for the purpose of this invention, is a mammal, including a human,
in need of treatment for the particular condition or disease. Therefore, the present
10 invention includes pharmaceutical compositions which are comprised of a
pharmaceutically acceptable carrier and a pharmaceutically effective amount of a
compound, or salt thereof, of the present invention. A pharmaceutically acceptable
carrier is any carrier which is relatively non-toxic and innocuous to a patient at
concentrations consistent with effective activity of the active ingredient so that any
15 side effects ascribable to the carrier do not vitiate the beneficial effects of the active
ingredient. A pharmaceutically effective amount of compound is that amount which
produces a result or exerts an influence on the particular condition being treated.
The compounds of the present invention can be administered with pharmaceutically-
acceptable carriers well known in the art using any effective conventional dosage unit
20 forms, including immediate, slow and timed release preparations, orally, parenterally,
topically, nasally, ophthalmically, otically, sublingually, rectally, vaginally, and the like.
For oral administration, the compounds can be formulated into solid or liquid
preparations such as capsules, pills, tablets, troches, lozenges, melts, powders,
solutions, suspensions, or emulsions, and may be prepared according to methods
25 known to the art for the manufacture of pharmaceutical compositions. The solid unit
dosage forms can be a capsule which can be of the ordinary hard- or soft-shelled
gelatin type containing, for example, surfactants, lubricants, and inert fillers such as
lactose, sucrose, calcium phosphate, and corn starch.
In another embodiment, the compounds of this invention may be tableted with
30 conventional tablet bases such as lactose, sucrose and cornstarch in combination
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with binders such as acacia, corn starch or gelatin, disintegrating agents intended to
assist the break-up and dissolution of the tablet following administration such as
potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia,
lubricants intended to improve the flow of tablet granulation and to prevent the
5 adhesion of tablet material to the surfaces of the tablet dies and punches, for
example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring
agents, and flavoring agents such as peppermint, oil of wintergreen, or cherry
flavoring, intended to enhance the aesthetic qualities of the tablets and make them
more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms
10 include dicalcium phosphate and diluents such as water and alcohols, for example,
ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition
of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent.
Various other materials may be present as coatings or to otherwise modify the
physical form of the dosage unit. For instance tablets, pills or capsules may be
15 coated with shellac, sugar or both.
Dispersible powders and granules are suitable for the preparation of an

aqueous suspension. They provide the active ingredient in admixture with a
dispersing or wetting agent, a suspending agent and one or more preservatives.
20 Suitable dispersing or wetting agents and suspending agents are exemplified by
those already mentioned above. Additional excipients, for example those
sweetening, flavoring and coloring agents described above, may also be present.
The pharmaceutical compositions of this invention may also be in the form of

25 oil-in-water emulsions. The oily phase may be a vegetable oil such as liquid paraffin
or a mixture of vegetable oils. Suitable emulsifying agents may be (1) naturally
occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring
phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form
fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4)
30 condensation products of said partial esters with ethylene oxide, for example,
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polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening

and flavoring agents.
Oily suspensions may be formulated by suspending the active ingredient in a

5 vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or
in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening
agent such as, for example, beeswax, hard paraffin, or cetyl alcohol. The
suspensions may also contain one or more preservatives, f~r example, ethyl or n-
propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring
10 • agents; and one or more sweetening agents such as sucrose or saccharin.
Syrups and elixirs may be formulated with sweetening agents such as, for
example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also
contain a demulcent, and preservative, such as methyl and propyl parabens and
flavoring and coloring agents.
15
The compounds of this invention may also be administered parenterally, that

is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or
interperitoneally, as injectable dosages of the compound in a physiologically
acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or
20 mixture of liquids such as water, saline, aqueous dextrose and related sugar
solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols
such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-
1,1-dioxolane-4-methanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty
acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride,
25 with or without the addition of a pharmaceutically acceptable surfactant such as a
soap or a detergent, suspending agent such as pectin, carbomers, methycellulose,
hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agent and
other pharmaceutical adjuvants.
30 Illustrative of oils which can be used in the parenteral formulations of this

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invention are those of petroleum, animal, vegetable, or synthetic origin, for example,
peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and
mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and
myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl
5 myristate. Suitable soaps include fatty acid alkali metal, ammonium, and
triethanolamine salts and suitable detergents include cationic detergents, for
example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine
acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl,
olefin, ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents,
10 for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-
oxypropylene)s or ethylene oxide or propylene oxide copolymers; and amphoteric
detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline
quarternary ammonium salts, as well as mixtures.
15 The parenteral compositions of this invention will typically contain from about
0.5% to about 25% by weight of the active ingredient in solution. Preservatives and
buffers may also be used advantageously. In order to minimize or eliminate irritation
at the site of injection, such compositions may contain a non-ionic surfactant having
a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of
20 surfactant in such formulation ranges from about 5% to about 15% by weight. The
surfactant can be a single component having the above HLB or can be a mixture of
two or more components having the desired HLB.
Illustrative of surfactants used in parenteral formulations are the class of

25 polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the
high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by
the condensation of propylene oxide with propylene glycol.
The pharmaceutical compositions may be in the form of sterile injectable

30 aqueous suspensions. Such suspensions may be formulated according to known
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methods using suitable dispersing or wetting agents and suspending agents such as,
for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-
cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;
dispersing or wetting agents which may be a naturally occurring phosphatide such as
5 lecithin, a condensation product of an alkylene oxide with a fatty acid, for example,
polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain
aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation
product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol
such as polyoxyethylene sorbitol monooleate, or a condensation product of an
10 ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride,
for example polyoxyethylene sorbitan monooleate.
The sterile injectable preparation may also be a sterile injectable solution or

suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and
15 solvents that may be employed are, for example, water, Ringer's solution, isotonic
sodium chloride solutions and isotonic glucose solutions. In addition, sterile fixed oils
are conventionally employed as solvents or suspending media. For this purpose, any
bland, fixed oil may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid can be used in the preparation of injectables.
20
A composition of the invention may also be administered in the form of

suppositories for rectal administration of the drug. These compositions can be
prepared by mixing the drug with a suitable non-irritation excipient which is solid at
ordinary temperatures but liquid at the rectal temperature and will therefore melt in
25 the rectum to release the drug. Such material are, for example, cocoa butter and
polyethylene glycol.
Another formulation employed in the methods of the present invention

employs transdermal delivery devices ("patches"). Such transdermal patches may be
30 used to provide continuous or discontinuous infusion of the compounds of the
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present invention in controlled amounts. The construction and use of transdermal

patches for the delivery of pharmaceutical agents is well known in the art (see, e.g.,
US Patent No. 5,023,252, issued June 11, 1991, incorporated herein by reference).
Such patches may be constructed for continuous, pulsatile, or on demand delivery of
5 pharmaceutical agents.
Controlled release formulations for parenteral administration include

liposomal, polymeric microsphere and polymeric gel formulations which are known in
the art.
10
It may be desirable or necessary to introduce the pharmaceutical composition

to the patient via a mechanical delivery device. The construction and use of
mechanical delivery devices for the delivery of pharmaceutical agents is well known
in the art. Direct techniques for, for example, administering a drug directly to the
15 brain usually involve placement of a drug delivery catheter into the patient's
ventricular system to bypass the blood-brain barrier. One such implantable delivery
system, used for the transport of agents to specific anatomical regions of the body, is
described in US Patent No. 5,011,472, issued April 30, 1991.
20 The compositions of the invention can also contain other conventional

pharmaceutically acceptable compounding ingredients, generally referred to as
carriers or diluents, as necessary or desired. Conventional procedures for preparing
such compositions in appropriate dosage forms can be utilized. Such ingredients
and procedures include those described in the following references, each of which is
25 incorporated herein by reference: Powell, M.F. et al, "Compendium of Excipients for
Parenteral Formulations" PDA Journal of Pharmaceutical Science & Technology
1998, 52(5), 238-311; Strickley, R.G "Parenteral Formulations of Small Molecule
Therapeutics Marketed in the United States (1999)-Part-1" PDA Journal of
Pharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S. et al,
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"Excipients and Their Use in Injectable Products" PDA Journal of Pharmaceutical

Science & Technology 1997, 51(4), 166-171.
Commonly used pharmaceutical ingredients which can be used as appropriate

5 to formulate the composition for its intended route of administration include:
acidifying agents (examples include but are not limited to acetic acid, citric
acid, fumaric acid, hydrochloric acid, nitric acid);
alkalinizing agents (examples include but are not limited to ammonia
10 solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium
hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine,
trolamine );
adsorbents (examples include but are not limited to powdered cellulose and
activated charcoal);
15 aerosol propellants (examples include but are not limited to carbon dioxide,
CC'2F2,F2CIC-CCIF2and CCIF3)
air displacement agents (examples include but are not limited to nitrogen
and argon);
antifungal preservatives (examples include but are not limited to benzoic
20 acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate);
antimicrobial preserv:aitives (examples include but are not limited to
benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium
chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and
thimerosal);
25 antioxidants (examples include but are not limited to ascorbic acid, ascorbyl
palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid,
monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium
formaldehyde sulfoxylate, sodium metabisulfite);
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binding materials (examples include but are not limited to block polymers,
natural and synthetic rubber, polyacrylates, polyurethanes, silicones, polysiloxanes
and styrene-butadiene copolymers);
buffering agents (examples include but are not limited to potassium
s metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydrous
and sodium citrate dihydrate)
carrying agents (examples include but are not limited to acacia syrup,
aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn
oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and
10 bacteriostatic water for injection)
chelating agents (examples include but are not limited to edetate disodium
and edetic acid)
colorants (examples include but are not limited to FD&C Red No. 3, FD&C
Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange
15 No. 5, D&C Red No. 8, caramel and ferric oxide red);
clarifying agents (examples include but are not limited to bentonite);
emulsifying agents (examples include but are not limited to acacia,
cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate,
polyoxyethylene 50 monostearate);
20 encapsulating agents (examples include but are not limited to gelatin and
cellulose acetate phthalate)
flaivornnts (examples include but are not limited to anise oil, cinnamon oil,
cocoa, menthol, orange oil, peppermint oil and vanillin);
humectants (examples include but are not limited to glycerol, propylene
25 glycol and sorbitol);
levigating agents (examples include but are not limited to mineral oil and
glycerin);
oils (examples include but are not limited to arachis oil, mineral oil, olive oil,
peanut oil, sesame oil and vegetable oil);
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ointment bases (examples include but are not limited to lanolin, hydrophilic
ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white
ointment, yellow ointment, and rose water ointment);
penetration enhancers (transdermal delivery) (examples include but are
5 not limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalent alcohols,
saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters,
saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives,
cephalin, terpenes, amides, ethers, ketones and ureas)
plasticizers (examples include but are not limited to diethyl phthalate and
10 glycerol);
solvents (examples include but are not limited to ethanol, corn oil, cottonseed
oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for
injection, sterile water for injection and sterile water for irrigation);
stiffening agents (examples include but are not limited to cetyl alcohol, cetyl
15 esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow
wax);
suppository bases (examples include but are not limited to cocoa butter and
polyethylene glycols (mixtures));
surfactants (examples include but are not limited to benzalkonium chloride,
20 nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan mono-
palmitate);
suspending agents (examples include but are not limited to agar, bentonite,
carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl
cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and
25 veegum);
sweetening agents (examples include but are not limited to aspartame,
dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and
sucrose);
tablet anti-adherents (examples include but are not limited to magnesium
30 stearate and talc);
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tablet binders (examples include but are not limited to acacia, alginic acid,
carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid
glucose, methylcellulose, non-crosslinked polyvinyl pyrrolidone, and pregelatinized
starch);
5 tablet and capsule diluents (examples include but are not limited to dibasic
calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered
cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate,
sorbitol and starch);
tablet coating agents (examples include but are not limited to liquid glucose,
10 hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac);
tablet direct compression excipients (examples include but are not limited
to dibasic calcium phosphate);
tablet disintegrants (examples include but are not limited to alginic acid,
15 carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium,
cross-linked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate and
starch);
tablet glidants (examples include but are not limited to colloidal silica, corn
starch and talc);
20 tablet lubricants (examples include but are not limited to calcium stearate,
magnesium stearate, mineral oil, stearic acid and zinc stearate);
tablet/capsule opaquants ·(examples include but are not limited to titanium
dioxide);
tablet polishing agents (examples include but are not limited to carnuba wax
25 and white wax);
thickening agents (examples include but are not limited to beeswax, cetyl
alcohol and paraffin);
tonicity agents (examples include but are not limited to dextrose and sodium
chloride);
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viscosity increasing agents (examples include but are not limited to alginic
acid, bentonite, carbomers, ·carboxymethylcellulose sodium, methylcellulose,
polyvinyl pyrrolidone, sodium alginate and tragacanth); and
wetting agents (examples include but are not limited to heptadecaethylene
5 oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and
polyoxyethylene stearate ).
It is believed that one skilled in the art, utilizing the preceding information, can
utilize the present invention to its fullest extent. Nevertheless, the following are
10 examples of pharmaceutical formulations that can be used in the method of the
present invention. They are for illustrative purposes only, and are not to be
construed as limiting the invention in any way.
Pharmaceutical compositions according to the present invention can be

15 illustrated as follows:
Sterile IV Solution: A 5 mg/ml solution of the desired compound of this invention is

made using sterile, injectable water, and the pH is adjusted if necessary. The
solution is diluted for administration to 1 - 2 mg/ml with sterile 5% dextrose and is
20 administered as an IV infusion over 60 minutes.
Lyophilized powder for IV administration: A sterile preparation can be prepared

with (i) 100 - 1000 mg of the desired compound of this invention as a lypholized
powder, (ii) 32- 327 mg/ml sodium citrate, and (iii) 300 - 3000 mg Dextran 40. The
25 formulation is reconstituted with sterile, injectable saline or dextrose 5% to a
concentration of 10 to 20 mg/ml, which is further diluted with saline or dextrose 5%
to 0.2 - 0.4 mg/ml, and is administered either IV bolus or by IV infusion over 15 - 60
minutes.
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Intramuscular suspension: The following solution or suspension can be prepared,

for intramuscular injection:
50 mg/ml of the desired, water-insoluble compound of this invention
5 mg/ml sodium carboxymethylcellulose
5 4 mg/ml TWEEN 80
9 mg/ml sodium chloride
9 mg/ml benzyl alcohol
Hard Shell Capsules: A large number of unit capsules are prepared by filling
10 standard two-piece hard galantine capsules each with 100 mg of powdered active
ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
Soft Gelatin Capsules: A mixture of active ingredient in a digestible oil such as

soybean oil, cottonseed oil or olive oil is prepared and injected by means of a
15 positive displacement pump into molten gelatin to form soft gelatin capsules
containing 100 mg of the active ingredient. The capsules are washed and dried.
The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin
and sorbitol to prepare a water miscible medicine mix.
20 Tablets: A large number of tablets are prepared by conventional procedures so that

the dosage unit was 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5
mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch,
and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be
applied to increase palatability, improve elegance and stability or delay absorption.
25
Immediate Release Tablets/Capsules: These are solid oral dosage forms made by
conventional and novel processes. These units are taken orally without water for
immediate dissolution and delivery of the medication. The active ingredient is mixed
in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners.
30 These liquids are solidified into solid tablets or caplets by freeze drying and solid
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state extraction techniques. The drug compounds may be compressed with

viscoelastic and thermoelastic sugars and polymers or effervescent components to
produce porous matrices intended for immediate release, without the need of water.
5 Method of treating hyper-proliferative disorders

The present invention relates to a method for using the compounds described
above (Compounds of Formula I), including salts and esters thereof and
compositions thereof, to treat mammalian hyper-proliferative disorders. This method
comprises administering to a mammal in need thereof, including a human, an
10 amount of a compound of this invention, or a pharmaceutically acceptable salt or
ester thereof, which is effective to treat the disorder. Hyper-proliferative disorders
include but are not limited to solid tumors, such as cancers of the breast, respiratory
tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head
and neck, thyroid, parathyroid and their distant metastases. Those disorders also
15 include lymphomas, sarcomas, and leukemias.
Examples of breast cancer include, but are not limited to invasive ductal
carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular
carcinoma in situ.
20
Examples of cancers of the respiratory tract include, but are not limited to
small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and
pleuropulmonary blastoma.
25 Examples of brain cancers include, but are not limited to brain stem and
hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma,
ependymoma, as well as neuroectodermal and pineal tumor.
Tumors of the male reproductive organs include, but are not limited to prostate
30 and testicular cancer. Tumors of the female reproductive organs include, but are not
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limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as

sarcoma of the uterus.
Tumors of the digestive tract include, but are not limited to anal, colon,
5 colorectal, esophag~al, gallbladder, gastric, pancreatic, rectal, small-intestine, and
salivary gland cancers.
Tumors of the urinary tract include, but are not limited to bladder, penile,
kidney, renal pelvis, ureter, and urethral cancers.
10
Eye cancers include, but are not limited to intraocular melanoma and
retinoblastoma.
Examples of liver cancers include, but are not limited to hepatocellular

15 carcinoma (liver cell carcinomas with or without fibrolamellar variant),
cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular
cholangiocarcinoma.
Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's
20 sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin
cancer.
Head-and-neck cancers include, but are not limited to laryngeal /

hypopharyngeal / nasopharyngeal / oropharyngeal cancer, and lip and oral cavity
25 cancer.
Lymphomas include, but are not limited to AIDS-related lymphoma, non-

Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and
lymphoma of the central nervous system.
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Sarcomas include, but are not limited to sarcoma of the soft tissue,
osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and
rhabdomyosarcoma.
5 Leukemias include, but are not limited to acute myeloid leukemia, acute
lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous
leukemia, and hairy cell leukemia.
These disorders have been well characterized in humans, but also exist with a
10 similar etiology in other mammals, •and can be treated by administering
pharmaceutical compositions of the present invention.
The compounds of this invention can be administered as the sole

pharmaceutical agent or in combination with one or more other pharmaceutical
15 agents where the combination causes no unacceptable adverse effects. For
example, the compounds of this invention can be combined with known anti-hyper-
proliferative or other indication agents, and the like, as well as with admixtures and
combinations thereof.
20 Optional anti-hyper-proliferative agents which can be added to the

composition include but are not limited to compounds listed on the cancer
chemotherapy drug regimens in the 11th Edition of the Merck Index, (1996), which is
hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin,
carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine,
25 dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin,
etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan,
leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate,
mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen,
streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and
30 vindesine.
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Other anti-hyper-proliferative agents suitable for use with the composition of

the invention include but are not limited to those compounds acknowledged to be
used in the treatment of neoplastic diseases in Goodman and Gilman's The
Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by
5 McGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated by reference,
such as aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine,
busulfan, diethylstilbestrol, 2', 2'-difluorodeoxycytidine, docetaxel,
erythrohydroxynonyladenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5-
fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone,
10 flutamide, hydroxyprogesterone caproate, idarubicin, interferon,
medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel,
pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine,
teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and
vinorelbine.
15
Other anti-hyper-proliferative agents suitable for use with the composition of

the invention include but are not limited to other anti-cancer agents such as
epothilone and its derivatives, irinotecan, raloxifen and topotecan.
20 Generally, the use of cytotoxic and/or cytostatic agents in combination with a

compound or composition of the present invention will serve to:
(1) yield better efficacy in reducing the growth of a tumor or even eliminate the
tumor as compared to administration of either agent alone,
25 (2) provide for the administration of lesser amounts of the administered
chemotherapeutic agents,
(3) provide for a chemotherapeutic treatment that is well tolerated in the
patient with fewer deleterious pharmacological complications than observed with
single agent chemotherapies and certain other combined therapies,
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(4) provide for treating a broader spectrum of different cancer types in

mammals, especially humans,
(5) provide for a higher response rate among treated patients,
(6) provide for a longer survival time among treated patients compared to
5 standard chemotherapy treatments,
(1) provide a longer time for tumor progression, and/or
(8) yield efficacy and tolerability results at least as good as those of the agents
used alone, compared to known instances where other cancer agent combinations
produce antagonistic effects.
10
Method of treating inflammatory disorders

Clinical studies have linked abnormal tumor necrosis factor (TNF) production
and/or signaling to a number of inflammatory and immunomodulatory diseases.
These diseases include, but are not limited to rheumatoid arthritis, psoriasis, acute
15 rheumatic fever, sepsis, septic shock, endotoxic shock, toxic shock syndrome,
systemic inflammatory response syndrome, inflammatory bowel diseases including
Crohn's disease, ulcerative colitis, Jarisch-Herxheimer reactions, asthma, adult
respiratory distress syndrome, acute pulmonary fibrotic diseases, and chronic
obstrusive pulmonary disease.
20
A number of diseases are thought to be mediated by excess or undesired

matrix-destroying metalloprotease (MMP) activity or by an imbalance in the ratio of
the MMPs to the tissue inhibitors of metalloproteinases (TIMPs). These include, but
are not limited to osteoarthritis, rheumatoid arthritis, septic arthritis, degenerative
25 cartilage loss following traumatic joint injury, osteopenias mediated by MMP activity,
and tempera mandibular joint disease.
Because inhibition of p38 leads to inhibition of TNF production and MMP

production, inhibition of mitogen activated protein (MAP) kinase p38 enzyme
30 provides an approach to the treatment of the above listed inflammatory diseases.
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Release of the active principle

Upon dosing in a mammal, the compounds of the present invention undergo a
biotransformation. This transformation is either catalyzed by an enzyme of the
5 subject treated, or by in vivo hydrolysis, which takes place, for example, in the acidic
medium of the stomach after oral administration. As a result, a diary! urea of formula
A-NH-CO-NH-B, which carries potent biological activity as described in the art, is
formed upon dosing a mammal with a compound of Formula I. Therefore,
compounds of Formula I are useful for the treatment of diseases such as raf-
10 mediated, angiogenesis-mediated, and p38-mediated diseases. Dosing a compound
of Formula I instead of the corresponding urea of Formula A-NH-CO-NH-B may
carry one or more of the following advantages:
(1) the compound of Formula I may modify overall aqueous solubility, when
15 compared to ureas of formula A-NH CO-NH-B, and bring more desirable
physicochemical properties,
(2) the safety and tolerability of the drug may be improved when compared to ureas
of formula A-NH CO-NH-B,
(3) the stability of the compounds of Formula I could be modulated to produce the
20 optimal delivery of the urea of formula A-NH-CO-NH-B to the subject.
Dosage of the compounds of the present invention

Based upon standard laboratory techniques known to evaluate compounds
useful for the treatment of hyper-proliferative, angiogenesis, and inflammatory
25 disorders, by standard toxicity tests and by standard pharmacological assays for the
determination of treatment of the conditions identified above in mammals, and by
comparison of these results with the results of known medicaments that are used to
treat these conditions, the effective dosage of the compounds of this invention can
readily be determined for treatment of each desired indication. The amount of the
30 active ingredient to be administered in the treatment of one of these conditions can
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vary widely according to such considerations as the particular compound and dosage
unit employed, the mode of administration, the period of treatment, the age and sex
of the patient treated, and the nature and extent of the condition treated.
5 The total amount of the active ingredient to be administered will generally

range from about 0.001 mg/kg to about 200mg/kg bodyweight per day, and
preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day. It should
be noted that the choice of dosing schedules is particularly important to maximize the
efficacy and safety of drugs for the treatment of proliferative disorders, and
10 inflammatory disorders. Clinically useful dosing schedules will range from three times
a day dosing to once every four weeks dosing. In addition, "drug holidays" in which a
patient is not dosed with a drug for a certain period of time, may be beneficial to the
overall balance between pharmacological effect and tolerability. A unit dosage may
contain from about 0.5 mg to about 1500 mg of active ingredient, and can be
15 administered one or more times per day. The average daily dosage for administration
by injection, including intravenous, intramuscular, subcutaneous and parenteral
injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of
total body weight. The average daily rectal dosage regimen will preferably be from
0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen
20 will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily
topical dosage regimen will preferably be from 0.1 to 200 mg administered between
one to four times daily. The transdermal concentration will preferably be that required
to maintain a daily dose of from 0.01 to 200 mg/kg. The average daily inhalation
dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
25
Of course the specific initial and continuing dosage regimen for each patient
will vary according to the nature and severity of the condition as determined by the
attending diagnostician, the activity of the specific compound employed, the age and
general condition of the patient, time of administration, route of administration, rate of
30 excretion of the drug, drug combinations, and the like. The desired mode of
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treatment and number of doses of a compound of the present invention or a

pharmaceutically acceptable salt or ester or composition thereof can be ascertained
by those skilled in the art using conventional treatment tests.
5 It is believed that one skilled in the art, using the preceding information and
information available in the art, can utilize the present invention to its fullest extent.
It should be apparent to one of ordinary skill in the art that changes and
modifications can be made to this invention without departing from the spirit or scope
10 of the invention as it is set forth herein.
Examples
Abbreviations used in this specification

15
™Cremophor non-ionic emulsifier from BASF, Germany

®
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DMF N,N-dimethyl formamide
DMSO dimethyl sulphoxide
HPLC high pressure liquid chromatography
LC-MS liquid chromatography - coupled mass
spectroscopy
LC RT liquid chromatography retention time
MP melting point
NMR nuclear resonance spectroscopy
TLC thin layer chromatography
The yield percentages of the following examples refer to the starting

component which was used in the lowest molar amount.
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MS method used in the Examples (HPLC/MS):
MS equipment: Micromass Quattro LCZ

5 ionisation mode: ESI positive/ negative
HPLC equipment: HP 1100

UV detection: 208-400 nm
temperature: 40 °C
10
Column: ™Symmetry C 18
50 mm x2.1 mm 3.5 µm
Supplier: Waters
15 Gradient: Time A:% B:% Flow

[min.] [ml/min.]
0.00 90.0 10.0 0.50
4.00 10.0 90.0 0.50
6.00 10.0 90.0 0.50
20
A: 0.05% strength solution of formic acid in water

B: 0.05% strength formic acid in acetonitrile
25
Example 1
1-(4-chloro-3(trifluoromethyl)phenyl)-3-(4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)phenyl)-2-oxo-( 1,3,5-perhydrotriazapine)
30
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A mixture of methylamine hydrochloride (79.9 mg, 1.18 mmol) and 37% aqueous
formaldehyde (3.25 ml, 40.3 mmol) was neutralized with N,N-diisopropylethylamine
s and stirred for 10 min. N-(4-chloro-3(trifluoromethyl)phenyl)-N'-(4-(2-(N-
methylcarbamoyl)-4-pyridyloxy)phenyl) urea (Intermediate 1, preparation described
in WO0042012, 250 mg, 0.54 mmol) and toluene (3 ml) were added and the
reaction was heated at reflux for 16 hr. The reaction was allowed to cool to room
temperature and was extracted with EtOAc (3 x 10 ml). The combined organic
10 extracts were dried (MgSO4) and concentrated. The crude product was purified by
preparative HPlC, which afforded 30 mg (0.0583 mmol, 11%) of Example 1 as a
white solid. MP: 82-85 °C; 1H-NMR (C03O0) 8 2.89 (s, 3H), 2.94 (s, 3H), 4.77 (s,
2H), 4.81 (s, 2H), 7.05 - 7.09 (m, 1H), 7.20 (d, J = 8.6, 2H), 7.46 (d, J = 9.2, 2H),
7.54 - 7.65(m, 3H), 7.80 (d, J = 2.3, 1H) 8.46 (d, J = 6.5, 1H); MS (HPlC/ES) m/z =
15 520.08 (M + 1).
E2mmple 2
4-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-5-(2-methoxy-ethyl)-2-oxo-
20 [1,3,S]triazinan-1-yl]-3-fluoro-phenoxy}-pyridine-2-carboxylic acid methylamide
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A mixture of methoxyethylamine (46.7 mg, 0.62 mmol), 4-{4-[3-(4-chloro-3-

trifluoromethyl-phenyl)-ureido]-3-fluoro-phenoxy}-pyridine-2-carboxylic acid
methylamide (300 mg, 0.62 mmol) and 0.8 ml 37% aqueous formaldehyde were
stirred at 40 °C for 10-15 min in a 50-ml flask equipped with a Dean-Stark trap.
5 Diisopropylethylamine (120 mg, 0.93 mmol) and toluene (10 ml) were added, and
the temperature was raised to 107 °C. During a 90-minute period, additional toluene
(15 ml) was added to the reaction mixture, and approximately 10 ml distillate was
collected. The reaction was cooled and concentrated to afford a solid residue.
Chromatography on silica gel using 3:2 ethyl acetate/hexane as the eluant afforded
10 92.4 mg (yield 25.6%) of Example 2 as a white solid. 1H NMR (400 MHz, DMSO) 8
8.80 (bs, 1 H), 8.50 (d, 1 H), 7.80 (s, 1 H), 7.70 (d, 1 H), 7.65 (d, 1 H), 7.55 (d, 1 H),
7.50 (d, 1 H), 7.40 (d, 1 H), 7.20 (d, 1 H), 7.10 (d, 1 H), 4.85 (s, 2 H), 4.70 (s, 2 H),
3.50 (t, 2 H), 3.25 (s, 3 H), 3.20 (t, 2 H), 2.80 (s, 3 H); MS (HPLC/ES) m/z 582.1
(MH+).
15
Example 3
4-{ 4-[3-( 4-C h Ioro-3-trifl uoromethyl-phenyl)-5-(2-hyd roxy-ethyl)-2-mm-
[1,3 ,S]triazinan-1-yl]-3-fl uoro-phenoxy}-pyridine-2-carboxyl ic acid methylamide
20
The compound of Example 3 (10 mg, yield 6%) was prepared by using the same
method as Example 2. MS (HPlC/ES) m/z 568.1 (MH+), RT = 2.85 min.
25
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Example 4
4-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-5-(3-hydroxy-propyl)-2-oxo-
[1,3,S]triazinan-1-yl]-3-fluoro-phenoxy}-pyridine-2-carboxylic acid methylamide
5
The compound of Example 4 (16.3 mg, yield 4.5%) was also prepared by the same
method as described in Example 2. MS (HPLC/ES) m/z 582.6 (MH+), RT= 2.82 min.
10
Example 5
4-{3-Fluoro-4-[5-methyl-2-oxo-3-(2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxin-6-yl)-
[1,3,5]triazinan-1-yl]-phenoxy}-pyridine-2-carbonitrile
15
Methylamine hydrochloride (77.63 mg, 1.15 mmol) was weighed into a flask and 37%
formaldehyde (3.25 ml, 43.37 mmol) was added. The solution was then neutralized
20 with diisopropylethylamine. A solution of N-(6-(2,2,4,4-tetrafluoro-4H-
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benzo[1,3]dioxinyl)}-N'-(4-(2-cyano-4-pyridyloxy) phenyl) urea (250 mg, 0.52 mmol)

in toluene (3 ml) in a separate flask and added to the reaction vessel. The mixture
was heated to reflux for 18 hrs, at which point the incomplete reaction was extracted
with EtOAc. The organic fractions were combined, dried with sodium sulfate and
s concentrated in vacuo. The resulting oil was purified via flash chromatography (40:60
to 60:40, EtOAc:Hexanes) to yield 31.3 mg ( 11.23 %) of the purified product. MS:
M+H: 534.0. TLC: RF= 0.17 (50% EtOAc in hexanes).
10 Example 6
4-{3-Fluoro-4-[5-methyl-2-oxo-3-(2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxin-6-yl)-
[1,3,5]triazinan-1-yl]-phenoxy}-pyridine-2-carboxylic acid methylamide
15 The title compound was synthesized using the same procedure as example 5 above,
using 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-3-fluoro-phenoxy}-pyridine-2-
carboxylic acid methylamide as starting material. Yield: 14.36%, MS: M+H = 538.1.
TLC: RF= 0.39 (100% EtOAc).
20 Biological Tests
Pharmacokinetics in the Mouse

Female ICr mice received single doses of Example 1 by oral gavage at 30
mg/kg body weight. The vehicle used for administration consisted of 12.5%
25 Cremophor, 12.5% ethanol and 75% saline. Blood samples were collected by
cardiac puncture under anesthesia and plasma was isolated by centrifugation. Three
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animals were used for each time point of 0.5, 1 and 5 hours post dosing. Plasma
levels of Example 1 and Intermediate 1 were measured by LC-MS.
Calibration samples (1 to 5,000 ng/mL) were prepared by spiking drug-free

5 mouse plasma with known concentrations of Example 1 and Intermediate 1 and then
processed with the study samples. An internal standard (close analog) was spiked
at a final concentration of 100 ng/ml. Plasma samples were extracted via protein
precipitation using acetonitrile (3:1). After vortexing for 1 minute, samples were
centrifuged at 2500 rpm for 15 minutes. Supernatant was transferred to 96-well
10 microtiter plates for LC-MS analysis. Analytes (Example 1 and Intermediate 1) and
the internal standard were monitored using MRM transitions consisting of their
protonated molecular ions to prominent fragment ions (Example 1 m/z 520 to m/z
270; Intermediate 1 m/z 465 to 252; internal standard m/z 469 to m/z 256). The
calibration curve was constructed using least squares linear regression and utilized
15 peak area ratios of the analyte and internal standard. Pharmacokinetic analysis of
the measured plasma concentrations was conducted using the Watson® Drug
Metabolism Laboratory Information Management System (lnnaphase Corp,
Philadelphia, PA). The results of the experiment indicate that
20 (i) the prodrug from Example 1 is very well absorbed in mice.

(ii) significant levels of Intermediate 1 (BAY 43-9006) were detected in plasma after
oral administration of the pro-drug Example 1 to mice.
By changing the nature of substituent Q in Formula (I), it is possible to impact the

25 stability, i.e., the speed of hydrolysis) of the prodrug, and therefore to modulate the
plasma exposure to the pharmacologically active compound. High stabilities will lead
to extended release of the drug, while low stabilities will contribute to high Cmax and
short duration of action.
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Table 1 contains a summary of the plasma concentrations and pharmacokinetic

parameters.
Time (Hours) Example 1 Intermediate 1

0.5 12.1 0.1
Mean Plasma
1 13.0 0.2
concentration (µM)
5 9.4 0.5
AUC (µM.hr) - 53.1 1.0
Cmax (µM) - 13.0 0.3
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What is claimed is:
1. A compound of formula I,
or a pharmaceutically acceptable salt thereof,

wherein
A and B are, independently, 5-10 membered cyclic moieties which are optionally
10 substituted with 1-4 substituents independently selected from the group consisting of
R1, OR1, NR 1R2, S(O)pR1, SO2NR 1R2, C(O)NR 1R2, C(NR 1)R 2, NR 1SO2R2, C(O)R1,
NR 1C(O)R 2, NR 1C(O)OR 2, halogen, cyano, and nitro, and A is additionally
1
C(O)OR ,
C3 to C5 linear or branched alkyl;

L is a bridging group selected from the group consisting of:
1s (a) -(CH2)m-O-(CH2)1-,
(b) -(CH2)m-(CH2)1-,
(c) -(CH2)m-C(O)-(CH2)1-,
(d) -(CH2)m-NR3-(CH2)1-,
3
(e) -(CH2)m-NR C(O)-(CH2)1-,
20 (f) -(CH2)m-S-(CH2)1-,
(g) -(CH2)m-C(O)NR3 -(CH2)1-,
(h) -(CH2)m-CFr(CH2)1-,
(i) -(CH2)m-CClr(CH2)1-,
U) -(CH2)m-CHF-(CH2)1-,
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(k) -(CH2)m-CH(OH)-(CH2)1-;
(I) -(CH2)m-C=C-(CH2)1-;and
(m) -(CH2)m-C=C-(CH2)1-;
wherein m and I are integers independently selected from 0-4,
5
Mis
5 4
the group consisting of R4, OR4, NR4 R5 , S(O)qR4, S0 2NR4 R5 , C(O)NR 4 R , C(NR )R5,
5
NR4 S0 2R5 , C(O)R4, C(O)OR4, NR4 C(O)R 5 , NR 4C(O)OR , halogen, cyano, and nitro;
10 (ii) naphthyl, optionally substituted with 1-3 substituents independently selected from
5 4 5
the group consisting of R4, OR4, NR4 R5, S(O)qR4, S0 2NR4 R5 , C(O)NR 4 R , C(NR )R ,
4 5 4 5 4 5
NR S0 2R , C(O)R4, C(O)OR4, NR C(O)R , NR C(O)OR , halogen, cyano, and nitro;
(iii) 5 and 6 membered monocyclic heteroaryl, having 1-3 heteroatoms
independently selected from the group consisting of 0, N and S, optionally
15 substituted with 1-3 substituents independently selected from the group consisting
4 5
R4 , OR4, NR4 R5, S(O)qR4 , S02NR 4R5, C(O)NR R5 , C(NR 4)R5, NR4S02R , C(O)R4,
C(O)OR4, NR 4 C(O)R 5 , NR4C(O)OR5, halogen, cyano, nitro and oxides;
20 substituents independently selected from the group consisting of R4, OR4, NR 4 R5 ,
S(O)qR4, S02NR 4 R5 , C(O)NR 4 R5, C(NR 4 )R 5 , NR'~S02 R5 , C(O)R4, C(O)OR4,
4 5 4
NR C(O)R , NR C(O)OR5, halogen, cyano, nitro and oxides;
(v) saturated and partially saturated C3-C7 monocyclic carbocyclic moiety optionally
5
25 R4, OR4, NR 4 R , S(O)qR4, S02NR 4 R5, C(O)NR 4 R5, C(NR 4)R 5, NR4S0 2 R5, C(O)R 4 ,
4 5 4
C(O)OR4, NR C(O)R , NR C(O)OR 5 , halogen, cyano, and nitro;
(vi) saturated and partially saturated Cs-C12 bicyclic carbocyclic moiety, optionally
4 5 4
R4, OR4, NR R , S(O)qR4, S02NR R5 , C(O)NR 4 R5 , C(NR 4 )R5, NR4S0 2R5 , C(O)R4,
30 C(O)OR4, NR 4C(O)R 5, NR4C(O)OR5, halogen, cyano, and nitro;
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(vii) saturated and partially saturated 5 to 7 membered monocyclic heterocyclic

moiety, having 1-3 heteroatoms independently selected from the group consisting of
O, N and S, optionally substituted with 1-3 substituents independently selected from
4 5 4 5
the group consisting of R4, OR4, NR4 R5, S(O)qR4,SO2 NR R5, C(O)NR4 R , C(NR )R ,
5 NR4 SQ R5, C(O)R4, C(O)OR4, NR4C(O)R5, NR4 C(O)OR5, halogen, cyano, nitro and
2
oxides (e.g. =O, -o- or-OH); or

(viii) saturated and partially saturated 7 to 12 membered bicyclic heterocyclic moiety,
having 1-6 heteroatoms independently selected from the group consisting of 0, N
and S, optionally substituted with 1-3 substituents independently selected from the
5 5
group consisting of R4, OR4, NR4 R5, S(O)qR4, SO2 NR4 R5, C(O)NR4 R , C(NR )R ,
4
10
NR4SO R5, C(O)R4, C(O)OR4, NR4C(O)R5, NR4 C(O)OR5, halogen, cyano, nitro and
2
oxides; and
each R1, R2 , R3 , R4, R5 and Q is, independently,

15 (a) hydrogen,
(b) C1-C5 linear, branched, or cyclic alkyl, optionally substituted with 1-3 substituents
independently selected from the group consisting of C1-C5 linear or branched alkyl,
up to perhalo substituted C1-C5 linear or branched alkyl, C1-C3 alkoxy, hydroxy,
carboxy, amino, C1-C3 alkylamino, C1-C5 dialkylamino, halogen, cyano, and nitro;
20 (c) phenyl, optionally substituted with 1-3 substituents independently selected from
the group consisting of C1-C5 linear or branched alkyl, up to perhalo substituted Cr
C5 linear or branched alkyl, C1-C3 alkoxy, hydroxy, carboxy, amino, C1-C3 alkylamino,
C1-C6 dialkylamino, halogen, cyano, and nitre;
(d) 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms selected from the
25 group consisting of 0, N and S or 8-10 membered bicyclic heteroaryl having 1-6
heteroatoms selected from the group consisting of 0, N and S, optionally substituted
with 1-3 substituents independently selected from the group consisting of C1-C5
linear or branched alkyl, up to perhalo substituted C1-C5 linear or branched alkyl, C1-
C3 alkoxy, hydroxy, carboxy, amino, C1-C3 alkylamino, C1-C6 dialkylamino, halogen,
30 cyano, and nitro;
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(e) C1-C3 alkyl-phenyl, optionally substituted with 1-3 substituents independently

selected from the group consisting of C1-Cslinear or branched alkyl, up to perhalo
substituted C1-C linear or branched alkyl, C1-C3alkoxy, hydroxy, carboxy, amino,
5
C1-C3 alkylamino, C1-C dialkylamino, halogen, cyano, and nitro;

6
5 (f) C1-C3 heteroaryl-alkyl having 1-4 heteroatoms selected from the group consisting
of 0, N and S, wherein said heteroaryl group is a 5-6 membered monocyclic
heteroaryl or a 8-10 membered bicyclic heteroaryl, optionally substituted with 1-3
substituents independently selected from the group consisting of C1-Cs linear or
branched alkyl, up to perhalo substituted C1-Cs linear or branched alkyl, C1-C3
10 alkoxy, hydroxy, carboxy, amino, C1-C3 alkylamino, C1-C5 dialkylamino, halogen,
cyano, and nitro; or
(g) up to per-halo substituted C -C linear, branched or cyclic alkyl and when not
1 5
perhalo substituted, optionally substituted with 1-3 substituents independently

selected from the group consisting of CrC 5 linear or branched alkyl, up to perhalo
15 substituted C1-Cs linear or branched alkyl, C1-C3 alkoxy, hydroxy, carboxy, amino,
C1-C3alkylamino, C1-C5dialkylamino, halogen, cyano, and nitro.
2. A compound as in claim 1 wherein A is

20 the group consisting of R1, OR1, NR1R S(O)pR1,SO NR1R NR1SO R C(O)R1,
2
,
2
2
,
2
2
C(O)OR1, C(O)NR R NR C(O)R NR C(O)OR halogen, cyano, and nitro;

1 2
,
1 2
,
1 2
the group consisting of R1, OR1, NR1R2 , S(O)pR1, SO NR1R2 , NR1SO R2 , C(O)R1, 2 2
C(O)OR1, C(O)NR1R2 , NR1C(O)R2 , NR1C(O)OR2 , halogen, cyano, and nitro;

25 (iii) 5 and 6 membered monocyclic heteroaryl, having 1-3 heteroatoms independently
substituents independently selected from the group consisting of R1, OR1, NR R 1 2
S(O)pR1, SO2NR1R2, NR1SO2R2 , C(O)R1, C(O)OR1, C(O)NR1R2, NR1C(O)R2,

NR1C(O)OR2, halogen, cyano, and nitro;
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1 1 1 2
substituents independently selected from the group consisting of R , OR , NR R ,
1 2 1
S(O)pR1, SO NR1R2 , NR1SO2R2 , C(O)R1, C(O)OR1, C(O)NR R , NR C(O)R ,
2
2
5 NR1C(O)OR2 , halogen, cyano, and nitro; or

(v) a group of the formula
consisting of R1, OR1, NR1R2 , S(O)pR1, SO2NR R NR SO2R C(O)R C(O)OR
1 2 1 1
1 2
10 , , , ,
C(O)NR1R2 , NR1C(O)R2 , NR1C(O)OR2 , halogen, cyano, and nitro.
3. A compound as in claim 1 or 2 wherein B is

(i) phenyl or naphthyl, optionally substituted with 1-3 substituents independently
15 selected from the group consisting of C1-C5linear or branched alkyl, C1~C5linear or
branched haloalkyl up to perhalo, C1-C3alkoxy, CrC 3 haloalkoxy up to per
haloall<oxy,hydroxy, amino, C1-C3 alkylamino, C1-C6 dialkylamino, halogen, cyano,
and nitro; or
(ii) 5-6 membered monocyclic heteroaryl groups, having 1-4 heteroatoms
20 independently selected from the group consisting of 0, N and S, optionally
C1-C5linear or branched alkyl, CrC 5 linear or branched haloalkyl up to perhalo, C1-
C3 alkoxy, C 1-C3 haloalkoxy up to per haloalkoxy, hydroxy, amino, C1-C3 alkylamino,
C1-C6 dialkylamino, halogen, cyano, and nitro.
25
4. A compound as in claim 1 or 2 wherein Bis phenyl, naphthyl, or pyridyl,

69
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consisting of C1-C5 linear or branched alkyl, C1-Cs linear or branched haloalkyl, C1-C3
alkoxy, hydroxy, amino, C1-C3 alkylamino, C1-C5 dialkylamino, halogen, cyano, and
nitro.
5 5. A compound as in claim 1, 2, 3 or 4 where M is

(i) 5 and 6 membered monocyclic heteroaryl, having at least one nitrogen atom,
optionally substituted with 1-3 substituents independently selected from the. group
consisting R4, OR4, NR4 R5 , S(O)qR4,SO2NR4 R5, C(O)NR4 R5 , C(NR4 )R5, NR4 SO2R5.
C(O)R4, C(O)OR4, NR4 C(O)R5 , NR4 C(O)OR5 , halogen, cyano, nitro and oxides;
10 (ii) 8 to 10 membered bicyclic heteroaryl, having at least one nitrogen atom,
consisting of R4, OR4, NR4 R5 , S(O)qR4, SO2NR4 R5 , C(O)NR4 R5 , C(NR4 )R5 ,
NR4 SO2 R5 , C(O)R4, C(O)OR4, NR4 C(O)R5, NR4 C(O)OR5 , halogen, cyano, nitro and
oxides (e.g. =O, -o- or-OH);
15 (iii) saturated and partially saturated 5 to 7 membered monocyclic heterocyclic
moiety, having at least one nitrogen atom, optionally substituted with 1-3
substituents independently selected from the group consisting of R4, OR4, NR4 R5 ,
4
S(O)qR4, SO2NR R5 , C(O)NR4 R5 , C(NR4 )R5 , NR4 SO2R5 , C(O)R4, C(O)OR4,
4 4
NR C(O)R5, NR C(O)OR 5 , halogen, cyano, nitro and oxides (e.g. =O, -o- or -OH);
20 or
(iv) saturated and partially saturated 7 to 12 membered bicyclic heterocyclic moiety,
having at least one nitrogen atom, optionally substituted with 1-3 substituents
independently selected from the group consisting of R4, OR4, NR4 R5, S(O)qR4,
4 5
SO2NR R , C(O)NR4 R5, C(NR4 )R5 , NR4 SO2 R5, C(O)R4, C(O)OR4, NR4 C(O)R5,
4
25 NR C(O)OR5, halogen, cyano, nitro and oxides.
6. A compound as in claim 1, 2 or 3 wherein M is optionally substituted

pyridine, quinoline, morpholine, indazole, isoquinoline, pyrimidine, or benzimidazole.
30
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7. A compound as in claim 1, 3 or 5 wherein A is optionally substituted

furyl, thienyl, thiadiazolyl, pyrrolyl, pyrazolyl, isoxazolyl, pyridyl, pyrimidyl, pyridazinyl,
pyrazinyl, quinolyl, indazolyl, benzimidazolyl, phenyl, tetrahydro-4H-
benzo[1,3]dioxinyl or naphthyl.
5
8. A compound as in claim 1 wherein A is optionally substituted furyl,

thienyl, thiadiazolyl, pyrrolyl, pyrazolyl, isoxazolyl, pyridyl, pyrimidyl, pyridazinyl,
pyrazinyl, quinolyl, isoquinolyl, indazolyl, benzimidazolyl, phenyl, tetrahydro-4H-
benzo[1,3]dioxinyl or naphthyl, and
10 B is optionally substituted phenyl, naphthyl, quinolyl, or pyridyl.
9. A compound as in claim 1 wherein B is optionally substituted by one or

more of methyl, trifluoromethyl, ethyl, n-propyl, n-butyl, n-pentyl, i-propyl, t-butyl,
methoxy, ethoxy, propoxy, Cl, Br, F, cyano, nitro, hydroxy, amino, methylamino,
15 dimethylamino, ethylamino or diethylamino.
10. A compound as in claim 1 or 9 wherein A is optionally substituted by

one or more of methyl, trifluoromethyl, ethyl, n-propyl, n-butyl, n-pentyl, isopropyl,
terl-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, 4-methyl-phenyl,
20 methoxy, ethoxy, propoxy, Cl, Br , F, cyano, nitro, hydroxy, amino, methylamino,
dimethylamino, ethylamino or diethylamino.
11. A compound as in claim 1 where L is -0- and M is optionally substituted

morpholine, pyridine, quinoline, isoquinoline, benzimidazole, indazole, or pyrimidine.
25
12. A compound as in claim 1 wherein

A is optionally substituted phenyl or tetrahydro-4H-benzo[1,3]dioxinyl,
B is phenyl or naphthyl, optionally substituted with halogen,
Lis -0-,
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and M is optionally substituted pyridine, quinoline, isoquinoline, benzimidazole,

indazole, or pyrimidine.
13. A compound as in claim 1 wherein

s A is optionally substituted pyrazolyl,
B is phenyl or naphthyl, optionally substituted with halogen,
L is -(CH2 )m-O-(CH2 ) 1-, and M is morpholine.
14. A compound which releases a urea of the formula
A"-._
N
I
Jl /N
I
B "--
L
/ M
H H
when administered to a patient, wherein A, B, Land M are as defined in claim1.
15. A compound as in claim 1 which releases a urea of the formula
15
when administered to a patient.
16. A compound as in claim 2 which releases a urea of the formula

20
72
IITRUE COPY!I
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A'-----._
N
Jl /N
B '-----./
L
M
I I
H H
when administered to a patient.
s 17. A compound is in claim 1 which releases N-(4-chloro-3-

(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyl oxy)-2-fluoro-phenyl)
urea, or N-(6-(2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxinyl))-N'-(4-(2-cyano-4-pyridyloxy)
phenyl) urea, when administered to a patient.
10 18. A compound as in claim 1

wherein A is 2-(4-methyl-phenyl)-5-tert-butyl-2H-pyrazole-3-yl,Bis naphthyl, L
is -O-(CH 2 )2- and M is rnorpholine, which releases 1-(5-tert-butyl-2-(4-methyl-phenyl)-
2H-pyrazole-3-yl)-3-[4-(2-morpholinylethoxy)naphthalene-1-yl]ureawhen
administered to a patient.
15
19. A compound as in claim 1
wherein A is 3-trifluoramethylA-chlaro-phenyl, B is phenyl, L is -0- and M is 2-
methylcarbamoyl-pyridine-4-yl, which releases N-(4-chloro-3-(trifluoromethyl)phenyl)-
N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea when administered to a
20 patient.
20. A compound which is:

• 1-(4-chloro-3(trifluoromethyl)phenyl)-3-(4-(2-(N-methylcarbamoyl)-4-
(pyridyloxy)phenyl)-2-oxo-( 1,3,5-perhyd rotriazapine)
25 • -{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-5-(2-methoxy-ethyl)-2-oxo-
[1 ,3,5]triazinan-1-yl]-3-fluoro-phenoxy}-pyrid ine-2-carboxylic acid methyl amide
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• 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-5-(2-hydroxy-ethyl)-2-oxo-
[1,3,5]triazinan-1-yl]-3-fluoro-phenoxy}-pyridine-2-carboxylic acid methylamide
• 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-5-(3-hydroxy-propyl)-2-oxo-
[1,3,5]triazinan-1-yl]-3-fluoro-phenoxy}-pyridine-2-carboxylic acid methylamide
s • 4-{3-fluoro-4-[5-methyl-2-oxo-3-(2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxin-6-yl)-
[1,3,5]triazinan-1-yl]-phenoxy}-pyridine-2-carbonitrile or
• 4-{3-fluoro-4-[5-methyl-2-oxo-3-(2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxin-6-yl)-
[1,3,5]triazinan-1-yl]-phenoxy}-pyridine-2-carboxylic acid methylamide
10 21. The compound which is 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(2-

(N-methylcarbamoyl)-4-pyridyloxy)phenyl)-2-oxo-(1,3,5-perhydrotriazapine) which
releases N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)phenyl) urea (BAY 43-9006) when administered to a patient.
15 22. A pharmaceutical composition with an effective amount of at least one

compound of claim1 and a physiologically acceptable carrier.
23. A method for treating or preventing a hyper-proliferative disorder in a

human or other mammal comprising administering to a human or other mammal in
20 need thereof a compound of claim 1.

need thereof a compound of claim 1 and an additional anti-proliferative agent.
25

need thereof a compound of claim 1 and a cytotoxic agent or cytostatic
chemotherapeutic agent.
30
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26. A method for treating or preventing a disease in a human or other

mammal regulated by tyrosine kinase, associated with an aberration in the tyrosine
kinase signal transduction pathway, comprising administering to a human or other
mammal in need thereof a compound of claim 1.
5

mammal mediated by the VEGF-induced signal transduction pathway, comprising
administering to a human or other mammal in need thereof a compound of claim 1.
10 28. A method for treating or preventing a disease in a human or other

mammal characterized by abnormal angiogenesis or hyperpermeability processes,
comprising administering to a human or other mammal in need thereof a compound
of claim 1.
15 29. A method for treating or preventing a disease in a human or other

mammal characterized by abnormal angiogenesis or hyperpermeability processes,
comprising administering to a human or other mammal in need thereof a compound
of claim 1, a salt form of a compound of simultaneously with another angiogenesis
inhibiting agent in the same formulation or in separate formulations.
20
30. A method for treating or preventing one or more of the following

conditions in humans and/or other mammals: tumor growth, retinopathy, ischemic
retinal-vein occlusion, retinopathy of prematurity, age related macular degeneration;
rheumatoid arthritis, psoriasis, a bolos disorder associated with subepidermal blister
25 formation, including bullous pemphigoid, erythema multiforme, or dermatitis
herpetiformis,
comprising administering to a human or other mammal in need thereof a
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conditions in humans and/or other mammals: tumor growth, retinopathy, ischemic
retinal-vein occlusion, retinopathy of prematurity, age related macular degeneration;
rheumatoid arthritis, psoriasis, a bullous disorder associated with subepidermal
5 blister formation, including bullous pemphigoid, erythema multiforme, or dermatitis
herpetiformis in combination with another condition selected from the group
consisting of:
rheumatic fever, bone resorption, postmenopausal osteoporosis, sepsis,
gram negative sepsis, septic shock, endotoxic shock, toxic shock syndrome,
10 systemic inflammatory response syndrome, inflammatory bowel disease (Crohn's
disease and ulcerative colitis), Jarisch-Herxheimer reaction, asthma, adult respiratory
distress syndrome, acute pulmonary fibrotic disease, pulmonary sarcoidosis, allergic
failure, liver disease during acute inflammation, severe alcoholic hepatitis, malaria
15 (Plasmodium falciparum malaria and cerebral malaria), non-insulin-dependent
sclerosis (demyelation and oligiodendrocyte loss in multiple sclerosis), advanced
20 inflammation and cancer, myelodysplastic syndromes, systemic lupus
erythematosus, biliary cirrhosis, bowel necrosis, radiation injury/ toxicity following
administration of monoclonal antibodies, host-versus-graft reaction (ischemia
reperfusion injury and allograft rejections of kidney, liver, heart, and skin), lung
allograft rejection (obliterative bronchitis) and complications due to total hip
25 replacement,

30 conditions in humans and/or other mammals: tumor growth, retinopathy, diabetic
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retinopathy, ischemic retinal-vein occlusion, retinopathy of prematurity, age related

macular degeneration; rheumatoid arthritis, psoriasis, bullous disorder associated
with subepidermal blister formation, bullous pemphigoid, erythema multiforme, and
dermatitis herpetiformis,
5 in combination with an infectious disease selected from the group consisting
of:
disease resulting from Trypanosoma cruzi infection, effects of Shiga-like toxin
resulting from E. coli infection, effects of enterotoxin A resulting from Staphylococcus
10 infection, meningococcal infection, and infections from Borrelia burgdorferi,
Treponema pallidum, cytomegalovirus, influenza virus, Theiler's encephalomyelitis
virus, and the human immunodeficiency virus (HIV),
compound of claim I.
15

mammal mediated by the VEGF-induced signal transduction pathway comprising
administering the compound 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(2-(N-
20 methylcarbamoyl)-4-pyridyloxy)phenyl)-2-oxo-(1,3,5-perhydrotriazapine).

mammal administering the compound 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(2-
(N-methylcarbamoyl)-4-pyridyloxy)phenyl)-2-oxo-(1,3,5-perhydrotriazapine).
25
35. A method for treating or preventing p38 mediated diseases, comprising

administering a compound of formula I wherein A is 2-(4-methyl-phenyl)-5-tert-butyl-
2H-pyrazole-3-yl, B is naphthyl, L is -O-(CH2 )z- and M is morpholine, which releases
1-(5-tert-butyl-2-(4-methyl-phenyl)-2H-pyrazole-3-yl)-3-[4-(2-
30 morpholinylethoxy)naphthalene-1-yl]urea (BIRB 796) as an active ingredient.
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36. A method for treating or preventing inflammatory and

immunomodulatory diseases, such as rheumatoid arthritis, osteoarthritis, psoriasis,
acute rheumatic fever, sepsis, septic shock, endotoxic shock, toxic shock syndrome,
s systemic inflammatory response syndrome, inflammatory bowel diseases including
Crohn's disease, ulcerative colitis, Jarisch-Herxheimer reactions, asthma, adult
respiratory distress syndrome, acute pulmonary fibrotic diseases, chronic obstrusive
pulmonary disease, septic arthritis, degenerative cartilage loss following traumatic
joint injury, osteopenias mediated by MMP activity, and tempera mandibular joint
10 disease, comprising administering a compound of formula I wherein A is 2-(4-methyl-
phenyl)-5-terl-butyl-2H-pyrazole-3-yl, B is naphthyl, L is -O-(CH2 )z- and M is
morpholine, which releases 1-(5-tert-butyl-2-(4-methyl-phenyl)-2H-pyrazole-3-yl)-3-
[4-(2-morpholinylethoxy)naphthalene-1-yl]urea (BIRB 796) as an active ingredient.
15 37. A method for treating or preventing a disease which is a VEGF

mediated disorder which comprises administering a compound of Formula I, a salt
form of a compound of Formula I, or an isomer of a compound of claim 1.
38. A method for regulating the tyrosine kinase signal transduction

20 comprising administering to a human or other mammal a compound of claim 1.
39. A compound of formula I:
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wherein
A of formula I is phenyl, optionally substituted with 1-3 substituents independently
1 2
selected from the group consisting of R1, OR1, NR R2 , S(O)pR1, S0 NR R ,
1
2
5 NR1S0 2 R2 , C(O)R1, C(O)OR1, C(O)NR1R2 , NR1C(O)R2 , NR1C(O)OR2 , halogen,

cyano, and nitro;
B is phenyl, optionally substituted with 1-3 substituents independently selected from

the group consisting of C1-C5 linear or branched alkyl, C1-Cs linear or branched
10 haloalkyl up to perhalo, C1-Ca alkoxy, C 1-Ca haloalkoxy up to per haloalkoxy,
Lis -0- or-S-,
15 M is phenyl, pyridine, quinoline, morpholine, indazole, isoquinoline, pyrimidine, or

benzimidazole, optionally substituted with 1-3 substituents independently selected
from the group consisting of R4, OR4, NR4 R5, S(O)qR4, S0 2 NR4 R5 , C(O)NR4 R5 ,
C(NR4 )R5, NR4S0 2 R5 , C(O)R4, C(O)OR4, NR4 C(O)R5 , NR4 C(O)OR5, halogen,
cyano, and nitro;
20
2
each R1,R , R4. R5 and Q is independently selected from the group consisting of:
(a) hydrogen,
(b) C1-Cs linear, branched, or cyclic alkyl,
(c) C1-Cslinear or branched hydroxy alkyl,
25 (d) C1-Cslinear or branched alkoxy substituted - C1-C5 linear or branched alkyl,
(e) phenyl,
(f) pyridinyl
(g) C1-Caalkyl-phenyl,
(h) CrCa alkyl-pyridinyl or
30 (i) up to per-halo substituted C1-C5 linear, branched or cyclic alkyl and
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40. A compound of claim 39 wherein, Mis phenyl or pyridine.

5
10 A of formula I is pyridinyl, optionally substituted with 1-3 substituents independently

selected from the group consisting of R1, OR1, NR R S(O)pR1, SO NR R
1 2 1 2
, ,
2
NR1SO2R2, C(O)R1, C(O)OR1, C(O)NR1R2, NR1C(O)R2, NR1C(O)OR2, halogen,

cyano, and nitro;
15 B is phenyl, optionally substituted with 1-3 substituents independently selected from

the group consisting of C1-C5 linear or branched all<yl, C1-Cs linear or branched
haloalkyl _up to perhalo, C1-C3 alkoxy, C1-C3 haloalkoxy up to per haloalkoxy,
20 Lis -0- or-S-,
M is phenyl, pyridine, quinoline, morpholine, indazole, isoquinoline, pyrimidine, or

benzimidazole, optionally substituted with 1-3 substituents which independently are
R4, OR4, NR4 R5 , S(O)qR4,SO2NR4 R5 , C(O)NR4 R5 , C(NR4 )R5, NR4 SO2R5. C(O)R4,
25 C(O)OR4, NR4 C(O)R5, NR4C(O)OR5 , halogen, cyano, or nitro;
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each R1, R2 , R4, R5 and Q is independently:

(a) hydrogen,
(b) C1-C5 linear, branched, or cyclic alkyl,
5 (c) C1-C5 linear or branched hydroxy alkyl,
(e) phenyl,
(f) pyridinyl
10 (h) C 1-C3 alkyl-pyridinyl or
(i) up to per-halo substituted C1-C5linear, branched or cyclic alkyl and
42. A compound of claim 41 wherein Mis phenyl or pyridine.

• 15
20 or a pharmaceutically acceptable salt thereof,

wherein
A of formula I is pyrazole, optionally substituted with 1-3 substituents independently
selected from the group consisting of R1, OR1, NR R2, S(O)pR SO2NR R
1 1
,
1 2
1 2
NR SO2R , C(O)R1, C(O)OR1, C(O)NR1R2, NR1C(O)R2, NR1C(O)OR2 , halogen,
25 cyano, and nitre;
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B is phenyl or naphthyl, optionally substituted with 1-3 substituents independently

selected from the group consisting of C1-C5 linear or branched alkyl, C1-Cs linear or
branched haloalkyl up to perhalo, C1-C3 alkoxy, C1-C3 haloalkoxy up to per
5 haloalkoxy, hydroxy, amino, C1-C3alkylamino, C1-C5dialkylamino, halogen, cyano,
and nitro;
Lis -0- or-S-,
10 M is phenyl, pyridine, quinoline, morpholine, indazole, isoquinoline, pyrimidine, or

benzimidazole, optionally substituted with 1-3 substituents which independently are
R4, OR4, NR4 R5 , S(O)qR4, SO2NR4 R5 , C(O)NR4 R5 , C(NR4 )R5, NR4SO2R5. C(O)R4,
C(O)OR4, NR4C(O)R5 , NR4C(O)OR5 , halogen, cyano, or nitro;
15 each R1, R2 , R4, R5 and Q is independently:

(a) hydrogen,
(b) C1-Cs linear, branched, or cyclic alkyl,
(c) C1-Cslinear or branched hydroxy alkyl,
(d) C1-Cslinear or branched alkoxy substituted - C1-C5 linear or branched alkyl,
20 (e) phenyl,
(f) pyridinyl
(i) up to per-halo substituted C1-Cslinear, branched or cyclic alkyl and
44. A compound of claim 43 wherein M is phenyl or pyridine.

30
82
IITRUE COPYII
WO 2004/078746 PCT/US2004/006283

wherein
s A is phenyl, optionally substituted with 1-3 substituents independently selected from
the group consisting of R1, OR1 and halogen;

the group consisting of C1-C5 linear or branched alkyl, C1-C5 linear or branched
10 haloalkyl up to perhalo, C1-C3 alkoxy, C1-C3 haloalkoxy up to per haloalkoxy,
L is -0- or -S-:
15 M is pyridinyl, optionally with 1-3 substituents independently selected from the group
consisting R4, OR4, NR4R5, S(O)qR4 , S02NR4 R5, C(O)NR4 R5, C(NR4)R5, NR4S0 R5, 2
C(O)R4, C(O)OR4, NR C(O)R5, NR4 C(O)OR5, halogen, cyano, nitro and oxides;
4
each R4 , R5 and Q is independently :

20 (a) hydrogen,
(c) C1-C5linear or branched hydroxy alkyl,
(d) C1-C5linear or branched alkoxy substituted - CrC 5 linear or branched alkyl,
(e) phenyl,
83
IITRUE COPYII
WO 2004/078746 PCT/0S2004/006283
(f) pyridinyl,
(g) CrC3 alkyl-phenyl,
(i) up to per-halo substituted C 1-Cs linear, branched or cyclic alkyl and
s the variables p and q are integers independently selected from 0, 1, or 2.
10

wherein
A is of the formula X:
15
where A is optionally substituted with 1-4 substituents independently selected from

the group consisting of R1, OR1, NR R 1 2
, S(O)pR1, SO NR R2
1 2
, NR SO R
1
2
2
, C(O)R1,
20 C(O)OR1, C(O)NR R NR C(O)R NR C(O)OR
1 2
,
1 2
,
1 2
, halogen, cyano, and nitro,

84
IITRUE COPYII
WO 2004/078746 PCT /0S2004/006283

the group consisting of C1-C5 linear or branched alkyl, C1-C5 linear or branched
5 hydroxy, amino, C 1-C3 alkylamino, C1-C5 dialkylamino, halogen, cyano, and nitro;
L is -0- or -S-:
Mis:
10 (i) phenyl, optionally substituted with 1-3 substituents independently selected from
the group consisting of R4, OR4, NR4 R5, S(O)qR4,SO NR4 R5, C(O)NR4 R5, C(NR4 )R5,
2
NR SO2 R5, C(O)R4, C(O)OR4, NR4C(O)R5, NR4 C(O)OR5, halogen, cyano, and nitro;
4
or
(ii) pyridinyl optionally with 1-3 substituents independently selected from the group
15 consisting R4, OR4, NR4 R5, S(O)qR4,SO NR4 R5, C(O)NR4 R5, C(NR4)R5, NR4SO R5,
2 2
C(O)R , C(O)OR4, NR4 C(O)R5, NR C(O)OR5, halogen, cyano, nitro and oxides;
4 4
where R4. R5 and Q are independently :

(a) hydrogen,
(b) C1-C5 linear, branched, or cyclic alkyl,
20 (c) C1-C5linear or branched hydroxy alkyl,
(d) C1-C5 linear or branched alkoxy substituted~ C 1-C5 linear or branched alkyl,
(e) phenyl,
(f) up to per-halo substituted C1-C5 linear, branched or cyclic alkyl,
and the variables p and q are integers independently selected from 0, 1, or 2.
25
30
85
IITRUE COPY!I

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IN THE HIGH COURT OF DELHI AT NEW DELHI

(Original Commercial Jurisdiction – IP Division)

CS (Comm.) No. 660 of 2022

In the matter of:

LIST OF DOCUMENTS FILED ON BEHALF OF

CS (Comm.) No. 660 of 2022

In the matter of:

LIST OF DOCUMENTS FILED ON BEHALF OF

Legal Status : Inforce

Due date of next renewal : 22/07/2023

Patent Number : 240207 Date of Patent : 22/07/2004

Application Number : 402/DELNP/2006 Date of Grant : 29/04/2010

Type of Application : PCT NATIONAL PHASE APPLICATION Date of Recordal : 29/04/2010

Parent Application : --- Appropriate Oﬃce : DELHI

PCT International : PCT/US2004/023500 PCT International Filing Date : 22/07/2004

Grant Title : "A FLUORO SUBSTITUTED OMEGA-CARBOXYARYL DIPHENYL UREA COMPOUND OR

1 BAYER HEALTHCARE LLC 555 WHITE PLAINS ROAD,TARRYTOWN,NEW YORK 10591,USA

Information u/s 146 (Working of Patents)

1 240207 2013-2014 View Document

2 240207 2014-2015 View Document

3 240207 2015-2016 View Document

4 240207 2016-2017 No Document

5 240207 2017-2018 View Document

6 240207 2018-2019 View Document

7 240207 2019-2020 View Document

1. We, BAYER PHARMACEUTICALS CORPORATION, a corporation

2. JACQUES DUMAS, a French citizen of 98 Farmview Road,

3. "FLUORO SUBSTITUTED OMEGA-CARBOXYARYL DIPHENYL

4. That our address for service in India is:

[e] "FLUORO SUBSTITUTED OMEGA-CARBOXYARYL DIPHENYL

6. Particulars for filing National phase application

JACQUES DUMAS STEPHEN BOYER

BERND RIEDL SCOTT WILHELM

Declaration by the applicant(s):

I/We, the applicant(s) hereby declare(s) that:-

Dated this 23/1/2006

BAYER PHARMACEUTICALS CORPORATION,

THE CONTROLLER OF PATENTS,

1. We, BAYER PHARMACEUTICALS CORPORATION, a corporation

2. JACQUES DUMAS, a French citizen of 98 Farmview Road,

3. "FLUORO SUBSTITUTED OMEGA-CARBOXYARYL DIPHENYL

4. That our address for service in India is:

[e] "FLUORO SUBSTITUTED OMEGA-CARBOXYARYL DIPHENYL

6. Particulars for filing National phase application

JACQUES DUMAS STEPHEN BOYER

BERND RIEDL SCOTT WILHELM

Declaration by the applicant(s):

I/We, the applicant(s) hereby declare(s) that:-

Dated this 23/1/2006

BAYER PHARMACEUTICALS CORPORATION,

THE CONTROLLER OF PATENTS,

[i] We JACQUES DUMAS, a French citizen, of 98 Fannview Road, Bethany, CT

Country Filing date Application no. Status Publicati Grant Patent

Dated this 5th day of January, 2010.

Armenia 200600317 010485

Azeftlc$!n 200600317 010485 Gralted

Ctina 200480021091.1 ~ished

Jamaica 18/1/4339 3663