Pyrimidine or pyridine compounds, preparation method therefor and pharmaceutical uses thereof

Abstract

The present invention disclosed a class of pyrimidine or pyridine compounds, pharmaceutically acceptable salts, stereoisomers, prodrugs and solvates thereof, preparation method therefor and pharmaceutical compositions and pharmaceutical uses thereof. The compounds can inhibit the variants of EGFR (Epidermis Growth Factor Receptor) proteinases, and therefore can inhibit the growth of a variety of tumor cells effectively. The compounds can be used to prepare antitumor drugs, used for the treatment, combined therapy or prevention of various different cancers. The compounds can overcome the drug resistance induced by the existing first-generation EGFR inhibitors such as gefitinib, erlotinib and so on. Particularly, the compounds can be used to prepare drugs for treating or preventing diseases, disturbances, disorders or conditions mediated by epidermis growth factor receptor variants (such as L858R activated mutants, Exon19 deletion activated mutants and T790M resistant mutants).

1 . A pyrimidine compound represented by the following formula (I) or a pharmaceutically acceptable salt, stereoisomer, prodrug molecule or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein, 
         R 1  is hydrogen, deuterium, halogen or cyano; 
         R 2  is a C1-C6 alkyl, CD 3 , or halogen-substituted C1-C6 alkyl; 
         X is NR 3  or o; 
         Y is NHC(═O) or NHS(═O) 2 , and the nitrogen in the NHC(═O) or NHS(═O) 2  is bonded to the benzene ring in formula (I); 
         R 3  is a C1-C6 alkyl, C1-C6 alkoxy, CD 3 , C1-C6 alkoxy C1-C6 alkyl; 
         R 4  is a C1-C3 alkyl, unsubstituted or substituted with 1-3 substituents, wherein said substituent is a C1-C3 alkyl, CD 3 , C1-C3 alkoxy, methanesulfonyl, NR 7 R 8  or a 3- to 6-membered heterocyclic group containing 1 to 2 heteroatoms selected from N and O, unsubstituted or substituted with hydroxy or C1-C3 alkyl; 
         or, R 3  and R 4 , together with the nitrogen atom to which they are bonded, form a 4-6 membered heterocyclic ring containing 1 to 4 nitrogen or oxygen and having one or more substituents, and the substituent is amino, dimethylamino, C1-C3 alkoxy, or a 4- to 6-membered heterocyclic group containing 1 to 2 heteroatoms selected from N and O, unsubstituted or substituted with C1-C3 alkyl; 
         R 5  is a fused ring formed by two rings, and the fused ring formed by two rings is optionally substituted with 1-3 substituents, wherein the two rings forming the fused ring are each independently benzene, a 5-7-membered heterocyclic ring or a 5-7-membered heteroaromatic ring, wherein the 5-7 membered heterocyclic or 5-7 membered heteroaromatic ring contains 1-4 heteroatoms selected from S, N or O, and the substituent is oxo group (═O) or R 6 , 
         R 6  is hydrogen, C1-C3 alkyl, CD 3 , C1-C3 alkylsulfonyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered heteroaryl, or halogen-substituted C1-C3 alkyl, wherein the 4-6 membered heterocyclyl or 4-6 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S and is optionally substituted with C1-C2 alkyl; 
         R 7  and R 8  are each independently C1-C3 alkyl, CD 3 , C1-C3 alkoxy or C3-C5 cycloalkyl; 
         and when R 1  is hydrogen, R 2  is methyl, X is NCH 3 , Y is NHC(═O), R 4  is dimethylaminoethyl, R 5  cannot be 
       
       
         
           
           
               
               
           
         
         when R 1  is hydrogen, R 2  is methyl, X is NR 3 , Y is NHC(═O), R 3  is methyl, R 4  is dimethylaminoethyl, R 5  is 
       
       
         
           
           
               
               
           
         
         R 6  is methyl, no hydrogen in any one of R 1 , R 2 , R 3 , R 4  and R 6  can be substituted by deuterium. 
       
     
     
         2 . The pyrimidine compound, or pharmaceutically acceptable salt, stereoisomer, prodrug molecule or solvate thereof according to  claim 1 , wherein
 R 1  is hydrogen, deuterium, fluorine, chlorine or cyano;   R 2  is a C1-C3 alkyl, CD 3 , or C1-C3 alkyl substituted with 1 to 3 fluorines or chlorines;   X is NR 3  or O;   R 3  is a C1-C3 alkyl, CD 3 , or C1-C3 alkoxyC1-C3alkyl;   Y is NHC(═O) or NHS(═O) 2 ;   R 4  is selected from the following groups:   
       
         
           
           
               
               
           
         
         or, when X is NR 3 , R 3  and R 4 , together with the nitrogen atom to which they are bonded, form a nitrogen-containing heterocyclic ring with substituent(s), and the nitrogen-containing heterocyclic ring with substituent(s) is selected from the following heterocyclic groups 
       
       
         
           
           
               
               
           
         
         R 5  is group selected from the following groups: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 6  is hydrogen, methyl, CD 3 , ethyl, isopropyl, methylsulfonyl, C3-C6 cycloalkyl, or fluorine-substituted C1-C3 alkyl; 
         and when R 1  is hydrogen, R 2  is methyl, X is NCH 3 , Y is NHC(═O), R 4  is dimethylaminoethyl, R 5  cannot be 
       
       
         
           
           
               
               
           
         
         when R 1  is hydrogen, R 2  is methyl, X is NR 3 , Y is NHC(═O), R 3  is methyl, R 4  is dimethylaminoethyl, R 5  is 
       
       
         
           
           
               
               
           
         
         R 6  is methyl, no hydrogen in any one of R 1 , R 2 , R 3 , R 4  and R 6  can be substituted by deuterium. 
       
     
     
         3 . The pyrimidine compound or pharmaceutically acceptable salt, stereoisomer, prodrug molecule or solvate thereof according to  claim 1 , wherein
 R 1  is hydrogen, R 2  is methyl or CD 3 , X is NR 3 , R 3  is CH 3 , CD 3 , ethyl or methoxyethyl, Y is NHC(═O) or NHS(═O) 2 , R 4  is dimethylaminoethyl, R 5  is selected from the following groups:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein, R 6  is hydrogen, methyl, CD 3 , ethyl, isopropyl, methylsulfonyl, C3-C6 cycloalkyl, or fluorine-substituted C1-C3 alkyl. 
       
     
     
         4 . A pyrimidine compound represented by the following formula (I), or a pharmaceutically acceptable salt, stereoisomer, prodrug molecule or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein, 
         R 1  is hydrogen, deuterium, halogen or cyano; 
         R 2  is a C1-C6 alkyl, CD 3 , or halogen-substituted C1-C6 alkyl; 
         X is NR 3  or O; 
         Y is NHC(═O) or NHS(═O) 2 , and the nitrogen in the NHC(═O) or NHS(═O) 2  is bonded to the benzene ring in formula (I); 
         R 3  is a C1-C6 alkyl, C1-C6 alkoxy, CD 3 , C1-C6 alkoxy C1-C6 alkyl; 
         R 4  is a C1-C3 alkyl unsubstituted or substituted with 1-3 substituents, wherein said substituent is a C1-C3 alkyl, CD 3 , C1-C3 alkoxy, methanesulfonyl, NR 7 R 8  or a 3- to 6-membered heterocyclic group containing 1 to 2 heteroatoms selected from N and O unsubstituted or substituted with hydroxyl or C1-C3 alkyl; 
         or, R 3  and R 4 , together with the nitrogen atom to which they are bonded, form a 4-6 membered heterocyclic ring containing 1 to 4 nitrogen or oxygen and having one or more substituents, and the substituent is amino, dimethylamino, C1-C3 alkoxy, or a 4- to 6-membered heterocyclic group containing 1 to 2 heteroatoms selected from N and O unsubstituted or substituted with C1-C3 alkyl; 
         R 5  is a fused ring formed by two rings, and the fused ring formed by two rings is optionally substituted with 1-3 substituents, wherein the two rings forming the fused ring are each independently benzene, a 5-7-membered heterocyclic ring or a 5-7-membered heteroaromatic ring, wherein the 5-7 membered heterocyclic or 5-7 membered heteroaromatic ring contains 1-4 heteroatoms selected from S, N or O, and the substituent is oxo group (═O) or R, 
         R 6  is hydrogen, C1-C3 alkyl, CD 3 , C1-C3 alkylsulfonyl; 
         R 7  and R 8  are each independently C1-C3 alkyl, CD 3 , C1-C3 alkoxy or C3-C5 cycloalkyl; 
         and when R 1  is hydrogen, R 2  is methyl, X is NCH 3 , Y is NHC(═O), R 4  is dimethylaminoethyl, R 5  cannot be 
       
       
         
           
           
               
               
           
         
         when R 1  is hydrogen, R 2  is methyl, X is NR 3 , Y is NHC(═O), R 3  is methyl, R 4  is dimethylaminoethyl, R 5  is 
       
       
         
           
           
               
               
           
         
         R 6  is methyl, no hydrogen in any one of R 1 , R 2 , R 3 , R 4  and R 6  can be substituted by deuterium. 
       
     
     
         5 . The pyrimidine compound, or pharmaceutically acceptable salt, stereoisomer, prodrug molecule or solvate thereof according to  claim 4 , wherein
 R 1  is hydrogen, deuterium, fluorine, chlorine or cyano;   R 2  is a C1-C3 alkyl, CD 3 , or C1-C3 alkyl substituted with 1 to 3 fluorines or chlorines;   X is NR 3  or O;   R 3  is a C1-C3 alkyl, CD 3 , or C1-C3 alkoxyC1-C3alkyl;   Y is NHC(═O) or NHS(═O) 2 ;   R 4  is selected from the following groups:   
       
         
           
           
               
               
           
         
         or, when X is NR 3 , R 3  and R 4 , together with the nitrogen atom to which they are bonded, form a nitrogen-containing heterocyclic ring with substituent(s), and the nitrogen-containing heterocyclic ring with substituent(s) is selected from the following heterocyclic groups: 
       
       
         
           
           
               
               
           
         
         R 5  is a group selected from the following groups: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       R 6  is hydrogen, methyl, CD 3 , ethyl, isopropyl, or methylsulfonyl;
 and when R 1  is hydrogen, R 2  is methyl, X is NCH 3 , Y is NHC(═O), R 4  is dimethylaminoethyl, R 5  cannot be 
 
       
         
           
           
               
               
           
         
         when R 1  is hydrogen, R 2  is methyl, X is NR 3 , Y is NHC(═), R 3  is methyl, R 4  is dimethylaminoethyl, R 5  is 
       
       
         
           
           
               
               
           
         
         R 6  is methyl, no hydrogen in any one of R 1 , R 2 , R 3 , R 4  and R 6  can be substituted by deuterium. 
       
     
     
         6 . The pyrimidine compound or pharmaceutically acceptable salt, stereoisomer, prodrug molecule or solvate thereof according to  claim 4 , wherein
 R 1  is hydrogen, R 2  is methyl or CD 3 , X is NR 3 , R 3  is CH 3 , CD 3 , ethyl or methoxyethyl, Y is NHC(═O) or NHS(═O) 2 , R 4  is dimethylaminoethyl, R 5  is selected from the following groups:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein, R 6  is hydrogen, methyl, CD 3  ethyl, isopropyl or methylsulfonyl. 
       
     
     
         7 . The pyrimidine compound or pharmaceutically acceptable salt, stereoisomer, prodrug molecule or solvate thereof according to  claim 4 , wherein
 R 1  is hydrogen, R 2  is methyl or CD 3 , X is NR 3 , R 3  is CH 3 , CD 3 , ethyl or methoxyethyl, Y is NHC(═O) or NHS(═O) 2 , R 4  is dimethylaminoethyl, R 5  is selected from the following groups:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         8 . The pyrimidine compound or pharmaceutically acceptable salt, stereoisomer, prodrug molecule or solvate thereof according to  claim 4 , wherein
 R 1  is hydrogen, R 2  is methyl or CD 3 , X is NR 3 , R 3  is CD 3  or ethyl, Y is NHC(═O) or NHS(═O) 2 , R 4  is selected from the following groups:   
       
         
           
           
               
               
           
         
         R 5  is selected from the following groups: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein R 6  is selected from hydrogen, methyl, CD 3 , ethyl, isopropyl, or methylsulfonyl. 
       
     
     
         9 . The pyrimidine compound or pharmaceutically acceptable salt, stereoisomer, prodrug molecule or solvate thereof according to  claim 4 , wherein
 R 1  is hydrogen, R 2  is methyl or CD 3 , X is NR 3 , R 3  is CD 3  or ethyl, Y is NHC(═O) or NHS(═O) 2 , R 4  is selected from the following groups:   
       
         
           
           
               
               
           
         
         R 5  is selected from the following groups: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         10 . A pyrimidine or pyridine compound, or a pharmaceutically acceptable salt, stereoisomer, prodrug molecule or solvate thereof, wherein the pyrimidine or pyridine compound is the following compound: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         11 . A pharmaceutical composition, comprising a therapeutically effective amount of one or more of the compound, pharmaceutically acceptable salt thereof, stereoisomer, prodrug molecule and/or solvate thereof according to any one of  claims 1  to  10 , and one or more pharmaceutical excipients. 
     
     
         12 . An use of the compound, pharmaceutically acceptable salt thereof, stereoisomer, prodrug molecule and/or solvate thereof according to any one of  claims 1  to  10 , in the preparation of a medicament for treating or preventing a disorder or disease mediated by EGFR in the form of an activated or resistant mutant, preferably, the disorder or disease mediated by the EGFR in the form of an activated or resistant mutant is ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, cholangiocarcinoma, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma or mesothelioma.