含有4-苯基-1,2,3-三氮唑的苯丙氨酸衍生物及其制备方法与应用与流程

本发明属于有机化合物合成与医药应用技术领域，具体涉及一种含有4-苯基-1,2,3-三氮唑的苯丙氨酸衍生物及其制备方法与应用。

背景技术：

艾滋病(acquiredimmunedeficiencysyndrome,aids)是主要由人类免疫缺陷病毒i型(humanimmunodeficiencyvirustype1,hiv-1)引起的危害人类生命健康的重大传染性疾病。当前，临床应用的治疗艾滋病的药物依据作用靶标的不同，主要分为：逆转录酶抑制剂、蛋白酶抑制剂、整合酶抑制剂以及融合抑制剂四大类。“高效抗逆转录疗法”(highlyactiveantiretroviraltherapy，haart)在很大程度上延长了患者的生存时间，改善了患者的生存质量，但是耐药问题、药物毒副作用、潜伏感染以及长期服用药物的高额费用等问题大大降低了该疗法的功效，限制了该疗法的应用，进而迫使研究者研发新靶点、新机制、新结构的抗艾滋病药物。

hiv-1衣壳是由gag前体蛋白的一部分剪切得到衣壳蛋白单元以后组装形成的。未成熟的病毒粒子转变为成熟病毒粒子的过程中，衣壳蛋白装配成衣壳，将病毒rna及与核相关的蛋白(逆转录酶、蛋白酶、整合酶等)包裹在内，形成成熟的hiv-1病毒粒子。成熟的病毒粒子方才具有传染性，可以进行病毒的下一轮复制。近年来，随着研究者对衣壳蛋白结构的深入了解，其晶体结构的相关信息也被陆续报道。因而，hiv-1的衣壳蛋白可以作为新的抗hiv-1的作用靶点。

pfizer公司通过化合物库的高通量筛选得到能显著抑制hiv-1复制的化合物pf-74，对其进行构效关系和机制研究表明，这类化合物通过结合hiv-1衣壳蛋白，进而干扰病毒的脱壳和形成感染颗粒的过程。尽管pf-74结构新颖、机制独特、靶点明确，但是，pf-74相对于目前已上市的抗hiv-1的药物疗效较低，类药性质较差而且极易诱发耐药性。因此，研发更为高效且具有良好类药性和耐药性的衣壳蛋白抑制剂成为近年来抗艾滋病药物研发领域中引人关注的方向。

本发明根据pf-74与hiv-1衣壳蛋白结合位点的晶体结构特征，通过合理药物设计、化学合成、生物活性评价发现了全新结构的4-苯基-1,2,3-三氮唑的苯磺酰胺的苯丙氨酸类hiv-1衣壳蛋白抑制剂，有望缓解现有hiv-1衣壳蛋白抑制剂类药性质差和耐药性问题。

技术实现要素：

针对现有技术的不足，本发明提供了一种含有4-苯基-1,2,3-三氮唑的苯丙氨酸衍生物及其制备方法，本发明还提供上述化合物作为hiv-1衣壳蛋白抑制剂的活性筛选结果及其应用。

本发明的技术方案如下：

1.含有4-苯基-1,2,3-三氮唑的苯丙氨酸衍生物

含有4-苯基-1,2,3-三氮唑的苯丙氨酸衍生物，或其药学上可接受的盐、酯或前药，具有通式i所示的结构：

其中，

胺基为苯环邻位取代、间位取代或对位取代；r为：h、乙酰基、苯甲酰基、4-甲基苯甲酰基、3-甲基苯甲酰基、2-甲基苯甲酰基、2-甲氧基苯甲酰基、3-甲氧基苯甲酰基、4-甲氧基苯甲酰基、4-甲酸甲酯苯甲酰基、3-甲酸甲酯苯甲酰基、2-甲酸甲酯苯甲酰基、4-氰基苯甲酰基、3-氰基苯甲酰基、2-氰基苯甲酰基、2-氟苯甲酰基、3-氟苯甲酰基、4-氟苯甲酰基、4-苯基苯甲酰基、3-苯基苯甲酰基、2-苯基苯甲酰基。

根据本发明优选的，含有4-苯基-1,2,3-三氮唑的苯丙氨酸衍生物是下列化合物之一：

本发明中所述的“药学上可接受的盐”是指在可靠的医药评价范围内，化合物的盐类适于与人或较低等动物的组织相接触而无不适当的毒性、刺激及过敏反应等，具有相当合理的收益与风险比例，通常是水或油可溶的或可分散的，并可有效地用于其预期的用途。包括药学上可接受的酸加成盐和药学上可接受的碱加成盐，在这里是可做预期的用途并与式i化合物的化学性质相容的。适宜的盐的列表参见s.m.birge等，j.pharm.sci.,1977,66,1-19页。

本发明中所述的“前药”是指药学上可接受的衍生物，以便这些衍生物所得的生物转换产物是如式i化合物所定义的活性药物。

2.含有4-苯基-1,2,3-三氮唑的苯丙氨酸衍生物的制备方法

含有4-苯基-1,2,3-三氮唑的苯丙氨酸衍生物的制备方法，步骤包括：以boc-l-苯丙氨酸(1)为起始原料，二氯甲烷作为反应溶剂，通过酰胺缩合反应与n-甲基-4-氨基苯甲醚生成中间体2；然后中间体2溶解在适量二氯甲烷中，在三氟乙酸的作用下脱去boc基团，得到中间体3；接着，中间体3与叠氮乙酸发生酰胺缩合反应得到带有叠氮基团的中间体4；中间体4再与相应取代的氨基苯乙炔在抗坏血酸钠与五水硫酸铜条件下，通过cu(i)催化的叠氮-炔husigen-click环加成反应生成化合物5a-5c；最后化合物5a-5c再与相应的酰氯经酰化反应得目标化合物6a-(1-12)，6b-(1-12)和6c-(1-12)。

合成路线如下：

试剂及条件：(i)n-甲基-4-氨基苯甲醚，1h-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐，n,n-二异丙基乙胺，二氯甲烷，0℃转至室温；(ii)三氟乙酸，二氯甲烷，室温；(iii)叠氮乙酸，o-(7-氮杂苯并三唑-1-基)-n,n,n',n'-四甲基脲六氟磷酸盐，n,n-二异丙基乙胺，乙腈，0℃转至室温；(iv)相应取代的氨基苯乙炔，抗坏血酸钠，五水硫酸铜，水/四氢呋喃，室温；(v)相应的酰氯，三乙胺，二氯甲烷，0℃转至室温。

其中，r如上述通式i中所述。

所述的取代的氨基苯乙炔为2-氨基苯乙炔、3-氨基苯乙炔、4-氨基苯乙炔。

所述的酰氯为乙酰氯、苯甲酰氯、4-甲基苯甲酰氯、2-甲氧基苯甲酰氯、3-甲氧基苯甲酰氯、4-甲氧基苯甲酰氯、4-甲酸甲酯苯甲酰氯、4-氰基苯甲酰氯、2-氟苯甲酰氯、3-氟苯甲酰氯、4-氟苯甲酰氯、4-苯基苯甲酰氯。

本发明所述的室温为20-30℃。

根据本发明优选的，含有4-苯基-1,2,3-三氮唑的苯丙氨酸衍生物的制备方法，具体步骤如下：

(1)将boc-l-苯丙氨酸(1)、1h-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐加入到二氯甲烷中，冰浴条件下搅拌30min；随后向反应液中加入n,n-二异丙基乙胺和n-甲基-4-氨基苯甲醚，撤去冰浴转入室温，tlc监测；反应完毕，减压蒸除溶剂，然后向瓶内残留物中加入饱和碳酸氢钠溶液，二氯甲烷萃取，分取有机相，加入1nhcl溶液洗涤，分取有机相，加入饱和氯化钠溶液洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品经硅胶柱层析分离纯化后得到中间体2；

(2)将上步得到的中间体2加入到二氯甲烷中，然后向此溶液中缓慢滴加过量三氟乙酸，室温条件下搅拌1h；然后加入饱和碳酸氢钠溶液调节反应液ph为7，再加入二氯甲烷溶液萃取；分取有机相，饱和氯化钠溶液洗涤3次，无水硫酸钠干燥有机相，过滤，减压蒸干溶剂，硅胶柱层析分离得到中间体3；

(3)将叠氮乙酸、o-(7-氮杂苯并三唑-1-基)-n,n,n',n'-四甲基脲六氟磷酸盐加入到乙腈中，冰浴条件搅拌1h；随后向此溶液中加入中间体3和n,n-二异丙基乙胺，撤去冰浴后，室温搅拌12h；反应毕，减压蒸除溶剂，然后向瓶内残留物中加入饱和碳酸氢钠溶液，二氯甲烷萃取，分取有机相，加入1nhcl溶液洗涤，分取有机相，加饱和氯化钠溶液洗涤，有机相用无水硫酸钠干燥，过滤，减压蒸干溶剂，硅胶柱层析分离得到中间体4；

(4)将中间体4、取代的氨基苯乙炔、抗坏血酸钠、五水硫酸铜加入到体积比1:1的四氢呋喃和水的混合溶剂中，室温搅拌12h；反应完毕，向反应液中加入适量的饱和氯化钠溶液，用二氯甲烷萃取，分取有机相，无水硫酸钠干燥，过滤，减压蒸干溶剂，硅胶柱层析分离；乙酸乙酯/石油醚重结晶得到化合物5a-5c；

(5)将化合物5a-5c、三乙胺加入到二氯甲烷中，冰浴条件搅拌下向其中缓慢加入相应的酰氯，随后撤去冰浴转入室温，tlc监测；反应完毕，减压蒸除溶剂，然后向瓶内残留物中加入饱和氯化钠溶液，二氯甲烷萃取，分取有机相，用无水硫酸钠干燥，过滤，减压蒸干溶剂，硅胶柱层析分离得到目标化合物粗品，再经硅胶制备板纯化得目标化合物纯品6a-(1-12)，6b-(1-12)和6c-(1-12)。

3.含有4-苯基-1,2,3-三氮唑的苯丙氨酸衍生物的应用

本发明公开了含4-苯基-1,2,3-三氮唑的苯丙氨酸衍生物抗hiv-1活性筛选结果及其作为hiv-1抑制剂的首次应用。通过实验证明本发明的含4-苯基-1,2,3-三氮唑的苯丙氨酸衍生物可作为hiv-1抑制剂用于制备抗艾滋病药物。本发明还提供上述化合物抗hiv药物中的应用。

目标化合物的抗hiv-1活性和毒性实验

对按照上述方法合成的一类含有4-苯基-1,2,3-三氮唑的苯丙氨酸衍生物进行了细胞水平的抗hiv-1活性和毒性测试，它们的抗hiv-1活性和毒性数据列于表1中，以文献报道的衣壳蛋白抑制剂pf-74为阳性对照。

本发明新合成的含4-苯基-1,2,3-三氮唑的苯丙氨酸衍生物呈现出显著的抗hiv-1活性。例如，化合物5a、6a-1、6a-2、6a-9、6a-10、6a-11、5b抗hiv-1活性在3.13–3.99μm范围内，其中化合物6a-9的抗hiv-1活性(ec50＝3.13±0.91μm,cc50>16.48,si>5.27)尤为突出，具有进一步研究的价值。

本发明的一类含有4-苯基-1,2,3-三氮唑的苯丙氨酸衍生物可作为hiv-1抑制剂应用。具体地说，作为hiv-1抑制剂用于制备抗艾滋病药物。

一种抗hiv-1药物组合物，包括本发明的一类含有4-苯基-1,2,3-三氮唑的苯丙氨酸衍生物和一种或多种药学上可接受载体或赋形剂。

本发明提供了一类含有4-苯基-1,2,3-三氮唑的苯丙氨酸衍生物及其制备方法，本发明还提供了部分化合物抗hiv-1活性筛选结果及其在抗病毒领域中的首次应用。经过试验证明，本发明的一类含有4-苯基-1,2,3-三氮唑的苯丙氨酸衍生物可作为hiv-1抑制剂应用并具有很高的应用价值。具体地说，作为hiv-1抑制剂用于制备抗艾滋病药物。

具体实施方式

通过下述实施例有助于理解本发明，但是不能限制本发明的内容，所述百分比数均为质量百分比。

实施例1：(s)-(1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙烷-2-基)氨基甲酸叔丁酯(2)的制备

将起始原料boc-l-苯丙氨酸(1)(2.90g,10.93mmol,1.5eq.)、1h-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(5.69g,10.93mmol,1.5eq.)加入到20ml的二氯甲烷中，冰浴条件下搅拌30min；然后加入n,n-二异丙基乙胺(3.61ml,21.87mmol,3eq.)和n-甲基-4-氨基苯甲醚(1.0g7.29mmol,1eq.)，撤去冰浴转入室温搅拌，tlc监测；6h后反应完毕，减压蒸除溶剂，然后向瓶内残留物中加入饱和碳酸氢钠溶液40ml，二氯甲烷40ml萃取，分取有机相，加入1nhcl溶液40ml洗涤，分取有机相，加入饱和氯化钠溶液40ml洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品经硅胶柱层析分离(洗脱剂ea:pe＝1:8v/v)得到中间体(s)-(1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙烷-2-基)氨基甲酸叔丁酯(2)的粗品2.48g，黄色油状物，产率88％。

波谱数据：¹hnmr(400mhz,dmso-d6)δ7.22(d,j＝8.3hz,2h,ph-h),7.20–7.11(m,3h,ph-h),7.09(d,j＝8.2hz,1h,nh),7.03(d,j＝8.6hz,2h,ph-h),6.79(d,j＝7.3hz,2h,ph-h),4.27–4.06(m,1h,ch),3.81(s,3h,och3),3.13(s,3h,nch3),2.75(dd,j＝13.4,3.8hz,1h,phch),2.61(dd,j＝13.3,10.3hz,1h,phch),1.30(s,9h,c(ch3)3).¹³cnmr(100mhz,dmso-d6)δ172.22(c＝o),158.98,155.75(c＝o),138.53(2×c),136.12(2×c),129.28(2×c),128.47(2×c),126.70,115.21(2×c),78.33,55.94,53.55,37.86,37.07,28.65(3×c).esi-ms:m/z385.4(m+1),407.5(m+23).c22h28n2o4[384.5].

实施例2：(s)-2-氨基-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(3)的制备

将中间体2(4.0g,10.40mmol,1.0eq.)加入到30ml二氯甲烷中，然后向此溶液中缓慢加入三氟乙酸(3.86ml,52.02mmol,5.0eq.)，室温搅拌，tlc监测；1h后反应完毕，然后用饱和碳酸氢钠溶液调节反应液ph至7，加入二氯甲烷40ml萃取，分取有机相，饱和氯化钠溶液洗涤(20ml×3次)，无水硫酸钠干燥，过滤，减压浓缩，得到中间体(s)-2-氨基-n-(4-甲氧基苯基)-n-甲基-3-苯丙酰胺(3)的粗品2.36g，黄色油状物，产率80％。

波谱数据：¹hnmr(400mhz,dmso-d6)δ7.29–7.13(m,3h,ph-h),7.03–6.75(m,6h,ph-h),3.77(s,3h,och3),3.44–3.35(m,1h,ch),3.06(s,3h,nch3),2.75(dd,j＝12.8,6.7hz,1h,phch),2.45(dd,j＝12.9,7.1hz,1h,phch),1.87(s,2h,nh2).¹³cnmr(100mhz,dmso-d6)δ174.89(c＝o),158.75,139.00,136.35,129.51(2×c),128.93(2×c),128.47(2×c),126.55,115.04(2×c),55.85,53.35,42.19,37.45.esi-ms:m/z285.05(m+1).c17h20n2o2[284.36].

实施例3：中间体(s)-2-(2-叠氮基乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(4)的制备

将叠氮乙酸(40mg,0.40mmol,1.2eq.)、o-(7-氮杂苯并三唑-1-基)-n,n,n',n'-四甲基脲六氟磷酸盐(188mg,0.50mmol,1.5eq.)加入到15ml乙腈中，冰浴条件搅拌1h；随后向此溶液中加入中间体3(94mg,0.33mmol,1eq.)和n,n-二异丙基乙胺(109μl,0.66mmol,2eq.)，撤去冰浴后，室温搅拌，tlc监测；12h后反应毕，减压蒸除溶剂，然后向瓶内残留物中加入饱和碳酸氢钠溶液20ml，二氯甲烷20ml萃取，分取有机相，加入1nhcl溶液10ml洗涤，分取有机相，加饱和氯化钠溶液洗涤(10ml×3次)，有机相用无水硫酸钠干燥，过滤，减压蒸干溶剂，硅胶柱层析分离(洗脱剂ea:pe＝1:4)得到中间体中间体(s)-2-(2-叠氮基乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(4)47mg，黄色油状物，产率39％。

波谱数据：¹hnmr(400mhz,methanol-d4)δ7.27–7.13(m,3h,ph-h),7.11–6.59(m,6h,ph-h),4.67(t,j＝7.4hz,1h,nh),3.82(s,3h,och3),3.81–3.74(m,1h,ch),3.31(dt,j＝3.1,1.6hz,2h,n3ch2),3.16(s,3h,nch3),2.97(dd,j＝13.3,7.0hz,1h,phch),2.73(dd,j＝13.3,7.9hz,1h,phch).¹³cnmr(100mhz,methanol-d4)δ171.05(c＝o),167.29(c＝o),158.67,135.77,134.23,128.05(2×c),127.49,127.30(2×c),125.75(2×c),113.66(2×c),53.79,51.03,50.30,36.99,36.05.esi-ms:m/z368.3(m+1),390.3(m+23),406.5(m+39).c19h21n5o3[367.4].

实施例4：关键中间体(目标化合物)5a-5c的制备

将中间体4(110mg,0.30mmol,1eq.)、相应取代的氨基苯乙炔(42mg,0.36mmol,1.2eq.)、抗坏血酸钠(7.5mg,0.03mmol,0.1eq.)、五水硫酸铜(17.8mg,0.09mmol,0.3eq.)加入到四氢呋喃和水的混合溶剂(v/v＝1:1,6ml)中，室温搅拌，tlc监测；12h后反应完毕，向反应液中加入20ml饱和氯化钠溶液，用20ml二氯甲烷萃取，分取有机相，无水硫酸钠干燥，过滤，减压蒸干溶剂，硅胶柱层析分离(洗脱剂ea:pe＝1:1)得到化合物5a-5c。

取代的氨基苯乙炔选用2-氨基苯乙炔与中间体4反应制得(s)-2(2-(4-(2-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5a)120mg，白色固体，产率83％，熔点：94-95℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ8.90(d,j＝7.6hz,1h,nh),8.33(s,1h,triazole-h),7.42(d,j＝7.5hz,1h,ph-h),7.29–7.14(m,3h,ph-h),7.14–6.98(m,3h,ph-h),6.91(dd,j＝16.8,7.5hz,4h,ph-h),6.76(d,j＝8.1hz,1h,ph-h),6.59(t,j＝7.3hz,1h,ph-h),6.16(s,2h,nh2),5.25–4.99(m,2h,triazolech2),4.46(q,j＝8.1hz,1h,ch),3.75(s,3h,och3),3.11(s,3h,nch3),2.92(dd,j＝13.2,4.7hz,1h,phch),2.69(dd,j＝13.1,9.4hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.18(c＝o),165.40(c＝o),159.02,147.54,145.05,137.68,135.78,129.33(2×c),129.10(2×c),128.88,128.70(2×c),127.93,127.03,123.22,116.40,116.25,115.10(2×c),113.02,55.85,52.10,51.85,37.87,37.77.esi-ms:m/z485.5(m+1),507.4(m+23).c27h28n6o3[484.6].

取代的氨基苯乙炔选用3-氨基苯乙炔与中间体4反应制得(s)-2(2-(4-(3-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5b)126mg，白色固体，产率87％，熔点：90-91℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ8.88(d,j＝7.8hz,1h,nh),8.20(s,1h,triazole-h),7.29–7.14(m,3h,ph-h),7.13–7.02(m,4h,ph-h),6.91(dd,j＝17.6,8.2hz,5h,ph-h),6.52(d,j＝7.6hz,1h,ph-h),5.17(s,2h,phnh2),5.13(d,j＝16.4hz,1h,triazolech),5.02(d,j＝16.2hz,1h,triazolech),4.45(q,j＝8.2hz,1h,ch),3.75(s,3h,och3),3.10(s,3h,nch3),2.92(dd,j＝13.4,4.8hz,1h,phch),2.69(dd,j＝13.2,9.3hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.20(c＝o),165.53(c＝o),159.01,149.51,147.15,137.69,135.79,131.59,129.81,129.33(2×c),129.11,128.71(2×c),127.03,122.90,115.09(2×c),113.97,113.36,110.80(2×c),55.85,52.10,51.73,37.85,37.77.esi-ms:m/z485.5(m+1),507.5(m+23).c27h28n6o3[484.6].

取代的氨基苯乙炔选用4-氨基苯乙炔与中间体4反应制得(s)-2(2-(4-(4-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5c)70mg，白色固体，产率48％，熔点：105-106℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ8.86(d,j＝7.8hz,1h,nh),8.07(s,1h,triazole-h),7.47(d,j＝8.4hz,2h,ph-h),7.27–7.13(m,3h,ph-h),7.06(d,j＝6.6hz,2h,ph-h),6.93(d,j＝9.0hz,2h,ph-h),6.91–6.82(m,2h,ph-h),6.60(d,j＝8.4hz,2h,ph-h),5.23(s,2h,nh2),5.09(d,j＝16.3hz,1h,triazolech),4.98(d,j＝16.3hz,1h,triazolech),4.45(td,j＝8.5,5.5hz,1h,ch),3.75(s,3h,och3),3.10(s,3h,nch3),2.91(dd,j＝13.6,5.2hz,1h,phch),2.68(dd,j＝13.4,9.1hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.19(c＝o),165.58(c＝o),159.01,149.03,147.48,137.69,135.80,129.33(2×c),129.10(2×c),128.69(2×c),127.02,126.55(2×c),121.07,118.78,115.09(2×c),114.39(2×c),55.85,52.06,51.71,37.87,37.77.esi-ms:m/z485.5(m+1),507.4(m+23),523.5(m+39).c27h28n6o3[484.6].

实施例5：目标化合物6a-(1-12)、6b-(1-12)、6c-(1-12)的制备

将化合物5a-5c(0.12g,0.25mmol,1eq.)、三乙胺(69μl,0.50mmol,2eq.)加入到10ml二氯甲烷中，冰浴条件搅拌下向其中缓慢加入相应的酰氯(0.37mmol,1.5eq.)，随后撤去冰浴转入室温，tlc监测；10h后反应完毕，减压蒸除溶剂，然后向瓶内残留物中加入10ml饱和氯化钠溶液，10ml二氯甲烷萃取，水相用二氯甲烷萃取(10ml×3次)，合并有机相，用无水硫酸钠干燥，过滤，减压蒸干溶剂，硅胶柱层析分离(洗脱剂ea:pe＝1:1)得到目标化合物粗品，再经硅胶制备板纯化得目标化合物6a-(1-12)、6b-(1-12)、6c-(1-12)纯品。

相应的酰氯选用乙酰氯(26μl)与(s)-2(2-(4-(2-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5a)反应制得(s)-2(2-(4-(2-乙酰氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(6a-1)61mg，白色固体，产率47％，熔点：95-96℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ10.71(s,1h,phnh),8.95(d,j＝7.8hz,1h,nh),8.47(s,1h,triazole-h),8.10(d,j＝8.1hz,1h,ph-h),7.77(d,j＝7.6hz,1h,ph-h),7.33(t,j＝7.4hz,1h,ph-h),7.29–7.15(m,4h,ph-h),7.14–7.01(m,2h,ph-h),6.93(d,j＝8.9hz,2h,ph-h),6.89(d,j＝6.6hz,2h,ph-h),5.23(d,j＝16.3hz,1h,triazolech),5.12(d,j＝16.3hz,1h,triazolech),4.54–4.38(m,1h,ch),3.75(s,3h,och3),3.11(s,3h,nch3),2.93(dd,j＝13.5,5.0hz,1h,phch),2.70(dd,j＝13.4,9.3hz,1h,phch),2.12(s,3h,coch3).¹³cnmr(100mhz,dmso-d6)δ171.18(c＝o),168.89(c＝o),165.29(c＝o),159.03,145.45,137.66,135.86,135.78,129.32(2×c),129.10(2×c),128.77,128.71(2×c),128.07,127.04,125.03,124.76,123.43,120.94,115.09(2×c),55.86,52.15,51.94,37.85,37.77,24.89.esi-ms:m/z527.4(m+1),544.5(m+18),549.4(m+23),565.4(m+39).c29h30n6o4[526.6].

相应的酰氯选用苯甲酰氯(43μl)与(s)-2(2-(4-(2-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5a)反应制得(s)-n-(2-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)苯甲酰胺(6a-2)78mg，白色固体，产率53％，熔点：103-104℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ12.11(s,1h,phnh),8.98(d,j＝7.8hz,1h,nh),8.65(s,1h,triazole-h),8.61(d,j＝8.3hz,1h,ph-h),8.06(d,j＝7.0hz,2h,ph-hh),7.81(d,j＝7.8hz,1h,ph-h),7.70–7.50(m,3h,ph-h),7.41(t,j＝7.8hz,1h,ph-h),7.30–7.14(m,4h,ph-h),7.06(d,j＝6.5hz,2h,ph-h),6.93(d,j＝9.0hz,2h,ph-h),6.88(d,j＝6.7hz,2h,ph-h),5.26(d,j＝16.4hz,1h,triazolech),5.15(d,j＝16.4hz,1h,triazolech),4.46(td,j＝8.5,5.5hz,1h,ch),3.74(s,3h,och3),3.11(s,3h,nch3),2.92(dd,j＝13.4,5.0hz,1h,phch),2.69(dd,j＝13.4,9.2hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.14(c＝o),165.34(c＝o),165.15(c＝o),159.02,146.34,137.65,136.27,135.76,135.16,132.45,129.35(2×c),129.32(2×c),129.09(2×c),129.06,128.70(2×c),128.01,127.63(2×c),127.02,125.07,124.58,121.91,119.22,115.10(2×c),55.84,52.14,52.12,37.87,37.77.esi-ms:m/z589.4(m+1),606.4(m+18),611.3(m+23),627.4(m+39).c34h32n6o4[588.7].

相应的酰氯选用4-甲基苯甲酰氯(49μl)与(s)-2(2-(4-(2-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5a)反应制得(s)-n-(2-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)-4-甲基苯甲酰胺(6a-3)105mg，白色固体，产率70％，熔点：118-119℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ12.07(s,1h,phnh),8.99(d,j＝7.8hz,1h,nh),8.64(s,1h,triazole-h),8.61(d,j＝8.3hz,1h,ph-h),7.96(d,j＝8.1hz,2h,ph-h),7.80(d,j＝7.7hz,1h,ph-h),7.40(t,j＝6.7hz,3h,ph-h),7.20(tt,j＝14.2,7.3hz,4h,ph-h),7.13–6.99(m,2h,ph-h),6.93(d,j＝8.9hz,2h,ph-h),6.88(d,j＝6.8hz,2h,ph-h),5.26(d,j＝16.4hz,1h,triazolech),5.15(d,j＝16.4hz,1h,triazolech),4.61–4.34(m,1h,ch),3.74(s,3h,och3),3.11(s,3h,nch3),2.92(dd,j＝13.4,5.0hz,1h,phch),2.69(dd,j＝13.4,9.2hz,1h,phch),2.40(s,3h,phch3).¹³cnmr(100mhz,dmso-d6)δ171.14(c＝o),165.27(c＝o),165.16(c＝o),159.02,146.39,142.52,137.65,136.37,135.76,132.40,129.88(2×c),129.32(2×c),129.09(2×c),129.04,128.70(2×c),127.99,127.64(2×c),127.02,125.04,124.42,121.80,119.04,115.09(2×c),55.84,52.12,52.11,37.87,37.77,21.49.esi-ms:m/z603.4(m+1),620.5(m+18),625.4(m+23),641.3(m+39).c35h34n6o4[602.7].

相应的酰氯选用2-甲氧基苯甲酰氯(67μl)与(s)-2(2-(4-(2-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5a)反应制得(s)-2-甲氧基-n-(2-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)苯甲酰胺(6a-4)125mg，白色固体，产率65％，熔点：99-100℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ11.66(s,1h,phnh),8.95(d,j＝7.9hz,1h,nh),8.55(d,j＝8.3hz,1h,ph-h),8.47(s,1h,triazole-h),7.93(d,j＝6.9hz,1h,ph-h),7.64(d,j＝7.6hz,1h,ph-h),7.60–7.50(m,1h,ph-h),7.40(t,j＝7.8hz,1h,ph-h),7.28–7.13(m,5h,ph-h),7.15–6.99(m,3h,ph-h),6.93(d,j＝8.9hz,2h,ph-h),6.88(d,j＝6.6hz,2h,ph-h),5.23(d,j＝16.3hz,1h,triazolech),5.13(d,j＝16.3hz,1h,triazole-ch),4.47(td,j＝8.5,5.4hz,1h,ch),3.87(s,3h,och3),3.75(s,3h,och3),3.11(s,3h,nch3),2.92(dd,j＝13.5,5.0hz,1h,phch),2.69(dd,j＝13.4,9.2hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.16(c＝o),165.27(c＝o),164.08(c＝o),159.02,157.36,145.64,137.66,136.09,135.77,133.66,131.58,129.32(2×c),129.10,128.89,128.82,128.69(2×c),127.02,125.08,124.45,123.07,122.82,121.13(2×c),120.14,115.10(2×c),112.51,56.29,55.85,52.12,51.97,37.85,37.77.esi-ms:m/z619.5(m+1),636.4(m+18),641.4(m+23),657.4(m+39).c35h34n6o5[618.7].

相应的酰氯选用3-甲氧基苯甲酰氯(65μl)与(s)-2(2-(4-(2-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5a)反应制得(s)-3-甲氧基-n-(2-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)苯甲酰胺(6a-5)150mg，白色固体，产率79％，熔点：99-100℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ12.13(s,1h,phnh),8.97(d,j＝7.8hz,1h,nh),8.65(s,1h,triazole-h),8.62(d,j＝8.3hz,1h,ph-h),7.82(d,j＝7.5hz,1h,ph-h),7.65(d,j＝7.8hz,1h,ph-h),7.62(s,1h,ph-h),7.51(t,j＝7.9hz,1h,ph-h),7.42(t,j＝7.6hz,1h,ph-h),7.21(dp,j＝16.5,7.4hz,5h,ph-h),7.06(d,j＝6.6hz,2h,ph-h),6.93(d,j＝8.9hz,2h,ph-h),6.89(d,j＝6.8hz,2h,ph-h),5.26(d,j＝16.4hz,1h,triazolech),5.16(d,j＝16.3hz,1h,triazolech),4.47(td,j＝8.4,5.5hz,1h,ch),3.87(s,3h,och3),3.75(s,3h,och3),3.11(s,3h,nch3),2.93(dd,j＝13.5,5.1hz,1h,phch),2.70(dd,j＝13.4,9.2hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.14(c＝o),165.15(c＝o),165.05(c＝o),159.96,159.02,146.36,137.65,136.59,136.24,135.76,130.51,129.32(2×c),129.10(2×c),128.71(2×c),128.01,127.03,125.10,124.57,121.72,119.80(2×c),119.08,118.43,115.09(2×c),112.60,55.84,55.77(2×c),52.14,37.86,37.77.esi-ms:m/z619.5(m+1),636.4(m+18),641.4(m+23),657.4(m+39).c35h34n6o5[618.7].

相应的酰氯选用4-甲氧基苯甲酰氯(79mg)与(s)-2(2-(4-(2-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5a)反应制得(s)-4-甲氧基-n-(2-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)苯甲酰胺(6a-6)130mg，白色固体，产率68％，熔点：110-111℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ12.03(s,1h,phnh),8.97(d,j＝7.8hz,1h,nh),8.64(s,1h,triazole-h),8.62(d,j＝8.1hz,1h,ph-h),8.04(d,j＝8.8hz,2h,ph-h),7.85–7.76(m,1h,ph-h),7.45–7.36(m,1h,ph-h),7.26–7.16(m,4h,ph-h),7.14(d,j＝8.9hz,2h,ph-h),7.06(d,j＝6.8hz,2h,ph-h),6.93(d,j＝9.0hz,2h,ph-h),6.89(d,j＝6.6hz,2h,ph-h),5.26(d,j＝16.4hz,1h,triazolech),5.16(d,j＝16.4hz,1h,triazolech),4.47(td,j＝8.5,5.3hz,1h,ch),3.86(s,3h,och3),3.75(s,3h,och3),3.11(s,3h,nch3),2.93(dd,j＝13.4,5.1hz,1h,phch),2.70(dd,j＝13.5,9.1hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.15(c＝o),165.18(c＝o),164.85(c＝o),162.62,159.02,146.45,137.66,136.51,135.76,129.53(2×c),129.32(2×c),129.10(2×c),129.04,128.71(2×c),127.96,127.26,127.03,125.04,124.25,121.69,118.87,115.09(2×c),114.59(2×c),55.95,55.84,52.16,52.11,37.85,37.77.esi-ms:m/z619.5(m+1),641.3(m+23).c35h34n6o5[618.7].

相应的酰氯选用4-甲酸甲酯苯甲酰氯(74mg)与(s)-2(2-(4-(2-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5a)反应制得(s)-4-((2-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙烷-2-基)氨基)-2-(甲基)氧代乙基)-1h-1,2,3-三唑-4-基)苯基)氨基甲酰基)苯甲酸甲酯(6a-7)121mg，白色固体，产率76％，熔点：130-131℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ12.04(s,1h,phnh),8.95(d,j＝7.8hz,1h,nh),8.61(s,1h,triazole-h),8.50(d,j＝8.2hz,1h,ph-h),8.22–8.10(m,4h,ph-h),7.83(d,j＝7.2hz,1h,ph-h),7.43(t,j＝7.4hz,1h,ph-h),7.28(t,j＝7.5hz,1h,ph-h),7.19(q,j＝8.7,7.5hz,3h,ph-h),7.06(d,j＝7.4hz,2h,ph-h),6.92(d,j＝8.9hz,2h,ph-h),6.88(d,j＝6.6hz,2h,ph-h),5.25(d,j＝16.3hz,1h,triazolech),5.15(d,j＝16.3hz,1h,triazolech),4.47(td,j＝8.5,5.5hz,1h,ch),3.90(s,3h,cooch3),3.74(s,3h,och3),3.11(s,3h,nch3),2.92(dd,j＝13.5,5.1hz,1h,phch),2.69(dd,j＝13.4,9.1hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.12(c＝o),166.06(c＝o),165.14(c＝o),164.61(c＝o),159.03,146.07,139.27,137.64(2×c),135.89(2×c),135.78,132.84,130.05(2×c),129.32(2×c),129.06(2×c),128.69(2×c),128.09(2×c),127.00,125.08(2×c),122.58,120.11,115.10(2×c),55.84(2×c),52.91,52.12,37.91,37.76.esi-ms:m/z647.5(m+1),664.5(m+18),669.4(m+23),685.5(m+39).c35h34n6o5[646.7].

相应的酰氯选用4-氰基苯甲酰氯(62mg)与(s)-2(2-(4-(2-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5a)反应制得(s)-4-氰基-n-(2-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)苯甲酰胺(6a-8)93mg，白色固体，产率61％，熔点：142-143℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ12.04(s,1h,phnh),8.95(d,j＝7.8hz,1h,nh),8.61(s,1h,triazole-h),8.47(d,j＝8.2hz,1h,ph-h),8.18(d,j＝8.2hz,2h,ph-h),8.07(d,j＝8.3hz,2h,ph-h),7.83(d,j＝7.7hz,1h,ph-h),7.43(t,j＝7.7hz,1h,ph-h),7.28(t,j＝7.5hz,1h,ph-h),7.20(q,j＝8.8,7.6hz,3h,ph-h),7.06(d,j＝7.3hz,2h,ph-h),6.92(d,j＝8.8hz,2h,ph-h),6.88(d,j＝6.8hz,2h,ph-h),5.25(d,j＝16.3hz,1h,triazolech),5.15(d,j＝16.3hz,1h,triazolech),4.47(td,j＝8.4,5.4hz,1h,ch),3.75(s,3h,och3),3.11(s,3h,nch3),2.92(dd,j＝13.5,5.0hz,1h,phch),2.69(dd,j＝13.3,9.3hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.14(c＝o),165.17(c＝o),164.02(c＝o),159.04,146.01,139.17,137.65,135.78,135.71,133.36(2×c),129.31(2×c),129.07(2×c),128.70(2×c),128.53(2×c),128.12,127.02,125.28,125.12,122.71,120.32,118.69(2×c),115.11(2×c),114.68,55.85,52.16,52.10,37.90,37.77.esi-ms:m/z614.3(m+1),631.4(m+18),636.4(m+23),652.5(m+39).c35h31n7o4[613.7].

相应的酰氯选用2-氟苯甲酰氯(44μl)与(s)-2(2-(4-(2-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5a)反应制得(s)-2-氟-n-(2-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)苯甲酰胺(6a-9)114mg，白色固体，产率76％，熔点：105-106℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ11.76(s,1h,phnh),8.95(d,j＝7.9hz,1h,nh),8.58(s,1h,triazole-h),8.48(d,j＝8.1hz,1h,ph-h),7.87(t,j＝7.1hz,1h,ph-h),7.78(d,j＝7.7hz,1h,ph-h),7.64(q,j＝6.0hz,1h,ph-h),7.50–7.33(m,3h,ph-h),7.27(t,j＝7.5hz,1h,ph-h),7.19(q,j＝8.3,7.3hz,3h,ph-h),7.11–6.99(m,2h,ph-h),6.93(d,j＝9.0hz,2h,ph-h),6.88(d,j＝6.5hz,2h,ph-h),5.22(d,j＝16.4hz,1h,triazolech),5.12(d,j＝16.3hz,1h,triazolech),4.46(td,j＝8.5,5.4hz,1h,ch),3.75(s,3h,och3),3.11(s,3h,nch3),2.92(dd,j＝13.5,5.0hz,1h,phch),2.69(dd,j＝13.4,9.1hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.13(c＝o),165.14(c＝o),162.58(c＝o),159.69(d,¹jcf＝248.4hz),159.02,145.90,137.64,135.72(d,³jcf＝9.7hz),133.94(d,³jcf＝8.6hz),130.84(d,⁴jcf＝2.1hz),129.32(2×c),129.08(2×c),128.99,128.69(2×c),128.21,127.01,125.41(d,⁴jcf＝3.4hz),125.07,124.98,124.13(d,²jcf＝13.4hz),122.63,119.87,117.13,116.90,115.10(2×c),55.84,52.11,52.03,37.89,37.77.esi-ms:m/z607.4(m+1),624.5(m+18),645.5(m+39).c34h31fn6o4[606.7].

相应的酰氯选用3-氟苯甲酰氯(45μl)与(s)-2(2-(4-(2-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基]-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5a)反应制得(s)-3-氟-n-(2-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)苯甲酰胺(6a-10)88mg，白色固体，产率59％，熔点：109-110℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ12.06(s,1h,phnh),8.97(d,j＝7.8hz,1h,nh),8.64(s,1h,triazole-h),8.52(d,j＝8.2hz,1h,ph-h),7.91(d,j＝7.7hz,1h,ph-h),7.83(t,j＝7.8hz,2h,ph-h),7.66(q,j＝7.8hz,1h,ph-h),7.51(dt,j＝8.3,4.4hz,1h,ph-h),7.42(t,j＝7.6hz,1h,ph-h),7.27(t,j＝7.5hz,1h,ph-h),7.20(q,j＝9.3,7.8hz,3h,ph-h),7.13–6.99(m,2h,ph-h),6.93(d,j＝8.8hz,2h,ph-h),6.89(d,j＝6.8hz,2h,ph-h),5.26(d,j＝16.4hz,1h,triazolech),5.16(d,j＝16.3hz,1h,triazolech),4.47(q,j＝8.3hz,1h,ch),3.75(s,3h,och3),3.11(s,3h,nch3),2.92(dd,j＝13.4,5.0hz,1h,phch),2.70(dd,j＝13.3,9.2hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.13(c＝o),165.16(c＝o),164.02(d,⁴jcf＝2.3hz,c＝o),162.67(d,¹jcf＝243.5hz),159.02,146.17,137.65(2×c),137.58(d,³jcf＝6.7hz),135.92,135.76,131.56(d,³jcf＝7.7hz),129.32(2×c),129.08(2×c),128.70(2×c),128.05,127.01,125.10,124.96,123.69(d,⁴jcf＝2.3hz),122.32,119.78,119.37(d,²jcf＝20.8hz),115.09(2×c),114.63(d,²jcf＝22.8hz),55.84,52.13,52.11,37.88,37.76.esi-ms:m/z607.4(m+1),624.4(m+18),629.4(m+23),645.4(m+39).c34h31fn6o4[606.7].

相应的酰氯选用4-氟苯甲酰氯(44μl)与(s)-2(2-(4-(2-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5a)反应制得(s)-4-氟-n-(2-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)苯甲酰胺(6a-11)101mg，白色固体，产率67％，熔点：123-124℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ12.01(s,1h,phnh),8.97(d,j＝7.8hz,1h,nh),8.63(s,1h,triazole-h),8.54(d,j＝8.2hz,1h,ph-h),8.12(dd,j＝8.7,5.5hz,2h,ph-h),7.88–7.78(m,1h,ph-h),7.43(q,j＝8.3,7.7hz,3h,ph-h),7.32–7.23(m,1h,ph-h),7.23–7.15(m,3h,ph-h),7.06(d,j＝6.8hz,2h,ph-h),6.93(d,j＝9.0hz,2h,ph-h),6.88(d,j＝6.7hz,2h,ph-h),5.26(d,j＝16.4hz,1h,triazolech),5.15(d,j＝16.3hz,1h,triazolech),4.47(td,j＝8.5,5.4hz,1h,ch),3.75(s,3h,och3),3.11(s,3h,nch3),2.93(dd,j＝13.4,5.0hz,1h,phch),2.69(dd,j＝13.4,9.2hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.15(c＝o),165.18(c＝o),164.72(d,¹jcf＝243.5hz),164.32(c＝o),159.03,146.23,137.65,136.12,135.76,131.67(d,⁴jcf＝2.3hz),130.41,130.32,129.31(2×c),129.09,129.04,128.70(2×c),128.03,127.02,125.08,124.74,122.22,119.61,116.44(2×c),116.22,115.09(2×c),55.84,52.16,52.09,37.86,37.76.esi-ms:m/z607.4(m+1),624.4(m+18),629.4(m+23),645.4(m+39).c34h31fn6o4[606.7].

相应的酰氯选用4-苯基苯甲酰氯(81mg)与(s)-2(2-(4-(2-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5a)反应制得(s)-n-(2-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)-[1,1'-联苯]-4-甲酰胺(6a-12)95mg，白色固体，产率58％，熔点：120-121℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ12.16(s,1h,phnh),8.98(d,j＝7.8hz,1h,nh),8.67(s,1h,triazole-h),8.63(d,j＝8.3hz,1h,ph-h),8.16(d,j＝8.2hz,2h,ph-h),7.91(d,j＝8.2hz,2h,ph-h),7.83(d,j＝7.7hz,1h,ph-h),7.79(d,j＝7.6hz,2h,ph-h),7.52(t,j＝7.5hz,2h,ph-h),7.30–7.15(m,5h,ph-h),7.11–7.04(m,2h,ph-h),6.95–6.85(m,5h,ph-h),5.27(d,j＝16.4hz,1h,triazolech),5.18(d,j＝13.5hz,1h,triazolech),4.51–4.42(m,1h,ch),3.73(s,3h,och3),3.11(s,3h,nch3),2.93(dd,j＝13.4,5.0hz,1h,phch),2.70(dd,j＝13.3,9.3hz,1h,phch).¹³cnmr(101mhz,dmso-d6)δ171.15(c＝o),165.18(c＝o),165.00(c＝o),159.02,146.36,146.05,143.92,139.41,137.65,136.30,135.76,133.90,129.54(2×c),129.32(2×c),129.09(2×c),128.70(2×c),128.34(2×c),127.53(2×c),127.42(2×c),127.02,125.10,124.60,132.22,121.99,119.27,116.26,115.09(2×c),55.83,52.15,52.11,37.87,37.76.esi-ms:m/z665.4(m+1),682.5(m+18).c40h36n6o4[664.8].

相应的酰氯选用乙酰氯(26μl)与(s)-2(2-(4-(3-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5b)反应制得(s)-2-(2-(4-(3-乙酰氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(6b-1)68mg，白色固体，产率52％，熔点：206-207℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ10.05(s,1h,phnh),8.91(d,j＝7.8hz,1h,nh),8.34(s,1h,triazole-h),8.12(s,1h,ph-h),7.56(d,j＝8.0hz,1h,ph-h),7.45(d,j＝7.7hz,1h,ph-h),7.36(t,j＝7.9hz,1h,ph-h),7.27–7.14(m,3h,ph-h),7.14–7.00(m,2h,ph-h),6.94(d,j＝8.9hz,2h,ph-h),6.89(d,j＝6.4hz,2h,ph-h),5.17(d,j＝16.3hz,1h,triazolech),5.06(d,j＝16.3hz,1h,triazolech),4.46(td,j＝8.5,5.4hz,1h,ch),3.76(s,3h,och3),3.11(s,3h,nch3),2.92(dd,j＝13.5,5.0hz,1h,phch),2.70(dd,j＝13.5,9.2hz,1h,phch),2.07(s,3h,coch3).¹³cnmr(100mhz,dmso-d6)δ171.18(c＝o),168.87(c＝o),165.46,159.02,146.43,140.33,137.67,135.79,131.54,129.75,129.33(2×c),129.10,128.70(2×c),127.03,123.36(2×c),120.40,118.85,115.92,115.10(2×c),55.85,52.09,51.80,37.88,37.77,24.53.esi-ms:m/z527.4(m+1),544.5(m+18),549.4(m+23),565.5(m+39).c29h30n6o4[526.6].

相应的酰氯选用苯甲酰氯(43μl)与(s)-2(2-(4-(3-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5b)反应制得(s)-n-(3-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)苯甲酰胺(6b-2)106mg，白色固体，产率73％，熔点：135-136℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ10.38(s,1h,phnh),8.93(d,j＝7.8hz,1h,nh),8.37(s,1h,ph-h),8.34(s,1h,triazole-h),8.00(d,j＝7.1hz,2h,ph-h),7.78(d,j＝8.0hz,1h,ph-h),7.62-7.52(m,4h,ph-h),7.42(t,j＝7.9hz,1h,ph-h),7.23-7.18(m,3h,ph-h),7.08–7.06(m,2h,ph-h),6.95-6.88(m,4h,ph-h),5.18(d,j＝16.3hz,1h,triazolech),5.07(d,j＝16.3hz,1h,triazolech),4.46(td,j＝8.5,5.5hz,1h,ch),3.75(s,3h,och3),3.11(s,3h,nch3),2.92(dd,j＝13.4,5.0hz,1h,phch),2.69(dd,j＝13.5,9.2hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.19(c＝o),166.06(c＝o),165.48(c＝o),159.02,146.45,140.20,137.68,135.79,135.30,132.10,131.52,129.70,129.34(2×c),129.11,128.87(2×c),128.71(2×c),128.16(2×c),127.04,123.43(2×c),121.04,120.22,117.40,115.10(2×c),55.85,52.11,51.82,37.87,37.78.esi-ms:m/z589.5(m+1),606.4(m+18),611.4(m+23),627.4(m+39).c34h32n6o4[588.7].

相应的酰氯选用4-甲基苯甲酰氯(49μl)与(s)-2(2-(4-(3-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5b)反应制得(s)-n-(3-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)-4-甲基苯甲酰胺(6b-3)94mg，白色固体，产率63％，熔点：212-213℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ10.28(s,1h,phnh),8.92(d,j＝7.8hz,1h,nh),8.37(s,1h,ph-h),8.34(s,1h,triazole-h),7.92(d,j＝8.0hz,2h,ph-h),7.78(d,j＝7.9hz,1h,ph-h),7.53(d,j＝7.7hz,1h,ph-h),7.42(t,j＝7.9hz,1h,ph-h),7.35(d,j＝8.0hz,2h,ph-h),7.21(q,j＝7.9,7.0hz,3h,ph-h),7.15–7.01(m,2h,ph-h),6.94(d,j＝8.9hz,2h,ph-h),6.90(d,j＝6.6hz,2h,ph-h),5.18(d,j＝16.3hz,1h,triazolech),5.07(d,j＝16.3hz,1h,triazolech),4.47(td,j＝8.4,5.3hz,1h,ch),3.76(s,3h,och3),3.11(s,3h,nch3),2.93(dd,j＝13.4,5.0hz,1h,phch),2.70(dd,j＝13.4,9.2hz,1h,phch),2.40(s,3h,phch3).¹³cnmr(100mhz,dmso-d6)δ171.19(c＝o),165.85(c＝o),165.48(c＝o),159.02,146.47,142.11,140.27,137.68,135.79,132.40,131.49,129.67,129.39(2×c),129.34(2×c),129.12,128.71(2×c),128.19(2×c),127.04,123.41(2×c),120.92,120.21,117.39,115.10(2×c),55.85,52.10,51.81,37.87,37.78,21.50.esi-ms:m/z603.4(m+1),620.5(m+18),625.4(m+23),641.3(m+39).c35h34n6o4[602.7].

相应的酰氯选用2-甲氧基苯甲酰氯(54μl)与(s)-2(2-(4-(3-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5b)反应制得(s)-2-甲氧基-n-(3-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)苯甲酰胺(6b-4)99mg，白色固体，产率65％，熔点：125-126℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ10.23(s,1h,phnh),8.93(d,j＝7.8hz,1h,nh),8.37(s,1h,ph-h),8.29(s,1h,triazole-h),7.68(dd,j＝11.9,8.0hz,2h,ph-h),7.52(t,j＝9.4hz,2h,ph-h),7.41(t,j＝7.9hz,1h,ph-h),7.30–7.15(m,4h,ph-h),7.08(t,j＝7.3hz,3h,ph-h),6.94(d,j＝8.8hz,2h,ph-h),6.90(d,j＝6.6hz,2h,ph-h),5.18(d,j＝16.3hz,1h,triazolech),5.07(d,j＝16.3hz,1h,triazolech),4.47(td,j＝8.4,5.4hz,1h,ch),3.92(s,3h,och3),3.76(s,3h,och3),3.12(s,3h,nch3),2.93(dd,j＝13.4,5.0hz,1h,phch),2.70(dd,j＝13.4,9.2hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.18(c＝o),165.46(c＝o),165.10(c＝o),159.02,156.96,146.43,140.06,137.68,135.79,132.52,131.62,130.13,129.76,129.34(2×c),129.11,128.71(2×c),127.03,125.41,123.45,120.95(2×c),120.88,119.65,116.75,115.10(2×c),112.46,56.37,55.85,52.10,51.83,37.89,37.77.esi-ms:m/z619.5(m+1),636.4(m+18),641.3(m+23),657.3(m+39).c35h34n6o5[618.7].

相应的酰氯选用3-甲氧基苯甲酰氯(54μl)与(s)-2(2-(4-(3-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5b)反应制得(s)-3-甲氧基-n-(3-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)苯甲酰胺(6b-5)73mg，白色固体，产率48％，熔点：115-116℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ10.34(s,1h,phnh),8.92(d,j＝7.6hz,1h,nh),8.37(s,1h,ph-h),8.33(s,1h,triazole-h),7.79(d,j＝7.7hz,1h,ph-h),7.59(d,j＝7.5hz,1h,ph-h),7.54(s,2h,ph-h),7.45(dt,j＝13.0,7.9hz,2h,ph-h),7.29–7.13(m,4h,ph-h),7.08(d,j＝6.6hz,2h,ph-h),6.94(d,j＝8.5hz,2h,ph-h),6.90(d,j＝6.5hz,2h,ph-h),5.19(d,j＝16.3hz,1h,triazolech),5.08(d,j＝16.3hz,1h,triazolech),4.48(q,j＝7.9hz,1h,ch),3.86(s,3h,och3),3.76(s,3h,och3),3.12(s,3h,nch3),2.93(dd,j＝13.2,4.6hz,1h,phch),2.71(dd,j＝13.0,9.4hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.19(c＝o),165.75(c＝o),165.47(c＝o),159.65,159.02,146.44,140.12,137.68,136.68,135.79,131.52,130.03,129.69,129.34(2×c),129.10,128.71(2×c),127.03,123.42,121.09,120.38(2×c),120.31,117.87,117.49,115.11(2×c),113.36,55.85,55.82,52.10,51.83,37.89,37.78.esi-ms:m/z619.5(m+1),636.4(m+18),641.3(m+23),657.5(m+39).c35h34n6o5[618.7].

相应的酰氯选用4-甲氧基苯甲酰氯(63mg)与(s)-2(2-(4-(3-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5b)反应制得(s)-4-甲氧基-n-(3-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)苯甲酰胺(6b-6)97mg，白色固体，产率63％，熔点：199-200℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ10.20(s,1h,phnh),8.91(d,j＝7.8hz,1h,nh),8.36(s,1h,ph-h),8.32(s,1h,triazole-h),8.01(d,j＝8.7hz,2h,ph-h),7.78(d,j＝8.1hz,1h,ph-h),7.52(d,j＝7.7hz,1h,ph-h),7.41(t,j＝7.9hz,1h,ph-h),7.26–7.16(m,3h,ph-h),7.08(d,j＝8.7hz,4h,ph-h),6.94(d,j＝8.9hz,2h,ph-h),6.89(d,j＝6.6hz,2h,ph-h),5.18(d,j＝16.3hz,1h,triazolech),5.07(d,j＝16.3hz,1h,triazolech),4.47(td,j＝8.4,5.6hz,1h,ch),3.85(s,3h,och3),3.76(s,3h,och3),3.11(s,3h,nch3),2.93(dd,j＝13.5,5.1hz,1h,phch),2.70(dd,j＝13.4,9.2hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.19(c＝o),165.47(c＝o),165.40(c＝o),162.40,159.02,146.50,140.37,137.68,135.79,131.47,130.10(2×c),129.63,129.34(2×c),129.11,128.71(2×c),127.30,127.03,123.38(2×c),120.80,120.19,117.38,115.11(2×c),114.08(2×c),55.91,55.85,52.10,51.83,37.89,37.78.esi-ms:m/z619.5(m+1),636.4(m+18),641.4(m+23),657.5(m+39).c35h34n6o5[618.7].

相应的酰氯选用4-甲酸甲酯苯甲酰氯(74mg)与(s)-2(2-(4-(3-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5b)反应制得(s)-4-((3-(1-(2-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙烷-2-基)氨基)-2-(甲基)氧代乙基)-1h-1,2,3-三唑-4-基)苯基)氨基甲酰基)苯甲酸甲酯(6b-7)94mg，白色固体，产率58％，熔点：153-154℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ12.04(s,1h,phnh),8.95(d,j＝7.8hz,1h,nh),8.61(s,1h,triazole-h),8.49(d,j＝8.2hz,1h,ph-h),8.21–8.09(m,4h,ph-h),7.83(d,j＝7.4hz,1h,ph-h),7.43(t,j＝7.5hz,1h,ph-h),7.28(t,j＝7.5hz,1h,ph-h),7.19(q,j＝8.7,7.5hz,3h,ph-h),7.06(d,j＝6.9hz,2h,ph-h),6.92(d,j＝8.9hz,2h,ph-h),6.88(d,j＝6.7hz,2h,ph-h),5.25(d,j＝16.3hz,1h,triazolech),5.15(d,j＝16.3hz,1h,triazolech),4.47(td,j＝8.4,5.6hz,1h,ch),3.90(s,3h,cooch3),3.74(s,3h,och3),3.11(s,3h,nch3),2.92(dd,j＝13.5,5.0hz,1h,phch),2.69(dd,j＝13.4,9.1hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.13(c＝o),166.05(c＝o),165.16(c＝o),164.61(c＝o),159.02,146.05,139.26,137.65,135.86,135.76,132.82,130.06(2×c),129.31(2×c),129.07(2×c),128.70(2×c),128.11(2×c),127.01(2×c),125.11(2×c),122.60(2×c),120.12,115.09(2×c),55.84,52.94,52.14,52.08,37.86,37.76.esi-ms:m/z647.4(m+1),664.4(m+18),669.4(m+23),685.5(m+39).c36h34n6o6[646.7].

相应的酰氯选用4-氰基苯甲酰氯(62mg)与(s)-2(2-(4-(3-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5b)反应制得(s)-4-氰基-n-(3-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)苯甲酰胺(6b-8)55mg，白色固体，产率36％，熔点：224-225℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ10.61(s,1h,phnh),8.93(d,j＝7.8hz,1h,nh),8.39(s,1h,ph-h),8.34(s,1h,triazole-h),8.15(d,j＝8.3hz,2h,ph-h),8.05(d,j＝8.3hz,2h,ph-h),7.78(d,j＝8.1hz,1h,ph-h),7.57(d,j＝7.7hz,1h,ph-h),7.45(t,j＝7.9hz,1h,ph-h),7.21(q,j＝7.8,7.0hz,3h,ph-h),7.13–7.02(m,2h,ph-h),6.94(d,j＝8.9hz,2h,ph-h),6.89(d,j＝6.6hz,2h,ph-h),5.19(d,j＝16.3hz,1h,triazolech),5.08(d,j＝16.3hz,1h,triazolech),4.47(td,j＝8.5,5.1hz,1h,ch),3.76(s,3h,och3),3.12(s,3h,nch3),2.93(dd,j＝13.4,5.0hz,1h,phch),2.70(dd,j＝13.4,9.2hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.19(c＝o),165.46(c＝o),164.67(c＝o),159.02,146.33,139.79,139.31,137.68,135.79,132.95(2×c),131.61,129.81,129.33(2×c),129.11,129.03(2×c),128.71(2×c),127.03,123.48(2×c),121.47,120.27,118.80,117.43,115.10(2×c),114.36,55.85,52.11,51.83,37.88,37.77.esi-ms:m/z614.3(m+1),631.5(m+18),636.3(m+23),652.4(m+39).c35h31n7o4[613.7].

相应的酰氯选用2-氟苯甲酰氯(44μl)与(s)-2(2-(4-(3-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5b)反应制得(s)-2-氟-n-(3-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)苯甲酰胺(6b-9)92mg，白色固体，产率61％，熔点：114-115℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ10.55(s,1h,phnh),8.93(d,j＝7.9hz,1h,nh),8.38(s,1h,ph-h),8.30(s,1h,triazole-h),7.70(t,j＝7.7hz,2h,ph-h),7.65–7.57(m,1h,ph-h),7.55(d,j＝7.8hz,1h,ph-h),7.43(t,j＝7.9hz,1h,ph-h),7.36(q,j＝9.0,7.4hz,2h,ph-h),7.26–7.16(m,3h,ph-h),7.14–7.01(m,2h,ph-h),6.94(d,j＝8.9hz,2h,ph-h),6.90(d,j＝6.4hz,2h,ph-h),5.18(d,j＝16.3hz,1h,triazolech),5.07(d,j＝16.3hz,1h,triazolech),4.47(td,j＝8.4,5.5hz,1h,ch),3.76(s,3h,och3),3.11(s,3h,nch3),2.93(dd,j＝13.4,5.0hz,1h,phch),2.70(dd,j＝13.4,9.2hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.19(c＝o),165.46(c＝o),163.35(c＝o),159.36(d,¹jcf＝247.0hz),159.02,146.34,139.88,137.68,135.79,133.02(d,³jcf＝8.4hz),131.67,130.38(d,⁴jcf＝2.7hz),129.86,129.34(2×c),129.11,128.71(2×c),127.03,125.44(d,²jcf＝15.0hz),125.04(d,⁴jcf＝3.4hz),123.47,121.25,119.63,116.75(2×c),116.53,115.10(2×c),55.85,52.10,51.82,37.88,37.77.esi-ms:m/z607.4(m+1),624.4(m+18),629.4(m+23),645.4(m+39).c34h31fn6o4[606.7].

相应的酰氯选用3-氟苯甲酰氯(45μl)与(s)-2(2-(4-(3-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5b)反应制得(s)-3-氟-n-(3-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)苯甲酰胺(6b-10)112mg，白色固体，产率75％，熔点：167-168℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ10.44(s,1h,phnh),8.93(d,j＝7.8hz,1h,nh),8.39(s,1h,ph-h),8.34(s,1h,triazole-h),7.83(dt,j＝24.4,8.0hz,3h,ph-h),7.61(q,j＝7.9hz,1h,ph-h),7.56(d,j＝7.7hz,1h,ph-h),7.46(dt,j＝16.2,7.3hz,2h,ph-h),7.29–7.15(m,3h,ph-h),7.15–7.01(m,2h,ph-h),6.94(d,j＝8.8hz,2h,ph-h),6.90(d,j＝6.5hz,2h,ph-h),5.19(d,j＝16.3hz,1h,triazolech),5.08(d,j＝16.3hz,1h,triazolech),4.54–4.41(m,1h,ch),3.76(s,3h,och3),3.12(s,3h,nch3),2.93(dd,j＝13.4,5.0hz,1h,phch),2.70(dd,j＝13.4,9.3hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.19(c＝o),165.47(c＝o),164.64(d,⁴jcf＝2.4hz,c＝o),162.39(d,¹jcf＝242.7hz),159.02,146.39,139.92,137.68,137.57(d,³jcf＝6.8hz),135.79,131.56,131.11,131.03,129.75,129.34(2×c),129.11,128.71(2×c),127.03,124.40(d,⁴jcf＝2.6hz),123.45,121.28,120.28,119.01(d,²jcf＝21.4hz),117.46,115.10(2×c),114.88,55.85,52.11,51.83,37.88,37.77.esi-ms:m/z607.4(m+1),624.4(m+18),629.4(m+23),645.4(m+39).c34h31fn6o4[606.7].

相应的酰氯选用4-氟苯甲酰氯(44μl)与(s)-2(2-(4-(3-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5b)反应制得(s)-4-氟-n-(3-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)苯甲酰胺(6b-11)45mg，白色固体，产率30％，熔点：173-174℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ10.44(s,1h,phnh),8.95(d,j＝7.8hz,1h,nh),8.37(s,1h,ph-h),8.34(s,1h,triazole-h),8.11(dd,j＝8.1,5.7hz,2h,ph-h),7.79(d,j＝7.8hz,1h,ph-h),7.53(d,j＝7.6hz,1h,ph-h),7.48–7.31(m,3h,ph-h),7.21(q,j＝7.2,6.4hz,3h,ph-h),7.12–6.99(m,2h,ph-h),6.94(d,j＝8.7hz,2h,ph-h),6.90(d,j＝6.7hz,2h,ph-h),5.19(d,j＝16.3hz,1h,triazolech),5.08(d,j＝16.2hz,1h,triazolech),4.46(q,j＝8.1hz,1h,ch),3.76(s,3h,och3),3.11(s,3h,nch3),2.92(dd,j＝13.5,4.8hz,1h,phch),2.70(dd,j＝13.3,9.3hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.17(c＝o),165.47(c＝o),165.00(d,¹jcf＝245.0hz),164.93(c＝o),159.02,146.43,140.13,137.71,135.82,130.99(2×c),130.90,129.67,129.35(2×c),129.10,128.69(2×c),127.01,123.40,121.09,120.31,117.50,115.89(2×c),115.67(2×c),115.11(2×c),55.87,52.13,51.85,37.88,37.78.esi-ms:m/z607.4(m+1),624.4(m+18),629.4(m+23),645.3(m+39).c34h31fn6o4[606.7].

相应的酰氯选用4-苯基苯甲酰氯(81mg)与(s)-2(2-(4-(3-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5b)反应制得(s)-n-(3-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)-[1,1'-联苯]-4-甲酰胺(6b-12)96mg，白色固体，产率58％，熔点：170-171℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ10.43(s,1h,phnh),8.94(d,j＝7.8hz,1h,nh),8.39(s,1h,ph-h),8.38(s,1h,triazole-h),8.12(d,j＝8.2hz,2h,ph-h),7.86(d,j＝8.3hz,2h,ph-h),7.82(d,j＝8.4hz,1h,ph-h),7.78(d,j＝7.6hz,2h,ph-h),7.53(q,j＝7.4hz,3h,ph-h),7.44(dt,j＝7.8,4.3hz,2h,ph-h),7.22(q,j＝7.8,7.0hz,3h,ph-h),7.14–7.01(m,2h,ph-h),6.95(d,j＝8.8hz,2h,ph-h),6.90(d,j＝6.6hz,2h,ph-h),5.19(d,j＝16.3hz,1h,triazolech),5.08(d,j＝16.3hz,1h,triazolech),4.47(q,j＝8.4hz,1h,ch),3.76(s,3h,och3),3.12(s,3h,nch3),2.93(dd,j＝13.4,5.0hz,1h,phch),2.71(dd,j＝13.4,9.2hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.19(c＝o),165.66(c＝o),165.48(c＝o),159.02,146.47,143.62,140.23,139.57,137.69,135.79,134.03,131.54,129.71,129.54(2×c),129.34(2×c),129.11(2×c),128.88(2×c),128.71(2×c),128.63,127.40(2×c),127.07(2×c),123.43(2×c),121.05,120.24,117.41,115.11(2×c),55.85,52.11,51.83,37.88,37.78.esi-ms:m/z665.4(m+1),682.5(m+18),687.4(m+23).c40h36n6o4[664.8].

相应的酰氯选用乙酰氯(26μl)与(s)-2(2-(4-(4-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5c)反应制得(s)-2-(2-(4-(4-乙酰氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(6c-1)61mg，白色固体，产率47％，熔点：134-135℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ10.04(s,1h,phnh),8.89(d,j＝7.8hz,1h,nh),8.30(s,1h,triazole-h),7.75(d,j＝8.5hz,2h,ph-h),7.65(d,j＝8.5hz,2h,ph-h),7.21(q,j＝7.2,6.7hz,3h,ph-h),7.06(d,j＝6.6hz,2h,ph-h),6.93(d,j＝8.9hz,2h,ph-h),6.89(d,j＝6.5hz,2h,ph-h),5.15(d,j＝16.4hz,1h,triazolech),5.04(d,j＝16.3hz,1h,triazolech),4.46(q,j＝8.3hz,1h,ch),3.75(s,3h,och3),3.11(s,3h,nch3),2.92(dd,j＝13.5,5.0hz,1h,phch),2.69(dd,j＝13.3,9.2hz,1h,phch),2.06(s,3h,coch3).¹³cnmr(100mhz,dmso-d6)δ171.18(c＝o),168.78(c＝o),165.48(c＝o),159.02,146.40,139.44,137.68,135.80,129.33(2×c),129.10,128.70(2×c),127.02,125.97(2×c),125.89,122.70(2×c),119.67(2×c),115.10(2×c),55.85,52.09,51.80,37.89,37.77,24.51.esi-ms:m/z527.4(m+1),544.5(m+18),549.4(m+23),565.4(m+39).c29h30n6o4[526.6].

相应的酰氯选用苯甲酰氯(43μl)与(s)-2(2-(4-(4-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5c)反应制得(s)-n-(4-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)苯甲酰胺(6c-2)70mg，白色固体，产率48％，熔点：171-172℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ10.36(s,1h,phnh),8.91(d,j＝7.8hz,1h,nh),8.35(s,1h,triazole-h),7.98(d,j＝7.2hz,2h,ph-h),7.89(d,j＝8.7hz,2h,ph-h),7.83(d,j＝8.6hz,2h,ph-h),7.61(t,j＝7.2hz,1h,ph-h),7.55(t,j＝7.3hz,2h,ph-h),7.22(q,j＝7.3,6.7hz,3h,ph-h),7.07(d,j＝6.5hz,2h,ph-h),6.94(d,j＝8.9hz,2h,ph-h),6.90(d,j＝6.5hz,2h,ph-h),5.17(d,j＝16.3hz,1h,triazolech),5.06(d,j＝16.3hz,1h,triazolech),4.47(td,j＝8.4,5.6hz,1h,ch),3.76(s,3h,och3),3.12(s,3h,nch3),2.93(dd,j＝13.4,5.1hz,1h,phch),2.71(dd,j＝13.6,9.2hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.18(c＝o),166.03(c＝o),165.49(c＝o),159.03,145.38,139.29,137.69,135.80,135.39,132.06,129.34(2×c),129.10(2×c),128.86(2×c),128.71(2×c),128.13(2×c),127.03,126.53,125.87(2×c),122.87,121.05(2×c),115.11(2×c),55.86,52.09,51.83,37.90,37.78.esi-ms:m/z589.4(m+1),606.4(m+18),611.3(m+23),627.4(m+39).c34h32n6o4[588.7].

相应的酰氯选用4-甲基苯甲酰氯(49μl)与(s)-2(2-(4-(4-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5c)反应制得(s)-n-(4-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)-4-甲基苯甲酰胺(6c-3)72mg，白色固体，产率48％，熔点：138-139℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ10.27(s,1h,phnh),8.91(d,j＝7.7hz,1h,nh),8.35(s,1h,triazole-h),7.99–7.85(m,4h,ph-h),7.82(d,j＝8.3hz,2h,ph-h),7.35(d,j＝7.6hz,2h,ph-h),7.22(q,j＝8.0,6.9hz,3h,ph-h),7.07(d,j＝7.0hz,2h,ph-h),6.94(d,j＝8.4hz,2h,ph-h),6.90(d,j＝6.4hz,2h,ph-h),5.17(d,j＝16.3hz,1h,triazolech),5.06(d,j＝16.3hz,1h,triazolech),4.47(q,j＝7.7hz,1h,ch),3.76(s,3h,och3),3.12(s,3h,nch3),2.93(dd,j＝13.2,4.5hz,1h,phch),2.76–2.64(m,1h,phch),2.40(s,3h,phch3).¹³cnmr(100mhz,dmso-d6)δ171.18(c＝o),165.82(c＝o),165.49(c＝o),159.02,146.40,142.08,139.36,137.68,135.80,132.48,129.38(2×c),129.34(2×c),129.10(2×c),128.70(2×c),128.17(2×c),127.03,126.42,125.85(2×c),122.84,121.03(2×c),115.10(2×c),55.86,52.09,51.83,37.90,37.78,21.49.esi-ms:m/z603.4(m+1),620.5(m+18),625.5(m+23),641.4(m+39).c35h34n6o4[602.7].

相应的酰氯选用2-甲氧基苯甲酰氯(54μl)与(s)-2(2-(4-(4-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5c)反应制得(s)-2-甲氧基-n-(4-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)苯甲酰胺(6c-4)53mg，白色固体，产率34％，熔点：146-147℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ10.23(s,1h,phnh),8.91(d,j＝7.7hz,1h,nh),8.35(s,1h,triazole-h),7.92–7.77(m,4h,ph-h),7.66(d,j＝7.3hz,1h,ph-h),7.52(t,j＝7.6hz,1h,ph-h),7.21(t,j＝8.2hz,4h,ph-h),7.08(t,j＝7.2hz,3h,ph-h),6.94(d,j＝8.6hz,2h,ph-h),6.90(d,j＝6.7hz,2h,ph-h),5.17(d,j＝16.3hz,1h,triazolech),5.06(d,j＝16.3hz,1h,triazolech),4.47(q,j＝8.2hz,1h,ch),3.92(s,3h,och3),3.76(s,3h,och3),3.12(s,3h,nch3),2.93(dd,j＝13.4,4.9hz,1h,phch),2.71(dd,j＝13.4,9.3hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.18(c＝o),165.49(c＝o),164.97(c＝o),159.03,156.95,146.38,139.15,137.69,135.81,132.52,130.13,129.34(2×c),129.10,128.70(2×c),127.03,126.39,125.96(2×c),125.39,122.83,120.96(2×c),120.42(2×c),115.11(2×c),112.47,56.37,55.86,52.09,51.82,37.91,37.78.esi-ms:m/z619.5(m+1),636.4(m+18),641.4(m+23).c35h34n6o5[618.7].

相应的酰氯选用3-甲氧基苯甲酰氯(54μl)与(s)-2(2-(4-(4-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5c)反应制得(s)-3-甲氧基-n-(4-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)苯甲酰胺(6c-5)80mg，白色固体，产率52％，熔点：141-142℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ10.32(s,1h,phnh),8.91(d,j＝7.8hz,1h,nh),8.35(s,1h,triazole-h),7.87(d,j＝8.7hz,2h,ph-h),7.83(d,j＝8.7hz,2h,ph-h),7.56(d,j＝7.6hz,1h,ph-h),7.51(s,1h,ph-h),7.46(t,j＝7.9hz,1h,ph-h),7.26–7.15(m,4h,ph-h),7.07(d,j＝6.5hz,2h,ph-h),6.94(d,j＝8.8hz,2h,ph-h),6.90(d,j＝6.5hz,2h,ph-h),5.17(d,j＝16.3hz,1h,triazolech),5.06(d,j＝16.3hz,1h,triazolech),4.47(q,j＝8.3hz,1h,ch),3.85(s,3h,och3),3.76(s,3h,och3),3.12(s,3h,nch3),2.93(dd,j＝13.4,5.0hz,1h,phch),2.70(dd,j＝13.4,9.2hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.18(c＝o),165.74(c＝o),165.48(c＝o),159.65,159.03,146.38,139.20,137.68,136.79,135.81,130.03,129.34(2×c),129.10,128.70(2×c),127.02,126.58,125.86(2×c),122.87,121.13(2×c),120.35(2×c),117.81,115.11(2×c),113.39,55.82(2×c),52.09,51.84,37.91,37.78.esi-ms:m/z619.5(m+1),636.4(m+18),641.3(m+23),657.4(m+39).c35h34n6o5[618.7].

相应的酰氯选用4-甲氧基苯甲酰氯(63mg)与(s)-2(2-(4-(4-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5c)反应制得(s)-4-甲氧基-n-(4-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)苯甲酰胺(6c-6)85mg，白色固体，产率55％，熔点：141-142℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ10.20(s,1h,phnh),8.92(d,j＝7.1hz,1h,nh),8.34(s,1h,triazole-h),7.98(d,j＝7.8hz,2h,ph-h),7.86(d,j＝7.5hz,2h,ph-h),7.81(d,j＝7.6hz,2h,ph-h),7.26–7.15(m,3h,ph-h),7.08(d,j＝7.2hz,4h,ph-h),6.94(d,j＝8.1hz,2h,ph-h),6.89(d,j＝6.0hz,2h,ph-h),5.16(d,j＝16.1hz,1h,triazolech),5.06(d,j＝16.3hz,1h,triazolech),4.46(q,j＝8.5hz,1h,ch),3.85(s,3h,och3),3.76(s,3h,och3),3.11(s,3h,nch3),2.99–2.87(m,1h,phch),2.76–2.62(m,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.19(c＝o),165.50(c＝o),165.36(c＝o),162.39,159.02,146.42,139.47,137.69,135.80,130.08(2×c),129.34(2×c),129.11(2×c),128.71(2×c),127.37,127.03,126.29,125.83(2×c),122.82,120.99(2×c),115.10(2×c),114.08(2×c),55.91,55.85,52.10,51.82,37.88,37.78.esi-ms:m/z619.5(m+1),636.4(m+18),641.4(m+23),657.4(m+39).c35h34n6o5[618.7].

相应的酰氯选用4-甲酸甲酯苯甲酰氯(74mg)与(s)-2(2-(4-(4-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5c)反应制得(s)-4-((4-(((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙烷-2-基)氨基)-2-(甲基)氧代乙基)-1h-1,2,3-三唑-4-基)苯基)氨基甲酰基)苯甲酸甲酯(6c-7)123mg，白色固体，产率77％，熔点：129-130℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ10.54(s,1h,phnh),8.90(d,j＝7.7hz,1h,nh),8.35(s,1h,triazole-h),8.10(s,4h,ph-h),7.89(d,j＝8.6hz,2h,ph-h),7.84(d,j＝8.6hz,2h,ph-h),7.28–7.14(m,3h,ph-h),7.07(d,j＝6.6hz,2h,ph-h),6.94(d,j＝8.7hz,2h,ph-h),6.90(d,j＝6.7hz,2h,ph-h),5.17(d,j＝16.3hz,1h,triazolech),5.06(d,j＝16.3hz,1h,triazolech),4.48(q,j＝8.2hz,1h,ch),3.91(s,3h,och3),3.76(s,3h,och3),3.11(s,3h,nch3),2.93(dd,j＝13.4,5.0hz,1h,phch),2.70(dd,j＝13.3,9.1hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.18(c＝o),166.15(c＝o),165.49(c＝o),165.17(c＝o),159.03,146.33,139.47,139.00,137.68,135.80,132.51,129.66(2×c),129.34(2×c),129.10(2×c),128.70(2×c),128.58(2×c),127.02,126.83,125.92(2×c),122.94,121.15(2×c),115.10(2×c),55.86,52.91,52.10,51.84,37.90,37.77.esi-ms:m/z647.5(m+1),664.4(m+18),669.4(m+23).c36h34n6o6[646.7].

相应的酰氯选用4-氰基苯甲酰氯(62mg)与(s)-2(2-(4-(4-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5c)反应制得(s)-4-氰基-n-(4-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)苯甲酰胺(6c-8)109mg，白色固体，产率71％，熔点：140-141℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ10.60(s,1h,phnh),8.92(d,j＝7.8hz,1h,nh),8.36(s,1h,triazole-h),8.13(d,j＝8.3hz,2h,ph-h),8.04(d,j＝8.3hz,2h,ph-h),7.88(d,j＝8.9hz,2h,ph-h),7.84(d,j＝8.9hz,2h,ph-h),7.28–7.13(m,3h,ph-h),7.13–7.00(m,2h,ph-h),6.94(d,j＝8.8hz,2h,ph-h),6.90(d,j＝6.5hz,2h,ph-h),5.17(d,j＝16.4hz,1h,triazolech),5.06(d,j＝16.3hz,1h,triazolech),4.47(q,j＝8.4hz,1h,ch),3.76(s,3h,och3),3.11(s,3h,nch3),2.93(dd,j＝13.4,5.0hz,1h,phch),2.70(dd,j＝13.6,9.3hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.18(c＝o),165.49(c＝o),164.62(c＝o),159.02,146.28,139.39,138.84,137.69,135.80,132.95(2×c),129.33(2×c),129.10(2×c),129.02(2×c),128.70(2×c),127.02,126.96,125.93(2×c),122.98,121.16(2×c),118.80,115.10(2×c),114.33,55.85,52.10,51.82,37.89,37.77.esi-ms:m/z614.3(m+1),631.5(m+18),636.4(m+23).c35h31n7o4[613.7].

相应的酰氯选用2-氟苯甲酰氯(44μl)与(s)-2(2-(4-(4-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5c)反应制得(s)-2-氟-n-(4-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)苯甲酰胺(6c-9)64mg，白色固体，产率42％，熔点：122-123℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ10.53(s,1h,phnh),8.91(d,j＝7.8hz,1h,nh),8.35(s,1h,triazole-h),7.82(s,4h,ph-h),7.73–7.65(m,1h,ph-h),7.64–7.55(m,1h,ph-h),7.38(d,j＝10.4hz,1h,ph-h),7.33(d,j＝7.0hz,1h,ph-h),7.26–7.15(m,3h,ph-h),7.12–7.01(m,2h,ph-h),6.94(d,j＝9.0hz,2h,ph-h),6.89(d,j＝6.3hz,2h,ph-h),5.17(d,j＝16.3hz,1h,triazolech),5.06(d,j＝16.3hz,1h,triazolech),4.46(td,j＝8.4,5.5hz,1h,ch),3.76(s,3h,och3),3.11(s,3h,nch3),2.92(dd,j＝13.4,5.1hz,1h,phch),2.70(dd,j＝13.4,9.2hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.18(c＝o),165.48(c＝o),163.23(c＝o),159.33(d,¹jcf＝247.2hz),159.02,146.30,138.95,137.69,135.80,133.00(d,³jcf＝8.5hz),130.37(d,⁴jcf＝2.9hz),129.33(2×c),129.11,128.71(2×c),127.03,126.73,126.01(2×c),125.46(d,²jcf＝15.2hz),125.04(d,⁴jcf＝3.4hz),122.93,120.45(2×c),116.75,116.53,115.10(2×c),55.86,52.10,51.82,37.89,37.78.esi-ms:m/z607.4(m+1),624.5(m+18),629.4(m+23).c34h31fn6o4[606.7].

相应的酰氯选用3-氟苯甲酰氯(45μl)与(s)-2(2-(4-(4-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5c)反应制得(s)-3-氟-n-(4-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)苯甲酰胺(6c-10)70mg，白色固体，产率46％，熔点：120-121℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ10.43(s,1h,phnh),8.92(d,j＝7.8hz,1h,nh),8.36(s,1h,triazole-h),7.85(q,j＝8.6hz,5h,ph-h),7.79(d,j＝9.7hz,1h,ph-h),7.61(q,j＝7.9hz,1h,ph-h),7.46(td,j＝8.6,2.2hz,1h,ph-h),7.21(q,j＝7.4,6.8hz,3h,ph-h),7.13–7.02(m,2h,ph-h),6.94(d,j＝8.8hz,2h,ph-h),6.89(d,j＝6.6hz,2h,ph-h),5.17(d,j＝16.4hz,1h,triazolech),5.06(d,j＝16.3hz,1h,triazolech),4.46(td,j＝8.4,5.5hz,1h,ch),3.76(s,3h,och3),3.11(s,3h,nch3),2.93(dd,j＝13.4,5.0hz,1h,phch),2.70(dd,j＝13.5,9.3hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.19(c＝o),165.49(c＝o),164.61(d,⁴jcf＝2.4hz,c＝o),162.38(d,¹jcf＝242.7hz),159.02,146.32,138.98,137.69(2×c),137.62,135.80,131.07(d,³jcf＝7.9hz),129.34(2×c),129.10,128.71(2×c),127.03,126.77,125.90(2×c),124.38(d,⁴jcf＝2.7hz),122.94,121.14(2×c),118.98(d,²jcf＝21.1hz),115.10(2×c),114.87,55.85,52.10,51.82,37.88,37.78.esi-ms:m/z607.4(m+1),624.5(m+18),629.4(m+23).c34h31fn6o4[606.7].

相应的酰氯选用4-氟苯甲酰氯(44μl)与(s)-2(2-(4-(4-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5c)反应制得(s)-4-氟-n-(4-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)苯甲酰胺(6c-11)52mg，白色固体，产率35％，熔点：125-126℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ10.37(s,1h,phnh),8.91(d,j＝7.8hz,1h,nh),8.35(s,1h,triazole-h),8.06(dd,j＝8.6,5.6hz,2h,ph-h),7.84(q,j＝8.8hz,4h,ph-h),7.38(t,j＝8.8hz,2h,ph-h),7.21(q,j＝7.3,6.7hz,3h,ph-h),7.07(d,j＝6.6hz,2h,ph-h),6.94(d,j＝8.9hz,2h,ph-h),6.89(d,j＝6.5hz,2h,ph-h),5.17(d,j＝16.3hz,1h,triazolech),5.06(d,j＝16.3hz,1h,triazolech),4.46(td,j＝8.5,5.6hz,1h,ch),3.76(s,3h,och3),3.11(s,3h,nch3),2.93(dd,j＝13.5,5.1hz,1h,phch),2.70(dd,j＝13.4,9.2hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.18(c＝o),165.49(c＝o),164.90(c＝o),164.55(d,¹jcf＝247.6hz),159.02,146.35,139.18,137.69,135.80,131.80(d,⁴jcf＝2.8hz),130.93(2×c),130.84,129.33(2×c),129.10,128.70(2×c),127.02,126.60,125.88(2×c),122.89,121.08(2×c),115.92(2×c),115.71,115.10,55.86,52.10,51.82,37.89,37.78.esi-ms:m/z607.4(m+1),624.4(m+18),629.4(m+23).c34h31fn6o4[606.7].

相应的酰氯选用4-苯基苯甲酰氯(81mg)与(s)-2(2-(4-(4-氨基苯基)-1h-1,2,3-三唑-1-基)乙酰氨基)-n-(4-甲氧基苯基)-n-甲基-3-苯基丙酰胺(5c)反应制得(s)-n-(4-(1-(2-((1-((4-甲氧基苯基)(甲基)氨基)-1-氧代-3-苯基丙-2-基)氨基)-2-氧代乙基)-1h-1,2,3-三唑-4-基)苯基)-[1,1'-联苯]-4-甲酰胺(6c-12)68mg，白色固体，产率41％，熔点：160-161℃。

波谱数据：¹hnmr(400mhz,dmso-d6)δ10.41(s,1h,phnh),8.92(d,j＝7.8hz,1h,nh),8.36(s,1h,triazole-h),8.09(d,j＝8.3hz,2h,ph-h),7.91(d,j＝8.7hz,2h,ph-h),7.85(t,j＝8.1hz,4h,ph-h),7.78(d,j＝7.5hz,2h,ph-h),7.52(t,j＝7.6hz,2h,ph-h),7.43(t,j＝7.3hz,1h,ph-h),7.27–7.16(m,3h,ph-h),7.07(d,j＝6.4hz,2h,ph-h),6.94(d,j＝9.0hz,2h,ph-h),6.90(d,j＝6.3hz,2h,ph-h),5.17(d,j＝16.4hz,1h,triazolech),5.06(d,j＝16.3hz,1h,triazolech),4.47(td,j＝8.5,5.4hz,1h,ch),3.76(s,3h,och3),3.11(s,3h,nch3),2.93(dd,j＝13.4,5.1hz,1h,phch),2.70(dd,j＝13.5,9.2hz,1h,phch).¹³cnmr(100mhz,dmso-d6)δ171.19(c＝o),165.63(c＝o),165.50(c＝o),159.02,146.39,143.60,139.56,139.31,137.69,135.80,134.11,129.54(2×c),129.34(2×c),129.11(2×c),128.86(2×c),128.71(2×c),128.63,127.40(2×c),127.07(2×c),127.04,126.53,125.88(2×c),122.89,121.05(2×c),115.10(2×c),55.86,52.10,51.82,37.88,37.78.esi-ms:m/z665.4(m+1),682.5(m+18),687.4(m+23),703.5(m+39).c40h36n6o4[664.8].

实施例6.目标化合物的体外抗hiv-1活性测试(tzm-bl细胞)实验

原理：荧光素酶报告基因实验(nef基因缺失的hiv-1nl4-3)

测试方法：

在tzm-bl细胞中的抗hiv-1感染试验

以单轮病毒感染tzm-bl细胞后荧光素酶基因表达水平的降低程度来测定化合物对hiv-1感染的抑制活性。简言之，在不同浓度的化合物(5a-5c，6a-(1-12)，6b-(1-12)，6c-(1-12)及pf-74)存在下，使用200tcid50的病毒(nl4-3)感染tzm-bl细胞。感染2天后，移除培养液，并向每孔中加入100μlbrightglo试剂(promega，sanluisobispo，ca)再使用victor2光度计检测其荧光活性。化合物抑制hiv-1菌株的有效浓度(ec50)定义为与病毒对照孔相比导致荧光素酶活性(相对光单位)降低50％的浓度。

细胞毒性试验

使用cytotox-glo荧光细胞毒性试剂盒(购自promega)测定合成化合物的细胞毒性。与抗hiv-1活性试验平行测定，tzm-bl细胞在不同浓度的化合物(5a-5c，6a-(1-12)，6b-(1-12)，6c-(1-12)及pf-74)的存在下培养1天。然后根据试剂盒要求的操作步骤，确定所测试目标化合物的细胞毒性(cc50)，即目标化合物使细胞生存率降低50％时所需的浓度。

表1.部分含有4-苯基-1,2,3-三氮唑的苯丙氨酸衍生物抗hiv活性、毒性及选择指数(tzm-bl细胞)

^aec50：保护50％感染hiv-1的细胞免于细胞病变的化合物浓度；

^bcc50：使50％未感染hiv-1的细胞发生病变的化合物浓度；

^csi：选择性系数，cc50/ec50的比值；

pf-74：已报道的一类hiv-1衣壳蛋白抑制剂，作为阳性对照。

实验结论分析：如表1所示，本发明新合成的含4-苯基-1,2,3-三氮唑的苯丙氨酸衍生物呈现出显著的抗hiv-1活性。例如，化合物5a、6a-1、6a-2、6a-9、6a-10、6a-11、5b抗hiv-1活性在3.13–3.99μm范围内，其中化合物6a-9的抗hiv-1活性(ec50＝3.13±0.91μm,cc50>16.48,si>5.27)尤为突出，具有进一步研究的价值。