Novel pyrido[2,3-b]indole compounds for the treatment and prophylaxis of bacterial infection

Abstract

The present invention relates to novel compounds of formula (I), wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as described herein, and their pharmaceutically acceptable salt, enantiomer or diastereomer thereof, and compositions including the compounds and methods of using the compounds.

1 - 35 . (canceled) 
     
     
         36 . A compound of formula (I), 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is 
       
       
         
           
           
               
               
           
         
       
       wherein
   R 7  is H;   R 8  is carboxy;   R 9  is H;   R 10  is C 1-6 alkyl or C 1-6 alkylamino; and   R 11  is H;   
 R 2  is heterocyclyl; 
 R 3  is H, halogen or cyano; 
 R 4  is halogen; 
 R 5  is H; and 
 R 6  is C 1-6 alkyl; 
 
       or a pharmaceutically acceptable salt, or enantiomer or diastereomer thereof. 
     
     
         37 . The compound of  claim 36 , wherein R 2  is selected from the group consisting of
 pyrrolidinyl;   2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrolyl;   2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrolyl;   2,3,3a,5,6,6a-hexahydropyrrolo[3,2-b]pyrrolyl;   2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl; and   3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrolyl, and   
       wherein each R 2  is optionally substituted with C 1-6 alkyl or (C 1-6 alkyl) 2 amino. 
     
     
         38 . The compound of  claim 36 , wherein R 2  is selected from the group consisting of
 pyrrolidinyl substituted with (C 1-6 alkyl) 2 amino;   2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrolyl substituted with C 1-6 alkyl;   2,3,3a,5,6,6a-hexahydropyrrolo[3,2-b]pyrrolyl substituted with C 1-6 alkyl;   2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl substituted with C 1-6 alkyl;   2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrolyl substituted by (C 1-6 alkyl) 2 amino; and   3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrolyl substituted with (C 1-6 alkyl) 2 amino.   
     
     
         39 . The compound of  claim 36 , wherein R 2  is selected from the group consisting of
 (dimethylamino)pyrrolidinyl;   methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrolyl;   methyl-2,3,3a,5,6,6a-hexahydropyrrolo[3,2-b]pyrrolyl;   methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl;   dimethylamino-2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrolyl; and   dimethylamino-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrolyl.   
     
     
         40 . The compound of  claim 36 , wherein R 3  is H, fluoro, chloro or cyano. 
     
     
         41 . The compound of  claim 36 , wherein R 4  is fluoro or chloro. 
     
     
         42 . The compound of  claim 36 , wherein R 6  is methyl. 
     
     
         43 . The compound of  claim 36 , wherein
 R 3  is H, fluoro, chloro or cyano;   R 4  is fluoro or chloro; and   R 6  is methyl.   
     
     
         44 . The compound of  claim 36 , wherein R 10  is methyl or methylamino. 
     
     
         45 . A compound of formula (I), 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is 
       
       
         
           
           
               
               
           
         
       
       wherein
   R 7  is H;   R 8  is carboxy;   R 9  is H;   R 10  is C 1-6 alkyl or C 1-6 alkylamino; and   R 11  is H;   
 R 2  is selected from the group consisting of 
 pyrrolidinyl; 
 2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrolyl; 
 2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrolyl; 
 2,3,3a,5,6,6a-hexahydropyrrolo[3,2-b]pyrrolyl; 
 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl; and 
 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrolyl, 
 
       wherein each R 2  is optionally substituted with C 1-6 alkyl or (C 1-6 alkyl) 2 amino;
 R 3  is H, halogen or cyano; 
 R 4  is halogen; 
 R 5  is H; and 
 R 6  is C 1-6 alkyl; 
 
       or a pharmaceutically acceptable salt, or enantiomer or diastereomer thereof. 
     
     
         46 . The compound of  claim 45 , wherein
 R 10  is methyl or methylamino;   R 2  is selected from the group consisting of (dimethylamino)pyrrolidinyl; methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrolyl; dimethylamino-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrolyl; dimethylamino-2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrolyl; and methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl;   R 3  is H, fluoro, chloro or cyano;   R 4  is fluoro or chloro; and   R 6  is methyl,   
       or a pharmaceutically acceptable salt, or enantiomer or diastereomer thereof. 
     
     
         47 . The compound of  claim 36 , wherein said compound is selected from the group consisting of
 6-(6-chloro-4-(3-(dimethylamino)pyrrolidin-1-yl)-8-(methylamino)-9H-pyrido[2,3-b]indol-3-yl)-1-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid;   6-[4-[cis-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-1-yl]-5-chloro-6-fluoro-8-(methylamino)-9H-pyrido[2,3-b]indol-3-yl]-1-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid;   6-[4-[cis-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-1-yl]-5,6-dichloro-8-(methylamino)-9H-pyrido[2,3-b]indol-3-yl]-1-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid;   6-[4-[(3aS,6aS)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-1-yl]-5-cyano-6-fluoro-8-(methylamino)-9H-pyrido[2,3-b]indol-3-yl]-1-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid;   6-[4-[(3aS,6aS)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-1-yl]-5-cyano-6-fluoro-8-(methylamino)-9H-pyrido[2,3-b]indol-3-yl]-1-(methylamino)-4-oxo-1,8-naphthyridine-3-carboxylic acid;   6-[5,6-difluoro-8-(methylamino)-4-[(3aS,6aS)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-1-yl]-9H-pyrido[2,3-b]indol-3-yl]-1-(methylamino)-4-oxo-1,8-naphthyridine-3-carboxylic acid;   6-[4-[(3aS,6aS)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-1-yl]-5,6-difluoro-8-(methylamino)-9H-pyrido[2,3-b]indol-3-yl]-1-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid;   6-[4-[(3aS,6aS)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-1-yl]-6-fluoro-8-(methylamino)-9H-pyrido[2,3-b]indol-3-yl]-1-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid;   6-[4-[(3aS,6aS)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-1-yl]-6-fluoro-8-(methylamino)-9H-pyrido[2,3-b]indol-3-yl]-1-(methylamino)-4-oxo-1,8-naphthyridine-3-carboxylic acid;   6-[4-[(3aR,6aR)-1-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-5-yl]-5,6-difluoro-8-(methylamino)-9H-pyrido[2,3-b]indol-3-yl]-1-(methylamino)-4-oxo-1,8-naphthyridine-3-carboxylic acid;   6-[4-[(3aS,6aS)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-1-yl]-6-chloro-8-(methylamino)-9H-pyrido[2,3-b]indol-3-yl]-1-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid;   6-[4-[(3aR,6aR)-1-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-5-yl]-6-chloro-8-(methylamino)-9H-pyrido[2,3-b]indol-3-yl]-1-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid;   6-[5,6-difluoro-4-(cis-1-methyl-2,3,3a,5,6,6a-hexahydropyrrolo[3,2-b]pyrrol-4-yl)-8-(methylamino)-9H-pyrido[2,3-b]indol-3-yl]-1-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid;   6-[5,6-difluoro-4-(cis-1-methyl-2,3,3a,5,6,6a-hexahydropyrrolo[3,2-b]pyrrol-4-yl)-8-(methylamino)-9H-pyrido[2,3-b]indol-3-yl]-1-(methylamino)-4-oxo-1,8-naphthyridine-3-carboxylic acid;   6-[6-chloro-4-[cis-3-(dimethylamino)-2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl]-8-(methylamino)-9H-pyrido[2,3-b]indol-3-yl]-1-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid;   6-[4-cis-(4R)-(dimethylamino)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-5,6-difluoro-8-(methylamino)-9H-pyrido[2,3-b]indol-3-yl]-1-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid;   6-[6-chloro-8-(methylamino)-4-[cis-(4R)-(dimethylamino)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-9H-pyrido[2,3-b]indol-3-yl]-1-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid; and   6-[4-[(4aS,7aR)-4-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl]-5,6-difluoro-8-(methylamino)-9H-pyrido[2,3-b]indol-3-yl]-1-(methylamino)-4-oxo-1,8-naphthyridine-3-carboxylic acid;   
       or a pharmaceutically acceptable salt, or enantiomer or diastereomer thereof. 
     
     
         48 . A pharmaceutical composition comprising a compound of  claim 36  and a therapeutically inert carrier. 
     
     
         49 . A method for the treatment of bacterial infection in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound of  claim 36 . 
     
     
         50 . The method according to  claim 49 , wherein the bacterial infection is caused by a pathogen selected from the group consisting of  Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Enterobacter  spp. species,  Proteus  spp. species,  Serratia marcescens, Staphylococcus aureus , Coag. Neg. Staphylococci,  Haemophilus influenzae, Bacillus anthraces, Mycoplasma pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Chlamydia trachomatis, Legionella pneumophila, Mycobacterium tuberculosis, Helicobacter pylori, Staphylococcus saprophyticus, Staphylococcus epidermidis, Francisella tularensis, Yersinia pestis, Clostridium difficile, Bacteroides  spp. species  Neisseria gonorrhoeae, Neisseria meningitidis, Burkholderia pseudomallei, Burkholderia mallei, Borrelia burgdorferi, Mycobacterium avium  complex,  Mycobacterium abscessus, Mycobacterium kansasii, E. coli  and  Mycobacterium ulcerans.    
     
     
         51 . The method of  claim 50 , wherein the bacterial infection is caused by  Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus  or  E. coli.    
     
     
         52 . A method of reducing resistance in a subject treated for bacterial infection, said method comprising administering to said subject an effective amount of a compound of  claim 36 . 
     
     
         53 . A process for the preparation of a compound of  claim 36 , said process comprising the reaction of compound of formula (Ii), 
       
         
           
           
               
               
           
         
         with an acid, wherein 
         R 1  is 
       
       
         
           
           
               
               
           
         
       
       wherein
 R 7  is H; 
 R 8  is carboxy; 
 R 9  is H; 
 R 10  is C 1-6 alkyl or C 1-6 alkylamino; 
 R 11  is H; 
 R 2  is heterocyclyl; 
 R 3  is H, halogen or cyano; 
 R 4  is halogen; 
 R 5  is H; and 
 R 6  is C 1-6 alkyl. 
 
     
     
         54 . A compound having the structure of formula Ig 
       
         
           
           
               
               
           
         
         wherein 
         X 3  and X 4  are each independently halogen; 
         R 3  is H, halogen or cyano; 
         R 4  is halogen; 
         R 5  is H; and 
         R 6  is C 1-6 alkyl. 
       
     
     
         55 . A compound having the structure of 
       
         
           
           
               
               
           
         
       
       wherein
 R 7  is H; 
 R 9  is H; 
 R 10  is C 1-6 alkyl or C 1-6 alkylamino; and 
 R 11  is H.