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PI3Kalpha selective inhibitor and preparation method and application thereof

A technology selected from C3-C8, applied in non-central analgesics, anti-inflammatory agents, pharmaceutical formulations, etc., can solve the problems of unsatisfactory clinical results and achieve good inhibitory effect

Active Publication Date: 2021-08-03
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, for the PI3Kα inhibitors currently under development, the clinical feedback on solid tumors is not only effective for breast cancer, but the clinical results of other solid tumors are not satisfactory. Therefore, researchers need to explore new PI3Kα selective inhibitors. in the treatment of more cancers

Method used

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  • PI3Kalpha selective inhibitor and preparation method and application thereof
  • PI3Kalpha selective inhibitor and preparation method and application thereof
  • PI3Kalpha selective inhibitor and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0116] 1) 5-(4-(4-(methylsulfonyl)piperazin-1-yl)-6-morpholino-1,3,5-triazin-2-yl)benzo[d]oxazole -Synthesis of 2-amine (I-1):

[0117]

[0118] Dissolve intermediates M2 (100mg, 1.0eq.) and M12 (91mg, 1.0eq.) in ethylene glycol dimethyl ether, dissolve sodium carbonate (74.2mg, 2.0eq.) as a base with a small amount of water and add to the reaction flask , added tetrakis(triphenylphosphine)palladium (40.5mg, 0.1eq.) as a catalyst, protected by argon, and reacted at 92°C for 24h. The reaction was monitored by TLC. After the reaction was completed, it was filtered while hot to remove salt and metal catalysts. The remaining reaction solution was extracted with DCM for 3 times. The organic layer was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and further purified by flash preparative liquid chromatography, white Solid 109mg, yield 68%, 1 H NMR (400MHz, DMSO-d 6 )δ8.16(d, J=1.7Hz, 1H), 8.08(dd, J=8.3, 1.7Hz, 1H), 7.53(s, 2H), 7.39(d, J=8.3Hz, 1H)...

Embodiment 2

[0120] 2) 5-(4-(4-ethylpiperazin-1-yl)-6-morpholino-1,3,5-triazin-2-yl)benzo[d]oxazol-2-amine Synthesis of (I-2):

[0121]

[0122] With reference to the synthesis of Example 1, white solid, yield 82%, 1 H NMR (400MHz, DMSO-d 6 )δ8.13(d, J=1.6Hz, 1H), 8.06(dd, J=8.4, 1.7Hz, 1H), 7.52(s, 2H), 7.37(d, J=8.4Hz, 1H), 3.79– 3.64(m,12H),2.41–2.35(m,6H),1.03(t,J=7.1Hz,3H)ppm; HRMS(ESI)m / z calcd.forC 20 h 26 N 8 o 2 (M+H)+411.2251, found: 411.2247.

Embodiment 3

[0124] 3) 5-(4-(4-isopropylpiperazin-1-yl)-6-morpholino-1,3,5-triazin-2-yl)benzo[d]oxazole-2- Synthesis of amine (I-3):

[0125]

[0126] With reference to the synthesis of Example 1, white solid, yield 67%, 1 H NMR (400MHz, DMSO-d 6 )δ8.14(d, J=1.6Hz, 1H), 8.06(dd, J=8.4, 1.7Hz, 1H), 7.52(s, 2H), 7.38(d, J=8.4Hz, 1H), 3.86– 3.65(m,12H),2.73-2.66(m,1H),2.51-2.47(m,4H),0.99(d,J=6.5Hz,6H)ppm; HRMS(ESI)m / zcalcd.for C 21 h 28 N 8 o 2 (M+H) + 425.2408,found: 425.2406.

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Abstract

The invention discloses a PI3Kalpha selective inhibitor and a preparation method and application thereof, a triazine ring benzoxazole compound and a preparation method and application thereof, and the structural formula of the compound is shown as a formula I or a pharmaceutically acceptable salt thereof. Biochemical activity tests show that the compounds have good inhibitory activity on PI3K alpha, so that the compounds can provide effective inhibitors with better selectivity for treatment of diseases regulated by PI3K, and target drugs for treating diseases related to PI3K signal pathways, such as gastric cancer, breast cancer, ovarian cancer and leukemia, are expected to be developed.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a PI3Kα selective inhibitor and its preparation method and application. Background technique [0002] Cancer has been considered to be the main cause of death in every country in the world, and it seriously threatens human life and health. Globally, there will be 19.3 million new cancer cases and nearly 10 million cancer deaths in 2020, according to the latest research report from the International Agency for Research on Cancer. So regardless of the level of human development, this disease is a significant cause of morbidity and mortality around the world. At present, the clinical drugs for cancer treatment are mainly divided into traditional cytotoxic drugs and new molecular targeted drugs. In recent years, targeted molecular drugs have begun to enter the center stage of the global anti-cancer market due to the fact that targeted molecular drugs have a clearer ta...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/04C07D413/14C07D417/04A61K31/5377A61K31/53A61P35/00A61P37/06A61P29/00
CPCC07D413/04C07D413/14C07D417/04A61P35/00A61P37/06A61P29/00
Inventor 杨鹏张芳后毅闵文剑袁凯谢胜男
Owner CHINA PHARM UNIV
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