1,2,4-oxadiazole and 1,2,4-thiadiazole beta-lactamase inhibitors

Abstract

β-Lactamase inhibitor compounds (BLIs) are disclosed, including compounds that have activity against class A, class C or class D β-lactamases. Methods of manufacturing the BLIs, and uses of the compounds in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed.

1 .- 37 . (canceled) 
     
     
         38 . A pharmaceutical composition comprising aztreonam or a pharmaceutically acceptable salt thereof and a compound of Formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         Z is selected from a 1,2,4-oxadiazole or a 1,2,4-thiadiazole; 
         R is selected from 
       
       
         
           
           
               
               
           
         
       
       and
 R 1  is selected from: 
 hydrogen, 
 
       
         
           
           
               
               
           
         
         wherein R 2  is selected from 
       
       
         
           
           
               
               
           
         
         wherein each of R 3 , R 4  and R 5  is independently selected from hydrogen, (C 1 -C 3 )-alkyl, aminoalkyl, aminocycloalkyl, or hydroxyalkyl, and n is selected from 1, 2 or 3, 
         amino, 
       
       
         
           
           
               
               
           
         
         wherein R 6  is selected from H, (C 1 -C 3 )-unsubstituted alkyl, amino-(C 2 -C 3 )-alkyl, aminocycloalkyl, hydroxyalkyl, 
       
       
         
           
           
               
               
           
         
         and each of p and q is independently selected from 1 or 2; and 
         —CH 2 (R 7 )CH 2 NH 2    
         wherein R 7  is selected from amino or hydroxyl. 
       
     
     
         39 . The pharmaceutical composition of  claim 38  wherein Z—R 1  is 
       
         
           
           
               
               
           
         
       
       wherein X is selected from O or S and wherein R and R 1  are as previously described. 
     
     
         40 . The pharmaceutical composition of  claim 38  wherein Z—R 1  is 
       
         
           
           
               
               
           
         
       
       wherein X is selected from O or S and wherein R and R 1  are as previously described. 
     
     
         41 . The pharmaceutical composition of  claim 38  wherein the compound of Formula (I) exhibits a binding affinity for the KPC-2 β-lactamase enzyme of at least 250 mM −1 s −1 . 
     
     
         42 . The pharmaceutical composition of  claim 38  wherein the compound is selected from the group consisting of Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII) and Formula (VIII), and pharmaceutically acceptable salts thereof: 
       
         
           
           
               
               
           
         
       
     
     
         43 . The pharmaceutical composition of  claim 38  wherein the compound or a pharmaceutically acceptable salts thereof has the Formula: 
       
         
           
           
               
               
           
         
       
     
     
         44 . The pharmaceutical composition of  claim 38  wherein the compound or a pharmaceutically acceptable salts thereof has the Formula: 
       
         
           
           
               
               
           
         
       
     
     
         45 . A pharmaceutical composition comprising meropenem or a pharmaceutically acceptable salt thereof and a compound of Formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         Z is selected from a 1,2,4-oxadiazole or a 1,2,4-thiadiazole; 
         R is selected from 
       
       
         
           
           
               
               
           
         
       
       and
 R 1  is selected from: 
 hydrogen, 
 
       
         
           
           
               
               
           
         
         wherein R 2  is selected from 
       
       
         
           
           
               
               
           
         
         wherein each of R 3 , R 4  and R 5  is independently selected from hydrogen, (C 1 -C 3 )-alkyl, aminoalkyl, aminocycloalkyl, or hydroxyalkyl, and n is selected from 1, 2 or 3, 
         amino, 
       
       
         
           
           
               
               
           
         
         wherein R 6  is selected from H, (C 1 -C 3 )-unsubstituted alkyl, amino-(C 2 -C 3 )-alkyl, aminocycloalkyl, hydroxyalkyl, 
       
       
         
           
           
               
               
           
         
         and each of p and q is independently selected from 1 or 2; and 
         —CH 2 (R 7 )CH 2 NH 2    
         wherein R 7  is selected from amino or hydroxyl. 
       
     
     
         46 . The pharmaceutical composition of  claim 45  wherein Z—R 1  is 
       
         
           
           
               
               
           
         
       
       wherein X is selected from O or S and wherein R and R 1  are as previously described. 
     
     
         47 . The pharmaceutical composition of  claim 45  wherein Z—R 1  is 
       
         
           
           
               
               
           
         
       
       wherein X is selected from O or S and wherein R and R 1  are as previously described. 
     
     
         48 . The pharmaceutical composition of  claim 45  wherein the compound of Formula (I) exhibits a binding affinity for the KPC-2 β-lactamase enzyme of at least 250 mM −1 s −1 . 
     
     
         49 . The pharmaceutical composition of  claim 45  wherein the compound is selected from the group consisting of Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII) and Formula (VIII), and pharmaceutically acceptable salts thereof: 
       
         
           
           
               
               
           
         
       
     
     
         50 . The pharmaceutical composition of  claim 45  wherein the compound or a pharmaceutically acceptable salts thereof has the Formula: