Germazane-guaiacane sesquiterpene dimer and preparation method and application thereof

Abstract

The present invention provides a new germane-guaiacyl sesquiterpene dimer shown in a structural formula, a pharmaceutical composition thereof, a preparation method thereof and an application thereof, and belongs to the field of pharmaceutical technology. The preparation method of the present invention comprises preparing a germane-guaiacyl sesquiterpene dimer by Diels–Alder reaction / deprotection of a guaiacyl diene and a germane-type sesquiterpene, and further derivatizing to obtain a plurality of germane-guaiacyl sesquiterpene dimers. The germane-guaiacyl sesquiterpene dimer of the present invention has inhibitory activity against human liver cancer cell lines HepG2, Huh7 and SK-Hep-1, can be combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition, and can be used to prepare anti-liver cancer drugs.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and in particular, the present invention relates to a novel germarane-guaiacyl sesquiterpene dimer, a preparation method thereof, and a pharmaceutical composition for treating liver cancer using the compound as an active ingredient, as well as the use of the compound and the pharmaceutical composition thereof in the preparation of anti-liver cancer drugs. Background Art

[0002] Liver cancer is one of the common malignant tumors, including primary liver cancer and secondary liver cancer, of which hepatocellular carcinoma (HCC) accounts for more than 90%. Globally, the incidence of HCC ranks sixth among malignant tumors. Currently, there are more than 800,000 new cases of liver cancer worldwide each year, and more than 460,000 cases in my country each year. Liver cancer has the characteristics of hidden onset, long latency, strong invasiveness, easy metastasis, and high malignancy. For patients with unresectable or advanced disease, the 5-year survival rate is only 13%. More than 422,000 people die from liver cancer in my country each year. At present, the main clinical drugs for the treatment of liver cancer are 4 small molecule synthetic drugs that act on tyrosine kinase inhibitors: sorafenib, regoratinib, lenvatinib; and 3 antibody drugs: nivolumab, pembrolizumab and ramucirumab. These drugs have played a significant role in the clinical treatment of liver cancer, but they still have disadvantages such as low objective remission rate (<20%), easy drug resistance, intolerance of some liver cancer patients, obvious toxic and side effects, and high price, and their effects are not satisfactory.

[0003] Germazane-guaiacane sesquiterpene dimers are a class of natural products with complex structures and a backbone of at least 30 carbon atoms, which are composed of a guaiacane sesquiterpene connected to a germarane sesquiterpene unit. A large number of proteins responsible for cellular functions in living organisms exist in the form of dimers or need to be activated by dimerization before mediating certain signaling pathways. Targeting both monomers of dimeric proteins at the same time is an important strategy for drug research. Since sesquiterpene dimers have the potential to act on both monomers of dimeric proteins at the same time, it is of great significance to synthesize dimers and derivatives based on sesquiterpene with anti-liver cancer activity.

[0004] There is no report on the derivatization synthesis of the relevant germane-guaiacane sesquiterpene dimer in the prior art, nor on the pharmaceutical composition thereof as an active ingredient, nor on the application of the new germane-guaiacane sesquiterpene dimer and its pharmaceutical composition in the preparation or treatment of liver cancer drugs. Summary of the invention

[0005] The purpose of the present invention is to provide a new germarane-guaiacyl sesquiterpene dimer 1-34 and a pharmaceutical composition thereof and a preparation method and application thereof. The preparation method of the present invention uses arglabin as a raw material to prepare a new germarane-guaiacyl sesquiterpene dimer. The raw materials of the method are easy to obtain, easy to operate, and suitable for industrial production. The method has good substrate universality and can be used to prepare germarane-guaiacyl sesquiterpene dimers substituted with various functional groups.

[0006] In order to achieve the above-mentioned object of the present invention, the present invention provides the following technical solutions:

[0007] The present invention provides a novel germarane-guaiacyl sesquiterpene dimer 1-34 (compound 1-34) shown in the following structural formula:

[0008]

[0009] The present invention also provides a method for preparing a germarane-guaiacyl sesquiterpene dimer, the method comprising: preparing a germarane-guaiacyl sesquiterpene dimer by subjecting a guaiacyl diene and a germarane-type sesquiterpene through a Diels-Alder reaction / demethylation of the dimethylamine group,

[0010]

[0011] The synthesis method of the germane-guaiacane sesquiterpene dimer 1-34 (Compound 1-34) mainly includes the following six key reaction steps:

[0012] Preparation of compound 1-3: Under appropriate conditions, a guaiacyl diene is reacted with a germarane-type sesquiterpene dienophile by Diels–Alder reaction / demethylamination to obtain the germarane-guaiacyl sesquiterpene dimer 1-3. The appropriate conditions for the Diels–Alder reaction are that the diene and the dienophile are heated to react under solvent-free conditions.

[0013] Preparation of compound 4: Using dichloromethane as solvent, compound 2 was reacted with DAST at -78°C to obtain fluorine-substituted compound 4.

[0014] Preparation of compound 5-11: Compound 2 is subjected to esterification reaction and oxygenation reaction with an acid anhydride and an aromatic halide under appropriate conditions to prepare compound 5-7 and compound 8-11, respectively. The appropriate conditions for the esterification reaction are dichloromethane as solvent and DMAP as condensation agent, and compound 2 reacts with the acid anhydride at room temperature; the appropriate conditions for the oxygenation reaction are dichloromethane as solvent and compound 2 reacts with the aromatic halide in the presence of silver oxide at room temperature.

[0015] Preparation of compound 12-15: Compound 2 is reacted with N,N'-carbonylbis(1,2,4-triazole) and benzylamine under appropriate conditions to obtain compound 12-15. The appropriate reaction condition is dichloromethane as solvent, and compound 2 reacts with N,N'-carbonylbis(1,2,4-triazole) and benzylamine at room temperature.

[0016] Preparation of compounds 16-19: Using tetrahydrofuran as solvent, compound 2 was reacted with DPPA and DBU at 0°C to prepare azide compound 16; using tetrahydrofuran-water as solvent, compound 16 was reacted with triphenylphosphine at room temperature to prepare amino compound 17; using dichloromethane as solvent, compound 17 was reacted with benzoic anhydride and triethylamine at room temperature to prepare amide compound 18; using tetrahydrofuran as solvent, compound 17 was reacted with 2-phenylethyl isocyanate and triethylamine at 0°C to obtain compound 19.

[0017] Preparation of compound 20-34: Using acetonitrile-water as solvent, azide compound 16 reacts with an alkynyl compound, cuprous iodide and triethylamine at room temperature to prepare compound 20-34.

[0018] The present invention also provides the application of the novel germarane-guaiacane sesquiterpene dimer 1-34 in the preparation of anti-liver cancer drugs.

[0019] The present invention also provides a pharmaceutical composition, which comprises at least one of the above-mentioned compounds 1-34 and a pharmaceutically acceptable carrier.

[0020] In the present invention, the pharmaceutically acceptable carrier is preferably a solid, semisolid or liquid diluent, a filler and a pharmaceutical product adjuvant. The present invention has no particular limitation on the pharmaceutically acceptable carrier, and any pharmaceutically acceptable carrier well known in the art, non-toxic and inert to humans and animals can be selected.

[0021] The present invention has no particular limitation on the method for preparing the pharmaceutical composition. At least one of compounds 1-34 may be directly mixed with a pharmaceutically acceptable carrier. The present invention has no particular limitation on the mixing process. A pharmaceutical composition may be obtained by selecting a process well known in the art.

[0022] The present invention provides the use of the pharmaceutical composition of the above technical solution in the preparation of anti-liver cancer drugs. The present invention has no special limitation on the method of the application, and any method well known in the art can be used.

[0023] In the present invention, when the pharmaceutical composition is used to prepare an anti-liver cancer drug, the content of the composition in the drug is preferably 0.1-99%; in the pharmaceutical composition, the content of at least one of the compounds 1-34 in the pharmaceutical composition is preferably 0.5-90%. The pharmaceutical composition of the present invention is preferably used in the form of a dosage per unit body weight. In the present invention, the prepared drug is preferably administered in two forms: injection (intravenous injection, intramuscular injection) and oral administration.

[0024] Compared with the prior art, the present invention has the following advantages:

[0025] 1. The present invention provides a series of novel germarane-guaiacane sesquiterpene dimers 1-34 (compounds 1-34).

[0026] 2. The present invention provides a new method for preparing new compound 1-34, which has readily available raw materials, simple process and easy operation.

[0027] 3. The present invention provides a pharmaceutical composition with new compound 1-34 as an active ingredient, which provides a new anti-liver cancer drug with better medicinal effects.

[0028] 4. Compounds 1-34 of the present invention have strong cytotoxic activity against three liver cancer cell lines (HepG2, SK-Hep-1 and Huh7). It was found that compared with sorafenib, 25 compounds had enhanced cytotoxic activity against HepG2, 15 compounds had enhanced cytotoxic activity against Huh7, and 17 compounds had enhanced cytotoxic activity against SK-Hep-1. Compound 16 had the strongest inhibitory activity against HepG2 cells, with an IC 50 The value was 3.6 μM; Compound 19 had the strongest inhibitory activity against Huh7 cells, IC 50 The value was 2.1 μM; Compound 23 had the strongest inhibitory activity against Huh7 cells, IC 50 The compound 23 showed obvious cytotoxicity, IC 50 The values ​​were 4.4 (HepG2), 3.7 (Huh7) and 3.1 μM (SK-Hep-1), respectively.

[0029] 5. The synthesized compound sesquiterpene dimer 1-34 can be used as a drug to treat liver cancer-related diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 It is a schematic diagram of the structural formula of the germarane-guaiacane sesquiterpene dimer 1-34 (Compound 1-34) of the present invention. DETAILED DESCRIPTION

[0031] In order to better understand the present invention, the substantial content of the present invention is further described below with reference to the accompanying drawings using embodiments of the present invention, but the present invention is not limited thereto.

[0032] Embodiment 1:

[0033] Preparation of compound 1-3.

[0034]

[0035] At room temperature, costunolide (100 mg, 0.43 mmol, 1 equiv) / Soulangianollide A (100 mg, 0.43 mmol, 1 equiv) / 1,4-oxomelampolide (100 mg, 0.43 mmol, 1 equiv) were dissolved in dichloromethane (5 mL) with diene (125 mg, 0.43 mmol, 1 equiv), concentrated under reduced pressure, heated to 50 ° C in an oil bath, and reacted for 24 h. The crude product was separated by column chromatography and used for the next reaction. The sample was dissolved in methanol (5 mL) at room temperature, and iodomethane (0.5 mL, 4.3 mmol, 10 equiv) was added under stirring, and the reaction was continued for 3 h. The solvent was removed by concentration under reduced pressure, and 5 mL of saturated sodium bicarbonate solution and 5 mL of dichloromethane were added. The mixture was transferred to a separatory funnel and mixed until the solid was completely dissolved. The organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, and the solvent was removed by concentration under reduced pressure. The crude product was separated by column chromatography (petroleum ether-ethyl acetate, 5:1) to obtain compound 1-3.

[0036] Compound 1

[0037] Yield: 33% (68 mg)

[0038] Molecular formula: C 30 H 38 O5

[0039] Molecular weight: 478.6290

[0040] Appearance: Light yellow solid

[0041] Optical rotation: (c 0.099, chloroform)

[0042] HRMS(ESI,m / z):[M+H] + [C 30 H 38 O5] + Calculated value: 479.2792, measured value: 479.2784.

[0043] 1H NMR(400MHz,CDCl3)δ6.15(1H,d,J=3.2Hz,H-13a'),5.52(1H,d,J=10.4Hz,H-6'),5.44(1H,d,J=8.0Hz,H-1),5.42(1H,d,J=3.0Hz,H-13'b),4.94(1H,d,J=10.0Hz,H-5),4.54(1H,t,J=10.1Hz,H-6),4.18(1H,d,J=10.0Hz,H-14a),4.06(1H,d,J=10.1Hz,H-14b),3.02(1H,br s,H-2'),2.83-2.77(1H,m,H-7'),2.31(1H,dd,J=12.0,H-3a'),2.28-2.25(1H,m,H-7),2.20(1H,d,J=11.0Hz,H-9a),2.16-2.13(2H,m,H-13),2.12-2.08(2H,m,H-8),2.03-2.01(1H,m,H-8a'),2.00-1.99(1H,m,H-2a),1.99-1.96(1H,m,H-9a'),1.94-1.92(1H,m,H-9b),1.85-1.83(1H,m,H-2b),1.82(3H,s,H-15),1.79-1.77(1H,m,H-9b'),1.64-1.62(1H,m,H-8b'),1.51-1.50(1H,m,H-3a),1.49(1H,s,H-3b'),1.47(3H,s,H-15'),1.40(3H,s,H-14'),1.31(1H,d,J=10.0,H-3b). 13C NMR (100MHz, CDCl3) δ181.3(C,C-12),170.1(C,C-12'),150.1(C,C-1'),146.1(C,C-11'),139.9(C,C-4),139.6(C,C-5'),136.8(C,C -10),128.0(CH,C-1),127.3(CH,C-5),118.8(CH2,C-13'),84.1(CH,CH-6'),79.0(CH,C-6),72.4(C,C-10'),61.7(C,C-11),56.8(C, C-4'),53.5(CH2,C-3),51.3(CH,C-7'),47.1(CH,C-7),43.0(CH,C-2'),39.4(CH2,C-9'),38.6(CH2,C-13),35.4(CH2,C-3'),28.0(C H3,C-14'),26.2(CH2,C-9),26.0(CH2,C-8),23.9(CH2,C-2),22.7(CH2,C-8'),17.8(CH3,C-15'),17.2(CH3,C-15),16.3(CH3,C-14).

[0044] Compound 2

[0045] Yield: 36% (76 mg)

[0046] Molecular formula: C 30 H 38 O6

[0047] Molecular weight: 494.6280

[0048] Appearance: White solid

[0049] Optical rotation: (c 0.143, chloroform)

[0050] HRMS(ESI,m / z):[M+H] + [C 30 H 38 O6] + Calculated value 495.2741, measured value 495.2738

[0051] 1H NMR(500MHz,CDCl3)δ6.13(1H,d,J=3.5Hz,H-13a'),5.54(1H,d,J=10.0Hz,H-6'),5.48(1H,t,J=8.0Hz,H-1),5.42(1H,d,J=3.0Hz,H-13'b),4.94(1H,d,J=10.0Hz,H-5),4.54(1H,t,J=10.1Hz,H-6),4.18(1H,d,J=10.0Hz,H-14a),4.06(1H,d,J=10.1Hz,H-14b),3.02(1H,s,H-2'),2.83-2.77(1H,m,H-7'),2.31(1H,dd,J=12.0,H-3a'),2.28-2.25(1H,m,H-7),2.20(1H,d,J=11.0Hz,H-9a),2.16-2.13(2H,m,H-13),2.12-2.08(2H,m,H-8),2.03-2.01(1H,m,H-8a'),2.00-1.99(1H,m,H-2a),1.99-1.96(1H,m,H-9a'),1.94-1.92(1H,m,H-9b),1.85-1.84(1H,m,H-2b),1.81(3H,s,H-15),1.79-1.77(1H,m,H-9b'),1.64-1.62(1H,m,H-8b'),1.51-1.50(1H,m,H-3a),1.49(1H,s,H-3b'),1.47(3H,s,H-15'),1.39(3H,s,H-14'),1.31(1H,d,J=10.0,H-3b). 13C NMR (125MHz, CDCl3) δ181.0(C,C-12),170.1(C,C-12'),150.5(C,C-1'),145.2(C,C-11'),141.1(C,C-4),140.0(C,C-5'),137.2(C, C-10),126.0(CH,C-1),125.0(CH,C-5),118.9(CH2,C-13'),83.8(CH,CH-6'),77.5(CH,C-6),72.5(C,C-10'),66.4(C,C-14),60.6(C ,C-11),56.6(C,C-4'),53.5(CH2,C-3),46.8(CH,C-7'),46.0(CH,C-7),42.7(CH,C-2'),39.5(CH2,C-9'),38.3(CH2,C-13),34.8(CH 2,C-3'),27.8(CH3,C-14'),24.5(CH2,C-9),24.4(CH2,C-8),23.8(CH2,C-2),23.7(CH2,C-8'),17.5(CH3,C-15'),17.1(CH3,C-15).

[0052] Compound 3

[0053] Yield: 56% (119 mg)

[0054] Molecular formula: C 30 H 36 O6

[0055] Molecular weight: 492.6120

[0056] Appearance: White solid

[0057] Optical rotation: (c 0.135, chloroform)

[0058] HRMS(ESI,m / z):[M+H] + [C 30 H 36 O6] + Calculated value 493.2585, measured value 493.2592

[0059] 1H NMR(500MHz,CDCl3)δ9.39(1H,br s,H-14),6.48(1H,t,J=9.0Hz,H-1),6.04(1H,d,J=3.5Hz,H-13a'),5.42(1H,d,J=10.0Hz,H-6'),5.36(1H,d,J=3.0Hz,H-13b'),4.85(H,d,J=10.0Hz,H-5),4.54(1H,t,J=10.0Hz,H-6),3.02(1H,br s,H-2'),2.76-2.70(1H,m,H-7'),2.59-2.52(1H,m,H-3a'),2.49(1H,br s,H-7),2.40-2.36(1H,m,H-9a),2.31-2.22(2H,m,H-13),2.21-2.17(2H,m,H-8),2.06-2.02(1H,m,H-8a'),2.00-1.97(1H,m,H-2a),1.95-1.88(3H,m,H-2b,H-9b,H-9b'),1.77(3H,s,H-15),1.75-1.72(1H,m,H-9b'),1.70-1.67(1H,m,H-8b'),1.55-1.51(1H,m,H-3a),1.50-1.46(1H,m,H-3b'),1.42-1.39(1H,m,H-3b),1.31(3H,s,H-15'),1.26(3H,s,H-14'). 13C NMR (125MHz, CDCl3) δ195.7(C,C-14),180.8(C,C-12),169.9(C,C-12'),153.3(C,C-1),150.5(C,C-1'),144.8(C,C-11'),144.5(C, C-4),139.9(C,C-5'),135.8(C,C-10),126.4(CH,C-5),118.5(CH2,C-13'),83.6(CH,CH-6'),77.5(CH,C-6),72.0(C,C-10'),60.8(C ,C-11),56.0(C,C-4'),53.2(CH2,C-3),46.4(CH,C-7'),45.8(CH,C-7),42.5(CH,C-2'),38.0(CH2,C-9'),36.8(CH2,C-13),34.5(CH 2,C-3'),27.5(CH3,C-14'),25.7(CH2,C-9),23.5(CH2,C-8),23.0(CH2,C-2),22.7(CH2,C-8'),16.8(CH3,C-15'),16.4(CH3,C-15).

[0060] Embodiment 2:

[0061] Preparation of compound 4.

[0062]

[0063] Under argon protection, compound 2 (100 mg, 0.2 mmol, 1 equiv) was dissolved in dry dichloromethane (3 mL) in a 10 mL three-necked flask, cooled to -78 °C, and DAST (324 mg, 2 mmol, 10 equiv) was added and stirred for ten minutes, and then stirred at room temperature for 2 h. Saturated sodium bicarbonate solution was added to quench, and dichloromethane was extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to remove the solvent. The crude product was separated by column chromatography (petroleum ether-ethyl acetate, 5:1) to obtain compound 4.

[0064] Compound 4

[0065] Yield: 27% (27 mg)

[0066] Molecular formula: C 30 H 38 FO5

[0067] Molecular weight: 496.6194

[0068] Appearance: white solid;

[0069] Optical rotation: (c 0.091, chloroform)

[0070] HRMS(ESI,m / z):[M+H] + [C 30 H 38 FO5] + Calculated value 497.2698, measured value 497.2695

[0071] 1 H NMR (400MHz, CDCl3) δ6.16(1H,d,J=3.6Hz,H-13a'),5.61-5.59(1H,m,H-1),5.57(1H,d,J=10.0Hz,H-6'),5.43(1H,d ,J=3.2Hz,H-13b'),5.03-4.96(2H,m,H-5,H-14a),4.90-4.81(1H,m,H-14b),4.55(1H,t,J=10.1Hz,H-6),3.04(1H,br s,H-2'),2.85-2.76(1H,m,H-7'),2.34-2.31(2H,m,H-7,H-3a'),2.21-2.13(3H,m,H-9a,H-13),2.10-2.07(1H,m,H-8a),2.04-1.98(4H ,m,H-2a,H-8b,H-8a',H-9a'),1.89-1.86(1H,m,Hb),1.83(3H,s,H-15),1.79-1.76(1H,m,H-2b),1.70-1.67(1H,m,H-9b'),1.65(1H,br s,H-8b'),1.55-1.53(1H,m,H-3a),1.49(3H,s,H-15'),1.47(1H,br s,H-3b'),1.41(3H,s,H-14'),1.34(1H,d,J=8.8Hz,H-3b). 13C NMR (100MHz, CDCl3) δ180.8(C,C-12),170.0(C,C-12'),150.0(C,C-1'),145.1(C,C-11'),140.0(C,C-4),137.4(C,C-5'),137.3(C,C -10),130.4(CH,C-1),125.2(CH,C-5),118.7(CH2,C-13'),87.7(CH2,C-14),83.8(CH,CH-6'),77.5(CH,C-6),72.5(C,C-10'),60.7( C,C-11),56.6(C,C-4'),53.4(CH2,C-3),46.8(CH,C-7'),45.8(CH,C-7),42.7(CH,C-2'),38.6(CH2,C-9'),37.9(CH2,C-13),34.8(C H2,C-3'),27.8(CH3,C-14'),24.9(CH2,C-9),24.5(CH2,C-8),24.2(CH2,C-2),23.8(CH2,C-8'),17.2(CH3,C-15'),17.1(CH3,C-15).

[0072] Embodiment 3:

[0073] Preparation of compound 5-7.

[0074]

[0075] At room temperature, compound 2 (100 mg, 0.2 mmol, 1.0 equiv) was dissolved in dichloromethane (5 mL), stirred, and the corresponding anhydride (2.0 equiv) and DMAP (6.0 mg, 0.05 mmol, 0.25 equiv) were added. The reaction was continued for 3 h, quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phases were combined and concentrated under reduced pressure to remove the solvent. The crude product was separated by column chromatography (petroleum ether-ethyl acetate, 5:1) to obtain the corresponding compound.

[0076] Compound 5

[0077] Yield: 80% (86 mg)

[0078] Molecular formula: C 32 H 40 O7

[0079] Molecular weight: 536.6650

[0080] Appearance: white solid;

[0081] Optical rotation: (c 0.097, chloroform)

[0082] HRMS(ESI, m / z): [M+H] + [C 32 H 40 O7] + Calculated value: 537.2847, Measured value: 537.2868

[0083] 1 H NMR (500 MHz, CDCl3) δ 6.13 (1H, d, J = 3.5 Hz, H-13a'), 5.55 (1H, t, J = 7.5 Hz, H-1), 5.54 (1H, d, J = 10.0 Hz, H-6'), 5.42 (1H, d, J = 3.5 Hz, H-13b'), 4.95 (1H, d, J = 10.0 Hz, H-5), 4.73 (1H, d, J = 12.0 Hz, H-14a), 4.53 (1H, t, J = 10.5 Hz, H-6), 4.43 (1H, d, J = 12.5 Hz, H-14b), 3.03 (1H, s, H-2'), 2.82 - 2.77 (1H, m, H-7'), 2.32 (1H, dd, J = 12.5 Hz, H-3a'), 2.18 - 2.16 (1H, m, H-7), 2.15 - 2.14 (1H, m, H-9a), 2.13 - 2.09 (2H, m, H-13), 2.06 - 2.05 (1H, m, H-8a), 2.05 (3H, s, H-2”), 2.03 - 2.01 (1H, m, H-8b), 2.00 - 1.96 (2H, m, H-8a', H-2a), 1.94 - 1.91 (1H, m, H-9a'), 1.88 - 1.86 (1H, m, H-9b), 1.85 - 1.83 (1H, m, H-2b), 1.82 (3H, s, H-15), 1.79 - 1.75 (2H, m, H-9b', H-8b'), 1.52 - 1.51 (1H, m, H-3a), 1.50 (3H, s, H-15'), 1.49 (1H, s, H-3b'), 1.40 (3H, s, H-14'), 1.31 (1H, d, J = 9.0 Hz, H-3b). 13C NMR(125MHz,CDCl3)δ180.9(C,C-12),170.6(C,C-1"),170.0(C,C-12'),150.5(C,C-1'),145.0(C,C-11'),140.0(C,C-4),137.1(C,C-5'),13 6.3(C,C-10),129.0(CH,C-1),125.2(CH,C-5),118.8(CH2,C-13'),83.8(CH,CH-6'),77.5(CH,C-6),72.4(C,C-10'),66.8(CH2,C-14),60.8(C ,C-11),56.5(C,C-4'),53.5(CH2,C-3),46.8(CH,C-7'),45.7(CH,C-7),42.7(CH,C-2'),38.5(CH2,C-9'),38.1(CH2,C-13),34.8(CH2,C-3') ,27.8(CH3,C-14'),24.7(CH2,C-9),24.6(CH2,C-8),24.1(CH2,C-2),23.8(CH2,C-8'),21.0(CH3,C-2"),17.5(CH3,C-15'),17.1(CH3,C-15).

[0084] Compound 6

[0085] Yield: 90% (99 mg)

[0086] Molecular formula: C 33 H 42 O7

[0087] Molecular weight: 550.6920

[0088] Appearance: white solid;

[0089] Optical rotation: (c 0.105, chloroform)

[0090] HRMS(ESI,m / z):[M+H] + [C 33 H 42 O7] + Calculated value 551.3003, measured value 551.3017

[0091] 1H NMR(400MHz,CDCl3)δ6.15(1H,d,J=3.4Hz,H-13a'),5.56(2H,m.H-1,H-6'),5.44(1H,d,J=3.0Hz,H-13b'),4.98(1H,d,J=10.0Hz,H-5),4.75(1H,d,J=12.4Hz,H-14a),4.55(1H,t,J=10.1Hz,H-6),4.47(1H,d,J=12.5Hz,H-14b),3.05(1H,s,H-2'),2.83-2.79(1H,m,H-7'),2.38-2.33(2H,m,H-2”),2.32-2.27(2H,m,H-3a',H-7),2.19-2.13(2H,m,H-9a,H-13a),2.09-2.04(2H,m,H-8a,H-13b),2.01-1.96(4H,m,H-2a,H-8b,H-8a',H-9a'),1.89-1.87(1H,m,H-9b),1.80-1.76(1H,m,H-2b),1.83(3H,s,H-15),1.67-1.65(2H,m,H-8b',H-9b'),1.52(3H,s,H-15'),1.50-1.46(2H,m,H-3a,H-3b'),1.42(3H,s,H-14'),1.37(1H,d,J=8.6Hz,H-3b),1.15(3H,t,J=7.5Hz,H-3”),0.88-0.84(1H,m). 13C NMR(100MHz, CDCl3)δ180.9(C,C-12),174.0(C,C-1"),170.0(C,C-12'), 150.4(C,C-1'),145.2(C,C-11'),140.0(C,C-4),137.1(C,C-5'),136.4( C,C-10),128.6(CH,C-1),125.2(CH,C-5),118.7(CH2,C-13'),83.8(CH,CH-6'),77.5(CH,C-6),72.5(C,C-10'),66.6(CH2,C-14),60.8(C,C-11), 56.5(C,C-4'),53.4(CH2,C-3),46.8(CH,C-7'),45.7(CH,C-7),42.8(CH,C-2'),38.6(CH2,C-9'),38.1(CH2,C-13),34.8(CH2,C-3'),27.9(CH3,C -14'),27.6(CH2,C-2"),24.7(CH2,C-9),24.6(CH2,C-8),24.1(CH2,C-2),23.8(CH2,C-8'),17.4(CH3,C-15'),17.1(CH3,C-15),9.2(CH3,C-3").

[0092] Compound 7

[0093] Yield: 85% (102 mg)

[0094] Molecular formula: C 37 H 42 O7

[0095] Molecular weight: 598.7360

[0096] Appearance: white solid;

[0097] Optical rotation: (c 0.116, chloroform)

[0098] HRMS(ESI,m / z):[M+H] + [C 37 H 42 O7] + Calculated value 599.3003, measured value 599.3005

[0099] 1H NMR(500MHz,CDCl3)δ8.03-8.01(2H,m,H-3”,H-7”),7.58-7.54(1H,m,H-5”),7.45-7.42(2H,m,H-4”,H-6”),6.14(1H,d,J=3.5Hz,H-13a'),5.64(1H,t,J=7.5Hz,H-1),5.55(1H,d,J=10.0Hz,H-6'),5.43(1H,d,J=3.0Hz,H-13b'),5.01(1H,d,J=10.1Hz,H-5),4.97(1H,d,J=12.5Hz,H-14a),4.74(1H,d,J=13.0Hz,H-14b),4.56(1H,t,J=10.0Hz,H-6),3.05(1H,br s,H-2'),2.83-2.76(1H,m,H-7'),2.39-2.37(1H,m,H-7),2.32(1H,dd,J=12.0,3.5Hz,H-3a'),2.20-2.17(2H,m,H-9a,H-13a),2.12-2.09(1H,m,H-13b),2.07(1H,br s,H-8a),2.04-2.00(2H,m,H-8b,H-8a'),1.98-1.96(1H,m,H-2a),1.90-1.85(2H,m,H-9b,H-9a'),1.84(3H,s,H-15),1.79-1.77(1H,m,H-2b),1.76-1.75(1H,m,H-9b'),1.72-1.69(1H,m,H-8b'),1.55(3H,s,H-15'),1.53-1.48(2H,m,H-3a,H-3b'),1.41(3H,s,H-14'),1.37-1.35(1H,m,H-3b). 13C NMR(125MHz, CDCl3)δ180.9(C,C-12),170.0(C,C-12'),166.0(C,C-1"),150.4( C,C-1'),145.1(C,C-11'),140.0(C,C-4),137.1(C,C-10),136.3(C,C-5'),133 .1(C,C-5"),130.1(C,C-2"),129.6(2CH,C-3",C-7"),128.6(CH,C-1),128.4(2 CH,C-4",C-6"),125.2(CH,C-5),118.8(CH2,C-13'),83.8(CH,CH-6'),77.3(CH, C-6), 72.5 (C, C-10'), 67.3 (CH2, C-14), 60.8 (C, C-11), 56.5 (C, C-4'), 53.5 (CH2, C-3), 46.8 (CH, C-7'), 45.7 (CH, C-7), 42.8 (CH, C-2'), 38.6 (CH2, C-9'), 38.1 (CH2, C-13), 34.9 (CH2, C-3'), 27.9 (CH3, C-14'), 24.8 (CH2, C-9), 24.6 (CH2, C-8), 24.1 (CH2, C-2), 23.8 (CH2, C-8'), 17.5 (CH3, C-15'), 17.1 (CH3, C-15). Example 4:

[0100] Preparation of compounds 8-11.

[0101]

[0102] At room temperature, compound 2 (100 mg, 0.2 mmol, 1.0 equiv) and silver oxide (93 mg, 0.4 mmol, 2.0 equiv) were dissolved in DCM (5 mL), stirred, and the corresponding substituted benzyl bromide (2.0 equiv) was added. The mixture was reacted for 3 days, filtered, and concentrated under reduced pressure to remove the solvent. The crude product was separated by column chromatography (petroleum ether-ethyl acetate, 5:1) to obtain the compound.

[0103] Compound 8

[0104] Yield: 49% (57 mg)

[0105] Molecular formula: C 37 H 44 O6

[0106] Molecular weight: 584.7530

[0107] Appearance: White solid

[0108] Optical rotation: (c 0.050, chloroform)

[0109] HRMS(ESI,m / z):[M+H] + [C 37 H 44 O6] + Calculated value 585.3211, measured value 585.3229

[0110] 1 H NMR (400MHz, CDCl3) δ7.36-7.26 (5H,m,H-3",H-4",H-5",H-6",H-7"),6.15(1H,d,J=3. 2Hz,H-13a'),5.55(1H,d,J=10.4Hz,H-6'),5.54-5.50(1H,m,H-1),5.43(1H,d,J=2.8Hz ,H-13b'),4.95(1H,d,J=10.0Hz,H-5),4.57-4.51(2H,m,H-6,H-1a”),4.37(1H,d,J=12 .0Hz,H-14a),4.15(1H,d,J=11.2Hz,H-14b),3.83(1H,d,J=11.2Hz,H-1b”),3.03(1H,br s,H-2'),2.84-2.77(1H,m,H-7'),2.31(1H,dd,J=12.0,3.6Hz,H-3a'),2.23-2.20(1H,m,H-7),2 .18-2.15(2H,m,H-13),2.13-2.10(1H,m,H-9a),2.04-1.97(4H,m,H-2a,H-8,H-8a'),1.92(1H,br s,H-9a'),1.89-1.84(2H,m,H-2b,H-9b),1.83(3H,s,H-15),1.80-1.76(1H,m,H-9b'),1 .65-1.60(2H,m,H-3a,H-8b'),1.50-1.47(1H,m,H-3b'),1.41(3H,s,H-15'),1.38(1H,br s,H-3b),1.37(3H,s,H-14'). 13C NMR(400MHz, CDCl3)δ180.9(C,C-12),170.0(C,C-12'),150.4(C,C-1'),145.2 (C,C-11'),140.1(C,C-4),138.3(C,C-5'),138.2(C,C-10),137.1(C,C-2"),12 8.5(2CH,C-4",C-6"),127.9(CH,C-1),127.8(2CH,C-3",C-7"),127.7(C,C-5") ,125.0(CH,C-5),118.6(CH2,C-13'),83.8(CH,CH-6'),77.5(CH,C-6),73.5(CH 2,C-14),72.5(C,C-10'),71.9(CH2,C-1"),60.6(C,C-11),56.6(C,C-4'),53. 5(CH2,C-3),46.8(CH,C-7'),46.0(CH,C-7),42.7(CH,C-2'),38.6(CH2,C-9'), 38.3(CH2,C-13),34.8(CH2,C-3'),27.8(CH3,C-14'),24.7(CH2,C-9),24.5(CH 2,C-8),24.0(CH2,C-2),23.7(CH2,C-8'),17.4(CH3,C-15'),17.1(CH3,C-15).

[0111] Compound 9

[0112] Yield: 53% (65 mg)

[0113] Molecular formula: C 38 H 46 O7

[0114] Molecular weight: 614.7790

[0115] Appearance: White solid

[0116] Optical rotation: (c 0.140, chloroform)

[0117] HRMS(ESI,m / z):[M+H] + [C 38 H 46 O7] + Calculated value 615.3316, measured value 615.3309

[0118] 1H NMR(500MHz,CDCl3)δ7.21-7.19(2H,m,),7.15-7.13(2H,m,),6.15(1H,d,J=3.5Hz,H-13a'),5.55(1H,d,J=10.0Hz,H-6'),5.50(1H,t,J=9.0Hz,H-1),5.43(1H,d,J=3.0Hz,H-13b'),4.94(1H,d,J=10.0Hz,H-5),4.56-4.48(2H,m,H-6,H-1a”),4.33(1H,d,J=10.0Hz,H-14a),4.15(1H,d,J=11.5Hz,H-14b),3.81(1H,d,J=11.5Hz,H-1b”),3.03(1H,br s,H-2'),2.83-2.77(1H,m,H-7'),2.35(3H,s,H-8”),2.32-2.29(1H,m,H-3a'),2.25 -2.23(1H,m,H-7),2.21-2.18(1H,m,H-9a),2.17-2.16(1H,m,H-13a),2.15-2.09(2H,m,H-8a,H-13b),2.03-2.00(1H,m,H-8b),1.98-1.97(1H,m,H-8a'),1.96-1.93(2H,m,H-2a,H-9a'),1.91-1.87(1H,m,H-9b),1.86-1.84(1H,m,H-2b),1.82(3H,s,H-15),1.80-1.75(1H,m,H-9b'),1.63-1.61(2H,m,H-3a,H-8b'),1.50-1.47(1H,m,H-3b'),1.41(3H,s,H-15'),1.39(1H,br s,H-3b),1.37(3H,s,H-14'). 13C NMR (125MHz, CDCl3) δ180.9(C,C-12),170.1(C,C-12'),150.4(C,C-1'),145.2( C,C-11'),140.1(C,C-4),138.3(C,C-5'),137.4(C,C-10),135.1(2C,C-2",C-5" ),129.2(2CH,C-4",C-6"),128.0(2CH,C-3",C-7"),127.8(CH,C-1),124.9(CH, C-5),118.8(CH2,C-13'),83.9(CH,CH-6'),77.5(CH,C-6),73.2(CH2,C-14),72. 5(C,C-10'),71.8(CH2,C-1"),60.6(C,C-11),56.6(C,C-4'),53.4(CH2,C-3),4 6.9(CH,C-7'),45.9(CH,C-7),42.7(CH,C-2'),38.6(CH2,C-9'),38.3(CH2,C-13 ),34.8(CH2,C-3'),27.8(CH3,C-14'),24.7(CH2,C-9),24.5(CH2,C-8),23.9(CH 2,C-2),23.7(CH2,C-8'),21.2(CH3,C-8"),17.4(CH3,C-15'),17.1(CH3,C-15).

[0119] Compound 10

[0120] Yield: 61% (73 mg)

[0121] Molecular formula: C 38 H 46 O6

[0122] Molecular weight: 598.7800

[0123] Appearance: White solid

[0124] Optical rotation: (c 0.080, chloroform)

[0125] HRMS(ESI,m / z):[M+H] + [C 38 H 46 O6] + Calculated value 599.3367, measured value 599.3373

[0126] 1H NMR(500MHz,CDCl3)δ7.24(2H,d,J=8.5Hz,H-4",H-6"),6.87(2H,d,J=8.6Hz,H-3",H-7"),6.15(1H,d,J=3.4Hz,H-13a'),5.55(1H,d,J=10.1Hz,H-6'),5.50(1H,t,J=7.6Hz,H-1),5.44(1H,d,J=3.1Hz,H-13b'),4.94(1H,d,J=10.0Hz,H-5),4.53(1H,t,J=10.1Hz,H-6),4.48(1H,d,J=11.7Hz,H-14a),4.30(1H,d,J=11.6Hz,H-14b),4.11(1H,d,J=11.2Hz,H-1a"),3.80(3H,s,H-8”),3.78(1H,br s,H-1b"),3.03(1H,br s,H-2'),2.83-2.78(1H,m,H-7'),2.31(1H,dd,J=12.2,3.5Hz,H-3a'),2.26 -2.20(2H,m,H-7,H-9a),2.17-2.15(1H,m,H-13),2.13-2.08(2H,m,H-8a,H-13b),2.05-2.00(2H,m,H-8b,H-8a'),1.96-1.92(2H,m,H-2a,H-9a'),1.90-1.86(2H,m,H-2b,H-9b),1.82(3H,s,H-15),1.80-1.76(1H,m,H-9b'),1.68(1H,br s,H-8b'),1.63(1H,d,J=12.1Hz,H-3a),1.50-1.47(1H,m,H-3b'),1.41(3H,s,H-15'),1.40(1H,br s,H-3b),1.38(3H,s,H-14'). 13C NMR(125MHz, CDCl3)δ181.0(C,C-12),170.1(C,C-12'),159.2(C,C-5"),150.5(C ,C-1'),145.1(C,C-11'),140.0(C,C-4),138.3(C,C-5'),130.2(C,C-10),130.2( C,C-2"),129.5(2CH,C-3",C-7"),127.9(CH,C-1),124.9(CH,C-5),118.8(CH2,C -13'),113.9(2CH,C-4",C-6"),83.8(CH,CH-6'),77.5(CH,C-6),73.1(CH2,C-14) ,72.5(C,C-10'),71.6(CH2,C-1"),60.5(C,C-11),56.6(C,C-4'),55.3(CH3,C-8 "),53.4(CH2,C-3),46.8(CH,C-7'),46.0(CH,C-7),42.7(CH,C-2'),38.6(CH2,C- 9'),38.3(CH2,C-13),34.8(CH2,C-3'),27.8(CH3,C-14'),24.7(CH2,C-9),24.5( CH2,C-8),23.9(CH2,C-2),23.7(CH2,C-8'),17.4(CH3,C-15'),17.1(CH3,C-15).

[0127] Compound 11

[0128] Yield: 23% (28 mg)

[0129] Molecular formula: C 37 H 43 FO6

[0130] Molecular weight: 602.7434

[0131] Appearance: White solid

[0132] Optical rotation: (c 0.040, chloroform)

[0133] HRMS(ESI,m / z):[M+H] + [C 37 H 43 FO6] + Calculated value 603.3116, measured value 603.3129

[0134] 1H NMR(400MHz,CDCl3)δ7.3-7.28(1H,m,H-6”),7.07(1H,d,J=11.7Hz,H-7”),7.05-7.03(1H,m,H-5”),6.99-6.96(1H,m,H-3”),6.16(1H,d,J=3.2,H-13a'),5.55(1H,d,J=8.0Hz,H-6'),5.52(1H,t,J=6.8Hz,H-1),5.44(1H,d,J=2.8Hz,H-13b'),4.95(1H,d,J=8.0Hz,H-5),4.56-4.52(2H,m,H-6,H-1a”),4.36(1H,d,J=10.0Hz,H-14a),4.17(1H,d,J=8.8Hz,H-14b),3.83(1H,d,J=8.8Hz,H-1b”),3.03(1H,br s,H-2'),2.84-2.78(1H,m,H-7'),2.32(1H,dd,J=8.0,4.0Hz,H-3a'),2.26 -2.23(1H,m,H-7),2.21-2.19(1H,m,H-9a),2.18 -2.15(2H,m,H-13),2.13-2.10(1H,m,H-8'a),2.03-2.00(2H,m,H-8),1.98(1H,br s,H-2a),1.93(1H,br s,H-9a'),1.89-1.85(2H,m,H-2b,H-9b),1.83(3H,s,H-15),1.80-1.77(1H,m,H-9b'),1.67-1.65(1H,m,H-8b'),1.62(1H,br s,H-3a),1.49(1H,dd,J=9.6,1.6Hz,H-3b'),1.42(3H,s,H-14'),1.41(1H,br s,H-3b),1.38(3H,s,H-15'). 13C NMR(400MHz, CDCl3)δ180.9(C,C-12),170.1(C,C-12'),163.9(C,C-4"),150.4(C, C-1'),145.1(C,C-11'),141.0(C,C-2"),140.0(C,C-4),138.1(C,C-5'),137.1(C ,C-10),130.0(CH,C-6"),128.3(CH,C-1),125.0(CH,C-5),123.1(CH,C-3"),118. 8(CH2,C-13'),114.7(CH,C-5"),114.5(CH,C-7"),83.8(CH,CH-6'),77.4(CH,C-6 ),73.7(CH2,C-14),72.5(C,C-10'),71.1(CH2,C-1"),60.5(C,C-11),56.6(C,C-4 '),53.4(CH2,C-3),46.8(CH,C-7'),46.0(CH,C-7),42.7(CH,C-2'),38.6(CH2,C- 9'),38.2(CH2,C-13),34.8(CH2,C-3'),27.8(CH3,C-14'),24.6(CH2,C-9),24.5( CH2,C-8),23.9(CH2,C-2),23.7(CH2,C-8'),17.4(CH3,C-15'),17.1(CH3,C-15).

[0135] Embodiment 5:

[0136] Preparation of compounds 12-15.

[0137]

[0138] At room temperature, compound 2 (100 mg, 0.2 mmol, 1.0 equiv) and N,N'-carbonylbis(1,2,4-triazole) (102 mg, 0.4 mmol, 0.62 equiv) were dissolved in DCM (5 mL), stirred for 1 h, the reaction was quenched with water, extracted with dichloromethane, the organic phases were combined, and the solvent was removed by concentration under reduced pressure. The crude product was separated by column chromatography to obtain the intermediate; the intermediate (100 mg, 0.17 mmol, 1.0 equiv) was dissolved in DCM (5 mL), the corresponding benzylamine (1.1 equiv) was added, stirred at room temperature, reacted for 4 h, concentrated under reduced pressure to remove the solvent, and the crude product was separated by column chromatography (petroleum ether-ethyl acetate, 3:1) to obtain the corresponding compound.

[0139] Compound 12

[0140] Yield: 42% (55 mg)

[0141] Molecular formula: C 39 H 47 NO8

[0142] Molecular weight: 657.8040

[0143] Appearance: White solid

[0144] Optical rotation: (c 0.107, chloroform)

[0145] HRMS(ESI,m / z):[M+H] + [C 39 H 47 NO8] + Calculated value 658.3374, measured value 658.3385

[0146] 1 H NMR(500MHz,CDCl3)δ7.25(2H,d,J=7.0Hz,H-5",H-6"),6.90(1H,t,J=7.5Hz,H-7"),6.86(1H,d ,J=8.5Hz,H-8"),6.14(1H,d,J=3.5Hz,H-13a'),5.54-5.53(2H,m,H-1,H-6'),5.42(1H,d,J=3.0 Hz,H-13b'),4.94(1H,d,J=10.0Hz,H-5),4.72(1H,d,J=12.5Hz,H-14a),4.51(1H,t,J=10.0Hz, H-6),4.40(1H,d,J=12.5Hz,H-14b),4.33(2H,d,J=6.0Hz,H-2”),3.84(3H,s,H-9”),3.03(1H,br s,H-2'),2.83-2.76(1H,m,H-7'),2.30-2.28(2H,m,H-7,H-3a'),2.16-2.09(4H,m,H-8a,H- 9a,H-13),2.03-1.97(3H,m,H-2a,H-8b,H-8a'),1.94-1.92(1H,m,H-9a'),1.85-1.82(1H,m, H-9b),1.81(3H,s,H-15),1.79-1.75(2H,m,H-2b,H-9b'),1.65-1.62(1H,m,H-8b'),1.51(3H ,s,H-15'),1.49-1.47(2H,m,H-3a,H-3b'),1.41(3H,s,H-14'),1.33(1H,d,J=4.0Hz,H-3b).13 C NMR(125MHz, CDCl3)δ181.1(C,C-12),170.0(C,C-12'),157.5(C,C-4"),156.1(C,C- 1"),150.5(C,C-1'),145.1(C,C-11'),140.1(2C,C-4,C-5'),137.0(C,C-10),129.5( CH,C-8"),128.9(CH,C-6"),128.5(CH,C-1),126.5(C,C-3"),125.1(CH,C-5),120.6 (CH,C-5"),118.7(CH2,C-13'),110.3(CH,C-7"),83.8(CH,CH-6'),77.5(CH,C-6),72 .4(C,C-10'),67.2(CH2,C-14),60.9(C,C-11),56.5(C,C-4'),55.3(CH2,C-3),53.4 (CH,C-9"),46.8(CH,C-7'),45.7(CH,C-7),42.8(CH,C-2'),41.1(CH2,C-2"),38.5(C H2,C-9'),38.1(CH2,C-13),34.8(CH2,C-3'),27.9(CH3,C-14'),24.9(CH2,C-9),24 .6(CH2,C-8),24.2(CH2,C-2),23.8(CH2,C-8'),17.4(CH3,C-15'),17.1(CH3,C-15).

[0147] Compound 13

[0148] Yield: 47% (62 mg)

[0149] Molecular formula: C 39 H 47 NO8

[0150] Molecular weight: 657.8040

[0151] Appearance: White solid

[0152] Optical rotation: (c 0.102, chloroform)

[0153] HRMS(ESI,m / z):[M+H] + [C 39 H 47 NO8] + Calculated value 658.3374, measured value 658.3380

[0154] 1 H NMR(500MHz,CDCl3)δ7.21(1H,t,J=7.5Hz,H-7"),6.76(2H,dd,J=8.0,2.5Hz,H-6",H-8"),6.73(1H,s,H-4"),6.14(1H,d,J=3.5Hz,H-13a'),5.55(1H,d,J=10.0Hz,H-6'),5.53(1H,t,J=9.0Hz,H-1),5.43(1H,d,J=3.0Hz,H-13b'),4.96(1H,d,J=10.0Hz,H-5),4.72(1H,d,J=12.0Hz,H-14a),4.53(1H,t,J=10.0Hz,H-6),4.43(1H,d,J=12.5Hz,H-14b),3.79(3H,s,H-9"),3.43(2H,dd,J=8.0,6.5Hz,H-2"),3.03(1H,br s,H-2'),2.80-2.77(1H,m,H-7'),2.30(2H,d,J=12.5,4.0Hz,H-7,H-3a'),2.18 -2.14(2H,m,H-13),2.13-2.10(1H,m,H-9a),2.08-2.05(1H,m,H-8a),2.03 -2.01(1H,m,H-8b),2.00-1.98(2H,m,H-2a,H-8a'),1.96-1.94(1H,m,H-9a'),1.89 -1.84(1H,m,H-9b),1.82(3H,s,H-15),1.80-1.76(1H,m,H-2b),1.68-1.64(2H,m H-8b',H-9b'),1.53(3H,s,H-15'),1.52-1.49(2H,m,H-3a,H-3b'),1.41(3H,s,H-14'),1.33(1H,d,J=10.0Hz,H-3b). 13C NMR(125MHz, CDCl3)δ181.0(C,C-12),170.0(C,C-12'),159.8(C,C-5"),156.0(C,C- 1"),150.4(C,C-1'),145.1(C,C-11'),140.0(2C,C-4,C-3"),137.2(C,C-5'),136.9( C,C-10),129.6(CH,C-7"),128.3(CH,C-1),125.2(CH,C-5),121.1(CH,C-4"),118.8 (CH2,C-13'),114.5(CH,C-6"),111.8(CH,C-8"),83.8(CH,CH-6'),77.5(CH,C-6),72 .5(C,C-10'),67.2(CH2,C-14),60.9(C,C-11),56.5(C,C-4'),55.2(CH,C-9"),53.5 (CH2,C-3),46.8(CH,C-7'),45.7(CH,C-7),42.8(CH,C-2'),42.0(CH2,C-2"),38.6(C H2,C-9'),38.1(CH2,C-13),34.9(CH2,C-3'),27.9(CH3,C-14'),24.8(CH2,C-9),24 .6(CH2,C-8),24.1(CH2,C-2),23.8(CH2,C-8'),17.5(CH3,C-15'),17.1(CH3,C-15).

[0155] Compound 14

[0156] Yield: 60% (79 mg)

[0157] Molecular formula: C 39 H 47 NO8

[0158] Molecular weight: 657.8040

[0159] Appearance: White solid

[0160] Optical rotation: (c 0.124, chloroform)

[0161] HRMS(ESI,m / z):[M+H] + [C 39 H 47 NO8] + Calculated value 658.3374, measured value 658.3383

[0162] 1H NMR(500MHz,CDCl3)δ7.20(2H,d,J=10.5Hz,H-5",H-7"),6.86(2H,d,J=10.5Hz,H-4",H-8"),6.15(1H,d,J=3.0Hz,H-13a'),5.56-5.54(2H,m,H-1,H-6'),5.43(1H,d,J=3.0Hz,H-13b'),4.98-4.92(1H,m),4.72(1H,t,J=12.5Hz,H-6),4.53(1H,t,J=10.0Hz,H-14a),4.48(1H,d,J=12.5Hz,H-14b),4.30-4.28(1H,m,H-2"),3.03(1H,br s,H-2'),2.83-2.77(1H,m,H-7'),2.32-2.29(2H,m,H-3a',H-7),2.22-2.13(2H,m,H-9a,H-13a),2.12 -2.08(1H,m,H-13b),2.03-2.00(3H,m,H-8,H-8a'),1.96-1.94(1H,m,H-2a),1.89-1.84(2H,m,H-9b,H-9a'),1.82(3H,s,H-15),1.80-1.76(1H,m,H-2b),1.65(3H,br s,H-3a,H-8b',H-9b'),1.52(3H,s,H-15'),1.49-1.47(1H,m,H-3b,H-3b'),1.41(3H,s,H-14'),1.36-1.34(1H,m,H-3). 13C NMR(125MHz, CDCl3)δ181.0(C,C-12),170.0(C,C-12'),159.0(C,C-6"),156.1(C,C -1"),150.4(C,C-1'),145.2(C,C-11'),140.0(2C,C-4,C-5'),136.8(2C,C-10,C-3 "),130.5(C,C-6"),129.0(2CH,C-4",C-8"),128.4(CH,C-1),125.1(CH,C-5),118. 7(CH2,C-13'),114.1(2CH,C-5",C-7"),83.8(CH,CH-6'),77.5(CH,C-6),72.5(C,C -10'),67.4(CH2,C-14),60.9(C,C-11),56.5(C,C-4'),55.3(CH3,C-9"),53.5(CH2 ,C-3),46.8(CH,C-7'),45.7(CH,C-7),44.6(CH2,C-2"),42.8(CH,C-2'),38.6(CH2 ,C-9'),38.1(CH2,C-13),34.8(CH2,C-3'),27.9(CH3,C-14'),24.8(CH2,C-9),24. 6(CH2,C-8),24.1(CH2,C-2),23.8(CH2,C-8'),17.5(CH3,C-15'),17.1(CH3,C-15).

[0163] Compound 15

[0164] Yield: 46% (65 mg)

[0165] Molecular formula: C 38 H 44 BrNO7

[0166] Molecular weight: 706.6740

[0167] Appearance: White solid

[0168] Optical rotation: (c 0.077, chloroform)

[0169] HRMS(ESI,m / z):[M+H] + [C 38 H 44 BrNO7] + Calculated value 706.2374, measured value 706.2388

[0170] 1H NMR(500MHz,CDCl3)δ7.41(2H,d,J=8.5Hz,H-5",H-7"),7.06(2H,dd,J=8.0Hz,H-4",H-8"),6.15(1H,d,J=3.5Hz,H-13a'),5.55(1H,d,J=10.0Hz,H-6'),5.52(1H,t,J=6.5Hz,H-1),5.43(1H,d,J=3.0Hz,H-13b'),4.96(1H,d,J=10.0Hz,H-5),4.69(1H,t,J=12.5Hz,H-6),4.53(1H,d,J=10.0Hz,H-14a),4.41(1H,d,J=12.0Hz,H-14b),3.42(2H,dd,J=13,6.5Hz,H-2"),3.03(1H,br s,H-2'),2.81-2.76(1H,m,H-7'),2.31(1H,dd,J=12.0,3.5Hz,H-3a'),2.17 -2.15(1H,m,H-7),2.13 -2.10(1H,m,H-9a),2.04 -2.00(2H,m,H-13),1.99-1.96(2H,m,H-8),1.94 -1.90(1H,m,H-8a'),1.87 -1.85(1H,m,H-2a),1.82(3H,s,H-15),1.80-1.76(2H,m,H-2b,H-9a'),1.64-1.61(3H,m,H-9b,H-8b',H-9b'),1.52(3H,s,H-15'),1.50-1.47(2H,m,H-3a,H-3b'),1.42(3H,s,H-14'),1.36(1H,d,J=9.0Hz,H-3b). 13C NMR(125MHz, CDCl3)δ181.0(C,C-12),170.0(C,C-12'),156.0(C,C-3"),150.3( C,C-1'),145.2(C,C-11'),140.0(2C,C-4,C-5'),137.7(C,C-10),137.3(C,C-1" ),,136.8(C,C-6"),131.7(2CH,C-5",C-7"),130.6(2CH,C-4",C-8"),128.5(CH ,C-1),125.2(CH,C-5),118.8(CH2,C-13'),83.8(CH,CH-6'),77.5(CH,C-6),72. 5(C,C-10'),67.3(CH2,C-14),60.8(C,C-11),56.5(C,C-4'),53.5(CH2,C-3),4 6.8(CH,C-7'),45.7(CH,C-7),42.8(CH,C-2'),41.9(CH2,C-2"),38.6(CH2,C-9' ),38.1(CH2,C-13),34.9(CH2,C-3'),27.9(CH3,C-14'),24.8(CH2,C-9),24.6(C H2,C-8),24.1(CH2,C-2),23.8(CH2,C-8'),17.5(CH3,C-15'),17.1(CH3,C-15).

[0171] Embodiment 6:

[0172] Preparation of compound 16.

[0173]

[0174] Under argon protection, compound 2 (200 mg, 0.4 mmol, 1 equiv) was dissolved in dry tetrahydrofuran (5 mL) in a 25 mL three-necked flask, and DPPA (130 μL, 0.6 mmol, 1.5 equiv) and DBU (90 μL, 0.6 mmol, 1.5 equiv) were slowly added under ice bath. After the addition, the mixture was reacted at room temperature for 4 h. Saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to remove the solvent. The crude product was separated by column chromatography (petroleum ether-ethyl acetate, 5:1) to obtain the compound.

[0175] Compound 16

[0176] Yield: 60% (125 mg)

[0177] Molecular formula: C 30 H37 N3O5

[0178] Molecular weight: 519.6420

[0179] Appearance: White solid

[0180] Optical rotation: (c 0.173, chloroform)

[0181] HRMS(ESI,m / z):[M+H] + [C 30 H 37 N3O5] + Calculated value 520.2806, measured value 520.2812

[0182] 1 H NMR(500MHz, CDCl3) δ6.13(1H,d,J=4.0Hz,H-13a'),5.56(1H,d,J=8.0Hz,H-6'),5.50 (1H,t,J=8.5Hz,H-1),5.45(1H,d,J=4.0Hz,1H,H-13b'),4.97(1H,d,J=7.5Hz,1H,H-5) ,4.54(1H,t,J=12.5Hz,1H,H-6),3.81(1H,d,J=16.5Hz,H-14a),3.79(1H,d,J=16.5Hz, H-14b),3.03(1H,m,H-2'),2.83-2.78(1H,m,H-7'),2.30(1H,dd,J=15.5Hz,H,H-3a'), 2.21-2.19(1H,m,H-7),2.15(2H,dd,J=7.0Hz,H-13),2.12-2.09(2H,m,H-8),2.04-1. 93(4H,m,H-2a,H-9a,H-8a',H-9a'),1.87-1.83(1H,m,H-9b),1.81(3H,s,H-15),1.78- 1.76(1H,m,H-2b),1.77-1.72(1H,m,H-9b'),1.69-1.65(1H,m,H-8b'),1.52-1.48(2H, m,H-3a,H-3b'),1.46(3H,s,H-15'),1.39(3H,s,H-14'),1.34(1H,d,J=11.1Hz,H-3b). 13C NMR (125MHz, CDCl3) δ180.6(C,C-12),170.0(C,C-12'),150.8(C,C-1'),144.8(C,C-11'),140.0(C,C-4),137.1(C,C-5'),135.9(C,C -10),129.8(CH,C-1),125.2(CH,C-5),118.7(CH2,C-13'),83.7(CH,CH-6'),77.4(CH,C-6),72.4(C,C-10'),60.5(C,C-11),56.5(C, C-4'),56.2(CH2,C-14),53.5(CH2,C-3),46.8(CH,C-7'),45.9(CH,C-7),42.7(CH,C-2'),38.5(CH2,C-9'),38.1(CH2,C-13),34.8(C H2,C-3'),27.7(CH3,C-14'),24.9(CH2,C-9),24.5(CH2,C-8),23.9(CH2,C-2),23.7(CH2,C-8'),17.5(CH3,C-15'),17.1(CH3,C-15).

[0183] Embodiment 7:

[0184] Preparation of compound 17.

[0185]

[0186] Under argon protection, compound 2 (100 mg, 0.2 mmol, 1.0 equiv) was dissolved in 5 mL THF-H2O (10:1), stirred, and triphenylphosphine (101 mg, 0.4 mmol, 2.0 equiv) was slowly added. The reaction was carried out for 12 h, quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phases were combined and concentrated under reduced pressure to remove the solvent. The crude product was separated by column chromatography (petroleum ether-ethyl acetate-triethylamine, 5:1:0.6) to obtain a white solid.

[0187] Compound 17

[0188] Yield: 81% (80 mg)

[0189] Molecular formula: C 30 H 39 NO5

[0190] Molecular weight: 493.6440

[0191] Appearance: White solid

[0192] Optical rotation: (c 0.189, chloroform)

[0193] HRMS (ESI, m / z): [M+H] + [C 30 H 39 NO5] + Calculated value 494.2901, measured value 494.2907

[0194] 1 H NMR (400 MHz, CDCl3) δ 6.13 (1H, d, J = 3.2 Hz, H-13a'), 5.54 (1H, d, J = 10.0 Hz, H-6'), 5.42 (1H, d, J = 2.8 Hz, H-13'b), 5.40 - 5.38 (1H, m, H-1), 4.95 (1H, d, J = 10.0 Hz, H-5), 4.52 (1H, t, J = 10.0 Hz, H-6), 3.36 (1H, t, J = 6.8 Hz, H-14a), 3.32 - 3.29 (1H, m, H-14b), 3.03 (1H, br s, H-2'), 2.82 - 2.76 (1H, m, H-7'), 2.33 - 2.29 (2H, m, H-7, H-3a'), 2.25 - 2.22 (1H, m, H-9a), 2.12 - 2.06 (3H, m, H-8a, H-13), 2.02 - 1.96 (4H, m, H-2a, H-8b, H-8a', H-9a'), 1.91 (1H, br s, H-9b), 1.81 (3H, s, H-15), 1.78 - 1.74 (1H, m, H-8b'), 1.66 - 1.64 (1H, m, H-3a), 1.51 (1H, br s, H-3b'), 1.48 (3H, s, H-15'), 1.40 (3H, s, H-14'), 1.34 - 1.31 (1H, m, H-3b). 13CNMR(100MHz,CDCl3)δ180.8(C,C-12),170.0(C,C-12'),150.6(C,C-1'),145.0(C,C-11'),140.1(2C,C-10,C-5'),137.1(C,C-4 ),125.0(CH,C-1),123.9(CH,C-5),118.6(CH2,C-13'),83.8(CH,CH-6'),77.5(CH,C-6),72.4(C,C-10'),60.7(C,C-11),56.5(2 C,C-14,C-4'),53.5(CH2,C-3),46.8(CH,C-7'),45.8(CH,C-7),42.7(CH,C-2'),38.5(CH2,C-9'),34.8(CH2,C-13),34.4(CH2,C -3'),27.8(CH3,C-14'),24.8(CH2,C-9),24.5(CH2,C-8),24.0(CH2,C-2),23.7(CH2,C-8'),17.5(CH3,C-15'),17.1(CH3,C-15).

[0195] Embodiment 8:

[0196] Preparation of compound 18.

[0197]

[0198] At room temperature, in a 10 mL three-necked flask, compound 17 (100 mg, 0.2 mmol, 1 equiv) was dissolved in dichloromethane (3 mL), acetic anhydride (20 μL, 0.2 mmol, 1 equiv) and triethylamine (140 μL, 1 mmol, 5 equiv) were added, stirred for 2 h, and concentrated under reduced pressure to remove the solvent. The crude product was separated by column chromatography (petroleum ether-ethyl acetate-triethylamine, 3:1:0.4) to obtain 38 mg of a white solid with a yield of 87%;

[0199] Compound 18

[0200] Yield: 87% (104 mg)

[0201] Molecular formula: C 37 H 43 NO6

[0202] Molecular weight: 597.7520

[0203] Appearance: White solid

[0204] Optical rotation: (c 0.155, chloroform)

[0205] HRMS(ESI, m / z): [M+H] + [C 37 H 43 NO6] + Calculated value: 598.3163, Measured value: 598.3157

[0206] 1 H NMR (500 MHz, CDCl3) δ 7.76 - 7.74 (2H, m, H-3", H-7"), 7.51 - 7.47 (1H, m, H-5"), 7.44 - 7.40 (2H, m, H-4", H-6"), 6.13 (1H, d, J = 3.5 Hz, H-13a'), 5.56 (1H, d, J = 10.0 Hz, H-6'), 5.45 (1H, overlap, H-1), 5.43 (1H, overlap, H-13b), 4.98 (1H, d, J = 10.0 Hz, H-5), 4.54 (1H, t, J = 10.0 Hz, H-6), 4.51 - 4.47 (1H, m, H-14a), 3.66 (1H, dd, J = 15.0, 3.5 Hz, H-14b), 3.03 (1H, br s, H-2'), 2.83 - 2.77 (1H, m, H-7'), 2.37 - 2.35 (1H, m, H-3a'), 2.34 - 2.31 (1H, m, H-7), 2.17 - 2.14 (2H, m, H-9a, H-13a), 2.13 - 2.09 (3H, m, H-8, H-13b), 2.05 - 1.97 (2H, m, H-2a, H-8a'), 1.94 - 1.89 (1H, m, H-9a'), 1.87 - 1.84 (1H, m, H-9b), 1.82 (3H, s, H-15), 1.80 - 1.75 (1H, m, H-2b), 1.73 (1H, br s, H-9b'), 1.68 - 1.66 (1H, m, H-8b'), 1.63 (3H, s, H-15'), 1.60 (1H, br s, H-3a), 1.50 - 1.47 (1H, m, H-3b'), 1.41 (3H, s, H-14'), 1.39 (1H, br s, H-3b). 13C NMR(125MHz, CDCl3)δ181.3(C,C-12),170.1(C,C-12'),167.3(C,C-1"),150.3 (C,C-1'),145.2(C,C-11'),140.0(2C,C-4,C-5'),138.7(C,C-10),136.9(C,), 134.5(C,C-2"),131.5(CH,C-5"),128.6(2CH,C-4",C-6"),126.9(CH,C-3",C-7 "),126.4(CH,C-1),125.4(CH,C-5),118.8(CH2,C-13'),83.9(CH,CH-6'),77.7 (CH,C-6),72.4(C,C-10'),61.2(C,C-11),56.5(C,C-4'),53.6(CH2,C-3),46.8 (CH,C-7'),45.5(CH,C-7),43.9(CH2,C-14),42.9(CH,C-2'),38.5(CH2,C-9'), 38.2(CH2,C-13),34.9(CH2,C-3'),28.1(CH3,C-14'),24.9(CH2,C-9),24.8(CH 2,C-8),24.4(CH2,C-2),24.0(CH2,C-8'),17.5(CH3,C-15'),17.1(CH3,C-15).

[0207] Embodiment 9:

[0208] Preparation of compound 19.

[0209]

[0210] Under argon protection, compound 17 (90 mg, 0.18 mmol, 1.0 equiv) was dissolved in dry THF (1 mL), and 2-phenylethyl isocyanate (33 μL, 0.21 mmol, 1.05 equiv) and triethylamine (38 μL, 0.27 mmol, 1.5 equiv) were added under ice bath, and the reaction was continued for 12 h. The reaction was quenched with dilute hydrochloric acid solution, extracted with ethyl acetate, the organic phases were combined, and the solvent was removed by concentration under reduced pressure. The crude product was separated by column chromatography (petroleum ether-ethyl acetate-triethylamine, 3:1:0.4) to obtain a white solid.

[0211] Compound 19

[0212] Yield: 77% (89 mg)

[0213] Molecular formula: C 39 H 48 N2O6

[0214] Molecular weight: 640.8210

[0215] Appearance: White solid

[0216] Optical rotation: (c 0.157, chloroform)

[0217] HRMS(ESI,m / z):[M+H] + [C 39 H 48 N2O6] + Calculated value 641.3585, measured value 641.3579

[0218] 1 H NMR (500MHz, CDCl3) δ7.30-7.27(2H,m,H-4”,H-5”),7.23-7.21(2H,m,H-6”,H-7” ),7.18-7.17(1H,m,H-8”),6.13(1H,d,J=3.5Hz,H-13a'),5.54(1H,d,J=10.0Hz, H-6'),5.44(1H,d,J=3.0Hz,H-1),5.31(1H,t,J=8.0Hz,H-13b'),4.91(1H,d,J=1 0.0Hz,H-5),4.53-4.49(2H,m,H-14),3.48-3.41(4H,m,H-2”,H-3”),3.03(1H,br s,H-2'),2.82-2.76(1H,m,H-7'),2.30(1H,dd,J=12.5,3.5Hz,H-3a'),2.21(1H, s,H-7),2.18(2H,s,H-13),2.11-1.99(4H,m,H-2a,H-8,H-9a),1.91(1H,d,J=10. 5Hz,H-8a'),1.85(3H,s,H-15),1.79(1H,dd,J=5.2Hz,H-9a'),1.70(2H,d,J=6.5 Hz,H-2b,H-9b),1.56(3H,s,H-15'),1.54-1.50(2H,m,H-8b',H-9b'),1.49(2H,br s, H-3a, H-3b'), 1.42 (3H, s, H-14'), 1.37 (1H, d, J = 8.7Hz, H-3b). 13C NMR(125MHz, CDCl3)δ181.2(C,C-12),170.2(C,C-12'),158.3(C,C-1"),150.6(C, C-1'),144.8(C,C-11'),140.0(C,C-4),139.4(C,C-4"),139.2(C,C-5'),137.2(C, C-10),128.8(2CH,C-6",C-8"),128.5(2CH,C-5",C-9"),126.3(2CH,C-1,C-7"),1 25.1(CH,C-5),118.9(CH2,C-13'),84.0(CH,CH-6'),77.6(CH,C-6),72.3(C,C-10' ), 60.8 (C, C-11), 56.5 (C, C-4'), 53.5 (CH2, C-3), 46.8 (CH, C-7'), 46.2 (CH2, C-14), 45.7 (CH, C-7), 42.8 (CH, C-2'), 41.5 (C, C-2"), 38.4 (CH2, C-9'), 38.3 (CH2, C-13), 36.4 (C, C-3"), 34.8 (CH2, C-3'), 28.0 (CH3, C-14'), 24.9 (CH2, C-9), 24.6 (CH2, C-8), 24.1 (CH2, C-2), 23.9 (CH2, C-8'), 17.5 (CH3, C-15'), 17.1 (CH3, C-15). Example 10:

[0219] Preparation of compounds 20-34.

[0220]

[0221] At room temperature, compound 16 (50 mg, 0.1 mmol, 1 equiv) was dissolved in 5 mL of acetonitrile-water (9:1) in a 10 mL round-bottom flask, and the corresponding substituted acetylene compound (1.5 equiv), cuprous iodide (19 mg, 0.01 mmol, 0.1 equiv) and triethylamine (357 μL, 0.1 mmol, 1 equiv) were added. The reaction was allowed to react at room temperature for 6 h, and water was added to quench the reaction. The mixture was extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to remove the solvent. The crude product was separated by column chromatography (petroleum ether-ethyl acetate, 4:1) to obtain the corresponding compound.

[0222] Compound 20

[0223] Yield: 71% (44 mg)

[0224] Molecular formula: C 38 H 43N3O5

[0225] Molecular weight: 621.7780

[0226] Appearance: White solid

[0227] Optical rotation: (c 0.066, chloroform)

[0228] HRMS(ESI,m / z):[M+H] + [C 38 H 43 N3O5] + Calculated value 622.3275, measured value 622.3273

[0229] 1 H NMR(500MHz, CDCl3)δ7.82(2H,d,J=7.3Hz,H-4",H-8"),7.72(1H,s,H-1"),7.42(2H,t,J=7.5Hz ,H-5",H-7"),7.34(1H,d,J=7.5Hz,H-3"),6.16(1H,d,J=3.3Hz,H-13a'),5.67(1H,t,J=8.0Hz,H -1),5.59(1H,d,J=10.0Hz,H-6'),5.46(1H,d,J=3.1Hz,H-13b'),5.32(1H,d,J=14.5Hz,H-5),5. 02(1H,d,J=10.9Hz,H-14a),4.73(1H,d,J=14.5Hz,H-14b),4.57(1H,t,J=9.6Hz,H-6),3.04(1H, s,H-2'),2.85-2.81(1H,m,H-7'),2.30(1H,dd,J=16.0Hz,H-3a'),2.24-2.20(2H,m,H-7,H-9a) ,2.17-2.06(2H,m,H-13),2.04-2.01(2H,m,H-8),1.95-1.91(2H,m,H-2a,H-8a'),1.83(3H,s,H- 15),1.80-1.77(1H,m,H-9a'),1.74-1.71(2H,m,H-2b,H-9b),1.68(3H,s,H-15'),1.66-1.65(2H ,m,H-8b',H-9b'),1.60-1.58(2H,m,H-3a,H-3b'),1.53-1.50(1H,m,H-3b),1.43(3H,s,H-14'). 13C NMR (125MHz, CDCl3) δ180.9(C,C-12),170.1(C,C-12'),150.3(C,C-1'),148.1( C,C-2"),145.2(C,C-11'),140.0(2C,C-4,C-5'),136.5(C,C-10),130.8(CH,C-1 "),130.5(C,C-3"),128.8(2CH,C-5",C-7"),128.9(CH,C-1),125.6(2CH,C-4", C-8"),125.5(CH,C-5),118.9(CH,C-6"),118.9(CH2,C-13'),83.9(CH,CH-6'),7 7.3(CH,C-6),72.4(C,C-10'),60.9(C,C-11),56.5(C,C-4'),55.7(CH2,C-14), 53.7(CH2,C-3),46.8(CH,C-7'),45.8(CH,C-7),42.8(CH,C-2'),38.6(CH2,C-9' ),38.0(CH2,C-13),34.9(CH2,C-3'),28.1(CH3,C-14'),24.9(CH2,C-9),24.0(C H2,C-8),24.0(CH2,C-2),23.6(CH2,C-8'),17.8(CH3,C-15'),17.1(CH3,C-15).

[0230] Compound 21

[0231] Yield: 35% (22 mg)

[0232] Molecular formula: C 39 H 45 N3O5

[0233] Molecular weight: 635.8050

[0234] Appearance: White solid

[0235] Optical rotation: (c 0.114, chloroform)

[0236] HRMS(ESI,m / z):[M+H] + [C 39 H 45 N3O5] + Calculated value 636.3432, measured value 636.3436

[0237] 1H NMR(500MHz,CDCl3)δ7.75(1H,dd,J=6.5,3.5Hz,H-8"),7.60(1H,s,H-1"),7.26-7.24(3H,m,H-5",H-6",H-7"),6.16(1H,d,J=3.0Hz,H-13a'),5.67(1H,t,J=7.5Hz,H-1),5.58(1H,d,J=10.0Hz,H-6'),5.45(1H,d,J=3.0Hz,H-13b'),5.32(1H,d,J=14.5Hz,H-5),5.03(1H,d,J=10.0Hz,H-14a),4.76(1H,d,J=14.5Hz,H-14b),4.56(1H,t,J=10.0Hz,H-6),3.03(1H,br s,H-2'),2.85-2.79(1H,m,H-7'),2.46(3H,s,H-9"),2.40-2.34(1H,m,H-3a'),2.30(1H,dd,J=11.5,6.0Hz,H-7),2.22-2.20(2H,m,H-9a,H-13a),2.15-2.11(1H,m,H-13b),2.09-2.08(1H,m,H-8a),2.02-1.99(2H,m,H-8b,H-8a'),1.94-1.88(2H,m,H-2a,H-9a'),1.83(3H,s,H-15),1.81-1.79(1H,m,H-9b),1.78-1.76(1H,m,H-2b),1.72-1.69(2H,m,H-8b',H-9b'),1.67(3H,s,H-15'),1.65-1.62(1H,m,H-3a),1.60-1.58(1H,m,H-3b'),1.53-1.50(1H,m,H-3b),1.43(3H,s,H-14'). 13C NMR (125MHz, CDCl3) δ180.9(C,C-12),170.1(C,C-12'),150.4(C,C-1'),147.5(C,C- 11'),145.1(C,C-4),140.0(2C,C-5',C-2"),136.5(C,C-10),135.4(C,C-4"),130.9( CH,C-5"),130.8(CH,C-1"),129.8(C,C-3"),128.8(CH,C-7"),128.2(CH,C-8"),126 .1(CH,C-1),125.5(CH,C-5),121.1(CH,C-6"),118.9(CH2,C-13'),83.9(CH,CH-6'), 77.3(CH,C-6),72.4(C,C-10'),60.9(C,C-11),56.5(C,C-4'),55.6(CH2,C-14),53. 7(CH2,C-3),46.8(CH,C-7'),45.8(CH,C-7),42.8(CH,C-2'),38.5(CH2,C-9'),38.0( CH2,C-13),34.9(CH2,C-3'),28.0(CH3,C-14'),24.9(CH2,C-9),24.1(CH2,C-8),23. 9(CH2,C-2),23.7(CH2,C-8'),21.5(CH3,C-9"),17.8(CH3,C-15'),17.1(CH3,C-15).

[0238] Compound 22

[0239] Yield: 43% (27 mg)

[0240] Molecular formula: C 39 H 45 N3O5

[0241] Molecular weight: 635.8050

[0242] Appearance: White solid

[0243] Optical rotation: (c 0.075, chloroform)

[0244] HRMS(ESI,m / z):[M+H] + [C 39 H 45 N3O5] + Calculated value 636.3432, measured value 636.3432

[0245] 1H NMR(500MHz,CDCl3)δ7.70(1H,s,H-4"),7.67(1H,s,H-1"),7.59(1H,d,J=7.5Hz,H-8"),7.30(1H,t,J=7.5Hz,H-7"),7.14(1H,d,J=8.0Hz,H-6"),6.16(1H,d,J=3.5Hz,H-13a'),5.67(1H,t,J=7.0Hz,H-1),5.58(1H,d,J=10.0Hz,H-6'),5.45(1H,d,J=3.0Hz,H-13b'),5.31(1H,d,J=14.0Hz,H-5),5.02(1H,d,J=9.5Hz,H-14a),4.72(1H,d,J=14.5Hz,H-14b),4.56(1H,t,J=10.0Hz,H-6),3.03(1H,br s,H-2'),2.86-2.80(1H,m,H-7'),2.40(3H,s,H-9"),2.37-2.34(1H,m,H-7),2.30(1H,dd,J=12.0,3.5Hz,H-3a'),2.23-2.20(2H,m,H-9a,H-13a),2.16-2.12(1H,m,H-13b),2.03-1.99(3H,m,H-8,H-8a'),1.96-1.92(1H,m,H-2a),1.90-1.86(1H,m,H-9a'),1.83(3H,s,H-15),1.81-1.77(1H,m,H-9b),1.73-1.70(1H,m,H-2b),1.68(3H,s,H-15'),1.65-1.62(2H,m,H-8b',H-9b'),1.59-1.57(H,m,H-3a),1.50(1H,dd,J=12.5,2.5Hz,H-3b'),1.44-1.43(1H,m,H-3b),1.42(3H,s,H-14'). 13C NMR (125MHz, CDCl3) δ180.9(C,C-12),170.1(C,C-12'),150.3(C,C-1'),148.2(C,C- 11'),145.2(C,C-4),140.0(C,C-5'),138.5(C,C-2"),136.5(2C,C-10,C-3"),130.8( CH,C-4"),130.3(CH,C-5"),129.0(CH,C-6"),128.8(CH,C-7"),126.3(CH,C-1),125. 5(CH,C-5),122.7(CH,C-8"),118.9(CH2,C-13'),118.9(CH,C-1"),83.9(CH,CH-6'), 77.3(CH,C-6),72.4(C,C-10'),60.9(C,C-11),56.6(C,C-4'),55.7(CH2,C-14),53. 7(CH2,C-3),46.8(CH,C-7'),45.8(CH,C-7),42.8(CH,C-2'),38.6(CH2,C-9'),38.0( CH2,C-13),34.9(CH2,C-3'),28.1(CH3,C-14'),24.8(CH2,C-9),24.0(CH2,C-8),24. 0(CH2,C-2),23.6(CH2,C-8'),21.4(CH3,C-9"),17.8(CH3,C-15'),17.1(CH3,C-15).

[0246] Compound 23

[0247] Yield: 33% (21 mg)

[0248] Molecular formula: C 39 H 45 N3O5

[0249] Molecular weight: 635.8050

[0250] Appearance: White solid

[0251] Optical rotation: (c 0.187, chloroform)

[0252] HRMS(ESI,m / z):[M+H] + [C 39 H 45 N3O5] + Calculated value 636.3432, measured value 636.3397

[0253] 1H NMR(500MHz,CDCl3)δ7.70(2H,d,J=8.5Hz,H-4",H-8"),7.67(1H,s,H-1"),7.21(2H,d,J=8.0Hz,H-5",H-7"),6.15(1H,d,J=3.5Hz,H-13a'),5.65(1H,t,J=7.5,H-1),5.57(1H,d,J=10.0Hz,H-6'),5.44(1H,d,J=3.0Hz,H-13b'),5.28(1H,d,J=14.5Hz,H-5),5.00(1H,d,J=10.0Hz,H-14a),4.71(1H,d,J=14.5Hz,H-14b),4.55(1H,t,J=10.0Hz,H-6),3.04(1H,br s,H-2'),2.85-2.78(1H,m,H-7'),2.36(3H,s,H-9”),2.28(1H,dd,J=12.0,3.5,H-3a'),2.21-2.18(2H,m,H-7,H-9a),2.13-2.11(2H,m,H-13),2.03-1.97(3H,m,H-8,H-8a'),1.90-1.84(2H,m,H-2a,H-9a'),1.81(3H,s,H-15),1.79-1.76(2H,m,H-2b,H-9b),1.71-1.69(1H,m,H-9b'),1.66(3H,s,H-15'),1.61-1.59(1H,m,H-8b'),1.58-1.56(1H,m,H-3a),1.50(1H,dd,J=12.0,2.0Hz,H-3b'),1.42(1H,br s,H-3b),1.41(3H,s,H-14'). 13C NMR(125MHz, CDCl3)δ180.9(C,C-12),170.1(C,C-12'),150.5(C,C-2"),148.2(C, C-1'),145.0(C,C-11'),140.0(C,C-4,C-5'),138.1(C,C-6"),137.0(C,C-3"),13 6.5(C,C-10),130.7(CH,C-1),129.5(2CH,C-5",C-7"),127.7(CH,C-5),125.5(2C H,C-4",C-8"),118.9(CH2,C-13'),118.6(CH,C-1"),83.9(CH,CH-6'),77.2(CH,C- 6),72.4(C,C-10'),60.9(C,C-11),56.5(C,C-4'),55.7(CH2,C-14),53.7(CH2,C- 3),46.8(CH,C-7'),45.8(CH,C-7),42.8(CH,C-2'),38.5(CH2,C-9'),38.0(CH2,C -13),34.9(CH2,C-3'),28.0(CH3,C-14'),24.8(CH2,C-9),24.0(CH2,C-8),23.9( CH2,C-2),23.6(CH2,C-8'),21.3(CH3,C-9"),17.7(CH3,C-15'),17.1(CH3,C-15).

[0254] Compound 24

[0255] Yield: 57% (36 mg)

[0256] Molecular formula: C 38 H 42 FN3O5

[0257] Molecular weight: 639.7684

[0258] Appearance: White solid

[0259] Optical rotation: (c 0.164, chloroform)

[0260] HRMS(ESI,m / z):[M+H] + [C 38 H 42 FN3O5] + Calculated value 640.3181, measured value 640.3175

[0261] 1H NMR(500MHz,CDCl3)δ7.79(2H,dd,J=10.5,7.0Hz,H-4",H-8"),7.67(1H,s,H-1"),7.10(2H,t,J=10.5Hz,H-5",H-7"),6.16(1H,d,J=4.0Hz,H-13a'),5.67(1H,t,J=10.0Hz,H-1),5.58(1H,d,J=8.5Hz,H-6'),5.45(1H,d,J=3.5Hz,H-13b'),5.31(1H,d,J=18.5Hz,H-5),5.02(1H,d,J=12.5Hz,H-14a),4.72(1H,d,J=18.0Hz,H-14b),4.56(1H,t,J=12.0Hz,H-6),3.04(1H,br s,H-2'),2.87-2.78(1H,m,H-7'),2.38-2.36(1H,m,H-3a'),2.31-2.28(2H,m,H-7,H-9a),2.26-2.20(2H,m,H-13),2.17-2.12(1H,m H-8a'),2.05-1.98(2H,m,H-8),1.94-1.89(2H,m,H-2a,H-9a'),1.83(3H,s,H-15),1.78-1.77(1H,m,H-9b),1.73(1H,br s,H-2b),1.67(3H,s,H-15'),1.65-1.61(1H,m,H-9b'),1.58(2H,d,J=11.0Hz,H-3a,H-8b'),1.53-1.50(2H,m,H-3b,H-3b'),1.42(3H,s). 13C NMR(125MHz, CDCl3)δ180.8(C,C-12),170.1(C,C-12'),163.7(C,C-6"),161.7(C,C -1'),150.3(C,C-2"),147.3(C,C-11'),145.5(C,C-4),139.9(C,C-5'),137.0(C,C -10),136.4(C,C-3"),130.9(C,C-1"),127.4(CH,C-8"),127.3(CH,C-4"),125.5(C ,C-1),118.9(CH2,C-13'),118.7(CH,C-5),115.8(C,C-5"),115.7(C,C-7"),83.9(C H,CH-6'),77.3(CH,C-6),72.4(C,C-10'),60.9(C,C-11),56.5(C,CH2-14),55.7(C ,C-4'),53.7(CH2,C-3),46.8(CH,C-7'),45.8(CH,C-7),42.8(CH,C-2'),38.6(CH2 ,C-9'),37.9(CH2,C-13),34.9(CH2,C-3'),28.1(CH3,C-14'),24.9(CH2,C-9),24. 1(CH2,C-8),24.0(CH2,C-2),24.0(CH2,C-8'),17.8(CH3,C-15'),17.1(CH3,C-15).

[0262] Compound 25

[0263] Yield: 66% (43 mg)

[0264] Molecular formula: C 38 H 42 ClN3O5

[0265] Molecular weight: 656.2200

[0266] Appearance: White solid

[0267] Optical rotation: (c 0.083, chloroform)

[0268] HRMS(ESI,m / z):[M+H] + [C 38 H 42 ClN3O5] + Calculated value 656.2886, measured value 656.2873

[0269] 1H NMR(500MHz,CDCl3)δ7.75(2H,d,J=11.5Hz,H-5",H-7"),7.70(1H,s,H-1"),7.38(2H,d,J=9.0Hz,H-4",H-8"),6.16(1H,d,J=3.5Hz,H-13a'),5.68(1H,t,J=7.5Hz,H-1),5.58(1H,d,J=10.5Hz,H-6'),5.45(1H,d,J=3.0Hz,H-13b'),5.32(1H,d,J=14.5Hz,H-5),5.02(1H,d,J=10.5Hz,H-14a),4.73(1H,d,J=13.5Hz,H-14b),4.56(1H,t,J=10.0Hz,H-6),3.04(1H,br s,H-2'),2.86-2.80(1H,m,H-7'),2.38-2.33(1H,m,H-7),2.30(1H,dd,J=12.0,4.0Hz,H-3a'),2.24-2.21(2H,m,H-9a,H-13a),2.17-2.12(1H,m,H-13b),2.04-2.03(1H,m,H-8a),2.02-1.99(2H,m,H-8b,H-8a'),1.95-1.92(1H,m,H-2a),1.91-1.88(1H,m,H-9a'),1.83(3H,s,H-15),1.81-1.78(1H,m,H-9b),1.73-1.70(1H,m,H-2b),1.68(3H,s,H-15'),1.62(2H,br s,H-8b',H-9b'),1.59-1.57(1H,m,H-3a),1.53-1.51(1H,m,H-3b'),1.44(1H,br s,H-3b),1.42(3H,s). 13C NMR(125MHz, CDCl3)δ180.8(C,C-12),170.1(C,C-12'),150.3(C,C-1'),147.1 (C,C-11'),145.1(2C,C-4,C-2"),139.9(2C,C-5',C-3"),136.4(C,C-10),134. 0(CH,C-6"),131.0(CH,C-1"),129.1(2CH,C-5",C-7"),126.9(2CH,C-4",C-8" ),125.5(CH,C-1),119.0(CH,C-5),118.9(CH2,C-13'),83.9(CH,CH-6'),77.3( CH,C-6),72.4(C,C-10'),60.9(C,C-11),56.5(C,C-4'),55.8(CH2,C-14),53. 7(CH2,C-3),46.8(CH,C-7'),45.8(CH,C-7),42.8(CH,C-2'),38.6(CH2,C-9'), 37.9(CH2,C-13),34.9(CH2,C-3'),28.1(CH3,C-14'),24.9(CH2,C-9),24.0(CH 2,C-8),24.0(CH2,C-2),23.6(CH2,C-8'),17.8(CH3,C-15'),17.1(CH3,C-15).

[0270] Compound 26

[0271] Yield: 52% (35 mg)

[0272] Molecular formula: C 38 H 42 N4O7

[0273] Molecular weight: 666.7750

[0274] Appearance: White solid

[0275] Optical rotation: (c 0.048, chloroform)

[0276] HRMS(ESI,m / z):[M+H] + [C 38 H 42 N4O7] + Calculated value 667.3126, measured value 667.3120

[0277] 1H NMR(500MHz,CDCl3)δ8.28(2H,d,J=8.5Hz,H-5",H-7"),8.00(2H,d,J=9.0Hz,H-4",H-8"),7.90(1H,s,H-1"),6.16(1H,d,J=3.5Hz,H-13'),5.70(1H,t,J=7.0Hz,H-1),5.58(1H,d,J=10.0Hz,H-6'),5.46(1H,d,J=3.0Hz,H-13a'),5.35(1H,d,J=14.5Hz,H-5),5.02(1H,d,J=10.0Hz,H-14a),4.77(1H,d,J=14.0Hz,H-14b),4.57(1H,t,J=10.5Hz,H-6),3.04(1H,br s,H-2'),2.87-2.80(1H,m,H-7'),2.30(1H,dd,J=12.5Hz,H-3a'),2.25-2.21(1H,m,H-7),2.17-2.12(1H,m,H-9a),2.10-2.05(1H,m,H-8a),2.04-1.99(3H,m,H-8b,H-13),1.96-1.92(1H,m,H-2a),1.90-1.87(1H,m,H-9a'),1.83(3H,s,H-15),1.82-1.78(1H,m,H-9b),1.75-1.70(2H,m,H-2b,H-9b'),1.67(3H,s,H-15'),1.65-1.63(1H,m,H-8b'),1.58-1.52(2H,m,H-3a,H-3b'),1.45-1.44(1H,m,H-3b),1.42(3H,s,H-14'). 13C NMR (125MHz, CDCl3) δ180.7(C,C-12),170.1(C,C-12'),150.5(C,C-1'),147.4(C,C -2"),146.0(C,C-11'),145.0(C,C-5'),139.9(C,C-4),137.0(C,C-6"),136.7(C,C -10),136.1(C,C-3"),131.3(CH,C-1"),126.1(2CH,C-5",C-7"),125.5(CH,C-1),1 24.3(2CH,C-4",C-8"),120.6(CH,C-5),119.0(CH2,C-13'),115.7(C,C-7"),83.9(C H,CH-6'),77.2(CH,C-6),72.4(C,C-10'),60.8(C,C-11),56.5(C,C-4'),55.9(CH2 ,C-14),53.7(CH2,C-3),46.8(CH,C-7'),45.8(CH,C-7),42.8(CH,C-2'),38.6(CH2 ,C-9'),37.9(CH2,C-13),34.9(CH2,C-3'),28.0(CH3,C-14'),24.9(CH2,C-9),24. 1(CH2,C-8),23.9(CH2,C-2),23.6(CH2,C-8'),17.8(CH3,C-15'),17.1(CH3,C-15).

[0278] Compound 27

[0279] Yield: 53% (35 mg)

[0280] Molecular formula: C 39 H 45 N3O6

[0281] Molecular weight: 651.8040

[0282] Appearance: White solid

[0283] Optical rotation: (c 0.069, chloroform)

[0284] HRMS(ESI,m / z):[M+H] + [C 39 H 45 N3O6] + Calculated value 652.3381, measured value 652.3396

[0285] 1H NMR(500MHz,CDCl3)δ7.74(2H,d,J=9.0Hz,H-5",H-7"),7.62(1H,s,H-1"),6.95(2H,t,J=9.0Hz,H-4",H-8"),6.17(1H,d,J=3.5Hz,H-13a'),5.67(1H,t,J=7.5Hz,H-1),5.59(1H,d,J=10.0Hz,H-6'),5.45(1H,d,J=3.0Hz,H-13b'),5.30(1H,d,J=14.5Hz,H-5),5.02(1H,d,J=10.0Hz,H-14a),4.71(1H,d,J=14.5Hz,H-14b),4.56(1H,t,J=10.0Hz,H-6),3.84(3H,s,H-9"),3.04(1H,br s,H-2'),2.86-2.80(1H,m,H-7'),2.39-2.33(1H,m,H-3a'),2.32-2.30(2H,m,H-7,H-9a),2.23-2.20(2H,m,H-13),2.17-2.12(1H,m,H-8a),2.04-2.00(3H,m,H-8b,H-8a'),1.96-1.92(2H,m,H-2a,H-9a'),1.90-1.87(1H,m,H-9b),1.83(3H,s,H-15),1.81-1.78(1H,m,H-2b),1.73-1.70(1H,m,H-9b'),1.68(3H,s,H-15'),1.61-1.59(2H,m,H-3a,H-8b'),1.53-1.50(1H,m,H-3b'),1.45-1.41(1H,br s,H-3b),1.43(3H,s,H-14'). 13C NMR(125MHz, CDCl3)δ180.9(C,C-12),170.1(C,C-12'),159.6(C,C-6"),150.3(C,C -2"),148.0(C,C-11'),145.2(C,C-4),139.9(2C,C-1',C-5'),136.6(C,C-10),130. 7(CH,C-1"),129.6(C,C-2"),126.9(2CH,C-4",C-8"),125.5(C,C-1),123.2(C,C-3" ),118.9(CH2,C-13'),118.1(CH,C-5),114.3(CH,C-5",C-7"),83.9(CH,CH-6'),77. 3(CH,C-6),72.4(C,C-10'),61.0(C,C-11),56.5(C,C-4'),55.6(CH2,C-14),55.3(C H3,C-9"),53.7(CH2,C-3),46.8(CH,C-7'),45.8(CH,C-7),42.8(CH,C-2'),38.6(CH 2,C-9'),38.0(CH2,C-13),34.9(CH2,C-3'),28.1(CH3,C-14'),24.9(CH2,C-9),24. 0(CH2,C-8),24.0(CH2,C-2),23.6(CH2,C-8'),17.8(CH3,C-15'),17.1(CH3,C-15).

[0286] Compound 28

[0287] Yield: 31% (20 mg)

[0288] Molecular formula: C 39 H 45 N3O5

[0289] Molecular weight: 635.8050

[0290] Appearance: White solid

[0291] Optical rotation: (c 0.053, chloroform)

[0292] HRMS(ESI,m / z):[M+H] + [C 39 H 45 N3O5] + Calculated value 636.3432, measured value 636.3440

[0293] 1H NMR(400MHz,CDCl3)δ7.32-7.22(5H,m,H-5”,H-6”,H-7”,H-8”,H-9”),7.12(1H,s,H-1”),6.16(1H,d,J=3.2Hz,H-13a'),5.58-5.52(2H,m,H-1,H-6'),5.44(1H,d,J=3.2Hz,H-13b'),5.22(1H,d,J=14.4Hz,H-5),4.98(1H,d,J=9.6Hz,H-14a),4.60(1H,d,J=14.4,H-14b),4.53(1H,t,J=10.0Hz,H-6),4.05(2H,d,J=9.6Hz,H-1”),3.03(1H,br s,H-2'),2.86-2.78(1H,m,H-7'),2.31-2.27(2H,m,H-7,H-3a'),2.22 -2.09(4H,m,H-9a,H-8a,H-13),1.99 -1.92(2H,m,H-8b,H-8a'),1.90-1.88(2H,m,H-2a,H-9a'),1.81(3H,s,H-15),1.78-1.75(1H,m,H-9b),1.68(1H,br s,H-2b),1.63(3H,s,H-15'),1.62(1H,br s,H-9b'),1.57-1.55(2H,m,H-3a,H-8b'),1.51-1.48(1H,m,H-3b'),1.42(3H,s,H-14'),1.41(1H,br s,H-3b). 13C NMR (400MHz, CDCl3) δ180.9(C,C-12),170.1(C,C-12'),150.3(C,C-1'),148.0(C,C -11'),145.1(C,C-4),140.0(C,C-5'),139.0(C,C-10),137.0(C,C-4"),136.4(C,C- 2"),130.5(CH,C-1"),128.7(2CH,C-5",C-9"),128.6(2CH,C-6",C-8"),126.5(CH, C-1),125.5(CH,C-5),120.7(CH,C-7"),118.9(CH2,C-13'),83.9(CH,CH-7'),77.3( CH,C-6),72.4(C,C-10'),60.9(C,C-11),56.5(C,C-4'),55.5(CH2,C-14),53.7(CH 2,C-3),46.8(CH,C-7'),45.7(CH,C-7),42.8(CH,C-2'),38.6(CH2,C-9'),37.9(CH2 ,C-13),34.9(CH2,C-3'),32.3(CH2,C-3”),28.1(CH3,C-14’),24.8(CH2,C-9),24. 0(CH2,C-8),24.0(CH2,C-2),23.6(CH2,C-8'),17.7(CH3,C-15'),17.1(CH3,C-15).

[0294] Compound 29

[0295] Yield: 33% (24 mg)

[0296] Molecular formula: C 38 H 43 N3O6

[0297] Molecular weight: 637.7770

[0298] Appearance: White solid

[0299] Optical rotation: (c 0.119, chloroform)

[0300] HRMS(ESI,m / z):[M+H] + [C 38 H 43 N3O6] + Calculated value 638.3225, measured value 638.3306

[0301] 1H NMR(400MHz,CDCl3)δ7.56(1H,s,H-1”),7.31-7.27(2H,m,H-4”,H-8”),6.99-6.95(3H,m,H-5”,H-6”,H-7”),6.15(1H,d,J=2.8Hz,H-13a'),5.63-5.56(2H,m,H-1,H-6'),5.45(1H,d,J=3.2Hz,H-13b'),5.26(1H,d,J=14.4,H-5),5.01(1H,d,J=10.0Hz,H-14a),4.69(1H,d,J=14.4Hz,H-14b),4.56(1H,t,J=10.0Hz,H-6),3.04(1H,br s,H-2'),2.88-2.78(1H,m,H-7'),2.36-2.27(2H,m,H-7,H-3a'),2.21-2.17(4H,m,H-8a,H-9a,H-13),2.13 -2.11(1H,m,H-8b),2.05-2.00(2H,m,H-2a,H-8a'),1.98-1.95(1H,m,H-9a'),1.92-1.86(2H,m,H-2b,H-9b),1.82(3H,s,H-15),1.79-1.76(1H,m,H-9b'),1.71-1.67(1H,m,H-8b'),1.64(3H,s,H-15'),1.57-1.56(2H,m,H-3a,H-3b'),1.42(3H,s,H-14'),1.40(1H,br s,H-3b). 13C NMR(400MHz, CDCl3)δ180.7(C,C-12),170.0(C,C-12'),158.2(C,C-3"),150.6(C ,C-1'),144.9(C,C-11'),144.6(C,C-4),140.0(C,C-5'),136.9(C,C-10),136.2( C,C-2"),130.9(CH,C-1"),129.5(2CH,C-5",C-7"),125.6(CH,C-1),122.1(CH,C -5),121.3(CH,C-6"),118.8(CH2,C-13'),114.8(2CH,C-4",C-8"),83.8(CH,CH-6 '),77.3(CH,C-6),72.4(C,C-10'),60.8(C,C-11),56.5(C,C-4'),55.5(CH2,C-1 4),53.7(CH2,C-3),46.8(CH,C-7'),45.8(CH,C-7),42.8(CH,C-2'),38.5(CH2,C- 9'),37.9(CH2,C-13),34.9(CH2,C-3'),28.0(CH3,C-14'),24.8(CH2,C-9),24.1( CH2,C-8),23.9(CH2,C-2),23.6(CH2,C-8'),17.7(CH3,C-15'),17.0(CH3,C-15).

[0302] Compound 30

[0303] Yield: 30% (19 mg)

[0304] Molecular formula: C 39 H 43 N3O6

[0305] Molecular weight: 649.7880

[0306] Appearance: White solid

[0307] Optical rotation: (c 0.057, chloroform)

[0308] HRMS(ESI,m / z):[M+H] + [C 39 H 43 N3O6] + Calculated value 650.3225, measured value 650.3217

[0309] 1H NMR(500MHz,CDCl3)δ8.42(2H,dd,J=8.5,1.5Hz,H-5",H-9"),8.23(1H,s,H-1"),7.62(1H,t,J=7.0Hz,H-7"),7.52(2H,t,J=8.0Hz,H-6",H-8"),6.16(1H,d,J=3.5Hz,H-13a'),5.74(1H,t,J=6.5,H-1),5.58(1H,d,J=10.0Hz,H-6'),5.46(1H,d,J=3.0Hz,H-13b'),5.36(1H,d,J=14.0Hz,H-4),5.03(1H,d,J=9.5Hz,H-14a),4.79(1H,d,J=14.0Hz,H-14b),4.56(1H,t,J=10.0Hz,H-6),3.04(1H,br s,H-2'),2.88-2.80(1H,m,H-7'),2.38-2.33(1H,m,H-7),2.30(2H,dd,J=11.5,3.5Hz,H-3a'),2.23-2.21(2H,m,H-9a,H-13a),2.16-2.12(1H,m,H-13b),2.03-2.01(1H,m,H-8a),1.98-1.96(1H,m,H-8b),1.91-1.88(1H,m,H-8a'),1.84(3H,s,H-15),1.81-1.76(1H,m,H-2a),1.71(1H,br s,H-9a'),1.67(3H,s,H-15'),1.60(4H,br s,H-2b,H-9b,H-8b',H-9b'),1.56-1.54(2H,m,H-3a,H-3b'),1.43(1H,br s,H-3b),1.43(3H,s,H-14'). 13C NMR(125MHz, CDCl3)δ185.7(C,C-3"),180.7(C,C-12),170.1(C,C-12'),150.4(2C ,C-1',C-2"),148.5(C,C-11'),145.1(C,C-4),139.9(C,C-5'),136.4(C,C-10),13 5.7(C,C-4"),132.2(CH,C-7"),132.1(CH,C-1"),130.6(CH,C-5"),128.4(CH,C-6" ),128.4(CH,C-8"),127.8(CH,C-1),125.5(CH,C-5),118.9(CH2,C-13'),83.8(CH, CH-6'),77.2(CH,C-6),72.5(C,C-10'),60.8(C,C-11),56.5(C,C-4'),55.8(CH2, C-14),53.7(CH2,C-3),46.8(CH,C-7'),45.8(CH,C-7),42.8(CH,C-2'),38.6(CH2, C-9'),37.8(CH2,C-13),34.9(CH2,C-3'),28.0(CH3,C-14'),24.9(CH2,C-9),23.9 (CH2,C-8),23.8(CH2,C-2),23.6(CH2,C-8'),17.8(CH3,C-15'),17.1(CH3,C-15).

[0310] Compound 31

[0311] Yield: 55% (35 mg)

[0312] Molecular formula: C 38 H 49 N3O5

[0313] Molecular weight: 627.8260

[0314] Appearance: White solid

[0315] Optical rotation: (c 0.085, chloroform)

[0316] HRMS(ESI,m / z):[M+H] + [C 38 H 49 N3O5] + Calculated value 628.3686, measured value 628.3701

[0317] 1H NMR(400MHz,CDCl3)δ7.17(1H,s,H-1”),6.15(1H,d,J=3.4Hz,H-13a'),5.59-5.55(2H,m,H-1,H-6'),5.43(1H,d,J=3.2Hz,H-13b'),5.21(1H,d,J=14.4Hz,H-5),5.00(1H,d,J=10.0Hz,H-14a),4.61(1H,d,J=14.4Hz,H-14b),4.54(1H,t,J=10.0Hz,H-6),3.01(1H,br s,H-2'),2.85-2.77(1H,m,H-7'),2.75-2.68(1H,m,H-3a'),2.36-2.33(1H,m,H-3”),2.30-2.25(2H,m,H-7,H-3a'),2.20-2.18(2H,m,H-13),2.16-2.13(1H,m,H-9a),2.11(1H,br s,H-8a),2.02-1.98(4H,m,H-2a,H-8b,H-8a',H-9a'),1.95-1.89(2H,m,H-4a”,H-8a”),1.86-1.84(1H,m,H-2b),1.81(3H,s,H-15),1.79-1.77(3H,m H-9b',H-4b”,H-8b”),1.72-1.68(2H,m,H-8b',H-5a”),1.63(3H,s,H-15'),1.62(1H,br s,H-7a”),1.57-1.55(2H,m,H-5b”,H-7b”),1.51-1.48(1H,m H-3a),1.43(1H,br s,H-3b'),1.41(3H,s,H-14'),1.37(2H,br s,H-6”),1.35(1H,br s,H-3b). 13C NMR(400MHz, CDCl3)δ180.9(C,C-12),170.0(C,C-12'),154.0(C,C-2"),150.4(C, C-1'),145.1(C,C-11'),140.0(C,C-4),136.7(C,C-5'),130.2(C,C-10),129.4(CH ,C-1),125.6(CH,C-5),118.7(CH2,C-13'),118.6(CH,C-1"),83.9(CH,CH-6'),77. 3(CH,C-6),72.4(C,C-10'),61.0(C,C-11),56.5(C,C-4'),55.4(CH2,C-14),53.7( CH2,C-3),46.8(CH,C-7'),45.8(CH,C-7),42.8(CH,C-2'),38.6(CH2,C-9'),38.0 (CH2,C-13),35.3(CH,C-3"),34.9(CH2,C-3'),33.0(CH2,C-4"),32.9(CH2,C-8"), 28.1(CH3,C-14'),26.1(2CH2,C-5",C-7"),26.0(CH2,C-6"),24.8(CH2,C-9),24.1 (CH2,C-8),23.9(CH2,C-2),22.4(CH2,C-8'),17.7(CH3,C-15'),17.0(CH3,C-15).

[0318] Compound 32

[0319] Yield: 27% (17 mg)

[0320] Molecular formula: C 38 H 49 N3O5

[0321] Molecular weight: 615.8150

[0322] Appearance: White solid

[0323] Optical rotation: (c 0.050, chloroform)

[0324] HRMS(ESI,m / z):[M+H] + [C 38 H 49 N3O5] + Calculated value 616.3745, measured value 616.3727

[0325] 1H NMR(500MHz,CDCl3)δ7.20(1H,s,H-1"),6.16(1H,d,J=3.5Hz,H-13'),5.59(1H,t,J=8.5Hz,H-1),5.57(1H,d,J=10.5Hz,H-6'),5.45(1H,d,J=3.0Hz,H-13a'),5.23(1H,d,J=14.5Hz,H-5),5.00(1H,d,J=10.0Hz,H-14a),4.63(1H,d,J=14.5Hz,H-14b),4.54(1H,t,J=10.0Hz,H-6),3.03(1H,br s,H-2'),2.85-2.79(1H,m,H-7'),2.67(2H,td,J=7.5,4.0Hz,H-3"),2.37-2.33(1H,m,H-7),2.30(1H,dd,J=12.5,4.0Hz,H-3a'),2.23-2.18(2H,m,H-9a,H-13a),2.17-2.12(1H,m,H-13b),2.05-2.02(1H,m,H-8a),2.01-1.96(3H,m,H-2a,H-8b,H-8a'),1.94-1.89(2H,m,H-9a,H-9a'),1.88-1.86(1H,m,H-2b),1.82(3H,s,H-15),1.80-1.77(1H,m,H-9b'),1.69-1.67(1H,m,H-8b'),1.65(3H,s,H-15'),1.64-1.62(2H,m,H-4"),1.58-1.56(2H,m,H-3a,H-3b'),1.51(1H,dd,J=12.5,2.5Hz,H-3b),1.42(3H,s,H-14'),1.34-1.31(4H,m,H-5",H-6"),0.88(3H,t,J=10.0Hz,H-7"). 13CNMR(125MHz,CDCl3)δ180.9(C,C-12),170.1(C,C-12'),150.3(C,C-1'),148.9( C,C-11'),145.2(C,C-4),139.9(C,C-5'),136.7(2C,C-10,C-2"),130.3(CH,C-1 ),125.5(CH,C-5),119.9(CH,C-1"),118.9(CH2,C-13'),83.9(CH,CH-6'),77.4( CH,C-6),72.4(C,C-10'),61.0(C,C-11),56.5(C,C-4'),55.4(CH2,C-14),53.7(C H2,C-3),46.8(CH,C-7'),45.7(CH,C-7),42.8(CH,C-2'),38.6(CH2,C-9'),38.0 (CH2,C-13),34.9(CH2,C-3'),31.4(CH2,C-3"),29.1(CH2,C-5"),28.1(CH3,C-1 4'),25.7(CH2,C-4"),24.8(CH2,C-9),24.0(CH2,C-8),24.0(CH2,C-2),23.7(CH 2,C-8'),22.4(CH2,C-6"),17.7(CH3,C-15'),17.1(CH3,C-15),14.0(CH3,C-7").

[0326] Compound 33

[0327] Yield: 48% (30 mg)

[0328] Molecular formula: C 36 H 41 SN3O5

[0329] Molecular weight: 627.8000

[0330] Appearance: White solid

[0331] Optical rotation: (c 0.084, chloroform)

[0332] HRMS(ESI,m / z):[M+H] + [C 36 H 41 SN3O5] + Calculated value 628.2840, measured value 628.2843

[0333] 1H NMR(500MHz,CDCl3)δ7.75(1H,d,J=8.7Hz,H-1"),7.42(2H,td,J=16.6,4.4Hz,H-4",H-6"),7.12(1H,dd,J=13.4,5.1Hz,H-5"),6.17(1H,d,J=3.4Hz,H-13a'),5.67(1H,t,J=6.4Hz,H-1),5.59(1H,d,J=10.1Hz,H-6'),5.45(1H,d,J=3.1Hz,H-13b'),5.23(1H,d,J=14.6Hz,H-5),5.06(1H,d,J=10.1Hz,H-14a),4.93(1H,d,J=14.5Hz,H-14b),4.57(1H,t,J=9.9Hz,H-6),3.04(1H,br s,H-2'),2.85-2.79(1H,m,H-7'),2.41-2.37(1H,m,H-3a'),2.36-2.31(1H,m,H-7),2.20-2.16(1H,m,H-9a),2.15-2.11(1H,m,H-13a),2.05-2.02(1H,m,H-13b),2.01-1.97(2H,m,H-8),1.94-1.90(2H,m,H-2a,H-8a'),1.88-1.85(1H,m,H-9a'),1.83(3H,s,H-15),1.80-1.78(1H,m,H-9b),1.70-1.66(1H,m,H-2b),1.67(3H,s,H-15'),1.62-1.60(3H,m,H-3a,H-8b',H-9b'),1.53-1.50(2H,m,H-3b,H-3a'),1.43(3H,s,H-14'). 13C NMR(125MHz,CDCl3)δ180.8(C,C-12),170.1(C,C-12'),150.3(C,C-1'),14 5.2(C,C-11'),144.6(C,C-4),140.0(C,C-5'),137.2(C,C-3"),132.2(C,C- 2"),130.7(CH,C-1"),129.6(CH,C-4"),127.7(CH,C-5"),126.0(CH,C-1), 125.2(CH,C-5),118.9(CH2,C-13'),83.9(CH,CH-6'),77.43(CH,C-6),72.5 (C,C-10'),60.8(C,C-11),56.5(C,C-4'),54.6(CH2,C-14),53.7(CH2,C-3 ),46.8(CH,C-7'),45.8(CH,C-7),42.8(CH,C-2'),38.6(CH2,C-9'),38.0(C H2,C-13),34.9(CH2,C-3'),28.1(CH3,C-14'),24.8(CH2,C-9),24.5(CH2,C -8),23.9(CH2,C-2),23.7(CH2,C-8'),17.8(CH3,C-15'),17.1(CH3,C-15).

[0334] Compound 34

[0335] Yield: 63% (39 mg)

[0336] Molecular formula: C 37 H 42 N4O5

[0337] Molecular weight: 622.7660

[0338] Appearance: White solid

[0339] Optical rotation: (c 0.036, chloroform)

[0340] HRMS(ESI,m / z):[M+H] + [C 37 H 42 N4O5] + Calculated value 623.3228, measured value 623.3203

[0341] 1H NMR(500MHz,CDCl3)δ8.57-8.51(1H,m,H-1"),8.17-8.15(1H,m,H-1"),8.11(s,1H),7.78(1H,td,J=7.5,2.0Hz,H-4",H-6"),6.16(1H,d,J=3.5Hz,H-13a'),5.72(1H,t,J=6.4Hz,H-1),5.59(1H,d,J=10.1Hz,H-6'),5.45(1H,d,J=3.0Hz,H-13b'),5.34(1H,d,J=14.5Hz,H-5),5.02(1H,d,J=10.0Hz,H-14a),4.74(1H,d,J=16.0Hz,H-14b),4.55(1H,t,J=10.0Hz,H-6),3.04(1H,br s,H-2'),2.85-2.79(1H,m,H-7'),2.39-2.34(1H,m,H-7),2.30(1H,dd,J=12.5,4.0Hz,H-3a'),2.23-2.19(2H,m,H-9a,H-13a),2.17-2.12(1H,m,H-13b),2.03-1.99(2H,m,H-8),1.96-1.90(2H,m,H-2a,H-8a'),1.82(3H,s,H-15),1.80-1.76(1H,m,H-9a'),1.73(1H,br s,H-9b),1.68(3H,s,H-15'),1.64(2H,br s,H-2b,H-9b'),1.61(1H,br s,H-8b'),1.58-1.57(1H,m,H-3a),1.52(1H,dd,J=14.5Hz,H-3b'),1.44(1H,br s,H-3b),1.43(3H,s,H-14'). 13C NMR (125MHz, CDCl3) δ180.8(C,C-12),170.1(C,C-12'),150.3(C,C-1'),150.2( C,C-3"),149.4(CH,C-7"),148.7(C,C-11'),145.2(C,C-4),140.0(C,C-5'),13 7.0(CH,C-5"),136.1(C,C-10),131.5(CH,C-1"),125.5(CH,C-1),123.0(CH,C- 5),121,3(CH,C-4"),120.2(CH,C-6"),118.9(CH2,C-13'),83.9(CH,CH-6'),77. 3(CH,C-6),72.4(C,C-10'),60.9(C,C-11),56.5(C,C-4'),55.8(C,CH2-14),53 .7(CH2,C-3),46.8(CH,C-7'),45.8(CH,C-7),42.8(CH,C-2'),38.6(CH2,C-9') ,37.9(CH2,C-13),34.9(CH2,C-3'),28.1(CH3,C-14'),24.9(CH2,C-9),23.9(C H2,C-8),23.9(CH2,C-2),23.6(CH2,C-8'),17.7(CH3,C-15'),17.1(CH3,C-15).

[0342] Embodiment 11:

[0343] To evaluate the cytotoxic activity of germane-guaiacyl sesquiterpene dimers 1-34 against hepatoma cell lines.

[0344] 1. Materials and Methods

[0345] 1.1 Materials

[0346] Hepatocellular carcinoma cell lines (HepG2, Huh7 and SK-Hep-1) were purchased from Shanghai Jining Biotechnology Co., Ltd.; culture medium (Dulbecco's Modified Eagle Medium, DMEM) was purchased from Thermo Fisher Scientific (Suzhou, China); serum (fetal bovine serum, FBS) was purchased from Life Technologies (NY, USA); RPMI-1640 was purchased from ThermoFisher Biochemical Products (Beijing, China).

[0347] 1.2 Instruments

[0348] Flex Station 3 multifunctional microplate reader (Bio-RAD 680, USA); analytical balance (AG135, Metler Toledo, China); constant temperature box (DHP-9082, Shanghai).

[0349] 1.3 Experimental process

[0350] 1). Take the hepatoma cells in logarithmic phase, discard the old culture medium, wash twice with PBS, and discard the PBS;

[0351] 2) Digest the cells with 0.25% trypsin. When the cell outline becomes darker and tends to become round under the microscope, quickly remove the trypsin.

[0352] 3) Use DMEM complete medium containing 10% FBS to stop digestion and resuspend the cells. Take 10 μL of cell suspension, count with a cell counter, and adjust the cell concentration to 1×10 4 / mL, inoculated on a 96-well plate, 100 μL of cell suspension was added to each well, and incubated in a 37°C, 5% CO2 incubator for 24 h to allow the cells to adhere;

[0353] 4). Aspirate the culture medium and add the diluted sample to the plate, add 100 μL to each well, set up 3 replicate wells for each concentration, and continue incubating in the incubator for 48 hours;

[0354] 5). Aspirate the culture medium, add the prepared MTT solution (1 mg / mL), add 100 μL to each well, and incubate in the incubator for 4 hours;

[0355] 6). Aspirate the MTT solution, add DMSO, add 100 μL to each well, and incubate in the incubator for 10 minutes;

[0356] 7). Use an ELISA reader to measure the absorbance at 490 nm, and calculate the cell inhibition rate using the formula: inhibition rate = (negative - experimental group) / (negative - blank group) × 100%, and use the statistical software GraphPad prism 5 to calculate IC 50 , the experiment was repeated 3 times.

[0357] 2. Results

[0358] The cytotoxic activities of compounds 1-34 against three liver cancer cell lines (HepG2, Huh7 and SK-Hep-1) are shown in Table 1. Most of the compounds have certain cytotoxic activities against the three liver cancer cell lines, among which compound 23 has the best activity, with IC 50 The values ​​were 4.4, 3.7, and 3.1 μM, respectively, which were better than the positive drug sorafenib. The fluorine-substituted derivative 4 had obvious cytotoxicity, and the IC 50The values ​​were 6.0 (HepG2), 4.4 (Huh7) and 9.9 μM (SK-Hep-1), respectively. The enhanced cytotoxicity of compounds 5-7 indicated that C-14' esterification was beneficial to anti-hepatocarcinoma activity. The phenylated products 8-10 showed similar cytotoxicity to compound 2, while compound 11 with a para-fluorine substituent on the aromatic ring enhanced the cytotoxicity. Among the carbamate derivatives 12-15, the para-substituted compounds 14 and 15 showed better activity than the ortho-substituted and meta-substituted compounds (12 and 13). The cytotoxicity of azide 16 was 3.3 times, 1.6 times and 2.5 times that of sorafenib, respectively, with an IC 50 The values ​​were 3.6, 5.1 and 3.5 μM, respectively. Compound 17, which contains a primary amine group, is the weakest compound among the dimers. The urea-containing analogue 19 has the strongest inhibitory effect on Huh7 cells, with an IC 50 The value was 2.1 μM, which was 4 times stronger than sorafenib. Compounds 20-34 had different groups of activity in the 1,2,3-triazole part, IC 50 The values ​​ranged from 3.1 to 69.2 μM. For compounds 20-27 with an aromatic group at the C-4 position of the 1,2,3-triazole moiety, the methyl-substituted derivative 23 showed stronger activity than the ortho-methyl and meta-methyl-substituted derivatives, and its cytotoxicity was 2.7, 2.2, and 2.8 times that of sorafenib. When the methyl substituent was replaced by fluorine, chlorine, methoxy, or nitro, the obtained compounds 24-27 had relatively weaker cytotoxicity. Compounds 28-32 and compound 34 had stronger anti-hepatocellular carcinoma activity, with IC 50 The values ​​were 4.9-29.1 μM.

[0359] Table 1. Inhibitory activity of compounds 1-34 against three liver cancer cells

[0360]

[0361]

[0362] 3. Conclusion

[0363] The above results indicate that the new germarane-guaiacane sesquiterpene dimer 1-34 is cytotoxic to three liver cancer cell lines (HepG2, Huh7 and SK-Hep-1) and can be used as a drug to treat liver cancer-related diseases.

[0364] Formulation Examples 1-7:

[0365] In the following formulation examples, conventional reagents are selected and the formulations are prepared according to conventional methods. This application example only reflects that at least one of the compounds 1-34 described in the present invention can be prepared into different formulations, and the specific reagents and operations are not specifically limited:

[0366] 1. Dissolve at least one of the compounds 1-34 in DMSO, add water for injection according to conventional methods, filter, and sterilize by filling to prepare an injection solution, wherein the concentration of the injection solution is 0.5 to 5 mg / mL.

[0367] 2. Dissolve at least one of the compounds 1-34 in DMSO, dissolve it in sterile water for injection, stir to dissolve it, filter it with a sterile suction funnel, filter it with sterile fine filtration, pack it into ampoules, freeze-dry it at low temperature, and seal it with sterile sealing to obtain a powder injection.

[0368] 3. Add at least one of compounds 1-34 to an excipient at a mass ratio of 9:1 to the excipient to prepare a powder.

[0369] 4. Add at least one of compounds 1-4 to the excipient at a mass ratio of 5:1, and granulate and tablet.

[0370] 5. Prepare at least one of the compounds 1-34 into an oral liquid according to a conventional oral liquid preparation method.

[0371] 6. Add at least one of the compounds 1-34 to the excipient at a mass ratio of 5:1 to the excipient to prepare capsules.

[0372] 7. Add at least one of the compounds 1-34 to the excipient at a mass ratio of 5:1 to the excipient to prepare granules.

[0373] From the above examples, it can be seen that the present invention provides a preparation method and application of a germarane-guaiacyl sesquiterpene dimer, a pharmaceutical composition and its application. The new germarane-guaiacyl sesquiterpene dimer 1-34 provided by the present invention has different degrees of cytotoxic activity against liver cancer cells, can be combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition, and can be used to prepare an anti-liver cancer drug.

[0374] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. Germazane-guaiacyl sesquiterpene dimer 1-34 as shown in the following structural formula, 2. The method for preparing the germazane-guaiacane sesquiterpene dimer 1-34 represented by the structural formula according to claim 1, characterized in that: The reaction formula is as follows: Wherein, the structures of R and R1 correspond to the structures of compounds 1-34 in claim 1 respectively; The key reaction steps are: Preparation of the germarane-guaiacane sesquiterpene dimer 1-3, i.e., compound 1-3: a guaiacane-type diene is reacted with a germarane-type sesquiterpene dienophile under appropriate conditions through a Diels–Alder reaction and dedimethylamine to obtain the germarane-guaiacane sesquiterpene dimer 1-3, wherein the appropriate conditions for the Diels–Alder reaction are that the diene and the dienophile are heated to react under solvent-free conditions; Preparation of Germazane-Guaiacene Sesquiterpene Dimer 4, i.e., Compound 4: Compound 2 was reacted with DAST at -78°C using dichloromethane as solvent to obtain fluorinated compound 4; Preparation of the germane-guaiacane sesquiterpene dimer 5-11, i.e., compound 5-11: Compound 2 is subjected to esterification reaction and substitution reaction with an acid anhydride and an aromatic halide under appropriate conditions to obtain compounds 5-7 and 8-11, respectively. The appropriate conditions for the esterification reaction are: using dichloromethane as a solvent and DMAP as a condensing agent, and reacting compound 2 with an acid anhydride at room temperature; the appropriate conditions for the substitution reaction are: using dichloromethane as a solvent, and reacting compound 2 with an aromatic halide in the presence of silver oxide at room temperature; Preparation of the germarane-guaiacane sesquiterpene dimer 12-15, i.e., compound 12-15: Compound 2 is reacted with N,N'-carbonylbis(1,2,4-triazole) and a benzylamine compound under appropriate conditions to obtain compound 12-15, wherein the appropriate conditions are that dichloromethane is used as a solvent, and compound 2 reacts with N,N'-carbonylbis(1,2,4-triazole) and a benzylamine compound at room temperature; Preparation of the germane-guaiacyl sesquiterpene dimer 16-19, i.e., compound 16-19: using tetrahydrofuran as solvent, compound 2 reacts with DPPA and DBU at 0°C to prepare azide compound 16; using tetrahydrofuran-water as solvent, compound 16 reacts with triphenylphosphine at room temperature to prepare amino compound 17; using dichloromethane as solvent, compound 17 reacts with benzoic anhydride and triethylamine at room temperature to prepare amide compound 18; using tetrahydrofuran as solvent, compound 17 reacts with 2-phenylethyl isocyanate and triethylamine at 0°C to obtain compound 19; Preparation of the germane-guaiacane sesquiterpene dimer 20-34, i.e., compound 20-34: Using acetonitrile-water as solvent, the azide compound 16 reacts with an alkynyl compound, cuprous iodide, and triethylamine at room temperature to prepare compound 20-34.

3. Use of the germarane-guaiacane sesquiterpene dimer 1-34 shown in the structural formula of claim 1 in the preparation of anti-liver cancer drugs.

4. A pharmaceutical composition comprising at least one of the germarane-guaiacane sesquiterpene dimers 1-34 shown in the structural formula of claim 1 and a pharmaceutically acceptable carrier.

5. Use of the pharmaceutical composition according to claim 4 in the preparation of anti-liver cancer drugs.

6. The method for preparing the pharmaceutical composition according to claim 4, characterized in that: The method comprises the following steps: preparing compound 1-34 by the preparation method according to claim 2, taking at least one of the compounds 1-34, and adding a pharmaceutically acceptable carrier.

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