Aminoquinazolinone and aminoisoquinolinone derivatives and application thereof

Abstract

The invention provides aminoquinazolinone and aminoisoquinolinone derivatives. Through multiple experiments, it is validated that the synthesized compounds have excellent PI3Kalpha and PI3Kgamma inhibition effects, and most of the compounds have a significant inhibition effect on PI3Kalpha, and show a potent growth inhibition effect on tumor cell lines such as a PIK3CA-mutated human breast cancercell line (MCF7). Therefore, the aminoquinazolinone and aminoisoquinolinone derivatives can be applied to preparing antitumor and anti-inflammatory drugs, and can be applied to drugs for the treatmentof human or animal cell proliferation-related tumors as a PI3Kalpha inhibitor. The drugs are prepared from any one or more of the derivatives, and pharmaceutically acceptable salt and solvate of thederivatives, and a pharmaceutically acceptable carrier. The general formulas a and b of the compounds are shown in the description.

Description

technical field [0001] The invention relates to the field of medicines, in particular to an aminoquinazolinone and aminoisoquinolinone derivatives, a pharmaceutical composition containing them and their applications in the fields of anti-tumor and anti-inflammatory diseases. Background technique [0002] Although great progress has been made in early diagnosis and treatment of tumors in recent years, and anticancer drugs have been able to control or delay the development of some tumors, such as leukemia, the treatment of solid tumors, which account for more than 90% of malignant tumors, is far from satisfactory. The PI3K / Akt / mTOR signaling pathway regulates various cellular processes such as cell division and growth. Studies have found that this signaling pathway is often overactivated in tumor cells, and the key kinase PI3K, that is, phosphatidylinositol 3-kinase, is often found in tumor cells. In the state of overexpression, PI3K has many subtypes, including the inhibition...

AI Technical Summary

Problems solved by technology

[0004] Although many PI3K inhibitors have been developed by people, there are still some defects in the two drugs that have been marketed. For example, Idelalisib can cause elevated transaminases in CLL patients and has certain toxic side effects on the liver; while Copanlisib has multiple subtypes of PI3K. The activity of Copanlisib is very high, but the selectivity is poor, and the physical and chemical properties of Copanlisib are not good, so its pharmacokinetic properties are not good, the volume of distribution is large, reaching 32.6L / kg, and it is easy to store in the patient's body, thus causing corresponding toxicity. Response, so the clinical drug is given by injection on the 1st, 8th and 15th days of the 28-day treatment cycle

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