Pyrazolo [1, 2] diaza compound

Abstract

The invention provides a pyrazolo [1, 2] diaza compound as well as a preparation method and application thereof. The compound provided by the invention has a remarkable selective BTK kinase inhibition effect, effectively improves the off-target effect phenomenon of the existing BTK inhibitor, and can improve the drug targeting property, so that the toxic and side effects are reduced.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a pyrazolo[1,2]diazepine BTK inhibitor, a preparation method and application of the inhibitor. Background technique [0002] BTK (Bruton's Tyrosine Kinase) is a key regulator of the B cell receptor (BCR) signaling pathway. It is widely expressed in different types of malignant hematological diseases and participates in the proliferation, differentiation and apoptosis of B cells. Therefore, it is used as a therapeutic Important target for hematologic malignancies. BTK belongs to the tyrosine kinase inhibitor receptor, which plays a vital role in the process of cell proliferation, angiogenesis, tumor invasion, metastasis and apoptosis. Studies have shown that there are overexpression or abnormal mutations of BTK in many solid tumors, and the growth of tumors can be inhibited by inhibiting the kinase activity of BTK tyrosine. By analyzing the structure of BTK, selecti...

AI Technical Summary

Problems solved by technology

In 2016, Ibrutinib’s global sales exceeded US$3 billion, making it the world’s best-selling leukemia drug. Adverse events such as arthralgia and bleeding have occurred from time to time, and ibrutinib is also known to have gastrointestinal side effects, which are considered to be the result of secondary EGFR inhibitory activity, mainly because of the low selectivity of ibrutinib, While having an inhibitory effect on BTK, it also has a considerable inhibitory effect on other kinases such as EGFR, TEC, ITK, HER-2, so the more common side effect is the off-target effect on other kinases

In addition, there are quite a few patients whose treatment is not obvious, suggesting the limitations of the single-drug effect of BTK inhibitors. Studies have found that the combined treatment of BTK inhibitors and certain targeted drugs or chemotherapy drugs may be better than single-drug efficacy, but It is foreseeable that the problems of acquired resistance of patients and toxic side effects of drugs have not been completely resolved, so there is still a need in this field to continuously develop new drugs with BTK inhibitory activity, especially those that can target and inhibit the C481S mutant Inhibitors, thus providing new precise treatment options

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