C-Linked Hydroxamic Acid Derivatives Useful As Antibacterial Agents

Abstract

The present invention is directed to a new class of hydroxamic acid derivatives, their use as LpxC inhibitors, and more specifically their use to treat bacterial infections.

1 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       in which:
 R 1  is represented by C 1 -C 3  alkyl; 
 R 2  is represented by hydrogen or C 1 -C 3  alkyl; 
 X is represented CH 2 , 0, NH, S or SO 2 , 
 A is represented by phenyl or a 6-membered heteroaryl as depicted below: 
 
       
         
           
           
               
               
           
         
         R 3  is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxy, amino, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, and trifluoromethoxy; 
         L is absent, or is represented by S, SH, OH, —(CH 2 ) p —O—(CH 2 ) n , —(CH 2 ) p —O—(CH 2 ) z —O—(CH 2 ) n —, S—(CH 2 ) z , or (CH 2 ) z —S; 
         n is represented by an integer ranging from 0 to 3; 
         p is represented by an integer ranging from 0 to 3; 
         z is represented by an integer ranging from 1 to 3; 
         D is absent, or is represented by a substituent selected from the group consisting of:
 i) (C 3 -C 10 )cycloalkyl, optionally substituted, 
 ii) (C 3 —O 10 )cycloalkyl(C 1 -C 6 )alkyl, in which the alkyl and cycloalkyl moieties may each be optionally substituted, 
 iii) (C 6 -C 10 )aryl optionally substituted, 
 iv) (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, in which the alkyl and aryl moieties may each be optionally substituted, 
 v) heteroaryl, optionally substituted, 
 vi) heteroaryl(C 1 -C 6 )alkyl, in which the heteroaryl and alkyl moieties may each be optionally substituted, 
 vii) heterocyclic, optionally substituted, 
 viii) heterocyclic(C 1 -C 6 )alkyl, in which the alkyl and heterocyclic moieties may each be substituted; 
 
         T is absent, or is represented by —(CH 2 ) z —, —(CH 2 ) n —C(O)—(CH 2 ) p —, O—(CH 2 ) z —, —(CH 2 ), —O—, or —O—(CH 2 ) p —C(O)—(CH 2 ) n — and; 
         G is absent, or is represented by a substituent selected from the group consisting of: 
         i) (C 3 -C 10 )cycloalkyl, optionally substituted; 
         ii) (C 6 -C 10 )aryl optionally substituted; 
         iii) heteroaryl, optionally substituted, or; 
         iv) heterocyclic, optionally substituted; 
         with the proviso that:
 a) at least one of D or L must be present 
 b) if D is absent, then T and G are also absent. 
 
       
     
     
         2 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof in which in which X is CH 2 . 
     
     
         3 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof in which R 1  and R 2  are each methyl. 
     
     
         4 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof in which A is phenyl. 
     
     
         5 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof in which A is a 6-membered heteroaryl. 
     
     
         6 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof in which L is absent. 
     
     
         7 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof in which D is optionally substituted phenyl. 
     
     
         8 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof in which D is optionally substituted heteroaryl. 
     
     
         9 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof in which D is optionally substituted heterocyclic. 
     
     
         10 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof in which G and T are both absent. 
     
     
         11 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof in which G is optionally substituted heteroaryl. 
     
     
         12 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof in which said compound is the R enantiomer. 
     
     
         13 . A pharmaceutical comprising a compound according to  claim 1  or a pharmaceutically acceptable salt thereof in admixture with at least one pharmaceutically acceptable excipient. 
     
     
         14 . A method of treating a bacterial infection in a patient, the method comprising administering a compound according to  claim 1  or a pharmaceutically acceptable salt thereof to a patient in need thereof. 
     
     
         15 . (canceled) 
     
     
         16 . A compound selected from;
 (2R)-4-(4′-cyanobiphenyl-4-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;   (2R)-4-(4′-fluorobiphenyl-4-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;   4-(2′-fluorobiphenyl-4-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;   N-hydroxy-4-(4′-methoxybiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide;   N-hydroxy-4-[4-(1H-indol-5-yl)phenyl]-2-methyl-2-(methylsulfonyl)butanamide;   4-[4-(5-cyano-2-thienyl)phenyl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;   (2R)-4-[4-(1,3-benzodioxol-5-yl)phenyl]-N-hydroxy-2-methyl-2-(methylsulfonyl) butanamide;   (2R)—N-hydroxy-4-[4-(1H-indol-2-yl)phenyl]-2-methyl-2-(methylsulfonyl)butanamide;   (2R)-4-biphenyl-4-yl-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;   4-(2,4′-difluorobiphenyl-4-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;   (2R)-4-(4′-glycoloylbiphenyl-4-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;   (2R)—N-hydroxy-4-[4-(6-methoxypyrid in-3-yl)phenyl]-2-methyl-2-(methylsulfonyl) butanamide;   4-[4-(3,6-dihydro-2H-thiopyran-4-yl)phenyl]-N-hydroxy-2-methyl-2-(methylsulfonyl) butanamide;   4-(4′-cyano-3-fluorobiphenyl-4-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;   N-hydroxy-4-[4′-(4-hydroxybutoxy)biphenyl-4-yl]-2-methyl-2-(methylsulfonyl) butanamide;   (2R)—N-hydroxy-4-(4′-hydroxybiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide;   4-[4-(benzyloxy)phenyl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;   (2R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-4-[4′-(3-morpholin-4-ylpropoxy)biphenyl-4-yl]butanamide;   4-[3-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-N-hydroxy-2-methyl-2-(methylsulfonyl) butanamide;   4-(4-cyclohex-1-en-1-ylphenyl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;   N-hydroxy-2-methyl-2-(methylsulfonyl)-4-[4-(4-methyl-2-thienyl)phenyl]butanamide;   4-(3-fluoro-4-quinolin-6-ylphenyl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;   N-hydroxy-2-methyl-2-(methylsulfonyl)-4-{6-[4-(methylthio)phenyl]pyridin-3-yl}butanamide;   4-[5-(4-fluorophenyl)pyridin-2-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; and   4′-[(3R)-4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl]biphenyl-4-yl dihydrogen phosphate;   
       or a pharmaceutically acceptable salt thereof.