A pyrimidine egfr t790m Inhibitor and its synthesis method and application

Abstract

The invention discloses pyrimidine EGFRT790M inhibitors and their medicinal salt. The pyrimidine EGFRT790M inhibitors have a general structural formula shown in the following description. By a classical drug design and a structure-function relationship research method, an oxygen atom on a substituent group at a 4-site of a WZ4002 pyrimidine ring is replaced by an imino group, a methoxy group at the 2-site of a phenyl ring is further removed, the substituent group at a 4-site of the phenyl ring is subjected to structural modification, the modified structure replaces the original Michael receptor, seven unknown novel pyrimidine compounds are designed and synthesized so that more structure types of the pyrimidine EGFRT790M inhibitors are obtained. An in-vitro tumor activity test result shows that the compounds 8a and 8f have strong EGFRT790M kinase propagation inhibition activity. The pyrimidine EGFRT790M inhibitors provide reference for further design and synthesis of novel EGFRT790M inhibitors with higher activity and better selectivity.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a pyrimidine EGFR T790M Inhibitor and its synthesis method and application. Background technique [0002] In recent years, epidermal growth factor receptor (EGFR) inhibitors have been paid attention to by chemists and pharmacologists as targeted therapy drugs for non-small cell lung cancer. At present, a variety of EGFR inhibitor drugs have entered the clinical trial stage or have been launched into the market one after another. Among them, Iressa (Gefinib), Tarceva (Erlotinib), which are considered to be the first generation of EGFR inhibitors, and Icotinib (launched in 2012), which is independently developed and marketed in my country, have obtained clinical approval in the treatment of NSCLC patients. Great success. However, after 6 to 12 months of treatment, obvious secondary drug resistance often occurs, which greatly limits the prolongation of the patient's survival tim...

AI Technical Summary

Problems solved by technology

However, Afatinib also strongly inhibits wild-type EGFR (EGFR WT ), prevent normal tissue EGFR in vivo WT Phosphorylation of kinases and activation of related signaling pathways, resulting in greater drug toxicity

[0003] In 2009, Zhou et al. reported the first third-generation pyrimidine irreversible inhibitor WZ4002 (chemical name N-[3-[[5-chloro-2-[[2-methoxy-4-(4-methyl -1-piperazinyl)phenyl]amino]-4-pyrimidinyl]oxyl]phenyl]-2-acrylamide), the compound showed good EGFR in subsequent in vivo and in vitro tests T790M Selective inhibitory effect, but eventually stopped further research and development due to intellectual property disputes

In addition, the existing second and third generation inhibitors of EGFR are designed to improve the anti-EGFR T790M The inhibitory effect of the target protein is usually introduced into the structure of Michael receptors (α,β-unsaturated carbonyl structural fragments) that can covalently bind to the target protein, resulting in non-specific binding to a variety of proteins, making them preclinical and Significant side effects and risks in clinical trials

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