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Triaromatic ring compounds targeting STAT3 bifunctional phosphorylation site and application thereof

A dual-function, phosphorylation technology, applied in the field of medicine, can solve problems such as limited application prospects and weak anti-tumor activity

Active Publication Date: 2021-02-02
SHANGHAI YUYAO BIOTECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Existing STAT3 inhibitors mainly target and inhibit STAT3 by regulating the canonical STAT3 signaling pathway Y705 The site inhibits the transcriptional activity of STAT3, but clinical results and related articles show that its anti-tumor activity in vivo is weak, and its application prospects are limited

Method used

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  • Triaromatic ring compounds targeting STAT3 bifunctional phosphorylation site and application thereof
  • Triaromatic ring compounds targeting STAT3 bifunctional phosphorylation site and application thereof
  • Triaromatic ring compounds targeting STAT3 bifunctional phosphorylation site and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0140] Example 1, 1-methyl-(6-((5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyrazin-2-yl)oxy)-1H-ind Synthesis of Indol-2-yl)(4-(4-(2,2,2-trifluoroethoxy)benzyl)piperazin-1-yl)methanone (1a).

[0141] Weigh the intermediate 5-((1-methyl-2-(4-(4-(2,2,2-trifluoroethoxy)benzyl)piperazine-1-carbonyl)-1H-indole- 6-yl)oxy)pyrazine-2-carboxylic acid (284 mg, 0.5 mmol), benzamide oxime (136 mg, 1.0 mmol) and HATU (380 mg, 1.0 mmol) were dissolved in 5 ml of DMF, and DIEA ( 0.17ml, 1.0mmol) and stirred at room temperature for 8 hours. After the reaction was detected by TLC, 50 milliliters of distilled water was added, and the precipitated solid was filtered and dried for subsequent use; the dried solid was dissolved in DMF and heated to 140 degrees for 4 hours to obtain the target product 1-methyl-(6 -((5-(3-Phenyl-1,2,4-oxadiazol-5-yl)pyrazin-2-yl)oxy)-1H-indol-2-yl)(4-(4 -(2,2,2-Trifluoroethoxy)benzyl)piperazin-1-yl)methanone (1a, 167 mg, 50%). 1 H NMR (500MHz, CDCl 3)δ9.01(d, J=1.3Hz, 1H)...

Embodiment 2

[0142] Example 2, (6-((5-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)pyrazin-2-yl)oxy)-1-methyl Synthesis of 1H-indol-2-yl)(4-(4-(2,2,2-trifluoroethoxy)benzyl)piperazin-1-yl)methanone (1b)

[0143] According to the synthetic method of Example 1, benzamide oxime (136mg, 1.0mmol) was replaced with 4-fluorobenzamide oxime (154mg, 1.0mmol) to obtain the target product (6-((5-(3-(4- Fluorophenyl)-1,2,4-oxadiazol-5-yl)pyrazin-2-yl)oxy)-1-methyl-1H-indol-2-yl)(4-(4- (2,2,2-Trifluoroethoxy)benzyl)piperazin-1-yl)methanone (1b, 297 mg, 87%). 1 H NMR (500MHz, CDCl 3 )δ9.00(d, J=1.2Hz, 1H), 8.64(d, J=1.2Hz, 1H), 8.20(dd, J=8.8, 5.4Hz, 2H), 7.68(d, J=8.6Hz, 1H), 7.30(d, J=8.1Hz, 2H), 7.22-7.18(m, 3H), 6.97(dd, J=8.5, 2.0Hz, 1H), 6.92(d, J=8.6Hz, 2H), 6.62(s,1H),4.35(q,J=8.1Hz,2H),3.88-3.75(m,7H),3.54-3.53(m,2H),2.51-2.50(m,4H). 13 C NMR (125MHz, CDCl 3 )δ172.79,168.51,165.88,163.87,162.66,162.20,149.07,142.79,138.22,136.39,133.41,130.71,130.03,129.96,124.77,122.90,122.73,122.71,116.34,1...

Embodiment 3

[0144] Example 3, (6-((5-(3-(2-fluorophenyl)-1,2,4-oxadiazol-5-yl)pyrazin-2-yl)oxy)-1-methyl Synthesis of 1H-indol-2-yl)(4-(4-(2,2,2-trifluoroethoxy)benzyl)piperazin-1-yl)methanone (1c)

[0145] According to the synthetic method of Example 1, benzamide oxime (136mg, 1.0mmol) was replaced with 2-fluorobenzamide oxime (154mg, 1.0mmol) to obtain the target product (6-((5-(3-(2- Fluorophenyl)-1,2,4-oxadiazol-5-yl)pyrazin-2-yl)oxy)-1-methyl-1H-indol-2-yl)(4-(4- (2,2,2-Trifluoroethoxy)benzyl)piperazin-1-yl)methanone (1c, 212 mg, 62%). 1 HNMR (500MHz, CDCl 3 )δ9.02(d, J=1.3Hz, 1H), 8.65(d, J=1.3Hz, 1H), 8.21(td, J=7.6, 1.7Hz, 1H), 7.68(d, J=8.6Hz, 1H),7.55-7.51(m,1H),7.33-7.29(m,3H),7.25(d,J=6.5Hz,1H),7.22(d,J=1.9Hz,1H),6.98(dd,J =8.5,2.1Hz,1H),6.92(d,J=8.5Hz,2H),6.63(s,1H),4.35(q,J=8.1Hz,2H),3.88-3.75(m,7H),3.53 -3.52(m,2H),2.51-2.50(m,4H). 13 C NMR (125MHz, CDCl 3 )δ172.34,166.21,166.17,162.67,162.22,149.09,142.88,138.24,136.40,133.38,133.24,133.17,131.13,130.69,124.76,124.6...

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Abstract

The invention discloses triaromatic ring compounds targeting an STAT3 bifunctional phosphorylation site. The triaromatic ring compounds are compounds shown as formulas (I)-(V) or pharmaceutically acceptable salts, hydrates, solvates, metabolites or prodrugs thereof. The invention further provides a pharmaceutical composition containing the compounds shown in the formulas (I)-(V). The invention also provides application of the triaromatic ring compounds in preparation of medicines for preventing and / or treating diseases caused or regulated by STAT3 bifunctional phosphorylation site activation.

Description

technical field [0001] The present invention relates to the field of medical technology, in particular to a class of high-efficiency, novel and specific triaromatic ring compounds and related analogs targeting STAT3 bifunctional phosphorylation site inhibition, as well as such compounds or pharmaceutical compositions containing such compounds Application in the preparation of medicines for treating various malignant tumors and diseases related to tumor metastasis. Background technique [0002] Mitochondria are the factories of energy and metabolites in cells, and are an important part of maintaining the life activities of the body. Under normal physiological conditions, the body provides energy and metabolites through mitochondrial oxidative phosphorylation, but this process is mainly completed through glycolysis in tumor cells. The latest research has found that the oxidative phosphorylation of mitochondria in tumor cells is also involved in the glycolysis process (aerobic...

Claims

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Application Information

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IPC IPC(8): C07D413/14A61K31/497A61P35/00A61P13/12A61P11/00A61P19/02A61P17/06A61P37/02A61P29/00A61P1/04
CPCC07D413/14A61P35/00A61P13/12A61P11/00A61P19/02A61P17/06A61P37/02A61P29/00A61P1/04A61K31/497A61K45/06
Inventor 陈益华周文波陈煌易正芳逄秀凤刘明耀
Owner SHANGHAI YUYAO BIOTECH LTD
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