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 R A , R AA , subscript n, ring A, X 2 , L, subscript m, X 1 , R 1 , R 2 , R 3 , R 4 , R 5 , and R N have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.

1 . 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 C 2-7  heterocycle, 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 heterocyclic 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, F, Cl, Br, I, —CN, C 1-8  alkyl, C 1-8  haloalkyl, C 1-8  alkoxy, C 3-8  cycloalkyl and C 2-7  heterocycle, wherein said C 3-8  cycloalkyl and C 2-7  heterocycle 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; 
         the subscript m represents the integer 0 or 1; 
         X 1  and X 2  are each independently 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), and wherein if the subscript m is 0 then one of X 1  or X 2  is absent; 
         the subscript in is an integer from 0 to 5; 
         the ring A is a C 2-11  heterocycle comprising a nitrogen atom and further optionally comprising 1-2 heteroatoms selected from N, O and S; 
         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 —(X RB ) 0-1 OR A1 , C 6-10  aryl-(X RA )—, C 1-20  heteroaryl-(X RA )—, C 3-12  carbocycle-(X RA )—, —R A2 , —S(O) 2 —R A2 , and C 2-11  heterocycle-(X RA )—, wherein said C 6-10  aryl, C 5-9  heteroaryl, C 3-12  carbocycle and C 2-11  heterocycle of R A  is optionally substituted with from 1 to 5 substitutents selected from 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, C 1-4  dialkylamino, C 1-4  alkanoyl, C 1-4  alkyl-OC(═O)—, C 1-4  alkyl-S(O) 2 —, C 3-6 carbocycle, and phenyl that is optionally substituted with one or more substituents selected from fluoro, chloro, and bromo; 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 oxo (═O), fluoro, amino, C 1-4  alkylamino and C 1-4  dialkylamino; X RA  is selected from the group consisting of absent, —O—, —S—, —N(H)—, —N(C 1-4  alkyl)-, —S(O)—, —S(O) 2 —, —C(═O)—, C 1-4  alkylene, C 1-4  heteroalkylene, C 2-4  alkenylene and C 2-4  alkynylene; X RB  is selected from the group consisting of absent, C 1-4  alkylene, C 1-4  heteroalkylene, C 2-4  alkenylene and C 2-4  alkynylene; wherein any C 1-4  alkylene, C 1-4  heteroalkylene, C 2-4  alkenylene and C 2-4  alkynylene of X RA  or X RB  is optionally substituted with 1 to 3 substituents selected from the group consisting of C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  heteroalkyl, oxo (═O), hydroxy, and phenyl that is optionally substituted with 1 to 5 substitutents selected from 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; or wherein X RA  or X RB  is optionally substituted with 2 substituents that combine to form a 3 to 5 membered carbocycle or a 3-5 membered heterocycle; 
         provided the compound of formula I is not: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         2 - 64 . (canceled)