FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION (Sec section 10, rule 13) *5~ 14- lAZETTOW-S-\lJOX\) HEWLJ -l-PHENYl.-SH-THIAZOLO |5,4-C| PYRIDIN-4-ONE DERIVATIVES AND THEIR USE AS MCH RECEPTOR ANTAGONISTS" ELI LILLY AND COMPANY, a corporation of the State of Indiana, having a principal place of business at Lilly Corporate Center, City of Indianapolis. State of Indiana 46285, United States of America. The following specification particularly describes the invention and the manner in which it is to be performed. WO 2008/076562 PCT/US20H7/WJ4812 5- [4 - (AZETIDIN-3-YLOXY) - PHENYL] -2-PHENYL-5H-THIAZOLO [5.4-CJPYRIDIN-4-ONE DERIVATIVES AND THEIR USE AS MCH RECEPTOR Field oflnvention The present invention is in the field of medicine, particularly in the treatment of 5 obesity and diseases related to obesity. More specifically> the present invention relates to selective antagonists of melanin concentrating hormone (MCH) useful for treating, preventing or ameliorating obesity and related diseases. Background of the Invention 10 MCH over-expressing transgenic mice are mildly obese, and both MCH-/- and MCHRI-/- mice arc characterized by reduced weigh! gain relative to wild type controls. MCH-induccd body weight gain and hypcrphagia are absent in MCHRI null mice. Non-pepiide small molecule MCHRI antagonists attenuate food intake stimulated by MCH. The forgoing support the hypothesis to treat obesity and related diseases with compounds lb that are effective antagonists ofMCHRl. PCT application number WO2003/033476A1 discloses compounds reportedly useful as antagonists of the MCH receptor. PCT application number WO 2OO3/03348OA1 discloses compounds reportedly useful as antagonists of the MCH receptor. PCT application WO 20067066174A1 discloses compounds useful in the 2 0 treatment, prevention or amelioration of symptoms associated with obesity and related diseases. Current treatments targeted at obesity have not proven effective for all patients and for sustainable periods of time. Examples of such treatments include various over-the-counter appetite suppressants, various dietary regimens and/or exercise. Therefore, there 25 is a need for new and/or improved therapeutically effective agents useful for treating, preventing and/or ameliorating the effects of obesity. Antagonists ofMCHRl would be expected to be useful to treat or prevent obesity and related diseases. There is a need to find potent antagonises ofMCHRl. There is also a need to find compounds that selectively bind MCHRI relative to MCHR2. There also 3D exists a need to find MCHRI antagonists having an improved safety profile over the prior an compounds. The present invention provides such potent, selective MCHRI WO 2008/076562 PCT/US2007/0848I2 antagonists having an improved safety profile for (he treatment of obesity and related diseases. Summary of Invention 5 The present invention relates to a compound of formula I (I) wherein " '' is absent or is optionally a bond; 10 i] is 1 or 2; K1 is independently selected from hydrogen, -C1-C2 alky], halo, hydroxy, -CI-CJ haloalkyl, -CVCj alkoxy, cyano, -O-C3-C4 cycloalkyl, and -OC1-C3 haloalkyl; R^ is selected from the group consisting of hydrogen, -C1-C1 alkyl, hydroxy, -C|-C.i alkoxy, cyano, -Ct C2 haloalkyl, -OCi-C* haloalkyl, and halo; 15 R3 is selected from the group consisting of hydrogen, -C\_-Ct alkyl, -C2-C4 haloalkyl, -CrC4 alkylOH, -Cj-Q cycloalkyl, -CH2C3-C;and RJ is hydrogen. -CHj, -CHjCHiF, -CH2CHF3, cyclopropyl, or cyclobutyl wherein the cyclopropy] or cyclobutyl group is optionally substituted with a group selected from rhc group consisting of fluoro, hydroxy and methyl. 15 Also preferred is a compound of formula 1 wherein li' is chloro, mcthoxy, cyclopropoxy, fluoro, ortrifluuromcthyl; q is 1; R2 is chluTO or -OCHj; and Rj is hydrogen, -CHj, -CH2CH2F, -CH3CHF2, cyclopropyl, or cyclobutyl wherein the 20 cyclopropyl or cyclobutyl group is optionally substituted with a group selected from the group consisting of fluoro, hydroxy and methyl Also preferred is a compound of formula 1 wherein R1 is chloro, fluoro, mcthoxy, or trifluoromcthyl; q is 1; 2 5 R2 is -OCH, or cyano; and R3 is hydrogen, -CH,i( -CHJCHIF, -CH2CHF2, cyclopropyl, Or cyclobutyl wherein the cyclopropyl or cyclobulyl group is optionally substituted with a group selected from the t;roup consisting of fluoro, hydroxy and methyl. Also preferred is a compound of formula I wherein 30 R1 is chloro; q is 1: R: isH,OCH\;and WO 2008/076562 PCTAIS21KW0848I2 R is hydrogen, -CHj, cyclopropyl, or cyclobutyl wherein the cyclopropyl or cyclobutyl group is optionally substituted with a group selected from the group consisting of fluuro, hydroxy and methyl. Also preferred is a compound of formula I wherein 5 R1 is chloro, mclhoxy, cyclopropoxy, fluoro, or trifluoromethyl; cj is ) or 2; R3 U H, -CN or -OCH5; and R] is hydrogen, -CHj, -CHJCHJOR -CHJCHJF, -CH2CHF3, isopropyl, cyclopropyl, -CHacyclopropyl, or cyclobutyl wherein the cyclopropyl or cyclobutyl group is optionally 10 substituted with one or two groups iiidcpendeitlly selected from the group consisting of fluoro and methyl. Also preferred is a compound according of formula 1 wherein R is chloro; q 1S J; 15 R2 iaH, -OCH,;and R3 is hydrogen, -CH,, cyclopropyl, or cycloburyl wherein the cyclopropyl or cyclobutyl group is optionally substituted with a group selected from the group consisting of fluoro, hydroxy and methyl. Also preferred is a compound of formula n wherein 20 R1 is chloro, metboxy, cyclopropoxy, fluoro, ortrifluoromethyl; qis 1, R2 is -CN or -OCH3; \md R4 is CHj. Also preferred is a compound of formula [I wherein 25 R1 is chloro, methoxy, cyclopropoxy, fluoro, or trifluoromcthyl; q is I; R* is -OCHj; and R" is CH3. The compounds of formula (I) or (II) can be prepared by a variety of procedure 30 known in the an and those described below. However, the following discussion is not intended lobe limiting to the scope of the present invention in anyway. Kor example, the specific synthetic steps for each of the routes described may be combined in different WO JOOa/076562 PCT/US2007/084812 10 IS ways, or in conjunction with steps from different schemes, to prepare additional compounds of formula (I) or (II). The products of each step in the Schemes below can be recovered by conventional methods including extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like. As used herein, the following terms have the meanings indicated: "McQH" refers to methanol; "EtOH" refers to eihanol; "EtOAc" refers to ethyl acetate; "DMF" refers to dimcthylformamide; "DMSO" refers to dimethyl sulfoxide; 'TFA" refers to Iriiluoroacctic acid, "EtjO" refers lo diethyl ether; *THF" refers to tctrahydrofuran; "LDA" refers to lithium diisopropylflmide; "n-BuLj" refers to n-butyl lithium; "p-'I'sOK" refers 10 p-ioluenesulfonic acid; "/er/-BuOK" refers to potassium w-z-butoxidc; "DIBAL." refers to diisubutylaLiminmm hydride, "TEMPO" refers to 2,?-,6,6-'etramc(hyt-l-pipcridinyloxy, free radical; "DEAD" refers to diethyl azodicarboxylate; "D1AD" refers to diisopropyl diazodicarboxylatc; "tBOC or "Boc" refers to le/*/-butoxycarbortyl; "TLC" refers to thin layer chromatography; and "HPLC" refers to high performance liquid chromatography Formal iun of an intermediate of formula (8) can be carried out in accordance with 20 reactions as depicted in Scheme I. An appropriate compound of formula (8) is one in which (R')q, is as defined for formula 1. WO 2008/076562 PCT/US2007/0848U In Scheme 1, Step A, a thiazole acetic acid ester of formula (1) is reduced to a thiazole ethanol of formula (2). As will be apparent to the skilled artisan there are numerous reducing agents, such as UA1HU, NaBFU, UBH4, and the like, suitable for use in such a transformation. The preferred method uses DIBAL, in an aprotic solvent, such 5 as ether, toluene, or preferably THF, at a temperature of about -80 to 60 °C In Scheme I, Step B, a thiazole of formula (2) is carboxylated to form a thiazole carboxylic acid of formula (3). For example, the thiazole (2) is treated with 2 to 3 eq. of a suitable base such as LDA, lithium bis(trimethylsilyl)amide, Of preferably n-butyl lithium, in THF or diethyl ether, at a temperature of about -80 to -70 °C over about 2 to 4 10 h The resulting dianiott is then treated with a solution of CO? gas in THF or diethyl ether to obtain the thiazole carbaxylic acid of formula (3), In Step C, a thiazole carboxylic acid of formula (3) is dehydrated under anhydrous conditions to form a thiazole lactone of formula (4). For example, a solution of a carboxylic acid of formula (3) in anhydrous toluene or benzene is treated with an acid 15 catalyst, such as /wra-tolucnesulfonic acid and heated to reflux for 4 to 24 h to cyclize TO a lactone of formula (4). The use of a Dean-Stark trap accelerates the reaction by removing water as it is produced. In Scheme 1, Step D, a thiazole lactone of formula (4) is trans-cstcrified to an ester alcohol of formula (5) using a mineral acid, such as concentrated sulfuric acid, in the 20 presence of methanol, Subsequently, in Slep E, an alcohol of formula (5) is oxidized to an aldehyde of formula (6). It will be recognized by the skilled artisan that there arc numerous methods for such an oxidation. The preferred method uses TEMPO in an inert solvent, such as dichtoromc thane, in the presence of potassium bromide, sodium hypochlorite, and sodium bicarbonate. 25 in Scheme 1, Step F, an aldehyde of formula (6) is converted to an aceta] of formula (7). There are various methods for acetal formation available to one skilled in the an. The preferred conditions use an acidic ion exchange resin with trimethyl orthoformatc in McOH. In Step G, an acctal-esrer of formula (7) is hydrolyzcd to an acid of formula (8) using an inorganic base, such as sodium hydroxide in a suitable polar 30 solvent, such as ethanol. As will be readily appreciated, a compound of formula (1) can be prepared by methods similar to those described herein using procedures that arc well-known and WO 2008/076562 PCT/US2U07/QS4812 appreciated in the an. For example, compounds of formula (1) are prepared by cyclizftt'ion of a thioumide with an haloacctoacetate. If not commercially available Ihioamides are easily prepared from substituted benzamides using methods known in the art, such as with Lawesson's reagent or phosphorous pentasulfide. Formation of compounds of formula (]), can be carried out in accordance with methods depicted in Scheme 2. An appropriate compound of formula (8) is one in which 10 (R1).,, is as defined in formula (I) and an appropriate compound of formula (9) is one in which R2 is as defined in formula (J). In Scheme 2, Step A, an acid of formula (8) is acylatcd with an amine of formula (9). It will be well recognized by the skilled artisan that there arc a variety of methods available for acylation of car-boxylic acids. The preferred method uses I- 1 b hydroxybenzolriazolc hydrate and I -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in the presence of an amine, such as diisopropylethyl amine, in an inert solvent such as dichloromethane, acetonitrile, or preferably THF. In Scheme 2, Step B, a thiazole-amide of formula (10) undergoes intramolecular cyclization to form a thiazole-pyridinone of formula (11) with concomitanl loss of the 20 tBOC prolecting group to give an N-unsubstituted azeiidine. The cyclization is performed in an inert solvent such as ethanol in the presence of an inorganic acid, such as concentrated HC1, and healed at the reflux temperature of the solvent for 1 to 24 h. WO 2008/076562 PCT/UStW7«HW8U The N-unsubstituted azetidine of formula (] 1), while itself a desired product for purposes of the invention, can also be substituted to obtain other compounds of the invention. For example, in Scheme 2, Step C, the imsubstituted azetidine (11) is reductively alkylated with formaldehyde, acetone, cyclobmanone or other aldehydes and 5 ketones using sodium cyanoborohydride or sodium triacetoxy borohydride. The azetidine (11) is also reductively alkylated with ketals or acetals such as [(I-ethoxycyclopropyl)oxytrimethyIsilane or 2,5-dihydro*y-l,4-dioxanc. Such ketones, aldehydes, kctais, or acetals can be optionally substinncd using procedures known in the an. In addition, the azetidine (11) is acylated with optionally substituted acyl chlorides, 10 chloroformates, Or activated carboxylic acids, such as trifluoropropiunyl chloride or acetyl chloride. As will be readily appreciated, compounds of formula (9) can be prepared by mcihods and procedures that arc described herein, or that are known in the art. For example, compounds of formula (9) are prepared by nucleophilic aromatic substitution of 15 a fiuoro or chlpro-nitrobenzene with commercially available 3-hydroxy-azctidinc-l -carboxylic acid teri-buly\ esler. Subsequent reduction of the nitro group to the amine provides the aniline (9). WO 2008/076562 PCT/US2007/084812 Formalion of compounds of formula (I), can be carried out in accordance with methods depicted in Scheme 3. An appropriaie compound of formula (4) is one in which 5 (R %, is as defined in formula (1) and an appropriate compound of formula (9) is one in which R2 is as defined in formula (])- In Scheme 3, Step A., a thiazole lactone of formula (4) is reacted with an amine, of formula (9), using a typical Wcinreb protocol (Basha, Anwer; Upton, M.; Wcinreb, Sioven M. Tetrahedron Letters, 1977, 48, 4171-4174) to form an amide of formula (12). 1 0 For example, amine (9) is dissolved in an aprolic solvent, such as CH2C12 or preferably toluene, and treated with a 2-2.SM solution of trimcihylaluminum in toluene. The resulting solution is stirTed at a temperature from about 0 °C to room temperature for about 5 to 60 minutes, and then treated with a thiazole lactone of formula (4). The resulting solution is stirred at a range of between about room temperature and 110 °C for 1$ about 3 to 24 hours to give an amide of formula (12). In Scheme 3, Step B, the thiazole amide of formula (12) iscyclizcd using Mitsunohu conditions (Maligres, P. E.; et. al. J, Het. Chem. 2003. 40(2), 229-241) to form a thiazole lactam of formula (13). For example, the amide of formula (12) is treated with a trialkyl- or triarylphosplunc such as MC3P, PhjP, or preferably Bu>P, and a dialkyla^o- WO 2008/076562 PCT/US2OO7/084812 dicarboxylate such as DEAD or DlAD. The reaction is performed in an inert solvent, such as toluene, CH2CI2, or preferably THF. In Step C, the tBOCthiazolc lactam azetidine of formula (13) is deprotcctcd to the unsubstiiuted azetidine of formula (14). Common deprotcction conditions for removing a 5 tBOC group are well know by those skilled in the an and can be found in the text of T. W. Green and P. G. M. Wuts in "Protective Groups in Organic Synthesis", John Wiley & Sons, Inc., 1991, 328-330, Preferred conditions use mfluoroaceric acid or alternatively 37% hydrochloric acid in a solvent of n-propanol at room temperature to about 90 °C. The unsubstituted azetidine of formula (14) while itself a desired product for 10 purposes of the invention, can also be substituted tD obtain other compounds of the invention as shown in Sciicmc }, Step D, in a manner similar to that described in Scheme 2, Sttip C. 15 An alternate route for the formation of compounds of formula (1), can be carried out in accordance with methods depicted in Scheme 4. In Schemed, Step A, a ihiazolyl dicarboxylic acid of formula (15) is selectively cstcrificd to an Ihiazolyl cslcr-acid of formula (16). The estcrification conditions use an alcoholic solvent, such as methanol, in the presence of a mineral acid, such as sulfuric 20 acid al a temperature of about 50 °Cto the reflux temperature of the solvent. 2<* MAY 200V WO 2008/076562 PCTMS20G7/084KI2 In Scheme 4, Step B, a thiazolyl ester-acid of formula (16) is acylatcd with an amine of formula (9) lo give a thiazolyl ester-amide of formula (17). It will be recognized by the skilled artisan that there are a variety of methods available for acylation of carboxylic acids. The preferred method uses, l-prapanephosphonic acid cyclic 5 anhydride as a coupling reagent, in an inert solvent, such as THF, in the presence of an organic amine, such as N-methylmorpholine. In Step C, an ester-amide of formula (17) is reduced to an alkylhydroxy-amidc of formula (18). One skilled in the art will recognize that there arc a variety of methods to reduce esters to alcohols such as lithium aluminum hydride, diisoburylaluminum hydride, 1 0 bo nine-methyl sulfide complex, or lithium borohydride, The preferred conditions use lithium borohydride in an inert solvent such as TH1in Scheme 4, Step D.an alkylhydroxy amide of formula (18) is cyclized to a thiazoic-pyridmone of formula (19). The alcohol is first oxidized to the formaldehyde using sulfur irioxide pyridine complex, which then cyclizes with the amide in situ to form J b the pyridinone. The reaction proceeds in an inert solvent, such as DMSO at room temperature to about 100 °C. In Step E, a thiazole-pyridinone azetidine of formula (19) is deprotected using methods previously described for Scheme 3, Sicp D. The resulting unsubstitutcd azetidine is further reacted to give compounds of the invention, depicted in formula (I), a.*> 20 previously described for Scheme 2, Step C, As will be readily appreciated, compounds of formula (15) can be prepared by methods and procedures that are described herein, or that are known in the art. For example, 3-oxo-pemanedioic acid diethyl ester can be chlorinated with sulfuryl chloride and then subsequently reacted with a thiobenzamide to provide the 2-pheny]-4-25 ethoxycarbonylmethyl-thia20le-5-carboxylic acid ethyl ester. The diethyl ester is then hydrolyzed to the diacid of formula (15)- WO 2008/076562 PCT/US2007/08481Z Formation of an intermediate of formula (22) can be carried out in accordance 5 with reactions as depicted in Scheme 5. An appropriate compound of formula (22) is one which (R'V is as defined for formula I. in Scheme 5, Step A, 3-(2-bromo-thiaiol-4-yt)-acryIic acid (20) is converted to an acyl azide, which subsequently undergoes a Curtius rearrangement to the isocyanatc which cyclizes to bromo thiazolo-pyridinone of formula (21). The acid chloride is LO conveniently generated with oxalyl chloride in an inert solvent, such as dicfiioromothane. Following evaporation the acid chloride is reacted with sodium azide in a solvent mixture such as waicr/acetone/dioxane or THF to give the acyl azide. After workup the acyl ay.ide is heated to a high temperature of about 180 to 250 "C in Dowrhcrm® A and dioxanc for about 30 minutes to 4 hours. The isocyanate is formed in situ and undergoes 15 intramolecular reaction with the thiazole to form the bromo thiazolo-pyridinone of formula (21). In Step B, the bromo thiazolo-pyridinone of formula [21) is reacted with a phenyl boronic acid to provide a phenyl thiazolo-pyridinone of formula (22) in a Suzuki cross-coupling reaction. The skilled artisan will recognize that there are a variety of conditions 20 useful for facilitating such cross-coupling reactions. The reaction conditions make use of a suitable solvcni such as dioxanc, toluene, or dimethoxyethane with the addition of WO 2008/076561 PCI7US2007/OHJ812 cthanol and water. A solution of an inorganic base is added, such as sodium of potassium carbonate. The reaction takes place in the presence of a palladium catalyst, such as tetrakistriphenyl phosphirie palladium (0) under an inert atmosphere at temperature of about 70 to 100 *C for about 8 to 24 hours. 5 Alternatively, a phenyl thiazolo-pyridtnone of formula (22) can be obtained from a lactone of formula (4) as shown in Steps C, D, and £, In Scheme 5, Step C, a lactone of formula (4) is reacted with 2,4-dimcthoxybcnzylaminc in a Wcinrcb protocol as described for Scheme 3, Step A to provide a thiazole-amide of formula (23). 10 In Step D, the amide of formula (23) is cyclizcd to the benzyl thia^olo-pyridinunc of formula (24). The alcohol is oxidized to the aldehyde using I -hydroxy-1 -oxo-1H-benzo[d][ 1,2]iodoxol-3-onc and then subsequently reacted with the amide. The rcaciion takes place in an inert solvent, such as ethyl acetate, at a temperature of 40 °C to the refluxing temperature of the solvent. 15 In Step E, the 2,4-dcmethoxybenzyI protecting group is removed using neat TFA at a temperature of 50 to 100 °C to obtain a thiazolo-pyridinone of formula (22). ]i will be appreciated, that a bromothiazole of formula (20) can be prepared by methods and procedures that are described herein, or that arc known in the an. For example, 2-bromotViiazole-4"Carpaldehyde can be extended 10 the acrylic acid methyl 20 ester with methyl(triphenylphosphoranylidene)acetate in. a Wittig reaction followed by hydrolysis to obtain the bromothiazole acrylic acid of formula (20). WO 2008/076562 PCT/US2007/084812 Depicted in Scheme 6 is yet another route for obtaining compounds of formula (I) utilizing a phenyl thiazolo-pyridinone of formula (22). In Scheme 6, Step A, a phenyl thiazolo-pyridinone of formula (22) is coupled with a phenyl bromide of formula (25a) or (25b) to give a thiazolo-pyridinone of formula (19) 5 or formula (I). The reaction takes place in an inert solvent such as THF, or preferably diuxane with an inorganic base added, such as cesium carbonate. A copper catalyst is used, such as copper (I) iodide in the presence of sym-dimethy I ethylene diamine. The reaction is heated ai a temperature of about 70 °C to the reflux temperature of the solvent. In Step B, it is recognized that the protected azetidine of formula (19) can be 10 easily convened to the final products of formula (I) as described previously, such as in Scheme J, Steps C and 1> Scheme 7 15 Formaiion of compounds of formula (II), can be carried out in accordance wiih the method depicted in Scheme 7, wherein RA is as defined for formula (II). An azetidine of formula (la) is oxidized to an azetidine N-oxide of formula (11) using /Ti-chloropcroxybenzoic acid in an inert solvent such as dichloromcihanc. 20 |2SJ-MCH binding and functional GTPy3SS binding assays arc used to demonstrate potency of the compounds of the present invention as MCHRl antagonsits. One of skill in the art is able to perform both the ,25I-MCH binding and functional GTPY"S binding assays using the procedures herein or procedures disclosed in the art. For binding assay, see for example, Macdonald, D., ct al., 2000. Molecular characterization of the mtlanin- 2 b concentrating hormone/receptor complex: identification of critical residues involved in binding and activation. Mol Pharmacol 58, 217-225. ForGTPgammaS functional assay, see for example, Gao, X„ et a|., 2004. Europium-labeled melanin-concentrating hormone uruilogues: iigands for measuring binding to melanin-concentrating hormone receptors I and 2. Anal Biochem 328, 187-195, WO 2008/076562 PCT/US20()7/0848i2 All ligands, radioligands, solvenls and reagents useful in these assays are readily available from commercial sources or can be readily prepared by those skilled in the art, I-MCH binding and functional GTPy"S binding assays employing membranes isolated from AV-12 cells transected with the human MCHRl (Swiss-Prot Accession number 5 Q99705) were used to demonstrate the effectivenss of compounds disclosed herein as MCHRJ antagonists. Binding of compounds to MCHRJ is assessed in a competitive binding assay employing 1ISI-MCH, compound of the invention, and clone 43 membranes using scintillation proximity techniques. IC» values (defined as the concentration of test compound required io reduce specific binding of m!-MCH by 50%) are determined by 10 fitting the concentration-response data to a 4-parameier model (max response, min response, Hill coefficient, ICW) using a spreadsheet, K., values arc calculated from ICy, values using the Cheng-Prusoff approximation as described by Cheng et a\. {Biochem. /^/■m«ew/.,22:30yy-3108(1973). Exemplified compounds show a Ki of'<■ 1 pMinihe binding assay disclosed herein. Specifically, the compound of Example 37 exhibits an 15 average MCHRl K.i of about 4 nM. Therefore, compounds of the invention are effective as potent MCHRJ amagonists. Functional antagonism of MCH activity is assessed by measuring the ability of a test compound to inhibit MCH-stimutated binding of GTPy^S to membranes isolated from AV-12 cells expressing rhe human MCHRl using & scintillation proximity assay. 20 IC50 values (defined as the concentration of test compound required to reduce MCH- stimulated GTPy"S binding by 50%) are determined by fitting the concentration-response data to a 4-parameter model (max response, min response, Hill coefficient, ICs«) using a spreadsheet. After verifying competitive antagonism by Schlld analysis, Kb values arc calculated from the ICjo values for each antagonist and the EC3tJ for MCH (determined 25 independently) using a modification of the Cheng-Pnisoff approximation as described by Left nMDaui*\ {Trends Pharmacol. Sci,(\991) 14: U0-U2). Exemplified compounds show Kb values of < 1 |jM in (he functional assay disclosed herein. Specifically, the compound of Example 28 shows a MCHRl Kb value of about 6 nM. Thus, compounds uf the invention are effective as potent MCHRl antagonists. 30 To demonstrate in vivo efficacy, compounds of the invention are administered by oral gavage to diet-induced obese male Long-Evans rats (Harlan, IN) weighing 450-500 g. Animals are housed individually in a temperature regulated room (24 °C) with a WO 2008/076562 PCT7US2007/084812 All ligands, radioligands, solvents and reagents useful in these assays arc readily available from commercial sources or can be readily prepared by those skilled in the art. m]-MCH binding and functional GTPy3SS binding assays employing membranes isolaicd from AV-12 cells transected with the human MCHR1 (Sv/iss-Prot Accession number b Q99705) were used to demonstrate the effectivenss of compounds disclosed herein as MCHRl antagonists. Binding of compounds to MCHR] is assessed in a competitive binding assay employing mL-MCH, compound of the invention, and clone 43 membranes using Scintillation proximity techniques. Ida values (defined as the concentration of test compound required to reduce specific binding of '"l-MCH by 50%) are determined by 10 fining the concentration-response data to a 4-parametcr model (max response, min response. Hill coefficient, IC}0) using a spreadsheet. K, values arc calculated from lC>c values using the Chcng-Prusoff approximation as described by Cheng ei a!. (Biochem-Phurnwcol, 22; 3099-3108 (1973). Exemplified compounds show a Ki of < 1 ^M in the binding assay disclosed herein. Specifically, the compound of Example 37 exhibits an 15 average MCliRI K.i of about 4 nM. Therefore, compounds of the invention are effective as potent MCHRl antagonists. Functional antagonism of MCH activity is assessed by measuring the ability of a lest compound to inhibit MCH-stimulated binding of GTPy^S to membranes isolated from AV-12 cells expressing the human MCHRl using a scintillation proximity assay. 20 Ido values (defined as the concentration of test compound required to reduce MCH- stimulatcd GTPyJ5S binding by 50%) are determined by fitting the concentration-response data to a 4-parameier model (max response, min response. Hill coefficient, ICjo) using a spreadsheet. After verifying competitive antagonism by Schild analysis, Kb values are calculated from the ICsovalues for each antagonist and the ECM for MCH (determined 25 independently) using a modification of the Cheng-Prusoff approximation as described by Lcff and Dougal {'/rends Pharmacol. ScL (1993) 14: 110-112). Exemplified compounds show Kb values of < 1 pM in the functional assay disclosed herein. Specifically, the compound of Example 28 shows a MCHRl Kb value of about 6 nM. Thus, compounds of the invention are effective as potent MCHRl antagonists. 30 To demonstrate in vivo efficacy, compounds of lhe invention are administered by oral gavage to dict-induccd obese male Long-Evans rats (Harlan, IN) weighing 450-500 g. Animals are housed individually in a temperature regulated room (24 *C) with a WO 2008/076562 PCT/US2O07/O84812 reverse 12 hour light/dark cycle (dark 10:00/22:00). Water and food (Teklad 95217, Harlan, Wl) were available ad libitum. Compounds are administered orally in a vehicle thai consists of 10% acacia and 0.15% saccharin in water once a day before onset of the dark period for 3 days. Food intake and body weight are measured daily for the 2 day b period. The compound of Example 29 produces an average body weight reduction of about 7 grams at a dose of J D mg/Kg when compared to vehicle control. The results show that compounds of the invention arc useful in treating obesity. As antagonists of the MCHRl binding, a compound of the present invention is useful in treaiing conditions in human and non-human (especially companion) animals in LO which the MCHRl receptor has been demonstrated to play a role or diseases related to die effect ot'MCH The diseases, disorders or conditions for which compounds of the present invention are useful in treating or preventing include disease disclosed herein and in PCT application WO 2007/1066174. The compounds of the invention may also be used in combination with other approved therapeutic agents for treating, preventing and/or 15 ameliorating obesity and related diseases. In this format, the compounds of the present invention enhance the positive effects of such approved combination treatments while minimizing the side effects due to the potential requirement of lower doses of such combination compounds. Such combination therapies may be delivered individually or in a combined formulation. Examples of compounds useful in combination with a 2 0 compound of formula 1 or 11 include weight loss agents (Meridia™, Xenical™). cholesterol lowering agents (such as for example, lovastatin, simvastatin pravastatin, fluvastatin, and atorvastatin), glucose level control or modulating agents, cannabinoid CB-1 antagonist compounds (such as for example rimonanbant) and the like. In treating non-human, non-companion animals, the compounds of the present 2 5 invention ere useful for reducing weight gain and/or improving the feed utilization efficiency and/or increasing lean body mass. The compound of formula I or II is preferably formulated in a unit dosage form prior to administration. Therefore, yet another embodiment of the present invention is a pharmaceutical formulation comprising a compound of formula I or 11 and a 30 pharmaceutical carrier. The present pharmaceutical formulations are prepared by known procedures using well-known and readily available ingredients. In making the formulations of the present WO 2008/076562 PCT/US2U07/084812 invention, the active ingredient (formula 1 or II compound) wifl usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a liquid, tablet, capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semisolid or liquid material which acts as a vehicle, excipient 5 or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosol (as a solid or in a liquid medium), soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders. One of skill in the an is aware of methods, reagents and conditions for preparing ID various siandard formulations or can assess such information without undue experimentation. The compositions of the invention may be formulated so as IO pro\ ide quick, sustained or delayed release of the active ingredient after administration to ihe patient. The specific dose administered is determined by the particular circumstances 1 5 surrounding each situation. These circumstances include, the route of administration, the prior medical history of the paliem, the pathological condition or symptom being treated, the severity of the condition/symptom being treated, and the age and sex of die recipient However, it will be understood that the therapeutic dosage administered will be determined by the physician in the light of the relevant circumstances, or by the 20 veterinarian for non-human recipients. Generally, an effective minimum daily dose of a compound of formula J or II is about 0.1 mg to about 0.5 tug per kilogram. An effective maximum dose is about I mg to about 5 mg per kilogram. The exact dose appropriate for a particular recipient is n determination 10 be made by the treating physician based on the particular circumstances 25 of the patient. The appropriate dose may also be determined, in accordance with the * standard practice in the medical arts of "dose titrating" the recipient; that is, initially administering a low dose of the compound, and gradually increasing the dose until the desired therapeutic effect is observed. The compounds may be administered by a variety of routes including the oral, 30 rectal, transdermal, subcutaneous, topical, intravenous, intramuscular or intranasal routes. A preferred route of administration is oral. A phiirrttaeeulical composition of the present invention comprising a compound of formula such as herein described and a pharmaceutical^ acceptable carrier and/or diluent showed surprising and enhanced effects. Therefore, the said composition is synergistic in nature- WO 2008/070562 POYUS2007/084SI2 Examples Without further elaboration, it is believed that one skilled in the an can, using the preceding description, practice the present invention to its lullest extent. The following preparations and examples are provided to describe the invcnlion in further detail. They 5 are intended to illusirate and not to limit the invention in any way whatsoever. The reagents and starting materials are readily available to, or may be readily synthesized by, one of ordinary skill in the art. Those skilled in the art will promptly recognize appropriate variations from the procedures described in the examples. The names of the compounds of the present invention are provided by ChemDraw Ultra® version 7.0.1. 10 Preparation 1 \2-(4-CMoro-phenyl)-trtia?,(ri-4-ylJ -acetic Qctd e\hy\ cslur Dissolve 4-chlorothiobenzamide (74,0 g, 431,1 mmol) in EtOH (470 mL) and treat with ethyl-4-chloroacetoacctate (58.0 mL, 70.1 g, 426.0 mmol). Stir the resulting 15 solution mechanically at reflux for 2 h. Cool to room temperature, add water (1000 mL), and extract with Ei20 (2000 mL, (hen 2 * 500 mL). Combine the organic solutions and wash with brine (950 mL). Concentrate in vacuo to give an oil that solidifies upon standing (121.8 g). Recrystallize the crude material from isopropanolAvater to give the title compound (107.3 g, 89% yield). ES/MS m/z ("CI) 282.1 [M+l]\ 20 Preparation 2 J»|2'(4-Chloro-phenylHhiazol-4~yl]-ethanol Dissolve [2-(4-chloro-phenyl)-thiazol-4-yI]^acelic acid ethyl ester (107.4 g, 381.2 mmol) in THF (800 mL) and cool to 0-5 °C. Slowly add DlBAL (1.0 M in THF, H00 mL, 2b 800 mmol) over approximately 35 h keeping the temperature < 5 °C, After the addition is complete warm the resulting solution to room temperature and stir mechanically overnight. Cool the solution to 0-5 °C and slowly add additional DIBAL (150 mL) keeping the temperature < 5 °C. Stir at room temperature for 2.5 h, then cool to 0-5 °C and slowly quench over 5 h with aqueous saturated Rochclie's salt (2900 mL) keeping the 30 temperature < 10 °C. Extract the mixture with EtOAc (2 * 3300 mL). Combine the organic solutions and concentrate in vacuo to give an oil (112.9 g). Dissolve the oil in WO 2008/076S62 PCTAJS2O07/O84812 toluene (600 mL) and concentrate in vacuo, then repeat. Dry the residue in vacuo for 6 I) to give a residue weighing 107.4 g (110%). ES/MS m/z (,SCI) 240,1 [M-tl]+. Preparation 3 5 2-(4-Chloro-phenyl)-4-<2-hydr'oxy-ethylHhlazole-5-carboxyncacid Dissolve 2-[2-(4-chloro-phcnyl)-thiazol-4-yl]-(jthanol (107 g gross, 91 g net, 380 mmol) in THF (1210 mL) and cool to about -75 ftC. Evacuate the chilled solution under vacuum and fill with nitrogen three times. Slowly add /z-BuLi (1.6 M in hcxanes, 530 mL, 848 mmol) over approximately 4 h, keeping the temperature < -70 °C. Slowly add 10 the red-purple solution via cannula over 3.5 h to a flask containing -75 °C THF thai has been saturated with C02 gas (approximately 390 g) keeping the temperature < -60 "C GYtfrgtfm-c resorting 6rown si'urry vrfctt stfdtiioast COi gas ("approximately 3SS gjantf then allow the slurry to come to room temperature while stirring mechanically overnight. Quench the reaction with I N HC1 (3000 mL), cool to 16 °C, and collect the precipitate 15 by filtration. Rinse the solid with hexanes (1400 mL) and dry under vacuum to give 81.3 g (75%) of the title compound. ES/MS m/z("CI) 284.0 [M+l]Preparation 4 2-(4-C)jJoro-phenyl)-6,7-dihydro-pyrfliio|4,3w/]thJazDl-4-Dn(' 20 ° Mix 2-(4-chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazolc-5-carboxy3Jc acid (81.2 g, 286.2 mmol) with p-TsOH monohydrate (32.0 g, 168.2 mmol) and toluene (1200 mL). Heat the slurry to reflux during which time the solids dissolve. Stir the resulting tan solution mechanically for 2 h, using a Dean-Stark trap to collect water (21 mL). Cool the 25 solution lo room temperature and add saturated aqueous NaHCOj (1700 mL) and EtOAc (J 700 mL). Separate the organic solution, then extract the aqueous layer with EtOAc (2 * 1700 mL). Combine the organic solutions, wash with brine (1700 mL), and concentrate in vacuo to give a solid. Mix the solid with CHaCh (500 mL) and concentrate in vacuo and repeat two times to give 60.1 g (79%) of the title compound, ES/MS m/2 (i5Cl) 266,0 30 fM + l]". WO JQ08/U76562 PCT/US2007/084S12 Preparation 5 2-(4-Cliloro-phenyl)-4-(2-hydroxy-ethyl)-thia«ile-S-carboxylic acid methyl ester Dissolve 2-(4-chloro-p)jeny))-6,7-dihydro-pyrano[4,3-d]thiazol-4-oue (500 g, 5 1882 mmol) in MeOH (5 L) and add concentralcd sulfuric acid (31 mL). Stir the solucion at 55 "C for 15 h, then warm to 66 "C and continue stirring for an additional 4.5 h. Cooi the solution to 45 °C and concentrate in vacuo to one half of the volume. Continue to cool the slurry to 20 °C. Isolate the precipitate by filtration and wash the solid with cold MeOH. Dry the solid (420.5 g) under vacuum overnight. Concentrate the filtrate to 10 about 600 mL, filter, and wash with cold MeOH to obtain more solid (40. 7 g). Purify ihe crude materials by flash chromatography, using 10%EtOAc/CH;Cb as ciuciu, to give a loial of {442 g, 80%) of the title compound. 'H NMR (400 MJI2, CDC13): 6 1M (dl, J -8.8, 4.7 Hz, 2H). 7.43 (dt, J = 8.7, 4.3 Hz, 2H), 4.05 (t, J = 5.6 Hz, 2H), 3.90 (s. 3H), 3.43 (U = 5.uta.2H), 3.32(bs, IH). 15 Preparation 6 2-(4"Chloro-phenyl)-4-(2-oxo-ethyl}-thiazole-5-carboxylic acid methyl ester Dissolve 2-(4-chloro-phenyl)-4-{2-hydroxy-ethyl)-thiazo!e-5-carboxylic acid methyl ester (100 g, 336 mmol) in CH3CI2 (2 L) and treat with potassium bromide (4,0 g, 20 33.6 mmul) and TEMPO (1.1 g, 7-0 mmo]). Cool the solution 10 -10 °C and add a soJulion of sodium hypochlorite (1 L, 0.25 M in water) and aqueous sodium bicarbonate (1 L, 1.4 M). Stir the resulting slurry at 0°C for 15 min and (hen dilute with water (3.2 L) and CH2Cb (1.3 L). Remove the organic solution and extract the aqueous phase with CH3CI2 (1 -3 L). Combine the organic solutions and wash with brine (1.3 L), then dry, 25 filter, and concentrate to give (91.5 g, 92%) of the title compound. 'HNMR (400 MHz, CDCb): 8 y.86 (t, J - 1.5 Hz, IH), 7.90 (dt, J * 8.4,4.4 Hz, 2H)( 7,43 (dl, J = 8.6,4.4 Hz. 2H), 4.32 (d, J = 1 -8 Hz, 2H), 3.89 (s, 3H). Preparation 7 30 2-(4-Chloro-phenyl)-4-(2,2-^^imethoxy-e(hyl)-th^a^o]^5-carboxy]ir, acid methyl ester Mix 2-<4-chlaro-phcnylH-(2-o>;o-ethyl)-thiazole-5-carboxylic acid methyl esier (96.4 g, 308 mmol), Dowfix™ 50X8 ion exchange resin (33.3 g), and trimethyl WO 2008/076562 PCT/US2007/084812 orthoformate (J 47 mL) in MeOH (670 mL). Stir the slurry overnight at room temperature. Filter through a plug of diatomaceous earth and rinse with MeOH (3 * 300 mL). Stir the filtrate at 0 'C for 2 h and then concentrate to a volume of approximately 250 mL. Collect the solid by filtration, rinse with cold MeOH, and dry overnight at room 5 temperature to obtain 88.2 g (84%) of the tilled compound. ES/MS m/z (3iCl) 342.0 [M+]VPreparation H 2-(4-Ch!oro-phenyl)-4-<2,2-diniethoxy-ethylHhio7.ole-5-carboxylic acid 10 Mix 2-('4-chlofO-phenyl>4-(2,2'dimethoxy-ethyl)-thiazole-5-ca.rboxylic acid methyl ester (3.6 g, 10.5 mmol) in EtOH (40 mL) and then add 2 M NaOH (6.8 mL). Stir the slurry mechanically overnight and then concentrate in vacuo. Dissolve the solid in water (40 mL), cool to 0 *C, and adjust (he pH to 5-6 with 1 N HCI (13 mL)- Stir the slurry tor IS min, collect the precipitate, and wash the solid with water(4 * 20 mL). Dry 15 the solid in a vacuum oven overnight to give 3.3 g(96%) of the title compound. ES/MS m/z (35C1) 326.0 (M-)]". Preparation 9 3-(2-Methoxy-4-nitro-phenoxy>-azetidine-l-carboxylic acid /ert-butyl ester 20 Dissolve l-fltioro-2-methoxyj4-nitro-benzene(H8 g, 689 mmol) and 3-hydroxy-azelidine-I-carboxylic acid/ert-butyl ester (125 g, 724 mmol) in THF(8O0 mL) and cool to 0 °C under nitrogen. To the above solution, add dropwise a i M THF solution of teri> BuOK (I L). After the addition is complete, stir the dark brown solution for 30 min at 0 25 0Cartd then dilute with water (1 L) over a 10 mill period. Stir the mixture for 5 min, then extract with rerf-butyl methyl ether (2* ). Combine the organic solutions and wash with brine (2 * 700 mL), then dry and concentrate, Dry the solid in vacuo at 45 °C for 20 h to obtain 216 g (95%) of the title compound as a yellow solid. lH NMR (300 MHz, CDClj) <£6.47, G.46(sf 2H), 4.76(m. IH), 4.20 (dd,2H,.7=4.4, 10.4), 4.02 (dd, 2H,y= 6.2, 10.6), 3,48 (bs, 2H), 1.42 (s,9H). 5 Preparation 19 3_(4-{j2-(4^Chloro-phenyl)-4-(2,2-dimethoxy-ethyl)-thiaiole-5-carbonyl|-amino}-2- methoxy.phenoiL-y>-azt!tidine-l-carboxyUc acid tert-butyl cslcr Dissolve 2-(4-chloro-phcnyl)-4<2,2-dimethoxy-ethyl)-thiazole-5-carboxylic acid 10 (147 g, 448 mmol), 3-(4-amino-2-mcthoxy-phcnoxy)-azctidinc-l-carboxylic acid ten-bulyl ester (120 g, 402 mmol), find 1-hydroxybcnzorriazole hydrate (75 g, 490 mmol) in THF (1.2 L) and cool to about 10 °C under a nitrogen atmosphere Treat the above solution with diisopropylethylamine (J 17 mL, 673 mmol) (Jropwisc over 2 min while keeping the temperature between 10- 15 °C. Add l-(3-dimethylaminopropyl)-3-15 ethylcarbodiimide hydrochloride (93 g, 489 mmol) to the solution and stir at room temperature for 19 h. Cool the solution to 0°C and dilute with water (1.2 L). COI1L*CI the precipitate by filtration and triturate with water (5 * 700 mL). Dry the tan solid for 3 days at 50 °C under vacuum to obtain 219 g (90%) of the title compound. lH NMR (300 MHz, CDCb) 5: 10.03 (s, IH), 7.90 (m, 2H), 7.66 (d, IH, J= 2,4), 7.42 (m, 2H), 6.88 20 (dd, 111, J = 2.4, 8,6), 6.57 (d, IH, J= 8.6), 4.86 (m, IH), 4.84 (t, IH, .7= 5.7), 4.26 (dd, 2H, J*= 6.7, 10.6), 4.08 (dd, 2H, J- 4.3, 10-6), 3.90 (s, 3H)t 3.53 (s, 6H), 3.37 (d, 2H. J -5.5), 1.43 (s,9H). WO 2008/076562 PCT/US2007/0848I2 Preparation 20 ^-(4-{[2-(4-Chloro-phenyl)-4-(2-hydroxy-elhyl)-(hiaw>Ie-S-«arbonyIJ-a[nino|-2- niethoxy-plienoxyVazetidme-1-carboxylic acid rert-butyl ester 5 Dissolve 3-(4-amino-2-rncthoxy-phenoxy)-azetidine-l-carboxylic acid feri-butyl ester (9.1 g, 30.9 mmol) in toluene (100 mL) at room temperature and treat wit!) minetliylaluminum (22.0 mL. 2.0 M in toluene). Stir the dark red solution ai room icmpuryiure for one hour and add solid 2-(4-chioru-pi]cnyi)-6,7-d]hydro-pyrano(4v3-d]thitt2ol-4-onc (7.97 g, 30,0 mmol). Warm the solution to 50 °C and slir for 2 h. Cool to 10 room temperature and slowly quench with saturated Rochclle's salt solution (5 mL). After the bubbling subsides add additional Rochclle's salt solution (30 mL) and stir vigorously for 2 h. Separate the organic phase and extract the aqueous phase with CHJCIJ (2 x 50 mL). Combine the organic portions and wash with saturated Rochclle's salt solution (2 * 25 mL) and brine (25 mL). Dry, filter, and concentrate the organic 15 solution. Purify the crude material by flash chromatography, using 5% MeOH (2M NHjVCHzCfe as elucnt, 10 give an orange solid. Fu/ibw purify the material by iriiuraiion with Li CHaCljidiethyl ether, followed by filtration to give 12.77 g, (76%) of the title compound as a white solid. ES/MS m/z (JiCl) 558.2 [M-l]Prepare the alcohol-amide compounds in the table below. Preparations 21 to 25, 20 by essentially following the procedure as described in Preparation 20, WO 2008/076562 PCTAJS2O07/l»848n Preparation 2(i 3-i4-J2-(4-Chloro.phenyl)-4-oxo-6,7-dihydro-4IMhjazoio/5,4-cIpyridin-S->'IJ-2- mcthoxy-phenovyj-flzetidine-1-carboxylic acid fm-butyl ester Dissolve 3-(4-([2-<'t-chloro-phenyl)-4-(2-hydroxy-ethyl)-thia2olc-5-CHrbonyl]-amino) -2-methoxy-phenoxy)-azeiidine-1 -carboxyltc acid ttrt-butyl ester (9.1 g, 30.9 mmol) in THF (100 mL) at room temperature and treat with tri-n-butylphosphinc (6.2 mL, 24.8 mmol) and diisopropyl azodicarboxylate (5.0 g, 24.7 mmol)- Srir the solution a£ 10 50 °C for 5 h, then cool to room temperature and concentrate in vacuo to V* volume. Dilute the yellow mixture with diethyl ether (100 mL) and collect the light yellow powder by filtration, washing with additional diethyl ether (50 mL). Dry the solid in vacuo io obiain 9.7 g (79%) of the title compound as a light yellow solid. ES/MS m/z (3SC1) 542.2 [M+lf, 564.2 [M+NaJ*. WO 2008/076562 PCT/US20G7/0848X2 Prepare the lactam compounds in the table beIo\v, Preparations 27 to 31, by essentially following the procedure as described in Preparation 26. WO 2008/076562 FCT/US2007/084812 Dissolve:h(4-{[2'(4-ch\or(Hphenyl)-4-i2,2-diiridthoxy^thy\)-tb'}zzo\c-5-carbonyI]-amino}-2-methoxy-phenaxy)-azelidine'l-carboxylic acid tert-butyl ester (18.9 g, 31.28 mmol) and p-tolucnesulfonic acid monohydiatc (19,7 g, 103.56 mmol) in dry toluene (460 mL) and stir mechanically at 95 °C overnight. Cool the reaction mixture b and add 1 NNaOH. Stir the mixture vigorously at room-temperature for one hour. Extract the aqueous layer with CH2Cli (2 * 700 mL). Combine the organic portions, wash with brine (700 mL), dry over MgS04, and filter. Concentrate the filtrate in vacuo to give 13.0 g (85%) of the title compound- ES/MS m/z (,SC1) 440,0 [M+lf. 1U Example la 5-[4-(A/etidin-^-yloxy)-3'merhoxy-phenyll-2-(4-chloro-pheiiyl)-5H-thia/.olo|S,4-c|pyridin-4-one, hydrochloride salt Mix 3-(4-{[2-(4-chloro-pheny])-4-(2,2-dimcthoxy-ethyl)-thiazole-5-carbonyl]- 15 amino}-2-methoxy-phenoxy)-azctidinc-l-carboxylic acid /erf-butyl ester (208 g. 344 mmol) in EtOM (2.2 L) and treat with concentrated HC1 (208 mL). Heat the mixture to reflux for one hour and then cool to 0 °C, Collect the solid by filtration and rinse with ice-cold Et?0 (4 * 500 mL). Dry the solid under vacuum at 55 °C for 2 days to give 159 g (97%) of the title compound as an off-white solid. 'H NMR (300 MHz, DMSO-J6) S: 20 9.37 (s, 2H), 8.15 (m, 2H), 7.75 (d, 1H, J - 7,6), 7.66 (m, 2H), 7.22 (d, 1H, J -7.5), 7.05 (d. \H.J =7.3), 7.01 (dd. 1H, J= 2.5, 8,7), 6.92 (d, 1H, J" 8.6), 5.09 (m, 1H), 4.45 (m, 2H),4.04(m,2H),3.S2(s, 3H). Preparation 32 25 3-{4-12-(4-Chloro-phenyl)-4-oxo-4H-thiawIol5,4-c|pyridin-5-yl)-2-nuoro-phcnoxy}- azetidine-l-carboxylic acid /trf-butyl ester Dissolve 3-(4-{[2<4M;hloro-phcnyl)-4-(2-hydroxy-cihyl)-thiazole-5-carbonyl]-aimno}-2-fluoro-pheiioxy)-azetidine-l-carboxylic acid /erf-butyl ester (260 mg, 0.474 mmol) in dry DMSO (3.16 mL) followed by addition of tricthylamine (0.125 mL, 0.901 30 mmol). Chill the mixture to 15 °C and add portion-wise sulfur trioxide pyridine complex (133 mg, 0.820 mmol). Stir for approximately 2 h. (Note; additional PyT*SOj may be WO ZOOS/076562 PCT/\)S2M7MH4iil2 needed until starting material is consumed). Quench the mixture with water (10 mL) and exln^ with CH2Ci2 (2 x 25 mL). Dry, filler, and concentrate to dryness. Redissolve the crude material in OfcCfe (1.9 mL) and add TFA (0.558 mL, 7.38 mniQl) and stir until the reaction is complete by TLC (1:1 EtOAc/hcxancs), Quench the 5 mixtUre with water (10 mL) and 5 N NaOH solution to pH » 8-30. Extract aqueous layer with CH2CI2 (2 »< 25 mL), Dry, filter, and concentrate to a white solid. Triturate with E'JQ to give 46 mg (22%) of a tan solid. ES/MS m/z (3iCl) 428.0 [M+ i]T- Example2 10 ^-(^(ji^oro.pheTiyO-fi-^-tl-cyclohutyl-azetidin-S-yloxy^-methoxy-phtnyll-SH- thiazolo[5,4-c)pyridin-4-onc> hydrochloride sail Method 1: Dissolve 3-(4-{(2-(4-chloro-pheny))-4-(2,2-dimcihoxy-ethyl)^thiazoli:-5^ car^nyl]-amino}-?--rnethoxy-phcnoxy)-azetidine-l -carboxylic acid ferf-butyl ester (18,9 15 g. 31_28 mmoi) and p-toluenesulfonic acid monohydrate (19.7 g, 103.56 inmol) in dry toluune (4G(| mLj and stir mechanically at 95 "C overnight. Cool the reaction mixture and add 1 NNaGH. Siir the mixture vigorously at room temperature for one hour. Extract the aqueous layer with Cti?Ch (2 * 700 mL), Combine the organic portions, wash with 20 brint; (700 mL), dry over MgSC>4, and filter. Concentrate the filtrate in vacuo to give 13.0 & (85%) of 5-[4-(azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4-chloro-phenyl)-5H- *iazolo[5,4-c]rryridin-4-one. ES/MS m/z 440.0 ("CI) [M+l]Dissolve 5"[4-(azetidinO-yloxy)-3-methoxy-phenyl]-2-(4-chlorO'phenyl>5H- thiazolo[5,4-c]pyridin-4-one (300 mg, 0.680 mmol) and cyclobutanonc (76 (iL, 1.02 25 mmoijjntjry 1,2-djchloroethane (6.66 mL). Mix well and add sodium tnac^tuxyborohydride (500 mg, 2.26 mmol). Stir overnight at room temperature. Add I N Na.OH solution and extract with CH2CI2 (2 * 10 mL). Combine the organic portions and Vash with water (2 * 5 mL). Dry with NaiSO*, filter, and concentrate in vacuo. Purify the crude material by silica gel chromaiography using a gradient of 0-10% 2 N 30 NHj/jvJeOH in CH2O2. Collect the desired fractions and remove solvent via reduced WO 2008/076562 PCT/US2007/0S4812 pressure. Rc-dissolve material in CHCh and add 1 N HCI solution (about 300 u.L), Remove the solvent via reduced pressure and dry in vacuo at room temperature overnight to give 161 mg (44%) of the title compound. ES/MS mMW.O(MCI)[M-Hf. Method 2: 5 Dissolve 3-{4-[2-(4-chloro-phenylH-oxo-4H-thiazolo[514-c]pyridin-5-yl]-2- methoxy-phenoxy}-azeiidine-l -carboxylic acid wrf-buty] ester (156 g, 28.9 mmol) in CHClj (156 mL) and MeOH (156 mL). Add concentrated aqueous HCI (6 mfc,-79,2 nutiol). Heat the resulting solution at 55-60 °C overnight. Cool the reaction to room Icmpcralurc. Add cyclobutfmonc (12 g, 171.2 mmol) at 5-10 °C. Then add portionwthc 10 sodium triactHOx.yborohydri.de (43.6 g, 205/7 mmol). Stir the mixture at room lernperature overnight. Quench ihe reaction slowly with a solution of Na3CCh (210 mL) in water (300 mL) to bring the mixture to a pH = 8. Add water (90 mL) and CHClj (120 mL) and filler. Collect the filtrate and wash the organic layer with water (150 mL). Concentrate in vacuo to give a white solid 11.2 g(7K%) of the title compound. 15 Example 3 2-(4-Cliloro-phenyI)-5-|4-(]-cyclopropyl-azetidin-3-ylO)[y)-3-methoxy-phenyl|-5H-thiazolo[5,4-c|pyridin-4^me, hydrochloride salt Mix molecular sieves (100 mg, type 3A), 5-[4-(azetidin-3-yloxy)-3-methoxy- ?0 phcnylJ-2-(4-chloro-phenyl)-5H-thiazolo[5,4-c]pyridin-4-one (1.00 g, 2 27 mmol), and [(l-cthoxycyclopropyl)oxy]tnmethylsilane (688.3 uL, 3.41 mmol), and acetic acid (651.3 pL, 11.37 mmoles) in dry methanol (11 mL) and reflux the mixture for 3 h. Cool the reaction to room temperature, then add sodium cyanoborohydride (376 mg. 5.68 mmoles) and slowly warm to 40 °C for one hour. Cool the mixture and add 1 N NaOH solution, 25 (hen extract the aqueous layer with CHClj (3 * 25 mL). Dry the organic layer with NajSO*, filter, and concentrate. Purify the crude material on silica gel chromatography using a gradient of 0-10% 2 N NHj/McOH in CHClj. Collect the desired fractions and remove the solvent via reduced pressure. Re-dissolve the resulting material in CHCb and add 1 N HCl/Ei^O solution (2.27 mL). Remove the solvent and dry under vacuum lo give 30 40« mg (35%) of the title compound. ES/MS m/z (3SC1) 4800 [M+1] WO 2008/076562 PCT/US2D07/OS4812 Example 4 S-(4-(l-Acetyl-a7ftidin-3-yIoxyH-niflhovy-phfnyl|-2-(4-chlorci-phenylVSH- thiazolo|St4-cjpyridin-4-one Dissolve 5-[4-(azelidin-3~yloxy)0-methoxy-pheny!]-2-(4-chloro-phcrtyl)-5H-5 lhiazolo[5,4-c]pyridin~4-one (75 mg, 0.171 mmol) and trietliylamine (52.5 uL, 0.376 mmol) in dry CH2CI2 (700 jiL). Chill to 0 °C and add accfylchloride(13.4 nl, 0.188 mmol). Allow to warm lo room temperature overnight. Add 1 N HC1 solution and extract with CH2C!2 (3*5 mL). Combine the organic portions and wash with water (2 * 5 mi,). Dry the organic layer with Na2S04, filler, and concentrate in vacuo. Purify the 10 resulting residue on HPLC wiih 5 urn 30 * 75 mm XRridge CI 8 column, clueni: 34% water (with 10 mM NH4HCO3 added to pH = 10/aceiontirilc (isocratic) to give 39 mg, (48%). ES/MS m/z (35C1) 481.8 [M+l]+. Example 5 15 2-(4-Chloro-phenyl)-5-|3-mi;thoxy-4-(l-metriyl-a2etidin'3-yloxy)-phenyl3'5H- thiazolo[5,4-c|pyridin-4-Orte Cool a mixture of 5-[4-(azetidin-3-yloxy)-3-mcthoxy-phcnyl]-2-(4-chloro-phcnyI)-5H-lhia2olo[5,4-c]pyridin-4-onc, hydrochloride salt (20 g, 42.0 mmol) in 20 methanol (600 mL) to 15 °C. Add acetic acid (12.1 mL, 211.6 mmol) and sodium cyaiioborohydride (7 g, 111 mmol). Add formaldehyde (10.2 mL, 136.45 mmol, as a solution in water to ihe thick mixture and stir for 15 h at room temperature. Cool the mixture to 5 °C, add saturated aqueous NaHCOj (320 mL), and stir the mixture for one hour at room temperature. Extract the mixture with CHClj (3 * 1 L). Combine the 25 organic solutions and wash with brine, then dry, filter, and concentrate. Dissolve the residue in CHClj (240 mL) and dilute with tert-butyi methyl ether (700 mL). Collect Ihe precipitate by filtration and rinse the solids with additional ten-butyl methyl ether. Dry the *olid under vacuum for 5 h at room temperature to obtain 5.4 g (81%) of the title compound. ES/MS m/z ("Cl) 454 [M+lf. WO 2008/076562 PCT/US2007/OB:J812 Example 5a 2-(4-ChIoro-phenyl)-5-|3-inethoiy'4-(i-nicthy)-azeiidiii-3-yJoxy)-pheny]I-5II-thia/oIof5,4-c|pyridin-4-one, hydrochloride salt Dissolve 2-(4-chloro-phenyl)-5-[3-mct!ioxy-4-(l-methyl-azctidin-3-yloxy>phcnylJ-5H-thiazolo[5,4-cJpyridin-4-onc(106gl 5 234 mmol) in CHCh (2.1 L) and cool the solution to 1S *C. To the above solution, add dropwise HCI (140 mL, 2 M in diethyl ether) over 10 min. Stir the mixture for one hour and dilute with wrt-butyl methyl ether (2 L). Collect the precipitate by filtration and wash the solid with ter/-butyJ methyl ether (3 * 660 mL). Dry the solid ai room temperature for 4 days under vacuum to give 115 g(100%). ES/MS m/z (?iCl) 454 10 [M+l]+. Example 5b 2-(4-Chioro-phenyl)-5-|3-methoxy-4-(l-methyl-azetidin-3-yloxy)-plienyl|-511- tht(Molo|5,4-c]pyridirM-orte, furnarate salt \b Dissolve 2-(4-chIoro-phenyl)-5-(3-metrioxy-4-(l-methyl-a2etidiii-3-yloxy)- pheny[>5H-thiazolo[5,4-c]pyridin-4-one(638mg, 1.41 rnmol) in 1,4-dioxanc ai JO0°C. To the above solution, add a solution of fumaric acid (5.64 mL, 1A1 mmol, 0.25 M in water). Stir the resulting solution at 100 °C for 5 min, then ar 50 °C for one hour. Concentrate the solution with a stream of nitrogen gas to V* volume. Warm the mixture 20 up to 100 °C until all the solids dissolve, then slowly cool to -10 °C. Collect the white precipitate by filtration and wash the solids with cold dioxane (10 mL). Dry the solid at room temperature over the weekend to obtain 500 mg (62%) of the title compound as a fine white powder. ES/MS m/z (3iCI) 454 [M+I]*. Alternate route to Example 5b 25 Step 1: 2-Chloro-3-oxo-pentpnedioic acid diethyl ester Dissolve 3-oxo-pemanedioie acid diethyl estcr(l 122 g, 5.327 mo!) in CH2CI3 (3 L) and cool to -9 °C. To the above solution, slowly add a solution of sulfuryl chloride (374 g, 2.69 mol) in CH2CI3 (3 L) over 3 h. Upon completion, add a second charge of sulfuryl chloride (374 g, 2.69 mol) in CH2C13 (3 L) over 4 h. Stir the resulting cooled 30 solution for one hour, then warm to room temperature and stir overnight. Cool the solution in an ice bath and slowly add waier (8 L). Stir for 15 min, then separate the layers.. Extract the aqueous layer with additional CH2Cl?- Combine the organic phases WO 1008/0^562 PCT/US2007/084812 and wash with saturated NaHCOj (3 L). Dry and concentrate the organic solution to obtain 1370 g(l05%) of the title compound as a colorless oil. Use the material as-is in me next reaction without further purification. ES/MS m/z ("CI) 235 [M-l ]". Step 2: 2-(4-Chloro-phenyl>4-elhoxycarbonylmethyl-thiazole-5-5 curboxylic acid ethyl eiter Dissolve 2-thlaro-3-oxo-penlancdioic acid diethyl ester (1370 g, 5.50 mol) in EtOH fS-5 L) and add 4-chloro-thiobenzamidc (885 g, 5.00 mol), Heat the mixture to 75 °C and S(if mechanically for 5.5 h. Cool the mixture to 45 °C, then slowly add water (3.5 L) and -thia7ole-S-carbonyl}-umino}-2-methQxy-plienoxy)-azetidine-]-c9rbaXylic acid wrf-butyl ester Charge to a llask under an inert atmosphere a 2 M THF solution of lithium 2 0 borohydride (1140 mL, 2280 mmol) and apply ice bath cooling. Meanwhile in a separate vessel dissolve 3-(4-{[2-(4-cliloro-phcnyl)-4-mcthoxycarbonylmethyl-tlua7,ole-5-carbonyl]-aminu}-2-methoxy-phenoxy)-azelidine-l-carboxylic acid /en-butyl ester (2058 g, 3500 mmol) in THF (12.35 L). Agitate until complete dissolution is obtained. Transfer this solution to an addition funnel and begin the slow stream addition to the 25 reducing agent. Once the addition is complete, remove the ice bath and stir for 30 - 90 mill. Quench the reaction by adding acetone (407 g, 7008 mmol). Stir at ambiem temperature for 30 min and add ethyl acetate (8230 mL) with water (8230 mL). Separate the layers and wash the upper organic layer a second time with water (8230 mL) followed by 5% brine (K230 mL), Distill off the solvent until <5% solvent composition is THF, by 30 adding EiOAc as needed. Reduce the volume of the slurry to 6200 mL and add heptane (2050 mL). Allow the slurry to slowly cool back to room temperature, filer the WO 2008/0765 560 [M+-1 y. Step 7:3-{4-[2-(4~ChIoro-phenyl)-»-oxo-4i/-thi2olo|S,4-c]pyridine-5-yi]-2-methoxy-phcnoxy}-a/,etidme-l-carboxylic acid tert-butyl ester b Charge lo the reaction vessel 3-(4-t[2-(4-chloro-pheiiyl)-4-(2-hydroxy-ethyl)- thiazolc-5-carbonylJ-amino}-2-mcthoxy-phenoxy)-azetidirte-l-carboxylic acid tert-butyl ester (2520 g, 4499 mmol), DMSO (5040 ml), and trteihylamine (1932 g, 18901 mmol). Cool the brown slurry to 15 °C. In a separate vessel, dissolve sulfur trioxidc-pyridine complex (2923 g, 17997 mmol) in DMSO (12,6 L). Add slowly the SO,,-pyridinc solution 10 to the reaction mixture in such a manner as to keep any exoihcrm below 22 "C. When the addition is complete heat the reaction to 65 T. for 16 h After completion of the reaction maintain the temperature at 65 °C and add water (17.64 L) in a slow to moderate stream. Stir (be resulting slurry at 65 °C for 90 min and filter off the crude product without cooling. Rinse the crude cake twice with water, then give the wet cake a displacement 15 wash with ice cold methanol. Pull dry the MeOH wet cake for 30 min and then return it to the reaction vessel and slurry in methanol (20.16 L). Heat to 65 °C for 10 min, slowly cool buck to room temperature, filter, wash with methanol, and dry to constant weight in a vacuum oven at 40 °C to obtain 2192 g (90%) of the title compound. ES/MS m/z (3SCl) 484 [M-zen+lf. 20 Step8:5-14-(Azetidin-3-yloxy)-3-methoxy-phenylJ-2-(4-chloro-phenyl)-51I-tlnazolo|5,4-cJpyridiii-4-one, hydrochloride salt To a reaction vessel charge 3-{4-[2-(4-chloro-phenyl)-4-oxo-4//-thizolo[5,4-f.']pyridine-5-yl]-2-metrioxy-phenoxy}-a2etidine-1-carboxylic acid tert-butyl ester (5.00 g, 9.26 mrnol) and n-propanal (100 mL) and stir as a thin slurry. Add 37% HCI(2.0mL, 25 23,2 nimol) at room temperature in one portion and heat to 65 °C for 16 h. Remove from heat and cool to room temperature. Filter and rinse with n-PrOH (10 mL) to obtain an off-white solid. Dry the filter cake in a vacuum oven at 45 °C to constant weight to obtain 4.216 g (96%) of the title compound. ES/MS m/z (35C1) 440 [M+l]\ Step 9: 2-(4-Chloro-phenyl)-5-13-methoxy-4-(l-methyl-azetidin-3-yloxy)-phenyl)-5H- 30 thiiuolo[5,4-cJpyridiii-4-one Combine methanol (480 mL), 3-{4-[2-(4-chlorO-phcnyl)-4-oxo^l//-thizolo[5,d-c]pyridine-5-yl]-2'mcthoxy-pheuoxy}-a2Ctidine-l-carboxylic acid ter/-butyi ester (60.00 WO 200W076562 PCT/US2Q07rtl84R12 g, lll.l mmol), and chloroform (480 mL). To this solution add slowly 35% aqueous HCI (28.4 g, 277 mmol). Heat the reaction mixture to 50 °C for 15 h. Cool the reaction mixture lo 10 °C. A thick slurry arises around 35 °C. Once at 10 °C, add formaldehyde (27.33 g, 333 mmol) and the thick slurry becomes thinner while stirring for 2.5 h. Add sodium tnacetoxyborohydride (76.53 g. 361 mmol) in three equal portions and warm the reaction mixture to room temperature. Charge sodium carbonate solution lo the reaction until pH = 8.1 and allow the layers to separate. Wash the organic layer with waier (300 mL). Distill off the solvent until die solution volume is 240 mL and add back ethyl acetate (240 mL) to obtain a nice slurry. Cool reaction to Toom temperature and filter Rinse with ethyl acetate (180 mL), and dry to constant weight under vacuum at 50 °C to oLilum 45.57 g (91%) of the title compound. ES/MS m/z (35CI) 454 [:VM ]'. Step 10: 2-(4-Chloro-pheny|)-S-[3-methoxy-4-(l-methyl-azetidin-3-yIoxy)-phtnyl|-5H-thia/.olo[5,4-c|pyridin-4-one, fumarate salt Dissolve fumaric acid (59,41 g, 0,5118 mot)methane l/wacer (1900 mL.l/l) by heating to 60 "C. In a separate vessel dissolve 2-(4-chloro-phcnyI)-5-[3-methoxy-4-{ I -mcthyl-a2ctidin-3-yloxy)-phenylJ-5H-thiazolo[5,4-c]pyridin-4-onc (200.0 g, 0.4406 mol) in methanol (2000 mL) and heat to 65 °C. Add fumaric acid solution hot as quickly as possible. Allow the lemperature to recover to 65 eC and hold for 15 mm. Cool to 25 "C at 0.25 "C/min and hold for one hour. Filter and wash the reactor twice with methanol (100 mL), and rinse the filter cake twice with methanol (250 mL) each. Dry under vacuum at 40 °C until constant weight to provide 223 g (89%) of the title compound. Preparation 33 3,4-Dinuoro-thiobenzainide Dissolve 3,4-difluorobenzamide (4.95 g, 31,5 mmol) in diethyl ether (70 mL) and cool the mixture to 0 °C. Add phosphorus pentasulfide (7.0 g, 31.5 mmol) and warm the mixture lo room temperature overnight. Filter the mixture and concentrate the filtfatc to obtain 55 g (100%) of a yellow solid. 'H NMR (300 MHz, DMSQ-d6) S: 9.99 (bs. 111). 9.54 (bs, 1H), 7.89 (m.lH), 7.75 (m, 1H), 7.46 (m, lH). Prepare the thiazolo-pyridone compounds in the table below, using 4-trifluoromcthyl-ihiobenzamide and 3,4-difluoro-thiobcnzamide, by essentially following the procedures in the alternate route of Example 5b, Steps 1 to 7. WO 2008/076562 PCT/VS2O07/0H4H\2 Prtparalion 36 5-t4-(Aieiidin-3-yloxy)-3-mcihoxy-phcnyl]-2-('i-trinuoromcthyl-phcnyl)-SH- thia2olo[5,4-c]pyridin^-onc 5 Dissolve 3- {2-mtitho)cy-4-[4-oxo-2-(4-trifliior(jmethyl-phenylHH-(hia2Qlof5,4- c]pyridin-5-yl]-phenoxy)-&zetidine-l-carboxylic acid tetf.butyl ester (1.3 (J, 2.27 mmol) in dichloromethane (12 mL) and slowly add irifluoroacetic acid (6 mL). Slir the mixture for one hour and then evaporate. Apply the residue to a lOgSCX column with dichloromethane. Wash the column with methanol thtri etute the materia] using 1:1 10 dicliloromclhanc:2N ammonia/mcthanol. Concentrate to give 0.909 g (85%) of the desired product as a white solid. MS/ES m/z 474.0 [M+l]*. Prepare the free amine compound in the table below by essentially following the procedure in Preparation 36. Prep Product (Chemical name) ES/MS/m/z 37 5-l4-(Azctidin-3-y]oxy)-3-melhoxy- phcnyl)-2<3,4-difluoro-pheny]>$H- thiazolQtSAclpyridiri^-onc 442.0 [M-Hf lb WO 2008/076562 POYU52007/084H12 10 Example 6 5-f4-(I-CycJobutyl-azeridm-3-yIox)')-3-iiiethoxy-phenyI{-2-(4-trinuorometfiyl- pherty])-5II-thiazolo[S,4-c|pyridiil-4-one Dissolve 5-[4-(azetidin-3-y]o)£y)-3-methoKy-phenyl]-2-(4-trif|uoromclhyl-phenyl)-5H-thiazolo[5,4-c]pyridin-4-one (0.909 g, 1.92 mmol) in dichloro ethane (25 mL) and add cyclobulanone (0.502 mL, 6.72 mmol). sodium triaccloxyborohydride (0,814 g, 3.84 mmol), and acetic acid (0.22 mL, 3.84 mmol). Stir the mixiure overnight, add saturated sodium bicarbonate, and extract with dichloromethane (3*). Dry the mixture using sodium sulfate, fitter, and conctnlrate. Purify via silica gel cniomaAography using a 0-4.5% gradient of 2N ammonia in mcthaiiol/mclilarornetharic to give 0.400 j> (¥)%) of the desired product. MS/ES m/z 52K.0 [M+l ]~. Prepare the compounds in the tabic below by essentially following the procedure in Example 7 using the appropriate ketone. 15 Example 9 2-(4-Chloro-phenyl)-.V{3-metlioxy-4-ll-(tetrohydro-pyrfln-4-yl>a/etidin-3-yloxyI-phenylj-5H-thiazolo|S,4-c|pyridin-4-one, hydrochloride salt WO 2008/0765*2 PCT/llSluu7/u8<811 Suspend 5-[4-(zzetidin-3-y!oxy)-3-methoxy-phenyl]-2-(4^cliloro-plienyl)-5H-thiazolo[5,4-c]pyiidiii-4-one (50 mg, 0.I1 mmol) in MeOH (5.68 mL). Add tctrahydrr> 4H-pymn-4^onc (15.7 nL. 0.17 mmol) and acetic acid (9.8 uL, 0.17 mrnol) and siir at room temperature for 10 min. Add sodium cyanoborohydridc (7,1 mg, 0.11 mmol) and sur fit room temperaiure for 6 h. Add dichloromethane to the reaction mixture to dissolve the solid material. POUT onto a 2 g SCX2 ion exchange column wet with MeOH and elute under gravity. Elute SCX cartridge with MeOH (approximately 3 volumes) under reduced pressure and discard. Elute SCX cartridge with 7N NH3 in MeOH:dichloromethane (1:1) (approximately 5 volumes) under reduced pressure and then concentrate in vacuo. Dissolve the resultant solid in dichloromethane (5 mL) and add 4 N HC1 in dioxanc solution (25 uL). Evaporate the solvent and suspend (he solid in water. Frcezc-dry to give (51 mg. 83%) of the title compound as a while solid. ES/MS rn/2["C])524[M+lJ+. Prepare the compounds in the table below, Examples 10 to 17, by essentially following the procedure in Example 9 using the appropriate aldehyde or ketone. WO 2(108/076562 PCT/US?007/fl848]2 10 Dissolve 2-{4-chloro-phenyl)-5-[3-mcthoxy-4-(|-mcthyl-azctidin-3-yloxy)-phejiyl]-5H-thiazolo[5,4-c]pyridin-4-onc (402 mg, 0.886 mmol) in CH3CI2 (9 mL) and cool toO°C. Treat the soluiion wilh m-chloropcroxybenzoic acid (190 my, 1.10 mmolcs). Slir the solution at 0 °C for 30 ttiin and then collect the precipitate by filtration and wash wilh additional CHzCh (approximately 10 mL) and dry in vacuo. I'urify the WO 2008/076562 PCT7US2007/084812 mixture of N-oxides (cis & trans) by flash chromatography, elutmg with 25% MeGH (2N NH3)/ CH2CI1 to give pure stereoisomer 1 (220 mg), Concentrate the filtrate from above and purify by flash chromatography, eiuiing with 25% MeOH (2N NH3)/ CH2CI2 to give pure stereoisomer 1 (110 mg) and pure stereoisomer 2 (47 mg). Combine and triturate 5 isomer 1 materials with ether, then dry under vacuum to give 320 mg. Triturate isomer 2 whh ether, then dry under vacuum to give 16 mg. Isomer I; ES/MS m/z(3Sd)470 [M+l]f; Example |8a. Isomer 2; ES/MS m/z (JiCl) 470 [M+l]+; Example 18b. 10 Examples 2-(4-Chloro-phcnyl)-5-{4-(l-(2t2-difluoro-tthyl)-a2etidin-3-yIo.\y]-3-incthoxy-phenyff-SH-thiai[olo[5,4-c|pyridin-4-one, hydrochloride salt Dissolve N-methy-N-methoxydifluoroacetamidc (1.0 mL, 6.97 mmol) in dry IMF (617 mL), Chill the solution to 0 °C and add diisobuTylaluminium hydride (1.39 mL, 15 !.39 mmol). Stirfor one hour or until complete by TLC (1:1 EtOAc/hexanc, KMnO* stain used to detect non uv aldehyde formation). Add 5% HCl/EtOH solution to the reaction mixture and extract with 1:1 CHjClj/EtiO. Combine the organic layers and wa--;h with brine. Dry and filter with NajSCv Concentrate to minimal amounts of organic solvent. (Note: do not dry aldehyde due to low molecular weight and possible high 20 volatility). Add the aldehyde solution to a suspension of 5'[4-(azclidin-3-yloxy)-3-mcthoxy-phenyO-S^A-chlorD-phenylJ-SH-thiazolotS^-clpyridin^'One (350 mg, O.HOO mmol) in MeOH (2.65 mL). Add acetic acid (0.227 mL, 3.98 mmol) and stir vigorously. Add sodium cyanoborohydride (131.5 mg, 2.0 mmol). Stir Overnight at room temperature. 25 Add saturated NaHCOj solution (10 mL), stir for 30 min, and then extract with CH2CU (2 * 10 mL). Dry, filter, and concentrate the organic solution. Purify the crude material by flash chromatography, using 0-10% MeOH (2M NHiVCHiClj as cluent, to give a white solid. Rcdissolve in CHCb and add HCl/Et30 (0.320 mL). Filter the HCt salt to give 177 mg (41 %) of the title compound, ES/MS m/z (3iCI) 504.0 [M+1 ]+. 30 Example 20 WO 2008/076562 PCl7US2007/Gtf4812 2-(4-Chloro-pht;nyJ>-5'(3-methoxy-4-|l-(3,3,3-triiluoro-propy])-azelidiii-3-yloxyl-pheny]]-5H-thiazolo!5,4-c|pyridin-4~oiie, hydrochloride suit Add 3,3,3-trifluoropropanal (120 mg, 1.06 mmol) to a suspension of 5-[4-(azctldin-3-yloxy)-3-methoxy-phenyl]-2-(4-ch)oro-phcny])-5H-lhia20lo[5,4-c']pyridin-4' 5 one (390 mg, 0,89 mmol) in MeOH (2.96 mL). Add acetic acid (0.254 mL, 4.43 mmol) and stir vigorously. Add sodium cyanoborohydridc (146.6 mg, 2.22 mmol). Stir overnight at room temperature. Add saturated NaHCOs (10 mL) and stir for 30 min. Extract the mixture widi CH3CI3 (2 x 10 mL). Combine the organic layer and wash with water (5 mL). Dry, filter, and concentrate Ihe organic solution. Purify the crude material 1G by flash chromatography, using 0-40%THF(l%NHi/MeOH) in heptane aselucnt, to give a white solid. Redissolve in CHCh and add HCl/Et30 (0.32 mL). Filter the HCl salt 10 provide 37 mg (7%) of the title compound. ES/MS m/z 536.0 (MC1) [M+l ]*. Prepare the compound in the tabic below by essentially following the procedure as described in Example 20. 15 Preparation 38 3-(2-Bromo-thia*ol-4-yl)-acrylic acid methyl ester Dissolve 2-bro mot hiazole-4-carb aldehyde (3.00 g, 15.62 mmol) in tctrahydrofuran (52 mL) and add methyl(triphcnylpho5phorarty]idcnc)acelate (5.33 g. 20 15.62 mmol). Stir the mixture overnight at room temperature. Dilute the mixture with water and extract twice using diethyl ether. Dry the combined organics over sodium sulfate, filter, and concentrate. Purify via silica gel chromatography using a 0-30% gradient of FJOAc/hcxanes to give 3.13 g (81%) of the title compound as a white solid. 25 Preparation 39 3-(2-Bromo-thia2o|-4-yl)-iicryu'c acid WO 2008/076562 FCT/US20Q7/084812 Dissolve 3-(2-bromo-lhiazol-4-yl)-acry]ic acid methyl ester (5.9 g, 23.78 mmol) in tetrahythofuran (48 mL) and add a solution of lithium hydroxide (636 ing, 26.16 mmol) in water (10 mL). Stir the mixture overnight. Extract the mixture with ethyl acetate and wash twice with water. Acidify the aqueous layer with IN HCl in water until 5 the mixture is at pH 3-4. Filter the resulting white solid, then wash the solid with ethyl acetate, followed by diethyl ether and then water. Dry the white solid to give 5.05 g (91%) of the desired materia!. Preparation 40 10 2-Bromo-5H-thia2olo(S,4-clpyridin-4-ane o Suspend 3-(2-bromo-thiazol-4-yl)-acryIic acid (2.00 g, 8.54 mmol) in dichloromethane (17 mL) and add oxalyl chloride (1.48 mL, 17.09 mmol) and 2 drops of dimemylformamide. Stir the mixture at room temperature for 2 h and evaporate. 15 Dissolve sodium azidc (1.67 g, 25.63 mmol) in water(12 mL) and acetone (12 mL) and cool loO°C. Dissolve the acid chloride in 1,4-dioxane (J2 mL) and add to the sodium anide. Stir the mixture for one hour at 0 °C. Dilute the mixture with water and extract three times wiih ethyl acetate. Dry the combined organic layers with sodium sulfate, filter and evaporate to give a yellow solid. 20 Heat Dowtherm® A (20 mL) to 230°C and add the yellow solid from above in dioxanc (12 mL). When the addition is complete, stir the mixture at 230 °C for one hour. Cool the mixture to room temperature and stir overnight. Dilute the mixture with diethyl ether, filter the resulting brown solid, and wash with diethyl ether three times. Dissolve the bulk of the solid with tctrahydrofuran and filter off the remaining brown materials. 25 Concentrate and purify via silica gel chromatography using a 0-10% gradient of methflnol/dichloromeihane to give 0.425 g (22% yield) of the title compound as a yellow solid, 'HNMR(300MHz, DMSO-d6) £ 11.95(138, lH),7(44(d. 1H, 7=7.1 Hz), 6.82 , (33 mg, ^■27 (imol) and then warm to 85 °C under an argon atmosphere. After 18 h, evaporate the mixture t0 a slurry. Dilute the mixture with water and stir for one hour. Filter and wash the Solids with diethyl ether, then water, and then diethyl ether again. Dry the solids at 0 rooni temperature overnight to give the desired material as a brown solid (0.214 g, 80%). lH NMR (300 MHz, DMSO-d6) $ U-7(bs, IH), 8.01 (d, 2H, J= 8.8 Hz), 7.42 (d, IHj * 6.7(m, 2H). 5 Prepare the thiazole pyridone in the table below by essentially following the Procedure as described in Preparation 41. Prep Product (Chemical Name) ES/MS m/z 42 4-{4-Qxo-415-dihydro-thiazolo[5,4-c}pyridin-2 -yfy-benzonitrite 254.0 [M+!]+ Preparation 43 benzylamide Dissolve 2,4-dimethoxybenzylamine (22.4 g, 134.0 mmol) in CH2C12 (300 mL) andc0ol toO "C, To the above solution, slowly add a solution oftrimethylaluminum (HO mL, 220 mmol'2 M in toluene) over 35 min while keeping the temperature below '0 °C?. Stir the resulting solution at room temperature for 45 min and then rc-cool to 0 °C Add 2-(4-chloro'pheny])-6,7-dihydro-pyrano[4J3-d]thia2ol-4-one (52.2 g, 120.6 mmol), then allow the resulting slurry to warm to room temperature and stir overnight Cool the reaction and carefully quench with saturated Rochellc's salt solution (300 mL) Qtfcr 30 min. Add CH2C13 (750 mL), water (400 mL) and diatomaceous earth (100 u) WO 2008/076562 PCT/US3007/0S4S12 and stir the mixture at room temperature for 30 min, then filter. Collect the solids and triturate with CH2Cla (i L) at 35 °C for 3 h, then filler. Concentrate the filtrate to obtain the title compound (32.2 g). Repeat the trituration step with the second solid cake and obtain an additional 20 g of title compound (90% total yield). 'H NMR (400 MHz, 5 DMSO-d6)J9.0l(brs, lH),7.96(d,2H,y-8.5),7.S7(d,2H,J=8.5),7.I5(d, 1H,J = 7.9), 6.57 (d, 1H, J- 2.6), 6.48 (dd, 1H, J= 2,6,8.5), 5.34 (tt IH, J- 4.3),4.34 (d, 2H, J - 6.6), 3.81 (s, 3H), 3.79 (m, 2H), 3.75 (s, 3H), 3.11 (t, 3H. J= 6.6). Preparation 44 10 2-(4-Chloro-pheiiyl)-S-(2,4-dimethoxy-benzyl)-5H-thiazolo|5,4-c|p>Tidin'4-ont' Mix 2-{4-chloro-phenyl)-4-{2-hyd[Oxy-ethyl)-thiazole-5-carboxyhc acid 2,4-dimetlioxy-bcnzylamide(l9.7g,45.5 mmol)with EtOAc (400 mL) and treat the resulting slurry with 1-hydroxy-!-oxo-lH-bcmzo[d][l,2]iodoxo].3-one (36.0g, 57.8mmol). Stir the mixture at 60 °C for 1.5 h. Add additional l-hydroxy-l-oxo-!H-bertzo(d][l,2]iodoxol-3- 15 one (18,0 g, 28.9 mmo]) and stir the mixture at 70 °C overnight. Cool the mixture io room temperature and then dilute with CH;CI; (600 mL). Filter the mixture and wash the solids with additional CH2Cb (3 *■ 500 mL), Wash the filtrate with NaHC03 (4 * 300 mL) and water (300 mL), Dry the organic portion, filter, and concentrate in vacuo. Purify the crude material by flash chromatography, using 0.5% McOH/CH3Clj as clueni, 20 togivc 13.1 g (70%) of the title compound as a light yellow-orange solid. 'HNMR(4Q0 MHz, CDC1?) SIM (d, 2H , J - 8.1), 7.50 (d, 1H, J = 7.4), 7.45 (d, 2H, J = 8.8), 7.38 (d, 1H, J- 8.8), 6.84 (d, 1H, y- 6.4), 6.46 (m, 2H), 5.16 (s, 2H), 3.84 (s, 3H), 3.78 (s, 3H). Preparation 45 25 2-(4-Chloro-phenyl)-5H-thiazolo|5,4-c|pyridin-4-one Mix2-(4-chloro-phenyl>5-(2,4-dimethoxy-benzyl)-5H-thiazolo[5,4-c)pyridin-4-one (24.6 g, 59.6 mmol) in trifluoroacetic acid (143 mL) and heat at 70 °C for 2 h. Cool the mixture to room temperalure and add water (325 mL) and saturated NaHCOi (710 mL) with stirring. Add acetone (180 mL) and stir the resulting slurry for one hour at 30 room temperature. Filter and wash the solids with water (110 mL) and then acetone (110 mL). Dry the solids in a vacuum oven at 60 °C overnight, Triturate the solids three times with CHjCN (700 mL) at 60 °C and filter. Dry the solids in a vacuum oven at 60 °C WO 2008/076562 PCT/IJS2007/084«i2 ovcmighi toobtainl8.3 g (117%) of the utle compound thai still contains salt impurities. lH NMR (400 MHz, DMSO-d6) S11.86 (s, IH), 8.12 (d, 2H , J = 8.2), 7.65 (d, 2H, J = 8.7), 7.49 (t, IH,y = 6.0), 6.91 (IH. J = 6,6). 5 Preparation 46 3-<4-Bromo-2-methoxy-phtnoxy)-azet!dine-l-carboxylic acid fcrrf-butyl ester Add sodium hydride (2.77 g, 60% w/w, 69,2 mmol) to a solution of 3-hydroxy-azetidine-1 -tarboxylic acid /err-buty] ester (10.9 g, 62,9 mmol) in dimethyl sulfoxide (100 mL). Stir the mixture for30min and then add 3-bromo-6-tluoroanisole (15.5 g, 10 75.5 mmol). Heat the mixture to 65 °C overnight. Coot the mixture to room temperature and then dilute the solution with saturated ammonium chloride and brine and extract with ethyl acclfltc. Wash the organics five times with brine, then dry over sodium sulfate and filter Concentrate and purify via silica gel chromatography using a 0-45% gradient of eiliyl aCetate/Ttexane to give 10.4 g (46%) of the title compound as a clear oil. Preparation 47 3-(4-Bromo-2-mcthoj:y-phcnOxy)-azetidine Dissolve 3-(4-bromo-2-melhoxy-phenoxy)-a2;elidine-1-carboxylic acid wn-butyl ester (2.9 g, 8.10 mmol) in dichluromethane (45 mL) and slowly add triftuoroacctic acid 20 (15ml.). Stir the mixture for one hour and then evaporate. Apply (he residue to two 10 g SCX columns with methanol. Wash the columns with methanol, then elute the material using 2N arnmonia/mcthanol. Concentrate to give 2.09 g (88%) of the title compound as a clear oil. 25 Preparation 48 3-{4-Bromo-2-methoxy-phenoxy}-l-cyclobutyl-azetidine Dissolve 3-(4-bromo-2-mcthoxy-phcnoxy)-azetiditte (1.84 g, 7.13 mmol) in dichloroethane (80 mL). Add cyclobutanone (1.86 mL, 25 mmol), sodium triacetoxyborohydride (3.02 g, 14.3 mmol) and acetic acid (0.82 mL, 14.3 mmol). Stir 30 the mixture overnight, then add saturated sodium bicarbonate and extract three limes using dichloromethane. Dry the combined organic portions over sodium sulfate, filter, WO 2008/076562 PCmiS2G07/(KU8l2 and concentrate. Purify by silica ficl chromatography using a 0-3% gradient of mclhanol/dichloromethane to give 1.26 g (56%) of the title compound. Prcparathit 49 5 3~{4-Bromo-phetioxy)-azetidine-l-carboxyItc acid tert-bvtyl ester Combine I -bromo^fluorobcnzcnc (10.1 gt 577 mmol) and tert-buty\ 3-hydroxyazetidine-1 -carboxy]ate (5.0 g, 28.9 mmol) in THF (144 mL) and stir at room temperature. Add slowly potassium tert-butoxide (75.7 mL, 57.7 mmol, 1M in THF). Heat the mixture at 70 °C for 4 h, Monitor the reaction completion via gas 10 chromatography. Cool the mixture to room temperature and quench with water. Dilute the mixture with ether. Wash the organic purtion with saturated NH^Cl. Back extract the aqueous with ether. Dry the combined organics with NajSQ*, filter, and coaccntrate. Purify the material by flash chromatography using 5-10% EtOAc/homncs to give 1.84 g (19% yield) of the title compound as a white solid. 15 Example 11 5-|4-(l-Cyclobutyl-azi(tidin-3-yloxy)-3-methoxy-phenyll-2-(4-cyclopropox>'-phenyl)-5H-thiazoloI5,4-c}pyridin-4-one Suspend 3-(4-bromo-2-methoxy-pheiioxy)-l-cyclobutyl-azetidine (0.233 g, 0.746 20 mmol), 2-(4-cyclopropoxy-phenyl)-5H-thia2olo[5,4-c]pyridin-4-one (0.212 g, 0.746 mmol), cesium carbonate (0.486 g, 1.49 mmol), and 1,4-dioxane (5 mL) in a flask. Sparge with subsurface nitrogen for 15 min. Charge this mixture with copper (1) iodide (0.057 g> 0.298 mmol) followed by sym-di methyl ethylene diamine (64 JJL, 0.596 mmol). Heat the mixture to 110 °C under nitrogen overnight. 25 Bring the reaction to room temperature and dilute with water followed by ammonium hydroxide. Extract the mixture using dichloromethane (3*). Dry the combined organics using sodium sulfate, filter, and concentrate. Purify the material by Hash chromatography using 4.5% MeOH (2N NHjyCH2Cl2 to give S3 mg (22%) of the title compound as a white solid. MS/ES m/z 516.0 [M-t-lJ*. 30 Prepare the thiazole pyridone in the table below by essentially following the procedure as described in Example 22. WO 2008/076562 PCTYUS2(K)7/084IJ12 Add 37% aqeuous HC1 (0.25 mL, 2.94 mmol) to a solution of «#v-butyt 3-(4-(2-(4-chlorophciiyl)-4-oxolhiazolol.5,4-c]pyridin-5(4H)'yl)phenQxy)azctidine-l-carbQxylatc (0.5 g, 0.98 mmol) in methanol (20 mL). Heat the mixture at 50 *C for 2 h. Cool the mixture to 10 °C and then add 37 % formaldehyde (0.37 mL, 4.98 mmol) followed by 3 0 Sodium triaceroxyborohydride (1.3 g, 5,88 mmol). Stir the mixture ai room temperature for 2 h. Dilute the mixture wiih dichloromethane. Wash with saturated NajCOi solution and water Dry the organic portion over NazSCu, filter, and cOncciilraie. Purify the crude material by flash chromatography, using 5-10% MeOH/CHaCb as elueni. Dissolve the solid product in dichloromethane, Add butanedioic acid (1 cq). Stir 15 the solution for 15 min and then concentrate to dryness. Filter the solid with ether to give 0.14 g (26%) of the title compound. ES/MS m/z ("Ct) 424 (M+J J*. WO 2008/076562 PCT/IJS2007/084812 Preparation bl 5_(4.(azetidin-3-y)oxy)phenyl)-2-(4-chloropheiiyJ)thia2Dlo(St4-c]pyridin-4(5If)-onc Add 37% aqueous HC1 (0.25 mL, 2.94 mmol) to a solution of ten-butyl 3-(4-(2-(4-chlorophenyl)-4-o)tothiazolo[5,4-c]pyridin-5(4H)-yl)pl]enoxy)azetidine'l-carboxylate 5 (0.5 g, 0.98 mmol) in methanol (20 mL) and chlorofonn (20 mL). Heat the mixture at 50 °C for 2 h- Coo) the mixture to room temperature and dilute with dichloromcthanc. Wash the mixture with saturated Na2C03 solution and water. Dry the organic portion over N^SCu, filter, and concentrate to give 0.44 g (97%) of the title compound. ES/MS m/z(3SCI)4IO[M+l]10 Example 25 2-(4-clilorQ^nenyl)-SK4K*^yclo^uly^'«tWiii-3-ylo!i^)phei\yl)thiay.olQ[5,4-cjpyridin- 4(5H)-one, hydrochloride salt Add cyclobutanonc (0.4 mL, 5.4 mmol) to a solution o( 5-(4-(azciidin-3- 1 b yloxy)chenyl)-2-(4'Chlorophenyl)thiazolo[5,4-c]pyridin-4(5H)-one (0.44g, 1,08 mmol) in methanol (54 mL) and acetic acid (0.31 mL, 5.4 mmol). Stir the mixture at room temperature for one hour, add sodium triacetoxyborohydridc (1,4 g, 6.48 mmol) and continue stirring at room temperature overnight. Dilute the mixture with dichloromethane, then wash with saturated NaHCCh solution and water. Dry the organic 20 portion over Na2S04, filter, and concentrate. Purify the crude material by flash chromatography, using 0-10% MeOH/CHjC^ as clucnt. Dissolve the solid with dichloromethane and add 1 MHCl/ether(leq). Stir the solution for 15min. Concentrate the solid and filter with ether to give 0.31 g (58%) of the title compound. ES/MS m/z, (iSCI)464[M+l]+. 25 Example 26 5_[4^{Azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4-cliloro-phenyl)-617-dihydro-5H- thiazolo|5,4-c]pyridin-4-one Dissolve 3-{4-[2-(4-chloro-phcnyl)-4-oxo-6,7-dihydro-4H-thiazolo[514-cjpyridin-30 5-y|]-2-methoxy-plienoxy}-azctidine-l-carboxylicacid«n-butyl ester (2.71 g, 5.00 mmol) in CHjCh (20 mL). Add trifhioroacetic acid (5.88 mL, 77.79 mmol). Stir at room tempcrfl'ure for one hour and then add 5 N NaOH to pH *= 8-10. Collect a white/yellow WO 2008/076562 PCIYUS2007/0S4812 precipitate via vacuum filtration, and wash the solid with ElOAc followed by Et20. Dry the solid overnight in vacuo at about 50 °C to give 2,2\ g (>99%) of the title compound. ES/MS m/z (JSC1) 442.0 [M-H]+. Example 26a S-^^Azetidin-S-yloxy^we^o^y-phenylJ-l^chloro-phenyl^^-diliydro-SH- thiazolD[5,4-cipyridin-4-one, hydrochloride salt Dissolve 3-{4-(2-(4-cf!loro-phcnyt)-4-oxo-6>7-Jihydro-4H-tInazolof5,4-clpyridin-5-y]]-2-methoxy-phcnoxy}-azetidinc-l-carboxylic acid terr-butyl ester (3.33 g, 6.16 mmol) in CHjCh (21 mL) and add trifluoroacctic acid (7.25 mL). Stir for one hour at room temperature and then add 1 N NaOH (o adjust to pH = 8-10. Extract with ElOAc (3 * 50 mL) and wash with water (2 * 50 mL). Collect art off-white solid via vacuum filtration (2.15 g. 79%). Rc-dissolvc a portion of the crude material (300 mg, 0.6H mmol) in CHCh and add 4 N HCl/dioxane solution (about 200 uL). Remove the organic solvent via reduced pressure to dryness to give 316 mg of the titled compound. ES/MS m/z ( CI) 442.0 fM+»f, Prepare the free base lactam compounds in the table below, Preparation 52 to 55, by essentially following the procedure as described in Example 26. 29 MAY 2009 WO 2008/070562 PCT/US1007/O848U Example 27 2i4-Chloro-phenyl)-5-|3-methoxy-4-(l-methyl-azetidin-3-yloxy)-phenyl|-6,7- dihydr&-5H-thiazolo|5t4-clpyridin-4-one s Mix5-[4-(azc[idin-3-yloxy)-3-met}iojcy-pheny]]-2<4-chloro-pheny))-6,7-dihydro- 5H-tn'a2olo[5,4-c]pyridin-4-one (3.1 g, 7.01 mmol) with anhydrous McOH (100 mL) and solulio,, jn water). Stir the mixture at room temperature for 30 min and then treat with sodiuir, cyanoborohydridc (1-3 g, !9.6 mmol). Stir the mixture at room temperature 10 uvemitjht an(j concentrate in vacuo. Partition the resulting residue between CH3C|j (100 mL) arl(j saturated NaHCCh (100 mL). Remove the organic solution and extract the aqucoiis pnase wjth additional CHjClj (2 * 100 mL). Combine the organic solutions and wash v^h water (50 mL), then dry, filter, and concentrate in vacuo. Purify the crude mmcriy by flash chromatography, using 8% MeOH (2M NH3)/ CH?Cl2 as eluent, to give 15 1.6 g (50%) of the title compound as a yellow solid. ES/MS m/z ("CI) 456 [M+1 ]'. WO 2008/076562 PCT/US2007/084812 Example 27a 2-(4-Ch[oro-phenyl)-5^3-methoxy-4^1-mMhyl-Dzetidiii-3-yloxy)-phenyl|.6,7- dihydro-5H-lhiflzolo[S,4-cIpyridin-4-one, hydrochloride suit Dissolve 2-(4^chloro-phenyl)-S-[3-meihoxy-4-(l-methyl-azctidin-3-yloxy)-5 phenyl^-e^-dihydro-iH-thiazoIofJ^-clpyridin^-one (2.1 g, 4,6 mmol) in ClfcClj (25 mL) and treat with 4.0 M HCI (1.3 mL, 5.2 mmol, solution in diethyl ether). Stir the solution for 10 min. Add additional diethyl ether (25 mL) and isolate the precipitate by filtration. Wash the solid with dielhyl ether and dry under vacuum to give 2.08 g (92%) of the title compound, ES/MS m/z (3SC1) 456 [M+1 ]10 Example 2H 2-(4-Chloro-phenyl)-5-14-(Nisopropyl-a7etidin-3-ylnxy)-3-methQxy-phenyl]-6,7- dihydro-5lI-thia7.olo(5,4-t|pyridin-4-flne, hydrochloride salt Dissolve 5-[4-(azctidni"3-y)oxy)-3-mcthoxy-phenylJ-2-(4-chloro-phcnyl)-6,7-15 d(hydro-5H-thiazo[o[S,4-cJpyridm-4-Qne(I.0g, 2.26 tnraol) and acetone (250 nL, 3.39 mmol) in dry 1,2-dichloroethane. Add sodium triacctoxyborohydride (1.0 y, 4.53 mmol) and stir overnight a! room temperature, Add I N NaOH solution to (he reaction mixture and extract with CHjClj (2 * 25 mL). Combine the organic portions and wash with water (2 * 25 mL). Dry the organic layer with Na3S04, then filter, and concentrate in vacua. 20 Triturate the crude yellow solid with EtjO and filter. Wash the solid with EtiG several times and re-dissolve in CHC13. Add 1 NHC1/Et20 solution (1.5 mL) and remove the solvent in vacuo to give 630 mg (53%) of the title compound. ES/MS nVz (iSCl) 484.2 [M+l]Prepare the compounds in the lahle below, Examples 29 to 35, by essentially 25 following the procedure as described in Example 28 using the appropriate free base and the appropriate aldehyde, respectively. Product ES/MS Ex (Chemical Name) nVz 2-<4-Chloro-phenyl)-5-[4'(l-cyclobutyl-azetidtn^- ("CI) 29 yloxy>3-mcthoxy^prienyl]-6,7-dihydro-5H- 496.0 thiazolo[5,4-c]pyridin-4-onc, hydrochloride salt [M+l]' WO 1O08W6561 PCT/US2M7JDB48U Example 36 l-(4-C W-a7.etfdro-5H-thiazoloi5,4-c}pyridin-4-one, hydrochloride salt Mix molecular sieves (60 mg, type 3A), 5-[4-(azetidin-.3_-yIoxy)-3-melhoxy-pheny]J-2-(4-chloro-phenyl)-6,7-dihydro-5H-thia2o!o[5,4-c]pyridin-4-one (1.00 g, 2.26 mmoles), [(l-emoxycyclopropy))oxy]trimcthylsilanc(685.2 uL, 3.39 mmoles). and acclic lG acid (648 u.L, 1131 mmofcs) in dry methanol (It. 4 mL). Reflux the mixture for 3 h. Cool the mixture to room temperature, add sodium cyanoboiohydride (300 rny, 4.53 (ninol) and slowly warm to 40 °C for I h, Cool the mixture and add I N NaOH solution Extract the aqueous layer with CHCIj (3 * 25 mL). Purify on HPLC, 4,6 « 150 mm KromasiKg) silica, Elueni: 40% THF/heptane 0.1%N,N*-dimcthylethylaminc, I mL/rnin. 15 Re-dissolve the material in CHClj and add 1 N HCl/Et20 solution (750 nL). Concentrate the solvent in vacuo lo give 375 mg (34%) of the litle compound. ES/MS mlz (1SC1) 482.2 [M+l]+. Example 38 20 2-(4-ClilorO'phenyl)-S-J3-metho]iy-4-ll-(3,3,3-trinuoro-prDpionyl)-5u.cUdin-3-yloxyt-phenyl}'6,7-dihydro-5H-thiazolo(5,4-clpyridin-4-one Dissolve 5-[4-(azetidin"3-yloxy)-3-methoxy-pheny]]-2^(4-chloro-phcnyl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-onc (100 mg, 0.226 mmol), and 3,3,3-irifluoropropionyl chloride (137 mg, 0,905 mmol) in dry pyridine (754.3 \iL). Add 4- 25 A1, W-dimethy [pyridine (2,9 mg, 0.0226 mmol) and stir the solution overnight. Add NaHSCu solution and extract with EtOAc (2 x 20 mL). Combine the organic portion? and wash with waler (10 mL). Dry the organic solution with NajSO*, filter, and concentrate in vacuo, Purify the crude material on silica gel chromatography, using an isoevwtic gradient of 80% EtOAc in hcxanes, to give 88 nig (70%) of the title compound 30 as a yellow solid. ES/MS nVz(3JCl) 552.8 [M-H]*. WECLAIM: I. A compound of formula wherein 5 " •' is absent or is optionally a bond; q is 1 or 2; R1 is independently selected from hydrogen, -CrC2 alkyl, halo, hydroxy, -C1-C2 haloalkyl, -CrC3 alkoxy, cyano, -O-C3-C4 cycloalkyl, and -OCi-C2 haloalkyl; R2 is selected from the group consisting of hydrogen, -C1-C3 alkyL hydroxy, -C,-C3 0 alkoxy, cyano, -C,-C2 haloalkyl, -OC1-C2 haloalkyl, and halo: R is selected from the group consisting of hydrogen, -C|-C4 alkyl. -CVO haloalkyl, -C2-C4 alkylOH. -CvCh cycloalkyl. -CH:C1-C6 cycloalkyl, -C2-C4 alkyl-O-C-d alkyl, -C(0)C1-C4 alkyl, -C(0)CrC4 haloalkyl, -CH2-thiazole, phenyl, benzyl, tetrahydrothiopyranyl, and tetrahydropyranyl, wherein the cycloalkyl, b tetrahydrothiopyranyl. tetrahydropyranyl and thiazolyl group is optionally substituted with one or two groups independently selected from the group consisting of halo, hydroxy. CV C2 alkyl, and -C1-C2 haloalkyl; or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof. 0 2. A compound according to Claim 1 wherein R1 is chloro. methoxy, cyclopropoxy, fluoro, or trifluoromethyl; q is 1 or 2; R2isH, -CNor-OCH3;and R3 is hydrogen, -CH3. -CH2CH?OH, -CH2CH2F, -CH2CHF2, isopropyl, cyclopropyl, 5 -CH2cyclopropyl, or cyclobutyl wherein the cyclopropyl or cyclobutyl group is optionally substituted with one or two groups independently selected from the group consisting of fluoro and methyl, or a pharmaceutical^ acceptable salt, enantiomer, diastereomer or mixture thereof, 30 3. A compound selected from the group consisting of: 5-[4-(azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4^chloro-phenyI)-5h-thiazolor5,4-c]pyridin-4-one, 2-(4-chloro-phenyI)-5-[4-(l-cyclQbutyl-azetidin-3-yloxy)-3-methoxy-phenyl]-5h-thiazolo[5,4-cJpyridin-4-one, 5 2-(4-chloro-phenyl)-5-[4-(l-cyclopropyl-azelidin-3-ybxy)-3-methoxy-phcnyll-5h-thiazolo[5,4-c]pyridin-4-one, 5-[4-(]-acetyl-azetidin-3"yloxy)-3-methoxy-phenyI]-2-(4-ch!oro-phenyl>5h-thiazolo[5,4-cJpyridin-4-one, 2-(4-chloro-phenyi)"5-f3-methoxy-4"(l-rnethyJ-azetidin-3-yloxy)-phenyl]-5h-10 thiazolo[5,4-c]pyridin-4-one, 5-[4-(azetidin-3-yloxy)-3-methoxy-phenyI]-2-(4-cliloro-phenyl)-6,7-dihydro-5h-thiazolo(5,4-c]pyrtdin-4-one, 2-(4-chloro-ph(;nyI)-5-l3-methoxy-4-(l-melhyl-azciidin-3-yloxy)-plicnyl|-6.7-diliydrQ-5h- thia/.oto(5.4-c]pyridin-4-one, i b 2-(4-chloro-phenyl)-5-f4-(l-isopi,opyi-azclidin-3-yk'>xyV3-mcthoxy-phenyl]-6.7-dihydrO' 5h-Thiazolo[5,4-c]pyridin'4-one; 2-(4-chloro-phenyl)-5-[4-( I -cycIobutyl-azetidin-3-yloxy)~3-methoxy-phenyl |-6.7-dihydro- 5h-thiazoJof5.4-c]pyrjdin-4-one; 2-{4-chloro-phenyl)-5-{3-methoxy-4-[]-(2-methoxy-ethyl)-azetidin-3-yloxy]-phenyl}-6.7-: 0 dihydro-5h-lhia?olo[5,4-cjpyridin-4-one; 2-(4-chlorophenyl)-5-{4-| l-(2-hydroxy-ethy|)-azetidin-3-yloxy]-3-methoxy-phenyl}-6,7- dihydro-5h-thiazolo|5,4-cjpyridin-4-one; 2-(4-chloro-phenyl)-5-[4-('-^yclc>propyl-azetidin-3-yloxy)-3-methoxy-phenyl]-6,7- dihydro-5h-thiazolo[5,4-c]pyridiiv4-one;and 2 5 2-(4-chloro-phenyl)-5-{3-methoxy-4-[l-(333-trifluoro-propionyl)-azeti(iin-3-yloxy]- phenyl}-6,7-dihydro-5lvthiazoiol5,4-c]pyridin-4'One, 4, The compound 5-[4-(azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4-chloro' phenyl)-5Il-thiazolo[5,4-c]pyridin-4-one or a pharmaceutical^ acceptable salt thereof. 5. The compound 2-(4-chloro-phenyl)-5-[4'(l-cyclobutyl-a^etidin-3-yloxy)-5 3-methoxy-phenyl]-5H-thiazolo[5,4-c]pyridin-4-one, or a pharmaceutically acceptable salt thereof. 6. The compound 2-(4-chloro-phenyl)-5-[3-mcthoxy-4~( I -mclhyl-azeiidin-3- 10 y!oxy)-phenyl]-5HHhiazolo[5,4-c]pyridin-4-one or a pharmaceutically acceptable salt thereof. 7, The compound 2-(4-Chloro-phenyl)-5-[4-(l-isopropyl-azetidin-3-yloxy)-3- 1S methoxy-phenyll-6,7-dihydro-5H-thiazolo|5,4-c]pyridin-4'one, or pharmaceutically acceptable salt thereof. 8. A pharmaceutical composition comprising a compound of any one of 20 Claims 1-15 and a pharmaceutically acceptable carrier and/or diluent. 9. A compound according to any one of Claims 1-7 or a pharmaceuticaliy acceptable salt, enantiomer, diastereomer or mixture thereof in the manufacture of a medicament. 10. Use ofa compound according to any one of Claims 1-7 ora -pharmaceuticaliy acceptable salt thereof for the manvifacture ofa medicament for treating, preventing or ameliorating diseases related to obesity including eating disorders, diabetes, diabetic complications, diabetic retinopathy, depression, and anxiety. Dated this 28th day of May. 2009 79 MAY 2009