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Pyrazolone pyrimidine compound as well as preparation method and application thereof

A technology of pyrazolone and pyrimidine, which is applied in the field of pyrazolone and pyrimidine compounds, and can solve the problems of poor inhibitory activity and the like

Pending Publication Date: 2019-05-28
SHANGAI PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The technical problem to be solved by the present invention is that the existing compounds have poor inhibitory activity to WEE1 kinase. Therefore, the present invention provides a kind of pyrazolopyrimidine compound, its preparation method and application, and the inhibitory effect of the compound on WEE1 kinase better activity

Method used

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

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Experimental program
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Effect test

Embodiment 1

[0512]

[0513] first step:

[0514] 2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-methylthiopyrazolo[3,4-d]pyrimidine-3 -Ketone (270mg, 0.75mmol) (compound as shown in formula 1A) and 4-chloroperoxybenzoic acid (143mg, 0.83mmol) were dissolved in toluene (20ml), stirred at room temperature for 1 hour, and then added N,N- Diisopropylethylamine (291mg, 2.26mmol) and 6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (243mg, 0.98mmol) (as shown in formula 2 Compound), continue to stir at room temperature for 16 hours, the reaction solution was concentrated, purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100% to 50%) to obtain the compound represented by formula I-1-a tert-butyl 6-[ [2-Allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-3-oxo-pyrazolo[3,4-d]pyrimidine-6 -Yl]amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid ethyl ester (270 mg, 0.48 mmol). LC-MS:m / z:(M+H) + = 558.3, 1 H NMR(400MHz, CDCl 3 )δ8.88(s,1H),7.91(...

Embodiment 2

[0518]

[0519] The 2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-(1,2,3,4-tetrahydroisoquinoline-6 -Ylamino)pyrazolo[3,4-D]pyrimidin-3-one (40mg, 0.087mmol) (compound as shown in formula I-1) was dissolved in methanol (5ml), and then an aqueous formaldehyde solution ( 0.1ml, 40%) and sodium triacetylborohydride (46mg, 0.22mmol) were stirred at room temperature for 4 hours. The reaction solution was concentrated, dissolved with a mixture of dichloromethane and methanol (10 / 1, 20ml), washed twice with saturated sodium bicarbonate, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the formula I-2 The compound shown is 2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-[(2-methyl-3,4-dihydro- 1H-Isoquinolin-6-yl)amino]pyrazolo[3,4-d]pyrimidin-3-one (40 mg, 0.085 mmol). LC-MS:m / z:(M+H) + =472.3, 1 H NMR(400MHz, DMSO-d 6 )δ10.23(s,1H),8.89(s,1H),8.05(t,J=7.9Hz,1H),7.80(d,J=8.0Hz,1H),7.66(m,2H),7.40( d,J=7.6Hz,1H), 7.01(d,J=8....

Embodiment 5

[0521]

[0522] The 2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-(1,2,3,4-tetrahydroisoquinoline-6 -Amino)pyrazolo[3,4-D]pyrimidin-3-one (40mg, 0.087mmol) (compound as shown in formula I-1) was dissolved in dichloromethane (5ml), and then acetone ( 0.1ml, 40%) and sodium triacetylborohydride (46mg, 0.22mmol), heated to reflux and stirred for 48 hours. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane / methanol=100% to 10%, then dichloromethane / methanol / ammonia methanol solution=100 / 10 / 1.5) to obtain the compound represented by formula I-5 2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-[(2-isopropyl-3,4-dihydro-1H- Isoquinolin-6-yl)amino]pyrazolo[3,4-d]pyrimidin-3-one (30 mg, 0.06 mmol). LC-MS:m / z:(M+H) + =496.2, 1 H NMR(400MHz, MeOD-d 4 )δ8.87(s,1H), 8.05(t,J=7.8Hz,1H),7.86-7.76(m,2H),7.70(d,J=7.8Hz,1H),7.51(d,J=7.6 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 5.74 (dq, J = 11.0, 6.2 Hz, 1H), 5.06 (d, J = 10.1 Hz, 1H)...

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Abstract

The invention discloses a pyrazolone pyrimidine compound as well as a preparation method and application thereof. The invention provides the pyrazolone pyrimidine compound shown as a formula I, and anenantiomer, a diastereomer, a tautomer, a crystal form, a medically acceptable salt, a solvent compound, a metabolite or a prodrug thereof. The inhibition activity of the compound on WEE1 kinase is high. The formula I is shown in the description.

Description

Technical field [0001] The invention relates to a pyrazolone and pyrimidine compound, its preparation method and application. Background technique [0002] The cell cycle is closely related to the process of DNA damage repair. The cell cycle refers to the entire process of cell division, which is divided into two phases: interphase and mitotic phase (M). Cell cycle checkpoint (checkpoint) is a key point for regulating the cell cycle. Its main function is to ensure that each event in the cycle can be completed in time and orderly, and to adjust the cell state to adapt to the external environment. The main check points of the cell are: 1) G 1 / S check point: It is called R (restriction) point in mammals, which controls cells from static G 1 Enter the DNA synthesis phase; 2) S phase check point: whether DNA replication is complete; 3) G 2 / M checkpoint: It is the control point that regulates the cell entering the division phase; 4) Mid-late checkpoint: also known as the spindle ass...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D519/00A61P35/00A61P35/02A61K31/519A61K31/5377A61K31/55
CPCA61K31/4045A61K31/437A61K31/519A61K31/5377A61K31/55A61P35/00A61P35/02C07D209/04C07D215/06C07D217/04C07D223/16C07D471/04C07D487/04C07D519/00Y02P20/55
Inventor 王倩夏广新霍国永舒思杰石辰张霖葛辉张智慧毛煜余建鑫刘彦君
Owner SHANGAI PHARMA GRP CO LTD
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