Substituted imidazo[1,2-α]pyrazines for treating spinal muscular atrophy

Patent metadata

Field	Value
Publication number	US-9975900-B2
Application number	US-201615379057-A
Country	US
Kind code	B2
Filing date	Dec 14, 2016
Priority date	Jun 25, 2014
Publication date	May 22, 2018
Grant date	May 22, 2018

Abstract

The present invention provides compounds of formula (I)

wherein A, X 1 , X 2 , R 1 , R 2 , R 3 , R 4 and R 5 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):

or a pharmaceutically acceptable salt thereof, wherein
X 1 is CR 5 or N;
X 2 is CR 5 or N; with the proviso that not both X 1 and X 2 are N;
R 1 is hydrogen or C 1-7 -alkyl;
R 2 is hydrogen, cyano, C 1-7 -alkyl, C 1-7 -haloalkyl or C 3-8 -cycloalkyl;
R 3 is hydrogen, halo, C 1-7 -alkyl, or C 1-7 -alkoxy;
R 4 is hydrogen, halo, C 1-7 -alkyl, or C 1-7 -alkoxy;
R 5 is independently selected from hydrogen, halo, C 1-7 -alkyl, or C 1-7 -alkoxy;
A is N-heterocycloalkyl or NR 7 R 8 , wherein N-heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3 or 4 substituents selected from R 6 ;
R 6 is independently selected from hydrogen, C 1-7 -alkyl, amino, amino-C 1-7 -alkyl, C 3 -8-cycloalkyl, heterocycloalkyl and C 1-7 -alkoxy-heterocycloalkyl or two R 6 together form C 1-7 -alkylene;
R 7 is heterocycloalkyl comprising 1 nitrogen ring atom, wherein heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from R 6 ; and
R 8 is hydrogen, C 1-7 -alkyl or C 3-8 -cycloalkyl;
with the proviso that if A is N-heterocycloalkyl which comprises only 1 nitrogen ring atom, then A is substituted with 1, 2, 3 or 4 substituents selected from the group consisting of amino or amino-C 1-7 -alkyl.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
X 1 is CH or N;
X 2 is CR 5 ;

R 1 is C 1-7 -alkyl;
R 2 is hydrogen, C 1-7 -alkyl, C 1-7 -haloalkyl or C 3-8 -cycloalkyl;
A is N-heterocycloalkyl, wherein N-heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3 or 4 substituents selected from R 6 ; and
R 6 is independently selected from hydrogen, C 1-7 -alkyl, amino, amino-C 1-7 -alkyl, C 3-8 -cycloalkyl, heterocycloalkyl and C 1-7 -alkoxy-heterocycloalkyl or two R 6 together form C 1-7 -alkylene
with the proviso that if A is N-heterocycloalkyl which comprises only 1 nitrogen ring atom, then A is substituted with 1, 2, 3 or 4 substituents selected from the group consisting of amino or amino-C 1-7 -alkyl.

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein

A is wherein
Y is N or CH;

R 9 is hydrogen, C 1-7 -alkyl, or —(CH 2 ) m —NR 14 R 15 ;
R 10 is hydrogen or C 1-7 -alkyl;
R 11 is hydrogen or C 1-7 -alkyl;
R 12 is hydrogen or C 1-7 -alkyl;
R 13 is hydrogen or C 1-7 -alkyl;
R 14 and R 15 are independently selected from hydrogen, C 1-7 -alkyl and C 3-8 -cycloalkyl;
n is 0, 1 or 2;
m is 0, 1, 2 or 3;
or R 9 and R 10 together form C 1-7 -alkylene;
or R 9 and R 12 together form C 1-7 -alkylene;
or R 10 and R 11 together form C 2-7 -alkylene;
or R 10 and R 12 together form C 1-7 -alkylene;
or R 10 and R 14 together form C 1-7 -alkylene;
or R 12 and R 13 together form C 2-7 -alkylene;
or R 12 and R 14 together form C 1-7 -alkylene;
or R 14 and R 15 together form C 2-7 -alkylene which is optionally substituted with alkoxy;
with the proviso that if Y is CH then R 9 is —(CH 2 ) m —NR 14 R 15 ; and
with the proviso that if Y is N and R 9 is —(CH 2 ) m —NR 14 R 15 , then m is 2 or 3.

4. The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein Y is CH and R 9 is —(CH 2 ) m —NR 14 R 15 .

5. The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 9 is hydrogen, pyrrolidinyl, or methoxy-azetidinyl.

6. The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 10 is hydrogen, methyl, ethyl or isopropyl.

7. The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 together form propylene.

8. The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 10 and R 11 together form ethylene.

9. The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 14 and R 15 together form propylene or butylene.

10. The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein A is selected from the group of:

wherein R 16 is hydrogen or C 1-7 -alkyl and R 17 is C 1-7 -alkoxy.

11. The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein A is selected from the group of:

wherein R 17 is C 1-7 -alkoxy.

12. The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein A is

13. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is piperazinyl, diazepanyl, pyrrolidinyl or hexahydropyrrolo[1,2-a]pyrazinyl, each optionally substituted with 1, 2, 3 or 4 substituents selected from R 6 .

14. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is NR 7 R 8 .

15. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
2-fluoro-N-(2-methylimidazo[1,2-a]pyrazin-6-yl)-4-piperazin-1-ylbenzamide;
N-(2-methylimidazo[1,2-a]pyrazin-6-yl)-4-piperazin-1-ylbenzamide;
4-[(8aS)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-ethoxy-N-(2-methylimidazo[1,2-a]pyrazin-6-yl)benzamide;
2-ethoxy-N-(2-methylimidazo[1,2-a]pyrazin-6-yl)-4-[(3S)-3-methylpiperazin-1-yl]benzamide;
2-ethoxy-N-(2-methylimidazo[1,2-a]pyrazin-6-yl)-4-[(3R)-3-methylpiperazin-1-yl]benzamide;
4-[(8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-ethoxy-N-(2-methylimidazo[1,2-a]pyrazin-6-yl)benzamide;
4-[(8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-fluoro-N-(2-methylimidazo[1,2-a]pyrazin-6-yl)benzamide;
4-[(8aS)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-fluoro-N-(2-methylimidazo[1,2-a]pyrazin-6-yl)benzamide;
4-(1,4-diazepan-1-yl)-2-ethoxy-N-(2-methylimidazo[1,2-a]pyrazin-6-yl)benzamide;
4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2-ethoxy-N-(2-methylimidazo[1,2-a]pyrazin-6-yl)benzamide;
N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-2-fluoro-4-[(3R)-3-methylpiperazin-1-yl]benzamide;
4-[(8aS)-3,4,6,7, 8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-N-(2, 8-dimethylimidazo[1,2-a]pyrazin-6-yl)-2-ethoxybenzamide;
4-[(8aS)-3,4,6,7, 8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-N-(2, 8-dimethylimidazo[1,2-a]pyrazin-6-yl)-2-fluorobenzamide;
N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-2,6-difluoro-4-[(3R)-3-methylpiperazin-1-yl]benzamide;
N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-2-ethoxy-4-[(3R)-3-methylpiperazin-1-yl]benzamide;
4-[(8aS)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-N-(8-ethyl-2-methylimidazo[1,2-a]pyrazin-6-yl)-2-fluorobenzamide;
4-[(8aS)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-N-(8-cyclopropyl-2-methylimidazo[1,2-a]pyrazin-6-yl)-2-fluorobenza

Assignees

• Hoffmann La Roche

Inventors

• Pinard Emmanuel
• Ratni Hasane
• Green Luke
• Williamson Patrick

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61P21/00

  Drugs for disorders of the muscular or neuromuscular system · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title