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CN-122010857-A - Selective mTOR inhibitor and preparation method and application thereof

CN122010857ACN 122010857 ACN122010857 ACN 122010857ACN-122010857-A

Abstract

The invention discloses a selective mTOR inhibitor and a preparation method and application thereof, and relates to the technical field of medicines, wherein the compound is shown as a formula (I) or (II) or (III) or (IV), or prodrug, deuterated matters and pharmaceutically acceptable salt thereof, can specifically identify an ATP pocket of mTOR, greatly reduce cross-bonding of PI3K family, remarkably improve kinase selectivity, and has strong proliferation inhibition activity on non-small cell lung cancer cells, particularly has outstanding sensitivity on specific mutant tumor cells, is rapidly absorbed after oral administration, has sufficient in vivo exposure and excellent bioavailability, expands the treatment application range of the mTOR inhibitor, provides a tumor targeting treatment scheme with higher safety and more convenient medicine application, and has important clinical conversion value and scientific research reference significance.

Inventors

  • ZENG MING
  • XIE YING
  • WANG SHAN
  • Hu Yingxuan
  • LIN HAO
  • DAI JUN
  • ZHAO LAN
  • SHANG FANFAN
  • JIANG DENGZHAO

Assignees

  • 九江学院

Dates

Publication Date
20260512
Application Date
20251217

Claims (10)

  1. 1. A compound shown as a formula (I) or (II) or (III) or (IV), or a prodrug, a deuteride and a pharmaceutically acceptable salt thereof, which is characterized in that, , In the formula I, R is selected from-H, , , , , , , , , , , ; In formula II, R 1 is selected from , , R 2 is selected from , , , , , , , , ,-H; In formula III, ar is selected from , , , , , ; In formula IV, M is selected from , , , , Wherein X, Y, Z are each independently selected from N, O, S.
  2. 2. The compound of formula (I) or (II) or (III) or (IV), or a prodrug, deuterate, or a pharmaceutically acceptable salt thereof according to claim 1 wherein: when R 1 is selected from When R 2 is selected from , , , , , , ; When R 1 is selected from When R 2 is selected from ; When R 1 is selected from When R 2 is selected from , ,-H。
  3. 3. A pharmaceutical composition comprising a compound of formula (I) or (II) or (III) or (IV) as defined in any one of claims 1 to 2, or a prodrug, deuterate, pharmaceutically acceptable salt thereof, and pharmaceutically acceptable adjuvant.
  4. 4. A selective mTOR inhibitor comprising a compound of formula (I) or (II) or (III) or (IV) according to any one of claims 1 to 2, or a prodrug, deuterate, pharmaceutically acceptable salt thereof.
  5. 5. A method of preparing a selective mTOR inhibitor, wherein the method of preparing is for preparing the selective mTOR inhibitor of claim 4, the method of preparing comprising: 2,4, 6-trichloro-1, 3, 5-triazine is taken as a starting material and reacts with a nitrogen-containing heterocyclic compound to obtain an intermediate I; under the action of a catalyst and an alkali reagent, carrying out a Suzuki coupling reaction on the intermediate I and 4-aminophenylboronic acid pinacol ester to generate an intermediate II; Reacting the intermediate II with N, N' -thiocarbonyldiimidazole to obtain an intermediate III; reacting the intermediate III with an amine compound to obtain the selective mTOR inhibitor.
  6. 6. The method for producing a selective mTOR inhibitor according to claim 5, characterized in that the method further comprises: 2,4, 6-trichloro-1, 3, 5-triazine is taken as a starting material and reacts with a nitrogen-containing heterocyclic compound to obtain a triazine ring monosubstituted intermediate; The triazine ring monosubstituted intermediate is substituted by secondary heterocycle to obtain an intermediate I.
  7. 7. The method of claim 6, wherein the catalyst is tetrakis- (triphenylphosphine) palladium and the base agent is sodium carbonate.
  8. 8. Use of a compound of formula (I) or (II) or (III) or (IV) as defined in any one of claims 1 to 2, or a prodrug, deuterate or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease associated with excessive mTOR activation.
  9. 9. The use according to claim 8, wherein the disease associated with excessive mTOR activation comprises non-small cell lung cancer, breast cancer or renal cell carcinoma.
  10. 10. The use according to claim 8, wherein the pharmaceutical dosage form is an oral formulation selected from the group consisting of tablets, capsules, granules or suspensions.

Description

Selective mTOR inhibitor and preparation method and application thereof Technical Field The invention relates to the technical field of medicines, in particular to a selective mTOR inhibitor and a preparation method and application thereof. Background Rapamycin target proteins (mTOR) are members of the phosphatidylinositol 3-kinase related kinase (PIKKs) family, which are highly conserved eukaryotic serine/threonine protein kinases that play a central role in the regulation of cell growth, proliferation, metabolism, migration, autophagy, and apoptosis. mTOR is located downstream of the Receptor Tyrosine Kinase (RTKs) and phosphatidylinositol 3-kinase (PI 3K) signaling pathways, and when RTKs bind to ligands such as insulin, insulin-like growth factor-1 (IGF-1), PI3K is activated and catalyzes the conversion of phosphatidylinositol (4, 5) -diphosphate to phosphatidylinositol (3, 4, 5) -triphosphate, thereby activating protein kinase B (Akt) and phosphatidylinositol-dependent kinase 1 (PDK 1), and the activated Akt ultimately activates mTOR by phosphorylating nodular sclerosis complex 1/2 (TSC 1/2), promoting cell growth and survival. Abnormal activation of the PI3K/Akt/mTOR signaling pathway is closely related to tumorigenesis, and mutation or excessive activation of PI3K can lead to continuous activation of downstream Akt and mTOR, which promotes proliferation of tumor cells. At present, PI3K, mTOR double-target inhibitors in clinical application and research have double inhibition activity due to high homology of ATP pocket of PI3K and mTOR, but are easy to cause glucagon elevation after long-term use, thus causing side effects such as hyperglycemia, immunosuppression, inflammation signal blocking and the like. In addition, the existing mTOR inhibitor is mainly used for treating breast cancer, has limited curative effects on other tumor types, and generally has the problem of low oral bioavailability, so that the clinical application range and curative effects of the mTOR inhibitor are limited. Therefore, development of mTOR inhibitors with novel structure, high selectivity for mTOR, efficacy against tumors such as non-small cell lung cancer, and excellent oral bioavailability has become a key requirement for current development of tumor therapeutic drugs. Disclosure of Invention Aiming at the defects of the prior art, the invention aims to provide a selective mTOR inhibitor, a preparation method and application thereof, and aims to solve at least one problem in the background art. In a first aspect, the present invention provides a compound of formula (I) or (II) or (III) or (IV), or a prodrug, deuteride, or a pharmaceutically acceptable salt thereof, characterized in that, , In the formula I, R is selected from-H,,,,,,,,,,,; In formula II, R 1 is selected from,,R 2 is selected from,,,,,,,,,-H; In formula III, ar is selected from,,,,,; In formula IV, M is selected from,,,,Wherein X, Y, Z are each independently selected from N, O, S. According to one aspect of the above solution, in formula II: when R 1 is selected from When R 2 is selected from,,,,,,; When R 1 is selected fromWhen R 2 is selected from; When R 1 is selected fromWhen R 2 is selected from,,-H。 In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or (II) or (III) or (IV) as described above, or a prodrug, deuteride, pharmaceutically acceptable salt thereof, and pharmaceutically acceptable adjuvant. In a third aspect the present invention provides a selective mTOR inhibitor comprising a compound of formula (I) or (II) or (III) or (IV) as described above, or a prodrug, deuterate, pharmaceutically acceptable salt thereof. A fourth aspect of the present invention is to provide a method for producing a selective mTOR inhibitor as described above, comprising: 2,4, 6-trichloro-1, 3, 5-triazine is taken as a starting material and reacts with a nitrogen-containing heterocyclic compound to obtain an intermediate I; under the action of a catalyst and an alkali reagent, carrying out a Suzuki coupling reaction on the intermediate I and 4-aminophenylboronic acid pinacol ester to generate an intermediate II; Reacting the intermediate II with N, N' -thiocarbonyldiimidazole to obtain an intermediate III; reacting the intermediate III with an amine compound to obtain the selective mTOR inhibitor. Further, the method further comprises: 2,4, 6-trichloro-1, 3, 5-triazine is taken as a starting material and reacts with a nitrogen-containing heterocyclic compound to obtain a triazine ring monosubstituted intermediate; The triazine ring monosubstituted intermediate is substituted by secondary heterocycle to obtain an intermediate I. Further, the catalyst is tetra- (triphenylphosphine) palladium, and the alkali agent is sodium carbonate. In a fifth aspect, the present invention provides the use of a compound of formula (I) or (II) or (III) or (IV), or a prodrug, deuteride, or a pharmaceutically acceptable