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Tri-heterocyclic compound and application thereof

A compound and hydrate technology, applied in the field of biomedicine, can solve the problem of lack of small molecule binding cavities on the surface of KRAS protein, and achieve the effect of excellent cell activity

Pending Publication Date: 2021-05-04
WUHAN YUXIANG PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the lack of good small molecule binding cavities on the surface of KRAS protein, the research and development of small molecule inhibitors based on KRAS has always been one of the difficulties in the field of medicine. Inhibitors have great clinical value and broad market prospects

Method used

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  • Tri-heterocyclic compound and application thereof
  • Tri-heterocyclic compound and application thereof
  • Tri-heterocyclic compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0099] Embodiment 1: the preparation of the compound shown in formula I-1

[0100]

[0101] synthetic route:

[0102]

[0103] Preparation:

[0104] Step 1: Synthesis of Compound I-1B

[0105] Dissolve the raw material 1-1A (31g, 200mmol) in DCM (300mL), then add a few drops of DMF, cool to 0 to 5 degrees, slowly add oxalyl chloride (30.5g, 240mmol) dropwise at this temperature, then stir at room temperature After 3 hours, TLC showed that the reaction was completed, and spin-dried to obtain crude compound 1-1B (36.2 g, light yellow liquid), yield: 100%, which was directly used in the next step without further purification.

[0106] Step 2: Synthesis of compound I-1C

[0107]Sodium hydroxide (18.5g, 463mmol) was dissolved in water (400ml), then cooled to 0°C, and S-methylisothiourea hydrogen sulfate (51.5g, 185mmol) was slowly added in batches, and mixed after addition The solution was stirred at 0°C for 30 minutes, then the compound 1-1B (18g, 100mmol) obtained in th...

Embodiment 2

[0138] Embodiment 2 Pharmacodynamics detection experiment

[0139] Determination of the activity of the compound of the present invention on highly expressed KRAS G12C human non-small cell lung cancer cell NCI-H358 and human pancreatic cancer cell Mia Paca-2

[0140] The following methods were used to determine the effect of compounds of the present invention on tumor cell proliferation.

[0141] For the KRAS G12C subtype, the highly expressed KRAS G12C human non-small cell lung cancer cell NCI-H358 and the human pancreatic cancer cell Mia Paca-2 were used to test the anti-cancer activity of the compound. The NCI-H358 cells were cultured in 10% fetal bovine serum , 100 U penicillin and 100 μg / mL streptomycin in DMEM medium. Culture at 37 degrees 5% CO 2 Inside the incubator. Cancer cell activity through the use of Cell The kit (Luminescent Cell Viability Assay kit, refer to the manufacturer's instructions for usage) was used to measure the content of ATP to evaluate cell ...

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Abstract

The invention relates to a compound as well as a preparation method and an application thereof. The compound is a compound shown in a formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof, and R1-R6 and X, Y, Z, L and K groups are defined in the specification. The compound provided by the invention can be used for preparing medicines for treating and / or preventing cancers.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and relates to a triheterocyclic compound and its application. Background technique [0002] In the field of cancer research, KRAS is one of the most well-known oncogenes. Oncogene RAS frequently mutates in human tumors, accounting for about one-third of all human malignant tumor mutations. The RAS family includes HRAS, NRAS and KRAS. As the main subtype of the RAS protein family, KRAS mutations account for 86% of all RAS protein mutations, and are more common in pancreatic cancer, colorectal cancer and lung cancer. In non-small cell lung cancer (NSCLC), 15% to 30% of patients have KRAS gene mutation, of which lung adenocarcinoma accounts for 30% to 50%, which is higher than EGFR, ALK, etc.; the probability of abnormal KRAS gene mutation in colorectal cancer patients is 30% %-35%; In pancreatic cancer, more than 90% of patients have KRAS mutations. The KRAS signaling pathway is an importan...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/22A61K31/553A61P35/00
CPCC07D498/22A61P35/00
Inventor 方华祥张晓林刘呈祥陶进峰
Owner WUHAN YUXIANG PHARM TECH CO LTD
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