Spiroheterocyclic compounds and their uses as therapeutic agents

Abstract

This invention is directed to spiroheterocyclic compounds of formula (I): wherein k, j, p, Q, R 1 , R 3a , R 3b , R 3e , and R 3d are as defined herein, as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof, that are useful for the treatment and/or prevention of sodium channel-mediated diseases or conditions, such as pain. Pharmaceutical compositions comprising the compounds and methods of using the compounds are also disclosed.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         p is 1 to 2; 
         j and k are each independently 0, 1, 2 or 3; 
         Q is —O—; 
       
       
         
           
           
               
               
           
         
       
       is a fused thienyl ring;
 R 1  is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, —R 8 —OR 5 , —R 8 —CN, —R 9 —P(O)(OR 5 ) 2 , or —R 9 —O—R 9 —OR 5 ; 
 or R 1  is aralkyl substituted by —C(O)N(R 6 )R 7  where:
 R 6  is hydrogen, alkyl, aryl or aralkyl; and 
 R 7  is hydrogen, alkyl, haloalkyl, —R 9 —CN, —R 9 —OR 5 , —R 9 —N(R 4 )R 5 , aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; 
 or R 6  and R 7 , together with the nitrogen to which they are attached, may form a heterocyclyl or heteroaryl; 
 and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups for R 6  and R 7  may be optionally substituted by one or more substituents selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, —R 8 —CN, —R 8 —OR 5 , heterocyclyl and heteroaryl; 
 
 or R 1  is aralkyl optionally substituted by —R 8 —OR 5 , —C(O)OR 5 , halo, haloalkyl, alkyl, nitro, cyano, aryl (optionally substituted by cyano), aralkyl (optionally substituted by one or more alkyl groups), heterocyclyl or heteroaryl; 
 or R 1  is —R 9 —N(R 10 )R 11 , —R 9 —N(R 12 )C(O)R 11  or —R 9 —N(R 10 )C(O)N(R 10 )R 11  where:
 each R 10  is hydrogen, alkyl, aryl or aralkyl; 
 each R 11  is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 9 —OC(O)R 5 , —R 9 —C(O)OR 5 , —R 9 —C(O)N(R 4 )R 5 , —R 9 —C(O)R 5 , —R 9 —OR 5 , or —R 9 —CN; and 
 R 12  is hydrogen, alkyl, aryl, aralkyl or —C(O)R 5 ; 
 and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups for R 10  and R 11  may be optionally substituted by one or more substituents selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, nitro, —R 8 —CN, —R 8 —OR 5 , —R 8 —C(O)R 5 , heterocyclyl and heteroaryl; 
 
 or R 1  is heterocyclylalkyl or heteroarylalkyl where the heterocyclylalkyl or the heteroarylalkyl group is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, —R 8 —OR 5 , —R 8 —C(O)OR 5 , aryl and aralkyl; 
 each R 2  is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 8 —CN, —R 8 —NO 2 , —R 8 —OR 5 , —R 8 —N(R 4 )R 5 , —N═C(R 4 )R 5 , —S(O) m R 4 , —R 8 —C(O)R 4 , —C(S)R 4 , —C(R 4 ) 2 C(O)R 5 , —R 8 —C(O)OR 4 , —C(S)OR 4 , —R 8 —C(O)N(R 4 )R 5 , —C(S)N(R 4 )R 5 , —N(R 5 )C(O)R 4 , —N(R 5 )C(S)R 4 , —N(R 5 )C(O)OR 4 , —N(R 5 )C(S)OR 4 , —N(R 5 )C(O)N(R 4 )R 5 , —N(R 5 )C(S)N(R 4 )R 5 , —N(R 5 )S(O) n R 4 , —N(R 5 )S(O) n N(R 4 )R 5 , —R 8 —S(O) n N(R 4 )R 5 , —N(R 5 )C(═NR 5 )N(R 4 )R 5 , and —N(R 5 )C(═N—CN)N(R 4 )R 5 , wherein each m is independently 0, 1, or 2 and each n is independently 1 or 2;
 and wherein each of the cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups for each R 2  may be optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 8 —CN, —R 8 —NO 2 , —R 8 —OR 5 , —R 8 —N(R 4 )R 5 , —S(O) m R 4 , —R 8 —C(O)R 4 , —R 8 —C(O)OR 4 , —R 8 —C(O)N(R 4 )R 5 , —N(R 5 )C(O)R 4 , and —N(R 5 )S(O) n R 4 , wherein each m is independently 0, 1, or 2 and each n is independently 1 or 2; 
 
 or two adjacent R 2  groups, together with the fused heteroaryl ring or the fused heterocyclyl ring atoms to which they are directly attached, may form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and the remaining R 2  groups, if present, are as described above; 
 R 3a , R 3b , R 3c  and R 3d  are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 8 —CN, —R 8 —NO 2 , —R 8 —OR 5 , —R 8 —N(R 4 )R 5 , —N═C(R 4 )R 5 , —S(O) m R 4 , —R 8 —C(O)R 4 , —C(S)R 4 , —C(R 4 ) 2 C(O)R 5 , —R 8 —C(O)OR 4 , —C(S)OR 4 , —R 8 —C(O)N(R 4 )R 5 , —C(S)N(R 4 )R 5 , —N(R 5 )C(O)R 4 , —N(R 5 )C(S)R 4 , —N(R 5 )C(O)OR 4 , —N(R 5 )C(S)OR 4 , —N(R 5 )C(O)N(R 4 )R 5 , —N(R 5 )C(S)N(R 4 )R 5 , —N(R 5 )S(O) n R 4 , —N(R 5 )S(O) n N(R 4 )R 5 , —R 8 —S(O) n N(R 4 )R 5 , —N(R 5 )C(═NR 5 )N(R 4 )R 5 , and —N(R 5 )C(N═C(R 4 )R 5 )N(R 4 )R 5 , wherein each m is independently 0, 1, or 2 and each n is independently 1 or 2; 
 or R 3a  and R 3b , or R 3b  and R 3c , or R 3c  and R 3d , together with the carbon ring atoms to which they are directly attached, may form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and the remaining R 3a , R 3b , R 3c  or R 3d  group is as defined above; 
 each R 4  and R 5  is independently selected from group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and heteroaryl; 
 or when R 4  and R 5  are each attached to the same nitrogen atom, then R 4  and R 5 , together with the nitrogen atom to which they are attached, may form a heterocyclyl or heteroaryl; and 
 each R 8  is a direct bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and 
 each R 9  is a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; 
 as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof; 
 or a pharmaceutically acceptable salt, solvate or prodrug thereof. 
 
     
     
         2 . The compound of  claim 1  wherein:
 p is 1 or 2; 
 at least one of j and k is 1 and the other is 0 or 1; 
 Q is —O—; 
 
       
         
           
           
               
               
           
         
       
       is a fused thienyl ring;
 R 1  is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, —R 8 —OR 5 , —R 8 —CN, —R 9 —P(O)(OR 5 ) 2 , or —R 9 —O—R 9 —OR 5 ; 
 or R 1  is aralkyl substituted by —C(O)N(R 6 )R 7  where:
 R 6  is hydrogen, alkyl, aryl or aralkyl; and 
 R 7  is hydrogen, alkyl, haloalkyl, —R 9 —CN, —R 9 —OR 5 , —R 9 —N(R 4 )R 5 , aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; 
 or R 6  and R 7 , together with the nitrogen to which they are attached, may form a heterocyclyl or heteroaryl; 
 and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups for R 6  and R 7  may be optionally substituted by one or more substituents selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, —R 8 —CN, —R 8 —OR 5 , heterocyclyl and heteroaryl; 
 
 or R 1  is aralkyl optionally substituted by —R 8 —OR 5 , —C(O)OR 5 , halo, haloalkyl, alkyl, nitro, cyano, aryl (optionally substituted by cyano), aralkyl (optionally substituted by one or more alkyl groups), heterocyclyl or heteroaryl; 
 or R 1  is —R 9 —N(R 10 )R 11 , —R 9 —N(R 12 )C(O)R 11  or —R 9 —N(R 10 )C(O)N(R 10 )R 11  where:
 each R 10  is hydrogen, alkyl, aryl or aralkyl; 
 each R 11  is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 9 —OC(O)R 5 , —R 9 —C(O)OR 5 , —R 9 —C(O)N(R 4 )R 5 , —R 9 —C(O)R 5 , —R 9 —OR 5 , or —R 9 —CN; and 
 R 12  is hydrogen, alkyl, aryl, aralkyl or —C(O)R 5 ; 
 and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups for R 10  and R 11  may be optionally substituted by one or more substituents selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, nitro, —R 8 —CN, —R 8 —OR 5 , —R 8 —C(O)R 5 , heterocyclyl and heteroaryl; 
 
 or R 1  is heterocyclylalkyl or heteroarylalkyl where the heterocyclylalkyl or the heteroarylalkyl group is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, —R 8 —OR 5 , —R 8 —C(O)OR 5 , aryl and aralkyl; 
 each R 2  is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 8 —CN, —R 8 —NO 2 , —R 8 —OR 5 , —R 8 —N(R 4 )R 5 , —N═C(R 4 )R 5 , —S(O) m R 4 , —R 8 —C(O)R 4 , —C(S)R 4 , —C(R 4 ) 2 C(O)R 5 , —R 8 —C(O)OR 4 , —C(S)OR 4 , —R 8 —C(O)N(R 4 )R 5 , —C(S)N(R 4 )R 5 , —N(R 5 )C(O)R 4 , —N(R 5 )C(S)R 4 , —N(R 5 )C(O)OR 4 , —N(R 5 )C(S)OR 4 , —N(R 5 )C(O)N(R 4 )R 5 , —N(R 5 )C(S)N(R 4 )R 5 , —N(R 5 )S(O) n R 4 , —N(R 5 )S(O) n N(R 4 )R 5 , —R 8 —S(O) n N(R 4 )R 5 , —N(R 5 )C(═NR 5 )N(R 4 )R 5 , and —N(R 5 )C(═N—CN)N(R 4 )R 5 , wherein each m is independently 0, 1, or 2 and each n is independently 1 or 2;
 and wherein each of the cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups for each R 2  may be optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 8 —CN, —R 8 —NO 2 , —R 8 —OR 5 , —R 8 —N(R 4 )R 5 , —S(O) m R 4 , —R 8 —C(O)R 4 , —R 8 —C(O)OR 4 , —R 8 —C(O)N(R 4 )R 5 , —N(R 5 )C(O)R 4 , and —N(R 5 )S(O) n R 4 , wherein each m is independently 0, 1, or 2 and each n is independently 1 or 2; 
 
 or two adjacent R 2  groups, together with the fused heteroaryl ring atoms to which they are directly attached, may form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and the remaining R 2  groups, if present, are as described above; 
 R 3a , R 3b , R 3c  and R 3d  are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 8 —CN, —R 8 —NO 2 , —R 8 —OR 5 , —R 8 —N(R 4 )R 5 , —N═C(R 4 )R 5 , —S(O) m R 4 , —R 8 —C(O)R 4 , —C(S)R 4 , —C(R 4 ) 2 C(O)R 5 , —R 8 —C(O)OR 4 , —C(S)OR 4 , —R 8 —C(O)N(R 4 )R 5 , —C(S)N(R 4 )R 5 , —N(R 5 )C(O)R 4 , —N(R 5 )C(S)R 4 , —N(R 5 )C(O)OR 4 , —N(R 5 )C(S)OR 4 , —N(R 5 )C(O)N(R 4 )R 5 , —N(R 5 )C(S)N(R 4 )R 5 , —N(R 5 )S(O) n R 4 , —N(R 5 )S(O) n N(R 4 )R 5 , —R 8 —S(O) n N(R 4 )R 5 , —N(R 5 )C(═NR 5 )N(R 4 )R 5 , and —N(R 5 )C(N═C(R 4 )R 5 )N(R 4 )R 5 , wherein each m is independently 0, 1, or 2 and each n is independently 1 or 2; 
 or R 3a  and R 3b , or R 3b  and R 3c , or R 3c  and R 3d , together with the carbon ring atoms to which they are directly attached, may form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and the remaining R 3a , R 3b , R 3c  or R 3d  group is as defined above; 
 each R 4  and R 5  is independently selected from group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and heteroaryl; 
 or when R 4  and R 5  are each attached to the same nitrogen atom, then R 4  and R 5 , together with the nitrogen atom to which they are attached, may form a heterocyclyl or heteroaryl; and 
 each R 8  is a direct bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and 
 each R 9  is a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain. 
 
     
     
         3 . The compound of  claim 2  wherein:
 p is 1 or 2; 
 j is 0 and k is 1; 
 Q is —O—; 
 
       
         
           
           
               
               
           
         
       
       is a fused thienyl ring;
 R 1  is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, —R 6 —OR 5 , —R 8 —CN, —R 9 —P(O)(OR 5 ) 2 , or —R 9 —O—R 9 —OR 5 ; 
 or R 1  is aralkyl substituted by —C(O)N(R 6 )R 7  where:
 R 6  is hydrogen, alkyl, aryl or aralkyl; and 
 R 7  is hydrogen, alkyl, haloalkyl, —R 9 —CN, —R 9 —OR 5 , —R 9 —N(R 4 )R 5 , aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; 
 or R 6  and R 7 , together with the nitrogen to which they are attached, may form a heterocyclyl or heteroaryl; 
 and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups for R 6  and R 7  may be optionally substituted by one or more substituents selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, —R 8 —CN, —R 8 —OR 5 , heterocyclyl and heteroaryl; 
 
 or R 1  is aralkyl optionally substituted by —R 8 —OR 5 , —C(O)OR 5 , halo, haloalkyl, alkyl, nitro, cyano, aryl (optionally substituted by cyano), aralkyl (optionally substituted by one or more alkyl groups), heterocyclyl or heteroaryl; 
 or R 1  is —R 9 —N(R 10 )R 11 , —R 9 —N(R 12 )C(O)R 11  or —R 9 —N(R 10 )C(O)N(R 10 )R 11  where:
 each R 10  is hydrogen, alkyl, aryl or aralkyl; 
 each R 11  is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 9 —OC(O)R 5 , —R 9 —C(O)OR 5 , —R 9 —C(O)N(R 4 )R 5 , —R 9 —C(O)R 5 , —R 9 —OR 5 , or —R 9 —CN; and 
 R 12  is hydrogen, alkyl, aryl, aralkyl or —C(O)R 5 ; 
 and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups for R 10  and R 11  may be optionally substituted by one or more substituents selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, nitro, —R 8 —CN, —R 8 —OR 5 , —R 8 —C(O)R 5 , heterocyclyl and heteroaryl; 
 
 or R 1  is heterocyclylalkyl or heteroarylalkyl where the heterocyclylalkyl or the heteroarylalkyl group is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, —R 8 —OR 5 , —R 8 —C(O)OR 5 , aryl and aralkyl; 
 each R 2  is each independently selected from the group consisting of hydrogen and alkyl; 
 R 3a , R 3b , R 3c  and R 3d  are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 8 —CN, —R 8 —NO 2 , —R 8 —OR 5 , —R 8 —N(R 4 )R 5 , —N═C(R 4 )R 5 , —S(O) m R 4 , —R 8 —C(O)R 4 , —C(S)R 4 , —C(R 4 ) 2 C(O)R 5 , —R 8 —C(O)OR 4 , —C(S)OR 4 , —R 8 —C(O)N(R 4 )R 5 , —C(S)N(R 4 )R 5 , —N(R 5 )C(O)R 4 , —N(R 5 )C(S)R 4 , —N(R 5 )C(O)OR 4 , —N(R 5 )C(S)OR 4 , —N(R 5 )C(O)N(R 4 )R 5 , —N(R 5 )C(S)N(R 4 )R 5 , —N(R 5 )S(O) n R 4 , —N(R 5 )S(O) n N(R 4 )R 5 , —R 8 —S(O) n N(R 4 )R 5 , —N(R 5 )C(═NR 5 )N(R 4 )R 5 , and —N(R 5 )C(N═C(R 4 )R 5 )N(R 4 )R 5 , wherein each m is independently 0, 1, or 2 and each n is independently 1 or 2; 
 or R 3a  and R 3b , or R 3b  and R 3c , or R 3c  and R 3d , together with the carbon ring atoms to which they are directly attached, may form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and the remaining R 3a , R 3b , R 3c  or R 3d  group is as defined above; 
 each R 4  and R 5  is independently selected from group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and heteroaryl; 
 or when R 4  and R 5  are each attached to the same nitrogen atom, then R 4  and R 5 , together with the nitrogen atom to which they are attached, may form a heterocyclyl or heteroaryl; 
 each R 8  is a direct bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and 
 each R 9  is a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain. 
 
     
     
         4 .- 8 . (canceled) 
     
     
         9 . The compound of  claim 3  wherein:
 p is 1 or 2; 
 j is 0 and k is 1; 
 Q is —O—; 
 
       
         
           
           
               
               
           
         
       
       is a fused thienyl ring;
 R 1  is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, —R 6 —OR 5 , —R 8 —CN, —R 9 —P(O)(OR 5 ) 2 , or —R 9 —O—R 9 —OR 5 ; 
 or R 1  is aralkyl substituted by —C(O)N(R 6 )R 7  where:
 R 6  is hydrogen, alkyl, aryl or aralkyl; and 
 R 7  is hydrogen, alkyl, haloalkyl, —R 9 —CN, —R 9 —OR 5 , —R 9 —N(R 4 )R 5 , aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; 
 or R 6  and R 7 , together with the nitrogen to which they are attached, may form a heterocyclyl or heteroaryl; 
 and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups for R 6  and R 7  may be optionally substituted by one or more substituents selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, —R 8 —CN, —R 8 —OR 5 , heterocyclyl and heteroaryl; 
 
 or R 1  is aralkyl optionally substituted by —R 8 —OR 5 , —C(O)OR 5 , halo, haloalkyl, alkyl, nitro, cyano, aryl (optionally substituted by cyano), aralkyl (optionally substituted by one or more alkyl groups), heterocyclyl or heteroaryl; 
 or R 1  is —R 9 —N(R 10 )R 11 , —R 9 —N(R 12 )C(O)R 11  or —R 9 —N(R 10 )C(O)N(R 10 )R 11  where:
 each R 10  is hydrogen, alkyl, aryl or aralkyl; 
 each R 11  is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 9 —OC(O)R 5 , —R 9 —C(O)OR 5 , —R 9 —C(O)N(R 4 )R 5 , —R 9 —C(O)R 5 , —R 9 —OR 5 , or —R 9 —CN; and 
 R 12  is hydrogen, alkyl, aryl, aralkyl or —C(O)R 5 ; 
 and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups for R 10  and R 11  may be optionally substituted by one or more substituents selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, nitro, —R 8 —CN, —R 8 —OR 5 , —R 8 —C(O)R 5 , heterocyclyl and heteroaryl; 
 
 or R 1  is heterocyclylalkyl or heteroarylalkyl where the heterocyclylalkyl or the heteroarylalkyl group is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, —R 8 —OR 5 , —R 8 —C(O)OR 5 , aryl and aralkyl; 
 each R 2  is each independently selected from the group consisting of hydrogen and alkyl; 
 R 3a  and R 3d  are each hydrogen; 
 R 3b  and R 3c , together with the carbon ring atoms to which they are directly attached, form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; 
 each R 4  and R 5  is independently selected from group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and heteroaryl; 
 or when R 4  and R 5  are each attached to the same nitrogen atom, then R 4  and R 5 , together with the nitrogen atom to which they are attached, may form a heterocyclyl or heteroaryl; and 
 each R 8  is a direct bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and 
 each R 9  is a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain. 
 
     
     
         10 . The compound of  claim 9  wherein:
 p is 1 or 2; 
 j is 0 and k is 1; 
 Q is —O—; 
 
       
         
           
           
               
               
           
         
       
       is a fused thienyl ring;
 R 1  is hydrogen or alkyl; 
 or R 1  is aralkyl substituted by —C(O)N(R 6 )R 7  where:
 R 6  is hydrogen, alkyl, aryl or aralkyl; and 
 R 7  is hydrogen, alkyl, haloalkyl, —R 9 —CN, —R 9 —OR 5 , —R 9 —N(R 4 )R 5 , aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; 
 or R 6  and R 7 , together with the nitrogen to which they are attached, may form a heterocyclyl or heteroaryl; 
 and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups for R 6  and R 7  may be optionally substituted by one or more substituents selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, —R 8 —CN, —R 8 —OR 5 , heterocyclyl and heteroaryl; 
 
 or R 1  is —R 9 —N(R 10 )R 11 , —R 9 —N(R 12 )C(O)R 11  or —R 9 —N(R 10 )C(O)N(R 10 )R 11  where:
 each R 10  is hydrogen, alkyl, aryl or aralkyl; 
 each R 11  is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 9 —OC(O)R 5 , —R 9 —C(O)OR 5 , —R 9 —C(O)N(R 4 )R 5 , —R 9 —C(O)R 5 , —R 9 —OR 5 , or —R 9 —CN; and 
 R 12  is hydrogen, alkyl, aryl, aralkyl or —C(O)R 5 ; 
 and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups for R 10  and R 11  may be optionally substituted by one or more substituents selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, nitro, —R 8 —CN, —R 8 —OR 5 , —R 8 —C(O)R 5 , heterocyclyl and heteroaryl; 
 
 each R 2  is each independently selected from the group consisting of hydrogen and alkyl; 
 R 3a  and R 3d  are each hydrogen; 
 R 3b  and R 3c , together with the carbon ring atoms to which they are directly attached, form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; 
 each R 4  and R 5  is independently selected from group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and heteroaryl; 
 or when R 4  and R 5  are each attached to the same nitrogen atom, then R 4  and R 5 , together with the nitrogen atom to which they are attached, may form a heterocyclyl or heteroaryl; and 
 each R 8  is a direct bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and 
 each R 9  is a straight or branched alkylene chain, a straight or branched alkenylene chain or a 
 straight or branched alkynylene chain. 
 
     
     
         11 . The compound of  claim 10  wherein:
 p is 1 or 2; 
 j is 0 and k is 1; 
 Q is —O—; 
 
       
         
           
           
               
               
           
         
       
       is a fused thienyl ring;
 R 1  is hydrogen or alkyl; 
 each R 2  is each independently selected from the group consisting of hydrogen and alkyl; 
 R 3a  and R 3d  are each hydrogen; and 
 R 3b  and R 3c , together with the carbon ring atoms to which they are directly attached, form a fused dioxolyl ring. 
 
     
     
         12 . The compound of  claim 11  wherein:
 p is 1; 
 j is 0 and k is 1; 
 Q is —O—; 
 
       
         
           
           
               
               
           
         
       
       is a fused thienyl ring;
 R 1  is pentyl; 
 each R 2  is each independently selected from the group consisting of hydrogen; 
 R 3a  and R 3d  are each hydrogen; and 
 R 3b  and R 3c , together with the carbon ring atoms to which they are directly attached, form a fused dioxolyl ring. 
 
     
     
         13 . The compound of  claim 12  which is 4′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,6′-thieno[3,2-b]pyrrol]-5′(4′H)-one. 
     
     
         14 . A method of treating, preventing or ameliorating a disease or a condition in a mammal, wherein the disease or condition is selected from the group consisting of pain, depression, cardiovascular diseases, respiratory diseases, and psychiatric diseases, or combinations thereof, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of  claim 1 , as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof. 
     
     
         15 . A method of  claim 14 , wherein said disease or condition is selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain, childbirth pain, labor pain, neurogenic bladder, ulcerative colitis, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine headache, dental pain, sinus headache, tension headache, phantom limb pain, peripheral nerve injury, and combinations thereof. 
     
     
         16 . A method of  claim 14 , wherein said disease or condition is selected from the group consisting of pain associated with HIV, HIV treatment induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, eudynia, heat sensitivity, tosarcoidosis, irritable bowel syndrome, Crohns disease, pain associated with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritic, rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin related Illnesses, familial erythromelalgia, primary erythromelalgia, familial rectal pain, cancer, epilepsy, partial and general tonic seizures, restless leg syndrome, arrhythmias, fibromyalgia, neuroprotection under ischaemic conditions caused by stroke or neural trauma, tachy-arrhythmias, atrial fibrillation and ventricular fibrillation. 
     
     
         17 . A method of treating pain through inhibition of ion flux through a voltage-dependent sodium channel in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of  claim 1 , as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof. 
     
     
         18 . A method of decreasing ion flux through a voltage-dependent sodium channel in a cell in a mammal, wherein the method comprises contacting the cell with a compound of  claim 1 , as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof. 
     
     
         19 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of  claim 1 , as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof.