Compounds and their methods of use

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 - 74 . (canceled) 
     
     
         75 . A compound of Formula (V): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is hydrogen, C 1  alkyl, C 1-6 haloalkyl, or C 3-8 carbocyclyl, wherein C 1  alkyl, C 1-6 haloalkyl, or C 3-8 carbocyclyl is optionally substituted by one or more 3-8 membered heterocyclyl, or —OR c ; 
 R 2  is independently hydrogen, C 1-6 alkyl, or halo; 
 R 3  is C 1-6 alkyl, halo, cyano, nitro, C 3-8 carbocyclyl, 3-8 membered heterocyclyl, —OR c , —N(R d ) 2 , —C(O)R c , —C(O)OR c , or —C(O)N(R d ) 2 , wherein C 1-6 alkyl, C 3-8 carbocyclyl, or 3-8 membered heterocyclyl is optionally substituted with one or more R 5 ; 
 R 4  is C 1-6 alkyl, halo, cyano, nitro, C 3-8 carbocyclyl, 3-8 membered heterocyclyl, —OR c , —N(R d ) 2 , —C(O)R c , —C(O)OR c , or —C(O)N(R d ) 2 , wherein C 1-6 alkyl, C 3-8 carbocyclyl, or 3-8 membered heterocyclyl are optionally substituted with one or more R 5 ; 
 m is 1 or 2; 
 each R 5  is independently halo, cyano, nitro, C 1-6 alkyl, C 3-8 carbocyclyl, 3-8 membered heterocyclyl, —OR c , —C(O)N(R d ) 2 , —SO 2 R c , —SO 2 OR c , —SO 2 N(R d ) 2 , —NR d C(O)(R c ), or —N(R d ) 2 ; 
 each R c  is independently hydrogen or C 1-6 alkyl, wherein each C 1-6 alkyl is optionally substituted with one or more R 6 ; 
 each R d  is independently hydrogen or C 1-6 alkyl; 
 each R 6  is independently halogen, cyano, C 3-8 carbocyclyl, or 3-8 membered heterocyclyl; 
 
         wherein the C 3-8 carbocyclyl is optionally substituted with one or more halogens or cyano; and
 R 7  is C 1-6 alkyl or C 3-8 carbocyclyl wherein C 1-6 alkyl or C 3-8 carbocyclyl is optionally substituted with one or more R 6 . 
 
       
     
     
         76 . The compound of  claim 75 , wherein R 1  is C 1-6 haloalkyl optionally substituted with —OR c  or C 3-4 carbocyclyl optionally substituted with one or two halogens. 
     
     
         77 . The compound of  claim 76 , wherein R 1  is CF 3  or CHF 2 . 
     
     
         78 . The compound of  claim 75 , wherein R 2  is hydrogen. 
     
     
         79 . The compound of  claim 75 , wherein R 3  is —OR 7 . 
     
     
         80 . The compound of  claim 75 , wherein R 7  is C 1-6 alkyl optionally substituted with 1, 2, or 3 substituents selected from halogen or cyano; C 1-6 alkyl substituted with C 3-8 carbocyclyl optionally substituted with 1, 2, or 3 substituents selected from halogen or cyano; or C 3-8 carbocyclyl optionally substituted with 1, 2, or 3 substituents selected from halogen or cyano. 
     
     
         81 . The compound of  claim 80 , wherein R 7  is C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens. 
     
     
         82 . The compound of  claim 79 , wherein R 3  is —OCF 3  or —O—CH 2 CF 3 . 
     
     
         83 . The compound of  claim 75 , wherein R 4  is independently C 1-6  alkyl, —OR c , or halogen. 
     
     
         84 . The compound of  claim 83 , wherein R 4  is methyl. 
     
     
         85 . The compound of  claim 83 , wherein R 4  is fluoride. 
     
     
         86 . The compound of  claim 75 , wherein m is 1. 
     
     
         87 . The compound of  claim 75 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         88 - 194 . (canceled) 
     
     
         195 . A pharmaceutical composition comprising a compound of  claim 75 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         196 . A method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof a compound of  claim 75 , or a pharmaceutically acceptable salt thereof. 
     
     
         197 . A method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof a pharmaceutical composition of  claim 195 .