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WO 2015/150995 Al 8 October 2015 (08.10.2015) P O P C T

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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/150995 Al 8 October 2015 (08.10.2015) P O P C T (51) International Patent Classification: Somerset, New Jersey 08873 (US). DEHNHARDT, C07D 207/26 (2006.01) C07D 487/04 (2006.01) Christoph Martin; 1803-4400 Buchanan Street, Burnaby, C07D 207/273 (2006.01) C07D 491/056 (2006.01) British Columbia V5C 0E3 (CA). GAVRIN, Lori Krim; C07D 209/52 (2006.01) C07D 498/04 (2006.01) 306 Clairemont Road, Villanova, Pennsylvania 19085 C07D 215/48 (2006.01) C07C 69/94 (2006.01) (US). GOLDBERG, Joel Adam; 2 116 Short Street, New C07D 217/02 (2006.01) C07C 235/66 (2006.01) Orleans, Louisiana 701 18 (US). HAN, Seungil; 286 Deer- C07D 217/22 (2006.01) C07F 7/18 (2006.01) field Ridge Drive, Mystic, Connecticut 06355 (US). HEP- C07D 217/24 (2006.01) A61K 31/47 (2006.01) WORTH, David; 282 Sudbury Road, Concord, Massachu C07D 239/86 (2006.01) A61K 31/4709 (2006.01) setts 01742 (US). HUANG, Horng-Chih; 1126 Nooning C07D 239/88 (2006.01) A61K 31/472 (2006.01) Tree Drive, Chesterfield, Missouri 63017 (US). LEE, Ar¬ C07D 263/24 (2006.01) A61K 31/4725 (2006.01) thur; 7400 Damascus Road, Gaithersburg, Maryland C07D 401/12 (2006.01) A61K 31/517 (2006.01) 20882 (US). LEE, Katherine Lin; 167 Adams Avenue, C07D 401/14 (2006.01) A61P 19/02 (2006.01) West Newton, Massachusetts 02465 (US). LOVERING, C07D 403/12 (2006.01) A61P 29/00 (2006.01) Frank Eldridge; 2 Sutton PI, Acton, Massachusetts 01720 C07D 405/12 (2006.01) A61P 11/06 (2006.01) (US). LOWE, Michael Dennis; 4 Martine Avenue, # 118, C07D 405/14 (2006.01) A61P 13/12 (2006.01) White Plains, New York 10606 (US). MATHIAS, John C07D 413/12 (2006.01) A61P 17/06 (2006.01) Paul; 1338 Main Street, Concord, Massachusetts 01742 C07D 417/12 (2006.01) (US). PAPAIOANNOU, Nikolaos; 743 East 4th Street, (21) International Application Number: Boston, Massachusetts 02127 (US). PATNY, Akshay; 600 PCT/IB20 15/05225 1 Trapelo Road, Unit 11, Waltham, Massachusetts 02452 (US). PIERCE, Betsy Susan; 237 Grassy Hill Road, East (22) International Filing Date: Lyme, Connecticut 06333 (US). SAIAH, Eddine; 19 Ken 26 March 2015 (26.03.2015) wood Street, Brookline, Massachusetts 02446 (US). (25) Filing Language: English STROHBACH, Joseph Walter; 114 Crockett Creek, Wentzville, Missouri 63385 (US). TRZUPEK, John Dav¬ (26) Publication Language: English id; 55 Station Landing, #51 5, Medford, Massachusetts 02155 (US). VARGAS, Richard; 12 Jonathan Lane, Bed (30) Priority Data: ford, Massachusetts 01730 (US). WANG, Xiaolun; 13572 61/975,473 4 April 2014 (04.04.2014) US Golden Cypress PI, San Diego, California 92130 (US). (71) Applicant: PFIZER INC. [US/US]; 235 East 42nd Street, WRIGHT, Stephen Wayne; 1 Whitman Lane, Old Lyme, New York, New York 10017 (US). Connecticut 06371 (US). ZAPF, Christoph Wolfgang; 48 Kinder Circle, Marlborough, Massachusetts 01752 (US). (72) Inventors: ANDERSON, David Randolph; 32 Fawn Run, Salem, Connecticut 06420 (US). BUNNAGE, Mark Ed¬ (74) Agent: KLEIMAN, Gabriel L.; 235 East 42nd Street, MS ward; 39 Southfield Circle, Concord, Massachusetts 235/9/64, New York, New York 10017 (US). 01742 (US). CURRAN, Kevin Joseph; 18 Grouser Road, [Continued on nextpage] (54) Title: BICYCLIC-FUSED HETEROARYL OR ARYL COMPOUNDS AND THEIR USE AS IRAK4 INHIBITORS (la) © (57) Abstract: Compounds, tautomers and pharmaceutically acceptable salts of the compounds are disclosed, wherein the com pounds have the structure of Formula la, as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed. w o 2015/150995 Ai nn linn ilin II I I rr r II I r rrI r Irr ri I i (81) Designated States (unless otherwise indicated, for every TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, kind of national protection available): AE, AG, AL, AM, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, Declarations under Rule 4.17: KP, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, W, MX, MY, MZ, NA, NG, NI, — as to the identity of the inventor (Rule 4.17(i)) NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, — as to applicant's entitlement to apply for and be granted RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, a patent (Rule 4.1 7(H)) TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. — as to the applicant's entitlement to claim the priority of the earlier application (Rule 4.17(Hi)) (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, Published: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, — with international search report (Art. 21(3)) TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, BICYCLIC-FUSED HETEROARYL OR ARYL COMPOUNDS FIELD OF THE INVENTION This invention pertains to compounds useful for the treatment of autoimmune and inflammatory diseases associated with lnterleukin-1 Receptor Associated Kinase (IRAK) and more particularly compounds that modulate the function of IRAK4. BACKGROUND OF THE INVENTION Protein kinases are families of enzymes that catalyze the phosphorylation of specific residues in proteins, broadly classified in tyrosine and serine/threonine kinases. Inappropriate activity arising from dysregulation of certain kinases by a variety of mechanisms is believed to underlie the causes of many diseases, including but not limited to, cancer, cardiovascular diseases, allergies, asthma, respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative diseases. As such, potent and selective inhibitors of kinases are sought as potential treatments for a variety of human diseases. There is considerable interest in targeting the innate immune system in the treatment of autoimmune diseases and sterile inflammation. Receptors of the innate immune system provide the first line of defense against bacterial and viral insults. These receptors recognize bacterial and viral products as well as pro-inflammatory cytokines and thereby initiate a signaling cascade that ultimately results in the up-regulation of inflammatory cytokines such as TNFa, IL6, and interferons. Recently it has become apparent that self-generated ligands such as nucleic acids and products of inflammation such as high-mobility group protein B 1 (HMGB1) and Advanced Glycated End-products (AGE) are ligands for Toll-like receptors (TLRs) which are key receptors of the innate immune system (O'Neill 2003, Kanzler et al 2007, Wagner 2006). This demonstrates the role of TLRs in the initiation and perpetuation of inflammation due to autoimmunity. lnterleukin-1 receptor associated kinase 4 (IRAK4) is a ubiquitously expressed serine/threonine kinase involved in the regulation of innate immunity (Suzuki & Saito 2006). IRAK4 is responsible for initiating signaling from TLRs and members of the IL- / 8 receptor family. Kinase-inactive knock-ins and targeted deletions of IRAK4 in mice were reported to cause reductions in TLR and IL-1 induced pro-inflammatory cytokines (Kawagoe et al 2007; Fraczek et al. 2008; Kim et al. 2007). IRAK4 kinase-dead knock-in mice have also been shown to be resistant to induced joint inflammation in the antigen-induced-arthritis (AIA) and serum transfer-induced (K/BxN) arthritis models (Koziczak-Holbro 2009). Likewise, humans deficient in IRAK4 also appear to display the inability to respond to challenge by Toll ligands and IL-1 (Hernandez & Bastian 2006). However, the immunodeficient phenotype of IRAK4-null individuals is narrowly restricted to challenge by gram positive bacteria, but not gram negative bacteria, viruses or fungi. This gram positive sensitivity also lessens with age, implying redundant or compensating mechanisms for innate immunity in the absence of IRAK4 (Lavine et al 2007). These data indicate that inhibitors of IRAK4 kinase activity should have therapeutic value in treating cytokine driven autoimmune diseases while having minimal immunosuppressive side effects. Additional recent studies suggest that targeting IRAK4 may be useful in other inflammatory pathologies such as atherosclerosis and diffuse large B-cell lymphoma (Rekhter et al 2008; Ngo et al 201 1). Therefore, inhibitors of IRAK4 kinase activity are potential therapeutics for a wide variety of diseases including but not limited to autoimmunity, inflammation, cardiovascular diseases, cancer, and metabolic diseases. See the following references for additional information: N . Suzuki and T. Saito, Trends in Immunology, 2006, 27, 566. T . Kawagoe, S. Sato, A . Jung, M . Yamamoto, K . Matsui, H . Kato, S. Uematsu, O. Takeuchi and S. Akira, Journal of Experimental Medicine, 2007, 204, 1013. J. Fraczek, T. W. Kim, H . Xiao, J. Yao, Q . Wen, Y . Li, J.-L. Casanova, J. Pryjma and X . Li, Journal of Biological Chemistry, 2008, 283, 31697. T. W . Kim, K . Staschke, K . Bulek, J. Yao, K . Peters, K.-H. Oh, Y . Vandenburg, H . Xiao, W . Qian, T. Hamilton, B. Min, G . Sen, R . Gilmour and X . Li, Journal of Experimental Medicine, 2007, 204, 1025. M . Koziczak-Holbro, A . Littlewood- Evans, B. Pollinger, J. Kovarik, J. Dawson, G . Zenke, C. Burkhart, M . Muller and H . Gram, Arthritis & Rheumatism, 2009, 60, 1661.
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  • Us 2018 / 0296525 A1

    Us 2018 / 0296525 A1

    UN US 20180296525A1 ( 19) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2018/ 0296525 A1 ROIZMAN et al. ( 43 ) Pub . Date: Oct. 18 , 2018 ( 54 ) TREATMENT OF AGE - RELATED MACULAR A61K 38 /1709 ( 2013 .01 ) ; A61K 38 / 1866 DEGENERATION AND OTHER EYE (2013 . 01 ) ; A61K 31/ 40 ( 2013 .01 ) DISEASES WITH ONE OR MORE THERAPEUTIC AGENTS (71 ) Applicant: MacRegen , Inc ., San Jose , CA (US ) (57 ) ABSTRACT ( 72 ) Inventors : Keith ROIZMAN , San Jose , CA (US ) ; The present disclosure provides therapeutic agents for the Martin RUDOLF , Luebeck (DE ) treatment of age - related macular degeneration ( AMD ) and other eye disorders. One or more therapeutic agents can be (21 ) Appl. No .: 15 /910 , 992 used to treat any stages ( including the early , intermediate ( 22 ) Filed : Mar. 2 , 2018 and advance stages ) of AMD , and any phenotypes of AMD , including geographic atrophy ( including non -central GA and Related U . S . Application Data central GA ) and neovascularization ( including types 1 , 2 and 3 NV ) . In certain embodiments , an anti - dyslipidemic agent ( 60 ) Provisional application No . 62/ 467 ,073 , filed on Mar . ( e . g . , an apolipoprotein mimetic and / or a statin ) is used 3 , 2017 . alone to treat or slow the progression of atrophic AMD Publication Classification ( including early AMD and intermediate AMD ) , and / or to (51 ) Int. CI. prevent or delay the onset of AMD , advanced AMD and /or A61K 31/ 366 ( 2006 . 01 ) neovascular AMD . In further embodiments , two or more A61P 27 /02 ( 2006 .01 ) therapeutic agents ( e . g ., any combinations of an anti - dys A61K 9 / 00 ( 2006 . 01 ) lipidemic agent, an antioxidant, an anti- inflammatory agent, A61K 31 / 40 ( 2006 .01 ) a complement inhibitor, a neuroprotector and an anti - angio A61K 45 / 06 ( 2006 .01 ) genic agent ) that target multiple underlying factors of AMD A61K 38 / 17 ( 2006 .01 ) ( e .