Antimicrobial [3.1.0] bicyclohexylphenyl- oxazolidinone derivatives and analogues

Abstract

The present invention provides certain [3.1.0]bicyclic oxazolidinone derivatives of Formula I I or pharmaceutically acceptable salts or prodrugs thereof that are antibacterial agents, pharmaceutical compositions containing them, methods for their use, and methods for preparing these compounds.

1 . A compound of Formula I:  
       
         
           
           
               
               
           
         
         wherein A is a structure i, ii, iii, or iv  
         
           
             
             
                 
                 
             
           
         
         where the dashed line in formula iii represents an optional double bond;  
         n is an integer equal to 0 or 1;  
         Y is selected from the group consisting of —SO m —, —O— and —N(R 8 )—; where m is an integer equal to 0, 1, or 2;  
         Z is selected from the group consisting of C(═Q)R 1 , —NHC(═Q)R 1 , C(═Q)NHR 1 , —NHC(═NCN)R 1 , —NHC(═NNO 2 )R 1 , —SO 2 R 1 , —NH 2 , —NH-het 1 , —O-het 1 , —S-het 1 , and -het 2 ;  
         Q is oxygen or sulfur;  
         W is selected from the group consisting of —CH 2 —, —C(═O)—, —C(═NOH)—, and —C(═NOC 1-4 alkyl)-;  
         R 1  is selected from the group consisting of —H, OH, —NH 2 , —NHC 1-4 alkyl, —C 1-4 alkyl, —C 2-4 alkenyl, —(CH 2 ) p C(═O)C 1-4 alkyl, —OC 1-4 alkyl, —SC 1-4 alkyl, —(CH 2 ) p C 3-6 cycloalkyl, —CH═CH-aryl, —CH═CH-het 1 , —CH 2 C(═O)-aryl, and —CH 2 C(═O)-het 1 ; where p is an integer equal to 0, 1 or 2;  
         R 2  and R 3  are independently selected from the group consisting of —H and —F;  
         R 4  and R 5  are independently selected from the group consisting of —H, —Cl, —F, —CH 3 , —NH 2 , and —OH;  
         R 6  and R 7  are independently selected from the group consisting of —H and —C 1-4 alkyl;  
         R 8  is independently selected from the group consisting of —H, —OH, —NR 9 R 10 , —C 1-4 alkyl, —C 3-6 cycloalkyl, —C 1-4 heteroalkyl, -aryl, -het 1 , —C 1-4 alkylNR 9 R 10 , —(CH 2 ) p C(═O)C 1-4 alkyl, —(CH 2 ) p C(═O)C 1-4 heteroalkyl, —C(═O)H, —(CH 2 ) p C(═O)OR 9 , —(CH 2 ) p C(═O)C 1-4 alkylOR 9 , —(CH 2 ) p C(═O)NR 9 R 10 , —(CH 2 ) p C(═O)NR 9 OR 10 , —(CH 2 ) p C(═NOC 1-4 alkyl)H, —(CH 2 ) p C(═NOC 1-4 alkyl)C 1-4 alkyl, —(CH 2 ) p C(═O)het 1 , and —(CH 2 ) p C(═NOC 1-4 alkyl)het 1 ; where p and het 1  are as defined herein;  
         where each R 9  and R 10  are independently —H, —C 1-4 alkyl, —C 3-6 cycloalkyl, -aryl, -het 1 , —C(═O)C 1-4 alkyl, —C(═O)aryl, —C(═O)het 1 , —SO 2 C 1-4 alkyl, or —SO 2 NH 2 ;  
         and a pharmaceutically acceptable salts thereof;  
         with the proviso that when Y is —O— or —SO m —, then W is —CH 2 —.  
       
     
     
         2 . The compound according to  claim 1 , wherein A is an optical configuration of structure i, ii, or iii:  
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound according to  claim 1 , wherein A is an optical configuration of structure i:  
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 3 , wherein R 1  is C 1-4 alkyl.  
     
     
         5 . The compound of  claim 3 , wherein R 1  is selected from the group consisting of H, methyl, difluoromethyl, ethyl, 2-fluoroethyl, or 2,2-difluoroethyl.  
     
     
         6 . The compound of  claim 3 , wherein R 4  and R 5  are independently H or F.  
     
     
         7 . The compound of  claim 3 , wherein R 6  and R 7  are H.  
     
     
         8 . The compound of  claim 3 , wherein W is CH 2 .  
     
     
         9 . A compound selected from the group consisting of 
 N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;    N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;    N-[((5S)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3-fluorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;    N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;    N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;    2,2-difluoro-N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo [3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]ethanethioamide;    methyl exo-(1R,5S)-6-(4-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate;    N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-formyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;    N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-((2S)-2,3-dihydroxypropanoyl)-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;    exo-(1R,5S)-6-(4-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxamide;    exo-(1R,5S)-6-[4-((5S)-5-{[(2,2-difluoroethanethioyl)amino]methyl}-2-oxo-1,3-oxazolidin-3-yl)-2-fluorophenyl]-3-azabicyclo[3.1.0]hexane-3-carboxamide;    N-[((5S)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;    N-[((5S)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3,5-difluorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;    N-[((5S)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;    N-[((5S)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;    N-[((5S)-3-{4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;    N-[((5S)-3-{4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;    N-[((5S)-3-{4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;    N-[((5S)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;    (5R)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3-fluorophenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;    (5R)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3-fluorophenyl}-N-methyl-2-oxo-1,3-oxazolidine-5-carboxamide;    (5R)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3,5-difluorophenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;    (5R)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3,5-difluorophenyl}-N-methyl-2-oxo-1,3-oxazolidine-5-carboxamide;    (5R)—N-ethyl-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3,5-difluorophenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;    (5R)—N-(2-fluoroethyl)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3,5-difluorophenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;    (5R)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;    (5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;    (5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-N-methyl-2-oxo-1,3-oxazolidine-5-carboxamide;    (5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;    (5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-N-methyl-2-oxo-1,3-oxazolidine-5-carboxamide;    (5R)—N-ethyl-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;    (5R)-3-{4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;    (5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;    (5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;    (5R)-3-{4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;    (5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;    (5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-N-methyl-2-oxo-1,3-oxazolidine-5-carboxamide;    (5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;    (5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-N-methyl-2-oxo-1,3-oxazolidine-5-carboxamide;    (5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;    (5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-N-methyl-2-oxo-1,3-oxazolidine-5-carboxamide;    (5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;    (5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-N-methyl-2-oxo-1,3-oxazolidine-5-carboxamide;    N-[((5S)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]propanamide;    N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]propanamide;    N-[((5S)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3,5-difluorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]propanamide;    N-[((5S)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3-fluorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]propanamide;    N-[((5S)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]propanamide;    N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]propanamide;    N-[((5S)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]propanamide;    N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]propanamide;    (5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;    (5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;    (5R)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3-fluorophenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;    (5R)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3,5-difluorophenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;    (5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;    (5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;    (5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;    (5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;    N-[((5S)-3-{3-fluoro-4-[(1S,5R,6R)-2-oxo-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;    N-[((5S)-3-{3,5-difluoro-4-[(1S,5R,6R)-2-oxo-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;    (5R)-3-{3-fluoro-4-[(1S,5R,6R)-2-oxo-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;    (5R)-3-{3,5-difluoro-4-[(1S,5R,6R)-2-oxo-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;    (1S,5R,6R)-6-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}-3-azabicyclo[3.1.0]hexan-2-one;    (1S,5R,6R)-6-{2,6-difluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}-3-azabicyclo[3.1.0]hexan-2-one;    N-{[4-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3,5-difluorophenyl}-5-oxoisoxazol-2(5H)-yl]methyl}acetamide; 
 and pharmaceutically acceptable salts thereof.  
   
     
     
         10 . A method for the treatment of microbial infection in a mammal which method comprises administering to said mammal an effective amount of the compound of  claim 1 .  
     
     
         11 . The method of  claim 10  wherein said compound of  claim 1  is administered to the mammal in a pharmaceutical composition orally, parenterally, transdermally, or topically.  
     
     
         12 . The method of  claim 10  wherein said compound is administered in an amount of from about 0.1 to about 100 mg/kg of body weight/day.  
     
     
         13 . The method of  claim 10  wherein said compound is administered in an amount of from about 1 to about 50 mg/kg of body weight/day.  
     
     
         14 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier.