A triazole-fused piperidinone derivative, its preparation method and application

Abstract

This invention relates to the field of medicinal chemistry, specifically disclosing a triazole-fused piperidinone derivative, its preparation method, and its application. The triazole-fused piperidinone derivative has the structure shown in Formula I; wherein, R... 1 Selected from alkyl, phenyl, substituted phenyl, naphthyl ring, furan ring, thiophene ring, or pyridine ring; R 2 Selected from alkyl, allyl, or benzyl; R 3 The derivatives are selected from alkyl, phenyl, substituted phenyl, acyl, or sulfonyl groups. Studies have shown that the triazole-fused piperidinone derivatives described herein possess certain antiviral activity. Furthermore, the preparation method described in this invention can be carried out under mild conditions, is simple to operate, involves few steps, has good functional group compatibility, and yields high results. Therefore, this method has promising application prospects in pharmaceutical industrial production.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a triazole-fused piperidinone derivative, its preparation method, and its application. Background Technology

[0002] Piperidone and triazole ring systems are core structural units constituting many natural products and bioactive molecules. Due to the presence of highly electronegative heteroatoms such as oxygen and nitrogen, they exhibit strong intermolecular forces with many biomolecules, making them a class of structurally unique and active compounds, widely regarded as "advantageous structures" in drug design. Although triazole-fused piperidinone compounds are widely found in various drug and bioactive molecules, the efficient synthesis of these skeletons remains a challenge, with only a few synthetic methods reported to date.

[0003] In 2007, Ioffe's group reported a method for synthesizing triazole piperidinones from α-azidosubstituted oximes and methyl butynedioate (Russ. J. Org. Chem., 2007, 43, 1218-1222). The reaction mechanism involves the cycloaddition of azido and butynedioate esters and the high-pressure reductive lactamation of the oxime. Because the reduction of the oxime requires hydrogen at 80 atmospheres, the reaction conditions are extremely harsh, limiting the widespread application of this method.

[0004]

[0005] In 2019, Kuduk's group reported a method for synthesizing triazolepiperidone from amino-substituted oxetane and triazolecarboxylic acid (Org. Lett. 2019, 21, 9642−9645). The reaction mechanism involves dehydration condensation of amino-substituted oxetane and triazolecarboxylic acid followed by base-promoted intramolecular nucleophilic substitution ring-opening. It is readily apparent that Kuduk's group's synthetic method suffers from drawbacks such as a long route and difficulty in modifying the product structure.

[0006] Furthermore, there is limited research on the antiviral activity of triazole-fused piperidinone structures; therefore, developing efficient synthetic methods for triazole-fused piperidinones and providing triazole-fused piperidinone compounds with antiviral activity, especially those with excellent antiviral activity, has significant application value. Summary of the Invention

[0007] To overcome at least one technical problem existing in the prior art, the present invention provides a triazole fused piperidinone derivative, its preparation method and application; studies have shown that the triazole fused piperidinone derivative has antiviral activity and can be used to further develop drugs with antiviral activity.

[0008] The technical solution of the present invention is as follows: A triazole-fused piperidinone derivative having the structure shown in Formula I: Formula I; Where R 1 Selected from alkyl, phenyl, substituted phenyl, naphthyl ring, furan ring, thiophene ring or pyridine ring; R 2 Selected from alkyl, allyl, or benzyl; R 3 It is selected from alkyl, phenyl, substituted phenyl, acyl or sulfonyl groups.

[0009] 2. The triazole-fused piperidinone derivative according to claim 1, characterized in that: Where R 1 Selected from alkyl, phenyl, substituted phenyl, naphthyl ring, furan ring, thiophene ring or pyridine ring; R 2 Selected from alkyl, allyl, or benzyl; R 3 It is selected from alkyl, phenyl, substituted phenyl, acyl or sulfonyl groups.

[0010] Preferably, R 1 It is selected from methyl, phenyl, substituted phenyl or thiophene ring.

[0011] Preferably, R 2 Selected from benzyl, phenethyl and cyclopropylmethyl.

[0012] Preferably, R 3 It is selected from benzenesulfonyl, substituted benzenesulfonyl and benzoyl.

[0013] Preferably, the triazole-fused piperidinone derivative is selected from compounds having the following structure:

[0014]

[0015]

[0016]

[0017]

[0018]

[0019] .

[0020] The present invention also provides a method for preparing the above-mentioned triazole fused piperidinone derivatives, which uses propargylamide compounds and sodium azide as raw materials, then adds solvent and alkali, and carries out the reaction under heating conditions. After the reaction is completed, the target product is separated to obtain the triazole fused piperidinone derivatives.

[0021] This invention provides a novel method for preparing triazole-fused piperidinone derivatives. This innovative method utilizes a thermally promoted, sequential [3+2] cycloaddition / intramolecular nucleophilic substitution ring-opening reaction of propargylamide compounds and sodium azide to efficiently construct triazole-fused piperidinone derivatives in one step. Using propargylamide compounds and sodium azide as substrates, the method yields triazole-fused piperidinone compounds through cycloaddition / nucleophilic substitution ring-opening under heating and alkaline conditions. It offers advantages such as readily available starting materials, no transition metal catalysts, simple synthesis conditions, few steps, high yield, and wide substrate applicability, making it suitable for large-scale production and application in the pharmaceutical and chemical industries.

[0022] Preferably, the propyne amide compounds have the structure shown in Formula II; Formula II; In Equation II, R 1 Selected from alkyl, phenyl, substituted phenyl, naphthyl ring, furan ring, thiophene ring, or pyridine ring; R 2 Selected from alkyl, allyl, or benzyl; R 3 It is selected from alkyl, phenyl, substituted phenyl, acyl or sulfonyl groups.

[0023] More preferably, R 1 Selected from methyl, phenyl, substituted phenyl, or thiophene rings; Preferably, R 2 Selected from benzyl, phenethyl and cyclopropylmethyl.

[0024] Preferably, R 3 It is selected from benzenesulfonyl, substituted benzenesulfonyl and benzoyl.

[0025] Preferably, the solvent is water, dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran, toluene, and N,N-dimethylformamide.

[0026] Preferably, the alkali is K2CO3, Cs2CO3, K3PO4, NaHCO3, NaOH, KOH, CSOH, CsF, or tBuOLi.

[0027] Most preferably, the solvent is dimethyl sulfoxide.

[0028] Most preferably, the alkali is NaHCO3.

[0029] Preferably, the molar ratio of the base to the propyne amide compound is 0.5 to 1.5:1.

[0030] More preferably, the molar ratio of the base to the propyne amide compound is 1:1.

[0031] Preferably, the molar ratio of the propyne amide compound to sodium azide is 1 to 2:1.

[0032] Preferably, the reaction temperature is 30~100 ℃.

[0033] Most preferably, the preparation method of triazole fused piperidinone derivative is as follows: a propargylamide compound and sodium azide are dissolved in an organic solvent, an alkali is added, and the mixture is reacted at 80 °C for 12 hours. The triazole fused piperidinone compound 2 is obtained by column chromatography.

[0034] The present invention also provides the application of the above-mentioned triazole fused piperidinone derivative in the preparation of a drug with antiviral activity.

[0035] Preferably, the virus is herpes simplex virus.

[0036] Beneficial effects: (1) This invention provides a novel triazole-fused piperidinone derivative, and studies have shown that the triazole-fused piperidinone derivative has a certain anti-herpes simplex effect.

[0037] (2) The inventors discovered in their research that, in the core structure of the triazole-fused piperidinone derivatives described in this invention, R 1 R 2 R 3 The compounds obtained by substituting different groups exhibit significantly different anti-herpes simplex effects; among them, R... 3 Compounds substituted with benzenesulfonyl groups exhibit better anti-herpes simplex virus activity compared to R. 3 Compounds substituted with acyl and benzyl groups showed significantly enhanced antiviral activity against herpes simplex virus. The inventors were surprised to discover in further research that R... 2The substitution of the functional groups with cyclopropylmethylene and cyclobutylmethylene groups results in excellent anti-herpes simplex virus activity; compared to compounds obtained by substitution with other functional groups, the anti-herpes simplex virus activity is significantly improved. In summary, the triazole-fused piperidinone derivatives described in this invention have broad application prospects for developing drugs with anti-herpes simplex virus activity.

[0038] (3) In addition, the present invention provides a novel, efficient and simple method for preparing triazole-fused piperidinone derivatives; it does not require expensive transition metal catalysts, the reaction is carried out under mild conditions, the operation is simple, the steps are few, the functional groups are compatible and the yield is high; therefore, this method has good application prospects in pharmaceutical industrial production. Attached Figure Description

[0039] Figure 1 This is a synthetic route diagram of the triazole-fused piperidinone derivatives of the present invention. Detailed Implementation

[0040] The present invention will be further illustrated below with reference to specific embodiments, but the embodiments do not limit the scope of protection of the present invention. Unless otherwise specified, the reagents, methods and equipment used in the following embodiments are conventional reagents, methods and equipment in the art.

[0041] Example 1: Preparation of Compound 1 The starting compound 1 of this invention is prepared by the dehydration condensation reaction of a propynic acid compound with an amino-substituted nitrogen-containing heterocyclic butane. The specific synthetic method is as follows: 25 mL of dry dichloromethane (DCM) and carbodicyclohexylimine (DCC) (6 mmol) were added sequentially to a reaction flask containing propynic acid compound S-1 (5 mmol) and amino-substituted nitrogen-containing heterocyclic butane S2 (5 mmol). The reaction mixture was stirred at 25 °C for 12 hours, then concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain a white solid product 1 (overall reaction yield 65-80%). The synthetic reaction formula is shown below: ; Where R 1 Selected from alkyl, phenyl, substituted phenyl, naphthyl ring, furan ring, thiophene ring, or pyridine ring; R 2 Selected from alkyl, allyl, or benzyl; R 3 It is selected from alkyl, phenyl, substituted phenyl, acyl or sulfonyl groups.

[0042] Preferably, R 1 Selected from methyl, phenyl, substituted phenyl, or thiophene rings; Preferably, R 2 Selected from benzyl, phenethyl and cyclopropylmethyl.

[0043] Preferably, R 3 It is selected from benzenesulfonyl, substituted benzenesulfonyl and benzoyl.

[0044] Those skilled in the art, according to R 1 R 2 and R 3 By using the above selection and the above method, compounds with the structures shown in 1a~1u can be prepared.

[0045] The synthetic reaction formula for compound 1a is shown below:

[0046] 25 mL of dry dichloromethane (DCM) was added sequentially to reaction flasks containing propargylamide S1a (730.0 mg, 5.0 mmol), S2a (1.58 g, 5.0 mmol), and DCC (1.23 g, 6.0 mmol). The reaction mixture was stirred at room temperature for 12 hours, followed by concentration under reduced pressure to remove the solvent. The residue was separated by column chromatography to give a white solid product 1a (1.52 g, yield 71%). 1 H NMR (400 MHz, CDCl3, two rotamers). δ 7.84-7.81(m, 2H), 7.77-7.47 (m, 4H), 7.44-7.24 (m, 7H), 7.16-6.98 (m, 2H), 5.35&4.81 (m, 1H), 4.80&4.51 (s, 2H), 4.07-3.79 (m, 4H). 13 C NMR (100 MHz, CDCl3, two rotamers) δ155.6, 154.7, 136.5, 134.3, 133.6, 133.5, 132.5, 132.5, 130.7, 130.5, 129.5,129.3, 129.1, 128.9, HRMS (ESI) calcd forC 25 H 23 N2O3S + (M+H) + 431.1424, found 431.1425. The synthetic reaction formula for compound 1b is shown below:

[0047] 25 mL of dry dichloromethane (DCM) was added sequentially to reaction flasks containing propargylamide S1a (730.0 mg, 5.0 mmol), S2b (1.58 g, 5.0 mmol), and DCC (1.23 g, 6.0 mmol). The reaction mixture was stirred at room temperature for 12 hours, followed by concentration under reduced pressure to remove the solvent. The residue was separated by column chromatography to give a white solid product 1b (1.91 g, yield 86%). 1 H NMR (400 MHz, CDCl3, two rotamers). δ 7.73-7.67 (m, 2H), 7.61-7.45 (m, 1H), 7.44-7.25 (m, 9H), 7.16-6.99 (m, 2H), 5.33&4.83 (m, 1H), 4.80&4.51(m, 2H), 4.03-3.75 (m, 4H), 2.53&2.51 (m, 3H). 13 C NMR (100 MHz, CDCl3, two rotamers) δ 155.6, 144.4, 136.5, 132.5, 132.5, 131.1, 130.4, 130.1,129.9, 129.1, 128.8, 128.7, 128.5, HRMS (ESI)calcd for C 26 H 25 N2O3S + (M+H) + 445.1580, found 445.1576. The synthetic reaction formula for compound 1c is shown below:

[0048] 25 mL of dry dichloromethane (DCM) was added sequentially to reaction flasks containing propargylamide S1a (730.0 mg, 5.0 mmol), S2c (1.73 g, 5.0 mmol), and DCC (1.23 g, 6.0 mmol). The reaction mixture was stirred at room temperature for 12 hours, followed by concentration under reduced pressure to remove the solvent. The residue was separated by column chromatography to give a white solid product 1c (1.85 g, yield 78%). 1 H NMR (400 MHz, CDCl3, two rotamers). δ 8.42-8.38 (m, 2H), 8.0-7.96 (m, 2H), 7.58-7.48 (m, 1H), 7.44-7.37 (m, 3H), 7.37-7.30 (m, 4H), 7.18-7.05 (m, 2H), 5.36&4.62 (m, 1H), 4.84&4.67 (2s, 2H), 4.12-3.93 (m, 4H). 13 CNMR (100 MHz, CDCl3, two rotamers) δ155.6, 150.5, 140.8, 136.2, 132.5, 130.6,129.4, 129.2, 128.6, 128.3, 126.5, 124.5, 119.6, 91.1, 55.7, 55.2, 51.3,44.9. HRMS (ESI) calcd for C 25 H 22 N3O5S + (M+H) + 476.1275, found 476.1278. The synthetic reaction formula for compound 1d is shown below:

[0049] 25 mL of dry dichloromethane (DCM) was added sequentially to reaction flasks containing propargylamide S1a (730.0 mg, 5.0 mmol), S2d (1.73 g, 5.0 mmol), and DCC (1.23 g, 6.0 mmol). The reaction mixture was stirred at room temperature for 12 hours, followed by concentration under reduced pressure to remove the solvent. The residue was separated by column chromatography to give a white solid product 1d (1.59 g, yield 67%). 1 H NMR (400 MHz, CDCl3, two rotamers). δ 8.09-7.96 (m, 1H), 7.83-7.67 (m, 3H), 7.63-7.46 (m, 1H), 7.45-7.38 (m, 3H), 7.38-7.29 (m, 4H), 7.27-7.17 (m, 2H), 5.41&4.75 (m, 2H), 4.98&4.84 (m, 1H), 4.34-4.11 (m, 4H). 13 C NMR(100 MHz, CDCl3, two rotamers) δ 155.6, 136.3, 133.9, 132.5, 132.1, 132.0,131.4, 130.8, 130.5, 129.2, 128.9, 128.7, 128.6, 128.2, 126.8, 126.6, 124.4,119.8, 90.9, 56.4, 55.90, 51.0, 46.7, 45.2, 44.2. HRMS (ESI) calcd forC 25 H 22 N3O3S + (M+H) + 444.1376, found 444.1382. The synthetic reaction formula for compound 1e is shown below:

[0050] 25 mL of dry dichloromethane (DCM) was added sequentially to reaction flasks containing propargylamide S1a (730.0 mg, 5.0 mmol), S2e (1.60 g, 5.0 mmol), and DCC (1.23 g, 6.0 mmol). The reaction mixture was stirred at room temperature for 12 hours, followed by concentration under reduced pressure to remove the solvent. The residue was separated by column chromatography to give a white solid product 1e (1.45 g, yield 65%). 1 H NMR (400 MHz, CDCl3, two rotamers). δ 7.87-7.79 (m, 2H), 7.60-7.47 (m, 1H), 7.46-7.22 (m, 9H), 7.20-7.02 (m, 2H), 4.83 (s, 1H), 5.36&4.76(m, 1H), 4.83&4.61 (s, 1H), 4.07-3.80 (m, 4H). 13C NMR (100 MHz, CDCl3, tworotamers) δ 166.9&164.3 (2d, J = 260.0 Hz), 155.6, 154.7, 136.7, 136.4,132.5, 131.1, 131.0, 130.7, 130.5, 129.1, 128.9&128.8 (2d, J = 10.0 Hz), 128.6, 128.1, 127.6, 126.3, 119.7, 116.9, 116.7, 116.7& 116.5 (2d, J = 20.0Hz), 92.4, 91.0, 81.3, 55.4, 55.1, 50.5, 46.9, 44.9, 44.2. HRMS (ESI) calcdfor C 25 H 22 FN2O3S + (M+H) + 449.1330, found 449.1323. The synthetic reaction formula for compound 1f is shown below:

[0051] 25 mL of dry dichloromethane (DCM) was added sequentially to reaction flasks containing propargylamide S1a (730.0 mg, 5.0 mmol), S2f (1.40 g, 5.0 mmol), and DCC (1.23 g, 6.0 mmol). The reaction mixture was stirred at room temperature for 12 hours, followed by concentration under reduced pressure to remove the solvent. The residue was separated by column chromatography to give a white solid product 1f (1.38 g, yield 68%). 1 H NMR (400 MHz, CDCl3, two rotamers) δ 7.57-7.46 (m, 2H), 7.44-7.39 (m, 2H), 7.39-7.34 (m, 2H), 7.34-7.22 (m, 6H), 7.16 (d, J = 8.1 Hz, 2H),5.44&4.81(m, 2H), 5.19-4.88 (m, 2H), 4.53-4.23 (m, 4H), 2.78&2.35 (s, 3H). 13CNMR (100 MHz, CDCl3, two rotamers) δ 170.4, 155.6, 154.9, 141.8, 141.6,137.2, 136.6, 132.5, 132.5, 130.6, 130.4, 129.9, 129.7, 129.1, 129.1, 129.0,128.9, 128.7, 128.6, 128.1, 127.9, 127.9, 127.6, 126.8, 126.7, 119.9, 119.9,92.2, 90.7, 81.7, 51.1, 48.5, 45.9, 45.5, 38.6, 21.5. HRMS (ESI) calcd forC 27 H 25 N2O2 + (M+H) + 409.1911, found 409.1919. The synthesis reaction formula for 1g of compound is shown below:

[0052] 25 mL of dry dichloromethane (DCM) was added sequentially to reaction flasks containing propargylamide S1a (730.0 mg, 5.0 mmol), S2g (1.26 g, 5.0 mmol), and DCC (1.23 g, 6.0 mmol). The reaction mixture was stirred at room temperature for 12 hours, followed by concentration under reduced pressure to remove the solvent. The residue was separated by column chromatography to give 1 g (1.15 g, yield 61%) of a white solid product. 1 H NMR (400 MHz, CDCl3, two rotamers) δ 7.59 (dd, J = 8.3, 1.6Hz, 1H), 7.48-7.41 (m, 2H), 7.41-7.37 (m, 2H), 7.37-7.29 (m, 6H), 7.28-7.22(m, 4H), 5.01&4.90 (s, 2H), 5.18&4.65 (m, 1H), 3.64-3.55 (m, 4H), 3.22-3.12(m, 2H). 13 C NMR (100 MHz, CDCl3, two rotamers) δ 155.3, 154.9, 137.7, 137.6,137.4, 137.3, 132.5, 130.2, 130.1, 128.9, 128.7, 128.7, 128.6, 128.5, 128.5,128.5, 128.4, 127.7, 127.3, 127.3, 127.1, 126.9, 126.7, 120.3, 120.3, 91.5,90.0, 82.1, 63.3, 63.2, 59.3, 59.0, 50.8, 49.1, 46.5, 45.7. HRMS (ESI) calcdfor C 26 H 25 N2O2 + (M+H) + 381.1961, found 381.1957. The synthetic reaction formula for compound 1h is shown below:

[0053] 25 mL of dry dichloromethane (DCM) was added sequentially to reaction flasks containing propargylamide S1b (800.0 mg, 5.0 mmol), S2b (1.58 g, 5.0 mmol), and DCC (1.23 g, 6.0 mmol). The reaction mixture was stirred at room temperature for 12 hours, followed by concentration under reduced pressure to remove the solvent. The residue was separated by column chromatography to give a white solid product 1 h (1.83 g, yield 80%). 1 H NMR (400 MHz, CDCl3, two rotamers). δ 7.74-7.50 (m, 2H), 7.42-7.21 (m, 7H), 7.18-6.96 (m, 3H), 5.40&4.81 (m, 1H), 4.82&4.51 (s, 2H), 4.05-3.74 (m, 4H), 2.55&2.15 (m, 6H). 13 C NMR (100 MHz, CDCl3, two rotamers) δ 155.8, 154.9, 144.7, 144.4, 141.6, 141.5, 136.8, 136.5, 133.1, 133.1, 131.1, 130.8, 130.7, 130.5, 130.1, 130.0, 129.9, 129.7, 129.0, 128.8, 128.5, 128.4, 127.9, 127.5, 126.3, 126.1, 125.9, 125.8, 119.6, 91.5, 90.0, 85.1, 84.4, 55.4, 55.1, 49.8, 46.9, 44.7, 43.7, 21.7, 20.4. HRMS (ESI) calcd forC 27 H 27 N2O3S + (M+H) + 459.1737, found 459.1732. The synthetic reaction formula for compound 1i is shown below:

[0054] 25 mL of dry dichloromethane (DCM) was added sequentially to reaction flasks containing propargylamide S1c (800.0 mg, 5.0 mmol), S2b (1.58 g, 5.0 mmol), and DCC (1.23 g, 6.0 mmol). The reaction mixture was stirred at room temperature for 12 hours, followed by concentration under reduced pressure to remove the solvent. The residue was separated by column chromatography to give a white solid product 1i (1.83 g, yield 80%). 1 H NMR (400 MHz, CDCl3, two rotamers). δ 7.69 (m, 2H), 7.43-7.25(m, 6H), 7.22-6.96 (m, 5H), 5.33&4.81 (m, 1H), 4.78&4.49 (m, 2H), 4.05-3.73(m, 4H), 2.52&2.49 (m, 3H), 2.39&2.29 (m, 3H). 13C NMR (100 MHz, CDCl3, tworotamers) δ 155.7, 154.8, 144.6, 144.4, 138.6, 138.4, 136.8, 136.6, 132.9,131.5, 131.4, 131.1, 130.9, 130.1, 129.9, 129.7, 129.6, 129.0, 128.8, 128.6,128.5, 128.4, 127.9, 127.5, 126.3, 126.3, 119.6, 119.5, 92.7, 91.3, 81.1,55.5, 55.1, 49.9, 46.9, 44.8, 43.8, 21.7, 21.7, 21.2, 21.1. HRMS (ESI) calcdfor C 27 H 27 N2O3S + (M+H) + 459.1737, found 459.1741. The synthetic reaction formula for compound 1j is shown below:

[0055] 25 mL of dry dichloromethane (DCM) was added sequentially to reaction flasks containing propargylamide S1d (800.0 mg, 5.0 mmol), S2b (1.58 g, 5.0 mmol), and DCC (1.23 g, 6.0 mmol). The reaction mixture was stirred at room temperature for 12 hours, followed by concentration under reduced pressure to remove the solvent. The residue was separated by column chromatography to give a white solid product 1j (1.67 g, yield 73%). 1 H NMR (400 MHz, CDCl3, two rotamers). δ 7.71-7.68 (m, 2H), 7.49-7.41 (m, 1H), 7.41-7.30 (m, 4H), 7.29-7.21 (m, 3H), 7.18-6.96 (m, 3H), 5.33&4.82 (m, 1H), 4.79&4.50 (m, 2H), 4.06-3.75 (m, 4H), 2.53&2.50 (m, 3H), 2.42&2.35 (m, 3H). 13C NMR (100 MHz, CDCl3, two rotamers) δ 155.8, 154.9, 144.6,144.4, 141.3, 141.1, 136.8, 136.6, 132.5, 132.5, 131.1, 130.9, 130.1, 129.9,129.5, 129.3, 129.0, 128.8, 128.3, 128.4, 127.9, 127.5, 126.3, 126.3, 116.7,116.6, 92.9, 91.5, 81.1, 55.5, 55.1, 49.9, 46.9, 44.8, 43.7, 21.7, 21.7,21.7. HRMS (ESI) calcd for C 27 H 27 N2O3S + (M+H) + 459.1737, found 459.1743. The synthetic reaction formula for compound 1k is shown below:

[0056] 25 mL of dry dichloromethane (DCM) was added sequentially to reaction flasks containing propargylamide S1e (880.0 mg, 5.0 mmol), S2b (1.58 g, 5.0 mmol), and DCC (1.23 g, 6.0 mmol). The reaction mixture was stirred at room temperature for 12 hours, and the solvent was removed by concentration under reduced pressure. The residue was separated by column chromatography to give a white solid product 1k (1.68 g, yield 71%). 1 H NMR (400 MHz, CDCl3, two rotamers). δ 7.69 (m, 2H), 7.55-7.40 (m,1H), 7.40-7.22 (m, 6H), 7.13 (d, J = 8.3 Hz, 1H), 7.01 – 6.90 (m, 1H), 6.85 –6.77 (m, 1H), 5.32&4.82 (m, 1H), 4.77&4.48 (m, 2H), 4.40&3.90 (m, 2H), 3.87 –3.78 (m, 4H), 3.78-3.75 (m, 1H), 2.52&2.49 (s, 3H). 13C NMR (100 MHz, CDCl3, two rotamers) δ 161.5, 161.3, 155.9, 155.0, 144.6, 144.4, 136.8, 136.7,134.4, 134.4, 131.1, 130.9, 130.1, 129.9, 129.0, 128.8, 128.4, 128.4, 127.8,127.4, 126.2, 126.2, 114.4, 114.2, 111.6, 111.5, 93.1, 91.7, 80.9, 55.5,55.4, 55.1, 49.9, 46.9, 44.8, 43.7, 21.7, 21.7. HRMS (ESI) calcd forC 27 H 27 N2O4S + (M+H) + 475.1686, found 475.1673. The synthetic reaction formula for compound 1l is shown below:

[0057] 25 mL of dry dichloromethane (DCM) was added sequentially to reaction flasks containing propargylamide S1l (820.0 mg, 5.0 mmol), S2b (1.58 g, 5.0 mmol), and DCC (1.23 g, 6.0 mmol). The reaction mixture was stirred at room temperature for 12 hours, followed by concentration under reduced pressure to remove the solvent. The residue was separated by column chromatography to give 1l (1.67 g, 77% yield) of a white solid product. 1 H NMR (400 MHz, CDCl3, two rotamers). δ 7.73-7.66 (m, 2H),7.63-7.53 (m, 1H), 7.42-7.31 (m, 5H), 7.30-7.25 (m, 1H), 7.14-7.11 (m, 2H),7.04-6.96 (m, 2H), 5.31&4.83 (m, 1H), 4.78&4.49 (m, 2H), 4.03-3.75 (m, 4H),2.52&2.50 (m, 3H). 13 C NMR (100 MHz, CDCl3, two rotamers) δ 164.9&162.4 (2d, J= 250.0 Hz), 155.5, 154.6, 144.7, 144.4, 136.6, 136.5, 134.8, 134.8, 134.8,134.7, 131.1, 130.9, 130.1, 130.1, 129.9&129.1 (2d, J = 80.0 Hz), 128.8,128.7, 128.5, 128.4, 128.3, 127.9, 127.5, 127.1, 126.9, 126.28, 126.2, 116.4,116.2, 116.2&115.9 (2d, J = 30.0 Hz), 115.9, 115.9, 91.3, 89.9, 81.3, 55.4,55.0, 49.9, 46.9, 44.9, 43.7, 21.70, 21.7. HRMS (ESI) calcd for C 26 H 24 N2FO3S + (M+H) + 463.1486, found 463.1481. The synthetic reaction formula for compound 1m is shown below:

[0058] 25 mL of dry dichloromethane (DCM) was added sequentially to reaction flasks containing propargylamide S1 g (895.0 mg, 5.0 mmol), S2b (1.58 g, 5.0 mmol), and DCC (1.23 g, 6.0 mmol). The reaction mixture was stirred at room temperature for 12 hours, followed by concentration under reduced pressure to remove the solvent. The residue was separated by column chromatography to give a white solid product 1 m (1.86 g, yield 78%). 1 H NMR (400 MHz, CDCl3, two rotamers). 1 H NMR (400 MHz, CDCl3, two rotamers). δ 7.69 (s, 2H), 7.53-7.32 (m, 5H), 7.31-7.24 (m, 4H), 7.12-6.96 (m, 2H), 5.31&4.82 (m, 1H), 4.77&4.49 (s, 2H), 4.06-3.74 (m, 4H), 2.51&2.49 (s, 3H). 13C NMR (100 MHz, CDCl3, two rotamers) δ 161.5, 161.3, 155.9, 155.0, 144.6, 144.4, 136.8, 136.7, 134.4, 134.4, 131.1, 130.9, 130.1, 129.9, 129.0, 128.8, 128.5, 128.4, 127.9, 127.5, 126.3, 126.2, 114.4, 114.3, 111.6, 111.5, 93.1, 91.7, 80.9, 55.5, 55.5, 55.4, 55.1, 49.9, 46.9, 44.8, 43.7,21.7, 21.7. HRMS (ESI) calcd for C 26 H 24 ClN2O3S + (M+H) + 479.1191, found 479.1196. The synthetic reaction formula for compound 1n is shown below:

[0059] 25 mL of dry dichloromethane (DCM) was added sequentially to reaction flasks containing propargylamide S1h (1.15 g, 5.0 mmol), S2b (1.58 g, 5.0 mmol), and DCC (1.23 g, 6.0 mmol). The reaction mixture was stirred at room temperature for 12 hours, followed by concentration under reduced pressure to remove the solvent. The residue was separated by column chromatography to give a white solid product 1n (1.98 g, yield 76%). 1 H NMR (400 MHz, CDCl3, two rotamers). δ 7.73-7.53 (m, 3H), 7.49-7.41 (m, 2H), 7.40-7.29 (m, 5H), 7.23-7.18 (m, 1H), 7.15-6.96 (m, 2H), 5.30&4.83 (m, 1H), 4.79&4.50 (m, 2H), 4.03-3.75 (m, 4H), 2.52&2.50 (s, 3H). 13C NMR(100 MHz, CDCl3, two rotamers) δ 155.4, 144.7, 144.40, 136.6, 136.4, 133.8,133.8, 132.1, 131.9, 131.2, 130.1, 129.9, 129.1, HRMS (ESI) calcd for C 26 H 24 BrN2O3S + (M+H) + 523.0686, found 523.0681. The synthetic reaction formula for compound 1o is shown below:

[0060] 25 mL of dry dichloromethane (DCM) was added sequentially to reaction flasks containing propargylamide S1i (980.0 mg, 5.0 mmol), S2b (1.58 g, 5.0 mmol), and DCC (1.23 g, 6.0 mmol). The reaction mixture was stirred at room temperature for 12 hours, followed by concentration under reduced pressure to remove the solvent. The residue was separated by column chromatography to give a white solid product 1o (1.70 g, yield 69%). 8.26-7.76 (m, 3H), 7.71-7.59 (m, 3H), 7.54-7.44 (m, 1H), 7.44-7.26 (m, 7H), 7.20-7.02 (m, 2H), 5.49&4.98 (m, 1H), 4.89&4.52 (s, 2H), 4.10-3.76 (m, 4H), 2.49 (s, 3H). 13 C NMR (100 MHz, CDCl3, two rotamers) δ 155.8, 154.8, 144.6, 144.4, 136.8, 136.7, 133.4, 133.3, 133.1, 132.9, 132.6, 132.5, 131.3, 131.1, 131.0, 130.9, 130.1, 130.0, 129.2, 128.9, 128.7, 128.5, 128.5, 127.9, 127.8, 127.5, 127.0, 126.8, 126.4, 126.0, 125.5, 125.4, 125.2, 125.1, 117.4, 89.3, 85.9, 85.3, 55.5, 55.2, 49.7, 47.1, 44.9, 43.67, 21.7. HRMS(ESI) calcd for C 30 H 27 N2O3S + (M+H) + 495.1737, found 495.1732. The synthetic reaction formula for compound 1p is shown below:

[0061] 25 mL of dry dichloromethane (DCM) was added sequentially to reaction flasks containing propargylamide S1j (755.0 mg, 5.0 mmol), S2b (1.58 g, 5.0 mmol), and DCC (1.23 g, 6.0 mmol). The reaction mixture was stirred at room temperature for 12 hours, followed by concentration under reduced pressure to remove the solvent. The residue was separated by column chromatography to give a white solid product 1p (1.46 g, yield 65%). 7.72-7.65 (m, 2H), 7.50-7.26 (m, 7H), 7.13-7.07 (m, 2H), 7.02-6.94 (m, 1H), 5.24&4.80 (m, 1H), 4.73&4.48 (m, 2H), 4.06-3.73 (m, 4H), 2.52&2.49 (m, 3H). 13C NMR (100 MHz, CDCl3, two rotamers) δ 155.4, 154.5, 144.7,144.4, 136.7, 136.5, 135.9, 135.8, 131.0, 131.0, 130.8, 130.1, 130.0, 129.2,129.1, 128.8, 128.7, 128.5, 128.4, 128.4, 1280.0, 127.7, 127.5, 127.5, 126.3,126.2, 119.4, 86.3, 85.6, 84.9, 84.8, 55.4, 55.1, 49.9, 46.8, 44.8, 43.8,21.7, 21.7. HRMS (ESI) calcd for C 24 H2N2O3S2 + (M+H) + 451.1154, found 451.1151. The synthetic reaction formula for compound 1q is shown below:

[0062] 25 mL of dry dichloromethane (DCM) was added sequentially to reaction flasks containing propargylamide S1k (420.0 mg, 5.0 mmol), S2b (1.58 g, 5.0 mmol), and DCC (1.23 g, 6.0 mmol). The reaction mixture was stirred at room temperature for 12 hours, followed by concentration under reduced pressure to remove the solvent. The residue was separated by column chromatography to give a white solid product 1q (1.35 g, yield 71%). 1 H NMR (400 MHz, CDCl3, two rotamers). δ 7.76-7.62 (m, 2H), 7.44-7.21 (m, 5H), 7.06&6.91 (d, J =8.0 Hz, 2H), 5.26&4.27 (m, 1H), 4.69&4.41 (m,2H), 4.01-3.66 (m, 4H), 2.51&2.48 (s, 3H), 2.14&1.90 (s, 3H). 13C NMR (100MHz, CDCl3, two rotamers) δ 155.6, 154.7, 144.6, 144.3, 136.8, 136.6, 131.1,130.9, 130.1, 129.9, 129.0, 128.7, 128.4, 128.4, 127.9, 127.4, 126.2, 126.2,91.5, 90.1, 73.2, 72.6, 55.4, 55.0, 49.9, 46.8, 44.6, 43.7, 33.9, 25.7, 24.9,21.7, 21.7, 4.2, 4.0. HRMS (ESI) calcd for C 21 H 23 N2O3S + (M+H) + 383.1424, found 383.1427. The synthetic reaction formula for compound 1r is shown below:

[0063] 25 mL of dry dichloromethane (DCM) was added sequentially to reaction flasks containing propargylamide S1a (730.0 mg, 5.0 mmol), S2h (1.65 g, 5.0 mmol), and DCC (1.23 g, 6.0 mmol). The reaction mixture was stirred at room temperature for 12 hours, followed by concentration under reduced pressure to remove the solvent. The residue was separated by column chromatography to give a white solid product 1r (1.69 g, yield 74%). 1 H NMR (400 MHz, CDCl3, two rotamers). δ 7.77-7.71 (m, 2H), 7.59-7.44 (m, 2H), 7.43-7.33 (m, 4H), 7.32-7.25 (m, 2H), 7.21-7.10 (m, 2H), 5.20&4.71 (m, 1H), 4.25&3.30 (m, 1H), 4.01-3.90 (m, 2H), 3.85-3.55 (m, 3H), 3.34-3.26 (m, 1H), 2.94-2.72 (m, 2H), 2.47&2.41 (m, 3H). 13C NMR (100 MHz, CDCl3, two rotamers) δ 155.0, 154.3, 144.7, 144.5, 138.3, 137.7, 137.4, 132.5,131.1, 130.8, 130.6, 130.5, 130.1, 129.9, 129.9, 128.9, 128.9, 128.8, 128.7,128.7, 128.7, 128.5, 128.5, 128.4, 127.1, 126.8, 126.6, 119.9, 119.8, 91.4,90.4, 81.6, 57.9, 55.6, 55.2, 47.9, 46.7, 44.0, 43.8, 37.07, 35.3, 34.4,21.6. HRMS (ESI) calcd for C 24 H 27 N2O3S + (M+H) + 459.1737, found 459.1741. The synthetic reaction formula for compound 1s is shown below:

[0064] 25 mL of dry dichloromethane (DCM) was added sequentially to reaction flasks containing propargylamide S1a (730.0 mg, 5.0 mmol), S2i (1.40 g, 5.0 mmol), and DCC (1.23 g, 6.0 mmol). The reaction mixture was stirred at room temperature for 12 hours, followed by concentration under reduced pressure to remove the solvent. The residue was separated by column chromatography to give a white solid product 1r (1.10 g, yield 54%). 1 H NMR (400 MHz, CDCl3, two rotamers). δ 7.80-7.76 (m, 2H), 7.75-7.49 (m, 2H), 7.47-7.36 (m, 5H), 5.24&4.76 (m, 1H), 4.17-3.87 (m, 4H), 3.47&3.08 (d, J = 4.0 Hz, 2H), 2.49&2.48 (m, 3H), 0.89&0.76 (m, 1H), 0.59&0.43 (m,2H), 0.35&0.18 (m, 2H). 13 C NMR (100 MHz, CDCl3, two rotamers) δ 155.1, 154.6,144.7, 144.4, 132.4, 132.4, 131.3, 130.9, 130.5, 130.4, 130.1, 129.9, 129.9,128.7, 128.7, 128.5, 128.5, 120.1, 119.9, 91.6, 90.4, 81.7, 55.9, 55.2, 50.9,46.4, 45.9, 43.9, 21.6, 11.5, 10.6, 4.5, 4.3. HRMS (ESI) calcd for C 27 H 27 N2O3S + (M+H) + 459.1737, found 459.1743. The synthesis reaction formula for compound 1t is shown below:

[0065] 25 mL of dry dichloromethane (DCM) was added sequentially to reaction flasks containing propargylamide S1a (730.0 mg, 5.0 mmol), S2j (1.47 g, 5.0 mmol), and DCC (1.23 g, 6.0 mmol). The reaction mixture was stirred at room temperature for 12 hours, followed by concentration under reduced pressure to remove the solvent. The residue was separated by column chromatography to give 1 t (1.51 g, yield 72%) of white solid product. 1 H NMR (400 MHz, CDCl3, two rotamers). δ 7.81-7.69 (m, 2H), 7.46-7.36 (m, 2H), 7.47-7.35 (m, 5H), 5.17&4.57 (m, 1H), 4.14-3.77 (m, 4H), 3.56&3.12 (d, J = 40.0 Hz, 2H), 2.49&2.48 (m, 3H), 2.35& 2.24 (m, 1H), 2.05-1.96(m, 1H), 1.92-1.80 (m, 2H), 1.77-1.54 (m, 3H). 13 C NMR (100 MHz, CDCl3, tworotamers) δ 155.2, 154.6, 144.8, 144.5, 132.4, 132.4, 131.2, 130.7, 130.5,130.4, 130.1, 129.9, 128.7, 128.6, 128.5, 120.1, 119.9, 91.5, 90.5, 81.8,56.0, 55.2, 51.7, 47.0, 46.5, 44.3, 35.7, 35.0, 26.7, 26.1, 21.7, 18.2, 18.0.HRMS (ESI) calcd for C 24 H 27 N2O3S + (M+H) + 423.1737, found 423.1733. The synthetic reaction formula for compound 1u is shown below:

[0066] 25 mL of dry dichloromethane (DCM) was added sequentially to reaction flasks containing propargylamide S1a (730.0 mg, 5.0 mmol), S2k (1.54 g, 5.0 mmol), and DCC (1.23 g, 6.0 mmol). The reaction mixture was stirred at room temperature for 12 hours, followed by concentration under reduced pressure to remove the solvent. The residue was separated by column chromatography to give a white solid product 1u (1.09 g, yield 50%). 1 H NMR (400 MHz, CDCl3, two rotamers). δ 7.83-7.74 (m, 2H), 7.55-7.47 (m, 2H), 7.46-7.35 (m, 5H), 5.17&4.52 (m, 1H), 4.17-3.80 (m, 4H), 3.46&3.07 (d, J = 8.0 Hz, 2H), 2.48&2.47 (s, 3H), 1.97-1.80 (m, 1H), 1.70-1.44 (m,6H), 1.29-1.01 (m, 2H). 13C NMR (100 MHz, CDCl3, two rotamers) δ 155.1, 154.7,144.8, 144.4, 132.4, 132.3, 131.3, 130.6, 130.5, 130.3, 130.1, 129.9, 128.7,128.7, 128.6, 128.5, 120.1, 119.9, 91.5, 90.5, 81.7, 55.9, 55.1, 51.6, 46.6,46.4, 44.8, 40.1, 39.6, 30.4, 30.1, 24.9, 24.8, 21.6. HRMS (ESI) calcd forC 25 H 29 N2O3S + (M+H) + 437.1893, found 437.1891. Example 2 Synthesis of compound 2a The synthetic reaction formula for compound 2a is shown below:

[0067] Two mL of dry dimethyl sulfoxide (DMSO) was added sequentially to reaction flasks containing propargylamide 1a (86.0 mg, 0.2 mmol), NaN3 (13.0 mg, 0.2 mmol), and NaHCO3 (16.8 mg, 0.2 mmol). The reaction mixture was stirred in an oil bath at 80 °C for 12 hours, and then quenched with 25 mL of deionized water. Subsequently, the reaction mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were separated and combined, dried, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain a white solid product 2a (81.2 mg, yield 86%).

[0068] 1H NMR (400 MHz, CDCl3). δ 8.21-8.18 (m, 2H), 7.78-7.69 (m, 2H), 7.60-7.50 (m, 1H), 7.49-7.36 (m, 10H), 7.32 (s, 1H), 5.32 (d, J = 14.5 Hz, 1H), 5.02 (d, J = 13.4 Hz, 1H), 4.36 (d, J = 14.4 Hz, 1H), 4.26 (dd, J = 13.8, 4.6Hz, 1H), 4.18-4.13 (m, 1H), 3.14-3.03 (m, 1H), 2.82 (dd, J = 14.8, 10.1 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 155.8, 148.7, 139.7, 136.4, 132.8, 129.7,129.2, 129.1, 128.9, 128.8, 128.6, 128.5, 128.3, 126.7, 123.7, 55.8, 48.8,46.1, 41.6. HRMS (ESI) calcd for C 25 H 24 N5O3S + (M+H) + 474.1594, found 474.1595. Example 3 Synthesis of compound 2b The synthesis reaction formula for compound 2b is shown below:

[0069] Two mL of dry dimethyl sulfoxide (DMSO) was added sequentially to reaction flasks containing propargylamide 1b (88.8 mg, 0.2 mmol), NaN3 (13.0 mg, 0.2 mmol), and NaHCO3 (16.8 mg, 0.2 mmol). The reaction mixture was stirred in an oil bath at 80 °C for 12 hours, and then quenched with 25 mL of deionized water. Subsequently, the reaction mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were separated and combined, dried, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain a white solid product 2b (89.3 mg, yield 92%).

[0070] 1H NMR (400 MHz, CDCl3). δ 8.27-8.14 (m, 2H), 7.66-7.56 (m, 2H), 7.50-7.42 (m, 5H), 7.41-7.37 (m, 3H), 7.21 (d, J = 8.2 Hz, 2H), 7.11 (t, J = 6.4Hz, 1H), 5.33 (d, J = 14.6 Hz, 1H), 5.05-4.94 (m, 1H), 4.33 (d, J = 14.5 Hz,1H), 4.28-4.21 (m, 1H), 4.16-4.11 (m, 1H), 3.10-3.01 (m, 1H), 2.84-2.76 (m, 1H), 2.40 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 155.8, 148.7, 143.7, 136.7,136.4, 129.8, 129.6, 129.1, 128.8, 128.8, 128.6, 128.5, 128.3, 126.8, 123.7,55.7, 48.8, 46.1, 41.6, 21.5. HRMS (ESI) calcd for C 26 H 26 N5O3S + (M+H) + 488.1751, found 488.1756. Example 4 Synthesis of compound 2c The synthetic reaction formula for compound 2c is shown below:

[0071] Two mL of dry dimethyl sulfoxide (DMSO) was added sequentially to reaction flasks containing propargylamide 1c (95.0 mg, 0.2 mmol), NaN3 (13.0 mg, 0.2 mmol), and NaHCO3 (16.8 mg, 0.2 mmol). The reaction mixture was stirred in an oil bath at 80 °C for 12 hours, and then quenched with 25 mL of deionized water. Subsequently, the reaction mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were separated and combined, dried, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain a white solid product 2c (90.1 mg, yield 87%).

[0072] 1H NMR (400 MHz, DMSO-d6) δ 8.38-8.31 (m, 2H), 8.28-8.20 (m, 2H), 8.00-7.90 (m, 2H), 7.50-7.41 (m, 3H), 7.40-7.33 (m, 4H), 7.32-7.27 (m, 1H), 5.21 (d, J = 15.4 Hz, 1H), 4.86 (d, J = 13.4 Hz, 1H), 4.70 (dd, J = 13.9, 5.0Hz, 1H), 4.34 (d, J = 15.4 Hz, 1H), 3.95 (q, J = 5.9 Hz, 1H), 3.00-2.87 (m,2H). 13 C NMR (101 MHz, DMSO-d6) δ 156.4, 150.1, 147.2, 146.1, 137.4, 130.2,129.4, 129.1, 128.8, 128.6, 128.5, 128.2, 127.9, 125.1, 124.3, 55.0, 48.6,46.5, 42.8. HRMS (ESI) calcd for C 25 H 23 N6O5S + (M+H) + 519.1445, found 519.1441. Example 5 Synthesis of compound 2d The synthetic reaction formula for compound 2d is shown below:

[0073] Two mL of dry dimethyl sulfoxide (DMSO) was added sequentially to reaction flasks containing propargylamide 1d (95.0 mg, 0.2 mmol), NaN3 (13.0 mg, 0.2 mmol), and NaHCO3 (16.8 mg, 0.2 mmol). The reaction mixture was stirred in an oil bath at 80 °C for 12 hours, and then quenched with 25 mL of deionized water. Subsequently, the reaction mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were separated and combined, dried, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain a white solid product 2d (86.7 mg, yield 83%).

[0074] 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.29-8.20 (m, 2H), 7.97 (d,J = 7.8 Hz, 1H), 7.90-7.77 (m, 3H), 7.51-7.41 (m, 3H), 7.40-7.33 (m, 4H),7.32-7.27 (m, 1H), 5.22 (d, J = 15.4 Hz, 1H), 4.90 (d, J = 13.7 Hz, 1H), 4.69(dd, J = 13.9, 5.0 Hz, 1H), 4.33 (d, J = 15.3 Hz, 1H), 4.00 (t, J = 5.8 Hz,1H), 3.05 (d, J = 6.7 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 156.3, 148.0,147.2, 137.4, 134.7, 133.4, 132.8, 130.2, 129.9, 129.3, 129.1, 128.8, 128.6,128.2, 128.0, 125.2, 124.3, 55.1, 48.6, 46.4, 42.9. HRMS (ESI) calcd forC 25 H 23 N6O5S + (M+H) + 519.1445, found 519.1440. Example 6 Synthesis of compound 2e The synthetic reaction formula for compound 2e is shown below:

[0075] Two mL of dry dimethyl sulfoxide (DMSO) was added sequentially to reaction flasks containing propargylamide 1e (89.6 mg, 0.2 mmol), NaN3 (13.0 mg, 0.2 mmol), and NaHCO3 (16.8 mg, 0.2 mmol). The reaction mixture was stirred in an oil bath at 80 °C for 12 hours, and then quenched with 25 mL of deionized water. Subsequently, the reaction mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were separated and combined, dried, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain a white solid product 2e (83.4 mg, yield 83%).

[0076] 1H NMR (400 MHz, DMSO-d6) δ 8.33 (td, J = 5.6, 2.3 Hz, 2H), 7.95 (s,1H), 7.57 (d, J = 8.2 Hz, 2H), 7.40-7.27 (m, 9H), 5.19 (d, J = 15.4 Hz, 1H), 4.88 (d, J = 13.6 Hz, 1H), 4.68 (dd, J = 14.0, 5.1 Hz, 1H), 4.34 (d, J = 15.4Hz, 1H), 3.94 (q, J = 6.4 Hz, 1H), 2.83 (d, J = 6.6 Hz, 2H), 2.35 (s, 3H). 13 CNMR (100 MHz, DMSO-d6) δ 162.9 (d, J = 245.0 Hz), 156.3, 146.3, 143.4, 137.5 (d, J = 20.0 Hz), 131.1, 131.0, 130.2, 129.1, 128.2, 128.0, 126.9, 126.7,126.70 124.3, 115.6 (d, J = 11.0 Hz), 55.2, 48.7, 46.5, 42.7, 21.4. HRMS(ESI) calcd for C 26 H 25 FN5O3S + (M+H) + 506.1657, found 506.1651. Example 7 Synthesis of compound 2f The synthetic reaction formula for compound 2f is shown below:

[0077] Two mL of dry dimethyl sulfoxide (DMSO) was added sequentially to reaction flasks containing propargylamide 1f (81.6 mg, 0.2 mmol), NaN3 (13.0 mg, 0.2 mmol), and NaHCO3 (16.8 mg, 0.2 mmol). The reaction mixture was stirred in an oil bath at 80 °C for 12 hours, and then quenched with 25 mL of deionized water. Subsequently, the reaction mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were separated and combined, dried, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain a white solid product 2f (66.8 mg, yield 74%).

[0078] 1 H NMR (400 MHz, CDCl3) δ 8.33 (t, J = 5.9 Hz, 1H), 8.09-8.02 (m,2H), 7.78-7.71 (m, 2H), 7.50-7.44 (m, 2H), 7.41-7.30 (m, 6H), 7.09 (d, J =8.3 Hz, 2H), 5.62 (d, J = 14.7 Hz, 1H), 5.00 (d, J = 12.8 Hz, 1H), 4.33-4.22(m, 3H), 3.91-3.85 (m, 1H), 3.17-3.10 (m, 1H), 2.35 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 168.7, 156.0, 148.7, 142.4, 136.7, 130.6, 129.4, 129.2, 129.0,128.9, 128.9, 128.6, 128.3, 128.1, 127.3, 124.1, 53.3, 48.3, 46.7, 39.8,21.5. HRMS (ESI) calcd for C 27 H 26 N5O2S + (M+H) + 452.2018 was found to be 452.2022. Example 8 Synthesis of Compound 2g The synthesis reaction formula for compound 2g is shown below:

[0079] 2 mL of dry dimethyl sulfoxide (DMSO) was added sequentially to reaction flasks containing 1 g (76.0 mg, 0.2 mmol) of propargylamide, 13.0 mg (0.2 mmol) of NaN3, and 16.8 mg (0.2 mmol) of NaHCO3. The reaction mixture was stirred in an oil bath at 80 °C for 12 hours, and then quenched with 25 mL of deionized water. Subsequently, the reaction mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were separated and combined, dried, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain 2 g (49.1 mg, yield 58%) of white solid product.

[0080] 1H NMR (400 MHz, CDCl3) δ 8.44-8.32 (m, 2H), 7.53-7.47 (m, 2H), 7.46-7.42 (m, 1H), 7.39-7.30 (m, 3H), 7.33-7.29 (m, 4H), 7.28-7.21 (m, 3H), 5.45(d, J = 14.9 Hz, 1H), 5.09 (dd, J = 13.4, 1.3 Hz, 1H), 4.28 (dd, J = 13.4,4.8 Hz, 1H), 4.11 (d, J = 14.9 Hz, 1H), 3.71 (d, J = 5.7 Hz, 2H), 3.68-3.64(m, 1H), 2.77 (dd, J = 13.0, 4.5 Hz, 1H), 2.56 (dd, J = 13.1, 9.7 Hz, 1H). 13 CNMR (100 MHz, CDCl3) δ 156.5, 148.6, 139.5, 136.6, 129.6, 129.3, 129.1,128.9, 128.6, 128.3, 128.2, 128.2, 128.0, 127.4, 123.8, 54.9, 53.9, 48.5,48.0, 46.6. HRMS (ESI) calcd for C 26 H 26 N5O + (M+H) + 424.2132, found 424.2128. Example 9 Synthesis of Compound 2h The synthetic reaction formula for compound 2h is shown below:

[0081] Two mL of dry dimethyl sulfoxide (DMSO) was added sequentially to reaction flasks containing propargylamide 1h (91.6 mg, 0.2 mmol), NaN3 (13.0 mg, 0.2 mmol), and NaHCO3 (16.8 mg, 0.2 mmol). The reaction mixture was stirred in an oil bath at 80 °C for 12 hours, and then quenched with 25 mL of deionized water. Subsequently, the reaction mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were separated and combined, dried, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain a white solid product 2h (79.1 mg, yield 79%).

[0082] 1 H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 7.5 Hz, 1H), 7.39-7.29 (m, 9H), 7.26 (dd, J = 7.3, 2.0 Hz, 1H), 5.12 (d, J = 15.3 Hz, 1H), 4.89 (d, J = 13.7 Hz, 1H), 4.71 (dd, J = 14.0, 5.1Hz, 1H), 4.29 (d, J = 15.3 Hz, 1H), 3.95 (t, J = 5.9 Hz, 1H), 2.85 (d, J =6.2 Hz, 2H), 2.37 (s, 3H), 2.25 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 156.0,147.3, 143.4, 137.6, 137.5, 137.4, 131.4, 130.4, 130.2, 130.0, 129.2, 129.1,128.2, 127.9, 126.9, 125.6, 125.2, 55.2, 48.3, 46.5, 43.0, 21.4, 20.4. HRMS(ESI) calcd for C 27 H 28 N5O3S + (M+H) + 502.1907 was found to be 502.1911. Example 10 Synthesis of Compound 2i The synthetic reaction formula for compound 2i is shown below:

[0083] Two mL of dry dimethyl sulfoxide (DMSO) was added sequentially to reaction flasks containing propargylamide 1i (91.6 mg, 0.2 mmol), NaN3 (13.0 mg, 0.2 mmol), and NaHCO3 (16.8 mg, 0.2 mmol). The reaction mixture was stirred in an oil bath at 80 °C for 12 hours, and then quenched with 25 mL of deionized water. Subsequently, the reaction mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were separated and combined, dried, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain a white solid product 2i (83.4 mg, yield 83%).

[0084] 1 H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 7.9 Hz, 2H), 7.95 (s, 1H), 7.57 (d, J = 8.3 Hz, 2H), 7.31-7.29 (m, 8H), 7.24 (d, J = 7.8 Hz, 1H), 5.21(d, J = 15.4 Hz, 1H), 4.87 (d, J = 13.3 Hz, 1H), 4.67 (dd, J = 13.9, 5.0 Hz,1H), 4.32 (d, J = 15.4 Hz, 1H), 3.91 (q, J = 6.2 Hz, 1H), 2.84 – 2.79 (m,2H), 2.38 (s, 3H), 2.35 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 156.3, 147.3,143.3, 137.7, 137.6, 137.5, 130.1, 130.1, 130.0, 129.3, 129.1, 128.5, 128.2,127.9, 126.9, 126.1, 124.3, 55.1, 48.7, 46.5, 42.7, 21.6, 21.4. HRMS (ESI)calcd for C 27 H 28 N5O3S + (M+H) + 502.1907 was found to be 502.1912. Example 11 Synthesis of Compound 2j The synthetic reaction formula for compound 2j is shown below:

[0085] Two mL of dry dimethyl sulfoxide (DMSO) was added sequentially to reaction flasks containing propargylamide 1j (91.6 mg, 0.2 mmol), NaN3 (13.0 mg, 0.2 mmol), and NaHCO3 (16.8 mg, 0.2 mmol). The reaction mixture was stirred in an oil bath at 80 °C for 12 hours, and then quenched with 25 mL of deionized water. Subsequently, the reaction mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were separated and combined, dried, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain a white solid product 2j (86.7 mg, yield 89%).

[0086] 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 8.2 Hz, 2H), 7.95 (s, 1H), 7.57 (d, J = 8.3 Hz, 2H), 7.38-7.31 (m, 7H), 7.28 (d, J = 8.2 Hz, 3H), 5.19(d, J = 15.3 Hz, 1H), 4.86 (d, J = 13.6 Hz, 1H), 4.66 (dd, J = 13.9, 5.0 Hz,1H), 4.33 (d, J = 15.4 Hz, 1H), 3.92 (q, J = 6.3, 5.9 Hz, 1H), 2.86-2.75 (m,2H), 2.36 (s, 3H), 2.35 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 156.4, 147.3,143.4, 138.9, 137.6, 137.5, 130.2, 129.2, 129.1, 128.7, 128.18, 127.9, 127.4,126.9, 124.0, 55.1, 48.7, 46.4, 42.7, 21.4. HRMS (ESI) calcd for C 27 H 28 N5O3S + (M+H) + 502.1907 was found to be 502.1911. Example 12 Synthesis of Compound 2k The synthetic reaction formula for compound 2k is shown below:

[0087] Two mL of dry dimethyl sulfoxide (DMSO) was added sequentially to reaction flasks containing propargylamide 1k (94.8 mg, 0.2 mmol), NaN3 (13.0 mg, 0.2 mmol), and NaHCO3 (16.8 mg, 0.2 mmol). The reaction mixture was stirred in an oil bath at 80 °C for 12 hours, and then quenched with 25 mL of deionized water. Subsequently, the reaction mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were separated and combined, dried, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain a white solid product 2k (85.1 mg, yield 82%).

[0088] 1 H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.2Hz, 2H), 7.34 (dd, J = 11.4, 5.9 Hz, 7H), 7.03 (d, J = 8.7 Hz, 2H), 5.18 (d,J = 15.4 Hz, 1H), 4.85 (d, J = 13.8 Hz, 1H), 4.64 (dd, J = 13.9, 4.3 Hz, 1H), 4.33 (d, J = 15.3 Hz, 1H), 3.97-3.86 (m, 1H), 3.81 (s, 3H), 2.80 (d, J = 5.6Hz, 2H), 2.35 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 160.3, 156.5, 147.2,143.4, 137.6, 137.5, 130.3, 130.2, 129.1, 128.2, 127.92, 126.9, 123.5, 122.6,114.1, 55.7, 55.2, 48.7, 46.4, 42.7, 21.4. HRMS (ESI) calcd for C 27 H 28 N5O4S + (M+H) + 518.1857, found 518.1861. Example 13 Synthesis of Compound 2l The synthetic reaction formula for compound 2l is shown below:

[0089] Two mL of dry dimethyl sulfoxide (DMSO) was added sequentially to reaction flasks containing 1 L of propargylamide (92.4 mg, 0.2 mmol), NaN3 (13.0 mg, 0.2 mmol), and NaHCO3 (16.8 mg, 0.2 mmol). The reaction mixture was stirred in an oil bath at 80 °C for 12 hours, and then quenched with 25 mL of deionized water. Subsequently, the reaction mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were separated and combined, dried, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain 2 L of white solid product (83.4 mg, yield 83%).

[0090] 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (td, J = 5.6, 2.3 Hz, 2H), 7.95 (s,1H), 7.57 (d, J = 8.2 Hz, 2H), 7.40-7.27 (m, 9H), 5.19 (d, J = 15.4 Hz, 1H), 4.88 (d, J = 13.6 Hz, 1H), 4.68 (dd, J = 14.0, 5.1 Hz, 1H), 4.34 (d, J = 15.4Hz, 1H), 3.94 (q, J = 6.4 Hz, 1H), 2.83 (d, J = 6.6 Hz, 2H), 2.35 (s, 3H). 13 CNMR (100 MHz, DMSO-d6) δ 162.9 (d, J = 245.0 Hz), 156.3, 146.3, 143.4, 137.5 (d, J = 20.0 Hz), 131.1, 131.0, 130.2, 129.1, 128.2, 128.0, 126.9, 126.7,126.70 124.3, 115.6 (d, J = 11.0 Hz), 55.2, 48.7, 46.5, 42.7, 21.4. HRMS(ESI) calcd for C 26 H 25 FN5O3S + (M+H) + 506.1657, found 506.1651. Example 14 Synthesis of Compound 2m The synthetic reaction formula for compound 2m is shown below:

[0091] Two mL of dry dimethyl sulfoxide (DMSO) was added sequentially to reaction flasks containing 1 mM of propargylamide (95.6 mg, 0.2 mmol), NaN3 (13.0 mg, 0.2 mmol), and NaHCO3 (16.8 mg, 0.2 mmol). The reaction mixture was stirred in an oil bath at 80 °C for 12 hours, and then quenched with 25 mL of deionized water. Subsequently, the reaction mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were separated and combined, dried, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain a white solid product 2 mM (85.3 mg, yield 82%).

[0092] 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 8.7 Hz, 2H), 7.94 (s, 1H), 7.56 (t, J = 8.6 Hz, 4H), 7.34 (dd, J = 13.0, 7.0 Hz, 7H), 5.19 (d, J = 15.3Hz, 1H), 4.88 (d, J = 13.8 Hz, 1H), 4.68 (dd, J = 13.9, 4.9 Hz, 1H), 4.33 (d,J = 15.4 Hz, 1H), 3.94 (d, J = 5.5 Hz, 1H), 2.84 (d, J = 7.3 Hz, 2H), 2.34(s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 156.3, 146.0, 143.4, 137.6, 137.4, 134.1,130.5, 130.2, 129.1, 129.1, 128.8, 128.2, 128.0, 126.9, 124.6, 55.2, 48.7,46.5, 42.7, 21.4. HRMS (ESI) calcd for C 26 H 25 ClN5O3S + (M+H) + 522.1361, found 522.1360. Example 15 Synthesis of Compound 2n The synthetic reaction formula for compound 2n is shown below:

[0093] Two mL of dry dimethyl sulfoxide (DMSO) was added sequentially to reaction flasks containing propargylamide 1n (104.4 mg, 0.2 mmol), NaN3 (13.0 mg, 0.2 mmol), and NaHCO3 (16.8 mg, 0.2 mmol). The reaction mixture was stirred in an oil bath at 80 °C for 12 hours, and then quenched with 25 mL of deionized water. Subsequently, the reaction mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were separated and combined, dried, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain a white solid product 2n (89.6 mg, yield 80%).

[0094] 1 H NMR (400 MHz, DMSO-d6) δ 8.30-8.16 (m, 2H), 7.94 (s, 1H), 7.72-7.66(m, 2H), 7.57 (d, J = 8.3 Hz, 2H), 7.40-7.27 (m, 7H), 5.19 (d, J = 15.4 Hz, 1H), 4.88 (d, J = 13.7 Hz, 1H), 4.68 (dd, J = 13.9, 5.1 Hz, 1H), 4.33 (d, J =15.4 Hz, 1H), 3.93 (d, J = 5.5 Hz, 1H), 2.90 – 2.81 (m, 2H), 2.35 (s, 3H). 13 CNMR (100 MHz, DMSO-d6) δ 156.3, 146.0, 143.4, 137.6, 137.4, 131.7, 130.8,130.2, 129.5, 129.1, 128.2, 128.0, 126.9, 124.7, 122.8, 55.2, 48.7, 46.5,42.7, 21.4. HRMS (ESI) calcd for C 26 H 25 BrN5O3S + (M+H) + 566.0856, found 566.0862. Example 16 Synthesis of Compound 2o The synthetic reaction formula for compound 2o is shown below:

[0095] Two mL of dry dimethyl sulfoxide (DMSO) was added sequentially to reaction flasks containing propargylamide 1o (98.8 mg, 0.2 mmol), NaN3 (13.0 mg, 0.2 mmol), and NaHCO3 (16.8 mg, 0.2 mmol). The reaction mixture was stirred in an oil bath at 80 °C for 12 hours, and then quenched with 25 mL of deionized water. Subsequently, the reaction mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were separated and combined, dried, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain a white solid product 2o (95.6 mg, yield 89%).

[0096] 1 H NMR (400 MHz, DMSO-d6) δ 8.09-7.97 (m, 3H), 7.94 (d, J = 8.3 Hz, 1H), 7.73 (dd, J = 7.1, 1.3 Hz, 1H), 7.66-7.61 (m, 2H), 7.61-7.49 (m, 3H), 7.40-7.26 (m, 7H), 5.10 (d, J = 15.4 Hz, 1H), 4.95 (d, J = 13.3 Hz, 1H), 4.78 (dd, J = 13.9, 5.3 Hz, 1H), 4.27 (d, J = 15.4 Hz, 1H), 4.03-3.92 (m, 1H),2.94 (dt, J = 9.8, 5.5 Hz, 2H), 2.37 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ155.9, 146.4, 143.4, 137.7, 137.5, 133.6, 131.7, 130.2, 129.6, 129.6, 129.1,128.6, 128.2, 127.9, 127.7, 127.0, 126.9, 126.4, 126.3, 126.1, 125.5, 55.2,48.2, 46.7, 43.1, 21.4. HRMS (ESI) calcd for C 30 H 28 N5O3S + (M+H) + 538.1907, found 538.1900. Example 17 Synthesis of Compound 2p The synthetic reaction formula for compound 2p is shown below:

[0097] Two mL of dry dimethyl sulfoxide (DMSO) was added sequentially to reaction flasks containing propargylamide 1p (90.0 mg, 0.2 mmol), NaN3 (13.0 mg, 0.2 mmol), and NaHCO3 (16.8 mg, 0.2 mmol). The reaction mixture was stirred in an oil bath at 80 °C for 12 hours, and then quenched with 25 mL of deionized water. Subsequently, the reaction mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were separated and combined, dried, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain a white solid product 2p (89.7 mg, yield 90%).

[0098] 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (dd, J = 3.7, 1.3 Hz, 1H), 7.95 (t, J= 6.2 Hz, 1H), 7.66 (dd, J = 5.1, 1.3 Hz, 1H), 7.61-7.56 (m, 2H), 7.40-7.29(m, 7H), 7.19 (dd, J = 5.1, 3.7 Hz, 1H), 5.20 (d, J = 15.3 Hz, 1H), 4.88 (d,J = 13.2 Hz, 1H), 4.66 (dd, J = 13.9, 5.1 Hz, 1H), 4.35 (d, J = 15.4 Hz, 1H),3.98-3.90 (m, 1H), 2.82 (q, J = 7.6, 6.4 Hz, 2H), 2.35 (s, 3H). 13 C NMR (100MHz, DMSO-d6) δ 156.1, 143.4, 142.6, 137.6, 137.4, 132.2, 130.2, 129.2,129.1, 128.3, 128.2, 128.0, 126.9, 122.7, 79.7, 55.2, 48.5, 46.4, 42.7, 21.4.HRMS (ESI) calcd for C 24 H 24 N5O3S2 + (M+H) + 494.1315, found 494.1322. Example 18 Synthesis of compound 2q The synthesis reaction formula for compound 2q is shown below:

[0099] Two mL of dry dimethyl sulfoxide (DMSO) was added sequentially to reaction flasks containing propargylamide 1q (76.4 mg, 0.2 mmol), NaN3 (13.0 mg, 0.2 mmol), and NaHCO3 (16.8 mg, 0.2 mmol). The reaction mixture was stirred in an oil bath at 80 °C for 12 hours, and then quenched with 25 mL of deionized water. Subsequently, the reaction mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were separated and combined, dried, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain a white solid product 2q (55.2 mg, yield 65%).

[0100] 1 H NMR (400 MHz, DMSO-d6) δ 7.96-7.90 (m, 1H), 7.65 (d, J = 8.9 Hz,1H), 7.59-7.53 (m, 2H), 7.48-7.43 (m, 1H), 7.35 (dd, J = 9.0, 2.2 Hz, 5H), 5.13 (d, J = 15.4 Hz, 1H), 4.77 (d, J = 13.0 Hz, 1H), 4.54 (dd, J = 13.9, 5.0Hz, 1H), 4.26 (d, J = 15.4 Hz, 1H), 3.84 (q, J = 4.9 Hz, 1H), 2.82-2.76 (m,1H), 2.75-2.65 (m, 1H), 2.44 (s, 3H), 2.37 (s, 3H). 13 C NMR (100 MHz, DMSO-d6)δ 156.7, 144.9, 143.4, 137.6, 137.5, 130.2, 129.1, 128.2, 127.9, 126.9,124.5, 55.5, 47.9, 45.9, 42.6, 21.4, 11.2. HRMS (ESI) calcd for C 21 H 24 N5O3S + (M+H) + 426.1594, found 426.1589. Example 19 Synthesis of Compound 2r The synthetic reaction formula for compound 2r is shown below:

[0101] Two mL of dry dimethyl sulfoxide (DMSO) was added sequentially to reaction flasks containing propargylamide 1r (91.6 mg, 0.2 mmol), NaN3 (13.0 mg, 0.2 mmol), and NaHCO3 (16.8 mg, 0.2 mmol). The reaction mixture was stirred in an oil bath at 80 °C for 12 hours, and then quenched with 25 mL of deionized water. Subsequently, the reaction mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were separated and combined, dried, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain a white solid product 2r (95.6 mg, yield 89%).

[0102] 1 H NMR (400 MHz, DMSO-d6) δ 8.28-8.21 (m, 2H), 7.92 (s, 1H), 7.63-7.58(m, 2H), 7.49-7.42 (m, 3H), 7.33 (t, J = 7.7 Hz, 4H), 7.28-7.21 (m, 3H), 4.83(d, J = 13.4 Hz, 1H), 4.49 (dd, J = 13.8, 5.1 Hz, 1H), 4.23-4.16 (m, 1H), 3.87 (q, J = 6.4 Hz, 1H), 3.27-3.10 (m, 1H), 3.00-2.86 (m, 2H), 2.84-2.77 (m,2H), 2.34 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 155.9, 146.9, 143.4, 139.2,137.7, 130.4, 130.2, 129.3, 129.2, 129.0, 128.7, 128.6, 126.9, 124.5, 57.6,56.0, 48.4, 46.5, 43.1, 34.05, 21.4. HRMS (ESI) calcd for C 27 H 28 N5O3S + (M+H) + 502.1907 was found to be 502.1914. Example 20 Synthesis of Compound 2s The synthetic reaction formula for compound 2s is shown below:

[0103] Two mL of dry dimethyl sulfoxide (DMSO) was added sequentially to reaction flasks containing propargylamide 1s (81.6 mg, 0.2 mmol), NaN3 (13.0 mg, 0.2 mmol), and NaHCO3 (16.8 mg, 0.2 mmol). The reaction mixture was stirred in an oil bath at 80 °C for 12 hours, and then quenched with 25 mL of deionized water. Subsequently, the reaction mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were separated and combined, dried, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain a white solid product 2s (75.4 mg, yield 84%).

[0104] 1 H NMR (400 MHz, DMSO-d6) δ 8.27-8.20 (m, 2H), 8.00 (s, 1H), 7.68-7.59(m, 2H), 7.48-7.40 (m, 3H), 7.35 (d, J = 8.2 Hz, 2H), 4.93 (d, J = 13.2 Hz, 1H), 4.74 (dd, J = 13.8, 4.9 Hz, 1H), 4.17-4.13 (m, 1H), 3.70 (dd, J = 14.1,7.0 Hz, 1H), 3.13 (dd, J = 14.1, 6.9 Hz, 1H), 2.94 (dd, J = 14.0, 5.0 Hz,1H), 2.77 (dd, J = 14.0, 8.6 Hz, 1H), 2.34 (s, 3H), 1.13-1.00 (m, 1H), 0.55-0.41 (m, 2H), 0.36-0.22 (m, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 156.0, 147.0,143.4, 137.7, 130.2, 129.3, 128.8, 128.6, 126.9, 124.4, 55.3, 50.0, 46.4,42.8, 21.4, 10.2, 4.1, 3.8. HRMS (ESI) calcd for C 23 H 26 N5O3S + (M+H) + 452.1751, found 452.1745. Example 21 Synthesis of compound 2t The synthesis reaction formula for compound 2t is shown below:

[0105] Two mL of dry dimethyl sulfoxide (DMSO) was added sequentially to reaction flasks containing 1 t of propargylamide (84.4 mg, 0.2 mmol), NaN3 (13.0 mg, 0.2 mmol), and NaHCO3 (16.8 mg, 0.2 mmol). The reaction mixture was stirred in an oil bath at 80 °C for 12 hours, and then quenched with 25 mL of deionized water. Subsequently, the reaction mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were separated and combined, dried, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain 2 t of white solid product (77.5 mg, yield 83%).

[0106] 1 H NMR (400 MHz, DMSO-d6) δ 8.25-8.19 (m, 2H), 7.95 (s, 1H), 7.63 (d,J = 8.3 Hz, 2H), 7.51-7.39 (m, 3H), 7.36 (d, J = 8.3 Hz, 2H), 4.88 (d, J =13.6 Hz, 1H), 4.69 (dd, J = 13.9, 4.8 Hz, 1H), 4.00 (dd, J = 13.7, 7.6 Hz,1H), 3.96-3.90 (m, 1H), 3.08 (dd, J = 13.8, 7.3 Hz, 1H), 2.79 (d, J = 6.8 Hz,2H), 2.61 (p, J = 7.6 Hz, 1H), 2.35 (s, 3H), 2.04-1.91 (m, 2H), 1.89-1.78 (m, 2H), 1.76-1.63 (m, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 156.1, 146.9, 143.4,137.7, 130.2, 130.2, 129.3, 128.8, 128.6, 126.9, 124.4, 55.5, 50.6, 46.4,42.8, 34.1, 26.2, 26.1, 21.4, 18.4. HRMS (ESI) calcd for C 24 H 28 N5O3S+ (M+H) + 466.1907, found 466.1914. Example 22 Synthesis of compound 2u The synthetic reaction formula for compound 2u is shown below:

[0107] Two mL of dry dimethyl sulfoxide (DMSO) was added sequentially to reaction flasks containing 1 u of propargylamide (87.2 mg, 0.2 mmol), NaN3 (13.0 mg, 0.2 mmol), and NaHCO3 (16.8 mg, 0.2 mmol). The reaction mixture was stirred in an oil bath at 80 °C for 12 hours, and then quenched with 25 mL of deionized water. Subsequently, the reaction mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were separated and combined, dried, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain a white solid product of 2 u (82.5 mg, yield 86%).

[0108] 1 H NMR (400 MHz, DMSO-d6) δ 8.29-8.19 (m, 2H), 7.95 (s, 1H), 7.63 (d,J = 8.2 Hz, 2H), 7.48-7.41 (m, 3H), 7.36 (d, J = 8.2 Hz, 2H), 4.89 (d, J =13.8 Hz, 1H), 4.74 (dd, J = 13.9, 4.9 Hz, 1H), 4.04-3.92 (m, 2H), 2.88 (dd, J= 13.6, 7.4 Hz, 1H), 2.82 (d, J = 6.7 Hz, 2H), 2.35 (s, 3H), 2.27-2.17 (m,1H), 1.77-1.56 (m, 4H), 1.52-1.46 (m, 2H), 1.29-1.14 (m, 3H). 13 C NMR (100MHz, DMSO-d6) δ 156.1, 147.0, 143.4, 137.7, 130.2, 129.3, 128.8, 128.6, 126.9,124.5, 55.4, 50.1, 46.4, 42.8, 38.7, 30.4, 30.1, 25.1, 24.8, 21.4. HRMS (ESI)calcd for C 25H 30 N5O3S + (M+H) + 480.2064, found 480.2067. Experimental Example 1: Antiviral Activity Test of the Triazole-Fused Piperidinone Derivative of the Present Invention MDCK cells were placed into 96-well cell culture plates. After the cells grew into a confluent monolayer, they were washed with Eagle's solution. After washing, the supernatant was discarded, and then 80 µL of 100 TCID45 solution was added to each well of the 96-well cell culture plate. 50 The cell culture plate was filled with type I herpes simplex virus (SM44 strain), and then 80 µL of the test compound diluted with MEM was added to each well. After the drug was added, the cell culture plate was placed in an incubator and incubated at 37°C, 5% CO2, and saturated humidity for 48 h. After incubation, the old solution in the 96-well plate was discarded, and then 10 µL of CCK8 solution was added to each well. Incubation was continued for 1 h, and then the absorbance at 450 nm was measured using a microplate reader. The IC50 was calculated. 50 Values; This experiment also included a virus control group and a cell control group; The test results are shown in Table 1.

[0109] Plotting drug concentration on the X-axis and cell viability on the Y-axis in Origin, the IC50 value is calculated as the drug concentration corresponding to 50% cell viability. 50 ; Cell viability = (OD value of drug-treated well - OD value of virus control group) / (OD value of cell control group - OD value of virus control group) × 100%.

[0110] Table 1. Antiviral activity of triazole ions and piperidinone derivatives

[0111]

[0112]

[0113]

[0114] As can be seen from the experimental data in Table 1, the triazole-fused piperidinone derivatives prepared in Examples 2-22 of this invention all showed anti-herpes simplex activity; indicating that the triazole-fused piperidinone derivatives of this invention have a certain anti-herpes simplex effect.

[0115] Furthermore, the experimental data in Table 1 also show that in the core structure of the triazole-fused piperidinone derivatives described in this invention, R 1 R 2 R 3The compounds obtained by substituting different groups exhibit significantly different anti-herpes simplex effects; among them, R... 3 The compounds obtained by sulfonyl substitution in Examples 2-6 all had IC50 values ​​less than 10 μM, exhibiting good anti-herpes simplex virus activity; compared to the R prepared in Examples 7 and 8 3 Compounds substituted with benzoyl and benzyl groups exhibited significantly lower IC50 values. This indicates that in the core structure of the triazole-fused piperidinone derivatives described in this invention, R... 3 The compound obtained by substitution with a sulfonyl group, relative to R 1 Compounds without sulfonyl groups exhibit significantly enhanced anti-herpes simplex virus activity.

[0116] Furthermore, the experimental data in Table 1 also show that the R prepared in Examples 20 and 21... 2 These are compounds substituted with cyclopropylmethylene and cyclobutylmethylene, and their IC50 values ​​are all less than 1 μM, which is significantly lower than that of other compounds, indicating excellent anti-herpes simplex virus activity. This demonstrates that in the core structure of the triazole-fused piperidinone derivative described in this invention, R... 2 Compounds obtained by substituting the radical group with a cyclomethylene group exhibit significantly enhanced anti-herpes simplex virus activity compared to compounds obtained by substituting other radical groups, demonstrating excellent anti-herpes simplex virus activity. Especially when R... 3 The compound obtained by substituting the group with cyclopropylmethylene has an IC50 value of 0.27 μM and exhibits the best anti-herpes simplex virus activity.

Claims

1. A triazole-fused piperidinone derivative, characterized in that, It has the structure shown in Equation I: Formula I; Where R 1 Selected from alkyl, phenyl, substituted phenyl, naphthyl ring, furan ring, thiophene ring or pyridine ring; R 2 Selected from alkyl, allyl, or benzyl; R 3 It is selected from alkyl, phenyl, substituted phenyl, acyl or sulfonyl groups.

2. The triazole-fused piperidinone derivative according to claim 1, characterized in that: R 1 Selected from alkyl, phenyl, substituted phenyl, naphthyl ring, furan ring, thiophene ring or pyridine ring; R 2 Selected from alkyl, allyl, or benzyl; R 3 It is selected from alkyl, phenyl, substituted phenyl, acyl or sulfonyl groups.

3. The triazole-fused piperidinone derivative according to claim 1, characterized in that, R 1 It is selected from alkyl, phenyl, substituted phenyl, naphthyl ring, furan ring, thiophene ring or pyridine ring.

4. The triazole-fused piperidinone derivative according to claim 1, characterized in that, R 2 Selected from alkyl, allyl, or benzyl.

5. The triazole-fused piperidinone derivative according to claim 1, characterized in that, R 3 It is selected from alkyl, phenyl, substituted phenyl, acyl or sulfonyl groups.

6. The triazole-fused piperidinone derivative according to claim 1, characterized in that, The triazole-fused piperidinone derivatives are selected from compounds having the following structures: ； ； ； ； ； ； 。 7. The method for preparing the triazole-fused piperidinone derivative according to any one of claims 1 to 7, characterized in that, Using propargylamide compounds and sodium azide as raw materials, a solvent and alkali are added to carry out the reaction. After the reaction is completed, the target product is separated to obtain the triazole fused piperidinone derivative.

8. The preparation method according to claim 7, characterized in that, Propylamide compounds have the structure shown in Formula II: Formula II; In Equation II, R 1 Selected from alkyl, phenyl, substituted phenyl, naphthyl ring, furan ring, thiophene ring, or pyridine ring; R 2 Selected from alkyl, allyl, or benzyl; R 3 It is selected from alkyl, phenyl, substituted phenyl, acyl or sulfonyl groups.

9. The use of the triazole-fused piperidinone derivative according to any one of claims 1 to 7 in the preparation of a drug with antiviral activity.

10. The application according to claim 9, characterized in that, The virus in question is herpes simplex virus.

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