Ion channel modulators and methods of use

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein

R′ 1 and R 1 are independently —Z A R 4 , wherein each Z A is independently a bond or an optionally substituted branched or straight C 1-12 aliphatic chain wherein up to three carbon units of Z A are optionally and independently replaced by —C(O)—, —C(S)—, —C(O)NR A —, —C(O)NR A NR A —, —C(O)O—, —NR A C(O)O—, —O—, —NR A C(O)NR A —, —NR A NR A —, —S—, —SO—, —SO 2 —, —NR A —, —SO 2 NR A —, or —NR A SO 2 NR A —;

R 4 is independently R A , halo, —OH, —CN, —NO 2 , —NH 2 , or —OCF 3 ;

R A is independently hydrogen, an optionally substituted aryl, or an optionally substituted heteroaryl; or

R′ 1 and R 1 together with the nitrogen atom to which they are attached form a heterocycloaliphatic that is substituted with two of —Z B R 5 , wherein each Z B is independently a bond or an optionally substituted branched or straight C 1-6 aliphatic chain wherein up to three carbon units of Z B are optionally and independently replaced by —C(O)—, —C(S)—, —C(O)NR B —, —C(O)NR B NR B —, —C(O)O—, —NR B C(O)O—, —O—, —NR B C(O)NR B —, —NR B NR B —, —S—, —SO—, —SO 2 —, —NR B —, —SO 2 NR B —, or —NR B SO 2 NR B —;

R 5 is independently R B , halo, —OH, —CN, —NO 2 , —NH 2 , ═O, or —OCF 3 ;

R B is independently hydrogen, or an optionally substituted heteroaryl;

R 2 is —Z C R 6 , wherein each Z C is independently a bond or an optionally substituted branched or straight C 1-6 aliphatic chain wherein up to two carbon units of Z C are optionally and independently replaced by —C(O)—, —C(S)—, —C(O)NR C —, —C(O)NR C NR C —, —C(O)O—, —NR C C(O)O—, —O—, —NR C C(O)NR C —, —NR C NR C —, —S—, —SO—, —SO 2 —, —SO 2 NR C —, or —NR C SO 2 NR C —;

R 6 is independently R C , halo, —OH, —CN, —NO 2 , —NH 2 , or —OCF 3 ;

R C is independently hydrogen, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl, or optionally substituted heteroaryl;

R 3 is —Z D R 7 , wherein each Z D is independently a bond or an optionally substituted branched or straight C 1-6 aliphatic chain wherein up to two carbon units of Z D are optionally and independently replaced by —C(O)—, —C(S)—, —C(O)NR D —, —C(O)NR D NR D —, —C(O)O—, —NR D C(O)O—, —O—, —NR D C(O)NR D —, —NR D NR D —, —S—, —SO—, —SO 2 —, —NR D —, —SO 2 NR D —, or —NR D SO 2 NR D —;

R 7 is independently R D , halo, —OH, —CN, —NO 2 , —NH 2 , or —OCF 3 ; and

R D is independently hydrogen, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl, or optionally substituted heteroaryl.

2. The compound of claim 1 , wherein R′ 1 and R 1 are independently

or -Q A , wherein R 10A and R 10B are independently hydrogen, unsubstituted straight or branched C 1-3 aliphatic, or R 10A and R 10B together form an oxo group; R 11A and R 11B are independently hydrogen, optionally substituted straight or branched C 1-5 aliphatic, or R 11A and R 11B together with the carbon atom to which they are attached form an unsubstituted 3-5 membered cycloaliphatic; T is independently a bond, —O—, —NR 10A —, or —CH 2 —; and Q A is hydrogen or an optionally substituted bicyclic heteroaryl, each of which is optionally substituted with 1-3 of halo, hydroxy, optionally substituted C 1-3 alkoxy, or optionally substituted C 1-3 aliphatic.

3. The compound of claim 2 , wherein R 10A and R 10B together form an oxo group; one of R 11A and R 11B is hydrogen and the remaining R 11A or R 11B is optionally substituted straight or branched C 1-5 aliphatic or hydrogen; T is a bond, —O—, —NR 10A —, or —CH 2 —; and Q A is bicyclic heteroaryl, optionally substituted with 1-3 of halo, —OH, —CN, optionally substituted C 1-3 aliphatic, or combinations thereof.

4. The compound of claim 2 , wherein, one of R 11A and R 11B is hydrogen and the remaining R 11A or R 11B is optionally substituted straight or branched C 1-5 alkyl, optionally substituted straight or branched C 2-5 alkenyl, or hydrogen.

5. The compound of claim 2 , wherein one of R 11A and R 11B is hydrogen and the remaining R 11A or R 11B is optionally substituted straight or branched C 1-5 alkyl.

6. The compound claim 2 , wherein one of R 11A and R 11B is hydrogen and the remaining R 11A or R 11B is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tertbutyl, each of which is optionally substituted with hydroxy.

7. The compound of claim 2 , wherein T is independently a bond, —O—, —NR 10A —, or —CH 2 —, wherein —NR 10A — is —NH—.

8. The compound of claim 2 , wherein Q A is an optionally substituted bicyclic heteroaryl, optionally substituted with 1-3 of halo, —OH, —CN, optionally substituted C 1-3 alkoxy, optionally substituted C 1-3 aliphatic, or combinations thereof.

9. The compound of claim 2 , wherein Q A is a phenyl that is substituted with 1-3 of halo, unsubstituted C 1-3 alkyl, or unsubstituted C 1-3 alkoxy.

10. The compound of claim 2 , wherein Q A is an optionally substituted 9-10 membered bicyclic aryl.

11. The compound of claim 2 , wherein Q A is naphthylene-yl or 2,3-dihydro-1H-indene-yl, either of which is unsubstituted.

12. The compound of claim 2 , wherein Q A is a bicyclic heteroaryl, optionally substituted with 1-3 of halo, —OH, —CN, optionally substituted C 1-3 alkoxy, optionally substituted C 1-3 aliphatic, or combinations thereof.

13. The compound of claim 2 , wherein Q A is an optionally substituted bicyclic heteroaryl.

14. The compound of claim 2 , wherein Q A is an optionally substituted 9-10 membered bicyclic heteroaryl having 1-3 heteroatoms selected from N, O, and S.

15. The compound of claim 2 , wherein Q A is indolizine-yl, indole-yl, isoindole-yl, 3H-indole-yl, indoline-yl, 1,2,3,4-tetrahydroquinoline-yl, benzo[d][1,3]dioxole-yl, quinoline-yl, each of which is optionally substituted with 1-3 of halo, —OH, —CN, optionally substituted C 1-3 alkoxy, optionally substituted C 1-3 aliphatic, or combinations thereof.

16. The compound of claim 1 , wherein one of R′ 1 and R 1 is hydrogen and the remaining R′ 1 or R 1 is selected from:

17. The compound of claim 1 , wherein R 3 is one selected from: —CH 3 , —NH 2 ,

18. The compound of claim 1 having formula Ia:

or a pharmaceutically acceptable salt thereof, wherein:

A 1 is —NR 21 —, wherein R 21 is —Z E R 22 , wherein each Z E is independently a bond or an optionally substituted branched or straight C 1-6 aliphatic chain wherein up to three carbon units of Z E are optionally and independently replaced by —C(O)—, —C(O)NR E —, —C(O)O—, —NR E C(O)O—, —O—, or —NR E —;

R 22 is independently R E , halo, —OH, —CN, —NO 2 , —NH 2 , or

—OCF 3 ;

R E is independently hydrogen, an optionally substituted aryl, or an optionally substituted heteroaryl;

R 20 is —Z F R 30 , wherein each Z F is independently a bond or an optionally substituted branched or straight C 1-6 aliphatic chain wherein up to three carbon units of Z F are optionally and independently replaced by —C(O)—, —C(O)NR F —, —C(O)O—, —NR F C(O)O—, —O—, or —NR F —;

R 30 is independently R F , halo, —OH, —CN, —NO 2 , —NH 2 , or —OCF 3 ; and

R F is independently hydrogen, or an optionally substituted heteroaryl.

19. A compound selected from

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