WO2012177956A1 - Ppar-sparing compounds for use in the treatment of diabetes and other metabolic diseases - Google Patents

Abstract

The present invention relates to compounds 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 FOR USE IN THE TREATMENT OF DIABETES

AND OTHER METABOLIC DISEASES

CROSS REFERENCE TO RELATED APPLICATION

[0001] This PCT application claims the benefit of U.S. Patent Application Serial Nos.

61/500,378, filed June 23, 2011 , and 61/557,443, filed November 9, 2011. The entire contents of these applications are incorporated herein by reference in their entireties.

TECHNICAL FIELD OF THE INVENTION

[0002] The present invention provides compounds and pharmaceutical compositions containing such compounds for use in treating and/or preventing diabetes or other metabolic disease states (e.g., obesity or 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:

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 -O-aryl, -O-heteroaryl, -0-CH₂-aryl, or -0-CH₂- heteroaryl, wherein either of the aryl or heteroaryl groups are optionally substituted with 1-2 substituents independently selected from halo, alkyl, alkoxy, or cyano; or R^la and R^lb taken together form oxo; each of R^2a and R^2b is independently selected from halo, hydrogen, -OH, -N(R⁶)₂, C^ alkyl optionally substituted with 1-3 halo, or C alkoxy optionally substituted with 1-3 halo, or R^2a and R^2b taken together form oxo, or R^2a and R ^b taken together form =N-R^J; R^J is C alkyl optionally substituted with 1-3 halo, or CM alkoxy optionally substituted with 1-3 halo; is a single bond, or a double bond when one of R^la and R^lb is absent; ring A is selected

each R⁴ is independently selected from hydrogen, -N(R⁶)₂, C1.3 alkyl optionally substituted with 1-3 halo, or Ci-3 alkoxy optionally substituted with 1-3 halo; x is 0-2; each R⁵ is independently selected from hydrogen or CM alkyl; and each R⁶ is independently selected from hydrogen, C_M alkyl, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein the C_M alkyl is optionally substituted with a 6-10 membered monocyclic or bicyclic aryl or a 5-10 membered monocyclic or bicyclic heteroaryl having 1-3 heteroatoms independently selected from N, 0, or S, and wherein each R⁷ is independently hydrogen or CM alkyl.

[0011] In some embodiments, ring A is

[0012] In some embodiments, x is 1 or 2 and at least one R⁴ is C_1-3 alkoxy optionally substituted with 1-3 halo. For example, x is 1 or 2 and at least one R⁴ is selected from -OCH3 or -OCH₂CH₃. Or, x is 1. In other embodiments, R⁴ is -OCH₃ that is attached to the meta position on the phenyl group of ring A.

[0013] In some embodiments, one of R^2a and R^2b is hydrogen and the other is selected from hydrogen, halo, -OH, -CH₃, -CH₂CH₃, -OCH₃, or -OCH₂CH₃.

[0014] In some embodiments, both of R^2a and R ^b are independently selected from hydrogen, halo, -CH₃, -CH₂CH₃, -OCH₃, or -OCH₂CH₃. For example, both of R^2a and R^2b are halo.

[0015] In other embodiments, R^2a and R^2b taken together are oxo.

[0016] In other embodiments, one of R^2a and R^2b is hydrogen and the other is -OH.

[0017] In other embodiments, R^2a and R^2b taken together form =N-R³, and R³ is selected from CM alkyl optionally substituted with 1-3 halo or CM alkoxy optionally substituted with 1-3 halo. For example, R^2a and R^2b taken together form =N-0-CH₃. [0018] In other embodiments, one of R^2a and R^2b is hydrogen and the other is -N(R⁶)₂, wherein each R⁶ is independently selected from hydrogen, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein each R⁷ is independently hydrogen or Ci_-4 alkyl. In other embodiments, one ofR^2a and R^2b is hydrogen and the other is -NHR⁶, wherein R⁶ is independently selected from hydrogen, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein each R⁷ is independently hydrogen or CM alkyl.

[0019] In other embodiments, one of R^la and R^lb is independently selected from -O-aryl, -O-heteroaryl, -0-CH2-aryl, or -0-CH₂-heteroaryl, wherein the aryl group is a 6-10 membered monocyclic or bicyclic ring and the heteroaryl is a 5-10 membered monocyclic or bicyclic ring containing 1-3 heteroatoms independently selected from N, O, or S; and the aryl or heteroaryl groups are optionally substituted with 1-2 substituents independently selected from halo, alkyl, alkoxy, or cyano.

[0020] In other embodiments, ring A is

[0021] In some of these embodiments, x is 1 or 2 and at least one R⁴ is C_1-3 alkyl optionally substituted with 1-3 halo or Ci_-3 alkoxy optionally substituted with 1-3 halo. For example, x is 1 or 2 and at least one R⁴ is selected from -C¾ or -CH₂CH₃. In other examples, x is 1. And, in some examples, R⁴ is -CH2CH3 that is attached to the 5 position on the pyridine-yl group of ring A.

[0022] In other embodiments, one of R^2a and R^2b is hydrogen and the other is selected from hydrogen, halo, -OH, -CH₃, -CH₂CH₃, -OCH₃, or -OCH₂CH₃.

[0023] In other embodiments, both of R^2a and R^2b are independently selected from hydrogen, halo, -OH, -CH₃, -CH₂CH₃, -OCH₃, or -OCH₂CH₃. For instance, one of R^2a and R^2b is hydrogen and the other is -OH.

[0024] In other embodiments, R^2a and R ^b taken together are oxo.

[0025] In other embodiments, R^2a and R^2b taken together form =N-R³, and R³ is selected from CM alkyl optionally substituted with 1-3 halo or C_1-4 alkoxy optionally substituted with

1-3 halo. For example, R³ is Q.3 alkoxy optionally substituted with 1-3 halo. In other examples, R³ is -OCH₃ or -OCF3. In other examples, R^2a and R^2b taken together form

=N-0-CH₃.

[0026] In some embodiments, one of R² and R^2b is hydrogen and the other is -N(R⁶)₂, wherein each R⁶ is independently selected from hydrogen, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein each R⁷ is independently hydrogen or C_1-4 alkyl. In other embodiments, one of R^2a and R² is hydrogen and the other is -NHR⁶, wherein R⁶ is independently selected from hydrogen, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein each R⁷ is independently hydrogen or C_1-4 alkyl.

[0027] In other embodiments, one of R^la and R^lb is independently selected from -O-aryl, -O-heteroaryl, -0-CH₂-aryl, or -0-CH2-heteroaryl, wherein the aryl group is a 6-10 membered monocyclic or bicyclic ring and the heteroaryl is a 5-10 membered monocyclic or bicyclic ring containing 1-3 heteroatoms independently selected from N, O, or S; and the aryl or heteroaryl groups are optionally substituted with 1-2 substituents independently selected from halo, alkyl, alkoxy, or cyano.

[0028] In other embodiments, one of R^la and R^lb is hydrogen and the other is selected from hydrogen, -CH₃, -CH₂CH₃, -OC¾, or -OCH₂CH₃.

[0029] In some embodiments, is a double bond and one of R^la and R^lb is absent.

[0030] In some embodiments, R⁵ is selected from hydrogen and -CH2CH3.

[0031] Another aspect of the present invention provides a pharmaceutical composition comprising a compound as described above and a pharmaceutically acceptable carrier.

[0032] In some embodiments, 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 and -2 agonists; or combinations thereof.

[0033] Another aspect of the present invention provides a method of treating or reducing the symptoms of diabetes comprising administering to a patient in need thereof 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 -O-aryl, -O-heteroaryl, -0-CH₂-aryl, or

-0-CH₂-heteroaryl, wherein either of the aryl or heteroaryl groups are optionally substituted with 1-2 substituents independently selected from halo, alkyl, alkoxy, or cyano; or R^la and

R taken together form oxo; each of R and R is independently selected from halo, hydrogen, -OH, -N(R⁶)₂, C_M alkyl optionally substituted with 1-3 halo, or CM alkoxy optionally substituted with 1-3 halo, or R^2a and R^2b taken together form oxo, or R^2a and R^2b taken together form =N-R³; R³ is CM alkyl optionally substituted with 1-3 halo, or C_M alkoxy optionally substituted with 1-3 halo; is a single bond, or a double bond when one of R^la and R^lb is absent: ring A is selected from

each R⁴ is independently selected from hydrogen, -N(R⁶)₂, C_1-3 alkyl optionally substituted with 1-3 halo, or C_1-3 alkoxy optionally substituted with 1-3 halo; x is 0-2; each R⁵ is independently selected from hydrogen or C alkyl; and each R⁶ is independently selected from hydrogen, CM alkyl, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein the C_M alkyl is optionally substituted with a 6-10 membered monocyclic or bicyclic aryl or a 5-10 membered monocyclic or bicyclic heteroaryl having 1-3 heteroatoms independently selected from N, O, or S, and wherein each R⁷ is independently hydrogen or C alkyl.

[0034] Another aspect of the present invention provides a method of reducing the body weight of a patient comprising 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 CM alkoxy optionally substituted with 1-3 halo, or -O-aryl, -O-heteroaryl, -0-CH₂-aryl, or

-0-CH₂-heteroaryl, wherein either of the aryl or heteroaryl groups are optionally substituted with 1-2 substituents independently selected from halo, alkyl, alkoxy, or cyano; or R^la and R^lb taken together form oxo; each of R^2a and R^2b is independently selected from halo, hydrogen, -OH, -N(R⁶)₂, C_1-4 alkyl optionally substituted with 1-3 halo, or CM alkoxy optionally substituted with 1-3 halo, or R^2a and R^2b taken together form oxo, or R^2a and R taken together form =N-R³; R³ is CM alkyl optionally substituted with 1-3 halo, or CM alkoxy optionally substituted with 1-3 halo; is a single bond, or a double bond when one of R^la and R^lb is absent;

each R⁴ is independently selected from hydrogen, -N(R⁶)₂, C1.3 alkyl optionally substituted with 1-3 halo, or Ci_-3 alkoxy optionally substituted with 1-3 halo; x is 0-2; each R⁵ is independently selected from hydrogen or C alkyl; and each R⁶ is independently selected from hydrogen, CM alkyl, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein the C_M alkyl is optionally substituted with a 6-10 membered monocyclic or bicyclic aryl or a 5-10 membered monocyclic or bicyclic heteroaryl having 1-3 heteroatoms independently selected from N, O, or S, and wherein each R⁷ is independently hydrogen or C_1-4 alkyl.

[0035] Another aspect of the present invention provides a method of treating dyslipidemia comprising administering to a p 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 CM alkoxy optionally substituted with 1-3 halo, or -O-aryl, -O-heteroaryl, -0-CH₂-aryl, or

-0-CH₂-heteroaryl, wherein either of the aryl or heteroaryl groups are optionally substituted with 1-2 substituents independently selected from halo, alkyl, alkoxy, or cyano; or R^la and R^lb taken together form oxo; each of R^2a and R^2b is independently selected from halo, hydrogen, -OH, -N(R⁶)₂, M alkyl optionally substituted with 1-3 halo, or CM alkoxy optionally substituted with 1-3 halo, or R^2a and R^2b taken together form oxo, or R^2a and R^2b taken together form =N-R³; R³ is CM alkyl optionally substituted with 1-3 halo, or CM alkoxy optionally substituted with 1-3 halo; is a single bond, or a double bond when one ofR^la and R^Ib is absent;

each R⁴ is independently selected from hydrogen, -N(R⁶)₂, Ci_-3 alkyl optionally substituted with 1-3 halo, or Q.3 alkoxy optionally substituted with 1-3 halo; x is 0-2; each R⁵ is independently selected from hydrogen or CM alkyl; and each R⁶ is independently selected from hydrogen, C_M alkyl, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein the C_M alkyl is optionally substituted with a 6-10 membered monocyclic or bicyclic aryl or a 5-10 membered monocyclic or bicyclic heteroaryl having 1-3 heteroatoms independently selected from N, O, or S, and wherein each R⁷ is independently hydrogen or CM alkyl. DETAILED DESCRIPTION OF THE INVENTION

[0036] The present invention provides novel PPARy-sparing compounds and

pharmaceutical composition that are useful for treating diabetes and other metabolic diseases. In one aspect, the present invention provides 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_M alkoxy optionally substituted with 1-3 halo, or -O-aryl, -O-heteroaryl, -0-CH₂-aryl, or

-0-CH₂-heteroaryl, wherein either of the aryl or heteroaryl groups are optionally substituted with 1-2 substituents independently selected from halo, alkyl, alkoxy, or cyano; or R^la and R^,b taken together form oxo; each of R^2a and R^2b is independently selected from halo, hydrogen, -OH, -N(R⁶)₂, CM alkyl optionally substituted with 1-3 halo, or C alkoxy optionally substituted with 1-3 halo, or R^2a and R^2b taken together form oxo, or R^2a and R^2b taken together form =N-R³; R³ is C_1-4 alkyl optionally substituted with 1-3 halo, or CM alkoxy optionally substituted with 1-3 halo; is a single bond, or a double bond when one of R^la and R^lb is absent;

each R⁴ is independently selected from hydrogen, -N(R⁶)₂, Ci_-3 alkyl optionally substituted with 1-3 halo, or C_1-3 alkoxy optionally substituted with 1-3 halo; x is 0-2; each R⁵ is independently selected from hydrogen or C alkyl; and each R is independently selected from hydrogen, C_M alkyl, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein the C_M alkyl is optionally substituted with a 6-10 membered monocyclic or bicyclic aryl or a 5-10 membered monocyclic or bicyclic heteroaryl having 1-3 heteroatoms independently selected from N, O, or S, and wherein each R⁷ is independently hydrogen or CM alkyl.

[0037] In some embodiments, each of R^LA and R^LB is independently selected from hydrogen, -OH, C alkyl optionally substituted with 1-3 halo, or CM alkoxy optionally substituted with 1-3 halo, or -O-aryl, -O-heteroaryl, -0-CH₂-aryl, or -0-CH2-heteroaryl, wherein either of the aryl or heteroaryl groups are optionally substituted with 1-2 substituents independently selected from halo, alkyl, alkoxy, or cyano; or R^LA and R^IB taken together form oxo; each of R^2A and R^2B is independently selected from halo, hydrogen, -OH, -NHR⁶, CM alkyl optionally substituted with 1-3 halo, or C_M alkoxy optionally substituted with 1-3 halo, or R^2a and R^2b taken together form oxo, or R^2a and R^2b taken together form =N-R³; R³ is C alkyl optionally substituted with 1-3 halo, or C_1-4 alkoxy optionally substituted with 1-3 halo;

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

each R⁴ is independently selected from hydrogen, C1-3 alkyl optionally substituted with 1-3 halo, or Ci_-3 alkoxy optionally substituted with 1-3 halo; x is 0-2; each R⁵ is independently selected from hydrogen or d.4 alkyl; and each R⁶ is independently selected from hydrogen, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein each R⁷ is independently hydrogen or C alkyl.

[0038] PPARy-sparing compounds of the present invention effectively stimulate BAT stores, and are useful for treating obesity and other metabolic diseases such as diabetes.

[0039] I. DEFINITIONS

[0040] As used herein, the following definitions shall apply unless otherwise indicated.

[0041] 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.

[0042] 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.

[0043] As used herein the term "aliphatic" encompasses the terms alkyl, alkenyl, alkynyl, each of which being optionally substituted as set forth below.

[0044] 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-SCV], 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.

[0045] 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-S0₂-, 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. [0046] 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-S0₂-, 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.

[0047] 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.

[0048] 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, ((cycloaJiphatic)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.

[0049] 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 C_4-8 carbocyclic moieties. An aryl is optionally substituted with one or more substituents including aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy;

(cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic ring of a benzofused bicyclic or tricyclic aryl); nitro; carboxy; amido; acyl [e.g., (aliphatic)carbonyl; (cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl;

(heterocycloaliphatic)carbonyl; ((heterocycloaliphatic)aliphatic)carbonyl; or

(heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphatic-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.

[0050] Non-limiting examples of substituted aryls include haloaryl [e.g., mono-, di (such as w-dihaloaryl), and (trihalo)aryl]; (carboxy)aryl [e.g., (alkoxycarbonyl)aryl,

((aralkyl)carbonyioxy)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;

((heterocycIoaliphatic)carbonyl)aryl; ((alkylsulfonyl)alkyl)aryl; (cyanoalkyl)aryl;

(hydroxyalkyl)aryl; (alkylcarbonyl)aryl; alkylaryl; (trihaloalkyl)aryl; -amino-m- alkoxycarbonylaryl; -amino-m-cyanoaryl; 7-halo-w-aminoaryl; or

(/w-(heterocycloaliphatic)-0-(alkyl))aryl. [0051] As used herein, an "araliphatic" such as an "aralkyl" group refers to an aliphatic group (e.g., a C 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.

[0052] 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.

[0053] 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.

[0054] As used herein, a "cycloaliphatic" group encompasses a "cycloalkyl" group and a "cycloalkenyl" group, each of which being optionally substituted as set forth below.

[0055] 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 .

[0056] 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. [0057] 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-S0 -], sulfinyl [e.g., alkyl-S(O)-], sulfanyl [e.g., alkyl-S-], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0058] As used herein, the term "heterocycloaliphatic" encompasses a heterocycloalkyl group and a heterocycloalkenyl group, each of which being optionally substituted as set forth below.

[0059] 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[£>]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, 1 -aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2. l]octyI, and 2,6-dioxa-tricyclo[3.3.1.0³'⁷]nonyl. A monocyclic

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

[0060] 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. [0061] 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.

[0062] 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-indoIyl, indolinyl, benzo [6]furyl, benzo[0]thiophenyl, quinolinyl, or isoquinolinyl). Some examples of heteroaryl are pyridyl, lH-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[l,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo- 1,2,5-thiadiazolyl, or 1,8-naphthyridyl.

[0063] 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. [0064] Without limitation, bicyclic heteroaryls include indolizyl, indolyi, isoindolyl, 3H- indolyl, indolinyl, benzo[0]furyl, benzo[b]thiophenyl, quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indolyi, 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.

[0065] 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.

[0066] Non-limiting examples of substituted heteroaryls include (halo)heteroaryl [e.g., mono- and di-(halo)heteroaryl]; (carboxy)heteroaryl [e.g., (alkoxy carbonyl)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]. [0067] A "heteroaraliphatic (such as a heteroaralkyl group) as used herein, refers to an aliphatic group (e.g., a C_1-4 alkyl group) that is substituted with a heteroaryl group.

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

[0068] 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.

[0069] 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.

[0070] 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, 1 -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. [0071] 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.

[0072] 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.

[0073] As used herein, an "alkoxy" group refers to an alkyl-O- group where "alkyl" has been defined previously.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] As used herein, a "mercapto" group refers to -SH.

[0078] As used herein, a "sulfo" group refers to -S0₃H or -S0₃R^x when used terminally or -S(0)₃- when used internally.

[0079] As used herein, a "sulfamide" group refers to the structure -NR^x-S(0)₂-NR^YR^z when used terminally and -NR^x-S(0)₂-NR^Y- when used internally, wherein R^x, R^Y, and R^z have been defined above.

[0080] As used herein, a "sulfamoyl" group refers to the structure -0-S(0)₂-NR^YR^z wherein R^Y and R^z have been defined above.

[0081] As used herein, a "sulfonamide" group refers to the structure -S(0)₂-NR^xR^Y 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.

[0082] 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.

[0083] As used herein a "sulfinyl" group refers to -S(0)-R^x 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. [0084] 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.

[0085] As used herein, a "sulfoxy" group refers to -0-SO-R^x or -SO-0-R^x, when used terminally and -0-S(0)- or -S(0)-0- when used internally, where R^x has been defined above.

[0086] As used herein, a "halogen" or "halo" group refers to fluorine, chlorine, bromine or iodine.

[0087] 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)-.

[0088] As used herein, an "alkoxyalkyl" refers to an alkyl group such as alkyl-O-alkyl-, wherein alkyl has been defined above.

[0089] As used herein, a "carbonyl" refer to -C(O)-.

[0090] As used herein, an "oxo" refers to =0.

[0091] 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.

[0092] As used herein, an "aminoalkyl" refers to the structure (R^x)2N-alkyl-.

[0093] As used herein, a "cyanoalkyl" refers to the structure (NC)-alkyl-.

[0094] 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.

[0095] 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.

[0096] As used herein, the term "amidino" group refers to the structure -C=(NR^X)N(R^XR^Y) wherein R^x and R^Yhave been defined above.

[0097] 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. [0098] 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.

[0099] 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(0)-) and alkylcarboxyaryl (e.g., alkyl-C(0)0-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groups used internally.

[0100] 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 -[CH₂]_v-₅ 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.

[0101] 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^2b, 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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.

[0106J 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 ' βι -adrenergic agonist').

[0107] 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.

[0108] Chemical structures and nomenclature are derived from ChemDraw, version 11.0.1,

Cambridge, MA.

[0109] II. COMPOUNDS

[0110] 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 or dyslipidemia.

[0111] One aspect of the pres 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 -O-aryl, -O-heteroaryl, -0-CH₂-aryl, or

-0-CH₂-heteroaryl, wherein either of the aryl or heteroaryl groups are optionally substituted with 1-2 substituents independently selected from halo, alkyl, alkoxy, or cyano; or R^la and R^lb taken together form oxo; each of R^2a and R^2b is independently selected from halo, hydrogen, -OH, -N(R⁶)₂, CM alkyl optionally substituted with 1-3 halo, or CM alkoxy optionally substituted with 1-3 halo, or R^2a and R^2b taken together form oxo, or R^2a and R^2b taken together form =N-R³; R³ is C_1-4 alkyl optionally substituted with 1-3 halo, or C

alkoxy optionally substituted with 1-3 halo; is a single bond, or a double bond when one of R^la and R^lb is absent; ring A is selected from

each R⁴ is independently selected from hydrogen, -N(R⁶)₂, Ci,₃ alkyl optionally substituted with 1-3 halo, or Ci-3 alkoxy optionally substituted with 1-3 halo; x is 0-2; each R⁵ is independently selected from hydrogen or C alkyl; and each R⁶ is independently selected from hydrogen, C_M alkyl, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein the CM alkyl is optionally substituted with a 6-10 membered monocyclic or bicyclic aryl or a 5-10 membered monocyclic or bicyclic heteroaryl having 1-3 heteroatoms independently selected from N, O, or S, and wherein each R⁷ is independently hydrogen or CM alkyl.

[0112] In some embodiments, each of R^la and R^lb is independently selected from hydrogen, -OH, CM alkyl optionally substituted with 1-3 halo, or C alkoxy optionally substituted with 1-3 halo, or -O-aryl, -O-heteroaryl, -0-CH₂-aryl, or -0-CH₂-heteroaryl, wherein either of the aryl or heteroaryl groups are optionally substituted with 1-2 substituents independently selected from halo, alkyl, alkoxy, or cyano; or R^la and R^lb taken together form oxo; each of R^2a and R² is independently selected from halo, hydrogen, -OH, -NHR⁶, CM alkyl optionally substituted with 1-3 halo, or C alkoxy optionally substituted with 1-3 halo, or R^2a and R^2b taken together form oxo, or R^2a and R^2b taken together form =N-R³; R³ is CM alkyl optionally substituted with 1-3 halo, or C alkoxy optionally substituted with 1-3 halo; is a single bond, or a double bond when one of R^la and R^lb is absent ring A is selected from

each R⁴ is independently selected from hydrogen, C_1-3 alkyl optionally substituted with 1-3 halo, or Ci_-3 alkoxy optionally substituted with 1-3 halo; x is 0-2; each R⁵ is independently selected from hydrogen or C alkyl; and each R⁶ is independently selected from hydrogen, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein each R⁷ is independently hydrogen or C_M alkyl.

[0113] In some embodiments, each of R^la and R^lb is independently selected from hydrogen, -OH, CM alkyl optionally substituted with 1-3 halo, or CM alkoxy optionally substituted with 1-3 halo, or -O-aryl, -O-heteroaryl, -0-CH₂-aryl, or -0-CH₂-heteroaryl, wherein either of the aryl or heteroaryl groups are optionally substituted with 1-2 substituents independently selected from halo, alkyl, alkoxy, or cyano; or R^la and R^lb taken together form oxo.

[0114] In other embodiments, one of R^la and R^lb is hydrogen and the other is CM alkoxy optionally substituted with 1-3 halo. For example, one of R^la and R^lb is hydrogen and the other is -0-CH₂CH₃.

[0115] In some embodiments, ring A is

[0116] In some of these embodiments, x is 1 or 2 and at least one R⁴ is Ci_-3 alkoxy optionally substituted with 1-3 halo. In other instances, x is 1 or 2 and at least one R⁴ is selected from -OCH₃ or -OCH₂CH₃. For example, x is 1. In other examples, x is 1, and R⁴ is -OCH3 that is attached to the meta position on the phenyl group of ring A.

[0117] In other embodiments, x is 1 or 2 and at least one R⁴ is -N(R⁶)₂. For example, x is 1 , R⁴ is -N(R⁶)₂, one R⁶ is hydrogen and the other R⁶ is selected from C_1-4 alkyl, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein the C alkyl is optionally substituted with a 6-10 membered monocyclic or bicyclic aryl or a 5-10 membered monocyclic or bicyclic heteroaryl having 1-3 heteroatoms independently selected from N, O, or S, and wherein each R⁷ is independently hydrogen or C alkyl. In other examples, x is 1, and R⁴ is -NH₂, -NH(CM alkyl), or -N(CM alkyl)₂.

[0118] In other embodiments, one of R^2a and R^2b is hydrogen and the other is selected from hydrogen, halo, -OH, -CH₃, -CH₂CH₃, -OCH₃, or -OCH₂CH₃. For instance, one of R^2a and R^2b is hydrogen and the other is -OH. In other examples, both of R^2a and R^2b are

independently selected from hydrogen, halo, -CH₃, -CH₂CH₃, -OCH3, or -OCH₂CH₃. In some examples, R^2a and R^2b taken together are oxo. And, in some examples, R^2a and R^2b taken together form =N-R³, and R³ is selected from C_1-4 alkyl optionally substituted with 1-3 halo or C alkoxy optionally substituted with 1-3 halo. For instance, R^2a and R^2b taken together form =N-0-CH₃.

[0119] In some embodiments, one of R^2a and R^2b is hydrogen and the other is -N(R⁶)₂, wherein each R⁶ is independently selected from hydrogen, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein each R⁷ is independently hydrogen or C_1-4 alkyl. For example, one ofR^2a and R^2b is hydrogen and the other is -NHR⁶, wherein R⁶ is independently selected from hydrogen, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein each R⁷ is independently hydrogen or C_M alkyl.

[0120] In some embodiments, ring A is

[0121] In several of these embodiments, x is 1 or 2 and at least one R⁴ is Q.3 alkyl optionally substituted with 1-3 halo or Ci_-3 alkoxy optionally substituted with 1-3 halo. In some examples, at least one R⁴ is selected from -CH3 or -CH₂CH₃. For instance, x is 1. In other instances, R⁴ is -CH2CH3 that is attached to the 5 position on the pyridine-yl group of ring A.

[0122] In some of these embodiments, x is 1 or 2 and at least one R⁴ is -N(R⁶)₂. For example, x is l, R is -N(R⁶)₂, one R⁶ is hydrogen and the other R⁶ is selected from C alkyl, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein the C alkyl is optionally substituted with a 6-10 membered monocyclic or bicyclic aryl or a 5-10 membered monocyclic or bicyclic heteroaryl having 1-3 heteroatoms independently selected from N, O, or S, and wherein each R⁷ is independently hydrogen or C_1-4 alkyl. In other examples, x is 1, and R⁴ is -NH₂,

-NH(C_M alkyl), or -N(CM alkyl)₂.

[0123] In some embodiments, one of R^2a and R^2b is hydrogen and the other is selected from hydrogen, halo, -OH, -CH₃, -CH₂CH₃, -OCH3, or -OCH₂CH₃. For example, one of R^2a and R^2b is hydrogen and the other is -OH. In other embodiments, both of R^2a and R^2b are independently selected from hydrogen, halo, -OH, -CH₃, -CH₂CH₃, -OCH3, or -OCH₂CH₃. In some embodiments, R^2a and R^2b taken together are oxo. In other embodiments, R² and R^2b taken together form =N-R³, and R³ is selected from C alkyl optionally substituted with 1-3 halo or C_1-4 alkoxy optionally substituted with 1-3 halo. For instance, R^2a and R^2b taken together form =N-0-CH₃.

[0124] In some embodiments, one of R^2a and R^2b is hydrogen and the other is -N(R⁶)₂, wherein each R⁶ is independently selected from hydrogen, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein each R⁷ is independently hydrogen or C alkyl. For example, one ofR^2a and R^2b is hydrogen and the other is -NHR⁶, wherein R⁶ is independently selected from hydrogen, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein each R⁷ is independently hydrogen or CM alkyl.

[0125] In some embodiments, R³ is C1.3 alkoxy optionally substituted with 1-3 halo. For example, R³ is -OCH3 or -OCF₃.

[0126] In some embodiments, is a double bond and one of R^la and R^lb is absent. In other embodiments, ΓΤ^Π is a single bond and one of R^la and R^lb is hydrogen and the other is selected from hydrogen, -CH₃, -CH₂CH₃, -OCH3, or -OCH₂CH₃.

[0127] In some embodiments, the compound of Formula I is selected from a compound of Formula IA:

or a pharmaceutically acceptable salt thereof, wherein each of R^Ia and R^Ib 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; each of R^2a and R^2b is independently selected from halo, hydrogen, -OH, C alkyl optionally substituted with 1-3 halo or CM alkoxy optionally substituted with 1 -3 halo, or R^2a and R^2b taken together form oxo, or R^2a and R^2b taken together form =N-R³; R³ is CM alkyl optionally substituted with 1-3 halo, or CM alkoxy optionally substituted with 1-3 halo; is a single bond, or a double bond when one of R^la and R^lb is absent; ring A is selected from

each R⁴ is independently selected from hydrogen, C₁.₃ alkyl optionally substituted with 1-3 halo, or C₁.₃ alkoxy optionally substituted with 1-3 halo; and x is 0-2.

[0128] In some embodiments, the compound of Formula I is selected from a compound of Formula II, III, IV, or V:

i v

wherein each of R^la, R^lb, R^2a, R^2b, R⁴, and x are defined above.

[0129] In some embodiments, the compound of Formula I is selected from a compound of Formula IVA, IVB, IVC, IVD, or IVE:

IVA IVB

, or

R^2a

IVE

wherein each of R^la, R^2a, R⁴, and x are defined above.

[0130] In some embodiments, the compound of Formula I is selected from a compound of Formula VA, VB, VC, VD, or VE:

wherein each of R^la, R^2a, R⁴, and x are defined above.

[0131] Examples of compounds of Formula I include those provided in Table A:

Table A: Exemplary compounds of Formula I.

[0132] III. PHARMACEUTICAL COMPOSITIONS

[0133] 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^IB is independently selected from hydrogen, -OH, C_1-4 alkyl optionally substituted with 1-3 halo, or C alkoxy optionally substituted with 1-3 halo, or -O-aryl, -O-heteroaryl, -0-CH₂-aryl, or -0-CH₂- heteroaryl, wherein either of the aryl or heteroaryl groups are optionally substituted with 1-2 substituents independently selected from halo, alkyl, alkoxy, or cyano; or R^LA and R^LB taken together form oxo; each of R^2A and R^2B is independently selected from halo, hydrogen, -OH, -NHR⁶, CM alkyl optionally substituted with 1-3 halo, or C_1-4 alkoxy optionally substituted with 1-3 halo, or R^2A and R^2B taken together form oxo, or R^2A and R^2B taken together form =N-R³; R³ is CM alkyl optionally substituted with 1-3 halo, or CM alkoxy optionally substituted with 1-3 halo; is a single bond, or a double bond when one of R^LA and R¹¹ is absent; ring A is selected

each R⁴ is independently selected from hydrogen, Ci-3 alkyl optionally substituted with 1-3 halo, or C_1-3 alkoxy optionally substituted with 1-3 halo; x is 0-2; each R⁵ is independently selected from hydrogen or CM alkyl; and each R⁶ is independently selected from hydrogen, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein each R⁷ is independently hydrogen or C_1-4 alkyl; and a pharmaceutically acceptable carrier. [0134] 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 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; each of R^2a and R^2b is independently selected from halo, hydrogen, -OH, C alkyl optionally substituted with 1-3 halo or CM alkoxy optionally substituted with 1-3 halo, or R^2a and R^2b taken together form oxo, or R^2a and R^2b taken together form =N-R³; R³ is C alkyl optionally substituted with 1-3 halo, or CM alkoxy optionally substituted with 1-3 halo; is a single bond, or a double bond when one of ^Ia and R^Ib is absent; ring A is selected from

each R⁴ is independently selected from hydrogen, C_1-3 alkyl optionally substituted with 1-3 halo, or C1-3 alkoxy optionally substituted with 1-3 halo; and x is 0-2, and a pharmaceutically acceptable carrier.

[0135] In some embodiments, the pharmaceutical composition comprises a compound of Formula IVA-IVE or VA-VE, wherein said compound has a purity of about 70 e.e. % or more. For example, the pharmaceutical composition comprises a compound of Formula IVA-IVE or VA-VE, 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).

[0136] 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.

[0137] In another embodiment, the pharmaceutical composition further comprises a GLP analogue such as Exenatide (e.g., Exendin-4), Liraglutide, Taspoglutide, or any combination thereof.

[0138] In some embodiments, the pharmaceutical composition further comprises a DPP4 inhibitor such as sitagliptin, vildagliptin, saxagliptin, linagliptin, dutogliptin, gemigliptin, alogliptin, Berberine, or any combination thereof.

[0139] 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 t e like), or compounds that augment sympathomimetic activity such as ephedrine or its various salts.

[0140] 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.

[0141] IV. METHODS OF TREATING DIABETES AND OTHER METABOLIC DISEASES

[0142] A. Diabetes

[0143] 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.

[0144] 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.

[0145] 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, 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. [0146] 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.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] 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).

[0154] 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.

[0155] 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.

[0156] 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).

[0157] 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.

[0158] 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).

[0159] 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.

[0160] 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.

[0161] 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 HbAl C 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.

[0162] 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).

[0163] 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).

[0164] 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.

[0165] 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.

[0166] 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.

[0167] 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).

[0168] 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).

[0169] B. Obesity

[0170] 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.

[0171] 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. [0172] 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).

[0173] 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.

[0174] 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.

[0175] 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).

[0176] 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.

[0177] 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).

[0178] According to yet another embodiment, the present invention provides a method of treating or reducing the severity of central obesity.

[0179] 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. [0180] C. Dyslipidemia

[0181] 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.

[0182] V. GENERAL SYNTHETIC SCHEMES

[0183] 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.

1-4 1-5 I

[0185] Referring to Scheme 1, the hydroxy group of starting material 1-1 is protected with a alcohol protecting group (e.g., benzyl (Bn)) to form the protected intermediate 1-2. The primary amine group of intermediate 1-2 is converted to an R^lb group (e.g., -OH via treatment withNaN0₂ under acidic conditions) to form intermediate 1-3. Intermediate 1-3 is deprotected via hydrogenolysis to form intermediate 1-4, and intermediate 1-4 is reacted with reagent 1-5 under basic conditions to form a compound of Formula I.

[

R' = C_1-4 alkyl

R^1a = H

[0187] Referring to Scheme 2, the starting material 2-1 is protected with an alcohol protecting group (e.g., benzyl (Bn)) to form the intermediate 2-2. Intermediate 2-2 is diazotized in the presence of an aqueous acid to generate intermediate 2-3. Intermediate 2-3 is esterified to generate intermediate 2-4. Intermediate 2-4 is deprotected via a

hydrogenolysis reaction to generate intermediate 2-5, which is reacted with reagent 2-6 under basic conditions to form intermediate 2-7. Intermediate 2-7 undergoes sapponification to form the a-alkoxy acid 2-8. In steps a and b, intermediate 2-7 may undergo chiral reduction, when R^2a and R^2b form oxo, to generate their corresponding chiral alcohols, 2-9 and 2-10. Chiral alcohols, 2-9 and 2-10, may then undergo sapponification to form their corresponding α-alkoxy acid compounds 2-11 and 2-12, wherein compounds 2-8, 2-11, and 2-12 are compounds of Formula I.

[0188] In Scheme 3, below, ring A is an alkyl substituted pyridine, R^2a and R^2b together form oxo, R^la is absent, R^2b is alkoxy, and is a double bond. [0189] Scheme 3:

[0190] Starting material 3-1 is acylated to form ketone 3-2, and ketone 3-2 is alkylated to generate intermediate 3-3. Intermediate 3-3 is halogenated to generate intermediate 3-4, and intermediate 3-4 is converted to the oxime 3-5 (e.g., via a condensation reaction). Oxime 3-5 is reacted with the a-alkoxy ester 3-6 to generate intermediate 3-7, which undergoes sapponification to generate the corresponding a-alkoxy acid 3-8, which is a compound of Formula I.

[0191] VI. USES, FORMULATIONS, AND ADMINISTRATION

[0192] As discussed above, the present invention provides compounds that are useful as treatments for obesity and/or reducing a patient's bodyweight.

[0193] 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.

[0194] It will also be appreciated that certain of the 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. [0195] 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.

[0196] 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 ⁺(C_1-4alkyl)₄ 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. [0197] 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 form lator.

[0198] 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).

[0199] 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.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] 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.

[0204] 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.

[0205] 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.

[0206] 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.

[0207] 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, polyvmylpyrrolidinone, 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.

[0208] 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.

[0209] 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.

[0210] 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.

[0211] As described generally above, the compounds of the invention are useful as treatments for metabolic diseases.

[0212] 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.

[0213] 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".

[0214] 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.

[0215] 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.

[0216] 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, IIA, IIB, IIC, IIIA, IIIB, IV, IVA or IVB. 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.

[0217] 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.

[0218] VII. EXAMPLES

[0219] Example 1: Preparation of (ZVethyl 2-ethoxy-3-(4-(2-(3-methoxyphenvn-2- oxoethoxyrohenyDacrylate

[0220] To a stirring solution of ethyl (2Z)-2-ethoxy-3-(4-hydroxyphenyl)acrylate (1.20 g, 5.08 mmol; Supplier = alexsyn; Lot = 903-TTP-179) in acetone (25ml) was added

2-Bromo-3'-methoxyacetophenone (1.1 g, 4.9 mmol; Supplier = Aldrich) and potassium carbonate (0.700 g, 5.06 mmol). After stirring at RT for 4 hours, LCMS indicated that the desired product was the major component. The reaction mixture was evaporated in vacuo. The residue was partitioned between EtOAc and water, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na₂S04), filtered and evaporated in vacuo. The residue was chromatographed eluting with 10-30%

EtOAc/hexanes to afford (Z)-ethyl 2-ethoxy-3-(4-(2-(3-methoxyphenyl)-2- oxoethoxy)phenyl)acrylate (1.41 g) as a clear, colorless oil.

[0221] Example 2: Preparation of ethyl 2-ethoxy-3-(4-(2-hvdroxy-2-(3- methoxyphenvOethoxy)phenvDpropanoate

[0222] To a solution of the olefin (0.68g) in EtOAc (15ml) was added 10% Pd/C (0.7g) and the mixture was shaken on a Parr apparatus under 50 psi hydrogen. After 4 hours, the reaction mixture was filtered through a pad of Celite and evaporated in vacuo. The residue was chromatographed eluting with 10-50% ether/hexanes. Fractions containing product were combined and evaporated in vacuo to give ethyl 2-ethoxy-3-(4-(2-hydroxy-2-(3- methoxyphenyl)ethoxy)phenyl)propanoate (0.716 g) as a clear, colorless oil.

[0223] Example 3; Preparation of ethyl 2-ethoxy-3-(4-(2-(3-methoxyphenylV2- oxoethoxy)phenyl)propanoate

[0224] To a stirring solution of ethyl 2-ethoxy-3 -(4-(2-hydroxy-2-(3 - methoxyphenyl)ethoxy)phenyl)propanoate (0.71 g, 1.8 mmol) in EtOAc (25 ml) was added 1 -hydroxy- l,2-benziodoxol-3(lH)-one 1-oxide (1.5 g, 5.5 mmol) and the mixture was refluxed for 4 hours, then allowed to cool to RT. The reaction mixture was concentrated in vacuo and the crude product was purified by chromatography eluting 0-20% acetone:DCM to afford ethyl 2-ethoxy-3-(4-(2-(3-methoxyphenyl)-2-oxoethoxy)phenyl)propanoate (0.69 g).

[0225] Example 4; Preparation of 2-ethoxy-3-(4-(2-(3-methoxyphenyD-2- oxoethoxytphenyDpropanoic acid

[0226] To a stirring solution of ethyl ester (0.56g, 1.4mmol) in THF (4ml) was added 1.0 M of lithium hydroxide monohydrate in water (4.3 mL, 4.3 mmol), and the solution was heated to reflux. After 2 hours at reflux, the reaction is complete and cooled to RT, and concentrated in vacuo. EtOAc was added and the biphasic mixture stirred as 1M KHS0₄ was added until pH of aqueous phase was ca. 4. The aqueous phase was extracted with EtOAc. The combined organic phases were dried (Na₂S04), filtered and evaporated in vacuo. The residue was chromatographed eluting with 0-5% MeOH/DCM. Fractions containing product were combined and evaporated in vacuo to give 2-ethoxy-3-(4-(2-(3-methoxyphenyl)-2- oxoethoxy)phenyl)propanoic acid (0.363 g) as a yellow oil/glass.

[0227] Example 5: Preparation of (RV2-ethoxy-3-(4-(2-hvdroxy-2-(3-

[0228] A mixture of dichloro(p-cymene)ruthenium(II) dimer (1.3 mg, 0.0000021 mol), (lS,2S)-(+)-N-p-tosyl-l,2-diphenylethylenediamine (1.5 mg, 0.0000042 mol) and

triethylamine (0.003 mL, 0.00002 mol) in isopropyl alcohol (0.8 mL, 0.01 mol) was refluxed for 30 minutes. The reaction mixture was allowed to cool to RT and then evaporated in vacuo. To the residue was added a solution of 2-ethoxy-3-(4-(2-(3-methoxyphenyl)-2- oxoethoxy)phenyl)propanoic acid (85 mg, 0.00024 mol; Supplier = Kalexsyn; Lot = 903-TTP-193) in DMF (2ml) followed by formic acid triethylamine complex (89 mg, 0.00060 mol), and the reaction mixture was left to stir at RT overnight. LCMS indicated that the reaction was complete. The reaction mixture was partitioned between DCM and saturated NaHC0₃, and the aqueous phase was extracted with DCM. The combined organic phases were dried (Na₂S0₄), filtered and evaporated in vacuo (Jouan w/heat). The residue was chromatographed on a small Biotage column eluting with 0-20% ether/DCM then 5%

MeOH/DCM. Fractions containing product were combined and evaporated in vacuo to give 22 mg of (R)-2-ethoxy-3-(4-(2-hydroxy-2-(3-methoxyphenyl)ethoxy)phenyl)propanoic acid as a tinted oil.

[0229] Example 6: Preparation of (SV2-ethoxy-3-f4-(2-hvdroxy-2-(3- methoxyphenyl ethoxy)phenyl^propanoic acid

[0230] A stirring mixture of (lR,2R)-(-)-N-p-tosyl-l,2-diphenylethylenediamine (1.8 mg, 0.0000049 mol), dichloro(p-cymene)ruthenium(II) dimer (1.5 mg, 0.0000025 mol) and triethylamine (3 μί, 0.00002 mol) in isopropyl alcohol (1.0 mL, 0.013 mol) was heated at reflux for 30 minutes, allowed to cool to RT, and then evaporated in vacuo. To the residue was added a solution of 2-ethoxy-3-{4-[2-(3-methoxyphenyl)-2-oxoethoxy]phenyl}propanoic acid (98 mg, 0.00027 mol; Supplier = Kalexsyn; Lot = 903-TTP-193) in DMF (2ml) followed by formic acid triethylamine complex (0.10 g, 0.00071 mol), which was left to stir at RT overnight. The reaction mixture was partitioned between DCM and saturated aq. NaHCC>3. The organic phase was dried (Na₂S0₄), filtered and evaporated in vacuo (Jouan w/heat). The residue was chromatographed on the PrepStar. Fractions showing correct mass were combined and evaporated in vacuo. The residue was partitioned between DCM and saturated NaHC(¼, and the organic phase was extracted with saturated NaHCC^. The combined aqueous phases were treated with 1M KHS0₄ until pH ca. 5 when it was extracted with DCM. Added 1M KHS0₄ until pH ca. 1 and it was extracted with DCM. Combined organic phases dried (Na₂S0₄), filtered and evaporated to give 15 mg dark brown oil.

Chromatographed on a small pipette column, eluting with 0-10% acetone/DCM. Fractions containing product were combined and evaporated to give 15mg of (S)-2-ethoxy-3-(4-(2- hydroxy-2-(3-methoxyphenyl)ethoxy)phenyl)propanoic acid as a tinted oil.

[0231] Example 7: Preparation of (SVethyl 3-(4-(benzyloxytohenylV2- ethoxypropanoate

[0232] To a stirring solution of (S)-3-[4-(benzyloxy)phenyl]-2-hydroxypropanoic acid (0.98 §, 0,0036 mol; Supplier = Kalexsyn; Lot = 1103-TTP-140; Zeng, Q.L.; Wang, H.Q.; Liu, Z.R.; Li, B.G.; Zhou, Y.F. Amino Acids 2007, 33, 537-541) in DMSO (2ml) was added crushed potassium hydroxide (0.606 g, 0.0108 mol) followed by sulfuric acid, and diethyl ester (1.41 mL, 0.0108 mol). After 3 hours, 0.3g KOH and 0.6ml Et₂S0₄ was added to the reaction mixture, which was left to stir at RT overnight. The reaction mixture was partitioned between EtOAc and water, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water, brine, dried (Na₂S0₄), filtered and evaporated in vacuo. The light yellow oil was chromatographed eluting with 10-20% EtO Ac/hex. Fractions containing product were combined and evaporated in vacuo to give (S)-ethyl 3-(4- (benzyloxy)phenyl)-2-ethoxypropanoate (0.78g) as a clear, colorless oil.

[0233] Example 8; Preparation of (S)-ethyl 2-ethoxy-3-(4-hvdroxyphenvQpropanoate

[0234] A mixture of (S)-ethyl 3-(4-(benzyloxy)phenyl)-2-ethoxypropanoate (0.78 g, 2.4 mmol; Supplier = Kalexsyn; Lot = 1103-TTP-150) and 10% Pd/C (200mg) in absolute EtOH (8ml) was shaken on a Parr apparatus under 30 PSI of hydrogen. After 2 hours, the reaction was complete. The reaction mixture was filtered through a pad of Celite and evaporated in vacuo to give (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate (0.56g) as a slightly brown oil.

[0235] Example 9; Preparation of (S)-ethyl 2-ethoxy-3-(4-(2-(3-methoxyphenvn-2~

[0236] To a stirring solution of (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate (560 mg, 2.4 mmol; Supplier = Kalexsyn; Lot = 1103-TTP-153), 2-bromo-3'- methoxyacetophenone (590 mg, 2.6 mmol), in acetone (5ml) was added potassium carbonate

(390 mg, 2.8 mmol), which was left to stir at RT overnight. The reaction mixture was partitioned between EtOAc and water, and the aq. phase was extracted with EtOAc. The combined organic phases were dried (Na₂S0₄), filtered and evaporated in vacuo. The resulting yellow oil was chromatographed on eluting with 0-20% acetone/DCM. Fractions containing product were combined and evaporated in vacuo to give (S)-ethyl 2-ethoxy-3-(4 (2-(3-methoxyphenyl)-2-oxoethoxy)phenyl)propanoate (347 mg) as an oil.

[0237] Example 10: Preparation of (SV2-ethoxy-3-(4-(2-(3-methoxyphenvn-2-

[0238] To a stirring solution of (S)-ethyl 2-ethoxy-3-(4-(2-(3-methoxyphenyl)-2- oxoethoxy)phenyl)propanoate (70 mg, 0.2 mmol; Supplier = Kalexsyn; Lot = 1103-TTP-155) in MeOH (2ml) was added 2M LiOH until pH ca. 10. After 3 hours, HPLC indicates that the reaction is complete. Added 6M HCl dropwise until pH ca. 3-4. Extracted 2x with EtOAc, and the combined extracts were dried (Na₂S0₄), filtered and evaporated in vacuo. The yellow oil was chromatographed on a small pipette eluting with 0-5% acetone/DCM.

Fractions containing product were combined and evaporated in vacuo to give 38 mg of (S)-2-ethoxy-3-(4-(2-(3-methoxyphenyl)-2-oxoethoxy)phenyl)propanoic acid as a tinted oil.

[0239] Example 11: Preparation of (R ethyl 3-(4-(benzyloxy)phenvn-2- ethoxypropanoate

[0240] To a stirring solution of (R)-3-[4-(benzyloxy)phenyl]-2-hydroxypropanoic acid (1.56 g, 0.00573 mol; Supplier = Kalexsyn; Lot = 1103-TTP-141; Zeng, Q.L.; Wang, H.Q.; Liu, Z.R.; Li, B.G.; Zhou, Y.F. Amino Acids 2007, 33, 537-541; Parmenon, C; Guillard, J.; Caignard, D-H.; Hennuyer, N.; Staels, B.; Audinot-Bouchez, V.; Boutin, J-A.; Dacquet, C; Ktorza, A.; Viaud-Massuard, M-C. Bioorg. Med. Chem. Lett. 2008, 18, 1617-1622) in DMSO (2ml) was added potassium hydroxide (2.15 g, 0.0384 mol) followed by sulfuric acid, diethyl ester (5.0 mL, 0.038 mol), which was left to stir at RT overnight. The reaction mixture was partitioned between EtOAc and water, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water, brine, dried (Na₂S0₄), filtered and evaporated in vacuo. The light yellow oil was chromatographed eluting with 0-20% EtO Ac/hex. Fractions containing the higher Rf spot (desired) were combined and evaporated in vacuo to give (R)-ethyl 3-(4-(benzyloxy)phenyl)-2-ethoxypropanoate (0.937g) as an oil.

[0241] Example 12: Preparation of (RVethyl 2-ethoxy-3-(4-h.vdroxyphenyl)propanoate

[0242] A mixture of (R)-ethyl 3-(4-(benzyloxy)phenyl)-2-et oxypropanoate (0.93 g, 2.8 mmol; Supplier = Kalexsyn; Lot = 1103-TTP-149) and 10% Pd/C (60mg) in absolute EtOH (8ml) was shaken on a Parr apparatus under 20 PSI of hydrogen. After 2 hours, there has been little to no reaction. Added 10% Pd/C (70mg) and increased pressure to 30 PSI. After 2 hours, SM has been consumed. The reaction mixture was filtered through a pad of Celite and evaporated in vacuo to give (R)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate (0.67g) as an oil.

[0243] Example 13: Preparation of iRVethyl 2-ethoxy-3-(4-(2-(3-methoxyphenyr)-2- oxoethoxy)phenyl)propanoate

[0244] To a stirring solution of (R)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate (205 mg, 0.860 mmol; Supplier = Kalexsyn; 1103-TTP-151), 2-bromo-3'-methoxyacetophenone (220 mg, 0.95 mmol), in acetone (5ml) was added potassium carbonate (140 mg, 1.0 mmol). Stirred at RT overnight. The reaction mixture was partitioned between EtOAc and water, and the aq. phase was extracted with EtOAc. The combined organic phases were dried (Na₂S0₄), filtered and evaporated in vacuo to afford (R)-ethyl 2-ethoxy-3-(4-(2-(3-methoxyphenyl)-2- oxoethoxy)phenyl)propanoate (234 mg).

[0245] Example 14: Preparation of (R)-2-ethoxy-3-f4-(2-(3-methoxyphenyl)-2-

[0246] To a stirring solution of (R)-ethyl 2-ethoxy-3-(4-(2-(3-methoxyphenyl)-2- oxoethoxy)phenyl)propanoate (70 mg, 0.2 mmol; Supplier = Kalexsyn; Lot = 1103-TTP-152) in MeOH (2ml) was added 2M LiOH until pH ca. 10. After 3 hours, HPLC indicates that the reaction is complete. Added 6M HC1 dropwise until pH ca. 3-4. Extracted 2x with EtOAc, and the combined extracts were dried (Na2S04), filtered and evaporated in vacuo. The yellow oil was chromatographed on a small pipette eluting with 0-5% acetone/DCM.

Fractions containing product were combined and evaporated in vacuo to give 38 mg of (R)-2-ethoxy-3-(4-(2-(3-methoxyphenyl)-2-oxoethoxy)phenyl)propanoic acid (58%) as a tinted oil.

[0247] Example 15; Preparation of (SV2-ethoxy-3-i4-((RV2-hvdroxy-2-(3- methoxyphenyltethoxy)phenyr>propanoic acid

[0248] To a stirring solution of (S)-ethyl 2-ethoxy-3-(4-((R)-2-hydroxy-2-(3- methoxyphenyl)ethoxy)phenyl)propanoate (112 mg, 0.000287 mol; Supplier = Kalexsyn; Lot = 1103-TTP-160) in MeOH (2ml) was added 2N LiOH until pH ca. 10-12. After 2 hours, HPLC showed reaction was complete. Evaporated in vacuo. The residue was partitioned between water and EtOAc and the aqueous phase was extracted with EtOAc. The combined organic phases were dried (Na₂S0 ), filtered and evaporated in vacuo. The resulting pale pink oil was chromatographed on a small pipette column eluting with 0-10% acetone/DCM. Fractions containing product were combined and evaporated in vacuo to give 68 mg of (S)-2-ethoxy-3-(4-((R)-2-hydroxy-2-(3-methoxyphenyl)ethoxy)phenyl)propanoic acid as a tinted oil.

[0249] Example 16: Preparation of (R)-2-ethoxy-3-(4-((R)-2-hvdroxy-2-(3-

[0250] To a stirring solution of (R)-ethyl 2-ethoxy-3-(4-((R)-2-hydroxy-2-(3- methoxyphenyl)ethoxy)phenyl)propanoate (90 mg, 0.2 mmol) in MeOH (2ml) was added 2N LiOH until pH ca. 10. Stirred at RT for 2 hours at which time HPLC indicated the reaction was complete. Evaporated in vacuo. The residue was partitioned between water and EtOAc and formic acid was added until pH ca. 3. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic phases were dried (Na₂S04), filtered and evaporated in vacuo. The residue was chromatographed on a small pipette column eluting with 0-10% acetone/DCM. Fractions containing product were combined and evaporated in vacuo to give 53 mg of (R)-2-ethoxy-3-(4-((R)-2-hydroxy-2-(3- methoxyphenyl)ethoxy)phenyl)propanoic acid as a slightly tinted oil.

[0251] Example 17; Preparation of (SV2-ethoxy-3-(4-«SV2-hvdroxy-2-(3-

[0252] To a stirring solution of (S)-ethyl 2-ethoxy-3-(4-((S)-2-hydroxy-2-(3- methoxyphenyl)ethoxy)phenyl)propanoate (50 mg, 0.1 mmol) in MeOH (2ml) was added 2N LiOH until pH ca. 12. After 2 hours, HPLC indicated that the reaction was complete.

Evaporated in vacuo. The residue was partitioned between water and EtOAc and HC0₂H was added until pH ca. 3. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were combined, dried (Na₂S0₄), filtered and evaporated in vacuo. The residue was partitioned on a small pipette column eluting with 0- 10% ether/DCM. Fractions containing product were combined and evaporated in vacuo to give 26 mg of (S)-2-ethoxy-3-(4-((S)-2-hydroxy-2-(3- methoxyphenyl)ethoxy)phenyl)propanoic acid.

[0253] Example 18: Preparation of <^-2-ethoxy-3-(4-f2^3-methoxyphenvn-2- oxoethoxywhenvDacrylic acid

[0254] To a stirring solution of (Z)-ethyl 2-ethoxy-3 -(4-(2-(3 -methoxyphenyl)-2- oxoethoxy)phenyl)acrylate (83 mg, 0.22 mmol; Supplier = Kalexsyn; Lot = 1103-TTP-67) in EtOH (1ml) was added 2M NaOH (1ml). Left to stir at RT overnight. Reaction is a deep magenta color, appears to be complete by HPLC. Evaporated in vacuo. Partitioned between water and EtOAc. Added aq. HCl until pH ca. 3. EtOAc phase dried (Na₂S0₄), filtered and evaporated in vacuo. Chromatographed on a pipette column to give 45 mg off-white solid. There is a contaminant (HPLC, 1H-NMR). Rechromatographed and triturated with ether/hexanes to give 14 mg of (Z)-2-ethoxy-3-(4-(2-(3-methoxyphenyl)-2- oxoethoxy)phenyl)acrylic acid as a tinted oil.

[0255] Exam^ple 19; Preparation of 2-ethoxy-3-⁽4-(2-(methoxyimino)-2-(3- methoxyphenvOethoxy nhenvDpropanoic acid

[0256] To a stirring solution of ethyl 2-ethoxy-3-(4-(2-(methoxyimino)-2-(3- methoxyphenyl)ethoxy)phenyl)propanoate (185 mg, 0.446 mmol; Supplier = Kalexsyn; Lot = 1103-TTP-62) in EtOH (2ml) was added 1M NaOH dropwise until pH ca. 10. Left to stir at RT overnight. 03/03/2011 HPLC shows reaction is complete. LCMS shows mass for desired and also mass for the corresponding ketone. HPLC suggests that the material is not the ketone. Added 1M NaOH until pH ca. 3. Extracted with EtOAc. Extracts dried (Na₂S0₄), filtered and evaporated in vacuo to give 160 mg crude material. Chromatographed on a pipette column eluting with 10% EtOAc/DCM to give 105 mg of 2-ethoxy-3-(4-(2- (methoxyimino)-2-(3-methoxyphenyl)ethoxy)phenyl)propanoic acid as a clear, colorless oil.

[0257] Example 20; Preparation of (2Z)-2-ethoxy-3-(4-(2-(methoxyimino)-2-(3-

[0258] To a stirring solution of (2Z)-ethyl 2-ethoxy-3 -(4-(2-(methoxyimino)-2-(3 - methoxyphenyl)ethoxy)phenyl)acrylate (191 mg, 0.463 mmol; Supplier = Kalexsyn; Lot = 1103-TTP-57) in EtOH (2ml) was added 5 drops of 2M NaOH ~ pH ca. 10. Left to stir at RT overnight. Reaction is only ca. 75% complete. Added 2 drops 2M NaOH. After 5 hours, only a trace of SM remains. Evaporated in vacuo. Partioned between water and EtOAc; added HO Ac until pH ca. 3. The organic phase was separated, dried (Na2S04), filtered and evaporated in vacuo to give an off-white solid. Chromatographed on a small MM column eluting with 0-10% EtOAc/DCM, then 10% acetone/DCM. Fractions containing product were combined and evaporated in vacuo to give 90 mg of (2Z)-2-ethoxy-3-(4-(2- (methoxyimino)-2-(3-methoxyphenyl)ethoxy)phenyl)acrylic acid as a tinted oil.

[0259] Example 21: Preparation of 2-ethoxy-3-(4-(2-(3-methoxyphenyr>-2-

[0260] A stirring solution of ethyl 2-ethoxy-3-(4-(2-(methoxyimino)-2-(3- methoxyphenyl)ethoxy)phenyl)propanoate (150 mg, 0.36 mmol; Supplier = Kalexsyn; Lot = 1103-TTP-62) in 6M HC1 (2ml) was added acetic acid, oxo- (107 mg, 0.724 mmol) and the solution was heated at 75 °C. Heated for one hour. Product has definitely been formed as evidenced by LCMS. LCMS also shows a mass for SM, but it appears that little or no SM remains by HPLC. Adjusted pH to 3-4 with aq. NaOH and extracted 2x with EtOAc. The combined extracts were dried (Na2S04), fitered and evaporated in vacuo to give a yellow/brown soild/oil. Chromatographed on a pipette column to give 65 mg of

2-ethoxy-3-(4-(2-(3-methoxyphenyl)-2-oxoethoxy)phenyl)propanoic acid as a white solid.

[0261] Example 22: Preparation of (SVethyl 2-ethoxy-3-(4-(2-(5-ethylpyridin-2-yr>-2- oxoethoxy>phenyl)propanoate

[0262] To a stirring solution of 2-bromo- 1 -(5~ethylpyridin-2-yl)ethanone hydrobromide (1.49 g, 4.83 mmol) and ethyl-(2S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate (1.15 g, 4.83 mmol) in N,N-dimethylformamide (62 mL, 8.0E2 mmol) was added cesium carbonate (3.93 g, 12.1 mmol). The mixture was left to stir at RT overnight and partitioned between EtOAc and water, and the aqueous phase was extracted with EtOAc. The extracts were combined and washed 2x with water, brine. The resulting mixture was dried (MgS0₄), filtered, evaporated in vacuo, and chromatographed on silica with 0-20% ethylacetate in hexane. The chromatograph showed a single UV peak. 'HNMR showed a couple of substantial impurities. The product was used without further attempts at purification.

[0263] Example 23: Preparation of (S)-2-ethoxy-3-(4-a-(5-ethylpyridin-2-yl)-2- oxoethoxy)phenyl)propanoic acid

[0264] To a stirring mixture of ethyl-(2S)-2-ethoxy-3-{4-[2-(5-ethylpyridin-2-yl)-2- oxoethoxy]phenyl}propanoate (220 mg, 0.57 mmol; Supplier = Kalexsyn; Lot = 1103-MPA- 94) in MeOH (3ml) was added 2M LiOH until pH ca. 10-12. Left to stir at RT overnight. HPLC shows the reaction is complete. Evaporated in vacuo. Partitioned between EtOAc and water. Added HC0₂H until pH ca. 3. Separated phases and extracted the aqueous phase with EtOAc. Combined organic phases dried (MgS0₄), filtered and evaporated in vacuo. Chromatographed on a small pipette column eluting with 0-10% Et 0/DCM. Fractions containing product were combined and evaporated in vacuo to afford 65mg of the product.

[0265] Example 24: Preparation of fRVethyl 2-ethoxy-3-(4-a-i5-ethylpyridin-2-vn-2- oxoethoxytphenvQpropanoate

[0266] To a stirring solution of 2-bromo-l-(5-ethylpyridin-2-yl)ethanone hydrobromide (1.04g, 3.35mmol) and ethyl-(2R)-2-ethoxy-3-(4-hydroxyphenyl)propanoate (799mg, 3.35mmol) in DMF (43ml) was added cesium carbonate (2.73g, 8.38mmol) and the mixture was left to stir at RT overnight. Partitioned between EtOAc and water and the aqueous phase was extracted with EtOAc. Combined extracts dried (MgS0₄), filtered and evaporated in vacuo. 1H-NMR showed very clean product. Used without further purification.

[0267] Example 25: Preparation of (R)-2-ethoxy-3-(4-(2-(5-ethylpyridin-2-vn-2- oxoethoxy)phenyl)propanoic acid

[0268] To a stirring solution of ethy (2R)-2-ethoxy-3-{4-[2-(5-ethylpyridin-2-yl)-2- oxoethoxy]phenyl}propanoate (540mg, 1.4mml) in methanol (30ml) was added a 1.0M solution of lithium hydroxide in water (10ml, lOmmol). Left to stir at RT overnight. HPLC shows reaction is complete. Primary product is the desired. Nuetralized to pH ~3 with 2.0 M HC1. Extracted with EtOAc (2x), washed with brine. Extracts dried (Na₂S0₄), filtered and evaporated in vacuo. Chromatographed on silica, eluting with 0-5% MeOH:CHCl₃ to give a light yellow oil. Contained some impurities by HPLC. Trituration with MTBE failed to produce a nice solid, so the material was Chromatographed via rotary chromatography in the same solvent system and the desired material was isolated, 57mg (11%).

[0269] Example 26: Assays

[0270] Assays useful for evaluating the biological properties of compounds of Formula I may be assayed using the following assay methods.

[0271] Assays for Measuring Reduced PPARy Receptor Activation.

[0272] 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.

[0273] 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).

[0274] 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 PP AR-LBD/Fluormone PP AR 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.

[0275] 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 293 H 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).

[0276] 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.

[0277] Glucose, Insulin, and Triglyceride in Diabetic KKAy Mice Treated with

Exemplary Compounds of the Present Invention.

[0278] 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 Hofinann 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.

[0279] 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.

[0280] BAT Differentiation.

[0281] 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. [0282] 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 g/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.

[0283] 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.

[0284] 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.

[0285] Mitochondrial Membrane Competitive Binding Crosslinking Assay

[0286] 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.Έ252-Ε260. 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 x 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.

[0287] 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- oxoe1hoxy)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.

[0288] It is noted that in Table B, indicates that no data is available. OTHER EMBODIMENTS

[0289] 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 :

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 -O-aryl, -O-heteroaryl, -0-CH2-aryl, or -0-CH₂-heteroaryl, wherein either of the aryl or heteroaryl groups are optionally substituted with 1 -2 substituents independently selected from halo, alkyl, alkoxy, or cyano; or

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

Each of R^2a and R^2b is independently selected from halo, hydrogen, -OH, -N(R⁶)₂, Ci-4 alkyl optionally substituted with 1 -3 halo, or C alkoxy optionally substituted with 1 -3 halo, or

R^2a and R^2b taken together form oxo, or

R^2a and R^2b taken together form =N-R³;

R³ is C alkyl optionally substituted with 1-3 halo, or C alkoxy optionally substituted with 1 -3 halo;

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

Ring A is selected fr

Each R⁴ is independently selected from hydrogen, -N(R⁶)₂, Ci.₃ alkyl optionally substituted with 1 -3 halo, or C_1-3 alkoxy optionally substituted with 1 -3 halo;

x is 0-2;

Each R⁵ is independently selected from hydrogen or C_1-4 alkyl; and

Each R⁶ is independently selected from hydrogen, C_1-4 alkyl, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein the C alkyl is optionally substituted with a 6- 10 membered monocyclic or bicyclic aryl or a 5-10 membered monocyclic or bicyclic heteroaryl having 1 -3 heteroatoms independently selected from N, O, or S, and wherein each R is independently hydrogen or C alkyl.

2. The compound of claim 1 ,

3. The compound of claim 2, wherein x is 1 or 2 and at least one R⁴ is C_1-3 alkoxy optionally substituted with 1-3 halo.

4. The compound of claim 3, wherein x is 1 or 2 and at least one R⁴ is selected from -OCH3 or -OCH2CH3.

5. The compound of claim 4, wherein x is 1.

6. The compound of claim 5, wherein R⁴ is -OCH3 that is attached to the meta position on the phenyl group of ring A.

7. The compound of claim 2, wherein one of R^2a and R^2b is hydrogen and the other is selected from hydrogen, halo, -OH, -CH₃, -C¾CH₃, -OCH₃, or -OCH₂CH₃.

8. The compound of claim 2, wherein both of R^2a and R^2b are independently selected from hydrogen, halo, -CH₃, -CH₂CH₃, -OCH3, or -OCH₂CH₃.

9. The compound of claim 2, wherein R^2a and R^2b taken together are oxo.

10. The compound of claim 7, wherein one of R^2a and R^2b is hydrogen and the other is -OH.

11. The compound of claim 2, wherein R^2a and R^2b taken together form =N-R³, and R³ is selected from C alkyl optionally substituted with 1-3 halo or C_M alkoxy optionally substituted with 1-3 halo.

12. The compound of claim 11 , wherein R^2a and R^2b taken together form =N-0-CH₃.

13. The compound of claim 2, wherein one of R and R is hydrogen and the other is -N(R⁶)₂, wherein each R⁶ is independently selected from hydrogen, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein each R⁷ is independently hydrogen or C_1-4 alkyl.

14. The compound of claim 2, wherein one of R^Ia and R^lb is independently selected from -O-aryl, -O-heteroaryl, -0-CH₂-aryl, or -0-CH₂-heteroaryl, wherein the aryl group is a 6-10 membered monocyclic or bicyclic ring and the heteroaryl is a 5-10 membered monocyclic or bicyclic ring containing 1-3 heteroatoms independently selected from N, 0, or S; and the aryl or heteroaryl groups are optionally substituted with 1-2 substituents independently selected from halo, alkyl, alkoxy, or cyano.

15. The compound of claim 1 ,

16. The compound of claim 15, wherein x is 1 or 2 and at least one R⁴ is Ci-3 alkyl optionally substituted with 1-3 halo or Ci-3 alkoxy optionally substituted with 1-3 halo.

17. The compound of claim 16, wherein x is 1 or 2 and at least one R⁴ is selected from

18. The compound of claim 17, wherein x is 1.

19. The compound of claim 18, wherein R⁴ is -CH₂CH₃ that is attached to the 5 position on the pyridine-yl group of ring A.

20. The compound of claim 15, wherein one of R^2a and R^2b is hydrogen and the other is selected from hydrogen, halo, -OH, -CH₃, -CH₂CH₃, -OCH₃, or -OCH₂CH₃.

21. The compound of claim 15, wherein both of R^2a and R^2b are independently selected from hydrogen, halo, -OH, -CH₃, -CH₂CH₃, -OCH3, or -OCH₂CH₃.

22. The compound of claim 15, wherein R^2a and R^2b taken together are oxo.

23. The compound of claim 20, wherein one of R and R is hydrogen and the other is -OH.

24. The compound of claim 15, wherein R^2a and R^2b taken together form =N-R³, and R³ is selected from C_1-4 alkyl optionally substituted with 1-3 halo or C_1-4 alkoxy optionally substituted with 1-3 halo.

25. The compound of claim 24, wherein R³ is C_1-3 alkoxy optionally substituted with 1-3 halo.

26. The compound of claim 25, wherein R is -OCH3 or -OCF3.

27. The compound of claim 24, wherein R^2a and R^2b taken together form =N-0-CH₃.

28. The compound of claim 15, wherein one of R^2a and R^2b is hydrogen and the other is -NHR⁶, wherein R⁶ is independently selected from hydrogen, -C(0)-R⁷, -C(0)0-R⁷,

-S(0)₂-R⁷, wherein each R⁷ is independently hydrogen or C_1-4 alkyl.

29. The compound of claim 15, wherein one of R^la and R^,b is independently selected from -O-aryl, -O-heteroaryl, -0-CH₂-aryl, or -0-CH₂-heteroaryl, wherein the aryl group is a 6-10 membered monocyclic or bicyclic ring and the heteroaryl is a 5-10 membered monocyclic or bicyclic ring containing 1-3 heteroatoms independently selected from N, O, or S; and the aryl or heteroaryl groups are optionally substituted with 1-2 substituents independently selected from halo, alkyl, alkoxy, or cyano.

30. 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.

31. The compound of claim 1 , wherein is a double bond and one ofR^la and R^l is absent.

The compound of claim 1, wherein R^s is selected from hydrogen and -CH₂CH₃

3. A compound selected from

34. A pharmaceutical composition comprising a compound as described in any one of claims 1-32 and a pharmaceutically acceptable carrier.

35. The pharmaceutical composition of claim 34, 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 and -2 agonists; or combinations thereof.

36. A method of treating or reducing the symptoms of diabetes comprising administering to a patient in need thereof 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 -O-aryl, -O-heteroaryl, -0-CH₂-aryl, or -0-CH₂-heteroaryl, wherein either of the aryl or heteroaryl groups are optionally substituted with 1-2 substituents independently selected from halo, alkyl, alkoxy, or cyano; or

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

Each of R^2a and R^2b is independently selected from halo, hydrogen, -OH, -N(R⁶)₂, CM alkyl optionally substituted with 1-3 halo, or C alkoxy optionally substituted with 1-3 halo, or

R^2a and R^2b taken together form oxo, or

R^2a and R^2b taken together form =N-R³;

R³ is C alkyl optionally substituted with 1-3 halo, or C_1-4 alkoxy optionally substituted with 1-3 halo;

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

Ring A is selected fr

Each R⁴ is independently selected from hydrogen, -N(R⁶)₂, C_1-3 alkyl optionally substituted with 1-3 halo, or C_1-3 alkoxy optionally substituted with 1-3 halo;

x is 0-2;

Each R⁵ is independently selected from hydrogen or C_M alkyl; and

Each R⁶ is independently selected from hydrogen, CM alkyl, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein the CM alkyl is optionally substituted with a 6-10 membered monocyclic or bicyclic aryl or a 5-10 membered monocyclic or bicyclic heteroaryl having 1-3

heteroatoms independently selected from N, O, or S, and wherein each R⁷ is independently hydrogen or CM alkyl.

The method of claim 36, wherein ring A

38. The method of claim 37, wherein x is 1 or 2 and at least one R⁴ is d-₃ alkoxy optionally substituted with 1-3 halo.

39. The method of claim 38, wherein x is 1 or 2 and at least one R⁴ is selected from

-OCH3 or -OCH2CH3.

40. The method of claim 39, wherein x is 1.

41. The method of claim 40, wherein R⁴ is -OCH3 that is attached to the meta position on the phenyl group of ring A.

42. The method of claim 37, wherein one of R^2A and R ^B is hydrogen and the other is selected from hydrogen, halo, -OH, -CH₃, -CH₂CH₃, -OCH₃, or -OCH₂CH₃.

43. The method of claim 37, wherein both of R^2A and R^2B are independently selected from hydrogen, halo, -CH₃, -CH₂CH₃, -OCH₃, or -OCH₂CH₃.

44. The method of claim 37, wherein R^2A and R^2B taken together are oxo.

45. The method of claim 43, wherein one of R^2A and R^2B is hydrogen and the other is -OH.

46. The method of claim 37, wherein R^2A and R^2B taken together form =N-R³, and R³ is selected from C_1-4 alkyl optionally substituted with 1-3 halo or C_1-4 alkoxy optionally substituted with 1-3 halo.

47. The method of claim 46, wherein R^2A and R^2B taken together form =N-0-CH₃.

48. The method of claim 37, wherein one of R^2A and R^2B is hydrogen and the other is -N(R⁶)₂, wherein each R⁶ is independently selected from hydrogen, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein each R⁷ is independently hydrogen or C alkyl.

49. The method of claim 37, wherein one of R^LA and R^LB is independently selected from -O-aryl, -O-heteroaryl, -0-CH₂-aryl, or -0-CH₂-heteroaryl, wherein the aryl group is a 6-10 membered monocyclic or bicyclic ring and the heteroaryl is a 5-10 membered monocyclic or bicyclic ring containing 1-3 heteroatoms independently selected from N, O, or S; and the aryl or heteroaryl groups are optionally substituted with 1-2 substituents independently selected from halo, alkyl, alkoxy, or cyano. The method of claim 36, wherein ring A

51. The method of claim 50, wherein x is 1 or 2 and at least one R⁴ is Q.3 alkyl optionally substituted with 1-3 halo or C1.3 alkoxy optionally substituted with 1-3 halo.

52. The method of claim 51 , wherein x is 1 or 2 and at least one R⁴ is selected from -CH3 or -CH2CH3.

53. The method of claim 52, wherein x is 1.

54. The method of claim 53, wherein R⁴ is -CH₂CH3 that is attached to the 5 position on the pyridine-yl group of ring A.

55. The method of claim 50, wherein one of R^2a and R^2b is hydrogen and the other is selected from hydrogen, halo, -OH, -CH₃, -CH₂CH₃, -OCH3, or -OCH₂CH₃.

56. The method of claim 50, wherein both of R^2a and R² are independently selected from hydrogen, halo, -OH, -CH₃, -CH₂CH₃, -OCH3, or -OCH₂CH₃.

57. The method of claim 50, wherein R^2a and R^2b taken together are oxo.

58. The method of claim 56, wherein one of R^2a and R^2b is hydrogen and the other is -OH.

59. The method of claim 50, wherein R^2a and R^2b taken together form =N-R³, and R³ is selected from C alkyl optionally substituted with 1-3 halo or C_1-4 alkoxy optionally substituted with 1-3 halo.

60. The method of claim 59, wherein R³ is C 1.3 alkoxy optionally substituted with 1-3 halo.

61. The method of claim 60, wherein R³ is -OCH3 or -OCF3.

62. The method of claim 59, wherein R^ia and R^2b taken together form =N-0-CH₃.

63. The method of claim 50, wherein one of R^2a and R^2b is hydrogen and the other is -N(R⁶)₂, wherein each R⁶ is independently selected from hydrogen, -C(0)-R⁷, -C(0)0-R⁷, -S(0)2-R⁷, wherein each R⁷ is independently hydrogen or Ci_-4 alkyl.

64. The method of claim 50, wherein one of R^la and R^lb is independently selected from -O-aryl, -O-heteroaryl, -0-CH2-aryl, or -O-Ct^-heteroaryl, wherein the aryl group is a 6-10 membered monocyclic or bicyclic ring and the heteroaryl is a 5-10 membered monocyclic or bicyclic ring containing 1-3 heteroatoms independently selected from N, O, or S; and the aryl or heteroaryl groups are optionally substituted with 1-2 substituents independently selected from halo, alkyl, alkoxy, or cyano.

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

66. The method of claim 36, wherein is a double bond and one of ^,a and R^,b is absent.

The method of claim 36, wherein R⁵ is selected from hydrogen or -CH2CH3

The method of claim 36, wherein the compound of Formula I is selected from

69. A method of reducing the body weight of 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 -O-aryl, -O-heteroaryl, -0-CH₂-aryl, or -0-CH2-heteroaryl, wherein either of the aryl or heteroaryl groups are optionally substituted with 1-2 substituents independently selected from halo, alkyl, alkoxy, or cyano; or

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

Each of R^2a and R² is independently selected from halo, hydrogen, -OH, -N(R⁶)₂, C_1-4 alkyl optionally substituted with 1-3 halo, or C_1-4 alkoxy optionally substituted with 1-3 halo, or

R ^a and R taken together form oxo, or

R^2a and R^2b taken together form =N-R³;

R³ is C alkyl optionally substituted with 1-3 halo, or C_1-4 alkoxy optionally substituted with 1-3 halo;

^ZZTT. is a single bond, or a double bond when one of ^la and R^lb is absent;

Ring A is selected fr

Each R⁴ is independently selected from hydrogen, -N(R⁶)₂, Ci-3 alkyl optionally substituted with 1-3 halo, or alkoxy optionally substituted with 1-3 halo;

x is 0-2; Each R⁵ is independently selected from hydrogen or C alkyl; and

Each R⁶ is independently selected from hydrogen, C alkyl, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein the C 1-4 alkyl is optionally substituted with a 6-10 membered monocyclic or bicyclic aryl or a 5-10 membered monocyclic or bicyclic heteroaryl having 1-3

heteroatoms independently selected from N, O, or S, and wherein each R⁷ is independently hydrogen or C alkyl.

70. The method of claim 69, wherein ring A is

71. The method of claim 70, wherein x is 1 or 2 and at least one R⁴ is C_1-3 alkoxy optionally substituted with 1-3 halo.

72. The method of claim 71, wherein x is 1 or 2 and at least one R⁴ is selected from -OCH₃ or -OCH₂CH₃.

73. The method of claim 72, wherein x is 1.

74. The method of claim 73, wherein R⁴ is -OCH3 that is attached to the meta position on the phenyl group of ring A.

75. The method of claim 70, wherein one of R^2a and R^2b is hydrogen and the other is selected from hydrogen, halo, -OH, -CH₃, -CH₂CH₃, -OCH3, or -OCH₂CH₃.

76. The method of claim 70, wherein both of R^2a and R^2b are independently selected from hydrogen, halo, -CH₃, -CH₂CH₃, -OCH₃, or -OCH₂CH₃.

77. The method of claim 70, wherein R^2a and R² taken together are oxo.

78. The method of claim 75, wherein one of R^2a and R^2b is hydrogen and the other is -OH.

79. The method of claim 70, wherein R^2A and R^2B taken together form =N-R³, and R³ is selected from CM alkyl optionally substituted with 1 -3 halo or C_1-4 alkoxy optionally substituted with 1-3 halo.

80. The method of claim 70, wherein R^2A and R^2B taken together form =N-0-CH₃.

81. The method of claim 70, wherein one of R^2A and R^2B is hydrogen and the other is -N(R⁶)₂, wherein each R⁶ is independently selected from hydrogen, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein each R⁷ is independently hydrogen or C alkyl.

82. The method of claim 70, wherein one of R^LA and R^LB is independently selected from -O-aryl, -O-heteroaryl, -0-CH₂-aryl, or -0-CH₂-heteroaryl, wherein the aryl group is a 6-10 membered monocyclic or bicyclic ring and the heteroaryl is a 5-10 membered monocyclic or bicyclic ring containing 1 -3 heteroatoms independently selected from N, O, or S; and the aryl or heteroaryl groups are optionally substituted with 1 -2 substituents independently selected from halo, alkyl, alkoxy, or cyano.

83. The method of claim 69, wherein ring A is

84. The method of claim 83, wherein x is 1 or 2 and at least one R⁴ is C1-3 alkyl optionally substituted with 1-3 halo or C_1-3 alkoxy optionally substituted with 1 -3 halo.

85. The method of claim 84, wherein x is 1 or 2 and at least one R⁴ is selected from -CH₃ or -CH₂CH₃.

86. The method of claim 85, wherein x is 1.

87. The method of claim 86, wherein R⁴ is -CH₂CH₃ that is attached to the 5 position on the pyridine-yl group of ring A.

88. The method of claim 83, wherein one of R^2A and R^2B is hydrogen and the other is selected from hydrogen, halo, -OH, -CH₃, -CH₂CH₃, -OCH₃, or -OCH₂CH₃.

89. The method of claim 83, wherein both of R and R are independently selected from hydrogen, halo, -OH, -CH₃, -CH₂CH₃, -OCH₃, or -OCH₂CH₃.

90. The method of claim 83, wherein R^2a and R^2b taken together are oxo.

91. The method of claim 89, wherein one of R^2a and R^2b is hydrogen and the other is -OH.

92. The method of claim 83, wherein R^2a and R^2b taken together form =N-R³, and R³ is selected from C_1-4 alkyl optionally substituted with 1-3 halo or C alkoxy optionally substituted with 1-3 halo.

93. The method of claim 92, wherein R is C_1-3 alkoxy optionally substituted with 1-3 halo.

94. The method of claim 93, wherein R³ is -OCH₃ or -OCF₃.

95. The method of claim 83, wherein R^2a and R^2b taken together form =N-0-CH₃.

96. The method of claim 83, wherein one of R^2a and R^2b is hydrogen and the other is -N(R⁶)₂, wherein each R⁶ is independently selected from hydrogen, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein each R⁷ is independently hydrogen or C alkyl.

97. The method of claim 83, wherein one of R^la and R^lb is independently selected from -O-aryl, -O-heteroaryl, -0-CH₂-aryl, or -0-CH₂-heteroaryl, wherein the aryl group is a 6-10 membered monocyclic or bicyclic ring and the heteroaryl is a 5-10 membered monocyclic or bicyclic ring containing 1-3 heteroatoms independently selected from N, O, or S; and the aryl or heteroaryl groups are optionally substituted with 1-2 substituents independently selected from halo, alkyl, alkoxy, or cyano.

98. The method of claim 69, wherein is a double bond and one ofR^la and R^lb is absent.

99. The method of claim 69, wherein R⁵ is selected from hydrogen and -CH₂CH₃.

100. The method of claim 69, wherein the compound of Formula I is selected from

101. A method of treating dyslipidemia comprising administering to a patient in need thereof 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 alkoxy optionally substituted with 1-3 halo, or -O-aryl, -O-heteroaryl, -0-CH₂-aryl, or -0-CH₂-heteroaryl, wherein either of the aryl or heteroaryl groups are optionally substituted with 1-2 substituents independently selected from halo, alkyl, alkoxy, or cyano; or

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

Each of R^2a and R^2b is independently selected from halo, hydrogen, -OH, -N(R⁶)₂, C alkyl optionally substituted with 1-3 halo, or C alkoxy optionally substituted with 1-3 halo, or

R^2a and R^2b taken together form oxo, or

R^2a and R^2b taken together form =N-R³; R is C alkyl optionally substituted with 1-3 halo, or CM alkoxy optionally substituted with 1-3 halo;

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

Ring A is selected fr

Each R⁴ is independently selected from hydrogen, -N(R⁶)₂, Q.3 alkyl optionally substituted with 1-3 halo, or Ci_-3 alkoxy optionally substituted with 1-3 halo;

x is 0-2;

Each R⁵ is independently selected from hydrogen or C alkyl; and

Each R⁶ is independently selected from hydrogen, C alkyl, -C(0)-R⁷, -C(0)0-R⁷, -S(0)2-R⁷, wherein the CM alkyl is optionally substituted with a 6-10 membered monocyclic or bicyclic aryl or a 5-10 membered monocyclic or bi cyclic heteroaryl having 1-3 heteroatoms independently selected from N, O, or S, and wherein each R⁷ is independently hydrogen or C alkyl.

102. The method of claim 101, wherein ring A is

103. The method of claim 102, wherein x is 1 or 2 and at least one R⁴ is C1.3 alkoxy optionally substituted with 1-3 halo.

104. The method of claim 103, wherein x is 1 or 2 and at least one R⁴ is selected from -OCH3 or -OCH2CH3.

105. The method of claim 104, wherein x is 1.

106. The method of claim 105, wherein R⁴ is -OCH3 that is attached to the meta position on the phenyl group of ring A.

107. The method of claim 102, wherein one of R^2a and R ^b is hydrogen and the other is selected from hydrogen, halo, -OH, -CH₃, -CH₂CH₃, -OCH₃, or -OCH₂CH₃.

108. The method of claim 102, wherein both of R and R are independently selected from hydrogen, halo, -CH₃, -CH₂CH₃, -OCH₃, or -OCH₂CH₃.

109. The method of claim 102, wherein R^2A and R^2B taken together are oxo.

110. The method of claim 108, wherein one of R^2A and R^2B is hydrogen and the other is

-OH.

1 1 1. The method of claim 102, wherein R^2A and R^2B taken together form =N-R³, and R³ is selected from C alkyl optionally substituted with 1-3 halo or C alkoxy optionally substituted with 1-3 halo.

112. The method of claim 111, wherein R^2A and R^2B taken together form =N-0-CH₃.

113. The method of claim 102, wherein one of R^2A and R^2B is hydrogen and the other is -N(R⁶)₂, wherein each R⁶ is independently selected from hydrogen, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein each R⁷ is independently hydrogen or C alkyl.

114. The method of claim 102, wherein one of R^LA and R^LB is independently selected from -O-aryl, -O-heteroaryl, -0-CH₂-aryl, or -0-CH₂-heteroaryl, wherein the aryl group is a 6-10 membered monocyclic or bicyclic ring and the heteroaryl is a 5-10 membered monocyclic or bicyclic ring containing 1-3 heteroatoms independently selected from N, O, or S; and the aryl or heteroaryl groups are optionally substituted with 1-2 substituents independently selected from halo, alkyl, alkoxy, or cyano.

115. The method of claim 101, wherein ring A is

116. The method of claim 115, wherein x is 1 or 2 and at least one R⁴ is C_1-3 alkyl optionally substituted with 1-3 halo or C_1-3 alkoxy optionally substituted with 1-3 halo.

117. The method of claim 116, wherein x is 1 or 2 and at least one R⁴ is selected from

-CH₃ or -CH₂CH₃.

1 18. The method of claim 1 17, wherein x is 1.

1 19. The method of claim 1 18, wherein R⁴ is -CH₂CH₃ that is attached to the 5 position on the pyridine-yl group of ring A.

120. The method of claim 1 15, wherein one of R^2A and R^2B is hydrogen and the other is selected from hydrogen, halo, -OH, -CH₃, -CH₂CH₃, -OCH₃, or -OCH₂CH₃.

121. The method of claim 1 15, wherein both of R^2A and R^2B are independently selected from hydrogen, halo, -OH, -CH₃, -CH₂CH₃, -OCH₃, or -OCH₂CH₃.

122. The method of claim 1 15, wherein R^2A and R^2B taken together are oxo.

123. The method of claim 121 , wherein one of R^2A and R^2B is hydrogen and the other is -OH.

124. The method of claim 115, wherein R^2A and R^2B taken together form =N-R³, and R³ is selected from C_1-4 alkyl optionally substituted with 1 -3 halo or C alkoxy optionally substituted with 1-3 halo.

125. The method of claim 124, wherein R³ is C_1-3 alkoxy optionally substituted with 1-3 halo.

126. The method of claim 125, wherein R³ is -OCH₃ or -OCF₃.

127. The method of claim 124, wherein R^2A and R² taken together form =N-0-CH₃.

128. The method of claim 1 15, wherein one of R^2A and R^2B is hydrogen and the other is -N(R⁶)₂, wherein each R⁶ is independently selected from hydrogen, -C(0)-R⁷, -C(0)0-R⁷, -S(0)₂-R⁷, wherein each R⁷ is independently hydrogen or C alkyl.

129. The method of claim 1 15, wherein one of R^LA and R^LB is independently selected from -O-aryl, -O-heteroaryl, -0-CH₂-aryl, or -0-CH₂-heteroaryl, wherein the aryl group is a 6-10 membered monocyclic or bicyclic ring and the heteroaryl is a 5-10 membered monocyclic or bicyclic ring containing 1-3 heteroatoms independently selected from N, O, or S; and the aryl or heteroaryl groups are optionally substituted with 1-2 substituents independently selected from halo, alkyl, alkoxy, or cyano.

130. The method of claim 101, wherein is a double bond and one of R^la and R^Ib is absent.

The method of claim 101, wherein R⁵ is selected from hydrogen and -CH2CH3.

132. The method of claim 101, wherein the compound of Formula I is selected from