3-(2-pyrimidineamino) phenylacrylamide compound and its application

Abstract

The present invention discloses a 3-(2-pyrimidine amino) phenyl acrylic amide compound in the structure of formula (I) or a pharmaceutically acceptable salt or a stereisomer or a prodrug molecule. The 3-(2-pyrimidine amino) phenyl acrylic amide compound or the pharmaceutically acceptable salt can effectively inhibit the growth of various tumor cells, and inhibit EGFR (epidermal growth factor receptor), HER (human epidermal receptor2) family other protease, can be used in the preparation of antitumor drugs, and can overcome the drug resistance induced by gefitinib, erlotinib and the like.

Description

technical field [0001] The invention belongs to the technical field of antitumor drugs, and in particular relates to 3-(2-pyrimidineamino)phenylacrylamide compounds and their application in the preparation of antitumor drugs. 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 metastasis occurs, and the opportunity for surgical treatment is lost. In this case, drug treatment is particularly important. [0003] In the traditional cancer...

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 to methionine, resulting in steric hindrance that hinders the combination of the inhibitor with the ATP binding region and ultimately 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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