TROPOMYOSIN-RELATED KINASE (TRK) INHIBITORS

摘要

Tropomyosin-related kinase inhibitors (Trk inhibitors) are small molecule compounds useful in the treatment of disease. Trk inhibitors can be used as pharmaceutical agents and in pharmaceutical compositions. Trk inhibitors are useful in the treatment of inflammatory diseases, autoimmune disease, defects of bone metabolism and/or cancer, and are particularly useful in the treatment of osteoarthritis (OA), pain, and pain associated with OA. Trk inhibitors are also useful for inhibiting tropomyosin-related kinase A (TrkA), tropomyosin-related kinase B (TrkB), tropomyosin-related kinase C (TrkC), and/or c-FMS (the cellular receptor for colony stimulating factor-1 (CSF-1)).

主权项

1. A compound comprising the structure of Formula (I): wherein: n is 1, 2, 3, 4 or 5; m is 0, 1, 2, 3 or 4; Q1 is H, halo or (C6-C14)aryl, (C2-C9)heteroaryl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl,
wherein the (C6-C14)aryl, (C2-C9)heteroaryl, (C3-C10)cycloalkyl, or (C2-C9)heterocycloalkyl is optionally substituted by one to four groups selected from (C1-C10)alkyl, (C2-C9)heteroalkyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C14)aryl, (C2-C9)heteroaryl, (C1-C10)alkylamine, (C1-C10)alkyl-C(O)O—, COOH—(C1-C10)alkyl, COOH—(C3-C10)cycloalkyl, (C1-C10)alkyl-O—, —OH, —NH2, R7R8N—, R7R8N(O)C—, R7(O)CR8N—, F3C—, NC—, (C3-C10)alkyl(O)P—, (C3-C10)alkyl-S—, (C3-C10)cycloalkyl-S—, (C6-C14)aryl-S—, (C2-C9)heteroalkyl-S—, (C2-C9)heterocycloalkyl-S—, (C2-C9)heteroaryl-S—, (C3-C10)alkyl(O)S—, (C3-C10)cycloalkyl(O)S—, (C6-C14)aryl(O)S—, (C2-C9)heteroalkyl(O)S—, (C2-C9)heterocycloalkyl(O)S—, (C2-C9)heteroaryl(O)S—, (C3-C10)alkyl-O2S—, (C3-C10)cycloalkyl-O2S—, (C6-C14)aryl-O2S—, (C2-C9)heteroalkyl-O2S—, (C2-C9)heterocycloalkyl-O2S—, (C2-C9)heteroaryl-O2S—, or R7R8NO2S—,
wherein R7 and R8 is each independently H, (C1-C10)alkyl, (C2-C9)heteroalkyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C14)aryl, (C2-C9)heteroaryl; Q2 is (C6-C14)aryl, (C2-C9)heteroaryl, (C3-C10)cycloalkyl, or (C2-C9)heterocycloalkyl,
wherein the (C6-C14)aryl, (C2-C9)heteroaryl, (C3-C10)cycloalkyl, or (C2-C9)heterocycloalkyl is optionally substituted by one to four groups selected from (C1-C10)alkyl, (C2-C9)heteroalkyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C14)aryl, (C2-C9)heteroaryl, (C1-C10)alkylamine, (C1-C10)alkyl-C(O)O—, COOH—(C1-C10)alkyl, COOH—(C3-C10)cycloalkyl, (C1-C10)alkyl-O—, —OH, —NH2, R7R8N—, R7R8N(O)C—, R7(O)CR8N—, F3C—, NC—, (C3-C10)alkyl(O)P—, (C3-C10)alkyl-S—, (C3-C10)cycloalkyl-S—, (C6-C14)aryl-S—, (C2-C9)heteroalkyl-S—, (C2-C9)heterocycloalkyl-S—, (C2-C9)heteroaryl-S—, (C3-C10)alkyl(O)S—, (C3-C10)cycloalkyl(O)S—, (C6-C14)aryl(O)S—, (C2-C9)heteroalkyl(O)S—, (C2-C9)heterocycloalkyl(O)S—, (C2-C9)heteroaryl(O)S—, (C3-C10)alkyl-O2S—, (C3-C10)cycloalkyl-O2S—, (C6-C14)aryl-O2S—, (C2-C9)heteroalkyl-O2S—, (C2-C9)heterocycloalkyl-O2S—, (C2-C9)heteroaryl-O2S—, or R7R8NO2S—,
wherein R7 and R8 is each independently H, (C1-C10)alkyl, (C2-C9)heteroalkyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C14)aryl, (C2-C9)heteroaryl; X is CH, N, halo or CR9,
wherein R9 is (C1-C10)alkyl, (C2-C9)heteroalkyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C14)aryl, (C2-C9)heteroaryl, (C1-C10)alkylamine, (C1-C10)alkyl-C(O)O—, COOH—(C1-C10)alkyl, COOH—(C3-C10)cycloalkyl, (C1-C10)alkyl-O—, —OH, —NH2; R1 is H, halo, (C1-C10)alkyl, (C2-C9)heteroalkyl, (C1-C10)alkylamine, or NH2; R2 is H, halo, (C1-C10)alkyl, (C2-C9)heteroalkyl, (C1-C10)alkylamine, (C1-C10)alkyl-O—, or NH2; R3 and R4 are each independently H, (C1-C10)alkyl, (C2-C9)heteroalkyl, (C1-C10)alkylamine, O—(C1-C10)alkyl, or NH2 or R3 and R4 are taken together with the carbon to which they are attached to form a 3 to 10 member ring,
wherein the 3 to 10 member ring is optionally substituted by one to four groups selected from (C1-C10)alkyl, (C2-C9)heteroalkyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C14)aryl, (C2-C9)heteroaryl, (C1-C10)alkylamine, (C1-C10)alkyl-C(O)O—, COOH—(C1-C10)alkyl, COOH—(C3-C10)cycloalkyl, (C1-C10)alkyl-O—, —OH, —NH2; and R5 and R6 are each independently H, (C1-C10)alkyl, (C2-C9)heteroalkyl, (C1-C10)alkylamine, O—(C1-C10)alkyl, or NH2 or R5 and R6 are taken together with the carbon to which they are attached to form a 3 to 10 member ring,
wherein the 3 to 10 member ring is optionally substituted by one to four groups selected from (C1-C10)alkyl, (C2-C9)heteroalkyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C14)aryl, (C2-C9)heteroaryl, (C1-C10)alkylamine, (C1-C10)alkyl-C(O)O—, COOH—(C1-C10)alkyl, COOH—(C3-C10)cycloalkyl, (C1-C10)alkyl-O—, —OH, —NH2;or a pharmaceutically acceptable salt thereof.