N-substituted benzamides and methods of use thereof

Abstract

The invention provides novel compounds having the general formula: and pharmaceutically acceptable salts thereof, wherein the variables R A , subscript n, ring A, X 2 , L, subscript m, X 1 , B, 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 selected from a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof, wherein in Formula I:
 R 1  is C 1-8  alkyl, C 1-8  haloalkyl, C 1-8  alkoxy, C 3-12  cycloalkyl, C-linked C 2-11  heterocycloalkyl, heteroaryl, 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, (6-10 membered aryl)-(X R1 ) 0-1 —, (5-10 membered heteroaryl)-(X R1 ) 0-1 —, and wherein R 1A  and R 1B  are optionally combined to form a 3 to 9 membered heterocyclic ring optionally comprising 1 additional heteroatom selected from N, O and S and optionally fused thereto is a benzene or pyridine ring; X R1  is selected from the group consisting of C 1-4  alkylene, C 1-4  heteroalkylene, C 2-4  alkenylene, C 2-4  alkynylene; and wherein the aliphatic and aromatic portions of R 1  are optionally substituted with from 1 to 5 R R1  substituents selected from the group consisting of C 1-8  alkyl, C 1-8  haloalkyl, F, Cl, Br, I, —OH, —CN, —NO 2 , ═O, —(X 1R ) 0-1 NR R1a R R1b , —(X 1R ) 0-1 OR R1a , —(X 1R ) 0-1 SR R1a , —(X 1R ) 0-1 N(R R1a )C(═O)OR R1c , —(X 1R ) 0-1 OC(═O)N(R R1a )(R R1b ), —(X 1R ) 0-1 N(R R1a )C(═O)N(R R1a )(R R1b ), —(X 1 R) 0-1 C(═O)N(R R1a )(R Rb ), —(X 1R ) 0-1 N(R R1a )C(═)R R1b , —(X 1R ) 0-1 C(═O)OR R1a , —(X 1R ) 0-1 OC(═O)R R1a , —(X 1R ) 0-1 —P(═O)(OR R1a )(OR R1b ), —(X 1R ) 0-1 S(O) 1-2 R R1c , —(X 1R ) 0-1 S(O) 1-2 N(R R1a )(R R1b ), —(X 1R ) 0-1 N(R R1a )S(O) 1-2 N(R R1a )(R R1b ) and —(X 1R ) 0-1 N(R R1a )S(O) 1-2 (R R1c ), wherein X 1R  is selected from the group consisting of C 1-4  alkylene, C 1-4  heteroalkylene, C 2-4  alkenylene and C 2-4  alkynylene; wherein R R1a  and R Rib  are independently selected from the group consisting of hydrogen, C 1-8  alkyl, C 1-8  haloalkyl, C 3-8  cycloalkyl, phenyl, benzyl, heteroaryl, and C 2-7  heterocycloalkyl; R R1c  is selected from the group consisting of C 1-8  alkyl, C 1-8  haloalkyl, C 3-8  cycloalkyl, phenyl, benzyl, heteroaryl, and C 2-7  heterocycloalkyl; 
 R N  is hydrogen, C 1-4  alkyl or C 1-4  haloalkyl; 
 B is C or N; 
 R 2 , R 3  and R 4  are each independently 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, and R 3  is absent when B is nitrogen; 
 R 5  is selected from the group consisting of H, F, Cl, Br, I, —CN, C 1-8  alkyl, C 2-8  alkenyl, C 1-8  haloalkyl, C 1-8  alkoxy, C 3-8  cycloalkyl, C 2-7  heterocycloalkyl, phenyl and 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O and S, wherein said 5-6 membered heteroaryl, C 1-8  alkyl, C 3-8  cycloalkyl or C 2-7  heterocycloalkyl is further optionally substituted with from 1 to 3 R 5a  substituents selected from F, Cl, Br, I, —OH, ═O, C 3-6  cycloalkyl, —CN, C 1-4  alkyl, —C 1-4  alkyl-O—C 1-4  alkyl, C 1-4  haloalkyl and C 1-4  alkoxy; 
 L is a linker selected from the group consisting of C 1-4  alkylene, C 2-4  alkenylene, C 2-4  alkynylene, and C 1-4  heteroalkylene, wherein L is optionally substituted with from 1 to 3 R L  substituents selected from the group consisting of ═O, —OH, —OCH2.phenyl, C 1-4  alkyl, C 1-4  haloalkyl and C 1-4  acyl; 
 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  acyl or —S(O) 2 (C 1-8  alkyl), and wherein if the subscript m is 0 then at least one of X 1  or X 2  is absent; 
 the subscript n is an integer from 0 to 5; 
 A is selected from the group consisting of hydrogen, C 3-12  cycloalkyl, C 2-11  heterocycloalkyl, phenyl having a 3-8 membered carbocyclic or heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O and S fused thereto or a 5 to 6 membered heteroaryl having a 3-8 membered carbocyclic or heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O and S fused thereto, and wherein if A is hydrogen then the subscript n is 0; and 
 R A  is selected from the group consisting of C 1-8  alkyl, C 3-8  cycloalkyl, C 1-8  haloalkyl, F, Cl, Br, I, —OH, —CN, —NO 2 , ═O, heteroaryl, —(X RA ) 0-1 NR A1 R A2 , —(X RA ) 0-1 OR A1 , —(X RA ) 0-1 SR A1 , —(X RA ) 0-1 N(R A1 )C(═O)OR A3 , —(X RA ) 0-1 OC(═O)N(R A1 )(R A2 ), —(X RA ) 0-1 N(R A1 )C(═O)N(R A1 )(R A2 ), —(X RA ) 0-1 C(═O)N(R A1 )(R A2 ), —(X RA ) 0-1 N(R A1 )C(═O)R A2 , —(X RA ) 0-1 C(═O)OR A1 , —(X RA ) 0-1 OC(═O)R A1 , —P(═O)(OR A1 )(OR A2 ), —(X RA ) 0-1 S(O) 1-2 R A3 , —(X RA ) 0-1 S(O) 1-2 N(R A1 )(R A2 ), —(X RA ) 0-1 N(R A1 )S(O) 1-2 N(R A1 )(R A2 ) and —(X RA ) 0-1 N(R A1 )S(O) 1-2 (R A3 ), wherein X RA  is selected from the group consisting of C 1-4  alkylene, C 1-4  heteroalkylene, C 2-4  alkenylene and C 2-4  alkynylene; wherein R A1  and R A2  are independently selected from the group consisting of hydrogen, C 1-8  alkyl, C 2-8  alkenyl, C 1-8  haloalkyl, C 3-8  cycloalkyl, tetrahydronapthalene, phenyl, benzyl, heteroaryl, and C 2-7  heterocycloalkyl; R A3  is selected from the group consisting of C 1-8  alkyl, C 1-8  haloalkyl, C 3-8  cycloalkyl, tetrahydronapthalene, phenyl, benzyl, heteroaryl, and C 2-7  heterocycloalkyl; wherein if A is a monocyclic C 3-12  carbocycloalkyl or monocyclic C 2-11  heterocycloalkyl, then any two R A  substituents attached to adjacent atoms on the A ring are optionally combined to form a benzene or a 5 to 6 membered heteroaryl ring; and wherein the aliphatic and aromatic portions of a R A  substitutent is optionally substituted with from 1 to 5 R R1  substitutents selected from, F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , ═O, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy, C 1-4 (halo)alkyl-C(═O)—, C 1-4  (halo)alkyl-S(O) 0-2 —, C 1-4 (halo)alkyl-C(═O)N(H)—, C 1-4  (halo)alkyl-N(H)—C(═O)—, ((halo)alkyl) 2 N—C(═O)—, C 1-4 (halo)alkyl-OC(═O)N(H)—, C 1-4 (halo)alkyl-OC(═O)N(H)—, (halo)alkyl-N(H)—C(═O)O—, ((halo)alkyl) 2 N—C(═O)O—, C 1-4  alkylamino, C 1-4  dialkylamino, C 3-6  cycloalkyl, C 3-6  cycloalkoxy, C 2-5  heterocycloalkoxy, tetrahydronaphthalene and phenyl wherein phenyl is optionally substituted with 1-3 fluoro, chloro, bromo, CN, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 1-6  alkoxy, C 1-6  alkylamino, or C 1-6 dialkylamino; 
 with the proviso that a compound of Formula I is not 4-(cyclohexylmethoxy)-N-(methylsulfonyl)benzamide; 4-(cyclopentylmethoxy)-N-(methylsulfonyl)benzamide or 4-(cyclobutylmethoxy)-2,5-difluoro-N-(methylsulfonyl)benzamide. 
 
     
     
         2 . The compound of  claim 1  wherein the compound has the formula 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1  wherein B is N and R 3  is absent. 
     
     
         4 . The compound of  claim 1  wherein B is C. 
     
     
         5 . The compound of  claim 1  wherein R 2 , R 3  and R 4  are each independently selected from H, F, or Cl. 
     
     
         6 . The compound of  claim 1  wherein R 2  is H, F or Cl; R 3  and R 4  are each H; and R 5  is an optionally substituted group selected from the group consisting of H, F, Cl, Br, I, —CN, C 1-8  alkyl, C 1-8  haloalkyl, C 3-8  cycloalkyl, and C 1-8  alkoxy. 
     
     
         7 . The compound of  claim 1  wherein R 1  is C 1-8  alkyl, C 1-8  haloalkyl, C 3-10  cycloalkyl or —NR 1A R 1 . 
     
     
         8 . The compound of  claim 7 , wherein R 1  is selected from the group consisting of methyl, ethyl, propyl, trifluoromethyl, difluoromethyl, monofluoromethyl, isopropyl and cyclopropyl. 
     
     
         9 . The compound of  claim 1  wherein, R 1  is selected from the group consisting of: —NH(CH 3 ), —N(CH 3 ) 2 , 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 1  wherein R 1  is selected from the group consisting of: methyl, ethyl, tert-butyl, dimethylamino, methylamino, amino, morpholino, azetidino, imidazolyl, 3-hydroxyazetidino, 3-fluoroazetidino, cyclopropyl, pyrrolidinyl, 3,3-difluoroazetidino, tert-butyl, ethyl, 2-methoxyethyl, 3-methoxyazetidino, 2-hydroxyethyl, 3-hydroxypyrrolidinyl, N-methylimidazolyl, tetrahydorofuranyl, 2-isopropoxyethyl, 3-cyanoazetidino, 2-ethoxyethyl, 2-methoxypropyl, 2-hydroxypropyl, 4-hydroxypiperidinyl and 3-methoxypyrrolidinyl and the following formulas: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1  wherein R 1  is selected from the group consisting of: methyl, ethyl, tert-butyl, dimethylamino, methylamino, amino, morpholino, azetidino, imidazolyl, 3-hydroxyazetidino, 3-fluoroazetidino, cyclopropyl, pyrrolidinyl, 3,3-difluoroazetidino, tert-butyl, ethyl, 2-methoxyethyl, 3-methoxyazetidino, 2-hydroxyethyl, 3-hydroxypyrrolidinyl, and N-methylimidazolyl. 
     
     
         12 . The compound of  claim 1  wherein X 1  is —O— or —N(H)—; X 2  is absent; the subscript m is 1; and -(L)- is an optionally substituted group selected from the group consisting of C 1-4  alkylene, C 2-4  alkenylene or C 2-4  alkynylene. 
     
     
         13 . The compound of  claim 1 , wherein X 1  is —O— or —N(H)—; X 2  is absent; the subscript m is 1; and -(L)- is selected from the group consisting of —CH 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 —. 
     
     
         14 . The compound of  claim 13 , wherein X 1  is —O—; the subscript m is 1 and -(L)-is —CH 2 — or —CH 2 —CH 2 —. 
     
     
         15 . 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 —. 
     
     
         16 . The compound of  claim 1  wherein X 1  and X 2  are 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 —. 
     
     
         17 . The compound of  claim 1  wherein X 1  and X 2  are absent; the subscript m is 1; and -(L)- is an optionally substituted C 1-4  heteroalkylene. 
     
     
         18 . The compound of  claim 1  wherein m is 0; X 1  is selected from —O—, and —N(H)—; and X 2  is absent. 
     
     
         19 . The compound of  claim 1  wherein A is an optionally substituted ring selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, adamantane, bicyclo[2.1.1]hexane, bicyclo[2.2.2]octane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[4.1.1]octane, bicyclo[3.3.1]nonane and 1,2,3,4-tetrahydro-1,4-methanonaphthalene, 1,2,3,4-tetrahydroisoquinoline and chroman. 
     
     
         20 . The compound of  claim 1  wherein ring A is an optionally substituted ring selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, adamantane, cubane, bicyclo[2.2.2]octane, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, piperidinyl, tetrahydrofuranyl, tetrahydronaphthyl, spiro[2,5]octanyl, norpinanyl, spiro[3.5]nonanyl, 8-azabicyclo[3.2.1]octanyl, norbornanyl, spiro[4.5]decanyl, bicyclo[4.1.0]heptane and spiro[5.5]undecanyl. 
     
     
         21 - 34 . (canceled)