The Design Of Benzyl Ether EGER Inhibitors For The Non Small Cell Lung Cancer, Synthesis And Activity Studies

Non-small cell lung cancer(NSCLC) is the largest subgroup of lung cancer, occurring at the frequency of about 80%. The current standard of care for NSCLC is far from satisfactory, with 5 year survival rate below 20%. According to literature, almost 50%~80% NSCLC patients showed over-expression of EGFR, therefore the development of small-molecule tyrosine kinase inhibitors(TKIs) that target EGFR hasrevolutionized the management of NSCLC.The first-generation EGFR-TKIs such as gefitinib and erlotinib have achieved great success for the treatment of NSCLC. Progression-free survival and the quality-of-life have been significantly improved. Meanwhile, compared with chemotherapy, they did not cause side effects such as myelosuppression, nausea and neurotoxicity. However, EGFR mutation-positive patients eventually develop resistance to erlotinib or gefitinib after 9-12 months of treatment. The second-generation EGFR-TKIs, including afatinib, dacomitinib and neratinib, can better differentiate the cancer cell and normal cell, which reduce the side effect. However, they showed low selectivity of T790 M mutations. The third-generation EGFR-TKIs irreversibly inhibit activating EGFR mutations including the most common T790 M mutation.The third generation EGFR-TKIs not only demonstrated significantly improved safety by sparing EGFRWT, but also exhibited better potency and drug resistancy profile.In order to get with independent intellectual property rights of the new structure of the third generation tyrosine kinase inhibitors, we co-1686 AZD-9291 as a lead compound, by structure activity relationship studies and literature research, according to the principle and the principle of split electronic exhaust, designed and synthesized a series of compounds. Compounds with CO-1686 as the lead compound were used as the core framework of the compound, and the 4 sites of the pyridine ring were modified to be a competitive test of benzyl ethers and ATP. Because of the presence of a non reversible Michael addition reaction with protein cysteine sites, we showed higher inhibitory activity, so as to further enhance the inhibitory activity of three 2. So AZD-9291 was designed as the lead compound, and the 4 bit of AZD-9291 was introduced into the benzyl ether, and the 2 remained unchanged.In this paper, 10 benzyl ether compounds were synthesized by simple synthesis route. Target compounds were identified by mass spectrometry and nuclear magnetic resonance spectra. Plus luminescence kinase assay kit Kinase-Glo(Promega) was used to test the biological activity of the target compounds. It was detected by quantitative analysis of the content of ATP in the kinase activity of the kinase. The fluorescence signal in the test was correlated with the content of ATP, CO-1686 and AZD-9291 were used as the control drug, and the 11 target compounds were determined by the activity of kinase inhibition. Preliminary activity test results show that these compounds have high activity in the EGFR receptor, which contains both L858 R and T790 M, and some of them are better than the basic drugs, which can be used as the first step in the study of the drug.