Substituted pyrimidines for treating bacterial infections

Abstract

The present teachings relate to hydroxypyridinone and hydroxypyrimidinone derivatives, pharmaceutical compositions thereof, and methods of using such compounds to treat bacterial infections.

What is claimed is: 
     
         1 . A compound of Formula II: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 wherein: 
 R 1  is H, C 1-6  alkyl, or C 1-6  alkoxy; 
 R 2  is H, —OR a , —N(R a ) 2 , C 1-6  alkyl, or C 1-6  alkoxy; 
 R 3  is —OH, —NH 2 , or SH; 
 Z is O or S; 
 L 1  is a bivalent radical selected from a bond, —C(═O)—, —(C(═O)O)—, —(C(═O)NR b )—, —N(R b )C(═O)—, —(C 1-4  alkylene)-O—, —(C 1-4  alkylene)-N(R b ), —(C 1-4  alkylene)-S—, or —(C 1-4  alkylene)-S(═O) 2 —; 
 L 2  is a bivalent radical selected from —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-, —(C(R 4 )(R 5 )) n —C 0-3  alkylene)-(C—OR c )—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-C(═O)—, —(C(R 4 (R 5 )) n —(C 0-3  alkylene)-C(═N—OH)—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-(C(═O)NR 5 ) n —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-N(R 5 )C(═O)—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-O—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-N(R 5 )—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-S(═O) 2 —, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-S(═O) 2 N(R 5 )—, or —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-N(R 5 )S(═O) 2 —; 
 wherein each R 4  is H or optionally substituted C 1-6  alkyl; and 
 each R 5  is independently H, an optionally substituted C 1-6  alkyl, an optionally substituted C 1-6  alkenyl, an optionally substituted C 1-6  alkynyl, an optionally substituted C 6-14  aryl, an optionally substituted 5- to 14-membered heteroaryl, an optionally substituted C 3 -C 8  cycloalkyl, on optionally substituted —(C 0-4  alkylene)-OR f , —(C 0-4  alkylene)-(C 1-4  alkene), —(C 0-4  alkylene)-(C 1-4  alkyne), C 2 -C 7  heterocycle, —(C 0-4  alkylene)-C(═O)—(C 1 -C 6  alkyl), —(C 0-4  alkylene)-C(═O)H, —(C 0-4  alkylene)-C(═O)OR f , —(C 0-4  alkylene)-CN, —(C 0-4  alkylene)-halo, —(C 0-4  alkylene)-NO 2 , —(C 0-4  alkylene)-N(R f ) 2 , —(C 0-4  alkylene)-S(═O) 2 —(R 1 ), —(C 0-4  alkylene)-(C 6-14  aryl), —(C 1-4  alkylene)-(5- to 14-membered heteroaryl), —(C 0-4  alkylene)-C(═O)NR b R f  or —(C 0-4  alkylene)-NR b C(═O)R f ; 
 wherein each R f  is independently H, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted alkoxy; 
 L 3  is a bivalent radical selected from —(C 2-6  alkenylene)- or —(C 2-6  alkynylene)-; 
 L 4  is a bivalent radical selected from —C(═O)—, —(C(═O)O)—, —(C(═O)NR e )—, —N(R e )C(═O)—, or —(C 1-4  alkylene)-; 
 G 1  and G 2  are each independently, at each occurrence, a bivalent radical selected from —(C 6-14  arylene)- or -(5- to 14-membered heteroarylene)-; 
 G 3  is H, C 3-7  cycloalkyl, C 3-10  heterocycloalkyl, C 6-14  aryl, 5- to 14-membered heteroarylene, (C 1-4  alkylene)-(C 1-4  heteroalkyl), (C 3-10  heterocycloalkylene)-(C 1-4  alkyl), (C 3-10  heterocycloalkylene)-(C 1-4  heteroalkyl), an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted alkoxy; 
 R a , R b , R c , R d , and R e  are each independently, at each occurrence, H or C 1-6  alkyl; and 
 n is 1 or 2. 
 
     
     
         2 . The compound of  claim 1 , wherein:
 R 1  is H or C 1-6  alkyl;   R 2  is H, —OR a , C 1-6  alkyl, or C 1-6  alkoxy;   R 3  is —OH:   Z is O:   L 1  is a bivalent radical selected from a bond, —C(═O)—, —(C(═O)O)—, —(C(═O)NR b )—, —N(R b )C(═O)—, —(C 1-4  alkylene)-N(R b )—, or —(C 1-4  alkylene)-S(═O) 2 —;   L 2  is a bivalent radical selected from —(C(R 4 )(R 5 ))—(C 0-3  alkylene)-, —(C(R 4 )(R 5 )) n —C 0-3  alkylene)-(C—OR c )—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-C(═O)—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-C(═N—OH)—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-(C(═O)NR 5 )—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-N(R 5 )C(═O)—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-O—, or —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-N(R 5 )—;   wherein each R 4  is H or C 1-6  alkyl; and   each R 5  is independently H, C 1-6  alkyl, —(C 1-4  alkylene)-OR d , —(C 1-4  alkylene)-N(R d ) 2 , or —(C 1-4  alkylene)-S(═O) 2 —(R d );   L 3  is a bivalent radical —(C 1-6  alkynylene)-;   L 4  is a bivalent radical selected from —C(═O)—, —(C(═O)O)—, —(C(═O)NR e )—, —N(R e )C(═O)—, or —(C 1-4  alkylene)-;   G 1  and G 2  are each independently, at each occurrence, a bivalent radical selected from —(C 6  arylene)- or -(5- to 6-membered heteroarylene)-;   G 3  is H, C 3-7  cycloalkyl, C 3-10  heterocycloalkyl, C 6-14  aryl, 5- to 14-membered heteroarylene, (C 1-4  alkylene)-(C 1-4  heteroalkyl), (C 3-10  heterocycloalkylene)-(C 1-4  alkyl), (C 3-10  heterocycloalkylene)-(C 1-4  heteroalkyl), an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted alkoxy;   R a , R b , R c , R d , and R e  are each independently, at each occurrence, H or C 1-6  alkyl; and   n is 1 or 2.   
     
     
         3 . The compound of  claim 1 , wherein:
 R 1  is H or C 1-6  alkyl;   R 2  is H or C 1-6  alkyl;   R 1  is —OH:   Z is O;   L 1  is a bivalent radical selected from a bond, —C(═O)—, —(C(═O)O)—, —(C(═O)NR b )— , or —N(R b )C(═O)—;   L 2  is a bivalent radical —(C(R 4 )(R 5 )) n —(C 1-3  alkylene)-;   wherein each R 4  is H or C 1-6  alkyl; and   each R 5  independently is H, or C 1-6  alkyl;   L 3  is a bivalent radical —(C 1-6  alkynylene)-;   L 4  is a bivalent radical selected from —C(═O)— or —(C 1-4  alkylene)-;   G 1  and G 2  are each independently, at each occurrence, a bivalent radical selected from —(C 6  arylene)- or -(5- to 6-membered heteroarylene)-;   G 3  is H, C 3-7  cycloalkyl, C 3-10  heterocycloalkyl, C 6-14  aryl, 5- to 14-membered heteroarylene, (C 1-4  alkylene)-(C 1-4  heteroalkyl), (C 3-10  heterocycloalkylene)-(C 1-4  alkyl), (C 3-10  heterocycloalkylene)-(C 1-4  heteroalkyl), an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted alkoxy;   R b  is H or C 1-6  alkyl; and   n is 1.   
     
     
         4 . The compound of  claim 1 , wherein
 L 1  bivalent radical selected from a bond, —(C 1-4  alkylene)-O—, —(C 1-4  alkylene)-N(R b )—, —(C 1-4  alkylene)-S—, or —(C 1-4  alkylene)-S(═O) 2 —;   R 2  is H, —OR a , —N(R a ) 2 , C 1-6  alkyl, or C 1-6  alkoxy; and   R b  is H or C 1-6  alkyl.   
     
     
         5 . The compound of  claim 1 , wherein R 5  is —(C 1-4  alkylene)-OR d , —(C 1-4  alkylene)-N(R d ) 2 , —(C 1-4  alkylene)-S(═O) 2 —(R d ), —(C 1-4  alkylene)-(C 6-14  aryl), or —(C 1-4  alkylene)-(5- to 14-membered heteroaryl). 
     
     
         6 . A compound of Formula IV: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 wherein: 
 R 1  is H or C 1-6  alkyl; 
 R 2  is H, —OR a , —N(R a ) 2 , C 1-6  alkyl, or C 1-6  alkoxy; 
 L 1  is a bivalent radical selected from a bond, —C(═O)—, —(C(═O)O)—, —OC(═O)—, —(C(═O)NR b )—, —N(R b )C(═O)—, —N(R b )—, —S(═O) 2 —, —(C 1-4  alkylene)-, —(C 1-4  alkylene)-O—, —(C 1-4  alkylene)-N(R b )—, —(C 1-4  alkylene)-S—, or —(C 1-4  alkylene)-S(═O) 2 —: 
 L 2  is a bivalent radical selected from —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-, —(C(R 4 )(R 5 )) n —C 0-3  alkylene)-(C—OR c )—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-C(═O)—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-C(═N—OH)—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-(C(═O)NR 5 )—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-N(R 5 )C(═O)—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-O—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-N(R 5 )—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-S(═O) 2 —, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-S(═O) 2 N(R 5 )—, or —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-N(R 5 )S(═O) 2 —; 
 wherein each R 4  is H or optionally substituted C 1-6  alkyl; and 
 each R 5  is independently H, an optionally substituted C 1-6  alkyl, an optionally substituted C 1-6  heteroalkyl, an optionally substituted C 1-6  alkenyl, an optionally substituted C 1-6  alkynyl, an optionally substituted C 6-14  aryl, an optionally substituted 5- to 14-membered heteroaryl, an optionally substituted C 3 -C 8  cycloalkyl, on optionally substituted —(C 0-4  alkylene)-OR f , —(C 0-4  alkylene)-(C 1-4  alkene), —(C 0-4  alkylene)-(C 1-4  alkyne), C 2 -C 7  heterocycle, —(C 0-4  alkylene)-C(═O)—(C 1 -C 6  alkyl), —(C 1-4  alkylene)-C(═O)H, —(C 0-4  alkylene)-C(═O)OR f , —(C 0-4  alkylene)-CN, —(C 0-4  alkylene)-halo, —(C 0-4  alkylene)-NO 2 , —(C 1-4  alkylene)-N(R f ) 2 , —(C 1-4  alkylene)-S(═O) 2 —(R f ), —(C 0-4  alkylene)-(C 6-14  aryl), —(C 1-4  alkylene)-(5- to 14-membered heteroaryl), —(C 0-4  alkylene)-C(═O)NR b R f  or —(C 1-4  alkylene)-NR b C(═O)R f : 
 wherein each R f  is independently H, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted alkoxy; 
 L 3  is a bivalent radical selected from —(C 2-6  alkenylene)- or —(C 2-6  alkynylene)-; 
 L 4  is a bivalent radical selected from —C(═O)—, —(C(═O)O)—, —(C(═O)NR e )—, —N(R e )C(═O)—, or —(C 1-4  alkylene)-; 
 G 1  and G 2  are each independently, at each occurrence, a bivalent radical selected from —(C 6-14  arylene)- or -(5- to 14-membered heteroarylene)-; 
 G 3  is H, C 3-7  cycloalkyl, C 3-10  heterocycloalkyl, (C 1-4  alkylene)-(C 1-4  heteroalkyl), (C 3-10  heterocycloalkylene)-(C 1-4  alkyl), (C 3-10  heterocycloalkylene)-(C 1-4  heteroalkyl), an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted alkoxy; and 
 R a , R b , R c , R d , and R e  are each independently, at each occurrence, H or C 1-6  alkyl; and 
 n is 1 or 2. 
 
     
     
         7 . The compound of  claim 6 , wherein:
 R 1  is H or C 1-6  alkyl;   R 2  is H or C 1-6  alkyl;   L 1  is a bivalent radical selected from a bond, —(C(═O)O)—, —(C(═O)NR b )—, —N(R b )C(═O)—, a bond, —(C 1-4  alkylene)-O—, —(C 1-4  alkylene)-N(R b )—, or —(C 1-4  alkylene)-S(═O) 2 —;   L 2  is a bivalent radical is selected from —(C(R 4 )(R 5 )) n —(C 0-3  alkylene), or —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-N(R 5 )—:   wherein each R 4  is H or an optionally substituted C 1-6  alkyl; and   each R 5  is H or C 1-6  alkyl, —C(═O)NR b R f  or —(C 1-4  alkylene)-NR b C(═O)R f ;   wherein R f  is H, an optionally substituted C 1-6  alkyl, an optionally substituted C 1-6  heteroalkyl, an optionally substituted C 1-6  alkenyl, an optionally substituted C 1-6  alkynyl, an optionally substituted C 6-14  aryl, an optionally substituted 5- to 14-membered heteroaryl, an optionally substituted C 3 -C 8  cycloalkyl;   L 4  is a bivalent radical selected from —C(═O)—, —(C(═O)O)—, —(C(═O)NR e )—, —N(R e )C(═O)—, or —(C 1-4  alkylene)-;   G 1  and G 2  are each independently, at each occurrence, a bivalent radical selected from —(C 6-14  arylene)- or -(5- to 14-membered heteroarylene)-;   G 3  is H, C 3-7  cycloalkyl, C 3-10  heterocycloalkyl, C 6-14  aryl, 5- to 14-membered heteroarylene, (C 1-4  alkylene)-(C 1-4  heteroalkyl), (C 3-10  heterocycloalkylene)-(C 1-4  alkyl), (C 3-10  heterocycloalkylene)-(C 1-4  heteroalkyl), an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted alkoxy; and   R b  and R c  are each independently, at each occurrence, H or C 1-6  alkyl; and   n is 1 or 2.   
     
     
         8 . The compound of  claim 6 , wherein
 L 1  bivalent radical selected from a bond, —(C 1-4  alkylene)-O—, —(C 1-4  alkylene)-N(R b )—, —(C 1-4  alkylene)-S—, or —(C 1-4  alkylene)-S(═O) 2 —;   R 2  is H, —OR a , —N(R a ) 2 , C 1-6  alkyl, or C 1-6  alkoxy; and   R b  is H or C 1-6  alkyl.   
     
     
         9 . The compound of  claim 6 , wherein each R 5  is independently —(C 1-4  alkylene)-OR d , —(C 1-4  alkylene)-N(R d ) 2 , —(C 1-4  alkylene)-S(═O) 2 —(R d ), —(C 1-4  alkylene)-(C 6-14  aryl), —(C 1-4  alkylene)-(5- to 14-membered heteroaryl), —C(═O)NR b R f  or —(C 1-4  alkylene)-NR b C(═O)R f ;
 wherein R f  is H, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted cycloalkyl or an optionally substituted heterocyclyl, 
 
     
     
         10 . The compound of any one of  claims 6 - 9 , wherein the compound has the structure of Formula IVA: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The compound of  claim 10 , wherein
 L 2  is a bivalent radical selected from —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-, —(C(R 4 )(R 5 )) n —C 0-3  alkylene)-(C—OR c )—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-C(═O)—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-O—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-N(R 5 )—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-S(═O) 2 —;   wherein each R 4  is H or optionally substituted C 1-6  alkyl; and   each R 5  is independently H, an optionally substituted C 1-6  alkyl, an optionally substituted C 1-6  heteroalkyl, an optionally substituted C 1-6  alkenyl, an optionally substituted C 1-6  alkynyl, an optionally substituted C 6-14  aryl, an optionally substituted 5- to 14-membered heteroaryl, an optionally substituted C 3 -C 8  cycloalkyl, on optionally substituted —(C 0-4  alkylene)-OR f , —(C 1-4  alkylene)-(C 1-4  alkene), —(C 0-4  alkylene)-(C 1-4  alkyne), C 2 -C 7  heterocycle, —(C 0-4  alkylene)-C(═O)—(C 1 -C 6  alkyl), —(C 0-4  alkylene)-C(═O)H, —(C 0-4  alkylene)-C(═O)OR f , —(C 0-4  alkylene)-CN, —(C 0-4  alkylene)-halo, —(C 0-4  alkylene)-NO 2 , —(C 1-4  alkylene)-N(R f ) 2 , —(C 1-4  alkylene)-S(═O) 2 —(R f ), —(C 0-4  alkylene)-(C 6-14  aryl), —(C 1-4  alkylene)-(5- to 14-membered heteroaryl), —(C 0-4  alkylene)-C(═O)NR b R f  or —(C 0-4  alkylene)-NR b C(═O)R f :   wherein each R f  is independently H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted alkoxy:   L 3  is —(C 2-6  alkynylene)-;   L 4  is a bivalent radical selected from —C(═O)—, —(C(═O)O)—, —(C(═O)NR e )—, —N(R e )C(═O)—, or —(C 1-4  alkylene)-;   G 1  and G 2  are each independently, at each occurrence, —(C 6-14  arylene)-;   G 3  is H, C 3-7  cycloalkyl, C 3-10  heterocycloalkyl, C 6-14  aryl, 5- to 14-membered heteroarylene, (C 1-4  alkylene)-(C 1-4  heteroalkyl), (C 3-10  heterocycloalkylene)-(C 1-4  alkyl), (C 3-10  heterocycloalkylene)-(C 1-4  heteroalkyl), an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted alkoxy; and   R a , R b , R c , R d , and R e  are each independently, at each occurrence, H or C 1-6  alkyl; and   n is 1 or 2.   
     
     
         12 . The compound of either of  claim 10  or  11 , wherein
 L 2  is —(C(R 4 )(R 5 )) n —(C 1-3  alkylene)-, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-N(R 5 )—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-S(═O) 2 —; 
 wherein each R 4  is H or optionally substituted C 1-6  alkyl; and 
 each R 5  is independently H, an optionally substituted C 1-6  alkyl, an optionally substituted C 1-6  heteroalkyl, an optionally substituted C 1-6  alkenyl, an optionally substituted C 1-6  alkynyl, an optionally substituted C 6-14  aryl, an optionally substituted 5- to 14-membered heteroaryl, an optionally substituted C 3 -C 8  cycloalkyl, on optionally substituted —(C 0-4  alkylene)-OR f , —(C 0-4  alkylene)-(C 1-4  alkene), —(C 0-4  alkylene)-(C 1-4  alkyne), C 2 -C 7  heterocycle, —(C 0-4  alkylene)-C(═O)—(C 1 -C 6  alkyl), —(C 0-4  alkylene)-C(═O)H, —(C 0-4  alkylene)-C(═O)OR f , —(C 0-4  alkylene)-CN, —(C 0-4  alkylene)-halo, —(C 0-4  alkylene)-NO 2 , —(C 0-4  alkylene)-N(R f ) 2 , —(C 0-4  alkylene)-S(═O) 2 —(R f ), —(C 0-4  alkylene)-(C 6-14  aryl), —(C 1-4  alkylene)-(5- to 14-membered heteroaryl), —(C 0-4  alkylene)-C(═O)NR b R f  or —(C 0-4  alkylene)-NR b C(═O)R f : 
 wherein each R f  is independently H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted alkoxy; 
 L 3  is —(C 1-6  alkynylene)-; 
 L 4  is —C(═O)—, —(C(═O)O)—, —(C(═O)NR e )—, or —(C 1-4  alkylene)-; 
 G 1  and G 2  are each independently, at each occurrence, —(C 6-14  arylene)-; 
 G 3  is H, C 3-7  cycloalkyl, C 3-10  heterocycloalkyl, C 6-14  aryl, 5- to 14-membered heteroarylene, (C 1-4  alkylene)-(C 1-4  heteroalkyl), (C 1-4  alkylene)-(C 1-4  heterocycloalkyl), (C 3-10  heterocycloalkylene)-(C 1-4  alkyl), (C 3-10  heterocycloalkylene)-(C 1-4  heteroalkyl), (C 3-10  heterocycloalkylene)-(C 3-10  heterocycloalkyl), C 1-6  alkyl, or (C 3-10  heterocycloalkylene)-hydroxy; and 
 R a , R b , R c , R d , and R e  are each independently, at each occurrence, H or C 1-6  alkyl; and 
 n is 1 or 2. 
 
     
     
         13 . The compound of any one of  claims 10 - 12 , wherein G 3  is H, C 3-10  heterocycloalkyl, (C 1-4  alkylene)-(C 1-4  heteroalkyl), (C 1-4  alkylene)-(C 1-4  heterocycloalkyl), (C 1-10  heterocycloalkylene)-(C 1-4  heteroalkyl), (C 3-10  heterocycloalkylene)-(C 3-10  heterocycloalkyl), C 1-6  alkyl, (C 3-10  heterocycloalkylene)-hydroxy, or tetrazolyl. 
     
     
         14 . The compound of any one of  claims 6 - 9 , wherein the compound has the structure of Formula IVB: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The compound of  claim 14 , wherein
 L 2  is a bivalent radical selected from —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-, —(C(R 4 )(R 5 )) n —C 0-3  alkylene)-(C—OR c )—, —(C(R 4 )(R 5 )) n —(C 1-3  alkylene)-C(═O)—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-O—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-N(R 5 )—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-S(═O) 2 —;   wherein each R 5  is H or optionally substituted C 1-6  alkyl; and   each R 5  is independently H, an optionally substituted C 1-6  alkyl, an optionally substituted C 1-6  heteroalkyl, an optionally substituted C 1-6  alkenyl, an optionally substituted C 1-6  alkynyl, an optionally substituted C 6-14  aryl, an optionally substituted 5- to 14-membered heteroaryl, an optionally substituted C 3 -C 8  cycloalkyl, on optionally substituted —(C 0-4  alkylene)-OR f , —(C 0-4  alkylene)-(C 1-4  alkene), —(C 0-4  alkylene)-(C 1-4  alkyne), C 2 -C 7  heterocycle, —(C 0-4  alkylene)-C(═O)—(C 1 -C 6  alkyl), —(C 1-4  alkylene)-C(═O)H, —(C 0-4  alkylene)-C(═O)OR f , —(C 0-4  alkylene)-CN, —(C 0-4  alkylene)-halo, —(C 0-4  alkylene)-NO 2 , —(C 1-4  alkylene)-N(R f ) 2 , —(C 0-4  alkylene)-S(═O) 2 —(R f ), —(C 0-4  alkylene)-(C 6-14  aryl), —(C 1-4  alkylene)-(5- to 14-membered heteroaryl), —(C 1-4  alkylene)-C(═O)NR b R f  or —(C 1-4  alkylene)-NR b C(═O)R f ;   wherein each R f  is independently H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted alkoxy:   L 3  is —(C 2-6  alkynylene)-;   L 4  is a bivalent radical selected from —C(═O)—, —(C(═O)O)—, —(C(═O)NR e )—, —N(R e )C(═O)—, or —(C 1-4  alkylene)-;   G 3  is H, C 3-7  cycloalkyl, C 3-10  heterocycloalkyl, C 6-14  aryl, 5- to 14-membered heteroarylene, (C 1-4  alkylene)-(C 1-4  heteroalkyl), (C 3-10  heterocycloalkylene)-(C 1-4  alkyl), (C 3-10  heterocycloalkylene)-(C 1-4  heteroalkyl), an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted alkoxy; and   R a , R b , R c , R d , and R e  are each independently, at each occurrence, H or C 1-6  alkyl; and   n is 1 or 2.   
     
     
         16 . The compound of either of  claim 14  or  15 , wherein
 L 2  is —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-N(R 5 )—, —(C(R 4 )(R 5 ))—(C 0-3  alkylene)-S(═O) 2 —: 
 wherein each R 4  is H or optionally substituted C 1-6  alkyl; and 
 each R 5  is independently H, an optionally substituted C 1-6  alkyl, an optionally substituted C 1-6  heteroalkyl, an optionally substituted C 1-6  alkenyl, an optionally substituted C 1-6  alkynyl, an optionally substituted C 6-14  aryl, an optionally substituted 5- to 14-membered heteroaryl, an optionally substituted C 3 -C 8  cycloalkyl, on optionally substituted —(C 0-4  alkylene)-OR f , —(C 1-4  alkylene)-(C 1-4  alkene), —(C 0-4  alkylene)-(C 1-4  alkyne), C 2 -C 7  heterocycle, —(C 0-4  alkylene)-C(═O)—(C 1 -C 6  alkyl), —(C 0-4  alkylene)-C(═O)H, —(C 0-4  alkylene)-C(═O)OR f , —(C 0-4  alkylene)-CN, —(C 0-4  alkylene)-halo, —(C 0-4  alkylene)-NO 2 , —(C 1-4  alkylene)-N(R f ) 2 , —(C 0-4  alkylene)-S(═O) 2 —(R f ), —(C 0-4  alkylene)-(C 6-14  aryl), —(C 1-4  alkylene)-(5- to 14-membered heteroaryl), —(C 0-4  alkylene)-C(═O)NR b R f  or —(C 1-4  alkylene)-NR b C(═O)R f ; 
 wherein each R f  is independently H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted alkoxy: 
 L 3  is —(C 2-6  alkynylene)-; 
 L 4  is —C(═O)—, —(C(═O)O)—, —(C(═O)NR c )—, or —(C 1-4  alkylene)-; 
 G 3  is H, C 3-7  cycloalkyl, C 3-10  heterocycloalkyl, C 6-14  aryl, 5- to 14-membered heteroarylene, (C 1-4  alkylene)-(C 1-4  heteroalkyl), (C 1-4  alkylene)-(C 1-4  heterocycloalkyl), (C 3-10  heterocycloalkylene)-(C 1-4  alkyl), (C 3-10  heterocycloalkylene)-(C 1-4  heteroalkyl), (C 3-10  heterocycloalkylene)-(C 3-10  heterocycloalkyl), C 1-6  alkyl, or (C 3-10  heterocycloalkylene)-hydroxy; and 
 R a , R b , R c , R d , and R e  are each independently, at each occurrence, H or C 1-6  alkyl; and 
 n is 1 or 2. 
 
     
     
         17 . The compound of any one of  claims 14 - 16 , wherein G 3  is H, C 3-10  heterocycloalkyl, (C 1-4  alkylene)-(C 1-4  heteroalkyl), (C 1-4  alkylene)-(C 1-4  heterocycloalkyl), (C 3-10  heterocycloalkylene)-(C 1-4  heteroalkyl), (C 3-10  heterocycloalkylene)-(C 3-10  heterocycloalkyl), C 1-6  alkyl, (C 3-10  heterocycloalkylene)-hydroxy, or tetrazolyl. 
     
     
         18 . A compound of Formula V: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 wherein: 
 R 1  is H, —OH, —NH 2 , or SH; 
 R 2  is H, —OR a , —N(R a ) 2 , C 1-6  alkyl, or C 1-6  alkoxy; 
 R 3  is H, —OH, —NH 2 , or SH; 
 R 6  and R 7  are each independently, at each occurrence, —OH, —NH 2 , —CN, —NO 2 , —C(═O)OR b , —C(═O)N(R b ) 2 , —N(R b )C(═O)OR b , halo, C 1-6  alkyl, C 1-6  alkoxy, ═O, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted alkoxy; 
 ring R is C 3-7  cycloalkyl, C 3-10  heterocycloalkyl, C 6-14  aryl, or a 5- to 14-membered heteroaryl; 
 ring T is C 3-7  cycloalkyl, C 3-10  heterocycloalkyl, C 6-14  aryl, or a 5- to 14-membered heteroaryl; 
 X is CH, S, or N; 
 Z is O or S; 
 L 1  is a bivalent radical selected from a bond, —C(═O)—, —(C(═O)O)—, —OC(═O)—, —(C(═O)NR c )—, —N(R c )C(═O)—, —N(R c )—, —S(═O) 2 —, —(C 1-4  alkylene)-, —(C 1-4  alkylene)-O—, —(C 1-4  alkylene)-N(R f )—, —(C 1-4  alkylene)-S—, or —(C 1-4  alkylene)-S(═O) 2 —; 
 L 2  is a bivalent radical selected from —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-, —(C(R 4 )(R 5 )) n —C 0-3  alkylene)-(C—OR c )—, —(C(R 4 )(R 5 )) n —(C 1-3  alkylene)-C(═O)—, —(C(R 4 )(R 5 )) n —(C 1-3  alkylene)-C(═N—OH)—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-(C(═O)NR 5 )—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-N(R 5 )C(═O)—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-O—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-N(R 5 )—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-S(═O) 2 —, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-S(═O) 2 N(R 5 )—, or —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-N(R 5 )S(═O) 2 —; 
 wherein each R 4  is H or optionally substituted C 1-6  alkyl; and 
 each R 5  is independently H, an optionally substituted C 1-6  alkyl, an optionally substituted C 1-6  heteroalkyl, an optionally substituted C 1-6  alkenyl, an optionally substituted C 1-6  alkynyl, an optionally substituted C 6-14  aryl, an optionally substituted 5- to 14-membered heteroaryl, an optionally substituted C 3 -C 8  cycloalkyl, on optionally substituted —(C 0-4  alkylene)-OR f , —(C 0-4  alkylene)-(C 1-4  alkene), —(C 0-4  alkylene)-(C 1-4  alkyne), C 2 -C 7  heterocycle, —(C 0-4  alkylene)-C(═O)—(C 1 -C 6  alkyl), —(C 0-4  alkylene)-C(═O)H, —(C 0-4  alkylene)-C(═O)OR f , —(C 0-4  alkylene)-CN, —(C 0-4  alkylene)-halo, —(C 0-4  alkylene)-NO 2 , —(C 0-4  alkylene)-N(R f ) 2 , —(C 0-4  alkylene)-S(═O) 2 —(R f ), —(C 0-4  alkylene)-(C 6-14  aryl), —(C 1-4  alkylene)-(5- to 14-membered heteroaryl), —(C 0-4  alkylene)-C(═O)NR b R f  or —(C 0-4  alkylene)-NR b C(═O)R f : 
 wherein each R f  is independently H, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted alkoxy; 
 L 3  is a bivalent radical selected from a bond, —(C 1-6  alkylene)-, —(C 2-6  alkenylene)-, or —(C 2-6  alkynylene)-, —(C 3-10  heterocycloalkylene)-, —(C 6-14  arylene)-, -(5- to 14-membered heteroarylene)-; 
 R a , R b , R c , R d , and R e  are each independently, at each occurrence, H or C 1-6  alkyl; 
 n is 1 or 2; 
 p is 0, 1, 2, or 3; and 
 r is 0, 1, 2, or 3. 
 
     
     
         19 . The compound of  claim 18 , wherein R k  is —(C 1-4  alkylene)OR d , —(C 1-4  alkylene)-N(R d ) 2 , —(C 1-4  alkylene)-S(═O) 2 —(R d ), —(C 1-4  alkylene)-(C 6-14  aryl), or —(C 1-4  alkylene)-(5- to 14-membered heteroaryl). 
     
     
         20 . The compound of either one of  claim 18  or  19 , wherein p is 1, and R 6  is ═O. 
     
     
         21 . A compound of Formula VI: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 wherein: 
 R 1  is H, C 1-6  alkyl, —OH, —NH 2 , or SH; 
 R 2  is H, —OR a , —N(R a ) 2 , C 1-6  alkyl, or C 1-6  alkoxy; 
 R 1  is H, C 1-6  alkyl, —OH, —NH 2 , or SH; 
 R 6  and R 7  are each independently, at each occurrence, —OH, —NH 2 , —CN, —NO 2 , —C(═O)OR b , —C(═O)N(R b ) 2 , —N(R b )C(═O)OR b , halo, C 1-6  alkyl, C 1-6  alkoxy, ═O, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted alkoxy: 
 ring R is C 3-7  cycloalkyl, C 3-10  heterocycloalkyl, C 6-14  aryl, or a 5- to 14-membered heteroaryl; 
 ring T is C 3-7  cycloalkyl, C 3-10  heterocycloalkyl, C 6-14  aryl, or a 5- to 14-membered heteroaryl; 
 X is C(H), S, or N; 
 Z is O or S; 
 L 1  is a bivalent radical selected from a bond, —C(═O)—, —(C(═O)O)—, —OC(═O)—, —(C(═O)NR b )—, —N(R b )C(═O)—, —N(R b )—, —S(═O) 2 —, —(C 1-4  alkylene)-, —(C 1-4  alkylene)-O—, —(C 1-4  alkylene)-N(R b )—, —(C 1-4  alkylene)-S—, or —(C 1-4  alkylene)-S(═O) 2 —; 
 L 2  is a bivalent radical selected from —(C(R 4 )(R 5 )),—(C 0-3  alkylene)-, —(C(R 4 )(R 5 )) n —C 0-3  alkylene)-(C—OR c )—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-C(═O)—, —(C(R 4 )(R 5 )) n —(C 1-3  alkylene)-C(═N—OH)—, —(C(R a )(R 5 )) n —(C 0-3  alkylene)-(C(═O)NR 5 )—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-N(R 5 )C(═O)—, —(C(R 4 )(R 5 )) n (C 0-3  alkylene)-O—, —(C(R 4 )(R 5 )) n (C 0-3  alkylene)-N(R 5 )—, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-S(═O) 2 —, —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-S(═O) 2 N(R 5 )—, or —(C(R 4 )(R 5 )) n —(C 0-3  alkylene)-N(R 5 )S(═O) 2 —; 
 wherein each R 4  is H or optionally substituted C 1-6  alkyl; and 
 each R 5  is independently H, an optionally substituted C 1-6  alkyl, an optionally substituted C 1-6  heteroalkyl, an optionally substituted C 1-6  alkenyl, an optionally substituted C 1-6  alkynyl, an optionally substituted C 6-14  aryl, an optionally substituted 5- to 14-membered heteroaryl, an optionally substituted C 3 -C 8  cycloalkyl, on optionally substituted —(C 0-4  alkylene)-OR f , —(C 0-4  alkylene)-(C 1-4  alkene), —(C 0-4  alkylene)-(C 1-4  alkyne), C 2 -C 7  heterocycle, —(C 0-4  alkylene)-C(═O)—(C 1 -C 6  alkyl), —(C 0-4  alkylene)-C(═O)H, —(C 0-4  alkylene)-C(═O)OR f , —(C 0-4  alkylene)-CN, —(C 0-4  alkylene)-halo, —(C 0-4  alkylene)-NO 2 , —(C 0-4  alkylene)-N(R f ) 2 , —(C 0-4  alkylene)-S(═O) 2 —(R f ), —(C 0-4  alkylene)-(C 6-14  aryl), —(C 1-4  alkylene)-(5- to 14-membered heteroaryl), —(C 0-4  alkylene)-C(═O)NR b R f  or —(C 0-4  alkylene)-NR b C(═O)R f : 
 wherein each R f  is independently H, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted alkoxy; 
 L 3  is a bivalent radical selected from a bond, —(C 1-6  alkylene)-, —(C 2-6  alkenylene)-, or —(C 2-6  alkynylene)-, —(C 3-10  heterocycloalkylene)-, —(C 6-14  arylene)-, -(5- to 14-membered heteroarylene)-; 
 R a , R b , R c , R d , and R e  are each independently, at each occurrence, H or C 1-6  alkyl; 
 n is 1 or 2; 
 p is 0, 1, 2, or 3; and 
 r is 0, 1, 2, or 3. 
 
     
     
         22 . The compound of  claim 21 , wherein R 5  is —(C 1-4  alkylene)-OR d , —(C 1-4  alkylene)-N(R d ), —(C 1-4  alkylene)-S(═O) 2 —(R d ), —(C 1-4  alkylene)-(C 6-14  aryl), or —(C 1-4  alkylene)-(5- to 14-membered heteroaryl). 
     
     
         23 . The compound of either one of  claim 21  or  22 , wherein p is 1, and R 6  is ═O. 
     
     
         24 . A method of modulating the activity of UDP-{3-O—[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase in a subject in need thereof comprising administering a therapeutically effective amount of a compound of any one of  claims 1 - 23  or a pharmaceutically acceptable salt thereof. 
     
     
         25 . A method of treating a gram-negative bacterial infection in a subject comprising administering to the subject a pharmaceutical composition comprising the compound of any one of  claims 1 - 23 , or a pharmaceutically acceptable salt thereof. 
     
     
         26 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of  claims 1 - 23 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.