C5-anilinoquinazoline compounds and their use in treating cancer

Patent metadata

Field	Value
Publication number	US-10273227-B2
Application number	US-201815963122-A
Country	US
Kind code	B2
Filing date	Apr 26, 2018
Priority date	Apr 27, 2017
Publication date	Apr 30, 2019
Grant date	Apr 30, 2019

Abstract

The invention concerns compounds of Formula (I):

or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 and R 4 have any of the meanings hereinbefore defined in the description; process for their preparation; pharmaceutical compositions containing them and their use in treating KIT mediated diseases.

First claim

The invention claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from hydrogen and fluoro;
R 2 is selected from fluoro and C 1-2 alkoxy;
R 3 is selected from hydrogen and methoxy; and
R 4 is a C 1-3 alkyl, optionally substituted with a group selected from C 1-3 alkoxy and NR 5 R 6 , wherein R 5 and R 6 are each independently hydrogen or methyl; or a 4 to 6 membered heterocyclyl ring containing one oxygen atom.

2. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein R 1 hydrogen.

3. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein R 2 is fluoro.

4. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein R 3 is hydrogen.

5. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein R 4 is selected from methyl, ethyl, isopropyl, oxetanyl, tetrahydrofuranyl, oxanyl, 2-dimethylaminoethyl and 2-methoxyethyl.

6. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 5 , wherein R 4 is 2-methoxyethyl.

7. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein the compound is selected from the group consisting of:
N-{4-[(5,7-Dimethoxyquinazolin-4-yl)amino]-3-fluorophenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;
N-{4-[(5-Fluoro-6,7-dimethoxyquinazolin-4-yl)amino]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;
(R)—N-(4-{[5-Ethoxy-7-(tetrahydrofuran-3-yloxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;
(S)—N-(4-{[5-Ethoxy-7-(tetrahydrofuran-3-yloxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;
N-(4-((5-Ethoxy-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide;
N-(4-((7-(2-(Dimethylamino)ethoxy)-5-ethoxyquinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide;
N-(4-((5-Ethoxy-7-methoxyquinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide;
N-(4-((5-Ethoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide;
N-(4-((5-Ethoxy-7-(oxetan-3-yloxy)quinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide;
N-(4-{[5-Methoxy-7-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;
2-[4-(Propan-2-yl)-1H-1,2,3-triazol-1-yl]-N-{4-[(5,6,7-trimethoxyquinazolin-4-yl)amino]phenyl}acetamide;
N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;
(R)-2-(4-Isopropyl-1H-1,2,3-triazol-1-yl)-N-(4-((5-methoxy-7-((tetrahydrofuran-3-yl)oxy)quinazolin-4-yl)amino)phenyl)acetamide;
(S)-2-(4-Isopropyl-1H-1,2,3-triazol-1-yl)-N-(4-((5-methoxy-7-((tetrahydrofuran-3-yl)oxy)quinazolin-4-yl)amino)phenyl)acetamide;
N-(4-{[5-Methoxy-7-(propan-2-yloxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;
N-(4-{[5-Methoxy-7-(oxetan-3-yloxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;
N-[4-({7-[2-(Dimethylamino)ethoxy]-5-methoxyquinazolin-4-yl}amino)phenyl]-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;
N-{4-[(7-Ethoxy-5-methoxyquinazolin-4-yl)amino]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;
N-{4-[(5,7-Diethoxyquinazolin-4-yl)amino]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;
N-(4-{[5-Methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;
N-{4-[(5-Fluoro-7-methoxyquinazolin-4-yl)amino]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide; and
N-{4-[(5,7-Dimethoxyquinazolin-4-yl)amino]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide.

8. A pharmaceutical composition which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , and at least one pharmaceutically acceptable diluent or carrier.

9. A method for treating cancer in a warm-blooded animal in need of such treatment, which comprises administering to the warm-blooded animal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , and wherein the cancer is selected from the group consisting of gastrointestinal stromal tumour, melanoma, lung cancer, glioblastoma, leukemias, testicular carcinomas, and head and neck cancers.

10. N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide.

11. A pharmaceutically acceptable salt of N-(4-{[5-Fluoro-7-(2-methoxy-ethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide.

12. The pharmaceutically acceptable salt, as claimed in claim 11 , wherein the salt is a tosylate salt of N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]-amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide.

13. A pharmaceutical composition which comprises N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]-acetamide, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent or carrier.

14. The pharmaceutical composition, as claimed in claim 13 , wherein the composition comprises N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}-phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide.

15. The pharmaceutical composition, as claimed in claim 13 , wherein the composition comprises a pharmaceutically acceptable salt of N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]-acetamide.

16. The pharmaceutical composition, as claimed in claim 13 , wherein the composition comprises a pharmaceutically acceptable tosylate salt of N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]-acetamide.

17. The pharmaceutical composition, as claimed in claim 13 , wherein the composition is an oral pharmaceutical composition.

18. A method for treating cancer in a human in need of such treatment, which comprises administering to the human a therapeutically effective amount of N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide, or a pharmaceutically acceptable salt thereof, and wherein the cancer is selected from the group consisting of gastrointestinal stromal tumour, melanoma, lung cancers, glioblastoma, leukemias, testicular carcinomas, and head and neck cancers.

19. The method of treating, as claimed in claim 18 , wherein the cancer is gastrointestinal stromal tumour.

20. The method of treating, as claimed in claim 18 , wherein the cancer is glioblastoma.

21. The method of treating, as claimed in claim 18 , wherein the cancer is lung cancer.

22. The method of treating, as claimed in claim 21 , wherein the lung cancer is squamous carcinoma of the lung.

23. The method of treating, as claimed in claim 18 , wherein the cancer is leukemia.

24. The method of treating, as claimed

Assignees

• Astrazeneca Ab

Inventors

• Kettle Jason
• Pearson Stuart
• Packer Martin
• Smith James

Classifications

• A61K2121/00

  Preparations for use in therapy · CPC title

• C07D403/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title