 Synthesis for thiazolidinedione compounds
专利摘要:
The present invention provides novel methods for synthesizing PPARy sparing compounds, e.g., thiazolidinediones, that are useful for preventing and/or treating metabolic disorders such as diabetes, obesity, hypertension, and inflammatory diseases. 公开号:AU2011289627A1 申请号:U2011289627 申请日:2011-08-09 公开日:2013-02-21 发明作者:Gerald D. Artman Lll；Robert C. Gadwood；Scott D. Larsen；Timothy Parker；Steven P. Tanis；James R. Zeller 申请人:Metabolic Solutions Development Co LLC； IPC主号:C07D417-12
专利说明:
WO 2012/021467 PCT/US2011/046992 SYNTHESIS FOR THIAZOLIDINEDIONE COMPOUNDS CROSS-REFERENCE TO RELATED APPLICATION [0001] This PCT application claims the benefit of U.S. provisional application serial no. 61/372,269, filed on August 10, 2010, which is hereby incorporated by reference in its entirety. TECHNICAL FIELD OF THE INVENTION [0002] The present invention provides novel methods for synthesizing PPARy sparing compounds, e.g., thiazolidinediones, that are useful for preventing and/or treating metabolic disorders such as diabetes, obesity, hypertension, dyslipidemia, and inflammatory diseases. BACKGROUND OF THE INVENTION [0003] Over the past several decades, scientists have postulated that PPARy is the generally accepted site of action for insulin sensitizing thiazolidinedione compounds. [00041 Peroxisome Proliferator Activated Receptors (PPARs) are members of the nuclear hormone receptor super-family, which are ligand-activated transcription factors regulating gene expression. PPARs have been implicated in autoimmune diseases and other diseases, i.e., diabetes mellitus, cardiovascular and gastrointestinal disease, and Alzheimer's disease. [00051 PPAR is a key regulator of adipocyte differentiation and lipid metabolism. PPARy is also found in other cell types including fibroblasts, myocytes, breast cells, human bone marrow precursors, and macrophages/monocytes. In addition, PPARy has been shown in macrophage foam cells in atherosclerotic plaques. [0006] Thiazolidinediones, such as pioglitazone, developed originally for the treatment of type-2 diabetes, generally exhibit high affinity as PPARy ligands. The finding that thiazolidinediones might mediate their therapeutic effects through direct interactions with PPARy helped to establish the concept that PPAR is a key regulator of glucose and lipid homeostasis. However, compounds that involve the activation of PPARy, such as pioglitazone, also trigger sodium reabsorption and other unpleasant side effects. SUMMARY OF THE INVENTION [0007] In general, the invention relates to methods of synthesizing compounds that have reduced binding and activation of the nuclear transcription factor PPARy when compared with high affinity PPARy ligands such as pioglitazone and rosiglitazone. These novel methods are scalable for industrial production and employ safer, more stable, and/or less costly starting materials and process conditions. WO 2012/021467 PCT/US2011/046992 [0008] Compounds exhibiting PPARy activity induce transcription of genes that favor sodium reabsorption. Advantageously, the compounds produced by the syntheses of this invention have reduced binding or activation of the nuclear transcription factor PPARy when compared with traditional high affinity PPARy ligands (e.g., pioglitazone or rosiglitazone), and therefore produce fewer or diminished side effects (e.g., reduced augmentation of sodium reabsorption) that are associated with traditional high affinity PPARy ligands, and are therefore more useful in treating hypertension, dyslipidemia, diabetes, and inflammatory diseases. Moreover, the reduced PPARy binding and reduced activity exhibited by these compounds, as compared with traditional high affinity PPARy ligands, are particularly useful for treating hypertension, diabetes, dyslipidemia, and inflammatory diseases both as single agents and in combination with other classes of antihypertensive agents. As hypertension and inflammatory diseases pose major risk factors in the onset of diabetes and pre-diabetes, these compounds are also useful for the treatment and prevention of diabetes and other inflammatory diseases. In fact, compounds synthesized by the present invention may induce remission of the symptoms of diabetes in a human patient. [0009] One aspect of the present invention provides a novel synthesis for generating thiazolidine compounds that are useful for the treatment of metabolic disorders. This synthetic method is useful for preparing a compound of Formula I: 0 R2 O NH 0 I or a pharmaceutically acceptable salt thereof, wherein each of R, and R 2 is independently selected from H, halo, aliphatic (e.g., C 1 - 6 alkyl), or alkoxy (e.g., C 1 - 6 alkoxy), wherein the aliphatic or alkoxy is optionally substituted with 1-3 of halo; comprising the step of converting a compound of Formula 2A into a compound of Formula I R2 ONH SA NOR 3 wherein R 3 is hydrogen or an optionally substituted C 1 - 6 alkyl. In some embodiments, the compound of Formula 2A undergoes hydrolysis to generate a compound of Formula I. In some examples, the compound of Formula 2A is treated with an acid to generate the 2 WO 2012/021467 PCT/US20111/046992 compound of Formula I. In other examples, the compound of Formula 2A is treated with an acid and heat to generate a compound of Formula I. [0010] In some embodiments, R 3 is methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl, each of which is optionally substituted. In other embodiments, R 3 is methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl, each of which is unsubstituted. And, in some embodiments, R 3 is hydrogen. [0011] Some embodiments further comprise reacting a compound of Formula 3A with a compound of Formula 4A: HNH R HOO N 3A and 4A N-"OR3 wherein X 1 is a leaving group, to generate the compound of Formula 2A. In some " N I , 4A1X1 embodiments, the compound of Formula 4A comprises 4A1 N"OR 3 . In other X1 embodiments, the compound of Formula 4A comprises 4A2 N-OCH3. And in some N- Br embodiments, the compound of Formula 4A comprises 4A3 N"OCH 3 . [0012] Some embodiments further comprise converting a compound of Formula 5A R2 5A o wherein X, is a leaving group, to a compound of Formula 4A. In some embodiments, X, is a halo (e.g., Cl or Br) or triflyl group. [0013] In some embodiments, the compound of Formula 5A comprises N X1 5A1 0 3 WO 2012/021467 PCT/US2011/046992 wherein X, is Cl or Br. [0014] Some embodiments further comprise converting a compound of Formula 6A R 2 6A 0 to a compound of Formula 5A. For example, the compound of Formula 6A undergoes halogenation to generate a compound of Formula 5A. [0015] In some embodiments, the compound of Formula 6A comprises r I Ny 6A1 0 wherein R, is selected from a C 1 6 alkyl or C- 6 alkoxy, either of which is optionally substituted with 1-3 halo, and R 2 is -H or halo. [0016] In some embodiments, Ri is a C 1 - 6 alkyl optionally substituted with 1-3 halo. For example, R, is selected from methyl, ethyl, or propyl, any of which is optionally substituted with 1-3 halo. [0017] In some embodiments, the compound of Formula 6A comprises O 0* NCHO [0018] Some embodiments further comprise reacting the compound HOCH with 0 NH the compound S ; under condensation conditions to form a compound of Formula 3B 0 HO NH 3B 0 and reducing the compound of Formula 3B to generate the compound of Formula 3A. [0019] Another aspect of the present invention provides compounds that are useful in the methods of the present invention. One embodiment provides a compound of Formula 10A, 10B, or 10C 4 WO 2012/021467 PCT/US2011/046992 N OR 3 R, N OR 3 NOR3 N )X N X R NXA, XA ,or R 1 XA 1OA 10B 10C wherein Ri is halo, C 1 - 6 alkyl optionally substituted with 1-3 halo, or C 1 - 6 alkoxy optionally substituted with 1-3 halo; R 3 is hydrogen or unsubstituted C 1 . 6 alkyl (e.g., unsubstituted C14 alkyl); and XA is a leaving group (e.g., halo or triflyl) or hydrogen. [0020] Another aspect of the present invention provides a compound of Formula 10D, 10E, or 10F NOH R 1 NOH NOH )(N X R1 N XA , N XA or R 1 XA 10D 10E 1OF wherein R, and XA are defined above. [0021] In several embodiments, R 3 of Formula 10A, 10B, or 10C is hydrogen. In other embodiments, R 3 of Formula 10A, 10B, or 10C is methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl, each of which is unsubstituted. [0022] Another aspect of the present invention provides a compound Formula 11A-11M. N OR 3 N OR 3 N OR 3 N OR 3 NOR3 XA C XA F N XA I XA C XA .- N ,N KN C -, N 11A iB 11C ID 11E NOR3 NOR3 CI N'OR3 F N OR 3 N OR 3 - XA XA XA XA XA F N N -N KN 11F 1iG 1lH 11l 11J NOR3 N OR 3 NOR3 XA XA N XA C, F or 11K 11L 11M wherein XA is a leaving group or hydrogen and R 3 is hydrogen or C 1 . 3 unsubstituted alkyl. 5 WO 2012/021467 PCT/US2011/046992 [0023] In some embodiments, XA is a leaving group selected from -Br, -Cl, -I, -OMs, -OTs, -OTf, -OBs, -ONs, -0-tresylate, or -OPO(OR4) 2 , wherein each R4 is independently C 1 . 4 alkyl or two of R 4 together with the oxygen and phosphorous atoms to which they are attached form a 5-7 membered ring. In other embodiments, XA is hydrogen. [0024] Another aspect of the present invention provides a compound of Formula 2A 0 R20 NH R 3 0,N 2A wherein each of R 1 , R 2 , and R 3 is defined above. For example, in one embodiment, the compound of Formula 2A comprises 0 0 0 H N H~ R20 2 O NH3'N HO, N 2A1 H3CO' 2A2 or [0025] And, another aspect of the present invention provides a compound selected from 0 0 NH NH N' S.J I I S- 1 O OR 3 'OR 3 O 0 O NH F NH N"OR3 N OR3 C1 0 F O O NH O NH NI NH O NH -o S-- NO N , or N NOR3 NOR3 wherein R 3 is defined above. 6 WO 2012/021467 PCT/US2011/046992 DETAILED DESCRIPTION [00261 The present invention provides novel methods for preparing thiazolidinedione compounds having reduced PPARy activity and compounds useful in these methods. [0027] As used herein, the following definitions shall apply unless otherwise indicated. [0028] I. DEFINITIONS [0029] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which arp hereby incorporated by reference. [0030] As described herein, "protecting group" refers to a moiety or functionality that is introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction. Standard protecting groups are provided in Greene and Wuts : "Greene's Protective Groups in Organic Synthesis" 4th Ed, Wuts, P.G.M. and Greene, T.W., Wiley-Interscience, New York:2006. [0031] As described herein, compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. [0032] As used herein, the term "hydroxyl" or "hydroxy" refers to an -OH moiety. [0033] As used herein the term "aliphatic" encompasses the terms alkyl, alkenyl, alkynyl, each of which being optionally substituted as set forth below. [0034] As used herein, an "alkyl" group refers to a saturated aliphatic hydrocarbon group containing 1-12 (e.g., 1-8, 1-6, or 1-4) carbon atoms. An alkyl group can be straight or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl. An alkyl group can be substituted (i.e., optionally substituted) with one or more substituents such as halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino alkylaminocarbonyl, cycloalkylaminocarbonyl, 7 WO 2012/021467 PCT/US2011/046992 heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g., aliphaticamino, cycloaliphaticamino, or heterocycloaliphaticamino], sulfonyl [e.g., aliphatic-S0 2 -], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy. Without limitation, some examples of substituted alkyls include carboxyalkyl (such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (alkyl-S0 2 -amino)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl, or haloalkyl. [0035] As used herein, an "alkenyl" group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-12, 2-6, or 2-4) carbon atoms and at least one double bond. Like an alkyl group, an alkenyl group can be straight or branched. Examples of an alkenyl group include, but are not limited to allyl, isoprenyl, 2-butenyl, and 2-hexenyl. An alkenyl group can be optionally substituted with one or more substituents such as halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g., aliphaticamino, cycloaliphaticamino, heterocycloaliphaticamino, or aliphaticsulfonylamino], sulfonyl [e.g., alkyl-S0 2 -, cycloaliphatic-S0 2 -, or aryl-S0 2 -), sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy. Without limitation, some examples of substituted alkenyls include cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl)alkenyl, (sulfonylamino)alkenyl (such as (alkyl-S0 2 -amino)alkenyl), aminoalkenyl, amidoalkenyl, (cycloaliphatic)alkenyl, or haloalkenyl. [0036] As used herein, an "alkynyl" group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-12, 2-6, or 2-4) carbon atoms and has at least one triple bond. An alkynyl group can be straight or branched. Examples of an alkynyl group include, but are not limited to, propargyl and butynyl. An alkynyl group can be optionally substituted with one or more 8 WO 2012/021467 PCT/US2011/046992 substituents such as aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, sulfanyl [e.g., aliphaticsulfanyl or cycloaliphaticsulfanyl], sulfinyl [e.g., aliphaticsulfinyl or cycloaliphaticsulfinyl], sulfonyl [e.g., aliphatic-S0 2 -, aliphaticamino-S0 2 -, or cycloaliphatic SO 2 -], amido [e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (cycloalkylalkyl)carbonylamino, heteroaralkylcarbonylamino, heteroarylcarbonylamino or heteroarylaminocarbonyll, urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, alkylcarbonyloxy, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, acyl [e.g., (cycloaliphatic)carbonyl or (heterocycloaliphatic)carbonyl], amino [e.g., aliphaticamino], sulfoxy, oxo, carboxy, carbamoyl, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, or (heteroaryl)alkoxy. [0037] As used herein, an "amido" encompasses both "aminocarbonyl" and "carbonylamino". These terms when used alone or in connection with another group refer to an amido group such as -N(Rx)-C(O)-Ry or -C(O)-N(Rx) 2 , when used terminally, and -C(O) N(Rx)- or -N(Rx)-C(O)- when used internally, wherein RX and RY can be aliphatic, cycloaliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl or heteroaraliphatic.. Examples of amido groups include alkylamido (such as alkylcarbonylamino or alkylaminocarbonyl), (heterocycloaliphatic)amido, (heteroaralkyl)amido, (heteroaryl)amido, (heterocycloalkyl)alkylamido, arylamido, aralkylamido, (cycloalkyl)alkylamido, or cycloalkylamido. [0038] As used herein, an "amino" group refers to -NRxRY wherein each of Rx and RY is independently hydrogen, aliphatic, cycloaliphatic, (cycloaliphatic)aliphatic, aryl, araliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl, or (heteroaraliphatic)carbonyl, each of which being defined herein and being optionally substituted. Examples of amino groups include alkylamino, dialkylamino, or arylamino. When the term "amino" is not the terminal group (e.g., alkylcarbonylamino), it is represented by -NRX-, where RX has the same meaning as defined above. [0039] As used herein, an "aryl" group used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl" refers to monocyclic (e.g., phenyl); bicyclic (e.g., 9 WO 2012/021467 PCT/US2011/046992 indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g., fluorenyl tetrahydrofluorenyl, or tetrahydroanthracenyl, anthracenyl) ring systems in which the monocyclic ring system is aromatic or at least one of the rings in a bicyclic or tricyclic ring system is aromatic. The bicyclic and tricyclic groups include benzofused 2-3 membered carbocyclic rings. For example, a benzofused group includes phenyl fused with two or more C 4 . 8 carbocyclic moieties. An aryl is optionally substituted with one or more substituents including aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic ring of a benzofused bicyclic or tricyclic aryl); nitro; carboxy; amido; acyl [e.g., (aliphatic)carbonyl; (cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl; (heterocycloaliphatic)carbonyl; ((heterocycloaliphatic)aliphatic)carbonyl; or (heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphatic-S0 2 - or amino-SO 2 -]; sulfinyl [e.g., aliphatic-S(O)- or cycloaliphatic-S(O)-]; sulfanyl [e.g., aliphatic-S-1; cyano; halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, an aryl can be unsubstituted. [0040] Non-limiting examples of substituted aryls include haloaryl [e.g., mono-, di (such as p,m-dihaloaryl), and (trihalo)aryl]; (carboxy)aryl [e.g., (alkoxycarbonyl)aryl, ((aralkyl)carbonyloxy)aryl, and (alkoxycarbonyl)aryl]; (amido)aryl [e.g., (aminocarbonyl)aryl, (((alkylamino)alkyl)aminocarbonyl)aryl, (alkylcarbonyl)aminoaryl, (arylaminocarbonyl)aryl, and (((heteroaryl)amino)carbonyl)aryl]; aminoaryl [e.g., ((alkylsulfonyl)amino)aryl or ((dialkyl)amino)aryl]; (cyanoalkyl)aryl; (alkoxy)aryl; (sulfamoyl)aryl [e.g., (aminosulfonyl)aryl]; (alkylsulfonyl)aryl; (cyano)aryl; (hydroxyalkyl)aryl; ((alkoxy)alkyl)aryl; (hydroxy)aryl, ((carboxy)alkyl)aryl; (((dialkyl)amino)alkyl)aryl; (nitroalkyl)aryl; (((alkylsulfonyl)amino)alkyl)aryl; ((heterocycloaliphatic)carbonyl)aryl; ((alkylsulfonyl)alkyl)aryl; (cyanoalkyl)aryl; (hydroxyalkyl)aryl; (alkylcarbonyl)aryl; alkylaryl; (trihaloalkyl)aryl; p-amino-m alkoxycarbonylaryl; p-amino-m-cyanoaryl; p-halo-m-aminoaryl; or (m-(heterocycloaliphatic) o-(alkyl))aryl. [0041] As used herein, an "araliphatic" such as an "aralkyl" group refers to an aliphatic group (e.g., a C 1 4 alkyl group) that is substituted with an aryl group. "Aliphatic," "alkyl," and "aryl" are defined herein. An example of an araliphatic such as an aralkyl group is benzyl. 10 WO 2012/021467 PCT/US2011/046992 [0042] As used herein, an "aralkyl" group refers to an alkyl group (e.g., a CIA alkyl group) that is substituted with an aryl group. Both "alkyl" and "aryl" have been defined above. An example of an aralkyl group is benzyl. An aralkyl is optionally substituted with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl, including carboxyalkyl, hydroxyalkyl, or haloalkyl such as trifluoromethyl], cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido [e.g., aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, or heteroaralkylcarbonylamino], cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. [0043] As used herein, a "bicyclic ring system" includes 8-12 (e.g., 9, 10, or 11) membered structures that form two rings, wherein the two rings have at least one atom in common (e.g., 2 atoms in common). Bicyclic ring systems include bicycloaliphatics (e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatics, bicyclic aryls, and bicyclic heteroaryls. [0044] As used herein, a "cycloaliphatic" group encompasses a "cycloalkyl" group and a "cycloalkenyl" group, each of which being optionally substituted as set forth below. [0045] As used herein, a "cycloalkyl" group refers to a saturated carbocyclic mono- or bicyclic (fused or bridged) ring of 3-10 (e.g., 5-10) carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2)octyl, bicyclo[3.3.1)nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, adamantyl, or ((aminocarbonyl)cycloalkyl)cycloalkyl. [0046] A "cycloalkenyl" group, as used herein, refers to a non-aromatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or more double bonds. Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, bicyclo[2.2.2]octenyl, or bicyclo[3.3. 1]nonenyl. [0047] A cycloalkyl or cycloalkenyl group can be optionally substituted with one or more substituents such as phosphor, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, 11 WO 2012/021467 PCT/US2011/046992 (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino, ((heterocycloaliphatic)aliphatic)carbonylamino, (heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkyl-S0 2 - and aryl-S0 2 -], sulfinyl [e.g., alkyl-S(O)-], sulfanyl [e.g., alkyl-S-], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. [0048] As used herein, the term "heterocycloaliphatic" encompasses heterocycloalkyl groups and heterocycloalkenyl groups, each of which being optionally substituted as set forth below. [0049] As used herein, a "heterocycloalkyl" group refers to a 3-10 membered mono- or bicylic (fused or bridged) (e.g., 5- to 10-membered mono- or bicyclic) saturated ring structure, in which one or more of the ring atoms is a heteroatom (e.g., N, 0, S, or combinations thereof). Examples of a heterocycloalkyl group include piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl, octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl, octahydrobenzo[b]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl, 3-aza bicyclo[3.2.1 ]octyl, and 2,6-dioxa-tricyclo[3.3.1 .0 3 ' 7 ]nonyl. A monocyclic heterocycloalkyl group can be fused with a phenyl moiety to form structures, such as tetrahydroisoquinoline, which would be categorized as heteroaryls. [0050] A "heterocycloalkenyl" group, as used herein, refers to a mono- or bicylic (e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom (e.g., N, 0, or S). Monocyclic and bicyclic heterocycloaliphatics are numbered according to standard chemical nomenclature. [0051] A heterocycloalkyl or heterocycloalkenyl group can be optionally substituted with one or more substituents such as phosphor, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., 12 WO 2012/021467 PCT/US2011/046992 (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic) aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino, ((heterocycloaliphatic) aliphatic)carbonylamino, (heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], nitro, cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkylsulfonyl or arylsulfonyl], sulfinyl [e.g., alkylsulfinyl], sulfanyl [e.g., alkylsulfanyll, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. [0052] A "heteroaryl" group, as used herein, refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms wherein one or more of the ring atoms is a heteroatom (e.g., N, 0, S, or combinations thereof) and in which the monocyclic ring system is aromatic or at least one of the rings in the bicyclic or tricyclic ring systems is aromatic. A heteroaryl group includes a benzofused ring system having 2 to 3 rings. For example, a benzofused group includes benzo fused with one or two 4 to 8 membered heterocycloaliphatic moieties (e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl, or isoquinolinyl). Some examples of heteroaryl are pyridyl, lH-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl,cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridyl. [00531 Without limitation, monocyclic heteroaryls include furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4-H-pranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl. Monocyclic heteroaryls are numbered according to standard chemical nomenclature. [0054] Without limitation, bicyclic heteroaryls include indolizyl, indolyl, isoindolyl, 3H indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indolyl, benzo[b]furyl, bexo[b]thiophenyl, indazolyl, benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, or pteridyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature. [0055] A heteroaryl is optionally substituted with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic; 13 WO 2012/021467 PCT/US2011/046992 heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl); carboxy; amido; acyl [ e.g., aliphaticcarbonyl; (cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl; (heterocycloaliphatic)carbonyl; ((heterocycloaliphatic)aliphatic)carbonyl; or (heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphaticsulfonyl or aminosulfonyl]; sulfinyl [e.g., aliphaticsulfinyl]; sulfanyl [e.g., aliphaticsulfanyl]; nitro; cyano; halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, a heteroaryl can be unsubstituted. [0056] Non-limiting examples of substituted heteroaryls include (halo)heteroaryl [e.g., mono- and di-(halo)heteroaryl]; (carboxy)heteroaryl [e.g., (alkoxycarbonyl)heteroaryll; cyanoheteroaryl; aminoheteroaryl [e.g., ((alkylsulfonyl)amino)heteroaryl and ((dialkyl)amino)heteroaryl]; (amido)heteroaryl [e.g., aminocarbonylheteroaryl, ((alkylcarbonyl)amino)heteroaryl, ((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl, (((heteroaryl)amino)carbonyl)heteroaryl, ((heterocycloaliphatic)carbonyl)heteroaryl, and ((alkylcarbonyl)amino)heteroaryl]; (cyanoalkyl)heteroaryl; (alkoxy)heteroaryl; (sulfamoyl)heteroaryl [e.g., (aminosulfonyl)heteroaryl]; (sulfonyl)heteroaryl [e.g., (alkylsulfonyl)heteroaryl]; (hydroxyalkyl)heteroaryl; (alkoxyalkyl)heteroaryl; (hydroxy)heteroaryl; ((carboxy)alkyl)heteroaryl; (((dialkyl)amino)alkyl]heteroaryl; (heterocycloaliphatic)heteroaryl; (cycloaliphatic)heteroaryl; (nitroalkyl)heteroaryl; (((alkylsulfonyl)amino)alkyl)heteroaryl; ((alkylsulfonyl)alkyl)heteroaryl; (cyanoalkyl)heteroaryl; (acyl)heteroaryl [e.g., (alkylcarbonyl)heteroaryl]; (alkyl)heteroaryl; or (haloalkyl)heteroaryl [e.g., trihaloalkylheteroaryl). [0057] A "heteroaraliphatic" (such as a heteroaralkyl group) as used herein, refers to an aliphatic group (e.g., a Ci 4 alkyl group) that is substituted with a heteroaryl group. "Aliphatic", "alkyl", and "heteroaryl" have been defined above. [0058] A "heteroaralkyl" group, as used herein, refers to an alkyl group (e.g., a CIA alkyl group) that is substituted with a heteroaryl group. Both "alkyl" and "heteroaryl" have been defined above. A heteroaralkyl is optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, 14 WO 2012/021467 PCT/US2011/046992 aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. [0059] As used herein, "cyclic moiety" and "cyclic group" refer to mono-, bi-, and tri-cyclic ring systems including cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, each of which has been previously defined. [0060] As used herein, a "bridged bicyclic ring system" refers to a bicyclic heterocyclicalipahtic ring system or bicyclic cycloaliphatic ring system in which the rings are bridged. Examples of bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, bicyclo[3.2.1loctyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl, 3 azabicyclo[3.2.l]octyl, and 2,6-dioxa-tricyclo[3.3.1.0 3 7 ]nonyl. A bridged bicyclic ring system can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. [0061] As used herein, an "acyl" group refers to a formyl group or RX-C(O)- (such as alkyl-C(O)-, also referred to as "alkylcarbonyl") where Rx and "alkyl" have been defined previously. Acetyl and pivaloyl are examples of acyl groups. [0062] As used herein, an "aroyl" or "heteroaroyl" refers to an aryl-C(O)- or a heteroaryl-C(O)-. The aryl and heteroaryl portion of the aroyl or heteroaroyl is optionally substituted as previously defined. [0063] As used herein, an "alkoxy" group refers to an alkyl-O- group where "alkyl" has been defined previously. 15 WO 2012/021467 PCT/US2011/046992 [0064] As used herein, a "carbamoyl" group refers to a group having the structure -O-CO-NRxRY or -NRx-CO-0-Rz, wherein RX and RY have been defined above and Rz can be aliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic. [0065] As used herein, a "carboxy" group refers to -COOH, -COORx, -OC(O)H, -OC(O)Rx, when used as a terminal group; or -OC(O)- or -C(O)O- when used as an internal group. [0066] As used herein, a "haloaliphatic" group refers to an aliphatic group substituted with 1-3 halogen. For instance, the term haloalkyl includes the group -CF 3 . [0067] As used herein, a "mercapto" group refers to -SH. [0068] As used herein, a "sulfo" group refers to -SO 3 H or -SO 3 Rx when used terminally or -S(0) 3 - when used internally. [00691 As used herein, a "sulfamide" group refers to the structure -NRx-S(O) 2 -NRYRz when used terminally and -NRx-S(O) 2 -NRY- when used internally, wherein Rx, R , and Rz have been defined above. [0070] As used herein, a "sulfamoyl" group refers to the structure -O-S(O) 2 -NRYRz wherein RY and Rz have been defined above. [0071] As used herein, a "sulfonamide" group refers to the structure -S(O) 2 -NRxRY or -NRx-S(O) 2 -Rz when used terminally; or -S(O) 2 -NRx- or -NRx -S(O) 2 - when used internally, wherein Rx, R , and Rz are defined above. [0072] As used herein a "sulfanyl" group refers to -S-Rx when used terminally and -S when used internally, wherein RX has been defined above. Examples of sulfanyls include aliphatic-S-, cycloaliphatic-S-, aryl-S-, or the like. [0073] As used herein a "sulfinyl" group refers to -S(O)-Rx when used terminally and S(O)- when used internally, wherein Rx has been defined above. Exemplary sulfinyl groups include aliphatic-S(O)-, aryl-S(O)-, (cycloaliphatic(aliphatic))-S(O)-, cycloalkyl-S(O)-, heterocycloaliphatic-S(O)-, heteroaryl-S(O)-, or the like. [0074] As used herein, a "sulfonyl" group refers to-S(O) 2 -Rx when used terminally and -S(O) 2 - when used internally, wherein RX has been defined above. Exemplary sulfonyl groups include aliphatic-S(O) 2 -, aryl-S(O) 2 -, (cycloaliphatic(aliphatic))-S(O) 2 -, cycloaliphatic-S(O) 2 -, heterocycloaliphatic-S(O) 2 -, heteroaryl-S(O) 2 -, (cycloaliphatic(amido(aliphatic)))-S(O) 2 -or the like. [0075] As used herein, a "sulfoxy" group refers to -O-SO-Rx or -SO-O-Rx, when used terminally and -O-S(O)- or -S(O)-O- when used internally, where RX has been defined above. 16 WO 2012/021467 PCT/US2011/046992 [0076] As used herein, a "halogen" or "halo" group refers to fluorine, chlorine, bromine or iodine. [0077] As used herein, an "alkoxycarbonyl," which is encompassed by the term carboxy, used alone or in connection with another group refers to a group such as alkyl-O-C(O)-. [0078] As used herein, an "alkoxyalkyl" refers to an alkyl group such as alkyl-O-alkyl-, wherein alkyl has been defined above. [00791 As used herein, a "carbonyl" refer to -C(O)-. [0080] As used herein, an "oxo" refers to =0. [0081] As used herein, the term "phospho" refers to phosphinates and phosphonates. Examples of phosphinates and phosphonates include -P(O)(RP) 2 , wherein RP is aliphatic, alkoxy, aryloxy, heteroaryloxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy aryl, heteroaryl, cycloaliphatic or amino. [0082] As used herein, an "aminoalkyl" refers to the structure (Rx) 2 N-alkyl-. [0083] As used herein, a "cyanoalkyl" refers to the structure (NC)-alkyl-. [0084] As used herein, a "urea" group refers to the structure -NRx-CO-NRYRz and a "thiourea" group refers to the structure -NRx-CS-NRYRz when used terminally and -NRx-CO-NRY- or -NRx-CS-NRY- when used internally, wherein Rx, R", and Rz have been defined above. [0085] As used herein, a "guanidine" group refers to the structure -N=C(N(RxRY))N(RxRY) or -NRX-C(=NRx)NRXRY wherein RX and RY have been defined above. [0086] As used herein, the term "amidino" group refers to the structure -C=(NRx)N(RxRY) wherein Rx and RY have been defined above. [0087] In general, the term "vicinal" refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to adjacent carbon atoms. [0088] In general, the term "geminal" refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to the same carbon atom. [0089] The terms "terminally" and "internally" refer to the location of a group within a substituent. A group is terminal when the group is present at the end of the substituent not further bonded to the rest of the chemical structure. Carboxyalkyl, i.e., RxO(O)C-alkyl is an example of a carboxy group used terminally. A group is internal when the group is present in the middle of a substituent of the chemical structure. Alkylcarboxy (e.g., alkyl-C(0)O- or 17 WO 2012/021467 PCT/US2011/046992 alkyl-OC(O)-) and alkylcarboxyaryl (e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groups used internally. [0090] As used herein, an "aliphatic chain" refers to a branched or straight aliphatic group (e.g., alkyl groups, alkenyl groups, or alkynyl groups). A straight aliphatic chain has the structure -[CH 2 ]v-, where v is 1-12. A branched aliphatic chain is a straight aliphatic chain that is substituted with one or more aliphatic groups. A branched aliphatic chain has the structure -[CQQ],- where Q is independently a hydrogen or an aliphatic group; however, Q shall be an aliphatic group in at least one instance. The term aliphatic chain includes alkyl chains, alkenyl chains, and alkynyl chains, where alkyl, alkenyl, and alkynyl are defined above. [0091] The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." As described herein, compounds of the invention can optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. As described herein, the variables R 1 , R 2 , R 3 , and other variables contained in Formulae described herein encompass specific groups, such as alkyl and aryl. Unless otherwise noted, each of the specific groups for the variables R 1 , R 2 , R 3 , and other variables contained therein can be optionally substituted with one or more substituents described herein. Each substituent of a specific group is further optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, cycloaliphatic, heterocycloaliphatic, heteroaryl, haloalkyl, and alkyl. For instance, an alkyl group can be substituted with alkylsulfanyl and the alkylsulfanyl can be optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. As an additional example, the cycloalkyl portion of a (cycloalkyl)carbonylamino can be optionally substituted with one to three of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. When two alkoxy groups are bound to the same atom or adjacent atoms, the two alkxoy groups can form a ring together with the atom(s) to which they are bound. [0092] In general, the term "substituted," whether preceded by the term "optionally" or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described above in the definitions and below in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or 18 WO 2012/021467 PCT/US2011/046992 different at every position. A ring substituent, such as a heterocycloalkyl, can be bound to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings share one common atom. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds. [0093] The phrase "stable or chemically feasible," as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 *C or less, in the absence of moisture or other chemically reactive conditions, for at least a week. [00941 As used herein, an "effective amount" is defined as the amount required to confer a therapeutic effect on the treated patient, and is typically determined based on age, surface area, weight, and condition of the patient. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep., 50: 219 (1966). Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970). As used herein, "patient" refers to a mammal, including a human. [0095] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a "C- or ' 4 C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as therapeutic agents. [0096] Chemical structures and nomenclature are derived from ChemDraw, version 11.0.1, Cambridge, MA. 19 WO 2012/021467 PCT/US2011/046992 [0097] II. COMMONLY USED ABBREVIATIONS [0098] The following abbreviations are used: PG protecting group LG leaving group DCM dichloromethane Ac acetyl DMF dimethylformamide EtOAc ethyl acetate DMSO dimethyl sulfoxide MeCN acetonitrile TCA trichloroacetic acid ATP adenosine triphosphate EtOH ethanol Ph phenyl Me methyl Et ethyl Bu butyl DEAD diethylazodicarboxylate HEPES 4-(2-hydroxyethyl)- 1 -piperazineethanesulfonic acid BSA bovine serum albumin DTT dithiothreitol MOPS 4-morpholinepropanesulfonic acid NMR nuclear magnetic resonance HPLC high performance liquid chromatography LCMS liquid chromatography-mass spectrometry TLC thin layer chromatography Rt retention time HOBt hydroxybenzotriazole Ms mesyl Ts tosyl Tf triflyl Bs besyl Ns nosyl Cbz carboxybenzyl 20 WO 2012/021467 PCT/US2011/046992 Moz p-methoxybenzyl carbonyl Boc tert-butyloxycarbonyl Fmoc 9-fluorenylmethyloxycarbonyl Bz benzoyl Bn benzyl PMB p-methoxybenzyl DMPM 3,4-dimethoxybenzyl PMP p-methoxyphenyl [0099] III. METHODS OF SYNTHESIZING COMPOUNDS OF FORMULA I [0100] One aspect of the present invention provides a novel synthesis for generating thiazolidine compounds that are useful for the treatment of metabolic disorders. This synthetic method is useful for preparing a compound of Formula I: 0 R2 O NH 0 0 I or a pharmaceutically acceptable salt thereof, wherein each of R, and R 2 is independently selected from H, halo, aliphatic, and alkoxy, wherein the aliphatic or alkoxy is optionally substituted with 1-3 of halo; comprising the step of: converting a compound of Formula 2A into a compound of Formula I 0 R2 NH N- OR3 2A wherein R 3 is hydrogen or an optionally substituted C 1 - 6 alkyl. In some embodiments, the compound of Formula 2A undergoes hydrolysis to generate a compound of Formula I. For example, the compound of Formula 2A is treated with an acid to generate the compound of Formula I. In other examples, the compound of Formula 2A is treated with an acid and heat to generate a compound of Formula I. [0101] In some embodiments, R3 is methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl, each of which is optionally substituted. In other embodiments, R3 is methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl, each of which is unsubstituted. And, in some embodiments, R3 is hydrogen. 21 WO 2012/021467 PCT/US2011/046992 [0102] Some embodiments further comprise reacting a compound of Formula 3A with a compound of Formula 4A: HO NH R O N 3A and 4A NOR 3 wherein X, is a leaving group (e.g., halo or triflyl), to generate the compound of Formula 2A. [0103] In some embodiments, the compound of Formula 4A comprises X1 4A1 N-OR3 [0104] In some embodiments, the compound of Formula 4A comprises IX1 4A2 N-"OCH3. [0105] In some embodiments, the compound of Formula 4A comprises N Br 4A3 N-OCH3 [0106] In some embodiments, the compound of Formula 4A comprises IX1 4A4 N-OH [0107] Some embodiments further comprise converting a compound of Formula 5A RR 5A o wherein X, is a leaving group, to a compound of Formula 4A. [0108] In some embodiments, X, is a halo (e.g., Cl or Br) or triflyl group. In some embodiments, the compound of Formula 5A is treated with a reagent R 3 0NH 2 eCl, wherein R 3 is defined above. In some examples, the reagent comprises HONH 2 -HCl, TMSNHOTMS, 22 WO 2012/021467 PCT/US2011/046992 (H 2 NOH) 2 -H 2 S0 4 , CH 3 0NH 2 *HCl, or any combination thereof to generate a compound of Formula 4A. [0109] In some embodiments, the compound of Formula 5A comprises IX1 5A1 0 wherein X, is Cl or Br. [0110] Some embodiments further comprise converting a compound of Formula 6A R2 6A 0 to a compound of Formula 5A. For example, the compound of Formula 6A undergoes halogenation to generate a compound of Formula 5A. [0111] In some embodiments, the compound of Formula 6A comprises R2 Ny 6A1 0 wherein R, is selected from a C 1 - 6 alkyl or C- 6 alkoxy, either of which is optionally substituted with 1-3 halo, and R 2 is -H or halo. [01121 In some embodiments, R, is a C 1 6 alkyl optionally substituted with 1-3 halo. For example, R, is selected from methyl, ethyl, or propyl, any of which is optionally substituted with 1-3 halo. [0113] In other embodiments, the compound of Formula 6A comprises N 0* CHO [0114] Some embodiments further comprise reacting the compound HOa with 0 N the compound S ; under condensation conditions to form a compound of Formula 3B 23 WO 2012/021467 PCT/US2011/046992 0 HO ~NH 3B O0. [01151 Other embodiments further comprise reducing the compound of Formula 3B to generate a compound of Formula 3A 0 HO NH 3A 0 [0116] Another aspect of the present invention provides a novel synthesis for generating a compound of Formula I: 0 R2 O NH 0 I or a pharmaceutically acceptable salt thereof, wherein each of Ri and R 2 is independently selected from H, halo, aliphatic, and alkoxy, wherein the aliphatic or alkoxy is optionally substituted with 1-3 of halo; comprising the step of: converting a compound of Formula 2A into a compound of Formula I 0 NH N- OR3 2A wherein R 3 is hydrogen or an optionally substituted C 1 - 6 alkyl. In some embodiments, the compound of Formula 2A undergoes hydrolysis to generate a compound of Formula I. For example, the compound of Formula 2A is treated with an acid to generate the compound of Formula I. In other examples, the compound of Formula 2A is treated with an acid and heat to generate a compound of Formula I. [0117] In some embodiments, R 3 is methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl, each of which is optionally substituted. In other embodiments, R 3 is methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl, each of which is unsubstituted. And, in some embodiments, R 3 is hydrogen. 24 WO 2012/021467 PCT/US2011/046992 [0118] Some embodiments further comprise converting a compound of Formula 7A into a compound of Formula 2A: 0 R2 O NH N-OR3 7A [0119] In some embodiments, the compound of Formula 7A is converted to a compound of Formula 2A under reduction conditions. For example, the compound of Formula 2A is generated by treating the compound of Formula 7A with a reducing reagent comprising NaBH 4 (e.g., NaBI 4 and CoCl 2 ). [0120] In some embodiments, the compound-of Formula 7A comprises 0 O . NH N "OR3 7A1 [0121] Some embodiments further comprise reacting a compound of Formula 8A R R NO CHO N-OR3 8A K' NH S- with the compound 0 to generate a compound of Formula 7A. [0122] In some embodiments, the compound of Formula 8A is reacted with the compound 0 NH 0 under condensation conditions. For example, the compound of Formula 8A is 0 K-NH S- reacted with the compound 0 in the presence of an acid (e.g., benzoic acid) and heat. 25 WO 2012/021467 PCT/US2011/046992 [0123] In some embodiments, the compound of Formula 8A comprises OCHO N" OR3 8A1 [0124] Some embodiments further comprise reacting a compound of Formula 4A, as defined above, with the compound HO CHO to generate a compound of Formula 8A. [0125] Some embodiments further comprise converting a compound of Formula 5A R, R2 5A 0 wherein X, is a leaving group, to a compound of Formula 4A. [0126] In some embodiments, X, is a halo (e.g., Cl or Br) or triflyl group. In some embodiments, the compound of Formula 5A is treated with a reagent of the general formula R 3 0NH 2 eHCl or (R 3 0NH 2 ) 2 -H 2 SO 4 , wherein R 3 is defined above. In some instances, R 3 0NH 2 comprises HONH 2 , TMSNHOTMS, CH 3 0NH 2 , CH 3 CH 2 ONH 2 , or any combination thereof to generate a compound of Formula 4A. [0127] In some embodiments, the compound of Formula 5A comprises IX1 5A1 0 wherein X, is Cl or Br. [01281 Some embodiments further comprise converting a compound of Formula 6A R2- 6A 0 to a compound of Formula 5A. For example, the compound of Formula 6A undergoes halogenation to generate a compound of Formula 5A. [0129] In some embodiments, the compound of Formula 6A comprises r I Ny 6A1 0 26 WO 2012/021467 PCT/US2011/046992 wherein Ri is selected from a C 1 - 6 alkyl or C 1 - 6 alkoxy, either of which is optionally substituted with 1-3 halo, and R 2 is -H or halo. [0130] In some embodiments, R, is a C 1 . 6 alkyl optionally substituted with 1-3 halo. For example, R, is selected from methyl, ethyl, or propyl, any of which is optionally substituted with 1-3 halo. [01311 In other embodiments, the compound of Formula 6A comprises N 0. [0132] IV. EXEMPLARY SYNTHESES [0133] The following synthetic schemes illustrate some examples of methods for generating compounds of Formula I according to the present invention. [0134] Scheme 1: O 1) KOBu R2 0 DMSO R 1 O NH HO-a S 2) N 1 0 R1- N-"OR30 3A 4A N-OR 3 2A R2 0 6M HC , R NH CKO 2 H N 0 A A02 0 wherein R 1 , R 2 , R 3 , and Xi are defined above. [0135] A compound of Formula I can be synthesized according to Scheme 1, wherein a thiazolidine-2,4-dione of Formula 3A is alkylated by an alkoxylimine of Formula 4A to form a compound of Formula 2A, wherein X, is a leaving group such as halo, tosyl, mesyl, or trifluoromethane sufonyl. The alkylation can be accomplished under basic conditions. Exemplary solvents are polor aprotic solvents such as DMSO or DMF, and the base can be a strong base, such as potassium tert-butoxide. The intermediate 2A is treated with an acid (e.g., 6M HCl in acetic acid) to generate a compound of Formula I. This transformation can also be performed under elevated temperatures. [0136] In some embodiments, the compound of Formula 3A is generated according to Scheme IA: 27 WO 2012/021467 PCT/US2011/046992 [0137] Scheme 1A: H KnoCHO Kn gel HO NH hydrogenation 3 HO NH 0 0 3A [0138] A compounds of Formula 3A can be synthesized according to Scheme 1A, wherein 4-hydroxybenzaldehyde is condensed with thiazolidine-2,4-dione under Knoevenagel conditions to produce (E)-5-(4-hydroxybenzylidene)thiazolidine-2,4-dione. This intermediate can then be reduced to the compound of Formula 3A by, for example, hydrogenation. [0139] In several embodiments, the compound of Formula 4A is formed according to Scheme IB: [0140] Scheme 1B: R2 1) BuLi (R 1 ) 2 Zn R2 BrN THF Pd(dppf)C1 2 R1 N r2) R 5 Ndioxane 6 N O 6A O R'S R 1 is unsubstituted C 1 - 3 alkyl R2 H - HX R 3 ONH 2 0 HCI R X2 RH RK HX/HOAc N NH 5A O N"OR3 4A NR 3 X1 = Halo (e.g., Cl or Br) [0141] The synthesis of intermediate 4A can be accomplished first by acetylation of a 2 pyridyl lithium species produced from contacting a 2-bromopyridine species with n butyllithium, with an appropriate acetamide compound. The resulting acetyl compound, having another bromine substituent, can then be coupled with an unsubstituted C 1 3 alkyl substituent using a palladium catalyst to generate the intermediate compound 6A. Halogenation of the alpha position of intermediate 6A using a molecular halogen compound provides the halogenated intermediate compound 5A. Compound of Formula 4A can then be produced by exposure of 5A with the appropriate alkoxylamine compound under acidic alcoholic conditions. An example of the production of a compound of Formula 4A from a compound of Formula 5A is provided in Scheme IC. As shown in the scheme, treatment of a 28 WO 2012/021467 PCT/US2011/046992 compound of Formula 5A, wherein X is Br, with O-alkoxylamine hydrochloride in ethanol provides a compound of Formula 4A. [0142] In other embodiments, the compound of Formula I is generated according to Scheme 2. [0143] Scheme 2: R1DS R CHO R -DMSO Nj N N) N 4A NOR3 HO CHO 8A N"OR3 r-NH R2 O o N-I I H NaBH 4 S RO NH ONH N-OR 3 7A 0 benzoic acid, A R20 R20 R1 NH' RNONH NH In _r r N O A N O N..OR3 2A 0 wherein R 1 , R 2 , R 3 , and X, are defined above. [0144] 4-hydroxybenzaldehyde is first alkylated by an alkoxylimine of Formula 4A to provide intermediate 8A. Enol condensation of a compound of Formula 4A with thiazolidine-2,4-dione under acidic conditions using pyrrolidine as the solvent provides a compound of Formula 7A. Further reduction of the olefin using cobalt chloride and sodium borohydride provides a compound of Formula 2A, which can be converted to the ketone using an acid such as glyoxylic acid or pyruvic acid at elevated temperatures. [0145] V. NOVEL COMPOUNDS [0146] Another aspect of the present invention provides a compound of Formula 10A, 10B, or 10C N OR 3 R 1 N ,OR 3 NOR3 R1 N XA, N XA ,or R 1 .- N XA 10A 10B 10C 29 WO 2012/021467 PCT/US2011/046992 wherein R, is halo, C 1 . 6 alkyl optionally substituted with 1-3 halo, or C 1 . 6 alkoxy optionally substituted with 1-3 halo; R 3 is hydrogen or unsubstituted C 1 . 6 alkyl; and XA is a leaving group or hydrogen. [0147] In several embodiments, R 3 of Formula 10A, 10B, or 10C is hydrogen. In other embodiments, R 3 of Formula 10A, 10B, or 10C is methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl, each of which is unsubstituted. [0148] Another aspect of the present invention provides a compound of Formula 10D, 10E, or 1OF NOH R 1 NOH NOH R1 N XA N XA ,or R, XA 10D 10E 1OF wherein Ri and XA are defined above. [0149] Another aspect of the present invention provides a compound Formula 11A-11M NOR3 NOR3 NOR3 NOR 3 NOR3 XA CI XA Fr XA XA CI XA 11A 11B 11C 11D 11E N,OR 3 OR 3 NOR 3 NR3 R3 F NXA XA XA XA 11F 11G 11H 11I 11J N ,OR3 NR3 NOR3 XK X A F- N NKN C1 F ,or iK iL 11M wherein XA and R 3 are defined above. [0150] In some embodiments, XA is a leaving group selected from -Br, -Cl, -I, -OMs, -OTs, -OTf, -OBs, -ONs, -0-tresylate, or -OPO(OR 4 ) 2 , wherein each R4 is independently C 1 . 4 alkyl or two of R 4 together with the oxygen and phosphorous atoms to which they are attached form a 5-7 membered ring. In other embodiments, XA is hydrogen. 30 WO 2012/021467 PCT/US2011/046992 [0151] Another aspect of the present invention provides a compound of Formula 2A 0 R2 ONH N-OR3 2A wherein each of R 1 , R 2 , and R 3 is defined above. For example, in one embodiment, the compound of Formula 2A comprises 0 0 R2 NH R2O N HON 2A1 H 3 CO, N 2A2 or [0152] And, another aspect of the present invention provides a compound selected from 0 0 NH NH N 00 N N0 'OR 3 'OR 3 0 0 O NH F NH N' 0 N'1 N OR3 N OR CI 0 F 0 O NH NH N 0 N-OR3 N OR 3 0 0 NH ON N 0'0 ,or N NO NOR3 NOR3 0 wherein R 3 is defined above. 31 WO 2012/021467 PCT/US2011/046992 [0153] VI. EXAMPLES [0154] Example 1: Preparation of 1-(5-bromopyridin-2-yl)ethanone Br 1) BuLi Br nBr THF N Br 2 ) 0N 0 [01551 In a 3-neck 1000 ml round bottom flask, 2,5-dibromopyridine (10.0 g, 42.2 mmol) was dissolved in toluene (400ml) and cooled to -40 *C (CH 3 CN/dry ice). 1.6 M of n butyllithium in tetrahydrofuran (26.38 mL, 42.21 mmol) was slowly added to the cooled solution to form a deep reddish solution, which was stirred at -40 *C for 40 minutes. N,N Dimethylacetamide (7.14 mL, 76.8 mmol) was added with no discernable change. The mixture was allowed to slowly warm to room temperature. Then, the mixture was quenched by adding 25ml sat'd ammonium chloride. Added 100ml H20 and extracted with EtOAc (250ml). The organic phase was washed with water (200 ml). The combined aqueous phases were extracted with EtOAc (100ml). The combined organic extracts were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated in vacuo to generate 6.31 g of a tan solid. 'H-NMR (CDCl 3 ): 5 8.74(d, J=1.9Hz, 1H), 7.96(m, 2H), 2.70(s, 3H). HPLC: RT=3.237min., 60area% @ 210nm; RT=3.238min., 87area% @254nm. LCMS: MS (ESI-) for C 8 H7BrO m/z 201.0 (M+H)*. [0156] Example 2: Preparation of (1-(5-ethylpyridin-2-yl)ethanone Br Et 2 Zn N Pd(dppf) N N tolueneN 0 0 [0157] A mixture of 1-(5-bromopyridin-2-yl)ethanone (6.30 g, 31.5 mmol; Supplier = Kalexsyn; Lot = 90) and [1,1 '-B is(diphenylphosphino)ferrocene]dichloropalladium(II) (560 mg, 0.76 mmol) in dioxane (120ml) was degassed by sparging with N 2 for 10 minutes. Added a solution (15%w/w) of diethyl zinc in hexane (50ml) slowly, dropwise and heated to 50 'C. The orange mixture turned dark, ultimately generating a dark orange with yellow solids as it stirred at 50 'C for 30 minutes. Allowed to cool to room temperature. The reaction mixture was partitioned between EtOAc (200ml) and water (200ml), and the aqueous phase was extracted 2x with EtOAc. The combined organic phases were washed with brine (500ml), dried (Na 2 SO4, filtered and evaporated in vacuo to give 4.14 g brown oil. Distilled under high vac using short-path distillation apparatus. BP = 55 'C @ 0.32 torr to 32 WO 2012/021467 PCT/US2011/046992 give 2.249 g of slightly tinted oil. 'H-NMR (CDCl 3 ): 8 8.50(d, J=1.9Hz, 1H), 7.96(d, J=7.9Hz, 1H), 7.63(dd, J=8.0, 2.2Hz, 1H), 2.71(m, 2H), 2.69(s, 3H), 1.27(t, J=7.6Hz, 3H). HPLC: 2.01 1min., 57 area% @ 21Onm; 2.012min., 75 area% @ 254 nm. LCMS: MS (ESI-) for C 10 H 1 2 0 m/z 150.1 (M+H)*. [0158] Example 3: Preparation of 22-bromo-1-(5-ethylpyridin-2-yl)ethanone hydrogen bromide Br 2 HBr/HOAc Br 0 HBr O [0159] To a stirring solution of 1-(5-ethylpyridin-2-yl)ethanone (634 mg, 4.25 mmol; Supplier = Kalexsyn; Lot = 1003-TTP- 112) in 33% HBr/HOAc (w/w, 5ml) at 10 'C (water bath with a little ice) was added 0.173ml bromine dropwise. Stirred for 1 hour at room temperature at which time the reaction appeared complete by HPLC. Added ether (5ml) and stirred for 15 minutes. The orange solids were collected by suction filtration, washed with ether, and dried under high vac. 1.042 g orange solid. 'H-NMR (DMSO-d6): 8 9.65(brs, 1H), 8.62(d, J=1.9Hz, LH), 7.97(m, 111), 7.91(d, J=2.lHz, 1H), 4.99(s, 211), 2.74(q, J=7.5Hz, 2H), 1.22(t, J=7.6Hz, 3H). HPLC: 3.747 min., 83 area% @ 2540 nm; 3.747 min., 95 area% @ 210 nm. MS (ESI-) for C 9 HioBrNO m/z 229.1 (M+H)*. [0160] Example 4: Preparation of 2-bromo-1-(5-ethylpyridin-2-yl)ethanone 0-methyl oxime BCH 3 0NH 2 .HCI N Br EtOH NBr -HBr 0 N-"OCH3 [0161] To a stirring solution of 2-bromo-1-(5-ethylpyridin-2-yl)ethanone hydrobromide (1.024 g, 3.314 mmol; Supplier = Kalexsyn; Lot = 1003-TTP-185) in EtOH (10 ml) was added methoxylamine hydrochloride (553.5 mg, 6.628 mmol). Left to stir at RT overnight. The reaction mixture was evaporated in vacuo. The residue was dissolved in DCM and an equal volume of saturated NaHCO 3 was added and the biphasic mixture stirred for 30 minutes. The phases were separated and the aqueous phase was extracted with DCM. The combined organic phases were dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford a pale yellow oil which crystallized upon standing. 'H-NMR (CDCl 3 ): 8 8.50(s, 1H), 7.87(d, J=8.3Hz, 1H), 7.59(m, 1H), 4.79(s, 1H), 4.64(s, 1HI), 4.13(d, J=4.4Hz, 3H), 2.70(q, J=7.7Hz, 2H), 1.28(t, J=7.7Hz, 3H). HPLC: 3.429 min., 30 area% and 3.621 min., 31 area% @ 210 33 WO 2012/021467 PCT/US2011/046992 nm; 3.414 min., 36 area% and 3.618 min., 36 area% @ 210nm. MS (ESI-) for CjoH 1 3 BrN 2 0 m/z 258.2 (M+H)*. [0162] Example 5: Preparation of 5-(4-(2-(5-ethylpyridin-2-yl)-2 (methoxyimino)ethoxy)benzyl)thiazolidine-2,4-dione O 1) 2 eq. KOtBu 0 O NH DMSO O NH HO'C --- (- OJ S 10 O 2) NBr N"OCH3 N OCH 3 [0163] To a stirring solution of 5-(4-hydroxybenzyl)thiazolidine-2,4-dione (210 mg, 0.941 mmol) in DMSO was added potassium tert-Butoxide (227 mg, 2.02 mmol) in a single portion. Stirred at RT for 15 minutes. Added a solution of (lZ)-2-bromo-1-(5-ethylpyridin-2 yl)ethanone 0-methyloxime (242 mg, 0.941 mmol; Supplier = Kalexsyn; Lot = 1003-TTP 186) in DMSO (2ml). Added IM HCI until pH of mixture was about 3. Extracted with EtOAc. The extract was washed with water, dried (Na 2 SO 4 ), filtered and evaporated in vacuo to give an off-white foam. 278mg. 'H-NMR (DMSO-d6): 512.05(brs, 1H), 8.47(d, J=1.7Hz, 1H), 7.77(m, 1H), 7.70m, 1H), 7.14(d, J=8.5Hz, 2H), 6.90(d, J=8.5Hz, 2H), 5.17(s, 2H), 4.87(dd, J=8.9, 4.4Hz, IH), 4.01(s, 311), 3.30(dd, J=14.2, 4.5Hz, 1H), 3.06(dd, J=14.1, 9.1Hz, 1H), 2.64(q, J=7.7Hz, 2H), 1.19(t, J=7.6Hz, 3H). HPLC: 3.103min., 82area% and 3.379min., 18 area% @254nm; 3.109min., 91area% and 3.379min., 9area% @ 254nm. MS (ESI-) for C 20 H 21 N 3 0 4 S m/z 400.3 (M+H); mlz 398.3 (M-H)^ [0164] Example 6: Preparation of 5-(4-(2-(5-ethylpyridin-2-yl)-2 oxoethoxy)benzyl)thiazolidine-2,4-dione O 0 6M HCI N COT0 2 H O N "OCH3 [0165] A stirring solution of 5-(4-{[(2Z)-2-(5-ethylpyridin-2-yl)-2 (methoxyimino)ethyl]oxy}benzyl)-1,3-thiazolidine-2,4-dione (81 mg, 0.20 mmol; Supplier = Kalexsyn; Lot = 1003-TTP-194) in 6M HCI (2ml) and pyruvic acid (0.5ml) was heated at 75 *C. After 2h at 75 *C HPLC showed reaction was complete. Neutralized with sat'd NaHCO 3 and extracted with EtOAc. Extract dried (Na 2 SO 4 ), filtered and evaporated in vacuo to give 45mg (60%) pale yellow oil. 'H-NMR (DMSO-d6): 612.02(brs, 111), 8.64(s, 1H), 7.91(m, 34 WO 2012/021467 PCT/US2011/046992 111), 7.14(d, J=8.5Hz, 211), 6.88(d, J=8.5Hz, 2H), 5.66(s, 211), 4.87(dd, J=9.2, 4.3Hz, 1H), 3.31(m, 111), 3.05(dd, J=14.1, 9.1Hz, 1H), 2.74(q, J=7.7Hz, 2H), 1.23(t, J=7.7Hz, 3H). HPLC (3.860min., 100area% @ 210 and 254nm. MS (ESI-) for C 19 H 18 N 2 0 4 S m/z 371.3 (M+H); m/z 369.4 (M-H)~ [0166] Example 7: Assays [0167] Assays for Measuring Reduced PPARy Receptor Activation [0168] Whereas activation of the PPAR7 receptor is generally believed to be a selection criteria to select for molecules that may have anti-diabetic and insulin sensitizing pharmacology, this invention finds that activation of this receptor should be a negative selection criterion. Molecules will be chosen from this chemical space because they have reduced, not just selective, activation of PPARy. The optimal compounds have at least a 10 fold reduced potency as compared to pioglitazone and less than 50% of the full activation produced by rosiglitazone in assays conducted in vitro for transactivation of the PPARy receptor. The assays are conducted by first evaluation of the direct interactions of the molecules with the ligand binding domain of PPARy. This can be performed with a commercial interaction kit that measures the direct interaction by florescence using rosiglitazone as a positive control. Further assays can be conducted in a manner similar to that described by Lehmann et al. [Lehmann JM, Moore LB, Smith-Oliver TA: An Antidiabetic Thiazolidinedione is a High Affinity Ligand for Peroxisome Proliferator activated Receptor (PPAR) J. Biol. Chem.(1995) 270: 12953] but will use luciferase as a reporter as in Vosper et al. [Vosper, H., Khoudoli, GA, Palmer, CN (2003) The peroxisome proliferators activated receptor d is required for the differentiation of THP- 1 moncytic cells by phorbol ester. Nuclear Receptor 1:9]. Compound stocks will be dissolved in DMSO and added to the cell cultures at final concentrations of 0.1 to 100 pM and the relative activation will be calculated as induction of the reporter gene (luciferase) as corrected for by the expression of the control plasmid (coding for galactosidase). Pioglitazone and rosiglitazone will be used as reference compounds as described above. [0169] In addition to showing the reduced activation of the PPARy receptor in vitro, the compounds will not produce significant activation of the receptor in animals. Compounds dosed to full effect for insulin sensitizing actions in vivo (see below) will be not increase activation of PPARy in the liver as measured by the expression of a P2, a biomarker for ectopic adipogenesis in the liver [Matsusue K, Haluzik M, Lambert G, Yim S-H, Oksana Gavrilova 0, Ward JM, Brewer B, Reitman ML, Gonzalez FJ. (2003) Liver-specific 35 WO 2012/021467 PCT/US2011/046992 disruption of PPAR in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. J. Clin. Invest.; 111: 737] in contrast to pioglitazone and rosiglitazone, which do increase a P2 expression under these conditions. [0170] The insulin sensitizing and antidiabetic pharmacology are measured in the KKAY mice as previously reported [Hofmann, C., Lornez, K., and Colca, J.R. (1991). Glucose transport deficiency corrected by treatment with the oral anti-hyperglycemic agent Pioglitazone. Endocrinology, 129:1915-1925]. Compounds are formulated in 1% sodium carboxy methylcellulose, and 0.01% tween 20 and dosed daily by oral gavage. After 4 days of once daily treatment, treatment blood samples are taken from the retro-orbital sinus and analyzed for glucose, triglycerides, and insulin as described in Hofmann et al. Doses of compounds that produce at least 80% of the maximum lowering of glucose, triglycerides, and insulin will not significantly increase the expression of a P2 in the liver of these mice. OTHER EMBODIMENTS [0171] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. 36
权利要求:
Claims (41) [1] 2. The method of claim 1, further comprising reacting a compound of Formula 3A with a compound of Formula 4A: HO NH NX O N 3A and 4A "OR 3 wherein Xi is a leaving group, to generate the compound of Formula 2A. [2] 3. The method of claim 2, wherein the compound of Formula 4A comprises IX1 4A1 N-OR3 [3] 4. The method of claim 3, wherein R 3 is methyl, ethyl, propyl, isopropyl, butyl, or tert butyl, each of which is optionally substituted. [4] 5. The method of claim 4, wherein the compound of Formula 4A comprises 37 WO 2012/021467 PCT/US2011/046992 X1 4A2 N"OCH3 [5] 6. The method of claim 5, wherein the compound of Formula 4A comprises N Br 4A3 N-"OCH3 [6] 7. The method of any one of claims 2-6, further comprising converting a compound of Formula 5A R2 5A 0 wherein X, is a leaving group, to a compound of Formula 4A. [7] 8. The method of claim 7, wherein X, is a halo or triflyl group. [8] 9. The method of either of claims 7 or 8, wherein the compound of Formula 5A comprises IX1 5A1 0 wherein X, is Cl or Br. [9] 10. The method of claim 7, further comprising converting a compound of Formula 6A R2 NZ~ 6A 0 to a compound of Formula 5A. [10] 11. The method of claim 10, further comprising halogenating the compound of Formula 6A to generate the compound of Formula 5A. [11] 12. The method of claim 10, wherein the compound of Formula 6A comprises 38 WO 2012/021467 PCT/US2011/046992 R 2 r / Ny 6A1 0 wherein R 1 is selected from a C- 6 alkyl or C 1 . 6 alkoxy, either of which is optionally substituted with 1-3 halo, and R 2 is -H or halo. [12] 13. The method of claim 12, wherein Ri is a C 1 . 6 alkyl optionally substituted with 1-3 halo. [13] 14. The method of claim 13, wherein R, is selected from methyl, ethyl, or propyl, any of which is optionally substituted with 1-3 halo. [14] 15. The method of claim 10, wherein the compound of Formula 6A comprises N 0. [15] 16. The method of any of claims 2-15, further comprising reacting the compound CHO O N O HO with the compound S ; under condensation conditions to form a compound of Formula 3B 0 HO NH HOO 3B and reducing the compound of Formula 3B to form a compound of Formula 3A. [16] 17. The method of claim 1, further comprising converting a compound of Formula 7A into a compound of Formula 2A: 39 WO 2012/021467 PCT/US2011/046992 0 NH N-"OR3 7A [17] 18. The method of claim 17, wherein the compound of Formula 7A is converted to a compound of Formula 2A under reduction conditions. [18] 19. The method of either of claims 17 or 18, wherein the compound of Formula 2A is generated by treating the compound of Formula 7A with a reducing reagent comprising NaBH 4 . [19] 20. The method of any one of claims 17-19, wherein the compound of Formula 7A comprises 0 O NH N 0 S -O37A1 [20] 21. The method of claim 17, further comprising reacting a compound of Formula 8A R2 R O CHO N-OR3 8A 0 KkNH S with the compound 0 to generate a compound of Formula 7A. [21] 22. The method of claim 21, wherein the compound of Formula 8A is reacted with the 0 NH compound 0 under condensation conditions. 40 WO 2012/021467 PCT/US2011/046992 [22] 23. The method of claim 22, wherein the compound of Formula 8A is reacted with the 0 NH compound 0 in the presence of an acid and heat. [23] 24. The method of any of claims 21-23, wherein the compound of Formula 8A comprises O CHO N 0 N-OR3 8A1 [24] 25. The method of claim 21, further comprising reacting a compound of Formula 4A R2 4A N-OR 3 CHO with the compound HO CHO to generate a compound of Formula 8A. [25] 26. The method of claim 25, wherein the compound of Formula 4A comprises NX1 4A1 N-OR3 [26] 27. The method of claim 26, wherein R 3 is methyl, ethyl, propyl, isopropyl, butyl, or tert butyl, each of which is optionally substituted. [27] 28. The method of claim 27, wherein the compound of Formula 4A comprises NX1 4A2 N-OCH3 [28] 29. The method of claim 28, wherein the compound of Formula 4A comprises 41 WO 2012/021467 PCT/US2011/046992 Br 4A3 N-OCH3 [29] 30. The method of any one of claims 25-29, further comprising converting a compound of Formula 5A R2 5A 0 wherein Xi is a leaving group, to a compound of Formula 4A. [30] 31. The method of claim 30, wherein Xi is a halo or triflyl group. [31] 32. The method of either of claims 30 or 31, wherein the compound of Formula 5A comprises X1 5A1 0 wherein X, is Cl or Br. [32] 33. The method of claim 30, further comprising converting a compound of Formula 6A R2 6A 0 to a compound of Formula 5A. [33] 34. The method of claim 33, further comprising halogenating the compound of Formula 6A to generate the compound of Formula 5A. [34] 35. The method of claim 33, wherein the compound of Formula 6A comprises r I Ny 6A1 0 42 WO 2012/021467 PCT/US2011/046992 wherein R, is selected from a CI- 6 alkyl or C 1 . 6 alkoxy, either of which is optionally substituted with 1-3 halo, and R 2 is -H or halo. [35] 36. The method of claim 35, wherein R, is a C 1 . 6 alkyl optionally substituted with 1-3 halo. [36] 37. The method of claim 36, wherein R 1 is selected from methyl, ethyl, or propyl, any of which is optionally substituted with 1-3 halo. [37] 38. The method of claim 33, wherein the compound of Formula 6A comprises 'N 0* [38] 39. A compound selected from 0 0 O NH O NH NN. 0"0 J NOR 3 OR 3 O 0 O NH F NH N 0 N 0 NOR3 N "OR 3 CI 0 F O O NH O NH N' ~S-..tN I N ~0 CN 10: S N-"OR3 N-"OR3 o 0 N NH O NH N 0O , or N 0 N-OR3 N-OR3 wherein R 3 is hydrogen or an unsubstituted C 1 . 6 alkyl. [39] 40. The compound of claim 39, wherein R 3 is an unsubstituted C1. 3 alkyl. 43 WO 2012/021467 PCT/US2011/046992 [40] 41. The compound of claim 40, wherein R 3 is methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl, each of which is unsubstituted. [41] 42. The compound of claim 41, wherein R 3 is methyl. 44
类似技术:
公开号 | 公开日 | 专利标题 DK2513070T3|2018-01-22|PPAR-sparing thiazolidinedione salts for the treatment of metabolic disorders AU2011242955A1|2012-11-01|Novel synthesis for thiazolidinedione compounds US8946435B2|2015-02-03|Synthesis for thiazolidinedione compounds AU2011242956B2|2015-01-22|Novel synthesis for thiazolidinedione compounds AU2011289543B2|2015-03-19|Novel synthesis for thiazolidinedione compounds AU2013200104B2|2014-05-15|Thiazolidinedione analogues for the treatment of metabolic inflammation mediated disease
同族专利:
公开号 | 公开日 MX342289B|2016-09-23| EP2603507B1|2016-06-29| NZ606597A|2014-12-24| KR20130097750A|2013-09-03| RU2013110311A|2014-09-20| HUE029488T2|2017-02-28| US8895748B2|2014-11-25| AU2011289627B2|2015-01-15| US20130211092A1|2013-08-15| US20140378687A1|2014-12-25| CN103153991B|2016-06-29| CN103153991A|2013-06-12| JP2013535503A|2013-09-12| ES2588769T3|2016-11-04| EP2603507A1|2013-06-19| CA2807815C|2018-10-02| CA2807815A1|2012-02-16| KR101857307B1|2018-05-11| MX2013001475A|2013-04-29| JP5851506B2|2016-02-03| US8946435B2|2015-02-03| RU2594725C2|2016-08-20| PL2603507T3|2016-12-30| WO2012021467A1|2012-02-16|
引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题 CN1003445B|1984-10-03|1989-03-01|武田药品工业株式会社|The preparation method of thiazolidine diketone derivative| SU1766260A3|1989-11-04|1992-09-30|Пфайзер Инк |Method of synthesis of thiazolidinedione-2,4 derivatives or their pharmaceutically acceptable salts with alkaline metals| US5143930A|1990-02-07|1992-09-01|Sankyo Company, Limited|Thiazolidine derivatives with anti-diabetic activity, their preparation and their use| CZ196693A3|1991-04-11|1994-05-18|Upjohn Co|Thiazolidinedione derivatives, and process for preparing thereof| SE9702305D0|1997-06-17|1997-06-17|Astra Ab|New thiazolidinedione, oxazolidinedione and oxadiazolidinedione derivatives| AP869A|1998-01-05|2000-09-04|Pfizer|2,3-Substituted indole compounds as anti-inflammatory and analgesic agents.| US7407978B2|1999-04-06|2008-08-05|Theracos, Inc.|Heterocyclic analogs of diphenylethylene compounds| US6768008B2|2000-04-24|2004-07-27|Aryx Therapeutics|Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis| WO2002043807A2|2000-12-01|2002-06-06|Novartis Ag|Combinations of an angiotensin receptor antagonist and an anti-hypertensive drug or a statin, for the treatment of sexual dysfunction| WO2003029251A1|2001-09-28|2003-04-10|Biocon Limited|Novel process for the synthesis of thiazolidinedione derivatives| FR2861069B1|2003-10-17|2005-12-09|Galderma Res & Dev|NOVEL RAR RECEPTOR ACTIVATOR LIGANDS, USE IN HUMAN MEDICINE AND COSMETICS| UA96441C2|2006-03-16|2011-11-10|Метаболик Солюшнз Девелопмент Компани|Pharmaceutical composition comprosing thiazolidinedione analogues for the treatment of metabolic inflammation mediated disease| WO2008118327A1|2007-03-23|2008-10-02|University Of Toledo|Conformationally restrained epothilone analogues as anti-leukemic agents| CN101848901B|2007-09-14|2012-11-21|新陈代谢解决方案开发公司|Thiazolidinedione analogues for the treatment of hypertension| WO2009148195A1|2008-06-02|2009-12-10|Daebong Ls, Ltd.|5-thiazolidine-2,4-dione as intermediate for synthesis of thiazolidinedione based compounds and process for preparing the same| EP2563767A2|2010-04-19|2013-03-06|Metabolic Solutions Development Company LLC|Novel synthesis for thiazolidinedione compounds| US8937182B2|2010-04-19|2015-01-20|Metabolic Solutions Development Company, Llc|Synthesis for thiazolidinedione compounds| KR101988203B1|2010-08-10|2019-06-11|씨리우스 테라퓨틱스, 엘엘씨|Novel synthesis for thiazolidinedione compounds|US8937182B2|2010-04-19|2015-01-20|Metabolic Solutions Development Company, Llc|Synthesis for thiazolidinedione compounds| KR101988203B1|2010-08-10|2019-06-11|씨리우스 테라퓨틱스, 엘엘씨|Novel synthesis for thiazolidinedione compounds| CN104496935A|2014-11-24|2015-04-08|苏州乔纳森新材料科技有限公司|Synthetic method of insulin sensitizer intermediate| DK3436434T3|2016-03-31|2020-09-21|Oncternal Therapeutics Inc|INDOLIN ANALOGS AND USES THEREOF|
法律状态:
2015-05-14| FGA| Letters patent sealed or granted (standard patent)|
优先权:
[返回顶部]
申请号 | 申请日 | 专利标题 US37226910P| true| 2010-08-10|2010-08-10|| US61/372,269||2010-08-10|| PCT/US2011/046992|WO2012021467A1|2010-08-10|2011-08-09|Synthesis for thiazolidinedione compounds| 相关专利
Sulfonates, polymers, resist compositions and patterning process
Washing machine
Washing machine
Device for fixture finishing and tension adjusting of membrane
Structure for Equipping Band in a Plane Cathode Ray Tube
Process for preparation of 7 alpha-carboxyl 9, 11-epoxy steroids and intermediates useful therein an
国家/地区
|