Design,Synthesis And Structure-activity Relationship Study Of Dihydroquinoxalinone EGFR^T790M Inhibitors

Lung cancer is one of the malignant tumors that threaten human life and health,and it also occupies the forefront of cancer deaths in our country.Non-Small Cell Lung Cancer（NSCLC）accounts for about 80%of all lung cancers,including large cell carcinoma,adenocarcinoma,and squamous cell carcinoma.NSCLC cells spread and Metastasize relatively late,and their growth and division are relatively slow.At the time of diagnosis,most patients are already in the advanced stage.At present,chemotherapy and radiotherapy have very limited effects on prolonging the survival period and improving the quality of life of patients with advanced NSCLC.Therefore,small molecule drug targeted therapy for NSCLC is the first choice for clinical medication,and the development of corresponding small molecule targeted drugs is also the current hot spot of new drug development and research.Epidermal growth factor receptor（EGFR）is a transmembrane receptor whose signal transduction pathway can regulate cell growth,proliferation and differentiation.Inhibiting the activity of EGFR can block the activation of the EGFR pathway,thereby achieving the effect of inhibiting non-small cell lung cancer.At present,there are a variety of EGFR tyrosine kinase inhibitors（EGFR-TKI）targeting NSCLC on the market.These inhibitors have a certain therapeutic effect to a certain extent,but the EGFR T790M mutation that occurs in advanced patients can lead to drug resistance and reduce the efficacy of the drug.Based on the discovery and structure-activity relationship of new EGFRT790M inhibitors,this thesis mianly focused on the design,synthesis and structure-activity relationship research of dihydroquinoxalinone EGFRT790M inhibitors and construction of pyrazole based EGFR inhibitors.The construction of the library works as follows:Design,synthesis and structure-activity relationship study of dihydroquinoxalinone EGFR^T790M inhibitors:Dihydroquinoxalinone is a nitrogen-containing heterocycle formed by the combination of a benzene ring and a dihydropyrazinone ring,and it can provide target compounds with multiple sites that generate hydrogen bonds with target amino acid residues.In this thesis,dihydroquinoxalinone based structures were designed and synthesized with various drug design principles including bioisosterism substitution,and the third-generation EGFR inhibitor osimertinib was employed as the lead compound.Totally,35 target compounds in 8 categories were obtained.Most of the compounds showed excellent EGFR^L858R/T790M inhibitory activities and selectivities against WT EGFR.Among them,the inhibitory activities of compounds A19and A23 on EGFR^L858R/T790M were equivalent to the positive control AZD-9291.In addition,compound A19 also displayed good NCI-H1975 and PC-9 cell proliferation inhibitory activities.Further structural optimization and in vivo anti-cancer activity evaluation of compound A19 are underway.Construction of pyrazole pharmacophore based EGFR inhibitor library:Heterocyclic compounds play a very important role in many fields of research,including organic chemistry and medicinal chemistry.Pyrazole heterocyclic compounds and their derivatives belong to an important class of five-membered heterocyclic analogues,which occupies an important position in medicinal chemistry with diverse biological activities including anti-tumor,anti-bacterial and anti-inflammatory activities.After a reasonable analysis of the binding mode of osimeretinib and EGFR^T790M,we found that the Methylindole structure only occupies a part of the corresponding active pocket,and only has a hydrophobic interaction with Met790.For the wide application of pyrazole compounds in the field of anti-tumor,we hope to find a module containing pyrazole core to replace the Methylindole in osimeretinib to discovery a new type EGFR^T790M inhibitors with novel structure,good activity and high selectivity.In this work,we have developed a synthetic Method for bromo Methyl substituted pyrazole compounds,and based on this Method,we have successfully constructed a bromo Methyl substituted pyrazole based on the pharmacophore of EGFR inhibitors.The highlights of this work are:1.Can synthesize pyrazole compounds with different substituents in for using;2.The bromo Methyl group can be used as a functional"C"unit and thus introduce pyrazole fragments into our designed inhibition In the backbone of the agent molecule;3.With this functional"C"unit,the pyrazole fragment has better swing after being connected to the pyrimidine ring,which can increase the possibility of a better affinity between the pyrazole ring and the amino acid residues in EGFR.