An amide compound, its preparation method and application

Abstract

This invention belongs to the field of pharmaceutical technology, specifically providing an amide compound, its preparation method, and its application. The general structural formula of the amide compound is shown in Formula I. The compounds of this invention can act as palmitoyltransferase inhibitors, inhibiting the palmitoylation process of proteins related to tumorigenesis and immune escape by inhibiting the activity of palmitoyltransferase, thereby exerting an anti-tumor effect. Examples show that the amide compounds of this invention have varying degrees of anti-proliferative activity against different cancer cells. Compared with the positive control drugs cisplatin and 2-BP, most compounds exhibit better inhibitory activity against cancer cells and can be further developed into a new generation of anti-tumor drugs.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, and in particular relates to an amide compound, its preparation method and application. Background Technology

[0002] Due to the complex pathogenesis of tumors, poor treatment efficacy, high recurrence and metastasis rates, and significant side effects of treatment, the search for anticancer drugs with novel mechanisms of action and targets has always been a hot topic of interest for pharmaceutical researchers.

[0003] Unlike traditional treatments, tumor immunotherapy activates the body's immune system to eliminate tumor tissue and cells, establishes immune memory, and prevents tumor recurrence, drug resistance, and metastasis. T cells are the main cells in the immune system, responsible for recognition, response, and regulation, playing a dominant or central role. Immune checkpoints are inhibitory signaling pathways distributed throughout the body's immune system, regulating the strength and duration of immune responses, preventing tissue damage, and maintaining the body's tolerance. Tumors can exploit the inhibitory effects of immune checkpoint pathways to evade recognition by immune cells, particularly by suppressing T cell immune responses, thus achieving immune escape. Immune checkpoint inhibitors can restore T cell immune responses by blocking the transmission of inhibitory signaling pathways between antigen-presenting cells and T cells, enabling them to attack and kill tumor cells. To date, identified immune checkpoints include PD-1 / PD-L1, CTLA-4, LAG3, TIM3, and VISTA. Among these, programmed death-1 (PD-1) / programmed death-ligand 1 (PD-L1) is one of the most promising targets in immunotherapy.

[0004] PD-L1 is the major ligand of PD-1. Some tumor cells can rely on their expressed PD-L1 to bind to PD-1 on the surface of T cells, leading to T cell exhaustion and allowing tumor cells to evade the surveillance and killing effects of the host immune system. Recent studies have found that PD-L1 is not only expressed on the cell surface but also exists intracellularly in the Golgi apparatus, circulating endosomes, and microvesicles. Furthermore, intracellular PD-L1 has a pro-cancer function and can be retransported to the cell surface. Palmitoyltransferase (DHHC3) can palmitoylate the PD-L1 Cys272 site in colorectal cancer cells, blocking PD-L1 ubiquitination and preventing the transport of the essential endosomal sorting complex (ESCRT) to multivesicles (MVBs), thereby inhibiting lysosomal degradation of PD-L1. 2-Bromopalmitate (2-BP), by inhibiting PD-L1 palmitoylation, can activate anti-tumor immunity in vitro and in vivo in mice, thereby killing tumor cells. Therefore, small molecules that regulate PD-L1 expression by inhibiting palmitoylation will become a new approach in immunotherapy. Researchers have designed a peptide, CPP-S1, to competitively inhibit PD-L1 palmitoylation (Han Yao, et al. Nature Biomedical Engineering, 2019, 3(4):306-317). In 2024, Zhang Weidong et al. discovered that a small molecule natural marine product (Benzosceptrin C) can act on the target protein DHHC3, degrading PD-L1 through the lysosomal pathway to reduce its expression, thereby enhancing the anti-tumor effect of T cells (Wang Qun, et al. Cellreports, 2024, 5(2):101357). Summary of the Invention

[0005] The purpose of this invention is to provide an amide compound, its preparation method, and its application.

[0006] To achieve the above objectives, the technical solution of the present invention is as follows:

[0007] An amide compound or a pharmaceutically acceptable salt thereof, the general structural formula of said amide compound being shown in Formula I:

[0008]

[0009] In the formula, R 1 It is vinyl or chloromethyl;

[0010] When R 1 When the form is vinyl, the amide compound is an acrylamide compound, R 2It is cyclopentyl, cyclohexyl, 4-ethylphenyl, 4-butylphenyl, 4-phenoxyphenyl, 4-ethoxyphenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 4-(4-chlorophenoxy)phenyl, 4-benzoylphenyl, 4-ethoxycarboxyphenyl, 3-methyl-4-ethoxycarboxyphenyl, 5-methylpyridin-2-yl, benzo[d]thiazol-2-yl, 6-methylbenzo[d]thiazol-2-yl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl or 4-methoxybenzyl;

[0011] When R 1 When the methyl group is chloromethyl, the amide compound is an α-chloroacetamide compound, R 2 It is cyclopropyl, cyclopentyl, cyclohexyl, 4-ethylphenyl, 4-butylphenyl, 4-acetylphenyl, 4-phenoxyphenyl, 4-ethoxyphenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 4-(4-chlorophenoxy)phenyl, 4-phenylaminophenyl, 4-benzoylphenyl, 4-ethoxycarboxyphenyl, 3-methyl-4-ethoxycarboxyphenyl, 5-methylpyridin-2-yl, benzo[d]thiazol-2-yl, 6-methylbenzo[d]thiazol-2-yl, benzo[d]imidazol-2-yl, 4-ethoxycarboxythiazol-2-yl and 4-oxoethoxyacetylthiazol-2-yl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl or 4-methoxybenzyl.

[0012] This invention also provides a method for preparing the above-mentioned amide compounds, the synthetic route of which is as follows:

[0013]

[0014] In the formula, R 1 and R 2 The definition is the same as before;

[0015] Specifically, the following steps are included:

[0016] i: Under nitrogen protection, using N,N-dimethylformamide as solvent, N,N-diisopropylethylamine as activator, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate as condensing agent, Boc-4-aminophenylacetic acid reacts with amine compounds at room temperature for 10-12 h to generate intermediate product 1;

[0017] ii: Using dichloromethane as a solvent, intermediate 1 reacts with trifluoroacetic acid at room temperature for 7-8 hours to generate intermediate 2;

[0018] iii: Dissolve intermediate 2 and triethanolamine in dichloromethane, add acyl chloride compound dropwise under ice bath conditions, and react for 10 h to generate target compound I.

[0019] Furthermore, in step i, the molar ratio of Boc-4-aminophenylacetic acid, amine compounds, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine is 1:1:1.2:1.5.

[0020] Furthermore, in step i, under nitrogen protection, in the presence of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine, Boc-4-aminophenylacetic acid is activated for 1 h, and then an amine compound is added to react with it.

[0021] Furthermore, in step ii, the molar ratio of intermediate product 1 to trifluoroacetic acid is 1:3.

[0022] Furthermore, in step iii, the molar ratio of intermediate product 2, acyl chloride compound, and triethanolamine is 1:3:3.

[0023] The present invention also provides the use of the above-mentioned amide compounds or pharmaceutically acceptable salts thereof in the preparation of antitumor drugs.

[0024] Preferably, the tumor is a human breast cancer cell MCF-7, a human liver cancer cell Hepg-2, a mouse colon cancer cell MC38, or a mouse liver cancer cell Hepal-6.

[0025] The present invention also provides a palmityltransferase inhibitor, which uses the above-mentioned amide compounds or their pharmaceutically acceptable salts as active ingredients.

[0026] Beneficial effects:

[0027] This invention synthesizes a novel class of amide compounds, specifically acrylamides or α-chloroacetamides. These compounds act as palmitoyltransferase inhibitors, inhibiting PD-L1 palmitoylation by suppressing DHHC protein activity, thereby promoting PD-L1 degradation, inhibiting tumor immune escape, and exerting anti-tumor effects. Examples demonstrate that the acrylamide and α-chloroacetamide compounds of this invention exhibit varying degrees of anti-proliferative activity against different cancer cells. Compared to the positive control drugs cisplatin and 2-bromoyl lactate (2-BP), most of these compounds show better inhibitory activity against cancer cells and can be further developed into next-generation anti-tumor drugs. Detailed Implementation

[0028] The following examples are provided to further illustrate the present invention, but do not limit the invention in any way. In the following examples, 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.

[0029] This invention provides an amide compound, the synthetic route of which is as follows:

[0030]

[0031] In the formula, when R 1 When R is vinyl, the amide compound is an acrylamide compound, denoted as the target compound series of formula I-1; when R 1 When the methyl group is chloromethyl, the amide compound is an α-chloroacetamide compound, denoted as the target compound series of formula I-2.

[0032]

[0033] Example 1: Preparation of the target compounds of Formula I-1

[0034] (1) Dissolve 18 mmol of Boc-4-aminophenylacetic acid, 21 mmol of HATU and 27 mmol of DIEA in 30 mL of LDMF, place in a 100 mL three-necked flask, stir for 1 h under N2 protection, and then add 18 mmol of amine compound R. 2 -NH2 was placed at room temperature and stirred for 10-12 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction solution was extracted, the solvent was recovered by rotary evaporation, and purified by column chromatography to obtain compound 1 with a yield of 77-90%.

[0035] (2) Dissolve 10 mmol of compound 1 in 20 mL of DCM and place it in a 100 mL round-bottom flask. Slowly add 20 mL of trifluoroacetic acid in a fume hood. Place the flask at room temperature and stir for 7-8 h. Monitor the reaction progress by TLC. After the reaction is complete, remove the solvent by rotary evaporation. Add saturated NaHCO3 solution (0.6 mol / L) until no more bubbles are generated. Extract the reaction solution with ethyl acetate and recover the solvent by rotary evaporation to obtain compound 2 with a yield of 85-95%.

[0036] (3) Dissolve 10 mmol of compound 2 and 30 mmol of triethanolamine in 30 mL of DCM, place in a 100 mL round-bottom flask, place in an ice bath, slowly add 30 mmol of acryloyl chloride in a fume hood, stir for 10 h, monitor the reaction progress by TLC, after the reaction is complete, extract the reaction solution with water, remove the solvent by rotary evaporation, and purify by column chromatography to obtain the target compound of formula I-1, with a yield of 33-70%.

[0037] The specific structures of the corresponding compounds obtained when using different types of amine compounds in step (1) are shown in Table 1.

[0038] Table 1

[0039]

[0040]

[0041] The characterization data of compounds I-1a to I-1s are as follows:

[0042] I-1a: White solid, yield 35%. mp 191.2~191.8℃; 1 H NMR (600MHz, DMSO-d6) δ10.08(s,1H,-NH),7.97(d,J=7.2Hz,1H,-NH),7.57(d,J=8.2Hz,2H,Ar- H),7.18(d,J=8.2Hz,2H,Ar-H),6.43(dd,J=17.0,10.2Hz,1H,=CH),6.24(dd,J=17.0,2.0Hz,1H, =CH2),5.74(dd,J=10.1,2.0Hz,1H,=CH2),3.98-3.93(m,1H,-CH),3.32(s,2H,-CH2),1.80-1.75 (m,2H,-CH2),1.64-1.61(m,2H,-CH2),1.51-1.48(m,2H,-CH2),1.38-1.33(m,2H,-CH2); HR-ESI - -MS Calcd for C 16 H 20 N₂O₂; m / z [MH] - :271.1452found 271,1452.

[0043] I-1b: White solid, yield 39%. mp 197.4~197.9℃; 1 H NMR (600MHz, DMSO-d6) δ10.08(s,1H,-NH),7.87(d,J=7.8Hz,1H,-NH),7.57(d,J=8.2Hz,2H,Ar-H),7.1 9(d,J=8.2Hz,2H,Ar-H),6.43(dd,J=17.0,10.1Hz,1H,=CH),6.24(dd,J=17.0,2.0Hz,1H,=CH2),5.74( dd,J=10.2,1.9Hz,1H,=CH2),3.51-3.47(m,1H,-CH),3.32(s,2H,-CH2),1.73-1.70(m,2H,-CH2),1.68 -1.65(m,2H,-CH2),1.56-1.53(m,1H,-CH2),1.27-1.21(m,2H,-CH2),1.17-1.11(m,3H,-CH2); HR-ESI --MS Calcd for C 17 H 22 N₂O₂; m / z [MH] - :285.1606found285.1597.

[0044] I-1c: White solid, yield 49%. mp 227.5~227.8℃; 1 H NMR(600MHz,DMSO-d6)δ10.11(s,1H,-NH),10.03(s,1H,-NH),7.61(d,J=8.3Hz,2H,Ar-H),7 .49(d,J=8.5Hz,2H,Ar-H),7.27(d,J=8.3Hz,2H,Ar-H),7.12(d,J=8.3Hz,2H,Ar-H),6.43(d d,J=16.9,10.1Hz,1H,=CH),6.25(dd,J=16.9,2.0Hz,1H,=CH2),5.74(dd,J=10.1,2.0Hz,1H ,=CH2),3.57(s,2H,-CH2),2.54(q,J=7.6Hz,2H,-CH2),1.15(t,J=7.6Hz,3H,-CH3); HR-ESI - -MS Calcdfor C 19 H 20 N₂O₂; m / z [MH] - :307.1450found 307.1441.

[0045] I-1d: White solid, yield 56%. mp 236.1~236.7℃; 1 H NMR (600MHz, DMSO-d6) δ10.11(s,1H,-NH),10.03(s,1H,-NH),7.60(d,J=8.4Hz,2H,Ar-H),7.48(d,J=8. 4Hz,2H,Ar-H),7.27(d,J=8.3Hz,2H,Ar-H),7.10(d,J=8.3Hz,2H,Ar-H),6.43(dd,J=17.0,10.2Hz,1H,=C H),6.25(dd,J=10.1,2.0Hz,1H,=CH2),5.74(dd,J=10.1,2.0Hz,1H,=CH2),3.57(s,2H,-CH2),2.52(t,J =6.8Hz,2H,-CH2),1.54-1.49(m,2H,-CH2),1.31-1.25(m,2H,-CH2),0.88(t,J=7.4Hz,3H,-CH3); HR-ESI- -MS Calcd for C 21 H 24 N₂O₂; m / z [MH] - :335.1764found335.1754.

[0046] I-1e: White solid, yield 55%. mp 222.1~222.9℃; 1 H NMR(600MHz,DMSO-d6)δ10.16(s,1H,-NH),10.12(s,1H,-NH),7.62(d,J=8.6Hz,4H,Ar-H),7 .36(t,J=7.4Hz,2H,Ar-H),7.28(d,J=8.3Hz,2H,Ar-H),7.09(t,J=7.4Hz,1H,Ar-H),6.98(d ,J=8.9Hz,2H,Ar-H),6.95(d,J=8.6Hz,2H,Ar-H),6.43(dd,J=17.0,10.1Hz,1H,=CH),6.25( dd,J=17.0,2.0Hz,1H,=CH2),5.74(dd,J=10.1,2.0Hz,1H,=CH2),3.59(s,2H,-CH2); HR-ESI - -MSCalcd for C 23 H 20 N₂O₃; m / z [MH] - :371.1403found 371.1390.

[0047] I-1f: White solid, yield 53%. mp 235.7~236.2℃; 1 H NMR(600MHz,DMSO-d6)δ10.11(s,1H,-NH),9.97(s,1H,-NH),7.61(d,J=8.3Hz,2H,Ar-H),7 .48(d,J=9.0Hz,2H,Ar-H),7.27(d,J=8.5Hz,2H,Ar-H),6.85(d,J=9.0Hz,2H,Ar-H),6.43(d d,J=17.0,10.1Hz,1H,=CH),6.25(dd,J=17.0,2.0Hz,1H,=CH2),5.74(dd,J=10.1,2.0Hz,1H ,=CH2),3.97(q,J=7.0Hz,2H,-CH2),3.55(s,2H,-CH2),1.30(t,J=7.0Hz,3H,-CH3); HR-ESI - -MS Calcd forC19 H 20 N₂O₂; m / z [MH] - :323.1400found 323.1390.

[0048] I-1g: White solid, yield 57%. mp 197.3~197.8℃; 1 H NMR (600MHz, DMSO-d6) δ10.18(s,1H,-NH),10.11(s,1H,-NH),7.62(d,J=3.3H z,2H,Ar-H),7.60(d,J=4.5Hz,2H,Ar-H),7.27(d,J=8.3Hz,2H,Ar-H),7.13(t ,J=8.9Hz,2H,Ar-H),6.43(dd,J=16.9,10.1Hz,1H,=CH),6.25(dd,J=17.0,2. 0Hz, 1H, = CH2), 5.74 (dd, J = 10.1, 2.0Hz, 1H, = CH2), 3.58 (s, 2H, -CH2); HR-ESI - -MS Calcd for C 17 H 15 FN2O3; m / z [MH] - :297.1042found 297.1033.

[0049] I-1h: White solid, yield 55%. mp 231.7~232.1℃; 1 H NMR(600MHz,DMSO-d6)δ10.50(s,1H,-NH),10.12(s,1H,-NH),7.81(d,J=8.4H z,2H,Ar-H),7.67(d,J=8.4Hz,2H,Ar-H),7.62(d,J=8.2Hz,2H,Ar-H),7.28(d ,J=8.2Hz,2H,Ar-H),6.43(dd,J=17.0,10.1Hz,1H,=CH),6.25(dd,J=17.0,1. 9Hz, 1H, = CH2), 5.74 (dd, J = 10.2, 2.0Hz, 1H, = CH2), 3.65 (s, 2H, -CH2); HR-ESI - -MS Calcd for C 18 H 15 F3N2O2;m / z[MH] - 347.1009 found 348.1002.

[0050] I-1i: White solid, yield 62%. mp 216.7~217.1℃; 1 H NMR(600MHz,DMSO-d6)δ10.18(s,1H,-NH),10.11(s,1H,-NH),7.64-7.61(m,4H,Ar- H),7.40(d,J=8.9Hz,2H,Ar-H),7.28(d,J=8.4Hz,2H,Ar-H),7.01(d,J=8.9Hz,2H,A r-H),6.97(d,J=8.9Hz,2H,Ar-H),6.43(dd,J=17.0,10.1Hz,1H,=CH),6.25(dd,J=1 7.0, 2.0Hz, 1H, = CH2), 5.74 (dd, J = 10.1, 2.0Hz, 1H, = CH2), 3.59 (s, 2H, -CH2); HR-ESI - -MS Calcd for C 23 H 19 ClN2O2; m / z [MH] - :405.1010found 405.1000.

[0051] Ⅰ-1j: White solid, yield 42%. mp 201.1~202.1℃; 1 H NMR (600MHz, DMSO-d6) δ10.53(s,1H,-NH),10.12(s,1H,-NH),7.78(d,J=8.8Hz,2H,Ar-H),7.74(d, J=8.8Hz,2H,Ar-H),7.70(d,J=6.8Hz,2H,Ar-H),7.66(t,J=7.5Hz,1H,Ar-H),7.62(d,J=8.5Hz,2H, Ar-H),7.55(d,J=7.7Hz,2H,Ar-H),7.29(d,J=8.6Hz,2H,Ar-H),6.43(dd,J=16.9,10.2Hz,1H,=CH) ,6.25(dd,J=17.0,2.0Hz,1H,=CH2),5.74(dd,J=10.1,2.0Hz,1H,=CH2),3.66(s,2H,-CH2); HR-ESI - -MS Calcd for C 24 H 20 N₂O₃; m / z [MH] - :383.1404found 383.1390.

[0052] I-1k: White solid, yield 57%. mp 201.3~202.2℃; 1 H NMR(600MHz,DMSO-d6)δ10.47(s,1H,-NH),10.12(s,1H,-NH),7.91(d,J=8.8Hz,2H,Ar-H),7 .74(d,J=8.8Hz,2H,Ar-H),7.62(d,J=8.4Hz,2H,Ar-H),7.28(d,J=8.2Hz,2H,Ar-H),6.43(d d,J=17.0,10.1Hz,1H,=CH),6.25(dd,J=17.0,2.0Hz,1H,=CH2),5.74(dd,J=10.2,2.0Hz,1H ,=CH2),4.28(q,J=7.1Hz,2H,-CH2),3.64(s,2H,-CH2),1.31(t,J=7.1Hz,3H,-CH3); HR-ESI - -MS Calcd forC 20 H 20 N₂O₄; m / z [MH] - :351.1344found 351.1339.

[0053] I-1l: White solid, yield 62%. mp 230.0~230.6℃; 1 H NMR (600MHz, DMSO-d6) δ10.36(s,1H,-NH),10.13(s,1H,-NH),7.81(d,J=9.2Hz,1H,Ar-H),7.61( d,J=8.5Hz,2H,Ar-H),7.55(d,J=6.5Hz,2H,Ar-H),7.28(d,J=8.5Hz,2H,Ar-H),6.43(dd,J=17.0 ,10.1Hz,1H,=CH),6.25(dd,J=17.0,2.0Hz,1H,=CH2),5.74(dd,J=10.1,2.0Hz,1H,=CH2),4.25( q,J=7.1Hz,2H,-CH2),3.62(s,2H,-CH2),2.49(s,3H,-CH3),1.30(t,J=7.1Hz,3H,-CH3); HR-ESI - -MS Calcd for C 21 H 22 N₂O₄; m / z [MH] - :365.1501found 365.1495.

[0054] I-1m: White solid, yield 36%. mp 198.1~199.2℃; 1 H NMR(600MHz,DMSO-d6)δ10.55(s,1H,-NH),10.12(s,1H,-NH),8.14(s,1H,pyridine-H),7.9 4(d,J=8.4Hz,1H,pyridine-H),7.57(d,J=8.4Hz,1H,pyridine-H),7.53(d,J=8.3Hz,2H,Ar- H),7.39(d,J=8.3Hz,2H,Ar-H),6.33(dd,J=17.0,10.2Hz,1H,=CH),6.24(dd,J=17.0,1.9Hz ,1H,=CH2),5.71(dd,J=10.2,1.9Hz,1H,=CH2),3.63(s,2H,-CH2),2.25(s,3H,-CH3); HR-ESI - -MS Calcdfor C 17 H 16 N3O2; m / z [MH] - :294.1243found 294.1248.

[0055] I-1n: White solid, yield 51%. mp 211.5~212.1℃; 1 H NMR(600MHz,DMSO-d6)δ12.57(s,1H,-NH),10.14(s,1H,-NH),7.97(d,J=7.9Hz,1H,Ar-H),7 .75(d,J=8.1Hz,1H,Ar-H),7.63(d,J=8.3Hz,2H,Ar-H),7.43(t,J=7.1Hz,1H,Ar-H),7.30(d ,J=8.4Hz,2H,Ar-H),7.27(d,J=8.3Hz,1H,Ar-H),6.43(dd,J=17.0,10.1Hz,1H,=CH),6.25( dd,J=16.9,1.8Hz,1H,=CH2),5.75(dd,J=10.0,1.9Hz,1H,=CH2),3.79(s,2H,-CH2); HR-ESI - -MSCalcd for C 18 H 12 N3O2S; m / z [MH] - :336.0812found 336.0801.

[0056] I-1o: White solid, yield 49%. mp 219.2~220.1℃; 1 H NMR(600MHz,DMSO-d6)δ12.49(s,1H,-NH),10.14(s,1H,-NH),7.75(s,1H,Ar-H), 7.63(dd,J=8.4,3.0Hz,3H,Ar-H),7.30(d,J=8.2Hz,2H,Ar-H),7.24(d,J=8.3Hz, 1H,Ar-H),6.43(dd,J=17.0,10.1Hz,1H,=CH),6.25(dd,J=17.0,2.0Hz,1H,=CH2) ,5.75(dd,J=10.2,2.0Hz,1H,=CH2),3.77(s,2H,-CH2),2.40(s,3H,-CH3); HR-ESI - -MS Calcd for C 19 H 17 N3O2S; m / z [MH] - 350.0967 found 350.0957.

[0057] I-1p: White solid, yield 60%. mp 218.3~219.1℃; 1 H NMR(600MHz,DMSO-d6)δ10.10(s,1H,-NH),8.51(t,J=6.0Hz,1H,-NH),7.58(dd,J=8.5, 5.7Hz,2H,Ar-H),7.26(d,J=8.5,2H,Ar-H),7.21(d,J=8.5Hz,2H,Ar-H),7.13(t,J=8.9H z,2H,Ar-H),6.43(dd,J=16.9,10.1Hz,1H,=CH),6.25(dd,J=17.0,2.0Hz,1H,=CH2),5. 74(dd,J=10.1,2.0Hz,1H,=CH2),4.24(d,J=5.9Hz,2H,-CH2),3.42(s,2H,-CH2); HR-ESI - -MS Calcd forC 18 H 17 FN2O2; m / z [MH] - :311.1203found 311.1190.

[0058] I-1q: White solid, yield 59%. mp 229.1.7~230.0℃; 1H NMR (600MHz, DMSO-d6) δ10.09(s,1H,-NH),8.53(t,J=6.1Hz,1H,-NH),7.59(d,J=8.1 Hz, 2H, Ar-H), 7.36 (d, J = 8.0Hz, 2H, Ar-H), 7.25 (d, J = 8.0Hz, 2H, Ar-H), 7.21 (d, J = 8. 0Hz,2H,Ar-H),6.43(dd,J=16.9,10.1Hz,1H,=CH),6.25(J=10.1,2.0Hz,1H,=CH2),5 .74(J=10.1,2.0Hz,1H,=CH2),4.25(d,J=6.0Hz,2H,-CH2),3.43(s,2H,-CH2); HR-ESI - -MS Calcd for C 18 H 17 ClN2O2; m / z [MH] - :327.0905found 327.0894.

[0059] I-1r: White solid, yield 62%. mp 223.7~224.0℃; 1 H NMR (600MHz, DMSO-d6) δ10.14(s,1H,-NH),8.56(t,J=6.0Hz,1H,-NH),7.59(d,J=8.3H z,2H,Ar-H),7.50(d,J=8.3Hz,2H,Ar-H),7.21(d,J=8.2Hz,2H,Ar-H),7.19(d,J=8.2Hz ,2H,Ar-H),6.44(dd,J=17.0,10.1Hz,1H,=CH),6.25(dd,J=17.0,1.9Hz,1H,=CH2),5.7 4(dd,J=10.1,2.0Hz,1H,=CH2),4.23(d,J=6.0Hz,2H,-CH2),3.43(s,2H,-CH2); HR-ESI - -MS Calcd for C 18 H 17 BrN3O2; m / z [MH] - :371.0400found 371.0389.

[0060] I-1s: White solid, yield 63%. mp 212.6~213.1℃; 1H NMR (600MHz, DMSO-d6) δ10.08(s,1H,-NH),8.41(t,J=5.9Hz,1H,-NH),7.58(d,J=8.3Hz,2H ,Ar-H),7.21(d,J=8.5Hz,2H,Ar-H),7.15(d,J=8.5Hz,2H,Ar-H),6.87(d,J=8.6Hz,2H,Ar-H ),6.43(dd,J=16.9,10.2Hz,1H,=CH),6.25(dd,J=17.0,2.0Hz,1H,=CH2),5.74(dd,J=10.2, 2.0Hz,1H,=CH2),4.19(d,J=5.8Hz,2H,-CH2),3.72(s,3H,-CH3),3.41(s,2H,-CH2); HR-ESI - -MS Calcdfor C 19 H 20 N₂O₃; m / z [MH] - :323.1401found 323.1390.

[0061] Example 2: Preparation of the target compounds of Formula I-2 series

[0062] The preparation method is the same as in Example 1, except that acryloyl chloride in step (3) is replaced with chloroacetyl chloride to obtain the target compounds of formula I-2. The specific structures of the corresponding compounds obtained when different types of amine compounds are used in step (1) are shown in Table 2.

[0063] Table 2

[0064]

[0065]

[0066]

[0067] The characterization data of compounds I-2a to I-2y are as follows:

[0068] I-2a: White solid, yield 77%. mp 209.4~210.0℃; 1H NMR (600MHz, DMSO-d6) δ10.26(s,1H,-NH),8.10(d,J=4.2Hz,1H,-NH),7.49(d,J=8.5Hz,2H,Ar-H),7.18(d,J=8.4Hz,2H,Ar -H),4.24(s,2H,-CH2),3.29(s,2H,-CH2),2.57-2.61(m,1H,-CH),0.61-0.58(m,2H,-CH2),0.39-0.36(m,2H,-CH2); HR-ESI - -MS Calcd for C 13 H 15 ClN2O2; m / z [MH] - :265.0748found265.0738.

[0069] Ⅰ-2b: White solid, yield 60%. mp 234.1~235.0℃; 1 H NMR (600MHz, DMSO-d6) δ10.24(s,1H,-NH),7.98(d,J=7.3Hz,1H,-NH),7.49(d,J=8.1Hz,2H,Ar-H),7.19(d,J=8.1Hz,2H,Ar-H),4.24(s,2H,-CH2),3 .98-3.92(m,1H,-CH),3.32(s,2H,-CH2),1.80-1.75(m,2H,-CH2),1.65-1 .62(m,2H,-CH2),1.51-1.47(m,2H,-CH2),1.38-1.33(m,2H,-CH2); HR-ESI - -MSCalcd for C 15 H 19 ClN2O2; m / z [MH] - :293.1058found 293.1051.

[0070] I-2c: White solid, yield 52%. mp 211.8~212.5℃; 1H NMR (600MHz, DMSO-d6) δ10.24(s,1H,-NH),7.88(d,J=7.9Hz,1H,-NH),7.49(d,J =8.5Hz,2H,Ar-H),7.20(d,J=8.5Hz,2H,Ar-H),4.23(s,2H,-CH2),3.51-3.47(m, 1H,-CH),3.33(s,2H,-CH2),1.73-1.70(m,2H,-CH2),1.68-1.65(m,2H,-CH2),1 .56-1.52(m,1H,-CH2),1.28-1.21(m,2H,-CH2),1.17-1.10(m,3H,-CH2); HR-ESI - -MS Calcd for C 16 H 21 ClN2O2; m / z [MH] - :307.1216found 307.1207.

[0071] I-2d: White solid, yield 73%. mp 236.9~237.6℃; 1 H NMR (600MHz, DMSO-d6) δ10.27(s,1H,-NH),10.05(s,1H,-NH),7.53(d,J=8.5Hz,2H,Ar-H),7.49(d,J=8.5Hz,2H,Ar-H),7.28(d,J=8.5Hz,2H ,Ar-H),7.12(d,J=8.4Hz,2H,Ar-H),4.24(s,2H,-CH2),3.57(s,2H,-CH2),2.55(q,J=7.6Hz,2H,-CH2),1.14(t,J=7.6Hz,3H,-CH3); HR-ESI - -MS Calcd forC 18 H 19 ClN2O2; m / z [MH] - :329.1064found 329.1051.

[0072] I-2e: White solid, yield 75%. mp 219.2~220.0℃; 1H NMR(600MHz,DMSO-d6)δ10.27(s,1H,-NH),10.04(s,1H,-NH),7.53(d,J=8.4Hz,2 H,Ar-H),7.48(d,J=8.4Hz,2H,Ar-H),7.28(d,J=8.5Hz,2H,Ar-H),7.10(d,J=8.5 Hz,2H,Ar-H),4.24(s,2H,-CH2),3.57(s,2H,-CH2),2.52(t,J=5.8Hz,2H,-CH2), 1.55-1.47(m,2H,CH2),1.24-1.31(m,2H,CH2),0.88(t,J=7.4Hz,3H,CH3); HR-ESI - -MS Calcd for C 20 H 23 ClN2O2; m / z [MH] - :357.1370found357.1364.

[0073] I-2f: White solid, yield 63%. mp 228.7~229.2℃; 1 H NMR (600MHz, DMSO-d6) δ10.47(s,1H,-NH),10.27(s,1H,-NH),7.92(d,J=8.7Hz,2H,Ar-H),7.73(d,J=8.5Hz,2H,Ar-H),7 .54(d,J=8.2Hz,2H,Ar-H),7.29(d,J=8.2Hz,2H,Ar-H),4.24(s,2H,-CH2),3.65(s,2H,-CH2),2.52(s,3H,-CH3); HR-ESI - -MS Calcd for C 18 H 17 ClN2O3; m / z [MH] - :343.0852found343.0843.

[0074] I-2g: White solid, yield 67%. mp 225.5~225.8℃; 1H NMR (600MHz, DMSO-d6) δ10.27(s,1H,-NH),10.17(s,1H,-NH),7.61(d,J=9.0Hz,2H,Ar-H),7.54(d,J=8.4Hz,2H,Ar-H),7.36(d,J=8.6Hz,2H,Ar-H),7.29( d,J=8.4Hz,2H,Ar-H),7.10(t,J=7.4Hz,1H,Ar-H),6.98(d,J=9.0Hz,2H,Ar- H),6.95(d,J=7.7Hz,2H,Ar-H),4.24(s,2H,-CH2),3.59(s,2H,-CH2); HR-ESI - -MS Calcd for C 22 H 19 ClN2O3; m / z [MH] - :393.1007found 393.1000.

[0075] Ⅰ-2h: White solid, yield 57%. mp 238.7~239.1℃; 1 H NMR (600MHz, DMSO-d6) δ10.26(s,1H,-NH),9.97(s,1H,-NH),7.53(d,J=8.5Hz,2H,Ar-H),7.48(d,J=9.0Hz,2H,Ar-H),7.28(d,J=8.5Hz,2H ,Ar-H),6.85(d,J=9.0Hz,2H,Ar-H),4.24(s,2H,-CH2),3.97(q,J=7.0Hz,2H,-CH2),3.55(s,2H,-CH2),1.30(t,J=6.9Hz,3H,-CH3); HR-ESI - -MS Calcd forC 18 H 19 ClN2O3; m / z [MH] - :345.1012found 345.1000.

[0076] I-2i: White solid, yield 49%. mp 229.1~229.8℃; 11H NMR (600 MHz, DMSO-d6) δ 10.27 (s, 1H, -NH), 10.19 (s, 1H, -NH), 7.60 (d, J = 9.0 Hz, 2H, Ar-H), 7.53 (d, J = 8.5 Hz, 2H, Ar-H), 7.28 (d, J = 8.5 Hz, 2H, Ar-H), 7.13 (t, J = 8.9 Hz, 2H, Ar-H), 4.24 (s, 2H, -CH2), 3.59 (s, 2H, -CH2); HR-ESI - -MS Calcd for C 16 H 14 ClFN2O2; m / z [M-H] - : 319.0652 found 319.0644。

[0077] Ⅰ-2g: White solid, yield 53%. m.p. 207.6 - 208.1 °C; 1 1H NMR (6�0 MHz, DMSO-d6) δ 10.50 (s, 1H, -NH), 10.27 (s, 1H, -NH), 7.80 (d, J = 8.4 Hz, 2H, Ar-H), 7.67 (d, J = 8.5 Hz, 2H, Ar-H), 7.54 (d, J = 8.5 Hz, 2H, Ar-H), 7.29 (d, J = 8.5 Hz, 2H, Ar-H), 4.24 (s, 2H, -CH2), 3.65 (s, 2H, -CH2); HR-ESI - -MS Calcd for C 17 H 14 ClF3N2O2; m / z [M-H] - : 369.0624 found 369.0612。

[0078] Ⅰ-2k: White solid, yield 60%. m.p. 236.0 - 236.7 °C; 1 1H NMR (600 MHz, DMSO-d6) δ 10.27 (s, 1H, -NH), 10.19 (s, 1H, -NH), 7.62 (d, J = 9.0 Hz, 2H, Ar-H), 7.54 (d, J = 8.2 Hz, 2H, Ar-H), 7.40 (d, J = 9.8 Hz, 2H, Ar-H), 7.29 (d, J = 8.2 Hz, 2H, Ar-H), 7.01 (d, J = 8.6 Hz, 2H, Ar-H), 6.97 (d, J = 8.7 Hz, 2H, Ar-H), 4.24 (s, 2H, -CH2), 3.59 (s, 2H, -CH2); HR-ESI - -MS Calcd forC22 H 18 Cl2N2O3; m / z [MH] - :427.0614found 427.0610.

[0079] Ⅰ-2l: gray solid, yield 66%. mp 227.6~228.4℃; 1 H NMR(600MHz,DMSO-d6)δ10.27(s,1H,-NH),9.97(s,1H,-NH),8.01(s,1H,-NH),7. 53(d,J=8.3Hz,2H,Ar-H),7.46(d,J=8.8Hz,2H,Ar-H),7.29(d,J=8.4Hz,2H,Ar-H ),7.19(t,J=7.2Hz,2H,Ar-H),7.01(d,J=8.8Hz,2H,Ar-H),6.99(d,J=7.7Hz,2H, Ar-H), 6.76 (t, J = 7.2Hz, 1H, Ar-H), 4.24 (s, 2H, -CH2), 3.56 (s, 2H, -CH2); HR-ESI - -MS Calcd for C 22 H 20 ClN3O2; m / z [MH] - :392.1166found392.1160.

[0080] I-2m: White solid, yield 54%. mp 224.1~225.0℃; 1 H NMR (600MHz, DMSO-d6) δ10.54(s,1H,-NH),10.28(s,1H,-NH),7.78(d,J=8.8Hz,2H,Ar-H),7.74(d,J=8.8Hz,2H,Ar-H),7.70(d,J=6.9Hz,2H HR-ESI - -MS Calcd forC 23 H 19 ClN2O3; m / z [MH] - :405.1006found 405.1000.

[0081] I-2n: White solid, yield 67%. mp 228.2~229.0℃; 1 H NMR (600MHz, DMSO-d6) δ10.47(s,1H,-NH),10.27(s,1H,-NH),7.91(d,J=8.8Hz,2H,Ar-H),7.73(d,J=8.8Hz,2H,Ar-H),7.54(d,J=8.4Hz,2H ,Ar-H),7.29(d,J=8.3Hz,2H,Ar-H),4.28(q,J=7.1Hz,2H,-CH2),4.24(s,2H,-CH2),3.64(s,2H,-CH2),1.31(t,J=7.1Hz,3H,-CH3); HR-ESI - -MS Calcd forC 19 H 19 ClN2O4; m / z [MH] - :373.0962found 373.0949.

[0082] I-2O: White solid, yield 65%. mp 209.1~209.6℃; 1 H NMR (600MHz, DMSO-d6) δ10.35(s,1H,-NH),10.27(s,1H,-NH),7.81(d,J=9.0Hz,1H,Ar-H),7.55-7.53(m,4H,Ar-H),7.29(d,J=8.4Hz ,2H,Ar-H),4.26(q,J=7.1Hz,2H,-CH2),4.23(s,2H,-CH2),3.62(s,2H,-CH2),2.49(s,3H,-CH3),1.30(t,J=7.1Hz,3H,-CH3); HR-ESI - -MS Calcd for C 20 H 21 ClN2O4; m / z [MH] - 387.1115found 387.1106.

[0083] I-2p: White solid, yield 71%. mp 201.3~201.7℃; 1H NMR (600MHz, DMSO-d6) δ10.55(s,1H,-NH),10.26(s,1H,-NH),8.14(s,1H,pyridine-H),7.94(d,J=8.4Hz,1H,pyridine-H),7.57(d,J=8.4Hz ,1H,pyridine-H),7.52(d,J=8.4Hz,2H,Ar-H),7.29(d,J=8.4Hz,2H,Ar-H),4.24(s,2H,-CH2),3.65(s,2H,-CH2),2.23(s,3H,-CH3); HR-ESI - -MS Calcd forC 16 H 16 ClN3O2; m / z [MH] - 316.0855found 316.0847.

[0084] Ⅰ-2q: White solid, yield 59%. mp 225.8~226.7℃; 1 H NMR (600MHz, DMSO-d6) δ12.59(s,1H,-NH),10.31(s,1H,-NH),7.96(d,J=8.4Hz,1H,Ar-H),7.75(d,J=8.1Hz,1H,Ar-H),7.5 6(d,J=8.5Hz,2H,Ar-H),7.44(t,J=7.7Hz,1H,Ar-H),7.32-7.30(m,3H,Ar-H),4.25(s,2H,-CH2),3.80(s,2H,-CH2); HR-ESI - -MS Calcd for C 17 H 14 ClN3O2S; m / z [MH] - :358.0419found358.0411.

[0085] I-2r: White solid, yield 68%. mp 229.1~229.9℃; 1H NMR (600MHz, DMSO-d6) δ12.49(s,1H,-NH),10.29(s,1H,-NH),7.75(s,1H,Ar-H),7.63(d,J=8.2Hz,1H,Ar-H),7.55(d,J=8.4Hz,2H HR-ESI - -MS Calcd for C 18 H 16 ClN3O2S; m / z [MH] - 372.0573 found 372.0568.

[0086] I-2s: White solid, yield 62%. mp 222.1~224.9℃; 1 H NMR (600MHz, DMSO-d6) δ12.13(s,1H,-NH),11.74(s,1H,Imidazole-NH),10.29(s,1H,-NH),7.56(d,J=8.5Hz,2H,Ar-H),7.43(dd,J =5.6,3.6Hz,2H,Ar-H),7.33(d,J=8.5Hz,2H,Ar-H),7.07(dd,J=6.0,3.2Hz,2H,Ar-H),4.24(s,2H,-CH2),3.74(s,2H,-CH2); HR-ESI - -MS Calcd for C 17 H 15 ClN4O2; m / z [MH] - :341.0804found 341.0799.

[0087] Ⅰ-2t: White solid, yield 48%. mp 246.5~247.2℃; 1H NMR (600MHz, DMSO-d6) δ12.78(s,1H,-NH),10.30(s,1H,-NH),8.04(s,1H,Thiazole-H),7.54(d,J=8.4Hz,2H,Ar-H),7.28(d ,J=8.3Hz,2H,Ar-H),4.26(q,J=7.1Hz,2H,-CH2),4.24(s,2H,-CH2),3.72(s,2H,-CH2),1.29(t,J=7.1Hz,3H,-CH3); HR-ESI - -MS Calcd for C 16 H 16 ClN3O4S; m / z [MH] - :380.0469found380.0466.

[0088] I-2u: White solid, yield 66%. mp 212.7~214.2℃; 1 H NMR (600MHz, DMSO-d6) δ12.80(s,1H,-NH),10.29(s,1H,-NH),8.47(s,1H,Ar-H),7.54(d,J=8.5Hz,2H,Ar-H),7.29(d,J= 8.5Hz,2H,Ar-H),4.37(q,J=7.2Hz,2H,-CH2),4.24(s,2H,-CH2),3.76(s,2H,-CH2),1.32(t,J=7.1Hz,3H,-CH3); HR-ESI - -MS Calcd for C 17 H 16 ClN3O5S; m / z [MH] - :408.0416found408.0415.

[0089] I-2v: White solid, yield 71%. mp 216.7~218.5℃; 1 H NMR (600MHz, DMSO-d6) δ10.25(s,1H,-NH),8.51(t,J=6.0Hz,1H,-NH),7.51(d,J=8.5Hz,2H,Ar-H),7.26(dd,J=8.5,5.7H z,2H,Ar-H),7.22(d,J=8.6Hz,2H,Ar-H),7.13(t,J=8.9Hz,2H,Ar-H),4.25-4.24(m,4H,-CH2),3.43(s,2H,-CH2); HR-ESI --MS Calcd for C 17 H 15 ClFN2O2; m / z [MH] - :333.0811found 333.0800.

[0090] Ⅰ-2w: White solid, yield 71%. 1 H NMR (600MHz, DMSO-d6) δ10.25(s,1H,-NH),8.54(t,J=6.0Hz,1H,-NH),7.51(d,J=8.1Hz,2H,Ar-H),7.36(d,J=8.5Hz,2 HR-ESI - -MS Calcd for C 17 H 16 Cl2N2O2; m / z [MH] - :349.0516found 349.0505.

[0091] I-2x: White solid, yield 65%. mp 221.7~223.0℃; 1 H NMR (600MHz, DMSO-d6) δ10.26(s,1H,-NH),8.53(t,J=6.0Hz,1H,-NH),7.50(t,J=8.3Hz,4H,Ar-H),7.22(d,J=8.1H z,2H,Ar-H),7.19(d,J=8.5Hz,2H,Ar-H),4.24(s,2H,-CH2),4.23(d,J=6.0Hz,2H,-CH2),3.42(s,2H,-CH2); HR-ESI - -MS Calcd for C 17 H 15 BrClN3O2; m / z [MH] - :394.9970found394.9999.

[0092] Ⅰ-2y: White solid, yield 63%. mp 190.3~191.1℃; 1H NMR (600MHz, DMSO-d6) δ10.25(s,1H,-NH),8.43(t,J=5.9Hz,1H,-NH),7.50(d,J=8.4Hz,2H,Ar-H),7.22(d,J=8.3Hz,2H,Ar-H),7.15(d,J= HR-ESI - -MS Calcd forC 18 H 18 ClN2O3; m / z [MH] - :345.1011found 345.1000.

[0093] Example 3: Determination of the antiproliferative activity of the compounds of the present invention against cancer cells.

[0094] (1) Experimental materials

[0095] The target compound and positive control cisplatin, positive control 2-BP, trypsin, PBS, fetal bovine serum (Sijiqing), human breast cancer cells MCF-7, human liver cancer cells Hepg-2, mouse colon cancer cells MC38, mouse liver cancer cells Hepa1-6, mouse embryonic fibroblasts NIH3T3, microplate reader and 96-well plate, DMEM medium and 1640 medium, CCK8 reagent, etc.

[0096] (2) Experimental methods

[0097] The antitumor activity of the compounds against MCF-7, Hepg-2, MC38, Hepa1-6, and NIH3T3 cells was detected using the CCK8 assay. First, the cells were diluted to 4 × 10⁻⁶ cells. 4 Cells / mL were seeded into 96-well plates, with 90 μL of diluted cells added to each well. After 12 h of incubation, different concentrations of the drug were added to the wells. Each concentration was used in triplicate. After incubation at 37 °C for 48 h, 10 μL of CCK8 solution (5 mg / mL) was added to each well of the culture plate (containing 100 μL of culture medium), and after incubation for another 1.5 h, the optical density was read at 450 nm using a Bio-Tek microplate reader.

[0098] First, calculate the inhibition rate as follows:

[0099] Inhibition rate = (1-A / A0)×100%

[0100] Where A is the absorbance value measured after cell administration, and A0 is the absorbance value measured in the negative control.

[0101] Then, Graphpad 8.0 software was used for analysis. Linear regression was performed between the logarithm of sample concentration and cell inhibition rate to calculate the half-maximal inhibitory concentration (IC50) of the compound on each cell type. 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 experimental results are shown in Table 3.

[0102] Table 3. Antiproliferative activity and toxicity of the compounds of this invention against different cancer cells and normal cells.

[0103]

[0104]

[0105] Experimental results show that most of the compounds synthesized in this invention have good anti-proliferative activity against four types of cancer cells: MCF-7, HepG2, Hepa1-6, and MC38. Some compounds exhibit better anti-proliferative activity than the positive controls cisplatin and 2-BP, and have less toxicity to normal cells NIH3T3.

[0106] 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 easily 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. An amide compound or a pharmaceutically acceptable salt thereof, characterized in that, The general structural formula of the amide compounds is shown in Formula I: ； In the formula, R 1 It is vinyl or chloromethyl; When R 1 When it is vinyl, R 2 It is cyclopentyl, cyclohexyl, 4-ethylphenyl, 4-butylphenyl, 4-ethoxyphenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 4-(4-chlorophenoxy)phenyl, 4-benzoylphenyl, 4-ethoxycarboxyphenyl, 3-methyl-4-ethoxycarboxyphenyl, 5-methylpyridin-2-yl, benzo[d]thiazol-2-yl, 6-methylbenzo[d]thiazol-2-yl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl or 4-methoxybenzyl; When R 1 When it is chloromethyl, R 2 It is cyclopropyl, cyclopentyl, cyclohexyl, 4-ethylphenyl, 4-butylphenyl, 4-acetylphenyl, 4-ethoxyphenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 4-(4-chlorophenoxy)phenyl, 4-phenylaminophenyl, 4-benzoylphenyl, 4-ethoxycarboxyphenyl, 3-methyl-4-ethoxycarboxyphenyl, 5-methylpyridin-2-yl, benzo[d]thiazol-2-yl, 6-methylbenzo[d]thiazol-2-yl, benzo[d]imidazol-2-yl, 4-ethoxycarboxythiazol-2-yl and 4-oxoethoxyacetylthiazol-2-yl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl or 4-methoxybenzyl.

2. The method for preparing the amide compound according to claim 1, characterized in that, The synthesis route is as follows: ； In the formula, R 1 and R 2 The definition is the same as before; Includes the following steps: i: Under nitrogen protection, using N,N-dimethylformamide as solvent, N,N-diisopropylethylamine as activator, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate as condensing agent, Boc-4-aminophenylacetic acid reacts with amine compounds at room temperature for 10-12 h to generate intermediate product 1; ii: Using dichloromethane as a solvent, intermediate 1 reacts with trifluoroacetic acid at room temperature for 7-8 h to generate intermediate 2; iii: Dissolve intermediate 2 and triethanolamine in dichloromethane, add acyl chloride compound dropwise under ice bath conditions, and react for 10 h to generate target compound I.

3. The preparation method according to claim 2, characterized in that, In step i, the molar ratio of Boc-4-aminophenylacetic acid, amine compounds, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine is 1:1:1.2:1.

5.

4. The preparation method according to claim 2, characterized in that, In step i, under nitrogen protection, in the presence of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine, Boc-4-aminophenylacetic acid is activated for 1 h, and then an amine compound is added to react with it.

5. The preparation method according to claim 2, characterized in that, In step ii, the molar ratio of intermediate product 1 to trifluoroacetic acid is 1:

3.

6. The preparation method according to claim 2, characterized in that, In step iii, the molar ratio of intermediate 2, acyl chloride compound, and triethanolamine is 1:3:

3.

7. The use of the amide compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an antitumor drug, characterized in that, The tumors are human breast cancer cells MCF-7, human liver cancer cells Hepg-2, mouse colon cancer cells MC38, or mouse liver cancer cells Hepal-6.

8. A palmityltransferase inhibitor, characterized in that, The palmityltransferase inhibitor uses the amide compound of claim 1 or a pharmaceutically acceptable salt thereof as the active ingredient.

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