The Design,Synthesis And Application Of The Fourth Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

Lung cancer is a malignant tumor with the highest morbidity and mortality in China,and it has always been a difficult problem to choose an appropriate treatment method.As an ideal treatment method,targeted therapy has few side effects and remarkable effect.The Epidermal Growth Factor Receptor is an important target for the treatment of non-small cell lung cancer currently.Nowadays,there are two types of drugs targeting EGFR,one is small molecule kinase inhibitors,and the other is monoclonal antibodies.At present,a number of small molecule kinase inhibitors（for example Gefitinib,Afatinib and Osimertinib）have been widely used in the treatment of patients with EGFR^m+non-small cell lung cancer clinically,and have achieved excellent efficacy.However,after using the EGFR-TKIs for a period of time,drug resistance occurred,among which T790M and C797S are important drug resistance mutations.T790M mutation appears in a considerable part of patients who are resistant to the 1^st and 2^nd generation EGFR-TKIs.C797S appears in some patients who are resistant to 3^rd EGFR tyrosine kinase inhibitors.Although there have been relevant studies on the triple mutations of EGFR^{L858R/T790M/C797S} and EGFR^{del19/T790M/C797S},there are no targeted drugs that have been approved clinically.Based on the I-018 developed by Boehringer Ingelheim and the TQB-3804developed by Chia Tai Tianqing,this thesis conducted in-depth research on related patents to find opportunities for breakthrough patents,and obtain compounds with equivalent and better effects than the patented compounds.34 compounds were designed and synthesized in this thesis.The synthesized compounds above were divided into two categories:part one was aminobenzimidazole compounds,and the carboxylic acid part of its amide has been modified,the strategies were scaffold hooping,patent modifications and introduction of fused ring system.Part 2 is arylphosphine oxide compounds,the phosphine oxygen contained aromatic ring part,aniline part and the piperazine ring were modified,the strategies were introducing a tricyclic system,the introduction of pyrazole and the modification of piperazine tail.All target compounds were characterized by ¹H-NMR and LC-MS.Some target compounds were characterized by ¹³C-NMR.All synthesized target compounds were evaluated for their anti-proliferative activity in vitro,and IC₅₀ were evaluated.Compounds 20,29,30,31 and 32 showed strong inhibitory activities in both kinase assay and cell assay.Among them,we identified the hit compound 32,which showed extremely potent inhibitory activity against both PC-9^{EGFRdel19/T790M/C797S} and Ba F3^{EGFRdel19/T790M/C797S} cell lines with IC50values of 1.5 n M and 66.7 n M,respectively.Meanwhile,compound 32 retained its selectivity for A431 with EGFR^wt with an IC₅₀ value of 108.7 n M.In the follow-up experiments,the kinase activity of the compound was measured in detail,32 exhibited biochemically strong potencies against EGFR^{del19/T790M/C797S},EGFR^{L858R/T790M/C797S} and other clinically relevant EGFR-mutants.Moreover,DMPK properties of 32 were also determined.The results demonstrated that 32 exhibited good DMPK profile in female CD-1 mice PK study.Compound 32 had a moderate T_1/2 and a high C_max with good oral bioavailability,it had potential for further drug development.The further evaluation of this compound is still in progress.