Claims for Patent: 9,969,754

Summary for Patent: 9,969,754

Title:	Compounds for treating spinal muscular atrophy
Abstract:	The present invention provides compounds of formula (I) ##STR00001## wherein A, R.sup.1, R.sup.2 and R.sup.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.
Inventor(s):	Ratni; Hasane (Basel, CH), Green; Luke (Basel, CH), Weetall; Marla L. (South Plainfield, NJ), Naryshkin; Nikolai A. (South Plainfield, NJ)
Assignee:	HOFFMANN-LA ROCHE INC. (Little Falls, NJ) PTC THERAPEUTICS, INC. (South Plainfield, NJ)
Application Number:	15/351,267
Patent Claims:	1. A compound of formula (I): ##STR00062## wherein R.sup.1 is hydrogen or C.sub.1-7-alkyl; R.sup.2 is hydrogen, cyano, C.sub.1-7-alkyl, C.sub.1-7-haloalkyl or C.sub.3-8-cycloalkyl; R.sup.3 is hydrogen, C.sub.1-7-alkyl, or C.sub.3-8-cycloalkyl; A is N-heterocycloalkyl or NR.sup.12R.sup.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.sup.14; R.sup.12 is heterocycloalkyl comprising 1 nitrogen ring atom, wherein heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from R.sup.14; R.sup.13 is hydrogen, C.sub.1-7-alkyl or C.sub.3-8-cycloalkyl; R.sup.14 is independently selected from hydrogen, C.sub.1-7-alkyl, amino, amino-C.sub.1-7-alkyl, C.sub.3-8-cycloalkyl and heterocycloalkyl or two R.sup.14 together form C.sub.1-7-alkylene; with the proviso that if A is N-heterocycloalkyl comprising only 1 nitrogen ring atom, then at least one R.sup.14 substituent is amino or amino-C.sub.1-7-alkyl; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein R.sup.1 is hydrogen or C.sub.1-7-alkyl; R.sup.2 is hydrogen, cyano, C.sub.1-7-alkyl, C.sub.1-7-haloalkyl or C.sub.3-8-cycloalkyl; R.sup.3 is hydrogen, C.sub.1-7-alkyl, or C.sub.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.sup.14; R.sup.14 is independently selected from hydrogen, C.sub.1-7-alkyl, amino, amino-C.sub.1-7-alkyl, C.sub.3-8-cycloalkyl and heterocycloalkyl or two R.sup.14 together form C.sub.1-7-alkylene; with the proviso that if A is N-heterocycloalkyl comprising only 1 nitrogen ring atom, then at least one R.sup.14 substituent is amino or amino-C.sub.1-7-alkyl; or a pharmaceutically acceptable salt thereof. 3. A compound according to claim 1, wherein R.sup.1 is C.sub.1-7-alkyl. 4. A compound according to claim 1, wherein R.sup.1 is methyl. 5. A compound according to claim 1, wherein R.sup.2 is hydrogen or C.sub.1-7-alkyl. 6. A compound according to claim 1, wherein R.sup.2 is hydrogen or methyl. 7. A compound according to claim 1, wherein R.sup.3 is hydrogen or C.sub.1-7-alkyl. 8. A compound according to claim 1, wherein R.sup.3 is hydrogen or methyl. 9. A compound according to claim 1, wherein R.sup.12 is piperidinyl optionally substituted with 1, 2, 3 or 4 substituents selected from R.sup.14. 10. A compound according to claim 1, wherein A is ##STR00063## wherein X is N or CH; R.sup.4 is hydrogen, C.sub.1-7-alkyl or --(CH.sub.2).sub.m--NR.sup.9R.sup.10; R.sup.5 is hydrogen or C.sub.1-7-alkyl; R.sup.6 is hydrogen or C.sub.1-7-alkyl; R.sup.7 is hydrogen or C.sub.1-7-alkyl; R.sup.8 is hydrogen or C.sub.1-7-alkyl; R.sup.9 and R.sup.10 are independently selected from hydrogen, C.sub.1-7-alkyl and C.sub.3-8-cycloalkyl; R.sup.13 is hydrogen, C.sub.1-7-alkyl or C.sub.3-8-cycloalkyl; n is 0, 1 or 2; m is 0, 1, 2 or 3; or R.sup.4 and R.sup.5 together form C.sub.1-7-alkylene; or R.sup.4 and R.sup.7 together form C.sub.1-7-alkylene; or R.sup.5 and R.sup.6 together form C.sub.2-7-alkylene; or R.sup.5 and R.sup.7 together form C.sub.1-7-alkylene; or R.sup.5 and R.sup.9 together form C.sub.1-7-alkylene; or R.sup.7 and R.sup.8 together form C.sub.2-7-alkylene; or R.sup.7 and R.sup.9 together form C.sub.1-7-alkylene; or R.sup.9 and R.sup.10 together form C.sub.2-7-alkylene; with the proviso that if X is CH then R.sup.4 is --(CH.sub.2).sub.m--NR.sup.9R.sup.10; and with the proviso that if X is N and R.sup.4 is --(CH.sub.2).sub.m--NR.sup.9R.sup.10 then m is 2 or 3. 11. A compound according to claim 1, wherein A is ##STR00064## wherein X is N or CH; R.sup.4 is hydrogen, C.sub.1-7-alkyl or --(CH.sub.2).sub.m--NR.sup.9R.sup.10; R.sup.5 is hydrogen or C.sub.1-7-alkyl; R.sup.6 is hydrogen or C.sub.1-7-alkyl; R.sup.7 is hydrogen or C.sub.1-7-alkyl; R.sup.8 is hydrogen or C.sub.1-7-alkyl; R.sup.9 and R.sup.10 are independently selected from hydrogen, C.sub.1-7-alkyl and C.sub.3-8-cycloalkyl; n is 0, 1 or 2; m is 0, 1, 2 or 3; or R.sup.4 and R.sup.5 together form C.sub.1-7-alkylene; or R.sup.4 and R.sup.7 together form C.sub.1-7-alkylene; or R.sup.5 and R.sup.6 together form C.sub.2-7-alkylene; or R.sup.5 and R.sup.7 together form C.sub.1-7-alkylene; or R.sup.5 and R.sup.9 together form C.sub.1-7-alkylene; or R.sup.7 and R.sup.8 together form C.sub.2-7-alkylene; or R.sup.7 and R.sup.9 together form C.sub.1-7-alkylene; or R.sup.9 and R.sup.10 together form C.sub.2-7-alkylene; with the proviso that if X is CH then R.sup.4 is --(CH.sub.2).sub.m--NR.sup.9R.sup.10; and with the proviso that if X is N and R.sup.4 is --(CH.sub.2).sub.m--NR.sup.9R.sup.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.sup.6 is hydrogen, methyl or --(CH.sub.2).sub.m--NR.sup.9R.sup.10. 15. A compound according to claim 1, wherein R.sup.6 is hydrogen or methyl. 16. A compound according to claim 1, wherein R.sup.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.sup.4 and R.sup.5 together form propylene. 19. A compound according to claim 1, wherein R.sup.5 and R.sup.6 together form ethylene. 20. A compound according to claim 1, wherein R.sup.9 and R.sup.10 together form butylene. 21. A compound according to claim 1, wherein A is selected from the group of: ##STR00065## 22. A compound according to claim 1, wherein A is selected from the group of: ##STR00066## ##STR00067## 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)py- rido[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-methy- limidazo[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-dim- ethylimidazo[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-dim- ethylimidazo[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-dimethylpiper- azin-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]p- yrido[1,2-a]pyrimidin-4-one; 2-(2-methylimidazo[1,2-b]pyridazin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]p- yrido[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)-3,5-dimethylpiperazin-1-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-methy- limidazo[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-- methylimidazo[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-- methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-[(3R)-3-pyrrolidin-1-ylpyr- rolidin-1-yl]pyrido[1,2-a]pyrimidin-4-one; 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2-methylimidazo[1,2-b]pyridazin-6-yl- )pyrido[1,2-a]pyrimidin-4-one; 7-(4,7-diazaspiro[2.5]octan-7-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-[(3R)-3-pyrrolidin-1-ylpyrroli- din-1-yl]pyrido[1,2-a]pyrimidin-4-one; 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-(3,3-dimethylpiperazin-1-y- l)pyrido[1,2-a]pyrimidin-4-one; 7-(3,3-dimethylpiperazin-1-yl)-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)py- rido[1,2-a]pyrimidin-4-one; 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-9-methyl-7-[(3S)-3-methylpip- erazin-1-yl]pyrido[1,2-a]pyrimidin-4-one; 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-9-methyl-7-[(3R)-3-methylpip- erazin-1-yl]pyrido[1,2-a]pyrimidin-4-one; 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-[(3R,5S)-3,5-dimethylpiper- azin-1-yl]-9-methyl-pyrido[1,2-a]pyrimidin-4-one; 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-(3,3-dimethylpiperazin-1-y- l)-9-methyl-pyrido[1,2-a]pyrimidin-4-one; 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-- 6-yl)-9-methyl-pyrido[1,2-a]pyrimidin-4-one; 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-[(3S,5S)-3,5-dimethylpiper- azin-1-yl]pyrido[1,2-a]pyrimidin-4-one; 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-[(3S)-3-pyrrolidin-1-ylpyr- rolidin-1-yl]pyrido[1,2-a]pyrimidin-4-one; 2-(2-methylimidazo[1,2-b]pyridazin-6-yl)-7-[(3S)-3-pyrrolidin-1-ylpyrroli- din-1-yl]pyrido[1,2-a]pyrimidin-4-one; 7-[(3S,5S)-3,5-dimethylpiperazin-1-yl]-2-(2-methylimidazo[1,2-b]pyridazin- -6-yl)pyrido[1,2-a]pyrimidin-4-one; 9-methyl-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)-7-[(3S)-3-methylpiperaz- in-1-yl]pyrido[1,2-a]pyrimidin-4-one; 9-methyl-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)-7-[(3R)-3-methylpiperaz- in-1-yl]pyrido[1,2-a]pyrimidin-4-one; 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-9-methyl-2-(2-methylimidazo[1,2-b]- pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; 7-(3,3-dimethylpiperazin-1-yl)-9-methyl-2-(2-methylimidazo[1,2-b]pyridazi- n-6-yl)pyrido[1,2-a]pyrimidin-4-one; 7-(4,7-diazaspiro[2.5]octan-7-yl)-9-methyl-2-(2-methylimidazo[1,2-b]pyrid- azin-6-yl)pyrido[1,2-a]pyrimidin-4-one; 7-[(3S,5S)-3,5-dimethylpiperazin-1-yl]-9-methyl-2-(2-methylimidazo[1,2-b]- pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; and 7-[(3R)-3-ethylpiperazin-1-yl]-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)py- rido[1,2-a]pyrimidin-4-one; or a pharmaceutically acceptable salt thereof. 24. A compound according to claim 1, selected from the group consisting of: 7-[(8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-(2-m- ethylimidazo[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-dim- ethylimidazo[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-dim- ethylimidazo[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-dimethylpiper- azin-1-yl]pyrido[1,2-a]pyrimidin-4-one; 7-[(3R,5S)-3,5-dimethylpiperazin-1-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-methy- limidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2-methylimidazo[1,2-b]pyridazin-6-yl- )pyrido[1,2-a]pyrimidin-4-one; 7-(4,7-diazaspiro[2.5]octan-7-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)-9-methyl-7-[(3S)-3-methylpip- erazin-1-yl]pyrido[1,2-a]pyrimidin-4-one; 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-- 6-yl)-9-methyl-pyrido[1,2-a]pyrimidin-4-one; 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-9-methyl-2-(2-methylimidazo[1,2-b]- pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one; and 7-(4,7-diazaspiro[2.5]octan-7-yl)-9-methyl-2-(2-methylimidazo[1,2-b]pyrid- azin-6-yl)pyrido[1,2-a]pyrimidin-4-one; or a pharmaceutically acceptable salt thereof. 25. The compound of formula (VI): ##STR00068## wherein R.sup.1, R.sup.2 and R.sup.3 are as described in claim 1; Y is halogen or trifluoromethanesulfonate; or a pharmaceutically acceptable salt thereof. 26. A compound of formula (VI) according to claim 25, selected from the group consisting of: 7-fluoro-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4- -one; 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-fluoro-pyrido[1,2-a]p- yrimidin-4-one; 7-fluoro-9-methyl-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]py- rimidin-4-one; 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-fluoro-9-methyl-pyrido[1,2- -a]pyrimidin-4-one; or a pharmaceutically acceptable salt thereof. 27. A pharmaceutical composition comprising a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 28. A method for the treatment of spinal muscular atrophy in a human, which method comprises administering a therapeutically effective amount of a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, to a human in need of such treatment. 29. A compound of claim 24, wherein the compound is 7-[(8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-(2-methy- limidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof. 30. A compound of claim 24, wherein the compound is 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2-methylimidazo[1,2-b]pyridazin-6-yl- )pyrido[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof. 31. A compound of claim 24, wherein the compound is 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-- 6-yl)pyrido[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof. 32. A compound of claim 24, wherein the compound is 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-- 6-yl)-9-methyl-pyrido[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof. 33. A compound of claim 24, wherein the compound is 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-9-methyl-2-(2-methylimidazo[1,2-b]- pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof. 34. A compound of claim 24, wherein the compound is 7-[(8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-(2-methy- limidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one. 35. A compound of claim 24, wherein the compound is 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2-methylimidazo[1,2-b]pyridazin-6-yl- )pyrido[1,2-a]pyrimidin-4-one. 36. A compound of claim 24, wherein the compound is 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-- 6-yl)pyrido[1,2-a]pyrimidin-4-one. 37. A compound of claim 24, wherein the compound is 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-- 6-yl)-9-methyl-pyrido[1,2-a]pyrimidin-4-one. 38. A compound of claim 24, wherein the compound is 7-(4,7-diazaspiro[2.5]octan-7-yl)-9-methyl-2-(2-methylimidazo[1,2-b]pyrid- azin-6-yl)pyrido[1,2-a]pyrimidin-4-one.