Compounds for treating spinal muscular atrophy

Patent metadata

Field	Value
Publication number	US-9969754-B2
Application number	US-201615351267-A
Country	US
Kind code	B2
Filing date	Nov 14, 2016
Priority date	May 15, 2014
Publication date	May 15, 2018
Grant date	May 15, 2018

Abstract

The present invention provides compounds of formula (I)

wherein A, R 1 , R 2 and R 3 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
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, C 1-7 -alkyl, or C 3-8 -cycloalkyl;
A is N-heterocycloalkyl or NR 12 R 13 , wherein N-heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3 or 4 substituents selected from R 14 ;
R 12 is heterocycloalkyl comprising 1 nitrogen ring atom, wherein heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from R 14 ;
R 13 is hydrogen, C 1-7 -alkyl or C 3-8 -cycloalkyl;
R 14 is independently selected from hydrogen, C 1-7 -alkyl, amino, amino-C 1-7 -alkyl, C 3-8 -cycloalkyl and heterocycloalkyl or two R 14 together form C 1-7 -alkylene;
with the proviso that if A is N-heterocycloalkyl comprising only 1 nitrogen ring atom, then at least one R 14 substituent is amino or amino-C 1-7 -alkyl;
or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein
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, C 1-7 -alkyl, or C 3-8 -cycloalkyl;
A is N-heterocycloalkyl comprising 1 or 2 nitrogen ring atoms, wherein N-heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from R 14 ;
R 14 is independently selected from hydrogen, C 1-7 -alkyl, amino, amino-C 1-7 -alkyl, C 3-8 -cycloalkyl and heterocycloalkyl or two R 14 together form C 1-7 -alkylene;
with the proviso that if A is N-heterocycloalkyl comprising only 1 nitrogen ring atom, then at least one R 14 substituent is amino or amino-C 1-7 -alkyl;
or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 , wherein R 1 is C 1-7 -alkyl.

4. A compound according to claim 1 , wherein R 1 is methyl.

5. A compound according to claim 1 , wherein R 2 is hydrogen or C 1-7 -alkyl.

6. A compound according to claim 1 , wherein R 2 is hydrogen or methyl.

7. A compound according to claim 1 , wherein R 3 is hydrogen or C 1-7 -alkyl.

8. A compound according to claim 1 , wherein R 3 is hydrogen or methyl.

9. A compound according to claim 1 , wherein R 12 is piperidinyl optionally substituted with 1, 2, 3 or 4 substituents selected from R 14 .

10. A compound according to claim 1 , wherein
A is

wherein
X is N or CH;
R 4 is hydrogen, C 1-7 -alkyl or —(CH 2 ) m —NR 9 R 10 ;
R 5 is hydrogen or C 1-7 -alkyl;
R 6 is hydrogen or C 1-7 -alkyl;
R 7 is hydrogen or C 1-7 -alkyl;
R 8 is hydrogen or C 1-7 -alkyl;
R 9 and R 10 are independently selected from hydrogen, C 1-7 -alkyl and C 3-8 -cycloalkyl;
R 13 is hydrogen, C 1-7 -alkyl or C 3-8 -cycloalkyl;
n is 0, 1 or 2;
m is 0, 1, 2 or 3;
or R 4 and R 5 together form C 1-7 -alkylene;
or R 4 and R 7 together form C 1-7 -alkylene;
or R 5 and R 6 together form C 2-7 -alkylene;
or R 5 and R 7 together form C 1-7 -alkylene;
or R 5 and R 9 together form C 1-7 -alkylene;
or R 7 and R 8 together form C 2-7 -alkylene;
or R 7 and R 9 together form C 1-7 -alkylene;
or R 9 and R 10 together form C 2-7 -alkylene;
with the proviso that if X is CH then R 4 is —(CH 2 ) m —NR 9 R 10 ; and
with the proviso that if X is N and R 4 is —(CH 2 ) m —NR 9 R 10 then m is 2 or 3.

11. A compound according to claim 1 , wherein A is

wherein
X is N or CH;
R 4 is hydrogen, C 1-7 -alkyl or —(CH 2 ) m —NR 9 R 10 ;
R 5 is hydrogen or C 1-7 -alkyl;
R 6 is hydrogen or C 1-7 -alkyl;
R 7 is hydrogen or C 1-7 -alkyl;
R 8 is hydrogen or C 1-7 -alkyl;
R 9 and R 10 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 4 and R 5 together form C 1-7 -alkylene;
or R 4 and R 7 together form C 1-7 -alkylene;
or R 5 and R 6 together form C 2-7 -alkylene;
or R 5 and R 7 together form C 1-7 -alkylene;
or R 5 and R 9 together form C 1-7 -alkylene;
or R 7 and R 8 together form C 2-7 -alkylene;
or R 7 and R 9 together form C 1-7 -alkylene;
or R 9 and R 10 together form C 2-7 -alkylene;
with the proviso that if X is CH then R 4 is —(CH 2 ) m —NR 9 R 10 ; and
with the proviso that if X is N and R 4 is —(CH 2 ) m —NR 9 R 10 then m is 2 or 3.

12. A compound according to claim 1 , wherein X is N.

13. A compound according to claim 1 , wherein n is 1.

14. A compound according to claim 1 , wherein R 6 is hydrogen, methyl or
—(CH 2 ) m —NR 9 R 10 .

15. A compound according to claim 1 , wherein R 6 is hydrogen or methyl.

16. A compound according to claim 1 , wherein R 7 is hydrogen or methyl.

17. A compound according to claim 1 , wherein m is 0.

18. A compound according to claim 1 , wherein R 4 and R 5 together form propylene.

19. A compound according to claim 1 , wherein R 5 and R 6 together form ethylene.

20. A compound according to claim 1 , wherein R 9 and R 10 together form butylene.

21. A compound according to claim 1 , wherein A is selected from the group of:

22. A compound according to claim 1 , wherein A is selected from the group of:

23. A compound according to claim 1 selected from the group consisting of:
2-(2-methylimidazo[1,2-b]pyridazin-6-yl)-7-(4-methylpiperazin-1-yl)pyrido[1,2-a]pyrimidin-4-one;
7-[(8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;
7-[(8aS)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;
7-[(8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;
7-[(8aS)-8a-methyl-1,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrazin-2-yl]-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;
7-[(8aR)-8a-methyl-1,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrazin-2-yl]-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;
2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-[(3S,5R)-3,5-dimethylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one;
2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one;
2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one;
7-(1,4-diazepan-1-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;
2-(2-methylimidazo[1,2-b]pyridazin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one;
2-(2-methylimidazo[1,2-b]pyridazin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one;
7-(1,4-diazepan-1-yl)-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;
7-[(3R,5S

Assignees

• Hoffmann La Roche
• Ptc Therapeutics Inc

Inventors

• Ratni Hasane
• Green Luke
• Weetall Marla L
• Naryshkin Nikolai A

Classifications

• C07D519/00 Primary

  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

• 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

• A61P21/02

  Muscle relaxants, e.g. for tetanus or cramps · CPC title

• A61P21/00 Primary

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