Antibacterial agents

Abstract

Antibacterial compounds of formula I are provided: As well as stereoisomers, pharmaceutically acceptable salts, esters, and prodrugs thereof; pharmaceutical compositions comprising such compounds; methods of treating bacterial infections by the administration of such compounds; and processes for the preparation of the compounds.

1 . A compound according to the formula IA: 
     
       
         
         
             
             
         
       
       or a stereoisomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein 
       D is absent or selected from the group consisting of
 (1) substituted or unsubstituted C 3 -C 8 -cycloalkyl; 
 (2) substituted or unsubstituted aryl; 
 (3) substituted or unsubstituted heterocyclyl; and 
 (4) substituted or unsubstituted heteroaryl; 
 
       Y is selected from the group consisting of
 (1) substituted or unsubstituted C 3 -C 8 -cycloalkyl; 
 (2) substituted or unsubstituted aryl; 
 (3) substituted or unsubstituted heterocyclyl; and 
 (4) substituted or unsubstituted heteroaryl; 
 
       R 4  is H or substituted or unsubstituted C 1 -C 6 -alkyl; 
       A is selected from the group consisting of
 (1) —C(R 1a ,R 2a )OR 3a ; and 
 (2) —C(R 1a ,R 2a )N(R 4a ,R 5a );
 wherein R 1a , R 2a , R 4a , and R 5a  are independently selected from the group consisting of 
 
 (1) H; and 
 (2) substituted and unsubstituted C 1 -C 6 -alkyl. 
 
     
   
   
       2 . The compound of  claim 1 , wherein A is —C(R 1a ,R 2a )OR 3a . 
   
   
       3 . The compound of  claim 2 , wherein A is —CH 2 OH. 
   
   
       4 . The compound of  claim 2 , wherein A is —CH(CH 3 )OH. 
   
   
       5 . The compound of  claim 1 , wherein A is —C(R 1a ,R 2a )N(R 4a ,R 5a ). 
   
   
       6 . The compound of  claim 5 , wherein A is —CH(CH 3 )NH 2 . 
   
   
       7 . The compound of  claim 1 , wherein D is absent and Y is a substituted or unsubstituted aryl. 
   
   
       8 . The compound of  claim 1 , wherein D is a substituted or unsubstituted aryl and Y is a substituted or unsubstituted aryl. 
   
   
       9 . A compound according to the formula IB: 
     
       
         
         
             
             
         
       
       or a stereoisomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein 
       D is absent or selected from the group consisting of
 (1) substituted or unsubstituted C 3 -C 8 -cycloalkyl; 
 (2) substituted or unsubstituted aryl; 
 (3) substituted or unsubstituted heterocyclyl; and 
 (4) substituted or unsubstituted heteroaryl; 
 
       G is —C≡C—C≡C—; 
       Y is selected from the group consisting of
 (1) substituted or unsubstituted C 3 -C 8 -cycloalkyl; 
 (2) substituted or unsubstituted aryl; 
 (3) substituted or unsubstituted heterocyclyl; and 
 (4) substituted or unsubstituted heteroaryl; 
 
       R 4  is H or substituted or unsubstituted C 1 -C 6 -alkyl; 
       A is —C(R 1a ,R 2a )N(R 4a ,R 5a ), wherein R 1a , R 2a , R 4a , and R 5a  are independently selected from the group consisting of
 (1) H; and 
 (2) substituted and unsubstituted C 1 -C 6 -alkyl. 
 
     
   
   
       10 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable excipient. 
   
   
       11 . A pharmaceutical composition comprising the compound of  claim 9  and a pharmaceutically acceptable excipient. 
   
   
       12 . A pharmaceutical composition comprising a compound of  claim 1 , a second agent, and a pharmaceutically acceptable excipient, wherein the second agent is an antibacterial agent, and antiendotoxin agent or an inhaled non-antibacterial agent for the treatment of respiratory tract infection. 
   
   
       13 . A pharmaceutical composition comprising a compound of  claim 9 , a second agent, and a pharmaceutically acceptable excipient, wherein the second agent is an antibacterial agent, and antiendotoxin agent or an inhaled non-antibacterial agent for the treatment of respiratory tract infection. 
   
   
       14 . A method of inhibiting LpxC comprising administering to a patient in need thereof, an effective amount of the compound of  claim 1 . 
   
   
       15 . A method of inhibiting LpxC comprising administering to a patient in need thereof, an effective amount of the compound of  claim 9 . 
   
   
       16 . A method of inhibiting LpxC comprising administering to a patient in need thereof, an effective amount of the compound of  claim 1  and an effective amount of a second agent, wherein the second agent is an antibacterial agent, an antiendotoxin agent or an inhaled non-antibacterial agent for the treatment of respiratory tract infection. 
   
   
       17 . A method of inhibiting LpxC comprising administering to a patient in need thereof, an effective amount of the compound of  claim 9  and an effective amount of a second agent, wherein the second agent is an antibacterial agent, an antiendotoxin agent or an inhaled non-antibacterial agent for the treatment of respiratory tract infection. 
   
   
       18 . A method of treating an infection comprising administering to a patient in need thereof, an effective amount of the compound of  claim 1 . 
   
   
       19 . A method of treating an infection comprising administering to a patient in need thereof, an effective amount of the compound of  claim 9 . 
   
   
       20 . A method of treating an infection comprising administering to a patient in need thereof, an effective amount of the compound of  claim 1  and an effective amount of a second agent, wherein the second agent is an antibacterial agent, an antiendotoxin agent or an inhaled non-antibacterial agent for the treatment of respiratory tract infection. 
   
   
       21 . A method of treating an infection comprising administering to a patient in need thereof, an effective amount of the compound of  claim 9  and an effective amount of a second agent, wherein the second agent is an antibacterial agent, an antiendotoxin agent or an inhaled non-antibacterial agent for the treatment of respiratory tract infection.