Supporting Information

 Copyright Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2009

Modulation on C- and N-Terminal Moieties of a Series of

Potent and Selective Linear Tachykinin NK2 Receptor
Antagonists
Martina Gensini,*[a] Maria Altamura,[a] Tula Dimoulas,[a] Valentina Fedi,[a] Danilo Giannotti,[a]
Sandro Giuliani,[b] Antonio Guidi,[a] Nicholas J. S. Harmat,[a] Stefania Meini,[b]
Rossano Nannicini,[a] Franco Pasqui,[a] Manuela Tramontana,[b] Antonio Triolo,[a] and
Carlo Alberto Maggi[b]

cmdc_200900389_sm_miscellaneous_information.pdf
 Supporting Information

Table of Contents

1. Synthetic Procedures and Compound Characterization Data

2. cLog D and cLog P Data Tables

1. Synthetic Procedures and Compound Characterization Data

1.1 General Notes

All reagents and solvents were used without further purification or drying. All reagents were
purchased from Sigma-Aldrich (Milan, Italy) unless otherwise specified. Commercial grade
anhydrous solvents were purchased from J. T. Baker (Deventer, Holland). Naphthalene-2-
carboxylic acids 9, 22, 23, 26, 34e-k, benzo[b]furan-2-carboxylic acid, 5-chloro-, 5-bromo- and 5-
methoxy-benzo[b]furan-2-carboxylic acid were commercially available. Reactions were performed
under an atmosphere of nitrogen, unless otherwise specified. Silica gel (Merck, Kieselgel 60) was
used for analytical thin-layer chromatography (TLC, F254 plates) and flash chromatography (230-
400 mesh). Melting points were measured in capillary tubes with a digital elecrothermal apparatus
Buchi B-540 and were uncorrected. 1H NMR spectra were acquired on a Varian 200 MHz and 600
MHz instruments and recorded in parts per million (ppm) δ values, relative to CHCl3 (δ 7.27),
CH3OH (δ 3.31) or DMSO (δ 2.50) as the internal standards. The data were processed using the
program MestReC 4.9.9.9. The LC–MS system was a Thermofinnigan LCQ mass spectrometer,
interfaced with an Agilent series 1100 liquid chromatograph, with binary pump, well-plate sampler,
column thermostat and diode-array UV detector. Either Electrospray (ESI) or Atmospheric Pressure
Chemical Ionization (APCI) were used as the ionization techniques. Ion polarity was positive,
unless otherwise specified. The samples were analyzed by MS and data-dependent tandem MS,
using an isolation width of 2 Th, an activation q of 0.25, and a relative normalized collision energy
of 30–35%. Chromatographic separation was achieved using a Luna® C8-2 column (Phenomenex, 3
µm, length of 7.5 cm, internal diameter of 4.6 mm). The mobile phases A and B were 0.1% TFA in
water and 0.1% TFA in acetonitrile, respectively. A gradient elution was performed from 5% to
95% B in 3 minutes, followed by a 2 minutes isocratic step at 95% B, at a flow rate of 1 mL/min.
Two UV signals, at wavelengths 220 and 270 nm, were also monitored. The HRMS system was a

1
Micromass Q-Tof micro mass spectrometer, equipped with Electrospray ion source with LockSpray
nebulizer, interfaced with an Agilent series 1200 liquid chromatograph, with binary pump, well-
plate sampler, column thermostat and variable wavelength UV detector. The mass spectrometer was
calibrated with 0.1% phosphoric acid in H2O/MeCN 1:1. This mixture was used also as internal
reference compound during ESI-MS accurate mass experiments and was introduced via the
LockSpray channel using an infusion pump. Chromatographic separation was achieved using a
Synergi Fusion column (Phenomenex, 2 µm, length of 2.0 cm, internal diameter of 2.0 mm). The
mobile phases A and B were 0.1% formic acid in water and 0.1% formic acid in acetonitrile,
respectively. A gradient elution was performed from 30% to 95% B in 0.1 minutes, at a flow rate of
0.2 mL/min. HPLC were recorded using the following methods. Method (A) parameters are as
follows: HP-1100 Agilent analytic HPLC system, Zorbax® SB-18 (Agilent), 100 Å, 50 x 4.6 mm,
H2O + 0.1% TFA / MeCN + 0.1% TFA, 95/5 → 5/95 in 6.5 min + 1 min isocratic, flow rate
3mL/min, λ = 220 nm. Method (B) parameters are as follows: Waters 2695 analytic HPLC system
Symmetry® C18 (Waters), 100 Å, 5 micron, 250 x 4.6 mm, H2O + 0.1% TFA / MeCN + 0.1% TFA,
85/15 → 5/95 in 20 min, flow rate 1 mL/min, λ = 220. The HPLC purities of tested compounds,
observed at 220 and 280 nm, were ≥95% and are reported after the retention time values.

1.2 Compounds corresponding to Scheme 1

6-Amino-7-bromo-naphthalene-2-carboxylic acid methyl ester (4). Bromine (1.3 mL, 24.70

mmol) was added dropwise to a solution of methyl ester 3 (2.00 g, 9.89 mmol) in AcOH (36 mL)
and heated at 50°C. Then sodium acetate (1.60 g, 19.80 mmol) was added and the mixture was
heated at 50°C for 2.5 h. Further bromine (0.5 mL, 9.90 mmol) and sodium acetate (0.80 g, 9.90
mmol) were added and the mixture heated for 1 h. Then AcOH (70 mL), a 48% aq. HBr solution
(69 mL, 0.61 mol) and sodium sulfite (14.90 g, 0.12 mol) were added. The reaction mixture was
refluxed for 30 minutes and left without stirring overnight. A 10% aq. NaOH solution was added to
pH 5, aqueous phase was extracted with dichloromethane several times and the combined organic
extracts were filtered though a IST phase separator column. The solvent was removed under
reduced pressure, the residue was treated with n-hexane and the solvent removed under reduced
pressure. The aqueous phase containing a precipitate was filtered off and the black solid was
combined with the residue. The latter was dissolved in MeOH (76 mL) and thionyl chloride (1.1
mL, 14.80 mmol) was added dropwise to this solution. The mixture was stirred at room temperature
for 3 h and then refluxed for 3 h. Then the solvent was removed under reduced pressure and the
residue was treated with diethyl ether and a 10% aq. K2CO3 solution. The organic phase was
2
separated and washed with a 10% aq. K2CO3 solution, dried over Na2SO4 and, after removal of the
solvent under reduced pressure, compound 4 (2.64 g, 95%) was obtained as an oil. HPLC: (B) 15.8
min, 98% purity; 1H NMR (600 MHz, [D6]DMSO): δ = 8.38 (s, 1H), 8.29 (s, 1H), 7.79 (dd, J = 8.7,
1.7 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.11 (s, 1H), 5.94 (br s, 2H), 3.86 ppm (s, 3H); MS (ESI): m/z
calcd for C12H10BrNO2: 279, found: 280.1 [M+H]+.

7-Bromo-naphthalene-2-carboxylic acid methyl ester (5). A mixture of compound 4 (272 mg,

0.97 mmol) in DMF (6 mL) was added to a solution of tert-butyl nitrite (173 L, 1.40 mmol) in
DMF (1.5 mL) heated at 50°C. Heating was maintained for 1 h, then diethyl ether (40 mL) was
added at room temperature and the organic phase was washed with a 20% aq. HCl solution (3 × 30
mL), dried over Na2SO4 and the solvent was removed under reduced pressure to give ester 5 (207
mg, 80%). 1H NMR (200 MHz, CD3OD): δ = 8.57 (bs, 1H), 8.23 (d, J = 1.9 Hz, 1H), 8.06 (dd, J =
8.6, 1.6 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.71 (dd, J = 8.8, 1.9 Hz, 1H),
3.97 ppm (s, 3H).

6-Diethylamino-naphthalene-2-carboxylic acid methyl ester (7). Iodoethane (EtI, 1.7 mL, 21.00
mmol) and K2CO3 (0.92 g, 6.70 mmol) were added to a solution of methyl ester 3 (250 mg, 1.24
mmol) in acetonitrile (74 mL), then the reaction mixture was heated to reflux for 7 h. Further
iodoethane (0.8 mL, 10.50 mmol) was added and the mixture refluxed for 7 h. The procedure of
adding 0.8 mL of iodoethane and refluxing for 7 h was repeated for further six times. The solvent
was removed under reduced pressure and the residue was treated with ethyl acetate. The organic
phase was washed with a saturated aqueous (sat. aq.) NaHCO3 solution, dried over Na2SO4 and,
after removal of the solvent under reduced pressure, diethylamino derivative 7 (280 mg, 97%) was
obtained as a brown solid. HPLC: (B) 10.1 min, 92% purity; 1H NMR (200 MHz, CD3OD): δ =
8.36 (br s, 1H), 7.85–7.75 (m, 2H), 7.59 (d, J = 8.7 Hz, 1H), 7.19 (dd, J = 9.2, 2.6 Hz, 1H), 6.91–
6.88 (m, 1H), 3.91 (s, 3H), 3.53 (q, J = 7.0 Hz, 4H), 1.24 ppm (t, J = 7.0 Hz, 6H).

5-Bromo-naphthalene-2-carboxylic acid (10). Bromine (77 µL, 1.51 mmol) was added to a
boiling solution of carboxylic acid 9 (300 mg, 1.74 mmol) in AcOH (1.5 mL) and the mixture was
heated to reflux for 1.5 h. Then it was allowed to warm to room temperature and a solid
precipitated. The latter was filtered off, washed with AcOH and purified by crystallization (AcOH)
to give bromo derivative 8 (169 mg, 39%). 1H NMR (200 MHz, CD3OD): δ = 8.63 (br s, 1H), 8.31–
8.27 (m, 1H), 8.16 (dd, J = 8.9, 1.6 Hz, 1H), 8.06–8.02 (m, 1H), 7.97–7.92 (m, 1H), 7.5–7.42 ppm
(t, J = 7.9 Hz, 1H).

3
7-Methyl-naphthalene-2-carboxylic acid (12) and naphthalene-2,7-dicarboxylic acid (13). A
hot (80 °C) solution of KMnO4 (2.70 g, 17.40 mmol) in water (14 mL) was added to a solution of
naphthalene 11 (850 mg, 5.40 mmol) in pyridine (10 mL) pre-heated at 120°C. The mixture was
refluxed for 1.5 h, pyridine (6 mL) and a hot solution of KMnO4 (1.70 g, 10.76 mmol) in water (9
mL) were further added and the reaction mixture was refluxed for 1.5 h. The brown mixture was
allowed to cool to room temperature and filtered off. Water (15 mL) was added to the filtrated
solution and the precipitate was filtered off. The solution was treated with a 37% aq. HCl solution
to pH=1, the solid formed was filtered off and dried to give a mixture of compounds 12 and 13 (230
mg) in a 12/13 ratio of 3 : 1. HPLC: (B) 10.4 (13) and 14.49 (12) min; 1H NMR (200 MHz,
CD3OD): δ = 8.74 (br s, 2H, 13-H), 8.52 (br s, 1H, 12-H), 8.17 (dd, J = 8.5, 1.6 Hz, 2H, 13-H),
8.04–7.76 (m, 5H, 12-H), 7.47 (dd, J = 8.5, 1.6 Hz, 2H, 13-H), 2.53 ppm (s, 3H, 12-H); MS (12)
(APCI–): m/z calcd for C12H10O2: 186.1, found: 185.1 [M–H]–.

6-Methyl-naphthalene-2-carboxylic acid (15). Bromine (0.83 mL, 16.50 mmol) was added to an
aq. 5 M NaOH solution (10 mL) at 0°C. After 10 minutes, a solution of ketone 14 (1.00 g, 5.45
mmol) in 1,4-dioxane (5 mL) was added dropwise to the reaction mixture. After 2.5 h stirring,
water (2.5 mL) and Na2S2O5 (2.5 mL) were added then the mixture was treated with a 37% aq. HCl
solution to pH=3. The white precipitate was filtered off, washed with water and dried to yield
carboxylic acid 15 (1.45 g, quant.). 1H NMR (200 MHz, CD3OD): δ = 8.48 (br s, 1H), 7.99 (dd, J =
8.6, 1.6 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.67 (bs, 1H), 7.38 (dd, J = 8.4,
1.6 Hz, 1H), 2.52 ppm (s, 3H).

2-[Acetoxy-(2-fluoro-3-methyl-phenyl)-methyl]-acrylic acid methyl ester (19). A mixture of 2-

fluoro-3-methylbenzaldehyde (16) (11.60 g, 84.06 mmol), methyl acrylate (17) (8.10 mL, 90.00
mmol) and DABCO® (4.65 g, 41.00 mmol) was stirred at room temperature for 15 h. The reaction
mixture was diluted with tert-butyl methyl ether, washed with an aq. 1 M HCl solution and water.
The organic phase was dried over Na2SO4 and, after removal of the solvent under reduced pressure,
the crude product 18 (16.3 g, 86%) was re-dissolved in dry toluene (40 mL) and pyridine (6.7 mL,
83.00 mmol) at 0°C and acetyl chloride (5.9 mL, 82.00 mmol) was added dropwise. After stirring at
room temperature for 3 h, the reaction mixture was diluted with tert-butyl methyl ether and washed
with an ice cold aq. 1 M HCl solution, water and a sat. aq. NaHCO3 solution. The organic phase was
dried over Na2SO4 and the removal of the solvent under reduced pressure gave the acetyl derivative
19 (18.60 g, 96%). HPLC: (B) 15.8 min. 1H NMR (200 MHz, CDCl3): δ = 7.18–7.11 (m, 2H),
7.04–6.97 (m, 1H), 6.93 (br s, 1H), 6.44 (s, 1H), 5.83–5.80 (m, 1H), 3.73 (s, 3H), 2.27 (d, J = 2.2
Hz, 3H), 2.11 ppm (s, 3H).

4
5-Methyl-naphthalene-2-carboxylic acid methyl ester (20). Nitromethane (1.5 mL, 28.00
mmoles) was added to a mixture of cesium carbonate (11.80 g, 36.20 mmoles) in DMSO (80 mL)
pre-heated at 50 °C under nitrogen. After 20 minutes at 50 °C, a solution of ester 19 (2.55 g, 9.60
mmoles) in DMSO (240 mL) was added dropwise over 3 h into the stirred pale yellow, warm
solution. The mixture was stirred at 50 °C for further 3 h and left overnight at room temperature.
The reaction mixture was partitioned between tert-butyl methyl ether (TBME) and ice-water. The
aqueous phase was separated and extracted with TBME. The combined organic phases were washed
with water, brine and dried over Na2SO4. After removal of the solvent under reduced pressure, the
crude product was purified by flash chromatography (cyclohexane/CHCl3 5 : 1) and compound 20
(0.95 g, 49%) was obtained as an oil. HPLC: (B) 6.5 min, 95% purity; 1H NMR (200 MHz, CDCl3):
δ = 8.59 (d, J = 1.6 Hz, 1H), 8.08 (dd, J = 8.8, 1.6 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.82–7.77 (m,
1H), 7.46–7.39 (m, 2H), 3.97 (s, 3H), 2.69 ppm (s, 3H).

1.3 Compounds corresponding to Scheme 2

7-Methyl-naphthalene-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-(tetrahydropyran-4-ylmethyl)-

piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)cyclopentyl]amide Trifluoroacetate (25d).
Amide 25d was obtained according to GP 1 as a white freeze-dried material after preparative HPLC
(Jupiter column C18, 300 Å, 250 mm × 21.20 mm, 15 µm, H2O + 0.1% TFA / MeCN + 0.1% TFA,
gradient 15–95% MeCN in 40 min). HPLC: (B) 13.1 min, 98% purity; mp: 76–79 °C; 1H NMR
(600 MHz, [D6]DMSO): δ = 8.79 (s, 1H), 8.41 (s, 1H), 7.97–7.88 (s, 3H), 7.84–7.81 (s, 2H), 7.66
(br t, J = 5.9 Hz, 1H), 7.48 (dd, J = 8.6, 1.2 Hz, 1H), 7.21–7.13 (m, 5H), 4.47–4.42 (m, 1H), 3.86–
3.80 (m, 2H), 3.32–3.26 (m, 2H), 3.17 (dd, J = 13.8, 4.1 Hz, 1H), 3.13–3.10 (m, 1H), 3.06–2.92 (m,
2H), 2.87 (dd, J = 14.0, 10.6 Hz, 1H), 2.81–2.77 (m, 3H), 2.70–2.63 (m, 1H), 2.51 (s, 3H), 2.27 (dt,
J = 13.0, 7.7 Hz, 1H), 1.98–1.90 (m, 2H), 1.76–1.64 (m, 12H), 1.37–1.30 (m, 2H), 1.22–1.13 ppm
(m, 2H); MS (ESI): m/z: 639.3 [M+H]+; HRMS: m/z [M+H]+ calcd for C39H51N4O4: 639.3910,
found: 639.3897.

5-Bromo-naphthalene-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-(tetrahydropyran-4-ylmethyl)-

piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)cyclopentyl]amide (25e). Amide 25e was
obtained according to GP 1 as a white solid after crystallization from TBME/MeOH 5 : 1. HPLC:
(B) 13.5 min, 97% purity; mp: 204–205 °C; 1H NMR (600 MHz, [D6]DMSO): δ = 8.90 (s, 1H),
8.59 (s, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.13 (dd, J = 8.8, 1.6 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 8.00

5
(dd, J = 7.4, 0.8 Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.45 (br t, J = 5.7 Hz,
1H), 7.20–7.12 (m, 5H), 4.47 (ddd, J = 10.5, 8.9, 4.2 Hz, 1H), 3.80–3.76 (m, 2H), 3.26–3.17 (m,
3H), 3.01–2.96 (m, 1H), 2.87–2.83 (m, 2H), 2.54–2.48 (m, 2H), 2.31 (dt, J = 13.3, 8.1 Hz, 1H),
1.99–1.94 (m, 1H), 1.92–1.85 (m, 2H), 1.81–1.76 (m, 1H), 1.72–1.38 (m, 12H), 1.26–1.20 (m, 1H),
1.05–0.91 ppm (m, 4H); MS (ESI): m/z: 703.4 [M+H]+; HRMS: m/z [M+H]+ calcd for
C38H48BrN4O4: 703.2859, found: 703.2845.

7-Bromo-naphthalene-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-(tetrahydropyran-4-ylmethyl)-

piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)cyclopentyl]amide (25g). Amide 25g was
obtained according to GP 1 as a white solid after purification on silica gel (CHCl3/MeOH 10 : 1).
HPLC: (B) 13.61 min, 97% purity; mp: 207–208 °C; 1H NMR (600 MHz, [D6]DMSO): δ = 8.80 (s,
1H), 8.47 (br s, 1H), 8.28 (s, 1H), 8.04 (s, 2H), 7.98 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H),
7.75 (dd, J = 8.7, 2.0 Hz, 1H), 7.47 (br t, J = 5.8 Hz, 1H), 7.20–7.12 (m, 5H), 4.46 (ddd, J = 10.4,
8.8, 4.1 Hz, 1H), 3.80–3.76 (m, 2H), 3.26–3.16 (m, 3H), 3.01–2.97 (m, 1H), 2.89–2.83 (m, 2H),
2.58–2.53 (m, 2H), 2.29 (dt, J = 13.4, 8.0 Hz, 1H), 1.98–1.90 (m, 3H), 1.81–1.76 (m, 1H), 1.70–
1.45 (m, 12H), 1.31–1.23 (m, 1H), 1.06–0.93 ppm (m, 4H); MS (ESI): m/z: 703.4 [M+H]+; HRMS:
m/z [M+H]+ calcd for C38H48BrN4O4: 703.2859, found: 703.2834.

6-Iodo-naphthalene-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-(tetrahydropyran-4-ylmethyl)-

piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)cyclopentyl]amide (25h). Amide 25h was
obtained according to GP 1 as a white solid after purification on silica gel (EtOAc/MeOH 4 : 1).
HPLC: (B) 14.0 min, 96% purity; 1H NMR (600 MHz, [D6]DMSO): δ = 8.85 (s, 1H), 8.51 (s, 1H),
8.50 (s, 1H), 8.00–7.95 (m, 2H), 7.90–7.82 (m, 3H), 7.63 (br t, J = 5.8 Hz, 1H), 7.21–7.12 (m, 5H),
4.47–4.41 (m, 1H), 3.86–3.83 (m, 2H), 3.38–3.27 (m, 3H), 3.18 (dd, J = 14.0, 4.1 Hz, 1H), 3.13–
3.10 (m, 1H), 3.05–2.98 (m, 1H), 2.96–2.92 (m, 1H), 2.87 (dd, J = 13.9, 10.8 Hz, 1H), 2.81 (br t, J
= 6.2 Hz, 2H), 2.70–2.53 (m, 2H), 2.31–2.24 (m, 1H), 1.99–1.90 (m, 2H), 1.83–1.47 (m, 11H),
1.37–1.15 ppm (m, 4H); MS (ESI): m/z: 751.3 [M+H]+; HRMS: m/z [M+H]+ calcd for C38H48IN4O4:
751.2720, found: 751.2697.

6-Methoxy-naphthalene-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-(tetrahydropyran-4-

ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)cyclopentyl]amide (25i). Amide
25i was obtained according to GP 1 as a white solid after purification on silica gel (EtOAc/MeOH 4
: 1). HPLC: (B) 12.4 min, 98% purity; mp: 128–131 °C; 1H NMR (600 MHz, [D6]DMSO): δ =
8.69 (s, 1H), 8.45 (s, 1H), 7.95 (dd, J = 8.6, 1.6 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.88 (d, J = 8.6
Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.51 (br t, J = 8.6 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.24 (dd, J =
8.9, 2.5 Hz, 1H), 7.20–7.11 (m, 5H), 4.46 (ddd, J = 10.3, 9.0, 4.1 Hz, 1H), 3.91 (s, 3H), 3.81–3.77

6
(m, 2H), 3.26–3.20 (m, 2H), 3.18 (dd, J = 14.0, 4.1 Hz, 1H), 3.00–2.95 (m, 1H), 2.90–2.83 (m, 2H),
2.62–2.57 (m, 2H), 2.29 (dt, J = 13.2, 7.9 Hz, 1H), 1.98–1.92 (m, 3H), 1.80–1.75 (m, 1H), 1.70–
1.44 (m, 12H), 1.31–1.23 (m, 1H), 1.06–0.95 ppm (m, 4H); MS (ESI): m/z: 655.2 [M+H]+; HRMS:
m/z [M+H]+ calcd for C39H51N4O5: 655.3859, found: 655.3853.

6-Diethylamino-naphthalene-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-(tetrahydropyran-4-

ylmethyl)piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)cyclopentyl]amide
Trifluoroacetate (25j). Amide 25l was obtained according to GP 1 as a white freeze-dried material
after preparative HPLC (Jupiter column C18, 300 Å, 250 mm × 21.20 mm, 15 µm, H2O + 0.1% TFA
/ MeCN + 0.1% TFA, gradient 15–95% MeCN in 40 min). HPLC: (B) 9.4 min, 97% purity; 1H
NMR (600 MHz, [D6]DMSO): δ = 8.59 (s, 1H), 8.32 (s, 1H), 7.84–7.80 (m, 2H), 7.68–7.63 (m,
2H), 7.23–7.13 (m, 5H), 6.93 (br s, 1H), 4.46–4.42 (m, 1H), 3.85–3.82 (m, 2H), 3.48 (br q, J = 6.8
Hz, 4H), 3.37 (br t, J = 14.1 Hz, 2H), 3.30–3.26 (m, 2H), 3.19 (dd, J = 13.9, 3.9 Hz, 1H), 3.13–3.12
(m, 1H), 3.05–2.98 (m, 1H), 2.99–2.91 (m, 1H), 2.88 (dd, J = 13.9, 10.8 Hz, 1H), 2.74–2.73 (m,
2H), 2.31–2.22 (m, 1H), 1.99–1.90 (m, 2H), 1.79–1.45 (m, 10H), 1.37–1.26 (m, 2H), 1.17 ppm (br
t, J = 7.0 Hz, 6H); MS (ESI): m/z: 696.3 [M+H]+; HRMS: m/z [M+H]+ calcd for C42H58N5O4:
696.4489, found: 696.4468.

1.4 Compounds corresponding to Scheme 3

4-Chloro-2-methoxybenzoic acid methyl ester (31a). Compound 31a was obtained from methyl
ester 30a according to GP 2. 1H NMR (200 MHz, CDCl3): δ = 7.76 (d, J = 8.8 Hz, 1H), 7.01–6.94
(m, 2H), 3.91 (s, 3H), 3.88 (s, 3H).

4-Bromo-2-methoxybenzoic acid methyl ester (31b). Compound 31b was obtained from methyl
ester 30b according to GP 2. 1H NMR (200 MHz, CDCl3): δ = 7.71 (d, J = 8.7 Hz, 1H), 7.18–7.12
(m, 2H), 3.90 (s, 3H), 3.89 (s, 3H).

4-Chloro-2-methoxybenzyl Alcohol (32a). Compound 32a was obtained from methyl ester 31a
according to GP 3. 1H NMR (200 MHz, CDCl3): δ = 7.21 (d, J = 8.0 Hz, 1H), 6.96–6.86 (m, 2H),
4.64 (s, 2H), 3.86 (s, 3H).

4-Bromo-2-methoxybenzyl Alcohol (32b). Compound 32b was obtained from methyl ester 31b
according to GP 3. 1H NMR (200 MHz, CDCl3): δ = 7.18–7.01 (m, 3H), 4.62 (s, 2H), 3.84 (s, 3H).

7
4-Bromo-2-methoxybenzaldehyde (33b). Compound 33b was obtained from benzyl alcohol 32b
according to GP 4. 1H NMR (200 MHz, CDCl3): δ = 10.40 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.22–
7.15 (m, 2H), 3.94 ppm (s, 3H).

4-Methyl-2-methoxybenzaldehyde (33c). Compound 33c was obtained from benzyl alcohol 32c
according to GP 4. 1H NMR (200 MHz, CDCl3): δ = 10.40 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 6.87–
6.78 (m, 2H), 3.92 (s, 3H), 2.41 ppm (s, 3H).

4-Chloro-2-hydroxybenzaldehyde (34a). Compound 34a was obtained from aldehyde 33a

according to GP 5. 1H NMR (200 MHz, CDCl3): δ = 11.17 (s, 1H), 9.87 (s, 1H), 7.50 (d, J = 8.8 Hz,
1H), 7.04–6.98 (m, 2H).

4-Bromo-2-hydroxybenzaldehyde (34b). Compound 34b was obtained from aldehyde 33b

according to GP 5. 1H NMR (200 MHz, CDCl3): δ = 11.09 (s, 1H), 9.86 (s, 1H), 7.41 (d, J = 8.1 Hz,
1H), 7.21–7.14 (m, 2H).

5-Fluoro-2-hydroxybenzaldehyde (34d). Compound 34d was obtained from aldehyde 33d

according to GP 5. 1H NMR (200 MHz, CDCl3): δ = 10.79 (s, 1H), 9.86 (s, 1H), 7.33–7.23 (m, 2H),
7.02–6.94 (m, 1H).

tert-Butyl 6-chlorobenzo[b]furan-2-carboxylate (35a). Compound 35a was obtained from

aldehyde 34a according to GP 6. 1H NMR (200 MHz, CDCl3): δ = 7.60–7.55 (m, 2H), 7.39 (s, 1H),
7.31–7.24 (m, 1H), 1.63 ppm (s, 9H).

tert-Butyl 6-bromobenzo[b]furan-2-carboxylate (35b). Compound 35b was obtained from

aldehyde 34b according to GP 6. 1H NMR (200 MHz, CDCl3): δ = 7.75 (s, 1H), 7.52 (d, J = 8.4 Hz,
1H), 7.44–7.38 (m, 2H), 1.62 ppm (s, 9H).

tert-Butyl 5-fluorobenzo[b]furan-2-carboxylate (35d). Compound 35d was obtained from

aldehyde 34d according to GP 6. 1H NMR (200 MHz, CDCl3): δ = 7.52 (dd, J = 8.9, 4.0 Hz, 1H),
7.38 (s, 1H), 7.30 (dd, J = 8.2, 2.6 Hz, 1H), 7.15 (dt, J = 9.1, 2.6 Hz, 1H), 1.62 ppm (s, 9H).

tert-Butyl 5-iodobenzo[b]furan-2-carboxylate (35e). Compound 35e was obtained from aldehyde

34e according to GP 6. 1H NMR (200 MHz, CDCl3): δ = 7.58 (d, J = 8.8 Hz, 1H), 7.46–7.29 (m,
3H), 1.63 ppm (s, 9H).

8
tert-Butyl 5-methylbenzo[b]furan-2-carboxylate (35f). Compound 35f was obtained from
aldehyde 34f according to GP 6. 1H NMR (200 MHz, CDCl3): δ = 7.58–7.24 (m, 4H), 1.63 ppm (s,
9H).

tert-Butyl 5-tert-butylbenzo[b]furan-2-carboxylate (35g). Compound 35g was obtained from

aldehyde 34g according to GP 6. 1H NMR (200 MHz, CDCl3): δ = 7.63–7.27 (m, 4H), 1.63 (s, 9H),
1.38 ppm (s, 9H).

tert-Butyl 5-trifluoromethoxybenzo[b]furan-2-carboxylate (35h). Compound 35h was obtained

from aldehyde 34h according to GP 6. 1H NMR (200 MHz, CDCl3): δ = 7.58 (d, J = 8.9 Hz, 1H),
7.52 (s, 1H), 7.42 (s, 1H), 7.32–7.27 (m, 1H), 1.63 ppm (s, 9H).

tert-Butyl 7-methylbenzo[b]furan-2-carboxylate (35i). Compound 35i was obtained from

aldehyde 34i according to GP 6. 1H NMR (200 MHz, CDCl3): δ = 7.50–7.37 (m, 2H), 7.24–7.14
(m, 2H), 2.58 (s, 3H), 1.63 ppm (s, 9H).

tert-Butyl 7-tert-butylbenzo[b]furan-2-carboxylate (35j). Compound 35j was obtained from

aldehyde 34j according to GP 6. 1H NMR (200 MHz, CDCl3): δ = 7.50 (dd, J = 7.5, 1.4 Hz, 1H),
7.39 (s, 1H), 7.32 (dd, J = 7.6, 1.4 Hz, 1H), 7.23 (d, J = 7.55 Hz, 1H), 1.62 (s, 9H), 1.53 ppm (s,
9H).

tert-Butyl 5-nitrobenzo[b]furan-2-carboxylate (35k). Compound 35k was obtained from

aldehyde 34k according to GP 6. 1H NMR (200 MHz, CDCl3): δ = 8.62 (d, J = 2.3 Hz, 1H), 7.35
(dd, J = 9.1, 2.3 Hz, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.54 (s, 1H), 1.64 ppm (s, 9H).

6-Bromobenzo[b]furan-2-carboxylic acid (36b). Compound 36b was obtained from tert-butyl

ester 35b according to GP 7. 1H NMR (200 MHz, [D6]DMSO): δ = 7.95 (s, 1H), 7.78 (d, J = 2.3
Hz, 1H), 7.60 (s, 1H), 7.44–7.38 (m, 1H).

5-Fluorobenzo[b]furan-2-carboxylic acid (36d). Compound 36d was obtained from tert-butyl

ester 35d according to GP 7. 1H NMR (200 MHz, [D6]DMSO): δ = 7.71–7.63 (m, 2H), 7.20 (d, J =
8.6 Hz, 1H), 7.06–6.98 (m, 1H).

5-tert-Butylbenzo[b]furan-2-carboxylic acid (36g). Compound 36g was obtained from tert-butyl

ester 35g according to GP 7. 1H NMR (200 MHz, [D6]DMSO): δ = 7.69–7.66 (m, 2H), 7.57–7.55
(m, 2H), 1.39 ppm (s, 9H).

9
5-Trifluoromethoxybenzo[b]furan-2-carboxylic acid (36h). Compound 36h was obtained from
tert-butyl ester 35h according to GP 7. 1H NMR (200 MHz, [D6]DMSO): δ = 7.88–7.83 (m, 2H),
7.71 (s, 1H), 7.50 ppm (dd, J = 8.7, 2.3 Hz, 1H).

6-Methyl-benzo[b]furan-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-(tetrahydropyran-4-

ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)cyclopentyl]amide (37c).
Compound 37c was synthesized from carboxylic acid 36c. Compound 37c was purified by flash
column chromatography on silica gel (EtOAc/MeOH 3 : 1). HPLC: (B) 12.7 min, 98% purity; mp:
95–98 °C; 1H NMR (600 MHz, [D6]DMSO): δ = 8.72 (s, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.66 (d, J =
8.0 Hz, 1H), 7.57 (d, J = 0.83 Hz, 1H), 7.49 (br t, J = 5.8 Hz, 1H), 7.46 (s, 1H), 7.20–7.11 (m, 6H),
4.44 (ddd, J = 10.5, 8.7, 4.3 Hz, 1H), 3.81–3.78 (m, 2H), 3.25 (ddt, J = 11.5, 6.6, 2.0 Hz, 1H), 3.16
(dd, J = 13.9, 4.2 Hz, 1H), 3.00–2.95 (m, 1H), 2.92–2.87 (m, 1H), 2.83 (dd, J = 13.9, 10.6 Hz, 1H),
2.70–2.67 (m, 2H), 2.47 (s, 3H), 2.25 (dt, J = 13.4, 8.1 Hz, 1H), 2.02–2.00 (m, 2H), 1.96–1.90 (m,
1H), 1.80–1.43 (m, 14H), 1.43–1.31 (m, 1H), 1.10–1.00 ppm (m, 4H); MS (ESI): m/z: 629.5
[M+H]+; calcd for C37H49N4O5: 629.3703, found: 629.3683.

5-Methyl-benzo[b]furan-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-(tetrahydropyran-4-

ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)cyclopentyl]amide (37d).
Compound 37d was synthesized from carboxylic acid 36f. Compound 37d was purified by flash
column chromatography on silica gel (EtOAc/MeOH 3 : 1). HPLC: (B) 12.7 min, 98% purity; 1H
NMR (600 MHz, [D6]DMSO): δ = 8.76 (s, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.58–7.54 (m, 3H), 7.49
(br t, J = 5.9 Hz, 1H), 7.31 (dd, J = 8.4, 1.4 Hz, 1H), 7.21–7.12 (m, 5H), 4.45 (ddd, J = 10.6, 9.0,
4.3 Hz, 1H), 3.83–3.79 (m, 2H), 3.29–3.23 (m, 2H), 3.17 (dd, J = 13.9, 4.2 Hz, 1H), 3.02–2.97 (m,
1H), 2.93–2.88 (m, 1H), 2.84 (dd, J = 13.9, 10.6 Hz, 1H), 2.71–2.68 (m, 2H), 2.44 (s, 3H), 2.26 (dt,
J = 13.4, 8.2 Hz, 1H), 2.03–2.01 (m, 2H), 1.97–1.92 (m, 1H), 1.81–1.76 (m, 1H), 1.74–1.41 (m,
11H), 1.39–1.24 (m, 2H), 1.11–1.02 ppm (m, 4H); MS (ESI): m/z calcd for C37H48N4O5: 628.4,
found: 629.5 [M+H]+.

7-tert-Butyl-benzo[b]furan-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-(tetrahydropyran-4-

ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)cyclopentyl]amide (37e).
Compound 37e was synthesized from carboxylic acid 36j. Compound 37e was purified by flash
column chromatography on silica gel (EtOAc/MeOH 3 : 1). HPLC: (B) 15.1 min, 98% purity; mp:
91–94 °C; 1H NMR (600 MHz, [D6]DMSO): δ = 8.62 (s, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.73 (s,
1H), 7.65 (dd, J = 7.7, 1.2 Hz, 1H), 7.57 (br t, J = 5.9 Hz, 1H), 7.32 (dd, J = 7.6, 1.2 Hz, 1H), 7.27
(t, J = 7.6 Hz, 1H), 7.18–7.10 (m, 5H), 4.47 (ddd, J = 10.6, 8.7, 4.3 Hz, 1H), 3.81–3.79 (m, 2H),
3.27–3.22 (m, 2H), 3.17 (dd, J = 13.9, 4.3 Hz, 1H), 3.00–2.95 (m, 1H), 2.92–2.87 (m, 1H), 2.84 (dd,

10
J = 13.9, 10.7 Hz, 1H), 2.71–2.69 (m, 1H), 2.63–2.61 (m, 1H), 2.24 (dt, J = 13.3, 8.0 Hz, 1H), 2.02–
1.99 (m, 2H), 1.92–1.86 (m, 1H), 1.81–1.76 (m, 1H), 1.73–1.46 (m, 20H), 1.42–1.36 (m, 2H), 1.11–
0.98 ppm (m, 4H); MS (ESI): m/z calcd for C40H54N4O5: 670.4, found: 671.6 [M+H]+.

5-tert-Butyl-benzo[b]furan-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-(tetrahydropyran-4-

ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)cyclopentyl]amide (37f).
Compound 37f was synthesized from carboxylic acid 36g. Compound 37f was purified by flash
column chromatography on silica gel (EtOAc/MeOH 3 : 1). HPLC: (B) 14.97 min, 99% purity; mp:
96–98 °C; 1H NMR (600 MHz, [D6]DMSO): δ = 8.75 (s, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.76–7.74
(m, 1H), 7.58–7.54 (m, 3H), 7.47 (br t, J = 5.8 Hz, 1H), 7.20–7.11 (m, 5H), 4.45 (ddd, J = 10.4, 8.8,
4.4 Hz, 1H), 3.80–3.78 (m, 2H), 3.24 (ddt, J = 11.6, 6.6, 1.9 Hz, 1H), 3.16 (dd, J = 13.9, 4.3 Hz,
1H), 3.00–2.95 (m, 1H), 2.92–2.87 (m, 1H), 2.82 (dd, J = 13.9, 10.5 Hz, 1H), 2.60–2.66 (m, 2H),
2.25 (dt, J = 13.3, 8.0 Hz, 1H), 2.00–1.93 (m, 3H), 1.80–1.75 (m, 1H), 1.72–1.43 (m, 12H), 1.35 (s,
9H), 1.33–1.23 (m, 2H), 1.09–0.99 ppm (m, 4H); MS (ESI): m/z: 671.5 [M+H]+; HRMS: m/z
[M+H]+ calcd for C40H55N4O5: 671.4172, found: 671.4158.

5-Fluoro-benzo[b]furan-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-(tetrahydropyran-4-

ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)cyclopentyl]amide (37g).
Compound 37g was synthesized from carboxylic acid 36d. Compound 37g was purified by flash
column chromatography on silica gel (EtOAc/MeOH 3 : 1). HPLC: (B) 12.1 min, 98% purity; mp:
98–101 °C; 1H NMR (600 MHz, [D6]DMSO): δ = 8.84 (s, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.71 (dd, J
= 9.0, 4.0 Hz, 1H), 7.64 (dd, J = 8.6, 2.7 Hz, 1H), 7.61 (d, J = 0.8 Hz, 1H), 7.47 (br t, J = 5.8 Hz,
1H), 7.35 (dt, J = 9.2, 2.7 Hz, 1H), 7.20–7.11 (m, 5H), 4.44 (ddd, J = 10.5, 8.7, 4.3 Hz, 1H), 3.82–
3.78 (m, 2H), 4.44 (ddt, J = 11.6, 7.7, 2.0 Hz, 2H), 3.15 (dd, J = 13.9, 4.3 Hz, 1H), 3.00–2.95 (m,
1H), 2.92–2.87 (m, 1H), 2.82 (dd, J = 13.9, 10.5 Hz, 1H), 2.68 (br t, J = 10.8 Hz, 2H), 2.25 (dt, J =
13.3, 8.1 Hz, 1H), 2.02–2.00 (m, 2H), 1.96–1.90 (m, 1H), 1.80–1.75 (m, 1H), 1.72–1.43 (m, 11H),
1.37–1.30 (m, 2H), 1.09–1.01 ppm (m, 4H); MS (ESI): m/z: 633.5 [M+H]+; HRMS: m/z [M+H]+
calcd for C36H46FN4O5: 633.3452, found: 633.3456.

5-Chloro-benzo[b]furan-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-(tetrahydropyran-4-

ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)cyclopentyl]amide (37h).
Compound 37h was purified by flash column chromatography on silica gel (EtOAc/MeOH 3 : 1).
HPLC: (B) 12.8 min, 98% purity; mp: 99–102 °C; 1H NMR (600 MHz, [D6]DMSO): δ = 8.87 (s,
1H), 7.92 (d, J = 2.2 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 0.8 Hz,
1H), 7.51 (dd, J = 8.8, 2.2 Hz, 1H), 7.45 (br t, J = 5.8 Hz, 1H), 7.20–7.11 (m, 5H), 4.44 (ddd, J =
10.3, 8.8, 4.3 Hz, 1H), 3.82–3.78 (m, 2H), 3.28–3.22 (m, 2H), 3.16 (dd, J = 13.9, 4.3 Hz, 1H), 3.01–

11
2.96 (m, 1H), 2.91–2.84 (m, 1H), 2.82 (dd, J = 13.9, 10.6 Hz, 1H), 2.68–2.65 (m, 2H), 2.25 (dt, J =
13.3, 8.0 Hz, 1H), 2.01–1.98 (m, 2H), 1.95–1.90 (m, 1H), 1.80–1.75 (m, 1H), 1.71–1.43 (m, 12H),
1.36–1.29 (m, 1H), 1.10–1.00 ppm (m, 4H); MS (ESI): m/z: 649.5 [M+H]+; HRMS: m/z [M+H]+
calcd for C36H46ClN4O5: 649.3157, found: 649.3146.

5-Bromo-benzo[b]furan-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-(tetrahydropyran-4-

ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)cyclopentyl]amide (37i).
Compound 37i was purified by flash column chromatography on silica gel (EtOAc/MeOH 3 : 1).
HPLC: (B) 13.1 min, 98% purity; mp: 95–98 °C; 1H NMR (600 MHz, [D6]DMSO): δ = 8.88 (s,
1H), 8.06 (d, J = 2.0 Hz, 1H), 7.67–7.60 (m, 3H), 7.44 (br t, J = 5.9 Hz, 1H), 7.20–7.11 (m, 5H),
4.44 (ddd, J = 10.6, 8.8, 4.3 Hz, 1H), 3.82–3.78 (m, 2H), 3.29–3.22 (m, 2H), 3.16 (dd, J = 13.9, 4.2
Hz, 1H), 3.01–2.96 (m, 1H), 2.90–2.86 (m, 1H), 2.82 (dd, J = 13.9, 10.6 Hz, 1H), 2.68–2.64 (m,
2H), 2.25 (dt, J = 13.3, 8.1 Hz, 1H), 2.01–1.98 (m, 2H), 1.95–1.90 (m, 1H), 1.80–1.74 (m, 1H),
1.70–1.42 (m, 12H), 1.36–1.22 (m, 1H), 1.10–0.99 ppm (m, 4H); MS (ESI): m/z: 693.5 [M+H]+;
HRMS: m/z [M+H]+ calcd for C36H46BrN4O5: 693.2652, found: 693.2638.

5-Iodo-benzo[b]furan-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-(tetrahydropyran-4-ylmethyl)-

piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)cyclopentyl]amide (37j). Compound 37j was
synthesized from carboxylic acid 36e. Compound 37j was purified by flash column
chromatography on silica gel (EtOAc/MeOH 3 : 1). HPLC: (B) 13.4 min, 98% purity; mp: 100–103
°C; 1H NMR (600 MHz, [D6]DMSO): δ = 8.87 (s, 1H), 8.22 (d, J = 1.8 Hz, 1H), 7.86 (d, J = 8.6
Hz, 1H), 7.76 (dd, J = 8.7, 1.8 Hz, 1H), 7.58 (d, J = 0.8 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.43 (br t,
J = 5.8 Hz, 1H), 7.20–7.11 (m, 5H), 4.44 (ddd, J = 10.6, 8.7, 4.3 Hz, 1H), 3.83–3.78 (m, 2H), 3.30–
3.23 (m, 2H), 3.16 (dd, J = 14.0, 4.2 Hz, 1H), 3.01–2.97 (m, 1H), 2.89–2.85 (m, 1H), 2.82 (dd, J =
13.9, 10.6 Hz, 1H), 2.67–2.63 (m, 2H), 2.25 (dt, J = 13.3, 8.2 Hz, 1H), 2.00–1.98 (m, 2H), 1.95–
1.90 (m, 1H), 1.78–1.74 (m, 1H), 1.69–1.40 (m, 12H), 1.35–1.22 (m, 1H), 1.10–0.99 ppm (m, 4H);
MS (ESI): m/z: 741.5 [M+H]+; HRMS: m/z [M+H]+ calcd for C36H46IN4O5: 741.2513, found:
741.2498.

6-Chloro-benzo[b]furan-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-(tetrahydropyran-4-

ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)cyclopentyl]amide (37k).
Compound 37k was synthesized from carboxylic acid 36a. Compound 37k was purified by flash
column chromatography on silica gel (EtOAc/MeOH 3 : 1). HPLC: (B) 13.0 min, 97% purity; mp:
97–100 °C; 1H NMR (600 MHz, [D6]DMSO): δ = 8.84 (s, 1H), 7.85–7.80 (m, 3H), 7.66 (d, J = 0.9
Hz, 1H), 7.46 (br t, J = 5.8 Hz, 1H), 7.42 (dd, J = 8.4, 1.8 Hz, 1H), 7.20–7.11 (m, 5H), 4.44 (ddd, J
= 10.4, 8.7, 4.3 Hz, 1H), 3.82–3.78 (m, 2H), 3.29–3.22 (m, 2H), 3.16 (dd, J = 13.9, 4.3 Hz, 1H),

12
3.01–2.96 (m, 1H), 2.91–2.87 (m, 1H), 2.82 (dd, J = 13.9, 10.6 Hz, 1H), 2.69–2.65 (m, 2H), 2.25
(dt, J = 13.4, 8.1 Hz, 1H), 2.01–1.98 (m, 2H), 1.95–1.88 (m, 1H), 1.80–1.75 (m, 1H), 1.72–1.43 (m,
12H), 1.37–1.30 (m, 1H), 1.09–0.99 ppm (m, 4H); MS (ESI): m/z: 649.3 [M+H]+; HRMS: m/z
[M+H]+ calcd for C36H46ClN4O5: 649.3157, found: 649.3151.

6-Bromo-benzo[b]furan-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-(tetrahydropyran-4-

ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)cyclopentyl]amide (37l).
Compound 37l was synthesized from carboxylic acid 36b. Compound 37l was purified by flash
column chromatography on silica gel (EtOAc/MeOH 4 : 1). HPLC: (B) 13.2 min, 98% purity; mp:
99–102 °C; 1H NMR (600 MHz, [D6]DMSO): δ = 8.45 (s, 1H), 7.95 (br s, 1H), 7.85 (d, J = 8.6 Hz,
1H), 7.78 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 0.9 Hz, 1H), 7.54 (dd, J = 8.4, 1.7 Hz, 1H), 7.45 (br t, J =
5.9 Hz, 1H), 7.20–7.11 (m, 5H), 4.44 (ddd, J = 10.5, 8.8, 4.4 Hz, 1H), 3.82–3.78 (m, 2H), 3.29–3.22
(m, 2H), 3.16 (dd, J = 13.9, 4.6 Hz, 1H), 3.01–2.96 (m, 1H), 2.91–2.86 (m, 1H), 2.82 (dd, J = 13.9,
10.5 Hz, 1H), 2.68–2.65 (m, 2H), 2.25 (dt, J = 13.3, 8.1 Hz, 1H), 2.01–1.99 (m, 2H), 1.95–1.90 (m,
1H), 1.79–1.74 (m, 1H), 1.71–1.43 (m, 13H), 1.09–0.99 ppm (m, 4H); MS (ESI): m/z: 693.3
[M+H]+; calcd for C36H46BrN4O5: 693.2652, found: 693.2671.

5-Methoxy-benzo[b]furan-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-(tetrahydropyran-4-

ylmethyl)piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)cyclopentyl]amide (37m).
Compound 37m was purified by flash column chromatography on silica gel (CH2Cl2/MeOH 7 : 1).
HPLC: (B) 12.0 min, 99% purity; mp: 94–98 °C; 1H NMR (600 MHz, [D6]DMSO): δ = 8.74 (s,
1H), 7.83 (d, J = 8.6 Hz, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.53 (s, 1H), 7.58–7.54 (m, 2H), 7.50 (br t, J
= 5.9 Hz, 1H), 7.29 (d, J = 2.6 Hz, 1H), 7.20–7.11 (m, 5H), 7.08 (dd, J = 9.0, 2.6 Hz, 1H), 4.44
(ddd, J = 10.3, 8.7, 4.3 Hz, 1H), 3.81 (s, 3H), 3.81–3.79 (m, 2H), 3.28–3.22 (m, 2H), 3.15 (dd, J =
13.9, 4.3 Hz, 1H), 3.00–2.88 (m, 2H), 2.82 (dd, J = 13.8, 10.6 Hz, 1H), 2.70–2.68 (m, 2H), 2.25 (dt,
J = 13.4, 8.1 Hz, 1H), 2.01–1.90 (m, 2H), 1.80–1.33 (m, 15H), 1.09–1.03 ppm (m, 4H); MS (ESI):
m/z: 645.5 [M+H]+; HRMS: m/z [M+H]+ calcd for C37H49N4O6: 645.3652, found: 645.3641.

5-Trifluoromethoxy-benzo[b]furan-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-(tetrahydropyran-

4-ylmethyl)piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)cyclopentyl]amide (37n).
Compound 37n was synthesized from carboxylic acid 36h. Compound 37n was purified by flash
column chromatography on silica gel (CH2Cl2/MeOH 10 : 1). HPLC: (B) 13.7 min, 98% purity;
mp: 95–97 °C; 1H NMR (600 MHz, [D6]DMSO): δ = 8.90 (s, 1H), 7.88 (d, J = 1.3 Hz, 1H), 7.83 (d,
J = 8.6 Hz, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 0.7 Hz, 1H), 7.49 (dd, J = 9.0, 1.9 Hz, 1H),
7.45 (br t, J = 5.7 Hz, 1H), 7.20–7.11 (m, 5H), 4.45 (ddd, J = 10.5, 8.7, 4.4 Hz, 1H), 3.81–3.78 (m,
2H), 3.24 (ddt, J = 11.7, 6.8, 2.0 Hz, 2H), 3.16 (dd, J = 13.9, 4.2 Hz, 1H), 3.00–2.95 (m, 1H), 2.92–

13
2.87 (m, 1H), 2.82 (dd, J = 13.9, 10.6 Hz, 1H), 2.70–2.64 (m, 2H), 2.25 (dt, J = 13.3, 8.0 Hz, 1H),
2.00–1.90 (m, 3H), 1.81–1.76 (m, 1H), 1.68–1.43 (m, 12H), 1.36–1.32 (m, 1H), 1.09–1.02 ppm (m,
4H); MS (ESI): m/z: 699.4 [M+H]+; HRMS: m/z [M+H]+ calcd for C37H46F3N4O6: 699.3369, found:
699.3361.

5-Diethylamino-benzo[b]furan-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-(tetrahydropyran-4-

ylmethyl)piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)cyclopentyl]amide (37o).
Compound 37o was synthesized from carboxylic acid 36l. Compound 37o was purified by flash
column chromatography on silica gel (CH2Cl2/MeOH 7 : 1). HPLC: (B) 8.6 min, 97% purity; mp:
105–108 °C; 1H NMR (600 MHz, [D6]DMSO): δ = 8.66 (s, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.47 (br
s, 1H), 7.45 (d, J = 9.1 Hz, 1H), 7.41 (s, 1H), 7.20–7.12 (m, 5H), 6.94 (dd, J = 9.1, 2.6 Hz, 1H),
6.92 (d, J = 2.4 Hz, 1H), 4.45 (ddd, J = 10.5, 8.9, 4.3 Hz, 1H), 3.35 (q, J = 7.1 Hz, 4H), 3.27–3.22
(m, 2H), 3.16 (dd, J = 13.9, 4.2 Hz, 1H), 3.06–2.96 (m, 1H), 2.91–2.87 (m, 1H), 2.82 (dd, J = 13.6,
10.8 Hz, 1H), 2.69–2.67 (m, 2H), 2.25 (dt, J = 13.3, 8.1 Hz, 1H), 2.06–1.90 (m, 3H), 1.72–1.42 (m,
16H), 1.10 (q, J = 7.0 Hz, 6H), 1.11–1.01 ppm (m, 4H); MS (ESI): m/z: 686.6 [M+H]+; HRMS: m/z
[M+H]+ calcd for C40H56N5O5: 686.4281, found: 686.4235.

1.5 Compounds corresponding to Scheme 5

1
C-[1-(4-Methoxy-tetrahydropyran-4-ylmethyl)-piperidin-4-yl]-methylamine (50b). H NMR
(200 MHz, CDCl3): δ = 3.70–3.62 (m, 6H), 3.18 (s, 3H), 2.91–2.85 (m, 1H), 2.55–2.50 (m, 3H),
2.16–2.04 (m, 1H), 1.78–1.51 (m, 8H), 1.22–1.10 ppm (m, 2H); MS (ESI) m/z calcd for
C13H26N2O2: 242.2, found: 243.3 [M+H]+.

C-[1-(4-Methoxymethyl-tetrahydropyran-4-ylmethyl)-piperidin-4-yl]-methylamine (50c). MS
(ESI) m/z calcd for C14H28N2O2: 256.2, found: 257.3 [M+H]+.

1
C-[1-(4-Methyl-tetrahydropyran-4-ylmethyl)-piperidin-4-yl]-methylamine (50d). H NMR
(200 MHz, CDCl3): δ = 3.79–3.47 (m, 4H), 2.83–2.67 (m, 2H), 2.59–2.48 (m, 2H), 2.30–2.10 (m,
2H), 2.10 (s, 2H), 1.69–1.08 (m, 9H), 0.94 ppm (s, 3H); MS (ESI) m/z calcd for C13H26N2O: 226.2,
found: 227.2 [M+H]+.

6-Methyl-benzo[b]thiophene-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-(4-methoxy-tetrahydro-

pyran-4-ylmethyl)piperidin-4-ylmethyl]carbamoyl}ethylcarbamoyl)cyclopentyl]-amide
Trifluoroacetate (52b). Amide 52b was obtained according to GP 9 as a white freeze-dried

14
material after preparative HPLC (Symmetry C18, 300 Å, 300 mm × 19 mm, 7 µm, H2O + 0.1% TFA
/ MeCN + 0.1% TFA, gradient 30 to 60% MeCN in 60 min, flow rate 20 mL/min). HPLC: (A) 3.8
min, 99% purity; mp: 105–109 °C; 1H NMR (600 MHz, [D6]DMSO): δ = 8.86 (s, 1H), 8.25 (s, 1H),
7.90–7.86 (m, 2H), 7.80 (s, 1H), 7.59 (br t, J = 5.9 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.21–7.12 (m,
5H), 4.46–4.41 (m, 1H), 3.66–3.50 (m, 4H), 3.25–3.18 (m, 4H), 3.16 (s, 3H), 3.08–2.89 (m, 4H),
2.86 (dd, J = 14.1, 10.7 Hz, 1H), 2.45 (s, 3H), 2.26–2.19 (m, 1H), 1.93–1.89 (m, 1H), 1.79–1.45
ppm (m, 16H); MS (ESI): m/z: 675.4 [M+H]+; HRMS: m/z [M+H]+ calcd for C38H51N4O5S:
675.3580, found: 675.3560.

6-Methyl-benzo[b]thiophene-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-(4-methoxymethyl-

tetrahydro-pyran-4-ylmethyl)piperidin-4-ylmethyl]carbamoyl}ethylcarbamoyl)cyclopentyl]-
amide (52c). HPLC: (A) 3.9 min, 99% purity; mp: 82–84 °C; 1H NMR (600 MHz, [D6]DMSO): δ =
8.86 (s, 1H), 8.25 (s, 1H), 7.89–7.86 (m, 2H), 7.80 (s, 1H), 7.59 (br t, J = 5.9 Hz, 1H), 7.30 (d, J =
8.3 Hz, 1H), 7.21–7.13 (m, 5H), 4.46–4.41 (m, 1H), 3.64–3.52 (m, 6H), 3.31 (s, 3H), 3.20–3.14 (m,
4H), 3.10–2.89 (m, 5H), 2.86 (dd, J = 13.9, 10.7 Hz, 1H), 2.45 (s, 3H), 2.26–2.19 (m, 1H), 1.93–
1.89 (m, 1H), 1.81–1.45 ppm (m, 15H); MS (ESI): m/z: 689.4 [M+H]+; HRMS: m/z [M+H]+ calcd
for C39H53N4O5S: 689.3737, found: 689.3733.

6-Methyl-benzo[b]thiophene-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-(4-methyl-tetrahydro-

pyran-4-ylmethyl)piperidin-4-ylmethyl]carbamoyl}ethylcarbamoyl)cyclopentyl]-amide (52d).
HPLC: (A) 3.8 min, 97% purity; mp: 107–110 °C; 1H NMR (600 MHz, [D6]DMSO): δ = 8.81 (s,
1H), 8.22 (s, 1H), 7.86–7.83 (m, 2H), 7.80 (s, 1H), 7.48 (br t, J = 5.8 Hz, 1H), 7.28 (dd, J = 8.2, 0.8
Hz, 1H), 7.20–7.12 (m, 5H), 4.45 (ddd, J = 10.6, 8.9, 4.3 Hz, 1H), 3.58–3.55 (m, 2H), 3.49–3.44
(m, 2H), 3.19–3.16 (m, 1H), 2.93 (t, J = 6.4 Hz, 2H), 2.83 (dd, J = 13.8, 10.7 Hz, 1H), 2.64–2.60
(m, 2H), 2.44 (s, 3H), 2.23 (dt, J = 13.5, 8.2 Hz, 1H), 2.09–2.05 (m, 2H), 2.02 (s, 2H), 1.92–1.87
(m, 1H), 1.79–1.74 (m, 1H), 1.70–1.31 (m, 10H), 1.11–1.05 (m, 4H), 0.89 ppm (s, 3H); MS (ESI):
m/z: 659.4 [M+H]+; HRMS: m/z [M+H]+ calcd for C38H51N4O4S: 659.3631, found: 659.3611.

1.6 Compounds corresponding to Scheme 6

6-Methyl-benzo[b]thiophene-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-([1,3]dioxan-2-

ylmethyl)piperidin-4-ylmethyl]carbamoyl}ethylcarbamoyl)cyclopentyl]-amide (56b). HPLC:
(A) 3.9 min, 99% purity; mp: 93–96 °C; 1H NMR (600 MHz, [D6]DMSO): δ = 8.81 (s, 1H), 8.24 (s,
1H), 7.88–7.84 (m, 3H), 7.48 (br t, J = 5.8 Hz, 1H), 7.29 (dd, J = 8.2, 0.8 Hz, 1H), 7.21–7.12 (m,
5H), 4.59 (t, J = 4.4 Hz, 1H), 4.46 (ddd, J = 10.7, 8.8, 4.2 Hz, 1H), 3.98–3.95 (m, 2H), 3.68 (ddt, J

15
= 12.0, 6.3, 2.5 Hz, 2H), 3.20–3.16 (m, 1H), 3.00–2.90 (m, 2H), 2.85 (dd, J = 13.9, 10.7 Hz, 1H),
2.79–2.76 (m, 2H), 2.45 (s, 3H), 2.32–2.30 (m, 2H), 2.23 (dt, J = 13.4, 8.2 Hz, 1H), 1.93–1.76 (m,
5H), 1.71–1.30 (m, 9H), 1.12–1.04 ppm (m, 2H); MS (ESI): m/z calcd for C36H46N4O5S: 646.3,
found: 647.3 [M+H]+.

6-Methyl-benzo[b]thiophene-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-(4-aminotetrahydro-

pyran-4-carbonyl)piperidin-4-ylmethyl]carbamoyl}ethylcarbamoyl)cyclopentyl]-amide (56c).
For a similar synthesis see compound 25c. HPLC: (A) 3.7 min, 98% purity; mp: 148–150 °C; 1H
NMR (600 MHz, [D6]DMSO): δ = 8.81 (s, 1H), 8.23 (s, 1H), 7.86–7.82 (m, 3H), 7.54 (br t, J = 5.8
Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H), 7.20–7.11 (m, 5H), 4.64 (br s, 2H), 4.46–4.42 (m, 1H), 3.69–3.65
(m, 2H), 3.52–3.49 (m, 2H), 3.17 (dd, J = 13.9, 3.9 Hz, 1H), 3.02–2.98 (m, 1H), 2.95–2.90 (m, 1H),
2.85 (dd, J = 13.8, 10.7 Hz, 1H), 2.68–2.59 (m, 2H), 2.45 (s, 3H), 2.21 (dt, J = 14.0, 8.1 Hz, 1H),
2.01–1.41 (m, 16H), 1.04–0.95 ppm (m, 2H); MS (ESI): m/z: 674.2 [M+H]+; calcd for
C37H48N5O5S: 674.3376, found: 674.3381.

1.7 Compounds corresponding to Scheme 7

Ethyl tetrahydro-2H-pyran-4-carbimidate Hydrochloride (60). A 4 M HCl solution in dioxane

(4.8 mL) was added to a solution of nitrile 59 (0.50 g, 4.50 mmol) in EtOH (0.3 mL). The solution
was left at 4 °C for 2 d, then Et2O was added to precipitated the product which was filtered off and
dried. Compound 60 (660 mg, 76%) was obtained as a hydrochloride. 1H NMR (200 MHz, CDCl3):
δ = 4.67 (q, J = 7.0 Hz, 2H), 4.02 (td, J = 11.7, 3.3 Hz, 2H), 3.55–3.41 (m, 2H), 3.33–3.37 (m, 1H),
1.92–1.81 (m, 4H), 1.50 ppm (q, J = 7.0 Hz, 3H).

6-Methyl-benzo[b]thiophene-2-carboxylic acid {1-[1-(R)-({1-[imino-(tetrahydropyran-4-yl)-

methyl]-piperidin-4-ylmethyl}-carbamoyl)-2-phenylethylcarbamoyl)-cyclopentyl}-amide
Trifluoroacetate (61a). Hydrochloride 60 (39.0 mg, 0.20 mmol) was added to a solution of amine
40 (100.0 mg, 0.18 mmol) and Et3N (38 µL, 0.27 mmol) in EtOH (3 mL). The resulting mixture
was heated at reflux for 24 h, then the solvent was removed under reduced pressure and the residue
was purified by preparative HPLC (Symmetry C18, 300 Å, 300 mm × 19 mm, 7 µm, H2O + 0.1%
TFA / MeCN + 0.1% TFA, gradient 30 to 60% MeCN in 40 min, flow rate 20 mL/min). HPLC: (A)
3.8 min, 98% purity; 1H NMR (600 MHz, [D6]DMSO): δ = 8.85 (d, J = 5.5 Hz, 1H), 8.64 (s, 1H),
8.51 (s, 1H), 8.25 (d, J = 2.2 Hz, 1H), 7.89–7.85 (m, 2H), 7.82 (s, 1H), 7.59 (dt, J = 8.3, 5.9 Hz,
1H), 7.29 (d, J = 8.2 Hz, 1H), 7.21–7.12 (m, 5H), 4.46–4.40 (m, 1H), 4.22–4.17 (m, 1H), 4.07–4.03

16
(m, 1H), 3.92–3.87 (m, 2H), 3.46–3.41 (m, 2H), 3.05–3.06 (m, 5H), 2.97–2.83 (m, 2H), 2.45 (s,
3H), 2.26–2.18 (m, 1H), 1.93–1.45 (m, 14H), 1.27–1.16 ppm (m, 2H); MS (ESI): m/z calcd for
C37H47N5O4S: 657.3, found: 658.4 [M+H]+.

6-Methyl-benzo[b]thiophene-2-carboxylic acid {1-[1-(R)-({1-[ethylimino-(tetrahydropyran-4-

yl)-methyl]-piperidin-4-ylmethyl}-carbamoyl)-2-phenylethylcarbamoyl)-cyclopentyl}-amide
Trifluoroacetate (61b). Triflic anhydride (98 µL, 0.57 mmol) was added to a solution of amide 62
(70 mg, 0.44 mmol) and pyridine (55 µL) in CH2Cl2 (3 mL) at –40 °C. The reaction mixture was
stirred at –40 °C for 2 h, then a mixture of amine 40 hydrochloride (244 mg, 0.42 mmol) in CH2Cl2
(10 mL) was added. The reaction mixture was stirred at –40 °C for 1 h, then warmed to room
temperature and stirred overnight. A 5% aq. NaHCO3 solution was added and the organic phase was
separated and dried. After removal of the solvent under reduced pressure the residue was purified
by preparative HPLC (Symmetry C18, 300 Å, 300 mm × 19 mm, 7 µm, H2O + 0.1% TFA / MeCN +
0.1% TFA, gradient 30 to 60% MeCN in 40 min, flow rate 20 mL/min). HPLC: (A) 4.0 min, 99%
purity; 1H NMR (600 MHz, [D6]DMSO): δ = 8.86 (s, 1H), 8.26 (s, 1H), 7.88 (d, J = 8.5 Hz, 1H),
7.86 (d, J = 8.2 Hz, 1H), 7.82 (s, 1H), 7.58 (br t, J = 5.6 Hz, 1H), 7.29 (dd, J = 8.2, 0.9 Hz, 1H),
7.21–7.12 (m, 5H), 4.44 (ddd, J = 10.9, 8.6, 4.2 Hz, 1H), 4.04 (br s, 2H), 3.92 (dd, J = 11.1, 3.9 Hz,
1H), 3.46–3.11 (m, 9H), 2.99–2.94 (m, 1H), 2.87 (dd, J = 13.9, 10.9 Hz, 1H), 2.45 (s, 3H), 2.22 (dt,
J = 13.4, 8.0 Hz, 1H), 1.93–1.45 (m, 14H), 1.26–1.23 (m, 2H), 1.18 ppm (t, J = 7.1 Hz, 3H); MS
(ESI): m/z calcd for C39H51N5O4S: 685.4, found: 686.4 [M+H]+.

1.8 Compounds corresponding to Scheme 8

6-Methyl-benzo[b]thiophene-2-carboxylic acid [1-(2-(R)-phenyl-1-{[1-(1-methyl-1-

tetrahydropyran-4-ylethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-
amide Trifluoroacetate (74b). Amide 74b was obtained as a white freeze-dried material after
preparative HPLC (Symmetry C18, 300 Å, 300 mm × 19 mm, 7 µm, H2O + 0.1% TFA / MeCN +
0.1% TFA, gradient 30 to 70% MeCN in 40 min, flow rate 20 mL/min). HPLC: (A) 3.9 min, 99%
purity; 1H NMR (600 MHz, [D6]DMSO): δ = 8.87 (s, 1H), 8.26 (s, 1H), 7.89 (d, J = 8.6 Hz, 1H),
7.87 (d, J = 8.2 Hz, 1H), 7.79 (s, 1H), 7.64 (br t, J = 5.9 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.22–
7.13 (m, 5H), 4.46 (ddd, J = 10.9, 8.8, 4.2 Hz, 1H), 3.92–3.89 (m, 2H), 3.50–3.30 (m, 4H), 3.20
(dd, J = 13.9, 4.0 Hz, 1H), 3.14–3.09 (m, 1H), 2.94–2.88 (m, 2H), 2.85 (dd, J = 13.9, 11.1 Hz, 1H),
2.45 (s, 3H), 2.24 (dt, J = 13.5, 8.1 Hz, 1H), 2.06–1.45 (m, 15H), 1.36 (dq, J = 12.4, 4.2 Hz, 2H),

17
1.21 ppm (s, 6H); MS (ESI): m/z: 673.3 [M+H]+; HRMS: m/z [M+H]+ calcd for C39H53N4O4S:
673.3788, found: 673.3807.

6-Methyl-benzo[b]thiophene-2-carboxylic acid [1-(2-(R)-phenyl-1-{[1-(tetrahydropyran-4-yl)-

cyclopropyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
Trifluoroacetate (74c). Amide 74c was obtained as a white freeze-dried material after preparative
HPLC (Symmetry C18, 300 Å, 300 mm × 19 mm, 7 µm, H2O + 0.1% TFA / MeCN + 0.1% TFA,
gradient 20 to 50% MeCN in 40 min, flow rate 20 mL/min). HPLC: (A) 3.9 min, 99% purity; 1H
NMR (600 MHz, [D6]DMSO): δ = 8.82 (s, 1H), 8.23 (br s, 1H), 7.87–7.84 (m, 2H), 7.80 (s, 1H),
7.51 (br s, 1H), 7.29 (dd, J = 8.2, 0.9 Hz, 1H), 7.21–7.12 (m, 5H), 4.45 (ddd, J = 10.8, 8.8, 4.2 Hz,
1H), 3.81–3.79 (m, 2H), 3.30–3.24 (m, 3H), 3.18 (dd, J = 13.9, 4.1 Hz, 1H), 3.00–2.90 (m, 3H),
2.84 (dd, J = 13.8, 10.8 Hz, 1H), 2.45 (s, 3H), 2.23 (dt, J = 13.5, 8.1 Hz, 1H), 1.93–1.88 (m, 1H),
1.78–1.40 (m, 12H), 1.24–1.17 (m, 5H), 0.21–0.25 ppm (m, 4H); MS (ESI): m/z (%): 671.3
[M+H]+; HRMS: m/z [M+H]+ calcd for C39H51N4O4S: 671.3631, found: 671.3632.

18
2. cLog D and cLog P Data Tables

Table A. cLog D6.4, cLog D7.4 and cLog P values are reported for compounds 1, 25a-j and 37a-o.

O H O
N
Ar N N O
H O H N

Entry Ar
cLog D6.4 cLog D7.4 cLog P
1
H3C S 2.28 3.15 4.82
25a
2.63 3.5 5.16

25b
3.17 4.04 5.70
CH3

25c
H3C
3.17 4.04 5.70
H3C
25d
3.17 4.04 5.70

25e
3.38 4.25 5.92
Br

25f
Br
3.38 4.25 5.92
Br
25g
3.38 4.25 5.92
25h
3.77 4.64 6.31
I

25i
H3CO
2.62 3.49 5.16
25j
3.41 4.41 6.14
Et2N

37a
O
2.47 3.34 5.01

37b
O 2.77 3.64 5.30
CH3

37c
O
3.02 3.89 5.55
H3C
H3C
37d
O
3.42 4.29 5.96

37e O 4.29 5.16 6.83

C(CH3)3

(H3C)3C
37f
O
4.29 5.16 6.83
F
37g
2.37 3.24 4.91
O

19
Entry Ar
cLog D6.4 cLog D7.4 cLog P
Cl
37h
3.17 4.04 5.71
O

37i Br
3.00 3.87 5.54
O
I
37j
O
3.39 4.26 5.93
37k
Cl O
3.06 3.93 5.60
37l
Br O
3.16 4.03 5.69
H3CO
37m
O
2.46 3.32 4.99
F3CO
37n
O
3.50 4.37 6.03
Et2N
37o
O
2.77 3.70 5.42

20
Table B. cLog D6.4, cLog D7.4 and cLog P values are reported for compounds 1, 41, 52a-d, 56a-c,
61a,b and 74a-c.

O H O
N
N N
S H O H N
H3C R

Entry R cLog D6.4 cLog D7.4 cLog P

1 O
2.28 3.15 4.82
41 HO O
1.48 2.34 4.05
HO
52a O
1.29 2.15 3.86
52b H3CO O
1.42 2.29 3.96
H3CO
52c O
1.97 2.84 4.50
52d H3C O
2.66 3.53 5.20
O
56a 2.00 2.92 4.31
O

56b O
1.63 2.54 3.96
O
H2N
56c O

O
0.71 1.64 2.54
61a O 1.74 1.74 3.74
HN

61b O
C2H5N 4.12 4.12 6.12
74a O
2.53 3.37 5.17
H3C

74b O
H3 C
CH3
2.60 3.10 5.58
74c O 2.47 3.29 5.15

21