Ccr9 inhibitors and methods of use thereof

Abstract

The invention relates to compounds represented by Structural Formula I, which can bind to CCR9 receptors and block the binding of a ligand (e.g., TECK) to the receptors. The invention also relates to a method of inhibiting a function of CCR9, and to the use compounds represented by Structural Formula I in research, therapeutic, prophylactic and diagnostic methods.

1 . A compound represented by the following structural formula (V): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X 1 , X 2 , and X 3  are each independently N or CR, provided that at least one of X 1 , X 2 , or X 3  is CR; 
         X 4  is CR, N or N + —O − ; 
         R, for each occurrence, is independently H, an aliphatic group, haloalkyl, aryl, arylalkyl, alkoxy, cycloalkoxy, haloalkoxy, aryloxy, arylalkoxy, alkylthio, halo, nitro, cyano, sulonamido, sulfone, sulfoxide, hydroxy, NR 11 CO 2 R 12 , C(O)N(R 11 ) 2 , C(O)R 12 , CO 2 R 12 , OC(O)N(R 11 ) 2 , OC(O)R 12 , N(R 11 ) 2 , or NR 11 C(O)R 12 ;
 wherein R 11 , for each occurrence is, independently, H or an aliphatic group, and R 12  is an aliphatic group; 
 
         R 1 , R 2 , R 3 , R 4  and R 5  are each independently aliphatic group, haloalkyl, halo, COOH, NO 2 , alkoxy or haloalkoxy; and 
         Ar 2  is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group. 
       
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . The compound of  claim 1 , wherein Ar 2  is a substituted or unsubstituted group selected from phenyl, naphthyl, thienyl, and thianaphthenyl. 
     
     
         5 . The compound of  claim 1 , wherein Ar 2  is a substituted or unsubstituted group selected from phenyl and pyridyl. 
     
     
         6 . The compound of  claim 1 , wherein Ar 2  is a substituted or unsubstituted group selected from phenyl and thienyl. 
     
     
         7 . The compound of  claim 1 , wherein Ar 2  is unsubstituted or is substituted with one or more substituents selected from substituted aliphatic, unsubstituted aliphatic, aryl, arylalkyl, substituted alkoxy, unsubstituted alkoxy, aryloxy, arylalkoxy, alkylthio, halo, nitro, cyano, S(O)-(aliphatic), S(O) 2 -(aliphatic), NR 11 S(O) 2 -(aliphatic), C(O)N(R 11 ) 2 , C(O)R 12 , N(R 11 ) 2 , NR 11 C(O) 2 R 12 , and NR 11 C(O)R 12 , wherein R 11  for each occurrence is independently H or an aliphatic group, and R 12  is an aliphatic group. 
     
     
         8 . The compound of  claim 1 , wherein Ar 2  is unsubstituted or is substituted with one or more substituents selected from aliphatic, alkoxy, and haloalkoxy. 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . The compound of  claim 1 ,
 wherein X 4  is N + —O − .   
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . The compound of  claim 6 , wherein:
 X 3  is CR 21 , wherein R 21  is halo, nitro, aliphatic carbonyl, or trihalomethyl.   
     
     
         19 . The compound of  claim 18 , wherein R 21  is Cl, Br, or NO 2 . 
     
     
         20 . A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and the compound of  claim 1 . 
     
     
         21 . A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and the compound of  claim 19 . 
     
     
         22 . A method of inhibiting a CCR9 receptor function in a subject in need thereof, comprising the step of administering to the subject an effective amount of a compound of  claim 1 . 
     
     
         23 . A method of inhibiting a CCR9 receptor function in a subject in need thereof, comprising the step of administering to the subject an effective amount of a compound of  claim 19 . 
     
     
         24 . A method of treating an inflammatory disease or condition in a subject in need thereof, comprising administering to the subject an effective amount of a compound of  claim 1 . 
     
     
         25 . A method of treating an inflammatory disease or condition in a subject in need thereof, comprising administering to the subject an effective amount of a compound of  claim 19 . 
     
     
         26 . The method of  claim 24 , wherein the inflammatory disease or condition is an inflammatory bowel disease (IBD). 
     
     
         27 . The method of  claim 24 , wherein the inflammatory bowel disease is ulcerative colitis, Crohn's disease, ileitis, Celiac disease, nontropical Sprue, enteritis, enteropathy associated with seronegative arthropathies, microscopic or collagenous colitis, eosinophilic gastroenteritis, or pouchtis resulting after proctocolectomy, or ileoanal anastomosis. 
     
     
         28 . The method of  claim 24 , wherein the inflammatory disease or condition is Crohn's disease or colitis. 
     
     
         29 . The method of  claim 24 , wherein the inflammatory disease or condition is Celiac's disease. 
     
     
         30 . A method of treating a disease or condition in a subject in need thereof, wherein the disease or condition is an inflammatory disease or condition, an allergic disease or condition, an autoimmune disease or condition, or graft rejection, comprising administering to the subject an effective amount of a compound of  claim 1 . 
     
     
         31 . The method of  claim 30 , wherein the disease or condition is inflammatory bowel disease, mastitis, vaginitis, cholecystitis, cholangitis or pericholangitis, chronic bronchitis, chronic sinusitis, systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies, psoriasis, inflammatory dermatoses, vasculitis, spondyloarthropathies, scleroderma, respiratory allergic diseases, arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, juvenile onset diabetes, glomerulonephritis and other nephritides, autoimmune thyroiditis, Behcet's disease, allograft rejection, graft-versus-host disease, atherosclerosis, restenosis, or myositis.