US 2011 0237625A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0237625 A1 Gaul et al. (43) Pub. Date: Sep. 29, 2011

(54) SUBSTITUTED PHENOXY A6IP3/00 (2006.01) THAZOLDINEDONES AS ESTROGEN A6IP 9/12 (2006.01) RELATED RECEPTOR-MODULATORS (52) U.S. Cl...... 514/326; 548/183: 514/369: 548/227; 514/376 (75) Inventors: Michael Gaul, Yardley, PA (US); Alexander Kim, Levittown, PA (57) ABSTRACT sity SNES." The present invention relates to compounds of Formula (I), Yardley, PA (US); Dionisios Rentzeperis, Downingtown, PA (US); Guozhang Xu, Bensalem, PA R2 (I) (US); Xizhen Zhu, Monmouth O Junction, NJ (US) X- O R3 (73) Assignee: Janssen Pharamceutica N.V., HN Beerse (BE) N R R4 (21) Appl. No.: 12/899,812 O (22) Filed: Oct. 7, 2010 methods for preparing these compounds, compositions, inter mediates and derivatives thereof and for treating a condition Related U.S. Application Data including but not limited to ankylosing spondylitis, arthero Sclerosis, arthritis (such as rheumatoid arthritis, infectious (62) Division of application No. 12/043,269, filed on Mar. arthritis, childhood arthritis, psoriatic arthritis, reactive 6, 2008, now Pat. No. 7,846,953. arthritis), bone-related diseases (including those related to (60) Provisional application No. 60/893,453, filed on Mar. bis formation), breast cancer (including those unresponsive 7, 2007. o anti-estrogen therapy), cardiovascular disorders, cartilage s related disease (such as cartilage injury/loss, cartilage degen O O eration, and those related to cartilage formation), chondrod Publication Classification ysplasia, chondrosarcoma, chronic back injury, chronic (51) Int. Cl. bronchitis, chronic inflammatory airway disease, chronic A6 IK 3L/454 (2006.01) obstructive pulmonary disease, diabetes, disorders of energy C07D 277/34 (2006.01) homeostasis, gout, pseudogout, lipid disorders, metabolic A6 IK 3/426 (2006.01) syndrome, multiple myeloma, obesity, osteoarthritis, osteo CO7D 263/44 (2006.01) genesis imperfecta, osteolytic bone metastasis, osteomalacia, A6 IK 3/42 (2006.01) osteoporosis, Paget's disease, periodontal disease, polymyal A6IP 9/00 (2006.01) gia rheumatica, Reiter's syndrome, repetitive stress injury, A6IP II/00 (2006.01) hyperglycemia, elevated blood glucose level, and insulin A6IP35/00 (2006.01) resistance. Patent Application Publication Sep. 29, 2011 Sheet 1 of 12 US 2011/0237625 A1

23% ediction - 2 Of food intake s xxarS S. 3. f s S S. were S. S. { -2.5 Example 1 - u -3.0 Vehicle 3rgikg 30 g/kg Example

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wo. A. Vehicle ot-B: Compound - 3mpk -a-. C. Compound 110mpk -X- D. Compound 1.30mpk

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Days

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FFA level (mEq/L) following oral dose of Compound -ac-os A. Weice -- B. Compound 1.3mpk -ar. C. Compound 4- 4 Ompk -X-D: Compound 1-30mpk Patent Application Publication Sep. 29, 2011 Sheet 3 of 12 US 2011/0237625 A1

3ufkg ip TT in ZDF Rats Treated 11-Days with Compound SOO.

m{w A. Vehicle 500 -E-B. Compound 1-3mpk ormano -A-C. Compound 1. Ompk -X-D: compound 1.30pk

AUC of a 3U.Kg ITT in ZDF Rats Treated 11 Days with Compound

C. A. Vehicle SB. Compound 1-3mpk a C. Compound 4- 4 Ompk ED: compound 1.30mpk Patent Application Publication Sep. 29, 2011 Sheet 4 of 12 US 2011/0237625 A1

FIG. 5A 4 hour fast blood glucose (ngldi) in ZDF Rats Treated 11 Days with Compound

wax

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A. Weice B: compound 1- C. Compound - D. Compound - 3 mpk 10 mpk 30 mpk

16 Hour Fasting Blood Glucose in ZDF Rats Treated with Compound for 4 Weeks 350 27. 300 G,049 250- 20 Sg 2. : 150 3

A vehicle 3. compound . C. compound - D: compound - 3rapk Ompk 30 mpk Patent Application Publication Sep. 29, 2011 Sheet 5 of 12 US 2011/0237625 A1

F.G. SA 1g Kg Oral Glucose tolerance Test in ZDF Rats treated 4 Weeks with Compound 1 800m

co-Ko A. Wehicle -C-B: Compound 1-3rnpk -A-C. Compound . Ompk -be-D' compound 30mpk

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2OOC

OOC

A: Werica B: Cornpound 1. C. compoundi. D. Compound 1. 3rnpk () ?pk 3Ornpk Patent Application Publication Sep. 29, 2011 Sheet 6 of 12 US 2011/0237625 A1

Plasma insulin level (ugit) following glkg Oral Glucose Folerance estin ZDF Rats Treated 4 Weeks with compound

co-Co A. Weice -- B. Compound 1.3mpk -A-C: Compound 4- 1 Ompk -X-D: Compound 4- 30mpk

AUC of insulin Following 1g/kg OGT in ZDF Rats Treated 4 Weeks with Coalpound

350

A. Vehicle B: compound 1. C. compound 1. D. Compound 1. 3 mpk 10 mpk 30 mpk Patent Application Publication Sep. 29, 2011 Sheet 7 of 12 US 2011/0237625 A1 Lae||?uaepunod:Daebaepunod: |gwaedu?aepunod:

Patent Application Publication Sep. 29, 2011 Sheet 8 of 12 US 2011/0237625 A1

G. 9A Fed Plasma insuin in ZDF Rats Treated with Compound 1

8 -o- A vehicle -- B. Compound 1.3mpk 6 -A-C: Compound 1- 10mpk -X. D: compound 1-30mpk

insulin Content (ugig of issue)

A: Weice B: compound 1. C. compound 1. D. Compound 1. 3 mpk Ompk 30 mpk Patent Application Publication Sep. 29, 2011 Sheet 9 of 12 US 2011/0237625 A1 F.G. 1 OA 3ul Kgip TT in ZDF Rats Treated 5-Days with Compound 450px0.05 Compared to Vehicle Group

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AUC of a 3U.Kg in ZDF Rats Treated 15 Days with Compound 35OOO "p<0.05 Compared to Vehicle Group

A. Vehicle 3000- B. compound 1- 0.08mpk w C: Compound -0.4mpk 2500 D: Compound -2mpk 20000 E. Coincid - ink 45000- N2 - “NS 10000 500 Patent Application Publication Sep. 29, 2011 Sheet 10 of 12 US 2011/0237625 A1

F.G. 11A 4 hour fast blood glucose (ngidi) in ZDF Rats Treated 15 Days with Compound “p<0.0 Compared to Vehicle Group 45 400 350 30 250 2 50 O SO A. Weice B C M O E. Compound Compound Compound COf Ouid 1- 0.03 m.pk 1-0.4mpk .2 mpk ... 10 mpk

16 Hour Fasting Blood Glucose in Male ZDF Ratsireated 3 weeks with Compound 3 O 244 2 5 c. (62 . .54

0.04

to OOOO 4. 150

A. Weice 8. C: M M : Compound Compound Compound Compound 1- 0.08 mpk - 0.4 mpk 1.2 mpk 10 mpk Patent Application Publication Sep. 29, 2011 Sheet 11 of 12 US 2011/0237625 A1

F.G. 12A 1g Kg OGT in Male ZDF Rats Treated for 3 weeks with Compound oxxon A. Vehicle 450- -- B.JN-35315208-0.08mpk i. -a-C: JNJ-3585208-04.mpk e -x-D: JNJ-35815208-2mpk 350- -b. * E. JN-35815208- Oripk

4) 8 12 SO Minutes

AUC of a glkg OG in Male ZDF Rats Treated with 3 weeks with Compund 60000

SCOOC MX XXX XXX XXX XXX F: G3 400

A. Vehicle B: Compound - C. Cornpound 1-D. Compound - E. Corpound - 0.08mpk 0.4mpk 2pk 10mpk Patent Application Publication Sep. 29, 2011 Sheet 12 of 12 US 2011/0237625 A1

F.G. 13 Fed Fasna Giucose in Male ZF Raisireated 3 weeks with Compound ax- A. Vehicle -- B.JNJ-3585208-0.08mpk -a-C: JNJ-35315208-04.mpk -x-D: JNJ-35315208-2mpk rx-E: JNJ-35315208-10mpk

Weeks

A. Vehicle B. Compound 1- C. Compound - D. Compound - E: COfypound - 0.08mpk O4mpk 2ngk 1 Ompk US 2011/0237625 A1 Sep. 29, 2011

SUBSTITUTED PHENOXY Top. Microbiol. Immunol. 2003, 274, 237-268). In the pres THAZOLIDNEDONES AS ESTROGEN ence of an agonist there is an exchange of co-repressors with RELATED RECEPTOR-MODULATORS co-activators that in turn recruit transcription factors that assemble into an ATP dependent chromatin-remodeling com CROSS REFERENCE TO RELATED plex. Histones are hyper-acetylated, causing the nucleosome APPLICATION to unfold, and repression is alleviated. The AF-2 domain acts as the ligand dependent molecular Switch for the exchange of 0001. This application claims the benefit of U.S. Provi co-regulatory proteins. In the presence of an agonist the AF-2 sional Application No. 60/893,453, filed Mar. 7, 2007, which domain undergoes a conformational transition and presents a is incorporated by reference herein. surface on the LBD for interaction with co-activator proteins. In the absence of an agonist or in the presence of an antagonist FIELD OF THE INVENTION the AF-2 domain presents a surface that promotes interactions 0002 The present invention relates to certain novel com with co-repressor proteins. The interaction Surfaces on the pounds, methods for preparing compounds, compositions, LBD for both co-activators, and co-repressors overlap and intermediates and derivatives thereof and for treating condi provide a conserved molecular mechanism for gene activa tions such as cancer, arthritis, inflammatory airway disease, tion or repression that is shared by the members of this family and metabolic disorders. More particularly, the compounds of of transcription factors (Xu, H. E. et al. Nature 2002, 415 the present invention are Estrogen Related Receptor alpha (6873), 813-817). (ERR-C) modulators useful for treating, ameliorating, slow 0005 Natural ligands that modulate the biological activity ing or inhibiting the progression of disease states, disorders, of nuclear receptors have been identified for only approxi and conditions mediated by ERR-O. activity. mately one half of known nuclear receptors. Receptors for which no natural ligand has been identified are termed BACKGROUND OF THE INVENTION "orphan receptors. The discovery of ligands or compounds 0003 Nuclear receptors are members of a superfamily of that interact with an orphan receptor will accelerate the under transcription factors. The members of this family share struc standing of the role of the nuclear receptors in physiology and tural similarities and regulate a diverse set of biological disease and facilitate the pursuit of new therapeutic effects (Olefsky, J. M. J. Biol. Chem. 2001, 276(40), approaches. A Sub-class of these receptors where no natural 3.6863-36864). Ligands activate or repress these transcription ligand has been identified is for the estrogen related receptors factors that control genes involved in metabolism, differen (ERRS). tiation and reproduction (Laudet, V. and H. Gronmeyer. The 0006 ERR-C. (also known as ERR-1), an orphan receptor, Nuclear Receptor Factbooks. 2002, San Diego: Academic is the first of the three identified members of the estrogen Press). Presently, the human genome project has identified receptor related subfamily of orphan nuclear receptors (ERR about 48 members for this family and cognate ligands have C. B. Y). The ERR subfamily is closely related to the estrogen been identified for about 28 of them (Giguere, V. Endocrine receptors (ER-C. and ER-B). ERR-C. and ER-B were first Rev. 1999, 20(5), 689-725). This protein family is composed isolated by a low Stringency hybridization screen (Giguere, V. of modular structural domains that can be interchanged et al. Nature 1988, 331, 91-94) followed later with the dis within the members of the family without loss of function. A covery of ERR-Y (Hong, H. et al. J. Biol. Chem. 1999, 274, typical nuclear receptor contains a hyperVariable N-terminus, 22618-22626). The ERRs and ERs share sequence similarity a conserved DNA binding domain (DBD), a hinge region, and with the highest homology observed in their DBDs, approxi a conserved ligand-binding domain (LBD). The function of mately 60%, and all interact with the classical DNA estrogen the DBD is targeting of the receptor to specific DNA response element. Recent biochemical evidence Suggested sequences (NHR response elements or NREs), and the func that the ERRS and ERS share target genes, including pS2, tion of the LBD is recognition of its cognate ligand. Within lactoferin, aromatase and osteopontin, and share co-regulator the sequence of the nuclear receptor there are regions proteins (Giguere, V. Trends in Endocrinol. Metab. 2002, 13, involved in transcriptional activation. The AF-1 domain is 220-225; Vanacker, J. M. et al. EMBO J. 1999, 18, 4270 situated at the N-terminus and constitutively activates tran 4279; Kraus, R. J. et al. J. Biol. Chem. 2002, 272, 24286 scription (Rochette-Egly, C. et al. Cell 1997, 90, 97-107; 24834; Hong et al., 1999; Zhang, Z. and C. T. Teng. J. Biol. Rochette-Egly, C. et al. Mol. Endocrinol. 1992, 6, 2197 Chem. 2000, 275,20387-20846). Therefore, one of the main 2209), while the AF-2 domain is embedded within the LBD functions of ERR is to regulate the response of estrogen and its transcriptional activation is ligand dependent (Wurtz, responsive genes. The effect of the steroid hormone estrogen J. M. et al. Nat. Struct. Biol. 1996, 3, 87-94). Nuclear recep is primarily mediated in the breast, bone and endometrium. tors can exist as monomers, homodimers or heterodimers and Thus, the identification of compounds that will interact with bind to direct or inverted nucleotide repeats (Laudet and ERRs should provide a benefit for the treatment of bone Gronmeyer, 2002; Aranda, A. and A. Pascual. Physiol. Rev. related disease, breast cancer and reproduction. 2001, 81(3), 1269-1304). 0007 ERR-C. is shown to be present both in normal and 0004. The members of this family exist either in an acti breast cancertissue (Ariazi, E. A. et al. Cancer Res. 2002, 62. vated or repressed basal biological state. The basic mecha 6510-6518). It has been reported that the main function of nism of gene activation involves ligand dependent exchange ERR-C. in normal breast tissue is that of a repressor forestro of co-regulatory proteins. These co-regulatory proteins are gen responsive genes. In breast cancers or cell lines that are referred to as co-activators or co-repressors (McKenna, L. J. non-estrogen responsive (ER-O. negative), ERR-C. has been et al. Endocrine Rev. 1999, 20, 321-344). A nuclear receptor reported to be in an activated state (Ariazi et al., 2002). in the repressed state is bound to its DNA response element Therefore, compounds that will interact with ERR-O. may be and is associated with co-repressor proteins that recruit his useful agents for the treatment of breast cancer that is ER-C. tone de-acetylases (HDACs) (Jones, P. L. and Y.B. Shi. Curr. negative and non-responsive to classical anti-estrogenic US 2011/0237625 A1 Sep. 29, 2011

therapy, or may be used as an adjunct agent for anti-estrogen energy metabolism (Luo, J. et al. Mol. Cell. Biol. 2003, responsive breast cancers. These agents may act as antago 23(22), 7947-7956). More recently it has been shown that nists by reducing the biological activity of ERR-C. in these ERR-C. regulates the expression of endothelial nitric oxide particular tissues. synthase, a gene that has a protective mechanism against 0008. Many post-menopausal women experience arteriosclerosis (Sumi. D. and L. J. Ignarro. Proc Natl. Acad. osteoporosis, a condition that is a result of the reduction of Sci. 2003, 100, 14451-14456). The biochemical evidence estrogen production. Reduction of estrogen levels results in supports the involvement of ERR-C. in metabolic homeostasis an increase of bone loss (Turner, R. T. et al. Endocrine Rev. and differentiation of cells into adipocytes. Therefore, com 1994, 15(3), 275-300). An anabolic effect on bone develop pounds interacting with ERR-C. can affect energy homeosta ment has been observed on the administration of estrogens to sis and may therefore provide a benefit for the treatment of postmenopausal patients with osteoporosis (Pacifici, R. J. obesity and metabolic syndrome related disease indications, Bone Miner. Res. 1996, 11 (8), 1043-1051) but the molecular including arteriosclerosis and diabetes (Grundy, S. M. et al. mechanism is unknown since ER-C. and ER-b knock-out ani Circulation 2004, 109(3), 433-438). mals have minor skeletal defects, where the action of estro 0011 Lion Bioscience AG has disclosed the use of certain gens is typically mediated (Korach, K. S. Science 1994, 266, pyrazole derivatives as antagonists of ERR-C. for treating 1524-1527: Windahl, S. H. et al. J. Clin. Invest. 1999, 104(7), cancer, osteoporosis, obesity, lipid disorders and cardiovas 895-901). Expression of ERR-C. in bone is regulated by estro cular disorders and for regulating fertility (European Pub gen (Bonnelye, E. et al. Mol. Endocrin. 1997, 11, 905-916: lished Patent Application 1398029). Bonnelye, E. et al. J. Cell Biol. 2001, 153,971-984). ERR-O. 0012. There is a continuing need for new ERR-C. inverse is maintained throughout osteoblast differentiation stages. agonists. There is also a need for ERR-C. inverse agonists Over-expression of ERR-C. in rat calvaria osteoblasts, an useful for the treatment of conditions including but not lim accepted model of bone differentiation, results in an increase ited to bone-related disease, bone formation, breast cancer of bone nodule formation, while treatment of rat calvaria (including those unresponsive to anti-estrogen therapy), car osteoblasts with ERR-O. antisense results in a decrease of tilage formation, cartilage injury, cartilage loss, cartilage bone nodule formation. ERR-O. also regulates osteopontin, a degeneration, cartilage injury, ankylosing spondylitis, protein believed to be involved in bone matrix formation. chronic back injury, gout, osteoporosis, osteolytic bone Therefore compounds that will modulate ERR-C. by increas metastasis, multiple myeloma, chondrosarcoma, chondrod ing its activity can have ananabolic effect for the regeneration ysplasia, osteogenesis imperfecta, osteomalacia, Paget's dis of bone density and provide a benefit over current approaches ease, polymyalgia rheumatica, pseudogout, arthritis, rheuma that prevent bone loss, but have no anabolic effect. Such toid arthritis, infectious arthritis, osteoarthritis, psoriatic compounds can enhance the activity of the receptor by two arthritis, reactive arthritis, childhood arthritis, Reiter's syn possible mechanisms: i) enhancing the association of the drome, repetitive stress injury, periodontal disease, chronic receptor with proteins that enhance its activity or improve the inflammatory airway disease, chronic bronchitis, chronic stability of the receptor; and ii) increasing the intracellular obstructive pulmonary disease, metabolic syndrome, obesity, concentrations of the receptor and consequently increasing its disorders of energy homeostasis, diabetes, lipid disorders, activity. Conversely, with respect to bone diseases that are a cardiovascular disorders, artherosclerosis, hyperglycemia, result of abnormal bone growth, compounds that will interact elevated blood glucose level, and insulin resistance. with ERR-C. and decrease its biological activity may provide a benefit for the treatment of these diseases by retarding bone SUMMARY OF THE INVENTION growth. 0013. In its many embodiments, the present invention pro 0009 Antagonism of the association of the receptor with vides novel compounds useful as, for example, ERR-C. co-activator proteins decreases the activity of the receptor. inverse agonists, methods of preparing Such compounds, 00.10 ERR-C. is also present in cardiac, adipose, and pharmaceutical compositions comprising one or more Such muscle tissue and forms a transcriptional active complex with compounds, methods of preparing pharmaceutical composi the PGC-1 co-activator family, co-activators implicated with tions comprising one or more Such compounds, and methods energy homeostasis, mitochondria biogenesis, hepatic gluco of treatment, prevention, inhibition or amelioration of one or neogenesis and in the regulation of genes involved in fatty more diseases associated with ERR-C. using Such compounds acid beta-oxidation (Kamei, Y. et al. Proc. Natl. Acad. Sci. or pharmaceutical compositions. USA 2003, 100(21), 12378-12383). ERR-C. regulates the 0014. One aspect of the present invention features a com expression of the medium chain acyl-CoA dehydrogenase pound of Formula (I) promoter (MCAD). Medium chain acyl-CoA dehydrogenase is a gene involved in the initial reaction in fatty acid beta oxidation. It is believed that in the adipose tissue ERR-C. (I) regulates energy expenditure through the regulation of O R2 MCAD (Sladek, R. et al. Mol. Cell. Biol. 1997, 17, 5400 O R3 5409; Vega, R. B. and D. P. Kelly. J. Biol. Chem. 1997, 272, X 31693-31699). In antisense experiments in rat calvaria osteo HN blasts, in addition to the inhibition of bone nodule formation, S R R4 there was an increase in adipocyte differentiation markers including aP2 and PPAR-Y (Bonnelye, E. etal. Endocrinology O 2002, 143,3658-3670). Recently an ERR-C knockout model has been described that exhibited reduced fat mass relative to wherein the wildtype and DNA chip analysis data indicated alteration 0015 R is halo, optionally substituted Calkyl, option of the expression levels of genes involved in adipogenesis and ally Substituted Calkoxy, or hydroxyl; US 2011/0237625 A1 Sep. 29, 2011

0016 R is selected from halo substituted C-alkyl, in male ZDF rat diabetic model. The panel on the left shows cyano, halo. —C(O)NH2, and —C(O)C)—Calkyl, or alter reduction of glucose levels upon intraperitoneal delivery of natively R is linked together to R to form an aryl fused to the insulin is seen for all compound 1 treatment groups normal phenyl ring to which R and R are shown attached; izing glucose levels at the 30 minute time point. The panel on 0017 R is H, or alternatively R is linked together to R to the right shows reduction of AUC of glucose during the ITT at form an aryl fused to the phenyl ring to which R and R are the 0-60 and 0-120 minute time points. shown attached; 0030 FIG. 5 illustrates the reduction in fasted glucose 0018 R is halo, cyano. —C=CH, halo substituted levels upon treatment of Compound 1 in ZDF rats. The panel Calkyl, -C(O)C)—C alkyl, —C(O)NH2 or —S(O)— on the left panel shows four-hour fasting glucose at day Calkyl, and eleven of treatment. The panel on the right shows 16-hour 0019 X is S or O: fasting glucose at day 20 of treatment. 0020 or an optical isomer, enantiomer, diastereomer, cis 0031 FIG. 6 illustrates the effect of Compound 1 in glu trans isomer, racemate, prodrug or pharmaceutically accept cose excursion in an OGTT in male ZDF rats. The panel at the able salt thereof. left shows the blood glucose levels at various time points 0021. Another aspect of the present invention features a relative to glucose injection. The panel at the right shows the pharmaceutical composition comprising at least one com AUC of glucose from 0-120 minutes from the OGTT. pound of Formula (I) and at least one pharmaceutically acceptable carrier. 0032 FIG. 7 illustrates the effect of Compound 1 on insu 0022. The present invention also features a method of lin release during an OGTT in male ZDF rats. The panel on treating a Subject Suffering from or diagnosed with a disease, the left shows blood insulin levels at various time points. The disorder, or condition mediated by ERR-C. activity, compris panel on the right shows AUC of insulin from 0-120 minutes ing administering to the Subject a therapeutically effective from the OGTT. amount of at least one compound of Formula (I). Such dis 0033 FIG. 8 illustrates the effect of compound 1 on gly ease, disorder, or condition can include bone-related disease, cemic control in male ZDF rats. The panel on the left shows bone formation, breast cancer (including those unresponsive the fed glucose levels throughout the first three weeks of the to anti-estrogen therapy), cartilage formation, cartilage study. The panel on the right shows the glycosylated hemo injury, cartilage loss, cartilage degeneration, cartilage injury, globin concentration after 26 days treatment. ankylosing spondylitis, chronic back injury, gout, osteoporo 0034 FIG. 9 illustrates the effect of Compound 1 on insu sis, osteolytic bone metastasis, multiple myeloma, chondro lin levels in the ZDF rat model. The panel on the left shows the sarcoma, chondrodysplasia, osteogenesis imperfecta, osteo fed plasma insulin levels. The panel on the right shows total malacia, Paget's disease, polymyalgia rheumatica, pancreatic insulin content. pseudogout, arthritis, rheumatoid arthritis, infectious arthri 0035 FIG. 10 illustrates the effect of compound 1 on tis, osteoarthritis, psoriatic arthritis, reactive arthritis, child circulating glucose levels during an ITT at 11 days post dos hood arthritis, Reiter's syndrome, repetitive stress injury, ing in male ZDF rat diabetic model. The panel on the left periodontal disease, chronic inflammatory airway disease, shows reduction of glucose levels upon intraperitoneal deliv chronic bronchitis, chronic obstructive pulmonary disease, ery of insulin is seen for all compound 1 treatment groups metabolic syndrome, obesity, disorders of energy homeosta normalizing glucose levels at the 30 minute time point. The sis, diabetes, lipid disorders, cardiovascular disorders, arth panel on the right shows reduction of AUC of glucose during erosclerosis, hyperglycemia, elevated blood glucose level. the ITT at the 0-60 and 0-120 minute time point. and insulin resistance. The therapeutically effective amount 0036 FIG. 11 illustrates the reduction in fasted glucose of the compound of Formula (I) can be from about 0.1 mg/day levels upon treatment of compound 1 in ZDF rats. The panel to about 5000 mg/day for an average human. on the left shows four hour fasting glucose at day sixteen of 0023 The present invention further features a process for treatment. The panel on the right shows 16 hour fasting glu making a pharmaceutical composition comprising admixing cose at day 22 of treatment. any of the compounds according to Formula (I) and a phar 0037 FIG. 12 illustrates the effect of compound 1 in glu maceutically acceptable carrier. cose excursion in an OGTT in male ZDF rats. The panel on 0024. Additional embodiments and advantages of the the left shows the blood glucose levels at various time points invention will become apparent from the detailed discussion, and the panel on the right shows the AUC of glucose from schemes, examples, and claims below. 0-160 minutes from the OGTT. 0038 FIG. 13 illustrates the effect of compound 1 on BRIEF DESCRIPTION OF THE DRAWINGS glycemic control in male ZDF rats. The chart shows fed 0025. The foregoing and other features and advantages of glucose levels throughout the first three weeks of the study. the invention will be apparent from the following, more par 0039 FIG. 14 illustrates the effect of compound 1 on ticular description of preferred embodiments of the invention, insulin levels in the ZDF rat model. The chart shows total as illustrated in the accompanying drawings. pancreatic insulin content in treated ZDF animals. 0026 FIG. 1 illustrates the effects of Compound 1 (Ex ample 1) on weight and food intake. DETAILED DESCRIPTION OF THE INVENTION 0027 FIG. 2 illustrates the effect of Compound 1 on glu cose excursion in an OGTT in male C57BL6 mice after 14 0040. This invention relates to novel ERR-C. modulators days of treatment and compositions thereof for treatment, amelioration, pre 0028 FIG. 3 illustrates the effect of Compound 1 on fed vention or inhibition of numerous conditions including but triglyceride and FFA levels in ZDF rats. not limited to cancer, arthritis, inflammatory airway disease, 0029 FIG. 4 illustrates the effect of compound 1 on cir bone-related diseases, metabolic disorders, and associated culating glucose levels during an ITT at 11 days post dosing symptoms or complications thereof. US 2011/0237625 A1 Sep. 29, 2011

0041. One aspect of the present invention features a com 0054 Particularly, R is Br, cyano, CF, -C=CH, pound of Formula (I) —C(O)C CH —C(O)NH, or—S(O)—CH. More par ticularly, R is cyano. —C(O)O CH, or—C(O)NH2. 0.055 Particularly, X is S. (I) R 0056 Particularly, the present invention includes a com O 2 pound of Formula (I) wherein O R3 0057 R is OH, Calkyl, Calkoxy, F, Cl, or Br; X HN 0.058 R is CF, C(O)NHCN, C(O)C CH, Cl, N or Br; or alternatively R is linked together to R to form R R4 a phenyl fused to the phenyl ring to which R and R are O shown attached; 0059 R is H, or alternatively R is linked togetherto R wherein to form a phenyl fused to the phenyl ring to which R and 0042 R is halo, optionally substituted Calkyl, option R2 are shown attached; ally substituted Calkoxy, or hydroxyl: 0060 R is Br, cyano, CF, -C=CH, -C(O)O- 0043 R is selected from halo substituted C-alkyl, CH, —C(O)NH, or —S(O)—CH; and cyano, halo. —C(O)NH2, and —C(O)C)—Calkyl, alterna 0061 X is S; tively R is linked together to Rs to form an aryl fused to the or an optical isomer, enantiomer, diastereomer, racemate, phenyl ring to which R and R are shown attached; cis-trans isomer, prodrug or pharmaceutically acceptable salt 0044 R is H, or alternatively R is linked together to R to thereof. form an aryl fused to the phenyl ring to which R and R are 0062 More particularly, an example of the present inven shown attached; tion includes compounds of Formula (I) wherein 0045 R is halo, cyano. —C=CH, halo substituted 0063 R is Calkoxy; Calkyl, -C(O)C)—C alkyl, —C(O)NH2 or —S(O)— 0.064 R is CF, or alternatively R is linked together to Calkyl, and R to form a phenyl fused to the phenyl ring to which R 004.6 X is S or O: and R are shown attached; 0047 or an optical isomer, enantiomer, diastereomer, cis 0065 R is H, or alternatively R is linked togetherto R trans isomer, racemate, prodrug or pharmaceutically accept to form a phenyl fused to the phenyl ring to which R and able salt thereof. Rare shown attached; R is cyano. —C=CH, —C(O) 0048. In particular, the present invention includes a cis O CH, —C(O)NH2 or —S(O) CH; and X is S. trans isomer of the compound of Formula (I), which has the 0066. In one embodiment of the present invention, there is following structure: a compound of Formula (I) wherein 0067 R is - O CH: 0068 R is CF; O 0069 R is H; X- X 0070 R is cyano; and HN (0071 X is S. H 0072. It is an embodiment of the present invention to pro N vide a compound selected from: O

OCH CF R O 3 3 O R O R3 S HN S CN O OCH C O 0049 Particularly, R is OH, C-alkyl, Calkoxy, F, Cl, O or Br. More particularly, R is —O—CH or —O CHCH. S In one embodiment, R is —O—CH HN 0050 Particularly, R is CF, -C(O)NH, CN, C(O) N CF O CH, Cl, or Br. O OCH Br 0051 Particularly, R is H. O 0052 Particularly, R is linked together to R to form a O phenyl fused to the phenyl ring to which RandR are shown S attached. HN 0053 Particularly, R is CF and R is H, or alternatively N SOCH3 R is linked togetherto R to form a phenyl fused to the phenyl ring to which R and R are shown attached. US 2011/0237625 A1 Sep. 29, 2011

-continued -continued OCH C OCH2CH3 CF ) O )-1S-1Ne1 O SOCH O C. OCH CF

CF

C Br X O OCH CF OHNOO N OCH2CH o CONH O OCH CONH y X y-1S-1Ne. S. S B r CF 3 OHNO OCH CN ) l X-1S1 Na O ) OCH COCH3 S-1S-1N2 O OCH CF C CF 3

C COCH SS O OX-Oy-Oy-O X OCH l S. X-1S-1N2 S. O OCH B r X l N OHNHNO O US 2011/0237625 A1 Sep. 29, 2011

-continued -continued OCH C OCF CF O O S HN S. CN C CN O O OCH Br OCH CF O O S y HN N CN Y-1S-1Ne. Cl and O O F CF O OCH O X O HN N C. N CN O

O OCH 0073 Particularly, the present invention provides a com O pound selected from: S HN OCH CF N COCH3 O

OCH O CN: O C O S HN OCH CF N CONH2 O CF CF O 3 3 C COCH3: O O S HN OCH2CH3 N CN O y 1N CF y-1S-1Ne. O O S. O S OCH HN S NH2 O X O Y-1S-1N2 CF O 3 S. O O S OCH HN S NH2 y O O )-1S-1Ne. S. COCH3 O US 2011/0237625 A1 Sep. 29, 2011 7

0075. In particular, the present invention provides -continued OCH CF OCH O O O O S S HN HN N N CN. CONH2 and O O 0076. In particular, the present invention provides F O

HNX- S O O OCH N CN. X- S O O HNBluo CN. 0074 More particularly, the present invention provides a O compound selected from: 0077. In particular, the present invention provides

OCH CF O OCH CF O O S O HN S HN S CN: N O COCH3. O OCH CF3 O 0078. Another aspect of the present invention features a O pharmaceutical composition comprising at least one com HN S poundd of Formula (I) and at least one pharmaceuticallyh ticall acceptable carrier. Particularly, a pharmaceutical composi N tion of the present invention can further comprise at least one COCH3: additional agent, drug, medicament, antibody and/or inhibi O tor for treating, ameliorating or slowing a ERR-C. mediated disease. More particularly, a pharmaceutical composition of OCH2CH the present invention comprises a compound selected from: O

X O OCH CF N CN: X O HN

O OCH 3 CN O X- O O OCH C HN S X- O CN; and HN S O N CF OCH O O OCH B X- S O O 3 r HN X S O N CONH2. HN O SOCH US 2011/0237625 A1 Sep. 29, 2011

-continued -continued OCH C y O OCH2CH CF S-1S-1N21 O SOCH3 O OCH CF luc C. CF o Br X O OCH CF OHNOO N C. o CONH OCH2CH3 O OCH CONH y X X-1S-1N21 O S. N

CF 3 OHNO OCH CN ) S HN ) N )-1S-1Ne. C. O O OCH COCH3 O O S X HN )-1S-1Ne. N O S. O C CF OCH CF O 3 O S HN N C COCH3 C. O O

CH3 O OCH O O S S HN N N S. O S. F CF 3 OCH X l N C OHNHNO O US 2011/0237625 A1 Sep. 29, 2011

-continued -continued OCH C OCF CF OX HN N C CN C CN O O OCH Br OCH CF3 OX HN S o CN C Cl and O O F CF OCH O X O HN S X- s C. N CN O

OCH 0079 More particularly, a pharmaceutical composition of O the present invention comprises a compound selected from: X- S O HN S OCH COCH O X

O OCH S O O S OCH C F 3 HN N CONH2 O CF CF O 3 3 C COCH3: O O S HN OCH2CH N CN y O X-1S-1N21 O 1N CF CN: O OCH HN N O C, NH2 x luc O )-1S-1N2 CN: CF O O OCH HN N NH2 x O O )-1S-1Nea COCH3 O US 2011/0237625 A1 Sep. 29, 2011 10

I0085. According to another aspect of the invention, the -continued disclosed compounds and compositions are useful for the OCH amelioration of symptoms associated with, the treatment of O slowing and/or inhibiting the progression of the following conditions and diseases: periodontal disease, chronic inflam X- S O matory airway disease, chronic bronchitis, and chronic HN obstructive pulmonary disease. N CONH2 and I0086 According to a further aspect of the invention, the O disclosed compounds and compositions are useful for the F amelioration of symptoms associated with, the treatment of O slowing and/or inhibiting the progression of breast cancer. S I0087. According to yet another aspect of the invention, the HN disclosed compounds and compositions are useful for the X- s amelioration of symptoms associated with, the treatment of N CN. slowing and/or inhibiting the progression of the following O conditions and diseases: metabolic syndrome, obesity, disor ders of energy homeostasis, diabetes, lipid disorders, cardio vascular disorders, artherosclerosis, hyperglycemia, elevated 0080. The present invention also features a method of blood glucose level, and insulin resistance. treating a Subject Suffering from or diagnosed with a disease, I0088 Particularly, a method of the present invention com disorder, or condition mediated by ERR-C. activity, compris prises administering to the Subject a therapeutically effective ing administering to the Subject a therapeutically effective amount of (a) at least one compound of Formula (I); and (b) amount of at least one compound of Formula (I). at least one additional agent selected from a second ERR-C. 0081. The present invention also features a method for inverse agonist, an ERR-C. antagonist, a glucokinase modu slowing or inhibiting the progression of an ERR-O-mediated lator, an anti-diabetic agent, an anti-obesity agent, a lipid condition in a subject in need thereof, comprising adminis lowering agent, an anti-thrombotic agent, direct thrombin tering to said Subject a therapeutically effective amount of at inhibitor, and a blood pressure lowering agent, said adminis least one compound of Formula (I). tration being in any order. More particularly, the additional 0082. The present invention also features a method for agent in (b) is a second ERR-C. inverse agonist different from treating a prediabetic condition in a Subject in need thereof, the compound in (a). More particularly, the additional agent comprising administering to said subject a therapeutically in (b) is an anti-obesity agent selected from CB1 antagonists, monoamine reuptake inhibitors, and lipase inhibitors. More effective amount of at least one compound of Formula (I). particularly, the additional agent in (b) is selected from 0083. Such disease, disorder, or condition can include rimonabant, Sibutramine, and orlistat. bone-related disease, bone formation, breast cancer (includ ing those unresponsive to anti-estrogen therapy), cartilage I0089. The present invention also features a method for formation, cartilage loss, cartilage degeneration, cartilage treating or inhibiting the progression of one or more ERR-C- injury, ankylosing spondylitis, chronic back injury, gout, mediated conditions, said method comprising administering osteoporosis, osteolytic bone metastasis, multiple myeloma, to a patient in need of treatment a pharmaceutically effective chondrosarcoma, chondrodysplasia, osteogenesis imper amount of a composition of the invention. fecta, osteomalacia, Paget's disease, polymyalgia rheu 0090. It is a further embodiment of the invention to pro matica, pseudogout, arthritis, rheumatoid arthritis, infectious vide a process for making a pharmaceutical composition arthritis, osteoarthritis, psoriatic arthritis, reactive arthritis, comprising admixing any of the compounds according to childhood arthritis, Reiter's syndrome, repetitive stress Formula (I) and a pharmaceutically acceptable carrier. injury, periodontal disease, chronic inflammatory airway dis 0091. The invention also features pharmaceutical compo ease, chronic bronchitis, chronic obstructive pulmonary dis sitions which include, without limitation, one or more of the ease, metabolic syndrome, obesity, disorders of energy disclosed compounds, and pharmaceutically acceptable car homeostasis, diabetes, lipid disorders, cardiovascular disor riers or excipients. ders, artherosclerosis, hyperglycemia, elevated blood glucose 0092. In a further embodiment of the invention, a method level, and insulin resistance. for treating or ameliorating an ERR-O-mediated condition in 0084. According to one aspect of the invention, the dis a Subject in need thereof comprises administering to the Sub closed compounds and compositions are useful for the ame ject a therapeutically effective amount of at least one com lioration of symptoms associated with, the treatment of, and/ pound of Formula (I), wherein the therapeutically effective or inhibiting the progression of the following conditions and amount of the compound of Formula (I) is from about 0.1 diseases: bone-related disease, bone formation, cartilage for mg/dose to about 5 g/dose. In particular, the therapeutically mation, cartilage loss, cartilage degeneration, cartilage effective amount of the compound of Formula (I) is from injury, ankylosing spondylitis, chronic back injury, gout, about 0.5 mg/dose to about 1000 mg/dose. More particularly, osteoporosis, osteolytic bone metastasis, multiple myeloma, the therapeutically effective amount of the compound of For chondrosarcoma, chondrodysplasia, osteogenesis imper mula (I) is from about 1 mg/dose to about 100 mg/dose. In a fecta, osteomalacia, Paget's disease, polymyalgia rheu further embodiment of the invention, the number of doses per matica, pseudogout, arthritis, rheumatoid arthritis, infectious day of a compound of Formula (I) is from 1 to 3 doses. In a arthritis, osteoarthritis, psoriatic arthritis, reactive arthritis, further embodiment of the invention, the therapeutically childhood arthritis, Reiter's syndrome, and repetitive stress effective amount of the compound of Formula (I) is from injury. about 0.001 mg/kg/day to about 30 mg/kg/day. More particu US 2011/0237625 A1 Sep. 29, 2011

larly, the therapeutically effective amount of the compound of —S(O), N(R')(R"), wherein R' and R" are independently Formula (I) is from about 0.01 mg/kg/day to about 2 mg/kg/ selected from H. Co-alkyl, aryl, heteroaryl, and/or hetero day. cyclyl. 0093. In a further embodiment of the invention, a method (0099. The term “alkenyl refers to an unsaturated for slowing or inhibiting the progression of an ERR-O-medi branched, straight-chain or cyclic monovalent hydrocarbon ated condition in a Subject in need thereof comprises admin radical, which has at least one carbon-carbon double bond, istering to the Subject a therapeutically effective amount of at derived by the removal of one hydrogen atom from a single least one compound of Formula (I), wherein the therapeuti carbon atom of a parent alkene. The radical may be in either cally effective amount of the compound of Formula (I) is from the cis or trans conformation about the double bond(s). Typi about 0.1 mg/dose to about 5 g/dose. In particular, the thera cal alkenyl groups include, but are not limited to, ethenyl: peutically effective amount of the compound of Formula (I) is propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en from about 1 mg/dose to about 100 mg/dose. In a further 1-yl, prop-2-en-2-yl, cycloprop-1-en-1-yl, cycloprop-2-en embodiment of the invention, the number of doses per day of 1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl a compound of Formula (I) is from 1 to 3 doses. In a further prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, embodiment of the invention, the therapeutically effective buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, amount of the compound of Formula (I) is from about 0.001 cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the mg/kg/day to about 30 mg/kg/day. More particularly, the like. In some embodiments, the alkenyl is substituted with therapeutically effective amount of the compound of Formula one to five, preferably one to three groups including, but not (I) is from about 0.01 mg/kg/day to about 2 mg/kg/day. limited to, oxo, amino, alkoxy, carboxy, heterocyclyl, 0094. In yet another embodiment of the invention, a hydroxyl, and halo. method for treating a prediabetic condition in a Subject in 0100. The term “alkynyl refers to an unsaturated need thereof, comprises administering to said Subject athera branched, straight-chain or cyclic monovalent hydrocarbon peutically effective amount of at least one compound of For radical, which has at least one carbon-carbon triple bond, mula (I), wherein the therapeutically effective amount of the derived by the removal of one hydrogen atom from a single compound of Formula (I) is from about 0.1 mg/dose to about carbon atom of a parent alkyne. Typical alkynyl groups 5 g/dose. In particular, the therapeutically effective amount of include, but are not limited to, ethynyl; propynyls such as the compound of Formula (I) is from about 1 mg/dose to prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1- about 100 mg/dose. In a further embodiment of the invention, yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. In the number of doses per day of a compound of Formula (I) is some embodiments, the alkynyl is substituted with one to from 1 to 3 doses. In a further embodiment of the invention, five, preferably one to three groups including, but not limited the therapeutically effective amount of the compound of For to, oxo, amino, alkoxy, carboxy, heterocyclyl, hydroxyl, and mula (I) is from about 0.001 mg/kg/day to about 30 mg/kg/ halo. day. More particularly, the therapeutically effective amount 0101 The term "heteroaryl refers to a monovalent het of the compound of Formula (I) is from about 0.01 mg/kg/day eroaromatic radical derived by the removal of one hydrogen to about 2 mg/kg/day. atom from a single atom of a parent heteroaromatic ring 0095. The invention is further described below. system. Typical heteroaryl groups include monocyclic and bicyclic systems where one or both rings are heteroaromatic A) TERMS Heteroaromatic rings may contain 1-4 heteroatoms selected 0096. Some terms are defined below and by their usage from O, N, and S. Examples include but are not limited to, throughout this disclosure. radicals derived from carbazole, imidazole, indazole, indole, 0097. Unless otherwise noted, “alkyl as used herein, indolizine, isolindole, isoquinoline, isothiazole, isoxazole, whether used alone or as part of a Substituent group, refers to naphthyridine, oxadiazole, oxazole, purine, pyrazine, pyra a saturated, branched, or straight-chain monovalent hydrocar Zole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, bon radical derived by the removal of one hydrogen atom quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, from a single carbon atom of a parent alkane. Typical alkyl thiadiazole, thiazole, thiophene, triazole, Xanthene, and the groups include, but are not limited to, methyl; ethyls such as like. In some embodiments, “heteroaryl is substituted. For ethanyl; propyls such as propan-1-yl, propan-2-yl, cyclopro instance, "heteroaryl' can be substituted with, e.g., optionally pan-1-yl.; butyls such as butan-1-yl, butan-2-yl, 2-methyl Substituted Calkyl, Calkenyl, C-alkynyl, halo, propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl and the hydroxyl, —CN, —C(O)OH, -C(O)O Calkyl, —C(O) like. In preferred embodiments, the alkyl groups are NR'R" OR', SR C(O)R', N(R')(R"), S(O) R', Calkyl, with C- being particularly preferred. "Alkoxy” and —S(O), N(R')(R"), wherein R' and R" are indepen radicals are oxygen ethers formed from the previously dently selected from H. Co-alkyl, aryl, heteroaryl, and/or described Straight or branched chain alkyl groups. In some heterocyclyl. embodiments, the alkyl or alkoxy are independently Substi 0102) The term “heterocyclyl or “heterocycle” is a 3- to tuted with one to three groups including, but not limited to, 8-member Saturated, or partially saturated single or fused ring oxo, amino, alkoxy, carboxy, hydroxyl, and halo (F, Cl, Br, or system which consists of carbon atoms and from 1 to 6 het I). eroatoms selected from N, O and S. The heterocyclyl group 0098. The term “aryl, as used herein, refers to aromatic may be attached at any heteroatom or carbon atom which groups comprising a stable six-membered monocyclic, or results in the creation of a stable structure. Example of het ten-membered bicyclic or fourteen-membered tricyclic aro erocyclyl groups include, but are not limited to, 2-imidazo matic ring system which consists of carbonatoms. Examples line, imidazolidine; morpholine, oxazoline, 2-pyrroline, of aryl groups include, but are not limited to, phenyl or naph 3-pyrroline, pyrrolidine, pyridone, pyrimidone, piperazine, thalenyl. In some embodiments, “aryl' is substituted. For piperidine, indoline, tetrahydrofuran, 2-pyrroline, 3-pyrro instance, “aryl can be substituted with, e.g., optionally Sub line, 2-imidazoline, 2-pyrazoline, and indolinone. In some stituted C-alkyl, Calkenyl, C-alkynyl, halo, hydroxyl, embodiments, “heterocyclyl or "heterocycle” are indepen —CN, -C(O)CH, -C(O)O Calkyl, -C(O)NR'R", dently substituted. For instance, "heterocyclyl or "hetero —SR', OR', C(O)R', N(R')(R"), S(O) R', and cycle' can be substituted with, e.g., optionally substituted US 2011/0237625 A1 Sep. 29, 2011

Calkyl, Calkenyl, C-alkynyl, halo, hydroxyl. —CN. disclosed pharmaceutical compositions or the disclosed drug —C(O)OH, -C(O)O Calkyl, -C(O)NR'R" OR', combinations, whether or not formulated in the same compo —SR' C(O)R', N(R')(R"), S(O) R', and—S(O)— sition. For therapeutic purposes, the term “therapeutically N(R')(R"), wherein R and R" are independently selected effective amount as used herein, means that amount of each from H. Co-alkyl, aryl, heteroaryl, and/or heterocyclyl. active compound or pharmaceutical agent, alone or in com 0103) The term “oxo' whether used alone or as part of a bination, that elicits the biological or medicinal response in a substituent group refers to an O— to either a carbon or a tissue system, animal or human that is being sought by a Sulfur atom. For example, phthalimide and saccharin are researcher, Veterinarian, medical doctor or other clinician, examples of compounds with oxo Substituents. which includes alleviation of the symptoms of the disease or 0104. The term “cis-trans isomer refers to stereoisomeric disorder being treated. For prophylactic purposes (i.e., inhib olefins or cycloalkanes (or hetero-analogues) which differ in iting the onset or progression of a disorder), the term “thera the positions of atoms (or groups) relative to a reference peutically effective amount” refers to that amount of each plane: in the cis-isomer the atoms are on the same side; in the active compound or pharmaceutical agent, alone or in com trans-isomer they are on opposite sides. bination, that treats or inhibits in a subject the onset or pro 0105. The term “substituted refers to a radical in which gression of a disorder as being sought by a researcher, Veteri one or more hydrogenatoms are each independently replaced narian, medical doctor or other clinician. Thus, the present with the same or different substituent(s). invention provides combinations of two or more drugs 0106 The term “composition' is intended to encompass a wherein, for example, (a) each drug is administered in an product comprising the specified ingredients in the specified independently therapeutically or prophylactically effective amounts, as well as any product which results, directly or amount; (b) at least one drug in the combination is adminis indirectly, from combinations of the specified ingredients in tered in an amount that is Sub-therapeutic or Sub-prophylactic the specified amounts. if administered alone, but is therapeutic or prophylactic when 0107 The term “subject as used herein, refers to an ani administered in combination with the second or additional mal, preferably a mammal, most preferably a human, who is drugs according to the invention; or (c) both (or more) drugs the object of treatment, observation or experiment. are administered in an amount that is sub-therapeutic or Sub 0108. It is intended that the definition of any substituent or prophylactic if administered alone, but are therapeutic or variable at a particular location in a molecule be independent prophylactic when administered together. of its definitions elsewhere in that molecule. It is understood 0112 The term “pharmaceutically acceptable salt” refers that Substituents and Substitution patterns on the compounds to non-toxic pharmaceutically acceptable salts (Ref. Interna of this invention can be selected by one of ordinary skill in the tional J. Pharm., 1986, 33, 201-217: J. Pharm. Sci., 1997 art to provide compounds that are chemically stable and that (January), 66, 1, 1). Other salts well known to those in the art can be readily synthesized by techniques known in the art as may, however, be useful in the preparation of compounds well as those methods set forth herein. according to this invention or of their pharmaceutically 0109 The term “inverse agonist’ as used herein refers to acceptable salts. Representative organic or inorganic acids compounds or Substances that have the ability to decrease the include, but are not limited to, hydrochloric, hydrobromic, constitutive level of receptor activation in the absence of an hydriodic, perchloric, Sulfuric, nitric, phosphoric, acetic, pro agonist instead of only blocking the activation induced by pionic, glycolic, lactic, Succinic, maleic, fumaric, malic, tar agonist binding at the receptor. taric, citric, benzoic, mandelic, methanesulfonic, hydroxy 0110 Metabolic disorders, diseases, or conditions ethanesulfonic, benzenesulfonic, oxalic, pamoic, include, but are not limited to, diabetes, obesity, and associ 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexane ated symptoms or complications thereof. They include Such Sulfamic, Salicylic, saccharinic or trifluoroacetic acid. Repre conditions as IDDM (insulin-dependent diabetes mellitus), sentative organic or inorganic bases include, but are not lim NIDDM (non insulin-dependent diabetes mellitus), IGT (Im ited to, basic or cationic salts such as benzathine, paired Glucose Tolerance), IFG (Impaired Fasting Glucose), chloroprocaine, choline, diethanolamine, ethylenediamine, Syndrome X (or Metabolic Syndrome), hyperglycemia, meglumine, procaine, aluminum, calcium, lithium, magne elevated blood glucose level, and insulin resistance. A condi sium, potassium, Sodium and zinc. tion such as IGT or IFG is also known as a “prediabetic condition' or “prediabetic state.” B) COMPOUNDS 0111 Methods are known in the art for determining effec 0113 Representative compounds of the present invention tive doses for therapeutic and prophylactic purposes for the are listed in Table I below:

TABLE 1

STRUCTURE COMPOUND if NAME

OCH CF 1 4-4-(2,4-Dioxo-thiazolidin-5- ylidenemethyl)-2-methoxy-phenoxy 3-trifluoromethyl-benzonitrile

CN US 2011/0237625 A1 Sep. 29, 2011

TABLE 1-continued

STRUCTURE COMPOUND if NAME OCH C 2 5-4-(2-Chloro-4-trifluoromethyl O phenoxy)-3-methoxy-benzylidene O thiazolidine-2,4-dione S HN S CF O O OCH Br 3 5-4-(2-Bromo-4-methanesulfonyl phenoxy)-3-methoxy-benzylidene X- S O thiazolidine-2,4-dione HN N SOCH3 O

OCH C 4 5-4-(2-Chloro-4-methanesulfonyl O phenoxy)-3-methoxy-benzylidene O thiazolidine-2,4-dione S HN N SOCH3 O O OCH CF 5 5-4-(4-Bromo-2-trifluoromethyl phenoxy)-3-methoxy-benzylidene X- S O thiazolidine-2,4-dione HN N Br O

O OCH CF 6 4-4-(2,4-Dioxo-thiazolidin-5- X O ylidenemethyl)-2-methoxy-phenoxy3-trifluoromethyl-benzamide S HN N CONH O

O OCH CONH2 7 2-4-(2,4-Dioxo-thiazolidin-5- XN O ylidenemethyl)-2-methoxy-phenoxy5-trifluoromethyl-benzamide S HN N CF O

O OCH CN 8 2-4-(2,4-Dioxo-thiazolidin-5- X- O ylidenemethyl)-2-methoxy-phenoxy5-trifluoromethyl-benzonitrile S HN N CF O

OCH COCH3 9 2-4-(2,4-Dioxo-thiazolidin-5- ylidenemethyl)-2-methoxy-phenoxy 5-trifluoromethyl-benzoic acid methyl ester

C CF O

US 2011/0237625 A1 Sep. 29, 2011

TABLE 1-continued

STRUCTURE COMPOUND if NAME

17 4-(4-(2,4-Dioxo-thiazolidin-5- O F ylidenemethyl)-2-fluoro-phenoxy O naphthalene-1-carbonitrile S HN N CN O

C CF 18 4-2-Chloro-4-(2,4-dioxo-thiazolidin OX- O 5-ylidenemethyl)-phenoxy-3-trifluoromethyl-benzonitrile S HN N CN O

19 4-4-(2,4-Dioxothiazolidin-5- O OCH ylidenemethyl)-2-methoxyphenoxy O naphthalene-1-carbonitrile S HN S CN O

O OCH Br 2O 5-(4-(2-Bromo-4-trifluoromethyl phenoxy)-3-methoxybenzylidene X- S O thiazolidine-2,4-dione HN N CF O

OCH C 21 3-Chloro-4-4-(2,4-dioxothiazolidin-5- OX- O ylidenemethyl)-2-methoxyphenoxybenzonitrile S HN N CN O

O OCH Br 22 3-Bromo-4-4-(2,4-dioxothiazolidin X- O methoxyphenoxybenzonitrile5-ylidenemethyl)-2- S HN N CN O

23 4-4-(2,4-Dioxo-oxazolidin-5- OCH ylidenemethyl)-2-methoxy-phenoxy X naphthalene-1-carbonitrile )-1S-1N21 CN O

US 2011/0237625 A1 Sep. 29, 2011

TABLE 1-continued

STRUCTURE COMPOUND if NAME

O OCH3 CF3 30 5-4-(4-Chloro-2-trifluoromethyl phenoxy)-3-methoxy-benzylidene O thiazolidine-2,4-dione S HN S C O

O F CF 3 31 5-(4-(4-Chloro-2-trifluoromethyl phenoxy)-3-fluoro-benzylidene O thiazolidine-2,4-dione S HN N C O

C) SYNTHESIS (0132 h or hr (hour(s)) 0114. The invention provides methods of making the dis 0.133 HATU (O-(7-AZabenzotriazol-1-yl)-N,N,N',N'- closed compounds according to traditional organic synthetic tetramethyluronium hexafluorophosphate) methods as well as matrix or combinatorial synthetic meth 0134 HMPA (Hexamethylphosphoramide) ods. Scheme 1 describes Suggested synthetic routes. Using 0135 HOBt (1-Hydroxybenzotriazole monohydrate) the scheme, the guidelines below, and the examples, a person 0.136 LCMS (high pressure liquid chroatography with of skill in the art may develop analogous or similar methods mass spectrometer) for a given compound that is within the invention. These 0137 LDA (Lithium diisopropylamide) methods are representative of the synthetic schemes, but are 0138 LHMDS (lithium hexamethyl disilazide) not to be construed as limiting the Scope of the invention. 0139 Me (methyl) 0115 Furthermore, some of the crystalline forms for the 0140 Mg (milligram) compounds may exist as polymorphs and as such are intended 0141 MOM (Methoxymethyl) to be included in the present invention. In addition, some of 0.142 NaHMDS (sodium hexamethyl disilazide) the compounds may form solvates with water (i.e., hydrates) 0143 NaO'Bu (sodium tert-butoxide) or common organic solvents, and Such solvates are also 0144 NBS (N-Bromosuccinimide) intended to be encompassed within the scope of this inven (0145 NMP (N-Methyl Pyrrolidinone) tion. 0146 rt or RT (room temperature) 0116 Examples of the described synthetic routes include 0147 SPE (solid phase extraction) Scheme 1. Examples 1 through 31, and General Procedures 0148 TBTU (O-Benzotriazol-1-yl-N,N,N',N'-tetram A-D. Compounds analogous to the target compounds of these ethyluronium hexafluorophosphate) examples can be made according to similar routes. The dis 0149 TEMPO (2.2.6,6-tetramethyl-1-piperidinyloxy, closed compounds are useful as pharmaceutical agents as free radical) described herein. 0150 TFA (trifluoroacetic acid); 0117. Abbreviations or acronyms useful herein include: 0151. THF (tetrahydrofuran) 0118 AIBN (2,2'-Azobisisobutyronitrile) 0152 TLC (thin layer chromatography) 0119 Boc (tert butyl carbamate) I0120 BOP (Benzotriazol-1-yloxy)tris(dimethylamino) phosphonium hexyluorophosphate) General Guidance I0121 BuLi (butyllithium) O153 0.122 DIBAL-H (Diisobutylaluminum hydride) I0123 DMAP (4-(dimethylamino)pyridine) (0.124 DME (Ethylene glycol dimethyl ether) Scheme 1 (0.125 DMF (dimethylformamide) OH (0.126 DMPU(1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)- base pyrimidinone) -- (O127 DMSO (methylsulfoxide) OHC R F R3 I0128 EDC(N-(3-Dimethylaminopropyl)-N'-ethylcar II bodiimide) I0129 EDCI (1-(3-Dimethylaminopropyl)-3-ethylcar bodiimide hydrochloride) 0.130 Et (ethyl) III I0131 EtOAc (ethyl acetate) US 2011/0237625 A1 Sep. 29, 2011 18

(2 mL) was added and the mixture heated to 75° C. for 10 -continued minutes. The mixture was cooled to RT and the product was R O collected by filtration, dissolved in acetone, dried over NaSO and concentrated in vacuo to afford the pure product. O R3 X-y 0158 General Procedure D: To a mixture of thiazolidine HN 2,4-dione (117 mg, 1.0 mmol) and aldehyde from Procedure OHC R R4 A (1.0 mmol) was added acetic acid (1.0 mL) and NHOAc IV O (2.0 mmol). The suspension was heated at 100°C. (aluminum V heating block) for 2 h. The product was collected by filtration, washed with water and triturated with EtOAc/hexanes to O R2 afford a pure product. O R3 X Example 1 HN 4-4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2- N R R4 methoxy-phenoxy-3-trifluoromethyl-benzonitrile O I 0159)

0154 The compounds of Formula I, wherein X. R. R. R. O OCH CF and Ra are defined herein, can be synthesized as outlined by O the general synthetic route illustrated in Scheme 1. Treatment S of an appropriate hydroxybenzaldehyde II and aryl fluoride HN III, both of which are either commercially available or can be S CN made from commercially available starting materials, with a base such as KCO in a solvent such as DMF at a temperature O preferably between 25-150° C. can provide the phenoxyalde hyde IV. Knoevenagel reaction of aldehyde IV with the cyclic 0.160 A. 4-(4-Formyl-2-methoxy-phenoxy)-3-trifluo dione V in the presence of a catalytic amount of base Such as romethyl-benzonitrile was prepared from vanillin and piperidine and an acid such as benzoic acid can provide the 4-fluoro-3-trifluoromethylbenzonitrile following Gen compounds of Formula (I). The Knoevenage reaction is typi eral Procedure A. H NMR (400 Hz, CDC1) & 10.00 (s, cally performed in an aprotic solvent Such as toluene at a 1H), 8.00 (m, 1H), 7.68 (dd. 1H), 7.58-7.53 (m, 2H), temperature of, preferably, 100-200°C. The reaction between 7.29 (d. 1H), 6.75 (d. 1H), 3.83 (s, 3H); LC/MS (m/z) aldehyde IV and cyclic dione V may also be performed with M+1 322.1 (calculated for CHFNO. 322.06). a base Such as sodium acetate in a solvent Such as acetonitrile (0161 B. 4-4-(2,4-Dioxo-thiazolidin-5-ylidenem at an elevated temperature preferably between 50-150° C. or ethyl)-2-methoxy-phenoxy-3-trifluoromethyl-ben in the presence of ammonium acetate inacetic acid at elevated Zonitrile was prepared using 4-(4-Formyl-2-methoxy temperatures preferably between 50-150° C. phenoxy)-3-trifluoromethyl-benzonitrile following General Procedure B. "H NMR (400 Hz, DMSO-d6) & EXAMPLES 12.68 (NH), 8.32 (d. 1H), 8.00 (dd. 1H), 7.83 (s, 1H), 0155 General Procedure A: A solution of an appropriate 7.49 (d. 1H), 7.36 (d. 1H), 7.26 (dd. 1H), 6.90 (d. 1H), substituted benzaldehyde (1.65 g, 10.86 mmol) and aryl fluo 3.77 (s.3H); LC/MS (m/z)M+1" 421.0 (calculated for ride (10.26 mmol) in DMF (15 mL) was treated with KCO CoHFNOS, 421.04). (2.83 g, 21.72 mmol), and the mixture was heated in an oil bath at 80° C. for 12 h. The reaction was cooled to RT and Example 2 partitioned between EtOAc and H.O.The organic phase was 5-4-(2-Chloro-4-trifluoromethyl-phenoxy)-3-meth washed with water (3x), dried over NaSO and concentrated oxy-benzylidene-thiazolidine-2,4-dione in vacuo. Silica gel chromtagraphy (EtOAC/hexanes) afforded the pure product. (0162 0156 General Procedure B: Thiazolidine-2,4-dione (2.55 g, 21.79 mmol) and aldehyde from Procedure A (21.79 mmol) OCH C were dissolved in toluene (150 mL) and treated with benzoic O acid (3.27 mmol) and piperidine (2.83 mmol). The flask was O equipped with a Dean-Stark trap, and the reaction was S refluxed in a 130° C. oil bath for 12h. After cooling to RT, the HN product was collected by filtration and triturated with hexanes N CF to afford a pure product. (O157 General Procedure C. Thiazolidine-2,4-dione (19 O mg, 0.16 mmol), aldehyde from Procedure A above (0.098 mmol) and sodium acetate (30 mg, 0.37 mmol) were sus 0.163 A, 4-(2-Chloro-4-trifluoromethyl-phenoxy)-3- pended in CHCN (2 mL) and heated to 105°C. (aluminum methoxy-benzaldehyde was prepared from vanillin and heating block). The CHCN was allowed to evaporate over 3-chloro-1-fluoro-4-trifluoromethylbenzene following 10-12 minutes then repeated using two additional portions of General Procedure A. LC/MS (m/z) MI" 330.0 (calcu CHCN (2 mL). The solid residue was cooled to RT, then H2O lated for CHCIF.O., 330.03). US 2011/0237625 A1 Sep. 29, 2011 19

0164 B. 5-4-(2-Chloro-4-trifluoromethyl-phenoxy)- 2H), 6.98 (d. 1H), 3.91 (s, 3H), 3.18 (s, 3H); LC/MS 3-methoxy-benzylidene-thiazolidine-2,4-dione was (m/z) M+1' 440.8 (calculated for CHCINOS, prepared using 4-(2-Chloro-4-trifluoromethyl-phe 440.0). noxy)-3-methoxy-benzaldehyde following General Procedure C. "H NMR (400 Hz, acetone-d6) & 7.89 (d. Example 5 1H), 7.84 (s, 1H), 7.62 (dd. 1H), 7.47 (d. 1H), 7.33 (s, 5-4-(4-Bromo-2-trifluoromethyl-phenoxy)-3-meth 1H), 7.32 (s, 1H), 6.97 (d. 1H), 3.91 (s, 3H); LC/MS oxy-benzylidene-thiazolidine-2,4-dione (m/z) M+1' 430.8 (calculated for CHCIFNOS, 430.00). 0170 Example 3 OCH CF 5-4-(2-Bromo-4-methanesulfonyl-phenoxy)-3- methoxy-benzylidene-thiazolidine-2,4-dione (0165 Br

OCH Br

0171 A. 4-(4-Bromo-2-trifluoromethyl-phenoxy)-3- methoxy-benzaldehyde was prepared from vanillin and SOCH 4-Bromo-1-fluoro-2-trifluoromethylbenzene following General Procedure A. H NMR (400 Hz, CDC1) & 9.95 (s, 1H), 7.81 (d. 1H), 7.547 (dd. 1H), 7.545 (d. 1H), 7.47 (dd. 1H), 7.09 (d. 1H), 6.70 (d. 1H), 3.88 (s.3H); LC/MS 0166 A. 4-(2-Bromo-4-methanesulfonyl-phenoxy)-3- (m/z) M+1+41. 416.7 (calculated for CH BrFO, methoxy-benzaldehyde was prepared from vanillin and 374.98). 2-Bromo-1-fluoro-4-methanesulfonylbenzene follow (0172 B, 5-4-(4-Bromo-2-trifluoromethyl-phenoxy)- ing General Procedure A. H NMR (400 Hz, CDC1) & 3-methoxy-benzylidene-thiazolidine-2,4-dione was 9.98 (s, 1H), 8.22 (d. 1H), 7.77 (dd. 1H), 7.57 (d. 1H), prepared using 4-(4-Bromo-2-trifluoromethyl-phe 7.52 (dd. 1H), 7.14 (d. 1H), 6.80 (d. 1H), 3.88 (s, 3H), noxy)-3-methoxy-benzaldehyde following General 3.08 (s.3H). Procedure C. "HNMR(400 Hz, CDC1,) 88.50 (bs, NH), 0.167 B. 5-4-(2-Bromo-4-methsnesulfonyl-phenoxy)- 7.84 (s, 1H), 7.80 (d. 1H), 7.52 (dd. 1h), 7.10 (m, 3H), 3-methoxy-benzylidene-thiazolidine-2,4-dione was 6.69 (d. 1H), 3.86 (s.3H); LC/MS (m/z) M+1" 474.9 prepared using 4-(2-Bromo-4-methanesulfonyl-phe (calculated for CHBrFNOS, 474.95). noxy)-3-methoxy-benzaldehyde following General Procedure C. "H NMR (400 Hz, acetone-d6) & 8.20 (s, Example 6 1H), 7.85 (m, 2H), 7.48 (s, 1H), 7.36 (m, 2H), 6.94 (d. 4-4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2- 1H), 3.91 (s, 3H), 3.19 (s.3H); LC/MS (m/z) M+1" methoxy-phenoxy-3-trifluoromethyl-benzamide 484.8 (calculated for CHBrNOS, 483.9). 0173 OCH C OCH CF

SOCH CONH

0168 A. 4-(2-Chloro-4-methanesulfonyl-phenoxy)-3- methoxy-benzaldehyde was prepared from vanillin and 2-chloro-1-fluoro-4-methanesulfonylbenzene follow 0.174 A. 4-(4-Formyl-2-methoxy-phenoxy)-3-trifluo ing General Procedure A. H NMR (400 Hz, CDC1) & romethyl-benzamide was prepared from Vanillin and 9.98 (s, 1H), 8.06 (d. 1H), 7.73 (dd. 1H), 7.58 (d. 1H), 4-Fluoro-3-trifluoromethylbenzamide following Gen 7.52 (dd. 1H), 7.17 (d. 1H), 6.85 (d. 1H), 3.89 (s.3H), eral Procedure A. H NMR (400 Hz, CDC1) & 9.98 (s, 3.08 (s.3H). 1H), 8.08 (m, 2H), 7.53 (m, 2H), 7.27 (m, 1H), 6.79 (d. 0169 B. 5-4-(2-Chloro-4-methanesulfonyl-phenoxy)- 1H), 3.85 (s.3H); LC/MS (m/z) M+1+41' 380.9 (cal 3-methoxy-benzylidene-thiazolidine-2,4-dione was culated for CHFNO. 340.07). prepared using 4-(2-Chloro-4-methanesulfonyl-phe 0.175 B. 4-4-(2,4-Dioxo-thiazolidin-5-ylidenem noxy)-3-methoxy-benzaldehyde following General ethyl)-2-methoxy-phenoxy-3-trifluoromethyl-benza Procedure C. "H NMR (400 Hz, acetone-d6) & 8.06 (d. mide was prepared using 4-(4-Formyl-2-methoxy-phe 1H), 7.84 (s, 1H), 7.82 (dd. 1H), 7.48 (d. 1H), 7.36 (m, noxy)-3-trifluoromethyl-benzamide following General US 2011/0237625 A1 Sep. 29, 2011 20

Procedure C. "H NMR (400 Hz, CDOD) 88.25 (d. 1H), 0181 B. 2-4-(2,4-Dioxo-thiazolidin-5-ylidenem 8.00 (dd. 1H), 7.84 (s, 1H), 7.34 (m, 1H), 7.26 (m, 2H), ethyl)-2-methoxy-phenoxy-5-trifluoromethyl-ben 6.79 (d. 1H), 3.82 (s.3H); LC/MS (m/z) M+1" 439.0 Zonitrile was prepared using 2-(4-Formyl-2-methoxy (calculated for CHFNOS, 439.05). phenoxy)-5-trifluoromethyl-benzonitrile following General Procedure C. "H NMR (400 MHz, CDC1) & Example 7 8.11 (brs, 1H), 7.94 (d. 1H), 7.85 (s, 1H), 7.67 (dd. 1H), 2-4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2- 7.29 (s, 1H), 7.19 (dd. 1H), 7.14 (d. 1H), 6.78 (d. 1H), methoxy-phenoxy-5-trifluoromethyl-benzamide 3.83 (s.3H); LC/MS (m/z) M+1" molec ion not found (calculated for CHFNOS, 420.04). (0176) Example 9 OCH CONH 2-4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2- methoxy-phenoxy-5-trifluoromethyl-benzoic acid methyl ester CF 0182

OCH COCH 0177 A. 2-(4-Formyl-2-methoxy-phenoxy)-5-trifluo romethyl-benzamide was prepared from Vanillin and 2-Fluoro-5-trifluoromethylbenzamide following Gen eral Procedure A. H NMR (400 MHz, CDC1,) 89.93 (s, 1H), 8.46 (d. 1H), 7.55-7.47 (m, 3H), 7.44 (brs, 1H), CF 7.22 (d. 1H), 6.74 (d. 1H), 5.82 (brs, NH), 3.81 (s.3H): LC/MS (m/z) M+41+1" 381.0 (calculated for CHFNO. 339.07). 0.178 B. 2-4-(2,4-Dioxo-thiazolidin-5-ylidenem ethyl)-2-methoxy-phenoxy-5-trifluoromethyl-benza 0183 A. 2-Fluoro-5-trifluoromethylbenzoic acid mide was prepared using 2-(4-Formyl-2-methoxy-phe methyl ester. To a solution of 2-fluoro-5-(trifluorom noxy)-5-trifluoromethyl-benzamide following General ethyl)benzoic acid (500 mg, 2.404 mmol) in MeOH (2.5 Procedure C. "H NMR (400 MHz, CDC1) & 8.48 (d. mL) was added sulfuric acid (0.2 mL). The mixture was 1H), 8.36 (brs, NH), 7.78 (s, 1H), 7.54 (dd. 1H), 7.46 (br irradiated in a microwave at 150° C. for 2 minutes and s, NH), 7.18-7.08 (m, 3H), 6.74 (d. 1H), 5.97 (brs, NH), the reaction was allowed to cool to room temperature. 3.81 (s.3H); LC/MS (m/z)M+41+1" 479.9 (calculated The reaction was partitioned between ethyl ether (5 mL) for CHFNOS, 438.05). and water (5 mL). Then, the organic layer was washed with saturated sodium bicarbonate (5 mL) and brine (5 Example 8 mL). The combined organic layers were dried (NaSO), 2-4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2- filtered and concentrated to provide the title compound methoxy-phenoxy-5-trifluoromethyl-benzonitrile as a white liquid. "H NMR (300 MHz, CDC1) & 8.25 (dd. 1H), 7.82-7.78 (m, 1H), 7.28 (t, 1H), 3.97 (s, 3H): 0179 LC/MS (m/z) M+1" molec ion not found (calculated for CHFO, 222.03). 0.184 B. 2-(4-Formyl-2-methoxy-phenoxy)-5-trifluo OCH CN romethyl-benzoic acid methyl ester was prepared from vanillin and 2-Fluoro-5-trifluoromethylbenzoic acid methyl ester following General Procedure A. H NMR (400 MHz, CDC1) 89.94 (s, 1H), 8.24 (d. 1H), 7.69 (dd. CF 1H), 7.55 (d. 1H), 7.44 (dd. 1H), 7.01-6.95 (m, 2H), 3.91 (s, 3H), 3.86 (s, 3H); LC/MS (m/z) M+1" 354.9 (cal culated for CHFOs, 354.07). 0185. C. 2-4-(2,4-Dioxo-thiazolidin-5-ylidenem 0180 A. 2-(4-Formyl-2-methoxy-phenoxy)-5-trifluo ethyl)-2-methoxy-phenoxy-5-trifluoromethyl-benzoic romethyl-benzonitrile was prepared from vanillin and acid methyl ester was prepared using 2-(4-Formyl-2- 2-Fluoro-5-trifluoromethylbenzonitrile following Gen methoxy-phenoxy)-5-trifluoromethyl-benzoic acid eral Procedure A. H NMR (400 MHz, CDC1) & 10.0 (s, methyl ester following General Procedure B. "H NMR 1H), 7.94 (d. 1H), 7.67 (dd. 1H), 7.58-7.54 (m, 2H), 7.32 (300 MHz, CDC1) & 8.24 (d. 1H), 7.81 (s, 1H), 7.67 (dd, (d. 1H), 6.76 (d. 1H), 3.85 (s.3H); LC/MS (m/z)M+1" 1H), 7.12-7.09 (m, 2H), 7.01 (dd. 1H), 6.92 (d. 1H), 3.90 molec ion not found (calculated for CHFNO. 321. (s, 3H), 3.89 (s.3H); LC/MS (m/z) M+1453.9 (cal 06). culated for CHFNOS, 453.05).

US 2011/0237625 A1 Sep. 29, 2011 24

1H), 7.22 (dd. 1H), 6.84 (d. 1H), 3.80 (s.3H); LC/MS 1H), 7.24 (dd. 1H), 6.79 (d. 1H), 3.80 (s, 3H); LC/MS (m/z) M+1: 474.9 (calculated for CH BrFNOS, (m/z) M+1": 431.8 (calculated for CH BrNOS, 474.25). 431.26). Example 21 Example 23 4-4-(2,4-Dioxo-oxazolidin-5-ylidenemethyl)-2- 3-Chloro-4-4-(2,4-dioxothiazolidin-5-ylidenem methoxy-phenoxy-naphthalene-1-carbonitrile ethyl)-2-methoxyphenoxybenzonitrile 0226 0220

OCH C O OCH O O O O S HN HN N CN N CN O O 0227. To a mixture of oxazolidine-2,4-dione (50.5 mg, 0221 A. 4-(2-Chloro-4-cyanophenoxy)-3-methoxy 0.50 mmol), LiCl (128 mg, 3.0 mmol) and anhydrous THF benzaldehyde was prepared from vanillin and 3-Chloro (5.0 mL) cooled to -78°C. was added dropwise 1.7 M tert 4-fluorobenzonitrile following General Procedure A. "H butyllithium solution in pentane (0.616 mL, 1.05 mmol). NMR (400 Hz, CDC1) & 9.95 (s, 1H), 7.76 (d. 1H), 7.56 After stirring at -78°C. for 20 minutes, the reaction mixture (brs, 1H), 7.50 (d. 1H), 7.45 (brid, 1H), 7.15 (d. 1H), was warmed to 0°C. for 5 minutes. The mixture was recooled 6.78 (d. 1H), 3.90 (s, 3H). to -78° C. and a solution of 4-(4-formyl-2-methoxy-phe 0222 B. 3-Chloro-4-4-(2,4-dioxothiazolidin-5- noxy)-naphthalene-1-carbonitrile (Example 19a) was added ylidenemethyl)-2-methoxyphenoxy-benzonitrile was dropwise. After stirring at -78°C. for 15 minutes, 1 NHCl prepared using 4-(2-Chloro-4-cyanophenoxy)-3-meth (1.05 mL, 1.05 mol) was added dropwise. The reaction mix oxybenzaldehyde following General Procedure C. "H ture was allowed to warm up to room temperature. After NMR (300 Hz, DMSO-d) & 12.62 (brs, 1H), 8.17 (d. evaporation of most of the solvent, p-toluenesulfonic acid H), 7.83 (s, 1H), 7.71 (dd. 1H), 7.48 (d. 1H), 7.32 (d. monohydrate (85 mg 0.5 mmol) and toluene (25 mL) were 1H), 7.24 (dd. 1H), 6.83 (d. 1H), 3.79 (s.3H); LC/MS added. The mixture was heated to reflux with a Dean-Stark (m/z) M+1": 385.9 (calculated for CHCINOS, trap for 5 hours. After removal of solvent, the residue was 386.81). taken up with a mixture of DMF and methanol and purified on a preparative HPLC Waters XTerra(R. Prep MS O, OBDTM Example 22 Column (5um, 30x50mm) using a gradient mixture of 0.1% aqueous TFA and acetonitrile). H NMR (400 Hz, DMSO-d) 3-Bromo-4-4-(2,4-dioxothiazolidin-5-ylidenem & 12.45 (s, 1H), 8.43 (d. 1H), 8.16 (s, 1H), 8.11 (d. 1H), 8.00 ethyl)-2-methoxyphenoxybenzonitrile (d. 1H), 7.88 (t, 1H), 7.77 (t, 1H), 7.65 (d. 1H), 7.32 (d. 1H), 7.09 (s.1H), 6.63 (d. 1H), 3.73 (s.3H); LC/MS (m/z) M+1)* 0223 386.9 (calculated for CHNO 386.1). Example 24 OCH Br O 4-4-(2,4-Dioxo-oxazolidin-5-ylidenemethyl)-2- O S methoxy-phenoxy-naphthalene-1-carboxylic acid HN methyl ester S CN 0228 O

OCH 0224 A. 4-(2-Bromo-4-cyanophenoxy)-3-methoxy O benzaldehyde was prepared from vanillin and 3-Bromo 4-fluorobenzonitrile following General Procedure A. "H S su NMR (400 Hz, CDC1) & 9.95 (s, 1H), 7.93 (d. 1H), 7.56 HN (br. S, 1H) 7.54-7.44 (m, 2H), 7.16 (d. 1H), 6.73 (d. 1H), N OCH 3.85 (s.3H). 0225 B. 3-Bromo-4-4-(2,4-dioxothiazolidin-5- ylidenemethyl)-2-methoxyphenoxy-benzonitrile was prepared using 4-(2-Bromo-4-cyanophenoxy)-3-meth 0229. A. 4-Fluoro-naphthalene-1-carboxylic acid oxybenzaldehyde following General Procedure C. "H methyl ester. A mixture of 4-fluoro-naphthalene-1-car NMR (300 Hz, DMSO-d) 812.62 (brs, 1H), 8.28 (d. boxylic acid (475 mg, 0.25 mmol), methanol (3.5 mL) H), 7.83 (s, 1H), 7.74 (dd. 1H), 7.47 (d. 1H), 7.30 (d. and concentrated Sulfuric acid (1 drop) was heated at US 2011/0237625 A1 Sep. 29, 2011

160° C. for 30 minina Biotage Initiator microwave. The trated and purified by preparative TLC with hexanes/ mixture was poured onto 2 MSodium carbonate Solution ethyl acetate (4:1). A white solid was obtained (420 mg). (50 mL) and extracted with ethyl acetate (30 mL). The H NMR (400 Hz, acetone-d) & 9.08 (d. 1H), 8.59 (t, organic layer was washed with 2 M Sodium carbonate 1H), 8.24 (d. 1H), 7.83-7.74 (m, 2H), 7.54-7.33 (m, 6H). solution (15 mL), water (20 mL) and brine (20 mL). The 0234 B. 4-(4-Formyl-2-methoxy-phenoxy)-naphtha organic layer was dried over anhydrous sodium Sulfate. lene-1-carboxylic acid phenyl ester was prepared from Evaporation of solvent provided a brown solid (480 mg). vanillin and 4-Fluoro-naphthalene-1-carboxylic acid "H NMR (400 Hz, CDC1) 89.01 (d. 1H), 8.22 (dd. 1H), phenyl ester following General Procedure A. H NMR 8.17 (d. 1H), 7.68 (t, 1H), 7.60 (t, 1H), 7.16 (dd. 1H), (400 Hz, CDC1) & 9.96 (s, 1H), 9.18 (d. 1H), 8.44 (d. 3.99 (s.3H); LC/MS (m/z) M+1204.9 (calculated for 1H), 8.43 (d. 1H), 7.71 (t, 1H), 7.64-7.60 (m, 2H), 7.50 CHFO, 204.1). 7.44 (m, 3H), 7.31-7.26 (m, 3H), 7.16 (d. 1H), 6.80 (d. 0230 B. 4-(4-Formyl-2-methoxy-phenoxy)-naphtha 1H), 3.90 (s, 3H); LC/MS (m/z) M+1" 398.8 (calcu lene-1-carboxylic acid methyl ester was prepared from lated for C.H.O.,398.1). vanillin and 4-Fluoro-naphthalene-1-carboxylic acid 0235 C. 4-(4-Formyl-2-methoxy-phenoxy)-naphtha methyl ester following General Procedure A. H NMR lene-1-carboxylic acid amide. To a 5-mL microwave (400 Hz, acetone-d) & 10.04 (s, 1H), 9.07 (d. 1H), 8.42 tube was added 4-(4-Formyl-2-methoxy-phenoxy)- (d. 1H), 8.17 (d. 1H), 7.75-7.65 (m, 4H), 7.38 (d. 1H), naphthalene-1-carboxylic acid phenyl ester (154 mg) 6.77 (d. 1H), 3.94 (s, 3H), 3.90 (s, 3H); LC/MS (m/z) and anhydrous methanol (2 mL). To the mixture, cooled M+1' 337.0 (calculated for CHOs, 336.1). to -78°C., was bubbled in anhydrous ammonia (ca. 0.5 0231 C. 4-4-(2,4-Dioxo-oxazolidin-5-ylidenem mL). The tube was sealed and stirred at room tempera ethyl)-2-methoxy-phenoxy-naphthalene-1-carboxylic ture overnight. After evaporation of ammonia, dichlo acid methyl ester. A mixture of 4-(4-Formyl-2-methoxy romethane was added to form a clear solution. The solu phenoxy)-naphthalene-1-carboxylic acid methyl ester tion was loaded onto a preparative TLC plate and (33.6 mg, 0.10 mmol), thiazolidine-2,4-dione (14.3 mg, developed with hexanes/ethyl acetate (4:1). A yellowish 0.11 mmol), Sodium acetate (24.6 mg, 0.30 mmol), pip solid was obtained (120 mg). LC/MS (m/z) M+1 eridine (1 drop) and ethanol (2 mL)/acetonitrile (4 mL) 322.1 (calculated for CHNO. 322.1). was heated at reflux overnight. The solvent was evapo 0236 D. 4-4-(2,4-Dioxo-oxazolidin-5-ylidenem rated to ~2 mL. Volume. After cooling to room tempera ethyl)-2-methoxy-phenoxy-naphthalene-1-carboxylic ture, the precipitate was collected by filtration and acid amide. A mixture of 4-(4-Formyl-2-methoxy-phe washed with acetonitrile and water. "H NMR (400 Hz, noxy)-naphthalene-1-carboxylic acid amide (117 mg, DMSO-d) & 8.91 (d. 1H), 8.40 (d. 1H), 8.08 (d. 1H), 0.36 mmol), thiazolidine-2,4-dione (47.5 mg, 0.36 7.73 (t, 1H), 7.65 (t, 1H), 7.4 (d. 1H), 7.35 (s, 1H), 7.28 mmol), Sodium acetate (164 mg, 2.0 mmol) and ethanol (d. 1H), 7.21 (d. 1H), 6.60 (d. 1H), 3.87 (s.3H), 3.73 (s, (3 mL) was heated at reflux overnight. To the mixture 3H); LC/MS (m/z) M+1" 436.3 (calculated for was added acetic acid, followed by addition of 3 drops of CHNOS, 436.1). water, to form a clear solution. This solution was loaded onto a preparative HPLC Waters XTerra(R) Prep MS Os Example 25 OBDTM Column (5 um, 30x50 mm) and eluted with a gradient mixture of 0.1% aqueous TFA and acetonitrile. 4-4-(2,4-Dioxo-oxazolidin-5-ylidenemethyl)-2- After triturating with methanol and drying, the pure methoxy-phenoxy-naphthalene-1-carboxylic acid product was obtained. "H NMR (400 Hz, DMSO-d6) & amide 12.64 (s, 1H), 8.41 (d. 1H), 8.21 (d. 1H), 7.93 (s, 1H), 0232 7.83 (s, 1H), 7.65-7.57 (m, 2H), 7.55 (d. 1H), 7.50 (s, 1H), 7.48 (s, 1H), 7.21 (d. 1H), 7.16 (d. 1H), 6.68 (d. 1H), 3.81 (s, 3H); LC/MS (m/z) M+1" 421.0 (calcu lated for CH7NO.S. 421.1). O OCH O 0237 Examples 26-31 were prepared as described by Example 1 using the appropriate benzaldehyde and aryl fluo X- S O ride. HN N NH2 Example 26 O O 4-4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2- trifluoromethyl-phenoxy-3-trifluoromethyl-benzoni 0233 A. 4-Fluoro-naphthalene-1-carboxylic acid phe- trile nyl ester. To a solution of 4-fluoronaphthoic acid (380 0238 mg, 2.0 mmol) and oxalyl chloride (0.7 mL, 8.0 mmol) in anhydrous dichloromethane (10 mL) was added DMF (1 drop). The mixture was stirred until bubbling stopped. CF CF A clear solution was obtained. After evaporation of sol- O vent, the residue was dissolved in anhydrous dichlo- X- O romethane. Solvent was again evaporated. A white Solid HN was obtained. To it was added anhydrous dichlo- N romethane (10 mL), phenol (200 mg, 2.1 mmol) and CN triethylamine (0.1 mL). The mixture was stirred at room O temperature over the weekend. The mixture was concen US 2011/0237625 A1 Sep. 29, 2011 26

0239 H NMR (400 Hz, CDC1) & 8.28 (bs, 1H), 8.05 (d. 0245 H NMR (400 Hz, CDC1) & 8.03 (d. 1H), 7.82 (s, 1H), 7.89 (d. 1H), 7.82 (m, 2H), 7.70 (dd. 1H), 7.12 (d. 1H), 1H), 7.78 (dd. 1H), 7.56 (s, 1H), 7.51 (dd. 1H), 7.25 (d. 1H), 7.00 (d. 1H); (calculated for C.H.F.N.O.S, 458.33). 6.92 (d. 1H); (calculated for CHFNOS, 474.33). Example 27 Example 30 4-4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2- 5-4-(4-Chloro-2-trifluoromethyl-phenoxy)-3-meth ethoxy-phenoxy-3-trifluoromethyl-benzamide oxy-benzylidene-thiazolidine-2,4-dione 0240 0246

O OCH3 CF 3 O 1N CF O S S HN HN N C N NH2 juco, O O O 0247 'H NMR (400 Hz, DMSO) 87.85 (d. 2H), 7.66 (dd, 0241 H NMR (400 Hz, DMSO) 88.26 (d. 1H), 8.14 (bs, 1H), 7.50 (s, 1H), 7.24 (d. 2H), 6.85 (d. 1H), 3.81 (s, 3H): 1H), 8.06 (dd. 1H), 7.84 (s, 1H), 7.48 (bs, 1H), 7.44 (d. 1H), LC/MS (m/z) M+1" 430.9 (calculated for 7.34 (d. 1H), 7.26 (dd. 1H), 6.87 (d. 1H), 4.05 (qt, 2H), 1.10 CHCIFNOS, 429.80). (t, 3H); LC/MS (m/z) M+1" 453.0 (calculated for Example 31 CHFNOS, 452.40). 5-4-(4-Chloro-2-trifluoromethyl-phenoxy)-3-fluoro Example 28 benzylidenethiazolidine-2,4-dione 4-4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2- 0248 methyl-phenoxy-3-trifluoromethyl-benzamide 0242 O F CF O S O CF3 HN O N C S HN O N NH2

O 0249 H NMR (400 Hz, DMSO) 87.93 (d. 1H), 7.81 (s, O 1H), 7.74 (m, 2H), 7.47 (dd. 1H), 7.37 (t, 1H), 7.20 (d. 1H): LC/MS (m/z)|M+1" 418.9 (calculated for CHCIFNOS, 0243 H NMR (400 Hz, DMSO) 88.30 (d. 1H), 8.18 (bs, 417.76). 1H), 8.12 (dd. 1H), 7.77 (s, 1H), 7.63 (d. 1H), 7.52 (m, 2H), D) GENERAL ADMINISTRATION, 7.15 (d. 1H), 6.98 (d. 1H), 2.22 (s.3H); LC/MS (m/z)M+1" FORMULATION, AND DOSAGES 423.0 (calculated for CHFNOS, 422.38). 0250. The present compounds are ERR-C. inverse agonists Example 29 and are therefore useful in treating, slowing, or inhibiting the progression of ERR-C. mediated conditions such as ankylos 4-4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2- ing spondylitis, artherosclerosis, arthritis (such as rheuma trifluoromethoxy-phenoxy-3-trifluoromethyl-ben toid arthritis, infectious arthritis, childhood arthritis, psoriatic Zonitrile arthritis, reactive arthritis), bone-related diseases (including those related to bone formation), breast cancer (including 0244 those unresponsive to anti-estrogen therapy), cardiovascular disorders, cartilage-related disease (such as cartilage injury/ loss, cartilage degeneration, and those related to cartilage O OCF CF3 formation), chondrodysplasia, chondrosarcoma, chronic back injury, chronic bronchitis, chronic inflammatory airway S disease, chronic obstructive pulmonary disease, diabetes, dis HN orders of energy homeostasis, gout, pseudogout, lipid disor X- S o CN ders, metabolic syndrome, multiple myeloma, obesity, O osteoarthritis, osteogenesis imperfecta, osteolytic bone metastasis, osteomalacia, osteoporosis, Paget's disease, peri odontal disease, polymyalgia rheumatica, Reiter's syndrome, US 2011/0237625 A1 Sep. 29, 2011 27 repetitive stress injury, hyperglycemia, elevated blood glu the patient may be taking, as is well known to those skilled in cose level, and insulin resistance and other disorders, dis the art. Furthermore, it is evident that said effective daily eases, or conditions related thereto. amount may be lowered or increased depending on the 0251. The invention features a method for treating a sub response of the treated patient and/or depending on the evalu ject with an ERR-C. mediated disease, said method compris ation of the physician prescribing the compounds of the ing administering to the Subject a therapeutically effective instant invention. The effective daily amount ranges men amount of a pharmaceutical composition comprising a com tioned herein are therefore only guidelines in practicing the pound of the invention. In particular, the invention also pro present invention. vides a method for treating or inhibiting the progression of (0257 Preferably, the method for the treatment of the breast cancer, arthritis, inflammatory airway disease, or meta ERR-C. disorders described in the present invention using any bolic disorders, and associated symptoms or complications of the compounds as defined herein, the dosage form will thereof in a subject, wherein the method comprises adminis contain a pharmaceutically acceptable carrier containing tering to the Subject a therapeutically effective amount of a between from about 0.1 mg to about 5000 mg; particularly pharmaceutical composition comprising a compound of the from about 0.5 mg to about 1000 mg; and, more particularly, invention. from about 1 mg to about 100 mg of the compound, and may 0252. The present invention includes within its scope pro be constituted into any form suitable for the mode of admin drugs of the compounds of this invention. In general. Such istration selected. The dosages, however, may be varied prodrugs will be functional derivatives of the compounds depending upon the requirement of the Subjects, the severity which are readily convertible in vivo into the required com of the condition being treated and the compound being pound. Thus, in the methods of treatment of the present inven employed. The use of either daily administration or post tion, the term "administering shall encompass the treatment periodic dosing may be employed. of the various disorders described with the compound spe 0258. The pharmaceutical compositions herein will con cifically disclosed or with a compound which may not be tain, per unit dosage unit, e.g., tablet, capsule, powder, injec specifically disclosed, but which converts to the specified tion, Suppository, teaspoonful and the like, of from about compound in vivo after administration to the Subject. Con 0.001 mg/kg/day to about 10 mg/kg/day (particularly from ventional procedures for the selection and preparation of about 0.01 mg/kg/day to about 1 mg/kg/day; and, more par Suitable prodrug derivatives are described, for example, in ticularly, from about 0.1 mg/kg/day to about 0.5 mg/kg/day) “Design of Prodrugs’, ed. H. Bundgaard, Elsevier, 1985. and may be given at a dosage of from about 0.001 mg/kg/day 0253) Some of the crystalline forms for the compounds to about 30 mg/kg/day (particularly from about 0.01 mg/kg/ may exist as polymorphs and as such are intended to be day to about 2 mg/kg/day, more particularly from about 0.1 included in the present invention. In addition, some of the mg/kg/day to about 1 mg/kg/day and even more particularly compounds may form Solvates with water (i.e., hydrates) or from about 0.5 mg/kg/day to about 1 mg/kg/day). common organic solvents, and Such Solvates are intended to 0259 Preferably these compositions are in unit dosage be encompassed within the scope of this invention. forms from Such as tablets, pills, capsules, dry powders for 0254. Where the processes for the preparation of the com reconstitution or inhalation, granules, lozenges, sterile pounds according to the invention give rise to mixtures of parenteral Solutions or Suspensions, metered aerosol or liquid Stereoisomers, these isomers may be separated by conven sprays, drops, ampoules, autoinjector devices or Supposito tional techniques such as preparative chromatography. The ries for administration by oral, intranasal, Sublingual, compounds may be prepared in racemic form or as individual intraocular, transdermal, parenteral, rectal, vaginal, dry pow enantiomers or diasteromers by either Stereospecific synthe der inhaler or other inhalation or insufflation means. Alterna sis or by resolution. The compounds may, for example, be tively, the composition may be presented in a form Suitable resolved into their component enantiomers or diastereomers by standard techniques, such as the formation of stereoiso for once-weekly or once-monthly administration; for meric pairs by salt formation with an optically active base, example, an insoluble salt of the active compound, Such as the followed by fractional crystallization and regeneration of the decanoate salt, may be adapted to provide a depot preparation free acid. The compounds may also be resolved by formation for intramuscular injection. of stereoisomeric esters or amides, followed by chromato 0260 For preparing solid pharmaceutical compositions graphic separation and removal of the chiral auxiliary. Alter Such as tablets, the principal active ingredient is mixed with a natively, the compounds may be resolved using a chiral pharmaceutical carrier, e.g. conventional tableting ingredi HPLC column. It is to be understood that all stereoisomers, ents such as diluents, binders, adhesives, disintegrants, lubri racemic mixtures, diastereomers, cis-trans isomers, and cants, antiadherents and gildants. Suitable diluents include, enantiomers thereofare encompassed within the scope of the but are not limited to, starch (i.e. corn, wheat, or potato starch, present invention. which may be hydrolized), lactose (granulated, spray dried or anhydrous), Sucrose, Sucrose-based diluents (confectioner's Sugar, Sucrose plus about 7 to 10 weight percent invert Sugar, E) USE Sucrose plus about 3 weight percent modified dextrins; 0255 1. Dosages Sucrose plus invert Sugar, about 4 weight percent invert Sugar, 0256 Those of skill in the treatment of disorders, diseases, about 0.1 to 0.2 weight percent cornstarch and magnesium or conditions mediated by ERR-O. can determine the effective Stearate), dextrose, inositol, mannitol, Sorbitol, microcrystal daily amount from the test results presented hereinafter and line cellulose (i.e. AVICELTM microcrystalline cellulose other information. The exact dosage and frequency of admin available from FMC Corp.), dicalcium phosphate, calcium istration depends on the particular compound of invention sulfate dihydrate, calcium lactate trihydrate and the like. Suit used, the particular condition being treated, the severity of the able binders and adhesives include, but are not limited to condition being treated, the age, weight and general physical acacia gum, guar gum, tragacanth gum, Sucrose, gelatin, glu condition of the particular patient as well as other medication cose, starch, and cellulosics (i.e. methylcellulose, sodium US 2011/0237625 A1 Sep. 29, 2011 28 carboxymethylcellulose, ethylcellulose, hydroxypropylm by film coating or wet granulation using slightly soluble or ethylcellulose, hydroxypropylcellulose, and the like), water insoluble Substances in Solution (which for a wet granulation soluble or dispersible binders (i.e. alginic acid and salts acts as the binding agents) or low melting Solids a molten thereof, magnesium aluminum silicate, hydroxyethylcellu form (which in a wet granulation may incorporate the active lose i.e. TYLOSETM available from Hoechst Celanese, ingredient). These materials include natural and synthetic polyethylene glycol, polysaccharide acids, bentonites, poly polymers waxes, hydrogenated oils, fatty acids and alcohols vinylpyrrolidone, polymethacrylates and pregelatinized (i.e. beeswax, carnauba wax, cetyl alcohol, cetylstearyl alco starch) and the like. Suitable disintegrants include, but are not hol, and the like), esters of fatty acids metallic Soaps, and limited to, starches (corn, potato, etc.), sodium starch glyco other acceptable materials that can be used to granulate, coat, lates, pregelatinized starches, clays (magnesium aluminum entrap or otherwise limit the solubility of an active ingredient silicate), celluloses (such as crosslinked sodium carboxym to achieve a prolonged or Sustained release product. ethylcellulose and microcrystalline cellulose), alginates, 0262 The liquid forms in which the novel compositions of pregelatinized starches (i.e. corn starch, etc.), gums (i.e. agar, guar, locust bean, karaya, pectin, and tragacanth gum), cross the present invention may be incorporated for administration linked polyvinylpyrrolidone and the like. Suitable lubricants orally or by injection include, but are not limited to aqueous and antiadherents include, but are not limited to, Stearates Solutions, Suitably flavored syrups, aqueous or oil Suspen (magnesium, calcium and Sodium), Stearic acid, talc waxes, sions, and flavored emulsions with edible oils such as cotton Stearowet, boric acid, Sodium chloride, DL-leucine, carbo seed oil, Sesame oil, coconut oil or peanut oil, as well as elixirs wax 4000, carbowax 6000, sodium oleate, sodium benzoate, and similar pharmaceutical vehicles. Suitable Suspending Sodium acetate, Sodium lauryl Sulfate, magnesium lauryl Sul agents for aqueous Suspensions, include synthetic and natural fate and the like. Suitable gildants include, but are not limited gums such as, acacia, agar, alginate (i.e. propylene alginate, to, talc, cornstarch, silica (i.e. CAB-O-SILTM silica available Sodium alginate and the like), guar, karaya, locust bean, pec from Cabot, SYLOIDTM silica available from W.R. Grace/ tin, tragacanth, and Xanthan gum, cellulosics such as sodium Davison, and AEROSILTM silica available from Degussa) and carboxymethylcellulose, methylcellulose, hydroxymethyl the like. Sweeteners and flavorants may be added to chewable cellulose, hydroxyethylcellulose, hydroxypropyl cellulose solid dosage forms to improve the palatability of the oral and hydroxypropyl methylcellulose, and combinations dosage form. Additionally, colorants and coatings may be thereof, synthetic polymers such as polyvinyl pyrrolidone, added or applied to the solid dosage form for ease of identi carbomer (i.e. carboxypolymethylene), and polyethylene fication of the drug or for aesthetic purposes. These carriers glycol; clays such as bentonite, hectorite, attapulgite or sepio are formulated with the pharmaceutical active to provide an lite; and other pharmaceutically acceptable Suspending accurate, appropriate dose of the pharmaceutical active with agents such as lecithin, gelatin or the like. Suitable Surfactants a therapeutic release profile. include but are not limited to Sodium docusate, sodium lauryl 0261 Generally these carriers are mixed with the pharma Sulfate, polysorbate, octoxynol-9, nonoxynol-10, polysor ceutical active to form a solid preformulation composition bate 20, polysorbate 40, polysorbate 60, polysorbate 80, poly containing a homogeneous mixture of the pharmaceutical oxamer 188, polyoxamer 235 and combinations thereof. Suit active form of the present invention, or a pharmaceutically able deflocculating or dispersing agent include acceptable salt thereof. Generally the preformulation will be pharmaceutical grade lecithins. Suitable flocculating agent formed by one of three common methods: (a) wet granula include but are not limited to simple neutral electrolytes (i.e. tion, (b) dry granulation and (c) dry blending. When referring Sodium chloride, potassium, chloride, and the like), highly to these preformulation compositions as homogeneous, it is charged insoluble polymers and polyelectrolyte species, meant that the active ingredient is dispersed evenly through water soluble divalent or trivalent ions (i.e. calcium salts, out the composition so that the composition may be readily alums or Sulfates, citrates and phosphates (which can be used Subdivided into equally effective dosage forms such as tab jointly informulations as pH buffers and flocculating agents). lets, pills and capsules. This solid preformulation composi Suitable preservatives include but are not limited to parabens tion is then subdivided into unit dosage forms of the type (i.e. methyl, ethyl, n-propyl and n-butyl), Sorbic acid, thime described above containing from about 0.1 mg to about 500 rosal, quaternary ammonium salts, benzyl alcohol, benzoic mg of the active ingredient of the present invention. The acid, chlorhexidine gluconate, phenylethanol and the like. tablets or pills containing the novel compositions may also be There are many liquid vehicles that may be used in liquid formulated in multilayer tablets or pills to provide a sustained pharmaceutical dosage forms, however, the liquid vehicle or provide dual-release products. For example, a dual release that is used in a particular dosage form must be compatible tablet or pill can comprise an inner dosage and an outer with the Suspending agent(s). For example, nonpolar liquid dosage component, the latter being in the form of an envelope vehicles such as fatty esters and oils liquid vehicles are best over the former. The two components can be separated by an used with Suspending agents such as low HLB (Hydrophile enteric layer, which serves to resist disintegration in the stom Lipophile Balance) Surfactants, Stearalkonium hectorite, ach and permits the inner component to pass intact into the water insoluble resins, water insoluble film forming polymers duodenum or to be delayed in release. A variety of materials and the like. Conversely, polar liquids such as water, alcohols, can be used for Such enteric layers or coatings, such materials polyols and glycols are best used with Suspending agents such including a number of polymeric materials such as shellac, as higher HLB Surfactants, clays silicates, gums, water cellulose acetate (i.e. cellulose acetate phthalate, cellulose soluble cellulosics, water soluble polymers and the like. For acetate trimetlitate), polyvinyl acetate phthalate, hydrox parenteral administration, sterile Suspensions and solutions ypropyl methylcellulose phthalate, hydroxypropyl methyl are desired. Liquid forms useful for parenteral administration cellulose acetate Succinate, methacrylate and ethylacrylate include sterile solutions, emulsions and Suspensions. Isotonic copolymers, methacrylate and methyl methacrylate copoly preparations which generally contain Suitable preservatives mers and the like. Sustained release tablets may also be made are employed when intravenous administration is desired. US 2011/0237625 A1 Sep. 29, 2011 29

0263. Furthermore, compounds of the present invention positions have been described in numerous publications such can be administered in an intranasal dosage form via topical as Pharmaceutical Dosage Forms. Tablets, Second Edition, use of Suitable intranasal vehicles or via transdermal skin Revised and Expanded. Volumes 1-3, edited by Lieberman et patches, the composition of which are well known to those of al; Pharmaceutical Dosage Forms. Parenteral Medications, ordinary skill in that art. To be administered in the form of a Volumes 1-2, edited by Avis et al; and Pharmaceutical Dos transdermal delivery system, the administration of a thera age Forms. Disperse Systems, Volumes 1-2, edited by Lieber peutic dose will, of course, be continuous rather than inter man et al; published by Marcel Dekker, Inc. mittent throughout the dosage regimen. (0271 3. Combination Therapy 0264 Compounds of the present invention can also be 0272. The compounds of the present invention may be administered in the form of liposome delivery systems, such used in combination with one or more pharmaceutically as Small unilamellar vesicles, large unilamellar vesicles, mul active agents. These agents include ERR-O. antagonists, glu tilamellar vesicles and the like. Liposomes can be formed cokinase modulators, anti-diabetic agents, other lipid lower from a variety of phospholipids, such as cholesterol, Steary ing agents, direct thrombin inhibitor (DTI), as well as lipid lamine, phosphatidylcholines and the like. lowering agents such as statin drugs and the fibrates. 0265. The daily dose of a pharmaceutical composition of 0273 ERR-C. antagonists include, for example, all the the present invention may be varied over a wide range from compounds disclosed in US-2006-0014812-A1, particularly about 0.1 mg to about 5000 mg; preferably, the dose will be in those of the formula the range of from about 1 mg to about 100 mg per day for an average human. For oral administration, the compositions are preferably provided in the form of tablets containing, 0.01, R3 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, X Z 200, 250 or 500 milligrams of the active ingredient for the N-1 R5 symptomatic adjustment of the dosage to the Subject to be treated. Advantageously, a compound of the present invention may be administered in a single daily dose or the total daily R4 4n. dosage may be administered in divided doses of two, three or four times daily. wherein: 0266. It is also apparent to one skilled in the art that the 0274 n is 0 or 1: therapeutically effective dose for active compounds of the 0275 Z is - O -, - S - >NH, or >NR where R is invention or a pharmaceutical composition thereof will vary alkyl, cycloalkyl, phenyl, or heterocycloalkyl; according to the desired effect. Therefore, optimal dosages to 0276 X is an aryl or heteroaryl group; be administered may be readily determined by those skilled in (0277 R is -H or -O-alkyl unsubstituted or substi the art, and will vary with the particular compound used, the tuted with one or more substituents independently mode of administration, the strength of the preparation, and Selected from the group consisting of —OH, halo, the advancement of the disease condition. In addition, factors - CN, O-alkyl, and N(R")R’ where R" and R are associated with the particular subject being treated, including each independently —H or alkyl, Subject age, weight, diet and time of administration, will (0278) R' is selected from the group consisting of H, result in the need to adjust the dose to an appropriate thera halo. —O-alkyl, —CN, NO, and —COOH; and peutic level. The above dosages are thus exemplary of the (0279 R and R are each independently –CN: average case. There can, of course, be individual instances —COOH, or a moiety selected from the group consist where higher or lower dosage ranges are merited, and Such are ing of COO-alkyl, —(C=O)alkyl, —(S—(O))-aryl within the scope of this invention. where m is 0, 1, or 2, cycloalkyl, heterocycloalkyl, 0267 Compounds of this invention may be administered —(C=O)phenyl, heteroaryl, and —(C=O)heterocy in any of the foregoing compositions and dosage regimens or cloalkyl: or Rand R taken together with the carbon to by means of those compositions and dosage regimens estab which they are attached form an optionally benzofused lished in the art whenever use of the compounds of the inven heterocycloalkyl or cycloalkyl moiety; tion as ERR-C. inverse agonists is required for a Subject in 0280 wherein each such moiety is unsubstituted or sub need thereof. stituted with one or more substituents independently 0268 2. Formulations selected from the group consisting of —OH:=O;=S: 0269. To prepare the pharmaceutical compositions of this alkyl optionally substituted with —OH, -O-alkyl, phe invention, one or more compounds of Formula (I) or salt nyl, -NH2, —NH(alkyl). —N(alkyl), halo. —CF, thereofas the active ingredient, is intimately admixed with a —COON, or —COO-alkyl; —O-alkyl; phenyl: —O- pharmaceutical carrier according to conventional pharma phenyl; benzyl; —O-benzyl, cycloalkyl; —O-cy ceutical compounding techniques, which carrier may take a cloalkyl:—CN:- NO; N(R)R where RandR are wide variety of forms depending of the form of preparation each independently —H, alkyl, or—(C=O)alkyl, or R' desired for administration (e.g. oral or parenteral). Suitable and R taken together with the nitrogen to which they are pharmaceutically acceptable carriers are well known in the attached form a heterocycloalkyl wherein one carbon art. Descriptions of some of these pharmaceutically accept ring atom is optionally replaced with >O, >NH or able carriers may be found in The Handbook of Pharmaceu >N-alkyl and where one carbon ring atom is optionally tical Excipients, published by the American Pharmaceutical substituted with -OH or =O; —(C=O)N(R)R: Association and the Pharmaceutical Society of Great Britain. -(N-R)SO-alkyl where R is - Horalkyl:—(C=O) 0270. The compounds of the present invention may be alkyl; —(S—(O))alkyl where n is 0, 1 or 2: —SON formulated into various pharmaceutical forms for administra (R)R where R” and R are as defined above:-SCF; tion purposes. Methods of formulating pharmaceutical com halo. —CF; —OCF; —COOK and —COOalkyl: US 2011/0237625 A1 Sep. 29, 2011 30 or a pharmaceutically acceptable salt, pharmaceutically 0293 9. Paroxetine (GEOMATRIX drug delivery sys acceptable prodrug, or pharmaceutically active metabolite of tem) (piperidine.3-((1,3-benzodioxol-5-yloxy)methyl)- Such compound. 4-(4-fluorophenyl)(3S-trans)-, also known as paroxet 0281 Anti-obesity agents can be classified into several ine, GEOMATRIX, PAXIL CR): categories based upon the mechanism of action. These agents 0294 10. Escitalopram (1S)-1-(3-(dimethylamino) include selective serotonin reuptake inhibitors (SSRIs), sero propyl)-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofu tonin agonists, serotonin and norepinephrine reuptake inhibi ran carbonitrile, or 5-Isobenzofurancarbonitrile, 1-(3- tors, pancreatic lipase inhibitors, 33-adrenoreceptoragonists, (dimethylamino)propyl)-1-(4-fluorophenyl)-1,3- NPY antagonists, melanocortin receptor agonists, leptin-tar dihydro (S)-, also known as escitalopram, Xalate geted agents, CB1 antagonists (e.g. Rimonabant), monoam (USAN), citalopram, (S)-(+)-citalopram, LU 26042, LU ine reuptake inhibitors (e.g. Sibutramine), and lipase inhibitor 26054, Lu26-054, or CIPRALEX): S (e.g. Orlistat). 0295) 11. Litoxetine (4-(2-Naphthalenyl)methoxypi 0282 Serotonin agonist agents such as dexfenfluramine peridine, also known as SL 81 0385): and fenfluramine were reported to cause cardiac valvular 0296 12. (S)-Fluoxetine (S)-N-methyl-gamma-(4-(tri abnormalities when used at the prescribed dosage in combi fluoromethyl)phenoxy)benzenepropanamine); nation with phentermine. Selective serotonin reuptake inhibi 0297 13. Cericlamine ((+,-)-3,4-dichloro-beta-(dim tors (SSRIs) are generally used for the treatment of depres ethylamino)-beta-methylbenzenepropanol, also known Sion. These agents include fluoxetine (Prozac), paroxetine, as JO 1017(+-), JO 1239(-), or JO 1240(+)); fluvoxamine and Sertraline. 0298. 14. Dapoxetine ((+)-(S)- N,N-dimethyl-alpha 0283 Representative serotonin modulators are listed (2-(1-naphthyl-oxy)ethyl)benzylamine HCl, also below: known as LY-210448 or LY-243917); 0284 (A) Selective serotonin reuptake inhibitors (SS 0299. 15. 6-Nitroquipazine derivatives; RIs) 0300 16. Series of substituted 6-nitroquipazines (Phar 0285 1. Citalopram (1-(3-(dimethylamino)propyl)-1- maprojects No. 3391); (4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarboni 0301 17. AAL 13 (2-(4-(3-chloropropyl)-1-piperazi trile, also known as citalopram hydrobromide (USAN), nyl)cquinoline); nitalopram, nitalapram, ZD 211, LU 10171, Lu 10-171, 0302 18. Depression therapy (by Vita Invest, Spain); LU 10171-B, CIPRAMIL SEROPRAM, CIPRAM, 0303) 19. DUP 631 (CHNOS); ELOPRAM, LUPRAM, SEPRAM, PRISDAL, or CEL 0304 20. FI 4503 (by Ferrer, Spain): EXA); 0305 21. Series of indolylcyclohexylamines (Phar 0286 2. Fluoxetine (benzenepropanamine, N-Methyl maprojects No. 6443, American Home Products); gamma-4-(trifluoromethyl)phenoxy-, (t) hydrochlo (0306 22. LY 280253 (N-Methyl-N-3-4-(methylthio) ride, also known as LY 110140, RENEURON, phenoxy)-3-phenylpropylamine); SARAFEM, or PROZAC); 0307 23. LY 285974 (by Lilly): 0287 3. Fluvoxamine (5-methoxy-1-(4-(trifluorom 0308 24. Omiloxetine (Ethanone,2-((3R,4S)-3-((1,3- ethyl)phenyl)-1-pentanone (E)-O-(2-aminoethyl) benzodioxol-5-yloxy)methyl)-4-(4-fluorophenyl)-1-pi oxime, also known as fluvoxamine maleate (USAN), peridinyl)-1-(4-fluorophenyl) rel-, also known as DU 23000, MK 264, SME 3110, FEVARIN, FLOXY FI-4500, FI-4501, FI-4503); and FRAL, LUVOX, DUMYROX, DUMIROX, FLA 0309 25. WF 31 (8-Methyl-2beta-propanoyl-3beta-(4- VOXYL, FAVERIN, or DEPROMEL); (1-methylethyl)-phenyl)-8-azabicyclo[3.2.1]); 0288 4. Indeloxazine ((+,-)-2-((indel-7-yloxy)methyl) 0310 (B) Serotonin agonists and partial agonists morpholine, also known as ideloxazine, YM 08054, 0311 1. Dexfenfluramine; and CI-874, ELEN, or NOIN); 0312. 2. Fenfluramine: (0289 5. Paroxetine hydrochloride ((3S,4R)-3-((1,3- 0313 (C) Serotonin reuptake inhibitor with serotonin benzodioxol-5-yloxy)methyl)-4-(4-fluorophenyl)pip agonist activity eridine hydrochloride, or piperidine, 3-((1,3-benzo 0314) 1. EMD-68843 (2-benzofurancarboxamide, 5-(4- dioxol-5-yloxy)methyl)-4-(4-fluorophenyl)- (3S (4-(5-cyano-1H-indol-3-yl)butyl)-1-piperazinyl)-, also trans)-, also known as FR 7051, FG-7051, BRL 29060, known as SB-659746-A); BRL 29060A, NNC 207051, S1211103, CASBOL, 0315 2. OPC-14523 (2(1H)-quinolinone, 1-(3-(4-(3- SEROXAT, AROPAX, PAXIL, TAGONIS, FROSI chlorophenyl)-1-piperazinyl)propyl)-3,4-dihydro-5- NOR, DEROXAT, SEREUPIN, MOTIVAN, or PAXIL methoxy); CR): 0316 3. Vilazodone (5-4-4-(5-Cyano-3-indolyl)-bu 0290 6. Sertraline (1-naphthalenamine, 4-(3,4-dichlo tyl-1-piperazinyl-benzofuran-2-carboxamide, also rophenyl)-1,2,3,4-tetrahydro-N-methyl-, (1S-cis)- or known as EMD 68843 or SB 659746A): 1-Naphthalenamine, 4-(3,4-dichlorophenyl)-1,2,3,4- 0317 4. Series of condensed thiazoles (3-(benzo (b) tetrahydro-N-methyl-, (1S-cis), also known as CP thiophen-3-yl)-5,6-dihydroimidazo (2,1-b)thiazolem 51974, CP 51974 01, AREMIS, BESITRAN, GLA onohydrobromide dihydrate, Pharmaprojects No. 5274, DEM, LUSTRAL SERAD, SERLAIN, SERLIFT, Abbott); and TATIG, or ZOLOFT): 0318 5. VN-2222 (VN-8522, by Vita Invest, Spain). 0291 7. Tianeptine (7-((3-chloro-6,11-dihydro-6-me 0319 Preferred examples of serotonin modulators include thyldibenzo(c.f) (1,2)thiazepin-11-yl)amino)heptanoic selective serotonin reuptake inhibitors such as Citalopram, acid S.S.-dioxide, also known as S 1574, or STABLON); Fluoxetine, Fluvoxamine, Indeloxazine, Paroxetine hydro 0292 8. Centpropazine (1-(p-propionylphenoxy)-3- chloride, Sertraline, Tianeptine, Centpropazine, Paroxetine, (NSup(4)-henylpiperaZynyl)-propan-2-ol); Escitalopram, and Litoxetine. US 2011/0237625 A1 Sep. 29, 2011 31

0320 The following are also anti-obesity agents useful in 0353 6. Melanocortin receptor modulators (Phar the combination therapies of the present invention: maprojects No. 5224, Neurocrine Biosciences, US); 0321 (A) Amylin and amylin analogs 0354 7. Pharmaprojects No. 5967, Trega/Novartis; 0322 1. Pramlintide (1-Lysyl-l-cysteinyl-l-asparaginyl 0355 (F) NPY antagonists 1-threonyl-l-alanyl-l-threonyl-l-cysteinyl-l-alanyl-l- 0356 1. AXC 0216; threonyl-l-glutaminyl-l-arginyl-l-leucyl-l-alanyl-l-as 0357 2. AXC 1829: paraginyl-1-phenylalanyl-l-leucyl-l-Valyl-l-histidyl-l- 0358. 3. SA-0204 (Neuropeptide Yantagonist, Apopto seryl-l-seryl-l-asparaginyl-l-asparaginyl-l- sis stimulator, Lipid metabolism modulator); phenylalanylglycyl-l-prolyl-l-isoleucyl-l-leucyl-l- 0359 4. Alpha-trinositol (D-myo-Inositol, 1.2,6-tris prolyl-l-prolyl-l-threonyl-l-asparaginyl-l-Valylglycyl-l- (dihydrogen phosphate), also known as PP-56); seryl-l-asparaginyl-l-threonyl-l-tyrosinamide cyclic 0360 5. H 40922 (H 409/22); (2-7)-disulfide, also known as pramlintide acetate, AC 0361 6. BMS-192548 (1,11(4H,5H)-naphthacenedi 137, ACO 137, AC 0137, SYMLIN, Tripro-amylin, or one, 2-acetyl-4a, 12a-dihydro-3,4-a, 10.12.12a-pentahy NORMYLIN); droxy-8-methoxy-, TAN 1612 isomer); 0323 2. Amylin agonists; 0362 7. Alanex (1,4-bis-(4-amino-6-methoxypheny 0324 3. ACO 253 (AC 253, GG 747, GR 1150747A, or lamino-1,2-dihydro-1,3,5-triazin-2-yl)-4- ANTAM); phenoxymethylbenzene, Neuropeptide Y derivatives); 0325 (B) Ciliary neurotrophic factors (CNTF) 0363 8. PD-160170 (6-(2-isopropyl-benzenesulfonyl)- 0326 1. AXOKINE; 5-nitro-quinolin-8-ylamine); 0327 2. PEG-AXOKINE; 0364. 9. 2,4-Diaminopyridine derivatives (6-(5-ethyl-1, 0328. 3. Peptide mimic of ciliary neurotrophic factor 3,4-thiadiazol-2-ylthiomethyl)-4-morpholino-2-(3-(2- (CNTF mimic, also known as MYELOS); propenyloxycarbonylamino) benzylamino)pyridine, 0329 4. Ciliary neurotrophic factor (CNTF by Fidia, Pharmaprojects No. 5618, Banyu/Merck); Italy); 0365. 10. Arpromidine analogs; 0330 (C) Glucagon-like peptide-1 0366 11. Neuropeptide Yantagonist (Pharmaprojects 0331 1. AC-2993 (also known as exendin-4, AC-2993 LAR, Medisord Exendin, AC-2993, Medisorb, or exten No. 4990, Pfizer); din-4, Amylin); 0367. 12.4 Methyl substituted benzimidazoles (NPY-1 0332 2. Exendin 4 (His-Gly-Glu-Gly-Thr-Phe-Thr antagonist, NPY-2 antagonist); Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-V-al 0368 13. LY-366337 (Neuropeptide Y1 antagonist); Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro 0369. 14. S-2501, S-25579, S-25584, S-25585, Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-amide, also known as S-19528, S-34354 (all Neuropeptide Y1/5 antagonists): AC 2993, AC 2993 LAR, Medisord Exendin, or 0370 15. Neuropeptide Yantagonist (subtypes 1 and 5) AC-2993, Medisorb); and Galanin receptor antagonist (Pharmaprojects No. 0333 3. GLP-1 (Glucagon-like peptide-17-36 amide); 4897, Bristol-Myers Squibb): 0334 4. Glucagon-like peptide-1 oral transmucosal for 0371. 16. Benzylamine derivatives (1-arylpiperazinyl mulation; 1-alkyloxyphenyl-4-alkylcycloalkanes); 0335. 5. Exendin 3 (His-Ser-Asp-Gly-Thr-Phe-Thr 0372) 17. J-104870 (Neuropeptide Y1 antagonist, Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-V-al Appetite Suppressant); Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro 0373) 18. LY-357897 (Neuropeptide Y1 antagonist); Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-amide); 0374) 19. Neuropeptide Y1 antagonist (Pfizer/Neuro 0336 (D) Leptin & leptin mimetics gen); 0337 1. Leptin (2nd-generation); 0375 20. SR-120107A (Neuropeptide Y1 antagonist); 0338 2. Leptin agonists; 0376) 21. BIBO-3304 ((R)-N-(4-(aminocarbony 0339) 3. Leptin expression modulators; laminomethyl)-phenyl)methyl)-N2-(diphenylacetyl)- 0340 4. Leptin signalling pathway modulators; argininamide trifluoroacetate); 0341 5. Leptin modulator; 0377. 22. BIBP 3226 ((R)-N-(4-((aminoiminom 0342 6. Leptin (by IC Innovations, UK); ethyl)amino)-1-((((4-hydroxyphenyl)methyl)amino) 0343 7. Leptin receptor, Monoclonal antibodies: carbonyl)butyl)-alpha-phenylbenzeneacetamide, O 0344 8. Recombinant native leptin: benzeneacetamide, N-((1R)-4-((aminoiminomethyl) 0345 9. LY-355101; amino)-1-((((4-hydroxyphenyl)methyl)amino) carbo 0346) 10. Leptin, Amylin nyl)butyl)-alpha-phenyl-); 0347 (E) Melanocortin receptor agonist (MC4) 0378. 23. SR 120819A (benzenepropanamide, N-(1- 0348 1. HP-228 (Glycinamide, N-acetyl-L-norleucyl ((4-((((4-(dimethylamino) methyl)cyclohexyl)methyl) L-glutaminyl-L-histidyl-D-phenylalanyl-L-arginyl-D- amino)iminomethyl)phenyl)methyl)-2-oxo-2-(1-pyrro tryptophyl-); lidinyl)ethyl)-alpha-((2-naphthalenylsulfonyl)amino)-. 0349 2. Melanocortin-4 receptor agonist (by Palatin, (alphaR-(N(R*(cis)),alphaR*))-); USA); 0379 24. NGD-95-1 (CP-422935, NGD 951); 0350 3. Melanocortin 8 agonist (by Pharmacopeia, 0380. 25. Compounds with benzazepine nuclei (Neu Roche); ropeptide Y1 antagonist); 0351. 4. MC-4 agonists (by Millennium, Chiron) 0381 26. Neuropeptide Y1 antagonist (by Yamanouchi 0352 5. Melanocortin-4 agonist (by Melacure Thera Pharmaceutical): peutics, Sweden); 0382) 27. GI-264879A (Neuropeptide Y1 antagonist); US 2011/0237625 A1 Sep. 29, 2011 32

(0383 28. GW-1229 (2',4,2,4'homodimer of Ile-Glu 0413) 19. UCL-1390 (4-(3-(1H-imidazol-4-yl)pro Pro-Dpr-Tyr-Arg-Leu-Arg-Tyr-CONH2, where Dpr is poxy)benzonitrile); diaminopropionic acid, also known as 1229U91, 0414 20. UCL-1409 ((phenoxyalkyl)imidazoles): MN-24, GR-231118); 0415 21. UCL-1972 (by University College London): 0384 29. BIIE-O246 (Cyclopentaneacetamide, N-(1S)-4-(aminoiminomethyl)amino-1-(2-(3,5-di 0416 22. Verongamine (benzenepropanamide, oXo-1,2-diphenyl-1,2,4-triazolidin-4-yl)ethylamino 3-bromo-alpha.-(hydroxyimino)-N-2-(1H-imidazol carbonylbutyl-1-(2-4-(6,11-dihydro-6-oxo-5H 4-yl)ethyl-4-methoxy-, (E)-); dibenZb.elazepin-1-yl)-1-piperazinyl-2-oxoethyl-); 0417. 23. VUF-9153 (Carbamimidothioic acid, (4- 0385 30. Neuropeptide Y2 antagonist (by Neurogen, chlorophenyl)methyl-, 3-(1H-imidazol-4-yl)propyl USA); ester, also known as Clobenpropit); 0386 31. Amide derivatives (Neuropeptide Y5 antago 0418 (H) Pancreatic lipase inhibitors nist); 0419 1. Orlistat (L-Leucine, N-formyl-, 1-((3-hexyl-4- 0387 32. Neuropeptide Yagonist and antagonist—sub oxo-2-oxetanyl)methyl) dodecyl ester, (2S-(2alpha types 1 and 5 (Schering-Plough) (R*).3beta)-, or N-formyl-L-leucine (2S-(2alpha(R), 0388 33. N-(sulfonamido)alkyl-3a.4.5.9b-tetrahydro 3beta))-1-((3-hexyl-4-oxo-2-oxetanyl)methyl) dodecyl 1H-benzoelindol-2-yl)amine (RWJPRI): ester, also known as Orlipastat, RO 180647. Tetrahydro (0389) 34. Neuropeptide Y5 antagonist (by Novartis); lipstatin (THL), XENICAL, or ZENICAL): 0390 35. Neuropeptide Y5 antagonist (by Pfizer/Neu 0420 2. ATL 962 (also known as AZM 119 or rogen); Alizyme): 0391 36. Pyrrolo3.2-dpyrimidine based neuropeptide 0421 3. GelTex (Anti-obesity therapeutics): Y5 antagonists; 0422 4. AZM-131 (by Yakurigaku Chuo Kenkyushof 0392 37. CGP-7 1683 (Pharmaprojects No. 5651, CGP Institute of Food Research); 71683A); 0393 38. Neuropeptide Y5 agonist/antagonist (Phar 0423) 5. RED 103004 (XiMed Group (United King maprojects No. 5664, Bayer); dom)/BioClin); 0394 (G) Histamine H3 receptor antagonists 0424 ) Alpha melanocyte stimulating hormone ana 0395 1. GT-2331 (3-((1R,2R)-2-(5,5-dimethyl-1- logues hexynyl)cyclopropyl)-1H-imidazole, also known as 0425 1. Melanotan II (acetyl-norleucyl-aspartyl-histi PERCEPTIN); dyl-D-phenylalanyl-arginyl-tryptophyl-lysinamide 0396 2. Ciproxifan (Cyclopropyl-(4-(3-1H-imidazol C-4.2-N-6,7-lactam, also known as MT II); 4-yl)propyloxy)phenyl)methanone, also known as BP 0426 2. MBU-23, MBU-23, MBU-24, MBU-27, 2359 or Compound 359); MBU-28 and MBU-29 (all described in WO 0397 3. Compound 421 (imidazoylpropanol derivative, 0098.27113): INSERM (France)/Bioprojet); 0427 3. MSH fusion toxin (also known aS 0398. 4. FUB 181 (3-(4-chlorophenyl)propyl-3-(1H DAB389MSH, antimelanoma, chimaera) imidazol-4-yl)propyl ether); 0428 4. SHU-9119 (L-Lysinamide, N-acetyl-L-nor 0399 5. GR 175737 (3-((4-chlorophenyl)methyl)-5-(2- leucyl-L-alpha.-aspartyl-L-histidyl-3-(2-naphthale (1H-imidazol-4-yl)ethyl)-1,2-oxadiazole); nyl)-D-alanyl-L-arginyl-L-tryptophyl-, (2.fwdarw.7)- (0400. 6. GT 2227 (4-(6-cyclohexyl-3(Z)-hexenyl)imi lactam, also known as MBX 36) dazole maleate); 0401 7. GT 2394 ((1R,2R)-(trans-2-Imidazol-4-ylcy 0429. 5. SHU-9005 (a substituted derivative of alpha clopropyl)-(cyclohexylmethoxy) carboxamide); MSH) 0402 8. GT-2016 (piperidine, 1-(5-cyclohexyl-1-oxo 0430. 6. ZYC-200 (alpha-MSH, Schepens/ZYCOS pentyl)-4-(1H-imidazol-4-yl)-); with BIOTOPE expression cassette system) 0403 9. Imoproxifan (1-(4-(3-(1H-imidazol-4-yl)pro 0431 (J) Mixed serotonin reuptake inhibitor with sero poxy)phenyl)ethan-1-one oxime); tonin or alpha adrenergic antagonist activity 0404 10. Impentamine (by Berlin Free University); 0432 1. Nefazodone (2-(3-(4-(3-chlorophenyl)-1-pip 04.05 11. Abbott Laboratories H3 antagonist for Atten erazinyl)propyl)-5-ethyl-2,4-dihydro-4-(2-phenoxy tion deficit Hyperactivity Disorder (ADHD); ethyl)-3H-1,2,4-triazol-3-one, also known as MJ 13754, 0406 12. Gliatech (USA) H3 antagonist for eating dis MS 13754, BMY 13754, BMY 137541, SERZONE, order; DUTONIN, RESERIL, NEFADAR, NIFEREL, MEN 0407 13. Series of novel carbamates as derivatives of FAZONA, RULIVAN, DEPREFAX, or SERZONIL); 3-(1H-imidazol-4-yl)propanol with an N-alkyl chain; 0433 2.YM992 (S)-2-(((7-fluoro-2,3-dihydro-1H-in 0408. 14. Series of analogs with a neutral linker leading den-4-yl)oxy)methyl)morpholine hydrochloride, or (S)- to 4-(1H-imidazol-4-ylmethyl)benzene: 2-(((7-fluoro-2,3-dihydro-1H-inden-4-yl)oxy)methyl) 04.09 15. Urea, N-4-(1H-imidazol-4-ylmethyl)phenyl morpholine hydrochloride, also known as YM 35992); methyl-N'-(3,5-dichlorophenyl)-, monohydrochloride; 0434 3. A 80426 ((R)-N-methyl-N-((1,2,3,4-tetrahy 0410) 16. Sch-50971 (1H-imidazole, 4-(3R,4R)-4-me dro-5-methoxy-1-naphthalenyl)methyl)-6-benzo thyl-3-pyrrolidinyl-); furanethanamine); 0411 17. Thioperamide (N-cyclohexyl-4-(1H-imida 0435 4.5-HT1A antagonist (by Vita-Invest, Spain); Zol-4-yl)-1-piperidinecarbothioamide, also known as 0436 5. Nefazodone metabolite (by Sepracor, USA); MR 12842): 0437 6. Serotonin reuptake inhibitors/serotonin 1A 0412 18. UCL-1283 (by University College London): antagonists (Wyeth-Ayerst) US 2011/0237625 A1 Sep. 29, 2011 33

0438 (K) Appetite-suppressants acting through adren 0468 9. S 33005 ((-)-1-(1-Dimethylaminomethyl-5- ergic mechanisms methoxybenzocyclobutan-1-yl)cyclopentanol); 0439) 1... benzphetamine: 0469 10. Tacrine analogues, SIDR; 0440 2. phenmetrazine; 0470 (O) Serotonin, norepinephrine and dopamine 0441 3. phentermine; reuptake inhibitors 0442. 4. diethylpropion; 0471 1. Sibutramine (cyclobutanemethanamine, 1-(4- 0443) 5. mazindol; chlorophenyl)-N,N-dimethyl-alpha-(2-methylpropyl)- 0444 6. sibutramine: or 1-(4-chlorophenyl)-N,N-dimethyl-alpha-(2-methyl 0445 7. phenylpropanolamine: propyl)cyclobutanemetha namine hydrochloride mono 0446 8. ephedrine hydrate, also known as Sibutramine hydrochloride 0447 (L) Mixed serotonin & dopaminereuptake inhibi monohydrate, BTS-54354, BTS-54505, BTS-54524, tOrS KES-524, MERIDIA, REDUCTIL, RADUCTIL, 0448 1. BL-1834 (1-propanamine, 3-dibenz(b.e)ox REDUCTASE, PLENTY, ECTIVA): epin-11 (6H)-ylidene-N,N-dimethyl); 0472. 2. Venlafaxine (cyclohexanol, 1-2-(dimethy 0449 2. NS-2389 or NS-2347 (GW-650250A, GW lamino)-1-(4-methoxyphenyl)ethyl, also known as WY 650250); 45030, WY 45651, WY 45655, DOBUPAL, EFECTIN, 0450 3. (R)-Sibutramine: EFEXOR, EFFEXOR, ELAFAX, VANDRAL, TRE 0451. 4. NS-2359 (by NeuroSearch, Denmark); VILOR): 0452 5. RTI-112 or RTI-113 or RTI-177 (8-Azabicyclo 0473. 3. Venlafaxine XR (cyclohexanol, 1-(2-(dimethy (3.2.1)octane-2-carboxylic acid, 3-(4-chloro-3-meth lamino)-1-(4-methoxyphenyl)ethyl)-, hydrochloride, ylphenyl)-8-methyl-, methyl ester, hydrochloride, (1R, also known as EFFEXOR XRI EFFEXOR ER, 2S,3S,5S)); EFFEXOR XL, EFFEXOR LP, DOBUPAL RETARD, 0453 6. BSF-74681 (Abbott); VANDRAL RETARD, EFFEXOR-EXEL 75, EFEXOR 0454. 7. Hyperforin trimethoxybenzoate (IDN-5491); XR, EFEXOR DEPOT, ELAFAXXR); 0455 (M) Mixed serotonin reuptake inhibitors and 0474 4. Venlafaxine (drug delivery system, OROS oral dopamine antagonist controlled release, also known as Venlafaxine, OROS, or 0456 1. SLV-310 (Solvay, Belgium); EFEXOR XR) 0457 2. EMD 86006 (3-(2-(3-(4-fluorophenyl)benzy 0475 5. (+)-Desmethylsibutramine (also known as lamino)ethoxy)benzonitrile); DDMS, Didesmethylsilbutramine-Sepracor); 0458. 3. SLV 301 (by Solvay); 0476 6. BTS-74398 (1-1-(3,4-Dichlorophenyl)cy 0459 (N) Norepinephrine & serotonin reuptake inhibi clobutyl-2-(3-dimethylaminopropylthio)ethanone, tors (NSRI) 0460) 1. Milnacipran (Cyclopropanecarboxamide, Abbott Pharmaprojects No. 6247); 2-(aminomethyl)-N,N-diethyl-1-phenyl-, cis-(+/-)-, or 0477 7. Desmethylvenlafaxine (by Sepracor); (+)-cis-2-(Aminomethyl)-N-diethyl-1-phenyl cyclo 0478 (P) Appetite-suppressant agents acting through propane carboxamide hydrochloride, also known as dopamine mechanisms F-2207, F-2641, TN-912, DALCIPRAN, IXEL, 0479 1. Apomorphine; MIDACIPRAN, MIDALCIPRAN, MILNACIPRAN 0480 (Q) Selective norepinephrine (noradrenaline) SR, TOLEDOMIN); reuptake inhibitors 0461) 2. Tramadol, Purdue (cyclohexanol, 2-(dimethy 0481 1. Reboxetine ((2S)-rel-2-((R)-(2-ethoxyphe lamino)methyl)-1-(3-methoxyphenyl)-, cis-(+/-), also noxy)phenylmethyl) morpholine, or morpholine, 2-(2- known as TRAMADOL, Tramadol, CR, or Toray); ethoxyphenoxy)phenylmethyl-, (R.S)-, methane 0462. 3. Milnacipran (drug delivery system, sustained sulfonate, also known as reboxetine mesylate (USAN), release); 0463 4. Duloxetine (S) N-methyl-gamma-(1-naph FCE 20124, FCE 21684, PNU 155950E, EDRONAX, thalenyloxy)-2-thiophenepropanamine, or (+)-(S)-N- PROLIFT, VESTRA, IRENON, NOREBOX): Methyl-gamma-(1-naphthyloxy)-2-thiophene-propy 0482 2. Tomoxetine ((gamma.R)—N-methyl-gamma lamine hydrochloride, also known as LY 248686, (2-methylphenoxy)benzenepropanamine, or (-)-N-Me dulloxetine oxalate, LY-223332, LY-223743, thyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochlo LY-223,994, LY-227750, LY-227942, LY-228993, ride, also known as LY 139603, LY 135252, LY LY-248686, LY-264452, LY-264453, LY-267826* 13.9602); 0464 5. Naltrexone--tramadol (morphinan-6-one, 17 0483 3. Hydroxynortriptyline ((E)-10-11-dihydro-5- (cyclopropylmethyl)-4,5-epoxy-3, 14-dihydroxy(5al (3-(methylamino) propylidene)-5H-dibenzo-(a,d)cy pha)-, mixt withcyclohexanol. 2-(dimethylamino)me clohepten-10-ol); thyl)-1-(3-methoxyphenyl)-, cis-(+/-)-, also known as 0484. 4. LY 368975 ((R)-N-Methyl-3-2-(methylsul PTI-601, tramadol--naltrexone, Pain T) fanyl)phenoxy-3-phenyl-propylamine hydrochlor 0465 6. (S) sibutramine ((S)-1-(4-chlorophenyl)-N,N- oide); dimethyl-alpha-(2-methylpropyl)cyclobutanemetha 0485 (R) Combined norepinephrine and dopamine namine); reuptake inhibitors 0466 7. Tramadol, Labopharm (cyclohexanol, 2-(dim 0486 1. Bupropion (1-(3-chlorophenyl)-2-((1,1-dim ethylamino)methyl)-1-(3-methoxyphenyl)-, cis-(+/-), ethylethyl)amino)-1-propanone, also known as bupro also known as tramadol, Contramid); pion hydrochloride (USAN), bupropin, amfebutamone, 0467 8. F98214TA (by FAES, Spain): BW 323U, WELLBUTRIN, QUOMEM, or ZYBAN); US 2011/0237625 A1 Sep. 29, 2011 34

0487. 2. GW 320659 ((2S-(2alpha,3alpha,5alpha))-2- 0525. Other agents useful for the combination therapy of (3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol the present invention include glucokinase modulators hydrochloride, also known as 1555, 1555U88, BW include: 1555U88); 0488. 3. Hydroxybupropion (also known as bupropion, R—, or R-bupropion); 0489 4. (-) Didesmethylsilbutramine (also known as (S)-didesmethylsibutramine, desmethylsilbutramine, (-)-DDMS or MERIDIA (urogenital)); 0490other neurotransmitter(S) Mixed norepinephrine antagonists reuptake inhibitor and O)S 0491 1. Zotepine (2-((8-chlorodibenzo(b.f)thiepin-10- O N / yl)oxy)-N,N-dimethylethylamine, also known as SO2Me LODOPIN, NIPOLEPT ZOLEPTIL, ZOPITE, SET- RO-28-1675 OUS, MAJORPIN); 0492(piperazin-1-yl)-3a,7a-dihydrothieno 2. MC1-225 (4-(2-fluorophenyl)-2-methyl-6- (2,3-d) pyrimi- ()a dine, or 4-(2-Fluorophenyl)-6-methyl-2-piperazi- s nothieno2,3-dipyrimidine hydrochloride hydrate); 0493 3. A 75200 ((R*,R)-(+-)-3-phenyl-1-((6,7,8,9- NH tetrahydronaphtho (1,2-d)-1,3-dioxol-6-yl)methyl)pyr- O NH2 rolidine); 0494 (T) Combined serotonin reuptake inhibitors and sigma receptor antagonists / 0495 1. E-5296 (by Esteve, Spain): N 0496 2. E-6276 (by Esteve, Spain): } S F 0497 3. E-5842 (pyridine, 4-(4-fluorophenyl)-1,2,3,6- M tetrahydro-1-(4-(1H-1,2,4-triazol-1-yl)butyl)-, 2-hy- N droxy-1,2,3-propanetricarboxylate (1:1)); Banyu Merck glucokinase activator 0498 4. E. 5826 (citrate salt of E-5842): 0499tonin or(u) norepinephrine Other neurotransmitter uptake inhibitor modulators activity with sero lsO - S ). 0500) 1. Pirlindole (1H-pyrazino (3,2,1-jk) carbazole, N HN N N 2.3.3a,4,5,6-hexahydro-8-methyl-, also known as CAS- O H COOEt 125, Pyrazidol, pirazidol, LIFRIL, IMPLEMENTOR): O O (0501) 2. NS-2330 (by NeuroSearch, Denmark); (0502. 3. VAN-H36 (by Vita-Invest, Spain): (0503 4. UR 1827 (2-(1-Benzylpiperidin-4-yl)-1-4-(5- F methylpyrimidin-4-ylamino)phenyl-1-ethanone); (0504 (V) C-75 (Fatty acid synthase inhibitor) Novo Nordisk IV (0505 (W) S 15261 (L-4-(2-(2-(9-Fluorenyl)aceta N mido)romethyl)phenyl)ethylamino)ethyl ethyl)benzoic acid 2-(2-methoxy-2-(3-(trifluo ester) N- O N1 X-cool (0506 (X) S100B (Neurotrophic factor) O S 0507 (Y) Stimulators of uncoupling protein function N 0508 (Z) Cholecystokinin agonists (0509 (AA) Androgens 0510) 1. dehydroepiandrosterone: 0511 2. dehydroepiandrosterone derivatives (such as O etiocholandione); 0512 (BB) Testosterone 0513 (CC) Anabolic steroids (eg. oxandrolone) e 0514 (DD) Steroidal hormones S. S 0515 (EE) Amylase inhibitors 0516 (FF) Enterostatin agonists/mimetics AstraZeneca glucokinase activator 0517 (GG) Orexin/hypocretin antagonists 0518 (HH) Urocortin antagonists 0526 Anti-diabetic agents include RXR modulators such 0519 (II) Bombesin agonists aS 0520 (JJ) Modulators of protein kinase A 0527 (1) bexarotene (4-(1-(3.5,5,8,8-pentamethyl-5,6,7, 0521 (KK) Corticotropin-releasing factor mimetics 8-tetrahydro-2-naphthalenyl)ethenyl)benzoic acid, known 0522 (LL) Cocaine- and amphetamine-regulated tran- as TARGRETIN, TARGRETYN, TARGREXIN; also Script mimetics known as LGD 1069, LG 100069, LG 1069, LDG 1069, 0523 (MM) Calcitonin-gene related peptide mimetics LG 69, RO 264455); 0524 (NN) Nizatidine (Axid) 0528 (2) 9-cis-retinoic acid; US 2011/0237625 A1 Sep. 29, 2011

0529 (3) AGN-4326 (also known as ALRT-4204, AGN (0547 (1) AD 5075; 4204, ALRT-326, ALRT-324, or LGD 1324); (0548 (2) R 119702 ((+-)-5-(4-(5-Methoxy-1H-benz 0530 (4) LGD 1324 (ALRT 324); imidazol-2-ylmethoxy)benzyl)thiazolin-2,4-dione 0531 (5) LG 100754; hydrochloride, or CI 1037 or CS 011): 0532 (6) LY-510929; (0549 (3) CLX-0940 (peroxisome proliferator-acti 0533 (7) LGD 1268 (6-(1,1,4,4,6-pentamethyl-1,2,3, vated receptor alpha agonist/peroxisome proliferator 4-tetrahydro-naphth-7-ylcycloprop-1-yl)nicotinic acid, activated receptor gamma agonist); known as ALRT 268 or LG 100268); and 0550 (4) LR-90 (2.5.5-tris(4-chlorophenyl)-1,3-diox 0534 (8) LG 100264. ane-2-carboxylic acid, PPARdelta/Yagonist); 0535 Anti-diabetic agents also include thiazolidinedione 0551 (5) Tularik (PPARYagonist); and non-thiazolidinedione insulin sensitizers, which decrease peripheral insulin resistance by enhancing the effects of insu 0552 (6) CLX-0921 (PPARy agonist); lin at target organs and tissues. 0553 (7) CGP-52608 (PPAR agonist); 0536 The following agents are known to bind and activate 0554 (8) GW-4098.90 (PPAR agonist); the nuclear receptor peroxisome proliferator-activated recep 0555 (9) GW-7845 (PPAR agonist); tor-gamma (PPARY) which increases transcription of specific 0556 (10) L-764406 (PPAR agonist); insulin-responsive genes. Examples of PPAR-gamma ago 0557 (11) LG-101280 (PPAR agonist); nists are thiazolidinediones such as: 0558 (12) LM-4156 (PPAR agonist); 0537 (1) rosiglitazone (2,4-thiazolidinedione.5-((4-(2- 0559 (13) Risarestat (CT-112); (methyl-2-pyridinylamino) ethoxy)phenyl)methyl)-. 0560 (14)YM 440 (PPAR agonist); (Z)-2-butenedioate (1:1) or 5-((4-(2-(methyl-2-pyridi 0561 (15) AR-H049020 (PPAR agonist); nylamino)ethoxy)phenyl)methyl)-2,4-thiazolidinedi 0562 (16) GW 0072 (4-(4-((2S,5S)-5-(2-(bis(phenyl one, known as AVANDIA; also known as BRL 49653, methyl)amino)-2-oxoethyl)-2-heptyl-4-oxo-3-thiazo BRL 49653C, BRL 49653c, SB 210232, or rosiglita lidinyl)butyl)benzoic acid); Zone maleate); 0538 (2) pioglitazone (2,4-thiazolidinedione, 5-((4-(2- 0563 (17) GW409544 (GW-544 or GW-409544); (5-ethyl-2-pyridinyl)ethoxy)phenyl)methyl)-, monohy 0564) (18) NN 2344 (DRF 2593); drochloride, (+-)- or 5-((4-(2-(5-ethyl-2-pyridyl) 0565 (19) NN 622 (DRF 2725); ethoxy)phenyl)methyl)-2,4-thiazolidinedione, known as 0566 (20) AR-H039242 (AZ-242): ACTOS, ZACTOS, or GLUSTIN; also known as AD 0567 (21) GW 9820 (fibrate); 4833, U 72107, U 72107A, U 72107E, pioglitazone 0568 (22) GW 1929 (N-(2-benzoylphenyl)-O-(2-(me hydrochloride (USAN)); thyl-2-pyridinylamino) ethyl)-L-tyrosine, known as 0539 (3) troglitazone (5-((4-((3,4-dihydro-6-hydroxy GW 2331, PPAR alpha/Yagonist); 2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy) 0569 (23) SB 219994 (S)-4-(2-(2-benzoxazolylm phenyl)methyl)-2,4-thiazolidinedione, known as NOS ethylamino)ethoxy)-alpha-(2.2.2-trifluoroethoxy)ben CAL REZULIN, ROMOZIN, or PRELAY; also known Zen epropanoic acid or 3-(4-1-(2-(N-(2-benzoxazolyl)- as CI-991, CS 045, GR 92132, GR 92.132x): N-methylamino)ethoxy)phenyl)-2(S)-(2.2.2- 0540 (4) isaglitazone ((+)-5-6-(2-fluorophenyl) trifluoroethoxy) propionic acid or benzenepropanoic methoxy-2-naphthalenylmethyl-2,4-thiazolidinedi acid.4-(2-(2-benzoxazolylmethylamino)ethoxy)-alpha one or 5-((6-((2-fluorophenyl)methoxy)-2-naphthale (2.2.2-trifluoroethoxy)-, (alphaS)-, PPARalpha/y ago nyl)methyl-2,4-thiazolidinedione O 5-(6-(2- nist); fluorobenzyloxy) naphthalen-2-ylmethyl)thiazolidine 0570 (24) L-796449 (PPAR alpha/Yagonist); 2,4-dione, also known as MCC-555 or neoglitazone); 0571 (25) Fenofibrate (Propanoic acid, 2-4-(4-chlo and robenzoyl)phenoxy-2-methyl-, 1-methylethyl ester, (0541 (5) 5-BTZD. known as TRICOR, LIPCOR, LIPANTIL, LIPIDIL 0542. Additionally, the non-thiazolidinediones that act as MICRO PPAR alpha agonist); insulin sensitizing agents include, but are not limited to: 0572 (26) GW-9578 (PPAR alpha agonist); (0543 (1).JT-501 (JTT 501, PNU-1827, PNU-7.6-MET 0573 (27) GW-2433 (PPAR alpha/y agonist); 0096, or PNU 182716: isoxazolidine-3,5-dione, 4-(4- 0574 (28) GW-0207 (PPARy agonist); (2-phenyl-5-methyl)-1,3-oxazolyl)ethylphenyl-4)me thyl-); (0575 (29) LG-100641 (PPARy agonist); (0544 (2) KRP-297 (5-(2,4-dioxothiazolidin-5-ylm 0576 (30) LY-300512 (PPARy agonist); ethyl)-2-methoxy-N-(4-(trifluoromethyl)benzyl)benza 0577 (31) NID525-209 (NID-525); mide or 5-((2,4-dioxo-5-thiazolidinyl)methyl)-2-meth 0578 (32) VDO-52 (VDO-52); oxy-N-(4-(trifluoromethyl)phenyl)methyl) 0579 (33) LG 100754 (peroxisome proliferator-acti benzamide); and vated receptor agonist); 0545 (3) Fargilitazar (L-tyrosine, N-(2-benzoylphe 0580 (34) LY-510929 (peroxisome proliferator-acti nyl)-O-(2-(5-methyl-2-phenyl-4-oxazolyl)ethyl)- O vated receptor agonist); N-(2-benzoylphenyl)-O-(2-(5-methyl-2-phenyl-4-ox 0581 (35) bexarotene (4-(1-(3,5,5,8,8-pentamethyl-5, azolyl)ethyl)-L-tyrosine, or GW2570 or GI-262570). 6,7,8-tetrahydro-2-naphthalenyl)ethenyl)benzoic acid, 0546. Other anti-diabetic agents have also been shown to known as TARGRETIN, TARGRETYN, TARGR have PPAR modulator activity such as PPARgamma, SPPAR EXIN; also known as LGD 1069, LG 100069, LG 1069, gamma, and/or PPAR delta/gamma agonist activity. LDG 1069, LG 69, RO 264455); and Examples are listed below: 0582 (36) GW-1536 (PPAR alpha/Yagonist). US 2011/0237625 A1 Sep. 29, 2011 36

0583. Other insulin sensitizing agents include, but are not 0618 (35) DRF-NPCC: limited to: 0619 (36) CLX 0100, CLX0101, CLX 0900, or CLX 0584 (1) INS-1 (D-chiro inositol or D-1,2,3,4,5,6- 0901; hexahydroxycyclohexane); 0620 (37) IkappaB Kinase (IKKB) Inhibitors 0585 (2) protein tyrosine phosphatase 1 B (PTP-1B) inhibitors; 0621 (38) mitogen-activated protein kinase (MAPK) 0586 (3) glycogen synthase kinase-3 (GSK3) inhibi inhibitors p38 MAPK Stimulators tors; 0622 (39) phosphatidyl-inositide triphosphate 0587 (4) beta 3 adrenoceptoragonists such as ZD2079 0623 (40) insulin recycling receptor inhibitors ((R)-N-(2-(4-(carboxymethyl)phenoxy)ethyl)-N-(2- 0624 (41) glucose transporter 4 modulators hydroxy-2-phenethyl)ammonium chloride, also known 0625 (42) TNF-C. antagonists as ICID 2079) or AZ 40140; 0626 (43) plasma cell differentiation antigen-1 (PC-1) 0588 (5) glycogen phosphorylase inhibitors; Antagonists 0589 (6) fructose-1,6-bisphosphatase inhibitors; 0627 (44) adipocyte lipid-binding protein (ALBP/aP2) 0590 (7) chromic picolinate, vanadyl sulfate (vana dium oxysulfate); inhibitors 0591 (8) KP 102 (organo-Vanadium compound); 0628 (45) phosphoglycans 0592 (9) chromic polynicotinate: 0629 (46) Galparan: 0593 (10) potassium channel agonist NN414: 0630 (47) Receptron: 0594) (11)YM268 (5.5'-methylene-bis(1,4-phenylene) 0631 (48) islet cell maturation factor; bismethylenebis (thiazolidine-2,4-dione); 0632 (49) insulin potentiating factor (IPF or insulin 0595 (12) TS971; potentiating factor-1); 0596 (13) T 174 ((+-)-5-(2,4-dioxothiazolidin-5-ylm ethyl)-2-(2-naphthylmethyl)benzoxazole); 0633 (50) somatomedin C coupled with binding pro 0597 (14) SDZ PGU 693 ((+)-trans-2(S-((4-chlo tein (also known as IGF-BP3, IGF-BP3, SomatoKine): rophenoxy)methyl)-7alpha-(3,4-dichlorophenyl)tet 0634 (51) Diab II (known as V-411) or Glucanin, pro rahydropyrrolo (2,1-b) oxazol-5(6H)-one); duced by Biotech Holdings Ltd. or Volque Pharmaceu 0598 (15) S 15261 ((-)-4-(2-((9H-fluoren-9-ylacetyl) tical; amino)ethyl)benzoic acid 2-((2-methoxy-2-(3-(trifluo 0635 (52) glucose-6 phosphatase inhibitors; romethyl)phenyl)ethyl)amino)ethyl ester); 0636 (53) fatty acid glucose transport protein; 0599 (16) AZM 134 (Alizyme): 0637 (54) glucocorticoid receptor antagonists; and 0600 (17) ARIAD; 0638 (55) glutamine:fructose-6-phosphate amidot 0601 (18)R 1023.80; 0602 (19) PNU 140975 (1-(hydrazinoiminomethyl) ransferase (GFAT) modulators. hydrazino) acetic acid; 0639 Anti-diabetic agents can further include biguanides, 0603 (20) PNU 106817 (2-(hydrazinoiminomethyl) which decreases liver glucose production and increases the hydrazino) acetic acid; uptake of glucose. Examples of biguanides include met 0604 (21) NC 2100 (5-((7-(phenylmethoxy)-3-quino formin Such as: linyl)methyl)-2,4-thiazolidinedione: 0640 (1) 1,1-dimethylbiguanide (e.g., Metformin— 0605 (22) MXC 3255; DepoMed, Metformin Biovail Corporation, or MET 0606 (23) MBX 102; FORMINGR (metformin gastric retention polymer)); 0607 (24) ALT 4037; and 0608 (25) AM 454; 0641 (2) metformin hydrochloride (N,N-dimethylimi 0609 (26) JTP 20993 (2-(4-(2-(5-methyl-2-phenyl-4- dodicarbonimidic diamide monohydrochloride, also oxazolyl)ethoxy)benzyl)-malonic acid dimethyl known as LA 6023, BMS. 207150, GLUCOPHAGE, or diester); GLUCOPHAGEXR. 0610 (27) Dexlipotam (5(R)-(1,2-dithiolan-3-yl)pen 0642 Additionally, anti-diabetic agents include alpha tanoic acid, also known as (R)-alpha lipoic acid or (R)- glucosidase inhibitors, which inhibit alpha-glucosidase. thioctic acid); Alpha-glucosidase converts fructose to glucose, thereby 0611 (28) BM 170744 (2,2-Dichloro-12-(p-chlorophe delaying the digestion of carbohydrates. The undigested car nyl)dodecanoic acid); bohydrates are Subsequently broken down in the gut, reduc 0612) (29) BM 152054 (5-(4-(2-(5-methyl-2-(2-thie ing the post-prandial glucose peak. Examples of alpha-glu nyl)oxazol-4-yl)ethoxy)benzothien-7-ylmethyl)thiazo cosidase inhibitors include, but are not limited to lidine-2,4-dione); 0643 (1) acarbose (D-glucose, O-4,6-dideoxy-4-(((1S 0613 (30)BM 131258 (5-(4-(2-(5-methyl-2-phenylox (1alpha,4alpha.5beta,6alpha))-4,5,6-trihydroxy-3-(hy azol-4-yl)ethoxy)benzothien-7-ylmethyl)thiazolidine droxymethyl)-2-cyclohexen-1-yl)amino)-alpha-D-glu 2,4-dione); copyranosyl-(1-4)-O-alpha-D-glucopyranosyl-(1-4)-. 0614 (31) CRE 16336 (EML 16336): also known as AG-5421, Bay-g-542, BAY-g-542, GLU 0615 (32) HQL 975 (3-(4-(2-(5-methyl-2-phenylox COBAY, PRECOSE, GLUCOR, PRANDASE, GLU azol-4-yl)ethoxy)phenyl)-2(S)-(propylamino)propi MIDA, or ASCAROSE): onic acid); 0644 (2) Miglitol (3,4,5-piperidinetriol, 1-(2-hydroxy 0616 (33) DRF 2189 (5-((4-(2-(1-Indolyl)ethoxy)phe ethyl)-2-(hydroxymethyl)-, (2R(2alpha,3beta,4alpha, nyl)methyl)thiazolidine-2,4-dione); 5beta))- or (2R,3R.4R,5S)-1-(2-hydroxyethyl)-2-(hy 0617 (34) DRF 554.158: droxymethyl-3,4,5-piperidinetriol, also known as BAY US 2011/0237625 A1 Sep. 29, 2011 37

1099, BAY M1099, BAY-m-1099, BAYGLITOL, DIA 0662 (13) regular insulin injection such as ILETIN II STABOL, GLYSET, MIGLIBAY, MITOLBAY, PLU Regular, NOVOLINR, VELOSULIN BR, NOVOLINR MAROL): PenFill, NOVOLINR Prefilled, HUMULINR, or Regu 0645 (3) CKD-711 (0-4-deoxy-4-((2,3-epoxy-3-hy lar U-500 (Concentrated): droxymethyl-4,5,6-trihydroxycyclohexane-1-yl) 0663 (14) ARIAD; amino)-alpha-b-glucopyranosyl-(1-4)-alpha-D-glu 0664) (15) LY 197535: copyranosyl-(1-4)-D-glucopyranose); 0665 (16) L-783281; and 0646 (4) emiglitate (4-(2-((2R,3R,4R,5S)-3,4,5-trihy 0.666 (17) TE-17411. droxy-2-(hydroxymethyl)-1-piperidinyl)ethoxy)ben 0667 Anti-diabetic agents can also include insulin secre Zoic acid ethyl ester, also known as BAYo 1248 or MKC tion modulators such as: 542): 0668 (1) glucagon-like peptide-1 (GLP-1) and its (0647 (5) MOR14 (3,4,5-piperidinetriol, 2-(hydroxym mimetics; ethyl)-1-methyl-, (2R-(2alpha,3beta,4alpha.5beta)-. 0669 (2) glucose-insulinotropic peptide (GIP) and its also known as N-methyldeoxynoirimycin or N-methyl mimetics; moranoline); and 0670 (3) exendin and its mimetics; 0648 (6) Voglibose (3,4-dideoxy-4-((2-hydroxy-1- 0671 (4) dipeptyl protease (DPP or DPPIV) inhibitors (hydroxymethyl)ethyl)amino)-2-C-(hydroxymethyl)- Such as D-epi-inositol or D-epi-Inositol.3,4-dideoxy-4-((2-hy 0672 (4a) DPP-728 or LAF 237 (2-pyrrolidinecar droxy-1-(hydroxymethyl)ethyl)amino)-2-C- bonitrile, 1-(((2-((5-cyano-2-pyridinyl)amino)ethyl) (hydroxymethyl)-, also known as A 71 100, AO 128, amino)acetyl), known as NVP-DPP-728. DPP-728A, BASEN, GLUSTAT, VOGLISTAT. LAF-237): 0649 Anti-diabetic agents also include insulins such as 0673 (4b) Sitagliptin, also known as Januvia; regular or short-acting, intermediate-acting, and long-acting 0674 (4c) P 3298 or P32/98 (di-(3N-((2S,3S)-2- insulins, non-injectable or inhaled insulin, tissue selective amino-3-methyl-pentanoyl)-1,3-thiazolidine) fuma insulin, glucophosphokinin (D-chiroinositol), insulin ana rate); logues such as insulin molecules with minor differences in the 0675 (4d) TSL 225 (tryptophyl-1,2,3,4-tetrahy natural amino acid sequence and Small molecule mimics of droisoquinoline-3-carboxylic acid); insulin (insulin mimetics), and endoSome modulators. 0676 (4e) Valine pyrrolidide (valpyr); Examples include, but are not limited to: 0677 (4f) 1-aminoalkylisoquinolinone-4-carboxy 0650 (1) Biota: lates and analogues thereof; 0651 (2) LP 100; 0678 (4g) SDZ 272-070 (1-(L-Valyl)pyrrolidine); 0652 (3) (SP-5-21)-oxobis(1-pyrrolidinecarbodithio 0679 (4h) TMC-2A, TMC-2B, or TMC-2C; ato-S,S)vanadium, 0680 (4i) Dipeptide nitriles (2-cyanopyrrolodides); 0653 (4) insulin aspart (human insulin (28B-L-aspartic 0681 (4) CD26 inhibitors; and 0682 (4k) SDZ 274-444; acid) or B28-Asp-insulin, also known as insulin X14, 0683 (5) glucagon antagonists such as AY-279955; and INA-X14, NOVORAPID, NOVOMIX, or NOVOLOG); 0684 (6) amylin agonists which include, but are not 0654 (5) insulin detemir (Human 29B-(N6-(1-oxotet limited to, pramlintide (AC-137, Symlin, tripro-amylin radecyl)-L-lysine)-(1A-21A), (1B-29B)-Insulin or NN or pramlintide acetate). 304); 0685 Well-known anti-diabetic agents include insulin, 0655 (6) insulin lispro (“28B-L-lysine-29B-L-proline Sulfonylureas, biguanides, meglitinides, AGI’s (Alpha-Glu human insulin, or Lys(B28), Pro(B29) human insulin cosidase Inhibitors; e.g., Glyset), PPAR alpha agonists, and analog, also known as lys-pro insulin, LY 275585, PPARgamma agonists, and dual PPAR alpha/gamma ago HUMALOG, HUMALOG MIX 75/25, or HUMALOG nists. MIX 50/50); 0686 Examples of lipid lowering agents include bile acid 0656 (7) insulin glargine (human (A21-glycine, B31 sequestrants, fibric acid derivatives, nicotinic acid, and arginine, B32-arginine) insulin HOE 901, also known as HMGCoA reductase inhibitors. Specific examples include LANTUS, OPTISULIN); statins such as LIPITORR), ZOCORR, PRAVACHOL(R), 0657 (8) Insulin Zinc Suspension, extended (Ul LESCOLR), and MEVACORR), and pitavastatin (nisvastatin) tralente), also known as HUMULIN U or (Nissan, Kowa Kogyo, Sankyo, Novartis) and extended ULTRALENTE: release forms thereof, such as ADX-159 (extended release 0658 (9) Insulin Zinc suspension (Lente), a 70% crys lovastatin), as well as Colestid, Locholest, Questran, Atro talline and 30% amorphous insulin Suspension, also mid, Lopid, and Tricor. known as LENTE ILETINII, HUMULIN L, or NOVO 0687 Examples of blood pressure lowering agents include LIN L, anti-hypertensive agents, such as angiotensin-converting 0659 (10) HUMULIN 50/50 (50% isophane insulin enzyme (ACE) inhibitors (Accupril. Altace, Captopril, and 50% insulin injection); Lotensin, Mavik, Monopril, Prinivil, Univasc, Vasotec, and 0660 (11) HUMULIN 70/30 (70% isophane insulin Zestril), adrenergic blockers (such as Cardura, Dibenzyline, NPH and 30% insulin injection), also known as NOVO Hylorel, Hytrin, Minipress, and Minizide) alpha/beta adren LIN 70/30, NOVOLIN 70/30 PenFill, NOVOLIN 70/30 ergic blockers (such as Coreg, Normodyne, and Trandate), Prefilled; calcium channel blockers (such as Adalat, Calan, Cardene, 0661 (12) insulin isophane suspension such as NPH Cardizem, Covera-HS, Dilacor, DynaCirc, Isoptin, Nimotop, ILETIN II, NOVOLIN N, NOVOLIN N PenFill, Norvace, Plendil, Procardia, Procardia XL, Sula, Tiazac, Vas NOVOLINN Prefilled, HUMULINN; cor, and Verelan), diuretics, angiotensin II receptor antago US 2011/0237625 A1 Sep. 29, 2011

nists (such as Atacand, Avapro, Cozaar, and Diovan), beta adrenergic blockers (such as Betapace, Blocadren, Brevibloc, TABLE II-continued Cartrol, Inderal, Kerlone, Lavatol, Lopressor, Sectral, Ten ormin, Toprol-XL, and Zebeta), Vasodilators (such as TR-FRET data Deponit, Dilatrate, SR, Imdur, Ismo, Isordil, Isordil Titra dose, Monoket, Nitro-Bid, Nitro-Dur. Nitrolingual Spray, COMPOUND if TR-FRET EC50 (M) 17 O.10 Nitrostat, and Sorbitrate), and combinations thereof (such as 18 O.S2 Lexxel, Lotrel, Tarka, Teczem, Lotensin HCT, Prinzide, 19 O.12 Uniretic, Vaseretic, Zestoretic). 2O O.38 0688. In addition, a second ERR-C modulator, as 21 O43 22 O48 described above in Sections B) and E), may also be utilized as 23 O48 a third antidiabetic agent, provided that it is different from the 24 O.OO1 first ERR-O. modulator. 25 O.O15 26 1 27 O.33 F) BIOLOGICAL EXAMPLE 28 0.44 29 O.18 TR-FRET Assay 30 O.OO8 0689 Time-Resolved Fluorescence Resonance Energy 31 O.O33 Transfer (TR-FRET) experiments were performed to exam ine the functional response of ERR1 (also known as ERR-C. or ERR-1) ligands. The TR-FRET assay described herein relied In Vivo Studies on the conformation of ERR1 for binding to a co-activator peptide: when a test compound binds to ERR1 and alters its conformation, it can disrupt the binding of the co-activator AKR/J Mouse Obesity Model peptide. The components of this homogeneous secondary 0692 AKR/J mice are a polygenic model of diet-induced assay included: the His-tagged-ERR1LBD, a GST-labeled obesity characterized by hypertriglyceridemia and hyperin hSRC2 co-activator polypeptide and a fluorescent donor/ac ceptor pair from CIS bio international htrf/bioassays (Bed sulinemia. AKR/J mice were received at seven weeks of age ford, Mass.) using both an O-GST Europium Cryptate (Eu) and allowed to acclimate for one week and then placed on label and an O'His-XL665 (allophycocyanin) fluorophore. high fat diet (45% of the calories from fat) for five weeks. 0690. For TR-FRET measurements, the reaction was buff Animals were treated for five days with 3 mpk(mg/kg) and 30 ered in 25 mM Tris pH 8, 2.5 mM Hepes, 20 mM KC1, 1 mM mpk Compound 1 (Example 1) given orally twice a day. Food DTT, and 0.05 mg/mL BSA (-lipids). The final concentra intake was measured at day four. On day five, prior to necrop tions of reagents were 6 nM of ERR1LBD, 6 nM GST-SRC-2 sies, body weight was recorded and body composition was peptide, 30 nM Eu cryptate, and 7.5 nM XL665. Reactions measured by Q-NMR (Quantitative Nuclear Magnetic Reso were allowed to reach equilibrium at 25°C. for 4-18 hours nance). Animals were anesthetized with carbon dioxide and before collecting data on the Analyst from LJL Biosystems blood was collected by cardiac puncture. Plasma was (Molecular Devices Sunnyvale, Calif.). As a time-resolved obtained by centrifugation and used to determine circulating method, the samples were excited at 340 nM and emission insulin levels and clinical chemistries, including liver func was collected for 1 ms at both 615 and 665 nm with delays of tions tests, using commercially available kits as per manufac 400 and 75us, respectively. Dose response curves were fitted turers instructions. Several tissues were harvested, frozen in using a hyperbolic equation and the data reported is the aver liquid nitrogen and stored at -80° C. for further use. age of 3 independent experiments. 0693 Results of this study using Compound 1 are shown 0691 Compounds listed in Tables II below were tested in in FIG. 1 and Tables III and IV (significance used in all in vivo the above assay, and they are all active modulators of ERR1. studies: * indicates p<0.05: ** indicates p<0.01: *** indi cates p<0.001). TABLE II 0694. As shown in FIG. 1, Compound 1 (Example 1) TR-FRET data reduces body weight and reduces food intake. Similarly, Table III demonstrates a reduction in total body fat as well as COMPOUND if TR-FRET EC50 (M) percent body fat versus vehicle control. 1 O.OS4 2 O.13 TABLE III 3 1.03 4 0.55 5 0.57 Effect of Compound 1 (Example 1) on body composition. 6 O.S1 Vehicle 3 mpk 30 mpk 8 0.55 9 O.48 Total body fat (g) 3.96 O.35 3.87 0.29 2.70.2** 10 O.O12 Lean Mass (g) 20.5 + 0.4 2O2 (0.3 2O.O. O.2 11 O.48 % body fat 13.5 - 1.2 12.70.8 9.30.6** 12 O.15 13 O.18 14 O.20 15 O.O37 0695 Table IV demonstrates a reduction of circulating 16 O.60 insulin levels and lowering of triglyceride levels versus vehicle control. US 2011/0237625 A1 Sep. 29, 2011 39

TABLE IV TABLE VI Effect of Compound 1 (Example 1) on metabolic parameters Effect of Compound 1 on AUC (Area. Under the Curve) of glucose in the C57BL6 DIO OGTT after 14 days of treatment Vehicle 3 mpk 30 mpk AUC 0-60 min AUC 0-120 min Insulin ng/mL. 8.5 - O.9 9.6 1.5 2.8 O.8*** Treatment (mg/dL 1 hr) (mg/dLi2hr) Triglyceride 159.1 - 19.5 16O.O. 18.9 80.0 9.8** (mg/dL) Vehicle 17043 298.63 Glucose (mg/dL) 1639 - 6.8 1650 S.O 1850 - 10.01 Compound 110 mpk 15077 27984 FFA (Free Fatty O.53 O.04 O.S9 O.O7 O41 O.OS Compound 130 mpk 14425* 28S4O Acids): NEFA (Non Esterified Fatty Acids), mM 3-hydroxy-butyrate 8.9 O.8 8.3 O.9 1261.8 TABLE VII (x10-5) Effect of Compound 1 on metabolic parameters in DIO C57BL6 treated for 18 days C57/1316 Diet Induced Obesity Mouse Model Vehicle 10 mpk 30 mpk 0696 C57/B16 mice placed on a high fat diet are charac Triglyceride (mg/dL) 174 123 58* * * terized by hypertriglyceridemia, impaired glucose tolerance Glucose (mg/dL) 192 176 174 FFA (NEFA, mEq) O.70 O49 0.38: and develop hepatic steatosis. Forty C57/BL6 male mice were 3-hydroxy-butyrate (x10-5) 6.1 6.O 9.1% received at seven weeks of age, allowed to acclimate for one LDL mg/dL 12 12 7: week, placed on high fat diet (Test Diet 58Y1 60% of the calories from fat) for 6 weeks, and then single housed on the same diet for an additional five weeks. Body mass composi ZDF Diabetic rat model tion and insulin were used to randomize the animals into three 0698. The ZDF rat is a monogenic model of Type II Dia groups. Mice were dosed once a day with vehicle, 10 mpk and betes. It has a mutation on the fa gene truncating the leptin 30 mpk of Example 1 for eighteen days. The vehicle used in receptor and preventing its interaction with its peptide hor this study consisted of 15% vitamin E-TEPG (Tocopherol mone. This mutation results in a hyperphagic phenotype and Polyethylene Glycol), 30% PEG400 and 55% water. Ten the rodent develops obesity, hyperlipidemia, fasting hyperg additional animals were maintained on a low fat diet (4% lycemia and Type II Diabetes. The model at 7 weeks of age calories from fat) and during the course of the study were develops hyperinsulinemia followed by a loss of glucose given vehicle orally once a day. Blood was collected from the stimulated insulin secretion due to beta islet failure. Fifty tail to evaluate glucose, triglyceride, FFA and insulin levels. ZDF fa/fa male rats were received at four weeks of age and Body weight and body composition were also recorded. Upon allowed to acclimate for one week. At five week of age the necropsy animals were bled through the orbital sinus under animals were single housed in cages in a temperature-con CO:O anesthesia, sacrificed, and several tissues were col trolled room with 12-hour light/dark cycle. They were lected and frozen in liquid nitrogen for storage at -80°C. for allowed ad libitum access to water and food and throughout further use. Serum plasma samples were prepared by cen the study were maintained on a Purina 5008 diet. Animals trifugation in EDTA containing tubes, transferred to 96 well were sorted into five groups based first on glucose levels and plates and stored at -80° C. Insulin, FFA and triglyceride then at body weight (average fed glucose levels and body levels were obtained via Day 10 tailbleed. On day fourteen an weight at 7 weeks of age were 488 mg/dL and 282 grams, OGTT (Oral Glucose Tolerance Test) was done to determine respectively). Animals were given Compound 1 orally once a glucose disposal rates in C57B16 mice treated with com day for 25 days in the morning at 3 mpk, 10 mpk and 30 mpk. pound. A separate group was dosed daily with vehicle. The vehicle used for Compound 1 in this study consisted of 15% VE 0697 Results of this study using Compound 1 are shown TEPG, 30% PEG400 and 55% water. Food intake, body in FIG. 2 and Tables V-VII. As shown in FIG. 2 and Table VI, weight, glucose, insulin, triglyceride and free fatty acid levels Compound 1 (Example 1) reduces fasting plasma glucose were monitored throughout the study using blood collected following an oral glucose tolerance test. Similarly, Tables V from the tail vein. At day 11 of the study an insulin tolerance and VII demonstrate a reduction in metabolic parameters test (ITT) was done to evaluate peripheral insulin sensitivity. Such as triglycerides, free fatty acids and insulin levels versus On day 19 an OGTT was done to assess glucose disposal vehicle control on a high fat diet. rates. Body composition analysis, as judged by Q-NMR, was TABLEV done at day 0 and day 19 of the study. On the day of the Effect on metabolic parameters after 10-Days treatment of C57BI6 mice necropsy the rats were bled through the orbital sinus under with Compound 1 CO2:O2 anesthesia. Animals were sacrificed and several tis Sues were collected, frozen in liquid nitrogen and stored at Weh Veh, High Compound 1 chow -80° C. Serum plasma samples were prepared by centrifuga Fat Diet 10 mpk Compound 1 (low fat tion in EDTA containing tubes, transferred into 96 well plates (HFD) (HFD) 30 mpk (HFD) diet) and stored at -80°C. Results of this study using Compound 1 are shown in FIGS. 3-9 and Tables VIII-IX. Triglyceride, mg/dL 72 58* * 59: 67 FFA, mEq/L O.64 0.38: 0.40% O.49 (0699. As shown in FIG. 3, Compound 1 (Example 1) Insulin, Ig/L 2.5 14: 1.3% 1.3% reduces fed triglyceride and free fatty acid levels versus vehicle control. FIG. 4 demonstrates a reduction in circulat ing glucose levels upon intraperitoneal delivery of insulin. US 2011/0237625 A1 Sep. 29, 2011 40

FIG. 5 displays a reduction in fasting glucose levels after a 16 0701. As shown in FIG. 10, Compound 1 (Example 1) hour fast. FIG. 6 illustrates the effects of Compound 1 on demonstrates a reduction in circulating glucose levels upon lowering fasting plasma glucose following an oral glucose intraperitoneal delivery of insulin. FIG. 11 displays a reduc tolerance test while FIG. 7 illustrates an increase on insulin tion in fasting glucose levels after a 4 and 16 hour fast. FIG. 12 release levels following an oral glucose tolerance test. FIG. 8 illustrates the effects of Compound 1 on reducing fasting demonstrates a lowering of fed glucose levels as well as a plasma glucose following an oral glucose tolerance test. FIG. reduction in Hb1Ac levels and FIG. 9 shows the effect of 13 demonstrates the lowering of fed plasma glucose levels Compound 1 on increasing fed plasma insulin levels and while FIG. 14 illustrates the effect on total pancreatic insulin pancreatic insulin content. Table VIII illustrates the effect of release levels. Table X illustrates the effect of Compound 1 on Compound 1 on body weight and food intake and Table IX body weight and food intake and Table XI demonstrates a demonstrates a lowering of triglyceride and plasma ketone lowering of plasma glucose and ketone levels. levels. TABLE X TABLE VIII Effect of Compound 1 on body weight, food intake and body composition. Effect of Example 1 on body weight, food intake and body composition. Body weight change Total food intake Body weight (0-28 day) (0-28 days) change Total food intake % Fat Vehicle 694 821.O (0-25 day) (0-25 days) Day 18 0.08 mpk compound 1 71.7 804.5 Vehicle 46.3 774 55 0.4 mpk compound 1 61.9 792.3 3 mpk Compound 1 62.78 727 58** 2.0 mpk compound 1 804 792.6 10 mpk Compound 1 49.3 720 59** 10 mpk compound 1 95.4 7714 30 mpk Compound 1 65.3% 703** 60* * *

TABLE XI TABLE IX Effect of Example 1 on Metabolic Parameters in the 28 day ZDF efficacy Effect of Compound 1 on Metabolic Parameters in the 26 day ZDF Rat study Efficacy Study Vehicle 0.08 mpk 0.4 mpk 2.0 mpk 10.0 mpk Vehicle 3 mpk 10 mpk 30 mpk Triglycerides 7.4 770 672 60S SO6 Triglycerides (mg/dL) 608.56 596.33 402.39** 320.94*** (mg/dL) Glucose (mg/dL) 609.92 S84.88 549.63 S45.64 Glucose (mg/dL) 445 444 419 376 274: FFA (NEFA, mM) O.62 O.65 O.S4 O48 FFA (NEFA, O.93 1.2 O.61 O.87 0.75 ketone (umol/L) 192.99 183.97 144.61 134.84 mM) cholesterol mg/dL 138.91 145.70 156.08% 169.92** ketone (umol/L) 133 162 113 95: 85* cholesterol mg/dL 113 118 119 117 121 % Hb1Ac 10.1 10.1 1O.O 8.8 7.7

ZDF Diabetic Rat Model at 0.08, 0.4, 2 and 10 mpk 0702 While the foregoing specification teaches the prin (0700 Briefly, sixty-five ZDF fa/fa male rats were received ciples of the present invention, with examples provided for at four weeks of age and allowed to acclimate for one week. the purpose of illustration, it will be understood that the At five week of age the animals were single housed in cages practice of the invention encompasses all of the usual varia in a temperature-controlled room with 12-hour light/dark tions, adaptations and/or modifications as come within the cycle. They were allowed ad libitum access to water and food Scope of the following claims and their equivalents. and throughout the study were maintained on a Purina 5008 diet. Animals were sorted into five groups based first on glucose levels and then at body weight (average fed glucose ... (canceled) levels and body weight at 7 weeks of age were 517 mg/dL and ... (canceled) 293 grams, respectively). Animals were given Compound 1 ... (canceled) orally once a day for 28 days in the morning at 0.08, 0.4, 2.0 ... (canceled) and 10 mpk. The vehicle used for Compound 1 in this study ... (canceled) consisted of 15% VE-TEPG, 30% PEG400 and 55% water. Food intake, body weight, glucose, insulin, triglyceride and ... (canceled) free fatty acid levels were monitored throughout the study 7. (canceled) using blood collected from the tail vein. At day 16 of the study 8. (canceled) an insulintolerance test (ITT) was done to evaluate peripheral 9. (canceled) insulin sensitivity. On day 22 an OGTT was done to assess 10. (canceled) glucose disposal rates. On the day of the necropsy the rats 11. (canceled) were bled through the orbital sinus under CO2:O2 anesthesia. 12. (canceled) Animals were sacrificed and several tissues were collected, frozen in liquid nitrogen and stored at -80° C. Serum plasma 13. (canceled) samples were prepared by centrifugation in EDTA containing 14. (canceled) tubes, transferred into 96 well plates and stored at -80° C. 15. (canceled) Results of this study using Compound 1 are shown in FIGS. 16. (canceled) 10-14 and Tables X-XI. 17. (canceled) US 2011/0237625 A1 Sep. 29, 2011 41

18. A pharmaceutical composition comprising at least one compound of -continued OCH C

Formula (I)

(I) SOCH3 X-y OCH CF N R4R3 Y-1S-1N21S)-1S1NeS OHNO X-OX Br O wherein OCH CF R is halo, optionally Substituted Calkyl, optionally Sub stituted Calkoxy, or hydroxyl; R is selected from halo Substituted C-alkyl, cyano, halo, —C(O)NH2, and —C(O)O Calkyl, alternatively R o CONH is linked to etherto R to forman aryl fused to the phenyl O ring to which R and R are shown attached; OCH CONH R is H or alternatively R is linked together to R to form an aryl fused to the phenyl ring to which R and R2 are X shown attached; N R is halo, cyano. —C=CH halo Substituted C-alkyl, —C(O)C)—Calkyl, -C(O)NH, or —S(O)—C. OHNO OCH CN 4alkyl, and X is S or O: or an optical isomer, enantiomer, diastereomer, cis-trans iso mer, racemate, prodrug or pharmaceutically acceptable salt thereof, at least one pharmaceutically acceptable carrier, at O o least one additional agent, drug, medicament, antibody and/ or inhibitor for treating, ameliorating or slowing the progres OCH COCH3 sion of an ERR-C. mediated disease. 19. The pharmaceutical composition of claim 18 compris ing at least one compound selected from O o OCH CF3 O OCH CF O

X S O X- S O HN HN N N CN COCH3 O O O OCH3 C CH3 O O S S HN N CF N CN O OCH Br O O S HN N SOCH3 S CN US 2011/0237625 A1 Sep. 29, 2011 42

-continued -continued O OCH2CH CF OCH C O O O S S HN HN N CN N CN O O OCH Br O CH3 CF3 O O O S S HN HN N N CN CN O O

O OCH

O OCH2CH X- O O

S HN O N CN N CN O

O O OCH O O

HN O Br O CF X- S O HNX- S C O N COCH N CN O O OCH O S HN S. CONH2 O CF CF l O 3 3 S. O S C CF 3 HN N CN O

N O 1N CF

OCH HN X N O C, NH2 l luc O CF S. O OCH B r HN OHNOOHNHNOy N NH2 O )-1S-1N-21 O O US 2011/0237625 A1 Sep. 29, 2011

-continued -continued OCF CF O OCH O S HN o CN N CONH2 and O O OCH CF3 F O O S HN Cl and C N CN. O F CF O X 21. A method of treating a Subject Suffering from or diag nosed with a disease, disorder, or condition mediated by N ERR-C. activity, comprising administering to the Subject a C. therapeutically effective amount of at least one compound of OHNO claim 18. 22. A method according to claim 21, wherein the disease, 20. The pharmaceutical composition of claim 19 compris disorder, or medical condition is selected from the group ing at least one compound selected from consisting of bone-related disease, bone formation, cartilage formation, cartilage loss, cartilage degeneration, cartilage injury, ankylosing spondylitis, chronic back injury, gout, OCH CF osteoporosis, osteolytic bone metastasis, multiple myeloma, chondrosarcoma, chondrodysplasia, osteogenesis imper fecta, osteomalacia, Paget’s disease, polymyalgia rheu y matica, pseudogout, arthritis, rheumatoid arthritis, infectious arthritis, osteoarthritis, psoriatic arthritis, reactive arthritis, )-1S-1N21 childhood arthritis, Reiter's syndrome, and repetitive stress O injury. OCH CF3 23. A method according to claim 21, wherein the disease, disorder, or condition is selected from the group consisting of periodontal disease, chronic inflammatory airway disease, chronic bronchitis, and chronic obstructive pulmonary dis CaSC. C COCH3: 24. A method according to claim 21, wherein the disease, O disorder, or condition is breast cancer. OCH2CH 25. A method according to claim 21, wherein the disease, disorder, or condition is selected from the group consisting of y metabolic syndrome, obesity, disorders of energy homeosta sis, diabetes, lipid disorders, cardiovascular disorders, arth Y-1S-1Ne. erosclerosis, hyperglycemia, elevated blood glucose level. CN: and insulin resistance. O 26. The method of claim 21 comprising administering to OCH the subject a therapeutically effective amount of (a) at least one compound of claim 1; and (b) at least one additional agent selected from a second ERR-C. inverse agonist, an ERR-C. y antagonist, a glucokinase modulator, an anti-diabetic agent, an anti-obesity agent, a lipid lowering agent, an anti-throm )-1S-1S21 CN: botic agent, direct thrombin inhibitor, and a blood pressure O lowering agent, said administration being in any order. OCH 27. The method of claim 26 wherein the additional agent in (b) is a second ERR-C. inverse agonist different from the compound in (a). X 28. The method of claim 26 wherein the additional agent in (b) is an anti-obesity agent selected from CB1 antagonists, )-1S-1N21 COCH3 monoamine reuptake inhibitors, and lipase inhibitors. O 29. The method of claim 26 wherein the additional agent in (b) is selected from rimonabant, Sibutramine, and orlistat. US 2011/0237625 A1 Sep. 29, 2011 44

30. A method for treating or inhibiting the progression of 33. The method of claim 32 wherein the therapeutically an ERR-O-mediated condition in a subject in need thereof, effective amount of the compound of claim 18 is from about comprising administering to said subject a therapeutically 0.5 mg/dose to about 1000 mg/dose. effective amount of at least one compound according to claim 18. 34. The method of claim 32 wherein the therapeutically 31. A method for treating prediabetic condition in a subject effective amount of the compound of claim 18 is from about in need thereof, comprising administering to said Subject a 1 mg/dose to about 100 mg/dose. therapeutically effective amount of at least one compound 35. A process for making a pharmaceutical composition according to claim 18. comprising admixing any of the compounds according to 32. The method of claim 21, 30 or 31 wherein the thera claim 18 and a pharmaceutically acceptable carrier. peutically effective amount of the compound of claim 18 is from about 0.1 mg/dose to about 5 g/dose. c c c c c