Pyrazolone-fused pyrimidine compound as well as preparation method and application thereof

A pyrazolone and pyrimidine technology, applied in the field of pyrazolone pyrimidine compounds, can solve problems such as single structure

Pending Publication Date: 2020-12-29
SHANGAI PHARMA GRP CO LTD
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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 that the existing compounds with inhibitory activity on WEE1 kinase have a relatively single structure. Therefore, the present invention provides a pyrazolopyrimidine compound, its preparation method and application. better inhibitory activity

Method used

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  • Pyrazolone-fused pyrimidine compound as well as preparation method and application thereof
  • Pyrazolone-fused pyrimidine compound as well as preparation method and application thereof
  • Pyrazolone-fused pyrimidine compound as well as preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0399]

[0400] first step:

[0401] 1,2-Chloro-6,7-dihydro-5H-cyclopenta[b]pyridine (1 g, 6.51 mmol) (I-1-a) was added to 30 mL of toluene, followed by phosphorus oxybromide (4g, 13.95mmol), heated and stirred at 130°C for three days. After cooling and concentrating the reaction solution, slowly add saturated sodium bicarbonate solution until the pH value is approximately equal to 10, then extract three times with dichloromethane (3*30ml), dry over anhydrous sodium sulfate and concentrate to obtain a crude product, which is purified by column (acetic acid Ethyl ester: petroleum ether=0-15%), 2-bromo-6,7-dihydro-5H-cyclopentadiene [b] pyridine (I-1-b) 0.84g, brown solid, yield : 65%. LC-MS: m / z: (M+H) + =198.

[0402] Step two:

[0403] 2-Bromo-6,7-dihydro-5H-cyclopentadieno[b]pyridine (I-1-b) (0.8g, 4mmol) was added to 25ml of dichloromethane, and then 77% m-chloro Peroxybenzoic acid (1.34g, 6mmol) was also added to 25ml of dichloromethane, and this solution was adde...

Embodiment 2

[0413]

[0414] 2-allyl 1-(7-hydroxy-6,7-dihydro-5H-cyclopentadien[b]pyridin-2-yl)-6-(methylthio)-1,2-di Hydrogen-3H-pyrazolo[3,4d]pyrimidin-3-one (40mg, 0.11mmol) (I-1-g) and 3-chlorophenylperoxycarboxylic acid (30.2mg, 0.135mmol) were dissolved in 15ml In toluene, the resulting solution was stirred at room temperature for 2 h. 4-(4-Ethylpiperazin-1-yl)aniline (30mg, 0.14mmol) and N,N-diisopropylethylamine (29.0mg, 0.22mmol) were added to the above solution, and the reaction solution was heated at 90 °C under nitrogen protection and stirred for 16 hours. The reaction solution was concentrated, and the obtained solid was separated by thin-layer chromatography (dichloromethane:methanol=10:1) to obtain a crude product, which was then separated by preparative HPLC to obtain 2-allyl-6-((4-(4- Ethylpiperazin-1-yl)phenyl)amino)-1-(7-hydroxy-6,7-dihydro-5H-cyclopentadien[b]pyridin-2-yl)--1,2 -Dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (I-2) 38.6 mg, white solid, yield 66.9%. 1H...

Embodiment 5

[0416]

[0417] first step:

[0418] Dissolve 67mg (0.25mmol) of N,N-dimethyl-1-(1-(4-nitrophenyl)piperidin-4-yl)methanamine (I-5-a) in 5ml of methanol under hydrogen , reacted for half an hour under palladium-carbon catalyzed conditions. The reaction solution was filtered and concentrated to obtain 56 mg of 4-(4-(dimethylamino)methyl)piperidin-1-yl)aniline (I-5-b) as a yellow solid with a yield of 97%. LC-MS: m / z: (M+H) + =234.

[0419] Step two:

[0420] 2-allyl-1-(7-hydroxyl 6,7-5H-cyclopenta[b]pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyr Azo[3,4-d]pyridin-3-one (I-1-g) was dissolved in 10ml of toluene, 30mg (0.17mol, 77%) of 3-chloroperoxybenzoic acid was added, and the toluene was dissolved after stirring at room temperature for 15 minutes. Spin dry, then add 40mg (0.11mmol) 4-(4-(dimethylamino)methyl)piperidin-1-yl)aniline (I-5-b) dissolved in 5ml dimethyl sulfoxide, add 0.4ml trifluoroacetic acid, heated to 60°C and stirred for about 18 hours. The reaction ...

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Abstract

The invention discloses a pyrazolone-fused pyrimidine compound as well as a preparation method and application thereof. The invention provides a pyrazolone-fused pyrimidine compound as shown in a formula I which is described in the specification. The pyrazolone-fused pyrimidine compound has better inhibitory activity on WEE1 kinase.

Description

technical field [0001] The invention relates to a pyrazolopyrimidine compound, its preparation method and application. Background technique [0002] The cell cycle is closely related to the DNA damage repair process. The cell cycle refers to the whole process of cell division, which is divided into two stages: interphase and mitotic phase (M). The cell cycle checkpoint (checkpoint) is a key point in the regulation of the cell cycle. Its main function is to ensure that each event in the cycle can be completed in a timely and orderly manner, and to adjust the cell state to adapt to the external environment. [0003] The main checkpoints of cells are: 1) G1 / S checkpoint: called R (restriction) point in mammals, which controls the cell to enter the DNA synthesis period from the static G1 phase; 2) S phase checkpoint: whether DNA replication is completed ; 3) G2 / M checkpoint: it is a control point that regulates cell division; 4) Mid-late checkpoint: also called spindle assembl...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D519/00A61K31/519A61K45/06A61P35/00A61P35/02
CPCC07D487/04C07D519/00A61P35/00A61P35/02A61K45/06A61K31/519A61K2300/00C07D205/08
Inventor 王倩霍国永夏广新楼江松舒思杰葛辉张霖石辰张弛张智慧毛煜张冰宾余建鑫柯樱刘彦君
Owner SHANGAI PHARMA GRP CO LTD
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