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

[0004] 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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0694]

[0695]first step:

[0696]4-Bromoaniline (I-1-a) (58.1mmol) was dissolved in toluene (250mL), potassium carbonate (87.2mmol) and benzyl chloride (87.2mmol) were added to the reaction solution, and the reaction solution was kept at room temperature. Stir for 16 hours. The reaction solution was filtered, and the filtrate was evaporated to dryness. The crude product was washed with ethyl acetate to obtain the target compound benzyl (4-bromophenyl) carbamate (I-1-b) (15.2 g, 85.4%) as a gray solid . LC-MS:m / z:(M+H)+= 307.0.

[0697]Step 2:

[0698]The benzyl (4-bromophenyl) carbamate (16.0 mmol) (I-1-b) was dissolved in 1,2-dimethoxyethane (50 mL), and 4,4, 5,5-Tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborane (as in formula I-1 -c) (16.0mmol), sodium carbonate (42.0mmol) and tetrakistriphenylphosphine (1.6mmol), the reaction solution was heated to 80°C and stirred for 16 hours. The reaction solution was filtered, and the filtrate was evaporated to dryness to obtain a crud...

Embodiment 3

[0708]

[0709]Compound (I-3-1) and compound (I-3-2) can be synthesized by using cyclopentane as a raw material in the same manner as in Example 1.

[0710]details as follows:

[0711]

[0712]first step:

[0713]Add tert-butyl carbamate (4'-oxo-2', 3', 4', 5'-tetrahydro-[1,1'-biphenyl]-4-yl) carbamate (0.46g, 1.6mmol) (I-8-c) and tetrahydropyrrole (0.28g, 3.9mmol) were added sodium acetate borohydride (0.85g, 4mmol) in a solution of 20ml of dichloromethane, and stirred overnight at room temperature. The reaction solution was saturated with Sodium carbonate aqueous solution (20ml), water (2*10ml) and saturated brine are washed, the organic phase is dried with anhydrous sodium sulfate and then mixed with silica gel and passed through the column {7M ammonia methanol: (dichloromethane: ethyl acetate = 12 : 2)=0-15%}, to obtain compound I-3-a, 200 mg of white solid. The yield was 40%. LC-MS: m / z: (M+H)+=343.

[0714]The second step:

[0715]Add (4'-(pyrrolidin-1-yl)-2', 3', 4', 5'-tetrahydro-[1,1'-biphenyl]...

Embodiment 4

[0723]

[0724]first step:

[0725]The 1-bromo-4-nitrobenzene) (I-4-a) (692mg, 3.43mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Cyclopentane-2-yl) ethyl cyclohex-3-ene-1-carboxylate (I-4-b) (800mg, 2.85mmol), tetrakistriphenylphosphonium palladium (330mg, 0.286mmol), three Phenylphosphine (75mg, 0.286mmol) and potassium carbonate (789mg, 5.71mmol) were dissolved in 1,4-dioxane (20ml), heated to 90°C under argon protection and stirred for about 16 hours. Then the reaction solution was concentrated and purified by column chromatography (silica gel, petroleum ether / ethyl acetate=100% to 90%) to obtain 450 mg of the compound represented by formula I-4-c as a white solid. Yield: 47%.1H NMR(400MHz, CDCl3)δ8.23–8.16(m,2H), 7.57–7.49(m,2H), 6.33(dd,J=5.1,2.8Hz,1H), 4.26–4.15(m,2H), 2.72–2.61(m, 1H), 2.59–2.51 (m, 4H), 2.24 (ddd, J = 9.3, 8.0, 3.9 Hz, 1H), 1.90 (dddd, J = 13.1, 11.0, 8.8, 6.7 Hz, 1H), 1.31 (dd, J = 9.2, 5.1 Hz, 3H).

[0726]Step 2:

[0727]Dissolve 4-(4-nitrophenyl)cyclohex-3-ene-1-ca...

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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 II 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 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 cells are: 1) G1 / S check point: called R (restriction) point in mammals, which controls the cell to enter the DNA synthesis phase from the resting G1 phase; 2) S phase check point: whether DNA replication is complete ; 3) G2 / M check point: it is the control point that regulates the cell entering the division phase; 4) mid-late check point: also known as the spindle assembly...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D205/04C07D295/135C07D213/73C07C211/49C07C229/46A61P35/00A61P35/02A61K31/519A61K31/5377
CPCC07D487/04C07D205/04C07D295/135C07D213/73C07C211/49C07C229/46A61P35/00A61P35/02C07C2601/14C07C2601/04A61K45/06A61K31/519A61K31/5377
Inventor 王倩舒思杰夏广新葛辉张冰宾霍国永张霖石辰楼江松张弛张智慧毛煜余建鑫柯樱刘彦君
Owner SHANGAI PHARMA GRP CO LTD
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