Pyrimidine derivatives as her2 tyrosine kinase inhibitors and applications thereof

A technology of tyrosine kinase, CH2, applied in the field of pyrimidine derivatives

Active Publication Date: 2020-04-21
武汉九州钰民医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The technical problem to be solved by the present invention is to overcome the defects of existing HER2 targeting drugs, and provide a pyrimidine derivative as a HER2 tyrosine kinase inhibitor and its application. The compound has good activity and selectivity to HER2. Stronger, more permeable, and able to penetrate the blood-brain barrier to achieve effective therapeutic concentrations

Method used

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  • Pyrimidine derivatives as her2 tyrosine kinase inhibitors and applications thereof
  • Pyrimidine derivatives as her2 tyrosine kinase inhibitors and applications thereof
  • Pyrimidine derivatives as her2 tyrosine kinase inhibitors and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Embodiment 1: the preparation of the compound shown in formula I-1

[0088]

[0089] Under the condition of -5°C to 0°C, 19.1 g (0.102 moles) of the compound shown in formula a-1 was added to the reaction flask, and 35.8 g (0.1 moles) of the compound shown in formula g-1 and 160 A solution consisting of one milliliter of N-methylpyrrolidone was added within 20 minutes and reacted at room temperature for 12 hours. After TLC detected that the reaction was complete, an appropriate amount of water was added, and the resulting mixed solution was adjusted to pH 10.0 to 11.0 with 2 mol / liter aqueous sodium hydroxide solution, and a large amount of solid was precipitated, filtered by suction, washed, and dried to obtain a crude off-white solid. Recrystallized from methanol / acetone (methanol / acetone=3:1 (v / v)), purified to obtain a white solid product, 22.2 g of the compound shown in formula I-1, with a yield of 45.6% and a purity of 99.2%.

[0090] LCMS:511(M+1) + .

Embodiment 2

[0091] Embodiment 2: the preparation of the compound shown in formula I-2

[0092]

[0093] Under the condition of -5°C to 0°C, add 9.45g (0.105 moles) of the compound shown in formula a-2 into the reaction flask, and dropwise add 35.8g (0.1 moles) of the compound shown in formula g-1 and 160 A solution consisting of one milliliter of N-methylpyrrolidone was added within 30 minutes and reacted at room temperature for 10 hours. After TLC detected that the reaction was complete, an appropriate amount of water was added, and the resulting mixed solution was adjusted to pH 10.0 to 11.0 with 2 mol / liter aqueous sodium hydroxide solution, and a large amount of solid was precipitated, filtered by suction, washed, and dried to obtain a crude off-white solid. Recrystallize with isopropanol / acetone (isopropanol / acetone=2:1 (v / v)), and purify to obtain a white solid powder, which is 25.6 g of the compound shown in formula I-2, with a yield of 62.1% and a purity of 99.4 %.

[0094] L...

Embodiment 3

[0095] Embodiment 3: the preparation of the compound shown in formula I-3

[0096] The preparation method of the compound shown in formula I-3 is the same as that of Example 2, the only difference being that the reaction raw materials are different. Yield 55.7%, purity 98.6%.

[0097] LCMS: 413 (M+1) + .

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PUM

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Abstract

The invention discloses a novel pyrimidine derivative. The pyrimidine derivative is a compound shown by the formula I and a pharmaceutically acceptable salt thereof. The compound can be used for preparing drugs for treating and / or preventing tumors.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and relates to pyrimidine derivatives as HER2 tyrosine kinase inhibitors and applications thereof. Background technique [0002] Human epidermal growth factor receptor-2 (HER2), also known as ErbB2, is a member of the epidermal growth factor (EGF) receptor family, and other family members include HER1 (EGFR), HER3, and HER4. HER2 is distributed on the surface of the cell membrane and is in the upstream of the cell signal transduction pathway. After dimerization with other family receptors, HER2 activates the downstream cell signal transduction pathway, such as the MAPK signaling pathway and the PI3K-AKT-mTOR signaling pathway, thereby triggering cell differentiation , survival, migration, invasion, adhesion and other biological effects. The overexpression of HER2 leads to the upregulation of cell signaling pathways, thereby promoting cell proliferation, inhibiting cell apoptosis, increasing ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/048C07D487/04C07D401/12A61K31/517A61K31/519A61P35/00A61P35/02A61K31/5377
CPCA61P35/00A61P35/02C07D401/12C07D487/04C07D491/048
Inventor 范昭泽于静罗亚琼余艳平柳少群黄璐许勇
Owner 武汉九州钰民医药科技有限公司
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