Dehydrocostunolide derivative as well as preparation method and medical application thereof

Abstract

The invention discloses a dehydrocostunolide derivative as well as a preparation method and medical application thereof, and belongs to the technical field of chemical synthesis, the dehydrocostunolide derivative is shown as a general formula I. The compound has a certain inhibition effect on HBsAg and HBeAg, can be used for preparing anti-HBV drugs, and can be used for preparing medicines for treating HBV. More efficient and safe candidate drug molecules are provided for clinical anti-hepatitis B virus treatment. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a dehydrocostus lactone derivative and a preparation method and medical application thereof. Background Art

[0002] Hepatitis B virus (HBV) can cause acute and chronic hepatitis in humans, induce cirrhosis or liver cancer, and affect the lives and livelihoods of more than 2 billion people worldwide. Although the hepatitis B vaccine has been successfully developed and used, there are still more than 350 million HBV carriers in the world, and 500,000 to 1.5 million people die from hepatitis B virus infection every year. China is the largest country infected with hepatitis B virus, with about 130 million HBV carriers and about 300,000 people dying from HBV infection every year. Nucleoside drugs act on HBV DNA polymerase. Although they have obvious anti-hepatitis B virus effects, they cannot completely eliminate the virus in the patient's body, and long-term use is prone to drug resistance. Therefore, anti-hepatitis B virus drugs have limited structural types, a single target, high toxicity in clinical application, and are prone to drug resistance. At the same time, there are also problems of low bioavailability and rapid metabolism.

[0003] Natural products play an important role in the research of antiviral drugs as prototype drugs or lead compounds. Dehydrocostus lactone has significant anti-HBV activity, but it has problems such as poor water solubility, poor stability, and low oral bioavailability. Therefore, it is structurally modified in the hope of obtaining low-toxicity, high-activity, and high-bioavailability costus lactone derivatives. Summary of the invention

[0004] In view of this, one of the purposes of the present invention is to provide dehydrocostus lactone derivatives and preparation methods and medical applications thereof, so as to provide more efficient and safe candidate drugs for clinical anti-HBV treatment.

[0005] In order to achieve the above object, the present invention provides the following technical solutions:

[0006] Dehydrocostus lactone derivatives, the structure of which is shown in general formula I:

[0007]

[0008] In the formula,

[0009] R1 is selected from hydrogen, hydroxyl;

[0010] R2 is selected from hydrogen, hydroxyl, and ester;

[0011] Z is selected from -C=CH2, -CR3CH2R4;

[0012] R3 is selected from hydrogen, hydroxyl;

[0013] R4 is selected from hydroxyl group and ester group;

[0014] Q is selected from one of alkenyl, alkyl, oxirane, and difluorocyclopropyl;

[0015] W is selected from alkenyl, alkyl, ethylene oxide, and difluorocyclopropyl.

[0016] Preferably, R1 is hydrogen or hydroxyl;

[0017] R2 is hydrogen, hydroxyl, or ester;

[0018] Z is -C=CH2, -CR3CH2R4;

[0019] R3 is hydrogen or hydroxyl;

[0020] R4 is an ester group;

[0021] Q is selected from alkenyl, ethylene oxide;

[0022] W is selected from alkenyl and ethylene oxide.

[0023] Furthermore, the dehydrocostus lactone derivative is any one of the following compounds:

[0024]

[0025]

[0026]

[0027] The present application also provides a pharmaceutically acceptable salt of the above-mentioned dehydrocostus lactone derivative, wherein the pharmaceutically acceptable salt is a hydrochloride, a bromate, an iodate, a sulfate, a nitrate, a trifluoroacetate or an acetate.

[0028] The present application also provides a method for preparing the above-mentioned dehydrocostus lactone derivative, which is as follows:

[0029] a. Preparation of dehydrocostus lactone derivatives I-1 to 33: reacting dehydrocostus lactone with different amines in tetrahydrofuran in the presence of triethylamine to obtain costus lactone derivatives I-1 to 33 represented by general formula I;

[0030] b. Preparation of intermediate II: In the presence of potassium osmate dihydrate and N-methylmorpholine-N-oxide, dehydrocostus lactone is oxidized in a mixed solution of tert-butyl alcohol / tetrahydrofuran / water to obtain intermediate II;

[0031]

[0032] c. Preparation of dehydrocostus lactone derivative I-34: In the presence of DMAP, EDCI and DIPEA, intermediate II is subjected to esterification reaction with nicotinic acid in tetrahydrofuran to obtain dehydrocostus lactone derivative I-34 represented by general formula I;

[0033] d. Preparation of intermediates III and IV: In the presence of selenium dioxide and tert-butyl hydroperoxide, dehydrocostus lactone is subjected to allylic oxidation in anhydrous dichloromethane to obtain intermediates III and IV;

[0034]

[0035] e. Preparation of dehydrocostus lactone derivatives I-35-37: In the presence of m-chloroperbenzoic acid, the intermediate III is oxidized in anhydrous dichloromethane to obtain dehydrocostus lactone derivatives I-35-37 represented by general formula I;

[0036] f. Preparation of dehydrocostus lactone derivatives I-38-46: In the presence of DMAP, EDCI and DIPEA, intermediate III is subjected to esterification reaction with different carboxylic acids in tetrahydrofuran to obtain dehydrocostus lactone derivatives I-38-46 represented by general formula I;

[0037] g. Preparation of dehydrocostus lactone derivatives I-47 to 49: In the presence of triethylamine, the intermediate III is reacted with different amines in tetrahydrofuran to obtain costus lactone derivatives I-47 to 49 represented by the general formula I;

[0038] h. Preparation of dehydrocostus lactone derivatives I-50 and I-51: In the presence of m-chloroperbenzoic acid, the intermediate IV is oxidized in anhydrous dichloromethane to obtain dehydrocostus lactone derivatives I-50 and I-51 represented by general formula I;

[0039] i. Preparation of dehydrocostus lactone derivatives I-52-61: In the presence of DMAP, EDCI and DIPEA, intermediate IV is subjected to esterification reaction with different carboxylic acids in tetrahydrofuran to obtain dehydrocostus lactone derivatives I-52-61 represented by general formula I;

[0040] j. Preparation of dehydrocostus lactone derivatives I-62-64: In the presence of triethylamine, the intermediate IV is reacted with different amines in tetrahydrofuran to obtain costus lactone derivatives I-62-64 represented by the general formula I;

[0041] Preferably,

[0042] In step a, the ratio of the amount of dehydrocostus lactone to triethylamine and amine substance is 1:1:3;

[0043] In step b, the molar ratio of dehydrocostus lactone to potassium osmate dihydrate and N-methylmorpholine-N-oxide is 1:0.5:1.5;

[0044] In step c, the molar ratio of the intermediate II to DMAP, EDCI, DIPEA and nicotinic acid is 1:0.2:2:2:2;

[0045] In step d, the ratio of the amount of dehydrocostus lactone to selenium dioxide and tert-butyl hydroperoxide is 1:1:0.004;

[0046] In step e, the molar ratio of the intermediate III to meta-chloroperbenzoic acid is 1:3;

[0047] In step f, the molar ratio of the intermediate III to DMAP, EDCI, DIPEA and carboxylic acid is 1:0.2:2:2:2;

[0048] In step g, the ratio of the amount of the intermediate III to triethylamine and the amine substance is 1:1:3;

[0049] In step h, the molar ratio of the intermediate IV to meta-chloroperbenzoic acid is 1:3;

[0050] In step i, the molar ratio of the intermediate IV to DMAP, EDCI, DIPEA and carboxylic acid is 1:0.2:2:2:2;

[0051] In step j, the ratio of the amount of the intermediate IV to triethylamine and the amount of the amine substance is 1:1:3.

[0052] The present application also provides the use of the above-mentioned dehydrocostus lactone derivatives in the preparation of anti-HBV drugs.

[0053] The present application also provides the use of the pharmaceutically acceptable salt of the above-mentioned dehydrocostus lactone derivative in the preparation of anti-HBV drugs.

[0054] The present application also provides an anti-HBV pharmaceutical preparation of the above-mentioned dehydrocostus lactone derivative.

[0055] The present application also provides an anti-HBV pharmaceutical preparation of a pharmaceutically acceptable salt of the above-mentioned dehydrocostus lactone derivative.

[0056] The technical solution provided by the embodiments of the present application may have the following beneficial effects:

[0057] It can be seen from the above embodiments that the present application provides dehydrocostus lactone derivatives, preparation methods and medical applications thereof. The present invention designs and synthesizes a series of dehydrocostus lactone derivatives based on the modification of different sites of dehydrocostus lactone. These compounds have been found to have certain inhibitory activity against HBsAg and HbeAg through in vitro HBV activity detection, and can be used to prepare HBV drugs, providing more efficient and safe candidate drug molecules for clinical anti-hepatitis B virus treatment.

[0058] It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the present application. DETAILED DESCRIPTION

[0060] The terms used in this application are for the purpose of describing specific embodiments only and are not intended to limit this application. The singular forms of "a", "said" and "the" used in this application and the appended claims are also intended to include plural forms unless the context clearly indicates other meanings. It should also be understood that the term "and / or" used herein refers to and includes any or all possible combinations of one or more associated listed items.

[0061] Example 1. Preparation of Compound I-1

[0062]

[0063] A mixture of dehydrocostus lactone (86.80 μmol, 1 equiv), triethylamine (86.80 μmol, 1 equiv), n-hexylamine (26.00 mmol, 3 equiv) and tetrahydrofuran (0.3 mL) was heated at 50° C. for 2 hours. After the reaction was completed, the solvent was removed under vacuum to obtain a crude product, which was further purified by silica gel column chromatography to obtain a colorless oily compound I-1 (40.0%). 1H NMR (600MHz, CDCl3-d) δ5.18(q,J=2.5Hz,1H),5.04(q,J=2.4Hz,1H),4.87(s,1H),4.76(s,1H),3.96(t,J=9.5Hz,1H),2.90(dd,J=12.1,4.3Hz ,1H),2.87(dd,J=8.1,4.2Hz,1H),2.84–2.80(m,1H),2.79–2.76(m,1H) ,2.60(q,J=7.0Hz,2H),2.57–2.47(m,2H),2.47–2.43(m,1H),2.41(dd, J=7.3,4.3Hz,1H),2.24(tdd,J=11.7,9.5,3.1Hz,1H),2.15–2.09(m,1H),2.03(td,J=12.3,5.2Hz,1H),1.94(ddt,J=13.3,9.5,7.8Hz,1H),1.8 8–1.82(m,1H),1.49(dq,J=14.8,7.4Hz,2H),1.31(d,J=5.3Hz,1H),1.30(d,J=3.9Hz,2H),1.28(q,J=2.0Hz,2H),1.24(s,2H),0.88(s,2H)ppm; 13 C NMR (150MHz, CDCl3-d) δ178.2,151.9,150.0,112.0,109.3,86.0,52.0,50.4, 48.1,47.3,47.1,45.4,37.8,32.7,32.7,31.9,30.3,29.9,27.1,22.8,14.2.

[0064] Example 2. Preparation of Compound I-2

[0065]

[0066] According to the steps of Example 1, only 3-isopropoxypropylamine was used to replace n-hexylamine, and other reaction conditions remained unchanged. The colorless oily compound I-2 (44.8%) was obtained by purification by silica gel column chromatography. 1H NMR (600MHz, CDCl3-d) δ5.21–5.12(m,1H),5.03(q,J=2.3Hz,1H),4.86(d,J=1.3 Hz,1H),4.76(t,J=1.3Hz,1H),3.95(t,J=9.5Hz,1H),3.56–3.52(m,1H),3.47(td ,J=6.3,1.5Hz,2H),2.90(dd,J=12.2,4.3Hz,1H),2.87(dd,J=8.0,4.2Hz,1H),2. 84–2.80(m,1H),2.80–2.77(m,1H),2.70(td,J=6.9,2.2Hz,2H),2.51(dddd,J=19 .5,17.8,8.7,3.2Hz,2H),2.45(t,J=4.5Hz,1H),2.40(ddd,J=11.4,6.8,4.3Hz, 1H),2.26(tdd,J=11.7,9.7,3.2Hz,1H),2.12(ddt,J=12.8,5.1,3.6Hz,1H),2.03 (td,J=12.2,5.2Hz,1H),1.94(ddt,J=13.3,9.6,7.9Hz,1H),1.88–1.82(m,1H),1 .74(p,J=6.4Hz,2H),1.34(dtd,J=13.0,11.6,5.0Hz,1H),1.16–1.13(m,6H)ppm; 13 C NMR (150MHz, CDCl3-d) δ178.1,151.9,150.0,112.0,109.3,85.9,71.6,66.5,52.0,48.1,47.8,47.4,47.1,45.4,37.8,32.7,32.7,30.3,22.2ppm.

[0067] Example 3. Preparation of Compound I-3

[0068]

[0069] According to the steps of Example 1, only cyclopropylmethylamine was used to replace n-hexylamine, and other reaction conditions remained unchanged. The colorless oily compound I-3 (45.6%) was obtained by purification by silica gel column chromatography. 1H NMR (600MHz, CDCl3-d) δ5.18(q,J=2.5Hz,1H),5.03(q,J=2.4Hz,1H),4.86(s,1H),4.76(s,1H),3.95(t,J=9.5Hz,1H),2.92(dd,J=12.1,4.2Hz,1H),2 .88(td,J=8.2,4.1Hz,1H),2.82(d,J=7.3Hz,1H),2.80(d,J=7.3Hz,1H),2. 54(ddd,J=17.1,8.5,2.0Hz,1H),2.47(d,J=6.5Hz,2H),2.45(d,J=1.9Hz,1 H),2.41(ddd,J=11.6,7.2,4.3Hz,1H),2.25(tdd,J=12.1,9.6,3.3Hz,1H), 2.15–2.12(m,1H),2.12–2.09(m,1H),2.04(td,J=12.3,5.1Hz,1H),1.96–1 .90(m,1H),1.85(tq,J=8.7,4.2Hz,1H),1.34(qd,J=11.7,5.0Hz,1H),0.93 (ddt,J=9.8,7.2,3.8Hz,1H),0.49–0.46(m,2H),0.12(q,J=4.7Hz,2H)ppm; 13 C NMR (150MHz, CDCl3-d)178.2,151.9,150.0,112.0,109.2,85.9,55.3,52.0,48.0,47.4,47.1,45.4,37.8,32.7,32.6,30.3,11.2,3.6,3.5ppm.

[0070] Example 4. Preparation of Compound I-4

[0071]

[0072] According to the steps of Example 1, only N-tert-butyloxycarbonyl-1,2-ethylenediamine was used to replace n-hexylamine, and other reaction conditions remained unchanged. White solid compound I-4 (72.3%) was obtained by purification by silica gel column chromatography. 1H NMR (600MHz, CDCl3-d) δ5.15(s,1H),5.02(s,1H),4.85(s,1H),4.75(s,1H),3.94(t,J=9. 5Hz, 1H), 3.21 (q, J=5.8Hz, 2H), 2.88 (ddd, J=21.7, 10.0, 4.1Hz, 2H), 2.78 (td, J=14.3, 12. 2,7.9Hz,1H),2.72(t,J=5.9Hz,2H),2.58–2.41(m,2H),2.40–2.33(m,1H),2.30–2.20(m,1 H),2.17–1.97(m,2H),1.97–1.88(m,1H),1.87–1.79(m,1H),1.42(s,9H),1.32(m,1H)ppm; 13 C NMR (150MHz, CDCl3-d) δ177.9,156.1,151.7,149.8,112.0,109.2,85.8,79.2,5 1.9,49.2,47.3,47.1,47.0,45.1,39.9,37.7,32.6,32.5,30.2,28.4,28.4ppm.

[0073] Example 5. Preparation of Compound I-5

[0074]

[0075] According to the steps of Example 1, only phenethylamine was used to replace n-hexylamine, and other reaction conditions remained unchanged. The colorless oily compound I-5 (44.3%) was obtained by purification by silica gel column chromatography. 1H NMR (600MHz, CDCl3-d) δ7.30(t,J=7.6Hz,2H),7.22(d,J=2.7Hz,1H),7.20(d,J=3.8Hz,2H),5.18(p,J=2.8Hz,1H),5.04(q,J=2.3Hz,1H),4.86( s,1H),4.76(s,1H),3.94(t,J=9.5Hz,1H),2.94(dd,J=12.1,4.4Hz,1H) ,2.91–2.87(m,2H),2.87(d,J=3.2Hz,1H),2.85(d,J=3.7Hz,1H),2.84–2 .82(m,1H),2.80(t,J=6.8Hz,2H),2.52(dddt,J=14.6,10.2,7.8,2.1Hz,2H),2.45(dt,J=13.0,4.4Hz,1H),2.38(ddd,J=11.4,6.8,4.4Hz,1H),2 .22(tdd,J=11.8,9.6,3.2Hz,1H),2.10–2.04(m,1H),2.00(td,J=12.2, 5.2Hz,1H),1.97–1.91(m,1H),1.88–1.81(m,1H),1.36–1.27(m,1H)ppm; 13 C NMR (150MHz, CDCl3-d) δ178.1,151.9,150.0,140.0,128.9,128.8,126.3,112.0, 109.3,85.9,52.0,51.7,47.9,47.4,47.1,45.3,37.8,36.5,32.7,32.7,30.3ppm.

[0076] Example 6. Preparation of Compound I-6

[0077]

[0078] According to the steps of Example 1, only 3,4-dimethoxyphenethylamine was used to replace n-hexylamine, and other reaction conditions remained unchanged. The colorless oily compound I-6 (24.2%) was obtained by purification by silica gel column chromatography. 1H NMR (600MHz, CDCl3-d) δ7.45–7.36(m,2H),7.11–7.06(m,2H),5.17(p,J=2.3Hz,1H),5.04(q,J=2.3Hz,1H),4.87(d,J=1.3Hz,1H ),4.76(t,J=1.3Hz,1H),3.94(t,J=9.5Hz,1H),2.93(dd,J=12.1,4.3Hz,1H),2.90–2.84(m,2H),2.84–2.80(m,1H),2.79(d,J=5 .3Hz,1H),2.78(s,1H),2.74(t,J=7.7Hz,2H),2.57–2.48(m,2H),2.48–2.43(m,1H),2.37(ddd,J=11.3,6.8,4.3Hz,1H),2.21(t dd,J=11.8,9.7,3.1Hz,1H),2.08–2.02(m,1H),2.02–1.97(m,1H),1.97–1.91(m,1H),1.88–1.82(m,1H),1.35–1.27(m,1H)ppm; 13 C NMR (150MHz, CDCl3-d) δ178.1,151.9,150.0,139.1,131.6,130.6,120.1,112.1, 109.3,86.0,52.0,51.5,47.8,47.5,47.1,45.2,37.8,35.9,32.7,32.7,30.3ppm.

[0079] Example 7. Preparation of Compound I-7

[0080]

[0081] According to the steps of Example 1, only 4-bromophenethylamine was used to replace n-hexylamine, and other reaction conditions remained unchanged. The colorless oily compound I-7 (22.1%) was obtained by purification by silica gel column chromatography. 1H NMR (600MHz, CDCl3-d) δ6.80(d,J=7.9Hz,1H),6.75(d,J=2.0Hz,1H),6.73(d,J =2.2Hz,1H),5.17(q,J=2.4Hz,1H),5.03(q,J=2.3Hz,1H),4.86(s,1H),4.76(s, 1H),3.94(t,J=9.5Hz,1H),3.87(s,3H),3.85(s,3H),2.93(dd,J=12.1,4.4Hz, 1H),2.89–2.83(m,2H),2.83–2.82(m,1H),2.80(d,J=5.7Hz,1H),2.77(dd,J=8. 7,1.8Hz,1H),2.74(t,J=7.3Hz,2H),2.50(tdd,J=10.3,4.8,2.4Hz,2H),2.44( dt,J=13.0,4.4Hz,1H),2.38(ddd,J=11.4,6.9,4.4Hz,1H),2.21(tdd,J=11.8,9 .6,3.2Hz,1H),2.10–2.04(m,1H),2.00(td,J=12.2,5.1Hz,1H),1.93(ddt,J=13 .3,9.6,7.9Hz,1H),1.87–1.81(m,1H),1.32(dtd,J=12.9,11.5,5.0Hz,1H)ppm; 13 C NMR (150MHz, CDCl3-d) δ178.0,151.8,149.9,148.9,147.5,132.6,120.6,112.0,112.0,111.2 ,109.3,85.9,56.0,55.9,52.0,51.9,48.0,47.4,47.1,45.3,37.8,36.0,32.7,32.6,30.3ppm.

[0082] Example 8. Preparation of Compound I-8

[0083]

[0084] According to the steps of Example 1, only 3-(2-aminoethyl)pyridine was used to replace n-hexylamine, and other reaction conditions remained unchanged. The colorless oily compound I-8 (62.9%) was obtained by purification by silica gel column chromatography. 1H NMR (600MHz, CDCl3-d) δ8.52(d,1H),7.59(td,J=7.6,1.9Hz,1H),7.17(d,J=7.8Hz,1H),7.11(d d,J=7.6,4.9Hz,1H),5.16(s,1H),5.02(s,1H),4.85(s,1H),4.74(s,1H),3.92(t,J=9.5Hz,1H) ,3.08–2.93(m,5H),2.84(dd,J=12.1,6.4Hz,2H),2.78(t,J=9.3Hz,1H),2.55–2.36(m,5H),2.3 0–2.18(m,1H),2.10–2.04(m,1H),2.03–1.96(m,1H),1.95–1.89(m,1H),1.87–1.77(m,1H)ppm; 13 CNMR(150MHz, CDCl3-d)δ177.8,160.0,151.8,149.9,149.3,136.5,123.4,121.4,111 .9,109.1,85.8,51.9,49.6,47.6,47.2,47.0,45.1,38.1,37.7,32.6,32.5,30.2ppm.

[0085] Example 9, Preparation of Compound I-9

[0086]

[0087] According to the steps of Example 1, only 2-phenoxyethylamine was used to replace n-hexylamine, and other reaction conditions remained unchanged. The colorless oily compound I-9 (63.2%) was obtained by purification by silica gel column chromatography. 1 H NMR(600MHz, CDCl3-d)δ7.41–7.11(m,3H),7.05–6.70(m,3H),5.19(s,1H),5.05( s,1H),4.87(s,1H),4.78(s,1H),4.07(t,J=5.2Hz,2H),3.96(t,J=9.4Hz,1H),3.0 6–2.95(m,3H),2.95–2.79(m,2H),2.63–2.37(m,3H),2.33–2.22(m,1H),2.14(dq ,J=12.8,4.0Hz,1H),2.07–1.90(m,2H),1.89–1.82(m,1H),1.40–1.24(m,1H)ppm; 13C NMR (150MHz, CDCl3-d) δ177.8,158.7,151.8,149.9,129.5,120.9,114.5,111.9,109 .2,85.8,67.2,51.9,49.0,47.8,47.4,47.0,47.0,45.1,37.7,32.7,32.6,30.2ppm.

[0088] Example 10. Preparation of Compound I-10

[0089]

[0090] According to the steps of Example 1, only glycine methyl ester was used to replace n-hexylamine, and other reaction conditions remained unchanged. The colorless oil compound I-10 (45.6%) was obtained by purification by silica gel column chromatography. Colorless oil, 40.1% yield. 1 H NMR (600MHz, CDCl3-d) δ5.18(q,J=2.4Hz,1H),5.04(q,J=2.3Hz,1H),4.87(d,J=1.3Hz,1H),4.77(t,J=1.2Hz,1H),3.96(t,J=9.4H z,1H),3.73(s,3H),3.45(s,2H),2.94(dd,J=12.1,4.3Hz,1H),2.89(dd,J=8.4,4.2Hz,1H),2.88–2.85(m,1H),2.85–2.80(m,1H),2 .57–2.46(m,2H),2.45(d,J=4.5Hz,1H),2.38(ddd,J=11.6,6.0,4.3Hz,1H),2.35–2.27(m,1H),2.13(ddt,J=12.7,5.1,3.6Hz,1H), 2.05(td,J=13.0,12.6,5.2Hz,1H),1.94(ddt,J=13.3,9.6,7.9Hz,1H),1.89–1.82(m,1H),1.34(dtd,J=12.9,11.5,5.0Hz,1H)ppm; 13 CNMR (150MHz, CDCl3-d) δ177.7,172.7,151.8,150.0,112.0,109.3,85.9,52.0,52.0,51.3,47.9,47.42,47.1,45.1,37.8,32.8,32.7,30.3ppm.

[0091] Example 11. Preparation of Compound I-11

[0092]

[0093] According to the steps of Example 1, only proline methyl ester was used to replace n-hexylamine, and other reaction conditions remained unchanged. The colorless oil compound I-11 (31.9%) was obtained by purification by silica gel column chromatography. H NMR (600MHz, CDCl3-d) δ5.18 (q, J = 2.4 Hz, 1H), 5.04 (q, J = 2.3 Hz, 1H), 4.87 (d, J = 1.3 Hz, 1H), 4.77 (t, J = 1.2 Hz, 1H), 3.96 (t, J = 9.4 Hz, 1H,), 3.73 (s, 3H), 3.45 (s, 2H), 2.94 (dd, J = 12.1, 4.3 Hz, 1H), 2.89 (dd, J = 8.4, 4.2 Hz, 1H), 2.88–2.85 (m, 1H), 2.85–2.80 (m, 1H), 2 .57–2.46(m,2H),2.45(d,J=4.5Hz,1H),2.38(ddd,J=11.6,6.0,4.3Hz,1H),2.35–2.27(m,1H),2.13(ddt,J=12.7,5.1,3.6Hz,1H), 2.05(td,J=13.0,12.6,5.2Hz,1H),1.94(ddt,J=13.3,9.6,7.9Hz,1H),1.89–1.82(m,1H),1.34(dtd,J=12.9,11.5,5.0Hz,1H)ppm; 13 C NMR (150MHz, CDCl3-d) δ177.7,172.7,151.8,150.0,112.0,109.3,85.9,52.0,52.0,51.3,47.8,47.4,47.1,45.1,37.8,32.8,32.7,30.3ppm.

[0094] Example 12. Preparation of Compound I-12

[0095]

[0096] According to the steps of Example 1, except that n-hexylamine was replaced by piperazine, other reaction conditions remained unchanged, and the compound I-12 (36.8%) was obtained as a colorless oil by purification by silica gel column chromatography. 1H NMR (600MHz, CDCl3-d) δ5.19(q,J=2.4Hz,1H),5.05(q,J=2.3Hz,1H),4.87(s,1H),4.77(s,1H),3.93(t,J=9.5Hz,1H),3.69(dp,J=11.7,6 .9,6.1Hz,4H),2.90(td,J=8.2,4.4Hz,1H),2.81(d,J=4.4Hz,1H),2.79(d,J=4.7Hz,1H),2.61(dd,J=13.1,7.5Hz,1H),2.58–2.44(m,4H) ,2.45(t,J=4.7Hz,2H)2.42(t,J=6.1Hz,1H),2.39(dt,J=7.5,4.3Hz,1H),2.33(ddt,J=13.0,8.7,3.9Hz,1H),2.26(tdd,J=11.6,9.5,3.3 Hz,1H),2.07(td,J=12.3,5.2Hz,1H),1.95(ddt,J=13.2,9.6,7.8Hz,1H),1.86(ddt,J=13.5,8.8,5.1Hz,1H),1.30(q,J=3.5,2.5Hz,1H). 13 C NMR (150MHz, CDCl3-d) δ177.7,151.8,150.1,111.9,109.4,85.5,67.0,58.3,54.1,52.1,47.4,47.2,44.9,37.8,33.0,32.7,30.3ppm.

[0097] Example 13. Preparation of Compound I-13

[0098]

[0099] According to the steps of Example 1, only 1-(2-methoxyphenyl)piperazine was used to replace n-hexylamine, and other reaction conditions remained unchanged. White solid compound I-13 (51.2%) was obtained by purification by silica gel column chromatography. 1H NMR (600MHz, CDCl3-d) δ5.19(q,J=2.4Hz,1H),5.05(q,J=2.3Hz,1H),4.87(s,1H),4.77(s,1H),3.93(t,J=9.5Hz, 1H),3.69(dp,J=11.7,6.9,6.1Hz,4H),2.90(td,J=8.2,4.4Hz,1H),2.81(d,J=4.4Hz,1H),2.79(d,J=4.7Hz,1H,2 .61(dd,J=13.1,7.5Hz,1H),2.58–2.44(m,4H),2.45(t,J=4.7Hz,2H)2.42(t,J=6.1Hz,1H),2.39(dt,J=7.5,4.3H z,1H),2.33(m,1H),2.26(tdd,J=11.6,9.5,3.3Hz,1H,m),2.07(m,1H),1.95(m,1H),1.86(m,1H),1.30(m,1H)ppm; 13 C NMR (150MHz, CDCl3-d) δ177.6,151.8,150.2,111.9,109.4,85.4,58.2,54.1,52.1,47.4,47.2,46.7,44.8,37.8,33.1,32.6,30.3ppm.

[0100] Example 14. Preparation of Compound I-14

[0101]

[0102] According to the steps of Example 1, only n-hexylamine was replaced by imidazole, and other reaction conditions remained unchanged. The colorless oily compound I-14 (49.6%) was obtained by purification by silica gel column chromatography. 1H NMR(600MHz, CDCl3-d)δ7.00(td,J=7.5,2.1Hz,1H),6.96–6.89(m,2H),6.86(d,1H),5.29(s,2H),5.20(s ,1H),5.05(s,1H),4.87(s,1H),4.77(s,1H),3.94(t,J=9.5Hz,1H),3.86(s,3H),3.06(s,4H),2.93–2.87 (m,2H),2.80(t,1H),2.70–2.63(m,0H),2.58–2.43(m,3H),2.38(dq,J=12.9,4.2Hz,1H),2.27(qd,J=11. 3,3.3Hz,1H),2.07(td,J=12.2,5.1Hz,1H),2.02–1.90(m,1H),1.90–1.81(m,1H),1.37–1.27(m,1H)ppm; 13 C NMR (150MHz, CDCl3-d) δ177.8,152.2,151.8,150.1,141.2,123.0,120.9,118.1,111.7,111 .1,109.3,85.4,58.0,55.4,53.5,52.0,50.6,47.9,47.1,44.8,37.7,33.5,32.6,30.2ppm.

[0103] Example 15. Preparation of Compound I-15

[0104]

[0105] According to the steps of Example 1, only 2-methylimidazole was used to replace n-hexylamine, and other reaction conditions remained unchanged. White solid compound I-15 (57.2%) was obtained by purification by silica gel column chromatography. 1H NMR (600MHz, CDCl3-d) δ7.51 (s, 1H), 7.06 (s, 1H), 6.94 (s, 1H), 5.10 (d, J = 2.9Hz, 1H), 5.00 (d, J = 2. 8Hz,1H),4.83(s,1H),4.73(s,1H),4.38(dd,J=14.8,4.7Hz,1H),4.25(dd,J=14.8,4.7Hz,1H),3.93 (t,J=9.5Hz,1H),2.75(td,J=8.1,4.3Hz,1H),2.61(t,J=9.2Hz,1H),2.56(dt,J=11.7,4.7Hz,1H),2 .52–2.36(m,3H),1.96–1.83(m,2H),1.78(dq,J=13.0,4.2Hz,2H),1.28(qd,J=12.0,5.0Hz,1H)ppm; 13 C NMR (150MHz, CDCl3-d) δ175.3,151.4,149.2,137.6,130.2,119.6,112.4,109.4,85.5,51.7,48.6,46.9,44.4,44.3,37.3,32.5,32.2,30.1ppm.

[0106] Example 16. Preparation of Compound I-16

[0107]

[0108] According to the steps of Example 1, only 2-aminoimidazole was used to replace n-hexylamine, and other reaction conditions remained unchanged. White solid compound I-16 (43.9%) was obtained by purification by silica gel column chromatography. 1H NMR(600MHz, CDCl3-d)δ6.96(s,1H),6.91(d,J=1.4Hz,1H),5.19(q,J=2.4Hz,1H),5.04(q,J=2.4Hz,1H),4.87–4.85(m,1H),4 .75(t,J=1.4Hz,1H),3.92(t,J=9.5Hz,1H),2.94–2.89(m,1H),2.89–2.86(m,1H),2.83–2.78(m,1H),2.70(dd,J=12.8,4.9Hz ,1H),2.58–2.48(m,2H),2.46(s,3H),2.44(dt,J=13.0,4.5Hz,1H),2.37–2.32(m,1H),2.32–2.27(m,1H),2.27–2.24(m,1H), 2.07(td,J=12.3,5.1Hz,1H),1.94(ddt,J=13.3,9.6,7.9Hz,1H),1.89–1.82(m,1H),1.31(dtd,J=12.8,11.4,5.0Hz,1H)ppm; 13 C NMR (150MHz, CDCl3-d) δ175.4,151.5,149.1,144.7,128.0,119.8,112.6,109.5,85.7,52.0,48.4,47.1,45.0,44.2,37.2,32.6,30.2,13.3ppm.

[0109] Example 17. Preparation of Compound I-17

[0110]

[0111] According to the steps of Example 1, only 2-chloroimidazole was used to replace n-hexylamine, and other reaction conditions remained unchanged. White solid compound I-17 (35.8%) was obtained by purification by silica gel column chromatography. 1H NMR(600MHz, CDCl3-d)δ6.62(s,1H),6.43(s,1H),5.10(s,1H),5.01(s,1H),4.86(s,1H),4.76 (s,1H),4.17(dd,J=15.3,3.8Hz,1H),4.04–3.94(m,2H),2.82(td,J=8.1,4.3Hz,1H),2.71(t, J=9.3Hz,1H),2.58(dt,J=12.3,4.3Hz,1H),2.54–2.44(m,3H),2.19(tdd,J=12.3,9.5,3.0Hz, 1H),2.08–1.97(m,2H),1.91(dq,J=13.0,8.2Hz,1H),1.85–1.77(m,1H),1.47–1.15(m,2H)ppm; 13 C NMR (150MHz, CDCl3-d) δ176.7,151.4,149.3,148.8,124.5,115.8,112.3,109.3,86.1,51.6,48.5,46.9,44.2,41.6,37.4,32.5,32.1,30.1ppm.

[0112] Example 18. Preparation of Compound I-18

[0113]

[0114] According to the steps of Example 1, only 2-hydroxymethylimidazole was used to replace n-hexylamine, and other reaction conditions remained unchanged. White solid compound I-18 (62.0%) was obtained by purification by silica gel column chromatography. 1 H NMR (600MHz, CDCl3-d) δ7.05(s,1H),6.97(s,1H),5.12(d,J=1.5Hz,1H),5.02(d,J=1.3Hz ,1H),4.85(s,1H),4.75(s,1H),4.33(dt,J=20.1,7.5Hz,2H),3.99–3.93(m,1H),2.79(td, J=8.0,4.2Hz,1H),2.68–2.59(m,2H),2.50(dd,J=13.5,4.8Hz,1H),2.44–2.39(m,1H),1. 99–1.92(m,3H),1.85–1.78(m,1H),1.33–1.28(m,1H),1.24(s,1H),0.92–0.85(m,1H)ppm; 13C NMR (150MHz, CDCl3-d) δ175.2,151.5,149.2,132.1,128.9,121.9,112.3,109.2,85.9,51.8,48.3,46.8,44.1,43.8,37.4,32.5,32.5,30.1ppm.

[0115] Example 19. Preparation of Compound I-19

[0116]

[0117] According to the steps of Example 1, only triazole was used to replace n-hexylamine, and other reaction conditions remained unchanged. White solid compound I-19 (48.3%) was obtained by purification by silica gel column chromatography. 1 H NMR(600MHz, CDCl3-d)δ7.00(s,1H),6.90(s,1H),5.14(s,1H),5.03(s,1H),4.81(s,1H),4.72(s,1H),4.62 (q,2H),4.48(dd,J=14.7,5.1Hz,1H),4.30(dd,J=14.7,6.2Hz,1H),3.96(t,J=9.4Hz,1H),2.80(dq,J=12.2 ,6.9,6.3Hz,2H),2.71(t,J=9.3Hz,1H),2.55–2.45(m,2H),2.33(dt,J=13.1,4.4Hz,1H),2.18(qd,J=11.6, 11.1,5.6Hz,1H),1.98–1.85(m,1H),1.85–1.76(m,1H),1.67(dq,J=12.8,4.0Hz,1H),1.27–1.20(m,1H)ppm; 13 C NMR (150MHz, CDCl3-d) δ175.7,151.4,149.4,148.2,127.3,120.5,112.0,1 09.1,85.8,55.1,53.4,51.8,48.1,46.8,45.0,44.4,37.3,32.4,30.0ppm.

[0118] Example 20. Preparation of Compound I-20

[0119]

[0120] According to the steps of Example 1, only 2-(2-methyl-1H-imidazol-1-yl)ethylamine was used to replace n-hexylamine. Other reaction conditions remained unchanged, and white solid compound I-20 (62.2%) was obtained by purification by silica gel column chromatography. 1H NMR(600MHz, CDCl3-d)δ8.18(s,1H),7.93(s,1H),5.10(s,1H),5.01(s,1H),4.85(s, 1H),4.74(s,1H),4.52(qd,J=14.5,4.7Hz,2H),3.94(t,J=9.5Hz,1H),3.45(s,0H),2 .79(td,J=8.2,4.4Hz,1H),2.71(dt,J=11.9,4.7Hz,1H),2.66(t,1H),2.53–2.39(m, 3H),2.17–2.08(m,1H),2.00–1.85(m,2H),1.84–1.77(m,1H),1.38–1.25(m,2H)ppm; 13 C NMR (150MHz, CDCl3-d) δ175.2,152.2,151.4,149.4,144.4,112.3,109.5,85.7,51.7,48.0,47.0,46.8,44.9,37.4,32.5,32.2,30.2ppm.

[0121] Example 21. Preparation of Compound I-21

[0122]

[0123] According to the steps of Example 1, only triazole-3-mercapto replaced n-hexylamine, and other reaction conditions remained unchanged, and white solid compound I-21 (47.2%) was obtained by purification by silica gel column chromatography. 1 H NMR (600MHz, CDCl3-d) δ6.88(d,J=1.4Hz,1H),6.84(d,J=1.4Hz,1H),5.13(d,J=2 .7Hz,1H),5.01(d,J=3.8Hz,1H),4.84(s,1H),4.73(s,1H),3.96–3.88(m,4H),2.9 6–2.79(m,3H),2.78–2.68(m,2H),2.54–2.38(m,3H),2.37(s,3H),2.36–2.23(m, 2H),2.06–1.86(m,3H),1.82(ddt,J=13.5,9.2,4.9Hz,1H),1.33–1.20(m,2H)ppm; 13C NMR (150MHz, CDCl3-d) δ177.8,151.8,149.8,127.0,119.4,112.0,109.2,85.9, 51.9,50.1,47.6,47.5,47.0,46.3,44.8,37.6,32.6,32.6,30.2,30.2,13.2ppm.

[0124] Example 22. Preparation of Compound I-22

[0125]

[0126] According to the steps of Example 1, only 5-aminomethylthiazole was used to replace n-hexylamine, and other reaction conditions remained unchanged. The light yellow solid compound I-22 (39.1%) was obtained by purification by silica gel column chromatography. 1 H NMR(600MHz, CDCl3-d)δ7.72(d,J=3.3Hz,1H),7.27(d,1H),5.17(s,1H),5.04(s, 1H),4.86(s,1H),4.77(s,1H),4.16(d,J=4.1Hz,2H),3.97(t,J=9.2Hz,1H),3.05 (dd,J=12.2,4.0Hz,1H),2.97–2.87(m,1H),2.86–2.75(m,2H),2.61–2.30(m,6H) ,2.08–1.99(m,2H),1.99–1.90(m,1H),1.89–1.81(m,1H),1.37–1.27(m,2H)ppm; 13 C NMR (150MHz, CDCl3-d) δ177.7,171.8,151.7,149.8,142.6,119.1,112.0,1 09.2,86.0,53.5,51.9,51.0,47.5,47.1,46.8,44.7,37.6,32.5,30.2ppm.

[0127] Example 23. Preparation of Compound I-23

[0128]

[0129] According to the steps of Example 1, only 1,4,5,6-tetrahydropyrrolo-[3,4-C]-pyrazole was used to replace n-hexylamine. Other reaction conditions remained unchanged, and light yellow solid compound I-23 (71.2%) was obtained by purification by silica gel column chromatography. 1H NMR(600MHz, CDCl3-d)δ8.21(s,1H),5.11(s,1H),5.00(s,1H),4.82(s,1H),4.72 (s,1H),3.96(t,J=9.2Hz,1H),3.61(dd,J=14.3,4.8Hz,1H),3.42(dd,J=14.3,5. 4Hz,1H),2.87–2.68(m,3H),2.54–2.38(m,3H),2.38–2.26(m,2H),1.92(ddd,J=2 4.5,12.6,6.7Hz,2H),1.80(ddt,J=13.5,9.0,4.8Hz,1H),1.35–1.22(m,1H)ppm; 13 C NMR (150MHz, CDCl3-d) δ177.2,151.7,149.7,112.0,109.1,86.0,51.8,47.5,47.0,46.2,37.4,32.6,32.5,30.8,30.1ppm.

[0130] Example 24. Preparation of Compound I-24

[0131]

[0132] According to the steps of Example 1, only 4,5,6,7-tetrahydro-3H-imidazo[4,5-C]pyridine was used to replace n-hexylamine. Other reaction conditions remained unchanged, and light yellow solid compound I-24 (35.9%) was obtained by purification by silica gel column chromatography. 1 H NMR (600MHz, CDCl3-d) δ7.21 (s, 1H), 5.19 (q, J = 2.5Hz, 1H), 5.04 (d, J = 2.6Hz, 1H), 4.86 (s, 1H), 4.75 (s, 1H), 3.96 (t,J=9.1Hz,1H),3.89(d,J=12.1Hz,1H),3.82(d,J=10.0Hz,3H),3.23(dd,J=13.1,4.0Hz,1H),3.16(dd,J=13.1, 5.3Hz,1H),2.89(td,J=8.2,4.1Hz,1H),2.84–2.78(m,1H),2.57–2.37(m,4H),2.31(ddd,J=12.7,6.4,3.2Hz,1H) ,2.09–1.99(m,1H),1.93(ddt,J=15.8,9.6,7.9Hz,1H),1.84(ddt,J=13.4,9.1,5.0Hz,1H),1.40–1.30(m,1H)ppm; 13C NMR (150MHz, CDCl3-d) δ177.6,151.9,150.1,121.6,121.2,111.9,109.3, 85.7,54.6,52.5,52.3,52.0,47.1,47.0,46.1,37.9,32.9,32.7,30.3ppm.

[0133] Example 25. Preparation of Compound I-25

[0134]

[0135] According to the steps of Example 1, only 1,5-dihydropyrrolo[3,4-b]pyrrole was used to replace n-hexylamine, and other reaction conditions remained unchanged. The light yellow solid compound I-25 (32.7%) was obtained by purification by silica gel column chromatography. 1 H NMR(600MHz, CDCl3-d)δ7.29(s,1H),5.17(s,1H),5.03(s,1H),4.84(s,1H ),4.74(s,1H),3.97–3.91(m,1H),3.53(q,2H),2.99(dd,J=13.3,4.7Hz,1H ),2.89–2.71(m,7H),2.56–2.38(m,4H),2.34–2.26(m,2H),2.01(td,J=12. 5,5.1Hz,1H),1.97–1.88(m,1H),1.87–1.79(m,1H),1.36–1.26(m,1H)ppm. 13 C NMR (150MHz, CDCl3-d) δ177.8,151.8,150.0,146.2,137.8,113.8,111.7,109.2, 85.6,56.5,51.9,51.0,49.7,47.0,46.9,45.8,37.8,32.9,32.6,30.2,22.7ppm.

[0136] Example 26. Preparation of Compound I-26

[0137]

[0138] According to the steps of Example 1, only 5H-pyrrolo[3,2-D]pyrimidine was used to replace n-hexylamine, and other reaction conditions remained unchanged. White solid compound I-26 (27.8%) was obtained by purification by silica gel column chromatography. 1H NMR(600MHz, CDCl3-d)δ8.21(s,1H),6.93(s,1H),6.84(s,1H),5.09(s,1H),4.98(s,1H ),4.85(s,1H),4.74(s,1H),4.54(m,2H),3.94(t,J=9.5Hz,1H),3.45(s,0H),2.79(td, J=8.2,4.4Hz,1H),2.71(dt,J=11.9,4.7Hz,1H),2.66(t,1H),2.56(s,2H),2.53–2.39( m,3H),2.17–2.08(m,1H),2.00–1.85(m,2H),1.84–1.77(m,1H),1.38–1.25(m,2H)ppm; 13 C NMR (150MHz, CDCl3-d) δ178.0,149.2,150.4,143.9,137.9,130.1,125.62,110.3, 110.0,108.1,85.4,80.1,52.0,47.4,45.7,44.9,43.1,35.4,33.4,31.7,16.5ppm.

[0139] Example 27. Preparation of Compound I-27

[0140]

[0141] According to the steps of Example 1, only 4-aminopyrrolo[3,2-D]pyrimidine was used to replace n-hexylamine, and other reaction conditions remained unchanged. White solid compound I-27 (39.6%) was obtained by purification by silica gel column chromatography. 1 H NMR (600MHz, CDCl3-d) δ8.97(s,1H),8.86(s,1H),7.37(d,J=3.6Hz,1H),6.57(d,J=3.6H z,1H),5.10(d,J=2.6Hz,1H),4.99(d,J=2.3Hz,1H),4.80–4.74(m,2H),4.67(s,1H),4.56 (dd,J=14.7,4.3Hz,1H),3.93(t,J=9.5Hz,1H),2.70(dt,J=12.0,4.5Hz,1H),2.60(td,J =8.1,4.2Hz,1H),2.55–2.32(m,4H),2.12(dq,J=12.8,4.0Hz,1H),1.89–1.71(m,4H)ppm. 13C NMR (150MHz, CDCl3-d) δ175.0,150.5,150.4,150.1,148.5,148.4,129.0,117.5,1 10.9,108.0,99.3,84.8,50.7,47.6,45.8,43.5,40.1,36.3,31.4,31.1,29.0ppm.

[0142] Example 28. Preparation of Compound I-28

[0143]

[0144] According to the steps of Example 1, only indole-3-carboxylic acid methyl ester was used to replace n-hexylamine, and other reaction conditions remained unchanged. White solid compound I-28 (41.8%) was obtained by purification by silica gel column chromatography. 1 H NMR(600MHz, CDCl3-d)δ8.33(s,1H),7.96(s,1H),6.27(s,2H),5.08(s,1H),4.99(s,1H) ,4.82(s,1H),4.71(s,1H),4.55(qd,J=14.7,4.3Hz,2H),4.10(q,J=7.2Hz,1H),3.95(t,J =9.5Hz,1H),3.47(s,2H),2.72(dt,J=12.2,4.4Hz,1H),2.66(td,J=8.1,4.1Hz,1H),2.57 (t,J=9.3Hz,1H),2.51–2.36(m,2H),2.28(dq,J=12.8,4.0Hz,1H),2.00–1.73(m,3H)ppm. 13 C NMR (150MHz, CDCl3-d) δ175.8,155.7,153.1,151.6,150.6,149.6,141.6,119. 0,112.2,109.2,86.0,51.7,48.5,46.9,44.6,40.4,37.5,32.5,32.3,30.1ppm.

[0145] Example 29, Preparation of Compound I-29

[0146]

[0147] According to the steps of Example 1, only 6,7-diethoxy-1,2,3,4-tetrahydroisoquinoline was used to replace n-hexylamine. Other reaction conditions remained unchanged, and white solid compound I-29 (36.8%) was obtained by purification by silica gel column chromatography. 1H NMR (600MHz, CDCl3-d) δ8.20(d,J=7.9Hz,1H),8.17(s,1H),7.50(d,J=8.2Hz,1H),7.26(t,J=7.4Hz,1H),7.20(t,J=7. 5Hz,1H),5.04(d,J=2.8Hz,1H),4.92(s,1H),4.69(s,1H),4.63(q,J=8.3,6.8Hz,2H),4.46(dd,J=14.9,6.9Hz,1H),3.9 3(t,J=9.4Hz,1H),2.98–2.91(m,1H),2.71(td,J=8.2,4.1Hz,1H),2.62(t,J=9.2Hz,1H),2.46(s,3H),2.44–2.38(m,2H ), 2.18(tt,J=18.6,6.4Hz,2H),1.81(ddd,J=13.4,9.4,6.5Hz,1H),1.74(dp,J=16.6,5.9,5.3Hz,2H),1.38(m,1H)ppm; 13 C NMR (150MHz, CDCl3-d) δ196.1,178.1,153.6,151.2,138.8,138.6,127.4,124.7,123.8,123.4,1 18.1,112.2,111.2,109.0,87.3,52.0,50.2,48.3,46.5,46.4,38.2,33.4,33.1,31.0,27.3ppm.

[0148] Example 30. Preparation of Compound I-30

[0149]

[0150] According to the steps of Example 1, only 1-(2H)-phthalazinone was used to replace n-hexylamine, and other reaction conditions remained unchanged. The colorless oily compound I-30 (56.3%) was obtained by purification by silica gel column chromatography. 1H NMR(600MHz, CDCl3-d)δ6.60(s,1H),6.53(s,1H),5.20(s,1H),5.05(s,1H),4.85(s,1H), 4.75(s,1H),3.95(t,J=9.4Hz,1H),3.85(d,J=4.8Hz,6H),3.68–3.54(m,2H),2.99–2.93(m ,1H),2.93–2.86(m,1H),2.84–2.73(m,6H),2.72–2.64(m,1H),2.58–2.46(m,3H),2.46–2. 39(m,1H),2.37–2.32(m,2H),2.07–1.99(m,1H),1.99–1.89(m,1H),1.89–1.81(m,1H)ppm; 13 C NMR (150MHz, CDCl3-d) δ177.8,151.8,150.1,147.5,147.2,126.0,111.7,111.2,109.3,109.2 ,85.6,57.3,56.2,55.9,55.9,51.9,51.2,47.0,47.0,45.4,37.8,32.9,32.6,30.2,28.7ppm.

[0151] Example 31. Preparation of Compound I-31

[0152]

[0153] According to the steps of Example 1, only cytosine was used to replace n-hexylamine, and other reaction conditions remained unchanged. White solid compound I-31 (41.2%) was obtained by purification by silica gel column chromatography. 1 H NMR(600MHz, CDCl3-d)δ7.58(d,J=7.2Hz,1H),5.76(d,J=7.2Hz,1H),5.04(s,1 H),4.93(s,1H),4.80(s,1H),4.69(s,1H),4.03(dd,J=14.1,6.4Hz,1H),3.95(q ,J=9.3,8.4Hz,2H),2.84(ddt,J=26.7,11.5,4.8Hz,2H),2.73(t,J=9.3Hz,1H), 2.50–2.35(m,3H),2.26–2.18(m,1H),2.10–1.73(m,4H),1.42–1.15(m,1H)ppm; 13C NMR (150MHz, CDCl3-d) δ178.6,168.0,159.0,153.7,151.6,148.5,112.0,109.0,95.5,87.4,53.3,48.2,47.2,46.5,38.7,33.5,33.5,31.1ppm.

[0154] Example 32. Preparation of Compound I-32

[0155]

[0156] According to the steps of Example 1, only thymine was used to replace n-hexylamine, and other reaction conditions remained unchanged. White solid compound I-32 (43.7%) was obtained by purification by silica gel column chromatography. 1 H NMR (600MHz, CDCl3-d) δ7.85(d,J=3.0Hz,1H),7.62(d,J=7.5Hz,1H),7.42(d,J=9.3Hz,1H),7.31(dd,J=9.2, 3.1Hz,1H),6.29(d,J=7.5Hz,1H),5.14(s,1H),5.03(s,1H),4.82(dd,J=15.3,4.5Hz,1H),4.77(s,1H),4.72( s,1H),4.10(ddd,J=15.3,7.7,2.9Hz,1H),3.92(s,3H),3.47(s,1H),2.87–2.72(m,3H),2.52–2.42(m,2H),2. 30–2.19(m,2H),2.03(s,1H),1.94–1.82(m,1H),1.82–1.75(m,1H),1.55–1.50(m,1H),1.27–1.21(m,1H)ppm; 13 C NMR (150MHz, CDCl3-d) δ177.6,175.2,156.5,151.2,148.7,142.5,133.8,128.5,123.4,116.5,1 12.6,109.6,109.4,106.5,85.5,55.9,53.1,51.9,47.2,47.0,46.0,36.7,32.5,32.4,30.1ppm.

[0157] Example 33. Preparation of Compound I-33

[0158]

[0159] According to the steps of Example 1, only 6-methoxyquinoline-4-one was used to replace n-hexylamine, and other reaction conditions remained unchanged. White solid compound I-33 (47.1%) was obtained by purification by silica gel column chromatography. 1 H NMR (600MHz, CDCl3-d) δ8.82(s,1H),7.22(s,1H),5.26(s,1H),5.10(d,J=2.6H z,1H),5.00(d,J=2.3Hz,1H),4.83(s,1H),4.72(s,1H),4.02(dd,J=14.5,5.7H z,1H),3.98–3.92(m,2H),2.82(s,1H),2.77–2.71(m,1H),2.59–2.36(m,4H),2 .36–2.28(m,1H),2.11–2.03(m,1H),2.01–1.92(m,1H),1.92–1.75(m,4H)ppm; 13 C NMR (150MHz, CDCl3-d) δ176.4,164.2,151.7,151.4,149.7,141.7,112.2,111. 1,109.3,86.3,51.8,47.8,47.0,45.5,45.1,37.8,32.6,32.5,30.2,12.5ppm.

[0160] Example 34, Preparation of Intermediate II

[0161]

[0162] A mixture of K2OsO4·2H2O (217.10 μmol, 0.5 equiv), N-methylmorpholine-N-oxide (651.30 μmol, 1.5 equiv) and tert-butyl alcohol / tetrahydrofuran / water (v / v / v=4:1:1, 3 mL) was stirred at room temperature for 40 minutes, dehydrocostus lactone (434.20 μmol, 1 equiv) was added, and then reacted at room temperature for 4 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, ethyl acetate was added to expand the volume, water was added to wash three times, and finally dried over anhydrous sodium sulfate, the organic phase was distilled under reduced pressure and purified by silica gel column chromatography to obtain intermediate II (21.8%). 1H NMR(600MHz, CDCl3-d)δ5.19(s,1H),5.07(d,J=1.1Hz,1H),4.89(s,1H),4.81(s,1H ),4.31(t,J=9.6Hz,1H),3.79(d,J=11.9Hz,1H),3.64(d,J=11.9Hz,1H),3.35(s,1H) ,2.88(dd,J=13.9,7.5Hz,1H),2.75(t,J=8.8Hz,1H),2.57–2.43(m,3H),2.07–1.99( m,2H),1.96–1.91(m,1H),1.85(ddd,J=13.3,8.5,4.4Hz,1H),1.81–1.69(m,3H)ppm; 13 C NMR (150MHz, CDCl3-d) δ178.0,151.3,149.5,112.6,109.9,85.2,75.2,64.6,52.1,47.5,47.3,36.2,32.4,30.2,25.4ppm.

[0163] Example 35. Preparation of Compound I-34

[0164]

[0165] A mixture of nicotinic acid (113.50 μmol, 2 equiv), DMAP (11.35 μmol, 0.2 equiv), EDCI (113.50 μmol, 2 equiv), DIPEA (113.50 μmol, 2 equiv) and tetrahydrofuran (1 mL) was stirred at room temperature for 10 minutes, and then Z intermediate II (56.79 μmol, 1 equiv) was added and reacted at room temperature for 8 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, ethyl acetate was added, and the organic phase was washed with a 10% K2CO3 aqueous solution, neutralized with a HCl solution (1 M), and the aqueous phase was removed by suction. After the organic phase was dried over anhydrous sodium sulfate, it was purified by silica gel column chromatography to obtain the product I-34 (47.7%). 1H NMR (600MHz, CDCl3-d) δ9.27(s,1H),8.83(s,1H),8.38(d,J=7.6Hz,1H),7.52(s,1H),5.19(d,J=9.3Hz, 1H),5.07(s,1H),4.89(s,1H),4.81(s,1H),4.62(d,J=11.5Hz,1H),4.48(d,J=11.5Hz,1H),4.30(t,J=9. 5Hz,1H),2.89(dd,J=14.1,7.4Hz,1H),2.78(t,J=8.7Hz,1H),2.59–2.44(m,3H),2.31–2.26(m,1H),2.0 8–2.02(m,1H),1.97–1.91(m,2H),1.85(dt,J=14.0,6.3Hz,1H),1.77(ddd,J=16.5,12.0,4.9Hz,2H)ppm. 13 C NMR (150MHz, CDCl3-d) δ173.96,163.22,151.44,150.13,148.76,148.28,137.57,123.03,111 .47,108.82,83.20,74.01,64.30,50.97,50.94,47.13,46.37,34.89,31.24,29.02,24.31ppm.

[0166] Example 36, Preparation of Intermediate III

[0167]

[0168] To a solution of selenium dioxide (1 equiv) in dichloromethane (25 mL), tert-butyl hydroperoxide (34.74 μmol, 0.004 equiv) was added. After 40 minutes of reaction, dehydrocostus lactone (8.68 mmol, 1 equiv) was added and the mixture was transferred to room temperature for reaction. After 3 hours, TLC monitoring showed that the reaction was complete. Saturated sodium thiosulfate and saturated sodium bicarbonate solution (v / v=1:1, 10 mL) were added to the reaction solution for quenching. The quenching lasted for 40 minutes, and then ethyl acetate was added for expansion. The organic phase was collected and dried over anhydrous sodium sulfate, and then dried under reduced pressure to obtain a red mixture. The red mixture was purified by silica gel column chromatography to obtain a white solid intermediate III (14.0%). 1H NMR(600MHz, CDCl3-d)δ6.22(d,J=3.5Hz,1H),5.50(d,J=3.6Hz,2H),5.36(d,J=1.9Hz,1H), 4.93(s,1H),4.78(s,1H),4.69(t,J=6.7Hz,1H),3.90(t,J=9.1Hz,1H),3.10(pd,J=9.1,3.3 Hz,2H),2.86(ddd,J=12.1,8.6,3.7Hz,1H),2.52(dt,J=13.1,4.8Hz,1H),2.27–2.16(m,2H) ,2.15–2.07(m,1H),1.87(dt,J=13.7,6.9Hz,1H),1.79(s,1H),1.39(qd,J=11.6,5.1Hz,1H). 13 C NMR (150MHz, CDCl3-d) δ170.3,154.2,148.6,139.5,120.7,113.4,113.2,85.1,74.7,49.6,45.6,44.2,40.0,36.9,31.1ppm.

[0169] Example 37, Preparation of Intermediate IV

[0170]

[0171] The same operation as in Example 36 was performed to obtain white solid intermediate IV (26.3%). 1 H NMR (600MHz, CDCl3-d) δ6.25(d,J=3.4Hz,1H),5.68(s,1H),5.55(d,J=2.9Hz,1H),5.46( s,1H),4.94(s,1H),4.75(s,1H),4.71(t,J=6.7Hz,1H),4.12(d,J=8.7Hz,1H),3.28(ddd, J=11.7,8.6,3.3Hz,1H),2.84(dd,J=8.5,3.2Hz,1H),2.67(s,1H),2.53(dd,J=8.3,3.8Hz ,1H),2.27–2.21(m,1H),2.16(dt,J=15.0,10.1Hz,2H),1.41(qd,J=11.9,5.4Hz,1H)ppm; 13C NMR(150MHz, CDCl3-d)δ170.5,156.4,147.5,139.2,121.5,114.9,114.3,86.1,80.3,74.8,53.2,40.2,38.8,37.7,31.5ppm.HRMS(ESI)calcd for C 15 H 18 O4Na[M+Na] + ,285.1103;found,285.1097.

[0172] Example 38. Preparation of Compound I-35

[0173]

[0174] A mixture of intermediate III (1 equiv), meta-chloroperbenzoic acid (3 equiv) and dichloromethane was reacted at room temperature for 3 hours. After the reaction, it was purified by preparative reverse phase medium pressure preparative liquid phase to obtain compound I-35 (10.1%). 1 HNMR(600MHz, CDCl3-d)δ6.30–6.19(m,1H),5.58–5.49(m,1H),4.10(s,1H),4.07(s,1H),3.49–3.45(m,1H),2.93(s,1H),2.91–2.86(m, 1H),2.81–2.74(m,1H),2.66(s,1H),2.55–2.49(m,1H),2.25(s,1H),2.08(s,1H),1.92–1.83(m,1H),1.63(s,1H),1.52–1.42(m,1H)ppm; 13 C NMR (151MHz, CDCl3-d) δ169.46,138.70,121.40,81.29,70.75,67.41,57.76,51.93,50.11,48.23,45.91,42.03,33.63,32.71,26.27ppm.

[0175] Example 39. Preparation of Compound I-36

[0176]

[0177] The same operation as Example 38 was performed to obtain white solid compound I-36 (11.0%). 1H NMR(600MHz, CDCl3-d)δ6.24(d,J=3.4Hz,1H),5.53(d,J=3.0Hz,1H),4.40–4.32(m,1H),4.00– 3.90(m,1H),3.54(d,J=4.5Hz,1H),2.96(t,J=7.8Hz,1H),2.89(d,J=4.4Hz,1H),2.85(d,J=4.5 Hz,1H),2.75–2.68(m,1H),2.57(d,J=4.4Hz,1H),2.15(s,1H),2.09(ddd,J=13.2,7.4,3.7Hz, 1H),1.95–1.89(m,1H),1.85(dd,J=12.9,6.5Hz,1H),1.76–1.68(m,2H),1.67–1.59(m,2H)ppm; 13 C NMR (151MHz, CDCl3-d) δ169.75,138.62,120.91,82.40,71.04,67.41,59.12,54.54,50.10,47.56,47.02,39.62,34.90,34.37,25.21ppm.

[0178] Example 40, Preparation of Compound I-37

[0179]

[0180] The same operation as Example 38 was performed to obtain white solid compound I-37 (14.3%). 1H NMR (600MHz, CDCl3-d) δ6.22(d,J=3.4Hz,1H),5.51(d,J=3.1Hz,1H),5.00(d,J=18.7Hz,2H),4.27(t,J=7.4Hz,1H),4.06 (dd,J=11.0,9.0Hz,1H),3.59(d,J=4.5Hz,1H),3.17(dt,J=13.6,4.7Hz,1H),2.91(d,J=4.5Hz,1H),2.75(ddd,J=11.9,8. 7,3.6Hz,1H),2.61–2.56(m,1H),2.52(t,J=10.4Hz,1H),2.32(ddd,J=13.3,6.3,4.9Hz,1H),2.25(ddd,J=15.9,10.2,5. 7Hz,1H),2.13–2.06(m,1H),1.94(td,J=13.6,8.5Hz,1H),1.63(d,J=6.7Hz,1H),1.41(ddd,J=24.3,11.5,5.0Hz,1H)ppm; 13 C NMR (150MHz, CDCl3-d) δ169.70,148.29,138.82,121.05,114.14,82.76,70.45,66.94,49.63,49.46,46.86,41.78,38.25,36.76,30.90ppm.

[0181] Example 41, Preparation of Compound I-38

[0182]

[0183] According to the steps of Example 35, intermediate III was esterified with p-fluorobenzoic acid to prepare red solid compound I-38 (39.0%). 1H NMR(600MHz, CDCl3-d)δ8.06(dd,J=8.3,5.7Hz,2H),7.11(t,J=8.5Hz,2H),6.25(d,J=3.3Hz,1H),5.90(s, 1H),5.62(s,1H),5.54–5.47(m,2H),4.99(s,1H),4.88(s,1H),3.96(t,J=9.3Hz,1H),3.19(t,J=9.2Hz,1H) ,3.14(dd,J=8.0,4.4Hz,1H),2.94–2.87(m,1H),2.57(dt,J=12.7,4.3Hz,1H),2.43(ddd,J=13.6,6.8,4.6H z,1H),2.27(dd,J=8.7,4.3Hz,1H),2.15(td,J=12.2,5.4Hz,1H),2.11–2.03(m,1H),1.47–1.42(m,1H)ppm; 13 C NMR (150MHz, CDCl3-d) δ170.19,166.78,165.50,165.09,149.02,148.14,139.31,132.35,132.29,126.64,126. 62,120.89,116.08,115.75,115.60,113.76,85.23,53.59,51.05,50.04,45.44,44.81,37.60,37.04,31.18ppm.

[0184] Example 42, Preparation of Compound I-39

[0185]

[0186] According to the procedure of Example 35, intermediate III was esterified with 4-chloro-3-fluorobenzoic acid to prepare white solid compound I-39 (56.7%). 1H NMR (600MHz, CDCl3-d) δ7.79(t,J=8.6Hz,2H),7.48(t,J=7.2Hz,1H),6.25(s,1H),5.90(s,1 H),5.63(s,1H),5.53(s,1H),5.50(s,1H),4.99(s,1H),4.86(s,1H),3.96(t,J=9.2Hz,1H),3 .17(dt,J=17.6,6.7Hz,2H),2.91(t,J=8.4Hz,1H),2.57(d,J=13.1Hz,1H),2.45–2.38(m,1H ),2.30–2.25(m,1H),2.16(td,J=12.1,5.3Hz,1H),2.11–2.03(m,1H),1.47–1.39(m,1H)ppm; 13 C NMR (150MHz, CDCl3-d) δ170.14,164.62,158.80,157.14,148.76,148.06,139.25,130.87,126.15,1 20.92,117.86,117.71,116.46,113.78,85.10,77.53,50.00,45.43,44.84,37.50,36.94,31.16ppm.

[0187] Example 43. Preparation of Compound I-40

[0188]

[0189] According to the procedure of Example 35, intermediate III was esterified with 4-ethoxybenzoic acid to prepare white solid compound I-40 (33.7%). 1H NMR (600MHz, CDCl3-d) δ7.98(d,J=8.8Hz,2H),6.90(d,J=8.8Hz,2H),6.25(d,J=3.4Hz,1H),5.88(t,J=6.1Hz,1H ),5.60(s,1H),5.55–5.47(m,2H),4.98(s,1H),4.89(s,1H),4.08(q,J=7.0Hz,2H),3.96(t,J=9.3Hz,1H),3.18( t,J=9.3Hz,1H),3.12(td,J=8.5,4.4Hz,1H),2.93–2.86(m,1H),2.56(dt,J=12.9,4.4Hz,1H),2.42(ddd,J=13.8 ,6.9,4.5Hz,1H),2.29–2.24(m,1H),2.17–2.11(m,1H),2.05(dd,J=14.1,7.6Hz,1H),1.43(t,J=7.0Hz,3H)ppm; 13 C NMR (150MHz, CDCl3-d) δ170.22,166.24,162.96,149.27,148.21,139.38,131.79,122.55,120.81, 115.71,114.16,113.73,85.32,76.41,63.83,50.05,45.45,44.76,37.67,37.08,31.19,14.80ppm.

[0190] Example 44. Preparation of Compound I-41

[0191]

[0192] According to the steps of Example 35, intermediate III was esterified with nicotinic acid to prepare red solid compound I-41 (34.2%). 1H NMR(600MHz, CDCl3-d)δ9.23(s,1H),8.78(d,J=3.9Hz,1H),8.32(d,J=7.7Hz,1H),7.44–7.40(m,1H), 6.25(d,J=3.0Hz,1H),5.95(d,J=5.7Hz,1H),5.64(s,1H),5.55–5.49(m,2H),5.00(s,1H),4.87(s,1H ),3.96(t,J=9.1Hz,1H),3.19(dd,J=20.6,10.5Hz,2H),2.92(dd,J=14.0,5.8Hz,1H),2.60–2.53(m,1 H),2.47–2.40(m,1H),2.31–2.25(m,1H),2.13(ddd,J=20.6,13.2,5.9Hz,2H),1.48–1.40(m,1H)ppm; 13 C NMR (150MHz, CDCl3-d) δ170.13,164.98,153.32,150.79,148.72,148.04,139.25,137.55,12 6.43,123.59,120.92,116.57,113.80,85.06,49.97,45.44,44.88,37.50,36.87,31.15ppm.

[0193] Example 45. Preparation of Compound I-42

[0194]

[0195] According to the procedure of Example 35, intermediate III was esterified with 2-pyridinecarboxylic acid to prepare white solid compound I-42 (30.0%). 1H NMR (600MHz, CDCl3-d) δ8.17(d,J=8.1Hz,2H),7.72(d,J=8.1Hz,2H),6.27(d,J=3.2Hz,1H),5.94( t,J=6.2Hz,1H),5.65(s,1H),5.58–5.49(m,2H),5.01(s,1H),4.89(s,1H),3.98(t,J=9.2Hz,1H), 3.18(ddd,J=16.3,15.7,8.9Hz,2H),2.96–2.89(m,1H),2.58(dt,J=12.7,4.3Hz,1H),2.48–2.41( m,1H),2.32–2.26(m,1H),2.17(td,J=12.2,5.4Hz,1H),2.13–2.08(m,1H),1.48–1.41(m,1H)ppm; 13 C NMR (150MHz, CDCl3-d) δ170.16,165.25,148.82,148.08,139.26,130.18,125.58,125.5 5,120.94,116.41,113.79,85.16,77.48,50.04,45.43,44.86,37.56,37.00,31.18ppm.

[0196] Example 46. Preparation of Compound I-43

[0197]

[0198] According to the procedure of Example 35, intermediate III was esterified with thiophene-2-carboxylic acid to prepare light yellow solid compound I-43 (61.0%). 1H NMR (600MHz, CDCl3-d) δ7.81(d,J=2.9Hz,1H),7.56(d,J=4.6Hz,1H),7.10(t,J=4.3Hz,1H),6.24(d,J=3.3H z,1H),5.87(t,J=6.1Hz,1H),5.61(s,1H),5.53–5.47(m,2H),4.98(s,1H),4.86(s,1H),3.95(t,J=9.3Hz,1 H),3.21–3.10(m,2H),2.95–2.86(m,1H),2.56(dt,J=12.8,4.4Hz,1H),2.40(ddd,J=13.6,6.7,4.7Hz,1H), 2.31–2.25(m,1H),2.14(td,J=12.3,5.4Hz,1H),2.12–2.04(m,1H),1.42(ddd,J=16.6,11.9,5.3Hz,1H)ppm; 13 C NMR (150MHz, CDCl3-d) δ170.18,162.12,148.85,148.14,139.32,133.99,133.65,132.68,1 27.91,120.83,116.18,113.71,85.20,77.03,49.94,45.43,44.76,37.49,36.99,31.17ppm.

[0199] Example 47. Preparation of Compound I-44

[0200]

[0201] According to the procedure of Example 35, intermediate III was esterified with furan-2-carboxylic acid to prepare gray solid compound I-44 (41.3%). 1H NMR (600MHz, CDCl3-d) δ7.58(s,1H),7.19(d,J=2.5Hz,1H),6.51(s,1H),6.24(d,J=2.5Hz,1H ),5.90(t,J=5.9Hz,1H),5.62(s,1H),5.51(d,J=11.1Hz,2H),4.98(s,1H),4.85(s,1H),3.94( t,J=9.2Hz,1H),3.20–3.11(m,2H),2.91(d,J=8.4Hz,1H),2.58–2.51(m,1H),2.42–2.35(m,1 H),2.29–2.22(m,1H),2.16–2.10(m,1H),2.08(dd,J=14.0,7.3Hz,1H),1.46–1.39(m,1H)ppm; 13 C NMR (150MHz, CDCl3-d) δ170.18,158.62,148.79,148.09,146.55,144.77,139.31,120.85,1 18.27,116.46,113.74,112.01,85.19,76.82,49.99,45.37,44.84,37.49,36.92,31.16ppm.

[0202] Example 48, Preparation of Compound I-45

[0203]

[0204] According to the procedure of Example 35, intermediate III was esterified with thiazole-5-carboxylic acid to prepare red solid compound I-45 (49.3%). 1 H NMR (600MHz, CDCl3-d) δ8.95(s,1H),8.51(s,1H),6.25(d,J=3.0Hz,1H),5.90(t,J=5.9Hz,1H ),5.63(s,1H),5.52(d,J=10.9Hz,2H),4.98(s,1H),4.84(s,1H),3.94(t,J=9.1Hz,1H),3.20 –3.11(m,2H),2.91(t,J=8.2Hz,1H),2.58–2.52(m,1H),2.43–2.38(m,1H),2.30–2.24(m,1H) ,2.18–2.13(m,1H),2.12–2.06(m,1H),1.61(s,1H),1.43(ddd,J=24.0,11.6,5.3Hz,1H)ppm; 13C NMR (150MHz, CDCl3-d) δ170.12,161.07,158.35,149.08,148.52,148.02,139.22,129.9 8,120.93,116.73,113.75,85.05,77.81,49.92,45.40,44.84,37.41,36.90,31.15ppm.

[0205] Example 49. Preparation of Compound I-46

[0206]

[0207] According to the procedure of Example 35, intermediate III was esterified with 2-methylthiazole-5-carboxylic acid to prepare white solid compound I-46 (35.8%). 1 H NMR (600MHz, CDCl3-d) δ8.24(s,1H),6.25(d,J=2.9Hz,1H),5.87(t,J=5.6Hz,1H),5.62(s,1H),5.51 (d,J=20.7Hz,2H),4.98(s,1H),4.84(s,1H),3.94(t,J=9.1Hz,1H),3.15(dt,J=16.7,6.5Hz,2H),2.9 0(d,J=8.1Hz,1H),2.75(s,2H),2.56(dd,J=8.6,4.5Hz,1H),2.42–2.34(m,1H),2.30–2.21(m,1H),2 .17–2.11(m,1H),2.07(dd,J=13.9,6.9Hz,1H),1.67(s,1H),1.43(ddd,J=16.8,12.0,5.3Hz,1H)ppm; 13 CNMR(150MHz, CDCl3-d)δ170.14,161.19,148.63,148.43,148.07,139.27,129.26,120. 90,116.55,113.76,85.10,77.48,49.94,45.43,44.82,37.45,36.95,31.17,19.91ppm.

[0208] Example 50, Preparation of Compound I-47

[0209]

[0210] According to the steps of Example 1, intermediate III was subjected to Michael addition reaction with 2-methylimidazole to prepare white solid compound I-47 (54.9%).1 H NMR(600MHz,CD3OD-d4)δ7.00(s,1H),6.79–6.76(m,1H),5.26(s,1H),5.22(s,1H),4.81(s,1H),4.66(s,1H ),4.54(t,J=7.1Hz,1H),4.30(dd,J=14.8,5.5Hz,1H),4.17(dd,J=14.8,6.9Hz,1H),3.90(t,J=9.4Hz,1H),2 .93(dtd,J=24.7,9.0,2.9Hz,2H),2.82(dt,J=11.9,6.1Hz,1H),2.34(s,3H),2.17–2.06(m,2H),1.88(td,J =12.4,5.1Hz,1H),1.73(dt,J=14.3,7.4Hz,1H),1.51(dq,J=12.8,4.0Hz,1H),1.22(qd,J=12.0,4.9Hz,1H). 13 C NMR(150MHz,CD3OD-d4)δ177.6,155.9,150.8,146.4,127.2,121.4,112.7, 112.4,87.1,74.9,51.0,48.6,46.7,45.5,44.9,40.7,38.7,33.2,12.7ppm.

[0211] Example 51, Preparation of Compound I-48

[0212]

[0213] According to the steps of Example 1, intermediate III and 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine were subjected to Michael addition reaction to prepare light yellow solid compound I-47 (38.2%). 1H NMR (600MHz, CD3OD-d4) δ7.26(d,J=46.7Hz,1H),5.43(s,1H),5.29(s,1H),5.23(s,1H),4.83(s,1H),4.66(s,1H),4.56(t,J=7 .3Hz,1H),3.93–3.85(m,1H),3.49(s,2H),2.98(dd,J=7.0,2.9Hz,2H),2.90(dd,J=13.4,4.9Hz,1H),2.83(q,J=9.5,7.7Hz,1H) ,2.75(dd,J=13.2,6.3Hz,1H),2.69(m,3H),2.59(dt,J=11.4,5.6Hz,1H),2.42(dt,J=13.0,4.3Hz,1H),2.32–2.19(m,2H),2.11 (ddd,J=13.7,7.2,2.6Hz,1H),1.98(td,J=12.5,5.0Hz,1H),1.75(ddd,J=14.7,10.0,4.8Hz,1H),1.31(qd,J=12.2,4.7Hz,1H). 13 C NMR (150MHz, CD3OD-d4) δ178.6,154.7,150.0,113.4,111.0,110.9,85.9,73.6,56.2,53.4,49.6,49.2,46.8,45.1,43.5,39.3,37.8,32.5ppm.

[0214] Example 52, Preparation of Compound I-49

[0215]

[0216] According to the steps of Example 1, intermediate III and 1-hydroxyphthalazine were subjected to Michael addition reaction to prepare white solid compound I-47 (47.2%). 1H NMR(600MHz, CDCl3-d)δ8.43(d,J=7.9Hz,1H),8.20(s,1H),7.82(dt,J=26.0,7.4Hz,2H),7.7 3(d,J=7.7Hz,1H),5.45(d,J=2.5Hz,1H),5.35(d,J=2.4Hz,1H),4.82(s,1H),4.75–4.64(m,3H ),4.51(dd,J=13.8,7.7Hz,1H),3.89(t,J=9.6Hz,1H),3.09–2.97(m,3H),2.37–2.31(m,2H), 2.19–2.12(m,1H),1.86(ddt,J=20.8,13.9,6.0Hz,2H),1.77–1.71(m,2H),1.28–1.17(m,1H). 13 C NMR (150MHz, CDCl3-d) δ175.9,159.9,154.5,149.1,138.3,133.6,132.2,129.6,127.6,1 27.0,126.4,113.1,112.7,85.1,74.6,49.9,49.6,46.8,45.6,43.8,39.8,37.8,32.9ppm.

[0217] Example 53. Preparation of Compound I-50

[0218]

[0219] According to the steps of Example 38, only intermediate III was replaced by intermediate IV, and other reaction conditions remained unchanged. White solid compound I-50 (11.3%) was obtained by purification by silica gel column chromatography. 1 H NMR (600MHz, CDCl3-d) δ6.26(d,J=3.6Hz,1H),5.55(d,J=3.2Hz,1H),4.38(d,J=9.0Hz,1H),4.10(t,J=7.9Hz,1H),3.58(d,J=4.4Hz,1H),3 .05(d,J=4.4Hz,1H),2.90(d,J=4.4Hz,1H),2.75(s,1H),2.63–2.56(m,2H),2.11(dq,J=13.2,4.2Hz,1H),2.06–1.87(m,4H),1.72(m,1H). 13C NMR (151MHz, CDCl3-d) δ169.8,138.9,121.1,83.9,77.4,69.0,68.4,58.5,54.6,51.2,49.7,40.0,34.1,33.6,25.6ppm.

[0220] Example 54. Preparation of Compound I-51

[0221]

[0222] The same operation as Example 53 was performed to obtain white solid compound I-51 (9.3%). 1 H NMR (600MHz, CDCl3-d) δ6.23(d,J=3.6Hz,1H),5.53(d,J=3.2Hz,1H),5.04(s,1H),4.98(s,1H) ,4.40(q,J=8.2,7.5Hz,1H),4.12(d,J=8.6Hz,1H),3.64(d,J=4.5Hz,1H),3.35(ddt,J=12.1,7 .4,3.6Hz,1H),3.08(d,J=4.5Hz,1H),2.86(dd,J=9.4,4.2Hz,1H),2.72(s,1H),2.57(dt,J=13 .3,3.9Hz,1H),2.33(ddd,J=13.7,7.1,4.1Hz,1H),2.23(tq,J=16.1,5.2Hz,2H),2.09(m,2H). 13 C NMR (150MHz, CDCl3-d) δ169.8,147.0,139.0,121.2,115.1,84.2,77.4,69.6,68.1,52.6,51.0,40.0,37.1,36.5,31.1ppm.

[0223] Example 55. Preparation of Compound I-52

[0224]

[0225] According to the procedure of Example 35, intermediate IV was esterified with p-ethoxybenzoic acid to prepare white solid compound I-52 (24.3%). 1H NMR (600MHz, CDCl3-d) δ7.94(d,J=8.7Hz,2H),6.84(d,J=8.7Hz,2H),6.22(d,J=3.4Hz,1H),5.92(t,J= 7.4Hz,1H),5.77(s,1H),5.53–5.49(m,2H),4.96(s,1H),4.85(s,1H),4.12(d,J=8.8Hz,1H),4.02(q,J= 6.9Hz,2H),3.23(ddd,J=11.7,8.7,3.2Hz,1H),2.85–2.81(m,1H),2.53–2.48(m,1H),2.40–2.35(m,1H ),2.32(s,1H),2.23–2.17(m,1H),2.14(dd,J=12.4,5.6Hz,1H),1.56(s,1H),1.37(t,J=7.0Hz,3H)ppm; 13 C NMR (150MHz, CDCl3-d) δ170.21,166.35,163.05,152.95,147.10,139.06,131.89,122.36,121.51, 117.10,114.76,114.20,86.32,80.29,75.83,63.85,53.52,40.34,37.83,36.00,31.50,14.81ppm.

[0226] Example 56. Preparation of Compound I-53

[0227]

[0228] According to the procedure of Example 35, intermediate IV was esterified with isonicotinic acid to prepare white solid compound I-53 (11.5%). 1 H NMR(600MHz, CDCl3-d)δ8.75(s,1H),7.91(s,1H),7.20(s,2H),6.24(s,1H), 5.97(s,1H),5.81(s,1H),5.54(s,2H),4.97(s,1H),4.79(s,1H),4.13(d,J=8 .0Hz,1H),3.23(s,1H),2.87(s,1H),2.52(d,J=7.1Hz,1H),2.43–2.35(m,2H ),2.21(d,J=8.9Hz,1H),2.17(dd,J=11.6,6.8Hz,1H),1.45–1.35(m,1H)ppm; 13C NMR (150MHz, CDCl3-d) δ170.11,164.60,152.10,149.44,146.99,138.81,123.71,121.77,118.28,11 4.69,86.12,86.03,80.42,77.60,75.03,53.57,40.31,39.00,37.84,35.96,31.52,29.84,22.83ppm.

[0229] Example 57. Preparation of Compound I-54

[0230]

[0231] According to the steps of Example 35, intermediate IV was esterified with piperic acid to prepare white solid compound I-54 (33.2%). 1 H NMR(600MHz, CDCl3-d)δ7.67(s,1H),7.49(s,1H),7.27(s,1H),6.84(s,2H),6.29( s,1H),6.05(s,2H),5.97(d,J=5.8Hz,1H),5.84(s,1H),5.59–5.50(m,2H),5.03(s, 1H),4.91(s,1H),4.18(s,1H),3.29(dd,J=8.4,3.0Hz,1H),2.90(d,J=8.6Hz,1H),2 .56(s,1H),2.44–2.35(m,2H),2.24(dd,J=18.1,6.2Hz,1H),1.49–1.38(m,1H)ppm; 13 CNMR(150MHz, CDCl3-d)δ170.22,152.82,151.90,147.87,147.10,139.05,125.69,124.20,121.55,1 17.25,114.76,109.71,108.13,101.99,86.27,80.29,76.11,53.50,40.31,37.78,35.95,31.47ppm.

[0232] Example 58. Preparation of Compound I-55

[0233]

[0234] According to the procedure of Example 35, intermediate IV was esterified with 2-methylthiazole-5-carboxylic acid to prepare white solid compound I-55 (17.6%). 1H NMR (600MHz, CDCl3-d) δ8.27 (s, 1H), 6.29 (d, J = 3.4Hz, 1H), 5.96 (t, J = 7.3Hz, 1H), 5.85 (s, 1H), 5.5 8(d,J=4.5Hz,2H),5.02(s,1H),4.85(s,1H),4.17(d,J=8.8Hz,1H),3.29(ddd,J=11.8,8.7,3.2Hz,1 H),2.89(dd,J=8.2,2.8Hz,1H),2.76(s,3H),2.60–2.55(m,1H),2.42(dd,J=11.4,5.7Hz,1H),2.37 (d,J=6.7Hz,1H),2.30–2.25(m,1H),2.21(d,J=6.0Hz,1H),1.45(ddd,J=17.3,11.9,5.7Hz,1H)ppm; 13 C NMR (151MHz, CDCl3-d) δ168.96,160.18,151.10,147.46,145.85,137.75,120.48,116. 73,113.55,85.01,79.16,75.70,52.32,39.16,36.70,34.73,30.34,28.68,18.75ppm.

[0235] Example 59. Preparation of Compound I-56

[0236]

[0237] According to the steps of Example 35, intermediate IV was esterified with 3,4-dimethoxycinnamic acid to prepare white solid compound I-56 (25.8%). 1H NMR (600MHz, CDCl3-d) δ7.66(d,J=15.9Hz,1H),7.11(d,J=8.2Hz,1H),7.06(s,1H),6.87(d,J=8.3Hz,1H),6.36(d,J= 15.9Hz,1H),6.29(d,J=3.4Hz,1H),5.92(s,1H),5.83(s,1H),5.60–5.54(m,2H),5.01(s,1H),4.88(s,1H),4.17(d,J =8.8Hz,1H),3.91(s,6H),3.28(td,J=8.6,4.3Hz,1H),2.88(d,J=8.6Hz,1H),2.56(dd,J=8.6,3.9Hz,1H),2.43–2.39 (m,1H),2.33(dd,J=14.9,6.7Hz,1H),2.28–2.24(m,1H),2.23–2.18(m,1H),1.44(ddd,J=20.2,12.4,5.6Hz,1H)ppm; 13 C NMR (150MHz, CDCl3-d) δ170.19,167.19,152.94,151.29,149.27,147.05,145.34,138.98,127.37,122.97,121.57, 117.31,115.69,114.72,111.05,109.52,86.28,80.37,75.61,56.09,55.99,53.51,40.29,37.78,36.06,31.49ppm.

[0238] Example 60, Preparation of Compound I-57

[0239]

[0240] According to the steps of Example 35, intermediate IV was esterified with 6-quinoxalinecarboxylic acid to prepare white solid compound I-57 (12.5%). 1H NMR (600MHz, Chloroform-d) δ8.96–8.92 (m, 2H), 8.85 (dt, J=2.2, 1.3 Hz, 1H), 8.37 (ddt, J=8.8, 2.7, 1.2 Hz, 1H), 8.17 (d, J=8.2 Hz, 1H), 6.29 (d, J=3.4 Hz, 1H), 6.10 (tt, J=7.5 ,2.0Hz,1H),5.89(d,J=2.0Hz,1H),5.64(d,J=1.7Hz,1H),5.58(d,J=3.1Hz,1H),5.04 (s,1H),4.92(s,1H),4.21(d,J=8.8Hz,1H),3.36–3.29(m,1H),2.97(dd,J=7.7,4.4Hz,

[0241] 1H),2.61–2.56(m,1H),2.51–2.48(m,2H),2.31–2.21(m,2H),1.71(s,1H),1.52–1.44(m,

[0242] 1H).

[0243] Example 61. Preparation of Compound I-58

[0244]

[0245] According to the steps of Example 35, intermediate IV was esterified with cyclopentanecarboxylic acid to prepare white solid compound I-58 (29.3%). 1H NMR(600MHz,Chloroform-d)δ6.28(d,J=3.5Hz,1H),5.81–5.75(m,2H),5.56(d,J=3.2Hz,1H),5.45(d,J=1.7Hz ,1H),4.99(s,1H),4.84(s,1H),4.14(d,J=8.7Hz,1H),3.27(ddq,J=12.0,8.6,3.3Hz,1H),2.84(dd,J=8.9,3.1 Hz,1H),2.80–2.73(m,1H),2.55(ddd,J=13.1,5.6,3.1Hz,1H),2.32(t,J=1.5Hz,1H),2.27–2.17(m,3H),1.94– 1.87(m,2H),1.81(m,J=14.6,11.4,7.7,5.5,2.6Hz,2H),1.71(ddt,J=6.7,4.7,2.3Hz,1H),1.61(s,2H),1.47–

[0246] 1.41(m,1H),1.28(s,1H).

[0247] Example 62, Preparation of Compound I-59

[0248]

[0249] According to the procedure of Example 35, intermediate IV was esterified with 1-methylpiperidine-4-carboxylic acid to prepare white solid compound I-59 (19.0%). 1 H NMR (400MHz, CDCl3-d) δ6.25(d,J=3.5Hz,1H),5.76(d,J=1.3Hz,2H),5.54(d,J=3.1Hz,1H),5.43(d,J=1 .7Hz,1H),4.97(s,1H),4.82(s,1H),4.12(d,J=8.8Hz,1H),3.31–3.22(m,1H),2.83(dd,J=8.8,3.4Hz,3H ),2.73(s,2H),2.56–2.49(m,1H),2.33–2.30(m,1H),2.27(s,3H),2.21(q,J=2.9,2.5Hz,1H),2.20–2.15 (m,1H),2.09–2.01(m,2H),1.96–1.89(m,2H),1.82(tdd,J=13.4,3.8,2.4Hz,2H),1.46–1.38(m,1H)ppm; 13C NMR (100MHz, CDCl3-d) δ174.9,170.1,152.8,147.1,139.1,121.4,116.9,11 4.6,86.2,80.1,75.5,54.8,53.6,46.3,40.2,37.6,35.8,31.4,28.1,28.0.

[0250] Example 63. Preparation of Compound I-60

[0251]

[0252] According to the procedure of Example 35, intermediate IV was esterified with 2-pyridinecarboxylic acid to prepare white solid compound I-60 (25.8%). 1 H NMR(400MHz,Chloroform-d)δ8.77(dt,J=4.8,1.2Hz,1H),8.12(dt,J=7.8,1.1Hz,1H),7.84(td,J=7.7,1.8Hz,1H),7 .48(ddd,J=7.7,4.8,1.2Hz,1H),6.28(d,J=3.5Hz,1H),6.08(tt,J=7.4,1.9Hz,1H),5.87(d,J=1.9Hz,1H),5.63(d,J =1.7Hz,1H),5.56(d,J=3.1Hz,1H),5.02(s,1H),4.89(s,1H),4.18(d,J=8.8Hz,1H),3.32(tq,J=9.9,3.3Hz,1H),2.9 5(t,J=6.2Hz,1H),2.61–2.53(m,1H),2.46(dd,J=7.6,5.9Hz,2H),2.31–2.19(m,2H),1.91(s,1H),1.49–1.39(m,1H).

[0253] Example 64. Preparation of Compound I-61

[0254]

[0255] According to the steps of Example 35, intermediate IV was esterified with 4-pyrimidinecarboxylic acid to prepare white solid compound I-61 (25.8%). 1H NMR (400MHz, Chloroform-d) δ9.43 (d, J = 1.5 Hz, 1H), 9.00 (dd, J = 5.1, 1.9 Hz, 1H), 8.01 (dt, J = 5.0, 1.7 Hz, 1H), 6.28 (dd, J = 3.6, 1.9 Hz, 1H), 6.07 (td, J = 7.1, 1.9 Hz, 1H), 5.88 (d, J = 1.9 Hz, 1H), 5.63 (t, J = 1.8 Hz, 1H), 5.57 (d, J = 3.1Hz,1H),5.02(s,1H),4.85(s,1H),4.17(dd,J=8.8,1.9Hz,1H),3.30(ddt,J=12.1,6.8,3.3Hz,1H),2.95(t,J =6.2Hz,1H),2.60–2.53(m,1H),2.47(dd,J=7.4,6.0Hz,2H),2.32–2.20(m,2H),1.77(s,1H),1.52–1.40(m,1H).

[0256] Example 65. Preparation of Compound I-62

[0257]

[0258] According to the steps of Example 1, intermediate IV was subjected to Michael addition reaction with 2-methylimidazole to prepare white solid compound I-62 (51.2%). 1 H NMR (600MHz, CDCl3-d) δ6.91(d,J=7.8Hz,1H),6.89(d,J=8.5Hz,1H),5.59(d,J=1.9Hz,1H ),5.45(t,J=3.7Hz,1H),4.91(s,1H),4.74(s,1H),4.69(t,J=7.1Hz,1H),4.34(dd,J=14.9 ,4.8Hz,1H),4.17–4.03(m,2H),2.78(dd,J=8.9,3.9Hz,1H),2.67–2.45(m,3H),2.42(s,3H ),2.40(s,1H),2.29–2.05(m,2H),1.98(ddd,J=25.0,14.7,4.9Hz,1H),1.57–1.46(m,1H). 13C NMR (150MHz, CDCl3-d) δ175.1,156.7,147.3,127.9,119.7,114.5,114.2,86.2,80.1,74.6,53.1,47.9,45.0,40.5,38.7,38.1,32.9,13.3ppm.

[0259] Example 66. Preparation of Compound I-63

[0260]

[0261] According to the steps of Example 1, intermediate IV was subjected to Michael addition reaction with 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine to prepare light yellow solid compound I-63 (29.4%). 1 H NMR(600MHz,CD3OD-d4)δ7.26(s,1H),5.51(d,J=2.4Hz,1H),5.43(s,0H),5.31(d,J= 2.1Hz,1H),4.78(s,1H),4.61(dd,J=9.3,6.7Hz,1H),4.07(d,J=9.0Hz,1H),3.48(s, 2H),2.91(dd,J=13.1,4.8Hz,1H),2.86–2.72(m,2H),2.71–2.64(m,4H),2.41(dt,J= 12.9,5.0Hz,1H),2.19–2.02(m,2H),1.98–1.85(m,1H),1.37(qd,J=11.2,5.4Hz,1H). 13 C NMR (150MHz, CD3OD-d4) δ179.9,158.6,149.9,121.0,114.9,114.0,113.4,87.5,80.7,73.7,54.7,50.5,46.6,41.9,38.6,37.7,33.8ppm.

[0262] Example 67. Preparation of Compound I-64

[0263]

[0264] According to the steps of Example 1, intermediate IV and 1-hydroxyphthalazine were subjected to Michael addition reaction to prepare white solid compound I-64 (38.1%). 1H NMR (600MHz, CDCl3-d) δ8.43(d,J=7.7Hz,1H),8.20(s,1H),7.82(dt,J=24.3,7.3Hz,2H),7.72(d,J=7.9Hz,1H),5.63( s,1H),5.44(s,1H),5.30(s,0H),4.87(s,1H),4.81(dd,J=13.8,5.5Hz,1H),4.75–4.67(m,2H),4.53–4.43(m,1H),4.1 4(d,J=9.5Hz,1H),3.01(dt,J=11.9,6.2Hz,1H),2.77–2.69(m,2H),2.38(dt,J=13.3,4.3Hz,1H),2.24(ddd,J=14.1,7 .5,3.2Hz,1H),2.13(ddd,J=14.7,8.9,6.8Hz,1H),1.97(td,J=12.7,5.4Hz,1H),1.87–1.82(m,1H),1.36–1.26(m,1H). 13 C NMR (150MHz, CDCl3-d) δ176.0,159.9,157.0,147.7,138.3,133.6,132.1,129.7,127.7,1 26.9,126.5,114.4,113.7,86.2,80.5,75.1,52.7,49.6,45.2,40.6,39.1,38.7,33.2ppm.

[0265] Example 68: In vitro anti-HBV activity of dehydrocostus lactone derivatives

[0266] Determination of anti-HBV activity: The ELISA method was used to determine the effects of dehydrocostus lactone derivatives on the secretion of HBeAg and HBsAg antigens. The specific experimental operation steps are as follows: First, the HepG2.2.15 cells with appropriate cell status were washed with PBS, trypsin was added to disperse the cells, culture medium was added and pipetted into a single cell suspension; then, the suspension was transferred to an EP tube, centrifuged to remove the supernatant, and complete culture medium (MEM+10% FBS+380μg / mL G418) was added and pipetted into a single cell suspension, re-inoculated in a 48-well plate, with about 3000 cells per well, and placed in an incubator (37oC, 5% CO2) for 24 hours; finally, the culture medium was aspirated and the cells were treated with the prepared sample solution (30μM), dehydrocostus lactone was used as a positive control, and cells without sample treatment were used as blank controls, and the culture medium was collected after 72 hours of culture in an incubator (37℃, 5% CO2). The samples were tested using HBeAg and HBsAg detection kits, and the absorbance value (OD value) was measured using an enzyme marker at a detection wavelength of 450nm and a reference wavelength of 630nm. The inhibition rate of the compound on HBsAg and HBeAg was calculated according to the formula:

[0267]

[0268] Table 1. In vitro anti-HBV activity of dehydrocostus lactone derivatives prepared in Examples 1-68

[0269]

[0270]

[0271]

[0272] As can be seen from Table 1, the toxicity of most of the Michael addition products in the present invention is greatly reduced, and some compounds have good inhibitory activity against HBeAg, especially the inhibitory rate of imidazole derivative I-15 against HBsAg is comparable to that of the parent dehydrocostus lactone, but the toxicity is reduced by about 5.5 times. The anti-HBV activity of the allylic esterification products I-52 to 61 is significantly better than that of I-38 to 46, which may be due to the presence of hydroxyl groups that increase their water solubility. Among them, compound I-57 not only shows low toxicity to cells (survival rate: 106.60±0.72%) but also exhibits good inhibitory activity against HBsAg (inhibition rate: 83.91±1.62%) compared to the parent dehydrocostus lactone.

[0273] Example 69: Pharmaceutical Use of Dehydrocostus Lactone Derivatives

[0274] According to the above test results, the dehydrocostus lactone derivatives of the present invention have good HBV activity and can be made into anti-HBV drugs for clinical use. These drugs can be either single-prescription preparations, such as dehydrocostus lactone derivatives of a structure and pharmaceutically acceptable excipients; or compound preparations, such as dehydrocostus lactone derivatives of a structure and existing anti-HBV active ingredients and pharmaceutically acceptable excipients, or several dehydrocostus lactone derivatives of different structures and pharmaceutically acceptable excipients. The preparation types include but are not limited to tablets, capsules, powders, granules, pills, injections, powder injections, solutions, suspensions, emulsions, suppositories, ointments, gels, films, aerosols, transdermal absorption patches and other dosage forms, as well as various sustained-release, controlled-release preparations and nano preparations.

[0275] 1. Preparation of Compound I-15 Tablets

[0276] Prescription: Compound I-15 10 g, corn starch 50 g, lactose 187 g, magnesium stearate 3.0 g, and an appropriate amount of 70% by volume ethanol solution, making a total of 1000 tablets.

[0277] Preparation method: Dry corn starch at 105°C for 5 hours for later use; mix compound I-15 with lactose and corn starch evenly, use 70% ethanol solution to make a soft material, sieve to make wet granules, then add magnesium stearate and press into tablets; each tablet weighs 250 mg and contains 10 mg of active ingredient.

[0278] 2. Preparation of Compound I-57 Capsules

[0279] Prescription: Compound I-57 25g, modified starch (120 mesh) 12.5g, microcrystalline cellulose (100 mesh) 7.5g, low-substituted hydroxypropyl cellulose (100 mesh) 2.5g, talcum powder (100 mesh) 2.0g, sweetener 1.25g, orange flavor 0.25g, appropriate amount of pigment, appropriate amount of water, made into 1000 tablets.

[0280] Preparation method: The prescribed amount of compound I-57 is micronized and crushed into extremely fine powder, and then mixed with the prescribed amount of modified starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, talcum powder, sweetener, orange flavor and pigment, and the mixture is made into a soft material with water, granulated with a 12-14 mesh sieve, dried at 40-50°C, sieved through the whole granules, and filled into empty capsules to obtain the product; each tablet weighs 50 mg and contains 25 mg of active ingredient.

[0281] 3. Preparation of Compound I-15 Granules

[0282] Prescription: Compound I-15 26g, dextrin 120g, sucrose 280g.

[0283] Preparation method: Mix compound I-15, dextrin and sucrose evenly, granulate by wet method, dry at 60°C, and package to obtain the product.

[0284] 4. Preparation of Compound I-57 Injection

[0285] Prescription: Compound I-57 10 g, propylene glycol 500 mL, water for injection 500 mL, a total of 1000 mL.

[0286] Preparation method: Weigh compound I-57, add propylene glycol and injection water, stir to dissolve, then add 1g of activated carbon, stir thoroughly and let stand for 15 minutes, filter with a 5μm titanium rod to remove carbon, and then filter with microporous filter membranes with pore sizes of 0.45μm and 0.22μm in turn, finally fill into a 10mL ampoule, and sterilize with circulating steam at 100℃ for 45 minutes.

[0287] 5. Preparation of Compound I-15 Powder Injection

[0288] Preparation method: The intermediate I-15 sterile powder is packaged under aseptic conditions to obtain the product.

[0289] Preparation method: Weigh gelatin and glycerin, add distilled water to 100 mL, heat in a water bath at 60°C until it melts into a paste, add compound I-15, stir evenly, pour into a vaginal suppository mold when it is almost solidified, and cool and solidify to obtain the product.

[0290] Those skilled in the art will readily appreciate other embodiments of the present application after considering the specification and practicing the contents disclosed herein. The present application is intended to cover any variations, uses or adaptations of the present application, which follow the general principles of the present application and include common knowledge or customary technical means in the art that are not disclosed in the present application.

Claims

1. A dehydrocostus lactone derivative, characterized in that: The structure is shown in general formula I: In the formula, R1 is selected from hydrogen, hydroxyl; R2 is selected from hydrogen, hydroxyl, and ester; Z is selected from -C=CH2, -CR3CH2R4; R3 is selected from hydrogen, hydroxyl; R4 is selected from hydroxyl group and ester group; Q is selected from one of alkenyl, alkyl, oxirane, and difluorocyclopropyl; W is selected from alkenyl, alkyl, ethylene oxide, and difluorocyclopropyl.

2. The dehydrocostus lactone derivative according to claim 1, characterized in that R1 is hydrogen or hydroxyl; R2 is hydrogen, hydroxyl, or ester; Z is -C=CH2, -CR3CH2R4; R3 is hydrogen or hydroxyl; R4 is an ester group; Q is selected from alkenyl, ethylene oxide; W is selected from alkenyl and ethylene oxide.

3. The dehydrocostus lactone derivative according to claim 1, characterized in that Any one of the following compounds:

4. A pharmaceutically acceptable salt of a dehydrocostus lactone derivative according to any one of claims 1 to 3, characterized in that: The pharmaceutically acceptable salt is hydrochloride, bromate, iodide, sulfate, nitrate, trifluoroacetate or acetate.

5. A method for preparing the dehydrocostus lactone derivative according to claim 3, characterized in that: The method is as follows: a. Preparation of dehydrocostus lactone derivatives I-1 to 33: reacting dehydrocostus lactone with different amines in tetrahydrofuran in the presence of triethylamine to obtain costus lactone derivatives I-1 to 33 represented by general formula I; b. Preparation of intermediate II: In the presence of potassium osmate dihydrate and N-methylmorpholine-N-oxide, dehydrocostus lactone is oxidized in a mixed solution of tert-butyl alcohol / tetrahydrofuran / water to obtain intermediate II; c. Preparation of dehydrocostus lactone derivative I-34: In the presence of DMAP, EDCI and DIPEA, intermediate II is subjected to esterification reaction with nicotinic acid in tetrahydrofuran to obtain dehydrocostus lactone derivative I-34 represented by general formula I; d. Preparation of intermediates III and IV: In the presence of selenium dioxide and tert-butyl hydroperoxide, dehydrocostus lactone is subjected to allylic oxidation in anhydrous dichloromethane to obtain intermediates III and IV; e. Preparation of dehydrocostus lactone derivatives I-35-37: In the presence of m-chloroperbenzoic acid, the intermediate III is oxidized in anhydrous dichloromethane to obtain dehydrocostus lactone derivatives I-35-37 represented by general formula I; f. Preparation of dehydrocostus lactone derivatives I-38-46: In the presence of DMAP, EDCI and DIPEA, intermediate III is subjected to esterification reaction with different carboxylic acids in tetrahydrofuran to obtain dehydrocostus lactone derivatives I-38-46 represented by general formula I; g. Preparation of dehydrocostus lactone derivatives I-47 to 49: In the presence of triethylamine, the intermediate III is reacted with different amines in tetrahydrofuran to obtain costus lactone derivatives I-47 to 49 represented by the general formula I; h. Preparation of dehydrocostus lactone derivatives I-50 and I-51: In the presence of m-chloroperbenzoic acid, the intermediate IV is oxidized in anhydrous dichloromethane to obtain dehydrocostus lactone derivatives I-50 and I-51 represented by general formula I; i. Preparation of dehydrocostus lactone derivatives I-52-61: In the presence of DMAP, EDCI and DIPEA, intermediate IV is subjected to esterification reaction with different carboxylic acids in tetrahydrofuran to obtain dehydrocostus lactone derivatives I-52-61 represented by general formula I; j. Preparation of dehydrocostus lactone derivatives I-62-64: In the presence of triethylamine, the intermediate IV is reacted with different amines in tetrahydrofuran to obtain costus lactone derivatives I-62-64 represented by the general formula I.

6. The method according to claim 5, characterized in that In step a, the ratio of the amount of dehydrocostus lactone to triethylamine and amine substance is 1:1:3; In step b, the molar ratio of dehydrocostus lactone to potassium osmate dihydrate and N-methylmorpholine-N-oxide is 1:0.5:1.5; In step c, the molar ratio of the intermediate II to DMAP, EDCI, DIPEA and nicotinic acid is 1:0.2:2:2:2; In step d, the ratio of the amount of dehydrocostus lactone to selenium dioxide and tert-butyl hydroperoxide is 1:1:0.004; In step e, the molar ratio of the intermediate III to meta-chloroperbenzoic acid is 1:3; In step f, the molar ratio of the intermediate III to DMAP, EDCI, DIPEA and carboxylic acid is 1:0.2:2:2:2; In step g, the ratio of the amount of the intermediate III to triethylamine and the amine substance is 1:1:3; In step h, the molar ratio of the intermediate IV to meta-chloroperbenzoic acid is 1:3; In step i, the molar ratio of the intermediate IV to DMAP, EDCI, DIPEA and carboxylic acid is 1:0.2:2:2:2; In step j, the ratio of the amount of the intermediate IV to triethylamine and the amount of the amine substance is 1:1:

3.

7. Use of the dehydrocostus lactone derivative according to any one of claims 1 to 3 in the preparation of anti-HBV drugs.

8. Use of the pharmaceutically acceptable salt of the dehydrocostus lactone derivative according to claim 4 in the preparation of anti-HBV drugs.

9. An anti-HBV pharmaceutical preparation containing the dehydrocostus lactone derivative according to any one of claims 1 to 3.

10. An anti-HBV pharmaceutical preparation containing the pharmaceutically acceptable salt of the dehydrocostus lactone derivative according to claim 4.

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