Unlock instant, AI-driven research and patent intelligence for your innovation.

Heteropyridopyrimidinone derivatives as cdk inhibitors and their applications

A technology of hetero-substituted pyridine and pyrimidinone, which is applied in the field of drug preparation and can solve problems such as large toxic and side effects

Active Publication Date: 2019-07-02
SHANGHAI XUNHE PHARMA TECH CO LTD
View PDF3 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the analysis of serious toxic and side effects, it was found that some CDK inhibitor drugs lack selectivity for CDK subtypes, thus producing relatively large toxic and side effects

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Heteropyridopyrimidinone derivatives as cdk inhibitors and their applications
  • Heteropyridopyrimidinone derivatives as cdk inhibitors and their applications
  • Heteropyridopyrimidinone derivatives as cdk inhibitors and their applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Compound (I-1) 6,6-Dimethyl-8-isopropyl-2-(5-(1-piperazinyl)-pyridine-2-amino)-6H-pyrimidine[5,4-b] [1,4]oxazin-7(8H)-one

[0044] Step 1: 2,4-dichloro-5-methoxypyrimidine (1.0 g, 5.59 mmol), isopropylamine (0.33 g, 5.59 mmol), N,N-diisopropylethylamine (7.2 g, 55.9 mmol ) into isopropanol (IPA, 10mL), N 2 Under the protection of 100 ℃ reaction 6h. Concentrate the solvent to dryness, add H to the residue 2 O (50mL) / dichloromethane (DCM, 50mL) was stirred and extracted, the organic layer was dried, filtered, and concentrated to give a pale yellow solid 2-chloro-N-isopropyl-5-methoxypyrimidine-4-ammonia (0.78g , crude product yield 69.3%).

[0045] Step 2: 2-Chloro-N-isopropyl-5-methoxypyrimidine-4-ammonia (0.78g, 3.88mmol) was added to DCM (15mL), and BBr was added dropwise under ice bath 3 (14.5g, 58.2mmol) in DCM (15mL), the dropwise addition was completed, warmed up to room temperature and stirred for 10h, then methanol (10mL) was added dropwise to quench the rea...

Embodiment 2

[0050] Compound (I-2) 6,6-Dimethyl-8-cyclopentyl-2-(5-(1-piperazinyl)-pyridine-2-amino)-6H-pyrimidine[5,4-b] [1,4]oxazin-7(8H)-one

[0051] The synthesis of compound I-2 was carried out according to the method in Example 1, and the starting material was 2-chloro-6,6-dimethyl-8-cyclopentyl-6H-pyrimidine[5,4-b][1,4] Oxazin-7(8H)-one (synthesis method is similar to Example 1, starting materials are 2,4-dichloro-5-methoxypyrimidine and cyclopentylamine) and 4-(6-aminopyridine-3 -yl) tert-butyl piperazine-1-carboxylate. The final product 6,6-dimethyl-8-cyclopentyl-2-(5-(1-piperazinyl)-pyridine-2-amino)-6H-pyrimidine[5,4-b][1, 4] Oxazin-7(8H)-one hydrochloride (I-2), pale yellow solid. MS(m / z): 424[M+H] + . 1 H NMR (DMSO-d 6 ): δ: 11.88 (br, 1H), 9.77 (br, 2H), 8.26 (s, 1H), 8.24-8.22 (d, J=8.0Hz, 1H), 7.93 (s, 1H), 7.70-7.68 ( d, J=8.0Hz, 1H), 5.37-5.23(m, 1H), 4.61(m, 4H), 3.45(m, 4H), 2.05-1.55(m, 8H), 1.48(s, 6H).

Embodiment 3

[0053] Compound (I-3) 6,6-Dimethyl-8-cyclopentyl-2-(5-(4-ethyl-1-piperazinyl)methyl-pyridine-2-amino)-6H-pyrimidine [5,4-b][1,4]oxazin-7(8H)-one

[0054] The synthesis of compound I-3 was carried out according to the method in Example 1, and the starting material was 2-chloro-6,6-dimethyl-8-cyclopentyl-6H-pyrimidine[5,4-b][1,4] Oxazin-7(8H)-one and 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine. The final product 6,6-dimethyl-8-cyclopentyl-2-(5-(4-ethyl-1-piperazinyl)methyl-pyridine-2-amino)-6H-pyrimidine [5, 4-b][1,4]oxazin-7(8H)-one hydrochloride (I-3), white solid. MS(m / z): 466[M+H] + . 1 H NMR (DMSO-d 6 ): δ: 12.04 (br, 1H), 11.83 (br, 1H), 8.53 (s, 1H), 8.36-8.34 (d, J=8.0Hz, 1H), 8.19 (s, 1H), 7.72-7.70 ( d, J=8.0Hz, 1H), 5.29-5.21(m, 1H), 4.41(m, 4H), 3.59-3.51(m, 6H), 3.08(m, 2H), 1.99-1.47(m, 8H) , 1.39 (s, 6H), 1.19-1.15 (t, J=8.0Hz, 3H).

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The present invention relates to a heterocyclic-substituted pyridinopyrimidinone derivative and the use thereof as a therapeutically effective cyclin-dependent kinase (CDK) inhibitor. In particular, the present invention relates to the use of a new heterocyclic-substitute pyridinopyrimidinone derivative as shown in formula (I) and a pharmaceutical composition thereof as a selective CDK4 / 6 inhibitor in preventing or treating diseases related to CDK4 / 6.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a heteropyridopyrimidinone derivative as a CDK inhibitor and its application. Background technique [0002] Cyclin-dependent kinase (CDK) and cyclin (cyclin) are important factors in cell cycle regulation. CDK can combine with cyclin to form a heterodimer, in which CDK is the catalytic subunit and cyclin is the regulatory subunit, forming various cyclin-CDK complexes, phosphorylating different substrates, and promoting and promoting different phases of the cell cycle. Transformation. [0003] There are at least nine CDKs in mammals. Cell transition from G1 phase to S phase is mainly controlled by CDK kinases in G1 phase. CDK kinases that bind to cyclins in the G1 phase mainly include CDK2, CDK4 and CKD6. Cyclin D mainly binds to CDK4 and CKD6 and regulates the activity of the latter; cyclin E binds to CDK2 in the G1 / S phase, presenting the kinase activity of CDK ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/04C07D498/10C07D513/04A61P35/00A61P35/02
CPCC07D498/04C07D498/10C07D513/04A61P35/00
Inventor 郑永勇金华周峰黄美花孟欣
Owner SHANGHAI XUNHE PHARMA TECH CO LTD