NOVEL COMPOUNDS USEFUL FOR THE TREATMENT OF DEGENERATIVE AND INFLAMMATORY DISEASES

摘要

[1,2,4]triazolo[1,5-a]pyridine compounds are disclosed that have a formula represented by the following:;;The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, diseases involving cartilage degradation, bone and/or joint degradation, for example osteoarthritis; and/or conditions involving inflammation or immune responses, such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin-driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), diseases involving impairment of cartilage turnover (e.g. diseases involving the anabolic stimulation of chondrocytes), congenital cartilage malformations, diseases associated with hypersecretion of IL6 and transplantation rejection (e.g. organ transplant rejection) and proliferative diseases.

主权项

1. A method for the treatment and/or prevention of diseases involving cartilage degradation, bone and/or joint degradation, for example osteoarthritis; and/or conditions involving inflammation or immune responses, such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin-driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), diseases involving impairment of cartilage turnover (e.g. diseases involving the anabolic stimulation of chondrocytes), congenital cartilage malformations, diseases associated with hypersecretion of IL6 and transplantation rejection (e.g. organ transplant rejection) or proliferative diseases,
said method comprising administering a therapeutically effective amount of a compound according to Formula I:wherein
Cy1 is selected from aryl and heteroaryl; L1 is selected from a single bond, —O—, —C(O)—, —C[═N(R4a)]—, —N(R4a)—, —CON(R4a)—, —SO2N(R4a)—, —S(O)2—, —N(R4a)CO—, —CH2—N(R4a)— or —N(R4a)SO2—; each R1 is independently selected from C1-C6 alkyl, substituted C1-C6 alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted amido, substituted or unsubstituted amino, substituted sulfinyl, substituted sulfonyl, substituted or unsubstituted aminosulfonyl, sulfonic acid, sulfonic acid ester, carboxy, cyano, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, halo, and hydroxyl; each R3a is independently selected from C1-C6 alkyl, substituted C1-C6 alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted amido, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyloxy, substituted arylalkyloxy, substituted or unsubstituted amino, aryl, substituted aryl, arylalkyl, substituted sulfanyl, substituted sulfinyl, substituted sulfonyl, substituted or unsubstituted aminosulfonyl, sulfonic acid, sulfonic acid ester, azido, carboxy, cyano, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, halo, substituted or unsubstituted heteroaryl, hydroxyl, nitro, and thiol; R2a is selected from substituted or unsubstituted C1-C6 alkyl and substituted or unsubstituted C3-C7 cycloalkyl; R3b is independently selected from substituted or unsubstituted aryl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl; or R3b is independently selected from O—R3c, NH—R3c, CO—R3c, and CON(R4a)—R3c; and R3c is independently selected from substituted C1-C6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl; each R4a, R4b and R4c is independently selected from H, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C7 cycloalkyl, or substituted C3-C7 cycloalkyl, substituted or unsubstituted acyl; m1 is 0, 1, or 2; m2 is 0, 1,2, or 3; and n1 is 0, 1,2,3, or 4; provided that
i) when L1 is —O—, —N(R4a)—, —CH2—N(R4a)—, —CON(R4a)—, or —SO2N(R4a)—, and R3b is other than cycloalkyl, aryl or 5-10 membered heteroaryl, then n1 is 1, 2, 3, or 4;ii) when Cy1 is Ph, L1 is a bond, n1 is 0, and R3b is —OR3c, then R3c is other than Me or CF3; or a pharmaceutically acceptable salt thereof.