Heterocyclic chromene-spirocyclic piperidine amides as modulators of ion channels

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence and optionally substituted, as valency allows, with one or more substituents selected from the group consisting of halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl:

R 1 is C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR 7 , N(R 7 ) 2 , NR 7 SO 2 R 7 , SO 2 R 7 , SR 7 , SOR 7 , CO 2 R 7 , NR 7 COR 7 , NR 7 CO 2 R 7 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , CF 3 , OCF 3 , OCHF 2 , heterocycloalkyl, aryl, heteroaryl or (C1-C6)-R 8 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 , NR 7 ;

R 2 is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, aryl, an electron withdrawing group, CH 2 CF 3 , CHF 2 , CF 3 , CN, OH, OR 7 , CON(R 7 ) 2 , SO 2 R 7 , SR 7 , SOR 7 , SO 2 N(R 7 ) 2 , or (C1-C6)-R 8 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 , CF 2 , or NR 7 ;

R 3 is halo, C1-C6 alkyl or C3-C8 cycloalkyl, wherein up to two CH 2 units may be replaced by O, CO, S, SO, SO 2 , or NR 8 , or 2 occurrences of R 3 taken together form a C3-C8 cycloalkyl group;

R 7 is H, C1-C6 alkyl, CHF 2 , CF 3 , or C3-C8 cycloalkyl, or 2 R 7 taken together with the atoms to which they are attached form a heterocyclic or heteroaromatic ring;

R 8 is H, CF 3 , CO 2 R 7 , OH, aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R 7 ) 2 , NR 7 COR 7 , CON(R 7 ) 2 , CN, or SO 2 R 7 ;

A is aryl, heteroaryl or heterocyclic;

X is N, S, or CR 2 wherein at least one X is N;

W is N or CH, wherein up to 2 W are N;

a - - - - line denotes an optionally double bond depending on the identity of X;

m is an integer from 0 to 4 inclusive;

n is an integer from 0 to 3 inclusive; and

o is an integer from 0 to 4 inclusive.

2. The compound of claim 1 , wherein all W's are CH.

3. The compound of claim 1 , wherein one W is N.

4. The compound of claim 1 , wherein R 1 is C1-C6 alkyl, C1-C6 alkoxy, halo, CN, CON(R 7 ) 2 , or (C1-C6)-R 8 wherein up to two CH 2 units may be replaced with O or NR 7 .

5. The compound of claim 1 , wherein R 1 is F, Cl, CH 3 , CN, OCH 3 , CH 2 OH, CH 2 N(CH 3 ) 2 , CH 2 NH 2 , CONHCH 3 , CON(CH 3 ) 2 , CH 2 OCH 3 .

6. The compound of claim 1 , wherein R 2 is C1-C6 alkyl, C1-C6 haloalkyl, halo, CN, CF 3 , CON(R 7 ) 2 , SO 2 R 7 , or (C1-C6)-R 8 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 , CF 2 , or NR 7 .

7. The compound of claim 1 , wherein R 2 is CH 3 , CF 3 , CHF 2 , C 2 H 5 , CH 2 OH, F, CN, (CH 2 ) 2 OCH 3 , SO 2 CH 3 , SOCH 3 , CH 2 CF 3 , CH 2 NH 2 , CH 2 NHCOCH 3 , CH 2 NHCOH, COCH 3 , or CONHCH 3 .

8. The compound of claim 1 , wherein R 3 is C1-C6 alkyl.

9. The compound of claim 1 , wherein R 3 is methyl.

10. The compound of claim 1 , wherein 2 occurrences of R 3 taken together form a C3-C8 cycloalkyl group.

11. The compound of claim 1 , wherein A is

wherein:

R 4 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR 7 , N(R 7 ) 2 , NR 7 SO 2 R 7 , SO 2 R 7 , SR 7 , SOR 7 , CO 2 R 7 , NR 7 COR 7 , NR 7 CO 2 R 7 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , CHF 2 , CF 3 , OCF 3 , OCHF 2 , heterocycloalkyl, aryl, heteroaryl, or a straight chain, branched, or cyclic (C1-C8)-R 8 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 7 ;

R 5 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, halo, CN, OH, OR 7 , N(R 7 ) 2 , NR 7 SO 2 R 7 , SO 2 R 7 , SR 7 , SOR 7 , CO 2 R 7 , NR 7 COR 7 , NR 7 CO 2 R 7 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , CF 3 , OCF 3 , OCHF 2 , heterocycloalkyl, aryl, heteroaryl, or a straight chain, branched, or cyclic (C1-C8)-R 8 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 7 ;

R 6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR 7 , N(R 7 ) 2 , NR 7 SO 2 R 7 , SR 7 , SOR 7 , SO 2 R 7 , CO 2 R 7 , NR 7 COR 7 , NR 7 CO 2 R 7 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , CF 3 , OCF 3 , OCHF 2 , heterocycloalkyl, aryl, heteroaryl, or a straight chain, branched, or cyclic (C1-C8)-R 8 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 7 ; or

two occurrences of R 4 and R 5 , or R 5 and R 6 are both C1-C6 alkyl and together with the carbons to which they are attached form an optionally substituted ring comprising up to 2 heteroatoms.

12. The compound of claim 11 , wherein R 4 is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR 7 , CON(R 7 ) 2 , NR 7 SO 2 R 7 , SO 2 R 7 , SOR 7 , SR 7 , CO 2 R 7 , NR 7 CO 2 R 7 , CHF 2 , CF 3 , OCF 3 , OCHF 2 , heteroaryl, or a straight chain, branched, or cyclic (C1-C8)-R 8 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 7 .

13. The compound of claim 11 , wherein R 4 is H, F, Cl, OH, CH 3 , CHF 2 , CF 3 , OCH 3 , OCHF 2 , OCF 3 , SO 2 CH 3 , CN, NHSO 2 CH 3 , C 2 H 5 , OC 2 H 5 , OCF 2 CHFCl, OCH 2 CF 3 , O(CH 2 ) 2 CH 3 , OCH(CH 3 ) 2 , O(CH 2 ) 2 OH, OCH 2 OCH 3 , CO 2 CH 3 , CH 2 OH, SCH 3 , CON(CH 3 ) 2 , NHCO 2 tBu,

14. The compound of claim 11 , wherein R 5 is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR 7 , NR 7 SO 2 R 7 , SO 2 R 7 , SR 7 , SOR 7 , CO 2 R 7 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , CF 3 , OCF 3 , or a straight chain, branched, or cyclic (C1-C8)-R 8 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 7 .

15. The compound of claim 11 , wherein R 5 is H, F, Cl, CH 3 , C 2 H 5 , CH(CH 3 ) 2 , tBu, OH, OCH 3 , OC 2 H 5 , OCH(CH 3 ) 2 , CH 2 OH, CF 3 , OCF 3 , CN, CO 2 CH 3 , CONH 2 , N(CH 3 )SO 2 CH 3 , SO 2 NH 2 or SO 2 CH 3 .

16. The compound of claim 11 , wherein R 6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR 7 , SR 7 , SOW, SO 2 R 7 , NR 7 COR 7 , SO 2 N(R 7 ) 2 , CON(R 7 ) 2 , CF 3 , OCF 3 , OCHF 2 , heterocycloalkyl, heteroaryl or a straight chain, branched, or cyclic (C1-C8)-R 8 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 7 .

17. The compound of claim 11 , wherein R 6 is H, F, Cl, CH 3 , CF 3 , OCH 3 , OC 2 H 5 , CH 2 CH 2 OH, OCF 3 , OCHF 2 , SOCH(CH 3 ) 2 , SO 2 CH 3 , SO 2 CH(CH 3 ) 2 , SO 2 CHF 2 , SO 2 CF 3 , SO 2 C 2 H 5 , SO 2 CH 2 CH(CH 3 ) 2 , SO 2 tBu, OH, CN, CH 2 CH 3 , OCH 2 CF 3 , O(CH 2 ) 2 OH, NHC(═O)CH 3 , OCH 2 C(═O)NH 2 ,

O(CH 2 ) 2 CH 3 ,

O(CH 2 ) 3 OH, O(CH 2 ) 2 OCH 3 ,

O(CH 2 ) 2 OCF 3 ,

O(CH 2 ) 2 SO 2 CH 3 , tBu,

OtBu,

O(CH 2 ) 3 OCH 3 , O(CH 2 ) 2 OC 2 H 5 ,

O(CH 2 ) 2 N(CH 3 ) 2 ,

OCH 2 Ph, SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHCH 2 CH 3 , SO 2 N(CH 3 )CH(CH 3 ) 2 , SO 2 CH 2 CH 2 OH, CONHCH(CH 3 ) 2 or OCH 2 CO 2 H.

18. The compound of claim 11 , wherein two occurrences of R 4 and R 5 are both C1-C6 alkyl and together with the carbons to which they are attached form an optionally substituted ring comprising up to 2 heteroatoms.

19. The compound of claim 11 , wherein two occurrences of R 5 and R 6 are C1-C6 alkyl and together with the carbons to which they are attached form an optionally substituted ring comprising up to 2 heteroatoms.

20. The compound of claim 11 , wherein R 4 is H.

21. The compound of claim 11 , wherein R 5 is halo, CF 3 , C1-C6 alkyl, or C1-C6 alkoxy.

22. The compound of claim 11 , wherein R 5 is C1-C6 alkoxy.

23. The compound of claim 11 , wherein R 6 is C1-C6 alkyl or C1-C6 alkoxy.

24. The compound of claim 11 , wherein R 6 is C1-C6 alkyl.

25. The compound of claim 11 , wherein R 4 is H or alkoxy; R 5 is H, halo, CF 3 , C1-C6 alkyl, or C1-C6 alkoxy; and R 6 is H, (C1-C6)-R 8 wherein two methylene units have been replaced with O, or SO 2 R 7 .

26. The compound of claim 11 , wherein R 4 is H or OCHF 2 , and R 5 and R 6 are H.

27. The compound of claim 11 , wherein R 4 and R 5 are H, and R 6 is (C1-C6)-R 8 wherein two methylene units have been replaced with O.

28. The compound of claim 11 , wherein R 4 is halo, R 5 is H, and R 6 is alkoxy.

29. The compound of claim 11 , wherein R 4 and R 5 are H, and R 6 is SO 2 R 7 .

30. The compound of claim 11 , wherein

is selected from:

31. The compound of claim 1 , wherein A is heteroaryl or heterocyclic.

32. The compound of claim 31 , wherein A is selected from:

33. The compound of claim 1 , wherein the compound has formula IA:

wherein:

R 4 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR 7 , N(R 7 ) 2 , NR 7 SO 2 R 7 , SO 2 R 7 , SR 7 , SOR 7 , CO 2 R 7 , NR 7 COR 7 , NR 7 CO 2 R 7 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , CF 3 , OCF 3 , OCHF 2 , heterocycloalkyl, aryl, heteroaryl or a straight chain, branched, or cyclic (C1-C8)-R 8 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 7 ;

R 5 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, halo, CN, OH, OR 7 , N(R 7 ) 2 , NR 7 SO 2 R 7 , SO 2 R 7 , SR 7 , SOR 7 , CO 2 R 7 , NR 7 COR 7 , NR 7 CO 2 R 7 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , CF 3 , OCF 3 , OCHF 2 , heterocycloalkyl, aryl, heteroaryl or a straight chain, branched, or cyclic (C1-C8)-R 8 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 7 ;

R 6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR 7 , N(R 7 ) 2 , NR 7 SO 2 R 7 , SOR 7 , SO 2 R 7 , SR 7 , CO 2 R 7 , NR 7 COR 7 ,NR 7 CO 2 R 7 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , CF 3 , OCF 3 , OCHF 2 , heterocycloalkyl, aryl, heteroaryl or a straight chain, branched, or cyclic (C1-C8)-R 8 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 7 ; or

two occurrences of R 4 and R 5 , or R 5 and R 6 are both C1-C6 alkyl and together with the carbons to which they are attached form an optionally substituted ring comprising up to 2 heteroatoms.

34. The compound of claim 33 , wherein R 1 is C1-C6 alkyl, C1-C6 alkoxy, halo, CN, CON(R 7 ) 2 , or (C1-C6)-R 8 wherein up to two CH 2 units may be replaced with O or NR 7 .

35. The compound of claim 33 , wherein R 1 is F, Cl, CN, CH 3 , CH 2 OH, CH 2 N(CH 3 ) 2 , CH 2 NH 2 , CONHCH 3 , CON(CH 3 ) 2 , CH 2 OCH 3 .

36. The compound of claim 33 , wherein R 2 is C1-C6 alkyl, CN, CF 3 , CON(R 7 ) 2 , SO 2 R 7 , or (C1-C6)-R 8 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 7 .

37. The compound of claim 33 , wherein R 2 is CH 3 , CF 3 , CH 2 OH, CN, SO 2 CH 3 , SOCH 3 , CH 2 NH 2 , CH 2 NHCOCH 3 , CH 2 NHCOH, COCH 3 , or CONHCH 3 .

38. The compound of claim 33 , wherein R 3 is C1-C6 alkyl or 2 occurrences of R 3 taken together form a C3-C8 cycloalkyl group.

39. The compound of claim 33 , wherein R 3 is CH 3 .

40. The compound of claim 33 , wherein 2 occurrences of R 3 taken together form a C3-C8 cycloalkyl group.

41. The compound of claim 33 , wherein R 4 is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR 7 , CHF 2 , CF 3 , OCF 3 , OCHF 2 , SO 2 R 7 , SR 7 , SOR 7 , NR 7 CO 2 R 7 , heteroaryl, or a straight chain, branched, or cyclic (C1-C8)-R 8 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 7 .

42. The compound of claim 33 , wherein R 4 is H, F, Cl, OH, CH 3 , CHF 2 , CF 3 , OCH 3 , OCHF 2 , OCF 3 , CO 2 CH 3 , CH 2 OH, SO 2 CH 3 , CN, NHCO 2 tBu, C 2 H 5 , OCF 2 CHFCl,

43. The compound of claim 33 , wherein R 5 is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR 7 , NR 7 SO 2 R 7 , SO 2 R 7 , SR 7 , SOR 7 , CO 2 R 7 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , CF 3 , OCF 3 , or a straight chain, branched, or cyclic (C1-C8)-R 8 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 7 .

44. The compound of claim 33 , wherein R 5 is H, F, Cl, CH 3 , C 2 H 5 , tBu, OH, OCH 3 , OC 2 H 5 , OCH(CH 3 ) 2 , CH 2 OH, CF 3 , OCF 3 , CN, CO 2 CH 3 , CONH 2 , N(CH 3 )SO 2 CH 3 , SO 2 NH 2 or SO 2 CH 3 .

45. The compound of claim 33 , wherein R 6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR 7 , SO 2 R 7 , SR 7 , SOR 7 , NR 7 COR 7 , SO 2 N(R 7 ) 2 , CF 3 , OCF 3 , heteroaryl, or a straight chain, branched, or cyclic (C1-C8)-R 8 , wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 7 .

46. The compound of claim 33 , wherein R 6 is H, F, CH 3 , CF 3 , OCH 3 , OCF 3 , SO 2 CH 3 , SO 2 C 2 H 5 , SO 2 CH(CH 3 ) 2 , SO 2 CH 2 CH(CH 3 ) 2 , SO 2 tBu, SO 2 CHF 2 , CN, CH 2 CH 3 , tBu, CH 2 CH 2 OH, C(CH 3 ) 2 OH, OCH 2 CF 3 , O(CH 2 ) 2 OH, NHC(═O)CH 3 , OCH 2 C(═O)NH 2 ,

O(CH 2 ) 2 CH 3 ,

O(CH 2 ) 3 OH, O(CH 2 ) 2 OCH 3 ,

O(CH 2 ) 2 OCF 3 ,

O(CH 2 ) 2 SO 2 CH 3 ,

OtBu,

O(CH 2 ) 3 OCH 3 , O(CH 2 ) 2 OC 2 H 5 ,

O(CH 2 ) 2 N(CH 3 ) 2 ,

OCH 2 Ph, SO 2 NHCH 3 , SO 2 NHCH 2 CH 3 , SO 2 CH 2 CH 2 OH or OCH 2 CO 2 H.

47. The compound of claim 33 , wherein o is 2, and the two occurrences of R 3 form a C3-C8 cycloalkyl group.

48. The compound of claim 33 , wherein

is selected from:

49. The compound of claim 1 , wherein the compound has formula IB:

wherein:

R 4 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR 7 , N(R 7 ) 2 , NR 7 SO 2 R 7 , SO 2 R 7 , SR 7 , SOR 7 , CO 2 R 7 , NR 7 COR 7 , NR 7 CO 2 R 7 , CON(R) 2 , SO 2 N(R 7 ) 2 , CF 3 , OCF 3 , OCHF 2 , heterocycloalkyl, aryl, heteroaryl or a straight chain, branched, or cyclic (C1-C8)-R 8 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 7 ;

R 5 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, halo, CN, OH, OR 7 , N(R 7 ) 2 , NR 7 SO 2 R 7 , SO 2 R 7 , SR 7 , SOR 7 , CO 2 R 7 , NR 7 COR 7 , NR 7 CO 2 R 7 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , CF 3 , OCF 3 , OCHF 2 , heterocycloalkyl, aryl, heteroaryl or a straight chain, branched, or cyclic (C1-C8)-R 8 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 7 ;

R 6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR 7 , N(R 7 ) 2 , NR 7 SO 2 R 7 , SOR 7 , SO 2 R 7 , SR 7 , CO 2 R 7 , NR 7 COR 7 ,NR 7 CO 2 R 7 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , CF 3 , OCF 3 , OCHF 2 , heterocycloalkyl, aryl, heteroaryl or a straight chain, branched, or cyclic (C1-C8)-R 8 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 7 ; or

two occurrences of R 4 and R 5 , or R 5 and R 6 are both C1-C6 alkyl and together with the carbons to which they are attached form an optionally substituted ring comprising up to 2 heteroatoms.

50. The compound of claim 49 , wherein R 1 is halo or C1-C6 alkoxy.

51. The compound of claim 49 , wherein R 1 is F, Cl or OCH 3 .

52. The compound of claim 49 , wherein R 2 is C1-C6 alkyl, CF 3 or (C1-C6)-R 8 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 7 .

53. The compound of claim 49 , wherein R 2 is CH 3 , CF 3 , C 2 H 5 , CH(CH 3 ) 2 , CH 2 CF 3 , or (CH 2 ) 2 OCH 3 .

54. The compound of claim 49 , wherein R 4 is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR 7 , CON(R 7 ) 2 , NR 7 SO 2 R 7 , SO 2 R 7 , SR 7 , SOR 7 , CO 2 R 7 , NR 7 CO 2 R 7 , CHF 2 , CF 3 , OCF 3 , OCHF 2 , heteroaryl, or a straight chain, branched, or cyclic (C1-C8)-R 8 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 7 .

55. The compound of claim 49 , wherein R 4 is H, F, Cl, OH, CH 3 , CHF 2 , CF 3 , OCH 3 , OCHF 2 , OCF 3 , SO 2 CH 3 , CN, NHSO 2 CH 3 , C 2 H 5 , OC 2 H 5 , OCF 2 CHFCl, OCH 2 CF 3 , O(CH 2 ) 2 CH 3 , OCH 2 OCH 3 , OCH(CH 3 ) 2 , O(CH 2 ) 2 OH, SCH 3 , CON(CH 3 ) 2 , NHCO 2 tBu,

56. The compound of claim 49 , wherein R 5 is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR 7 , CF 3 , OCF 3 , SO 2 R 7 , SR 7 , SOR 7 , or a straight chain, branched, or cyclic (C1-C8)-R 8 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 7 .

57. The compound of claim 49 , wherein R 5 is H, F, Cl, CH 3 , CF 3 , OCH 3 , CH(CH 3 ) 2 , OCH 2 CH 3 , CH 2 OH, OCF 3 , CN, SO 2 CH 3 or tBu.

58. The compound of claim 49 , wherein R 6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, OH, OR 7 , SOR 7 , SO 2 R 7 , SR 7 , SO 2 N(R 7 ) 2 , CON(R) 2 , CF 3 , OCF 3 , OCHF 2 , heterocycloalkyl, heteroaryl, a straight chain, branched, or cyclic (C1-C8)-R 8 , wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 7 .

59. The compound of claim 49 , wherein R 6 is H, F, Cl, OH, CH 3 , CF 3 , OCH 3 , OCF 3 , OCHF 2 , SOCH(CH 3 ) 2 , SO 2 CH 3 , SO 2 CHF 2 , SO 2 CF 3 , SO 2 C 2 H 5 , SO 2 CH(CH 3 ) 2 , SO 2 CH 2 CH(CH 3 ) 2 , SO 2 tBu, SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHCH 2 CH 3 , SO 2 N(CH 3 )CH(CH 3 ) 2 , CONHCH(CH 3 ) 2 , CH 2 CH 3 , OCH 2 CH 3 ,

O(CH 2 ) 2 CH 3 ,

O(CH 2 ) 2 OCH 3 , O(CH 2 ) 2 OCF 3 , tBu,

OtBu,

or OCH 2 Ph.

60. The compound of claim 49 , wherein two occurrences of R 4 and R 5 are both C1-C6 alkyl and together with the carbons to which they are attached form an optionally substituted ring comprising up to 2 heteroatoms.

61. The compound of claim 49 , wherein two occurrences of R 5 and R 6 are both C1-C6 alkyl and together with the carbons to which they are attached form an optionally substituted ring comprising up to 2 heteroatoms.

62. The compound of claim 49 , wherein

is selected from:

63. The compound of claim 1 , wherein the compound is selected from Table 1:

64. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

65. A method of inhibiting a voltage-gated sodium ion channel in:

(a) a patient; or

(b) a biological sample;

comprising administering to the patient, or contacting the biological sample, with the compound of claim 1 .

66. The method of claim 65 , wherein the voltage-gated sodium ion channel is NaV 1.7.

67. A method of treating or lessening the severity in a subject of acute, chronic, neuropathic, or inflammatory pain, migraine, cluster headaches, trigeminal neuralgia, herpatic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, dipolar disorder, myotonia, arrhythmia, movement disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, cancer pain, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress- or exercise induced angina, palpitations, hypertension, migraine, or abormal gastro-intestinal motility, comprising administering an effective amount of a compound of claim 1 .

68. The method according to claim 67 , wherein said method is used for treating or lessening the severity of femur cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic; IBS pain; chronic and acute headache pain; migraine; tension headache, cluster headaches; chronic and acute neuropathic pain, post-herpatic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy induced neuropathic pain; radiotherapy-induced neuropathic pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom pain; intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury/exercise pain; acute visceral pain, abdominal pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory, burn and trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain, sinusitis pain, dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladder and urogenital disease, urinary incontinence; hyperactivity bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS), type I and type II; widespread pain, paroxysmal extreme pain, pruritis, tinnitis, or angina-induced pain.