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WO 2016/147053 Al 22 September 2016 (22.09.2016) P O P C T

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WO 2016/147053 Al 22 September 2016 (22.09.2016) P O P C T (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 2016/147053 Al 22 September 2016 (22.09.2016) P O P C T (51) International Patent Classification: (71) Applicant: RESVERLOGIX CORP. [CA/CA]; 300, A61K 31/551 (2006.01) A61P 37/02 (2006.01) 4820 Richard Road Sw, Calgary, AB, T3E 6L1 (CA). A61K 31/517 (2006.01) C07D 239/91 (2006.01) (72) Inventors: WASIAK, Sylwia; 431 Whispering Water (21) International Application Number: Trail, Calgary, AB, T3Z 3V1 (CA). KULIKOWSKI, PCT/IB20 16/000443 Ewelina, B.; 31100 Swift Creek Terrace, Calgary, AB, T3Z 0B7 (CA). HALLIDAY, Christopher, R.A.; 403 (22) International Filing Date: 138-18th Avenue SE, Calgary, AB, T2G 5P9 (CA). GIL- 10 March 2016 (10.03.2016) HAM, Dean; 249 Scenic View Close NW, Calgary, AB, (25) Filing Language: English T3L 1Y5 (CA). (26) Publication Language: English (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (30) Priority Data: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 62/132,572 13 March 2015 (13.03.2015) US BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 62/264,768 8 December 2015 (08. 12.2015) US DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, [Continued on nextpage] (54) Title: COMPOSITIONS AND THERAPEUTIC METHODS FOR THE TREATMENT OF COMPLEMENT-ASSOCIATED DISEASES (57) Abstract: The invention comprises methods of modulating the complement cascade in a mammal and for treating and/or preventing diseases and disorders as sociated with the complement pathway by administering a compound of Formula I or Formula II, such as, for example, 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)- 5,7-dimethoxyquinazolin-4(3H)-one or a pharmaceutically acceptable salt thereof. w o 2016/147053 A i III II II 11 I Illlll 111 III III 11 lllll lllll Hill lllll 111 llll 11llll HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). ZA, ZM, ZW. Published: (84) Designated States (unless otherwise indicated, for every — with international search report (Art. 21(3)) kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, COMPOSITIONS AND THERAPEUTIC METHODS FOR THE TREATMENT OF COMPLEMENT-ASSOCIATED DISEASES [0001] This application clai ms priority from U.S. Provisiona l Patent Application No. 62/132,572, filed March 13, 2015, and U.S. Provisiona l Patent Application No. 62/264,768, filed Decem ber 8, 2015, which are hereby incorporated by reference in their enti rety. [0002] The present disclosure relates to methods of treating or preventi ng com plement-associated diseases or disorders by administering to a su bject in need thereof, a com pound of Form ula I or Formu la II or a stereoisomer, tautomer, pharmaceutical ly acceptable sa lt, or hydrate thereof. Thera peutic strategies for mod ulating the com plement system to treat or prevent diseases or disorders associated with aberra nt complement system activity are disclosed. [0003] Com pou nds of Form ula I and methods of making those com pounds have previously been descri bed in U.S. Patent 8,053,440, incorporated herein by reference. Com pounds of Form ula I include : Form ula I andstereoisomers, tautomers, pha rmaceutica lly accepta ble salts, or hydrates thereof, wherein : R i and R3 are each independently selected from alkoxy, alkyl, amino, halogen, and hydrogen; R2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, ami no, halogen, and hydrogen; R5 and R are each independently selected from alkyl, alkoxy, amino, halogen, and hydrogen; R6 is selected from amino, amide, alkyl, hydrogen, hydroxyl, piperazinyl, and alkoxy; and W is CH or N. In some embodiments, when R6 is selected from alkoxy, it is optionally substituted with one or more groups chosen from amide, amine, aryl, benzyloxy, carbamate, carboxy, heterocyclyl, hydroxyl, methoxy, and sulfonamide. [0004] Compounds of Formula II and methods of making those compounds have previously been described in US Patent No. 8,569,288 and PCT Publication No. WO2010/049466, incorporated herein by reference. Compounds of Formula II include: Formula II and stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, wherein: R and RB are independently selected from hydrogen, methyl, -(CH 2)nRF, - (CH 2)nO RF, and -CH 2C(0)ORG; Rc is selected from hydrogen, para-halogen, and -OCH 20 - or -OCH 2CH20 - connected to the ortho and meta positions or connected to the meta and para positions of the phenyl ring; RD and RE are independently selected from hydrogen and methyl; R is selected from methyl, ethyl, and -CH 2CH2OCH 3; RG is selected from methyl, Ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl; and n is selected from 1,2,3, and 4 . [0005] The main function of the human immune system is host defense. This system distinguishes locally-produced entities, including tissues, cells and molecules, from foreign entities, referred to as pathogens, and eliminates these potentially harmful molecules and cells from the body. Additionally, the immune system has the ability to recognize and remove abnormal cells that are derived from host tissues. Molecules that are recognized as foreign entities by the immune system are termed antigens. The immune system is composed of two responses, the innate response and the adaptive response. Several molecular components, such as, complement proteins, cytokines and acute phase proteins, act in both the innate and adaptive immune responses. [0006] Adaptive immunity is known as the antigen-specific immune response. It functions through a sequence of recognition and processing events that result in either an antibody or cell-mediated response. Two main classes of lymphocytes (white blood cells), T cells and B cells, are involved in adaptive immunity. The recognition of foreign antigens by a vast array of antigen-specific receptors on these lymphocytes enables specific identification and elimination of pathogens. This process may take several days or weeks to develop, but the adaptive immune response employs immunological memory to incur a stronger, more rapid response upon subsequent exposure to the specific antigen. [0007] In contrast, innate immunity refers to the non-specific immune response that is activated immediately following the introduction of an entity recognized as foreign into the body. The innate immune response is not adaptable and does not change over the course of an individual's lifetime. The components of the innate immune response, including monocytes, neutrophils, eosinophils, basophils and natural killer cells, circulate in the blood and are readily activated and localized at the site of an immune breach. [0008] The complement system contains a network of tightly regulated proteins when taken together are a key part of the innate immune response. The complement system represents one of the major effector mechanisms of the innate immune response, and comprises more than 30 blood soluble or membrane- associated proteins. The concentration of these proteins in the plasma totals more tha n 3 g per liter. Wal port (2001) "Com plement First of two parts." N Engl J Med 344 (14) : 1058-1066. [0009] Most com plement proteins circulate as pro-proteins and the com plement system remai ns inactive until triggered. The array of complement proteins are orga nized in a hiera rchy of proteolytic cascades that are triggered by the recognition of antigen-anti body com plex or sim ply an antigen on the surface of a pathogen. Antibodies are serum proteins that are produced by B cells in the ada ptive immune response to ena ble more rapid recognition of known antigens. Therefore, if a li ke-a ntigen is reintrod uced, the circu lating anti bodies are readi ly availa ble t o bind the antigen and create the antigen-a nti body com plex, which is su bseq uently recognized by T cells or the com plement system . [0010] The activation of the com plement system involves zymogenic protei ns (inactive enzymatic protein) that are subsequently cleaved and activated by a series of proteases. Com plement activation is known t o occur t hrough three pri ncipa l pathways: classica l, alternative and lecti n. Though various factors ca n initiate com plement activation, the three main pathways converge at the cleavage of C3, the most abunda nt com plement protein in the blood. Dun kel berger and Song (2010) "Com plement and its role in innate and ada ptive immune responses" Cell Res 20 (1) : 34-50. [0011] The initiation of the classica l pathway is triggered via the recognition of antigen-anti body (im mune) com plexes on the surface of foreign cells by com plement protein Clq in com plex with Clr and Cls (the CI com plex). Sa rma and Ward (2011) "The com plement system" Cell Tissue Res 343 (1): 227-235.
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