Acetylenic piperazines as metabotropic glutamate receptor antagonists

1 . A compound of formula I:

wherein:

Ar 1 is an optionally substituted aryl or heteroaryl group, wherein the substituents are selected from the group consisting of F, Cl, Br, I, OH, nitro, C 1-6 -alkyl, C 1-6 -alkylhalo, OC 1-6 -alkyl, OC 1-6 -alkylhalo, C 2-6 -alkenyl, C 2-6 -alkynyl, —CN, CO 2 R 2 , SR 2 , S(O)R 2 , SO 2 R 2 , aryl, heteroaryl, cycloalkyl and heterocycloalkyl, wherein any cyclic group may be further substituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, nitro, C 1-6 -alkyl, C 1-6 -alkylhalo, OC 1-6 -alkyl, OC 1-6 -alkylhalo, C 2-6 -alkenyl, C 2-6 -alkynyl, —CN, CO 2 R 2 , SR 2 , S(O)R 2 and SO 2 R 2 ;

A is selected from the group consisting of Ar 1 , CO 2 R 2 , CONR 2 R 3 , S(O)R 2 and SO 2 R 2 ;

B is selected from the group consisting of vinylene and ethynylene, wherein the vinylene group is optionally substituted with up to 2 independently-selected C 1-6 -alkyl groups;

R 1 , in each instance, is independently selected from the group consisting of F, Cl, Br, I, OH, CN, nitro, C 1-6 -alkyl, OC 1-6 -alkyl, C 1-6 -alkylhalo, OC 1-6 -alkylhalo, (CO)R 2 , O(CO)R 2 , O(CO)OR 2 , CO 2 R 2 , —CONR 2 R 3 , C 1-6 -alkyleneOR 2 , OC 2-6 -alkyleneOR 2 and C 1-6 -alkylenecyano;

R 2 and R 3 are independently selected from the group consisting of H, C 1-6 -alkyl, C 1-6 -alkylhalo, C 2-6 -alkenyl, C 2-6 -alkynyl and cycloalkyl;

m is an integer selected from the group consisting of 0, 1, 2, 3 and 4; and

n is an integer selected from the group consisting of 1, 2 and 3;

or a pharmaceutically acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof

2 . A compound according to claim 1 wherein B is an ethynylene group.

3 . A compound according to claim 2 wherein Ar 1 is selected from the group consisting of an optionally-substituted phenyl group and an optionally-substituted pyridyl group.

4 . A compound according to claim 3 wherein A is selected from the group consisting of an optionally-substituted pyridyl group and an optionally-substituted pyrazinyl group.

5 . A compound according to claim 4 wherein A is selected from the group consisting of an optionally-substituted 2-pyridyl group and an optionally-substituted 2-pyrazinyl group

6 . A compound selected from the group consisting of:

(±)-Methyl(6R,8aS)-6-[(3-chlorophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate,

(±)-ethyl(6R,9aS)-6-[(3-chlorophenyl)ethynyl]octahydro-2H-pyrido[1,2-a]pyrazine-2-carboxylate,

ethyl(6S,8aS)-6-[(3-chloro-phenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate,

methyl(6S,8aS)-6-[(3-chloro-phenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate,

(6S,8aS)-N-2-chloroethyl)-6-[(3-chlorophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide,

(±)-ethyl(6R,8aS)-6-[(3-chloro-phenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate,

(±)-ethyl(6R,9aS)-6-[(E)-2-(3-chlorophenyl)vinyl]octahydro-2H-pyrido[1,2-a]pyrazine-2-carboxylate,

(±)-3-[(6R,8aS)-6-[(3-chlorophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

(±)-6-{(6R,9aS)-6-[(3-chlorophenyl)ethynyl]octahydro-2H-pyrido[1,2-a]pyrazin-2-yl}nicotinonitrile,

6-[(6S,8aS)-6-[(3-chlorophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]nicotinonitrile,

2-[(6S,8aS)-6-[(3-chlorophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]nicotinonitrile,

(6S,8aS)-6-[(3-chlorophenyl)ethynyl]-2-(5-nitropyridin-2-yl) octahydropyrrolo[1,2-a]pyrazine,

2-[(6S,8aS)-6-[(3-chlorophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]isonicotinonitrile,

(±)-2-[(6R,8aS)-6-[(3-chlorophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]nicotinonitrile,

(±)-2-{(6R,9aS)-6-[(E)-2-(3-chloro-phenyl)vinyl]octahydro-2H-pyrido[1,2-a]pyrazin-2-yl}nicotinonitrile,

(±)-2-{(6R,9aS)-6-[(3-chlorophenyl)ethynyl]octahydro-2H-pyrido[1,2-a]pyrazin-2-yl}nicotinonitrile,

(±)-3-{(6R,9aS)-6-[(3-chlorophenyl)ethynyl]octahydro-2H-pyrido[1,2-a]pyrazin-2-yl}pyrazine-2-carbonitrile,

(±)-2-[(6R,8aS)-6-[(3-cyanophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]nicotinonitrile,

(±)-methyl 2-[(6R,8aS)-6-[(3-chloro-phenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]nicotinate,

(±)-2-[(6R,8aS)-6-[(3-chlorophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-5-fluoro-nicotinonitrile,

(±)-2-[(6R,8aS)-6-[(3-cyanophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-5-fluoro-nicotinonitrile,

(±)-3-[(6R,8aS)-6-[(3-cyanophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

(±)-tert-butyl (6R,9aS)-6-[(3-chlorophenyl)ethynyl]octahydro-2H-pyrido[1,2-a]pyrazine-2-carboxylate,

(±)-3-[(6R,8aS)-6-[(2-chlorophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

(±)-3-[(6R,8aS)-6-[(3-methoxy-phenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

(±)-3-[(6R,8aS)-6-[(2,4-dichloro-phenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

(±)-3-[(6R,8aS)-6-[(5-chloro-2-fluorophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

(±)-3-[(6R,8aS)-6-(phenylethynyl)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

(±)-3-[(6R,8aS)-6-[(3-fluorophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

(±)-3-[(6R,8aS)-6-[(4-chlorophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

(±)-3-[(6R,8aS)-6-[(2-bromophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

(±)-3-[(6R,8aS)-6-[(3-bromophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

(±)-3-[(6R,8aS-6-[(3,5-difluoro-phenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

(±)-3-[(6R,8aS)-6-[(2,4-difluoro-phenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

(±)-3-[(6R,8aS)-6-[(2,5-dichlorophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

(±)-3-[(6R,8aS)-6-[(4-cyanophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

(±)-3-[(6R,8aS)-6-(pyridin-2-yl-ethynyl)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

(±)-3-[(6R,8aS-6-[(5-cyanopyridin-3-yl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

(±)-2-[(6R,8aS)-6-(pyridin-2-yl-ethynyl)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]nicotinonitrile,

(±)-2-[(6R,8aS)-6-[(6-methylpyridin-2-yl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]nicotinonitrile,

(±)-5-fluoro-2-[(6R,8aS)-6-(pyridin-2-ylethynyl)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]nicotinonitrile,

(±)-5-fluoro-2-[(6R,8aS)-6-[(6-methylpyridin-2-yl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]nicotinonitrile,

(±)-3-[(6R,8aS-6-[(4-methylpyridin-2-yl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(11H)-yl]pyrazine-2-carbonitrile,

(±)-3-[(6R,9aS)-6-(pyridin-2-yl-ethynyl)octahydro-2H-pyrido[1,2-a]pyrazin-2-yl]pyrazine-2-carbonitrile,

(±)-3-{(6R,9aS)-6-[(6-methylpyridin-2-yl)ethynyl]octahydro-2H-pyrido[1,2-a]pyrazin-2-yl}pyrazine-2-carbonitrile,

(±)-3-{(6R,9aS)6-[(4-methylpyridin-2-yl)ethynyl]octahydro-2H-pyrido[1,2-a]pyrazin-2-yl}pyrazine-2-carbonitrile,

(±)-3-[(6R,8aS)-6-(1,3-thiazol-2-yl-ethynyl)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

(±)3-[(6R,8aS)-6-(pyrimidin-2-yl-ethynyl)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

(±)-3-[(6R,8aS)-6-[(5-fluoropyridin-2-yl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

(±)-3-[(6R,8aS)-[(6-methylpyridin-2-yl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

(±)-3-[(6R,8aS)-6-(1,3-thiazol-4-ylethynyl)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

(±)-2-[(6R,8aS)-6-[(3-chlorophenyl)Ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]nicotinic acid,

(±)-2-[(6R,8aS)-6-[(3-chlorophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]nicotinamide,

(±)-(6R,8aS)-6-[(3-chlorophenyl)ethynyl]-2-[3-(2H-tetrazol-5-yl)pyridin-2-yl]octahydropyrrolo[1,2-a]pyrazine,

(±)-3-{(6R,9aS)-[(3-chlorophenyl)ethynyl]octahydro-2H-pyrido[1,2-a]pyrazin-2-yl}pyrazine-2-carbonitrile,

(±)-2-{(6R,9aS)-6-[(6-methylpyridin-2-yl)ethynyl]octahydro-2H-pyrido[1,2-a]pyrazin-2-yl}nicotinonitrile,

(±)-2-{(6R 19 aS)-6-[(3-cyanophenyl)ethynyl]octahydro-2H-pyrido[1,2-a]pyrazin-2-yl}nicotinonitrile,

(±)-2-{(6R,9aS)-6-(pyridin-2-yl-ethynyl)octahydro-2H-pyrido[1,2-a]pyrazin-2-yl}nicotinonitrile,

(±)-2-{(6R,9aS)-6-[(3-cyanophenyl)ethynyl]octahydro-2H-pyrido[1,2-a]pyrazin-2-yl}-5-fluoronicotinonitrile,

(±)-2-{(6R,9aS)-6-[(3-chlorophenyl)ethynyl]octahydro-2H-pyrido[1,2-a]pyrazin-2-yl}-5-fluoronicotinonitrile,

(±)-5-fluoro-2-[(6R,9aS)-6-(pyridin-2-ylethynyl)octahydro-2H-pyrido[1,2-a]pyrazin-2-yl]nicotinonitrile,

(±)-5-fluoro-2-{(6R,9aS)-6-[(6-methylpyridin-2-yl)ethynyl]octahydro-2H-pyrido[1,2-a]pyrazin-2-yl}nicotinonitrile,

(±)-3-[(6R,8aS-6-[(6-methoxypyridin-2-yl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

(±)-3-[(6R,8aS)-6-[(6-cyanopyridin-2-yl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

(±)-3-[(6R,8aS)-6-{[6-(fluoromethyl)pyridin-2-yl]ethynyl}hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

3-[(6R,8aS)-6-[(3-chlorophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

3-[(6S,8aR)-6-[(3-chlorophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

3-[(6R,8aS-6-[(3-cyanophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

3-[(6S,8aR)-6-[(3-cyanophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

3-[(6R,8aS)-6-(pyridin-2-ylethynyl)hexahydro-pyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

3-[(6S,8aR)-6-(pyridin-2-ylethynyl)hexahydro-pyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

2-[(6R,8aS)-6-[(3-cyanophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-5-fluoronicotinonitrile,

2-[(6S,8aR)-6-[(3-cyanophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-5-fluoronicotinonitrile,

2-[(6R,8aS)-6-[(3-cyanophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]nicotinonitrile,

2-[(6S,8aR)-6-[(3-cyanophenyl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]nicotinonitrile,

3-[(6R,9aS)-6-(pyridin-2-ylethynyl)octahydro-2H-pyrido[1,2-a]pyrazin-2-yl]pyrazine-2-carbonitrile,

3-[(6S,9aR)-6-(pyridin-2-ylethynyl)octahydro-2H-pyrido[1,2-a]pyrazin-2-yl]pyrazine-2-carbonitrile,

2-[(6R,8aS)-6-(pyridin-2-ylethynyl)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]nicotinonitrile,

2-[(6S,8aR-6-pyridin-2-ylethynyl)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]nicotinonitrile,

2-[(6R,8aS)-6-[(6-methylpyridin-2-yl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]nicotinonitrile,

2-[(6S,8aR)-6-[(6-methylpyridin-2-yl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]nicotinonitrile,

3-[(6R,8aS)-6-[(6-methylpyridin-2-yl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

3-[(6S,8aR)-6-[(6-methylpyridin-2-yl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

3-[(6R,8aS)-6-[(6-methoxypyridin-2-yl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

3-[(6S,8aR)-6-[(6-methoxypyridin-2-yl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

3-[(6R,8aS)-6-[(6-cyanopyridin-2-yl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

3-[(6S,8aR)-6-[(6-cyanopyridin-2-yl)ethynyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile,

3-[(6R,8aS)-6-{[6(fluoromethyl)pyridin-2-yl]ethynyl}hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile, and

3-[(6S,8aR)-6-{[6-(fluoromethyl)pyridin-2-yl]ethynyl}hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyrazine-2-carbonitrile.

7 . A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the compound according to claim 1 , in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.

8 . The pharmaceutical composition according to claim 7 , for use in the treatment of mGluR5-mediated disorders.

9 . The compound according to claim 1 for use in therapy.

10 . The compound according to claim 1 for use in treatment of mGluR5-mediated disorders.

11 . Use of the compound according to claim 1 , in the manufacture of a medicament for the treatment of mGluR5-mediated disorders.

12 . A method of treatment of mGluR5-mediated disorders, comprising administering to a mammal a therapeutically effective amount of the compound according to claim 1 .

13 . The method according to claim 12 , wherein the mammal is a human.

14 . The method according to claim 12 , wherein the disorders are neurological disorders.

15 . The method according to claim 12 , wherein the disorders are psychiatric disorders.

16 . The method according to claim 12 , wherein the disorders are chronic and acute pain disorders.

17 . The method according to claim 12 , wherein the disorders are gastrointestinal disorders.

18 . A method for inhibiting activation of mGluR5 receptors, comprising treating a cell containing said receptor with an effective amount of the compound according to claim 1.