Selective substituted pyrazine ligands for neuronal nicotinic receptors

1. A compound having formula (I)

or a pharmaceutically acceptable salt thereof, wherein

X is N;

R 1 is hydrogen, alkyl, alkenyl, or heteroarylalkyl; wherein the heteroaryl moiety of the heteroarylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents as represented by R x ;

m, n, p and q are each independently 1;

R 2 is hydrogen, halogen, C 1-3 haloalkyl, C 1-3 alkyl, CN, NO 2 , C(O)H, C 1-3 alkoxy, C 1-3 haloalkoxy, or NH 2 ;

L 1 is a bond, —C(═Y)N(R a )—, —N(R a )C(═Y)—, O, N(R b ), S, S(O), S(O) 2 , C(═Y), —C(R c )═N—O, —C(R c )═N—N(R c′ ), or —C(R c )═N—N(R c″ )C(O)—; wherein each occurrence of Y is independently O or S;

R 3 is —C 2-4 alkenylenyl-G 1 , G 2 , or —(CR d R e ) t -G 3 ; provided that when R 3 is G 2 , then L 1 is other than a bond;

t is 1, 2, 3, or 4;

R d and R e , at each occurrence, are independently hydrogen, alkyl, haloalkyl, halogen, OR f , N(R f )(R g ), —(C 1-6 alkylenyl)-OR f , or —(C 1-6 alkylenyl)-N(R f )(R g );

R a , R b , R c , R c′ , R c″ , R f , and R g , at each occurrence, are each independently hydrogen, alkyl, or haloalkyl;

G 1 , G 2 , and G 3 , are each independently aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl, wherein each ring as represented by G 1 , G 2 and G 3 , are each independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, oxo, CN, NO 2 , O(R 4 ), S(R 4 ), S(O)R 5 , S(O) 2 R 5 , S(O) 2 N(R 6 )(R 7 ), OC(O)(R 4 ), C(O)R 4 , C(O)ON(R 4 ), C(O)N(R 6 )(R 7 ), N(R 6 )(R 7 ), N(R 6 )S(O) 2 (R 5 ), N(R 6 )C(O)O(R 4 ), N(R 6 )C(O)N(R 6 )(R 7 ), N(R 6 )S(O) 2 N(R 6 )(R 7 ), haloalkyl, —(C 1-6 alkylenyl)-CN, —(C 1-6 alkylenyl)-NO 2 , (C 1-6 alkylenyl)-O(R 4 ), —(C 1-6 alkylenyl)-S(R 4 ), —(C 1-6 alkylenyl)-S(O)R 5 , —(C 1-6 alkylenyl)-S(O) 2 R 5 , —(C 1-6 alkylenyl)-S(O) 2 N(R 6 )(R 7 ), —(C 1-6 alkylenyl)-OC(O)(R 4 ), —(C 1-6 alkylenyl)-C(O)R 4 , —(C 1-6 alkylenyl)-C(O)O(R 4 ), —(C 1-6 alkylenyl)-C(O)N(R 6 )(R 7 ), —(C 1-6 alkylenyl)-N(R 6 )(R 7 ), —(C 1-6 alkylenyl)-N(R 6 )S(O) 2 (R 5 ), —(C 1-6 alkylenyl)-N(R 6 )C(O)O(R 4 ), —(C 1-6 alkylenyl)-N(R 6 )C(O)N(R 6 )(R 7 )—(C 1-6 alkylenyl)-N(R 6 )S(O) 2 N(R 6 )(R 7 ), G 4 , and —(C 1-6 alkylenyl)-G 4 ;

R 4 and R 7 , at each occurrence, are each independently hydrogen, alkyl, haloalkyl, G 5 , or —(C 1-6 alkylenyl)-G 5 ;

R 5 , at each occurrence, is independently alkyl, haloalkyl, G 5 , or —(C 1-6 alkylenyl)-G 5 ;

R 6 , at each occurrence, is independently hydrogen, alkyl, or haloalkyl;

G 4 and G 5 , are each independently aryl, heteroaryl, heterocyclyl, cycloalkyl or cycloalkenyl; each of which is independently unsubstituted or substituted by 1, 2, 3, 4, or 5 substituents as represented by R 8 ; and

each occurrence of R 8 and R x are independently alkyl, alkenyl, alkynyl, halogen, oxo, CN, NO 2 , O(R 9 ), S(R 9 ), S(O)R 10 , S(O) 2 R 10 , S(O) 2 N(R 11 )(R 12 ), OC(O)(R 9 ), C(O)R 9 , C(O)O(R 9 ), C(O)N(R 11 )(R 12 ), N(R 11 )(R 12 ), N(R 11 )S(O) 2 (R 10 ), N(R 11 )C(O)O(R 9 ), N(R 11 )C(O)N(R 11 )(R 12 ), N(R 11 )S(O) 2 N(R 11 )(R 12 ), haloalkyl, —(C 1-6 alkylenyl)-CN, —(C 1-6 alkylenyl)-NO 2 , —(C 1-6 alkylenyl)-O(R 9 ), —(C 1-6 alkylenyl)-S(R 9 ), —(C 1-6 alkylenyl)-S(O)R 10 , —(C 1-6 alkylenyl)-S(O) 2 e, —(C 1-6 alkylenyl)-S(O) 2 N(R 11 )(R 12 ), —(C 1-6 alkylenyl)-OC(O)(R 9 ), —(C 1-6 alkylenyl)-C(O)R 9 , —(C 1-6 alkylenyl)-C(O)O(R 9 ), —(C 1-6 alkylenyl)-C(O)N(R 11 )(R 12 ), (C 1-6 alkylenyl)-N(R 11 )(R 12 ), —(C 1-6 alkylenyl)-N(R 11 )S(O)(R 10 ), —(C 1-6 alkylenyl)-N(R 11 )C(O)O(R 9 ), —(C 1-6 alkylenyl)-N(R 11 )C(O)N(R 11 )(R 12 ), or —(C 1-6 alkylenyl)-N(R 11 )S(O) 2 N(R 11 )(R 12 ); wherein R 9 , R 11 , and R 12 , at each occurrence, are each independently hydrogen, alkyl, or haloalkyl; and R 10 , at each occurrence, is independently alkyl or haloalkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:

L 1 is —C(═Y)N(R a );

Y is O;

R a is hydrogen; and

R 3 is G 2 , wherein G 2 is aryl.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:

L 1 is —C(═Y)N(R a );

Y is O;

R a is hydrogen or alkyl;

R 3 is —(CR d R e ) t -G 3 , wherein G 3 is aryl; and

R d and R e , at each occurrence, are each independently hydrogen or alkyl.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:

L 1 is O;

R 3 is —(CR d R e ) t -G 3 , wherein G 3 is aryl; and

R d and R e , at each occurrence, are each independently hydrogen, alkyl, or haloalkyl.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:

L 1 is —N(R a )C(═Y);

Y is O;

R a is hydrogen; and

R 3 is G 2 , wherein G 2 is aryl.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:

L 1 is a bond; and

R 3 is —C 2-4 alkenylenyl-G 1 , wherein G 1 is aryl.

7. The compound according to claim 1 , that is selected from the group consisting of

N-(3,5-dimethylphenyl)-6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxamide;

6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(3-iodophenyl)pyrazine-2-carboxamide;

N-(4-chlorophenyl)-6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxamide;

N-(3,5-difluorophenyl)-6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxamide;

N-(3,4-dichlorobenzyl)-6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxamide;

N-(3-chlorophenyl)-6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxamide;

6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-phenethylpyrazine-2-carboxamide;

6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(3-isopropylphenyl)pyrazine-2-carboxamide;

N-benzyl-6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxamide;

6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(1-phenylethyl)pyrazine-2-carboxamide;

N-benzyl-6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-methylpyrazine-2-carboxamide;

6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(2-methylbenzyl)pyrazine-2-carboxamide;

6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-m-tolylpyrazine-2-carboxamide;

N-(3,5-dimethoxyphenyl)-6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxamide;

6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(3-isopropoxyphenyl)pyrazine-2-carboxamide;

(3aR,6aS)-2-(6-(3,5-difluorobenzyloxy)pyrazin-2-yl)octahydropyrrolo[3,4-c]pyrrole;

(3aR,6aS)-2-(6-(4-fluorophenethoxy)pyrazin-2-yl)octahydropyrrolo[3,4-c]pyrrole;

(3aR,6aS)-2-(6-(2,2,2-trifluoro-1-phenylethoxy)pyrazin-2-yl)octahydropyrrolo[3,4-c]pyrrole;

(3aR,6aS)-2-(6-(benzyloxy)pyrazin-2-yl)octahydropyrrolo[3,4-c]pyrrole;

(3aR,6aS)-2-(6-(4-fluorobenzyloxy)pyrazin-2-yl)octahydropyrrolo[3,4-c]pyrrole;

N-(6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazin-2-yl)-3-methylbenzamide; and

(3aR,6aS)-2-(6-styrylpyrazin-2-yl)octahydropyrrolo[3,4-c]pyrrole;

or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

9. A method of modulating α4β2 NNR activity in a mammal, said method comprising administering to the mammal having or susceptible to said disorder with a therapeutically effective amount of a compound of the formula (I) of claim 1 or a pharmaceutically acceptable salt thereof.