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

Patent metadata

Field	Value
Publication number	US-10077266-B2
Application number	US-201715621761-A
Country	US
Kind code	B2
Filing date	Jun 13, 2017
Priority date	Dec 20, 2013
Publication date	Sep 18, 2018
Grant date	Sep 18, 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. A compound of formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is selected from the group consisting of C 3-8 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl, and 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 ;
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, C 3-8 cycloalkyl, C 6-10 aryl, C 1-10 heteroaryl, and C 3-6 heterocyclyl;
X 3 is selected from the group consisting of CH and CR 4 and X 4 is NR 8 ; or
X 3 is NR 8 and X 4 is selected from the group consisting of CH and CR 4 ;
R 8 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —S(O) 2 —R 9 , —C(O)—R 10 , —C(O)—N(R 11 )(R 12 ), and —C(O)—OR 13 ;
R 9 is selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, and phenyl;
R 10 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, C 1-10 heteroaryl, and C 3-6 heterocyclyl;
R 11 is selected from the group consisting of hydrogen and C 1-6 alkyl;
R 12 is selected from the group consisting of hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl; or
R 11 and R 12 , taken together with the nitrogen atom to which they are attached, form a 4- to 7-membered saturated ring optionally having an additional ring heteroatom selected from the group consisting of N, O and S and optionally substituted on any of the ring carbon atoms with 1, 2, 3, 4 or 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 further substituted on any additional ring nitrogen by hydrogen or a substituent selected from the group consisting of C 3-8 cycloalkyl and C 1-6 alkyl; and
R 13 is selected from the group consisting of C 1-6 alkyl and C 3-8 cycloalkyl.

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

3. The compound according to claim 2 , wherein Z is —O—, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3 , wherein R 2 is —NR 6 R 7 , or a pharmaceutically acceptable salt thereof.

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

6. The compound according to claim 5 , wherein X 3 is selected from the group consisting of CH and CR 4 and X 4 is NR 8 , or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 6 , wherein R 1 is C 6-10 aryl, or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 7 , wherein Z is C 1-6 alkylene, or a pharmaceutically acceptable salt thereof.

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

10. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

11. A method for treating Parkinson's disease in a patient, comprising administering to the patient in need thereof an effective amount of a compound according to claim 1 .

Assignees

• 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

• A61P25/24

  Antidepressants · CPC title

• A61P25/36

  Opioid-abuse · 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