Substituted [1,2,4]triazolo[4,3-a]pyridines, their preparation and their use as pharmaceuticals

Abstract

This application relates to substituted [1,2,4]triazolo[4,3-a]pyridines of formula (I), 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 [1,2,4]triazolo[4,3-a]pyridines 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): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, 
       wherein:
 R 1  is —C(R a )(R b )(R c ), where R a  and R b  independently represent hydrogen or a linear or branched C 1 -C 6 alkyl, or R a  and R b  are linked together to form a C 3 -C 6 cycloalkyl or a 3-7 membered heterocycloalkyl, and R c  is linear or branched C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 3-7 membered heterocycloalkyl, 5-8 membered heteroaryl, (C 3 -C 6 cycloalkyl)C 1 -C 6 alkyl, (3-7 membered heterocycloalkyl)C 1 -C 6 alkyl, (C 6 -C 10 aryl)C 1 -C 6 alkyl or (5-8 membered heteroaryl)C 1 -C 6  alkyl; 
 R 2  and R 5  are each independently hydrogen, halogen, linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, —C(O)R 6 , —NH 2 , —NHR 6 , —N(R 6 )(R 6′ ), —C(O)NH 2 , —C(O)NH(R 6 ), —C(O)N(R 6 )(R 6′ ) or —NHC(O)R 6 ; 
 one of R 3  and R 4  is hydrogen, halogen, a linear or branched C 1 -C 6 alkyl, —C(O)R 6 , —NH 2 , —NHR 6 , —N(R 6 )(R 6′ ), —C(O)NH 2 , —C(O)NH(R 6 ), —C(O)N(R 6 )(R 6′ ) or —NHC(O)R 6 ; and the other of R 3  and R 4  is a group of Formula II: 
 
       
         
           
           
               
               
           
         
         wherein: 
         X 1 , X 2  and X 3  are each independently N or C, wherein when X 1 , X 2  or X 3  is N, 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  is C; 
         R 7 , R 8  and R 10  are each independently hydrogen, halogen, CN, linear or branched C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —OR 6 , —SR 6 , —NHR 6 , —N(R 6 )(R 6′ ), —NHC(O)R 6  or —N(R 6 )C(O)R 6′ , provided that at least one of R 7 , R 8  and R 10  is other than hydrogen; 
         R 9  is a C 1 -C 3 alkyl or C 3 -C 5 cycloalkyl group; 
         R 6  and R 6′ , which are the same or different, represent a linear or branched C 1 -C 6 alkyl group; 
         and 
         each alkyl is unsubstituted or substituted with 1 to 3 groups being halogen, CN, alkoxy or haloalkoxy, and each of cycloalkyl, aryl, heterocycloalkyl and heteroaryl is unsubstituted or substituted by 1 to 3 groups being halogen, CN, alkyl, haloalkyl, alkoxy or haloalkoxy. 
       
     
     
         2 . The compound of  claim 1 , wherein R 1  is —C(R a )(R b )(R c ), where R a  is H or methyl, R b  is H or methyl, or R a  and R b  are linked together to form a C 3 -C 6 cycloalkyl or a 3-7 membered heterocycloalkyl being optionally substituted by 1 to 3 halogen, CN, alkyl, haloalkyl, alkoxy or haloalkoxy, and R c  is (C 5 -C 6 aryl)C 1 -C 3 alkyl or a group cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, [1,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl or tetrahydropyranyl, each group R c  being optionally substituted by 1 to 3 halogen, alkyl, haloalkyl, alkoxy or haloalkoxy. 
     
     
         3 . The compound of  claim 1 , wherein R 1  is —C(R a )(R b )(R c ), where R a  is H or methyl, R b  is H or methyl, or R a  and R b  are linked together to form a C 3 -C 6 cycloalkyl or a 3-6 membered heterocycloalkyl, and R c  is benzyl, cyclohexyl, phenyl or tetrahydropyranyl, each group R being optionally substituted by 1 to 3 halogen, alkyl, haloalkyl, alkoxy or haloalkoxy. 
     
     
         4 . The compound of  claim 1 , wherein R 1  is —C(R a )(R b )(R c ), where R a  is H or methyl, R b  is H or methyl, or R a  and R b  are linked together to form a C 3 -C 6 cycloalkyl, and R c  is benzyl, cyclohexyl, phenyl or tetrahydropyranyl, each group R c  being optionally substituted by 1 or 2 halogen being F or Cl, methyl or —CF 3 . 
     
     
         5 . The compound of  claim 1 , wherein R 1  is one of the following groups: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein X is F or Cl. 
       
     
     
         6 . The compound of  claim 1 , wherein R 1  is one of the following groups: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1 , wherein R 2  and R 5  are hydrogen. 
     
     
         8 . The compound of  claim 1 , wherein R 4  is a group of Formula II. 
     
     
         9 . The compound of  claim 1 , wherein X 1 , X 2  and X 3  are all carbon atoms and R 9  is an unsubstituted C 1 -C 3 alkyl or C 3 -C 5 cycloalkyl group. 
     
     
         10 .- 12 . (canceled) 
     
     
         13 . The compound of  claim 9 , wherein R 7  and R 10  are each hydrogen atoms and R 8  is Cl, CN, NHR 6  or a substituted or unsubstituted C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl group. 
     
     
         14 . The compound of  claim 1 , wherein the group of Formula II is the following group: 
       
         
           
           
               
               
           
         
       
     
     
         15 .- 16 . (canceled) 
     
     
         17 . The compound of  claim 1 , having the following Formula IIIa: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 8 , R 9  and R 10  are as defined in  claim 1 , 
       
       or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. 
     
     
         18 . The compound of  claim 17 , 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 Cl, CN, NHR 6  or a substituted or unsubstituted C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl group. 
     
     
         19 .- 20 . (canceled) 
     
     
         21 . The compound of  claim 17 , wherein R 8  and R 9  are each independently a methyl, ethyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl or difluorocyclopropyl group. 
     
     
         22 . The compound of  claim 1 , having the following Formula IIIb: 
       
         
           
           
               
               
           
         
         wherein R 1  is as defined in  claim 1 , 
       
       or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. 
     
     
         23 . The compound of  claim 1  or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein the compound is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         24 . A pharmaceutical composition, comprising a compound of  claim 1 , together with a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         25 .- 51 . (canceled) 
     
     
         52 . 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 . 
     
     
         53 .- 62 . (canceled) 
     
     
         63 . 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 . 
     
     
         64 .- 66 . (canceled) 
     
     
         67 . The method of  claim 63 , 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. 
     
     
         68 .- 70 . (canceled)