1, 2-diphenylethyl propiolamide compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of anti-cancer drugs, and particularly discloses a 1, 2-diphenylethyl propiolamide compound as well as a preparation method and application thereof. The 1, 2-diphenylethyl propyne amide compound disclosed by the invention is novel in structure and relatively good in activity, has relatively good anti-tumor activity as an inhibitor, and has relatively good inhibition activity on various tumor cells such as human non-small cell lung cancer cells, human pancreatic cancer cells and human breast cancer cells; the compound can be applied to preparation of anti-tumor drugs. The invention provides a total synthesis method and a derivative preparation method of a 1, 2-diphenylethyl propyne amide compound. The preparation method has the advantages of cheap and easily available raw materials, short reaction period, simple operation and the like.

Description

Technical Field

[0001] The present invention belongs to the technical field of anti-cancer drugs, and particularly relates to a 1,2-diphenylethyl propynamide compound, a preparation method thereof, and an application thereof. Background Art

[0002] Small molecule covalent inhibitor drugs (TCI) with electrophilicity can form covalent bonds with nucleophilic amino acid residues of endogenous target proteins, irreversibly changing the functions of target proteins. Due to the prolonged binding time with proteins, the compounds can continuously enhance pharmacological effects, achieve selective inhibition of isomers, and overcome acquired drug resistance of tumor cells. At the present stage, covalent inhibitor drugs are continuously being developed in the field of cancer, and their applications in the field of cancer are becoming more and more extensive. The most typical one is the covalent receptor tyrosine kinase EGFR inhibitor, which has evolved from the first-generation gefitinib and erlotinib to the second-generation afatinib and then to the third-generation osimertinib; in cancer treatment, there is still no corresponding drug to treat cancers caused by the KRAS target mutation that has long troubled doctors and patients. In 2021, the FDA approved the KRAS G12C mutation inhibitor Sotorasib for marketing, and at present, a total of three KRAS G12C mutation inhibitors have been approved for marketing. It can be said that covalent inhibitor drugs are becoming increasingly important in the field of cancer treatment.

[0003] α,β-unsaturated amide-based Michael receptors are the most widely used targeting heads in TCI. There are currently 8 TCI targeting tyrosine kinases such as epidermal growth factor receptor (EGFR) and Bruton's tyrosine kinase (BTK) using this as the targeting head that have been approved by the FDA for marketing to treat cancer. As the targeting heads of these TCI drugs, acrylamide or 2-butynamide irreversibly inactivate target proteins by covalently binding to the sulfhydryl group of cysteine at the ATP binding site of the target kinase. Activity-based protein profiling (ABPP) further corroborates its covalent binding mode. Among them, the BTK inhibitors acalabrutinib and tirabrutinib using 2-butynamide as the targeting head have been successfully marketed. However, there are still certain limitations: on the one hand, some targeting heads may cause non-selective binding due to excessive reactivity, leading to off-target toxicity; on the other hand, existing synthesis methods often involve multiple steps, high raw material costs, or low yields, restricting the development of structural diversity. In addition, new covalent inhibitors targeting key oncogenic targets such as KRAS still need to further optimize their pharmacodynamic and pharmacokinetic properties.

[0004] Therefore, developing covalent inhibitors with novel targeting head structures, simple synthesis, and high selectivity is of great significance for expanding the research and development path of anti-cancer drugs and overcoming the defects of existing drugs. Summary of the Invention

[0005] To solve the above technical problems, the present invention provides a 1,2-diphenylethyl propiolamide compound, a preparation method thereof, and an application thereof.

[0006] In a first aspect, the 1,2-diphenylethyl propiolamide compound of the present invention has the following structural formula:

[0007]

[0008] wherein R is aryl, substituted aryl, substituted formyl, substituted sulfonyl, propiolyl, or cyclobutyl.

[0009] The structure of the compound further includes the following structural formula:

[0010]

[0011] In the formula, R1 is phenyl, tert-butyl, naphthyl, p-tolyl, biphenyl, p-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl, 3-cyanophenyl, ethynyl, benzyloxy, or tert-butoxy; R2 is phenyl, pyridin-2-yl, cyclobutyl, methanesulfonyl, p-toluenesulfonyl, p-trifluoromethylphenyl, 3-trifluoromethylphenyl, benzyl, p-trifluoromethylbenzyl, 6-bromo-pyridin-2-yl, or pyrazin-2-yl.

[0012] The structure shown in formula (2) is selected from any one of the following structures:

[0013]

[0014]

[0015] The structure shown in formula (3) is selected from any one of the following structures:

[0016]

[0017]

[0018] In a second aspect, a preparation method of the 1,2-diphenylethyl propiolamide compound of the present invention is to subject 1,2-diphenyl diamine to amide condensation or Buchwald coupling reaction, and then to amide condensation to prepare the 1,2-diphenylethyl propiolamide compound. The reaction formula I is as follows:

[0019]

[0020] Preferably, the preparation method includes the following steps:

[0021] S1: In a first solvent, under the action of an organic base, one of the amino groups of 1,2-diphenyldiamine is subjected to amide condensation using an amide condensation reagent to obtain compound A;

[0022] S2: In a second solvent, under the action of an amide condensation reagent, propiolic acid is subjected to amide condensation reaction with the compound A to obtain the final product of formula (2); the reaction formula is as follows:

[0023]

[0024] Preferably, the amide condensation reagent in S1 includes 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide, benzyl chloroformate, di-tert-butyl dicarbonate, methanesulfonyl chloride, p-toluenesulfonyl chloride; the organic base includes one or more of N,N-diisopropylethylamine, triethylamine, etc.; the first solvent includes one or more of dichloromethane, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, etc.; the reaction temperature is 0 °C to room temperature, and the reaction time is 2 to 8 hours.

[0025] Preferably, the amide condensation reagent in S2 includes 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide; the second solvent includes dichloromethane, N,N-dimethylformamide; the compound A is 1 equivalent, the amide condensation reagent is 1 to 2 equivalents, the propiolic acid is 1 to 1.5 equivalents, and the second solvent is 10 equivalents; the reaction temperature is 0 °C to room temperature; the reaction temperature is 0 °C; the reaction time is 1 to 4 hours.

[0026] Preferably, the preparation method includes the following steps:

[0027] S1: In a third solvent, under the action of an organic base, one of the amino groups of 1,2-diphenyldiamine is subjected to Buchwald coupling or substitution reaction using a coupling reagent to obtain compound B;

[0028] S2: In a fourth solvent, under the action of an amide condensation reagent, propiolic acid is subjected to amide condensation reaction with the compound A to obtain the final product of formula (3); the reaction formula is as follows:

[0029]

[0030] Preferably, the organic base in S1 includes one or more of sodium tert-butoxide, sodium ethoxide, and potassium carbonate; the coupling reagent includes palladium acetate, bis(dibenzylideneacetone)palladium, 2-bis(cyclohexylphosphino)-2',6'-dimethoxy-1,1'-biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; the third solvent is one or more of toluene, 1,4-dioxane, acetonitrile, etc.; the third solvent is toluene; the compound B is 1 equivalent, and the third solvent is 10 equivalents; the reaction temperature is 90-150 °C; the reaction time is 2-10 hours; the reaction time is 7 hours.

[0031] Thirdly, the application of the 1,2-diphenylethylpropiolamide compound of the present invention in the preparation of anti-tumor drugs and drugs for inhibiting tumor cells.

[0032] Preferably, the drug is formulated into an injectable fluid, aerosol, cream, gel, pill, capsule, syrup, transdermal patch or excipient.

[0033] Preferably, the tumor cells include human non-small cell lung cancer cell A549, human breast cancer cell MCF-7, and human pancreatic cancer cell MIA-PACA-2.

[0034] Compared with the prior art, the beneficial effects of the present invention are:

[0035] The 1,2-diphenylethylpropiolamide compound of the present invention has a novel structure, good activity, and the compound has good anti-tumor activity as an inhibitor, and has good inhibitory activity against a variety of tumor cells (such as human non-small cell lung cancer cells, human pancreatic cancer cells, human breast cancer cells, etc.), and can be applied to the preparation of anti-tumor drugs. The present invention provides a total synthesis and derivative preparation method of the 1,2-diphenylethylpropiolamide compound. This preparation method has the advantages of cheap and easily available raw materials, short reaction cycle, and simple operation. Specific Embodiments

[0036] The following further describes the specific embodiments of the present invention. It should be noted here that the description of these embodiments is for helping to understand the present invention, but does not constitute a limitation to the present invention.

[0037] A 1,2-diphenylethylpropiolamide compound, the compound has the structure shown in formula (1):

[0038]

[0039] In the formula, R is aryl, substituted aryl, substituted formyl, substituted sulfonyl, propiolyl, or cyclobutyl.

[0040] The 1,2-diphenylethylpropiolamide compounds in this example include 32 compounds.

[0041] Example 1

[0042] Synthesis of Compound 1:

[0043] The chemical reaction equation for the synthesis is as follows:

[0044]

[0045] The specific synthesis method includes the following steps:

[0046] Step 1: Weigh benzoic acid (244 mg, 2 mmol) and N,N-diisopropylethylamine DIPEA (23.05 g, 6 mmol) and dissolve them in N,N-dimethylformamide (10 mL). Stir in an ice bath. After the solution becomes slightly clear, slowly add 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate HATU (912 mg, 2.4 mmol) to the reaction system. Stir at 0 °C for 15 min, and slowly add it to (1R,2R)-1,2-diphenylethylenediamine (424 mg, 2 mmol) stirred at 0 °C. Slowly raise the temperature to room temperature and continue stirring for 4 hours. After the reaction is completed, wash the organic phase successively with 10% citric acid, saturated sodium bicarbonate, and saturated brine. Finally, dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate the filtrate to obtain a pale yellow oily crude product. Purify it by column chromatography to obtain 322 mg of product A with a yield of 51%.

[0047] Step 2: Weigh the reaction product A (316 mg, 1 mmol) from the previous step and dissolve it in dichloromethane (10 mL). Add propargylic acid (84 mg, 1.2 mmol) and N,N'-diisopropylcarbodiimide DIC (151 mg, 1.2 mmol) to the reaction system at 0 °C. Raise the temperature to room temperature and react for 2 hours. After the raw materials react completely, filter to remove the solid, concentrate it under vacuum, and purify it by column chromatography to obtain 310 mg of product B with a yield of 84%.

[0048] Compound 1 11H NMR (400 MHz, DMSO-d6) δ 9.52 (d, J = 8.9 Hz, 1H), 8.70 (d, J = 8.9 Hz, 1H), 7.83–7.71 (m, 2H), 7.34–7.30 (m, 2H), 7.29–7.24 (m, 3H), 7.21 (ddd, J = 7.8, 4.4, 1.9 Hz, 4H), 7.18–7.11 (m, 2H), 7.04–6.98 (m, 2H), 5.48 (dt, J = 26.5, 8.0 Hz, 2H), 4.18 (s, 1H), 3.81 (s, 3H). HRMS (ESI): calculated for C 24 H 20 N2O2 [M + H] + = 369.1598; found 369.1600.

[0049] Example 2

[0050] Synthesis of Compound 2:

[0051] The chemical reaction formula for the synthesis is as follows:

[0052]

[0053] Specific synthesis method: The same as the synthesis of Compound 1.

[0054] Compound 2 1 1H NMR (400 MHz, DMSO-d6) δ 9.28 (d, J = 8.5 Hz, 1H), 8.74 (d, J = 8.2 Hz, 1H), 7.62–7.51 (m, 6H), 7.45–7.40 (m, 1H), 7.35 (td, J = 7.1, 2.8 Hz, 5H), 7.32–7.27 (m, 2H), 7.25–7.18 (m, 1H), 5.56–5.43 (m, 2H), 4.05 (s, 1H). HRMS (ESI): calculated for C 24 H 20 N2O2 [M + H] + = 369.1598; found 369.1600.

[0055] Example 3

[0056] Synthesis of Compound 3:

[0057] The chemical reaction formula for the synthesis is as follows:

[0058]

[0059] Specific synthesis method: same as that of Compound 1.

[0060] Compound 3 1 H NMR(500MHz,DMSO-d6)δ9.53(d,J=9.0Hz,1H),8.88(d,J=9.0Hz,1H),7.80–7.75(m,2H),7.56–7.51(m,1H),7.48(dd,J=8.2,6.6Hz,2H),7.34–7.12(m,10H),5.49(dt,J=35.9,7.9Hz,2H),4.19(s,1H).HRMS(ESI):calculated for C 24 H 20 N2O2[M+H] + =369.1598;found 369.1600.

[0061] Example 4

[0062] Synthesis of Compound 4:

[0063] The chemical reaction formula for the synthesis is as follows:

[0064]

[0065] Specific synthesis method: same as that of Compound 1.

[0066] Compound 4 1 H NMR(400MHz,DMSO-d6)δ9.37(d,J=8.8Hz,1H),7.75(d,J=8.8Hz,1H),7.33(s,1H),7.30–7.21(m,7H),7.17(d,J=6.7Hz,2H),5.40(p,J=7.2Hz,2H),4.18(s,1H),1.01(s,9H).HRMS(ESI):calculated for C 22 H 24 N2O2[M+H] + =349.1911;found349.1906.

[0067] Example 5

[0068] Synthesis of Compound 5:

[0069] The chemical reaction formula for the synthesis is as follows:

[0070]

[0071] Specific synthesis method: same as that of Compound 1.

[0072] Compound 5 1 H NMR(400 MHz, DMSO-d6) δ 9.55 (d, J=9.0 Hz, 1H), 9.05 (d, J=9.0 Hz, 1H), 8.36 (d, J=1.7 Hz, 1H), 8.09–7.96 (m, 3H), 7.85 (dd, J=8.6, 1.8 Hz, 1H), 7.62 (td, J=6.6, 5.9, 3.6 Hz, 2H), 7.41–7.29 (m, 4H), 7.28–7.20 (m, 4H), 7.20–7.13 (m, 2H), 5.54 (dt, J=38.3, 8.2 Hz, 2H), 4.17 (s, 1H). HRMS(ESI): calculated for C 28 H 22 N2O2[M+H] + =419.1754; found 419.1755.

[0073] Example 6

[0074] Synthesis of Compound 6:

[0075] The chemical reaction formula for the synthesis is shown below:

[0076]

[0077] Specific synthesis method: The same as the synthesis of Compound 1.

[0078] Compound 6 1 H NMR(400 MHz, DMSO-d6) δ 9.52 (d, J=9.0 Hz, 1H), 8.77 (d, J=8.9 Hz, 1H), 7.75–7.64 (m, 2H), 7.34–7.30 (m, 2H), 7.27 (ddd, J=8.4, 4.7, 3.2 Hz, 5H), 7.24–7.19 (m, 4H), 7.19–7.11 (m, 2H), 5.55–5.49 (m, 1H), 5.48–5.42 (m, 1H), 4.18 (s, 1H), 2.35 (s, 3H). HRMS(ESI): calculated for C 25 H 22 N2O2[M+H] + =383.1754; found 383.1754.

[0079] Example 7

[0080] Synthesis of Compound 7:

[0081] The chemical reaction formula for the synthesis is shown below:

[0082]

[0083] Specific synthesis method: same as the synthesis of Compound 1.

[0084] Compound 7 1 H NMR(500MHz, DMSO-d6) δ 9.59(d, J=9.0Hz, 1H), 8.96(d, J=9.0Hz, 1H), 7.90(d, J=8.1Hz, 2H), 7.79(d, J=8.2Hz, 2H), 7.76–7.71(m, 2H), 7.50(t, J=7.6Hz, 2H), 7.42(t, J=7.4Hz, 1H), 7.37–7.33(m, 2H), 7.29(d, J=7.2Hz, 2H), 7.24(td, J=7.5, 5.7Hz, 4H), 7.17(dd, J=7.8, 5.9Hz, 2H), 5.52(dt, J=41.0, 8.2Hz, 2H), 4.21(s, 1H). HRMS(ESI): calculated for C 30 H 24 N2O2[M + H] + =445.1911; found 445.1911.

[0085] Example 8

[0086] Synthesis of Compound 8:

[0087] The chemical reaction equation for the synthesis is as follows:

[0088]

[0089] Specific synthesis method: same as the synthesis of Compound 1.

[0090] Compound 8 1 H NMR(400MHz, DMSO-d6) δ 9.52(d, J=8.8Hz, 1H), 8.71(d, J=8.9Hz, 1H), 7.82–7.74(m, 2H), 7.37–7.30(m, 2H), 7.24(dtd, J=15.1, 8.1, 7.5, 2.1Hz, 7H), 7.15(tt, J=7.1, 3.9Hz, 3H), 7.04–6.98(m, 2H), 5.48(dt, J=26.6, 8.0Hz, 2H), 4.19(s, 1H), 3.81(s, 3H). HRMS(ESI): calculated for C 25 H 22 N2O3[M + H]+ = 399.1703; found 379.1700.

[0091] Example 9

[0092] Synthesis of Compound 9:

[0093] The chemical reaction formula for the synthesis is as follows:

[0094]

[0095] Specific synthesis method: The same as the synthesis of Compound 1.

[0096] Compound 9 1 H NMR (400 MHz, DMSO-d6) δ 9.39 (d, J = 9.1 Hz, 1H), 8.89 (d, J = 9.1 Hz, 1H), 7.53 (tdd, J = 7.6, 5.2, 1.9 Hz, 1H), 7.38 (td, J = 7.4, 1.9 Hz, 1H), 7.34–7.28 (m, 4H), 7.26 (d, J = 2.1 Hz, 3H), 7.24 (dd, J = 7.9, 2.0 Hz, 3H), 7.21–7.15 (m, 2H), 5.54–5.33 (m, 2H), 4.17 (s, 1H). HRMS (ESI): calculated for C 24 H 19 FN2O2 [M+H] + = 387.1503; found 387.1500.

[0097] Example 10

[0098] Synthesis of Compound 10:

[0099] The chemical reaction formula for the synthesis is as follows:

[0100]

[0101] Specific synthesis method: The same as the synthesis of Compound 1.

[0102] Compound 10 11H NMR (400 MHz, DMSO-d6) δ 9.53 (d, J = 8.7 Hz, 1H), 8.97 (d, J = 8.7 Hz, 1H), 7.64 (dd, J = 7.7, 1.4 Hz, 1H), 7.55 (ddt, J = 9.8, 7.9, 4.0 Hz, 2H), 7.40 (td, J = 8.5, 2.7 Hz, 1H), 7.30 (d, J = 7.2 Hz, 2H), 7.23 (dp, J = 7.8, 5.1, 3.4 Hz, 6H), 7.18–7.12 (m, 2H), 5.47 (dt, J = 24.7, 8.3 Hz, 2H), 4.19 (s, 1H). HRMS (ESI): calculated for C 24 H 19 FN2O2 [M+H] + = 387.1503; found 387.1501.

[0103] Example 11

[0104] Synthesis of Compound 11:

[0105] The chemical reaction equation for the synthesis is as follows:

[0106]

[0107] Specific synthesis method: The same as the synthesis of Compound 1.

[0108] Compound 11 1 1H NMR (400 MHz, DMSO-d6) δ 9.52 (d, J = 8.8 Hz, 1H), 8.89 (d, J = 8.9 Hz, 1H), 7.90–7.80 (m, 2H), 7.36–7.28 (m, 4H), 7.24 (dtd, J = 12.1, 8.1, 7.6, 3.1 Hz, 6H), 7.15 (tq, J = 6.8, 4.2, 2.8 Hz, 2H), 5.47 (dt, J = 26.1, 8.1 Hz, 2H), 4.19 (s, 1H). HRMS (ESI): calculated for C 24 H 19 FN2O2 [M+H] + = 387.1503; found 387.1499.

[0109] Example 12

[0110] Synthesis of Compound 12:

[0111] The chemical reaction equation for the synthesis is as follows:

[0112]

[0113] Specific synthesis method: the same as compound 1.

[0114] Compound 12 1 H NMR (500MHz, DMSO-d6) δ9.54(d,J=9.0Hz,1H),8.96(d,J=8.9Hz,1H),7.83–7.78(m,2H),7.59–7.55(m,2H),7.33–7. 28(m,2H),7.26–7.19(m,6H),7.18–7.12(m,2H),5.46(dt,J=33.3,8.3Hz,2H),4.19(s,1H).HRMS(ESI):calculated forC 24 H 19 ClN2O2[M+H] + =403.1208; found 403.1205.

[0115] Example 13

[0116] Synthesis of compound 13:

[0117] The chemical reaction formula of the synthesis is as follows:

[0118]

[0119] Specific synthesis method: the same as compound 1.

[0120] Compound 13 1 H NMR(500MHz,DMSO-d6)δ9.53(d,J=8.9Hz,1H),8.96(d,J=8.9Hz,1H),7.76–7.68(m,4H),7.32–7.28(m,2H),7.2 2(dt,J=14.9,7.3Hz,6H),7.18–7.12(m,2H),5.46(dt,J=33.1,8.3Hz,2H),4.19(s,1H).HRMS(ESI):calculated for C 24 H 19 BrN2O2[M+H] + =447.0703; found 447.0700.

[0121] Embodiment 14

[0122] Synthesis of compound 14:

[0123] The chemical reaction formula of the synthesis is as follows:

[0124]

[0125] Specific synthesis method: same as that of Compound 1.

[0126] Compound 14 1 H NMR(500MHz, DMSO-d6) δ9.56(d, J=8.9Hz, 1H), 9.25(d, J=8.9Hz, 1H), 8.39–8.31(m, 2H), 8.06–7.99(m, 2H), 7.33–7.30(m, 2H), 7.27–7.20(m, 6H), 7.19–7.13(m, 2H), 5.48(dt, J=36.4, 8.4Hz, 2H), 4.20(s, 1H). HRMS(ESI): calculated for C 24 H 19 N3O4[M + H] + =414.1448; found 414.1450.

[0127] Example 15

[0128] Synthesis of Compound 15:

[0129] The chemical reaction formula for the synthesis is as follows:

[0130]

[0131] Specific synthesis method: same as that of Compound 1.

[0132] Compound 15 1 H NMR(400MHz, DMSO-d6) δ9.55(d, J=8.8Hz, 1H), 9.14(d, J=8.9Hz, 1H), 7.98(d, J=8.1Hz, 2H), 7.89(d, J=8.2Hz, 2H), 7.35–7.29(m, 2H), 7.28–7.20(m, 6H), 7.19–7.12(m, 2H), 5.52(t, J=8.4Hz, 1H), 5.44(t, J=8.4Hz, 1H), 4.20(s, 1H). HRMS(ESI): calculated for C 25 H 19 F3N2O2[M + H] + =437.1471; found 437.1470.

[0133] Example 16

[0134] Synthesis of Compound 16:

[0135] The chemical reaction equation for the synthesis is as follows:

[0136]

[0137] Specific synthesis method: same as the synthesis of Compound 1. Compound 16 1 H NMR(400MHz,DMSO-d6)δ9.54(d,J=8.7Hz,1H),9.12(d,J=8.7Hz,1H),8.21(t,J=1.7Hz,1H),8.09(dt,J=7.9,1.5Hz,1H),8.03(dt,J=7.8,1.4Hz,1H),7.72(t,J=7.8Hz,1H),7.32–7.27(m,2H),7.22(tq,J=7.9,3.9Hz,6H),7.15(tq,J=5.4,1.7Hz,2H),5.49(t,J=8.6Hz,1H),5.42(t,J=8.6Hz,1H),4.19(s,1H).HRMS(ESI):calculated for C 25 H 19 N3O2[M+H] + =394.1550;found 394.1550。

[0138] Example 17

[0139] Synthesis of Compound 17:

[0140] The chemical reaction equation for the synthesis is as follows:

[0141]

[0142] The specific synthesis method includes the following steps:

[0143] Step 1: Weigh the product A (212 mg, 1 mmol) from the previous step reaction, dissolve it in dichloromethane (10 mL), add propargylic acid (84 mg, 1.2 mmol), N,N'-diisopropylcarbodiimide DIC (151 mg, 1.2 mmol) to the reaction system at 0 °C, and raise the temperature to room temperature and react for 2 hours. After the raw materials are reacted completely, filter to remove the solid, concentrate under vacuum and purify by column chromatography to obtain 288 mg of product B with a yield of 91%.

[0144] Compound 17 1 H NMR(500MHz,DMSO-d6)δ9.42(dt,J=8.3,4.1Hz,2H),7.24–7.15(m,10H),5.28–5.22(m,2H),4.23(s,2H).HRMS(ESI):calculated for C20 H 16 N2O2[M+H] + = 317.1285; found 317.1289.

[0145] Example 18

[0146] Synthesis of Compound 18:

[0147] The chemical reaction equation for the synthesis is as follows:

[0148]

[0149] The specific synthesis method includes the following steps:

[0150] Step 1: Weigh (1S,2S)-1,2-diphenylethylenediamine (424 mg, 2 mmol), N,N-diisopropylethylamine DIPEA (23.05 g, 6 mmol) and dissolve them in dichloromethane (10 mL). Stir in an ice bath. After the solution becomes slightly clear, slowly add benzyl chloroformate (341 mg, 2 mmol) to the reaction system. Stir at 0 °C for 4 hours. After the reaction is completed, filter, and rotary evaporate the filtrate to obtain a pale yellow oily crude product. Purify it by column chromatography to obtain 374 mg of product A with a yield of 54%.

[0151] Step 2: The same as Step 2 in the synthesis of Compound 1.

[0152] Compound 18 1 H NMR (500 MHz, DMSO-d6) δ 9.31 (d, J = 9.2 Hz, 1H), 8.02 (d, J = 9.6 Hz, 1H), 7.33 (dt, J = 15.5, 6.9 Hz, 3H), 7.24 (t, J = 5.0 Hz, 10H), 7.17 (ddt, J = 11.5, 5.1, 3.1 Hz, 2H), 5.25 (dd, J = 9.2, 7.3 Hz, 1H), 5.07–4.98 (m, 2H), 4.92 (s, 1H), 4.20 (s, 1H). HRMS (ESI): calculated for C 25 H 22 N2O3[M+H] + = 399.1703; found 399.1700.

[0153] Example 19

[0154] Synthesis of Compound 19:

[0155] The chemical reaction equation for the synthesis is as follows:

[0156]

[0157] The specific synthesis method includes the following steps:

[0158] Step 1: Weigh (1S,2S)-1,2-diphenylethylenediamine (424 mg, 2 mmol) and N,N-diisopropylethylamine DIPEA (23.05 g, 6 mmol), dissolve them in dichloromethane (10 mL), stir in an ice bath, and then slowly add di-tert-butyl dicarbonate (437 mg, 2 mmol) dropwise to the reaction system. Stir at 0 °C for 4 hours. After the reaction is completed, filter, rotary evaporate the filtrate to obtain a pale yellow oily crude product, and purify it by column chromatography to obtain 318 mg of product A with a yield of 51%.

[0159] Step 2: The same as step 2 in the synthesis of compound 1.

[0160] Compound 19 1 H NMR (400 MHz, Chloroform-d) δ 7.50 (s, 1H), 7.24–7.14 (m, 6H), 7.13–7.01 (m, 4H), 5.24 (td, J=8.3, 5.0 Hz, 2H), 4.91 (dd, J=10.7, 8.3 Hz, 1H), 2.77 (s, 1H), 1.47 (s, 9H). HRMS (ESI): calculated for C 22 H 24 N2O3 [M+H] + =365.1860; found 365.1859.

[0161] Example 20

[0162] Synthesis of compound 20:

[0163] The chemical reaction formula for the synthesis is as follows:

[0164]

[0165] The specific synthesis method includes the following steps:

[0166] Step 1: Dissolve (1S,2S)-1,2-diphenylethylenediamine (424 mg, 2 mmol) in dichloromethane, add N,N-diisopropylethylamine (756 mg, 6 mmol), stir at 0 °C for 5 min, slowly add methanesulfonyl chloride (275 mg, 2.4 mmol), and react at 0 °C for 4 hours. Filter, rotary evaporate the filtrate to obtain an oily crude product, and purify the crude product by column chromatography to obtain 244 mg of a yellow oily product with a yield of 42%.

[0167] Step 2: The same as step 2 in the synthesis of compound 1.

[0168] Compound 20 11H NMR (500 MHz, DMSO-d6) δ 9.32 (d, J = 9.3 Hz, 1H), 7.96 (d, J = 9.4 Hz, 1H), 7.29–7.20 (m, 8H), 7.20–7.14 (m, 2H), 5.23 (t, J = 8.7 Hz, 1H), 4.69 (t, J = 8.7 Hz, 1H), 4.25 (s, 1H), 2.26 (s, 3H). HRMS (ESI): calculated for C 18 H 18 N2O3S [M+H] + = 341.1111; found 341.1110.

[0169] Example 21

[0170] Synthesis of Compound 21:

[0171] The chemical reaction equation for the synthesis is as follows:

[0172]

[0173] The specific synthesis method includes the following steps:

[0174] Step 1: Dissolve (1S,2S)-1,2-diphenylethylenediamine (424 mg, 2 mmol) in dichloromethane, add N,N-diisopropylethylamine (756 mg, 6 mmol), stir at 0 °C for 5 min, slowly add p-toluenesulfonyl chloride (458 mg, 2.4 mmol), and react at 0 °C for 4 h. Filter, rotary evaporate the filtrate to obtain an oily crude product, and purify the crude product by column chromatography to obtain 315 mg of a yellow oily product with a yield of 43%.

[0175] Step 2: The same as Step 2 in the synthesis of Compound 1.

[0176] Compound 21 1 1H NMR (500 MHz, DMSO-d6) δ 9.33 (d, J = 9.3 Hz, 1H), 8.31 (d, J = 9.7 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.10 (s, 5H), 6.96 (d, J = 16.6 Hz, 7H), 5.10 (t, J = 8.8 Hz, 1H), 4.67 (dd, J = 9.6, 8.2 Hz, 1H), 4.24 (s, 1H), 2.22 (s, 3H). HRMS (ESI): calculated for C 24 H 22 N2O3S [M+H] + = 419.1424; found 419.1424.

[0177] Example 22

[0178] Synthesis of Compound 22:

[0179] The chemical reaction equation for the synthesis is as follows:

[0180]

[0181] The specific synthesis method includes the following steps:

[0182] Step 1: Palladium acetate (44.8 mg, 0.2 mmol), 2 - dicyclohexylphosphino - 2',6'-dimethoxy - 1,1'-biphenyl (SPhos, 82 mg, 0.4 mmol), and sodium tert - butoxide (290 mg, 3 mmol) were dissolved in toluene (3 mL). Under nitrogen protection, the mixture was stirred at room temperature for 0.5 h. (1R,2R)-1,2 - diphenylethylenediamine (424 mg, 2 mmol) and iodobenzene (408 mg, 2 mmol) dissolved in toluene were gradually added to the reaction system, and the reaction was carried out under reflux at 110 °C for 7 h. The reaction solution was filtered through diatomaceous earth, and the filtrate was collected. It was extracted three times with saturated ammonium chloride solution and ethyl acetate. The EA layers were combined and washed with saturated brine. Finally, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain an oily crude product. The crude product was separated and purified by column chromatography to obtain 236 mg of a yellow oily product with a yield of 41%.

[0183] Step 2: The same as Step 2 in the synthesis of Compound 1.

[0184] Compound 22 1 H NMR (500 MHz, Chloroform - d) δ 7.25 (t, J = 3.2 Hz, 3H), 7.16 (d, J = 6.5 Hz, 3H), 7.10–7.02 (m, 6H), 6.65 (t, J = 7.3 Hz, 1H), 6.61 (d, J = 8.1 Hz, 1H), 6.53 (d, J = 8.0 Hz, 2H), 5.28 (t, J = 8.2 Hz, 1H), 4.66 (d, J = 8.3 Hz, 1H), 2.80 (s, 1H). HRMS (ESI): calculated for C 23 H 20 N2O [M + H] + = 341.1648; found 341.1648.

[0185] Example 23

[0186] Synthesis of Compound 23:

[0187] The chemical reaction equation for the synthesis is as follows:

[0188]

[0189] Specific synthesis method: same as the synthesis method of Compound 22.

[0190] Compound 23 1 H NMR(500MHz,Chloroform-d)δ7.25(t,J=3.2Hz,3H),7.16(d,J=6.6Hz,3H),7.08(ddt,J=7.3,5.4,3.1Hz,4H),7.04(dd,J=6.7,3.0Hz,2H),6.66(t,J=7.3Hz,1H),6.57(d,J=8.1Hz,1H),6.53(d,J=8.0Hz,2H),5.28(t,J=8.2Hz,1H),4.73(d,J=18.9Hz,1H),4.67(d,J=8.3Hz,1H),2.81(s,1H).HRMS(ESI):calculated for C 23 H 20 N2O[M+H] + =341.1638;found 341.1638.

[0191] Example 24

[0192] Synthesis of Compound 24:

[0193] The chemical reaction formula for the synthesis is as follows:

[0194]

[0195] Specific synthesis method: same as the synthesis method of Compound 22.

[0196] Compound 24 1 H NMR(500MHz,Chloroform-d)δ7.31–7.21(m,6H),7.13–7.06(m,2H),7.03–6.97(m,2H),6.92–6.87(m,2H),6.78(d,J=8.8Hz,1H),6.72–6.66(m,1H),6.58–6.52(m,2H),5.55(dd,J=8.9,3.8Hz,1H),4.90(dd,J=8.6,3.8Hz,1H),4.33(d,J=8.6Hz,1H),2.84(s,1H).HRMS(ESI):calculated for C 23 H 20 N2O[M+H] + =341.1648;found 341.1647.

[0197] Example 25

[0198] Synthesis of Compound 25:

[0199] The chemical reaction equation for the synthesis is as follows:

[0200]

[0201] Specific synthesis method: The same as the synthesis method of Compound 22.

[0202] Compound 25 1 H NMR(500MHz,Chloroform-d)δ8.85(d,J=6.0Hz,1H),8.18(dd,J=5.1,1.8Hz,1H),7.41(ddd,J=8.6,7.1,1.9Hz,1H),7.27–7.13(m,10H),6.67(dd,J=7.1,5.1Hz,1H),6.42(d,J=8.3Hz,1H),5.34–5.24(m,2H),4.99(d,J=5.2Hz,1H),2.67(s,1H).HRMS(ESI):calculated for C 22 H 19 N3O[M+H] + =342.1601;found 342.1600。

[0203] Example 26

[0204] Synthesis of Compound 26:

[0205] The chemical reaction equation for the synthesis is as follows:

[0206]

[0207] The specific synthesis method includes the following steps:

[0208] Step 1: Dissolve (1S,2S)-1,2-diphenylethylenediamine (424 mg, 2 mmol) and potassium carbonate (828 mg, 6 mmol) in acetonitrile (3 mL), stir at room temperature for 0.5 h under nitrogen protection, gradually add 1,4-dibromobutane (432 mg, 2 mmol) to the reaction system, and react at reflux at 110 °C for 7 hours. Filter the reaction solution, rotary evaporate the filtrate to obtain an oily crude product, and purify the crude product by column chromatography to obtain 240 mg of a yellow oily product with a yield of 45%.

[0209] Step 2: The same as Step 2 of the synthesis of Compound 1.

[0210] Compound 261 H NMR (400 MHz, Chloroform-d) δ 7.47 (s, 1H), 7.24 (s, 2H), 7.21–7.08 (m, 8H), 5.19 (dd, J=8.2, 3.6 Hz, 1H), 3.85 (d, J=8.0 Hz, 1H), 2.81 (s, 1H), 2.52–2.38 (m, 4H), 1.65 (s, 4H). HRMS (ESI): calculated for C 21 H 22 N2O [M+H] + =319.1805; found 319.1800.

[0211] Example 27

[0212] Synthesis of Compound 27:

[0213] The chemical reaction equation for the synthesis is shown below:

[0214]

[0215] Specific synthesis method: The same as the synthesis method of Compound 22.

[0216] Compound 27 1 H NMR (400 MHz, Chloroform-d) δ 7.32–7.26 (m, 5H), 7.16 (p, J=3.8, 3.4 Hz, 3H), 7.09–6.98 (m, 4H), 6.52 (dd, J=13.5, 8.3 Hz, 3H), 5.46 (d, J=6.3 Hz, 1H), 5.29 (t, J=8.5 Hz, 1H), 4.69 (dd, J=8.9, 6.3 Hz, 1H), 2.86 (s, 1H). HRMS (ESI): calculated for C 24 H 19 F3N2O [M+H] + =409.1522; found 409.1521.

[0217] Example 28

[0218] Synthesis of Compound 28:

[0219] The chemical reaction equation for the synthesis is shown below:

[0220]

[0221] Specific synthesis method: The same as the synthesis method of Compound 22.

[0222] Compound 28 11H NMR (400 MHz, Chloroform-d) δ 7.28 (d, J = 2.7 Hz, 2H), 7.22–7.11 (m, 4H), 7.11–6.99 (m, 4H), 6.87 (d, J = 7.7 Hz, 1H), 6.74 (d, J = 2.1 Hz, 1H), 6.65 (dd, J = 8.2, 2.3 Hz, 1H), 6.46 (d, J = 8.1 Hz, 1H), 5.30 (t, J = 8.4 Hz, 1H), 5.20 (d, J = 6.4 Hz, 1H), 4.69 (dd, J = 8.7, 6.4 Hz, 1H), 2.87 (s, 1H). HRMS (ESI): calculated for C 24 H 19 F3N2O [M+H] + = 409.1522; found 409.1521.

[0223] Example 29

[0224] Synthesis of Compound 29:

[0225] The chemical reaction equation for the synthesis is as follows:

[0226]

[0227] The specific synthesis method includes the following steps:

[0228] Step 1: Dissolve (1S,2S)-1,2-diphenylethylenediamine (424 mg, 2 mmol) in acetonitrile, add potassium carbonate (6 mmol), raise the reaction solution to 80 °C, slowly dropwise add benzyl bromide (342 mg, 2 mmol), react for 5 hours, filter, rotary evaporate the filtrate to obtain an oily crude product, and purify the crude product by column chromatography to obtain 260 mg of a yellow oily product with a yield of 43%.

[0229] Step 2: The same as Step 2 in the synthesis of Compound 1.

[0230] Compound 29 1 1H NMR (400 MHz, Chloroform-d) δ 7.36–7.23 (m, 12H), 7.21–7.14 (m, 2H), 7.11–7.05 (m, 3H), 5.11 (dd, J = 7.7, 4.8 Hz, 1H), 4.02 (d, J = 4.8 Hz, 1H), 3.67 (d, J = 13.4 Hz, 1H), 3.40 (d, J = 13.5 Hz, 1H), 2.80 (s, 1H). HRMS (ESI): calculated for C 24 H 22 N2O [M+H]+ = 355.1805; found 355.1800.

[0231] Example 30

[0232] Synthesis of Compound 30:

[0233] The chemical reaction formula for the synthesis is as follows:

[0234]

[0235] The specific synthesis method includes the following steps:

[0236] Step 1: Dissolve (1S,2S)-1,2-diphenylethylenediamine (424 mg, 2 mmol) in acetonitrile, add potassium carbonate (6 mmol), raise the reaction solution to 80 °C, slowly add 4-(trifluoromethyl)benzyl bromide (478 mg, 2 mmol) dropwise, react for 5 hours, filter, concentrate the filtrate to obtain an oily crude product, and purify the crude product by column chromatography to obtain 304 mg of a yellow oily product with a yield of 41%.

[0237] Step 2: The same as Step 2 in the synthesis of Compound 1.

[0238] Compound 30 1 H NMR (400 MHz, Chloroform-d) δ 7.52 (d, J = 7.9 Hz, 2H), 7.37–7.23 (m, 10H), 7.18 (dd, J = 9.3, 7.4 Hz, 4H), 6.96 (d, J = 7.9 Hz, 1H), 5.15 (dd, J = 7.9, 5.1 Hz, 1H), 3.99 (d, J = 5.0 Hz, 1H), 3.72 (d, J = 14.1 Hz, 1H), 3.47 (d, J = 14.1 Hz, 1H), 2.81 (s, 1H). HRMS (ESI): calculated for C 25 H 21 F3N2O [M+H] + = 423.1679; found 423.1680.

[0239] Example 31

[0240] Synthesis of Compound 31:

[0241] The chemical reaction formula for the synthesis is as follows:

[0242]

[0243] The specific synthesis method: The same as the synthesis method of Compound 22.

[0244] Compound 311 1H NMR (400 MHz, Chloroform-d) δ 7.68 (d, J = 7.9 Hz, 1H), 7.25–7.17 (m, 7H), 7.17–7.07 (m, 4H), 6.78 (d, J = 7.4 Hz, 1H), 6.31 (d, J = 8.2 Hz, 1H), 5.33 (t, J = 8.4 Hz, 1H), 5.22 (q, J = 7.1 Hz, 2H), 2.74 (s, 1H). HRMS (ESI): calculated for C 22 H 18 BrN3O [M+H] + = 420.0706; found 420.0705.

[0245] Example 32

[0246] Synthesis of Compound 32:

[0247] The chemical reaction equation for the synthesis is as follows:

[0248]

[0249] Specific synthesis method: The same as the synthesis method of Compound 22.

[0250] Compound 32 1 1H NM (400 MHz, Chloroform-d) δ 7.98 (dd, J = 2.9, 1.5 Hz, 1H), 7.91 (d, J = 1.5 Hz, 1H), 7.81 (d, J = 2.8 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.23–7.12 (m, 10H), 5.74 (d, J = 7.1 Hz, 1H), 5.42–5.29 (m, 2H), 2.71 (s, 1H). HRMS (ESI): calculated for C 21 H 18 N4O [M+H] + = 343.1553; found 343.1550.

[0251] Bioactivity test section of Example 33:

[0252] Determination of the inhibitory activity of 32 1,2-diphenylethyl propynamide compounds in this example against tumor cells:

[0253] Among them, the tumors refer to human breast cancer cells, human non-small cell lung cancer cells, and human pancreatic cancer cells.

[0254] (1) Tumor cells used in the test: human breast cancer cells (MCF-7) (purchased from Guangzhou Saiku Biotechnology Co., Ltd.), human non-small cell lung cancer cells (A549) (purchased from Guangzhou Saiku Biotechnology Co., Ltd.), human pancreatic cancer cells (MIA-PACA) (Wuhan Punosai Life Science Co., Ltd.)

[0255] (2) Test method: The CCK-8 method was used to determine the proliferation inhibitory effect of 1,2-diphenylethyl propynamide compounds on human breast cancer cells, human non-small cell lung cancer cells, and human pancreatic cancer cells. The specific test process is as follows:

[0256] 1. The above tumor cell lines were respectively made into single-cell suspensions with the corresponding complete culture medium. The concentration of the single-cell suspension was 50,000 cells / mL. 100 μL of the cell suspension was taken and inoculated into a 96-well culture plate, and cultured in a CO2 incubator (37 °C, 5% CO2, 95% air) for 24 h; among them, human breast cancer cells (MCF-7) and human pancreatic cancer cells (MIA-PACA) were cultured with DMEM medium (containing 10% fetal bovine serum, 1% double antibody); human non-small cell lung cancer cells (A549) were cultured with Ham’s F-12K medium (containing 10% fetal bovine serum, 1% double antibody).

[0257] 2. Compounds 1-32 were dissolved in DMSO respectively and prepared into a stock solution of 10 mM, and then diluted to a drug-containing medium with a concentration of 1 μM using the complete culture medium. The original culture medium was discarded, and 100 μL of the drug-containing medium was added to each well of the above cells. Two parallel wells were set for each concentration of the compound. The negative control group and the blank control group were added with 1.0 μL of DMSO and cultured in a CO2 incubator for 48 hours. The negative control group was cells with a concentration of 50,000 cells / mL, treated with 0.5 μL of DMSO, used to deduct the interference of the DMSO originally contained in the drug; the blank control group was without cells, containing 100 μL of complete culture medium, used to deduct the background interference).

[0258] 3. After culturing for 48 h, the culture medium was removed and replaced with fresh culture medium, and then 10 μL of CCK-8 (Cell Counting Kits-8) reagent was added to each well of the cells. After incubating at 37 °C for 2 hours, the absorbance A at 450 nm was measured using a Biotek multifunctional microplate reader, and the inhibition rate of compounds 1 to 40 on tumor cell growth was calculated; the calculation method of the inhibition rate was: [1 - (A drug treatment group - A blank control) / (A negative control group - A blank control)] × 100%, where A is the absorbance.

[0259] 4. Test Results: A list of the tumor inhibitory activities of some compounds is shown in Table 1. Generally speaking, the 1,2-diphenethyl propynamide compounds of the present invention have potential application value in the research and development of anti-cancer drugs against these 4 types of tumors.

[0260] Table 1 Inhibitory effects of some 1,2-diphenethyl propynamide compounds on various cancer cell lines

[0261]

[0262]

[0263] As shown in Table 1, the activities against A549 and MCF-7 cell lines are relatively poor compared to the MIA-PACA cell line, but still have anti-tumor activity; however, they show a better inhibitory effect on the MIA-PACA cell line. Specifically:

[0264] For MIA-PACA, the IC 50 of Compound 3 is 187.04 nM, the IC 50 of Compound 8 is 106.28 nM, the IC 50 of Compound 10 is 142.99 nM, the IC 50 of Compound 11 is 184.02 nM, the IC 50 of Compound 12 is 138.43 nM, the IC 50 of Compound 13 is 141.04 nM, the IC 50 of Compound 14 is 194.15 nM, the IC 50 of Compound 15 is 236.18 nM, the IC 50 of Compound 17 is 113.77 nM, the IC 50 of Compound 23 is 77.58 nM, the IC 50 of Compound 27 is 24.40 nM. Thus, it can be seen that the compounds of the present invention exhibit good tumor inhibitory activity and have good application prospects in the preparation of anti-tumor drugs and drugs for inhibiting tumor cells.

[0265] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the technical field to which the present invention belongs. The terms used in the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

Claims

1. A 1,2-diphenylethyl propynamide compound, characterized in that, The structural formula of the said compound is as follows: Wherein, R is aryl, substituted aryl, substituted formyl, substituted sulfonyl, propioloyl, cyclobutyl.

2. The 1,2-diphenylethyl propynamide compound according to claim 1, characterized in that, The structure of the said compound also includes the following structural formula: In the formula, R1 is phenyl, tert-butyl, naphthyl, p-tolyl, biphenyl, p-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl, 3-cyanophenyl, ethynyl, benzyloxy, tert-butoxy; R2 is phenyl, pyridin-2-yl, cyclobutyl, methanesulfonyl, p-toluenesulfonyl, p-trifluoromethylphenyl, 3-trifluoromethylphenyl, benzyl, p-trifluoromethylbenzyl, 6-bromo-pyridin-2-yl, pyrazin-2-yl.

3. The 1,2-diphenylethyl propynamide compound according to claim 2, characterized in that, The structure shown in the said formula (2) is selected from any one of the following structures:

4. The 1,2-diphenylethyl propynamide compound according to claim 2, characterized in that, The structure shown in the said formula (3) is selected from any one of the following structures:

5. The preparation method of the 1,2-diphenylethyl propynamide compound according to any one of claims 1-4, characterized in that, 1,2-Diphenyldiamine is subjected to amide condensation or Buchwald coupling reaction, and then amide condensation is carried out to prepare the said 1,2-diphenylethyl propiolamide compound. The reaction formula I is as follows:

6. The preparation method of the 1,2-diphenylethyl propynamide compound according to claim 5, characterized in that, The said preparation method includes the following steps: S1: In a first solvent, under the action of an organic base, one of the amino groups of 1,2-diphenyldiamine is subjected to amide condensation with an amide condensation reagent to obtain compound A; S2: In a second solvent, under the action of an amide condensation reagent, propiolic acid is subjected to amide condensation reaction with the said compound A to obtain the final product of formula (2). The reaction formula is as follows:

7. The preparation method of the 1,2-diphenylethyl propynamide compound according to claim 6, characterized in that, The amide condensation reagent in the said S1 includes 2-(7-azabenzotriazol)-N,N,N',N'-tetramethylurea hexafluorophosphate, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide, benzyl chloroformate, di-tert-butyl dicarbonate, methanesulfonyl chloride, p-toluenesulfonyl chloride; the organic base includes one or more of N,N-diisopropylethylamine, triethylamine, etc.; the first solvent includes one or more of dichloromethane, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, etc.; the temperature of the reaction is 0°C to room temperature, and the reaction time is 2 to 8 hours.

8. The preparation method of the 1,2-diphenylethyl propynamide compound according to claim 6, characterized in that, The amide condensation reagent in the said S2 includes 2-(7-azabenzotriazol)-N,N,N',N'-tetramethylurea hexafluorophosphate, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide; the second solvent includes dichloromethane, N,N-dimethylformamide; the compound A is 1 equivalent, the amide condensation reagent is 1 to 2 equivalents, the propiolic acid is 1 to 1.5 equivalents, the second solvent is 10 equivalents; the temperature of the reaction is 0°C to room temperature; the temperature of the reaction is 0°C; the reaction time is 1 to 4 hours.

9. The preparation method of the 1,2-diphenylethyl propynamide compound according to claim 5, characterized in that, The said preparation method includes the following steps: S1: In a third solvent, under the action of an organic base, one of the amino groups of 1,2-diphenyldiamine is subjected to Buchwald coupling or substitution reaction with a coupling reagent to obtain compound B; S2: In a fourth solvent, under the action of an amide condensation reagent, propiolic acid is subjected to amide condensation reaction with the said compound A to obtain the final product of formula (3); the reaction formula is as follows:

10. The preparation method of the 1,2-diphenylethyl propynamide compound according to claim 9, characterized in that, The organic base in the said S1 includes one or more of sodium tert-butoxide, sodium ethoxide, potassium carbonate; the coupling reagent includes palladium acetate, bis(dibenzylideneacetone)palladium, 2-bis(cyclohexylphosphino)-2',6'-dimethoxy-1,1'-biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; the third solvent is one or more of toluene, 1,4-dioxane, acetonitrile, etc.; the third solvent is toluene; the compound B is 1 equivalent, the third solvent is 10 equivalents; the temperature of the reaction is 90-150 °C; the time of the reaction is 2-10 hours; the time of the reaction is 7 hours.

11. Use of a 1,2-diphenylethyl propiolamide compound in the preparation of an anti-tumor drug and a drug for inhibiting tumor cells.

12. Use of the 1,2-diphenylethyl propynamide compound according to claim 11, characterized in that, The said drug is formulated into an injectable fluid, aerosol, cream, gel, pill, capsule, syrup, transdermal patch or excipient.

13. Use of the 1,2-diphenylethyl propynamide compound according to claim 11, characterized in that, The said tumor cells include human non-small cell lung cancer cell A549, human breast cancer cell MCF-7, human pancreatic cancer cell MIA-PACA-2.

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