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CDK6/DYRK2 double-target inhibitor as well as preparation method and application thereof

A CH2, C1-C8 technology, applied in the field of CDK6/DYRK2 dual-target inhibitors and their preparation, can solve problems such as drug resistance

Active Publication Date: 2021-02-23
JIANGSU TASLY DIYI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Purpose of the invention: In order to solve the problem of drug resistance of existing drugs for single-target therapy, the present invention utilizes the synergistic effect of CDK6 and DYRK2 to provide a compound or a pharmaceutically acceptable salt thereof that can simultaneously target CDK6 and DYRK2 DYRK2, the compound is a CDK6 / DYRK2 dual-target inhibitor. By inhibiting DYRK2 and blocking the compensatory pathway of CDK6 at the same time, it can improve the anticancer activity of the compound and reduce the drug resistance of CDK6 single-target drugs.

Method used

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  • CDK6/DYRK2 double-target inhibitor as well as preparation method and application thereof
  • CDK6/DYRK2 double-target inhibitor as well as preparation method and application thereof
  • CDK6/DYRK2 double-target inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0148] (6-((4-(Benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amine)pyridin-3-yl)(4-ethylpiperazin-1-yl)methanone (I -1) Synthesis:

[0149]

[0150] Compounds 6-(2-chloro-5-fluoropyrimidin-4-yl)benzothiazole (133 mg, 0.5 mmol) and 6-aminopyridin-3-yl)(4-ethylpiperazin-1-yl)methyl Ketone (141 mg, 0.6 mmol) was dissolved in dioxane (5 mL), then Pd was added 2 (dba) 3 (23 mg, 0.025 mmol), Xantphos (58 mg, 0.1 mmol), cesium carbonate (326 mg, 1.0 mmol), replace argon three times, heat to 100°C, and react for 12 h. Cooling filtration concentration column chromatography (DCM~DCM / MeOH=10:1) obtains compound (6-((4-(benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amine)pyridine-3 -yl)(4-ethylpiperazin-1-yl)methanone (88 mg, 38% yield). 1 H NMR (300 MHz, CDCl 3 ) δ 9.68 (s, 1H), 9.15 (s, 1H), 8.76– 8.75 (m, 1H), 8.61 – 8.58 (m, 2H), 8.52 (dd, J = 8.7, 0.9 Hz, 1H), 8.33 –8.26 (m, 2H), 7.86 (dd, J = 8.7, 2.3 Hz, 1H), 3.80 – 3.61 (m, 4H), 2.51 –2.44 (m, 6H), 1.12 (t, J = 7.2 Hz, 3H). ...

Embodiment 2

[0152] 4-(benzothiazol-6-yl)-N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine (I -2) Synthesis:

[0153]

[0154] Referring to the synthetic method of compound (I-1), the yield was 43%. 1 H NMR (300 MHz, CDCl3) δ 9.15 (s,1H), 9.11 (s, 1H), 8.78 – 8.76 (m, 1H), 8.54 (d, J = 3.5 Hz, 1H), 8.41 (d, J = 8.6 Hz, 1H), 8.35 – 8.26 (m, 3H), 7.73 (dd, J = 8.6, 2.3 Hz, 1H), 3.52 (s,2H), 2.58 – 2.47 (m, 10H), 1.14 (t, J = 7.2 Hz, 3H).

Embodiment 3

[0156] tert-Butyl 4-((6-((4-(benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amine)pyridin-3-yl)methyl)piperazine-1-carboxylic acid Synthesis of ester (I-3):

[0157]

[0158] Referring to the synthetic method of compound (I-1), the yield was 52%. 1 H NMR (400 MHz, CDCl 3 ) δ 9.14 (s,1H), 8.83 (s, 1H), 8.77 (d, J = 1.5 Hz, 1H), 8.52 (d, J = 3.5 Hz, 1H), 8.41(d, J = 8.6 Hz, 1H), 8.34 – 8.27 (m, 3H), 7.75 – 7.73 (m, 1H), 3.50 (s, 2H),3.45 – 3.43 (m, J = 5.2 Hz, 4H), 2.43 – 2.40 (m, 4H), 1.46 (s, 9H).

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Abstract

The present invention discloses a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. The invention also discloses a preparation method of the compound and application of the compound in prevention and / or treatment of cancers or tumor-related diseases, especially breast cancer, prostate cancer, lung cancer, multiple myeloma, leukemia, gastric cancer, ovarian cancer, colon cancer, liver cancer, pancreatic cancer, human glioma and other diseases. The compound provided by the invention is expected to be developed into a new generation of anti-cancer drugs.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a CDK6 / DYRK2 dual-target inhibitor and its preparation method and application. Background technique [0002] Cyclin-dependent kinase 6 (CDK6 ) is a serine / tyrosine kinase that regulates the transition from the G1 phase to the S phase of the cell cycle. In the early stage of the G1 phase of the cell cycle, cyclin D binds to CDK6 and activates CDK6, and the formed cyclin D-CDK6 complex can promote the phosphorylation of retinoblastoma protein (Rb). Phosphorylation of Rb leads to the release of the transcription factor E2F, which accelerates the progression of the cell cycle from G1 phase to S phase. The up-regulation of the proto-oncogene CDK6 will lead to the acceleration of the process of cell cycle from G1 phase to S phase, resulting in the acceleration of cell cycle and cell proliferation. Uncontrolled cell proliferation is the main feature of cancer, therefore, the inhibit...

Claims

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Application Information

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IPC IPC(8): C07D417/14A61K31/506A61P35/00A61P35/02
CPCC07D417/14A61P35/00A61P35/02A61K31/506
Inventor 杨鹏袁凯肖易倍郝海平王晓邝文彬
Owner JIANGSU TASLY DIYI PHARMA CO LTD