Tetrahydropyridopyrazines as modulators of GPR6

Patent metadata

Field	Value
Publication number	US-10179783-B2
Application number	US-201515118447-A
Country	US
Kind code	B2
Filing date	Feb 13, 2015
Priority date	Feb 14, 2014
Publication date	Jan 15, 2019
Grant date	Jan 15, 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. A compound of the formula

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, and halo, wherein the C 1-4 alkyl and C 1-4 alkoxy R 1 substituents are optionally substituted with 1 to 6 substituents independently selected from the group consisting of halo;
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 C 1-6 alkylene;
when X 1 is CH, Z is C 1-6 alkylene and;
R 2 is NR 6 R 7 ;
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 which is optionally substituted with halo or hydroxy, and C 3-6 heterocyclyl;
X 3 is CCH 3 and X 4 is N; or
X 3 is N and X 4 is CCH 3 ;
excluding the compounds:
N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine;
3-(4-(5-chloro-2-fluorobenzyl)piperazin-1-yl)-N-cyclopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine;
N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine;
N-cyclopropyl-2-(4-(2,4-difluorobenzyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-3-amine;
N-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine;
3-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-N-cyclopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine; and

N-cyclopropyl-3-(1-(2,4-difluorobenzyl)piperidin-4-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine.

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 X 3 is CCH 3 and X 4 is N.

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 according to claim 1 , which is selected from the group consisting of:
3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine;
3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine;
(S)-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine;
(S)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine;
(R)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine;
(R)-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine;
N-cyclopropyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine;
cis-3-((3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-yl)amino)cyclobutanol;
cis-3-((3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-yl)amino)cyclobutanol;
trans-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(3-fluorocyclobutyl)-7-methylpyrido[3,4-b]pyrazin-2-amine;
trans-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-(3-fluorocyclobutyl)-7-methylpyrido[3,4-b]pyrazin-2-amine;
trans-3-((3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-yl)amino)cyclobutanol;
trans-3-((3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-yl)amino)cyclobutanol;
3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methyl-N-(oxetan-3-yl)pyrido[3,4-b]pyrazin-2-amine;
3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-N-(oxetan-3-yl)pyrido[3,4-b]pyrazin-2-amine;
3-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-7-methyl-N-(oxetan-3-yl)pyrido[3,4-b]pyrazin-2-amine;
3-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine;
N-cyclopropyl-3-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-′7-methylpyrido[3,4-b]pyrazin-2-amine;
(R)-3-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine;
(S)-3-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine;
3-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine;
N-cyclopropyl-3-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine;
(R)-3-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine;
(S)-3-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine;
3-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine;
N-cyclopropyl-3-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-′7-methylpyrido[3,4-b]pyrazin-2-amine;
(R)-3-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine;
(S)-3-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine;
2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-3-amine;
N-cyclopropyl-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazin-3-amine;
(S)-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine;
(R)-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine;
N-cyclopropyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-3-amine;
2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-3-amine;
(R)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine;
(S)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine;
2-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-3-amine;
N-cyclopropyl-2-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-′7-methylpyrido[3,4-b]pyrazin-3-amine;
(R)-2-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine;
(S)-2-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine;
2-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-3-amine;
N-cyclopropyl-2-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazin-3-amine;
(R)-2-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine;
(S)-2-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine;
2-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-3-amine;
N-cyclopropyl-2-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-′7-methylpyrido[3,4-b]pyrazin-3-amine;
(R)-2-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine;
(S)-2-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine; and
2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methyl-N-(oxetan-3-yl)pyr

Assignees

• Takeda Pharmaceuticals Co
• Taketa Pharmaceutical Company Ltd

Inventors

• Hitchcock Stephen
• Hopkins Maria
• Kikuchi Shota
• Monenschein Holger
• Reichard Holly
• Sun Huikai
• Macklin Todd

Classifications

• 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

• A61P25/24

  Antidepressants · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title