A stilbene compound, pharmaceutical composition and use thereof

Abstract

The application provides a stilbene compound, a pharmaceutical composition and application thereof, relates to the technical field of medicinal chemistry, and the main skeleton of the compound is a stilbene with a urea group; a series of high-activity stilbene compounds are obtained by expanding different substituents on both sides of the urea group and synthesizing a stilbene side skeleton containing an advantage structure of a natural product; the IC50 value of the high-activity stilbene compound to soluble epoxide hydrolase inhibition reaches the nanomolar level, indicating that the stilbene compound has a high inhibition effect on soluble epoxide hydrolase inhibition enzyme, so that the inhibition effect on inflammation can be realized by inhibiting soluble epoxide hydrolase inhibition enzyme, and the stilbene compound has a good application prospect.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry, and in particular to a stilbene compound, a pharmaceutical composition, and its applications. Background Technology

[0002] Inflammation is a common symptom and a complex pathophysiological process involving multiple enzymes, mediators, and receptors. Typical physiological features of inflammation include redness, swelling, fever, pain, and even organ dysfunction. Current research indicates that the arachidonic acid (AA) pathway produces active mediators that regulate a range of different inflammatory processes. Cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 are the three main pathways regulating arachidonic acids.

[0003] Epoxyeicosatrienoic acids (EETs), produced via the cytochrome P450 pathway, are beneficial arachidonic acid metabolites and important signaling molecules in organisms, playing roles in regulating gene expression, ion transport, anti-apoptosis, vasodilation, and anti-inflammation. EETs are degraded in vivo through multiple pathways, including hydrolysis by soluble epoxide hydrolase (sEH) to produce dihydroxydi(2-hydroxy)-2-ethylhexylene( ...

[0004]

[0005] Dihydroxyeicosatrienoic acids (DHETs) are the most important metabolic pathway. Decreased EET concentrations and increased DHET concentrations in the body can induce inflammation. Therefore, inhibiting sEH activity to increase EET concentrations in the body can effectively treat inflammation and related diseases. Current research also indicates that sEH is closely related to cardiovascular, central nervous system, and metabolic diseases.

[0006] To date, AR9281, GSK2256294, and EC5026 have entered clinical trials, but no sEH inhibitor drugs are currently on the market. Numerous compounds in natural products have also shown inhibitory effects on sEH, such as natural ureas, triterpenoids, flavonoids, and phenylpropionic acid. Unfortunately, many compounds reported as sEH inhibitors have low IC50 values. 50 The values ​​were all at the micromolar level and were not valuable for further preclinical research.

[0007] Therefore, there is an urgent need for an IC50 inhibitor targeting the anti-inflammatory target of soluble epoxide hydrolases.50 A novel skeleton-soluble epoxide hydrolase inhibitory compound with values ​​all at the nanomolar level. Summary of the Invention

[0008] This invention provides a stilbene compound, a pharmaceutical composition, and their applications, to address the IC50 limitations of existing soluble epoxide hydrolase inhibitors. 50 The problem is that the drug value is relatively high, but the drug-like properties are poor.

[0009] In a first aspect, the present invention provides a stilbene compound having the following general structural formula I:

[0010]

[0011] In equation I, R 1 R 2 The groups can be combined to form a methylenedioxy group, or independently selected from methoxy, hydroxy, hydrogen, and any one of the following R1-R9 groups, the structural formulas of which are as follows:

[0012]

[0013] R 3 Selected from any one of the groups: methoxy or hydrogen;

[0014] R 4 Selected from C 1-4 Alkyl, tetrahydropyranyl, N-(C 1-4 Any one of the groups selected from alkylformyl)piperidinyl and 4-trifluoromethoxyphenyl;

[0015] X and Y are each selected from any one of the following groups: methyl, hydrogen, fluorine, and chlorine.

[0016] Based on the first aspect, when the urea group of the compound is located at the para position of the stilbene skeleton, the general structural formula is shown in Formula II:

[0017]

[0018] In formula II, R 1 R 2 R 3 R 4 X and Y are defined in the same way as the groups described in claim 1.

[0019] Based on the first aspect, when the urea group of the compound is located in the meta position of the stilbene skeleton, and when X = Y = H, the general structural formula is shown in formula Ш:

[0020]

[0021] In the formula Ш, R 1 R 2 R 3 R 4 X and Y are defined in the same way as the groups described in claim 1.

[0022] Based on the first aspect, the compound according to claim 1, characterized in that the R of the compound... 1 R 2 Combined to form a methylenedioxy group, or independently selected from any one of the groups R1-R9;

[0023] R 3 Selected from any one of the groups: methoxy or hydrogen;

[0024] R 4 It is selected from any one of the following groups: isopropyl, isobutyl, tetrahydropyranyl, N-acetylpiperidinyl, N-propionylpiperidinyl, and 4-trifluoromethoxyphenyl.

[0025] Based on the first aspect, X of the compound is selected as hydrogen, and Y of the compound is selected as hydrogen.

[0026] Based on the first aspect, the R of the compound 1 R 2 R was chosen as methylenedioxy. 3 Hydrogen was chosen, R 4 X is selected as a tetrahydropyranyl group, and Y is selected as hydrogen; or

[0027] The compound's R 1 Selected as methoxy, R 2 Hydrogen was chosen, R 3 It is a methoxy group, R 4 X is selected as a tetrahydropyranyl group, and Y is selected as hydrogen; or

[0028] The compound's R 1 Choose any one of the R1-R9 groups, R 2 Hydrogen was chosen, R 3 Hydrogen was chosen, R 4 X is selected as a tetrahydropyranyl group, and Y is selected as hydrogen; or

[0029] The compound's R 2 Choose any one of the R1-R9 groups, R 1 Hydrogen was chosen, R 3 Hydrogen was chosen, R 4 X was chosen as tetrahydropyranyl, Y was chosen as hydrogen.

[0030] Furthermore, the structural formula of the compound is as follows:

[0031]

[0032] Based on the first aspect, the specific structural formula of the compound is as follows:

[0033]

[0034]

[0035] In a second aspect, the present invention provides a stilbene compound pharmaceutical composition comprising at least one of the compounds, isotope labels thereof, solvates, polymorphs thereof, pharmaceutically acceptable salts thereof, or prodrug compounds thereof, as described in any one of the first aspects above.

[0036] Thirdly, the present invention provides the use of a stilbene compound as described in any of the first aspects above, or a stilbene compound pharmaceutical composition as described in the second aspect above, in the preparation of an anti-inflammatory drug.

[0037] This invention has the following advantages:

[0038] (1) The present invention provides a stilbene compound, which is a derivative of a novel stilbene skeleton, and the IC50 of the compound against soluble epoxy hydrolases is at the nanomolar level, which is higher than that of natural products at the micromolar level.

[0039] (2) The skeleton of the stilbene compound prepared by the present invention contains the dominant structure of natural product - stilbene, which can improve the drug-likeness of soluble epoxy compound hydrolase inhibitory drug composition. Detailed Implementation

[0040] The following embodiments are provided to better understand the present invention and are not limited to the preferred embodiments described. They do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the protection scope of the present invention.

[0041] Specific experimental steps or conditions are not specified in the examples; however, they can be performed according to conventional experimental procedures or conditions described in the prior art. All chemicals used in this invention are commercially available, and the nuclear magnetic resonance and mass spectrometry instruments used to determine the structures of the following compounds were provided by the Analysis and Testing Center of Beijing Institute of Technology.

[0042] The first aspect of this invention provides a stilbene compound having the general formula shown in Formula I:

[0043]

[0044] In equation I, R 1 R 2 The groups can be combined to form a methylenedioxy group, or independently selected from methoxy, hydroxy, hydrogen, and any one of the following R1-R9 groups, the structural formulas of which are as follows:

[0045]

[0046] R 3 Selected from any one of the groups: methoxy or hydrogen;

[0047] R 4 Selected from C 1-4 Alkyl, tetrahydropyranyl, N-(C 1-4 Any one of the groups selected from alkylformyl)piperidinyl and 4-trifluoromethoxyphenyl;

[0048] X and Y are each selected from any one of the following groups: methyl, hydrogen, fluorine, and chlorine.

[0049] The above C 1-4 Alkyl groups represent straight-chain or branched saturated monovalent hydrocarbon groups having 1 to 4 carbon atoms. For example, C 1-4 Alkyl refers to straight-chain and branched alkyl groups having 1, 2, 3, or 4 carbon atoms, such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, etc.

[0050] The above C 1-4 alkylformyl group is represented by RC (=O)-, where R is C 1-4 Alkyl group. The alkyl formyl group is, for example, acetyl, propionyl, butyryl, valeryl, isobutyryl, etc.

[0051] In a second aspect, embodiments of the present invention also provide a stilbene compound pharmaceutical composition comprising at least one of the compounds described in the first aspect above, their isotopic labels, solvates, polymorphs, pharmaceutically acceptable salts, or prodrug compounds.

[0052] In a third aspect, embodiments of the present invention also provide the use of the stilbene compound described in the first aspect above, or the stilbene compound pharmaceutical composition described in the second aspect above, in the preparation of anti-inflammatory drugs.

[0053] This invention also provides a method for preventing and / or treating inflammation-related diseases, comprising administering to a patient a preventive or therapeutically effective amount of at least one of the following: a compound of formula (I), its racemic mixture, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable salt, its prodrug compound, or the pharmaceutical composition thereof.

[0054] In some alternative implementations, the patient is a mammal, preferably a human.

[0055] The pharmaceutical compositions in the embodiments of this invention also include any and all solvents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic agents, and absorption delay agents for pharmaceutically active substances, which are reagents and materials known in the art. The use of any conventional media or reagents in the pharmaceutical compositions is contemplated, except for any conventional media or reagents incompatible with the compound, and complementary compounds may also be added to the compositions.

[0056] In embodiments of the present invention, various pharmaceutically acceptable acids can form pharmaceutically acceptable salts on the basic nitrogen of the compound. The acid can be an inorganic or organic acid; the inorganic acid is hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, or phosphoric acid; the organic acid is acetic acid, malonic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, citric acid, maleic acid, fumaric acid, malic acid, or citric acid.

[0057] The prodrug compounds in this specification are compounds that, although not disclosed in structure, are administered to the human body but are metabolized or converted into the compounds disclosed herein, and exert their pharmacological effects as active ingredients. Conventional methods for the preparation of prodrugs are described in *Design of Prodrugs* (H. Bundgaad, Elsevier, 1985).

[0058] The term "patient" refers to any animal, including mammals. In this embodiment of the invention, mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates are preferred, with humans being the most preferred.

[0059] The therapeutically effective amount refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians are searching for in tissues, systems, animals, individuals, or humans to elicit a biological or medical response, and includes one or more of the following: (1) prevention of disease: for example, prevention of disease, disorder, or condition in individuals who are susceptible to disease, disorder, or symptom but have not yet experienced or developed the pathology or symptoms of the disease. (2) suppression of disease: for example, suppression of disease, disorder, or symptom in individuals who are experiencing or developing the pathology or symptoms of the disease (i.e., preventing further development of the pathology and / or symptoms). (3) relief of disease: for example, relief of disease, disorder, or symptom in individuals who are experiencing or developing the pathology or symptoms of the disease (i.e., reversal of the pathology and / or symptoms).

[0060] To enable those skilled in the art to further understand the technical solution of the present invention, the following specific embodiments are provided to further illustrate a stilbene compound, a pharmaceutical composition and its application provided by the present invention.

[0061] The following is a brief description of the synthesis method of the stilbene compounds of the present invention. In the synthesis examples listed below, the synthesis of intermediates mainly involves Heck reactions, reduction reactions, and acylation reactions.

[0062] Specifically, the following provides methods for synthesizing representative compounds of the present invention.

[0063] Synthesis Example 1 - Synthesis of Compound C1:

[0064]

[0065] The synthetic route for compound C1-1a is as follows:

[0066]

[0067] Methyltriphenylphosphine bromide (60 mmol, 21.42 g) was dissolved in 120 mL of dry tetrahydrofuran solution, and potassium tert-butoxide (100 mmol, 11.2 g) was added. The reaction was carried out at 0 °C for 10 min under argon protection. Then, piperonaldehyde (40 mmol, 6 g) was added to the reaction system, and the mixture was stirred for another 5 h. After the reaction was completed, saturated ammonium chloride solution was added to terminate the reaction. The mixture was extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, concentrated by rotary evaporation, and dried to obtain crude piperonethylene. Column chromatography (100-200 mesh silica gel, mobile phase: V(petroleum ether):V(ethyl acetate) = 15:1) yielded a colorless, transparent liquid compound, piperonethylene (compound C1-1a).

[0068] The synthetic route for compound C1-1b is as follows:

[0069]

[0070] Piperine (compound C1-1a) (13.5 mmol, 1.71 mL) was dissolved in 50 mL of dry DMF, and potassium acetate (20.25 mmol, 1.99 g), palladium acetate (0.621 mmol, 0.14 g), tetrabutylammonium bromide (18.23 mmol, 5.88 g), and 4-nitro-1-iodobenzene (11.5 mmol, 2.86 g) were added. The reaction system was purged with argon five times and stirred at 80 °C for 5 h under argon protection. After the reaction was completed, distilled water was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The upper organic phase was washed successively with water and saturated brine, concentrated by rotary evaporation, and dried to obtain a solid (compound C1-1b).

[0071] The synthetic route for compound C1-1 is as follows:

[0072]

[0073] Compound C1-1b was dissolved in ethanol / water (1:1), and ammonium chloride (16.1 mmol, 0.86 g) and iron powder (25.7 mmol, 1.44 g) were added. The mixture was stirred at 95 °C for 5 h. After the reaction was complete, the mixture was extracted with ethyl acetate. The upper organic phase was washed successively with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution. The mixture was concentrated by rotary evaporation and dried to obtain a solid compound. Column chromatography (200-300 mesh silica gel, mobile phase: V(petroleum ether):V(ethyl acetate) = 10:1) yielded a pale yellow powdery solid compound C1-1 (1.68 g, yield 61.2%).

[0074] The synthetic route for compound C1 is as follows:

[0075]

[0076] Compound C1-1 (0.418 mmol, 0.1 g) was dissolved in 10 mL of dichloromethane, and 4-dimethylaminopyridine (DMAP) (0.84 mmol, 0.102 g) was added. Finally, carbonyl diimidazole (CDI) (0.84 mmol, 0.136 g) was added, and the reaction was carried out at room temperature for 6 h under an argon atmosphere. After the reaction was completed, the solid was concentrated by rotary evaporation. The obtained solid compound was redissolved in dry DMF, and isobutylamine (1.045 mmol, 0.1 mL) was added. The mixture was stirred at room temperature for 5 h. After the reaction was completed, distilled water was added to terminate the reaction. The mixture was extracted twice with ethyl acetate, and the organic phases were combined and washed successively with water, saturated ammonium chloride solution, and saturated sodium chloride solution. The mixture was concentrated by rotary evaporation and dried to give a pale yellow solid (compound C1) (0.103 g, yield 72.84%).

[0077] HRMS(ESI)(M+H) + m / z 339.1696, calcd for C 20 H 23 N2O3 + 339.1703.mp 237.1-239.6℃

[0078] 1 H NMR (400MHz, DMSO-d6) δ8.48(s,1H),7.39(q,4H),7.23(d,J=1.7Hz,1H),7.00(t,2H),6.98(dd,J=8.1,1.7Hz,1H),6.89(d,J =8.0Hz,1H),6.20(t,J=5.9Hz,1H),6.02(s,2H),2.92(t,J=6.3Hz,2H),1.69(dt,J=13.4,6.7Hz,1H),0.87(d,J=6.7Hz,6H). 13CNMR(100MHz,DMSO-d6)δ155.59,148.31,147.02,140.46,132.51,130.50,12 7.21,126.12,121.57,118.02,108.85,105.55,101.45,46.98,28.94,20.48.

[0079] Example 2 - Synthesis of compound C2:

[0080]

[0081] The synthetic route for compound C2 is as follows:

[0082]

[0083] Compound C1-1 (0.418 mmol, 0.1 g) was dissolved in 10 mL of dichloromethane, followed by the addition of 4-dimethylaminopyridine (0.84 mmol, 0.102 g), and finally carbonyl diimidazole (0.84 mmol, 0.136 g). The reaction was carried out under an argon atmosphere at room temperature for 6 h. After the reaction was complete, the mixture was concentrated by rotary evaporation to obtain a solid. The obtained solid compound was redissolved in dry DMF, and 4-aminomethyltetrahydropyran (1.045 mmol, 0.12 mL) was added. The mixture was stirred at room temperature for 5 h. After the reaction was complete, distilled water was added to terminate the reaction. The mixture was extracted twice with ethyl acetate, and the organic phases were combined and washed successively with water, saturated ammonium chloride solution, and saturated sodium chloride solution. The mixture was concentrated by rotary evaporation and dried to obtain a pale yellow solid (compound C2) (0.122 g, yield 76.73%). HRMS(ESI)(M+H) + m / z 381.1801, calcd for C 22 H 25 N2O4 + 381.1809.mp 257.7-259.3℃

[0084] 1H NMR (400MHz, DMSO-d6) δ8.51 (s, 1H), 7.44–7.35 (m, 4H), 7.22 (d, J = 1.7Hz, 1H), 7. 07–6.94(m,3H),6.89(d,J=8.0Hz,1H),6.25(t,J=5.9Hz,1H),6.02(s,2H),3.85( ddd,J=11.3,4.5,1.9Hz,2H),3.30–3.16(m,2H),3.00(t,J=6.2Hz,2H),1.64(ddt ,J=11.3,8.2,4.2Hz,1H),1.56(ddd,J=13.0,4.0,1.9Hz,2H),1.25–1.10(m,2H). 13 C NMR(100MHz,DMSO-d6)δ155.64,148.30,147.03,140.41,132.50,130.55,127.20,12 7.06,126.15,121.57,118.07,108.85,105.56,101.45,67.24,45.24,35.82,30.78.

[0085] Example 3 - Synthesis of compound C3:

[0086]

[0087] The synthetic route for compound C3 is as follows:

[0088]

[0089] Compound C1-1 (0.418 mmol, 0.1 g) was dissolved in 10 mL of dichloromethane, followed by the addition of 4-dimethylaminopyridine (0.84 mmol, 0.102 g), and finally carbonyl diimidazole (0.84 mmol, 0.136 g). The reaction was carried out under an argon atmosphere at room temperature for 6 h. After the reaction was complete, the mixture was concentrated by rotary evaporation to obtain a solid. The obtained solid compound was redissolved in dry DMF, and isoamylamine (1.045 mmol, 0.123 mL) was added. The mixture was stirred at room temperature for 5 h. After the reaction was complete, distilled water was added to terminate the reaction. The mixture was extracted twice with ethyl acetate, and the organic phases were combined and washed successively with water, saturated ammonium chloride solution, and saturated sodium chloride solution. The mixture was concentrated by rotary evaporation and dried to obtain a white solid (compound C3) (0.117 g, yield 79.59%). HRMS(ESI)(M+H) + m / z353.1851, calcd for C 21 H 25 N2O3 +353.1860.mp 216.5-218.2℃

[0090] 1 H NMR (400MHz, DMSO-d6) δ8.46(s,1H),7.46–7.31(m,4H),7.22(d,J=1.7Hz,1H),6.98(d,J=14.9Hz,3H),6.89(d,J=8.0Hz,1 H), 6.10 (t, J = 5.7Hz, 1H), 6.02 (s, 2H), 3.16–3.04 (m, 2H), 1.66–1.53 (m, 1H), 1.33 (q, J = 7.1Hz, 2H), 0.89 (d, J = 6.6Hz, 6H). 13 C NMR(100MHz,DMSO-d6)δ155.51,148.31,147.03,140.47,132.52,130.51,127.19,12 7.09,126.13,121.55,118.08,108.84,105.57,101.45,39.25,37.73,25.61,22.87.

[0091] Example 4 - Synthesis of compound C4:

[0092]

[0093] The synthetic route for compound C4-1 is as follows:

[0094]

[0095] Compound C1-1a (1.875 mmol, 0.24 mL) was dissolved in 5 mL of dry DMF. Potassium acetate (2.813 mmol, 0.28 g), palladium acetate (0.0938 mmol, 0.021 g), tetrabutylammonium bromide (2.531 mmol, 0.816 g), and 2-fluoro-4-iodoaniline (1.688 mmol, 0.4 g) were added. The reaction system was purged three times with argon and reacted at 80 °C for 5 h. After the reaction was completed, distilled water was added to terminate the reaction. The mixture was extracted with ethyl acetate, washed with water, saturated sodium bicarbonate, and saturated sodium chloride, respectively, concentrated by rotary evaporation, and dried to give a dark brown solid compound. Column chromatography (200-300 mesh silica gel, mobile phase: V(petroleum ether):V(ethyl acetate) = 10:1) gave a brownish-yellow powdery solid (compound C4-1) (0.26 g, yield 59.87%).

[0096] The synthetic route for compound C4 is as follows:

[0097]

[0098] Compound C4-1 (0.389 mmol, 0.1 g) was dissolved in 10 mL of dichloromethane, followed by the addition of 4-dimethylaminopyridine (0.778 mmol, 0.095 g), and finally carbonyl diimidazole (0.778 mmol, 0.126 g). The reaction was carried out at room temperature for 6 h under an argon atmosphere. After the reaction was completed, the mixture was concentrated by rotary evaporation to obtain solid compound C4-2. The obtained solid compound C4-2 was redissolved in dry DMF, and isobutylamine (0.973 mmol, 0.097 mL) was added. The mixture was stirred at room temperature for 5 h. After the reaction was completed, distilled water was added to terminate the reaction. The mixture was extracted twice with ethyl acetate, and the organic phases were combined and washed successively with water, saturated ammonium chloride solution, and saturated sodium chloride solution. The mixture was concentrated by rotary evaporation and dried to give a white solid (compound C4) (0.098 g, yield 70.71%). HRMS(ESI)(M+H) + m / z 357.1603, calcd for C 20 H 22 FN2O3 + 357.1609.226.9-229.8℃

[0099] 1 H NMR (400MHz, DMSO-d6) δ8.32(d,J=2.7Hz,1H),8.13(t,J=8.7Hz,1H),7.40(dd,J=13.0,1.9Hz,1H),7.27–7.20(m,2H),7.11–6.96(m ,3H),6.90(d,J=8.0Hz,1H),6.67(t,J=5.8Hz,1H),6.03(s,2H),2.97–2.91(m,2H),1.69(hept,J=6.7Hz,1H),0.88(d,J=6.7Hz,6H). 13 C NMR(100MHz,DMSO-d6)δ155.24,153.29,150.90,148.34,147.32,132.12,131.55,131.48,128.06,127.96,127.77 ,126.02,126.00,123.16,123.14,121.91,120.13,112.39,112.20,108.88,105.63,101.53,46.99,28.87,20.45.

[0100] Example 5 - Synthesis of compound C5:

[0101]

[0102] The synthetic route for compound C5-1 is as follows:

[0103]

[0104] C1-1a (1.875 mmol, 0.24 mL) was dissolved in 5 mL of dry DMF, and potassium acetate (2.813 mmol, 0.28 g), palladium acetate (0.0938 mmol, 0.021 g), tetrabutylammonium bromide (2.531 mmol, 0.816 g), and 3-fluoro-4-iodoaniline (1.688 mmol, 0.4 g) were added. The reaction system was purged with argon five times and then reacted at 80 °C for 5 h. After the reaction was completed, distilled water was added to terminate the reaction. The mixture was extracted with ethyl acetate, washed with water, saturated sodium bicarbonate, and saturated sodium chloride, respectively, concentrated by rotary evaporation, and dried to give a dark brown solid compound. Column chromatography (200-300 mesh silica gel, mobile phase V(petroleum ether):V(ethyl acetate) = 10:1) gave a brown powdery solid (compound C5-1) (0.23 g, yield 52.96%).

[0105] The synthetic route for compound C5 is as follows:

[0106]

[0107] Compound C5-1 (0.389 mmol, 0.1 g) was dissolved in 10 mL of dichloromethane, followed by the addition of 4-dimethylaminopyridine (0.778 mmol, 0.095 g), and finally carbonyl diimidazole (0.778 mmol, 0.126 g). The reaction was carried out under an argon atmosphere at room temperature for 6 h. After the reaction was complete, the mixture was concentrated by rotary evaporation to obtain a solid. The obtained solid compound was redissolved in dry DMF, and isobutylamine (0.973 mmol, 0.097 mL) was added. The mixture was stirred at room temperature for 5 h. After the reaction was complete, distilled water was added to terminate the reaction. The mixture was extracted twice with ethyl acetate, and the organic phases were combined and washed successively with water, saturated ammonium chloride solution, and saturated sodium chloride solution. The mixture was then concentrated by rotary evaporation and dried to obtain a white solid (compound C5) (0.102 g, yield 73.60%). HRMS(ESI)(M+H) + m / z357.1593, calcd for C 20 H 22 FN2O3 + 357.1609.mp 222.1-225.1℃

[0108] 1H NMR (400MHz, DMSO-d6) δ8.70(s,1H),7.55(t,J=8.8Hz,1H),7.48(dd,J=14.0,2.1Hz,1H),7.24(d,J=1.7Hz,1H),7.08–6.97(m,4H ),6.90(d,J=8.0Hz,1H),6.28(t,J=5.8Hz,1H),6.03(s,2H),2.96–2.90(m,2H),1.70(hept,J=6.7Hz,1H),0.87(d,J=6.8Hz,6H). 13 C NMR (100MHz, DMSO-d6) δ161.47,159.03,155.39,148.37,147.37,141.91,141.79,132.26,128.71,128.66,127.84,127.79 ,121.87,119.20,119.17,117.64,117.51,114.02,113.99,108.87,105.73,104.85,104.57,101.54,46.98,28.88,20.45.

[0109] Example 6 - Synthesis of compound C6:

[0110]

[0111] The synthetic route for compound C6-1a is as follows:

[0112]

[0113] C1-1a (1.875 mmol, 0.24 mL) was dissolved in 5 mL of dry DMF, and potassium acetate (2.813 mmol, 0.28 g), palladium acetate (0.0938 mmol, 0.021 g), tetrabutylammonium bromide (2.531 mmol, 0.816 g), and 3-methyl-4-iodonitrobenzene (1.688 mmol, 0.444 g) were added. The reaction system was protected with argon and reacted at 80 °C for 5 h. After the reaction was completed, distilled water was added to terminate the reaction. The mixture was extracted with ethyl acetate, washed with water, saturated sodium bicarbonate, and saturated sodium chloride, respectively, concentrated by rotary evaporation, and dried to obtain a dark brown solid compound (C6-1a).

[0114] The synthetic route for compound C6-1 is as follows:

[0115]

[0116] The obtained solid compound C6-1a was dissolved in ethanol / water (1:1), and ammonium chloride (4.22 mmol, 0.226 g) and iron powder (6.752 mmol, 0.377 g) were added. The mixture was stirred at 95 °C for 5 h. After the reaction was complete, the mixture was extracted with ethyl acetate. The upper organic phase was washed successively with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, and concentrated by rotary evaporation. Column chromatography (200-300 mesh silica gel, mobile phase: V(petroleum ether):V(ethyl acetate) = 10:1) yielded a brown powdery solid (compound C6-1) (0.24 g, yield 56.13%).

[0117] The synthetic route for compound C6 is as follows:

[0118]

[0119] Compound C6-1 (0.395 mmol, 0.1 g) was dissolved in 10 mL of dichloromethane, followed by the addition of 4-dimethylaminopyridine (0.79 mmol, 0.097 g), and finally carbonyl diimidazole (0.79 mmol, 0.128 g). The reaction was carried out under an argon atmosphere at room temperature for 6 h. After the reaction was complete, the solid was concentrated by rotary evaporation. The obtained solid compound was redissolved in dry DMF, and isobutylamine (0.988 mmol, 0.098 mL) was added. The mixture was stirred at room temperature for 5 h. After the reaction was complete, distilled water was added to terminate the reaction. The mixture was extracted twice with ethyl acetate, and the organic phases were combined and washed successively with water, saturated ammonium chloride solution, and saturated sodium chloride solution. The mixture was then concentrated by rotary evaporation and dried to give a white solid (compound C6) (0.083 g, yield 59.62%).

[0120] HRMS(ESI)(M+H) + m / z 353.1851, calcd for C 21 H 25 N2O3 + 353.1860.mp 190.6-192.8℃

[0121] 1 H NMR(400MHz, DMSO-d6)δ8.37(s,1H),7.48(d,J=8.5Hz,1H),7.27(d,J=1.7Hz,1H),7.26–7.11(m,3H),7.00(dd,J=8.2,1.7Hz,1H), 6.94–6.83(m,2H),6.16(t,J=5.8Hz,1H),6.02(s,2H),2.92(t,2H),2.33(s,3H),1.69(hept,J=6.7Hz,1H),0.87(d,J=6.7Hz,5H). 13C NMR(100MHz,DMSO-d6)δ155.60,148.30,147.04,140.25,136.29,132.78,129.29,127.45,12 5.80,124.56,121.68,119.45,115.94,108.81,105.82,101.45,46.99,28.95,20.48,20.25.

[0122] Example 7 - Synthesis of compound C7:

[0123]

[0124] The synthetic route for compound C7-1 is as follows:

[0125]

[0126] C1-1a (1.875 mmol, 0.24 mL) was dissolved in 5 mL of dry DMF, and potassium acetate (2.813 mmol, 0.28 g), palladium acetate (0.0938 mmol, 0.021 g), tetrabutylammonium bromide (2.531 mmol, 0.816 g), and 2-methyl-4-iodoaniline (1.688 mmol, 0.39 g) were added. The reaction system was protected with argon and reacted at 80 °C for 5 h. After the reaction was completed, distilled water was added to terminate the reaction. The mixture was extracted with ethyl acetate, washed with water, saturated sodium bicarbonate, and saturated sodium chloride, respectively, concentrated by rotary evaporation, and dried to give a dark brown solid compound. Column chromatography (200-300 mesh silica gel, mobile phase V(petroleum ether):V(ethyl acetate) = 10:1) gave a brownish-yellow powdery solid (compound C7-1) (0.23 g, yield 53.47%).

[0127] The synthetic route for compound C7 is as follows:

[0128]

[0129] Compound C7-1 (0.395 mmol, 0.1 g) was dissolved in 10 mL of dichloromethane, and 4-dimethylaminopyridine (0.79 mmol, 0.097 g) was added. Finally, carbonyl diimidazole (0.79 mmol, 0.128 g) was added, and the reaction was carried out at room temperature for 6 h under argon protection. After the reaction was completed, the solid was concentrated by rotary evaporation. The obtained solid compound was redissolved in dry DMF, and isobutylamine (0.988 mmol, 0.098 mL) was added. The mixture was stirred at room temperature for 5 h. After the reaction was completed, distilled water was added to the reaction solution to terminate the reaction. The mixture was extracted twice with ethyl acetate, and the organic phases were combined and washed successively with water, saturated ammonium chloride solution, and saturated sodium chloride solution. The mixture was concentrated by rotary evaporation and dried to give a white solid (compound C7) (0.096 g, yield 68.96%).

[0130] HRMS(ESI)(M+H) + m / z 353.1862, calcd for C 21 H 25 N2O3 + 353.1860.mp 220.6-222.2℃

[0131] 1 H NMR (400MHz, DMSO-d6) δ7.88(d,J=8.4Hz,1H),7.65(s,1H),7.32(d,J=2.1Hz,1H),7.27(dd,J=8.5,2.2Hz,1H),7.22(d,J=1.7Hz,1H),7.07–6.93(m, 3H),6.89(d,J=8.0Hz,1H),6.64(t,J=5.8Hz,1H),6.02(s,2H),2.93(t,J= 6.2Hz, 2H), 2.20 (s, 3H), 1.70 (hept, J = 6.7Hz, 1H), 0.89 (d, J = 6.7Hz, 6H). 13 C NMR(100MHz,DMSO-d6)δ155.75,148.31,147.04,138.33,132.51,130.96,128.43,127.09,12 6.63,126.33,124.77,121.56,120.32,108.85,105.57,101.45,47.08,28.95,20.54,18.46.

[0132] Example 8 - Synthesis of compound C8:

[0133]

[0134] The synthetic route for compound C8-1a is as follows:

[0135]

[0136] C1-1a (1.875 mmol, 0.24 mL) was dissolved in 5 mL of dry DMF, and potassium acetate (2.813 mmol, 0.28 g), palladium acetate (0.0938 mmol, 0.021 g), tetrabutylammonium bromide (2.531 mmol, 0.816 g), and 3-chloro-4-iodonitrobenzene (1.688 mmol, 0.478 g) were added. The reaction system was protected with argon and reacted at 80 °C for 5 h. After the reaction was completed, distilled water was added to terminate the reaction. The mixture was extracted with ethyl acetate, washed with water, saturated sodium bicarbonate, and saturated sodium chloride, respectively, concentrated by rotary evaporation, and dried to obtain a dark brown solid (compound C8-1a).

[0137] The synthetic route for compound C8-1 is as follows:

[0138]

[0139] The obtained solid compound C8-1a was dissolved in ethanol / water (1:1), and ammonium chloride (4.22 mmol, 0.226 g) and iron powder (6.752 mmol, 0.377 g) were added. The mixture was stirred at 95 °C for 5 h. After the reaction was complete, the mixture was extracted with ethyl acetate. The upper organic phase was washed successively with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, and concentrated by rotary evaporation. Column chromatography (200-300 mesh silica gel, mobile phase: V(petroleum ether):V(ethyl acetate) = 10:1) yielded a yellow powdery solid (compound C8-1) (0.21 g, yield 45.45%).

[0140] The synthetic route for compound C8 is as follows:

[0141]

[0142] Compound C8-1 (0.365 mmol, 0.1 g) was dissolved in 10 mL of dichloromethane, and 4-dimethylaminopyridine (0.79 mmol, 0.097 g) was added. Finally, carbonyl diimidazole (0.79 mmol, 0.128 g) was added, and the reaction was carried out at room temperature for 6 h under an argon atmosphere. After the reaction was completed, the solid was concentrated by rotary evaporation. The obtained solid compound was redissolved in dry DMF, and isobutylamine (0.988 mmol, 0.098 mL) was added. The mixture was stirred at room temperature for 5 h. After the reaction was completed, distilled water was added to the reaction solution to terminate the reaction. The mixture was extracted twice with ethyl acetate, and the organic phases were combined and washed successively with water, saturated ammonium chloride solution, and saturated sodium chloride solution. The mixture was concentrated by rotary evaporation and dried to give a white solid (compound C8) (0.113 g, yield 83.09%).

[0143] HRMS(ESI)(M+H) + m / z 274.0624, calcd for C 15 H 13 ClNO2 + 274.0629.

[0144] 1 H NMR(400MHz,DMSO-d6)δ7.49(d,J=8.6Hz,1H),7.18–7.09(m,2H),6.97(dd,J=8.1,1.7Hz,1H),6 .93–6.85(m,2H),6.62(d,J=2.3Hz,1H),6.55(dd,J=8.5,2.3Hz,1H),6.02(s,2H),5.57(s,2H). 13 C NMR(100MHz,DMSO-d6)δ150.04,148.31,147.04,133.31,132.56,127.53, 126.31,122.94,122.17,121.29,113.88,113.79,108.93,105.65,101.48.

[0145] Example 9 - Synthesis of compound C9:

[0146]

[0147] The synthetic route for compound C9-1a is as follows:

[0148]

[0149] The synthesis steps of compound C9-1a are similar to those of compound C1-1a. For details, please refer to the synthesis steps of compound C1-1a.

[0150] The synthetic route for compound C9-1b is as follows:

[0151]

[0152] The synthesis steps of compound C9-1b are similar to those of compound C1-1b. For details, please refer to the synthesis steps of compound C1-1b.

[0153] The synthetic route for compound C9-1 is as follows:

[0154]

[0155] The synthesis steps of compound C1-1 are similar to those of compound C1-1. For details, please refer to the synthesis steps of compound C1-1.

[0156] The synthetic route for compound C9 is as follows:

[0157]

[0158] Compound C9-1 (0.314 mmol, 0.08 g) was dissolved in 10 mL of dichloromethane, followed by the addition of 4-dimethylaminopyridine (0.627 mmol, 0.077 g), and finally carbonyl diimidazole (0.627 mmol, 0.102 g). The reaction was carried out under an argon atmosphere at room temperature for 6 h. After the reaction was complete, the mixture was concentrated by rotary evaporation to obtain a solid. The obtained solid compound was redissolved in dry DMF, and isobutylamine (1.568 mmol, 0.16 mL) was added. The mixture was stirred at room temperature for 5 h. After the reaction was complete, distilled water was added to terminate the reaction. The mixture was extracted twice with ethyl acetate, and the organic phases were combined and washed successively with water, saturated ammonium chloride solution, and saturated sodium chloride solution. The mixture was then concentrated by rotary evaporation and dried to obtain a pale yellow solid (compound C9) (0.084 g, yield 75.43%). HRMS(ESI)(M+H) + m / z355.2007, calcd for C 21 H 27 N2O3 + 355.2016.mp 166.6-168.3℃

[0159] 1 H NMR (400MHz, DMSO-d6) δ8.49(s,1H),7.49–7.35(m,4H),7.17(d,J=16.5Hz,1H),7.00(d,J=16.4Hz,1H),6.73(d,J=2.3Hz,2H), 6.38(t,J=2.2Hz,1H),6.20(t,J=5.8Hz,1H),3.77(s,6H),2.97–2.87(m,2H),1.69(hept,J=6.7Hz,1H),0.88(d,J=6.6Hz,6H). 13 C NMR (100MHz, DMSO-d6) δ161.12,155.58,140.85,139.98,130.16,129.30,127.55,126.33,118.02,104.62,99.92,55.65,47.00,28.94,20.47.

[0160] Example 10 - Synthesis of compound C10:

[0161]

[0162] The synthetic route for compound C10 is as follows:

[0163]

[0164] Compound C9-1 (0.2 mmol, 0.05 g) was added to a 100 mL round-bottom flask and dissolved with 10 mL of anhydrous dichloromethane. CDI (0.4 mmol, 0.065 g) and DMAP (0.4 mmol, 0.05 g) were added, and the mixture was allowed to react overnight for 12 h. After the reaction was complete, the solvent was evaporated to dryness, yielding a white powder. DMF (10 mL) was added and dissolved with stirring. 4-Aminomethyltetrahydropyran (0.5 mmol, 0.06 g) was added, and the mixture was allowed to react for 6 h. After the reaction was complete, distilled water was added to terminate the reaction. The mixture was extracted with ethyl acetate, and the organic phase was separated. The liquid phase was washed with saturated brine, evaporated to dryness, and recrystallized from the solvent using an ethyl acetate / petroleum ether system to give a white solid (compound C10) (0.054 g, yield 68.09%).

[0165] HRMS(ESI)(M+H) + m / z 397.2118, calcd for C 23 H 29 N2O4 + 397.2122.mp 188.4-190.2℃

[0166] 1 H NMR(400MHz, DMSO-D6)δ:8.57(s,1H),7.57–7.37(m,4H),7.17(d,J=16.4Hz,1H),7.01(d,J= 16.4Hz,1H),6.73(d,J=2.3Hz,2H),6.38(t,J=2.2Hz,1H),6.29(t,J=5.9Hz,1H),3.85(ddd, J=11.3,4.5,1.8Hz,2H),3.77(s,6H),3.27(td,J=11.7,2.1Hz,2H),3.00(t,J=6.2Hz,2H),1 .65(dqt,J=10.9,6.9,3.3Hz,1H),1.56(ddd,J=12.9,4.0,1.9Hz,2H),1.25–1.10(m,2H).13C NMR(100MHz,DMSO)δ161.11,155.62,140.81,139.97,130.17,129.62,129.29,12 7.54,126.33,118.03,106.89,104.60,99.91,67.24,55.64,45.23,35.82,30.78.

[0167] Example 11 - Synthesis of compound C11:

[0168]

[0169] The synthetic formula of compound C11-1 is as follows:

[0170]

[0171] In a 100 mL round-bottom flask under ice bath conditions, 4-aminomethylpiperidine (2.4 mmol, 0.274 g), 20 mL anhydrous dichloromethane, pyridine (2.64 mmol, 0.213 mL), and DMAP (0.24 mmol, 0.29 g) were added sequentially. Then, propionic anhydride (2.64 mmol, 0.339 mL) was dissolved in 10 mL anhydrous dichloromethane and added dropwise to the reaction mixture. The reaction was monitored by TLC with an iodine indicator. The reaction was terminated after 1 h. The solvent was evaporated to dryness, yielding a colorless, transparent liquid mixture. This mixture was then subjected to column chromatography (200-300 mesh silica gel) with a mobile phase of (V(DCM):V(ethanol):V(ammonia) = 10:1:0.1) to obtain a colorless, transparent liquid, 1-(4-(aminomethyl)piperidin-1-yl)propane-1-one (compound C11-1) (0.18 g, yield 44.05%), for later use.

[0172] The synthetic route for compound C11 is as follows:

[0173]

[0174] Compound C9-1 (0.2 mmol, 0.05 g) was added to a 100 mL round-bottom flask and dissolved with 10 mL of anhydrous dichloromethane. CDI (0.4 mmol, 0.065 g) and DMAP (0.4 mmol, 0.05 g) were added, and the mixture was allowed to react overnight for 12 h. After the reaction was complete, the solvent was evaporated to dryness, yielding a white powder C11-2. DMF (10 mL) was added and dissolved with stirring. Reserved C11-1 (0.5 mmol, 0.085 g) was added, and the mixture was allowed to react for 6 h. After the reaction was complete, distilled water was added to terminate the reaction. The mixture was extracted with ethyl acetate, and the organic phase was separated. The organic phase was washed with saturated brine, evaporated to dryness, and recrystallized from the solvent using an ethyl acetate / petroleum ether system to give a white solid (compound C11) (0.07 g, yield 77.7%).

[0175] HRMS(ESI)(M+H) + m / z 452.2505, calcd for C 26 H 34 N3O4 + 452.2553.mp 80.1-81.5℃

[0176] 1H NMR (400MHz, DMSO-D6) δ: 8.53 (s, 1H), 7.57–7.37 (m, 4H), 7.17 (d, J = 16.4Hz, 1H), 7.01 (d, J=16.3Hz,1H),6.73(d,J=2.3Hz,2H),6.38(t,J=2.2Hz,1H),6.28(t,J=5.9Hz,1H),4.39(d ,J=13.0Hz,1H),3.85(d,J=13.7Hz,1H),3.77(s,5H),3.04–2.89(m,3H),2.50(m,1H),2.2 9(q,J=7.4Hz,2H),1.71–1.61(m,3H),1.08(td,J=12.7,4.1Hz,1H),0.98(t,J=7.4Hz,4H). 13 C NMR(100MHz,DMSO)δ:171.44,161.11,155.60,140.78,139.96,130.20,129.29,127.54,126 .35,118.04,104.61,99.91,55.64,45.14,44.80,41.39,36.88,30.52,29.73,26.09,10.01.

[0177] Example 12 - Synthesis of compound C12:

[0178]

[0179]

[0180] The synthetic route for compound C12 is as follows:

[0181]

[0182] Methyltriphenylphosphine bromide (60 mmol, 21.42 g) was dissolved in a dry tetrahydrofuran solution, and potassium tert-butoxide (100 mmol, 11.2 g) was added. The mixture was stirred at 0 °C for 10 min under argon protection. 3-hydroxy-4-methoxybenzaldehyde (40 mmol, 6.086 g) was then added to the reaction system, and stirring continued for 5 h. After the reaction was complete, a saturated ammonium chloride solution was added to the reaction system, and the mixture was extracted three times with dichloromethane. The combined organic phases were washed with saturated sodium chloride solution, concentrated by rotary evaporation, and subjected to column chromatography (200-300 mesh silica gel, mobile phase: V(petroleum ether):V(ethyl acetate) = 15:1) to obtain a colorless, transparent liquid compound, 3-hydroxy-4-methoxystyrene, for later use. Using the method for compound C1, 4-iodoaniline (2.283 mmol, 0.5 g) was reacted with CDI and DMAP to introduce a carbonyl imidazole group, followed by reaction with isobutylamine. The reaction was then carried out by column chromatography (200-300 mesh silica gel, mobile phase: V(petroleum ether):V(ethyl acetate) = 10:1) and dried to give a white solid compound C12-1 (0.584 g, 80.41%). ¹H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.56–7.48 (m, 2H), 7.28–7.20 (m, 2H), 6.20 (t, J = 5.8 Hz, 1H), 2.91 (dd, J = 6.7, 5.8 Hz, 2H), 1.77–1.59 (m, J = 6.7 Hz, 1H), 0.86 (d, J = 6.7 Hz, 6.8 Hz, 6.8 Hz, 1H). H). Using the method for synthesizing compound C1, compound C12-1 (0.5 mmol, 0.16 g) underwent a Heck coupling reaction with 3-hydroxy-4-methoxystyrene (0.1 mL, 0.63 mmol), and the resulting white solid compound (compound C12) (0.086 g, 50.59%) was obtained by column chromatography (200-300 mesh silica gel, V(dichloromethane):V(ethanol) = 10:0.1).

[0183] HRMS(ESI)(M+H) + m / z 341.1865, calcd for C 20 H 25 N2O3 + 341.1860.mp 209.7-212.3℃.

[0184] 1H NMR (400MHz, DMSO-d6) δ8.96(s,1H),8.49(s,1H),7.39(q,J=8.9Hz,4H),7.00(d,J=1.9Hz,1H),6.97–6.83(m,4 H), 6.21 (t, J = 5.9Hz, 1H), 3.77 (s, 3H), 2.92 (t, J = 6.3Hz, 2H), 1.69 (hept, J = 6.7Hz, 1H), 0.87 (d, J = 6.7Hz, 7H). 13 C NMR(100MHz,DMSO-d6)δ155.62,147.81,147.07,140.31,131.01,130.65,12 7.12,126.37,118.47,118.02,113.16,112.71,56.11,46.99,28.94,20.48.

[0185] Example 13 - Synthesis of compound C13:

[0186]

[0187] The synthetic route for compound C13-1 is as follows:

[0188]

[0189] Add p-nitrostyrene (6.705 mmol, 1 g), iron powder (26.82 mmol, 1.5 g), and ammonium chloride (16.733 mmol, 0.9 g) to a 100 ml round-bottom flask, then add 30 ml of water and stir. Reflux at 95 °C for 2 h. After the reaction is complete, extract with ethyl acetate, filter to remove the residue, wash the liquid with saturated sodium bicarbonate, separate the liquid phase, wash the organic phase with saturated brine, and evaporate the solvent. Then, perform column chromatography (200-300 mesh silica gel, mobile phase V(petroleum ether):V(ethyl acetate) = 10:1) to obtain a colorless liquid p-aminostyrene (0.7 g, yield 87.72%). p-Aminostyrene (5.875 mmol, 0.7 g) and DMAP (11.7 mmol, 1.435 g) were added to a 100 mL round-bottom flask, followed by 20 mL of dichloromethane (DCM) and stirring to dissolve. Finally, CDI (11.71 mmol, 1.9 g) was added, and the reaction was allowed to proceed overnight. The solvent was then evaporated to dryness, and 20 mL of N,N-dimethylformamide (DMF) and 4-aminomethyltetrahydropyran (20.1 mmol, 2.315 g) were added. The reaction was allowed to proceed for 6 h. Water was added, and the mixture was extracted with ethyl acetate, washed with saturated brine, evaporated to dryness, and recrystallized from the ethyl acetate / petroleum ether system to give a white solid C13-1a (1.02 g, yield 65.4%). The obtained white solid C13-1a (1.536 mmol, 0.4 g), m-iodoaniline (1.706 mmol, 0.374 g), tetrabutylammonium bromide (2.303 mmol, 0.742 g), potassium acetate (2.559 mmol, 0.251 g), and palladium acetate (0.0853 mmol, 0.02 g) were added sequentially to a pressure flask, 10 mL of DMF was added, and the mixture was reacted under argon protection at 80 °C for 5 h. After the reaction was completed, distilled water was added to terminate the reaction. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried under evaporation. The solid was then subjected to column chromatography (200-300 mesh silica gel, V(DCM):V(methanol) = 10:0.1) to give a pink solid (compound C13-1) (0.2 g, yield 37.04%).

[0190] The synthetic route for compound C13 is as follows:

[0191]

[0192] 2-Pyridinecarboxylic acid (0.2736 mmol, 0.034 g) was added to a 100 mL round-bottom flask. Diisopropylethylamine (DIEA) (0.684 mmol, 0.088 g) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (0.2736 mmol, 0.104 g) were added to 30 mL DMF and stirred until dissolved. Finally, compound C13-1 (0.228 mmol, 0.08 g) was added. The reaction was terminated by adding distilled water. The mixture was extracted with ethyl acetate, and the organic phase was separated and washed with saturated ammonium chloride, saturated sodium bicarbonate, and saturated brine, respectively. The solvent was evaporated to dryness, and the mixture was recrystallized from the ethyl acetate / petroleum ether system to give a white solid (compound C13) (0.084 g, yield 80.77%).

[0193] HRMS(ESI)(M+H) + m / z 457.2228, calcd for C 27 H 29 N4O3 + 457.2234.mp 232.4-235.2℃

[0194] 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),8.76(d,J=4.7Hz,1H),8.51(s,1H),8.18(d,J=7. 8Hz,1H),8.14–8.05(m,2H),7.79(d,J=7.7Hz,1H),7.69(dd,J=7.6,4.8Hz,1H),7.48(d ,J=8.4Hz,2H),7.44–7.28(m,4H),7.11(q,J=16.4Hz,2H),6.24(t,J=5.9Hz,1H),3.89– 3.81(m,2H),3.27–3.13(m,2H),3.00(t,J=6.2Hz,2H),1.57(m,3H),1.25–1.07(m,2H).

[0195] 13 C NMR (100MHz, DMSO) δ162.93,155.66,150.32,148.92,140.89,139.13,138.65,138.46,130.14,129.46, 129.14,127.57,127.44,126.15,122.82,122.62,119.60,118.11,118.04,67.25,45.24,35.84,30.80.

[0196] Example 14 - Synthesis of compound C14:

[0197]

[0198] The synthetic route for compound C14 is as follows:

[0199]

[0200] 2-Pyridineacetic acid hydrochloride (0.2736 mmol, 0.047 g) was added to a 100 mL round-bottom flask. Then, DIEA (0.684 mmol, 0.088 g) and HATU (0.2736 mmol, 0.104 g) were added to 30 mL DMF and stirred until dissolved. Finally, compound C13-1 (0.228 mmol, 0.08 g) was added. The reaction was terminated by adding distilled water. The mixture was extracted with ethyl acetate, and the organic phase was separated. The organic phase was washed with saturated ammonium chloride, saturated sodium bicarbonate, and saturated brine, respectively. The solvent was evaporated to dryness, and the mixture was recrystallized from the ethyl acetate / petroleum ether system to give a white solid (compound C14) (0.062 g, yield 57.94%).

[0201] HRMS(ESI)(M+H) + m / z 471.2396, calcd for C 28 H 31 N4O3 + 471.2391.mp 193.7-195.2℃

[0202] 1 H NMR (400MHz, DMSO-d6) 1 H NMR (400MHz, DMSO-d6) δ10.25(s,1H),8.51(d,J=4.6Hz,2H),7.87–7.72(m,2H),7.43(dt,J=22.0,8.2Hz,6H),7.33–7.21(m,3H),7.05(s,2H),6. 24(t,J=5.9Hz,1H),3.85(d,J=13.5Hz,4H),3.27(td,J=12.0,2.4Hz,2H) ,3.00(t,J=6.3Hz,2H),1.70–1.52(m,3H),1.17(tt,J=12.2,6.0Hz,2H). 13C NMR (100MHz, DMSO) δ168.71,156.50,155.60,149.45,140.81,139.99,138.39,137.02,130.15,129.47,128.91 ,127.56,126.27,124.46,122.38,121.78,118.60,118.06,117.14,67.24,55.37,46.36,45.25,35.81,30.79.

[0203] Example 15 - Synthesis of compound C15:

[0204]

[0205] The synthetic route for compound C15 is as follows:

[0206]

[0207] 3-Pyridineacetic acid hydrochloride (0.2736 mmol, 0.047 g) was added to a 100 mL round-bottom flask. Then, DIEA (0.684 mmol, 0.088 g) and HATU (0.2736 mmol, 0.104 g) were added to 30 mL DMF and stirred until dissolved. Finally, compound C13-1 (0.228 mmol, 0.08 g) was added. The reaction was terminated by adding distilled water. The mixture was extracted with ethyl acetate, and the organic phase was separated. The organic phase was washed with saturated ammonium chloride, saturated sodium bicarbonate, and saturated brine, respectively. The solvent was evaporated to dryness, and the mixture was recrystallized from the ethyl acetate / petroleum ether system to give a white solid (compound C15) (0.046 g, yield 42.99%).

[0208] HRMS(ESI)(M+H) + m / z 471.2371, calcd for C 28 H 31 N4O3 + 471.2391.mp 198.2-200.3℃

[0209] 1H NMR (400MHz, DMSO-d6) δ10.29(s,1H),8.65(s,1H),8.55(d,J=2.3Hz,1H),8.47(dd,J= 4.8,1.7Hz,1H),7.82–7.74(m,2H),7.50–7.34(m,6H),7.31–7.21(m,2H),7.04(s,2H), 6.34(t,J=5.9Hz,1H),3.85(ddd,J=11.4,4.5,1.9Hz,2H),3.73(s,2H),3.27(td,J=11 .7,2.1Hz,2H),3.00(t,J=6.2Hz,2H),1.71–1.53(m,3H),1.18(qd,J=12.1,4.7Hz,2H).

[0210] 13 C NMR (100MHz, DMSO) δ169.07,155.66,150.68,148.27,140.88,139.90,138.42,137.23,132.12,130.08, 129.49,128.96,127.56,126.18,123.85,121.86,118.64,118.00,117.19,67.24,45.24,35.83,30.80.

[0211] Example 16 - Synthesis of compound C16:

[0212]

[0213] The synthetic route for compound C16 is as follows:

[0214]

[0215] Add 4-pyridineacetic acid hydrochloride (0.2736 mmol, 0.047 g) to a 100 mL round-bottom flask, add DIEA (0.684 mmol, 0.088 g) and HATU (0.2736 mmol, 0.104 g) to 30 mL DMF, stir to dissolve, and finally add compound C13-1 (0.228 mmol, 0.08 g). After the reaction is complete, add distilled water to terminate the reaction, extract with ethyl acetate, separate the liquid to obtain the organic phase, wash with saturated ammonium chloride, saturated sodium bicarbonate, and saturated brine, respectively, evaporate the solvent, recrystallize from the ethyl acetate / petroleum ether system to give a white solid (compound C16) (0.038 g, yield 35.51%).

[0216] HRMS(ESI)(M+H) +m / z 471.2386, calcd for C 28 H 31 N4O3 + 471.2391.mp 212.6-214.8℃

[0217] 1 H NMR (400MHz, DMSO-d6) δ10.27(s,1H),8.57–8.45(m,3H),7.79(t,J=1.8Hz,1H),7.50–7.23(m,9H),7.05(s,2H),6.27(t,J=6.0Hz,1H),3.85(d dd,J=11.2,4.5,1.9Hz,2H),3.72(s,2H),3.27(td,J=11.6,2.0Hz,2H),3.00(t,J=6.2Hz,2H),1.72–1.52(m,3H),1.18(qd,J=12.1,4.6Hz,2H). 13 C NMR (100MHz, DMSO) δ168.35,155.61,149.96,145.17,140.85,139.81,138.44,130.11,129.51,128 .98,127.57,126.19,125.13,121.92,118.65,118.04,117.22,67.24,45.24,42.90,35.82,30.79.

[0218] Example 17 - Synthesis of compound C17:

[0219]

[0220] The synthetic route for compound C17 is as follows:

[0221]

[0222] 2-Chloropyridine-5-acetic acid (0.2736 mmol, 0.047 g) was added to a 100 mL round-bottom flask, followed by 30 mL of DMF, DIEA (0.684 mmol, 0.088 g), and HATU (0.2736 mmol, 0.104 g). The mixture was stirred until dissolved, and finally compound C13-1 (0.228 mmol, 0.08 g) was added. After the reaction was complete, distilled water was added to terminate the reaction. The mixture was extracted with ethyl acetate, and the organic phase was separated. The organic phase was washed with saturated ammonium chloride, saturated sodium bicarbonate, and saturated brine, respectively. The solvent was evaporated to dryness, and the mixture was recrystallized from the ethyl acetate / petroleum ether system to give a white solid (compound C17) (0.046 g, yield 41.74%).

[0223] HRMS(ESI)(M+H) + m / z 505.1972, calcd for C 28 H 30 ClN4O3 + 505.2001.mp 207.7-208.9℃

[0224] 1 H NMR (400MHz, DMSO-d6) δ10.27(s,1H),8.54(s,1H),8.37(d,J=2.5Hz,1H),7.87–7.77(m,2H ),7.45(ddd,J=28.3,13.0,8.4Hz,6H),7.33–7.22(m,2H),7.05(s,2H),6.27(t,J=5.8Hz,1H ),3.85(ddd,J=11.4,4.7,1.9Hz,2H),3.75(s,2H),3.27(td,J=11.7,2.1Hz,2H),3.00(t,J =6.1Hz,2H),1.71–1.61(m,1H),1.56(dd,J=14.2,3.4Hz,2H),1.18(qd,J=12.0,4.6Hz,2H). 13 C NMR (100MHz, DMSO) δ168.69,155.60,150.84,149.05,141.15,140.84,139.81,138.42,131.67,130.09, 129.53,128.95,127.58,126.18,124.32,121.91,118.63,118.02,117.18,67.24,45.24,35.81,30.78.

[0225] Example 18 - Synthesis of compound C18:

[0226]

[0227] The synthetic route for compound C18 is as follows:

[0228]

[0229] N-Indoleacetic acid (0.2736 mmol, 0.048 g) was added to a 100 mL round-bottom flask. Then, DIEA (0.684 mmol, 0.088 g) and HATU (0.2736 mmol, 0.104 g) were added to 30 mL DMF and stirred until dissolved. Finally, compound C13-1 (0.228 mmol, 0.08 g) was added. The reaction was terminated by adding distilled water. The mixture was extracted with ethyl acetate, and the organic phase was separated. The organic phase was washed with saturated ammonium chloride, saturated sodium bicarbonate, and saturated brine, respectively. The solvent was evaporated to dryness, and the mixture was recrystallized from the ethyl acetate / petroleum ether system to give a pink solid (compound C18) (0.038 g, yield 35.51%).

[0230] HRMS(ESI)(M+Na) + m / z 531.2370, calcd for C 31 H 32 N4O3Na + 531.2367.mp 228.5-230.2℃

[0231] 1 H NMR (400MHz, DMSO-d6) δ10.44(s,1H),8.59(s,1H),7.83(t,J=1.8Hz,1H),7.57(d,J=7.8Hz,1 H),7.49–7.36(m,7H),7.35–7.23(m,2H),7.13(ddd,J=8.2,7.0,1.2Hz,1H),7.04(d,J=3.3Hz ,3H),6.50–6.42(m,1H),6.30(t,J=5.8Hz,1H),5.08(s,2H),3.85(ddd,J=11.4,4.5,1.8Hz,2 H),3.26(td,J=11.7,2.0Hz,2H),2.99(t,J=6.2Hz,2H),1.71–1.52(m,3H),1.24–1.14(m,2H). 13 C NMR (100MHz, DMSO) δ166.94,155.62,140.87,139.58,138.49,136.91,130.46,130.05,129.60,129.00,128.63,127.58,12 6.11,122.08,121.60,120.80,119.59,118.55,117.99,117.03,110.24,101.26,67.24,49.65,45.23,35.82,30.79,0.58.

[0232] Example 19 - Synthesis of compound C19:

[0233]

[0234] The synthetic route for compound C19 is as follows:

[0235]

[0236] 6-Quinolineacetic acid (0.2736 mmol, 0.051 g) was added to a 100 mL round-bottom flask. Then, DIEA (0.684 mmol, 0.088 g) and HATU (0.2736 mmol, 0.104 g) were added to 30 mL DMF and stirred until dissolved. Finally, compound C13-1 (0.228 mmol, 0.08 g) was added. The reaction was terminated by adding distilled water. The mixture was extracted with ethyl acetate, and the organic phase was separated. The organic phase was washed with saturated ammonium chloride, saturated sodium bicarbonate, and saturated brine, respectively. The solvent was evaporated, and the mixture was recrystallized from the ethyl acetate / petroleum ether system to give a pale yellow solid (compound C19) (0.064 g, yield 54.24%).

[0237] HRMS(ESI)(M+H) + m / z 521.2551, calcd for C 32 H 33 N4O3 + 521.2547.mp 182.7-184.3℃

[0238] 1 H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.87(dt,J=4.6,2.3Hz,1H),8.51(s,1H),8.36(dd,J=8.3,1.8Hz,1 H),8.03–7.95(m,1H),7.91(d,J=2.0Hz,1H),7.85–7.72(m,2H),7.53(dd,J=8.3,4.2Hz,1H),7.49–7.35(m ,5H),7.32–7.23(m,2H),7.05(s,2H),6.25(t,J=5.9Hz,1H),3.89(s,2H),3.85(ddd,J=11.5,4.5,1.8Hz, 2H), 3.26 (td, J=11.7, 2.1Hz, 2H), 3.00 (t, J=6.3Hz, 2H), 1.70–1.52 (m, 3H), 1.18 (qd, J=12.1, 4.5Hz, 2H). 13CNMR(100MHz,DMSO)δ169.38,155.59,150.65,147.28,140.81,139.97,138.40,136.16,134.85,131.78,130.12,129.51,12 9.27,128.92,128.25,128.16,127.58,126.22,122.04,121.84,118.65,118.04,117.18,67.23,45.24,43.61,35.80,30.78.

[0239] Example 20 - Synthesis of compound C20:

[0240]

[0241] The synthetic route for compound C20 is as follows:

[0242]

[0243] N-Carbazoleacetic acid (0.2736 mmol, 0.069 g) was added to a 100 mL round-bottom flask. Then, DIEA (0.684 mmol, 0.088 g) and HATU (0.2736 mmol, 0.104 g) were added to 30 mL DMF and stirred until dissolved. Finally, compound C13-1 (0.228 mmol, 0.08 g) was added. The reaction was terminated by adding distilled water. The mixture was extracted with ethyl acetate, and the organic phase was separated. The organic phase was washed with saturated ammonium chloride, saturated sodium bicarbonate, and saturated brine, respectively. The solvent was evaporated to dryness, and the mixture was recrystallized from the ethyl acetate / petroleum ether system to give a white solid (compound C20) (0.086 g, yield 67.7%).

[0244] HRMS(ESI)(M+H) + m / z 559.2712, calcd for C 32 H 33 N4O3 + 559.2704.mp 292.2-293.4℃

[0245] 1H NMR (400MHz, DMSO-d6) δ10.76 (s, 1H), 8.90 (s, 1H), 8.18 (dt, J = 7.8, 0.9Hz, 2H), 7.87 (t,J=1.8Hz,1H),7.63(d,J=8.2Hz,2H),7.49–7.36(m,6H),7.34–7.19(m,5H),7.03( s,2H),6.52(t,J=5.9Hz,1H),5.34(s,2H),3.84(ddd,J=11.5,4.5,1.8Hz,2H),3.26( td,J=11.7,2.0Hz,2H),2.99(t,J=6.1Hz,2H),1.68–1.53(m,3H),1.26–1.10(m,2H). 13 CNMR(100MHz,DMSO)δ166.91,155.73,141.24,140.98,139.66,138.48,129.93,129.57,128.98,127.55,126.19 ,126.03,122.73,122.11,120.65,119.51,118.54,117.88,116.95,109.86,67.24,46.42,45.21,35.85,30.80.

[0246] Example 21 - Synthesis of compound C21:

[0247]

[0248] The synthetic route for compound C21 is as follows:

[0249]

[0250] C13-1a (1.536 mmol, 0.4 g), p-iodoaniline (1.706 mmol, 0.374 g), tetrabutylammonium bromide (2.303 mmol, 0.742 g), potassium acetate (2.559 mmol, 0.251 g), and palladium acetate (0.0853 mmol, 0.02 g) were added sequentially to a pressure flask. 10 mL of DMF was added, and the mixture was reacted under argon protection at 80 °C for 5 h. After the reaction was complete, distilled water was added to terminate the reaction. The mixture was extracted with ethyl acetate, washed with saturated brine, and evaporated to dryness. The solid was then subjected to column chromatography (200-300 mesh silica gel, V(DCM):V(methanol) = 10:0.1) to give a white solid 36 (0.24 g, yield 44.44%). 2-Pyridineacetic acid hydrochloride (0.2736 mmol, 0.047 g) was added to a 100 mL round-bottom flask. Then, DIEA (0.684 mmol, 0.088 g) and HATU (0.2736 mmol, 0.104 g) were added to 30 mL DMF and stirred until dissolved. Finally, the aforementioned white solid (0.228 mmol, 0.08 g) was added. The reaction was terminated by adding distilled water. The mixture was extracted with ethyl acetate, and the organic phase was separated. The organic phase was washed with saturated ammonium chloride, saturated sodium bicarbonate, and saturated brine, respectively. The solvent was evaporated, and the mixture was recrystallized from the ethyl acetate / petroleum ether system to give a white solid (compound C21) (0.070 g, yield 65.42%).

[0251] HRMS(ESI)(M+H) + m / z 471.2397, calcd for C 28 H 31 N4O3 + 471.2391.mp 200.3-202.5℃

[0252] 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),8.74(s,1H),8.53–8.48(m,1H),7.76(td,J=7 .7,1.9Hz,1H),7.62(d,J=8.5Hz,2H),7.54–7.36(m,7H),7.27(ddd,J=7.6,4.9,1.2 Hz,1H),7.09–6.96(m,2H),6.41(t,J=5.9Hz,1H),3.86(m,4H),3.28(dd,J=11.8,2. 1Hz,2H),2.99(t,J=6.2Hz,2H),1.65(m,2H),1.60–1.51(m,2H),1.25–1.10(m,2H). 13CNMR(100MHz,DMSO)δ168.54,156.53,155.72,149.45,140.60,138.73,137.02,133.00,130.46,12 7.47,127.25,126.99,125.89,124.44,122.37,119.69,118.01,67.25,46.35,45.23,35.85,30.80.

[0253] Example 22 - Synthesis of compound C22:

[0254]

[0255] The synthetic route for compound C22-1 is as follows:

[0256]

[0257] Reagents and conditions for the reaction: a. 3-iodoaniline, tetrabutylammonium bromide, palladium acetate, potassium acetate, argon, 85℃; b. HATU, DIEA, DMF, 2-pyridineacetic acid; c. iron powder, ammonium chloride, water, 90℃;

[0258] 3-Iodoaniline (13.5 mmol, 3.348 g), p-nitrostyrene (16.2 mmol, 2.416 g), potassium acetate (20.25 mmol, 1.99 g), palladium acetate (0.621 mmol, 0.14 g), and tetrabutylammonium bromide (18.23 mmol, 5.88 g) were sequentially added to a 100 mL pressure flask, and 20 mL of dry DMF was added to dissolve the compounds. The reaction system was purged five times with argon gas and stirred at 80 °C for 5 h under argon protection. After the reaction was completed, distilled water was added to terminate the reaction. The mixture was extracted with ethyl acetate, and the upper organic phase was washed successively with water and saturated brine. The solvent was evaporated, and the mixture was then subjected to column chromatography (100-200 mesh silica gel, mobile phase pure DCM) to give a yellow solid (compound C22-1a).

[0259] Add the above yellow solid C22-1a (0.2736 mmol, 0.057 g) to a 100 ml round-bottom flask, dissolve it with 30 ml of dry DCM by stirring, add DIEA (0.684 mmol, 0.088 g), HATU (0.2736 mmol, 0.104 g), and finally add 2-aminomethylpyridine (0.228 mmol, 0.08 g). After the reaction was complete, distilled water was added to terminate the reaction. The mixture was extracted with ethyl acetate, and the organic phase was separated. The organic phase was washed with saturated ammonium chloride, saturated sodium bicarbonate, and saturated brine, respectively. The solvent was evaporated to dryness. The resulting solid mixture C22-1b was placed in a 100 ml round-bottom flask, and iron powder (26.82 mmol, 1.5 g) and ammonium chloride (16.733 mmol, 0.9 g) were added. 30 ml of water was added and the mixture was stirred and refluxed at 95 °C for 2 h. After the reaction was complete, the mixture was extracted with ethyl acetate, and the residue was removed by filtration. The liquid was washed with saturated sodium bicarbonate, and the organic phase was separated and washed with saturated brine. The solvent was evaporated to dryness. Column chromatography (200-300 mesh silica gel, mobile phase V(DCM):V(methanol) = 10:0.1) yielded a white solid (compound C22-1) (0.073 g, 81.1%).

[0260] 1 H NMR(400MHz, DMSO-d6)δ10.21(s,1H),8.51(ddd,J=4.9,1.9,1.0Hz,1H),7.81–7.72(m,2H),7.41(dt,J=7.9,1.2Hz,2H),7.31–7.2 2(m,4H),7.19(dt,J=7.8,1.4Hz,1H),6.97(d,J=16.3Hz,1H),6.85(d,J=16.3Hz,1H),6.60–6.52(m,2H),5.30(s,2H),3.86(s,2H).

[0261] The synthetic route for compound C22 is as follows:

[0262]

[0263] Compound C22-1 (0.209 mmol, 0.05 g) was added to a 100 mL round-bottom flask and dissolved with 10 mL of anhydrous dichloromethane. CDI (0.418 mmol, 0.068 g) and DMAP (0.418 mmol, 0.051 g) were added, and the mixture was allowed to react overnight for 12 h. After the reaction was complete, the solvent was evaporated to dryness, yielding a white powder. DMF (10 mL) was added and dissolved with stirring. 1-(4-(aminomethyl)piperidin-1-yl)propane-1-one (0.5 mmol, 0.036 g) was added, and the mixture was allowed to react for 6 h. After the reaction was complete, distilled water was added to terminate the reaction. The mixture was extracted with ethyl acetate, and the organic phase was separated. The liquid phase was washed with saturated brine, the solvent was evaporated to dryness, and the mixture was recrystallized from the ethyl acetate / petroleum ether system to give a white solid (compound C22) (0.061 g, yield 79.14%).

[0264] HRMS(ESI)(M+H) + m / z 526.2813, calcd for C 31 H 36 N5O3 + 526.2813.mp 183.2-184.8℃.

[0265] 1 H NMR(400MHz,DMSO-d6)δ10.28(d,J=5.1Hz,1H),8.64–8.43(m,2H),7.87–7.73 (m,2H),7.57–7.36(m,6H),7.35–7.22(m,3H),7.08(d,J=18.9Hz,2H),6.26(t, J=5.9Hz,1H),4.39(d,J=12.9Hz,1H),3.87(d,J=2.6Hz,3H),3.04–2.89(m,2H) ,2.48(s,1H),2.30(q,J=7.4Hz,2H),1.71–1.61(m,3H),0.98(t,J=7.4Hz,3H). 13 C NMR (100MHz, DMSO) δ171.43,168.73,156.50,155.57,149.47,140.78,139.99,138.37,137.04,130.13,129.50,128.88,127.58,1 26.25,124.49,122.40,121.76,118.71,118.55,118.02,117.09,46.35,45.13,44.79,41.38,36.87,30.52,29.73,26.09,10.02.

[0266] Example 23 - Synthesis of compound C23:

[0267]

[0268] The synthetic route for compound C23 is as follows:

[0269]

[0270] Compound C22-1 (0.209 mmol, 0.05 g) was added to a 100 mL round-bottom flask and dissolved with 10 mL of anhydrous dichloromethane. CDI (0.418 mmol, 0.068 g) and DMAP (0.418 mmol, 0.051 g) were added, and the mixture was allowed to react overnight for 12 h. After the reaction was complete, the solvent was evaporated to dryness, yielding a white powder. DMF (10 mL) was added and dissolved with stirring. 4-Trifluoromethoxybenzylamine (0.5 mmol, 0.096 g) was added, and the mixture was allowed to react for 6 h. After the reaction was complete, distilled water was added to terminate the reaction. The mixture was extracted with ethyl acetate, and the organic phase was separated. The liquid phase was washed with saturated brine, the solvent was evaporated to dryness, and the mixture was recrystallized from the ethyl acetate / petroleum ether system to give a white solid (compound C23) (0.066 g, yield 57.9%).

[0271] HRMS(ESI)(M+H) + m / z 547.1962, calcd for C 31 H 36 N5O3 + 547.1952.mp 220.5-221.8℃.

[0272] 1 H NMR (400MHz, DMSO-d6) δ10.26(s,1H),8.73(s,1H),8.52(dd,J=4.8,1.9Hz,1H),7.83(d,J=2.2Hz,1H),7.77(td,J=7.7,1.9Hz,1H),7.52–7.40( m,7H),7.41(d,J=2.2Hz,1H),7.34(d,J=8.3Hz,2H),7.33–7.22(m,3H),7.06(s,2H),6.73(t,J=6.0Hz,1H),4.34(d,J=5.9Hz,2H),3.87(s,2H). 13C NMR (100MHz, DMSO) δ168.73,156.50,155.55,149.46,147.57,140.62,140.51,139.99,138.35,137.03,130.34,129. 50,129.37,128.85,127.57,126.37,124.48,122.39,121.77,121.45,119.31,118.58,118.23,117.11,46.35,42.52.

[0273] Example 24 - Synthesis of compound C24:

[0274]

[0275] The synthetic route for compound C24 is as follows:

[0276]

[0277] 3-Iodobenzoic acid (13.5 mmol, 3.348 g), p-nitrostyrene (16.2 mmol, 2.416 g), potassium acetate (20.25 mmol, 1.99 g), palladium acetate (0.621 mmol, 0.14 g), and tetrabutylammonium bromide (18.23 mmol, 5.88 g) were sequentially added to a 100 mL pressure flask, and 20 mL of dry DMF was added to dissolve the precipitate. The reaction system was purged five times with argon gas and stirred at 80 °C for 5 h under argon protection. After the reaction was completed, distilled water was added to terminate the reaction. The mixture was extracted with ethyl acetate, and the upper organic phase was washed successively with water and saturated brine. The solvent was evaporated, and the mixture was then subjected to column chromatography (100-200 mesh silica gel, mobile phase pure DCM) to obtain a red solid C24-1a. Add C24-1a (0.2736 mmol, 0.048 g) to a 100 ml round-bottom flask, dissolve it with 30 ml of dry DCM by stirring, add DIEA (0.684 mmol, 0.088 g), HATU (0.2736 mmol, 0.104 g), and finally add 2-aminomethylpyridine (0.228 mmol, 0.08 g). After the reaction was complete, distilled water was added to terminate the reaction. The mixture was extracted with ethyl acetate, and the organic phase was separated. The organic phase was washed with saturated ammonium chloride, saturated sodium bicarbonate, and saturated brine, respectively. The solvent was evaporated to dryness. The resulting solid mixture C24-1b was placed in a 100 ml round-bottom flask, and iron powder (26.82 mmol, 1.5 g) and ammonium chloride (16.733 mmol, 0.9 g) were added. 30 ml of water was added, and the mixture was stirred and refluxed at 95 °C for 2 h. After the reaction was complete, the mixture was extracted with ethyl acetate, and the residue was removed by filtration. The liquid was washed with saturated sodium bicarbonate, and the organic phase was washed with saturated brine after separation. The solvent was evaporated to dryness. Column chromatography (200-300 mesh silica gel, mobile phase V(DCM):V(methanol) = 10:0.1) yielded a white solid C24-1c. Compound C24-1c (0.209 mmol, 0.05 g) was added to a 100 mL round-bottom flask and dissolved with 10 mL of anhydrous dichloromethane. CDI (0.418 mmol, 0.068 g) and DMAP (0.418 mmol, 0.051 g) were added, and the mixture was allowed to react overnight for 12 h. After the reaction was complete, the solvent was evaporated to dryness, yielding a white powder. DMF (10 mL) was added and dissolved with stirring. 4-Aminomethyltetrahydropyran (0.5 mmol, 0.036 g) was added, and the mixture was allowed to react for 6 h. After the reaction was complete, distilled water was added to terminate the reaction. The mixture was extracted with ethyl acetate, and the organic phase was separated. The liquid phase was washed with saturated brine, evaporated to dryness, and recrystallized from the ethyl acetate / petroleum ether system to give a white solid (compound C24) (0.054 g, yield 77.14%).

[0278] HRMS(ESI)(M+H) + m / z 471.2402, calcd for C 28 H31 N4O3 + 471.2391.mp 212.4-214.1℃

[0279] 1 H NMR(400MHz, DMSO-d6)δ9.47–9.43(s,1H),9.30(t,J=6.0Hz,1H),8.52(dt,J=4.9,1.4Hz,1H),8 .18(s,1H),7.84–7.67(m,3H),7.52–7.41(m,5H),7.36(d,J=8.0Hz,1H),7.33–7.25(m,2H),7.1 4(d,J=16.4Hz,1H),6.89(d,J=6.3Hz,1H),4.60(d,J=5.9Hz,2H),3.84(ddd,J=11.3,4.6,1.7Hz ,2H),3.26(td,J=11.7,1.9Hz,2H),2.99(t,J=6.0Hz,2H),1.69–1.55(m,3H),1.25–1.10(m,2H). 13 C NMR (100MHz, DMSO) δ166.82,159.34,155.93,149.26,141.31,138.16,137.22,135.04,129.85,129.77, 129.56,129.19,127.58,126.42,125.38,125.07,122.54,121.40,117.75,67.26,45.17,35.92,30.83.

[0280] Example 25 - Synthesis of compound C25:

[0281]

[0282] The synthetic route for compound C25-1 is as follows:

[0283]

[0284] C1-1a (6.75 mmol, 1 g), m-iodoaniline (6.075 mmol, 1.33 g), tetrabutylammonium bromide (9.113 mmol, 2.938 g), potassium acetate (10.125 mmol, 1 g), and palladium acetate (0.3375 mmol, 0.076 g) were added sequentially to a pressure flask, followed by the addition of 10 mL of DMF. The mixture was then reacted under argon protection at 80 °C for 5 h. After the reaction was complete, distilled water was added to terminate the reaction. The mixture was extracted with ethyl acetate, washed with saturated brine, and evaporated to dryness. The solid was then subjected to column chromatography (200-300 mesh silica gel, V(petroleum ether):V(ethyl acetate) = 10:1) to give a yellow solid (compound C25-1) (0.9 g, yield 63.7%).

[0285] The synthetic route for compound C25 is as follows:

[0286]

[0287] Compound C25-1 (0.209 mmol, 0.05 g) was added to a 100 mL round-bottom flask and dissolved with 10 mL of anhydrous dichloromethane. CDI (0.418 mmol, 0.068 g) and DMAP (0.418 mmol, 0.051 g) were added, and the mixture was allowed to react overnight for 12 h. After the reaction was complete, the solvent was evaporated to dryness, yielding a white powder. DMF (10 mL) was added and dissolved with stirring. Isobutylamine (0.5 mmol, 0.036 g) was added, and the reaction was allowed to continue for 6 h. After the reaction was complete, distilled water was added to terminate the reaction. The mixture was extracted with ethyl acetate, and the organic phase was separated. The liquid phase was washed with saturated brine, and the solvent was evaporated to dryness. The mixture was recrystallized from the ethyl acetate / petroleum ether system to give a white solid (compound C25) (0.054 g, yield 77.14%).

[0288] HRMS(ESI)(M+H) + m / z 339.1702, calcd for C 20 H 23 N2O3 + 339.1703.mp 219.8-221.6℃. 1H NMR (400MHz, DMSO-d6) δ8.40(s,1H),7.59(t,J=1.9Hz,1H),7.28(d,J=1.7Hz,1 H),7.24(dt,J=8.1,1.6Hz,1H),7.20(t,J=7.7Hz,1H),7.10(dt,J=7.6,1.6Hz,1 H),7.03(d,J=12.6Hz,3H),6.90(d,J=8.0Hz,1H),6.20(t,J=5.9Hz,1H),6.03(s ,2H),2.93(t,J=6.3Hz,2H),1.77–1.63(m,J=6.7Hz,1H),0.88(d,J=6.6Hz,6H). 13 C NMR(101MHz,DMSO)δ155.76,148.36,147.43,141.40,138.08,132.04,129.37,128.40, 127.50,122.08,119.58,117.29,115.85,108.85,105.89,101.54,47.01,28.96,20.48.

[0289] Example 26 - Synthesis of compound C26:

[0290]

[0291] The synthetic route for compound C26 is as follows:

[0292]

[0293] Compound C25-1 (0.209 mmol, 0.05 g) was added to a 100 mL round-bottom flask and dissolved with 10 mL of anhydrous dichloromethane. CDI (0.418 mmol, 0.068 g) and DMAP (0.418 mmol, 0.051 g) were added, and the mixture was allowed to react overnight for 12 h. After the reaction was complete, the solvent was evaporated to dryness, yielding a white powder. DMF (10 mL) was added and dissolved with stirring. 4-Aminomethyltetrahydropyran (0.5 mmol, 0.06 g) was added, and the mixture was allowed to react for 6 h. After the reaction was complete, distilled water was added to terminate the reaction. The mixture was extracted with ethyl acetate, and the organic phase was separated. The organic phase was washed with saturated brine, evaporated to dryness, and recrystallized from the solvent using an ethyl acetate / petroleum ether system to give a white solid (compound C26) (0.066 g, yield 83.1%).

[0294] HRMS(ESI)(M+H) + m / z 381.1803, calcd for C 22 H 25 N2O4 +381.1809.mp 207.0-208.6℃

[0295] 1 H NMR(400MHz, DMSO-D6)δ:8.42(s,1H),7.59(t,J=1.8Hz,1H),7.29(d,J=1.6Hz,1H),7.27–7.16( m,2H),7.10(dt,J=7.3,1.6Hz,1H),7.04(d,J=11.7Hz,3H),6.91(d,J=8.0Hz,1H),6.24(t,J=5.9 Hz,1H),6.04(s,2H),3.85(m,J=11.5,4.6,1.9Hz,2H),3.27(td,J=11.7,2.1Hz,2H),3.00(t,J=6 .2Hz,2H),1.66(m,J=10.6,6.6,3.2Hz,1H),1.56(m,J=12.9,4.0,1.9Hz,2H),1.25–1.11(m,2H). 13 C NMR(100MHz,DMSO)δ:155.78,148.36,147.43,141.34,138.07,132.02,129.38,128.40,127 .47,122.11,119.61,117.31,115.87,108.86,105.87,101.54,67.25,45.25,35.84,30.80.

[0296] Example 27 - Synthesis of compound C27:

[0297]

[0298] The synthetic route for compound C27 is as follows:

[0299]

[0300] The specific steps included: adding compound C25-1 (0.209 mmol, 0.05 g) to a 100 ml round-bottom flask, dissolving it with 10 ml of anhydrous dichloromethane, adding CDI (0.418 mmol, 0.068 g) and DMAP (0.418 mmol, 0.051 g), reacting overnight for 12 h, and then evaporating the solvent to obtain a white powder. Adding DMF (10 ml) and stirring to dissolve the powder, then adding isoamylamine (0.5 mmol, 0.044 g), and reacting for 6 h. After the reaction was complete, distilled water was added to terminate the reaction. The mixture was extracted with ethyl acetate, the organic phase was separated, washed with saturated brine, and the solvent was evaporated. Recrystallization was performed using an ethyl acetate / petroleum ether system to obtain a white solid (compound C27) (0.053 g, yield 72.0%).

[0301] HRMS(ESI)(M+H) + m / z 353.1844, calcd for C 21 H 25 N2O3 + 353.1860.mp 208.1-212.2℃

[0302] 1 H NMR(400MHz, DMSO-D6)δ:8.46(s,1H),7.59(t,J=1.9Hz,1H),7.29(d,J=1.8H z,1H),7.26–7.16(m,2H),7.09(dt,J=7.3,1.6Hz,1H),7.03(d,J=12.1Hz,3H ),6.91(d,J=8.0Hz,1H),6.15(t,J=5.6Hz,1H),6.03(s,2H),3.16–3.06(m,2 H),1.69–1.54(m,J=6.7Hz,1H),1.33(q,J=7.0Hz,2H),0.90(d,J=6.6Hz,6H). 13 C NMR(100MHz,DMSO)δ155.70,148.35,147.42,141.42,138.04,132.03,129.35,128.37, 127.50,122.10,119.54,117.29,115.86,108.85,105.87,101.54,37.71,25.61,22.88.

[0303] Example 28 - Synthesis of compound C28:

[0304]

[0305] The synthetic route for compound C28-1a is as follows:

[0306]

[0307] Add 3,5-dimethoxybenzaldehyde (6.02 mmol, 1 g), methyltriphenylphosphine bromide (9.03 mmol, 3.226 g), and potassium tert-butoxide (10.03 mmol, 1.126 g) to a 100 mL round-bottom flask, then add 30 mL of tetrahydrofuran and stir to dissolve. React under argon protection in an ice bath for 2 h. After the reaction is complete, quench with saturated ammonium chloride solution, extract with dichloromethane, separate the liquid phase, wash with saturated brine, and evaporate the solvent to obtain an orange liquid. Then, perform column chromatography (100-200 mesh silica gel, mobile phase V(petroleum ether):V(ethyl acetate) = 15:1) to obtain a colorless transparent liquid (compound C28-1a) (0.8 g, yield 80.97%).

[0308] The synthetic route for compound C28-1 is as follows:

[0309]

[0310] C28-1a (5.483 mmol, 0.9 g), m-iodoaniline (4.935 mmol, 1.081 g), tetrabutylammonium bromide (7.402 mmol, 2.386 g), potassium acetate (8.225 mmol, 0.807 g), and palladium acetate (0.274 mmol, 0.062 g) were added sequentially to a pressure flask. 10 mL of DMF was added, and the mixture was reacted under argon protection at 80 °C for 5 h. After the reaction was complete, distilled water was added to terminate the reaction. The mixture was extracted with ethyl acetate, washed with saturated brine, and evaporated to dryness. The solid was subjected to column chromatography (200-300 mesh silica gel, V(petroleum ether):V(ethyl acetate) = 10:1) to give a brown viscous liquid (compound C28-1) (0.68 g, yield 53.97%). 1 H NMR(400MHz, DMSO-D6)δ7.11(d,J=16.4Hz,2H),7.07–6.95(m,2H),6.80–6.72(m,2H) ,6.50(ddd,J=7.9,2.3,1.0Hz,2H),6.40(t,J=2.2Hz,2H),5.07(s,2H),3.78(s,6H).

[0311] The synthetic route for compound C28 is as follows:

[0312]

[0313] Compound C28-1 (0.2 mmol, 0.05 g) was added to a 100 mL round-bottom flask and dissolved with 10 mL of anhydrous dichloromethane. CDI (0.418 mmol, 0.068 g) and DMAP (0.418 mmol, 0.051 g) were added, and the mixture was allowed to react overnight for 12 h. After the reaction was complete, the solvent was evaporated to dryness, yielding a white powder. DMF (10 mL) was added and dissolved with stirring. Isobutylamine (0.5 mmol, 0.037 g) was added, and the reaction was allowed to continue for 6 h. After the reaction was complete, distilled water was added to terminate the reaction. The mixture was extracted with ethyl acetate, and the organic phase was separated. The liquid phase was washed with saturated brine, and the solvent was evaporated to dryness. The mixture was recrystallized from the ethyl acetate / petroleum ether system to give a white solid (compound C28) (0.053 g, yield 74.76%).

[0314] HRMS(ESI)(M+H) + m / z 355.2022, calcd for C 21 H 27 N2O3 + 355.2106.mp 160.1-163.5℃.

[0315] 1 H NMR(400MHz,)δ8.74(s,1H),7.68(t,J=1.9Hz,1H),7.30–7.17(m,3H),7.17–6.99(m,2H),6.78 (d,J=2.2Hz,2H),6.49–6.38(m,2H),3.78(s,6H),2.93(t,J=6.2Hz,2H),0.88(d,J=6.7Hz,6H). 13 CNMR(100MHz,DMSO)δ165.88,160.64,146.31,144.27,142.46,134.55,134.14 ,133.35,124.49,122.33,120.71,109.65,105.22,60.44,51.72,33.74,25.26.

[0316] Example 29 - Synthesis of compound C29:

[0317]

[0318] The synthetic route for compound C29 is as follows:

[0319]

[0320] Compound C28-1 (0.2 mmol, 0.05 g) was added to a 100 mL round-bottom flask and dissolved with 10 mL of anhydrous dichloromethane. CDI (0.4 mmol, 0.065 g) and DMAP (0.4 mmol, 0.05 g) were added, and the mixture was allowed to react overnight for 12 h. After the reaction was complete, the solvent was evaporated to dryness, yielding a white powder. DMF (10 mL) was added and dissolved with stirring. 4-Aminomethyltetrahydropyran (0.5 mmol, 0.06 g) was added, and the mixture was allowed to react for 6 h. After the reaction was complete, distilled water was added to terminate the reaction. The mixture was extracted with ethyl acetate, and the organic phase was separated. The organic phase was washed with saturated brine, evaporated to dryness, and recrystallized from the ethyl acetate / petroleum ether system to give a white solid (compound C29) (0.062 g, yield 78.18%).

[0321] HRMS(ESI)(M+H) + m / z 397.2123, calcd for C 23 H 29 N2O4 + 397.2122.mp 159.4-162.8℃

[0322] 1 H NMR(400MHz,DMSO-d6)δ8.43(s,1H),7.68(s,1H),7.26–7.17(m,3H),7.14(t,J=4.7Hz,1H ),7.06(d,J=16.4Hz,1H),6.78(d,J=2.2Hz,2H),6.42(d,J=2.3Hz,1H),6.26(t,J=5.9Hz, 1H),3.85(ddd,J=11.3,4.7,1.8Hz,2H),3.78(s,6H),3.29–3.21(m,2H),3.01(t,J=6.2Hz ,2H),1.66(dqd,J=10.6,6.7,2.7Hz,1H),1.60–1.52(m,2H),1.18(qd,J=12.1,4.5Hz,2H). 13 C NMR (100MHz, DMSO) δ161.15,155.80,141.39,139.51,137.77,129.77,129.42,128 .67,119.91,117.72,116.14,104.95,100.46,67.25,55.70,45.26,35.85,30.80.

[0323] The following demonstrates the technical effects and advantages of the present invention by applying the stilbene compound of the present invention to inhibit soluble epoxide hydrolases.

[0324] Specifically, the verification method for the stilbene compound in this embodiment of the invention to inhibit soluble epoxide hydrolase involves co-incubating the stilbene compound in this embodiment of the invention with a sample containing soluble epoxide hydrolase and the endogenous hydrolysis substrate 14,15-EET of the hydrolase, detecting the content of the hydrolysis product 14,15-DHET, and using its relative amount to reflect the inhibitory effect of the compound on soluble epoxide hydrolase. The specific steps are as follows:

[0325] Add 1:10 (mg / μL) pre-cooled PBS (phosphate buffer saline) (pH=7.4) to the collected brain tissue samples of adult (25-30g) male C57BL / 6J mice, homogenize for 30 seconds (4℃, 4500rpm) using a BertinPrecellys 24-Dual homogenizer, and then centrifuge at 9000g for 15 minutes at 4℃ using a small low-temperature centrifuge. Take the supernatant and dilute it 20 times. Add 160 μL of PBS, 20 μL of tissue fluid diluted 20 times, and 2 μL of compounds with concentration gradients of 10000, 5000, 1000, 500, 100, 50, 10, 1, 0.1, and 0.01 μg / mL (final concentrations of 100, 50, 10, 5, 1, 0.5, 0.1, 0.01, 0.001, and 0.0001 μg / mL) to an EP (Eppendorf) tube. Incubate at room temperature for 15 minutes. The negative control is PBS without tissue dilution but with added solvent (180 μL PBS plus 2 μL DMSO). The positive control is the same concentration of sample dilution plus an equal volume of solvent (160 μL PBS plus 20 μL of tissue fluid diluted 20 times plus 2 μL DMSO). After incubation at room temperature, all samples were placed on ice, and the enzyme reaction substrate (10 μL of 14,15-EET (10 μg / mL)) was quickly added and mixed. The mixture was then incubated at 37°C in a shaker. After incubation, the samples were placed on ice, and 10 μL of 800 nM t-TUCB (No. 6757, Tocris Bioscience, UK, Bristol) was quickly added to terminate the reaction, resulting in a final reaction volume of 200 μL. To detect enzyme activity, the concentration of the reaction product 14,15-DHET was determined using high-performance liquid chromatography-mass spectrometry (HPLC-MS / MS). The pretreatment process was as follows: 1. Add an equal volume (200 μL) of a 50 / 50, v / v mixture of methanol and acetonitrile to the sample. The mixture contained 0.4% acetic acid and internal standards 11,12-EET-d11 and 11,12-DHET-d11 (20 ng / mL); 2. Homogenize at 4500 rpm for 10 minutes and incubate at -20°C for 2 hours to precipitate the protein; 3. Centrifuge the sample for 10 minutes (14000 rpm) and collect the supernatant for UPLC-MS / MS analysis. The relative enzyme activity of sEH was calculated by comparing the amount of 14,15-DHET produced at a certain concentration of the tested compound with that produced without inhibitor. The inhibition rate was 100% minus the relative enzyme activity.

[0326] Wherein, inhibition rate %@5μg / mL is the inhibition rate of the compound against sEH at 5μg / mL.

[0327] The positive control compounds were TPPU and EC5026.

[0328] The verification results of the stilbene compounds prepared in this invention are shown in Table 1:

[0329] Table 1: Inhibitory activity of the stilbene compounds prepared in this application against soluble epoxide hydrolases:

[0330]

[0331]

[0332]

[0333] The results for the positive control compounds are shown in Table 2:

[0334] Table 2. Inhibitory activity of positive control compounds against soluble epoxide enzymes under the same conditions.

[0335]

[0336] Table 3. Inhibitory activity of weakly active control compounds against soluble epoxide enzymes under the same conditions

[0337]

[0338]

[0339] As shown in Tables 1 and 2, the IC50 values ​​of the positive control compounds TPPU and EC5026 against soluble epoxide hydrolase (sEH) were 44 nm and 19 nm, respectively. However, the stilbene skeleton compounds prepared in this invention exhibited comparable or superior sEH inhibitory activity (especially when the urea group was in the para position of stilbene, i.e., the IC50 of all compounds in formula II was less than 9 nm), indicating that the stilbene skeleton can enhance the interaction with sEH. WS-54 and WS-82 are known compounds, but their sEH inhibitory activity has not been reported. As shown in Table 3, the inhibition rates of the control compounds WS-54 and WS-82 against sEH were reduced to approximately 12% and 91%, respectively, and the IC50 of the control compound WS-82 reached 644 nm, indicating that the urea group with NH groups on both sides in the general formula is one of the characteristic structures for inhibiting sEH. Compared with the control compounds XWS-50 and XWS-65, the inhibition rate and IC50 of sEH show that a methylene group needs to be retained between the R4 group and the NH group of the urea group in the general formula to obtain a better inhibition rate of sEH and a lower IC50. Therefore, the present invention provides a novel sEH inhibitory compound by introducing the stilbene described in general formula I, which has a better inhibition rate of sEH and an IC50 as low as about 1 nm.

[0340] In summary, the main skeleton of the stilbene compounds prepared by this invention is stilbene with a urea group. By expanding the urea group side with different substituents and growing different groups on the stilbene side skeleton containing the dominant structure of natural products, a series of highly active stilbene compounds were obtained. Moreover, the IC50 values ​​of the compounds that inhibit sEH reached the nanomolar level, indicating that the stilbene compounds have a highly efficient inhibitory effect on sEH. Thus, the inhibitory effect on inflammation can be achieved by inhibiting sEH, which has good application prospects.

[0341] The above provides a detailed description of a stilbene compound, a pharmaceutical composition, and their applications provided by the present invention. Specific examples have been used to illustrate the principles and implementation methods of the present invention. The descriptions of the above embodiments are only for the purpose of helping to understand the method and core ideas of the present invention. At the same time, for those skilled in the art, there will be changes in the specific implementation methods and application scope based on the ideas of the present invention. Therefore, the content of this specification should not be construed as a limitation of the present invention.

Claims

1. A stilbene compound, characterized in that, The stilbene compound has the following general structural formula (Form I): Formula I In equation I, R 1 R 2 Combined to form methylenedioxy, or the R 1 R 2 Each is selected from methoxy, hydroxy, hydrogen, and any one of the following R1-R9 groups, and R 1 R 2 They are not the same; the structural formulas of the R1-R9 groups are as follows: R 3 Selected from any one of the groups: methoxy or hydrogen; R 4 The group is selected from any one of C1-4 alkyl, tetrahydropyranyl, N-(C1-4 alkylformyl)piperidinyl, and 4-trifluoromethoxyphenyl; X and Y are each selected from any one of the following groups: methyl, hydrogen, fluorine, and chlorine. The urea group of the stilbene compound is located at the para or meta position of the stilbene skeleton.

2. The compound according to claim 1, characterized in that, When the urea group of the compound is located at the para position of the stilbene skeleton, the general structural formula is shown in Formula II: Formula II In formula II, R 1 R 2 R 3 R 4 X and Y are defined in the same way as the groups described in claim 1.

3. The compound according to claim 1, characterized in that, When the urea group of the compound is located in the meta position of the stilbene skeleton, and X=Y=H, the general structural formula is shown in formula Ш: Style Ш In the formula Ш, R 1 R 2 R 3 R 4 X and Y are defined in the same way as the groups described in claim 1.

4. The compound according to claim 1, characterized in that, The compound's R 1 R 2 Combined to form a methylenedioxy group, or independently selected from any one of the groups R1-R9; R 3 Selected from any one of the groups: methoxy or hydrogen; R 4 It is selected from any one of the following groups: isopropyl, isobutyl, tetrahydropyranyl, N-acetylpiperidinyl, N-propionylpiperidinyl, and 4-trifluoromethoxyphenyl.

5. The compound according to claim 1, characterized in that, X of the compound is selected as hydrogen, and Y of the compound is selected as hydrogen.

6. The compound according to claim 1, characterized in that, The compound's R 1 R 2 R was chosen as methylenedioxy. 3 Hydrogen was chosen, R 4 X is selected as a tetrahydropyranyl group, and Y is selected as hydrogen; or The compound's R 1 Selected as methoxy, R 2 Hydrogen was chosen, R 3 It is a methoxy group, R 4 X is selected as a tetrahydropyranyl group, and Y is selected as hydrogen; or The compound's R 1 Choose any one of the R1-R9 groups, R 2 Hydrogen was chosen, R 3 Hydrogen was chosen, R 4 X is selected as a tetrahydropyranyl group, and Y is selected as hydrogen; or The compound's R 2 Choose any one of the R1-R9 groups, R 1 Hydrogen was chosen, R 3 Hydrogen was chosen, R 4 X was chosen as tetrahydropyranyl, Y was chosen as hydrogen.

7. The compound according to claim 6, characterized in that, The structural formula of the compound is:

8. The compound according to claim 1, characterized in that, The specific structural formula of the compound is as follows:

9. A stilbene compound pharmaceutical composition, characterized in that, The stilbene compound pharmaceutical composition comprises the compound according to any one of claims 1-8.

10. The use of a stilbene compound as described in any one of claims 1-8 or a pharmaceutical composition of a stilbene compound as described in claim 9 in the preparation of an anti-inflammatory drug.

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