Dehydrocostus lactone derivatives, processes for their preparation and medical uses thereof

Abstract

The application discloses a dehydrocostus lactone derivative, a preparation method and medical application thereof, and belongs to the technical field of chemical synthesis. The dehydrocostus lactone derivative is shown as a general formula I. The compound has certain inhibiting effect on HBsAg and HBeAg, can be used for preparing anti-HBV drugs, and provides more efficient and safe candidate drug molecules for clinical anti-HBV treatment.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to dehydroaromatic lactone derivatives, their preparation methods, and pharmaceutical applications. Background Technology

[0002] Hepatitis B virus (HBV) can cause acute and chronic hepatitis in humans, leading to cirrhosis or liver cancer. Nucleoside analogues act on HBV DNA polymerase, exhibiting significant anti-HBV activity, but they cannot completely eliminate the virus from the patient's body, and long-term use easily leads to drug resistance. Therefore, anti-HBV drugs have limited structural types, single targets, high toxicity in clinical application, and are prone to drug resistance. They also suffer from low bioavailability and rapid metabolism.

[0003] Natural products play a crucial role in antiviral drug research as prototype drugs or lead compounds. Dehydroauracene lactone exhibits significant anti-hepatitis B virus activity, but it suffers from poor water solubility, poor stability, and low oral bioavailability. Therefore, structural modification is sought to obtain aauracene lactone derivative with low toxicity, high activity, and high bioavailability. Summary of the Invention

[0004] In view of this, one of the objectives of the present invention is to provide dehydroauracene lactone derivatives, their preparation methods and pharmaceutical applications, thereby providing more efficient and safe candidate drugs for clinical anti-HBV treatment.

[0005] To achieve the above objectives, the present invention provides the following technical solution:

[0006] Dehydrocostane lactone derivatives, with structures shown in general formula I:

[0007] ;

[0008] In the formula,

[0009] R1 is selected from hydrogen or hydroxyl group;

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

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

[0012] R3 is selected from hydrogen or hydroxyl groups;

[0013] R4 is selected from hydroxyl or ester groups;

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

[0015] W is selected from one of alkenyl, alkyl, epoxy ethyl, and difluorocyclopropyl.

[0016] Preferably, R1 is hydrogen or hydroxyl;

[0017] R2 can be hydrogen, hydroxyl, or ester group;

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

[0019] R3 represents hydrogen or a hydroxyl group;

[0020] R4 is an ester group;

[0021] Q is selected from alkenyl or epoxy ethyl;

[0022] W is selected from alkenyl or epoxy ethyl.

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

[0024]

[0025]

[0026]

[0027]

[0028]

[0029]

[0030]

[0031]

[0032]

[0033]

[0034]

[0035]

[0036]

[0037]

[0038]

[0039]

[0040]

[0041] .

[0042] This application also provides pharmaceutically acceptable salts of the above-mentioned dehydroauric acid lactone derivatives, wherein the pharmaceutically acceptable salts are hydrochloride, bromate, iodate, sulfate, nitrate, trifluoroacetate, or acetate.

[0043] This application also provides a method for preparing the above-mentioned dehydroacostal lactone derivative, the method being as follows:

[0044] a. Preparation of dehydrocostane lactone derivatives I-1~33: In the presence of triethylamine, dehydrocostane lactone is reacted with different amines in tetrahydrofuran to obtain costane lactone derivatives I-1~33 as shown in general formula I.

[0045] b. Preparation of intermediate II: In potassium osmium dihydrate and N -Methylmorpholine- N - In the presence of oxides, dehydroauric acid lactone was oxidized in a mixed solution of tert-butanol / tetrahydrofuran / water to prepare intermediate II;

[0046]

[0047] c. Preparation of dehydroauric acid lactone derivative I-34: In the presence of DMAP, EDCI and DIPEA, intermediate II was esterified with nicotinic acid in tetrahydrofuran to obtain dehydroauric acid lactone derivative I-34 as shown in general formula I.

[0048] d. Preparation of intermediates III and IV: In the presence of selenium dioxide and tert-butyl hydrogen peroxide, dehydroaromatic lactone was allylated in anhydrous dichloromethane to obtain intermediates III and IV.

[0049]

[0050] e. Preparation of dehydroauric acid lactone derivatives I-35-37: In the presence of m-chloroperoxybenzoic acid, intermediate III was oxidized in anhydrous dichloromethane to obtain dehydroauric acid lactone derivatives I-35~37 as shown in general formula I.

[0051] f. Preparation of dehydroauric acid lactone derivatives I-38~46: In the presence of DMAP, EDCI and DIPEA, intermediate III was esterified with different carboxylic acids in tetrahydrofuran to obtain dehydroauric acid lactone derivatives I-38~46 as shown in general formula I.

[0052] g. Preparation of dehydroaromatic lactone derivatives I-47~49: In the presence of triethylamine, intermediate III was reacted with different amines in tetrahydrofuran to obtain the aromatic lactone derivatives I-47~49 represented by general formula I.

[0053] h. Preparation of dehydroauric acid lactone derivatives I-50 and I-51: In the presence of m-chloroperoxybenzoic acid, intermediate IV was oxidized in anhydrous dichloromethane to obtain dehydroauric acid lactone derivatives I-50 and I-51 as shown in general formula I.

[0054] i. Preparation of dehydroauric acid lactone derivatives I-52~61: In the presence of DMAP, EDCI and DIPEA, intermediate IV was esterified with different carboxylic acids in tetrahydrofuran to obtain dehydroauric acid lactone derivatives I-52~61 as shown in general formula I.

[0055] j. Preparation of dehydroaromatic lactone derivatives I-62~64: In the presence of triethylamine, intermediate IV was reacted with different amines in tetrahydrofuran to obtain the aromatic lactone derivatives I-62~64 represented by general formula I.

[0056] Preferably,

[0057] In step a, the molar ratio of the dehydroauric acid lactone to triethylamine and amine is 1:1:3;

[0058] In step b, the dehydroauric acid lactone and potassium osmium dihydrate and N -Methylmorpholine- N - The molar ratio of the oxides is 1:0.5:1.5;

[0059] In step c, the molar ratio of intermediate II to DMAP, EDCI, DIPEA and nicotinic acid is 1:0.2:2:2:2;

[0060] In step d, the molar ratio of the dehydroaromatic lactone to selenium dioxide and tert-butyl hydrogen peroxide is 1:1:0.004.

[0061] In step e, the molar ratio of intermediate III to m-chloroperoxybenzoic acid is 1:3;

[0062] In step f, the molar ratio of intermediate III to DMAP, EDCI, DIPEA and carboxylic acid is 1:0.2:2:2:2;

[0063] In step g, the molar ratio of intermediate III to triethylamine and amine is 1:1:3;

[0064] In step h, the molar ratio of intermediate IV to m-chloroperoxybenzoic acid is 1:3;

[0065] In step i, the molar ratio of intermediate IV to DMAP, EDCI, DIPEA and carboxylic acid is 1:0.2:2:2:2;

[0066] In step j, the molar ratio of intermediate IV to triethylamine and amine is 1:1:3. Detailed Implementation

[0067] The terminology used in this application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. The singular forms “a,” “the,” and “the” used in this application and the appended claims are also intended to include the plural forms unless the context clearly indicates otherwise. It should also be understood that the term “and / or” as used herein refers to and includes any or all possible combinations of one or more of the associated listed items.

[0068] Example 1: Preparation of Compound I-1

[0069]

[0070] A mixture of dehydroauronil (86.80 μmol, 1 equiv), triethylamine (86.80 μmol, 1 equiv), n-hexylamine (26.00 mmol, 3 equiv), and tetrahydrofuran (0.3 mL) was prepared at 50 mL. o Heating at C for 2 hours. After the reaction was complete, the solvent was removed under vacuum to obtain the crude product, which was further purified by silica gel column chromatography to obtain colorless oily compound I-1 (40.0%). 1 H NMR (600 MHz, CDCl3- d ) d 5.18 (q, J = 2.5 Hz, 1H), 5.04 (q, J = 2.4 Hz,1H), 4.87 (s, 1H), 4.76 (s, 1H), 3.96 (t, J = 9.5 Hz, 1H), 2.90 (dd, J = 12.1, 4.3 Hz, 1H), 2.87 (dd, J = 8.1, 4.2 Hz, 1H), 2.84 – 2.80 (m, 1H), 2.79 – 2.76(m, 1H), 2.60 (q, J = 7.0 Hz, 2H), 2.57 – 2.47 (m, 2H), 2.47 – 2.43 (m, 1H), 2.41 (dd, J = 7.3, 4.3 Hz, 1H), 2.24 (tdd, J= 11.7, 9.5, 3.1 Hz, 1H), 2.15 –2.09 (m, 1H), 2.03 (td, J = 12.3, 5.2 Hz, 1H), 1.94 (ddt, J = 13.3, 9.5, 7.8 Hz,1H), 1.88 – 1.82 (m, 1H), 1.49 (dq, J = 14.8, 7.4 Hz, 2H), 1.31 (d, J = 5.3 Hz, 1H), 1.30 (d, J = 3.9 Hz, 2H), 1.28 (q, J = 2.0 Hz, 2H), 1.24 (s, 2H), 0.88 (s,2H) ppm; 13 C NMR (150 MHz, CDCl3- d ) d 178.2, 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.

[0071] Example 2, Preparation of Compound I-2

[0072]

[0073] Following the steps of Example 1, only 3-isopropoxypropylamine was used to replace n-hexylamine, while other reaction conditions remained unchanged. The colorless oily compound I-2 (44.8%) was obtained by silica gel column chromatography purification. 1 H NMR (600 MHz, CDCl3- d ) d 5.21 –5.12 (m, 1H), 5.03 (q, J = 2.3 Hz, 1H), 4.86 (d, J = 1.3 Hz, 1H), 4.76 (t, J = 1.3Hz, 1H), 3.95 (t, J = 9.5 Hz, 1H), 3.56 – 3.52 (m, 1H), 3.47 (td, J = 6.3, 1.5Hz, 2H), 2.90 (dd,J = 12.2, 4.3 Hz, 1H), 2.87 (dd, J = 8.0, 4.2 Hz, 1H), 2.84 –2.80 (m, 1H), 2.80 – 2.77 (m, 1H), 2.70 (td, J = 6.9, 2.2 Hz, 2H), 2.51 (dddd, J = 19.5, 17.8, 8.7, 3.2 Hz, 2H), 2.45 (t, J = 4.5 Hz, 1H), 2.40 (ddd, J = 11.4,6.8, 4.3 Hz, 1H), 2.26 (tdd, J = 11.7, 9.7, 3.2 Hz, 1H), 2.12 (ddt, J = 12.8,5.1, 3.6 Hz, 1H), 2.03 (td, J = 12.2, 5.2 Hz, 1H), 1.94 (ddt, J = 13.3, 9.6, 7.9Hz, 1H), 1.88 – 1.82 (m, 1H), 1.74 (p, J = 6.4 Hz, 2H), 1.34 (dtd, J = 13.0,11.6, 5.0 Hz, 1H), 1.16 – 1.13 (m, 6H) ppm; 13 C NMR (150 MHz, CDCl3- d ) d 178.1,151.9, 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, 22.2 ppm.

[0074] Example 3: Preparation of Compound I-3

[0075]

[0076] Following the steps of Example 1, simply replace n-hexylamine with cyclopropylmethylamine while keeping other reaction conditions unchanged, and obtain a colorless oily compound I-3 (45.6%) by silica gel column chromatography. 1 H NMR (600 MHz, CDCl3-d ) d 5.18 (q, J =2.5 Hz, 1H), 5.03 (q, J = 2.4 Hz, 1H), 4.86 (s, 1H), 4.76 (s, 1H), 3.95 (t, J =9.5 Hz, 1H), 2.92 (dd, J = 12.1, 4.2 Hz, 1H), 2.88 (td, J = 8.2, 4.1 Hz, 1H),2.82 (d, J = 7.3 Hz, 1H), 2.80 (d, J = 7.3 Hz, 1H), 2.54 (ddd, J = 17.1, 8.5, 2.0Hz, 1H), 2.47 (d, J = 6.5 Hz, 2H), 2.45 (d, J = 1.9 Hz, 1H), 2.41 (ddd, J = 11.6,7.2, 4.3 Hz, 1H), 2.25 (tdd, J = 12.1, 9.6, 3.3 Hz, 1H), 2.15 – 2.12 (m, 1H),2.12 – 2.09 (m, 1H), 2.04 (td, J = 12.3, 5.1 Hz, 1H), 1.96 – 1.90 (m, 1H), 1.85(tq, J = 8.7, 4.2 Hz, 1H), 1.34 (qd, J = 11.7, 5.0 Hz, 1H), 0.93 (ddt, J = 9.8,7.2, 3.8 Hz, 1H), 0.49 – 0.46 (m, 2H), 0.12 (q, J = 4.7 Hz, 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, 3.5 ppm.

[0077] Example 4: Preparation of Compound I-4

[0078]

[0079] Following the steps in Example 1, simply use N Replacing n-hexylamine with tert-butyloxycarbonyl-1,2-ethylenediamine, and keeping other reaction conditions unchanged, yielded a white solid compound I-4 (72.3%) by silica gel column chromatography. 1 H NMR (600 MHz, CDCl3- d )δ 5.15 (s, 1H), 5.02 (s, 1H), 4.85 (s, 1H), 4.75 (s, 1H), 3.94 (t, J = 9.5 Hz, 1H), 3.21 (q, J = 5.8 Hz, 2H), 2.88 (ddd, J = 21.7, 10.0, 4.1 Hz, 2H), 2.78 (td, J = 14.3, 12.2, 7.9 Hz, 1H), 2.72 (t, J = 5.9 Hz, 2H), 2.58 – 2.41 (m, 2H), 2.40 – 2.33 (m, 1H), 2.30 – 2.20 (m, 1H), 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 (150 MHz, CDCl3-) d ) δ 177.9, 156.1, 151.7, 149.8, 112.0, 109.2, 85.8, 79.2, 51.9, 49.2,47.3, 47.1, 47.0, 45.1, 39.9, 37.7, 32.6, 32.5, 30.2, 28.4, 28.4 ppm.

[0080] Example 5: Preparation of Compound I-5

[0081]

[0082] Following the steps of Example 1, simply replace n-hexylamine with phenylethylamine while keeping other reaction conditions unchanged, and obtain a colorless oily compound I-5 (44.3%) by silica gel column chromatography. 1 H NMR (600 MHz, CDCl3- d ) d 7.30 (t, J = 7.6Hz, 2H), 7.22 (d, J = 2.7 Hz, 1H), 7.20 (d, J = 3.8 Hz, 2H), 5.18 (p, J = 2.8 Hz, 1H), 5.04 (q, J = 2.3 Hz, 1H), 4.86 (s, 1H), 4.76 (s, 1H), 3.94 (t, J = 9.5 Hz, 1H), 2.94 (dd, J = 12.1, 4.4 Hz, 1H), 2.91 – 2.87 (m, 2H), 2.87 (d, J = 3.2 Hz, 1H), 2.85 (d, J = 3.7 Hz, 1H), 2.84 – 2.82 (m, 1H), 2.80 (t, J = 6.8 Hz, 2H), 2.52 (dddt, J = 14.6, 10.2, 7.8, 2.1 Hz, 2H), 2.45 (dt, J = 13.0, 4.4 Hz, 1H),2.38 (ddd, J = 11.4, 6.8, 4.4 Hz, 1H), 2.22 (tdd, J = 11.8, 9.6, 3.2 Hz, 1H),2.10 – 2.04 (m, 1H), 2.00 (td, J = 12.2, 5.2 Hz, 1H), 1.97 – 1.91 (m, 1H), 1.88 – 1.81 (m, 1H), 1.36 – 1.27 (m, 1H) ppm; 13 C NMR (150 MHz, CDCl3- d ) d178.1,151.9, 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, 30.3 ppm.

[0083] Example 6: Preparation of Compound I-6

[0084]

[0085] Following the steps of Example 1, only 3,4-dimethoxyphenethylamine was used to replace n-hexylamine, while other reaction conditions remained unchanged. The colorless oily compound I-6 (24.2%) was obtained by silica gel column chromatography purification. 1 H NMR (600 MHz, CDCl3- d ) d 7.45– 7.36 (m, 2H), 7.11 – 7.06 (m, 2H), 5.17 (p, J = 2.3 Hz, 1H), 5.04 (q, J = 2.3Hz, 1H), 4.87 (d, J = 1.3 Hz, 1H), 4.76 (t, J = 1.3 Hz, 1H), 3.94 (t, J = 9.5 Hz, 1H), 2.93 (dd, J = 12.1, 4.3 Hz, 1H), 2.90 – 2.84 (m, 2H), 2.84 – 2.80 (m, 1H), 2.79 (d, J = 5.3 Hz, 1H), 2.78 (s, 1H), 2.74 (t, J = 7.7 Hz, 2H), 2.57 – 2.48 (m,2H), 2.48 – 2.43 (m, 1H), 2.37 (ddd, J = 11.3, 6.8, 4.3 Hz, 1H), 2.21 (tdd, J=11.8, 9.7, 3.1 Hz, 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 (150 MHz, CDCl3- d ) d 178.1, 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, 30.3 ppm.

[0086] Example 7: Preparation of Compound I-7

[0087]

[0088] Following the steps of Example 1, simply replace n-hexylamine with 4-bromophenylethylamine while keeping other reaction conditions unchanged, and obtain a colorless oily compound I-7 (22.1%) by silica gel column chromatography. 1 H NMR (600 MHz, CDCl3- d ) d 6.80 (d, J =7.9 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.73 (d, J = 2.2 Hz, 1H), 5.17 (q, J = 2.4Hz, 1H), 5.03 (q, J = 2.3 Hz, 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, 4.4 Hz, 1H), 2.89 –2.83 (m, 2H), 2.83 – 2.82 (m, 1H), 2.80 (d, J = 5.7 Hz, 1H), 2.77 (dd, J = 8.7, 1.8 Hz, 1H), 2.74 (t,J = 7.3 Hz, 2H), 2.50 (tdd, J = 10.3, 4.8, 2.4 Hz, 2H),2.44 (dt, J = 13.0, 4.4 Hz, 1H), 2.38 (ddd, J = 11.4, 6.9, 4.4 Hz, 1H), 2.21(tdd, J = 11.8, 9.6, 3.2 Hz, 1H), 2.10 – 2.04 (m, 1H), 2.00 (td, J = 12.2, 5.1Hz, 1H), 1.93 (ddt, J = 13.3, 9.6, 7.9 Hz, 1H), 1.87 – 1.81 (m, 1H), 1.32 (dtd, J = 12.9, 11.5, 5.0 Hz, 1H) ppm; 13 C NMR (150 MHz, CDCl3- d ) d 178.0, 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, 30.3 ppm.

[0089] Example 8: Preparation of Compound I-8

[0090]

[0091] Following the steps of Example 1, only 3-(2-aminoethyl)pyridine was used to replace n-hexylamine, while other reaction conditions remained unchanged. The colorless oily compound I-8 (62.9%) was obtained by silica gel column chromatography purification. 1 H NMR (600 MHz, CDCl3- d ) δ8.52 (d, 1H), 7.59 (td, J = 7.6, 1.9 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.11 (dd, J= 7.6, 4.9 Hz, 1H), 5.16 (s, 1H), 5.02 (s, 1H), 4.85 (s, 1H), 4.74 (s, 1H), 3.92 (t, J = 9.5 Hz, 1H), 3.08 – 2.93 (m, 5H), 2.84 (dd, J = 12.1, 6.4 Hz, 2H), 2.78 (t, J = 9.3 Hz, 1H), 2.55 – 2.36 (m, 5H), 2.30 – 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 (150 MHz, CDCl3- d ) δ 177.8, 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, 30.2 ppm.

[0092] Example 9: Preparation of Compound I-9

[0093]

[0094] Following the steps of Example 1, simply replace n-hexylamine with 2-phenoxyethylamine while keeping other reaction conditions unchanged, and obtain a colorless oily compound I-9 (63.2%) by silica gel column chromatography. 1 H NMR (600 MHz, CDCl3- d ) δ 7.41 –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 = 5.2 Hz, 2H), 3.96 (t, J= 9.4 Hz, 1H), 3.06 – 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, 4.0 Hz, 1H), 2.07 – 1.90 (m, 2H), 1.89 – 1.82 (m, 1H), 1.40 – 1.24(m, 1H) ppm; 13 C NMR (150 MHz, CDCl3- d ) δ 177.8, 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, 30.2 ppm.

[0095] Example 10: Preparation of Compound I-10

[0096]

[0097] Following the steps of Example 1, only glycine methyl ester was used to replace n-hexylamine, while other reaction conditions remained unchanged. The resulting colorless oil compound I-10 (45.6%) was purified by silica gel column chromatography. 1 H NMR (600 MHz, CDCl3-) d ) d 5.18 (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, 4.3 Hz, 1H), 2.35 – 2.27 (m, 1H), 2.13 (ddt, J = 12.7, 5.1, 3.6 Hz, 1H), 2.05 (td, J = 13.0, 12.6, 5.2 Hz, 1H), 1.94 (ddt, J =13.3, 9.6, 7.9 Hz, 1H), 1.89 – 1.82 (m, 1H), 1.34 (dtd, J = 12.9, 11.5, 5.0 Hz, 1H) ppm; 13 C NMR (150 MHz, CDCl3- d ) d 177.7, 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, 30.3 ppm.

[0098] Example 11, Preparation of Compound I-11

[0099]

[0100] Following the steps of Example 1, only proline methyl ester was replaced with hexylamine, while other reaction conditions remained unchanged. The colorless oily compound I-11 (31.9%) was obtained by silica gel column chromatography purification. ¹H NMR (600 MHz, CDCl₃-) d ) d 5.18 (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 = 1.2Hz, 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 = 4.5 Hz, 1H), 2.38 (ddd, J = 11.6,6.0, 4.3 Hz, 1H), 2.35 – 2.27 (m, 1H), 2.13 (ddt, J = 12.7, 5.1, 3.6 Hz, 1H),2.05 (td, J = 13.0, 12.6, 5.2 Hz, 1H), 1.94 (ddt, J = 13.3, 9.6, 7.9 Hz, 1H),1.89 – 1.82 (m, 1H), 1.34 (dtd, J = 12.9, 11.5, 5.0 Hz, 1H) ppm; 13 C NMR (150MHz, CDCl3- d ) d 177.7, 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, 30.3 ppm.

[0101] Example 12, Preparation of Compound I-12

[0102]

[0103] Following the steps of Example 1, simply replace n-hexylamine with piperazine while keeping other reaction conditions unchanged, and obtain a colorless oily compound I-12 (36.8%) by silica gel column chromatography. 1 H NMR (600 MHz, CDCl3- d ) d 5.19 (q, J = 2.4 Hz, 1H), 5.05 (q, J= 2.3 Hz, 1H), 4.87 (s, 1H), 4.77 (s, 1H), 3.93 (t, J = 9.5 Hz, 1H), 3.69 (dp, J = 11.7, 6.9, 6.1 Hz, 4H), 2.90 (td, J = 8.2, 4.4 Hz, 1H), 2.81(d, J = 4.4 Hz, 1H), 2.79 (d, J = 4.7 Hz, 1H), 2.61 (dd, J = 13.1, 7.5 Hz, 1H),2.58 – 2.44 (m, 4H), 2.45 (t, J = 4.7 Hz, 2H)2.42 (t, J = 6.1 Hz, 1H), 2.39 (dt, J = 7.5, 4.3 Hz, 1H), 2.33 (ddt, J = 13.0, 8.7, 3.9 Hz, 1H), 2.26 (tdd, J = 11.6,9.5, 3.3 Hz, 1H), 2.07 (td, J = 12.3, 5.2 Hz, 1H), 1.95 (ddt, J = 13.2, 9.6, 7.8Hz, 1H), 1.86 (ddt, J = 13.5, 8.8, 5.1 Hz, 1H), 1.30 (q, J = 3.5, 2.5 Hz, 1H). 13 CNMR (150 MHz, CDCl3- d ) d 177.7, 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, 30.3 ppm.

[0104] Example 13, Preparation of Compound I-13

[0105]

[0106] Following the steps of Example 1, simply replace n-hexylamine with 1-(2-methoxyphenyl)piperazine while keeping other reaction conditions unchanged, and obtain a white solid compound I-13 (51.2%) by silica gel column chromatography. 1 H NMR (600 MHz, CDCl3- d ) d 5.19 (q, J = 2.4 Hz, 1H), 5.05 (q, J = 2.3 Hz, 1H), 4.87 (s, 1H), 4.77 (s, 1H), 3.93 (t, J = 9.5 Hz, 1H), 3.69 (dp, J = 11.7, 6.9, 6.1 Hz, 4H), 2.90 (td, J =8.2, 4.4 Hz, 1H), 2.81 (d, J = 4.4 Hz, 1H), 2.79 (d, J = 4.7 Hz, 1H, 2.61 (dd, J = 13.1, 7.5 Hz, 1H), 2.58 – 2.44 (m, 4H), 2.45 (t, J = 4.7 Hz, 2H)2.42 (t, J =6.1 Hz, 1H), 2.39 (dt, J = 7.5, 4.3 Hz, 1H), 2.33 (m, 1H), 2.26 (tdd, J = 11.6,9.5, 3.3 Hz, 1H, m), 2.07 (m, 1H), 1.95 (m, 1H), 1.86 (m, 1H), 1.30 (m, 1H)ppm; 13 C NMR (150 MHz, CDCl3- d ) d 177.6, 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, 30.3 ppm.

[0107] Example 14, Preparation of Compound I-14

[0108]

[0109] Following the steps of Example 1, only imidazole was replaced with n-hexylamine, while other reaction conditions remained unchanged. The colorless oily compound I-14 (49.6%) was obtained by silica gel column chromatography purification. 1 H NMR (600 MHz, CDCl3- d ) δ 7.00 (td, J = 7.5,2.1 Hz, 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 = 9.5 Hz, 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, 4.2 Hz, 1H), 2.27 (qd, J = 11.3, 3.3 Hz, 1H), 2.07 (td, J = 12.2, 5.1 Hz, 1H), 2.02 – 1.90 (m, 1H), 1.90 – 1.81 (m, 1H),1.37 – 1.27 (m, 1H) ppm; 13 C NMR (150 MHz, CDCl3- d ) δ 177.8, 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, 30.2 ppm.

[0110] Example 15: Preparation of Compound I-15

[0111]

[0112] Following the steps of Example 1, only 2-methylimidazole was used to replace n-hexylamine, while other reaction conditions remained unchanged. The white solid compound I-15 (57.2%) was obtained by silica gel column chromatography purification. 1H NMR (600 MHz, CDCl3- d ) δ 7.51 (s,1H), 7.06 (s, 1H), 6.94 (s, 1H), 5.10 (d, J = 2.9 Hz, 1H), 5.00 (d, J = 2.8 Hz,1H), 4.83 (s, 1H), 4.73 (s, 1H), 4.38 (dd, J = 14.8, 4.7 Hz, 1H), 4.25 (dd, J =14.8, 4.7 Hz, 1H), 3.93 (t, J = 9.5 Hz, 1H), 2.75 (td, J = 8.1, 4.3 Hz, 1H), 2.61(t, J = 9.2 Hz, 1H), 2.56 (dt, J = 11.7, 4.7 Hz, 1H), 2.52 – 2.36 (m, 3H), 1.96 –1.83 (m, 2H), 1.78 (dq, J = 13.0, 4.2 Hz, 2H), 1.28 (qd, J = 12.0, 5.0 Hz, 1H)ppm; 13 C NMR (150 MHz, CDCl3- d ) δ 175.3, 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, 30.1 ppm.

[0113] Example 16: Preparation of Compound I-16

[0114]

[0115] Following the steps of Example 1, only 2-aminoimidazole was used to replace n-hexylamine, while other reaction conditions remained unchanged. The white solid compound I-16 (43.9%) was obtained by silica gel column chromatography purification. 1 H NMR (600 MHz, CDCl3- d ) d 6.96 (s, 1H), 6.91 (d, J= 1.4 Hz, 1H), 5.19 (q, J = 2.4 Hz, 1H), 5.04 (q, J = 2.4 Hz, 1H),4.87 – 4.85 (m, 1H), 4.75 (t, J = 1.4 Hz, 1H), 3.92 (t, J = 9.5 Hz, 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, 4.5 Hz, 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, 5.1 Hz, 1H), 1.94 (ddt, J = 13.3, 9.6, 7.9 Hz, 1H), 1.89 – 1.82 (m, 1H), 1.31 (dtd, J = 12.8, 11.4, 5.0 Hz, 1H) ppm; 13 C NMR (150 MHz, CDCl3- d ) δ 175.4,151.5, 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, 13.3 ppm.

[0116] Example 17, Preparation of Compound I-17

[0117]

[0118] Following the steps of Example 1, only 2-chloroimidazole was used to replace n-hexylamine, while other reaction conditions remained unchanged. The white solid compound I-17 (35.8%) was obtained by silica gel column chromatography purification. 1 H NMR (600 MHz, CDCl3- d) δ 6.62 (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, 3.8 Hz, 1H), 4.04 – 3.94 (m, 2H), 2.82 (td, J = 8.1, 4.3 Hz, 1H), 2.71 (t, J = 9.3 Hz, 1H), 2.58 (dt, J = 12.3, 4.3 Hz, 1H), 2.54 – 2.44 (m,3H), 2.19 (tdd, J = 12.3, 9.5, 3.0 Hz, 1H), 2.08 – 1.97 (m, 2H), 1.91 (dq, J =13.0, 8.2 Hz, 1H), 1.85 – 1.77 (m, 1H), 1.47 – 1.15 (m, 2H) ppm; 13 C NMR (150MHz, CDCl3- d ) δ 176.7, 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, 30.1 ppm.

[0119] Example 18: Preparation of Compound I-18

[0120]

[0121] Following the steps of Example 1, only 2-hydroxymethylimidazole was used to replace n-hexylamine, while other reaction conditions remained unchanged. The white solid compound I-18 (62.0%) was obtained by silica gel column chromatography purification. 1 H NMR (600 MHz, CDCl3- d ) δ 7.05 (s,1H), 6.97 (s, 1H), 5.12 (d, J = 1.5 Hz, 1H), 5.02 (d, J = 1.3 Hz, 1H), 4.85 (s,1H), 4.75 (s, 1H), 4.33 (dt, J= 20.1, 7.5 Hz, 2H), 3.99 – 3.93 (m, 1H), 2.79(td, J = 8.0, 4.2 Hz, 1H), 2.68 – 2.59 (m, 2H), 2.50 (dd, J = 13.5, 4.8 Hz, 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; 13 C NMR (150 MHz, 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, 30.1 ppm.

[0122] Example 19, Preparation of Compound I-19

[0123]

[0124] Following the steps of Example 1, only triazole was used to replace n-hexylamine, while other reaction conditions remained unchanged. The white solid compound I-19 (48.3%) was obtained by silica gel column chromatography purification. 1 H NMR (600 MHz, CDCl3- d ) δ 7.00 (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, 5.1 Hz, 1H), 4.30 (dd, J = 14.7, 6.2 Hz, 1H), 3.96(t, J = 9.4 Hz, 1H), 2.80 (dq, J = 12.2, 6.9, 6.3 Hz, 2H), 2.71 (t, J = 9.3 Hz,1H), 2.55 – 2.45 (m, 2H), 2.33 (dt, J= 13.1, 4.4 Hz, 1H), 2.18 (qd, J = 11.6,11.1, 5.6 Hz, 1H), 1.98 – 1.85 (m, 1H), 1.85 – 1.76 (m, 1H), 1.67 (dq, J =12.8, 4.0 Hz, 1H), 1.27 – 1.20 (m, 1H) ppm; 13 C NMR (150 MHz, CDCl3- d ) δ 175.7,151.4, 149.4, 148.2, 127.3, 120.5, 112.0, 109.1, 85.8, 55.1, 53.4, 51.8,48.1, 46.8, 45.0, 44.4, 37.3, 32.4, 30.0 ppm.

[0125] Example 20: Preparation of Compound I-20

[0126]

[0127] Following the steps of Example 1, simply replace n-hexylamine with 2-(2-methyl-1H-imidazol-1-yl)ethylamine while keeping other reaction conditions unchanged, and obtain a white solid compound I-20 (62.2%) by silica gel column chromatography. 1 H NMR (600 MHz, CDCl3-) d ) δ 8.18 (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, 4.7 Hz, 2H), 3.94 (t, J = 9.5 Hz, 1H), 3.45 (s, 0H), 2.79 (td, J = 8.2, 4.4 Hz, 1H), 2.71 (dt, J = 11.9, 4.7 Hz, 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; 13C NMR (150 MHz, 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, 30.2 ppm.

[0128] Example 21: Preparation of Compound I-21

[0129]

[0130] Following the steps of Example 1, only the triazole-3-mercapto group was replaced with n-hexylamine, while other reaction conditions remained unchanged. The white solid compound I-21 (47.2%) was obtained by silica gel column chromatography purification. 1 H NMR (600 MHz, CDCl3- d ) δ 6.88 (d, J =1.4 Hz, 1H), 6.84 (d, J = 1.4 Hz, 1H), 5.13 (d, J = 2.7 Hz, 1H), 5.01 (d, J = 3.8Hz, 1H), 4.84 (s, 1H), 4.73 (s, 1H), 3.96 – 3.88 (m, 4H), 2.96 – 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, 4.9 Hz, 1H), 1.33 – 1.20(m, 2H) ppm; 13 C NMR (150 MHz, CDCl3- d ) δ 177.8, 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, 13.2 ppm.

[0131] Example 22, Preparation of Compound I-22

[0132]

[0133] Following the steps of Example 1, only 5-aminomethylthiazole was used to replace n-hexylamine, while other reaction conditions remained unchanged. The pale yellow solid compound I-22 (39.1%) was obtained by silica gel column chromatography purification. 1 H NMR (600 MHz, CDCl3- d ) δ 7.72(d, J = 3.3 Hz, 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 = 4.1 Hz, 2H), 3.97 (t, J = 9.2 Hz, 1H), 3.05 (dd, J =12.2, 4.0 Hz, 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 (150 MHz, CDCl3- d ) δ 177.7, 171.8, 151.7, 149.8,142.6, 119.1, 112.0, 109.2, 86.0, 53.5, 51.9, 51.0, 47.5, 47.1, 46.8, 44.7,37.6, 32.5, 30.2ppm.

[0134] Example 23: Preparation of Compound I-23

[0135]

[0136] Following the steps of Example 1, only 1,4,5,6-tetrahydropyrrolo-[3,4-C]-pyrazole was used to replace n-hexylamine, while keeping other reaction conditions unchanged. The pale yellow solid compound I-23 (71.2%) was obtained by silica gel column chromatography purification. 1 H NMR (600MHz, CDCl3- d) δ 8.21 (s, 1H), 5.11 (s, 1H), 5.00 (s, 1H), 4.82 (s, 1H), 4.72(s, 1H), 3.96 (t, J = 9.2 Hz, 1H), 3.61 (dd, J = 14.3, 4.8 Hz, 1H), 3.42 (dd, J =14.3, 5.4 Hz, 1H), 2.87 – 2.68 (m, 3H), 2.54 – 2.38 (m, 3H), 2.38 – 2.26 (m,2H), 1.92 (ddd, J = 24.5, 12.6, 6.7 Hz, 2H), 1.80 (ddt, J = 13.5, 9.0, 4.8 Hz,1H), 1.35 – 1.22 (m, 1H) ppm; 13 C NMR (150 MHz, CDCl3- d ) δ 177.2, 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, 30.1 ppm.

[0137] Example 24, Preparation of Compound I-24

[0138]

[0139] Following the steps of Example 1, simply replace n-hexylamine with 4,5,6,7-tetrahydro-3H-imidazo[4,5-C]pyridine, while keeping other reaction conditions unchanged, and obtain a pale yellow solid compound I-24 (35.9%) by silica gel column chromatography. 1 H NMR (600MHz, CDCl3- d ) δ 7.21 (s, 1H), 5.19 (q, J = 2.5 Hz, 1H), 5.04 (d, J = 2.6 Hz, 1H), 4.86 (s, 1H), 4.75 (s, 1H), 3.96 (t, J = 9.1 Hz, 1H), 3.89 (d, J = 12.1 Hz, 1H), 3.82 (d, J = 10.0 Hz, 3H), 3.23 (dd,J = 13.1, 4.0 Hz, 1H), 3.16 (dd, J = 13.1, 5.3Hz, 1H), 2.89 (td, J = 8.2, 4.1 Hz, 1H), 2.84 – 2.78 (m, 1H), 2.57 – 2.37 (m,4H), 2.31 (ddd, J = 12.7, 6.4, 3.2 Hz, 1H), 2.09 – 1.99 (m, 1H), 1.93 (ddt, J =15.8, 9.6, 7.9 Hz, 1H), 1.84 (ddt, J = 13.4, 9.1, 5.0 Hz, 1H), 1.40 – 1.30 (m,1H) ppm; 13 C NMR (150 MHz, CDCl3- d ) δ 177.6, 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.

[0140] Example 25: Preparation of Compound I-25

[0141]

[0142] Following the steps of Example 1, only 1,5-dihydropyrrolo[3,4-b]pyrrole was used to replace n-hexylamine, while keeping other reaction conditions unchanged. The pale yellow solid compound I-25 (32.7%) was obtained by silica gel column chromatography purification. 1 H NMR (600 MHz, CDCl3-) d ) δ 7.29 (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, 4.7 Hz, 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 CNMR (150 MHz, CDCl3- d ) δ 177.8, 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, 22.7 ppm.

[0143] Example 26: Preparation of Compound I-26

[0144]

[0145] Following the steps of Example 1, only 5H-pyrrolo[3,2-D]pyrimidine was used to replace n-hexylamine, while other reaction conditions remained unchanged. The white solid compound I-26 (27.8%) was obtained by silica gel column chromatography purification. 1 H NMR (600 MHz, 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 = 9.5 Hz, 1H), 3.45 (s, 0H), 2.79 (td, J = 8.2, 4.4 Hz, 1H), 2.71 (dt, J = 11.9, 4.7 Hz, 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 (150 MHz, 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, 16.5 ppm.

[0146] Example 27, Preparation of Compound I-27

[0147]

[0148] Following the steps of Example 1, only 4-aminopyrrolo[3,2-D]pyrimidine was used to replace n-hexylamine, while other reaction conditions remained unchanged. The white solid compound I-27 (39.6%) was obtained by silica gel column chromatography purification. 1 H NMR (600 MHz, CDCl3- d )δ 8.97 (s, 1H), 8.86 (s, 1H), 7.37 (d, J = 3.6 Hz, 1H), 6.57 (d, J = 3.6 Hz, 1H), 5.10 (d, J = 2.6 Hz, 1H), 4.99 (d, J = 2.3 Hz, 1H), 4.80 – 4.74 (m, 2H), 4.67 (s,1H), 4.56 (dd, J = 14.7, 4.3 Hz, 1H), 3.93 (t, J = 9.5 Hz, 1H), 2.70 (dt, J = 12.0, 4.5 Hz, 1H), 2.60 (td, J = 8.1, 4.2 Hz, 1H), 2.55 – 2.32 (m, 4H), 2.12 (dq, J =12.8, 4.0 Hz, 1H), 1.89 – 1.71 (m, 4H) ppm. 13 C NMR (150 MHz, CDCl3- d) δ 175.0,150.5, 150.4, 150.1, 148.5, 148.4, 129.0, 117.5, 110.9, 108.0, 99.3, 84.8,50.7, 47.6, 45.8, 43.5, 40.1, 36.3, 31.4, 31.1, 29.0 ppm.

[0149] Example 28: Preparation of Compound I-28

[0150]

[0151] Following the steps of Example 1, only methyl indole-3-carboxylate was used to replace n-hexylamine, while keeping other reaction conditions unchanged. The white solid compound I-28 (41.8%) was obtained by silica gel column chromatography purification. 1 H NMR (600 MHz, CDCl3- d ) δ 8.33(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, 4.3 Hz, 2H), 4.10 (q, J = 7.2 Hz, 1H), 3.95 (t, J = 9.5 Hz, 1H), 3.47 (s, 2H), 2.72 (dt, J = 12.2, 4.4 Hz, 1H), 2.66(td, J = 8.1, 4.1 Hz, 1H), 2.57 (t, J = 9.3 Hz, 1H), 2.51 – 2.36 (m, 2H), 2.28(dq, J = 12.8, 4.0 Hz, 1H), 2.00 – 1.73 (m, 3H) ppm. 13 C NMR (150 MHz, 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, 30.1 ppm.

[0152] Example 29, Preparation of Compound I-29

[0153]

[0154] Following the steps of Example 1, only 6,7-diethoxy-1,2,3,4-tetrahydroisoquinoline was used to replace n-hexylamine, while keeping other reaction conditions unchanged. The white solid compound I-29 (36.8%) was obtained by silica gel column chromatography purification. 1 H NMR (600 MHz, CDCl3-) d ) δ 8.20 (d, J = 7.9 Hz, 1H), 8.17 (s, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.26(t, J = 7.4 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 5.04 (d, J = 2.8 Hz, 1H), 4.92 (s,1H), 4.69 (s, 1H), 4.63 (q, J = 8.3, 6.8 Hz, 2H), 4.46 (dd, J = 14.9, 6.9 Hz, 1H), 3.93 (t, J = 9.4 Hz, 1H), 2.98 – 2.91 (m, 1H), 2.71 (td, J = 8.2, 4.1 Hz, 1H), 2.62 (t, J = 9.2 Hz, 1H), 2.46 (s, 3H), 2.44 – 2.38 (m, 2H), 2.18 (tt, J =18.6, 6.4 Hz, 2H), 1.81 (ddd, J = 13.4, 9.4, 6.5 Hz, 1H), 1.74 (dp, J = 16.6,5.9, 5.3 Hz, 2H), 1.38 (m, 1H) ppm; 13 C NMR (150 MHz, CDCl3- d) δ 196.1, 178.1,153.6, 151.2, 138.8, 138.6, 127.4, 124.7, 123.8, 123.4, 118.1, 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, 27.3 ppm.

[0155] Example 30: Preparation of Compound I-30

[0156]

[0157] Following the steps of Example 1, only 1-(2H)-phthalazinone was used to replace n-hexylamine, while other reaction conditions remained unchanged. The colorless oily compound I-30 (56.3%) was obtained by silica gel column chromatography purification. 1 H NMR (600 MHz, CDCl3- d ) δ 6.60 (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 = 9.4 Hz, 1H), 3.85 (d, J = 4.8 Hz, 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 (150 MHz, CDCl3- d ) δ 177.8, 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, 28.7 ppm.

[0158] Example 31: Preparation of Compound I-31

[0159]

[0160] Following the steps of Example 1, only cytosine was used to replace n-hexylamine, while other reaction conditions remained unchanged. The white solid compound I-31 (41.2%) was obtained by silica gel column chromatography purification. 1 H NMR (600 MHz, CDCl3- d ) δ 7.58 (d, J = 7.2Hz, 1H), 5.76 (d, J = 7.2 Hz, 1H), 5.04 (s, 1H), 4.93 (s, 1H), 4.80 (s, 1H), 4.69 (s, 1H), 4.03 (dd, J = 14.1, 6.4 Hz, 1H), 3.95 (q, J = 9.3, 8.4 Hz, 2H), 2.84 (ddt, J = 26.7, 11.5, 4.8 Hz, 2H), 2.73 (t, J = 9.3 Hz, 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; 13 C NMR (150 MHz, CDCl3-) d ) δ 178.6, 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, 31.1 ppm.

[0161] Example 32, Preparation of Compound I-32

[0162]

[0163] Following the steps of Example 1, only thymine was replaced with n-hexylamine, and other reaction conditions remained unchanged. The white solid compound I-32 (43.7%) was obtained by silica gel column chromatography purification. 1 H NMR (600 MHz, CDCl3- d ) δ 7.85 (d,J =3.0 Hz, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.42 (d, J = 9.3 Hz, 1H), 7.31 (dd, J = 9.2, 3.1 Hz, 1H), 6.29 (d, J = 7.5 Hz, 1H), 5.14 (s, 1H), 5.03 (s, 1H), 4.82 (dd, J =15.3, 4.5 Hz, 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 (150 MHz, CDCl3- d ) δ177.6, 175.2, 156.5, 151.2, 148.7, 142.5, 133.8, 128.5, 123.4, 116.5, 112.6,109.6, 109.4, 106.5, 85.5, 55.9, 53.1, 51.9, 47.2, 47.0, 46.0, 36.7, 32.5,32.4, 30.1 ppm.

[0164] Example 33: Preparation of Compound I-33

[0165]

[0166] Following the steps of Example 1, only 6-methoxyquinoline-4-one was used to replace n-hexylamine, while other reaction conditions remained unchanged. The white solid compound I-33 (47.1%) was obtained by silica gel column chromatography purification. 1 H NMR (600 MHz, CDCl3- d) δ 8.82(s, 1H), 7.22 (s, 1H), 5.26 (s, 1H), 5.10 (d, J = 2.6 Hz, 1H), 5.00 (d, J = 2.3Hz, 1H), 4.83 (s, 1H), 4.72 (s, 1H), 4.02 (dd, J = 14.5, 5.7 Hz, 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 (150 MHz, CDCl3- d ) δ 176.4, 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, 12.5 ppm.

[0167] Example 34: Preparation of Intermediate II

[0168]

[0169] A mixture of K₂O₄•₂H₂O (217.10 μmol, 0.5 equiv), N-methylmorpholine-N-oxide (651.30 μmol, 1.5 equiv), and tert-butanol / tetrahydrofuran / water (v / v / v = 4:1:1, 3 mL) was stirred at room temperature for 40 minutes. Dehydroaulantolide (434.20 μmol, 1 equiv) was added, and the reaction was continued at room temperature for 4 hours. After the reaction was complete, the solvent was removed by vacuum distillation, and ethyl acetate was added to expand the volume. The mixture was washed three times with water and finally dried over anhydrous sodium sulfate. The organic phase was purified by vacuum distillation and silica gel column chromatography to obtain intermediate II (21.8%). 1 H NMR (600 MHz, CDCl3- d ) δ 5.19 (s, 1H), 5.07 (d, J= 1.1 Hz, 1H), 4.89 (s, 1H), 4.81 (s, 1H), 4.31 (t, J = 9.6 Hz, 1H), 3.79 (d, J = 11.9 Hz, 1H), 3.64 (d, J = 11.9 Hz, 1H), 3.35 (s, 1H), 2.88(dd, J = 13.9, 7.5 Hz, 1H), 2.75 (t, J = 8.8 Hz, 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, 4.4 Hz, 1H), 1.81– 1.69 (m, 3H) ppm; 13 C NMR (150 MHz, CDCl3- d ) δ 178.0, 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, 25.4 ppm.

[0170] Example 35: Preparation of Compound I-34

[0171]

[0172] 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. Then, intermediate II (56.79 μmol, 1 equiv) was added, and the reaction was carried out at room temperature for 8 hours. After the reaction was completed, the solvent was removed by vacuum distillation, ethyl acetate was added, and the organic phase was washed with 10% K2CO3 aqueous solution. After neutralization with HCl solution (1 M), the aqueous phase was removed, and the organic phase was dried over anhydrous sodium sulfate. The product I-34 (47.7%) was purified by silica gel column chromatography. 1 H NMR (600MHz, CDCl3- d ) δ 9.27 (s, 1H), 8.83 (s, 1H), 8.38 (d, J= 7.6 Hz, 1H), 7.52 (s,1H), 5.19 (d, J = 9.3 Hz, 1H), 5.07 (s, 1H), 4.89 (s, 1H), 4.81 (s, 1H), 4.62(d, J = 11.5 Hz, 1H), 4.48 (d, J = 11.5 Hz, 1H), 4.30 (t, J = 9.5 Hz, 1H), 2.89(dd, J = 14.1, 7.4 Hz, 1H), 2.78 (t, J = 8.7 Hz, 1H), 2.59 – 2.44 (m, 3H), 2.31 –2.26 (m, 1H), 2.08 – 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, 4.9 Hz, 2H) ppm. 13 C NMR (150 MHz, 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, 29.02,24.31 ppm.

[0173] Example 36: Preparation of Intermediate III

[0174]

[0175] To a solution of selenium dioxide (1 equiv) in dichloromethane (25 mL), tert-butyl hydroperoxide (34.74 μmol, 0.004 equiv) was added. After reacting for 40 minutes, dehydroauronil (8.68 mmol, 1 equiv) was added, and the mixture was transferred to room temperature. TLC monitoring after 3 hours showed the reaction was complete. The reaction solution was quenched by adding saturated sodium thiosulfate and saturated sodium bicarbonate solution (v / v = 1:1, 10 mL) for 40 minutes. Ethyl acetate was then added to expand the volume. The organic phase was collected and dried over anhydrous sodium sulfate, then evaporated 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%). 1 H NMR (600 MHz, CDCl3- d ) δ 6.22 (d, J = 3.5 Hz, 1H), 5.50 (d, J = 3.6 Hz, 2H), 5.36 (d, J = 1.9 Hz, 1H), 4.93 (s, 1H), 4.78 (s,1H), 4.69 (t, J = 6.7 Hz, 1H), 3.90 (t, J = 9.1 Hz, 1H), 3.10 (pd, J = 9.1, 3.3 Hz, 2H), 2.86 (ddd, J = 12.1, 8.6, 3.7 Hz, 1H), 2.52 (dt, J = 13.1, 4.8 Hz, 1H), 2.27– 2.16 (m, 2H), 2.15 – 2.07 (m, 1H), 1.87 (dt, J = 13.7, 6.9 Hz, 1H), 1.79 (s,1H), 1.39 (qd, J = 11.6, 5.1 Hz, 1H). 13 C NMR (150MHz, CDCl3- d ) δ 170.3, 154.2,148.6, 139.5, 120.7, 113.4, 113.2, 85.1, 74.7, 49.6, 45.6, 44.2, 40.0, 36.9,31.1 ppm.

[0176] Example 37: Preparation of Intermediate IV

[0177]

[0178] The same procedure as in Example 36 yielded white solid intermediate IV (26.3%). 1 H NMR (600 MHz, CDCl3- d )δ 6.25 (d, J = 3.4 Hz, 1H), 5.68 (s, 1H), 5.55 (d, J = 2.9 Hz, 1H), 5.46 (s, 1H), 4.94 (s, 1H), 4.75 (s, 1H), 4.71 (t, J = 6.7 Hz, 1H), 4.12 (d, J = 8.7 Hz, 1H), 3.28 (ddd, J = 11.7, 8.6, 3.3 Hz, 1H), 2.84 (dd, J = 8.5, 3.2 Hz, 1H), 2.67 (s,1H), 2.53 (dd, J = 8.3, 3.8 Hz, 1H), 2.27 – 2.21 (m, 1H), 2.16 (dt, J = 15.0,10.1 Hz, 2H), 1.41 (qd, J = 11.9, 5.4 Hz, 1H) ppm; 13 C NMR (150 MHz, 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, 31.5 ppm. HRMS (ESI) calcd for C 15 H 18 O4Na [M + Na] + ,285.1103; found, 285.1097.

[0179] Example 38, Preparation of Compound I-35

[0180]

[0181] The mixture of intermediate III (1 equiv), m-chloroperoxybenzoic acid (3 equiv) and dichloromethane was reacted at room temperature for 3 hours. After the reaction was completed, the mixture was purified by preparing a reverse-phase medium-pressure preparative liquid phase to obtain compound I-35 (10.1%). 1 HNMR (600 MHz, CDCl3- d ) δ 6.30 – 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 (151 MHz, CDCl3-) d ) δ 169.46, 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, 26.27 ppm.

[0182] Example 39, Preparation of Compound I-36

[0183]

[0184] The same procedure as in Example 38 yielded a white solid compound I-36 (11.0%). 1 H NMR (600 MHz, CDCl3- d ) δ 6.24 (d, J = 3.4 Hz, 1H), 5.53 (d, J= 3.0 Hz, 1H), 4.40 – 4.32 (m, 1H), 4.00 – 3.90 (m, 1H), 3.54 (d, J = 4.5 Hz, 1H), 2.96 (t, J = 7.8 Hz, 1H), 2.89(d, J = 4.4 Hz, 1H), 1.95 –1.89 (m, 1H), 1.85 (dd, J = 12.9, 6.5 Hz, 1H), 1.76 – 1.68 (m, 2H), 1.67 –1.59 (m, 2H) ppm; 13 C NMR (151 MHz, CDCl3- d ) δ 169.75, 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.

[0185] Example 40: Preparation of Compound I-37

[0186]

[0187] The same procedure as in Example 38 yielded a white solid compound I-37 (14.3%). 1 H NMR (600 MHz, CDCl3- d ) δ 6.22 (d, J = 3.4 Hz, 1H), 5.51 (d, J = 3.1 Hz, 1H), 5.00 (d, J = 18.7 Hz, 2H), 4.27 (t, J = 7.4 Hz, 1H), 4.06 (dd, J = 11.0, 9.0 Hz, 1H), 3.59 (d, J = 4.5 Hz, 1H), 3.17 (dt, J = 13.6, 4.7 Hz, 1H), 2.91 (d, J= 4.5 Hz, 1H), 2.75 (ddd, J =11.9, 8.7, 3.6 Hz, 1H), 2.61 – 2.56 (m, 1H), 2.52 (t, J = 10.4 Hz, 1H), 2.32(ddd, J = 13.3, 6.3, 4.9 Hz, 1H), 2.25 (ddd, J = 15.9, 10.2, 5.7 Hz, 1H), 2.13 –2.06 (m, 1H), 1.94 (td, J = 13.6, 8.5 Hz, 1H), 1.63 (d, J = 6.7 Hz, 1H), 1.41(ddd, J = 24.3, 11.5, 5.0 Hz, 1H) ppm; 13 C NMR (150 MHz, CDCl3- d ) δ 169.70,148.29, 138.82, 121.05, 114.14, 82.76, 70.45, 66.94, 49.63, 49.46, 46.86,41.78, 38.25, 36.76, 30.90 ppm.

[0188] Example 41: Preparation of Compound I-38

[0189]

[0190] Following the steps of Example 35, intermediate III was esterified with p-fluorobenzoic acid to prepare red solid compound I-38 (39.0%). 1 H NMR (600 MHz, CDCl3- d ) δ 8.06 (dd, J = 8.3, 5.7 Hz, 2H), 7.11 (t, J = 8.5 Hz, 2H), 6.25 (d, J = 3.3 Hz, 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 = 9.3 Hz, 1H), 3.19(t, J= 9.2 Hz, 1H), 3.14 (dd, J = 8.0, 4.4 Hz, 1H), 2.94 – 2.87 (m, 1H), 2.57(dt, J = 12.7, 4.3 Hz, 1H), 2.43 (ddd, J = 13.6, 6.8, 4.6 Hz, 1H), 2.27 (dd, J =8.7, 4.3 Hz, 1H), 2.15 (td, J = 12.2, 5.4 Hz, 1H), 2.11 – 2.03 (m, 1H), 1.47 –1.42 (m, 1H) ppm; 13 C NMR (150 MHz, CDCl3- d ) δ 170.19, 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, 31.18 ppm.

[0191] Example 42, Preparation of Compound I-39

[0192]

[0193] Following the steps of Example 35, intermediate III was esterified with 4-chloro-3-fluorobenzoic acid to prepare a white solid compound I-39 (56.7%). 1 H NMR (600 MHz, CDCl3- d ) δ 7.79 (t, J = 8.6 Hz, 2H), 7.48(t, J = 7.2 Hz, 1H), 6.25 (s, 1H), 5.90 (s, 1H), 5.63 (s, 1H), 5.53 (s, 1H), 5.50 (s, 1H), 4.99 (s, 1H), 4.86 (s, 1H), 3.96 (t, J = 9.2 Hz, 1H), 3.17 (dt, J=17.6, 6.7 Hz, 2H), 2.91 (t, J = 8.4 Hz, 1H), 2.57 (d, J = 13.1 Hz, 1H), 2.45 –2.38 (m, 1H), 2.30 – 2.25 (m, 1H), 2.16 (td, J = 12.1, 5.3 Hz, 1H), 2.11 – 2.03(m, 1H), 1.47 – 1.39 (m, 1H) ppm; 13 C NMR (150 MHz, CDCl3- d ) δ 170.14, 164.62,158.80, 157.14, 148.76, 148.06, 139.25, 130.87, 126.15, 120.92, 117.86,117.71, 116.46, 113.78, 85.10, 77.53, 50.00, 45.43, 44.84, 37.50, 36.94,31.16 ppm.

[0194] Example 43, Preparation of Compound I-40

[0195]

[0196] Following the steps of Example 35, intermediate III was esterified with 4-ethoxybenzoic acid to prepare a white solid compound I-40 (33.7%). 1 H NMR (600 MHz, CDCl3- d ) δ 7.98 (d, J = 8.8 Hz, 2H), 6.90(d, J = 8.8 Hz, 2H), 6.25 (d, J = 3.4 Hz, 1H), 5.88 (t, J = 6.1 Hz, 1H), 5.60 (s,1H), 5.55 – 5.47 (m, 2H), 4.98 (s, 1H), 4.89 (s, 1H), 4.08 (q, J = 7.0 Hz, 2H), 3.96 (t, J = 9.3 Hz, 1H), 3.18 (t, J = 9.3 Hz, 1H), 3.12 (td, J= 8.5, 4.4 Hz, 1H),2.93 – 2.86 (m, 1H), 2.56 (dt, J = 12.9, 4.4 Hz, 1H), 2.42 (ddd, J = 13.8, 6.9,4.5 Hz, 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 = 7.0 Hz, 3H) ppm; 13 C NMR (150 MHz, CDCl3- d ) δ 170.22,166.24, 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, 14.80 ppm.

[0197] Example 44, Preparation of Compound I-41

[0198]

[0199] Following the steps of Example 35, intermediate III was esterified with nicotinic acid to prepare red solid compound I-41 (34.2%). 1 H NMR (600 MHz, CDCl3- d ) δ 9.23 (s, 1H), 8.78 (d, J = 3.9 Hz, 1H), 8.32 (d, J = 7.7 Hz, 1H), 7.44 – 7.40 (m, 1H), 6.25 (d, J = 3.0 Hz, 1H), 5.95 (d, J = 5.7 Hz, 1H), 5.64 (s, 1H), 5.55 – 5.49 (m, 2H), 5.00 (s, 1H), 4.87 (s,1H), 3.96 (t, J = 9.1 Hz, 1H), 3.19 (dd, J= 20.6, 10.5 Hz, 2H), 2.92 (dd, J =14.0, 5.8 Hz, 1H), 2.60 – 2.53 (m, 1H), 2.47 – 2.40 (m, 1H), 2.31 – 2.25 (m,1H), 2.13 (ddd, J = 20.6, 13.2, 5.9 Hz, 2H), 1.48 – 1.40 (m, 1H) ppm; 13 C NMR (150 MHz, CDCl3-) d ) δ 170.13, 164.98, 153.32, 150.79, 148.72, 148.04, 139.25,137.55, 126.43, 123.59, 120.92, 116.57, 113.80, 85.06, 49.97, 45.44, 44.88,37.50, 36.87, 31.15 ppm.

[0200] Example 45: Preparation of Compound I-42

[0201]

[0202] Following the steps of Example 35, intermediate III was esterified with 2-pyridinecarboxylic acid to prepare a white solid compound I-42 (30.0%). 1 H NMR (600 MHz, CDCl3- d ) δ 8.17 (d, J = 8.1 Hz, 2H), 7.72 (d, J = 8.1 Hz, 2H), 6.27 (d, J = 3.2 Hz, 1H), 5.94 (t, J = 6.2 Hz, 1H), 5.65 (s, 1H), 5.58 – 5.49 (m, 2H), 5.01 (s, 1H), 4.89 (s, 1H), 3.98 (t, J = 9.2 Hz, 1H), 3.18(ddd, J = 16.3, 15.7, 8.9 Hz, 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, 5.4 Hz,1H), 2.13 – 2.08 (m, 1H), 1.48 – 1.41 (m, 1H) ppm; 13 C NMR (150 MHz, CDCl3- d ) δ170.16, 165.25, 148.82, 148.08, 139.26, 130.18, 125.58, 125.55, 120.94,116.41, 113.79, 85.16, 77.48, 50.04, 45.43, 44.86, 37.56, 37.00, 31.18 ppm.

[0203] Example 46, Preparation of Compound I-43

[0204]

[0205] Following the steps of Example 35, intermediate III was esterified with thiophene-2-carboxylic acid to prepare a pale yellow solid compound I-43 (61.0%). 1 H NMR (600 MHz, CDCl3- d ) δ 7.81 (d, J = 2.9 Hz, 1H), 7.56(d, J = 4.6 Hz, 1H), 7.10 (t, J = 4.3 Hz, 1H), 6.24 (d, J = 3.3 Hz, 1H), 5.87 (t, J =6.1 Hz, 1H), 5.61 (s, 1H), 5.53 – 5.47 (m, 2H), 4.98 (s, 1H), 4.86 (s, 1H), 3.95 (t, J = 9.3 Hz, 1H), 3.21 – 3.10 (m, 2H), 2.95 – 2.86 (m, 1H), 2.56 (dt, J =12.8, 4.4 Hz, 1H), 2.40 (ddd, J = 13.6, 6.7, 4.7 Hz, 1H), 2.31 – 2.25 (m, 1H), 2.14 (td,J = 12.3, 5.4 Hz, 1H), 2.12 – 2.04 (m, 1H), 1.42 (ddd, J = 16.6, 11.9, 5.3 Hz, 1H) ppm; 13 C NMR (150 MHz, CDCl3- d ) δ 170.18, 162.12, 148.85, 148.14,139.32, 133.99, 133.65, 132.68, 127.91, 120.83, 116.18, 113.71, 85.20, 77.03,49.94, 45.43, 44.76, 37.49, 36.99, 31.17 ppm.

[0206] Example 47, Preparation of Compound I-44

[0207]

[0208] Following the steps of Example 35, intermediate III was esterified with furan-2-carboxylic acid to prepare gray solid compound I-44 (41.3%). 1 H NMR (600 MHz, CDCl3- d ) δ 7.58 (s, 1H), 7.19 (d, J = 2.5 Hz,1H), 6.51 (s, 1H), 6.24 (d, J = 2.5 Hz, 1H), 5.90 (t, J = 5.9 Hz, 1H), 5.62 (s,1H), 5.51 (d, J = 11.1 Hz, 2H), 4.98 (s, 1H), 4.85 (s, 1H), 3.94 (t, J = 9.2 Hz,1H), 3.20 – 3.11 (m, 2H), 2.91 (d, J = 8.4 Hz, 1H), 2.58 – 2.51 (m, 1H), 2.42 –2.35 (m, 1H), 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; 13C NMR (150 MHz, CDCl3- d ) δ 170.18, 158.62,148.79, 148.09, 146.55, 144.77, 139.31, 120.85, 118.27, 116.46, 113.74,112.01, 85.19, 76.82, 49.99, 45.37, 44.84, 37.49, 36.92, 31.16 ppm.

[0209] Example 48, Preparation of Compound I-45

[0210]

[0211] Following the steps of Example 35, intermediate III was esterified with thiazol-5-carboxylic acid to prepare red solid compound I-45 (49.3%). 1 H NMR (600 MHz, CDCl3- d ) δ 8.95 (s, 1H), 8.51 (s, 1H), 6.25(d, J = 3.0 Hz, 1H), 5.90 (t, J = 5.9 Hz, 1H), 5.63 (s, 1H), 5.52 (d, J = 10.9 Hz,2H), 4.98 (s, 1H), 4.84 (s, 1H), 3.94 (t, J = 9.1 Hz, 1H), 3.20 – 3.11 (m, 2H), 2.91 (t, J = 8.2 Hz, 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, 5.3 Hz, 1H) ppm; 13 C NMR (150 MHz, CDCl3- d) δ 170.12, 161.07,158.35, 149.08, 148.52, 148.02, 139.22, 129.98, 120.93, 116.73, 113.75,85.05, 77.81, 49.92, 45.40, 44.84, 37.41, 36.90, 31.15 ppm.

[0212] Example 49, Preparation of Compound I-46

[0213]

[0214] Following the steps of Example 35, intermediate III was esterified with 2-methylthiazol-5-carboxylic acid to prepare a white solid compound I-46 (35.8%). 1 H NMR (600 MHz, CDCl3- d ) δ 8.24 (s, 1H), 6.25 (d, J =2.9 Hz, 1H), 5.87 (t, J = 5.6 Hz, 1H), 5.62 (s, 1H), 5.51 (d, J = 20.7 Hz, 2H), 4.98 (s, 1H), 4.84 (s, 1H), 3.94 (t, J = 9.1 Hz, 1H), 3.15 (dt, J = 16.7, 6.5 Hz, 2H), 2.90 (d, J = 8.1 Hz, 1H), 2.75 (s, 2H), 2.56 (dd, J = 8.6, 4.5 Hz, 1H), 2.42– 2.34 (m, 1H), 2.30 – 2.21 (m, 1H), 2.17 – 2.11 (m, 1H), 2.07 (dd, J = 13.9,6.9 Hz, 1H), 1.67 (s, 1H), 1.43 (ddd, J = 16.8, 12.0, 5.3 Hz, 1H) ppm; 13 C NMR (150 MHz, CDCl3-) d) δ 170.14, 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, 19.91 ppm.

[0215] Example 50: Preparation of Compound I-47

[0216]

[0217] Following the steps of Example 1, intermediate III was reacted with 2-methylimidazole via a Michael addition reaction to prepare a white solid compound I-47 (54.9%). 1 H NMR (600 MHz, CD3OD- d 4) δ 7.00 (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 =7.1 Hz, 1H), 4.30 (dd, J = 14.8, 5.5 Hz, 1H), 4.17 (dd, J = 14.8, 6.9 Hz, 1H), 3.90 (t, J = 9.4 Hz, 1H), 2.93 (dtd, J = 24.7, 9.0, 2.9 Hz, 2H), 2.82 (dt, J =11.9, 6.1 Hz, 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, 7.4 Hz, 1H), 1.51 (dq, J = 12.8, 4.0 Hz, 1H), 1.22(qd, J = 12.0, 4.9 Hz, 1H). 13 C NMR (150 MHz, CD3OD- d4) δ 177.6, 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, 12.7 ppm.

[0218] Example 51: Preparation of Compound I-48

[0219]

[0220] Following the steps of Example 1, intermediate III was reacted with 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine via a Michael addition reaction to prepare a pale yellow solid compound I-47 (38.2%). 1 H NMR (600 MHz, CD3OD- d 4) δ7.26 (d, J = 46.7 Hz, 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 = 7.3 Hz, 1H), 3.93 – 3.85 (m, 1H), 3.49 (s, 2H), 2.98 (dd, J = 7.0, 2.9 Hz, 2H), 2.90 (dd, J = 13.4, 4.9 Hz, 1H), 2.83 (q, J = 9.5, 7.7 Hz, 1H), 2.75 (dd, J = 13.2, 6.3 Hz, 1H), 2.69 (m, 3H), 2.59 (dt, J = 11.4, 5.6 Hz, 1H), 2.42 (dt, J = 13.0, 4.3 Hz, 1H), 2.32 – 2.19 (m, 2H), 2.11 (ddd, J =13.7, 7.2, 2.6 Hz, 1H), 1.98 (td, J = 12.5, 5.0 Hz, 1H), 1.75 (ddd, J = 14.7,10.0, 4.8 Hz, 1H), 1.31 (qd, J= 12.2, 4.7 Hz, 1H). 13 C NMR (150 MHz, CD3OD- d 4) 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, 32.5 ppm.

[0221] Example 52, Preparation of Compound I-49

[0222]

[0223] Following the steps of Example 1, intermediate III was reacted with 1-hydroxyphthalazine via a Michael addition reaction to prepare a white solid compound I-47 (47.2%). 1 H NMR (600 MHz, CDCl3- d ) δ 8.43 (d, J = 7.9 Hz, 1H), 8.20(s, 1H), 7.82 (dt, J = 26.0, 7.4 Hz, 2H), 7.73 (d, J = 7.7 Hz, 1H), 5.45 (d, J =2.5 Hz, 1H), 5.35 (d, J = 2.4 Hz, 1H), 4.82 (s, 1H), 4.75 – 4.64 (m, 3H), 4.51(dd, J = 13.8, 7.7 Hz, 1H), 3.89 (t, J = 9.6 Hz, 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, 6.0 Hz, 2H), 1.77– 1.71 (m, 2H), 1.28 – 1.17 (m, 1H). 13 C NMR (150 MHz, CDCl3- d) δ 175.9, 159.9,154.5, 149.1, 138.3, 133.6, 132.2, 129.6, 127.6, 127.0, 126.4, 113.1, 112.7,85.1, 74.6, 49.9, 49.6, 46.8, 45.6, 43.8, 39.8, 37.8, 32.9 ppm.

[0224] Example 53: Preparation of Compound I-50

[0225]

[0226] Following the steps of Example 38, simply replace intermediate III with intermediate IV while keeping other reaction conditions unchanged, and obtain a white solid compound I-50 (11.3%) by silica gel column chromatography. 1 H NMR (600 MHz, CDCl3- d ) δ 6.26 (d, J = 3.6 Hz, 1H), 5.55 (d, J = 3.2 Hz, 1H), 4.38 (d, J = 9.0 Hz, 1H), 4.10 (t, J =7.9 Hz, 1H), 3.58 (d, J = 4.4 Hz, 1H), 3.05 (d, J = 4.4 Hz, 1H), 2.90 (d, J = 4.4Hz, 1H), 2.75 (s, 1H), 2.63 – 2.56 (m, 2H), 2.11 (dq, J = 13.2, 4.2 Hz, 1H), 2.06 – 1.87 (m, 4H), 1.72 (m, 1H). 13 C NMR (151 MHz, CDCl3- d ) δ 169.8, 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.

[0227] Example 54, Preparation of Compound I-51

[0228]

[0229] The same procedure as in Example 53 yielded a white solid compound I-51 (9.3%). 1 H NMR (600 MHz, CDCl3- d )δ 6.23 (d, J = 3.6 Hz, 1H), 5.53 (d, J = 3.2 Hz, 1H), 5.04 (s, 1H), 4.98 (s, 1H), 4.40 (q, J = 8.2, 7.5 Hz, 1H), 4.12 (d, J = 8.6 Hz, 1H), 3.64 (d, J = 4.5 Hz, 1H), 3.35 (ddt, J = 12.1, 7.4, 3.6 Hz, 1H), 3.08 (d, J = 4.5 Hz, 1H), 2.86 (dd, J = 9.4,4.2 Hz, 1H), 2.72 (s, 1H), 2.57 (dt, J = 13.3, 3.9 Hz, 1H), 2.33 (ddd, J = 13.7,7.1, 4.1 Hz, 1H), 2.23 (tq, J = 16.1, 5.2 Hz, 2H), 2.09 (m, 2H). 13 C NMR (150MHz, CDCl3- d ) δ 169.8, 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, 31.1 ppm.

[0230] Example 55: Preparation of Compound I-52

[0231]

[0232] Following the steps of Example 35, intermediate IV was esterified with p-ethoxybenzoic acid to prepare a white solid compound I-52 (24.3%). 1 H NMR (600 MHz, CDCl3- d ) δ 7.94 (d, J = 8.7 Hz, 2H), 6.84(d, J= 8.7 Hz, 2H), 6.22 (d, J = 3.4 Hz, 1H), 5.92 (t, J = 7.4 Hz, 1H), 5.77 (s,1H), 5.53 – 5.49 (m, 2H), 4.96 (s, 1H), 4.85 (s, 1H), 4.12 (d, J = 8.8 Hz, 1H), 4.02 (q, J = 6.9 Hz, 2H), 3.23 (ddd, J = 11.7, 8.7, 3.2 Hz, 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, 5.6 Hz, 1H), 1.56 (s, 1H), 1.37 (t, J = 7.0 Hz, 3H) ppm; 13 C NMR (150 MHz, CDCl3- d ) δ 170.21, 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, 14.81 ppm.

[0233] Example 56: Preparation of Compound I-53

[0234]

[0235] Following the steps of Example 35, intermediate IV was esterified with p-isonicotinic acid to prepare a white solid compound I-53 (11.5%). 1 H NMR (600 MHz, CDCl3- d) δ 8.75 (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 = 8.0 Hz, 1H), 3.23 (s, 1H), 2.87 (s, 1H), 2.52 (d, J =7.1 Hz, 1H), 2.43 – 2.35 (m, 2H), 2.21 (d, J = 8.9 Hz, 1H), 2.17 (dd, J = 11.6,6.8 Hz, 1H), 1.45 – 1.35 (m, 1H) ppm; 13 C NMR (150 MHz, CDCl3- d ) δ 170.11,164.60, 152.10, 149.44, 146.99, 138.81, 123.71, 121.77, 118.28, 114.69,86.12, 86.03, 80.42, 77.60, 75.03, 53.57, 40.31, 39.00, 37.84, 35.96, 31.52,29.84, 22.83 ppm.

[0236] Example 57: Preparation of Compound I-54

[0237]

[0238] Following the steps of Example 35, intermediate IV was esterified with piperic acid to prepare a white solid compound I-54 (33.2%). 1 H NMR (600 MHz, CDCl3- d ) δ 7.67 (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 = 5.8 Hz, 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, 3.0 Hz, 1H), 2.90 (d, J = 8.6 Hz, 1H), 2.56 (s, 1H), 2.44 – 2.35(m, 2H), 2.24 (dd, J = 18.1, 6.2 Hz, 1H), 1.49 – 1.38 (m, 1H) ppm; 13 C NMR (150MHz, CDCl3- d ) δ 170.22, 152.82, 151.90, 147.87, 147.10, 139.05, 125.69,124.20, 121.55, 117.25, 114.76, 109.71, 108.13, 101.99, 86.27, 80.29, 76.11,53.50, 40.31, 37.78, 35.95, 31.47 ppm.

[0239] Example 58: Preparation of Compound I-55

[0240]

[0241] Following the steps of Example 35, intermediate IV was esterified with 2-methylthiazol-5-carboxylic acid to prepare a white solid compound I-55 (17.6%). 1 H NMR (600 MHz, CDCl3- d ) δ 8.27 (s, 1H), 6.29 (d, J =3.4 Hz, 1H), 5.96 (t, J = 7.3 Hz, 1H), 5.85 (s, 1H), 5.58 (d, J = 4.5 Hz, 2H), 5.02 (s, 1H), 4.85 (s, 1H), 4.17 (d, J = 8.8 Hz, 1H), 3.29 (ddd, J = 11.8, 8.7,3.2 Hz, 1H), 2.89 (dd, J = 8.2, 2.8 Hz, 1H), 2.76 (s, 3H), 2.60 – 2.55 (m, 1H), 2.42 (dd, J = 11.4, 5.7 Hz, 1H), 2.37 (d, J= 6.7 Hz, 1H), 2.30 – 2.25 (m, 1H), 2.21 (d, J = 6.0 Hz, 1H), 1.45 (ddd, J = 17.3, 11.9, 5.7 Hz, 1H) ppm; 13 C NMR (151MHz, CDCl3- d ) δ 168.96, 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, 18.75 ppm.

[0242] Example 59: Preparation of Compound I-56

[0243]

[0244] Following the steps of Example 35, intermediate IV was esterified with 3,4-dimethoxycinnamic acid to prepare a white solid compound I-56 (25.8%). 1 H NMR (600 MHz, CDCl3- d ) δ 7.66 (d, J = 15.9 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 7.06 (s, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.36 (d, J = 15.9Hz, 1H), 6.29 (d, J = 3.4 Hz, 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 = 8.8 Hz, 1H), 3.91 (s, 6H), 3.28(td, J = 8.6, 4.3 Hz, 1H), 2.88 (d, J = 8.6 Hz, 1H), 2.56 (dd, J= 8.6, 3.9 Hz,1H), 2.43 – 2.39 (m, 1H), 2.33 (dd, J = 14.9, 6.7 Hz, 1H), 2.28 – 2.24 (m, 1H), 2.23 – 2.18 (m, 1H), 1.44 (ddd, J = 20.2, 12.4, 5.6 Hz, 1H) ppm; 13 C NMR (150MHz, CDCl3- d ) δ 170.19, 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, 31.49 ppm.

[0245] Example 60: Preparation of Compound I-57

[0246]

[0247] Following the steps of Example 35, intermediate IV was esterified with 6-quinoxaloline carboxylic acid to prepare a white solid compound I-57 (12.5%). ¹H NMR (600 MHz, Chloroform- d ) δ 8.96 – 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 = 8.2Hz, 1H), 6.29 (d, J = 3.4 Hz, 1H), 6.10 (tt, J = 7.5, 2.0 Hz, 1H), 5.89 (d, J = 2.0Hz, 1H), 5.64 (d, J = 1.7 Hz, 1H), 5.58 (d, J = 3.1 Hz, 1H), 5.04 (s, 1H), 4.92(s, 1H), 4.21 (d,J = 8.8 Hz, 1H), 3.36 – 3.29 (m, 1H), 2.97 (dd, J = 7.7, 4.4Hz, 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, 1H).

[0248] Example 61, Preparation of Compound I-58

[0249]

[0250] Following the steps of Example 35, intermediate IV was esterified with cyclopentanoic acid to prepare a white solid compound I-58 (29.3%). 1 H NMR (600 MHz, Chloroform- d ) δ 6.28 (d, J = 3.5 Hz, 1H), 5.81 –5.75 (m, 2H), 5.56 (d, J = 3.2 Hz, 1H), 5.45 (d, J = 1.7 Hz, 1H), 4.99 (s, 1H), 4.84 (s, 1H), 4.14 (d, J = 8.7 Hz, 1H), 3.27 (ddq, J = 12.0, 8.6, 3.3 Hz, 1H),2.84 (dd, J = 8.9, 3.1 Hz, 1H), 2.80 – 2.73 (m, 1H), 2.55 (ddd, J = 13.1, 5.6,3.1 Hz, 1H), 2.32 (t, J = 1.5 Hz, 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, 2.6 Hz, 2H), 1.71 (ddt, J = 6.7, 4.7, 2.3Hz, 1H), 1.61 (s, 2H), 1.47 – 1.41 (m, 1H), 1.28 (s, 1H).

[0251] Example 62, Preparation of Compound I-59

[0252]

[0253] Following the steps of Example 35, intermediate IV was esterified with 1-methylpiperidine-4-carboxylic acid to prepare a white solid compound I-59 (19.0%). 1 H NMR (400 MHz, CDCl3- d ) δ 6.25 (d, J = 3.5 Hz, 1H), 5.76 (d, J = 1.3 Hz, 2H), 5.54 (d, J = 3.1 Hz, 1H), 5.43 (d, J = 1.7 Hz, 1H), 4.97(s, 1H), 4.82 (s, 1H), 4.12 (d, J = 8.8 Hz, 1H), 3.31 – 3.22 (m, 1H), 2.83 (dd, J = 8.8, 3.4 Hz, 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, 2.5 Hz, 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, 2.4 Hz, 2H), 1.46 –1.38 (m, 1H) ppm; 13 C NMR (100 MHz, CDCl3- d ) δ 174.9, 170.1, 152.8, 147.1,139.1, 121.4, 116.9, 114.6, 86.2, 80.1, 75.5, 54.8, 53.6, 46.3, 40.2, 37.6,35.8, 31.4, 28.1, 28.0.

[0254] Example 63, Preparation of Compound I-60

[0255]

[0256] Following the steps of Example 35, intermediate IV was esterified with 2-pyridinecarboxylic acid to prepare a white solid compound I-60 (25.8%). 1 H NMR (400 MHz, Chloroform- d ) δ 8.77 (dt, J = 4.8, 1.2 Hz, 1H), 8.12 (dt, J = 7.8, 1.1 Hz, 1H), 7.84 (td, J = 7.7, 1.8 Hz, 1H), 7.48 (ddd, J =7.7, 4.8, 1.2 Hz, 1H), 6.28 (d, J = 3.5 Hz, 1H), 6.08 (tt, J = 7.4, 1.9 Hz, 1H), 5.87 (d, J = 1.9 Hz, 1H), 5.63 (d, J = 1.7 Hz, 1H), 5.56 (d, J = 3.1 Hz, 1H), 5.02(s, 1H), 4.89 (s, 1H), 4.18 (d, J = 8.8 Hz, 1H), 3.32 (tq, J = 9.9, 3.3 Hz, 1H), 2.95 (t, J = 6.2 Hz, 1H), 2.61 – 2.53 (m, 1H), 2.46 (dd, J = 7.6, 5.9 Hz, 2H), 2.31 – 2.19 (m, 2H), 1.91 (s, 1H), 1.49 – 1.39 (m, 1H).

[0257] Example 64, Preparation of Compound I-61

[0258]

[0259] Following the steps of Example 35, intermediate IV was esterified with 4-pyrimidine carboxylic acid to prepare a white solid compound I-61 (25.8%). ¹H NMR (400 MHz, Chloroform- d ) δ 9.43 (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, 1.9Hz, 1H), 6.07 (td, J = 7.1, 1.9 Hz, 1H), 5.88 (d, J = 1.9 Hz, 1H), 5.63 (t, J = 1.8Hz, 1H), 5.57 (d, J = 3.1 Hz, 1H), 5.02 (s, 1H), 4.85 (s, 1H), 4.17 (dd, J = 8.8, 1.9 Hz, 1H), 3.30 (ddt, J = 12.1, 6.8, 3.3 Hz, 1H), 2.95 (t, J = 6.2 Hz, 1H), 2.60 – 2.53 (m, 1H), 2.47 (dd, J = 7.4, 6.0 Hz, 2H), 2.32 – 2.20 (m, 2H), 1.77(s, 1H), 1.52 – 1.40 (m, 1H).

[0260] Example 65: Preparation of Compound I-62

[0261]

[0262] Following the steps of Example 1, intermediate IV was reacted with 2-methylimidazole via a Michael addition reaction to prepare a white solid compound I-62 (51.2%). 1 H NMR (600 MHz, CDCl3- d ) δ 6.91 (d, J = 7.8 Hz, 1H), 6.89(d, J = 8.5 Hz, 1H), 5.59 (d, J = 1.9 Hz, 1H), 5.45 (t, J = 3.7 Hz, 1H), 4.91 (s,1H), 4.74 (s, 1H), 4.69 (t, J = 7.1 Hz, 1H), 4.34 (dd, J= 14.9, 4.8 Hz, 1H), 4.17 – 4.03 (m, 2H), 2.78 (dd, J = 8.9, 3.9 Hz, 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, 4.9 Hz,1H), 1.57 – 1.46 (m, 1H). 13 C NMR (150 MHz, CDCl3- d ) δ 175.1, 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, 13.3 ppm.

[0263] Example 66: Preparation of Compound I-63

[0264]

[0265] Following the steps of Example 1, intermediate IV was reacted with 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine via a Michael addition reaction to prepare a pale yellow solid compound I-63 (29.4%). 1 H NMR (600 MHz, CD3OD- d 4) δ7.26 (s, 1H), 5.51 (d, J = 2.4 Hz, 1H), 5.43 (s, 0H), 5.31 (d, J = 2.1 Hz, 1H), 4.78 (s, 1H), 4.61 (dd, J = 9.3, 6.7 Hz, 1H), 4.07 (d, J = 9.0 Hz, 1H), 3.48 (s,2H), 2.91 (dd, J = 13.1, 4.8 Hz, 1H), 2.86 – 2.72 (m, 2H), 2.71 – 2.64 (m, 4H), 2.41 (dt, J= 12.9, 5.0 Hz, 1H), 2.19 – 2.02 (m, 2H), 1.98 – 1.85 (m, 1H), 1.37(qd, J = 11.2, 5.4 Hz, 1H). 13 C NMR (150 MHz, CD3OD- d 4) δ 179.9, 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, 33.8 ppm.

[0266] Example 67, Preparation of Compound I-64

[0267]

[0268] Following the steps of Example 1, intermediate IV was reacted with 1-hydroxyphthalazine via a Michael addition reaction to prepare a white solid compound I-64 (38.1%). 1 H NMR (600 MHz, CDCl3- d ) δ 8.43 (d, J = 7.7 Hz, 1H), 8.20(s, 1H), 7.82 (dt, J = 24.3, 7.3 Hz, 2H), 7.72 (d, J = 7.9 Hz, 1H), 5.63 (s, 1H), 5.44 (s, 1H), 5.30 (s, 0H), 4.87 (s, 1H), 4.81 (dd, J = 13.8, 5.5 Hz, 1H), 4.75– 4.67 (m, 2H), 4.53 – 4.43 (m, 1H), 4.14 (d, J = 9.5 Hz, 1H), 3.01 (dt, J =11.9, 6.2 Hz, 1H), 2.77 – 2.69 (m, 2H), 2.38 (dt, J = 13.3, 4.3 Hz, 1H), 2.24(ddd, J = 14.1, 7.5, 3.2 Hz, 1H), 2.13 (ddd, J = 14.7, 8.9, 6.8 Hz, 1H), 1.97(td,J = 12.7, 5.4 Hz, 1H), 1.87 – 1.82 (m, 1H), 1.36 – 1.26 (m, 1H). 13 C NMR (150 MHz, CDCl3-) d ) δ 176.0, 159.9, 157.0, 147.7, 138.3, 133.6, 132.1, 129.7,127.7, 126.9, 126.5, 114.4, 113.7, 86.2, 80.5, 75.1, 52.7, 49.6, 45.2, 40.6,39.1, 38.7, 33.2 ppm.

[0269] Example 68: In vitro anti-HBV activity of dehydrocostane lactone derivatives

[0270] Assay for anti-HBV activity: The effect of dehydroausene lactone derivative on HBeAg and HBsAg antigen secretion was determined by ELISA. The specific experimental procedures are as follows: First, HepG2.2.15 cells in suitable condition were washed with PBS, trypsin was added to disperse the cells, culture medium was added, and the cells were pipetted into a single-cell suspension. Then, the suspension was transferred to EP tubes, centrifuged to remove the supernatant, and complete culture medium (MEM + 10% FBS + 380 μg / mL G418) was added and pipetted into a single-cell suspension. The cells were then re-seeded in 48-well plates with approximately 3000 cells per well and incubated in an incubator (37°C, 5% CO2) for 24 hours. Finally, the culture medium was aspirated, and the cells were treated with the prepared sample solution (30 μM). Dehydroausene lactone was used as a positive control, and cells without sample treatment were used as a blank control. The cells were incubated in an incubator (37°C, 5% CO2) for 72 hours, and the culture medium was collected. The samples were tested using HBeAg and HBsAg detection kits. The absorbance (OD value) was measured using a microplate reader at a detection wavelength of 450 nm and a reference wavelength of 630 nm. The inhibition rate of the compounds against HBsAg and HBeAg was calculated using the following formula:

[0271]

[0272] Table 1. In vitro anti-HBV activity of dehydroaromatic lactone derivatives prepared in Examples 1-68

[0273]

[0274]

[0275] As shown in Table 1, the toxicity of most Michael addition products in this invention is significantly reduced. Some compounds exhibit excellent inhibitory activity against HBeAg, especially the imidazole derivative I-15, whose inhibition rate against HBsAg is comparable to that of the parent compound dehydroaurin lactone, but with approximately 5.5 times lower toxicity. The allyl esterification products I-52~61 show significantly better anti-HBV activity than I-38~46, possibly due to the increased water solubility caused by the presence of hydroxyl groups. Among them, compound I-57, compared to the parent compound dehydroaurin lactone, not only exhibits low toxicity to cells (survival rate: 106.60 ± 0.72%) but also shows good inhibitory activity against HBsAg (inhibition rate: 83.91 ± 1.62%).

[0276] Example 69: Pharmaceutical Uses of Dehydrocostane Lactone Derivatives

[0277] Based on the above test results, the dehydroauric acid lactone derivatives of the present invention exhibit good HBV activity and can be formulated into anti-hepatitis B virus drugs for clinical use. These drugs can be single-component formulations, such as those composed of a single-structure dehydroauric acid lactone derivative and pharmaceutically acceptable excipients; or they can be compound formulations, such as those composed of a single-structure dehydroauric acid lactone derivative, existing anti-HBV active ingredients, and pharmaceutically acceptable excipients, or those composed of several dehydroauric acid lactone derivatives with different structures and pharmaceutically acceptable excipients. The formulation types include, but are not limited to, tablets, capsules, powders, granules, drop pills, injections, powder for injection, solutions, suspensions, emulsions, suppositories, ointments, gels, films, aerosols, transdermal patches, and various sustained-release, controlled-release, and nano-formulations.

[0278] 1. Preparation of Compound I-15 Tablets

[0279] Prescription: Compound I-15 10 g, corn starch 50 g, lactose 187 g, magnesium stearate 3.0 g, and an appropriate amount of 70% ethanol solution, to make 1000 tablets.

[0280] Preparation: Dry corn starch at 105 °C for 5 hours for later use; mix compound I-15 with lactose and corn starch evenly, prepare a soft mass with 70% ethanol solution, sieve to make wet granules, add magnesium stearate, compress into tablets to obtain the product; each tablet weighs 250 mg and contains 10 mg of active ingredient.

[0281] 2. Preparation of Compound I-57 Capsules

[0282] Prescription: Compound I-57 25 g, modified starch (120 mesh) 12.5 g, microcrystalline cellulose (100 mesh) 7.5 g, low-substituted hydroxypropyl cellulose (100 mesh) 2.5 g, talc (100 mesh) 2.0 g, sweetener 1.25 g, orange flavoring 0.25 g, coloring as needed, water as needed, to make 1000 capsules.

[0283] Preparation: The prescribed amount of compound I-57 is micronized and pulverized into an extremely fine powder, then mixed with the prescribed amounts of modified starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, talc, sweetener, orange flavoring, and coloring. The mixture is then softened with water, granulated through a 12–14 mesh sieve, dried at 40–50 ℃, sieved again, and filled into empty capsules to obtain the final product. Each capsule weighs 50 mg and contains 25 mg of active ingredient.

[0284] 3. Preparation of Compound I-15 Granules

[0285] Prescription: Compound I-1526 g, dextrin 120 g, sucrose 280 g.

[0286] Preparation method: Mix compound I-15, dextrin and sucrose evenly, wet granulate, dry at 60 ℃, and package to obtain the product.

[0287] 4. Preparation of Compound I-57 Injection

[0288] Prescription: Compound I-5710 g, propylene glycol 500 mL, water for injection 500 mL, to prepare a total of 1000 mL.

[0289] Preparation: Weigh compound I-57, add propylene glycol and water for injection, stir to dissolve, then add 1 g of activated carbon, stir thoroughly and let stand for 15 minutes, filter with a 5 µm titanium rod to remove carbon, then filter with microporous membranes with pore sizes of 0.45 µm and 0.22 µm in sequence, and finally fill into 10 mL ampoules and sterilize with flowing steam at 100 °C for 45 minutes to obtain the product.

[0290] 5. Preparation of Compound I-15 Powder for Injection

[0291] Preparation method: The intermediate I-15 aseptic powder is dispensed under aseptic conditions to obtain the product.

[0292] Preparation: Weigh gelatin and glycerin, add distilled water to 100 mL, heat in a water bath at 60 ℃ until melted into a paste, add compound I-15, stir well, pour into a vaginal suppository mold when it is almost solidified, and cool and solidify to obtain the product.

[0293] Other embodiments of this application will readily occur to those skilled in the art upon consideration of the specification and practice of the disclosure herein. This application is intended to cover any variations, uses, or adaptations of this application that follow the general principles of this application and include common knowledge or customary techniques in the art not disclosed herein.

Claims

1. A dehydroaristolochic acid lactone derivative, characterized in that, It is any one of the following compounds: 。 2. A pharmaceutically acceptable salt of the dehydrocostane lactone derivative as described in claim 1, characterized in that, The pharmaceutically acceptable salts are hydrochloride, bromate, iodate, sulfate, nitrate, trifluoroacetate, or acetate.

3. A method for preparing the dehydroaristolochic acid lactone derivative according to claim 1, characterized in that, The method is as follows: a. Preparation of intermediates III and IV: In the presence of selenium dioxide and tert-butyl hydrogen peroxide, dehydroaromatic lactone was allylated in anhydrous dichloromethane to obtain intermediates III and IV. ； b. Preparation of dehydroauric acid lactone derivative I-40: In the presence of DMAP, EDCI and DIPEA, intermediate III was esterified with different carboxylic acids in tetrahydrofuran to obtain dehydroauric acid lactone derivative I-40. c. Preparation of dehydroauric acid lactone derivatives I-52, I-55, I-58-I-61: In the presence of DMAP, EDCI and DIPEA, intermediate IV was esterified with different carboxylic acids in tetrahydrofuran to obtain dehydroauric acid lactone derivatives I-52, I-55, I-58-I-61.

4. The preparation method according to claim 3, characterized in that, In step a, the molar ratio of the dehydroauric acid lactone to selenium dioxide and tert-butyl hydrogen peroxide is 1:1:0.

004. In step b, the molar ratio of intermediate III to DMAP, EDCI, DIPEA and carboxylic acid is 1:0.2:2:2:2; In step c, the molar ratio of intermediate IV to DMAP, EDCI, DIPEA and carboxylic acid is 1:0.2:2:2:

2.

5. The use of the dehydroauracene lactone derivative as described in claim 1 in the preparation of anti-HBV drugs.

6. The use of the pharmaceutically acceptable salt of the dehydroauracene lactone derivative as described in claim 2 in the preparation of anti-HBV drugs.

7. An anti-HBV drug formulation containing the dehydroaurin lactone derivative of claim 1.

8. An anti-HBV pharmaceutical preparation containing a pharmaceutically acceptable salt of the dehydroaurin lactone derivative of claim 2.

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