Bis-substituted phenyl acrylamide / ester compound as well as preparation method and application thereof

Abstract

The invention provides a bis-substituted phenyl acrylamide / ester compound as well as a preparation method and application thereof. The structural formula of the compound is shown as a formula (I) or a formula (II). The compound provided by the invention can be used as a covalent inhibitor of DHHC family proteins, and inhibits proliferation, migration and invasion of tumor cells and plays an anti-tumor role by inhibiting the activity of DHHC palmitoyltransferase and blocking the palmitoylation modification process of substrate proteins. Experimental results show that the bis-substituted phenylacrylamide / ester compound has remarkable anti-proliferative activity on various tumor cells, the inhibition effect of the compound is superior to that of a positive control drug 2-BP, and the bis-substituted phenylacrylamide / ester compound has the potential of being further developed into a new generation of efficient and low-toxicity anti-tumor drugs.

Description

Technical Field

[0001] This invention relates to the field of antitumor compound preparation, and more specifically to a disubstituted phenylacrylamide / ester compound, its preparation method, and its application. Background Technology

[0002] DHHC (Asp-His-His-Cys protein), also known as palmitoyltransferase, is a key enzyme involved in the S-palmitoylation modification of proteins. Studies have shown that DHHC is overexpressed in most tumor cells, and its inhibitors have an inhibitory effect on tumor growth.

[0003] DHHC inhibitors are compounds that inhibit DHHC enzyme activity, thereby blocking protein palmitoylation. Currently, the number of reported DHHC inhibitors is limited, with 2-BP (2-bromopalmitic acid) being the most extensively studied, along with CMA (N-cyanomethyl-N-cinnamamide), physcynin, and tunicamycin. However, these inhibitors generally suffer from low activity and poor specificity, limiting their prospects for basic research and clinical application. Therefore, the development of novel, highly efficient, and highly selective DHHC inhibitors is urgently needed. Summary of the Invention

[0004] One objective of this invention is to provide a disubstituted phenylacrylamide / ester compound or a pharmaceutically acceptable salt thereof to address the problems of low activity, poor specificity, and limited variety of existing DHHC inhibitors.

[0005] Another object of the present invention is to provide a method for preparing the above-mentioned compounds and their pharmaceutical salts.

[0006] A further objective of this invention is to provide the use of the above-mentioned compounds and their pharmaceutical salts in the preparation of antitumor drugs.

[0007] To achieve the above objectives, the technical solution of the present invention is as follows: A disubstituted phenylacrylamide / ester compound or a pharmaceutically acceptable salt thereof, the general structural formula of said compound being shown in formula (I) or (II): ,

[0008] Wherein, X is an oxygen atom or a nitrogen atom; R1 is selected from hydrogen atom, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group; R2 is selected from hydrogen atom, substituted or unsubstituted aliphatic substituent, substituted or unsubstituted alicyclic substituent, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, amino protecting group; the carbon-carbon double bond is in trans configuration (E type).

[0009] Preferred: X is an oxygen atom or a nitrogen atom; R1 is selected from a hydrogen atom, a benzene ring, a 3-pyridine ring, or a 4-pyridine ring; R2 is selected from a hydrogen atom, phenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-methylphenyl, o-fluorophenyl, 2-thienyl, 2-furanyl, cyclohexyl, tert-butoxy, n-propyl, isobutyl, n-butyl, 2,6-dichlorophenyl, or 3-pyridyl; the carbon-carbon double bond is in the trans configuration (E type).

[0010] More preferably, X is an oxygen atom or a nitrogen atom; R1 is a hydrogen atom, a benzene ring or a 3-pyridine ring; R2 is phenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-methylphenyl, o-fluorophenyl, 2-thienyl, 2-furanyl, cyclohexyl, tert-butoxy, n-propyl, isobutyl, n-butyl, 2,6-dichlorophenyl or 3-pyridyl; the carbon-carbon double bond is in the trans configuration (E type).

[0011] More preferably, the compound is selected from one of the following structures: , , , , , , , , , , , , , .

[0012] The pharmaceutical salts of the compounds include, but are not limited to, acetates, ascorbic acid salts, benzoates, benzenesulfonates, citrates, fumarates, hydrochlorides, hydrobroms, maleates, and mesylates.

[0013] The present invention also provides a method for preparing the above-mentioned compound, the synthetic route and steps of which are as follows.

[0014] When X is a nitrogen atom and R1 is a hydrogen atom, the synthetic route of the compound shown in formula (I) is as follows: .

[0015] The specific steps are as follows: Step i: An acyl chloride (compound A) with an R2 substituent undergoes a substitution reaction with N-vinylformamide to generate compound B; Step ii: Compound B undergoes a coupling reaction with tert-butyl (4-bromophenylethyl) carbamate to generate compound C; Step iii: Compound C undergoes deBOC removal to yield compound D; Step iv: Compound D undergoes a substitution reaction with acryloyl chloride to produce product E.

[0016] Specifically, in step i, compound A, N-vinylformamide, 4-dimethylaminopyridine, and triethylamine react in anhydrous tetrahydrofuran under nitrogen protection for 24 h, followed by the dropwise addition of NaOH solution at 0°C to obtain compound B. The molar ratio of N-vinylformamide, compound A, 4-dimethylaminopyridine, triethylamine, and NaOH is 1:1.2:0.05:1.2:3. Specifically, in step ii, compound B and 9-boronbicyclo[3.3.1]nonane reacted in anhydrous tetrahydrofuran under nitrogen protection for 8 h, followed by the addition of NaOH solution at 0 °C for 2 h. Then, tert-butyl(4-bromophenylethyl)carbamate and tetra(triphenylphosphine)palladium were added, and the mixture was heated to 85 °C and refluxed for 20 h to obtain compound C. The molar ratio of compound B, 9-boronbicyclo[3.3.1]nonane, tert-butyl(4-bromophenylethyl)carbamate, tetra(triphenylphosphine)palladium, and NaOH was 1:3:0.6:0.06:1.5. Specifically, in step iii, compound C reacts with trifluoroacetic acid in dichloromethane to obtain compound D, wherein the molar ratio of compound C to trifluoroacetic acid is 1:3.

[0017] Specifically, in step iv, compound D reacts with acryloyl chloride and triethylamine in dichloromethane to produce product E, wherein the molar ratio of compound D to acryloyl chloride and triethylamine is 1:1.5:1.5.

[0018] When X is a nitrogen atom and R1 is a benzene ring, the synthetic route of the compound shown in formula (I) is as follows: .

[0019] The specific steps are as follows: Step v: Cinnamyl chloride undergoes a substitution reaction with 4-bromophenylethylamine to generate compound G; Step vi: Compound G undergoes a coupling reaction with compound B to generate compound H.

[0020] Specifically, in step v, cinnamyl chloride, 4-bromophenylethylamine, and triethylamine react in dichloromethane to produce compound G. The molar ratio of cinnamyl chloride, 4-bromophenylethylamine, and triethylamine is 1:1:1.2.

[0021] Specifically, in step vi, compound B and 9-boronbicyclo[3.3.1]nonane react in anhydrous tetrahydrofuran under nitrogen protection for 8 h, followed by the addition of NaOH solution at 0 °C for 2 h. Then, compound G and tetra(triphenylphosphine)palladium are added, and the mixture is heated to 85 °C and refluxed for 20 h to obtain compound H. The molar ratio of compound 2, 9-boronbicyclo[3.3.1]nonane, compound G, tetra(triphenylphosphine)palladium, and NaOH is 1:3:0.6:0.06:1.5.

[0022] When X is a nitrogen atom and R1 is 3-pyridine or 4-pyridine, the synthetic route of the compound shown in formula (I) is as follows: .

[0023] The specific steps are as follows: Step vii: (E)-3-(pyridin-3-yl)acrylic acid undergoes a substitution reaction with 4-bromophenylethylamine to generate compound J; Step viii: Compound J undergoes a coupling reaction with compound B to generate compound K.

[0024] Specifically, in step vii: (E)-3-(pyridin-3-yl)acrylic acid, 4-bromophenylethylamine and N,N'-carbonyldiimidazole are reacted in anhydrous tetrahydrofuran at 40°C to obtain compound J, wherein the molar ratio of (E)-3-(pyridin-3-yl)acrylic acid, 4-bromophenylethylamine and N,N'-carbonyldiimidazole is 1:1:1.2; Specifically, in step viii: compound B and 9-boronbicyclo[3.3.1]nonane are reacted in anhydrous tetrahydrofuran under nitrogen protection for 8 h, followed by the addition of NaOH solution at 0 °C for 2 h. Then, compound J and tetra(triphenylphosphine)palladium are added, and the mixture is heated to 85 °C and refluxed for 20 h to obtain compound K. The molar ratio of compound B, 9-boronbicyclo[3.3.1]nonane, compound J, tetra(triphenylphosphine)palladium, and NaOH is 1:3:0.6:0.06:1.5.

[0025] When X is an oxygen atom and R1 is a benzene ring, the synthetic route of the compound shown in formula (I) is as follows: .

[0026] The specific steps are as follows: Step ix: Cinnamyl chloride undergoes a substitution reaction with 4-bromophenylethanol to produce compound L; Step x: Compound L undergoes a coupling reaction with compound B to generate compound M.

[0027] Specifically, in step ix: cinnamyl chloride, 4-bromophenylethanol, and triethylamine react in dichloromethane to produce compound L. The molar ratio of cinnamyl chloride, 4-bromophenylethanol, and triethylamine is 1:1:1.2.

[0028] Specifically, in step x: compound B and 9-boronbicyclo[3.3.1]nonane react in anhydrous tetrahydrofuran under nitrogen protection for 8 h, followed by the addition of NaOH solution at 0 °C for 2 h. Then, compound L and tetra(triphenylphosphine)palladium are added, and the mixture is heated to 85 °C and refluxed for 20 h to obtain compound M. The molar ratio of compound B, 9-boronbicyclo[3.3.1]nonane, compound L, tetra(triphenylphosphine)palladium, and NaOH is 1:3:0.6:0.06:1.5.

[0029] When R1 is a benzene ring or a 3-pyridine ring, the synthetic route of the compound shown in formula (II) is as follows:

[0030] The specific steps are as follows: Step xi: Compound N undergoes deBOC removal in trifluoroacetic acid to generate compound O; The present invention also provides the use of the aforementioned disubstituted phenylacrylamide / ester compounds or pharmaceutically acceptable salts thereof in the preparation of antitumor drugs.

[0031] The tumor is breast cancer, liver cancer, colon cancer, or lymphoma.

[0032] The present invention also provides a palmityltransferase inhibitor comprising the compound described herein or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable carriers and / or excipients.

[0033] This invention synthesizes a novel class of DHHC-targeting small molecule compounds. These compounds can act as covalent inhibitors of DHHC family proteins. By inhibiting the activity of DHHC palmitoyltransferase, they block the palmitoylation modification process of substrate proteins, thereby inhibiting the proliferation, migration, and invasion of tumor cells and exerting anti-tumor effects.

[0034] Experimental results show that the disubstituted phenylacrylamide / ester compounds of the present invention have significant anti-proliferative activity against a variety of tumor cells. The inhibitory effect of the compounds is better than that of the positive control drug 2-BP, and they have the potential to be further developed into a new generation of highly effective and low-toxicity anti-tumor drugs. Detailed Implementation

[0035] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art, and the reagents used, unless otherwise specified, are commercially available analytical grade or chromatographic grade.

[0036] Example 1: Preparation of compounds 1-6 (a series of compounds of formula (I) where X is a nitrogen atom and R1 is a hydrogen atom) (1) N-vinylformamide (5 mmol), triethylamine (6 mmol), and DMAP (0.25 mmol) were added to 30 mL of anhydrous tetrahydrofuran. Under nitrogen protection, acyl chloride compounds A with different R2 substitutions (6 mmol) were added dropwise at 0 °C with stirring. The addition was continued for 30 minutes. After the addition was completed, the temperature was raised to room temperature, and the reaction was detected by TLC. After about 24 h of reaction, NaOH solution (5 M, 3 mL) was added dropwise at 0 °C with stirring, and the reaction was continued for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate (60 mL × 3) and saturated brine (60 mL × 3). The organic layer was dried with anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (ethyl acetate: petroleum ether = 1:10) to obtain white or brown solid compound B, with a yield of 68%-80%.

[0037] (2) Under nitrogen protection at 0°C, 9-BBN (0.5 M in THF, 4.50 mmol) was slowly added to an anhydrous THF (3 mL) solution of compound B (1.50 mmol). The mixture was slowly heated to 25°C and then stirred for 6 h until TLC analysis showed that the olefin was completely consumed. NaOH solution (2 M, 2.25 mL) was added dropwise at 0°C, and the reaction was carried out for 2 h. Anhydrous THF 30 mL was added, followed by the sequential addition of tert-butyl(4-bromophenylethyl)carbamate (1 mmol) and Pd(PPh3)4 (0.09 mmol). The reaction was heated, refluxed at 80°C, and stirred for 20 h. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (60 mL × 3) and saturated brine (60 mL × 3). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the dark brown crude product compound C. The solid was washed with dichloromethane and directly proceeded to the next step of the reaction.

[0038] (3) Dissolve compound C in a small amount of dry dichloromethane, add 5 mL of a mixed solution of trifluoroacetic acid and dichloromethane (1:1), monitor by TLC, quench with water after the reaction is complete, extract with ethyl acetate (30 mL × 3) and saturated saline (30 mL × 3), separate the organic layer, dry with anhydrous sodium sulfate and filter, and evaporate to dryness to obtain crude product compound D about 0.1 g, yield 71%.

[0039] (4) Dissolve compound D in dry dichloromethane (5 ml) and add triethylamine (0.5 mmol). Add acryloyl chloride (0.5 mmol) to the reaction mixture while stirring at 0 °C. React at room temperature for 1 h and monitor by TLC. After the reaction is complete, extract with ethyl acetate (20 mL × 3) and saturated brine (20 mL × 3) to separate the organic layer. Dry the organic layer with anhydrous sodium sulfate and filter. Wash with dichloromethane to give white product compound E with a yield of 40.3%.

[0040] The specific structures of the R2 substituent and the corresponding compounds are shown in Table 1.

[0041] Table 1

[0042] The characterization data of compounds 1-6 are as follows: Compound 1: 1 H NMR (600 MHz, DMSO-d6) δ 8.55 (t, J = 5.6 Hz, 1H, -NH), 8.16 (t, J = 5.7 Hz, 1H, -NH), 7.85 – 7.80 (m, 2H, Ar-H), 7.55 – 7.49 (m, 1H, Ar-H), 7.48 – 7.43 (m, 2H, Ar-H), 7.19 – 7.13 (m, 4H, Ar-H), 6.20 (dd, J =17.1, 10.1 Hz, 1H, =CH), 6.07 (dd, J = 17.1, 2.2 Hz, 1H, =CH2), 5.56 (dd, J =10.2, 2.2 Hz, 1H, =CH2), 3.50 – 3.43 (m, 2H, -CH2), 3.36 – 3.33 (m, 2H, -CH2), 2.82 (t, J = 7.5 Hz, 2H, -CH2), 2.71 (t, J = 7.4 Hz, 2H, -CH2). 13 C NMR (151MHz, MeOD) δ 167.42, 165.81, 138.55, 138.40, 135.90, 133.11, 132.34, 129.92,129.89, 129.55, 128.39, 126.22, 42.19, 41.51, 36.02, 35.95.HR-ESI + -MScalculated for C 20 H 22N2O2 m / z [M+H] + : 323.1760; found: 323.1761。

[0043] Compound 2: 1 H NMR (600 MHz, Chloroform- d ) δ 7.69 (t, J J = 1.9 Hz, 1H, -NH), 7.56 (dt, J J = 7.8, 1.3 Hz, 1H, Ar-H), 7.45 (dd, J J = 7.8, 2.1 Hz, 1H, Ar-H), 7.35 (t, J J = 7.9 Hz, 1H, Ar-H), 7.20 – 7.12 (m, 4H, Ar-H), 6.25 (dd, J J = 16.9, 1.4 Hz, 1H, =CH2), 6.22 (d, J J = 5.3 Hz, 1H, -NH), 6.03 (dd, J J = 17.0, 10.3 Hz, 1H, =CH), 5.66 (t, J J = 6.1 Hz, 1H), 5.61 (dd, J J = 10.4, 1.4 Hz, 1H, =CH2), 3.72 – 3.66 (m, 2H, -CH2), 3.64 – 3.51 (m, 2H, -CH2), 2.91 (t, J J = 7.0 Hz, 2H, -CH2), 2.84 (t, J J = 7.0 Hz, 2H, -CH2). 13 C NMR (151 MHz, CDCl3) δ 166.21, 165.55, 137.19, 137.01, 136.44, 134.76, 131.49, 130.80, 129.93, 129.15, 129.11, 127.27, 126.48, 124.91, 41.30, 40.69, 35.26, 35.22. HR-ESI + -MS calculated for C 20 H 21 ClN2O2 m / z [M+H] + : 357.1370; found: 357.1371。

[0044] Compound 3: 1 H NMR (600 MHz, Chloroform-d) δ 7.62 (dd, J = 7.5, 1.7 Hz,1H, Ar-H), 7.38 – 7.28 (m, 3H, Ar-H), 7.21 (d, J = 7.7 Hz, 2H, Ar-H), 7.15(d, J = 7.7 Hz, 2H, Ar-H), 6.25 (dd, J = 16.9, 1.4 Hz, 1H, =CH2), 6.23 – 6.18(m, 1H, -NH), 6.02 (dd, J = 16.9, 10.3 Hz, 1H, =CH), 5.61 (dd, J = 10.4, 1.4Hz, 1H, =CH2), 5.56 (s, 1H, -NH), 3.77 – 3.71 (m, 2H, -CH2), 3.62 – 3.56 (m,2H, -CH2), 2.94 (t, J = 6.9 Hz, 2H, -CH2), 2.84 (t, J = 7.0 Hz, 2H, -CH2). 13 CNMR (151 MHz, CDCl3) δ 166.44, 165.50, 137.13, 136.99, 135.07, 131.30,130.83, 130.57, 130.23, 130.19, 129.19, 129.11, 127.12, 126.45, 41.26, 40.67,35.20, 35.11. HR-ESI + -MS calculated for C 20 H 21 ClN2O2m / z [M+H] + : 357.1370;found: 357.1372。

[0045] Compound 4: 1 H NMR (600 MHz, DMSO- d 6) δ 8.16 (t, J = 5.6 Hz, 1H, -NH), 7.73(t, J = 5.6 Hz, 1H, -NH), 7.15 – 7.10 (m, 4H, Ar-H), 6.20 (dd, J= 17.1, 10.2 Hz, 1H, =CH), 6.07 (dd, J = 17.0, 2.2 Hz, 1H, =CH2), 5.56 (dd, J = 10.1, 2.2 Hz, 1H, =CH2), 3.35 – 3.31 (m, 2H, -CH2), 3.24 – 3.19 (m, 2H, -CH2), 2.71 (t, J = 7.5 Hz, 2H, -CH2), 2.65 (t, J = 7.4 Hz, 2H, -CH2), 2.04 (tt, J = 11.6, 3.5 Hz, 1H, -CH), 1.68 (dt, J = 12.4, 3.1 Hz, 2H, -CH2), 1.66 – 1.57 (m, 3H, -CH2), 1.30 (qd, J = 12.2, 3.1 Hz, 2H, -CH2), 1.24 – 1.09 (m, 3H, -CH2). 13 C NMR (151 MHz, DMSO) δ 175.51, 165.00, 137.76, 137.49, 132.29, 129.10, 128.98, 125.41, 44.45, 40.71, 40.53, 35.28, 35.13, 29.67, 25.95, 25.75. HR-ESI + -MS calculated for C 20 H 28 N2O2 m / z [M+H] + : 329.2229; found: 329.2233。

[0046] Compound 5: 1H NMR (600 MHz, Chloroform-d) δ 7.16 (s, 4H, Ar-H), 6.28(dd, J = 16.9, 1.3 Hz, 1H, =CH2), 6.06 (dd, J = 16.9, 10.3 Hz, 1H, =CH), 5.65(dd, J = 10.4, 1.4 Hz, 1H, =CH2), 5.51 (s, 1H, -NH), 3.66 – 3.58 (m, 2H, -CH2), 3.57 – 3.50 (m, 2H, -CH2), 2.86 (t, J = 7.0 Hz, 2H, -CH2), 2.81 (t, J =7.0 Hz, 2H, -CH2), 2.13 (t, J = 7.5 Hz, 2H, -CH2), 1.65 (p, J = 7.4 Hz, 2H, -CH2), 0.94 (t, J = 7.4 Hz, 3H, -CH3). 13 C NMR (151 MHz, CDCl3) δ 173.02,165.52, 137.21, 136.99, 130.79, 129.08, 129.03, 126.47, 40.70, 40.54, 38.72,35.39, 35.21, 19.15, 13.75. HR-ESI + -MS calculated for C 17 H 24 N2O2m / z [M+H] + :289.1916; found: 289.1918。

[0047] Compound 6: 1H NMR (600 MHz, Chloroform-d) δ 7.16 (s, 4H, Ar-H), 6.28(dd, J = 17.0, 1.3 Hz, 1H, =CH2), 6.06 (dd, J = 16.9, 10.3 Hz, 1H, =CH), 5.65(dd, J = 10.3, 1.4 Hz, 1H, =CH2), 5.60 (s, 1H, -NH), 5.46 (s, 1H, -NH), 3.62(dt, J = 6.7, 6.2 Hz, 2H, -CH2), 3.52 (dt, J = 8.7, 6.1 Hz, 2H, -CH2), 2.86(t, J = 7.0 Hz, 2H, -CH2), 2.81 (t, J = 6.9 Hz, 2H, -CH2), 2.30 (p, J = 6.9Hz, 1H, -CH), 1.13 (d, J = 6.9 Hz, 6H, -CH3). 13 C NMR (151 MHz, DMSO) δ 172.19,160.77, 132.52, 132.23, 126.06, 124.39, 124.28, 121.73, 35.94, 35.71, 30.94,30.63, 30.46, 14.87.HR-ESI + -MS calculated for C 17 H 24 N₂O₂m / z [M+H] + : 289.1916;found: 289.1920.

[0048] Example 2: Preparation of compound 7-21 (a series of compounds of formula (I) where X is a nitrogen atom and R1 is a benzene ring) (1) Add 4-bromophenylethylamine (4 mmol) to 10 mL of dry dichloromethane, stir the solution, and add triethylamine (4.8 mmol). Add cinnamoyl chloride (4 mmol) to the reaction mixture at 0 °C. Then stir at room temperature for 16–20 h until the starting material is completely consumed by TLC. After the reaction is complete, quench the reaction with water, extract with dichloromethane (60 mL × 3) and saturated brine (60 mL × 3), dry the organic layer with anhydrous sodium sulfate, and dry the solid obtained by rotary evaporation under vacuum to give compound G, with a yield of 96%.

[0049] (2) Under nitrogen protection at 0°C, 9-BBN (0.5 M in THF, 4.50 mmol) was slowly added to a solution of compound B (1.50 mmol) in anhydrous THF (3 mL). The mixture was slowly heated to 25°C and stirred for 6 h until TLC analysis showed that the olefin was completely consumed. NaOH solution (2 M, 2.25 mL) was added dropwise at 0°C, and the reaction was carried out for 2 h. Then, 30 mL of anhydrous THF was added, followed by the sequential addition of compound G (1 mmol) and Pd(PPh3)4 (0.1 mmol). The reaction was heated, refluxed at 80°C, and stirred for 20 h. After the reaction was completed, water was added to quench the reaction. The mixture was extracted with ethyl acetate (60 mL × 3) and saturated brine (60 mL × 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 1:60) to obtain a white solid compound H with a yield of 30%.

[0050] The specific structures of the R2 substituent and the corresponding compounds are shown in Table 2.

[0051] Table 2

[0052]

[0053] The characterization data of compound 7-21 are as follows: Compound 7: 1 H NMR (600 MHz, DMSO- d 6) δ 8.55 (t, J = 5.6 Hz, 1H, -NH), 8.18(t, J = 5.7 Hz, 1H, -NH), 7.82 (d, J = 7.5 Hz, 2H, Ar-H), 7.58 – 7.53 (m, 2H, Ar-H), 7.53 – 7.49 (m, 1H, Ar-H), 7.48 – 7.43 (m, 2H, Ar-H), 7.43 – 7.35 (m, 4H,-CH2, Ar-H), 7.21 – 7.15 (m, 4H, Ar-H), 6.62 (d, J = 15.8 Hz, 1H, =CH), 3.47(dt, J = 7.2, 6.5 Hz, 2H , -CH2), 3.40 (dt, J = 7.0, 6.5 Hz, 2H , -CH2), 2.82 (t, J= 7.5 Hz, 2H, -CH2), 2.75 (t, J = 7.4 Hz, 2H, -CH2). 13 C NMR (151 MHz, DMSO) δ166.61, 165.36, 139.00, 137.74, 137.63, 135.40, 135.09, 131.53, 129.88, 129.41, 129.13, 129.10, 128.73, 127.97, 127.57, 122.72, 41.38, 40.83, 35.23, 35.22. HR-ESI + -MS calculated for C 26 H 26 N2O2 m / z [M+H] + : 399.2073; found: 399.2074。

[0054] Compound 8: 1 H NMR (600 MHz, DMSO- d 6) δ 8.69 (t, J = 5.6 Hz, 1H, -NH), 8.18 (t, J = 5.7 Hz, 1H, -NH), 7.85 (t, J = 2.0 Hz, 1H, Ar-H), 7.78 (dt, J = 7.8, 1.3 Hz, 1H, Ar-H), 7.61 – 7.53 (m, 3H, Ar-H, =CH), 7.50 (t, J = 7.9 Hz, 1H, Ar-H), 7.44 – 7.39 (m, 3H, Ar-H), 7.39 – 7.34 (m, 1H, Ar-H), 7.17 (s, 4H, Ar-H), 6.62 (d, J = 15.8 Hz, 1H, =CH), 3.50 – 3.43 (m, 2H, -CH2), 3.43 – 3.36 (m, 2H, -CH2), 2.81 (t, J = 7.5 Hz, 2H, -CH2), 2.75 (t, J = 7.4 Hz, 2H, -CH2). 1313C NMR (151 MHz, DMSO) δ 164.27, 164.10, 137.92, 136.61, 136.55, 135.97, 134.33, 132.55, 130.34, 129.73, 128.81, 128.33, 128.04, 126.89, 126.35, 125.29, 121.65, 40.39, 39.76, 39.00, 34.16, 33.98. HR-ESI + -MS calculated for C 26 H 25 ClN2O2 m / z [M+H] + : 433.1683; found: 433.1686。

[0055] Compound 9: 1 1H NMR (600 MHz, DMSO- d d6) δ 8.27 (t, J J = 5.7 Hz, 1H, -NH), 8.19 (t, J J = 5.6 Hz, 1H, -NH), 7.57 – 7.53 (m, 2H, Ar-H), 7.45 – 7.39 (m, 3H, Ar-H, =CH), 7.39 – 7.34 (m, 1H, Ar-H), 7.30 – 7.26 (m, 1H, Ar-H), 7.25 – 7.22 (m, 1H, Ar-H), 7.21 – 7.14 (m, 6H, Ar-H), 6.62 (d, J J = 15.8 Hz, 1H, =CH), 3.47 – 3.42 (m, 2H, -CH2), 3.42 – 3.38 (m, 2H, -CH2), 2.80 (t, J J = 7.4 Hz, 2H, -CH2), 2.76 (t, J J = 7.5 Hz, 2H, -CH2), 2.25 (s, 3H, -CH3). 1313C NMR (151 MHz, DMSO) δ168.84, 164.76, 138.40, 137.24, 137.05, 137.00, 134.94, 134.80, 130.19,129.28, 128.95, 128.81, 128.58, 128.43, 127.37, 126.75, 125.28, 122.12,40.25, 40.21, 34.63, 34.49, 19.13. HR-ESI + -MS calculated for C 27 H 28 N2O2m / z [M+H] + : 413.2229; found: 413.2227。

[0056] Compound 10: 1 1H NMR (600 MHz, DMSO- d 6) δ 8.50 (t, J J = 5.6 Hz, 1H, -NH), 8.19(t, J J = 5.7 Hz, 1H, -NH), 7.55 (d, J J = 7.5 Hz, 2H, Ar-H), 7.49 – 7.44 (m, 1H, Ar-H), 7.45 – 7.30 (m, 7H, Ar-H, =CH), 7.22 – 7.16 (m, 4H, Ar-H), 6.62 (d, J J=15.8 Hz, 1H, =CH), 3.42 (dq, J J = 21.0, 6.8 Hz, 4H, -CH2), 2.80 (t, J J = 7.5 Hz,2H, -CH2), 2.76 (t, J J = 7.4 Hz, 2H, -CH2). 13 13C NMR (151 MHz, DMSO) δ 166.12,164.79, 138.43, 137.08, 137.01, 136.94, 134.83, 130.51, 129.76, 129.45,129.31, 128.84, 128.65, 128.62, 128.49, 127.40, 126.92, 122.15, 40.46, 40.28,34.66, 34.40.HR-ESI+ -MS calculated for C 26 H 25 ClN2O2 m / z [M+H] + : 433.1683; found: 433.1685。

[0057] Compound 11: 1 H NMR (600 MHz, DMSO- d 6) δ 9.01 (t, J J = 5.7 Hz, 1H, -NH), 8.19 (t, J J = 5.5 Hz, 1H, -NH), 7.57 – 7.53 (m, 2H, Ar-H), 7.44 – 7.39 (m, 3H, Ar-H, -CH2), 7.40 – 7.34 (m, 1H, Ar-H), 7.23 – 7.15 (m, 4H, Ar-H), 6.62 (d, J J = 15.8 Hz, 1H, -CH2), 3.52 – 3.44 (m, 2H), 3.43 – 3.37 (m, 3H), 2.80 (t, J J = 7.2 Hz, 2H), 2.76 (t, J J = 7.5 Hz, 2H). 13 C NMR (151 MHz, DMSO) δ 165.36, 156.97, 139.00, 137.80, 137.12, 135.39, 129.88, 129.40, 129.17, 129.09, 127.96, 122.70, 41.42, 40.84, 35.22, 34.76. HR-ESI + -MS calculated for C 26 H 21 F5N2O2 m / z [M+H] + : 489.1601; found: 489.1603。

[0058] Compound 12: 1 H NMR (600 MHz, DMSO- d 6) δ 8.18 (t, J J = 5.6 Hz, 1H, -NH), 7.73 (t, J= 5.6 Hz, 1H, -NH), 7.58 – 7.53 (m, 2H, Ar-H), 7.45 – 7.39 (m, 3H, Ar-H, =CH), 7.39 – 7.34 (m, 1H, Ar-H), 7.17 – 7.09 (m, 4H, Ar-H), 6.62 (d, J = 15.8Hz, 1H, =CH), 3.42 – 3.36 (m, 2H), 3.24 – 3.18 (m, 2H, -CH2), 2.74 (t, J = 7.4Hz, 2H, -CH2), 2.65 (t, J = 7.4 Hz, 2H, -CH2), 2.04 (tt, J = 11.6, 3.5 Hz, 1H, -CH), 1.70 – 1.56 (m, 5H, -CH2), 1.29 (qd, J = 12.3, 3.1 Hz, 2H, -CH2), 1.24 –1.08 (m, 3H, -CH2). 13 C NMR (151 MHz, DMSO) δ 175.51, 165.36, 139.00, 137.77, 137.54, 135.39, 129.88, 129.40, 129.12, 129.00, 127.97, 122.71, 44.45, 40.85, 40.47, 35.29, 35.22, 29.67, 25.94, 25.75. HR-ESI + -MS calculated for C 26 H 32 N2O2 m / z [M+H] + : 405.2542; found: 405.2540。

[0059] Compound 13: 1 H NMR (600 MHz, DMSO- d 6) δ 8.58 (t, J = 5.7 Hz, 1H, -NH), 8.19(t, J= 5.7 Hz, 1H, -NH), 7.75 – 7.70 (m, 2H, Ar-H), 7.58 – 7.54 (m, 2H, Ar-H), 7.45 – 7.40 (m, 3H, Ar-H, =CH), 7.39 – 7.35 (m, 1H, Ar-H), 7.18 (s, 4H, Ar-H), 7.13 (dd, J = 4.9, 3.8 Hz, 1H), 6.62 (d, J = 15.8 Hz, 1H, =CH), 3.47 – 3.37 (m, 4H, -CH2), 2.81 (t, J = 7.6 Hz, 2H, -CH2), 2.76 (t, J = 7.4 Hz, 2H, -CH2). 13 13C NMR (151 MHz, DMSO) δ 165.37, 161.52, 140.62, 139.01, 137.69, 137.68, 137.61, 135.40, 131.03, 129.88, 129.41, 129.12, 128.32, 128.31, 127.97, 122.72, 41.25, 40.84, 35.28, 35.24. HR-ESI + -MS calculated for C 24 H 24 N2O2S m / z [M+H] + : 405.1637; found: 405.1635。

[0060] Compound 14: 1 1H NMR (600 MHz, DMSO- d 6) δ 8.42 (t, J = 5.7 Hz, 1H, -NH), 8.18 (t, J = 5.6 Hz, 1H, -NH), 7.82 – 7.79 (m, 1H, Ar-H), 7.57 – 7.53 (m, 2H, Ar-H), 7.44 – 7.39 (m, 3H, Ar-H, =CH), 7.39 – 7.34 (m, 1H, Ar-H), 7.16 (s, 4H, Ar-H), 7.06 (d, J= 3.5 Hz, 1H, Ar-H), 6.65 – 6.58 (m, 2H, =CH, Ar-H), 3.44 – 3.37(m, 4H, -CH2), 2.78 (d, J = 7.2 Hz, 2H, -CH2), 2.75 (t, J = 7.4 Hz, 2H, -CH2). 13 C NMR (151 MHz, DMSO) δ 165.37, 158.16, 148.49, 145.32, 139.00, 137.65, 137.57, 135.39, 129.88, 129.41, 129.11, 129.08, 127.97, 122.72, 113.60, 112.24, 40.83, 40.55, 35.24. HR-ESI + -MS calculated for C 24 H 24 N2O3 m / z [M+H]​​​​​​​​​​​​​​​​​​​​​​​​= 7.7, 5.9 Hz, 2H, -CH2), 3.40 (dt, J = 8.0, 6.3 Hz, 2H, -CH2), 2.83 (t, J = 7.5 Hz, 2H, -CH2), 2.76 (t, J = 7.4 Hz, 2H, -CH2). 13 C NMR(151 MHz, DMSO) δ 165.36, 165.20, 152.24, 148.77, 139.00, 137.70, 137.59, 135.39, 135.33, 130.52, 129.88, 129.40, 129.14, 129.12, 127.97, 123.93, 122.71, 41.38, 40.84, 35.23, 35.10. HR-ESI + -MS calculated for C 25 H 25 N3O2 m / z [M+H] + : 400.2025; found: 400.2023。

[0062] Compound 16: 1 H NMR (600 MHz, DMSO- d 6) δ 8.19 (t, J = 5.7 Hz, 1H, -NH), 7.82(t, J = 5.6 Hz, 1H, -NH), 7.58 – 7.53 (m, 2H, Ar-H), 7.44 – 7.39 (m, 3H, Ar-H, =CH), 7.39 – 7.35 (m, 1H, Ar-H), 7.18 – 7.12 (m, 4H, Ar-H), 6.62 (d, J = 15.8Hz, 1H, =CH), 3.44 – 3.37 (m, 2H, -CH2), 3.27 – 3.20 (m, 2H, -CH2), 2.75 (t, J =7.4 Hz, 2H, -CH2), 2.67 (t, J = 7.5 Hz, 2H, -CH2), 2.04 (q, J = 7.6 Hz, 2H, -CH2), 0.97 (t, J= 7.6 Hz, 3H, -CH3). 13 C NMR (151 MHz, DMSO) δ 173.23, 165.36, 139.00,137.75, 137.57, 135.39, 129.89, 129.41, 129.09, 129.05, 127.97, 122.71,40.84, 40.62, 35.32, 35.22, 28.97, 10.43. HR-ESI + -MS calculated forC 22 H 26 N2O2m / z [M+H] + : 351.2073; found: 351.2073。

[0063] Compound 17: 1 H NMR (600 MHz, DMSO- d 6) δ 8.37 (t, J = 6.0 Hz, 1H, -NH), 8.19(t, J = 5.6 Hz, 1H, -NH), 7.59 – 7.53 (m, 3H, Ar-H), 7.53 – 7.47 (m, 1H, Ar-H),7.45 – 7.39 (m, 3H, Ar-H, =CH), 7.37 (t, J = 7.2 Hz, 1H, Ar-H), 7.29 – 7.23 (m,2H, Ar-H), 7.21 – 7.15 (m, 4H, Ar-H), 6.62 (d, J = 15.8 Hz, 1H, =CH), 3.49 –3.43 (m, 2H, -CH2), 3.43 – 3.37 (m, 2H, -CH2), 2.80 (t, J = 7.5 Hz, 2H, -CH2),2.76 (t, J = 7.4 Hz, 2H, -CH2). 1313C NMR (151 MHz, DMSO) δ 164.28, 163.00, 159.30, 157.66, 137.92, 136.60, 136.50, 134.33, 131.66, 131.61, 129.40, 129.38, 128.80, 128.33, 128.08, 128.01, 126.90, 123.85, 123.82, 123.69, 123.60, 121.66, 115.55, 115.40, 40.25, 39.77, 34.16, 33.99. HR-ESI + -MS calculated for C 26 H 25 FN2O2 m / z [M+H] + : 417.1978; found: 417.1979。

[0064] Compound 18: 1 1H NMR (600 MHz, DMSO- d d6) δ 8.75 (t, J J = 5.7 Hz, 1H, -NH), 8.19 (t, J J = 5.6 Hz, 1H, -NH), 7.57 – 7.51 (m, 2H, Ar-H), 7.49 – 7.45 (m, 2H, Ar-H), 7.44 – 7.34 (m, 5H, Ar-H, =CH), 7.23 – 7.15 (m, 4H, Ar-H), 6.62 (d, J J = 15.8 Hz, 1H, =CH), 3.46 (dt, J J = 7.8, 5.9 Hz, 2H, -CH2), 3.40 (dt, J J = 7.9, 6.0 Hz, 2H, -CH2), 2.81 (t, J J = 7.5 Hz, 2H, -CH2), 2.75 (t, J J = 7.5 Hz, 2H, -CH2). 1313C NMR (151 MHz, DMSO) δ 164.78, 163.36, 138.41, 137.10, 136.79, 136.57, 134.83, 131.06, 130.76, 129.31, 128.84, 128.60, 128.49, 127.94, 127.40, 122.17, 40.32, 40.28, 34.66, 34.33. HR-ESI + -MS calculated for C 26 H 24 Cl2N2O2 m / z [M+H] + : 467.1293; found: 467.1287。

[0065] Compound 19: 1 1H NMR (600 MHz, DMSO- d 6) δ 8.18 (qt, J J = 5.7 Hz, 1H, -NH), 7.83 (t, J J = 5.6 Hz, 1H, -NH), 7.57 – 7.53 (m, 2H, Ar-H), 7.44 – 7.40 (m, 3H, Ar-H, =CH), 7.39 – 7.34 (m, 1H, Ar-H), 7.18 – 7.11 (m, 4H, Ar-H), 6.62 (d, J J = 15.8 Hz, 1H, =CH), 3.42 – 3.36 (m, 2H, -CH2), 3.27 – 3.20 (m, 2H, -CH2), 2.74 (t, J J = 7.4 Hz, 2H, -CH2), 2.66 (t, J J = 7.5 Hz, 2H, -CH2), 2.01 (t, J J = 7.3 Hz, 2H, -CH2), 1.53 – 1.44 (m, 2H, -CH2), 0.82 (t, J J = 7.4 Hz, 3H, -CH3). 1313C NMR (151 MHz, CDCl3) δ 171.72, 164.76, 138.40, 137.16, 136.98, 134.81, 129.29, 128.82, 128.50, 128.45, 127.38, 122.14, 40.26, 39.98, 37.24, 34.77, 34.64, 18.55, 13.50. HR-ESI + -MS calculated for C 23 H 28 N2O2 m / z [M+H] + : 365.2229; found: 365.2224。

[0066] Compound 20: 1 1H NMR (600 MHz, Chloroform- d ) δ 7.62 (d, J J = 15.6 Hz, 1H, =CH), 7.52 – 7.44 (m, 2H, Ar-H), 7.40 – 7.31 (m, 3H, Ar-H), 7.16 (d, J J = 2.3 Hz, 4H, Ar-H), 6.32 (d, J J = 15.6 Hz, 1H, =CH), 5.62 (t, J J = 5.9 Hz, 1H, -NH), 4.55 (s, 1H, -NH), 3.68 – 3.62 (m, 2H, -CH2), 3.41 – 3.34 (m, 2H, -CH2), 2.87 (t, J J = 6.9 Hz, 2H, -CH2), 2.78 (t, J J = 7.1 Hz, 2H, -CH2), 1.43 (s, 9H, -CH3). 13 13C NMR(151 MHz, CDCl3) δ 165.84, 155.88, 141.12, 137.30, 136.94, 134.83, 129.68, 129.14, 129.02, 128.81, 127.80, 120.57, 79.26, 41.80, 40.80, 35.86, 35.27, 28.41. HR-ESI + -MS calculated for C 24 H30 N₂O₃m / z [M+Na] + : 417.2154; found:417.2153.

[0067] Compound 21: 1 H NMR (600 MHz, DMSO-d6) δ 8.20 (t, J = 5.7 Hz, 1H, -NH), 7.78 (t, J = 5.6 Hz, 1H, -NH), 7.57 – 7.52 (m, 2H, Ar-H), 7.44 – 7.34 (m, 4H,Ar-H, =CH), 7.18 – 7.09 (m, 4H, Ar-H), 6.63 (d, J = 15.8 Hz, 1H, =CH), 3.42 –3.36 (m, 2H, -CH2), 3.25 – 3.20 (m, 2H, -CH2), 2.74 (t, J = 7.4 Hz, 2H, -CH2),2.66 (t, J = 7.4 Hz, 2H, -CH2), 2.31 (hept, J = 6.8 Hz, 1H, -CH), 0.96 (d, J= 6.9 Hz, 6H, -CH3). 13 C NMR (151 MHz, CDCl3) δ 175.81, 164.78, 138.38, 137.18,136.98, 134.83, 129.30, 128.83, 128.55, 128.44, 127.39, 122.17, 40.27, 39.95,34.71, 34.65, 33.85, 19.47. HR-ESI + -MS calculated for C 23 H 28 N₂O₂m / z [M+H] + :365.2229; found: 365.2229.

[0068] Example 3: Preparation of compounds 22-34 (X is a nitrogen atom, R1 is a series of compounds of formula (I) of 3-pyridine) (1) Add (E)-3-(pyridin-3-yl)acrylic acid (5 mmol) and N,N'-carbonyldiimidazole (6 mmol) to dry THF (40 ml), stir at room temperature for 2 h until the solid is completely dissolved, and add 4-bromophenylethylamine (5 mmol). Then stir overnight at room temperature until the starting material is completely consumed by TLC. After the reaction is complete, quench the reaction with water, extract with dichloromethane (60 mL × 3) and saturated brine (60 mL × 3), dry the organic layer with anhydrous sodium sulfate, and separate and purify by column chromatography (ethyl acetate: petroleum ether = 1:60) to give a white solid (compound J) in 85% yield.

[0069] (2) Under nitrogen protection at 0°C, 9-BBN (0.5 M in THF, 4.50 mmol) was slowly added to a solution of compound B (1.50 mmol) in anhydrous THF (3 mL). The mixture was slowly heated to 25°C and then stirred for 6 h until TLC analysis showed that the olefin was completely consumed. NaOH solution (2 M, 2.25 mL) was added dropwise at 0°C, and the reaction was carried out for 2 h. Then, 30 mL of anhydrous THF was added, followed by the sequential addition of compound J (1 mmol) and Pd(PPh3)4 (0.1 mmol). The reaction was heated, refluxed at 80°C, and stirred for 20 h. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate (60 mL × 3) and saturated brine (60 mL × 3), separated the organic layer, dried with anhydrous sodium sulfate, concentrated to obtain the crude product, and purified by column chromatography with gradient elution (DCM:MeOH = 1:100, DCM:MeOH = 1:60, DCM:MeOH = 1:40) to obtain a white solid (compound K), with a yield of 34%.

[0070] The specific structures of the R2 substituent and the corresponding compounds are shown in Table 3.

[0071] Table 3

[0072]

[0073] The characterization data of compounds 22-35 are as follows: Compound 22: 1 H NMR (600 MHz, DMSO- d 6) δ 8.75 (d, J = 2.2 Hz, 1H, Ar-H),8.59 – 8.53 (m, 2H, -NH, Ar-H), 8.26 (t, J = 5.7 Hz, 1H, -NH), 7.97 (dt, J= 8.0, 2.0 Hz, 1H, Ar-H), 7.84 – 7.80 (m, 2H, Ar-H), 7.54 – 7.48 (m, 1H, Ar-H), 7.48– 7.41 (m, 4H, Ar-H, =CH), 7.21 – 7.15 (m, 4H, Ar-H), 6.73 (d, J = 15.9 Hz, 1H), 3.46 (dt, J = 8.2, 5.9 Hz, 2H, -CH2), 3.44 – 3.37 (m, 2H, -CH2), 2.82 (d, J = 7.8 Hz, 2H, -CH2), 2.75 (t, J = 7.4 Hz, 2H, -CH2). 13 C NMR (151 MHz, DMSO) δ166.03, 164.37, 150.00, 149.01, 137.19, 137.01, 135.12, 134.52, 133.81, 130.95, 130.61, 128.56, 128.52, 128.15, 127.00, 124.13, 123.87, 40.80, 40.28, 34.63, 34.60. HR-ESI + -MS calculated for C 25 H 25 N3O2 m / z [M+H] + : 400.2025; found: 400.2023。

[0074] Compound 23: 1 H NMR (600 MHz, DMSO- d 6) δ 8.75 (d, J = 2.3 Hz, 1H, Ar-H), 8.71 (t, J = 5.6 Hz, 1H, -NH), 8.55 (dd, J = 4.7, 1.6 Hz, 1H, Ar-H), 8.27 (t, J = 5.7 Hz, 1H, -NH), 7.97 (dt, J = 8.0, 2.0 Hz, 1H, Ar-H), 7.86 (t, J = 1.9 Hz, 1H, Ar-H), 7.79 (dt,J = 7.7, 1.4 Hz, 1H, Ar-H), 7.59 (ddd, J = 8.0, 2.2, 1.0 Hz, 1H,Ar-H), 7.50 (t, J = 7.9 Hz, 1H, Ar-H), 7.47 – 7.42 (m, 2H, =CH), 7.20 – 7.16(m, 4H, Ar-H), 6.73 (d, J = 15.8 Hz, 1H, =CH), 3.49 – 3.44 (m, 2H, -CH2), 3.41(dt, J = 7.8, 6.1 Hz, 2H, -CH2), 2.82 (t, J = 7.5 Hz, 2H, -CH2), 2.76 (t, J = 7.4Hz, 2H, -CH2). 13 C NMR (151 MHz, DMSO) δ 165.17, 164.95, 150.58, 149.58,137.63, 137.03, 135.68, 134.38, 133.62, 131.41, 131.19, 130.80, 129.14,129.11, 129.05, 127.43, 126.37, 124.71, 124.44, 41.46, 40.85, 35.17, 35.06.HR-ESI + -MS calculated for C 25 H 24 ClN3O2m / z [M+H] + : 434.1635; found: 434.1638。

[0075] Compound 24: 1 H NMR (600 MHz, DMSO- d 6) δ 8.75 (d, J = 2.3 Hz, 1H, Ar-H),8.55 (dd, J = 4.7, 1.6 Hz, 1H, Ar-H), 8.29 – 8.22 (m, 2H, -NH), 7.97 (dt, J =7.9, 2.0 Hz, 1H, Ar-H), 7.48 – 7.41 (m, 2H, Ar-H), 7.28 (td,J = 7.4, 1.6 Hz, 1H, Ar-H), 7.24 – 7.22 (m, 1H, Ar-H), 7.21 – 7.16 (m, 6H, =CH, Ar-H), 6.72(d, J = 15.8 Hz, 1H, =CH), 3.48 – 3.38 (m, 4H, -CH2), 2.83 – 2.73 (m, 4H, -CH2), 2.25 (s, 3H, -CH3). 13 C NMR (151 MHz, DMSO) δ 168.83, 164.35, 149.99, 148.99, 137.25, 137.08, 136.96, 135.12, 134.95, 133.80, 130.59, 130.20, 128.96, 128.60, 128.44, 126.77, 125.29, 124.10, 123.86, 40.29, 40.24, 34.60, 34.52, 19.16. HR-ESI + -MS calculated for C 26 H 27 N3O2 m / z [M+H] + : 414.2182; found: 414.2176。

[0076] Compound 25: 1 H NMR (600 MHz, DMSO- d 6) δ 8.75 (d, J = 2.2 Hz, 1H, Ar-H), 8.55 (dd, J = 4.7, 1.6 Hz, 1H, Ar-H), 8.50 (t, J = 5.6 Hz, 1H, -NH), 8.25 (t, J = 5.7 Hz, 1H, -NH), 7.97 (dt, J = 7.9, 2.0 Hz, 1H, Ar-H), 7.49 – 7.39 (m, 4H, Ar-H, =CH), 7.39 – 7.32 (m, 2H, Ar-H), 7.23 – 7.16 (m, 4H, Ar-H), 6.73 (d, J= 15.9 Hz, 1H, =CH), 3.47 – 3.38 (m, 4H, -CH2), 2.81 (t, J = 7.4 Hz, 2H, -CH2), 2.77 (t, J = 7.4 Hz, 2H, -CH2). 13 C NMR (151 MHz, DMSO) δ 166.68, 164.95, 150.58, 149.58, 137.61, 137.59, 137.54, 135.71, 134.39, 131.18, 131.09, 130.33, 130.02, 129.22, 129.19, 129.06, 127.50, 124.69, 124.44, 41.04, 40.87, 35.18, 34.98. HR-ESI + -MS calculated for C 25 H 24 ClN3O2 m / z [M+H] + : 434.1635; found: 434.1632。

[0077] Compound 26: 1 H NMR (600 MHz, DMSO- d 6) δ 8.75 (d, J = 2.3 Hz, 1H, Ar-H), 8.55 (dd, J = 4.8, 1.6 Hz, 1H, Ar-H), 8.24 (t, J = 5.7 Hz, 1H, -NH), 7.97 (dt, J = 8.1, 2.0 Hz, 1H, Ar-H), 7.72 (t, J = 5.6 Hz, 1H, -NH), 7.47 – 7.42 (m, 2H, =CH), 7.17 – 7.10 (m, 4H, Ar-H), 6.72 (d, J = 15.9 Hz, 1H, =CH), 3.43 – 3.37 (m, 2H, -CH2), 3.21 (dt, J = 7.9, 6.0 Hz, 2H, -CH2), 2.75 (t, J = 7.4 Hz, 2H, -CH2), 2.65 (t, J= 7.4 Hz, 2H, -CH2), 2.04 (tt, J = 11.6, 3.5 Hz, 1H, -CH), 1.70 – 1.56(m, 5H, -CH2), 1.29 (qd, J = 12.3, 3.2 Hz, 2H, -CH2), 1.22 – 1.09 (m, 3H, -CH2). 13 C NMR (151 MHz, DMSO) δ 175.49, 164.93, 150.58, 149.57, 137.78, 137.48, 135.70, 134.39, 131.18, 129.12, 128.99, 124.68, 124.44, 44.45, 40.86, 40.53, 35.28, 35.16, 29.67, 25.94, 25.75. HR-ESI + -MS calculated for C 25 H 31 N3O2m / z [M+H] + : 406.2495; found: 406.2498。

[0078] Compound 27: 1 H NMR (600 MHz, DMSO- d 6) δ 8.75 (d, J = 2.3 Hz, 1H, Ar-H), 8.55 (dd, J = 4.8, 1.6 Hz, 1H, Ar-H), 8.42 (t, J = 5.8 Hz, 1H, -NH), 8.24 (t, J = 5.7 Hz, 1H, -NH), 7.97 (dt, J = 8.0, 2.0 Hz, 1H, Ar-H), 7.81 (dd, J = 1.7, 0.8Hz, 1H, Ar-H), 7.48 – 7.41 (m, 2H, Ar-H, =CH), 7.16 (s, 4H, Ar-H), 7.06 (d, J = 3.2 Hz, 1H, Ar-H), 6.72 (d, J = 15.9 Hz, 1H, =CH), 6.60 (dd, J= 3.4, 1.7 Hz, 1H, Ar-H), 3.45 – 3.37 (m, 4H, -CH2), 2.81 – 2.72 (m, 4H, -CH2). 13 C NMR (151 MHz, DMSO) δ 164.37, 157.58, 150.00, 149.00, 147.92, 144.75, 137.03, 137.02, 135.14, 133.82, 130.61, 128.53, 128.51, 124.11, 123.87, 113.02, 111.67, 40.27, 39.98, 34.66, 34.60. HR-ESI + -MS calculated for C 23 H 23 N3O3 m / z [M+H] + : 390.1818; found: 390.1821。

[0079] Compound 28: 1 H NMR (600 MHz, DMSO- d 6) δ 8.75 (d, J = 2.3 Hz, 1H, Ar-H), 8.64 (t, J = 5.6 Hz, 1H, -NH), 8.55 (dd, J = 4.7, 1.6 Hz, 1H, Ar-H), 8.24 (t, J = 5.7 Hz, 1H, -NH), 7.97 (dt, J = 8.2, 2.0 Hz, 1H, Ar-H), 7.86 – 7.82 (m, 2H, Ar-H), 7.55 – 7.51 (m, 2H, Ar-H), 7.48 – 7.41 (m, 2H, =CH), 7.17 (s, 4H, Ar-H), 6.72 (d, J = 15.9 Hz, 1H, =CH), 3.48 – 3.43 (m, 2H, -CH2), 3.43 – 3.37 (m, 2H, -CH2), 2.81 (t, J = 7.5 Hz, 2H, -CH2), 2.75 (t, J = 7.4 Hz, 2H, -CH2). 1313C NMR (151 MHz, DMSO) δ 164.97, 164.37, 150.01, 149.01, 137.10, 137.04, 135.80, 135.14, 133.82, 133.21, 130.61, 128.95, 128.56, 128.53, 128.26, 124.11, 123.88, 40.86, 40.28, 34.60, 34.55. HR-ESI + -MS calculated for C 25 H 24 ClN3O2 m / z [M+H] + : 434.1635; found: 434.1637。

[0080] Compound 29: 1 1H NMR (600 MHz, DMSO- d d6) δ 8.75 (d, J J = 2.3 Hz, 1H, Ar-H), 8.55 (dd, J J = 4.7, 1.6 Hz, 1H, Ar-H), 8.25 (t, J J = 5.7 Hz, 1H -NH), 7.97 (dt, J J = 8.1, 1.9 Hz, 1H, Ar-H), 7.82 (t, J J = 5.6 Hz, 1H -NH), 7.48 – 7.42 (m, 2H, Ar-H, =CH), 7.18 – 7.10 (m, 4H, Ar-H), 6.73 (d, J J = 15.9 Hz, 1H, =CH), 3.44 – 3.37 (m, 2H, -CH2), 3.26 – 3.21 (m, 2H, -CH2), 2.75 (t, J J = 7.4 Hz, 2H, -CH2), 2.67 (t, J J = 7.5 Hz, 2H, -CH2), 2.04 (q, J J = 7.6 Hz, 2H, -CH2), 0.97 (t, J J = 7.6 Hz, 3H, -CH3). 1313C NMR (151 MHz, DMSO) δ 173.19, 164.93, 150.56, 149.56, 137.75, 137.51, 135.68, 134.37, 131.17, 129.08, 129.03, 124.68, 124.43, 40.85, 40.61, 35.32, 35.17, 28.97, 10.43. HR-ESI + -MS calculated for C 21 H 25 N3O2 m / z [M+H] + : 352.2025; found: 352.2022。

[0081] Compound 30: 1 1H NMR (600 MHz, DMSO- d d6) δ 8.75 (d, J J = 2.3 Hz, 1H, Ar-H), 8.55 (dd, J J = 4.7, 1.6 Hz, 1H, Ar-H), 8.37 (t, J J = 5.6 Hz, 1H, -NH), 8.25 (t, J J = 5.7 Hz, 1H, -NH), 7.97 (dt, J J = 7.9, 2.0 Hz, 1H, Ar-H), 7.56 (td, J J = 7.5, 1.8 Hz, 1H, Ar-H), 7.54 – 7.49 (m, 1H, Ar-H), 7.49 – 7.41 (m, 2H, Ar-H, =CH), 7.30 – 7.23 (m, 2H, Ar-H), 7.22 – 7.15 (m, 4H, Ar-H), 6.73 (d, J J = 15.9 Hz, 1H, =CH), 3.49 – 3.38 (m, 4H), 2.83 – 2.73 (m, 4H, -CH2), -3.76 (s, 1H, -CH2). 13CNMR (151 MHz, DMSO) δ 163.87, 163.00, 159.30, 157.65, 149.50, 148.50, 136.54, 136.51, 134.63, 133.32, 131.66, 131.61, 130.10, 129.38, 128.08, 128.01, 123.85, 123.82, 123.68, 123.61, 123.60, 123.37, 115.54, 115.40, 40.24, 39.78, 34.10, 33.98. HR-ESI + -MS calculated for C 25 H 24 FN3O2 m / z [M+H] + : 418.1931; found: 418.1932。

[0082] Compound 31: 1 H NMR (600 MHz, DMSO- d 6) δ 8.76 (m, 2H, -NH, Ar-H), 8.55 (dd, J = 4.7, 1.6 Hz, 1H, Ar-H), 8.25 (t, J = 5.6 Hz, 1H, -NH), 7.97 (dt, J = 7.9, 2.0 Hz, 1H, Ar-H), 7.50 – 7.43 (m, 4H, Ar-H, =CH), 7.40 (dd, J = 8.9, 7.2 Hz, 1H, Ar-H), 7.21 (d, J = 8.1 Hz, 2H, Ar-H), 7.17 (d, J = 8.1 Hz, 2H, Ar-H), 6.73 (d, J = 15.9 Hz, 1H, =CH), 3.50 – 3.43 (m, 2H, -CH2), 3.43 – 3.38 (m, 2H, -CH2), 2.81 (t, J = 7.5 Hz, 2H, -CH2), 2.76 (t, J = 7.4 Hz, 2H, -CH2). 1313C NMR (151 MHz, DMSO) δ 164.38, 163.37, 150.00, 149.00, 137.04, 136.81, 136.57, 135.13, 133.82, 131.06, 130.76, 130.61, 128.61, 128.48, 127.94, 124.12, 123.87, 40.33, 40.30, 34.60, 34.32. HR-ESI + -MS calculated for C 25 H 23 Cl2N3O2 m / z [M+H] + : 468.1246; found: 468.1251。

[0083] Compound 32: 1 1H NMR (600 MHz, DMSO- d 6) δ 8.75 (d, J J = 2.3 Hz, 1H, Ar-H), 8.55 (dd, J J = 4.8, 1.6 Hz, 1H, Ar-H), 8.26 (t, J J = 5.7 Hz, 1H, -NH), 7.97 (dt, J J = 8.0, 2.0 Hz, 1H, Ar-H), 7.84 (t, J J = 5.6 Hz, 1H, -NH), 7.48 – 7.41 (m, 2H, Ar-H, =CH), 7.14 (q, J J = 8.1 Hz, 4H, Ar-H), 6.73 (d, J J = 15.9 Hz, 1H, =CH), 3.43 – 3.37 (m, 2H, -CH2), 3.27 – 3.21 (m, 2H, -CH2), 2.75 (t, J J = 7.4 Hz, 2H, -CH2), 2.67 (t, J J = 7.5 Hz, 2H, -CH2), 2.01 (t, J J = 7.3 Hz, 2H, -CH2), 1.48 (h, J J = 7.4 Hz, 2H, -CH2), 0.82 (t, J J = 7.4 Hz, 3H, -CH3). 1313C NMR (151 MHz, DMSO) δ 172.30, 164.93, 150.56, 149.56, 137.75, 137.50, 135.68, 134.37, 131.17, 129.07, 129.02, 124.68, 124.43, 40.86, 40.56, 37.82, 35.35, 35.17, 19.13, 14.09. HR-ESI + -MS calculated for C 22 H 27 N3O2 m / z [M+H] + : 366.2182; found: 366.2185。

[0084] Compound 33: 1 1H NMR (600 MHz, DMSO- d 6) δ 8.75 (d, J J = 2.5 Hz, 1H, Ar-H), 8.55 (dd, J J = 4.8, 1.6 Hz, 1H, Ar-H), 8.24 (t, J J = 5.7 Hz, 1H, -NH), 7.97 (dt, J J = 8.1, 2.0 Hz, 1H, Ar-H), 7.49 – 7.41 (m, 2H, Ar-H, =CH), 7.15 (d, J J = 7.8 Hz, 2H, Ar-H), 7.12 (d, J J = 7.9 Hz, 2H, Ar-H), 6.86 (t, J J = 5.6 Hz, 1H, -NH), 6.72 (d, J J = 15.9 Hz, 1H, =CH), 3.40 (dt, J J = 7.7, 6.3 Hz, 2H, -CH2), 3.11 (dt, J J = 8.3, 6.2 Hz, 2H, -CH2), 2.75 (t, J J = 7.4 Hz, 2H, -CH2), 2.65 (t, J J = 6.9 Hz, 2H, -CH2), 2.62 (s, 2H), 1.36 (s, 9H, -CH3). 1313C NMR (151 MHz, DMSO) δ 164.36, 155.41, 150.00, 149.00, 137.07, 136.92, 135.12, 133.81, 130.61, 128.52, 128.46, 124.11, 123.87, 77.38, 41.45, 40.28, 35.02, 34.60, 28.16. HR-ESI + -MS calculated for C 23 H 29 N3O3 m / z [M+H] + : 396.2287; found: 396.2285。

[0085] Compound 34: 1 1H NMR (600 MHz, DMSO- d 6) δ 8.75 (d, J J = 2.2 Hz, 1H, Ar-H), 8.55 (dd, J J = 4.7, 1.6 Hz, 1H, Ar-H), 8.28 (t, J J = 5.6 Hz, 1H, -NH), 7.97 (dt, J J = 8.2, 2.1 Hz, 1H, Ar-H), 7.79 (t, J J = 5.6 Hz, 1H, -NH), 7.47 – 7.42 (m, 2H, Ar-H, =CH), 7.16 (d, J J = 8.0 Hz, 2H, Ar-H), 7.13 (d, J J = 7.9 Hz, 2H, Ar-H), 6.74 (d, J J = 15.9 Hz, 1H, =CH), 3.43 – 3.37 (m, 2H, -CH2), 3.25 – 3.20 (m, 2H, -CH2), 2.75 (t, J J = 7.4 Hz, 2H, -CH2), 2.67 (t, J J = 7.4 Hz, 2H, -CH2), 2.31 (p, J J = 6.9 Hz, 1H, -CH), 0.96 (d, J J = 6.8 Hz, 6H, -CH3). 1313C NMR (151 MHz, DMSO) δ 175.85, 164.38, 150.00, 148.99, 137.19, 136.92, 135.12, 133.82, 130.60, 128.56, 128.43, 124.11, 123.87, 40.28, 39.94, 34.70, 34.58, 33.86, 19.45. HR-ESI + -MScalculated for C 22 H 27 N3O2m / z [M+H] + : 366.2182; found: 366.2183。

[0086] Compound 35: 1 1H NMR (600 MHz, DMSO- d 6) δ 8.60 (d, J J = 5.1 Hz, 2H, Ar-H), 8.49 (t, J J = 5.6 Hz, 1H, -NH), 8.33 (t, J J = 5.7 Hz, 1H, -NH), 7.51 (d, J J = 5.1 Hz, 2H, Ar-H), 7.46 (d, J J = 7.9 Hz, 1H, Ar-H), 7.43 – 7.32 (m, 5H, Ar-H, =CH), 7.22– 7.16 (m, 4H, Ar-H), 6.83 (d, J J = 15.8 Hz, 1H, =CH), 3.42 (m, 4H, -CH2), 2.80(t, J J = 7.4 Hz, 2H, -CH2), 2.76 (t, J J = 7.4 Hz, 2H, -CH2). 13C NMR (151 MHz, DMSO) δ 166.09, 164.06, 150.23, 142.04, 137.00, 136.97, 135.97, 130.50, 129.74, 129.43, 128.63, 128.61, 128.47, 126.91, 126.57, 125.58, 121.54, 40.46, 40.32, 34.53, 34.40. HR-ESI +-MS calculated for C 25 H 24 ClN3O2m / z [M+H] + : 434.1635; found:434.1637. Example 4: Preparation of compounds 36-41 (a series of compounds of formula (I) where X is an oxygen atom and R1 is a benzene ring) (1) Under nitrogen protection, 4-bromophenylethanol (4 mmol) and triethylamine (4.8 mmol) were added to dry dichloromethane (10 ml). Cinnamyl chloride (4 mmol) was added to the reaction mixture while stirring at 0 °C. The mixture was then stirred at room temperature for 16–20 h until the starting material was completely consumed by TLC. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with dichloromethane (60 mL × 3) and saturated brine (60 mL × 3). The organic layer was dried over anhydrous sodium sulfate and purified by column chromatography (EA:PE = 1:40) to obtain a white solid (compound L) in 80% yield.

[0087] (2) Under nitrogen protection at 0°C, 9-BBN (0.5 M in THF, 4.50 mmol) was slowly added to an anhydrous THF (3 mL) solution of compound B (1.50 mmol). The mixture was slowly heated to 25°C and then stirred for 6 h until TLC analysis showed that the olefin was completely consumed. NaOH solution (1.5 M, 3 mL) was added dropwise at 0°C, and the reaction was carried out for 2 h. Anhydrous THF 30 mL was added, followed by the sequential addition of compound L (1 mmol) and Pd(PPh3)4 (0.1 mmol). The reaction was heated, refluxed at 80°C, and stirred for 20 h. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (60 mL × 3) and saturated brine (60 mL × 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 1:60) to obtain a white solid (compound M), with a yield of 29%.

[0088] The specific structures of the R2 substituent and the corresponding compounds are shown in Table 4.

[0089] Table 4

[0090] The characterization data of compounds 36-41 are as follows: Compound 36: 1 H NMR (600 MHz, Chloroform- d) δ 7.74 – 7.67 (m, 2H, Ar-H, =CH), 7.58 – 7.51 (m, 3H, Ar-H), 7.48 – 7.44 (m, 1H, Ar-H), 7.43 – 7.39 (m,3H, Ar-H), 7.35 (t, J = 7.8 Hz, 1H, Ar-H), 7.26 (d, J = 7.9 Hz, 2H, Ar-H), 7.21(d, J = 7.8 Hz, 2H, Ar-H), 6.44 (d, J = 16.0 Hz, 1H, =CH), 6.11 (t, J = 5.8 Hz, 1H,-NH), 4.44 (t, J = 7.0 Hz, 2H, -CH2), 3.76 – 3.70 (m, 2H, -CH2), 3.03 (t, J = 7.1Hz, 2H, -CH2), 2.94 (t, J = 6.9 Hz, 2H, -CH2). 13 C NMR (151 MHz, CDCl3) δ 166.93,166.16, 144.95, 136.98, 136.47, 136.35, 134.79, 134.38, 131.48, 130.36,129.91, 129.37, 128.99, 128.93, 128.11, 127.30, 124.84, 118.01, 65.01, 41.25,35.24, 34.82. HR-ESI + -MS calculated for C 26 H 24 ClNO3m / z [M+H] + : 434.1523; found:434.1526。

[0091] Compound 37: 1 H NMR (600 MHz, Chloroform- d ) δ 7.70 (d, J = 16.0 Hz, 1H, =CH), 7.64 (dd, J= 7.3, 2.0 Hz, 1H, Ar-H), 7.57 – 7.51 (m, 2H, Ar-H), 7.43 –7.39 (m, 3H, Ar-H), 7.38 – 7.28 (m, 5H, Ar-H), 7.24 (s, 4H, Ar-H), 6.45 (d, J =16.0 Hz, 1H, =CH), 6.21 (t, J = 5.6 Hz, 1H, -NH), 4.43 (t, J = 7.0 Hz, 2H, -CH2), 3.80 – 3.74 (m, 2H, -CH2), 3.02 (t, J = 7.1 Hz, 2H, -CH2), 2.97 (t, J = 6.9 Hz, 2H, -CH2). 13 C NMR (151 MHz, CDCl3) δ 166.93, 166.44, 144.91, 136.94, 136.26,135.07, 134.41, 131.25, 130.60, 130.34, 130.21, 130.18, 129.29, 129.04,128.92, 128.12, 127.07, 118.05, 65.03, 41.24, 35.09, 34.81. HR-ESI + -MScalculated for C 26 H 24 ClNO3m / z [M+H] + : 434.1523; found: 434.1526。

[0092] More information: 38: 1 1H NMR (600 MHz, Chloroform- d ) δ 7.68 (d, J = 16.1 Hz, 1H, =CH), 7.54 – 7.50 (m, 2H, Ar-H), 7.42 – 7.37 (m, 3H, Ar-H), 7.21 (d, J = 7.8 Hz, 2H, Ar-H), 7.14 (d, J = 7.8 Hz, 2H, Ar-H), 6.43 (d, J= 16.0 Hz, 1H, =CH), 5.43(t, J = 5.4 Hz, 1H, -NH), 4.41 (t, J = 7.1 Hz, 2H, -CH2), 3.53 – 3.47 (m, 2H, -CH2), 3.00 (t, J = 7.1 Hz, 2H, -CH2), 2.79 (t, J = 6.9 Hz, 2H, -CH2), 2.01 (tt, J =11.7, 3.5 Hz, 1H, -CH), 1.82 – 1.75 (m, 4H, -CH2), 1.66 – 1.61 (m, 1H, -CH2),1.38 (qd, J = 12.1, 3.3 Hz, 2H, -CH2), 1.27 – 1.16 (m, 3H, -CH2). 13 C NMR (151MHz, CDCl3) δ 176.04, 166.92, 144.93, 137.29, 136.07, 134.38, 130.35, 129.20,128.98, 128.92, 128.10, 118.01, 65.04, 45.54, 40.35, 35.35, 34.80, 29.67,25.73, 25.71. HR-ESI + -MS calculated for C 26 H 31 NO3m / z [M+H] + : 406.2382; found:406.2385。

[0093] Compound 39: 1 H NMR (600 MHz, Chloroform- d ) δ 7.70 (d, J = 16.0 Hz, 1H, =CH), 7.56 – 7.52 (m, 2H, Ar-H), 7.45 (d, J = 5.0 Hz, 1H, Ar-H), 7.44 – 7.38 (m,4H, Ar-H), 7.25 (d, J = 7.7 Hz, 2H, Ar-H), 7.21 (d, J= 7.8 Hz, 2H, Ar-H), 7.05(t, J = 4.4 Hz, 1H, Ar-H), 6.45 (d, J = 16.0 Hz, 1H, =CH), 6.00 – 5.96 (m, 1H, -NH), 4.44 (t, J = 7.0 Hz, 2H, -CH2), 3.73 – 3.67 (m, 2H, -CH2), 3.03 (t, J = 7.0Hz, 2H, -CH2), 2.93 (t, J = 6.9 Hz, 2H, -CH2). 13 C NMR (151 MHz, CDCl3) δ 166.93,161.81, 144.93, 138.97, 137.05, 136.28, 134.40, 130.36, 129.77, 129.34,129.03, 128.93, 128.11, 127.90, 127.60, 118.03, 65.02, 41.09, 35.39, 34.83.HR-ESI + -MS calculated for C 24 H 23 NO3Sm / z [M+H] + : 406.1477; found: 406.1471。

[0094] Compound 40 7.43 – 7.36 (m, 3H, Ar-H), 7.23 – 7.19 (m, 2H, Ar-H), 7.17 –7.12 (m, 2H, Ar-H), 6.43 (d, J = 16.0 Hz, 1H, =CH), 5.52 – 5.39 (m, 1H, -NH),4.41 (t, J = 7.0 Hz, 2H, -CH2), 3.51 (q, J = 6.6 Hz, 2H, -CH2), 3.00 (t, J =7.1 Hz, 2H, -CH2), 2.80 (t, J = 7.0 Hz, 2H, -CH2), 2.16 (q, J = 7.6 Hz, 2H, -CH2), 1.12 (t, J = 7.6 Hz, 3H, -CH3). 1313C NMR (151 MHz, CDCl3) δ 173.76, 166.92, 144.93, 137.19, 136.13, 134.38, 130.36, 129.23, 128.95, 128.92, 128.10, 118.01, 65.02, 40.51, 35.30, 34.80, 29.75, 9.86. HR-ESI + -MS calculated for C 22 H 25 NO3 m / z [M+H] + : 352.1913; found: 352.1912。

[0095] Compound 41: 1 1H NMR (600 MHz, Chloroform- d ) δ 8.09 (td, J J = 7.9, 2.0 Hz, 1H, Ar-H), 7.68 (d, J J = 16.0 Hz, 1H, =CH), 7.52 (dd, J J = 6.6, 3.0 Hz, 2H, Ar-H), 7.43 (tdd, J J = 7.6, 5.1, 1.9 Hz, 1H, Ar-H), 7.40 – 7.36 (m, 3H, Ar-H), 7.25 – 7.18 (m, 5H, Ar-H), 7.05 (ddd, J J = 12.2, 8.3, 1.1 Hz, 1H, Ar-H), 6.79 – 6.72 (m, 1H, -NH), 6.43 (d, J J = 16.0 Hz, 1H, =CH), 4.42 (t, J J = 7.1 Hz, 2H, -CH2), 3.77 – 3.71 (m, 2H, -CH2), 3.01 (t, J J = 7.1 Hz, 2H, -CH2), 2.92 (t, J J = 7.0 Hz, 2H, -CH2). 13C NMR (151 MHz, CDCl3) δ 166.93, 163.23, 161.44, 159.80, 144.89,137.10, 136.18, 134.42, 133.22, 133.16, 132.05, 130.32, 129.27, 128.98,128.91, 128.11, 124.80, 124.78, 121.10, 121.03, 118.07, 116.05, 115.89,65.04, 41.33, 35.26, 34.82. + -MS calculated for C 26 H 24 FNO3m / z [M+H] + :418.1818; found: 418.1820.

[0096] Example 5: Preparation of compounds 42 and 43 (R1 is a compound of formula (II) with a benzene ring and a 3-pyridine ring) (1) Dissolve compound 20 or compound 33 (0.5 mmol) in a small amount of dry dichloromethane, add 5 mL of a mixture of trifluoroacetic acid and dichloromethane (1:1), monitor by TLC, quench with water after the reaction is complete, extract with ethyl acetate (30 mL × 3) and saturated saline (30 mL × 3), separate the organic layer, dry with anhydrous sodium sulfate, filter, and evaporate to dryness to obtain product compound 42 or 43, with yields of about 50% and 25%, respectively.

[0097] Table 5

[0098] The characterization data of compounds 42-43 are as follows: Compound 42: 1 H NMR (600 MHz, DMSO- d 6) δ 8.22 (t, J = 5.6 Hz, 1H, -NH), 7.84(s, 2H, -NH2), 7.57 – 7.53 (m, 2H, Ar-H), 7.44 – 7.39 (m, 3H, Ar-H, =CH), 7.39 – 7.34 (m, 1H, Ar-H), 7.23 – 7.17 (m, 4H, Ar-H), 6.63 (d, J= 15.8 Hz, 1H, =CH), 3.43 – 3.37 (m, 2H, -CH2), 3.04 – 2.99 (m, 2H, -CH2), 2.85 – 2.80 (m, 2H, -CH2), 2.76 (t, J = 7.4 Hz, 2H, -CH2). 13 C NMR (151 MHz, DMSO) δ 164.30, 137.93, 137.31, 134.44, 134.31, 128.83, 128.35, 128.28, 128.05, 126.90, 121.64, 39.72, 39.46, 34.13, 32.18. HR-ESI + -MS calculated for C 19 H 22 N2Om / z [M+H] + : 295.1810; found: 295.1811. Compound 43: 1 H NMR (600 MHz, Methanol- d 4) δ 8.70 (d, J = 2.2 Hz, 1H, Ar-H), 8.51 (dd, J = 4.9, 1.6 Hz, 1H, Ar-H), 8.03 (dt, J = 8.0, 2.0 Hz, 1H, Ar-H), 7.53 (d, J = 15.8 Hz, 1H, =CH), 7.46 (dd, J = 8.0, 4.9 Hz, 1H, Ar-H), 7.23 – 7.15 (m, 4H, Ar-H), 6.69 (d, J = 15.8 Hz, 1H, =CH), 3.53 (t, J = 7.4 Hz, 2H, -CH2), 2.95 – 2.89 (m, 2H, -CH2), 2.85 (t, J = 7.3 Hz, 2H, -CH2), 2.77 (t, J = 7.4 Hz, 2H, -CH2). 13C NMR (151 MHz, MeOD) δ 167.78, 150.80, 149.74, 138.73, 138.28, 137.55,136.33, 132.95, 130.17, 130.02, 125.60, 124.79, 43.68, 42.33, 38.35,36.19.HR-ESI + -MS calculated for C 18 H 21 N3Om / z [M+H] + : 296.1763; found: 296.1763. Example 6: Study on the effects of the series of compounds of the present invention on cancer cell proliferation (1) Experimental materials: The series of compounds of this invention and positive control 2-BP, trypsin digestion solution, PBS buffer, fetal bovine serum, human breast cancer cells MCF-7, human colon cancer cells HCT116, human colon cancer cells HCT15, mouse colon cancer cells MC38, mouse colon cancer cells CT26, mouse liver cancer cells Hepa1-6, human diffuse histiocytic lymphoma cells SU-DHL-6, MC116 human lymphoma cells MC116, ELISA reader and 96-well plates, DMEM high glucose medium and RPMI 1640 medium, cell proliferation and toxicity assay kit (CCK-8), etc. The MCF-7, HCT116, HCT15, MC38, Hepa1-6, CT26, SU-DHL-6 and MC116 cell lines used in this study were all obtained from the Shanghai Cell Bank of the Chinese Academy of Sciences.

[0099] (2) Experimental method: Cells in the logarithmic growth phase were digested with trypsin and resuspended in the appropriate culture medium containing 10% fetal bovine serum to prepare a uniformly dispersed single-cell suspension. The cell suspension was seeded into 96-well plates at a density of 6000 cells / well at 100 µL per well and incubated at 37℃ in a 5% CO2 incubator for 24 h until the cells were completely adhered. SU-DHL-6 and MC116 were suspension cells and no digestion step was required.

[0100] The test compounds were dissolved in dimethyl sulfoxide and serially diluted to create concentration gradients. The medium was replaced with the drug-treated medium the following day, with three replicates for each concentration. A negative control group (containing cells, culture medium, and an equal volume of solvent) and a blank group (containing only culture medium, no cells) were also set up. After incubating the culture plates for 48 h, 10 µL of CCK-8 reagent was added to each well, and incubation continued for another 4 h. The absorbance (OD value) at 450 nm was measured using a microplate reader. Inhibition rate = 1 - [(OD experimental group - OD blank group) / (OD negative control - OD blank group)] × 100%. Analysis was performed using Graphpad 7.0 software. First, the 50 µM inhibition rate of all compounds was calculated, and compounds with an inhibition rate greater than 80% were selected for IC50 analysis. 50 Value (mean ± standard deviation). Half-maximal inhibitory concentration (IC50) 50 The lower the value, the stronger the inhibitory effect of the compound on cancer cells. The test results are shown in Tables 5 and 6.

[0101] Table 6. Inhibition rates of the 50 µM compounds of this invention against different cancer cells.

[0102]

[0103] Table 7. IC50 values ​​of the compounds of this invention against different cancer cells.

[0104] The above embodiments demonstrate that the present invention has discovered compounds with higher anticancer activity than the positive control 2-BP, wherein compounds 22-34 show better inhibitory effects, indicating that they can be further developed into drugs targeting DHHC.

[0105] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the above descriptions are merely preferred embodiments of the present invention and are not intended to limit the invention. Any partial changes to the formulation and process therein should be within the scope of protection of the present invention.

Claims

1. A disubstituted phenylacrylamide / ester compound or a pharmaceutically acceptable salt thereof, characterized in that, The general structural formula of the compound is shown in formula (I) or (II): （I） (II) Wherein, X is an oxygen atom or a nitrogen atom; R1 is selected from any one of hydrogen atom, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R2 is selected from any one of substituted or unsubstituted aliphatic, substituted or unsubstituted alicyclic, substituted or unsubstituted aromatic, substituted or unsubstituted heteroaromatic, and amino protecting group; the carbon-carbon double bond is in trans configuration.

2. The disubstituted phenylacrylamide / ester compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, X is an oxygen atom or a nitrogen atom; R1 is selected from any one of hydrogen atom, benzene ring, 3-pyridine ring, and 4-pyridine ring; R2 is selected from any one of phenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-methylphenyl, o-fluorophenyl, 2-thienyl, 2-furanyl, cyclohexyl, tert-butoxy, n-propyl, isobutyl, n-butyl, 2,6-dichlorophenyl, or 3-pyridyl; the carbon-carbon double bond is in the trans configuration.

3. The disubstituted phenylacrylamide / ester compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, X is a nitrogen atom; R1 is selected from any one of hydrogen atom, benzene ring, 3-pyridine ring, and 4-pyridine ring; R2 is selected from any one of phenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-methylphenyl, o-fluorophenyl, 2-thienyl, 2-furanyl, cyclohexyl, tert-butoxy, n-propyl, isobutyl, n-butyl, 2,6-dichlorophenyl, or 3-pyridyl; the carbon-carbon double bond is in the trans configuration.

4. A method for preparing a compound of formula (I), characterized in that, When X is a nitrogen atom and R1 is a hydrogen atom, the synthesis route is as follows: ； When X is a nitrogen atom and R1 is a benzene ring, the synthetic route is as follows: ； When X is a nitrogen atom and R1 is 3-pyridine or 4-pyridine, the synthetic route is as follows: ； When X is an oxygen atom and R1 is a benzene ring, the synthetic route is as follows: ； In the formula, R2 is defined as in claim 1.

5. A method for preparing a compound of formula (II), characterized in that, The synthesis route is as follows: 。 6. The preparation method according to claim 4, characterized in that, Step i: Compound A reacts with N-vinylformamide in the presence of triethylamine and 4-dimethylaminopyridine to generate compound B; Step ii: Compound B first undergoes a boronization reaction with 9-boronbicyclo[3.3.1]nonane, and then undergoes a coupling reaction with tert-butyl(4-bromophenylethyl)carbamate under tetra(triphenylphosphine)palladium catalysis to generate compound C; Step iii: Compound C is deprotected to give compound D; Step iv: Compound D undergoes a substitution reaction with acryloyl chloride in the presence of triethylamine to produce product E; Step v: Cinnamyl chloride reacts with 4-bromophenylethylamine in the presence of triethylamine to produce compound G; Step vi: Compound B first undergoes a boronization reaction with 9-boronbicyclo[3.3.1]nonane, and then undergoes a coupling reaction with compound G under tetra(triphenylphosphine)palladium catalysis to obtain compound H; Step vii: (E)-3-(pyridin-3-yl)acrylic acid reacts with 4-bromophenylethylamine under N,N'-carbonyldiimidazole catalysis to produce compound J; Step viii: Compound B first undergoes a boronization reaction with 9-boronbicyclo[3.3.1]nonane, and then undergoes a coupling reaction with compound J under tetra(triphenylphosphine)palladium catalysis to obtain compound K; Step ix: Cinnamyl chloride reacts with 4-bromophenylethanol in the presence of triethylamine catalysis to produce compound L; Step x: Compound B first undergoes a boronization reaction with 9-boronbicyclo[3.3.1]nonane, and then undergoes a coupling reaction with compound L under tetra(triphenylphosphine)palladium catalysis to obtain compound M.

7. The preparation method according to claim 6, characterized in that, In step i, the molar ratio of N-vinylformamide, compound A, 4-dimethylaminopyridine, and triethylamine is 1:1.2:0.05:1.2; In step ii, the molar ratio of compound B, 9-boronbicyclo[3.3.1]nonane, tert-butyl(4-bromophenylethyl)carbamate, and tetrakis(triphenylphosphine)palladium is 1:3:0.6:0.06; In step iv, the molar ratio of compound D to acryloyl chloride and triethylamine is 1:1.5:1.5; In step v, the molar ratio of cinnamyl chloride, 4-bromophenylethylamine, and triethylamine is 1:1:1.2; In step vi, the molar ratio of compound B, 9-boronbicyclo[3.3.1]nonane, compound G and tetra(triphenylphosphine)palladium is 1:3:0.6:0.06; In step vii, the molar ratio of (E)-3-(pyridin-3-yl)acrylic acid, 4-bromophenylethylamine, and N,N'-carbonyldiimidazole is 1:1:1.2; In step viii, the molar ratio of compound B, 9-boronbicyclo[3.3.1]nonane, compound J and tetra(triphenylphosphine)palladium is 1:3:0.6:0.06; In step ix, the molar ratio of cinnamyl chloride, 4-bromophenylethanol, and triethylamine is 1:1:1.2; In step x, the molar ratio of compound B, 9-boronbicyclo[3.3.1]nonane, compound L and tetra(triphenylphosphine)palladium is 1:3:0.6:0.

06.

8. Use of the compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof in the preparation of an antitumor drug.

9. The application according to claim 8, characterized in that, The tumor is breast cancer, liver cancer, colon cancer, or lymphoma.

10. A palmityltransferase inhibitor, characterized in that, It comprises the compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable carriers or excipients.

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