Novel CDK4/6 inhibitor as well as preparation method and application thereof

A C3-C6, C2-C6 technology, applied in the field of CDK4/6 inhibitor compounds, can solve the problem of drug resistance

Active Publication Date: 2021-07-13
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Three marketed CDK4 / 6 inhibitors play an important role in the treatment of breast cancer, but there have been incidents of resistance to them

Method used

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  • Novel CDK4/6 inhibitor as well as preparation method and application thereof
  • Novel CDK4/6 inhibitor as well as preparation method and application thereof
  • Novel CDK4/6 inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] The preparation of embodiment 1,6-(2-chloro-5-fluoropyrimidin-4-yl)quinoxaline

[0046] The first step: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline

[0047]

[0048] 6-bromoquinoxaline (0.42g, 2.0mmol) was dissolved in DMF (10mL), then added pinacol borate (0.53g, 2.1mmol), Pd(dppf)Cl 2 (22mg, 0.06mmol), potassium acetate (0.59g, 6.0mmol), argon was replaced three times, heated to 80°C, and reacted for 24h. Cooling, filtration, concentration column chromatography (PE / EA=10:1) gave compound 6-( 2-Chloro-5-fluoropyrimidin-4-yl)quinoxaline, white solid (0.43g, 84% yield).

[0049] 1 HNMR (300MHz, CDCl 3 )δ8.88–8.86(m,2H),8.61(d,J=1.2Hz,1H),8.16–8.07(m,2H),1.40(s,12H).

[0050] The second step: the synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)quinoxaline

[0051]

[0052] Weigh compound 2,4-dichloro-5-fluoropyrimidine (0.23g, 1.4mmol) into a 250mL three-necked flask, then add Pd(PPh 3 ) 2 Cl 2 (21mg, 0.03mmol), sodium carbonate (...

Embodiment 2

[0054] The preparation of embodiment 2, 5-((4-ethylpiperazin-1-yl) methyl) pyridin-2-amine

[0055]

[0056] 2-Amino-5-formylpyridine (0.32g, 2.6mmol) and N-ethylpiperazine (0.45g, 3.9mmol) were dissolved in 1,2-dichloroethane (20mL), stirred at room temperature for 2h, then added Sodium triacetylborohydride (0.87g, 4.1mmol), stirred at room temperature for 8h, quenched by adding 1M NaOH (30mL), extracted with DCM (20Ml*3), dried over anhydrous sodium sulfate, concentrated and column chromatography (DCM / MeOH =10:1) The compound 5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-amine was obtained as a white solid (0.52 g, 91%).

[0057] 1 HNMR (300MHz, CDCl 3 )δ7.94(d, J=2.3Hz, 1H), 7.40(dd, J=8.3, 2.4Hz, 1H), 6.46(d, J=8.3Hz, 1H), 4.57(s, 2H), 3.36( s,2H),2.47–2.37(m,10H),1.07(t,J=7.2Hz,3H).

Embodiment 3

[0058] Embodiment 3, the preparation of tert-butyl 4-((6-aminopyridin-3-yl) methyl) piperazine-1-carboxylate

[0059]

[0060] Preparation of compound tert-butyl 4-((6-aminopyridin-3-yl)methyl)piperazine-1-carboxylate Reference compound 5-((4-ethylpiperazin-1-yl)methyl ) from the preparation of pyridin-2-amine.

[0061] 1 HNMR (300MHz, CDCl 3 ): δ7.94(d, J=2.3Hz, 1H), 7.40(dd, J=8.4, 2.3Hz, 1H), 6.48(d, J=8.4Hz, 1H), 4.54(s, 2H), 3.40 (t,J=5.1Hz,4H),3.36(s,2H),2.35(t,J=5.1Hz,4H),1.45(s,9H).

[0062] Preparation of I-a and I-b

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Abstract

The invention discloses a novel CDK4/6 inhibitor and a preparation method and application thereof.The novel CDK4/6 inhibitor is shown in the formula (I), has CDK4/6 inhibitory activity and has a treatment effect on CDK4/6 regulation related diseases including multiple myeloma, lung cancer, liver cancer, prostatic cancer, breast cancer and the like.

Description

technical field [0001] The present invention relates to a class of compounds that are CDK4 / 6 inhibitors, which are effective in treating diseases and disorders of malignant proliferation of cells. Background technique [0002] Cell cycle-dependent kinase (cyclin-dependent kinase, CDK) plays an important role in the process of regulating the cell cycle. CDK4 / 6 is a serine (Ser) / threonine (Thr) kinase with a similar structure and function, which plays an important role in the cell cycle. In the early stage of G1 phase, cyclin D binds and activates CDK4 / 6, and the formed cyclin D-CDK4 / 6 complex promotes the phosphorylation of retinoblastoma protein (Rb), thereby releasing the transcription factor E2F , promote the process of cell cycle from G1 phase to S phase. [0003] CDK4 / 6 is the key promoter protein of the cell cycle from G1 phase to S phase. The inhibition of CDK4 / 6 can arrest the cell cycle in G1 phase, thereby reducing cell proliferation, and plays an important role in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61K31/506A61P35/00
CPCC07D401/14A61K31/506A61P35/00
Inventor 杨鹏袁凯
Owner CHINA PHARM UNIV
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