A macrolide cinnamic acid ester derivative, its preparation method and application

Abstract

This invention relates to the field of pharmaceutical chemistry, specifically to a macrolide cinnamic acid ester derivative, its preparation method, and its application. A macrolide cinnamic acid ester derivative is characterized by having the structure shown in formula (I). Data from the examples show that the macrolide cinnamic acid ester derivative provided by this invention has good inhibitory effects on HCoV-229E, and some compounds also have good inhibitory effects on HCoV-OC43, while exhibiting low cytotoxicity. Therefore, the macrolide cinnamic acid ester derivative of this invention shows promise as a new anti-coronavirus drug. Formula (I).

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry, specifically to a macrolide cinnamic acid ester derivative, its preparation method, and its application. Background Technology

[0002] The development and application of vaccines have played a crucial role in reducing severe illness and mortality rates, but the continuous mutability of coronaviruses makes it difficult for existing vaccines to maintain stable protective efficacy in the long term. Furthermore, currently marketed anti-coronavirus drugs generally suffer from drawbacks such as single-target therapy, susceptibility to drug resistance, and insufficient broad-spectrum antiviral activity. Therefore, developing novel broad-spectrum anti-coronavirus drugs is of great significance for overcoming the limitations of existing drugs and building a drug reserve system to cope with future emerging coronavirus outbreaks. Summary of the Invention

[0003] The purpose of this invention is to provide a macrolide cinnamic acid ester derivative, its preparation method and application. The macrolide cinnamic acid ester derivative provided by this invention can be used to prepare drugs for the prevention and / or treatment of diseases caused by coronavirus or coronavirus infection.

[0004] To achieve the above objectives, the present invention provides the following technical solution:

[0005] This invention provides a macrocyclic lactone cinnamic acid ester derivative having the structure shown in formula (I):

[0006] Formula (I);

[0007] In formula (I), R1 is H, C1~C6 alkyl, C3~C6 cycloalkyl, halogen, CN, NO2, NH2, N(CH3)2, OH, C1~C6 alkoxy, benzyloxy, OCH2O, CF3, CHO, COCH3, NHCOCH3, OCHCH or NHCHCH; R2 is H, C1~C6 alkyl, halogen, CN, OH, C1~C6 alkoxy or CF3; R3 is H, CH3 or CN; R4 is H, CH3 or CN; R5 is H or COCH3; R6 is H, COCH3 or COCH2CH3.

[0008] Data from the examples show that the macrolide cinnamic acid ester derivatives provided by this invention have good inhibitory effects on HCoV-229E, and some compounds also have good inhibitory effects on HCoV-OC43, while exhibiting low cytotoxicity. Therefore, the macrolide cinnamic acid ester derivatives of this invention show promise as a new anti-coronavirus drug. Detailed Implementation

[0009] This invention provides a macrocyclic lactone cinnamic acid ester derivative having the structure shown in formula (I):

[0010] Formula (I);

[0011] In formula (I), R1 is H, C1~C6 alkyl, C3~C6 cycloalkyl, halogen, CN, NO2, NH2, N(CH3)2, OH, C1~C6 alkoxy, benzyloxy, OCH2O, CF3, CHO, COCH3, NHCOCH3, OCHCH or NHCHCH;

[0012] R2 is H, C1~C6 alkyl, halogen, CN, OH, C1~C6 alkoxy or CF3;

[0013] R3 is H, CH3, or CN;

[0014] R4 is H, CH3, or CN;

[0015] R5 is H or COCH3;

[0016] R6 is H, COCH3, or COCH2CH 3。

[0017] In one embodiment of the present invention, the halogen group includes F, Cl, Br, and I.

[0018] This invention also provides a method for preparing the macrocyclic lactone cinnamic ester derivatives described in the above technical solution, including the following three cases:

[0019] Type 1:

[0020] Compound II and acetic anhydride were mixed and subjected to an acylation reaction to obtain compound III;

[0021] Compound II;

[0022] In one embodiment of the present invention, compound II is preferably used in the form of a compound II solution, wherein the solvent of the compound II solution can be one or more of acetonitrile, acetone, dichloromethane, and tetrahydrofuran. In another embodiment of the present invention, the molar ratio of compound II to acetic anhydride can be 1:0.8 to 1.2, specifically 1:1. In yet another embodiment of the present invention, the acylation reaction temperature can be room temperature, and the acylation reaction time can be 10 to 15 hours, specifically 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, or 15 hours.

[0023] In one embodiment of the present invention, after the acylation reaction, the reaction solution is further subjected to vacuum concentration, pH adjustment, and dichloromethane extraction in sequence. The resulting organic phase is dried and filtered in sequence. The filtrate is concentrated and purified by silica gel column chromatography to obtain compound III. The eluent for the silica gel column chromatography purification is a dichloromethane-methanol system, and the volume ratio of dichloromethane to methanol in the dichloromethane-methanol system can be 30:1 to 10:1.

[0024] The reaction equation for the acylation reaction of this invention is as follows:

[0025] .

[0026] After obtaining compound III, the present invention mixes compound III and compound IV-1 and performs a first esterification reaction to obtain a first macrocyclic lactone cinnamic ester derivative having the structure shown in formula I-1 and R1 being H, C1~C6 alkyl, C3~C6 cycloalkyl, halogen, CN, NO2, N(CH3)2, OH, C1~C6 alkoxy, benzyloxy, OCH2O, CF3, CHO, COCH3, NHCOCH3, OCHCH or NHCHCH;

[0027] Formula I-1;

[0028] Formula IV-1.

[0029] In one embodiment of the present invention, the first esterification reaction step specifically includes:

[0030] Compound IV-1 was dissolved, activated under catalytic conditions, and then mixed with compound III to carry out the first esterification reaction.

[0031] In one embodiment of the present invention, the solvent for dissolution can be one or more of dichloromethane, tetrahydrofuran, DMF, and DMA; the catalyst can be DCC and PPY; the molar ratio of compound IV-1, DCC, and PPY can be 5~7:5~7:1, specifically 6:6:1. In another embodiment of the present invention, the activation temperature can be room temperature, and the activation time can be 0.5~1 h.

[0032] In one embodiment of the present invention, the molar ratio of compound III to compound IV-1 can be 5:5 to 7, specifically 5:6. In another embodiment of the present invention, the temperature of the first esterification can be room temperature, and the time can be 12 to 24 hours, specifically 12 hours, 16 hours, 20 hours, or 24 hours.

[0033] In one embodiment of the present invention, after the first esterification reaction, the reaction solution is further subjected to vacuum concentration, diluted with ethyl acetate, washed, filtered, and the filtrate is concentrated and purified by silica gel column chromatography; the eluent for the silica gel column chromatography purification is a dichloromethane-methanol system, and the volume ratio of dichloromethane to methanol in the dichloromethane-methanol system can be 30:1 to 10:1.

[0034] The reaction equation for the first esterification reaction of this invention is as follows:

[0035]

[0036] The second method: In this invention, compound III and compound IV-2 are mixed and subjected to a second esterification reaction and deprotection to obtain a second macrocyclic lactone cinnamic acid ester derivative having the structure shown in formula I-1 and R1 being NH2.

[0037] Compound IV-2;

[0038] In one embodiment of the present invention, the second esterification reaction step is specifically as follows:

[0039] Compound IV-2 is dissolved, activated under catalytic conditions, and then mixed with compound III to carry out a second esterification reaction. As one embodiment of the invention, the solvent, catalyst, and activation conditions are preferably the same as those for the activation of compound IV-1, and will not be repeated here.

[0040] In one embodiment of the present invention, the molar ratio of compound III to compound IV-2 can be 5:5 to 7, specifically 5:6. In another embodiment of the present invention, the temperature and time parameters for the second esterification are preferably set the same as those for the first esterification reaction, and will not be repeated here.

[0041] In one embodiment of the present invention, after the second esterification reaction, the reaction solution is further subjected to vacuum concentration, diluted with ethyl acetate, washed, filtered, and the filtrate is concentrated to obtain an intermediate product for deprotection.

[0042] As one embodiment of the present invention, the deprotection step is preferably:

[0043] The intermediate product was dissolved in dichloromethane and mixed with CF3COOH for deprotection.

[0044] In one embodiment of the present invention, the deprotection temperature can be room temperature, and the time can be 1 to 5 hours, specifically 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours. In another embodiment of the present invention, after deprotection, the reaction solution is further concentrated, the pH is adjusted, extracted with ethyl acetate, the resulting organic phase is dried and filtered, and the filtrate is concentrated and purified by silica gel column chromatography; the eluent for the silica gel column chromatography purification is a dichloromethane-methanol system, and the volume ratio of dichloromethane to methanol in the dichloromethane-methanol system can be 30:1 to 10:1.

[0045] The reaction equation for the second scenario is as follows:

[0046]

[0047] The third method: The present invention involves performing an alcoholysis reaction on a first macrocyclic lactone cinnamic acid ester derivative or a second macrocyclic lactone cinnamic acid ester derivative having the structure shown in Formula I-1 to obtain a third macrocyclic lactone cinnamic acid ester derivative having the structure shown in Formula I-2.

[0048] Formula I-2.

[0049] In one embodiment of the present invention, the alcohol used for alcoholysis preferably includes methanol. In another embodiment, the alcoholysis reaction temperature can be 50-70°C, specifically 60°C, and the reaction time can be 10-12 hours, specifically 10, 11, or 12 hours. In yet another embodiment, after the alcoholysis reaction, the reaction solution is concentrated under reduced pressure and then purified by silica gel column chromatography; the eluent for the silica gel column chromatography purification is a dichloromethane-methanol system, and the volume ratio of dichloromethane to methanol in the dichloromethane-methanol system can be 30:1 to 10:1.

[0050] In this invention, the reaction equation for alcoholysis is:

[0051]

[0052] The present invention also provides the use of the macrolide cinnamic acid ester derivatives or pharmaceutically acceptable salts thereof described in the above technical solutions in the preparation of medicaments for the prevention of coronavirus-induced diseases or coronavirus infection, the preparation of medicaments for the treatment of coronavirus-induced diseases or coronavirus infection, or the preparation of coronavirus inhibitors.

[0053] In one embodiment of the present invention, the coronavirus can be an alpha coronavirus and / or a beta coronavirus, specifically selected from at least one of human coronaviruses HCoV-229E, HCoV-OC43, SARS-CoV, and MERS-CoV. The diseases caused by the coronavirus can be respiratory infections and / or digestive system infections. The respiratory infections are respiratory tract infections and / or lung infections; the respiratory tract infections can be nasopharyngitis, rhinitis, pharyngitis, tracheitis, and / or bronchitis; the lung infections can be pneumonia; and the digestive system infections can be diarrhea. In the present invention, the diseases caused by the coronavirus typically include viral pneumonia, severe acute respiratory syndrome, etc. In the present invention, coronavirus infection typically causes diseases such as viral pneumonia and severe acute respiratory syndrome.

[0054] As one embodiment of the present invention, the pharmaceutically acceptable salts of macrolide cinnamic acid ester derivatives include one or more of the following: hydrochloride, nitrate, sulfate, hydrogen sulfate, trifluoroacetate, phosphate, hydrogen phosphate, acetate, oxalate, lactate, citrate, tartrate, and maleate.

[0055] As one embodiment of the present invention, the macrolide cinnamic acid ester derivatives or their pharmaceutically acceptable salts described in the above technical solution can be used as one of the effective / active ingredients of the drug, or as the sole effective / active ingredient.

[0056] In one embodiment of the present invention, when preparing a drug using the macrolide cinnamic acid ester derivatives or their pharmaceutically acceptable salts described in the above technical solution, a carrier material may also be added. The carrier material includes water-soluble carrier materials (such as polyethylene glycol, polyvinylpyrrolidone, organic acids, etc.), poorly soluble carrier materials (such as ethyl cellulose, cholesterol stearate, etc.), or enteric carrier materials (such as cellulose acetate phthalate and carboxymethyl ethyl cellulose, etc.).

[0057] As one embodiment of the present invention, the pharmaceutical dosage forms prepared using the macrolide cinnamic acid ester derivatives or their pharmaceutically acceptable salts described in the above technical solutions include tablets, capsules, pellets, aerosols, pills, powders, solutions, injections, suspensions, emulsions, granules, liposomes, transdermal preparations, lozenges, suppositories, or lyophilized powder injections. They can also be ordinary preparations, sustained-release preparations, controlled-release preparations, and various particulate delivery systems.

[0058] To formulate unit-dose dosage forms into tablets, a wide variety of carriers known in the art can be used, such as diluents and absorbents like starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, and aluminum silicate; humectants and binders like water, glycerin, polyethylene glycol, ethanol, propanol, starch paste, dextrin, syrup, honey, glucose solution, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, and poly… Vinylpyrrolidone, etc.; disintegrants, such as dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitol fatty acid esters, sodium lauryl sulfonate, methylcellulose, ethylcellulose, etc.; disintegration inhibitors, such as sucrose, tristearate, cocoa butter, hydrogenated oil, etc.; absorption promoters, such as quaternary ammonium salts, sodium lauryl sulfate, etc.; lubricants, such as talc, silica, corn starch, stearates, boric acid, liquid paraffin, polyethylene glycol, etc. Tablets can also be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or bilayer and multilayer tablets.

[0059] To formulate unit-dose dosage forms into pills, a wide variety of carriers known in the art can be used, such as diluents and absorbents, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, kaolin, talc, etc.; binders such as gum arabic, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or flour paste, etc.; disintegrants such as agar powder, dried starch, alginate, sodium dodecyl sulfonate, methylcellulose, ethylcellulose, etc.

[0060] To formulate unit-dose dosage forms into suppositories, a wide variety of carriers known in the art can be used, such as polyethylene glycol, lecithin, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc.

[0061] To formulate unit-dose dosage forms into injectable preparations, such as solutions, emulsions, lyophilized powders for injection, and suspensions, all diluents commonly used in the art can be used, such as water, ethanol, polyethylene glycol, 1,3-propanediol, ethoxylated isostearyl alcohol, polyoxyethylene isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. Additionally, to prepare isotonic injections, appropriate amounts of sodium chloride, glucose, or glycerol can be added to the injectable formulation. Furthermore, conventional solubilizers, buffers, pH adjusters, etc., can also be added. Furthermore, if necessary, colorants, preservatives, flavorings, tasters, sweeteners, or other materials can be added to the pharmaceutical preparation. These dosage forms can be administered via injection, including subcutaneous, intravenous, intramuscular, and intracavitary injections; via cavities, such as rectal and vaginal; and via the respiratory tract, such as nasal or mucosal administration.

[0062] To further illustrate the present invention, the following detailed description of the embodiments is provided in conjunction with the present invention, but these descriptions should not be construed as limiting the scope of protection of the present invention.

[0063] Example 1

[0064] 1.1 Compound 1 (4.2 g, 5.0 mmol) was dissolved in acetonitrile (25 mL), and acetic anhydride (0.51 g, 5.0 mmol) was added. The mixture was stirred at room temperature for 12 h. After the reaction was completed, the solution was concentrated under reduced pressure, the pH was adjusted to approximately 8.0 with saturated sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography using dichloromethane-methanol (20:1) as the eluent to obtain compound 2 (3.7 g, 84%).

[0065] 1.2 Compound 3a (89 mg, 0.6 mmol) was dissolved in dichloromethane (2 mL). Under an inert atmosphere (Ar) and on an ice bath, DCC (124 mg, 0.6 mmol) and PPY (15 mg, 0.1 mmol) were added. After stirring at room temperature for 1 h, compound 2 (442 mg, 0.5 mmol) was added, and the mixture was stirred at room temperature for 15 h. After the reaction was complete, the solution was concentrated under reduced pressure and diluted with ethyl acetate. The solution was washed successively with NH4Cl solution, saturated NaHCO3 solution, and saturated NaCl solution, and dried over anhydrous Na2SO4. The solution was filtered, concentrated, and purified by silica gel column chromatography using dichloromethane-methanol (30:1–10:1) as the eluent to obtain compound 4a (132 mg, 26%).

[0066] The NMR 1H spectrum data of compound 4a are as follows:

[0067] 1 H NMR (600 MHz, Chloroform- d ) δ 9.81 (s, 1H), 7.74 (d, J = 15.9 Hz, 1H), 7.54 (dd, J = 6.6, 3.0 Hz, 2H), 7.41-7.36 (m, 3H), 6.59 (d, J = 15.9 Hz, 1H), 6.24 (dd, J = 15.1, 10.5 Hz, 1H), 5.98 (dd, J = 14.9, 10.7 Hz, 1H), 5.67(dd, J = 15.1, 9.7 Hz, 1H), 5.55 (ddd, J= 15.1, 11.1, 4.0 Hz, 1H), 5.29 (ddd, J =11.5, 6.3, 3.2 Hz, 1H), 5.10 (d, J = 3.7 Hz, 1H), 4.99 (dd, J = 10.5, 7.7 Hz,1H), 4.76-4.68 (m, 2H), 4.46 (dq, J = 9.9, 6.1 Hz, 1H), 4.38 (d, J = 7.7 Hz, 1H), 4.32 (s, 1H), 4.16-4.09 (m, 2H), 4.03 (dd, J = 9.7, 4.1 Hz, 1H), 3.79 (d, J =11.1 Hz, 1H), 3.46 (s, 3H), 3.45-3.41 (m, 1H), 3.34-3.28 (m, 2H), 3.02-2.98(m, 1H), 2.82-2.64 (m, 3H), 2.49 (dt, J = 12.8, 3.6 Hz, 1H), 2.44 (s, 6H), 2.32-2.19 (m, 9H), 2.09 (dd, J = 24.9, 11.4 Hz, 2H), 2.04 (s, 3H), 1.95-1.83(m, 4H), 1.50-1.45 (m, 2H), 1.30 (d, J = 6.3 Hz, 3H), 1.28-1.19 (m, 8H), 1.18-1.15 (m, 6H), 0.97 (d, J = 6.6 Hz, 3H).

[0068] The reaction equation is:

[0069]

[0070] Example 2

[0071] The difference from 1.2 is that compound 3a in 1.2 is replaced with compound 3b, and the amount of compound 3b is (97 mg, 0.6 mmol), resulting in compound 4b (112 mg, 22%).

[0072] The NMR 1H spectrum data of compound 4b are as follows:

[0073] 1 H NMR (600 MHz, Chloroform- d ) δ 9.81 (s, 1H), 7.72 (d, J = 15.9 Hz,1H), 7.43 (d, J = 7.7 Hz, 2H), 7.19 (d, J = 7.7 Hz, 2H), 6.54 (d, J = 15.9 Hz, 1H),6.24 (dd, J = 15.2, 10.5 Hz, 1H), 5.98 (dd, J = 15.1, 10.5 Hz, 1H), 5.66 (dd, J =15.1, 9.6 Hz, 1H), 5.55 (ddd, J = 15.2, 11.1, 4.0 Hz, 1H), 5.29 (ddd, J = 10.3,6.4, 3.2 Hz, 1H), 5.10 (d, J = 3.8 Hz, 1H), 4.99 (dd, J = 10.5, 7.7 Hz, 1H), 4.74(d, J = 10.1 Hz, 1H), 4.69 (d, J = 7.7 Hz, 1H), 4.46 (dq, J = 12.2, 6.3 Hz, 1H),4.38 (d, J = 8.4 Hz, 1H), 4.31 (s, 1H), 4.18-4.08 (m, 2H), 4.03 (dd, J = 9.7, 4.1Hz, 1H), 3.79 (d, J = 11.1 Hz, 1H), 3.46 (s, 4H), 3.35-3.28 (m, 2H), 2.99 (d, J =9.0 Hz, 1H), 2.82-2.64 (m, 3H), 2.49 (d, J = 13.9 Hz, 1H), 2.43 (s, 6H), 2.37(s, 4H), 2.35-2.18 (m, 9H), 2.13-2.05 (m, 2H), 2.03 (d, J= 4.8 Hz, 3H), 1.94-1.83 (m, 4H), 1.53-1.42 (m, 3H), 1.31-1.21 (m, 10H), 1.16 (s, 6H), 0.97 (d, J =6.6 Hz, 3H).

[0074] The reaction equation is:

[0075]

[0076] Example 3

[0077] The difference from 1.2 is that compound 3a in 1.2 is replaced with compound 3b, and the amount of compound 3b is (100 mg, 0.6 mmol), to obtain compound 4c (151 mg, 29%).

[0078] The NMR 1H spectrum data of compound 4c are as follows:

[0079] 1 H NMR (500 MHz, Chloroform- d ) δ 9.81 (s, 1H), 7.64 (dd, J = 15.9, 0.9Hz, 1H), 7.61-7.55 (m, 2H), 7.22-7.14 (m, 2H), 6.36 (d, J = 15.9 Hz, 1H), 6.09-5.92 (m, 2H), 5.82-5.73 (m, 1H), 5.67-5.58 (m, 1H), 5.30 (dd, J = 5.1, 2.6 Hz, 1H), 5.16 (dd, J = 9.3, 5.1 Hz, 1H), 5.11-5.05 (m, 1H), 5.05-4.98 (m, 1H), 4.86-4.81 (m, 1H), 4.75-4.69 (m, 1H), 4.44-4.35 (m, 1H), 4.31-4.21 (m, 1H),4.12-4.05 (m, 1H), 3.94 (dd, J = 8.2, 7.5 Hz, 1H), 3.91-3.86 (m, 1H), 3.86-3.81(m, 1H), 3.70 (tq, J= 7.4, 1.5 Hz, 1H), 3.62-3.50 (m, 2H), 3.42-3.35 (m, 4H), 3.30-3.21 (m, 1H), 2.86-2.71 (m, 2H), 2.59-2.42 (m, 3H), 2.40-2.27 (m, 14H),2.22-2.09 (m, 2H), 2.06 (s, 3H), 2.01-1.91 (m, 3H), 1.91-1.82 (m, 1H), 1.72-1.60 (m, 2H), 1.56 (dt, J = 13.0, 8.5 Hz, 1H), 1.31 (d, J = 6.4 Hz, 3H), 1.23(dd, J = 22.3, 6.0 Hz, 6H), 1.21-1.14 (m, 7H), 0.93 (dd, J = 7.4, 1.5 Hz, 3H).

[0080] The reaction equation is:

[0081]

[0082] Example 4

[0083] The difference from 1.2 is that compound 3a in 1.2 is replaced with compound 3d, and the amount of compound 3d is (116 mg, 0.6 mmol), to obtain compound 4d (165 mg, 31%).

[0084] The NMR 4H spectrum data of compound 4d are as follows:

[0085] 1 H NMR (500 MHz, Chloroform- d ) δ 9.81 (s, 1H), 8.28-8.22 (m, 2H), 8.07-8.01 (m, 2H), 7.67 (dd, J = 15.9, 0.9 Hz, 1H), 6.47 (d, J = 15.9 Hz, 1H), 6.09-5.92 (m, 2H), 5.82-5.73 (m, 1H), 5.67-5.58 (m, 1H), 5.30 (dd, J = 5.1, 2.6Hz, 1H), 5.16 (dd, J= 9.3, 5.1 Hz, 1H), 5.11-5.05 (m, 1H), 5.05-4.98 (m, 1H), 4.86-4.81 (m, 1H), 4.75-4.69 (m, 1H), 4.44-4.35 (m, 1H), 4.31-4.21 (m, 1H),4.12-4.05 (m, 1H), 3.94 (dd, J = 8.2, 7.5 Hz, 1H), 3.91-3.86 (m, 1H), 3.86-3.81(m, 1H), 3.70 (tq, J = 7.4, 1.5 Hz, 1H), 3.62-3.50 (m, 2H), 3.42-3.35 (m, 4H), 3.30-3.21 (m, 1H), 2.86-2.71 (m, 2H), 2.59-2.42 (m, 3H), 2.40-2.27 (m, 14H),2.22-2.09 (m, 2H), 2.06 (s, 3H), 2.01-1.91 (m, 3H), 1.91-1.82 (m, 1H), 1.72-1.60 (m, 2H), 1.60-1.51 (m, 1H), 1.31 (d, J = 6.4 Hz, 3H), 1.23 (dd, J = 22.3,6.0 Hz, 6H), 1.21-1.14 (m, 7H), 0.93 (dd, J = 7.4, 1.5 Hz, 3H).

[0086] The reaction equation is:

[0087]

[0088] Example 5

[0089] The difference from 1.2 is that compound 3a in 1.2 is replaced with compound 3e, and the amount of compound 3e is (115 mg, 0.6 mmol), resulting in compound 4d (163 mg, 31%).

[0090] The NMR 1H spectrum data of compound 4e are as follows:

[0091] 1 H NMR (400 MHz, Chloroform- d ) δ 9.82 (s, 1H), 7.68 (d, J= 15.8 Hz, 1H), 7.43 (d, J = 8.8 Hz, 2H), 6.66 (d, J = 8.7 Hz, 2H), 6.36 (d, J = 15.8 Hz, 1H), 6.24 (dd, J = 15.2, 10.5 Hz, 1H), 6.01 (dd, J = 15.0, 10.5 Hz, 1H), 5.68 (dd, J = 15.1, 9.5 Hz, 1H), 5.56 (ddd, J = 15.1, 11.0, 4.0 Hz, 1H), 5.31 - 5.27 (m, 1H), 5.10 (d, J = 3.7 Hz, 1H), 4.73 (d, J = 10.1 Hz, 1H), 4.51 (dd, J = 12.4, 6.8 Hz, 2H), 4.40 - 4.35 (m, 1H), 4.12 (dd, J = 8.9, 1.8 Hz, 1H), 4.09 - 4.01 (m, 2H), 3.80 (d, J = 10.9 Hz, 1H), 3.51 (s, 4H), 3.47 - 3.39 (m, 1H), 3.34 - 3.28 (m, 2H), 3.09 (d, J = 1.6 Hz, 1H), 3.02 (s, 6H), 2.83 - 2.76 (m, 1H), 2.72 - 2.65 (m, 1H), 2.53 (d, J = 7.2 Hz, 8H), 2.39 - 2.19 (m, 11H), 2.16 - 2.00 (m, 3H), 1.98 - 1.84 (m, 4H), 1.55 - 1.43 (m, 3H), 1.30 (d, J = 6.3 Hz, 3H), 1.24 (d, J = 5.7 Hz, 7H), 1.17 (d, J = 6.6 Hz, 6H), 0.98 (d, J = 6.5 Hz, 3H).

[0092] The reaction equation is:

[0093]

[0094] Example 6

[0095] The difference from 1.2 is that compound 3a in 1.2 is replaced with compound 3f, and the amount of compound 3f is (130 mg, 0.6 mmol), resulting in compound 4f (133 mg, 25%).

[0096] The NMR 1H spectrum data of compound 4f are as follows:

[0097] 1 H NMR (400 MHz, Chloroform- d ) δ 9.81 (s, 1H), 7.75 (d, J = 16.0 Hz,1H), 7.64 (s, 4H), 6.66 (d, J = 16.0 Hz, 1H), 6.24 (dd, J = 15.1, 10.5 Hz, 1H),5.98 (dd, J = 15.1, 10.5 Hz, 1H), 5.66 (dd, J = 15.1, 9.6 Hz, 1H), 5.55 (ddd, J =15.0, 11.0, 4.0 Hz, 1H), 5.34-5.27 (m, 1H), 5.10 (d, J = 3.6 Hz, 1H), 4.99 (dd, J = 10.5, 7.7 Hz, 1H), 4.77-4.67 (m, 2H), 4.47 (dq, J = 12.3, 6.2 Hz, 1H), 4.41-4.31 (m, 2H), 4.17-4.10 (m, 2H), 4.03 (dd, J = 9.7, 4.1 Hz, 1H), 3.79 (d, J =11.0 Hz, 1H), 3.46 (s, 3H), 3.45-3.40 (m, 1H), 3.34-3.28 (m, 2H), 2.99 (d, J=8.9 Hz, 1H), 2.83-2.63 (m, 3H), 2.53-2.47 (m, 1H), 2.43 (s, 6H), 2.33-2.18(m, 10H), 2.04 (s, 5H), 1.91-1.84 (m, 3H), 1.47 (q, J = 9.2 Hz, 3H), 1.29 (d, J =6.3 Hz, 3H), 1.24 (dd, J = 9.0, 4.4 Hz, 7H), 1.19-1.15 (m, 6H), 0.97 (d, J = 6.6Hz, 3H).

[0098] The reaction equation is:

[0099]

[0100] Example 7

[0101] The difference from 1.2 is that compound 3a in 1.2 is replaced with compound 3g, and the amount of compound 3g is (107 mg, 0.6 mmol), resulting in compound 4g (105 mg, 20%).

[0102] The NMR 1H spectrum data of compound 4g are as follows:

[0103] 1 H NMR (500 MHz, Chloroform- d ) δ 9.81 (s, 1H), 7.69-7.62 (m, 1H), 7.59-7.53 (m, 2H), 6.96-6.90 (m, 2H), 6.36 (d, J = 15.9 Hz, 1H), 6.09-5.92 (m,2H), 5.82-5.73 (m, 1H), 5.67-5.58 (m, 1H), 5.30 (dd, J = 5.1, 2.6 Hz, 1H), 5.16(dd, J = 9.3, 5.1 Hz, 1H), 5.11-5.05 (m, 1H), 5.05-4.98 (m, 1H), 4.86-4.81 (m,1H), 4.75-4.69 (m, 1H), 4.44-4.35 (m, 1H), 4.31-4.21 (m, 1H), 4.12-4.05 (m,1H), 3.94 (dd,J = 8.2, 7.5 Hz, 1H), 3.89 (d, J = 5.7 Hz, 1H), 3.88-3.81 (m, 1H), 3.80 (s, 3H), 3.70 (tq, J = 7.4, 1.5 Hz, 1H), 3.62-3.50 (m, 2H), 3.42-3.35 (m,4H), 3.30-3.21 (m, 1H), 2.86-2.71 (m, 2H), 2.59-2.42 (m, 3H), 2.40-2.34 (m,7H), 2.34-2.27 (m, 7H), 2.22-2.09 (m, 2H), 2.06 (s, 3H), 2.01-1.91 (m, 3H), 1.91-1.82 (m, 1H), 1.72-1.60 (m, 2H), 1.60-1.51 (m, 1H), 1.31 (d, J = 6.4 Hz, 3H), 1.23 (dd, J = 22.3, 6.0 Hz, 6H), 1.21-1.14 (m, 7H), 0.93 (dd, J = 7.4, 1.5Hz, 3H).

[0104] The reaction equation is:

[0105]

[0106] Example 8

[0107] The difference from 1.2 is that compound 3a in 1.2 is replaced with compound 3h, and the amount of compound 3h is (113 mg, 0.6 mmol), resulting in compound 4g (96 mg, 18%).

[0108] The NMR 1H spectrum data of compound 4h are as follows:

[0109] 1 H NMR (500 MHz, Chloroform- d ) δ 9.81 (s, 1H), 7.62 (t, J = 1.0 Hz,1H), 7.40-7.34 (m, 2H), 7.27-7.21 (m, 2H), 6.34 (s, 1H), 5.99 (d, J = 0.9 Hz, 1H), 5.81 (t, J= 1.0 Hz, 1H), 5.72 (s, 1H), 5.65 (s, 1H), 5.21 (s, 1H), 5.05(s, 1H), 4.93-4.85 (m, 3H), 4.80 (s, 1H), 4.43 (d, J = 4.9 Hz, 1H), 4.15 (d, J =0.9 Hz, 1H), 4.11 (d, J = 4.9 Hz, 1H), 4.05 (s, 1H), 3.94 (s, 1H), 3.82 (s,1H), 3.77 (d, J = 2.0 Hz, 2H), 3.72 (s, 1H), 3.39 (s, 3H), 3.31 (d, J = 5.1 Hz,2H), 2.85 (s, 1H), 2.61 (d, J = 9.7 Hz, 2H), 2.54-2.48 (m, 2H), 2.39 (t, J = 1.0Hz, 1H), 2.35-2.26 (m, 14H), 2.25 (d, J = 3.0 Hz, 1H), 2.21 (s, 1H), 2.06 (d, J =16.9 Hz, 4H), 1.97 (s, 1H), 1.92 (s, 1H), 1.74-1.65 (m, 5H), 1.58 (s, 1H), 1.43 (d, J = 4.9 Hz, 2H), 1.37 (d, J = 1.1 Hz, 6H), 1.31 (d, J = 13.9 Hz, 4H), 1.21(d, J = 8.2 Hz, 6H), 0.98 (s, 3H).

[0110] The reaction equation is:

[0111]

[0112] Example 9

[0113] The difference from 1.2 is that compound 3a in 1.2 is replaced with compound 3i, and the amount of compound 3i is (115 mg, 0.6 mmol), to obtain compound 4i (101 mg, 19%).

[0114] The NMR 1H spectrum data of compound 4i are as follows:

[0115] 1 H NMR (500 MHz, Chloroform- d ) δ 9.81 (s, 1H), 7.58 (t, J = 1.0 Hz,1H), 7.13-7.07 (m, 2H), 6.89-6.84 (m, 1H), 6.35 (s, 1H), 5.99 (d, J = 0.9 Hz,1H), 5.97 (s, 2H), 5.81 (t, J = 1.0 Hz, 1H), 5.72 (s, 1H), 5.65 (s, 1H), 5.21(s, 1H), 5.05 (s, 1H), 4.93-4.85 (m, 3H), 4.80 (s, 1H), 4.43 (d, J = 4.9 Hz, 1H), 4.15 (d, J = 0.9 Hz, 1H), 4.11 (d, J = 4.9 Hz, 1H), 4.05 (s, 1H), 3.94 (s,1H), 3.82 (s, 1H), 3.77 (d, J = 2.0 Hz, 2H), 3.72 (s, 1H), 3.39 (s, 3H), 3.31(d, J = 5.1 Hz, 2H), 2.85 (s, 1H), 2.61 (d, J = 9.7 Hz, 2H), 2.54-2.48 (m, 2H), 2.35-2.23 (m, 15H), 2.21 (s, 1H), 2.06 (d, J = 16.9 Hz, 4H), 1.97 (s, 1H), 1.92(s, 1H), 1.72 (s, 1H), 1.68 (d, J = 4.4 Hz, 2H), 1.58 (s, 1H), 1.37 (d, J = 1.1Hz, 6H), 1.31 (d, J = 13.9 Hz, 4H), 1.21 (d, J = 8.2 Hz, 6H), 0.98 (s, 3H).

[0116] The reaction equation is:

[0117]

[0118] Example 10

[0119] The difference from 1.2 is that compound 3a in 1.2 is replaced with compound 3j, and the amount of compound 3j is (113 mg, 0.6 mmol), resulting in compound 4j (146 mg, 23%).

[0120] The NMR 1H spectrum data of compound 4j are as follows:

[0121] 1 H NMR (500 MHz, Chloroform- d ) δ 9.81 (s, 1H), 8.03 (s, 1H), 7.88 (s,1H), 7.61 (s, 1H), 7.57 (s, 1H), 7.42 (s, 1H), 6.94 (s, 1H), 6.35 (s, 1H), 5.99 (d, J = 0.9 Hz, 1H), 5.81 (t, J = 1.0 Hz, 1H), 5.72 (s, 1H), 5.65 (s, 1H), 5.21 (s, 1H), 5.05 (s, 1H), 4.93-4.85 (m, 3H), 4.80 (s, 1H), 4.43 (d, J = 4.9Hz, 1H), 4.15 (d, J = 0.9 Hz, 1H), 4.11 (d, J = 4.9 Hz, 1H), 4.05 (s, 1H), 3.94(s, 1H), 3.82 (s, 1H), 3.77 (d, J = 2.0 Hz, 2H), 3.72 (s, 1H), 3.39 (s, 3H), 3.31 (d, J = 5.1 Hz, 2H), 2.85 (s, 1H), 2.61 (d, J = 9.7 Hz, 2H), 2.54-2.48 (m,2H), 2.35-2.26 (m, 14H), 2.25 (d, J = 3.0 Hz, 1H), 2.21 (s, 1H), 2.06 (d, J=16.9 Hz, 4H), 1.97 (s, 1H), 1.92 (s, 1H), 1.72 (s, 1H), 1.68 (d, J = 4.4 Hz, 2H), 1.58 (s, 1H), 1.37 (d, J = 1.1 Hz, 6H), 1.31 (d, J = 13.9 Hz, 4H), 1.21 (d, J = 8.2 Hz, 6H), 0.98 (s, 3H).

[0122] The reaction equation is:

[0123]

[0124] Example 11

[0125] The difference from 1.2 is that compound 3a in 1.2 is replaced with compound 3k, and the amount of compound 3k is (112 mg, 0.6 mmol), resulting in compound 4k (138 mg, 26%).

[0126] The NMR 1H spectrum data of compound 4j are as follows:

[0127] 1 H NMR (500 MHz, Chloroform- d ) δ 9.69 (s, 1H), 9.81 (s, 1H), 7.73 (s,1H), 7.61 (s, 1H), 7.49 (s, 1H), 7.42 (s, 1H), 7.28 (s, 1H), 6.58 (s, 1H), 6.35 (s, 1H), 5.99 (d, J = 0.9 Hz, 1H), 5.81 (t, J = 1.0 Hz, 1H), 5.72 (s, 1H),5.65 (s, 1H), 5.21 (s, 1H), 5.05 (s, 1H), 4.93-4.85 (m, 3H), 4.80 (s, 1H),4.43 (d, J = 4.9 Hz, 1H), 4.15 (d, J = 0.9 Hz, 1H), 4.11 (d, J = 4.9 Hz, 1H), 4.05(s, 1H), 3.94 (s, 1H), 3.82 (s, 1H), 3.77 (d,J = 2.0 Hz, 2H), 3.72 (s, 1H), 3.39 (s, 3H), 3.31 (d, J = 5.1 Hz, 2H), 2.85 (s, 1H), 2.61 (d, J = 9.7 Hz, 2H),2.54-2.48 (m, 2H), 2.35-2.26 (m, 14H), 2.25 (d, J = 3.0 Hz, 1H), 2.21 (s, 1H), 2.06 (d, J = 16.9 Hz, 4H), 1.97 (s, 1H), 1.92 (s, 1H), 1.72 (s, 1H), 1.68 (d, J =4.4 Hz, 2H), 1.58 (s, 1H), 1.37 (d, J = 1.1 Hz, 6H), 1.31 (d, J = 13.9 Hz, 4H), 1.21 (d, J = 8.2 Hz, 6H), 0.98 (s, 3H).

[0128] The reaction equation is:

[0129]

[0130] Example 12

[0131] The difference from 1.2 is that compound 3a in 1.2 is replaced with compound 3l, and the amount of compound 3l is (105 mg, 0.6 mmol), resulting in compound 4l (151 mg, 29%).

[0132] The NMR 1H spectrum data of compound 4l are as follows:

[0133] 1 H NMR (500 MHz, Chloroform- d ) δ 9.94 (t, J = 1.0 Hz, 1H), 9.81 (s,1H), 7.90-7.84 (m, 2H), 7.62 (t, J = 1.0 Hz, 1H), 7.57-7.50 (m, 2H), 6.34 (s,1H), 5.99 (d, J = 0.9 Hz, 1H), 5.81 (t, J= 1.0 Hz, 1H), 5.72 (s, 1H), 5.65 (s,1H), 5.21 (s, 1H), 5.05 (s, 1H), 4.93-4.85 (m, 3H), 4.80 (s, 1H), 4.43 (d, J =4.9 Hz, 1H), 4.15 (d, J = 0.9 Hz, 1H), 4.11 (d, J = 4.9 Hz, 1H), 4.05 (s, 1H), 3.94 (s, 1H), 3.82 (s, 1H), 3.77 (d, J = 2.0 Hz, 2H), 3.72 (s, 1H), 3.39 (s,3H), 3.31 (d, J = 5.1 Hz, 2H), 2.85 (s, 1H), 2.61 (d, J = 9.7 Hz, 2H), 2.54-2.48(m, 2H), 2.35-2.29 (m, 13H), 2.29-2.23 (m, 2H), 2.21 (s, 1H), 2.06 (d, J = 16.9Hz, 4H), 1.97 (s, 1H), 1.92 (s, 1H), 1.72 (s, 1H), 1.68 (d, J = 4.4 Hz, 2H),1.58 (s, 1H), 1.37 (d, J = 1.1 Hz, 6H), 1.31 (d, J = 13.9 Hz, 4H), 1.21 (d, J = 8.2Hz, 6H), 0.98 (s, 3H).

[0134] The reaction equation is:

[0135]

[0136] Example 13

[0137] The difference from 1.2 is that compound 3a in 1.2 is replaced with compound 3m, and the amount of compound 3m is (123 mg, 0.6 mmol), resulting in compound 4m (134 mg, 25%).

[0138] The NMR 1H spectrum data of compound 4m are as follows:

[0139] 11H NMR (500 MHz, Chloroform- d ) δ 9.81 (s, 1H), 9.07 (s, 1H), 7.60 (t, J J = 1.0 Hz, 1H), 7.55 - 7.48 (m, 2H), 7.47 - 7.41 (m, 2H), 6.35 (s, 1H), 5.99 (d, J J = 0.9 Hz, 1H), 5.81 (t, J J = 1.0 Hz, 1H), 5.72 (s, 1H), 5.65 (s, 1H), 5.21 (s,1H), 5.05 (s, 1H), 4.93 - 4.85 (m, 3H), 4.80 (s, 1H), 4.43 (d, J J = 4.9 Hz, 1H),4.15 (d, J J = 0.9 Hz, 1H), 4.11 (d, J J = 4.9 Hz, 1H), 4.05 (s, 1H), 3.94 (s, 1H),3.82 (s, 1H), 3.77 (d, J J = 2.0 Hz, 2H), 3.72 (s, 1H), �.39 (s, 3H), 3.31 (d, J J =5.1 Hz, 2H), 2.85 (s, 1H), 2.61 (d, J J = 9.7 Hz, 2H), 2.54 - 2.48 (m, 2H), 2.35 - 2.29 (m, 13H), 2.29 - 2.23 (m, 2H), 2.21 (s, 1H), 2.15 (s, 3H), 2.06 (d, J J = 16.9Hz, 4H), 1.97 (s, 1H), 1.9² (s, 1H), 1.72 (s, 1H), 1.68 (d, J J = 4.4 Hz, 2H),1.58 (s, 1H), 1.37 (d,<00_{00536>J = 1.1 Hz, 6H), 1.31 (d, J J = 13.9 Hz, 4H), 1.21 (d, J J = 8.2Hz, 6H), 0.98 (s, 3H). <000054_{0>The reaction equation is:

[0141]

[0142] Example 14

[0143] The difference from Example 1 is that compound 3a in 1.2 was replaced with compound 3n, and the amount of compound 3n was (124 mg, 0.6 mmol), resulting in compound 4n (152 mg, 28%).

[0144] The NMR 1H spectrum data of compound 4n are as follows:

[0145] 1 H NMR (500 MHz, Chloroform- d ) δ 9.81 (s, 1H), 8.31 (s, 1H), 7.70 (d, J = 1.1 Hz, 1H), 7.42 (dd, J = 7.5, 1.0 Hz, 1H), 7.12 (d, J = 2.0 Hz, 1H), 6.86(dd, J = 7.5, 2.0 Hz, 1H), 6.42 (s, 1H), 5.99 (d, J = 0.9 Hz, 1H), 5.81 (t, J = 1.0Hz, 1H), 5.72 (s, 1H), 5.65 (s, 1H), 5.21 (s, 1H), 5.05 (s, 1H), 4.93-4.85(m, 3H), 4.80 (s, 1H), 4.43 (d, J = 4.9 Hz, 1H), 4.15 (d, J = 0.9 Hz, 1H), 4.11(d, J = 4.9 Hz, 1H), 4.05 (s, 1H), 3.94 (s, 1H), 3.82 (s, 1H), 3.77 (d, J = 2.0Hz, 2H), 3.72 (s, 1H), 3.39 (s, 3H), 3.31 (d, J = 5.1 Hz, 2H), 2.85 (s, 1H), 2.64-2.58 (m, 5H), 2.54-2.48 (m, 2H), 2.35-2.26 (m, 14H), 2.25 (d, J= 3.0 Hz,1H), 2.21 (s, 1H), 2.06 (d, J = 16.9 Hz, 4H), 1.97 (s, 1H), 1.92 (s, 1H), 1.72(s, 1H), 1.68 (d, J = 4.4 Hz, 2H), 1.58 (s, 1H), 1.37 (d, J = 1.1 Hz, 6H), 1.31(d, J = 13.9 Hz, 4H), 1.21 (d, J = 8.2 Hz, 6H), 0.98 (s, 3H).

[0146] The reaction equation is:

[0147]

[0148] Example 15

[0149] The difference from 1.2 is that compound 3a in 1.2 is replaced with compound 3o, and the amount of compound 3o is (104 mg, 0.6 mmol), to obtain compound 4o (184 mg, 35%).

[0150] The NMR 1H spectrum data of compound 4o are as follows:

[0151] 1 H NMR (500 MHz, Chloroform- d ) δ 9.81 (s, 1H), 7.71-7.65 (m, 2H), 7.62-7.54 (m, 3H), 6.35 (s, 1H), 5.99 (d, J = 0.9 Hz, 1H), 5.81 (t, J = 1.0 Hz,1H), 5.72 (s, 1H), 5.65 (s, 1H), 5.21 (s, 1H), 5.05 (s, 1H), 4.93-4.85 (m,3H), 4.80 (s, 1H), 4.43 (d, J = 4.9 Hz, 1H), 4.15 (d, J = 0.9 Hz, 1H), 4.11 (d, J =4.9 Hz, 1H), 4.05 (s, 1H), 3.94 (s, 1H), 3.82 (s, 1H), 3.77 (d, J= 2.0 Hz,2H), 3.72 (s, 1H), 3.39 (s, 3H), 3.31 (d, J = 5.1 Hz, 2H), 2.85 (s, 1H), 2.61(d, J = 9.7 Hz, 2H), 2.54-2.48 (m, 2H), 2.35-2.29 (m, 13H), 2.29-2.23 (m, 2H), 2.21 (s, 1H), 2.06 (d, J = 16.9 Hz, 4H), 1.97 (s, 1H), 1.92 (s, 1H), 1.72 (s,1H), 1.68 (d, J = 4.4 Hz, 2H), 1.58 (s, 1H), 1.37 (d, J = 1.1 Hz, 6H), 1.31 (d, J =13.9 Hz, 4H), 1.21 (d, J = 8.2 Hz, 6H), 0.98 (s, 3H).

[0152] The reaction equation is:

[0153]

[0154] Example 16

[0155] The difference from 1.2 is that compound 3a in 1.2 is replaced with compound 3p, and the amount of compound 3p is (117 mg, 0.6 mmol), to obtain compound 4p (160 mg, 30%).

[0156] The NMR 1H spectrum data of compound 4p are as follows:

[0157] 1 H NMR (500 MHz, Chloroform- d ) δ 9.81 (s, 1H), 7.51-7.45 (m, 1H), 7.37-7.26 (m, 3H), 5.99 (d, J = 0.9 Hz, 1H), 5.90 (s, 1H), 5.81 (t, J= 1.0 Hz,1H), 5.72 (s, 1H), 5.65 (s, 1H), 5.21 (s, 1H), 5.05 (s, 1H), 4.94-4.85 (m,3H), 4.80 (s, 1H), 4.43 (d, J = 4.9 Hz, 1H), 4.15 (d, J = 0.9 Hz, 1H), 4.11 (d, J =4.9 Hz, 1H), 4.05 (s, 1H), 3.94 (s, 1H), 3.82 (s, 1H), 3.77 (d, J = 2.0 Hz,2H), 3.72 (s, 1H), 3.39 (s, 3H), 3.31 (d, J = 5.1 Hz, 2H), 2.85 (s, 1H), 2.61(d, J = 9.7 Hz, 2H), 2.54-2.48 (m, 2H), 2.36-2.26 (m, 17H), 2.25 (d, J = 3.0 Hz,1H), 2.21 (s, 1H), 2.06 (d, J = 16.9 Hz, 4H), 1.97 (s, 1H), 1.92 (s, 1H), 1.72(s, 1H), 1.68 (d, J = 4.4 Hz, 2H), 1.58 (s, 1H), 1.37 (d, J = 1.1 Hz, 6H), 1.31(d, J = 13.9 Hz, 4H), 1.21 (d, J = 8.2 Hz, 6H), 0.98 (s, 3H).

[0158] The reaction equation is:

[0159]

[0160] Example 17

[0161] The difference from 1.2 is that compound 3a in 1.2 is replaced with compound 3q, and the amount of compound 3q is (131 mg, 0.6 mmol), to obtain compound 4q (99 mg, 18%).

[0162] The NMR 1H spectrum data of compound 4q are as follows:

[0163] 1 H NMR (500 MHz, Chloroform- d ) δ 9.81 (s, 1H), 8.48 (s, 1H), 8.04 (t, J = 1.0 Hz, 1H), 7.23-7.18 (m, 1H), 7.13 (dd, J = 1.9, 0.9 Hz, 1H), 6.83 (d, J =7.5 Hz, 1H), 5.99 (d, J = 0.9 Hz, 1H), 5.81 (t, J = 1.0 Hz, 1H), 5.72 (s, 1H),5.65 (s, 1H), 5.21 (s, 1H), 5.05 (s, 1H), 4.88 (d, J = 13.5 Hz, 3H), 4.80 (s,1H), 4.43 (d, J = 4.9 Hz, 1H), 4.15 (d, J = 0.9 Hz, 1H), 4.11 (d, J = 4.9 Hz, 1H),4.01 (s, 1H), 3.94 (s, 1H), 3.84 (d, J = 12.1 Hz, 4H), 3.77 (d, J = 2.0 Hz, 2H),3.72 (s, 1H), 3.39 (s, 3H), 3.30 (s, 1H), 3.22 (s, 1H), 2.85 (s, 1H), 2.61(d, J = 9.7 Hz, 2H), 2.54-2.48 (m, 2H), 2.35-2.26 (m, 14H), 2.25 (d, J = 3.0 Hz,1H), 2.21 (s, 1H), 2.06 (d, J = 16.9 Hz, 4H), 1.97 (s, 1H), 1.92 (s, 1H), 1.72(s, 1H), 1.68 (d, J = 4.4 Hz, 2H), 1.58 (s, 1H), 1.37 (d, J = 1.1 Hz, 6H), 1.31(d, J= 13.9 Hz, 4H), 1.21 (d, J = 12.6 Hz, 6H), 0.98 (s, 3H).

[0164] The reaction equation is:

[0165]

[0166] Example 18

[0167] The difference from 1.2 is that compound 3a in 1.2 is replaced with compound 3r, and the amount of compound 3r is (97 mg, 0.6 mmol), resulting in compound 4r (140 mg, 27%).

[0168] The NMR 1H NMR data of compound 4r are as follows:

[0169] 1 H NMR (500 MHz, Chloroform- d ) δ 9.81 (s, 1H), 7.58 (t, J = 1.0 Hz, 1H), 7.49 (ddt, J = 6.6, 1.9, 1.0 Hz, 2H), 7.38-7.29 (m, 3H), 5.99 (d, J = 0.9Hz, 1H), 5.81 (t, J = 1.0 Hz, 1H), 5.72 (s, 1H), 5.65 (s, 1H), 5.21 (s, 1H), 5.05 (s, 1H), 4.95 (s, 1H), 4.88 (d, J = 13.2 Hz, 2H), 4.80 (s, 1H), 4.43 (d, J =4.9 Hz, 1H), 4.15 (d, J = 0.9 Hz, 1H), 4.11 (d, J = 4.9 Hz, 1H), 4.04 (s, 1H), 3.94 (s, 1H), 3.82 (s, 1H), 3.77 (d, J = 2.0 Hz, 2H), 3.72 (s, 1H), 3.39 (s,3H), 3.31 (d, J = 5.1 Hz, 2H), 2.85 (s, 1H), 2.61 (d, J= 9.7 Hz, 2H), 2.54-2.48(m, 2H), 2.35-2.29 (m, 13H), 2.29-2.23 (m, 2H), 2.21 (s, 1H), 2.06 (d, J = 16.9Hz, 4H), 1.99 (d, J = 16.7 Hz, 4H), 1.92 (s, 1H), 1.72 (s, 1H), 1.68 (d, J = 4.4Hz, 2H), 1.58 (s, 1H), 1.37 (d, J = 1.1 Hz, 6H), 1.31 (d, J = 13.9 Hz, 4H), 1.21(d, J = 8.2 Hz, 6H), 0.98 (s, 3H).

[0170] The reaction equation is:

[0171]

[0172] Example 19

[0173] Compound 3S (158 mg, 0.6 mmol) was dissolved in dichloromethane (2 mL). Under an inert atmosphere (Ar), DCC (124 mg, 0.6 mmol) and PPY (15 mg, 0.1 mmol) were added in an ice bath. After stirring at room temperature for 1 h, compound 2 (442 mg, 0.5 mmol) was added, and the mixture was stirred at room temperature for 15 h. After the reaction was complete, the solution was concentrated under reduced pressure and diluted with ethyl acetate. The solution was washed successively with NH4Cl, saturated NaHCO3, and saturated NaCl, and dried over anhydrous Na2SO4. The solution was filtered, concentrated, and dissolved in dichloromethane (5 mL). 2.5 mL of CF3COOH was added, and the mixture was stirred at room temperature for 1–5 h. After the reaction was complete, the solution was concentrated. The pH was adjusted to approximately 8.0 with saturated Na2CO3 solution, and the solution was extracted with ethyl acetate and dried over anhydrous Na2SO4. The solution was filtered, concentrated, and purified by silica gel column chromatography using dichloromethane-methanol (12:1) as the eluent to obtain compound 4S.

[0174] The NMR 1H spectrum data of compound 4S are as follows:

[0175] 1 H NMR (500 MHz, Chloroform- d ) δ 9.81 (s, 1H), 7.57 (t, J= 0.9 Hz, 1H), 7.35 - 7.27 (m, 2H), 6.94 (td, J = 1.8, 0.9 Hz, 1H), 6.78 (dt, J = 7.1, 2.1 Hz, 1H), 6.35 (s, 1H), 5.99 (d, J = 0.9 Hz, 1H), 5.81 (t, J = 1.0 Hz, 1H), 5.72 (s, 1H), 5.65 (s, 1H), 5.21 (s, 1H), 5.05 (s, 1H), 4.93 - 4.85 (m, 3H), 4.80 (s, 1H), 4.43 (d, J = 4.9 Hz, 1H), 4.15 (d, J = 0.9 Hz, 1H), 4.11 (d, J = 4.9 Hz, 1H), 4.05 (s, 1H), 3.94 (s, 1H), 3.82 (s, 1H), 3.77 (d, J = 2.0 Hz, 2H), 3.72 (s, 1H), 3.43 (s, 2H), 3.39 (s, �H), 3.31 (d, J = 5.1 Hz, 2H), 2.85 (s, 1H), 2.61 (d, J = 9.7 Hz, 2H), 2.54 - 2.48 (m, 2H), 2.35 - 2.29 (m, 13H), 2.29 - 2.23 (m, 2H), 2.21 (s, 1H), 2.06 (d, J = 16.9 Hz, 4H), 1.97 (s, 1H), 1.92 (s, 1H), 1.72 (s, 1H), 1.68 (d, J = 4.4 Hz, 2H), 1.58 (s, 1H), 1.37 (d, J = 1.1 Hz, 6H), 1.31 (d, J = 13.9 Hz, 4H), 1.21 (d, J = 8.2 Hz, 6H), 0.98 (s, 3H).

[0176] The reaction equation is:

[0177]

[0178] Example 20

[0179] The difference from 1.2 is that compound 3s is replaced with compound 3t, and the amount of compound 3t is (144 mg, 0.6 mmol), resulting in compound 4t (140 mg, 25%).

[0180] The NMR 1H2 spectra of compound 4t are as follows:

[0181] 1 H NMR (500 MHz, Chloroform- d ) δ 9.81 (s, 1H), 7.61 (t, J = 1.0 Hz,1H), 7.55-7.49 (m, 2H), 7.38-7.31 (m, 2H), 7.22-7.14 (m, 1H), 7.08-7.02 (m,2H), 7.02-6.95 (m, 2H), 6.35 (s, 1H), 5.99(d, J = 0.9 Hz, 1H), 5.81 (t, J = 1.0Hz, 1H), 5.72 (s, 1H), 5.65 (s, 1H), 5.21 (s, 1H), 5.05 (s, 1H), 4.93-4.85(m, 3H), 4.80 (s, 1H), 4.43 (d, J = 4.9 Hz, 1H), 4.15 (d, J = 0.9 Hz, 1H), 4.11(d, J = 4.9 Hz, 1H), 4.05 (s, 1H), 3.94 (s, 1H), 3.82 (s, 1H), 3.77 (d, J = 2.0Hz, 2H), 3.72 (s, 1H), 3.39 (s, 3H), 3.31 (d, J = 5.1 Hz, 2H), 2.85 (s, 1H), 2.61 (d, J = 9.7 Hz, 2H), 2.54-2.48 (m, 2H), 2.35-2.29 (m, 13H), 2.29-2.23 (m,2H), 2.21 (s, 1H), 2.06 (d, J= 16.9 Hz, 4H), 1.97 (s, 1H), 1.92 (s, 1H), 1.72(s, 1H), 1.68 (d, J = 4.4 Hz, 2H), 1.58 (s, 1H), 1.37 (d, J = 1.1 Hz, 6H), 1.31(d, J = 13.9 Hz, 4H), 1.21 (d, J = 8.2 Hz, 6H), 0.98 (s, 3H).

[0182] Reaction equation:

[0183]

[0184] Example 21

[0185] Compound 4a (101 mg, 0.1 mol) was dissolved in methanol (5 mL) and heated and stirred at 60 °C for 12 h. After the reaction was completed, the solution was concentrated under reduced pressure and purified by column chromatography with dichloromethane-methanol (12:1) as the eluent to give compound 5a (80 mg, 82%).

[0186] The NMR 1H spectrum data of compound 5a are as follows: 1 H NMR (600 MHz, Chloroform- d ) δ 9.82 (s, 1H), 7.75 (d, J = 15.9 Hz, 1H), 7.54 (dd, J = 6.6, 3.0 Hz, 2H), 7.41-7.37 (m, 3H), 6.59 (d, J = 16.0 Hz, 1H), 6.24 (dd, J = 15.1, 10.6 Hz, 1H), 6.01 (ddd, J = 15.0,10.5, 1.5 Hz, 1H), 5.68 (dd, J = 15.2, 9.6 Hz, 1H), 5.56 (ddd, J = 15.1, 11.1,4.1 Hz, 1H), 5.29 (ddt, J = 11.5, 6.3, 3.2 Hz, 1H), 5.10 (d, J = 3.8 Hz, 1H), 4.74 (d, J= 10.2 Hz, 1H), 4.54 (dd, J = 10.4, 6.0 Hz, 1H), 4.49 (d, J = 7.5 Hz,1H), 4.39-4.37 (m, 1H), 4.12 (dd, J = 8.9, 1.9 Hz, 1H), 4.08 (s, 1H), 4.05 (dd, J = 9.6, 4.1 Hz, 1H), 3.80 (d, J = 10.8 Hz, 1H), 3.56-3.49 (m, 4H), 3.45-3.41(m, 1H), 3.34-3.29 (m, 2H), 3.08 (dd, J = 8.8, 1.6 Hz, 1H), 2.82-2.77 (m, 1H), 2.68 (dd, J = 14.6, 11.0 Hz, 2H), 2.59-2.40 (m, 9H), 2.38-2.34 (m, 1H), 2.33-2.29 (m, 1H), 2.26-2.19 (m, 8H), 2.13-2.08 (m, 1H), 2.05 (d, J = 14.5 Hz, 1H), 1.94 (ddt, J = 11.5, 8.3, 4.4 Hz, 1H), 1.89-1.82 (m, 3H), 1.53-1.41 (m, 3H),1.29 (d, J = 6.4 Hz, 3H), 1.27-1.20 (m, 7H), 1.19-1.16 (m, 6H), 0.98 (d, J = 6.6Hz, 3H).

[0187] Reaction equation:

[0188] .

[0189] Example 22

[0190] The difference from Example 21 is that compound 4a was replaced with compound 4b, and the amount of compound 4b was (103 mg, 0.1 mol), to obtain compound 5b (90 mg, 91%).

[0191] The NMR 1H spectrum data of compound 5b are as follows: 1H NMR (600 MHz, Chloroform- d ) δ 9.83 (s, 1H),7.72 (d, J = 15.9 Hz, 1H), 7.44 (d, J = 7.9 Hz, 2H), 7.19 (d, J = 7.9 Hz, 2H), 6.54(d, J = 15.9 Hz, 1H), 6.24 (dd, J = 15.2, 10.6 Hz, 1H), 6.05-5.99 (m, 1H), 5.68(dd, J = 15.2, 9.6 Hz, 1H), 5.57 (ddd, J = 15.1, 11.1, 4.0 Hz, 1H), 5.31-5.28 (m,1H), 5.11 (d, J = 3.8 Hz, 1H), 4.74 (d, J = 10.1 Hz, 1H), 4.51 (t, J = 10.4 Hz,2H), 4.42-4.38 (m, 1H), 4.34 (s, 1H), 4.14-4.08 (m, 2H), 4.05 (dd, J = 9.6, 4.1Hz, 1H), 3.80 (d, J = 10.9 Hz, 1H), 3.51 (s, 4H), 3.47 (d, J = 8.3 Hz, 1H), 3.34-3.28 (m, 2H), 3.08 (d, J = 8.7 Hz, 1H), 2.82-2.66 (m, 3H), 2.51 (d, J = 31.9 Hz,8H), 2.40-2.21 (m, 13H), 2.13-2.03 (m, 2H), 1.89 (td, J = 16.2, 6.8 Hz, 4H),1.50 (td, J = 13.4, 4.0 Hz, 3H), 1.30 (d, J = 6.4 Hz, 6H), 1.24 (d, J = 5.1 Hz,4H), 1.19-1.15 (m, 6H), 0.98 (d,J = 6.6 Hz, 3H).

[0192] Reaction equation:

[0193]

[0194] Example 23

[0195] The difference from Example 21 is that compound 4a was replaced with compound 4c, and the amount of compound 4c was (103 mg, 0.1 mol), to obtain compound 5c (91 mg, 92%).

[0196] The NMR 1H spectrum data of compound 5b are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 9.81 (s, 1H), 7.64 (dd, J = 15.9, 0.9 Hz, 1H), 7.60-7.55 (m, 2H), 7.22-7.14 (m, 2H), 6.36 (d, J = 15.9 Hz, 1H), 6.09-5.92 (m, 2H), 5.82-5.73 (m, 1H), 5.67-5.58 (m, 1H), 5.11-5.05 (m, 1H), 5.05-4.98 (m, 1H), 4.86-4.81 (m, 1H), 4.72 (dq, J = 6.7, 1.5Hz, 1H), 4.47-4.35 (m, 2H), 4.26 (pd, J = 6.4, 3.7 Hz, 1H), 4.12-4.05 (m, 1H), 3.95 (dd, J = 8.4, 7.5 Hz, 1H), 3.91-3.81 (m, 3H), 3.70 (tq, J = 7.4, 1.5 Hz, 1H), 3.54 (dt, J = 9.0, 4.9 Hz, 1H), 3.42-3.33 (m, 5H), 3.30 (dd, J = 9.0, 5.9Hz, 1H), 2.86-2.71 (m, 2H), 2.59-2.52 (m, 2H), 2.52-2.47 (m, 2H), 2.47-2.42(m, 7H), 2.40-2.31 (m, 2H), 2.29 (d, J= 1.5 Hz, 6H), 2.22-2.09 (m, 2H), 2.01-1.89 (m, 3H), 1.89-1.82 (m, 1H), 1.72-1.61 (m, 2H), 1.56 (dt, J = 13.2, 8.6 Hz, 1H), 1.31 (d, J = 6.4 Hz, 3H), 1.28-1.22 (m, 5H), 1.22-1.14 (m, 9H), 0.93 (dd, J = 7.4, 1.5 Hz, 3H).

[0197] Reaction equation:

[0198]

[0199] Example 24

[0200] The difference from Example 21 is that compound 4a was replaced with compound 4d, and the amount of compound 4d was (106 mg, 0.1 mol), to obtain compound 5d (97 mg, 95%).

[0201] The NMR 1H spectrum data of compound 5d are as follows:

[0202] 1H NMR (500 MHz, Chloroform-d) δ 9.81 (s, 1H), 8.28-8.22 (m, 2H), 8.07-8.01 (m, 2H), 7.67 (dd, J = 15.9, 0.9 Hz, 1H), 6.47 (d, J = 15.9 Hz,1H), 6.09-5.92 (m, 2H), 5.82-5.73 (m, 1H), 5.67-5.58 (m, 1H), 5.11-5.05 (m,1H), 5.05-4.98 (m, 1H), 4.86-4.81 (m, 1H), 4.75-4.69 (m, 1H), 4.47-4.35 (m,2H), 4.31-4.21 (m, 1H), 4.12-4.05 (m, 1H), 3.95 (dd, J = 8.4, 7.5 Hz, 1H), 3.91-3.81 (m, 3H), 3.70 (tq, J = 7.4, 1.5 Hz, 1H), 3.54 (dt, J = 9.0, 4.9 Hz, 1H), 3.42-3.33 (m, 5H), 3.30 (dd, J = 9.0, 5.9 Hz, 1H), 2.86-2.71 (m, 2H), 2.59-2.41 (m, 10H), 2.40-2.31 (m, 2H), 2.29 (d, J = 1.5 Hz, 6H), 2.22-2.09(m, 2H), 2.01-1.89 (m, 3H), 1.89-1.82 (m, 1H), 1.72-1.61 (m, 2H), 1.56 (dt, J= 13.2, 8.6 Hz, 1H), 1.31 (d, J = 6.4 Hz, 3H), 1.28-1.14 (m, 13H), 0.93 (dd,J = 7.4, 1.5 Hz, 3H).

[0203] Reaction equation:

[0204]

[0205] Example 25

[0206] The difference from Example 21 is that compound 4a was replaced with compound 4e, and the amount of compound 4e was (106 mg, 0.1 mol), resulting in compound 5e (95 mg, 94%).

[0207] The ¹H NMR spectra of compound 5e are as follows: ¹H NMR (500 MHz, Chloroform-d) δ 9.81 (s, ¹H), 7.64 (dd, J = 16.0, 0.9 Hz, ¹H), 7.58–7.52 (m, 2H), 6.85–6.79 (m, 2H), 6.36 (d, J = 15.9 Hz, 1H), 6.09–5.92 (m, 2H), 5.82–5.73 (m, 1H), 5.67–5.58 (m, 1H), 5.11–5.05 (m, 1H), 5.05–4.98 (m, 1H), 4.86–4.81 (m, 1H), 4.75–4.69 (m, 1H). 4.47-4.35 (m, 2H), 4.31-4.21 (m, 1H), 4.12-4.05 (m, 1H), 3.95 (dd, J= 8.4, 7.5 Hz, 1H), 3.91-3.81 (m, 3H), 3.70 (tq, J = 7.4, 1.5 Hz, 1H), 3.58-3.50 (m, 1H), 3.42-3.33 (m, 5H), 3.30 (dd, J = 9.0, 5.9 Hz, 1H), 2.92 (s,6H), 2.86-2.71 (m, 2H), 2.59-2.41 (m, 10H), 2.40-2.27 (m, 8H), 2.22-2.09 (m,2H), 1.94 (s, 4H), 1.72-1.61 (m, 2H), 1.56 (dt, J = 13.2, 8.6 Hz, 1H), 1.31(d, J = 6.4 Hz, 3H), 1.28-1.22 (m, 5H), 1.22-1.14 (m, 8H), 0.93 (dd, J = 7.4,1.5 Hz, 3H).

[0208] Reaction equation:

[0209]

[0210] Example 26

[0211] The difference from Example 21 is that compound 4a was replaced with compound 4f, and the amount of compound 4f was (108 mg, 0.1 mol), to obtain compound 5f (96 mg, 92%).

[0212] The ¹H NMR data for compound 5f are as follows: ¹H NMR (400 MHz, Chloroform-d) δ 9.83 (s, ¹H), 7.75 (d, J = 16.0 Hz, ¹H), 7.64 (s, 4H), 6.66 (d, J = 16.0 Hz, 1H), 6.24 (dd, J = 15.1, 10.5 Hz, 1H), 6.06–5.97 (m, 1H), 5.68 (dd, J = 15.1, 9.5 Hz, 1H), 5.56 (ddd, J = 15.0, 11.0, 4.0 Hz, 1H), 5.34–5.26 (m, 1H), 5.11 (d, J = 3.6 Hz, 1H), 4.75 (d, J = 10.2 Hz, 1H), 4.55 (dd, J = 10.3, 6.0 Hz, 1H), 4.50 (d, J = 7.5 Hz, 1H), 4.40-4.37 (m, 1H), 4.14-4.03 (m, 3H), 3.80 (d, J = 10.9Hz, 1H), 3.51 (s, 4H), 3.44 (dd, J = 9.2, 6.0 Hz, 1H), 3.34-3.27 (m, 2H), 3.08 (d, J = 8.7 Hz, 1H), 2.83-2.63 (m, 3H), 2.51 (d, J = 22.3 Hz, 8H), 2.30(d, J = 28.8 Hz, 10H), 2.15-2.03 (m, 2H), 1.97-1.84 (m, 4H), 1.49 (ddd, J =15.0, 8.8, 3.2 Hz, 3H), 1.30 (d, J = 6.3 Hz, 3H), 1.27-1.22 (m, 7H), 1.20-1.16 (m, 6H), 0.98 (d, J = 6.6 Hz, 3H).

[0213] Reaction equation:

[0214]

[0215] Example 27

[0216] The difference from Example 21 is that compound 4a was replaced with compound 4g, and the amount of compound 4g was (104 mg, 0.1 mol) to prepare compound 5g (90 mg, 90%).

[0217] The NMR 1H spectrum data of compound 5g are as follows: 1 H NMR (500 MHz, Chloroform-d) δ 9.82 (s,1H), 7.69-7.62 (m, 1H), 7.59-7.53 (m, 2H), 6.96-6.90 (m, 2H), 6.36 (d, J =15.9 Hz, 1H), 6.09-5.92 (m, 2H), 5.82-5.73 (m, 1H), 5.67-5.58 (m, 1H), 5.11-5.05 (m, 1H), 5.05-4.98 (m, 1H), 4.86-4.81 (m, 1H), 4.75-4.69 (m, 1H), 4.47-4.35 (m, 2H), 4.31-4.21 (m, 1H), 4.12-4.05 (m, 1H), 3.95 (dd, J = 8.4, 7.5Hz, 1H), 3.91-3.81 (m, 3H), 3.80 (s, 3H), 3.74-3.66 (m, 1H), 3.58-3.50 (m,1H), 3.42-3.33 (m, 5H), 3.30 (dd, J = 9.0, 5.9 Hz, 1H), 2.86-2.71 (m, 2H), 2.59-2.48 (m, 3H), 2.48-2.44 (m, 1H), 2.43 (d, J = 1.5 Hz, 6H), 2.40-2.31 (m,2H), 2.29 (d, J = 1.4 Hz, 6H), 2.22-2.09 (m, 2H), 2.00-1.89 (m, 3H), 1.89-1.82 (m, 1H), 1.72-1.61 (m, 2H), 1.61-1.52 (m, 1H), 1.31 (d, J = 6.4 Hz, 3H), 1.28-1.22 (m, 5H), 1.22-1.14 (m, 8H), 0.93 (dd, J = 7.4, 1.5 Hz, 3H).

[0218] Reaction equation:

[0219]

[0220] Example 28

[0221] The difference from 1.1 is that compound 1 was replaced with compound 6 (4.4 g, 5.0 mmol) to obtain compound 7 (3.5 g, 76%).

[0222] 1 H NMR (500 MHz, Chloroform-d) δ 9.81 (s, 1H), 5.99 (d, J = 0.9 Hz,1H), 5.81 (t, J = 1.0 Hz, 1H), 5.72 (s, 1H), 5.65 (s, 1H), 5.29 (s, 1H), 5.21(s, 1H), 5.05 (s, 1H), 4.88 (d, J = 1.8 Hz, 2H), 4.80 (s, 1H), 4.15 (d, J =0.9 Hz, 1H), 3.97-3.92 (m, 2H), 3.87 (s, 1H), 3.81 (d, J = 8.4 Hz, 2H), 3.77(d, J = 2.0 Hz, 2H), 3.60 (s, 1H), 3.45-3.38 (m, 4H), 3.30 (s, 1H), 2.92 (s,1H), 2.67 (s, 1H), 2.62 (s, 1H), 2.54-2.48 (m, 2H), 2.33 (d, J = 1.3 Hz,12H), 2.29-2.21 (m, 4H), 2.07 (d, J = 12.3 Hz, 6H), 1.99 (d, J = 17.0 Hz,2H), 1.92 (s, 1H), 1.72 (s, 1H), 1.68 (d, J = 4.4 Hz, 2H), 1.58 (s, 1H), 1.37(s, 3H), 1.34-1.22 (m, 10H), 1.20 (s, 3H), 0.98 (s, 3H).

[0223] The difference from 1.2 is that compound 2 was replaced with compound 7 (463 mg, 0.5 mmol) to obtain compound 8a (96 mg, 18%).

[0224] The 1H NMR spectrum of compound 8a is as follows:

[0225] 1H NMR (500 MHz, Chloroform-d) δ 9.81 (s, 1H), 7.61 (t, J = 1.0 Hz,1H), 7.56-7.49 (m, 2H), 7.38-7.29 (m, 3H), 6.34 (s, 1H), 5.99 (d, J = 0.9 Hz,1H), 5.81 (t, J = 1.0 Hz, 1H), 5.72 (s, 1H), 5.65 (s, 1H), 5.29 (s, 1H), 5.21(s, 1H), 5.05 (s, 1H), 4.93-4.86 (m, 3H), 4.80 (s, 1H), 4.15 (d, J = 0.9 Hz,1H), 4.05 (s, 1H), 3.95 (s, 1H), 3.81 (d, J = 8.4 Hz, 2H), 3.77 (d, J = 2.0Hz, 2H), 3.43 (s, 3H), 3.31 (d, J = 5.1 Hz, 2H), 2.92 (s, 1H), 2.67 (s, 1H), 2.62 (s, 1H), 2.54-2.48 (m, 2H), 2.35-2.26 (m, 14H), 2.26-2.21 (m, 2H), 2.10-2.03 (m, 7H), 1.97 (s, 1H), 1.92 (s, 1H), 1.72 (s, 1H), 1.68 (d, J = 4.4 Hz, 2H), 1.58 (s, 1H), 1.37 (d, J = 1.1 Hz, 6H), 1.31 (d, J = 13.9 Hz, 4H), 1.21 (d, J = 8.2 Hz, 6H), 0.98 (s, 3H).

[0226] Reaction equation:

[0227] Example 29

[0228] The difference from Example 21 is that compound 4a was replaced with compound 8a (105 mg, 0.1 mol) to obtain compound 9a (96 mg, 95%).

[0229] The 1H NMR spectrum of compound 9a is as follows:

[0230] 1H NMR (500 MHz, Chloroform-d) δ 9.81 (s, 1H), 7.61 (t, J = 1.0 Hz,1H), 7.56-7.49 (m, 2H), 7.38-7.29 (m, 3H), 6.34 (s, 1H), 5.99 (d, J = 0.9 Hz,1H), 5.81 (t, J = 1.0 Hz, 1H), 5.72 (s, 1H), 5.65 (s, 1H), 5.29 (s, 1H), 5.03(s, 1H), 4.90 (d, J = 15.0 Hz, 2H), 4.80 (s, 1H), 4.57 (s, 1H), 4.49 (d, J =5.1 Hz, 1H), 4.15 (d, J = 0.9 Hz, 1H), 4.05 (s, 1H), 3.88 (s, 1H), 3.81 (d, J= 3.8 Hz, 2H), 3.77 (s, 1H), 3.72 (s, 1H), 3.61 (d, J = 4.9 Hz, 1H), 3.43 (s,3H), 3.31 (s, 1H), 3.25 (s, 1H), 2.92 (s, 1H), 2.67 (s, 1H), 2.62 (s, 1H),2.54-2.48 (m, 2H), 2.36-2.22 (m, 16H), 2.05 (d, J = 7.3 Hz, 4H), 1.97 (s,1H), 1.92 (s, 1H), 1.72 (s, 1H), 1.68 (d, J = 4.4 Hz, 2H), 1.58 (s, 1H), 1.37(s, 3H), 1.35-1.28 (m, 7H), 1.21 (d, J = 8.2 Hz, 6H), 0.98 (s, 3H).

[0231] Reaction equation:

[0232]

[0233] Example 30

[0234] The difference from 1.1 is that compound 1 is replaced with compound 10 (4.5 g, 5.0 mmol) to obtain compound 11 (3.0 g, 81%).

[0235] The 1H NMR spectrum of compound 11 is as follows:

[0236] 1 H NMR (500 MHz, Chloroform-d) δ 9.82 (s, 1H), 5.99 (d, J = 0.9 Hz,1H), 5.81 (t, J = 1.0 Hz, 1H), 5.72 (s, 1H), 5.65 (s, 1H), 5.32 (s, 1H), 5.21(s, 1H), 5.05 (s, 1H), 4.88 (d, J = 1.8 Hz, 2H), 4.80 (s, 1H), 4.15 (d, J =0.9 Hz, 1H), 3.97-3.92 (m, 2H), 3.87 (s, 1H), 3.82 (s, 1H), 3.79-3.73 (m,3H), 3.60 (s, 1H), 3.45-3.38 (m, 4H), 3.30 (s, 1H), 2.98 (s, 1H), 2.73 (s, 1H), 2.62 (s, 1H), 2.54-2.48 (m, 2H), 2.40-2.31 (m, 14H), 2.29-2.21 (m, 4H), 2.08 (s, 3H), 1.99 (d, J = 17.0 Hz, 2H), 1.92 (s, 1H), 1.72 (s, 1H), 1.68 (d,J = 4.4 Hz, 2H), 1.58 (s, 1H), 1.37 (s, 3H), 1.34-1.22 (m, 10H), 1.20 (s,3H), 1.12 (s, 3H), 0.98 (s, 3H).

[0237] The difference from 1.2 is that compound 2 is replaced with compound 11 (470 mg, 0.5 mmol) to obtain compound 12a (123 mg, 23%).

[0238] The 1H NMR spectrum of compound 12a is as follows:

[0239] 1H NMR (500 MHz, Chloroform-d) δ 9.82 (s, 1H), 7.61 (t, J = 1.0 Hz,1H), 7.56-7.49 (m, 2H), 7.38-7.29 (m, 3H), 6.34 (s, 1H), 5.99 (d, J = 0.9 Hz,1H), 5.81 (t, J = 1.0 Hz, 1H), 5.72 (s, 1H), 5.65 (s, 1H), 5.32 (s, 1H), 5.21(s, 1H), 5.05 (s, 1H), 4.93-4.86 (m, 3H), 4.80 (s, 1H), 4.15 (d, J = 0.9 Hz,1H), 4.05 (s, 1H), 3.95 (s, 1H), 3.82 (s, 1H), 3.79-3.73 (m, 3H), 3.43 (s,3H), 3.31 (d, J = 5.1 Hz, 2H), 2.98 (s, 1H), 2.73 1.97 (s, 1H), 1.92 (s, 1H), 1.72 (s, 1H), 1.68 (d, J =4.4 Hz, 2H), 1.58 (s, 1H), 1.37 (d, J = 1.1 Hz, 6H), 1.31 (d, J = 13.9 Hz, 4H), 1.21 (d, J = 8.2 Hz, 6H), 1.12 (s, 3H), 0.98 (s, 3H).

[0240] Reaction equation:

[0241] Example 31

[0242] The difference from Example 21 is that compound 4a was replaced with compound 12a (107 mg, 0.1 mol) to obtain compound 13a (96 mg, 93%).

[0243] The 1H NMR spectrum of compound 13a is as follows:

[0244] 1H NMR (500 MHz, Chloroform-d) δ 9.81 (s, 1H), 7.51-7.44 (m, 3H), 7.37-7.25 (m, 3H), 6.27 (s, 1H), 5.99 (d, J = 0.9 Hz, 1H), 5.81 (t, J = 1.0Hz, 1H), 5.72 (s, 1H), 5.65 (s, 1H), 5.32 (s, 1H), 5.03 (s, 1H), 4.89 (d, J =7.7 Hz, 2H), 4.80 (s, 1H), 4.57 (s, 1H), 4.49 (d, J = 5.1 Hz, 1H), 4.15 (d, J= 0.9 Hz, 1H), 4.05 (s, 1H), 3.88 (s, 1H), 3.81 (s, 1H), 3.79-3.71 (m, 3H), 3.61 (d, J = 4.9 Hz, 1H), 3.43 (s, 3H), 3.31 (s, 1H), 3.25 (s, 1H), 2.98 (s,1H), 2.73 (s, 1H), 2.62 (s, 1H), 2.54-2.48 (m, 2H), 2.34 (dd, J = 9.4, 7.4Hz, 14H), 2.31-2.22 (m, 4H), 2.04 (s, 1H), 1.97 (s, 1H), 1.92 (s, 1H), 1.72(s, 1H), 1.68 (d, J = 4.4 Hz, 2H), 1.58 (s, 1H), 1.37 (s, 3H), 1.35-1.28 (m,7H), 1.21 (d, J = 8.2 Hz, 6H), 1.12 (s, 3H), 0.98 (s, 3H).

[0245] Reaction equation:

[0246]

[0247] test

[0248] The inhibitory activity of compounds 4a-g and 5a-g in the examples against HCoV-229E in Huh7 cells and against HCoV-OC43 in H460 cells was determined using a cytopathic effect (CPE) assay.

[0249] Human hepatocellular carcinoma Huh7 cells / human lung cancer cells H460 cells were passaged and preserved by the Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences. They were cultured in DMEM or 1640 medium containing 10% inactivated fetal bovine serum and 1% penicillin and streptomycin in a 37°C, 5% CO2 incubator, and passaged every 2-3 days.

[0250] HCoV-229E was passaged in Huh7 cells, and HCoV-OC43 was passaged in H460 cells and stored at -80°C.

[0251] Add 3 ml of 0.25% Trypsin-EDTA (trypsin cell digestion solution) to a culture flask confluent with Huh7 / H460 cells, digest at 37°C for 1-2 minutes, discard the digestion solution, add culture medium and pipette, passage at a 1:4 ratio, passage every 2-3 days, prepare a solution of 200,000 cells per ml, seed 0.1 ml into 96-well cell culture plates, incubate overnight at 37°C with 5% CO2, and perform experiments after the cells have grown into a monolayer.

[0252] Anticoronavirus activity assay (CPE method): Huh7 cells were seeded at 20,000 cells / well in 96-well plates, and H460 cells were seeded at 15,000 cells / well in 96-well plates. After 24 hours of culture, HCoV-229E and HCoV-OC43 viral solutions (MOI=0.5) were used to infect Huh7 and H460 cells in the 96-well plates, respectively. The test drug was diluted with maintenance medium, and eight doses of the test drug were prepared by three-fold dilution for the experiment. Each dose was tested in two parallel wells. A control group without the drug was also included. The half-maximal inhibitory concentration (IC50) and selectivity index (SI=CC) of the drug against the virus were calculated using the Reed-Muench method (formula below). 50 / EC 50 ).

[0253] EC 50 =AntiLog[A+(B-50)×D / (50-C)]

[0254] Where: A = drug concentration with cumulative inhibition rate < 50%, B = inhibition rate with cumulative inhibition rate > 50%, C = inhibition rate with cumulative inhibition rate < 50%, D = log dilution factor.

[0255] Cytotoxicity assay (CCK-8 assay): Huh7 cells were seeded at 20,000 cells / well in 96-well plates, and H460 cells were seeded at 15,000 cells / well in 96-well plates. After 24 hours of culture, maintenance medium containing the test drug was added. The test drug was diluted three times to eight different doses for the experiment, and the cells were cultured again. Two days after drug administration, the cytotoxicity of the drug was observed under an inverted microscope, and the half-maximal toxic concentration (CMC) was calculated using the Reed-Muench method.50 The calculation formula is as follows:

[0256] CC 50 =AntiLog[A+(B-50)×D / (50-C)]

[0257] Where: A = drug concentration with cumulative inhibition rate < 50%, B = inhibition rate with cumulative inhibition rate > 50%, C = inhibition rate with cumulative inhibition rate < 50%, D = log dilution factor.

[0258] Using the anti-coronavirus drug Molnupiravir as a positive control, the inhibitory effects of compounds 4a-g and 5a-g on HCoV-229E and HCoV-OC43 in the examples were determined according to the above method. The results are shown in Table 1.

[0259] Table 1. Inhibitory activity of compounds against HCoV-229E and HCoV-OC43

[0260]

[0261] As demonstrated by the above embodiments, the macrolide cinnamic acid ester derivatives provided by this invention exhibit good inhibitory effects against HCoV-229E, and some compounds also show good inhibitory effects against HCoV-OC43, while exhibiting low cytotoxicity. Therefore, the macrolide cinnamic acid ester derivatives of this invention hold promise as a novel anti-coronavirus drug.

[0262] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. Other embodiments can be obtained based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A macrolide cinnamate derivative, characterized by, having the structure of any one of 4a, 4b, 4c, 4d, 4e, 4f, 4g, 5a, 5b, 5c, 5d, 5e, 5g: 。 2. The method of preparing the macrolide cinnamate derivative of claim 1, characterized in that, The following two cases are included: Compound II and acetic anhydride are mixed to perform acylation reaction to obtain compound III; Compound II; Compound III and compound IV-1 are mixed to perform first esterification reaction to obtain first macrocyclic lactone cinnamic acid ester derivative having the structure of formula I-1; the substitution of R6, R3, R4, R2 and R1 in the formula I-1 corresponds to each structural formula in claim 1; Formula I-1; Formula IV-1; The first macrocyclic lactone cinnamic acid ester derivative having the structure of formula I-1 is subjected to alcoholysis reaction to obtain third macrocyclic lactone cinnamic acid ester derivative having the structure of formula I-2; Formula I-2; the substitution of R6, R3, R4, R2and R1in Formula I-1 corresponds to the respective structural formula of claim 1.

3. The production method according to claim 2, wherein The molar ratio of compound II and acetic anhydride is 1:0.8-1.

2.

4. The production method according to claim 2, wherein The temperature of the acylation reaction is room temperature, and the time of the acylation reaction is 10-15 hours.

5. The production method according to claim 2, wherein In the first esterification reaction, the molar ratio of compound III and compound IV-1 is 5:5-7.

6. The production method according to claim 2, wherein The temperature of the first esterification reaction is room temperature, and the time of the first esterification reaction is 12-24h.

7. The production method according to claim 2, wherein The alcohol used in the alcoholysis is methanol.

8. The production method according to claim 2, wherein The temperature of the alcoholysis reaction is 50-70℃, and the time of the alcoholysis reaction is 10-12h.

9. Use of the macrocyclic lactone cinnamic acid ester derivative or pharmaceutically acceptable salt thereof according to claim 1 in the preparation of an HCoV-229E or HCoV-OC43 inhibitor.

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