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Nitrogen-containing condensed heterocyclic compound, its preparation method, intermediate, composition and application

A technology of compounds and fused heterocycles, applied in the direction of drug combinations, compounds containing elements of Group 3/13 of the periodic table, chemical instruments and methods, etc., can solve the problem of low inhibitory activity

Active Publication Date: 2022-05-03
SHANGAI PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The problem to be solved by the present invention is that the inhibitory activity of existing cell cycle regulators is not high, and a nitrogen-containing fused heterocyclic compound, its preparation method, intermediate, composition and application are provided

Method used

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  • Nitrogen-containing condensed heterocyclic compound, its preparation method, intermediate, composition and application
  • Nitrogen-containing condensed heterocyclic compound, its preparation method, intermediate, composition and application
  • Nitrogen-containing condensed heterocyclic compound, its preparation method, intermediate, composition and application

Examples

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Effect test

preparation example 1

[0350]

[0351] first step:

[0352] Dissolve 5-bromo-1,3-difluoro-2-nitrobenzene (2.38g, 10mmol) and isopropylamine (660mg, 11mmol) in tetrahydrofuran (50ml), stir at room temperature for 16 hours, filter, and concentrate the filtrate The compound 5-bromo-3-fluoro-N-isopropyl-2-nitroaniline (2.3 g, 8.3 mmol) represented by formula 1-b was obtained. LC-MS: m / z: (M+H) + = 277.1, 279.1.

[0353] Step two:

[0354] 5-Bromo-3-fluoro-N-isopropyl-2-nitroaniline (2.3g, 8.3mmol) (compound shown in formula 1-b) was dissolved in methanol (30ml), and Raney nickel was added (500mg, 8.5mmol), then slowly dropwise added hydrazine hydrate (1.5ml), stirred at room temperature for 16 hours, filtered, and the filtrate was concentrated to give the compound 5-bromo-3-fluoro-N1-isopropyl- Phenyl-1,2-diamine (1.8 g, 7.3 mmol). LC-MS: m / z: (M+H) + = 247.1, 249.1.

[0355] third step:

[0356] Dissolve 5-bromo-3-fluoro-N1-isopropyl-phenyl-1,2-diamine (1.8g, 7.3mmol) (compound shown in form...

preparation example 2

[0358]

[0359] first step:

[0360] 5-Bromobenzo[d]oxazol-2(3H)-one (500mg, 2.3362mmol) (compound as shown in formula 2-a), 2-iodopropane (0.8g, 4.7mmol) and potassium carbonate (1g, 7.25mmol) was added to 4ml of N,N-dimethylformamide and stirred overnight at room temperature. The reaction solution was filtered, and the obtained filtrate was concentrated to obtain a crude product. After passing through the column (ethyl acetate:petroleum ether=0-10%), 520 mg of the target product (compound shown in formula 2-b) was obtained as a white solid, with a yield of 87%. LC-MS: m / z: (M+H) + =256. 1 H NMR (400MHz, CDCl 3 )δ7.25(td, J=4.3,1.8Hz,2H),7.14–7.05(m,1H),4.54(dt,J=13.9,7.0Hz,1H),1.56(d,J=7.0Hz,6H ).

[0361] Step two:

[0362] 5-bromo-3-isopropylbenzo[d]oxazol-2(3H)-one (260mg, 1.015mmol) (compound as shown in formula 2-b), double pinacol borate ( 292mg, 1.15mmol), Pd(dppf)Cl 2 .CH 2 Cl 2 (82mg, 0.1mmol) and potassium acetate (200mg, 2.04mmol) were added to 5ml o...

preparation example 3

[0368]

[0369] first step:

[0370] Compound 5-bromo-2-cyanopyridine (1.4g, 7.7mmol) as shown in formula 3-a was dissolved in tetrahydrofuran (20ml), slowly added borane (276mg, 3equiv., 23mmol), then stirred at room temperature for about 16 hours, quenched with water, stirred at 60°C for about 20 minutes, added 2N hydrochloric acid (10ml) and continued to stir for about 20 minutes, cooled to room temperature, added 2N sodium hydroxide solution to adjust the pH value to 8, concentrated to remove water, and the solid was washed with methanol / The mixed solution of dichloromethane=10 / 1 was dissolved, filtered, and concentrated to give 5-bromo-2-aminomethylpyridine (1.4g, 7.5mmol, 98% yield) as shown in the formula 3-b compound, yellow oil , used directly in the next step without purification. LC-MS: M / Z=187, 189(M+H) +

[0371] Step two:

[0372] Compound 5-bromo-2-aminomethylpyridine (1.4g, 7.5mmol) as shown in formula 3-b was dissolved in methylene chloride (20ml), the...

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Abstract

The invention discloses a nitrogen-containing condensed heterocyclic compound, its preparation method, intermediate, composition and application. The compound of the present invention has higher inhibitory activity on different subtypes of CDK at the molecular level, better inhibitory activity on breast cancer cells at the cellular level, and also has inhibitory activity on tumor cells related to cyclin-dependent kinase activity at the animal level Significant inhibitory effect on proliferation, good stability to liver microsomes of humans and mice, no obvious inhibition of metabolic enzymes, good absorption properties in rats and mice, high bioavailability, and good druggability.

Description

technical field [0001] The present invention relates to a nitrogen-containing condensed heterocyclic compound, a preparation method, an intermediate, a composition and an application thereof. Background technique [0002] Tumor is a kind of cell cycle disease (Cell Cycle Disease, CCD), regulating or blocking cell cycle is one of the ways to treat tumor. At present, many molecules related to cell cycle regulation have been discovered, among which cyclin-dependent kinases (Cyclin-Dependent-Kinases, CDKs) are the core molecules of the cell cycle regulation network. CDKs are catalytic subunits, a class of serine (Ser) / threonine (Thr) kinases, as important signal transduction molecules in cells, and the CDK-cyclin complex formed by cyclin (cyclin), involved in cell growth , proliferate, rest or enter apoptosis. Cell cycle regulatory proteins play an important role in the regulation of cell proliferation. In tumor cells, the abnormality of cyclins and CDKs in G1 phase is the mos...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04C07D519/00C07F5/02C07D413/04C07D263/58C07D403/04C07D231/56A61K31/506A61P35/00
CPCC07D231/56C07D263/58C07D403/04C07D413/04C07D471/04C07D519/00C07F5/025Y02P20/55A61K31/506A61P35/00C07F5/02Y02P20/54
Inventor 夏广新王倩葛辉廖雪梅霍国永翟雄石辰段灵峻毛煜刘彦君
Owner SHANGAI PHARMA GRP CO LTD
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