Therapeutic agents useful for treating pain

Abstract

A compound of formula: wherein Ar, Ar 1 , Ar 2 , R 3 , R 4 , R 5 , R 6 , R 13 , m, t, and x are disclosed herein, or a pharmaceutically acceptable salt thereof (a “Hydroxyiminopiperazine Compound”); compositions comprising an effective amount of a Hydroxyiminopiperazine Compound; and methods for treating or preventing pain and other conditions in an animal comprising administering to an animal in need thereof an effective amount of a Hydroxyiminopiperazine Compound are disclosed.

1 . A compound of formula (IV): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is -halo, —CH 3 , —NO 2 , —CN, —OH, —OCH 3 , —NH 2 , —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo); each R 2  is independently:
 (a) -halo, —CN, —OH, —NO 2 , —O(C 1 -C 6 )alkyl, or —NH 2 ; 
 (b) —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered) heterocycle, or -(7- to 10-membered) bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 7  groups; or 
 (c) -phenyl, -naphthyl, —(C 14 )aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 8  groups; 
 
 each R 3  is independently:
 (a) -halo, —CN, —OH, —NO 2 , —O(C 1 -C 6 )alkyl, or —NH 2 ; 
 (b) —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered) heterocycle, or -(7- to 10-membered) bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 7  groups; or 
 (c) -phenyl, -naphthyl, —(C 14 )aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 8  groups; 
 
 R 4  is —H, —(C 1 -C 10 )alkyl, —C(O)R 9 , or —C(O)NHR 9 ; 
 R 5  is —H or —(C 1 -C 10 )alkyl; 
 R 6  is:
 (a) —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered) heterocycle, or -(7- to 10-membered) bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 7  groups; or 
 (b) -phenyl, -naphthyl, —(C 14 )aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 8  groups; 
 
 each R 7  and R 8  is independently —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -(3- to 5-membered) heterocycle, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, —OH, -halo, —N 3 , —NO 2 , —N(R 10 ) 2 , —CH═NR 10 , —NR 10 OH, —OR 10 ; —C(O)R 10 , —C(O)OR 10 , —OC(O)R 10 , —OC(O)OR 10 , —SR 10 , —S(O)R 10 , or —S(O) 2 R 10 ; 
 each R 9  is —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -(3- to 5-membered) heterocycle, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —OH, —N(R 10 ) 2 , —CH═NR 10 , —NR 10 OH, —OR 10 , or —SR 10 ; 
 each R 10  is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -(3- to 5-membered) heterocycle, —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo); 
 each halo is independently —F, —Cl, —Br, or —I; 
 p is an integer ranging from 0 to 2; and 
 m is an integer ranging from 0 to 2. 
 
     
     
         2 . The compound of  claim 1 , wherein:
 m is 0; and   R 6  is phenyl.   
     
     
         3 . The compound of  claim 2 , wherein the R 6  phenyl is unsubstituted. 
     
     
         4 . The compound of  claim 2 , wherein the R 6  phenyl is substituted with an R 8  group at the para-position. 
     
     
         5 . The compound of  claim 4 , wherein the para R 8  group is a —(C 1 -C 6 )alkyl group, -halo, —CF 3 , or —OCF 3 . 
     
     
         6 . The compound of  claim 5 , wherein the para R 8 —(C 1 -C 6 )alkyl group is a tert-butyl group or an iso-propyl group. 
     
     
         7 . The compound of  claim 1 , wherein:
 m is 1;   R 3  is methyl; and   R 6  is phenyl.   
     
     
         8 . The compound of  claim 7 , wherein the R 6  phenyl is unsubstituted. 
     
     
         9 . The compound of  claim 7 , wherein the R 6  phenyl is substituted with an R 8  group at the para-position. 
     
     
         10 . The compound of  claim 9 , wherein the para R 8  group is a —(C 1 -C 6 )alkyl group, -halo, —CF 3 , or —OCF 3 . 
     
     
         11 . The compound of  claim 10 , wherein the para R 8 —(C 1 -C 6 )alkyl group is a tert-butyl group or an iso-propyl group. 
     
     
         12 . The compound of  claim 1 , wherein R 4  is —H. 
     
     
         13 . The compound of  claim 1 , wherein R 4  is —C(C 1 -C 10 )alkyl. 
     
     
         14 . The compound of  claim 1 , wherein R 4  is —C(O)R 9 . 
     
     
         15 . The compound of  claim 1 , wherein R 4  is —C(O)NHR 9 . 
     
     
         16 . The compound of  claim 1 , wherein m is 1 and R 3  is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(═N—OR 4 )—NR 5 R 6  group. 
     
     
         17 . The compound of  claim 16 , wherein the carbon atom to which R 3  is attached is in the (R) configuration. 
     
     
         18 . The compound of  claim 17 , wherein R 3  is —CH 3 , —CF 3 , or —CH 2 CH 3 . 
     
     
         19 . The compound of  claim 1 , wherein:
 R 1  is -halo, —CH 3  or —C(halo) 3 ;   p is 1; and   R 2  is —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered) heterocycle, or -(7- to 10-membered) bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 7  groups.   
     
     
         20 . The compound of  claim 19 , wherein R 2  is —(C 1 -C 10 )alkyl substituted with two independently selected R 7  groups. 
     
     
         21 . A compound of formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 Ar 1  is 
 
       
         
           
           
               
               
           
         
         Ar 2  is 
       
       
         
           
           
               
               
           
         
         R 1  is —H, -halo, —CH 3 , —NO 2 , —CN, —OH, —OCH 3 , —NH 2 , —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo); 
         each R 2  is independently:
 (a) -halo, —CN, —OH, —NO 2 , —O(C 1 -C 6 )alkyl, or —NH 2 ; 
 (b) —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered) heterocycle, or -(7- to 10-membered) bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 7  groups; or 
 (c) -phenyl, -naphthyl, —(C 14 )aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 8  groups; 
 
         each R 3  is independently:
 (a) -halo, —CN, —OH, —NO 2 , —O(C 1 -C 6 )alkyl, or —NH 2 ; 
 (b) —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered) heterocycle, or -(7- to 10-membered) bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 7  groups; or 
 (c) -phenyl, -naphthyl, —(C 14 )aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 8  groups; 
 
         R 4  is —H, —(C 1 -C 10 )alkyl, —C(O)R 9 , or —C(O)NHR 9 ; 
         R 5  is —H or —(C 1 -C 10 )alkyl; 
         each R 7  and R 8  is independently —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -(3- to 5-membered) heterocycle, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, —OH, -halo, —N 3 , —NO 2 , —N(R 10 ) 2 , —CH═NR 10 , —NR 10 OH, —OR 10 , —C(O)R 10 , —C(O)OR 10 , —OC(O)R 10 , —OC(O)OR 10 , —SR 10 , —S(O)R 10 , or —S(O) 2 R 10 ; 
         each R 9  is —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -(3- to 5-membered) heterocycle, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —OH, —N(R 10 ) 2 , —CH═NR 10 , —NR 10 OH, —OR 10 , or —SR 10 ; 
         each R 10  is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -(3- to 5-membered) heterocycle, —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo); 
         each R 11  and R 12  is independently —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, —OH, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —OC(O)OR 7 , —SR 7 , —S(O)R 7 , or —S(O) 2 R 7 ; 
         each R 13  is independently —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -(3- to 5-membered) heterocycle, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), or -halo; 
         each halo is independently —F, —Cl, —Br, or —I; 
         s is an integer ranging from 0 to 4; 
         o is an integer ranging from 0 to 4; 
         q is an integer ranging from 0 to 6; 
         r is an integer ranging from 0 to 5; 
         t is an integer ranging from 0 to 2; 
         p is an integer ranging from 0 to 2; 
         m is an integer ranging from 0 to 2; and 
         x is the integer 0 or 1. 
       
     
     
         22 . The compound of  claim 21 , wherein:
 R 1  is -halo, —CH 3  or —C(halo) 3 ;   p is 1;   R 2  is —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered) heterocycle, or -(7- to 10-membered) bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 7  groups; and   t is 0.   
     
     
         23 . The compound of  claim 22 , wherein R 2  is —(C 1 -C 10 )alkyl substituted with two independently selected R 7  groups. 
     
     
         24 . The compound of  claim 23 , wherein Ar 2  is unsubstituted phenyl. 
     
     
         25 . The compound of  claim 23 , wherein Ar 2  is phenyl substituted with an R 11  group at the para-position. 
     
     
         26 . The compound of  claim 25 , wherein the para R 11  group is a —(C 1 -C 6 )alkyl group, -halo, —CF 3 , or —OCF 3 . 
     
     
         27 . The compound of  claim 26 , wherein the para R 11 —(C 1 -C 6 )alkyl group is a tert-butyl group or an iso-propyl group. 
     
     
         28 . A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of  claim 1  and a pharmaceutically acceptable carrier or excipient. 
     
     
         29 . A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of  claim 21  and a pharmaceutically acceptable carrier or excipient. 
     
     
         30 . A method for inhibiting VR1 function in a cell, comprising contacting a cell capable of expressing VR1 with an effective amount of the compound or a pharmaceutically acceptable salt of the compound of  claim 1 . 
     
     
         31 . A method for inhibiting VR1 function in a cell, comprising contacting a cell capable of expressing VR1 with an effective amount of the compound or a pharmaceutically acceptable salt of the compound of  claim 21 . 
     
     
         32 . A method for treating pain, comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of  claim 1 . 
     
     
         33 . A method for treating pain, comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of  claim 21 .