Macrocyclic compound as well as preparation method and application thereof

Abstract

The invention relates to a macrocyclic compound as well as a preparation method and application thereof, the macrocyclic compound has a structure as shown in a formula I, and A, B, D, R1, R2, R3, R4, R5, Z, X, m, n and p are defined in the specification. The macrocyclic compound disclosed by the invention not only can overcome EGFR C797S mutation, but also can overcome EGFR T790M mutation, and is relatively high in selectivity.

Description

technical field [0001] The present invention relates to macrocyclic compounds and their preparation methods and applications, in particular to compounds for inhibiting, regulating and / or regulating signal transduction of EGFR kinase, their preparation methods, pharmaceutical compositions containing them and their applications. Background technique [0002] Protein kinases are the enzymatic components of signaling pathways that catalyze the transfer of terminal phosphates from ATP to the hydroxyl groups of tyrosine, serine and / or threonine residues of proteins. Compounds that inhibit protein kinase function are therefore valuable tools for assessing the physiological consequences of protein kinase activity. Overexpression or inappropriate expression of normal or mutant protein kinases in mammals has been the subject of extensive research and has been demonstrated in many diseases, including diabetes, angiogenesis, psoriasis, restenosis, eye diseases, schizophrenia, It plays ...

AI Technical Summary

Problems solved by technology

The second-generation inhibitors, such as afatinib and dacomitinib, etc., have stronger binding activity to EGFR, but have poor selectivity for T790M mutants, and cannot reach effective concentrations in vivo at tolerable doses

[0005] The third-generation inhibitor osimertinib can be used not only as second-line treatment for patients with T790M mutation after first- and second-generation treatment, but also as first-line treatment for patients with EGFR-sensitive mutations who have not been treated with EGFR-TKIs. After 9.9-18.9 months of treatment with the EGFR inhibitor osimertinib, C797S (mutation of cysteine ​​to serine at position 797 of exon 20) drug resistance mutation will inevitably occur

[0008] In 2019, Boehringer Ingelheim reported in an article [J.Med.Chem.2019,62,10272-10293] a C797S triple mutation that can overcome resistance to osimertinib and has a high degree of wild-type wtEGFR Selective non-covalent macrocyclic compound BI-4020, but this compound has not entered the clinical stage

It is speculated that the reason may be that the activity of non-covalent compounds cannot overcome the drug resistance caused by the T790M double mutation

For the C797S mutation, there is currently no effective drug on the market to treat it. There are few drugs targeting the C797S mutation in clinical practice, and they are mainly reversible inhibitors targeting the C797S triple mutation. These drugs have weak activity against the T790M double mutation

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