Pyrrolopyrimidine compounds containing m-chloroaniline substituents as well as preparation method and application of pyrrolopyrimidine compounds

Abstract

The invention provides pyrrolopyrimidine compounds containing m-chloroaniline substituents as well as a preparation method and application of the pyrrolopyrimidine compounds, and particularly relatesto compounds represented by a formula (I) shown in the specification, and isomers, hydrates, solvates, pharmaceutically acceptable salts and prodrugs of the compounds, a preparation method of the compounds, and the isomers, hydrates, solvates, pharmaceutically acceptable salts and prodrugs of the compounds and applications of the compounds, and the isomers, hydrates, solvates, pharmaceutically acceptable salts and prodrugs of the compounds in preparation of drugs used as a kinase inhibitor. The compounds provided by the invention have good inhibitory activity on mutant EGFR<T790M> and EGFRC<797S> kinases, and shows moderate inhibitory activity on wild EGFR kinase at the same time.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a pyrrolopyrimidine compound containing m-chloroaniline substituents, a preparation method and an application thereof. Background technique [0002] Protein kinase is an important signal messenger for cell life activities, which can catalyze the transfer of the γ-phosphate group at the end of ATP to the hydroxyl receptor in the substrate amino acid residue (serine, threonine, tyrosine), thereby activating the target Protein (Johnson L.N., and Lewis R.J., Structural basis for control by phosphorylation, Cheminform, 2001, 101, 2209.). Protein kinases are involved in numerous physiological processes, including cell proliferation, survival, apoptosis, metabolism, transcription, and differentiation (Adams J.A., Kinetic and catalytic mechanisms of proteinkinases, Chemical reviews, 2001, 101, 2271.). Among the existing drug targets in the human body, members of the protein kinase family...

AI Technical Summary

Problems solved by technology

This type of inhibitor has inhibitory effects on wild-type and activating mutant EGFR at the same time, and has achieved great clinical success, but the drug resistance of recipient patients after taking it for a period of time, especially the drug resistance caused by the T790M mutation Sex reduces or loses efficacy

The second-generation EGFR inhibitor afatinib (Afatinib) is an irreversible inhibitor that contains a Michael receptor that can covalently bind to the cysteine ​​residue (Cys797) located at the entrance of the ATP binding pocket. The inhibitor shows strong activity against both T790M mutant EGFR kinase and wild-type EGFR kinase, and its inhibitory activity against T790M mutant EGFR kinase is higher than that of wild-type EGFR kinase, which makes the therapeutic window of the drug in clinical application narrower , the effect is not ideal (Camidge, D.R., et.al., Acquired resistance to TKIs in solid tumors: learning from lung cancer. Nature Reviews Clinical Oncology, 2014, 11, 473.)

However, when a secondary mutation of C797S occurs in a patient, the drug molecule loses its covalent binding to Cys797, resulting in the drug becoming ineffective (Harun Patel., et.al., 2017, Recent updates on third generation EGFR inhibitors and emergence of fourth generation EGFR inhibitors to combat C797Sresistance, Eur J Med Chem., 2017, 142, 32)

Images