CN109796418A

CN109796418A - Phenylalanine derivative and the preparation method and application thereof containing 4- phenyl -1,2,3- triazole

Info

Publication number: CN109796418A
Application number: CN201910141019.0A
Authority: CN
Inventors: 刘新泳; 孙林; 展鹏; 黄天广; 李国雄; 武高禅
Original assignee: Shandong University
Current assignee: Shandong University
Priority date: 2019-02-26
Filing date: 2019-02-26
Publication date: 2019-05-24
Anticipated expiration: 2039-02-26
Also published as: CN109796418B

Abstract

The present invention provides a kind of phenylalanine derivatives and its preparation method and application containing 4- phenyl -1,2,3- triazole.The derivative has structure shown in following general formula I.The application in anti-AIDS drug is being prepared the invention further relates to the preparation method of the analog derivative and its as hiv inhibitor.

Description

Phenylalanine derivative containing 4-phenyl-1, 2, 3-triazole and preparation method and application thereof

Technical Field

The invention belongs to the technical field of organic compound synthesis and medical application, and particularly relates to a phenylalanine derivative containing 4-phenyl-1, 2, 3-triazole as well as a preparation method and application thereof.

Background

Acquired Immune Deficiency Syndrome (AIDS) is a serious infectious disease that endangers Human life and health, mainly caused by Human Immunodeficiency Virus Type I (HIV-1). Currently, clinically applied drugs for treating aids mainly include: reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors and fusion inhibitors. The high-efficiency Antiretroviral Therapy (HAART) prolongs the survival time of patients to a great extent and improves the life quality of the patients, but the drug resistance problem, the drug toxic and side effects, the latent infection, the high cost of taking the drug for a long time and the like greatly reduce the efficacy of the Therapy, limit the application of the Therapy and further force researchers to develop anti-AIDS drugs with new targets, new mechanisms and new structures.

The HIV-1 capsid is assembled from a portion of the Gag precursor protein that is cleaved to yield capsid protein units. During the conversion of immature virions to mature virions, capsid proteins assemble into capsids, encapsulating viral RNA and nuclear-associated proteins (reverse transcriptase, protease, integrase, etc.) to form mature HIV-1 virions. The mature virion is infectious and can undergo the next round of replication of the virus. In recent years, with the researchers' deep knowledge of capsid protein structure, the related information of crystal structure is reported in succession. Thus, the capsid protein of HIV-1 can be used as a new anti-HIV-1 action target.

The Pfizer company obtains a compound PF-74 capable of obviously inhibiting HIV-1 replication through high-throughput screening of a compound library, and the structure-activity relationship and mechanism research of the compound shows that the compound interferes with the uncoating process of viruses and the process of forming infectious particles by combining HIV-1 capsid protein. Although PF-74 has novel structure, unique mechanism and definite target, PF-74 has lower curative effect, poorer drug-like property and is easy to induce drug resistance compared with the anti-HIV-1 drug on the market at present. Therefore, the development of capsid protein inhibitors with higher efficacy and good drug-like and drug-resistance has become an attractive direction in the development field of anti-aids drugs in recent years.

According to the crystal structure characteristics of the binding site of the PF-74 and HIV-1 capsid protein, the phenylalanine HIV-1 capsid protein inhibitor of benzene sulfonamide of 4-phenyl-1, 2, 3-triazole with a brand-new structure is discovered through reasonable drug design, chemical synthesis and biological activity evaluation, and the problems of poor drug property and drug resistance of the existing HIV-1 capsid protein inhibitor are hopefully relieved.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a phenylalanine derivative containing 4-phenyl-1, 2, 3-triazole and a preparation method thereof, and also provides an activity screening result of the compound as an HIV-1 capsid protein inhibitor and application thereof.

The technical scheme of the invention is as follows:

1. phenylalanine derivative containing 4-phenyl-1, 2, 3-triazole

The phenylalanine derivative containing 4-phenyl-1, 2, 3-triazole, or pharmaceutically acceptable salt, ester or prodrug thereof has a structure shown in a general formula I:

wherein,

the amido is ortho-substituted, meta-substituted or para-substituted of benzene ring; r is: H. acetyl, benzoyl, 4-methylbenzoyl, 3-methylbenzoyl, 2-methoxybenzoyl, 3-methoxybenzoyl, 4-methyl formate benzoyl, 3-methyl formate benzoyl, 2-methyl formate benzoyl, 4-cyanobenzoyl, 3-cyanobenzoyl, 2-fluorobenzoyl, 3-fluorobenzoyl, 4-phenylbenzoyl, 3-phenylbenzoyl, 2-phenylbenzoyl.

According to the invention, the phenylalanine derivative containing 4-phenyl-1, 2, 3-triazole is one of the following compounds:

as used herein, "pharmaceutically acceptable salts" means salts of the compounds which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and lower animals without undue toxicity, irritation, and allergic response and the like, are commensurate with a reasonable benefit-to-risk ratio, are generally water or oil soluble or dispersible, and are effective for their intended use. Including pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts, which are contemplated herein and are compatible with the chemical nature of the compounds of formula I. A list of suitable salts is found on pages 1-19 of s.m. berge et al, j.pharm.sci.,1977, 66.

The term "prodrug" as used herein refers to pharmaceutically acceptable derivatives such that the resulting biotransformation product of these derivatives is the active drug as defined for the compound of formula I.

2. Preparation method of phenylalanine derivative containing 4-phenyl-1, 2, 3-triazole

The preparation method of the phenylalanine derivative containing 4-phenyl-1, 2, 3-triazole comprises the following steps: generating an intermediate 2 with Boc-L-phenylalanine (1) as an initial raw material and dichloromethane as a reaction solvent through an amide condensation reaction and N-methyl-4-aminoanisole; then the intermediate 2 is dissolved in a proper amount of dichloromethane, and Boc groups are removed under the action of trifluoroacetic acid to obtain an intermediate 3; then, carrying out amide condensation reaction on the intermediate 3 and azido acetic acid to obtain an intermediate 4 with azido groups; the intermediate 4 and corresponding substituted aminophenylacetylene generate compounds 5a-5c through azide-alkyne Husigen-Click cycloaddition reaction catalyzed by Cu (I) under the condition of sodium ascorbate and copper sulfate pentahydrate; finally, the compounds 5a-5c and corresponding acyl chloride are subjected to acylation reaction to obtain the target compounds 6a- (1-12), 6b- (1-12) and 6c- (1-12).

The synthetic route is as follows:

reagents and conditions: (i) n-methyl-4-aminoanisole, 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate, N, N-diisopropylethylamine and dichloromethane are added, and the temperature is changed to room temperature at 0 ℃; (ii) trifluoroacetic acid, dichloromethane, room temperature; (iii) azidoacetic acid, O- (7-azabenzotriazole-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, N, N-diisopropylethylamine and acetonitrile, and the temperature is changed to room temperature at 0 ℃; (iv) corresponding substituted aminophenylacetylene, sodium ascorbate, copper sulfate pentahydrate, water/tetrahydrofuran, room temperature; (v) the corresponding acid chloride, triethylamine and dichloromethane are cooled to room temperature at 0 ℃.

Wherein R is as described in formula I above.

The substituted aminophenylacetylene is 2-aminophenylacetylene, 3-aminophenylacetylene or 4-aminophenylacetylene.

The acyl chloride is acetyl chloride, benzoyl chloride, 4-methylbenzoyl chloride, 2-methoxybenzoyl chloride, 3-methoxybenzoyl chloride, 4-methyl formate benzoyl chloride, 4-cyanobenzoyl chloride, 2-fluorobenzoyl chloride, 3-fluorobenzoyl chloride, 4-fluorobenzoyl chloride or 4-phenylbenzoyl chloride.

The room temperature of the invention is 20-30 ℃.

According to the preferable preparation method of the phenylalanine derivative containing 4-phenyl-1, 2, 3-triazole, the preparation method comprises the following specific steps:

(1) adding Boc-L-phenylalanine (1) and 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate into dichloromethane, and stirring for 30min under an ice bath condition; adding N, N-diisopropylethylamine and N-methyl-4-aminoanisole into the reaction solution, removing the ice bath, transferring to room temperature, and monitoring by TLC; after the reaction is finished, evaporating the solvent under reduced pressure, then adding a saturated sodium bicarbonate solution into the residue in the bottle, extracting with dichloromethane, separating an organic phase, adding a 1N HCl solution for washing, separating the organic phase, adding a saturated sodium chloride solution for washing, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating and purifying the obtained crude product by silica gel column chromatography to obtain an intermediate 2;

(2) adding the intermediate 2 obtained in the previous step into dichloromethane, then slowly dropwise adding excessive trifluoroacetic acid into the solution, and stirring for 1h at room temperature; then adding saturated sodium bicarbonate solution to adjust the pH value of the reaction solution to 7, and then adding dichloromethane solution for extraction; separating and taking an organic phase, washing the organic phase for 3 times by using a saturated sodium chloride solution, drying the organic phase by using anhydrous sodium sulfate, filtering, evaporating the solvent by reduced pressure, and separating by using silica gel column chromatography to obtain an intermediate 3;

(3) adding azidoacetic acid and O- (7-azabenzotriazole-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate into acetonitrile, and stirring for 1h under an ice bath condition; then adding the intermediate 3 and N, N-diisopropylethylamine into the solution, removing the ice bath, and stirring at room temperature for 12 h; after the reaction is finished, evaporating the solvent under reduced pressure, then adding a saturated sodium bicarbonate solution into the residue in the bottle, extracting with dichloromethane, separating an organic phase, adding a 1N HCl solution for washing, separating the organic phase, adding a saturated sodium chloride solution for washing, drying the organic phase with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and separating by silica gel column chromatography to obtain an intermediate 4;

(4) adding the intermediate 4, substituted aminophenylacetylene, sodium ascorbate and copper sulfate pentahydrate into a mixed solvent of tetrahydrofuran and water in a volume ratio of 1:1, and stirring at room temperature for 12 h; after the reaction is finished, adding a proper amount of saturated sodium chloride solution into the reaction solution, extracting with dichloromethane, separating and taking an organic phase, drying with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and separating by silica gel column chromatography; recrystallizing ethyl acetate/petroleum ether to obtain compounds 5a-5 c;

(5) adding the compounds 5a-5c and triethylamine into dichloromethane, slowly adding corresponding acyl chloride into the dichloromethane under the condition of ice bath and stirring, removing the ice bath, transferring to room temperature, and monitoring by TLC; and after the reaction is finished, evaporating the solvent under reduced pressure, then adding a saturated sodium chloride solution into the residue in the bottle, extracting with dichloromethane, separating an organic phase, drying with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, separating by silica gel column chromatography to obtain a crude product of the target compound, and purifying by using a silica gel preparation plate to obtain pure products 6a- (1-12), 6b- (1-12) and 6c- (1-12) of the target compound.

3. Application of phenylalanine derivative containing 4-phenyl-1, 2, 3-triazole

The invention discloses a screening result of anti-HIV-1 activity of a phenylalanine derivative containing 4-phenyl-1, 2, 3-triazole and application of the phenylalanine derivative as an HIV-1 inhibitor for the first time. Experiments prove that the phenylalanine derivative containing the 4-phenyl-1, 2, 3-triazole can be used as an HIV-1 inhibitor for preparing anti-AIDS medicaments. The invention also provides application of the compound in anti-HIV drugs.

anti-HIV-1 Activity and toxicity test of the target Compound

A class of phenylalanine derivatives containing 4-phenyl-1, 2, 3-triazole synthesized according to the method is subjected to anti-HIV-1 activity and toxicity tests at a cellular level, the anti-HIV-1 activity and toxicity data of the phenylalanine derivatives are listed in Table 1, and a capsid protein inhibitor PF-74 reported in the literature is taken as a positive control.

The newly synthesized phenylalanine derivative containing 4-phenyl-1, 2, 3-triazole has obvious anti-HIV-1 activity. Example (b)For example, compounds 5a, 6a-1, 6a-2, 6a-9, 6a-10, 6a-11, 5b have anti-HIV-1 activity in the range of 3.13-3.99. mu.M, with compounds 6a-9 having anti-HIV-1 activity (EC)₅₀＝3.13±0.91μM,CC₅₀>16.48,SI>5.27) is particularly outstanding and has value for further research.

The phenylalanine derivatives containing 4-phenyl-1, 2, 3-triazole can be used as HIV-1 inhibitors. In particular to the application of the compound as an HIV-1 inhibitor in preparing anti-AIDS drugs.

An anti-HIV-1 pharmaceutical composition comprises a phenylalanine derivative containing 4-phenyl-1, 2, 3-triazole and one or more pharmaceutically acceptable carriers or excipients.

The invention provides a phenylalanine derivative containing 4-phenyl-1, 2, 3-triazole and a preparation method thereof, and also provides a screening result of anti-HIV-1 activity of partial compounds and the first application thereof in the field of antivirus. Tests prove that the phenylalanine derivatives containing 4-phenyl-1, 2, 3-triazole can be used as HIV-1 inhibitors and have high application value. In particular to the application of the compound as an HIV-1 inhibitor in preparing anti-AIDS drugs.

Detailed Description

The invention will be understood by the following examples, which are given by way of illustration and are not intended to limit the scope of the invention.

Example 1: preparation of tert-butyl (S) - (1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) carbamate (2)

The starting material Boc-L-phenylalanine (1) (2.90g,10.93mmol,1.5eq.) and 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate (5.69g,10.93mmol,1.5eq.) were added to 20mL of dichloromethane and stirred under ice bath conditions for 30 min; then N, N-diisopropylethylamine (3.61mL,21.87mmol,3eq.) and N-methyl-4-aminoanisole (1.0g7.29mmol,1eq.) were added, the ice bath was removed and the mixture was stirred at room temperature, monitored by TLC; after 6h, the reaction was completed, the solvent was evaporated under reduced pressure, then 40mL of saturated sodium bicarbonate solution and 40mL of dichloromethane were added to the residue in the flask for extraction, the organic phase was separated and washed with 40mL of 1N HCl solution, the organic phase was separated and washed with 40mL of saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product of tert-butyl (S) - (1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) carbamate (2), which was an intermediate, 2.48g and was a yellow oily substance, with a yield of 88% by silica gel column chromatography (eluent EA: PE ═ 1:8 v/v).

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ7.22(d,J＝8.3Hz,2H,Ph-H),7.20–7.11(m,3H,Ph-H),7.09(d,J＝8.2Hz,1H,NH),7.03(d,J＝8.6Hz,2H,Ph-H),6.79(d,J＝7.3Hz,2H,Ph-H),4.27–4.06(m,1H,CH),3.81(s,3H,OCH₃),3.13(s,3H,NCH₃),2.75(dd,J＝13.4,3.8Hz,1H,PhCH),2.61(dd,J＝13.3,10.3Hz,1H,PhCH),1.30(s,9H,C(CH₃)₃).¹³C NMR(100MHz,DMSO-d₆)δ172.22(C＝O),158.98,155.75(C＝O),138.53(2×C),136.12(2×C),129.28(2×C),128.47(2×C),126.70,115.21(2×C),78.33,55.94,53.55,37.86,37.07,28.65(3×C).ESI-MS:m/z 385.4(M+1),407.5(M+23).C₂₂H₂₈N₂O₄[384.5].

example 2: preparation of (S) -2-amino-N- (4-methoxyphenyl) -N-methyl-3-phenylpropionamide (3)

Intermediate 2(4.0g,10.40mmol,1.0eq.) was added to 30mL of dichloromethane, and trifluoroacetic acid (3.86mL,52.02mmol,5.0eq.) was then added slowly to this solution, stirred at room temperature, monitored by TLC; after 1h, the reaction was completed, and then the reaction solution was adjusted to pH 7 with saturated sodium bicarbonate solution, extracted with 40mL of dichloromethane, the organic phase was separated, washed with saturated sodium chloride solution (20 mL. times.3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2.36g of a crude product of intermediate (S) -2-amino-N- (4-methoxyphenyl) -N-methyl-3-phenylacrylamide (3), as a yellow oil, in 80% yield.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ7.29–7.13(m,3H,Ph-H),7.03–6.75(m,6H,Ph-H),3.77(s,3H,OCH₃),3.44–3.35(m,1H,CH),3.06(s,3H,NCH₃),2.75(dd,J＝12.8,6.7Hz,1H,PhCH),2.45(dd,J＝12.9,7.1Hz,1H,PhCH),1.87(s,2H,NH₂).¹³C NMR(100MHz,DMSO-d₆)δ174.89(C＝O),158.75,139.00,136.35,129.51(2×C),128.93(2×C),128.47(2×C),126.55,115.04(2×C),55.85,53.35,42.19,37.45.ESI-MS:m/z 285.05(M+1).C₁₇H₂₀N₂O₂[284.36].

example 3: preparation of intermediate (S) -2- (2-azidoacetamido) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (4)

Azidoacetic acid (40mg,0.40mmol,1.2eq.) and O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate (188mg,0.50mmol,1.5eq.) were added to 15mL acetonitrile and stirred under ice-bath conditions for 1 h; intermediate 3(94mg,0.33mmol,1eq.) and N, N-diisopropylethylamine (109 μ L,0.66mmol,2eq.) were then added to this solution, and after removal of the ice bath, stirred at room temperature and monitored by TLC; after 12 hours, the reaction was completed, the solvent was distilled off under reduced pressure, then 20mL of a saturated sodium bicarbonate solution and 20mL of dichloromethane were added to the residue in the flask for extraction, the organic phase was separated, 10mL of a 1N HCl solution was added for washing, the organic phase was separated and washed with a saturated sodium chloride solution (10mL × 3 times), the organic phase was dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and silica gel column chromatography was performed (eluent EA: PE ═ 1:4) to obtain 47mg of an intermediate (S) -2- (2-azidoacetamido) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropionamide (4) as a yellow oily substance in 39% yield.

Spectral data:¹H NMR(400MHz,Methanol-d₄)δ7.27–7.13(m,3H,Ph-H),7.11–6.59(m,6H,Ph-H),4.67(t,J＝7.4Hz,1H,NH),3.82(s,3H,OCH₃),3.81–3.74(m,1H,CH),3.31(dt,J＝3.1,1.6Hz,2H,N₃CH₂),3.16(s,3H,NCH₃),2.97(dd,J＝13.3,7.0Hz,1H,PhCH),2.73(dd,J＝13.3,7.9Hz,1H,PhCH).¹³C NMR(100MHz,Methanol-d₄)δ171.05(C＝O),167.29(C＝O),158.67,135.77,134.23,128.05(2×C),127.49,127.30(2×C),125.75(2×C),113.66(2×C),53.79,51.03,50.30,36.99,36.05.ESI-MS:m/z 368.3(M+1),390.3(M+23),406.5(M+39).C₁₉H₂₁N₅O₃[367.4].

example 4: preparation of Key intermediates (Compounds of interest) 5a-5c

Adding intermediate 4(110mg,0.30mmol,1eq.), the corresponding substituted aminophenylacetylene (42mg,0.36mmol,1.2eq.), sodium ascorbate (7.5mg,0.03mmol,0.1eq.), copper sulfate pentahydrate (17.8mg,0.09mmol,0.3eq.) to a mixed solvent of tetrahydrofuran and water (v/v ═ 1:1,6mL), stirring at room temperature, and monitoring by TLC; after the reaction was completed for 12 hours, 20mL of saturated sodium chloride solution was added to the reaction mixture, and the mixture was extracted with 20mL of dichloromethane, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated to dryness under reduced pressure, and separated by silica gel column chromatography (eluent EA: PE ═ 1:1) to obtain compounds 5a to 5 c.

Substituted aminophenylacetylene selected from 2-aminophenylacetylene and the intermediate 4 were reacted to give (S) -2(2- (4- (2-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetamido) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropionamide (5a)120mg as a white solid, yield 83%, melting point: 94-95 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ8.90(d,J＝7.6Hz,1H,NH),8.33(s,1H,triazole-H),7.42(d,J＝7.5Hz,1H,Ph-H),7.29–7.14(m,3H,Ph-H),7.14–6.98(m,3H,Ph-H),6.91(dd,J＝16.8,7.5Hz,4H,Ph-H),6.76(d,J＝8.1Hz,1H,Ph-H),6.59(t,J＝7.3Hz,1H,Ph-H),6.16(s,2H,NH₂),5.25–4.99(m,2H,triazoleCH₂),4.46(q,J＝8.1Hz,1H,CH),3.75(s,3H,OCH₃),3.11(s,3H,NCH₃),2.92(dd,J＝13.2,4.7Hz,1H,PhCH),2.69(dd,J＝13.1,9.4Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.18(C＝O),165.40(C＝O),159.02,147.54,145.05,137.68,135.78,129.33(2×C),129.10(2×C),128.88,128.70(2×C),127.93,127.03,123.22,116.40,116.25,115.10(2×C),113.02,55.85,52.10,51.85,37.87,37.77.ESI-MS:m/z485.5(M+1),507.4(M+23).C₂₇H₂₈N₆O₃[484.6].

substituted aminophenylacetylene selected from 3-aminophenylacetylene and the intermediate 4 were reacted to give (S) -2(2- (4- (3-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropionamide (5b)126mg as a white solid, yield 87%, melting point: 90-91 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ8.88(d,J＝7.8Hz,1H,NH),8.20(s,1H,triazole-H),7.29–7.14(m,3H,Ph-H),7.13–7.02(m,4H,Ph-H),6.91(dd,J＝17.6,8.2Hz,5H,Ph-H),6.52(d,J＝7.6Hz,1H,Ph-H),5.17(s,2H,PhNH₂),5.13(d,J＝16.4Hz,1H,triazoleCH),5.02(d,J＝16.2Hz,1H,triazoleCH),4.45(q,J＝8.2Hz,1H,CH),3.75(s,3H,OCH₃),3.10(s,3H,NCH₃),2.92(dd,J＝13.4,4.8Hz,1H,PhCH),2.69(dd,J＝13.2,9.3Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.20(C＝O),165.53(C＝O),159.01,149.51,147.15,137.69,135.79,131.59,129.81,129.33(2×C),129.11,128.71(2×C),127.03,122.90,115.09(2×C),113.97,113.36,110.80(2×C),55.85,52.10,51.73,37.85,37.77.ESI-MS:m/z 485.5(M+1),507.5(M+23).C₂₇H₂₈N₆O₃[484.6].

the substituted aminophenylacetylene is prepared by reacting 4-aminophenylacetylene with the intermediate 4 to obtain 70mg of (S) -2(2- (4- (4-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetamido) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropionamide (5c) as a white solid with a yield of 48%, a melting point: 105 ℃ and 106 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ8.86(d,J＝7.8Hz,1H,NH),8.07(s,1H,triazole-H),7.47(d,J＝8.4Hz,2H,Ph-H),7.27–7.13(m,3H,Ph-H),7.06(d,J＝6.6Hz,2H,Ph-H),6.93(d,J＝9.0Hz,2H,Ph-H),6.91–6.82(m,2H,Ph-H),6.60(d,J＝8.4Hz,2H,Ph-H),5.23(s,2H,NH₂),5.09(d,J＝16.3Hz,1H,triazoleCH),4.98(d,J＝16.3Hz,1H,triazoleCH),4.45(td,J＝8.5,5.5Hz,1H,CH),3.75(s,3H,OCH₃),3.10(s,3H,NCH₃),2.91(dd,J＝13.6,5.2Hz,1H,PhCH),2.68(dd,J＝13.4,9.1Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.19(C＝O),165.58(C＝O),159.01,149.03,147.48,137.69,135.80,129.33(2×C),129.10(2×C),128.69(2×C),127.02,126.55(2×C),121.07,118.78,115.09(2×C),114.39(2×C),55.85,52.06,51.71,37.87,37.77.ESI-MS:m/z 485.5(M+1),507.4(M+23),523.5(M+39).C₂₇H₂₈N₆O₃[484.6].

example 5: preparation of target Compounds 6a- (1-12), 6b- (1-12), 6c- (1-12)

Adding the compounds 5a-5c (0.12g,0.25mmol,1eq.) and triethylamine (69 μ L,0.50mmol,2eq.) into 10mL of dichloromethane, slowly adding the corresponding acid chloride (0.37mmol,1.5eq.) thereto with stirring in an ice bath, then removing the ice bath and transferring to room temperature, and monitoring by TLC; after 10h, the reaction is finished, the solvent is evaporated under reduced pressure, then 10mL of saturated sodium chloride solution is added into the residue in the bottle, 10mL of dichloromethane is used for extraction, the water phase is extracted by dichloromethane (10mL multiplied by 3 times), the organic phases are combined and dried by anhydrous sodium sulfate, the filtration is carried out, the solvent is evaporated under reduced pressure, the crude target compound is obtained by silica gel column chromatography separation (eluent EA: PE ═ 1:1), and the pure target compounds 6a- (1-12), 6b- (1-12) and 6c- (1-12) are obtained by purification through silica gel preparation plates.

The corresponding acid chloride was reacted with (S) -2(2- (4- (2-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropionamide (5a) using acetyl chloride (26. mu.L) to give (S) -2(2- (4- (2-acetylaminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropionamide (6a-1)61mg, white solid, yield 47%, melting point: 95-96 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ10.71(s,1H,PhNH),8.95(d,J＝7.8Hz,1H,NH),8.47(s,1H,triazole-H),8.10(d,J＝8.1Hz,1H,Ph-H),7.77(d,J＝7.6Hz,1H,Ph-H),7.33(t,J＝7.4Hz,1H,Ph-H),7.29–7.15(m,4H,Ph-H),7.14–7.01(m,2H,Ph-H),6.93(d,J＝8.9Hz,2H,Ph-H),6.89(d,J＝6.6Hz,2H,Ph-H),5.23(d,J＝16.3Hz,1H,triazoleCH),5.12(d,J＝16.3Hz,1H,triazoleCH),4.54–4.38(m,1H,CH),3.75(s,3H,OCH₃),3.11(s,3H,NCH₃),2.93(dd,J＝13.5,5.0Hz,1H,PhCH),2.70(dd,J＝13.4,9.3Hz,1H,PhCH),2.12(s,3H,COCH₃).¹³C NMR(100MHz,DMSO-d₆)δ171.18(C＝O),168.89(C＝O),165.29(C＝O),159.03,145.45,137.66,135.86,135.78,129.32(2×C),129.10(2×C),128.77,128.71(2×C),128.07,127.04,125.03,124.76,123.43,120.94,115.09(2×C),55.86,52.15,51.94,37.85,37.77,24.89.ESI-MS:m/z 527.4(M+1),544.5(M+18),549.4(M+23),565.4(M+39).C₂₉H₃₀N₆O₄[526.6].

the corresponding acid chloride was selected from benzoyl chloride (43. mu.L) and (S) -2(2- (4- (2-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5a) to prepare (S) -N- (2- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) benzamide (6a-2)78mg, white solid, yield 53%, melting point: 103 ℃ and 104 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ12.11(s,1H,PhNH),8.98(d,J＝7.8Hz,1H,NH),8.65(s,1H,triazole-H),8.61(d,J＝8.3Hz,1H,Ph-H),8.06(d,J＝7.0Hz,2H,Ph-HH),7.81(d,J＝7.8Hz,1H,Ph-H),7.70–7.50(m,3H,Ph-H),7.41(t,J＝7.8Hz,1H,Ph-H),7.30–7.14(m,4H,Ph-H),7.06(d,J＝6.5Hz,2H,Ph-H),6.93(d,J＝9.0Hz,2H,Ph-H),6.88(d,J＝6.7Hz,2H,Ph-H),5.26(d,J＝16.4Hz,1H,triazoleCH),5.15(d,J＝16.4Hz,1H,triazoleCH),4.46(td,J＝8.5,5.5Hz,1H,CH),3.74(s,3H,OCH₃),3.11(s,3H,NCH₃),2.92(dd,J＝13.4,5.0Hz,1H,PhCH),2.69(dd,J＝13.4,9.2Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.14(C＝O),165.34(C＝O),165.15(C＝O),159.02,146.34,137.65,136.27,135.76,135.16,132.45,129.35(2×C),129.32(2×C),129.09(2×C),129.06,128.70(2×C),128.01,127.63(2×C),127.02,125.07,124.58,121.91,119.22,115.10(2×C),55.84,52.14,52.12,37.87,37.77.ESI-MS:m/z589.4(M+1),606.4(M+18),611.3(M+23),627.4(M+39).C₃₄H₃₂N₆O₄[588.7].

the corresponding acid chloride was selected from 4-methylbenzoyl chloride (49. mu.L) and (S) -2(2- (4- (2-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5a) to give (S) -N- (2- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) -4-methylbenzamide (6a-3)105mg, white solid, yield 70%, melting point: 118 ℃ and 119 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ12.07(s,1H,PhNH),8.99(d,J＝7.8Hz,1H,NH),8.64(s,1H,triazole-H),8.61(d,J＝8.3Hz,1H,Ph-H),7.96(d,J＝8.1Hz,2H,Ph-H),7.80(d,J＝7.7Hz,1H,Ph-H),7.40(t,J＝6.7Hz,3H,Ph-H),7.20(tt,J＝14.2,7.3Hz,4H,Ph-H),7.13–6.99(m,2H,Ph-H),6.93(d,J＝8.9Hz,2H,Ph-H),6.88(d,J＝6.8Hz,2H,Ph-H),5.26(d,J＝16.4Hz,1H,triazoleCH),5.15(d,J＝16.4Hz,1H,triazoleCH),4.61–4.34(m,1H,CH),3.74(s,3H,OCH₃),3.11(s,3H,NCH₃),2.92(dd,J＝13.4,5.0Hz,1H,PhCH),2.69(dd,J＝13.4,9.2Hz,1H,PhCH),2.40(s,3H,PhCH₃).¹³C NMR(100MHz,DMSO-d₆)δ171.14(C＝O),165.27(C＝O),165.16(C＝O),159.02,146.39,142.52,137.65,136.37,135.76,132.40,129.88(2×C),129.32(2×C),129.09(2×C),129.04,128.70(2×C),127.99,127.64(2×C),127.02,125.04,124.42,121.80,119.04,115.09(2×C),55.84,52.12,52.11,37.87,37.77,21.49.ESI-MS:m/z 603.4(M+1),620.5(M+18),625.4(M+23),641.3(M+39).C₃₅H₃₄N₆O₄[602.7].

the corresponding acid chloride was selected from 2-methoxybenzoyl chloride (67. mu.L) and (S) -2(2- (4- (2-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5a) to prepare 125mg of (S) -2-methoxy-N- (2- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) benzamide (6a-4), white solid, yield 65%, melting point: 99-100 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ11.66(s,1H,PhNH),8.95(d,J＝7.9Hz,1H,NH),8.55(d,J＝8.3Hz,1H,Ph-H),8.47(s,1H,triazole-H),7.93(d,J＝6.9Hz,1H,Ph-H),7.64(d,J＝7.6Hz,1H,Ph-H),7.60–7.50(m,1H,Ph-H),7.40(t,J＝7.8Hz,1H,Ph-H),7.28–7.13(m,5H,Ph-H),7.15–6.99(m,3H,Ph-H),6.93(d,J＝8.9Hz,2H,Ph-H),6.88(d,J＝6.6Hz,2H,Ph-H),5.23(d,J＝16.3Hz,1H,triazoleCH),5.13(d,J＝16.3Hz,1H,triazole-CH),4.47(td,J＝8.5,5.4Hz,1H,CH),3.87(s,3H,OCH₃),3.75(s,3H,OCH₃),3.11(s,3H,NCH₃),2.92(dd,J＝13.5,5.0Hz,1H,PhCH),2.69(dd,J＝13.4,9.2Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.16(C＝O),165.27(C＝O),164.08(C＝O),159.02,157.36,145.64,137.66,136.09,135.77,133.66,131.58,129.32(2×C),129.10,128.89,128.82,128.69(2×C),127.02,125.08,124.45,123.07,122.82,121.13(2×C),120.14,115.10(2×C),112.51,56.29,55.85,52.12,51.97,37.85,37.77.ESI-MS:m/z 619.5(M+1),636.4(M+18),641.4(M+23),657.4(M+39).C₃₅H₃₄N₆O₅[618.7].

the corresponding acid chloride was selected from 3-methoxybenzoyl chloride (65. mu.L) and (S) -2(2- (4- (2-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5a) to prepare (S) -3-methoxy-N- (2- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) benzamide (6a-5)150mg, white solid, yield 79%, melting point: 99-100 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ12.13(s,1H,PhNH),8.97(d,J＝7.8Hz,1H,NH),8.65(s,1H,triazole-H),8.62(d,J＝8.3Hz,1H,Ph-H),7.82(d,J＝7.5Hz,1H,Ph-H),7.65(d,J＝7.8Hz,1H,Ph-H),7.62(s,1H,Ph-H),7.51(t,J＝7.9Hz,1H,Ph-H),7.42(t,J＝7.6Hz,1H,Ph-H),7.21(dp,J＝16.5,7.4Hz,5H,Ph-H),7.06(d,J＝6.6Hz,2H,Ph-H),6.93(d,J＝8.9Hz,2H,Ph-H),6.89(d,J＝6.8Hz,2H,Ph-H),5.26(d,J＝16.4Hz,1H,triazoleCH),5.16(d,J＝16.3Hz,1H,triazoleCH),4.47(td,J＝8.4,5.5Hz,1H,CH),3.87(s,3H,OCH₃),3.75(s,3H,OCH₃),3.11(s,3H,NCH₃),2.93(dd,J＝13.5,5.1Hz,1H,PhCH),2.70(dd,J＝13.4,9.2Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.14(C＝O),165.15(C＝O),165.05(C＝O),159.96,159.02,146.36,137.65,136.59,136.24,135.76,130.51,129.32(2×C),129.10(2×C),128.71(2×C),128.01,127.03,125.10,124.57,121.72,119.80(2×C),119.08,118.43,115.09(2×C),112.60,55.84,55.77(2×C),52.14,37.86,37.77.ESI-MS:m/z 619.5(M+1),636.4(M+18),641.4(M+23),657.4(M+39).C₃₅H₃₄N₆O₅[618.7].

the corresponding acid chloride was selected from 4-methoxybenzoyl chloride (79mg) and (S) -2(2- (4- (2-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5a) to prepare (S) -4-methoxy-N- (2- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) benzamide (6a-6)130mg, white solid, yield 68%, melting point: 110-111 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ12.03(s,1H,PhNH),8.97(d,J＝7.8Hz,1H,NH),8.64(s,1H,triazole-H),8.62(d,J＝8.1Hz,1H,Ph-H),8.04(d,J＝8.8Hz,2H,Ph-H),7.85–7.76(m,1H,Ph-H),7.45–7.36(m,1H,Ph-H),7.26–7.16(m,4H,Ph-H),7.14(d,J＝8.9Hz,2H,Ph-H),7.06(d,J＝6.8Hz,2H,Ph-H),6.93(d,J＝9.0Hz,2H,Ph-H),6.89(d,J＝6.6Hz,2H,Ph-H),5.26(d,J＝16.4Hz,1H,triazoleCH),5.16(d,J＝16.4Hz,1H,triazoleCH),4.47(td,J＝8.5,5.3Hz,1H,CH),3.86(s,3H,OCH₃),3.75(s,3H,OCH₃),3.11(s,3H,NCH₃),2.93(dd,J＝13.4,5.1Hz,1H,PhCH),2.70(dd,J＝13.5,9.1Hz,1H,PhCH).¹³CNMR(100MHz,DMSO-d₆)δ171.15(C＝O),165.18(C＝O),164.85(C＝O),162.62,159.02,146.45,137.66,136.51,135.76,129.53(2×C),129.32(2×C),129.10(2×C),129.04,128.71(2×C),127.96,127.26,127.03,125.04,124.25,121.69,118.87,115.09(2×C),114.59(2×C),55.95,55.84,52.16,52.11,37.85,37.77.ESI-MS:m/z 619.5(M+1),641.3(M+23).C₃₅H₃₄N₆O₅[618.7].

the corresponding acid chloride was selected from methyl 4-carboxylate benzoyl chloride (74mg) and (S) -2(2- (4- (2-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5a) to prepare (S) -methyl 4- ((2- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2- (methyl) oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) carbamoyl) benzoate (6a-7)121mg, white solid, yield 76%, melting point: 130 ℃ and 131 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ12.04(s,1H,PhNH),8.95(d,J＝7.8Hz,1H,NH),8.61(s,1H,triazole-H),8.50(d,J＝8.2Hz,1H,Ph-H),8.22–8.10(m,4H,Ph-H),7.83(d,J＝7.2Hz,1H,Ph-H),7.43(t,J＝7.4Hz,1H,Ph-H),7.28(t,J＝7.5Hz,1H,Ph-H),7.19(q,J＝8.7,7.5Hz,3H,Ph-H),7.06(d,J＝7.4Hz,2H,Ph-H),6.92(d,J＝8.9Hz,2H,Ph-H),6.88(d,J＝6.6Hz,2H,Ph-H),5.25(d,J＝16.3Hz,1H,triazoleCH),5.15(d,J＝16.3Hz,1H,triazoleCH),4.47(td,J＝8.5,5.5Hz,1H,CH),3.90(s,3H,COOCH₃),3.74(s,3H,OCH₃),3.11(s,3H,NCH₃),2.92(dd,J＝13.5,5.1Hz,1H,PhCH),2.69(dd,J＝13.4,9.1Hz,1H,PhCH).¹³CNMR(100MHz,DMSO-d₆)δ171.12(C＝O),166.06(C＝O),165.14(C＝O),164.61(C＝O),159.03,146.07,139.27,137.64(2×C),135.89(2×C),135.78,132.84,130.05(2×C),129.32(2×C),129.06(2×C),128.69(2×C),128.09(2×C),127.00,125.08(2×C),122.58,120.11,115.10(2×C),55.84(2×C),52.91,52.12,37.91,37.76.ESI-MS:m/z647.5(M+1),664.5(M+18),669.4(M+23),685.5(M+39).C₃₅H₃₄N₆O₅[646.7].

the corresponding acid chloride was reacted with (S) -2(2- (4- (2-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5a) using 4-cyanobenzoyl chloride (62mg) to give (S) -4-cyano-N- (2- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) benzamide (6a-8)93mg, white solid, yield 61%, melting point: 142 ℃ and 143 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ12.04(s,1H,PhNH),8.95(d,J＝7.8Hz,1H,NH),8.61(s,1H,triazole-H),8.47(d,J＝8.2Hz,1H,Ph-H),8.18(d,J＝8.2Hz,2H,Ph-H),8.07(d,J＝8.3Hz,2H,Ph-H),7.83(d,J＝7.7Hz,1H,Ph-H),7.43(t,J＝7.7Hz,1H,Ph-H),7.28(t,J＝7.5Hz,1H,Ph-H),7.20(q,J＝8.8,7.6Hz,3H,Ph-H),7.06(d,J＝7.3Hz,2H,Ph-H),6.92(d,J＝8.8Hz,2H,Ph-H),6.88(d,J＝6.8Hz,2H,Ph-H),5.25(d,J＝16.3Hz,1H,triazoleCH),5.15(d,J＝16.3Hz,1H,triazoleCH),4.47(td,J＝8.4,5.4Hz,1H,CH),3.75(s,3H,OCH₃),3.11(s,3H,NCH₃),2.92(dd,J＝13.5,5.0Hz,1H,PhCH),2.69(dd,J＝13.3,9.3Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.14(C＝O),165.17(C＝O),164.02(C＝O),159.04,146.01,139.17,137.65,135.78,135.71,133.36(2×C),129.31(2×C),129.07(2×C),128.70(2×C),128.53(2×C),128.12,127.02,125.28,125.12,122.71,120.32,118.69(2×C),115.11(2×C),114.68,55.85,52.16,52.10,37.90,37.77.ESI-MS:m/z614.3(M+1),631.4(M+18),636.4(M+23),652.5(M+39).C₃₅H₃₁N₇O₄[613.7].

the corresponding acid chloride was selected from 2-fluorobenzoyl chloride (44. mu.L) and (S) -2(2- (4- (2-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5a) to give (S) -2-fluoro-N- (2- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) benzamide (6a-9)114mg, white solid, yield 76%, melting point: 105 ℃ and 106 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ11.76(s,1H,PhNH),8.95(d,J＝7.9Hz,1H,NH),8.58(s,1H,triazole-H),8.48(d,J＝8.1Hz,1H,Ph-H),7.87(t,J＝7.1Hz,1H,Ph-H),7.78(d,J＝7.7Hz,1H,Ph-H),7.64(q,J＝6.0Hz,1H,Ph-H),7.50–7.33(m,3H,Ph-H),7.27(t,J＝7.5Hz,1H,Ph-H),7.19(q,J＝8.3,7.3Hz,3H,Ph-H),7.11–6.99(m,2H,Ph-H),6.93(d,J＝9.0Hz,2H,Ph-H),6.88(d,J＝6.5Hz,2H,Ph-H),5.22(d,J＝16.4Hz,1H,triazoleCH),5.12(d,J＝16.3Hz,1H,triazoleCH),4.46(td,J＝8.5,5.4Hz,1H,CH),3.75(s,3H,OCH₃),3.11(s,3H,NCH₃),2.92(dd,J＝13.5,5.0Hz,1H,PhCH),2.69(dd,J＝13.4,9.1Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.13(C＝O),165.14(C＝O),162.58(C＝O),159.69(d,¹J_CF＝248.4Hz),159.02,145.90,137.64,135.72(d,³J_CF＝9.7Hz),133.94(d,³J_CF＝8.6Hz),130.84(d,⁴J_CF＝2.1Hz),129.32(2×C),129.08(2×C),128.99,128.69(2×C),128.21,127.01,125.41(d,⁴J_CF＝3.4Hz),125.07,124.98,124.13(d,²J_CF＝13.4Hz),122.63,119.87,117.13,116.90,115.10(2×C),55.84,52.11,52.03,37.89,37.77.ESI-MS:m/z 607.4(M+1),624.5(M+18),645.5(M+39).C₃₄H₃₁FN₆O₄[606.7].

the corresponding acid chloride was selected from 3-fluorobenzoyl chloride (45. mu.L) and (S) -2(2- (4- (2-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino ] -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5a) to give (S) -3-fluoro-N- (2- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) benzamide (6a-10)88mg, white solid, yield 59%, melting point: 109 ℃ and 110 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ12.06(s,1H,PhNH),8.97(d,J＝7.8Hz,1H,NH),8.64(s,1H,triazole-H),8.52(d,J＝8.2Hz,1H,Ph-H),7.91(d,J＝7.7Hz,1H,Ph-H),7.83(t,J＝7.8Hz,2H,Ph-H),7.66(q,J＝7.8Hz,1H,Ph-H),7.51(dt,J＝8.3,4.4Hz,1H,Ph-H),7.42(t,J＝7.6Hz,1H,Ph-H),7.27(t,J＝7.5Hz,1H,Ph-H),7.20(q,J＝9.3,7.8Hz,3H,Ph-H),7.13–6.99(m,2H,Ph-H),6.93(d,J＝8.8Hz,2H,Ph-H),6.89(d,J＝6.8Hz,2H,Ph-H),5.26(d,J＝16.4Hz,1H,triazoleCH),5.16(d,J＝16.3Hz,1H,triazoleCH),4.47(q,J＝8.3Hz,1H,CH),3.75(s,3H,OCH₃),3.11(s,3H,NCH₃),2.92(dd,J＝13.4,5.0Hz,1H,PhCH),2.70(dd,J＝13.3,9.2Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.13(C＝O),165.16(C＝O),164.02(d,⁴J_CF＝2.3Hz,C＝O),162.67(d,¹J_CF＝243.5Hz),159.02,146.17,137.65(2×C),137.58(d,³J_CF＝6.7Hz),135.92,135.76,131.56(d,³J_CF＝7.7Hz),129.32(2×C),129.08(2×C),128.70(2×C),128.05,127.01,125.10,124.96,123.69(d,⁴J_CF＝2.3Hz),122.32,119.78,119.37(d,²J_CF＝20.8Hz),115.09(2×C),114.63(d,²J_CF＝22.8Hz),55.84,52.13,52.11,37.88,37.76.ESI-MS:m/z 607.4(M+1),624.4(M+18),629.4(M+23),645.4(M+39).C₃₄H₃₁FN₆O₄[606.7].

the corresponding acid chloride was reacted with (S) -2(2- (4- (2-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5a) using 4-fluorobenzoyl chloride (44. mu.L) to give (S) -4-fluoro-N- (2- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) benzamide (6a-11)101mg, white solid, yield 67%, melting point: 123 ℃ and 124 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ12.01(s,1H,PhNH),8.97(d,J＝7.8Hz,1H,NH),8.63(s,1H,triazole-H),8.54(d,J＝8.2Hz,1H,Ph-H),8.12(dd,J＝8.7,5.5Hz,2H,Ph-H),7.88–7.78(m,1H,Ph-H),7.43(q,J＝8.3,7.7Hz,3H,Ph-H),7.32–7.23(m,1H,Ph-H),7.23–7.15(m,3H,Ph-H),7.06(d,J＝6.8Hz,2H,Ph-H),6.93(d,J＝9.0Hz,2H,Ph-H),6.88(d,J＝6.7Hz,2H,Ph-H),5.26(d,J＝16.4Hz,1H,triazoleCH),5.15(d,J＝16.3Hz,1H,triazoleCH),4.47(td,J＝8.5,5.4Hz,1H,CH),3.75(s,3H,OCH₃),3.11(s,3H,NCH₃),2.93(dd,J＝13.4,5.0Hz,1H,PhCH),2.69(dd,J＝13.4,9.2Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.15(C＝O),165.18(C＝O),164.72(d,¹J_CF＝243.5Hz),164.32(C＝O),159.03,146.23,137.65,136.12,135.76,131.67(d,⁴J_CF＝2.3Hz),130.41,130.32,129.31(2×C),129.09,129.04,128.70(2×C),128.03,127.02,125.08,124.74,122.22,119.61,116.44(2×C),116.22,115.09(2×C),55.84,52.16,52.09,37.86,37.76.ESI-MS:m/z 607.4(M+1),624.4(M+18),629.4(M+23),645.4(M+39).C₃₄H₃₁FN₆O₄[606.7].

the corresponding acid chloride was selected from 4-phenylbenzoyl chloride (81mg) and (S) -2(2- (4- (2-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5a) to give (S) -N- (2- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) - [1,1' -Biphenyl ] -4-carboxamide (6a-12)95mg, white solid, yield 58%, melting point: 120 ℃ and 121 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ12.16(s,1H,PhNH),8.98(d,J＝7.8Hz,1H,NH),8.67(s,1H,triazole-H),8.63(d,J＝8.3Hz,1H,Ph-H),8.16(d,J＝8.2Hz,2H,Ph-H),7.91(d,J＝8.2Hz,2H,Ph-H),7.83(d,J＝7.7Hz,1H,Ph-H),7.79(d,J＝7.6Hz,2H,Ph-H),7.52(t,J＝7.5Hz,2H,Ph-H),7.30–7.15(m,5H,Ph-H),7.11–7.04(m,2H,Ph-H),6.95–6.85(m,5H,Ph-H),5.27(d,J＝16.4Hz,1H,triazoleCH),5.18(d,J＝13.5Hz,1H,triazoleCH),4.51–4.42(m,1H,CH),3.73(s,3H,OCH₃),3.11(s,3H,NCH₃),2.93(dd,J＝13.4,5.0Hz,1H,PhCH),2.70(dd,J＝13.3,9.3Hz,1H,PhCH).¹³C NMR(101MHz,DMSO-d₆)δ171.15(C＝O),165.18(C＝O),165.00(C＝O),159.02,146.36,146.05,143.92,139.41,137.65,136.30,135.76,133.90,129.54(2×C),129.32(2×C),129.09(2×C),128.70(2×C),128.34(2×C),127.53(2×C),127.42(2×C),127.02,125.10,124.60,132.22,121.99,119.27,116.26,115.09(2×C),55.83,52.15,52.11,37.87,37.76.ESI-MS:m/z 665.4(M+1),682.5(M+18).C₄₀H₃₆N₆O₄[664.8].

the corresponding acid chloride was reacted with (S) -2(2- (4- (3-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropionamide (5b) using acetyl chloride (26. mu.L) to give (S) -2- (2- (4- (3-acetylaminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropionamide (6b-1)68mg, white solid, yield 52%, melting point: 206- & lt207 & gt.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ10.05(s,1H,PhNH),8.91(d,J＝7.8Hz,1H,NH),8.34(s,1H,triazole-H),8.12(s,1H,Ph-H),7.56(d,J＝8.0Hz,1H,Ph-H),7.45(d,J＝7.7Hz,1H,Ph-H),7.36(t,J＝7.9Hz,1H,Ph-H),7.27–7.14(m,3H,Ph-H),7.14–7.00(m,2H,Ph-H),6.94(d,J＝8.9Hz,2H,Ph-H),6.89(d,J＝6.4Hz,2H,Ph-H),5.17(d,J＝16.3Hz,1H,triazoleCH),5.06(d,J＝16.3Hz,1H,triazoleCH),4.46(td,J＝8.5,5.4Hz,1H,CH),3.76(s,3H,OCH₃),3.11(s,3H,NCH₃),2.92(dd,J＝13.5,5.0Hz,1H,PhCH),2.70(dd,J＝13.5,9.2Hz,1H,PhCH),2.07(s,3H,COCH₃).¹³C NMR(100MHz,DMSO-d₆)δ171.18(C＝O),168.87(C＝O),165.46,159.02,146.43,140.33,137.67,135.79,131.54,129.75,129.33(2×C),129.10,128.70(2×C),127.03,123.36(2×C),120.40,118.85,115.92,115.10(2×C),55.85,52.09,51.80,37.88,37.77,24.53.ESI-MS:m/z 527.4(M+1),544.5(M+18),549.4(M+23),565.5(M+39).C₂₉H₃₀N₆O₄[526.6].

the corresponding acid chloride was selected from benzoyl chloride (43. mu.L) and (S) -2(2- (4- (3-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5b) to prepare (S) -N- (3- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) benzamide (6b-2)106mg, white solid, yield 73%, melting point: 135 ℃ and 136 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ10.38(s,1H,PhNH),8.93(d,J＝7.8Hz,1H,NH),8.37(s,1H,Ph-H),8.34(s,1H,triazole-H),8.00(d,J＝7.1Hz,2H,Ph-H),7.78(d,J＝8.0Hz,1H,Ph-H),7.62-7.52(m,4H,Ph-H),7.42(t,J＝7.9Hz,1H,Ph-H),7.23-7.18(m,3H,Ph-H),7.08–7.06(m,2H,Ph-H),6.95-6.88(m,4H,Ph-H),5.18(d,J＝16.3Hz,1H,triazoleCH),5.07(d,J＝16.3Hz,1H,triazoleCH),4.46(td,J＝8.5,5.5Hz,1H,CH),3.75(s,3H,OCH₃),3.11(s,3H,NCH₃),2.92(dd,J＝13.4,5.0Hz,1H,PhCH),2.69(dd,J＝13.5,9.2Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.19(C＝O),166.06(C＝O),165.48(C＝O),159.02,146.45,140.20,137.68,135.79,135.30,132.10,131.52,129.70,129.34(2×C),129.11,128.87(2×C),128.71(2×C),128.16(2×C),127.04,123.43(2×C),121.04,120.22,117.40,115.10(2×C),55.85,52.11,51.82,37.87,37.78.ESI-MS:m/z 589.5(M+1),606.4(M+18),611.4(M+23),627.4(M+39).C₃₄H₃₂N₆O₄[588.7].

the corresponding acid chloride was selected from 4-methylbenzoyl chloride (49. mu.L) and (S) -2(2- (4- (3-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5b) to give (S) -N- (3- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) -4-methylbenzamide (6b-3)94mg, white solid, yield 63%, melting point: 212 ℃ and 213 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ10.28(s,1H,PhNH),8.92(d,J＝7.8Hz,1H,NH),8.37(s,1H,Ph-H),8.34(s,1H,triazole-H),7.92(d,J＝8.0Hz,2H,Ph-H),7.78(d,J＝7.9Hz,1H,Ph-H),7.53(d,J＝7.7Hz,1H,Ph-H),7.42(t,J＝7.9Hz,1H,Ph-H),7.35(d,J＝8.0Hz,2H,Ph-H),7.21(q,J＝7.9,7.0Hz,3H,Ph-H),7.15–7.01(m,2H,Ph-H),6.94(d,J＝8.9Hz,2H,Ph-H),6.90(d,J＝6.6Hz,2H,Ph-H),5.18(d,J＝16.3Hz,1H,triazoleCH),5.07(d,J＝16.3Hz,1H,triazoleCH),4.47(td,J＝8.4,5.3Hz,1H,CH),3.76(s,3H,OCH₃),3.11(s,3H,NCH₃),2.93(dd,J＝13.4,5.0Hz,1H,PhCH),2.70(dd,J＝13.4,9.2Hz,1H,PhCH),2.40(s,3H,PhCH₃).¹³C NMR(100MHz,DMSO-d₆)δ171.19(C＝O),165.85(C＝O),165.48(C＝O),159.02,146.47,142.11,140.27,137.68,135.79,132.40,131.49,129.67,129.39(2×C),129.34(2×C),129.12,128.71(2×C),128.19(2×C),127.04,123.41(2×C),120.92,120.21,117.39,115.10(2×C),55.85,52.10,51.81,37.87,37.78,21.50.ESI-MS:m/z603.4(M+1),620.5(M+18),625.4(M+23),641.3(M+39).C₃₅H₃₄N₆O₄[602.7].

the corresponding acid chloride was selected from 2-methoxybenzoyl chloride (54. mu.L) and (S) -2(2- (4- (3-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5b) to give (S) -2-methoxy-N- (3- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) benzamide (6b-4)99mg, white solid, yield 65%, melting point: 125 ℃ and 126 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ10.23(s,1H,PhNH),8.93(d,J＝7.8Hz,1H,NH),8.37(s,1H,Ph-H),8.29(s,1H,triazole-H),7.68(dd,J＝11.9,8.0Hz,2H,Ph-H),7.52(t,J＝9.4Hz,2H,Ph-H),7.41(t,J＝7.9Hz,1H,Ph-H),7.30–7.15(m,4H,Ph-H),7.08(t,J＝7.3Hz,3H,Ph-H),6.94(d,J＝8.8Hz,2H,Ph-H),6.90(d,J＝6.6Hz,2H,Ph-H),5.18(d,J＝16.3Hz,1H,triazoleCH),5.07(d,J＝16.3Hz,1H,triazoleCH),4.47(td,J＝8.4,5.4Hz,1H,CH),3.92(s,3H,OCH₃),3.76(s,3H,OCH₃),3.12(s,3H,NCH₃),2.93(dd,J＝13.4,5.0Hz,1H,PhCH),2.70(dd,J＝13.4,9.2Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.18(C＝O),165.46(C＝O),165.10(C＝O),159.02,156.96,146.43,140.06,137.68,135.79,132.52,131.62,130.13,129.76,129.34(2×C),129.11,128.71(2×C),127.03,125.41,123.45,120.95(2×C),120.88,119.65,116.75,115.10(2×C),112.46,56.37,55.85,52.10,51.83,37.89,37.77.ESI-MS:m/z 619.5(M+1),636.4(M+18),641.3(M+23),657.3(M+39).C₃₅H₃₄N₆O₅[618.7].

the corresponding acid chloride was selected from 3-methoxybenzoyl chloride (54. mu.L) and (S) -2(2- (4- (3-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5b) to prepare 73mg of (S) -3-methoxy-N- (3- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) benzamide (6b-5), white solid, yield 48%, melting point: 115 ℃ and 116 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ10.34(s,1H,PhNH),8.92(d,J＝7.6Hz,1H,NH),8.37(s,1H,Ph-H),8.33(s,1H,triazole-H),7.79(d,J＝7.7Hz,1H,Ph-H),7.59(d,J＝7.5Hz,1H,Ph-H),7.54(s,2H,Ph-H),7.45(dt,J＝13.0,7.9Hz,2H,Ph-H),7.29–7.13(m,4H,Ph-H),7.08(d,J＝6.6Hz,2H,Ph-H),6.94(d,J＝8.5Hz,2H,Ph-H),6.90(d,J＝6.5Hz,2H,Ph-H),5.19(d,J＝16.3Hz,1H,triazoleCH),5.08(d,J＝16.3Hz,1H,triazoleCH),4.48(q,J＝7.9Hz,1H,CH),3.86(s,3H,OCH₃),3.76(s,3H,OCH₃),3.12(s,3H,NCH₃),2.93(dd,J＝13.2,4.6Hz,1H,PhCH),2.71(dd,J＝13.0,9.4Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.19(C＝O),165.75(C＝O),165.47(C＝O),159.65,159.02,146.44,140.12,137.68,136.68,135.79,131.52,130.03,129.69,129.34(2×C),129.10,128.71(2×C),127.03,123.42,121.09,120.38(2×C),120.31,117.87,117.49,115.11(2×C),113.36,55.85,55.82,52.10,51.83,37.89,37.78.ESI-MS:m/z 619.5(M+1),636.4(M+18),641.3(M+23),657.5(M+39).C₃₅H₃₄N₆O₅[618.7].

the corresponding acid chloride was reacted with (S) -2(2- (4- (3-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5b) using 4-methoxybenzoyl chloride (63mg) to give (S) -4-methoxy-N- (3- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) benzamide (6b-6)97mg, white solid, yield 63%, melting point: 199 ℃ and 200 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ10.20(s,1H,PhNH),8.91(d,J＝7.8Hz,1H,NH),8.36(s,1H,Ph-H),8.32(s,1H,triazole-H),8.01(d,J＝8.7Hz,2H,Ph-H),7.78(d,J＝8.1Hz,1H,Ph-H),7.52(d,J＝7.7Hz,1H,Ph-H),7.41(t,J＝7.9Hz,1H,Ph-H),7.26–7.16(m,3H,Ph-H),7.08(d,J＝8.7Hz,4H,Ph-H),6.94(d,J＝8.9Hz,2H,Ph-H),6.89(d,J＝6.6Hz,2H,Ph-H),5.18(d,J＝16.3Hz,1H,triazoleCH),5.07(d,J＝16.3Hz,1H,triazoleCH),4.47(td,J＝8.4,5.6Hz,1H,CH),3.85(s,3H,OCH₃),3.76(s,3H,OCH₃),3.11(s,3H,NCH₃),2.93(dd,J＝13.5,5.1Hz,1H,PhCH),2.70(dd,J＝13.4,9.2Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.19(C＝O),165.47(C＝O),165.40(C＝O),162.40,159.02,146.50,140.37,137.68,135.79,131.47,130.10(2×C),129.63,129.34(2×C),129.11,128.71(2×C),127.30,127.03,123.38(2×C),120.80,120.19,117.38,115.11(2×C),114.08(2×C),55.91,55.85,52.10,51.83,37.89,37.78.ESI-MS:m/z 619.5(M+1),636.4(M+18),641.4(M+23),657.5(M+39).C₃₅H₃₄N₆O₅[618.7].

the corresponding acid chloride was selected from methyl 4-carboxylate benzoyl chloride (74mg) and (S) -2(2- (4- (3-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5b) to prepare methyl (S) -4- ((3- (1- (2-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2- (methyl) oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) carbamoyl) benzoate (6b-7)94mg, white solid, yield 58%, melting point: 153-.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ12.04(s,1H,PhNH),8.95(d,J＝7.8Hz,1H,NH),8.61(s,1H,triazole-H),8.49(d,J＝8.2Hz,1H,Ph-H),8.21–8.09(m,4H,Ph-H),7.83(d,J＝7.4Hz,1H,Ph-H),7.43(t,J＝7.5Hz,1H,Ph-H),7.28(t,J＝7.5Hz,1H,Ph-H),7.19(q,J＝8.7,7.5Hz,3H,Ph-H),7.06(d,J＝6.9Hz,2H,Ph-H),6.92(d,J＝8.9Hz,2H,Ph-H),6.88(d,J＝6.7Hz,2H,Ph-H),5.25(d,J＝16.3Hz,1H,triazoleCH),5.15(d,J＝16.3Hz,1H,triazoleCH),4.47(td,J＝8.4,5.6Hz,1H,CH),3.90(s,3H,COOCH₃),3.74(s,3H,OCH₃),3.11(s,3H,NCH₃),2.92(dd,J＝13.5,5.0Hz,1H,PhCH),2.69(dd,J＝13.4,9.1Hz,1H,PhCH).¹³CNMR(100MHz,DMSO-d₆)δ171.13(C＝O),166.05(C＝O),165.16(C＝O),164.61(C＝O),159.02,146.05,139.26,137.65,135.86,135.76,132.82,130.06(2×C),129.31(2×C),129.07(2×C),128.70(2×C),128.11(2×C),127.01(2×C),125.11(2×C),122.60(2×C),120.12,115.09(2×C),55.84,52.94,52.14,52.08,37.86,37.76.ESI-MS:m/z 647.4(M+1),664.4(M+18),669.4(M+23),685.5(M+39).C₃₆H₃₄N₆O₆[646.7].

the corresponding acid chloride was reacted with (S) -2(2- (4- (3-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5b) using 4-cyanobenzoyl chloride (62mg) to give (S) -4-cyano-N- (3- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) benzamide (6b-8)55mg, white solid, yield 36%, melting point: 224-225 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ10.61(s,1H,PhNH),8.93(d,J＝7.8Hz,1H,NH),8.39(s,1H,Ph-H),8.34(s,1H,triazole-H),8.15(d,J＝8.3Hz,2H,Ph-H),8.05(d,J＝8.3Hz,2H,Ph-H),7.78(d,J＝8.1Hz,1H,Ph-H),7.57(d,J＝7.7Hz,1H,Ph-H),7.45(t,J＝7.9Hz,1H,Ph-H),7.21(q,J＝7.8,7.0Hz,3H,Ph-H),7.13–7.02(m,2H,Ph-H),6.94(d,J＝8.9Hz,2H,Ph-H),6.89(d,J＝6.6Hz,2H,Ph-H),5.19(d,J＝16.3Hz,1H,triazoleCH),5.08(d,J＝16.3Hz,1H,triazoleCH),4.47(td,J＝8.5,5.1Hz,1H,CH),3.76(s,3H,OCH₃),3.12(s,3H,NCH₃),2.93(dd,J＝13.4,5.0Hz,1H,PhCH),2.70(dd,J＝13.4,9.2Hz,1H,PhCH).¹³CNMR(100MHz,DMSO-d₆)δ171.19(C＝O),165.46(C＝O),164.67(C＝O),159.02,146.33,139.79,139.31,137.68,135.79,132.95(2×C),131.61,129.81,129.33(2×C),129.11,129.03(2×C),128.71(2×C),127.03,123.48(2×C),121.47,120.27,118.80,117.43,115.10(2×C),114.36,55.85,52.11,51.83,37.88,37.77.ESI-MS:m/z 614.3(M+1),631.5(M+18),636.3(M+23),652.4(M+39).C₃₅H₃₁N₇O₄[613.7].

the corresponding acid chloride was selected from 2-fluorobenzoyl chloride (44. mu.L) and (S) -2(2- (4- (3-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5b) to give (S) -2-fluoro-N- (3- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) benzamide (6b-9)92mg, white solid, yield 61%, melting point: 114-.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ10.55(s,1H,PhNH),8.93(d,J＝7.9Hz,1H,NH),8.38(s,1H,Ph-H),8.30(s,1H,triazole-H),7.70(t,J＝7.7Hz,2H,Ph-H),7.65–7.57(m,1H,Ph-H),7.55(d,J＝7.8Hz,1H,Ph-H),7.43(t,J＝7.9Hz,1H,Ph-H),7.36(q,J＝9.0,7.4Hz,2H,Ph-H),7.26–7.16(m,3H,Ph-H),7.14–7.01(m,2H,Ph-H),6.94(d,J＝8.9Hz,2H,Ph-H),6.90(d,J＝6.4Hz,2H,Ph-H),5.18(d,J＝16.3Hz,1H,triazoleCH),5.07(d,J＝16.3Hz,1H,triazoleCH),4.47(td,J＝8.4,5.5Hz,1H,CH),3.76(s,3H,OCH₃),3.11(s,3H,NCH₃),2.93(dd,J＝13.4,5.0Hz,1H,PhCH),2.70(dd,J＝13.4,9.2Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.19(C＝O),165.46(C＝O),163.35(C＝O),159.36(d,¹J_CF＝247.0Hz),159.02,146.34,139.88,137.68,135.79,133.02(d,³J_CF＝8.4Hz),131.67,130.38(d,⁴J_CF＝2.7Hz),129.86,129.34(2×C),129.11,128.71(2×C),127.03,125.44(d,²J_CF＝15.0Hz),125.04(d,⁴J_CF＝3.4Hz),123.47,121.25,119.63,116.75(2×C),116.53,115.10(2×C),55.85,52.10,51.82,37.88,37.77.ESI-MS:m/z 607.4(M+1),624.4(M+18),629.4(M+23),645.4(M+39).C₃₄H₃₁FN₆O₄[606.7].

the corresponding acid chloride was selected from 3-fluorobenzoyl chloride (45. mu.L) and (S) -2(2- (4- (3-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5b) to give (S) -3-fluoro-N- (3- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) benzamide (6b-10)112mg, white solid, yield 75%, melting point: 167 ℃ and 168 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ10.44(s,1H,PhNH),8.93(d,J＝7.8Hz,1H,NH),8.39(s,1H,Ph-H),8.34(s,1H,triazole-H),7.83(dt,J＝24.4,8.0Hz,3H,Ph-H),7.61(q,J＝7.9Hz,1H,Ph-H),7.56(d,J＝7.7Hz,1H,Ph-H),7.46(dt,J＝16.2,7.3Hz,2H,Ph-H),7.29–7.15(m,3H,Ph-H),7.15–7.01(m,2H,Ph-H),6.94(d,J＝8.8Hz,2H,Ph-H),6.90(d,J＝6.5Hz,2H,Ph-H),5.19(d,J＝16.3Hz,1H,triazoleCH),5.08(d,J＝16.3Hz,1H,triazoleCH),4.54–4.41(m,1H,CH),3.76(s,3H,OCH₃),3.12(s,3H,NCH₃),2.93(dd,J＝13.4,5.0Hz,1H,PhCH),2.70(dd,J＝13.4,9.3Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.19(C＝O),165.47(C＝O),164.64(d,⁴J_CF＝2.4Hz,C＝O),162.39(d,¹J_CF＝242.7Hz),159.02,146.39,139.92,137.68,137.57(d,³J_CF＝6.8Hz),135.79,131.56,131.11,131.03,129.75,129.34(2×C),129.11,128.71(2×C),127.03,124.40(d,⁴J_CF＝2.6Hz),123.45,121.28,120.28,119.01(d,²J_CF＝21.4Hz),117.46,115.10(2×C),114.88,55.85,52.11,51.83,37.88,37.77.ESI-MS:m/z 607.4(M+1),624.4(M+18),629.4(M+23),645.4(M+39).C₃₄H₃₁FN₆O₄[606.7].

the corresponding acid chloride was selected from 4-fluorobenzoyl chloride (44. mu.L) and (S) -2(2- (4- (3-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5b) to give (S) -4-fluoro-N- (3- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) benzamide (6b-11)45mg, white solid, yield 30%, melting point: 173 ℃ and 174 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ10.44(s,1H,PhNH),8.95(d,J＝7.8Hz,1H,NH),8.37(s,1H,Ph-H),8.34(s,1H,triazole-H),8.11(dd,J＝8.1,5.7Hz,2H,Ph-H),7.79(d,J＝7.8Hz,1H,Ph-H),7.53(d,J＝7.6Hz,1H,Ph-H),7.48–7.31(m,3H,Ph-H),7.21(q,J＝7.2,6.4Hz,3H,Ph-H),7.12–6.99(m,2H,Ph-H),6.94(d,J＝8.7Hz,2H,Ph-H),6.90(d,J＝6.7Hz,2H,Ph-H),5.19(d,J＝16.3Hz,1H,triazoleCH),5.08(d,J＝16.2Hz,1H,triazoleCH),4.46(q,J＝8.1Hz,1H,CH),3.76(s,3H,OCH₃),3.11(s,3H,NCH₃),2.92(dd,J＝13.5,4.8Hz,1H,PhCH),2.70(dd,J＝13.3,9.3Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.17(C＝O),165.47(C＝O),165.00(d,¹J_CF＝245.0Hz),164.93(C＝O),159.02,146.43,140.13,137.71,135.82,130.99(2×C),130.90,129.67,129.35(2×C),129.10,128.69(2×C),127.01,123.40,121.09,120.31,117.50,115.89(2×C),115.67(2×C),115.11(2×C),55.87,52.13,51.85,37.88,37.78.ESI-MS:m/z 607.4(M+1),624.4(M+18),629.4(M+23),645.3(M+39).C₃₄H₃₁FN₆O₄[606.7].

the corresponding acid chloride was selected from 4-phenylbenzoyl chloride (81mg) and (S) -2(2- (4- (3-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5b) to give (S) -N- (3- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) - [1,1' -Biphenyl ] -4-carboxamide (6b-12)96mg, white solid, yield 58%, melting point: 170 ℃ and 171 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ10.43(s,1H,PhNH),8.94(d,J＝7.8Hz,1H,NH),8.39(s,1H,Ph-H),8.38(s,1H,triazole-H),8.12(d,J＝8.2Hz,2H,Ph-H),7.86(d,J＝8.3Hz,2H,Ph-H),7.82(d,J＝8.4Hz,1H,Ph-H),7.78(d,J＝7.6Hz,2H,Ph-H),7.53(q,J＝7.4Hz,3H,Ph-H),7.44(dt,J＝7.8,4.3Hz,2H,Ph-H),7.22(q,J＝7.8,7.0Hz,3H,Ph-H),7.14–7.01(m,2H,Ph-H),6.95(d,J＝8.8Hz,2H,Ph-H),6.90(d,J＝6.6Hz,2H,Ph-H),5.19(d,J＝16.3Hz,1H,triazoleCH),5.08(d,J＝16.3Hz,1H,triazoleCH),4.47(q,J＝8.4Hz,1H,CH),3.76(s,3H,OCH₃),3.12(s,3H,NCH₃),2.93(dd,J＝13.4,5.0Hz,1H,PhCH),2.71(dd,J＝13.4,9.2Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.19(C＝O),165.66(C＝O),165.48(C＝O),159.02,146.47,143.62,140.23,139.57,137.69,135.79,134.03,131.54,129.71,129.54(2×C),129.34(2×C),129.11(2×C),128.88(2×C),128.71(2×C),128.63,127.40(2×C),127.07(2×C),123.43(2×C),121.05,120.24,117.41,115.11(2×C),55.85,52.11,51.83,37.88,37.78.ESI-MS:m/z665.4(M+1),682.5(M+18),687.4(M+23).C₄₀H₃₆N₆O₄[664.8].

the corresponding acid chloride was reacted with (S) -2(2- (4- (4-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropionamide (5c) using acetyl chloride (26. mu.L) to give (S) -2- (2- (4- (4-acetylaminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropionamide (6c-1)61mg, white solid, yield 47%, melting point: 134 ℃ and 135 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ10.04(s,1H,PhNH),8.89(d,J＝7.8Hz,1H,NH),8.30(s,1H,triazole-H),7.75(d,J＝8.5Hz,2H,Ph-H),7.65(d,J＝8.5Hz,2H,Ph-H),7.21(q,J＝7.2,6.7Hz,3H,Ph-H),7.06(d,J＝6.6Hz,2H,Ph-H),6.93(d,J＝8.9Hz,2H,Ph-H),6.89(d,J＝6.5Hz,2H,Ph-H),5.15(d,J＝16.4Hz,1H,triazoleCH),5.04(d,J＝16.3Hz,1H,triazoleCH),4.46(q,J＝8.3Hz,1H,CH),3.75(s,3H,OCH₃),3.11(s,3H,NCH₃),2.92(dd,J＝13.5,5.0Hz,1H,PhCH),2.69(dd,J＝13.3,9.2Hz,1H,PhCH),2.06(s,3H,COCH₃).¹³C NMR(100MHz,DMSO-d₆)δ171.18(C＝O),168.78(C＝O),165.48(C＝O),159.02,146.40,139.44,137.68,135.80,129.33(2×C),129.10,128.70(2×C),127.02,125.97(2×C),125.89,122.70(2×C),119.67(2×C),115.10(2×C),55.85,52.09,51.80,37.89,37.77,24.51.ESI-MS:m/z 527.4(M+1),544.5(M+18),549.4(M+23),565.4(M+39).C₂₉H₃₀N₆O₄[526.6].

the corresponding acid chloride was selected from benzoyl chloride (43. mu.L) and (S) -2(2- (4- (4-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5c) to prepare (S) -N- (4- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) benzamide (6c-2)70mg, white solid, yield 48%, melting point: 171 ℃ and 172 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ10.36(s,1H,PhNH),8.91(d,J＝7.8Hz,1H,NH),8.35(s,1H,triazole-H),7.98(d,J＝7.2Hz,2H,Ph-H),7.89(d,J＝8.7Hz,2H,Ph-H),7.83(d,J＝8.6Hz,2H,Ph-H),7.61(t,J＝7.2Hz,1H,Ph-H),7.55(t,J＝7.3Hz,2H,Ph-H),7.22(q,J＝7.3,6.7Hz,3H,Ph-H),7.07(d,J＝6.5Hz,2H,Ph-H),6.94(d,J＝8.9Hz,2H,Ph-H),6.90(d,J＝6.5Hz,2H,Ph-H),5.17(d,J＝16.3Hz,1H,triazoleCH),5.06(d,J＝16.3Hz,1H,triazoleCH),4.47(td,J＝8.4,5.6Hz,1H,CH),3.76(s,3H,OCH₃),3.12(s,3H,NCH₃),2.93(dd,J＝13.4,5.1Hz,1H,PhCH),2.71(dd,J＝13.6,9.2Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.18(C＝O),166.03(C＝O),165.49(C＝O),159.03,145.38,139.29,137.69,135.80,135.39,132.06,129.34(2×C),129.10(2×C),128.86(2×C),128.71(2×C),128.13(2×C),127.03,126.53,125.87(2×C),122.87,121.05(2×C),115.11(2×C),55.86,52.09,51.83,37.90,37.78.ESI-MS:m/z 589.4(M+1),606.4(M+18),611.3(M+23),627.4(M+39).C₃₄H₃₂N₆O₄[588.7].

the corresponding acid chloride was reacted with (S) -2(2- (4- (4-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5c) using 4-methylbenzoyl chloride (49. mu.L) to give (S) -N- (4- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) -4-methylbenzamide (6c-3)72mg, white solid, yield 48%, melting point: 138 ℃ and 139 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ10.27(s,1H,PhNH),8.91(d,J＝7.7Hz,1H,NH),8.35(s,1H,triazole-H),7.99–7.85(m,4H,Ph-H),7.82(d,J＝8.3Hz,2H,Ph-H),7.35(d,J＝7.6Hz,2H,Ph-H),7.22(q,J＝8.0,6.9Hz,3H,Ph-H),7.07(d,J＝7.0Hz,2H,Ph-H),6.94(d,J＝8.4Hz,2H,Ph-H),6.90(d,J＝6.4Hz,2H,Ph-H),5.17(d,J＝16.3Hz,1H,triazoleCH),5.06(d,J＝16.3Hz,1H,triazoleCH),4.47(q,J＝7.7Hz,1H,CH),3.76(s,3H,OCH₃),3.12(s,3H,NCH₃),2.93(dd,J＝13.2,4.5Hz,1H,PhCH),2.76–2.64(m,1H,PhCH),2.40(s,3H,PhCH₃).¹³C NMR(100MHz,DMSO-d₆)δ171.18(C＝O),165.82(C＝O),165.49(C＝O),159.02,146.40,142.08,139.36,137.68,135.80,132.48,129.38(2×C),129.34(2×C),129.10(2×C),128.70(2×C),128.17(2×C),127.03,126.42,125.85(2×C),122.84,121.03(2×C),115.10(2×C),55.86,52.09,51.83,37.90,37.78,21.49.ESI-MS:m/z603.4(M+1),620.5(M+18),625.5(M+23),641.4(M+39).C₃₅H₃₄N₆O₄[602.7].

the corresponding acid chloride was reacted with (S) -2(2- (4- (4-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5c) using 2-methoxybenzoyl chloride (54. mu.L) to give (S) -2-methoxy-N- (4- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) benzamide (6c-4)53mg, white solid, yield 34%, melting point: 146 ℃ and 147 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ10.23(s,1H,PhNH),8.91(d,J＝7.7Hz,1H,NH),8.35(s,1H,triazole-H),7.92–7.77(m,4H,Ph-H),7.66(d,J＝7.3Hz,1H,Ph-H),7.52(t,J＝7.6Hz,1H,Ph-H),7.21(t,J＝8.2Hz,4H,Ph-H),7.08(t,J＝7.2Hz,3H,Ph-H),6.94(d,J＝8.6Hz,2H,Ph-H),6.90(d,J＝6.7Hz,2H,Ph-H),5.17(d,J＝16.3Hz,1H,triazoleCH),5.06(d,J＝16.3Hz,1H,triazoleCH),4.47(q,J＝8.2Hz,1H,CH),3.92(s,3H,OCH₃),3.76(s,3H,OCH₃),3.12(s,3H,NCH₃),2.93(dd,J＝13.4,4.9Hz,1H,PhCH),2.71(dd,J＝13.4,9.3Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.18(C＝O),165.49(C＝O),164.97(C＝O),159.03,156.95,146.38,139.15,137.69,135.81,132.52,130.13,129.34(2×C),129.10,128.70(2×C),127.03,126.39,125.96(2×C),125.39,122.83,120.96(2×C),120.42(2×C),115.11(2×C),112.47,56.37,55.86,52.09,51.82,37.91,37.78.ESI-MS:m/z 619.5(M+1),636.4(M+18),641.4(M+23).C₃₅H₃₄N₆O₅[618.7].

the corresponding acid chloride was selected from 3-methoxybenzoyl chloride (54. mu.L) and (S) -2(2- (4- (4-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5c) to prepare 80mg of (S) -3-methoxy-N- (4- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) benzamide (6c-5), white solid, yield 52%, melting point: 141 ℃ and 142 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ10.32(s,1H,PhNH),8.91(d,J＝7.8Hz,1H,NH),8.35(s,1H,triazole-H),7.87(d,J＝8.7Hz,2H,Ph-H),7.83(d,J＝8.7Hz,2H,Ph-H),7.56(d,J＝7.6Hz,1H,Ph-H),7.51(s,1H,Ph-H),7.46(t,J＝7.9Hz,1H,Ph-H),7.26–7.15(m,4H,Ph-H),7.07(d,J＝6.5Hz,2H,Ph-H),6.94(d,J＝8.8Hz,2H,Ph-H),6.90(d,J＝6.5Hz,2H,Ph-H),5.17(d,J＝16.3Hz,1H,triazoleCH),5.06(d,J＝16.3Hz,1H,triazoleCH),4.47(q,J＝8.3Hz,1H,CH),3.85(s,3H,OCH₃),3.76(s,3H,OCH₃),3.12(s,3H,NCH₃),2.93(dd,J＝13.4,5.0Hz,1H,PhCH),2.70(dd,J＝13.4,9.2Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.18(C＝O),165.74(C＝O),165.48(C＝O),159.65,159.03,146.38,139.20,137.68,136.79,135.81,130.03,129.34(2×C),129.10,128.70(2×C),127.02,126.58,125.86(2×C),122.87,121.13(2×C),120.35(2×C),117.81,115.11(2×C),113.39,55.82(2×C),52.09,51.84,37.91,37.78.ESI-MS:m/z 619.5(M+1),636.4(M+18),641.3(M+23),657.4(M+39).C₃₅H₃₄N₆O₅[618.7].

the corresponding acid chloride was reacted with (S) -2(2- (4- (4-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5c) using 4-methoxybenzoyl chloride (63mg) to give (S) -4-methoxy-N- (4- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) benzamide (6c-6)85mg, white solid, yield 55%, melting point: 141 ℃ and 142 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ10.20(s,1H,PhNH),8.92(d,J＝7.1Hz,1H,NH),8.34(s,1H,triazole-H),7.98(d,J＝7.8Hz,2H,Ph-H),7.86(d,J＝7.5Hz,2H,Ph-H),7.81(d,J＝7.6Hz,2H,Ph-H),7.26–7.15(m,3H,Ph-H),7.08(d,J＝7.2Hz,4H,Ph-H),6.94(d,J＝8.1Hz,2H,Ph-H),6.89(d,J＝6.0Hz,2H,Ph-H),5.16(d,J＝16.1Hz,1H,triazoleCH),5.06(d,J＝16.3Hz,1H,triazoleCH),4.46(q,J＝8.5Hz,1H,CH),3.85(s,3H,OCH₃),3.76(s,3H,OCH₃),3.11(s,3H,NCH₃),2.99–2.87(m,1H,PhCH),2.76–2.62(m,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.19(C＝O),165.50(C＝O),165.36(C＝O),162.39,159.02,146.42,139.47,137.69,135.80,130.08(2×C),129.34(2×C),129.11(2×C),128.71(2×C),127.37,127.03,126.29,125.83(2×C),122.82,120.99(2×C),115.10(2×C),114.08(2×C),55.91,55.85,52.10,51.82,37.88,37.78.ESI-MS:m/z 619.5(M+1),636.4(M+18),641.4(M+23),657.4(M+39).C₃₅H₃₄N₆O₅[618.7].

the corresponding acid chloride was selected from methyl 4-carboxylate benzoyl chloride (74mg) and (S) -2(2- (4- (4-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5c) to prepare (S) -methyl 4- ((4- (((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2- (methyl) oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) carbamoyl) benzoate (6c-7)123mg, white solid, yield 77%, melting point: 129 ℃ and 130 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ10.54(s,1H,PhNH),8.90(d,J＝7.7Hz,1H,NH),8.35(s,1H,triazole-H),8.10(s,4H,Ph-H),7.89(d,J＝8.6Hz,2H,Ph-H),7.84(d,J＝8.6Hz,2H,Ph-H),7.28–7.14(m,3H,Ph-H),7.07(d,J＝6.6Hz,2H,Ph-H),6.94(d,J＝8.7Hz,2H,Ph-H),6.90(d,J＝6.7Hz,2H,Ph-H),5.17(d,J＝16.3Hz,1H,triazoleCH),5.06(d,J＝16.3Hz,1H,triazoleCH),4.48(q,J＝8.2Hz,1H,CH),3.91(s,3H,OCH₃),3.76(s,3H,OCH₃),3.11(s,3H,NCH₃),2.93(dd,J＝13.4,5.0Hz,1H,PhCH),2.70(dd,J＝13.3,9.1Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.18(C＝O),166.15(C＝O),165.49(C＝O),165.17(C＝O),159.03,146.33,139.47,139.00,137.68,135.80,132.51,129.66(2×C),129.34(2×C),129.10(2×C),128.70(2×C),128.58(2×C),127.02,126.83,125.92(2×C),122.94,121.15(2×C),115.10(2×C),55.86,52.91,52.10,51.84,37.90,37.77.ESI-MS:m/z647.5(M+1),664.4(M+18),669.4(M+23).C₃₆H₃₄N₆O₆[646.7].

the corresponding acid chloride was reacted with (S) -2(2- (4- (4-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5c) using 4-cyanobenzoyl chloride (62mg) to give (S) -4-cyano-N- (4- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) benzamide (6c-8)109mg, white solid, yield 71%, melting point: 140 ℃ and 141 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ10.60(s,1H,PhNH),8.92(d,J＝7.8Hz,1H,NH),8.36(s,1H,triazole-H),8.13(d,J＝8.3Hz,2H,Ph-H),8.04(d,J＝8.3Hz,2H,Ph-H),7.88(d,J＝8.9Hz,2H,Ph-H),7.84(d,J＝8.9Hz,2H,Ph-H),7.28–7.13(m,3H,Ph-H),7.13–7.00(m,2H,Ph-H),6.94(d,J＝8.8Hz,2H,Ph-H),6.90(d,J＝6.5Hz,2H,Ph-H),5.17(d,J＝16.4Hz,1H,triazoleCH),5.06(d,J＝16.3Hz,1H,triazoleCH),4.47(q,J＝8.4Hz,1H,CH),3.76(s,3H,OCH₃),3.11(s,3H,NCH₃),2.93(dd,J＝13.4,5.0Hz,1H,PhCH),2.70(dd,J＝13.6,9.3Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.18(C＝O),165.49(C＝O),164.62(C＝O),159.02,146.28,139.39,138.84,137.69,135.80,132.95(2×C),129.33(2×C),129.10(2×C),129.02(2×C),128.70(2×C),127.02,126.96,125.93(2×C),122.98,121.16(2×C),118.80,115.10(2×C),114.33,55.85,52.10,51.82,37.89,37.77.ESI-MS:m/z 614.3(M+1),631.5(M+18),636.4(M+23).C₃₅H₃₁N₇O₄[613.7].

the corresponding acid chloride was selected from 2-fluorobenzoyl chloride (44. mu.L) and (S) -2(2- (4- (4-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5c) to give (S) -2-fluoro-N- (4- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) benzamide (6c-9)64mg, white solid, yield 42%, melting point: 122 ℃ and 123 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ10.53(s,1H,PhNH),8.91(d,J＝7.8Hz,1H,NH),8.35(s,1H,triazole-H),7.82(s,4H,Ph-H),7.73–7.65(m,1H,Ph-H),7.64–7.55(m,1H,Ph-H),7.38(d,J＝10.4Hz,1H,Ph-H),7.33(d,J＝7.0Hz,1H,Ph-H),7.26–7.15(m,3H,Ph-H),7.12–7.01(m,2H,Ph-H),6.94(d,J＝9.0Hz,2H,Ph-H),6.89(d,J＝6.3Hz,2H,Ph-H),5.17(d,J＝16.3Hz,1H,triazoleCH),5.06(d,J＝16.3Hz,1H,triazoleCH),4.46(td,J＝8.4,5.5Hz,1H,CH),3.76(s,3H,OCH₃),3.11(s,3H,NCH₃),2.92(dd,J＝13.4,5.1Hz,1H,PhCH),2.70(dd,J＝13.4,9.2Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.18(C＝O),165.48(C＝O),163.23(C＝O),159.33(d,¹J_CF＝247.2Hz),159.02,146.30,138.95,137.69,135.80,133.00(d,³J_CF＝8.5Hz),130.37(d,⁴J_CF＝2.9Hz),129.33(2×C),129.11,128.71(2×C),127.03,126.73,126.01(2×C),125.46(d,²J_CF＝15.2Hz),125.04(d,⁴J_CF＝3.4Hz),122.93,120.45(2×C),116.75,116.53,115.10(2×C),55.86,52.10,51.82,37.89,37.78.ESI-MS:m/z 607.4(M+1),624.5(M+18),629.4(M+23).C₃₄H₃₁FN₆O₄[606.7].

the corresponding acid chloride was selected from 3-fluorobenzoyl chloride (45. mu.L) and (S) -2(2- (4- (4-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5c) to give (S) -3-fluoro-N- (4- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) benzamide (6c-10)70mg, white solid, yield 46%, melting point: 120 ℃ and 121 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ10.43(s,1H,PhNH),8.92(d,J＝7.8Hz,1H,NH),8.36(s,1H,triazole-H),7.85(q,J＝8.6Hz,5H,Ph-H),7.79(d,J＝9.7Hz,1H,Ph-H),7.61(q,J＝7.9Hz,1H,Ph-H),7.46(td,J＝8.6,2.2Hz,1H,Ph-H),7.21(q,J＝7.4,6.8Hz,3H,Ph-H),7.13–7.02(m,2H,Ph-H),6.94(d,J＝8.8Hz,2H,Ph-H),6.89(d,J＝6.6Hz,2H,Ph-H),5.17(d,J＝16.4Hz,1H,triazoleCH),5.06(d,J＝16.3Hz,1H,triazoleCH),4.46(td,J＝8.4,5.5Hz,1H,CH),3.76(s,3H,OCH₃),3.11(s,3H,NCH₃),2.93(dd,J＝13.4,5.0Hz,1H,PhCH),2.70(dd,J＝13.5,9.3Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.19(C＝O),165.49(C＝O),164.61(d,⁴J_CF＝2.4Hz,C＝O),162.38(d,¹J_CF＝242.7Hz),159.02,146.32,138.98,137.69(2×C),137.62,135.80,131.07(d,³J_CF＝7.9Hz),129.34(2×C),129.10,128.71(2×C),127.03,126.77,125.90(2×C),124.38(d,⁴J_CF＝2.7Hz),122.94,121.14(2×C),118.98(d,²J_CF＝21.1Hz),115.10(2×C),114.87,55.85,52.10,51.82,37.88,37.78.ESI-MS:m/z 607.4(M+1),624.5(M+18),629.4(M+23).C₃₄H₃₁FN₆O₄[606.7].

the corresponding acid chloride was selected from 4-fluorobenzoyl chloride (44. mu.L) and (S) -2(2- (4- (4-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5c) to give 52mg of (S) -4-fluoro-N- (4- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) benzamide (6c-11), white solid, yield 35%, melting point: 125 ℃ and 126 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ10.37(s,1H,PhNH),8.91(d,J＝7.8Hz,1H,NH),8.35(s,1H,triazole-H),8.06(dd,J＝8.6,5.6Hz,2H,Ph-H),7.84(q,J＝8.8Hz,4H,Ph-H),7.38(t,J＝8.8Hz,2H,Ph-H),7.21(q,J＝7.3,6.7Hz,3H,Ph-H),7.07(d,J＝6.6Hz,2H,Ph-H),6.94(d,J＝8.9Hz,2H,Ph-H),6.89(d,J＝6.5Hz,2H,Ph-H),5.17(d,J＝16.3Hz,1H,triazoleCH),5.06(d,J＝16.3Hz,1H,triazoleCH),4.46(td,J＝8.5,5.6Hz,1H,CH),3.76(s,3H,OCH₃),3.11(s,3H,NCH₃),2.93(dd,J＝13.5,5.1Hz,1H,PhCH),2.70(dd,J＝13.4,9.2Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.18(C＝O),165.49(C＝O),164.90(C＝O),164.55(d,¹J_CF＝247.6Hz),159.02,146.35,139.18,137.69,135.80,131.80(d,⁴J_CF＝2.8Hz),130.93(2×C),130.84,129.33(2×C),129.10,128.70(2×C),127.02,126.60,125.88(2×C),122.89,121.08(2×C),115.92(2×C),115.71,115.10,55.86,52.10,51.82,37.89,37.78.ESI-MS:m/z 607.4(M+1),624.4(M+18),629.4(M+23).C₃₄H₃₁FN₆O₄[606.7].

the corresponding acid chloride was selected from 4-phenylbenzoyl chloride (81mg) and (S) -2(2- (4- (4-aminophenyl) -1H-1,2, 3-triazol-1-yl) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5c) to give (S) -N- (4- (1- (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) -1H-1,2, 3-triazol-4-yl) phenyl) - [1, 68mg of 1' -biphenyl ] -4-carboxamide (6c-12) as a white solid in 41% yield, melting point: 160 ℃ and 161 ℃.

Spectral data:¹H NMR(400MHz,DMSO-d₆)δ10.41(s,1H,PhNH),8.92(d,J＝7.8Hz,1H,NH),8.36(s,1H,triazole-H),8.09(d,J＝8.3Hz,2H,Ph-H),7.91(d,J＝8.7Hz,2H,Ph-H),7.85(t,J＝8.1Hz,4H,Ph-H),7.78(d,J＝7.5Hz,2H,Ph-H),7.52(t,J＝7.6Hz,2H,Ph-H),7.43(t,J＝7.3Hz,1H,Ph-H),7.27–7.16(m,3H,Ph-H),7.07(d,J＝6.4Hz,2H,Ph-H),6.94(d,J＝9.0Hz,2H,Ph-H),6.90(d,J＝6.3Hz,2H,Ph-H),5.17(d,J＝16.4Hz,1H,triazoleCH),5.06(d,J＝16.3Hz,1H,triazoleCH),4.47(td,J＝8.5,5.4Hz,1H,CH),3.76(s,3H,OCH₃),3.11(s,3H,NCH₃),2.93(dd,J＝13.4,5.1Hz,1H,PhCH),2.70(dd,J＝13.5,9.2Hz,1H,PhCH).¹³C NMR(100MHz,DMSO-d₆)δ171.19(C＝O),165.63(C＝O),165.50(C＝O),159.02,146.39,143.60,139.56,139.31,137.69,135.80,134.11,129.54(2×C),129.34(2×C),129.11(2×C),128.86(2×C),128.71(2×C),128.63,127.40(2×C),127.07(2×C),127.04,126.53,125.88(2×C),122.89,121.05(2×C),115.10(2×C),55.86,52.10,51.82,37.88,37.78.ESI-MS:m/z 665.4(M+1),682.5(M+18),687.4(M+23),703.5(M+39).C₄₀H₃₆N₆O₄[664.8].

example 6 in vitro anti-HIV-1 Activity test (TZM-bl cells) of Compounds of interest

The principle is as follows: luciferase reporter Gene experiments (nef Gene deleted HIV-1NL4-3)

The test method comprises the following steps:

anti-HIV-1 infection assay in TZM-bl cells

Infection of TZM-bl cells with a single round of virusThe degree of decrease in the expression level of the luciferase gene was measured to determine the inhibitory activity of the compound against HIV-1 infection. Briefly, 200TCID was used in the presence of varying concentrations of compounds (5a-5c, 6a- (1-12), 6b- (1-12), 6c- (1-12) and PF-74)₅₀The virus of (NL4-3) infects TZM-bl cells. After 2 days of infection, the culture broth was removed and 100 μ L of Bright Glo reagent (Promega, San Luis Obispo, CA) was added to each well and its fluorescence activity was measured using a Victor 2 luminometer. Effective concentration of compound (EC) for inhibiting HIV-1 strain₅₀) Defined as the concentration that results in a 50% decrease in luciferase activity (relative light units) compared to the virus control wells.

Cytotoxicity assays

Cytotoxicity of the synthesized compounds was determined using the CytoTox-Glo fluorescent cytotoxicity kit (purchased from Promega). TZM-bl cells were cultured for 1 day in the presence of different concentrations of compounds (5a-5c, 6a- (1-12), 6b- (1-12), 6c- (1-12) and PF-74), as determined in parallel with the anti-HIV-1 activity assay. The cytotoxicity (CC) of the tested target compound is then determined according to the procedure required by the kit₅₀) I.e., the concentration of the compound of interest required to reduce cell survival by 50%.

TABLE 1 phenylalanine derivatives containing in part 4-phenyl-1, 2, 3-triazole anti-HIV activity, toxicity and selection index (TZM-bl cells)

^aEC₅₀: concentration of compound that protects 50% of HIV-1 infected cells from cytopathic effects;

^bCC₅₀: (ii) concentration of compound that causes lesions in 50% of cells not infected with HIV-1;

^cand (3) SI: coefficient of selectivity, CC₅₀/EC₅₀The ratio of (A) to (B);

PF-74: a class of HIV-1 capsid inhibitors has been reported as positive controls.

And (4) experimental conclusion analysis: as shown in Table 1, the phenylalanine derivative containing 4-phenyl-1, 2, 3-triazole synthesized by the invention has obvious anti-HIV-1 activity. For example, compounds 5a, 6a-1, 6a-2, 6a-9, 6a-10, 6a-11, 5b have anti-HIV-1 activity in the range of 3.13-3.99. mu.M, with anti-HIV-1 activity (EC) of compounds 6a-9₅₀＝3.13±0.91μM,CC₅₀>16.48,SI>5.27) is particularly outstanding and has value for further research.

Claims

1. The phenylalanine derivative containing 4-phenyl-1, 2, 3-triazole, or pharmaceutically acceptable salt, ester or prodrug thereof has a structure shown in a general formula I:

wherein, the amido is ortho-substituted, meta-substituted or para-substituted on the benzene ring; r is: H. acetyl, benzoyl, 4-methylbenzoyl, 3-methylbenzoyl, 2-methoxybenzoyl, 3-methoxybenzoyl, 4-methyl formate benzoyl, 3-methyl formate benzoyl, 2-methyl formate benzoyl, 4-cyanobenzoyl, 3-cyanobenzoyl, 2-fluorobenzoyl, 3-fluorobenzoyl, 4-phenylbenzoyl, 3-phenylbenzoyl, 2-phenylbenzoyl.

2. The phenylalanine derivative containing 4-phenyl-1, 2, 3-triazole according to claim 1, wherein the compound is one of the following compounds:

3. the method for preparing the phenylalanine derivative containing 4-phenyl-1, 2, 3-triazole according to claim 1, comprising the following steps: generating an intermediate 2 with Boc-L-phenylalanine (1) as an initial raw material and dichloromethane as a reaction solvent through an amide condensation reaction and N-methyl-4-aminoanisole; then the intermediate 2 is dissolved in a proper amount of dichloromethane, and Boc groups are removed under the action of trifluoroacetic acid to obtain an intermediate 3; then, carrying out amide condensation reaction on the intermediate 3 and azido acetic acid to obtain an intermediate 4 with azido groups; the intermediate 4 and corresponding substituted aminophenylacetylene generate compounds 5a-5c through azide-alkyne Husigen-Click cycloaddition reaction catalyzed by Cu (I) under the condition of sodium ascorbate and copper sulfate pentahydrate; finally, the compounds 5a-5c and corresponding acyl chloride are subjected to acylation reaction to obtain target compounds 6a- (1-12), 6b- (1-12) and 6c- (1-12);

the synthetic route is as follows:

reagents and conditions: (i) n-methyl-4-aminoanisole, 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate, N, N-diisopropylethylamine and dichloromethane are added, and the temperature is changed to room temperature at 0 ℃; (ii) trifluoroacetic acid, dichloromethane, room temperature; (iii) azidoacetic acid, O- (7-azabenzotriazole-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, N, N-diisopropylethylamine and acetonitrile, and the temperature is changed to room temperature at 0 ℃; (iv) corresponding substituted aminophenylacetylene, sodium ascorbate, copper sulfate pentahydrate, water/tetrahydrofuran, room temperature; (v) the corresponding acyl chloride, triethylamine and dichloromethane are cooled to room temperature at 0 ℃;

wherein R is as defined in formula I in claim 1;

the substituted aminophenylacetylene is 2-aminophenylacetylene, 3-aminophenylacetylene or 4-aminophenylacetylene;

4. The preparation method of the phenylalanine derivative containing 4-phenyl-1, 2, 3-triazole according to claim 3, comprises the following steps:

5. The use of the phenylalanine derivative containing 4-phenyl-1, 2, 3-triazole according to claim 1 or 2 in the preparation of drugs for preventing and treating AIDS.

6. An anti-HIV pharmaceutical composition, which is characterized by comprising the phenylalanine derivative containing 4-phenyl-1, 2, 3-triazole or the pharmaceutically acceptable salt thereof according to claim 1 or 2 and one or more pharmaceutically acceptable carriers or excipients.