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US-12617792-B2 - Purine derivative, intermediate and application thereof in preparing anticancer medicine

US12617792B2US 12617792 B2US12617792 B2US 12617792B2US-12617792-B2

Abstract

The present invention disclosures a novel purine derivatives represented by formula (I) or a pharmaceutically acceptable salt thereof, intermediate and application thereof inpreparation of a medicament for treating or preventing a cancer. This compound is a novel PI3K inhibitor with an excellent inhibitory activity, and may be useful for treating a variety of malignant tumors.

Inventors

  • Fei ZHANG
  • Zixia Feng

Assignees

  • SUZHOU RAYMON PHARMACEUTICALS COMPANY, LTD.

Dates

Publication Date
20260505
Application Date
20201021
Priority Date
20191024

Claims (13)

  1. 1 . The purine derivative represented by Formula (I-1), or a stereoisomer or a pharmaceutically acceptable salt thereof,
  2. 2 . A method for preparing a medicine comprising: preparing the purine derivative represented by Formula (I-1), or a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1 .
  3. 3 . A pharmaceutical composition, wherein the pharmaceutical composition comprises: the purine derivative represented by Formula (I-1), or a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1 ; and a pharmaceutical acceptable carrier.
  4. 4 . The pharmaceutical composition according to claim 3 , wherein the pharmaceutical composition is a pharmaceutical composition.
  5. 5 . An intermediate for preparing a purine derivative represented by Formula (I-1)), or a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the intermediate has a structure represented by Formula (II-1): wherein THP is tetrahydro-2H-pyran-2-yl.
  6. 6 . A method for preparing the intermediate according to claim 5 , wherein the intermediate is prepared by reacting with a compound represented by Formula (III)
  7. 7 . The method according to claim 6 , wherein, in the process of preparing the intermediate represented by Formula (II-1), the reaction is carried out under an alkaline condition at a temperature of 30-120° C., or under an inert atmosphere.
  8. 8 . The method according to claim 7 , wherein, in the process of preparing the intermediate represented by Formula (II-1), the reaction is carried out at a temperature of 40-110° C.
  9. 9 . The method according to claim 8 , wherein, in the process of preparing the intermediate represented by Formula (II-1), the reaction is carried out at a temperature of 80-90° C.
  10. 10 . The method according to claim 7 , wherein the alkaline condition is formed by adding an alkaline substance selected from the group consisting of potassium acetate, potassium carbonate, potassium phenoxide, potassium phosphate, potassium tert-butoxide, sodium carbonate, sodium bicarbonate, sodium tert-butoxide, sodium methoxide, sodium ethoxide, triethylamine, tri-n-butylamine, diisopropylethylamine, and combinations thereof.
  11. 11 . The method according to claim 6 , wherein, in the process of preparing the intermediate represented by Formula (II-1), the reaction is carried out in the presence of 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl, and/or tris(dibenzylideneacetone) dipalladium.
  12. 12 . The method according to claim 11 , wherein, in the process of preparing the intermediate represented by Formula (II-1), the reaction is carried out in the co-presence of 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl and tris(dibenzylideneacetone) dipalladium.
  13. 13 . The method according to claim 7 , wherein, in the process of preparing the intermediate represented by Formula (II-1), the reaction is carried out at a temperature of 50-105° C.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is the U.S. National Phase under 35. U.S.C. § 371 of International Application PCT/CN2020/122436, filed Oct. 21, 2020, which claims priority to Chinese Patent Application No. 201911014796.5, filed Oct. 24, 2019. The disclosures of the above-described applications are hereby incorporated by reference in their entirety. TECHNICAL FIELD OF THE INVENTION The present disclosure belongs to the field of medicinal chemistry, and in particular relates to a class of novel purine derivatives and intermediates thereof, the novel purine derivatives have phosphatidylinositol-3-kinase (PI3K) inhibitory activity and can be used to prepare medicines for preventing and treating tumors. BACKGROUND OF THE INVENTION PI3K is an intracellular phosphatidylinositol kinase. Lewis C. Cantley, professor of cancer biomedicine at Weill Cornell Medical College, discovered the phosphatidylinositol-3-kinase (PI3K) signaling pathway and clarified its key role in tumor development. The PI3K signaling pathway is usually activated by receptors on the cell surface, such as receptors tyrosine kinases, GPCRs, and some oncogenes, such as RAS and the like. The activated p110 subunit catalyzes the conversion of PIP2 to PIP3 and activates Akt activity. Akt will further transmit signals to downstream molecules, such as mTORC1, GSK3, BCL-2 and the like to regulate different cellular physiological processes. mTORC2 activates the Akt molecules through phosphorylation of Ser at position 473. In contrast, PTEN can dephosphorylate PIP3 into PIP2. The downstream signaling pathways of PI3K molecules are more complex, including some feedback loops. Each of the four catalytic isomers of class I PI3K preferentially regulates specific signal transduction and tumor cell survival, depending on the type of malignant tumor and its genetic or epigenetic changes. For example, p110α is essential for the growth of tumor cells driven by PIK3CA mutations or oncogene RAS and receptor tyrosine kinases; p110β mediates the occurrence of PTEN-deficient tumors; and p110δ is highly expressed in white blood cells, thus making it has become an ideal target for the treatment of hematological malignancies. In the late 1980s, PI3 kinase (PI3K) was discovered to be an enzyme that phosphorylates the 3-position of the inositol ring of phosphatidylinositol (D. Whitman et al. (1988) Nature, 332664). PI3K was originally thought to be a single enzyme, but it has now been clarified that there are multiple subtypes in PI3K, and PI3Kα is one of them. PI3Kα has high-frequency activating mutations in breast cancer, which is closely related to the development and drug resistance of breast cancer, and has become an important target for the treatment of breast cancer. On Sep. 14, 2017, the U.S. FDA accelerated the approval of Bayer Healthcare Pharmaceuticals' Aliqopa® (Copanlisib), Aliqopa® is the trade name. It is used to treat patients suffering from recurrent follicular lymphoma. Copanlisib is a phosphatidylinositol-3-kinase (PI3K) inhibitor, which has good inhibitory activity against the PI3K-α and PI3K-δ subtypes expressed in malignant B cells. There are limited types of PI3Kα inhibitors and the efficacy of PI3Kα inhibitors in clinical trials varies greatly among individuals. It is desired to discover new PI3Kα inhibitors and biomarkers for efficacy prediction. In the first half of 2019, the U.S. FDA announced that it has approved Piqray (alpelisib) developed by Novartis (NVS.US) to be used in combination with endocrine therapy fulvestrant to treat patients with HR+/HER2− advanced or metastatic breast cancer carrying PIK3CA gene mutations. These patients continue to get worse after receiving endocrine therapy. This is the first PI3K inhibitor approved by the FDA for the treatment of breast cancer. The tumors of patients with metastatic breast cancer have spread to other parts of the body, and the most common metastatic organs include bones, lungs, liver, and brain. In HR+/HER2− advanced breast cancer, changes in the PI3K pathway are the most common cause of tumor deterioration, disease progression, and drug resistance in treatment. About 40% of HR+/HER2− advanced breast cancer patients carry PIK3CA gene mutations. Pigmy is an oral small molecule α-specific PI3K inhibitor developed by Novartis, namely PI3Kα inhibitor. In breast cancer cell lines carrying PIK3CA gene mutations, it has shown the potential to inhibit the PI3K pathway and has the effect of inhibiting cell proliferation. The present disclosure also uses PI3Kα as the starting point for target research of new drugs, especially in China, there is no PI3Kα inhibitor invented in China for the treatment of malignant tumors. The structure of the innovative research of the present disclosure will fill this gap in China. Such as the final listing will have significant social and economic benefits. SUMMARY OF THE INVENTION The technical problem to be solved by the present disclosure is t