MGluR5 modulators I
View Patent ↗The present invention is directed to novel compounds, to a process for their preparation, their use in therapy and pharmaceutical compositions comprising the novel compounds.
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;
Y is a bond;
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 hydrogen, fluoro or C 1 -C 3 alkyl;
as well as pharmaceutically acceptable salts, 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 fluoro.
5. A compound according to claim 2 , wherein R 1 is methyl.
6. A compound according to claim 2 , wherein R 1 is cyano.
7. A compound according to claim 1 , wherein R 2 is hydrogen.
8. A compound according to claim 1 , wherein R 3 is hydrogen or fluoro.
9. A compound according to claim 1 , wherein R 4 is C 1 -C 2 alkyl.
10. A compound according to claim 9 , wherein R 4 is methyl.
11. A compound according to claim 1 , wherein R 5 is hydrogen, C 1 -C 2 alkyl or C 1 -C 2 alkoxy.
12. A compound according to claim 1 , wherein R 6 is hydrogen, C 1 -C 2 alkyl or C 1 -C 2 alkoxy.
13. A compound according to claim 1 , wherein R 7 is hydrogen or fluoro.
14. A compound according to claim 1 , wherein Z is
15. A compound according to claim 14 , wherein Z is
16. A compound according to claim 14 , wherein Z is
17. A compound according to claim 14 , wherein Z is
18. A compound selected from;
3-{3-[(R)-1-(4-Methyl-5-pyrimidin-5-yl-4H-[1,2,4]triazol-3-yl)-pyrrolidin-2-yl]-isoxazol-5-yl}-benzonitrile;
3-{5-[(R)-1-(4-Methyl-5-pyrazin-2-yl-4H-[1,2,4]triazol-3-yl)-pyrrolidin-2-yl]-tetrazol-2-yl}-benzonitrile;
3-{3-[(R)-1-(4-Methyl-5-pyrazin-2-yl-4H-[1,2,4]triazol-3-yl)-pyrrolidin-2-yl]-isoxazol-5-yl}-benzonitrile;
5-(5-{(R)-2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyrimidine;
4-(5-{(R)-2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-1-methyl-1H-pyridin-2-one;
5-(5-{(R)-2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-1-methyl-1H-pyridin-2-one;
4-(5-{(R)-2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridazine;
(+/−)5-(5-{2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyrimidine;
2-(5-{(S)-2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyrazine;
4-(5-{(R)-2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-1-methyl-1H-pyridin-2-one;
4-(5-{(R)-2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-1H-pyridin-2-one;
4-(5-{(R)-2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-1H-pyridin-2-one;
6-(5-{(R)-2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-2-methyl-2H-pyridazin-3-one;
5-(5-{(R)-2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-2H-pyridazin-3-one;
5-(5-{(R)-2-[5-(3-Fluoro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-2H-pyridazin-3-one;
6-(5-{(R)-2-[5-(3-Fluoro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-2-methyl-2H-pyridazin-3-one;
1-Methyl-4-{4-methyl-5-[(R)-2-(5-m-tolylisoxazol-3-yl)pyrrolidin-1-yl]-4H-[1,2,4]triazol-3-yl}-1H-pyridin-2-one;
5-{4-Methyl-5-[(R)-2-(5-m-tolyl-isoxazol-3-yl)-pyrrolidin-1-yl]-4H-[1,2,4]triazol-3-yl}-2H-pyridazin-3-one;
4-(5-{(R)-2-[5-(3-Fluoro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-1H-pyridin-2-one;
2-Methyl-5-{4-methyl-5-[(R)-2-(5-m-tolyl-isoxazol-3-yl)-pyrrolidin-1-yl]-4H-[1,2,4]triazol-3-yl}-2H-pyridazin-3-one;
4-(5-{(R)-2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-1,6-dimethyl-1H-pyridin-2-one;
4-{4-Methyl-5-[(R)-2-(5-m-tolyl-isoxazol-3-yl)-pyrrolidin-1-yl]-4H-[1,2,4]triazol-3-yl}-1H-pyridin-2-one;
6-{4-Methyl-5-[(R)-2-(5-m-tolyl-isoxazol-3-yl)-pyrrolidin-1-yl]-4H-[1,2,4]triazol-3-yl}-3H-pyrimidin-4-one;
4-(5-{(R)-2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridazine;
5-(5-{(R)-2-[5-(3-Chlorophenyl)isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-2-methyl-2H-pyridazin-3-one;
5-(5-{(R)-2-[5-(3-Fluorophenyl)isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-2-methyl-2H-pyridazin-3-one;
6-(5-{(R)-2-[5-(3-Chlorophenyl)isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-3H-pyrimidin-4-one;
6-(5-{(R)-2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-1H-pyridin-2-one
5-(5-{(R)-2-[5-(2,5-Difluoro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-2H-pyridazin-3-one;
6-(5-{(R)-2-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H-1,2,4-triazol-3-yl)-3H-pyrimidin-4-one;
4-(5-{(R)-2-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-1H-pyridin-2-one;
5-(5-{(R)-2-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-2H-pyridazin-3-one;
4-(5-{(R)-2-[5-(2-Fluoro-5-methyl-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazol-3-yl)-1H-pyridin-2-one; and
as well as pharmaceutically acceptable salts, tautomers and/or enantiomers thereof.
19. A pharmaceutical composition comprising a compound according to claim 1 as an active ingredient, together with a pharmacologically and pharmaceutically acceptable carrier.
20. A combination comprising (i) at least one compound according to claim 1 and (ii) at least one acid secretion inhibiting agent.
21. A combination according to claim 20 wherein the acid secretion inhibiting agent is selected from cimetidine, ranitidine, omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole or leminoprazole.