Indolin-2-one and 1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one derivatives

Patent metadata

Field	Value
Publication number	US-10112938-B2
Application number	US-201615353355-A
Country	US
Kind code	B2
Filing date	Nov 16, 2016
Priority date	May 22, 2014
Publication date	Oct 30, 2018
Grant date	Oct 30, 2018

Abstract

The present invention is concerned with indolin-2-one and 1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one derivatives of general formula I wherein Ar 1 , A 2 , R 1 , R 2 , R 3 , X and n are as described herein and pharmaceutically acceptable salts thereof for treatment of central nervous system disorders

First claim

We claim:

1. A compound of formula (I)

wherein
Ar 1 is phenyl, pyridinyl or pyrimidinyl;
Ar 2 is selected from the group consisting of (i), (ii), (iv), (v), (vi), (vii), (viii), (ix), (x) and (xi);

R 1 is hydrogen, C 1-7 -alkyl, halogen or C 1-7 -alkoxy;
R 3 is hydrogen, C 1-7 -alkyl, C 1-7 -alkyl substituted by hydroxy, cycloalkyl, oxetan-3-yl, pyridinyl, imidazolyl, pyrazolyl, pyrimidinyl, which rings may optionally substituted by C 1-7 -alkyl, or is (CH 2 ) 3 —S(O) 2 -cyclopropyl;
X is CH or N;
n is 1 or 2; or,
or, a pharmaceutically acceptable salt thereof, a racemic mixture, an enantiomer, an optical isomer, a stereoisomer thereof.

2. The compound of claim 1 wherein said compound is of formula Id

3. The compound of claim 1 wherein said compound is of formula Ie

4. The compound of claim 1 wherein said compound is of formula If

5. The compound of claim 1 wherein said compound is of formula Ig

6. The compound of claim 1 wherein said compound is of formula Ih

7. The compound of claim 1 wherein said compound is of formula Ii

8. The compound of claim 1 wherein said compound is of formula Im or Im′

9. The compound of claim 1 wherein said compound is of formula In

10. The compound of claim 1 wherein said compound is of formula Iq

11. The compound of claim 1 wherein said compound is of formula Is

12. The compound of claim 1 which compounds are selected from the group consisting of:
1-Cyclopropyl-3,3-dimethyl-6-(3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl)indolin-2-one;
1-Cyclopropyl-3,3-dimethyl-6-(5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl)indolin-2-one;
3,3-Dimethyl-1-oxetan-3-yl-6-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)-1,3-dihydro-indol-2-one;
1,3,3-Trimethyl-6-(2-(pyridin-3-yl)oxazol-5-yl)indolin-2-one;
1-Cyclopropyl-3,3-dimethyl-6-(2-(pyridin-3-yl)oxazol-5-yl)indolin-2-one;
1-Cyclopropyl-3,3-dimethyl-6-(5-(pyridin-3-yl)oxazol-2-yl)indolin-2-one
1-Cyclopropyl-3,3-dimethyl-6-(2-(pyridin-4-yl)oxazol-5-yl)indolin-2-one
3,3-Dimethyl-1-(oxetan-3-yl)-6-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)indolin-2-one;
1-Cyclopropyl-3,3-dimethyl-6-(2-(2-methylpyridin-4-yl)oxazol-5-yl)indolin-2-one;
1,3,3-Trimethyl-6-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)indolin-2-one;
1-Cyclopropyl-3,3-dimethyl-6-(2-(2-methylpyridin-4-yl)thiazol-5-yl)indolin-2-one;
1-Cyclopropyl-3,3-dimethyl-6-(4-(pyridin-3-yl)oxazol-2-yl)indolin-2-one;
1-Cyclopropyl-3,3-dimethyl-6-(4-(pyridin-4-yl)oxazol-2-yl)indolin-2-one;
1-Cyclopropyl-3,3-dimethyl-6-(4-(2-methylpyridin-4-yl)oxazol-2-yl)indolin-2-one;
1,3,3-Trimethyl-6-(2-(2-methylpyridin-4-yl)thiazol-5-yl)indolin-2-one;
1-Cyclopropyl-3,3-dimethyl-6-(5-(2-methylpyridin-4-yl)oxazol-2-yl)indolin-2-one;
1,3,3-Trimethyl-6-(4-(pyridin-3-yl)oxazol-2-yl)indolin-2-one;
1,3,3-Trimethyl-6-(2-(2-methylpyridin-4-yl)oxazol-5-yl)indolin-2-one;
3,3-Dimethyl-1-(oxetan-3-yl)-6-(2-(pyridin-3-yl)oxazol-5-yl)indolin-2-one;
3,3-Dimethyl-6-(2-(6-methylpyridin-3-yl)oxazol-5-yl)-1-(oxetan-3-yl)indolin-2-one;
3,3-Dimethyl-6-(2-(pyridin-3-yl)oxazol-5-yl)indolin-2-one;
3,3-Dimethyl-6-(2-(2-methylpyridin-4-yl)oxazol-5-yl)-1-(oxetan-3-yl)indolin-2-one;
3,3-Dimethyl-6-(2-(6-methylpyridin-3-yl)oxazol-5-yl)indolin-2-one;
1-(2-Hydroxyethyl)-3,3-dimethyl-6-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)indolin-2-one;
1,3,3-Trimethyl-6-(4-methyl-2-(pyridin-3-yl)oxazol-5-yl)indolin-2-one;
1-Cyclopropyl-3,3-dimethyl-6-(2-(6-methylpyridin-3-yl)oxazol-5-yl)indolin-2-one;
3,3-Dimethyl-6-(2-(2-methylpyridin-4-yl)oxazol-5-yl)indolin-2-one;
1,3,3-Trimethyl-6-(4-methyl-2-(6-methylpyridin-3-yl)oxazol-5-yl)indolin-2-one;
1-Cyclopropyl-3,3-dimethyl-6-(4-methyl-2-(6-methylpyridin-3-yl)oxazol-5-yl)indolin-2-one;
1,3,3-Trimethyl-6-(4-methyl-2-(2-methylpyridin-4-yl)oxazol-5-yl)indolin-2-one;
1-Cyclopropyl-3,3-dimethyl-6-(4-methyl-2-(2-methylpyridin-4-yl)oxazol-5-yl)indolin-2-one;
1,3,3-Trimethyl-6-(3-pyridin-4-yl-isoxazol-5-yl)-1,3-dihydro-indol-2-one;
1,3,3-Trimethyl-6-(2-(pyridin-3-yl)oxazol-4-yl)indolin-2-one;
3,3-Dimethyl-6-(5-(2-methylpyridin-4-yl)-1,3,4-oxadiazol-2-yl)-1-(oxetan-3-yl)indolin-2-one;
1,3,3-Trimethyl-6-(4-(pyridin-4-yl)-1H-1,2,3-triazol-1-yl)indolin-2-one;
6-(2-(3-Methoxypyridin-4-yl)oxazol-5-yl)-3,3-dimethylindolin-2-one;
1,3,3-Trimethyl-6-(3-(2-methylpyridin-4-yl)isoxazol-5-yl)indolin-2-one;
1-Cyclopropyl-3,3-dimethyl-6-(3-(2-methylpyridin-4-yl)isoxazol-5-yl)indolin-2-one;
1,3,3-Trimethyl-6-(2-(2-methylpyridin-4-yl)pyrimidin-4-yl)indolin-2-one;
1,3,3-Trimethyl-6-(2-(6-methylpyridin-3-yl)pyrimidin-4-yl)indolin-2-one;
3,3-Dimethyl-6-(2-(6-methylpyridin-3-yl)pyrimidin-4-yl)-1-(oxetan-3-yl)indolin-2-one;
1-Cyclopropyl-3,3-dimethyl-6-[2-(2-methyl-pyridin-4-yl)-oxazol-5-yl]-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one;
6-(2-(5-Fluoro-2-methylpyridin-4-yl)oxazol-5-yl)-1,3,3-trimethylindolin-2-one;
3,3-Dimethyl-6-[5-(2-methyl-pyridin-4-yl)-[1,3,4]oxadiazol-2-yl]-1-oxetan-3-yl-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one;
6-(2-(2-Fluoro-5-methylpyridin-4-yl)oxazol-5-yl)-1,3,3-trimethylindolin-2-one;
6-(5-(5-Fluoro-2-methylpyridin-4-yl)-1,3,4-oxadiazol-2-yl)-1,3,3-trimethylindolin-2-one;
1,3,3-Trimethyl-6-(2-(6-methylpyridin-3-yl)pyrimidin-5-yl)indolin-2-one; and,
1,3,3-Trimethyl-6-[5-(3-methyl-4-pyridyl)isoxazol-3-yl]indolin-2-one; or,
a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound in accordance with claim 1 and at least one pharmaceutically acceptable carrier, diluent or excipient for the treatment of certain central nervous system disorders which are positive (psychosis) and negative symptoms of schizophrenia, substance abuse, alcohol and drug addiction, obsessive-compulsive disorders, cognitive impairment, bipolar disorders, mood disorders, major depression, treatment resistant depression, anxiety disorders, autism, Parkinson's disease, chronic pain, borderline personality disorder, sleep disturbances, chronic fatigue syndrome, stiffness, antiinflammatory effects in arthritis and balance problems.

Assignees

• Hoffmann La Roche
• Hoffmann La Roche

Inventors

• Hilpert Hans
• Kolczewski Sabine
• Limberg Anja
• Stoll Theodor

Classifications

• A61P25/22

  Anxiolytics · CPC title

• A61P3/02

  Nutrients, e.g. vitamins, minerals · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61P25/24

  Antidepressants · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title