Design,Synthesis And Biological Evaluation Of 2-Phenylaminopyrimidine EGFR Inhibitors

Lung cancer has affected human health seriously.It is one of the malignant tumors with highest incidence rate and mortality rate in China and worldwide.According to statistics,non-small cell lung cancer（NSCLC）accounts for about 80%of lung cancer,in which epidermal growth factor receptor（EGFR）gene mutation accounts for 60%～65%of NSCLC patients.The abnormal expression of EGFR can lead to the abnormal activation of downstream biological signal transmission,which leads to the disorder of the physiological processes of tumor cell proliferation,differentiation and apoptosis,and eventually leads to cancer.In recent years,the main progress of NSCLC treatment focus on targeted therapy and immunotherapy.EGFR exon20ins mutation is the third largest type of EGFR mutation,accounting for 5%～12%of all EGFR mutation types.Currently,targeted drugs targeting EGFR exon 20ins mutation NSCLC have not been approved worldwide.The existing EGFR inhibitors can not effectively inhibit exon20 insertion mutation,so it is urgent to research the EGFR inhibitor targeting this mutation.In this thesis,starting from the structure of compound Mobocertinib,and on the basis of summarizing its structure-activity relationship,three types of EGFR inhibitors with a total of20 new structures with 2-phenylaminopyrimidines as the mother nucleus were designed and synthesized.ClassⅠ compounds mainly modify the two positions of the mother nucleus.Modify the metabolism site of the nitrogen atom of the indole ring of Mobocertinib,in order to improve the metabolic stability of compounds,two compounds ⅠA-01～02 were obtained;five compounds ⅠB-01～05 were designed and synthesized by extending and closing the carbon chain of N,N,N’-trimethylethylenediamine,the substituent in the solvent accessible region at the C2position of benzene ring;three compounds ⅠC-01～03 were obtained by replacing the indole cyclic nitrogen atom methyl substituent with cyclopropyl substituent;two compounds ⅡA-01～02 were designed and synthesized by replacing the benzene ring with the ring isometric pyridine ring based on the principle of electron isometric;four compounds ⅡB-01～04 were designed and synthesized by replacing methoxy group in the hydrophobic region at the C4position of the pyridine ring with trifluoroethoxy group.Finally,the effects of different covalent binding groups on the activity of compounds were studied,and four compounds Ⅲ-01～04 were designed and synthesized.None of the target compounds designed and synthesized in this thesis have been reported in the literature,the structures of compounds were confirmed by MS and¹H-NMR.In this thesis,in vitro EGFR WT and EGFR（A763_Y764ins FQEA）kinase inhibitory activity of the target compounds were detected at 500 n M,and some compounds were selected to determine the ⅠC₅₀value of EGFR（A763_Y764ins FQEA）kinase.The experimental results show that among the class I compounds,compounds of class ⅠA and ⅠB show good inhibitory activity on EGFR WT and EGFR（A763_Y764ins FQEA）kinases as a whole.Among them,compounds ⅠA-01,ⅠA-02,ⅠB-01 and ⅠB-04 inhibit EGFR（A763_Y764ins FQEA）by more than97.0%.The inhibitory rates of ⅠC compounds on EGFR（A763_Y764ins FQEA）kinase are all lower than 92.0%.Comparing the activity data of ⅠB and ⅠC compounds,the inhibitory activity of ⅠC compounds is lower than that of ⅠB compounds.For class Ⅱ compounds,class ⅡA and class ⅡB compounds also showed significant inhibitory activity against EGFR WT and EGFR（A763_Y764ins FQEA）kinases.Among them,compounds ⅡA-01,ⅡB-01,ⅡB-02 and ⅡB-04have significant inhibitory activity against EGFR（A763_Y764ins FQEA）with all inhibitory rates greater than 99.0%.The inhibitory rate of all class Ⅲ compounds on EGFR（A763_Y764ins FQEA）kinase was lower than 94.0%,and the inhibitory activity of class Ⅲ compounds was lower than that of positive compounds.The ⅠC₅₀ values of compounds ⅠA-02,ⅠB-04 and ⅡB-04 on EGFR（A763_Y764ins FQEA）kinase are close to that of the positive compound.Through the research work of this thesis,new candidate compounds are provided for the further development of small molecule EGFR inhibitors with better activity.