Benzimidazole 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 compounds (e.g., compounds according to any of Formulas (I)-(XIII) or Compounds (1)-(236) of Table 1) that are useful in treatment of a variety of diseases and conditions. Formula (I)

What is claimed is: 
     
         1 .- 81 . (canceled) 
     
     
         82 . A compound having a structure according to the following formula, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein
 each of R 1 , R 2 , and R 3  is, independently, H, unsubstituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or halogen; 
 m is 1 or 2; 
 each R 4  and R 5  is, independently, H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 haloalkyl, or R 4  and R 5  combine to form an optionally substituted C3-C6 cycloalkyl, or R 4  and R 5  combine to form an oxo (C═O) group; 
 each of R 6  and R 8  is, independently, H or optionally substituted C1-C6 alkyl; or R 6  and R 8  combine to form an optionally substituted three-to-nine membered heterocyclyl, or R 6  and R 7A  combine to form an optionally substituted three-to-nine membered heterocyclyl; 
 n is 1 or 2; 
 each R 7A  and R 7B  is, independently H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 haloalkyl; or R 6  combines with R 7A  to form an optionally substituted three-to-nine heterocyclyl; or an R 7A  and R 7B  group on the same carbon combine to form an optionally substituted C3-C6 cycloalkyl; or, when n is 2, both R 7A  groups combine to form an optionally substituted C3-C6 cycloalkyl. 
 
     
     
         83 .- 117 . (canceled) 
     
     
         118 . The compound of  claim 82 , or a pharmaceutically acceptable salt or solvate thereof, wherein one of R 1 , R 2 , and R 3  is H. 
     
     
         119 . The compound of  claim 82 , or a pharmaceutically acceptable salt or solvate thereof, wherein two of R 1 , R 2 , and R 3  are, independently, CF 3 , Cl, or F. 
     
     
         120 . The compound of  claim 82 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 4  and R 5  are both H; or R 4  and R 5  are both CH 3 ; or R 4  and R 5  combine to form an optionally substituted C3-C6 cycloalkyl; or R 4  and R 5  combine to form an oxo (C═O) group. 
     
     
         121 . The compound of  claim 82 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 6  combines with R 7A  to form a three-to-six membered heterocyclyl ring, or wherein R 6  and R 8  combine to form an optionally substituted three-to-six membered heterocyclyl. 
     
     
         122 . The compound of  claim 82 , or a pharmaceutically acceptable salt or solvate thereof, having a structure according to the following formula, 
       
         
           
           
               
               
           
         
       
     
     
         123 . The compound of  claim 122 , or a pharmaceutically acceptable salt or solvate thereof, having a structure: 
       
         
           
           
               
               
           
         
       
     
     
         124 . A compound having a structure according to the following formula, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein
 each of R 1 , R 2 , R 3 , and R 4  is selected, independently, from H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C6-C10 aryl, or optionally substituted 5 to 6-membered heteroaryl, wherein at least one of R 1 , R 2 , R 3 , and R 4  is halogen or optionally substituted C1-C6 haloalkyl; 
 R 5  is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C10 heteroalkyl; 
 R 6  is —R 6A  or —CH 2 R 6B ; 
 R 6A  is NH 2 , optionally substituted cyclopropyl, optionally substituted azetidine, optionally substituted cyclopentyl, optionally substituted pyrazole, optionally substituted pyrrole, optionally substituted pyrrolidine, optionally substituted thiazolidine, optionally substituted thiazolidine-1,1-dioxide, optionally substituted pyrimidine, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C1-C10 alkoxyalkyl, optionally substituted C1-C10 haloalkyl, or optionally substituted C1-C10 alkylsulfonyl; or R 6A  has a structure according to 
 
       
         
           
           
               
               
           
         
       
       wherein
 n is an integer between 0-4; 
 Z 1  is CH 2 , NH, NCH 3 , or O; 
 L 1  is —CH 2 , —CHR 4A , —CH 2 C(═O), —C(═O)CH 2 , —CH 2 C(═O)NH, —CH 2 C(═O)NHCH 2 , or —CH 2 NHC(═O)CH 2 ; 
 each R 2A  and R 2C , when present, is selected from OH, N(R 2B ) 2 , halogen, and unsubstituted C1-C3 alkyl, or two R 2A  combine to form an oxo (═O) group, and wherein no more than two R 2A  combine to form an oxo group; and 
 each R 2B  is, independently, H or unsubstituted C1-C6 alkyl; 
 R 2D  is H, OH, or NH 2 ; 
 
       and
 R 6B  is optionally substituted cyclopropyl, optionally substituted azetidine, optionally substituted cyclopentyl, optionally substituted pyrazole, optionally substituted pyrrole, optionally substituted pyrrolidine, optionally substituted thiazolidine, optionally substituted thiazolidine-1,1-dioxide, or optionally substituted pyrimidine. 
 
     
     
         125 . The compound of  claim 124 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 6  comprises a —NH 2  substituent. 
     
     
         126 . The compound of  claim 124 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2  and R 4  are both CF 3 , F, or Cl. 
     
     
         127 . A pharmaceutical composition comprising the compound of  claim 82  and a pharmaceutically acceptable carrier or excipient. 
     
     
         128 . A method to treat a disease or condition, said method comprising administering to a subject in need of such treatment an effective amount of the compound of  claim 82 . 
     
     
         129 . The method of  claim 128 , wherein said condition is pain, epilepsy, Parkinson's disease, a mood disorder, psychosis, tinnitus, amyotropic lateral sclerosis, glaucoma, ischaemia, spasticity disorders, obsessive compulsive disorder, restless leg syndrome, or Tourette syndrome. 
     
     
         130 . The method of  claim 129 , wherein said subject is a fasted subject. 
     
     
         131 . The method of  claim 129 , wherein said subject is a fed subject. 
     
     
         132 . A method of inhibiting a voltage-gated sodium channel, said method comprising contacting a cell with the compound of  claim 82 .