3,4-dihydro-2H-isoquinoline-1-one and 2,3-dihydro-isoindol-1-one compounds

Patent metadata

Field	Value
Publication number	US-9695152-B2
Application number	US-201514947768-A
Country	US
Kind code	B2
Filing date	Nov 20, 2015
Priority date	May 27, 2013
Publication date	Jul 4, 2017
Grant date	Jul 4, 2017

Abstract

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.

First claim

The invention claimed is:

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)az

Assignees

• Hoffmann La Roche

Inventors

• Aebi Johannes
• Amrein Kurt
• Chen Wenming
• Hornsperger Benoit
• Kuhn Bernd
• Liu Yongfu
• Maerki Hans P
• Martin Rainer E
• Mayweg Alexander
• Tan Xuefei
• Wang Lisha
• Zhou Mingwei

Classifications

• A61P5/42

  for decreasing, blocking or antagonising the activity of mineralocorticosteroids · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P5/38

  of the suprarenal hormones · CPC title

• A61P43/00

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