mGluR5 modulators II

1 . A compound of formula (I)

wherein

R 1 is methyl, halogen or cyano;

R 2 is hydrogen or fluoro;

R 3 is hydrogen, fluoro or C 1 -C 3 alkyl;

R 4 is C 1 -C 3 alkyl or cyclopropyl;

X is

and Z is

wherein

R 5 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy; C 1 -C 3 haloalkoxy or halogen;

R 6 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy; C 1 -C 3 haloalkoxy or halogen;

R 7 is C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy; C 1 -C 3 haloalkoxy or halogen;

R 8 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy; C 1 -C 3 haloalkoxy or halogen;

R 9 is hydrogen, fluoro or C 1 -C 3 alkyl;

as well as pharmaceutically acceptable salts, hydrates, isoforms, tautomers and/or enantiomers thereof.

2 . A compound according to claim 1 , wherein R 1 is halogen or cyano.

3 . A compound according to claim 2 , wherein R 1 is chloro.

4 . A compound according to claim 2 , wherein R 1 is cyano.

5 . A compound according to claim 1 , wherein R 2 is hydrogen.

6 . A compound according to claim 1 , wherein R 3 is hydrogen or fluoro.

7 . A compound according to claim 1 , wherein R 4 is C 1 -C 2 alkyl.

8 . A compound according to claim 7 , wherein R 4 is methyl.

9 . A compound according to claim 1 , wherein R 5 is hydrogen, C 1 -C 2 alkyl or C 1 -C 2 alkoxy.

10 . A compound according to claim 1 , wherein R 6 is hydrogen, C 1 -C 2 alkyl or C 1 -C 2 alkoxy.

11 . A compound according to claim 1 , wherein R 7 is C 1 -C 2 alkyl or C 1 -C 2 alkoxy.

12 . A compound according to claim 1 , wherein R 8 is hydrogen, C 1 -C 2 alkyl or C 1 -C 2 alkoxy.

13 . A compound according to claim 1 , wherein R 9 is hydrogen or fluoro.

14 . A compound selected from

3-(5-{(R)-1-[5-(2-Methoxy-pyridin-4-yl)-4-methyl-4H-[1,2,4]triazol-3-yl]-piperidin-2-yl}-tetrazol-2-yl)-benzonitrile;

4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-2-methyl-pyridine;

3-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine;

4-(5-{2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-piperidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-2-methyl-pyridine;

3-(5-{2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-piperidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)- yl)-pyridine;

4-(5-{2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-piperidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-2-methoxy-pyridine;

4-(5-{2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-piperidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-2-methyl-pyridine;

3-(5-{2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-piperidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine;

3-{5-[1-(4-Methyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-yl)-piperidin-2-yl}-benzonitrile;

3-(5-{(R)-1-[4-Methyl-5-(2-methyl-pyridin-4-yl)-4H-[1,2,4]triazol-3-yl]-piperidin-2-yl}-tetrazol-2-yl)-benzonitrile;

3-(5-{1-[5-(2-Methoxy-pyridin-4-yl)-4-methyl-4H-[1,2,4]triazol-3-tetrazol-2-yl)-benzonitrile;

3-(5-{(R)-2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-piperidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine; and

3-(5-{(S)-2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-piperidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine

as well as pharmaceutically acceptable salts, hydrates, isoforms, tautomers and/or enantiomers thereof.

15 . A compound according to claim 1 for use in therapy.

16 . A pharmaceutical composition comprising a compound according to claim 1 as an active ingredient, together with a pharmacologically and pharmaceutically acceptable carrier.

17 . Use of a compound according to claim 1 , or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the inhibition of transient lower esophageal sphincter relaxations.

18 . Use of a compound according to claim 1 , or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for treatment or prevention of gastroesophageal reflux disease.

19 . Use of a compound according to claim 1 , or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for treatment or prevention of pain.

20 . Use of a compound according to claim 1 , or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for treatment or prevention of anxiety.

21 . Use of a compound according to claim 1 , or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for treatment or prevention of irritable bowel syndrome (IBS).

22 . A method for the inhibition of transient lower esophageal sphincter relaxations whereby an effective amount of a compound according to claim 1 is administered to a subject in need of such inhibition.

23 . A method for the treatment or prevention of gastroesophageal reflux disease, whereby an effective amount of a compound according to claim 1 is administered to a subject in need of such treatment or prevention.

24 . A method for the treatment or prevention of pain, whereby an effective amount of a compound according to claim 1 is administered to a subject in need of such treatment or prevention.

25 . A method for the treatment or prevention of anxiety, whereby an effective amount of a compound according to claim 1 is administered to a subject in need of such treatment or prevention.

26 . A method for the treatment or prevention of irritable bowel syndrome (IBS), whereby an effective amount of a compound according to claim 1 is administered to a subject in need of such treatment or prevention.

27 . A combination comprising (i) at least one compound according to claim 1 and (ii) at least one acid secretion inhibiting agent.

28 . A combination according to claim 27 wherein the acid secretion inhibiting agent is selected from cimetidine, ranitidine, omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole or leminoprazole.

29 . A compound selected from

(R)-2-[5-(3-Cyano-phenyl)-isoxazol-3-yl]-piperidine-1-carboxylic acid tert-butyl ester;

3-((R)-3-Piperidin-2-yl-isoxazol-5-yl)-benzonitrile;

(R)-2-[2-(3-Bromo-phenyl)-2H-tetrazol-5-yl]-piperidine-1-carboxylic acid tert-butyl ester;

2-[2-(3-Bromo-phenyl)-2H-tetrazol-5-yl]-piperidine-1-carboxylic acid tert-butyl ester;

(R)-2-[2-(3-Cyano-phenyl)-2H-tetrazol-5-yl]-piperidine-1-carboxylic acid tert-butyl ester;

2-[2-(3-Cyano-phenyl)-2H-tetrazol-5-yl]-piperidine-1-carboxylic acid tert-butyl ester;

2-[5-(3-Cyano-phenyl)-isoxazol-3-yl]-piperidine-1-carboxylic acid tert-butyl ester;

(R)-2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-piperidine-1-carboxylic acid tert-butyl ester;

3-(3-Piperidin-2-yl-isoxazol-5-yl)-benzonitrile;

3-((R)-3-Piperidin-2-yl-isoxazol-5-yl)-benzonitrile;

3-((R)-5-Piperidin-2-yl-tetrazol-2-yl)-benzonitrile;

3-(5-piperidin-2-yl-2H-tetrazol-2-yl)benzonitrile;

(R)-2-[5-(3-Cyano-phenyl)-isoxazol-3-yl]-piperidine-1-carbothioic acid methylamide;

2-[5-(3-Cyano-phenyl)-isoxazol-3-yl]-piperidine-1-carbothioic acid methylamide;

(R)-2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-piperidine-1-carbothioic acid methylamide;

(R)-2-[2-(3-Cyano-phenyl)-2H-tetrazol-5-yl]-piperidine-1-carbothioic acid methylamide;

2-[2-(3-Cyano-phenyl)-2H-tetrazol-5-yl]-piperidine-1-carbothioic acid methylamide;

(R)-2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-N-methyl-piperidine-1-carboximidothioic acid methyl ester;

(R)-2-[2-(3-Cyano-phenyl)-2H-tetrazol-5-yl]-N-methyl-piperidine-1-carboximidothioic acid methyl ester;

2-[2-(3-Cyano-phenyl)-2H-tetrazol-5-yl]-N-methyl-piperidine-1-carboximidothioic acid methyl ester;

(R)-2-(Hydroxyimino-methyl)-piperidine-1-carboxylic acid tert-butyl ester;

tert-Butyl(2R)-2-[chloro(hydroxyimino)methyl]piperidine-1-carboxylate;

tert-Butyl 2-[chloro(hydroxyimino)methyl]piperidine-1-carboxylate;

2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidine-1-carboxylic acid tert-butyl ester;

2-[3-(3-Chlorophenyl)-1,2,4-oxadiazol-5-yl]piperidine;

2-[3-(3-Chlorophenyl)-1,2,4-oxadiazol-5-yl]-N-methylpiperidine-1-carbothioamide;

Methyl 2-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-N-methylpiperidine-1-carbimidothioate;

(R)-2-[2-(3-Cyano-phenyl)-2H-tetrazol-5-yl]-piperidine-1-carboxylic acid tert-butyl ester;

2-[2-(3-Cyano-phenyl)-2H-tetrazol-5-yl]-piperidine-1-carboxylic acid tert-butyl ester; and

(R)-2-(2H-Tetrazol-5-yl)-piperidine-1-carboxylic acid tert-butyl ester.