Macrocyclic compounds as TRK kinase inhibitors
Compounds of Formula I: and pharmaceutically acceptable salts thereof, wherein ring A, ring B, W, m, R 2 , R 2a , R 3 , R 3a , 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.
1. A method for attenuating or ameliorating one or more symptoms of a cancerous tumor in a mammal in need thereof, the method comprising:
(a) detecting a cancerous tumor in a mammal that exhibits one or more of overexpression, activation, amplification, and mutation of a Trk kinase; and
(b) administering to the mammal a therapeutically effective amount of a compound of Formula (I)
or a pharmaceutically acceptable salt thereof, wherein:
ring A is ring A-1 having the structure:
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;
Y is H or F;
R 1 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 CH 2 , wherein when ring A is A-2, then W is CH 2 ;
m is 0, 1 or 2;
D is carbon, R 2 and R 2a are independently H, F, (1-3C)alkyl or OH (provided that R 2 and R 2a are not both OH), and R 3 and R 3a are independently H, (1-3C)alkyl or hydroxy(1-3 C)alkyl;
Z is *—NR 4a C(═O)—, wherein the asterisk indicates the point of attachment of Z to the carbon bearing R 3 ;
R 4a 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); and
R 5 and R 6 are independently H, halogen, OH, (1-6C)alkyl or hydroxy(1-6C)alkyl.
2. The method of claim 1 , wherein Y is F.
3. The method of claim 1 , wherein R 1 is H.
4. The method of claim 1 , wherein R 4a is hydrogen.
5. The method of claim 1 , wherein R 2 and R 2a are each hydrogen.
6. The method of claim 1 , wherein W is CH 2 .
7. The method of claim 1 , wherein m is 0.
8. The method of claim 1 , wherein m is 1.
9. The method of claim 1 , wherein the compound of Formula I is
(6R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0 2,6 .0 7,12 .0 21,25 ]pentacosa-1(24),7,9, 11,18(25),19,22-heptaen-17-one, or a pharmaceutically acceptable salt thereof.
10. The method of claim 1 , wherein the Trk kinase is selected from the group consisting of TrkA, TrkB, and TrkC.
11. The method of claim 1 , wherein the cancerous tumor is selected from the group consisting of: neuroblastoma, ovarian, pancreatic, colorectal, prostate, melanoma, head and neck cancer, gastric carcinoma, lung carcinoma, breast cancer, glioblastoma, medulloblastoma, secratory breast cancer, salivary gland cancer, and papillary thyroid carcinoma.
12. The method of claim 1 , wherein the cancerous tumor exhibits overexpression of a Trk kinase.
13. The method of claim 1 , wherein the cancerous tumor exhibits activation of a Trk kinase.
14. The method of claim 1 , wherein the cancerous tumor exhibits amplification of a Trk kinase.
15. The method of claim 1 , wherein the cancerous tumor exhibits mutation of a Trk kinase.