US009120776B2 (12) United States Patent (10) Patent No.: US 9,120,776 B2 Yamamoto et al. (45) Date of Patent: Sep. 1, 2015 (54) CONDENSED HETEROCYCLIC COMPOUND 2003/0171309 A1 9/2003 Halazy et al. 2003/0212012 A1 1 1/2003 Halazy et al. 2004, OO67988 A1 4/2004 Klein et al. (71) Applicant: Takeda Pharmaceutical Company 2004.0102634 A1 5/2004 Matsuura et al. Limited, Osaka-shi, Osaka (JP) 2006/0247307 A1 11/2006 Kitahara et al. 2006/0264486 A1 11/2006 Ma et al. (72) Inventors: Satoshi Yamamoto, Kanagawa (JP); 2008.0167318 A1 7/2008 Halazy et al. 2008. O176904 A1 7/2008 Govek et al. Junya Shirai, Kanagawa (JP); 2008/0221157 A1 9/2008 Chakravarty et al. Yoshiyuki Fukase, Kanagawa (JP); 2009,0163511 A1 6/2009 Darwish et al. Yoshihide Tomata, Kanagawa (JP); 2009,025.3758 A1 10, 2009 Miller Ayumu Sato, Kanagawa (JP); Atsuko 2009/0275609 A1 11/2009 Yu et al. 2009,0298854 A1 12/2009 Ma et al. Ochida, Kanagawa (JP); Kazuko 2010.0041721 A1 2, 2010 Miller Yonemori, Kanagawa (JP); Hideyuki 2011/0059958 A1 3/2011 Nishida et al. Nakagawa, Kanagawa (JP) 2011/O135650 A1 6/2011 Chackalamannil et al. 2011/0224267 A1 9, 2011 Miller (73) Assignee: Takeda Pharmaceutical Company 2011/0245222 A1 10/2011 Payan et al. Limited, Osaka (JP) 2011/0263.046 A1 10/2011 Deuschle et al. 2011/0319412 A1 12/2011 Sakagami et al. (*) Notice: Subject to any disclaimer, the term of this 2012/0108606 A1 5, 2012 Darwish et al. patent is extended or adjusted under 35 2013,0023660 A1 1/2013 Yu et al. U.S.C. 154(b) by 0 days. (Continued) (21) Appl. No.: 14/346,071 FOREIGN PATENT DOCUMENTS JP 2003-529584 10, 2003 (22) PCT Filed: Sep. 21, 2012 WO 86,067.17 11, 1986 (86). PCT No.: PCT/UP2012/074282 (Continued) S371 (c)(1), (2) Date: Mar. 20, 2014 OTHER PUBLICATIONS Registry STN Database accession No. 736964-37-7, Sep. 2004—1 (87) PCT Pub. No.: WO2013/042782 page. PCT Pub. Date: Mar. 28, 2013 (Continued) (65) Prior Publication Data US 2014/02284.09 A1 Aug. 14, 2014 Primary Examiner — Kristin Vajda (30) Foreign Application Priority Data (74) Attorney, Agent, or Firm — Hamre, Schumann, Mueller & Larson, P.C. Sep. 22, 2011 (JP) ................................. 2011-2O7358 (51) Int. Cl. (57) ABSTRACT A6 IK3I/403 (2006.01) A6 IK3I/404 (2006.01) The present invention provides a fused heterocyclic com CO7D 40/12 (2006.01) pound having an RORyt inhibitory action. The present inven CO7D 209/88 (2006.01) tion relates to a compound represented by the formula (I): C07D 209/08 (2006.01) (52) U.S. Cl. (I) CPC ............ C07D401/12 (2013.01); A61 K31/403 --R3A (2013.01); A61 K3I/404 (2013.01); C07D 209/08 (2013.01); C07D 209/88 (2013.01) : Q (58) Field of Classification Search R24 7 B -HCN USPC ........ 514/339, 411, 415: 546/276.7: 548/444, N SA 548/503 A See application file for complete search history. RIA (56) References Cited wherein each symbol is as defined in the specification, pro U.S. PATENT DOCUMENTS vided that 2-(2-((4-cyanophenyl)amino)-2-oxoethoxy)-N- (9-ethyl-9H-carbazol-3-yl)acetamide and N-(4-cyanophe 4,977,153 A 12/1990 Louis et al. nyl)-N'-(9-ethyl-9H-carbazol-3-yl)-3- 6,080,767 A 6, 2000 Klein et al. 6,140,504 A 10, 2000 Klein et al. methylpentanediamide are excluded, or a thereof. 6,277,865 B1 8, 2001 Klein et al. 6,323,227 B1 1 1/2001 Klein et al. 2002fOO16339 A1 2/2002 Klein et al. 12 Claims, 3 Drawing Sheets US 9,120,776 B2 Page 2 (56) References Cited Kumar, et al., “The Benzenesulfoamide T0901317 N-2.2.2 -Trifluoroethyl-N-4-2.2.2-trifluoro-1-hydroxy-1- U.S. PATENT DOCUMENTS (trifluoromethypethyl)ethnylphenyl-benzenesulfonamide Is a Novel Retinoic Acid Receptor-Related Orphan Receptor-O/Y Inverse 2013,011.6288 A1 5, 2013 Miller Agonist'. Mol. Pharmacol., vol. 77. No. 2, 2010, pp. 228-236. 2013/0211075 A1 8, 2013 Ushio et al. Huh, et al., “Digoxin and its derivatives suppress T17 cell differen 2014/0045882 A1 2/2014 Darwish et al. tiation by antagonizing RORytactivity”. Nature, vol. 472, Apr. 2011, pp. 486-490. FOREIGN PATENT DOCUMENTS Wang, et al., “Identification of SR1078, a Synthetic Agonist for the Orphan Nuclear Receptors RORO and RORY”. ACS Chemical Biol WO 97.241.18 7/1997 ogy, vol. 5, No. 11, pp. 1029-1034, 2010. WO 99.00356 1, 1999 Xu, et al., “Ursolic Acid Suppresses Interleukin-17 (IL-17) Produc WO O 1/72705 10, 2001 tion by Selectively Antagonizing the Function of RORyt Protein'. WO O 1/74769 10, 2001 The Journal of Biological Chemistry, vol. 286, 2011, pp. 22707 WO 02/100812 12/2002 22710. WO 2004/074236 9, 2004 Wang, et al., “Modulation of Retinoic Acid Receptor-related Orphan WO 2004/098498 11, 2004 WO 2006/005.941 1, 2006 Receptor C. and Y Activity by 7-Oxygenated Sterol Ligands'. The WO 2006/091496 8, 2006 Journal of Biological Chemistry, vol. 285, 2010, pp. 5013-5025. WO 2009,076631 6, 2009 Wang, et al., “A second class of nuclear receptors for oxysterols: WO 2010/049144 5, 2010 Regulation of RORO and RORY activity by 24S-hydroxycholesterol WO 2010/065717 6, 2010 (cerebrosterol)”. Biochimicaet Biophysica Acta, vol. 1801, 2010, pp. WO 2010, 10 1246 9, 2010 917-923. WO 2011/123681 10, 2011 Jin, et al., “Structural Basis for Hydroxycholesterols as Natural WO 2012/05O159 4/2012 Ligands of Orphan Nuclear receptor RORY”. Mol. Endocrinol, vol. 24, No. 5, 2010, pp. 923-929. OTHER PUBLICATIONS Registry STN Database accession No. 1036688-95-5. Jul. 2008—1 page. Registry STN Database accession No. 737780-18-6, Sep. 2004—1 Registry STN Database accession No. 1327387-55-2, Sep. 2011—1 page. page. Ivanov, et al., “The orphan Nuclear Receptor RORyt Directs the Registry STN Database accession No. 1036676-51-3, Jul. 2008—1 Differentiation Program of Proinflammatory IL-17'T Helper Cells'. page. Cell, vol. 126, Sep. 2006, pp. 1121-1133. Registry STN Database accession No. 1015722-56-1, Apr. 2008—1 Manel, et al., “The differentiation of human T-17 cells requires page. transforming growth factor-fi and induction of the nuclear receptor Registry STN Database accession No. 745025-44-9, Sep. 2004—1 RORyt”. Nature Immunology, vol. 9, No. 6, Jun. 2008, pp. 641-649. page. Solt, et al., “Suppression of T-17 differentiation and autoimmunity Registry STN Database accession No. 568539-93-5, Aug. 2003—1 by a synthetic ROR ligand’, Nature, vol. 472, Apr. 2011, p. 491. page. U.S. Patent Sep. 1, 2015 Sheet 1 of 3 US 9,120,776 B2 Fig. 1 Aouse LAVACTB 2.SE-04 (10) (25) (53) 2.0E-04 15E-04 1.OE-04 5 OE-05 0.0E+00 Normal Control 30 OO 300 The COImpound of Example 14 (mg/kg, p O) n = 6, mean+SE ##: p < 0.01 vs normal; student's t test, * : p < 0.025 vs control; William's test U.S. Patent Sep. 1, 2015 Sheet 2 of 3 US 9,120,776 B2 Fig. 2 Vouse IFNg/ACTB 6.OE-04 (-3) (2) (3) S.OE-04 4.OE-04 3.OE-04 2.OE-04 1.OE-04 O.OE-00 Normal Control 30 100 300 The Compound of Example 14 (Ing/kg, po) n = 6, meanic SE i ! : p < 0.01 vs normal; student's t test, * : p < 0.025 vs control; William's test U.S. Patent Sep. 1, 2015 Sheet 3 of 3 US 9,120,776 B2 Fig. 3 0.02 -17AmRNA O.O15 (29.4) S.S. O.01 (61.0) (66.6) t 0.005 - O rio ------------------------, vocroe, aw,go crg Normal Control 3O 100 300 The Compound of Example 1.4 (mg/kg, po) ?:6, means SE US 9,120,776 B2 1. 2 CONDENSED HETEROCYCLIC COMPOUND wherein rS and rô may together form TECHNICAL FIELD The present invention relates to a fused heterocyclic com \ / pound having an RORyt inhibitory action, a medicament con taining the compound, and the like. Y. W. BACKGROUND OF THE INVENTION 10 Th17 cell and inflammatory cytokine (IL-17A, IL-17F and ^ - the like) produced thereby cause various autoimmune disease such as inflammatory bowel disease (IBD), rheumatoid As a compound having an RORC. and RORY inverse ago arthritis, multiple Sclerosis or psoriasis, and a decrease in 15 nist activity, non-patent document 3 describes a compound QOL as a severe etiology cell and factor accompanying represented by the formula: enhancement of a systemic new immune response. However, the existing therapeutic drugs show only limited effects, and therefore, the earliest possible development of a novel thera peutic drug has been desired. O N H F Involvement of T cells, interalia, Th17 cell and inflamma us us S N F tory cytokines (IL-17A, IL-17F and the like) produced N S / \, OH thereby, in the pathology of these autoimmune disease has 25 F been drawing attention in recent years. F Moreover, it has been recently clarified that a Retinoid related Orphan Receptor (ROR) yt, which is one of the orphan nuclear receptors, plays an important role in the differentia (SR1001) tion of Th17 cells and production of IL-17A/IL-17F. That is, 30 it has been reported that RORyt is mainly expressed in Th17 and non-patent document 4 describes a compound repre cells and functions as a transcription factor of IL-17A and sented by the formula: IL-17F, as well as a master regulator of Th17 cell differentia tion (non-patent documents 1 and 2).