IP Library › Granted Patent US 9,902,741

Granted Patent B2

US 9,902,741 · App. 15/632,187 · Granted Feb 27, 2018

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.

C07D498/22 C07D471/22 C07D487/22

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 9,902,741
App. No.: 15/632,187
Granted: Feb 27, 2018
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

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 pharmaceutical composition comprising 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 and a pharmaceutically acceptable diluent or carrier.

2. The pharmaceutical composition 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 pharmaceutical composition 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 pharmaceutical composition 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 pharmaceutical composition 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 pharmaceutical composition 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 pharmaceutical composition 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 pharmaceutical composition 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 pharmaceutical composition 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 pharmaceutical composition 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 pharmaceutical composition 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 pharmaceutical composition 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 pharmaceutical composition 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 pharmaceutical composition of claim 1 , wherein the compound is selected from the group consisting of: