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WO 2018/005552 Al 04 January 2018 (04.01.2018) W!P O PCT

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WO 2018/005552 Al 04 January 2018 (04.01.2018) W!P O PCT (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 2018/005552 Al 04 January 2018 (04.01.2018) W!P O PCT (51) International Patent Classification: Published: A61K 31/517 (2006.01) C07D 401/14 (2006.01) — with international search report (Art. 21(3)) A61K 31/395 (2006.01) — before the expiration of the time limit for amending the (21) International Application Number: claims and to be republished in the event of receipt of PCT/US2017/039587 amendments (Rule 48.2(h)) (22) International Filing Date: 27 June 2017 (27.06.2017) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/355,273 27 June 2016 (27.06.2016) 62/471,799 15 March 20 17 (15.03.20 17) (71) Applicant: ACHILLION PHARMACEUTICALS, INC. [US/US]; 300 George Street, New Haven, CT 065 11 (US). (72) Inventors: WILES, Jason Allan; c/o Achillion Pharma ceuticals, Inc., 300 George Street, New Haven, CT 065 11 (US). PHADKE, Avinash; c/o Achillion Pharmaceuticals, Inc., 300 George Street, New Haven, CT 065 11 (US). (74) Agent: BELLOWS, Brent R. et al; Knowles Intellectu al Property Strategies, LLC, 400 Perimeter Center Terrace, Suite 200, Atlanta, GA 30346 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Declarations under Rule 4.17: — as to applicant's entitlement to apply for and be granted a patent (Rule 4.1 7(H)) — as to the applicant's entitlement to claim the priority of the earlier application (Rule 4.1 7(in)) ©o 00 o (54) Title: QUINAZOLINE AND INDOLE COMPOUNDS TO TREAT MEDICAL DISORDERS (57) Abstract: Compounds, methods of use, and processes for making inhibitors of Complement Factor B are provided. o QUINAZOLINE AND INDOLE COMPOUNDS TO TREAT MEDICAL DISORDERS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Application No. 62/355,273, filed June 27, 2016 and U.S. Application No. 62/471,799 filed March 15, 2017 each of which is incorporated by reference herein for all purposes. BACKGROUND The Complement system is a part of the innate immune system that does not adapt to changes over the course of the host' s life, but is recruited and used by the adaptive immune system. For example, it assists, or complements, the ability of antibodies and phagocytic cells to clear pathogens. This sophisticated regulatory pathway allows rapid reaction to pathogenic organisms while protecting host cells from destruction. Over thirty proteins and protein fragments make up the Complement system. These proteins act through opsonization (enhancing phagocytosis of antigens), chemotaxis (attracting macrophages and neutrophils), cell lysis (rupturing membranes of foreign cells) and agglutination (clustering and binding of pathogens together). The Complement system has three pathways: classical, alternative and lectin. Complement Factor B plays an early and central role in activation of the alternative pathway of the Complement cascade. Activation of the alternative Complement pathway is initiated by spontaneous hydrolysis of a thioester bond within C3 to produce C3(H20), which associates with Factor B to form the C3(H20)B complex. Complement Factor D acts to cleave Factor B within the C3(H20)B complex to form Ba and Bb. The Bb fragment remains associated with C3(H20 ) to form the alternative pathway C3 convertase C3(H20)Bb. Additionally, C3b generated by any of the C3 convertases also associates with Factor B to form C3bB, which Factor D cleaves to generate the later stage alternative pathway C3 convertase C3bBb. This latter form of the alternative pathway C3 convertase may provide important downstream amplification within all three of the defined Complement pathways, leading ultimately to the recruitment and assembly of additional factors in the Complement cascade pathway, including the cleavage of C5 to C5a and C5b. C5b acts in the assembly of factors C6, C7, C8, and C9 into the membrane attack complex, which can destroy pathogenic cells by lysing the cell. The dysfunction or excessive activation of Complement has been linked to certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer. For example, activation of the alternative pathway of the Complement cascade contributes to the production of C3a and C5a, both potent anaphylatoxins that also have roles in a number of inflammatory disorders. Therefore, in some instances, it is desirable to decrease the response of the Complement pathway, including the alternative Complement pathway. Some examples of disorders mediated by the Complement pathway include age-related macular degeneration (AMD), paroxysmal nocturnal hemoglobinuria (P H), multiple sclerosis, and rheumatoid arthritis. Age-related macular degeneration (AMD) is a leading cause of vision loss in industrialized countries. Based on a number of genetic studies, there is evidence of the link between the Complement cascade and macular degeneration. Individuals with mutations in the gene encoding Complement Factor H have a fivefold increased risk of macular degeneration and individuals with mutations in other Complement factor genes, including Factor B, also have an increased risk of AMD. Individuals with mutant Factor H also have increased levels of C-reactive protein, a marker of inflammation. Without adequate functioning Factor H, the alternative pathway of the Complement cascade is overly activated leading to cellular damage. Inhibition of the alternative pathway is thus desired. Paroxysmal nocturnal hemoglobinuria (PNH) is a non-malignant, hematological disorder characterized by the expansion of hematopoietic stem cells and progeny mature blood cells which are deficient in some surface proteins. PNH erythrocytes are not capable of modulating their surface Complement activation, which leads to the typical hallmark of PNH - the chronic activation of Complement mediated intravascular anemia. Currently, only one product, the anti- C5 monoclonal antibody eculizumab, has been approved in the U.S. for treatment of PNH. However, many of the patients treated with eculizumab remain anemic, and many patients continue to require blood transfusions. In addition, treatment with eculizumab requires life-long intravenous injections. Thus, there is an unmet need to develop novel inhibitors of the Complement pathway. Other disorders that have been linked to the Complement cascade include atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), abdominal aortic aneurysm, hemodialysis complications, hemolytic anemia, or hemodialysis, neuromyelitis ( MO), myasthenia gravis (MG), fatty liver disease, nonalcoholic steatohepatitis (NASH), liver inflammation, cirrhosis, liver failure, dermatomyositis, and amyotrophic lateral sclerosis. While initial attempts have been made to develop inhibitors of Factor B, there are currently no small molecule Factor B inhibitors in clinical trials. Examples of Factor B inhibitors are described in the following disclosures: Advanced Vision Therapies Inc. patent publication WO2008/106644 titled "Treatment of diseases characterized by inflammation"; Wellstate Immunotherapeutics 11c patent publication WO2012/151468 titled "Complement Factor B analogs and their uses"; William Marsh Rice University patent publication WO2014/035876 titled "Heat- inactivated Complement Factor B compositions and methods"; Muse. Foundation for Research Development patent publication US1999/023485 titled "Blocking factor b to treat complement- mediated immune disease"; and Novartis patent publication WO2013/192345 and US2015/126592 titled "Complement pathway modulators and uses thereof. Additional Factor B inhibitors are described in Novartis patent publications WO20 15/066241, US2016/3 11779, WO20 15/0096 16, US2016/152605, WO2014/143638, and US20 16/024079. Another example of Factor B inhibitors is the IONIS Pharmaceuticals Inc. patent publication WO2015/038939 titled "Modulators of Complement Factor B". Examples of granted patents covering Factor B inhibitors include US 9,452,990; US 9,676,728; US 9,682,968; and US 9,475,806. Given the wide variety of medical disorders that are caused by detrimental immune or inflammatory responses, new uses and compounds are needed for medical treatment. It is an object of the present invention to provide compounds which act as Complement Factor B inhibitors for the treatment of disorders in a host, including a human, associated with misregulation
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