Quinoxaline derivatives as GPR6 modulators

Patent metadata

Field	Value
Publication number	US-9487526-B2
Application number	US-201314421516-A
Country	US
Kind code	B2
Filing date	Aug 13, 2013
Priority date	Aug 13, 2012
Publication date	Nov 8, 2016
Grant date	Nov 8, 2016

Abstract

The present invention provides compounds of Formula (I):

that are GPR6 modulators and are therefore useful for the treatment of diseases treatable by modulation of GPR6, in particular treating Parkinson disease, levodopa induced dyskinesias, Huntington's disease, other dyskinesias, akinesias, and motor disorders involving dysfunction of the striatum, schizophrenia and drug addiction. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

First claim

What is claimed is:

1. A compound of the formula:

wherein:
R 1 is a heterocycloamino ring substituted with R a , R b , and R c wherein:
R a is —Z—Ar where Z is C 1-6 alkylene, C 1-6 haloalkylene, —O—, —C(O)—, —NH—, or —S(O)n- wherein n is 0, 1, or 2; and Ar is C 3-10 cycloalkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkenyl, C 6-10 aryl, or C 1-9 heteroaryl wherein C 3-10 cycloalkyl, C 3-7 heterocycloalkenyl, C 3-7 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1 to 3 substituents independently selected from C 1-6 alkyl, halo, hydroxy, oxo, C 1-6 alkoxy, C 1-6 thioalkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy, C 1-6 alkylcarbonyl, C 1-6 alkylsulphonyl, cyano, C 2-12 alkoxyalkyloxy, C 1-9 amide, or C 1-6 hydroxyalkyloxy; and
R b and R c are independently hydrogen, C 1-6 alkyl, hydroxy, or halo;

R 2 is —OR e or —NR d R e wherein R d is hydrogen or C 1-6 alkyl and R e is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-12 alkoxyalkyl, C 1-12 aminoalkyl, C 3-10 cycloalkyl, C 4-16 cycloalkylalkyl, C 6-10 aryl, C 1-9 heteroaryl, C 3-7 heterocyclyl, or C 3-7 heterocycloalkenyl wherein C 6-10 aryl, C 1-9 heteroaryl, C 3-7 heterocyclyl, and C 3-7 heterocycloalkenyl are optionally substituted with 1 to 3 substituents independently selected from C 1-6 alkyl, halo, hydroxy, oxo, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy, or cyano;
all X 1 -X 4 are carbon or one or two of X 1 -X 4 are N and the rest of X 1 -X 4 are carbon;
R 3 , R 4 , R 5 , and R 6 are independently absent, hydrogen, C 1-6 alkyl, halo, hydroxy, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-9 amide, C 3-7 heterocyclyl, C 1-8 alkylamino, or cyano;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein R 1 is piperidinyl.

3. The compound of claim 1 wherein R 1 is piperazinyl.

4. The compound of claim 3 wherein Z is C 1-6 alkylene.

5. The compound of claim 3 wherein Z is —C(O)—.

6. The compound of claim 4 wherein Ar is C 6-10 aryl optionally substituted with 1 to 3 substituents independently selected from C 1-6 alkyl, halo, hydroxy, oxo, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkylcarbonyl, C 1-6 alkylsulphonyl, cyano, C 2-12 alkoxyalkyloxy, C 1-9 amide, or C 1-6 hydroxyalkyloxy.

7. The compound of claim 4 wherein Ar is C 1-9 heteroaryl optionally substituted with 1 to 3 substituents independently selected from C 1-6 alkyl, halo, hydroxy, oxo, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkylcarbonyl, C 1-6 alkylsulphonyl, cyano, C 2-12 alkoxyalkyloxy, C 1-9 amide, or C 1-6 hydroxyalkyloxy.

8. The compound of claim 1 wherein R 2 is —NR d R e wherein R d is hydrogen and R e is C 1-6 alkyl or C 3-10 cycloalkyl.

9. The compound of claim 1 wherein all X 1 -X 4 are carbon.

10. The compound of claim 6 wherein all X 1 -X 4 are carbon.

11. The compound of claim 1 wherein all X 1 , X 3 , X 4 are carbon, R 6 is absent, and X 2 is N.

12. The compound of claim 1 wherein all X 1 , X 2 , X 4 are carbon, R 6 is absent, and X 3 is N.

13. The compound of claim 1 wherein all X 1 and X 4 are carbon, R 5 and R 6 are absent, and X 2 and X 3 are N.

14. The compound of claim 1 , which is selected from the group consisting of:
N-cyclopropyl-3-(4-(3-methylbenzyl)piperazin-1-yl)quinoxalin-2-amine;
(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(2,5-dichlorophenyl)methanone
2-(4-(3-chlorobenzyl)piperazin-1-yl)-N-phenylpyrido[2,3-b]pyrazin-3-amine;
3-(4-(4-bromobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine;
(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(3-isopropylphenyl)methanone;
N-cyclopropyl-3-(4-(2,5-dichlorophenethyl)piperazin-1-yl)quinoxalin-2-amine;
3-(4-((2-chloro-5-(trifluoromethyl)phenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile;
(4-chloro-2,6-difluorophenyl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone;
(S)-2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile;
(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(pyrrolidin-1-yl)methanone;
N-cyclobutyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-3-amine; and
a pharmaceutically acceptable salt of any one of the above-mentioned compounds.

15. The compound of claim 1 , which is N-cyclopropyl-3-(4-(2,4-difluorobenzyl) piperidin-1-yl)-5-methylpyrido[3,4-b]pyrazin-2-amine or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 , which is (R)-N-cyclopropyl-3-(4-((2,4-difluorophenyl) fluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 , which is 2-(cyclopropylamino)-3-(4-(2,4-difluorophenoxy) piperidin-1-yl)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1 , which is 3-(4-(2-fluoro-4-methoxyphenoxy) piperidin-1-yl)-N-i sopropylpyrazino[2,3-d[pyridazin-2-amine or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1 , which is 3-(4-(4-chloro-2-fluorophenoxy) piperidin-1-yl)-2-(isopropylamino)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1 , which is 3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropylpyrazino [2,3-d]pyridazin-2-amine or a pharmaceutically acceptable salt thereof.

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

Assignees

• Envoy Therapeutics Inc
• Takeda Pharmaceuticals Co

Inventors

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

Classifications

• A61P43/00

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

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · 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

• A61P25/16

  Anti-Parkinson drugs · CPC title