Oleanolic acid acylhydrazone derivative as well as preparation method and application thereof

Abstract

The invention discloses an oleanolic acid acylhydrazone derivative as well as a preparation method and application thereof. The oleanolic acid acylhydrazone derivatives have a structural formula shown in the following formula I. In the structural formula, R is selected from halogen-substituted pyridine and hydroxyl-substituted naphthyl. The invention provides a series of oleanolic acid acylhydrazone derivatives with novel structures, and the oleanolic acid acylhydrazone derivatives have relatively good inhibition effects on human breast cancer cells MDA-MB-231 and human pancreatic cancer cells Mia paca-2, and can be used for preparing an anti-cancer drug. The compound can be used for preparing anti-tumor drugs.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to an oleanolic acid hydrazone derivative, its preparation method, and its application. Background Technology

[0002] Cancer is the second leading cause of death worldwide. According to the World Health Organization's (IARC) "2022 World Cancer Report," approximately 9.7 million people died from cancer globally in 2022. Current treatments for cancer include surgery, cancer drugs, and radiation therapy. Among these, cancer drugs, due to their rapid distribution throughout the body after entering the body, have a killing effect on both local and metastatic cancer cells, effectively inhibiting tumor growth and spread, and providing temporary control over primary and metastatic lesions. Therefore, their research remains a very popular area in drug development. Currently, approximately 130-150 anticancer drugs have been approved for marketing worldwide. Research has found that traditional Chinese medicinal plants are a rich source of anticancer compounds, and their low toxicity to normal cells can reduce the toxic side effects of drugs.

[0003] Oleanolic acid is a pentacyclic triterpenoid compound widely found in the plant kingdom. Its biological activity against various diseases has attracted significant attention from the scientific community. However, due to limitations in the pharmaceutical development of oleanolic acid, its therapeutic effects are difficult to fully realize.

[0004] Therefore, it is of great significance to develop novel oleanolic acid hydrazone derivatives with anti-tumor effects. Summary of the Invention

[0005] The present invention aims to at least solve one of the technical problems existing in the prior art. To this end, the first aspect of the present invention proposes an oleanolic hydrazone derivative that can inhibit tumor cells and has an anti-tumor effect.

[0006] A second aspect of the present invention also provides a method for preparing oleanolic acid hydrazone derivatives.

[0007] A third aspect of the present invention also provides a pharmaceutical composition.

[0008] A fourth aspect of the present invention also provides an application.

[0009] According to a first aspect of the present invention, an oleanolic hydrazone derivative is provided, having the structural formula shown in Formula I:

[0010]

[0011] Wherein, R is selected from halogen-substituted pyridine, hydroxyl-substituted naphthyl, ...

[0012] R1 is one or more substituents; each is independently selected from halogens, C 1～6 alkyl, C 1～6 alkoxy, C 1～6 Halogenated alkyl, nitro, hydroxyl, carboxyl, amino, cyano, C 2～6 alkenyl, C 2～6 alkynyl group, C 2～6 Halogenated alkyl carbonyl,

[0013] When R is selected When R is not

[0014] R2 and R3 are independently selected from C 1～6 Alkyl groups.

[0015] The oleanolic acid hydrazone derivatives according to embodiments of the present invention have at least the following beneficial effects:

[0016] This invention provides a series of novel oleanolic acid acylhydrazone derivatives, and the IC of the oleanolic acid acylhydrazone derivatives. 50 Values ​​are all below 10μM, optimal IC 50 When the concentration reaches below 0.2 μM, it exhibits good inhibitory effects on human breast cancer cells MDA-MB-231 and human pancreatic cancer cells Mia paca-2, and can be used to prepare anti-tumor drugs.

[0017] According to some embodiments of the present invention, R1 is one or more substituents; each independently selected from halogens, C 1～4 alkyl, C 1～3 alkoxy, C 1～3 Halogenated alkyl, nitro, hydroxyl, carboxyl, amino, cyano, C 2～6 alkenyl, C 2～4 alkynyl group, C 2～4 Halogenated alkyl carbonyl, R2 and R3 are independently selected from C 1～3 Alkyl groups.

[0018] According to some embodiments of the present invention, the oleanolic acid hydrazone derivative is selected from one of the following structural formulas:

[0019]

[0020]

[0021]

[0022] A second aspect of the present invention provides a method for preparing the aforementioned oleanolic acid acylhydrazone derivative, comprising the following steps:

[0023] The compound of formula III is obtained by reacting it with compound 1;

[0024] The structural formulas of compound III and compound 1 are as follows:

[0025]

[0026] According to some embodiments of the present invention, the reaction temperature is 20–70°C.

[0027] According to some embodiments of the present invention, the reaction time is 3.5 to 12.5 h.

[0028] According to some embodiments of the present invention, the molar ratio of compound III to compound 1 is 1:(1 to 1.5).

[0029] According to some embodiments of the present invention, the reactants further include an organic solvent; the organic solvent is selected from ethanol.

[0030] According to some embodiments of the present invention, the reaction is further complicated by a purification step.

[0031] According to some embodiments of the present invention, the purification includes diluting the solution with ethyl acetate after the reaction is completed, extracting with ethyl acetate and water, retaining and drying the organic phase with anhydrous sodium sulfate, mixing the organic phase with silica gel, separating and purifying by column chromatography, and dissolving the obtained solid product in a small amount of ethyl acetate for recrystallization.

[0032] According to some embodiments of the present invention, the compound of formula III is prepared by the following method:

[0033] The compound of formula II, an organic solvent, and hydrazine hydrate are reacted to obtain the product.

[0034] The structural formula of compound II is as follows:

[0035]

[0036] According to some embodiments of the present invention, the reaction conditions include: a temperature of -20 to 0°C and a time of 5 to 12 hours.

[0037] According to some embodiments of the present invention, the organic solvent includes dichloromethane.

[0038] According to some embodiments of the present invention, the raw materials for the above reaction also include a mutual solvent, wherein the mutual solvent includes tetrahydrofuran.

[0039] According to some embodiments of the present invention, the molar ratio of the compound of formula II to hydrazine hydrate is 1:(10-20).

[0040] According to some embodiments of the present invention, the compound of formula II is prepared by the following method:

[0041] Oleanolic acid, oxaloyl chloride and N,N-dimethylformamide were reacted to give compound II;

[0042] The structural formula of oleanolic acid is as follows:

[0043]

[0044] According to some embodiments of the present invention, the reaction conditions include: a reaction temperature of -20°C to 0°C and a reaction time of 5h to 12h.

[0045] According to some embodiments of the present invention, the raw materials for the preparation of the reaction further include an organic solvent, wherein the organic solvent includes dichloromethane.

[0046] According to some embodiments of the present invention, the molar ratio of oleanolic acid to oxaloyl chloride is 1:(2-4).

[0047] According to some embodiments of the present invention, the N,N-dimethylformamide is used for catalysis, and its amount is 0.1% to 1% of the molar amount of oleanolic acid.

[0048] According to some embodiments of the present invention, after the reaction is completed, a post-processing is further included. The post-processing process is as follows: the oil pump is used to perform a vacuuming operation, the mixture is dissolved in a small amount of dichloromethane and then vacuumed, and the operation is repeated three times to obtain compound II.

[0049] A third aspect of the present invention provides a pharmaceutical composition comprising the oleanolic hydrazone derivatives described in the first aspect of the present invention, and pharmaceutically acceptable excipients.

[0050] The fourth aspect of this invention provides the use of an oleanolic acid hydrazone derivative of this invention or the pharmaceutical composition described in the third aspect of this invention in the preparation of therapeutic and / or preventive antitumor drugs;

[0051] The oleanolic acid hydrazone derivative has the structural formula shown in Formula II:

[0052]

[0053] Wherein, R4 is selected from halogen-substituted pyridine, hydroxyl-substituted naphthyl, ...

[0054] R5 is one or more substituents; each is independently selected from halogens, C 1～6 Alkyl group, CC111 ～6 alkoxy, C 1～6 Halogenated alkyl, nitro, hydroxyl, carboxyl, amino, cyano, C2～6 alkenyl, C 2～6 alkynyl group, C 2～6 Halogenated alkyl carbonyl,

[0055] R6 and R7 are independently selected from C 1～6 Alkyl groups.

[0056] According to some embodiments of the present invention, the oleanolic acylhydrazone derivative has the structural formula shown in Formula II:

[0057]

[0058] Wherein, R4 is selected from halogen-substituted pyridine, hydroxyl-substituted naphthyl, ...

[0059] R5 is one or more substituents; each is independently selected from halogens, C 1～6 alkyl, C 1～6 alkoxy, C 1～6 Halogenated alkyl, nitro, hydroxyl, carboxyl, amino, cyano, C 2～6 alkenyl, C 2～6 alkynyl group, C 2～6 Halogenated alkyl carbonyl,

[0060] When R4 is selected When R4 is not

[0061] R6 and R7 are independently selected from C 1～6 Alkyl groups.

[0062] According to some embodiments of the present invention, the tumor includes breast cancer and pancreatic cancer.

[0063] Other features and advantages of the invention will be set forth in the description which follows, and will be apparent in part from the description, or may be learned by practicing the invention. Detailed Implementation

[0064] The following are specific embodiments of the present invention, and the technical solutions of the present invention will be further described in conjunction with the embodiments, but the present invention is not limited to these embodiments.

[0065] Unless otherwise specified, the reagents, methods and equipment used in this invention are all conventional reagents, methods and equipment in this technical field.

[0066] Example 1

[0067] This example provides an oleanolic acid acylhydrazone derivative, the reaction equation of which is as follows, and the preparation steps are as follows:

[0068]

[0069] S1. Accurately weigh 4.56 g (10 mmol) of oleanolic acid using a 0.01 g balance and pour it into a 250 mL round-bottom flask. Then, use a 20 mL syringe to repeatedly draw 100 mL of ultra-dry dichloromethane and add it to the round-bottom flask while stirring at room temperature. Transfer the reaction system to an ice bath and stir for 5 min. Accurately draw 2.5 mL of oxaloyl chloride using a 5 mL syringe and add it dropwise to the round-bottom flask while in an ice bath. After the addition is complete, stir for 10 min. Then, add 3 drops of N,N-dimethylformamide and then stir at room temperature for 8 h to obtain compound II.

[0070] S2. 4.74 g (10 mmol) of compound II was dried using an oil pump (2 mL of ultra-dry dichloromethane could be added multiple times during this process before drying). 25 mL of dry dichloromethane was added. 5.16 mL (100 mmol) of 85% hydrazine hydrate was added to a 250 mL round-bottom flask using a 10 mL disposable syringe. 100 mL of tetrahydrofuran was accurately measured and mixed with 85% hydrazine hydrate using a graduated cylinder. The mixture was stirred at -20 °C for 30 min. Then, compound II was added dropwise to the 85% hydrazine hydrate solution using a 20 mL syringe. The mixture was reacted at -20 °C for 8 h. After the reaction was complete, the solvent was removed from the reaction solution under vacuum. After quenching with water, the mixture was extracted three times with 3 x 50 mL ethyl acetate. The organic phases were combined, washed successively with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under vacuum, and the compound III was purified by column chromatography.

[0071] S3. Weigh 141 mg (0.3 mmol) of compound III and 0.6 mmol of 2-hydroxy-4-methoxybenzaldehyde into a 10 mL reaction tube using a 0.01 g balance. Add 2 mL of anhydrous ethanol and stir at room temperature for 8 hours. After the reaction is complete, evaporate the reaction solution to dryness under vacuum, dilute with ethyl acetate, and extract with ethyl acetate and water. Retain the organic phase and dry it with anhydrous sodium sulfate. After separation and purification by column chromatography, the organic phase is recrystallized from ethyl acetate to obtain oleanolic acid hydrazone derivatives (pale yellow solid, yield 55.2%).

[0072] The NMR data of oleanolic acid acylhydrazone derivatives are as follows:

[0073] 1H NMR(500MHz,Chloroform-d)δ11.25(s,1H),8.80(s,1H),8.28(s,1H),7.08(d,J=8.6Hz,1H),6.52(d,J=2.4Hz,1H),6.46(dd,J=8.6,2 .3Hz,1H),5.57–5.52(m,1H),3.81(s,3H),3.22(d,J=10.5Hz,1H),2.60(d,J=12.3Hz,1H),2.09–2.04(m,1H),2.02–1.97(m,2H),1.88– 1.79(m,2H),1.76–1.68(m,2H),1.69–1.58(m,5H),1.53(s,1H),1.44(d,J=16.3Hz,1H),1.41–1.33(m,2H),1.28(d,J=3.9Hz,2H),1.2 5(d,J=7.2Hz,3H),1.20(s,3H),1.10(d,J=14.1Hz,1H),0.98(s,3H),0.93(s,6H),0.90(s,3H),0.77(s,3H),0.75(s,3H),0.72(s,1H).

[0074] 13 C NMR(126MHz,Chloroform-d)δ174.62,162.96,160.80,151.68,145.50,132. 15,123.91,111.16,107.06,101.56,55.55,55.18,47.64,46.82,46.54,42. 26,41.97,39.62,38.89,38.62,37.06,34.15,33.04,32.31,32.18,30.87,28.20,27.35,27.27,25.97,24.34,23.81,23.66,18.34,17.02,15.65,15.51.

[0075] Example 2

[0076] Example 2 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 2-hydroxy-6-methoxybenzaldehyde is used instead of 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0077]

[0078] Its NMR data are as follows:

[0079] Pale yellow solid, yield 45.5%;

[0080] 1 H NMR(500MHz,Chloroform-d)δ11.49(s,1H),8.91(s,1H),8.64(s,1H),7.21(t,J=8.3Hz,1H),6.60(d,J=8.3Hz,1H),6.36(d,J=8.3Hz,1H),5.57(t,J=3 .6Hz,1H),3.84(s,3H),3.21(dd,J=11.2,4.2Hz,1H),2.62(d,J=8.8Hz,1H) ,2.08(dd,J=13.8,3.9Hz,1H),2.02–1.93(m,2H),1.88–1.78(m,2H),1.77– 1.68(m,2H),1.62(dt,J=6.4,3.9Hz,6H),1.58(d,J=3.8Hz,1H),1.56–1.47 (m,2H),1.46–1.41(m,1H),1.37(td,J=13.3,12.5,3.7Hz,2H),1.29–1.26( m,1H),1.22(dd,J=4.3,2.4Hz,1H),1.20(s,3H),1.09(d,J=14.0Hz,1H),0. 98(s,3H),0.93(s,6H),0.90(s,3H),0.76(s,3H),0.73(s,3H),0.72(s,1H).

[0081] 13 C NMR(126MHz,Chloroform-d)δ174.25,160.21,158.93,146.79,145.40,132. 54,123.90,110.24,107.08,100.94,55.86,55.17,47.60,46.72,46.40,42. 19,41.95,39.58,38.86,38.57,37.02,34.11,33.03,32.27,32.18,30.83,28.17,27.34,27.22,25.94,24.26,23.75,23.64,18.30,17.02,15.63,15.39.

[0082] Example 3

[0083] Example 3 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 2-hydroxy-3-methoxybenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0084]

[0085] Its NMR data are as follows:

[0086] Pale yellow solid, yield 51.9%.

[0087] 1 H NMR(500MHz,Chloroform-d)δ11.01(s,1H),8.91(s,1H),8.57(s,1H),6.92(dd,J=7.3,2.2Hz,1H),6.89–6.79(m,2H),5.56(s,1H),3.91( s,3H),3.21(dd,J=11.3,4.2Hz,1H),2.62(dd,J=13.1,4.3Hz,1H),2.08(dd,J=13.8,3.9Hz,1H),2.03–1.93(m,2H),1.88–1.78(m,2H),1. 76–1.68(m,2H),1.66–1.57(m,6H),1.54(d,J=15.4Hz,2H),1.49–1.42(m,1H),1.41–1.33(m,2H),1.28(d,J=3.3Hz,2H),1.22(dd,J=4.6, 2.5Hz,1H),1.20(s,3H),1.10(d,J=13.9Hz,1H),0.98(s,3H),0.93(s,6H),0.89(s,3H),0.77(s,3H),0.75(s,3H),0.73(d,J=11.7Hz,1H).

[0088] 13 C NMR(126MHz,Chloroform-d)δ174.91,152.60,148.51,148.42,145.23,124. 06,122.80,119.04,117.98,114.02,56.35,55.16,47.60,46.75,46.66,42. 18,41.85,39.57,38.85,38.59,37.01,34.11,33.01,32.28,32.15,30.81,28.17,27.32,27.23,25.95,24.27,23.76,23.63,18.30,16.92,15.62,15.47.

[0089] Example 4

[0090] Example 4 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 2-hydroxy-4-nitrobenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0091]

[0092] Its NMR data are as follows:

[0093] Yellow solid, yield 59.3%.

[0094] 1 H NMR (500 MHz, DMSO-d6) δ 11.75 (s, 1H), 11.14 (s, 1H), 8.64 (s,1H), 7.81 (d, J = 8.6 Hz, 1H), 7.73 (dd, J = 8.6, 2.2 Hz, 1H), 7.67 (d, J = 2.3 Hz, 1H), 5.27 (s, 1H), 4.27 (d, J = 5.1 Hz, 1H), 2.98 (dt, J = 10.1,5.5 Hz, 1H), 2.92 (d, J = 10.1 Hz, 1H), 2.03 (d, J = 14.4 Hz, 1H), 1.81 (d,J= 6.7 Hz, 2H), 1.70 (t, J = 13.7 Hz, 2H), 1.59– 1.51 (m, 3H), 1.48 (t, J = 9.4 Hz, 2H), 1.45 – 1.39 (m, 3H), 1.36 (dd, J = 12.3, 4.3 Hz, 2H), 1.26(q, J = 13.2,11.9 Hz, 1H), 1.16 (ddd, J = 12.5, 8.5, 3.0 Hz, 3H), 1.10 (s,3H), 1.08 (s, 1H), 0.99 (d, J = 13.7 Hz, 1H), 0.91 (s,3H), 0.89 (s, 3H), 0.87 (s, 3H), 0.81 (s, 3H), 0.67 (s, 1H), 0.64 (s, 3H), 0.60 (s, 3H).

[0095] 13C NMR (126 MHz, DMSO-d6) δ 173.08, 157.09, 148.24, 143.71, 143.27,129.05, 125.89, 121.81, 114.13,110.87, 76.83, 47.11, 45.69, 45.39, 41.17,38.88, 38.36, 38.04, 36.56, 33.38, 32.83, 32.26, 32.04, 30.37, 28.21,27.05,26.94, 25.73, 23.59, 22.96, 21.95, 17.94, 16.71, 15.98, 15.05.

[0096] Example 5

[0097] Example 5 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 2-hydroxy-4-trifluoromethylbenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0098]

[0099] Its NMR data are as follows:

[0100] White solid, yield 40.5%.

[0101] 1H NMR (500 MHz, Chloroform-d) δ 11.26 (s, 1H), 9.02 (s, 1H), 8.46(s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.25(s, 1H), 7.13 (dd, J = 8.0, 1.8 Hz,1H), 5.57 (t, J = 3.6 Hz, 1H), 3.21 (d, J = 11.0 Hz, 1H), 2.62 (dd, J =13.1, 4.5Hz, 1H), 2.09 (td, J = 13.8, 3.9 Hz, 1H), 2.01 (t, J = 2.7 Hz,1H), 1.99 (d, J = 3.6 Hz, 1H), 1.82 (t, J = 13.1 Hz,2H), 1.71 (td, J =14.0, 4.2 Hz, 2H), 1.64 (s, 2H), 1.61 (d, J = 4.4 Hz, 2H), 1.57 – 1.52 (m,2H), 1.47 – 1.42 (m,1H), 1.41 – 1.33 (m, 2H), 1.32 – 1.27 (m, 2H), 1.23 (dd,J = 6.8, 2.7 Hz, 1H), 1.21 (s, 3H), 1.12 (d, J = 14.1 Hz,1H), 1.02 (d, J =4.2 Hz, 1H), 0.98 (s, 3H), 0.96 (s, 1H), 0.94 (s, 6H), 0.90 (s, 3H), 0.76 (s,3H), 0.74 (s, 1H), 0.73(s, 3H).

[0102] 13C NMR (126 MHz, Chloroform-d) δ 175.08, 158.68, 149.79, 145.33,131.29, 124.11, 120.47, 115.83 (d, J=3.9 Hz), 114.66 (d, J=3.9 Hz),55.16, 47.59, 46.77, 46.71, 42.25, 41.91, 39.60, 38.88, 38.60, 37.05, 34.08,33.00, 32.30, 32.15, 30.84, 28.19, 27.34, 27.25, 25.97, 24.39, 23.80, 23.63, 18.31, 16.97, 15.64, 15.50.

[0103] 19 F NMR (471 MHz, CDCl3) δ -63.18.

[0104] Example 6

[0105] Example 6 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 2-hydroxy-3-trifluoromethylbenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0106]

[0107] Its NMR data are as follows:

[0108] White solid, yield 43.4%.

[0109] 11H NMR (500 MHz, DMSO-d6) δ 13.07 (s, 1H), 11.28 (s, 1H), 8.55 (s, 1H), 7.70 (d, J = 7.0 Hz, 1H), 7.61 (d, J = 6.2 Hz, 1H), 7.06 (t, J = 7.7 Hz, 1H), 5.27 (t, J = 3.7 Hz, 1H), 4.27 (d, J = 5.2 Hz, 1H), 2.98 (dt, J = 10.2, 5.5 Hz, 1H), 2.91 (dd, J = 13.0, 4.1 Hz, 1H), 2.06 (td, J = 13.9, 3.9 Hz, 1H), 1.87–1.76 (m, 2H), 1.71 (t, J = 13.4 Hz, 2H), 1.61–1.51 (m, 3H), 1.48 (d, J = 2.7 Hz, 1H), 1.46 (s, 1H), 1.42 (dd, J = 8.5, 4.5 Hz, 3H), 1.38 (d, J = 4.1 Hz, 1H), 1.35 (s, 1H), 1.30–1.22 (m, 1H), 1.19 (s, 1H), 1.14 (s, 1H), 1.10 (s, 3H), 1.00 (d, J = 14.0 Hz, 1H), 0.92 (s, 3H), 0.89 (s, 3H), 0.87 (s, 3H), 0.81 (s, 3H), 0.67 (s, 1H), 0.64 (s, 3H), 0.60 (s, 3H).

[0110] 13 13C NMR (126 MHz, DMSO-d6) δ 173.04, 156.03, 147.47, 143.64, 134.97, 127.76, 124.88, 122.71, 121.96, 119.25, 118.85, 116.45, 116.21, 76.90, 47.15, 45.66, 45.33, 41.19, 38.41, 38.08, 36.60, 33.36, 32.85, 32.29, 32.14, 30.41, 28.24, 27.07, 26.96, 25.78, 23.61, 23.00, 22.01, 17.97, 16.72, 16.02, 15.09.

[0111] 19 19F NMR (471 MHz, DMSO) δ -61.19.

[0112] Example 7

[0113] Example 7 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 2-hydroxy-6-trifluoromethylbenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0114]

[0115] Its NMR data are as follows:

[0116] Pale yellow solid, yield 36.2%.

[0117] 1 H NMR (500MHz, DMSO-d6) δ12.95(s,1H),11.40(s,1H),8.82(s,1H),7.47(t,J=8.0Hz,1H),7.31(d,J=7.7Hz,1H),7.24(d,J=8.3Hz,1H),5.30–5.26(m ,1H),4.28(d,J=5.2Hz,1H),2.99(dt,J=10.2,5.4Hz,1H),2.94–2.88(m, 1H),2.14–2.06(m,1H),1.88–1.77(m,2H),1.72(t,J=13.8Hz,2H),1.58(d d,J=12.9,3.6Hz,3H),1.49(t,J=9.8Hz,2H),1.44(d,J=6.7Hz,3H),1.41 –1.33(m,2H),1.29(d,J=10.9Hz,1H),1.24(d,J=8.7Hz,1H),1.19(d,J=11 .4Hz,2H),1.13(s,1H),1.12(s,3H),1.08–0.97(m,1H),0.93(s,3H),0.91 (s,3H),0.88(s,3H),0.81(s,3H),0.67(s,1H),0.65(s,3H),0.60(s,3H).

[0118] 13C NMR(126MHz,DMSO-d6)δ172.97,159.38,143.56,130.83,127.50,127.26,1 25.13,122.94,122.03,121.91,116.89,113.96,76.84,47.09,45.60,45.26 ,41.15,38.86,38.36,38.04,36.55,33.29,32.78,32.23,32.03,30.34,28.19,27.04,26.93,25.71,23.57,22.93,22.05,17.91,16.58,15.95,14.99.

[0119] 19 F NMR (471MHz, DMSO) δ -56.34.

[0120] Example 8

[0121] Example 8 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 5-iodosalicylaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0122]

[0123] Its NMR data are as follows:

[0124] Pale yellow solid, yield 15.6%.

[0125] 1H NMR(500MHz,Chloroform-d)δ11.08(s,1H),8.96(s,1H),8.24(s,1H),7.53(dd,J=8.7,2.2Hz,1H),7.48(d,J=2.2Hz,1H),6.78(d,J =8.7Hz,1H),5.59–5.52(m,1H),3.21(d,J=9.3Hz,1H),2.61(d,J=12.9Hz,1H),2.12–2.05(m,1H),2.02–1.97(m,2H),1.82(t,J=13. 4Hz,2H),1.72(dd,J=14.8,5.7Hz,2H),1.69–1.60(m,4H),1.60(s,2H),1.49(s,1H),1.47–1.42(m,1H),1.41–1.32(m,2H),1.27(d, J=10.5Hz,4H),1.21(s,3H),1.11(d,J=14.0Hz,1H),0.99(s,3H),0.94(s,6H),0.91(s,3H),0.77(s,3H),0.74(s,1H),0.73(s,3H).

[0126] 13 C NMR(126MHz,Chloroform-d)δ174.84,158.48,149.15,145.38,140.20,138.93,124.04,120.10,119.81,79.05,55.16,47.60,46.73,46.66,42.24,4 1.90,39.59,38.88,38.61,37.05,34.09,33.01,32.27,32.15,30.84,28. 20,27.32,27.25,25.97,24.37,23.81,23.65,18.32,16.99,15.65,15.56.

[0127] Example 9

[0128] Example 9 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 2,4-dihydroxybenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0129]

[0130] Its NMR data are as follows:

[0131] White solid, yield 88.4%.

[0132] 1 H NMR(500MHz,DMSO-d6)δ11.60(s,1H),10.68(s,1H),9.89(s,1H),8.38(s,1H), 7.21(d,J=8.5Hz,1H),6.33(dd,J=8.4,2.3Hz,1H),6.27(d,J=2.3Hz,1H),5.28 (t,J=3.7Hz,1H),4.27(d,J=5.2Hz,1H),2.99(dt,J=10.2,5.5Hz,1H),2.94–2. 88(m,1H),2.03(t,J=11.8Hz,1H),1.82(dd,J=9.3,3.6Hz,2H),1.71(t,J=13.5H z,2H),1.57(ddd,J=20.1,11.7,5.0Hz,3H),1.52–1.46(m,3H),1.44(d,J=4.8H z,2H),1.38(p,J=5.4Hz,2H),1.31–1.24(m,1H),1.22–1.13(m,2H),1.11(s,3H) ,1.09(d,J=5.9Hz,1H),0.98(d,J=13.8Hz,1H),0.92(s,3H),0.89(d,J=6.7Hz, 6H),0.86(d,J=7.9Hz,1H),0.82(s,3H),0.68(s,1H),0.66(s,3H),0.61(s,3H).

[0133] 13 C NMR(151MHz,DMSO-d6)δ172.36,160.45,159.48,148.33,143.89,131.47,1 21.84,110.58,107.58,102.70,79.22,76.93,47.18,45.82,45.16,41.21, 40.10, 40.06, 38.95, 38.43, 38.10, 36.62, 33.49, 32.93, 32.31, 30.47, 28.27, 27.10, 26.98, 25.83, 23.66, 23.02, 22.10, 18.00, 16.79, 16.05, 15.11.

[0134] Example 10

[0135] Example 10 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 2,5-dihydroxybenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0136]

[0137] Its NMR data are as follows:

[0138] A light purple solid, yield 49.8%.

[0139] 1 H NMR(500MHz,DMSO-d6)δ10.80(s,1H),10.55(s,1H),8.93(s,1H),8.43(s,1H),6.84(d,J=2.5Hz,1H),6.73–6.67(m,2H),5.27(s,1H),4 .27(d,J=5.2Hz,1H),2.98(dt,J=10.1,5.5Hz,1H),2.95–2.87(m,1H),2.02(t,J=12.1Hz,2H),1.86–1.78(m,2H),1.74–1.66(m,2H),1.5 5(d,J=16.7Hz,3H),1.49(t,J=8.9Hz,3H),1.45–1.38(m,3H),1.35(d,J=6.8Hz,1H),1.31–1.24(m,1H),1.20(s,1H),1.14(s,1H),1.10( s,3H),1.09(s,1H),0.98(d,J=13.9Hz,1H),0.92(s,3H),0.89(s,3H),0.88(s,3H),0.81(s,3H),0.67(s,1H),0.65(s,3H),0.61(s,3H).

[0140] 13 C NMR (126MHz, DMSO-d6) δ172.57,150.19,149.79,146.86,143.83,121.80,118.84,118.50,116.96,114.32,76.88,47.16,45.78,45.22,41.18, 38.91,38.39,38.07,36.59,33.45,32.89,32.30,32.19,30.41,28.24, 27.07,26.97,25.78,23.62,22.99,22.04,17.98,16.75,16.01,15.07.

[0141] Example 11

[0142] Example 11 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 4-formyl-3-hydroxybenzonitrile replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0143]

[0144] Its NMR data are as follows:

[0145] White solid, yield 37.3%.

[0146] 1 H NMR (500MHz, DMSO-d6) δ12.34(s,1H),11.18(s,1H),8.54(s,1H),8.00(d,J=2.1Hz,1H),7.70(dd,J=8.6,2.1Hz,1H),7.05(d,J=8.6Hz,1H),5 .26(t,J=3.7Hz,1H),4.27(d,J=5.1Hz,1H),2.98(dt,J=10.1,5.4Hz,1H),2.92(dd,J=13.3,4.1Hz,1H),2.04(td,J=13.8,3.7Hz,1H),1.86–1. 79(m,2H),1.70(t,J=13.3Hz,2H),1.55(d,J=10.4Hz,3H),1.51–1.39( m,6H),1.39–1.31(m,2H),1.31–1.22(m,1H),1.19–1.13(m,2H),1.10(s ,3H),1.08(d,J=9.6Hz,1H),0.99(d,J=14.0Hz,1H),0.92(s,3H),0.88 (d,J=10.1Hz,6H),0.81(s,3H),0.67(s,1H),0.64(s,3H),0.60(s,3H).

[0147] 13 C NMR(126MHz,DMSO-d6)δ172.98,160.90,144.63,143.70,134.44,133.62 ,121.83,119.99,118.91,117.77,101.71,76.84,47.11,45.67,45.30,41 .16,38.88,38.37,38.04,36.57,33.36,32.84,32.27,32.08,30.38,28.2 2,27.05,26.94,25.75,23.59,22.95,21.95,17.94,16.69,15.99,15.06.

[0148] Example 12

[0149] Example 12 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 4-iodo-2-hydroxybenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0150]

[0151] Its NMR data are as follows:

[0152] Pale yellow solid, yield 46.1%.

[0153] 1 H NMR (500MHz, Chloroform-d) δ11.13(s,1H),8.94(s,1H),8.34(s,1H),7.39(d,J=1.7Hz,1H),7.23(dd,J=8.0,1.7Hz,1H),6.88(d,J=8.1Hz,1H),5. 55(t,J=3.5Hz,1H),3.21(dd,J=11.3,4.3Hz,1H),2.61(dd,J=12.6,3.7H z,1H),2.11–2.05(m,1H),2.00(s,1H),1.98(d,J=3.6Hz,1H),1.81(t,J=1 3.2Hz,2H),1.71(dd,J=14.0,4.2Hz,2H),1.68–1.63(m,1H),1.62(d,J=1 0.2Hz,3H),1.55(t,J=11.5Hz,3H),1.50–1.40(m,2H),1.36(t,J=13.2Hz, 2H),1.28(s,1H),1.25(s,1H),1.22(s,1H),1.20(s,3H),1.10(d,J=14.0 Hz,1H),0.98(s,3H),0.93(s,6H),0.89(s,3H),0.77(s,3H),0.72(s,4H).

[0154] 13C NMR(126MHz,Chloroform-d)δ174.91,158.94,150.65,145.38,131.83,128.66,126.70,124.04,117.34,97.79,55.17,47.60,46.75,46.69,42.24,4 1.92,39.60,38.88,38.61,37.05,34.10,33.01,32.29,32.15,30.84,28. 20,27.33,27.25,25.97,24.36,23.80,23.64,18.32,16.98,15.64,15.51.

[0155] Example 13

[0156] Example 13 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 3-nitrosalicylic acid is used instead of 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0157]

[0158] Its NMR data are as follows:

[0159] Yellow solid, yield 28.3%.

[0160] 1 H NMR (500MHz, DMSO-d6) δ13.18(s,1H),11.32(s,1H),8.62(s,1H),7.96(dd,J=8.2,1.6Hz,1H),7.82(d,J=7.7Hz,1H),7.09(t,J=7.9Hz,1H ),5.28(t,J=3.6Hz,1H),4.28(d,J=5.2Hz,1H),2.99(p,J=5.3Hz,1H),2.95–2.89(m,1H),2.07(td,J=13.8,3.7Hz,1H),1.86–1.80(m,2H), 1.72(t,J=13.4Hz,2H),1.61–1.53(m,3H),1.48(d,J=11.5Hz,3H),1.46–1.41(m,3H),1.41–1.35(m,2H),1.34–1.22(m,2H),1.20(s,1H),1 .16(s,1H),1.12(s,3H),1.01(d,J=14.1Hz,1H),0.93(s,3H),0.89(d,J=12.7Hz,6H),0.82(s,3H),0.68(s,1H),0.65(s,3H),0.62(s,3H).

[0161] 13 C NMR (126MHz, DMSO-d6) δ173.02,151.65,146.12,143.61,137.76,135.07,126.22,121.88,121.29,118.90,76.82,47.10,45.60,45.31,41.14, 38.86,38.36,38.03,36.55,33.31,32.81,32.25,32.05,30.36,28.20, 27.02,26.93,25.74,23.58,22.94,21.95,17.92,16.66,15.98,15.04.

[0162] Example 14

[0163] Example 14 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 4-formyl-3-hydroxybenzonitrile replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0164]

[0165] Its NMR data are as follows:

[0166] Pale yellow solid, yield 23.4%.

[0167] 1H NMR (500MHz, DMSO-d6) δ11.76(s,1H),11.15(s,1H),8.59(s,1H),7.69(d,J=7.9Hz,1H),7.32(dd,J=10.0,2.1Hz,2H),5.27(t,J=3.7Hz,1 H),4.27(d,J=5.2Hz,1H),2.98(dt,J=10.1,5.4Hz,1H),2.92(d,J=11.6Hz,1H),2.09–2.00(m,1H),1.81(d,J=6.8Hz,2H),1.70(t,J=13.2H z,2H),1.55(d,J=11.9Hz,3H),1.48(t,J=9.4Hz,3H),1.44–1.39(m,3H),1.39–1.32(m,2H),1.31–1.22(m,1H),1.19(s,1H),1.17(s,1H), 1.14(s,1H),1.11(s,3H),0.99(d,J=11.0Hz,1H),0.92(s,3H),0.88(d,J=9.9Hz,6H),0.81(s,3H),0.67(s,1H),0.64(s,3H),0.60(s,3H).

[0168] 13 C NMR(126MHz,DMSO-d6)δ173.02,156.99,144.55,143.69,129.78,123.79 ,122.80,121.84,119.58,118.52,112.33,76.84,47.11,45.67,45.35,41 .17,38.88,38.37,38.04,36.56,33.37,32.83,32.26,32.06,30.37,28.2 1,27.05,26.94,25.75,23.59,22.95,21.95,17.94,16.69,15.99,15.05.

[0169] Example 15

[0170] Example 15 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 5-trifluoromethyl-3-nitrosalicylic acid aldehyde is used instead of 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0171]

[0172] Its NMR data are as follows:

[0173] Yellow solid, yield 32.5%.

[0174] 1 H NMR(500MHz,DMSO-d6)δ10.74(s,1H),8.52(d,J=34.6Hz,1H),7.95(s,1H),7.71(s,1H),5.30(s,1H),4.29(s, 1H),3.02–2.91(m,2H),2.02(s,1H),1.82(d,J=8.7Hz,2H),1.72(d,J=12.3Hz,2H),1.56(d,J=20.7Hz,3H),1.5 0(d,J=8.6Hz,2H),1.45(d,J=13.1Hz,4H),1.38(d,J=13.4Hz,3H),1.25(d,J=13.4Hz,1H),1.16(s,1H),1.11(s ,3H),1.03(s,1H),0.98(s,1H),0.93(s,3H),0.88(s,6H),0.81(s,3H),0.67(s,1H),0.65(s,3H),0.62(s,3H).

[0175] Example 16

[0176] Example 16 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 5-trifluoromethyl-3-nitrosalicylic acid aldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0177]

[0178] Its NMR data are as follows:

[0179] Pale yellow solid, yield 42.5%.

[0180] 1H NMR (500MHz, DMSO-d6) δ11.18(s,2H),10.92(s,1H),8.84(s,1H),7.05(t,J=8.2Hz,1H),6.33(d,J=8.2Hz,2H),5.28(t,J=3.7Hz,1H),4.28(s ,1H),2.99(dd,J=9.7,6.0Hz,1H),2.94(dd,J=13.1,4.5Hz,1H),2.04(dd,J=13.8,3.8Hz,1H),1.82(d,J=7.2Hz,2H),1.71(t,J=13.4Hz,2H), 1.58(td,J=13.6,6.2Hz,2H),1.52(d,J=3.2Hz,1H),1.51–1.46(m,3H),1.44(s,3H),1.37(q,J=6.6,5.8Hz,2H),1.33–1.19(m,2H),1.18(s,1 H),1.14(s,1H),1.11(s,3H),0.98(d,J=13.7Hz,1H),0.93(s,3H),0.8 9(d,J=7.6Hz,6H),0.82(s,3H),0.68(s,1H),0.65(s,3H),0.61(s,3H).

[0181] 13 C NMR (126MHz, DMSO-d6) δ172.36,158.24,144.97,143.80,131.87,121.79,106.43,106.31,76.86,47.14,45.73,45.13,41.13,38.9 0,38.37,38.05,36.58,33.42,32.88,32.27,30.42,28.23,27.05,26.96,25.82,23.62,22.98,21.96,17.96,16.69,15.99,15.04.

[0182] Example 17

[0183] Example 17 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 3-formyl-4-hydroxybenzoic acid replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0184]

[0185] Its NMR data are as follows:

[0186] Pale yellow solid, yield 37.9%.

[0187] 1 H NMR(500MHz,DMSO-d6)δ12.63(s,1H),11.97(s,1H),11.01(s,1H),8.58(s,1H ),8.12(d,J=2.2Hz,1H),7.83(dd,J=8.6,2.2Hz,1H),6.98(d,J=8.6Hz,1H),5 .28(t,J=3.6Hz,1H),4.28(d,J=5.1Hz,1H),2.99(p,J=5.0Hz,1H),2.93(dd,J =13.2,3.7Hz,1H),2.04(td,J=13.7,3.6Hz,1H),1.83(dd,J=9.0,3.5Hz,2H), 1.71(t,J=13.3Hz,2H),1.61–1.54(m,3H),1.49(t,J=9.1Hz,3H),1.46–1.41( m,3H),1.37(dd,J=11.4,4.1Hz,2H),1.32–1.26(m,1H),1.22(d,J=16.2Hz,1H ),1.18(s,1H),1.15(s,1H),1.11(s,3H),1.00(d,J=13.9Hz,1H),0.93(s,3H) ,0.89(d,J=10.2Hz,6H),0.82(s,3H),0.68(s,1H),0.65(s,3H),0.62(s,3H).

[0188] 13 C NMR(126MHz,DMSO-d6)δ172.84,166.84,160.93,145.54,143.77,132.17 ,130.74,121.97,121.83,118.90,116.51,76.87,47.14,45.74,45.26,41 .18,38.91,38.38,38.07,36.58,33.42,32.87,32.29,32.11,30.40,28.2 3,27.07,26.96,25.76,23.61,22.98,22.02,17.96,16.74,16.00,15.08.

[0189] Example 18

[0190] Example 18 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 4-(diethylamino)salicylaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0191]

[0192] Its NMR data are as follows:

[0193] Pale yellow solid, yield 45.8%.

[0194] 1 H NMR (500MHz, DMSO-d6) δ11.54(s,1H),10.51(s,1H),8.30(s,1H),7.11(d,J=8.7Hz ,1H),6.24(dd,J=8.8,2.5Hz,1H),6.08(d,J=2.4Hz,1H),5.28(t,J=3.7Hz,1H),4. 29(d,J=5.2Hz,1H),3.35(s,3H),3.33(d,J=7.0Hz,3H),2.99(dt,J=10.2,5.5Hz,1 H),2.91(dd,J=13.3,4.2Hz,1H),2.09–1.99(m,1H),1.82(dd,J=9.1,3.7Hz,2H),1. 75–1.65(m,2H),1.63–1.55(m,2H),1.54(d,J=4.4Hz,1H),1.51–1.45(m,3H),1.44 (s,2H),1.41–1.33(m,2H),1.28(q,J=13.6,12.9Hz,1H),1.20(s,1H),1.16(s,1H) ,1.14(s,1H),1.11(s,3H),1.09(s,3H),1.08(s,2H),0.97(d,J=13.8Hz,1H),0.92 (s,3H),0.89(d,J=6.7Hz,6H),0.82(s,3H),0.68(s,1H),0.65(s,3H),0.61(s,3H).

[0195] 13 C NMR(126MHz,DMSO-d6)δ171.91,159.62,149.89,149.00,143.90,131.50, 121.78,106.53,103.49,97.58,76.86,47.15,45.82,45.03,43.79,41.16, 38.91,38.38,38.06,36.58,33.49,32.90,32.31,32.27,30.43,28.23,27. 06,26.96,25.79,23.62,22.98,22.12,17.97,16.74,16.00,15.06,12.54.

[0196] Example 19

[0197] Example 19 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 3-bromo-2-hydroxybenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0198]

[0199] Its NMR data are as follows:

[0200] Yellow solid, yield 53.8%.

[0201] 1 H NMR (500MHz, DMSO-d6) δ12.72(s,1H),11.22(s,1H),8.49(s,1H),7.59(dd,J=8.0,1.5Hz,1H),7.44(dd,J=7.7,1.5Hz,1H),6.89(t,J=7.8Hz,1H) ,5.30–5.25(m,1H),4.28(d,J=5.2Hz,1H),2.99(dt,J=10.2,5.5Hz,1H),2.92(d,J=9.8Hz,1H),2.07(t,J=12.1Hz,1H),1.83(dd,J=9.0,3.6Hz,2 H),1.72(t,J=13.3Hz,2H),1.57(d,J=12.7Hz,3H),1.52–1.47(m,3H),1.44(d,J=6.6Hz,4H),1.38(d,J=12.2Hz,2H),1.28(dd,J=25.9,12.6Hz,2 H),1.20(s,1H),1.12(s,3H),1.00(d,J=13.8Hz,1H),0.93(s,3H),0.91( s,3H),0.88(s,3H),0.82(s,3H),0.68(s,1H),0.65(s,3H),0.61(s,3H).

[0202] 13C NMR(151MHz,DMSO-d6)δ172.94,154.17,147.30,143.69,134.01,130.17,1 21.93,120.47,119.45,109.90,76.90,47.15,45.66,45.30,41.19,40.11, 40.06, 38.92, 38.41, 38.08, 36.60, 33.37, 32.87, 32.29, 32.13, 30.43, 28.25, 27.08, 26.97, 25.81, 23.63, 23.00, 22.02, 17.97, 16.68, 16.03, 15.09.

[0203] Example 20

[0204] Example 20 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 5-bromo-2-hydroxybenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0205]

[0206] Its NMR data are as follows:

[0207] Yellow solid, yield 57.6%.

[0208] 1H NMR (500MHz, DMSO-d6) δ11.43(s,1H),11.02(s,1H),8.49(s,1H),7.69(d,J=2.6Hz,1H),7.40(dd,J=8.7,2.6Hz,1H),6.87(d,J=8.7Hz,1H),5.27( s,1H),2.99(dd,J=9.9,5.9Hz,1H),2.92(dd,J=12.9,3.7Hz,1H),2.04(td,J=13.8,3.6Hz,1H),1.82(dd,J=9.3,3.8Hz,2H),1.71(t,J=13.2Hz,2H) ,1.60–1.53(m,3H),1.49(dd,J=10.9,6.9Hz,3H),1.44(q,J=3.5,2.9Hz, 3H),1.40–1.34(m,2H),1.25(dd,J=25.8,12.5Hz,2H),1.20(s,1H),1.14 (s,1H),1.11(s,3H),1.09(s,1H),0.99(d,J=14.2Hz,1H),0.92(s,3H),0 .89(d,J=8.7Hz,6H),0.82(s,3H),0.68(s,1H),0.65(s,3H),0.61(s,3H).

[0209] 13 C NMR(151MHz,DMSO-d6)δ173.34,156.83,145.13,144.22,133.71,131.14,1 22.26,121.68,119.12,110.76,77.31,55.24,47.57,46.16,45.74,41.63, 40.48,39.34,38.83,38.50,37.03,33.84,33.30,32.72,32.55,30.85,28.68,27.51,27.39,26.21,24.06,23.41,22.43,18.40,17.18,16.46,15.52.

[0210] Example 21

[0211] Example 21 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 6-bromo-2-hydroxybenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0212]

[0213] Its NMR data are as follows:

[0214] White solid, yield 63.2%.

[0215] 1 H NMR (500MHz, DMSO-d6) δ12.69(s,1H),11.36(s,1H),8.91(s,1H),7.21–7.16(m,2H),6.93(dd,J=7.4,2.1Hz,1H),5.26(t,J=3.7Hz,1H),4.27(d ,J=5.2Hz,1H),2.98(dt,J=9.8,5.7Hz,1H),2.91(dd,J=13.5,4.3Hz,1H),2.06(td,J=13.9,3.7Hz,1H),1.81(d,J=6.2Hz,2H),1.70(t,J=13.2H z,2H),1.62–1.53(m,3H),1.48(t,J=9.0Hz,2H),1.43(d,J=9.1Hz,3H), 1.40–1.33(m,2H),1.26(q,J=13.3,11.7Hz,1H),1.17(s,1H),1.14(d,J =12.3Hz,1H),1.10(s,3H),1.00(d,J=13.8Hz,1H),0.92(s,3H),0.90(s ,3H),0.87(s,3H),0.80(s,3H),0.66(s,1H),0.64(s,3H),0.60(s,3H).

[0216] 13 C NMR (126MHz, DMSO-d6) δ172.83,159.37,147.19,143.61,132.04,123.60,123.55,121.85,116.78,116.44,76.84,47.11,45.60,45.22,41.14, 38.86,38.35,38.03,36.56,33.32,32.81,32.25,32.09,30.35,28.20, 27.05,26.94,25.74,23.59,22.95,21.95,17.93,16.64,15.97,15.03.

[0217] Example 22

[0218] Example 22 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 2,3-dihydroxybenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0219]

[0220] Its NMR data are as follows:

[0221] Brown solid, yield 75.6%.

[0222] 1 H NMR (500MHz, DMSO-d6) δ11.35(s,1H),10.91(s,1H),9.10(s,1H),8.48(s,1H),6.84(ddd,J=19.0,7.9,1.6Hz,2H),6.71(t,J=7.8Hz,1H),5.28( s,1H),4.28(s,1H),3.02–2.96(m,1H),2.93(dd,J=13.5,4.1Hz,1H),2. 03(dt,J=13.6,8.1Hz,1H),1.82(dd,J=9.1,3.6Hz,2H),1.70(t,J=13.1H z,2H),1.57(qd,J=13.4,3.1Hz,3H),1.50(d,J=8.3Hz,1H),1.48–1.41(m,4H),1.36(d,J=13.0Hz,3H),1.27(q,J=13.2,12.7Hz,1H),1.20(s,1H ),1.15(s,1H),1.11(s,3H),0.99(d,J=14.0Hz,1H),0.93(s,3H),0.90( s,3H),0.88(s,3H),0.81(s,3H),0.67(s,1H),0.65(s,3H),0.62(s,3H).

[0223] 13 C NMR (126MHz, DMSO-d6) δ172.59,147.98,145.99,145.57,143.77,121.83,120.18,119.01,118.67,117.13,76.87,47.16,45.74,45.20,41.16, 38.91,38.39,38.07,36.58,33.42,32.89,32.28,32.16,30.41,28.24, 27.07,26.96,25.81,23.63,22.99,22.06,17.97,16.69,16.01,15.07.

[0224] Example 23

[0225] Example 23 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 5-tert-butyl-2-hydroxybenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0226]

[0227] Its NMR data are as follows:

[0228] White solid, yield 75.4%.

[0229] 1 H NMR (500MHz, DMSO-d6) δ11.18(s,1H),10.86(s,1H),8.55(s,1H),7.39(d,J=2. 5Hz,1H),7.29(dd,J=8.6,2.5Hz,1H),6.83(d,J=8.6Hz,1H),5.28(t,J=3.6Hz,1 H),4.28(d,J=5.1Hz,1H),2.99(dt,J=9.7,5.6Hz,1H),2.93(dd,J=13.5,4.0Hz, 1H),2.08–1.99(m,1H),1.82(d,J=5.4Hz,2H),1.70(t,J=13.5Hz,2H),1.57(qd, J=14.8,14.0,3.1Hz,3H),1.49(d,J=4.8Hz,1H),1.47–1.42(m,3H),1.40(d,J=5 .0Hz,1H),1.36(d,J=13.9Hz,2H),1.30(s,1H),1.25(s,9H),1.24(s,1H),1.18( d,J=12.5Hz,2H),1.12(s,1H),1.10(s,3H),0.98(d,J=12.8Hz,1H),0.93(s,3H) ,0.90(s,3H),0.88(s,3H),0.80(s,3H),0.67(s,1H),0.65(s,3H),0.61(s,3H).

[0230] 13C NMR(126MHz,DMSO-d6)δ172.58,155.24,147.88,143.76,141.32,128.16,1 25.80,121.82,117.84,115.98,76.84,47.12,45.72,45.21,41.15,38.88, 38.36,38.05,36.56,33.71,33.42,32.87,32.26,32.18,31.23,30.40,28.21,27.03,26.95,25.77,23.60,22.97,22.00,17.95,16.73,15.98,15.05.

[0231] Example 24

[0232] Example 24 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 3-tert-butyl-2-hydroxybenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0233]

[0234] Its NMR data are as follows:

[0235] White solid, yield 36.8%.

[0236] 1 H NMR (500MHz, DMSO-d6) δ12.47(s,1H),11.01(s,1H),8.49(s,1H),7.24(d,J=15.4Hz,2H),6.86(s,1H),5.28(s, 1H),4.29(s,1H),4.03(dt,J=7.6,3.5Hz,2H),2.95(d,J=30.9Hz,3H),2.06(s,2H),1.83(s,2H),1.72(s,2H),1 .57(d,J=12.1Hz,3H),1.49(s,2H),1.40–1.35(m,9H),1.27–1.22(m,3H),1.20(d,J=3.8Hz,1H),1.17–1.15(m, 1H),1.12(s,3H),1.00(d,J=12.7Hz,2H),0.92(d,J=11.8Hz,9H),0.82(s,3H),0.68–0.64(m,3H),0.64(s,3H).

[0237] 13C NMR (126MHz, DMSO-d6) δ172.64,156.82,149.46,143.67,136.26,129.23,128.16,121.87,118.64,117.78,76.84,47.13,45.71,45.23,41.18, 38.90,38.37,38.05,36.57,34.45,33.39,32.84,32.21,30.39,29.24, 28.22,26.95,25.73,23.57,22.98,22.00,17.96,16.81,15.99,15.06.

[0238] Example 25

[0239] Example 25 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 4-benzoxy-2-hydroxybenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0240]

[0241] Its NMR data are as follows:

[0242] White solid, yield 68.4%.

[0243] 1H NMR (500MHz, DMSO-d6) δ11.76(s,1H),10.79(s,1H),8.44(s,1H),7.44(d,J=6. 7Hz,2H),7.40(t,J=7.6Hz,2H),7.34(dd,J=7.9,5.5Hz,2H),6.60–6.53(m,2H) ,5.28(t,J=3.7Hz,1H),5.12(s,2H),4.28(d,J=5.1Hz,1H),2.99(dt,J=10.1,5 .4Hz,1H),2.95–2.89(m,1H),2.02(d,J=14.4Hz,1H),1.82(d,J=5.6Hz,1H),1.7 0(t,J=13.5Hz,1H),1.57(t,J=15.9Hz,1H),1.52–1.46(m,1H),1.44(d,J=5.3H z,1H),1.38(td,J=12.8,11.0,3.9Hz,1H),1.27(q,J=14.0,13.1Hz,0H),1.20( s,0H),1.17(s,0H),1.14(s,0H),1.11(s,3H),0.98(d,J=13.7Hz,0H),0.92(s, 3H),0.89(d,J=6.2Hz,6H),0.81(s,3H),0.67(s,1H),0.65(s,3H),0.61(s,3H).

[0244] 13 C NMR(126MHz,DMSO-d6)δ172.38,160.82,159.31,147.81,143.80,136.77,131.21, 128.46,127.91,127.70,121.78,111.93,107.03,102.05,76.84,69.31,47.12,45. 74,45.12,41.15,38.88,38.36,38.04,36.56,33.41,32.85,32.26,32.21,30.39,28.21,27.04,26.94,25.76,23.59,22.95,22.02,17.94,16.71,15.99,15.04. Example 26

[0245] Example 26 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 3-allyl-2-hydroxybenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0246]

[0247] Its NMR data are as follows:

[0248] White solid, yield 75.9%.

[0249] 1 H NMR(500MHz,DMSO-d6)δ12.09(s,1H),11.02(s,1H),8.49(s,1H),7.24(dd,J=7.7,1.7 Hz,1H),7.15(d,J=6.0Hz,1H),6.86(t,J=7.6Hz,1H),5.97(ddt,J=16.8,10.0,6.7Hz, 1H),5.28(t,J=3.7Hz,1H),5.06(dd,J=17.0,1.9Hz,1H),5.02(d,J=10.1Hz,1H),4.27 (d,J=5.1Hz,1H),2.99(dt,J=9.9,5.5Hz,1H),2.92(dd,J=12.7,3.8Hz,1H),2.04(td, J=13.8,3.7Hz,1H),1.82(dd,J=9.0,3.6Hz,2H),1.70(t,J=13.2Hz,2H),1.64–1.54(m ,3H),1.49(t,J=8.9Hz,3H),1.42(dd,J=17.1,6.2Hz,3H),1.39–1.31(m,2H),1.31–1. 22(m,1H),1.17(s,1H),1.14(d,J=5.3Hz,1H),1.11(s,3H),0.99(d,J=13.5Hz,1H),0. 93(s,3H),0.89(d,J=8.4Hz,6H),0.81(s,3H),0.67(s,1H),0.65(s,3H),0.61(s,3H).

[0250] 13 C NMR(126MHz,DMSO-d6)δ172.62,155.46,148.59,143.69,136.60,131.22,1 28.90,127.03,121.84,118.90,117.52,115.68,76.84,47.12,45.68,45.20 ,41.15,38.88,38.36,38.04,36.56,33.36,32.84,32.26,32.16,30.38,28.21,27.04,26.94,25.75,23.59,22.96,22.01,17.94,16.72,15.98,15.05.

[0251] Example 27

[0252] Example 27 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 5-bromo-3-fluorosalicylaldehyde is used instead of 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0253]

[0254] Its NMR data are as follows:

[0255] Yellow solid, yield 61.9%.

[0256] 1 H NMR (500MHz, DMSO-d6) δ12.52(s,1H),11.34(s,1H),8.46(s,1H),7.54(dd,J=8.0,3.0Hz,1H),7.41(dd,J=8.9,3.1Hz,1H),5.26(t,J=3.7Hz,1H),4.2 7(d,J=5.1Hz,1H),2.98(dt,J=9.0,5.1Hz,1H),2.91(dd,J=14.0,3.7Hz,1H ),2.03(dt,J=13.5,8.4Hz,1H),1.81(d,J=5.5Hz,2H),1.68(t,J=13.6Hz,2 H),1.56(d,J=15.8Hz,3H),1.48(d,J=8.4Hz,2H),1.44(d,J=8.4Hz,4H),1 .38–1.31(m,2H),1.25(q,J=14.0,12.6Hz,1H),1.16(s,1H),1.15(s,1H),1 .12(d,J=4.5Hz,1H),1.09(s,3H),0.98(d,J=13.6Hz,1H),0.91(s,3H),0.8 9(s,3H),0.87(s,3H),0.79(s,3H),0.65(s,1H),0.64(s,3H),0.59(s,3H).

[0257] 13C NMR (126MHz, DMSO-d6) δ172.99,155.45,153.55,150.94,145.93,143.61,121.88,120.7 0(d,J=25.9Hz),119.34(d,J=8.5Hz),115.68(d,J=23.7Hz),109.84(d,J=10.4Hz),76.86 ,47.13,45.63,45.31,41.13,38.87,38.37,38.05,36.56,33.34,32.84,32.26,32.03,30 .35,28.22,26.99(d,J=9.9Hz),25.76,23.59,22.97,21.98,17.95,16.65,15.97,15.05.

[0258] 19 F NMR (471MHz, DMSO) δ-123.58.

[0259] Example 28

[0260] Example 28 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 2-hydroxy-3-tert-butyl-5-bromobenzaldehyde is used instead of 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0261]

[0262] Its NMR data are as follows:

[0263] White solid, yield 55.4%.

[0264] 1H NMR (500MHz, DMSO-d6) δ12.70(s,1H),11.18(s,1H),8.43(s,1H),7.46(d,J=2.4Hz,1H),7.26(d,J=2.4Hz,1H),5.26(t,J=3.7Hz,1 H),4.27(d,J=5.1Hz,1H),2.98(q,J=9.3,7.7Hz,1H),2.91(dd,J=12.7,5.2Hz,1H),2.03(dd,J=14.8,10.8Hz,1H),1.81(d,J=5.3H z,2H),1.69(t,J=13.5Hz,2H),1.55(s,3H),1.51–1.38(m,6H),1.35(s,9H),1.34(s,1H),1.32–1.19(m,2H),1.15(s,1H),1.13(s, 1H),1.09(s,3H),0.98(d,J=13.4Hz,1H),0.91(s,3H),0.87(d,J=7.0Hz,6H),0.80(s,3H),0.65(s,1H),0.64(s,3H),0.61(s,3H).

[0265] 13 C NMR(126MHz,DMSO-d6)δ172.84,156.10,147.76,143.61,139.11,130.82,1 30.34,121.90,119.79,109.89,76.86,47.14,45.70,45.27,41.17,38.88, 38.37, 38.08, 36.57, 34.70, 33.40, 32.85, 32.27, 32.10, 30.36, 28.95, 28.22, 27.04, 26.95, 25.70, 23.56, 22.97, 22.00, 17.96, 16.78, 15.98, 15.07.

[0266] Example 29

[0267] Example 29 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 5-ethynyl-2-hydroxybenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0268]

[0269] Its NMR data are as follows:

[0270] White solid, yield 36.1%.

[0271] 1 H NMR(500MHz,DMSO-d6)δ11.75(s,1H),11.05(s,1H),8.50(s,1H),7.63(d,J= 2.2Hz,1H),7.36(dd,J=8.5,2.1Hz,1H),6.90(d,J=8.5Hz,1H),5.27(t,J=3.7 Hz,1H),4.28(d,J=5.1Hz,1H),4.02(s,1H),2.99(dt,J=9.7,5.2Hz,1H),2.92 (dd,J=13.1,4.1Hz,1H),2.03(td,J=13.5,3.5Hz,1H),1.82(d,J=5.4Hz,2H), 1.70(t,J=13.5Hz,2H),1.56(d,J=11.2Hz,3H),1.49(d,J=8.2Hz,2H),1.43(d ,J=7.2Hz,3H),1.40(d,J=5.3Hz,1H),1.36(d,J=12.6Hz,1H),1.34–1.20(m,2 H),1.17(s,1H),1.14(s,1H),1.10(s,3H),0.99(d,J=14.4Hz,1H),0.92(s,3H ),0.89(d,J=7.5Hz,6H),0.81(s,3H),0.67(s,1H),0.65(s,3H),0.61(s,3H).

[0272] 13 C NMR(126MHz,DMSO-d6)δ172.83,157.79,145.70,143.75,134.19,132.71,12 1.81,119.17,116.97,112.48,83.18,79.06,76.86,66.38,47.13,45.71,45. 25,41.17,38.89,38.38,38.06,36.58,33.40,32.86,32.28,32.10,30.39,28.23,27.06,26.95,25.76,23.60,22.97,21.99,17.96,16.71,16.00,15.07.

[0273] Example 30

[0274] Example 30 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 5-bromo-3-fluorosalicylaldehyde is used instead of 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0275]

[0276] Its NMR data are as follows:

[0277] Pale yellow solid, yield 62.5%.

[0278] 1 H NMR (500MHz, DMSO-d6) δ11.86(s,1H),11.21(s,1H),8.51(s,1H),7.54(s,1H),7.51(dd,J=10.3,2.3Hz,1H),5.26(t,J=3.7Hz,1H),4.28( d,J=5.0Hz,1H),2.98(q,J=5.0,4.6Hz,1H),2.94–2.88(m,1H),2.02(t,J=12.0Hz,1H),1.80(d,J=5.6Hz,2H),1.68(t,J=13.5Hz,2H),1.56 (d,J=13.3Hz,3H),1.48(d,J=8.4Hz,2H),1.44(d,J=9.0Hz,3H),1.34(dd,J=12.8,4.1Hz,3H),1.25(q,J=13.2,11.3Hz,1H),1.17(s,2H), 1.11(s,1H),1.09(s,3H),0.98(d,J=13.9Hz,1H),0.91(s,3H),0.88(d,J=7.5Hz,6H),0.80(s,3H),0.65(s,1H),0.64(s,3H),0.60(s,3H).

[0279] 13 C NMR (126MHz, DMSO-d6) δ173.05, 151.99, 150.03, 144.72 (d, J = 13.4Hz), 144.51, 143. 67,126.73,122.88(d,J=3.9Hz), 121.86,119.93(d,J=21.5Hz), 109.03(d,J=9.3Hz), 76.87,47.14,45.68,45.32,41.15,38.89,38.38,38.07,36.57,33.38,32.28,32.05,30.37,28.23,27.05,26.95,25.76,23.60,22.97,21.98,17.96,16.69,15.99,15.07.

[0280] 19 F NMR (471MHz, DMSO) δ -133.54.

[0281] Example 31

[0282] Example 31 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 2-hydroxy-5-chloromethylbenzaldehyde is used instead of 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0283]

[0284] Its NMR data are as follows:

[0285] Pale yellow solid, yield 46.2%.

[0286] 1 H NMR(500MHz,Chloroform-d)δ11.01(s,1H),8.95(s,1H),8.30(s,1H),7.24(d,J= 8.4Hz,1H),7.19(s,1H),6.95(d,J=8.3Hz,1H),5.57–5.51(m,1H),4.41(s,2H),3 .52(q,J=6.9Hz,2H),3.20(dd,J=11.3,4.1Hz,1H),2.62(dd,J=13.1,4.3Hz,1H), 2.08(dd,J=13.8,3.9Hz,1H),2.01–1.93(m,2H),1.86–1.82(m,1H),1.80(d,J=13. 4Hz,1H),1.76–1.68(m,2H),1.62–1.58(m,3H),1.53(d,J=16.9Hz,1H),1.46(dd, J=12.4,4.0Hz,1H),1.40(dd,J=13.2,3.8Hz,2H),1.34(dd,J=12.9,3.9Hz,1H),1 .24(d,J=3.5Hz,2H),1.23(s,1H),1.21(s,1H),1.19(s,3H),1.09(d,J=14.0Hz,1 H),0.97(s,3H),0.93(s,6H),0.89(s,3H),0.76(s,3H),0.73(s,3H),0.71(s,1H).

[0287] 13C NMR(126MHz,DMSO-d6)δ174.62,158.26,150.92,145.36,131.71,130.46,12 9.39,123.91,117.42,117.29,72.18,65.75,47.59,46.72,46.54,42.21,41. 88,39.55,38.85,38.58,37.01,34.08,33.00,32.26,32.15,30.81,28.17,27.31,27.22,25.94,24.29,23.78,23.63,18.29,16.97,15.63,15.49,15.32.

[0288] Example 32

[0289] Example 32 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 2-hydroxy-3-methylbenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0290]

[0291] Its NMR data are as follows:

[0292] White solid, yield 52.3%.

[0293] 1H NMR(500MHz,DMSO-d6)δ11.99(s,1H),11.01(s,1H),8.48(s,1H),7.19(dd,J= 13.8,7.5Hz,2H),6.82(t,J=7.5Hz,1H),5.28(t,J=3.7Hz,1H),4.28(d,J=5.2H z,1H),2.99(dt,J=10.1,5.6Hz,1H),2.95–2.90(m,1H),2.18(s,3H),2.05(td, J=14.0,3.8Hz,1H),1.83(dd,J=9.2,3.8Hz,2H),1.72(t,J=13.4Hz,2H),1.59( td,J=13.3,3.9Hz,3H),1.54–1.48(m,2H),1.47(s,1H),1.44(q,J=6.9,3.7Hz ,3H),1.37(dd,J=12.9,4.4Hz,2H),1.28(t,J=12.7Hz,1H),1.22(d,J=17.9Hz, 1H),1.18(s,1H),1.15(s,1H),1.11(s,3H),1.00(d,J=14.1Hz,1H),0.93(s,3H ),0.89(d,J=11.4Hz,6H),0.82(s,3H),0.68(s,1H),0.65(s,3H),0.61(s,3H).

[0294] 13 C NMR(126MHz,DMSO-d6)δ172.61,155.84,148.60,143.73,132.06,128.41 ,124.89,121.83,118.76,117.26,76.83,47.11,45.68,45.19,41.15,38. 88,38.37,38.04,36.57,33.37,32.85,32.25,32.15,30.40,28.21,27.0 5,26.94,25.77,23.60,22.96,22.01,17.94,16.69,15.99,15.41,15.05.

[0295] Example 33

[0296] Example 33 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 3,5-di-tert-butylsalicylaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0297]

[0298] Its NMR data are as follows:

[0299] Pale yellow solid, yield 36.8%.

[0300] 1 H NMR (500MHz, DMSO-d6) δ12.24(s,1H),10.93(s,1H),8.51(s,1H),7.28(d,J=2. 4Hz,1H),7.17(d,J=2.2Hz,1H),5.32–5.26(m,1H),4.28(d,J=5.2Hz,1H),2.99 (dt,J=10.1,5.5Hz,1H),2.93(dd,J=13.3,4.2Hz,1H),2.10–2.00(m,1H),1.83 (dd,J=9.2,3.8Hz,2H),1.72(t,J=13.2Hz,2H),1.61(d,J=13.1Hz,1H),1.55(q, J=3.7,3.2Hz,2H),1.51(d,J=3.6Hz,1H),1.48(d,J=9.3Hz,2H),1.45–1.41(m, 3H),1.39(s,9H),1.36(s,1H),1.30(s,1H),1.27(s,9H),1.24–1.20(m,1H),1. 17(s,1H),1.16–1.13(m,1H),1.11(s,3H),0.99(d,J=13.5Hz,1H),0.93(s,3H) ,0.90(s,3H),0.88(s,3H),0.82(s,3H),0.68(s,1H),0.65(s,3H),0.62(s,3H).

[0301] 13 C NMR(126MHz,DMSO-d6)δ172.61,154.55,150.10,143.70,140.31,135.55 ,125.55,125.19,121.88,117.08,47.12,45.24,41.18,38.90,38.38,38. 04,36.57,34.62,33.86,33.39,32.85,32.24,31.29,30.42,29.30,28.2 2,27.03,26.95,25.74,23.59,22.98,21.99,17.95,16.78,15.99,15.07.

[0302] Example 34

[0303] Example 34 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 2-hydroxy-6-methylbenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0304]

[0305] Its NMR data are as follows:

[0306] White solid, yield 65.9%.

[0307] 1 H NMR(500MHz,Chloroform-d)δ11.49(s,1H),9.00(s,1H),8.69(s,1H),7.15(t,J=7 .9Hz,1H),6.83(d,J=8.3Hz,1H),6.66(d,J=7.4Hz,1H),5.58(t,J=3.6Hz,1H),3.2 1(dd,J=11.4,4.3Hz,1H),2.65(dd,J=13.1,4.3Hz,1H),2.38(s,3H),2.07(td,J=1 3.7,3.9Hz,1H),1.99(dd,J=8.9,3.6Hz,2H),1.85(dt,J=14.2,3.5Hz,2H),1.80(d, J=13.2Hz,1H),1.72(dq,J=13.9,4.5Hz,3H),1.63(s,1H),1.60(d,J=4.5Hz,2H),1 .57–1.52(m,2H),1.46(dd,J=12.4,4.1Hz,1H),1.43–1.38(m,2H),1.37–1.33(m,1 H),1.27–1.24(m,2H),1.22(q,J=2.0Hz,1H),1.20(s,3H),1.12–1.08(m,1H),0.98 (s,3H),0.93(d,J=2.5Hz,6H),0.89(s,3H),0.76(s,3H),0.75(s,3H),0.72(s,1H).

[0308] 13C NMR(126MHz,Chloroform-d)δ174.76,159.62,149.39,145.58,138.16,132.00,124.07,121.35,115.72,55.19,47.59,46.78,46.59,42.26,41.99,3 9.66,38.89,38.59,37.05,34.14,33.03,32.22,32.14,30.87,28.19,27. 34,27.25,25.96,24.40,23.83,23.67,19.40,18.32,17.07,15.64,15.45.

[0309] Example 35

[0310] Example 35 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 2-hydroxy-6-nitrobenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0311]

[0312] Its NMR data are as follows:

[0313] Yellow solid, yield 57.3%.

[0314] 1H NMR (500MHz, Chloroform-d) δ12.24(s,1H),9.34(s,1H),8.56(s,1H),7.46(d,J=8.0Hz,1H),7.36(t,J=8.2Hz,1H),7.25(d,J=9.1Hz,1H),5.59(t,J=3.6 Hz,1H),3.20(dd,J=11.3,4.4Hz,1H),2.66(dd,J=13.1,4.2Hz,1H),2.11(dd ,J=13.8,3.9Hz,1H),2.08–2.03(m,1H),1.99(dt,J=19.0,5.3Hz,1H),1.88–1 .80(m,2H),1.73(dd,J=13.9,3.9Hz,2H),1.64(s,1H),1.60(dd,J=11.2,7.2 Hz,4H),1.56–1.53(m,1H),1.51(s,1H),1.44(d,J=13.3Hz,2H),1.36(ddd,J= 15.8,13.2,3.8Hz,2H),1.28–1.23(m,3H),1.20(s,3H),1.13–1.09(m,1H),0 .97(s,3H),0.93(s,6H),0.92(s,3H),0.75(s,3H),0.74(s,3H),0.71(s,1H).

[0315] 13 C NMR (126MHz, Chloroform-d) δ174.65,160.15,149.64,145.35,144.15,130.88,124.45,123.23,115.99,110.60,55.18,47.62,46.55,42.21,41. 96,39.61,38.87,38.57,37.05,34.06,33.01,32.15,32.09,30.84,28.1 8,27.35,27.25,25.94,24.43,23.78,23.62,18.30,17.10,15.62,15.40.

[0316] Example 36

[0317] Example 36 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 4-tert-butyl-2-hydroxybenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0318]

[0319] Its NMR data are as follows:

[0320] Pale yellow solid, yield 71.1%.

[0321] 1 H NMR(500MHz,Chloroform-d)δ10.90(s,1H),8.87(s,1H),8.33(s,1H),7.13(d,J= 8.1Hz,1H),7.03(d,J=1.9Hz,1H),6.93(dd,J=8.1,1.8Hz,1H),5.56(t,J=3.5Hz,1 H),3.21(d,J=9.5Hz,1H),2.61(d,J=12.9Hz,1H),2.07(td,J=13.7,3.5Hz,2H),1. 99(dd,J=7.2,3.5Hz,2H),1.87–1.84(m,1H),1.81(d,J=13.2Hz,1H),1.74(d,J=5. 1Hz,1H),1.70(dd,J=14.2,4.4Hz,1H),1.63(d,J=2.9Hz,1H),1.61(s,2H),1.57(s ,3H),1.52(s,1H),1.44(d,J=13.0Hz,1H),1.40(d,J=4.0Hz,1H),1.36(s,1H),1.3 3(s,1H),1.30(s,9H),1.28(s,1H),1.25(s,1H),1.20(s,3H),1.10(d,J=14.2Hz,1 H),0.98(s,3H),0.94(s,6H),0.89(s,3H),0.76(s,3H),0.74(s,1H),0.73(s,3H).

[0322] 13 C NMR(126MHz,Chloroform-d)δ174.97,156.34,151.47,145.82,130.85,124. 14,117.02,115.33,114.66,55.39,47.84,47.01,46.81,42.47,42.21,39.8 2,39.10,38.83,37.27,35.38,34.35,33.25,32.50,32.38,31.39,31.07,28.40,27.56,27.47,26.19,24.57,24.02,23.89,18.54,17.21,15.85,15.70.

[0323] Example 37

[0324] Example 37 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 2-hydroxy-5-bromoacetylbenzaldehyde is used instead of 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0325]

[0326] Its NMR data are as follows:

[0327] Yellow solid, yield 56.7%.

[0328] 1 H NMR(500MHz,Chloroform-d)δ11.84(s,1H),9.12(s,1H),8.37(s,1H),7.91(d,J=10.8Hz,2H),7.03(d,J=8.6Hz,1H),5.56(d,J=3.7Hz,1H), 4.41–4.34(m,2H),3.20(dd,J=11.2,4.2Hz,1H),2.64(dd,J=13.1,4.2Hz,1H),2.09(td,J=13.7,3.6Hz,1H),2.00(d,J=7.7Hz,2H),1.81(t,J =13.5Hz,3H),1.71(t,J=14.2Hz,3H),1.63(d,J=5.1Hz,1H),1.61(s,3H),1.58(s,1H),1.53(dd,J=14.4,2.7Hz,3H),1.43(dd,J=15.7,3.8Hz ,2H),1.40–1.35(m,2H),1.32(s,1H),1.20(s,3H),1.11(d,J=14.1Hz, 1H),0.97(s,3H),0.93(s,6H),0.90(s,3H),0.75(s,3H),0.72(s,3H).

[0329] 13C NMR(126MHz,Chloroform-d)δ189.64,174.90,163.50,149.32,145.24,132.76,125.77,124.09,118.01,117.82,55.14,47.58,46.65,42.21,41.82, 39.57,38.86,38.58,37.03,34.07,33.00,32.29,32.15,30.81,30.48,28. 19,27.33,27.24,25.96,24.33,23.80,23.63,18.30,16.99,15.64,15.53.

[0330] Example 38

[0331] Example 38 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 5-amino-2-hydroxybenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0332]

[0333] Its NMR data are as follows:

[0334] Pale yellow solid, yield 66.4%.

[0335] 1H NMR(500MHz,Chloroform-d)δ12.02(s,1H),9.15(s,1H),8.36(s,1H),8.17(d, J=8.2Hz,2H),7.06(d,J=9.4Hz,1H),5.58(t,J=3.6Hz,1H),3.21(dd,J=11.4,4. 2Hz,1H),2.64(dd,J=13.3,4.4Hz,1H),2.10(td,J=13.8,3.9Hz,1H),2.04–1.9 8(m,2H),1.82(t,J=13.5Hz,2H),1.72(dd,J=14.1,4.3Hz,2H),1.64(d,J=2.8Hz ,2H),1.62(d,J=2.3Hz,2H),1.59–1.55(m,2H),1.53(d,J=2.7Hz,1H),1.49–1. 39(m,2H),1.38–1.35(m,1H),1.33(d,J=3.2Hz,1H),1.28(s,1H),1.26(s,1H),1 .24(s,1H),1.21(s,3H),1.12(dt,J=14.1,3.4Hz,1H),1.01(s,1H),0.98(s,3H) ,0.96(s,1H),0.94(s,6H),0.91(s,3H),0.76(s,3H),0.74(s,1H),0.73(s,3H).

[0336] 13 C NMR(151MHz,Chloroform-d)δ175.04,164.00,148.07,145.33,140.41,127. 16,126.84,124.22,118.20,117.48,55.15,47.59,46.76,46.69,42.27,41. 88,39.61,38.89,38.61,37.06,34.07,33.00,32.14,31.56,30.84,30.32,28.20,27.33,27.26,25.98,24.44,23.83,23.64,18.32,17.00,15.65,15.58.

[0337] Example 39

[0338] Example 39 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 3-iodosalicylaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0339]

[0340] Its NMR data are as follows:

[0341] Pale yellow solid, yield 35.2%.

[0342] 1 H NMR (500MHz, DMSO-d6) δ12.90(s,1H),11.21(s,1H),8.42(s,1H),7.77(dd,J=7. 8,1.5Hz,1H),7.43(dd,J=7.7,1.6Hz,1H),6.75(t,J=7.7Hz,1H),5.27(t,J=3.7 Hz,1H),4.27(d,J=5.2Hz,1H),2.99(dt,J=10.1,5.6Hz,1H),2.92(dd,J=13.4,4 .4Hz,1H),2.06(td,J=14.0,4.1Hz,1H),1.82(dd,J=9.1,3.7Hz,2H),1.75–1.67( m,2H),1.61–1.57(m,1H),1.56(d,J=4.4Hz,2H),1.48(d,J=9.5Hz,2H),1.42(t, J=9.0Hz,3H),1.40–1.31(m,2H),1.26(q,J=11.4,10.8Hz,1H),1.18(s,1H),1.1 5(s,1H),1.13(d,J=4.5Hz,1H),1.11(s,3H),1.00(d,J=13.7Hz,1H),0.93(s,3H ),0.90(s,3H),0.88(s,3H),0.81(s,3H),0.67(s,1H),0.65(s,3H),0.61(s,3H).

[0343] 13 C NMR(151MHz,DMSO-d6)δ172.85,156.55,147.20,143.65,139.91,131.04 ,121.87,121.15,118.30,85.58,76.83,47.11,45.61,45.25,41.15,40. 06,38.88,38.37,38.04,36.57,33.32,32.83,32.25,32.10,30.39,28.2 1,27.04,26.94,25.77,23.60,22.95,21.98,17.93,16.67,15.99,15.06.

[0344] Example 40

[0345] Example 40 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that vanillin is used instead of 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0346]

[0347] Its NMR data are as follows:

[0348] White solid, yield 66.4%.

[0349] 1 H NMR (500MHz, DMSO-d6) δ10.36(s,1H),9.48(s,1H),8.24(s,1H),7.24(s,1H),7.00(dd,J=8.2,1.9Hz,1H),6.81(d,J=8.1Hz,1H),5.29(t,J= 3.6Hz,1H),4.29(d,J=5.2Hz,1H),3.80(s,3H),2.98(dt,J=10.2,5.5Hz,1H),2.92(dd,J=13.2,3.9Hz,1H),2.00(t,J=15.4Hz,2H),1.82(d, J=5.6Hz,2H),1.73–1.66(m,2H),1.61–1.53(m,3H),1.51–1.45(m,3H),1.43(s,2H),1.37(d,J=12.2Hz,2H),1.33–1.21(m,2H),1.13(s,1H) ,1.10(s,3H),1.08(s,1H),0.97(d,J=13.8Hz,1H),0.91(s,3H),0.88(d,J=4.2Hz,6H),0.82(s,3H),0.67(s,1H),0.65(s,3H),0.63(s,3H).

[0350] 13 C NMR(126MHz,Chloroform-d)δ174.82,148.45,147.80,147.30,145.57,126. 27,123.74,123.60,114.09,107.96,79.01,56.26,55.14,47.60,46.82,46. 39,42.25,42.09,39.56,38.84,38.58,37.01,34.12,33.03,32.24,30.81,28.18,27.33,27.20,25.92,24.19,23.78,23.66,18.32,17.09,15.63,15.47.

[0351] Example 41

[0352] Example 41 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 5-methylsalicylaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0353]

[0354] Its NMR data are as follows:

[0355] White solid, yield 56.8%.

[0356] 1 H NMR (500MHz, DMSO-d6) δ11.15(s,1H),10.88(s,1H),8.46(s,1H),7.23(s,1H),7.06(dd,J=8.5,2.2Hz,1H),6.78(d,J=8.3Hz,1H),5.27 (t,J=3.7Hz,1H),4.28(d,J=5.2Hz,1H),2.98(dt,J=10.1,5.5Hz,1H),2.94–2.89(m,1H),2.22(s,3H),2.02(td,J=13.8,3.8Hz,1H),1. 81(dd,J=9.2,3.7Hz,2H),1.73–1.67(m,2H),1.60–1.53(m,3H),1.51–1.39(m,6H),1.39–1.32(m,2H),1.30–1.22(m,1H),1.18(d,J=12 .5Hz,3H),1.10(s,3H),0.98(d,J=13.5Hz,1H),0.92(s,3H),0.88(d,J=8.4Hz,6H),0.81(s,3H),0.66(s,1H),0.64(s,3H),0.60(s,3H).

[0357] 13C NMR(151MHz,DMSO-d6)δ172.62,155.25,147.18,143.80,131.71,129.49,12 7.76,121.80,118.31,116.23,76.86,54.80,47.13,45.74,45.21,41.17,40. 04,38.89,38.38,38.05,36.57,33.42,32.87,32.27,32.16,30.41,28.22,27.06,26.95,25.77,23.62,22.97,22.03,19.96,17.96,16.72,16.00,15.07.

[0358] Example 42

[0359] Example 42 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 4-chloro-2-pyridinecarboxaldehyde is used instead of 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0360]

[0361] Its NMR data are as follows:

[0362] White solid, yield 63.4%.

[0363] 1 H NMR (500MHz, DMSO-d6) δ10.98(s,1H),8.56(d,J=5.4Hz,1H),8.40(s,1H),7.84(s,1H),7.53(dd,J=5.4,2.1Hz,1H),5.27(s,1H) ,4.28(d,J=5.1Hz,1H),2.98(dt,J=9.9,5.6Hz,1H),2.92(d,J=13.4Hz,1H),2.04(td,J=13.8,3.6Hz,1H),1.83–1.79(m,2H),1. 70(t,J=13.6Hz,2H),1.56(d,J=8.6Hz,3H),1.50–1.40(m,6H),1.36(dt,J=11.7,4.1Hz,2H),1.30–1.22(m,1H),1.21–1.12(m,3 H),1.10(s,3H),0.99(d,J=13.9Hz,1H),0.91(s,3H),0.88(d,J=8.8Hz,6H),0.81(s,3H),0.66(s,1H),0.64(s,3H),0.62(s,3H).

[0364] 13 C NMR(151MHz,DMSO-d6)δ173.27,155.41,151.02,144.84,143.72,143.41 ,123.98,121.78,119.26,76.83,54.79,47.10,45.74,45.50,41.21,40. 05,38.89,38.37,38.05,36.56,33.39,32.83,32.29,31.98,30.37,28.2 2,27.05,26.94,25.69,23.58,22.96,22.01,17.95,16.81,15.99,15.07.

[0365] Example 43

[0366] Example 43 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 3-chlorosalicylaldehyde replaces 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0367]

[0368] Its NMR data are as follows:

[0369] Pale yellow solid, yield 51.2%.

[0370] 1H NMR (500MHz, DMSO-d6) δ12.55(s,1H),11.19(s,1H),8.52(s,1H),7.45(d,J=7.9Hz,1H),7.40(d,J=7.9Hz,1H),6.94(t,J=7.8Hz,1H),5.2 7(d,J=3.9Hz,1H),4.27(d,J=5.2Hz,1H),2.98(dt,J=10.4,5.6Hz,1H),2.92(d,J=13.3Hz,1H),2.10–2.02(m,1H),1.82(dd,J=8.9,3.6Hz, 2H),1.71(t,J=13.3Hz,2H),1.57(dd,J=13.7,5.1Hz,3H),1.53–1.40(m,6H),1.37(d,J=12.5Hz,2H),1.27(q,J=12.6,12.2Hz,1H),1.22–1 .12(m,3H),1.11(s,3H),1.00(d,J=13.9Hz,1H),0.93(s,3H),0.89(d,J=12.6Hz,6H),0.81(s,3H),0.67(s,1H),0.64(s,3H),0.61(s,3H).

[0371] 13 C NMR(151MHz,DMSO-d6)δ172.85,153.17,147.25,143.65,130.97,129.33,1 21.86,120.20,119.86,119.58,76.82,54.77,47.10,45.62,45.25,41.14, 40.06,38.87,38.36,38.03,36.56,33.32,32.82,32.24,32.07,30.38,28.20,27.03,26.93,25.76,23.59,22.94,21.97,17.93,16.64,15.98,15.04.

[0372] Example 44

[0373] Example 44 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 2-hydroxy-5-trifluoromethylbenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0374]

[0375] Its NMR data are as follows:

[0376] White solid, yield 75.5%.

[0377] 1 H NMR(500MHz,Chloroform-d)δ11.50(s,1H),9.07(s,1H),8.36(s,1H),7.51(dd ,J=8.7,2.3Hz,1H),7.46(d,J=2.3Hz,1H),7.06(d,J=8.6Hz,1H),5.56(t,J=3. 6Hz,1H),3.21(dd,J=11.4,4.1Hz,1H),2.66–2.60(m,1H),2.09(td,J=13.9,4. 0Hz,1H),2.03–1.95(m,2H),1.82(t,J=13.6Hz,2H),1.74(s,1H),1.71(d,J=8. 3Hz,2H),1.62(d,J=9.1Hz,3H),1.58(t,J=4.6Hz,1H),1.54(d,J=13.7Hz,2H), 1.46–1.41(m,1H),1.38(dt,J=11.6,3.8Hz,2H),1.32(dd,J=12.5,3.2Hz,1H), 1.25(ddd,J=12.9,9.4,3.8Hz,3H),1.20(s,3H),1.11(dt,J=14.1,3.5Hz,1H), 0.98(s,3H),0.93(s,6H),0.90(s,3H),0.76(s,3H),0.73(s,3H),0.72(s,1H).

[0378] 13 C NMR(126MHz,Chloroform-d)δ174.94,161.20,149.47,145.30,128.53(d,J=3.9H z),128.09(d,J=4.2Hz),125.32,124.08,121.91,121.65,117.96,117.54,55.15, 47.59, 46.70, 42.24, 41.88, 39.58, 38.87, 38.60, 37.04, 34.07, 33.00, 32.31, 32.15, 30.82, 28.19, 27.33, 25.96, 24.35, 23.80, 23.63, 18.31, 16.98, 15.63, 15.53.

[0379] 19 F NMR (471MHz, CDCl3) δ -61.59.

[0380] Example 45

[0381] Example 45 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 2-hydroxy-6-methylbenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0382]

[0383] Its NMR data are as follows:

[0384] White solid, yield 41.8%.

[0385] 1 H NMR (500MHz, DMSO-d6) δ12.58(s,1H),11.32(s,1H),8.93(s,1H),7.28(t,J=8.2Hz,1H),7.01(d,J=7.9Hz,1H),6.90(d,J=8.4Hz,1H),5. 26(t,J=3.7Hz,1H),4.27(d,J=5.2Hz,1H),2.98(dt,J=10.1,5.4Hz,1H),2.94–2.88(m,1H),2.07(td,J=14.1,4.1Hz,1H),1.87–1.77(m,2 H),1.70(t,J=13.4Hz,2H),1.63–1.53(m,3H),1.52–1.40(m,6H),1.37(dd,J=11.2,6.7Hz,2H),1.26(q,J=12.8,11.8Hz,1H),1.21–1.11 (m,3H),1.10(s,3H),1.00(d,J=13.9Hz,1H),0.92(s,3H),0.90(s,3H),0.87(s,3H),0.81(s,3H),0.66(s,1H),0.64(s,3H),0.60(s,3H).

[0386] 13C NMR(151MHz,DMSO-d6)δ172.82,159.35,144.70,143.61,133.17,131.79,1 21.86,120.17,116.15,115.17,76.82,54.78,47.09,45.58,45.24,41.15, 40.06, 38.86, 38.35, 38.02, 36.55, 33.30, 32.80, 32.24, 32.12, 30.36, 28.20, 27.04, 26.93, 25.74, 23.58, 22.94, 21.93, 17.92, 16.63, 15.97, 15.03.

[0387] Example 46

[0388] Example 46 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 3-fluoro-salicylaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0389]

[0390] Its NMR data are as follows:

[0391] White solid, yield 54.8%.

[0392] 11H NMR (500 MHz, Chloroform-d) δ 11.15 (s, 1H), 8.97 (s, 1H), 8.51 (s, 1H), 7.11 (t, J = 10.2 Hz, 1H), 6.99 (d, J = 7.7 Hz, 1H), 6.82 (td, J = 7.9, 4.4 Hz, 1H), 5.59–5.53 (m, 1H), 3.21 (dd, J = 11.4, 4.2 Hz, 1H), 2.66–2.58 (m, 1H), 2.08 (td, J = 13.8, 3.8 Hz, 1H), 1.99 (dd, J = 7.3, 3.5 Hz, 2H), 1.82 (t, J = 13.3 Hz, 2H), 1.74 (d, J = 3.8 Hz, 1H), 1.70 (dd, J = 14.1, 4.2 Hz, 1H), 1.62 (d, J = 4.6 Hz, 5H), 1.56 (t, J = 12.4 Hz, 3H), 1.43 (dtd, J = 31.5, 13.9, 13.2, 3.6 Hz, 3H), 1.35–1.30 (m, 1H), 1.30–1.23 (m, 3H), 1.20 (s, 3H), 1.11 (dt, J = 14.0, 3.3 Hz, 1H), 0.98 (s, 3H), 0.93 (s, 6H), 0.90 (s, 3H), 0.76 (s, 3H), 0.74 (s, 3H).

[0393] 13 13C NMR (151 MHz, Chloroform-d) δ 175.11, 151.56, 147.10, 147.02, 145.33, 125.98 (d, J = 3.3 Hz), 124.14, 119.85 (d, J = 3.6 Hz), 118.92, 118.87, 118.27, 118.15, 55.18, 47.62, 46.78, 42.26, 41.92, 39.62, 38.90, 38.62, 37.06, 34.12, 33.03, 32.32, 32.16, 30.86, 28.21, 27.34, 27.27, 25.98, 24.38, 23.82, 23.65, 18.33, 16.97, 15.65, 15.52.

[0394] 19 19F NMR (565 MHz, CDCl3) δ -137.03.

[0395] Example 47

[0396] Example 47 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 6-fluoro-salicylaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0397]

[0398] Its NMR data are as follows:

[0399] White solid, yield 48.3%.

[0400] 1 H NMR(500MHz,Chloroform-d)δ11.32(s,1H),9.03(s,1H),8.48(s,1H),7.25–7.19(m,1H),6.77(d,J=8.4Hz,1H),6.62–6.53(m,1H),5.61–5. 54(m,1H),3.21(dd,J=11.3,4.2Hz,1H),2.63(dd,J=13.1,5.0Hz,1H),2.08(td,J=13.8,3.9Hz,1H),2.03–1.95(m,2H),1.87–1.79(m,2H),1 .74(dd,J=9.2,4.6Hz,1H),1.69(dd,J=14.2,4.4Hz,1H),1.63(d,J=3.7Hz,1H),1.60(dd,J=10.7,3.5Hz,5H),1.54(d,J=12.2Hz,2H),1.49– 1.31(m,4H),1.29–1.22(m,3H),1.20(s,3H),1.11(dt,J=14.1,3.4Hz, 1H),0.98(s,3H),0.94(s,6H),0.90(s,3H),0.76(s,3H),0.73(s,3H).

[0401] 13C NMR(151MHz,Chloroform-d)δ174.61,145.44,143.72(d,J=8.1Hz),132.45(d,J=10 .8Hz),124.11,113.29,107.12,107.04,105.54,105.40,79.08,55.19,47.62,46.7 5,46.60,42.27,41.98,39.62,38.90,38.61,37.06,34.11,33.04,32.28,32.17,30.86,28.21,27.36,27.27,25.98,24.40,23.81,23.66,18.33,17.02,15.64,15.48.

[0402] 19 F NMR (565MHz, CDCl3)δ-121.12.

[0403] Example 48

[0404] Example 48 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 5-fluorosalicylaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0405]

[0406] Its NMR data are as follows:

[0407] White solid, yield 49.7%.

[0408] 11H NMR (500 MHz, DMSO-d6) δ 11.16 (s, 1H), 11.00 (s, 1H), 8.50 (s, 1H), 7.32 (dd, J = 9.2, 3.2 Hz, 1H), 7.10 (td, J = 8.6, 3.1 Hz, 1H), 6.89 (dd, J = 9.0, 4.6 Hz, 1H), 5.27 (t, J = 3.6 Hz, 1H), 4.27 (d, J = 5.1 Hz, 1H), 2.98 (dt, J = 10.1, 5.5 Hz, 1H), 2.92 (dd, J = 13.4, 4.2 Hz, 1H), 2.03 (td, J = 13.8, 3.7 Hz, 1H), 1.81 (d, J = 6.3 Hz, 2H), 1.70 (t, J = 13.3 Hz, 2H), 1.55 (d, J = 12.5 Hz, 3H), 1.51–1.41 (m, 5H), 1.40–1.32 (m, 2H), 1.26 (q, J = 13.1, 12.4 Hz, 1H), 1.16 (t, J = 14.4 Hz, 3H), 1.10 (s, 3H), 0.98 (d, J = 14.3 Hz, 1H), 0.92 (s, 3H), 0.88 (d, J = 8.1 Hz, 6H), 0.81 (s, 3H), 0.67 (s, 1H), 0.64 (s, 3H), 0.60 (s, 3H).

[0409] 13 13C NMR (126 MHz, DMSO-d6) δ 172.80, 156.19, 154.33, 153.56, 145.38, 143.77, 121.79, 119.57 (d, J = 7.7 Hz), 117.71, 117.55 (d, J = 7.5 Hz), 114.37, 114.18, 76.84, 54.79, 47.11, 45.71, 45.27, 41.17, 38.89, 38.37, 38.04, 36.57, 33.39, 32.85, 32.27, 32.10, 30.39, 28.22, 26.99 (d, J = 12.6 Hz), 25.75, 23.60, 22.96, 21.96, 17.95, 16.72, 15.99, 15.05.

[0410] 19 19F NMR (471 MHz, DMSO) δ -125.10.

[0411] Example 49

[0412] Example 49 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 3-hydroxynaphthalene-2-carboxaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0413]

[0414] Its NMR data are as follows:

[0415] White solid, yield 47.8%.

[0416] 1 H NMR(500MHz,Chloroform-d)δ12.30(s,1H),9.30(s,1H),9.07(s,1H),7.95(d,J=8.5Hz,1H),7.78(dd,J=8.3,4.9Hz,2H),7.50(t,J=7.7Hz,1H),7.35(t, J=7.5Hz,1H),7.21(d,J=9.0Hz,1H),5.63(t,J=3.6Hz,1H),3.21(dd,J=11.5 ,4.3Hz,1H),2.69(dd,J=13.1,4.3Hz,1H),2.10(td,J=13.6,3.8Hz,1H),2.0 6–2.02(m,2H),1.86(q,J=13.7,13.3Hz,2H),1.76(td,J=13.9,4.2Hz,2H),1 .66–1.60(m,5H),1.59–1.50(m,2H),1.49–1.39(m,2H),1.39–1.31(m,2H),1 .29–1.24(m,3H),1.22(s,3H),1.13(dt,J=14.1,3.2Hz,1H),0.97(s,3H),0. 96(s,3H),0.95(s,3H),0.88(s,3H),0.78(s,3H),0.74(s,3H),0.72(s,1H).

[0417] 13C NMR(126MHz,Chloroform-d)δ174.77,159.27,148.18,145.53,133.22,132.25,12 9.30,128.25,127.59,124.05,123.56,119.88,119.62,108.09,55.19,47.63,46.7 9,46.64,42.28,42.01,39.65,38.87,38.61,37.06,34.16,33.05,32.33,32.17,30.88,28.19,27.38,27.25,25.99,24.38,23.87,23.69,18.31,17.09,15.62,15.45.

[0418] Example 50

[0419] Example 50 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 2-hydroxy-5-methoxybenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0420]

[0421] Its NMR data are as follows:

[0422] White solid, yield 57.8%.

[0423] 1H NMR(500MHz,Chloroform-d)δ10.57(s,1H),8.91(s,1H),8.38(s,1H),6.93(d,J=8.9Hz,1H),6.89(dd,J=9.0,2.8Hz,1H),6.71(d,J=2.8Hz,1H),5. 57–5.54(m,1H),3.77(s,3H),3.22(dd,J=11.2,4.2Hz,1H),2.62(d,J=12. 8Hz,1H),2.08(td,J=13.9,3.9Hz,1H),2.02–1.98(m,2H),1.87–1.80(m,2 H),1.73(d,J=13.8Hz,2H),1.62(d,J=7.6Hz,5H),1.50–1.45(m,1H),1.43 (s,1H),1.40(d,J=4.0Hz,1H),1.37(s,1H),1.34(s,1H),1.28(s,1H),1.2 5(s,2H),1.23(d,J=2.7Hz,1H),1.20(s,3H),1.11(d,J=14.0Hz,1H),0.98 (s,3H),0.94(s,6H),0.90(s,3H),0.77(s,3H),0.74(s,3H),0.72(s,1H).

[0424] Example 51

[0425] Example 51 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 5-nitrosalicylic acid is used instead of 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0426]

[0427] Its NMR data are as follows:

[0428] Yellow solid, yield 62.8%.

[0429] 1H NMR(500MHz,Chloroform-d)δ12.01(s,1H),9.12(s,1H),8.36(s,1H),8.18(d,J=8.1Hz,2H),7.09–7.04(m,1H),5.58(t,J=3.6 Hz,1H),3.21(dd,J=11.1,4.1Hz,1H),2.63(dd,J=13.1,4.7Hz,1H),2.10(td,J=13.8,3.9Hz,1H),2.04–1.98(m,2H),1.87–1.7 9(m,2H),1.71(td,J=13.9,4.2Hz,2H),1.62(d,J=9.3Hz,6H),1.57–1.53(m,2H),1.50–1.35(m,3H),1.27(tdd,J=12.5,6.8,1. 9Hz, 4H), 1.21 (s, 3H), 1.13 (dt, J=14.2, 3.5Hz, 1H), 0.98 (s, 3H), 0.94 (d, J=1.8Hz, 6H), 0.91 (s, 3H), 0.76 (s, 3H), 0.73 (s, 3H).

[0430] 13 C NMR(126MHz,Chloroform-d)δ175.07,164.00,148.08,145.35,140.41,127. 18,126.86,124.23,118.21,117.47,79.04,55.15,47.58,46.77,46.70,42. 27,41.89,39.61,38.89,38.61,37.06,34.06,32.99,32.27,32.14,30.84,28.20,27.33,27.25,25.98,24.45,23.83,23.63,18.31,17.00,15.65,15.58.

[0431] Example 52

[0432] Example 52 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 3,5-dibromosalicylaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0433]

[0434] Its NMR data are as follows:

[0435] White solid, yield 70.8%.

[0436] 1 H NMR(500MHz,Chloroform-d)δ11.84(s,1H),9.03(s,1H),8.44(s,1H),7.65(d,J=2.3Hz,1H),7.28(d,J=2.3Hz,1H),5.54(t,J=3.6Hz, 1H),3.21(d,J=10.7Hz,1H),2.61(dd,J=13.2,4.4Hz,1H),2.08(td,J=13.8,3.9Hz,1H),1.98(dd,J=9.1,3.6Hz,2H),1.84–1.78(m,2H ),1.71(dd,J=13.9,4.2Hz,2H),1.62(dd,J=9.2,4.0Hz,4H),1.59–1.52(m,3H),1.48–1.38(m,2H),1.37–1.31(m,2H),1.28–1.23(m,3 H),1.20(s,3H),1.10(dt,J=14.0,3.4Hz,1H),0.98(s,3H),0.93(s,6H),0.90(s,3H),0.77(s,3H),0.74(d,J=2.0Hz,1H),0.72(s,3H).

[0437] 13 C NMR(126MHz,Chloroform-d)δ175.18,154.47,149.25,145.24,136.88,132. 26,124.17,119.99,112.08,110.79,79.05,55.16,47.59,46.84,46.70,42. 23,41.86,39.58,38.88,38.61,37.05,34.07,33.00,32.28,32.15,30.83,28.20,27.30,27.25,25.97,24.34,23.80,23.65,18.32,16.97,15.65,15.57.

[0438] Example 53

[0439] Example 53 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 4-methyl-2-hydroxybenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0440]

[0441] Its NMR data are as follows:

[0442] White solid, yield 48.5%.

[0443] 1 H NMR(500MHz,Chloroform-d)δ10.95(s,1H),8.85(s,1H),8.32(s,1H),7.07(d,J=7.8Hz,1H),6.81(s,1H),6.71(d,J=7.8Hz,1H),5.55(s, 1H),3.21(dd,J=11.2,4.3Hz,1H),2.61(d,J=12.9Hz,1H),2.33(s,3H),2.08(dd,J=13.9,3.8Hz,1H),2.01–1.98(m,2H),1.87–1.82(m,2H ),1.71(td,J=14.1,4.7Hz,3H),1.62(d,J=8.6Hz,6H),1.47(d,J=12.5Hz,1H),1.43(s,1H),1.40(d,J=4.1Hz,1H),1.36(s,1H),1.33(s,1 H),1.29–1.27(m,2H),1.20(s,3H),1.10(d,J=14.1Hz,1H),0.98(s,3H),0.93(s,6H),0.89(s,3H),0.77(s,3H),0.74(s,3H),0.72(s,1H).

[0444] Example 54

[0445] Example 54 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 4-pyridine carboxaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0446]

[0447] Its NMR data are as follows:

[0448] White solid, yield 62.4%.

[0449] 1H NMR(500MHz,Chloroform-d)δ9.18(s,1H),8.64(d,J=6.1Hz,2H),8.25(s,1H),7.57(d,J=6.2Hz,2H),5.55(d,J=3.7Hz,1H),3.21(dd,J=1 1.3, 4.2Hz, 1H), 2.63 (d, J = 11.4Hz, 1H), 2.08 (td, J = 13.8, 3.9Hz, 1H), 1.99 (dd, J = 7.4, 3.4Hz, 2H), 1.84 (dd, J = 13.8, 8.2Hz, 2H), 1.71 (td, J=13.8,4.2Hz,4H),1.64–1.60(m,3H),1.58(t,J=3.6Hz,1H),1.56–1.52(m,1H),1.49–1.41(m,2H),1.41–1.35(m,2H),1.33(s,1H),1.28( s,1H),1.25(s,2H),1.20(s,3H),1.11(dt,J=14.1,3.4Hz,1H),0.98(s,3H),0.93(d,J=1.9Hz,6H),0.90(s,3H),0.76(s,3H),0.73(s,3H).

[0450] Example 55

[0451] Example 55 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 5-chlorosalicylaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0452]

[0453] Its NMR data are as follows:

[0454] Pale yellow solid, green solid, yield 81.4%.

[0455] 1H NMR (500MHz, CDCl3) δ11.04(s,1H),9.00(s,1H),8.27(s,1H),7.22(dd,J=8.8,2.6Hz,1H),7.16( d,J=2.6Hz,1H),6.92(d,J=8.8Hz,1H),5.55(t,J=3.7Hz,1H),3.21(dd,J=11.4,4.4Hz,1H),2.62( d,J=7.7Hz,1H),2.11–1.98(m,3H),1.84–1.63(m,6H),1.59–1.52(m,3H),1.48–1.22(m,8H),1.20 (s,3H),1.11(d,J=13.8Hz,2H),0.98(s,3H),0.93(s,6H),0.90(s,3H),0.76(s,3H),0.72(s,3H).

[0456] 13 C NMR (126MHz, CDCl3) δ174.8,157.3,149.5,145.4,131.6,130.0,124.1,123.9,118.9,118.7,79.0,55.2,47.6,46.7,42. 3,41.9,39.6,38.9,38.6,37.1,34.1,33.0,32.3,32.2,30.9,28.2,27.3,27.3,26.0,24.4,23.8,18.3,17.0,15.7,15.6.

[0457] Example 56

[0458] Example 56 provides an oleanolic acid hydrazone derivative with the following structural formula. The preparation method is the same as in Example 1, except that 4-fluoro-2-hydroxybenzaldehyde replaces the raw material 2-hydroxy-4-methoxybenzaldehyde in step S3.

[0459]

[0460] Its NMR data are as follows:

[0461] White solid, yield 64%.

[0462] 1H NMR(500MHz, CDCl3)δ10.82(s,1H),8.97(s,1H),8.33(s,1H),7.02–6.98(m,1H),6.94 –6.88(m,2H),5.56(t,J=3.6Hz,1H),3.21(dd,J=11.4,4.2Hz,1H),2.62(d,J=8.8Hz,1H ),2.11–1.98(m,3H),1.83–1.64(m,6H),1.57(t,3H),1.49–1.25(m,8),1.20(s,3H),1. 11(d,J=13.7Hz,2H),0.98(s,3H),0.93(s,6H),0.90(s,3H),0.77(s,3H),0.73(s,3H).

[0463] 13 C NMR (126MHz, CDCl3) δ174.9, 155.8 (d, J = 239.4Hz), 150.1, 145.4, 124.1, 118. 9,118.7,118.4(d,J=8.8Hz),117.7(d,J=8.8Hz),116.1(d,J=23.9Hz),79.1, 55.2,47.6,46.8,46.7,42.3,41.9,39.6,38.9,38.6,37.1,34.1,33.0,32.3,32.2,30.9,28.2,27.4,27.3,26.0,24.4,23.8,23.7,18.3,17.0,15.7,15.5.

[0464] 19 F NMR (471MHz, CDCl3) δ-125.5.

[0465] Performance testing

[0466] The oleanolic acid hydrazone derivatives prepared above were subjected to anti-human breast cancer cells MDA-MB-231 and human pancreatic cancer cells Mia paca-2 activity tests. The specific test methods are as follows:

[0467] 1. Experimental instruments and materials

[0468] Instrument: Multifunctional microplate reader

[0469] Material: CCK8 (Dojindo Molecular Technologies Inc., Japan)

[0470] 2. Experimental Methods

[0471] CCK8: After trypsin digestion and aspiration of cells in the logarithmic growth phase, an appropriate amount of DMEM medium was added, and the cells were gently pipetted to form a cell suspension. After cell counting, the cells were seeded in 96-well plates and incubated overnight (MDA-MB-231: 6000 / well, Miapac-2: 3000 / well). The next day, different concentrations of the compound were added for co-culture. After 72 hours, CCK8 (DojindoMolecular Technologies Inc., Japan) was added to each well and incubated for 2–4 hours. The absorbance values ​​of OD450 and OD650 were measured on an Envision multilabel Reader (Perkin Elmer). The cell viability (V%) per well was calculated using the formula: V(%) = (As-Ac) / (Ab-Ac) × 100. (A: OD450-OD650, s: sample, b: blank, c: control). The antiproliferative IC50 of the compound was calculated using GraphPadPrism 9.5 software. 50 Each dose was repeated three times. The experiment was then repeated at least three times. The results are shown in Table 1.

[0472] Table 1

[0473]

[0474]

[0475] As can be seen from Table 1, the IC50 of the oleanolic acid hydrazone derivatives provided by this invention is... 50 It has a low value and a strong inhibitory effect on human breast cancer cells MDA-MB-231 and human pancreatic cancer cells Mia paca-2.

[0476] The present invention has been described in detail above with reference to the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention.

Claims

1. An oleanolic acid acylhydrazone derivative, characterized in that, It has the following structural formula as shown in Equation I: Wherein, R is selected from halogen-substituted pyridine, hydroxyl-substituted naphthyl, ... R1 is one or more substituents; each is independently selected from halogens, C 1～6 alkyl, C 1～6 alkoxy, C 1～6 Halogenated alkyl, nitro, hydroxyl, carboxyl, amino, cyano, C 2～6 alkenyl, C 2～6 alkynyl group, C 2～6 Halogenated alkyl carbonyl, When R is selected When R is not R2 and R3 are independently selected from C 1～6 Alkyl groups.

2. The oleanolic acid acylhydrazone derivative according to claim 1, characterized in that, R1 is one or more substituents; each is independently selected from halogens, C 1～4 alkyl, C 1～3 alkoxy, C 1～3 Halogenated alkyl, nitro, hydroxyl, carboxyl, amino, cyano, C 2～6 alkenyl, C 2～4 alkynyl group, C 2～4 Halogenated alkyl carbonyl, R2 and R3 are independently selected from C 1～3 Alkyl groups.

3. The oleanolic acid acylhydrazone derivative according to claim 1 or 2, characterized in that, The oleanolic acid hydrazone derivatives are selected from one of the following structural formulas:

4. The method for preparing oleanolic acid acylhydrazone derivatives according to any one of claims 1 to 3, characterized in that, Includes the following steps: The compound of formula III is obtained by reacting it with compound 1; The structural formulas of compound III and compound 1 are as follows:

5. The preparation method according to claim 4, characterized in that, The reaction temperature is 20–70°C.

6. The preparation method according to claim 4, characterized in that, The reaction time is 3.5 to 12.5 hours.

7. The preparation method according to claim 4, characterized in that, The molar ratio of compound III to compound 1 is 1:(1 to 1.5).

8. A pharmaceutical composition, characterized in that, Includes the oleanolic acid hydrazone derivatives as described in any one of claims 1 to 3; and pharmaceutically acceptable excipients.

9. The use of an oleanolic acid hydrazone derivative or the pharmaceutical composition of claim 8 in the preparation of therapeutic and / or preventive antitumor drugs; The oleanolic acid hydrazone derivative has the structural formula shown in Formula II: in, R4 is selected from halogen-substituted pyridine, hydroxyl-substituted naphthyl, etc. R5 is one or more substituents; each is independently selected from halogens, C 1～6 alkyl, C 1～6 alkoxy, C 1～6 Halogenated alkyl, nitro, hydroxyl, carboxyl, amino, cyano, C 2～6 alkenyl, C 2～6 alkynyl group, C 2～6 Halogenated alkyl carbonyl, R6 and R7 are independently selected from C 1～6 Alkyl groups.

10. The application according to claim 9, characterized in that, The tumors include breast cancer and pancreatic cancer.

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