Antibacterial Agents

Abstract

Described herein are antibacterial compounds, methods for making the compounds, pharmaceutical compositions containing the compounds and methods of treating bacterial infections utilizing the compounds and pharmaceutical composition.

1 . (canceled) 
   
   
       2 . The compound of of formula I: 
     
       
         
         
             
             
         
       
       or a salt, solvate, or a hydrate thereof, 
       wherein:
 R 1  is a substituted or unsubstituted pyrazine; 
 R 2  and R 3  are independently H or substituted or unsubstituted C 1-6  alkyl; 
 R 4  and R 5  are independently H, a substituted or unsubstituted C 1-6  alkyl, a substituted or unsubstituted ether, substituted or unsubstituted —(CH 2 ) m NR 8 R 9 , substituted or unsubstituted benzyl, —O(CH 2 ) m aryl, —Obenzyl, —(CH 2 ) m NR 8 R 9 , —(CH 2 ) m OR 6 , —(CH 2 ) m OPO 3 (R p ) 2 , —(CH 2 ) m OC(═O)(CH 2 ) m CH 3 , —(CH 2 ) m OC(═O)(CH 2 ) m CO 2 R 6 , —(CH 2 ) m OC(═O)(CH 2 ) m NR 8 R 9 , —(CH 2 ) m OC(═O)E, or R 4 nd R 5  together with the atoms to which they are attached form a substituted or unsubstituted heterocyclic ring; 
 each m is independently 0, 1, 2 or 3; 
 E is a substituted or unsubstituted ether; 
 each R p  is independently H, C 1-6  alkyl, benzyl, substituted benzyl, phenyl, substituted phenyl, or (R p ) 2  together with the atoms to which they are attached form a substituted or unsubstituted heterocyclic ring; 
 each R 6  is independently H, C 1-6  alkyl, C 1-6  acyl or benzyl; 
 R 8  and R 9  are independently H, substituted or unsubstituted C 1-6  alkyl or R 8  and R 9  together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring; and 
 X and Y are independently H, halo, substituted or unsubstituted C 1-6  alkyl, —OR 6 , —CN, a substituted or unsubstituted ether, a substituted or unsubstituted heterocyclyl, or a substituted or unsubstituted amine wherein 
 
     
     
       
         
         
             
             
         
       
          indicates a point of attachment;
 R 7  is H, halo, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted heterocyclyl, a substituted or unsubstituted ether, —CN, —NR 8 R 9 , —OR 10 , —(CH 2 ) m OPO 3 (R p ) 2 , —(CH 2 ) m OC(═O)(CH 2 ) m CH 3 —(CH 2 ) m OC(═O)(CH 2 ) m CO 2 R 6 , —(CH 2 ) m OC(═O)(CH 2 ) m NR 8 R 9 , —(CH 2 ) m OC(═O)E, —(CH 2 ) m CO 2 (CH 2 ) m CH 3 , —(CH 2 ) m CO 2 (CH 2 ) m CO 2 R 6 , —(CH 2 ) m CO 2 (CH 2 ) m NR 8 R 9 , —(CH 2 ) m CO 2 E, —(CH 2 ) m C(═O)NR 6 (CH 2 ) m CO 2 R 6 , —(CH 2 ) m C(═O)NR 8 R 9 , —(CH 2 ) m NR 8 R 9 , —(CH 2 ) m PO 3 (R 11 ) 2 , —(CH 2 ) m OR 10 , which is optionally substituted with —OR 11 , —(CH 2 ) m C(═O)OR 11 , —(CH 2 ) m NR 11 SO n R 12 , —(CH 2 ) m SO n R 12 , —(CH 2 ) m SO n NR 8 R 9 , substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;   each n is independently is 0, 1 or 2;   R 10  is H, substituted or unsubstituted C 1-6  alkyl, —PO 3 H 2 , C(═O)R 13 , C(═O)OR 13  or C(═O)NR 8 R 9  and   
       R 11 , R 12  and R 13  are independently H, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenyl, an amino acid residue or a peptide residue. 
     
   
   
       3 . (canceled) 
   
   
       4 . (canceled) 
   
   
       5 . (canceled) 
   
   
       6 . (canceled) 
   
   
       7 . (canceled) 
   
   
       8 . (canceled) 
   
   
       9 . (canceled) 
   
   
       10 . The compound of formula I: 
     
       
         
         
             
             
         
       
       or a salt, solvate, or a hydrate thereof, 
       wherein:
 R 1  is a substituted or unsubstituted pyrazine; 
 R 2  and R 3  are independently H or substituted or unsubstituted C 1-6  alkyl; 
 R 4  and R 5  are independently H, a substituted or unsubstituted C 1-6  alkyl, a substituted or unsubstituted ether, substituted or unsubstituted —(CH 2 ) m aryl, substituted or unsubstituted benzyl, —O(CH 2 ) m aryl, —Obenzyl, —(CH 2 ) m NR 8 R 9 , —(CH 2 ) m OR 6 , —(CH 2 ) m OPO 3 (R p ) 2 , —(CH 2 ) m OC(═O)(CH 2 ) m CH 3 , —(CH 2 ) m OC(═O)(CH 2 ) m CO 2 R 6 , —(CH 2 ) m OC(═O)(CH 2 ) m NR 8 R 9 , —(CH 2 ) m OC(═O)E, or R 4 nd R 5  together with the atoms to which they are attached form a substituted or unsubstituted heterocyclic ring; 
 each m is independently 0, 1, 2 or 3; 
 E is a substituted or unsubstituted ether; 
 each R p  is independently H, C 1-6  alkyl, benzyl, substituted benzyl, phenyl, substituted phenyl, or (R p ) 2  together with the atoms to which they are attached form a substituted or unsubstituted heterocyclic ring; 
 each R 6  is independently H, C 1-6  alkyl, C 1-6  acyl or benzyl; 
 R 8  and R 9 , are independently H, substituted or unsubstituted C 1-6  alkyl or R 8  and R 9  together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring; and 
 
       X and Y are independently H, halo, substituted or unsubstituted C 1-6  alkyl, —OR 6 , —CN, a substituted or unsubstituted ether, a substituted or unsubstituted heterocyclyl, or a substituted or unsubstituted amine having a structure of compound set forth in Table 1, an enantiomer or diastereomer thereof or a salt, solvate, or hydrate thereof. 
     
   
   
       11 . (canceled) 
   
   
       12 . (canceled) 
   
   
       13 . (canceled) 
   
   
       14 . (canceled) 
   
   
       15 . A bacteriostatic and/or bactericidal method comprising:
 (a) contacting a bacteria with a compound of formula I:   
     
       
         
         
             
             
         
       
       
         or a salt, solvate, or a hydrate thereof, 
         wherein:
 R 1  is a substituted or unsubstituted pyrazine; 
 R 2  and R 3  are independently H or substituted or unsubstituted C 1-6  alkyl; 
 R 4  and R 5  are independently H, a substituted or unsubstituted C 1-6  alkyl, a substituted or unsubstituted ether, substituted or unsubstituted —(CH 2 ) m aryl, substituted or unsubstituted benzyl, —O(CH 2 ) m aryl, —Obenzyl, —(CH 2 ) m NR 8 R 9 , —(CH 2 ) m OR 6 , —(CH 2 ) m OPO 3 (R p ) 2 , —(CH 2 ) m OC(═O)(CH 2 ) m CH 3 , —(CH 2 ) m OC(═O)(CH 2 ) m CO 2 R 6 , —(CH 2 ) m OC(═O)(CH 2 ) m NR 8 R 9 , —(CH 2 ) m OC(═O)E, or R 4 nd R 5  together with the atoms to which they are attached form a substituted or unsubstituted heterocyclic ring; 
 each m is independently 0, 1, 2 or 3; 
 E is a substituted or unsubstituted ether; 
 each R p  is independently H, C 1-6  alkyl, benzyl, substituted benzyl, phenyl, substituted phenyl, or (R p ) 2  together with the atoms to which they are attached form a substituted or unsubstituted heterocyclic ring; 
 each R 6  is independently H, C 1-6  alkyl, C 1-6  acyl or benzyl; 
 R 8  and R 9 , are independently H, substituted or unsubstituted C 1-6  alkyl or R 8  and R 9  together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring; and
 X and Y are independently H, halo, substituted or unsubstituted C 1-6  alkyl, —OR 6 , —CN, a substituted or unsubstituted ether, a substituted or unsubstituted heterocyclyl, or a substituted or unsubstituted amine. 
 
 
       
     
   
   
       16 . The method of  claim 15  wherein (a) occurs in vitro or in vivo. 
   
   
       17 . A method of treating a bacterial infection in a mammal comprising administering an effective amount a compound of formula I: 
     
       
         
         
             
             
         
       
       or a salt, solvate, or a hydrate thereof, 
       wherein:
 R 1  is a substituted or unsubstituted pyrazine; 
 R 2  and R 3  are independently H or substituted or unsubstituted C 1-6  alkyl; 
 R 4  and R 5  are independently H, a substituted or unsubstituted C 1-6  alkyl, a substituted or unsubstituted ether, substituted or unsubstituted —(CH 2 ) m aryl, substituted or unsubstituted benzyl, —O(CH 2 ) m aryl, —Obenzyl, —(CH 2 ) m NR 8 R 9 , —(CH 2 ) m OR 6 , —(CH 2 ) m OPO 3 (R p ) 2 , —(CH 2 ) m OC(═O)(CH 2 ) m CH 3 , —(CH 2 ) m OC(═O)(CH 2 ) m CO 2 R 6 , —(CH 2 ) m OC(═O)(CH 2 ) m NR 8 R 9 , —(CH 2 ) m OC(═O)E, or R 4 nd R 5  together with the atoms to which they are attached form a substituted or unsubstituted heterocyclic ring; 
 each m is independently 0, 1, 2 or 3; 
 E is a substituted or unsubstituted ether; 
 each R p  is independently H, C 1-6  alkyl, benzyl, substituted benzyl, phenyl, substituted phenyl, or (R p ) 2  together with the atoms to which they are attached form a substituted or unsubstituted heterocyclic ring; 
 each R 6  is independently H, C 1-6  alkyl, C 1-6  acyl or benzyl; 
 R 8  and R 9 , are independently H, substituted or unsubstituted C 1-6  alkyl or R 8  and R 9  together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring; and 
 
       X and Y are independently H, halo, substituted or unsubstituted C 1-6  alkyl, —OR 6 , —CN, a substituted or unsubstituted ether, a substituted or unsubstituted heterocyclyl, or a substituted or unsubstituted amine. 
     
   
   
       18 . The method of  claim 17  comprising preventing a bacterial infection in a mammal by administering the effective amount of the compound of formula I: 
     
       
         
         
             
             
         
       
       or a salt, solvate, or a hydrate thereof, 
       wherein:
 R 1  is a substituted or unsubstituted pyrazine; 
 R 2  and R 3  are independently H or substituted or unsubstituted C 1-6  alkyl; 
 R 4  and R 5  are independently H, a substituted or unsubstituted C 1-6  alkyl, a substituted or unsubstituted ether, substituted or unsubstituted —(CH 2 ) m aryl, substituted or unsubstituted benzyl, —O(CH 2 ) m aryl, —Obenzyl, —(CH 2 ) m NR 8 R 9 , —(CH 2 ) m OR 6 , —(CH 2 ) m OPO 3 (R p ) 2 , —(CH 2 ) m OC(═O)(CH 2 ) m CH 3 , —(CH 2 ) m OC(═O)(CH 2 ) m CO 2 R 6 , —(CH 2 ) m OC(═O)(CH 2 ) m NR 8 R 9 , —(CH 2 ) m OC(═O)E, or R 4 nd R 5  together with the atoms to which they are attached form a substituted or unsubstituted heterocyclic ring; 
 each m is independently 0, 1, 2 or 3; 
 E is a substituted or unsubstituted ether; 
 each R p  is independently H, C 1-6  alkyl, benzyl, substituted benzyl, phenyl, substituted phenyl, or (R p ) 2  together with the atoms to which they are attached form a substituted or unsubstituted heterocyclic ring; 
 each R 6  is independently H, C 1-6  alkyl, C 1-6  acyl or benzyl; 
 R 8  and R 9 , are independently H, substituted or unsubstituted C 1-6  alkyl or R 8  and R 9  together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring; and 
 
       X and Y are independently H, halo, substituted or unsubstituted C 1-6  alkyl, —OR 6 , —CN, a substituted or unsubstituted ether, a substituted or unsubstituted heterocyclyl, or a substituted or unsubstituted amine. 
     
   
   
       19 . (canceled) 
   
   
       20 . (canceled) 
   
   
       21 . (canceled) 
   
   
       22 . (canceled) 
   
   
       23 . The method of making the compound of formula IIIa comprising:
 (b) reacting a compound of formula V with a compound of formula VI a to make the compound of formula IIIa,   
     
       
         
         
             
             
         
       
     
   
   
       24 . The method of  claim 23  wherein (b) occurs in the presence of a non-protic organic solvent and/or in the presence of a base. 
   
   
       25 . The method of  claim 24  wherein the base is an organic base or an inorganic base. 
   
   
       26 . The method of  claim 25  wherein the temperature of (b) is about 20 to about 100° C. 
   
   
       27 . The method of  claim 26  further comprising:
 (c)(i) performing a halogen metal exchange or deprotonation reaction on a compound of formula VII; and   (c)(ii) reacting the product of (c)(i) with a carbonyl donor to make the compound of formula V,   
     
       
         
         
             
             
         
       
       wherein Ha is hydrogen or a halogen. 
     
   
   
       28 . The method of  claim 27  wherein (c)(i) comprises contacting the compound of formula VII with a strong base. 
   
   
       29 . The method of  claim 28  wherein the strong base comprises alkyl lithium. 
   
   
       30 . The method of  claim 29  wherein (c)(i) comprises contacting the compounds of formula VII with a Grignard reagent in a non-protic organic solvent. 
   
   
       31 . The method of  claim 30  wherein the temperature of (c)(i) is about −78 to about 50° C. 
   
   
       32 . The method of  claim 31  wherein the carbonyl donor comprises one or more of dimethylformamide, N-formylmorpholine, or para-nitrophenylformate. 
   
   
       33 . The method of  claim 26  further comprising:
 (c) oxidizing a compound of formula VIII to make the compound of formula V,   
     
       
         
         
             
             
         
       
     
   
   
       34 . A method of making the compound of formula XVII comprising
 (a) reacting a compound of formula XVIII with a compound of formula VI a to make the compound of formula XVII,   
     
       
         
         
             
             
         
       
       wherein R 14  is a halogen, boronic acid, a boronate ester or a substituted or unsubstituted pyrazine; and 
       R 2  and R 3  are independently H or substituted or unsubstituted C 1-6  alkyl.