Indole carboxamide derivatives as P2X

1. A compound of the formula (I),

wherein

n represents 1, 2, 3 or 4;

R 1 represents hydrogen and R 2 represents hydroxy; hydroxy-(C 1 -C 3 )alkyl; (C 1 -C 3 )alkoxy; —NHR 11 ; —N(CH 3 ) 2 ; —CN; —CONH 2 ; (C 1 -C 4 )alkoxy-carbonyl; (C 1 -C 4 )alkylamino-carbonyl; aryl which is unsubstituted or mono- or di-substituted with (C 1 -C 3 )fluoroalkyl or halogen; or heteroaryl which is unsubstituted or mono- or di-substituted with (C 1 -C 4 )alkyl, (C 1 -C 3 ) fluoroalkyl or halogen; or

R 1 represents (C 1 -C 3 )alkyl or hydroxy-(C 1 -C 3 )alkyl and R 2 represents hydrogen;

R 3 represents hydrogen or fluoro;

R 4 represents hydrogen or fluoro;

R 5 represents hydrogen, (C 1 -C 4 )alkyl or halogen;

R 6 represents hydrogen, (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, (C 1 -C 4 )alkoxy-(C 2 -C 4 )alkoxy, hydroxy, amino, nitro or halogen;

R 7 represents hydrogen or (C 1 -C 3 )alkyl;

R 8 represents hydrogen, (C 1 -C 4 )alkyl or hydroxy;

R 9 represents hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkylthio, formyl or halogen;

R 10 represents fluoro, chloro, methyl, ethyl, (C 1 -C 2 )fluoroalkyl or methoxy; and

R 11 represents hydrogen, benzyl, (C 1 -C 4 )alkyl-carbonyl, (C 1 -C 4 )alkoxy-carbonyl or (C 1 -C 4 )alkyl-sulfonyl which is unsubstituted or mono-substituted with hydroxy or (C 1 -C 4 )alkoxy-carbonyl;

or a salt of such a compound.

2. The compound of formula (I) according to claim 1 , wherein n represents 2, 3 or 4;

R 1 represents hydrogen;

R 2 represents hydroxy; hydroxy-(C 1 -C 3 )alkyl; —NHR 11 ; —CN; or a 5- or 6-membered monocyclic heteroaryl group which group is unsubstituted or mono-substituted with (C 1 -C 4 )alkyl, (C 1 -C 3 ) fluoroalkyl or halogen;

R 3 represents hydrogen or fluoro;

R 4 represents hydrogen or fluoro;

R 5 represents hydrogen;

R 6 represents hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy or (C 1 -C 2 )alkoxy-(C 1 -C 4 )alkyl;

R 7 represents hydrogen;

R 8 represents hydrogen;

R 9 represents hydrogen, (C 1 -C 4 )alkyl or halogen;

R 10 represents chloro or methyl; and

R 11 represents (C 1 -C 4 )alkyl-sulfonyl which is unsubstituted or mono-substituted with hydroxy or (C 1 -C 4 )alkoxy-carbonyl;

or a salt of such a compound.

3. The compound of formula (I) according to claim 1 , wherein

n represents 2 or 3;

or a salt of such a compound.

4. The compound of formula (I) according to claim 1 , wherein

R 2 represents hydroxy; hydroxy-(C 1 -C 3 )alkyl; —NHR 11 ; or —CN; and

R 11 represents methyl-sulfonyl which is unsubstituted or mono-substituted with methoxy-carbonyl; or ethyl-sulfonyl which is mono-substituted with hydroxy;

or a salt of such a compound.

5. The compound of formula (I) according to claim 1 , wherein

R 2 represents a 5- or 6-membered monocyclic heteroaryl group which group is unsubstituted or mono-substituted with (C 1 -C 4 )alkyl, (C 1 -C 3 )fluoroalkyl or halogen;

or a salt of such a compound.

6. The compound of formula (I) according to claim 1 , wherein

R 6 represents (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy or (C 1 -C 2 )alkoxy-(C 1 -C 4 )alkyl;

or a salt of such a compound.

7. The compound of formula (I) according to claim 1 , wherein

R 5 , R 7 , R 8 and R 9 represent hydrogen;

or a salt of such a compound.

8. The compound of formula (I) according to claim 1 , wherein

R 10 represents chloro;

or a salt of such a compound.

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

wherein

n represents 2 or 3;

R 3 represents hydrogen or fluoro;

R 4 represents hydrogen or fluoro;

R 6 represents (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, hydroxy-(C 1 -C 4 )alkyl, hydroxy-(C 2 -C 4 )alkoxy, (C 1 -C 2 )alkoxy-(C 1 -C 4 )alkyl or halogen; and

R 10 represents chloro, methyl or trifluoromethyl;

or a salt of such a compound.

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

wherein

n represents 2 or 3;

X represents CH or N;

2S represents hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 3 )fluoroalkyl or halogen;

R 3 represents hydrogen or fluoro;

R 4 represents hydrogen or fluoro; and

R 6 represents hydrogen or (C 1 -C 4 )alkyl;

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 ((S)-1-cyclohexyl-2-hydroxy-ethyl)-amide;

4-Chloro-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;

4-Chloro-1H-indole-5-carboxylic acid (1-hydroxy-cycloheptylmethyl)-amide;

4-Chloro-1H-indole-5-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexylmethyl)-amide;

4-Chloro-1H-indole-5-carboxylic acid [(S)-1-(4,4-difluoro-cyclohexyl)-2-hydroxy-ethyl]-amide;

4-Chloro-l-methyl-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;

4-Chloro- 1-methyl- 1H-indole-5-carboxylic acid ((S)- 1-cyclohexyl-2-hydroxy-ethyl)-amide;

4-Chloro-3-formyl- 1H-indole-5-carboxylic acid ((S)- 1-cyclohexyl-2-hydroxy-ethyl)-amide;

4-Chloro-3-formyl-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;

4-Chloro-1H-indole-5-carboxylic acid (1-cycloheptyl-2-hydroxy-ethyl)-amide;

4-Chloro-1H-indole-5-carboxylic acid [1-(2-trifluoromethyl-pyrimidin-5-yl)-cyclohexylmethyl]-amide;

4-Chloro-1H-indole-5-carboxylic acid [1-(6-chloro-pyridin-3-yl)-cyclohexylmethyl]-amide;

4-Chloro-1H-indole-5-carboxylic acid [1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexylmethyl]-amide;

4-Chloro-1H-indole-5-carboxylic acid [1-(6-chloro-pyridin-3-yl)-4,4-difluoro-cyclohexylmethyl ]-amide;

4-Chloro-1H-indole-5-carboxylic acid [1-(4-chloro-phenyl)-cyclohexylmethyl]-amide;

4-Chloro-1H-indole-5-carboxylic acid [1-(4-trifluoromethyl-phenyl)-cyclohexylmethyl]-amide;

4-Chloro-1H-indole-5-carboxylic acid (1-pyridin-3-yl-cyclohexylmethyl)-amide;

4-Chloro-1H-indole-5-carboxylic acid (1-pyridin-3-yl-cyclopentylmethyl)-amide;

4-Chloro-1H-indole-5-carboxylic acid (1-pyridin-3-yl-cycloheptylmethyl)-amide;

4-Chloro-7-methyl-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;

4-Chloro-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid (1-hydroxy-cycloheptylmethyl)-amide;

4-Chloro-2-methyl-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;

4-Chloro-7-iodo-3-methylsulfanyl-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;

4-Chloro-7-methyl-1H-indole-5-carboxylic acid (4,4-difluoro- l -hydroxy-cyclohexylmethyl)-amide;

4-Chloro-7-methyl-1H-indole-5-carboxylic acid (1-hydroxy-cycloheptylmethyl)-amide;

4-Chloro-3-fluoro-1H-indole-5-carboxylic acid (1-hydroxy-cycloheptylmethyl)-amide;

4-Methoxy-1H-indole-5-carboxylic acid (1-hydroxy-cycloheptylmethyl)-amide;

3,4-Dichloro-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;

4-Chloro-7-nitro-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;

1-{[(4-Chloro-1H-indole-5-carbonyl)-amino]-methyl }-cyclohexanecarboxylic acid methyl ester;

4-Chloro-1H-indole-5-carboxylic acid (1-hydroxymethyl-cyclohexylmethyl)-amide;

7-Amino-4-chloro-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;

4-Chloro-3-methyl-1H-indole-5-carboxylic acid (1-hydroxy-cycloheptylmethyl)-amide;

4-Chloro-1H-indole-5-carboxylic acid (1-carbamoyl-cyclohexylmethyl)-amide;

4-Chloro-1H-indole-5-carboxylic acid (1-methylcarbamoyl-cyclohexylmethyl)-amide;

4-Chloro-1H-indole-5-carboxylic acid (1-cyano-cyclohexylmethyl)-amide;

(1-{[(4-Chloro-1H-indole-5-carbonyl)-amino]-methyl }-cyclohexyl)-carbamic acid tert-butyl ester;

4,6-Dichloro-1H-indole-5-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexylmethyl)-amide;

4-Chloro-1H-indole-5-carboxylic acid (1-amino-cyclohexylmethyl)-amide;

4-Chloro-6-methyl-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;

4-Chloro-1H-indole-5-carboxylic acid (1-hydroxy-cyclopentylmethyl)-amide;

4-Chloro-1H-indole-5-carboxylic acid (1-hydroxy-cyclooctylmethyl)-amide;

4-Chloro-1H-indole-5-carboxylic acid (1-methoxy-cyclohexylmethyl)-amide;

4-Chloro-1H-indole-5-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide;

4-Chloro-1H-indole-5-carboxylic acid ((R)- 1 -cyclohexyl-ethyl)-amide;

4-Chloro-1H-indole-5-carboxylic acid (1-acetylamino-cyclohexylmethyl)-amide;

4-Chloro-1H-indole-5-carboxylic acid (1-methanesulfonylamino-cyclohexylmethyl)-amide;

4-Chloro-1H-indole-5-carboxylic acid (1-dimethylamino-cyclohexylmethyl)-amide;

4-Chloro-1H-indole-5-carboxylic acid (1-benzylamino-cyclohexylmethyl)-amide;

3-Bromo-4-chloro-7-methyl-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;

(1-{[(4-Chloro-1H-indole-5-carbonyl)-amino]-methyl }-cyclohexylsulfamoyl)-acetic acid methyl ester;

4-Chloro-7-isobutyl-1H-indole-5-carboxylic acid (1-hydroxy-cycloheptylmethyl)-amide;

4-Chloro-7-(3-methoxy-propyl)-1H-indole-5-carboxylic acid (1-hydroxy-cycloheptylmethyl)-amide;

4-Chloro-7-isobutyl-1H-indole-5-carboxylic acid (4,4-difluoro-l-hydroxy-cyclohexylmethyl)-amide;

4-Chloro-7-(3-methoxy-propyl)-1H-indole-5-carboxylic acid (4,4-difluoro-l-hydroxy-cyclohexylmethyl) -amide;

4-Chloro-1H-indole-5-carboxylic acid [1-(2-hydroxy-ethanesulfonylamino)-cyclohexylmethyl]-amide;

4-Methyl-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;

4-Chloro-1H-indole-5-carboxylic acid [1-(2-methyl-pyrimidin-5-yl)-cyclohexylmethyl]-amide;

4-Chloro-7-methoxy-1H-indole-5-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexylmethyl)-amide;

4-Chloro-1H-indole-5-carboxylic acid [4,4-difluoro-1-(2-methyl-pyrimidin-5-yl)-cyclohexylmethyl ]-amide;

4-Chloro-7-methyl-1H-indole-5-carboxylic acid [4,4-difluoro-1-(2-methyl-pyrimidin-5-yl)-cyclohexylmethyl ]-amide;

4-Chloro-7-methyl-1H-indole-5-carboxylic acid [1-(2-methyl-pyrimidin-5-yl)-cyclohexylmethyl ]-amide;

4,7-Dimethyl-1H-indole-5-carboxylic acid (4,4-difluoro-l-hydroxy-cyclohexylmethyl)-amide;

4-Methyl-1H-indole-5-carboxylic acid (4,4-difluoro-l-hydroxy-cyclohexylmethyl)-amide;

4-Ethyl-1H-indole-5-carboxylic acid (4,4-difluoro-l-hydroxy-cyclohexylmethyl)-amide;

7-Acetyl-4-chloro-1H-indole-5-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexylmethyl)-amide;

4-Chloro-7-(1-hydroxy-ethyl)-1H-indole-5-carboxylic acid (4,4-difluoro- 1 -hydroxy-cyclohexylmethyl) -amide;

4-Chloro-7-(1-hydroxy-l-methyl-ethyl)-1H-indole-5-carboxylic acid (4,4-difluoro- 1-hydroxy-cyclohexylmethyl) -amide;

7-Methyl-4-trifluoromethyl-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;

7-Methyl-4-trifluoromethyl-1H-indole-5-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexylmethyl) -amide;

4,7-Dimethyl-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;

4-Chloro-7-ethyl-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;

4-Chloro-7-ethyl-1H-indole-5-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexylmethyl)-amide;

7-Chloro-4-methyl-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;

7-Chloro-4-methyl- 1H-indole-5-carboxylic acid (4,4-difluoro- 1 -hydro xy-c yclohexylmethyl)-amide;

4-Chloro-7-methoxy-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;

7-Methoxy-4-methyl- 1H-indole-5-carboxylic acid (4,4-difluoro- 1 -hydroxy-c yclohexylmethyl)-amide;

7-Methoxy-4-methyl- 1H-indole-5-carboxylic acid (1 -hydroxy- cyclohexylmethyl)- amide ;

4-Chloro-7-ethoxy- 1H-indole-5-carboxylic acid (1 -hydroxy- cyclohexylmethyl)- amide ;

4-Chloro-7-hydroxy-1H-indole-5-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexylmethyl)-amide;

4-Chloro-7-ethoxy- 1H-indole-5-carboxylic acid (4,4-difluoro- 1 -hydroxy-c yclohexylmethyl)-amide;

4-Chloro-7-propyl- 1H-indole-5-carboxylic acid (1 -hydroxy- cyclohexylmethyl)- amide ;

4-Chloro-7-propyl- 1H-indole-5-carboxylic acid (4,4-difluoro- 1 -hydroxy-c yclohexylmethyl)-amide;

7-(2-tert-Butoxy-ethoxy)-4-chloro- 1H-indole-5 -carboxylic acid (1 -hydroxy-c yclohexylmethyl)-amide;

7-(2-tert-Butoxy-ethoxy)-4-chloro- 1H-indole-5 -carboxylic acid (4,4-difluoro- 1 -hydroxy-cyclohexylmethyl) -amide ;

4-Chloro-7-(2-hydroxy-ethoxy)- 1H-indole-5 -carboxylic acid (1 -hydro xy-c yclohexylmethyl)-amide;

4-Chloro-7-(2-hydroxy-ethoxy)- 1H-indole-5 -carboxylic acid (4,4-difluoro- 1 -hydroxy-cyclohexylmethyl) - amide ;

7-Acetyl-4-chloro-1H-indole-5-carboxylic acid (1 -hydroxy- cyclohexylmethyl)- amide ;

4-Chloro-7-(1-hydroxy-1-methyl-ethyl)-1 H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl) -amide;

4,7-Difluoro- 1H-indole-5-carboxylic acid (1 -hydroxy- cyclohexylmethyl)- amide ;

4,7-Difluoro-1H-indole-5-carboxylic acid (4,4-difluoro- l -hydroxy-clohexylmethyl)-amide;

4-Fluoro-7-methoxy-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;

4-Fluoro-7-methoxy-1H-indole-5-carboxylic acid (4,4-difluoro- 1-hydroxy-cyclohexylmethyl)-amide;

4-Chloro-7-(2-ethoxy-ethyl)-1H-indole-5-carboxylic acid (4,4-difluoro-l-hydroxy-cyclohexylmethyl) -amide; and

4-Chloro-7-(1-methoxy-l-methyl-ethyl)-1H-indole-5-carboxylic acid (4,4-difluoro-l-hydroxy-cyclohexylmethyl) -amide;

or a salt of such a compound.

12. A pharmaceutical composition containing, as active principle, a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.

13. A method for the treatment of a P2X 7 -mediated disease selected from pain; neurodegenerative and neuroinflammatory diseases; bone and joint diseases; obstructive diseases of the airways; cardiovascular diseases; eye diseases; skin diseases; abdominal and gastrointestinal tract diseases; genitourinary diseases; cancer; auto-immune and allergic disorders selected from the group consisting of Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-IgE syndrome and antiphospholipid syndrome; and disorders with an inflammatory or immunological component selected from the group consisting of acquired immune deficiency syndrome (AIDS), leprosy, Sezary syndrome and paraneoplastic syndromes comprising administering to a subject a pharmaceutically active amount of the compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

14. A method for the treatment of a P2X 7 -mediated disease selected from pain; neurodegenerative and neuroinflammatory diseases; bone and joint diseases; obstructive diseases of the airways; cardiovascular diseases; eye diseases; skin diseases; abdominal and gastrointestinal tract diseases; genitourinary diseases; cancer; auto-immune and allergic disorders selected from the group consisting of Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-IgE syndrome and antiphospholipid syndrome; and disorders with an inflammatory or immunological component selected from the group consisting of acquired immune deficiency syndrome (AIDS), leprosy, Sezary syndrome and paraneoplastic syndromes component comprising administering to a subject a pharmaceutically active amount of the compound of formula (I HET ) according to claim 10 or a pharmaceutically acceptable salt thereof.