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Pyrazolo[3,4-d]pyrimidine-3-ketone derivative as well as drug composition and application thereof

A technology of derivatives and compounds, applied in pyrazolo[3,4-d]pyrimidin-3-one derivatives, its pharmaceutical composition and application field, which can solve the problems of drug marketing and other issues

Pending Publication Date: 2019-03-05
SHANGHAI DE NOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are currently no drugs targeting Wee1 on the market

Method used

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  • Pyrazolo[3,4-d]pyrimidine-3-ketone derivative as well as drug composition and application thereof
  • Pyrazolo[3,4-d]pyrimidine-3-ketone derivative as well as drug composition and application thereof
  • Pyrazolo[3,4-d]pyrimidine-3-ketone derivative as well as drug composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0219] Embodiment 1: the synthesis of compound 1.3

[0220]

[0221] Step 1: The N,N- Dimethylformamide (DMF) (15 mL) mixture was stirred at 70°C for 3 hours. The resulting mixture was cooled to room temperature, then poured into ice water (50 mL) and stirred, the mixture was extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with water and saturated brine successively, the organic phase was dried over anhydrous sodium sulfate, After filtration and concentration, the residue was purified by silica gel column chromatography (dichloromethane / methanol=20 / 1) to obtain compound 1.2 (700 mg, yield: 32%) as a colorless oily liquid.

[0222] Step 2: Compound 1.2 (700 mg, 3.0 mmol) was added to a mixture of palladium carbon (100 mg, 10%) in methanol (20 mL), and the reaction system was replaced with hydrogen for 3 times, and the resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered ...

Embodiment 2

[0223] Embodiment 2: the synthesis of compound 1.7

[0224]

[0225] Step 1: Under ice-bath conditions, sodium hydrogen (3.95g, 60%, 98.8mmol) was added in portions to a solution of 5-nitroindole (4g, 24.7mmol) in DMF (100mL), and the resulting mixture rose slowly to room temperature and stirred for 2 hours. Then the reaction solution was cooled in an ice bath, and 2-bromoethanol (12.3 g, 98.4 mmol) was added. The mixture was continued to stir at room temperature for 24 hours. Then the reaction system was diluted with ethyl acetate, washed with water and saturated brine successively, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol=20 / 1) Compound 1.4 (2.1 g, yield: 41%) was obtained as a colorless oil.

[0226] Step 2: To a solution of compound 1.4 (1 g, 4.85 mmol) in dichloromethane (20 mL) was added portionwise Dess-Martin reagent (6.2 g, 14.7...

Embodiment 3

[0229] Embodiment 3: the synthesis of compound 1.8~1.9

[0230] Using the synthetic method of compound 1.7, the azetidine in step 3 was replaced by pyrrolidine to obtain 1-(2-(pyrrolidin-1-yl) ethyl)-1H-indole-5-amine (compound 1.8 ), m / z:[M+H] + 230.0.

[0231] Using the synthetic method of compound 1.7, the azetidine in step 3 was replaced by piperidine to obtain 1-(2-(piperidin-1-yl) ethyl)-1H-indole-5-amine (compound 1.9 ), m / z:[M+H] + 244.0.

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Abstract

The invention relates to a pyrazolo[3,4-d]pyrimidine-3-ketone derivative as shown in formula (I) or (I') and / or a pharmaceutically-acceptable salt as well as a composition comprising a compound as shown in formula (I) or (I') and / or pharmaceutically-acceptable salt, a preparation method and a use thereof as a Wee1 inhibitor and a use as a sensitizer in a cancer chemical therapy or a cancer radioactive therapy. The pyrazolo[3.4-d]pyrimidine-3-ketone derivative of the invention can effectively inhibit Wee-1 as well as relevant signal channels and has good effect for treating and / or alleviating the cancer. (Shown in the description).

Description

technical field [0001] The invention relates to a pyrazolo[3,4-d]pyrimidin-3-one derivative and a pharmaceutically acceptable salt thereof capable of inhibiting Wee1 and its signaling pathway, including the derivative and its pharmaceutically acceptable The pharmaceutical composition of the salt, and the application of the derivative and the pharmaceutically acceptable salt thereof in the treatment of diseases mediated by Wee1 and the preparation of medicines for treating diseases mediated by Wee1. Background technique [0002] Wee1 (Wee1G2 checkpoint kinase; gene number: 7465) is a member of the serine / threonine protein kinase family, which can directly phosphorylate cyclin-dependent kinase 1 (CDK1), and the phosphorylation site is tyrosine of CDK1 Acid 15 residue, which is an inhibitory phosphorylation site, negatively regulates CDK1 activity. Activation of the G2 checkpoint is primarily through inhibition of mitosis and promotion of the cyclin B-CDK1 complex. Normal cel...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D519/00A61K31/519A61K31/5383A61P35/00
CPCA61P35/00C07D487/04C07D519/00A61K31/519A61K31/5383C07D471/04C07D498/04C07D513/04
Inventor 高大新赵志明陈寿军武志恒
Owner SHANGHAI DE NOVO PHARMA
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