Indole carboxamide derivatives as P2X7 receptor antagonist

Patent metadata

Field	Value
Publication number	US-9718774-B2
Application number	US-201314651922-A
Country	US
Kind code	B2
Filing date	Dec 11, 2013
Priority date	Dec 12, 2012
Publication date	Aug 1, 2017
Grant date	Aug 1, 2017

Abstract

The invention relates to indole carboxamide derivatives of formula (I),

wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in the description, their preparation and their use as pharmaceutically active compounds.

First claim

The invention claimed is:

1. A compound of the formula (I),

wherein
R 1 represents a heteroaryl or an aryl group which groups are independently unsubstituted, mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 3 )fluoroalkyl, (C 1 -C 3 )fluoroalkoxy, hydroxy, halogen and phenoxy;
R 2 represents
heterocyclyl which is unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )alkylcarbonyl, (C 1 -C 4 )alkoxycarbonyl, (C 1 -C 4 )alkylsulfonyl, and halogen;
heterocyclyloxy;
(C 3 -C 6 )cycloalkyl which is unsubstituted or mono- or di-substituted with halogen;
(C 3 -C 6 )cycloalkyloxy;
N—(C 3 -C 6 )cycloalkyl-amino;
N—(C 3 -C 6 )cycloalkylmethyl-amino;
(C 3 -C 6 )alkyl;
(C 2 -C 6 )alkoxy;
N—(C 1 -C 4 )alkylamino;
N,N-di-[(C 1 -C 4 )alkyl]-amino; or
N-arylmethyl-N—(C 1 -C 4 )alkyl-amino;

R 3 represents hydrogen or halogen;
R 4 represents hydrogen, fluoro, chloro, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkyl-carbonyl, hydroxy-(C 1 -C 4 )alkyl, hydroxy-(C 2 -C 4 )alkoxy, (C 1 -C 2 )alkoxy-(C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy -(C 2 -C 4 )alkoxy;
R 5 represents hydrogen or (C 1 -C 4 )alkyl; and
R 6 represents fluoro, chloro, methyl, ethyl or (C 1 -C 2 )fluoroalkyl;

or a salt of such a compound.

2. The compound of formula (I) according to claim 1 , wherein
R 1 represents a 5- or 6-membered monocyclic heteroaryl group which is unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from the group consisting of (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 3 )fluoroalkyl and halogen;
R 2 represents
heterocyclyl which is unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from methyl and fluoro; or
(C 3 -C 6 )cycloalkyl which is unsubstituted or mono- or di-substituted with fluoro;

R 3 represents hydrogen;
R 4 represents hydrogen or (C 1 -C 4 )alkyl;
R 5 represents hydrogen; and
R 6 represents chloro or methyl;

or a salt of such a compound.

3. The compound of formula (I) according to claim 1 , wherein
R 1 represents a 5- or 6-membered monocyclic heteroaryl or a phenyl group which groups are independently unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from the group consisting of (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 3 )fluoroalkyl and halogen;

or a salt of such a compound.

4. The compound of formula (I) according to claim 2 , wherein
R 2 represents heterocyclyl which is unsubstituted or mono- or di-substituted with fluoro;

or a salt of such a compound.

5. The compound of formula (I) according to claim 3 , wherein
R 2 represents (C 3 -C 6 )alkyl; or (C 3 -C 6 )cycloalkyl which is unsubstituted or mono- or di-substituted with fluoro;

or a salt of such a compound.

6. The compound of formula (I) according to claim 1 , which is also a compound of formula (I Ar )

wherein
A represents N or CH;
B represents N or CH;
R 2 represents heterocyclyl which is unsubstituted or mono- or di-substituted with fluoro, wherein the heterocyclyl is selected from pyrrolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl, azepanyl, 1,4-oxazepanyl and 6-oxa-3-azabicyclo[3.1.1]heptanyl; or
R 2 represents cyclohexyl which is unsubstituted or mono- or di-substituted with fluoro;
R 4 represents hydrogen, fluoro, chloro, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, hydroxy-(C 2 -C 4 )alkoxy or (C 1 -C 2 )alkoxy-(C 1 -C 4 )alkyl;
R 6 represents fluoro, chloro, methyl, ethyl or (C 1 -C 2 )fluoroalkyl; and
R 7 represents hydrogen, halogen, (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 4 )alkoxy or (C 1 -C 3 )fluoroalkyl;

or a salt of such a compound.

7. The compound of formula (I Ar ) according to claim 6 , wherein
A and B represent N and R 7 represents hydrogen, methyl, cyclopropyl or trifluoromethyl; or
A represents N, B represents CH and R 7 represents chloro, methyl, methoxy or trifluoromethyl; or
A and B represent CH and R 7 represents fluoro or chloro;
R 2 represents 3,3-difluoro-pyrrolidin-1-yl, piperidin-1-yl, 4-fluoro-piperidin-1-yl, 3,3-difluoro-piperidin-1-yl, 4,4-difluoro-piperidin-1-yl, tetrahydropyran-4-yl, morpholin-4-yl, azepan-1-yl, 1,4-oxazepan-4-yl, or 6-oxa-3-azabicyclo[3.1.1]heptan-3-yl;
R 4 represents hydrogen, chloro, methyl, ethyl, n-propyl, iso-butyl, methoxy, ethoxy, 2-hydroxy-ethoxy or 3-methoxy-prop-1-yl;
R 6 represents fluoro, chloro, methyl, ethyl or trifluoromethyl;

or a salt of such a compound.

8. The compound of formula (I Ar ) according to claim 6 , wherein
A and B represent N;

or a salt of such a compound.

9. The compound of formula (I) according to claim 1 , wherein
R 6 represents chloro;

or a salt of such a compound.

10. The compound of formula (I) according to claim 1 , wherein
R 6 represents methyl;

or a salt of such a compound.

11. The compound of formula (I) according to claim 1 , selected from the group consisting of:
4-Chloro-1H-indole-5-carboxylic acid [2-morpholin-4-yl-2-(2-trifluoromethyl-pyrimidin-5-yl)-ethyl]-amide;
4-Chloro-1H-indole-5-carboxylic acid [2-(6-chloro-pyridin-3-yl)-2-(4,4-difluoro-piperidin-1-yl)-ethyl]-amide;
4-Chloro-1H-indole-5-carboxylic acid [(R)-2-(2-methyl-pyrimidin-5-yl)-2-morpholin-4-yl-ethyl]-amide;
4-Chloro-1H-indole-5-carboxylic acid [(S)-2-(2-methyl-pyrimidin-5-yl)-2-morpholin-4-yl-ethyl]-amide;
4-Chloro-1H-indole-5-carboxylic acid [(R)-2-(4,4-difluoro-piperidin-1-yl)-2-(2-methyl-pyrimidin-5-yl)-ethyl]-amide;
4-Chloro-1H-indole-5-carboxylic acid [(S)-2-(4,4-difluoro-piperidin-1-yl)-2-(2-methyl-pyrimidin-5-yl)-ethyl]-amide;
4-Chloro-1H-indole-5-carboxylic acid [2-(6-methyl-pyridin-3-yl)-2-morpholin-4-yl-ethyl]-amide;
4-Chloro-1H-indole-5-carboxylic acid [2-(4,4-difluoro-piperidin-1-yl)-2-(2-trifluoromethyl-pyrimidin-5-yl)-ethyl]-amide;
4-Chloro-1H-indole-5-carboxylic acid [2-(2-cyclopropyl-pyrimidin-5-yl)-2-morpholin-4-yl-ethyl]-amide;
4-Chloro-1H-indole-5-carboxylic acid [2-morpholin-4-yl-2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amide;
4-Chloro-1H-indole-5-carboxylic acid [2-(6-methoxy-pyridin-3-yl)-2-morpholin-4-yl-ethyl]-amide;
4-Chloro-1H-indole-5-carboxylic acid [2-dimethylamino-2-(2-methyl-pyrimidin-5-yl)-ethyl]-amide;
4-Chloro-1H-indole-5-carboxylic acid [2-azetidin-1-yl-2-(2-methyl-pyrimidin-5-yl)-ethyl]-amide;
4-Chloro-1H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2-pyrrolidin-1-yl-ethyl]-amide;
4-Chloro-1H-indole-5-carboxylic acid [2-diethylamino-2-(2-methyl-pyrimidin-5-yl)-ethyl]-amide;
4-Chloro-1H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2-piperidin-1-yl-ethyl]-amide;
4-Chloro-1H-indole-5-carboxylic acid [2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethyl]-amide;
4-Chloro-1H-indole-5-carboxylic acid [2-(3,5-difluoro-phenyl)-2-morpholin-4-yl-ethyl]-amide;
4-{2-[(4-Chloro-1H-indole-5-carbonyl)-amino]-1-pyridin-3-yl-ethyl}-piperidine-1-carboxylic acid tert-butyl ester;
4-Chloro-1H-indole-5-carboxylic acid (2-piperidin-4-yl-2-pyridin-3-yl-ethyl)-amide;
4-Chloro-1H-indole-5-carboxylic acid [2-(1-methyl-piperidin-4-yl)-2-pyridin-3-yl-ethyl]-amide;
4-Chloro-1H-indole-5-carboxylic acid [2-(1-acetyl-piperidin-4-yl)-2-pyridin-3-yl-ethyl]-amide;
4-Chloro-1H-indole-5-carb

Assignees

• Actelion Pharmaceuticals Ltd
• Idorsia Pharmaceuticals Ltd

Inventors

• Hilpert Kurt
• Hubler Francis
• Kimmerlin Thierry
• Renneberg Dorte
• Stamm Simon

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P43/00

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

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title