Heterocyclic inhibitors of the sodium channel

Abstract

The invention relates to compounds useful in treating conditions associated with voltage-gated ion channel function, particularly conditions associated with sodium channel activity. More specifically, the invention concerns heterocyclic compounds (e.g., compounds according to any of Formulas (1)-(11 1) or Compounds (1)-(65) of Table 1) that are that are useful in treatment of conditions such as epilepsy, cancer, pain, migraine, Parkinson's Disease, mood disorders, schizophrenia, psychosis, tinnitus, amyotropic lateral sclerosis, glaucoma, ischaemia, spasticity disorders, obsessive compulsive disorder, restless leg syndrome and Tourette syndrome.

What is claimed is: 
     
         1 . A compound having a structure according to the following formula: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2  are independently H, a halogen, a nitrile, an optionally substituted C1-C3 alkyl, an optionally substituted 4-membered heterocyclic ring, an optionally substituted C1-C3 alkoxy, an optionally N-substituted amide wherein the N-substituents are independently chosen from H and C1-C4 alkyl, an optionally N-substituted amide wherein the two N-substituents may combine to form an unsubstituted 5-membered N-heterocyclic ring, or a —CO 2 R group, wherein R is H, Me, or Et; 
         R 3  and R 4  are independently H, a halogen, or a nitrile; 
         R 5  is a sulfonyl methyl, or a monocyclic ring with two substituted positions, wherein the substituents are chosen from H, a halogen, C1-C3 alkyl, hydroxyl or C1-C3 alkoxy, where R≠H; 
         Y is —CONH—, —NHSO 2 —, —SO 2 NR 6 , or SO 2 CH 2 ; 
         N is 0, 1, 2; 
         or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein R 1  and R 2  are both perfluoralkyl groups. 
     
     
         3 . The compound of  claim 1 , wherein R 1  and R 2  are both CF 3  groups. 
     
     
         4 . The compound of  claim 1 , wherein R 3  and R 4  are both a halogen. 
     
     
         5 . The compound of  claim 4 , wherein R 3  and R 4  are both F. 
     
     
         6 . The compound of  claim 1 , wherein at least one of R 3  and R 4  is H. 
     
     
         7 . The compound of  claim 1 , wherein at least one of R 1  and R 2  is H. 
     
     
         8 . The compound of  claim 1 , wherein at least one of R 3  and R 4  is a halogen. 
     
     
         9 . The compound of  claim 1 , wherein only one of R 1  and R 2  is CF 3 . 
     
     
         10 . The compound of  claim 1 , wherein only one of R 1  and R 2  is a halogen. 
     
     
         11 . The compound of  claim 9 , wherein said Y is —CONH— and R 5  is sulfonyl methyl. 
     
     
         12 . The compound of  claim 1 , wherein R 5  is an unsubstituted heterocyclic ring chosen from 
       
         
           
           
               
               
           
         
       
     
     
         13 . A compound having a structure according to the following formula, 
       
         
           
           
               
               
           
         
         (II), 
         wherein 
         R 1  and R 2  are independently H, a halogen, a nitrile group, an optionally substituted C1-C3 alkyl, an optionally substituted 4-membered heterocyclic ring, an optionally substituted C1-C3 alkoxy, an optionally N-substituted amide wherein the N-substituents are independently chosen from H and C1-C4 alkyl, an optionally N-substituted amide wherein the two N-substituents may combine to form an unsubstituted 5-membered N-heterocyclic ring, or a —CO 2 R group, wherein R is H, Me, or Et; 
         R 3  and R 4  are independently H, a halogen, or a nitrile group; 
         R 5  is a sulfonyl methyl, a methyl, or a monocyclic ring with two substituted positions, wherein the substituents are chosen from H, a halogen, C1-C3 alkyl, hydroxyl, C1-C3 alkoxy, benzyl, methylene methoxy, or methylene N-morpholine, such that R 5 ≠H and when R 5  is methyl, R 1-4 ≠H; 
         R 6  is independently H or CH3; 
         Y 1  is independently —NHSO 2 , —SO 2 NR 5 —, or —SO 2 CH 2 —; 
         n is 0, 1 or 2; 
         or a stereoisomer thereof; or a pharmaceutically acceptable salt thereof. 
       
     
     
         14 . The compound of  claim 13 , wherein R 1  and R 2  are both perfluoralkyl groups. 
     
     
         15 . The compound of  claim 13 , wherein R 1  and R 2  are both CF 3  groups. 
     
     
         16 . The compound of  claim 13 , wherein R 3  and R 4  are both halogen. 
     
     
         17 . The compound of  claim 13 , wherein R 3  and R 4  are both F. 
     
     
         18 . The compound of  claim 13 , wherein at least one of R 3  and R 4  is a halogen, nitrile, or H. 
     
     
         19 . The compound of  claim 13 , wherein Y is —SO 2 CH 2 —. 
     
     
         20 . The compound of  claim 13 , wherein only one of R 1  and R 2  is CF 3 . 
     
     
         21 . The compound of  claim 13 , wherein at least one of R 1  and R 2  is a halogen. 
     
     
         22 . The compound of  claim 13 , wherein one of R 1  or R 2  is chosen from —CO 2 H, nitrile, halogen, C1-C3 alkoxy, C1-C3 ester, —CONR x R y  or an optionally substituted 4-membered heterocycle. 
     
     
         23 . The compound of  claim 22 , wherein R x  and R y  are independently H, Methyl, Ethyl, or R x  combines R y  to form a 5-membered heterocycle. 
     
     
         24 . The compound of  claim 13 , wherein R 5  is a mono-substituted monocyclic heterocycle. 
     
     
         25 . The compound of  claim 24 , wherein said substituent is chosen from methyl, benzyl, methylene methoxy, or methylene N-morpholine. 
     
     
         26 . The compound of  claim 13 , wherein R 5  is a methyl or an unsubstituted heterocyclic ring chosen from 
       
         
           
           
               
               
           
         
       
     
     
         27 . A compound having a structure according to the following formula, 
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2  are independently H, a halogen, a nitrile, an optionally substituted C1-C3 alkyl, an optionally substituted 4-membered heterocyclic ring, an optionally substituted C1-C3 alkoxy, an optionally N-substituted amide wherein the N-substituents are independently chosen from H and C1-C4 alkyl, an optionally N-substituted amide wherein the two N-substituents may combine to form an unsubstituted 5-membered N-heterocyclic ring, or a —CO 2 R group, wherein R is H, Me, or Et; 
         R 3  and R 4  are independently H, a halogen, or a nitrile; 
         R 5  is a sulfonyl methyl, a methyl, or a monocyclic ring with two substituted positions, wherein the substituents are chosen from H, a halogen, —NH 2 , —SO 2 NHPh, C1-C3 alkyl, hydroxyl, C1-C3 alkoxy, benzyl, methylene methoxy, or N-methylene morpholine, wherein R 5 ≠a unsubstituted cyclohexyl or unsubstituted thiazole if R 1-4 =H; 
         R 6  is H or CH3; 
         Y 2  is independently —CONH—, —NMeCO—, —NHCO—, —NHSO 2 — or —SO 2 NR 6 —; n is independently 0, 1 or 2; 
         or a stereoisomer thereof; or a pharmaceutically acceptable salt thereof. 
       
     
     
         28 . The compound of  claim 27 , wherein R 1  and R 2  are both perfluoralkyl groups. 
     
     
         29 . The compound of  claim 27 , wherein R 1 and R2 are both CF3 groups. 
     
     
         30 . The compound of  claim 27 , wherein at least one of R3 and R 4  is a CF 3  group or H. 
     
     
         31 . The compound of  claim 27 , wherein the compound is selected from compounds 1-65 in Table 1. 
     
     
         32 .- 51 . (canceled)