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. 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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