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Aurora kinase inhibitors and use thereof

A technology for optical isomers and compounds, which is applied in the field of anti-tumor drug preparation, can solve the problems of insufficient Aurora kinase activity, need to improve anti-tumor activity, and poor oral absorption properties.

Inactive Publication Date: 2021-01-19
WIGEN BIOMEDICINE TECH SHANGHAI CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, LY-3295668 and other Aurora-A kinase inhibitors have some disadvantages, such as insufficient Aurora kinase activity, poor oral absorption properties, and in vivo anti-tumor activity to be improved

Method used

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  • Aurora kinase inhibitors and use thereof
  • Aurora kinase inhibitors and use thereof
  • Aurora kinase inhibitors and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Example 1 1-(3-chloro-2-fluorobenzyl)-4-((6-(3-fluoro-6-(thiazol-2-ylamino)pyridin-2-yl)methyl)-2- Synthesis of Methylpiperidine-4-Carboxylic Acid (Compound 1)

[0068]

[0069] 1-(tert-butyl)4-methyl 4-((3-fluoro-6-(thiazol-2-ylamino)pyridin-2-yl)methyl)-2-methylpiperidine-1,4- Bisformic acid ester

[0070] Add 1-(tert-butyl)4-methyl 4-((6-bromo-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-bismethyl into a 250mL one-mouth bottle Ester (5g, 11.23mmol, synthesized with reference to the method in patent WO2016077161), 2-aminothiazole (956mg, 9.55mmol), anhydrous potassium phosphate (6g, 28.08mmol), Xantphos (650mg, 1.123mmol) and Dioxane ( 100mL), adding Pd after Ar replacement protection 2 (dba) 3 (514mg, 0.562mmol), heated to reflux for 5h under the protection of Ar. After the completion of the reaction monitored by LC-MS, the system was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM / MeOH=50 / 0 to 50 / 1) to o...

Embodiment 2

[0081] Example 2 4-((3-fluoro-6-(thiazol-2-ylamino)pyridin-2-yl)methyl)-1-((3-fluoropyridin-4-yl)methyl)-2- Synthesis of Methylpiperidine-4-Carboxylic Acid (Compound 2)

[0082]

[0083] With 4-((3-fluoro-6-(thiazol-2-ylamino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid methyl ester hydrochloride and 4-(bromo Methyl)-3-fluoropyridine was used as a raw material, and the synthesis method in Example 1 was adopted to obtain the target compound.

[0084] 1 H NMR (400MHz, DMSO-d 6 )δ: 12.45(s, 1H), 11.45(s, 1H), 8.74(d, J=1.4Hz, 1H), 8.54(d, J=4.9Hz, 1H), 8.03(t, J=5.7Hz, 1H), 7.68(t, J=9.1Hz, 1H), 7.50(d, J=4.0Hz, 1H), 7.13(q, J=3.7, 3.3Hz, 2H), 4.71(d, J=13.3Hz, 1H), 4.43(dd, J=13.5, 7.9Hz, 1H), 3.93(s, 1H), 3.39(dt, J=14.8, 9.1Hz, 1H), 3.30-3.23(m, 2H), 3.09(d , J=13.1Hz, 1H), 2.08(t, J=15.2Hz, 3H), 1.92(d, J=15.2Hz, 1H), 1.51(d, J=6.2Hz, 3H); ESI-MS m / z:460.2[M+H] + .

Embodiment 3

[0085] Example 3 1-((2-chloro-3-fluoropyridin-4-yl)methyl)-4-((3-fluoro-6-(thiazol-2-ylamino)pyridin-2-yl)methyl )-2-methylpiperidine-4-carboxylic acid (compound 3) synthesis

[0086]

[0087] With 4-((3-fluoro-6-(thiazol-2-ylamino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid methyl ester hydrochloride and 4-(bromo Methyl)-2-chloro-3-fluoropyridine was used as raw material, and the synthesis method in Example 1 was adopted to obtain the target compound.

[0088] 1 H NMR (400MHz, DMSO-d 6 )δ: 11.22(s, 1H), 9.82(s, 1H), 8.39(s, 1H), 7.68(s, 1H), 7.57(t, J=9.1Hz, 1H), 7.37(d, J=3.6 Hz,1H),6.98-6.89(m,2H),4.76(m,1H),4.41(m,1H),3.89(s,2H),3.23(m,3H),2.13(m,2H),1.82 (m,2H),1.36(d,J=6.4Hz,3H);ESI-MS m / z:494.1[M+H] + .

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Abstract

The invention relates to novel pyridine compounds as well as a preparation method and use thereof. Specifically, the invention relates to compounds represented by a formula (1) and a preparation method thereof, and the use of the compounds represented by the formula (1) and pharmaceutically acceptable salt or ester thereof as Aurora Kinase inhibitors in preparation of antitumor drugs. The formula(1) is shown in the specification.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and more specifically relates to a new compound with inhibitory effect on Aurora Kinase, a preparation method thereof and the use of the compound in the preparation of antitumor drugs. Background technique [0002] Aurora kinases are a novel class of threonine / serine protein kinases that play crucial roles in important mitotic processes such as centrosome duplication, bipolar spindle formation, chromosome rearrangement, and chromosome checkpoint monitoring [Cancer Metastasis Rev., 2003, 22, 451]. Currently, there are three structurally and functionally related Aurora kinase subtypes in human cells: Aurora-A, Aurora-B and Aurora-C. Aurora-A is located around the centrosome in prophase, on microtubules near the spindle in midphase, and on polar microtubules in anaphase and telophase. It is mainly responsible for the duplication and separation of centrosomes, the aggregation of bipolar spindles,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/14C07D401/14A61K31/4545A61P35/02A61P35/00
CPCC07D417/14C07D401/14A61P35/02A61P35/00A61K31/4545C07B2200/05C07D471/14
Inventor 樊后兴谢雨礼
Owner WIGEN BIOMEDICINE TECH SHANGHAI CO LTD