Pyrazines as modulators of GPR6

Patent metadata

Field	Value
Publication number	US-10273225-B2
Application number	US-201815979069-A
Country	US
Kind code	B2
Filing date	May 14, 2018
Priority date	Feb 14, 2014
Publication date	Apr 30, 2019
Grant date	Apr 30, 2019

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 selected from the group consisting of optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-6 heterocyclyl, optionally substituted C 6-10 aryl, and optionally substituted C 1-10 heteroaryl;
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 0, 1, or 2;
s is 0, 1, or 2;
R 2 is —OR 5 or —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, optionally substituted 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 5 is selected from the group consisting of C 1-6 alkyl and C 3-8 cycloalkyl;
R 6 is selected from the group consisting of hydrogen and C 1-6 alkyl;
R 7 is selected from the group consisting of optionally substituted C 1-6 alkyl, C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-10 heteroaryl, and optionally substituted C 3-6 heterocyclyl;
R 8 is selected from the group consisting of optionally substituted C 1-6 alkyl, C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-10 heteroaryl, and optionally substituted C 3-6 heterocyclyl;
R 9 is selected from the group consisting of hydrogen and optionally substituted 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, optionally substituted C 3-6 heterocyclyl, C 1-9 amide, optionally substituted 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 optionally substituted 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 R 1 is optionally substituted C 6-10 aryl or a pharmaceutically acceptable salt thereof.

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

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

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

9. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 is —NR 6 R 7 .

10. A compound, which is selected from the group consisting of:
(R)-3-cyano-5-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-(2-(dimethylamino)ethyl)-6-(isopropylamino)-N-methylpyrazine-2-carboxamide;
6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(2-(dimethylamino)-ethyl)-5-(isopropylamino)-N-methylpyrazine-2-carboxamide; and
6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-(isopropylamino)-3-(methoxymethyl)pyrazine-2-carbonitrile; and
6-(4-(2,4-difluorobenzyl)piperazin-1-yl)-3-((2-(dimethylamino)ethoxy)methyl)-5-(isopropylamino)pyrazine-2-carbonitrile;

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

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

12. A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject a compound of formula I

or pharmaceutically acceptable salt thereof, wherein
R 1 is selected from the group consisting of optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-6 heterocyclyl, optionally substituted C 6-10 aryl, and optionally substituted C 1-10 heteroaryl;
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 0, 1, or 2;
s is 0, 1, or 2;
R 2 is —OR 5 or —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 optionally substituted C 1-6 alkyl, cyano, hydroxy, halo, optionally substituted 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 5 is selected from the group consisting of C 1-6 alkyl and C 3-8 cycloalkyl;
R 6 is selected from the group consisting of hydrogen and C 1-6 alkyl;
R 7 is selected from the group consisting of optionally substituted C 1-6 alkyl, C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-10 heteroaryl, and optionally substituted C 3-6 heterocyclyl;
R 8 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-10 heteroaryl, and optionally substituted C 3-6 heterocyclyl;
R 9 is selected from the group consisting of hydrogen and optionally substituted 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, optionally substituted C 3-6 heterocyclyl, C 1-9 amide, optionally substituted 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 optionally substituted C 1-6 alkyl; and

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

• A61P25/30

  for treating abuse or dependence · 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

• A61P25/24

  Antidepressants · CPC title