Prodrugs of fumarates and their use in treating various diseases

Abstract

The present invention provides compounds of formula (I), wherein: R 1 is unsubstituted C 1 -C 6 alkyl; L a is substituted or unsubstituted C 1 -C 6 alkyl linker, substituted or unsubstituted C 3 -C 10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; and R 2 and R 3 are each, independently, H, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 6 -C 10 aryl; or alternatively, R 2 and R 3 , together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S or a substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S. The invention also provides pharmaceutical compositions and methods for treating neurological diseases, such as multiple sclerosis.

1 . A compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is unsubstituted C 1 -C 6  alkyl; 
 L a  is substituted or unsubstituted C 1 -C 6  alkyl linker, substituted or unsubstituted C 3 -C 10  carbocycle, substituted or unsubstituted C 6 -C 10  aryl, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; and 
 R 2  and R 3  are each, independently, H, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 2 -C 6  alkenyl, substituted or unsubstituted C 2 -C 6  alkynyl, substituted or unsubstituted C 6 -C 10  aryl, substituted or unsubstituted C 3 -C 10  carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; 
 or alternatively, R 2  and R 3 , together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S or a substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S. 
 
     
     
         2 . The compound of  claim 1 , wherein R 1  is methyl. 
     
     
         3 . The compound according to  claim 1 , wherein L a  is substituted or unsubstituted C 1 -C 6  alkyl linker. 
     
     
         4 . The compound according to  claim 1 , wherein R 2  is substituted or unsubstituted C 1 -C 6  alkyl and R 3  is H. 
     
     
         5 . The compound according to  claim 1 , wherein R 2  and R 3 , together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S or a substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S. 
     
     
         6 . A compound of Formula (Ia), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is unsubstituted C 1 -C 6  alkyl; 
 L a  is substituted or unsubstituted C 1 -C 6  alkyl linker, substituted or unsubstituted C 3 -C 10  carbocycle, substituted or unsubstituted C 6 -C 10  aryl, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; and 
 R 2  is H, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 2 -C 6  alkenyl, substituted or unsubstituted C 2 -C 6  alkynyl, substituted or unsubstituted C 6 -C 10  aryl, substituted or unsubstituted C 3 -C 10  carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S. 
 
     
     
         7 . A compound of Formula (Ib), or a pharmaceutically acceptable polymorph, hydrate, solvate or co-crystal thereof: 
       
         
           
           
               
               
           
         
         A −  is a pharmaceutically acceptable anion; 
         R 1  is unsubstituted C 1 -C 6  alkyl; 
         L a  is substituted or unsubstituted C 1 -C 6  alkyl linker, substituted or unsubstituted C 3 -C 10  carbocycle, substituted or unsubstituted C 6 -C 10  aryl, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; 
         R 3 ′ is substituted or unsubstituted C 1 -C 6  alkyl; and 
         R 2  and R 3  are each, independently, H, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 2 -C 6  alkenyl, substituted or unsubstituted C 2 -C 6  alkynyl, substituted or unsubstituted C 6 -C 10  aryl, substituted or unsubstituted C 3 -C 10  carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; 
         or alternatively, R 2  and R 3 , together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or a substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S. 
       
     
     
         8 . A compound of Formula (II), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is unsubstituted C 1 -C 6  alkyl; 
 R 4  and R 5  are each, independently, H, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 2 -C 6  alkenyl, substituted or unsubstituted C 2 -C 6  alkynyl, substituted or unsubstituted C 6 -C 10  aryl, substituted or unsubstituted C 3 -C 10  carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; 
 R 6 , R 7 , R 8  and R 9  are each, independently, H, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 2 -C 6  alkenyl, substituted or unsubstituted C 2 -C 6  alkynyl or C(O)OR a ; and 
 R a  is H or substituted or unsubstituted C 1 -C 6  alkyl. 
 
     
     
         9 . A compound of Formula (III), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is unsubstituted C 1 -C 6  alkyl; 
 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         X is N, O, S or SO 2 ; 
         Z is C or N; 
         m is 0, 1, 2, or 3; 
         n is 1 or 2; 
         w is 0, 1, 2 or 3; 
         t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; 
         R 6 , R 7 , R 8  and R 9  are each, independently, H, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 2 -C 6  alkenyl, substituted or unsubstituted C 2 -C 6  alkynyl or C(O)OR a ; and 
         R a  is H or substituted or unsubstituted C 1 -C 6  alkyl; and 
         each R 10  is, independently, H, halogen, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 2 -C 6  alkenyl, substituted or unsubstituted C 2 -C 6  alkynyl, substituted or unsubstituted C 3 -C 10  carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; 
         or, alternatively, two R 10 's attached to the same carbon atom, together with the carbon atom to which they are attached, form a carbonyl, substituted or unsubstituted C 3 -C 10  carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; 
         or, alternatively, two R 10 's attached to different atoms, together with the atoms to which they are attached, form a substituted or unsubstituted C 3 -C 10  carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S. 
       
     
     
         10 . A method of treating a neurological disease by administering to a subject in need thereof a therapeutically effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof. 
     
     
         11 . The method of  claim 10 , wherein the neurological disease is multiple sclerosis. 
     
     
         12 . The method of  claim 10 , wherein the neurological disease is relapsing-remitting multiple sclerosis. 
     
     
         13 . The method of  claim 1 , wherein the compound of formula (I) is a pharmaceutically acceptable salt. 
     
     
         14 . A pharmaceutical composition comprising:
 (i) a therapeutically effective amount of a compound of  claim 1 ;   and   (ii) a pharmaceutically acceptable carrier or excipient.   
     
     
         15 . The composition of  claim 14 , wherein the therapeutically effective amount is sufficient for the treatment of multiple sclerosis. 
     
     
         16 . (canceled)