Antibacterial 3,5-diaminopiperidine-substituted aromatic and heteroaromatic compounds

Abstract

The invention relates to antibacterial 3,5-diaminopiperidine-substituted aromatic and heteroaromatic compounds and pharmaceutical compositions thereof. This invention also relates to a method of using such compounds in the treatment of bacterial infections in mammals, especially humans.

1 - 14 . (canceled)  
   
   
       15 . A method of inhibiting a microorganism comprising administering to the microorganism an effective amount of a composition comprising the compound of formula I  
     
       
         
         
             
             
         
       
     
     wherein: 
 Ring A is a 5- or 6-membered mono- or bicyclic aryl or heteroaryl;  
 M 1  and M 2  are independently —H, halo, —CF 3 , —CN, —NO 2 , —CONH 2 , —COOH, —OH, or —NHNH 2 , or an unsubstituted or substituted —(C 1 -C 6 )alkyl, aryl, heteroaryl, —(CH 2 ) n -aryl, —(CH 2 ) n -heteroaryl, —(CH 2 ) n -heterocycloalkyl, —(CH═CH) n -aryl, —(CH═CH) n -heteroaryl, —(C 2 -C 6 )alkenyl-aryl, —(C 2 -C 6 )alkenyl-heteroaryl, —(C≡C) n -aryl, —(C≡C) n -heteroaryl, —O—(C 1 -C 6 )alkyl, —O-aryl, —O-heteroaryl, —O-cycloalkyl, —O-heterocycloalkyl, —S—(C 1 -C 6 )alkyl, —S-aryl, —S-heteroaryl, —S-cycloalkyl, —S-heterocycloalkyl, —(C═O)(C 1 -C 6 )alkyl, —(C═O)aryl, —(C═O)heterocycloalkyl, —O(C═O)—(C 1 -C 6 )alkyl, —(C═O)O—(C 1 -C 6 )alkyl, —(S═O)aryl, —(S═O)heterocycloalkyl, —S(O) 2 aryl, —S(O) 2 heterocycloalkyl, —NHC(NH)-aryl, —NHNH-aryl, —NHNHC(O)-aryl, —NHNH-cycloheteroalkyl, —NHNHS(O) 2 -aryl, —NHOH, —NHO—(C 1 -C 6 )alkyl, —N(OH)—(C 1 -C 6 )alkyl, —N((C 1 -C 6 )alkyl)O—(C 1 -C 6 )alkyl, —NHNHC(S)NH—(C 1 -C 6 )alkyl, —NHNH-heteroaryl, or —N(R 1 )R 2 , wherein R 1  and R 2  are independently selected from —H, a substituted or unsubstituted alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, or R 1  and R 2  together with the N atom form a 4-, 5-, or 6-membered substituted or unsubstituted heterocycloalkyl, wherein n is an integer from 1-4;  
 X n  is independently selected from —H, halo, —CF 3 , —CN, —COOH, —OH, —NH 2 , —NO 2 , —C(O)N(R 3 )R 4  wherein R 3  and R 4  are independently —(C 1 -C 6 )alkyl or —H, and optionally substituted —O—(C 1 -C 6 )alkyl or —(C 1 -C 6 )alkyl;  
 or a pharmaceutically acceptable salt, hydrate, or solvate thereof.  
 
   
   
       16 . The method of  claim 15  wherein the compound is wherein Ring A is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       17 . The method of  claim 15  wherein the compound is wherein Ring A is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       18 . The method of  claim 15  wherein the compound is wherein Ring A is Formula Ia.  
   
   
       19 . The method of  claim 15  wherein the compound is wherein M 1  and M 2  are each —N(R 1 )R 2 .  
   
   
       20 . The method of  claim 15  wherein the compound is wherein the compound is M 1  and M 2  are independently selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       21 . The method of  claim 15  wherein the compound is wherein M 2  is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
   
   
       22 . The method of  claim 15  wherein the compound is wherein Ring A is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       23 . The method of  claim 15  wherein the compound is wherein Ring A is Formula Ia.  
   
   
       24 . A method of treating a bacterial infection in a mammal comprising administering to the mammal in need thereof an effective amount of a composition comprising the compound of formula I  
     
       
         
         
             
             
         
       
     
     wherein: 
 Ring A is a 5- or 6-membered mono- or bicyclic aryl or heteroaryl;  
 M 1  and M 2  are independently —H, halo, —CF 3 , —CN, —NO 2 , —CONH 2 , —COOH, —OH, or —NHNH 2 , or an unsubstituted or substituted —(C 1 -C 6 )alkyl, aryl, heteroaryl, —(CH 2 ) n -aryl, —(CH 2 ) n -heteroaryl, —(CH 2 ) n -heterocycloalkyl, —(CH═CH) n -aryl, —(CH═CH) n -heteroaryl, —(C 2 -C 6 )alkenyl-aryl, —(C 2 -C 6 )alkenyl-heteroaryl, —(C≡C) n -aryl, —(C≡C) n -heteroaryl, —O—(C 1 -C 6 )alkyl, —O-aryl, —O-heteroaryl, —O-cycloalkyl, —O-heterocycloalkyl, —S—(C 1 -C 6 )alkyl, —S-aryl, —S-heteroaryl, —S-cycloalkyl, —S-heterocycloalkyl, —(C═O)(C 1 -C 6 )alkyl, —(C═O)aryl, —(C═O)heterocycloalkyl, —O(C═O)—(C 1 -C 6 )alkyl, —(C═O)O—(C 1 -C 6 )alkyl, —(S═O)aryl, —(S═O)heterocycloalkyl, —S(O) 2 aryl, —S(O) 2 heterocycloalkyl, —NHC(NH)-aryl, —NHNH-aryl, —NHNHC(O)-aryl, —NHNH-cycloheteroalkyl, —NHNHS(O) 2 -aryl, —NHOH, —NHO—(C 1 -C 6 )alkyl, —N(OH)—(C 1 -C 6 )alkyl, —N((C 1 -C 6 )alkyl)O—(C 1 -C 6 )alkyl, —NHNHC(S)NH—(C 1 -C 6 )alkyl, —NHNH-heteroaryl, or —N(R 1 )R 2 , wherein R 1  and R 2  are independently selected from —H, a substituted or unsubstituted alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, or R 1  and R 2  together with the N atom form a 4-, 5-, or 6-membered substituted or unsubstituted heterocycloalkyl, wherein n is an integer from 1-4;  
 X n  is independently selected from —H, halo, —CF 3 , —CN, —COOH, —OH, —NH 2 , —NO 2 , —C(O)N(R 3 )R 4  wherein R 3  and R 4  are independently —(C 1 -C 6 )alkyl or —H, and optionally substituted —O—(C 1 -C 6 )alkyl or —(C 1 -C 6 )alkyl;  
 or a pharmaceutically acceptable salt, hydrate, or solvate thereof.  
 
   
   
       25 . The method of  claim 24  wherein the mammal is a human.  
   
   
       26 . The method of  claim 24  wherein the compound is wherein Ring A is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       27 . The method of  claim 24  wherein the compound is wherein Ring A is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       28 . The method of  claim 24  wherein the compound is wherein Ring A is Formula Ia.  
   
   
       29 . The method of  claim 24  wherein the compound is wherein M 1  and M 2  are each —N(R 1 )R 2 .  
   
   
       30 . The method of  claim 24  wherein the compound is wherein the compound is M 1  and M 2  are independently selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       31 . The method of  claim 24  wherein the compound is wherein M 2  is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
   
   
       32 . The method of  claim 24  wherein the compound is wherein Ring A is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       33 . The method of  claim 24  wherein the compound is wherein Ring A is Formula Ia.