Compounds useful as ccr9 modulators

Abstract

The present invention relates to compounds useful as CCR9 modulators, to compositions containing them, to methods of making them, and to methods of using them. In particular, the present invention relates to compounds capable of modulating the function of the CCR9 receptor by acting as partial agonists, antagonists or inverse agonists. Such compounds may be useful to treat, prevent or ameliorate a disease or condition associated with CCR9 activation, including inflammatory and immune disorder diseases or conditions such as inflammatory bowel diseases (IBD).

1 - 35 . (canceled) 
     
     
         36 . A method of treating, preventing, or ameliorating a disease or condition associated with CCR9 activation in a subject, the method comprising administering an effective amount of a compound of Formula (I), or a salt, solvate, or solvate of a salt thereof: 
       
         
           
           
               
               
           
         
         in which: 
         R 1  is selected from hydrogen, methyl, and ethyl; 
         X is selected from a direct bond and (CR 5 R 6 ) p ; 
         p is 1, 2, 3, 4, or 5; 
         each R 5  is independently selected from hydrogen, methyl, and fluoro; 
         each R 6  is independently selected from hydrogen, methyl, and fluoro; 
         R 2  is selected from optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted C 3-7 heterocycloalkyl; 
         each R 3  is independently selected from halo, cyano, C 1-6 alkyl, methanesulfonyl, C 1-6 alkoxy, haloalkyl, haloalkoxy, and C 3-7 cycloalkyl; 
         n is 0, 1, or 2; 
         each R 4  is Z q1 B; 
         m is 0, 1, 2, or 3; 
         q 1  is 0, 1, 2, 3, 4, 5, or 6; 
         each Z is independently selected from CR 7 R 8 , O, C═O, SO 2 , and NR 9 ; 
         each R 7  is independently selected from hydrogen, methyl, ethyl, and halo; 
         each R 8  is independently selected from hydrogen, methyl, ethyl, and halo; 
         each R 9  is independently selected from hydrogen, methyl, and ethyl; 
         each B is independently selected from hydrogen, halo, CN, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and A; 
         A is 
       
       
         
           
           
               
               
           
         
         Q is selected from CH 2 , O, NH, and NCH 3 ; 
         x is 0, 1, 2, 3, or 4, and y is 1, 2, 3, 4, or 5, the total of x and y being greater or equal to 1 and less than or equal to 5 (1≤x+y≤5). 
       
     
     
         37 . The method of  claim 36 , wherein R 1  is hydrogen. 
     
     
         38 . The method of  claim 36 , wherein X is a direct bond. 
     
     
         39 . The method of  claim 36 , wherein X is CH 2 . 
     
     
         40 . The method of  claim 36 , wherein R 2  is selected from optionally substituted aryl and optionally substituted heteroaryl. 
     
     
         41 . The method of  claim 40 , wherein R 2  is selected from optionally substituted phenyl, optionally substituted pyridyl, optionally substituted thiophenyl, optionally substituted pyrazolyl, optionally substituted pyrimidinyl, optionally substituted imidazolyl, and optionally substituted thiazolyl. 
     
     
         42 . The method of  claim 40 , wherein R 2  is selected from cyanophenyl, acetylphenyl, methoxy-phenyl, pyridine N-oxide, methyl-pyridine N-oxide, methoxy-pyridine N-oxide, ethoxy-pyridine N-oxide, pyridyl, methoxy-pyridyl, ethoxy-pyridyl, methyl-pyridyl, cyano-pyridyl, thiophenyl, carboxy-thiophenyl, carboxymethyl-thiophenyl, pyrazolyl, methyl-pyrazolyl, imidazolyl, and methyl-imidazolyl. 
     
     
         43 . The method of  claim 36 , wherein each R 3  is independently selected from halo, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, and cyclopropyl. 
     
     
         44 . The method of  claim 43 , wherein each R 3  is independently selected from chloro, cyano, methyl, methoxy, propoxy, isopropoxy, trifluoromethyl, and cyclopropyl. 
     
     
         45 . The method of  claim 36 , wherein n is 0 or 1. 
     
     
         46 . The method of  claim 36 , wherein R 4  is Z q1 B; q 1  is 0; and each B is independently selected from halo, CN, optionally substituted aryl, optionally substituted heteroaryl, and A. 
     
     
         47 . The method of  claim 36 , wherein R 4  is Z q1 B; q 1  is 1, 2, or 3; each Z is independently C 1-3 alkyl; and each B is independently selected from halo, CN, optionally substituted aryl, optionally substituted heteroaryl, and A. 
     
     
         48 . The method of  claim 36 , wherein R 4  is Z q1 B; q 1  is 1, 2, 3, 4, 5, or 6; each Z is independently selected from CR 7 R 8 , O, C═O, and SO 2 ; each R 7  is independently selected from hydrogen, methyl, and halo; each R 8  is independently selected from hydrogen, methyl, and halo;
 and B is selected from hydrogen, halo, and cyano. 
 
     
     
         49 . The method of  claim 48 , wherein each R 4  is independently selected from butyl, tert-butyl, propyl, iso-propyl, methyl, COCH 3 , C(CH 3 )(CH 3 )CN, trifluoromethyl, trifluoromethoxy, difluoromethoxy, and methoxy. 
     
     
         50 . The method of  claim 36 , wherein m is 1 or 2. 
     
     
         51 . The method of  claim 50 , wherein m is 1 and R 4  is para to the sulphonamide 
     
     
         52 . The method of  claim 50 , wherein m is 2 and one R 4  group is meta to the sulphonamide, and the other R 4  group is para to the sulfonamide. 
     
     
         53 . The method of  claim 50 , wherein R 1  is hydrogen; X is CH 2 ; R 2  is an optionally substituted heteroaryl; n is 0; m is 1; and R 4  is trifluoromethoxy. 
     
     
         54 . The method of  claim 50 , wherein R 1  is hydrogen; X is a direct bond; R 2  is selected from optionally substituted aryl and optionally substituted heteroaryl; n is 0; m is 2; one R 4  group is halo; and the other R 4  group is trifluoromethyl. 
     
     
         55 . The method of  claim 50 , wherein R 1  is hydrogen; X is a direct bond; R 2  is selected from optionally substituted aryl and optionally substituted heteroaryl; n is 0; m is 1; and R 4  is selected from butyl, tert-butyl, trifluoromethyl, trifluoromethoxy, and difluoromethoxy. 
     
     
         56 . The method of  claim 36 , wherein R 1  is hydrogen; X is a direct bond or CH 2 ; R 2  is selected from optionally substituted aryl and optionally substituted heteroaryl; n is 1; R 3  is halo or cyano; m is 1; and R 4  is butyl or tert-butyl. 
     
     
         57 . The method of  claim 56 , wherein R 2  is selected from optionally substituted pyridyl, optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, and optionally substituted thiophenyl, wherein optional substituents are selected from O − , OCH 3 , OC 2 H 5 , CH 3 , carboxy, carboxymethyl, and CN; R 3  is chloro; and R 4  is tert-butyl. 
     
     
         58 . The method of  claim 36 , wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a salt, solvate, or solvate of a salt thereof. 
       
     
     
         59 . The method of  claim 36 , wherein the disease or condition is an inflammatory disease or condition, an immune disorder, or cancer. 
     
     
         60 . The method of  claim 36 , wherein the disease or condition is an inflammatory bowel disease, an allergic disease, an autoimmune disease, an inflammatory dermatosis, a spondyloarthropathy, a graft rejection, a graft versus host disease, atherosclerosis, a neurodegenerative disease, a liver disease, or cancer. 
     
     
         61 . The method of  claim 36 , wherein the disease or condition is an inflammatory bowel disease. 
     
     
         62 . The method of  claim 61 , wherein the inflammatory bowel disease is collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's disease, indeterminate colitis, ileitis, enteritis, Crohn's disease, or ulcerative colitis. 
     
     
         63 . The method of  claim 61 , wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis. 
     
     
         64 . A process for the preparation of a compound of Formula (I) of  claim 36 , the process comprising reacting an anhydride (A) with a primary amine (B) to produce a phthalimide (C), reducing the nitro group in the phthalimide (C) to form an aminophthalimide (D), then:
 (i) converting the aminophthalimide (D) to a secondary sulfonamide (F) using a sulfonyl chloride (E), and optionally derivatizing the secondary sulfonamide (F) to a tertiary sulfonamide (H); or   (ii) converting the aminophthalimide (D) to a secondary amine (G), and converting the secondary amine (G) to a tertiary sulfonamide (H) using a sulfonyl chloride (E); and   (iii) optionally adding appropriate substituents to an R 2 , R 3 , or R 4  group of the secondary sulfonamide (F) or of the tertiary sulfonamide (H);   
       
         
           
           
               
               
           
         
       
       wherein Z is a halogen; R 1 , X, R 2 , R 3 , n, R 4 , and m have the meanings given for the compound of Formula (I) in claim  1 , and R 1 , R 2 , R 3 , R 4  in intermediate compounds may represent protected forms of these groups.