Selective substituted pyridine ligands for neuronal nicotinic receptors

1. A compound having formula (I)

or a pharmaceutically acceptable salt, or a combination thereof, wherein

X is CH;

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 and q are each independently 1 or 2;

n and p are each independently 0, 1, or 2;

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)—, 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)O(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 , or —(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 R 10 , —(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) 2 )(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

m and n are each independently 1;

q is 2;

p is 0;

L 1 is —C(═Y)N(R a )—;

Y is O;

R a is hydrogen;

R 3 is G 2 or —(CR d R e ) t -G 3 ; wherein G 2 and G 3 are each independently aryl;

R d and R e are each independently hydrogen; and

t is as described in claim 1 .

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

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

L 1 is —C(═Y)N(R a )—;

Y is S;

R a is hydrogen; and

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

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

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

L 1 is —C(R c )═N—O—;

R c is hydrogen or alkyl; and

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

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

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

L 1 is —C(R c )═N—O—;

R c is hydrogen; R 3 is —(CR d R e ), G 3 wherein G 3 is aryl;

R d and R e are each independently hydrogen; and t is as described in claim 1 .

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein

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

L 1 is C(═Y);

Y is O; and

R 3 is G 2 ; wherein G 2 is heterocyclyl.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein

p and q are each independently 1;

m is 2;

n is 0;

L 1 is —C(═Y)N(R a )—;

R a is hydrogen;

Y is O; and

R 3 is G 2 wherein G 2 is aryl.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein m, n, p and q are each independently 1.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof wherein

L 1 is N(R b );

R b is hydrogen;

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

R d and R e are are each independently hydrogen; and

t is as described in claim 1 .

10. The compound of claim 8 or a pharmaceutically acceptable salt thereof wherein

L 1 is a bond; and

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

11. The compound of claim 8 or a pharmaceutically acceptable salt thereof wherein

L 1 is a bond;

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

R d and R e are each independently hydrogen; and

t is as described in claim 1 .

12. The compound of claim 8 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;

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

t is as described in claim 1 .

13. The compound of claim 8 or a pharmaceutically acceptable salt thereof wherein

L 1 is —C(═Y)N(R a )—;

Y is O;

R a is hydrogen;

R 3 is —(CR d R e ), G 3 or G 2 ; wherein G 2 and G 3 are each independently heteroaryl;

R d and R e are each independently hydrogen; and

t is as described in claim 1 .

14. The compound of claim 8 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.

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

N-benzyl-5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-amine;

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

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

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

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

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

5-((3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-N-(2-methylbenzyl)nicotinamide;

5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(2-(trifluoromethyl)benzyl)nicotinamide;

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

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

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

5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N—((R)-1-phenylethyl)nicotinamide;

5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N—((S)-1-phenylethyl)nicotinamide;

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

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

5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(2-(thiophen-2-yl)ethyl)nicotinamide;

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

N-(2,3-dihydro-1H-inden-1-yl)-5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)nicotinamide;

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

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

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

N-(benzo[d]thiazol-6-yl)-5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)nicotinamide;

N-(3,5-bis(trifluoromethyl)phenyl)-5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)nicotinamide;

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

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

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

N-(3-fluoro-5-(trifluoromethyl)benzyl)-5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)nicotinamide;

N-(3,5-difluorophenyl)-5-((3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)nicotinamide;

N-(3,5-difluorophenyl)-5-((3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)nicotinamide;

N-(3,5-difluorophenyl)-5-((3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)nicotinamide;

(3,4-dihydroisoquinolin-2(1H)-yl)(5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)methanone;

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

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

(3aR,6aS)-5-(5-(4-Chlorophenoxyimino)methyl)pyridin-3-yl)hexahydropyrrolo[3,4-c]pyrrole;

(3aR,6aS)-5-(5-(4-Benzyloxyimino)methyl)pyridin-3-yl)hexahydropyrrolo[3,4-c]pyrrole; and

1-(5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)ethanone O-4-chlorophenyl oxime;

or a pharmaceutically acceptable salt thereof.

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