Oxazolidinone compounds and methods of use thereof as antibacterial agents

Abstract

The present invention relates to oxazolidinone compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein A, E, and R1 are as defined herein. The present invention also relates to compositions which comprise at least one oxazolidinone compound of the invention. The invention also provides methods for inhibiting growth of mycobacterial cells as well as a method of treating mycobacterial infections by Mycobacterium tuberculosis comprising administering a therapeutically effective amount of an oxazolidinone of the invention and/or a pharmaceutically acceptable salt thereof, or a composition comprising such compound and/or salt.

What is claimed is: 
     
         1 . A compound of formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 1  is —CH 2 N(R 2 ) 2 , —CH 2 NR 2 COR 3 , —CH 2 NR 2 COOR 3 , —CH 2 NR 2 CON(R 2 ) 2 , —CH 2 NR 2 CONR 2 N(R 2 ) 2 , —CH 2 NR 2 SO 2 R 3 , —CON(R 2 ) 2 , —C═NOR 3 , —CH 2 OR 4 , —CH 2 NR 2 R 4 , or —CH 2 R 6 . 
         each occurrence of R 2  is independently selected from H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, and C 3 -C 6  cycloalkyl, wherein said C 1 -C 6  alkyl, said C 2 -C 6  alkenyl, and said C 3 -C 6  cycloalkyl can be optionally substituted with up to four substituents, which are independently selected from halogen, —OCH 3 , —OH, —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 ; 
         R 3  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, and C 3 -C 6  cycloalkyl, wherein said C 1 -C 6  alkyl, said C 2 -C 6  alkenyl and said C 3 -C 6  cycloalkyl can be optionally substituted with up to four substituents, which are independently selected from halogen, —OCH 3 , —OH, —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 ; 
         R 4  is a 5- or 6-membered heterocycle, which is optionally substituted with R 5 ; 
         R 5  is selected from H, halogen, C 1 -C 6  alkyl, C 3 -C 6  alkenyl, and C 3 -C 6  cycloalkyl, wherein said C 1 -C 6  alkyl, said C 3 -C 6  alkenyl, and said C 3 -C 6  cycloalkyl can be optionally substituted with up to four substitutents, which are independently selected from halogen, —OCH 3 , —OH, —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 ; 
         R 6  is H, C 1 -C 6  alkyl, or a 5-membered heterocycle, wherein said 5-membered heterocycle is optionally substituted with up to two R 7 ; 
         each occurrence of R 7  is H, halogen, oxo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 3 -C 6  cycloalkyl, wherein said C 1 -C 6  alkyl and said C 3 -C 6  cycloalkyl can be optionally substituted with from one to four substituents which are independently selected from halogen, —OCH 3 , —OH, —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 ; 
         E is a 6-membered aryl or a 5- or 6-membered heteroaryl containing from one to three heteroatoms independently selected from S, O, and N, wherein said aryl and said heteroaryl are optionally substituted with up to four substituents, which are independently selected from halogen, —CN, —CF 3 , —CHF 2 , —CH 2 NH 2 , —CH 2 NHCOCH 3 , —OCF 3 , —OCHF 2 , —OH, —O—(C 1 -C 6 )alkyl, C 1 -C 6  alkyl, and C 3 -C 6  cycloalkyl; 
         A is a heterocycle optionally substituted with up to four R 8 , or an aryl optionally substituted with up to four R 8 ; 
         each occurrence of R 8  is independently selected from H, halogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 3 -C 6  heterocycloalkyl, benzyl, —OCF 3 , —OCHF 2 , —OR 3 , ═O, —CN, —NO 2 , —SR 3 , —SF 5 , —SCF 3 , —SOR 3 , —SO 2 R 3 , —S(═O)(═NH)R 2 , —N(R 2 ) 2 , —NR 2 COR 3 , —SO 2 N(R 2 ) 2 , —NR 2 SO 2 R 3 , —COOH, —COOR 3 , —CON(R 2 ) 2 , and —C(R 9 ) 2 N(R 2 ) 2 , wherein said C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 3 -C 6  heterocycloalkyl, and benzyl are optionally substituted with up to four F, —OCH 3 , —OH, ═O, NH 2 , NHCH 3 , and N(CH 3 ) 2 ; and 
         each occurrence of R 9  is independently selected from H, C 1 -C 6  alkyl, and C 3 -C 6  cycloalkyl. 
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein: R 1  is —CH 2 OR 4  or —CH 2 NR 2 R 4 ; and
 R 4  is selected from: 
 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is CH 2 R 6  and R 6  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is: 
       
         
           
           
               
               
           
         
         wherein R 8  represents up to four optional ring carbon substituents, which can be the same or different. 
       
     
     
         5 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is: 
       
         
           
           
               
               
           
         
         wherein: 
         m=is 0, 1, 2, or 3; 
         each occurrence of R 8  is independently selected from H, halogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 3 -C 6  heterocycloalkyl, benzyl, —OCF 3 , —OCHF 2 , —OR 3 , ═O, —CN, —NO 2 , —SR 3 , —SF 5 , —SCF 3 , —SOR 3 , —SO 2 R 3 , —S(═O)(═NH)R 2 , —N(R 2 ) 2 , —NR 2 COR 3 , —SO 2 N(R 2 ) 2 , —NR 2 SO 2 R 3 , —COOH, —COR 9 , —COOR 3 , —CON(R 2 ) 2 , and —C(R 9 ) 2 N(R 2 ) 2 , wherein said C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 3 -C 6  heterocycloalkyl, and benzyl are optionally substituted with up to four F, —OCH 3 , —OH, ═O, NH 2 , NHCH 3 , and N(CH 3 ) 2 ; 
         R 10  is selected from H, C 1 -C 6  alkyl and C 3 -C 6  cycloalkyl, wherein said C 1 -C 6  alkyl and said C 3 -C 6  cycloalkyl are optionally substituted with from one to four substituents, which are independently selected from F, —OCH 3 , —OH, NH 2 , NHCH 3 , and N(CH 3 ) 2 ; 
         R 11  is selected from H, C 1 -C 6  alkyl and C 3 -C 6  cycloalkyl, —COR 9 , —COOR 5 , —CON(R 9 ) 2 , and —SO 2 R 9 ; 
         each occurrence of R 12  is independently selected from H, halogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, benzyl, —OCF 3 , —OCHF 2 , —OR 3 , —CN, —NO 2 , —SR 3 , —SF 5 , —SCF 3 , —SOR 3 , —SO 2 R 3 , —S(═O)(═NH)R 2 , —N(R 2 ) 2 , —NR 2 COR 3 , —SO 2 N(R 2 ) 2 , —NR 2 SO 2 R 3 , —COOH, —COR 9 , —COOR 3 , —CON(R 2 ) 2 , and —C(R 9 ) 2 N(R 2 ) 2 , wherein said C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, and benzyl are optionally substituted with up to four F, —OCH 3 , —OH, NH 2 , NHCH 3 , and N(CH 3 ) 2 ; 
         R 11  is selected from H, halogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, benzyl, —OCF 3 , —OCHF 2 , —OR 3 , —CN, —NO 2 , —SR 3 , —SF 5 , —SCF 3 , —SOR 3 , —SO 2 R 3 , —S(═O)(═NH)R 2 , —N(R 2 ) 2 , —NR 2 COR 3 , —SO 2 N(R 2 ) 2 , —NR 2 SO 2 R 3 , —COOH, —COR 9 , —COOR 3 , —CON(R 2 ) 2 , and —C(R 9 ) 2 N(R 2 ) 2 , wherein said C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, and benzyl are optionally substituted with up to four F, —OCH 3 , —OH, NH 2 , NHCH 3 , and N(CH 3 ) 2 ; and 
         W is selected from O, S, SO, SO 2 , and S(═O)(═NH); and 
         and wherein   represents a double or a single bond. 
       
     
     
         6 . The compound of  claim 4 , or a pharmaceutically acceptable salt thereof, having the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is —CH 2 NH 2 , —CH 2 NHC(O)CH 3 , —CH 2 NHC(O)—C 3 -C 6 cycloalkyl, or CH 2 R 6 . 
       
     
     
         7 . The compound of  claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 1  is —CH 2 NH 2 . 
     
     
         8 . The compound of  claim 6 , or a pharmaceutically acceptable salt thereof, wherein A is: 
       
         
           
           
               
               
           
         
         wherein R 8  represents up to four optional ring carbon substituents, which can be the same or different. 
       
     
     
         9 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, having the structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 9 , or a pharmaceutically acceptable salt thereof, having the structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         11 . A pharmaceutical composition which comprises a therapeutically effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         12 . A method for treating a bacterial infection which comprises administering to a subject in need of such treatment (i) a therapeutically effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The method of  claim 12 , wherein the bacterial infection is due to  Mycobacterium tuberculosis.    
     
     
         14 . The method according to  claim 12 , wherein the compound or the pharmaceutically acceptable salt thereof is administered orally, parentally, or topically. 
     
     
         15 . The method according to  claim 13 , wherein the  M. tuberculosis  is a drug resistant mycobacterial strain. 
     
     
         16 . The method according to  claim 13 , further comprising the step of administering a second therapeutic agent for treating  M. tuberculosis.    
     
     
         17 . The method of  claim 16 , wherein the second therapeutic agent is selected from the group consisting of: ethambutol, pyrazinamide, isoniazid, levofloxacin, moxifloxacin, gatifloxacin, ofloxacin, kanamycin, amikacin, capreomycin, streptomycin, ethionamide, prothionamide, cycloserine, terididone, para-aminosalicylic acid, clofazimine, clarithromycin, amoxicillin-clavulanate, thiacetazone, meropenem-clavulanate, and thioridazine. 
     
     
         18 . (canceled)