NZ612116B2 - Compositions comprising and methods of using inhibitors of sodium-glucose cotransporters 1 and 2 - Google Patents

Abstract

Disclosed herein are pharmaceutical dosage forms comprising (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol, croscarmellose sodium, silicon dioxide, microcrystalline cellulose, and magnesium stearate. Such compositions are useful as an inhibitor of sodium-glucose cotransporters (SGLT) 1 and 2 and are intended for the treatment of conditions such as diabetes and related metabolic disorders. f sodium-glucose cotransporters (SGLT) 1 and 2 and are intended for the treatment of conditions such as diabetes and related metabolic disorders.

Description

COMPOSITIONS COMPRISING AND METHODS OF USING INHIBITORS OF SODIUM-GLUCOSE COTRANSPORTERS 1 AND 2 This ation claims priority to U.S. provisional patent application no. 61/430,027, filed January 5, 2011, the ty of which is incorporated herein by reference. 1. HELDOFTHEINVENHON This invention relates to methods of improving the cardiovascular and/or metabolic health of patients, ularly those suffering from type 2 diabetes, and to compounds and pharmaceutical compositions useful therein. 2. BACKGROUND Type 2 diabetes mellitus (T2DM) is a disorder characterized by elevated serum glucose.

One way of reducing serum glucose in patients suffering from the disease is by inhibiting glucose reabsorption in the kidney. The kidney plays an important role in the overall control of glucose, since glucose is filtered h the glomeruli at the rate of approximately 8 g/h and is almost completely reabsorbed in the al tubule via sodium—glucose cotransporters (SGLTs).

Komoroski, B., et al., Clin Pharmacol Ther. 85(5):513-9 (2009). Sodium—glucose cotransporter 2 (SGLT2) is one of 14 transmembrane-domain SGLTs, and is responsible for reabsorbing most of the glucose filtered at the glomerulus. Thus, inhibition of SGLT2 is a rational approach to treating T2DM. Id.

A large number of SGLT2 inhibitors have been reported. See, e.g., U.S. patent nos. 2O 6,414,126; 6,555,519; and 7,393,836. One of them, dapagliflozin, has been administered to T2DM patients with promising results. In particular, ts randomized to the compound in a 14-day study exhibited reduced fasting plasma levels and improved glucose tolerance compared to placebo. Komoroski at 513. In a 12-week study, patients randomized to the compound exhibited an improvement in obin A1c, some weight loss, and some improvement in systolic blood re ed to placebo. List, J.F., et al., Diabetes Care. 32(4):650-7 (2009).

Most pharmaceutical efforts directed at discovering and developing inhibitors of SGLT2 “have focused on devising inhibitors selective for the SG LT2 transporter. " Washburn, W.N., Expert Opin. Ther. Patents :1485,1499, 1486 (2009). This is apparently based, at least in part, on the fact that while humans lacking a functional SGLT2 gene appear to live normal lives— apart from ting high urinary e excretion—those bearing a SGLT1 gene on ence glucose-galactose malsorption. Id. Unlike SGLT2, which is expressed exclusively in the human kidney, SGLT1 is also sed in the small intestine and heart. Id. 1 LEX—1321 PCT/U82012/020042 3. SUMMARY OF THE INVENTION This invention is directed, in part, to a method of ing the vascular and/or metabolic health of a patient, which comprises administering to a patient in need thereof a safe and cious amount of a dual inhibitor of sodium-glucose cotransporters 1 and 2 (“dual SGLT1/2 inhibitor") that also has a structure of formula I: or a pharmaceutically acceptable salt thereof, the various substituents of which are defined herein. In a particular embodiment, the t is concurrently taking another therapeutic agent, such as an iabetic agent, anti-hyperglycemic agent, hypolipidemic/lipid lowering agent, anti- obesity agent, anti-hypertensive agent, or appetite suppressant.

In one embodiment of the invention, the administration effects a decrease in the patient’s plasma glucose. In one embodiment, the stration effects an improved oral glucose tolerance in the patient. In one embodiment, the administration lowers the patient’s post-prandial plasma glucose level. In one embodiment, the administration lowers the patient’s plasma fructosamine level. In one ment, the administration lowers the patient’s HbAlc level. In one embodiment, the administration reduces the patient’s blood pressure (e.g., systolic and diastolic). In one ment, the administration reduces the patient’s triglyceride levels.

In a particular embodiment of the invention, the dual SGLT1/2 inhibitor is a compound of 2O the formula: (R6)n .\ X/ / \ 'fiSthm HO ; OH or a pharmaceutically acceptable salt thereof, wherein: each RlA is independently hydrogen, alkyl, aryl or heterocycle; each R6 is independently en, yl, amino, alkyl, aryl, cyano, halogen, heteroalkyl, heterocycle, nitro, CECRGA, OR6A, SRGA, SORGA, SO2R6A, A, CO2R6A, CO2H, CON(R6A)(R6A), CONH(R6A), CONH2, NHC(O)R6A, or NHSO2R6A; each RGA is independently alkyl, aryl or heterocycle; each R7 is independently hydrogen, hydroxyl, amino, alkyl, aryl, cyano, halogen, heteroalkyl, heterocycle, nitro, CECR7A, OR7A, SR7A, SOR7A, SO2R7A, C(O)R7A, CO2R7A, CO2H, CON(R7A)(R7A), CONH(R7A), CONH2, NHC(O)R7A, or 7A; each R7A is independently 2 LEX—1321 alkyl, aryl or heterocycle; m is 1-4; n is 1-3; and p is 0-2; wherein each alkyl, aryl, heteroalkyl or heterocycle is optionally substituted with one or more of alkoxy, amino, cyano, halo, hydroxyl, or nitro.

In a ular embodiment, the safe and efficacious amount is 300 mg/day or less (e.g., 250, 200, 150, 100, or 50 mg/day or less). Particular patients are diabetic or abetic. 4. BRIEF DESCRIPTION OF THE FIGURES Certain aspects of this invention may be understood with nce to the figures.

Figures 1-10 show results obtained from a randomized, -blind, placebo controlled Phase 2a clinical trial, wherein 150 mg and 300 mg doses of (2S,3R,4R,5S,6R)—2-(4—chloro-3—(4- ethoxybenzyl)phenyl)—6—(methylthio)tetrahydro-2H-pyran-3,4,5-triol were orally administered in solution once daily to patients with type 2 diabetes mellitus. Figure 11 es results obtained from a Phase 1 clinical trial, wherein both solid and liquid oral dosage forms of the compound were administered to patients with type 2 diabetes mellitus. shows the plasma glucose levels of patients in the placebo group and in the 150 mg/day and 300 mg/day treatment groups over the course of the Phase 2a study. shows each group’s mean results in a glucose nce test administered over the course of the study. shows each group’s mean glucose plasma level area under the curve (AUC) over the course of the study. 2O shows the results of each group’s mean tatic model assessment (HOMA) value. Measurements were obtained before the study began and again on day 27. provides measurements of each group’s mean post-prandial e level over the course of the study. provides ements of each group’s mean plasma fructosamine level over the course of the study. provides each group’s mean percent change in hemoglobin Alc level over the course of the study. shows the change in each group’s mean diastolic blood re as measured on day 28 of the study compared to baseline. 3O shows the change in each group’s mean systolic blood pressure as measured on day 28 of the study compared to baseline. shows the change in each group’s mean arterial re as measured on day 28 of the study compared to baseline. shows the effects of a single dose of one of two solid formulations (6X50 mg tablets or 2x150 mg tablets) and a liquid formulation of (2S,3R,4R,5S,6R)—2-(4-chIoro(4- ethoxybenzyl)phenyl)—6—(methylthio)tetrahydro-2H-pyran-3,4,5-triol on the total GLP-1 levels of patients with type 2 diabetes mellitus, as determined in a Phase 1 study. 3 LEX—1321 . DETAILED PTION This invention is based, in part, on findings obtained from a randomized, double-blind, placebo controlled Phase 2a clinical trial, wherein 150 mg/day and 300 mg/day doses of a nd of the invention were orally administered in a liquid to patients with type 2 diabetes mellitus. The compound was (2S,3R,4R,5S,6R)(4-chloro(4-ethoxybenzyl)phenyl) (methylthio)tetrahydro-2H-pyran-3,4,5-triol, which has the structure: VO‘SO0 0 S "11,1, “\\\ \ HO . OH This invention is further based on findings obtained from a randomized, double-blind, placebo controlled Phase 1 clinical trial that compared liquid and solid dosage forms of the compound. .1. Definitions Unless otherwise indicated, the term “about,” when used in ation with a numerical value, means the value should be considered as ing the error (e.g., standard error) associated with obtaining or ng it.

Unless ise ted, the term “alkenyl” means a straight chain, branched and/or cyclic hydrocarbon having from 2 to 20 (e.g., 2 to 10 or 2 to 6) carbon atoms, and including at least one carbon-carbon double bond. Representative alkenyl moieties include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, enyl, 3-methylbutenyl, 2-methylbutenyl, 2,3—dimethylbutenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1- 2O octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, nyl, 1-decenyl, 2-decenyl and 3- decenyl.

Unless otherwise indicated, the term y” means an —O—alkyl group. es of alkoxy groups include, but are not limited to, -OCH3, -OCH2CH3, -O(CH2)2CH3, -O(CH2)3CH3, - O(CH2)4CH3, and -O(CH2)5CH3.

Unless otherwise indicated, the term “alkyl” means a straight chain, branched and/or cyclic (“cycloalkyl”) hydrocarbon having from 1 to 20 (e.g., 1 to 10 or 1 to 4) carbon atoms. Alkyl moieties having from 1 to 4 carbons are referred to as “lower alkyl." Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, , 4,4-dimethylpentyl,°Ctyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl. Cycloalkyl moieties may be monocyclic or multicyclic, and examples include ropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. Additional examples of alkyl moieties have 4 LEX—1321 PCT/U82012/020042 linear, branched and/or cyclic portions (e.g., 1-ethylmethyl-cyclohexyl). The term “alkyl" includes saturated hydrocarbons as well as alkenyl and l moieties.

Unless otherwise indicated, the term aryl” or “alkyl-aryl" means an alkyl moiety bound to an aryl moiety.

Unless otherwise indicated, the term “alkylheteroaryl” or “alkyl-heteroaryl" means an alkyl moiety bound to a heteroaryl moiety.

Unless otherwise indicated, the term “alkylheterocycle” or “alkyl-heterocycle" means an alkyl moiety bound to a heterocycle moiety.

Unless otherwise indicated, the term “alkynyl” means a straight chain, branched or cyclic hydrocarbon having from 2 to 20 (e.g., 2 to 20 or 2 to 6) carbon atoms, and including at least one carbon-carbon triple bond. Representative alkynyl es include acetylenyl, propynyl, 1- butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1—butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5- hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8- nonynyl, 1-decynyl, 2-decynyl and 9-decynyl.

Unless otherwise indicated, the term “aryl” means an aromatic ring or an aromatic or partially ic ring system composed of carbon and hydrogen atoms. An aryl moiety may comprise multiple rings bound orfused together. Examples of aryl moieties include, but are not limited to, anthracenyl, yl, biphenyl, fluorenyl, indan, indenyl, naphthyl, phenanthrenyl, phenyl, 1,2,3,4-tetrahydro-naphthalene, and tolyl. 2O Unless ise indicated, the term “arylalkyl” or “aryl-alkyl” means an aryl moiety bound to an alkyl .

Unless otherwise indicated, the term “dual SGLT1/2 inhibitor” refers to a compound having a ratio of SGLTl |C50 to SG LT2 |C50 of less than about 75, 50, or 25.

Unless otherwise indicated, the terms “halogen" and “halo” encompass fluorine, chlorine, bromine, and .

Unless otherwise indicated, the term “heteroalkyl” refers to an alkyl moiety (e.g., linear, branched or cyclic) in which at least one of its carbon atoms has been replaced with a heteroatom (e.g., N, O or 8).

Unless ise indicated, the term “heteroaryl” means an aryl moiety n at least 3O one of its carbon atoms has been replaced with a heteroatom (e.g., N, O or 8). Examples include, but are not limited to, acridinyl, benzimidazolyl, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzoquinazolinyl, benzothiazolyl, benzoxazolyl, furyl, imidazolyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, phthalazinyl, pyrazinyl, lyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolyl, quinazolinyl, inyl, tetrazolyl, thiazolyl, and triazinyl.

Unless otherwise ted, the term “heteroarylalkyl” or “heteroaryl-alkyl" means a heteroaryl moiety bound to an alkyl .

LEX—1321 PCT/U82012/020042 Unless otherwise indicated, the term “heterocycle" refers to an aromatic, partially ic or non-aromatic monocyclic or polycyclic ring or ring system comprised of carbon, hydrogen and at least one heteroatom (e.g., N, O or S). A heterocycle may comprise multiple (i.e., two or more) rings fused or bound together. Heterocycles include heteroaryls. Examples include, but are not d to, benzo[1,3]dioxolyl, 2,3—dihydro-benzo[1,4]dioxinyl, cinnolinyl, furanyl, hydantoinyl, morpholinyl, oxetanyl, oxiranyl, zinyl, piperidinyl, pyrrolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetra hydropyranyl, tetra hydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, ydrothiopyranyl and valerolactamyl.

Unless otherwise indicated, the term “heterocyclealkyl” or “heterocycle-alkyl" refers to a heterocycle moiety bound to an alkyl moiety.

Unless ise indicated, the term “heterocycloalkyl” refers to a non-aromatic heterocycle.

Unless otherwise indicated, the term “heterocycloalkylalkyl" or “heterocycloalkyl-alkyl" refers to a heterocycloalkyl moiety bound to an alkyl moiety.

Unless otherwise indicated, the terms “manage,7: u managing" and “management" encompass preventing the recurrence of the specified disease or er in a patient who has already suffered from the disease or er, and/or lengthening the time that a patient who has suffered from the disease or er remains in remission. The terms encompass modulating the threshold, development and/or duration of the disease or er, or changing 2O the way that a t responds to the disease or disorder.

Unless otherwise indicated, the term “pharmaceutically acceptable salts" refers to salts prepared from ceutically able non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N’- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and c acids such as acetic, alginic, nilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, 3O glutamic, glycolic, hydrobromic, hydrochloric, isethionic, , maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and methanesulfonic acids. es of ic salts thus include hydrochloride and mesylate salts. Others are well- known in the art. See, e.g., Remington’ 5 Pharmaceutical es, 18th ed. (Mack Publishing, Easton PA: 1990) and Remington: The Science and Practice of Pharmacy, 19th ed. (Mack Publishing, Easton PA: 1995). 6 LEX—1321 PCT/U82012/020042 Unless otherwise ted, the terms “prevent,” “preventing" and ntion" contemplate an action that occurs before a patient begins to suffer from the specified disease or disorder, which inhibits or reduces the severity of the disease or disorder. In other words, the terms encompass prophylaxis.

Unless otherwise indicated, a “prophylactically effective amount" of a compound is an amount sufficient to prevent a disease or condition, or one or more ms associated with the disease or condition, or prevent its recurrence. A “prophylactically effective amount" of a compound means an amount of therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the tion of the disease. The term “prophylactically effective " can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

Unless otherwise indicated, the term l05o" is the |C50 of a compound determined using the in vitro human SGLTl inhibition assay described in the Examples, below.

Unless otherwise indicated, the term “SGLT2 leo" is the |C50 of a compound ined using the in vitro human SGLT2 inhibition assay described in the Examples, below.

Unless otherwise indicated, the term “substituted," when used to describe a chemical structure or moiety, refers to a derivative of that structure or moiety wherein one or more of its hydrogen atoms is substituted with an atom, chemical moiety or functional group such as, but not d to, alcohol, aldehylde, alkoxy, alkanoyloxy, alkoxycarbonyl, alkenyl, alkyl (e.g., methyl, 2O ethyl, propyl, t-butyl), l, alkylcarbonyloxy (-OC(O)alkyl), amide (-C(O)NH-alkyl- or - C(O)alkyl), amidinyl (-C(NH)NH-alkyl or -C(NR)NH2), amine (primary, secondary and tertiary such as alkylamino, arylamino, arylalkylamino), aroyl, aryl, aryloxy, azo, oyl (-NHC(O)O- alkyl- or —OC(O)NH-alkyl), carbamyl (e.g., CONH2, as well as CONH-alkyl, CONH-aryl, and CONH- kyl), carbonyl, carboxyl, carboxylic acid, carboxylic acid anhydride, carboxylic acid chloride, cyano, ester, epoxide, ether (e.g., methoxy, ethoxy), guanidino, halo, haloalkyl (e.g., -CCI3, -CF3, -C(CF3)3), alkyl, hemiacetal, imine (primary and ary), isocyanate, isothiocyanate, ketone, nitrile, nitro, oxygen (i.e., to e an oxo group), phosphodiester, sulfide, sulfonamido (e.g., SO2NH2), sulfone, sulfonyl (including alkylsulfonyl, arylsulfonyl and arylalkylsulfonyl), sulfoxide, thiol (e.g., sulfhydryl, thioether) and urea (-NHCONH-alkyl-). In a particular 3O embodiment, the term substituted refers to a derivative of that structure or moiety wherein one or more of its en atoms is substituted with alcohol, alkoxy, alkyl (e.g., methyl, ethyl, propyl, t-butyl), amide (-C(O)NH-alkyl- or HC(O)alkyl), amidinyl (-C(NH)NH-alkyl or -C(NR)NH2), amine (primary, secondary and tertiary such as alkylamino, arylamino, arylalkylamino), aryl, carbamoyl (-NHC(O)O-alkyl- or -OC(O)NH-alkyl), carbamyl (e.g., CON H2, as well as CON H-alkyl, ryl, and CONH-arylalkyl), halo, haloalkyl (e.g., -CCI3, -CF3, -C(CF3)3), heteroalkyl, imine (primary and secondary), isocyanate, isothiocyanate, thiol (e.g., sulfhydryl, thioether) or urea (-NHCONH-alkyl-). 7 LEX—1321 PCT/U82012/020042 Unless otherwise indicated, a “therapeutically ive amount" of a compound is an amount sufficient to provide a eutic benefit in the treatment or management of a disease or condition, or to delay or minimize one or more symptoms associated with the e or condition. A “therapeutically ive amount" of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of the disease or condition. The term “therapeutically effective amount" can ass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

Unless otherwise indicated, the terms “treat, 71 utreating” and “treatment" contemplate an action that occurs while a patient is suffering from the specified disease or disorder, which reduces the severity of the disease or disorder, or retards or slows the progression of the disease or disorder.

Unless otherwise indicated, the term “include” has the same g as “include, but are not limited to," and the term “includes" has the same meaning as “includes, but is not limited to." rly, the term “such as" has the same meaning as the term “such as, but not d to." Unless otherwise indicated, one or more adjectives immediately preceding a series of nouns is to be construed as applying to each of the nouns. For e, the phrase “optionally 2O substituted alky, aryl, or heteroaryl” has the same meaning as “optionally substituted alky, optionally substituted aryl, or optionally substituted heteroaryl.” It should be noted that a chemical moiety that forms part of a larger compound may be described herein using a name commonly ed it when it exists as a single le or a name commonly accorded its l. For e, the terms “pyridine” and “pyridyl” are accorded the same meaning when used to describe a moiety attached to other chemical moieties. Thus, the two s “XOH, wherein X is pyridyl” and “XOH, wherein X is pyridine" are accorded the same meaning, and encompass the compounds pyridinol, pyridinol and pyridinol.

It should also be noted that if the stereochemistry of a structure or a n of a structure is not indicated with, for example, bold or dashed lines, the structure or the portion of the structure is to be interpreted as encompassing all stereoisomers of it. Moreover, any atom shown in a drawing with unsatisfied es is assumed to be attached to enough hydrogen atoms to satisfy the valences. In addition, chemical bonds depicted with one solid line parallel to one dashed line encompass both single and double (e.g., aromatic) bonds, if valences permit. 8 LEX—1321 PCT/U82012/020042 .2. Compounds This invention is directed, in part, to itions comprising and methods of using dual SG LT1/2 inhibitors that are also of the formula: and pharmaceutically acceptable salts thereof, wherein: A is optionally substituted aryl, cycloalkyl, or heterocycle; X is 0,8 or NR3; when X is 0, R1 is R1A,SOR1A,SO2R1A or N(R1A)2; when X is 8, R1 is hydrogen, 0R1A, SRlA, SOR1A, or SO2R1A; when X is NR3, R1 is R1A,SOR1A, SO2R1A, or R1A; each RlA is independently hydrogen or ally substituted alkyl, aryl or heterocycle; R2 is fluoro or 0R2A; each of R2A, R23, and R2c is independently hydrogen, optionally substituted alkyl, kyl, C(0)aryl or aryl; R3 is hydrogen, C(O)R3A, CO2R3A, CON(R35)2, or optionally substituted alkyl, aryl or heterocycle; each R3A is independently optionally substituted alkyl or aryl; and each R35 is independently hydrogen or optionally tuted alkyl or aryl. These compound can be prepared by methods known in the art. See, e.g., US. patent application publication nos. 20080113922 and 20080221164.

Particular compounds are of the formula: Some are of the formula: Some are of the formula: «3 LEX—1321 PCT/U82012/020042 One embodiment of the invention encompasses compounds of the formula: R200 : R2 5a,, and pharmaceutically acceptable salts thereof, n: A is optionally substituted aryl, cycloalkyl, or heterocycle; B is optionally substituted aryl, cycloalkyl, or heterocycle; X is O, S or NR3; Y is O, 8, 80, 802, NR4, (C(R5)2)p, (C(R5)2)q-C(O)-(C(R5)2)q, (C(R5)2)q-C(O)O-(C(R5)2)q, (C(R5)2)q- OC(O)—(C(R5)2)q, (C(R5)2)q-C(O)NR4-(C(R5)2)q, (C(R5)2)q-N R4C(O)—(C(R5)2)q, or (C(R5)2)q-N R4C(O)NR4- (C(R5)2)q; when X is 0, R1 is OR1A,SR1A,SOR1A, SO2R1A or N(R1A)2; when X is 8, R1 is en, OR1A,SR1A,SOR1A, or SO2R1A; when X is NR3, R1 is OR1A,SR1A,SOR1A,SO2R1A, or R1A; each RlA is ndently hydrogen or optionally substituted alkyl, aryl or heterocycle; R2 is fluoro or OR2A; each of R2A, R23, and R2c is independently hydrogen, optionally substituted alkyl, C(O)alkyl, C(O)aryl, or aryl; R3 is hydrogen, C(O)R3A, CO2R3A, 5)2, or optionally substituted alkyl, aryl or heterocycle; each R3A is independently optionally substituted alkyl or aryl; each R35 is independently hydrogen or optionally substituted alkyl or aryl; each R4 is independently en or optionally substituted alkyl; each R5 is independently hydrogen, hydroxyl, halogen, amino, cyano, ORSA, SRSA, or ally substituted alkyl; each RSA is independently optionally tuted alkyl; p is 0-3; and each q is independently 0-2. ular compounds are of the formula: R200 ; R2 ORZB Some are of the formula: LEX—1321 PCT/U82012/020042 Some are of the formula: dam@301; Some are of the formula: (R6)n chOJ/\/\E ORzB wherein: each R6 is independently hydrogen, hydroxyl, halogen, amino, cyano, nitro, CECReA, OR6A, SReA, SOReA, SO2R6A, C(O)R6A, CO2R6A, CO2H, A)(R6A), CONH(R6A), CONH2, R6A, NHSO2R6A, or optionally substituted alkyl, aryl or heterocycle; each RGA is independently optionally substituted alkyl, aryl or heterocycle; each R7 is independently hydrogen, hydroxyl, halogen, amino, cyano, nitro, CECR7A, OR7A, SR7A, SOR7A, SO2R7A, A, CO2R7A, CO2H, CON(R7A)(R7A), CONH(R7A), CONH2, NHC(O)R7A, NHSO2R7A, or optionally substituted alkyl, aryl or heterocycle; each Rm is independently optionally substituted alkyl, aryl or heterocycle; m is 1-3; and n is 1-3.

Some are of the formula: (R7>m® (R6)n Some are of the a: 11 LEX—1321 2012/020042 Some are of the formula: XRg RgA RZCO 5 R2 (:DRZB and pharmaceutically acceptable salts thereof, wherein: A is ally substituted aryl, cycloalkyl, or heterocycle; X is O or NR3; R2 is fluoro or OR2A; each of R2A, R23, and R2c is independently hydrogen, optionally substituted alkyl, C(O)alkyl, C(O)aryl or aryl; R3 is hydrogen or optionally substituted alkyl, aryl or heterocycle; R8 is hydrogen or C(O)R8A; R8A is hydrogen or optionally substituted alkyl, alkoxy or aryl; R9A and R95 are each independently OR9C or SR9C, or are taken together to provide 0,8 or NRgc; and each R9c is independently optionally tuted alkyl, aryl or heterocycle.

With regard to the various formulae disclosed herein, as applicable, particular compounds of the invention are such that A is optionally substituted 6-membered aryl or cycle. In others, A is optionally substituted 5-membered heterocycle. In some, A is an optionally substituted fused bicyclic heterocycle.

In some, B is optionally substituted 6-membered aryl or heterocycle. In others, B is optionally substituted 5-membered heterocycle. In others, B is an optionally substituted fused bicyclic heterocycle. 2O In some, X is O. In , X is S. In others, X is NR3.

In some, Y is (C(R4)2)p and, for example, p is 1. In some, Y is (C(R5)2)q-C(O)-(C(R5)2)q and, for example, each q is independently O or 1.

In some, R1 is ORlA. In others, R1 is SRlA. In others, R1 is SORlA. In , R1 is SO2R1A.

In others, R1 is N(R1A)2. In others, R1 is hydrogen. In others, R1 is RlA.

In some, RlA is hydrogen. In others, RlA is optionally tuted alkyl (e.g., optionally substituted lower alkyl).

In some, R2 is fluoro. In , R2 is OR2A.

In some, R2A is hydrogen.

In some, R25 is en. 12 LEX—1321 PCT/U82012/020042 In some, R2c is hydrogen.

In some, R3 is hydrogen. In others, R3 is optionally substituted lower alkyl (e.g., ally substituted methyl).

In some, R4 is hydrogen or optionally substituted lower alkyl.

In some, each R5 is hydrogen or optionally substituted lower alkyl (e.g., methyl, ethyl, CF3).

In some, R6 is hydrogen, hydroxyl, halogen, ORGA or optionally substituted lower alkyl (e.g., optionally halogenated methyl, ethyl, or isopropyl). In some, R6 is hydrogen. In some, R6 is halogen (e.g., ). In some, R6 is hydroxyl. In some, R6 is ORGA (e.g., methoxy, ethoxy). In some, R6 is optionally substituted methyl (e.g., CF3).

In some, R7 is hydrogen, CECR7A, OR7A or optionally substituted lower alkyl (e.g., optionally halogenated methyl, ethyl, or isopropyl). In some, R7 is en. In some, R7is CECR7A and R7A is, for example, optionally substituted (e.g., with lower alkyl or halogen) monocyclic aryl or cycle. In some, R7 is OR7A (e.g., methoxy, ). In some, R7 is acetylenyl or optionally substituted methyl or ethyl.

Particular compounds of the invention are of the a: \/0”/fio—Cl HO ; OH |(a) Others are of the formula: \/O”/HS—R1ACI HO OH Others are of the formula: \/0 CI 0,," X “8—R1A 13 LEX—1321 PCT/U82012/020042 Others are of the formula: \/0 CI 0,“. X LiM“S\\_ R1A0 HO ; OH |(d) Others are of the formula: \/0”0CI S O—R1A |(e) Others are of the formula: 0 O 3 III," N \ R1A In particular compounds of formulae |(a)—(d), X is O. In others, X is S. In others, X is NR3 and R3 is, for example, hydrogen. In particular compounds of formulae f), RlA is hydrogen. In others, RlA is optionally substituted methyl or ethyl.

Specific compounds of the invention include: ,4R,5S,6R)—2—(4-chIoro-3—(4—ethoxybenzyl)phenyl)—6—(methylthio)tetrahydro-2H-pyran-3,4,5- triol; (2S,3R,4R,5S,6R)—2—(4-chIoro-3—(4—ethoxybenzyl)phenyl)—6—(methylsuIfonyl)—tetrahydro—2H-pyran- triol; (2S,3R,4R,5S)—2—[4-Ch Ioro(4-eth oxy-benzyl)—phenyl]—6—meth trahydro-pyran-3,4,5-triol; (3S,4R,5R,68)—6—[4-Chloro-3—(4-eth oxy-benzyl)—phenyI]-tetrahydro-pyran-2,3,4,5-tetraol; 2O ( 2S,3R,4R,5S)—2—[4-ChIoro(4-ethoxy-benzyl)-phenyl]-6—ethoxy—tetra hydro-pyran-3,4,5-triol; (2S,3R,4R,5S,68)—2—[4-ChIoro-3—(4-ethoxy—benzyI)-phenyl]isopropoxy—tetrahydro-pyran-3,4,5- triol; (2S,3R,4R,5S,6R)—2—[4-ChIoro(4-ethoxy—benzyI)-phenyl]isopropoxy—tetrahydro-pyran-3,4,5- triol; (2S,3R,4R,5S,6R)—2—[4-ChIoro(4-ethoxy-benzyl)-phenyl]methoxy—tetrahydro-pyran-3,4,5-triol; 14 LEX—1321 PCT/U82012/020042 (2S,3R,4R,5S,6S)—2—[4-Ch|oro—3—(4—ethoxy—benzyI)-phenyl]—6-methoxy—tetrahydro—pyran-3,4,5-triol; N-{(2S,3S,4R,5R,6S)-6—[4-Ch Ioro(4-eth nzyl)—pheny|]—3,4,5-tri hyd roxy—tetrahyd ro—pyran-2— yI}-N-propyI-acetamide; (2R,3S,4S,5S)[4-Ch|oro—3—(4-ethoxy-benzy|)-phenyl]—2,3,4,5-tetrahydroxy—pentanal oxime; (3S,4R,5R,6S)—6—[4-ChIoro(4-eth oxy—benzyl)—phenyl]—3,4,5-trihydroxy-tetrahydro-pyran-2—one oxime; (2S,3R,4R,5R)—2—[4-ChIoro—3—(4-eth oxy-benzyI)-phenyI]f|uoro—6-meth oxy—tetra hydro-pyran-3,4- diol; (2S,3R,4R,5S)-2—[4-ChIoro—3—(4-hydroxy-benzyI)-phenyI]meth oxy-tetra hydro-pyran-3,4,5—triol; ( 2S,3R,4S,5R)—2—[4-ChIoro(4-ethoxy-benzyl)—phenyl]—tetrahydro—pyran-3,4,5-triol; (2S,3S,4S,5R)-2—[4-ChIoro(4-hydroxy—benzyI)-phenyl]—piperidine-3,4,5-triol; (2S,3R,4R,5S,6R)—2—[4-ChIoro—3—(4-ethoxy—benzyl)-phenyl]—6—ethanesuIfinyI-tetrahydro—pyran-3,4,5- triol; (2S,3R,4R,5S,6R)—2—[4-ChIoro—3—(4-ethoxy—benzyl)—phenyl]—6-ethanesuIfonyI-tetrahydro-pyran- triol; Acetic acid (2R,3S,4R,5S,6S)-4,5-diacetoxy—6-[4-chIoro(4 ethoxy-benzyl)—phenyl]—2— methylsuIfanyI-tetrahydro—pyran-3—yl ester; (2S,3R,4R,5S,6R)—2—[4-ChIoro—3—(4-ethoxy—benzyl)—phenyl]—6—methanesuIfonyI-tetrahydro-pyran- 3,4,5-triol; 2O ,3S,4S,5R)-2—[4-Ch|oro—3—(4-ethoxy—benzyI)-phenyl]—3,4,5-trihydroxy—piperidin-l—y|}-ethanon; (28,38,48,5R)—2—[4-Ch|oro—3—(4-ethoxy-benzyI)-phenyl]—3,4,5-trihydroxy—piperidine-l—carboxylic acid methyl ester; ,48,5R)—2—[4-Ch|oro—3—(4-ethoxy-benzyI)-phenyl]—3,4,5-trihydroxy—piperidine-l—carboxylic acid aIIyI amide; (2S,3S,4S,5R)-2—[4-ChIoro(4-ethoxy—benzyl)-pheny|]—1—methyI-piperidine-3,4,5-triol; (2S,3S,4R,5R,6R)—2—[3—(4-Ethoxy—benzyI)-phenyl]-6—hydroxymethyl-l—methyI-piperidine-3,4,5-triol; (2S,3R,4R,5S,6R)—2—(4-chIoro(4-ethoxybenzy|)phenyl)—6—methoxytetrahydro-2H-thiopyran-3,4,5- triol; (2S,3S,4R,5R,6R)—2—[4-Ch|oro—3—(4—ethoxy—benzyI)-phenyl]—6—hydroxymethyI-piperidine-3,4,5-triol; 3O (2S,3S,4R,5R,6R)—2—[4-ChIoro(4-ethoxy-benzyl)-phenyl]—6—hydroxymethyl-l—methyl-piperidine- 3,4,5-triol; (28,3R,4R,5S)-2—[3—(4—Ethoxy-benzyl)-phenyl]—6—methoxy—tetrahydro—pyran-3,4,5—triol; (2S,3R,4R,5S,6S)—2—[4-ChIoro—3—(4-ethoxy—benzyl)-phenyl]—6—(2—hydroxy—ethoxy)-tetrahydro—pyran- 3,4,5-triol; (38,4R,5R,6S)-2—Benzyloxy—6—[4-chIoro(4-ethoxy—benzyI)-pheny|]-tetrahydro—pyran-3,4,5-triol; (28,3R,4R,5S)-2—(4‘-Ethoxy—biphenyIyI)methoxy-tetrahydro—pyran-3,4,5-triol; LEX—1321 2012/020042 (2S,3R,4R,5S)—2—[4-Ch Ioro(4-ethoxy-benzyl)-phenyl]—6—(2,2,2—trifl uoro—eth oxy)—tetra hyd ro—pyran- 3,4,5-triol; (2S,3R,4R,5S)—2—[4-ChIoro—3—(4-ethoxy-benzyl)-phenyl]—6—(2—methoxy—ethoxy)-tetrahydro—pyran- 3,4,5-triol (2S,3R,4R,5S)—2—[4-ChIoro—3—(4-ethoxy-benzyI)-phenyI](2-dimethylamino—ethoxy)—tetrahydro— pyran-3,4,5-triol; (2S,3R,4R,5S)—2—[4-ChIoro—3—(4-ethoxy-benzyI)-phenyI]propylsuIfanyI-tetrahydro-pyran-3,4,5- triol; ,4R,5S)—2—[4-ChIoro(4-ethoxy-benzyl)-phenyl]—6—imidazol-l—yI-tetrahydro-pyran-3,4,5-triol; {(38,4R,5R,6S)—6—[4-ChIoro(4-eth oxy-benzyI)-phenyI]-3,4,5-trihydroxy—tetra hydro-pyran-2—yloxy}- acetic acid methyl ester; (2S,3R,4R,5S)—2—[4-ChIoro(4-ethoxy-benzyI)-phenyl]-6—(4-methyI-piperidin-l—yl)—tetrahydro—pyran- 3,4,5-triol; (2S,3R,4R,5S)—2—[4-ChIoro(4-ethoxy—benzyl)-pheny|]—6—(5-methyl-thiazol-2—ylamino)—tetrahydro— pyran-3,4,5-triol; (2S,3R,4R,5S,6R)—2—[4-ChIoro(4-ethoxy—benzyl)-pheny|]—6—phenoxy—tetrahydro—pyran-3,4,5-triol; ,3S,4R,5R,6S)-6—[4-ChIoro(4-ethoxy-benzyl)—phenyl]—3,4,5-trihyd roxy—tetrahyd ro—pyran-2— yI}-N-methyI-acetamide; Acetic acid (2S,3S,4R,5S,6S)-4,5-diacetoxy—6—[4-ch|oro—3—(4-ethoxy-benzyI)-phenyI]methoxy- 2O tetrahydro—pyran-3—yl ester; (2S,3R,4R,5S)-2—[4-ChIoro—3—(4-ethoxy-phenoxy)-phenyl]—6—methoxy—tetrahydro—pyran-3,4,5—triol; (2S,3R,4R,5S)—2—[4-ChIoro—3—(4-methoxy—phenylsuIfanyl)-phenyl]—6—methoxy—tetrahydro—pyran- 3,4,5-triol; (2S,3R,4R,5S)-2—[4-ChIoro—3—(4-methoxy—benzenesuIfinyl)-phenyl]—6—methoxy—tetrahydro—pyran- 3,4,5-triol; (2S,3R,4R,5S)—2—[4-ChIoro—3—(4-ethoxy-benzyI)-phenyI](3-hydroxy—propoxy)—tetrahydro—pyran- 3,4,5-triol; (2S,3R,4R,5S,6R)—2—[4-ChIoro(4-ethoxy-benzyl)-phenyl]—6—(2—hyd roxy—ethylsu|fany|)—tetra hyd ro- pyran-3,4,5-triol; 3O (2S,3R,4R,5S)—2—[4-ChIoro—3—(4-ethoxy-benzyl)—phenyl](2—mercapto—ethoxy)-tetra hydro-pyran- 3,4,5-triol; (2S,3R,4R,5S)—2—[4-ChIoro—3—(4-ethoxy—benzyl)-phenyl]—6—(2,3—dihydroxy—propoxy)-tetrahydro-pyran- 3,4,5-triol; (2S,3R,4R,5S)—2—{4-ChIoro—3—[4-(2—methoxy-ethoxy)-benzyl]-phenyl}methoxy—tetrahydro—pyran- triol; (2S,3R,4R,5S,6R)—2—[4-ChIoro—3—(4-ethoxy—benzyl)-phenyl]—6—ethylsuIfanyI-tetra hydro-pyran-3,4,5- triol; 16 LEX—1321 PCT/U82012/020042 (2S,3R,4R,5S,6R)—2—[4-ChIoro—3—(4-ethoxy—benzyl)-phenyl]—6—methylsuIfanyI-tetrahydro-pyran-3,4,5- triol; [2—Ch|oro((2S,3R,4R,5S,6S)—3,4,5-trihyd roxy—6—methoxy—tetrahydro—pyranyl)—phenyl]—(4-ethoxy— phenyI)-methanone; (2S,3R,4R,5S,6S)—2—{4-ChIoro—3—[(4—eth oxy-phenyI)-hydroxy-methyl]—phenyI}meth oxy—tetrahydro— pyran-3,4,5-triol; (2S,3R,4R,5S)-2—[3—(4—Ethoxy—benzyI)methyl-phenyl]—6—methoxy—tetra hyd ro—pyran-3,4,5-triol; (2S,3R,4R,5S)—2—{4-ChIoro—3—[4-(2—methylsuIfanyI-ethoxy)-benzyI]-phenyl}-6—methoxy—tetrahydro- pyran-3,4,5-triol; (2S,3R,4R,5S)—2—{4-ChIoro—3—[4-(pyridinyloxy)—benzyI]-phenyI}meth trahydro—pyran-3,4,5- triol; (2S,3R,4R,5S,6S)—2—(4-Ch |oro-3—{(4—eth enyl)-[(Z)—propyli mino]-methy|}-phenyl)—6—methoxy— tetra hyd ro—pyran-3,4,5-triol; (2S,3R,4R,5S)—2—{4-ChIoro—3—[4-(thiazoIyloxy)-benzyl]—phenyI}meth oxy-tetrahydro-pyran-3,4,5- triol; (28,3R,4R,5S)—2—{4-ChIoro[4-(pyri midinyloxy)—benzyl]-pheny|}-6—meth oxy—tetrahyd ro—pyran- 3,4,5-triol; (2S,3R,4R,5S)—2—{4-Ch |oro-3—[4-(2,6—d i meth oxy—pyri mid i nyloxy)-benzyl]—phenyl}-6—meth oxy- tetrahydro—pyran-3,4,5-triol; 2O 2—{(2 R,3S,4R,5R,6S)-6—[4-Ch Ioro(4-eth oxy—benzy|)-phenyl]—3,4,5—trihyd roxy—tetrahyd ro—pyra n-2— yIsquanyI}-acetamide; (2S,3R,4R,5S,6R)—2—[4-Ch Ioro(4-ethoxy-benzyl)—phenyl]—6—(fu ra n-2—yl methylsu IfanyI)-tetra hyd ro- pyran-3,4,5-triol; (2S,3R,4R,5S,6S)—2—{4-Ch —[(4—eth oxy—phenyI)-i mino—methyl]—phenyl}-6—meth oxy—tetra hyd ro- pyran-3,4,5-triol; (2S,3R,4R,5S,6S)—2—{3—[(4-Ethoxy—phenyI)-hydroxy—methyl]-phenyl}-6—methoxy—tetra hyd ro—pyran- triol; (28,38,48,5R)—2—[4-Ch|oro—3—(4-ethoxy-benzyI)-phenyl]—3,4,5-trihydroxy—piperidine—l—carboxylic acid benzyl ester; 3O ,48,5R)—2—[4-Ch|oro—3—(4-ethoxy-benzyI)-phenyl]—3,4,5-trihydroxy—piperidine—l—carboxylic acid allylamide; N-(2-{(2R,3S,4R,5R,6S)-6—[4-ChIoro—3—(4-ethoxy-benzyl)-phenyl]—3,4,5-trihydroxy—tetrahydro—pyran- 2—ylsuIfanyI}-ethyI)-acetamide; (2S,3R,4R,5S,6R)—2—[4-Ch Ioro(4-ethoxy-benzyl)—phenyl](2,2,2—trifluoro—ethylsu Ifa ny|)- tetra hyd ro—pyran-3,4,5-triol; (2S,3R,4R,5S,6S)—2—{4-ChIoro—3—[1—(4-ethoxy—phenyl)—1—hydroxy—ethyl]-pheny|}-6—methoxy- tetra hyd ro—pyran-3,4,5-triol; 17 LEX—1321 PCT/U82012/020042 DimethyI-thiocarbamic acid O-{4—[2—ch|oro((2S,3R,4R,5S)—3,4,5-trihydroxy—6—methoxy— tetrahydro—pyrany|)-benzyI]-phenyl} ester; (2S,3R,4R,5S,6S)—2—{3—[1—(4-Ethoxy—phenyl)-ethyl]—phenyl}-6—methoxy—tetrahydro—pyran-3,4,5-triol; DiethyI-dithiocarbamic acid (2R,3S,4R,5R,6S)—6—[4-ch|oro—3—(4-ethoxy-benzyl)—phenyl]—3,4,5- trihydroxy-tetrahydro—pyran-2—yl ester; ,4R,5S,6S)—2—(4-Ch|oro-3—{4-[(R)—(tetrahyd ro—fu ran-3—yl)oxy]—benzyl}-pheny|)—6—methoxy— tetrahydro—pyran-3,4,5-triol; (2S,3R,4R,5S,6R)—2—[4-ChIoro—3—(4-ethoxy—benzyl)-phenyl]—6—ethanesuIfinyI-tetrahydro—pyran-3,4,5- triol; (2S,3R,4R,5S)-2—{4-Ch|oro-3—[4-((S)—1—methyI-pyrrolidin-3—yloxy)—benzy|]-pheny|}-6—methoxy— tetrahydro—pyran-3,4,5-triol; (2S,3R,4R,5S)-2—{4-ChIoro—3—[4-(tetrahydro—pyranyloxy)—benzyl]-phenyl}-6—methoxy—tetrahydropyran-3 ,4,5-triol; (2S,3R,4R,5S)—2—(4-ChIoro{4-hydroxy—3—[1—(2—methylamino—ethyl)—a||y|]-benzy|}-pheny|)—6— methoxy—tetrahydro—pyran-3,4,5—triol; (2S,3R,4R,5S)—2—{4-ChIoro[4-(1-methyI-piperidinyloxy)—benzyl]—phenyl}-6—methoxy—tetrahydro- pyran-3,4,5-triol; (2S,3R,4R,5S,6R)—2—[4-ChIoro(4-ethoxy-benzyl)—phenyl]—6—methanesuIfinyI-tetrahydro-pyran- 3,4,5-triol; 2O (28,38,485R)—1—BenzyI[4-chIoro(4-ethoxy—benzy|)-phenyI]-piperidine-3,4,5-triol; (28,3R,4R,5S)-2—{3—[4—(2—Benzyloxy—ethoxy)—benzyI]chIoro—phenyl}methoxy—tetrahydro—pyran- 3,4,5-triol; ,4R,5S)—2—{3—[4-(2—Hydroxy-ethoxy)-benzyl]-phenyI}methoxy-tetrahydro—pyran-3,4,5-triol; (2S,3R,4R,5S)-2—{4-ChIoro—3—[4-(2—hydroxy-ethoxy)-benzyl]-phenyl}methoxy—tetrahydro—pyran- 3,4,5-triol; 2—{(2S,3S,4S,5R)—2—[4—Ch|oro—3—(4—ethoxy—benzyI)-phenyl]—3,4,5-trihydroxy—piperidin-l—y|}- acetamide; (2S,3S,4S,5R)-2—[4-ChIoro(4-ethoxy-benzyl)—phenyl]—1—isobutyI-piperidine—3,4,5-triol; (2S,3R,4R,5S,6R)—2—[4-ChIoro—3—(4—ethoxy-benzyl)-phenyl]—6—(2—methyI-tetra hydro-furan-3— 3O yIsquanyI)-tetra hydro-pyran-3,4,5-triol; (R)-2—Amino—3—{(2R,3S,4R,5R,6S)—6—[4-ch|oro—3—(4-ethoxy—benzyl)-phenyl]—3,4,5-trihydroxy— tetrahydro—pyranylsuIfanyI}-propionic acid; ,4R,5S,6R)—2—[4-ChIoro—3—(4-ethoxy—benzyI)-phenyl]—6-cyclopentylsulfanyI-tetrahydro—pyran- 3,4,5-triol; (2S,3R,4R,5S,6R)—2—[4-ChIoro(4-ethoxy-benzyI)-phenyl]—6—cyclohexylsuIfanyI-tetrahydro-pyran- 3,4,5-triol; 18 LEX—1321 (2S,3R,4R,5S,6R)—2—[4—Chloro(4-ethoxy-benzyl)-phenyl](3—methyl-butylsulfanyl)-tetra hydro- pyran-3,4,5-triol; (28,3R,4R,5S)[3—(4—Ethoxy-benzyl)-phenyl]methoxy-tetrahydro-pyran-3,4,5-triol; 1—{(2S,3S,4S,5R)—2-[4—Chloro(4-ethoxy-benzyl)—phenyl]—3,4,5-trihydroxy-piperidin-1—yl}-ethanone; (28,38,48,5R)—2-[4—Chloro(4-ethoxy-benzyl)-phenyl]—3,4,5-trihydroxy-piperidine-1—carboxylic acid benzyl ester; (2S,3S,4S,5R)—1—Benzyl[4—chloro(4-ethoxy-benzyl)-phenyl]-piperidine-3,4,5-triol; 2-{(2S,3S,4S,5R)—2-[4—Chloro(4-ethoxy-benzyl)-phenyl]—3,4,5-trihydroxy-piperidinyl}- acetamide; (2S,3S,4S,5R)[4—Chloro(4-ethoxy-benzyl)—phenyl]—1—isobutyl-piperidine-3,4,5-triol; (3S,4R,5R)—2-[4—Chloro(4-ethoxy-benzyl)—phenyl]—6—hydroxymethyl-piperidine-3,4,5-triol; and pharmaceutically acceptable salts thereof.

A particular dual SGLT1/2 inhibitor is ,4R,5S,6R)—2-(4—chloro(4- ethoxybenzyl)phenyl)-6—(methylthio)tetrahydro-2H-pyran-3,4,5-triol, and pharmaceutically acceptable salts thereof. Applicants have found that this nd has an SGLT1 |C501 SGLT2 |C50 ratio of about 20. lline solid forms of this compound are described in International Application Publication No. W0 09197, and include anhydrous forms 1 and 2.

Crystalline anhydrous (2S,3R,4R,5S,6R)—2-(4—chloro(4-ethoxybenzyl)phenyl) (methylthio)tetrahydro-2H-pyran-3,4,5-triol Form 1 has a ential scanning calorimetry (DSC) 2O endotherm at about 124°C. In this context, the term “about” means : 50°C. In one ment, the form provides an X-ray powder ction (XRPD) pattern that contains peaks at one or more of about 4.0, 8.1, 9.8, 14.0 and/or 19.3 degrees 20. In this context, the term “about” means i 0.3 degrees.

Crystalline anhydrous Form 2 has a DSC endotherm at about 134°C. In this context, the term “about” means : 50°C. In one embodiment, the form provides an XRPD pattern that contains peaks at one or more of about 4.4, 4.8, 14.5, 14.7, 15.5, 21.2, 22.1 and/or 23.8 degrees 20. In this context, the term ” means i 0.3 degrees. .3. Methods of Use This invention encompasses methods improving the cardiovascular and/or metabolic 3O health of a patient, which comprise stering to a patient in need thereof a safe and efficacious amount of a dual SGLT1/2 inhibitor of the invention.

Patients in need of such improvement include those suffering from diseases or ers such as atherosclerosis, cardiovascular disease, diabetes (Type 1 and 2), disorders associated with hemoconcentration (e.g., hemochromatosis, polycythemia vera), hyperglycaemia, hypertension, gnesemia, hyponatremia, lipid disorders, obesity, renal failure (e.g., stage 1, 2, or 3 renal failure), and Syndrome X. Particular patients suffer from, or are at risk of suffering from, type 2 diabetes mellitus. 19 LEX—1321 PCT/U82012/020042 In one embodiment of the invention, the administration effects a decrease in the patient’s plasma glucose. In one embodiment, the administration effects an improved oral glucose tolerance in the patient. In one embodiment, the administration lowers the patient’s post-prandial plasma glucose level. In one embodiment, the administration lowers the patient’s plasma fructosamine level. In one embodiment, the administration lowers the patient’s HbA1c level. In one embodiment, the administration reduces the patient’s blood pressure (e.g., systolic and diastolic). In one embodiment, the administration reduces the patient’s triglyceride levels.

In a particular embodiment, the patient is concurrently taking another therapeutic agent.

Other therapeutic agents include known therapeutic agents useful in the treatment of the entioned disorders including: anti-diabetic agents; anti-hyperglycemic agents; hypolipidemic/lipid lowering agents; anti-obesity agents; anti-hypertensive agents and appetite suppressants. es of le anti-diabetic agents include biguanides (e.g., metformin, phenformin), glucosidase inhibitors (e.g., acarbose, miglitol), insulins (including insulin secretagogues and insulin sensitizers), meglitinides (e.g., repaglinide), ylureas (e.g., glimepiride, glyburide, gliclazide, chlorpropamide, and glipizide), biguanide/glyburide combinations (e.g., Glucovance), lidinediones (e.g., troglitazone, rosiglitazone, and pioglitazone), PPAR-alpha agonists, PPAR-gamma agonists, PPAR alpha/gamma dual agonists, glycogen phosphorylase inhibitors, tors of fatty acid binding protein (aP2), glucagon-like 2O peptide-1(GLP—1)or other agonists of the GLP—1 receptor, and dipeptidyl peptidase lV (DPP4) inhibitors.

Examples of meglitinides e nateglinide (Novartis) and KAD1229 (PF/Kissei).

Examples of thiazolidinediones include Mitsubishi's MCC-555 (disclosed in U.S. Pat. No. ,594,016), Glaxo-Welcome‘s GL-262570, englitazone (OP-68722, Pfizer), darglitazone (CP- 86325, Pfizer, isaglitazone (MlT/J&J),JiT—501(JPNT/P&U), L-895645 (Merck), R-119702 (Sankyo/WL), NN-2344 (Dr. Reddy/NN), or YM-440 (Yamanouchi).

Examples of PPAR-alpha ts, PPAR-gamma agonists and PPAR gamma dual agonists e muraglitizar, itazar, AR-H039242 (Astra/Zeneca), GW-409544 (Glaxo- Wellcome), GW-501516 (Glaxo-Wellcome), KRP297 (Kyorin Merck) as well as those disclosed by 3O Murakami et al, Diabetes 47, 1841-1847 (1998), W0 01/21602 and in U.S. Pat. No. 6,653,314. es of aP2 inhibitors include those disclosed in U.S. ation Ser. No. 09/391,053, filed Sep. 7, 1999, and in U.S. application Ser. No. ,079, filed Mar. 6, 2000, ing dosages as set out herein.

Examples of DPP4 inhibitors include sitagliptin (Janiuvia®, Merck), vildagliptin s®, Novartis), saxagliptin (0nglyza®, 7118), linagliptin (Bl-1356), iptin (PHX1149T), gemigliptin(LG Life Sciences), alogliptin(SYR-322, Takeda), those disclosed in 8501, W099/46272, W099/67279 (PROBIODRUG), W099/67278 (PROBIODRUG), and W099/61431 2O LEX—1321 (PROBIODRUG), P728A (1-[[[2-[(5-cyanopyridinyl)amino]ethyl]amino]acetyl]cyano-(S)- pyrro- lidine) (Novartis) as disclosed by Hughes et al, Biochemistry, 38(36), 11597-11603, 1999, TSL-225 (tryptophyl-1,2,3,4-tetrahydroisoquinolinecarboxylic acid (disclosed by Ya mada et al, Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540), 2-cyanopyrrolidides and 4-cyanopyrrolidides, as disclosed by Ashworth et al, Bioorg. & Med. Chem. Lett., Vol. 6, No. 22, pp 1163-1166 and 2745-2748 (1996), the compounds disclosed in U.S. application Ser. No. 10/899,641, W0 603 and U.S. Pat. No. 6,395,767, employing dosages as set out in the above references.

Examples of anti-hyperglycemic agents include glucagon-like peptide-1 (G LP-1), GLP-1(1— 36) amide, GLP-1(7-36) amide, GLP—1(7-37) (as disclosed in U.S. Pat. No. 5,614,492), exenatide (Amylin/Lilly), LY-315902 (Lilly), liraglutide (NovoNordisk), ZP—10 (Zealand Pharmaceuticals A/S), CJC—1131(Conjuchem Inc), and the compounds sed in W0 671.

Examples of hypolipidemic/lipid lowering agents include MTP inhibitors, HMG CoA reductase inhibitors, squalene synthetase inhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors, Nat/bile acid co-transporter inhibitors, up-regulators of LDL receptor activity, bile acid trants, cholesterol ester transfer protein (e.g., CETP inhibitors, such as CP-529414 (Pfizer) and JiT—705 (Akros )), and nicotinic acid and derivatives f.

Examples of MTP inhibitors include those disclosed in U.S. Pat. No. 5,595,872, U.S. Pat.

No. 5,739,135, U.S. Pat. No. 5,712,279, U.S. Pat. No. 5,760,246, U.S. Pat. No. 5,827,875, U.S. 2O Pat. No. 5,885,983 and U.S. Pat. No. 5,962,440.

Examples of HMG CoA reductase tors include mevastatin and related compounds, as sed in U.S. Pat. No. 3,983,140, lovastatin (mevinolin) and related compounds, as disclosed in U.S. Pat. No. 4,231,938, pravastatin and related compounds, such as disclosed in U.S. Pat. No. 4,346,227, simvastatin and d compounds, as sed in U.S. Pat. Nos. 4,448,784 and 4,450,171. Other HMG CoA ase tors which may be employed herein include, but are not limited to, fluvastatin, disclosed in U.S. Pat. No. 5,354,772, cerivastatin, as disclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080, atorvastatin, as sed in U.S. Pat. Nos. 4,681,893, 5,273,995, 5,385,929 and 5,686,104, atavastatin (Nissan/Sankyo's nisvastatin (NK-104)), as disclosed in U.S. Pat. No. 5,011,930, visastatin (Shionogi-Astra/Zeneca (ZD- 3O 4522)), as disclosed in U.S. Pat. No. 5,260,440, and related statin compounds disclosed in U.S.

Pat. No. 5,753,675, pyrazole analogs of mevalonolactone derivatives, as disclosed in U.S. Pat.

No. 4,613,610, indene analogs of mevalonolactone derivatives, as disclosed in PCT application W0 86/03488, substituted-pyrrolyl)-alkyl)pyranones and derivatives f, as sed in U.S. Pat. No. 4,647,576, Searle‘s 80-45355 (a 3-substituted pentanedioic acid derivative) roacetate, imidazole analogs of mevalonolactone, as disclosed in PCT application W0 86/07054, 3-carboxyhydroxy-propane-phosphonic acid derivatives, as disclosed in French Patent No. 2,596,393, 2,3—disubstituted pyrrole, furan and thiophene 21 LEX—1321 derivatives, as disclosed in European Patent ation No. 0221025, naphthyl analogs of nolactone, as disclosed in U.8. Pat. No. 4,686,237, octahydronaphthalenes, such as disclosed in U.8. Pat. No. 289, keto analogs of mevinolin (lovastatin), as disclosed in European Patent Application No. 0142146 A2, and quinoline and pyridine derivatives, as disclosed in U.8. Pat. Nos. 5,506,219 and 5,691,322.

Examples of hypolipidemic agents include pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin, and ZD-4522.

Examples of inic acid compounds useful in inhibiting HMG CoA reductase include those disclosed in GB 2205837.

Examples of squalene synthetase inhibitors include or-phosphono—sulfonates disclosed in U.8. Pat. No. 5,712,396, those disclosed by Biller et al., J. Med. Chem. 1988, Vol. 31, No. 10, pp 1869-1871, including isoprenoid (phosphinyl-methyl)phosphonates, as well as other known squalene synthetase inhibitors, for example, as disclosed in U.8. Pat. Nos. 4,871,721 and 024 and in Biller, 8. A., et al., Current Pharmaceutical Design, 2, 1-40 (1996).

Examples of additional squalene synthetase inhibitors suitable for use herein include the terpenoid pyrophosphates sed by P. Ortiz de Montellano et al., J. Med. Chem., 1977, 20, 243-249, the yl diphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs as disclosed by Corey and Volante, J. Am. Chem. Soc. 1976, 98, 1291-1293, phosphinylphosphonates reported by McClard, R. W. et al.,L08, 1987, 109, 5544 and 2O ropanes ed by Capson, T. L., PhD dissertation, June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp 16, 17, 40-43, 48-51, y.

Examples of fibric acid derivatives which may be employed in combination the compounds of this invention include fenofibrate, gemfibrozil, clofibrate, brate, ciprofibrate, clinofibrate and the like, probucol, and related nds, as disclosed in U.8. Pat. No. 3,674,836, probucol and gemfibrozil being preferred, bile acid sequestrants, such as cholestyramine, colestipol and DEAE-8ephadex (8echolex, Policexide), as well as lipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolamine derivative), il 02), tetrahydrolipstatin (THL), istigmastanylphos-phorylcholine (8PC, Roche), aminocyclodextrin (Tanabe 8eiyoku), Ajinomoto AJ-814 (azulene derivative), mide (8umitomo), 8andoz 58- 3O 035, American Cyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinic acid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin, poly(diallylmethylamine) tives, such as disclosed in U.8. Pat. No. 4,759,923, quaternary amine poly(diallyldimethylammonium chloride) and ionenes, such as disclosed in U.8. Pat. No. 4,027,009, and other known serum cholesterol ng agents.

Examples of ACAT inhibitor that may be employed in combination compounds of this invention include those disclosed in Drugs of the Future 24, 9-15 (1999), (Avasimibe); Nicolosi et al., Atherosclerosis (8hannon, lrel). (1998), 137(1), 77-85; Ghiselli, Giancarlo, vasc. Drug 22 LEX—1321 Rev. (1998), 16(1), 16-30; Smith, C., et al., . Med. Chem. Lett. (1996), 6(1), 47-50; Krause etal., Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A., Inflammation: Mediators ys (1995), 173-98, Publisher: CRC, Boca Raton, Fla.; Sliskovic et al., Curr. Med. Chem. (1994), 1(3), ; Stout et al., acts: Org. Chem. (1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co. Ltd).

Examples of hypolipidemic agents include up-regulators of LD2 receptor ty, such as MD-7OO (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).

Examples of terol tion inhibitors include SCH48461 (Schering—Plough), as well as those disclosed in sclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998).

Examples of ileal Nat/bile acid co-transporter inhibitors include compounds as disclosed in Drugs of the Future, 24, 425-430 .

Examples of lipoxygenase inhibitors include 15-lipoxygenase (15-LO) inhibitors, such as benzimidazole derivatives, as disclosed in WO 97/12615, 15-LO inhibitors, as disclosed in WO 97/12613, isothiazolones, as disclosed in WO 44, and 15-LO inhibitors, as disclosed by Sendobry et al., Brit. J. Pharmacology (1997) 120, 1199-1206, and Cornicelli et al.,M Pharmaceutical Design, 1999, 5, 11-20.

Examples of suitable anti-hypertensive agents for use in combination with compounds of this invention include beta adrenergic blockers, calcium channel blockers (L-type and T-type; e.g., zem, verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g., thiazide, 2O hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, iazide, benzthiazide, ynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetamide, triamtrenene, amiloride, spironolactone), renin tors, ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT—1 receptor antagonists (e.g., losartan, irbesartan, valsartan), ET or antagonists (e.g., sitaxsentan, atrsentan and compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), Dual ET/All antagonist (e.g., compounds disclosed in WO 00/01389), neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP—ACE inhibitors) (e.g., omapatrilat and gemopatrilat), and nitrates.

Examples anti-obesity agents include beta 3 adrenergic agonists, a lipase inhibitors, 3O serotonin (and dopamine) reuptake inhibitors, thyroid receptor beta drugs, 5HT2c agonists, (such as Arena APD-356); MCH R1 antagonists such as Synaptic SNAP-7941 and Takeda T-226926, melanocortin receptor (MC4R) agonists, melanin-concentrating hormone receptor (MCHR) antagonists (such as Synaptic 941 and Takeda T-226926), galanin receptor tors, orexin nists, CCK agonists, NPY1 or NPY5 antagonsist, NPY2 and NPY4 modulators, corticotropin releasing factor agonists, histamine receptor-3 (H3) modulators, 11—beta-HSD-1 inhibitors, adinopectin receptor modulators, monoamine reuptake inhibitors or releasing agents, a ciliary neurotrophic factor (CNTF, such as AXOKINE by Regeneron), BDNF (brain-derived 23 LEX—1321 rophic factor), leptin and leptin receptor tors, cannabinoid-1 or antagonists (such as 716 (Sanofi) or SLV-319 (Solvay)), and/or an anorectic agent. es of beta 3 adrenergic agonists include AJ9677 (Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other known beta 3 agonists, as disclosed in US. Pat. Nos. ,541,204, 5,770,615, 5,491,134, 5,776,983 and 5,488,064.

Examples of lipase inhibitors e orlistat and ATL—962 (Alizyme).

Examples of serotonin (and dopoamine) reuptake inhibitors (or serotonin receptor agonists) e BVT-933 (Biovitrum), sibutramine, mate (Johnson & Johnson) and axokine (Regeneron).

Examples of thyroid receptor beta compounds e thyroid receptor ligands, such as those disclosed in W097/21993 (U. Cal SF), W099/00353 (KaroBio) and GB98/284425 (KaroBio).

Examples of monoamine reuptake inhibitors include fenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, sertraline, chlorphentermine, cloforex, clortermine, picilorex, sibutramine, dexamphetamine, phentermine, phenylpropanolamine and ol.

Examples of anorectic agents include dexamphetamine, rmine, phenylpropanolamine, and mazindol. .4. PharmaceuticalFormulations This ion encompasses pharmaceutical compositions comprising one or more dual 2O 2 tor of the invention, optionally in combination with one or more second active ingredients, such as those described above in Section 5.3.

A particular dual SGLT1/2 inhibitor is (2S,3R,4R,5S,6R)(4—chloro(4- ethoxybenzyl)phenyl)—6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol. Dosage forms comprising the compound are preferably made using a crystalline solid form, e.g., crystalline anhydrous form 1 or 2, described herein.

Certain pharmaceutical compositions are single unit dosage forms suitable for oral administration to a patient. Discrete dosage forms suitable for oral administration include tablets (e.g., chewable s), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain ermined amounts of active ingredients, and may be prepared by 3O methods of cy well known to those skilled in the art. See, e.g., Remington’s Pharmaceutical es, 18th ed. (Mack Publishing, Easton PA: 1990).

Typical oral dosage forms are prepared by combining the active ingredient(s) in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms can be prepared by conventional methods of pharmacy. In general, pharmaceutical compositions and dosage forms 24 LEX—1321 PCT/U82012/020042 are prepared by uniformly and intimately admixing the active ingredients with pharmaceutically acceptable excipients and/or diluents, and then shaping the product into the desired presentation if necessary. Disintegrants may be incorporated in solid dosage forms to facility rapid dissolution. Lubricants may also be incorporated to facilitate the manufacture of dosage forms (e.g., tablets). 6. EXAMPLES 6.1. In Vitro Human SGLT2 Inhibition Assay Human sodium/glucose co-transporter type 2 (SGLT2; accession number P31639; GI:400337) was cloned into leESpuro2 vectorfor mammalian sion (construct: HA-SGLT2- ro2).

HEK293 cells were transfected with the human HA-SG LT2-leESpuro2 vector and the bulk stable cell line was selected in presence of 0.5 ug/ml of puromycin. Human HA-SGLT2 cells were maintained in DMEM media containing 10% FBS, 1% GPS and 0.5 ug/ml of puromycin.

The HEK293 cells expressing the human HA—SGLT2 were seeded in 384 well plates (30,000 cells/well) in DMEM media containing 10% FBS, 1% GPS and 0.5 ug/ml of puromycin, then incubated ght at 37 C, 5% C02. Cells were then washed with uptake buffer (140 mM NaCl, 2 mM KCI, 1 mM CaCI2, 1 mM MgCI2, 10 mM HEPES, 5 mM Tris, 1 mg/ml bovine serum n (BSA), pH 7.3). Twenty microliters of uptake buffer with or without testing compounds were added to the cells. Then, 20 microliters of uptake buffer ning 14C—AMG (100 nCi) were 2O added to the cells. The cell plates were incubated at 37°C, 5% CO2 for 1-2 hours. After washing the cells with uptake , scintillation fluid was added (40 microliters/well) and G uptake was measured by counting radioactivity using a scintillation coulter (TopCoulter NXT; Packard Instruments). 6.2. In Vitro Human SGLT1 Inhibition Assay Human sodium/glucose co-transporter type 1 (SG LT1; accession number NP_000334; GI: 4507031) was cloned into leESpuro2 vector for mammalian expression ruct: HA- SG LT1-leESpuro2 ).

HEK293 cells were transfected with the human HA-SG LT1-leESpuro2 vector and the bulk stable cell line was selected in presence of 0.5 ug/ml of puromycin. Human T1 cells 3O were ined in DMEM media containing 10% FBS, 1% GPS and 0.5 ug/ml of puromycin.

The HEK293 cells expressing the human HA—SGLT1 were seeded in 384 well plates (30,000 cells/well) in DMEM media containing 10% FBS, 1% GPS and 0.5 ug/ml of cin, then incubated overnight at 37 C, 5% C02. Cells were then washed with uptake buffer (140 mM NaCl, 2 mM KCI, 1 mM CaCI2, 1 mM MgCI2, 10 mM HEPES, 5 mM Tris, 1 mg/ml bovine serum albumin (BSA), pH 7.3). Twenty microliters of uptake buffer with or without testing compounds LEX—1321 were added to the cells. Then, 20 microliters of uptake buffer containing 14C—AMG (100 nCi) were also added to cells. The cell plates were incubated at 37°C, 5% CO2 for 1-2 hours. After washing the cells with uptake buffer, scintillation fluid was added (40 microliters/well) and l4C-AMG uptake was measured by counting radioactivity using a scintillation coulter (TopCoulter NXT; Packard Instruments). 6.1. Synthesis of ((3aS,5R,6S,6aS)—6—hydroxy—2,2—dimethyltetrahydrofurol2,3- d||1,3|dioxol—5—yl)(morpholino)methanone To a 12L three-necked round bottom flask with mechanical stirrer, rubber septum with ature probe and gas bubbler was charged L-(-)-Xylose (504.40 g, 3.360 mol), acetone (5L, reagent grade) and anhydrous Mg804 powder (811.23g, 6.740 mol / 2.0 equiv). The suspension was set stirring at ambient and then concentrated H2804 (50 mL, 0.938 mol / 0.28 equiv) was added. A slow mild exotherm was noticed (temperature rose to 24°C over about 1 hr) and the reaction was d to stir at ambient overnight. After 16.25 hours, TLC suggested all L-xylose had been consumed, with the major product being the bis-acetonide along with some (3aS,5S,6R,6aS)—5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxolol. The reaction mixture was filtered and the ted solids were washed twice with acetone (500 mL per wash). The stirring yellow filtrate was neutralized with concentrated NH40H solution (39 mL) to pH = 8.7. After stirring for 10 min, the suspended solids were removed by filtration. The te was concentrated to afford crude bis-acetonide intermediate as a yellow oil (725.23 g). 2O The yellow oil was ded in 2.5 L water stirring in a 5L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler. The pH was adjusted from 9 to 2 with 1N aq. HCl (142 mL) and stirred at room temperature for 6 h until GC showed sufficient sion of the bis-acetonide intermediate to (3aS,5S,6R,6aS)—5— (hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxolol. The reaction was neutralized by the addition of 50% w/w aq. K2HP04 until pH=7. The solvent was then evaporated and ethyl acetate (1.25L) was added to give a white suspension which was filtered. The filtrate was trated in vacuo to afford an orange oil which was dissolved in 1 L methyl tert-butyl ether.

This solution had KF 0.23 wt% water and was concentrated to afford (3aS,5S,6R,6aS)—5- (hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxolol as an orange oil (551.23g, 86% 3O yield, 96.7 area% pure by GC). 1H NMR (400 MHZ, DMSO-da) 8 1.22 (s, 3 H) 1.37 (s, 3 H) 3.51 (dd, J=11.12, 5.81 Hz, 1 H) 3.61 (dd, J=11.12, 5.05 Hz, 1 H) 3.93 - 4.00 (m, 1 H) 3.96 (s, 1 H) 4.36 (d, J=3.79 HZ, 1 H) 4.86 (br. s., 2 H) 5.79 (d, J=3.54 HZ, 1 H). 13C NMR z, s) 8 26.48, 27.02, 59.30, 73.88, 81.71, 85.48, 104.69, 110.73.

To a solution of (3aS,5S,6R,6aS)—5—(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3- d][1,3]dioxolol (25.0g, 131 mmol) in acetone (375 mL, 15X) and H20 (125 mL, 5X) was added NaHC03 (33.0g, 3.0 equiv), NaBr (2.8g, 20 mol%) and TEMPO (0.40g, 2 mol%) at 20°C. The mixture was cooled to 05°C and solid oroisocyanuric acid (TCCA, 30.5 g, 1.0 equiv) was 26 LEX—1321 then added in portions. The suspension was stirred at 20°C for 24h. Methanol (20 mL) was added and the mixture was stirred at 20°C for 1h. A white suspension was formed at this point.

The mixture was filtered, washed with e (50 mL, 2X). The organic solvent was removed under vacuum and the s layer was ted with EtOAc (300 mL, 12X x3) and the combined organic layers were concentrated to afford an oily mixture with some solid residue.

Acetone (125 mL, 5X) was added and the mixture was filtered. The acetone solution was then concentrated to afford the desired acid ((3aS,5R,6S,6aS)—6-hydroxy-2,2- yltetrahydrofuro[2,3-d][1,3]dioxolecarboxylic acid) as a yellow solid (21.0g, 79%). 1H NMR (methanol-d4), 8 6.00 (d, J = 3.2 Hz, 1H), 4.72 d, J = 3.2 Hz, 1H), 4.53 (d, J = 3.2 Hz, 1H), 4.38 (d, J = 3.2 Hz, 1H), 1.44 (s, 3H), 1.32 (s, 3H).

To a solution of (3aS,5R,6S,6aS)—6—hydroxy—2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole- -carboxylic acid (5.0g, 24.5 mmol) in THF (100 mL, 20X) was added TBTU (11.8g, 1.5 equiv), N- methylmorpholine (NMM, 4.1 mL, 1.5 equiv) and the mixture was stirred at 20°C for 30 min.

Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20°C for an additional 6h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2X x2). The organic on was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4:1) to afford 4.3 g of the desired morpholine amide (64%) as a white solid. 1H NMR (CDCI3), 8 6.02 (d, J = 3.2 Hz, 1H), .11 (br s, 1H), 4.62 (d, J = 3.2 HZ, 1H), 4.58 (d, J = 3.2 HZ, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 2O 1.35 (s, 3H). 6.2. Alternative synthesis of ((3aS,5R,63,6aS)—6-hydroy—2,2— dimethyltetrahydrofurol 2,3—d M 1,3 |dioxol-5—yl)(morpholino)methanone A solution of the diol (3aS,5S,6R,6aS)—5—(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3- ]dioxolol in acetonitrile (5.38 kg, 65% w/w, 3.50 kg active, 18.40 mol), acetonitrile (10.5 L) and TEMPO (28.4 g, 1 mol %) were added to a solution of K2HP04 (0.32 kg, 1.84 mol) and KH2PO4 (1.25 kg, 9.20 mol) in water (10.5 L). A on of NaClO2 (3.12 kg, 80% w/w, 27.6 mole, 1.50 eq) in water (7.0 L) and a solution of K2HP04 (2.89 kg, 0.90 eq) in water (3.0 L) were ed with cooling. Bleach (3.0L, approximate 6% household grade) was mixed with the K2HP04 solution. Approximately 20% of the NaCl02 solution (1.6 L) and bleach/K2HP04 solution 3O (400 mL, ~1 mol %) were added. The remainders of the two solutions were added simultaneously. The reaction mixture turned dark red brown and slow exotherm was observed.

The addition rate of the NaCl02 solution was about 40 mL/min (3-4 h addition) and the addition rate for the /K2HP04 solution was about 10-12 mL/min (10 hr addition) while maintaining the batch at 15-25°C. Additional charges of TEMPO (14.3g, 0.5 mol%) were performed every 5-6 hr until the reaction went to tion (usually two charges are sufficient). Nitrogen sweep of the headspace to a scrubber with aqueous was performed to keep the green-yellowish gas from accumulating in the . The reaction mixture was cooled to < 10°C and quenched with 27 LEX—1321 Na2803 (1.4 kg, 0.6 eq) in three portions over 1 hr. The reaction mixture was then acidified with H3P04 until pH reached 2.0-2.1(2.5-2.7 L) at 515°C. The layers were separated and the aqueous layer was extracted with acetonitrile (10.5 L x 3). The combined organic layer was concentrated under vacuo (~100-120 torr) at < 35°C (28-32 °C vapor, 45-50°C bath) to low volume (~ 67 L) and then flushed with acetonitrile (40 L) until KF of the solution reached < 1% when diluted to volume of about 12-15Lwith acetonitrile. Morpholine (1.61 L, 18.4 mol, 1.0 eq) was added over 4-6 h and the slurry was aged overnight under nitrogen. The mixture was cooled to 05°C and aged for 3 hours then filtered. The filter cake was washed with acetonitrile (10 L).

Drying under flowing nitrogen gave 4.13 kg of the morpholine salt of ((3aS,5R,6S,6aS)hydroxy— 2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxolecarboxylic acid as a white solid % pure based on 1H NMR with 1,4-dimethoxybenzene as the internal standard), 72-75% yield corrected for purity. 1H NMR (D20) 8 5.96 (d, J = 3.6 Hz, 1H), 4.58 (d, J = 3.6 Hz, 1H), 4.53 (d, J = 3.2 Hz, 1H), 4.30 (d, J = 3.2 HZ, 1H), 3.84 (m, 2H), 3.18 (m, 2H), 1.40 (s, 1H), 1.25 (s, 1H). 13H NMR (D20) 8 174.5, 112.5, 104.6, 84.2, 81.7, 75.0, 63.6, 43.1, 25.6, 25.1.

The morpholine salt of ((3aS,5R,6S,6aS)—6-hydroxy-2,2-dimethyltetrahydrofuro[2,3- ]dioxolecarboxylic acid (7.85 kg, 26.9 mol), morpholine (2.40 L, 27.5 mol) and boric acid (340 g, 5.49 mol, 0.2 eq) were added to toluene (31 L). The resulting slurry was degassed and heated at reflux with a Dean-Stark trap under nitrogen for 12 h and then cooled to room temperature. The mixture was filtered to remove insolubles and the filter cake washed with 2O toluene (5 L). The filtrate was concentrated to about 14 L and flushed with toluene (~80 L) to remove excess morpholine. When final volume reached ~12 L, heptane (14 L) was added slowly at 60-70°C. The ing slurry was cooled gradually to room temperature and aged for 3 h. It was then filtered and washed with heptane (12 L) and dry under nitrogen gave a slightly pink solid (6.26 kg, 97% pure, 98% yield). mp: 136°C (DSC). 1H NMR (CDCI3), 8 6.02 (d, J = 3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J = 3.2 HZ, 1H), 4.58 (d, J = 3.2 HZ, 1H), 5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H). 130 NMR (methanol-d4) 8 26.84, 27.61, 44.24, 47.45, 68.16, 77.14, 81.14, 86.80, 106.87, 113.68, 169.05. 6.3. Synthesis of 1—chloro—2—(4—ethoxybenyl)—4—iodobenzene A 2L three-necked round bottom flask with mechanical stirrer, rubber septum with 3O temperature probe and pressure-equalized addition funnel with gas bubbler was charged with 2- chloroiodobenzoic acid (199.41 g, 0.706 mol), romethane (1.2L, KF = 0.003 wt% water) and the suspension was set stirring at t temperature. Then methylformamide (0.6 mL, 1.1 mol %) was added ed by oxalyl chloride (63 mL, 0.722 mol, 1.02 equiv) which was added over 11 min. The reaction was allowed to stir at t overnight and became a solution. After 18.75hours, additional oxalyl chloride (6 mL, 0.069 mol, 0.10 equiv) was added to consume unreacted starting material. After 2 hours, the reaction mixture was trated in 28 LEX—1321 vacuo to afford crude 2-chloroiodobenzoyl chloride as a pale yellow foam which will be carried forward to the next step.

Ajacketed 2L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and pressure-equalized addition funnel with gas bubbler was d with aluminum chloride (97.68 g, 0.733 mol, 1.04 equiv), dichloromethane (0.65 L, KF = 0.003 wt% water) and the sion was set stirring under nitrogen and was cooled to about 6°C.

Then ethoxybenzene (90 mL, 0.712 mol, 1.01 equiv) was added over 7 minutes keeping internal temperature below 9°C. The resulting orange solution was diluted with romethane (75mL) and was cooled to -7°C. Then a solution of 2-chloroiodobenzoyl de (S 0.706 mol) in 350 mL dichloromethane was added over 13 minutes keeping the internal temperature below +3°C.

The reaction mixture was warmed slightly and held at +5°C for 2 hours. HPLC analysis suggested the reaction was complete and the reaction was quenched into 450mL oled (~5°C) 2N aq. HCI with stirring in a jacketed round bottom flask. This quench was done in portions over 10min with internal temperature remaining below 28°C. The quenched biphasic mixture was stirred at 20°C for 45min and the lower organic phase was washed with 1N aq. HCI (200mL), twice with saturated aq. sodium bicarbonate (200mL per wash), and with saturated aq. sodium chloride ). The washed extract was concentrated on a rotary evaporator to afford crude (2-chloroiodophenyl)(4-ethoxyphenyl)methanone as an off-white solid (268.93g, 99.0 area% by HPLC at 220nm, 1.0 area% regioisomer at 200nm, 98.5 % “as-is" yield). 2O Ajacketed 1 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged with crude (2-chloroiodophenyl)(4- ethoxyphenyl)methanone (30.13 g, 77.93 mmol), acetonitrile (300mL, KF = 0.004 wt% water) and the sion was set stirring under nitrogen and was cooled to about 5°C. Then triethylsilane (28mL, 175.30 mmol, 2.25 equiv) was added followed by boron trifluoride- diethyletherate (24mL, 194.46mmol, 2.50 equiv) which was added over about 30 seconds. The reaction was warmed to t over 30min and was stirred for 17 hours. The reaction was diluted with methyl utyl ether (150mL) followed by saturated aq sodium onate (150mL) which was added over about 1 minutes. Mild gas evolution was noticed and the biphasic solution was stirred at ambient for 45 minutes. The upper organic phase was washed 3O with saturated aq. sodium bicarbonate (100 mL), and with ted aq. sodium chloride (50mL).

The washed extract was concentrated on a rotary evaporator to about one half of its original volume and was diluted with water (70 mL). Further tration in vacuo at 45°C was done until white prills formed which were allowed to cool to ambient while stirring. After about 30 minutes at ambient, the suspended solids were isolated by tion, washed with water (30 mL), and were dried in vacuo at 45°C. After about 2.5 hours, this afforded 1-chloro(4- ethoxybenzyl)iodobenzene as a slightly waxy white granular powder (28.28 g, 98.2 area % by HPLC at 220nm, 97.4 % “as-is" . 29 LEX—1321 6.4. Synthesis of (4—chloro—3—(4ethoxybenzyl)phenyl)((3aS,5R,6S,6aS)—6—hydroxy—2,2— dimethyltetrahyd l 2,3—d M 1,3 |dioxol—5—yl)methanone To a solution of 1-chloro(4-ethoxybenzyl)iodobenzene (500mg, 1.34 mmol) in THF (5.0 mL) was added i-PngCl (2.0M in THF, 1.0 mL, 2.00 mmol) at 05°C, and the mixture was stirred for 1.5 h at 05°C. A solution of (3aS,5R,6S,6aS)—6-hydroxy-2,2- yltetrahydrofuro[2,3-d][1,3]dioxolyl)(morpholino)methanone (146.5 mg, 0.536 mmol) in THF (1.0 mL) was added dropwise at 05°C and the mixture was kept stirring for 1h, warmed to °C and stirred at 20°C for 2 hours. The reaction was quenched with saturated aq NH4CI, extracted with MTBE, washed with brine. The organic layer was concentrated and the residue was purified by silica gel column chromatography to afford the desired ketone (178 mg, 76%) as a white solid. 1H NMR (CDCI3) 8 7.88 (dd, J = 8.4, 2.0 HZ, 1H), 7.82 (d, J = 2.0 HZ, 1H), 7.50 (d, J = 8.4 HZ, 1H), 7.12 (d, J = 8.4 HZ, 2H), 6.86 (d, J = 8.4 HZ, 2H), 6.07 (d, J = 3.2 HZ, 1H), 5.21 (d, J = 3.2 HZ, 1H), 4.58 (d, J = 3.2 HZ, 1H), 4.56 (d, J = 3.2 HZ, 1H), 4.16 (d, J = 7.2 HZ, 2H), 4.03 (q, J = 7.2 HZ, 2H), 1.54 (s, 3H), 1.42 (t, J = 7.2 HZ, 3H), 1.37 (s, 3H). 6.5. Alternative synthesis of (4—chloro—3—(4—ethoybenyl)phenyl)((3aS,5R,6S,6aS)—6— —2,2—dimethyltetrahyd rofu ro| 2,3—d M 1,3 l—5—yl)methanone To a 20 L reactor equipped with a mechanical stirrer, a temperature controller and a nitrogen inlet was charged with the iodide (3.00 kg, 8.05 mol) and THF (8 L, 4X to the morpholinoamide) at room temperature and cooled to -5°C. To the above solution was added 2O se a solution of i—PngCl in THF (Aldrich 2 M, 4.39 L, 8.82 mol) at -5°C over 3 hours. This Grignard solution was used in the ketone formation below.

To a 50 L reactor equipped with a mechanical r, a temperature controller, and a nitrogen inlet was charged the morpholinoamide (HPLC purity = 97 wt%, 2.01 kg, 7.34 mol) and THF (11 L, 5.5X) at room temperature and d for 45 minutes at room temperature and for 15 minutes at 30°C. The homogeneous solution was then cooled to -25°C. To this solution was added a solution of t—BuMgCl in THF (Aldrich 1 M, 7.32 L, 7.91 mol) at -25°C over 3 hours. Then the above Grignard solution was added to this solution at -20 over 41 minutes. The resulting solution was further stirred at -20°C before . The reaction mixture was added to 10 wt% aqueous NH4CI (10 L, 5X) at 0°C with vigorous stirring, and stirred for 30 minutes at 0°C. To this 3O mixture was added slowly 6 N HCl (4 L, 2X) at 0°C to obtain a clear solution and stirred for 30 minutes at 10°C. After phase split, the organic layer was washed with 25 wt% aq NaCl (5 L, 2.5X). Then the organic layer was concentrated to a 3X solution under the conditions (200 mbar, bath temp 50°C). EtOAc (24 L, 12X) was added, and evaporated to a 3X solution under the conditions (150 mbar, bath temp 50°C). After removed solids by a polish filtration, EtOAc (4 L, 2X) was added and concentrated to dryness (150 mbar, bath temp 50°C). The wet cake was then transferred to a 50 L reactor equipped with a mechanical stirrer, a temperature ller and a nitrogen inlet. After EtOAc was added, the sion was heated at 70°C to obtain a LEX—1321 PCT/U82012/020042 2.5X homogeneous solution. To the ing homogeneous solution was added slowly heptane (5 L, 2.5X) at the same temperature. A neous solution was seeded and heptane (15 L, 7.5X) was added slowly to a little cloudy solution at 70°C. After stirred for 0.5 h at 70°C, the suspension was slowly cooled to 60°C and stirred for 1 h at 60°C. The suspension was then slowly cool to room temperature and stirred for 14 h at the same temperature. The crystals were collected and washed with heptane (8 L, 4X), dried under vacuum at 45°C to give the desired ketone as fluffy solids (2.57 kg, 100 wt% by HPLC, purity-adjusted yield: 81%). 6.6. Synthesis of (23,38.4R,5$,6R)—2—(4—chloroB—(4—ethoybenyl)phenyl)—6- (methylthio)tetrahydro—2H-pyran—3,4,5—triyl triacetate To a solution of the ketone oro(4-ethoxybenzyl)phenyl)-((3aS,5R,6S,6aS)—6- hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxolyl)methanone (114.7 g, 0.265 mol) in MeOH (2 L, 17X) was added CeCl3'7H20 (118.5g, 1.2 equiv) and the mixture was stirred at 20°C until all solids were dissolved. The mixture was then cooled to -78°C and NaBH4 (12.03g, 1.2 equiv) was added in portions so that the temperature of the reaction did not exceed -70°C. The mixture was stirred at -78°C for 1 hour, slowly warmed to 0°C and ed with saturated aq NH4CI (550 mL, 5X). The mixture was concentrated under vacuum to remove MeOH and then extracted with Et0Ac (1.1L, 10X x2) and washed with brine (550 mL, 5X). The ed organics were concentrated under vacuum to afford the d l as a colorless oil (crude, 115g).

To this colorless oil was added Ac0H (650 mL) and H20 (450 mL) and the mixture was heated to 2O 100°C and stirred for 15 hours. The mixture was then cooled to room temperature (20°C) and concentrated under vacuum to give a yellow oil (crude, ~118 g). To this crude oil was added pyridine (500 mL) and the mixture was cooled to 0°C. Then, AC20 (195 mL, ~8.0 equiv) was added and the mixture was warmed to 20°C and d at 20°C for 2h. The reaction was quenched with H20 (500 mL) and diluted with Et0Ac (1000 mL). The organic layer was separated and concentrated under vacuum to remove Et0Ac and pyridine. The residue was diluted with Et0Ac (1000 mL) and washed with aq NaHSO4 (1N, 500 mL, x2) and brine (300 mL).

The organic layer was concentrated to afford the desired tetraacetate intermediate as a yellow foam (~133g).

To a solution of tetraacetate (133 g, 0.237 mol assuming pure) and thiourea (36.1, 2.0 3O equiv) in dioxane (530 mL, 4X) was added trimethylsilyl trifluoromethanesulfonate (TMSOTf) (64.5 mL, 1.5 equiv) and the reaction mixture was heated to 80°C for 3.5 hours. The mixture was cooled to 20°C and Mel (37 mL, 2.5 equiv) and N,N-diisopropylethylamine (DiPEA) (207 mL, .0 equiv) was added and the mixture was stirred at 20°C for 3h. The e was then diluted with methyl tertiary-butyl ether (MTBE) (1.3 L, 10X) and washed with H20 (650 mL, 5X x2). The organic layer was separated and concentrated under vacuum to give a yellow solid. To this yellow solid was added MeOH (650 mL, 5X) and the mixture was reslurried at 60°C for 2h and then cooled to 0°C and stirred at 0°C for 1 hour. The mixture was filtered and the cake was 31 LEX—1321 WO 94293 washed with MeOH (0°C, 70 mL, x3). The cake was dried under vacuum at 45°C overnight to afford the d triacetate (2S,3S,4R,5S,6R)—2-(4-chloro(4-ethoxybenzyl)phenyl) (methylthio)tetrahydro—2H-pyran-3,4,5-triyl triacetate (88 g, 60% over 4 steps) as a pale yellow solid. 1H NMR (CDCI3) 8 7.37 (d, J = 8.0 HZ, 1H), 7.20 (dd, J = 8.0, 2.0 HZ, 1H), 7.07 (m, 2H), 6.85 (m, 2H), 5.32 (t, J = 9.6 HZ, 1H), 5.20 (t, J = 9.6 HZ, 1H), 5.05 (t, J = 9.6 HZ, 1H), 4.51 (d, J = 9.6 Hz, 1H), 4.38 (d, J = 9.6 Hz, 1h), 4.04 (m, 2H), 2.17 (s, 3H), 2.11 (s, 3H), 2.02 (s, 3H), 1.73 (s, 3H), 1.42 (t, J = 7.2 HZ, 3H). 6.7. Alternative synthesis of (2S,3$,4R,5$,6R)—2—(4—chloro—3—(4—ethoxybenyl)phenyl)- 6—(methylthio)tetrahydro—2H-pyran—3,4,5—triyl triacetate To a 50 L reactor under en atmosphere, 40 L MeOH was charged, ed with the ketone (2.50 kg, 5.78 mol) and CeCl3'7H20 (2.16 kg, 1.0 equiv). Methanol (7.5 L) was added as rinse (totally 47.5 L, 19X). A y prepared solution of NaBH4 (87.5 g, 0.4 equiv) in aqueous 1 N NaOH (250 mL) was added slowly (35 min) at 15-25°C. The mixture was then stirred for 15 min. HPLC analysis of the reaction e showed approximately 90:10 diastereomeric ratio.

The reaction was quenched with 10 wt% aq NH4CI (2.5 L, 1X) and the mixture was concentrated under vacuum to 5X, diluted with water (10 L, 4X) and MTBE (12.5L, 5X). The mixture was cooled to 10°C and 6 N aq HCl was added until the pH of the mixture reached 2.0. Stirring was continued for 10 s and the layers were separated. The organic layer was washed with H20 (5L, 2X). The combined aqueous layer was extracted with MTBE (12.5 L, 5X). The combined 2O organic layers were washed with brine (2.5 L, 1X) and concentrated under vacuum to 3X. MeCN (15 L, 6X) was added. The mixture was concentrated again to 10 L (4X) and any solid residue was removed by a polish filtration. The cake was washed with minimal amount of MeCN.

The organic filtrate was transferred to 50 L reactor, and a pre-prepared 20 mol% aqueous H2804 solution (61.8 mL 98% concentrated H2804 and 5 L H20) was added. The mixture was heated to 80°C for 2 hours and then cooled to 20°C. The on was quenched with a solution of saturated aqueous K2C03 (5 L, 2X) and diluted with MTBE (15 L, 6X). The organic layer was separated, washed with brine (5 L, 2X) and concentrated under vacuum to 5 L (2X). MeCN (12.5 L, 5X) was added and the mixture was concentrated to 7.5 L (3X).

The above MeCN solution of (3S,4R,5R,6S)—6-(4-chloro(4- 3O ethoxybenzyl)phenyl)tetrahydro-2H-pyran-2,3,4,5-tetraol was cooled to 10°C, added with dimethylaminopyridine (17.53 g, 2.5 mol%), followed by slow addition of acetic anhydride (3.23 L, 6.0 equiv) and triethylamine (5 L, 2X, 6.0 equiv) so that the temperature of the mixture was kept below 20°C. The reaction was then warmed to 20°C and stirred for 1 hour and diluted with MTBE (15 L, 6X). The mixture was slowly quenched with water (7.5 L, 3X). The organic layer was ted and washed with saturated aqueous KHC03 (5L, 2X), 1 N NaHSO4 (5 L, 2X), and brine (5 L, 2X) in sequence. 32 LEX—1321 The organic layer was then concentrated under vacuum to 5 L (2X). MeCN (12.5 L, 5X) was added and the solution was concentrated to 7.5 L (3X) (KF = 0.08%). e (12.5 L, 5X) was added and the solution was concentrated to 7.50 L (3X) (KF = 0.02%). Any residual solid was removed by a polish filtration and the cake was washed with minimal amount of dioxane (500 mL).

To the above filtrate was added ea (880 g, 2.0 equiv) and TMSOTf (1.57 L, 1.5 equiv). The reaction mixture was heated to 80°C for 3 hours (>97% conversion). The mixture was cooled to 20°C and methyl iodide (541 mL, 1.5 equiv) and diethylisopropylamine (3.02 L, 3.0 equiv) were added and the mixture was stirred at 20°C for 18 hours. An extra methyl iodide charge (90 mL, 0.25 equiv) was added and the mixture was stirred at 20°C for 1 hours. The mixture was then diluted with MTBE (25 L, 10X) and washed with water (12.5 L, 5X x2). The organic layer was separated and concentrated under vacuum to ~5 L (2X). MeOH (12.5 L, 5X) was added and the mixture was concentrated to 5X to afford a slurry. The mixture was then heated at 60°C for 1 hour and cooled to 0°C and stirred at 0°C for 1 hour. The mixture was filtered and the cake was washed with MeOH (0°C, 2.5 L, 1X x2, 1.0 L, 0.4X). The cake was dried under vacuum at 45°C overnight to afford the desired triacetate (1.49 kg, 47% over 4 steps) as a pale yellow/off-white solid. 6.8. Synthesis of (2S,3R,4R,5$,6R)—2—(4—chloro—3—(4—ethoxybenyl)phenyl)—6— (methylthio)tetrahydro2H-pyran-3,4,5—triol 2O To a slurry of ,4R,5S,6R)(4-chloro(4-ethoxybenzyl)phenyl) (methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (90.0 g, 0.164mol) in MeOH (900 mL, 10X) was added NaOMe in MeOH (25 wt%, 18 mL, 0.2X) at 20°C and the mixture was d at 20°C for 2 hours until all solids disappeared. The mixture was then concentrated to 300 mL, added to H20 (1L) and stirred for 1 hour. The solid was filtered and washed with H20 (100 mL, x3) and the cake was dried under vacuum at 45°C overnight to afford the desired methyl te (67.0g, 95%). 1H NMR (CDCI3) 8 7.38 (d, J = 8.4 HZ, 1H), 7.22 (m, 2H), 7.11 (d, J = 8.8 HZ, 2H), 6.83 (d, J = 8.8 Hz, 2H), 4.35 (d,J = 9.6 Hz, 1H), 4.15 (d, J = 9.6 Hz, 1H), 4.10-3.95 (m, 3H), 3.64 (t, J = 8.8 HZ, 1H), 3.50 (m, 2H), 3.42 (br s, 1H), 2.95 (br s, 1H), 2.57 (br s, 1H), 2.17 (s, 3H), 1.40 (t, J = 7.2 HZ, 3H). 3O 6.9. Preparation of Cmstalline Anhydrous (23,3R,4R,58.6R)—2—(4chloro—3—(4— ethoybenzyl)phenyl)—6—(methylthio)tetrahydroZH-pyran—3,4,5-triol Form 1 Under slightly positive nitrogen pressure, to a 50 L r was charged MeOH (12 L) and the triacetate (1.70 Kg, 3.09 mol). Methanol (5L) was added as a rinse. The slurry was then added NaOMe in MeOH (25 wt%, 340 mL, 0.2X) in 15 minutes at 20°C and the mixture was stirred at 20°C for 2 hours until all solids disappeared. To the mixture was added slowly water (25.5 L, 15X) in 45 minutes with 5 g seeding (DSC 123°C). Solids d out and the mixture 33 LEX—1321 was stirred at 20°C for 1 hour, cooled to 0°C and stirred for 30 s. The solid was filtered and washed with water (1.7 L, 1X, X2) and the cake was dried under vacuum at 45°C overnight to afford the title compound (m.p. z 123 °C by DSC peak; 1.28 Kg, 97.7% yield). 6.10. ation of Cmstalline Anhydrous (23,3R,4R,58.6R)—2—(4chloro—3—(4— ethoybenzyl)phenyl)—6—(methylthio)tetrahydroZH-pyran—3,4,5-triol Form 2 Under slightly positive nitrogen re, to a 50 L reactor was charged MEK (2- butanone, 4 L) and (2S,3R,4R,5S,6R)—2-(4-chloro(4-ethoxybenzyl)phenyl)—6- (methylthio)tetrahydro-2H-pyran-3,4,5-triol Form 1 (1.49 Kg). MEK (3.45 L) was added as a rinse.

The mixture was heated to 80°C and heptane (14.9 L, 10X) was slowly added in 1.5 hours.

Solids started to crash out and the e was charged heptane (14.9 L, 10X) in 6 h. The mixture was stirred at 80°C for 15 hours. The e was cooled to 20°C in 3 hours and stirred at 20°C for 1 hour. The solids were filtered and the cake was washed with MEK/heptane (25:75, v/v, 1.49 L, 1X x2), dried under nitrogen for 12 hours and under vacuum at 50°C for 24 hours to afford the title compound as a white solid (mp. z 134 °C by DSC peak; 1.48 Kg, 98% recovery). 6.11. Alternative Preparation of Crystalline Anhydrous (23,3R,4R,5$,6R)—2—(4—chloro—3— (4—ethoxybenyl)phenyl)—6—(methylthio)tetrahydro—2H-pyran-3,4,5—triol Form 2 To a 250 L reactor was charged the triacetate (10 kg) and methanol (75 kg). Sodium methoxide (1.6 kg, 30% solution) was added with 5 kg methanol rinse. The mixture was stirred 2O at room temperature for at least 2 hours or until the reaction was complete. al (Darco G- 60, 1 kg) was added with 5 kg methanol rinse. This mixture was heated at 40°C for 1 h, cooled to room temperature, and filtered through celite. The cake was washed with ol (10 kg).

Water (100 kg) was added and the mixture was concentrated under vacuum. MTBE (200 kg) and water (50 kg) were added and phases were split. The organic layer was washed with water (100 kg) and concentrated under vacuum. MEK (100 kg) was added and the same about of t was distilled under vacuum. This MEK on and distillation was repeated to dry the solution.

Enough MEK was added to produce a solution of (28,3R,4R,5S,6R)(4-chloro(4— ethoxybenzyl)phenyl)(methylthio)tetrahydro-2H-pyran-3,4,5-triol in 50 L MEK. This solution was polish filtered and heptane (100 L) was added at about 80°C. Form 2 seeds (0.1 kg) were added followed by slow addition of heptane (100 L) as 80°C. Heating was continued for 8 h more at 80°C, cooled to 20°C over at least 3 hours, held at this temperature for at least 2 hours, filtered, and washed with MEK/heptane. The cake was dried at 50°C under vacuum to afford the title compound as a white solid (6.6 kg, 86% yield). 34 LEX—1321 6.12. Solid Oral Dosage Form of l2S,3R,4R,5$,6R)—2—(4—chloro(4— ethoybenzyl)phenyl)—6—(methylthio)tetrahydro2H-pyran-3,4,5—triol Tablets comprising the active pharmaceutical ingredient (API), (2S,3R,4R,5S,6R)(4- chloro—3-(4-ethoxybenzyl)phenyl)(methylthio)tetrahydro—2H-pyran-3,4,5-triol, were ed from a common blend, bed below in Table 1, which was blended and roller compacted in the first stage of manufacture.

Table 1 — Common Blend Material Percent kg Active Ingredient (API) 70.107 3856* Croscarmellose , NF 2.944 0.147 Colloidal silicon dioxide, NF 0.916 0.046 Microcrystalline cellulose, NF (Avicel PH 102) 25.379 1.269 ium stearate, NF 0.654 0.033 TOTAL 100.00 5.00 * Includes a 10% overage to account for processing loss during initial milling The API (crystalline anhydrous (2S,3R,4R,5S,6R)(4-chloro(4-ethoxybenzyl)phenyl) (methylthio)tetrahydro—2H-pyran-3,4,5-triol Form 2) was deagglomerated using a conical mill equipped with a 032R screen. The deagglomerated drug nce was d with the intragranular excipients croscarmellose sodium, collodial silicon e, and microcrystalline cellulose (Avicel PH 102) for 10 minutes using a V-blender. The ranular portion of the magnesium stearate was then added to the materials and blended for an additional two minutes.

The intragranular blend was then passed through a roller compactor for granulation. The roller compacted ribbons were milled using a conical mill equipped with a 790 screen. The milled granules were then passed h the conical mill a second time using a finer 55R screen in order to achieve the desired granule particle size.

Part of the rystalline cellulose (Avicel PH 200) was then passed through a 20 mesh 2O screen and charged into a V-blend. The appropriate quantity of the resulting common intragranulation blend was passed through a 20 mesh screen and charged into the V-blender.

The requisite amount of the extragranular excipients croscarmellose sodium, colloidal silicon dioxide, talc, and the remaining microcrystalline cellulose (Avicel PH 200) were passed through a mesh screen and charged into the same V-blender and blended for 10 minutes. The ranular portion of the magnesium stearate was then added to the V-blender and blended for an additional two minutes. The final blends were compressed into 50 mg and 150 mg tablets. The tablet cores were subsequently coated with an s sion of Opadry ll Clear for an approximate weight gain of 3%. Tables 2 and 3 provide the batch formula for the 50 and 150 mg tablets, respectively.

LEX—1321 Table 2 — Batch Formula for 50 mg Tablets Material Percent mg/tablet Common Blend 28.528 71.320 1.141 Croscarmellose sodium, NF 3.660 9.161 0.146 Colloidal n dioxide, NF 1.000 2.600 0.030 Microcrystalline cellulose, NF (Avicel PH 200) 66.260 163.160 2.610 Talc, USP 0.738 1.846 0.040 Magnesium stearate, NF 0.814 2.034 0.033 Total (Core Tablet) 100.00 250.00 m Opadry ll Clear 5O 3.00 0.120 Total (Coated Tablet) * 71.320 mg of Common Blend results in 50 mg of API in the final product.

Table 3 — Batch Formula for 150 mg s Material Percent mg/tablet Common Blend 76.414 213.960* 3.057 Croscarmellose sodium, NF 2.260 6.300 0.090 Colloidal silicon dioxide, NF 1.000 2.800 0.012 Microcrystalline cellulose, NF (Avicel PH 200) 19.636 64.700 Talc, USP 0.300 0.840 0.040 Magnesium stearate, NF 0.600 1.400 0.020 Total (Core Tablet) 100.00 280.00 m Opadry ll Clear 85F1925O 3.00 8.400 0.120 Total (Coated Tablet) * 213.960mg of Common Blend results in 150 mg of API in the final t. 6.13. Pharmacology of Liguid Oral Dosage Form of l23,3R,4R,5$,6R)—2—(4—chloro(4— ethoflbenzyl)phenyl)(methylthio)tetrahydro2H-pyran-3.4,5—triol Patients (n = 36) with type 2 diabetes mellitus received one of two oral doses of (2S,3R,4R,5S,6R)—2—(4-chloro(4-ethoxybenzyl)phenyl)—6-(methylthio)tetrahydro-2H-pyran-3,4,5- triol, given as 150 mg or 300 mg once daily, or matching placebo, for 28 days in solution.

Preliminary data showed significant and ned glucosuria over the 28-day dosing period for both dose levels when ed to placebo. Adverse events were generally mild and evenly distributed across all dose groups, ing placebo, and no evidence of dose-limiting toxicities was observed.

In this study, patients on metformin were taken off of the drug 16 days prior to day 0, the day dosing first began. As shown in the plasma e levels of patients in the placebo group and in the 150 mg/day and 300 mg/day treatment groups increased during that period. 36 LEX—1321 PCT/U82012/020042 Upon treatment, patients in both treatment groups exhibited a rapid, statistically significant decrease in plasma e levels.

Over the course of the study, the patients’ glucose tolerance was tested in a conventional manner. As shown in patients in both treatment groups exhibited greater glucose tolerance than those in the placebo group. shows the mean glucose plasma level area under the curve (AUC) of the ts.

Afterjust one day of treatment, both the 150 mg/day and 300 mg/day treatment groups exhibited statistically icant ses in their mean plasma glucose AUCs.

As shown in patients randomized to the 150 mg/day and 300 mg/day treatment groups showed improved insulin sensitivity compared to placebo. This figure provides a summary of the groups’ tatic model ment (HOMA) values.

As shown in patients in both ent groups exhibited a rapid, statistically significant decrease in post-prandial glucose levels compared to placebo.

Fructosamine (glycated albumin) is often measured to assess the short-term control of blood sugar. shows the effect of the compound on patients’ mean plasma fructosamine levels. shows patients’ mean percent change in glycated hemoglobin (hemoglobin Alc; HbAlc) levels. HbA1c is a form of obin used primarily to identify the average plasma glucose concentration over prolonged periods of time. Although this study was only four weeks in 2O duration, patients randomized to the 150 mg/day and 300 mg/day treatment groups exhibited a marked decrease in their mean HbAlc levels.

Surprisingly, patients in the 150 mg/day and 300 mg/day treatment groups also exhibited decreased mean diastolic and systolic blood pressures after 28 days of dosing compared to placebo. See FIGS. 8 and 9. And as shown in , the mean arterial pressures of patients in both treatment groups also sed.

As shown below in Table 4, it was found that administration of the compound also lowered patients’ serum triglyceride levels and effected weight loss: Table 4 Change from Baseline 150 mg (n =12) 300 mg (n=12) Placebo (n=12) These results demonstrate that within a four-week ent period, patients receiving the compound exhibited improvements in blood re control, weight ion, and triglyceride levels that were associated with improvements in glycemic parameters. 37 LEX—1321 WO 94293 6.14. Pharmacology of Solid Oral Dosage Form of (23,3R,4R,5$,6R)—2—(4chloro—3-(4— ethoybenzyl)phenyl)—6—(methylthio)tetrahydro2H-pyran-3,4,5—triol Patients (n = 12) with type 2 es mellitus ed one of three oral formulations of 300 mg of (2S,3R,4R,5S,6R)-2—(4-Ch|oro-3—(4-ethoxybenzyl)phenyl)—6—(methylthio)tetrahydro-2H- pyran-3,4,5-triol before breakfast: as two 150 mg tablets, six 50 mg tablets, or 30 mL of 10 mg/mL solution in a randomized sequence implementinga Latin Square crossover design, with a -day washout between doses.

The pharmacokinetics of the three formulations were able, and adverse events were infrequent. Changes in urinary glucose excretion, fasting plasma glucose (FPG), insulin, andial glucose (PPG), peptide YY (PYY), and glucagon-like peptide-1 (GLP-l) were measured at days -1, 1, 6, and 11. As evidenced by the results provided below in Table 5, single doses of the compound markedly improved patients’ FPG and PPG levels, which effects were associated with increased GLP—1 and PW levels. 38 LEX—1321 So: a- .222. mwcmco >3 we No.5 gowa- on? DQNWH- oom u5 >3 9:80 méw obofi $5 mwfifi W: HEN So: a- we >3 om mwcmco $8 waa- owfi- mmfiw édma- mfifim mb >3 9:80 Qt wafioa abom mam.“ YWN mbm ®.mm Hmmfikmj So: a- 226... we >3 03 mwcmco &.B DONH- and? E mwAmEH- RJVN QNHH N u5 >3 9:80 10; o.©©H 35 NNJVEH ofim 9mm mdm 6:: >3 we: QMWH 3mm mfioa NNNN me m.wm 62880: 52 :85: 52 52 950; 285 52 52 E85 E85 .@ came E85 2-0 882m :88 oee E85 .:\E._oeg .:\E._oee 03< 39:3 jEmEV _:E\E.3_3 CE _:o\E.m§ The The 558205 3% OnE 53mg :38 0% :38 2:2 Hoodva modva Hodva Hmc m Q o v? PCT/U82012/020042 Figure 11 further illustrates the effect of the 2 x 150 mg tablet, 6 x 50 mg tablet, and liquid dosage forms on the patients’ total GLP-l levels, wherein the asterisk indicates an area- under-the-curve difference from baseline p value of less than 0.05. The sed levels effected by all three forms is believed to be due to SGLTl inhibition.

All publications (e.g., patents and patent applications) cited above are incorporated herein by nce in their entireties. 4O LEX—1321

Claims (12)

1. A tablet comprising an API, croscarmellose sodium, n dioxide, microcrysalline celulose, and magnesium stearate, wherein the API is lline anhydrous 5 (2S,3R,4R,5S,6R)(4-chloro(4-ethoxybenzyl)phenyl)(methylthio)tetrahydro-2H-pyran-3,4,5- triol.

2. The tablet of claim 1, wherein the API is crystalline anhydrous (2S,3R,4R,5S,6R)- 2-(4-chloro(4-ethoxybenzyl)phenyl)(methylthio)tetrahydro-2H-pyran-3,4,5-triol having a melting point of 123°C. 10

3. The tablet of claim 1, wherein the API is crystalline anhydrous (2S,3R,4R,5S,6R)- 2-(4-chloro(4-ethoxybenzyl)phenyl)(methylthio)tetrahydro-2H-pyran-3,4,5-triol having a melting point of 134°C.

4. The tablet of claim 1, wherein the API is present in an amount of 300 mg or less.

5. The tablet of claim 1, which r comprises talc. 15

6. The tablet of claim 1, which is .

7. The tablet of claim 1, which further comprises a second eutic agent, which second therapeutic agent is an anti-diabetic agent, anti-hyperglycemic agent, pidemic/lipid lowering agent, anti-obesity agents, anti-hypertensive agent, or appetite suppressant.

8. The tablet of claim 7, wherein the second therapeutic agent is a DPP-4 inhibitor. 20

9. The tablet of claim 8, wherein the DPP-4 inhibitor is sitagliptin or dutogliptin.

10. A granule comprising an API, croscarmellose sodium, collodial silicon dioxide, and microcrystalline cellulose, wherein the API is (2S,3R,4R,5S,6R)(4-chloro(4- ethoxybenzyl)phenyl)(methylthio)tetrahydro-2H-pyran-3,4,5-triol.

11. The granule of claim 10, wherein the API is crystalline anhydrous 25 (2S,3R,4R,5S,6R)(4-chloro(4-ethoxybenzyl)phenyl)(methylthio)tetrahydro-2H-pyran-3,4,5- triol having a melting point of 123°C.

12. The granule of claim 10, wherein the API is crystalline anhydrous (2S,3R,4R,5S,6R)(4-chloro(4-ethoxybenzyl)phenyl)(methylthio)tetrahydro-2H-pyran-3,4,5- triol having a melting point of 134°C. 41 LEX-1321