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

A technology of pyrazolone and pyrimidine, applied in the field of pyrazolo 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 and Embodiment 39

[0560]

[0561] first step:

[0562] Compound (I-1-a)(3aR, 6aS)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylic acid tert-butyl ester (2000mg, 9.4211mmol) was dissolved in DMSO (30mL), then potassium carbonate (3eq, 28.263mmol) and 1-fluoro-4-nitro-benzene (I-1-b) (1eq, 9.4211mmol) were added, and The reaction was heated to 120°C and stirred for 2 hours. The reaction was poured into 5ml of water and a yellow solid formed. The solid was filtered, washed with water (2×5ml), collected and dried in vacuo to obtain compound (I-1-c) tert-butyl (3aR, 6aS)-2-(4-nitrophenyl)-1,3 , 3a,4,6,6a-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (3g, 8.998mmol), yield 95.51%, yellow solid. LC-MS: m / z: (M+H-tBu) + = 278.2.

[0563] Step two:

[0564] Compound (I-1-c)(3aR, 6aS)-2-(4-nitrophenyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole - Tert-butyl 5-carboxylate (0.4g, 1mmol) was dissolved in ethanol (70mL) and THF (10mL) solution, then Pd / C (0.1eq, 0.1mmol) a...

Embodiment 2

[0570]

[0571] Compound (I-1) 6-[4-[(3aR, 6aS)-2,3,3a, 4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl ]anilino]-2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]pyrazolo[3,4-d]pyrimidin-3-one (110mg, 0.2146mmol) was dissolved in methanol solution (6mL), then added formaldehyde (10eq, 2.146mmol, 37%) and glacial acetic acid (0.2mL), and the reaction was stirred at room temperature for 5 minutes. Then, sodium acetate borohydride (2eq, 0.4292mmol) was added thereto, and the reaction solution was stirred and reacted at room temperature for 12 hours. NaHCO for reaction 3 The aqueous solution was quenched and extracted with ethyl acetate (2×20 mL), the organic layer was washed with brine (1×20 mL), and washed with Na 2 SO 4 Dry, filter and concentrate to give crude product. The crude product was further purified by Pre-HPLC with CH 3 CN / water (0.1% HCOOH) was eluted from 20% to 50% to give compound (I-2) 6-[4-[(3aR,6aS)-2-methyl-1,3,3a,4,6 ,6a-Hexahydrohexahydropyrrolo[3,4...

Embodiment 15

[0573]

[0574] first step:

[0575] Dissolve 1 g of tert-butyl(3aR,6aS)-5-(4-nitrophenyl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-carboxylate (I-1-c) in 10 ml of trifluoroacetic acid was added to 40 ml of dichloromethane, reacted at room temperature for 1 h, and the reaction solution was spin-dried to obtain 0.7 g of yellow solid (I-15-a), with a yield of 91%. LC-MS: m / z: (M+H) + = 234.1.

[0576] Step two:

[0577] Dissolve (3aR,6aS)-2-(4-nitrophenyl)octahydropyrrole[3,4-c]pyrrole (I-15-a) (200mg, 0.26mmol) in 15ml of acetonitrile and add potassium carbonate (170 mg, 1.72 mmol) and bromoacetonitrile (I-15-b) (124 mg, 1 mmol). After reacting at room temperature for 18 hours, it was concentrated and then extracted with 30ml of dichloromethane and 10ml of water. Thin layer chromatography (DCM / CH 3 OH=10 / 1) was purified to obtain 40 mg of a yellow solid (I-15-c), with a yield of 56%. LC-MS: m / z: (M+H) + = 273.1.

[0578] third step:

[0579] 2-((3AR, 6AS)-5-(4-nitrophen...

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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 A 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): C07D519/00C07D487/04A61P35/00A61P35/02A61K31/519
CPCC07D519/00C07D487/04A61P35/00A61P35/02Y02P20/55
Inventor 王倩张霖夏广新楼江松葛辉霍国永舒思杰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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