IP Library › Granted Patent US 9,718,822
Granted Patent B2
US 9,718,822 · App. 15/401,839 · Granted Aug 1, 2017

Macrocyclic compounds as Trk kinase inhibitors

Inventors: Steven W. Andrews (Boulder, CO); Kevin Ronald Condroski (Boulder, CO); Julia Haas (Boulder, CO); Yutong Jiang (Boulder, CO); Gabrielle R. Kolakowski (Boulder, CO); Jeongbeob Seo (Boulder, CO); Hong-Woon Yang (Boulder, CO); Qian Zhao (Boulder, CO)
Assignee: Array BioPharma, Inc.
C07D471/22C07D498/22
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Quick Facts
Patent No.
US 9,718,822
App. No.
15/401,839
Granted
Aug 1, 2017
Kind
B2
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 (52)

1. A compound selected from the group consisting of:

(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,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)-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-2,11,13,16,20,21,24-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-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)-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; and

(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;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the compound is

(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, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the compound is

(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, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein the compound is

(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, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein the compound is

(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, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein the compound is

(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, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein the compound is

(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, or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein the compound is

(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, or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , wherein the compound is

(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, or a pharmaceutically acceptable salt thereof.

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

(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, or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , wherein the compound 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.

12. The compound of claim 1 , wherein the compound is

(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, or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , wherein the compound is

(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, or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , wherein the compound is selected from the group consisting of:

(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,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)-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-2,11,13,16,20,21,24-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-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)-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; and

(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.

15. The compound of claim 1 , wherein the compound is in the form of a pharmaceutically acceptable salt.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 19, 2017
From: ANDREWS, STEVEN W.; CONDROSKI, KEVIN RONALD; HAAS, JULIA; JIANG, YUTONG; KOLAKOWSKI, GABRIELLE R.; SEO, JEONGBEOB; YANG, HONG-WOON; ZHAO, QIAN
To: ARRAY BIOPHARMA, INC.
Reel/Frame 041017/0738 →
Continuity (6)
Continuation 15350888 · Nov 14, 2016
Continuation 14575663 · Dec 18, 2014
Continuation 13698922
Provisional Application 61426716 · Dec 23, 2010
Provisional Application 61346767 · May 20, 2010
Related Publication 20170114059A1 · Apr 27, 2017