Inhibitors with ALK and EGFR dual activity, and preparation method and application thereof

Abstract

The invention discloses inhibitors with ALK and EGFR dual activity, and a preparation method and an application thereof, and relates to N-(3-((4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidine-2-yl)amino)phenyl)acryloylamide analogs represented by formula (I), and stereoisomers or pharmaceutically acceptable salts thereof. The series of compounds have epidermal growth factor receptor (EGFR) L858R EGFR mutant, T790MEGFR mutant and exon 19 deleted active mutant inhibition activity, and also have ALK inhibition activity, so the series of compounds can be used to treat EGFR mutant and ALK activity individually or partially mediated diseases, can be widely applied to medicines for preventing and treating cancers and especially non-small cell lung cancers, and is hopeful to be developed into new generation EGFR or / and ALK inhibitors.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and specifically relates to an inhibitor with dual activities of ALK and EGFR, its preparation method and application. Background technique [0002] EGFR (Epidermal Growth Factor Receptor) is a member of the transmembrane protein tyrosine kinase erbB receptor family. EGFR can form homodimers on the cell membrane by binding to its ligands, such as epidermal growth factor (EGF), or form heterodimers with other receptors in the family (such as erbB2, erbB3, or erbB4) . The formation of these dimers can cause phosphorylation of key tyrosine residues in EGFR cells, thereby activating multiple downstream signaling pathways in cells. These intracellular signaling pathways play important roles in cell proliferation, survival and anti-apoptosis. Dysregulation of EGFR signaling pathway, including increased expression of ligands and receptors, EGFR gene amplification and mutation, can promote malignant tran...

AI Technical Summary

Problems solved by technology

The drug resistance of half of the patients is due to the secondary mutation of the EGFR gatekeeper gene residue T790M, which reduces the affinity of the drug and the target and produces drug resistance, resulting in tumor recurrence or disease progression

[0006] In view of the importance and prevalence of this mutation in drug resistance in lung cancer EGFR-targeted therapy, several drug R&D companies (Pfizer, BI, AZ, etc.) are trying to develop second-generation small molecule EGFR inhibitors, by inhibiting EGFR T790M mutation strains to treat such drug-resistant lung cancer patients, but all ended in failure due to poor selectivity

Even though afatinib has been approved by the FDA for the treatment of lung cancer, it is only used for the first-line treatment of patients with EGFR activating mutations; for patients with EGFR T790M mutations, because afatinib has a stronger inhibitory effect on wild-type EGFR, causing severe The skin and gastrointestinal toxicity limited the dosage, and did not show a therapeutic effect

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