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(12) Patent Application Publication (10) Pub. No.: US 2011/0237625 A1 Gaul Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2011/0237625 A1 Gaul Et Al 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 II veh Time, mi Patent Application Publication Sep. 29, 2011 Sheet 2 of 12 US 2011/0237625 A1 wo. A. Vehicle ot-B: Compound - 3mpk -a-. C. Compound 110mpk -X- D. Compound 1.30mpk i 5 O Days F.G. 3 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 sC 3s 35 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 kiinutes F.G. 6 AUC of a g/kg OGT in ZDF Rats Treated 4 Weeks with compound 1 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 orror A. Velicie --B: Compound 4-0.08mpk -&- C. Compound 1-0.4mpk --- D. Compound 1-2mpk -x-E. Compound 4- 10mpk tiri i. 1. * M - c. dped O 3. 6 3. vites 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.
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