Pyrazines as modulators of GPR6

Patent metadata

Field	Value
Publication number	US-10000468-B2
Application number	US-201515118461-A
Country	US
Kind code	B2
Filing date	Feb 13, 2015
Priority date	Feb 14, 2014
Publication date	Jun 19, 2018
Grant date	Jun 19, 2018

Abstract

The present invention provides compounds of formula I:

which are useful as modulators of GPR6, pharmaceutical compositions thereof, methods for treatment of conditions associated with GPR6, processes for making the compounds and intermediates thereof.

First claim

What is claimed is:

1. The compound of formula I

or a pharmaceutically acceptable salt thereof, wherein
R 1 is phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, cyano, halo, trifluoromethyl, and trifluoromethoxy;
X 1 is N and X 2 is CH; or
X 1 is CH and X 2 is N; or
X 1 is N and X 2 is N;
when X 1 is N, Z is selected from the group consisting of C 1-6 alkylene, C 1-6 haloalkylene, —C(O)—, and —S(O) 2 —;
when X 1 is CH, Z is selected from the group consisting of C 1-6 alkylene, C 1-6 haloalkylene, —O—, —C(O)—, —NH—, —S—, —S(O)—, and —S(O) 2 —;
q is 1;
s is 1;
R 2 is —NR 6 R 7 ;
R 3 , each time taken, is independently selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, and trifluoromethyl;
p is 0, 1, or 2;
R 4 , each time taken, is independently selected from the group consisting of C 1-6 alkyl, cyano, hydroxy, halo, C 3-6 heterocyclyl, —C(O)—R 8 , —C(O)—N(R 9 )(R 10 ), and —C(O)—OR 11 ;
r is 1 or 2;
R 6 is hydrogen;
R 7 is selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, and C 3-6 heterocyclyl;
R 8 is selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, C 1-10 heteroaryl, and C 3-6 heterocyclyl;
R 9 is selected from the group consisting of hydrogen and C 1-6 alkyl;
R 10 is selected from the group consisting of hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl; or
R 9 and R 10 are taken together with the nitrogen to which they are attached form a 4 to 7 membered, saturated, ring optionally having 1 additional ring heteroatom selected from the group N, O, and S and optionally substituted on any of the ring carbon atoms with 1 to 5 substituents independently selected from the group consisting of cyano, halo, hydroxy, amino, C 3-6 heterocyclyl, C 1-9 amide, C 1-6 alkyl, and C 1-4 alkoxy and substituted on any additional ring nitrogen by a substituent selected from the group consisting of hydrogen, C 3-8 cycloalkyl, and C 1-6 alkyl; and
R 11 is selected from the group consisting of hydrogen and C 3-8 cycloalkyl.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein X 1 is CH and X 2 is N.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein X 1 is N and X 2 is N.

4. The compound or pharmaceutically acceptable salt thereof according to claim 3 , wherein an R 4 is cyano.

5. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein Z is C 1-6 alkylene.

6. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein Z is —O—.

7. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein Z is —C(O)—.

8. The compound according to claim 1 , which is selected from the group consisting of:
5-(cyclopropylamino)-6-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrazine-2,3 -dicarbonitrile;
5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(isopropylamino)pyrazine-2,3-dicarbonitrile;
5-(4-(5-chloro-2-fluorobenzoyl)piperidin-1-yl)-6-(isopropylamino)pyrazine-2,3-dicarbonitrile;
(R)-5-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-6-(isopropylamino)pyrazine-2,3-dicarbonitrile;
5-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-6-(isopropyl amino)pyrazine-2,3-dicarbonitrile;
5-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-3-cyano-6-(isopropylamino)pyrazine-2-carboxylic acid;
6-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-3-cyano-5-(isopropylamino)pyrazine-2-carboxylic acid;
3-cyano-6-(cyclopropylamino)-5-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrazine-2-carboxylic acid;
3-cyano-5-(cyclopropylamino)-6-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrazine-2-carboxylic acid;
3-cyano-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(isopropylamino)pyrazine-2-carboxylic acid;
3-cyano-6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-(isopropylamino)pyrazine-2-carboxylic acid;
5-(4-(5-chloro-2-fluorobenzoyl)piperidin-1-yl)-3-cyano-6-(isopropylamino)pyrazine-2-carboxylic acid;
6-(4-(5-chloro-2-fluorobenzoyl)piperidin-1-yl)-3-cyano-5-(isopropylamino)pyrazine-2-carboxylic acid;
(R)-3-cyano-5-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-6-(isopropylamino)pyrazine-2-carboxylic acid;
(R)-3-cyano-6-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5-(isopropylamino)pyrazine-2-carboxylic acid;
6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-(isopropylamino)-pyrazine-2-carboxylic acid;
3-chloro-6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-(isopropylamino)pyrazine-2-carbonitrile;
5-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-3-cyano-6-(isopropylamino)-N,N-dimethylpyrazine-2-carboxamide;
3-cyano-6-(cyclopropylamino)-5-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N,N-dimethylpyrazine-2-carboxamide;
3-cyano-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(isopropylamino)-N,N-dimethylpyrazine-2-carboxamide;
3-cyano-6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-(isopropylamino)-N,N-dimethylpyrazine-2-carboxamide;
5-(4-(5-chloro-2-fluorobenzoyl)piperidin-1-yl)-3-cyano-6-(isopropylamino)-N,N-dimethylpyrazine-2-carboxamide;
6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-(isopropylamino)-N,N-dimethylpyrazine-2-carboxamide;
6-(4-(5-chloro-2-fluorobenzoyl)piperidin-1-yl)-5-(isopropylamino)-N,N-dimethylpyrazine-2-carboxamide;
(R)-6-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5-(isopropylamino)-N-methylpyrazine-2-carboxamide;
(S)-6-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5-(isopropylamino)-N-methylpyrazine-2-carboxamide;
(6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-(isopropylamino)pyrazin-2-yl)(3-fluoroazetidin-1-yl)methanone;
5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(isopropylamino)-N,N-dimethylpyrazine-2-carboxamide;
(R)-5-(cyclopropylamino)-6-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrazine-2-carbonitrile;
6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-(isopropylamino)pyrazine-2-carbonitrile;
5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(isopropylamino)pyrazine-2-carbonitrile;
5-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-6-(cyclopropylamino)pyrazine-2-carbonitrile;
(S)-5-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-6-(isopropylamino)pyrazine-2-carbonitrile;
(R)-5-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-6-(isopropylamino)pyrazine-2-carbonitrile; and
6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-(isopropylamino)-3-morpholinopyrazine-2-carbonitrile;

or a pharmaceutically acceptable salt of any one of the above-mentioned compounds.

9. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof as defined in claim 1 , and a pharmaceutically acceptable excipient.

10. A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject a compound or pharmaceutically acceptable salt thereof as defined in claim 1 , wherein the disease, disorder or condition is selected from Parkinson's disease, levodopa induced dyskinesias, Huntington's disease, drug addiction, eating disorders, cognitive disorders, schizophrenia, bipolar disorders, and depression.

Assignees

• Takeda Pharmaceuticals Co

Inventors

• Adams Mark E
• Brown Jason W
• Hitchcock Stephen
• Hopkins Maria
• Kikuchi Shota
• Lam Betty
• Monenschein Holger
• Reichard Holly
• Sun Huikai

Classifications

• A61P43/00

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

• A61P25/36

  Opioid-abuse · 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

• A61P25/30

  for treating abuse or dependence · CPC title