IP Library › Granted Patent US 9,493,476

Granted Patent B2

US 9,493,476 · App. 14/575,663 · Granted Nov 15, 2016

Macrocyclic compounds as trk kinase inhibitors

Inventors: Steven W. Andrews (Boulder, CO); Kevin Ronald Condroski (Wallingford, CT); Julia Haas (Boulder, CO); Yutong Jiang (Boulder, CO); Gabrielle R. Kolakowski (Boulder, CO); Jeongbeob Seo (Baltimore, MD); Hong-Woon Yang (Superior, CO); Qian Zhao (Louisville, CO)

Assignee: Array BioPharma, Inc.

C07D487/22 C07D471/22 C07D487/04 C07D498/22 C07D519/00

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Quick Facts

Patent No.: US 9,493,476
App. No.: 14/575,663
Granted: Nov 15, 2016
Kind: B2

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Abstract

Compounds of Formula I: and pharmaceutically acceptable salts thereof, wherein ring A, ring B, W, m, D, 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.

Claims (87)

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;

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 compound according to claim 1 , wherein ring A is ring A-1 having the structure

3. The compound according to claim 1 , wherein ring A is ring A-2 having the structure

4. The compound of claim 1 , wherein Y is F.

5. The compound of claim 1 , wherein R 1 is H.

6. The compound of claim 1 , wherein R 4a is hydrogen.

7. The compound of claim 1 , wherein R 2 and R 2a are each hydrogen.

8. The compound of claim 1 , wherein W is CH 2 .

9. The compound of claim 1 , wherein m is 0.

10. The compound of claim 1 , wherein m is 1.

11. The compound of claim 1 , selected from the group consisting of:

(6R)-9-fluoro-2,11,15,19,20,23-hexaazapentacyclo[15.5.2.1 7,11 .0 2,6 .0 20,24 ]pentacosa-1(23),7,9,17(24),18,21-hexaene-16,25-dione;

(6R)-9-fluoro-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;

(6R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;

(6R,13S)-9-fluoro-13-hydroxy-2,11,15,19,20,23-hexaazapentacyclo-[15.5.2.1 7,11 .0 2,6 .0 20,24 ]pentacosa-1(23),7,9,17(24),18,21-hexaene-16,25-dione;

(6R,15R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo-[17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;

(6R,13R)-9-fluoro-13-hydroxy-2,11,15,19,20,23-hexaazapentacyclo-[15.5.2.1 7,11 .0 2,6 .0 20,24 ]pentacosa-1(23),7,9,17(24),18,21-hexaene-16,25-dione;

(6R)-9-fluoro-13-oxa-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;

(6R)-9-fluoro-13-oxa-2,11,18,22,23,26-hexaazapentacyclo[18.5.2.0 2,6 .0 7,12 .0 23,27 ]heptacosa-1(26),7,9,11,20(27),21,24-heptaen-19-one;

(6R)-9-fluoro-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.1 7,11 .0 2,6 .0 21,25 ]hexacosa-1(24),7,9,18(25),19,22-hexaene-17,26-dione;

(6R)-9-fluoro-2,11,13,16,20,21,24-heptaazapentacyclo[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;

(6R)-9-fluoro-2,11,13,17,21,22,25-heptaazapentacyclo[17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;

(6R)-9-fluoro-14-oxa-2,11,18,19,22-pentaazapentacyclo[14.5.2.1 7,11 .0 2,6 .0 19,23 ]tetracosa-1(22),7,9,16(23),17,20-hexaene-15,24-dione;

(6R,13R)-9,13-difluoro-2,11,15,19,20,23-hexaazapentacyclo[15.5.2.1 7,11 .0 2,6 .0 20,24 ]pentacosa-1(23), 7,9,17(24),18,21-hexaene-16,25-dione;

(6R)-9-fluoro-17-methyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;

(6R)-9,15,15-trifluoro-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;

(6R)-9-fluoro-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;

(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;

(6R,13R)-9-fluoro-13-methyl-2,11,15,19,20,23-hexaazapentacyclo[15.5.2.1 7,11 .0 2,6 .0 20,24 ]pentacosa-1(23),7,9,17(24),18,21-hexaene-16,25-dione;

(6R,13S)-9-fluoro-13-methyl-2,11,15,19,20,23-hexaazapentacyclo [15.5.2.1 7,11 .0 2,6 .0 20,24 ]pentacosa-1(23),7,9,17(24),18,21-hexaene-16,25-dione;

(6R)-9-fluoro-15,15-dimethyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo [17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;

(6R)-9-fluoro-15,15-dimethyl-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; and

(6R)-9-fluoro-13,13-dimethyl-2,11,15,19,20,23-hexaazapentacyclo[15.5.2.1 7,11 .0 2,6 .0 20,24 ]pentacosa-1(23),7,9,17(24),18,21-hexaene-16,25-dione; or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , selected from: