Substituted benzamides and methods of use thereof

Abstract

The invention provides compounds having the general formula (I):and pharmaceutically acceptable salts thereof, wherein the variables RA, RAA, n, ring A, X2, L, m, R1, R2, R3, R4, R5, and RN have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.

We claim: 
     
         1 . A method of treating pain in a mammal comprising, administering to the mammal in need thereof a therapeutically effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is C 1-8  alkyl, C 2-8  alkenyl, C 1-8  haloalkyl, C 1-8  alkoxy, C 3-8  carbocycle, C-linked 3-15 membered heterocyclyl, or —NR 1A R 1B , wherein R 1A  and R 1B  are each independently selected from the group consisting of hydrogen, C 1-8  alkyl, C 1-8  alkoxy, and wherein R 1A  and R 1B  are optionally combined to form a 3 to 8 membered heterocyclyl ring optionally comprising 1 additional heteroatom selected from N, O and S; and wherein R 1  is optionally substituted with from 1 to 5 substituents selected from the group consisting of C 1-4  alkyl, C 1-4  haloalkyl, F, Cl, Br, I, —OH, —CN, —NO 2 , —NR R1a R R1b , —OR R1a , —SR R1a , —Si(R R1a ) 3  and C 3-6  carbocycle; wherein R R1a  and R R1b  are independently selected from the group consisting of hydrogen, C 1-8  alkyl, C 1-8  haloalkyl; 
         R N  is hydrogen, C 1-4  alkyl or C 1-4  haloalkyl; 
         R 2  is selected from the group consisting of H, F, Cl, Br, I, —CN, C 1-8  alkyl, C 1-8  haloalkyl and C 1-8  alkoxy; 
         R 3  is selected from the group consisting of H, F, Cl, Br, I, —CN, C 1-8  alkyl, C 1-8  haloalkyl and C 1-8  alkoxy; 
         R 4  is selected from the group consisting of H, F, Cl, Br, I, —CN, C 1-8  alkyl, C 1-8  haloalkyl and C 1-8  alkoxy; 
         R 5  is selected from the group consisting of H, C 1-8  alkyl, C 1-8  haloalkyl, C 1-8  alkoxy, and C 3-8  cycloalkyl, wherein said C 1-8  alkoxy, and C 3-8  cycloalkyl is optionally substituted with 1-3 substituents selected from F, Cl, Br and I; 
         L is a linker selected from the group consisting of C 1-4  alkylene, C 2-4  alkenylene, and C 2-4  alkynylene, wherein L is optionally substituted with from 1 to 3 substituents selected from the group consisting of ═O, C 1-4  alkyl, halo, and C 1-4  haloalkyl; 
         m is 0 or 1; 
         X 2  is selected from the group consisting of absent, —O—, —S(O)—, —S(O) 2 — and —N(R X )— wherein R x  is H, C 1-8  alkyl, C 1-8  alkanoyl, or —S(O) 2 (C 1-8  alkyl); 
         n is 0, 1, 2, 3, 4, or 5; 
         the ring A is a 3-15 membered carbocyclyl, a 6-12 membered aryl, a 5-12 membered heteroaryl, or a 3-15 membered heterocyclyl; 
         each R AA  is independently selected from the group consisting of C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, CN, F, Cl, Br and I; and 
         R A  is selected from the group consisting of H, —OR A1 , —(X RA )-(6-12 membered aryl), —(X RA )-(5-12 membered heteroaryl), and —R A2 , wherein said 6-12 membered aryl and 5-12 membered heteroaryl of R A  is optionally substituted with from 1 to 5 substituents independently selected from the group consisting of F, Cl, Br, I, C 1-4  alkyl, C 1-4  haloalkyl, and C 1-4 (halo)alkoxy; R A1  is selected from the group consisting of hydrogen, C 1-8  alkyl, C 2-8  alkenyl, C 1-8  haloalkyl, C 3-8  cycloalkyl, phenyl and benzyl; R A2  is selected from the group consisting of C 1-8  alkyl that is optionally substituted with one or more substituents selected from the group consisting of oxo (═O), fluoro, amino, C 1-4  alkylamino and di(C 1-4 alkyl)amino; X RA  is selected from the group consisting of absent, —C(═O)—, and C 1-4  alkylene; wherein any C 1-4  alkylene, of X RA  is optionally substituted with 1 to 3 substituents selected from the group consisting of C 1-4  alkyl, C 1-4  haloalkyl, and phenyl that is optionally substituted with 1 to 5 substituents selected from the group consisting of, F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy, C 1-4 (halo)alkoxy, C 1-4  alkylamino and C 1-4  dialkylamino. 
       
     
     
         2 . The method of  claim 1 , wherein the compound of formula (I) has the formula (Ia): 
       
         
           
           
               
               
           
         
       
     
     
         3 . The method of  claim 1 , wherein the compound of formula (I) has the formula (Ib): 
       
         
           
           
               
               
           
         
       
     
     
         4 . The method of  claim 1 , wherein R 2  is H. 
     
     
         5 . The method of  claim 1 , wherein R 3  is halo. 
     
     
         6 . The method of  claim 1 , wherein R 3  is F. 
     
     
         7 . The method of  claim 1 , wherein R 4  is H. 
     
     
         8 . The method of  claim 1 , wherein R 5  is C 1-4  alkyl or C 1-4  haloalkyl. 
     
     
         9 . The method of  claim 1 , wherein R 5  is methyl. 
     
     
         10 . The method of  claim 1 , wherein the compound of formula (I) has the formula (Ic): 
       
         
           
           
               
               
           
         
       
     
     
         11 . The method of  claim 1 , wherein the compound of formula (I) has the formula (Id): 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 1 , wherein the compound of formula (I) has the formula (Ie): 
       
         
           
           
               
               
           
         
       
     
     
         13 . The method of  claim 1 , wherein R is methyl, cyclopropyl, or 1-azetidinyl. 
     
     
         14 . The method of  claim 1 , wherein A is an optionally substituted piperidine, optionally substituted pyrrolidine, optionally substituted azetidine, optionally substituted tetrahydronaphthlene, optionally substituted cyclohexane, optionally substituted tetrahydropyran, optionally substituted adamantly, or optionally substituted pyridine ring. 
     
     
         15 . The method of  claim 1 , wherein: 
       
         
           
           
               
               
           
         
         is: 
       
       
         
           
           
               
               
           
         
         and A is a 3-15 membered heterocyclyl. 
       
     
     
         16 . The method of  claim 1 , wherein: 
       
         
           
           
               
               
           
         
         is: 
       
       
         
           
           
               
               
           
         
         and A is a 3-15 membered heterocyclyl. 
       
     
     
         17 . The method of  claim 1 , wherein each R A A is independently selected from the group consisting of F, Cl and C 1-4  haloalkyl. 
     
     
         18 . The method of  claim 1 , wherein: 
       
         
           
           
               
               
           
         
         is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         19 . The method of  claim 1 , wherein R A  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         20 . The method of  claim 1 , wherein the compound of formula (I) is selected from the group consisting of: