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Nitrogen-containing heterocyclic compounds as well as pharmaceutical composition and application thereof

A compound and heterocyclic technology, applied in the field of nitrogen-containing heterocyclic compounds and their pharmaceutical compositions, can solve problems such as weak activity

Active Publication Date: 2022-05-27
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the binding constant (Kd) of the small molecule inhibitors reported by them to the RIOK2 protein is above 150nM, and the activity is relatively weak

Method used

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  • Nitrogen-containing heterocyclic compounds as well as pharmaceutical composition and application thereof
  • Nitrogen-containing heterocyclic compounds as well as pharmaceutical composition and application thereof
  • Nitrogen-containing heterocyclic compounds as well as pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] 8-(6-Methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-trifluoromethylphenyl)-imidazo[1,5-a]quinoxaline -4(5H)-ketone (RI-101)

[0083] 8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)imidazo[1,5-a]quinoxalin-4(5H)-one(RI -101)

[0084]

[0085] Synthesis of compound 1-2a: In a 500 ml reaction flask, compound 1-1a (24 g, 100 mmol), N-Boc-piperazine (22.35 g, 120 mmol) and K 2 CO 3 (20.73 g, 150 mmol) was added to DMSO (100 ml), and the reaction was heated at 120° C. for 24 h. The reaction was completed, quenched by adding water, extracted with ethyl acetate (200ml×3), washed with water and saturated sodium chloride solution, the organic layers were combined, dried over anhydrous sodium sulfate, and rotary-evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography ( ethyl acetate:petroleum ether=1:10) to obtain compound 1-2a as a white solid 13g with a yield of 31%. 1 H NMR (400MHz, CDCl 3 )δ7....

Embodiment 2

[0094] 8-(6-Ethoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-trifluoromethylphenyl)-imidazo[1,5-a]quinoxaline -4(5H)-ketone (RI-102)

[0095] 8-(6-ethoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)imidazo[1,5-a]quino xalin-4(5H)-one( RI-102)

[0096]

[0097] The synthesis method was the same as that of Example 1, the white solid was 0.2 g, and the yield was 72%.

[0098] 1 H NMR (400MHz, CD 3 OD)δ8.08(s,2H),8.00(d,J=7.6Hz,1H),7.85(s,1H),7.81(d,J=8.0Hz,1H),7.57-7.59(m,2H) ,7.40(d,J=8.4Hz,1H),7.21(s,1H),6.71(d,J=8.4Hz,1H),4.32(q,J=6.8Hz,2H),3.16-3.21(m, 8H), 1.39 (t, J=6.8Hz, 3H); ESI-MS: m / z 535.1[M+H] + .

Embodiment 3

[0100] 1-(4-(Piperazin-1-yl)-3-trifluoromethylphenyl)-8-(pyridin-3-yl)-imidazo[1,5-a]quinoxaline-4(5H) - Ketone (RI-103)

[0101] 1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-8-(pyridin-3-yl)imidazo[1,5-a]quinoxalin-4(5H)-one(RI-103 )

[0102]

[0103] The synthesis method was the same as that of Example 1, the white solid was 0.13 g, and the yield was 78%.

[0104] 1 H NMR (400MHz, CD 3 OD)δ8.47-8.49(m,1H),8.44(d,J=1.6Hz,1H),8.05-8.08(m,2H),7.98(d,J=8.4Hz,1H),7.75(d, J=8.4Hz, 1H), 7.66-7.70(m, 2H), 7.45(d, J=8.4Hz, 1H), 7.38-7.41(m, 1H), 7.36(s, 1H), 2.98-3.11(m ,8H); ESI-MS: m / z 491.1 [M+H] + .

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Abstract

The invention provides a nitrogen-containing heterocyclic compound with a structure as shown in a formula I, or a pharmaceutically acceptable salt, a stereoisomer or a prodrug molecule thereof, and a pharmaceutical composition and application thereof. The compound and the pharmaceutically acceptable salt thereof can effectively inhibit the growth of various tumor cells, and can be used for preparing antitumor drugs.

Description

technical field [0001] The present invention relates to the technical field of chemical medicine, in particular to a class of nitrogen-containing heterocyclic compounds and pharmaceutical compositions and applications thereof. Background technique [0002] Malignant tumor (cancer) is a major malignant disease that threatens human health. Conventional treatments for cancer include radiation, chemotherapy, surgical resection, and drug therapy. However, these methods often have disadvantages such as large side effects, poor treatment effect, and tumor recurrence and metastasis. Therefore, there is an urgent need to develop new therapeutic techniques to address these issues in cancer treatment. Personalized therapy and targeted therapy are seen in recent years as the hope to break through the current bottleneck of cancer treatment. [0003] Tumor molecular targeted therapy is a new treatment method developed based on the regulation of key signaling pathways closely related to...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61P35/00A61P35/02A61K31/4985A61K31/506A61K31/551
CPCC07D487/04A61P35/00A61P35/02
Inventor 蔡倩欧阳溢凡
Owner JINAN UNIVERSITY