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Azaindole derivative containing aza amino acid as well as preparation and application thereof

A technology of heteroindole derivatives and amino acids, which is applied in the field of azaindole derivatives, can solve the problems of lack of influenza virus, and achieve great application value, good inhibitory effect, and low toxicity

Active Publication Date: 2021-06-18
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the process of transcription in eukaryotic cells, the capping of nascent mRNA is an essential process, but because influenza virus does not have the mechanism of synthesizing the cap structure, the virus steals it from the host mRNA by means of cap-snatching. Its cap is used for the synthesis of its own mRNA

Method used

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  • Azaindole derivative containing aza amino acid as well as preparation and application thereof
  • Azaindole derivative containing aza amino acid as well as preparation and application thereof
  • Azaindole derivative containing aza amino acid as well as preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1 N-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-N-neopentylglycine (Aza-01) ;

[0040] step:

[0041] Starting material 1: 3-Bromo-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine

[0042]

[0043] 3-Bromo-1H-pyrrolo[2,3-b]pyridine (10mmol) was dissolved in DMF, and NaH (15mmol) was added in batches under ice-cooling. After reacting for 30min, p-toluenesulfonyl chloride was added. TLC monitoring, after the disappearance of the raw materials, add water to the system to stop the reaction, a large amount of solid precipitated, continue stirring at room temperature for 30 min to completely precipitate the solid. A flesh-pink solid was obtained by suction filtration with a yield of 93%.

[0044] 1 H NMR (500MHz, CDCl 3 )δ8.33(dd, J=5.0,1.5Hz,1H),7.93(d,J=8.5Hz,2H),7.67-7.64(m,2H),7.15(s,1H),7.13-7.10(m ,2H), 2.23(s,3H).

[0045] Raw material 2: Preparation of tert-butyl 2-(2,2-dimethylpropylene)hydrazine-1-carboxylate:

[0046]

[0047]...

Embodiment 2

[0069] Example 2N-cyclopentyl-N-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)glycine (Aza-03)

[0070] Referring to the method of Example 1, except that N-((5-fluoro-2-(1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino )-N-Neopentylglycine ethyl ester was replaced by N-cyclopentyl-N-((5-fluoro-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridine-3- base) pyrimidin-4-yl) amino) glycine ethyl ester. White solid, 49% yield.

[0071] m.p.:>250℃; 1 H NMR (500MHz, DMSO-d 6 )δ12.13(s,1H),9.66(s,1H),8.9(d,J=7.5Hz,1H),8.25(dd,J=5.0,2.0Hz,1H),8.16(d,J=4.0 Hz,1H),8.10(s,1H),7.17-7.14(m,1H),3.70-3.65(m,1H),3.37(s,2H),1.67-1.65(m,6H),1.50-1.48( m,2H). 13 C NMR (125MHz, DMSO-d 6 )δ173.9, 158.5(d, J=6.25Hz), 152.1(d, J=7.50Hz), 149.1, 143.1, 142.1(d, J=261.25Hz), 130.4, 128.2(d, J=3.75Hz), 125.6 ,118.3,116.6,113.6,65.7,58.3,30.8,23.8.HRMS(ESI):m / z calcd for(C 18 h 19 FN 6 o 2 +H) + :371.1626; found: 371.1623.

Embodiment 3

[0072] Example 3 N-cyclohexyl-N-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)glycine (Aza-04)

[0073] Referring to the method of Example 1, except that N-((5-fluoro-2-(1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino )-N-Neopentylglycine ethyl ester was replaced by N-cyclohexyl-N-((5-fluoro-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl ) pyrimidin-4-yl) amino) glycine ethyl ester. White solid, yield 51%.

[0074] m.p.:>205.5-206.9℃; 1 H NMR (500MHz, DMSO-d 6 )δ12.09(s,1H),8.69(dd,J=8.0,1.5Hz,1H),8.27(dd,J=4.5,1.5Hz,1H),8.17-8.16(m,2H),7.20-7.17 (m,1H),4.79(s,2H),4.35–4.27(m,1H),1.86-1.82(m,2H),1.80-1.73(m,4H),1.68-1.66(m,1H),1.44 –1.37(m,2H),1.17-1.17(m,1H). 13 C NMR (125MHz, DMSO-d 6 )δ157.5(d, J=5.00Hz), 152.4(d, J=1.25Hz), 149.1, 143.3(d, J=253.75Hz), 143.1, 129.6, 128.7, 125.5, 118.0, 116.6, 113.5, 57.4 ,49.4,32.1,28.9,25.3.HRMS(ESI):m / z calcd for(C 19 h 21 FN 6 o 2 +H) + :385.1783; found: 385.1779.

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Abstract

The invention provides an azaindole derivative containing aza amino acid as well as preparation and application thereof. The compound has a good inhibition effect on influenza viruses in vitro, IC50 and EC50 in anti-influenza virus polymerase and anti-influenza virus replication reach the nanomole level, the toxicity of the compound is small, CC50 of most of the compound on MDCK cells and A549 cells is 30 muM or above, and the selectivity of the compound is good. The compound provided by the invention aims at the PB2 subunit of influenza virus RNA polymerase, can be used for preparing anti-influenza drugs, can solve the problem of drug resistance of the existing clinical anti-influenza drugs, and has a relatively high application value. The structural general formula (I) of the derivative is shown in the specification,.

Description

technical field [0001] The invention belongs to the field of pharmacy, and specifically relates to an azaindole derivative of nitrogen-containing heteroamino acid, a preparation method, an intermediate, and an application thereof. Background technique [0002] Influenza viruses can be divided into four types: A, B, C and D. The main ones that can cause human diseases are influenza A virus and influenza B virus. Each year, between 300,000 and 500,000 people die from seasonal flu. Since there is no effective method to accurately predict influenza virus strains in each influenza season or before a pandemic, vaccination against influenza has major limitations. Therefore, small molecule anti-influenza drugs are very important in the prevention and treatment of influenza. Antiviral drugs currently on the market mainly include oseltamivir, zanamivir and peramivir targeting neuraminidase inhibitors; adamantane and amantadine targeting M2 ion channels; Baloxavir, which targets the...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61P31/16
CPCC07D471/04A61P31/16Y02P20/55
Inventor 陈文腾应智敏王思函邵加安杜雨棽俞永平
Owner ZHEJIANG UNIV
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