Inhibitors of leukotriene a4 hydrolase

Abstract

This present disclosure is directed to compounds of formula (I): where R 1a , R 3 , Y, and Z are described herein, as single stereoisomers or as mixtures of stereoisomers, or pharmaceutically acceptable salts, solvates, clathrates, polymorphs, ammonium ions, N-oxides or prodrugs thereof; which are leukotriene A 4 hydrolase inhibitors and therefore useful in treating inflammatory disorders. Pharmaceutical compositions including the compounds described herein and methods of preparing the compounds described herein are also provided.

What is claimed is: 
     
         1 . A compound having the following formula (I): 
       
         
           
           
               
               
           
         
         wherein
 R 1a  is hydrogen, halo, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted amidinyl, optionally substituted guanidinyl, —R 13 —OR 10 , —R 13 —C(═O)OR 10 , or —R 13 —C(═O)R 10 ; 
 
         R 3  is a direct bond, —O—, —R 12 —O—, —O—R 12 —, —O—R 12 —O—, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain, —R 13 —C(═O)R 13 , —O—R 13 —C(═O)R 13 , —R 13 —O—R 13 —C(OH)—R 13 , or —NR 13 —; 
         Y is hydrogen, halo, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; and 
         Z is 
       
       
         
           
           
               
               
           
         
         each R 10  is independently hydrogen, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;
 each R 12  is independently an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; 
 each R 13  is independently a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; 
 
         as a single stereoisomer or as a mixture of stereoisomers; 
         or a pharmaceutically acceptable salt, ammonium ion, or N-oxide thereof. 
       
     
     
         2 . A compound according to  claim 1  wherein R 3  is —O— and Z is 
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound of  claim 1  wherein R 3  is —O— and Z is 
       
         
           
           
               
               
           
         
       
     
     
         4 . A compound of  claim 1  wherein R 3  is —O— and Z is 
       
         
           
           
               
               
           
         
       
     
     
         5 . A compound according to  claim 1  wherein R 3  is —O— and Z is 
       
         
           
           
               
               
           
         
       
     
     
         6 . A compound according to  claim 1  wherein R 1a  is halo and Z is 
       
         
           
           
               
               
           
         
       
     
     
         7 . A compound of  claim 1  wherein R 1a  is a halo and Z is 
       
         
           
           
               
               
           
         
       
     
     
         8 . A compound of  claim 1  wherein R 1a  is a halo and Z is 
       
         
           
           
               
               
           
         
       
     
     
         9 . A compound according to  claim 1  wherein R 1a  is halo and Z is 
       
         
           
           
               
               
           
         
       
     
     
         10 . A compound according to  claim 1  wherein R 1a  is optionally substituted heteroaryl and Z is 
       
         
           
           
               
               
           
         
       
     
     
         11 . A compound of  claim 1  wherein R 1a  is an optionally substituted heteroaryl and Z 
       
         
           
           
               
               
           
         
       
     
     
         12 . A compound of  claim 1  wherein R 1a  is an optionally substituted heteroaryl and Z 
       
         
           
           
               
               
           
         
       
     
     
         13 . A compound according to  claim 1  wherein R 1a  is optionally substituted heteroaryl and Z is 
       
         
           
           
               
               
           
         
       
     
     
         14 . A compound having the following formula (I-A): 
       
         
           
           
               
               
           
         
         wherein
 R 1a  is hydrogen, halo, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted amidinyl, optionally substituted guanidinyl, —R 13 —OR 10 , —R 13 —C(═O)OR 10 , or —R 13 —C(═O)R 10 ; 
 Y is hydrogen, halo, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; and 
 Z is 
 
       
       
         
           
           
               
               
           
         
         each R 10  is independently hydrogen, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;
   each R 12  is independently an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain;   each R 13  is independently a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain;   
 as a single stereoisomer or as a mixture of stereoisomers; 
 
         or a pharmaceutically acceptable salt, ammonium ion, or N-oxide thereof. 
       
     
     
         15 . A compound according to  claim 14  wherein R 1a  is halo and Z is 
       
         
           
           
               
               
           
         
       
     
     
         16 . A compound according to  claim 14  wherein R 1a  is optionally substituted heteroaryl and Z is 
       
         
           
           
               
               
           
         
       
     
     
         17 . A compound according to  claim 14  wherein the compound is 4-((3-(((4-(4-chlorophenoxy)phenyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid. 
     
     
         18 . A compound according to  claim 14  wherein the compound is 1-(2-(4-((4-(4-(oxazol-2-yl)phenoxy)phenyl)amino)piperidin-1-yl)acetyl)piperidine-4-carboxylic acid. 
     
     
         19 . A compound according to  claim 14  comprising a formula of any of the compounds in the Table below: 
       
         
           
                 
                 
                 
               
                     
                 
                   R 1a   
                   Y 
                   Z 
                 
                     
                 
                   H— 
                   H— 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Heteroaryl- 
                   H— 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   H— 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Halo- 
                   H— 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Cl— 
                   H— 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   H— 
                   H— 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Heteroaryl- 
                   H— 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   H— 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Halo- 
                   H— 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Cl— 
                   H— 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   H— 
                   H— 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Heteroaryl- 
                   H— 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   H— 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Halo- 
                   H— 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Cl— 
                   H— 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   H— 
                   H— 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Heteroaryl- 
                   H— 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   H— 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Halo- 
                   H— 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Cl— 
                   H—