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Dihydroisoindole-1H-pyrazolo[3,4-d]pyrimidone compound, and preparation method and application thereof

A compound, C1-C4 technology, applied in organic chemistry, drug combination, metabolic diseases, etc., can solve the problems of unlikely distribution of AZD1775, limited efficacy, limited applicability of brain tumor treatment, etc., and achieve good blood-brain barrier permeability , high therapeutic index, good safety effect

Active Publication Date: 2020-03-10
上海弘翊生物科技有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Preclinical evaluations suggest that AZD1775 is unlikely to distribute into neural compartments, which may limit its efficacy in brain tumors and limit its applicability for chemotherapy-needed brain tumor treatments

Method used

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  • Dihydroisoindole-1H-pyrazolo[3,4-d]pyrimidone compound, and preparation method and application thereof
  • Dihydroisoindole-1H-pyrazolo[3,4-d]pyrimidone compound, and preparation method and application thereof
  • Dihydroisoindole-1H-pyrazolo[3,4-d]pyrimidone compound, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0150] Example 1: 2-allyl-6-((1,3-dimethyldihydroisoindol-5-yl-)amino)-1-(6-(2-hydroxypropan-2-yl) Pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (HY-B001)

[0151]

[0152] A01 (58 mg) and DIEA (100 mg) were added to a DMF (5 mL) solution of compound Int-2 (120 mg) in an ice-water bath, and stirred at room temperature for 5 hours. Dilute with water, extract three times with ethyl acetate, wash the organic phase with sodium bicarbonate solution, dry over anhydrous sodium sulfate, and filter. The filtrate was concentrated and prepared by HPLC to obtain the target product HY-B001 (35 mg) as a white solid. LCMS (ES, m / z): 472.2 [M+H] + .

Embodiment 2

[0153] Example 2: 2-allyl-6-((1,3-dihydroisobenzofuran-5-yl)amino)-1-(6-(2-hydroxyprop-2-yl)pyridine-2 -yl)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one (HY-B002)

[0154]

[0155] To a toluene solution containing Compound Int-1 (100 mg) was added m-CPBA (72 mg), followed by stirring at room temperature overnight. DIEA (108 mg) and compound A02 (45 mg) were added to the solution, followed by further stirring at room temperature for 8 hours. Ethyl acetate (50 mL) was added, the organic phase was washed 3 times with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, the filtrate was removed in vacuo, and ethyl acetate (2 mL) was added to the residue to precipitate a white solid , filtered, and the solid was dried to obtain the target product HY-B002 (23 mg). LCMS (ES, m / z): 445.0 [M+H]+. 1H NMR (400MHz, CDCl 3 )δ1.59(s,6H),3.87(br s,1H),4.75(d,J=6.4Hz,2H),4.93(d,J=16.4Hz,1H),5.05(d,J=10.0Hz ,1H),5.12(s,4H),5.66-5.73(m,1H),7.21(d,J=7.6Hz,1H),7....

Embodiment 3

[0156] Example 3: 2-allyl-6-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-1-(6-( 2-Hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (HY-B003)

[0157]

[0158] To a toluene solution containing Compound Int-1 (100 mg), m-CPBA (97 mg) was added, followed by stirring at room temperature for 20 minutes. DIEA (108 mg) and compound A03 (51 mg) were added to the solution, followed by further stirring at room temperature overnight. Ethyl acetate (50 mL) was added, the organic phase was washed 3 times with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, the filtrate was removed in vacuo, and petroleum ether / ethyl acetate (3 mL, 2 : 1), a white solid was precipitated, filtered, and the solid was dried to obtain the target product HY-B003 (83mg). LCMS (ES, m / z): 461.0 [M+H] + . 1H NMR (400MHz, CDCl 3 )δ1.59(s,6H),3.91(br s,1H),4.26-4.30(m,4H),4.76(d,J=6.4Hz,2H),4.94(d,J=17.2Hz,1H) ,5.05(d,J=10.4Hz,1H),5.66-5.72(m...

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Abstract

The invention relates to a series of compounds represented as the formula (I), or pharmaceutically acceptable salts thereof, which can be used as new-generation Wee1 selective inhibitor. Compared withexisting Wee1 inhibitor, the compound has a higher selectivity on Wee1 kinase, so that the compound is safer and is higher in treatment index, and also has higher blood brain barrier permeability. The compound has better safety and a larger applicable range, and can be applied to treatment on various tumors, including brain tumor.

Description

technical field [0001] The invention relates to a class of dihydroisoindole-1H-pyrazolo[3,4-d]pyrimidinone compounds, a preparation method thereof, and a pharmaceutical composition containing the compound, which are used for preparing and treating cancer and precancerous syndrome drugs or supplementary drugs. [0002] Background of the invention [0003] Cell cycle checkpoints are a set of inspection mechanisms to ensure the quality of DNA replication and chromosome allocation during cell cycle progression. When abnormal events occur during the cell cycle process, such as DNA damage or DNA replication blockage, this kind of regulatory mechanism is activated to interrupt the progress of the cell cycle in time, and the cell cycle can only resume operation after the cell is repaired or the fault is eliminated. The core component of the cell cycle regulation system is the CDKs / Cyclins complex formed by the combination of cyclin-dependent kinases (CDKs) and cyclins (Cyclins), whi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D519/00A61P35/00A61P35/02A61P3/00A61P3/10A61P3/06A61P3/04A61P9/10A61P19/02A61P37/00A61P17/06
CPCC07D487/04C07D519/00A61P35/00A61P35/02A61P3/00A61P3/10A61P3/06A61P3/04A61P9/10A61P19/02A61P37/00A61P17/06
Inventor 吴荣光李佳易德武周宇波叶伟王培培向俊峰张凯祥胡小蓓
Owner 上海弘翊生物科技有限公司
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