Isoxazole 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 - 50 . (canceled) 
     
     
         51 . A pharmaceutical composition comprising ceftolozane or a pharmaceutically acceptable salt thereof and a compound of Formula (A-I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         R* is selected from 
       
       
         
           
           
               
               
           
         
       
       and
 R 1*  is selected from: 
 a. 
 
       
         
           
           
               
               
           
         
         wherein R 2*  is selected from 
       
       
         
           
           
               
               
           
         
       
       R 3*  is selected from hydrogen, (C 1 -C 3 )-alkyl, aminoalkyl, aminocycloalkyl, hydroxyalkyl, 
       
         
           
           
               
               
           
         
         each of R 4* , R 5* , R 6* and R 7*  is independently selected from hydrogen, (C 1 -C 6 )-alkyl, aminoalkyl, aminocycloalkyl, and hydroxyalkyl, provided that at least one of R 4* , R 5* , R 6* and R 7* is hydrogen, 
         n is selected from 1, 2, 3 and 4, and 
         m is selected from 1, 2 and 3; 
         b. 
       
       
         
           
           
               
               
           
         
         wherein R 8  is selected from —NH(C 1 -C 3 )-alkyl and 
       
       
         
           
           
               
               
           
         
       
       wherein each of R 4* , R 5* , R 6* and R 7* is as described previously;
 c. 
 
       
         
           
           
               
               
           
         
         wherein Z is selected from CR 9 R 10  and NR 11 , 
       
       each of R 9  and R 10  is independently selected from H, NH 2 , —NH(C 1 -C 3 )-alkyl and 
       
         
           
           
               
               
           
         
       
       wherein each of R 4* , R 5* , R 6  and R 7* is as described previously,
 alternatively, R 9  and R 10  together with the carbon to which they are attached, form a cycloalkyl or heterocyclyl ring containing 4-6 ring members, 
 R 11  is selected from H and 
 
       
         
           
           
               
               
           
         
       
       each of R 12 , R 13  and R 14  is independently selected from hydrogen, (C 1 -C 6 )-alkyl, amino alkyl, aminocycloalkyl, and hydroxyalkyl, provided that at least one of R 12 , R 13  and R 14  is hydrogen,
 R 15  is selected from NH 2  and 
 
       
         
           
           
               
               
           
         
       
       wherein each of R 4* , R 5* , R 6* and R 7* is as described previously, 
       each of p* and q* is independently selected from 0, 1, 2 and 3,
 T is selected from NH and O, 
 t is selected from 0, 1, 2, 3, and 4, and 
 each of r and y is independently selected from 0 and 1; 
 d. 
 
       
         
           
           
               
               
           
         
         wherein R 16  is selected from NH 2 , —NH(C 1 -C 3 )-alkyl and 
       
       
         
           
           
               
               
           
         
         wherein each of R 4* , R 5* , R 6* and R 7*  is as described previously, 
         s is selected from 0 and 1, and, 
         v is selected from 0, 1, 2, and 3; 
         e. 
       
       
         
           
           
               
               
           
         
         wherein R 18  is selected from NH 2  and 
       
       
         
           
           
               
               
           
         
       
       wherein each of R 4* , R 5* , R 6* and R 7*  is as described previously,
 R 17  is selected from amino and hydroxyl, and 
 w is selected from 0 and 1; 
 f. 
 
       
         
           
           
               
               
           
         
         wherein M is selected from NR 19 , CR 20 R 21  and O, 
         wherein R 19  is selected from H and 
       
       
         
           
           
               
               
           
         
       
       where each of R 12 , R 13  and R 14  is as described previously,
 each of R 20  and R 21  is independently selected from H, NH 2  and 
 
       
         
           
           
               
               
           
         
       
       wherein each of R 4* , R 5* , R 6* and R 7* is as described previously, and
 u is selected from 0, 1 and 2; and 
 g. 
 
       
         
           
           
               
               
           
         
       
     
     
         52 . The pharmaceutical composition according to  claim 51 , wherein the compound of Formula A-I has the stereochemistry specified in Formula A-II 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         53 . The pharmaceutical composition according to  claim 52 , wherein the compound, or a pharmaceutically acceptable salt thereof is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         54 . The pharmaceutical composition according to  claim 51 , wherein R 1*  is selected from 
       
         
           
           
               
               
           
         
       
     
     
         55 . The pharmaceutical composition according to  claim 53 , wherein the compound is selected from 
       
         
           
           
               
               
           
         
       
     
     
         56 . The pharmaceutical composition according to  claim 55 , wherein the compound or a pharmaceutically acceptable salt thereof has the Formula 
       
         
           
           
               
               
           
         
       
     
     
         57 . The pharmaceutical composition compound according to  claim 55 , wherein the compound or a pharmaceutically acceptable salt thereof has the Formula