Fused heteroaryl compounds, and methods thereof for treating diseases, disorders, and conditions relating to aberrant function of a sodium channel

Abstract

The present invention is directed to, in part, fused heteroaryl compounds and compositions useful for preventing and/or treating a disease or condition relating to aberrant function of a voltage-gated, sodium ion channel, for example, abnormal late/persistent sodium current. Methods of treating a disease or condition relating to aberrant function of a sodium ion channel including Dravet syndrome or epilepsy are also provided herein.

1 - 82 . (canceled) 
     
     
         83 . A compound represented by: 
       
         
           
           
               
               
           
         
       
        or a pharmaceutically acceptable salt thereof, wherein:
 X, Y, and X are independently N or CH, wherein at least one of X, Y, and Z is N; 
 R 1  is C 1-6 alkyl, cyano, C 1-6 haloalkyl, or C 3-8 carbocyclyl optionally substituted with one or more halogen, 
 R 2  is hydrogen, cyano, or C 1-6 haloalkyl, 
 R 3  is selected from the group consisting of: C 1-6 alkyl, cyano, C 3-10  carbocyclyl, —OR c , —C(O)R c , —C(O)OR c , and —C(O)N(R d ) 2 , wherein C 1-6  alkyl or C 3-10  carbocyclyl is optionally substituted with one or more R 5 ; 
 R 4  is C 1-6 alkyl, halo, or OR c , wherein C 1-6  alkyl is optionally substituted with one or more R 5 ; 
 m is 0, 1, or 2; 
 R 5  is independently C 1-6  alkyl, halo, cyano, nitro, or —OR c ; 
 each R c  is independently hydrogen, C 1-6 alkyl, C 3-8 carbocyclyl, C 1-6 alkylene-(C 3-  scarbocyclyl), 3-8 membered heterocyclyl, or 5-8 membered heteroaryl, wherein C 1-6 alkyl, C 3-  scarbocyclyl, C 1-6 alkylene-(C 3-8 carbocyclyl), 3-8 membered heterocyclyl, or 5-8 membered heteroaryl is optionally substituted by one or more R 7 ; 
 each R d  is independently hydrogen or C 1-6  alkyl; and 
 each R 7  is independently C 1-6  alkyl, C 1-6  haloalkyl, C 3-8  carbocyclyl, 3-8 membered heterocyclyl, halo, cyano, nitro, or —OH. 
 
     
     
         84 . The compound of  claim 83 , wherein R 1  is selected from the group consisting of: —CH 3 , CF 3 , CHF 2 , and cyclopropyl. 
     
     
         85 . The compound of  claim 83 , wherein R 1  is CF 3 . 
     
     
         86 . The compound of  claim 83 , wherein R 2  is hydrogen. 
     
     
         87 . The compound of  claim 83 , wherein R 3  is selected from the group consisting of CF 3 , —OCF 3 , —OCH 2 CF 3 , —CH 2 —CH 2 —cyclopropyl optionally substituted with —CN or CF 3 , and cyclopropyl optionally substituted with —CN or CF 3 . 
     
     
         88 . The compound of  claim 83 , wherein R 3  is —OR c , wherein R c  is selected from the group consisting of C 1-6 alkyl substituted with 1,2, or 3 halogens or C 3-8 carbocyclyl optionally substituted with cyano or CF 3 . 
     
     
         89 . The compound of  claim 83 , wherein R c  is selected from the group consisting of: —CF 3 , —CH 2 CF 3 , 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       . 
     
     
         90 . The compound of  claim 83 , wherein m is 0. 
     
     
         91 . The compound of  claim 83 , wherein R 4  is selected from the group consisting of methyl, F, —OMe, and —CH 2 —OMe. 
     
     
         92 . The compound of  claim 83 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
        and a pharmaceutically acceptable salt thereof. 
     
     
         93 . A pharmaceutical composition comprising the compound of  claim 83 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         94 . A method of treating a neurological disorder in a subject in need thereof, the method comprising administering to the subject a the compound of  claim 83 , wherein the neurological disorder is epilepsy. 
     
     
         95 . (canceled) 
     
     
         96 . A method of treating a neurological disorder in a subject in need thereof, the method comprising administering to the subject the compound of  claim 83 , wherein the neurological disorder is an epileptic encephalopathy. 
     
     
         97 . The method of  claim 96 , wherein the epileptic encephalopathy comprises Dravet syndrome, infantile spasms, or Lennox-Gastaut syndrome. 
     
     
         98 . The method of  claim 94 , wherein the subject is a human. 
     
     
         99 . The method of  claim 96 , wherein the subject is a human.