N-arylmethyl sulfonamide negative modulators of NR2A

1. A compound of formula I:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof

wherein:

A and D are N;

B and C are CR wherein each R is independently selected from the group consisting of H, halogen, C1-C5 alkyl, CN and O-alkyl;

R 1 is aryl or heteroaryl both of which are optionally substituted with one or more substitutents selected from the group consisting of halogen, C 1 -C 5 alkyl, CN and O-alkyl; or

R 1 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;

R 2 and R 2′ are independently selected from the group consisting of H, and C 1 -C 5 alkyl; or

R 2 and R 2′ may form, with the carbon to which they are connected, a cycloalkane;

X is C═O or SO 2 ;

Y is selected from the group consisting of H, C 1 -C 5 alkyl, and a group —CHP 1 P 2

P 1 is selected from the group consisting of H, and C 1 -C 5 alkyl;

P 2 is O(C 1 -C 5 )alkyl optionally substituted by one or more alkoxy and/or hydroxy groups;

or P 2 is selected from the group consisting of OC(O)R 4 , OC(O)OR 4 , OC(O)NHR 4 , OC(O)NR 4 R 5 , OC(O)-alkyl-NR 4 R 5 , and O(PO)O 2 −2 M 2 ; or P 1 and P 2 , form a cycloalkyl or a heterocycle; M is a monovalent metal cation;

R 4 and R 5 are independently selected from the group consisting of H, and C 1 -C 5 alkyl with the proviso that when P 2 is OC(O)OR 4 , R 4 is not hydrogen;

R 3 is -L 1 -Ar 1 , or

L 1 is straight or branched C 1 -C 5 alkyl;

Z is selected from the group consisting of H and C 1 -C 5 alkyl; or

Z and R 3 , with the nitrogen to which they are connected, may form a heterocycle;

Ar 1 is aryl optionally substituted with one or more substitutents selected from the group consisting of C 1 -C 5 alkyl, CN, and O-alkyl; or

Ar 1 is heteroaryl optionally substituted with one or more substitutents selected from the group consisting of C 1 -C 5 alkyl, CN, and O-alkyl; and

n is 1 or 2.

2. The compound of claim 1 wherein R 1 is aryl substituted with one or more substitutents selected from the group consisting of halogen, C 1 -C 5 alkyl, CN and O-alkyl.

3. The compound of claim 1 wherein R 1 is heteroaryl substituted with one or more substitutents selected from the group consisting of halogen, C 1 -C 5 alkyl, CN and O-alkyl.

4. The compound of claim 2 wherein R 1 is aryl substituted by one or more halogen.

5. The compound of claim 3 wherein R 1 is heteroaryl substituted by one or more halogen.

6. The compound of claim 4 wherein R 1 is phenyl substituted by one or more halogen.

7. The compound of claim 6 wherein R 1 is phenyl substituted by two halogens.

8. The compound of claim 7 wherein R 1 is

9. The compound of claim 2 wherein X is SO 2 .

10. The compound of claim 9 wherein Y is H.

11. The compound of claim 10 wherein n is 1.

12. The compound of claim 11 wherein R 2 is H.

13. The compound of claim 11 wherein R 2 is H.

14. The compound of claim 1 wherein Z is H.

15. The compound of claim 14 wherein R 3 is -L 1 -Ar 1 and L 1 is C 1 -C 3 alkyl.

16. The compound of claim 14 wherein L 1 is CH 2 .

17. The compound of claim 15 wherein Ar 1 is heteroaryl substituted with one or more of the following features: C 1 -C 5 alkyl, CN, and O-alkyl.

18. The compound of claim 17 wherein Ar 1 is pyridyl substituted with one or more of the following features: C 1 -C 5 alkyl, CN, and O-alkyl.

19. The compound of claim 17 wherein Ar 1 is pyridinazyl substituted with one or more of the following features: C 1 -C 5 alkyl, CN, and O-alkyl.

20. The compound of claim 17 wherein Ar 1 is thiazolyl substituted with one or more of the following features: C 1 -C 5 alkyl, CN, and O-alkyl.

21. The compound of claim 20 wherein thiazolyl is bonded to L 1 at the 5 position of the thiazolyl ring:

22. A compound selected from the group

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-(1,3-thiazol-5-ylmethyl)pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-[(4-methoxyphenyl)methyl]pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-[(5-fluoropyridin-3-yl)methyl]pyrazine-2-carboxamide;

5-[(3,5-dichlorobenzene)sulfonamidomethyl]-N-[(2-methyl-1,3-thiazol-5-yl)methyl]pyrazine-2-carboxamide;

5-[(3,4-dichlorobenzene)sulfonamidomethyl]-N-[(2-methyl-1,3-thiazol-5-yl)methyl]pyrazine-2-carboxamide;

5-[(2-fluorobenzene)sulfonamidomethyl]-N-[(2-methyl-1,3-thiazol-5-yl)methyl]pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-[(4-methylpyridin-3-yl)methyl]pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-(pyrimidin-4-ylmethyl)pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-(1,3-oxazol-4-ylmethyl)pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-[(2-methyl-1,3-thiazol-4-yl)methyl]pyrazine-2-carboxamide;

5-(((3-chloro-4-fluorophenyl)sulfonamido)methyl)-N-(1,1-dioxidotetrahydrothiophen-3-yl)pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-[(1-methyl-1H-imidazol-4-yl)methyl]pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-(pyridin-3-ylmethyl)pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-[(4-methyl-1,3-thiazol-5-yl)methyl]pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-(pyridin-4-ylmethyl)pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-(pyrazin-2-ylmethyl)pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-[(1-methyl-1H-pyrrol-2-yl)methyl]pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-[(1,5-dimethyl-1H-pyrrol-2-yl)methyl]pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-[(1-methyl-1H-pyrazol-5-yl)methyl]pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-[(1-methyl-1H-imidazol-5-yl)methyl]pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-(pyridin-2-ylmethyl)pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-[(5-methylpyrazin-2-yl)methyl]pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-[(6-methylpyridin-2-yl)methyl]pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-(1,3-thiazol-2-ylmethyl)pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-[(4-methyl-1,3-thiazol-2-yl)methyl]pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-[(1R)-1-(1,3-thiazol-5-yl)ethyl]pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-(pyrimidin-5-ylmethyl)pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-[(dimethyl-1,3-thiazol-5-yl)methyl]pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-[(2-methoxypyridin-4-yl)methyl]pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-[(1-methyl-1H-imidazol-2-yl)methyl]pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-[(5-methylthiophen-2-yl)methyl]pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-[(6-methoxypyridin-3-yl)methyl]pyrazine-2-carboxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-[1-(2-methyl-1,3-thiazol-5-yl)ethyl]pyrazine-2-carb oxamide;

5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}pyrazine-2-carboxamide;

5-[(4-chloro-3-fluorobenzene)sulfonamidomethyl]-N-[(2-methyl-1,3-thiazol-5-yl)methyl]pyrazine-2-carboxamide; and

5-[(3,4-difluorobenzene)sulfonamidomethyl]-N-[(2-methyl-1,3-thiazol-5-yl)methyl]pyrazine-2-carboxamide.

23. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

24. The compound 5-[(3-chloro-4-fluorobenzene)sulfonamidomethyl]-N-[(2-methyl-1,3-thiazol-5-yl)methyl]pyrazine-2-carboxamide.

25. The compound:

5-(3,4-difluorobenzenesulfonamidomethyl)-6-methyl-N-[(2-methyl-1,3-thiazol-5-yl)methyl]pyrazine-2-carboxamide; or

5-(3-chloro-4-fluorobenzenesulfonamidomethyl)-6-methyl-N-[(2-methyl-1,3-thiazol-5-yl)methyl]pyrazine-2-carboxamide.