Macrocyclic compounds as Trk kinase inhibitors
AssigneeArray BioPharma Inc.
InventorsSteven W. Andrews, Kevin Ronald Condroski, Julia Haas, Yutong Jiang, Gabrielle R. Kolakowski, Jeongbeob Seo, Hong-Woon Yang, Qian Zhao
Life of this patent
Estimating the term…
Abstract
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.
Claims29
A method for attenuating or ameliorating one or more symptoms of a cancerous tumor in a mammal in need thereof, the method comprising:
- (a) determining if the cancerous tumor exhibits one or more of overexpression, activation, amplification, and mutation of a Trk kinase;
- and
- (b) if the cancerous tumor is determined to exhibit one or more of overexpression, activation, amplification, and mutation of a Trk kinase, administering to the mammal a therapeutically effective amount of a compound selected from the group consisting of:
- (6R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.02,6.07,12.022,26] 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-[17.5.2.02,6.07,12.022,26] 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[16.5.2.02,6.07,12.021,25]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[18.5.2.02,6.07,12.023,27]heptacosa-1 (26),7,9,11,20(27),21,24-heptaen-19-one;
- (6R)-9-fluoro-2,11,13,16,20,21,24-heptaazapentacyclo[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;
- (6R)-9-fluoro-2,11,13,17,21,22,25-heptaazapentacyclo[17.5.2.02,6.07,12.022,26]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[17.5.2.02,6.07,12.022,26]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[17.5.2.02,6.07,12.022,26]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;
- (6R)-9-fluoro-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.02,6.07,12.021,25]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[16.5.2.02,6.07,12.021,25]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 [17.5.2.02,6.07,12.022,26]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[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;
- or a pharmaceutically acceptable salt thereof.
A method for attenuating or ameliorating one or more symptoms of a cancerous tumor exhibiting one or more of overexpression, activation, amplification, and mutation of a Trk kinase in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of a compound selected from the group consisting of:
- (6R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.02,6.07,12.022,26] 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-[17.5.2.02,6.07,12.022,26] 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[16.5.2.02,6.07,12.021,25]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[18.5.2.02,6.07,12.023,27]heptacosa-1 (26),7,9,11,20(27),21,24-heptaen-19-one;
- (6R)-9-fluoro-2,11,13,16,20,21,24-heptaazapentacyclo[16.5.2.02,6.07,12.021,25]pentacosa-1(24), 7,9,11,18(25),19,22-heptaen-17-one;
- (6R)-9-fluoro-2,11,13,17,21,22,25-heptaazapentacyclo[17.5.2.02,6.07,12.022,26]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[17.5.2.02,6.07,12.022,26] 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[17.5.2.02,6.07,12.022,26]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;
- (6R)-9-fluoro-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.02,6.07,12.021,25]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[16.5.2.02,6.07,12. 021,25]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 [17.5.2.02,6.07,12.022,26] 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[16.5.2.02,6.07,12.021,25]pentacosa-1 (24),7,9, 11,18(25),19,22-heptaen-17-one;
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.