CN116265440B - A salicylic acid spliced pyridone compound and its preparation method and application - Google Patents

Abstract

The invention discloses a salicyl ketone spliced pyridone compound, which is prepared by carrying out Michael addition initiated ring opening and re-closing reaction on various substituted 3-alkene chromone oxindole/benzofuranone 1 and various amine sources 2 in a solvent under the action of no catalyst and room temperature, wherein the salicyl ketone spliced pyridone compound 3 comprises a potential bioactive salicyl ketone skeleton and pyridone, can provide a compound source for bioactive screening, and has important application value for the screening of medicines and the pharmaceutical industry. And the skeleton compound can be used as a novel potential inhibitor of coronavirus 3CL hydrolase. The invention has simple and easy operation, cheap and easily obtained raw material synthesis, can be carried out in various organic solvents, has better air stability and wide applicability, and has good compatibility for various substituents.

Description

A salicylic acid spliced pyridone compound and its preparation method and application

Technical Field

The invention relates to the fields of chemical technology and pharmaceutical technology, in particular to a salicylic acid-spliced pyridone compound and a preparation method and application thereof.

Background Art

According to the active skeleton splicing principle of drug design, splicing two or more biologically active skeletons into a multi-skeleton molecule with potential biological activity is an extremely important research field in organic chemistry and medicinal chemistry. (1) Salicylone skeleton is widely present in many natural products and has strong biological activity, such as Tenellone A, Oxybenzone, Dioxybenzone, Mexenone and Sulisobenzone. These compounds play an important role in relieving pain and economic development. (2) Pyridone skeleton is also widely present in many natural products, such as Tenellin, Ilicicolin H, LeporinA, Leporin B and Sambutoxin, and occupies an important position in alkaloids. Due to its obvious biological activity and unique structure, it has attracted extensive attention from many chemists and medicinal chemistry teams. Given that the salicylone skeleton and pyridone skeleton have potential biological activity. Therefore, splicing the tea fragrance ketone skeleton to the oxidized indole skeleton to synthesize a series of new potential multi-active functional group salicylone spliced pyridone compounds can provide a compound source for biological activity screening, which has important application value for drug screening and the pharmaceutical industry.

The novel coronavirus 3CL hydrolase (3CLpro) can cut the viral replicase polyprotein into necessary functional proteins during viral replication. Therefore, it is of great significance to use the novel coronavirus 3CL hydrolase as a therapeutic target for COVID-19 for drug screening. Molecular docking technology can analyze the potential inhibitory effect of active ingredients through the chemical binding of specific targets and ligands.

Summary of the invention

The purpose of the present invention is to provide a salicylic acid spliced pyridone compound and a preparation method and application thereof. The salicylic acid spliced pyridone compound is an important class of pharmaceutical intermediate analogs and drug molecule analogs, has important application value in drug screening and the pharmaceutical industry, and the synthesis method thereof is very economical and simple.

The present invention also found that this type of compound can be used as a pharmaceutical inhibitor of the novel coronavirus 3CL hydrolase.

The present invention is achieved by: a salicylic acid-splicing pyridone compound having the following general formula (I):

In the formula, R ¹ is fluorine, chlorine, methoxy, hydroxyl or hydrogen; R ² is fluorine, chlorine, bromine, isopropyl, methyl, methoxy or hydrogen; R' is alkyl or hydrogen; X is NBoc or O.

Specifically, it is one of the following compounds:

The preparation method of salicylic acid spliced pyridone compounds comprises the following steps: various substituted 3-olefin chromone oxidized indole/benzofuranone 1 are reacted with various amine sources 2 in a solvent in the absence of a catalyst and at room temperature to undergo Michael addition-induced ring opening and re-ring closure reactions to obtain salicylic acid spliced pyridone compounds 3.

The synthetic route is exemplified as follows:

In the formula, R ¹ is fluorine, chlorine, methoxy, hydroxyl or hydrogen; R ² is fluorine, chlorine, bromine, isopropyl, methyl, methoxy or hydrogen; R' is alkyl or hydrogen; X is NBoc or O.

The reaction mechanism is exemplified below:

The various amine sources 2 are ammonium acetate, ammonium bicarbonate, ammonium carbonate, ammonia water or alkylamine.

The organic solvent is water, toluene, ethanol, dichloromethane, chloroform or acetonitrile.

Various substituted 3-olefin chromone oxidized indole/benzofuranone 1 are reacted with various amine sources 2 in a solvent in the absence of a catalyst and at room temperature to undergo Michael addition-induced ring opening and re-ring closure reactions to obtain salicylic acid-spliced pyridone compounds 3, with a reaction time of 2-6 hours.

Pharmaceutical application of salicylic acid-splicing pyridone compounds as potential inhibitors of novel coronavirus 3CL hydrolase.

By adopting the above technical scheme, various substituted 3-olefin chromone oxidized indole/benzofuranone 1 and various amine sources 2 are subjected to Michael addition-induced ring opening and re-ring closing reactions in a solvent without a catalyst and at room temperature to obtain salicylic acid spliced pyridone compounds 3, which contain potential biologically active salicylic acid skeletons and pyridones, and can provide a compound source for biological activity screening, which has important application value for drug screening and the pharmaceutical industry. And the skeleton compound can be used as a potential inhibitor of the new coronavirus 3CL hydrolase. The present invention is simple and easy to operate, the raw material synthesis is cheap and easy to obtain, it can be carried out in various organic solvents, and it also has good air stability, wide applicability, and good compatibility with various substituents.

BRIEF DESCRIPTION OF THE DRAWINGS

Figures 1 and 2 are spectral data of compound 3aa in an embodiment of the present invention;

Figures 3 and 4 are spectral data of compound 3ca of an embodiment of the present invention;

Figures 5 and 6 are the spectral data of compound 3ka of the embodiment of the present invention;

FIG7 is a single crystal image of compounds 3ab and 3ga according to an embodiment of the present invention;

Figure 8 is an information diagram of the novel coronavirus 3CL hydrolase protein of the present invention.

FIG9 is a schematic diagram of the molecular docking model of compounds 3ab and 3ga of the present invention.

DETAILED DESCRIPTION

Example 1 of the present invention: 116.7 mg of 3-olefin chromone oxidized indole 1a (0.30 mmol) and 1.5 mL of ammonia solution were added to a reaction tube in sequence, and the mixture was stirred at room temperature for 5 h. TLC was detected until the reaction was basically completed. After the solvent was dried, it was purified by column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = 7:1) to obtain 106.0 mg of compound 3aa as a light yellow solid, melting point: 189.8-190.5° C.; yield 87%. The results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows: ¹ H NMR (CDCl ₃ , 400MHz)δ:1.36(s,9H),6.81-6.85(m,1H),6.98(d,J＝8.4Hz,1H),7.03-7.07(m,1H),7.14(d,J＝7.6Hz,1H),7.26-7.30(m,1H),7.41-7.45(m,1H),7.50(d,J＝8.0Hz,1H),7.58(s,1H),7.65(br s,1H),7.84(s,1H),7.93(s,1H),11.35(br s,1H),13.14(br s,1H); ¹³ C NMR (CDCl ₃ ,100MHz)δ:27.3,79.4,117.6,117.7,118.2,118.3,123.1,123.6,127.4,128.5,130.0,130.8,135.5,135.8,138.3,141.4,152.8,161.5,162.7,1 94.0; HRMS (ESI-TOF) m/z: Calcd. for C ₂₃ H ₂₂ N ₂ NaO ₅ [M+Na] ⁺ :429.1421; Found: 429.1425.

The preparation methods of compounds 3ab to 3bg are the same as those of compound 3aa, and the feed ratios are the same as those of compound 3aa. The reaction yields are shown in Tables 1 and 2. However, it should be emphasized that the compounds of the present invention are not limited to those shown in Tables 1 and 2.

Table 1 is the chemical structure of a salicylic acid-pyridone compound

Table 2 shows the chemical structure of a salicylic acid-pyridone compound.

In this Example 1, compound 3ab was prepared: yellow solid, melting point: 228.2-229.3°C; yield 82%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.35 (s, 9H), 6.92 (d, J=8.8 Hz, 1H), 7.03-7.07 (m, 1H), 7.13-7.15 (m, 1H), 7.23-7.27 (m, 1H), 7.34-7.37 (m, 1H), 7.45 (s, 1H), 7.48 (s, 1H), 7.63 (br s, 1H), 7.77 (s, 1H), 7.89 (s, 1H), 11.12 (br s, 1H), 12.94 (br s, 1H); ¹³ C NMR (CDCl ₃ ,100MHz)δ:27.3,79.5,117.6,118.6,119.3,122.9,123.7,127.5,128.5,129.5,129.9,130.4,135.2,135.7,138.5,140.8,152.8,159.7,162.5,1 92.9; HRMS (ESI-TOF) m/z: Calcd. for C ₂₃ H ₂₁ ClN ₂ NaO ₅ [M+Na] ⁺ :463.1031; Found: 463.1026.

In this Example 1, compound 3ac was prepared: yellow solid, melting point: 200.1-201.3°C; yield 73%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.36 (s, 9H), 6.90 (d, J=9.2 Hz, 1H), 7.06-7.09 (m, 1H), 7.16-7.19 (m, 1H), 7.26-7.31 (m, 1H), 7.46 (s, 1H), 7.49-7.52 (m, 1H), 7.62 (s, 1H), 7.66 (br s, 1H), 7.82 (s, 1H), 7.91 (s, 1H), 11.16 (br s, 1H), 12.92 (br s, 1H); ¹³ C NMR (CDCl ₃ ,100MHz)δ:26.1,78.3,108.6,116.4,118.0,118.5,122.5,128.7,131.3,134.6,136.8,137.2,139.7,151.6,159.0,161.4,191.7; HRMS (ESI-TOF) m/z: Calcd. for C ₂₃ H ₂₁ BrN ₂ NaO ₅ [M+Na] ⁺ :507.0526; Found: 507.0527.

In this Example 1, compound 3ad was prepared: yellow solid, melting point: 192.9-193.5°C; yield 73%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.36 (s, 9H), 2.22 (s, 3H), 6.90 (d, J＝8.8 Hz, 1H), 7.05-7.09 (m, 1H), 7.15-7.18 (m, 1H), 7.24-7.31 (m, 3H), 7.55 (s, 1H), 7.67 (br s, 1H), 7.85 (s, 1H), 7.94 (s, 1H), 11.13 (br s, 1H), 13.16 (br s, 1H); ¹³ C NMR (CDCl ₃ ,100MHz)δ:20.7,28.3,80.4,118.5,118.6,119.5,124.6,128.5,129.5,131.0,131.2,131.4,136.9,137.7,139.1,142.5,153.8,160.5,163.8,19 5.0; HRMS (ESI-TOF) m/z: Calcd. for C ₂₄ H ₂₄ N ₂ NaO ₅ [M+Na] ⁺ :443.1577; Found: 443.1581.

In this Example 1, compound 3ae was prepared: yellow solid, melting point: 165.8-166.3°C; yield 84%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.12 (d, J = 7.2 Hz, 6H), 1.35 (s, 9H), 2.78-2.81 (m, 1H), 6.92 (d, J = 9.2 Hz, 1H), 7.02-7.06 (m, 1H), 7.14-7.17 (m, 1H), 7.24-7.28 (m, 1H), 7.31-7.34 (m, 2H), 7.56 (s, 1H), 7.64 (br s, 1H), 7.82 (d, J = 2.4Hz, 1H), 7.93 (d, J = 2.4Hz, 1H), 11.11 (br s, 1H), 13.06 (br s, 1H); ¹³ C NMR (CDCl ₃ , 100MHz) δ: 23.0, 27.3, 32.2, 79.4, 117.5, 117.6, 118.5,123.5,128.0,128.4,129.9,133.9,135.9,138.1,138.5,141.5,152.7,159.6,162.6,194.0; HRMS(ESI-TOF)m/z:Calcd.for C ₂₆ H ₂₈ N ₂ NaO ₅ [M+Na] ⁺ :471.1890; Found:471.1883.

In this Example 1, compound 3af was prepared: yellow solid, melting point: 237.2-237.8°C; yield 71%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.36 (s, 9H), 2.32 (s, 3H), 6.88 (s, 1H), 7.05-7.08 (m, 1H), 7.15-7.19 (m, 1H), 7.26-7.30 (m, 1H), 7.47 (s, 1H), 7.51 (s, 1H), 7.65 (br s, 1H), 7.81 (s, 1H), 7.91 (s, 1H), 11.23 (br s, 1H), 13.00 (br s, 1H); ¹³ C NMR (CDCl ₃ ,100MHz)δ:19.8,27.3,79.4,116.6,117.9,119.8,123.5,123.6,128.5,129.9,130.0,130.4,135.8,138.0,141.0,144.9,152.7,159.9,162.6,19 2.7; HRMS (ESI-TOF) m/z: Calcd. for C ₂₄ H ₂₃ ClN ₂ NaO ₅ [M+Na] ⁺ :477.1188; Found: 477.1193.

In this Example 1, compound 3ag was prepared: yellow solid, melting point: 151.2-151.9°C; yield 77%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400MHz) δ: 1.36 (s, 9H), 6.84-6.88 (m, 1H), 7.00 (d, J＝8.0Hz, 1H), 7.14 (d, J＝2.4Hz, 1H), 7.24-7.26 (m, 1H), 7.43-7.51 (m, 3H), 7.62 (br s, 1H), 7.92-7.95 (m, 2H); ¹³ C NMR (CDCl ₃ ,100MHz)δ:28.3,80.8,118.6,118.9,119.3,119.4,129.4,129.7,130.5,131.7,135.6,136.7,142.8,153.6,162.6,163.5,194.7; HRMS (ESI-TOF) m/z: Calcd. for C ₂₃ H ₂₁ ClN ₂ NaO ₅ [M+Na] ⁺ :463.1031; Found: 463.1036.

In this Example 1, compound 3ah was prepared: yellow solid, melting point: 208.2-209.7°C; yield 72%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.34 (s, 9H), 3.68 (s, 3H), 6.69 (d, J = 2.8 Hz, 1H), 6.81-6.86 (m, 2H), 6.98 (d, J = 8.0 Hz, 1H), 7.32 (br s, 1H), 7.40-7.45 (m, 2H), 7.49-7.52 (m, 1H), 7.85 (s, 1H), 7.93 (d, J = 2.8 Hz, 1H), 11.35 (br s, 1H), 13.15 (br s, 1H); ¹³ CNMR (CDCl ₃ ,100MHz)δ:28.4,55.6,80.2,114.7,116.0,118.7,119.1,119.3,129.7,130.8,131.8,136.5,139.5,142.2,156.8,162.5,163.5,195.0; HRMS (ESI-TOF )m/z:Calcd.for C ₂₄ H ₂₄ N ₂ NaO ₆ [M+Na] ⁺ :459.1527; Found:459.1531.

In this Example 1, compound 3ai was prepared: yellow solid, melting point: 245.7-246.8°C; yield 90%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 1.37 (s, 9H), 6.97-7.01 (m, 1H), 7.13-7.28 (m, 4H), 7.50-7.53 (m, 1H), 7.90 (s, 2H), 8.41 (br s, 1H), 10.14 (br s, 1H), 12.63 (br s, 1H); ¹³ C NMR (DMSO-d ₆ , 100 MHz) δ: 28.4, 79.4, 115.5 (d, J _CF ＝22.1 Hz), 115.9 (d, J _CF ＝24.4Hz),117.5(d,J _CF ＝20.5Hz),117.6,118.3(d,J _CF ＝7.3Hz),119.4(d,J _CF ＝23.3Hz),126.4(d,J _CF ＝6.7Hz),128.5,133.3,139.7,142.8,151.9,153.7,156.8(d,J _CF ＝233.7Hz),158.9(d,J _CF ＝240.2Hz),161.9,190.3；HRMS(ESI-TOF)m/z:Calcd.for C ₂₃ H ₂₀ F ₂ N ₂ NaO ₅ [M+Na] ⁺ :465.1232；Found:465.1230。

In this Example 1, compound 3aj was prepared: yellow solid, melting point: 223.4-224.3°C; yield 72%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.35 (s, 9H), 6.89-7.02 (m, 3H), 7.37-7.40 (m, 2H), 7.47 (s, 1H), 7.56 (br s, 1H), 7.90-7.92 (m, 1H), 11.10 (br s, 1H), 12.99 (br s, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ: 27.3, 79.7, 115.2 (d, J _CF ＝22.4 Hz), 116.2 (d, J _CF ＝23.4Hz),117.5,118.5,119.4,123.0,129.4,131.8,135.2,138.7,141.0,158.6(d,J _CF ＝237.7Hz),162.3,192.7; HRMS(ESI-TOF)m/z:Calcd.for C ₂₃ H ₂₀ Cl FN ₂ NaO ₅ [M+Na] ⁺ :481.0937; Found: 481.0941.

In this Example 1, compound 3ak was prepared: yellow solid, melting point: 240.5-241.4°C; yield 76%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.13 (d, J = 7.2 Hz, 6H), 1.34 (s, 9H), 2.78-2.82 (m, 1H), 6.88-6.94 (m, 2H), 6.96-7.01 (m, 1H), 7.31-7.35 (m, 2H), 7.44 (s, 1H), 7.57 (br s, 1H), 7.93-7.94 (m, 2H), 11.06 (br s, 1H), 13.07 (br s, 1H); ¹³ C NMR (CDCl ₃ ,100MHz)δ:23.0,27.2,32.2,79.5,115.1(d,J _CF =22.3Hz),116.2(d,J _CF =23.3Hz),117.4,117.7,118.4,127.9,131.8,131.9,134.0,138.5,138.6, 141.7, 152.9, 158.0 (d, J _CF = 240.1Hz), 159.6, 162.3, 193.8; HRMS (ESI-TOF) m/z: Calcd. for C ₂₆ H ₂₇ FN ₂ NaO ₅ [M+Na] ⁺ : 489.1796; Found: 489.1791.

In this Example 1, compound 3a1 was prepared: yellow solid, melting point: 161.4-161.9°C; yield 70%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.33 (s, 9H), 2.22 (s, 3H), 6.88 (d, J＝8.4 Hz, 2H), 6.96-7.01 (m, 1H), 7.24-7.27 (m, 1H), 7.43 (s, 1H), 7.57 (br s, 1H), 7.91-7.93 (m, 2H), 11.07 (br s, 1H), 13.13 (br s, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ: 19.6, 27.2, 79.6, 115.1 (d, J _CF =22.1Hz),116.2(d,J _CF =23.2Hz),117.4,117.6,118.4,127.5,130.2,131.8,136.7,138.4,141.6,152.9,158.7(d,J _CF =243.2Hz),159.6,162.4,1 93.7; HRMS (ESI-TOF) m/z: Calcd. for C ₂₄ H ₂₂ ClFN ₂ NaO ₅ [M+Na] ⁺ :495.1093; Found: 495.1094.

In this Example 1, compound 3am was prepared: yellow solid, melting point: 250.2-251.0°C; yield 84%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 1.35 (s, 9H), 6.94-6.97 (m, 1H), 7.09-7.12 (m, 1H), 7.19-7.24 (m, 1H), 7.34 (d, J＝2.4 Hz, 1H), 7.37-7.40 (m, 1H), 7.55 (d, J＝8.8 Hz, 1H), 7.84-7.87 (m, 2H), 8.47 (br s, 1H), 10.11 (br s, 1H), 12.61 (br s, 1H); ¹³ CNMR (DMSO-d ₆ ,100MHz)δ:28.4,79.7,115.9(d,J _CF =24.4Hz),117.5,118.3(d,J _CF =7.2Hz),119.5(d,J _CF =23.2Hz),126.1,126.3,126.4,128.4,128.6,130.7,132 .1,136.1,139.8,142.9,152.0,153.4,155.7(d,J _CF =235.6Hz),161.9,190.3; HRMS(ESI-TOF)m/z:Calcd.forC ₂₃ H ₂₀ ClFN ₂ NaO ₅ [M+Na] ⁺ :481.0937; Found:481.0941.

In this Example 1, compound 3an was prepared: yellow solid, melting point: 156.4-156.7°C; yield 71%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.37 (s, 9H), 6.98 (d, J = 8.8 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 7.26-7.29 (m, 1H), 7.40-7.43 (m, 2H), 7.49 (d, J = 2.4 Hz, 1H), 7.65 (br s, 1H), 7.92-7.95 (m, 2H), 11.13 (br s, 1H), 12.85 (br s, 1H); ¹³ C NMR (CDCl ₃ ,100MHz)δ:26.3,78.8,116.6,117.4,118.5,122.0,127.4,127.6,128.4,128.5,133.5,134.4,137.6,140.2,158.9,161.2,191.7; HRMS (ESI-TOF) m/z: Calcd. for C ₂₃ H ₂₀ Cl ₂ N ₂ NaO ₅ [M+Na] ⁺ :497.0641; Found: 497.0646.

In this Example 1, compound 3ao was prepared: yellow solid, melting point: 165.4-166.4°C; yield 73%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400MHz) δ: 1.36 (s, 9H), 2.24 (s, 3H), 6.91 (d, J＝8.4Hz, 1H), 7.16 (d, J＝2.4Hz, 1H), 7.25-7.29 (m, 3H), 7.49 (s, 1H), 7.65 (br s, 1H), 7.94-7.96 (m, 2H), 11.08 (br s, 1H), 13.10 (br s, 1H); ¹³ C NMR (CDCl ₃ ,100MHz)δ:19.6,27.3,79.7,117.3,117.7,118.5,127.5,128.4,129.6,130.2,134.6,136.8,138.3,141.8,152.5,159.5,162.3,193.7; HRMS (ESI-TOF )m/z:Calcd.for C ₂₄ H ₂₃ ClN ₂ NaO ₅ [M+Na] ⁺ :477.1188; Found:477.1191.

In this Example 1, compound 3ap was prepared: yellow solid, melting point: 197.7-198.5°C; yield 72%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 1.42 (s, 9H), 6.98-7.01 (m, 1H), 7.15-7.35 (m, 4H), 7.72 (s, 1H), 7.86-7.91 (m, 2H), 8.62 (br s, 1H), 10.15 (br s, 1H), 12.67 (br s, 1H); ¹³ C NMR (DMSO-d ₆ , 100 MHz) δ: 28.4, 80.0, 115.9 (d, J _CF ＝23.2 Hz), 117.6, 118.3 (d, J _CF =8.1Hz),119.4(d,J _CF =23.2Hz),123.2,124.2,126.4,126.5,128.5,128.7,132.9,133.2,138.6,139.9,142.8,151.9,153.3,155.6(d,J _CF =235. 3Hz), 162.0, 190.3; HRMS (ESI-TOF) m/z: Calcd.for C ₂₃ H ₂₀ ClFN ₂ NaO ₅ [M+Na] ⁺ : 481.0937; Found: 481.0951.

In this Example 1, compound 3aq was prepared: yellow solid, melting point: 200.2-200.5°C; yield 90%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 1.40 (s, 9H), 6.98 (d, J = 8.8 Hz, 1H), 7.20-7.23 (m, 1H), 7.30-7.32 (m, 2H), 7.40-7.43 (m, 1H), 7.69 (s, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 8.60 (br s, 1H), 10.41 (br s, 1H), 12.64 (br s, 1H); ¹³ CNMR (DMSO-d ₆ ,100MHz)δ:28.4,80.0,117.6,118.8,123.4,124.2,127.5,128.5,128.8,129.2,132.3,132.9,133.2,138.6,139.9,142.8,153.2,154.4,162.1,1 90.1; HRMS (ESI-TOF) m/z: Calcd. for C ₂₃ H ₂₀ Cl ₂ N ₂ NaO ₅ [M+Na] ⁺ :497.0641; Found: 497.0641.

In this Example 1, compound 3ar was prepared: yellow solid, melting point: 181.4-182.3°C; yield 75%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 1.44 (s, 9H), 6.98 (d, J = 8.8 Hz, 1H), 7.25-7.28 (m, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 2.4 Hz, 1H), 7.57-7.60 (m, 1H), 7.73 (d, J = 1..6 Hz, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 2.8 Hz, 1H), 8.64 (br s, 1H), 10.48 (br s, 1H), 12.68 (br s, 1H); ¹³ C NMR (DMSO-d ₆ ,100MHz) δ: 28.4, 80.0, 110.8, 117.6, 119.3, 123.2, 124.2, 128.0, 128.5, 128.7, 132.0, 132.9, 133.2, 135.2, 138.5, 139. 8,142.8,153.2,154.8,162.0,190.0; HRMS(ESI-TOF)m/z:Calcd.for C ₂₃ H ₂₀ BrClN ₂ NaO ₅ [M+Na] ⁺ :541.0136; Found:541.0142.

In this Example 1, compound 3as was prepared: yellow solid, melting point: 214.5-215.5°C; yield 72%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.34 (s, 9H), 3.70 (s, 3H), 6.70 (d, J = 2.8 Hz, 1H), 6.82-6.85 (m, 1H), 6.94-6.98 (m, 1H), 7.15-7.22 (m, 3H), 7.47 (br s, 1H), 7.88 (s, 1H), 7.92 (d, J = 2.4 Hz, 1H), 10.99 (br s, 1H), 13.04 (br s, 1H); ¹³ C NMR (CDCl ₃ ,100MHz)δ:26.3,53.6,78.3,112.9,114.7(d,J _CF =23.4Hz),116.6(d,J _CF =22.4Hz),118.1,121.9,127.7,137.5,139.7,153.6(d,J _CF =239.9Hz),15 4.9,156.6,161.5,192.0; HRMS(ESI-TOF)m/z:Calcd.for C ₂₄ H ₂₃ FN ₂ NaO ₆ [M+Na] ⁺ :477.1432; Found: 477.1435.

In this Example 1, compound 3at was prepared: yellow solid, melting point: 183.2-184.4°C; yield 84%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 1.36 (s, 9H), 3.77 (s, 3H), 6.87 (d, J = 3.2 Hz, 1H), 6.94-6.97 (m, 1H), 7.00 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.37-7.44 (m, 2H), 7.86-7.88 (m, 2H), 8.15 (br s, 1H), 10.42 (br s, 1H), 12.58 (br s, 1H); ¹³ C NMR (DMSO-d ₆ ,100MHz)δ:28.5,55.8,79.1,114.4,116.0,117.5,118.8,123.4,127.5,129.2,129.7,129.9,132.3,139.5,142.6,153.9,154.4,156.5,162.0,19 0.1; HRMS (ESI-TOF) m/z: Calcd.for C ₂₄ H ₂₃ ClN ₂ NaO ₆ [M+Na] ⁺ :493.1137; Found: 493.1138.

In this Example 1, compound 3au was prepared: yellow solid, melting point: 158.5-158.7°C; yield 87%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 1.27 (s, 9H), 3.68 (s, 3H), 6.78 (d, J = 2.8 Hz, 1H), 6.85-6.88 (m, 2H), 7.28 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.44-7.47 (m, 2H), 8.06 (br s, 1H), 10.36 (br s, 1H), 12.48 (br s, 1H); ¹³ C NMR (DMSO-d ₆ ,100MHz)δ:28.5,55.8,79.1,110.8,114.4,116.0,117.5,119.3,128.1,129.7,129.9,132.0,135.1,139.5,142.6,153.9,154.9,156.5,162.0,19 0.0; HRMS (ESI-TOF) m/z: Calcd.forC ₂₄ H ₂₃ BrN ₂ NaO ₆ [M+Na] ⁺ :537.0632; Found: 537.0627.

In this Example 1, compound 3av was prepared: yellow solid, melting point: 154.8-155.5°C; yield 70%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.13 (d, J = 7.2 Hz, 6H), 1.33 (s, 9H), 2.79-2.82 (m, 1H), 3.70 (s, 3H), 6.71 (d, J = 2.8 Hz, 1H), 6.81-6.84 (m, 1H), 6.93 (d, J = 7.2 Hz, 1H), 7.27-7.35 (m, 3H), 7.47 (br s, 1H), 7.86 (s, 1H), 7.94 (d, J = 2.4 Hz, 1H), 11.13 (br s, 1H), 13.07 (br s, 1H); ¹³ C NMR (CDCl ₃ , 100MHz) δ: 22.3, 26.6, 31.4, 53.8, 78.3, 113.0, 114.3, 116.7, 116.9, 117.6, 127.3, 128.0, 129.2, 133.1, 137.4, 137.8, 140 .5,152.5,155.0,158.9,161.7,193.3; HRMS(ESI-TOF)m/z:Calcd.for C ₂₇ H ₃₀ N ₂ NaO ₆ [M+Na] ⁺ :501.1996; Found:501.1992.

In this Example 1, compound 3aw was prepared: yellow solid, melting point: 152.3-152.9°C; yield 89%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 1.33 (s, 9H), 2.30 (s, 3H), 3.69 (s, 3H), 6.69 (d, J＝3.2 Hz, 1H), 6.79-8.02 (m, 1H), 6.87 (s, 1H), 7.27 (br s, 1H), 7.47-7.48 (m, 2H), 7.83 (d, J＝2.0 Hz, 1H), 7.89 (d, J＝2.4 Hz, 1H), 11.22 (br s, 1H), 13.02 (br s, 1H); ¹³ C NMR (DMSO-d ₆ ,100MHz)δ:19.8,27.3,54.5,79.2,113.9,114.7,116.7,117.6,119.7,123.5,128.7,130.0,130.1,138.3,140.8,144.8,155.8,159.8,162.4,192 .6; HRMS (ESI-TOF) m/z: Calcd. for C ₂₅ H ₂₅ ClN ₂ NaO ₆ [M+Na] ⁺ :507.1293; Found: 507.1297.

In this Example 1, compound 3ba was prepared: yellow solid, melting point: 102.7-102.9°C; yield 91%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 6.84-6.99 (m, 4H), 7.18-7.22 (m, 1H), 7.29-7.42 (m, 3H), 7.75 (s, 1H), 7.93-7.95 (m, 1H), 9.54 (br s, 1H), 10.23 (br s, 1H), 12.43 (br s, 1H); ¹³ C NMR (DMSO-d ₆ ,100MHz)δ:117.0,117.7,119.5,119.7,123.8,125.6,129.0,129.7,130.2,131.2,133.0,139.1,141.6,155.6,155.9,162.3,192.1; HRMS(ESI-TOF)m/ z:Calcd.for C ₁₈ H ₁₃ NNaO ₄ [M+Na] ⁺ :330.0737; Found: 330.0742.

In this Example 1, compound 3bb was prepared: yellow solid, melting point: 100.8-101.2°C; yield 89%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 6.87-7.02 (m, 3H), 7.20-7.34 (m, 4H), 7.81 (d, J＝2.4 Hz, 1H), 7.97 (s, 1H), 9.56 (br s, 1H), 10.15 (br s, 1H), 12.47 (brs, 1H); ¹³ C NMR (DMSO-d ₆ , 100 MHz) δ: 115.9 (d, J _CF ＝24.3 Hz), 116.9, 117.3, 118.1 (d, J _CF ＝7.3 Hz), 119.2 (d, J _CF =23.1Hz),119.5,123.7,126.6,126.7,129.1,129.7,131.2,138.7,142.1,151.8,155.4(d,J _CF =235.5Hz),155.5,162.3,190.5; HRMS(ESI-TOF)m/z:Calc d.forC ₁₈ H ₁₂ FNNaO ₄ [M+Na] ⁺ :348.0643; Found: 348.0641.

In this Example 1, compound 3bc was prepared: yellow solid, melting point: 103.2-104.4°C; yield 92%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 6.89-6.96 (m, 2H), 7.03 (d, J = 8.8 Hz, 1H), 7.23-7.27 (m, 1H), 7.33-7.35 (m, 1H), 7.40 (d, J = 2.8 Hz, 1H), 7.45-7.48 (m, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 9.55 (br s, 1H), 10.43 (br s, 1H), 12.46 (br s, 1H); ¹³ C NMR (DMSO-d 6 , 400 MHz) δ: 6.89-6.96 (m, 2H), 7.03 (d, J = 8.8 Hz, 1H), 7.23-7.27 (m, 1H), 7.33-7.35 (m, 1H), _6,100MHz )δ:116.9,117.2,118.7,119.4,123.3,123.7,127.7,129.1,129.2,129.7,131.2,132.1,138.6,142.1,154.3,155.5,162.3,190.2; HRMS (ESI-TOF) m/z: Calcd. for C ₁₈ H ₁₂ ClNNaO ₄ [M+Na] ⁺ :364.0347; Found: 364.0349.

In this Example 1, compound 3bd was prepared: yellow solid, melting point: 82.5-83.4°C; yield 91%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 3.71 (s, 3H), 6.84-6.91 (m, 4H), 6.98-7.01 (m, 1H), 7.18-7.22 (m, 1H), 7.28-7.30 (m, 1H), 7.76 (d, J＝2.4 Hz, 1H), 7.94 (d, J＝2.8 Hz, 1H), 9.53 (br s, 1H), 9.68 (br s, 1H), 12.41 (br s, 1H); ¹³ C NMR (DMSO-d ₆ ,100MHz)δ:56.0,114.0,117.0,117.6,118.0,119.1,119.5,123.8,126.0,129.0,129.7,131.2,139.0,141.8,149.4,152.5,155.6,162.3,191.6; HRMS(ESI-TOF)m/z:Calcd.forC ₁₉ H ₁₅ NNaO ₅ [M+Na] ⁺ :360.0842; Found: 360.0841.

In this Example 1, compound 3be was prepared: yellow solid, melting point: 123.2-124.3°C; yield 88%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 1.17 (d, J = 7.2 Hz, 6H), 2.81-2.88 (m, 1H), 6.84-6.93 (m, 3H), 7.18-7.22 (m, 2H), 7.26-7.31 (m, 2H), 7.78 (d, J = 2.4 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 9.56 (br s, 1H), 10.04 (br s, 1H), 12.44 (br s, 1H); ¹³ C NMR (DMSO-d ₆ ,100MHz)δ:24.4,32.9,117.0,117.1,117.8,119.6,123.9,125.1,127.7,129.0,129.7,131.0,131.2,139.3,139.6,141.6,154.1,155.6,162.4,1 92.3; HRMS (ESI-TOF) m/z: Calcd. for C ₂₁ H ₁₉ NNaO ₄ [M+Na] ⁺ :372.1206; Found: 372.1211.

In this Example 1, compound 3bf was prepared: yellow solid, melting point: 100.3-101.1°C; yield 90%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 6.67-6.70 (m, 1H), 6.75-6.80 (m, 2H), 7.00-7.03 (m, 1H), 7.21-7.31 (m, 2H), 7.82 (s, 1H), 7.98 (s, 1H), 8.84 (d, J＝7.6 Hz, 2H), 10.14 (br s, 1H), 12.52 (br s, 1H); ¹³ C NMR (DMSO-d ₆ , 100 MHz) δ: 115.9 (d, J _CF ＝24.4Hz),116.5,117.2,117.4,117.9,118.2,119.2(d,J _CF ＝23.0Hz),124.0,126.6(d,J _CF ＝6.1Hz),129.0,138.9,141.9,148.0,150.3,151.8,155 .6(d,J _CF = 234.4Hz), 162.4, 190.5; HRMS (ESI-TOF) m/z: Calcd. for C ₁₈ H ₁₂ FNNaO ₅ [M+Na] ⁺ : 364.0592; Found: 364.0592.

In this Example 1, compound 3bg was prepared: yellow solid, melting point: 120.7-120.9°C; yield 92%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 6.62-6.65 (m, 1H), 6.72 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.77 (s, 1H), 7.93 (s, 1H), 8.79 (d, J = 7.2 Hz, 2H), 10.38 (br s, 1H), 12.48 (br s, 1H); ¹³ C NMR (DMSO-d ₆ ,100MHz)δ:116.6,117.2,117.5,117.9,118.7,123.3,124.0,127.7,129.0,129.2,132.2,138.9,142.0,148.0,150.3,154.3,162.4,190.3; HRMS (ESI -TOF)m/z:Calcd.forC ₁₈ H ₁₂ ClNNaO ₅ [M+Na] ⁺ :380.0296; Found: 380.0291.

Example 2 of the present invention: 116.7 mg of 3-olefin chromone oxidindolone 1a (0.30 mmol), NH ₄ OAc (0.60 mmol) and 1.5 mL of ethanol solution were added to a reaction tube in sequence, and the mixture was stirred at room temperature for 5 h. TLC was used to detect that the reaction was basically completed. After the solvent was dried, the mixture was purified by column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = 7:1) to obtain 103.5 mg of compound 3aa with a yield of 85%.

The preparation method of compound 3 in Table 3 is the same as that of compound 3aa, and the feed ratio is the same as that of compound 3aa. The reaction yield is shown in Table 3, but it should be emphasized that the compounds of the present invention are not limited to the contents shown in Table 3.

Table 3 shows the chemical structure of a salicylic acid-compound spliced with pyridone

Example 3 of the present invention: 116.7 mg of 3-olefin chromone oxidized indole 1a (0.30 mmol), alkylamine (0.60 mmol) and 1.5 mL of ethanol solution were added to a reaction tube in sequence, and the reaction was stirred at room temperature for 5 h. TLC was detected until the reaction was basically completed. After the solvent was dried, it was purified by column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = 7:1) to obtain 119.7 mg of compound 3ca as a light yellow solid, melting point: 99.2-99.8°C; yield 86%. The results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows: ¹ H NMR (CDCl ₃ , 400MHz)δ:1.40(s,9H),3.31(s,3H),3.66-3.68(m,1H),4.23-4.25(m,1H),6.85-6.89(m,1H),7.00(d,J＝8.4Hz,1H),7.04-7.08(m,1H),7.14-7.16(m,1H),7.29-7.33(m,1H),7.42-7.47(m,1H),7.59-7.62(m,2H),7.71-7.74(m,1H),7.86(d,J＝2.4Hz,1H),8.02(d,J＝2.8Hz,1H),11.45(br s, 1H); ¹³ C NMR (CDCl ₃ , 100MHz) δ: 28.4, 51.2, 59.1, 69.7, 79.9, 117.2, 118.7, 118.8, 119.0, 124.0, 129.0, 129.3, 131.0, 132.0, 136.4, 137.0, 140 .7,144.2,153.8,161.4,162.7,195.2; HRMS(ESI-TOF)m/z:Calcd.for C ₂₆ H ₂₈ N ₂ NaO ₆ [M+Na] ⁺ :487.1840; Found: 487.1843.

The preparation methods of compounds 3cb to 3lc are the same as those of compound 3ca, and the feed ratios are the same as those of compound 3ca. The reaction yields are shown in Tables 4 to 5. However, it should be emphasized that the compounds of the present invention are not limited to those shown in Tables 4 to 5.

Table 4 shows the chemical structure of a salicylic acid-compound spliced with pyridone

Table 5 is the chemical structure of a salicylic acid-pyridone compound

In this Example 3, compound 3cb was prepared: yellow solid, melting point: 99.0-99.8°C; yield 90%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400MHz) δ: 1.41 (s, 9H), 3.32 (s, 3H), 3.66-3.68 (m, 1H), 4.24-4.26 (m, 1H), 6.85-6.89 (m, 1H), 6.99-7.08 (m, 3H), 7.43-7.47 (m, 1H), 7.58-7.60 (m, 1H), 7.66 (s, 1H), 7.83 (br s, 1H), 8.03 (d, J=2.4Hz, 1H), 11.41 (br s, 1H); ¹³ C NMR (CDCl ₃ ,100MHz)δ:27.3,50.2,58.1,68.6,79.4,116.2,117.7,117.8,118.0,122.3,123.1,125.9,128.9,130.9,134.1,135.5,137.2,139.8,143.4,152. 3,160.2,161.6,194.0; HRMS(ESI-TOF)m/z:Calcd.for C ₂₆ H ₂₇ ClN ₂ NaO ₆ [M+Na] ⁺ :521.1450; Found:521.1456.

In this Example 3, compound 3cc was prepared: yellow solid, melting point: 93.8-94.4°C; yield 91%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.39 (s, 9H), 3.35 (s, 3H), 3.64-3.67 (m, 1H), 4.22-4.25 (m, 1H), 6.94-6.97 (m, 1H), 7.05-7.08 (m, 1H), 7.15-7.21 (m, 2H), 7.29-7.35 (m, 2H), 7.51 (br s, 1H), 7.70-7.72 (m, 1H), 7.86 (d, J＝2.4 Hz, 1H), 8.02 (d, J＝2.4 Hz, 1H), 11.13 (br s, 1H); ¹³ C NMR (CDCl ₃ , 100MHz) δ: 28.4, 50.9, 59.0, 79.9, 116.4, 117.1 (d, J _CF = 24.4Hz), 118.4, 120.0, 120.1, 123.7 (d, J _CF = 23.3Hz), 124.4, 129.3, 131.0,131.5,137.0,140.2,144.5,153.6,154.8(d,J _CF =238.8Hz),158.7,161.3,194.1; HRMS(ESI-TOF)m/z:Calcd.for C ₂₆ H ₂₇ FN ₂ NaO ₆ [M+Na] ⁺ :505.1745; Found:505.1748.

In this Example 3, compound 3cd was prepared: yellow solid, melting point: 103.6-104.7°C; yield 74%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.40 (s, 9H), 3.37 (s, 3H), 3.66-3.68 (m, 2H), 4.26-4.28 (m, 2H), 6.98-7.01 (m, 1H), 7.17-7.24 (m, 2H), 7.27-7.30 (m, 1H), 7.32-7.35 (m, 1H), 7.44 (br s, 1H), 7.70 (d, J＝7.6 Hz, 1H), 7.88 (d, J＝2.4 Hz, 1H), 8.06 (d, J＝2.8 Hz, 1H), 11.13 (br s, 1H); ¹³ C NMR (CDCl ₃ , 100MHz) δ: 27.3, 49.9, 58.1, 68.7, 79.3, 115.3, 115.9 (d, J _CF = 24.1Hz), 117.3, 119.1 (d, J _CF = 7.3Hz), 122.9 (d, J _CF = 23.3Hz), 124.1,128.2,129.3,129.6,134.7,139.5,143.8,152.5,153.9(d,J _CF =238.7Hz),157.8,160.0,192.9; HRMS(ESI-TOF)m/z:Calcd.for C ₂₆ H ₂₆ ClFN ₂ NaO ₆ [M +Na] ⁺ :539.1356; Found:539.1353.

In this Example 3, compound 3ce was prepared: yellow solid, melting point: 135.7-136.6°C; yield 87%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400MHz) δ: 1.41 (s, 9H), 3.37 (s, 3H), 3.66-3.68 (m, 2H), 4.25-4.27 (m, 2H), 6.96-7.00 (m, 1H), 7.03-7.10 (m, 2H), 7.18-7.23 (m, 1H), 7.32-7.35 (m, 1H), 7.58 (br s, 1H), 7.85 (d, J＝2.8 Hz, 1H), 8.05 (d, J＝2.8 Hz, 1H), 11.12 (br s, 1H); ¹³ C NMR (CDCl ₃ ,100MHz)δ:27.3,49.9,58.0,68.7,79.4,115.4,115.9(d,J _CF =24.2Hz),117.3,119.1(d,J _CF =8.3Hz),122.4,122.8(d,J _CF =23.3Hz),123.2,125.8, 129.5,130.9,134.3,137.1,139.4,143.7,152.2,153.8(d,J _CF =238.8Hz),157.8,160.2,193.0; HRMS(ESI-TOF)m/z:Calcd.for C ₂₆ H ₂₆ ClFN ₂ NaO ₆ [M+Na] ⁺ :539.1356; Found:539.1357.

In this Example 3, compound 3cf was prepared: yellow solid, melting point: 103.5-104.4°C; yield 77%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.40 (s, 9H), 3.39 (s, 3H), 3.68-3.70 (m, 1H), 4.26-4.28 (m, 1H), 6.98 (d, J＝9.2 Hz, 1H), 7.08-7.12 (m, 1H), 7.18-7.20 (m, 1H), 7.32-7.36 (m, 1H), 7.40-7.43 (m, 1H), 7.50 (br s,1H),7.63(d,J＝2.4Hz,1H),7.73-7.74(m,1H),7.89(d,J＝2.4Hz,1H),8.01(d,J＝2.8Hz,1H),11.32(br s,1H); ¹³ C NMR (CDCl ₃ ,100MHz)δ:27.4,50.2,58.3,68.7,78.9,115.4,118.5,119.4,122.8,123.4,128.4,129.8,130.0,130.7,135.1,136.0,139.2,143.4,152.8,160. 1,160.3,193.1; HRMS(ESI-TOF)m/z:Calcd.for C ₂₆ H ₂₇ ClN ₂ NaO ₆ [M+Na] ⁺ :521.1450; Found:521.1456.

In this Example 3, compound 3cg was prepared: yellow solid, melting point: 154.5-155.3°C; yield 90%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.38 (s, 9H), 3.38 (s, 3H), 3.66-3.68 (m, 2H), 4.24-4.26 (m, 2H), 6.89-6.93 (m, 1H), 6.97 (d, J＝9.2 Hz, 1H), 7.00-7.05 (m, 1H), 7.35 (br s, 1H), 7.39-7.42 (m, 1H), 7.60-7.64 (m, 2H), 7.87 (d, J＝2.8 Hz, 1H), 8.10 (d, J＝2.4 Hz, 1H), 11.27 (br s, 1H); ¹³ C NMR (CDCl ₃ , 100MHz) δ: 27.3, 50.2, 58.2, 68.6, 79.0, 114.9 (d, J _CF = 21.5Hz), 115.3, 116.3 (d, J _CF = 23.4Hz), 118.4, 119.4, 122.8, 129.5, 1 29.8,132.0,135.2,139.5,143.8,152.8,158.8(d,J _CF =243.4Hz),160.0,192.8; HRMS(ESI-TOF)m/z:Calcd.for C ₂₆ H ₂₆ ClFN ₂ NaO ₆ [M+Na] ⁺ :539.1356; Found:539.1352.

In this Example 3, compound 3ch was prepared: yellow solid, melting point: 96.7-97.5°C; yield 79%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.39 (s, 9H), 3.38 (s, 3H), 3.66-3.68 (m, 2H), 4.24-4.26 (m, 2H), 6.97 (d, J＝8.8 Hz, 1H), 7.17-7.19 (m, 1H), 7.27-7.29 (m, 1H), 7.39-7.42 (m, 1H), 7.44 (br s, 1H), 7.61 (d, J = 2.4Hz, 1H), 7.69 (d, J = 7.6Hz, 1H), 7.88 (d, J = 2.4Hz, 1H), 8.02 (d, J = 2.4Hz, 1H), 11.27 (br s, 1H); ¹³ C NMR (CDCl ₃ ,100MHz)δ:27.3,50.2,58.2,68.6,79.2,115.4,118.4,119.4,122.8,128.2,128.3,129.3,129.6,129.8,134.7,135.2,139.6,143.8,152.4,160. 0,160.1,192.8; HRMS(ESI-TOF)m/z:Calcd.forC ₂₆ H ₂₆ Cl ₂ N ₂ NaO ₆ [M+Na] ⁺ :555.1060; Found: 555.1065.

In this Example 3, compound 3ci was prepared: yellow solid, melting point: 107.1-108.1°C; yield 76%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400MHz) δ: 1.37 (s, 9H), 3.39 (s, 3H), 3.67-3.69 (m, 2H), 3.74 (s, 3H), 4.25-4.27 (m, 2H), 6.73 (d, J＝2.8 Hz, 1H), 6.87-6.90 (m, 1H), 6.97 (d, J＝8.8 Hz, 1H), 7.19 (s, 1H), 7.40-7.43 (m, 1H), 7.54 (br s, 1H), 7.62 (d, J = 2.8Hz, 1H), 7.88 (d, J = 2.8Hz, 1H), 8.00 (d, J = 2.4Hz, 1H), 11.31 (br s, 1H); ¹³ C NMR (CDCl ₃ , 100MHz) δ: 27.4, 50.2, 54.6, 58.2, 68.7, 78. 7,113.8,114.9,115.3,118.5,119.4,122.8,128.9,129.8,130.5,135.1,139.1,143.5,153.1,155.6,160.1,193.0; HRMS(ESI-TOF)m/z:Calcd.for C ₂₇ H ₂₉ ClN ₂ NaO ₇ [M+Na] ⁺ :551.1556; Found:551.1554.

In this Example 3, compound 3cj was prepared: yellow solid, melting point: 114.9-115.5°C; yield 78%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ ,400MHz)δ:1.40(s,9H),3.39(s,3H),3.67-3.69(m,1H),4.24-4.26(m,1H),6.91(d,J＝8.8Hz,1H),7.07-7.11(m,1H),7.17-7.20(m,1H),7.31-7.35 (m,1H),7.50-7.55(m,2H),7.72-7.76(m,2H),7.88(d,J＝2.8Hz,1H),7.99(d,J＝2.8Hz,1H),11.31(br s,1H); ¹³ C NMR (CDCl ₃ ,100MHz)δ:27.4,50.3,58.3,68.6,78.9,109.7,115.4,119.2,119.7,123.4,128.4,130.0,130.7,132.8,136.0,137.9,139.2,143.4,152.7,160. 3,160.5,192.9; HRMS(ESI-TOF)m/z:Calcd.for C ₂₆ H ₂₇ BrN ₂ NaO ₆ [M+Na] ⁺ :565.0945; Found: 565.0948.

In this Example 3, compound 3ck was prepared: yellow solid, melting point: 149.3-150.2°C; yield 73%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.39 (s, 9H), 3.40 (s, 3H), 3.67-3.69 (m, 1H), 4.25-4.27 (m, 1H), 6.91-6.94 (m, 2H), 7.01-7.06 (m, 1H), 7.35 (br s, 1H), 7.53-7.56 (m, 1H), 7.64 (br s, 1H), 7.75 (d, J＝2.4 Hz, 1H), 7.88 (d, J＝2.8 Hz, 1H), 8.01 (d, J＝2.4 Hz, 1H), 11.29 (br s, 1H); ¹³ C NMR (CDCl ₃ , 100MHz) δ: 28.4, 51.4, 59.4, 69.6, 80.1, 110.7, 116.0 (d, J _CF = 21.4Hz), 116.4, 117.3 (d, J _CF = 23.5Hz), 120.1, 120.8, 130.6, 1 33.0,133.7,139.0,140.5,144.8,153.8,159.5(d,J _CF =230.4Hz),161.0,161.5,193.8; HRMS(ESI-TOF)m/z:Calcd.for C ₂₆ H ₂₆ BrFN ₂ NaO ₆ [M+Na] ⁺ :583.0850; Found:583.0854.

In this Example 3, compound 3cl was prepared: yellow solid, melting point: 143.6-143.9°C; yield 82%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.40 (s, 9H), 2.25 (s, 3H), 3.32 (s, 3H), 3.67-3.69 (m, 1H), 4.21-4.24 (m, 1H), 6.90 (d, J＝8.8 Hz, 1H), 7.05-7.08 (m, 1H), 7.15-7.18 (m, 1H), 7.25-7.33 (m, 2H), 7.40 (s, 1H), 7.60 (br s,1H),7.72-7.74(m,1H),7.87(d,J＝2.4Hz,1H),7.99(d,J＝2.4Hz,1H),11.23(br s,1H); ¹³ C NMR (CDCl ₃ ,100MHz) δ:19.6,27.4,58.1,68.7,78.8,116.3 ,117.5,123.3,127.2,128.2,130.0,130.1,130.6,136.0,136.3,139.7,143.1,152.7,159.5,160.3,194.1; HRMS(ESI-TOF)m/z:Calcd.forC ₂₇ H ₃₀ N ₂ NaO ₆ [M+Na] ⁺ :501.1996; Found:501.1997.

In this Example 3, compound 3cm was prepared: yellow solid, melting point: 95.4-95.7°C; yield 76%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400MHz) δ: 1.40 (s, 9H), 2.27 (s, 3H), 3.33 (s, 3H), 3.67-3.70 (m, 2H), 4.24-4.26 (m, 2H), 6.92 (d, J＝8.4 Hz, 1H), 7.17 (d, J＝2.4 Hz, 1H), 7.27-7.30 (m, 2H), 7.39 (s, 1H), 7.54 (br s, 1H), 7.70 (d, J = 6.8Hz, 1H), 7.88 (d, J = 2.4Hz, 1H), 8.02 (d, J = 2.4Hz, 1H), 11.21 (br s, 1H); ¹³ C NMR (CDCl ₃ , 100MHz) δ: 19.6, 27.3, 50.5, 58.2, 68.6, 79. 2,116.3,117.4,117.6,127.2,128.1,129.6,130.5,134.8,136.5,143.5,152.5,159.6,160.1,193.9; HRMS(ESI-TOF)m/z:Calcd.for C ₂₇ H ₂₉ ClN ₂ NaO ₆ [M +Na] ⁺ :535.1606; Found:535.1608.

In this Example 3, compound 3cn was prepared: yellow solid, melting point: 92.8-93.4°C; yield 87%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.18 (d, J = 7.2 Hz, 6H), 1.39 (s, 9H), 2.79-2.86 (m, 1H), 3.30 (s, 3H), 3.67-3.70 (m, 1H), 4.19-4.22 (m, 1H), 6.92 (d, J = 8.8 Hz, 1H), 7.04-7.08 (m, 1H), 7.17-7.19 (m, 1H), 7.28-7.35 (m, 2H), 7.44 (d, J = 2.4 Hz, 1H), 7.58 (br s, 1H), 7.72 (d, J = 7.2Hz, 1H), 7.89 (d, J = 2.8Hz, 1H), 7.99 (d, J = 7.2Hz, 1H), 11.20 (br s, 1H); ¹³ CNMR (CDCl ₃ , 100MHz) δ: 23.0, 27.3, 32.3, 50.8, 58.1, 68. 6,78.8,116.4,117.5,123.3,128.2,129.9,130.1,133.7,136.0,138.4,139.8,143.1,152.7,159.6,160.4,194.1; HRMS(ESI-TOF)m/z:Calcd.for C ₂₉ H _{3 4} N ₂ NaO ₆ [M+Na] ⁺ :529.2309; Found:529.2314.

In this Example 3, compound 3co was prepared: yellow solid, melting point: 140.2-141.0°C; yield 80%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.18 (d, J = 7.2 Hz, 6H), 1.37 (s, 9H), 2.81-2.85 (m, 1H), 3.31 (s, 3H), 3.70-3.72 (m, 2H), 3.73 (s, 3H), 4.21-4.23 (m, 2H), 6.74 (d, J = 3.2 Hz, 1H), 6.86-6.89 (m, 1H), 6.95 (d, J = 8.8 Hz, 1H), 7.28-7.36 (m, 2H), 7.44 (d, J = 2.4 Hz, 1H), 7.55 (br s, 1H), 7.91 (d, J = 2.4Hz, 1H), 7.98 (d, J = 2.4Hz, 1H), 11.21 (br s, 1H); ¹³ C NMR (CDCl ₃ , 100MHz) δ: 24.1, 28.4, 33.4, 51.9, 55.6, 59.1, 69.6, 79.6, 114.6, 116.0,117.3,118.5,118.6,129.2,130.0,131.1,134.7,139.4,140.6,144.2,154.2,156.6,160.7,161.2,195.1; HRMS(ESI-TOF)m/z:Calcd.for C ₃₀ H ₃₆ N ₂ NaO ₇ [M+Na] ⁺ :559.2415; Found:559.2412.

In this Example 3, compound 3cp was prepared: yellow solid, melting point: 150.8-151.1°C; yield 78%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.18 (d, J = 6.8 Hz, 6H), 1.38 (s, 9H), 2.81-2.84 (m, 1H), 3.30 (s, 3H), 3.68-3.70 (m, 2H), 4.21-4.23 (m, 2H), 6.91-6.95 (m, 2H), 6.98-7.03 (m, 1H), 7.33-7.36 (m, 1H), 7.41-7.43 (m, 2H), 7.64 (br s, 1H), 7.89 (d, J = 2.4Hz, 1H), 8.01 (d, J = 2.4Hz, 1H), 11.17 (br s, 1H); ¹³ C NMR (CDCl ₃ , 100MHz) δ: 24.0, 28.4, 33.4, 51.9, 59.1, 69.5, 80.0, 115.8 (d, J _CF =22.2Hz),117.3(d,J _CF =22.4Hz),118.4,118.6,129.1,133.1,134.8,139.5,141.1,144.5,153.8,159.5(d,J _CF =242.1Hz), 160.7, 161.1, 194.9; HRMS (ESI-TOF) m/z: Calcd. for C ₂₉ H ₃₃ FN ₂ NaO ₆ [M+Na] ⁺ :547.2215; Found: 547.2219.

In this Example 3, compound 3cq was prepared: yellow solid, melting point: 96.9-97.9°C; yield 80%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400MHz) δ: 1.40 (s, 9H), 2.34 (s, 3H), 3.39 (s, 3H), 3.67-3.69 (m, 2H), 4.24-4.26 (m, 2H), 6.90 (s, 1H), 7.066-7.10 (m, 1H), 7.17-7.19 (m, 1H), 7.30-7.35 (m, 1H), 7.53 (br s,1H),7.62(s,1H),7.72-7.74(m,1H),7.87(d,J＝2.4Hz,1H),7.99(d,J＝2.4Hz,1H),11.36(br s,1H); ¹³ C NMR (CDCl ₃ ,100MHz) δ:19.8,27.4,50.2,58.2 ,68.7,78.9,115.6,116.7,119.8,123.4,128.3,130.0,130.3,130.6,136.0 ,139.3,143.1,144.6,152.7,160.1,160.3,192.8; HRMS(ESI-TOF)m/z:Calcd .for C ₂₇ H ₂₉ ClN ₂ NaO ₆ [M+Na] ⁺ :535.1606; Found: 535.1605.

In this Example 3, compound 3cr was prepared: yellow solid, melting point: 94.7-95.5°C; yield 92%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.37 (s, 9H), 2.34 (s, 3H), 3.38 (s, 3H), 3.66-3.69 (m, 2H), 3.73 (s, 3H), 4.23-4.25 (m, 2H), 6.73 (d, J＝2.8 Hz, 1H), 6.86-6.90 (m, 2H), 7.25 (br s, 1H), 7.54 (br s, 1H), 7.61 (s, 1H), 7.88 (d, J＝2.4 Hz, 1H), 7.98 (d, J＝2.4 Hz, 1H), 11.35 (br s, 1H); ¹³ C NMR (CDCl ₃ , 100MHz) δ: 20.9, 28.4, 51.2, 55.6, 59.3, 69.7, 79.6, 114.8, 115.9, 116.6, 117.8, 120.8, 124.4, 130.0, 131.3, 131.4, 140.2 ,144.2,145.7,154.1,156.6,161.1,193.8; HRMS(ESI-TOF)m/z:Calcd.for C ₂₈ H ₃₁ ClN ₂ NaO ₇ [M+Na] ⁺ :565.1712; Found:565.1715.

In this Example 3, compound 3da was prepared: yellow solid, melting point: 95.4-96.6°C; yield 87%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ ,400MHz)δ:1.39(s,9H),2.87-2.90(m,2H),4.19-4.22(m,2H),6.86-6.90(m,1H),6.97(d,J＝7.6Hz,1H),7.06-7.09(m,1H),7.14-7.16(m,1H),7.30 -7.36(m,2H),7.42-7.46(m,1H),7.63-7.69(m,2H),7.87(d,J＝2.4Hz,1H),8.01(d,J＝2.4Hz,1H),11.30(br s,1H); ¹³ C NMR (CDCl ₃ ,100MHz)δ:17.3,28.4,47.9,80.3,117.0,118.5,118.6,118.7,119.4,124.7,129.6,131.0,131.4,132.2,136.7,136.8,141.2,142.4,153.7,161 .1,162.5,194.8; HRMS(ESI-TOF)m/z:Calcd.for C ₂₆ H ₂₅ N ₃ NaO ₅ [M+Na] ⁺ :482.1686; Found: 482.1689.

In this Example 3, compound 3db was prepared: yellow solid, melting point: 86.6-87.7°C; yield 81%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400MHz) δ: 1.39 (s, 9H), 2.91-2.94 (m, 2H), 4.25-4.28 (m, 2H), 6.95-6.99 (m, 1H), 7.08-7.12 (m, 1H), 7.15-7.20 (m, 2H), 7.29-7.36 (m, 3H), 7.68 (d, J＝7.6 Hz, 1H), 7.88 (d, J＝2.4 Hz, 1H), 8.03 (d, J＝2.8 Hz, 1H), 10.98 (br s, 1H); ¹³ CNMR (CDCl ₃ ,100MHz)δ:17.3,28.3,48.0,80.3,116.8(d,J _CF =28.4Hz),117.0,118.1,118.2,118.3,120.2(d,J _CF =7.4Hz),124.2(d,J _CF =23.3Hz),124.7,129.7 ,131.0,131.8,136.8,140.8,142.4,153.6,155.1(d,J _CF =246.4Hz),158.6,161.1,193.8; HRMS(ESI-TOF)m/z:Calcd.for C ₂₆ H ₂₄ FN ₃ NaO ₅ [M+Na] ⁺ :500.1592; Found:500.1592.

In this Example 3, compound 3de was prepared: yellow solid, melting point: 82.9-82.9°C; yield 92%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.37 (s, 9H), 2.23 (s, 3H), 2.92-2.95 (m, 2H), 4.23-4.26 (m, 2H), 6.88-6.92 (m, 2H), 7.00-7.05 (m, 1H), 7.21 (s, 1H), 7.25-7.28 (m, 1H), 7.43 (s, 1H), 7.60 (br s, 1H), 7.89 (d, J＝2.4 Hz, 1H), 8.01 (d, J＝2.4 Hz, 1H), 11.05 (br s, 1H); ¹³ C NMR (CDCl ₃ , 100MHz) δ: 17.3, 20.3, 28.3, 48.1, 80.4, 116.2 (d, J _CF = 21.3Hz), 116.9, 117.4 (d, J _CF = 24.4Hz), 118.3, 118.6, 129.1, 130.4, 131.4, 137.9, 141.5, 142.7, 153.8, 159.4 (d, J _CF = 243.1Hz), 160.4, 160.8, 194.6; HRMS (ESI-TOF) m/z: Calcd.forC ₂₇ H ₂₆ FN ₃ NaO ₅ [M+Na] ⁺ :514.1749; Found: 514.1752.

In this Example 3, compound 3ea was prepared: yellow solid, melting point: 88.7-89.9°C; yield 87%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 0.83-0.87 (m, 3H), 1.35 (s, 9H), 1.73-1.81 (m, 2H), 3.11 (s, 1H), 3.76 (d, J＝4.0 Hz, 2H), 4.98 (s, 1H), 6.81-6.84 (m, 1H), 6.96 (d, J＝8.0 Hz, 1H), 7.02-7.06 (m, 1H), 7.11-7.13 (m, 1H), 7.25-7.29 (m, 1H), 7.39-7.43 (m, 1H), 7.46 (br s,1H),7.52-7.55(m,1H),7.63(d,J＝6.4Hz,1H),7.79(d,J＝2.4Hz,1H),8.08(d,J＝2.4Hz,1H),11.40(br s,1H); ¹³ C NMR (CDCl ₃ ,100MHz)δ:9.5,22.2,27.3,59.4,62.0,79.0,116.7,117.7,117.8,118.1,123.1,123.6,128.2,128.5,129.4,129.8,130.9,135.3,135.7,138.9, 139.9,152.8,161.1,161.5,194.3; HRMS(ESI-TOF)m/z:Calcd.forC ₂₇ H ₃₀ N ₂ NaO ₆ [M+Na] ⁺ :501.1996; Found:501.1996.

In this Example 3, compound 3eb was prepared: yellow solid, melting point: 94.9-95.3°C; yield 78%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ ,400MHz)δ:0.86-0..90(m,3H),1.36(s,9H),1.81-1.86(m,2H),2.75(s,1H),3.84(s,2H),5.02(s,1H),6.94-6.98(m,1H),7.05-7.09(m,1H),7.15- 7.20(m,2H),7.27-7.32(m,2H),7.38(s,1H),7.65(d,J＝6.0Hz,1H),7.81(d,J＝2.4Hz,1H),8.12(d,J＝2.0Hz,1H),11.11(br s,1H); ¹³ C NMR (CDCl ₃ ,100MHz)δ:9.5,22.2,27.3,59.4,62.1,79.0,115.8(d,J _CF ＝24.3Hz),116.1,117.4,119.0(d,J _CF ＝8.2Hz),122.7(d,J _CF ＝24.5Hz),123.2,123.6,12 8.3,129.8,129.9,135.7,138.4,140.2,152.8,153.7(d,J _CF =238.8Hz),157.6,161.0,193.2; HRMS(ESI-TOF)m/z:Calcd.for C ₂₇ H ₂₉ FN ₂ NaO ₆ [M+Na] ⁺ :519.1902; Found:519.1908.

In this Example 3, compound 3ec was prepared: yellow solid, melting point: 97.6-98.5°C; yield 72%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 0.86-0.90 (m, 3H), 1.33 (s, 9H), 1.77-1.84 (m, 2H), 2.20 (s, 3H), 2.86 (s, 1H), 3.82 (d, J＝4.4 Hz, 2H), 5.02 (s, 1H), 6.86-6.89 (m, 2H), 6.95-7.00 (m, 1H), 7.23-7.34 (m, 3H), 7.56 (s, 1H), 7.82 (d, J＝2.4 Hz, 1H), 8.08 (s, 1H), 11.17 (br s, 1H); ¹³ C NMR (CDCl ₃ , 100MHz) δ: 9.5, 19.4, 22.2, 27.3, 59.5, 62.1, 79.1, 114.7 (d, J _CF = 22.4Hz), 116.1 (d, J _CF = 23.1Hz), 116.6, 117.4 (d, J _CF = 8.3Hz), 127. 3,128.5,130.6,131.8,136.4,139.1,152.9,158.7(d,J _CF =242.1Hz),159.4,160.7,194.0; HRMS(ESI-TOF)m/z:Calcd.for C ₂₈ H ₃₁ FN ₂ NaO ₆ [M+Na] ⁺ :533.2058; Found:533.2056.

In this Example 3, compound 3fa was prepared: yellow solid, melting point: 95.9-96.7°C; yield 74%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.37 (s, 9H), 1.41 (d, J＝7.2 Hz, 3H), 2.88 (br s,1H),3.72-3.76(m,1H),3.80-3.84(m,1H),5.16-5.21(m,1H),6.83-6..87(m,1H),6.99(d,J＝8.0Hz,1H),7.03-7.07(m,1H),7.11-7.13(m,1H),7 .27-7.31(m,1H),7.41-7.47(m,2H),7.55-7.57(m,1H),7.66(br s,1H),7.81(d,J＝2.4Hz,1H),8.11(d,J＝2.4Hz,1H),11.42(br s,1H); ¹³ C NMR (CDCl ₃ ,100MHz)δ:15.9,28.3,55.1,64.3,80.2,117.8,118.7,119.2,124.5,129.3,130.5,130.9,131.9,136.4,136.8,140.0,140.5,153.9,161.8,162. 6,195.4; HRMS(ESI-TOF)m/z:Calcd.for C ₂₆ H ₂₈ N ₂ NaO ₆ [M+Na] ⁺ :487.1840; Found: 487.1841.

In this Example 3, compound 3fb was prepared: yellow solid, melting point: 97.8-98.9°C; yield 72%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.37 (s, 9H), 1.44 (d, J＝6.8 Hz, 3H), 2.70 (br s, 1H), 3.76-3.80 (m, 1H), 3.84-3.87 (m, 1H), 5.22 (br s, 1H), 6.95-6.98 (m, 1H), 7.06-7.09 (m, 1H), 7.13-7.20 (m, 2H), 7.27-7.33 (m, 2H), 7.39 (br s, 1H), 7.67 (br s, 1H), 7.81 (d, J = 2.0Hz, 1H), 8.14 (d, J = 2.4Hz, 1H), 11.11 (br s, 1H); ¹³ C NMR (CDCl ₃ , 100MHz) δ: 15.8, 28.3, 54.8, 64.3, 80.2, 116.8 (d, J _CF = 24.1Hz), 1 17.1,118.4,118.5,120.1,123.8(d,J _CF =23.5Hz),124.6,129.3,130.9,136.8,139.5,140.8,153.8,154.7(d,J _CF =238.3Hz), 158.6, 161.7, 194.3; HRMS (ESI-TOF) m/z: Calcd.for C ₂₆ H ₂₇ FN ₂ NaO ₆ [M+Na] ⁺ :505.1745; Found: 505.1742.

In this Example 3, compound 3fc was prepared: yellow solid, melting point: 89.7-90.5°C; yield 87%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.35 (s, 9H), 1.40 (d, J＝7.2 Hz, 3H), 2.21 (s, 3H), 2.88 (br s, 1H), 3.73-3.76 (m, 1H), 3.81-3..85 (m, 1H), 5.21 (s, 1H), 6.84-6.90 (m, 2H), 6.96-7.01 (m, 1H), 7.24-7.31 (m, 1H), 7.32 (br s, 1H), 7.35 (s, 1H), 7.57 (brs, 1H), 7.81 (d, J = 2.4Hz, 1H), 8.12 (d, J = 2.0Hz, 1H), 11.17 (br s, 1H); ¹³ C NMR (CDCl ₃ , 100MHz) δ: 15.9, 20.5, 28.3, 54.7, 64. 2,80.3,115.8(d,J _CF =22.4Hz),117.3(d,J _CF =23.3Hz),117.6,118.4(d,J _CF =9.1Hz),128.4,131.6,132.9,137.5,140.1,141.0,154.0,159.8(d,J _CF =243.2Hz), 160.4, 161.4, 195.0; HRMS (ESI-TOF) m/z: Calcd. for C ₂₇ H ₂₉ FN ₂ NaO ₆ [M+Na] ⁺ : 519.1902; Found: 519.1906.

In this Example 3, compound 3ga was prepared: yellow solid, melting point: 120.7-121.8°C; yield 91%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 3.26 (s, 3H), 3.61-3.64 (m, 2H), 4.23-4.25 (m, 2H), 6.83-6.87 (m, 1H), 6.91-6.97 (m, 2H), 7.00 (d, J＝8.0 Hz, 1H), 7.17-7.22 (m, 1H), 7.27-7.30 (m, 1H), 7.38-7.44 (m, 2H), 7.87 (d, J＝2.4 Hz, 1H), 8.20 (d, J＝2.4 Hz, 1H), 9.43 (br s,1H),10.30(br s,1H); ¹³ C NMR (DMSO-d ₆ ,100MHz) δ:49.7,58.5,69.7,116.7,116.8,117.1,119.4,119.6,124.0,125.1,128.0,129.6,130.4,131 .4,133.2,138.7,145.7,155.4,156.6,161.3,192.5; HRMS(ESI-TOF)m/z:Calcd.for C ₂₁ H ₁₉ NNaO ₅ [M+Na] ⁺ :388.1155; Found:388.1152.

In this Example 3, compound 3gb was prepared: yellow solid, melting point: 100.6-101.2°C; yield 87%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ ,400MHz)δ:3.26(s,3H),3.60-3.63(m,2H),4.22-4.25(m,2H),6.83-6.86(m,1H),6.90-6.92(m,1H),7.00(d,J＝8.8Hz,1H),7.17-7.21(m,1H),7.26- 7.28(m,1H),7.34(d,J＝2.8Hz,1H),7.41-7.44(m,1H),7.85(d,J＝2.8Hz,1H),8.19(d,J＝2.8Hz,1H),9.41(br s,1H),10.39(br s,1H); ¹³ C NMR (DMSO-d ₆ ,100MHz)δ:49.6,58.5,69.6,116.4,116.6,118.8,119.3,123.2,123.9,127.4,128.1,129.2,129.6,131.4,132.2,138.2,146.2,154.8,155.4,16 1.2,190.5; HRMS (ESI-TOF)m/z:Calcd.forC ₂₁ H ₁₈ ClNNaO ₅ [M+Na] ⁺ :422.0766; Found: 422.0768.

In this Example 3, compound 3gc was prepared: yellow solid, melting point: 134.8-135.4°C; yield 89%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ ,400MHz)δ:3.27(s,3H),3.60-3.63(m,2H),4.22-4.24(m,2H),6.83-6.87(m,1H),6.90-6.92(m,1H),6.96(d,J=8.8Hz,1H),7.17-7.21(m,1H),7.26- 7.29(m,1H),7.46(d,J＝2.4Hz,1H),7.52-7.55(m,1H),7.85(d,J＝2.8Hz,1H),8.18(d,J＝2.4Hz,1H),9.41(br s,1H),10.42(br s,1H); ¹³ C NMR (DMSO-d ₆ ,100MHz)δ:49.6,58.5,69.6,110.6,116.5,116.7,119.3,123.9,128.0,128.1,129.6,131.4,132.0,135.1,138.2,146.2,155.2,155.4,161.3,19 0.4; HRMS (ESI-TOF) m/z:Calcd.forC ₂₁ H ₁₈ BrNNaO ₅ [M+Na] ⁺ :466.0261; Found: 466.0267.

In this Example 3, compound 3gd was prepared: yellow solid, melting point: 105.7-106.4°C; yield 90%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 2.31 (s, 3H), 3.28 (s, 3H), 3.62-3.64 (m, 2H), 4.23-4.26 (m, 2H), 6.77-6.92 (m, 4H), 7.17-7.21 (m, 1H), 7.27-7.29 (m, 1H), 7.35 (d, J＝7.6 Hz, 1H), 7.85 (d, J＝2.8 Hz, 1H), 8.20 (d, J＝2.4 Hz, 1H), 9.41 (br s, 1H), 10.47 (br s, 1H); ¹³ C NMR(DMSO-d ₆ ,100MHz)δ:21.7,49.7,58.6,70.0,116.7,116.8,117.6,119.3,120.6,121.6,124.0,127.9,129.6,131.0,131.4,139.0,144.4,145.4 ,155.4,157.7,161.2,192.7; HRMS(ESI-TOF)m/z:Calcd.for C ₂₂ H ₂₁ NNaO ₅ [M+Na] ⁺ :402.1312; Found:402.1317.

In this Example 3, compound 3ge was prepared: yellow solid, melting point: 100.8-101.3°C; yield 90%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 3.25 (s, 3H), 3.61-3.63 (m, 2H), 3.73 (s, 3H), 4.22-4.25 (m, 2H), 6.83-6.86 (m, 1H), 6.90-6.93 (m, 3H), 7.00-7.03 (m, 1H), 7.17-7.21 (m, 1H), 7.26-7.28 (m, 1H), 7.85 (d, J＝2.4 Hz, 1H), 8.21 (d, J＝2.4 Hz, 1H), 9.41 (br s, 1H), 9.74 (br s, 1H); ¹³ C NMR (DMSO-d ₆ ,100MHz) δ: 49.8, 56.0, 58.5, 69.7, 114.1, 116.7, 118.1, 119.3, 119.5, 124.0, 125.4, 127.9, 129.6, 131.4, 138.6, 145.8, 150.1,152.4,155.4,161.3,192.0; HRMS(ESI-TOF)m/z:Calcd.for C ₂₂ H ₂₁ NNaO ₆ [M+Na] ⁺ :418.1261; Found:418.1265.

In this Example 3, compound 3gf was prepared: yellow solid, melting point: 145.3-146.6°C; yield 91%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 1.19 (d, J = 6.8 Hz, 6H), 2.83-2.90 (m, 1H), 3.26 (s, 3H), 3.62-3.64 (m, 2H), 4.22-4.25 (m, 2H), 6.83-6.87 (m, 1H), 6.91-6.94 (m, 2H), 7.17-7.31 (m, 4H), 7.87 (d, J = 2.4 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H), 9.41 (br s, 1H), 10.09 (br s, 1H); ¹³ C NMR (DMSO-d ₆ ,100MHz) δ: 24.4, 33.0, 49.9, 58.6, 69.7, 116.7, 116.9, 117.1, 119.3, 124.0, 124.6, 127.9, 128.0, 129.6, 131.3, 131.4, 138.8, 13 9.4,145.7,154.8,155.5,161.3,192.6; HRMS(ESI-TOF)m/z:Calcd.for C ₂₄ H ₂₅ NNaO ₅ [M+Na] ⁺ :430.1625; Found: 430.1627.

In this Example 3, compound 3gg was prepared: yellow solid, melting point: 130.2-131.1°C; yield 93%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400MHz) δ: 2.29 (s, 3H), 3.34 (s, 3H), 3.62-3.65 (m, 2H), 4.20-4.22 (m, 2H), 6.84 (s, 1H), 6.87 (d, J＝7.6 Hz, 1H), 6.91 (d, J＝8.0 Hz, 1H), 7.17-7.22 (m, 2H), 7.53 (s, 1H), 7.93 (d, J＝7.2 Hz, 1H), 8.84 (s, 1H), 11.32 (s, 1H); ¹³ CNMR (CDCl ₃ ,100MHz)δ:20.9,51.4,59.2,69.6,117.7,117.8,119.7,120.8,121.0,124.2,124.5,130.6,130.8,131.3,131.4,140.3,143.1,145.8,156.0,161 .1,162.6,193.8; HRMS(ESI-TOF)m/z:Calcd.for C ₂₂ H ₂₀ ClNNaO ₅ [M+Na] ⁺ :436.0922; Found: 436.0927.

In this Example 3, compound 3gh was prepared: yellow solid, melting point: 120.3-121.3°C; yield 87%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 3.28 (s, 3H), 3.63-3.66 (m, 2H), 4.26-4.28 (m, 2H), 6.63-6.66 (m, 1H), 6.72-6.74 (m, 2H), 6.95-7.02 (m, 2H), 7.39-7.46 (m, 2H), 7.86 (d, J＝2.4 Hz, 1H), 8.21 (d, J＝2.4 Hz, 1H), 8.67 (br s, 1H), 8.80 (br s, 1H), 10.28 (br s, 1H); ¹³ C NMR (DMSO-d ₆ ,100MHz) δ: 49.8, 58.5, 69.6, 116.4, 116.9, 117.1, 117.4, 117.6, 119.6, 124.3, 125.1, 127.9, 130.4, 133.2, 138.9, 145.5, 147.8, 150. 2,156.5,161.3,192.5; HRMS(ESI-TOF)m/z:Calcd.for C ₂₁ H ₁₉ NNaO ₆ [M+Na] ⁺ :404.1105; Found:404.1109.

In this Example 3, compound 3ha was prepared: yellow solid, melting point: 110.6-111.1°C; yield 92%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 3.70 (s, 2H), 4.12-4.14 (m, 2H), 5.00 (s, 1H), 6.84-7.02 (m, 4H), 7.18-7.22 (m, 1H), 7.27-7.30 (m, 1H), 7.40-7.44 (m, 2H), 7.88 (s, 1H), 8.21 (d, J=2.4 Hz, 1H), 9.42 (br s, 1H), 10.30 (br s, 1H); ¹³ C NMR (DMSO-d ₆ ,100MHz)δ:53.2,589,116.6,116.8,117.2,119.4,119.6,124.1,125.2,127.9,129.6,130.4,131.4,133.2,138.9,145.9,155.5,156.5,161.4,19 2.5; HRMS (ESI-TOF) m/z: Calcd. for C ₂₀ H ₁₇ NNaO ₅ [M+Na] ⁺ :374.0999; Found: 374.0992.

In this Example 3, compound 3hb was prepared: yellow solid, melting point: 98.7-99.9°C; yield 90%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ ,400MHz)δ:3.68(s,2H),4.11-4.13(m,2H),4.97(s,1H),6.83-6.87(m,1H),6.91(d,J＝8.0Hz,1H),7.01(d,J＝8.8Hz,1H),7.17-7.21(m,1H),7.26-7. 28(m,1H),7.36(d,J＝2.8Hz,1H),7.40-7.43(m,1H),7.85(d,J＝2.8Hz,1H),8.21(d,J＝2.4Hz,1H),9.40(br s,1H),10.40(br s,1H); ¹³ C NMR (DMSO-d ₆ ,100MHz)δ:53.1,58.9,116.3,116.7,118.8,119..4,123.3,124.0,127.5,128.0,129.2,129.6,131.4,132.2,138.4,146.4,154.7,155.4,161.4, 190.6; HRMS (ESI-TOF) m/z:Calcd.forC ₂₀ H ₁₆ ClNNaO ₅ [M+Na] ⁺ :408.0609; Found: 408.0614.

In this Example 3, compound 3hc was prepared: yellow solid, melting point: 100.7-101.2°C; yield 92%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 2.32 (s, 3H), 3.68 (s, 2H), 4.11-4.13 (m, 2H), 4.97 (br s, 1H), 6.83-6.87 (m, 1H), 6.90 (d, J＝8.0 Hz, 1H), 6.95 (s, 1H), 7.17-7.21 (m, 1H), 7.26-7.28 (m, 1H), 7.38 (s, 1H), 7.84 (d, J＝2.8 Hz, 1H), 8.22 (d, J＝2.4 Hz, 1H), 9.40 (br s,1H),10.38(br s,1H); ¹³ C NMR (DMSO-d ₆ ,100MHz) δ:20.4,53.1,58.9,116.4,116.8,119.4,119.6,123.7,124.0,124.8,127.9,129.6,130.0,131 .4,138.6,140.5,146.2,155.1,155.4,161.3,190.7; HRMS(ESI-TOF)m/z:Calcd.for C ₂₁ H ₁₈ ClNNaO ₅ [M+Na] ⁺ :422.0766; Found: 422.0761.

In this Example 3, compound 3hd was prepared: yellow solid, melting point: 85.6-86.4°C; yield 89%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 3.72 (d, J = 4.0 Hz, 2H), 4.15-4.18 (m, 2H), 5.02 (s, 1H), 6.65-6.68 (m, 1H), 6.74-6.76 (m, 2H), 6.97-7.04 (m, 2H), 7.43-7.48 (m, 2H), 7.89 (d, J = 2.8 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 8.68 (br s, 1H), 8.83 (br s, 1H), 10.31 (br s, 1H); ¹³ C NMR(DMSO-d ₆ ,100MHz)δ:53.3,58.9,116.4,116.8,117.2,117.4,117.7,119.6,124.4,125.1,127.8,130.4,133.2,139.0,145.7,147.9,150.2,156 .5,161.4,192.5; HRMS(ESI-TOF)m/z:Calcd.for C ₂₀ H ₁₇ NNaO ₆ [M+Na] ⁺ :390.0948; Found: 390.0951.

In this Example 3, compound 3ia was prepared: yellow solid, melting point: 97.2-97.6°C; yield 92%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400 MHz) δ: 4.70-4.76 (m, 2H), 6.84-6.96 (m, 3H), 7.00 (d, J＝8.4 Hz, 1H), 7.15-7.17 (m, 1H), 7.23-7.27 (m, 1H), 7.44-7.50 (m, 2H), 7.87 (s, 1H), 7.94 (d, J＝2.4 Hz, 1H), 8.22 (br s, 1H), 11.28 (br s, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ: 49.5 (q, J _{C, F} ＝35.3Hz),118.5,119.0,119.4,119.8,120.0,121.3,121.7,123.7,124.4,124.6(q,J _C,F ＝270.4Hz),130.8,131.0,131.7,131.9,137.0,140.8,14 1.0,155.8,162.3,162.8,194.7; HRMS(ESI-TOF)m/z:Calcd.for C ₂₀ H ₁₄ F ₃ NNaO ₄ [M+Na] ⁺ :412.0767; Found: 412.0762.

In this Example 3, compound 3ib was prepared: yellow solid, melting point: 106.9-107.9°C; yield 77%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 5.04-5.11 (m, 2H), 6.61-6.64 (m, 1H), 6.71-6.74 (m, 2H), 6.93-7.00 (m, 2H), 7.35-7.43 (m, 2H), 7.87 (d, J＝2.4 Hz, 1H), 8.28 (d, J＝2.4 Hz, 1H), 8.73 (br s, 1H), 8.80 (br s, 1H), 10.23 (br s, 1H); ¹³ C NMR (DMSO-d ₆ , 100 MHz) δ: 48.0 (q, J _C,F ＝35.5Hz),116.5,117.1,117.2,117.4,117.8,119.7,123.1,123.6,124.3(q,J _C,F ＝270.5Hz),125.2,125.8,128.3,130.3,133.3,139.0,145.1 ,147.7,150.0,156.3,160.8,192.1; HRMS(ESI-TOF)m/z:Calcd.for C ₂₀ H ₁₄ F ₃ NNaO ₅ [M+Na] ⁺ :428.0716; Found: 428.0717.

In this Example 3, compound 3jc was prepared: yellow solid, melting point: 109.7-110.5°C; yield 83%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 2.25 (s, 3H), 5.04-5.11 (m, 2H), 6.62-6.65 (m, 1H), 6.72-6.74 (m, 2H), 6.89 (d, J＝8.4 Hz, 1H), 7.18 (d, J＝2.0 Hz, 1H), 7.21-7.24 (m, 1H), 7.87 (d, J＝2.8 Hz, 1H), 8.29 (d, J＝2.0 Hz, 1H), 8.73 (br s, 1H), 8.80 (br s, 1H), 10.03 (br s, 1H); ¹³ C NMR (DMSO-d ₆ , 100MHz) δ: 20.4, 48.1 (q, J _{C, F} = 35.8Hz), 116.5, 117.0, 117.2, 117.4, 117.8, 123.1, 123.6, 124.3 (q, J _{C, F} = 270.6Hz), 124.7, 125.9, 128.3,130.5,134.0,139.2,145.0,147.7,150.0,154.3,160.8,192.3; HRMS(ESI-TOF)m/z:Calcd.for C ₂₁ H ₁₆ F ₃ NNaO ₅ [M+Na] ⁺ :442.0873; Found: 442.0876.

In this Example 3, compound 3ja was prepared: yellow solid, melting point: 145.3-146.6°C; yield 87%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 2.99-3.00 (m, 2H), 4.29-4.32 (m, 2H), 6.79-6.83 (m, 1H), 6.87-6.92 (m, 2H), 6.96 (d, J＝8.0 Hz, 1H), 7.13-7.17 (m, 1H), 7.24-7.26 (m, 1H), 7.36-7.40 (m, 2H), 7.85 (d, J＝2.4 Hz, 1H), 8.35 (d, J＝2.4 Hz, 1H), 9.36 (br s, 1H), 10.27 (br s, 1H); ¹³ C NMR (DMSO-d ₆ ,100MHz) δ: 17.3, 46.3, 116.7, 117.3, 117.5, 118.7, 119.3, 119.7, 123.6, 124.9, 128.2, 129.7, 130.6, 131.4, 133.4, 139. 1,144.8,155.4,156.9,161.1,192.5; HRMS(ESI-TOF)m/z:Calcd.for C ₂₁ H ₁₆ N ₂ NaO ₄ [M+Na]+: 383.1002; Found: 383.1009.

In this Example 3, compound 3ka was prepared: yellow solid, melting point: 155.2-156.1°C; yield 91%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (CDCl ₃ , 400MHz) δ: 0.87-0.90 (m, 3H), 1.74-1.93 (m, 2H), 2.63 (br s,1H),3.85(d,J=4.0Hz,2H),5.03-5.09(m,1H),6.81-7.01(m,4H),7.15-7.18(m,1H),7.21-7.25(m,1H),7.42-7.46(m,1H),7.52-7.54(m,1H),7. 31(d,J＝2.4Hz,1H),8.10(d,J＝2.4Hz,1H),8.88(br s,1H),11.42(br s,1H); ¹³ C NMR (CDCl ₃ ,100MHz)δ:10.6,23.1,53.5,62.9,118.7,118.8,119.0,119.2,119.6,121.1,124.5,130.6,130.7,130.9,131.9,136.6,139.6,140.0,155.9,162 .7,163.2,195.5; HRMS(ESI-TOF)m/z:Calcd.for C ₂₂ H ₂₁ NNaO ₅ [M+Na] ⁺ :402.1312; Found: 402.1317.

In this Example 3, compound 3kb was prepared: yellow solid, melting point: 175.6-176.7°C; yield 87%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 0.85-0.88 (m, 3H), 1.17-1.20 (m, 6H), 1.67-1.74 (m, 1H), 1.81-1.88 (m, 1H), 2.83-2.89 (m, 1H), 3.62-3.65 (m, 1H), 3.73-3.76 (m, 1H), 4.91 (br s, 1H), 5.09 (br s,1H),6.84-6.88(m,1H),6.92-6.96(m,2H),7.18-7.22(m,1H),7.28-7.32(m,3H),7.88(d,J＝2.4Hz,1H),8.18(d,J＝2.4Hz,1H),9.41(br s,1H),10. 20(br s,1H); ¹³ C NMR(DMSO-d ₆ ,100MHz)δ:10.8,23.3,24.3,24.4,33.0,61.8,116.8,116.9,117.2,119.4,124.3,124.4,128.0,129.6,131.4,131.6,138.0,139.4,155.0,155.5 ,161.7,192.7; HRMS(ESI-TOF)m/z:Calcd.for C ₂₅ H ₂₇ NNaO ₅ [M+Na] ⁺ :444.1781; Found:444.1786.

In this Example 3, compound 31a was prepared: yellow solid, melting point: 135.9-136.2°C; yield 89%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 0.77 (d, J = 7.2 Hz, 3H), 1.04 (d, J = 6.4 Hz, 3H), 2.14 (br s, 1H), 3.64 (d, J = 10.4 Hz, 1H), 3.87 (d, J = 6.4 Hz, 1H), 4.71 (br s, 1H), 5.05 (br s,1H),6.84-6.88(m,1H),6.90-6.97(m,2H),7.00(d,J＝8.0Hz,1H),7.17-7.22(m,1H),7.27-7.30(m,1H),7.38-7.43(m,2H),7.87(d,J＝2.8Hz,1H) ,8.24(d,J＝2.4Hz,1H),9.40(br s,1H),10.28(br s,1H); ¹³ C NMR(DMSO-d ₆ ,100MHz)δ:19.6,21.2,28.5,60.2,116.8,116.9,117.1,119.4,119.7,124.4,125.2,127.9,129.5,130.4,131.4,133.2,137.9,155.5,156.4,161 .9,170.8,192.5; HRMS(ESI-TOF)m/z:Calcd.forC ₂₃ H ₂₃ NNaO ₅ [M+Na]+: 416.1468; Found: 416.1472.

In this Example 3, compound 31b was prepared: yellow solid, melting point: 126.5-127.2°C; yield 90%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 2.31 (s, 3H), 3.28 (s, 3H), 3.62-3.64 (m, 2H), 4.23-4.26 (m, 2H), 6.77-6.92 (m, 4H), 7.17-7.21 (m, 1H), 7.27-7.30 (m, 1H), 7.35 (d, J＝7.6 Hz, 1H), 7.84 (d, J＝2.8 Hz, 1H), 8.20 (d, J＝2.4 Hz, 1H), 9.41 (br s, 1H), 10.47 (br s, 1H); ¹³ C NMR (DMSO-d ₆ ,100MHz) δ: 19.6, 21.1, 28.5, 60.2, 115.9 (d, J _CF = 24.4Hz), 116.4, 116.7, 118.1 (d, J _CF = 7.3Hz), 119.3, 119.4 (d, J _CF = 23.3Hz), 124.3, 12 6.4,126.5,127.9,129.5,131.4,137.4,152.0,155.4,155.5(d,J _CF =234.5Hz),161.8,170.8,190.7; HRMS(ESI-TOF)m/z:Calcd.for C ₂₃ H ₂₂ FNNaO ₅ [M+Na]+:434.1374; Found:434.1374.

In this Example 3, compound 31c was prepared: yellow solid, melting point: 176.5-177.1°C; yield 87%; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 0.78 (d, J = 6.8 Hz, 3H), 1.05 (d, J = 6.4 Hz, 3H), 2.15 (s, 1H), 2.25 (s, 3H), 3.64 (d, J = 12.0 Hz, 1H), 3.87-3.89 (m, 1H), 4.71 (br s, 1H), 5.06 (br s,1H),6.83-6.92(m,3H),7.17-7.24(m,3H),7.27-7.30(m,1H),7.86(d,J＝2.8Hz,1H),8.24(s,1H),9.40(br s,1H),10.11(br s,1H); ¹³ C NMR(DMSO-d ₆ ,100MHz)δ:19.7,20.4,21.2,28.5,60.2,116.8,116.9,117.0,119.4,124.4,124.6,127.8,128.3,129.5,130.7,131.4,134.0,137.9,154.5,155. 4,161.8,192.6; HRMS(ESI-TOF)m/z:Calcd.for C ₂₄ H ₂₅ NNaO ₅ [M+Na]+: 430.1625; Found: 430.1627.

The compound of formula (1) of the present invention has potential important biological activity. The component target molecule docking screening active component test shows that the compound of formula (1) of the present invention has potential important biological activity and can be used as a potential inhibitor of the new coronavirus 3CL hydrolase.

Pharmacological Example: Ingredient-target Molecular Docking Screening for Active Ingredients

The specific method for preparing the molecular docking ligand and receptor is as follows: the mo12 structure of the compound of formula (1) of the present invention is energy optimized by selecting the MMFF94 force field through Open Babel GUI and saving it in mol2 format; assigning the ligand atom type and performing charge calculation through AutoDockTools-1.5.6, defining all flexible bonds as rotatable, and saving it in pdbqt format; downloading the PDB format of SARS-CoV-23CL hydrolase from the PDB database, importing it into PyMOL software to remove water molecules and separate proteins; importing it into AutoDockTools-1.5.6 to add polar hydrogen, calculate the Gasteiger charge and assign the charge, and saving it in pdbqt file.

The specific method for screening active ingredients by ingredient-target molecular docking is: AutoDockTools software sets the receptor grid parameter text file, energy_range=3, num_modes=10, exhaustiveness=8; Autodock Vina software is used to perform docking in a Linux virtual environment, and the compounds with small binding free energy and good conformation are selected as the results; compounds with binding energy ≤-5.0 kJ/mol are selected as active ingredients of potential inhibitors of the novel coronavirus 3CL hydrolase.

This patent uses the location of the ligand on the protein structure as the active site center and uses the molecular docking method to calculate the binding energy and potential binding mode of small molecule compounds and proteins. The active site is mainly composed of amino acids Thr26, His41, Met49, etc., most of which are neutral and hydrophilic amino acids (Figure 8), so the hydrophobic interaction between the active compound and the protein is weak.

Active site amino acid information,

The molecular docking model analysis results of the salicylic acid spliced pyridone compound-3CL hydrolase of formula (1) of the present invention show that 3ab and 3ga have the best results, with a binding energy of -7.8 kg/mol for 3ab and a binding energy of -8.6 kg/mol for 3ga. The molecular docking model diagram is shown in Figure 9, in which hydrogen bonds play a key role in the binding of ligands to receptors.

(1) Molecular docking results of small molecule 3ab and protein 6LU7; The protein structure 6LU7 was molecularly docked with small molecule 3ab, and its binding energy was -7.8 kg/mol. The hydroxyl group -OH on the benzene ring had hydrogen bonds with amino acids Glu166 and Phe140, and the bond lengths were and The nitrogen atom on the pyridine ring has a hydrogen bond with Ser144, and the bond length is The -N- atom connected to the benzene ring has a hydrogen bond with the amino acid Asn, and the bond length is

(2) Molecular docking results of small molecule 3ga and protein 6LU7: The protein structure 6LU7 was molecularly docked with small molecule 3ga, and its binding energy was -8.6 kg/mol. The hydroxyl group on the benzene ring had a hydrogen bond with the amino acid Gln189, and the bond length was The =O atom on the pyridine ring has a hydrogen bond with Gly143, and the bond length is The small molecule 3ga is distributed in the active site in a triangular shape, and the benzene ring and other groups are subject to strong hydrophobic forces and van der Waals forces.

Experimental conclusion: It is generally believed that the more stable the conformation of the ligand binding to the receptor, the lower the energy required, and the greater the possibility of its action. The binding energy of the ligand to the receptor is ≤-5.0kJ/mol, indicating that the active ingredient has good binding activity with the target related to the new coronary pneumonia. The present invention uses molecular docking technology to perform molecular docking screening on the active ingredients of the compound of formula (1) of the present invention. The screening shows that: with -5.0kcal/mol as the screening standard, 3CL hydrolase has good binding activity with the active ingredient of the compound of formula (1), indicating that the active ingredient of the salicylic one spliced pyridone compound shown in formula (1) may directly act on the replication process of the new coronavirus 3CL hydrolase, and can be used as a potential inhibitor of the new coronavirus 3CL hydrolase, which is worth further in-depth study.

Claims (5)

1. A salicylic acid-pyridone compound, characterized in that the compound has a structure as shown in the general formula (I): Specifically, it is one of the following structural formulas: 2. A method for preparing a salicylic acid-splicing pyridone compound as claimed in claim 1, characterized in that: various substituted 3-olefin chromone oxidized indole/benzofuranone 1 and various amine sources 2 are subjected to Michael addition-induced ring opening and re-ring closure reactions in a solvent in the absence of a catalyst and at room temperature to obtain a salicylic acid-splicing pyridone compound; the various amine sources 2 are ammonium acetate, ammonium bicarbonate, ammonium carbonate, ammonia water or alkylamine. 3. The method for preparing a salicylic acid-splicing pyridone compound according to claim 2, wherein the solvent is water, toluene, ethanol, dichloromethane, chloroform or acetonitrile. 4. The method for preparing a salicylic acid-pyridone compound according to claim 2, wherein the reaction time is 2-6 hours. 5. An application of the salicylic acid-spliced pyridone compound as claimed in claim 1 in the preparation of a drug for a potential inhibitor of 3CL hydrolase of the new coronavirus.