Substituted imidazopyridines, their preparation and their use as pharmaceuticals

Abstract

This application relates to substituted imidazopyridines, compositions comprising them and their uses in the treatment of diseases and conditions in which inhibition of a bromodomain is indicated. For example, the application relates to substituted imidazopyridines and to their use as bromodomain inhibitors. The present application is also related to the treatment or prevention of proliferative disorders, auto-immune disorders, inflammatory disorders, dermal disorders, and neoplasms, including tumors and/or cancers.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein,
 R 1  is a substituted or unsubstituted group selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, C 3 -C 10 cycloalkylC 1 -C 6 alkyl-, C 3 -C 10 heterocycloalkylC 1 -C 6 alkyl-, C 6 -C 10 arylC 1 -C 6 alkyl-, C 5 -C 10 heteroarylC 1 -C 6 alkyl-, C(O)R a , OR a , NHR a , N(R a ) 2 , C(O)NH 2 , C(O)NHR a , C(O)N(R a ) 2 , NHC(O)R a , N(R a )C(O)R a , NHC(O)NHR a , N(R a )C(O)NHR a , NHC(O)N(R a ) 2 , N(R a )C(O)N(R a ) 2 , NHSO 2 R a , N(R a )SO 2 R a , NHSO 2 NHR a , N(R a )SO 2 NHR a , NHSO 2 N(R a ) 2 , N(R a )SO 2 N(R a ) 2 , SO 2 R a , SO 2 NH 2 , SO 2 NHR a , and SO 2 N(R a ) 2 ; 
 R a  is, independently in each occurrence, a substituted or unsubstituted group selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, C 3 -C 10 cycloalkylC 1 -C 6 alkyl-, C 3 -C 10 heterocycloalkylC 1 -C 6 alkyl-, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, C 6 -C 10 arylC 1 -C 6 alkyl-, and C 5 -C 10 heteroarylC 1 -C 6 alkyl-; 
 R 2  is selected from H, NH 2 , CN or a substituted or unsubstituted group selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, C(O)R a , OR a , SR a , NHR a , N(R a ) 2 , C(O)NH 2 , C(O)NHR a , C(O)N(R a ) 2 , NHC(O)R a , SO 2 R a , SO 2 NHR a , SO 2 N(R a ) 2 , NHSO 2 R a , N(R a )SO 2 R a , NHSO 2 NHR a , N(R a )SO 2 NHR a , NHSO 2 N(R a ) 2 , and N(R a )SO 2 N(R a ) 2 ; 
 R 3  and R 6  are each independently H, halogen, NH 2 , CN or a substituted or unsubstituted group selected from C 1 -C 6 alkyl, C(O)R a , OR a , NHR a , N(R a ) 2 , C(O)NH 2 , C(O)NHR a , C(O)N(R a ) 2 , NHC(O)R a ; and 
 one of R 4  and R 5  is H, halogen, NH 2 , CN or a substituted or unsubstituted group selected from C 1 -C 6 alkyl, C(O)R a , NH 2 , NHR a , N(R a ) 2 , C(O)NH 2 , C(O)NHR a , C(O)N(R a ) 2 , and NHC(O)R a ; and the other of R 4  and R 5  is a group of Formula II: 
 
       
       
         
           
           
               
               
           
         
         wherein,
 R 7  and R 10  are each independently H, halogen, CN, or a substituted or unsubstituted group selected from C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl group, OC 1 -C 6 alkyl, OC 3 -C 6 cycloalkyl, SC 1 -C 6 alkyl, SC 3 -C 6 cycloalkyl, NHC 1 -C 6 alkyl, NHC 3 -C 6 cycloalkyl, N(C 1 -C 6 alkyl) 2 , NHC(O)C 1 -C 6 alkyl and NHC(O)C 3 -C 6 cycloalkyl; 
 R 8  is halogen, CN, or a substituted or unsubstituted group selected from C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl group, OC 1 -C 6 alkyl, OC 3 -C 6 cycloalkyl, SC 1 -C 6 alkyl, SC 3 -C 6 cycloalkyl, NHC 1 -C 6 alkyl, NHC 3 -C 6 cycloalkyl, N(C 1 -C 6 alkyl) 2 , NHC(O)C 1 -C 6 alkyl and NHC(O)C 3 -C 6 cycloalkyl; 
 R 9  is a substituted or unsubstituted C 1 -C 3 alkyl or C 3 -C 5 cycloalkyl group; 
 X 1 , X 2 , and X 3  are each selected from a nitrogen or carbon atom, wherein when X 1 , X 2 , or X 3  is a nitrogen atom, then the R 7 , R 8 , or R 10  attached thereto is absent, provided that at least two of X 1 , X 2 , and X 3  are C; 
 
         or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. 
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R 4  is a group of Formula II and R 5  is a hydrogen atom or a substituted or unsubstituted C 1 -C 3  alkyl. 
     
     
         3 .- 4 . (canceled) 
     
     
         5 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R 5  is a group of Formula II and R 4  is a hydrogen atom or a substituted or unsubstituted C 1 -C 3  alkyl. 
     
     
         6 .- 7 . (canceled) 
     
     
         8 . The compound of  claim 1 , wherein X 1 , X 2  and X 3  are all carbon atoms, said R 7  and R 10  are each hydrogen atoms and R 8  is selected from C 1 , CN, and a substituted or unsubstituted C 1 -C 3 alkyl, C 3 cycloalkyl, NHC 1 -C 3 alkyl, or NH(C 1 -C 3 alkyl) 2  group. 
     
     
         9 . The compound of  claim 1 , wherein X 1  is a nitrogen atom and R 10  is absent, X 2  and X 3  are carbon atoms, and R 9  is an unsubstituted C 1 -C 3 alkyl or C 3 -C 5 cycloalkyl group or a fluorinated C 1 -C 3 alkyl group or C 3 -C 5 cycloalkyl group. 
     
     
         10 .- 12 . (canceled) 
     
     
         13 . The compound of  claim 1 , wherein said R 3  is H or a substituted or unsubstituted C 1 -C 6 alkyl group and said R 6  is H or a substituted or unsubstituted C 1 -C 6 alkyl group. 
     
     
         14 .- 17 . (canceled) 
     
     
         18 . The compound of  claim 1 , wherein said compound is a compound of Formula III(a) or III(b): 
       
         
           
           
               
               
           
         
         wherein, 
         R 1 , R 2 , R 7 , R 8 , R 9 , and R 10  are as defined in  claim 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. 
       
     
     
         19 . (canceled) 
     
     
         20 . The compound of  claim 18 , wherein R 9  is an unsubstituted C 1 -C 3 alkyl or C 3 -C 5 cycloalkyl group, R 7  and R 10  are each hydrogen atoms and R 8  is selected from C 1 , CN, and a substituted or unsubstituted C 1 -C 3 alkyl, C 3 cycloalkyl, NHC 1 -C 3 alkyl, or NH(C 1 -C 3 alkyl) 2  group. 
     
     
         21 .- 22 . (canceled) 
     
     
         23 . The compound of  claim 18 , wherein R 8  and R 9  are each independently a methyl, ethyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, or difluorocyclopropyl group. 
     
     
         24 . The compound of  claim 1 , wherein R 2  is hydrogen or a substituted or unsubstituted group selected from C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, or C 3 -C 10 heterocycloalkyl group. 
     
     
         25 . (canceled) 
     
     
         26 . The compound of  claim 1 , wherein R 2  is hydrogen or a substituted or unsubstituted group selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl, piperidinyl, and pyrrolidinyl. 
     
     
         27 . (canceled) 
     
     
         28 . The compound of  claim 1 , wherein R 2  is hydrogen or methyl. 
     
     
         29 . The compound of  claim 1 , wherein R 1  is a branched or linear C 1 -C 6 alkyl group, unsubstituted or substituted with one or more group(s) selected from halogen, OH, NH 2 , CN, or a substituted or unsubstituted group selected from C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, C(O)R a , OR a , NHR a , N(R a ) 2 , C(O)NH 2 , C(O)NHR a , C(O)N(R a ) 2 , NHC(O)R a , N(R a )C(O)R a , NHC(O)NHR a , N(R a )C(O)NHR a , NHC(O)N(R a ) 2 , N(R a )C(O)N(R a ) 2 , NHSO 2 R a , N(R a )SO 2 R a , NHSO 2 NHR a , N(R a )SO 2 NHR a , NHSO 2 N(R a ) 2 , N(R a )SO 2 N(R a ) 2 , SO 2 R a , SO 2 NH 2 , SO 2 NHR a , and SO 2 N(R a ) 2 , wherein R a  is as defined in  claim 1 . 
     
     
         30 .- 31 . (canceled) 
     
     
         32 . The compound of  claim 1 , wherein R 1  is selected from C(O)R a , OR a , NHR a , N(R a ) 2 , C(O)NHR a , C(O)N(R a ) 2 , SO 2 R a , SO 2 NHR a , and SO 2 N(R a ) 2 , wherein R a  is as defined in  claim 1 . 
     
     
         33 . The compound of  claim 1 , wherein R 1  is selected from C(O)C 3 -C 10 heterocycloalkyl, OR a , NHR a , N(R a ) 2 , C(O)NHR a , SO 2 (C 3 -C 10 heterocycloalkyl), and SO 2 NHR a , wherein R a  is independently in each occurrence selected from a substituted or unsubstituted C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, C 6 -C 10 aryl, or C 5 -C 10 heteroaryl. 
     
     
         34 . (canceled) 
     
     
         35 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         36 . A pharmaceutical composition, comprising a compound of  claim 1 , together with a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         37 .- 63 . (canceled) 
     
     
         64 . A method for treating a disease or condition for which a bromodomain inhibitor is indicated, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         65 .- 74 . (canceled) 
     
     
         75 . A method for the treatment of a disease or condition selected from auto-immune disorders, inflammatory disorders, dermal disorders, and neoplasms, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         76 .- 78 . (canceled) 
     
     
         79 . The method of  claim 75 , wherein the disease or condition is a neoplasm selected from bladder cancer, leukemia, lymphoma, brain cancer, central nervous system cancer, breast cancer, cervix cancer, colorectal cancer, colon cancer, kidney cancer, liver cancer, lung cancer, mesothelioma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer or gastric cancer. 
     
     
         80 .- 82 . (canceled)