Linked purine pterin hppk inhibitors useful as antibacterial agents

Abstract

The disclosure provides linked purine pterin compounds and analogues thereof that are novel HPPK inhibitors. The HPPK inhibitors described herein are compounds and the pharmaceutically acceptable salts thereof of general Formula I: (I). The variables, e.g. A1 to A3, R1 to R4, L1, L2, B1, and B2 are described herein. Compounds and salts of Formula I bind to HPPK with high affinity and specificity. Pharmaceutical compositions containing an HPPK inhibitor of Formula I and methods of treating a bacterial infection in a patient by providing one or more HPPK inhibitors of Formula I to the patient are also provided. Processes and intermediates useful for preparing compounds of Formula I are also provided. Methods of using the disclosed compounds to guide the development of additional novel anti-bacterial agents are also provided.

1 - 2 . (canceled) 
     
     
         3 . A compound having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         A 1  is oxo; 
         A 3  are each independently hydrogen, halogen, methyl, or methoxy; 
         R 1  is methylene optionally substituted with oxo; 
         R 2  is NH; 
         R 3  is absent or R 3  is an amide, heteroalkylene, cycloalkyl, heterocycloalkyl, phenyl, or 5- or 6membered heteroaryl; and R 3  is unsubstituted or substituted with 1 or more substituents independently chosen from hydroxyl, halogen, amino, C 1 -C 4 alkyl, , C 1 -C 4 alkoxy, mono- and di-C 1 -C 4 alkylamino, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy; 
       
       R 4  in a group 
       
         
           
           
               
               
           
         
       
       is a 5- or 6-membered monosaccharide ring;
 L 1  is an alkylene linker having from 1 to 4 carbon atoms, wherein L 1  is unsubstituted or substituted with 1 or more substituents independently chosen from hydroxyl, halogen, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy. 
 L 2  is an alkylene linker having from 1 to 4 carbon atoms, optionally containing 1 heteroatom selected from oxygen, nitrogen, sulfur, and phosphorus and optionally containing 1 to 2 carbon-carbon double bonds, wherein L 2  is unsubstituted or substituted with 1 or more substituents independently chosen from oxo, hydroxyl, halogen, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy; and 
 B 1  and B 2  are independently chosen from hydrogen, halogen, hydroxyl, amino, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, mono- or di-C 1 -C 2 alkylamino, aminoC 1 -C 2 alkyl, C 1 -C 2 haloalkyl. and C 1 -C 2 haloalkoxy. 
 
     
     
         4 . (canceled) 
     
     
         5 . A compound or salt thereof of  claim 3 , wherein
 each A 3  methyl; and   R 1  is methylene substituted with oxo.   
     
     
         6 - 11 . (canceled) 
     
     
         12 . A compound or salt thereof of  claim 5 , wherein
 R 4  is a 5 or 6-membered monosaccharide ring.   
     
     
         13 . A compound or salt thereof of  claim 12 , wherein R 4  is d-ribose, d-arabinose, d-xylose or d-lyxose. 
     
     
         14 . A compound or salt thereof of  claim 13  wherein
 R 4  is d-ribose and B 1  and B 2  are both hydrogen. 
 
     
     
         15 - 17 . (canceled) 
     
     
         18 . A pharmaceutical composition comprising a compound or salt of  claim 3  and a pharmaceutically acceptable carrier. 
     
     
         19 . A method of treating a condition responsive to HPPK modulation, the method comprising providing a therapeutically effective amount of compound of  claim 3  to a patient having a condition response to HPPK modulation. 
     
     
         20 . The method of  claim 19 , wherein the condition is a bacterial infection. 
     
     
         21 - 27 . (canceled) 
     
     
         28 . A compound or salt of  claim 5 , wherein B 1  and B 2  are both hydrogen.