US-12617774-B2 - Substituted indole compounds and methods of use thereof

US12617774B2US 12617774 B2US12617774 B2US 12617774B2US-12617774-B2

Abstract

Provided herein are substituted indole compounds. In certain embodiments, the compounds are inhibitors of the alternative pathway of the complement system, and in particular, inhibitors of complement factor B (CFB). Also provided are compositions comprising the compounds and methods of use thereof. The compounds provided are useful in the treatment, prevention or amelioration of a disease, condition or disorder through inhibition of the complement alternative pathway.

Inventors

Brian P. Bestvater
Jinyue DING
Robert Gomez
Nicholas Anton Mateyko
Taro Oike
David Andrew POWELL
Victoria Elizabeth Rose
Tao Sheng

Assignees

NOVARTIS PHARMA AG

Dates

Publication Date: 20260505
Application Date: 20250530

Claims (16)

1 . A compound represented by: or a pharmaceutically acceptable salt thereof.
2 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
3 . The pharmaceutical composition of claim 2 , wherein the pharmaceutical composition is in a solid dosage form.
4 . A method of treating a disease or disorder mediated by complement factor B, comprising administering to a subject having the disease or disorder, a therapeutically effective amount of the compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein the disease or disorder is age-related macular degeneration.
5 . An isotopic variant of a compound represented by: or a pharmaceutically acceptable salt thereof.
6 . The pharmaceutical composition of claim 2 , wherein the compound of claim 1 in the pharmaceutical composition is enantiomerically pure.
7 . The pharmaceutical composition of claim 6 , wherein the compound of claim 1 is more than 85% by weight in the pharmaceutical composition to the exclusion of its corresponding non-superimposable mirror image.
8 . The pharmaceutical composition of claim 6 , wherein the compound of claim 1 is more than 90% by weight in the pharmaceutical composition to the exclusion of its corresponding non-superimposable mirror image.
9 . The pharmaceutical composition of claim 6 , wherein the compound of claim 1 is more than 95% by weight in the pharmaceutical composition to the exclusion of its corresponding non-superimposable mirror image.
10 . A method of treating a disease or disorder mediated by complement factor B, comprising administering to a subject having the disease or disorder the pharmaceutical composition of claim 2 , wherein the disease or disorder is age-related macular degeneration.
11 . A method of treating a disease or disorder mediated by complement factor B, comprising administering to a subject having the disease or disorder, a therapeutically effective amount of the compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein the disease or disorder is geographic atrophy.
12 . A method of treating a disease or disorder mediated by complement factor B, comprising administering to a subject having the disease or disorder the pharmaceutical composition of claim 2 , wherein the disease or disorder is geographic atrophy.
13 . A method of treating a disease or disorder mediated by complement factor B, comprising administering to a subject having the disease or disorder, a therapeutically effective amount of the compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein the disease or disorder is focal segmental glomerulosclerosis.
14 . A method of treating a disease or disorder mediated by complement factor B, comprising administering to a subject having the disease or disorder the pharmaceutical composition of claim 2 , wherein the disease or disorder is focal segmental glomerulosclerosis.
15 . A method of treating a disease or disorder mediated by complement factor B, comprising administering to a subject having the disease or disorder, a therapeutically effective amount of the compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein the disease or disorder is diabetic nephropathy.
16 . A method of treating a disease or disorder mediated by complement factor B, comprising administering to a subject having the disease or disorder the pharmaceutical composition of claim 2 , wherein the disease or disorder is diabetic nephropathy.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Non-Provisional application Ser. No. 18/566,259 filed on Dec. 1, 2023 which is a National Stage application under 35 U.S.C. § 371 of International Application No. PCT/US2022/032042 having an International Filing Date of Jun. 3, 2022, which claims the benefit of U.S. Provisional Patent Application Nos. 63/196,339, filed on Jun. 3, 2021, 63/290,019, filed on Dec. 15, 2021 and 63/346,120, filed on May 26, 2022. The disclosures of each of these applications are incorporated herein by reference in their entireties. FIELD OF THE INVENTION Provided herein are substituted indole compounds. In certain embodiments, the compounds are inhibitors of the alternative pathway of the complement system, and in particular, complement factor B (CFB). Also provided are compositions comprising the compounds and methods of use thereof. The compounds provided are useful in the treatment, prevention or amelioration of a disease, condition, or disorder through inhibition of the complement alternative pathway. BACKGROUND OF THE INVENTION The complement system is a key component of the innate immunity system with two main functions of host defense against microbial pathogens and clearance of apoptotic cells. Since first discovered by Jules Bordet and Paul Ehrlich in the 1890s, more than a century of research on complement has uncovered its diverse roles in immune response, surveillance, homeostasis, and metabolism (Hajishengallis, Nat Immunol 2017 18: 1288-1298; Sim, Immunobiology 2016 221(10):1037-1045; Ricklin, Nat Immunol 2010 11(9): 785-797). The complement system comprises a large number of soluble proteins that are found in circulation and tissue as inactive zymogens that are activated upon serine protease cleavage. Activation of complement is tightly regulated by both plasma and membrane-bound regulators. Dysregulation of complement activity through genetic mutation, autoantibodies or chronic inflammation has been found to cause tissue damage in various pathological conditions, including autoimmune, inflammatory, neurodegenerative and in a broad range of renal diseases (Zipfel, Nat Rev Immunol 2009 9: 729-749; Holers, Annu Rev Immunol 2014 32: 433-459). There are three activation pathways: the classical pathway (CP), lectin pathway (LP), and alternative pathway (AP) (Merle, Front Immunol 2015 6: 262). The CP is activated by immunoglobulins (IgG and IgM) and immune complexes through binding of C1q to the Fc domain (Botto, Annu Rev Immunol 2002 205:395-406). The LP is activated by a group of proteins that bind to sugars on the surface of bacteria, for example, mannose binding lectin (MBL) (Garred, Immunol Rev 2016 274(1): 74-97). In contrast to the other two pathways that require specific stimuli for activation, the AP maintains a low level of activation in plasma through a spontaneous hydrolysis process called “tickover” and can also be secondarily activated by the other two complement pathways (Lachmann, Adv Immunol 2009 104: 115-149). The AP forms a rapidly self-amplified loop unless inactivated by factor H and factor I. The three activation pathways generate protease complexes termed “C3 convertases” (C3bBb and C4b2a) to cleave C3, and form C3bBbC3b as C5 convertase. The terminal complement pathway assembles C5b with other complement proteins to form C5b-9 membrane attach complex (MAC), which mediates lysis of pathogens or apoptotic cells (Bhakdi, Immunol Today 1991 12: 318-320). Two soluble fragments of C3 and C5 cleavage products, C3a and C5a, also termed “anaphylatoxins” are potent chemo-attractants that trigger pro-inflammatory responses through their receptors (Klos, Mol Immunol 2009 46(14): 2753-2766). Complement overactivation and kidney deposition is observed in various chronic kidney diseases (CKDs) including atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), membranous nephropathy (MN), ANCA-associated vasculitis (AAV), focal segmental glomerulosclerosis (FSGS) and lupus nephritis (LN) (Harris, Semin Immunopathol 2018 40(1): 125-140; Willows, Clin Med 2020 20(2): 156-160). Pre-clinical and clinical evidence support the role of complement, especially the AP, in disease initiation and progression. Genetic defects in complement genes, such as CFH, CFI, CFHRs, CFB, C3 and MCP/CD46, have been directly linked to aHUS and C3G (Bu, J Am Soc Nephrol 2014 25(1): 55-64; Marinozzi, J Am Soc Nephrol 2015 25: 2053-2065; Xiao, Semin Thromb Hemost 2014 40(4): 465-471). Complement activation by autoantibodies and immune complexes in the kidney lead to renal injury and contribute to disease progression in multiple glomerular diseases (Corvillo, Front Immunol 2019 10: 886; Marinozzi, J Am Soc Nephrol 2017 28(5): 1603-1613; Seikrit, N Engl J Med 2018 379(25): 2479-2481). Recent studies provide evidence of kidney local production and activation of complement proteins in CKDs such as IgAN and diabetic kidney disease