Fluorinated 2-amino-4-(substituted amino)phenyl carbamate derivatives

Abstract

The application relates to 2-amino-4-(substituted amino)phenyl carbamate derivatives, or pharmaceutically acceptable salts or solvates thereof, as KCNQ2/3 potassium channel modulators, and methods of their uses.

1 . A compound of formula A: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, wherein:
 X 1 , X 2 , X 3 , and X 9  are each independently H, deuterium, F, NH 2 , or a C 1 -C 4  alkyl optionally substituted with one or more F; 
 X 10  is C(O)(C 7 X 7 ) n X 6  or CO 2 (C 7 X 7 ) n X 6 ; 
 X 4  is H, C 1 -C 4  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
 X 5  is phenyl-(CX 8 X 8 ) m , wherein the phenyl is substituted with one or more substituents independently selected from deuterium, C 1 -C 4  alkyl, C 1 -C 4  alkyl substituted with one or more F, F, and SF 5 , and wherein at least one substituent is selected from C 1 -C 4  alkyl substituted with one or more F, F, and SF 5 , or 
 X 4  and X 5 , together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from deuterium, C 1 -C 4  alkyl, C 1 -C 4  alkyl substituted with one or more F, F, and SF 5 , wherein at least one substituent is selected from C 1 -C 4  alkyl substituted with one or more F, F, and SF 5 , or two substituents attached to adjacent carbon atoms on the heterocyclic ring, together with the carbon atoms to which they are attached, form a phenyl substituted with one or more substituents independently selected from deuterium, C 1 -C 4  alkyl, C 1 -C 4  alkyl substituted with one or more F, F, and SF 5 , wherein the phenyl is substituted with at least one substituent selected from C 1 -C 4  alkyl substituted with one or more F, F, and SF 5 ; 
 X 6  is H or deuterium; 
 each X 7  is independently H, C 1 -C 4  alkyl, or deuterium, or two X 7 , together with the carbon atom to which they are attached, form a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S; 
 each X 5  is independently H, deuterium, C 1 -C 4  alkyl, C 1 -C 4  alkyl substituted with one or more F, or F; 
 m is 1, 2, or 3; and 
 n is 1, 2, or 3, 
 
         wherein when X 1 , X 2 , X 3 , and X 6  are each H, n is 2, each X 7  is H, X 5  is 4-fluorobenzyl, X 9  is NH 2 , and X 10  is CO 2 (C 7 X 7 ) n X 6 , then X 4  is not propenyl or propynyl. 
       
     
     
         2 . The compound of  claim 1 , wherein at least one of X 1 , X 2 , X 3 , and X 9  is NH 2 . 
     
     
         3 . The compound of  claim 1 , wherein one of X 1 , X 2 , X 3 , and X 9  is NH 2 . 
     
     
         4 . The compound of  claim 1 , wherein X 9  is NH 2 . 
     
     
         5 . The compound of  claim 1 , wherein at least one of X 1  and X 9  is methyl. 
     
     
         6 . The compound of  claim 1 , wherein X 1  and X 9  are each methyl. 
     
     
         7 . The compound of  claim 1 , of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 , X 2 , and X 3  are each independently H, deuterium, or F, 
         wherein when X 1 , X 2 , X 3 , and X 6  are each H, n is 2, each X 7  is H, and X 5  is 4-fluorobenzyl, then X 4  is not propenyl or propynyl. 
       
     
     
         8 . The compound of  claim 1 , of formula Ia: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, wherein X 2  and X 3  are each independently H, deuterium, or F. 
       
     
     
         9 . The compound of  claim 1 , wherein X 3  is F. 
     
     
         10 . The compound of  claim 1 , wherein X 4  is C 2 -C 6  alkenyl. 
     
     
         11 . The compound of  claim 1 , wherein X 4  is C 2 -C 6  alkynyl. 
     
     
         12 . The compound of  claim 1 , wherein X 5  is phenyl-(CX 8 X 8 ). 
     
     
         13 . The compound of  claim 1 , wherein X 4  and X 5 , together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclic ring substituted with two or more substituents, wherein two substituents attached to adjacent carbon atoms on the heterocyclic ring, together with the carbon atoms to which they are attached, form a phenyl substituted with one or more substituents independently selected from deuterium, C 1 -C 4  alkyl, C 1 -C 4  alkyl substituted with one or more F, F, and SF 5 . 
     
     
         14 . The compound of  claim 1 , of formula II or VI: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         15 . The compound of  claim 1 , of formula V or VII: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         16 . The compound of  claim 1 , of formula IIIa: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, wherein:
 t1 is 1, 2, 3, 4, or 5; and 
 each Z 1  is independently C 1 -C 4  alkyl, C 1 -C 4  alkyl substituted with one or more F, F, or SF 5 , wherein at least one Z 1  is C 1 -C 4  alkyl substituted with one or more F, F, or SF 5 , 
 
         wherein when X 3  is H, t1 is 1, and Z 1  is 4-fluoro, then X 4  is not propenyl or propynyl. 
       
     
     
         17 . The compound of  claim 1 , of formula IIIb or IIIc: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, wherein:
 t1 is 1, 2, 3, 4, or 5; and 
 each Z 1  is independently C 1 -C 4  alkyl, C 1 -C 4  alkyl substituted with one or more F, F, or SF 5 , wherein at least one Z 1  is C 1 -C 4  alkyl substituted with one or more F, F, or SF 5 . 
 
       
     
     
         18 . The compound of  claim 1 , of formula IVa, IVb, or IVc: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, wherein:
 q is 1, 2, or 3; 
 t2 is 1, 2, 3, or 4; and 
 each Z 2  is independently C 1 -C 4  alkyl, C 1 -C 4  alkyl substituted with one or more F, F, or SF 5 , wherein at least one Z 2  is C 1 -C 4  alkyl substituted with one or more F, F, or SF 5 , or two Z 2 , together with adjacent carbon atoms to which they are attached, form a phenyl substituted with one or more substituents independently selected from C 1 -C 4  alkyl, C 1 -C 4  alkyl substituted with one or more F, F, and SF 5 , wherein the phenyl is substituted with at least one substituent selected from C 1 -C 4  alkyl substituted with one or more F, F, and SF 5 . 
 
       
     
     
         19 . A pharmaceutical composition comprising at least one compound according to  claim 1  or a pharmaceutically acceptable salt or solvate thereof and one or more pharmaceutically acceptable carrier or excipient. 
     
     
         20 . A method of treating or preventing a disease or disorder which can be ameliorated by KCNQ2/3 potassium channel opening, comprising administering to a subject in need thereof a compound of  claim 1  or a pharmaceutically acceptable salt or solvate thereof.