Nitrogen-containing heterocyclic compound as well as preparation method and application thereof

A nitrogen-heterocyclic compound and solvate technology, which is applied in the field of nitrogen-containing heterocyclic compounds, can solve problems such as uncontrolled cell proliferation

Active Publication Date: 2020-04-21
SHANGAI PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] CDK4/6 is overactive in many tumors,

Method used

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  • Nitrogen-containing heterocyclic compound as well as preparation method and application thereof
  • Nitrogen-containing heterocyclic compound as well as preparation method and application thereof
  • Nitrogen-containing heterocyclic compound as well as preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 7

[0274]

[0275] first step:

[0276] 5-(2-chloropyrimidin-4-yl)-N-cyclopentyl-4-methyl-thiazol-2-amine (50mg, 0.17mmol), 4-(4-aminophenyl)piperidine-1 - tert-butylcarboxylate (50mg, 0.18mmol), cesium carbonate (100mg), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (10mg, 0.017mmol), tris(di Benzylideneacetone) dipalladium (10 mg) was added to 1,4-dioxane (3 ml), and the temperature was raised to 110° C. under the protection of argon to react for 12 hours. After cooling to room temperature, filter with diatomaceous earth, and the filtrate is concentrated and subjected to silica gel column chromatography (methanol / dichloromethane 0-5%) to obtain compound 4-[4-[[4-[2-(cyclopentylamino) -4-Methyl-thiazol-5-yl]pyrimidin-2-yl]amino]phenyl]piperidine-1-tert-butylcarboxylate (90mg, 0.168mmol).

[0277] Step two:

[0278] 4-[4-[[4-[2-(Cyclopentylamino)-4-methyl-thiazol-5-yl]pyrimidin-2-yl]amino]phenyl]piperidine-1-tert-butylcarboxy Add ester (90mg, 0.168mmol) to 2M HCl / MeOH solu...

Embodiment 8

[0282]

[0283] 5-(2-chloropyrimidin-4-yl)-N-cyclopentyl-4-methyl-thiazol-2-amine (50mg, 0.17mmol), 4-(1-methylpiperidin-4-yl ) aniline (34mg, 0.18mmol), cesium carbonate (100mg), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (10mg, 0.017mmol), tris(dibenzylideneacetone) Dipalladium (10 mg) was added into 1,4-dioxane (3 ml), and the temperature was raised to 110° C. under the protection of argon to react for 12 hours. After cooling to room temperature, filter with diatomaceous earth, and the filtrate is concentrated and subjected to silica gel column chromatography (methanol / dichloromethane 0-5%) to obtain the compound N-cyclopentyl-4-methyl-5-[2-[4 -(1-Methyl-4-piperidine)anilino]pyrimidin-4-yl]thiazol-2-amine (20 mg, 0.045 mmol).

[0284] 1 H NMR (400MHz, MeOD) δ8.26(d, J=5.5Hz, 1H), 7.65(d, J=8.5Hz, 2H), 7.20(d, J=8.5Hz, 2H), 6.90(d, J =5.5Hz,1H),4.12–3.92(m,1H),3.38(s,2H),2.90–2.62(m,6H),2.53(s,3H),2.14–1.85(m,7H),1.84– 1.73(m,2H),1.70–1.54(m,5H).

[0285] LC-MS: m...

Embodiment 14

[0287]

[0288] first step:

[0289] 5-(2-aminopyrimidin-4-yl)-N-cyclopentyl-4-methyl-thiazol-2-amine (90mg, 0.33mmol), 3-(4-bromophenyl)piperidine-1 - tert-butylcarboxylate (108mg, 0.32mmol), cesium carbonate (250mg), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (20mg), tris(dibenzylidene Acetone) dipalladium (20 mg) was added into 1,4-dioxane (6 ml), and the temperature was raised to 110° C. under the protection of argon to react for 12 hours. After cooling to room temperature, filter with diatomaceous earth, and the filtrate is concentrated and subjected to silica gel column chromatography (methanol / dichloromethane 0-5%) to obtain compound 3-[4-[[4-[2-(cyclopentylamino) -4-Methyl-thiazol-5-yl]pyrimidin-2-yl]amino]phenyl]piperidine-1-tert-butylcarboxylate (100mg, 0.187mmol).

[0290] Step two:

[0291] 3-[4-[[4-[2-(Cyclopentylamino)-4-methyl-thiazol-5-yl]pyrimidin-2-yl]amino]phenyl]piperidine-1-tert-butylcarboxy Add ester (100mg, 0.187mmol) to 2M HCl / MeOH solution (4...

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Abstract

The invention discloses a nitrogen-containing heterocyclic compound as well as a preparation method and application thereof. The compound is shown as a formula I. The compound has relatively high inhibitory activity on different CDK subtypes at a molecular level; the inhibitory activity on breast cancer cells at the cellular level is relatively good; the compound has a remarkable proliferation inhibition effect on tumor cells related to cyclin-dependent kinase activity at an animal level, has good stability on liver microsomes of human beings, mice and the like, does not obviously inhibit metabolic enzymes, has good in-vivo absorbability and high bioavailability in rats and mice, and has relatively good druggability.

Description

technical field [0001] The invention provides a nitrogen-containing heterocyclic compound, its preparation method and application. 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 , proliferation, dormancy and 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 most frequent, and there may be multiple mechanisms involved in...

Claims

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Application Information

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IPC IPC(8): C07D417/14C07D487/10C07F9/6584C07D487/08C07D498/04C07D417/04C07C211/40C07C211/60C07D211/26C07D295/135A61K31/506A61K31/5383A61K31/675A61P35/00
CPCC07D417/14C07D487/10C07F9/6584C07D487/08C07D498/04C07D417/04C07C211/40C07C211/60C07D211/26C07D295/135A61P35/00C07C2601/14C07C2602/10
Inventor 夏广新王倩翟雄张霖石辰霍国永廖雪梅毛煜刘彦君
Owner SHANGAI PHARMA GRP CO LTD
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