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

Patent metadata

Field	Value
Publication number	US-9505742-B2
Application number	US-201514947730-A
Country	US
Kind code	B2
Filing date	Nov 20, 2015
Priority date	May 27, 2013
Publication date	Nov 29, 2016
Grant date	Nov 29, 2016

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 , A, B, 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 6 , R 7 and R 9 are independently selected from H, alkyl, halogen and hydroxy;
R 8 and R 11 together form —CH 2 —CH 2 —;
R 10 is H or R 10 and R 11 together form —(CH 2 ) w —;
A is —C(O)— or —S(O) 2 —;
B is —C— or —N—;
R 12 is alkyl, 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 halogen;
m, n and p are independently selected from zero and 1;
w is 1, 2 or 3;
with the proviso that 2-[5-(1-acetyl-pyrrolidin-3-yl)-pyridin-3-yl]-5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one and 2-(1′-acetyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl-5-yl)-5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one are excluded;

or a and pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein R 1 and R 2 are independently selected from H and alkyl.

3. The compound according to claim 1 , wherein R 1 and R 2 are alkyl.

4. The compound according to claim 1 , wherein R 1 and R 2 are methyl.

5. The compound according to claim 1 , wherein m and n is zero.

6. The compound according to claim 1 , wherein p is 1.

7. The compound according to claim 1 wherein R 7 is H or halogen.

8. The compound according to claim 1 , wherein R 7 is H.

9. The compound according to claim 1 , wherein R 9 is H.

10. The compound according to claim 1 , wherein R 10 is H.

11. The compound according to claim 1 , wherein A is —S(O) 2 —.

12. The compound according to claim 1 , wherein R 12 is alkyl or cycloalkyl.

13. The compound according to claim 1 , wherein R 12 is alkyl.

14. The compound according to claim 1 , wherein R 12 is ethyl, propyl, isopropyl.

15. The compound according to claim 1 , wherein R 12 is ethyl.

16. The compound according to claim 1 , wherein R 13 is chloro.

17. The compound according to claim 1 , wherein R 14 is H.

18. The compound according to claim 1 , wherein R 1 and R 2 are methyl, R 7 , R 9 , R 10 and R 14 are H, R 13 is chloro, A is —S(O) 2 —, m and n are zero, p is 1 and R 12 is alkyl or cycloalkyl.

19. The compound according to claim 1 , wherein R 1 and R 2 are methyl, R 7 , R 9 , R 10 and R 14 are H, R 13 is chloro, A is —S(O) 2 —, m and n are zero, p is 1 and R 12 is alkyl.

20. The compound according to claim 1 , selected from
5-Chloro-3,3-dimethyl-2-[5-(1-propanoylpiperidin-4-yl)pyridin-3-yl]isoindol-1-one;
5-Chloro-2-[5-(1-ethylsulfonylpiperidin-4-yl)pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-Chloro-3,3-dimethyl-2-[5-(1-methylsulfonylpiperidin-4-yl)pyridin-3-yl]isoindol-1-one;
5-Chloro-2-[5-(1-ethylsulfonylpiperidin-3-yl)pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-Chloro-3,3-dimethyl-2-[5-[(3R or 3S)-1-methylsulfonylpiperidin-3-yl]pyridin-3-yl]isoindol-1-one;
5-Chloro-3,3-dimethyl-2-[5-[(3S or 3R)-1-methylsulfonylpiperidin-3-yl]pyridin-3-yl]isoindol-1-one;
5-Chloro-2-[5-(1-ethylsulfonylpyrrolidin-3-yl)pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-Chloro-3,3-dimethyl-2-[5-[(3R or 3S)-1-propylsulfonylpyrrolidin-3-yl]pyridin-3-yl]isoindol-1-one;
5-Chloro-3,3-dimethyl-2-[5-[(3S or 3R)-1-propylsulfonylpyrrolidin-3-yl]pyridin-3-yl]isoindol-1-one;
5-Chloro-3,3-dimethyl-2-[5-[(3R or 3S)-1-propan-2-ylsulfonylpyrrolidin-3-yl]pyridin-3-yl]isoindol-1-one;
5-Chloro-3,3-dimethyl-2-[5-[(3S or 3R)-1-propan-2-ylsulfonylpyrrolidin-3-yl]pyridin-3-yl]isoindol-1-one;
5-Chloro-2-[5-[(3R or 3S)-1-cyclopropylsulfonylpyrrolidin-3-yl]pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-Chloro-2-[5-[(3S or 3R)-1-cyclopropylsulfonylpyrrolidin-3-yl]pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-Chloro-2-[5-(3-fluoro-1-propan-2-ylsulfonylpyrrolidin-3-yl)pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-Chloro-3,3-dimethyl-2-[5-(1-propylsulfonylpiperidin-4-yl)pyridin-3-yl]isoindol-1-one;
5-Chloro-3,3-dimethyl-2-[5-(1-propan-2-ylsulfonylpiperidin-4-yl)pyridin-3-yl]isoindol-1-one;
5-Chloro-2-[5-(1-cyclopropylsulfonylpiperidin-4-yl)pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-Chloro-3,3-dimethyl-2-[5-[1-(4-methylpyridine-3-carbonyl)piperidin-4-yl]pyridin-3-yl]isoindol-1-one;
5-Chloro-2-[5-[1-(3-chloropyridine-4-carbonyl)piperidin-4-yl]pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-Chloro-2-[5-[1-(3-chloropyridine-2-carbonyl)piperidin-4-yl]pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-Chloro-2-[5-(1-ethylsulfonylpiperidin-4-yl)pyridin-3-yl]-3H-isoindol-1-one;
5-Chloro-2-[5-(1-propan-2-ylsulfonylpiperidin-4-yl)pyridin-3-yl]-3H-isoindol-1-one;
5-Chloro-2-[5-[1-(4-methylpyridine-3-carbonyl)piperidin-4-yl]pyridin-3-yl]-3H-isoindol-1-one;
(3R or 3S)-5-Chloro-2-[5-(1-ethylsulfonylpiperidin-4-yl)pyridin-3-yl]-3-methyl-3H-isoindol-1-one;
(3S or 3R)-5-Chloro-2-[5-(1-ethylsulfonylpiperidin-4-yl)pyridin-3-yl]-3-methyl-3H-isoindol-1-one;
(3R or 3S)-5-Chloro-3-methyl-2-[5-(1-propan-2-ylsulfonylpiperidin-4-yl)pyridin-3-yl]-3H-isoindol-1-one;
(3S or 3R)-5-Chloro-3-methyl-2-[5-(1-propan-2-ylsulfonylpiperidin-4-yl)pyridin-3-yl]-3H-isoindol-1-one;
(3R or 3S)-5-Chloro-3-methyl-2-[5-[1-(4-methylpyridine-3-carbonyl)piperidin-4-yl]pyridin-3-yl]-3H-isoindol-1-one;
(3S or 3R)-5-Chloro-3-methyl-2-[5-[1-(4-methylpyridine-3-carbonyl)piperidin-4-yl]pyridin-3-yl]-3H-isoindol-1-one;
5-Chloro-2-[5-(1-ethylsulfonyl-4-fluoropiperidin-4-yl)pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-Chloro-2-[5-(4-fluoro-1-propan-2-ylsulfonylpiperidin-4-yl)pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-Chloro-2-[5-(1-ethylsulfonylazetidin-3-yl)pyridin-3-yl]-3,3-dimethylisoindol-1-one;
2-[5-(1-Acetylazetidin-3-yl)pyridin-3-yl]-5-chloro-3,3-dimethylisoindol-1-one;
5-Chloro-3,3-dimethyl-2-[5-(1-propylsulfonylazetidin-3-yl)pyridin-3-yl]isoindol-1-one;
5-Chloro-2-[5-(1-cyclopropylsulfonylazetidin-3-yl)pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-Chloro-3,3-dimethyl-2-[5-[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]pyridin-3-yl]isoindol-1-one;
5-Chloro-2-[5-(4-fluoro-1-propylsulfonyl-4-piperidyl)-3-pyridyl]-3,3-dimethyl-isoindolin-1-one;
5-Chloro-2-[5-(1-cyclopropylsulfonyl-4-fluoro-4-piperidyl)-3-pyridyl]-3,3-dimethyl-isoindolin-1-one;
2-[5-(4-Fluoro-1-isopropylsulfonyl-4-piperidyl)-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile;
6-[5-(1-Ethylsulfonyl-4-fluoro-4-piperidyl)-3-pyridyl]-2-methoxy-7,7-dimethyl-pyrrolo[3,4-b]pyridin-5-one;
6-[5-[4-Fluoro-1-(1-methylpyrazole-4-carbonyl)-4-piperidyl]-3-pyridyl]-2-methoxy-7,7-dimethyl-pyrrolo[3,4-b]pyridin-5-one;
6-[5-(4-Fluoro-1-isopropylsulfonyl-4-piperidyl)-3-pyridyl]-2-methoxy-7,7-dimethyl-pyrrolo[3,4-b]pyridin-5-one;
6-[5-(4-Fluoro-1-propylsulfonyl-4-piperidyl)-3-pyridyl]-2-methoxy-7,7-dimethyl-pyrrolo[3,4-b]pyridin-5-one;
6-[5-[4-Fluoro-1-(1-methylimidazole-2-carbonyl)-4-piperidyl]-3-pyridyl]-2-methoxy-7,7-dimethyl-pyrrolo[3,4-b]pyridin-5-one;
6-[5-(1-Cyclopropylsulfonyl-4-fluoro-4-piperidyl)-3-pyridyl]-2-methoxy-7,7-dimethyl-pyrrolo[3,4-b]pyridin-5-one;
6-[5-(1-Ethylsulfonyl-4-piperidyl)-3-pyridyl]-2-methoxy-7,7-dimethyl-pyrrolo[3,4-b]pyridin-5-one;
2-Methoxy-7,7-dimethyl-6-[5-[1-(1-methylpyrazole-4-carbonyl)-4-piperidyl]-3-pyridyl]pyrrolo[3,4-b]pyridin-5-one;
2-Methoxy-7,7-dimethyl-6-[5-[1-(2-methylpyrazole-3-carbonyl)-4-piperidyl]-3-pyridyl]pyrrolo[3,4-b]py

Assignees

• Hoffmann La Roche

Inventors

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

Classifications

• A61P9/04

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

• A61P5/38

  of the suprarenal hormones · CPC title

• A61P5/40

  Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P43/00

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