Cyclopentylbenzamide derivatives and their use for the treatment of psychotic and cognitive disorders

Patent metadata

Field	Value
Publication number	US-9493432-B2
Application number	US-201415029356-A
Country	US
Kind code	B2
Filing date	Oct 14, 2014
Priority date	Oct 15, 2013
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein n, L, X, R a , R b , R 1 , R 2 and R 3 their preparation, pharmaceutical compositions containing them and their use in therapy.

First claim

The invention claimed is:

1. A compound of formula

wherein
R 1 represents an 8- to 10-membered fused bicyclic heteroaromatic group optionally substituted by at least one substituent selected from halogen, cyano, hydroxyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxycarbonyl, C 1 -C 3 alkoxycarbonylamino, C 1 -C 3 haloalkoxy, —NR 4 R 5 , C 3 -C 6 cycloalkylamino, C 1 -C 3 alkylcarbonyloxy, C 1 -C 3 alkylcarbonylamino, sulphonamido, C 1 -C 3 alkylsulphonyl, C 1 -C 3 alkylsulphonylamino and —C(O)NR 6 R 7 ;
L represents CH 2 , O, NH or N(CH 3 );
R a represents a hydrogen atom or a C 1 -C 3 alkyl or C 1 -C 3 haloalkyl group;
R b represents a hydrogen atom or a C 1 -C 3 alkyl or C 1 -C 3 haloalkyl group;
X represents CF 2 , CHR 8 , O or NC(O)R 9 ;
R 2 represents a hydrogen atom or a C 1 -C 6 alkyl group;
n is 0 or an integer 1, 2, 3, 4 or 5;
each R 3 independently represents halogen, hydroxyl, cyano, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 2 -C 4 alkenyl, C 1 -C 3 alkylcarbonyloxy, C 1 -C 3 alkoxycarbonyl, —NR 10 R 11 , —CONR 12 R 13 , C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, C 3 -C 6 cycloalkylmethyl or a 5- to 6-membered heteroaryl group, the heteroaryl group being optionally substituted by at least one substituent selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 1 -C 6 haloalkoxy;
R 4 and R 5 each independently represent a hydrogen atom or a C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl group, or R 4 and R 5 may together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring optionally substituted by at least one substituent selected from halogen and hydroxyl;
R 6 and R 7 each independently represent a hydrogen atom or a C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl group, or R 6 and R 7 may together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring optionally substituted by at least one substituent selected from halogen and hydroxyl;
R 8 represents a hydrogen or halogen atom or a hydroxyl group;
R 9 represents a C 1 -C 6 alkyl, C 1 -C 6 alkoxy, benzyloxy, C 6 -C 10 aryl, or heteroaryl group;
R 10 and R 11 each independently represent a hydrogen atom or a C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl group, or R 10 and R 11 may together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring optionally substituted by at least one substituent selected from halogen and hydroxyl; and
R 12 and R 13 each independently represent a hydrogen atom or a C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl group, or R 12 and R 13 may together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring optionally substituted by at least one substituent selected from halogen and hydroxyl;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein R 1 represents a 9- or 10-membered fused bicyclic heteroaromatic group containing one or two ring heteroatoms independently selected from nitrogen, oxygen and sulphur, the heteroaromatic group being optionally substituted by one or more halogen atoms.

3. A compound according to claim 1 , wherein the fused bicyclic heteroaromatic group is selected from quinoxalinyl, benzothiazolyl, benzoxazolyl, quinolinyl and quinazolinyl.

4. A compound according to claim 1 , wherein L represents CH 2 .

5. A compound according to claim 1 , wherein L represents NH.

6. A compound according to claim 1 , wherein X represents CHR 8 .

7. A compound according to claim 1 , wherein each R 3 independently represents fluorine, chlorine, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkoxy, cyclopropyl or a 5- to 6-membered heteroaryl group, the heteroaryl group being optionally substituted by one or two substituents independently selected from C 1 -C 2 alkyl, C 1 -C 2 alkoxy and C 1 -C 2 haloalkoxy.

8. A compound according to claim 1 , wherein, in R 3 the heteroaryl group is selected from triazolyl, pyrazolyl, oxadiazolyl, pyrimidinyl and imidazolyl.

9. A compound of formula (I) as defined in claim 1 selected from the group consisting of:
2,6-Dimethoxy-N-[(1S,2R)-2-[(quinoxalin-2-yl)amino]cyclopentyl]-benzamide,
2,6-Dimethoxy-N-((1S,2S)-2-(quinoxalin-2-ylamino) cyclopentyl)benzamide,
N-[(1S,2S)-2-[(6-Fluoro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-2,6-dimethoxybenzamide,
N-[(1S,2S)-2-[(1,3-Benzothiazol-2-yl)amino]cyclopentyl]-2,6-dimethoxybenzamide,
N-[(1S,2R)-2-[(1,3-Benzothiazol-2-yl)amino]cyclopentyl]-2,6-dimethoxybenzamide,
N-[(1S,2S)-2-[(5-Chloro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-2,6-dimethoxybenzamide,
N-[(1S,2R)-2-[(1,3-Benzoxazol-2-yl)amino]cyclopentyl]-2,6-dimethoxybenzamide,
N-[(1S,2S)-2-[(6-Fluoro-1,3-benzothiazol-2-yl)(methyl)amino]cyclopentyl]-2,6-dimethoxybenzamide,
N-[(1S,2S)-2-[(1,3-Benzoxazol-2-yl)amino]cyclopentyl]-2,6-dimethoxybenzamide,
N-[(1S,2S)-2-[(6-Chloro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-2,6-dimethoxy-benzamide,
N-[(1R,2R)-2-[(1,3-Benzothiazol-2-yl)amino]cyclopentyl]-2,6-dimethoxybenzamide,
N-[(1R,2R)-2-[(1,3-Benzoxazol-2-yl)amino]cyclopentyl]-2,6-dimethoxy-benzamide,
N-[(1R,2S)-2-[(6-Chloro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-2,6-dimethoxybenzamide,
N-[(1R,2R)-2-[(6-Chloro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-2,6-dimethoxybenzamide,
N-[(1S,2R)-2-[(6-Chloro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-2,6-dimethoxybenzamide,
N-[(1 S, 2S)-2-[(6-Fluoro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide,
N-[(1R,2S)-2-[(1,3-Benzoxazol-2-yl)amino]cyclopentyl]-2,6-diethoxy-benzamide,
N-[(1S,2R)-2-[(1,3-Benzoxazol-2-yl)amino]cyclopentyl]-2,6-diethoxy-benzamide,
N-[(1 S,2S)-2-[(1,3-Benzothiazol-2-yl)amino]cyclopentyl]-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide,
5-Methyl-N-[(1S,2S)-2-[(quinolin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide,
5-Methyl-N-((1 S, 2S)-2-(quinoxalin-2-ylamino)cyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide,
Benzyl cis-3-[(6-chloro-1,3-benzothiazol-2-yl)amino]-4-[(2,6-dimethoxybenzene)amido]pyrrolidine-1-carboxylate,
Ethyl cis-3-[(6-Chloro-1,3-benzothiazol-2-yl)amino]-4-[(2,6-dimethoxy-benzene)amido]pyrrolidine-1-carboxylate,
N-{cis-4-[(6-Chloro-1,3-benzothiazol-2-yl)amino]oxolan-3-yl}-2,6-dimethoxybenzamide,
N-[(1S,2R,4R)-2-[(6-Chloro-1,3-benzothiazol-2-yl)amino]-4-hydroxycyclo-pentyl]-2,6-dimethoxybenzamide,
N-[(1S,2R)-2-[(6-Chloro-1,3-benzothiazol-2-yl)amino]-4-fluorocyclo-pentyl]-2,6-dimethoxybenzamide,
5-Methyl-N-[2-(quinolin-2-ylmethyl)cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide,
2-Ethoxy-5-methyl-N-[2-(quinolin-2-ylmethyl)cyclopentyl]-benzamide,
2,6-Dimethoxy-N-[2-(quinolin-2-ylmethyl)cyclopentyl]benzamide,
2,6-Diethoxy-N-(2-(quinolin-2-ylmethyl)cyclopentyl)benzamide,
N-{2-[(6-Chloro-1,3-benzothiazol-2-yl)methyl]cyclopentyl}-2,6-dimethoxybenzamide,
N-{2-[(6-Chloro-1,3-benzothiazol-2-yl)methyl]cyclopentyl}-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide,
N-[(1S,2S)-2-[(6-Fluoro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-2,6-dimethoxy-N-methylbenzamide,
N-[(1S,2S)-2-[(6-Fluoro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-2-(1H-pyrazol-1-yl)benzamide,
5-Fluoro-N-[(1S,2S)-2-[(6-fluoro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide,
2-Chloro-N-[(1S,2S)-2-[(6-fluoro-1,3-benzothiazol-2-yl)amino]cyclopentyl]benzamide,
N-[(1S,2S)-2-[(6-Fluoro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-5-methyl-2-(1H-1,2,3-triazol-1-yl)benzamide,
N-[(1S,2S)-2-[(6-Fluoro-1,3-benzothiazol-2-yl)amino]c

Assignees

• Takeda Pharmaceuticals Co
• Takeda Pharmaceuticals Company Ltd

Inventors

• Fieldhouse Charlotte
• Glen Angela
• Robinson John Stephen
• Fujimoto Tatsuhiko

Classifications

• A61P25/18

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

• A61P25/30

  for treating abuse or dependence · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · 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