Potassium channel modulators

1. A compound of formula (1)

or a pharmaceutically acceptable salt thereof, wherein

J is absent, O, N(H), N(alkyl), S, S(O), or S(O) 2 ;

n is 1 or 2;

q is 0, 1, or 2;

ring G 1 is benzo which is unsubstituted or substituted with 1, 2, 3, or 4 substituents as represented by T, wherein each T is independently alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, —CN, —NO 2 , —OR a , —NR a R b , —SR a , —S(O)R a , —S(O) 2 R a , —OC(O)R a , —OC(O)NR a R b , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —S(O) 2 NR a R b , —N(R a )C(O)NR a R b , —N(R a )S(O) 2 NR a R b , —(CR za R zb ) m —CN, —(CR za R zb ) m —NO 2 , —(CR za R zb ) m —OR a , —(CR za R zb ) m —NR a R b , —(CR za R zb ) m —S(O)R a , —(CR za R zb ) m —S(O) 2 R a , —(CR za R zb ) m —OC(O)R a , —(CR za R zb ) m —OC(O)NR a R b , —(CR za R zb ) m —C(O)R a , —(CR za R zb ) m —C(O)OR a , —(CR za R zb ) m —C(O)NR a R b , —(CR za R zb ) m —S(O) 2 NR a R b , —(CR za R zb ) m —N(R a )C(O)NR a R b , or —(CR za R zb ) m —N(R a )S(O) 2 NR a R b ;

X is C(O);

R 1a and R 1b , at each occurrence, are each independently hydrogen, alkyl, halogen, or haloalkyl; R 1a and R 1b , together with the carbon atom to which they are attached, optionally form a 3-, 4-, 5-, or 6-membered monocyclic cycloalkyl when R 1a and R 1b are alkyl or haloalkyl;

k is 0 or 1;

X 1 , X 2 , and X 3 are each independently CH 2 , O, S, S(O), or S(O) 2 ; with the proviso that at least two of X 1 , X 2 , and X 3 are CH 2 ;

t is 0, 1, 2, 3, or 4;

R x is an optional substituent on any substitutable atom of the ring containing X 1 , X 2 , and X 3 , and each R x is independently alkyl, halogen, haloalkyl, OR a , SR a , or CN;

R 2 is hydrogen, alkyl, haloalkyl, —OR 2c , —OC(O)N(R 2c )(R 2f ), —S(O)R 2c , —S(O) 2 R 2c , —S(O) 2 N(R 2c )(R 2f ), —C(O)R 2c , —C(O)OR 2c , —C(O)N(R 2c )(R 2f ), —N(R 2d )(R 2e ), G 2a , —(CR 2a R 2b ) p -G 2a , —(CR 2a R 2b ) p —OR 2c , —(CR 2a R 2b ) p —OC(O)N(R 2c )(R 2f ), —(CR 2a R 2b ) p —SR 2c , —(CR 2a R 2b ) p —S(O)R 2c , —(CR 2a R 2b ) p —S(O) 2 R 2c , —(CR 2a R 2b ) p —S(O) 2 N(R 2c )(R 2f ), —(CR 2a R 2b ) p —C(O)R 2c , —(CR 2a R 2b ) p —C(O)OR 2c , —(CR 2a R 2b ) p —C(O)N(R 2c )(R 2f ), or —(CR 2a R 2b ) p —N(R 2d )(R 2e ),

R 2c , at each occurrence, is independently hydrogen, alkyl, haloalkyl, -alkylenyl-OR a , -alkylenyl-N(R 2 )(R 2g ), -alkylenyl-CN, G 2a , or —(CR 2a R 2b ) p -G 2a ;

R 2d and R 2e , at each occurrence, are each independently hydrogen, alkyl, haloalkyl, G 2a -(CR 2a R 2b ) p -G 2a , C(O)R 2c , C(O)OR 2c , S(O) 2 R 2c , -alkylenyl-OR a , -alkylenyl-N(R 2 )(R 2g ), or -alkylenyl-CN;

R 2f , at each occurrence, is independently hydrogen, alkyl, or haloalkyl;

R 2g , at each occurrence, is independently hydrogen, alkyl, haloalkyl, C(O)R c , C(O)OR c , or S(O) 2 R c ;

G 2a , at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; each of which is independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of G a , alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, —CN, —NO 2 , —OR a , —OC(O)R a , —OC(O)NR a R b , —NR a R b , —SR a , —S(O)R a , —S(O) 2 R a , —OC(O)R a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —S(O) 2 NR a R b , —N(R a )C(O)NR a R b , —N(R a )S(O) 2 NR a R b , —(CR za R zb ) m -G a , —(CR za R zb ) m —CN, —(CR za R zb ) m —NO 2 , —(CR za R zb ) m —OR a , —(CR za R zb ) m —OC(O)R a , —(CR za R zb ) m —OC(O)NR a R b , —(CR za R zb ) m —NR a R b , —(CR za R zb ) m —SR a —(CR za R zb ) m —S(O) 2 R a , —(CR za R zb ) m —OC(O)R a , —(CR za R zb ) m —C(O)R a , —(CR za R zb ) m —C(O)OR a , —(CR za R zb ) m —C(O)NR a R b , —(CR za R zb ) m —S(O) 2 NR a R b , —(CR za R zb ) m —N(R a )C(O)NR a R b , and —(CR za R zb ) m —N(R a )S(O) 2 NR a R b ,

G a , at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; each of which is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, —CN, —NO 2 , —OR a , —NR a R b , —SR a , —S(O)R a , —S(O) 2 R a , —OC(O)R a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —S(O) 2 NR a R b , —N(R a )C(O)NR a R b , —N(R a )S(O) 2 NR a R b , —(CR za R zb ) m —CN, —(CR za R zb ) m —NO 2 , —(CR za R zb ) m —OR a , —(CR za R zb ) m —NR a R b , —(CR za R zb ) m —SR a , —(CR za R zb ) m —S(O)R a , —(CR za R zb ) m —S(O) 2 R a , —(CR za R zb ) m —OC(O)R a , —(CR za R zb ) m —C(O)R a , —(CR za R zb ) m —C(O)OR a , —(CR za R zb ) m —C(O)NR a R b , —(CR za R zb ) m —S(O) 2 NR a R b , —(CR za R zb ) m —N(R a )C(O)NR a R b , and —(CR za R zb ) m —N(R a )S(O) 2 NR a R b ,

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

R c , at each occurrence, is independently alkyl or haloalkyl;

R za , R zb , R 2a , and R 2b , at each occurrence, are each independently hydrogen, alkyl, halogen, or haloalkyl; and

m and p, at each occurrence, are each independently 1, 2, 3, or 4;

wherein heteroaryl, at each occurrence, is independently optionally substituted monocyclic or bicyclic heteroaryl; and

wherein heterocycle, at each occurrence, is independently optionally substituted monocyclic, bicyclic, or tricyclic heterocycle.

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

X 1 , X 2 , and X 3 are CH 2 .

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein J is absent, O, or S.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen, alkyl, haloalkyl, G 2a , or NR 2d R 2e .

5. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R 2 is G 2a .

6. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen, alkyl, or haloalkyl.

7. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R 2 is NR 2d R 2e .

8. The compound of claim 1 of formula (I-d)

or a pharmaceutically acceptable salt thereof.

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

X 1 , X 2 , and X 3 are CH 2 .

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

R 2 is hydrogen alkyl, haloalkyl, G 2a , or NR 2d R 2e .

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

R 1a and R 1b are hydrogen or alkyl;

n is 1, and

q is 0 or 1.

12. The compound of formula (1) or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of

2-[(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]-N-[4-oxo-2-(propan-2-yl)quinazolin-3(4H)-yl]acetamide;

2-[(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]-N-(2-ethyl-4-oxoquinazolin-3(4H)-yl)acetamide;

N-(2-cyclopropyl-7-fluoro-4-oxoquinazolin-3(4H)-yl)-2-[(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]acetamide;

N-[2-cyclopropyl-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl]-2-[(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]acetamide;

N-(2-cyclopropyl-4-oxoquinazolin-3(4H)-yl)-2-[(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]acetamide;

2-[(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]-N-[4-oxo-2-(trifluoromethyl)quinazolin-3(4H)-yl]acetamide;

2-[(1S,2R,5S)-(6,6-dimethylbicyclo[3.1.1]hept-2-yl)methoxy]-N-[4-oxo-2-(propan-2-yl)quinazolin-3(4H)-yl]acetamide;

2-({[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl}sulfanyl)-N-[4-oxo-2-(propan-2-yl)quinazolin-3(4H)-yl]propanamide;

2-{2-[(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]ethoxy}-N-[4-oxo-2-(propan-2-yl)quinazolin-3(4H)-yl]acetamide;

3-({[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl}sulfanyl)-N-[4-oxo-2-(propan-2-yl)quinazolin-3(4H)-yl]propanamide;

2-({[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl}sulfanyl)-N-[4-oxo-2-(propan-2-yl)quinazolin-3(4H)-yl]acetamide;

2-[(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]-N-[6-fluoro-4-oxo-2-(propan-2-yl)quinazolin-3(4H)-yl]acetamide;

2-[(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]-N-[4-oxo-2-(2,2,2-trifluoroethyl)quinazolin-3(4H)-yl]acetamide;

2-[(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]-N-(4-oxoquinazolin-3(4H)-yl)acetamide;

2-[(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]-N-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide;

N-[6-chloro-4-oxo-2-(propan-2-yl)quinazolin-3(4H)-yl]-2-[(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]acetamide;

N-[2-(diethylamino)-4-oxoquinazolin-3(4H)-yl]-2-[(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]acetamide;

2-[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]-N-[4-oxo-2-(propan-2-yl)quinazolin-3(4H)-yl]acetamide;

(±)-2-(bicyclo[2.1.1]hex-2-yl)-N-[4-oxo-2-(propan-2-yl)quinazolin-3(4H)-yl]acetamide;

2-[(1R,3R,5S)-2-fluoro-6,6-dimethylbicyclo[3.1.1]hept-3-yl]-N-[4-oxo-2-(propan-2-yl)quinazolin-3(4H)-yl]acetamide;

2-[(1S,2S,3R,5R)-3-fluoro-6,6-dimethylbicyclo[3.1.1]hept-2-yl]-N-[4-oxo-2-(propan-2-yl)quinazolin-3(4H)-yl]acetamide; and

2-[(1R,3s,5S)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]-N-[4-oxo-2-(propan-2-yl)quinazolin-3(4H)-yl]acetamide.

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (1) according to claim 1 or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers.

14. A method for treating pain in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of formula (1) according to claim 1 , or a pharmaceutically acceptable salt thereof, alone or in combination with one or more pharmaceutically acceptable carrier.