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 . A compound of the formula (I), or a salt thereof: 
     
       
         
         
             
             
         
       
     
     where
 X represents from 1 to 4 substituents independently selected from the group consisting of 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 2-8  alkenyl, unsubstituted or substituted C 2-8  alkynyl, unsubstituted or substituted C 3-8  cycloalkyl, unsubstituted or substituted C 6-10  aryl, unsubstituted or substituted 5- to 10-membered heteroaryl, and unsubstituted or substituted 3- to 10-membered heterocyclyl;
 R 1 , R 2  and R 3  are each independently 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, unsubstituted or substituted C 2-6  alkynyl, unsubstituted or substituted C 6-10  aryl, unsubstituted or substituted 5- to 10-membered heteroaryl, unsubstituted or substituted aryl-C 1-4  alkyl, unsubstituted or substituted aryl-C 1-4  alkyl, and unsubstituted or substituted 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 an unsubstituted or substituted 5-, 6- or 7-membered ring; 
 
 Y represents from 1 to 3 substituents, each independently selected from the group consisting of halogen, —CN, —NO 2 , —OH, —OR 4 , —C(O)R 4 , —CO 2 R 4 , —SR 4 , —SOR 4 , —SO 2 R 4 , and unsubstituted or substituted C 1-4  alkyl;
 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; 
 
 L is —C(O)—, —S—, —SO— or —S(O) 2 —; and 
 Z represents either unsubstituted or substituted monocyclic or bicyclic C 5-10  heteroaryl or unsubstituted or substituted monocyclic or bicyclic C 3-10  heterocyclyl, with the proviso that when X is methyl, then Z is not 2-thiophene, 2-(3-hydroxy-1H-indole) or 3-(1-methylpyridinium). 
 
   
   
       2 . The compound of  claim 1 , where L is —CO—. 
   
   
       3 . The compound of  claim 2 , where X represents from 1 to 3 substituents independently selected from the group consisting of halogen, —CN, —NO 2 , —OH, —OR 1 , —C(O)R 1 , —CO 2 R 1 , —O(CO)R 1 , —OC(O)NR 1 R 2 , —SR 1 , —SOR 1 , —SO 2 R 1 , —NR 1 R 2 , —NR 1 C(O)R 2 , —NR 1 C(O) 2 R 2 , —NR 1 (CO)NR 1 R 2 , unsubstituted or substituted C 1-8  alkyl, 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 6-10  aryl, unsubstituted or substituted 5- or 6-membered heteroaryl, or unsubstituted or substituted 4- to 7-membered heterocyclyl. 
   
   
       4 . The compound of  claim 3 , where X represents 1 to 3 substituents independently selected from the group consisting of —NO 2 , —OR 1 , —C(O)R 1 , —SO 2 R 1 , —NR 1 R 2 , unsubstituted or substituted C 1-8  alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, or unsubstituted or substituted 5- or 6-membered heterocyclyl. 
   
   
       5 . The compound of  claim 2 , where at least one X substituent is situated para to the sulfonamido bond as defined in formula (I). 
   
   
       6 . The compound of  claim 2 , where X is unsubstituted C 1-8  alkyl, unsubstituted C 3-8  cycloalkyl, unsubstituted C 2-8  alkenyl, or unsubstituted C 2-8  alkynyl. 
   
   
       7 . The compound of  claim 2 , where X is substituted C 1-8  alkyl, substituted C 3-8  cycloalkyl, substituted C 2-8  alkenyl, or substituted C 2-8  alkynyl, each having from 1 to 5 substituents independently selected from the group consisting of halogen, —OH, —CN, —NO 2 , ═O, —OC(O)R 1 , —OR 1 , —C(O)R 1 , —CONR 1 R 2 , —OC(O)NR 1 R 2 , —NR 2 C(O)R 1 , —NR 1 C(O)NR 2 R 3 , —CO 2 R 1 , —NR 1 R 2 , —NR 2 CO 2 R 1 , —SR 1 , —SOR 1 , —SO 2 R 1 , —SO 2 NR 1 R 2 , —NR 1 SO 2 R 2 , unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heterocyclyl. 
   
   
       8 . The compound of  claim 7 , where X is substituted C 1-8  alkyl or substituted C 3-8  cycloalkyl, each having from 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —CN, ═O, —OC(O)R 1 , —OR 1 , —C(O)R 1 , —CONR 1 R 2 , —NR 2 C(O)R 1 , —CO 2 R 1 , —NR 1 R 2 , —SR 1 , —SOR 1 , —SO 2 R 1 , —NR 1 SO 2 R 2 , unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. 
   
   
       9 . The compound of  claim 8 , where X is substituted C 1-8  alkyl, having from 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —CN, ═O, —OC(O)R 1 , —OR 1 , —C(O)R 1 , —CONR 1 R 2 , —NR 2 C(O)R 1 , —CO 2 R 1 , —NR 1 R 2 , —SO 2 R 1 , unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. 
   
   
       10 . The compound of  claim 2 , where X is unsubstituted or substituted C 6-10  aryl, unsubstituted or substituted 5- to 1 0-membered heteroaryl, or unsubstituted or substituted 3- to 1 0-membered heterocyclyl, where when X is substituted is has from 1 to 4 substituents independently selected from the group consisting of halogen, unsubstituted or substituted C 1-8  alkyl, unsubstituted or substituted C 1-8  haloalkyl, —CN, —NO 2 , —OH, —OR 1 , ═O, —OC(O)R 1 , —CO 2 R 1 , —C(O)R 1 , —CONR 1 R 2 , —OC(O)NR 1 R 2 , —NR 2 C(O)R 1 , —NR 1 C(O)NR 2 R 3 , —NR 1 R 2 , —NR 2 CO 2 R 1 , —SR 1 , —SOR 1 , —SO 2 R 1 , —SO 2 NR 1 R 2 , and —NR 1 SO 2 R 2 . 
   
   
       11 . The compound of  claim 10 , where X is substituted C 6-10  aryl or unsubstituted or substituted 5- to 1 0-membered heteroaryl, where when X is substituted it has from 1 to 3 substituents independently selected from the group consisting of halogen, —CN, —OH, —OR 1 , ═O, —OC(O)R 1 , —CO 2 R 1 , —C(O)R 1 , —CONR 1 R 2 , —NR 2 C(O)R 1 , —NR 1 R 2 , —SR 1 , —SOR 1 , —SO 2 R 1 , —NR 1 SO 2 R 2 , unsubstituted or substituted C 1-8  alkyl, and C 1-8  unsubstituted or substituted haloalkyl. 
   
   
       12 . The compound of  claim 11 , where X is unsubstituted or substituted phenyl or unsubstituted or substituted 5- or 6-membered heteroaryl, where when X is substituted it has from 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR 1 , —C(O)R 1 , —CONR 1 R 2 , —NR 2 C(O)R 1 , —NR 1 R 2 , —SO 2 R 1 , unsubstituted or substituted C 1-8  alkyl, and unsubstituted or substituted C 1-8  haloalkyl. 
   
   
       13 . The compound of  claim 10 , where X is unsubstituted or substituted 4- to 7-membered heterocyclyl, where when X is substituted it has from 1 to 3 substituents independently selected from the group consisting of C 1-8  alkyl, C 1-8  haloalkyl, —OR 1 , —OH, —OC(O)R 1 , —CO 2 R 1 , —C(O)R 1 , —CONR 1 R 2 , —NR 1 R 2 , —SO 2 R 1 , and —NR 1 SO 2 R 2 . 
   
   
       14 . The compound of  claim 13 , where X is a unsubstituted or substituted 5- or 6-membered heterocyclyl, where when X is substituted it has 1 to 2 substituents independently selected from the group consisting of unsubstituted or substituted C 1-8  alkyl, unsubstituted or substituted C 1-8  haloalkyl, —OR 1 , —OH, —C(O)R 1 , —CONR 1 R 2 , —NR 1 R 2 , and —SO 2 R 1 . 
   
   
       15 . The compound of  claim 2 , where R 1 , R 2  and R 3  are unsubstituted. 
   
   
       16 . The compound of  claim 2 , where R 1 , R 2  and R 3 , when substituted, can have from 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR 1 , —OCOHNR 1 , —OCONR′ 2 , —SH, —SR′, —SO 2 NH 2 , —CONH 2 , —NHC(O)NH 2 , NR′C(O)NH 2 , —CO 2 H, —CN, —NO 2 , —NH 2 , —NHR′ and —NR′ 2 , —S(O)R′, —S(O) 2 R′, —CO 2 R′, —CONR′ 2 , —CONHR′, —C(O)R′, —NR′COR′, —NHCOR′, —NR′CO 2 R′, —NHCO 2 R′, —CO 2 R′, —NR′C(O)NR′ 2 , —NHC(O)NR′ 2 , —NR′C(O)NHR′, —NHC(O)NHR′, —NR′SO 2 R′, —NHSO 2 R′, —SO 2 NR′ 2 , and —SO 2 NHR′, where R′ is C 1-6 alkyl. 
   
   
       17 . The compound of  claim 2 , where Y represents from 1 to 2 substituents, each independently selected from the group consisting of halogen, —CN, —NO 2 , —OH, —OR 4 , —C(O)R 4 , —CO 2 R 4 , —SR 4 , —SOR 4 , —SO 2 R 4 , and unsubstituted or substituted C 1-4  alkyl. 
   
   
       18 . The compound of  claim 2 , where Y represents from 1 to 3 substituents independently selected from the group consisting of halogen, —CN, —NO 2 , —OR 4 , —C(O)R 4 , —SR 4 , —CF 3 , —SOR 4 , and —SO 2 R 4 . 
   
   
       19 . The compound of  claim 18 , where Y represents from 1 to 3 substituents independently selected from the group consisting of halogen, —CN, —NO 2 , —CF 3 , and —SO 2 R 4 . 
   
   
       20 . The compound of  claim 18 , where Y represents 1 or 2 substituents where at least halogen is present and optionally another substituent selected from the group consisting of halogen, —CN, —NO 2 , —OH, —OR 4 , —C(O)R 4 , —CO 2 R 4 , —SR 4 , —SOR 4 , —SO 2 R 4  and unsubstituted or substituted C 1-4  alkyl. 
   
   
       21 - 85 . (canceled)