Indole carboxamide derivatives and uses thereof

Abstract

A compound of Formula (1) is provided that has been shown to be useful for treating a disease, disorder or syndrome that is mediated by the transportation of essential molecules in the mmpL3 pathway: wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined herein.

1 . A compound of Formula (I) 
       
         
           
           
               
               
           
         
         wherein
 R 1  is H or methyl; 
 R 2  is H, methyl, halo, cyano, trifluoromethyl, or methoxy; 
 R 3  is H, methyl, or methoxy; 
 R 4  is H, methyl, halo, cyano, trifluoromethyl, methoxy, —(O(CH 2 ) m ) n -morpholinyl, piperidinyl, ((C 1 -C 4 )alkyl)NH—, or (phenyl)NH—, where m is 1 or 2 and n is 0 or 1; or 
 R 3  and R 4  taken together with the aromatic carbon atoms to which they are attached form a fused 1,3-dioxolo group; 
 R 5  is H or halo; 
 
         provided that R 2 , R 3 , R 4  and R 5  are not all hydrogen;
 R 6  is
 (i) (C 4 -C 6 )alkyl, where said (C 4 -C 6 )alkyl is optionally substituted with phenyl which is optionally substituted with one to two substituents each independently selected from (C 1 -C 4 )alkyl, fluoro-substituted (C 1 -C 4 )alkyl, methoxy, hydroxy(C 1 -C 4 )alkyl, methoxy(C 1 -C 4 )alkyl, ethynyl, cyano, halo, or hydroxy; 
 (ii) (C 5 -C 7 )cycloalkyl, or —CH 2 —(C 5 -C 7 )cycloalkyl, where said (C 5 -C 7 )cycloalkyls are optionally substituted with one to two substituents each independently selected from (C 1 -C 4 )alkyl, fluoro-substituted (C 1 -C 4 )alkyl, methoxy, hydroxy(C 1 -C 4 )alkyl, methoxy(C≡C 4 )alkyl, ethynyl, cyano, halo, or hydroxy, provided that R 6  is not an unsubstituted cyclohexyl, when R 2  and R 4  are both methyl; 
 (iii) spiral(C 8 -C 11 )cycloalkyl; or 
 (iv) phenyl, where said phenyl is optionally substituted with one to two substituents each independently selected from (C≡C 4 )alkyl, fluoro-substituted (C 1 -C 4 )alkyl, methoxy, hydroxy(C 1 -C 4 )alkyl, methoxy(C 1 -C 4 )alkyl, ethynyl, cyano, halo, or hydroxy, provided that R 6  is not an unsubstituted phenyl, when R 2  and R 4  are both methyl; 
 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound of  claim 1  wherein
 R 1  is H; 
 R 2  is H, methyl, trifluoromethyl, methoxy, chloro, bromo, fluoro, or cyano; 
 R 3  is H or methoxy; 
 R 4  is H, methyl, trifluoromethyl, methoxy, chloro, bromo, fluoro, cyano, —(O(CH 2 ) 2 )-morpholinyl, ((C 1 -C 4 )alkyl)NH—, or (phenyl)NH—; or 
 R 3  and R 4  taken together with the aromatic carbon atoms to which they are attached form a fused 1,3-dioxolo group; 
 R 5  is H or chloro; 
 provided that R 2 , R 3 , R 4  and R 5  are not all hydrogen; 
 R 6  is
 (i) C 5  alkyl; 
 (ii) (C 5 -C 7 )cycloalkyl, or —CH 2 -(cyclohexyl), where said (C 5 -C 7 )cycloalkyl is optionally substituted with one to two substituents each independently selected from halo, methyl, isopropyl, fluoro-substituted methyl, methoxy(C 1 -C 4 )alkyl, ethynyl, or cyano, provided that R 6  is not an unsubstituted cyclohexyl, when R 2  and R 4  are both methyl; 
 (iii) spiro[2.5]octan-6-yl; or 
 (iv) phenyl substituted with halo or methyl; 
 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         3 . The compound of  claim 1  wherein
 R 1  is H; 
 R 2  is H, methyl, trifluoromethyl, chloro, bromo, fluoro, or cyano; 
 R 3  is H; 
 R 4  is H, methyl, trifluoromethyl, chloro, bromo, fluoro, cyano, or (phenyl)NH—; 
 R 5  is H or chloro; 
 provided that R 2 , R 3 , R 4  and R 5  are not all hydrogen; 
 R 6  is (C 5 -C 7 )cycloalkyl or —CH 2 -(cyclohexyl), where said (C 5 -C 7 )cycloalkyl is optionally substituted with one to two substituents each independently selected from halo, methyl, isopropyl, fluoro-substituted methyl, or ethynyl, provided that R 6  is not an unsubstituted cyclohexyl, when R 2  and R 4  are both methyl; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         4 . The compound of  claim 1  selected from the group consisting of
 N-cycloheptyl-4,6-dimethyl-1H-indole-2-carboxamide; 
 4-bromo-N-cycloheptyl-6-(trifluoromethyl)-1H-indole-2-carboxamide; 
 4,6-dimethyl-N-(2-methylcyclohexyl)-1H-indole-2-carboxamide; 
 N-(cyclohexylmethyl)-4,6-dimethyl-1H-indole-2-carboxamide; 
 4,6-dimethyl-N-((1R,2S)-2-methylcyclohexyl)-1H-indole-2-carboxamide; 
 4,6-dimethyl-N-((1S,2R)-2-methylcyclohexyl)-1H-indole-2-carboxamide; 
 N-((1R,2S,3S)-2,3-dimethylcyclohexyl)-4,6-dimethyl-1H-indole-2-carboxamide; 
 N-((1R,2S,3R)-2,3-dimethylcyclohexyl)-4,6-dimethyl-1H-indole-2-carboxamide; 
 N-(trans-4-isopropylcyclohexyl)-4,6-dimethyl-1H-indole-2-carboxamide; 
 N-((1S,2R,3S)-2,3-dimethylcyclohexyl)-4,6-dimethyl-1H-indole-2-carboxamide; 4,6-difluoro-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide; 
 4,6-dichloro-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide; 
 N-(4-methylcyclohexyl)-4,6-bis(trifluoromethyl)-1H-indole-2-carboxamide; 
 N-((1S,2R,3R)-2,3-dimethylcyclohexyl)-4,6-dimethyl-1H-indole-2-carboxamide; 
 4,6-dichloro-N-((1R,2S)-2-methylcyclohexyl)-1H-indole-2-carboxamide; 
 4,6-dimethyl-N-((1R,2S)-2-methylcyclopentyl)-1H-indole-2-carboxamide; 
 4,6-dimethyl-N-(2-(trifluoromethyl)cyclohexyl)-1H-indole-2-carboxamide; 
 N-(4-isopropylcyclohexyl)-4,6-dimethyl-1H-indole-2-carboxamide; 
 N-(2-isopropylcyclohexyl)-4,6-dimethyl-1H-indole-2-carboxamide; 
 4,6-dichloro-N-(4,4-difluorocyclohexyl)-1H-indole-2-carboxamide; 
 4,6-dichloro-N-(cis-4-methylcyclohexyl)-1H-indole-2-carboxamide; 
 4,6-dichloro-N-(trans-4-methylcyclohexyl)-1H-indole-2-carboxamide; 
 4,6-dichloro-N-(4,4-dimethylcyclohexyl)-1H-indole-2-carboxamide; 
 4,6-dichloro-N-(4-(trifluoromethyl)cyclohexyl)-1H-indole-2-carboxamide; 
 N-(4,4-Dimethylcyclohexyl)-4,6-difluoro-1H-indole-2-carboxamide; 
 4,6-dichloro-N-(4-(fluoromethyl)cyclohexyl)-1H-indole-2-carboxamide; 
 4,6-dichloro-N-(1-ethynylcyclohexyl)-1H-indole-2-carboxamide; 
 6-chloro-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide; 
 6,7-dichloro-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide; 
 7-chloro-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide; 
 4-chloro-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide; 
 6-methyl-N-((1R,2S)-2-methylcyclohexyl)-1H-indole-2-carboxamide; 
 4-methyl-N-((1R,2S)-2-methylcyclohexyl)-1H-indole-2-carboxamide; 
 4-bromo-N-((1R,2S)-2-methylcyclohexyl)-1H-indole-2-carboxamide; 
 6-bromo-N-((1R,2S)-2-methylcyclohexyl)-1H-indole-2-carboxamide; 
 4-cyano-N-((1R,2S)-2-methylcyclohexyl)-1H-indole-2-carboxamide; 
 6-cyano-N-((1R,2S)-2-methylcyclohexyl)-1H-indole-2-carboxamide; 
 6-bromo-4-methyl-N-((1R,2S)-2-methylcyclohexyl)-1H-indole-2-carboxamide; 
 4-bromo-6-methyl-N-((1R,2S)-2-methylcyclohexyl)-1H-indole-2-carboxamide; 
 6-cyano-4-methyl-N-((1R,2S)-2-methylcyclohexyl)-1H-indole-2-carboxamide; 
 4-cyano-6-methyl-N-((1R,2S)-2-methylcyclohexyl)-1H-indole-2-carboxamide; 
 4-methyl-N-((1R,2S)-2-methylcyclohexyl)-6-(phenylamino)-1H-indole-2-carboxamide; 
 6-chloro-4-fluoro-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide; 
 4-chloro-6-fluoro-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide; 
 4,6-dicyano-N-(trans-4-methylcyclohexyl)-1H-indole-2-carboxamide; 
 4,6-difluoro-N-(trans-4-methylcyclohexyl)-1H-indole-2-carboxamide; 
 5,6-dichloro-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide; 
 4,6-dicyano-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide; and 
 4,6-dichloro-N-(1-ethynylcyclohexyl)-1H-indole-2-carboxamide; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         5 . The compound of  claim 1  selected from the group consisting of
 4,6-difluoro-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide; 
 4,6-dichloro-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide; 
 N-(4-methylcyclohexyl)-4,6-bis(trifluoromethyl)-1H-indole-2-carboxamide; 
 4,6-dichloro-N-((1R,2S)-2-methylcyclohexyl)-1H-indole-2-carboxamide; 
 4-bromo-N-cycloheptyl-6-(trifluoromethyl)-1H-indole-2-carboxamide; 
 5,6-dichloro-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide; 
 4,6-dichloro-N-(cis-4-methylcyclohexyl)-1H-indole-2-carboxamide; 
 4,6-dichloro-N-(trans-4-methylcyclohexyl)-1H-indole-2-carboxamide; 
 4,6-dicyano-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide; 
 4,6-Dichloro-N-(4,4-dimethylcyclohexyl)-1H-indole-2-carboxamide; 
 6-chloro-4-fluoro-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide; 
 4-chloro-6-fluoro-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide; 
 4,6-dichloro-N-(4-(trifluoromethyl)cyclohexyl)-1H-indole-2-carboxamide; 
 N-(4,4-Dimethylcyclohexyl)-4,6-difluoro-1H-indole-2-carboxamide; 
 4,6-dichloro-N-(4-(fluoromethyl)cyclohexyl)-1H-indole-2-carboxamide; and 4,6-difluoro-N-(trans-4-methylcyclohexyl)-1H-indole-2-carboxamide; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The compound of  claim 1  selected from the group consisting of
 4,6-Dichloro-N-(4,4-dimethylcyclohexyl)-1H-indole-2-carboxamide; and 
 N-(4,4-Dimethylcyclohexyl)-4,6-difluoro-1H-indole-2-carboxamide; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The compound of  claim 1  having the following structure 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 1  having the following structure 
       
         
           
           
               
               
           
         
       
     
     
         9 . A pharmaceutical composition comprising a compound of Formula (I) of  claim 1  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 
     
     
         10 . The pharmaceutical composition of  claim 9  further comprising at least one additional pharmaceutical agent. 
     
     
         11 . The pharmaceutical composition of  claim 10  wherein said at least one additional pharmaceutical agent is an antituberculosis agent. 
     
     
         12 . The pharmaceutical composition of  claim 11  wherein said antituberculosis agent is selected from the group consisting of isoniazid, rifampicin, pyrazinamide, ethambutol, streptomycin, kanarnvcin, amikacin, capreomycin, ofloxacin, levofloxacin, moxifloxacin, cycloserine, para-aninosalicylic acid, ethioamide, prothionamide, thioacetazone clofazimine, amoxicilin with clavulanate, imipenem, linezolid, clarithromycin, and thioridazine. 
     
     
         13 . A method for treating a disease, disorder or syndrome mediated by the transportation of essential molecules in the mmpL3 pathway comprising the step of administering to a patient in need thereof a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         14 .- 17 . (canceled) 
     
     
         18 . A method of treating tuberculosis comprising the step of administering to a patient in need thereof a pharmaceutical composition of  claim 10 . 
     
     
         19 .- 24 . (canceled) 
     
     
         25 . A method for treating a disease, disorder or syndrome mediated by the transportation of essential molecules in the mmpL3 pathway comprising the step of administering to a patient in need thereof
 (i) a first composition comprising any one of the compounds according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient; and   (ii) a second composition comprising at least one additional pharmaceutical agent and a pharmaceutically acceptable carrier or excipient.   
     
     
         26 .- 31 . (canceled)