Design,Synthesis And Biological Activity Evaluation Of EGFR Kinase Inhibitors Based On The Side Ring Of [3,2-d] Pyrimidine Compounds

The epidermal growth factor receptor(EGFR),a receptor tyrosine kinase,is a key mediator in cellular signaling related to cell growth,proliferation,survival,and migration.EGFR is a very important drug target for the development of therapeutics against non-small cell lung cancer(NSCLC).Until now,three generations of EGFR inhibitors have been developed and approved for clinical use,but most of patients will be found to develop drug resistance after a certain period of time.The third generation of EGFR tyrosine kinase inhibitors can effectively overcome the pathogenic mutation of EGFR and the T790M mutation,but the new EGFR-C797S drug-resistant mutation leads to a significantly reduced efficacy.Therefore,the development of novel drugs that can overcome both the pathogenic mutations of EGFR and the drug-resistant mutations of EGFR-T790M and EGFR-C797S is urgently needed.In this thesis,we designed new EGFR inhibitors that could overcome all the EGFR mutations using the third generation EGFR inhibitor Olmutinib(HM61713)as a lead.Eighty-six compounds based on the core skeletons of pyrrolidine[3,2-d]pyrimidine and thiophene[3,2-d]pyrimidine were designed and synthesized using the approaches of scaffold hopping and pharmacophore stitching.The systematic structure activity relationship(SAR)study revealed that R4 group of pyrrole ring,R6 group of isopropyl sulfonyl,and with elements of Y=N and W=O are key structural features to have good activities.Among the 43 compounds synthesized with thieno[3,2-d]pyrimidine as the core skeleton,compound 1-4 exhibited the best antiproliferative activities with IC50s of 80.36 nM,16.89 nM,13.89 nM,and 70.42 nM against EGFR-Del,EGFR-L858R,EGFR-Del/T790M and EGFR-L858R/T790M respectively.However,the inhibitory effect on EGFR-L858R/T790M/C797S was weak with IC50 of 3509 nM.Among the 43 compounds synthesized with pyrro[3,2-d]pyrimidine as the core skeleton,compound Ⅲ-19 has the best inhibitory activities with IC50s of 79.26 nM,52.49 nM,93.87 nM,and 43.2 nM against EGFR-Del,EGFR-L858R,EGFR-Del/T790M,and EGFR-L858R/T790M respectively.While the inhibitory effect was weak with IC50s of 4222 nM and 5727 nM against EGFR-Del/T790M/C797S and EGFR-L858R/T790M/C797S respectively.In summary,we haven’t succeeded in identification of new EGFR inhibitors that could overcome all EGFR mutaions.But the systematic SAR study based on the core skeletons of pyrrolidine[3,2-d]pyrimidine and thiophene[3,2-d]pyrimidine revealed the key structural features,which provides critical hints for designing new inhibitors.