Substituted Pyrazolo [1,5-A] Pyrimidine Compounds as TRK Kinase Inhibitors

摘要

Compounds of Formula I:;;and salts thereof in which R1, R2, R3, R4, X, Y and n have the meanings given in the specification, are inhibitors of Trk kinases and are useful in the treatment of diseases which can be treated with a Trk kinase inhibitor such as pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.

主权项

1. A method for treating a disease, condition or disorder mediated by Trk receptor activity in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of formula Ior a pharmaceutically acceptable salt thereof, wherein:
R1 is H or (1-6C alkyl); R2 is H, (1-6C)alkyl, -(1-6C)fluoroalkyl, -(1-6C)difluoroalkyl, -(1-6C)trifluoroalkyl, -(1-6C)chloroalkyl, -(2-6C)chlorofluoroalkyl, -(2-6C)difluorochloroalkyl, -(2-6C)chlorohydroxyalkyl, -(1-6C)hydroxyalkyl, -(2-6C)dihydroxyalkyl, -(1-6C alkyl)CN, -(1-6C alkyl)SO2NH2, -(1-6C alkyl)NHSO2(1-3C alkyl), -(1-6C alkyl)NH2, -(1-6C alkyl)NH(1-4C alkyl), -(1-6C alkyl)N(1-4C alkyl)2, -(1-6C alkyl)NHC(═O)O(1-4C alkyl), -(1-6C alkyl)hetCyc1, -(1-6C alkyl)hetAr1, hetAr2, hetCyc2, —O (1-6C alkyl) which is optionally substituted with halogen, OH or (1-4C)alkoxy, —O(3-6C cycloalkyl), Cyc1, -(1-6C alkyl)(3-6C cycloalkyl), -(1-6Calkyl)(1-4C alkoxy), -(1-6C hydroxyalkyl)(1-4C alkoxy), a bridged 7-membered cycloalkyl ring optionally substituted with (1-6C)hydroxyalkyl, or a bridged 7-8 membered heterocyclic ring having 1-2 ring nitrogen atoms; or NR1R2 forms a 4-6 membered azacyclic ring optionally substituted with one or more substituents independently selected from (1-6C)alkyl, OH, CO2H, (1-3C alkyl)CO2H, —O (1-6C alkyl) and (1-6C)hydroxyalkyl; hetCyc1 is a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc1 is optionally substituted with oxo, OH, halogen or (1-6C)alkyl; hetCyc2 is a 6 membered carbon-linked heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc2 is optionally substituted with F, SO2NH2, SO2(1-3C alkyl) or halogen; hetAr1 is a 5-membered heteroaryl ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with (1-4C)alkyl; hetAr2 is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms and optionally substituted with one or more substituents independently selected from (1-4C)alkyl, (3-6C)cycloalkyl, halogen and OH; Cyc1 is a 3-6 membered cycloalkyl ring which is optionally substituted with one or more substituents independently selected from -(1-4C alkyl), —OH, —OMe, —CO2H, -(1-4C alkyl)OH, halogen and CF3; Y is (i) phenyl optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkoxy, —CF3—CHF2, —O(1-4C alkyl)hetCyc3, -(1-4C alkyl)hetCyc3, —O(1-4C alkyl)O(1-3C alkyl) and —O(3-6C dihydroxyalkyl), or (ii) a 5-6 membered heteroaryl ring having a ring heteroatom selected from N and S, wherein said heteroaryl ring is optionally substituted with one or more substituents independently selected from halogen, —O(1-4C alkyl), (1-4C)alkyl and NH2, or (iii) a pyrid-2-on-3-yl ring optionally substituted with one or more substituents independently selected from halogen and (1-4C)alkyl; hetCyc3 is a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with (1-6C)alkyl; X is —CH2—, —CH2CH2—, —CH2O— or —CH2NRd—; Rd is H or -(1-4C alkyl); R3 is H or -(1-4C alkyl); each R4 is independently selected from halogen, -(1-4C)alkyl, —OH, -(1-4C)alkoxy, —NH2, —NH(1-4C alkyl) and —CH2OH; and n is 0, 1, 2, 3, 4, 5 or 6.