Pyrazole-amides and -sulfonamides

Abstract

Compounds, compositions and methods are provided which are useful in the treatment of diseases through the inhibition of sodium ion flux through voltage-dependent sodium channels. More particularly, the invention provides pyrazole-amides and -sulfonamides, compositions and methods that are useful in the treatment of central or peripheral nervous system disorders, particularly pain and chronic pain by blocking sodium channels associated with the onset or recurrance of the indicated conditions. The compounds, compositions and methods of the present invention are of particular use for treating neuropathic or inflammatory pain by the inhibition of ion flux through a channel that includes a PN3 subunit.

1 . A compound having the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
 R 1  and R 3  are each members independently selected from hydrogen, (C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 6 )heteroalkyl, amino, halo, cyano, nitro, hydroxy, aryl and heteroaryl;  
 R 2  is a member selected from hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 7 )cycloalkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, and heteroaryl(C 1 -C 4 )alkyl;  
 Y is a member selected from:  
                     
 wherein  
 X is a member selected from O, S and NR 8    
 wherein 
 R 8  is a member selected from the group of hydrogen, cyano, nitro, alkyl, acyl, aryl and SO 2 R 9    
 wherein 
 R 9  is a member selected from alkyl, aryl, heteroaryl and heterocycloalkyl;  
 
 R 4  and R 5  are each members independently selected from hydrogen, (C 1 -C 10 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 8 )heteroalkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, heteroaryl(C 1 -C 4 )alkyl and (C 3 -C 8 )heterocycloalkyl with the proviso that if R 4  is hydrogen, R 5  is not hydrogen; and R 4  and R 5  taken together with the nitrogen atom to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring;  
 R 6  is a member selected from hydrogen, (C 1 -C 6 )alkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, heteroaryl(C 1 -C 4 )alkyl and (C 1 -C 6 )heteroalkyl; and  
 R 7  is a member selected from (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 7 )alkenyl, (C 1 -C 6 )heteroalkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, heteroaryl(C 1 -C 4 )alkyl, amino, alkoxy, (C 3 -C 8 )heterocycloalkyl and amino(C 1 -C 5 )alkyl, and and R 6  and R 7  together with the atoms to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring.  
 
 
     
     
         2 . The compound of  claim 1  having the formula:  
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 2  wherein Y has a formula which is a member selected from:  
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 3  wherein 
 R 1  and R 3  are each members independently selected from hydrogen, (C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 4 )haloalkyl and (C 1 -C 5 )heteroalkyl; and    X is O.    
     
     
         5 . The compound of  claim 4  wherein R 2  is a member selected from aryl and heteroaryl.  
     
     
         6 . The compound of  claim 5  wherein R 3  is hydrogen.  
     
     
         7 . The compound according to  claim 6  wherein R 1  is a member selected from hydrogen, (C 1 -C 4 )alkyl, and (C 1 -C 4 )haloalkyl.  
     
     
         8 . The compound according to  claim 3  wherein R 4  is a member selected from heteroaryl and heterocycloalkyl; and 
 R 4  and R 5 , together with the nitrogen to which they are bonded are optionally joined to form a 4- to 8-membered heterocycloalkyl ring system.    
     
     
         9 . The compound according to  claim 8 , wherein R 4  and R 5  taken together with the nitrogen to which they are attached form a member selected from:  
       
         
           
           
               
               
           
         
       
     
     
         10 . A compound having the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
 R 1  and R 3  are each members independently selected from hydrogen, (C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 6 )heteroalkyl, amino, halo, cyano, nitro, hydroxy, aryl and heteroaryl;  
 R 2  is a member selected from hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 7 )cycloalkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, and heteroaryl(C 1 -C 4 )alkyl;  
 Y is a member selected from:  
                     
 wherein 
 X is a member selected from O, S and NR 8    
 wherein 
 R 8  is a member selected from hydrogen, cyano, nitro, alkyl, acyl, aryl and SO 2 R 9    
 wherein 
 R 9  is a member selected from alkyl, aryl, heteroaryl and heterocycloalkyl;  
 
 
 R 4  has a formula which is a member selected from:  
                     
 wherein 
 n is an integer from 0 to 4;  
 k is an integer from 1 to 3;  
 R 2a  and R 2b  are members independently selected from hydrogen and (C 1 -C 4 )alkyl, and R 2a  and R 2b  taken together with the carbon atom to which they are attached optionally form a 3- to 8-membered carbocyclic or heterocycloalkyl ring;  
 M is a member selected from NR 10 , O and S  
 wherein 
 R 10  is a member selected from hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 8 ) heteroalkyl aryl, heteroaryl and (C 3 -C 8 ) cycloalkyl;  
 
 A, B, D, E and G are independently members selected from N, N-oxide and CR 11  with the proviso that at most three of A, B, D, E and G is N; and at most one of A, B, D, E and G is N-oxide  
 wherein  
 R 11  is a member selected from hydrogen, halo, amino, hydroxy, cyano, nitro, (C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 7 )heteroalkyl, aryl, heteroaryl, (C 3 -C 8 )heterocycloalkyl, alkoxy, acyl, —C(NR 12 )R 13 , —SO 2 R 15 , —SO 2 NR 13 R 14 , —NR 12 SOR 15 , —NR 12 SO 2 NR 13 R 14 , —NR 12 C(N—CN)NR 13 R 14 , —NR 12 C(N—SO 2 R 15 )NR 13 R 14 , —NR 12 C(N—COR 15 )NR 13 R 14 , —CONR 13 R 14 , —NR 12 (C═CH—NO 2 )NR 13 R 14 , —NR 12 CONR 13 R 14 , —NR 12 CO—OR 15 , —OCONR 13 R 14  and R 11  and R 2a  taken together with the carbon atoms to which they are attached optionally form a 4- to 8-membered heterocycloalkyl group with the proviso that A is CR 11    
 wherein 
 R 11a  is a member selected from (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 8 )heterocycloalkyl, aryl and heteroaryl;  
 R 12 , R 13  and R 14  are members independently selected from hydrogen, (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 8 )heteroalkyl, aryl, heteroaryl, (C 3 -C 8 )heterocycloalkyl, aryl(C 1 -C 4 )alkyl, heteroaryl(C 1 -C 4 )alkyl, amino(C 1 -C 4 )alkyl and when R 13  and R 14  are attached to the same nitrogen atom, they are optionally combined to form a 5-, 6- or 7-membered ring;  
 R 15  is a member selected from (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 8 )heteroalkyl, aryl, heteroaryl and (C 3 -C 8 )heterocycloalkyl;  
 
 
 R 5  is a member selected from hydrogen and (C 1 -C 4 )alkyl; and R 5  and R 11  taken together with the atoms to which that are attached optionally form a 4- to 8-membered heterocycloalkyl ring with the proviso that A is CR 11    
 R 6  is a member selected from hydrogen, (C 1 -C 6 )alkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, heteroaryl(C 1 -C 4 )alkyl and (C 1 -C 6 )heteroalkyl; and  
 R 7  is a member selected from (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 7 )alkenyl, (C 1 -C 6 )heteroalkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, heteroaryl(C 1 -C 4 )alkyl, amino, alkoxy, (C 3 -C 8 )heterocycloalkyl and amino(C 1 -C 5 )alkyl, and R 6  and R 7  taken together with the atoms to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring.  
 
 
     
     
         11 . The compound of  claim 10  wherein R 1  and R 3  are each members independently selected from hydrogen, (C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 4 )haloalkyl and (C 1 -C 5 )heteroalkyl; and X is O.  
     
     
         12 . The compound of  claim 11  wherein R 2  is a member selected from aryl and heteroaryl.  
     
     
         13 . The compound of  claim 11  wherein one only of A, B, C, D or E is an N or N-oxide.  
     
     
         14 . A compound having the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
 R 1  and R 3  are each members independently selected from hydrogen, (C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 6 )heteroalkyl, amino, halo, cyano, nitro, hydroxy, aryl and heteroaryl;  
 R 2  is a member selected from hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 7 )cycloalkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, and heteroaryl(C 1 -C 4 )alkyl;  
 Y is a member selected from:  
                     R 4  has a formula which is a member selected from:                          
 wherein 
 W is a member selected from S, SO and SO 2 ;  
 n is an integer from 0 to 4;  
 R 2a  and R 2b  are members independently selected from hydrogen and (C 1 -C 4 )alkyl, and R 2a  and R 2b  taken together with the carbon atom to which they are attached optionally form a 3- to 8-membered carbocyclic or heterocycloalkyl ring;  
 R 15  is a member selected from (C 1 -C 4 )alkyl, (C 1 -C 6 )alkenyl, (C 3 -C 7 )cycloalkyl, aryl, heteroaryl, (C 1 -C 8 )heteroalkyl, NR 16 R 17    
 wherein 
 R 16  and R 17  are members independently selected from hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 7 )cycloalkyl, (C 1 -C 8 )heteroalkyl, (C 3 -C 8 )heterocycloalkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, heteroaryl(C 1 -C 4 )alkyl, amino(C 1 -C 4 )alkyl, with the proviso that when R 15  is amino W is SO 2 ;  
 
 T 1 , T 2 , T 3  and T 4  are each members independently selected from hydrogen, halo, amino, cyano, nitro, (C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 4 )haloalkyl, alkoxy, fluoro(C 1 -C 4 )alkoxy, (C 1 -C 7 )cycloalkyl, (C 1 -C 7 )heteroalkyl, aryl and heteroaryl, and T 1  and T 2  taken together with the carbon atoms to which they are attached optionally form a 4- to 8-membered carbocyclic or heterocycloalkyl ring; T 2  and T 3  taken together with the carbon atoms to which they are attached optionally form a 4- to 8-membered carbocyclic or heterocycloalkyl ring; T 3  and R 15  taken together with the atoms to which they are attached optionally form a 4- to 8-membered carbocyclic or heterocycloalkyl ring; and T 4  and R 15  taken together with the atoms to which they are attached optionally form a 4-to 8-membered carbocyclic or heterocycloalkyl ring; and  
 R 5  is a member selected from hydrogen and (C 1 -C 4 )alkyl; R 5  and T 1  taken together with the atoms to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring, and R 5  and T 4  taken together with the atoms to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring.  
 
 
     
     
         15 . The compound of  claim 14  wherein R 1  and R 3  are each members independently selected from hydrogen, (C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 4 )haloalkyl and (C 1 -C 5 )heteroalkyl; and X is O.  
     
     
         16 . The compound of  claim 14  wherein R 2  is a member selected from aryl and heteroaryl.  
     
     
         17 . The compound of  claim 15  wherein W is SO 2 ; and R 11  is selected from substituted or unsubstituted (C 1 -C 4 )alkyl and NR 16 R 17 ; and n is 0.  
     
     
         18 . A method of decreasing ion flow through voltage-dependent sodium channels in a cell, said method comprising contacting said cell with a sodium channel-inhibiting amount of a compound comprising a pyrazolyl moiety.  
     
     
         19 . The method according to  claim 18 , wherein said cell is in a human.  
     
     
         20 . A method of decreasing ion flow through voltage-dependent sodium channels in a cell, said method comprising contacting said cell with a sodium channel-inhibiting amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
 R 1  and R 3  are each members independently selected from hydrogen, (C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 6 )heteroalkyl, amino, halo, cyano, nitro, hydroxy, aryl and heteroaryl;  
 R 2  is a member selected from hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 7 )cycloalkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, and heteroaryl(C 1 -C 4 )alkyl;  
 Y is a member selected from:  
                     
 wherein  
 X is a member selected from O, S and NR 8    
 wherein 
 R 8  is a member selected from the group of hydrogen, cyano, nitro, alkyl, acyl, aryl and SO 2 R 9    
 wherein 
 R 9  is a member selected from alkyl, aryl, heteroaryl and heterocycloalkyl;  
 
 R 4  and R 5  are each members independently selected from hydrogen, (C 1 -C 10 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 8 )heteroalkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, heteroaryl(C 1 -C 4 )alkyl and (C 3 -C 8 )heterocycloalkyl with the proviso that if R 4  is hydrogen, R 5  is not hydrogen; and R 4  and R 5  taken together with the nitrogen atom to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring;  
 R 6  is a member selected from hydrogen, (C 1 -C 6 )alkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, heteroaryl(C 1 -C 4 )alkyl and (C 1 -C 6 )heteroalkyl; and  
 R 7  is a member selected from (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 7 )alkenyl, (C 1 -C 6 )heteroalkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, heteroaryl(C 1 -C 4 )alkyl, amino, alkoxy, (C 3 -C 8 )heterocycloalkyl and amino(C 1 -C 5 )alkyl, and and R 6  and R 7  together with the atoms to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring.  
 
 
     
     
         21 . A method of treating a central or peripheral nervous system disorder or condition through inhibition of a voltage-dependent sodium channel, said method comprising administering to a subject in need of such treatment, an effective amount of a compound comprising a pyrazolyl moiety.  
     
     
         22 . The method according to  claim 21 , said compound having the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
 R 1  and R 3  are each members independently selected from hydrogen, (C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 6 )heteroalkyl, amino, halo, cyano, nitro, hydroxy, aryl and heteroaryl;  
 R 2  is a member selected from hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 7 )cycloalkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, and heteroaryl(C 1 -C 4 )alkyl;  
 Y is a member selected from:  
                     
 wherein  
 X is a member selected from O, S and NR 8    
 wherein 
 R 8  is a member selected from the group of hydrogen, cyano, nitro, alkyl, acyl, aryl and SO 2 R 9    
 wherein 
 R 9  is a member selected from alkyl, aryl, heteroaryl and heterocycloalkyl;  
 
 R 4  and R 5  are each members independently selected from hydrogen, (C 1 -C 10 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 8 )heteroalkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, heteroaryl(C 1 -C 4 )alkyl and (C 3 -C 8 )heterocycloalkyl with the proviso that if R 4  is hydrogen, R 5  is not hydrogen; and R 4  and R 5  taken together with the nitrogen atom to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring;  
 R 6  is a member selected from hydrogen, (C 1 -C 6 )alkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, heteroaryl(C 1 -C 4 )alkyl and (C 1 -C 6 )heteroalkyl; and  
 R 7  is a member selected from (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 7 )alkenyl, (C 1 -C 6 )heteroalkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, heteroaryl(C 1 -C 4 )alkyl, amino, alkoxy, (C 3 -C 8 )heterocycloalkyl and amino(C 1 -C 5 )alkyl, and and R 6  and R 7  together with the atoms to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring.  
 
 
     
     
         23 . The method according to  claim 20 , wherein said disorder is pain selected from inflammatory pain, neuropathic pain and combinations thereof.  
     
     
         24 . A composition comprising a pharmaceutically acceptable excipient and a compound having the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
 R 1  and R 3  are each members independently selected from hydrogen, (C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 6 )heteroalkyl, amino, halo, cyano, nitro, hydroxy, aryl and heteroaryl;  
 R 2  is a member selected from hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 7 )cycloalkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, and heteroaryl(C 1 -C 4 )alkyl;  
 Y is a member selected from:  
                     
 wherein  
 X is a member selected from O, S and NR 8    
 wherein 
 R 8  is a member selected from the group of hydrogen, cyano, nitro, alkyl, acyl, aryl and SO 2 R 9    
 wherein 
 R 9  is a member selected from alkyl, aryl, heteroaryl and heterocycloalkyl;  
 
 R 4  and R 5  are each members independently selected from hydrogen, (C 1 -C 10 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 8 )heteroalkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, heteroaryl(C 1 -C 4 )alkyl and (C 3 -C 8 )heterocycloalkyl with the proviso that if R 4  is hydrogen, R 5  is not hydrogen; and R 4  and R 5  taken together with the nitrogen atom to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring;  
 R 6  is a member selected from hydrogen, (C 1 -C 6 )alkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, heteroaryl(C 1 -C 4 )alkyl and (C 1 -C 6 )heteroalkyl; and  
 R 7  is a member selected from (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 7 )alkenyl, (C 1 -C 6 )heteroalkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, heteroaryl(C 1 -C 4 )alkyl, amino, alkoxy, (C 3 -C 8 )heterocycloalkyl and amino(C 1 -C 5 )alkyl, and and R 6  and R 7  together with the atoms to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring.