Indole carboxamide derivatives and uses thereof

Abstract

A compound of Formula (I) 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 - 21 . (canceled) 
     
     
         22 . A method of treating tuberculosis comprising the step of administering to a human in need thereof a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, and at least one additional pharmaceutical agent, wherein said human has (i) a sputum smear-positive, sputum smear-negative, or extrapulmonary tuberculosis; (ii) tuberculosis caused by drug resistant  Mycobacterium tuberculosis  complex ( M. tuberculosis ) organisms; or (iii) tuberculosis combined with human immunodeficiency virus (HIV) infection, and wherein the compound of Formula I is: 
       
         
           
           
               
               
           
         
         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, trifluoromethoxy, 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 1 -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 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, provided that R 6  is not an unsubstituted phenyl, when R 2  and R 4  are both methyl. 
 
 
       
     
     
         23 . A compound for use in therapy, wherein the compound is 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 1 -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 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, provided that R 6  is not an unsubstituted phenyl, when R 2  and R 4  are both methyl: 
 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         24 . The compound of  claim 23  wherein said therapy is for the treatment of a disease, disorder, or syndrome mediated by the transportation of essential molecules in the mmpL3 pathway. 
     
     
         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 a compound, 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;
 wherein the compound is 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 1 -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 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, provided that R 6  is not an unsubstituted phenyl, when R 2  and R 4  are both methyl. 
 
       
     
     
         26 . The method of  claim 25  wherein said patient is human. 
     
     
         27 . The method of  claim 26  wherein said disease, disorder or syndrome is tuberculosis. 
     
     
         28 . The method of  claim 27  wherein said essential molecules is trehalose monomycolate. 
     
     
         29 . The method of  claim 26  wherein said human has (i) a sputum smear-positive, sputum smear-negative, or extrapulmonary tuberculosis; (ii) tuberculosis caused by drug resistant  Mycobacterium tuberculosis  complex ( M. tuberculosis ) organisms; or (iii) tuberculosis combined with human immunodeficiency virus (HIV) infection. 
     
     
         30 . The method of  claim 25 , wherein said first and second compositions are administered simultaneously. 
     
     
         31 . The method of  claim 25 , wherein said first and second compositions are administered sequentially in any order.