Imidazopyridine derivatives

Abstract

The present disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt thereof as described herein. The present disclosure also provides pharmaceutical compositions comprising a compound of Formula (I), processes for preparing compounds of Formula (I), and therapeutic methods for treating inflammatory disease.

1 - 47 . (canceled) 
     
     
         48 . A method for treating an inflammatory disease or condition associated with α4β7 integrin, comprising administrating to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 wherein R 1  is selected from A 1 , A 2 , and A 3 ;
 A 1  is 5-10 membered heteroaryl containing one to five heteroatoms or groups independently selected from S, N, and O; wherein A 1  optionally comprises one to three C(O); and wherein A 1  is optionally substituted with one to six R A1 : 
 A 2  is C 5-10 aryl, optionally substituted with one to six R A1 ; and 
 A 3  is —NR 1a R 1b ;
 wherein each R A1  is independently selected from halo, cyano, hydroxyl, —NR 1a R 1b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxyl, C 1-6 haloalkyl, C 1-6 haloalkoxyl, —S(O) m —C 1-4 alkyl, C 3-8 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, —O—C 3-8 cycloalkyl, —O-(3-6 membered heterocyclyl), —O—C 1-4 alkylene-C 3-8  cycloalkyl, and —O-phenyl; 
  wherein each C 3-8 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, —O—C 3-8 cycloalkyl, —O-(3-6 membered heterocyclyl), —O—C 1-4 alkylene-C 3-8 cycloalkyl, and —O-phenyl of R A1  is optionally substituted with one to three groups independently selected from halo, cyano, hydroxyl, —NR 1a R 1b , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, and C 1-6 haloalkoxyl; and 
  wherein each C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl of R A1  is optionally substituted with one to three R 1c  wherein each R 1c  is independently selected from C 1-4 alkoxyl, hydroxyl, cyano, —NR 1a R 1b , C 3-8 cycloalkyl, and 3-6 membered heterocyclyl; wherein each C 3-8 cycloalkyl and 3-6 membered heterocyclyl of R 1c  is independently optionally substituted with one to three R 1d ; and 
  wherein each R 1d  is independently selected from halo cyano, hydroxyl, —NR 1a R 1b , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, C 3-8  cycloalkyl, and 3-6 membered heterocyclyl; 
 
 
 R 2  is selected from 
 
       
       
         
           
           
               
               
           
         
         
            and C 3-8 cycloalkyl;
 wherein each R a , R b , R c , R d , and R e  is independently selected from H, halo, cyano, hydroxyl, C 1-6 alkyl, C 1-8 haloalkyl, C 1-6 alkoxyl, C 1-8 haloalkoxyl, —NR 2a R 2b , —NR 2a S(O) n R 2c , —S(O) m —R 2c , —S(O) n NR 2a R 2b , —CONR 2a R 2b , —NR 2a COOR 2b , —NR 2a COR 2c , C 3-6 cycloalkyl, C 6-10 aryl, 3-8 membered heterocyclyl, and 5-6 membered heteroaryl; 
 wherein each C 1-6 alkyl, C 1-8 haloalkyl, C 1-6 alkoxyl, and C 1-8 haloalkoxyl of R a , R b , R c , R d , and R e  is independently optionally substituted with one to two R 2d ; and 
 wherein each C 6-10 aryl, and 5-6 membered heteroaryl of R a , R b , R c , R d , and R e  is optionally substituted with one to four R 2f ; 
 wherein each C 3-6 cycloalkyl, and 3-8 membered heterocyclyl of R a , R b , R c , R d , and R e  is optionally substituted with one to six groups with one to six groups independently selected from ═CR 2a R 2b  and R 2f ; 
 wherein each R 2a  and R 2b  is independently selected from H, C 1-6 alkyl, and C 1-8 haloalkyl; each C 1-6 alkyl and C 1-8 haloalkyl of R 2a  and R 2b  is optionally substituted with one group selected from cyano, C 1-4 alkoxyl, C 3-6 cycloalkyl, phenyl, and 4-6 membered heterocyclyl; wherein each C 3-6 cycloalkyl, phenyl, and 4-6 membered heterocyclyl is optionally substituted with one to three groups independently selected from halo, cyano, —NR 1a R 1b , C 1-4 alkyl, C 1-4 alkoxyl, and C 1-4 haloalkyl; 
 wherein R 2c  is selected from C 1-6 alkyl, C 1-6 haloalkyl, and phenyl; wherein phenyl of R 2c  is optionally substituted with one to three groups independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, and 6 membered heteroaryl; and wherein the 6 membered heteroaryl is optionally substituted with one to three groups independently selected from halo, cyano, C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxyl; 
 wherein each R 2d  is independently selected from cyano, hydroxyl, C 1-4 alkoxyl, and —NR 1a R 1b ; 
 wherein each R 2f  is independently selected from halo, cyano, hydroxyl, —NR 1a R 1b , C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxyl; and 
 the C 3-8 cycloalkyl of R 2  is optionally substituted with one to three groups independently selected from halo, cyano, hydroxyl, —NR 1a R 1b , C 1-6 alkyl, C 1-6 alkoxyl, C 1-8 haloalkoxyl, and C 1-8 haloalkyl; 
 
           R 3  is selected from selected from H, methyl, ethyl, propyl, butyl, —CH 2 C(O)N(CH 3 ) 2 , —(CH 2 ) 2  N(CH 2 CH 3 ) 2 , —CH 2 —O—C(O)CH 3 , —(CH 2 ) 2 —O—C(O)CH 3 , —CH 2 —O—C(O)C(CH) 3 , —(CH 2 ) 2 —O—C(O)C(CH) 3 , —CH 2 —O—C(O)—O—CH 3 , —CH(CH 3 )—O—C(O)—O—CH 3 , —CH 2 —O—C(O)—O—CH 2 CH 3 , —CH 2 —O—C(O)—O—CH(CH 3 ) 2 , —CH 2 —O—C(O)—O—C(CH 3 ) 3 , —(CH 2 ) 2 C(O)CH 3 , 
         
       
       
         
           
           
               
               
           
         
         
            or 
           R 3  together with the N that attaches to R 9  forms a 5 membered heterocyclyl; wherein the 5 membered heterocyclyl is optionally substituted with one to two groups independently selected from halo, C 1-6 alkyl, C 1-6 alkoxyl, C 1-6 haloalkyl, and C 6-10 aryl; wherein the C 6-10 aryl is optionally substituted with one to three groups independently selected from halo, C 1-6 alkyl, C 1-6 alkoxyl, C 1-6 haloalkyl; 
           each R 4 , R 5 , R 6 , and R 7  is independently selected from H, halo, —NR 1a R 1b , C 1-4 alkyl, C 1-4 alkoxyl, C 1-4 haloalkyl, and C 3-6 cycyloalky; 
           R 9  is selected from H, C 1-4 alkyl, and C 1-4 haloalkyl; 
           each R 1a  and R 1b  is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl; 
           m is selected from 0, 1, and 2; 
           n is 1 or 2; and 
         
         at least one pharmaceutically acceptable carrier. 
       
     
     
         49 . The method of  claim 48 , wherein the disease or condition is an inflammatory disease. 
     
     
         50 . The method of  claim 49  wherein the inflammatory disease of condition is selected from inflammatory bowel disease (IBD), Ulcerative colitis (UC), Crohn's disease, graft-versus-host disease (GVHD), and primary sclerosing cholangitis (PSC). 
     
     
         51 . The method of  claim 48 , further comprising at least one or more additional therapeutic agent. 
     
     
         52 . The method of  claim 51 , wherein the at least one or more additional therapeutic agent is a JAK tyrosine kinase inhibitor, Tumor Progression Locus 2 (TPL2) inhibitors, Toll-like receptor 8 (TLR8) inhibitors, and IRAK4 inhibitors. 
     
     
         53 . The method of  claim 52 , wherein the as least one or more additional therapeutic agent is a JAK tyrosine kinase inhibitor and wherein the JAK tyrosine kinase inhibitor is fligotinib.