Substituted benzamides and methods of use thereof

Abstract

and pharmaceutically acceptable salts thereof, wherein the variables RA, RAA, subscript n, ring A, X2, L, subscript m, X1, 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.

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 n 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 - 4 . (canceled) 
     
     
         5 . The compound of  claim 1 , wherein the compound has the formula Ib: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , wherein the compound has the formula Ic: 
       
         
           
           
               
               
           
         
       
     
     
         7 - 13 . (canceled) 
     
     
         14 . The compound of  claim 1 , wherein R 5  is C 3-5  cycloalkyl. 
     
     
         15 - 17 . (canceled) 
     
     
         18 . The compound of  claim 1 , wherein X 1  is —O—; the subscript m is 1 and -(L)- is —CH 2 — or —CH 2 —CH 2 —. 
     
     
         19 . The compound of  claim 1 , wherein X 1  is absent; X 2  is —O— or —N(H)—; the subscript m is 1; and -(L)- is selected from the group consisting of —C(H) 2 —, —C(═O)—, —C(H)(CH 3 )—, —CH 2 —CH 2 —, —CH 2 —C(H)(CH 3 )—, —C(H)(CH 3 )—C(H 2 )—, —CH 2 CH 2 CH 2 —, —CH 2 —C(H)(CH 3 )—CH 2 — or —CH 2 CH 2 CH 2 CH 2 —. 
     
     
         20 . The compound of  claim 1 , wherein X 1  and X 2  is absent; the subscript m is 1; and -(L)- is selected from the group consisting of —C(H) 2 —, —C(═O)—, —C(H)(CH 3 )—, —CH 2 —CH 2 —, —CH 2 —C(H)(CH 3 )—, —C(H)(CH 3 )—C(H 2 )—, —CH 2 CH 2 CH 2 —, —CH 2 —C(H)(CH 3 )—CH 2 — or —CH 2 CH 2 CH 2 CH 2 —. 
     
     
         21 - 22 . (canceled) 
     
     
         23 . The compound of  claim 1 , wherein: 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound of  claim 1 , wherein: 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         25 - 30 . (canceled) 
     
     
         31 . The compound of  claim 1 , wherein R A  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         32 - 36 . (canceled) 
     
     
         37 . The compound of  claim 1 , wherein the compound has the formula Id: 
       
         
           
           
               
               
           
         
       
     
     
         38 . The compound of  claim 37  wherein R 1  is methyl, ethyl, cyclopropyl, or 1-azetidinyl. 
     
     
         39 . The compound of  claim 37 , wherein —X 2 -(L) m -X 1 — is —O—, —CH 2 —, —CH 2 —O—, or —CH 2 CH 2 —O—. 
     
     
         40 . The compound of  claim 37 , wherein: 
       
         
           
           
               
               
           
         
       
     
     
         41 . The compound of  claim 37 , wherein: 
       
         
           
           
               
               
           
         
       
     
     
         42 . The compound of  claim 37 , wherein A is optionally substituted azetidine, pyrrolidine, piperidine, morpholine, homopiperazine, and piperazine. 
     
     
         43 - 44 . (canceled) 
     
     
         45 . The compound of  claim 1 , wherein: 
       
         
           
           
               
               
           
         
       
       has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         46 . The compound of  claim 41 , wherein 
       
         
           
           
               
               
           
         
       
     
     
         47 - 49 . (canceled) 
     
     
         50 . The compound of  claim 1  which is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and salts thereof. 
     
     
         51 . (canceled) 
     
     
         52 . A method of treating a disease or condition in a mammal selected from the group consisting of pain, depression, cardiovascular diseases, respiratory diseases, and psychiatric diseases, and combinations thereof, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of formula I as described in  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         53 - 64 . (canceled)