Compounds of N-pyrrolidinyl, N'-pyrazolylurea, thiourea, guanidine and cyanoguanidine as Trka kinase inhibitors

摘要

A compound selected - from among the compounds of Formula I: ** (See formula) ** or pharmaceutically acceptable stereoisomers, tautomers or salts or solvates thereof, where ring B and the NH-C moiety ( = X) - NH are in trans configuration; Ra, Rb, Rc and Rd are independently selected from H and alkyl (1-3C), or Rc and Rd are independently selected from H and alkyl (1-3C), and Ra and Rb, together with the atom to which they are linked, they form a cyclopropyl ring; X is O, S, NH or N-CN; R1 is (1-3C alkoxy) (1-6C alkyl), (trifluoromethoxy) (1-6C) alkyl, (1-3C-sulfanyl) alkyl (1-6C), monofluoroalkyl (1-6C), difluoroalkyl (1 -6C), trifluoroalkyl (1-6C), tetrafluoroalkyl (2-6C), pentafluoroalkyl (2-6C), cyanoalkyl (1-6C), aminocarbonylalkyl (1-6C), hydroxyalkyl (1-6C), dihydroxyalkyl (2- 6C), alkyl (1-6C), (alkyl 1-3C-amino) alkyl (1-3C), (1-4C alkoxycarbonyl) alkyl (1-6C), aminoalkyl (1-6C), hydroxy (alkoxy 1-3C) (1-6C) alkyl, di (1-3C alkoxy) (1-6C) alkyl, (1-3C alkoxy) trifluoroalkyl (1-6C), hydroxytrifluoroalkyl (1-6C), (1-4C alkoxy -carbonyl) (1-3C alkoxy) (1-6C) alkyl or hydroxycarbonyl (1-3C alkoxy) (1-6C) alkyl; R2 is H, F or OH; ring B is Ar1 or hetAr1; Ar1 is phenyl optionally substituted with one or more substituents independently selected from halogen, CF3, CF3O-, alkoxy (1-4C), hydroxyalkyl (1-4C), alkyl (1-6C) and CN; hetAr1 is a 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from N, S and O, and optionally substituted with one or more substituents independently selected from alkyl (1-6C), halogen, OH, CF3, NH2 and hydroxyalkyl (1-2C); the C ring is ** (See formula) ** R3 is H, alkyl (1-6C), hydroxyalkyl (1-6C), Ar2, hetCyc1, cycloalkyl (3-7C), hetAr2, or a carbocyclic ring with C5 bridge -C8; Ar2 is phenyl optionally substituted with one or more substituents independently selected from halogen and (1-6C) alkyl; hetCyc1 is a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O; hetAr2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, and optionally substituted with one or more substituents independently selected from alkyl (1-6C) and halogen; R4 is selected from (1-6C alkyl) SO2-, (1-6C alkyl) -C ( = O) - and from the structures: ** (See formula) ** Rm is substituted (1-3C) alkyl with 1-3 fluoros or cycloalkyl (3-4C); Rq is (1-3C) alkyl optionally substituted with 1-3 fluoro; 1 Ry is F or (1-3C) alkyl optionally substituted with 1-3 fluoro; p is 0, 1 or 2; Rz is cycloalkyl (3-4C) or alkyl (1-3C) optionally substituted with 1-3 fluoro; and R5 is H, alkyl (1-6C), monofluoroalkyl (1-6C), difluoroalkyl (1-6C), trifluoroalkyl (1-6C), tetrafluoroalkyl (2-6C), pentafluoroalkyl (2-6C), halogen, CN , (1-4C) alkoxy, (1-4C) hydroxyalkyl, (1-3C alkoxy) (1-4C) alkyl, (1-4C alkyl) -OC ( = O) -, (1-6C) sulfanyl alkyl , phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy, (3-4C) cycloalkyl, amino, aminocarbonyl or trifluoro (1-3C alkyl) amido; or - from among the compounds of the following formulas: ** (See formula) ** or pharmaceutically acceptable salts or solvates thereof.