Cinnamoyl triazole compound as well as preparation method and application thereof in neuroprotection

Abstract

The invention discloses a cinnamyl triazole compound, a preparation method of the cinnamyl triazole compound and application of the cinnamyl triazole compound in neuroprotection, and the structure of the cinnamyl triazole compound is shown as a formula I, the compound can promote a non-amyloid protein pathway and inhibit an amyloid protein pathway to reduce generation of A beta and inhibit phosphorylation of Tau to relieve neurodegeneration. The cinnamyl triazole compound has exact effects on neuroprotection at the cellular level and AD resistance at the overall level of animals, can improve the learning ability and memory ability of mice, and is a novel AD-resistant active compound with dual effects of Abeta aggregation inhibition and AchE activity reduction. Therefore, the invention provides a new technical means for research and development of multi-target anti-AD drugs. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a preparation method of a cinnamoyl triazole compound and its use in neuroprotection, and belongs to the technical field of medicine. Background Art

[0002] At present, with the gradual aging of the global population, the incidence of Alzheimer's disease (AD) is also increasing. As a fatal neurodegenerative disease with complex pathology, the effect of existing therapeutic drugs is very limited. They can only temporarily relieve symptoms and cannot achieve the purpose of cure. Therefore, the development of anti-AD drugs is imminent. The research on new mechanisms and strategies for the treatment of AD is a current frontier hotspot and is urgently needed for clinical AD treatment. At the same time, in order to target the complex pathogenesis of AD, the multi-target ligand (MTDLs) strategy has also become a major trend in the development of anti-AD active compounds. However, at present, the cause of Alzheimer's disease (AD) is still unclear, and age factors, genetic factors and non-genetic factors are all considered to be related to the onset of AD. Age is the biggest risk factor, and the risk and probability of disease will increase further with age. The aging of the global population and the continuous increase in the number of elderly people (65 years old and above) mean that by 2050, AD cases will continue to increase by 15%-25%.

[0003] AD is an extremely complex neurodegenerative disease, and its pathogenesis involves changes in multiple physiological processes in the brain. Since the discovery of AD, scientists have conducted a lot of research to understand its pathological mechanism and find a cure for this complex disease. With the continuous efforts of several generations of scientific and medical personnel, although a complete cure has not yet been found, a variety of hypotheses related to the onset of AD have been gradually established, including the cholinergic (ChE) damage hypothesis, the amyloid protein (Aβ) cascade hypothesis, the Tau protein hypothesis, the metal ion homeostasis imbalance hypothesis in the brain, the neuroinflammation hypothesis, the oxidative stress hypothesis, etc., which provide a certain theoretical basis for subsequent research.

[0004] Donepezil has become the first choice drug for treating AD at present because of its high selective inhibition of acetylcholinesterase (AChE), almost no hepatotoxicity and certain effects on mild, moderate and severe AD. Based on the research progress reported in the above literature, the present invention maintains its anti-Aβ activity while improving the AChE inhibitory activity, and develops a new class of drugs for treating cognitive impairment in AD patients. A combination strategy is adopted to select suitable structures from the marketed anticholinergic drugs and connect their key pharmacophores to the cinnamic acid parent structure through triazole, thereby developing a series of multi-target substituted triazole cinnamamide or cinnamate derivatives. In vitro experiments show that these combined compounds have the inhibitory activity of inhibiting Aβ aggregation and AChE, and the preferred compounds can improve the memory and cognitive ability of the dementia mouse model. At the same time, the pharmacokinetic results show that the series of compounds also have a certain blood-brain barrier permeability. The in vitro neuroprotective effect and the in vivo and in vitro effect of improving the learning ability of model animals are definite, which provides an important basis for the development of new anti-AD drugs and has good development and application prospects. Summary of the invention

[0005] One of the objects of the present invention is to provide a cinnamic acid triazole derivative of formula I, a pharmaceutically acceptable salt or ester, solvate, isomer, polymorph, isotope-labeled compound, metabolite or prodrug compound thereof;

[0006] Another object of the present invention is to provide a method for synthesizing the compound of formula I;

[0007] Another object of the present invention is to provide the use of the compound of formula I, its pharmaceutically acceptable salts or esters, solvates, isotope labels, metabolites or prodrugs in the preparation of anti-Alzheimer's disease drugs.

[0008] In order to achieve the above object, the present invention adopts the following technical means:

[0009] A compound having a structure as described in Formula I of the present invention, a pharmaceutically acceptable salt or ester, solvate, polymorph, isotope-labeled compound, metabolite or prodrug thereof:

[0010]

[0011] in:

[0012] R1, R2, R3, R4, R5 each represent hydrogen, hydroxy, amino, alkyl containing 1-6 carbon atoms, alkoxy containing 1-6 carbon atoms, alkoxyacyl containing 1-6 carbon atoms, halogen, nitro or trifluoromethyl;

[0013] R6 represents hydrogen, halogen, nitro, alkyl containing 1 to 6 carbon atoms, alkoxy containing 1 to 6 carbon atoms, trifluoromethyl, hydroxyl, amino or cyano;

[0014] X represents imino, oxygen, methylene or sulfur.

[0015] Among them, preferably, the alkyl group containing 1-6 carbon atoms is methyl or tert-butyl; and the alkoxy group containing 1-6 carbon atoms is methoxy.

[0016] Wherein, preferably, when X is NH, R1 represents hydrogen, methyl or methoxy, R2, R3, R4, R5 represent hydrogen, and R6 is selected from hydrogen, halogen, nitro, methyl, methoxy, tert-butyl, trifluoromethyl, hydroxyl, amino or cyano;

[0017] Wherein, preferably, when X is NH, R1, R4, R5 represent hydrogen, R2 represents methoxy or hydroxy, R3 represents hydroxy, and R6 is selected from hydrogen, halogen, nitro, methyl, methoxy, tert-butyl, trifluoromethyl, hydroxy, amino or cyano;

[0018] Wherein, preferably, when X is O, R1, R4, R5 represent hydrogen, R2, R3 represent hydrogen or R2 represents methoxy R3 represents hydroxyl, and R6 is selected from hydrogen, halogen, nitro, methyl, methoxy, tert-butyl, trifluoromethyl, hydroxyl, amino or cyano;

[0019] Among them, preferably, when X is O, R1, R4, and R5 represent hydrogen, R2 and R3 represent hydroxyl, and R6 is selected from hydrogen, halogen, nitro, methyl, methoxy, tert-butyl, trifluoromethyl, hydroxyl, amino or cyano.

[0020] Wherein, preferably, the compound represented by formula I is:

[0021]

[0022]

[0023]

[0024]

[0025] Furthermore, the present invention also provides a method for preparing the compound of formula I, comprising the following steps:

[0026] Step 1: Synthesis of intermediate cinnamamide (3a-n) / cinnamate (3b-n)

[0027]

[0028] (1) Cinnamic acid or substituted cinnamic acid (1n) condenses with propargylamine to form 3a-n;

[0029] (2) Cinnamic acid or substituted cinnamic acid (1n) undergoes alkylation reaction with 3-bromopropyne to generate 3b-n;

[0030] Wherein, R1, R2, R3, R4, and R5 are as defined above;

[0031] Step 2: One-pot synthesis of In compounds

[0032]

[0033] At room temperature, compound 2 reacts with sodium azide in N,N-dimethylformamide (DMSO) to generate azide 4, and water is directly added to quench any remaining sodium azide; intermediate 3a-n or 3b-n is dissolved in N,N-dimethylformamide and added to the reaction, and the solvent is adjusted to DMSO / H2O (1:1 v / v), and then a reducing agent sodium ascorbate and a catalyst CuSO4·5H2O (20 mol%) are added, and the reaction is carried out for 12 h to obtain In compound;

[0034] Wherein, R1, R2, R3, R4, R5 and R6 are as defined above; and X represents amino or oxygen.

[0035] Furthermore, the present invention also proposes the use of the compound having the structure described in Formula I, its pharmaceutically acceptable salts or esters, solvates, polymorphs, isotope-labeled compounds, metabolites or prodrugs in the preparation of drugs for treating neurodegenerative diseases.

[0036] Among them, preferably, the neurodegenerative disease is Alzheimer's disease.

[0037] Preferably, the drug comprises oral solution, intravenous injection solution, intramuscular injection solution and other pharmaceutically acceptable dosage forms.

[0038] Still further, the present invention also provides a method for treating Alzheimer's disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention used alone or in combination with each other or with other compounds. The compounds herein include the compound of formula I, and pharmaceutically acceptable salts, solvates, isomers, polymorphs, isotope-labeled substances, metabolites or prodrugs of the compound of formula I.

[0039] Definition of terms

[0040] The terms used in the description of the present invention herein are only for describing specific embodiments and are not intended to limit the present invention. The nomenclature used herein and the laboratory operations in the organic chemistry, medicinal chemistry, and biology described herein are well known and commonly used in the art. Unless otherwise mentioned, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this art belongs.

[0041] As used in the description of the embodiments of the present invention and the appended claims, the singular forms "a", "an", "the" and "its" are intended to refer to both the singular and the plural, unless the context clearly dictates otherwise. For example, a compound includes one or more than one compound.

[0042] As used herein, "and / or" refers to and includes any and all possible combinations of one or more of the associated listed items.

[0043] As used herein, the term "disease" or "disorder" refers to any change in the state of the body or some organ that interrupts or interferes with the performance of its functions and / or causes symptoms.

[0044] As used herein, the term "treatment" is intended to alleviate or eliminate the disease state or condition being targeted. If a subject receives a therapeutic amount of a compound or a pharmaceutically acceptable salt, isomer, polymorph, solvate, isotope-labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition thereof according to the methods described herein, and one or more signs and symptoms of the subject show an observable and / or detectable decrease or improvement, then the subject is successfully "treated". It should also be understood that the treatment of the disease state or condition includes not only complete treatment, but also failure to achieve complete treatment, but achieving some biological or medically relevant results.

[0045] As used herein, the term "subject" may refer to a patient or other animal receiving the composition of the present invention to treat, prevent, alleviate and / or alleviate the disease or condition described in the present invention, and in the present invention, particularly refers to humans and mammals.

[0046] As used herein, "halo" or "halogen" may be fluoro, chloro, bromo or iodo.

[0047] As used herein, "pharmaceutically acceptable esters" refer to esters formed between -OH present in the compounds provided herein and a suitable acid (e.g., a carboxylic acid or an oxygen-containing inorganic acid). Suitable ester groups include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, ethylsuccinates, stearic acid esters or palmitates.

[0048] As used herein, "prodrug" means that the compound of formula I may also be in the form of a prodrug or in a form that can release the active ingredient after metabolic changes in the body. The selection and preparation of appropriate prodrug derivatives are well known to those skilled in the art.

[0049] The compounds and pharmaceutically acceptable salts thereof described herein can be prepared into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle delivery systems.

[0050] As used herein, "pharmaceutically acceptable carriers or excipients" include: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. Those skilled in the art will understand that certain pharmaceutically acceptable excipients can be used in more than one function and in alternative functions, depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation. For example, when used for oral administration, oral preparations can be prepared, such as tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules and pills, etc., containing fillers (for example, sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, dextrin and carboxymethyl starch; cellulose derivatives such as crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium; arabic The invention relates to a pharmaceutical composition comprising the following: a) a pharmaceutical composition comprising: ... Solubilizers or cosolvents, lecithin, hydroxypropyl-β-cyclodextrin, etc.; pH adjusters can be phosphates, acetates, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure regulators can be sodium chloride, mannitol, glucose, phosphates, acetates, etc. For example, when preparing lyophilized powder injections, mannitol, glucose, etc. can also be added as support agents. When used for rectal administration, the drug can be made into suppositories, etc. When used for pulmonary administration, the drug can be made into inhalants or sprays, etc. There are many resources available to those skilled in the art that describe pharmaceutically acceptable excipients and can be used to select suitable pharmaceutically acceptable excipients, such as books such as Remington's Pharmaceutical Encyclopedia, Chinese Pharmaceutical Annals, and Pharmacy.

[0051] The present invention can be administered by any suitable method known in the art, for example, orally, intravenously, intraperitoneally, intramuscularly, topically, transdermally, ocularly, nasally, by inhalation, subcutaneously, intramuscularly, buccally, sublingually, rectal administration, and the like.

[0052] Compared with the prior art, the present invention has the following beneficial effects:

[0053] The present invention has found that the compound described in the above formula I can promote non-amyloid protein pathways and inhibit amyloid protein pathways to reduce the production of Aβ and inhibit the phosphorylation of Tau to alleviate neurodegeneration. The cinnamoyl triazole derivatives have a definite neuroprotective effect at the cellular level and an anti-AD effect at the overall animal level. They can improve the learning ability and memory ability of mice, and are a new type of anti-AD active compound with dual effects of Aβ aggregation inhibition and AchE activity reduction. Therefore, the present invention provides a new technical means for the development of multi-target anti-AD drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 (A) Overview of the experimental design, including surgical procedures, drug treatments, and behavioral tests. BN is the effect of different doses of compounds I-12, I-33, and I-76 on Aβ 1-42 Improvement of learning and memory ability in mice. (B, C, D) Platform escape latency of mice treated with I-12, I-33, I-76 and AD mice in the MWM positioning navigation test; (E, F, G) Swimming speed of mice treated with I-12, I-33, I-76 and AD mice in the positioning navigation test; (H, I, J) Percentage of time in the target quadrant of mice treated with I-12, I-33, I-76 and AD mice in the spatial exploration test; (K, L, M) Number of times mice treated with I-12, I-33, I-76 and AD mice crossed the original position of the platform in the spatial exploration test. (N) Representative movement trajectories of different groups during the spatial exploration test. Data were analyzed using SPSS software version 25.0 (IBM, Armonk, NY, USA). Comparisons were calculated by repeated measures analysis of variance (A, B) and one-way analysis of variance (C, D). Comparisons were calculated by repeated measures ANOVA (BG) and one-way ANOVA (HM). Results are shown as mean ± SD, n = 9, #P < 0.05, ##P < 0.001, ###P < 0.0001 vs. Sham, *P < 0.05, **P < 0.01, ***P < 0.001 vs. Aβ + vehicle. DETAILED DESCRIPTION

[0055] The present invention is described below in conjunction with specific examples, which are not intended to limit the scope of the present invention, but to provide guidance for those skilled in the art to prepare and use the compounds and compositions of the present invention. The chemical names of the compounds described in this application are usually generated from ChemDraw Ultra (ChambridgeSoft) / or usually follow the principles of IUPAC nomenclature.

[0056] The compounds of this example were prepared by the following route:

[0057] Step 1: Synthesis of intermediate 3a-n / 3b-n

[0058] 1: Synthesis of intermediates 3a-n

[0059]

[0060] Right now:

[0061] 1. At room temperature, cinnamic acid derivatives (1a-1c) were reacted with propargylamine in the presence of dicyclohexylcarbodiimide and 4-dimethylaminopyridine in dichloromethane as solvent. The reaction lasted for 12 hours to obtain intermediates 3a-1-3a-3.

[0062] 2. At room temperature, ferulic acid (1d) / caffeic acid (1e) reacted with propargylamine in a mixed solvent of dichloromethane and N,N-dimethylformamide under the action of benzotriazole-1-oxytris(dimethylamino)phosphine hexafluorophosphate. The reaction was continued for 5 h to obtain intermediate 3a-4 / 3a-5.

[0063] 3: Synthesis of intermediate 3b-n

[0064]

[0065] Right now:

[0066] 1. Cinnamic acid derivatives (1a-1d) were reacted with 3-bromopropyne in N,N-dimethylformamide under the action of potassium carbonate at room temperature for 12 h to obtain intermediates 3b-1-3b-4.

[0067] At 2.0°C, caffeic acid (1e) was dissolved in hexamethylphosphoramidite (HMPA) and reacted with 3-bromopropyne using sodium carbonate and potassium iodide as bases to obtain intermediate 3a-5 after 12 hours.

[0068] Step 2: One-pot synthesis of series I compounds

[0069]

[0070] At room temperature, compound 2 (benzyl bromide or substituted benzyl bromide) reacts with sodium azide in N,N-dimethylformamide (DMSO) to generate azide 4, and water is directly added to quench any remaining sodium azide; intermediate 3a / 3b is dissolved in N,N-dimethylformamide and added to the reaction, and the solvent is adjusted to DMSO / H2O (1:1 v / v), and then a reducing agent sodium ascorbate and a catalyst CuSO4·5H2O (20 mol%) are added, and after reacting for 12 h, a series of compounds of compound I are obtained.

[0071] Example 1 N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)cinnamamide (I-1)

[0072]

[0073] 1 H NMR(500MHz,DMSO-d6)δ(ppm):8.63(t,J=5.7Hz,1H),8.06(s,1H),7.58(d,J=7.4Hz ,2H),7.53–7.33(m,9H),6.69(d,J=15.8Hz,1H),5.61(s,2H),4.47(d,J=5.6Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):165.30,145.46,139.46,136.60,135.30,129.97,129.41 ,129.21,128.60,128.49,127.99,123.50,122.35,53.20,34.81.HRMS(m / z):calcd.for C 19 H 18 N4O[M+H] + ,319.1553;found,319.1553.

[0074] Example 2 (E)-3-(2-methylphenyl)-N-((1-benzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-2)

[0075]

[0076] 1H NMR(500MHz,DMSO-d6)δ(ppm):8.04(t,J=5.6Hz,1H),7.61(s,1H),7.59–7.52(m,1H),7.51–7.45(m,1H),7 .37–7.22(m,8H),6.46(d,J=16.1Hz,1H),5.41–5.37(m,2H),4.57(d,J=5.5Hz,2H),2.40(d,J=0.7Hz,3H). 13 C NMR(125MHz,DMSO-d6)δ(ppm):167.26,141.76,138.87,137.80,135.08,131.95,129.89,129.72,12 9.08,128.78,128.73,128.15,127.07,124.25,121.46,53.97,31.44,19.51.HRMS(m / z):calcd.for C 20 H 20 N4O[M+H] + ,333.17099; found,333.17084

[0077] Example 3 (E)-3-(2-methoxyphenyl)-N-((1-benzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-3)

[0078]

[0079] 1 H NMR(500MHz,DMSO-d6)δ(ppm):7.98(t,J=5.6Hz,1H),7.64–7.57(m,3H),7.36(td,J=7.9,1.5Hz,1H),7.36–7.28(m,4H),7.30–7.23(m,1H), 7.05(td,J=7.7,1.4Hz,1H), 6.95(dd,J=8.1,1.4Hz,1H), 6.52(d,J=16.3Hz,1H), 5.39(d,J=1.0Hz,2H), 4.57(d,J=5.5Hz,2H), 3.87(s,3H). 13C NMR(125MHz,DMSO-d6)δ(ppm):166.95,157.96,141.76,136.53,131.95,131.30,129.14,128.78,12 8.73,128.15,126.91,124.25,121.79,121.33,114.07,55.51,53.97,31.44.HRMS(m / z):calcd.for C 20 H 20 N4O2[M+H] + ,349.16590; found,349.16593

[0080] Example 4 N-((1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)cinnamamide (I-4)

[0081]

[0082] mp:147-149℃. 1 H NMR(500MHz,DMSO-d6)δ(ppm):8.60(t,J=5.8Hz,1H),8.02(s,1H),7.61–7.54(m,2H),7.50– 7.35(m,6H),7.31–7.21(m,2H),6.67(d,J=15.8Hz,1H),5.66(s,2H),4.45(d,J=5.6Hz,2H). 13 C NMR (101MHz, DMSO-d6) δ (ppm): 165.35, 160.57 (d, J = 246.8Hz), 145.39, 139.52, 135.27, 131.28 (d, J = 3.4Hz), 131.19, 130.00, 129.42, 128 .01,125.31(d,J=3.6Hz),123.63,123.36(d,J=14.8Hz),122.29,116.10(d,J=20.9Hz),47.26(d,J=3.8Hz),34.76.HRMS(m / z):calcd.for C 19 H 17 FN4O[M+H] + ,337.1459; found,337.1445

[0083] Example 5 N-((1-(3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)cinnamamide (I-5)

[0084]

[0085] mp:159-161℃. 1 H NMR (500MHz, DMSO-d6) δ (ppm): 8.63 (t, J = 5.8Hz, 1H), 8.10 (s, 1H), 7.58 (d, J = 7.4Hz, 2H), 7.49 (d, J = 15.6Hz, 1H), 7.44 (t, J = 7 .6Hz,3H),7.41(d,J=7.0Hz,1H),7.19(td,J=7.2,6.7,3.4Hz,3H),6.68(d,J=15.8Hz,1H),5.63(s,2H),4.47(d,J=5.6Hz,2H). 13 C NMR (101MHz, DMSO-d6) δ (ppm): 165.31, 162.59 (d, J = 244.2Hz), 145.55, 139.48, 139.28 (d, J = 7.5Hz), 135.30, 131.31 (d, J = 8.4Hz), 129.98, 129. 42,127.99,124.56(d,J=2.9Hz),123.69,122.34,115.50(d,J=14.2Hz),115.28(d,J=15.3Hz),52.50(d,J=1.9Hz),34.80.HRMS(m / z):calcd.for C 19 H 17 FN4O[M+H] + ,337.1459; found 337.1458.

[0086] Example 6 N-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)cinnamamide (I-6)

[0087]

[0088] mp:161-163℃.\ 1 H NMR (500MHz, DMSO-d6) δ (ppm): 8.62 (s, 1H), 8.06 (s, 1H), 7.58 (d, J = 7.3Hz, 2H), 7.52–7.37 (m,6H),7.24(t,J=8.8Hz,2H),6.68(d,J=15.8Hz,1H),5.59(s,2H),4.45(d,J=5.6Hz,2H). 13C NMR (101MHz, DMSO-d6) δ (ppm): 165.31, 162.35 (d, J = 244.3Hz), 145.51, 139.48, 135.29, 132.86 (d, J = 3.2 Hz),130.81(d,J=8.4Hz),129.98,129.42,127.99,123.44,122.33,116.05(d,J=21.5Hz),52.39,34.79.C 19 H 17 FN4O[M+H] + ,337.1459; found,337.1458.HRMS(m / z):calcd.for C 19 H 17 FN4O[M+Na] + :359.1278; found:359.1278.

[0089] Example 7 N-((1-(2-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl)cinnamamide (I-7)

[0090]

[0091] mp:175-177℃. 1 H NMR(500MHz,DMSO-d6)δ(ppm):8.65(t,J=5.7Hz,1H),8.16(d,J=8.1Hz,1H),8.07(s,1H),7.77(t,J=7.6Hz,1H),7.66(t,J=7.8Hz ,1H),7.58(d,J=7.3Hz,2H),7.51–7.38(m,4H),7.08(d,J=7.8Hz,1H),6.69(d,J=15.8Hz,1H),5.97(s,2H),4.49(d,J=5.6Hz,2H). 13 C NMR (101MHz, DMSO-d6) δ (ppm): 165.31, 162.35 (d, J = 244.3Hz), 145.51, 139.48, 135.29, 132.86 (d, J = 3.2Hz), 130.8 1(d,J=8.4Hz),129.98,129.42,127.99,123.44,122.33,116.05(d,J=21.5Hz),52.39,34.79.HRMS(m / z):calcd.for C 19 H 17 N5O3[M+Na] +:386.1224;found:386.1223.

[0092] Example 8 N-((1-(3-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl)cinnamamide (I-8)

[0093]

[0094] mp:144-146℃. 1 H NMR(500MHz,DMSO-d6)δ(ppm):8.64(t,J=5.7Hz,1H),8.30–8.19(m,2H),8.16(s,1H),7.81(d,J=7.7Hz,1H),7.72(t ,J=7.9Hz,1H),7.58(d,J=7.3Hz,2H),7.51–7.37(m,4H),6.68(d,J=15.8Hz,1H),5.78(s,2H),4.47(d,J=5.6Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):165.36,148.34,145.67,139.53,138.66,135.27,130.89,13 0.00,129.42,128.00,123.84,123.62,123.33,122.29,52.14,34.79.HRMS(m / z):calcd.for C 19 H 17 N5O3[M+H] + :364.1404; found:364.1394.

[0095] Example 9 N-((1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl)cinnamamide (I-9)

[0096]

[0097] mp:184-186℃. 1 H NMR(500MHz,DMSO-d6)δ(ppm):8.65(t,J=5.9Hz,1H),8.27(d,J=8.2Hz,2H),8.14(s,1H),7.6 1–7.54(m,4H),7.52–7.37(m,4H),6.68(d,J=15.8Hz,1H),5.79(s,2H),4.48(d,J=5.6Hz,2H). 13C NMR(101MHz,DMSO-d6)δ(ppm):165.35,147.71,145.68,143.98,139.53,135.27,130.00 ,129.56,129.42,128.00,124.38,123.99,122.29,52.29,34.79.HRMS(m / z):calcd.for C 19 H 17 N5O3[M+Na] + :386.1224;found:386.1216.

[0098] Example 10 N-((1-(2-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)methyl)cinnamamide (I-10)

[0099]

[0100] mp:109-111℃。 1 H NMR (500MHz, DMSO-d6) δ (ppm): 8.64 (t, J = 5.8 Hz, 1H), 8.04 (s, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.59 (dd, J=15.5,7.6Hz,3H),7.49–7.39(m,4H),7.19(d,J=7.8Hz,1H),6.69(d,J=15.8Hz,1H),5.80(s,2H),4.48(d,J=5.7Hz,2H). 13 C NMR (101MHz, DMSO-d6) δ (ppm): 165.37, 145.48, 139.51, 135.27, 134.27 (d, J = 1.9Hz), 133.63, 130.67, 129.42, 129.35, 128.71 (d, J = 2.9Hz) ),128.01,127.57–126.73(m),126.67(q,J=5.6Hz),128.39–120.49(m),124.17,122.31,49.89(q,J=2.7Hz),34.77.HRMS(m / z):calcd.for C 20 H 17 F3N4O[M+H] + :387.1427;found:387.1425.

[0101] Example 11 N-((1-(3-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)methyl)cinnamamide (I-11)

[0102]

[0103] mp:153-155℃. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.61 (t, J = 5.7Hz, 1H), 8.11 (s, 1H), 7.77–7.70 (m, 2H), 7.66–7.60 (m, 2 H),7.59–7.53(m,2H),7.50–7.37(m,4H),6.65(d,J=15.8Hz,1H),5.70(s,2H),4.44(d,J=5.6Hz,2H). 13 C NMR (101MHz, DMSO-d6) δ (ppm): 165.31, 145.61, 139.48, 137.99, 135.29, 132.70, 130.42, 129.97, 129.67, 129.41, 127. 99,125.41(q,J=3.7Hz),125.18(q,J=3.8Hz),123.76,128.64–120.07(m),122.32,52.45,34.79.HRMS(m / z):calcd.for C 20 H 17 F3N4O[M+H] + :387.1427; found:387.1426.

[0104] Example 12 N-((1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)methyl)cinnamamide (I-12)

[0105]

[0106] mp:212-214℃. 1 H NMR(500MHz,DMSO-d6)δ(ppm):8.63(t,J=5.6Hz,1H),8.12(s,1H),7.78(d,J=8.0Hz ,2H),7.61–7.37(m,9H),6.68(d,J=15.8Hz,1H),5.73(s,2H),4.47(d,J=5.6Hz,2H). 13C NMR (101MHz, DMSO-d6) δ (ppm): 165.34, 145.62, 141.26, 139.51, 135.28, 129.99, 129.42, 129.16, 129.12 (q, J=32 .0Hz),128.00,126.15(q,J=3.8Hz),124.57(d,J=272.2Hz),123.84,122.31,52.52,34.80.HRMS(m / z):calcd.for C 20 H 17 F3N4O[M+H] + :387.1427;found:387.1418.

[0107] Example 13 N-((1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)cinnamamide (I-13)

[0108]

[0109] mp:119-121℃. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.60 (t, J=5.6Hz, 1H), 7.93 (s, 1H), 7.59–7.51 (m, 2H), 7.48–7.36 (m, 4H), 7.27–7 .16(m,3H),7.11(dd,J=7.3,1.4Hz,1H),6.66(d,J=15.8Hz,1H),5.59(s,2H),4.44(d,J=5.6Hz,2H),2.32(s,3H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):165.29,145.33,139.45,136.80,135.30,134.69,130.88,129.96,12 9.41,129.20,128.78,127.99,126.71,123.51,122.35,51.32,34.81,19.14.HRMS(m / z):calcd.for C 20 H 20 N4O[M+H] + :333.1710;found:333.1705.

[0110] Example 14 N-((1-(3-methylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)cinnamamide (I-14)

[0111]

[0112] mp:130-132℃. 1 H NMR(500MHz, DMSO-d6)δ(ppm):8.62(t,J=5.7Hz,1H),8.03(s,1H),7.58(d,J=7.4Hz,2H),7.52–7.37(m,4H),7. 28(t,J=7.5Hz,1H),7.21–7.09(m,3H),6.68(d,J=15.8Hz,1H),5.55(s,2H),4.46(d,J=5.6Hz,2H),2.31(s,3H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):165.32,145.42,139.49,138.44,136.45,135.29,129.98,129.42,12 9.24,129.13,129.09,127.99,125.63,123.45,122.33,53.22,34.81,21.39.HRMS(m / z):calcd.for C 20 H 20 N4O[M+H] + :333.1710; found:333.1708.

[0113] Example 15 N-((1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)cinnamamide (I-15)

[0114]

[0115] mp:182-184℃. 1 H NMR(500MHz,DMSO-d6)δ(ppm):8.61(t,J=5.7Hz,1H),8.00(s,1H),7.57(d,J=7.3Hz,2H),7.53–7.34(m,4H),7.25 (d,J=7.7Hz,2H),7.20(d,J=7.8Hz,2H),6.67(d,J=15.8Hz,1H),5.54(s,2H),4.45(d,J=5.6Hz,2H),2.30(s,3H). 13C NMR(101MHz,DMSO-d6)δ(ppm):165.31,145.42,139.49,137.96,135.28,133.56,129.98,12 9.74,129.41,128.55,128.00,123.32,122.32,53.02,34.80,21.16.HRMS(m / z):calcd.for C 20 H 20 N4O[M+H] + :333.1710;found:333.1710.

[0116] Example 16 N-((1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)cinnamamide (I-16)

[0117]

[0118] mp:135-137℃. 1 H NMR(500MHz,DMSO-d6)δ(ppm):8.62(d,J=5.8Hz,1H),8.02(s,1H),7.55(dd,J=17.2,7.5Hz,3H),7.42(td,J=1 6.3,15.4,8.0Hz,6H),7.25(dd,J=7.4,1.9Hz,1H),6.68(d,J=15.8Hz,1H),5.71(s,2H),4.47(d,J=5.6Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):165.37,145.33,139.51,135.27,133.80,133.08,130. 99,130.72,130.10,129.99,129.42,128.20,128.01,123.87,122.31,50.96,34.78.. HRMS(m / z):calcd.for C 19 H 17 N4OClNa[M+Na] + :375.09831; found:375.09955.

[0119] Example 17 N-((1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)cinnamamide (I-17)

[0120]

[0121] mp:126-128℃.1 H NMR (500MHz, DMSO-d6) δ (ppm): 8.63 (t, J = 5.7Hz, 1H), 8.10 (s, 1H), 7.61–7.55 (m, 2H), 7. 53–7.37(m,7H),7.31(s,1H),6.68(d,J=15.8Hz,1H),5.62(s,2H),4.46(d,J=5.6Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):165.34,145.56,139.51,138.97,135.28,133.72,131 .18,129.99,129.42,128.60,128.36,128.00,127.22,123.70,122.31,52.41,34.80. HRMS(m / z):Cacld for C 19 H 17 N4ClNa[M+H] + :375.09831,found:375.09933.

[0122] Example 18 N-((1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)cinnamamide (I-18)

[0123]

[0124] mp:186-188℃. 1 H NMR (500MHz, DMSO-d6) δ (ppm): 8.63 (t, J = 5.7Hz, 1H), 8.10 (s, 1H), 7.61–7.55 (m, 2H), 7. 53–7.37(m,7H),7.31(s,1H),6.68(d,J=15.8Hz,1H),5.62(s,2H),4.46(d,J=5.6Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):165.34,145.56,139.51,138.97,135.28,133.72,131.18,129. 99,129.42,128.60,128.36,128.00,127.22,123.70,122.31,52.41,34.80.HRMS(m / z):Cacld for C 19 H 17 N4OCl[M+H] + :375.09831,found:375.09964.

[0125] Example 19 N-((1-(2-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)cinnamamide (I-19)

[0126]

[0127] 1 H NMR(500MHz,DMSO-d6)δ(ppm):8.42(t,J=5.7Hz,1H),7.62–7.54(m,3H),7.52(dd,J=15.6,0.9Hz,1H),7.41–7.34(m,3H),7.22–7.14(m,2H),6. 96(ddd,J=7.7,7.0,1.0Hz,1H),6.82(dd,J=7.5,1.0Hz,1H),6.60(d,J=15.8Hz,1H),5.36(d,J=1.1Hz,2H),4.57(d,J=5.5Hz,2H),3.84(s,2H).. 13 C NMR(101MHz,DMSO-d6)δ(ppm):167.18,157.74,141.83,141.59,134.22,130.15,130.05,129.0 0,128.27,125.45,124.42,121.55,119.59,111.51,55.59,49.76,31.44.HRMS(m / z):calcd.for C 20 H 20 N4O2[M+H] + :349.16590; found:349.16588.

[0128] Example 20 N-((1-(3-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)cinnamamide (I-20)

[0129]

[0130] mp:109-111℃。 1H NMR(500MHz, DMSO-d6)δ(ppm):8.61(t,J=5.7Hz,1H),8.05(s,1H),7.57(d,J=7.3Hz,2H),7.51–7.36(m,5H),7. 31(t,J=7.7Hz,1H),6.97–6.84(m,3H),6.67(d,J=15.8Hz,1H),5.56(s,2H),4.45(d,J=5.6Hz,2H),3.76(s,3H). 13 CNMR(101MHz,DMSO-d6)δ(ppm):165.32,159.88,145.44,139.49,138.01,135.28,130.38 ,129.98,129.42,128.00,123.53,122.32,120.55,114.30,113.87,55.56,53.12,34.80. HRMS(m / z):Cacld for C 20 H 20 N4O2Na[M+Na] +: 371.14785, found:371.14865.

[0131] Example 21 N-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)cinnamamide (I-21)

[0132]

[0133] mp:97-99℃. 1 H NMR (500MHz, DMSO-d6) δ (ppm): 8.57 (d, J = 5.8 Hz, 1H), 7.97 (s, 1H), 7.58–7.54 (m, 2H), 7.49–7.38 (m, 4H), 7. 34–7.29(m,2H),6.97–6.91(m,2H),6.66(d,J=15.8Hz,1H),5.50(s,2H),4.43(d,J=5.6Hz,2H),3.75(s,3H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):165.34,159.60,145.39,139.53,135.26,130.15,130.00,12 9.42,128.47,128.00,123.14,122.28,114.57,55.60,52.76,34.79.HRMS(m / z):calcd.for C 20 H 20N4O2[M+H] + :349.1659; found:349.1663.

[0134] Example 22 N-((1-(2,4-dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)cinnamamide (I-22)

[0135]

[0136] 1 H NMR(500MHz,DMSO-d6)δ(ppm):8.37(t,J=5.7Hz,1H),7.60(s,1H),7.59–7.54(m, 2H),7.52(dd,J=15.7,0.9Hz,1H),7.41–7.34(m,2H),7.36–7.30(m,1H),7.09(dt ,J=7.5,1.1Hz,1H),6.60(d,J=15.8Hz,1H),6.51(dd,J=7.5,2.4Hz,1H),6.47(d, J=2.4Hz,1H),5.36(d,J=0.9Hz,2H),4.57(d,J=5.5Hz,2H),3.82(d,J=4.4Hz,6H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):167.18,160.02,158.52,141.83,141.59,134.22,130.72,130.15 ,129.00,128.26,124.39,121.24,119.59,107.20,98.73,55.64,49.72,31.44.HRMS(m / z):Cacld for C 21 H 22 N4O3Na[M+Na] + :401.15841,found:401.15901.

[0137] Example 23 N-((1-(3,5-dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)cinnamamide (I-23)

[0138]

[0139] mp:110-112℃. 1H NMR(500MHz,DMSO-d6)δ(ppm):8.61(t,J=5.8Hz,1H),8.04(s,1H),7.57(d,J=7.3Hz,2H),7.50–7.37(m,4 H),6.67(d,J=15.8Hz,1H),6.48(dd,J=11.2,2.3Hz,3H),5.50(s,2H),4.45(d,J=5.6Hz,2H),3.73(s,6H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):165.31,161.12,145.43,139.47,138.66,135.29,129.98 ,129.42,127.99,123.56,122.34,106.60,99.98,55.70,53.19,34.80.HRMS(m / z):Cacld for C 21 H 22 N4O3Na[M+Na] + :401.15841,found:401.15955.

[0140] Example 24 N-((1-(3,4-dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)cinnamamide (I-24)

[0141]

[0142] 1 H NMR(500MHz,DMSO-d6)δ(ppm):8.46(t,J=5.7Hz,1H),7.60(s,1H),7.59–7.54(m,2H),7.52(dd,J=15.7,0.8Hz,1H),7.41–7.34(m,2H),7.36– 7.30(m,1H),6.85(p,J=0.9Hz,1H),6.80(s,2H),6.60(d,J=15.8Hz,1H),5.41(t,J=0.9Hz,2H),4.57(d,J=5.5Hz,2H),3.82(d,J=4.0Hz,6H). 13C NMR(101MHz,DMSO-d6)δ(ppm):167.18,149.12,148.51,141.73,141.59,134.22,130.60,130.15,129 .00,128.26,124.28,122.71,119.59,112.81,112.47,55.88,55.80,52.48,31.44.HRMS(m / z):Cacld for C 21 H 22 N4O3Na[M+Na] + :401.15841,found:401.15946.

[0143] Example 25 N-((1-(2-(tert-butyl)benzyl)-1H-1,2,3-triazol-4-yl)methyl)cinnamamide (I-25)

[0144]

[0145] 1 H NMR(500MHz,DMSO-d6)δ(ppm):8.41(t,J=5.7Hz,1H),7.61(s,1H),7.59–7.48(m,3H),7.41–7.34(m,3H),7.34–7 .24(m,2H),7.23–7.15(m,2H),6.60(d,J=15.7Hz,1H),5.35(d,J=0.9Hz,2H),4.57(d,J=5.5Hz,2H),1.28(s,9H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):167.18,149.73,141.73,141.59,134.22,133.92,130.15,129.81,129.0 0,128.26,127.23,125.85,125.03,124.31,119.59,51.18,36.93,31.44,30.25.HRMS(m / z):calcd.for C 23 H 26 N4O[M+H] + :375.2179; found:375.2181.

[0146] Example 26 N-((1-(3-(tert-butyl)benzyl)-1H-1,2,3-triazol-4-yl)methyl)cinnamamide (I-26)

[0147]

[0148] 1 H NMR(500MHz,DMSO-d6)δ(ppm):8.46(t,J=5.7Hz,1H),7.62–7.48(m,4H),7.41–7.26(m,5H),7.25 –7.17(m,2H),6.60(d,J=15.7Hz,1H),5.40(t,J=1.0Hz,2H),4.57(d,J=5.5Hz,2H),1.32(s,9H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):167.18,150.71,141.76,141.59,136.56,134.22,130.15,129.00,1 28.89,128.26,126.37,124.25,123.99,119.59,52.70,34.56,31.44,31.23.HRMS(m / z):calcd.for C 23 H 26 N4O[M+H] + :375.2179; found:375.2192.

[0149] Example 27 N-((1-(4-(tert-butyl)benzyl)-1H-1,2,3-triazol-4-yl)methyl)cinnamamide (I-27)

[0150]

[0151] mp: 154-156℃. . 1 H NMR(400MHz, DMSO-d6)δ(ppm):8.59(t,J=5.7Hz,1H),8.01(s,1H),7.58–7.52(m,2H),7.48–7.34( m,6H),7.30–7.23(m,2H),6.65(d,J=15.8Hz,1H),5.52(s,2H),4.42(d,J=5.6Hz,2H),1.25(s,9H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):165.28,151.08,145.43,139.45,135.30,133.64,129.96,129.4 1,128.31,127.99,125.97,123.37,122.36,52.92,34.80,34.75,31.52.HRMS(m / z):calcd.for C 23 H 26 N4O[M+H]+ :375.2179; found:375.2169.

[0152] Example 28 (E)-3-(4-Hydroxy-3-methoxyphenyl)-N-((1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-28)

[0153]

[0154] 1 H NMR(400MHz, DMSO-d6)δ(ppm):7.93(t,J=5.6Hz,1H),7.61(s,1H),7.30(d,J=16.1Hz,1H),7.24(s,1H),7.20–7.06(m,5H),7.03–6.97( m,1H),6.86(d,J=8.2Hz,1H),6.59(d,J=16.1Hz,1H),5.33(d,J=1.0Hz,2H),4.57(d,J=5.5Hz,2H),3.83(s,3H),2.34(d,J=0.7Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):167.09,149.45,148.77,141.73,141.18,137.49,136.32,130.33,128.88,127.9 6,127.35,126.47,124.31,123.16,120.10,115.99,111.32,56.21,51.21,31.44,19.39.HRMS(m / z):calcd.for C 21 H 23 N4O3[M+H] + :379.17647; found:379.17689.

[0155] Example 29 (E)-3-(4-Hydroxy-3-methoxyphenyl)-N-((1-(3-methylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-29)

[0156]

[0157] 1H NMR(400MHz, DMSO-d6)δ(ppm):7.86(t,J=5.6Hz,1H),7.60(s,1H),7.30(d,J=16.1Hz,1H),7.29(s,1H),7.21–7.14(m,2H),7.13–7.06(m,3H),7. 03–6.97(m,1H),6.86(d,J=8.2Hz,1H),6.59(d,J=16.1Hz,1H),5.33(t, J=0.9Hz,2H),4.57(d,J=5.5Hz,2H),3.83(s,3H),2.32(d,J=1.3Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):167.09,149.45,148.77,141.76,141.18,138.37,136.45,129.26,128.70,128.2 8,127.96,126.36,124.25,123.16,120.10,115.99,111.32,56.21,52.57,31.44,21.32.HRMS(m / z):calcd.forC 21 H 23 N4O3[M+H] + :379.17647; found:379.17694.

[0158] Example 30 (E)-3-(4-Hydroxy-3-methoxyphenyl)-N-((1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-30)

[0159]

[0160] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.09 (t, J=5.6Hz, 1H), 7.60 (s, 1H), 7.41 (d, J= 16.1Hz,1H),7.24(s,1H),7.16(dt,J=7.4,1.0Hz,2H),7.11(d,J=2.0Hz,1H), 7.09–7.04(m,2H),7.03–6.97(m,1H),6.86(d,J=8.2Hz,1H),6.59(d,J=16.1H z,1H),5.38(t,J=1.0Hz,2H),4.57(d,J=5.5Hz,2H),3.83(s,3H),2.34(s,3H). 13C NMR(101MHz,DMSO-d6)δ(ppm):167.09,149.45,148.77,141.76,141.18,136.82,133.63,129.45,128.7 1,127.96,124.25,123.16,120.10,115.99,111.32,56.21,52.91,31.44,21.04.HRMS(m / z):calcd.for C 21 H 23 N4O3[M+H] + :379.17647; found:379.17710.

[0161] Example 31 (E)-3-(4-hydroxy-3-methoxyphenyl)-N-((1-(2-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-31)

[0162]

[0163] 1 H NMR(400MHz, DMSO-d6)δ(ppm):7.93(t,J=5.7Hz,1H),7.63(s,1H),7.55(dd,J=10.5,1.3Hz,1H),7.44(ddd,J=10.6,6.7,2.0Hz,1H),7.32–7.22(m,4H ),7.11(d,J=2.0Hz,1H),7.03–6.97(m,1H),6.86(d,J=8.2Hz,1H),6.59(d ,J=16.1Hz,1H),5.59(d,J=1.0Hz,2H),4.57(d,J=5.5Hz,2H),3.83(s,3H). 13 C NMR (101MHz, DMSO-d6) δ (ppm): δ167.09, 149.45, 148.77, 141.76, 141.18, 132.67 (d, J = 4.1Hz), 130.13 (d, J = 1.9Hz), 128.20 (d, J = 32.2Hz), 127.96, 1 27.27(q,J=1.9Hz),126.35(q,J=3.9Hz),125.65,124.41,123.16,120.10,115.99,111.32,56.21,50.79(d,J=1.9Hz),31.44.HRMS(m / z):calcd.for C 21 H 20 F3N4O3[M+H] +,433.14820;found,433.14766.

[0164] Example 32 (E)-3-(4-Hydroxy-3-methoxyphenyl)-N-((1-(3-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-32)

[0165]

[0166] 1 H NMR(400MHz, DMSO-d6)δ(ppm):8.11(t,J=5.6Hz,1H),7.62–7.57(m,2H),7.57–7.50(m,1H),7.48–7.41(m,2H),7.30(d,J=16.1Hz,1H),7.24(s,1H) ,7.11(d,J=2.0Hz,1H),7.03–6.97(m,1H),6.86(d,J=8.2Hz,1H),6.59(d, J=16.1Hz,1H),5.40(t,J=0.9Hz,2H),4.57(d,J=5.5Hz,2H),3.83(s,3H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):167.09,149.45,148.77,141.73,141.18,136 .70(d,J=2.1Hz),131.11(d,J=32.0Hz),129.42,129.03(d,J=1.9Hz),127.9 6,126.77(d,J=4.0Hz),124.25,123.67(d,J=4.0Hz),123.60(d,J=3.8Hz),1 23.16,120.10,115.99,111.32,56.21,52.55,31.44.HRMS(m / z):calcd.for C 21 H 20 F3N4O3[M+H] + ,433.14820;found,433.14798.

[0167] Example 33 (E)-3-(4-Hydroxy-3-methoxyphenyl)-N-((1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-33)

[0168]

[0169] mp:164-166℃. 1H NMR (400MHz, DMSO-d6) δ (ppm): 9.44 (s, 1H), 8.45 (t, J=

[0170] 5.7Hz,1H),8.08(s,1H),7.76(d,J=8.1Hz,2H),7.51(d,J=8.0Hz,2H),7.36(d,J=15.7Hz,1H),7.12(d,J=2.0Hz,1H),6.9 9(dd,J=8.2,2.0Hz,1H),6.80(d,J=8.1Hz,1H),6.48(d,J=15.7Hz,1H),5.71(s,2H),4.43(d,J=5.6Hz,2H),3.80(s,3H). 13 C NMR (101MHz, DMSO-d6) δ (ppm): 165.79, 148.81, 148.27, 145.83, 141.29, 139.89, 129.15, 129.11 (d, J = 31.8Hz), 12 8.63, 126.77, 126.15 (q, J = 3.9Hz), 124.57 (d, J = 272.1Hz), 123.77, 121.98, 119.05, 116.13, 55.97, 52.51, 34.79. HRMS(m / z):calcd.for C 21 H 20 F3N4O3[M+H] + ,433.14820;found,433.14746.

[0171] Example 34 (E)-3-(4-Hydroxy-3-methoxyphenyl)-N-((1-(2-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-34)

[0172]

[0173] 1H NMR (400MHz, DMSO-d6) δ (ppm): 8.11–8.04 (m, 1H), 7.99 (t, J = 5.6Hz, 1H), 7.86–7 .80(m,1H),7.60–7.52(m,3H),7.29(s,1H),7.24(s,1H),7.11(d,J=2.0Hz,1H), 7.03–6.97(m,1H),6.86(d,J=8.2Hz,1H),6.59(d,J=16.1Hz,1H),5.60(dd,J=14 .4,1.0Hz,1H),5.53(dd,J=14.4,1.0Hz,1H),4.57(d,J=5.5Hz,2H),3.83(s,3H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):167.09,149.45,148.77,147.15,141.84,141.18,132.72,131.11,130.44,12 8.31,127.96,125.17,124.65,123.16,120.10,115.99,111.32,56.21,51.28,31.44..HRMS(m / z):calcd.for C 20 H 19 N5O5[M+H] + :410.1459; found:410.1448.

[0174] Example 35 (E)-3-(4-hydroxy-3-methoxyphenyl)-N-((1-(3-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-35)

[0175]

[0176] 1 H NMR(600MHz,DMSO-d6)δ(ppm):8.19–8.11(m,2H),7.99(t,J=5.6Hz,1H),7.60(s,1H),7.58–7.50(m,2H),7.29(s,1H),7.24(s,1H),7.11(d ,J=2.0Hz,1H),7.03–6.97(m,1H),6.86(d,J=8.2Hz,1H),6.59(d,J=16.1Hz,1H),5.53(t,J=0.9Hz,2H),4.57(d,J=5.5Hz,2H),3.83(s,3H). 13C NMR(151MHz,DMSO-d6)δ(ppm):149.45,148.77,148.12,141.73,141.18,137.37,133.86,129.68,12 4.27,123.94,123.16,122.41,120.10,115.99,111.32,56.21,52.17,31.44.HRMS(m / z):calcd.for C 20 H 19 N5O5[M+H] + :410.1459; found:410.1454.

[0177] Example 36 (E)-3-(4-Hydroxy-3-methoxyphenyl)-N-((1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-36)

[0178]

[0179] mp:153-155℃. 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.43 (s, 1H), 8.45 (t, J = 5.7Hz, 1H), 8.25 (dd, J=8.8,2.3Hz,2H),8.09(s,1H),7.55(dd,J=8.7,2.4Hz,2H),7.36(d,J=15.7H z,1H),7.12(d,J=2.0Hz,1H),6.99(dd,J=8.2,2.0Hz,1H),6.79(d,J=8.1Hz, 1H), 6.47 (d, J = 15.7Hz, 1H), 5.77 (s, 2H), 4.43 (d, J = 5.6Hz, 2H), 3.80 (s, 3H). 13 C NMR(151MHz,DMSO-d6)δ(ppm):165.80,148.82,148.28,147.72,145.89,144.02,139.90,129.55,12 6.77,124.38,123.91,121.98,119.05,116.14,111.33,55.99,52.28,34.78.HRMS(m / z):calcd.for C 20 H 19 N5O5[M+H] + :410.1459; found:410.1444.

[0180] Example 37 (E)-3-(4-Hydroxy-3-methoxyphenyl)-N-((1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-37)

[0181]

[0182] 1 H NMR (500MHz, DMSO-d6) δ (ppm): δ8.68 (t, J = 5.6 Hz, 1H), 7.61 (s, 1H), 7.34–7.22 (m, 4H), 7.15–7.07 (m, 3H), 7.03–6. 97(m,1H),6.86(d,J=8.2Hz,1H),6.59(d,J=16.1Hz,1H),5.41(d,J=0.9Hz,2H),4.57(d,J=5.5Hz,2H),3.83(s,3H). 13 C NMR (101MHz, Acetone-d6) δ (ppm): 167.09, 161.14 (d, J = 252.1Hz), 149.45, 148.77, 141.83, 141.18, 131.11 (d, J = 8.1Hz), 129.37 (d, J = 8.1Hz), 127 .96,124.99(d,J=3.1Hz),124.76(d,J=20.0Hz),124.42,123.16,120.10, 115.99, 115.44 (d, J = 19.8Hz), 111.32, 56.21, 49.63 (d, J = 5.0Hz), 31.44.

[0183] Example 38 (E)-3-(4-Hydroxy-3-methoxyphenyl)-N-((1-(3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-38)

[0184]

[0185] 1 H NMR (500MHz, DMSO-d6) δ (ppm): 8.76 (t, J = 5.6 Hz, 1H), 7.60 (s, 1H), 7.35–7.27 (m, 2H), 7.24 (s, 1H), 7.14–7.08 (m, 2H), 7. 06–6.97(m,3H),6.86(d,J=8.2Hz,1H),6.59(d,J=16.1Hz,1H),5.41(t,J=1.0Hz,2H),4.57(d,J=5.5Hz,2H),3.83(s,3H). 13C NMR (101MHz, Acetone-d6) δ (ppm): 167.09, 162.89 (d, J = 252.1Hz), 149.45, 148.77, 141.73, 141.18, 138.45 (d, J = 8.1Hz), 129.96 (d, J = 7.9Hz), 127 .96,124.35(d,J=3.1Hz),124.27,123.16,120.10,115.98(d,J=1.2Hz), 115.82, 113.85 (d, J = 20.0Hz), 111.32, 56.21, 52.36 (d, J = 3.8Hz), 31.44.

[0186] Example 39 (E)-3-(4-Hydroxy-3-methoxyphenyl)-N-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-39)

[0187]

[0188] mp:97-99℃. 1 H NMR(500MHz,DMSO-d6)δ(ppm):9.43(s,1H),8.42(t,J=5.8Hz,1H),8.02(s,1H),7.44–7.34(m,3H),7.22(t,J=8.7Hz,2H),7.15–7.11 (m,1H),7.00(dd,J=8.3,1.8Hz,1H),6.81(d,J=8.0Hz,1H),6.48(d,J=15.7Hz,1H),5.58(s,2H),4.43(d,J=5.6Hz,2H),3.81(s,3H). 13 C NMR (101MHz, Acetone-d6) δ (ppm): 165.51, 162.56 (d, J = 245.0Hz), 148.35, 147.73, 145.76, 139.99, 132.42 (d, J = 3.3Hz), 130.3 0(d,J=8.4Hz),127.26,122.37,121.76,118.69,115.61,115.31(d,J=16.0Hz),110.39,55.32,52.45,34.70.HRMS(m / z):Cacld for C 20 H 19 N4O3FNa[M+Na] + :405.13334,found:405.13452.

[0189] Example 40 (E)-3-(4-Hydroxy-3-methoxyphenyl)-N-((1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-40)

[0190]

[0191] 1 H NMR(500MHz,DMSO-d6)δ(ppm):7.93(t,J=5.6Hz,1H),7.61(s,1H),7.39–7.33(m,1H),7.30(d,J=16.1Hz,1H),7.26–7.18(m,3H),7.13–7 .06(m,2H),7.03–6.97(m,1H),6.86(d,J=8.2Hz,1H),6.59(d,J=16.1Hz,1H),5.44(d,J=1.1Hz,2H),4.57(d,J=5.5Hz,2H),3.83(s,3H). 13 C NMR(151MHz,DMSO-d6)δ(ppm):167.09,149.45,148.77,141.74,141.18,134.32,134.27,130.78 ,129.54,129.24,127.96,127.67,124.38,123.16,120.10,115.99,111.32,56.21,51.58,31.44.

[0192] Example 41 (E)-3-(4-hydroxy-3-methoxyphenyl)-N-((1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-41)

[0193]

[0194] 1 H NMR (500MHz, DMSO-d6) δ (ppm): 7.99 (t, J=5.6Hz, 1H), 7.60 (s, 1H), 7.34–7.27 (m, 4H), 7.27–7.22 (m, 1H), 7.18 (dtd, J=6.8, 2.3, 0.9Hz, 1H) ,7.10(s,1H),7.03–6.97(m,1H),6.86(d,J=8.2Hz,1H),6.59(d,J=16.1Hz,1H),5.38(d,J=1.1Hz,2H),4.57(d,J=5.5Hz,2H),3.83(s,3H). 13C NMR (151MHz, DMSO-d6) δ (ppm): δ167.09,149.45,148.77,141.73,141.18,137.36,134.39,130.12 ,129.02,128.10,127.96,127.18,124.25,123.16,120.10,115.99,111.32,56.21,52.21,31.44.

[0195] Example 42 (E)-3-(4-Hydroxy-3-methoxyphenyl)-N-((1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-42)

[0196]

[0197] 1 H NMR(500MHz,DMSO-d6)δ(ppm):7.79(t,J=5.6Hz,1H),7.64(s,1H),7.38–7.32(m,2H),7.31–7.22(m,4H),7.11(d,J=2.0Hz,1H ),7.03–6.97(m,1H),6.86(d,J=8.2Hz,1H),6.59(d,J=16.1Hz,1H),5.43(t,J=1.0Hz,2H),4.57(d,J=5.5Hz,2H),3.83(s,3H). 13 C NMR(151MHz,DMSO-d6)δ(ppm):167.09,149.45,148.77,141.76,141.18,134.40,133.82 ,130.30,128.73,127.96,124.25,123.16,120.10,115.99,111.32,56.21,53.25,31.44.

[0198] Example 43 (E)-3-(4-hydroxy-3-methoxyphenyl)-N-((1-(2-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-43)

[0199]

[0200] 1H NMR (500MHz, DMSO-d6) δ (ppm): 7.80 (t, J=5.6Hz, 1H), 7.50 (s, 1H), 7.30 (d, J= 16.1Hz,1H),7.24(s,1H),7.22–7.14(m,2H),7.11(d,J=2.0Hz,1H),7.03–6.9 3(m,2H),6.86(d,J=8.2Hz,1H),6.82(dd,J=7.6,1.0Hz,1H),6.59(d,J=16.1H z,1H),5.36(d,J=1.1Hz,2H),4.57(d,J=5.5Hz,2H),3.84(s,3H),3.83(s,3H). 13 C NMR(151MHz,DMSO-d6)δ(ppm):167.09,157.74,149.45,148.77,141.83,141.18,130.05,128.27,12 7.96,125.45,124.42,123.16,121.55,120.10,115.99,111.51,111.32,56.21,55.59,49.76,31.44.

[0201] Example 44 (E)-3-(4-Hydroxy-3-methoxyphenyl)-N-((1-(3-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-44)

[0202]

[0203]

[0204] 1 H NMR (500MHz, DMSO-d6) δ (ppm): 7.97 (t, J = 5.6 Hz, 1H), 7.60 (s, 1H), 7.32 (d, J = 16 .1Hz,1H),7.27–7.20(m,2H),7.11(d,J=2.0Hz,1H),7.01(dddd,J=8.8,5.7,2.0, 0.8Hz,2H),6.86(d,J=8.2Hz,1H),6.81(dtd,J=6.1,2.2,1.2Hz,2H),6.59(d,J=1 6.1Hz, 1H), 5.41 (t, J = 1.0Hz, 2H), 4.57 (d, J = 5.5Hz, 2H), 3.82 (d, J = 10.6Hz, 6H). 13C NMR(151MHz,DMSO-d6)δ(ppm):167.09,159.81,149.45,148.77,141.73,141.18,137.18,129.71,12 7.96,124.27,123.16,122.02,120.10,115.99,113.96,113.17,111.32,56.21,55.14,52.49,31.44.

[0205] Example 45 (E)-3-(4-hydroxy-3-methoxyphenyl)-N-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-45)

[0206]

[0207] 1 H NMR(500MHz, DMSO-d6)δ(ppm):8.23(t,J=5.6Hz,1H),7.64(s,1H),7.35(d,J=16.1Hz,1H),7.26–7.18(m,3H),7.11(d,J=2.0Hz,1H), 7.03–6.97(m,1H),6.89–6.80(m,3H),6.59(d,J=16.1Hz,1H),5.38(t,J=1.0Hz,2H),4.57(d,J=5.5Hz,2H),3.83(s,3H),3.78(s,3H). 13 C NMR(151MHz,DMSO-d6)δ(ppm):167.09,159.41,149.45,148.77,141.76,141.18,129.77,12 9.74,127.96,124.25,123.16,120.10,115.99,113.84,111.32,56.21,55.32,53.21,31.44.

[0208] Example 46 (E)-3-(3,4-dihydroxyphenyl)-N-((1-(2-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-46)

[0209]

[0210] 1H NMR(500MHz,DMSO-d6)δ(ppm):7.91(t,J=5.6Hz,1H),7.87(s,1H),7.61(s,1H ),7.55(dd,J=10.5,1.2Hz,1H),7.44(ddd,J=10.6,6.7,2.0Hz,1H),7.32–7.2 3(m,3H),6.94(d,J=1.9Hz,1H),6.92–6.88(m,1H),6.79(d,J=8.3Hz,1H),6.5 9(d,J=16.1Hz,1H),5.98(s,1H),5.59(d,J=1.0Hz,2H),4.57(d,J=5.5Hz,2H). 13 C NMR (151MHz, DMSO-d6) δ (ppm): 167.09, 148.56, 147.21, 141.76, 141.04, 132.67 (d, J = 4.1Hz), 130.13 (d, J = 1.9Hz), 128.20 (q, J = 32.0Hz), 127.27 (q,J=1.9Hz),126.79,126.35(q,J=3.9Hz),125.65,124.41,122.91,120.27,116.44,114.97,50.79(d,J=1.9Hz),31.44.HRMS(m / z):calcd.forC 20 H 18 F3N4O3[M+H] + ,419.13255;found,419.13198.

[0211] Example 47 (E)-3-(3,4-dihydroxyphenyl)-N-((1-(3-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-47)

[0212]

[0213] 1H NMR (500MHz, DMSO-d6) δ (ppm): 7.96 (t, J = 5.6Hz, 1H), 7.87 (s, 1H), 7.62–7. 57(m,2H),7.57–7.50(m,1H),7.48–7.41(m,2H),7.28(dd,J=16.0,0.6Hz,1 H),6.94(d,J=1.9Hz,1H),6.92–6.88(m,1H),6.79(d,J=8.3Hz,1H),6.59(d ,J=16.1Hz,1H),5.98(s,1H),5.40(t,J=0.9Hz,2H),4.57(d,J=5.5Hz,2H). 13 C NMR (151MHz, DMSO-d6) δ (ppm): 167.09, 148.56, 147.21, 141.73, 141.04, 136.70 (d, J = 2.1Hz), 131.11 (d, J = 32.0Hz), 129.42, 129.0 3(d,J=1.9Hz),126.79,126.75,124.25,123.63(d,J=4.1Hz),122.91,120.27,116.44,114.97,52.55,31.44.HRMS(m / z):calcd.for C 20 H 18 F3N4O3[M+H] + ,419.13255;found,419.13182.

[0214] Example 48 (E)-3-(3,4-dihydroxyphenyl)-N-((1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-48)

[0215]

[0216] mp:106-108℃. 1H NMR (500MHz, DMSO-d6) δ (ppm): 9.36 (s, 1H), 9.12 (s, 1H), 8.47 (t, J = 5.7Hz, 1H), 8.08 (s, 1H), 7.77 (d, J = 7.9Hz, 2H), 7.53 (d, J = 7.9Hz, 2H), 7.29 (d, J =15.7Hz,1H),6.96(d,J=2.1Hz,1H),6.85(dd,J=8.2,2.0Hz,1H),6.76(d, J=8.1Hz,1H),6.37(d,J=15.7Hz,1H),5.72(s,2H),4.44(d,J=5.6Hz,2H). 13 C NMR (151MHz, DMSO-d6) δ (ppm): 165.82, 147.86, 146.01, 145.84, 141.27, 140.03, 129.17 (d, J = 2.8Hz), 126.7 5,126.14(q,J=3.8Hz),129.04–120.59(m),123.80,120.98,118.55,117.96,116.21,114.24,52.51,34.74. HRMS(m / z):calcd.for C 20 H 18 F3N4O3[M+H] + ,419.13255;found,419.13190.

[0217] Example 49 (E)-3-(3,4-dihydroxyphenyl)-N-((1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-49)

[0218]

[0219] 1 H NMR(500MHz,DMSO-d6)δ(ppm):7.93(t,J=5.6Hz,1H),7.86(s,1H),7.61(s,1H),7.34–7.23(m,3H),7.11(tdd,J=8.2,5.1,1.3Hz,2H),6.94( d,J=1.9Hz,1H),6.93–6.88(m,1H),6.79(d,J=8.3Hz,1H),6.59(d,J=16.1Hz,1H),5.98(s,1H),5.41(d,J=1.0Hz,2H),4.57(d,J=5.5Hz,2H). 13C NMR (101MHz, DMSO-d6) δ (ppm): 167.09, 161.14 (d, J = 252.1Hz), 148.56, 147 .21,141.83,141.04,131.11(d,J=8.1Hz),129.37(d,J=8.1Hz),126.79,12 4.99(d,J=3.1Hz),124.76(d,J=20.0Hz),124.42,122.91,120.27,116.44, 115.44(d,J=19.8Hz),114.97,49.63(d,J=5.0Hz),31.44.HRMS(m / z):Cacld forC 19 H 17 N4O3FNa[M+Na] + :391.11769,found:391.11896.

[0220] Example 50 (E)-3-(3,4-dihydroxyphenyl)-N-((1-(3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-50)

[0221]

[0222] 1 H NMR(500MHz,DMSO-d6)δ(ppm):7.89(t,J=5.6Hz,1H),7.87(s,1H),7.60(s, 1H),7.35–7.25(m,2H),7.14–7.08(m,1H),7.02(tdd,J=8.0,2.1,1.2Hz,2H ),6.94(d,J=1.9Hz,1H),6.92–6.88(m,1H),6.79(d,J=8.3Hz,1H),6.59(d, J=16.1Hz,1H),5.98(s,1H),5.41(t,J=1.0Hz,2H),4.57(d,J=5.5Hz,2H).. 13C NMR (101MHz, DMSO-d6) δ (ppm): 167.09, 162.89 (d, J = 252.1Hz), 148.56, 147 .21,141.73,141.04,138.45(d,J=8.1Hz),129.96(d,J=7.9Hz),126.79,12 4.35(d,J=3.1Hz),124.27,122.91,120.27,116.44,115.90(d,J=19.8Hz), 114.97,113.85(d,J=20.0Hz),52.36(d,J=3.8Hz),31.44.HRMS(m / z):Cacld for C 19 H 17 N4O3FNa[M+Na] + :391.11769,found:391.11879.

[0223] Example 51 (E)-3-(3,4-dihydroxyphenyl)-N-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-51)

[0224]

[0225] mp:147-149℃. 1 H NMR (500MHz, DMSO-d6) δ (ppm): 8.46 (t, J = 5.8 Hz, 1H), 8.02 (s, 1H), 7.45–7.38 (m, 2H), 7.32–7.18 (m, 3H), 6.96 (d, J = 2.1 Hz,1H),6.85(dd,J=8.1,2.0Hz,1H),6.76(d,J=8.1Hz,1H),6.36(d,J=15.7Hz,1H),5.58(s,2H),4.42(d,J=5.7Hz,2H). 13 C NMR (101MHz, DMSO-d6) δ (ppm): 165.79, 162.34 (d, J = 244.4Hz), 147.85, 146.00, 145.73, 140.01, 132.87 (d, J = 3.0Hz), 130 .81(d,J=8.4Hz),126.75,123.40,120.99,118.55,116.18(d,J=5.2Hz),115.94,114.22,52.37,34.73.HRMS(m / z):Cacld forC 19 H 17 N4O3FNa[M+Na] +:391.11769,found:391.11887.

[0226] Example 52 (E)-3-(3,4-dihydroxyphenyl)-N-((1-(2-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-52)

[0227]

[0228] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 8.10–8.04 (m, 1H), 7.96 (t, J = 5.6Hz, 1H), 7. 88–7.80(m,2H),7.60–7.52(m,3H),7.28(dd,J=16.0,0.6Hz,1H),6.94(d,J= 2.0Hz,1H),6.93–6.88(m,1H),6.79(d,J=8.3Hz,1H),6.59(d,J=16.1Hz,1H ),5.98(s,1H),5.63–5.56(m,1H),5.56–5.50(m,1H),4.57(d,J=5.5Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ(ppm):167.09,148.56,147.21,147.15,141.84,141.04,132.72,131.11,130.44 ,128.31,126.79,125.17,124.65,122.91,120.27,116.44,114.97,51.28,31.44.HRMS(m / z):calcd.forC 20 H 17 N5O5[M+H] + :396.1303; found:396.1307.

[0229] Example 53 (E)-3-(3,4-dihydroxyphenyl)-N-((1-(3-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-53)

[0230]

[0231] 1H NMR(600MHz,DMSO-d6)δ(ppm):8.19–8.11(m,2H),7.99(t,J=5.6Hz,1H),7.87(s,1H),7.60(s,1H),7.58–7.50(m,2H),7.28(dd,J=16.0,0.6Hz,1H) ,6.97(d,J=1.9Hz,1H),6.93–6.88(m,1H),6.82(d,J=8.3Hz,1H),6.59(d, J=16.1Hz,1H),5.98(s,1H),5.54(d,J=0.9Hz,2H),4.57(d,J=5.5Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ(ppm):167.09,148.56,148.12,147.21,141.73,141.04,137.37,133.86,129.68 ,126.79,124.27,123.94,122.91,122.41,120.27,116.44,114.97,52.17,31.44.HRMS(m / z):calcd.for C 20 H 17 N5O5[M+H] + :396.1303; found:396.1315.

[0232] Example 54 (E)-3-(3,4-dihydroxyphenyl)-N-((1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-54)

[0233]

[0234] mp:104-106℃。 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.37 (s, 1H), 9.13 (s, 1H), 8.49 (t, J = 5.7Hz, 1H), 8.28–8.22 (m, 2H), 8.10 (s, 1H), 7.57–7.52 (m, 2H), 7.28 (d, J = 15 .6Hz,1H),6.94(d,J=2.1Hz,1H),6.84(dd,J=8.3,2.1Hz,1H),6.75(d,J=8.1Hz,1H),6.36(d,J=15.7Hz,1H),5.76(s,2H),4.43(d,J=5.7Hz,2H). 13C NMR(151MHz,DMSO-d6)δ(ppm):165.82,147.86,147.71,146.01,145.91,144.01,140.04,129.56 ,126.74,124.38,123.94,120.98,118.53,116.21,114.23,52.28,34.74.HRMS(m / z):calcd.for C 20 H 17 N5O5[M+H] + :396.1303; found:396.1301.

[0235] Example 55 (E)-3-(3,4-dihydroxyphenyl)-N-((1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-55)

[0236]

[0237] 1 H NMR(600MHz,DMSO-d6)δ(ppm):8.32(t,J=5.6Hz,1H),7.87(s,1H),7.61(s,1H),7.28(dd,J=16.0,0.6Hz,1H),7.20–7.06(m,4H),6.94(d,J=1.9Hz,1H ),6.92–6.88(m,1H),6.79(d,J=8.3Hz,1H),6.59(d,J=16.1Hz,1H),5.98( s,1H),5.33(d,J=1.0Hz,2H),4.57(d,J=5.5Hz,2H),2.34(d,J=0.7Hz,3H). 13 C NMR(125MHz,DMSO-d6)δ(ppm):167.09,148.56,147.21,141.73,141.04,137.49,136.32,130.33,128.88,12 7.35,126.79,126.47,124.31,122.91,120.27,116.44,114.97,51.21,31.44,19.39.HRMS(m / z):calcd.for C 20 H 20 N4O3[M+H] + :365.16082; found:365.16076.

[0238] Example 56 (E)-3-(3,4-dihydroxyphenyl)-N-((1-(3-methylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-56)

[0239]

[0240] 1 H NMR(600MHz,DMSO-d6)δ(ppm):7.99(t,J=5.6Hz,1H),7.91(s,1H),7.60(s,1H),7.2 8(dd,J=16.0,0.6Hz,1H),7.21–7.14(m,2H),7.09(tt,J=1.6,0.9Hz,1H),7.08–7.04 (m,1H),6.94(d,J=1.9Hz,1H),6.93–6.88(m,1H),6.79(d,J=8.3Hz,1H),6.59(d,J= 16.1Hz,1H),5.98(s,1H),5.33(t,J=0.9Hz,2H),4.57(d,J=5.5Hz,2H),2.32(s,3H). 13 CNMR(125MHz,DMSO-d6)δ(ppm):δ167.09,148.56,147.21,141.76,141.04,138.37,136.45,129.26,128.70,1 28.28,126.79,126.36,124.25,122.91,120.27,116.44,114.97,52.57,31.44,21.32.HRMS(m / z):calcd.for C 20 H 20 N4O3[M+H] + :365.16082; found:365.16087.

[0241] Example 57 (E) -3-(3,4-dihydroxyphenyl)-N-((1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-57)

[0242]

[0243] 1H NMR(600MHz,DMSO-d6)δ(ppm):7.94(t,J=5.6Hz,1H),7.89(s,1H),7.71(s,1H),7 .28(dd,J=16.0,0.6Hz,1H),7.16(dt,J=7.4,1.1Hz,2H),7.09–7.03(m,2H),6.94( d,J=1.9Hz,1H),6.92–6.89(m,1H),6.79(d,J=8.3Hz,1H),6.59(d,J=16.1Hz,1H) ,5.98(s,1H),5.38(t,J=1.0Hz,2H),4.59(d,J=5.5Hz,2H),2.34(d,J=0.9Hz,3H). 13 C NMR(125MHz,DMSO-d6)δ(ppm):167.09,148.56,147.21,141.76,141.04,136.82,133.63,129.45,12 8.71,126.79,124.25,122.91,120.27,116.44,114.97,52.91,31.44,21.04.HRMS(m / z):calcd.forC 20 H 20 N4O3[M+H] + :365.16082; found:365.16077.

[0244] Example 58 (E)-3-(3,4-dihydroxyphenyl)-N-((1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-58)

[0245]

[0246] 1 H NMR (500MHz, DMSO-d6) δ (ppm): 8.29 (t, J = 5.6Hz, 1H), 7.96 (s, 1H), 7.61 (s, 1H) ),7.39–7.33(m,1H),7.28(dd,J=16.0,0.6Hz,1H),7.26–7.18(m,2H),7.12–7. 06(m,1H),6.94(d,J=1.9Hz,1H),6.92–6.88(m,1H),6.79(d,J=8.3Hz,1H),6.5 9(d,J=16.1Hz,1H),5.98(s,1H),5.44(d,J=1.1Hz,2H),4.57(d,J=5.5Hz,2H). 13C NMR (125MHz, DMSO-d6) δ (ppm): δ167.09,148.56,147.21,141.74,141.04,134.32,134.27,130.78,129.5 4,129.24,127.67,126.79,124.38,122.91,120.27,116.44,114.97,51.58,31.44.HRMS(m / z):calcd.for C 19 H 17 ClN4O3[M+H] + :385.10619; found:385.10627.

[0247] Example 59 (E) -3-(3,4-dihydroxyphenyl)-N-((1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-59)

[0248]

[0249] 1 H NMR(500MHz,DMSO-d6)δ(ppm):8.43(t,J=5.6Hz,1H),7.98(s,1H),7.62(s,1H) ,7.31(ddd,J=4.8,3.8,2.0Hz,2H),7.29–7.24(m,2H),7.18(dtd,J=6.8,2.3,1 .0Hz,1H),6.95(d,J=1.9Hz,1H),6.92–6.88(m,1H),6.79(d,J=8.3Hz,1H),6.5 9(d,J=16.1Hz,1H),5.98(s,1H),5.38(t,J=1.0Hz,2H),4.57(d,J=5.5Hz,2H). 13 C NMR(125MHz,DMSO-d6)δ(ppm):167.09,148.56,147.21,141.73,141.04,137.36,134.39,130.12,129.02 ,128.10,127.18,126.79,124.25,122.91,120.27,116.44,114.97,52.21,31.44.HRMS(m / z):calcd.For C 19 H 17 ClN4O3[M+H] + :385.10619; found:385.10625.

[0250] Example 60 (E)-3-(3,4-dihydroxyphenyl)-N-((1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-60)

[0251]

[0252] 1 H NMR (500MHz, DMSO-d6) δ (ppm): 7.95 (t, J = 5.6 Hz, 1H), 7.86 (s, 1H), 7.71 (s, 1H), 7.38–7.32 (m, 2H), 7.32–7.25 (m, 3H), 6.94 (d, J = 1.9 Hz,1H),6.92–6.88(m,1H),6.79(d,J=8.3Hz,1H),6.59(d,J=16.1Hz,1H),5.98(s,1H),5.43(t,J=1.0Hz,2H),4.57(d,J=5.5Hz,2H). 13 C NMR(125MHz,DMSO-d6)δ(ppm):167.09,148.56,147.21,141.76,141.04,134.40,133.82,130.30 ,128.73,126.79,124.25,122.91,120.27,116.44,114.97,53.25,31.44.HRMS(m / z):calcd.For C 19 H 17 ClN4O3[M+H] + :385.10619; found:385.10631.

[0253] Example 61 (E)-3-(3,4-dihydroxyphenyl)-N-((1-(2-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-61)

[0254]

[0255] 1H NMR(500MHz,DMSO-d6)δ(ppm):8.65(t,J=5.6Hz,1H),8.32(s,1H),7.72(s,1H),7.28(dd,J=16.0,0.6Hz,1H),7.22–7.14(m,2H),6.99–6.93( m,2H),6.93–6.88(m,1H),6.85–6.76(m,2H),6.59(d,J=16.1Hz,1H),5.98(s,1H),5.36(d,J=1.1Hz,2H),4.57(d,J=5.5Hz,2H),3.84(s,3H). 13 C NMR(125MHz,DMSO-d6)δ(ppm):167.09,157.74,148.56,147.21,141.83,141.04,130.05,128.27,126.79,12 5.45,124.42,122.91,121.55,120.27,116.44,114.97,111.51,55.59,49.76,31.44.HRMS(m / z):calcd.For C 20 H 20 N4O4[M+H] + :381.15573; found:381.15565.

[0256] Example 62 (E)-3-(3,4-dihydroxyphenyl)-N-((1-(3-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-62)

[0257]

[0258] 1 H NMR(500MHz,DMSO-d6)δ(ppm):8.49(t,J=5.6Hz,1H),8.37(s,1H),7.62(s,1H), 7.29(dd,J=16.0,0.7Hz,1H),7.25–7.20(m,1H),7.02(ddt,J=6.9,2.3,1.1Hz,1 H),6.94(d,J=1.9Hz,1H),6.93–6.88(m,1H),6.84–6.76(m,3H),6.59(d,J=16.1 Hz, 1H), 5.98 (s, 1H), 5.41 (t, J = 1.0Hz, 2H), 4.57 (d, J = 5.5Hz, 2H), 3.81 (s, 3H). 13C NMR(125MHz,DMSO-d6)δ(ppm):167.09,159.81,148.56,147.21,141.73,141.04,137.18,129.71,126.79,12 4.27,122.91,122.02,120.27,116.44,114.97,113.96,113.17,55.14,52.49,31.44.HRMS(m / z):calcd.For C 20 H 20 N4O4[M+H] + :381.15573; found:381.15579.

[0259] Example 63 (E)-3-(3,4-dihydroxyphenyl)-N-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide (I-63)

[0260]

[0261] 1 H NMR(500MHz,DMSO-d6)δ(ppm):8.36(t,J=5.6Hz,1H),8.13(s,1H),7.62(s,1H) ,7.28(dd,J=16.0,0.6Hz,1H),7.22(dt,J=7.5,1.0Hz,2H),6.94(d,J=1.9Hz,1H ),6.93–6.88(m,1H),6.86–6.80(m,2H),6.79(d,J=8.3Hz,1H),6.59(d,J=16.1 Hz,1H),5.98(s,1H),5.38(t,J=1.0Hz,2H),4.57(d,J=5.5Hz,2H),3.78(s,3H). 13 C NMR(125MHz,DMSO-d6)δ(ppm):167.09,159.41,148.56,147.21,141.76,141.04,129.77,129.74,12 6.79,124.25,122.91,120.27,116.44,114.97,113.84,55.32,53.21,31.44.HRMS(m / z):calcd.For C 20 H 20 N4O4[M+H] + :381.15573; found:381.15581.

[0262] Example 64 Methyl (1-benzyl-1H-1,2,3-triazol-4-yl)cinnamate (I-64)

[0263]

[0264] mp:123-125℃. 1 H NMR (500MHz, DMSO-d6) δ (ppm): 8.29 (s, 1H), 7.79–7.65 (m, 3H), 7.50–7.30 (m, 8H), 6.68 (d, J = 16.1Hz, 1H), 5.64 (s, 2H), 5.29 (s, 2H). 13 C NMR(100MHz,DMSO-d6)δ(ppm):166.40,145.54,142.66,136.42,134.39,131.07,129.40 ,129.26,128.91,128.68,128.52,125.43,118.09,57.74,53.31.HRMS(m / z):calcd.for C 19 H 17 N3O2[M+Na] + :342.1213; found:342.1217.

[0265] Example 65 (1-benzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(1-methylphenyl)acrylate (I-65)

[0266]

[0267] 1 H NMR (500MHz, DMSO-d6) δ (ppm): δ7.87 (s, 1H), 7.55 (d, J = 16.1Hz, 1H), 7.51–7.45 (m, 1H), 7.36 –7.23(m,9H),6.31(d,J=16.0Hz,1H),5.45–5.41(m,2H),5.30(s,2H),2.40(d,J=0.7Hz,3H). 13 C NMR(125MHz,DMSO-d6)δ(ppm):167.41,145.94,142.10,137.95,135.07,131.96,130.31,1 29.72,129.00,128.76(d,J=5.3Hz),128.15,127.05,125.42,117.68,53.93,53.51,19.56.

[0268] Example 66 (1-benzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(1-methoxyphenyl)acrylate (I-66)

[0269]

[0270] 1 H NMR (500MHz, DMSO-d6) δ (ppm): 7.87 (s, 1H), 7.78 (dd, J = 16.3, 0.7Hz, 1H), 7.60 (ddd ,J=7.7,1.5,0.7Hz,1H),7.36(td,J=7.9,1.5Hz,1H),7.33(dt,J=6.2,1.1Hz,1H),7 .33–7.27(m,3H),7.30–7.23(m,1H),7.04(td,J=7.7,1.3Hz,1H),6.95(dd,J=8.1,1 .4Hz,1H),6.41(d,J=16.5Hz,1H),5.44(d,J=1.0Hz,2H),5.30(s,2H),3.87(s,3H). 13 CNMR(125MHz,DMSO-d6)δ(ppm):167.11,158.24,145.94,139.74,131.96,131.30,129.99 ,128.78,128.73,128.15,126.99,125.42,121.78,117.87,114.58,55.51,53.93,53.51.

[0271] Example 67 (1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) cinnamic acid methyl ester (I-67)

[0272]

[0273] mp:80-82℃. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.25 (s, 1H), 7.75–7.65 (m, 3H), 7.48–7.35 (m, 5H) ),7.29–7.21(m,2H),6.67(d,J=16.0Hz,1H),5.69(d,J=1.0Hz,2H),5.27(s,2H). 13C NMR (101MHz, DMSO-d6) δ (ppm): 166.40, 160.59 (d, J=246.8Hz), 145.54, 142.57, 134.39, 131.39–131.21 (m), 131.07, 129.39, 129.27 (d, J= 160.6Hz),128.92,125.60,125.35(d,J=3.6Hz),123.23(d,J=14.9Hz),118.09,116.23,57.68,47.38(d,J=3.8Hz).HRMS(m / z):calcd.for C 19 H 16 FN3O2[M+Na] + :338.1299;found:338.1295.

[0274] Example 68 Methyl (1-(3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)cinnamate (I-68)

[0275]

[0276] mp:194-196℃. 1 H NMR(500MHz,DMSO-d6)δ(ppm):8.33(s,1H),7.76–7.69(m,3H),7.47–7.42(m,4H),7 .21(dd,J=12.1,8.6Hz,3H),6.69(dd,J=16.1,2.3Hz,1H),5.67(s,2H),5.30(s,2H). 13 C NMR (101MHz, DMSO-d6) δ (ppm): 166.40, 162.60 (d, J = 244.3Hz), 145.56, 142.74, 139.07 (d, J = 7.7Hz), 134.39, 131.37 (d, J = 8.3Hz), 131.08,129.40,128.92,125.60,124.61(d,J=2.9Hz),118.08,115.57(d,J=16.0Hz),115.36(d,J=17.2Hz).HRMS(m / z):calcd.for C 19 H 16 FN3O2[M+H] + :360.1119;found:360.1110.

[0277] Example 69 Methyl (1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)cinnamate (I-69)

[0278]

[0279] mp:167-169℃. 1 H NMR (500MHz, DMSO-d6) δ (ppm): 8.30 (s, 1H), 7.78–7.67 (m, 3H), 7.45 (t, J = 4.7Hz, 5 H),7.25(t,J=6.8Hz,2H),6.68(dd,J=16.1,4.3Hz,1H),5.64(s,2H),5.29(s,2H). 13 C NMR (101MHz, DMSO-d6) δ (ppm): 166.40, 162.39 (d, J = 244.4Hz), 145.55, 142.69, 134.37, 132.67 (d, J = 3.2Hz), 131.0 8,130.87(d,J=8.4Hz),129.40,128.91,125.36,118.07,116.10(d,J=21.6Hz),57.72,52.50.HRMS(m / z):calcd.for C 19 H 16 FN3O2[M+Na] + :360.1119;found:360.1113.

[0280] Example 70 Methyl (1-(2-nitrobenzyl)-1H-1,2,3-triazol-4-yl)cinnamate (I-70)

[0281]

[0282] mp:108-110℃. 1 H NMR (500MHz, DMSO-d6) δ (ppm): 8.29 (s, 1H), 8.17 (d, J = 8.2Hz, 1H), 7.80–7.65 (m, 5H), 7.45 (d d,J=5.2,1.9Hz,3H),7.13(d,J=7.8Hz,1H),6.70(d,J=16.0Hz,1H),6.01(s,2H),5.32(s,2H). 13C NMR(101MHz,DMSO-d6)δ(ppm):166.40,148.09,145.58,142.69,134.87,134.38,131.17,131.09 ,130.66,130.19,129.41,128.92,126.26,125.58,118.07,57.69,50.42.HRMS(m / z):calcd.for C 19 H 16 N4O4[M+Na] + :387.1064;found:387.1061.

[0283] Example 71 Methyl (1-(3-nitrobenzyl)-1H-1,2,3-triazol-4-yl)cinnamate (I-71)

[0284]

[0285] mp:97-99℃. 1 H NMR (500MHz, DMSO-d6) δ (ppm): 8.39 (s, 1H), 8.31–8.20 (m, 2H), 7.82 (d, J = 7.7Hz, 1H), 7.76– 7.68(m,4H),7.45(dd,J=5.3,2.0Hz,3H),6.69(d,J=16.0Hz,1H),5.83(s,2H),5.31(s,2H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):166.39,148.36,145.58,142.82,138.47,135.31,134.37,131.09 ,130.94,129.40,128.90,125.77,123.68,123.39,118.05,57.69,52.25.HRMS(m / z):calcd.for C 19 H 16 N4O4[M+Na] + :387.1064;found:387.1057.

[0286] Example 72 Methyl (1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)cinnamate (I-72)

[0287]

[0288] mp:113-115℃. 1H NMR (500MHz, DMSO-d6) δ (ppm): 8.37 (s, 1H), 8.27 (d, J = 8.6Hz, 2H), 7.78–7.68 (m, 3H), 7.58 (d ,J=8.4Hz,2H),7.45(dd,J=5.1,1.9Hz,3H),6.69(d,J=16.0Hz,1H),5.83(s,2H),5.31(s,2H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):166.40,147.75,145.59,143.78,142.84,134.36,131.10 ,129.61,129.41,128.91,125.90,124.42,118.05,57.69,52.40.HRMS(m / z):calcd.for C 19 H 16 N4O4[M+Na] + :387.1064; found:387.1068.

[0289] Example 73 Methyl (1-(2-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)cinnamate (I-73)

[0290]

[0291] mp:94-96℃. 1 H NMR(500MHz,DMSO-d6)δ(ppm):8.27(d,J=3.2Hz,1H),7.83(d,J=7.9Hz,1H),7.77–7.68(m,4H),7.61(t,J=7.9Hz,1H),7.4 4(h,J=5.0,3.8Hz,3H),7.23(d,J=7.8Hz,1H),6.68(dd,J=16.1,3.2Hz,1H),5.84(d,J=3.2Hz,2H),5.31(d,J=3.1Hz,2H). 13 C NMR (101MHz, DMSO-d6) δ (ppm): 166.40, 145.57, 142.66, 134.37, 134.01 (d, J = 1.8Hz), 133.67, 131.09, 130.86, 129.45, 1 29.41,128.91,127.58–126.62(m),126.72(q,J=5.5Hz),126.09,124.60(q,J=274.0Hz),118.06.HRMS(m / z):calcd.for C 20 H16 F3N3O2[M+Na] + :410.1087; found:410.1083.

[0292] Example 74 Methyl (1-(3-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)cinnamate (I-74)

[0293]

[0294] mp:103-105℃. 1 H NMR (500MHz, DMSO-d6) δ (ppm): 8.35 (s, 1H), 7.77 (s, 1H), 7.76–7.67 (m, 4H), 7.65 (dd, J = 4.1 ,1.9Hz,2H),7.44(dd,J=5.2,2.0Hz,3H),6.67(d,J=16.0Hz,1H),5.76(s,2H),5.29(s,2H). 13 C NMR(101MHz,Chloroform-d)δ(ppm):171.17,150.34,147.56,142.55,139.13,137.52,135.86,135.21–134.31(m),134.18 ,133.67,130.59,130.45,130.26(q,J=3.7Hz),129.98(q,J=3.8Hz),127.89,122.82,62.46,57.34.HRMS(m / z):calcd.for C 20 H 16 F3N3O2[M+Na] + :410.1087;found:410.1085.

[0295] Example 75 Methyl (1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)cinnamate (I-75)

[0296]

[0297] mp:177-179℃. 1 H NMR (500MHz, DMSO-d6) δ (ppm): 8.36 (s, 1H), 7.80 (d, J = 8.0Hz, 2H), 7.77–7.68 (m, 3H), 7. 56(d,J=8.0Hz,2H),7.48–7.42(m,3H),6.69(d,J=16.0Hz,1H),5.78(s,2H),5.31(s,2H).13 C NMR (101MHz, DMSO-d6) δ (ppm): 166.40, 145.58, 142.79, 141.06, 134.37, 131.09, 129.40, 129.21, 129.19 (d, J = 31. 8Hz),128.91,126.20(q,J=3.8Hz),125.76,124.56(d,J=272.3Hz),118.07,57.70,52.23.HRMS(m / z):calcd.forC 20 H 16 F3N3O2[M+Na] + :410.1087; found:410.1082.

[0298] Example 76 Methyl (1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl)cinnamate (I-76)

[0299]

[0300] mp:103-105℃. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.60 (t, J=5.6Hz, 1H), 7.93 (s, 1H), 7.59–7.51 (m, 2H), 7.48–7.36 (m, 4H), 7.27–7 .16(m,3H),7.11(dd,J=7.3,1.4Hz,1H),6.66(d,J=15.8Hz,1H),5.59(s,2H),4.44(d,J=5.6Hz,2H),2.32(s,3H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):165.29,145.33,139.45,136.80,135.30,134.69,130.88,129.96,12 9.41,129.20,128.78,127.99,126.71,123.51,122.35,51.32,34.81,19.14.HRMS(m / z):calcd.for C 20 H 19 N3O2[M+H] + :334.1550; found:334.1538.

[0301] Example 77 Methyl (1-(3-methylbenzyl)-1H-1,2,3-triazol-4-yl)cinnamate (I-77)

[0302]

[0303]

[0304] mp:96-98℃. 1 H NMR (500MHz, DMSO-d6) δ (ppm): 8.27 (s, 1H), 7.78–7.67 (m, 3H), 7.45 (dd, J = 5.2, 1.8Hz, 3H), 7.29 (t, J = 7 .5Hz,1H),7.17(dd,J=15.4,6.2Hz,3H),6.68(d,J=16.0Hz,1H),5.59(s,2H),5.29(s,2H),2.31(s,3H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):166.40,145.54,142.62,138.50,136.30,134.38,131.07,129.40,12 9.31,129.18,129.11,128.91,125.65,125.39,118.09,57.74,53.32,21.39.HRMS(m / z):calcd.forC 20 H 19 N3O2[M+H] + :334.1550; found:334.1544.

[0305] Example 78 Methyl (1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl)cinnamate (I-78)

[0306]

[0307] mp:108-110℃. 1 H NMR (500MHz, DMSO-d6) δ (ppm): 8.24 (s, 1H), 7.77–7.67 (m, 3H), 7.45 (dd, J = 5.2, 1.9Hz, 3H), 7.27 (d, J=7.8Hz,2H),7.21(d,J=7.8Hz,2H),6.68(d,J=16.0Hz,1H),5.58(s,2H),5.28(s,2H),2.31(s,3H). 13C NMR(101MHz,DMSO-d6)δ(ppm):166.40,145.53,142.61,138.04,134.38,133.41,131.07,12 9.78,129.40,128.91,128.58,125.26,118.09,57.73,53.12,21.16.HRMS(m / z):calcd.for C 20 H 19 N3O2[M+Na] + :356.1370; found:356.1364.

[0308] Example 79 Methyl (1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-yl)cinnamate (I-79)

[0309]

[0310] mp:88-90℃. 1 H NMR (500MHz, DMSO-d6) δ (ppm): 8.25 (s, 1H), 7.75–7.68 (m, 3H), 7.55 (dd, J = 7.6, 1.7Hz, 1H), 7. 45–7.37(m,5H),7.28(dd,J=7.3,2.1Hz,1H),6.68(d,J=16.0Hz,1H),5.75(s,2H),5.29(s,2H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):166.41,145.56,142.51,134.38,133.63,133.14,131.10,131.08 ,130.80,130.13,129.41,128.91,128.25,125.84,118.08,57.68,51.09.HRMS(m / z):calcd.for C 19 H 16 ClN3O2[M+H] + :354.1004; found:354.1003.

[0311] Example 80 Methyl (1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)cinnamate (I-80)

[0312]

[0313] mp:97-99℃. 1H NMR (500MHz, DMSO-d6) δ (ppm): 8.34 (s, 1H), 7.79–7.66 (m, 3H), 7.45 (t, J = 4.7H z, 6H), 7.33 (t, J = 4.4Hz, 1H), 6.69 (d, J = 16.0Hz, 1H), 5.67 (s, 2H), 5.30 (s, 2H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):166.40,145.56,142.75,138.78,134.38,133.76,131.22,131.08 ,129.40,128.91,128.68,128.43,127.26,125.62,118.08,57.72,52.52.HRMS(m / z):calcd.for C 19 H 16 N3ClNa[M+Na] + :376.08233; found:376.08334.

[0314] Example 81 Methyl (1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)cinnamate (I-81)

[0315]

[0316] mp:166-168℃. 1 H NMR(500MHz,DMSO-d6)δ(ppm):8.30(s,1H),7.77–7.67(m,3H),7.50–7.43(m, 5H),7.39(d,J=8.1Hz,2H),6.68(d,J=16.0Hz,1H),5.65(s,2H),5.29(s,2H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):166.40,145.56,142.71,135.40,134.38,133.40,131.08 ,130.48,129.40,129.27,128.91,125.50,118.07,57.71,52.49.HRMS(m / z):calcd.for C 19 H 16 ClN3O2[M+Na] + :376.0823; found:376.0813.

[0317] Example 82 Methyl (1-(2-methoxybenzyl)-1H-1,2,3-triazol-4-yl)cinnamate (I-82)

[0318]

[0319] 1 H NMR (500MHz, DMSO-d6) δ (ppm): 8.06 (s, 1H), 7.64–7.54 (m, 3H), 7.41–7.30 (m, 3H), 7.22–7.14 (m, 2H), 6.96 (ddd, J=7.7 ,7.0,1.0Hz,1H),6.82(dd,J=7.5,1.0Hz,1H),6.41(d,J=15.9Hz,1H),5.34(d,J=0.9Hz,2H),5.30(s,2H),3.84(s,3H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):167.35,157.74,145.89,145.41,134.51,130.15,130.05,128.94,12 8.63,128.27,125.44,122.01,121.55,116.70,111.51,55.59,53.51,49.76.HRMS(m / z):calcd.for C 20 H 19 N3O3[M+Na] + :372.13186; found:372.13269.

[0320] Example 83 Methyl (1-(3-methoxybenzyl)-1H-1,2,3-triazol-4-yl)cinnamate (I-83)

[0321]

[0322] mp:93-88℃. 1 H NMR(500MHz,DMSO-d6)δ(ppm):8.30(d,J=7.1Hz,1H),7.73(dt,J=23.1,6.6Hz,3H),7.46(d,J=6.6Hz,3H),7.34(t,J=7.9Hz ,1H),7.02–6.88(m,3H),6.70(dd,J=15.9,6.4Hz,1H),5.61(d,J=5.7Hz,2H),5.30(d,J=5.8Hz,2H),3.77(d,J=5.7Hz,3H). 13C NMR(101MHz,DMSO-d6)δ(ppm):166.40,159.91,145.54,142.65,137.84,134.38,131.07 ,130.43,129.40,128.91,125.46,120.58,118.09,114.31,113.97,57.74,55.57,53.23. HRMS(m / z):calcd.for C 20 H 19 N3O3[M+Na] + :372.13186; found:372.13297.

[0323] Example 84 Methyl (1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)cinnamate (I-84)

[0324]

[0325] mp:95-97℃. 1 H NMR(500MHz,DMSO-d6)δ(ppm):8.22(d,J=2.5Hz,1H),7.75–7.67(m,3H),7.46–7.40(m,3H),7.34(dd,J=8.7,2.4Hz,2H ), 6.95 (dd, J = 8.7, 2.4Hz, 2H), 6.66 (dd, J = 16.0, 2.4Hz, 1H), 5.54 (d, J = 2.4Hz, 2H), 5.27 (d, J = 2.4Hz, 2H), 3.75 (s, 3H). 13 CNMR(101MHz,Chloroform-d)δ(ppm):171.18,164.42,150.31,147.37,139.13,135.86,134.97 ,134.18,133.67,133.08,129.86,122.84,119.38,62.50,60.38,57.64.HRMS(m / z):calcd.for C 20 H 19 N3O3[M+Na] + :372.1319; found:372.1319.

[0326] Example 85 Methyl (1-(3,5-dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)cinnamate (I-85)

[0327]

[0328] mp:130-132℃. 1 H NMR (500MHz, DMSO-d6) δ (ppm): 8.29 (s, 1H), 7.77–7.66 (m, 3H), 7.44 (dt, J = 5.9, 2.8Hz, 3H), 6.6 9(dd,J=16.1,1.9Hz,1H),6.51(dd,J=13.6,2.2Hz,3H),5.55(s,2H),5.29(s,2H),3.75(s,6H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):166.40,161.16,145.54,142.64,138.49,134.38,131.07, 129.40,128.91,125.50,118.09,106.62,100.08,57.74,55.71,53.30.HRMS(m / z):Cacld for C 21 H 21 N3O4Na[M+Na] + :402.14243,found:402.14383.

[0329] Example 86 Methyl (1-(2,3-dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)cinnamate (I-86)

[0330]

[0331] 1 H NMR(500MHz, DMSO-d6)δ(ppm):8.27(s,1H),7.70(dd,J=15.9,0.8Hz,1H),7.57(ddd,J=6.9,1.5,0.7Hz,2H),7.42–7.30(m,3H),6.95(dq,J=7.1,1.0 Hz,1H),6.87(dd,J=8.1,7.0Hz,1H),6.80(dd,J=8.2,1.3Hz,1H),6.41(d, J=15.9Hz,1H),5.33(d,J=1.1Hz,2H),5.30(s,2H),3.84(d,J=9.2Hz,6H). 13C NMR(101MHz,DMSO-d6)δ(ppm):167.35,151.27,148.57,145.89,145.41,134.51,130.15,128.94,128 .63,127.86,123.62,122.84,122.01,116.70,111.71,60.66,55.78,53.51,49.69.HRMS(m / z):Cacld for C 21 H 21 N3O4Na[M+Na] + :402.14243,found:402.14345.

[0332] Example 87 Methyl (1-(3,4-dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)cinnamate (I-87)

[0333]

[0334] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.16 (s, 1H), 7.61 (dd, J=15.9, 0.9Hz, 1H), 7.59 (ddd, J=6.9, 1.5, 0.7Hz, 2H), 7.41–7.27 (m, 3H), 6.85 (p, J = 0.9Hz, 1H), 6.80 (s, 2H), 6.41 (d, J = 15.9Hz, 1H), 5.42 (t, J = 0.9Hz, 2H), 5.30 (s, 2H), 3.82 (d, J = 4.0Hz, 6H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):167.35,149.12,148.51,145.96,145.41,134.51,130.61,130.15,128 .94,128.63,125.43,122.71,116.70,112.81,112.47,55.88,55.80,53.51,52.48.HRMS(m / z):Cacld for C 21 H 21 N3O4Na[M+Na] + :402.14243,found:402.14367.

[0335] Example 88 Methyl (1-(2-tert-butylbenzyl)-1H-1,2,3-triazol-4-yl)cinnamate (I-88)

[0336]

[0337] 1 H NMR (400MHz, DMSO-d6) δ (ppm): δ8.30 (s, 1H), 7.66–7.53 (m, 3H), 7.42–7.31 (m, 3H), 7.29–7.24 (m ,1H),7.22–7.15(m,3H),6.41(d,J=15.9Hz,1H),5.33(d,J=0.9Hz,2H),5.30(s,2H),1.28(s,9H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):167.35,149.73,145.96,145.41,134.51,133.92,130.15,129.81,128 .94,128.63,127.23,125.85,125.03,121.91,116.70,53.51,51.18,36.93,30.25.HRMS(m / z):Cacld for C 23 H 25 O2N3Na[M+Na] + :398.18399,found:398.18549.

[0338] Example 89 Methyl (1-(3-tert-butylbenzyl)-1H-1,2,3-triazol-4-yl)cinnamate (I-89)

[0339]

[0340] 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.23(s,1H),7.64–7.52(m,3H),7.44–7.26(m,5H),7.26 –7.16(m,2H),6.41(d,J=15.9Hz,1H),5.39(t,J=1.0Hz,2H),5.30(s,2H),1.32(s,9H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):167.35,150.71,145.94,145.41,136.54,134.51,130.15,128.94,128 .89,128.88,128.63,126.37,125.42,123.99,116.70,53.51,52.71,34.56,31.23.HRMS(m / z):Cacld for C 23 H 25 O2N3Na[M+Na]+ :398.18399,found:398.18557.

[0341] Example 90 Methyl (1-(4-tert-butylbenzyl)-1H-1,2,3-triazol-4-yl)cinnamate (I-90)

[0342]

[0343] mp:147-149℃. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.25(s,1H),7.74–7.65(m,3H),7.45–7.36(m,5H), 7.30–7.26(m,2H),6.66(d,J=16.0Hz,1H),5.57(s,2H),5.26(s,2H),1.26(s,9H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):166.40,151.17,145.53,142.62,134.39,133.48,131.07,129 .39,128.91,128.34,126.02,125.32,118.11,57.74,53.01,34.77,31.51.HRMS(m / z):Cacld for C 23 H 25 O2N3Na[M+Na] + :398.18399,found:398.18561.

[0344] Example 91 (1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (I-91)

[0345]

[0346] mp:87-89℃. 1 H NMR (500MHz, DMSO-d6) δ (ppm): 8.15 (s, 1H), 7.58 (d, J=

[0347] 15.9Hz,1H),7.33(d,J=1.9Hz,1H),7.30–7.17(m,4H),7.16–7.09(m,2H),6.79(dd,J=14. 7,8.2Hz,1H),6.50(d,J=16.0Hz,1H),5.64(s,2H),5.25(s,2H),3.82(s,3H),2.34(s,3H).13 C NMR(101MHz,DMSO-d6)δ(ppm):166.82,149.93,148.40,146.06,142.71,136.82,134.56,130.92,129.22,128.8 5,126.76,125.97,125.38,123.79,115.94,114.45,111.68,57.45,56.15,51.40,19.13.HRMS(m / z):calcd.for C 21 H 21 N3O4[M+Na] + 402.14243; found,402.14237

[0348] Example 92 (1-(3-methylbenzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (I-92)

[0349]

[0350] 1 H NMR(500MHz,DMSO-d6)δ(ppm):7.91(s,1H),7.53(d,J=15.9Hz,1H),7.24(s,1H),7.20–7.16(m,2H),7.13(d,J=2.0Hz,1H),7.09(dp,J=2.5,0.9Hz,1H ),7.08–7.04(m,1H),7.02–6.97(m,1H),6.86(d,J=8.2Hz,1H),6.43(d,J= 16.1Hz,1H),5.33(t,J=0.8Hz,2H),5.30(s,2H),3.83(s,3H),2.32(s,2H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):167.25,149.45,148.99,146.39,145.94,138.37,136.45,129.26,128.70,128.2 8,127.95,126.37,125.42,124.05,115.79,115.77,112.26,56.21,53.51,52.57,21.32.HRMS(m / z):calcd.for C 21 H 21 N3O4[M+Na] + 402.14243; found,402.14241

[0351] Example 93 (1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (I-93)

[0352]

[0353] 1 H NMR (500MHz, DMSO-d6) δ (ppm): 8.01 (s, 1H), 7.58 (d, J = 16.1Hz, 1H), 7.24 (s, 1H), 7.19–7.11 (m, 3H), 7.09–7.03 (m, 2H), 7.0 3–6.97(m,1H),6.86(d,J=8.2Hz,1H),6.43(d,J=16.1Hz,1H),5.41(t,J=1.0Hz,2H),5.30(s,2H),3.83(s,3H),2.34(s,3H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):167.25,149.45,148.99,146.39,145.94,136.82,133.63,129.45,128.7 1,127.95,125.42,124.05,115.79,115.77,112.26,56.21,53.51,53.07,21.04.HRMS(m / z):calcd.for C 21 H 21 N3O4[M+Na] + 402.14243; found, 402.14235.

[0354] Example 94 (1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (I-94)

[0355]

[0356] 1 H NMR (500MHz, DMSO-d6) δ (ppm): 7.86 (s, 1H), 7.56 (d, J = 16.0Hz, 1H), 7.34–7.22 (m, 3H), 7.15–7.07 (m, 3H), 7.0 3–6.97(m,1H),6.86(d,J=8.2Hz,1H),6.43(d,J=16.1Hz,1H),5.40(d,J=1.1Hz,2H),5.30(s,2H),3.83(s,3H). 13C NMR (101MHz, DMSO-d6) δ (ppm): 167.25, 161.14 (d, J = 252.1Hz), 149.45, 148.9 9,146.39,145.89,131.14(d,J=7.9Hz),129.37(d,J=8.1Hz),127.95,124.99( d,J=3.1Hz),124.69(d,J=20.0Hz),124.05,122.01,115.79,115.77,115.44(d ,J=19.8Hz),112.26,56.21,53.51,49.64(d,J=5.0Hz).HRMS(m / z):calcd.for C 20 H 18 FN3O4[M+Na] + :406.11736; found:406.11732.

[0357] Example 95 (1-(3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (I-95)

[0358]

[0359] 1 H NMR (500MHz, DMSO-d6) δ (ppm): 7.91 (s, 1H), 7.66 (d, J = 16.0Hz, 1H), 7.35–7.26 (m, 1H), 7.24 (s, 1H), 7.15–7.08 (m, 2H), 7.06–7 .02(m,1H),7.02–6.97(m,2H),6.86(d,J=8.2Hz,1H),6.43(d,J=16.1Hz,1H),5.40(t,J=1.0Hz,2H),5.30(s,2H),3.83(s,3H). 13 CNMR (101MHz, DMSO-d6) δ (ppm): 167.25, 162.89 (d, J = 252.1Hz), 149.45, 14 8.99,146.39,145.96,138.45(d,J=8.1Hz),129.96(d,J=7.9Hz),127.95,1 25.43,124.37(d,J=3.1Hz),124.05,115.98,115.79,115.77,113.85(d,J= 20.0Hz),112.26,56.21,53.51,52.36(d,J=3.8Hz).HRMS(m / z):calcd.for C20 H 18 FN3O4[M+Na] + :406.11736; found:406.11734.

[0360] Example 96 (1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (I-96)

[0361]

[0362] 1 H NMR (500MHz, DMSO-d6) δ (ppm): 7.81 (s, 1H), 7.59 (d, J = 16.0Hz, 1H), 7.30 (ddt, J = 7.2, 5.0, 1.0Hz, 2H), 7.24 (s, 1H), 7.13 (d, J = 2.0Hz, 1H ),7.12–7.04(m,2H),7.03–6.97(m,1H),6.86(d,J=8.2Hz,1H),6.43(d,J=16.1Hz,1H),5.38(t,J=1.0Hz,2H),5.30(s,2H),3.83(s,3H). 13 C NMR (101MHz, DMSO-d6) δ (ppm): 167.25, 162.05 (d, J = 252.1Hz), 149.45, 148.99, 146.39, 145.94, 132.29 (d, J = 3.1Hz), 130. 56,130.49,127.95,125.42,124.05,115.79,115.77,115.43,115.27,112.26,56.21,53.51,52.90.HRMS(m / z):calcd.for C 20 H 18 FN3O4[M+Na] + :406.11736; found:406.11728.

[0363] Example 97 (1-(2-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (I-97)

[0364]

[0365] 1H NMR (500MHz, DMSO-d6) δ (ppm): 8.10–8.04 (m, 1H), 7.88 (s, 1H), 7.86–7.81 (m, 1H), 7.60–7.52 (m, 3H), 7.24 (s, 1H), 7.13 (d, J= 2.0Hz,1H),7.03–6.97(m,1H),6.86(d,J=8.2Hz,1H),6.43(d,J=16.1Hz,1H),5.54(d,J=1.1Hz,2H),5.30(s,2H),3.83(s,3H). 13 CNMR(101MHz,DMSO-d6)δ(ppm):167.25,149.45,148.99,147.15,146.39,145.86,132.72,131.11,130.44,1 28.31,127.95,125.17,124.05,122.06,115.79,115.77,112.26,56.21,53.49,51.28.HRMS(m / z):calcd.for C 20 H 18 N4O6[M+H] + :411.12991; found:411.12987.

[0366] Example 98 (1-(3-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (I-98)

[0367]

[0368] 1 H NMR(500MHz,DMSO-d6)δ(ppm):8.19–8.11(m,2H),7.87(s,1H),7.60–7.50(m,3H),7.24(s,1H),7.13(d,J=2.0Hz,1H ),7.03–6.97(m,1H),6.86(d,J=8.2Hz,1H),6.43(d,J=16.1Hz,1H),5.54(d,J=1.0Hz,2H),5.30(s,2H),3.83(s,3H). 13C NMR(101MHz,DMSO-d6)δ(ppm):167.25,149.45,148.99,148.12,146.39,145.96,137.29,133.86,129.68,12 7.95,125.45,124.05,123.94,122.41,115.79,115.77,112.26,56.21,53.51,52.33.HRMS(m / z):calcd.for C 20 H 18 N4O6[M+H] + :411.12991; found:411.12993.

[0369] Example 99 (1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (I-99)

[0370]

[0371] 1 H NMR(500MHz,DMSO-d6)δ(ppm):8.21–8.13(m,2H),7.89(s,1H),7.56(d,J=15.9Hz,1H),7.46(dt,J=7.4,1.0Hz,2H),7.24(s,1H),7.1 3(d,J=2.0Hz,1H),7.03–6.97(m,1H),6.86(d,J=8.2Hz,1H),6.43(d,J=16.1Hz,1H),5.52(t,J=1.0Hz,2H),5.30(s,2H),3.83(s,3H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):167.25,149.45,148.99,146.92,146.39,145.94,140.49,129.35,12 7.95,125.42,124.05,123.70,115.79,115.77,112.26,56.21,53.51,53.06.HRMS(m / z):calcd.for C 20 H 18 N4O6[M+H] + :411.12991; found:411.12981.

[0372] Example 100 (1-(2-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (I-100)

[0373]

[0374] 1 H NMR (500MHz, DMSO-d6) δ (ppm): 7.94 (s, 1H), 7.60–7.52 (m, 2H), 7.44 (ddd, J = 10.6, 6.7, 2.0Hz, 1H), 7.32–7.26 (m, 2H), 7.24 (s, 1H), 7. 13(d,J=2.0Hz,1H),7.03–6.97(m,1H),6.86(d,J=8.2Hz,1H),6.43(d,J=16.1Hz,1H),5.59(d,J=0.9Hz,2H),5.30(s,2H),3.83(s,3H). 13 C NMR (101MHz, DMSO-d6) δ (ppm): 167.25, 149.45, 148.99, 145.96, 132.63 (q, J = 4.0Hz), 130.06 (q, J = 2.0Hz), 127.95, 127.27 ( d,J=2.2Hz),126.35(q,J=3.9Hz),125.65,124.05,122.05,112.26,56.21,53.51,50.80(d,J=1.9Hz).HRMS(m / z):calcd.for C 21 H 18 F3N3O4[M+H] + :434.13222; found:434.13216.

[0375] Example 101 (1-(3-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (I-101)

[0376]

[0377] 1H NMR(500MHz,DMSO-d6)δ(ppm):7.87(s,1H),7.62–7.50(m,3H),7.48–7.41(m,2H),7.24(s,1H),7.13(d,J=2.0Hz,1H ),7.03–6.97(m,1H),6.86(d,J=8.2Hz,1H),6.43(d,J=16.1Hz,1H),5.41(t,J=0.9Hz,2H),5.30(s,2H),3.83(s,3H). 13 C NMR (101MHz, DMSO-d6) δ (ppm): 167.25, 149.45, 148.99, 146.39, 145.94, 136.70 (d, J=2.1Hz), 131.11 (q, J=32.1Hz), 129.42, 129.03 (q, J= 2.0Hz),126.77(q,J=3.9Hz),125.42,124.05,123.63(q,J=3.9Hz),115.79,115.77,112.26,56.21,53.51,52.55.HRMS(m / z):calcd.forC 21 H 18 F3N3O4[M+H] + :434.13222; found:434.13214.

[0378] Example 102 (1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (I-102)

[0379]

[0380] 1 H NMR (500MHz, DMSO-d6) δ (ppm): 7.91 (s, 1H), 7.60–7.53 (m, 2H), 7.52 (d, J = 1.2Hz, 1H), 7.33 (dt, J = 6.3, 1.0Hz, 2H), 7.24 (s, 1H), 7.13 (d,J=2.0Hz,1H),7.03–6.97(m,1H),6.86(d,J=8.2Hz,1H),6.43(d,J=16.1Hz,1H),5.42(t,J=1.0Hz,2H),5.30(s,2H),3.83(s,3H). 13C NMR (101MHz, DMSO-d6) δ (ppm): 167.25, 149.22 (d, J = 58.2Hz), 146.39, 145.94, 135.96, 129.68, 129.66, 129.28 (d, J = 32. 0Hz),127.95,126.10(q,J=3.9Hz),125.42,124.05,115.79,115.77,112.26,56.21,53.62,53.51.HRMS(m / z):calcd.for C 21 H 18 F3N3O4[M+H] + :434.13222; found:434.13218.

[0381] Example 103 (1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (I-103)

[0382]

[0383] 1 H NMR (500MHz, DMSO-d6) δ (ppm): 7.98 (s, 1H), 7.59 (d, J = 16.0Hz, 1H), 7.39–7.33 (m, 1H), 7.26–7.18 (m, 3H), 7.13 (d, J = 2.0Hz, 1H), 7. 11–7.06(m,1H),7.03–6.97(m,1H),6.86(d,J=8.2Hz,1H),6.43(d,J=16.1Hz,1H),5.43(d,J=1.1Hz,2H),5.30(s,2H),3.83(s,3H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):167.25,149.45,148.99,146.39,145.96,134.29,134.27,130.80,129.54,12 9.24,127.95,127.67,124.05,122.06,115.79,115.77,112.26,56.21,53.51,51.60.HRMS(m / z):calcd.for C 20 H 18 ClN3O4[M+H] + :400.10586; found:400.10584.

[0384] Example 104 (1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (I-104)

[0385]

[0386] 1 H NMR (500MHz, DMSO-d6) δ (ppm): 7.95 (s, 1H), 7.58 (d, J=16.0Hz, 1H), 7.34–7.26 (m, 3H), 7.24 (s, 1H), 7.18 (ddt, J=5.8, 2.4, 1.1Hz, 1H), 7 .13(d,J=2.0Hz,1H),7.03–6.97(m,1H),6.86(d,J=8.2Hz,1H),6.43(d,J=16.1Hz,1H),5.40(d,J=1.1Hz,2H),5.30(s,2H),3.83(s,3H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):167.25,149.45,148.99,146.39,145.96,137.36,134.39,130.12,129.02,12 8.10,127.95,127.19,125.42,124.05,115.79,115.77,112.26,56.21,53.51,52.21.HRMS(m / z):calcd.for C 20 H 18 ClN3O4[M+H] + :400.10586; found:400.10578.

[0387] Example 105 (1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (I-105)

[0388]

[0389] 1H NMR (500MHz, DMSO-d6) δ (ppm): 7.83 (s, 1H), 7.62 (d, J=16.0Hz, 1H), 7.38–7.32 (m, 2H), 7.31–7.26 (m, 2H), 7.24 (s, 1H), 7.13 (d, J=2.0Hz,1H),7.03–6.97(m,1H),6.86(d,J=8.2Hz,1H),6.43(d,J=16.1Hz,1H),5.38(t,J=1.0Hz,2H),5.30(s,2H),3.83(s,3H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):167.25,149.45,148.99,146.39,145.94,134.48,133.82,130.33,12 8.73,127.95,125.42,124.05,115.79,115.77,112.26,56.21,53.51,53.24.HRMS(m / z):calcd.for C 20 H 18 ClN3O4[M+H] + :400.10586; found:400.10580.

[0390] Example 106 (1-(2-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (I-106)

[0391]

[0392] 1 H NMR(500MHz,DMSO-d6)δ(ppm):7.86(s,1H),7.51(d,J=16.0Hz,1H),7.26–7.11(m,4H),7.03–6.93(m,2H) ,6.89–6.80(m,2H),6.43(d,J=16.1Hz,1H),5.34(d,J=0.9Hz,2H),5.30(s,2H),3.84(s,3H),3.83(s,3H). 13C NMR(101MHz,DMSO-d6)δ(ppm):167.25,157.74,149.45,148.99,146.39,145.89,130.05,128.27,127.95,125.4 4,124.05,122.01,121.55,115.79,115.77,112.26,111.51,56.21,55.59,53.51,49.76.HRMS(m / z):calcd.for C 21 H 21 N3O5[M+H] + :396.15540; found:396.15536.

[0393] Example 107 (1-(3-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (I-107)

[0394]

[0395] 1 H NMR (500MHz, DMSO-d6) δ (ppm): 7.96 (s, 1H), 7.72 (d, J=16.0Hz, 1H), 7.27–7.20 (m, 2H), 7.13 (d, J=2.0Hz, 1H), 7.04–6.97 (m, 2H), 6.86 (d ,J=8.2Hz,1H),6.81(dtd,J=6.1,2.2,1.2Hz,2H),6.43(d,J=16.1Hz,1H),5.43(t,J=0.9Hz,2H),5.30(s,2H),3.83(s,3H),3.81(s,3H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):167.25,159.81,149.45,148.99,146.39,145.96,137.19,129.71,127.95,125.4 3,124.05,122.02,115.79,115.77,113.96,113.17,112.26,56.21,55.14,53.51,52.49.HRMS(m / z):calcd.for C 21 H 21 N3O5[M+H] + :396.15540; found:396.15538.

[0396] Example 108 (1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (I-108)

[0397]

[0398] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.82 (s, 1H), 7.59 (d, J = 16.0Hz, 1H), 7.26–7.18 (m, 3H), 7.13 (d, J = 2.0Hz, 1H), 7.03–6 .97(m,1H),6.89–6.80(m,3H),6.43(d,J=16.1Hz,1H),5.39(t,J=1.0Hz,2H),5.30(s,2H),3.83(s,3H),3.78(s,3H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):167.25,159.41,149.45,148.99,146.39,145.94,129.77,129.73,127.9 5,125.42,124.05,115.79,115.77,113.84,112.26,56.21,55.32,53.51,53.21.HRMS(m / z):calcd.forC 21 H 21 N3O5[M+H] + :396.15540; found:396.15532.

[0399] Example 109 (1-(2-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(3,4-dihydroxyphenyl)acrylate (I-109)

[0400]

[0401] 1H NMR (400MHz, DMSO-d6) δ (ppm): δ7.89 (s, 1H), 7.86 (s, 1H), 7.58–7.51 (m, 2H), 7.44 (ddd, J = 10.6, 6.7, 2.0Hz, 1H), 7.31–7.23 (m, 2H), 7.04 (d, J =2.0Hz,1H),6.98(ddd,J=8.4,2.0,0.7Hz,1H),6.79(d,J=8.4Hz,1H),6.43(d,J=16.1Hz,1H),5.98(s,1H),5.59(d,J=0.9Hz,2H),5.30(s,2H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):167.25,148.56,147.28,146.32,145.96,132. 63(q,J=4.1Hz),130.06(q,J=2.0Hz),128.20(q,J=32.0Hz),127.27(d,J=2.1H z), 127.11, 126.35 (q, J = 3.9Hz), 125.65, 124.22 (d, J = 268.1Hz), 122.86, 122. 05,116.50,115.99,114.94,53.51,50.80(d,J=1.9Hz).HRMS(m / z):calcd.for C 20 H 16 F3N3O4[M+H] + :420.11657; found:420.11639.

[0402] Example 110 (1-(3-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(3,4-dihydroxyphenyl)acrylate (I-110)

[0403]

[0404] 1H NMR(400MHz, DMSO-d6)δ(ppm):7.88(d,J=9.5Hz,2H),7.59(dh,J=2.7,0.8Hz,1H),7.57–7.50(m,2H),7.48–7.41(m,2H),7.04(d,J=2.0H z,1H),6.98(ddd,J=8.4,2.0,0.7Hz,1H),6.79(d,J=8.4Hz,1H),6.43(d,J=16.1Hz,1H),5.98(s,1H),5.41(t,J=0.9Hz,2H),5.30(s,2H). 13 C NMR (101MHz, DMSO-d6) δ (ppm): 167.25, 148.56, 147.28, 146.32, 145.94, 136.70 (q, J=1.9Hz), 131.11 (q, J=32.1Hz), 129.42, 129.03 (d, J= 1.9Hz),127.11,126.77(q,J=3.9Hz),125.42,123.63(q,J=3.9Hz),122.86,116.50,115.99,114.94,53.51,52.55.HRMS(m / z):calcd.for C 20 H 16 F3N3O4[M+H] + :420.11657; found:420.11637.

[0405] Example 111 (1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(3,4-dihydroxyphenyl)acrylate (I-111)

[0406]

[0407] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.93 (d, J = 9.5Hz, 2H), 7.57–7.50 (m, 3H), 7.33 (dt, J = 6.3, 1.0Hz, 2H), 7.04 (d, J = 2.0Hz, 1H), 6. 98(ddd,J=8.4,2.0,0.7Hz,1H),6.79(d,J=8.4Hz,1H),6.43(d,J=16.1Hz,1H),5.98(s,1H),5.42(t,J=1.0Hz,2H),5.30(s,2H). 13C NMR (101MHz, DMSO-d6) δ (ppm): 167.25, 148.56, 147.28, 146.32, 145.94, 135.96, 129.67 (q, J = 1.9Hz), 129.28 (d, J = 32.0Hz), 127 .11,126.10(q,J=3.9Hz),125.42,124.16(d,J=268.1Hz),122.86,116.50,115.99,114.94,53.62,53.51.HRMS(m / z):calcd.forC 20 H 16 F3N3O4[M+H] + :420.11657; found:420.11653.

[0408] Example 112 (1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(3,4-dihydroxyphenyl)acrylate (I-112)

[0409]

[0410]

[0411] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.88 (d, J=10.3Hz, 2H), 7.54 (dd, J=16.1, 0.7Hz, 1H), 7.30–7.24 (m, 2H), 7.11 (tdd, J=8.2, 5.1, 1.3Hz, 2H), 7.04 (d ,J=2.0Hz,1H),6.98(ddd,J=8.4,2.0,0.7Hz,1H),6.79(d,J=8.4Hz,1H), 6.43(d,J=16.1Hz,1H),5.98(s,1H),5.40(d,J=1.1Hz,2H),5.30(s,2H). 13C NMR (101MHz, DMSO-d6) δ (ppm): 167.25, 161.14 (d, J = 252.1Hz), 148.56, 147.28, 146.32, 145.89, 131.11, 129.37 (d, J = 8.1Hz), 127.11, 124.99 (d, J =3.1Hz),124.69(d,J=20.0Hz),122.86,122.01,116.50,115.99,115.44(d,J=19.8Hz),114.94,53.51,49.64(d,J=5.0Hz).HRMS(m / z):calcd.forC 19 H 16 FN3O4[M+H] + :370.11976; found:370.11958.

[0412] Example 113 (1-(3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(3,4-dihydroxyphenyl)acrylate (I-113)

[0413]

[0414] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.99 (d, J=8.2Hz, 2H), 7.54 (dd, J=16.1, 0.7Hz, 1H), 7.34–7.26 (m, 1H), 7.11 (ddq, J=6.8, 2.2, 1.1Hz,1H),7.05–6.97(m,4H),6.79(d,J=8.4Hz,1H),6.43(d,J=16.1Hz,1H),5.98(s,1H),5.40(t,J=1.0Hz,2H),5.30(s,2H). 13 C NMR (101MHz, DMSO-d6) δ (ppm): 167.25, 162.89 (d, J = 252.1Hz), 148.56, 147.28, 146.32, 145.96, 138.45 (d, J = 8.1Hz), 129.96 (d, J = 7.9Hz), 127.1 1,125.43,124.37(d,J=3.1Hz),122.86,116.50,115.98,115.82,114.94,113.85(d,J=20.0Hz),53.51,52.36(d,J=3.8Hz).HRMS(m / z):calcd.for C 19 H 16FN3O4[M+H] + :370.11976; found:370.11964.

[0415] Example 114 (1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(3,4-dihydroxyphenyl)acrylate (I-114)

[0416]

[0417] 1 H NMR(400MHz, DMSO-d6)δ(ppm):8.10(d,J=9.5Hz,2H),7.73(dd,J=16.1,0.7Hz,1H),7.30(ddt,J=7.2,5.0,1.0Hz,2H),7.12–7.02(m,3 H),6.98(ddd,J=8.4,2.0,0.7Hz,1H),6.79(d,J=8.4Hz,1H),6.43(d,J=16.1Hz,1H),5.98(s,1H),5.38(t,J=1.0Hz,2H),5.30(s,2H). 13 C NMR (101MHz, DMSO-d6) δ (ppm): 167.25, 162.05 (d, J = 252.1Hz), 148.56, 147.28, 146.32, 145.94, 132.29 (d, J = 3.1Hz), 1 30.56,130.49,127.11,125.42,122.86,116.50,115.99,115.43,115.27,114.94,53.51,52.90.HRMS(m / z):calcd.for C 19 H 16 FN3O4[M+H] + :370.11976; found:370.11950.

[0418] Example 115 (1-(2-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(3,4-dihydroxyphenyl)acrylate (I-115)

[0419]

[0420] 1H NMR(400MHz, DMSO-d6)δ(ppm):8.11–8.04(m,1H),7.88(d,J=4.9Hz,2H),7.86–7.80(m,1H),7.58–7.52(m,3H),7.04(d,J=2.0Hz,1H ), 6.98(ddd,J=8.4,2.0,0.7Hz,1H),6.79(d,J=8.4Hz,1H),6.43(d,J=16.1Hz,1H),5.98(s,1H),5.54(d,J=1.1Hz,2H),5.30(s,2H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):167.25,148.56,147.28,147.15,146.32,145.86,132.72,131.11,130.44 ,128.31,127.11,125.17,122.86,122.06,116.50,115.99,114.94,53.49,51.28.HRMS(m / z):calcd.for C 19 H 16 N4O6[M+H] + :397.11426; found:397.11402.

[0421] Example 116 (1-(3-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(3,4-dihydroxyphenyl)acrylate (I-116)

[0422]

[0423] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.19–8.11 (m, 2H), 7.89 (d, J = 9.5Hz, 2H), 7.58–7.50 (m, 3H), 7.04 (d, J = 2.0Hz, 1H), 6.98 (d dd,J=8.4,2.0,0.7Hz,1H),6.79(d,J=8.4Hz,1H),6.43(d,J=16.1Hz,1H),5.98(s,1H),5.54(d,J=1.0Hz,2H),5.30(s,2H). 13C NMR(101MHz,DMSO-d6)δ(ppm):167.25,148.56,148.12,147.28,146.32,145.96,137.29,133.86,129.68 ,127.11,125.45,123.94,122.86,122.41,116.50,115.99,114.94,53.51,52.33.HRMS(m / z):calcd.for C 19 H 16 N4O6[M+H] + :397.11426; found:397.11408.

[0424] Example 117 (1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(3,4-dihydroxyphenyl)acrylate (I-117)

[0425]

[0426] 1 H NMR(400MHz, DMSO-d6)δ(ppm):8.19–8.13(m,2H),7.94(d,J=9.5Hz,2H),7.54(dd,J=16.1,0.7Hz,1H),7.46(dt,J=7.4,1.0Hz,2H),7.04(d,J= 2.0Hz,1H),6.98(ddd,J=8.4,2.0,0.7Hz,1H),6.79(d,J=8.4Hz,1H),6.43(d,J=16.1Hz,1H),5.98(s,1H),5.52(t,J=1.0Hz,2H),5.30(s,2H). 13 C NMR(101MHz,DMSO-d6)δ(ppm):167.25,148.56,147.28,146.92,146.32,145.94,140.49,129.35 ,127.11,125.42,123.70,122.86,116.50,115.99,114.94,53.51,53.06.HRMS(m / z):calcd.for C 19 H 16 N4O6[M+H] + :397.11426; found:397.11418.

[0427] Example 118 (1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-(3,4-dihydroxyphenyl)acrylate (I-118)

[0428]

[0429] mp:174-176℃. 1 H NMR(500MHz,DMSO-d6)δ(ppm):9.61(s,1H),9.13(s,1H),8.15(s,1H),7.51(d, J=15.9Hz,1H),7.29–7.24(m,2H),7.21(dt,J=6.9,3.7Hz,1H),7.13(d,J=7.4H z,1H),7.06(d,J=2.1Hz,1H),7.02(dd,J=8.2,2.1Hz,1H),6.77(d,J=8.1Hz,1H ),6.29(d,J=15.9Hz,1H),5.64(s,2H),5.24(s,2H),3.35(s,1H),2.34(s,3H). 13 C NMR (151MHz, DMSO-d6) δ (ppm): 166.74, 149.02, 146.11 (d, J = 22.0Hz), 142.75, 136.82, 134.54, 130.92, 129.23 ,128.84,126.76,125.89,125.38,121.99,116.18,115.39,113.90,57.46,51.40,19.13.HRMS(m / z):calcd.for C 20 H 19 N3O4[M+Na] + :388.1268;found:388.1263.

[0430] Experimental Example 1 Aβ inhibitory activity of APPswe cell model

[0431] Human neuroblastoma SH-SY5Y cells stably transfected with the Swedish mutant form of human amyloid precursor protein (abbreviated as “APPswe cells”) were used as AD cells to simulate the neurotoxicity of Aβ deposition triggered by copper sulfate (CuSO4). APPswe cells were cultured in Dulbecco’s modified eagle’s medium (DMEM) (Invitrogen, Carlsbad, CA, USA) supplemented with 10% fetal bovine serum (FBS; Invitrogen, Carlsbard, CA, US) and 1 μg / mL puromycin at 37°C and 5% CO2 until the cell confluence reached more than 80%. To study the neuroprotective activity of the cinnamic acid structural derivatives, the cells were seeded in 96-well plates at a density of 1×10 4 APPswe cells were treated with cinnamic acid derivatives and donepezil hydrochloride (Sigma Aldrich, Cambridge, MA, USA), memantine for 24 h and subjected to 300 μM Cu 2+ Induced excitotoxicity. The concentrations of cinnamic acid structural derivatives and donepezil hydrochloride and memantine were as follows: 0 (control), 0.032, 0.16, 0.8, 4, 20 and 100 μM.

[0432] Then WST-8 (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt) (CCK-8, Vazyme, Nanjing, China) was used to measure mitochondrial metabolism in living cells and study cell viability. Briefly, cells in each well were incubated with 90 μl of basal DMEM medium and 10 μl of CCK-8 working solution at 37 °C for 2 h according to the manufacturer's protocol. The optical density (OD) was measured at 450 nm using a Spark20 M multimode microplate reader (Mannidorf Tecan Group GmbH, Switzerland), which can reflect the number of living cells, and the inhibitory effect of cinnamic acid triazole derivatives on Aβ toxicity was evaluated as cell viability (%). Higher cell viability indicates that the compound has stronger neuroprotective activity.

[0433] First, the protection rates of compounds 1a, 1d, 1e, and some compounds in the I series were determined in APPswe cells. This model was used to test their ability to inhibit Aβ aggregation. Donepezil and memantine were used as positive control drugs. Preliminary experimental results showed that most of the experimental compounds showed certain cell protection activity in this cell model. The results are shown in Table 1.

[0434] Table 1 Inhibitory activity of target compounds against Aβ in APPswe cell model

[0435]

[0436]

[0437]

[0438]

[0439] Experimental Example 2: Determination of the inhibitory effect on AchE activity of APPswe cells

[0440] The activity of acetylcholinesterase (AChE) is upregulated by the aggregation of Aβ. The activity of AChE in APPswe cells should be higher than that in SY5Y cells. In this study, APPswe was selected as a model cell, and the inhibitory effect of the target compound on cholinesterase activity in APPswe cells was detected compared with SY5Y cells. Using the purchased acetylcholinesterase activity assay kit, the inhibitory ability of some compounds of the I series and three natural compounds, cinnamic acid (1a), ferulic acid (1d), and caffeic acid (1e) on acetylcholinesterase activity at a concentration of 20 μM was determined, and donepezil and memantine were selected as control drugs. The experimental results are shown in Table 2. Compared with the standard drug donepezil, the activity of the synthesized compounds is not very prominent, but compared with the lead structure cinnamic acid 1a (inhibition rate <5%), the inhibitory effect of the two series of compounds on the cholinesterase activity of the experimental cells was significantly increased.

[0441] Table 2 Inhibitory effect of target compounds on cholinesterase activity in APPswe cells

[0442]

[0443]

[0444]

[0445]

[0446] Among the I series of cinnamamide derivatives, some compounds showed a certain inhibitory effect on the AChE activity of experimental cells - that is, neuroprotective effect, among which I-10 (51.04±3.95%), I-12 (86.73±4.47%), I-33 (76.38±6.59%), I-67 (93.31±2.83%), I-69 (90.74±5.93%), and I-76 (96.57±3.71%) showed good AChE activity inhibition. Compared with the lead compound cinnamic acid 1a, the inhibitory effect of the two series of target compounds on AchE activity has been greatly improved.

[0447] Experimental Example 3: Effects of cinnamamide compounds on mouse behavior

[0448] The following behavioral studies were conducted on compounds I-12, I-33, and I-76 using the classic Morris water maze test. Two-month-old male C57BL / 6 mice were used as experimental subjects. On the first day, oligomeric Aβ 1-42 Aβ was injected into the lateral ventricle of ICR mice to establish a cognitive impairment model, while the sham-operated group was injected with the same volume of saline. One day after recovery from surgery, the Aβ-injected mice were randomly divided into the following treatment groups: Aβ 1-42 + vehicle group, Aβ 1-42 + Donepezil (2 mg / kg), Aβ 1-42 +I-121mg / kg group, Aβ 1-42 +I-12 5mg / kg group, Aβ 1-42 +I-12 25mg / kg group, Aβ 1-42 +I-33 1mg / kg group, Aβ 1-42 +I-33 5mg / kg group, Aβ 1-42 +I-33 25mg / kg group, Aβ 1-42 +I-76 1mg / kg group, Aβ 1-42 +I-76 5mg / kg group, Aβ 1-42 +I-76 25mg / kg group. From the 4th day to the 11th day, each group of mice was intraperitoneally injected with drugs at the following concentrations: donepezil (2mg / kg), I-12 or I-33 or I-76 (1mg / kg, 5mg / kg and 25mg / kg). From the 6th day to the 11th day, it was the Morris water maze experiment. The first 5 days were the training time, which was also the positioning route experiment. During the experiment, the platform was fixed in the fourth quadrant. Each mouse was placed in the water from two quadrants every day. During this period, the time it took for the mouse to find the platform and the swimming speed were recorded in real time. When the mouse found the platform and stayed still on the platform for 3 seconds, the recording stopped. In the spatial memory test conducted on the 11th day, the test items were changed. We placed the mice in the water from the first quadrant and assessed the memory retention ability of the mice by removing the hidden platform in the water maze. The swimming trajectory of the mice within 60 seconds, the time they stayed in each quadrant, the number of times they crossed the platform, and the time they stayed there were recorded. The time and method of drug administration in the water maze experiment followed the above method. Figure 1 .

[0449] from Figure 1 The results of Morris water maze experiments showed that compared with the control group, the Aβ 1-42The model group mice were treated with 1mg / kg, 5mg / kg, three different doses of I-12, I-33, and I-76. The latency period of the mice was significantly shortened ( Figure 1 B, P < 0.05; Figure 1 C, P < 0.05; Figure 1 D, P<0.05, P<0.001); the number of times the platform was crossed at its original position increased significantly, and the time spent in the target quadrant increased significantly. Compared with the positive control drug donepezil, the three cinnamoyl compounds had the same or even stronger therapeutic effects at each dose than donepezil ( Figure 1 H, I, J, K, L, M, N). There was no significant difference in swimming speed among the groups ( Figure 1 E, F, G), indicating that the peripheral motor function of mice was not affected by different treatment factors. 1-42 Compared with the model mice, 2mg / kg of the positive drug donepezil reduced Aβ 1-42 The latency of the model mice increased, the number of times the mice crossed the original position of the platform, and the time the mice stayed in the target quadrant increased, which significantly improved the Aβ 1-42 The target compound I-12 can significantly improve the learning and memory ability of mice within the dose range of 1 mg / kg to 25 mg / kg. 1-42 The learning ability and spatial memory ability of the model mice were dose-dependent at 1 mg / kg and 5 mg / kg. Compound I-33 can improve Aβ in the dose range of 1 mg / kg to 25 mg / kg. 1-42 The spatial learning and memory abilities of the model mice were dose-dependent at 1 mg / kg and 5 mg / kg. Compound I-76 improved Aβ in the dose range of 1 mg / kg to 25 mg / kg. 1-42 The spatial learning and memory ability of the model mice was improved, but there was no dose-effect dependence within this dose range. In summary, the Morris water maze experiment showed that the three experimental compounds all showed the effect of improving the learning and memory of the model mice, among which compound I-12 could improve Aβ at low, medium and high doses. 1-42 Spatial learning ability of mice, I-33 and I-76 can also improve Aβ at low and medium doses 1-42 The learning ability and spatial memory ability of mice were reduced at a dose of 25 mg / kg. At the same time, there was no significant difference in swimming speed among the groups, indicating that the peripheral motor function of mice was not affected by different treatment factors.

[0450] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A compound having the structure of Formula I, or a pharmaceutically acceptable salt or ester, solvate, polymorph, isotope-labeled compound, metabolite or prodrug thereof: in: R1, R2, R3, R4, R5 each represent hydrogen, hydroxy, amino, alkyl containing 1-6 carbon atoms, alkoxy containing 1-6 carbon atoms, alkoxyacyl containing 1-6 carbon atoms, halogen, nitro or trifluoromethyl; R6 represents hydrogen, halogen, nitro, alkyl containing 1 to 6 carbon atoms, alkoxy containing 1 to 6 carbon atoms, trifluoromethyl, hydroxyl, amino or cyano; X represents imino, oxygen, methylene or sulfur.

2. The compound having the structure of Formula I according to claim 1, its pharmaceutically acceptable salt or ester, solvate, isomer, polymorph, isotope-labeled compound, metabolite or prodrug, characterized in that: The alkyl group containing 1 to 6 carbon atoms is a methyl group or a tert-butyl group; the alkoxy group containing 1 to 6 carbon atoms is a methoxy group.

3. The compound having the structure of Formula I according to claim 1, its pharmaceutically acceptable salt or ester, solvate, isomer, polymorph, isotope-labeled compound, metabolite or prodrug, characterized in that: When X is NH, R1 represents hydrogen, methyl or methoxy, R2, R3, R4, R5 represent hydrogen, and R6 is selected from hydrogen, halogen, nitro, methyl, methoxy, tert-butyl, trifluoromethyl, hydroxy, amino or cyano; When X is NH, R1, R4, R5 represent hydrogen, R2 represents methoxy or hydroxy, R3 represents hydroxy, and R6 is selected from hydrogen, halogen, nitro, methyl, methoxy, tert-butyl, trifluoromethyl, hydroxy, amino or cyano; When X is O, R1, R4, R5 represent hydrogen, R2, R3 represent hydrogen or R2 represents methoxy R3 represents hydroxy, and R6 is selected from hydrogen, halogen, nitro, methyl, methoxy, tert-butyl, trifluoromethyl, hydroxy, amino or cyano; or When X is O, R1, R4, R5 represent hydrogen, R2, R3 represent hydroxyl, and R6 is selected from hydrogen, halogen, nitro, methyl, methoxy, tert-butyl, trifluoromethyl, hydroxyl, amino or cyano.

4. The compound having the structure of formula I as claimed in claim 1, its pharmaceutically acceptable salt or ester, solvate, polymorph, isotope-labeled compound, metabolite or prodrug, characterized in that: The compound shown in the formula I is:

5. A method for preparing a compound of formula I according to any one of claims 1 to 4, characterized in that: The following steps are involved: Step 1: Synthesis of intermediate cinnamamide (3a-n) / cinnamate (3b-n) (1) Cinnamic acid or substituted cinnamic acid (1n) condenses with propargylamine to form 3a-n; (2) Cinnamic acid or substituted cinnamic acid (1n) undergoes alkylation reaction with 3-bromopropyne to generate 3b-n; Wherein, R1, R2, R3, R4, and R5 are as defined in claim 1; Step 2: One-pot synthesis of In compounds At room temperature, compound 2 reacts with sodium azide in N,N-dimethylformamide (DMSO) to generate azide 4, and water is directly added to quench any remaining sodium azide; intermediate 3a-n or 3b-n is dissolved in N,N-dimethylformamide and added to the reaction, and the solvent is adjusted to DMSO / H2O (1:1 v / v), and then a reducing agent sodium ascorbate and a catalyst CuSO4·5H2O (20 mol%) are added, and the reaction is carried out for 12 h to obtain In compound; Wherein, R1, R2, R3, R4, R5, and R6 are as defined in claim 1; and X represents amino or oxygen.

6. Use of the compound having the structure described in Formula I as claimed in any one of claims 1 to 4, its pharmaceutically acceptable salt or ester, solvate, polymorph, isotope-labeled compound, metabolite or prodrug in the preparation of a drug for treating neurodegenerative diseases.

7. The use according to claim 6, characterized in that The neurodegenerative disease is Alzheimer's disease.

8. The use according to claim 6, characterized in that The drug may be in the form of oral solution, intravenous injection, intramuscular injection and other pharmaceutically acceptable dosage forms.

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