Substituted pyrido[3,4-b]pyrazines as GPR6 modulators

Patent metadata

Field	Value
Publication number	US-9708313-B2
Application number	US-201514883174-A
Country	US
Kind code	B2
Filing date	Oct 14, 2015
Priority date	Dec 20, 2013
Publication date	Jul 18, 2017
Grant date	Jul 18, 2017

Abstract

This present invention provides compounds of formula II:

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 II:

or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from the group consisting of C 3-8 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1-4 alkoxy, halo, hydroxy, and C 1-4 alkyl optionally substituted with C 1-4 alkoxy, halo, and hydroxy; C 3-6 heterocyclyl optionally substituted on ring carbons with 1 to 4 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1-9 amide, C 1-7 amido, amino, C 1-8 alkylamino, C 1-5 oxycarbonyl, cyano, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, halo, hydroxy, nitro, oxo, and phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1-9 amino, C 1-8 alkylamino, C 1-5 oxycarbonyl, cyano, halo, hydroxy, nitro, and trifluoromethyl and optionally substituted on any ring nitrogen with a substituent independently selected from the group consisting of C 1-4 alkyl, C 3-8 cycloalkyl, C 3-6 heterocyclyl, C 1-10 heteroaryl, and phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1-9 amino, C 1-8 alkylamino, C 1-5 oxycarbonyl, cyano, halo, hydroxy, nitro, and trifluoromethyl; C 6-10 aryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1-4 thioalkoxy, amino, C 1-8 alkylamino, C 1-9 amide, C 1-7 amido, C 1-5 oxycarbonyl, C 1-5 carbonyloxy, C 1-8 sulfonyl, C 1-5 carbamoyl, C 1-6 sulfonylamido, aminosulfonyl, C 1-10 aminosulfonyl, C 1-5 ureido, trifluoromethyl, trifluoromethoxy, cyano, halo, and hydroxy; and C 1-10 heteroaryl optionally substituted with 1 to 3 substituents on carbon independently selected from the group consisting of amino, C 1-8 alkylamino, C 1-9 amide, C 1-4 alkyl, C 1-4 alkoxy, cyano, halo, hydroxy, oxo, trifluoromethyl, and trifluoromethoxy and optionally substituted on a ring nitrogen with C 1-4 alkyl;
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 ;
each R 3 is independently selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, and trifluoromethyl;
p is 0, 1, or 2;
each R 4 is independently selected from the group consisting of C 1-6 alkyl, hydroxy, and halo;
r is 0 or 1;
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 C 1-6 alkyl optionally substituted with 1 to 7 substituents independently selected from the group consisting of C 1-4 alkoxy, C 1-9 amide, amino, C 1-8 alkylamino, C 1-5 oxycarbonyl, cyano, C 3-8 cycloalkyl, halo, hydroxy, C 3-6 heterocyclyl optionally substituted on any ring nitrogen by C 1-4 alkyl, C 1-10 heteroaryl, and phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1-9 amino, C 1-8 alkylamino, C 1-5 oxycarbonyl, cyano, halo, hydroxy, nitro, and trifluoromethyl; C 3-8 cycloalkyl; C 6-10 aryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, cyano, halo, hydroxy, amino, trifluoromethyl, and trifluoromethoxy; C 1-10 heteroaryl optionally substituted with 1 to 3 substituents on carbon independently selected from the group consisting of amino, C 1-8 alkylamino, C 1-9 amide, C 1-4 alkyl, C 1-4 alkoxy, cyano, halo, hydroxy, oxo, trifluoromethyl, and trifluoromethoxy and optionally substituted on a ring nitrogen with C 1-4 alkyl; and C 3-6 heterocyclyl optionally substituted on ring carbons with 1 to 4 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, halo, and hydroxy and optionally substituted on any ring nitrogen with C 1-4 alkyl; and
X 5 is selected from the group consisting of CH and CR 4 , and X 6 is selected from the group consisting of NH and N—CH 2 -(phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1-9 amino, C 1-8 alkylamino, C 1-5 oxycarbonyl, cyano, halo, hydroxy, nitro, and trifluoromethyl); or
X 5 is selected from the group consisting of NH and N—CH 2 -(phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1-9 amino, C 1-8 alkylamino, C 1-5 oxycarbonyl, cyano, halo, hydroxy, nitro, and trifluoromethyl) and X 6 is selected from the group consisting of CH and CR 4 .

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

3. The compound or pharmaceutically acceptable salt according to claim 2 , wherein X 5 is selected from the group consisting of CH and CR 4 and X 6 is NH.

4. The compound or pharmaceutically acceptable salt according to claim 2 , wherein X 5 is NH and X 6 is selected from the group consisting of CH and CR 4 .

5. The compound or pharmaceutically acceptable salt according to claim 2 , wherein X 5 is selected from the group consisting of CH and CR 4 , and X 6 is N—CH 2 -(phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1-9 amino, C 1-8 alkylamino, C 1-5 oxycarbonyl, cyano, halo, hydroxy, nitro, and trifluoromethyl).

6. The compound or pharmaceutically acceptable salt according to claim 2 , wherein X 6 is selected from the group consisting of CH and CR 4 , and X 5 is N—CH 2 -(phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1-9 amino, C 1-8 alkylamino, C 1-5 oxycarbonyl, cyano, halo, hydroxy, nitro, and trifluoromethyl).

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

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

9. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 1 is C 6-10 aryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1-4 thioalkoxy, amino, C 1-8 alkylamino, C 1-9 amide, C 1-7 amido, C 1-5 oxycarbonyl, C 1-5 carbonyloxy, C 1-8 sulfonyl, C 1-5 carbamoyl, C 1-6 sulfonylamido, aminosulfonyl, C 1-10 aminosulfonyl, C 1-5 ureido, trifluoromethyl, trifluoromethoxy, cyano, halo, and hydroxy.

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

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

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

13. The compound or pharmaceutically acceptable salt according

Assignees

• Brown Jason W
• Hitchcock Stephen
• Hopkins Maria
• Kikuchi Shota
• Monenschein Holger
• Reichard Holly
• Schleicher Kristin
• Sun Huikai
• Macklin Todd
• Takeda Pharmaceuticals Co

Inventors

• Brown Jason W
• Hitchcock Stephen
• Hopkins Maria
• Kikuchi Shota
• Monenschein Holger
• Reichard Holly
• Schleicher Kristin
• Sun Huikai
• Macklin Todd

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