Positive allosteric modulators of mGluR2

Patent metadata

Field	Value
Publication number	US-9682980-B2
Application number	US-201314406029-A
Country	US
Kind code	B2
Filing date	Jun 19, 2013
Priority date	Jun 21, 2012
Publication date	Jun 20, 2017
Grant date	Jun 20, 2017

Abstract

The disclosure generally relates to compounds of formula I, including their salts, as well as compositions and methods of using the compounds. The compounds modulate the mGluR2 receptor and may be useful for the treatment of various disorders of the central nervous system. Formula (I):

First claim

We claim:

1. A compound of formula I

wherein:
A and B together with the nitrogen to which they are attached form ring A which is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl, and is substituted with 1 Ar 2 or (Ar 2 )alkyl substituent and is also substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, hydroxy, alkoxy, and haloalkoxy;
or ring A and B together is selected from the group consisting of

R 1 is selected from the group consisting of cyano, halo, alkyl, haloalkyl, (cycloalkyl)alkyl, cycloalkyl, alkoxy, and haloalkoxy;
R 2 is selected from the group consisting of alkyl, haloalkyl, (cycloalkyl)alkyl, benzyl, and cycloalkyl;
R 3 is hydrogen, alkyl, haloalkyl, or cycloalkyl;
Ar 2 is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, hydroxy, alkoxy, (cycloalkyl)alkoxy, haloalkoxy, and alkoxycarbonyl;
X 1 is N;
X 2 is CR 3 or N; and
X 3 is CH or N;
provided that one of X 2 and X 3 is N, thus when X 2 is N, X 3 is CH and when X 3 is N, X 2 is CR 3 ;
or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 where X 2 is N and X 3 is CH.

3. A compound of claim 1 where X 2 is CH and X 3 is N.

4. A compound of claim 1 where R 1 is selected from the group consisting of halo, alkyl, haloalkyl, and alkoxy and R 2 is selected from the group consisting of alkyl, haloalkyl, (cycloalkyl)alkyl, and benzyl.

5. A compound of claim 1 where Ar 2 is phenyl, pyridinyl, or pyrimidinyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, hydroxy, alkoxy, (cycloalkyl)alkoxy, haloalkoxy, and alkoxycarbonyl.

6. A compound of claim 1 where ring A is piperidinyl substituted with 1 Ar 2 substituent and is also substituted with 0-1 hydroxy substituents.

7. A compound of claim 1 where ring A is selected from

8. A compound of claim 1 selected from the group consisting of
3-(cyclopropylmethyl)-7-(4-(3,6-difluoro-2-methoxyphenyl)piperidin-1-yl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine;
7-(4-(3,6-difluoro-2-methoxyphenyl)piperidin-1-yl)-3-(2,2,2-trifluoroethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine;
8-chloro-3-(cyclopropylmethyl)-7-(4-(2-(difluoromethoxy)-3,6-difluorophenyl)piperidin-1-yl)-[1,2,4]triazolo[4,3-b]pyridazine;
8-chloro-7-(4-(2-fluoro-6-methoxyphenyl)piperidin-1-yl)-3-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-b]pyridazine;
3-(cyclopropylmethyl)-7-(4-phenylpiperidin-1-yl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine;
8-chloro-3-(cyclopropylmethyl)-7-(4-(2-fluorophenyl)piperidin-1-yl)-[1,2,4]triazolo[4,3-c]pyrimidine; and
8-chloro-7-(4-(2-fluorophenyl)piperidin-1-yl)-3-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-c]pyrimidine;
or a pharmaceutically acceptable salt thereof.

9. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Assignees

• Bristol Myers Squibb Co

Inventors

• Mattson Ronald J
• Meng Zhaoxing
• Guernon Leatte R

Classifications

• A61P25/30

  for treating abuse or dependence · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title