Macrocyclic compounds as trk kinase inhibitors

摘要

Compounds of Formula I: and pharmaceutically acceptable salts thereof, wherein ring A, ring B, W, m, D, R2, R2a, R3, R3a, and Z are as defined herein, are inhibitors of Trk kinases and are useful in the treatment of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.;

主权项

1. A compound of Formula I or pharmaceutically acceptable salts thereof, wherein:
ring A is selected from rings A-1 and A-2 having the structures: wherein the wavy line labeled 1 indicates the point of attachment of ring A to ring B and the wavy line labeled 2 indicates the point of attachment of ring A to W;
X is N or CH;Y is H or F;R1 is H, (1-3C)alkyl, (1-3C)alkoxy or halogen;B is B-1: wherein the wavy line labeled 3 indicates the point of attachment to ring A and the wavy line labeled 4 indicates the point of attachment to the pyrazolo[1,5-a]pyrimidine ring of Formula I;
W is O, NH or CH2, wherein when ring A is A-2, then W is CH2;m is 0, 1 or 2;D is carbon, R2 and R2a are independently H, F, (1-3C)alkyl or OH (provided that R2 and R2a are not both OH), and R3 and R3a are independently H, (1-3C)alkyl or hydroxy(1-3 C)alkyl;Z is *—NR4aC(═O)—, wherein the asterisk indicates the point of attachment of Z to the carbon bearing R3;R4a is H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C alkyl) or dihydroxy(2-6C alkyl); andR5 and R6 are independently H, halogen, OH, (1-6C)alkyl or hydroxy(1-6C)alkyl.