Four Yuan Heterocyclic Small Molecule Modification, Synthesis And The Treatment Of Egfr Tyrosine Kinase Inhibitor Modification Research

In the optimization process of lead compounds, high potency and selectivity of the active compounds were frequently the focus, which frequently leads to the lead to difficulties in the selection of drug candidates and encounts problems in clinical trials because of the neglection of druggability (physico-chemical, bio-chemical, pharmacokinetic and toxicological characteristics)。Therefore,in the early drug discovery stage, we start the consideration of multi-dimensional optimization for hit to lead compounds. The requirements of high activity and selectivity, and the physical and chemical properties of compounds, pharmacological, toxicological, and other parameters have more stringent requirements.Recently, four-membered heterocycles(oxetane, azetidine, thietane, especially oxetane) have received increased attention. They were seldom covered in the patent protection.Recent studies indicate that the four-membered heterocycles have significent impacts on the pharmacokinetic properties of the compounds. Four-membered heterocycles can often significantly improve the solubility of drug molecules, regulate the pKa, and at the same time remain membrane permeability and metabolic stability. It is also possible to adjust the toxicity of the drug molecules. Therefore systematic reaearch on four-membered heterocycles including oxetane is of great significance to break patent protection, to improve the pharmacological properties of the compounds, as well as to develop small molecule drugs with independent intellectual property rights.In this thesis, firstly the synthetic processes of8four-membered heterocycles derivatives were optimized; secondly6novel four-membered heterocycles were prepared;and finally Gefitinib, a EGFR tyrosine kinase inhibitor was selected as the target molecule for modification with the synthesized building blocks,and5novel EGFR tyrosine kinase inhibitors were prepared.