Quinazolinone USP7 inhibitor as well as preparation method and application thereof

A quinazolinone and inhibitor technology, which is applied in the field of quinazolinone USP7 inhibitors and their preparation, can solve problems such as few reports of USP7 inhibitors, and is convenient for mass production and commercial application, and has few by-products. , the effect of mild reaction conditions

Active Publication Date: 2020-12-08
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In recent years, there have been more and more researches on USP7, but most of them are to explain the role of USP7 in the process of disease, and there are few reports on USP7 inhibitors

Method used

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  • Quinazolinone USP7 inhibitor as well as preparation method and application thereof
  • Quinazolinone USP7 inhibitor as well as preparation method and application thereof
  • Quinazolinone USP7 inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] compound The synthesis process is as follows:

[0046](1) Synthesis of Compound 3: Dissolve trimethylsulfoxide iodide (3.094g, 14.06mmol, 1.4eqv) in 15mL of anhydrous DMSO, and add sodium hydride (0.562g, 14.06mmol, 1.4eqv, 60% in kerosene), after adding, stir at 0°C for 30 minutes, add N-Boc-4-piperidone (2.0g, 10.04mmol, 1.0eqv), add at this temperature Stirring was continued for 4 hours; 40 mL of water was added, extracted with ethyl acetate (3×90 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was subjected to column chromatography (PE:EA=10:1, then PE:EA=5:1) to obtain compound 3 (1.285g, white waxy solid, yield 60%). 1 H NMR (400MHz, Chloroform-d) δ 3.71 (dt, J = 9.9, 4.9Hz, 2H), 3.43 (ddd, J = 13.3, 9.5, 3.7Hz, 2H), 2.69 (s, 2H), 1.80 ( ddd,J=13.8,9.4,4.5Hz,2H),1.47(s,11H). 13 C NMR (101MHz, Chloroform-d) δ154.79, 79.73, 77.28, 57.16, 53.74, 42.49, 28.44.

[0047] (2) Synthes...

Embodiment 2

[0051] compound The synthesis process is as follows:

[0052] Wherein the process of step (1) to (3) is with embodiment 1;

[0053] 3-phenylpropionic acid was replaced by benzoic acid, and other operations were the same as in Example 1 to obtain compound I-2 (colorless oil, yield 85%). 1 H NMR (400MHz, DMSO-d 6 )δ8.31(s,1H),8.16(d,J=8.6Hz,1H),7.75(d,J=2.1Hz,1H),7.57(dd,J=8.5,2.1Hz,1H),7.47– 7.42(m,3H),7.39(dd,J=6.7,3.0Hz,2H),5.05(s,1H),4.21(s,1H),4.04(s,2H),3.27(s,1H),3.15 (s,1H),1.63(s,2H),1.54(s,1H),1.36(d,J=13.6Hz,1H). 13 C NMR (101MHz, DMSO-d 6 )δ168.90, 160.18, 150.38, 148.98, 138.87, 136.30, 129.27, 128.41, 128.34, 127.12, 126.62, 126.19, 120.34, 69.40, 53.85. HRMS (ESI): Calcd.C 21 h 20 ClN 3 o 3 ,[M+H] + , m / z: 398.1193, found: 398.1262.

Embodiment 3

[0055] compound The synthesis process is as follows:

[0056] Wherein the process of step (1) to (3) is with embodiment 1;

[0057] 3-phenylpropionic acid was replaced by 2-pyrrole carboxylic acid, and other operations were the same as in Example 1 to obtain compound I-3 (brown solid, yield 45%). Melting point: 116.8-116.9°C. 1 H NMR (400MHz, DMSO-d 6 )δ11.41(s,1H),8.32(s,1H),8.17(d,J=8.6Hz,1H),7.76(d,J=2.2Hz,1H),7.58(dd,J=8.6,2.1 Hz, 1H), 6.87(s, 1H), 6.46(s, 1H), 6.10(q, J=2.8Hz, 1H), 5.04(s, 1H), 4.20–3.94(m, 4H), 3.30(s ,1H),1.72–1.55(m,2H),1.48(d,J=13.4Hz,2H). 13 C NMR (101MHz, DMSO-d 6 )δ161.39,160.18,150.39,148.99,138.89,128.44,127.15,126.21,124.37,120.82,120.34,111.34,108.22,69.50,53.81,34.75. 19 h 19 ClN 4 o 3 ,[M+H] + , m / z: 387.1146, found: 387.1208.

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Abstract

The invention discloses a quinazolinone USP7 inhibitor, which has a structure shown in a general formula I, has a good inhibition effect on ubiquitin-specific protease 7, can be used for preparing a medicine for inhibiting the ubiquitin-specific protease 7, and shows good inhibition activity on a gastric cancer cell line, especially an MGC803 cell line. A lead compound structure is provided for anti-cancer drugs, and the compound has a good application prospect. The invention further provides a preparation method of the quinazolinone USP7 inhibitor. The preparation method is simple, mild in reaction condition, few in by-product, high in reaction yield and convenient for batch production and commercial application.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a quinazolinone USP7 inhibitor and a preparation method and application thereof. Background technique [0002] The process of covalent binding of ubiquitin to target protein is called ubiquitination, which is a post-translational modification process of protein, which mainly regulates the stability, function and intracellular localization of target protein. In eukaryotic cells, the selective degradation of many short cycle proteins is achieved by the ubiquitin-proteasome pathway. In recent years, more and more studies have shown that the abnormal regulation of this pathway can cause many diseases, such as immune diseases, neurological diseases and tumors. [0003] Deubiquitinase is an important protease in the ubiquitin-proteasome pathway, which can deubiquitinate the ubiquitinated protein, and then reverse the fate of the protein being degraded by the proteasome. The human g...

Claims

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Application Information

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IPC IPC(8): C07D405/14C07D401/06A61P35/00
CPCC07D405/14C07D401/06A61P35/00
Inventor 刘宏民李鹏王志茹郑一超刘瀛
Owner ZHENGZHOU UNIV
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