Antibacterial agents

Abstract

Antibacterial compounds of formula (I) are provided: as well as stereoisomers and pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds; methods of treating bacterial infections by the administration of such compounds; and processes for the preparation of such compounds.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
 A is selected from the group consisting of:
 (a) substituted C 1 -C 6  alkyl, wherein at least one substituent is hydroxy; and 
 (b) substituted C 3 -C 6  cycloalkyl, wherein at least one substituent is selected from hydroxy and hydroxyalkyl; 
 
 G is selected from the group consisting of:
 (a) —CH═CH—C≡C—; 
 (b) —C≡C—CH═CH—; 
 
 (c) —C≡C—C≡C—; 
 
       
         
           
           
               
               
           
         
         D is: 
       
       
         
           
           
               
               
           
         
       
       wherein W is N or N + —O − ; and
 E is —C(CH 3 ) 2 SCH 3 , —C(CH 3 ) 2 S(O)CH 3 , —C(CH 3 ) 2 S(O) 2 CH 3 , or —C(O)NHCH 3 . 
 
     
     
         2 . A compound according to  claim 1 , wherein A is substituted C 1 -C 6  alkyl, wherein at least one substituent is hydroxy. 
     
     
         3 . A compound according to  claim 2 , wherein A is substituted C 1 -C 6  alkyl, wherein at least two substituents are hydroxy. 
     
     
         4 . A compound according to  claim 2 , wherein A is hydroxymethyl, hydroxyethyl, hydroxypropyl or dihydroxypropyl. 
     
     
         5 . A compound according to  claim 1 , wherein A is substituted C 3 -C 6  cycloalkyl, wherein at least one substituent is selected from hydroxy and hydroxyalkyl. 
     
     
         6 . A compound according to  claim 5 , wherein A is substituted C 3 -C 6  cycloalkyl, wherein at least one substituent is hydroxymethyl. 
     
     
         7 . A compound according to  claim 6 , wherein A is hydroxymethylcyclopropyl. 
     
     
         8 . A compound according to  claim 5 , wherein A is substituted C 3 -C 6  cycloalkyl, wherein at least one substituent is hydroxy. 
     
     
         9 . A compound according to  claim 1 , wherein G is —C≡C—C≡C—. 
     
     
         10 - 15 . (canceled) 
     
     
         16 . A compound according to  claim 1 , wherein E is —C(CH 3 ) 2 SCH 3 . 
     
     
         17 . A compound according to  claim 1 , wherein E is —C(CH 3 ) 2 S(O) 2 CH 3 . 
     
     
         18 . A compound according to  claim 1 , wherein E is —C(CH 3 ) 2 S(O)CH 3 . 
     
     
         19 . A compound according to  claim 1 , wherein E is —C(O)NHCH 3 . 
     
     
         20 . A compound, or a pharmaceutically acceptable salt thereof, of  claim 1 , selected from the group consisting of:
 N-hydroxy-2-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)phenyl)-1,6-naphthyridine-4-carboxamide (Compound 1);   N-hydroxy-2-(4-(6-hydroxyhexa-1,3-diynyl)phenyl)-1,6-naphthyridine-4-carboxamide (Compound 10);   N-hydroxy-2-(4-(5-hydroxypenta-1,3-diynyl)phenyl)-1,6-naphthyridine-4-carboxamide (Compound 11);   N-hydroxy-2-(4-(5-hydroxyhexa-1,3-diynyl)phenyl)-1,6-naphthyridine-4-carboxamide (Compound 12);   N-hydroxy-2-(4-(6-hydroxy-5-methylhexa-1,3-diynyl)phenyl)-1,6-naphthyridine-4-carboxamide (Compound 13);   2-(4-(5,6-dihydroxyhexa-1,3-diynyl)phenyl)-N-hydroxy-1,6-naphthyridine-4-carboxamide (Compound 14);   2-(4-(6,7-dihydroxyhepta-1,3-diynyl)phenyl)-N-hydroxy-1,6-naphthyridine-4-carboxamide (Compound 15);   N-hydroxy-2-(4-((3-(hydroxymethyl)cyclobutyl)buta-1,3-diynyl)phenyl)-1,6-naphthyridine-4-carboxamide (Compound 16);   N-hydroxy-2-(4-((3-hydroxycyclobutyl)buta-1,3-diynyl)phenyl)-1,6-naphthyridine-4-carboxamide (Compound 18);   N-hydroxy-2-(4-((3-(hydroxymethyl)cyclopentyl)buta-1,3-diynyl)phenyl)-1,6-naphthyridine-4-carboxamide (Compound 19);   N-hydroxy-2-(4-(((1R,2S)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)phenyl)-1,6-naphthyridine-4-carboxamide (Compound 20);   N-hydroxy-2-(4-(6-hydroxy-5-methoxyhexa-1,3-diynyl)phenyl)-1,6-naphthyridine-4-carboxamide (Compound 21);   N-hydroxy-2-(4-(7-hydroxy-6-methoxyhepta-1,3-diynyl)phenyl)-1,6-naphthyridine-4-carboxamide (Compound 22);   4-(hydroxycarbamoyl)-2-(4-(6-hydroxyhexa-1,3-diynyl)phenyl)-1,6-naphthyridine 6-oxide (Compound 23);   4-(hydroxycarbamoyl)-2-(4-(5-hydroxypenta-1,3-diynyl)phenyl)-1,6-naphthyridine 6-oxide (Compound 24);   4-(hydroxycarbamoyl)-2-(4-(5-hydroxyhexa-1,3-diynyl)phenyl)-1,6-naphthyridine 6-oxide (Compound 25);   2-(4-(6-hydroxy-5-methylhexa-1,3-diynyl)phenyl)-4-(hydroxycarbamoyl)-1,6-naphthyridine 6-oxide (Compound 26);   2-(4-(5,6-dihydroxyhexa-1,3-diynyl)phenyl)-4-(hydroxycarbamoyl)-1,6-naphthyridine 6-oxide (Compound 27);   2-(4-(6,7-dihydroxyhepta-1,3-diynyl)phenyl)-4-(hydroxycarbamoyl)-1,6-naphthyridine 6-oxide (Compound 28);   4-(hydroxycarbamoyl)-2-(4-((3-(hydroxymethyl)cyclobutyl)buta-1,3-diynyl)phenyl)-1,6-naphthyridine 6-oxide (Compound 29);   4-(hydroxycarbamoyl)-2-(4-((3-hydroxycyclobutyl)buta-1,3-diynyl)phenyl)-1,6-naphthyridine 6-oxide (Compound 30);   4-(hydroxycarbamoyl)-2-(4-((3-(hydroxymethyl)cyclopentyl)buta-1,3-diynyl)phenyl)-1,6-naphthyridine 6-oxide (Compound 31);   4-(hydroxycarbamoyl)-2-(4-(((1R,2S)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)phenyl)-1,6-naphthyridine 6-oxide (Compound 32);   2-(4-(6-hydroxy-5-methoxyhexa-1,3-diynyl)phenyl)-4-(hydroxycarbamoyl)-1,6-naphthyridine 6-oxide (Compound 33); and   2-(4-(7-hydroxy-6-methoxyhepta-1,3-diynyl)phenyl)-4-(hydroxycarbamoyl)-1,6-naphthyridine 6-oxide (Compound 34).   
     
     
         21 . (canceled) 
     
     
         22 . A compound of formula II: 
       
         
           
           
               
               
           
         
         or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
 A is selected from the group consisting of:
 (a) substituted C 1 -C 6  alkyl, wherein at least one substituent is hydroxy; and 
 (b) substituted C 3 -C 6  cycloalkyl, wherein at least one substituent is selected from hydroxy and hydroxyalkyl; 
 
 G is selected from the group consisting of:
 a) —CH═CH—C≡C—; 
 (b) —C≡C—CH═CH—; 
 
 
       
       
         
           
           
               
               
           
         
         
           D is selected from the group consisting of: 
         
       
       
         
           
           
               
               
           
         
         
           
             wherein:
 Q is O or NR, wherein R is hydrogen or an unsubstituted C 1 -C 3  alkyl; 
 R 1  and R 2  independently are selected from the group consisting of hydrogen, substituted C 1 -C 3  alkyl, and unsubstituted C 1 -C 3  alkyl, or R 1  and R 2 , together with the carbon atom to which they are attached, form an unsubstituted C 3 -C 6  cycloalkyl group or an unsubstituted 4-6 membered heterocyclic group; and 
 R 3  is selected from the group consisting of hydrogen, substituted C 1 -C 6 -alkyl, unsubstituted C 1 -C 6 -alkyl, substituted cycloalkyl, unsubstituted cycloalkyl, substituted cycloalkylalkyl, unsubstituted cycloalkylalkyl, substituted aryl, unsubstituted aryl, substituted arylalkyl, unsubstituted arylalkyl, substituted heterocyclyl, or unsubstituted heterocyclyl, substituted heterocyclylalkyl, unsubstituted heterocyclylalkyl, substituted heteroaryl, unsubstituted heteroaryl, substituted heteroarylalkyl, and unsubstituted heteroarylalkyl. 
 
           
         
       
     
     
         23 . The compound of  claim 22 , wherein A is substituted C 1 -C 6  alkyl, wherein at least one substituent is hydroxy. 
     
     
         24 . The compound of  claim 23 , wherein A is substituted C 1 -C 6  alkyl, wherein at least two substituents are hydroxy. 
     
     
         25 . The compound of  claim 23 , wherein A is hydroxymethyl, hydroxyethyl, hydroxypropyl or dihydroxypropyl. 
     
     
         26 . The compound of  claim 22 , wherein A is substituted C 3 -C 6  cycloalkyl, wherein at least one substituent is selected from hydroxy and hydroxyalkyl. 
     
     
         27 . The compound of  claim 26 , wherein A is substituted C 3 -C 6  cycloalkyl, wherein at least one substituent is hydroxymethyl. 
     
     
         28 . The compound of  claim 26 , wherein A is substituted C 3 -C 6  cycloalkyl, wherein at least one substituent is hydroxy. 
     
     
         29 . A compound, or a pharmaceutically acceptable salt thereof, according to  claim 22 , wherein the compound is selected from the group consisting of:
 N-hydroxy-4-(4-(4-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)ethynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 51);   N-hydroxy-4-(4-(4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)ethynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 52);   N-hydroxy-4-(4-(4-(((1R,2S)-2-(hydroxymethyl)cyclopropyl)ethynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 53);   N-hydroxy-4-(4-(4-(((1S,2R)-2-(hydroxymethyl)cyclopropyl)ethynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 54);   N-hydroxy-4-(4-(4-(3-hydroxyprop-1-ynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 55);   N-hydroxy-4-(4-(4-(4-hydroxybut-1-ynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 56);   N-hydroxy-4-(4-(4-(3-hydroxybut-1-ynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 57);   N-hydroxy-4-(4-(4-(4-hydroxy-3-methylbut-1-ynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 58);   4-(4-(4-(3,4-dihydroxybut-1-ynyl)phenyl)-2-oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (Compound 59);   4-(4-(4-(4,5-dihydroxypent-1-ynyl)phenyl)-2-oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (Compound 60);   N-hydroxy-4-(4-(4-((3-hydroxycyclobutyl)ethynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 61);   N-hydroxy-4-(4-(4-((3-(hydroxymethyl)cyclobutyl)ethynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 62);   N-hydroxy-4-(4-(4-((3-(hydroxymethyl)cyclopentyl)ethynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 63);   N-hydroxy-4-(4-(4-(4-hydroxy-3-methoxybut-1-ynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 64);   N-hydroxy-4-(4-(4-(5-hydroxy-4-methoxypent-1-ynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2 methyl-2-(methylsulfonyl)butanamide (Compound 65);   N-hydroxy-4-(4-(4-((E)-2-((1R,2S)-2-(hydroxymethyl)cyclopropyl)vinyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 83);   N-hydroxy-4-(4-(4-((E)-2-((1S,2R)-2-(hydroxymethyl)cyclopropyl)vinyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 84);   N-hydroxy-4-(4-(4-((E)-2-((1S,2S)-2-(hydroxymethyl)cyclopropyl)vinyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 85);   N-hydroxy-4-(4-(4-((E)-2-((1R,2R)-2-(hydroxymethyl)cyclopropyl)vinyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 86);   (E)-N-hydroxy-4-(4-(4-(3-hydroxyprop-1-enyl)phenyl)-2-oxopyridin-1(2H)-yl-2-methyl-2-(methylsulfonyl)butanamide (Compound 87);   (E)-N-hydroxy-4-(4-(4-(4-hydroxybut-1-enyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 88);   (E)-N-hydroxy-4-(4-(4-(3-hydroxybut-1-enyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 89);   (E)-N-hydroxy-4-(4-(4-(4-hydroxy-3-methylbut-1-enyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 90);   (E)-4-(4-(4-(3,4-dihydroxybut-1-enyl)phenyl)-2-oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (Compound 91);   (E)-4-(4-(4-(4,5-dihydroxypent-1-enyl)phenyl)-2-oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (Compound 92);   (E)-N-hydroxy-4-(4-(4-(2-(3-hydroxycyclobutyl)vinyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 93);   (E)-N-hydroxy-4-(4-(4-(2-(3-(hydroxymethyl)cyclobutyl)vinyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 94);   (E)-N-hydroxy-4-(4-(4-(2-(3-(hydroxymethyl)cyclopentyl)vinyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 95);   (E)-N-hydroxy-4-(4-(4-(4-hydroxy-3-methoxybut-1-enyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 96); and   (E)-N-hydroxy-4-(4-(4-(5-hydroxy-4-methoxypent-1-enyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 97).   
     
     
         30 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to  claim 1   
     
     
         31 . A method for treating a bacterial infection in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to  claim 1 . 
     
     
         32 . A method according to  claim 31 , wherein said bacterial infection is a gram-negative bacterial infection. 
     
     
         33 . A method according to  claim 32 , wherein said gram-negative bacterial infection is  Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Burkholderia cepacia, Alcaligenes xylosoxidans, Enterobacteriaceae, Haemophilus, Francisellaceae , or a  Neisseria  species. 
     
     
         34 . A method for treating a bacterial infection in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to  claim 30 . 
     
     
         35 . A method according to  claim 34 , wherein said bacterial infection is a gram-negative bacterial infection. 
     
     
         36 . A method according to  claim 35 , wherein said gram-negative bacterial infection is  Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Burkholderia cepacia, Alcaligenes xylosoxidans, Enterobacteriaceae, Haemophilus, Francisellaceae , or a  Neisseria  species. 
     
     
         37 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to  claim 22 . 
     
     
         38 . A method for treating a bacterial infection in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to  claim 22 . 
     
     
         39 . A method for treating a bacterial infection in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition, according to  claim 37 .