Antibacterial compounds

Abstract

The invention encompasses a new series of antibacterial compounds, compositions containing these compounds, and methods of treating Enterobacteriaceae bacterial diseases and infections using these compounds. The compounds find application in the treatment of infection with, and disease caused by Gram-negative bacteria Enterobacteriaceae species that have developed resistance to existing antibiotics.

1 - 38 . (canceled) 
     
     
         39 . A method of treating a bacterial disease or bacterial infection comprising administering to a subject in need thereof a compound, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or ester thereof, having the general formula (V): 
       
         
           
           
               
               
           
         
       
       wherein
 R 2  is NH 2  or methyl (—CH 3 ); 
 R 7  is a fused bicyclic system selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         wherein each R 11  is independently selected from hydrogen and halogen; and 
         R 12  is selected from hydrogen, C 1-4 alkyl, C 3-7 cycloalkyl, C 4-7 heterocyclyl, COR 13 , SO 2 R 13 , C 1-4 alkyl-CO 2 R 14 , C 1-4 alkyl-OR 14 , C 1-4 alky-NR 14 R 15 , C 1-4 alkyl-C 3-7 cycloalkyl, COC 1-4 alkyl-NR 14 R 15 , an amino acid, and a quaternary ammonium cation (NR 16   4   + ); 
         R 13  is selected from C 1-4 alkyl, C 3-7 cycloalkyl, phenyl, and monocyclic 5- or 6-membered heteroaryl, the phenyl or 5- or 6-membered heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-2 alkyl, O (oxo), S (sulfinyl), NR 3 R 4 , OR 3  and SR 3 ; 
         R 14  and R 15  are independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkyl-hydroxyl, C 3-7 cycloalkyl, phenyl, monocyclic 5- or 6-membered heteroaryl, and SO 2 R 13 , the phenyl or 5- or 6-membered heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-2 alkyl, O (oxo), S (sulfinyl), NR 3 R 4 , OR 3  and SR 3 ; 
         R 16  groups are independently selected from C 1-4 alkyl and phenyl, the phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-2 alkyl, O (oxo), S (sulfinyl), NR 3 R 4 , OR 3  and SR 3 ; 
         R 3  and R 4  are independently selected from the group consisting of hydrogen, C 1-3 alkyl, COR 5 , CONR 5 R 6 , CO 2 R 5 , C 1-2 alkyl-NR 5 R 6 ; 
         or R 3  and R 4  together with the nitrogen atom to which they are attached form a monocyclic 4- to 7-membered cyclic amine group, which group is optionally substituted with one or more substituents selected from the group consisting of NR 5 R 6 , C 1-2 alkoxy and oxo; 
         R 5  and R 6  are independently selected from hydrogen and C 1-4 alkyl; 
         R 10  is pyridyl is optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-4 alkyl, O (oxo), S (sulfinyl), C 1-4 alkoxy, CONR 3 R 4 , NR 3 R 4 , OR 8 , hydroxyl, OCF 3 , CF 3 , R 8 , C 3-7 cycloalkyl, C 4-7 heterocyclyl, COR 13 , SO 2 R 13 , C 1-4 alkyl-CO 2 R 14 , C 1-4 alkyl-OR 14 , C 1-4 alkyl-NR 14 R 15 , C 1-4 alkyl-C 3-7 cycloalkyl, COC 1-4 alkyl-NR 14 R 15 , an amino acid, and a quaternary ammonium cation (NR 16   4   + ), and 
         R 8  is selected from the group consisting of 3- to 5-membered cycloalkyl and CH 2 R 9 ; 
         R 9  is selected from the group consisting of phenyl, monocyclic 5- or 6-membered heteroaryl and monocyclic C 3-7 cycloalkyl, the phenyl or 5- or 6-membered heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-2 alkyl, O (oxo), S (sulfinyl), NR 3 R 4 , OR 3  and SR 3 . 
       
     
     
         40 . The method according to  claim 39 , wherein R 2  is NH 2 . 
     
     
         41 . The method according to  claim 39 , wherein each R 11  is independently selected from hydrogen and F. 
     
     
         42 . The method according to  claim 39 , having the general formula (V): 
       
         
           
           
               
               
           
         
         wherein R 2  is NH 2 ; 
         R 7  is a fused bicyclic system selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         wherein each R 11  is hydrogen and R 12  is selected from hydrogen, C 1-4 alkyl, C 3-7 cycloalkyl, C 4-7 heterocyclyl, COR 13 , SO 2 R 13 , C 1-4 alkyl-CO 2 R 14 , C 1-4 alkyl-OR 14 , C 1-4 alky-NR 14 R 15 , C 1-4 alkyl-C 3-7 cycloalkyl, COC 1-4 alkyl-NR 14 R 15 , an amino acid, and a quaternary ammonium cation (NR 16   4   + ); 
         R 13  is selected from C 1-4 alkyl, C 3-7 cycloalkyl, phenyl, and monocyclic 5- or 6-membered heteroaryl, the phenyl or 5- or 6-membered heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-2 alkyl, O (oxo), S (sulfinyl), NR 3 R 4 , OR 3  and SR 3 ; 
         R 14  and R 15  are independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkyl-hydroxyl, C 3-7 cycloalkyl, phenyl, monocyclic 5- or 6-membered heteroaryl, and SO 2 R 13 , the phenyl or 5- or 6-membered heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-2 alkyl, O (oxo), S (sulfinyl), NR 3 R 4 , OR 3  and SR 3 ; 
         R 16  groups are independently selected from C 1-4 alkyl and phenyl, the phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-2 alkyl, O (oxo), S (sulfinyl), NR 3 R 4 , OR 3  and SR 3 ; and 
         R 10  is pyridyl is optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-4 alkyl, O (oxo), S (sulfinyl), C 1-4 alkoxy, CONR 3 R 4 , NR 3 R 4 , OR 8 , hydroxyl, OCF 3 , CF 3 , R 8 , C 3-7 cycloalkyl, C 4-7 heterocyclyl, COR 13 , SO 2 R 13 , C 1-4 alkyl-CO 2 R 14 , C 1-4 alkyl-OR 14 , C 1-4 alkyl-NR 14 R 15 , C 1-4 alkyl-C 3-7 cycloalkyl, COC 1-4 alkyl-NR 14 R 15 , an amino acid, and a quaternary ammonium cation (NR 16   4   + ). 
       
     
     
         43 . The method according to  claim 39 , wherein
 R 2  is methyl (—CH 3 );   R 7  is a fused bicyclic system selected from the group consisting of:   
       
         
           
           
               
               
           
         
         wherein each R 11  is hydrogen and R 12  is selected from hydrogen, C 1-4 alkyl, C 3-7 cycloalkyl, C 4-7 heterocyclyl, COR 13 , SO 2 R 13 , C 1-4 alkyl-CO 2 R 14 , C 1-4 alkyl-OR 14 , C 1-4 alky-NR 14 R 15 , C 1-4 alkyl-C 3-7 cycloalkyl, COC 1-4 alkyl-NR 14 R 15 , an amino acid, and a quaternary ammonium cation (NR 16   4   + ); 
         R 13  is selected from C 1-4 alkyl, C 3-7 cycloalkyl, phenyl, and monocyclic 5- or 6-membered heteroaryl, the phenyl or 5- or 6-membered heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-2 alkyl, O (oxo), S (sulfinyl), NR 3 R 4 , OR 3  and SR 3 ; 
         R 14  and R 15  are independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkyl-hydroxyl, C 3-7  cycloalkyl, phenyl, monocyclic 5- or 6-membered heteroaryl, and SO 2 R 13 , the phenyl or 5- or 6-membered heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-2 alkyl, O (oxo), S (sulfinyl), NR 3 R 4 , OR 3  and SR 3 ; 
         R 16  groups are independently selected from C 1-4 alkyl and phenyl, the phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-2 alkyl, O (oxo), S (sulfinyl), NR 3 R 4 , OR 3  and SR 3 . 
       
     
     
         44 . The method according to  claim 39 , wherein R 10  is a pyridyl group optionally substituted with one or more substituents selected from the group consisting of Cl, F, NH 2 , NHMe, C 1-2 alkyl, C 1-2 alkoxy, CONH 2 , CONHMe, CONMe 2 , OCH 2 C 3 cycloalkyl, OC 3 cycloalkyl, OCF 3  and hydroxyl. 
     
     
         45 . The method of  claim 39  comprising administering a pharmaceutical composition comprising a compound according to  claim 39 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or ester thereof, and a pharmaceutically acceptable carrier. 
     
     
         46 . The method of  claim 39 , comprising an effective amount of the compound, wherein said effective amount is an amount effective for use in therapy or prophylaxis of an infection with, or disease caused by, Enterobacteriaceae. 
     
     
         47 . The method of  claim 39  wherein the infection or disease is caused by Enterobacteriaceae. 
     
     
         48 . The method of  claim 47 , wherein the infection or disease is caused by Enterobacteriaceae genera selected from the group consisting of  Arsenophonus, Brenneria, Buchnera, Budvicia, Buttiauxella, Cedecea, Citrobacter, Cosenzaea, Cronobacter, Dickeya, Edwardsiella, Enterobacillus, Enterobacter, Erwinia, Escherichia, Ewingella, Franconibacter, Gibbsiella, Hafnia, Izhakiella, Kosakonia, Klebsiella, Kluyvera, Leclercia, Lelliottia, Leminorella, Levinea, Lonsdalea, Mangrovibacter, Moellerella, Morganella, Obesumbacterium, Pantoea, Pectobacterium, Phaseolibacter, Photorhabdus, Plesiomonas, Pluralibacter, Pragia, Proteus, Providencia, Pseudocitrobacter, Rahnella, Raoultella, Rosenbergiella, Rouxiella, Saccharobacter, Salmonella, Samsonia, Serratia, Shigella, Shimwellia, Siccibacter, Sodalis, Tatumella, Thorsellia, Trabulsiella, Wigglesworthia, Xenorhabdus, Yersinia  and  Yokenella.    
     
     
         49 . The method of  claim 39 , wherein the compound of formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or ester thereof, is administered in an amount of about 0.01 micrograms per kilogram body weight (μg/kg) to about 100 milligrams per kilogram body weight (mg/kg). 
     
     
         50 . The method of  claim 39 , wherein the compound of formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or ester thereof, is administered enterally or parenterally. 
     
     
         51 . A method of treating an infection with, or a disease caused by, Enterobacteriaceae in a subject in need thereof, comprising administering to said subject an effective amount of a composition comprising a compound of  claim 39 .