3,4-dihydro-2H-isoquinoline-1-one and 2,3-dihydro-isoindol-1-one compounds
The invention provides novel compounds having the general formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , A, m, n and p are as described herein, compositions including the compounds and methods of using the compounds.
1. A Compound of formula (I)
wherein
R 1 , R 2 , R 3 and R 4 are independently selected from H, alkyl and cycloalkyl;
R 5 , R 7 and R 9 are independently selected from H or alkyl;
R 8 (i) is hydrogen and both R 6 and R 9 together are —CH 2 —, and, R 10 and R 11 together are —CH 2 —; or,
(ii) and R 6 , R 9 and R 11 are independently H or alkyl, and R 10 is H; or,
(iii) and both R 6 and R 9 are independently H or alkyl and R 10 and R 11 together are —CH 2 —; or,
(iv) and R 11 together are —CH 2 —CH 2 —; and R 6 and R 10 are independently H or alkyl;
A is —C(O)— or —S(O) 2 —;
B is —C— or —N—;
R 12 is cycloalkyl or substituted heteroaryl, wherein substituted heteroaryl is substituted with one to three substituent independently selected from H, alkyl, cycloalkyl, hydroxy, alkoxy, cyano and halogen;
R 13 is halogen, cyano, alkoxy or haloalkoxy;
R 14 is H, alkyl or cycloalkyl;
R 15 is H, alkyl, cycloalkyl or halogen;
m, n and p are independently selected from zero and 1;
w is 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , wherein A is —S(O) 2 —.
3. The compound according to claim 1 , wherein A is —C(O)—.
4. The compound according to claim 1 , wherein R 12 is cycloalkyl or substituted pyridinyl, wherein substituted pyridinyl is substituted with one to three substituent independently selected from H, alkyl and halogen.
5. The compound according to claim 1 , wherein R 12 is cycloalkyl or substituted pyridinyl, wherein substituted pyridinyl is substituted with one to three substituent independently selected from alkyl and halogen.
6. The compound according to claim 1 wherein R 12 is cycloalkyl.
7. The compound according to claim 1 , R 12 is substituted heteroaryl, wherein substituted heteroaryl is substituted with one to three substituent independently selected from alkyl and halogen.
8. The compound according to claim 1 , wherein R 12 is substituted pyridinyl, wherein substituted pididinyl is substituted with one to three substituent independently selected from alkyl and halogen.
9. The compound according to claim 1 wherein R 1 and R 2 are independently selected from H and alkyl.
10. The compound according to claim 1 wherein R 1 and R 2 are alkyl.
11. The compound according to claim 1 wherein R 1 and R 2 are methyl.
12. The compound according to claim 1 wherein m, n and p are zero.
13. The compound according to claim 1 wherein w is 1 or 2.
14. The compound according to claim 1 wherein R 3 and R 4 are H.
15. The compound according to claim 1 , wherein R 5 , R 7 and R 9 are H.
16. The compound according to claim 1 wherein R 9 is H and R 10 and R 11 together form —(CH 2 ) w —.
17. The compound according to claim 1 wherein R 14 is H.
18. The compound according to claim 1 wherein R 13 is chloro.
19. The compound according to claim 1 , wherein R 15 is H.
20. The compound according to claim 1 selected from
5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-Chloro-2-[5-[[(3R or 3 S)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-Chloro-2-[5-[[(3 S or 3R)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-Chloro-2-[5-[(1-cyclopropylsulfonylpiperidin-4-yl)-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-Chloro-2-[5-[[(3R or 3 S)-1-cyclopropylsulfonylpiperidin-3-yl]amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-Chloro-2-[5-[[(3 S or 3R)-1-cyclopropylsulfonylpiperidin-3-yl]amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-Chloro-3,3-dimethyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindol-1-one;
5-Chloro-3,3-dimethyl-2-[5-[[1-(5-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindol-1-one;
5-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3-methyl-3H-isoindol-1-one;
5-Chloro-3-methyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3H-isoindol-1-one;
5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3-methyl-3H-isoindol-1-one;
6-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one;
6-Chloro-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one;
6-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one;
6-Chloro-2-[5-[[1-(5-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one;
5-Chloro-3,3-dimethyl-2-[5-[[2-(4-methylpyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl]amino]pyridin-3-yl]isoindol-1-one;
5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one;
6-Chloro-2-[5-[[1-(3,5-dimethylisoxazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydroisoquinolin-1-one;
6-Chloro-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydroisoquinolin-1-one;
6-Chloro-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydroisoquinolin-1-one;
5-Chloro-2-[5-[[1-(3,5-dimethylisoxazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,3-dimethyl-isoindolin-1-one;
5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one;
(3R or 3 S)-5-Chloro-3-methyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one;
(3S or 3R)-5-Chloro-3-methyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one;
(3R or 3 S)-5-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3-methyl-isoindolin-1-one;
(3 S or 3R)-5-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3-methyl-isoindolin-1-one;
(3R or 3 S)-5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3-methyl-isoindolin-1-one;
(3 S or 3R)-5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3-methyl-isoindolin-1-one;
2-[5-[(1-Cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile;
3,3-Dimethyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;
3,3-Dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;
3,3-Dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;
2-[5-[(1-Cyclopropylsulfonyl-4-piperidyl)amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile;
2-[5-[[1-(3-Chloropyridine-2-carbonyl)-4-piperidyl]amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile;
3,3-Dimethyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;
2-[5-[[1-(3-Chloropyridine-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile;
3,3-Dimethyl-2-[5-[[1-(3-methylimidazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;
3,3-Dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;
3,3-Dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;
3,3-Dimethyl-2-[5-[[1-(3-methylimidazole-4-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;
or a pharmaceutically acceptable salt thereof.
21. The compound according to claim 1 selected from
5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-Chloro-2-[5-[[(3 S or 3R)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-Chloro-3,3-dimethyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindol-1-one;
5-Chloro-3,3-dimethyl-2-[5-[[1-(5-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindol-1-one;
5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one;
6-Chloro-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one;
6-Chloro-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydroisoquinolin-1-one;
5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one;
(3R or 3 S)-5-Chloro-3-methyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one;
2-[5-[(1-Cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile;
3,3-Dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;
or a pharmaceutically acceptable salt thereof.
22. A process to prepare a compound according to claim 1 comprising
a) the reaction of a compound of formula (II) in the presence of a compound of formula (III);
or
b) the reaction of a compound of formula (IV) in the presence of a compound of formula (V);
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , A, m, n and p are as defined in claim 1 and X in step a) is halogen or triflate and in step b) is halogen.
23. A pharmaceutical composition comprising a compound according to claim 1 and a therapeutically inert carrier.