WO2012178142A1

WO2012178142A1 - Ppar-sparing compounds and combinations fort the treatment of diabetes and other metabolic diseases

Info

Publication number: WO2012178142A1
Application number: PCT/US2012/043926
Authority: WO
Inventors: Gerard R. Colca; Steven P. Tanis; Scott D. Larsen
Original assignee: Metabolic Solutions Development Company, Llc
Priority date: 2011-06-23
Filing date: 2012-06-25
Publication date: 2012-12-27

Abstract

The present invention relates to compounds I and pharmaceutical compositions that are useful for treating and/or preventing diabetes or other metabolic diseases, optionally in combination with a second therapy such an active pharmaceutical agent or diet restriction or an increase in duration or exertion in physical activity.

Description

PPAR-SPARING COMPOUNDS AND COMBINATIONS FOR THE TREATMENT OF DIABETES AND OTHER METABOLIC DISEASES

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This PCT application claims the benefit of U.S. provisional application serial no. 61/500,401, filed on June 23, 2011, which is hereby incorporated by reference in its entirety.

TECHNICAL FIELD OF THE INVENTION

[0002] The present invention provides indole compounds, analogs thereof, and

pharmaceutical compositions containing such compounds for use in treating and/or preventing diabetes or other metabolic disease states (e.g., obesity and dyslipidemia).

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 compounds.

[0004] Peroxisome Proliferator Activated Receptors (PPARs) are members of the nuclear hormone receptor super family that 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.

[0005] PPARy 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] Thiazolidinedione compounds, 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 PPARy is a key regulator of glucose and lipid homeostasis. However, compounds that involve the activation of PPARy also trigger sodium reabsorption and other unpleasant side effects.

[0007] Brown adipose tissue (BAT) is responsible for cold- and diet-induced thermogenesis that significantly contributes to the control of body temperature and energy expenditure.

Physiol Rev. 2004; 84:277-359. Literature reports indicate that BAT thermogenesis is principally dependent on the β-adrenergically mediated activation of lipolysis and subsequent degradation of fatty acids, which generates heat dependent on uncoupling protein 1 (UCP1) that uncouples mitochondrial oxidative phosphorylation to dissipate the electrochemical gradient as heat instead of ATP synthesis. Diabetes 2009; 58:1526-1531. Traditional thiazolidinediones such as pioglitazone can increase differentiation of BAT and increase BAT stores in mammals. Biochemical Pharmacology 1996; 52:639-701. However, many thiazolidinediones evaluated for clinical development were shown to activate PPARy, which ultimately resulted in the transcription of genes favoring sodium reabsorption, fluid retention, and weight gain in patients. Guan, Y. et al, Nat. Med. (2005) 11 : 861-866. It is generally believed that this PPARy agonism is also responsible for the biological activity of these compounds including the differentiation of BAT. Petrovic et al., Am. J. Physiol. Endocrinol. Meta. (2008) 295: E287-E296. Recent studies indicate that these BAT stores are inversely proportional to body mass index, which is an index of obesity. N. Engl. J. Med., 2009;

360:1500-1508.

SUMMARY OF THE INVENTION

[0008] The present invention relates to compounds that have reduced binding and/or activation of the nuclear transcription factor PPARy. Contrary to the teachings of the literature, PPARy sparing compounds of the present invention are able to stimulate the differentiation of BAT and increase the amount of UCP1 protein.

[0009] The compounds of this invention have reduced binding and/or activation of the nuclear transcription factor PPARy, do not augment sodium re-absorption, and are useful in treating or preventing diabetes and other metabolic diseases such as obesity or dyslipidemia. Advantageously, the compounds having lower PPARy activity exhibit fewer side effects than compounds having higher levels of PPARy activity. Most specifically, by lacking PPARy binding and/or activation activity these compounds are particularly useful for treating and/or preventing diabetes and other metabolic diseases both as a single therapeutic agent or in combination with other agents that affect cellular cyclic nucleotide levels including phosphodiesterase inhibitors, adrenergic agonists, or various hormones.

[0010] In one aspect, the present invention provides a compound of Formula I:

I

or a pharmaceutically acceptable salt thereof, wherein each of R ^a and R is independently selected from hydrogen, -OH, C alkyl optionally substituted with 1-3 halo, or CM alkoxy optionally substituted with 1-3 halo, or R^la and R^lb taken together form oxo; X¹ is -O- or -CH2-, or -CH-; imm is a single bond or a double bond when X¹ is -CH- and one of R^la and R^lb is absent; Ring A is selected from

R is selected from hydrogen or C1-3 alkyl; R^J is selected from hydrogen, C_1-3 alkyl optionally substituted with 1-3 halo, or C1.3 alkoxy optionally substituted with 1-3 halo; and R⁴ is -Z^AR^A wherein Z^A is independently selected from a bond, a C1.3 alkylidene chain, or -C(O)-; and R^A is selected from hydrogen, C_1-3 alkyl, or phenyl optionally substituted with C1-3 alkyl or C1.3 alkoxy.

[0011] In some embodiments, ring

[0012] In some of these embodiments, R² is selected from hydrogen, methyl, or ethyl. For

9

example, R is hydrogen. In other examples, R is methyl.

[0013] In other embodiments, R³ is Q.3 alkoxy optionally substituted with 1-3 halo. For example, R³ is -OCH₃ or -OCF₃.

[0014] In some embodiments, R⁴ is -Z^AR^A, wherein Z^A is independently selected from a bond or -C(O)-; and R^A is selected from hydrogen, C1.3 alkyl, or phenyl optionally substituted with C1.3 alkyl or C1.3 alkoxy. For example, R⁴ is -Z^AR^A, wherein Z^A is independently selected from a bond or -C(O)-; and R^A is selected from hydrogen, d-3 alkyl, or phenyl substituted with -OCH₃ or -OCH₂CH₃. In some examples, R⁴ is hydrogen, -C¾, -CH₂CH₃, or -C(0)-CH₃. And, in other examples, R⁴ is -Z^AR^A, wherein Z^A is -C(O)-; and R^A is phenyl optionally substituted with Q-3 alkyl or d-3 alkoxy. For instance, R⁴ is -Z^AR^A, wherein Z^A is -C(0)-; and R^A is phenyl substituted at its para position with C_1-3 alkyl or C^ alkoxy.

[0015] In other embodiments, ring

[0016] In some of these embodiments, R² is selected from hydrogen, methyl, or ethyl. For example, R² is hydrogen. In other examples, R² is methyl.

[0017] In some embodiments, R is C 1.3 alkoxy optionally substituted with 1-3 halo. For example, R³ is -OCH₃ or -OCF₃.

[0018] In alternative embodiments, is a double bond, one ofR^la and R^lb is absent, and X¹ is -CH-. [0019] And, in some embodiments, one of R^la and R^lb is hydrogen and the other is selected from hydrogen, -CH₃, -CH₂CH₃, -OCH₃, or -OCH₂CH₃.

[0020] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of Formula I, as described above, and a pharmaceutically acceptable carrier.

[0021] In some embodiments, the pharmaceutical composition comprises a second active pharmaceutical ingredient. For example, the pharmaceutical composition further comprises a dipeptidyl peptidase IV (DPP-4) inhibitor, e.g., sitagliptin, vildagliptin, or the like; a

HMG-CoA reductase inhibitor (statin), e.g., atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, simvastatin, rosuvastatin, pravastatin, or any pharmaceutically acceptable combination thereof; GLP-1 or -2 agonists; or any combination thereof.

[0022] Another aspect of the present invention provides a method of treating or reducing the symptoms of diabetes comprising administering to a patient a compound of Formula I or a pharmaceutical composition, as described above.

[0023] Another aspect of the present invention provides a method of treating or delaying the onset of obesity comprising administering to a patient a compound of Formula I or a pharmaceutical composition, as described above. In some implementations, the obesity being treated is central obesity.

[0024] Some implementations of this method further comprise restricting the diet of the patient, performing additional physical exercise, or any combination thereof.

[0025] Another aspect of the present invention provides a method of treating or reducing the symptoms of dyslipidemia comprising administering to a patient a compound of Formula I or a pharmaceutical composition, as described above.

DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention provides novel PPARy-sparing compounds and

pharmaceutical compositions that are useful for treating diabetes and other metabolic diseases. In one aspect, the present invention provides a compound of Formula I:

I

or a pharmaceutically acceptable salt thereof, wherein each of R^la and R^lb is independently selected from hydrogen, -OH, C alkyl optionally substituted with 1-3 halo, or C alkoxy optionally substituted with 1-3 halo, or R^la and R^lb taken together form oxo; X¹ is -O- or -CH₂-, or -CH-; is a single bond or a double bond when X¹ is -CH- and one of R¹

substituted with 1-3 halo, or Ci-3 alkoxy optionally substituted with 1-3 halo; and R⁴ is -Z^AR^A wherein Z^A is independently selected from a bond, a Ci_-3 alkylidene chain, or -C(O)-; and R^A is selected from hydrogen,

alkyl, or phenyl optionally substituted with C_1-3 alkyl or Ci.₃ alkoxy.

[0027] PPARy-sparing compounds of the present invention effectively stimulate BAT stores, and are useful for treating obesity and other metabolic diseases such as diabetes.

[0028] I. DEFINITIONS

[0029] As used herein, the following definitions shall apply unless otherwise indicated.

[0030] 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 are hereby incorporated by reference.

[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 "aliphatic" encompasses the terms alkyl, alkenyl, alkynyl, each of which being optionally substituted as set forth below.

[0033] As used herein, an "alkyl" group refers to a saturated aliphatic hydrocarbon group containing 1-12 (e.g., 1-3, 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,

heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g., aliphaticamino, cycloaliphaticamino, or heterocycloaliphaticamino], sulfonyl [e.g., aliphatic-S02-], 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-S0₂-amino)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl, or haloalkyl.

[0034] 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-S0₂-, cycloaliphatic-SCh-, or aryl-S0₂-], 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-S0₂-amino)alkenyl), aminoalkenyl, amidoalkenyl, (cycloaliphatic)alkenyl, or haloalkenyl. [0035] 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 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-SC>2-, aliphaticamino-S0₂-, or

cycloaliphatic-S02-], amido [e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino, aralkylcarbonylamino,

(heterocycloalkyl)carbonylamino, (cycloalkylalkyl)carbonylamino,

heteroaralkylcarbonylamino, heteroarylcarbonylamino or heteroarylaminocarbonyl], 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.

[0036] 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(R^x)-C(0)-R^Y or -C(0)-N(R^x)₂, when used terminally, and -C(0)-N(R^x)- or -N(R^x)-C(0)- when used internally, wherein R^x and R^Y 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.

[0037] As used herein, an "amino" group refers to -NR^XR^Y wherein each of R^x and R^Y 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 -NR^X-. R^x has the same meaning as defined above.

[0038] 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., 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 benzo fused 2-3 membered carbocyclic rings. For example, a benzofused group includes phenyl fused with two or more C4.8 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-S0₂- or amino-S0₂-]; sulfinyl [e.g., aliphatic-S(O)- or cycloaliphatic-S(O)-]; sulfanyl [e.g., aliphatic-S-]; cyano; halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, an aryl can be unsubstituted.

[0039] Non-limiting examples of substituted aryls include haloaryl [e.g., mono-, di (such as 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; -amino-w-cyanoaryl; >-halo-m-aminoaryl; or (w-(heterocycloaliphatic)- o-(alkyl))aryl. [0040] As used herein, an "araliphatic" such as an "aralkyl" group refers to an aliphatic group (e.g., a C_M 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.

[0041] As used herein, an "aralkyl" group refers to an alkyl group (e.g., a C 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.

[0042] 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.

[0043] As used herein, a "cycloaliphatic" group encompasses a "cycloalkyl" group and a "cycloalkenyl" group, each of which being optionally substituted as set forth below.

[0044] 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.

[0045] 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. [0046] 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, (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-S0₂- and aryl-S0₂-], sulfinyl [e.g., alkyl-S(O)-], sulfanyl [e.g., alkyl-S-], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0047] As used herein, the term "heterocycloaliphatic" encompasses a heterocycloalkyl group and a heterocycloalkenyl group, each of which being optionally substituted as set forth below.

[0048] 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, O, 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 ' ]nonyl. A monocyclic

heterocycloalkyl group can be fused with a phenyl moiety to form structures, such as tetrahydroisoquinoline, which would be categorized as heteroaryls.

[0049] 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, O, or S).

Monocyclic and bicyclic heterocycloaliphatics are numbered according to standard chemical nomenclature. [0050] 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., (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., alkylsulfanyl], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0051] 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, O, 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[6]furyl, benzo[6]thiophenyl, quinolinyl, or isoquinolinyl). Some examples of heteroaryl are azetidinyl, pyridyl, lH-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[l,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl,cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo-l,2,5-thiadiazolyl, or 1,8-naphthyridyl.

[0052] Without limitation, monocyclic heteroaryls include furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thiazolyl, 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. [0053] Without limitation, bicyclic heteroaryls include indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[6]furyl, benzo[6]thiophenyl, quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indolyl, benzo[6]furyl, bexo[6]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.

[0054] A heteroaryl is optionally substituted with one or more substituents such as 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 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.

[0055] Non-limiting examples of substituted heteroaryls include (halo)heteroaryl [e.g., mono- and di-(halo)heteroaryl]; (carboxy)heteroaryl [e.g., (alkoxycarbonyl)heteroaryl];

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, and (haloalkyl)heteroaryl [e.g., trihaloalkylheteroaryl]. [0056] A "heteroaraliphatic (such as a heteroaralkyl group) as used herein, refers to an aliphatic group (e.g., a C alkyl group) that is substituted with a heteroaryl group.

"Aliphatic," "alkyl," and "heteroaryl" have been defined above.

[0057] A "heteroaralkyl" group, as used herein, refers to an alkyl group (e.g., a C_1-4 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, 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.

[0058] 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.

[0059] As used herein, a "bridged bicyclic ring system" refers to a bicyclic

heterocycloaliphatic 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[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, 2-oxabicyclo[2.2.2]octyl, l-azabicyclo[2.2.2]octyl, 3- azabicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.0³'⁷]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. [0060] As used herein, an "acyl" group refers to a formyl group or R^x-C(0)- (such as alkyl-C(O)-, also referred to as "alkylcarbonyl") where R^x and "alkyl" have been defined previously. Acetyl and pivaloyl are examples of acyl groups.

[0061] As used herein, an "aroyl" or "heteroaroyl" refers to an aryl-C(O)- or a

heteroaryl-C(O)-, respectively. The aryl and heteroaryl portion of the aroyl or heteroaroyl is optionally substituted as previously defined.

[0062] As used herein, an "alkoxy" group refers to an alkyl-O- group where "alkyl" has been defined previously.

[0063] As used herein, a "carbamoyl" group refers to a group having the structure

-0-CO-NR^xR^Y or -NR^x-CO-0-R^z, wherein R^x and R^Y have been defined above and R^z can be aliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic.

[0064] As used herein, a "carboxy" group refers to -COOH, -COOR^x, -OC(0)H,

-OC(0)R^x, when used as a terminal group; or -OC(O)- or -C(0)0- when used as an internal group.

[0065] As used herein, a "haloaliphatic" group refers to an aliphatic group substituted with 1-3 halogen. For instance, the term haloalkyl includes the group -CF₃.

[0066] As used herein, a "mercapto" group refers to -SH.

[0067] As used herein, a "sulfo" group refers to -SO3H or -S0₃R when used terminally or -S(0)₃- when used internally.

[0068] As used herein, a "sulfamide" group refers to the structure -NR^x-S(0)₂-NR^YR^z when

γ y Y

used terminally and -NR -S(0)₂-NR - when used internally, wherein R , R , and R have been defined above.

Y 7

[0069] As used herein, a "sulfamoyl" group refers to the structure -0-S(0)₂-NR R wherein R and R have been defined above.

y y

[0070] As used herein, a "sulfonamide" group refers to the structure -S(0)₂-NR R or -NR^x-S(0)₂-R^z when used terminally; or -S(0)₂-NR^x- or -NR^X -S(0)₂- when used internally, wherein R^x, R^Y, and R^z are defined above.

[0071] As used herein a "sulfanyl" group refers to -S-R^x when used terminally and -S- when used internally, wherein R^x has been defined above. Examples of sulfanyls include aliphatic-S-, cycloaliphatic-S-, aryl-S-, or the like.

[0072] As used herein a "sulfinyl" group refers to -S(0)-R when used terminally and -S(O)- when used internally, wherein R^x has been defined above. Exemplary sulfinyl groups include aliphatic-S(O)-, aryl-S(O)-, (cycloaliphatic(aliphatic))-S(0)-, cycloalkyl-S(O)-, heterocycloaliphatic-S(O)-, heteroaryl-S(O)-, or the like. [0073] As used herein, a "sulfonyl" group refers to-S(0)₂-R^x when used terminally and -S(0)₂- when used internally, wherein R^x has been defined above. Exemplary sulfonyl groups include aliphatic-S(0)2-, aryl-S(0)₂-, (cycloaliphatic(aliphatic))-S(0)₂-,

cycloaliphatic-S(0)₂-, heterocycloaliphatic-S(0)2-, heteroaryl-S(0)₂-,

(cycloaliphatic(amido(aliphatic)))-S(0)₂- or the like.

[0074] As used herein, a "sulfoxy" group refers to -0-SO-R^x or -SO-0-R^x, when used terminally and -O-S(O)- or -S(0)-0- when used internally, where R^x has been defined above.

[0075] As used herein, a "halogen" or "halo" group refers to fluorine, chlorine, bromine or iodine.

[0076] 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)-.

[0077] As used herein, an "alkoxyalkyl" refers to an alkyl group such as alkyl-O-alkyl-, wherein alkyl has been defined above.

[0078] As used herein, a "carbonyl" refer to -C(O)-.

[0079] As used herein, an "oxo" refers to =0.

[0080] As used herein, the term "phospho" refers to phosphinates and phosphonates.

Examples of phosphinates and phosphonates include -P(0)(R^p)₂, wherein R^p is aliphatic, alkoxy, aryloxy, heteroaryloxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy aryl, heteroaryl, cycloaliphatic or amino.

[0081] As used herein, an "aminoalkyl" refers to the structure (R^x)₂N-alkyl-.

[0082] As used herein, a "cyanoalkyl" refers to the structure (NC)-alkyl-.

[0083] As used herein, a "urea" group refers to the structure -NR^x-CO-NR^YR^z and a

"thiourea" group refers to the structure -NR^X-CS-NR^YR^Z when used terminally and

-NR^x-CO-NR^Y- or -NR^X-CS-NR^Y- when used internally, wherein R^x, R^Y, and R^z have been defined above.

[0084] As used herein, a "guanidine" group refers to the structure -N=C(N(R^XR^Y))N(R^XR^Y) or -NR^X-C(=NR^X)NR^XR^Y wherein R^x and R^Y have been defined above.

[0085] As used herein, the term "amidino" group refers to the structure -C=(NR^X)N(R^XR^Y) wherein R^x and R^Y have been defined above.

[0086] 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. [0087] 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.

[0088] 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., R^xO(0)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)0- or alkyl-OC(O)-) and alkylcarboxyaryl (e.g., alkyl-C(0)0-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groups used internally.

[0089] 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 -[Ώ½]_ν-, 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]_V- 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.

[0090] 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^la, R^lb, R^2a, R ^b, R³, R⁴, and other variables contained in Formula I, described herein, encompass specific groups, such as alkyl and aryl. Unless otherwise noted, each of the specific groups for the variables R^la, R^lb, R^2a, R^2b, R³, R⁴, 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 alkoxy groups can form a ring together with the atom(s) to which they are bound.

[0091] 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 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.

[0092] 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.

[0093] 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.

[0094] 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 ¹³C- or ¹⁴C- 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.

[0095] As used herein, an "adrenergic agonist" refers to any compound having agonistic activity toward any adrenergic receptor (e.g., βι, β₂, β₃). Note that the terms "beta- adrenergic" and " β-adrenergic" are used interchangeably. This usage also applies to subtypes of beta agonists, (e.g., 'beta- 1 -adrenergic agonist' is used interchangeable with ' βΐ- adrenergic agonist' and/or '

agonist').

[0096] As used herein, the term "delaying the onset" of a disease (e.g., obesity (e.g., central obesity)) refers to a delay of symptoms of a disease, wherein the delay caused by the administration of a therapeutic agent (e.g., compound or pharmaceutical composition). The delay of symptoms need not last for the duration of the patient's life, although the delay may last for this duration.

[0097] Chemical structures and nomenclature are derived from ChemDraw, version 1 1.0.1 ,

Cambridge, MA.

[0098] II. COMPOUNDS

[0099] Compounds of the present invention possess a reduced interaction with PPARy and are uniquely effective in treating, preventing, or reducing the symptoms of diabetes and/or other metabolic diseases such as obesity and dyslipidemia.

[0100] One aspect of the present invention provides a compound of Formula I:

I

or a pharmaceutically acceptable salt thereof, wherein each of R^la and R^lb is independently selected from hydrogen, -OH, C alkyl optionally substituted with 1-3 halo, or C alkoxy optionally substituted with 1-3 halo, or R^la and R^lb taken together form oxo; X¹ is -O- or

-CE-2-, or -CH-; is a single bond or a double bond when X¹ is -CH- and one of R^la and R^lb is absent; ring A is selected from

R² is selected from hydrogen or C_1-3 alkyl; R³ is selected from hydrogen, C_1-3 alkyl optionally substituted with 1-3 halo, or C_1-3 alkoxy optionally substituted with 1-3 halo; and R⁴ is -Z^AR^A wherein Z^A is independently selected from a bond, a C_1-3 alkylidene chain, or -C(O)-; and R^A is selected from hydrogen, C_1-3 alkyl, or phenyl optionally substituted with C_1-3 alkyl or C_1-3 alkoxy.

[0101] In some embodiments, ring A is

[0103] In other embodiments, R³ is C_1-3 alkoxy optionally substituted with 1-3 halo. For example, R³ is -OCH₃ or -OCF₃.

[0104] In some embodiments, R⁴ is -Z^AR^A, wherein Z^A is independently selected from a bond or -C(O)-; and R^A is selected from hydrogen, C_1-3 alkyl, or phenyl optionally substituted with C_1-3 alkyl or C_1-3 alkoxy. For example, R⁴ is -Z^AR^A, wherein Z^A is independently selected from a bond or -C(O)-; and R^A is selected from hydrogen, Ci_-3 alkyl, or phenyl substituted with -OCH₃ or -OCH₂CH₃. In some examples, R⁴ is hydrogen, -CH₃, -CH₂CH₃, or -C(0)-CH₃. And, in other examples, R⁴ is -Z^AR^A, wherein Z^A is -C(O)-; and R^A is phenyl optionally substituted with Ci_-3 alkyl or C_1-3 alkoxy. For instance, R⁴ is -Z^AR^A, wherein Z^A is -C(O)-; and R^A is phenyl substituted at its para position with C_1-3 alkyl or C1.3 alkoxy.

[0105] In other embodiments, ring

[0106] In some of these embodiments, R is selected from hydrogen, methyl, or ethyl. For example, R² is hydrogen. In other examples, R² is methyl.

[0107] In some embodiments, R is Cu₃ alkoxy optionally substituted with 1-3 halo. For example, R³ is -OCH₃ or -OCF3.

[0108] In alternative embodiments, is a double bond, one ofR^la and R^lb is absent, and X¹ is -CH-. [0109] And, in some embodiments, one of R^la and R^lb is hydrogen and the other is selected from hydrogen, -CH₃, -CH₂CH₃, -OCH₃, or -OCH₂CH₃.

[0110] In some embodiments, the compound of Formula I is selected from a compound of Formul

IV

wherein X^la is -O- or -CH₂- and each of R^la, R^lb, R², and R⁴, are defined above.

[0111] In some embodiments, the compound of Formula I is selected from a compound of

Formu

IIA IIB

IVA , or I A

wherein X^la is -O- or -CH₂- and each of R^la, R², and R⁴, are defined above.

[0112] Examples of compounds of Formula I include those provided in Table A: Table A: Exemplary compounds of Formula I.

[0113] III. PHARMACEUTICAL COMPOSITIONS

[0114] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein each of R^la and R^lb is independently selected from hydrogen, -OH, C_{1 -4} alkyl optionally substituted with 1-3 halo, or CM alkoxy optionally substituted with 1-3 halo, or R^la and R^lb taken together form oxo; X¹ is -O- or -CH2-, or -CH-; mrm is a single bond or a double bond when X¹ is -CH- and one of R^la and R is absent; ring A i

R² is selected from hydrogen or Cu alkyl; R³ is selected from hydrogen, C1.3 alkyl optionally substituted with 1-3 halo, or C_1-3 alkoxy optionally substituted with 1-3 halo; and R⁴ is -Z^AR^A wherein Z^A is independently selected from a bond, a C_1-3 alkylidene chain, or -C(O)-; and R^A is selected from hydrogen, C_1-3 alkyl, or phenyl optionally substituted with C1.3 alkyl or C 1.3 alkoxy, and a pharmaceutically acceptable carrier.

[0115] In some embodiments, the pharmaceutical composition comprises a compound of Formula IIA, IIB, IV A, or IVB, wherein said compound has a purity of about 70 e.e. % or more. For example, the pharmaceutical composition comprises a compound of Formula IIA, IIB, IVA, or IVB, wherein the compound has a purity of about 80 % e.e. or more (e.g., 90 % e.e. or more, 95 % e.e. or more, 97 % e.e. or more, or 99 % e.e. or more).

[0116] Pharmaceutical compositions of the present invention can also comprise one or more additional pharmaceutical agents or other drugs. In some embodiments, the pharmaceutical composition further comprises a diuretic, such as hydrochlorothiazide, chlorothaladone, chlorothiazide, or combinations thereof. In some embodiments, the pharmaceutical composition further comprises one or more agents that limit the activity of the rennin- angiotensin system such as angiotensin concerting enzyme inhibitors, i.e., ACE inhibitors, e.g. ramipril, captopril, enalapril, or the like, and/or angiotensin II receptor blockers, i.e., ARBs, e.g., candesartan, losartan, olmesartan, or the like; and/or rennin inhibitors. In other embodiments, the pharmaceutical composition further comprises a compound that limits hypertension by alternate means including β-adrenergic receptor blockers, and calcium channel blockers, e.g., amlodipine. In some embodiments, the pharmaceutical composition further comprises one or more statins, i.e., HMG-CoA reductase inhibitor, e.g., atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, simvastatin, rosuvastatin, pravastatin, or any pharmaceutically acceptable combination thereof.

[0117] In another embodiment, the pharmaceutical composition further comprises a GLP analogue and/or a DPP4 inhibitor.

[0118] In alternative embodiments, the pharmaceutical composition further comprises a phosphodiesterase inhibitor in combination with a beta-adrenergic agonist and at least one additional weight loss drug. Non-limiting examples of other weight loss drugs include appetite suppressants (e.g., Meridia, or the like), fat absorption inhibitors (e.g., Xenical, or the like), or compounds that augment sympathomimetic activity such as ephedrine or its various salts.

[0119] Exemplary pharmaceutical compositions according to the present invention include a single unit dosage form having about 1 mg to about 200 mg of a compound of Formula I, e.g., between about 10 mg to about 120 mg, between about 10 mg to about 100 mg, or about 15 mg to about 60 mg.

[0120] IV. METHODS OF TREATING DIABETES AND OTHER METABOLIC DISEASES

[0121] A. Diabetes

[0122] Another aspect of the present invention provides a method of treating, preventing, or reducing the symptoms of diabetes comprising administering to a patient a compound of Formula I or a pharmaceutical composition as described herein. [0123] Another aspect of the present invention provides a method for inducing remission of the symptoms of diabetes mellitus in a patient comprising administering to the patient a compound of Formula I or a pharmaceutical composition as described herein.

[0124] The present invention also provides methods of treating or delaying the onset, i.e., preventing, of diabetes mellitus in a patient comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof (e.g., an alkali earth metal salt), and administering a GLP analogue. The administration of the compound of Formula I can occur prior to, after, or concurrent with the administration of the GLP analogue.

[0125] In several embodiments, the method of treating or preventing diabetes mellitus in a patient comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof (e.g., an alkali earth metal salt); and a GLP analogue, wherein the administration further comprises administering a compound of Formula I prior to administering a GLP analogue. In several examples, the administration of the compound of Formula I, although beginning prior to the administration of the GLP analogue, continues for at least some duration of time wherein the GLP analogue is co-administered. In several examples, the administration of the compound of Formula I ceases once the administration of a GLP analogue begins. In several examples, the administration of the compound of Formula I begins prior to the administration of a GLP analogue and continues for at least the duration of time in which the GLP analogue is administered.

[0126] In alternative embodiments, the method of treating or preventing diabetes mellitus in a patient comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof (e.g., an alkali earth metal salt); and a GLP analogue, wherein the administration further comprises administering a compound or compound salt of Formula I concurrently with the administering of a GLP analogue.

[0127] In several embodiments, the method of treating or preventing diabetes mellitus in a patient comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof (e.g., an alkali earth metal salt); and a GLP analogue, wherein the administration further comprises administering a compound of Formula I after administering a GLP analogue. In several examples, the administration of the compound of Formula I, although starting after the administration of the GLP analogue, continues for at least some duration of time wherein the GLP analogue is co-administered. In several examples, the administration of the GLP analogue ceases once the administration of a compound of Formula I begins. In several examples, the administration of GLP analogue begins prior to the administration of the compound of Formula I GLP analogue and continues for at least the duration of time in which the compound of Formula I is administered.

[0128] The present invention also provides methods of treating or preventing diabetes mellitus in a patient comprising administering a compound of Formula I or a

pharmaceutically acceptable salt thereof (e.g., an alkali earth metal salt), and administering a DPP4 inhibitor. The administration of the compound or compound salt of Formula I can occur prior to, after, or concurrent with the administration of the DPP4 inhibitor.

[0129] In several embodiments, the method of treating or preventing diabetes mellitus in a patient comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof (e.g., an alkali earth metal salt); and a DPP4 inhibitor, wherein the administration further comprises administering a compound or compound salt of Formula I prior to administering a DPP4 inhibitor. In several examples, the administration of the compound of Formula I, although beginning prior to the administration of the DPP4 inhibitor, continues for at least some duration of time wherein the DPP4 inhibitor is co-administered. In several examples, the administration of the compound of Formula I ceases once the administration of a DPP4 inhibitor begins. In several examples, the administration of the compound of Formula I begins prior to the administration of a DPP4 inhibitor and continues for at least the duration of time in which the DPP4 inhibitor is administered.

[0130] In alternative embodiments, the method of treating or preventing diabetes mellitus in a patient comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof; and a DPP4 inhibitor, wherein the administration further comprises

administering a compound of Formula I concurrently with the administering of a DPP4 inhibitor.

[0131] In several embodiments, the method of treating or preventing diabetes mellitus in a patient comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof (e.g., an alkali earth metal salt); and a DPP4 inhibitor, wherein the administration further comprises administering a compound of Formula I after administering a DPP4 inhibitor. In several examples, the administration of the compound of Formula I, although starting after the administration of the DPP4 inhibitor, continues for at least some duration of time wherein the DPP4 inhibitor is co-administered. In several examples, the administration of the DPP4 inhibitor ceases once the administration of a compound of Formula I begins. In several examples, the administration of DPP4 inhibitor begins prior to the administration of the compound of Formula I and continues for at least the duration of time in which the compound of Formula I is administered. [0132] Another aspect of the present invention provides a method of treating or preventing diabetes mellitus in a patient comprising administering a pharmaceutical composition comprising a compound of Formula I and GLP analogue (e.g., GLP-1 analogue).

[0133] Another aspect of the present invention provides a method of treating or preventing diabetes mellitus in a patient comprising administering a pharmaceutical composition comprising a compound of Formula I and a DPP4 inhibitor.

[0134] Several methods further comprise the administration of an agent that increases a cyclic nucleotide level (e.g., increases cellular cAMP levels) in a patient. The administration of these ingredients can be sequential (e.g., the compound of Formula I is administered first in time, and the agent is administered second in time) or simultaneous, i.e., both ingredients are administered at substantially the same time, or administered as a single pharmaceutical composition.

[0135] Several embodiments comprise the step of administering to a patient a

pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and a phosphodiesterase inhibitor; and either a GLP analogue or a DPP4 inhibitor. Other embodiments further comprise the administration of an agent that increases a cyclic nucleotide level in a patient (e.g., a β-adrenergic agonist).

[0136] In one embodiment, the method of treating or preventing diabetes mellitus further comprises administering a co-therapy such as a third pharmaceutical agent, a restricted diet, increase the duration and/or exertion of a patient's physical activity, or any combination thereof.

[0137] Another aspect of the present invention provides a method of treating and/or preventing diabetes mellitus comprising administering a pharmaceutical composition comprising a compound of Formula I, wherein said compound has a purity of about 70 e.e.% or more. For example, the method treating diabetes mellitus comprises administering a pharmaceutical composition comprising a compound of Formula I and either a GLP analogue or a DPP4 inhibitor, wherein the compound of Formula I has a purity of about 80% e.e. or more (e.g., 90% e.e. or more, 95% e.e. or more, 97% e.e. or more, or 99% e.e. or more).

[0138] Another aspect of the present invention provides a method of inducing remission of the symptoms of diabetes mellitus (e.g., type-2 diabetes mellitus) comprising administering a compound of Formula I or a pharmaceutically acceptable salt (e.g., an alkali earth metal salt) thereof; and a GLP (e.g., GLP-1) analogue.

[0139] In several embodiments, the method comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof; and a GLP analogue to a patient having a HbAlC level of at least about 6.5 mmol/mol (e.g., at least about 7.0 mmol/mol or at least about 7.5 mmol/mol). In several examples, the patient suffers from type-2 diabetes.

[0140] In several embodiments, the method comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof; and a GLP analogue until the patient presents a HbAlC level of no more than about 6.0 mmol/mol (e.g., no more than about 5.9 mmol/mol). When the patient presents a HbAlC level of about 6.0 mmol or less, the administration is arrested and the patient is deemed to be in state of remission. In some instances, when the patient presents a HbAlC level of about 6.0 mmol or less, the

administration of the GLP analogue (e.g., administration by injection, oral administration, nasal administration, or rectal administration) is arrested while the administration of the compound of Formula I or its salt continues substantially throughout the remission period. In other instances, when the patient presents a HbAlC level of about 6.0 mmol or less, the administration of both the GLP analogue (e.g., administration by injection, oral

administration, nasal administration, or rectal administration) and the administration of the compound of Formula I or its salt is also arrested throughout the remission period. The return of an HbAlC level of about 6.0 or greater in a patient signals the end of the remission period, and the administration of the compound of Formula I and the GLP analogue resumes. Note that the administration that resumes at the conclusion of remission need not be identical (e.g., different compounds of Formula I, different dosages, different GLP analogues, or any combination thereof) to the administration that induced the preceding remission state.

[0141] As noted above, the administration of the compound of Formula I can occur prior to, after, or concurrent with the administration of the GLP analogue in methods for inducing remission. In several methods, the compound of Formula I is administered after a patient is administered a GLP analogue. In several embodiments, the method of inducing remission of the symptoms of diabetes mellitus (e.g., type-2 diabetes mellitus) comprises administering to a patient a compound of Formula I or a pharmaceutically acceptable salt thereof; and a GLP analogue (e.g., Exenatide (e.g., Byetta), Exendin-4, Liraglutide, Taspoglatide, or any combination thereof). For instance, the method comprises administering to a patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, prior to the

administration of a GLP analogue (e.g., Exenatide (e.g., Byetta), Exendin-4, Liraglutide, Taspoglatide, or any combination thereof). In another example, the method comprises administering to a patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, concurrently with the administration of a GLP analogue (e.g., Exenatide (e.g., Byetta), Exendin-4, Liraglutide, Taspoglatide, or any combination thereof). And in another example, the method comprises administering to a patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, after the administration of a GLP analogue (e.g., Exenatide (e.g., Byetta), Exendin-4, Liraglutide, Taspoglatide, or any combination thereof).

[0142] In several embodiments, the method of inducing remission of the symptoms of diabetes mellitus (e.g., type-2 diabetes mellitus) comprises administering to a patient a compound of Formula I or a pharmaceutically acceptable salt thereof; and a GLP analogue (e.g., Exenatide (e.g., Byetta), Exendin-4, Liraglutide, Taspoglatide, or any combination thereof). For instance, the method comprises administering to a patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, prior to the administration of a GLP analogue (e.g., Exenatide (e.g., Byetta), Exendin-4, Liraglutide, Taspoglatide, or any combination thereof). In another example, the method comprises administering to a patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, concurrently with the administration of a GLP analogue (e.g., Exenatide (e.g., Byetta), Exendin-4, Liraglutide, Taspoglatide, or any combination thereof). And in another example, the method comprises administering to a patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, after the administration of a GLP analogue (e.g., Exenatide (e.g., Byetta), Exendin-4, Liraglutide, Taspoglatide, or any combination thereof).

[0143] Another aspect of the present invention provides a method of inducing remission of the symptoms of diabetes mellitus (e.g., type-2 diabetes mellitus) comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof; and a DPP4 inhibitor.

[0144] In several embodiments, the method comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof; and a DPP4 inhibitor to a patient having a HbAlC level of at least about 6.5 mmol/mol (e.g., at least about 7.0 mmol/mol or at least about 7.5 mmol/mol). In several examples, the patient suffers from type-2 diabetes.

[0145] In several embodiments, the method comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof; and a DPP4 inhibitor until the patient presents a HbAlC level of no more than about 6.0 mmol/mol (e.g., no more than about 5.9 mmol/mol). When the patient presents a HbAlC level of about 6.0 mmol or less, the administration is arrested and the patient is deemed to be in state of remission. When the patient's HbAlC level rises to 6.0 or greater, the remission period is concluded and the administration of the compound of Formula I and the DPP4 inhibitor resumes. Note that the administration that resumes at the conclusion of remission need not be identical (e.g., different compounds of Formula I, different dosages, different DPP4 inhibitors, or any combination thereof) to the administration that induced the preceding remission state. [0146] As noted above, the administration of the compound of Formula I can occur prior to, after, or concurrent with the administration of the DPP4 inhibitor in methods for inducing remission. In several methods, the compound of Formula I is administered after a patient is administered a DPP4 inhibitor. In several embodiments, the method of inducing remission of the symptoms of diabetes mellitus (e.g., type-2 diabetes mellitus) comprises administering to a patient a compound of Formula I or a pharmaceutically acceptable salt thereof; and a DPP4 inhibitor (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof). For instance, the method comprises administering to a patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, prior to the administration of a DPP4 inhibitor (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof). In another example, the method comprises administering to a patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, concurrently with the administration of a DPP4 inhibitor (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof). And in another example, the method comprises administering to a patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, after the administration of a DPP4 inhibitor (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof).

[0147] In several methods, the compound of Formula I is administered after a patient is administered a DPP4 inhibitor. In several embodiments, the method of inducing remission of the symptoms of diabetes mellitus (e.g., type-2 diabetes mellitus) comprises administering to a patient a compound of Formula I or a pharmaceutically acceptable salt thereof; and a DPP4 inhibitor (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof). For instance, the method comprises administering to a patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, prior to the administration of a DPP4 inhibitor (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof). In another example, the method comprises administering to a patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, concurrently with the administration of a DPP4 inhibitor (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof). And in another example, the method comprises administering to a patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, after the administration of a DPP4 inhibitor (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof).

[0148] B. Obesity [0149] Another aspect of the present invention provides a method of treating or preventing obesity (e.g., central obesity) and/or reducing bodyweight in a patient comprising

administering a pharmaceutical composition comprising a compound of Formula I or a pharmaceutical composition as described herein.

[0150] Several embodiments comprise the step of administering to a patient a compound of Formula I and an agent that increases a cyclic nucleotide level (e.g., increases cellular cAMP levels) in a patient. The administration of these ingredients can be sequential (e.g., the compound of Formula I is administered first in time, and the agent is administered second in time) or simultaneous, i.e., both ingredients are administered at substantially the same time.

[0151] Several embodiments comprise the step of administering to a patient a

pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and a phosphodiesterase inhibitor; and an agent that increases a cyclic nucleotide level in a patient (e.g., a β-adrenergic agonist).

[0152] Another aspect of the present invention provides a method of treating or preventing diabetes in a patient comprising administering a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0153] Several methods comprise the step of administering to a patient a compound of

Formula I and an agent that increases a cyclic nucleotide level in a patient.

[0154] Several methods comprise the step of administering to a patient a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and a phosphodiesterase inhibitor; and an agent that increases a cyclic nucleotide level in a patient (e.g., a β-adrenergic agonist).

[0155] In one embodiment, the method of treating or preventing diabetes further comprises administering a co-therapy such as a third pharmaceutical agent, a restricted diet, increase the duration and/or exertion of a patient's physical activity, or any combination thereof.

[0156] Another aspect of the present invention provides a method of treating and/or preventing diabetes comprising administering a pharmaceutical composition comprising a compound of Formula I wherein said compound has a purity of about 70 e.e.% or more. For example, the method treating obesity and/or reducing a patient's bodyweight comprises administering a pharmaceutical composition comprising a compound of Formula I wherein the compound has a purity of about 80% e.e. or more (e.g., 90% e.e. or more, 95% e.e. or more, 97% e.e. or more, or 99% e.e. or more).

[0157] According to yet another embodiment, the present invention provides a method of treating or reducing the severity of central obesity. [0158] In one embodiment, the method of treating obesity (e.g., central obesity), reducing bodyweight in a patient, or treating diabetes further comprises administering a co-therapy such as a third pharmaceutical agent (e.g., weight loss drugs (e.g., appetite suppressants (e.g., Meridia, or the like), fat absorption inhibitors (e.g., Xenical, or the like), or compounds that augment sympathomimetic activity such as ephedrine or its various salts)), a restricted diet, increase the duration and/or exertion of a patient's physical activity, or any combination thereof.

[0159] C. Dyslipidemia

[0160] Another aspect of the present invention provides a method of treating, preventing, or reducing the symptoms of dyslipidemia comprising administering to a patient a compound of Formula I or a pharmaceutical composition as described herein. Another aspect of the present invention provides a method of lowering lipids in a patient comprising administering to a patient a compound of Formula I or a pharmaceutical composition as described herein.

[0161] V. GENERAL SYNTHETIC SCHEMES

[0162] The compounds of Formula I may be readily synthesized from commercially available or known starting materials by known methods. Exemplary synthetic routes to produce compounds of Formula I are provided in the Schemes below.

[0163] Scheme 1:

[0164] Referring to Scheme 1, 3-hydroxybenzaldehyde is treated with a triphenylphosphene reagent to generate 4-(3-hydroxyphenyl)but-3-en-2-one, which undergoes hydrogenation to form 4-(3-hydroxyphenyl)butan-2-one. 4-(3-hydroxyphenyl)butan-2-one is reacted with R³ substituted phenylhydrazine 1-1 to generate the indole intermediate 1-2. Intermediate 1-2 is reacted with the ester 1-3 to generate intermediate 1-4. Intermediate 1-4 may undergo deprotection to generate compound 1-5, or intermediate 1-4 may be further functionalized to generate intermediate 1-6 before undergoing deprotection to generate compound 1-7, wherein compounds 1-5 and 1-7 are compounds of Formula I.

[0165] Scheme 2:

[0166] Referring to Scheme 2, the carboxylic acid group of starting material 2-1 is protected as the allyl ester to form the protected intermediate 2-2. The intermediate 2-2 is amidated to form intermediate 2-3. Intermediate 2-3 is deprotected to form compound 2-4, which is a compound of Formula I.

[0167] Scheme 3:

[0168] Referring to Scheme 3, methyl 3-formylbenzoate is treated with a

triphenylphosphene reagent to generate methyl 3-(3-oxobut-l-enyl)benzoate, which is hydrogenated to form methyl 3-(3-oxobutyl)benzoate. Methyl 3-(3-oxobutyl)benzoate is reacted with R³ substituted phenylhydrazine 1-1 to generate the indole intermediate 3-1. Reduction of the ester functionality of intermediate 3-1 using a reducing agent such as Lithium Aluminum Hydride (LAH) provides the benzyl alcohol 3-2 which can then be oxidized to the benzaldehyde intermediate 3-2 using an oxidizing agent such as

o-iodoxybenzoic acid (IBX). Treatment with an alpha-triphenylphosphenium ester of formula 3-4 provides the olefin intermediate 3-5. Intermediate 3-5 can then be immediately hydrolyzed to the corresponding acid 3-6, or further functionalized at the ring nitrogen of the indole scaffold to produce a compound of 3-7 which can then be hydrolyzed to the corresponding acid of formula 3-8, wherein compounds 3-7 and 3-8 are compounds of Formula I.

[0169] Scheme 4:

[0170] Referring to Scheme 4, isophthalaldehyde is reduced using sodium borohydride to provide 3-(hydroxymethyl)benzaldehyde. The hydroxy functionality can then be protected as the tributylsilyl ether using a reagent such as TBSC1. Aldol condensation with an

alph-methylene ethyl ester, followed by dehydration provides the olefin intermediate 4-1. Chiral reduction of the olefin provides chiral intermediate 4-2, which can then be converted to the mesylate intermediate 4-3 by removal of the silyl protecting group using TBAF, followed by treatment with methanesulfonyl chloride. Nucleophilic substitution of the mesyl group with an indole of formula 4-4 in the presence of strong base such as sodium hydride or cesium carbonate provides intermediate 4-5. Saponification of 4-5 using an aqueous base such as sodium hydroxide provides a compound of formula 4-6, which is also a compound of Formula I.

[0171] VI. USES, FORMULATIONS, AND ADMINISTRATION

[0172] As discussed above, the present invention provides compounds that are useful as treatments for obesity and/or reducing a patient's bodyweight.

[0173] Accordingly, in another aspect of the present invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

[0174] It will also be appreciated that certain compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative or a prodrug thereof. According to the present invention, a pharmaceutically acceptable derivative or a prodrug includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

[0175] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.

[0176] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N^C_Malkyl^ salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0177] As described above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or

emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the

pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene- block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc;

excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. [0178] According to the invention an "effective amount" of the compound or pharmaceutically acceptable composition is that amount effective for treating, preventing, or lessening the severity of metabolic diseases such as obesity, i.e., weight loss, diabetes, and/or neurodegenerative diseases (e.g., Alzheimer's disease, dementia, or the like).

[0179] The pharmaceutical compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of obesity and/or obesity related diseases.

[0180] The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors known in the medical arts. The term "patient", as used herein, means an animal, for example, a mammal, and more specifically a human.

[0181] The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. Alternatively, the compounds of the invention may be

administered orally or parenterally at dosage levels of between 10 mg/kg and about 120 mg/kg. [0182] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0183] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0184] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0185] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0186] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0187] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0188] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. [0189] The active compounds can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0190] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0191] As described generally above, the compounds of the invention are useful as treatments for metabolic diseases.

[0192] The activity, or more importantly, reduced PPARy activity of a compound utilized in this invention as a treatment of obesity and/or reducing bodyweight may be assayed according to methods described generally in the art and in the examples provided herein.

[0193] It will also be appreciated that the compounds and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated".

[0194] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0195] The compounds of this invention or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters.

Accordingly, the present invention, in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. In still another aspect, the present invention includes an implantable device coated with a composition comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatings and the general preparation of coated implantable devices are described in US Patents 6,099,562; 5,886,026; and 5,304,121, each of which is incorporated by reference. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.

[0196] Another aspect of the invention relates to treating metabolic diseases in a biological sample or a patient (e.g., in vitro or in vivo), which method comprises administering to the patient, or contacting said biological sample with a pharmaceutical composition comprising a compound of Formula I, II, III, or IV. The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0197] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.

[0198] VII. EXAMPLES

[0199] Example 1; Preparation of 5-iil-(2-hvdroxy-2-phenylethvn-lH-indol-5- yllmethyl -thiazolidine-2,4-dio

[0200] Suspended (5Z)-5- { [1 -(2-hydroxy-2-phenylethyl)- 1 H-indol-5-yl]methylene} -1 ,3- thiazolidine-2,4-dione (1.09 g, 2.99 mmol; Supplier = Kalexsyn; Lot = 803-TTP-231) in THF (50ml) and H₂0 (50ml). Some solids dissolved, but not all. Added a small crystal of CoCl₂ and 2,2'-bipyridine. Added a small amount of NaBFL_t, which resulted in a deep blue color and gas evolution. When the blue color faded to yield an amber solution, small quantities of NaBFL; were added successively to regenerate the deep blue color. Additions of NaBH₄ were repeated until HPLC indicated that the reaction was complete. pH of the reaction mixture was adjusted to ca. 7 with HO Ac. Extracted with EtOAc. Extract washed with brine, dried (Na₂S0₄), filtered and evaporated in vacuo. The residue was chromatographed on a small Biotage column eluting with 0-20% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 0.94 g pale yellow oil.

[0201] HPLC: RT = 3.739, 100area% at 210 and 254 nm. MS (ESI+) for Ο-οΗΛΟ^ m/z 367.1 (M+H)⁺; MS (ESI-) for C₂₀Hi₈N₂O₃Si m/z 365.1 (M-H)\ 1H-NMR (CDC1₃)_: δ = 8.23 (s, 1H), 7.38 (s, 1H), 7.23 (m, 6H), 7.01 (dd, J=3.1, 1.9Hz, 1H), 6.96 (dd, J=8.5, 1.7Hz, 1H), 6.36 (d, J=3.1Hz, 1H), 4.95 (brs, 1H), 4.47 (m, 1H), 4.20 (M, 2H), 3.55 (m, 1H), 3.11 (M, 1H), 2.11 (brs, 1H).

[0202] Example 2: Preparation of (2S)-2-(3-([l-(4-methoxybenzovn-2-methyl-5- (trifluoromethoxyVlH-indol-3-yl]methvnphenoxy)propanoic acid

[0203] To a stirring solution of allyl (2S)-2-(3-{[l-(4-methoxybenzoyl)-2-methyl-5- (trifluoromethoxy)-lH-indol-3-yl]methyl}phenoxy)propanoate (400 mg, 0.7 mmol; Supplier = Kalexsyn; Lot = 1003-TTP-271) in DMF (7ml) was added N,N-Diisopropylethylamine (0.184 mL, 1.05 mmol), 5,5-Dimethylcyclohexane-l,3-dione (148 mg, 1.05 mmol) and Tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.04 mmol). Stirred at RT for 2 hours. HPLC indicates reaction is complete. Quenched with saturated NH₄CI and partitioned between DCM and water. The aqueous phase was extracted twice with DCM. The combined organic phases were dried (Na₂S0₄), filtered and evaporated in vacuo. The residue was chromatographed on a small Biotage column eluting with 0-5% MeOH/DCM. Fractions containing product were combined and evaporated in vacuo.

[0204] HPLC: RT = 5.019 min, 100area% at 210nm and 254nm. MS (ESI+) for

C₂8H₂₄F₃Ni0₆ m/z 528.1 (M+H)^+;MS (ESI-) forC₂₈H₂₄F₃N₁0₆ m/z 526.2 (M-H)\ 1H-NMR (CDC1₃)_: 6 = 7.74 (d, J=8.9Hz, 2H), 7.20 (m, 2H), 7.00 (d, J=8.7Hz, 3H), 6.89 (d, J=8.1Hz, 2H), 6.73 (m, 2H), 4.03 (s, 2H), 3.92 (s, 3H), 2.39 (s, 2H), 1.62 (d, J=6.8Hz, 3H).

[0205] Example 3; Preparation of (2S)-2-(3-([l-(4-methoxybenzovn-2-methyl-5- (trifluoromethoxy)-lH-indol-3-yll methyl) phenoxy)propanoic acid

[0206] To a stirring solution of allyl (2S)-2-(3-{[2-methyl-5-(trifluoromethoxy)-lH-indol- 3-yl]methyl}phenoxy)propanoate (250 mg, 0.58 mmol; Supplier = Kalexsyn; Lot = 1003- TTP-320) in DMF (3ml) was added N,N-Diisopropylethylamine (0.150 mL, 0.863 mmol), 5,5-Dimethylcyclohexane-l,3-dione (121 mg, 0.863 mmol) and

tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.03 mmol). Stirred at RT for 2 hours. HPLC indicates reaction is complete. Quenched with sat'd NH4C1 and partiontoned between DCM and water. The aqueous phase was extracted twice with DCM. The combined organic phases were dried (Na2S04), filtered and evaporated in vacuo. The residue was chromatographed on a small Biotage column eluting with 0-5% MeOH/DCM. Fractions containing product were combined and evaporated in vacuo.

[0207] HPLC: RT = 4.487 min, 98area% at210 and 100area% at 254nm. MS (ESI+) for C₂oH₁9F₃N₁04 m/z 394.1 (M+H)⁺; MS (ESI-) for C₂oH₁₉F₃N₁0₄ m/z 392.1 (M-H)^". 1H-NMR (CDC1₃); 5 = 7.84 (s, 1H), 7.19 (m, 3H), 6.96 (dd, J=8.8, 1.1Hz, 1H), 6.89 (d, J=7.7Hz, 1H), 6.70 (m, 2H), 4.72 (q, J=6.8Hz, 1H), 4.00 (s, 2H), 2.33 (s, 3H), 1.61 (d, J=6.8Hz, 3H).

[0208] Example 4; Preparation of (2S)-2-(3-i[1.2-dimethyl-5-(trifluoromethoxy)-lH- indol-3-yll methyl) phenoxy)propanoic acid

[0209] To a stirring solution of allyl (2S)-2-(3-{[l,2-dimethyl-5-(trifluoromethoxy)-lH- indol-3-yl]methyl}phenoxy)propanoate (220 mg, 0.49 mmol; Supplier = Kalexsyn; Lot = 1003-TTP-323) in DMF (3ml) was added N,N-Diisopropylethylamine (0.128 mL, 0.736 mmol), 5,5-Dimethylcyclohexane-l,3-dione (103 mg, 0.735 mmol) and

Tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.02 mmol). Stirred at RT for 2 hours. HPLC indicates reaction is complete. Quenched with saturated NH₄C1 and partitioned between DCM and water. The aqueous phase was extracted twice with DCM. The combined organic phases were dried (Na₂S0 ), filtered and evaporated in vacuo. The residue was chromatographed on a small Biotage column eluting with 0-5% MeOH/DCM. Fractions containing product were combined and evaporated in vacuo.

[0210] HPLC: RT = 4.835 min, 100area% at 210 and 254nm. m/z (M+H)⁺. MS (ESI+) for C₂₁H₂₀F₃N₁O₄ m/z 408.1 (M+H)⁺; MS (ESI-) for C₂iH₂₀F₃NiO₄ m/z 406.2 (M-H)\ 1H-NMR (CDCI₃): δ = 7.19 (m, 3H), 7.01 (d, J=8.7Hz, 1H), 6.87 (d, J=7.7Hz, 1H), 6.69 (m, 2H), 4.73 (q, J=6.8Hz, 1H), 4.03 (s, 2H), 3.67 (s, 3H), 2.35 (s, 4H), 1.60 (d, J=6.8Hz, 3H).

[0211] Example 5: Preparation of (2S)-2-(3-Ul-acetyl-2-methyl-5-ftrifluoromethoxyV lH-ind -3-yll methyl) phenoxy)propanoic acid

[0212] To a stirring solution of allyl (2S)-2-(3-{[l-acetyl-2-methyl-5-(trifluoromethoxy)- lH-indol-3-yl]methyl}phenoxy)propanoate (534 mg, 1.12 mmol) in DMF (3ml) was added

N,N-Diisopropylethylamine (0.293 mL, 1.68 mmol), 5,5-Dimethylcyclohexane-l,3-dione (235 mg, 1.68 mmol) and Tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.06 mmol). Stirred at RT for 2 hours. HPLC indicates reaction is complete. Quenched with saturated NH4CI and partitioned between DCM and water. The aqueous phase was extracted twice with DCM. The combined organic phases were dried (Na₂S0₄), filtered and evaporated in vacuo. The residue was chromatographed on a small Biotage column eluting with 0-5% MeOH/DCM. Fractions containing product were combined and evaporated in vacuo.

[0213] HPLC: RT= 4.671min, 100area% at 254nm. MS (ESI+) for C₂₂H₂₀F₃NiO₅ m/z 436.1 (M+H)⁺.

[0214] Example 6: Preparation of (2Z)-2-ethoxy-3-(3-i[2-methyl-5-(trifluoromethoxy)- lH-ind -3-yl] methyl) phenvDacrylic acid

[0215] To a stirring solution of ethyl (2Z)-2-ethoxy-3-(3-{[2-methyl-5-(trifluoromethoxy)- lH-indol-3-yl]methyl}phenyl)acrylate (77 mg, 0.17 mmol; Supplier = Kalexsyn; Lot = 1103- TTP-59) in EtOH (2ml) was added a few drops of 2M NaOH until pH ca. 10. After 5 hours, only a very small amount of SM remains. Left to stir at RT overnight. LCMS indicates that the reaction is complete. Evaporated in vacuo. Partitioned between water and EtOAc and added HO Ac until pH ca. 3. Separated organic phase which was dried (Na₂S0₄), filtered and evaporated in vacuo. Chromatographed on a pipette column eluting with 0-10%

EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo.

[0216] HPLC: RT = 4.720min, 100area% at 210 and 254nm. MS (ESI+) for C₂2H₂oF₃N₁0₄ m/z 420.0 (M+H)⁺. MS (ESI-) for C₂₂H₂₀F₃N₁O₄ m/z 418.0 (M-H)\ 1H-NMR (CDC1₃)_: δ = 7.93 (s, 1H), 7.60 (m, 2H), 7.26 (m, 4H), 7.10 (s, 1H), 6.98 (dd, J=8.6, 1.1Hz, 1H), 4.07 (s, 2H), 3.88 (q, J=7.1Hz, 2H), 2.41 (s, 3H), 1.18 (t, J=7.1Hz, 3H).

[0217] Example 7; Preparation of 2-ethoxy-3-(3-([2-methyl-5-(trifluoromethoxy H- indol-3-vU methyl)phenyl)propanoic acid

[0218] To a stirring solution of [A] ethyl (2Z)-2-ethoxy-3-(3-{ [2-methyl-5- (trifluoromethoxy)-lH-indol-3-yl]methyl}phenyl)acrylate (100 mg, 0.2 mmol; Supplier = Kalexsyn; Lot = 1103-TTP-88) in EtOH was added 2M aq. NaOH until pH ca. 10. Left to stir at RT overnight. The reaction is complete. Partitioned between water and EtOAc; added aq. HC1 until pH ca. 3. Organic phase separated and aqueous phase extracted with EtOAc. Combined organic phases dried (Na₂S0₄), filtered and evaporated in vacuo.

Chromatographed on a small RediSep column eluting with 0-25% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 66 mg amber oil.

[0219] HPLC: RT = 4.443min, 96area% at 254nm. MS (ESI+) for C₂2H22F₃N₁0₄ m/z 422.1 (M+H)⁺. MS (ESI-) for C₂₂H₂₂F₃N₁0₄ m/z 420.1 (M-H)-. 1H-NMR (CDC1₃)_: δ = 7.92 (brs, 1H), 7.20 (m, 3H), 7.08 (m, 3H), 6.96 (dd, J=8.7, 1.2Hz, 1H), 4.01 (q, J=3.9Hz, 4H), 3.50 (m, 1H), 3.31 (m, 1H), 3.08 (dd, J=14.0, 3.8Hz, 1H), 2.93 (dd, J=14.0, 8.2Hz, 1H), 2.40 (s, 3H), 1.04 (t, J=7.1Hz, 3H).

[0220] Example 8: Preparation of (2Z)-3-(3-ifl.2-dimethyl-5-(trifluoromethoxyVlH-

[0221] A stirring solution of ethyl (2Z)-3-(3-{[l,2-dimethyl-5-(trifluoromethoxy)-lH-indol- 3-yl]methyl}phenyl)-2-ethoxyacrylate (144 mg, 0.312 mmol; Supplier = Kalexsyn; Lot = 1103-TTP-92) in EtOH (2ml) and 2M NaOH (pH ca. 10) was left to stir at RT overnight. 03/25/2011 07:40 AM, EDT. The reaction is complete (HPLC, LCMS). Partitioned between water and EtOAc and added aq. HC1 until pH ca. 3. Separated phases and extracted aqueous phase with EtOAc. Combined organic phases dried (Na₂S0₄), filtered and evaporated in vacuo to give 102 mg cream colored solid. Chromatographed on a small MM column eluting with 0-10% EtOAc/DCM, then 10% acetone/DCM, then 7% MeOH/DCM. Fractions containing product were combined and evaporated in vacuo to give 45 mg of a white solid.

[0222] HPLC: RT = 5.041min, 100area% at 254nm. MS (ESI+) for C₂₃H₂2F₃N₁0₄ m/z 434.0 (M+H)⁺. MS (ESI-) for C₂₃H₂₂F₃N₁0₄ m/z 432.0 (M-H)^'. Ή-NMR (CDC1₃)_: δ = 7.59 (brs, 1H), 7.27 (m 2H), 7.21 (m, 3H), 7.08 (m, 1H), 7.01 (d, J=8.3, 1H), 4.08 (brs, 2H), 3.87 (q, J=7.05, 2H), 3.69 (s, 3H), 2.38 (s, 3H), 1.17 (t, 3H).

[0223] Example 9: Preparation of 3-(3-((1.2-dimethyl-5-(trifluoromethoxy)-lH-indol- 3-yl)methyl)phenvn-2-ethoxypropanoic acid

[0224] To a stirring solution of ethyl 3-(3- { [ 1 ,2-dimethyl-5-(trifluoromethoxy)- 1 H-indol-3- yl]methyl}phenyl)-2-ethoxypropanoate (306 mg, 0.661 mmol) in EtOH was added 2M NaOH until pH ca. 10. Left to stir at RT overnight. Reaction is complete. Evaporated in vacuo. Added water and EtOAc and adjusted pH of aqueous phase to ca. 3 with aq. HCl. Separated phases and extracted aq. phase with EtOAc. Combined organic phases dried (Na₂S0₄), filtered and evaporated in vacuo. Residue chromatographed on a small MM column eluting with 0-10% acetone/DCM. Fractions containing product were combined and evaporated in vacuo to give an amber liquid that crystallized upon standing, 97 mg.

[0225] HPLC: RT = 3.833min, 100area% at 254nm. MS (ESI+) for C₂₃H₂₄F₃N₁0₄ m/z 436.2 (M+H)⁺. MS (ESI-) for C₂₃H₂₄F₃N₁0₄ m/z 434.1 (M-H)\

[0226] Example 10; Preparation of (2Z)-2-ethoxy-3-(3-iil-(4-methoxybenzoyl)-2- methvI-5-(trifluoromethoxy)-lH-indol-3-yllmethv phenyl)acrylic acid

[0227] Allyl (2Z)-2-ethoxy-3-(3-{[l-(4-methoxybenzoyl)-2-methyl-5-(trifluoromethoxy)- lH-indol-3-yl]methyl}phenyl)acrylate (39 mg, 0.066 mmol; Supplier = Kalexsyn; Lot = 1103-TTP-129) and 1,3-Dimethylbarbituric acid (12.31 mg, 0.07884 mmol) were dissolved in Tetrahydrofuran (3 mL, 40 mmol) and purged with N₂. Then

Tetrakis(triphenylphosphine)palladium(0) (3.80 mg, 0.00328 mmol) was added and purged again with N₂ and left to stir at RT overnight. HPLC shows a new, major peak and LCMS confirms mass for the desired product. Partitioned between EtOAc and saturated NH4CI, and the aq. phase was extracted with EtOAc. Combined organic phases dried (Na₂S0₄), filtered and evaporated in vacuo to give 64 mg yellow-orange oil. Chromatographed in two batches on small pipette columns. Fractions containing product were combined and evaporated in vacuo to give a light yellow solid. HPLC is 100 area% at both 210 and 254 ran, however, a faint, slightly higher Rf spot is evident on TLC. 1H-NMR consistent with desired contaminated with 1,3 -dimethyl barituric acid.

[0228] HPLC: RT = 4.727min, 100area% at 254nm. MS (ESI+) for

m/z 554.1 (M+H)⁺. MS (ESI-) for CaoHzeFaNjOe m/z 552.2 (M-H)\

[0229] Example 11: Preparation of 3-(3-([l-acetyl-2-methyl-5-(trifluoromethoxyVlH- indol-3-yllmethyl|phenvD-2-ethoxypropanoic acid

[0230] Allyl 3-(3-{[l-acetyl-2-methyl-5-(trifluoromethoxy)-lH-indol-3-yl]methyl}phenyl)- 2-ethoxypropanoate (25 mg, 0.050 mmol; Supplier = Kalexsyn; Lot = 1103-TTP-126) and 1,3-Dimethylbarbituric acid (15.50 mg, 0.09930 mmol) were dissolved in Tetrahydrofuran (2 mL, 30 mmol) and purged with N₂. Then Tetrakis(triphenylphosphine)palladium(0) (2.87 mg, 0.00248 mmol) was added and purged again with N₂ and left to stir at RT overnight. HPLC shows a major new peak and LCMS confirms that it is desired. The reaction mixture was partitioned between EtOAc and saturated NH₄C1, and the aq. phase was extracted with EtOAc. The combined organic phases were dried (Na₂S0₄), filtered and evaporated in vacuo. The residue was chromatographed several times on small pipette columns (eluting with ether and EtOAc with hexane in varying %s).

[0231] HPLC: RT = 4.727 min, 85% at 254nm. MS (ESI+) for O^F^CM m/z 464.1 (M+H)⁺.

[0232] Example 12: Preparation of (2RV2-(3-(i2-methyl-5-(trifluoromethoxy)-lH- indol-3-yllmethvUphenoxy)propanoic acid

[0233] Methyl (2R)-2-(3-{[2-methyl-5-(trifluoromethoxy)-lH-indol-3- yl]methyl}phenoxy)propanoate (1.03 g, 2.53 mmol) was dissolved in Tetrahydrofuran (20 mL, 200 mmol) and was stirred at room temp. 2.00 M of Sodium hydroxide in water (2.53 mL, 5.06 mmol) was added and the mixture stirred overnight. HPLC shows complete consumption of starting material and formation of one new product with the desired mass. The mixture was diluted with water and ethyl acetate. pH adjusted to ~6 and extracted 2X with ethyl acetate, then washed the organics with brine, dried (Na₂S0₄), filtered and solvent removed in vacuo. Remainder dissolved in benzene, frozen at -78 °C and lyophilized to provide a light yellow powder.

[0234] Example 13; Preparation of methyl (2R)-2-(3-(H,2-dimethyl-5- (trifluoromethoxy H-indol-3-yllmethv phenoxy)propanoate [Bl and (2R)-2-(3-(fl,2- dimethyl-5-(trifluoromethoxy)-lH-indol-3-yllmethyl>phenoxy^')propanoic acid [CI

[B] [C]

[0235] To a stirring suspension of Sodium Hydride, 60% in mineral oil (60:40, Sodium hydride:Mineral Oil, 118 mg, 2.94 mmol) in THF (20ml) at 0 °C was added a solution of methyl (2R)-2-(3-{[2-methyl-5-(trifluoromethoxy)-lH-indol-3- yl]methyl}phenoxy)propanoate (0.880 g, 2.16 mmol) in THF (10ml) slowly, dropwise.

Stirred for 10 minutes before adding methyl iodide (229 uL, 3.68 mmol). Allowed to warm to RT. After lh, HPLC shows a mixture of starting material, intermediate [B], desired product [C], and saponified starting material. After 2h, reaction had essentially completely consumed starting material and progressed to a 3:1 ratio of [B]:[C]. At 5h, no further change. 5ml of water was added to quench the excess NaH, and 5ml of 2.00M NaOH was added and the mixture allowed to stir at room temperature overnight. HPLC showed that all of the material had progressed to the desired saponified final product (1.00 g). Partitioned between water and EtOAc. The organic phase was washed with brine, dried (Na₂S0₄), filtered and evaporated in vacuo. The residue was dissolved in benzene, frozen at -78 °C and lyophilized to provide a light green solid.

[0236] Example 14: Preparation of 2-ethoxy-3-(3-([l-(4-methoxybenzoyl)-2-methyl-5- ( trifluoromethoxy l H-indol-3-yll methyl} phenvDpropanoic acid

[0237] Allyl 2-ethoxy-3-(3-{[l-(4-methoxybenzoyl)-2-methyl-5-(trifluoromethoxy)-lH- indol-3-yl]methyl}phenyl)propanoate (17 mg, 0.028 mmol; Supplier = Kalexsyn; Lot = 1103- TTP-127) and 1,3-Dimethylbarbituric acid (5.348 mg, 0.03425 mmol) were dissolved in Tetrahydrofuran (1 mL, 20 mmol) and purged with N₂. Then

Tetrakis(triphenylphosphine)palladium(0) (1.65 mg, 0.00143 mmol) was added and purged again with N₂, and left to stir at RT overnight. HPLC shows a new, major peak and LCMS confirms mass for the desired product. Partitioned between EtOAc and saturated NH4CI, and the aq. phase was extracted with EtOAc. Combined organic phases dried (Na₂S0₄), filtered and evaporated in vacuo to give 12 mg amber glass.

[0238] HPLC: RT = 5.283 min. 100area% at 254nm. MS (ESI+) for C₃oH₂₈F₃N₁0₆ m/z

556.1 (M+H)⁺. MS (ESI+) for

m/z 554.2 (M+H)⁺.

[0239] Example 15: Preparation of (2E)-2-cvano-3- -DhenvI-lH-indoI-3-yl)acrylic acid

[0240] To a stirring solution of allyl (2S)-2-(3-{ [1 -(3,5-dibromo-4-methoxybenzoyl)-2- methyl-5-(trifluoromethoxy)-lH-indol-3-yl]methyl}phenoxy)propanoate (145 mg, 0.200 mmol; Supplier = Kalexsyn; Lot = 1103-TTP-329) in DMF (4ml) was added N,N- Diisopropylethylamine (0.0521 mL, 0.299 mmol), 1,3-Dimethylbarbituric acid (46.7 mg, 0.299 mmol) and Tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.01 mmol). Stirred at RT for 2 hours. HPLC indicates reaction is complete. Quenched with saturated NH₄CI and partitioned between DCM and water. The aqueous phase was extracted twice with DCM. The combined organic phases were dried (Na₂S0 ), filtered and evaporated in vacuo. The residue was divided into 2 portions and half of the material was chromatographed on a 12 g prepacked column using the CombiFlash system, eluting with 1% HC02H/DCM then 0-25% EtOAc/DCm (+1% HC02H). Two sets of fractions were combined and evaporated in vacuo.

[0241] HPLC: RT = 5.51 lmin, 71area% at 210nm and 5.501 min, 92area% at 254nm. MS (ESI+) for C₂₈H₂₂Br₂F₃N₁0₆ m/z 686.0 (M+H)⁺. MS (ESI-) for C₂₈H₂₂Br₂F₃N₁0₆ m/z 684.0 (M-H)-.

[0242] Example 16: Assays

[0243] Assays useful for evaluating the biological properties of compounds of Formula I may be assayed using the following assay methods.

[0244] Assays for Measuring Reduced PPARy Receptor Activation.

[0245] Whereas activation of the PPARy 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.

[0246] PPARy binding is measured by a TR-FRET competitive binding assay using Invitrogen LanthaScreen™ TR-FRET PPARy Competitive Binding Assay (Invitrogen #4894). This assay uses a terbium-labeled anti-GST antibody to label the GST tagged human PPARy ligand binding domain (LBD). A fluorescent small molecule pan-PPAR ligand tracer binds to the LBD causing energy transfer from the antibody to the ligand resulting in a high TR-FRET ratio. Competition binding by PPARy ligands displace the tracer from the LBD causing a lower FRET signal between the antibody and tracer. The TR-FRET ratio is determined by reading the fluorescence emission at 490 and 520 nm using a Synergy2 plate reader (BioTek).

[0247] The ability of compounds of the present invention to bind to PPARy may also be measured using a commercial binding assay (Invitrogen Corporation, Carlsbad, CA) that measures the test compounds ability to bind with PPAR-LBD/Fluormone PPAR Green complex. These assays are performed on three occasions with each assay using duplicate wells at each concentration of tested compound. The data are mean and SEM of the values obtained from the three experiments. Rosiglitazone or pioglitazone may be used as the positive control in each experiment. Compounds were added at the concentrations shown, which ranged from 0.1-100 micromolar.

[0248] PPARy activation in intact cells may be measured by a cell reporter assay using Invitrogen GeneBLAzer PPARy Assay (Invitrogen #1419). This reporter assay uses the human PPARy ligand binding domain (LBD) fused to the GAL4 DNA binding domain (DBD) stably transfected into HEK 293H cells containing a stably expressed beta-lactamase reporter gene under the control of an upstream activator sequence. When a PPARy agonist binds to the LBD of the GAL4/PPAR fusion protein, the protein binds to the upstream activator sequence activating the expression of beta-lactamase. Following a 16 hour incubation with the agonists the cells are loaded with a FRET substrate for 2 hours and fluorescence emission FRET ratios are obtained at 460 and 530 nm in a Synergy2 plate reader (BioTek).

[0249] 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, LambertG, Yim S-H, Oksana Gavrilova O, Ward JM, Brewer B,Reitman ML, Gonzalez FJ. (2003) Liver-specific 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.

[0250] Glucose, Insulin, and Triglyceride in Diabetic KKAy Mice Treated with

Exemplary Compounds of the Present Invention

[0251] The insulin sensitizing and antidiabetic pharmacology are measured in the KKA^Y mice as previously reported [Hofmann, C, Lomez, 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, 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.

[0252] Compounds were formulated by suspension and orally dosed to KKA^Y mice at 93 mg/kg for 4 days. The compounds were first dissolved in DMSO and then placed into aqueous suspension containing 7-10% DMSO, 1% sodium methylcarboxycellulose, and 0.01% Tween 20. On the fifth day, the mice were fasted and blood samples were obtained approximately 18 hours after the last dose. The parameters were measured by standard assay methods. Data are mean and SEM N=6-12 mice.

[0253] BAT Differentiation

[0254] Precursors of BAT are isolated from the interscapular adipose pad of either normal or diabetic mice and cultured in vitro as described below based on the modifications recited in Petrovic N, Shabalina IG, Timmons JA, Cannon B, Nedergaard J. Am. J. Physiol.

Endocrinol. Metab. 295:E287-E296, 2008, hereby incorporated by reference.

[0255] The brown fat pads are pooled and minced, digested for 45 minutes in isolation buffer containing 0.15% (wt/vol) collagenase. The cell suspension is filtered through a 100 μπι nylon filter and centrifuged at 200 x g for 5 minutes. The pellet containing the preadipocytes is resuspended in 1.2 ml/animal of DMEM containing 10% FBS, 10 mM HEPES, 25 μg/ml sodium ascorbate, 100 U/ml penicillin, and 100 μg/ml streptomycin. The resuspended preadipocytes are distributed into 6 well plates and grown at 37 °C in an atmosphere of 10% C0₂ in air with 80% humidity. The medium is changed on the first day and then every second day until confluent.

[0256] Cells are then treated with the compounds or compound salts being assayed for BAT differentiation. This treatment can occur simultaneously with, after, or before strategies to increase intracellular cyclic nucleotides. The development of the BAT phenotype is assessed by direct measure of the uncoupling protein 1 (UCPl), which is emblematic of brown adipose cells.

[0257] Following treatment of the cells, the growth medium is aspirated, rinsed with PBS, and lysed with KHM buffer containing 1% Igepal CA-630, and a protease inhibitor cocktail. The lysate is centrifuged at 8,000 x g for 5 minutes (4°C), the supernatant containing the cell lysate is collected and total protein analyzed using the BCA method. 20 μg/lane of cell lysate is run on 10-20% Tris glycine gels under reducing conditions and the proteins transferred to PVDF membranes. Western blotting is conducted using UCPl polyclonal 1° antibody, an HRP conjugated 2° antibody, and imaged using enhanced chemiluminescence reagents and imaging film. Densitometry is conducted on the scanned films using ImageJ software and analyzed using GraphPad Prism software.

[0258] Mitochondrial Membrane Competitive Binding Crosslinking Assay

[0259] A photoaffinity crosslinker was synthesized by coupling a carboxylic acid analog of pioglitazone to a p-azido-benzyl group containing ethylamine as in Amer. J. Physiol

256:E252-E260. The crosslinker was iodinated carrier free using a modification of the Iodogen (Pierce) procedure and purified using open column chromatography (PerkinElmer). Specific crosslinking is defined as labeling that is prevented by the presence of competing drug. Competitive binding assays are conducted in 50 mM Tris , pH 8.0. All crosslinking reactions are conducted in triplicate using 8 concentrations of competitor ranging from 0-25 uM. Each crosslinking reaction tube contains 20 ug of crude mitochondrial enriched rat liver membranes, 0.1 uCi of 125I-MSDC-1101, and ± competitor drug with a final concentration of 1% DMSO. The binding assay reaction is nutated at room temperature in the dark for 20 minutes and stopped by exposure to 180,000 uJoules. Following crosslinking, the membranes are pelleted at 20,000 * g for 5 minutes, the pellet is resuspended in Laemmli sample buffer containing 1% BME and run on 10-20% Tricine gels. Following

electrophoresis the gels are dried under vacuum and exposed to Kodak BioMax MS film at -80°C. The density of the resulting specifically labeled autoradiography bands are quantitated using ImageJ software (NIH) and IC₅₀ values determined by non-linear analysis using GraphPad PrismTM.

[0260] Data for each of the assays performed on compounds of Formula I is provided below in Table B:

Table B: Assay data for compound of Formula I.

¹ This data is provided as T/C wherein the control compound is 5-(4-(2-(5-ethylpyridin-2-yl)-2- oxoethoxy)benzyl)thiazolidine-2,4-dione for each of the concentrations tested.

² T/C data is test compound activity that is normalized with respect to the vehicle activity.

[0261] It is noted that in Table B, indicates that no data is available.

OTHER EMBODIMENTS

[0262] 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.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I:

I

or a pharmaceutically acceptable salt thereof, wherein

Each of R^la and R^lb is independently selected from hydrogen, -OH, C alkyl optionally substituted with 1-3 halo, or Ci_-4 alkoxy optionally substituted with 1-3 halo, or

R^la and R^lb taken together form oxo;

X¹ is -O- or -CH₂-, or -CH-;

is a single bond or a double bond when X¹ is -CH- and one of R^la and R^lb is absent;

Ring A is selected from

R is selected from hydrogen or C1.3 alkyl;

R³ is selected from hydrogen, C1.3 alkyl optionally substituted with 1-3 halo, or C_1-3 alkoxy optionally substituted with 1-3 halo; and

R⁴ is -Z^AR^A wherein Z^A is independently selected from a bond, a C_1-3 alkylidene chain, or -C(O)-; and R^A is selected from hydrogen, Ci_-3 alkyl, or phenyl optionally substituted with C_1-3 alkyl or C_)-3 alkoxy.

2. The compound of claim 1 ,

3. The compound of claim 2, wherein R² is selected from hydrogen, methyl, or ethyl.

4. The compound of claim 3, wherein R² is hydrogen.

5. The compound of claim 3, wherein R is methyl.

6. The compound of claim 2, wherein R³ is Ci_-3 alkoxy optionally substituted with 1-3 halo.

7. The compound of claim 6, wherein R³ is -OCH₃ or -OCF3.

8. The compound of claim 2, wherein R⁴ is -Z^AR^A, wherein Z^A is independently selected from a bond or -C(O)-; and R^A is selected from hydrogen, C_1-3 alkyl, or phenyl optionally substituted with .3 alkyl or C_1-3 alkoxy.

9. The compound of claim 8, wherein R⁴ is -Z^AR^A, wherein Z^A is independently selected from a bond or -C(O)-; and R^A is selected from hydrogen, C1.3 alkyl, or phenyl substituted with -OCH3 or -OCH2CH3.

10. The compound of claim 2, wherein R⁴ is hydrogen, -CH3, -CH2CH3, or -C(0)-CH3.

11. The compound of claim 2, wherein R⁴ is -Z^AR^A, wherein Z^A is -C(O)-; and R^A is phenyl optionally substituted with Q.3 alkyl or Ci.₃ alkoxy.

12. The compound of claim 11 , wherein R⁴ is -Z^AR^A, wherein Z^A is -C(O)-; and R^A is phenyl substituted at its para position with Ci-3 alkyl or C^ alkoxy.

13. The compound of claim 1 , wherein ring A is

14. The compound of claim 13, wherein R² is selected from hydrogen, methyl, or ethyl.

15. The compound of claim 14, wherein R² is hydrogen.

16. The compound of claim 14, wherein R² is methyl.

17. The compound of claim 13, wherein R³ is Q.3 alkoxy optionally substituted with 1-3 halo.

18. The compound of claim 13, wherein R³ is -OCH3 or -OCF3.

19. The compound of claim 1, wherein is a double bond, one of R^la and R^lb is absent, and X¹ is -CH-.

20. The compound of claim 1 , wherein one of R^la and R^lb is hydrogen and the other is selected from hydrogen, -CH₃, -CH₂CH₃, -OCH₃, or -OCH₂CH₃. compound selected from

22. A pharmaceutical composition comprising a compound of claim 1 and a

pharmaceutically acceptable carrier.

23. The pharmaceutical composition of claim 20, further comprising a dipeptidyl peptidase IV (DPP-4) inhibitor, e.g., sitagliptin, vildagliptin, or the like; a HMG-CoA reductase inhibitor (statin), e.g., atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, simvastatin, rosuvastatin, pravastatin, or any pharmaceutically acceptable combination thereof; GLP-1 or -2 agonists; or combinations thereof.

24. A method of treating or reducing the symptoms of diabetes comprising administering to a patient a compound of Formula I

I

or a pharmaceutically acceptable salt thereof, wherein

Each of R^la and R^lb is independently selected from hydrogen, -OH, C alkyl optionally substituted with 1-3 halo, or C^ alkoxy optionally substituted with 1-3 halo, or

R^la and R^lb taken together form oxo;

X¹ is -O- or -CH₂-, or -CH-;

Ring A is selected from

R is selected from hydrogen or Ci.₃ alkyl;

R⁴ is -Z^AR^A wherein Z^A is independently selected from a bond, a d-3 alkylidene chain, or -C(O)-; and R^A is selected from hydrogen, C_1-3 alkyl, or phenyl optionally substituted with Ci_-3 alkyl or Ci.₃ alkoxy.

The method of claim 24,

26. The method of claim 25, wherein R² is selected from hydrogen, methyl, or ethyl.

27. The method of claim 26, wherein R is hydrogen.

28. The method of claim 26, wherein R² is methyl.

29. The method of claim 25, wherein R³ is C_1-3 alkoxy optionally substituted with

1-3 halo.

30. The method of claim 29, wherein R³ is -OCH₃ or -OCF₃.

31. The method of claim 25, wherein R⁴ is -Z^AR^A, wherein Z^A is independently selected from a bond or -C(O)-; and R^A is selected from hydrogen, C_1-3 alkyl, or phenyl optionally substituted with C_1-3 alkyl or C_1-3 alkoxy.

32. The method of claim 31 , wherein R⁴ is -Z^AR^A, wherein Z^A is independently selected from a bond or -C(O)-; and R^A is selected from hydrogen, Ci_-3 alkyl, or phenyl substituted with -OCH₃ or -OCH₂CH₃.

33. The method of claim 25, wherein R⁴ is hydrogen, -CH₃, -CH₂CH₃, or -C(0)-CH₃.

34. The method of claim 32, wherein R⁴ is -Z^AR^A, wherein Z^A is -C(O)-; and R^A is phenyl optionally substituted with C_1-3 alkyl or Ci.₃ alkoxy.

35. The method of claim 34, wherein R⁴ is -Z^AR^A, wherein Z^A is -C(O)-; and R^A is phenyl substituted at its para position with Ci_-3 alkyl or C_1-3 alkoxy.

36. The method of claim 24, wherein ring A is

37. The method of claim 36, wherein R² is selected from hydrogen, methyl, or ethyl.

38. The method of claim 37, wherein R is hydrogen.

39. The method of claim 37, wherein R is methyl.

40. The method of claim 36, wherein R³ is Ci_-3 alkoxy optionally substituted with 1-3 halo.

41. The method of claim 40, wherein R³ is -OCH₃ or -OCF₃.

42. The method of claim 24, wherein is a double bond, one of R^la and R^lb is absent, and X¹ is -CH-.

43. The method of claim 24, wherein one of R^la and R^lb is hydrogen and the other is selected from hydrogen, -CH₃, -CH₂CH₃, -OCH₃, or -OCH₂CH₃.

The method of claim 24, wherein the compound of Formula I is selected from

45. A method of reducing the body weight of a patient comprising administering to a patient a compound of Formula I

I

or a pharmaceutically acceptable salt thereof, wherein

Each of R^la and R^lb is independently selected from hydrogen, -OH, C_1-4 alkyl optionally substituted with 1-3 halo, or Ci_-4 alkoxy optionally substituted with 1-3 halo, or

R^la and R^lb taken together form oxo;

X¹ is -O- or -CH₂-, or -CH-;

is a single bond or a double bond when X¹ is -CH- and one of R^la and R^lb is absent:

Ring A is selected from

or R² is selected from hydrogen or C 1.3 alkyl;

R³ is selected from hydrogen, C1.3 alkyl optionally substituted with 1-3 halo, or Q.3 alkoxy optionally substituted with 1-3 halo; and

R⁴ is -Z^AR^A wherein Z^A is independently selected from a bond, a Ci-3 alkylidene chain, or -C(O)-; and R^A is selected from hydrogen, Cj.3 alkyl, or phenyl optionally substituted with C1.3 alkyl or Q.3 alkoxy.

46. The method of claim 45, wherein ring A is

47. The method of claim 46, wherein R² is selected from hydrogen, methyl, or ethyl.

48. The method of claim 47, wherein R is hydrogen.

49. The method of claim 47, wherein R² is methyl.

50. The method of claim 46, wherein R³ is C_1-3 alkoxy optionally substituted with

1-3 halo.

51. The method of claim 50, wherein R³ is -OCH3 or -OCF3.

52. The method of claim 46, wherein R⁴ is -Z^AR^A, wherein Z^A is independently selected from a bond or -C(O)-; and R^A is selected from hydrogen, Cj-3 alkyl, or phenyl optionally substituted with C1-3 alkyl or C1.3 alkoxy.

53. The method of claim 52, wherein R⁴ is -Z^AR^A, wherein Z^A is independently selected from a bond or -C(O)-; and R^A is selected from hydrogen, C_1-3 alkyl, or phenyl substituted with -OCH3 or -OCH2CH3.

54. The method of claim 46, wherein R⁴ is hydrogen, -CH₃, -CH₂CH₃, or -C(0)-CH₃.

55. The method of claim 53, wherein R⁴ is -Z^AR^A, wherein Z^A is -C(O)-; and R^A is phenyl optionally substituted with C1.3 alkyl or d-3 alkoxy.

56. The method of claim 55, wherein R⁴ is -Z^AR^A, wherein Z^A is -C(O)-; and R^A is phenyl substituted at its para position with C_1-3 alkyl or C_1-3 alkoxy.

57. The method of claim 45,

58. The method of claim 57, wherein R² is selected from hydrogen, methyl, or ethyl.

59. The method of claim 58, wherein R² is hydrogen.

60. The method of claim 58, wherein R² is methyl.

61. The method of claim 57, wherein R³ is Ci_-3 alkoxy optionally substituted with 1-3 halo.

62. The method of claim 61, wherein R is -OCH3 or -OCF₃.

63. The method of claim 45, wherein is a double bond, one ofR^la and R^lb is absent, and X¹ is -CH-.

64. The method of claim 45, wherein one of R^la and R^lb is hydrogen and the other is selected from hydrogen, -CH₃, -CH₂CH₃, -OCH₃, or -OCH₂CH₃.

65. The method of claim 45, wherein the compound of Formula I is selected from

66. A method of lowering lipids in a patient comprising administering to a patient a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein

Each of R^la and R^lb is independently selected from hydrogen, -OH, C alkyl optionally substituted with 1-3 halo, or C_1-4 alkoxy optionally substituted with 1-3 halo, or

R^la and R^lb taken together form oxo;

X¹ is -O- or -CH2-, or -CH-;

Ring A is selected from

R² is selected from hydrogen or C 1-3 alkyl;

R³ is selected from hydrogen, C_1-3 alkyl optionally substituted with 1-3 halo, or C1.3 alkoxy optionally substituted with 1-3 halo; and

R⁴ is -Z^AR^A wherein Z^A is independently selected from a bond, a C_1-3 alkylidene chain, or -C(O)-; and R^A is selected from hydrogen, C_1-3 alkyl, or phenyl optionally substituted with C_1-3 alkyl or C1.3 alkoxy.

67. The method of claim 66, wherein ring A is

68. The method of claim 67, wherein R² is selected from hydrogen, methyl, or ethyl.

69. The method of claim 68, wherein R is hydrogen.

70. The method of claim 68, wherein R² is methyl.

71. The method of claim 67, wherein R is C_1-3 alkoxy optionally substituted with

1-3 halo.

72. The method of claim 71 , wherein R³ is -OCH₃ or -OCF₃.

73. The method of claim 67, wherein R⁴ is -Z^AR^A, wherein Z^A is independently selected from a bond or -C(O)-; and R^A is selected from hydrogen, Ci_-3 alkyl, or phenyl optionally substituted with C_1-3 alkyl or Cj_-3 alkoxy.

74. The method of claim 73, wherein R⁴ is -Z^AR^A, wherein Z^A is independently selected from a bond or -C(O)-; and R^A is selected from hydrogen, C]_-3 alkyl, or phenyl substituted with -OCH3 or -OCH2CH3.

75. The method of claim 67, wherein R⁴ is hydrogen, -CH₃, -CH₂CH₃, or -C(0)-CH₃.

76. The method of claim 73, wherein R⁴ is -Z^AR^A, wherein Z^A is -C(O)-; and R^A is phenyl optionally substituted with C1.3 alkyl or C_1-3 alkoxy.

77. The method of claim 76, wherein R⁴ is -Z^AR^A, wherein Z^A is -C(O)-; and R^A is phenyl substituted at its para position with C_1-3 alkyl or C_1-3 alkoxy.

78. The method of claim 66, wherein ring A is

79. The method of claim 78, wherein R² is selected from hydrogen, methyl, or ethyl.

80. The method of claim 79, wherein R is hydrogen.

81. The method of claim 79, wherein R² is methyl.

82. The method of claim 78, wherein R³ is C_1-3 alkoxy optionally substituted with 1-3 halo.

83. The method of claim 82, wherein R³ is -OCH₃ or -OCF₃.

84. The method of claim 66, wherein is a double bond, one of R^la and R^lb is absent, and X¹ is -CH-.

85. The method of claim 66, wherein one of R^la and R^lb is hydrogen and the other is selected from hydrogen, -CH₃, -CH₂CH₃, -OCH₃, or -OCH₂CH₃.

The method of claim 66, wherein the compound of Formula I is selected from

69