Spiral ring or bridged ring containing pyrimidine compound

Abstract

The invention discloses a spiral ring or bridged ring containing pyrimidine compound. The compound has a structure shown as formula I, and also can be an enantiomer, a diastereomer, a pharmaceutically acceptable salt, a prodrug molecule, a solvate, a tautomer, a resonant body and an isotope marker of formula I. Through the way, the spiral ring or bridged ring containing pyrimidine compound can effectively inhibit the growth of various tumor cells, also generates an inhibiting effect on EGFR (epidermal growth factor receptor), and other proteases of Her family, can be used for preparing antitumor drugs, and also can overcome the drug resistance induced by gefitinib, erlotinib and other existing drugs. Compared with similar non-spiral ring or bridged ring pyrimidine compounds, the spiral ring or bridged ring containing pyrimidine compound I can better improve the biological metabolic stability.

Description

technical field [0001] The present invention relates to a pyrimidine compound containing a spiro ring or a bridged ring, relates to a compound capable of inhibiting mutant EGFR so as to be used in the treatment of non-small cell lung cancer and a preparation method thereof, and also includes a drug combination containing these compounds and a method for applying these compounds method. Background technique [0002] In the past 30 years, the mortality rate of lung cancer has increased by 465%, and the incidence rate has increased by 26.9% every year. It has replaced liver cancer as the first cause of death from malignant tumors in my country. This disease with the highest mortality rate is a serious threat to human health. Among them, non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancers, only one-third of NSCLC patients have the opportunity for surgical treatment, and about 70% of patients are locally advanced at the time of treatment Or distant...

AI Technical Summary

Problems solved by technology

Further studies have confirmed that due to the T790M mutation of the EGFR gene, that is, the encoded threonine is converted into a methyl combine, which causes steric hindrance and hinders the binding of the inhibitor to the ATP binding region, which eventually leads to the loss of inhibitor activity.

At present, studies have also shown that the mutation of the T790M site does not directly affect the affinity of the inhibitor to EGFR, but the mutation leads to a great increase in the affinity of EGFR and ATP, which greatly reduces the affinity of the inhibitor to EGFR ( Inhibitors compete with ATP for binding)

The second-generation inhibitors, such as afatinib and Dacomitinib, are superior to the first-generation in that they have increased recognition of EGFR, which can distinguish tumor cells from normal cells, so that side effects will be reduced; but these molecules have no effect on EGFRT790M mutants. The selectivity of the drug is poor, resulting in a low clinically tolerated dose of the drug. At its maximum tolerated dose (MTD), the drug cannot reach its effective concentration in the body, making it ineffective for most drug-resistant patients

[0005] In short, the current EGFR-TKI still cannot solve the clinical pressure caused by drug resistance, and most of the existing drugs are EGFR reversible or irreversible inhibitors based on quinazoline or quinolineamine Toxic side effects caused by poor selectivity of wild-type cells are also inevitable

Therefore, there is an urgent need for new types, especially compounds with novel frameworks, to solve problems such as drug resistance and poor selectivity.

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