Substituted pyrrolo [1,2-a] pyrazines as calcium channel blockers

1. A compound of formula (I) or formula (II),

or a pharmaceutically acceptable salt, thereof,

wherein

R 1 is X, and R 2 is Y;

X is (i);

m and n, at each occurrence, are independently 1;

G 1 is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or azepanyl, wherein G 1 is connected through the nitrogen atom of said azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or azepanyl;

Y is —NR c Ar 1 , —NR c Ar 2 —Ar 1 , —NR c CH(Ar 1 ) 2 , —NR c (CR a R b ) p Ar 1 , —NR c (CR a R b ) p CH(Ar 1 ) 2 , —NR c -G 2 , —NR c -G 2 -Ar 1 , (iii), (iv), (v) or (vi);

Ar 1 , at each occurrence, is independently aryl or heteroaryl, wherein said aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from alkoxy, alkyl, cyano, haloalkyl, halogen, or —N(alkyl) 2 ;

Ar 2 is aryl or heteroaryl, wherein said aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from alkoxy, alkyl, cyano, haloalkyl, or halogen;

G 2 is cycloalkyl;

R a and R b are at each occurrence independently hydrogen, alkyl, or hydroxyalkyl;

R c is hydrogen or alkyl;

p is 1, 2, 3, or 4; and

R 3 , R 4 , R 5 and R 6 are each independently hydrogen, alkoxy, alkyl, or halogen.

2. The compound according to claim 1 of formula (I) or formula (II), wherein

Y is NR c Ar 1 .

3. The compound according to claim 2 of formula (I), wherein

Ar 1 is aryl; and

R 3 , R 4 , R 5 and R 6 are each independently hydrogen or halogen.

4. The compound according to claim 1 of formula (I) or formula (II), wherein

Y is —NR c CH(Ar 1 ) 2 , —NR c (CR a R b ) p CH(Ar 1 ) 2 , or (v)

5. The compound according to claim 4 of formula (I), wherein

R a and R b are at each occurrence hydrogen;

R c is hydrogen;

p is 1, 2 or 3;

Ar 1 , at each occurrence, is aryl; and

R 3 , R 4 , R 5 and R 6 are each independently hydrogen or halogen.

6. The compound according to claim 1 of formula (I) or formula (II), wherein

Y is —NR c Ar 2 —Ar 1 , —NR c (CR a R b ) p Ar 1 , —NR c -G 2 -Ar 1 , (iii), (iv), or (vi)

7. The compound according to claim 6 of formula (I), wherein

R a and R b are, at each occurrence, independently hydrogen or hydroxyalkyl;

R c is hydrogen;

p is 1, 2 or 3;

Ar 1 is aryl;

Ar 2 is aryl;

G 2 is cyclopropyl; and

R 3 , R 4 , R 5 and R 6 are each independently hydrogen or halogen.

8. The compound according to claim 6 of formula (H), wherein

R a and R b are, at each occurrence, independently hydrogen or hydroxyalkyl;

R c is hydrogen;

p is 1, 2 or 3;

Ar 1 is aryl;

Ar 2 is aryl;

G 2 is cyclopropyl; and

R 3 , R 4 , R 5 and R 6 are each independently hydrogen or halogen.

9. A compound of formula (III) or formula (IV),

or a pharmaceutically acceptable salt thereof, wherein

L 1 is C(O) or S(O) 2 ;

R 2 is X;

X is (i);

m and n, at each occurrence, are independently 1;

G 1 is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or azepanyl, wherein G 1 is connected through the nitrogen atom of said azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or azepanyl;

R 3 , R 4 , R 5 and R 6 are each independently hydrogen, alkoxy, alkyl, or halogen;

R 7 is —S(O) 2 Ar 3 , —C(O)Ar 3 , —S(O) 2 (CR a R b ) p Ar 3 , —C(O)(CR a R b ) p Ar 3 , —S(O) 2 (CR a R b ) p CH(Ar) 2 , —C(O)(CR a R b ) p CH(Ar 3 ) 2 , —C(O)CH (Ar 3 ) 2 , or —CH(Ar 3 ) 2 ;

Ar 3 , at each occurrence, is aryl or heteroaryl, wherein said aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from alkoxy, alkyl, cyano, haloalkyl, or halogen;

R a and R b are at each occurrence independently hydrogen, alkyl, or hydroxyalkyl;

p is 1, 2, 3, or 4; and

R c is hydrogen or alkyl.

10. The compound of claim 9 of formula (III), wherein

L 1 is C(O);

R 7 is —S(O) 2 Ar 3 , —C(O)Ar 3 , —S(O) 2 (CR a R b ) p Ar 3 , or —C(O)(CR a R b ) p Ar 3 and

Ar 3 , at each occurrence, is aryl, wherein said aryl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from alkoxy, alkyl, cyano, haloalkyl, or halogen.

11. The compound of claim 9 of formula (IV), wherein

L 1 is C(O);

R 7 is —S(O) 2 Ar 3 , —C(O)Ar 3 , —S(O) 2 (CR a R b ) p Ar 3 , or —C(O)(CR a R b ) p Ar 3 ; and

Ar 3 is aryl, wherein said aryl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from alkoxy, alkyl, cyano, haloalkyl, or halogen.

12. The compound of claim 9 of formula (III), wherein

L 1 is C(O);

R 7 is —S(O) 2 (CR a R b ) p CH(Ar 3 ) 2 , —C(O)(CR a R b ) p CH(Ar 3 ) 2 , —C(O)CH(Ar 3 ) 2 , or —CH(Ar 3 ) 2 ;

Ar 3 , at each occurrence, is aryl, wherein said aryl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from alkoxy, alkyl, cyano, haloalkyl, or halogen; and

p is 1, 2, or 3.

13. The compound of claim 9 of formula (IV), wherein

L 1 is C(O);

R 7 is —S(O) 2 (CR a R b ) p CH(Ar 3 ) 2 , —C(O)(CR a R b ) p CH(Ar 3 ) 2 , —C(O)CH(Ar 3 ) 2 , or —CH(Ar 3 ) 2 ;

Ar 3 , at each occurrence, is aryl, wherein said aryl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from alkoxy, alkyl, cyano, haloalkyl, or halogen; and

p is 1, 2, or 3.

14. The compound according to claim 1 or claim 9 or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[4-(trifluoromethyl)phenyl]benzenesulfonamide;

N-(2-fluorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

N-(3-fluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

N-(2,6-difluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

N-(4-fluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[3-(trifluoromethyl)phenyl]benzene sulfonamide;

N-(3-fluorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[4-(trifluoromethyl)phenyl]benzene sulfonamide;

N-(2-chlorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

N-(2-chlorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

N-(2,3-difluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

N-(2,5-difluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

N-(2,6-difluorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

N-(2,3-difluorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

N-(2,5-difluorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

N-(2,4-difluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

N-(2-fluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

N-(2,4-difluorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[2-(trifluoromethyl)phenyl]benzene sulfonamide;

4-chloro-2-fluoro-N-(2-fluorophenyl)-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

N-(3-chlorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

(8aR)-2-[3-({4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}sulfonyl)benzoyl]octahydropyrrolo[1,2-a]pyrazine;

(8aS)-2-[3-({4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}sulfonyl)benzoyl]octahydropyrrolo[1,2-a]pyrazine;

(8aR)-2-{3-[(4-benzhydrylpiperazin-1-yl)sulfonyl]benzoyl}octahydropyrrolo-[1,2-a]pyrazine;

N-(3-chlorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

N-(2,2-diphenylethyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[2-(trifluoromethyl)phenyl]benzene sulfonamide;

(8aS)-2-{3-[(4-benzhydrylpiperazin-1-yl)sulfonyl]benzoyl}octahydropyrrolo-[1,2-a]pyrazine;

N-(3,3-diphenylpropyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

N-(3,3-diphenylpropyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

N-(2,2-diphenylethyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

4-chloro-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[4-(trifluoromethyl)phenyl]benzenesulfonamide;

N-[2-(4-fluorophenyl)ethyl]-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

2-chloro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[4-(trifluoromethyl)phenyl]benzene sulfonamide;

(8aS)-2-(3-{[4-(4-fluorophenyl)piperazin-1-yl]sulfonyl}benzoyl)octahydropyrrolo[1,2-a]pyrazine;

N-1,1′-biphenyl-2-yl-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[(1S)-2-hydroxy-1-phenylethyl]benzene sulfonamide;

4-chloro-2-fluoro-N-(2-fluorophenyl)-5-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

4-chloro-N-(3,3-diphenylpropyl)-2-fluoro-5-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[(1R,2S)-2-phenylcyclopropyl]benzene sulfonamide;

4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[(1S)-2-hydroxy-1-phenylethyl]benzene sulfonamide;

(8aR)-2-[2-chloro-5-(2,3-dihydro-1H-indol-1-ylsulfonyl)-4-fluorobenzoyl]octahydropyrrolo[1,2-a]pyrazine;

2,4-dichloro-N-(2-fluorophenyl)-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2-(1H)-ylcarbonyl]benzenesulfonamide;

N-{2-fluoro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;

4-chloro-2-fluoro-N-(2-fluorophenyl)-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-methylbenzene sulfonamide;

(8aR)-2-(2-chloro-4-fluoro-5-{[4-(4-fluorophenyl)piperazin-1-yl]sulfonyl}benzoyl)octahydropyrrolo[1,2-a]pyrazine;

N-{2-chloro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-4-fluorobenzamide;

N-{3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-N-methyl-3-(trifluoromethyl)benzenesulfonamide;

4-chloro-N-(2,2-diphenylethyl)-2-fluoro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;

N-{2-chloro-4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-4-fluorobenzamide;

N-{4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-2-methylphenyl}-2-naphthamide;

3,5-dichloro-N-{2-fluoro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}benzamide;

N-{2-chloro-4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-2,2-diphenylacetamide;

N-{2-chloro-4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-2-naphthamide;

N-{3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-N-isopropyl-3-(trifluoromethyl)benzenesulfonamide;

N-{2-chloro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-2,2-diphenylacetamide;

N-benzhydryl-N-{2-chloro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}amine; and

N-benzhydryl-N-{3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}amine.

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or formula (II) according to claim 1 or, formula (III) or formula (IV) according to claim 9 or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.