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

A technology of fused heterocycles and compounds, applied in the field of nitrogen-containing fused heterocycles, can solve the problem of low inhibitory activity and achieve good inhibitory activity, good stability, and high bioavailability

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 to provide a nitrogen-containing fused heterocyclic compound, its preparation method, intermediate, composition and application in order to overcome the shortcomings of the existing cell cycle regulators in the prior art, such as the low inhibitory activity

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

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0254]

[0255] first step:

[0256] Compound 5-(2-aminopyrimidin-4-yl)-N-cyclopentyl-4-methylthiazol-2-amine (276 mg, 1 mmol) as shown in formula 1-1-a, 2-chloro-7 , 8-dihydro-1,6-naphthyridine-6(5H)-tert-butyl carboxylate (269mg, 1mmol), cesium carbonate (716mg, 2.2mmol), 4,5-bisdiphenylphosphine-9, 9-Dimethylxanthene (46mg, 0.08mmol), tris(dibenzylideneacetone) dipalladium (37mg, 0.04mmol) were added to 1,4-dioxane (8ml), under the protection of argon The temperature was raised to 110° C. for 12 hours. After cooling to room temperature, filter with diatomaceous earth, after the filtrate is concentrated, go through silica gel column chromatography (methanol / dichloromethane 0~10%) to obtain the compound 2-((4-(2- (Cyclopentylamino)-4-methylthiazol-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5hydrogen)-tert-butylcarboxy acid ester (280mg, 0.55mmol).

[0257] LC-MS: m / z: (M+H) + = 508.2.

[0258] Step two:

[0259] Compound 2-((4-(2-(cyclopentylamino)-4...

Embodiment 2

[0262]

[0263] first step:

[0264]Compound N-cyclopentyl-4-methyl-5-(2-((5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino as shown in formula 1-1 )pyrimidin-4-yl)thiazole-2-amine (140mg, 0.344mmol) and N-tert-butoxycarbonyl-(methylamino)acetaldehyde (130mg, 1.492mmol) and NaBH (OAc) 3 (220mg, 1.03mmol) was added into dichloromethane (10mL), and stirred at 45°C for 16 hours. The reaction solution was concentrated to obtain the compound (2-(2-((4-(2- (Cyclopentylamino)-4-methylthiazol-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5hydrogen)-yl)ethyl ) (Methyl) tert-butylcarboxylate (190 mg, 0.34 mmol) was used directly in the next step without further purification. LC-MS: m / z: (M+H) + = 565.3.

[0265] Step two:

[0266] Compound (2-(2-((4-(2-(cyclopentylamino)-4-methylthiazol-5-yl)pyrimidin-2-yl)amino)- 7,8-dihydro-1,6-naphthyridin-6(5hydro)-yl)ethyl)(methyl)tert-butylcarboxylate (190mg, 0.34mmol) was added to 2M HCl / EtOAc solution (2ml ), stirred at room ...

Embodiment 3

[0269]

[0270] Compound N-cyclopentyl-4-methyl-5-(2-((6-(2-(methylamino)ethyl)-5,6,7,8-tetrahydro as shown in formula 1-2 -1,6-naphthyridin-2-yl)amino)pyrimidin-4-yl)thiazole-2-ammonia (80mg, 0.17mmol) and aqueous formaldehyde (42mg, 0.51mmol) and NaBH (OAc) 3 (73 mg, 0.34 mmol) was added into methanol (5 mL), and stirred at room temperature for 16 hours. The reaction solution was concentrated and extracted with DCM / MeOH to obtain the compound N-cyclopentyl-5-(2-((6-(2-(dimethylamino)ethyl)-5,6,7,8-tetrahydro-1 , 6-naphthyridin-2-yl)amino)pyrimidin-4-yl)-4-methylthiazol-2-amine (80 mg, 0.167 mmol). 1 H NMR (400MHz, DMSO-d 6 )δ9.30(s,1H),8.36(d,J=5.4Hz,1H),8.21(d,J=6.9Hz,1H),8.03(d,J=8.4Hz,1H),7.42(d, J=8.5Hz, 1H), 6.95(d, J=5.5Hz, 1H), 3.99(dd, J=12.2, 5.8Hz, 1H), 3.57(s, 2H), 2.80(s, 4H), 2.59( t, J=6.9Hz, 2H), 2.49(s, 3H), 2.48-2.40(m, 2H), 2.18(s, 6H), 1.95(d, J=6.8Hz, 2H), 1.76-1.64(m ,2H),1.56(dt,J=10.3,6.3Hz,4H).

[0271] LC-MS: m / z: (M+H) + = 479.3.

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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 inhibition of 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): C07D471/04C07D519/00C07D471/14A61K31/506A61K31/519A61P35/00
CPCA61P35/00C07D471/04C07D471/14C07D519/00Y02P20/55
Inventor 夏广新王倩葛辉廖雪梅翟雄霍国永萧文博石辰
Owner SHANGAI PHARMA GRP CO LTD
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