«2) United States Patent Ellsworth et al. (54) C-ARYL GLUCOSIDE SGLT2 INHIBITORS. AND METHOD (75) Inventors: Bruce Ellsworth, Princeton; Willan N. Washburn, Titusville; Philip M. Sher, Plainsboro; Gang Wu, Princeton Wei Meng, Pennington, all of NI(US) (73). Assigace: Bristol-Myers Squibb Company, Princeton, NJ (US) (©) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35, US.C. 15446) by 0 days. (21) Appl. No. 09/679027 22) Filed: Oct. 4, 2000 Related US. Application Data (60) Provisional application No. 6O194,15, filed om Ap. 5, 20a penal spon No 8,73, on (1) Inc COTH 18/20, AIK 31/70 (2) US.CL S$36/17.2; 536/111; 536/17.3; $36/17-4; $36/175; 534)18-4, 514866, (58). Field of Seareh 536/111 17 536/173, 174, 175, 18:4 514866, 50) References Cited US. PATENT DOCUMENTS SA40S0 A 8/1995. Kogan a FOREIGN PATENT DOCUMENTS 077325 BL 5/1907 ip O8SI-988 AL 1/1908 ® Stowe: Stoo we siowess 24907 w sigsias 3907 iP 24539191998 Wo woo7mIsss 1907 WO WODSSIOO7 A__7/1008, Wo WOos3I67 + 71005 WO Wo2oI0IO47 + 3/2001 (OTHER PUBLICATIONS. Koribayashi etal. “C-glyeosylated aryl tins: versatile build ing blocks for ayl C-glyeoside glyoomimetes.” Jouraal of Carbohydrate Chemistry, vol. 18, No. 4, pp. 371-382, 1999." Friesen et al, “Hydraboration of C-arylglucals. Synthesis of the bota.-Carylalucoside nucleus of ehaetiacandia,” Tet rahedron Letters, (1990), 31(43), 6133-6136." T, Kuribayashi etal, Journal of Carbobydate Chemisty, (1999) vol. 18, No. 4, pp. 371-382, W. Galield eta, Tetrahedron, (1978) vol. 34, No. 20, pp 3089-3006, ‘USO06414126B1 US 6,414,126 BL Jul. 2, 2002 (10) Patent No.: (45) Date of Patent: Benhaddou etl, Carbohydrate Research 260 (1994) pp. 243-250, Hongu et al, Chemical Phar Bul, (1998) vol, 46,No. 10, p. 1545-1565, Teujihara etal. Chemical Pharm, Bul. (1996) vol. 44 No. 6 pp. 1174-1180, Hongu etal. Chem. Pharm, Bull. (1998) vol. 46. No. 1, pp. 23, (ku et al, Diabetes. vol, 48 (1999) pp. 1794-1800 * cited by examiner Primary Examiner—Ralpls Gitomer Assistant Examiner—Devesh Khsate (74) Attorney, Agent, or Firm-—donathan N. Provost on ABSTRACT SGLI2 inhibiting compounds are provided bawving the fore rule and R™ are independently hydrogen, OH, ORS, lower alkyl, CF,, OCHE,, OCF,, SR" or halogen, of two of R?, RE and R°* together with the carbons to ‘whieh they ae atached ean form an annelated five, six fr seven membered earhoeyele 0 heterocyele; Rand R’ ate independently hydrogen, OH, OR™, OAL, OCH,Aryl, lower alkyl, cyeloalkyl, CE, —OCHE., OCF, halogen, —CN, —CO.R™, —COsH, COR", —CH(OHR™, —CH(OR RE, SCONR'R™, —NHCOR*, —NHSO-RS*, SNUSO.Aryl, Acyl, —SR', —SORY, —SO.R", =S0.Aryl, or a five, six or seven’ membered bteroeyele, of R® and I together with the cartons to Whieb they aze attached form an anelated five, ix ot seven membered carbocyele or heterocycle, Re, Rm, RO, RIS, RY RY, ROE, ROM and RO ae independently lower alkyl: R°, R™, R, R and R are independently hydrogen, ftkyLaryl alkylaryl or eyetoalkyl, or R® and R’ togeticr with the nitrogen lo which they are attached form a annelaed five, six or seven membered hetero= cycles Ais 0, 8, Nil, or (C ‘A method is also provided for treating diabetes and related diseases employing an SGLT2 inhibiting amount of the above compound alone or in combination with another fntiabetic agent or other therapeutic agent 0c 1s, No DrawingsUS 6,414,126 BL 1 (C-ARYL GLUCOSIDE SGLI2 INHIBITORS AND METHOD ‘This application elsims priority fom U.S, Provisional Application Ser. No. 60/158,773, fled Oet. 12, 1999, and US. Provisional Application Ser. No, 6/194,615 fled Apr. 5, 2000. FIELD OF THE INVENTION ‘The present invention relates to C-aryl glucosides which fare inbibitors of sodium dependent glucose wansporers found in the intestine and kidoey (SGLT2) and to a method for treating diabetes, especially type II diabetes, as well as hyperglycemia, hyperinsulinemia, obesity, hypestriglyeeridemia, Syndrome X, diabetic complications, atherosclerosis and related diseases, employing Sich C-aryl slucosides alone or in combination with one, two or more ‘ther type antidiabetic agent andjor one, 860 oF more other Iype therapeutic agents such as bypolipidemie agents, BACKGROUND OF THE INVENTION Approximately 100 million people worldwide suffer fom 'ype Il diahetes (NIDDM), which is characterized by hyper: slycemia due to excessive hepatic glucose production and peripheral insulin resistance, the root causes for which are as yet unknown. Hyperglycemia is considered to be the major Tisk factor for the development of diabetic complications, dnd is likely to contribute diretly to the impairment of insulin seertion seen in advanced NIDDM. Normalization ‘of plasma glucose in NIDDM patients would be predicted 10 improve insulin action, and to offset the development of diabetic complications. An inhibitor of the sodium- dependent glucose transporter SGLT2 inthe kidoey would be expected to ad in the sormalization of plasma glucose levels, and perhaps body weight, by enhancing. glucose ‘The development of novel sa, an orally active anti ‘etic agents is also desired in order to complement existing therapies including the sulfonylureas, thiazoliinediones, metformin, and insulin, and to avoid the poteotial side clfcts associated with the use of these other agents Hyperglycomia is a hallmark of type TI diabetes (NIDDM); consistent control of plasma glucose levels in labetes can offset the development of diabetic complica- tions and beta cell failure secn ia advanced disease, Plasma _lucose is normally filtered in the kidaey in the glomerulus tnd actively reabsorbed in the proximal tubule, SGLI2 appears to be the major tcansporter responsible for the ‘euplake of glucose at this site. The SGLT specific inhibitor phlorizin o¢ closely related analogs inhibi this euptake process in diabetic rodents and dogs resulting in normaliza tion of plasma glicose levels by promoting ghicose exer tion without hypoglyeemic side effects. Long term (6 month) treatment of Zicker diabetic rats with an SGLT2 inhibitor has been reported to improve insulin response to glycemia, improve insulin sensitivity, and delay the onset of nephe- ‘opathy and neuropathy in these animals, with no detectable pathology in the kidaey and 90 electrolyte imbalance in plasma, Selective inhibition of SGLT2 in disbetc patients ‘would be expected to normalize plasma glucose by enhane- ing the excretion of glucose inthe urine, thereby improving insulin sensitivity, and delaying the development of diabetic ‘complications. Ninety pereat of glucose reuptake ia the kidney oceurs in the epitelial cells of the early SI segment of the renal cortical proximal tubule, and SGLT2 is likely tobe the major 2 lcansporter responsible for this reuptake, SGLT2 is 672 ‘amino ac protein containing 14 membrane-spanning seg- ments that is predominantly expressed in the early Si segment of the renal proximal tubules. The substrate Specificity, sodium dependence, and localization of SGLT2 are consistent withthe properties ofthe high capacity, low finity, sodium-dependent glucose leansporter previously ‘characterizedin human conical kidney proximal tubules. In addition, hybrid depletion studies implicate SGLT2 as the predominant Na gluease cotransporter inthe SI segment of the proximal tubule, since virwally all Na-dependent ghi- ‘ose transport activity encoded in mRNA from rat kidney ‘cortex is inhibited by an antisense oligonucleotide specific to Fat SGLT2. SGLT2 is candidate gene for some forms of familial glucosuria, a genetic abnormality in whieh renal tlucose reabsorption is impaired to varying degrees. None ‘of these syndromes investigated to date map to the SGLT2 locus on chromosome 16. However, the studies of highly homologous rodent SGLTS siongly implicate SGLT2 as the major renal sodiam-dependent transporter of glucose and ‘suggest that the glucosuria locus that has been mapped ‘encodes an SGLT2 regulator. Inhibition of SGLT2 would be predicted to reduce plasma glucose levels via enhanced lvcose exeretion in diabetic patients. SGLT1, another Na-dependent glucose cotransporter that 's 60% identi to SGLT2 at the amino ackd level, is ‘expressed in the small intestine and in the more distal S3 ‘segment ofthe ensl proximal tubule, Despite their sequence Similarities, human SGLTI and SGLT2 are biochemical distinguishable. For SGLTI, the molar ratio of Na* 10 slucose transported is 2:1, whereas for SGLT2, the ratio is LL. The K,, lot Na*is32 and 250-300 mM for SGLT and SGLT2, respectively. Ky, values for uptake of glucose and the nonmetabolizable. glucose analog a-methyl-D- slucopycunosice (AMG) are similar for SGLT! and SGLT2, [ee 08 and 1.6 mM (glucose) and 0.4 and L.6 mM (AMG) for SGLT1 and SGIT2 transporters, respectively. However, the 1Wo transporters do wary in their substrate specificities for sugars such as galactose, which isa substrate for SGLTI only, ‘Administration of phloriin, a specific inhibitor of SGLT activity, provided proof of concept in vivo by promoting _slucose excretion, lowering fasting ad fed plasma glucose, And promoting. glucose utilization without hypoglycemic side effects in several diabetic rodent models and in one ‘canine diabetes model, No adverse effects on plasma ion balance, renal function or renal morphology have been ‘observed as.a consequence of phiorizn teatment for as Tong, asiwo weeks. In addtion, no bypoglyeemic or other adverse ‘effects have been observed when phlorizin is administered (0 normal animals, despite the presence of glycosuria, Admin- istration ofan inhibitor of renal SGLTS for a 6-month period (nab Seiyak) was eeported to improve fasting and fed Plasma glucose, improve insulin secretion and utilization in fohese NIDDM rat models, and alset the development of nephropathy snd neuropathy inthe absence of hypoglycemic ‘or renal side effets. Phloriin itself is unattactive as am oral deug since itis a nonspecifie SGLTISGLT2 inhibitor that is hydrolyzed in the gut to its aglycone phloretin, which is a potent inhibitor fof facilitated glucose transport. Concurrent inhibition of facilitative glucose transporters (GLUTS) is undesirable since such inhibitors would be predicted to exacerbate peripheral insulin resistance as well 2s promote byposlyce- mia inthe CNS. Inhibition of SGLT could also have serious adverse consequences as i Mlustated by the hereditary syndrome glucose/gslactose malabsorption (GGM), inUS 6,414,126 BL 3 ‘which mutations in the SGLT cotransporter result in impaired glucose uptake inthe intestine, and life-threatening diarrhea and debydration, ‘The biochemical differences between SGLI2 and SGLT1, as well as the degree of sequence divergence between them, allow for identification of selective SGLT2 inhibitors, ‘The familial glycosuria syndromes are conditions in ‘whieh intestinal glucose transport, and renal transport of ‘ther ions and amino acids, are normal. Familial glycosuria patients appear t0 develop normally, have oomal plasma slucose levels, and appear to sulfer no major health deficits, 4s consequence oftheir disorder, despite sometimes quite high (110-114 ply levels of glucese exerted. The major sympioms evident in these patients include polyphasia, polyuria and polydipsia, andthe kidneys appear to be normal in structure and function, Thus, from the evidence available ths fa, defees in renal reuptake of glueose appear to bave minimal long term negative consequences in otherwise normal individuals. ‘The following references disclose O-aryl glucosides SGLT2 inhibitors for twating diabetes. EP S983S9A1 (180 JP 035988) (Tanabe Seiyaku) discloses compounds of the following structure A gc aoa! Ro Ro" be EP 08509481 discloses strictures of the following ,, ‘genus B Rio” “ont : oe JP 091886254 expands upon structure B to include ‘examples of B where Ris Hand where the 5 membered ring 4 is saturated as well as the counterparts of benzothiophenes (5) and indenes (O=CH,), Ro” “oR! JP O9124085A expands upon sinicture B for R°=H to Include derivatives of mono acylated C6 hydroxyl where the acyl group isa substituted benzoic or pyridyl caeboxyli acd ‘oF 8 uretbane generated Irom the corresponding phenol 10" “ont . on JP 09124684 discloses derivatives of structure B sUS 6,414,126 BL 5 EP 773226-A1 discloses derivatives of stvcture B 0" oa! JP 08027006.A discloses derivatives of structure A where various combinations of the glucose hydroxyl are aevlated and appears to be similar to EP S98359AL [EP 684254-AL appears to encompass derivatives of srt ture B disclosed in JP 091886254. Other disclosures and publications which disclose SGLT2 inhibitors include the following: K Tujbara etal, Chem Pharm. Bull 44, 1174-1180 (1996) IM. Hongu et al, Chem. Pharm. Bull. 46, 22-83 (1998) M. Hongu et al, Chem. Pharm. Bull, 46, 1545-1555 (1998) ‘A. Okt tal, Diabetes, 48, 1794-1800 (1999) JP 10245391 (Dainippon) discloses. 500 structures as hypoglycemic agents for treatment of diabetes. These are O-glucosides of hydroxylated coumarins, WO 98/31697 discloses compounds of the structure ( (or, Where Ar includes, among others, phenyl, biphenyl, liphenylmethane, diphenylethane, and diphenylether, and R’ is a glycoside, R* is H, OH, amino, halogen, carboxy, alkyl, cycloalkyl, or earboxamido, and R? is hydrogen, alkyl, of acyl, and K, m, and a are independently 14 A. subset of compounds disclosed in WO 98/31697 contains ‘compounds of the following structures 5 s on hich are disclosed for use inthe treatment or prevention of| inflammatory diseases, autoimmune diseases, infections, cancer, and cancer metastasis, repecfusion disorders, thrombosis, west, wounds, osteoporosis, diabetes. mellitus and atherosclerosis, among bers DESCRIPTION OF THE INVENTION In accordance with the present invention, Caryl gluco- side compounds are provided which have the structure “out ‘wherein RY, R* and R° are independently bydroxen, OH, OR, alkyl, CF, OCHE, OCF, SR™ or halogen, oF two of IR, Rand R° together wih the euebons to which they are attached can form an annelated five, six or seven membered carboeyele or heterocyele which may con- iin 1 10 4 heteroatoms in the ring which are N, O, 5, ‘and R' are independently hydrogen, OH, OR", OAry OCH,AryI alkyl cyeloalky, CFs, -OCHFs, OCF, bulogen, —CN, —-CO;R°*, —COcH, —COR™, —CH. COT)Res, —CHCOR™ RG —CONRER™, NIICOR™, —NHSO,R™, —NUSO.Aryl, Aryl, SR, SOR —$0,R'*,S0.Aryl, oF ive, six ‘orseven membered heterocycle which may contain 1 10 4 heteroatoms inthe ring which are N, 0, 8,0, and/or ‘ot R° and R* together with the carbons to which they ate attached form an annelated five, six or seven membered carbocyele or heterocyele Which may con- tain 1 to 4 heteroatoms inthe ring whieh are N, 0, S, 80, sadior SO. RE, RR RR RE RR RM and RS ate independently alkyl; R°, R, R®, R® and R are independently hydrogen, Alkyl, aryl, alkylaryl or eycloakyl, or R® and R™ togetier with the nitrogen to which they are attached orm an annelated five, six or seven membered betero- cele which may contain Ito 4 heteroatoms inthe ring whieh are N, 0, 8, SO, andior SOs;US 6,414,126 BL 7 Ais O, S, NHL, or (CH), where n is 0-3, and a pharmae ceutcaly acceptable salt thereof, all stereoisomers thereof, and all prodrug esters thereat. ‘The compourals of formula I of the invention as defined shove also include the proviso that where Ais (CH,), where 11180, 1,2, or 3.0r Ais O, and at feast one of RY, RE, and Ris Of or OR, then at east one of R",R° and Reis CF, OCF, oF OCH, andior atleast one of R® and Ris CF OCF, OCF, CHOR™R™, CHOHDR®, COR, SCN, “-€0,R3*, —NHCORS, —NHSO.R**, NHSO.Any1, Aryl, —SR", SOR, —SO.R of —S0.Ary1 Prefered compounds of formula 1 as defined shove inelude the proviso that where Ais (CH,), where is 0,12 ‘or 3 or \isO, and atleast one of RR, 2, RE ‘OF or OR®, then at least one of RE, RE, ‘OCF, oF OCH; andior atleast one of R® and Ris CE OCF, —OCE,, CN, —COR™, CHOR"R™, —NHCOR*, —NHSO.R, —NHSO.AryL, Aryl, SR" SOR, —S0,R°5, —SO-Ars or aloe. ‘The compounds of formula I possess activity as inhibitors of the sodium dependent glucose transporters found in the imtestine and kidney of mammals and are wseful in the tweatmeat of diabetes and the micto- and macrovascular complications of diabetes such as retinopathy, neuropathy, nephropathy and wound healing “The present inveation provides for compounds of formula I, pharmaceutical compositions employing sich compounds and for metbods of using such compounds mn addition, in accordance with the preseat invention, a method is provided fr weating or delaying the progression ‘or onset of diabetes, especially type I and type II diabetes, ineluding complications of diabetes, including retinopathy, neuropathy, nephropathy and delayed wound healing, and ‘elated diseases such as insulin resistance (impaired glucose homeostasis), hyperglycemia, hypernsulinemis, elevated blood levels of fatty acids oF glycerol, obesity, hyper demia including byperteiglyeeridemia, Syndrome X, athero- sclerosis and hypertension, and for increasing high density protein levels, wherein a therapeutically effective amount of a compound of structure I is administered to @ human patient in need of teatment Tn addition, in acconlanee with the present iaveaton, eating diabetes and related diseases ter, wherein a therapeutically effective amount ofa combination of a compound of sive ture [and another ype of antidisbetisagemt andor another |ype of therapeutic agent sich as a hypolipidemie ageat is, sxiministered to & human patient in need of tresiment ‘The conditions, diseases, and maladies collectively refered to as “Syndrome. X" (aso known as Metabolic Syndrome) re detailed in Jobanasson J. Clin. Endocrinol Metab, 82, 727-34 (1997) ‘The tem “orer type of therapeutic agents” as employed hein refers to one oF more antidiabetic agents (other than SGLT2 inhibitors of formula 1) ane oe more anti-abesty gens antichypertensive agents, antiplatelet agents, anti atherosclerotic agents andior one or more lipid-lowering gents (including aniatherosclross agents), Tn the above method ofthe invention, the compound of ucture I of the invention will be employed in a weight ratio to the on, two oF more antidiabetic agent andor one, two or more other type therapeutic agent (depending upon its mode of operation) within the rang from about 001-1 10 shout 30:1, preferably from about 0.11 to about 10:1 8 : er a B 10 ont ‘Ais CH, of O or S and is linked mets to the glucoside; RR, Rand R™ are independently selected from H, lower Alkyl, halogen, OR’, or OCH, or two of R?, R® and [R= are H and ihe other is lower alkyl, halogen, OR or och: lependently selected from lower alkyl, F., —SR™, OH, —CO.R®, 3 (OCHO, —CoR™, —CHOIR™, —CHOR™) | aryl, NHSO.Aryl, =NHSO.R, COOH, thisdiazole, tettazole, Fyl, -OCF,, OAryl, or H. More preferred are compounds of formula T where A is Cus, 0 is hydrogen, halogen or lower alkyl; RE and R™ are each Hi; Ris He R° is lower alkyl, COR, —CH(OH)R™, —CH(OR™) R™, RO, —-OCHP, OCF, of —SR™. Most preferred are compounds of formula Tof the strc ture IB s ‘where R? is hydrogen, halogen or lower alkyl and "is, «lower alkyl, R°°O, —OCHE,, or —SR™- Iti preferred that R’ be linked para to the glucoside bond and the R* sub- stituet be linked at the para position DETAILED DESCRIPTION OF THE INVENTION ‘The compounds of formula I of the invention ean be prepared a shown in the following reaction schemes andUS 6,414,126 BL 9 description thereof wherein dlogtees Centigrade peratures are expressed in Compounds of formula {ean be prepared as shown in. ¢ Scheme 1 by treatment of compounds of formula neo with Hz in the presence of a catalyst such as 1) PWC ‘employing a solvent such as MeOH or E:OH or 2) preferably. Pd(OH), using a solvent such as EIOAc. Alternatively ‘compounds of formula I ean be prepared by treatment of ‘compounds of formula I with «Lewis acid such BB, BCI, for BCI,.Me,S in a solvent soch as CH.CI. at ~78%, Com: pounds of formula Tan also be prepared by treatment of ‘compound of formula I ia a solvent such as E:SH con: taining BFE, a 20°. Compounds of formula I (which are novel intermediates) ‘ean he prepared by treatment of compounds of formula I with silanes such as E1,SiHT or preferably (iP9);Si in a solvent such as MeCN or mixtures of MeCNiCI taining a Lewis acid such as BFE at ~30° Py Compounds of formula III (which are novel intermediates) can be prepared by coupling of 4 compound of formula 1V swith compound V. s 10 “one pounds of formu LV are setivated for coupling by teeatment with n-BuLi of -BuLi at =78" in solvent sich as ‘THE prior to addition of lactone V. Preparation of lactone V is described in. R. Benhaddou, S Czernecki, eta, Carbo- Inyidr Res, 260 (1994), 243-250, ef bao” “ope ay 4. at Pi Compounds of formula IV where A is (Cl nneL-3 can be prepared as shown in Sebeme 2 by teatment ‘of compounds of formals VIUS 6,414,126 BL uw uw “Se OG" wile with silanes such as EL Sif] in 2 solvent such as MeCN oF ‘CHCl, containing a Lewis acid such as BE, E10 or TFA at =H" 10 60", Compounds of formula VI can be prepared by coupling ‘commercially avaiable beomobenzaldchsdes of formula VIT By ‘wit ether the lithium or magnesium organometaic deriva- tive of compounds of formula VII in a solvent such a8 E1,0 o¢ THE using conditions familiar te those skilled in the ar. Compounds of formula VI are either commercially available or readily prepared by slandard methods known 10 those skilled inthe at ‘Shem? . thy gat fool s Compounds of formula L where Ris CHOR*R™ can, be prepared by treatment of compounels of foeula I where Ris COR™ sequentially with 1) an aetylaing agent such a8 Ac.0 in a solvent such as pyridine alone or CHCl: ‘containing 1.5 equivalents of 2 base such as EIN, 2) a reducing agent such as NaBH, i a solvent such as EXOH, 3) an alkylating agent such as R°*Br or RMT inthe presence of base sich 38 NAH in a solvent such as DMF, and 4) tlkaine ester hydrolysis conditions sich as LiOH in a 2:31 mixture of THE/MeOHH.0, Compounds of fra I where Ris CH{OH)R™ ca be prepared by treatment of compounds of forma T where Re SCOR" witha reducing agent sich as NaBH in solvent such 38 E1OH. Compounds of formula T where R* is COR can be prepared by teatment of compounds of formula H where RE 55 COR" wilh 3 Lewis acid such a8 BCI, or BBey at 78° ina solvent sich as CHCL Compounds of formula Ht where A is CH and R* is COR" can be prepared as shown in Scheme 3by coupling ‘commercially available or readily accessible compounds of Formula 1X. x eee on Be" 7 e nc” “one by heating the two componcas ina solvent such as PhMe ia the presence of a catalyst such as Pa(PPh,), Compounels of formula X (which are novel intermediates) ‘ean be prepared from compounds of formula XIUS 6,414,126 BL xt i by treatment with (Bu,Sn), and a catalyst such as PACPD,P), ina solvent such as toluene Compounds of formula XI (which are novel itermediates) can be prepared from compounds of formula XI bby treatment with silanes such a iPr,SiH or El,SiH in a solvent such as MeCN containing a Lewis acid sich as BPEI,0 at -30°, Compounds of formula XII (which are novel imermediates) can be prepared by coupling compound V ‘with the organolithium obtained upon tealment of com pounds of formnula XII =a) with n-Bul i of Bul iat -78° in THR. ee one wa au a. 14 continued B10 Fy Br oP mat” Yom e Rm wc” on f ws < an ‘An alternative synthesis (Scheme 4) of compounds of formula TV where A is CH, entails reduction of compounds ‘of formula XIVUS 6,414,126 BL xv with «reducing agent such as Et,Sil] in a solvent such as MeCN or CHCl, or mixtures thereof containing a catalyst sch a8 BF EL0. ‘Compounds of formula XIV can be readily prepared by Friedel-Cralt aeylation of commercially available hydrocat ‘bons of formula XV ref ‘with ceadily available acid elorides of formula XVL { a in solvent such as CS. containing two equivalents of Lewis Acid such 38 AICI, of AIBry s 16 Compounds of formula IL where A is 2 bond ean be prepared as shown in Seheme 5 by coupling compounds of formula XI with compounds of formula XVII . if moO Coupling entails heating in the presence of «catalyst such as PuPPh,), employing a solvent such as 3:1 PhMe/EOH ‘containing Na,CO,, Compounds of formula XVIL at either ‘commercially available or canbe prepared upon treatment of ‘compouls of formula XVIL with BCI, ina solvent such a8, H.C, Compounds of formula XVII cua be prepared by heating compounds of formula XIX ye “OQ in solvent such as DMSO containing a catalyst such as PaClcppf anda base such as KOAc with compound XX. ok xxUS 6,414,126 BL 17 18, aE ST TSR yao? i nso” one Bo "OBn o J apn a = ‘of compounds of formula XXI 0" oi xxt 20 io ons a " = at Sone aa) with » base such as Nall followed by heating with com cs ©. ° Compounds of formula XXI ean be prepared from com- 3s = = .O « 7 x ® s uo “won by teatment with silanes such as ELSIF or EPr,SiH in aso solvent such as McCN containing a Lewis acid sich as BP, E10 at -30", Compounds of formula XXII can be prepared by coupling the compound of formula V with activated metallated derivatives of compounds of formula XXIIT Compounds of formula 1, where AO or NH, ean be prepared as shown in Scheme 7 by coupling compounds of Formula XXIV s t ‘which are prepared by sequential teatment of XXII with a. 6s base such as Nall, KH, or KOWBu followed by ao alkyl. with commercially available compounds of formula XXV lithium such as nBuL ior BuLjina solvent such asdry THF. where X=O or NHLUS 6,414,126 BL 19 “G by heating ina solvent such a5 pyridine containing hase such a5 ELN, a catalyst such as Cu(OAe), and molecular Compounds of formula XXIV (which are novel imermediates) ean be prepared by treating, compounds of formula XXVI with BCI, in a solvent such as CHCl, at 78" xxv Compounds of formula XXVI (which are novel intermediates) can be prepared by beating compounds of formula X1 with compound of formula XX ina salvent seh as DMSO containing a catalyst sueh as PaCI, dppf and a base such as KOAC, s cxloaen QO e xxv where =O 0° NL iO Compounds of formula IV where A is O or NH ean be prepared as shown in Seheme 8 by eoupling compounds of la XVII ‘with compounds of formula XXVI where X=O or NH x i by heating in a solvent such as pyridine containing a hase sich a8 EIN, 4 catalyst such a8 Cu(OAC), and moleculae he THOR “OUS 6,414,126 BL 2 continued Compounds of formula IV where A is S ean be prepared asshowa in Scheme 9 by coupling aryl disulfides of formula XXVIIL with the ganic upon metalation of com pounds of formula XII with n-BuLi or THE. “78° in Listed below are definitions of various terms used in the dlscripton ofthe instant invention. ‘These definitions apply to the terms as they are used throughout the specification (unless they are otherwise: limited in specific instances) either individually or a part of a larger group. ‘The following abbreviations are employed berein Phephenyl Basbenzvl ‘eBustertiary butyl Me~metbyl Etecthy "TMS=trimethylsiyl "TMSN, -irimethybilyl azide “TBSxtert-butylaimethysilyl THR-tetrahydrofuraa DMFedimethyl formamide McOHemethanol E:OH=ethanol i-PrOH isopropanol s 22 HOAc of AcOH=acetic acid TFAstrifhuoroacetic acid Pr,NEt=diisopropylethylamine Ex, Netriethylamine DMAP=-dimethylaminopyriine NaBH rsodium borohydride LLiAIH lithium aluminum hydride n-BuLisn-butylithiam Pu/Cepalladium on carbon KOI potassium hydroxide [NaOHtasodium hydroxide LiOHelithium hydroxide K,CO,=potassum carbonate NallCOsesodium bicarbonate EDC (or EDCHC) or EDCI (or EDCLHCD or EDACe: ‘ethyl-8-dimethylamino)propyl-carbodiimide hydcochlo- Fide (or 1-(3-dimethylaminopropyl)3-ethylearbodiimide hydrochloride) HOBT or HOBEH.O=1-hydroxybenzotriazole hydrate HOAT=1-Hydrony-T-arabenzotriazole Ph,Ptripheny phosphine PaO Ac). «Palladium acetate (Pb,P),PaP=tctrakistrphenylphosphine palladium Areargon Neenitrgen rmin=minue(s) hor brehour(s) Letiter mL-miliiter ALemicroiter Besram(s) mg=milligram(s) ‘mol=moles ‘imolemillimole(s) meqemillicguivalent T=room temperature sat or sa desaturated agaaqueous ‘TLC-thi layer chromatography HPLC=high porfoemance liquid chromatography LC/MS=high performance. liquid: chromatography/mass specttometty MS or Mass Spec=mass spectrom NMR-nuclear magnetic resonance mpemelting point ‘ppf=diphenylphosphinoferrocene Unless olberwise indicated, the term “lower alkyl” as ‘employed herein alone or as part of another group includes hath siraight and branched chain hydrocarbons containing 1 to 8 carbons, and the terms “alkyl” andl “alk” as employed herein alone or as part of another group includes both Straight and branched chain hydrocarbons containing 1 t0 20, ‘carbons, preferably 1 to 10 carbons, more preferably 1 to 8 carbons, i the normal chain, such as methyl, ethyl, props, isopropyl, butyl, butyl, isobutyl, pentyl, hexsl, Robexsl, heptyl, 44cimethylpentyl, octyl, 22,4-eimethylpentyh roy, decyl, undecyl, dodecyl the various branched ebai isomers thereof, andthe like as well as such groups includ- ing Ito 4 substituents such as halo, for example F, Br, Clof Tor CF, alkyl alkoxy, aryl aryloxy,aryltaryl) or diary, arylalkyl, arylalkyloxy, alkenyl, alkynyl, cycloalkyl, ‘cycloalkenyl, cycloalkylalkyl, cyeloalkylalkyloxy, option” ally substituted amino, hydroxy, hydroxyalkyl, acyl, alkanoyl, heteroaryl, beteroaryloxy, cycloheteroalkyl, arylheteroaryl, arylalkoxyearbonyl, heteroarylalkyl, heleroarylalkoxy, aryloxyalkyl, aryloxyaryl, alkylamido, alkanoylamino, arylearbonylamnino, altro, eyano, thiol, haloalkyl, trihaloalkyl andior alkylthio. eyUS 6,414,126 BL 23 Unless otherwise indicated, the term “cycloalky!” as «employed herein alone ot as part of another group includes. Saturated or pactially unsaturated (containing 1 or 2 double bonds) eyelie hycraearbon groups containing 1 to 3 rings including monoeyeticalky, bicyclicalky] and trieyclicalkyl, containing 2 total of 3 10 20 carbons forming the rings, preferably 3.010 carbons, forming the ring and which may be fused to 1 or 2 aromatic rings as described for aryl which include cyclopropyl, eyelobuty, eyelopeatyl, eyclobexyl, ceyelohepiyl, eyclooetyl, eyclodecyl and cyelododeeyl, ‘eyelohexens, Qe A CO .a any of which groups may be optionally substituted with 110 4 sustiuents such as halogen, alky, alkoxy, hydroxy, aryl, aryioxy, arylalkyl cycloalkyl, alkylamigo,allanoylamino, (x0, acyl, arylearbonylamino, amino, nto, cyano, thiol andlor alkylthio and/ot any of the alkyl substituents. “The term “cycloalkenyl” as employed herein alone oF a8 part of another group refers to eyclic hydrocarbons eontain Ing 3 0 12 carbons, preferably 5 to 10 carbons and 1 or 2 double bonds. Exemplary eycloalkenyl groups include ‘yelopenteayl, cyclohexeayl, cyclohepteayl, eyeloocteasl, cyelahexadienyl, and eyeloheptadienyl, which may be ‘optionally substituted as defined for eyeloalky "The term “alkanoyl” as used herein alone o¢ as past of another group refers to alkyl linked to eathony] group. Unless otherwise indicated, the term “lower alkenyl” as used herein by iself or as part of anotber group refers 10 ight or branched chain radicals of? to 8 carbons, and the ‘erm “alkenyl” as used herein by itself or a part of anther ‘group relers to steaight or branched chain redials of 21020 carbons, preferably 2 to 12 carbons, and more preferably 2 to 8 carbons in the normal chain, which include one to six OS and may he optionally substituted through available eatbon 6s 1, 2, or 3 groups selected from hydrogen, halo, icy, haloalkyl, alkoxy, haloatkoxy, alkenyl, 126 BL 26 teiftuocomethyt, triluoromettoxy, alkynyl, eyeloalkybalkyl, ‘cycloheteroalky|, cyeloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylearbonyl, ‘arylalkenyl, aminocarbonylaryl, arylihio, arylsullinyl, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryh, heteroaryioxy, hydroxy, nitro, eyano, amino, substituted amino wherein the amino includes 1 or 2 substituents (which ane alkyl, ary or any ofthe other aryl compounds mentioned inthe definitions), thiol, alkylthio, arytio, heteoarylthio, acytbioalkyl, alkoxyarylbio, alkylearboayl, arylearbooyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxyearbonyl, aminocarbonyl, alkylearbonyloxy, arylearbonyloxy, alkylearbonylamino, arylearbonylamino, arylsulfinyl, arylsulinylakyl, arylsulfonylamino and arylsulfonam nocarbony! andior any of the alkyl substiuents set out herein, Unless otherwise indicated, the term “lower alkoxy", alkoxy", “aryloxy” or “aralkoxy” as employed herein alone ‘oras pat of another group includes any of the above alkyl, aralkyl or ary] groups linked to an oxygen atom Unless otherwise indicated the term “substituted amino” as employed herein alone or as part of another group cefers to amino substituted with one or two substituents, which may be the same or different, such as alkyl, acy, arylalkyl, heteroaryl, heterourylalkyl, cycloheteroalkyl, cyclobeteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hycoxyalky, alkoxyalkyl and thioalkyl. These substituents may be further substituted with 2 carboxylic scidandior any of the alkyl substituents as set out above. Io addition, the amino substituents may be takea together with the nitrogen atom to which they are allached to form L-pyctolidinyl, L-piperidinyl, I-azepinyl, 4-morphotinyl, 4thiamorphoiinyl, I-piperazinyl, 4-alkyl-I-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-liarylalkyl-t-piperazinyl, Lpyraliiny, L-piperidinyl, or I-tzepinyl, optionally sub ‘titted with alkyl alkoxy, aliythi, halo, tifuoromethyl oF hydroxy. Unless otherwise indicated, the term “lower alkylthio", “alkylthio”, “arylthio” or “aralkylihio” as employed herein alone or as part of another group includes any of the above alkyl, rally] or aryl groups inked to a sulfur atom, Unless otherwise indicated, the term “lower alkylamino", “alkylamino", “arylamino", or “arylalkylamino” as ‘employed herein alone or a part of another group includes any of the above alkyl ary or arylalkyl groups linked to @ nitrogen atom, Unless otherwise indicated, the term “acyl” as employed hereinby iself ora part of another eroup, a8 defined herein, refers © an onganie radical Linked to a carbonyl (i) group; examples of acyl groups include any of the alkyl Substituents attached to a carbonyl, such as alkanoyl, alkenyl, aroyl, aralkanoyl, heteroaroyl, eyeloalkanoyl, ‘eyeloheteroalkanoyl and the like Unless otherwise indicated, the term “eycloheteroalky!” 1s used herein alone or as pur of another group refers to & 5, 6- or T-membered saturated o partially unsaturated ring ‘which includes 1 to 2 heteroatoms such as nitrogen, oxygen andlor sulfur, linked through a earbon atom or a heteroatom, ‘where possible, optionally via the linker (CHL), (were pis 1,2 0¢ 3), sueh asUS 6,414,126 BL and the like. The above groups may include 1 to 4 substi. ents sueh as alkyl, halo, oxo andior any of the alkyl Substituents set out herein, In addition, any of the eyelobet- ‘roalkyl rings can be fused to a eycloalkyl, aryl, Betroaryl or eyelobeteroalky! ring. Unless otherwise indicated, the term “heteroaryl” as used hoteia alone oF as part of another group refers to 8 5- or ‘amembered aromatic ring Which includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen or sulfur, and such rings fused to an aryl cycloalkyl, heteroaryl or eyeloheteroalky] ring (¢-.,henvotbiophenyl or indolyl), and ineludes possible Neoxides, The hetemaryl group may optionally include 1 10 substituents such as any ofthe the alkyl substituents set out shove, Examples of hetemaryl groups include the Following: 28 continued she ke “The tem “eyelohtecoalkyayl” as used herin alone of spat of snaee group refers to cyclobeteroalks] groups 38 ‘efined above linked through 2 © atom or heteroatom t 4 (CH), chain. The’ term “heteroaryl” or “eteoarylakenyI” as used herein alone oF as par of another group refersto heteroaryl {group as defined sow linked though a C atom or hetero tom to 4 (CH), chain, alkslene or alkenylene. a6 Aelined shove. “The term “ive, six or seven membered earbocyele o¢ hteroeyle” a6 employed beten refers to eSelalKs] of «yeloalkenyl groups a dened above or heteroaryl groups ‘oF eyelohetetoaryl groups as defied above, such as thiadiavaot, tears, imidaate, or oxazoe “The term “polyhslalksl” 88 used erein refers 0 an “aly” group as defined above which inches from 2t0 9, preferably feom 2 to, halo substtvets, such F of CT, Proferaly F, sich a CECH, CF, of CF C=C, “Te term “polybaloalklony” as used herein refers to an alkoxy” oF “alkylory” group as defined above which Indes from 2 to 9, preferably from 2 10 5, balo substiuents, such as For Cl, preferably F, such as CFyCH.O, €F,0 ov CF.CF.CHLO. “The lem “prodeug eles” as employed herein includes ‘esters and carbonates formed by reacting one or more hydroxyls of compounds of formula T with aks, alkoxy, of aryl substituted acylating_ agents employing procedures Keown to those skilled in the art Io. generale acct, pivalaes, methyleatbonates, Benzoates and the like, Io Sktiom, prodrug estes which are known inthe aft for ‘athoxyli and phosphors aid esters sich as methyls ety, benzyl andthe like Examples of such prod estes include eco —, acogt—, veamcost—, w I inns ° I cawotocte—. ‘Where the compounds of stracture [ae i sed form they may form a pharmaceutically acceptable salt such as alkali metal sats such as lithium, sodium or potassium, alkaline ‘earth metal salts such as caleium of magnesiam as well 35 zine or aluminum and olber cations such as ammonium, ‘choline, diethanolamine, lysine (D or L), ethylenediamine, ebutylamine, t-oetylamine, tris-(hydroxymethyl) aminomethane (TRIS), N-methy] glucosamine (NMG), tr- ‘ethanolamine and dehydroabietylamin, All stereoisomers of the compounds ofthe instant inven- tion are contemplated, either in admixture oF in pure of substantially pure form. The compounds of the preseal invention can have asymmettie centers at any ofthe earbon atoms including any one of the R substituents, Consequently, compounds of formula I can exist in enan- tiomerie or diastereomerie forms oe in mixtures thereol. The processes for preparation ean uilize racemates, enantiomersUS 6,414,126 BL 29 ‘or diastereomers as starting materials, When dasereomeric ‘enantiomeric products are prepared, they can be separated by conventional metbods for example, elvomatographic or fractional crystallization, ‘Where desire, the compounds of stvcture Lay be used in combination wth one of more other types of antidiabetic gents andor one or more othe types of therapeti agents ‘which may be administered orally in the sume dosage form, ina separate oral dosage form ot by injection ‘These typeof antidiabetic agent which may be option- ally employe ia combination wit te SOLT2 inhibitor of be 123 or more antidiabetic agents OF “ages incling insulin seeretagogues or insulin sensitizers, oF olberanidabeic agents preferably having @ mechanism of action diferent ftom SGLT2 ini Ihion and may include biguanides, sulfonyl uress, gluos 90% lactl followed hy 9.7 g of >80% purity one pro “oR To a sticred ~40 solution of Part C lactol (78 g, 0.019 rol) in 100 mL-of MeCN was added E1,SiH (3.42 mL, 0.04 ‘mo}) followed by BF.E1.0 (1.37 mL, 0.02 mol) Ate I hr, ‘whea tc showed the reaction to be compete, saturated 34 °0, (10 mi.) was added and the suspension tiered 1 br al 20° prior to extracting 3% with EVOAc, The combined ‘organic layers were washed with HO, brine, dried aver 0, and concentrated using a rotary evaporator to yield 8 of crude product. Chromatography on silica gel with S% E{OAc/hexane eluted nonpolar impurities followed by 0.92 2 of pure tile Petr-O-benzyl C-glucoside followed by a 165 g containing both anomers s Wo Ho" “out ‘The shove Iwo fictions of Part D compound were hydrogenated separately over 10% PU(OH). (2% by weight) for overnight at 1 alomosphere H, in E1OAc (125 mLg of Part D compound). After filtration and solvent cemova, the hydrogenolysis product of the mixed fractions was purified by prep HPLC using a YMC S10 reverse phase column. The ‘combined material yielded 1.85 g of pure fr anomer as a ‘white solid HPLC retention time: 6.04 min, Zorbax C-18 4.6475 mm column, 2.5 mL/min, detection at 220 nM; 8 min gradient (0-100% 3 hold 3 min at 100% B. Solvent A: 10% MeOH 1.0402 % 1,PO,. Solvent B: 90% MeOIH0402 % H,PO,. ILNMR (400 Milz, CD,0D)57.28(6, 1H), 7.24 (4 2H, Jn3 Hz), 7.09 (my 3H, 6.79 (, 21h, m7 He), 4.08 (4, 111, 388 Hz), 3:88 (5, 2H), 3.75 (d, IH, J=12 Ha), 3.73 (5, 3H), 3465 (dd 1H, J=12, 3 Hz), 34 (m, aH) 13C NMR (100 Miz, CD,OD) 6 1586, 142.1, 140. 1338, 130.0, 128.7, 12816, 1283, 1258, 829, 81.3, 790, 755, Th, OS, 55.1, 41, Anal Caled for C,H, LEMS (M-H) 359; found 359. EXAMPLE 3 10%" “ont ‘To a stirred -78° solution of m-dibromobenzene (12.6 2, 53 mmol) in 50 mL-of dry THE under At was added 20/ ml ‘of 2.56 M n-BuLi (51 mmol in hexane over 10 min. After 40 min, 23,4,6-tett-O-benzyl-f-D-glucolactone (12 wy, mmol) in’ 30° ml. of THE was added over 15 min. The solution was sted for I heat ~78° (complete by He) priorUS 6,414,126 BL 41 fo quenching with saturated ag. NHCI (40 mL). Afr ‘warming to 20°, the reaction was diluted 2 fold with EXOAc prior to washing with H,O followed by brine. Afr drying. ‘over Ng,SO, and concentration using a rary evaporator, 20, ‘gf crude tile lactel was obtained as aa ol that was artied forward without further purification Boo “ona “To a sired ~45° solution of crude Pact A lctol (20 0.2 rol) in 60 mL of MeCN was added ELSiH (78 mL, 45 7 mmol) followed by slow addition over 20 min of BE, E1,0 (42m, 22 mmol). When complete by tle after an hour, the reaction was quenched by addition of saturated aq, K:CO, (25 mL) and the mixture was extracted 3x with EtOAc, The ‘combined organic layers were washed wit brine, dried over Na,S0, and concentrated using a rotary evaporator. The resilting oil was titrated with 50 mi hexane whereupon soli precipitated after standing for 1. This material was. collected by filtration, washed with cold hexane twice and air dried to yield 8.9 g of the desired tle f-m-bromophenyl- Conlucoside Boo “ons solution of Part B f-m-bromoptenyl C-lueoside (1.36 8, 2 mmol), PA(PP.), (0 mg, 0.06 mmol), and hexabu- iylistansane 2.724 g, 6 mmol inde toluene (10 mL) was heated with string under Ar at 80° for 15 br After removal 6 toluene using a rotary evaporator the residue was chr ratographed on silica gel using 12:1 EKOAG hexane to cite the desied tile aeyl stunnane (761 mig), plus mixed fractions, which tera second eoluma yielded a ations) 92-mg of clean tile sannane for a total yield of 48%, followed by 230 mg of recovered starting Part 1 fem. ‘omophensI-C-ghicuside s 2 Bo A mixture of Part B stannane (2.66 2,3 mmol), putivoromethoxybenzyl chloride (1.04 g, 6 mmol, and Pa(PPA,), (100 mg, 0.09 mmol) was refluxed under Ar in ‘THE (I'm for 15 he After removal of THF with a rotary ‘evaporator, the residue was chromatographed on silica gel using 10-1 hexane/EIOAc to elute 1.3 g ofthe desiged tile tetrabenzyl ether. Conversion fo the final free glucoside was achieved by tiring 295 mg of Part D tetrabenzylether with P&(OHD) mg) in E}OAc 3 mL_)under 1 atmesof H, for 15 he. The ile product (108 mg) was isolated after filtation, Peep HPLC, tnd removal of solvent. HPLC retention time: 721 min, Zorbax C-18 4.6475 mm ‘column, 2.5 ml/min, detection si 220 aM; 8 min gradient (0-100% B hold 3 min at 100% B. Solvent A: 10% MeOH! 120402 % H,PO,, Solvent B: 90% MeOIH,0402 % H,PO,. 1H NMR (400 MHz, CD,OD) 6 73 (m, SH), 7.15 (on, 3H), 4.10 (4, IH, Fe88 Hz), 3.99 (6, 2H), 39 (0, 1H, Jo13 Hz), 3.7 (dd, LH, J=12, 3 Hz), 3.4 (mn, 4H). Anal Caled for C,oH,,P,0, LC-MS (M-H) 413; found 43 EXAMPLE 4 0" 0 “on onUS 6,414,126 BL a continued A mixture of Example 3 Part B B.n-bromopbeayl-C- ghicoside (3.0 g, 4:41 mmo) and PACPPA,), (153 mg, 0.13 mmol), and hexaburyldistannane (60 g, 13.2 mmol) ia dry toluene (Sm) was heated with sling under Av at 88° for 3 br whereupon ti analysis inated te eatin was 90% complete The reaction was terminated afler total of Sb ‘Aft removal of tohene using « rotary evaporator, the residue was chromatographed on sila gel using 18 E1OAC/ hexane wo elute the 295 of desired aryl stannane so" “ona A mixture of Patt A stannane (2.66. g, 3 mmol), pmethylihiobenzyl chloride (04 mg, 60° mmol), and 'etrakis(triphenylphosphine)palladium (100 mg, 0.08 mmol) was relluxed under Ar ia THE (S mL) for 15 br. After removal of THF witha rotary evaporator, the residue was chromatographed on sliea gel using 6:1 hexane’E!OAc 10 lute 1.2 g ofthe desired tte tera-O-benzyl eter followed by 600 mg of ttle teri-O-henzylether containing PhP. « 1M BCIYCHLCI, (6 mL, 8 mmol) was aded over 5 minutes to steed 78° solution of Part B tetrabenzsl ether (295 mg, 0.4 mmol) under Ar in CHK min, when tle analysis indicated the 30 mil. of 2:1 CH.CIx/PhMe followed by 2 ml. of MeOH ‘were added. The volume was reduced by ball wing a rotary evaporator and 10 mL-of MeOH added. After repeating this process 3x, all the voluiles were removed under vacuum, ‘The residue was chromatographed on silica gel using 5% s 44 MeOH/CH,CLio eluted 143 mg ofthe desired glucoside in 90% purty. This material was futher purified by reverse phase preparative HPLC to yield 104 mg ofthe final desired tplucoside, HPLC retention time: 6.69 min, Zorbax C-18 4.6475 am column, 2.5 mln, detection st 220 aM; 8 min gradient (0-100% B hold 3 min at 100% B. Solvent A: 10% MeOH 1,040.2% H,PO,. Solvent B: 90% MeOWH,040.2 % HPO,. 1HLNMR (400 MHz, CD,OD) 8 729 (, 11), 7.25 (4,28, JZ M2), 7.15 (m, SUD, 4.09 (4, HL Jo88 He), 392(5, 2), 3.86 (4, IH, Jo13 Hz), 3.68 (dl, TH, Jo12, 3 2), 34 (on, 4H), 243 31). 10,8 LOMS (M-H) 395; found EXAMPLE 5 Ow To a stirred suspension of 60% NaH (180 mg, 4.5 mmol) in THF (7 mL. under Ar was added 2-bromophenol (350 iL, 3 mmol). Alter stcring for 15 min, the reaction was cooled to 78° and 1.4 M e-BuLihexane (2:36 mL, 33 mmol) was auded dropwise. After 10 mia, the solution was tansferced Via canaula to a stirred 78° solution of 2.34,-tera-O- henzyl-f-D-glucolactone (1.62 g, 3.0 mmol) in THF (5 mL). ‘The reaction was quenched after 15 min by slow addition of sat, NH,CUH.O and then allowed to warm to 20° where- upon 200 ml-of EtOAc was added. The onganie layer Was ‘washed successively with HO and brine, dried over MgSO,, and concentrated. Chromatography on silica gel With 3:1 hexane/EIOAe yielded 390 mg. ofthe desired ile het Bro “one ‘To a sted 3:1 misture of MeCNICH,Cly (4 mL) con- taining Part A lacol (390 mg, 0.62 mmol) at ~S0° was addedUS 6,414,126 BL 45 ELSIH (197 a, 1.23 mmol) and BF,ELO (78 4, 0.62 mmol). After hr the reaction was quenched by addition of [Um of st. K,CO,, warmed 10 20° and diluted with 100 mf. EiOAe, The organic layer was washed successively with HO and brine, died over MgSO4, and concentrated. Chro- wraphy on silica gel with 3:1 bexane EIOAe yielded 269 mg of desired tlle phenolic C-glucoside ba “one ‘Toa PhMe solution (L1 mL) of Part B phenol (139 mg, (022 mmol) uxler Ar was added 60% NaH (II mg, 0.27 mmol) After 10 min, 4-methylbenzyl bromide (46 mg, 0.25 mmo) was added as a solid to the blue solution which was then heated at 80° for 35 he wail eomplete by tle analysis, After cooling followed by addition of aqueous NH,CI, the reaction was diluted with EIQAc, The organic layer was washed successively with HO and brine, dried over MgSO, and concentrated, Chromatography on silica gel with 5:1 hexane/E1OAc yielded 71 mg of the desired title benzylglucasie. Subsequent bydragenolysis of Part Ctetr-O-benzy ght coside over Pd/C in MeOH under 1 atmos H yielded the Final tile product which was purified by preparative HPLC using a C8 reverse phase column a 45-90% MeOHH.O ‘gradi over 10 mia to elute the desired [C-glucoside (2 mg) HPLC retention time: 6.754 min, 100% pure, YMC $3. ‘ODS 4.6550 mm, 2.5 ml min, detection a 220 nM § min ‘gradient 0-100% B hold $ min at 100% B. Solvent A: 10% MeOHH,0+0.2% H1,PO,, Solvent B: 90% MeOHH,O+ 0.2% H,PO,. AHLNMR (500 MHz, CD,OD) 6 7.15 (dd, 1H, Je1.1, 7.7 Hz), 7.07 6,211,812), 7.02 (8, 2H, J=8.3 11), 6.96 (8a, TH, Jol.2, 7.7 He), 6.77 (1H, Je7-7 Ha), 4.44 (1H, J=88 Hz), 3.89 (6, 2H), 387 (@, TH, Ja2.2 Hz), 3.75 (dd, 1H, Jot, 12.1), 349-341 (mn, AH), 226 (6, 3D. ‘Anal Caled for CHO, LC-MS [M11] 361; found 361 s 46 EXAMPLE 6 A. p-Chloromethylacetophenone ‘To a sired solution of p-chlorometbylbenzoyl chloride (390 mg, 2.06 mmol) in 8 mL THF at -20° under Ar was added tributylphosphine (406 mg, 2.29 mMol). Ate stirring the resulting yellow solution for 20 min at =20°—15°, 0.7 mL of 3M methyl magnesium bromide in ether (2.1 minol ‘was added in one portion to generate a red solution which subsequently became orange over a 10 min petiod. The reaction was quenched by aden of IN ag, HCI After lilution with H,0, the mixture was extracted 3% with E\OAc, wasbed with 10 prio to drying over Na-SO,. The residue obtained alter removal of volatiles was chromate graphed on silica gel using 5% EOAchexane to elute 171 mg (50%) of p-chloromethylacctophenone. D 2 one ‘A misture ofthe stannane described in Example 3 Past C 800 mg, 0.33 mmo), p-chloromethylacetophenone (114 mg, 0.66 mmol), and PAPA), (20 mg, 0.09 mmol), tcipheaylphosphine oxide (180 mg, 0,65 mol), K5CO, (73 ‘mg, 0.55 mmol) was heated at 70° under Ac in THE (0.3 ml) for 16 br. After removal of THF with rotary evaporator, the residue was chromatographed on silica gel using 20:1 10 10-1 hexane/EIOAc 10 elute the desized ttrabenzyl ether (170 mg, 70%).US 6,414,126 BL 47 A solution of Part B tetrabenzy! ether (60 mg, 0.08 mmol) in CHCl, G mL) under Ar was cooled to ~78° prior 6 the addition of 0.8 mL of 1 MBCl, in CHCl. After string for {brat -78",a second 0.8 mL portion of 1 M BCI, was added othe sired reaction, After a second bour, 0.5 mil. of PhMe ‘was added followed by dropwise addition of 0.5 mL of McOH, The volatiles were removed using a rotary evapo- ratot; the process repeated after adition of 3 mL of a 2:1 mixture of CHCl MeOH. Chromatography of the esting 2 reside on sles gel eluting with 5% MeOH/EIOAc yielded 20 mg of tetra final product in 67% yield HPLC retention time: 2.35 min, 100% pure, YMC $3 ‘ODS 4.650 mm, 2.5 ml imin, deeetion at 220 nM; 4 min ‘gradient 0-100% B hold 4 min at 100% B. Solvent A: 10% MeOHVH,0+0.2% HPO,, Solvent B: 90% MeOMHO+ 0.2% H,PO,. ATENMR (500 MHlz, CD,OD: 8 7.88 (d, 2H), 7.27-7.34 (on, SH), 7.13 (d, 1H), 4.09 (4, 1H), 405 (s, 2H), 385 (a, 11D, 3.68 (da, 11D, 3.35-3.48 (m, 41D), 255 (6, 31D) SCNMR (500 MHz, CD,OD): 8 200.3, 1488, 1414, 141.2, 1363, 1302, 129.7, 139.6, 1293, 1270, 88.6, 822, 798, 764, 719, 63:1, 42.7, 266 ‘Anal Caled for C2,H.,0,, LC-MS (M¢NH44): 390.2; Found: 390.2 EXAMPLE 7 A stirred solution of the final product of Example 6 (15 img, 0404 mmol in $ mL of EIOH was cooled to 20° ‘whereupon NaBH, (5 mg 0.13 mmol) was added, After 20, min being complete by tle analysis, the reaction was {quenched with a few drops of saturated aq. NIIJCL After removal of the volatiles, the residue was chromatographed cosilica gel Elution with 5% MeOH/EIOAc yielded 10 mg, (67%) ofthe desized pred. HPLC retention ime: 5.2 min, 1K pure, YMC S3 ODS 4.650 mm, 2.5 ml/min, detection at 230 aM; 8 min 48 gradient 0-100% B bold 5 min at 100% B. Solvent A: 10% McOH/H,040.2% H,PO,. Solvent B: 0% MeOHH,O+ 02% HPO, AHLNMR (500 Milz, CD,OD): 8 7.21-7.32(m, SED, 7.16 (2, 2H), 7.10-7.11 (my, 1H), 4.77 (q, 1H), 408 (6, 1H), 3.04 (6. 2H, 386 (Gd, 1H), 3.68 (dd, 1H), 334-348 (m, 4H, 1.40 (@, 38), SCANMR (500 MHz, CD,OD): 8 1452, 1425, 141.5, 1409, 1298, 129.6, 129.5, 1392, 126.7, 126.6, $3.7, 82.2, 798, 764, 72.0, 632, 42.5, 255 ‘Anal. Caled for CzHae0, LMS (M#NH44): 392. found: 392.1 EXAMPLE 8. A. 5-Bromo-2-methylbenzoie Acid A mixture of o-toluic acid (28 g, 206 mmol), ron powder (074 g,13 mmo, and Br. (42x, 260 mmol Were sired at (0 for 3 hr. AL this point the reaction, which had proceeded ~40%, was diluted with 25 mL of CHCl, to Facilitate String. The reaction was then heated at 43° for 16 hr to ‘rive o completion, Upon cooling, th reaction was diluted ‘with CHCl, washed 2x with 10% NaHiSO3, 1x with brine priot to drying over Na,S0,, After removal of te volatiles, the residue comprising a 2:1. mixture of S-bromo. 10 S:bromotoluie acid was recrystallized fom 95% EtOH 10 Yield 14.4 g of S-beomo-2-methylhenzoie acid B. 5-Bromo-2-methyl-# methoxybenizphenone ‘To astimed suspension of S-bromo-2-methylbenmic acid (4.29 g, 6 mmol) in 12 mL of CHCl containing oxalyl ‘chloride (8 mmol) was added 2 drops of DME. Once the Vigorous evolution of gas ceased, the reation was sted 6 hrprior to removal of the volatiles using a rotary evaporator. Aller dissolving the eaude S-bromo-2-methylbenzovl chlo- Tide in 15 ml of CS. the stirred mixture was cooled to 4° prot to adding anisole (07 g, 6:6 mmol followed by AICI, (1.7, 22mmal). The action, after warming to 20° over 1 hr, ws sited for 15 he prior to quenching with IN HCL Subsequently the suspension was diluted with 50 ml HO tnd sized uni all solids were in solution, Tae mixture Was ‘exacted 3 with E1OAc. The combined organic extracts were washed 1x with IN HCl H.0, aq NaHCO,, and brine prior io drying over Na,S0,, After removal of tx volatiles, the resulting tun solid was recrystallized from 95% EIT «© yield 1.6 of 5-bromo-2-methyl-4-methoxybenzophenone. . $-Bromo-2-methyl-#-methoxydiphenylmethane A solution of EL,SiH (2.5 mL, 15.5 mmol), BF, E1,0 (13 mL, 10 mmol), and 3-bromo-2-methyl-4~ methoxybenzophenone (6 g,5.25 mmol in 1 mLofa 1-4 mixture CH,ClyMeCN was sted overnight at 20°, SinceUS 6,414,126 BL 49 by HPLC 5% of stating ketone remained, the solution was. heated to 40° for 1 hr prior to quenching with 10% NaOH, ‘After dilution with ILO, the reaction was extracted 3x with EiOAe. The combined organie layers were washed 2x with 1,0 snd once with brie before drying over Na,S0,. After removal of the volatiles, the residue was chromatographed fn silica gel using hexane to elute S-bromo-2-melhyls™ methoxydiphenylmethane as a colorless oil (14, 95%) b, ove Bio" ‘To a sired 78° solution of Past C S-bromo-2-methyl- -#-methoxydiphenylmethane (03 g, 15 mmol) in 7 ml of dry THE under Ar was added dropwise 0.9 mL of L8 M n-BuLi in hexane. After 2 hr, 2,3 6tetra-O-benzylp-D- slucolactone (0.88 g, 1.6 mmol) in 3 mL of THE was added ‘over 1 min, The solution was tired for 2 he at -78° prior to quenching with saturated aq. NH,Cl. After warming 10 20°, the reaction was diluted 2 fold with H.O prior t 3 exactions with E(OAc. The combined EtOAc fractions ‘were washed with brine and dried over Na,S0,. After ‘concentration using a rotary evaporator, 1 g of the desired title actol was obtained asa colorless syrup that was carried forward without further purification, ons ‘To 4 stirred -30" solution of Part D lactol (Lil g L47 mmol) in 10 mL. of MeCN was added iPr,SiH (0.7 g, 45 mmol followed by BF, E10 (0.38 g, 2.6 mmol) After 3 br at —40°—30", the reaction was complete by tle showed. ‘Saturated ag. K,CO, was added and the suspension stirred 1 he at 20° prior 10 diluting with H;0 and EtOAc. The ‘combined organic layers from 3 EIOAe extractions were ‘wasled with brine, dried over Na,S0,, and concentrated using a rotary evaporator to yield 1.2 g of a light yellow syrup. Chromatogeaphy on silica gel with 10% EtOAc hextne eluted nonpolar impurities followed by the desired beta C-arylghucoside (0.54 2), B 10% “ont A solution of Part Etetra-O-benzy C-glucoside (515 mg, 07 mmal) ia OAc (10 mL) containing 10% Pa(OH). (80 mg) was stirred overnight under 1 atmos. H HPLC showed the reaction to be complete, the catalyst was filtered and the solvent removed using a rotary evaporator to ‘obtain 4 white glassy solid that was furlher purified by Preparative HPLC using a C,, reverse phase column to ‘obtsin 220 mg ofthe desired beta C-plncoside as a colorless syrup. HPLC retention time: 6.43 min, 100%% pure, YMC S5 C-18 46x50 mm column, 2-5 mi_min, detection a 220 aM; 8 min gradient 0-100% B bold S min at 100% B. Solvent A: 10% MeOH,0+0.2% H,PO,, Solvent B: 90% MeOH H,0+02% H,PO,. "HNMR (500 Miz, CD,OD) 57.20 6, 1H), 7.18 (, 1H, $7 M2), 7.11 (G, IN, F072), 689 (AB, 41), 4.07 (2, 1H, 4329 Hz), 3908, 2H), 387 (m, IH), 3.70, 31D, 3.68 (2, THD, 3.48-3.30 (m, 4H, 2.16 (5, 34, NMR (125 MHz, CD;0D) 8 1593, 1403, 138.3, 1374, 1387, BLO, 13058, 1306, 1269, 1147, 8355, 821, TDS, 76.3, 719, 63.1, 35.6, 59.6, 19. ‘Anal Caled for Cz age LC-MS [M-H]373; found 373, EXAMPLE 9 oct Me 0% “Won 1-4"-hydroxydiphenylmethane ‘To a sired -78" 10 mL. CH.CI, solution of S-brom0-2- imethyl-4-methoxydiphenyimethane (1.0 g, 3.4 mmolySee Example 8, Part C for preparation) was added 4.12 mL of a 1M BBr,/CH,Cl Afiee hr, th reaction was maintained at 40° for 20 hr whereupon HPLC indicated no starting ether remained. The reaction was quenched with aq. NaOH, ‘exacted 3 with CHCl, washed with brine prior to drying, fover NisSO,, After removal of the volatiles, O84 g of S-bromo-2-methyl-4'-bydroxydiphenylmethane was ‘obtained a a syrup which was used without further puri B. 5-Bromo-2-methyl-# benzyloxyeliphenylmethane A-10 mL. DMP solution contsining Part A. 5-bromo-2- methyl-4-bydoxydiphenylmethane (735 mg, 2.65 mmol),US 6,414,126 BL 51 (548 mg, 32 mmo), and K.Co, (732 a 53 mmol) was stined overnight, The reaction was then at 60 for 6 br to drive the conversion from 80% to 100% Afler dilution with HO, the reaction was extracted 3x with E1OAc, The combined EIOAc layers Were washed ‘with HO and brine prior to drying over Na,S0,, The reside, after solvent removal under vacuum was chromato= ‘graphed on silica gel using 39 E1OAcrhexane to elute 785 mg of S-bromo-2-methyl-f-benzyloxydiphenylmetbane a a colorless syrup. ‘To a stired 78° solution of Past Bt S-bromo-2-methyl- 4-benzyloxydipbenylmethane (0.43 g, 12 mmo) in 7 mL of dry THF under Ar was added 0.68 ml. of 1.9 M n-BuLi in hexane dropwise, Ater 30 min, 2,34,6-etra-O-benzyl-D- slucolactone (0.7 g, 13 mmol) in 3 mL of THE was added ‘over | mia, The solution was sired for 0.75 br al-78° prior to quenching with saturated aq. NH,Cl. After warming 10 20°, the reaction was diluted 2 fold with H.O prior 3 exactions with E(OAc. The combined EtOAc fractions ‘were washed with brine and dried over Na,SO,. After concentration using a rotary evaporator, 0.96 g ofthe desired title lctol was obtained asa colorless syrup that was carried forward without further purification 10 mo To a sticred ~30° solution of Part C lato! (0.96 g, 1.16 mmol in 10 ml. of MeCN was added iPr,Sifl (0.37 g, 2.3 mmol) followed by BF, £1,0 (02 g, 14 mmol). After 3 br at -40°——30°, saturated ag. K,CO, was added and the suspension sttted 1 he at 20° prior to diluting with H,O and EiOAe, The combined organic layers from 3 E1OAc ext: tions were washed with brine, dried over Na,SO,, and ‘concentrated using a rolary evaporator o yield 1.2 g of a light yellow syrup. Chromatography on silica el with 9% EiOAcihexane eluted nonpolar impurities; 10% E\OAc! hexane eluted the desired beta C-arylghucoside (0.26 g). 52 A solution of Pat D penta-o-penzyl C-glucoside (255 my 031 mmo) in EVOAe (10 mL) contsining 10% POH) (65 mg) was stieed 24 br under 1 atmos. H,. Alier HPLC Showed the reaction tobe complete the eatalyst was filtered tnd the solvent removed using a rotary evaporator to obtain 115 mg of awhite glassy solid that was used without further purification. ‘A threaded tube containing a magnetic stirrer, 4 mL. of iPrOW and Part E phenolic C-slueosie (80 mg, 0.16 mmol) ‘as cooled to ~78" whereupon 1.5 pof CHCIF, was added by condensing the gos. After adding 3 mL-of 25% ag. NaH, the tube was sealed witha Teflon stopper and heated 70° for 2 be. By HPLC reaction contained & 2:3 mixture of starting phenol to desired ether. (forts to drive the con- Version by prolonged reaction times were sot siecessful) Aer cooling, ullicient IN HCL was added 0 bring the pH 2 whereupon most volatiles were removed using a rotary ‘evaporator, The residue, after dissolution in 2:1 MeOH/H.0, ‘was purified by preparative HPLC equipped with a YMC (yp reverse phase column (203K mm) employing 10 min linear gradient with 45%-90% aq MeOH at 20 mL min 10 yiekd 40 mg of the desited phenolic ether HPLC retention time: 6.6 min, 95% pure, YMC $5 C-18. 4.6550 mm goluinn, 2.5 mL-min, detection at 220M 8 min gradient 0-100% Bod 5 min at 100% B. Solvent A: 10% MeOH/H,040.2% H,PO,. Solvent B: 1% MeOHH,O+ 0.2% HPO, SHLNMR (400 MHlz, CD,OD) 8 7.22 (s, 1), 7.20 (on, 1H), 7.12 (m, 1H), 7.06 (AB, 4H), 6.73 (C,H, J=27 He), 409 (d, 1H, J=9 Fiz), 3.98 (5, 2H), 389 (d, 1H), 3.68 (40, THD, 347-3.30 (m, 411), 2.17 (6, 34D, 8C NMR (100 Miz CDyy gp » 138.7, 138.2, 137.7, 136.6, 1303, 130.2, 130.1, 126.4, 1193, 1170, 82.7, 814, 790, 75.6, T11, 623, 49, 388, 18.6, ‘Anal Caled for C.H4F2og LC-MS [M+NH4] 428; found 428.US 6,414,126 BL 53 EXAMPLE 10 A. 5-Bromo- AICI, (535 mg, 4 mmol) was added to a 40 stirred $ mL solution of crude S-bromo-2-methylbenzoy] ebloride (406 mg, 2 mmol) (for preparation see Example 8, part B) and thioanisole 270 mg, 2.3 mmol). The reaction, after swarming to 20° over Ihr, was sired for 2 hr prior to {quenching with IN TICL, Subsequently, the suspension was lifted with 50 ml HO and stirred nti all solids were in solution, The mixture was extracted 3x with EXOAc. The ‘combined onganic extracts were washed 1x with IN HCl, HO, aq Nal1CO,, and brine prior (0 drying over Na.S0, ‘iter removal of the volatiles, the residue was chromato ‘graphed on silica gel using 15% EtOAcibexane to elute 450, ing. of S-bromo-2-methyl-#'thiomethylbenzophenone 3s ‘white solid methyl-#'hiomethylbeazophenone B, S-Bromo:2-methyl-= thiomethyldiphenylmethane A solution of E1,Sill (145 ml, 285 mmol, BF5.E1,0 (03 mL, 24 mmol), and Part A 5-beomo-2-methyl-s ‘hiomethylbenzophenone (450 mg, 1.4 mmol) in 3 mL of a MeCN was stirred overnight at 20°. ‘After quenching with 10% NaOH and dilution with H,O, the reaction was extracted 3x with E\OAc. The combined ‘organic layers were washed 2x with HO and once with brine before drying over Na,SO,. Afier removal of the volatiles, the eesidue was chromatographed on silica gel EtOActhexane 10 elute 416 mg of 5-brome2 thiomethyldiphenylmethane as « colorless oil “ono Bio To a stirred 78° solution of Part B 5-bromo-2-metbyl- 4hiomethyldiphenylmethane (200 mg, 0.65 mmol) in 10, mL of dry THF under Ar was ated dropwise 0.42 mL of 1.8 Ma-BuL iin hexane, After 2 hr this solution was tansfeced by cannula to a stirred ~78° solution of 23,4,0-tet2-O- benzyl-f-D-glucolacione (088 g, 1.6 mmol) in $ mL of ‘THE. The solution was stired for 2 hr at -78° before ‘quenching with saturated ag, NHLCL After warming 10 20°, s 54 the seaction was diluted 2 fold with HO prior 3 exteac- tions with E(OAc. The combined) EIOAC fractions were Washed with brine and dried over Na,SO,, Aller concentra tion using a eotary evaporator, 350 mg of the desired tile Tnetol was obtained as'4 colorless syrup that Was carcod forward without further puriieation b, 0 “ons ‘To stirred -40° solution of Part C lactl (550 mg, 0.72 mmol) ia 6 mL of MeCN was added iPriHl (0.22 ml, L0 mmol) followed by BF E1,0 (0.11 mL, 08 mol). After 15 he at 10°30", when tle showed the reaction to be ‘complete, saturated ay. KCO, was added and the suspen- Son tired Ihr at 20° prior to diluting wit ‘The combined organte layers from 3 HO and EYOAc ‘and concen Tealed using a rolary evaporator. Chromatography of the residue om silica gel using 9% EIQAchhexane as eluant luted 240 mg of the desired beta C-arylslucosie. A solution of Part D tera-O-benzyl C-phvcoside (70 mg, (041 mmol) in EXSH (1.5 mL) containing BF E.0 (0.24 m1, 2 mmol) was sted at 20° for 2 he, Aler 1 more be following addition of an additional 0.12 mL of BE, Ett the reaction was complete. The reaction was quenched by ‘low addition of €4 mL of pyridine prior dilution with a, NH{CL The combined organic ayers from 3 EtOAc extrac lions were wasbed with brine, dried over Na,SO,, and ‘concentrated using a rolary evaporator. The reste was purified by preparative HPLC using a C,, reverse phase ‘column 10 obiain 20 mg of the desired beta C-glucoside as, A white Iyophilae afer lyophilization, HPLC retention time: 38 mio, 95% pure, YMC $5 C18. 4.6450 mm column, 25 mL-min, detection at 220 aM; 4 min gradient 0-100% B hold 4 min at 100% B. Solvent A: 10% MeOHIH.0#0.2% H,PO,. Solvent B: 9% MeOHH,0+ 0.2% HPO, SH NMR (500 Milz, CD,OD) 5 721-7.11 (m, SID, 7.05 (4,21, 98.0 Hz), 4.08 (d, 1H, J=9.1 Hz), 3.98 6,24), 387 (@, 1H, Jo12.6 112), 3.68 (4d, 1H, 395.2, 12.1 Hz), 3.49-3.30 (a, 48), 2.41 (5, 30, BC NMR (135 MHz, CD,OD) 5 139.8, 1389, 138.4, 1375, 137.1, 131.1, 1309, 129.1, 1303, 1978, 271,836, 822, 798, 76.4, 730, 632, 395, 195, 16.1US 6,414,126 BL 55 ‘Anal Caled for Ca,H1:,0,8 LC-MS [M¢NH1,] 408; found 408. EXAMPLE 1 Ho 08%" “ont A. 5-Bromo-2-chloro-#-thiomethylbenzophenone ‘To a stirred suspension of commercial 5-bromo-2 chlorobenzoie acid (506 mg, 2.12 mmol) in 10 mL of ‘CHLCI, containing oxalylehioride (2.4 mmol) was added 2 Arops of DMF. Once the vigorous evolution of gas ceased, the restion was stirred I Shr before removal of the volatiles sing a rotary evaporator. After dissolving the crude Schaomo-2-chlorobenzayl chloride ia 8 ml of CS, the ‘iced mixture was cooled to 4 prior to adding thioanisole (260 mg, 2.12 mmol) followed by AICI, (566 mg, 425 aol), The reaction, after warming, 10 20" over Lar, was stirred for 20 be prior to quenching with IN HCL Subsequently, tbe suspension was diluted with SO ml HO ‘and sted unt all solids Were ia solution. The mixture as extracted 3x with E1OAc. The combined organic extracts ‘were washed 1x with IN HC, H.0, ag NaHCO,, and brine prior to drying aver Na,S0,, After removal ofthe volatiles, the 710 mg of crude’ of S-bromo-2-chloro-4"- ‘thiomethylbenzophenone ws not further purified. B, $-Biromo-2-chloro-#thiomelhyldiphenylmethane A solution of EL SiH (144 mL, 8:8 mmol), BF, E10 (083 mL, 6.6 mmol), and Part™A 5-bromo-2-chioro-# Thiomethylbenzaphenone (710 mg, 2.1 mmol) in 10 ml. of a [ef mixture CH,CIyMeCN was stirred 2 hr at 20°. After ‘quenching with 10% NaHCO, and dlution with H.0, the reaction was extracted 3 with E1OAc. The combined ‘organic layers were washed 2x with HO and once with brine before drying over Na,SO,. Aller removal of the volatiles, the eesidve was chromatographed on silica gel using 54% EtOAcexane to elute 630 mg of S-bromo-2- hloro-$thiomethyldiphenylmethane as colores oil, Son ‘To a sired ~78° solution of Part B 5-bromo-2-chloro: «hiomethyldiphenylmethane (200 mg, 0.61 mmol) in 6 56 mL of dry THF under Ar was added 048 mL of 15 M n-BuLi in hexane dropwise. After 35 minutes, his solution was transferred by cannula to a stirred ~78° solution of 2,3,4,6cetrs-O-benzyl-p-D-glucolactone (361 mg, 0.67 ‘mimol) in $ mL of THE. The solution was sted for 1.5 be at 78" prior to quenching with saturated aq, NHCL After ‘warming t0 20°, the reaction was diluted 2 fold with HO, prior to 3 extractions with E1OAc. The combined E:OAc Fractions were washed with brine and dred over Na,S0,. Afler concentration using 4 rotary evaporator, the reside ‘was chromatogeaphed on silica gel wsing 20% EVOAc) hhexane to elute 250 mg of the desired tlle lst. “ron ‘To a steed -30° solution of Part C act (250 mg, 0.32 mimo!) in mL-of MeCN was added iPr,SiH (0-10 ml, 0.56 ‘mmol followed by BF, E1.0 (0.048 mL, 0.38 mmol) After (05 hrat~30P, when tle showed the restion to be complet, saturated ag. NaHCO, was added and the suspension stirred Thr at 20" prior to diluting with HO and EXOAc, The ‘combined organic layers from 3 E(OAe extractions were ‘washed! with brine, dried over Na,S0,, and concentrated Using a rotaey evaporator. Chromatography of the reside on silica yel using 9% E1OActhexane as eluant eluted 200 mg, of the desired beta C-arylglueoside swe A solution of Part D tetra-O-benzyl C-ghveoside (60 mg, 0.1 mmol) in EISH @ mL) containing BF,.E1.0 (024 ml, 2 mmol) was sired at 20° for 3 hr. The reaction was ‘quenched by slow addition of 0.4 ml of pyridine prior to cliluion with aq, NCL The combined organie layers from 3 EiOAc extractions were washed with brine, dried over ‘Na,$O,, and concentrated using a rotary evaporator. The residue ‘was purified by preparative HPLC using a C,, reverse phase column to obtain 21.5 mg of the desired beta C-plucoside as a white lyophilate after lyophilization. HPLC retention time: 3.96 min, 95% pure, YMC S5 C-18. 4.6.50 mm column, 2.5 mL_min, detection at 20 aM; 4 min gradient 0-100% B hold 4 min at 100% B. Solvent A: 10% MeOH/H.040.2% H,PO,. Solvent B: 9% MeOHHO+ 0.2% HPO,US 6,414,126 BL 37 ALLNMR (400 MHlz, CD,OD) 8 7:36-7:27 (m, 3H), 7.15 (@, 2H, $48.3 12), 7.411 (@, 2H, Ja8.3 Hz), 4.10-4.04 (my, 31, 387 (4, IH, Ja12 Hz), 3.70 (dd, 1H, J=71, 11.8 Hi), 3A47-3.26 (m, 4), 242 (6, 31D. "°C NMR (100 MHz, CD,OD) 8 140.1, 139.3, 1380, 1375, 1345, 132.0, 1304, 1302, 128.4,1280, 82.9, 828, 822, 79.7, 165, 18, 681, 395, 16.1 Anal Caled for CH 408. 1C10,8 LEMS [M-H] 409; found EXAMPLE 12 OMe “ont A. 5-Bromo-2-chloro--methoxybenzophenone ‘To a stieeed suspension of commercial 5-bromo-2- chlorobenzoie acid (506 mg, 242 mmol) in 10 mL of CILC1, containing oxalylebioride (2.4 mmol) was added 2 ‘drops of DMF. Once the vigorous evolution of gas ceased, the reaction was stired 1.5 br prior to removal of the volatiles using a rotary evaporator, After dissolving. the cide S-bromo-2-chlorcheazoyl chloride in 8 ml of CS, the irred mixture was cooled to 4 prior o adding anisole (240 mg, 2.12 mmol) followed by AICI, (566 mg, 4.25 mmol) ‘The reaction, after warming to 20° over | hy, wis stirred for 20 be prior to quenching with IN HCL. Subsequently, the suspension was diluted with 50 ml H.O and sited ual all solids were in solution. The mixture was extracted 3x with EiOAc. The combined organic extracts were washed Ix with IN HII, H,0, aq NalICO,, and brine prior to drying over Na,S0,. Alter removal of the volatiles, the residue was ‘chromatographed on silica gel using 15% EXOAcrhexane 10 elute 450 mg of S-brome-2-chloro-4"- methoxybenzophenone. B. 5-Bromo-2-chloro- -methoxydiphenylmethane A solution of E1,SiH (0.45 mL, 285 mmo), BF,EL0 (0.3 mL, 2.4 mmol), and S-bromo-2-chloro- methoxybenzophenone (450 mg, 1.4 mmol) in3 mLof a 1:9 mixture CH,ClyMeCN was sitred overnight at 20°, After {quenching with 10% NaOH and dlition with HO, the reaction was extracted 3 with E1OAc. The combined organic layers were washed 2 with HO and once with briae before drying over N&3S0,. Alter removal of the volatiles, the residue was chromatographed on silica gel using 2% E1OAcibexane 10 elute 416 mg of 5S-bromo: hloro-s-methoxydliphenylmethane as colorless oil 58 « “To a sticred 31.78° solution of Part B S-beomo 4:methoxydiphenylmethane (212 mg, 0.68 mmo) i ‘of dry THF under Ar was added 0.36 ml. of L9 M n-BuLi in hexane dropwise, After 30 minutes, this solution was transferred by eannula to a stitred ~78" solution of 2.3.6. tetta-O-benryl-f-D-zlucolactone (0.39 g, 0.71 mmol) in 5 mL of THE. The solution was sired for 2 hr al ~78° prior lo quenching with saturated aq, NHLCL. After warming 20°, the reaction was diluted 2 fold with HO prior o 3 ‘exactions with E:OAc. The combined E:Ae fractions were washed with brine and dried over NasSO,, After ‘concentration using a rotary evaporator, the reside was ‘chromatographed on silica gel using 20% EIOAcrhexane 10 ‘elute 142 mg ofthe desired ttle Inet Ob ‘To a stirred -40° solution of Part Clactl (142 mg, 0.18 mmol) in 15 mL of MeCN was added iPr,SiH (0.041 mL, 0.2 mmol followed by BF5.E1.0 (0.026 ml, 0.2 mmol) ‘fier 2 hr at 40°, when ile shoved the reaction to be 1, NAHICO, was added and the diluted 1, The combined organic layers from 3 I, extractions were washed! with brine, dried over J, and concentrated using a rary evaporator. Chro- matography of the residue on silica gel using 25% EtOAc) hexane as eluant eluted 139 mg of the desired beta Carylelucoside, s foneUS 6,414,126 BL 59 A solution of Part D teta-0-benzsl C-glucoside (136 a 0.18 mmol) in ESSH (1.0 mL) containing BF, E10 (046 mL, 3.6 mmol) was stirred at 20° for 4h. The reaction was clilued with CHCl, and thea concentrated using a rotary fevaporatog. The resi, after being dissolved ia CHCl, was washed with ag, NH,Cl, H,0, brine, dried over 1Na,S0,, and concentrated using a Tolary evaporator. The ride product was purified by preparative HPLCusing a Cy reverse phase column to obtain 26 mg of the desired beta (Ceglacoside as a white Iyophilate after lyophilization, HPLC retention ime: 3.07 min, 95% pure, YMC SS C-18 4.6550 mm columo, 2.5 mL/min, detection ai 220 nM; 4 min ‘gradient 0-100% B hold 4 min at 100% B. Solvent A: 10% MeOIH1,0+0.2% H1,PO,, Solvent B: 90% MeOHH.O+ 02% H,PO,. "HNMR (500 MHz, CD,OD) 8 7.35-7.28 (m, 3H), 7.1 (@,2H, 368.8 Hz), 68 (4, 21, J-8.3 112), 4.05-3.90 mn, 3H), 3.80 (d, 1H, J=12.3 Hz), 3.67 (6, 3H), 3.61 (dd, 1H, 48, 11.9 Hi), 342-325 (m, 441) 1, °C NMR (125 MHz, CD,OD) 8 159.6, 140.0, 139.9, 1345, 1330, 131.9, 1308, 130.1, 11438, $9.9, 82.2, 798, 765, 719, 63.1, 55.6, 38.2 .C10, LC-MS [M#NH,] 412: found EXAMPLE 13, A. S-Bromo-2-methoxy-4'etylbenzhydrol “Toa sirred -78* solution of p-bromocthylbenzene (2.03 2,1 mmol io 10 mL of dry THF under Arwas added 5 mI ‘of 25 M n-Bul.i (12 mmol) in hexane over 10 min. The temperature was allowed to rise 1 ~10° aver 2 hr whereupon the reaction was cooled to ~78° before adding solid Scbromo-2-methoxybenzaldelyde (2.15 g, 10 mmol). fer ising overnight at 20°, the reaction was quenched with Saturated ag. NH,Cl and diluted 5 fold with HO prior to 3 extractions with E\OAc, The combined ELOAc fractions ‘were washed with brine and dried over Na,SO,. After concentration using a rolary evaporator, the residue was chromatographed on silica gel using 10% EXOAc‘hexane 10 lute 144 g of S-bromo: B, 5.Biromo-2-methoxy-- pasar 23. The combination as defined in claim 16 wherein the lipid Towering agent is an MTP inhibitor an MG. CoA Teds inhibitor, «squalene syle fabio,» fic tcid derivative, an upregultor of LDL. reooptor nevi 8 iporygenase tibitoy or an ACAT inhibit, 'oh The combination a defied a claun 23 where lipid lowering agent is pravastatin, vasa, simvastatin, orvasiatn, Sasa ovata, nisrastatia, visa, avast osuvasatin, fenofibrate, gemibrea, cofrae, dasimibe, TS962, MD-TO0, andor LY295497 35. The combination as defined in claim 28 wherein Ube 72 tabblo preset i Wei Cals Lo the lipid lowering agent witln the range fom about O01 to about Soo: "26 A method for trating or delaying the progression or conse of diabetes, diabetic retinopathy, disbetle neuropathy, diabetic nephropathy, delayed. wound healing, inulin ‘esitance, hyperglycemia, yperinsulinena, clevtied blood Ievels of fat acids or glveral hyperlipidemia, oes, a, Syndrome X, dabele complications, aMeroseleross or hypertension, of for inteasing high Jot. Sy lipoprotein levels, which comprises administering o 8 trummatan species iv eel of Westnet a therapeutically ‘Mfectve amu ofa compound sy dened in lam 127. The method dy defined in claim 26 where te SGLT2 inhibitor compouod bas tbe tructue the Py 28. A method for treating type II diabetes which com: prises administering to a mammalian species in need of Treatment a therapeutically elective amount of 2 compound as defined in claim 1 alone or in combination with anolher Antidiabetic agent, an agent fr treating the complications of liabetes, an anti-obesity agent, an antibypertensive agent, an fantiplatelet agent, an anti-athorosclerotic agent andior a hypolipidemie agen 4 seh “a ™ eo “oR eee eh. po “one ees . mo “mone _ RU? and R™ are independently hydrogen, OH, ORS, lower alkyl, CFs, OCH, OCF, SR" or halogen, of two of RY RE and R™ fogether with the carbons 10 which they are attached can form an annelated ive, six fr seven membered carboeyele or heteroeyele which ‘may contain 1 to 4 heteroatoms in the eng which are N, 0,8, SO, andlor SO. and R* are independealy hydrogen, OH, OR", OAry, OCH,AryL, ower alkyl, eyeloaly, Ci, CHF. —OCF,, hhalogen, —CN, — COR", —Co.li, SCONR RS, —NHCOR™, —NiISOARY, and is OH or OR", then atleast one of RR, and is CPs, OCF, of5 and/or at least one of R® at . a, CN, —CO.R™, CHORR™, US 6,414,126 BL R! ig CF, Oct CHOHR™, CO}, NHCO™, "CNHSO. SNIISO.Ar, Aryl, "SR, 80, Aryl oF haloge ‘or « compound of the structure SOR, SOR, 5 6 wherein RR, RE and R° are independently hydrogen, OH, OR, lower alkyl, CFs, OCHE, OCF, SR or halogen, of two of R, RE and RE together with the carbons t0 which they are attached ean form an annelated five, six or seven membered carbocyele or heterocycle which ‘may contain 1 to heteroatoms in the eng which are N, 0,5, 80, andor SO. and R¢ are independeatly hydrogen, OH, OR", Ary, A, ower alkyl, eyelolkyl, CF, —OCHF., . halogen, —CN, —CO.R™, —COali, —CONR™R, —NHCORS*, —NHSOR™, —NHSO,AnyL, Aryl, SR”, —SORY, —S0.R™, =S0,Aryl, oF a five, six or seven membered hetero- cycle which may contain 1 to 4 heteroatoms inthe ring which are N, 0, §, SO, andor 50, ot R? and Ri together wih the carbons to which they are attached form an annelated five, six or seven membered care beyele or heteoeyele which may contain 110 4 feteroatoms inthe ring which are N, O, S, SO, andor 80, SR, RM, RS, RM, R™, RY, ROP and RY ae inde- pendently lower alkyl R® and R™ ate independently hydrogen, alkyLaryl, alkylary, eycloalkyl, or R® and R™ together with the nitrogen to which they are attached form an annelated five, six or seven membered hetereyele which may contain 1 to 4 heteroatoms inthe ring which are N, O, 8,80, andor Ais 0, S, NH, or (CH), where n is 0-3, or a pharm: ceutically acceptable salt thereof, all sterosomers thereat, anda prodeg ester thereof 30. A compound having the structure os