Aryl Sulfonamides

Abstract

Compounds are provided that act as potent antagonists of the CCR9 receptor, and which have been further confirmed in animal testing for inflammation, one of the hallmark disease states for CCR9. The compounds are generally aryl sulfonamide derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR9-mediated diseases, and as controls in assays for the identification of CCR9 antagonists.

1 - 85 . (canceled) 
   
   
       86 . A compound of formula (I) or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein X is an unsubstituted or substituted C 1-8  alkyl;
 L is C(O); 
 Z is pyridyl, pyrimidyl, or pyrizinyl; and 
 Y is halogen or NO 2 . 
 
   
   
       87 . A compound or a pharmaceutically acceptable salt thereof which has one of the following formulae: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     where X′ and X″ are each independently selected from the group consisting of hydrogen, halogen, —CN, —NO 2 , —OH, —OR 1 , —C(O)R 1 , —CO 2 R 1 , —O(CO)R 1 , —C(O)NR 1 R 2 , —OC(O)NR 1 R 2 , —SR 1 , —SOR 1 , —SO 2 R 1 , —SO 2 NR 1 R 2 , —NR 1 R 2 , —NR 1 C(O)R 2 , —NR 1 C(O) 2 R 2 , —NR 1 SO 2 R 2 , —NR 1 (CO)NR 2 R 3 , unsubstituted or substituted C 1-8  alkyl, unsubstituted or substituted C 1-8  haloalkyl, unsubstituted or substituted C 2-8  alkenyl, unsubstituted or substituted C 2-8  alkynyl, unsubstituted or substituted C 3-8  cycloalkyl, unsubstituted or substituted C 1-10  aryl, unsubstituted or substituted 5- to 10-membered heteroaryl, and unsubstituted or substituted 3- to 10-membered heterocyclyl, with the proviso that X′ and X″ cannot both be hydrogen simultaneously;
 R 1 , R 2  and R 3  are each independently selected from the group consisting of hydrogen, C 1-6  haloalkyl, C 1-6  alkyl, C 3-6  cycloalkyl, C 2-6  alkenyl, C 2-6 alkynyl, C 6-10  aryl, 5- to 10-membered heteroaryl, aryl-C 1-4  alkyl, aryl-C 1-4  alkyl, and aryloxy-C 1-4  alkyl; or 
 two of R 1 , R 2  and R 3  together with the atom(s) to which they are attached, may form a 5-, 6- or 7-membered ring; 
 Y′ and Y″ are each independently selected from the group consisting of hydrogen, halogen, —CN, —NO 2 , —OH, —OR 4 , —C(O)R 4 , —CO 2 R 4 , —SR 4 , —SOR 4 , —SO 2 R 4 , unsubstituted or substituted C 1-4  alkyl, and unsubstituted or substituted C 1-4  haloalkyl, with the proviso that Y′ and Y″ cannot both be hydrogen simultaneously; 
 R 4  is selected from the group consisting of hydrogen, unsubstituted or substituted C 1-6  haloalkyl, unsubstituted or substituted C 1-6  alkyl, unsubstituted or substituted C 3-6  cycloalkyl, unsubstituted or substituted C 2-6  alkenyl, and unsubstituted or substituted C 2-6  alkynyl; 
 Z′ and Z″ are each independently selected from the group consisting of hydrogen, halogen, unsubstituted or substituted C 1-8  alkyl, unsubstituted or substituted C 3-8  cycloalkyl, unsubstituted or substituted C 2-8  alkenyl, unsubstituted or substituted C 2-8  alkynyl, unsubstituted or substituted C 1-8  alkoxy, ═O, —CN, —NO 2 , —OH, —OR 7 , —OC(O)R 7 , —CO 2 R 7 , —C(O)R 7 , —CONR 7 R 8 , —OC(O)NR 7 R 8 , —NR 7 C(O)R 8 , —NR 7 C(O)NR 8 R 9 , —NR 7 R 8 , —NR 7 CO 2 R 8 , —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 NR 7 R 8 , —NR 7 SO 2 R 8 , unsubstituted or substituted C 6-10  aryl, unsubstituted or substituted 5- or 6-membered heteroaryl and unsubstituted or substituted 3- to 7-membered heterocyclyl; and 
 where R 7 , R 8  and R 9  are each independently hydrogen, unsubstituted or substituted C 1-6  haloalkyl, unsubstituted or substituted C 1-6  alkyl, unsubstituted or substituted C 3-6  cycloalkyl, unsubstituted or substituted C 2-6 alkenyl, unsubstituted or substituted C 2-6  alkynyl, unsubstituted or substituted phenyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted aryl-C 1-4  alkyl, and unsubstituted or substituted aryloxy-C 1-4  alkyl; or 
 where any two of R 7 , R 8  and R 9  together with the atom(s) to which they are attached, may form a 5-, 6- or 7-membered ring. 
 
   
   
       88 . A pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt thereof of  claims 86  or  87  and a pharmaceutically acceptable carrier. 
   
   
       89 . A method of treating inflammatory bowel disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof of  claims 86  or  87 . 
   
   
       90 . The method of  claim 89 , wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.