Sesquiterpene derivatives, methods of making and anti-sars-cov-2 applications thereof

Abstract

The application discloses a sesquiterpene Asperterpenoid C derivative, a preparation method thereof and application of the sesquiterpene Asperterpenoid C derivative in resisting a novel coronavirus. The application modifies and transforms a natural product, the sesquiterpene Asperterpenoid C, to prepare a series of Asperterpenoid C derivatives with good activity in inhibiting the novel coronavirus, thereby providing a new possible selection for clinical treatment selection and providing a candidate drug for efficiently and low-toxicity treating a novel coronavirus infection (COVID-19).

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to sesquiterpene Asperterpenoid C derivatives, their preparation methods, and the application of their derivatives in the preparation of drugs against the novel coronavirus. Background Technology

[0002] The novel coronavirus infection (COVID-19) currently spreading globally is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clinical symptoms in mild cases include cough, fever, headache, and shortness of breath, while severe cases include multiple organ failure, acute respiratory distress syndrome, and inflammation. Furthermore, vascular leakage, coagulation abnormalities, and excessive inflammation caused by the novel coronavirus are also key factors contributing to the rapid deterioration and even death of these patients. Finding and developing novel and highly effective antiviral drugs is an urgent task.

[0003] The largest ecological environment on Earth is the ocean, which accounts for about 71% of the Earth's total surface area. The ocean is a special environment with high pressure, high salinity, low temperature, darkness and low nutrition. This has forced marine microorganisms to develop unique life mechanisms to adapt to these extreme conditions, resulting in the production of secondary metabolites with unique structures, rich diversity and significant biological activity. These products are an important basis for the source of new drugs and are considered a new treasure trove of natural medicinal resources.

[0004] Numerous compounds with anti-tumor, cardiovascular disease treatment, antibacterial, and antiviral activities have been discovered. By the end of 2016, over 28,000 new natural products had been discovered from marine organisms, including over 3,000 from marine fungi. Nine marketed drugs are derived from marine natural products or their derivatives, and another 23 marine-derived natural products are in Phase I, II, and III clinical trials. This demonstrates the immense potential for developing new drugs from the ocean.

[0005] Asperterpenoid C, a natural product, is a sesquiterpene compound extracted and isolated from the secondary metabolites of the endophytic fungus Aspergillus sp. 16-5C in Chinese mangroves. According to reports, this sesquiterpene compound inhibits the activity of Mycobacterium tuberculosis tyrosine phosphatase and can be used to prepare anti-tuberculosis drugs. It also inhibits acetylcholinesterase and can be used to prepare drugs for treating Alzheimer's disease. This invention, through structural modification of the natural product sesquiterpene compound Asperterpenoid C, yields a series of compounds with inhibitory activity against the novel coronavirus, providing new possible options for clinical treatment and offering candidate drugs for the highly effective and low-toxicity treatment of COVID-19 infection. Summary of the Invention

[0006] This invention aims to provide sesquiterpenoid C derivatives with inhibitory activity against the novel coronavirus, their preparation methods, and their application in anti-novel coronavirus drugs. This invention provides sesquiterpenoid C derivatives, and experiments have demonstrated that this series of sesquiterpenoid C derivatives exhibits significant anti-novel coronavirus activity against SARS-CoV-2 with low cytotoxicity, and can be used in the prevention and treatment of the novel coronavirus, particularly for the preparation of anti-novel coronavirus drugs.

[0007] The primary objective of this invention is to provide a sesquiterpene Asperterpenoid C derivative.

[0008] Another object of the present invention is to provide a method for preparing the sesquiterpene Asperterpenoid C derivative.

[0009] Another object of the present invention is to provide the use of the said sesquiterpene Asperterpenoid C derivative, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug compound thereof, in the preparation of an anti-novel coronavirus drug.

[0010] Another object of the present invention is to provide a drug for treating the novel coronavirus.

[0011] The technical solution to achieve the above objectives is as follows:

[0012] The derivatives of the natural product sesquiterpene Asperterpenoid C of this invention include ester derivatives and amide derivatives of sesquiterpene Asperterpenoid C. The chemical structures of the ester derivatives are shown in Formula I, and the amide derivatives are shown in Formula II.

[0013]

[0014] In Formula I, R is selected from C1-C8 straight-chain alkyl groups; C1-C4 halogen-substituted alkyl groups, wherein the halogens include: F, Cl, Br;

[0015] In Formula II, R is selected from C1-C6 straight-chain amino groups; amino groups connected to three-membered rings, five-membered rings, six-membered rings, phenyl groups, halogen-substituted phenyl groups, or toluene, wherein the halogen atom includes: I, Br; C1-C3 secondary amines connected to three-membered rings, five-membered rings, six-membered rings, phenyl groups, halogen-substituted phenyl groups, or toluene, wherein the halogen atom includes: I, Br; C3 secondary amines connected to six-membered heterocycles containing N and / or O; and C1-C3 secondary amines connected to five-membered heterocycles containing S or O.

[0016] As a preferred embodiment, the R group in the sesquiterpene Asperterpenoid C ester derivative shown in Formula I can be the following group:

[0017]

[0018] As a preferred embodiment, the structure of the sesquiterpene Asperterpenoid C ester derivative shown in Formula I can specifically be:

[0019]

[0020] The sesquiterpene C ester derivative of Formula I of this invention was synthesized via the synthetic route shown below:

[0021]

[0022] The method for preparing the sesquiterpene Asperterpenoid C ester derivatives of Formula I of the present invention is as follows: Asperterpenoid C reacts with a haloalkane compound under the catalysis of an alkali and under reflux at 30-80°C to obtain the corresponding Asperterpenoid C ester derivatives. The alkali is preferably selected from any one of K₂CO₃, Na₂CO₃, Cs₂CO₃, NaH, and NaOH.

[0023] As a preferred embodiment, the R group in the sesquiterpene Asperterpenoid C amide derivative of Formula II can be the following group:

[0024]

[0025] As a preferred embodiment, the structure of the sesquiterpene Asperterpenoid C amide derivative shown in Formula II can specifically be:

[0026]

[0027]

[0028] The sesquiterpene asperterpenoid C amide derivatives of Formula II of this invention were synthesized via the following synthetic route:

[0029]

[0030] The preparation method of the Asperterpenoid C amide derivative shown in Formula II of this invention includes the following steps:

[0031] S1: Asperterpenoid C first reacts with EDC (1-ethyl-(3-dimethylaminopropyl)carbodiimide imide) to form an addition intermediate, and then HOBT (1-hydroxyphenyltriazole) reacts with the intermediate to obtain the active intermediate ester;

[0032] S2: The active intermediate ester undergoes an amidation reaction with an amine compound to yield the corresponding sesquiterpene Asperterpenoid C amide derivative.

[0033] Those skilled in the art should understand that the preparation method of the Asperterpenoid C derivative described in this invention may also include a step of purifying the obtained product, for example, by extraction with an extractant, drying with a drying agent, and removing impurities by column chromatography or other methods.

[0034] Experiments show that the above-mentioned sesquiterpene Asperterpenoid C derivative has a significant inhibitory effect on the novel coronavirus and can be used for the prevention and treatment of the novel coronavirus.

[0035] Therefore, the use of the sesquiterpene Asperterpenoid C derivative, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug compound in the preparation of drugs against the novel coronavirus is also within the scope of protection of this invention.

[0036] Preferably, the novel coronavirus is SARS-CoV-2, B.1.1.7 variant (Alpha), B.1.351 variant (Beta), P.1 variant (Gamma), B.1.617.2 variant (Delta), or B.1.1.529 variant (Omicron).

[0037] The pharmaceutically acceptable salts of the sesquiterpene C derivative are its inorganic acid salts, inorganic alkali salts, or complex salts.

[0038] The inorganic acid salt is selected from any one or more of hydrochloric acid, hydroiodic acid, hydrobromic acid, nitric acid, boric acid, carbonic acid, sulfuric acid, phosphoric acid, silicic acid, acetic acid, propionic acid, malonic acid, butyric acid, lactic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, maleic acid, benzoic acid, succinic acid, picric acid, tartaric acid, citric acid, and fumaric acid.

[0039] The base of the inorganic base salt is selected from any one or more of sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide, ammonium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, trimethylamine, triethylamine, and pyridine.

[0040] The sesquiterpene Asperterpenoid C derivative prodrug refers to a substance that can be converted into the Asperterpenoid C derivative or its salt in vivo.

[0041] The present invention further provides a drug for combating the novel coronavirus, comprising the aforementioned sesquiterpene Asperterpenoid C derivative, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug compound thereof.

[0042] Preferably, the drug further includes a pharmaceutical carrier and / or excipients, and is formulated into different dosage forms.

[0043] The drug dosage forms include, but are not limited to, powders, tablets, granules, capsules, solutions, syrups, suspensions, injections, powder for injection, water for injection, aerosols, ointments, eye drops, or suppositories.

[0044] The administration methods of the drug include, but are not limited to, administration via the gastrointestinal tract, injection, inhalation, skin, mucosa, or cavity.

[0045] The present invention claims the use of the sesquiterpene Asperterpenoid C derivative, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug compound thereof, in the preparation of a drug for treating novel coronavirus, including but not limited to the use of the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug compound thereof, for the prevention or treatment of disease caused by novel coronavirus, for the relief of symptoms of disease caused by novel coronavirus, or for the alleviation of the development or onset of disease caused by novel coronavirus.

[0046] The sesquiterpene C derivatives, pharmaceutically acceptable salts thereof, stereoisomers thereof, or prodrug compounds claimed in this invention may be used in veterinary treatment of pets, introduced breeds of animals, and farm animals, including mammals and rodents, in addition to being beneficial to human treatment.

[0047] The present invention has the following beneficial effects:

[0048] This invention involves structural modification of the natural product Asperterpenoid C to obtain novel compounds. Preliminary pharmacological studies show that the EC50 of the synthesized Asperterpenoid C ester derivatives is [missing information]. 50 EC50 of 0.8-25.0 μM asperterpenoid C amide derivatives 50 The concentration ranges from 2.3 to 20.3 μM, indicating that the novel sesquiterpene C derivative synthesized in this invention exhibits significant anti-SARS-CoV-2 activity and can be used in the prevention and treatment of SARS-CoV-2. This provides a new option and approach for the research and development of new drugs against SARS-CoV-2 and has excellent research, development, and application prospects. Detailed Implementation

[0049] The present invention will be further illustrated below with specific embodiments, which provide data on the synthesis of representative new compounds, related structural identification, and compound activity. It must be noted that the following embodiments are illustrative of the invention and not intended to limit it. Simple modifications to the invention based on its essence are within the scope of protection claimed by the present invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, the reagents, methods, and equipment used in this invention are conventional reagents, methods, and equipment in this technical field.

[0050] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.

[0051] Example 1: Synthesis method, structural formula, and structural physicochemical data of compound 1A

[0052] Synthesis method: Asteipenoid C (0.04 mmol, 1 eq) was weighed into a 25 mL round-bottom flask and dissolved in 2 mL of ultra-dry pure acetonitrile. Then, K₂CO₃ (0.12 mmol, 3 eq) was added and the mixture was refluxed at 30 °C for 15–60 min. Next, 1 mL of iodobutane was added and the mixture was refluxed at the same temperature for approximately 4–6 h under nitrogen protection. The reaction was monitored by TLC. After the reaction was complete, the product was adjusted to pH 4–5 with 3 M hydrochloric acid, and then extracted three times with saturated brine using ethyl acetate (3 x 5 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using dichloromethane / methanol = 60:1 (V / V) as the eluent to obtain compound 1A.

[0053] The structural formula of compound 1A is:

[0054]

[0055] The structural and physicochemical data of compound 1A are as follows: colorless oil, yield 60%, mp: >300℃. 1 HNMR (δ) H , CDCl3, 600MHz): 0.18 (1H, m), 0.41 (1H, t, J = 5.0Hz), 0.71 (1H, dd, J = 8.6Hz, J = 4.3Hz), 0.76 (3H, s), 0.83 (3H, d, J = 6.8H z),0.86(3H,d,J=6.9Hz),0.93(3H,t,J=6.2Hz),0.97(3H,t,J=7.4Hz),1.01(1H,d,J=6.7Hz),1.24(2H,m),1.37-1.45(4 H,m),1.59(1H,d,J=13.5Hz),1.68-1.71(2H,m),1.76(1H,m),1.82(1H,m),1.97-2.01(3H,m),2.27-2.37(3H,m),2.60( 2H,m),3.51(1H,d,J=13.6Hz),3.61(1H,s),3.66(1H,d,J=7.6Hz),3.86-3.88(1H,dd,J=11.5Hz,J=3.8Hz),4.17(2H,m). 13 C

[0056] NMR (δ) C , CDCl3, 150MHz):167.9,159.3,127.7,78.3,64.6,61.2,57.0,48.0,47.6,45.9,45.9,44.9,43.1,32.8, 32.5,30.8,29.3,29.1,28.3,27.8,26.7,26.2,23.3,21.9,20.9,19.4,17.9,15.8,13.9.FTMS(ESI):m / z calcd for C 29 H 46 O4Na

[0057] ([M+Na)) + )481.32883,Found 481.32903.

[0058] Example 2: Synthesis method, structural formula, and structural physicochemical data of compound 2A

[0059] Synthesis method: Asteipenoid C (0.04 mmol, 1 eq) was weighed into a 25 mL round-bottom flask and dissolved in 2 mL of ultra-dry pure acetonitrile. Then, Na₂CO₃ (0.12 mmol, 3 eq) was added, and the mixture was refluxed at 40 °C for 15-60 min. Next, 1 mL of 1-bromo-2-chloroethane was added, and the mixture was refluxed at the same temperature for approximately 4-6 h under nitrogen protection. The reaction was monitored by TLC. After the reaction was complete, the product was adjusted to pH 4-5 with 3 M hydrochloric acid, and extracted three times with ethyl acetate (3 x 5 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using dichloromethane / methanol = 60:1 (V / V) as the eluent to obtain compound 2A.

[0060] The structural formula of compound 2A is:

[0061]

[0062] The structural and physicochemical data of compound 2A are as follows: colorless oil, yield 85%, mp: >300℃. 1 HNMR (δ) H , CDCl3, 600MHz): 0.18 (1H, m), 0.41 (1H, t, J = 5.0Hz), 0.69 (1H, dd, J = 8.6Hz, J = 4.3Hz), 0.74 (3H, s) ,0.81(3H,d,J=6.8Hz),0.84(3H,d,J=6.9Hz),0.91(3H,s),1.19-1.24(2H,m),1.36(1H,dd,J=15.2 Hz),1.42(1H,t,J=10.9Hz),1.59(1H,d,J=13.5Hz),1.67(1H,t,J=11.2Hz),1.74(1H,m),1.80(1H, m),1.96-2.08(3H,m),2.23-2.27(1H,m),2.30-2.35(2H,m),2.60,(2H,m),3.48(1H,d,J=13.6Hz),

[0063] 3.56-3.61(2H,s),3.64(1H,d,J=5.5Hz),3.72(2H,t,J=5.7Hz),4.40(2H,m). 13 CNMR(δ C,CDCl3,150MHz):167.3,161.1,126.9,78.3,64.2,61.3,57.0,47.9,47.6,45.8,45.8,45.0,43.1, 41.7,32.7,32.6,29.4,29.0,28.3,27.8,26.9,26.2,23.3,21.9,20.8,17.9,15.8.FTMS(ESI):m / z calcd for C 27 H 41 O4ClNa([M+Na]+)487.25856,Found487.25888.

[0064] Example 3: Synthesis method, structural formula, and structural physicochemical data of compound 3A

[0065] Synthesis method: Asteipenoid C (0.04 mmol, 1 eq) was weighed into a 25 mL round-bottom flask and dissolved in 2 mL of ultra-dry pure acetonitrile. Then, Cs₂CO₃ (0.12 mmol, 3 eq) was added and the mixture was refluxed at 50 °C for 15-60 min. Next, 1 mL of 1,4-dibromobutane was added and the mixture was refluxed at the same temperature for approximately 4-6 h under nitrogen protection. The reaction was monitored by TLC. After the reaction was complete, the product was adjusted to pH 4-5 with 3 M hydrochloric acid, and extracted three times with ethyl acetate (3 x 5 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using dichloromethane / methanol = 60:1 (V / V) as the eluent to obtain compound 3A.

[0066] The structural formula of compound 3A is:

[0067]

[0068] The structural and physicochemical data of compound 3A are as follows: colorless oil, yield 82%, mp: >300℃. 1 HNMR (δ) H, CDCl3, 600MHz): 0.18 (1H, m), 0.41 (1H, t, J = 5.0Hz), 0.69 (1H, dd, J = 8.6Hz, J = 4.3Hz), 0.73 (3H, s), 0.81 (3H, d, J = 6.8 Hz),0.83(3H,d,J=6.9Hz),0.91(3H,s),1.18-1.24(3H,m),1.34(1H,dd,J=15.1Hz),1.42(2H,t,J=10.9Hz),1.59(1H,d ,J=13.5Hz),1.67(1H,t,J=11.2Hz),1.73-1.86(4H,m),1.94-2.07(5H,m),2.23-2.34(3H,m),2.57(2H,m),3.44(1H,t ,J=6.6Hz), 3.47(1H,d,J=13.9Hz), 3.59(1H,m), 3.62(1H,d,J=5.5Hz), 3.78(1H,dd,J=8.23Hz), 4.18(2H,t,J=6.3Hz). 13 C

[0069] NMR (δ) C , CDCl3, 150MHz):167.7,160.1,127.3,78.3,63.8,61.2,57.0,47.9,47.6,45.9,45.9,44.96,43.1,33.2 ,32.8,32.6,29.6,29.4,29.1,28.3,27.8,27.4,26.7,26.2,23.3,21.9,20.8,17.9,15.8.FTMS(ESI):m / z calcd forC 29 H 46 O4Br([M+H)) + )537.25740,Found 537.25766.

[0070] Example 4: Synthesis method, structural formula, and structural physicochemical data of compound 4A

[0071] Synthesis method: Asteipenoid C (0.04 mmol, 1 eq) was weighed into a 25 mL round-bottom flask and dissolved in 2 mL of ultra-dry pure acetonitrile. Then, NaH (0.12 mmol, 3 eq) was added, and the mixture was refluxed at 60 °C for 15-60 min. Next, 1 mL of 1-bromo-4,4,4-trifluorobutane was added, and the mixture was refluxed at the same temperature for approximately 4-6 h under nitrogen protection. The reaction was monitored by TLC. After the reaction was complete, the product was adjusted to pH 4-5 with 3 M hydrochloric acid, and extracted three times with ethyl acetate (3 x 5 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using dichloromethane / methanol = 60:1 (V / V) as the eluent to obtain compound 4A.

[0072] The structural formula of compound 4A is:

[0073]

[0074] The structural and physicochemical data of compound 4A are as follows: colorless oil, yield 61%, mp: >300℃. 1 HNMR (δ) H , CDCl3, 600MHz): 0.19 (1H, m), 0.42 (1H, t, J = 5.0Hz), 0.72 (1H, dd, J = 8.6Hz, J = 4.3Hz), 0.76 (3H, s), 0.83 (3H, d, J = 6.8H z),0.86(3H,d,J=6.9Hz),0.93(3H,s),1.20-1.27(2H,m),1.38(1H,dd,J=15.2Hz),1.44(1H,t,J=10.9Hz),1.61(1H,d,J =13.5Hz),1.69(1H,t,J=11.2Hz),1.75-1.84(2H,m),1.96-2.01(3H,m),2.03-2.11(2H,m),2.19-2.29(3H,m),2.32-2. 36, (2H, m), 2.60 (2H, m), 3.50 (1H, d, J = 13.5Hz), 3.61 (1H, s), 3.66 (1H, d, J = 5.5Hz), 3.74 (1H, d, J = 9.0Hz), 4.23 (2H, m). 13 CNMR(δ C, CDCl3, 150MHz): 167.5, 160.7, 127.0 (t), 78.2, 62.9, 61.2, 57.0, 47.9, 47.6, 45.8, 45.8, 45.0, 43.1, 32.7, 32. 6,31.0(dd),29.8,29.4,29.1,28.2,27.8,26.7,26.2,23.3,21.9,21.7,20.8,17.9,15.8.FTMS(ESI):m / zcalcd forC 29 H 43 O4F3Na([M+Na) + )535.30057,Found 535.30099.

[0075] Example 5: Synthesis method, structural formula, and structural physicochemical data of compound 5A

[0076] Synthesis method: Asteipenoid C (0.04 mmol, 1 eq) was weighed into a 25 mL round-bottom flask and dissolved in 2 mL of ultra-dry pure acetonitrile. Then, NaOH (0.12 mmol, 3 eq) was added and the mixture was refluxed at 70 °C for 15-60 min. Next, 1 mL of 1-bromo-3-fluoropropane was added and the mixture was refluxed at the same temperature for approximately 4-6 h under nitrogen protection. The reaction was monitored by TLC. After the reaction was complete, the product was adjusted to pH 4-5 with 3 M hydrochloric acid, and then extracted three times with saturated brine using ethyl acetate (3 x 5 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using dichloromethane / methanol = 60:1 (V / V) as the eluent to obtain compound 5A.

[0077] The structural formula of compound 5A is:

[0078]

[0079] The structural and physicochemical data of compound 5A are as follows: colorless oil, yield 63%, mp: >300℃. 1 HNMR (δ) H, CDCl3, 600MHz): 0.18 (1H, m), 0.41 (1H, t, J = 5.0Hz), 0.71 (1H, dd, J = 8.6Hz, J = 4.3Hz), 0.76 (3H, s), 0.83 (3H, d, J = 6.8Hz), 0.85 (3 H,d,J=6.9Hz),0.93(3H,s),1.19-1.24(2H,m),1.36(1H,dd,J=15.2Hz),1.42(1H,t,J=11.0Hz),1.59(1H,d,J=13.5Hz),1.68-1.7 1(2H,m),1.74-1.84(2H,m),1.94-2.08(4H,m),2.09-2.13(1H,m),2.30-2.40(3H,m),2.5-2.60(2H,m),3.50(1H,d,J=13.5Hz),3. 58-3.61(1H,t,J=11.5Hz), 3.65(1H,d,J=5.5Hz), 3.77(1H,s), 4.30(2H,t,J=6.2Hz), 4.50(1H,t,J=5.9Hz), 4.60(1H,t,J=5.9Hz). 13 C NMR (δ) C ,CDCl3,150MHz):167.6,160.3,127.2,80.8,78.3(d),61.2,60.7,60.6,57.0,47.9,47.6,45.9,45.0,43 .1,32.8,32.6,29.9(t),29.4,29.1,28.3,27.8,26.7,26.2,23.3,21.9,20.8,17.9,15.8.FTMS(ESI):m / z calcd for C 28 H 44 O4F([M+H) + )463.32181,Found463.32193.

[0080] Example 6: Synthesis method, structural formula, and structural physicochemical data of compound 6A

[0081] Synthesis method: Asteipenoid C (0.04 mmol, 1 eq) was weighed into a 25 mL round-bottom flask and dissolved in 2 mL of ultra-dry pure acetonitrile. Then, K₂CO₃ (0.12 mmol, 3 eq) was added and the mixture was refluxed at 80 °C for 15-60 min. Next, 1 mL of n-octane bromide was added and the mixture was refluxed at the same temperature for approximately 4-6 h under nitrogen protection. The reaction was monitored by TLC. After the reaction was complete, the product was adjusted to pH 4-5 with 3 M hydrochloric acid, and then extracted three times with ethyl acetate (3 x 5 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using dichloromethane / methanol = 60:1 (V / V) as the eluent to obtain compound 6A.

[0082] The structural formula of compound 6A is:

[0083]

[0084] The structural and physicochemical data of compound 6A are as follows: colorless oil, yield 40%, mp: >300℃. 1 HNMR (δ) H , CDCl3, 600MHz): 0.15 (1H, m), 0.38 (1H, t, J = 5.0Hz), 0.68 (1H, dd, J = 8.6Hz, J = 4.3Hz), 0.73 (3H, s), 0.80 (3H, d, J = 6.8Hz ),0.83(3H,d,J=6.9Hz),0.88(3H,t,J=6.8Hz),0.90(3H,s),1.17-1.24(2H,m),1.24-1.32(9H,m),1.33-1.37(3H,m),1.4 1(1H,t,J=11.0Hz),1.56(1H,d,J=13.7Hz),1.63-1.68(3H,m),1.73-1.81(2H,m),1.93-2.07(3H,m),2.24-2.34(3H,m),2 .52-2.62(2H,m),3.48(1H,d,J=13.6Hz), 3.58-3.60(1H,m),3.63(1H,d,J=5.5Hz), 3.84(1H,dd,J=10.3Hz), 4.13(2H,m). 13 CNMR(δ C, CDCl3, 150MHz):167.7,159.2,127.5,78.16,64.8,61.0,56.8,47.8,47.4,45.7,45.7,44.8,43.0,32.7,32.4,31.8 ,29.2,29.2,29.2,29.0,28.6,28.2,27.6,26.5,26.1,26.0,23.2,22.6,21.8,20.7,17.8,15.6,14.1.FTMS(ESI):m / z calcd for C 33 H 55 O4([M+H)) + )515.40949,Found 515.40969.

[0085] Example 7: Synthesis method, structural formula, and structural physicochemical data of compound 1C

[0086] Synthesis method: Asteipenoid C (0.027 mmol, 1 eq) was weighed into a 25 mL round-bottom flask and dissolved in 2 mL of ultra-dry DCM. Then, EDC (0.052 mmol, 2 eq) and HOBT (14.6 mg, 0.108 mmol, 4 eq) were added, and the mixture was reacted at 0 °C or room temperature for 2-3 h under TLC monitoring. After the reaction was complete, 1 eq of N-aminopropylmorpholine was added, and the reaction continued for approximately 3-4 h. The reaction was monitored by TLC. After the reaction was complete, dichloromethane was removed by rotary evaporation. The product was dissolved in ethyl acetate or dichloromethane, washed three times with water (3 x 5 mL) to remove byproducts, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography using dichloromethane / methanol = 100:1 (V / V) as the eluent to obtain compound 1C.

[0087] The structural formula of compound 1C is:

[0088]

[0089] The structural and physicochemical data of compound 1C are as follows: colorless oil, yield 60%, mp: >300℃. 1 HNMR (δ) H, CDCl3, 600MHz): 0.16 (1H, m), 0.38 (1H, t, J = 5.2Hz), 0.68 (1H, dd, J = 8.6Hz, J = 4.3Hz), 0.73 (3H, s), 0.80 (3H ,d,J=6.8Hz),0.83(3H,d,J=6.9Hz),0.91(3H,s),1.15-1.23(3H,m),1.35(1H,dd,J=15.1Hz),1.41(1H,t,J=1 0.9Hz),1.52(1H,d,J=13.3Hz),1.66(2H,t,J=10.2Hz),1.73-1.81(5H,m),1.99-2.07(3H,m),2.24-2.34(3H ,m),2.50-2.57(6H,m),3.42(2H,m),3.55(1H,d,J=13.4Hz),3.61(2H,s),3.63(1H,d,J=5.5Hz),3.72(3H,m). 13 C NMR (δ) C , CDCl3, 150MHz):167.1,167.1,128.9,78.3,66.9,60.8,58.5,57.0,54.0,57.0,54.0,48.1,47.6,45.9,45.9, 44.9,43.3,39.8,33.7,32.2,29.2,28.3,27.7,26.6,26.2,24.4,23.3,22.1,20.8,17.9,15.8.FTMS(ESI):m / z calcd for C 32 H 53 O4N2([M+H) + )529.39998,Found 529.39985.

[0090] Example 8: Synthesis method, structural formula, and structural physicochemical data of compound 2C

[0091] Synthesis method: Asteipenoid C (10 mg, 0.027 mmol, 1 eq) was weighed into a 25 mL round-bottom flask and dissolved in 2 mL of ultra-dry DCM. Then, EDC (10.35 mg, 0.052 mmol, 2 eq) and HOBT (14.6 mg, 0.108 mmol, 4 eq) were added, and the reaction was carried out at 0 °C or room temperature for 2-3 h, monitored by TLC. After the reaction was complete, 1 eq of 2-thiophene methylamine was added, and the reaction continued for approximately 3-4 h. The reaction was monitored by TLC. After the reaction was complete, dichloromethane was removed by rotary evaporation. The product was dissolved in ethyl acetate or dichloromethane, washed three times with water (3 x 5 mL) to remove byproducts, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography using dichloromethane / methanol = 100:1 (V / V) as the eluent to obtain compound 2C.

[0092] The structural formula of compound 2C is:

[0093]

[0094] The structural and physicochemical data of compound 2C are as follows: colorless oil, yield 50%, mp: >300℃. 1 HNMR (δ) H , CDCl3, 600MHz): 0.17 (1H, m), 0.38 (1H, t, J = 5.0Hz), 0.68 (1H, dd, J = 8.6Hz, J = 4 .3Hz),0.73(3H,s),0.80(3H,d,J=6.8Hz),0.83(3H,d,J=6.9Hz),0.91(3H,s),1. 17-1.23(2H,m),1.35(1H,dd,J=15.4Hz,J=5.2Hz),1.41(1H,t,J=10.9Hz),1.52 (2H,d,J=13.5Hz),1.66(1H,t,J=11.2Hz),1.72-1.82(2H,m),1.99-2.07(3H,m),

[0095] 2.21-2.25(1H,m),2.29(1H,d,J=8.6Hz),2.32-2.36(1H,m),2.40-2.45(1H,m),2.57-2.59(1H,m),3.55(1H,d,J= 13.5Hz),3.61-3.63(2H,m),4.43(1H,s),4.68(2H,m),6.96(1H,m),7.00(1H,m),7.24(1H,dd,J=5.1Hz,J=1.2Hz). 13 C

[0096] NMR (δ)C , CDCl3, 150MHz):166.6,155.2,140.8,128.6,127.1,126.4,125.5,78.3,61.0,57.0,48.0,47.6,45.9,45.9, 44.9,43.3,38.4,33.3,32.6,29.3,29.2,28.3,27.7,26.5,26.2,23.3,22.1,20.8,17.9,15.8.FTMS(ESI):m / z calcd forC 30 H 44 O3NS([M+H) + )498.30364,Found 498.30409.

[0097] Example 9: Synthesis method, structural formula, and structural physicochemical data of compound 3C

[0098] Synthesis method: Asteipenoid C (10 mg, 0.027 mmol, 1 eq) was weighed into a 25 mL round-bottom flask and dissolved in 2 mL of ultra-dry DCM. Then, EDC (10.35 mg, 0.052 mmol, 2 eq) and HOBT (14.6 mg, 0.108 mmol, 4 eq) were added, and the reaction was carried out at 0 °C or room temperature for 2-3 h, monitored by TLC. After the reaction was complete, 1 eq of 2-furan ethylamine was added, and the reaction continued for approximately 3-4 h. The reaction was monitored by TLC. After the reaction was complete, dichloromethane was removed by rotary evaporation. The product was dissolved in ethyl acetate or dichloromethane, washed three times with water (3 x 5 mL) to remove byproducts, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography using dichloromethane / methanol = 100:1 (V / V) as the eluent to obtain compound 3C.

[0099] The structural formula of compound 3C is:

[0100]

[0101] The structural and physicochemical data of compound 3C are as follows: colorless oil, yield 43%, mp: >300℃. 1 HNMR (δ) H, CDCl3, 600MHz): 0.17 (1H, m), 0.40 (1H, t, J = 5.0Hz), 0.70 (1H, dd, J = 8.6Hz, J = 4.3Hz), 0.75 (3H, s) ,0.82(3H,d,J=6.8Hz),0.85(3H,d,J=6.9Hz),0.92(3H,s),1.18-1.25(2H,m),1.36-1.43(2H,m),1. 52(1H,d,J=13.4Hz),1.67(1H,t,J=13.9Hz),1.75-1.82(2H,m),1.98-2.10(3H,m),2.24-2.27(1H,m ),2.29(1H,d,J=8.5Hz),2.33-2.41(2H,m),2.54-2.60(1H,m),2.90(2H,m),3.53(1H,d,J=13.5Hz),

[0102] 3.59-3.66(5H,m),4.60(1H,br),6.10(1H,d,J=3.1Hz),6.33(1H,dd,J=3.1Hz,J=1.9Hz),7.36(1H,d,J=1.1Hz). 13 C NMR (δ) C , CDCl3, 150MHz):166.9,154.7,153.4,141.7,128.8,110.5,106.6,78.3,60.9,57.0,48.0,47.6,45.9 ,45.9,44.8,43.3,38.2,33.3,32.5,29.2,29.2,28.3,28.1,27.7,26.5,26.2,23.3,22.1,20.8,17.9,

[0103] 15.8.FTMS(ESI):m / z calcd for C 31 H 46 O4N([M+H)) + )496.34214,Found496.34224.

[0104] Example 10: Synthesis method, structural formula, and structural physicochemical data of compound 4C

[0105] Synthesis method: Asteipenoid C (10 mg, 0.027 mmol, 1 eq) was weighed into a 25 mL round-bottom flask and dissolved in 2 mL of ultra-dry DCM. Then, EDC (10.35 mg, 0.052 mmol, 2 eq) and HOBT (14.6 mg, 0.108 mmol, 4 eq) were added, and the reaction was carried out at 0 °C or room temperature for 2-3 h, monitored by TLC. After the reaction was complete, 1 eq of cyclopropylamine was added, and the reaction continued for approximately 3-4 h. The reaction was monitored by TLC. After the reaction was complete, dichloromethane was removed by rotary evaporation. The product was dissolved in ethyl acetate or dichloromethane, washed three times with water (3 x 5 mL) to remove byproducts, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography using dichloromethane / methanol = 100:1 (V / V) as the eluent to obtain compound 4C.

[0106] The structural formula of compound 4C is:

[0107]

[0108] The structural and physicochemical data of compound 4C are as follows: colorless oil, yield 43%, mp: >300℃. 1 HNMR (δ) H , CDCl3, 600MHz): 0.15 (1H, m), 0.37 (1H, t, J = 5.1Hz), 0.50-0.56 (2H, m), 0.66 (1H, dd, J = 8.6Hz, J = 4.3Hz),0.73(3H,s),0.80(3H,d,J=6.8Hz),0.80(2H,m),0.83(3H,d,J=6.9Hz),0.90(3H,s),1.15 -1.23(2H,m),1.33(1H,dd,J=15.2Hz,J=5.2Hz),1.42(1H,t,J=10.9Hz),1.52(1H,d,J=13.5Hz),1 .66(2H,t,J=11.2Hz),1.72-1.82(2H,m),1.95-2.07(3H,m),2.23-2.28(2H,m),2.32-2.39(2H,m),

[0109] 2.52-2.56(1H,m),2.80-2.82(1H,m),3.53(1H,d,J=13.4Hz),3.61-3.63(2H,m),4.56(1H,br). 13 C NMR (δ) C,CDCl3,150MHz):168.5,154.8,128.7,78.3,60.9,57.0,48.0,47.6,45.9,45.9,44.8,43.3,33.4,3 2.5,29.2,29.2,28.3,27.7,26.5,26.2,23.3,22.9,22.1,20.8,17.9,15.8,6.9,6.7.FTMS(ESI):m / z calcd forC 28 H 44 O3N([M+H)) + )442.33157,Found 442.33145.

[0110] Example 11: Synthesis method, structural formula, and structural physicochemical data of compound 5C

[0111] Synthesis method: Asteipenoid C (10 mg, 0.027 mmol, 1 eq) was weighed into a 25 mL round-bottom flask and dissolved in 2 mL of ultra-dry DCM. Then, EDC (10.35 mg, 0.052 mmol, 2 eq) and HOBT (14.6 mg, 0.108 mmol, 4 eq) were added, and the reaction was carried out at 0 °C or room temperature for 2-3 h, monitored by TLC. After the reaction was complete, 1 eq of cyclopentylamine was added, and the reaction continued for approximately 3-4 h. The reaction was monitored by TLC. After the reaction was complete, dichloromethane was removed by rotary evaporation. The product was dissolved in ethyl acetate or dichloromethane, washed three times with water (3 x 5 mL) to remove byproducts, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography using dichloromethane / methanol = 100:1 (V / V) as the eluent to obtain compound 5C.

[0112] The structural formula of compound 5C is:

[0113]

[0114] The structural and physicochemical data of compound 5C are as follows: colorless oil, yield 43%, mp: >300℃. 1 HNMR (δ) H, CDCl3, 600MHz): 0.16 (1H, m), 0.37 (1H, t, J = 5.0Hz), 0.67 (1H, dd, J = 8.6Hz, J = 4.3Hz),0.73(3H,s),0.80(3H,d,J=6.8Hz),0.83(3H,d,J=6.9Hz),0.90(3H,s) ,1.15-1.22(2H,m),1.33-1.41(5H,m),1.50(1H,d,J=13.4Hz),1.58-1.65(4H, m),1.70-1.81(2H,m),1.96-2.01(5H,m),2.24-2.28(2H,m),2.32-2.40(2H,m),

[0115] 2.55-2.59(1H,m),3.54(1H,d,J=13.4Hz),3.62(3H,m),4.28(1H,m),4.74(1H,br). 13 CNMR(δ C , CDCl3, 150MHz):166.6,154.5,128.8,78.3,60.9,57.0,51.2,48.1,47.6,45.9,45.9,44.8,43.3,33.5,33 .4,33.3,32.5,29.2,29.2,28.3,27.7,26.5,26.2,23.9,23.9,23.3,22.1,20.8,17.9,15.8.FTMS(ESI):m / z calcd forC 30 H 48 O3N([M+H)) + )470.36287,Found 470.3627.

[0116] Example 12: Synthesis method, structural formula, and structural physicochemical data of compound 6C

[0117] Synthesis method: Asteipenoid C (10 mg, 0.027 mmol, 1 eq) was weighed into a 25 mL round-bottom flask and dissolved in 2 mL of ultra-dry DCM. Then, EDC (10.35 mg, 0.052 mmol, 2 eq) and HOBT (14.6 mg, 0.108 mmol, 4 eq) were added, and the reaction was carried out at 0 °C or room temperature for 2-3 h, monitored by TLC. After the reaction was complete, 1 eq of phenylethylamine was added, and the reaction continued for approximately 3-4 h. The reaction was monitored by TLC. After the reaction was complete, dichloromethane was removed by rotary evaporation. The product was dissolved in ethyl acetate or dichloromethane, washed three times with water (3 x 5 mL) to remove byproducts, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography using dichloromethane / methanol = 100:1 (V / V) as the eluent to obtain compound 6C.

[0118] The structural formula of compound 6C is:

[0119]

[0120] The structural and physicochemical data of compound 6C are as follows: colorless oil, yield 87%, mp: >300℃. 1 HNMR (δ) H , CDCl3, 600MHz): 0.15 (1H, m), 0.37 (1H, t, J = 5.0Hz), 0.67 (1H, dd, J = 8.6Hz, J = 4.3Hz), 0.73 (3H, s), 0.80 (3H, d, J = 6.8Hz), 0.83 (3H, d, J = 6 .9Hz),0.90(3H,s),1.14-1.23(2H,m),1.35(1H,dd,J=10.0Hz,J=5.2Hz),1.41(1H,t,J=10.9Hz),1.50(1H,d,J=13.5Hz),1.64(1H,t,J=11. 1Hz),1.71-1.81(4H,m),1.93-2.07(3H,m),2.19(1H,m),2.25-2.35(3H,m),2.40-2.50(1H,m),2.85(2H,t,J=6.9Hz),3.48(1H,d,J=13.5H z),3.55-3.60(3H,m),3.63(1H,d,J=5.5Hz),4.54(1H,s),7.20(2H,d,J=7.4Hz),7.24(1H,t,J=7.3Hz),7.26(1H,s),7.32(1H,t,J=7.5Hz). 13 CNMR(δ C, CDCl3, 150MHz):165.8,153.2,138.0,127.8,127.8,127.8,127.6,127.6,125.5,77.1,59.7,55.83,46.8,46.4,44.8,4 4.7,43.6,42.1,39.5,34.5,32.1,31.4,28.1,28.0,27.1,26.6,25.3,25.0,22.1,21.0,19.6,16.7,14.6.FTMS(ESI):m / z calcd for C 33 H 48 O3N([M+H)) + )506.36287,Found 506.36311.

[0121] Example 13: Synthesis method, structural formula, and structural physicochemical data of compound 7C

[0122] Synthesis method: Asteipenoid C (10 mg, 0.027 mmol, 1 eq) was weighed into a 25 mL round-bottom flask and dissolved in 2 mL of ultra-dry DCM. Then, EDC (10.35 mg, 0.052 mmol, 2 eq) and HOBT (14.6 mg, 0.108 mmol, 4 eq) were added, and the reaction was carried out at 0 °C or room temperature for 2-3 h, monitored by TLC. After the reaction was complete, 1 eq of 2-(1-cyclohexenyl)ethylamine was added, and the reaction continued for approximately 3-4 h. The reaction was monitored by TLC. After the reaction was complete, dichloromethane was removed by rotary evaporation. The product was dissolved in ethyl acetate or dichloromethane, washed three times with water (3 x 5 mL) to remove byproducts, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography using dichloromethane / methanol = 100:1 (V / V) as the eluent to obtain compound 7C.

[0123] The structural formula of compound 7C is:

[0124]

[0125] The structural and physicochemical data of compound 7C are as follows: colorless oil, yield 43%, mp: >300℃. 1 HNMR (δ) H, CDCl3, 600MHz): 0.16 (1H, m), 0.37 (1H, t, J = 5.0Hz), 0.68 (1H, dd, J = 8.6Hz, J = 4.3Hz), 0.73 (3H, s), 0.80 (3H, d, J = 6.8 Hz),0.83(3H,d,J=6.9Hz),0.90(3H,s),1.17-1.25(2H,m),1.33-42(3H,m),1.50(1H,d,J=7.4Hz),1.53-1.58(2H,m),

[0126] 1.61-1.67(3H,m),1.73-1.82(2H,m),1.93(2H,m),2.00-2.06(4H,m),2.16(2H,m),2.26-2.36(4H,m),2.54-2.57(1H,m),3 .32-3.37(1H,m),3.40-3.44(1H,m),3.57(1H,d,J=13.4Hz),3.60(2H,s),3.63(1H,d,J=5.5Hz),4.86(1H,br),5.49(1H,s). 13 CNMR(δ C , CDCl3, 150MHz):165.2,153.8,138.1,137.9,137.9,130.7,122.3,122.3,87.6,78.2,61.4,57.4,47.8,47.5,46.0,45 .9,44.7,43.4,33.7,32.7,29.6,29.2,28.3,27.7,27.1,26.5,26.3,23.3,23.3,22.2,20.7,17.9,15.8.FTMS(ESI):m / z calcd for C 33 H 52 O3N([M+H)) + )510.39417,Found 510.39469.

[0127] Example 14: Synthesis method, structural formula, and structural physicochemical data of compound 8C

[0128] Synthesis method: Asteipenoid C (10 mg, 0.027 mmol, 1 eq) was weighed into a 25 mL round-bottom flask and dissolved in 2 mL of ultra-dry DCM. Then, EDC (10.35 mg, 0.052 mmol, 2 eq) and HOBT (14.6 mg, 0.108 mmol, 4 eq) were added, and the reaction was carried out at 0 °C or room temperature for 2-3 h, monitored by TLC. After the reaction was complete, 1 eq of p-toluidine was added, and the reaction continued for approximately 3-4 h. The reaction was monitored by TLC. After the reaction was complete, dichloromethane was removed by rotary evaporation. The product was dissolved in ethyl acetate or dichloromethane, washed three times with water (3 x 5 mL) to remove byproducts, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography using dichloromethane / methanol = 100:1 (V / V) as the eluent to obtain compound 8C.

[0129] The structural formula of compound 8C is:

[0130]

[0131] The structural and physicochemical data of compound 8C are as follows: colorless oil, yield 43%, mp: >300℃. 1 HNMR (δ) H , CDCl3, 600MHz): 0.18 (1H, m), 0.41 (1H, t, J = 5.0Hz), 0.70 (1H, dd, J = 8.6Hz, J = 4 .3Hz),0.74(3H,s),0.81(3H,d,J=6.8Hz),0.84(3H,d,J=6.9Hz),0.97(3H,s),1. 20-1.28(2H,m),1.35(1H,dd,J=15.1Hz,J=5.2Hz),1.44(1H,t,J=10.9Hz),1.60 (1H,d,J=13.7Hz),1.67(1H,t,J=10.9Hz),1.72-1.77(1H,m),1.74-1.82(1H,m),

[0132] 2.03-2.09(3H,m),2.18-2.21(1H,m),2.31(3H,s),2.33-2.37(2H,m),2.62-2.72(2H,m),3.51(1H,d,J=13.7Hz ),3.64(1H,d,J=5.5Hz),3.70(2H,s),4.21(1H,br),7.11(2H,d,J=8.2Hz),7.45(2H,d,J=8.3Hz),7.90(1H,s). 13 C NMR (δ) C, CDCl3, 150MHz):165.1,154.5,135.4,134.2,130.1,129.6,120.5,129.6,120.5,78.3,61.2,57.3,47.9,47.5,46.0 ,45.9,44.8,43.4,33.7,32.6,29.4,29.2,28.3,27.7,26.5,26.3,23.3,22.2,21.0,20.7,17.8,15.8.FTMS(ESI):m / z calcd for C 32 H 46 O3N([M+H)) + )492.34722,Found492.34763.

[0133] Example 15: Synthesis method, structural formula, and structural physicochemical data of compound 9C

[0134] Synthesis method: Asteipenoid C (10 mg, 0.027 mmol, 1 eq) was weighed into a 25 mL round-bottom flask and dissolved in 2 mL of ultra-dry DCM. Then, EDC (10.35 mg, 0.052 mmol, 2 eq) and HOBT (14.6 mg, 0.108 mmol, 4 eq) were added, and the reaction was carried out at 0 °C or room temperature for 2-3 h, monitored by TLC. After the reaction was complete, 1 eq of benzylamine was added, and the reaction continued for approximately 3-4 h. The reaction was monitored by TLC. After the reaction was complete, dichloromethane was removed by rotary evaporation. The product was dissolved in ethyl acetate or dichloromethane, washed three times with water (3 x 5 mL) to remove byproducts, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography using dichloromethane / methanol = 100:1 (V / V) as the eluent to obtain compound 9C.

[0135] The structural formula of compound 9C is:

[0136]

[0137] The structural and physicochemical data of compound 9C are as follows: colorless oil, yield 43%, mp: >300℃. 1 HNMR (δ) H, CDCl3, 600MHz): 0.17 (1H, m), 0.38 (1H, t, J = 5.0Hz), 0.68 (1H, dd, J = 8.6Hz, J = 4.3Hz), 0.74 (3H, s), 0.81 (3H, d, J = 6.8Hz), 0.83(3H,d,J=6.9Hz),0.92(3H,s),1.17-1.23(2H,m),1.35(1H,dd,J=15.2Hz,J=5.2Hz),1.42(1H,m),1.54(1H,d,J=13.4Hz ),1.66(1H,t,J=10.9Hz),1.72-1.82(2H,m),1.96-2.08(3H,m),2.22-2.26(1H,m),2.30(1H,d,J=8.8Hz),2.31-2.35(1H,m) ,2.39-2.43(1H,m),2.57-2.62(1H,m),3.57(1H,d,J=13.4Hz),3.63(3H,m),4.48-4.55(2H,m),4.58(1H,s),7.28-7.36(5H,

[0138] m). 13 C NMR (δ) C , CDCl3, 150MHz):166.8,155.3,138.2,128.9,128.9,128.6,128.2,128.2,127.8,78.3,61.0,57.0,48.0,47.6,45.9 ,45.9,44.9,43.8,43.3,33.4,32.6,29.3,29.2,28.3,27.7,26.5,26.2,23.3,22.1,20.8,17.9,15.8.FTMS(ESI):m / z calcd forC 32 H 46 O3N([M+H)) + )492.34722,Found 492.34763.

[0139] Example 16: Synthesis method, structural formula, and structural physicochemical data of compound 10C

[0140] Synthesis method: Asteipenoid C (10 mg, 0.027 mmol, 1 eq) was weighed into a 25 mL round-bottom flask and dissolved in 2 mL of ultra-dry DCM. Then, EDC (10.35 mg, 0.052 mmol, 2 eq) and HOBT (14.6 mg, 0.108 mmol, 4 eq) were added, and the reaction was carried out at 0 °C or room temperature for 2-3 h, monitored by TLC. After the reaction was complete, 1 eq of p-bromoaniline was added, and the reaction continued for approximately 3-4 h. The reaction was monitored by TLC. After the reaction was complete, dichloromethane was removed by rotary evaporation. The product was dissolved in ethyl acetate or dichloromethane, washed three times with water (3 x 5 mL) to remove byproducts, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography using dichloromethane / methanol = 100:1 (V / V) as the eluent to obtain compound 10C.

[0141] The structural formula of compound 10C is:

[0142]

[0143] The structural and physicochemical data of compound 10C are as follows: colorless oil, yield 43%, mp: >300℃. 1 HNMR (δ) H , CDCl3, 600MHz): 0.18 (1H, m), 0.42 (1H, t, J = 5.0Hz), 0.68 (1H, dd, J = 8.6Hz, J = 4.3Hz), 0.71 (3H, s), 0.74 (3H, d, J = 6.8 Hz),0.84(3H,d,J=6.9Hz),0.97(3H,s),1.22-1.28(2H,m),1.36(1H,dd,J=15.2Hz,J=5.2Hz),1.45(1H,t,J=10.9Hz),

[0144] 1.61-1.67(2H,m),1.72-1.74(1H,m),1.81-1.82(1H,m),2.05-2.10(2H,m),

[0145] 2.13-2.15(1H,m),2.34-2.37(2H,m),2.67-2.70(2H,m),3.40(1H,d,J=13.85Hz),3.64(1H,d,J=5.5Hz),3.72( 2H, t, J = 15.2Hz), 4.02 (1H, br), 7.40 (2H, dt, J = 8.8Hz, J = 2.0Hz), 7.50 (2H, dt, J = 8.8Hz, J = 2.0Hz), 8.40 (1H, s). 13 C

[0146] NMR (δ) C , CDCl3, 150MHz):165.3,153.6,137.4,132.0,132.0,130.8,122.0,122.0,116.9,78.2,61.3,57.5,47.8,47.5,46 .0,45.9,44.7,43.4,33.6,32.7,29.6,29.4,28.3,27.7,26.5,26.4,23.3,22.2,20.7,17.9,15.9.FTMS(ESI):m / z calcd for C 31 H 43 O3NBr([M+H)) + )556.24208,Found 556.24237.

[0147] Example 17: Synthesis method, structural formula, and structural physicochemical data of compound 11C

[0148] Synthesis method: Asteipenoid C (10 mg, 0.027 mmol, 1 eq) was weighed into a 25 mL round-bottom flask and dissolved in 2 mL of ultra-dry DCM. Then, EDC (10.35 mg, 0.052 mmol, 2 eq) and HOBT (14.6 mg, 0.108 mmol, 4 eq) were added, and the reaction was carried out at 0 °C or room temperature for 2-3 h, monitored by TLC. After the reaction was complete, 1 eq of p-iodoaniline was added, and the reaction continued for approximately 3-4 h. The reaction was monitored by TLC. After the reaction was complete, dichloromethane was removed by rotary evaporation. The product was dissolved in ethyl acetate or dichloromethane, washed three times with water (3 x 5 mL) to remove byproducts, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography using dichloromethane / methanol = 100:1 (V / V) as the eluent to obtain compound 11C.

[0149] The structural formula of compound 11C is:

[0150]

[0151] The structural and physicochemical data of compound 11C are as follows: colorless oil, yield 43%, mp: >300℃. 1 HNMR (δ) H, CDCl3, 600MHz): 0.18 (1H, m), 0.42 (1H, t, J = 5.0Hz), 0.70 (1H, dd, J = 8.6Hz, J = 4.3Hz), 0.74 (3H, s), 0.81 (3H, d, J = 6.8 Hz),0.84(3H,d,J=6.9Hz),0.97(3H,s),1.23-1.28(2H,m),1.34(1H,dd,J=15.2Hz,J=5.2Hz),1.45(1H,t,J=10.9Hz),

[0152] 1.61-1.68(2H,m),1.72-1.83(2H,m),1.06-2.15(3H,m),2.34-2.37(2H,m),

[0153] 2.32-2.37(2H,m),2.70(2H,m),3.41(1H,d,J=13.8Hz),3.65(1H,d,J=5.5Hz),3.72(2 H,t,J=11.0Hz),3.88(1H,s),7.38(2H,d,J=8.8Hz),7.69(1H,dt,J=8.8Hz,J=2.0Hz). 13 C NMR (δ) C , CDCl3, 150MHz):165.2,153.8,138.1,137.9,137.9,130.7,122.3,122.3,87.6,78.2,61.4,57.4,47.8,47.5,46.0,45.9, 44.7,43.4,33.7,32.7,29.6,29.2,28.3,27.7,27.1,26.5,26.3,23.3,23.3,22.2,20.7,17.9,15.8.FTMS(ESI):m / zcalcd forC 31 H 43 O3NI([M+H)) + )604.22821,Found 604.22859.

[0154] Example 18: Synthesis method, structural formula, and structural physicochemical data of compound 12C

[0155] Synthesis method: Asteipenoid C (10 mg, 0.027 mmol, 1 eq) was weighed into a 25 mL round-bottom flask and dissolved in 2 mL of ultra-dry DCM. Then, EDC (10.35 mg, 0.052 mmol, 2 eq) and HOBT (14.6 mg, 0.108 mmol, 4 eq) were added, and the reaction was carried out at 0 °C or room temperature for 2-3 h, monitored by TLC. After the reaction was complete, 1 eq of n-propylamine was added, and the reaction continued for approximately 3-4 h. The reaction was monitored by TLC. After the reaction was complete, dichloromethane was removed by rotary evaporation. The product was dissolved in ethyl acetate or dichloromethane, washed three times with water (3 x 5 mL) to remove byproducts, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography using dichloromethane / methanol = 100:1 (V / V) as the eluent to obtain compound 12C.

[0156] The structural formula of compound 12C is:

[0157]

[0158] The structural and physicochemical data of compound 12C are as follows: colorless oil, yield 43%, mp: >300℃. 1 HNMR (δ) H , CDCl3, 600MHz): 0.16 (1H, m), 0.38 (1H, t, J = 5.0Hz), 0.68 (1H, dd, J = 8.6Hz, J = 4.3Hz),0.73(3H,s),0.80(3H,d,J=6.8Hz),0.83(3H,d,J=6.9Hz),0.91(3H,s) ,0.94(3H,t,J=7.4Hz),1.17-1.23(2H,m),1.32-1.42(3H,m),1.50-1.59(3H,m ),1.65-1.68(1H,m),1.73-1.80(2H,m),1.97-2.07(3H,m),2.24-2.28(2H,m),

[0159] 2.32-2.36(1H,m),2.39-2.43(1H,m),2.56-2.61(1H,m),3.26-3.30(2H,m),3.55(1H,d,J=13.4Hz),3.61-3.63(2H,m),4.76(1H,t,J=7.3Hz). 13 C NMR (δ) C, CDCl3, 150MHz): δ167.0,154.6,128.8,78.3,60.9,57.0,48.0,47.6,45.9,45.9,44.8,43. 3,41.4,33.4,32.5,29.2,29.2,28.3,27.7,26.5,26.2,23.3,22.9,22.1,20.8,17.9,15.8,

[0160] 11.6.FTMS(ESI):m / z calcd for C 28 H 46 O3N([M+H)) + )444.34722,Found444.34746.

[0161] Comparative Example 1

[0162] Asperterpenoid C, a disesquiterpene, was designed as the first comparative case of this invention.

[0163] Comparative Example 2: Synthesis method, structural formula, and structural physicochemical data of the compound in Comparative Example 2.

[0164] Synthesis method: Asteipenoid C (0.04 mmol, 1 eq) was weighed into a 25 mL round-bottom flask and dissolved in 2 mL of ultra-dry pure acetonitrile. Then, K₂CO₃ (0.12 mmol, 3 eq) was added and the mixture was refluxed at 50 °C for 15-60 min. Next, 1 mL of methyl bromoacetate was added and the mixture was refluxed at the same temperature for approximately 4-6 h under nitrogen protection. The reaction was monitored by TLC. After the reaction was complete, the product was adjusted to pH 4-5 with 3 M hydrochloric acid, and then extracted three times with saturated brine using ethyl acetate (3 x 5 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using dichloromethane / methanol = 60:1 (V / V) as the eluent to obtain the compound of Comparative Example 2.

[0165] The structural formula of the compound in Comparative Example 2 is:

[0166]

[0167] The structural and physicochemical data of compound 2 are as follows: colorless oil, yield 63%, mp: >300℃. ¹H NMR (δH, CDCl₃, 600MHz): 0.18 (¹H, m), 0.41 (¹H, t, J = 5.0Hz), 0.71 (¹H, dd, J = 8.6Hz, J = 4.3Hz), 0.76 (³H, s), 0.83 (³H, d, J = 6.8Hz), 0.85 (³H, d, J = 6.9Hz), 0.94 (³H, s), 1.20–1.26 (²H, m), 1.38 (¹H, dd, J = 15.1Hz), 1.44 (¹H, t, J = 5.8Hz), 1.62 (¹H, d, J = 13.5Hz). Hz),1.70(1H,t,J=11.2Hz),1.74-1.79(1H,m),1.80-1.84(1H,m),1.99-2 .02(1H,m),2.05-2.10(2H,m),2.23-2.27(1H,m),2.25-2.28(1H,m),2.36, (2H,m),2.67(2H,m),3.53(1H,t,J=13.7Hz),3.60(1H,s),3.63(1H,s),3. 66(1H,d,J=5.5Hz),3.80(3H,s),4.64(1H,d,15.9),4.80(1H,d,15.9).13C NMR (δC, CDCl3, 150MHz): 168.5, 166.8, 161.6, 126.6, 78.3, 61.3, 60.7, 57.0, 52.5, 47.8, 47.5, 45.8, 45.8 ,45.0,43.0,32.8,32.6,29.4,29.0,28.3,27.8,26.7,26.2,23.3,21.9,20.8,17.9,15.8.FTMS(ESI):m / z calcd for C28H42O6Na([M+Na]+)497.28736,Found 497.28754.

[0168] Comparative Example 3: Synthetic methods, structural formulas, and structural physicochemical data of the compounds in Comparative Example 3.

[0169] Synthesis method: Asteipenoid C (10 mg, 0.027 mmol, 1 eq) was weighed into a 25 mL round-bottom flask and dissolved in 2 mL of ultra-dry DCM. Then, EDC (10.35 mg, 0.052 mmol, 2 eq) and HOBT (14.6 mg, 0.108 mmol, 4 eq) were added, and the reaction was carried out at 0 °C or room temperature for 2-3 h, monitored by TLC. After the reaction was complete, 1 eq of morpholine was added, and the reaction continued for approximately 3-4 h. The reaction was monitored by TLC. After the reaction was complete, dichloromethane was removed by rotary evaporation. The product was dissolved in ethyl acetate or dichloromethane, washed three times with water (3 x 5 mL) to remove byproducts, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography using dichloromethane / methanol = 100:1 (V / V) as the eluent to obtain the compound of Comparative Example 3.

[0170] The structural formula of the compound in Comparative Example 3 is:

[0171]

[0172] The structural and physicochemical data of the compound in Comparative Example 3 are as follows: colorless oil, yield 70%, mp: >300℃. 1 HNMR (δ) H , CDCl3, 600MHz): 0.19 (1H, m), 0.37 (1H, t, J = 5.0Hz), 0.66 (1H, dd, J = 8.6Hz, J = 4 .3Hz),0.72(3H,s),0.80(3H,d,J=6.8Hz),0.83(3H,d,J=6.9Hz),1.01(3H,s),1. 12-1.23(2H,m),1.33-1.41(2H,m),1.50(1H,d,J=13.6Hz),1.64(1H,t,J=11.2H z),1.71-1.81(2H,m),1.99-2.07(2H,m),2.12-2.17(2H,m),2.23(1H,d,J=9Hz),

[0173] 2.24-2.28(1H,m),2.32-2.37(1H,m),2.67(1H,d,J=13.7Hz),2.73(1H,m),3.30(1H,m),3.37(1H,m),3.45(1H,m ),3.52-3.58(2H,m),3.62(1H,d,J=5.5Hz),3.66(1H,m),3.70-3.76(3H,m),3.90(1H,d,J=13.5Hz),4.06(1H,s). 13 C

[0174] NMR (δ)C , CDCl3, 150MHz):169.9,147.4,132.3,78.2,67.3,67.0,60.6,54.3,47.5,47.4,47.2,46.0,45.9,44.3, 42.7,42.1,34.5,32.4,29.23,29.2,28.2,28.0,27.6,26.7,23.2,22.4,21.2,17.7,15.6.FTMS(ESI):m / z calcd forC 29 H 46 O4N([M+H)) + )472.34214,Found 472.34255.

[0175] Comparative Example 4: Synthetic methods, structural formulas, and structural physicochemical data of the compounds in Comparative Example 4.

[0176] Synthesis method: Asteipenoid C (10 mg, 0.027 mmol, 1 eq) was weighed into a 25 mL round-bottom flask and dissolved in 2 mL of ultra-dry DCM. Then, EDC (10.35 mg, 0.052 mmol, 2 eq) and HOBT (14.6 mg, 0.108 mmol, 4 eq) were added, and the reaction was carried out at 0 °C or room temperature for 2-3 h, monitored by TLC. After the reaction was complete, 1 eq of N-(2-aminoethyl)morpholine was added, and the reaction continued for approximately 3-4 h. The reaction was monitored by TLC. After the reaction was complete, dichloromethane was removed by rotary evaporation. The product was dissolved in ethyl acetate or dichloromethane, washed three times with water (3 x 5 mL) to remove byproducts, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography using dichloromethane / methanol = 100:1 (V / V) as the eluent to obtain the compound of Comparative Example 4.

[0177] The structural formula of the compound in Comparative Example 4 is:

[0178]

[0179] The structural and physicochemical data of the compound in Comparative Example 4 are as follows: colorless oil, yield 58%, mp: >300℃. 1 HNMR (δ) H, CDCl3, 600MHz): 0.16 (1H, m), 0.38 (1H, t, J = 5.0Hz), 0.68 (1H, dd, J = 8.6Hz, J = 4.3Hz), 0.73 (3H, s), 0.80 (3H, d, J =6.8Hz),0.83(3H,d,J=6.9Hz),0.91(3H,s),1.15-1.23(2H,m),1.35(1H,dd,J=15.1Hz),1.41(1H,t,J=10.9Hz),1 .52(1H,d,J=11.3Hz),1.66(1H,t,J=11.2Hz),1.73-1.81(3H,m),1.99-2.07(3H,m),2.26-2.36(3H,m),2.42-2.4 9(4H,m),2.54-2.62(3H,m),3.43(2H,m),3.56(1H,d,J=13.4Hz),3.61(2H,s),3.63(1H,d,J=5.5Hz),3.72(4H,m). 13 C NMR (δ) C , CDCl3, 150MHz):166.8,154.8,128.5,78.2,67.0,60.7,56.9,56.7,53.2,53.2,53.2,47.9,47.4,45.8,45.8, 44.7,43.2,35.4,33.2,32.34,29.1,29.1,28.1,27.6,26.4,26.1,23.2,22.0,20.7,17.8,15.6.FTMS(ESI):m / z calcd forC 31 H 51 O4N2([M+H) + )515.38433,Found 515.38481.

[0180] Comparative Example 5: Synthetic methods, structural formulas, and structural physicochemical data of the compounds in Comparative Example 5.

[0181] Synthesis method: Asteipenoid C (10 mg, 0.027 mmol, 1 eq) was weighed into a 25 mL round-bottom flask and dissolved in 2 mL of ultra-dry DCM. Then, EDC (10.35 mg, 0.052 mmol, 2 eq) and HOBT (14.6 mg, 0.108 mmol, 4 eq) were added, and the reaction was carried out at 0 °C or room temperature for 2-3 h, monitored by TLC. After the reaction was complete, 1 eq of 1-(2-aminoethyl)piperidine was added, and the reaction continued for approximately 3-4 h. The reaction was monitored by TLC. After the reaction was complete, dichloromethane was removed by rotary evaporation. The product was dissolved in ethyl acetate or dichloromethane, washed three times with water (3 x 5 mL) to remove byproducts, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography using dichloromethane / methanol = 100:1 (V / V) as the eluent to obtain compound 5 (Comparative Example).

[0182] The structural formula of the compound in Comparative Example 5 is:

[0183]

[0184] The structural and physicochemical data of the compound in Comparative Example 5 are as follows: colorless oil, yield 88%, mp: >300℃. 1 HNMR (δ) H , CDCl3, 600MHz): 0.14 (1H, m), 0.38 (1H, t, J = 5.0Hz), 0.66 (1H, dd, J = 8.6Hz, J = 4.3Hz), 0.73 (3H, s), 0.80 (3H, d, J = 6. 8Hz),0.83(3H,d,J=6.9Hz),0.91(3H,s),1.15-1.23(3H,m),1.29-1.36(5H,m),1.40(2H,m),1.53(2H,d,J=13.6Hz),

[0185] 1.71-1.79(5H,m),1.99-2.07(4H,m),2.21-2.26(2H,m),2.34(1H,m),2.58(1H,m) ,2.80(1H,m),3.10(2H,m),3.42(1H,d,J=13.5Hz),3.63-3.68(5H,m),3.82(1H,s). 13 CNMR(δ C,CDCl3,150MHz):129.5,78.4,60.8,57.1,57.1,54.8,48.0,47.6,46.0,45.9,44.8,43.4,33.3,32.6,2 9.9,29.9,29.9,29.3,29.2,29.1,28.3,27.7,26.5,26.4,23.3,22.2,20.8,17.9,15.8.FTMS(ESI):m / z calcd forC 32 H 53 O3N2([M+H)) + )513.40507,Found513.40532.

[0186] Comparative Example 6: Synthetic methods, structural formulas, and structural physicochemical data of the compounds in Comparative Example 6.

[0187] Synthesis method: Asteipenoid C (10 mg, 0.027 mmol, 1 eq) was weighed into a 25 mL round-bottom flask and dissolved in 2 mL of ultra-dry DCM. Then, EDC (10.35 mg, 0.052 mmol, 2 eq) and HOBT (14.6 mg, 0.108 mmol, 4 eq) were added, and the reaction was carried out at 0 °C or room temperature for 2-3 h, monitored by TLC. After the reaction was complete, 1 eq of n-heptylamine was added, and the reaction continued for approximately 3-4 h. The reaction was monitored by TLC. After the reaction was complete, dichloromethane was removed by rotary evaporation. The product was dissolved in ethyl acetate or dichloromethane, washed three times with water (3 x 5 mL) to remove byproducts, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography using dichloromethane / methanol = 100:1 (V / V) as the eluent to obtain compound 6 (Comparative Example).

[0188] The structural formula of compound 6 in Comparative Example is:

[0189]

[0190] The structural and physicochemical data of the compound in Comparative Example 6 are as follows: colorless oil, yield 43%, mp: >300℃. 1 HNMR (δ) H, CDCl3, 600MHz): 0.16 (1H, m), 0.38 (1H, t, J = 5.0Hz), 0.67 (1H, dd, J = 8.6Hz, J = 4.3Hz), 0.73 (3H, s), 0.80 (3H, d ,J=6.8Hz),0.84(3H,d,J=6.9Hz),0.90(3H,t,J=6.9Hz),0.91(3H,s),1.15-1.23(2H,m),1.25-1.29(8H,m),1.3 3-1.42(2H,m),1.49-1.54(3H,m),1.65(1H,t,J=11.0Hz),1.73-1.80(2H,m),1.97-2.07(3H,m),2.32-2.42(2H ,m),2.24-2.28(2H,m),2.56-2.60(1H,m),3.30(2H,m),3.55(1H,d,J=13.4Hz),3.60-3.63(3H,m),4.75(1H,m). 13 C NMR (δ) C , CDCl3, 150MHz):166.9,154.7,128.7,78.3,60.9,57.0,48.0,47.6,45.9,45.9,44.8,43.3,39.7,33.4,32.5, 31.9,29.8,29.2,29.1,28.3,27.7,27.1,26.5,26.0,23.3,22.7,22.1,20.8,17.9,15.8,14.2.FTMS(ESI):m / z calcd for C 32 H 54 O3N([M+H)) + )500.40982,Found 500.41023.

[0191] Application Example 1: Detection of antiviral activity of Asperterpenoid C derivatives against novel coronavirus at the cellular level (50% Effective Concentration, EC50) 50 )

[0192] The tested virus strain was the novel coronavirus strain SARS-CoV-2 (BA.2GDPCC 2.00299).

[0193] Cell line: hACE2-293T (a 293T cell line that highly expresses human angiotensin-converting enzyme 2)

[0194] Detection method:

[0195] RT-qPCR was used for testing. Asperterpenoid C derivative gradient doses (0, 1.563, 3.125, 6.25, 12.5, 25 μM or 0, 5, 10, 20, 40, 80 μM) were added to the supernatant of hACE2-293T cells 1 hour before viral infection. One hour after infection, the cells were replaced with virus-free medium containing the corresponding drug concentration and maintained for 48 hours. Cell supernatant was collected, and viral RNA was extracted using a QIAGEN viral nucleic acid extraction kit (QIAGEN, #74104), following the kit's instructions. The novel coronavirus 2019-nCoV nucleic acid detection kit (fluorescent PCR method) (Guangzhou Da'an Gene Co., Ltd., DA0932) was used for detection and result analysis, following the experimental procedures and parameter settings provided in the kit. The Ct values ​​of different compound dose groups and the solvent group (DMSO) after viral infection were detected by qPCR, and the inhibition rate of novel coronavirus RNA levels was calculated using the following formula.

[0196] The inhibition rate (%) of the corresponding treatment group is calculated as follows: 2^(Ct value of solvent control group - Ct value of treatment group) × 100%. Using the Forecast formula in EXCEL 2013, the concentration of the Asperterpenoid C derivative corresponding to an inhibition rate of 50% is used as the EC50 concentration. 50 The average value of three repeated experiments was taken.

[0197] Application Example 2: Asperterpenoid C derivative cytotoxic half-maximal inhibitory concentration (CMC) assay (50% Cytotoxic Concentration, CC) 50 )

[0198] The MTT method was used for testing. Cells were seeded at 8000–10000 cells / well in 96-well plates and incubated at 37°C in a 5% CO2 incubator. After 12 hours, gradient doses of Asperterpenoid C derivative (0, 1.563, 3.125, 6.25, 12.5, 25 μM or 0, 5, 10, 20, 40, 80 μM) were added to the supernatant of hACE2-293T cells. After 48 hours, 25 μL of thiazolyl blue (MTT) was added and the cells were incubated for 4 hours. The culture medium was then aspirated, and 160 μL of DMSO was added. The absorbance at 490 nm was measured and compared with that of the DMSO solvent control group. The inhibition rate (%) was calculated as (1 - absorbance at 490 nm of the treated group / absorbance at 490 nm of the solvent control group) × 100%. The Forecast formula in EXCEL 2013 was used to calculate the concentration of Asperterpenoid C derivative corresponding to an inhibition rate of 50%, which was taken as the CC value. 50 The average value of three repeated experiments was taken.

[0199] Table 1 shows the results of the anti-novel coronavirus activity of the Asperterpenoid C derivatives 1A to 6A of the present invention and related comparative examples.

[0200] Table 1. Anti-novel coronavirus activity of Asperterpenoid C derivatives 1A–6A and related comparative examples.

[0201]

[0202]

[0203] a The Selectivity Index (SI) is calculated as SI = CC. 50 / EC 50 .

[0204] b NS refers to the concentration of compounds smaller than the corresponding CC. 50 No activity against the novel coronavirus was detected within the specified range.

[0205] As shown in Table 1, compounds 1A-6A exhibit strong inhibitory effects against the novel coronavirus, with compound 4A showing the most significant inhibitory effect. 50 With a concentration of 0.8 μM, it also has the highest selectivity index (SI) of 19.1, demonstrating significant potential for developing drugs against the novel coronavirus. However, preliminary tests showed that Asperterpenoid C did not exhibit any inhibitory effect on the novel coronavirus.

[0206] Table 2 shows the results of the anti-novel coronavirus activity of compounds 1C to 12C of the present invention and related comparative examples.

[0207] Table 2. Anti-novel coronavirus activity of Asperterpenoid C derivatives 1C–12C and related comparative examples.

[0208]

[0209]

[0210]

[0211] a The Selectivity Index (SI) is calculated as SI = CC. 50 / EC 50

[0212] bNS refers to the concentration of compounds smaller than the corresponding CC. 50 No activity against the novel coronavirus was detected within the specified range.

[0213] As shown in Table 2, compounds 1C-12C exhibit strong inhibitory effects against the novel coronavirus, with compound 10C showing the most significant inhibitory effect. 50 The concentration was 2.3 μM, and its selectivity index (SI) was also relatively high at 4.0; compound 6C also had a relatively high selectivity index (SI) of 4.4. However, preliminary experimental results showed that Asperterpenoid C did not exhibit any inhibitory effect on the activity of the novel coronavirus.

[0214] The results above show that the Asperterpenoid C derivative protected by this invention has a good inhibitory effect on the novel coronavirus and has good safety for host cells at an effective antiviral dose. It can be prepared into a highly effective and low-toxicity anti-novel coronavirus drug for application, which is of great significance for the prevention and treatment of the novel coronavirus.

[0215] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively describe all embodiments here. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A disesquiterpene Asperterpenoid C derivative, characterized in that, Its chemical structures are as follows: ester derivatives of Formula I and amide derivatives of Formula II: In formula I, R is selected from C1-C8 straight-chain alkyl groups; C1-C4 halogen-substituted alkyl groups, wherein the halogens include: F, Cl, Br; R in Formula II is selected from An amino group attached to a phenyl group, a halogen-substituted phenyl group, or a toluene group, wherein the halogen atom includes: I, Br.

2. The Asperterpenoid C ester derivative according to claim 1, characterized in that, In Formula I, R is selected from the following groups:

3. The Asperterpenoid C amide derivative according to claim 1, characterized in that, In formula II, R is selected from the following groups:

4. The method for preparing the sesquiterpene C derivative according to any one of claims 1-3, characterized in that, The preparation method is as follows: (1) The preparation method of the Asperterpenoid C ester derivative is as follows: Asperterpenoid C reacts with haloalkanes under the conditions of alkali catalysis and heating under reflux to obtain the Asperterpenoid C ester derivative with the structure of Formula I; (2) The preparation method of the Asperterpenoid C amide derivative is as follows: Asperterpenoid C reacts with EDC and HOBT to obtain an active ester, and then the active ester reacts with an amine compound to obtain an Asperterpenoid C amide derivative with the structure of formula II.

5. The use of the sesquiterpene Asperterpenoid C derivative of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an anti-novel coronavirus drug.

6. The application according to claim 5, characterized in that, The novel coronavirus is SARS-CoV-2, B.1.1.7 variant (Alpha), B.1.351 variant (Beta), P.1 variant (Gamma), B.1.617.2 variant (Delta), or B.1.1.529 variant (Omicron).

7. A drug for treating novel coronavirus, characterized in that, It comprises the sesquiterpene Asperterpenoid C derivative of claim 1 or a pharmaceutically acceptable salt thereof.

8. The drug according to claim 7, characterized in that, It also includes pharmaceutical carriers and / or excipients, which are used to formulate different dosage forms.

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