Compounds for treating spinal muscular atrophy

Patent metadata

Field	Value
Publication number	US-10501482-B2
Application number	US-201815948444-A
Country	US
Kind code	B2
Filing date	Apr 9, 2018
Priority date	Jun 25, 2013
Publication date	Dec 10, 2019
Grant date	Dec 10, 2019

Abstract

The present invention provides compounds of formula (I) wherein A, B, X, Y, R1 and R2 are as described herein, as well as pharmaceutically acceptable salts thereof. Further the present invention is concerned with the manufacture of the compounds of formula (I), pharmaceutical compositions comprising them and their use as medicaments.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein:
X is N or CR 3 ;
Y is N or CR 4 ; with the proviso that not both X and Y are N;
A is a bicyclic 9-membered heteroaryl comprising two or three heteroatoms independently selected from N or O, wherein A can be optionally substituted with one, two or three R 5 ;
B is a saturated or partially unsaturated mono- or bicyclic 4 to 9-membered heterocycloalkyl comprising one or two ring nitrogen atoms, the remaining ring atoms being carbon, wherein B can be optionally substituted with one, two or three R 6 ;
R 1 is hydrogen, halo, C 1-7 -alkyl, C 1-7 -haloalkyl, C 1-7 -alkoxy or C 1-7 -haloalkoxy;
R 2 is hydrogen, halo, C 1-7 -alkyl, C 1-7 haloalkyl, C 1-7 -alkoxy or C 1-7 -haloalkoxy;
R 3 is hydrogen, halo, C 1-7 -alkyl, C 1-7 -haloalkyl, C 1-7 -alkoxy or C 1-7 -haloalkoxy;
R 4 is hydrogen, halo, C 1-7 -alkyl, C 1-7 -haloalkyl, C 1-7 -alkoxy or C 1-7 -haloalkoxy;
each R 5 is independently selected from halo, cyano, C 1-7 -alkyl, C 1-7 -haloalkyl or C 3-7 -cycloalkyl;
each R 6 is independently selected from C 1-7 -alkyl, or two R 6 together form a C 2-7 -alkylene;
or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein A is selected from the group of imidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-a]pyridinyl, and benzo[d]oxazolyl, which can be optionally substituted with one, two or three R 5 .

3. The compound according to claim 1 , wherein A is selected from the group of imidazo[1,2-a]pyrazin-2-yl substituted with two C 1-7 -alkyl, imidazo[1,2-a]pyridin-6-yl substituted with one or two C 1-7 -alkyl, imidazo[1,2-a]pyridin-6-yl substituted with one C 1-7 -alkyl and one halo, imidazo[1,2-a]pyridin-6-yl substituted with one C 1-7 -alkyl and one C 1-7 -haloalkyl, benzo[d]oxazol-6-yl substituted with one C 1-7 -alkyl, and benzo[d]oxazol-6-yl substituted with one C 1-7 -alkyl and one halo.

4. The compound according to claim 1 , wherein A is selected from 2-methylbenzo[d]oxazol-6-yl, 4-fluoro-2-methylbenzo[d]oxazol-6-yl, 6,8-dimethylimidazo[1,2-a]pyrazin-2-yl, 2-methylimidazo[1,2-a]pyridin-6-yl, 2,7-dimethylimidazo[1,2-a]pyridin-6-yl, 2,8-dimethylimidazo[1,2-a]pyridin-6-yl, 2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl, 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl, and 8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl.

5. The compound according to claim 1 , wherein each R 5 is independently selected from halo, C 1-7 -alkyl, or C 1-7 -haloalkyl.

6. The compound according to claim 1 , wherein each R 5 is independently selected from methyl, fluoro, chloro, and trifluoromethyl.

7. The compound according to claim 1 , wherein B as defined herein is further characterized in that one ring nitrogen atoms is basic.

8. The compound according to claim 1 , wherein B is selected from 1,2,3,6-tetrahydropyridinyl, 2,6-diazaspiro[3.3]heptanyl, hexahydropyrrolo[3,4-c]pyrrolyl, hexahydropyrrolo[1,2-a]pyrazinyl, piperazinyl, and piperidinyl, wherein each can be optionally substituted with one, two or three R 6 .

9. The compound according to claim 1 , wherein B is selected from piperazin-1-yl, 3-methyl-piperazin-1-yl, and 3,3-dimethylpiperazin-1-yl.

10. The compound according to claim 1 , wherein each R 6 is C 1-7 -alkyl.

11. The compound according to claim 1 , wherein each R 6 is independently selected from methyl, and ethyl.

12. The compound according to claim 1 , wherein X is CR 3 and Y is CR 4 , or X is N and Y is CR 4 , or X is CR 3 and Y is N.

13. The compound according to claim 1 , wherein X is CR 3 and Y is CR 4 .

14. The compound according to claim 1 , wherein X is N and Y is CR 4 .

15. The compound according to claim 1 , wherein R 1 is hydrogen, halo, C 1-7 -alkoxy or C 1-7 -haloalkoxy.

16. The compound according to claim 1 , wherein R 1 is hydrogen, fluoro, methoxy, ethoxy or trifluoroethoxy.

17. The compound according to claim 1 , wherein R 1 is hydrogen.

18. The compound according to claim 1 , wherein R 2 is hydrogen, halo, or C 1-7 -alkyl.

19. The compound according to claim 1 , wherein R 2 is hydrogen, fluoro or methyl.

20. The compound according to claim 1 , wherein R 2 is hydrogen.

21. The compound according to claim 1 , wherein R 3 is hydrogen or fluoro.

22. The compound according to claim 1 , wherein R 3 is hydrogen.

23. The compound according to claim 1 , wherein R 4 is hydrogen, halo or C 1-7 -alkoxy.

24. The compound according to claim 1 , wherein R 4 is hydrogen, fluoro, methoxy, ethoxy or trifluoroethoxy.

25. The compound according to claim 1 , wherein R 4 is hydrogen or fluoro.

26. The compound according to claim 1 , wherein R 4 is hydrogen, halo or C 1-7 -alkoxy.

27. The compound according to claim 1 , selected from the group consisting of:
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(piperazin-1-yl)benzamide;
rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(3-methylpiperazin-1-yl)benzamide;
N-(6,8-Dimethyl-imidazo[1,2-a]pyrazin-2-yl)-4-((S)-3-methyl-piperazin-1-yl)-benzamide;
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(4-methylpiperazin-1-yl)benzamide;
rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide;
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(4-methylpiperazin-1-yl)nicotinamide;
rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(4-ethylpiperazin-1-yl)nicotinamide;
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(4-methylpiperazin-1-yl)picolinamide;
rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(3-methylpiperazin-1-yl)picolinamide;
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(piperazin-1-yl)picolinamide;
rac-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;
6-(3,3-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)nicotinamide;
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;
6-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)nicotinamide;
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(2,6-diazaspiro[3.3]heptan-2-yl)nicotinamide;
rac-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin-1-yl)picolinamide;
rac-2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;
N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide:
rac-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;
(S)-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)nicotinamide;
6-(3,5-dimethylpiperazin-1-yl)-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)nicotinamide;
6-(3,5-dimethylpiperazin-1-yl)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)nicotinamide;
N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-6-(4-methylpiperazin-1-yl)nicotinamide;
(S)—N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinamide;
N-(4-Fluoro-2-methyl-benzooxazol-6-yl)-6-piperazin-1-yl-nicotinamide;
rac-N-(4-Fluoro-2-methyl-benzooxazol-6-yl)-6-(3-methyl-piperazin-1-yl)-nicotinamide;
N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)benzamide;

Assignees

• Hoffmann La Roche
• Ptc Therapeutics Inc
• Hoffmann—La Roche Inc

Inventors

• Dakka Amal
• Green Luke
• Karp Gary
• Narasimhan Jana
• Naryshkin Nikolai
• Pinard Emmanuel
• Qi Hongyan
• Ratni Hasane
• Risher Nicole
• Weetall Marla
• Woll Matthew

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/02

  for peripheral neuropathies · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P21/04

  for myasthenia gravis · CPC title