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Pyrazolopyrimidines used as kinase inhibitors and application thereof

A compound and alkyl technology, applied in the field of pyrazolopyrimidine compounds, can solve the problems of many adverse reactions and easy drug resistance

Active Publication Date: 2018-05-08
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

Regarding targeted drug therapy, FDA has approved sorafenib for first-line treatment of advanced liver cancer, and FDA has approved regorafenib for patients with liver cancer who are resistant or intolerant after sorafenib treatment, but it has been reported Liver cancer patients who take sorafenib and other drugs have more adverse reactions and are prone to drug resistance

Method used

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  • Pyrazolopyrimidines used as kinase inhibitors and application thereof
  • Pyrazolopyrimidines used as kinase inhibitors and application thereof
  • Pyrazolopyrimidines used as kinase inhibitors and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] The preparation of embodiment 1 compound I-1

[0059]

[0060] Under the protection of nitrogen, the compound shown in formula I-A1 (21.2g, 0.1mol), the compound shown in formula I-B1 (77.9g, 0.44mol), tetrakis triphenylphosphine palladium (4.6g, 0.004mol), Potassium carbonate (121g, 0.88mol), 800 milliliters of toluene, 600 milliliters of ethanol, add in the reactor and stir evenly, slowly heat up to 60~70 ℃ of reaction, through thin-layer chromatography (TLC) spot plate test reaction is complete, then drop to At 20°C, add 1000 ml of water and 1000 ml of dichloromethane, stir, separate layers, wash the toluene layer twice with water, dry over anhydrous sodium sulfate, filter to remove the desiccant, then pass through a silica gel column, and concentrate the eluent to dryness under reduced pressure. That is, 21.4 g of solid powder (69.4% yield) was used to obtain the product compound I-1 with a purity of 99.0% (HPLC).

[0061] LC / MS: [M+H]+309.

Embodiment 2

[0062] The preparation of embodiment 2 compound I-23

[0063]

[0064] Under nitrogen protection, the compound shown in formula I-A1 (21.2g, 0.1mol), the compound shown in formula I-B23 (95.5g, 0.44mol), tetrakis triphenylphosphine palladium (4.6g, 0.004mol), Potassium carbonate (121g, 0.88mol), 800 milliliters of toluene, 600 milliliters of ethanol, add in the reactor and stir evenly, slowly heat up to 60~70 ℃ of reaction, through thin-layer chromatography (TLC) spot plate test reaction is complete, then drop to At 20°C, add 1000 ml of water and 1000 ml of dichloromethane, stir, separate layers, wash the toluene layer twice with water, dry over anhydrous sodium sulfate, filter to remove the desiccant, then pass through a silica gel column, and concentrate the eluent to dryness under reduced pressure. That is, 25.1 g of solid powder (yield 72.0%) was used to obtain the product compound I-23 with a purity of 99.2% (high performance liquid phase).

[0065] LC / MS: [M+H]+349. ...

Embodiment 3

[0066] The preparation of embodiment 3 compound I-25

[0067]

[0068] Under the protection of nitrogen, the compound shown in formula I-A25 (24.2g, 0.1mol), the compound shown in formula I-B25 (96.8g, 0.44mol), tetrakistriphenylphosphine palladium (4.6g, 0.004mol), Potassium carbonate (121g, 0.88mol), 800 milliliters of toluene, 600 milliliters of ethanol, add in the reactor and stir evenly, slowly heat up to 60~70 ℃ of reaction, through thin-layer chromatography (TLC) spot plate test reaction is complete, then drop to At 20°C, add 1000 ml of water and 1000 ml of dichloromethane, stir, separate layers, wash the toluene layer twice with water, dry over anhydrous sodium sulfate, filter to remove the desiccant, then pass through a silica gel column, and concentrate the eluent to dryness under reduced pressure. That is, 28.6 grams of solid powder (yield 74.9%) obtained the product compound I-25 with a purity of 99.5% (high performance liquid phase).

[0069] LC / MS: [M+H]+382....

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Abstract

The invention discloses pyrazolopyrimidines used as kinase inhibitors and application of pyrazolopyrimidines used as the kinase inhibitors. The pyrazolopyrimidines are compounds as shown in the formula I, or pharmaceutically acceptable salts of the pyrazolopyrimidines. The compounds 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 pyrazolopyrimidine compounds used as kinase inhibitors and applications thereof. Background technique [0002] Liver cancer is a global problem. Primary liver cancer is divided into hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and mixed liver cancer, among which HCC is the most common, accounting for about 85% to 90%. Especially in China, because of the high incidence of hepatitis, liver cancer has long been ranked among the top ten cancer morbidity and death in my country. Taking 2015 as an example, the number of new cases of liver cancer in my country was 4.66 million, and the number of deaths was 4.22 million. Its incidence rate and mortality rate ranked fifth and second among malignant tumors, respectively. There are many factors that cause liver cancer, including hepatitis virus infection, chronic hepatitis, alcoholic liver disease, aflatoxin pollution and so ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D519/00A61K31/519A61P35/00A61P1/16
CPCC07D487/04C07D519/00
Inventor 许勇范昭泽于静胡仁军王浩
Owner 武汉九州钰民医药科技有限公司
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