N-type calcium channel blockers

1. A compound of the formula

or the salts thereof, including all stereoisomeric forms thereof, wherein:

X 1 is CR 3 or N;

W is L 2 -A 3 or X 1 (A 1 )(A 2 );

each of L 1 and L 2 is a C 1 -C 10 optionally substituted alkylene or C 2 -C 10 optionally substituted alkenylene, wherein one or more said C is optionally replaced by a heteroatom selected from N, O or S, or further substituted with ═O, or both;

each of A 1 , A 2 and A 3 is independently an optionally substituted 5-, 6- or 7-membered aliphatic or aromatic ring, and optionally fused to an additional aliphatic or aromatic ring;

each R 1 is an optionally substituted alkyl (1-10C), alkenyl (2-10C), or alkynyl (2-10C), each optionally having one or more C, generally 1-4C, replaced by heteroatoms (N, O and/or S), or R 1 may be selected from aryl (5-12 ring members), arylalkyl (7-16C), and arylalkenyl (7-16C);

R 2 is H or an optionally substituted alkyl (1-10C), alkenyl (2-10C), or alkynyl (2-10C), each optionally having one or more C, generally 1-4C, replaced by heteroatoms (N, O and/or S), or R 2 may be selected from aryl (5-12 ring members), arylalkyl (7-16C), and arylalkenyl (7-16C); and

R 3 is H or an optionally substituted alkyl (1-10C), alkenyl (2-10C), or alkynyl (2-10C), each optionally having one or more C, generally 1-4C, replaced by heteroatoms (N, O and/or S), or R 1 and R 2 may be selected from aryl (5-12 ring members), arylalkyl (7-16C), and arylalkenyl (7-16C);

n is 0-7;

with the proviso that if L 1 is less than three linking atoms, R 2 cannot be hydrogen or L 1 must contain a C═O if R 2 is hydrogen;

and with the further proviso that L 1 must contain at least three linking atoms if W is L 2 -A 3 .

2. The compound of claim 1 , wherein R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, each optionally substituted, and optionally containing one or more heteroatoms selected from O, N and S, or R 1 is an inorganic substituent, or two R 1 form ═O or ═NOH, and n is 0-3.

3. The compound of claim 1 , wherein said R 1 is halo, NO 2 , SO 2 , SO, NO, ═O, ═NOH, or COOR wherein R is H or C 1 -C 6 alkyl.

4. The compound of claim 1 , wherein R 2 is H, lower alkyl or lower alkenyl.

5. The compound of claim 4 , wherein R 2 is H or methyl.

6. The compound of claim 1 , wherein L 1 is C 1 -C 8 alkylene or C 1 -C 8 alkenylene, optionally substituted by ═O.

7. The compound of claim 1 , wherein L 1 is substituted by ═O.

8. The compound of claim 7 , wherein said ═O is adjacent to NR 2 in formula 1.

9. The compound of claim 1 , wherein each of A 1 , A 2 and A 3 is independently optionally substituted phenyl, cyclohexyl.

10. The compound of claim 9 , wherein said each of A 1 , A 2 and A 3 is substituted with a halo, alkoxy or alkyl.

11. The compound of claim 9 , wherein each of A 1 , A 2 and A 3 is independently phenyl or cyclohexyl.

12. The compound of claim 11 , each of A 1 , A 2 and A 3 is phenyl, optionally substituted with a halogen.

13. The compound of claim 1 , wherein W is L 2 -A 3 , and A 3 is phenyl or cyclohexyl, each optionally substituted with one or more substituents.

14. The compound of claim 13 , wherein A 3 is phenyl or pyridyl optionally substituted with a halo, alkoxy or alkyl.

15. The compound of claim 1 , selected from the group consisting of (R)-6,6-Bis(4-fluoro-phenyl)-hexanoic acid [1-(3,5-di-tert-butyl-4-methoxy-benzoyl)-pyrrolidin-3-yl]-methyl-amide;

(R)-N-(1-Benzhydryl-pyrrolidin-3-yl)-N-methyl-3,3-diphenyl-propionamide;

(S)-6,6-Bis-(4-fluoro-phenyl)-hexanoic acid[1-(3,5-di-tert-butyl-4-methoxy-benzoyl)-pyrrolidin-3-yl]-methyl-amide;

(S)-N-(1-Benzhydryl-pyrrolidin-3-yl)-N-methyl-3,3-diphenyl-propionamide;

(S)-N-(1-Benzhydryl-pyrrolidin-3-yl)-2-diphenylamino-N-methyl-acetamide;

(S)-2-[(1-Benzhydryl-pyrrolidin-3-yl)-methyl-amino]-N,N-diphenyl-acetamide;

(S)-3-Benzhydryl-1-(1-benzhydryl-pyrrolidin-3-yl)-1-methyl-urea;

(R)-[6,6-Bis-(4-fluoro-phenyl)-hexyl]-[1-(3,5-di-tert-butyl-4-methoxy-benzoyl)-pyrrolidin-3-yl]-methyl-amine;

(S)-[6,6-Bis-(4-fluoro-phenyl)-hexyl]-[1-(3,5-di-tert-butyl-4-methoxy-benzoyl)-pyrrolidin-3-yl]-methyl-amine;

(R)—N-{1-[(4-Chloro-phenyl)-phenyl-methyl]-pyrrolidin-3-yl }-N-methyl-3,3-diphenyl-propionamide;

(S)—N-{1-[(4-Chloro-phenyl)-phenyl-methyl]-pyrrolidin-3-yl}-N-methyl-3,3-diphenyl-propionamide;

(R)-N-{1-[(3-Chloro-phenyl)-phenyl-methyl]-pyrrolidin-3-yl}-N-methyl-3,3-diphenyl-propionamide;

(S)-N-{1-[(3-Chloro-phenyl)-phenyl-methyl]-pyrrolidin-3-yl}-N-methyl-3,3-diphenyl-propionamide;

(R)-N-{1-[(2-Chloro-phenyl)-phenyl-methyl]-pyrrolidin-3-yl}-N-methyl-3,3-diphenyl-propionamide;

(S)-N-{1-[(2-Chloro-phenyl)-phenyl-methyl]-pyrrolidin-3-yl}-N-methyl-3,3-diphenyl-propionamide;

(R)-6,6-Bis-(4-fluoro-phenyl)-hexanoic acid[1-(3,5-di-tert-butyl-benzoyl)-pyrrolidin-3-yl]-methyl-amide;

(S)-6,6-Bis-(4-fluoro-phenyl)-hexanoic acid[1-(3,5-di-tert-butyl-benzoyl)-pyrrolidin-3-yl]-methyl-amide;

(R)-6,6-Bis-(4-fluoro-phenyl)-hexanoic acid[1-(4-tert-butyl-benzoyl)-pyrrolidin-3-yl]-methyl-amide;

(S)-6,6-Bis-(4-fluoro-phenyl)-hexanoic acid[1-(4-tert-butyl-benzoyl)-pyrrolidin-3-yl]-methyl-amide;

4-[6,6-Bis-(4-fluoro-phenyl)-hexanoylamino]-1-(3,5-di-tert-butyl-4-methoxy-benzoyl)-pyrrolidine-2-carboxylic acid ethyl ester;

4-[6,6-Bis-(4-fluoro-phenyl)-hexanoylamino]-1-(3,5-di-tert-butyl-4-methoxy-benzoyl)-pyrrolidine-2-carboxylic acid;

1-Benzhydryl-4-(3,3-diphenyl-propionylamino)-pyrrolidine-2-carboxylic acid ethyl ester;

1-Benzhydryl-4-(3,3-diphenyl-propionylamino)-pyrrolidine-2-carboxylic acid;

N-(1-Benzhydryl-2-oxo-pyrrolidin-3-yl)-3,3-diphenyl-propionamide;

1-Benzhydryl-3-(1-benzhydryl-2-oxo-pyrrolidin-3-yl)-urea;

N-(1-Benzhydryl-2-oxo-pyrrolidin-3-yl)-2-diphenylamino-acetamide; and

2-(1-Benzhydryl-2-oxo-pyrrolidin-3-ylamino)-N,N-diphenyl-acetamide.

16. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

17. A pharmaceutical composition comprising a compound of claim 15 and a pharmaceutically acceptable excipient.

18. The compound of claim 1 , wherein L 1 is an alkylene or alkenylene chain having 3-6 members.

19. The compound of claim 18 , wherein L 1 is substituted with ═O at the carbon adjacent N.

20. The compound of claim 1 , wherein L 2 is an alkylene or alkenylene having 1-4 members.