Phenyl sulfonamides as modulators of ion channels

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof;

wherein:

ring Z is a 5-7 membered unsaturated or aromatic ring having 1-4 ring heteroatoms selected from O, S, or N, wherein Z is optionally substituted with up to q occurrences of R Z substitutents, wherein each R Z is independently selected from R 1 , R 2 , R 3 , R 4 , or R 5 ; and q is 0-4;

W is N and Y 1 is CH;

x and y each is independently 0-3; provided that x+y is 3;

w is 0-4;

v is 0;

z is 0-4;

V and X each is a bond;

Q is a bond;

R Q is a 3-7 membered monocyclic heterocyclic ring or an 8-12 membered bicyclic heterocyclic ring;

wherein R Q is optionally substituted with up to 4 substituents independently selected from R 1 , R 2 , R 3 , R 4 , or R 5 ;

R 11 is R 2 or Y;

R 22 is R 1 , R 2 , or R 4 ;

R 1 is oxo, ═NN(R 6 ) 2 , ═NN(R 7 ) 2 , ═NN(R 6 R 7 ), ═N—OR 6 , ═N—OR 7 , R 6 or (CH 2 ) n —Y; or two R 1 on adjacent ring atoms, taken together, form 1,2-methylenedioxy or 1,2-ethylenedioxy;

n is 0, 1 or 2;

Y is halo, CN, NO 2 , CF 3 , OCF 3 , OH, SR 6 , S(O)R 6 , SO 2 R 6 , NH 2 , NHR 6 , N(R 6 ) 2 , NR 6 R 8 , COOH, COOR 6 or OR 6 ;

R 2 is hydrogen or C1-C6 aliphatic, wherein each R 2 is optionally substituted with up to 2 substituents independently selected from R 1 , R 4 , or R 5 ;

R 3 is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10 heteroaryl ring, wherein each R 3 is optionally substituted with up to 3 substituents independently selected from R 1 , R 2 , R 4 or R 5 ;

R 4 is OR 5 , OR 6 , OC(O)R 6 , OC(O)R 5 , OC(O)OR 6 , OC(O)OR 5 , OC(O)N(R 6 ) 2 , OC(O)N(R 5 ) 2 , OC(O)N(R 6 R 5 ), OP(O)(OR 6 ) 2 , OP(O)(OR 5 ) 2 , OP(O)(OR 6 )(OR 5 ), SR 6 , SR 5 , S(O)R 6 , S(O)R 5 , SO 2 R 6 , SO 2 R 5 , SO 2 N(R 6 ) 2 , SO 2 N(R 5 ) 2 , SO 2 NR 5 R 6 , SO 3 R 6 , SO 3 R 5 , C(O)R 5 , C(O)OR 5 , C(O)R 6 , C(O)OR 6 , C(O)N(R 6 ) 2 , C(O)N(R 5 ) 2 , C(O)N(R 5 R 6 ), C(O)N(OR 6 )R 6 , C(O)N(OR 5 )R 6 , C(O)N(OR 6 )R 5 , C(O)N(OR 5 )R 5 , C(NOR 6 )R 6 , C(NOR 6 )R 5 , C(NOR 5 )R 6 , C(NOR 5 )R 5 , N(R 6 ) 2 , N(R 5 ) 2 , N(R 5 R 6 ), NR 5 C(O)R 5 , NR 6 C(O)R 6 , NR 6 C(O)R 5 , NR 6 C(O)OR 6 , NR 5 C(O)OR 6 , NR 6 C(O)OR 5 , NR 5 C(O)OR 5 , NR 6 C(O)N(R 6 ) 2 , NR 6 C(O)NR 5 R 6 , NR 6 C(O)N(R 5 ) 2 , NR 5 C(O)N(R 6 ) 2 , NR 5 C(O)NR 5 R 6 , NR 5 C(O)N(R 5 ) 2 , NR 6 C(S)N(R 6 ) 2 , NR 6 C(S)NR 5 R 6 , NR 6 C(S)N(R 5 ) 2 , NR 5 C(S)N(R 6 ) 2 , NR 5 C(S)NR 5 R 6 , NR 5 C(S)N(R 5 ) 2 , NR 6 SO 2 R 6 , NR 6 SO 2 R 5 , NR 5 SO 2 R 5 , NR 6 SO 2 N(R 6 ) 2 , NR 6 SO 2 NR 5 R 6 , NR 6 SO 2 N(R 5 ) 2 , NR 5 SO 2 NR 5 R 6 , NR 5 SO 2 N(R 5 ) 2 , N(OR 6 )R 6 , N(OR 6 )R 5 , N(OR 5 )R 5 , N(OR 5 )R 6 , P(O)(OR 6 )N(R 6 ) 2 , P(O)(OR 6 )N(R 5 R 6 ), P(O)(OR 6 )N(R 5 ) 2 , P(O)(OR 5 )N(R 5 R 6 ), P(O)(OR 5 )N(R 6 ) 2 , P(O)(OR 5 )N(R 5 ) 2 , P(O)(OR 6 ) 2 , P(O)(OR 5 ) 2 , or P(O)(OR 6 )(OR 5 );

R 5 is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10 heteroaryl ring, wherein each R 5 optionally substituted with up to 3 R 1 substituents;

R 6 is H or C1-C6 aliphatic, wherein R 6 is optionally substituted with a R 7 substituent;

R 7 is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10 heteroaryl ring, and each R 7 is optionally substituted with up to 2 substituents independently selected from C1-C6 aliphatic, or (CH 2 ) m -Z′ wherein m is 0-2;

Z′ is selected from halo, CN, NO 2 , C(halo) 3 , CH(halo) 2 , CH 2 (halo), —OC(halo) 3 , —OCH(halo) 2 , —OCH 2 (halo),OH, S—(C1-C6) aliphatic, S(O)—(C1-C6) aliphatic, SO 2 —(C1-C6)aliphatic, NH 2 , NH—(C1-C6)aliphatic, N((C1-C6)aliphatic) 2 , N((C1-C6)aliphatic)R 8 , COOH, C(O)O(—(C1-C6)aliphatic), or O—(C1-C6)aliphatic; and

R 8 is CH 3 C(O)—, C6-C10 aryl sulfonyl-, or C1-C6 alkyl sulfonyl-.

2. The compound according to claim 1 , wherein w is 0.

3. The compound according to claim 1 , wherein Z is selected from:

wherein Z has up to two R Z substituents independently selected from R 1 , R 2 , or R 5 .

4. The compound according to claim 3 , wherein Z is an optionally substituted ring having formula i, formula II, formula viii, formula ix or formula x.

5. The compound according to claim 1 , wherein R Q is an 8-12 membered saturated, or partially unsaturated bicyclic ring system having 1-5 heteroatoms independently selected from O, S, N, or NH, wherein R Q is optionally substituted with up to 4 substituents independently selected from R 1 , R 2 , R 3 , R 4 , or R 5 .

6. The compound according to claim 5 , wherein R Q is an optionally substituted ring selected from:

7. The compound according to claim 1 , wherein said compound has formula VIA or formula VIB:

wherein

U and T each is independently CH or N; provided that both U and T are not simultaneously N;

R 22 is R 1 or R 2 ;

R Z is selected from R 1 , R 2 , or R 5 ;

q is 0-2;

and

R Q is a 3-8-membered saturated, or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from O, S, N, or NH, or an 8-12 membered saturated, or partially unsaturated bicyclic heterocyclic ring system having 1-5 heteroatoms independently selected from O, S, N, or NH; wherein R Q is optionally substituted with up to 4 substituents independently selected from R 1 , R 2 , R 3 , R 4 , or R 5 .

8. The compound according to claim 7 , wherein said compound has formula VIA-i:

wherein:

R Q is

wherein ring B is a 5-6 membered heterocyclic ring having a single nitrogen heteroatom; wherein R Q is optionally substituted with up to 4 substituents independently selected from R 1 , R 2 , or R 3 .

9. The compound according to claim 8 , wherein U and T, both are CH.

10. The compound according to claim 8 , wherein R Q is selected from:

wherein R Q is optionally substituted with up to 4 substituents independently selected from R 1 , R 2 , or R 3 .

11. The compound according to claim 8 , wherein R Q is selected from:

R Q

12. The compound according to claim 7 , wherein said compound has formula VIA-iii:

wherein R Q is

and wherein R Q is optionally substituted with up to 4 substituents independently selected from R 1 , R 2 , or R 3 .

13. The compound according to claim 12 , wherein the phenyl ring attached to the piperazine in said R Q is selected from:

14. A compound selected from

15. A pharmaceutical composition comprising a compound according to any one of claims 1 - 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , and 12 - 14 , and a pharmaceutically acceptable carrier, adjuvant, or a vehicle.