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(12) United States Patent (10) Patent No.: US 8,580,832 B2 Gaul Et Al

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(12) United States Patent (10) Patent No.: US 8,580,832 B2 Gaul Et Al USOO858O832B2 (12) United States Patent (10) Patent No.: US 8,580,832 B2 Gaul et al. (45) Date of Patent: Nov. 12, 2013 (54) SUBSTITUTED PHENOXY Pacifici, R.J., “Estrogen, Cytokines, and Pathogenesis of AMINOTHAZOLONES AS ESTROGEN Postmenopausal Osteoporosis.”. Bone Miner. Res., 1996, vol. 11 (8), RELATED RECEPTOR-O MODULATORS pp. 1043-1051. International Search Report, PCT/US2008/056029, date of mailing (75) Inventors: Michael Gaul, Yardley, PA (US); of International Search Repont, Jul. 4, 2008. Alexander Kim, Levittown, PA (US); Written Opinion relating to PCT/US2008/056029. Lily Lee Searle, Waltham, MA (US); Strum et al., “Rosiglitazone Induces Mitochondrial Biogenesis in Dionisios Rentzeperis, Downingtown, Mouse Brain”, Journal of Alzheimer's Disease, 2007, vol. 11(1), pp. PA (US); Gilles C. Bignan, Brigewater, 45-51, IOS Press, Asterdam, NL. NJ (US) Grundy, S., et al. “Definition of Metabolic Syndrome'. Circulation 2004:109:433-438. (73) Assignee: Janssen Pharmaceutica N.V. (BE) Kamei, Y, et al. “PPARY Coactivator 13/ERR Ligand 1 is an ERR Protein Ligand, Whose Expression Induces a High-Energy Expendi (*) Notice: Subject to any disclaimer, the term of this ture and Antagonizes Obesity”, PNAS, vol. 100, No. 21, 2003, pp. patent is extended or adjusted under 35 12378-12383. U.S.C. 154(b) by 768 days. Jones, P. et al. “N-CoR-HDAC Corepressor Complexes: Roles in Transcriptional Regulation by Nuclear Hormone Receptors', Chap (21) Appl. No.: 12/043,311 ter 9, Curr. Top. Microbiol. Immunol. 2003, 274, pp. 237-268. Luo, J., et al. “Reduced Fat Mass in Mice Lacking Orphan Nuclear (22) Filed: Mar. 6, 2008 Receptor Estrogen-Related Receptor O'. Molecular and Cellular Biology, 2003, pp. 7947-7956. (65) Prior Publication Data Sumi. D., et al. “Estrogen-Related Receptor C.1 Up-Regulates US 2008/0221179 A1 Sep. 11, 2008 Endothelial Nitric Oxide Synthase Expression', PNAS, vol. 100, No. 24, 2003, pp. 14451-14456. Giguere, V., “To ERR in the Estrogen Pathway”. Trends in Endocri nology & Metabolism, vol. 13, No. 5, 2002, pp. 220-225. Related U.S. Application Data (60) Provisional application No. 60/893,464, filed on Mar. (Continued) 7, 2007. Primary Examiner — Noble Jarrell (51) Int. Cl. Assistant Examiner — Valerie Rodriguez-Garcia A6 IK3I/425 (2006.01) (74) Attorney, Agent, or Firm — Jeremy K. McKown C07D 277/08 (2006.01) C07D 277/12 (2006.01) (57) ABSTRACT (52) U.S. Cl. The present invention relates to compounds of Formula (I), USPC ............................ 514/369; 514/370: 548/184 (I) (58) Field of Classification Search Rs USPC ................................... 514/369,370: 548/184 See application file for complete search history. R-N R X- X O R3 (56) References Cited / N U.S. PATENT DOCUMENTS R R4 O 6,518,268 B1 2/2003 Chin et al. 2002/O128319 A1 9, 2002 Koo et al. methods for preparing these compounds, compositions, inter 2006/0014812 A1* 1/2006 Player et al. .................. 514,369 mediates and derivatives thereof and for treating a condition including but not limited to ankylosing spondylitis, arthero FOREIGN PATENT DOCUMENTS Sclerosis, arthritis (such as rheumatoid arthritis, infectious EP O537300 4f1995 arthritis, childhood arthritis, psoriatic arthritis, reactive EP 1398O29 A1 3, 2004 arthritis), bone-related diseases (including those related to WO WOO1.78721 A1 10, 2001 bone formation), breast cancer (including those unresponsive WO WOO3,O08635 A2 1, 2003 to anti-estrogen therapy), cardiovascular disorders, cartilage WO WO 2006/004555 A1 1, 2006 related disease (such as cartilage injury/loss, cartilage degen WO WO 2006/047269. A 5, 2006 eration, and those related to cartilage formation), chondrod ysplasia, chondrosarcoma, chronic back injury, chronic OTHER PUBLICATIONS bronchitis, chronic inflammatory airway disease, chronic Wolff, Manfred E. "Burger's Medicinal Chemistry, 5ed, Part I”, John obstructive pulmonary disease, diabetes, disorders of energy Wiley & Sons, 1995, pp.975-977.* homeostasis, gout, pseudogout, lipid disorders, metabolic Banker et al., “Modern Pharmaceutics, 3ed', Marcel Dekker, New syndrome, multiple myeloma, obesity, osteoarthritis, osteo York, 1996, pp. 451 and 596.* genesis imperfecta, osteolytic bone metastasis, osteomalacia, Jordan, V. C. Nature Reviews: Drug Discovery, 2, 2003, pp. 205 osteoporosis, Paget’s disease, periodontal disease, polymy 213).* algia rheumatica, Reiter's syndrome, repetitive stress injury, Berge et al., “Pharmaceutical Salts.”. J. Pharm.Sci., 1977, vol. 66(1), hyperglycemia, elevated blood glucose level, and insulin pp. 1-19. resistance. Gould P.L., “Salt Selection for Basic Drugs.”. International J. Pharm. 1986, vol. 33, pp. 201-217. 6 Claims, No Drawings US 8,580,832 B2 Page 2 (56) References Cited Windahl, S., et al. Increased Cortical Bone Mineral Content but unchanged Trabecular Bone Mineral Density in Female Erf-/-Mice, OTHER PUBLICATIONS Journal of Clinical Investigation, vol. 104, No. 7, 1999, pp. 895-901. Vanacker, J-M., et al. “Transcriptional Targets Shared by Estrogen Bonnelye, E., et al. “Estrogen Receptor-Related Receptor C. Receptor-Related Receptors (ERRs) and Estrogen Receptor (ER) C. Impinges on the Estrogen Axis in Bone: Potential Function in but Not by Erf”. The EMBO Journal, vol. 18, No. 15 1999, pp. Osteoporosis'. Endocrinology 143(9):3658-3670, 2002, pp. 3658 4270-4279. 3670. Bonnelye, E., etal. “The ERR-1 Orphan Receptor is a Transcriptional Ariazi, E. etal. “Estrogen-Related Receptor C. and Estrogen-Related Activator Expressed During Bone Development'. Molecular Endo Receptor Associate with Unfavorable and Favorable Biomarkers, Respectively, in Human Breast Cancer', Cancer Research 62. crinology, 1997, pp. 905-916. 2002, pp. 6510-6518. Sladek, R., et al. “The Orphan Nuclear Receptor Estrogen-Related Xu, H., et al. "Structural Basis for Antagonist-Mediated Recruitment Receptor C. is a Transcriptional Regulator of the Human Medium of Nuclear Co-Repressors by PPARO”. Letters to Nature, vol. 415/ Chain Acyl Coenzyme a Dehydrogenase Gene'. Molecular and Cel 14, 2002 p. 813-817. lular Biology, 1997, pp. 5400-5409. Aranda, A., et al. "Nuclear hormone Receptors and Gene Expres Rochette-Egly, C., et al., “Stimulation of RARO. Activation Function sion'. American Physiological Reviews, vol. 81, No. 3, 2001 pp. AF-1 Through Binding to the General Transcription Factor TFIIH 1269-1304. and Phosphorylation by CDK7, Cell, vol. 90, 1997, pp. 97-107. Kraus, R., et al. “Estrogen-Related Receptor O. 1 Actively antagonizes Vega, R., et al. "A Role for Estrogen-Related Receptor C. in the Estrogen Receptor-Regulated Transcription in MCF-7 Mammary Control of Mitochondrial Fatty Acid B-Oxidation During Brown Cells', the Journal of Biological Chemistry, vol. 277, No. 27, 2002, Adipocyte Differentiation”, Journal of Biological Chemistry, vol. pp. 24862-24834. 272, No. 50, 1997, pp. 31693-31699. Bonnelye, E., et al. “The Orphan Nuclear Estrogen Receptor-Related Wurtz, J., et al. "A Canonical Structure for the Legand-Binding Receptor C. (ERRO) Is Expressed Throughout Osteoblast Differen Domain of Nuclear Receptors', Nature Structural Biology, vol. 3, tiation and Regulates Bone Formation in Vitro”, Journal of Cell No. 1, 1996, pp. 87-94. Biology, vol. 153, No. 5, 2001, pp. 971-983. Korach, K., et al. “Insights from the Study of Animals Lacking Olefsky, J., et al. "Nuclear Receptor'. Journal of Biological Chem Functional Estrogen Receptor'. Science, vol. 266, 1994, pp. 1524 istry, vol. 278, No. 40, 2001, pp. 36863-36864. 1527. Zhang, Z. et al. “Estrogen Receptor-Related Receptor O. l Interacts Turner, R., etel. "Skeletal Effects of Estrogen'. Endocrine Reviews, with Coactivator and Constitutively Activates the Estrogen Response vol. 18, No. 2, 1994, pp. 275-300. Elements of the Human Lactoferrin Gene'. Journal of Biological Rochette-Egly, C., et al. “Retinoic Acid Receptor-B: Immunodetec Chemistry, vol. 275, No. 27, 2000, pp. 20837-20846. tion and Phosphorylatoin on Tyrosine Residues'. Molecular Endo McKenna, N., et al. "Nuclear Receptor Coregulators: Cellular and crinology, 1992, pp. 2197-2209. Molecular Biology, Endocrine Reviews 20(3) 1999, pp. 321-344. Giguere, V., et al. “Identification of a New Class of Steroid Hormone Giguere, V., et al. “Orphan Nuclear Receptors: From Gene to Func Receptors'. Letters to Nature, vol. 331, No. 7, 1988, pp. 91-94. tion”. Endocrine Reviews 2005) 1999, pp. 689-725. Abad et al., “Structural determination of estrogen-related receptor Y Hong, H., et al. “Hormone-Independent Transcriptional Activation in the presence of phenol derivative compounds.”. Journal of Steroid and Coactivator Binding by Novel Orphan Nuclear Receptor ERR3”. Biochemistry & Molecular Biology, 2008, pp. 44-54, vol. 108. Journal of Biological Chemistry, vol. 274, No. 32, 1999, pp. 22618 22626. * cited by examiner US 8,580,832 B2 1. 2 SUBSTITUTED PHENOXY Microbiol. Immunol. 2003, 274,237-268). In the presence of AMINOTHAZOLONES AS ESTROGEN an agonist there is an exchange of co-repressors with co RELATED RECEPTOR-O MODULATORS 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 This application claims the benefit of U.S. Provisional co-regulatory proteins. In the presence of an agonist the AF-2 Application No. 60/893.464, filed Mar. 7, 2007, which is domain undergoes a conformational transition
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