Peptide deformylase inhibitors

Abstract

PDF inhibitors and novel methods for their use are provided.

1 . A compound according to formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 R1 is selected from the group consisting of C 1-6 alkyl, —C 1-2 alkylAr, and Ar;  
 R2 is selected from the group consisting of hydrogen, C 1-6 alkyl, —(CH 2 ) m OH, —(CH 2 ) n Ar′, —(CH 2 ) n Het, —Ar′, —SO 2 R3, —C(O)R3, —C(O)NHR3, —C(O)OR3, —CH(R4)CONR5R6, and —CH(R4)CO 2 R7;  
 R3 is selected from the group consisting of C 1-6 alkyl, —C 1-2 alkylAr′, and Ar′;  
 R4 is hydrogen, or C 1-6 alkyl;  
 R5 and R6 are independently selected from the group consisting of hydrogen, C 1-6 alkyl,  
 —C 1-2 alkylAr′, and Ar′; or R5, R6 together form a five or six membered cycloalkyl ring which is optionally mono-substituted by —CH 2 OR7;  
 R7 is selected from the group consisting of hydrogen, and C 1-3 alkyl;  
 Ar is selected from the group consisting of phenyl, furyl, and thienyl, all of which may be optionally substituted by one or more Z 1  groups;  
 Ar′ is selected from the group consisting of phenyl, naphthyl, furyl, pyridyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, benzofuranyl, indolyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, and pyrimidyl, all of which may be optionally substituted by one or more Z 2  groups;  
 Het is selected from the group consisting of tetrahydrofuranyl and piperidinyl;  
 Z 1  is independently selected from the group consisting of hydrogen, C 1-3 alkyl, —CN, F, Cl, Br, and I;  
 Z 2  is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, —(CH 2 ) n CO 2 R4, —C(O)NR5R6, —CN, —(CH 2 ) n OH, —NO 2 , F, Cl, Br, I, —NR5R6, and —NHC(O)R1;  
 m is 2 to 5; and  
 n is 0 to 5; or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . A compound according to  claim 1  selected from the group consisting of: 
 N-[(3S,4R)-4-Butyl-1-(5-hydroxypentyl)-2-oxopyrrolidin-3-yl-methyl]-N-hydroxyformamide;    N-[(3R,4S)-4-Butyl-1-(5-hydroxypentyl)-2-oxopyrrolidin-3-yl-methyl]-N-hydroxyformamide;    (±)-(3RS,4SR)—N-[4-Butyl-2-oxo-1-(t-butylcarboxy)pyrrolidin-3-yl-methyl]-N-hydroxyformamide;    (±)-(3RS,4SR)—N-(4-Butyl-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyformamide;    (±)-(3RS,4SR)—N-(4-Butyl-2-oxo-1-pentanoylpyrrolidin-3-yl-methyl)-N-hydroxyformamide;    (±)-(3RS,4SR)—N-[4-Butyl-2-oxo-1-(2-phenylethanoyl)pyrrolidin-3-yl-methyl]-N-hydroxyformamide;    (±)-(3RS,4SR)—N-[4-Butyl-2-oxo-1-(1-phenylmethanoyl)pyrrolidin-3-yl-methyl]-N-hydroxyformamide;    (±)-(3RS,4SR)—N-(1-Benzenesulfonyl-4-butyl-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyformamide;    (±)-(3RS,4SR)—N-[1-(Butane-1-sulfonyl)-4-butyl-2-oxopyrrolidin-3-yl-methyl]-N-hydroxyformamide;    (±)-(3RS,4SR)—N-[4-Butyl-1-(naphthalen-2-ylmethanoyl)-2-oxopyrrolidin-3-yl-methyl]-N-hydroxyformamide;    (±)-(3RS,4SR)—N-(1-Benzyl-4-butyl-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyformamide;    (±)-(3RS,4SR)—N-{4-Butyl-1-[1-(4-ethoxyphenyl)methanoyl]-2-oxopyrrolidin-3-yl-methyl}-N-hydroxyformamide;    (±)-(3RS,4SR)—N-{4-Butyl-1-[1-(3-ethoxyphenyl)methanoyl]-2-oxopyrrolidin-3-yl-methyl}-N-hydroxyformamide;    (±)-(3RS,4SR)—N-{4-Butyl-1-[1-(2-ethoxyphenyl)methanoyl]-2-oxopyrrolidin-3-yl-methyl}-N-hydroxyformamide;    (±)-(3RS,4SR)—N-(4-Butyl-2-oxo-1-pyridin-3-ylmethylpyrrolidin-3-yl-methyl)-N-hydroxyformamide;    N-((3S,4R)-4-Butyl-1-{(S)-1-[1-((S)-2-methoxymethyl-pyrrolidin-1-yl)methanoyl]-3-methylbutyl}-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyformamide;    N-((3R,4S)-4-Butyl-1-{(S)-1-[1-((S)2-methoxymethylpyrrolidin-1-yl)-methanoyl]-3-methylbutyl}-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyformamide;    N-((3S,4R)-4-Butyl-1-{(S)-1-[1-(dimethylamino)methanoyl]-3,3-dimethylbutyl}-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyformamide;    (±)-(3RS,4SR)—N-[4-Butyl-1-(4-ethoxybenzyl)-2-oxopyrrolidin-3-yl-methyl]-N-hydroxyformamide;    (±)-(3RS,4SR)—N-[4-Butyl-1-(4-hydroxybenzyl)-2-oxopyrrolidin-3-yl-methyl]-N-hydroxyformamide;    (±)-(3RS,4SR)—N-{4-Butyl-1-[4-(2-morpholin-4-yl-2-oxoethoxy)benzyl]-2-oxopyrrolidin-3-yl-methyl}-N-hydroxyformamide;    (±)-(3RS,4SR)—N-{4-Butyl-1-[4-(4-carboxy-1-butoxy)benzyl]-2-oxopyrrolidin-3-yl-methyl}-N-hydroxyformamide;    (±)-(3RS,4SR)—N-{4-Butyl-1-[4-(3-hydroxybenzoxy)benzyl]-2-oxopyrrolidin-3-yl-methyl}-N-hydroxyformamide;    (±)-(3RS,4SR)—N-{4-Butyl-2-oxo-1-[4-(tetrahydrofuran-2-ylmethoxy)benzyl]pyrrolidin-3-yl-methyl}-N-hydroxyformamide;    (±)-(3RS,4SR)—N-{4-Butyl-1-[4-(furan-2-ylmethoxy)benzyl]-2-oxopyrrolidin-3-yl-methyl}-N-hydroxyformamide;    (±)-(3RS,4SR)—N-{4-Butyl-1-[4-(3-hydroxypropoxy)benzyl]-2-oxopyrrolidin-3-yl-methyl}-N-hydroxyformamide;    (±)-(3RS,4SR)—N-{4-Butyl-2-oxo-1-[4-(piperidin-3-ylmethoxy)benzyl]pyrrolidin-3-yl-methyl}-N-hydroxyformamide;    (±)-(3RS,4SR)—N-{4-Butyl-2-oxo-1-[4-(pyridin-3-ylmethoxy)benzyl]pyrrolidin-3-yl-methyl}-N-hydroxyformamide;    (±)-(3RS,4SR)—N-{4-Butyl-1-[4-(5-hydroxypentoxy)benzyl]-2-oxopyrrolidin-3-yl-methyl}-N-hydroxyformamide;    (±)-(3RS,4SR)—N-[4-Butyl-1-(2,3-dichlorobenzyl)-2-oxopyrrolidin-3-yl-methyl]-N-hydroxyformamide;    (±)-(3RS,4SR)—N-[4-Butyl-1-(3,4-dichlorobenzyl)-2-oxopyrrolidin-3-yl-methyl]-N-hydroxyformamide;    (±)-(3RS,4SR)—N-(4-Butyl-2-oxo-1-phenylpyrrolidin-3-yl-methyl]-N-hydroxyformamide;    (±)-(3RS,4SR)—N-{4-Butyl-1-[2-(2-hydroxyphenyl)-2-oxoethyl]-2-oxopyrrolidin-3-yl-methyl}-N-hydroxyformamide;    (±)-(3RS,4SR)—N-[4-Butyl-1-(3,5-dimethylisoxazol-4-ylmethyl)-2-oxopyrrolidin-3-yl-methyl]-N-hydroxyformamide; and    (±)-(3RS,4SR)—N-[4-Butyl-1-(2-methylthiazol-4-ylmethyl)-2-oxopyrrolidin-3-yl-methyl]-N-hydroxyformamide; or pharmaceutically acceptable salt thereof.    
     
     
         3 . A method of treating a bacterial infection by administering to a subject in need of treatment a compound according to  claim 1 .  
     
     
         4 . A pharmaceutical composition comprising a compound according to  claim 1  and one or more pharmaceutically-acceptable excipients.