具有肿瘤增殖抑制功能的化合物及其制备方法与应用与流程

技术领域本发明涉及化合物及其制备方法与应用，特别是涉及具有蛋白酶体和/或蛋白激酶抑制功能的化合物及其制备方法与应用。属于医药技术领域。

背景技术：
泛素-蛋白酶体通路是真核细胞内主要的蛋白质降解途径，对细胞活动起着重要的调节作用，包括细胞周期、转录调控、免疫应答和细胞凋亡等。蛋白酶体抑制剂被广泛用作抗肿瘤、抗炎、抗病毒以及免疫抑制药物。大量实验表明，肿瘤细胞对蛋白酶体抑制剂的敏感性远高于正常细胞，因此，蛋白酶体被认为是最具应用前景的抗肿瘤靶标之一。蛋白酶体抑制剂也在临床治疗中取得了不错的效果，其中Bortezomib，Carfilzomib和Marizomib分别于2003，2012和2014年被FDA批准上市，用于多发性骨髓瘤的治疗。蛋白酶体属于苏氨酸水解蛋白酶家族，存在于所有真核细胞的细胞质和细胞核中，是泛素-蛋白酶体通路中的核心组件。最常见的蛋白酶体是一种分子量为2.4MDa，具有多个亚单位，受ATP激活的中性蛋白水解酶的蛋白-复合体，沉降系数为26S，故称为26S蛋白酶体。26S蛋白酶体包含有一个20S蛋白酶体催化核心颗粒和两个19S调节颗粒。20S蛋白酶体具有3种活性β亚基，即β1、β2、β5亚基，分别可以发挥caspase-like(C-L，半胱天冬蛋白酶样活性)，倾向于在酸性氨基酸残基后水解肽键；trypsin-like(T-L，胰蛋白酶样活性)，即倾向于在碱性氨基酸残基后水解肽键；和chymotrypsin-like(CT-L，糜蛋白酶样活性)，即在疏水性氨基酸残基后水解肽键的酶解活性。蛋白酶体的主要作用是完全或部分降解细胞中半衰期短的、变性的、异常的蛋白质以及某些细胞生长和分化调节因子及信号转导因子，有时仅对某些蛋白质进行修饰，参与多种生理生化过程，表现出复杂的功能多样性。泛素-蛋白酶体系统调控的细胞活动包括：细胞周期、细胞凋亡、转录调控、DNA修复、免疫应答和蛋白质降解及质量控制等，尤其是通过降解细胞各通路的抑制因子或激活因子发挥上调或下调作用。因此，泛素-蛋白酶体系统功能的异常与多种疾病如恶性肿瘤、神经变异性疾病、遗传性疾病、炎症、心肌病的发生机制有着密切的关系。目前，蛋白酶体抑制剂在抗肿瘤领域的研究最为深入并且取得了不错的成绩，泛素-蛋白酶体通路主要通过对转录因子的调控、对肿瘤抑制因子p53的调节以及对细胞周期的调节这三种途径对肿瘤产生影响，除此之外还可以通过干预免疫应答、调节生长因子以及调节蛋白酪氨酸激酶而起到干预肿瘤的作用。目前，蛋白酶体抑制剂可以根据其与蛋白酶体催化活性位点的作用模式的不同，分为共价结合型和非共价结合型两大类。共价结合型抑制剂主要与蛋白酶体Thr1-Oγ形成共价键使蛋白酶体失活，这类抑制剂分子中通常都含有一个亲电中心，能接受γ-O的亲核进攻。包含有肽醛类、肽硼酸类、肽环氧酮类、肽乙烯砜(酯、酰胺)类、肽α-酮醛(酰胺)类、肽磺酰氟类及β-内酯类等。近几年，随着计算机技术和化合物筛选技术的飞速发展，非共价结合抑制剂被大量发现，这类抑制剂的作用机理主要是依靠抑制剂与蛋白酶体的氢键和疏水键作用与底物竞争结合活性位点。包含有羟基萘醌类、羟基脲类和金属络合物等。许多肿瘤中存在信号转导途径的异常，如一些受体的过度表达或者生长因子的过度表达导致受体的过度激活以及激酶突变激活等，进而导致下游信号途径的增强，最终导致细胞的转化、增殖和抗细胞凋亡、促细胞生存的改变，这些与肿瘤的发生、发展息息相关。目前，在所有的药理靶标中，超过1/4的靶标是蛋白激酶，在抗肿瘤领域中更是高达3/4，因此蛋白激酶抑制剂的研制已经成为当今抗肿瘤药物研究的重要途径之一。实验证实，在胰腺癌及前列腺癌等恶性肿瘤中，蛋白酶体功能抑制会激活部分抗凋亡因子如AKT和EGFR等，从而弱化抗肿瘤能力，因此可以一方面将蛋白酶体抑制剂和相应的蛋白激酶抑制剂联合用药，另一方面可以研发同时抑制蛋白酶体和相应蛋白激酶的药物，提高肿瘤治疗的效果。

技术实现要素：
本发明的目的是提供一类具有蛋白酶体和/或蛋白激酶抑制功能的化合物及其制备方法与应用。本发明所提供的具有蛋白酶体和/或蛋白激酶抑制功能的化合物，及其药学上可接受的盐，结构如式I所示：其中，n是0或1；X为R1、R2为氢，1到10个碳的直链、支链烷基或取代烷基，3-6元环烷基或取代环烷基，芳香环或取代芳香环，芳烷基或取代芳烷基，杂环或稠杂环类取代基；R3为-(C1-3亚烷基)-CONH-CHR4R5，-(C1-3亚烷基)-COOR6或-(C1-3亚烷基)-A-(C1-3亚烷基)n1Ar；其中，R4为氢或烷基，R5为氢或1到10个碳的直链、支链烷基或取代烷基，环烷烃基；R6为氢，1到10个碳的直链、支链烷基或取代烷基，环烷烃基；A为-Ο-，-NH-或-S(O)n2-，其中n2为0，1或2；n1为0或1，Ar为芳香烷基；Y存在或不存在，存在时为-CO-,-OCO-,-SO2-,-NR7CO-,-NR7CS-或-NR7SO2-，其中R7为氢或烷基；R8为1到10个碳的直链、支链烷基及取代烷基，取代羰基，芳香环或取代芳香环，芳烷基或取代芳烷基，杂环或稠杂环类取代基。在本发明中，优选的，所述的1到10个碳的直链、支链烷基及取代烷基包括甲基、乙基、正丙基、异丙基、丁基的各种同分异构体、戊基的各种同分异构体、羟甲基、甲氧羟甲基以及巯基甲基；所述的3-6元环烷烃基包括环丙基，环丙基甲基、环丁基、环戊基以及环己基；所述芳香环或取代芳香环包括苯基，4-甲基苯基，4-氯苯基，4-硝基苯基，4-甲氧基苯基，3,4-二甲氧基苯基，3-硝基苯基，2-氯苯基，3-氯苯基，2,4-二氯苯基，2-氯-4-氟苯基，2-碘苯基，2-氟苯基，2-甲基苯基，2-甲氧基苯基，2-硝基苯基，2-溴苯基，4-溴苯基，4-氟苯基，4-甲醛基苯基，4-羟甲基苯基以及1-萘基；所述芳烷基或取代芳烷基包括苄基，4-羟基苄基，4-甲氧基苄基，3,4-亚甲二氧苄基，对氟苄基以及4-硝基苄基；所述杂环或稠杂环包括吡嗪-2-基，呋喃-2-基，吡啶-2-基，吡啶-3-基，咪唑-2-基、四氢吡咯-2-基、吲哚-3-基以及苯并噻唑-2-基。在本发明中，优选的，所述的式I结构中：n是0或1；X为R1为丁基的各种同分异构体或羟基取代的苄基；R2为C1-4的烷基、经烷氧基取代的C1-4的烷基，苄基或经羟基、烷氧基或卤素取代的苄基；R3为C1-4的烷基、苄基、经羟基、烷氧基或卤素取代的苄基或-(C1-3亚烷基)-CONH-CHR4R5；其中R4为氢，R5为氢或1到4个碳的直链或支链烷基；Y为-CO-或不存在；R8为叔丁氧羰基，苄氧羰基，吡嗪基、经C1-4的烷基取代的吡啶基、呋喃基、3，4-亚甲二氧苄基、苯基、经C1-4的烷基，C1-4的烷氧基，硝基，卤素，羟甲基取代的苯基、萘基、苯磺酰基或经C1-4的烷基取代的苯磺酰基。更优选的，所述的式I结构中：n是0或1；X为R1为(CH3)2CHCH2-或(4-OH)PhCH2-；R2为CH3-，CH3OCH2-，(CH3)2CHCH2-，PhCH2-，(4-OH)PhCH2-，(4-OCH3)PhCH2-或(4-Cl)PhCH2-；R3为(CH3)2CHCH2-，PhCH2-，(4-OH)PhCH2-，(4-OCH3)PhCH2-，(4-Cl)PhCH2-，(CH3)3CCH2NHCOCH2-，(CH3)2CHCH2CH2NHCOCH2-或(CH3)2CHCH2NHCOCH2-；Y为-CO-或不存在；R8为叔丁氧羰基，苄氧羰基，吡嗪-2-基，呋喃-2-基，3，4-亚甲二氧苄基，苯基，对甲苯基，1-萘基，甲基吡啶基，4-氯苯基，4-硝基苯基，4-甲氧基，苯基，3,4-二甲氧基苯基，3-硝基苯基，2-氯苯基，3-氯苯基，2,4-二氯苯基，2-氯-4-氟苄基，2-碘苯基，2-氟苯基，邻甲苯基，2-甲氧基苯基，2-硝基苯基，2-溴苯基，4-(羟甲基)苯基，2-甲氧基苯基，2-溴苯基，乙酰基或对甲苯磺酰基。进一步的，本发明还提出了制备以上所述的化合物或其药学上接受的盐的方法，所述的式I结构中X为的化合物的制备方法，包括如下步骤：1)式II结构的带有叔丁氧羰基保护的氨基酸在肽缩合试剂作用下，与N,O-二甲基羟胺盐酸盐反应，得到式III结构化合物；2)式III结构化合物在有机锂试剂作用下与呋喃反应，得到式IV化合物；3)式IV化合物脱除叔丁氧羰基，得到式V化合物；4)将式VI结构的氨基酸与二氯亚砜反应，得到式VII结构的氨基酸甲酯；5)将式VIII结构的带有保护基的氨基酸与式VII结构的氨基酸甲酯进行缩合反应，得到式IX结构的二肽中间体；该二肽中间体在碱性条件下水解，得到式X结构的化合物；6)将式X结构的化合物与式V化合物进行缩合反应，得到相应式I的三肽呋喃酮终产物；7)将式VIII结构的带有保护基的氨基酸与式V在缩合剂作用下进行反应，得到式XI结构的二肽呋喃酮产物；8)将式XI结构化合物脱除保护基，得到式XII二肽中间体；将此二肽中间体与式VIII结构的化合物进行缩合反应，得到相应式I的三肽呋喃酮终产物；其中，R1、R2为氢，1到10个碳的直链、支链烷基或取代烷基，3-6元环烷基或取代环烷基，芳香环或取代芳香环，芳烷基或取代芳烷基，杂环或稠杂环类取代基；R3为-(C1-3亚烷基)-CONH-CHR4R5，-(C1-3亚烷基)-COOR6或-(C1-3亚烷基)-A-(C1-3亚烷基)n1Ar；其中，R4为氢或烷基，R5为氢或1到10个碳的直链、支链烷基或取代烷基，环烷烃基；R6为氢，1到10个碳的直链、支链烷基或取代烷基，环烷烃基；A为-Ο-，-NH-或-S(O)n2-，其中n2为0，1或2，n1为0或1，Ar为芳香烷基；Y存在或不存在，存在时为-CO-,-OCO-,-SO2-,-NR7CO-,-NR7CS-或-NR7SO2-，其中R7为氢或烷基；R8为1到10个碳的直链、支链烷基及取代烷基，取代羰基，芳香环或取代芳香环，芳烷基或取代芳烷基，杂环或稠杂环类取代基。其中，所述的缩合反应所用的肽缩合试剂为1-羟基苯并三唑，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐或氯甲酸异丁酯。所述的式I结构中X为化合物的制备方法，包括如下步骤：1)式II结构的带有叔丁氧羰基保护的氨基酸在肽缩合试剂作用下，与4-甲基苄胺反应，得到式III结构化合物；2)式III化合物脱除叔丁氧羰基，得到式IV化合物；3)将式V结构的带有保护基的氨基酸与式IV结构的化合物进行缩合反应，得到相应式I的终产物；其中，R1、R2为氢，1到10个碳的直链、支链烷基或取代烷基，3-6元环烷基或取代环烷基，芳香环或取代芳香环，芳烷基或取代芳烷基，杂环或稠杂环类取代基；Y存在或不存在，存在时为-CO-,-OCO-,-SO2-,-NR7CO-,-NR7CS-或-NR7SO2-，其中R7为氢或烷基；R8为1到10个碳的直链、支链烷基及取代烷基，羰基，烷氧基，芳香环或取代芳香环，芳烷基或取代芳烷基，芳香烷氧基，杂环或稠杂环类取代基。其中，所述的缩合反应所用的肽缩合试剂为1-羟基苯并三唑，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，或苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐。需要注意的是以上所描述的合成路径是为了阐明本发明化合物的制备，而制备决不仅限于此，即其他合成方法同样可行，所述方法是指熟练人员一般知识内的合成方法。如果需要，本发明化合物可以利用本领域已知的方法转变为它们的可药用盐形式。本发明的另一个目的是提供本发明化合物的用途。发明人通过实验证实，本发明化合物具有良好的抑制蛋白酶体的活性和/或抑制蛋白激酶的活性及抗肿瘤活性。本发明化合物对20S蛋白酶体的抑制实验中，抑制活性最高达到0.18μM；对人黑色素瘤细胞A375的抗增殖作用IC50值达到0.88μM；对人子宫癌细胞Hela的抗增殖作用IC50值达到0.67μM；对人胃癌细胞BGC-823的抗增殖作用IC50值达到0.77μM；对人结肠癌细胞HT-29的抗增殖作用IC50值达到0.73μM；对人肺癌细胞A549的抗增殖作用IC50值达到1.30μM；对人前列腺癌细胞PC3M1E8的抗增殖作用IC50值达到0.57μM；对人结肠癌细胞HCT-116的抗增殖作用IC50值达到0.28μM，活性接近甚至在某些肿瘤细胞系高于阳性对照MG132。而对人正常胚肾细胞HEK293在50μM浓度下并没有表现出明显的抑制作用，说明本发明中的化合物对肿瘤细胞具有很好的选择性。本发明化合物对多种蛋白激酶具有良好的抑制作用，在10μM浓度下对ALK激酶抑制活性最高达到92.77％，对IGF1-R激酶抑制活性最高达到91.17％，对SRC激酶抑制活性最高达到84.31％，对Aurora-B激酶抑制活性最高达到60.67％，对AXL激酶抑制活性最高达到50.74％，对FAK激酶抑制活性最高达到60.54％，对VEGF-R2激酶抑制活性最高达到62.03％。因此，在上述研究的基础上，本发明提出了所述化合物或其药学上接受的盐在制备蛋白酶体抑制剂中的应用，其中，优选的，所述的蛋白酶体为20S蛋白酶体。及所述化合物或其药学上接受的盐在制备蛋白激酶抑制剂中的应用，其中，优选的，所述的蛋白激酶为ALK，IGF1-R，SRC，AXL，Aurora-B，FAK，VEGF-R2，AKT1，ARK5，MEK1，NEK2，MET，NEK6PIM1，PLK1或PRK1。以及所述化合物或其药学上接受的盐在制备抗肿瘤药物中的应用。其中，优选的，所述的肿瘤为黑色素瘤，子宫癌，胃癌，结肠癌，肺或前列腺癌。本发明设计并合成了一类新结构类型的拟肽类具有蛋白酶体和/或蛋白激酶抑制功能的化合物，表现出较好的蛋白酶体抑制活性、蛋白激酶抑制活性和抗肿瘤作用，可以用于制备抗肿瘤药物，用于肿瘤性疾病的治疗。具体实施方式下面通过实验并结合实例对本发明做进一步说明，应该理解的是，这些实施例仅用于例证的目的，不限制本发明的保护范围。第一部分化合物的合成本发明的化合物的制备可按照如下过程进行：一、式I中X为2-取代呋喃化合物的制备：1.制备中间体式V化合物式III化合物的制备可以将叔丁氧羰基保护的氨基酸与缩合剂EDCl以及活化剂HOBt，在0℃下预先活化反应30分钟后，再加入N,O-二甲基羟胺盐酸盐和NMM，于室温反应过夜获得。有机相用酸洗、碱洗，然后用饱和食盐水洗，干燥剂干燥。滤除干燥剂，减压蒸除有机相，得到的油状物采用柱层析方法纯化得到式III化合物。-78℃下，将有机锂试剂(如：n-BuLi)缓慢加入呋喃的有机溶液(如：THF)中，升至0℃反应半小时，然后在-78℃加入式III化合物，继续反应2.5小时。反应结束后，将反应液倒入饱和NH4Cl溶液中淬灭，用有机溶剂(如：Et2O)萃取3次，有机相依次用水洗，饱和食盐水洗，干燥剂干燥。滤除干燥剂，蒸干溶剂后柱层析纯化，得式IV化合物。将式IV化合物溶于一定量的二氯甲烷中，加入12当量的HCl/1,4-dioxane溶液，室温反应结束后，加入无水乙醚，析出固体，滤出固体并用少量无水乙醚冲洗，得式V化合物。2.式I中n为1的化合物(式I/A)的制备将不带任何保护基的氨基酸(式VI)溶于无水甲醇中，-10℃下向其中加入二氯亚砜。室温反应5小时，蒸除溶剂，用甲醇和乙醚重结晶得氨基酸甲酯(式VII)。将带有保护基的氨基酸(式VIII)和氨基酸甲酯(式VII)溶于有机试剂(如DMF)，加入合适的肽缩合试剂(N-甲基吗啉、HOBt、EDCl)。室温反应过夜，反应液用有机溶剂(如：乙酸乙酯)稀释，有机相用酸洗(10％柠檬酸)，碱洗(饱和碳酸氢钠溶液)，饱和食盐水洗，干燥剂(无水硫酸钠)干燥。滤除干燥剂，蒸干溶剂后柱层析或者重结晶纯化得到式IX化合物。将式IX结构的二肽甲酯中间体溶于有机溶剂(THF)中，加入无机碱的水溶液(1NNaOH或1NLiOH)，室温反应直到TLC监测反应完全。然后用无机酸(1NHCl)将反应液的pH值调到2-3之间，用有机溶剂(乙酸乙酯)萃取，有机相用干燥剂干燥。滤除干燥剂，蒸除溶剂，得到产物(式X)，不经分离直接用于下步反应。将式X化合物和中间体式V化合物溶于有机试剂(如DMF)中，加入合适的肽缩合试剂(N-甲基吗啉、HOBt、EDCl)。室温反应过夜，反应液用有机溶剂(如：乙酸乙酯)稀释，有机相用酸洗(10％柠檬酸)，碱洗(饱和碳酸氢钠溶液)，饱和食盐水洗，干燥剂(无水硫酸钠)干燥。滤除干燥剂，蒸干溶剂后柱层析或者重结晶纯化得到式I/A终产物。3.式I中n为0的化合物(式I/B)的制备及式I/A的另一种制备方法将带有保护基的氨基酸式VIII化合物和中间体式V化合物溶于有机试剂(如DMF)中，加入合适的肽缩合试剂(N-甲基吗啉、HOBt、EDCl)。室温反应过夜，反应液用有机溶剂(如：乙酸乙酯)稀释，有机相用酸洗(10％柠檬酸)，碱洗(饱和碳酸氢钠溶液)，饱和食盐水洗，干燥剂(无水硫酸钠)干燥。滤除干燥剂，蒸干溶剂后柱层析或者重结晶纯化得到式I/B终产物。将叔丁氧羰基保护的式XI(即式I/B)化合物溶于一定量的二氯甲烷中，加入12当量的HCl/1,4-dioxane溶液，室温反应结束后，加入无水乙醚，析出固体，滤出固体并用少量无水乙醚冲洗，得式XII化合物。将式XII化合物和带有保护基的氨基酸式VIII化合物溶于有机试剂(如DMF)中，加入合适的肽缩合试剂(N-甲基吗啉、HOBt、EDCl)。室温反应过夜，反应液用有机溶剂(如：乙酸乙酯)稀释，有机相用酸洗(10％柠檬酸)，碱洗(饱和碳酸氢钠溶液)，饱和食盐水洗，干燥剂(无水硫酸钠)干燥。滤除干燥剂，蒸干溶剂后柱层析或者重结晶纯化得到式I/A终产物。二、式I中X为4-甲基苄胺化合物(式I/C)的制备：将叔丁氧羰基保护的氨基酸(式II)与4-甲基苄胺在缩合剂(HBTU+NMM)的作用下进行缩合反应，室温下搅拌反应过夜。反应结束后加入有机溶剂(乙酸乙酯)稀释反应，碱洗(饱和NaHCO3溶液)，干燥剂干燥。滤除干燥剂，浓缩后经重结晶纯化得到式III化合物。将式III化合物溶于一定量的二氯甲烷中，加入12当量的HCl/1,4-dioxane溶液，室温反应结束后，加入无水乙醚，析出固体，滤出固体并用少量无水乙醚冲洗，得式IV化合物。将式IV化合物和带有保护基的氨基酸式V化合物溶于有机试剂(如DMF)中，加入合适的肽缩合试剂(N-甲基吗啉、HOBt、EDCl)。室温反应过夜，反应液用有机溶剂(如：乙酸乙酯)稀释，有机相用酸洗(10％柠檬酸)，碱洗(饱和碳酸氢钠溶液)，饱和食盐水洗，干燥剂(无水硫酸钠)干燥。滤除干燥剂，蒸干溶剂后柱层析或者重结晶纯化得到式I/C终产物。以下以具体化合物的合成来描述：一、氨基酰呋喃片段的合成1.(S)-(N-甲氧基-N-甲基氨甲酰)-3-甲基丁基氨基甲酸叔丁酯(化合物1)的合成将Boc-L-Leu-OH(6.94g,30mmol)，HOBt(4.86g,36mmol)和EDC·HCl(6.90g,36mmol)溶于80mLDMF，冰浴下搅拌30min；另将N,O-二甲基羟胺盐酸盐(2.91g,30mmol)，NMM(10.2mL,90mmol)溶于80mLDMF，冰浴下搅拌30min，两者混合，室温反应24h。停止反应，反应液用乙酸乙酯稀释，有机相用10％柠檬酸洗，饱和NaHCO3洗，饱和NaCl洗，无水Na2SO4干燥。滤除干燥剂，蒸干溶剂后用乙酸乙酯/石油醚＝1/10柱层析分离，得无色透明油状液体7.85g(产率95.43％)。1HNMR(400MHz,CDCl3):δ＝0.95(dd,J＝6.5,14.3Hz,6H,CH3),1.43(s,11H,Boc,CH2),1.69-1.76(m,1H,CH),3.20(s,3H,NCH3),3.79(s,3H,OCH3),4.73(d,J＝4.2Hz,1H,CH),5.14ppm(d,J＝9.2Hz,1H,NH)；13CNMR(100MHz,CDCl3):δ＝21.5,23.3,24.6,28.3,32.0,42.0,48.9,61.5,79.3,155.6,173.8ppm；HRMS(ESI):m/z275.1967(M+H+),297.1787(M+Na+).2.(S)-1-(呋喃-2-基甲酰基)-1-(3-甲基丁基)-氨基甲酸叔丁酯(化合物2)的合成-78℃下，将n-BuLi(1.6M的正己烷溶液22mL，35mmol)缓慢加入呋喃(2.6mL，36mmol)的50mLTHF溶液中，升至0℃反应30min，然后在-78℃加入化合物1(2.60g，10mmol)的THF溶液，继续反应2.5h。反应结束后，将反应液倒入饱和NH4Cl溶液中淬灭，用Et2O萃取3次，有机相依次用水洗，饱和NaCl洗，无水Na2SO4干燥。滤除干燥剂，蒸干溶剂后用乙酸乙酯/石油醚＝1/50柱分，得2.42g(产率92％)，黄色油状液体。1HNMR(400MHz,DMSO-d6):δ＝0.90(dd,J＝6.4,19.3Hz,6H,CH3),1.20(s,1H,CH),1.35(s,9H,Boc),1.49-1.69(m,2H,CH2),4.68-4.74(m,1H,CH),6.72(d,J＝1.9Hz,1H,F-4),7.31(d,J＝7.6Hz,1H,NH),7.46(d,J＝3.4Hz,1H,F-3),8.01ppm(s,1H,F-5)；13CNMR(100MHz,DMSO-d6):δ＝21.7,23.5,25.0,28.2,28.6,54.8,78.6,113.0,118.9,148.3,150.9,156.0,188.9ppm；HRMS(ESI):m/z282.1701(M+H+),304.1519(M+Na+).3.(S)-2-氨基-1-(呋喃-2-基)-4-甲基戊-1-酮(化合物3)的合成将化合物2(281mg,1mmol)溶于0.76mL二氯甲烷中，加入3mL4NHCl/1,4-dioxane溶液，室温反应1h后，加入12mL无水乙醚，析出固体，滤出固体并用少量无水乙醚冲洗，得白色固体(210mg,96.77％)。1HNMR(400MHz,DMSO-d6):δ＝0.88(d,J＝6.4Hz,3H,CH3),0.96(d,J＝6.4Hz,3H,CH3),1.57-1.80(m,3H,CH2,CH),4.68-4.71(m,1H,CH),6.84(dd,J＝3.7,1.6Hz,1H,4’-H),7.70(d,J＝3.4Hz,1H,3’-H),8.16(d,J＝1.2Hz,1H,5’-H),8.55ppm(s,3H,NH2,HCl)；MS(ESI):m/z182.26(M+H+).二、式I中n为1的化合物(式I/A)的制备1.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-1-氧代-3-苯基丙-2-基氨基)-3-(4-甲氧基苯基)-1-氧代丙-2-基氨基甲酸叔丁酯(化合物PS-32)的合成第一步室温下，将Boc-Tyr-OH(2.81g,10mmol)溶于无水DMF(40mL)中，加入NaHCO3(1.68g,20mmol)和CH3I(1mL,16mmol)，室温搅拌5小时。向溶液中加入120mL水，用乙酸乙酯萃取3次，合并有机相，分别用10％Na2SO3溶液洗，水洗，饱和NaCl溶液洗，Na2SO4干燥。得到的产物不经分离，直接用于下步反应。室温下，将上述中间体(2.95g,10mmol)溶于无水DMF(40mL)中，加入K2CO3(2.76g,20mmol)和CH3I(1ml,16mmol)，室温搅拌5小时。向溶液中加入120mL水，用乙酸乙酯萃取3次，合并有机相，分别用10％Na2SO3溶液洗，水洗，饱和NaCl溶液洗，Na2SO4干燥。粗品用乙酸乙酯/石油醚＝1/6-1/3柱分，得到的Boc-(4-OMe)Phe-OMe为无色透明油状物2.61g(产率85％)。1HNMR(400MHz,DMSO-d6):δ＝1.35(s,9H,Boc),2.81-2.99(m,2H,CH2Ph),3.62(s,3H,OCH3),3.71(s,3H,OCH3),4.16-4.22(m,1H,CH),6.85(d,J＝8.3Hz,2H,Ph),7.20ppm(q,3H,NH,Ph)；13CNMR(100MHz,DMSO-d6):δ＝28.5,36.2,52.0,55.3,55.9,78.6,114.0,129.8,130.5,155.8,158.4,173.1ppm；MS(ESI):m/z332.40(M+Na+).第二步将Boc-(4-OMe)Phe-OMe溶于适量THF中，加入1NNaOH调节pH到12-13，室温搅拌反应2小时。减压蒸干溶剂，用少量EA溶解之后滴加1NHCl溶液调节pH到2-3，继续搅拌反应5min。用乙酸乙酯萃取3次，合并有机相，无水Na2SO4干燥，蒸除溶剂，得Boc-(4-OMe)Phe-OH为白色固体，直接用于缩合反应。第三步于-13℃下，将SOCl2(20mL)慢慢滴入H-Phe-OH(6.61g,40mmol)的无水甲醇(120mL)溶液中。室温反应5h，蒸除溶剂，用甲醇和乙醚重结晶得L-Phe-OMe·HCl为白色针状结晶(7.27g,80.20％)。第四步以Boc-(4-OMe)Phe-OH和L-Phe-OMe.HCl为原料，制备方法同化合物1，得到的2-(2-叔丁氧羰酰氨-3-(4-甲氧基-苯基)-丙酰氨)-3-苯基-丙酸甲酯为白色固体，产率为75％。mp:119-120℃；1HNMR(400MHz,DMSO-d6):δ＝1.29(s,9H,Boc),2.57-3.07(m,4H,PhCH2),3.58(s,3H,OCH3),3.71(s,3H,OCH3),4.08-4.14(m,1H,CH),4.48-4.53(m,1H,CH),6.79(s,1H,NH),6.81(d,J＝8.4Hz,2H,Ph),7.13(d,J＝8.4Hz,2H,Ph),7.22-7.30(m,5H,Ph),8.31ppm(d,J＝7.5Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝28.6,37.0,37.2,52.3,53.9,55.4,56.3,78.5,113.9,127.0,128.7,129.6,130.3,130.6,137.5,155.6,158.2,172.3,172.4ppm；MS(ESI):m/z479.54(M+Na+).第五步将上述的甲酯中间体(456mg,1mmol)溶于适量THF中，加入1NLiOH调节pH值至12-13，待反应结束后，蒸除THF加入适量乙酸乙酯，加入1NHCl调节pH值至2-3，搅拌反应5分钟。用乙酸乙酯萃取水层三次，合并有机层，无水Na2SO4干燥，不经处理直接进行下一步反应。将上步反应所得的产物溶于DMF中，在冰浴下加入EDC·HCl(230mg,1.2mmol)和HOBt(162mg,1.2mmol)，反应30分钟后加入化合物3(181mg,1mmol)和NMM(0.34mL,3mmol)，室温下继续反应12小时。停止反应，反应液用乙酸乙酯稀释，有机相分别用10％柠檬酸，饱和NaHCO3溶液和饱和NaCl溶液洗涤，无水Na2SO4干燥。滤除干燥剂，蒸干溶剂后用乙酸乙酯/石油醚＝3/1柱层析，得白色固体332mg(产率55％)。mp:142-143℃；1HNMR(400MHz,DMSO-d6):δ＝0.89-0.92(m,6H,CH3),1.29(s,9H,Boc),1.49-1.58(m,2H,CH2),1.65-1.67(m,1H,CH),2.57-3.00(m,4H,CH2Ph),3.70(s,3H,OCH3),4.02-4.10(m,1H,CH),4.60-4.63(m,1H,CH),5.01-5.07(m,1H,CH),6.74-6.82(m,4H,Ph),7.06-7.08(m,2H,F-4,NH),7.20(s,5H,Ph),7.47(d,J＝3.2Hz,1H,F-3),7.91(d,J＝8.8Hz,1H,NH),8.04(s,1H,F-5),8.49ppm(d,J＝7.4Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.5,24.9,28.6,37.1,38.2,52.9,53.7,55.4,56.6,78.5,113.1,113.9,119.5,126.7,128.4,129.7,130.3,130.6,137.8,148.7,150.8,155.5,158.2,171.4,171.8,187.5ppm；HRMS(ESI):m/z628.30057(M+Na+).2.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-3-(4-羟基苯基)-1-氧代丙-2-基氨基)-3-(4-甲氧基苯基)-1-氧代丙-2-基氨基甲酸叔丁酯(化合物PS-33)的合成第一步以Boc-(4-OMe)Phe-OH和L-Tyr-OMe.HCl为原料，制备方法同化合物1，得到的2-(-2-叔丁氧羰酰氨-3-(4-甲氧基-苯基)-丙酰氨)-3-(4-羟基-苯基)-丙酸甲酯为白色固体，产率为81％。mp:144-145℃；1HNMR(400MHz,DMSO-d6):δ＝1.30(s,9H,Boc),2.51-2.94(m,4H,CH2Ph),3.57(s,3H,OCH3),3.71(s,3H,OCH3),4.08-4.14(m,1H,CH),4.42(dd,J＝7.4,14.0Hz,1H,CH),6.66(d,J＝8.4Hz,2H,Ph),6.81(d,J＝8.4Hz,3H,NH,Ph),7.00(d,J＝8.3Hz,2H,Ph),7.13(d,J＝8.4Hz,2H,Ph),8.21(d,J＝7.5Hz,1H,NH),9.23ppm(s,1H,OH)；13CNMR(100MHz,DMSO-d6):δ＝28.6,36.5,37.0,52.2,54.3,55.4,56.3,78.5,113.9,115.5,127.4,130.3,130.5,130.6,155.6,156.5,158.2,172.3,172.4ppm；MS(ESI):m/z495.54(M+Na+).第二步以上述的甲酯和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为91％。mp:143-144℃；1HNMR(400MHz,DMSO-d6):δ＝0.89-0.92(m,6H,CH3),1.28(s,9H,Boc),1.45-1.55(m,2H,CH2),1.64-1.67(m,1H,CH),2.55-2.88(m,4H,CH2Ph),3.70(s,3H,OCH3),4.03-4.10(m,1H,CH),4.51-4.63(m,1H,CH),5.00-5.05(m,1H,CH),6.59(d,J＝8.2Hz,2H,Ph),6.73-6.84(m,4H,Ph),6.97(d,J＝8.2Hz,2H,Ph),7.07(d,J＝8.4Hz,2H,NH,F-4),7.46(d,J＝3.5Hz,1H,F-3),7.83(d,J＝8.3Hz,1H,NH),8.03(s,1H,F-5),8.45(d,J＝7.6Hz,1H,NH),9.12ppm(s,1H,OH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.5,24.8,28.6,37.1,37.4,52.9,54.0,55.4,56.6,78.6,113.1,113.9,115.2,119.5,127.8,130.4,130.5,130.6,148.6,150.8,155.5,156.3,158.2,171.5,171.7,187.5ppm；HRMS(ESI):m/z622.31385(M+H+).3.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-3-(4-甲氧基苯基)-1-氧代丙-2-基氨基)-1-氧代-3-苯基丙-2-基氨基甲酸叔丁酯(化合物PS-34)的合成第一步以Boc-(4-OMe)Phe-OMe为原料，操作和后处理同化合物3的制备，得到的H-(4-OMe)Phe-OMe直接用于下一步反应。第二步以Boc-Phe-OH和H-(4-OMe)Phe-OMe为原料，制备方法同化合物1，得到的2-(-2-叔丁氧羰酰氨-3-苯基-丙酰氨)-3-(4-甲氧基-苯基)-丙酸甲酯为白色固体，产率为77％。mp:151-152℃；1HNMR(400MHz,DMSO-d6):δ＝1.28(s,9H,Boc),2.64-3.00(m,4H,CH2Ph),3.58(s,3H,OCH3),3.71(s,3H,OCH3),4.15-4.21(m,1H,CH),4.42-4.48(m,1H,CH),6.83-6.87(m,3H,NH,Ph),7.13-7.27(m,7H,Ph),8.28ppm(d,J＝7.7Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝28.6,36.4,37.9,52.3,54.2,55.4,55.9,78.5,114.1,126.6,128.4,129.3,129.6,130.6,138.5,155.6,158.5,172.2,172.3ppm；MS(ESI):m/z479.60(M+Na+).第三步以上述的甲酯中间体和化合物3为原料，制备方法同PS-32，得到白色固体，产率为80％。mp:150-151℃；1HNMR(400MHz,DMSO-d6):δ＝0.89-0.92(m,6H,CH3),1.28(s,9H,Boc),1.45-1.54(m,2H,CH2),1.56-1.66(m,1H,CH),2.61-2.93(m,4H,CH2Ph),3.69(s,3H,OCH3),4.08-4.13(m,1H,CH),4.52-4.57(m,1H,CH),5.01-5.06(m,1H,CH),6.74-6.89(m,4H,Ph),7.09-7.18(m,5H,Ph),7.22(d,J＝6.8Hz,2H,NH,F-4),7.47(d,J＝3.6Hz,1H,F-3),7.90(d,J＝8.1Hz,1H,NH),8.05(s,1H,F-5),8.48ppm(d,J＝7.8Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.3,22.9,24.3,27.6,28.0,36.8,37.4,52.3,53.4,54.8,55.7,78.0,112.5,113.3,119.0,126.0,127.8,129.0,130.1,138.0,148.1,150.2,154.9,157.7,170.8,171.1,186.9ppm；HRMS(ESI):m/z628.30080(M+Na+).4.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-3-(4-甲氧基苯基)-1-氧代-2-基氨基)-3-(4-甲氧基苯基)-1-氧代丙-2-基氨基甲酸叔丁酯(化合物PS-35)的合成第一步以Boc-(4-OMe)Phe-OH和H-(4-OMe)Phe-OMe为原料，制备方法同化合物1，得到的2-(2-叔丁氧羰酰氨-3-(4-甲氧基-苯基)-丙酰氨)-3-(4-甲氧基-苯基)-丙酸甲酯为白色固体，产率为93％。mp:117-118℃；1HNMR(400MHz,DMSO-d6):δ＝1.29(s,9H,Boc),2.58-2.99(m,4H,CH2Ph),3.58(s,3H,OCH3),3.71(s,6H,OCH3),4.08-4.14(m,1H,CH),4.42-4.47(m,1H,CH),6.83(m,5H,NH,Ph),7.12-7.15(m,4H,Ph),8.26ppm(d,J＝7.6Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝28.6,36.4,37.0,52.3,54.2,55.4,56.2,78.5,113.9,114.1,129.2,130.3,130.6,155.6,158.2,158.5,172.3ppm；MS(ESI):m/z509.58(M+Na+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为66％。mp:162-164℃；1HNMR(400MHz,CDCl3):δ＝0.87(d,J＝6.3Hz,3H,CH3),0.98(d,J＝6.1Hz,3H,CH3),1.33(s,9H,Boc),1.40-1.45(m,1H,CH),1.53-1.60(m,2H,CH2),2.82-3.05(m,4H,CH2Ph),3.75(s,3H,OCH3),3.78(s,3H,OCH3),4.28-4.30(m,1H,CH),4.56-4.61(m,1H,CH),4.85(s,1H,NH),5.25-5.29(m,1H,CH),6.37(s,1H,NH),6.47(s,1H,NH),6.57(dd,J＝1.7,3.6Hz,1H,F-4),6.72(d,J＝8.6Hz,2H,Ph),6.82(d,J＝8.6Hz,2H,Ph),6.97(d,J＝8.6Hz,2H,Ph),7.10(d,J＝8.6Hz,2H,Ph),7.31(d,J＝3.6Hz,1H,F-3),7.64ppm(d,J＝1.0Hz,1H,F-5)；13CNMR(100MHz,CDCl3):δ＝21.8,23.2,24.8,28.2,37.2,41.8,52.7,54.4,55.1,55.2,55.9,80.4,112.5,114.0,114.2,118.9,128.0,128.3,130.3,130.3,147.1,150.9,155.4,158.7,158.7,170.1,171.0,186.9ppm；HRMS(ESI):m/z658.31033(M+Na+).5.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-4-甲基-1-氧代戊-2-基氨基)-3-(4-甲氧基苯基)-1-氧代丙-2-基氨基甲酸苄酯(化合物PS-36)的合成第一步以Cbz-Tyr-OH为原料，操作和后处理同化合物Boc-(4-OMe)Phe-OMe的制备，得到的Cbz-(4-OMe)Phe-OMe为无色透明油状物，产率为83％。1HNMR(400MHz,CDCl3):δ＝2.99-3.10(m,2H,CH2Ph),3.71(s,3H,OCH3),3.76(s,3H,OCH3),4.59-4.64(m,1H,CH),5.09(s,2H,OCH2Ph),5.28(d,J＝8.0Hz,1H,NH),6.80(d,J＝8.5Hz,2H,Ph),7.00(d,J＝8.5Hz,2H,Ph),7.32-7.33ppm(m,5H,Ph).13CNMR(100MHz,CDCl3):δ＝32.6,47.5,50.2,50.4,62.2,109.3,122.9,123.3,123.4,123.8,125.5,131.6,150.9,154.0,167.3ppm；MS(ESI):m/z366.43(M+Na+).第二步将Cbz-(4-OMe)Phe-OMe溶于适量THF中，加入1NNaOH调节pH到12-13，室温搅拌反应2小时。减压蒸干溶剂，用少量EA溶解之后滴加1NHCl溶液调节pH到2-3，继续搅拌反应5min。用乙酸乙酯萃取3次，合并有机相，无水Na2SO4干燥，蒸除溶剂，得到的Cbz-(4-OMe)Phe-OH为白色固体，直接用于下一步反应。第三步以Cbz-(4-OMe)Phe-OH和H-Leu-OMe为原料，制备方法同化合物1，得到的2-(2-(苄氧羰酰氨)-3-(4-甲氧基苯基)丙酰胺)-4-甲基戊酸甲酯为白色固体，产率为91％。mp:98-99℃；1HNMR(400MHz,DMSO-d6):δ＝0.85(d,J＝6.3Hz,3H,CH3),0.90(d,J＝6.4Hz,3H,CH3),1.50-1.66(m,3H,CH,CH2),2.66(dd,J＝10.9,13.5Hz,1H,CH2Ph),2.92(dd,J＝3.6,13.8Hz,1H,CH2Ph),3.62(s,3H,OCH3),3.72(s,3H,OCH3),4.21-4.34(m,2H,CH),4.94(s,2H,OCH2Ph),6.83(d,J＝8.4Hz,2H,Ph),7.20-7.33(m,7H,Ph),7.44(d,J＝8.7Hz,1H,NH),8.36ppm(d,J＝7.6Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.8,23.2,24.6,37.0,50.8,52.3,55.4,56.6,65.6,113.9,127.9,128.1,128.7,130.3,130.7,137.5,156.3,158.2,172.4,173.3ppm；MS(ESI):m/z479.54(M+Na+).第四步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为57％。mp:155-157℃；1HNMR(400MHz,DMSO-d6):δ＝0.83-0.92(m,12H,CH3),1.40-1.57(m,6H,CH,CH2),2.64-2.89(m,2H,CH2Ph),3.71(s,3H,OCH3),4.18-4.24(m,1H,CH),4.35-4.41(m,1H,CH),4.94(s,2H,OCH2Ph),4.99-5.04(m,1H,CH),6.73(d,J＝1.6Hz,1H,F-4),6.81(d,J＝8.6Hz,2H,Ph),7.19(d,J＝8.6Hz,2H,Ph),7.23-7.32(m,5H,Ph),7.40(d,J＝8.6Hz,1H,NH),7.47(d,J＝3.5Hz,1H,F-3),8.01-8.03(m,2H,NH,F-5),8.33ppm(d,J＝7.5Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.8,22.3,23.4,23.5,24.5,24.9,37.0,51.2,53.0,55.4,56.7,65.6,113.0,113.9,119.3,127.8,128.1,128.7,130.4,130.7,137.5,148.6,150.9,156.3,158.2,171.8,172.4,187.8ppm；HRMS(ESI):m/z606.31896(M+H+),628.30120(M+Na+).6.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-1-氧代-3-苯基丙-2-基氨基)-4-甲基-1-氧代戊-2-基氨基甲酸苄酯(化合物PS-37)的合成第一步以Cbz-Leu-OH和H-Phe-OMe为原料，制备方法同化合物1，得到的2-(2-(苄氧羰酰氨)-3-苯基丙酰胺-4-甲基戊酸甲酯为白色固体，产率为91％。mp:81-82℃；1HNMR(400MHz,DMSO-d6):δ＝0.85(q,J＝6.6Hz,6H,CH3),1.34-1.39(m,2H,CH2),1.53-1.60(m,1H,CH),2.92-3.05(m,2H,CH2Ph),3.56(s,3H,OCH3),4.07(q,J＝8.9Hz,1H,CH),4.84(q,J＝7.7Hz,1H,CH),5.02(s,2H,OCH2Ph),7.18-7.38(m,11H,NH,Ph),8.31ppm(d,J＝7.5Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝22.0,23.4,24.6,37.0,41.1,52.2,53.3,53.9,65.8,127.0,128.1,128.2,128.7,128.8,129.5,137.5,156.2,172.3,172.9ppm；MS(ESI):m/z449.49(M+Na+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为62％。mp:137-138℃；1HNMR(400MHz,DMSO-d6):δ＝0.79-0.91(m,12H,CH3),1.26-1.56(m,6H,CH,CH2),2.73-3.00(m,2H,CH2Ph),3.96-4.01(m,1H,CH),4.54-4.60(m,1H,CH),5.01(s,3H,CH,OCH2Ph),6.73(dd,J＝1.6,3.4Hz,1H,F-4),7.17(s,5H,Ph),7.31-7.40(m,6H,NH,Ph),7.47(d,J＝3.5Hz,1H,F-3),7.94(d,J＝8.2Hz,1H,NH),8.04(s,1H,F-5),8.39ppm(d,J＝7.6Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,22.0,23.4,23.5,24.5,24.8,37.9,41.2,52.9,53.7,65.8,113.1,119.5,126.6,128.1,128.2,128.4,128.8,129.6,137.5,137.9,148.7,150.8,156.3,171.4,172.4,187.5ppm；HRMS(ESI):m/z598.28982(M+Na+).7.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-1-氧代-3-苯基丙-2-基氨基)-1-氧代-3-苯基丙-2-基氨基甲酸苄酯(化合物PS-38)的合成第一步以Cbz-Phe-OH和H-Phe-OMe为原料，制备方法同化合物1，得到的2-(2-(苄氧羰酰氨)-3-苯基丙酰胺)-3-苯基丙酸甲酯为白色固体，产率为93％。mp:132-133℃；1HNMR(400MHz,DMSO-d6):δ＝2.66-3.08(m,4H,CH2Ph),3.58(s,3H,OCH3),4.26-4.32(m,1H,CH),4.48-4.53(m,1H,CH),4.93(s,2H,OCH2Ph),7.20-7.34(m,15H,Ph),7.47(d,J＝8.8Hz,1H,NH),7.49ppm(d,J＝7.5Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝37.1,37.8,52.3,54.1,56.3,65.6,126.7,127.0,127.9,128.1,128.5,128.7,129.5,129.6,137.5,138.4,156.2,172.2,172.3ppm；MS(ESI):m/z483.52(M+Na+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为73％。mp:168-169℃；1HNMR(400MHz,DMSO-d6):δ＝0.90-0.93(m,6H,CH3),1.49-1.57(m,2H,CH2),1.66-1.69(m,1H,CH),2.51-3.02(m,4H,CH2Ph),4.22-4.24(m,1H,CH),4.60-4.62(m,1H,CH),4.92(s,2H,OCH2Ph),5.03-5.06(m,1H,CH),6.74(dd,J＝1.6,3.5Hz,1H,F-4),7.21-7.32(m,15H,Ph),7.43(d,J＝8.8Hz,1H,NH),7.48(d,J＝3.5Hz,1H,F-3),8.05(d,J＝1.2Hz,1H,F-5),8.10(d,J＝8.3Hz,1H,NH),8.46ppm(d,J＝7.7Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.5,24.9,37.9,38.0,52.9,53.9,56.5,65.6,113.1,119.5,126.6,126.7,127.8,128.1,128.5,128.7,129.6,129.7,137.4,137.9,138.5,148.7,150.9,156.1,171.4,171.7,187.5ppm；HRMS(ESI):m/z610.29232(M+H+),632.27417(M+Na+).8.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-1-氧代-3-苯基丙-2-基氨基)-3-(4-甲氧基苯基)-1-氧代丙-2-基氨基甲酸苄酯(化合物PS-39)的合成第一步以Cbz-(4-OMe)Phe-OH和H-Phe-OMe为原料，制备方法同化合物1，得到的2-(2-(苄氧羰酰氨)-3-(4-甲氧基苯基)丙酰氨)-3-苯基丙酸甲酯为白色固体，产率为97％。mp:161-162℃；1HNMR(400MHz,DMSO-d6):δ＝2.58-3.07(m,4H,CH2Ph),3.58(s,3H,OCH3),3.72(s,3H,OCH3),4.19-4.25(m,1H,CH),4.49(q,J＝7.8Hz,1H,CH),4.93(s,2H,OCH2Ph),6.82(d,J＝8.3Hz,2H,Ph),7.16-7.33(m,12H,Ph),7.41(d,J＝8.8Hz,1H,NH),8.45ppm(d,J＝7.5Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝37.0,37.1,52.3,54.1,55.4,56.6,65.6,113.9,127.0,127.9,128.1,128.7,129.6,130.3,130.7,137.4,137.5,156.2,158.2,172.3ppm；MS(ESI):m/z513.57(M+Na+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为80％。mp:156-158℃；1HNMR(400MHz,DMSO-d6):δ＝0.89-0.93(m,6H,CH3),1.47-1.56(m,2H,CH2),1.66-1.69(m,1H,CH),2.51-3.02(m,4H,CH2Ph),3.71(s,3H,OCH3),4.14-4.19(m,1H,CH),4.59-4.61(m,1H,CH),4.92(s,2H,OCH2Ph),5.02-5.07(m,1H,CH),6.74(dd,J＝1.9,3.4Hz,1H,F-4),6.78(d,J＝8.4Hz,2H,Ph),7.12(d,J＝8.4Hz,2H,Ph),7.15-7.32(m,10H,Ph),7.37(d,J＝8.6Hz,1H,NH),7.48(d,J＝3.4Hz,1H,F-3),8.04(d,J＝1.9Hz,1H,F-5),8.08(d,J＝8.2Hz,1H,NH),8.46ppm(d,J＝7.5Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.5,24.9,37.1,38.0,52.9,53.9,55.4,56.8,65.6,113.1,113.9,119.5,126.7,127.8,128.1,128.4,128.7,129.7,130.3,130.6,137.5,137.9,148.7,150.9,156.1,158.2,171.4,171.8,187.5ppm；HRMS(ESI):m/z640.30293(M+H+),662.28438(M+Na+).9.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-3-(4-羟基苯基)-1-氧代丙-2-基氨基)-1-氧代-3-苯基丙-2-基氨基甲酸苄酯(化合物PS-40)的合成第一步以Cbz-Phe-OH和H-Tyr-OMe为原料，制备方法同化合物1，得到的2-(2-(苄氧羰酰氨)-3-苯基丙酰氨)-3-(4-羟基苯基)丙酸甲酯为白色固体，产率为98％。mp:135-136℃；1HNMR(400MHz,DMSO-d6):δ＝2.66-2.98(m,4H,CH2Ph),3.58(s,3H,OCH3),4.27-4.32(m,1H,CH),4.39-4.45(m,1H,CH),4.94(s,2H,OCH2Ph),6.68(d,J＝8.3Hz,2H,Ph),7.02(d,J＝8.3Hz,2H,Ph),7.20-7.35(m,10H,Ph),7.48(d,J＝8.8Hz,1H,NH),8.41(d,J＝7.4Hz,1H,NH),9.25ppm(s,1H,OH)；13CNMR(100MHz,DMSO-d6):δ＝36.4,37.8,52.2,54.5,56.3,65.7,115.5,126.7,127.4,127.9,128.1,128.5,128.7,129.7,130.5,137.5,138.5,156.2,156.5,172.1,172.4ppm；MS(ESI):m/z499.52(M+Na+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为77％。mp:182-184℃；1HNMR(400MHz,DMSO-d6):δ＝0.90-0.92(m,6H,CH3),1.49-1.56(m,2H,CH2),1.66-1.69(m,1H,CH),2.62-2.93(m,4H,CH2Ph),4.22-4.24(m,1H,CH),4.50-4.62(m,1H,CH),4.92(s,2H,OCH2Ph),5.03-5.06(m,1H,CH),6.60(d,J＝8.4Hz,2H,Ph),6.74(dd,J＝1.6,3.5Hz,1H,F-4),6.99(d,J＝8.4Hz,2H,Ph),7.18-7.32(m,10H,Ph),7.43-7.48(m,2H,F-3,F-5),7.43(d,J＝8.8Hz,1H,NH),8.02(d,J＝8.3Hz,1H,NH),8.42(d,J＝7.7Hz,1H,NH),9.14ppm(s,1H,OH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.5,24.8,37.3,37.9,52.9,54.3,56.6,65.7,113.1,115.3,119.5,126.7,127.9,127.9,128.1,128.5,128.7,129.6,130.6,137.4,138.5,148.6,150.9,156.2,156.3,171.5,171.6,187.6ppm；HRMS(ESI):m/z626.28752(M+H+),648.26996(M+Na+).10.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-3-(4-羟基苯基)-1-氧代丙-2-基氨基)-3-(4-甲氧基苯基)-1-氧代丙-2-基氨基甲酸叔丁酯(化合物PS-41)的合成第一步以Cbz-(4-OMe)Phe-OH和H-Tyr-OMe为原料，制备方法同化合物1，得到的2-(2-(苄氧羰酰氨)-3-(4-甲氧基苯基)丙酰氨)-3-(4-羟基苯基)丙酸甲酯为白色固体，产率为92％。mp:158℃；1HNMR(400MHz,DMSO-d6):δ＝2.59-2.94(m,4H,CH2Ph),3.57(s,3H,OCH3),3.72(s,3H,OCH3),4.19-4.25(m,1H,CH),4.38-4.43(m,1H,CH),4.93(s,2H,OCH2Ph),6.66(d,J＝8.3Hz,2H,Ph),6.81(d,J＝8.4Hz,2H,Ph),7.00(d,J＝8.2Hz,2H,Ph),7.16-7.32(m,7H,Ph),7.41(d,J＝8.7Hz,1H,NH),8.36(d,J＝7.4Hz,1H,NH),9.24ppm(s,1H,OH)；13CNMR(100MHz,DMSO-d6):δ＝36.4,37.0,52.2,54.4,55.4,56.6,65.6,113.9,115.5,127.4,127.9,128.1,128.7,130.3,130.5,130.7,137.5,156.2,156.5,158.2,172.2,172.4ppm；MS(ESI):m/z529.50(M+Na+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为65％。mp:165-167℃；1HNMR(400MHz,DMSO-d6):δ＝0.89-0.91(m,6H,CH3),1.48-1.56(m,2H,CH2),1.66-1.69(m,1H,CH),2.55-2.93(m,4H,CH2Ph),3.71(s,3H,OCH3),4.13-4.19(m,1H,CH),4.49-4.52(m,1H,CH),4.92(s,2H,OCH2Ph),5.01-5.05(m,1H,CH),6.60(d,J＝8.3Hz,2H,Ph),6.74(dd,J＝1.5,3.4Hz,1H,F-4),6.79(d,J＝8.5Hz,2H,Ph),6.99(d,J＝8.4Hz,2H,Ph),7.13(d,J＝8.5Hz,2H,Ph),7.22-7.32(m,5H,Ph),7.42(d,J＝8.7Hz,1H,NH),7.47(d,J＝3.5Hz,1H,F-3),8.03-8.05(m,2H,NH,F-5),8.45(d,J＝7.6Hz,1H,NH),9.17ppm(s,1H,OH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.5,24.8,37.1,37.3,52.9,54.2,55.4,56.8,65.6,113.1,113.9,115.3,119.5,127.8,127.9,128.1,128.7,130.4,130.5,130.6,137.5,148.6,150.9,156.1,156.2,158.2,171.5,171.7,187.6ppm；HRMS(ESI):m/z656.29735(M+H+),678.27998(M+Na+).11.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-3-(4-甲氧基苯基)-1-氧代丙-2-基氨基)-4-甲基-1-氧代戊-2-基氨基甲酸苄酯(化合物PS-42)的合成第一步以Cbz-Leu-OH和H-(4-OMe)Phe-OMe为原料，制备方法同化合物1，得到的2-(2-(苄氧羰酰氨)-4-甲基戊酰胺)-3-(4-甲氧基苯基)丙酸甲酯为白色固体，产率为75％。mp:91-92℃；1HNMR(400MHz,DMSO-d6):δ＝0.90(q,J＝6.6Hz,6H,CH3),1.33-1.42(m,2H,CH2),1.53-1.60(m,1H,CH),2.85-2.97(m,2H,CH2Ph),3.57(s,3H,OCH3),3.70(s,3H,OCH3),4.03-4.09(m,1H,CH),4.38-4.44(m,1H,CH),5.02(s,2H,OCH2Ph),6.81(d,J＝8.4Hz,2H,Ph),7.11(d,J＝8.4Hz,2H,Ph),7.35-7.37(m,6H,NH,Ph),8.24ppm(d,J＝7.4Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝22.0,23.4,24.6,36.2,41.1,52.2,53.3,54.2,55.4,65.8,114.1,128.1,128.2,128.8,129.3,130.6,137.5,156.2,158.4,172.4,172.8ppm；MS(ESI):m/z479.54(M+Na+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为76％。mp:153-155℃；1HNMR(400MHz,DMSO-d6):δ＝0.84-0.91(m,12H,CH3),1.24-1.65(m,6H,CH,CH2),2.66-2.93(m,2H,CH2Ph),3.68(s,3H,OCH3),3.96-4.01(m,1H,CH),4.49-4.55(m,1H,CH),5.02(s,3H,CH,OCH2Ph),6.72-6.74(m,3H,F-4,Ph),7.08(d,J＝8.3Hz,2H,Ph),7.31-7.35(m,5H,Ph),7.39(d,J＝8.4Hz,1H,NH),7.46(d,J＝3.4Hz,1H,F-3),7.87(d,J＝8.1Hz,1H,NH),8.05(s,1H,F-5),8.37ppm(d,J＝7.4Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.3,21.4,22.8,22.9,24.0,24.2,36.5,52.3,53.1,53.3,54.7,65.3,112.5,113.2,118.9,127.5,127.6,128.2,129.1,130.1,136.9,148.1,150.3,155.7,157.6,170.8,171.7,186.9ppm；HRMS(ESI):m/z606.31884(M+H+),628.30109(M+Na+).12.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-3-(4-甲氧基苯基)-1-氧代丙-2-基氨基)-1-氧代-3-苯基丙-2-基氨基甲酸苄酯(化合物PS-43)的合成第一步以Cbz-Phe-OH和H-(4-OMe)Phe-OMe为原料，制备方法同化合物1，得到的2-(2-(苄氧羰酰氨)-3-苯基丙酰氨)-3-(4-甲氧基苯基)丙酸甲酯为白色固体，产率为74％。mp:130-131℃；1HNMR(400MHz,DMSO-d6):δ＝2.66-3.00(m,4H,CH2Ph),3.58(s,3H,OCH3),3.70(s,3H,OCH3),4.26-4.32(m,1H,CH),4.42-4.47(m,1H,CH),4.93(s,2H,OCH2Ph),6.83(d,J＝8.5Hz,2H,Ph),7.14(d,J＝8.5Hz,2H,Ph),7.22-7.32(m,10H,Ph),7.47(d,J＝8.8Hz,1H,NH),8.43ppm(d,J＝7.4Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝36.3,37.8,52.3,54.4,55.4,56.3,65.6,114.1,126.7,127.9,128.1,128.5,128.7,129.2,129.7,130.6,137.5,138.4,156.2,158.5,172.2,172.3ppm；MS(ESI):m/z513.50(M+Na+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为51％。mp:154-156℃；1HNMR(400MHz,DMSO-d6):δ＝0.89-0.93(m,6H,CH3),1.49-1.56(m,2H,CH2),1.64-1.69(m,1H,CH),2.62-2.95(m,4H,CH2Ph),3.68(s,3H,OCH3),4.22-4.25(m,1H,CH),4.51-4.57(m,1H,CH),4.92(s,2H,OCH2Ph),5.02-5.07(m,1H,CH),6.73-6.77(m,3H,F-4,Ph),7.12(d,J＝8.6Hz,2H,Ph),7.19-7.32(m,10H,Ph),7.46-7.49(m,2H,NH),8.05-8.10(m,2H,F-3,F-5),8.47ppm(d,J＝7.7Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.5,24.8,37.2,37.9,52.9,54.2,55.4,56.5,65.6,113.1,113.9,119.6,126.7,127.8,128.1,128.5,128.7,129.6,129.7,130.7,137.4,138.5,148.7,150.8,156.2,158.2,171.4,171.7,187.5ppm；HRMS(ESI):m/z640.30293(M+H+),662.28410(M+Na+).13.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-3-(4-甲氧基苯基)-1-氧代丙-2-基氨基)-3-(4-甲氧基苯基)-1-氧代丙-2-基氨基甲酸苄酯(化合物PS-44)的合成第一步以Cbz-(4-OMe)Phe-OH和H-(4-OMe)Phe-OMe为原料，制备方法同化合物1，得到的2-(2-(苄氧羰酰氨)-3-(4-甲氧基苯基)丙酰氨)-3-(4-甲氧基苯基)丙酸甲酯为白色固体，产率为72％。mp:152-153℃；1HNMR(400MHz,DMSO-d6):δ＝2.58-2.99(m,4H,CH2Ph),3.58(s,3H,OCH3),3.70(s,3H,OCH3),3.72(s,3H,OCH3),4.20-4.25(m,1H,CH),4.41-4.47(m,1H,CH),4.93(s,2H,OCH2Ph),6.81-6.85(m,4H,Ph),7.13-7.33(m,9H,Ph),7.44(d,J＝8.8Hz,1H,NH),8.43ppm(d,J＝7.5Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝36.3,37.0,52.3,54.3,55.3,55.4,56.6,65.6,113.9,114.1,127.9,128.1,128.7,129.3,130.3,130.6,130.7,137.5,156.2,158.2,158.5,172.2,172.3ppm；MS(ESI):m/z543.48(M+Na+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为82％。mp:172-174℃；1HNMR(400MHz,DMSO-d6):δ＝0.89-0.92(m,6H,CH3),1.49-1.56(m,2H,CH2),1.65-1.67(m,1H,CH),2.62-2.94(m,4H,CH2Ph),3.68(s,3H,OCH3),3.71(s,3H,OCH3),4.14-4.19(m,1H,CH),4.51-4.54(m,1H,CH),4.92(s,2H,OCH2Ph),5.01-5.05(m,1H,CH),6.73-6.80(m,5H,F-4,Ph),7.10-7.14(m,4H,Ph),7.21-7.32(m,5H,Ph),7.38(d,J＝8.6Hz,1H,NH),7.48(d,J＝3.5Hz,1H,F-3),8.03-8.04(m,2H,NH,F-5),8.43ppm(d,J＝7.5Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.5,24.8,37.1,37.2,52.9,54.2,55.4,56.4,56.8,65.6,113.1,113.9,119.6,127.8,127.9,128.1,128.7,129.7,130.3,130.6,130.7,137.5,137.6,148.7,150.9,156.1,158.3,171.4,171.7,187.5ppm；HRMS(ESI):m/z670.31382(M+H+),692.29596(M+Na+).14.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-3-(4-氯苯基)-1-氧代丙-2-基氨基)-3-(4-甲氧基苯基)-1-氧代丙-2-基氨基甲酸叔丁酯(化合物PS-45)的合成第一步以Boc-(4-OMe)Phe-OH和H-(4-Cl)Phe-OMe为原料，制备方法同化合物1，得到的2-(2-叔丁氧羰酰氨-3-(4-甲氧基-苯基)-丙酰氨)-3-(4-氯-苯基)-丙酸甲酯为白色固体，产率为78.52％。mp:147-148℃；1HNMR(400MHz,DMSO-d6):δ＝1.29(s,9H,Boc),2.57-2.63(m,1H,CH2Ph),2.77-2.82(m,1H,CH2Ph),2.91-2.97(m,1H,CH2Ph),3.02-3.07(m,1H,CH2Ph),3.59(s,3H,OCH3),3.71(s,3H,OCH3),4.06-4.12(m,1H,CH),4.48-4.53(m,1H,CH),6.80(t,J＝6.2,8.4Hz,3H,NH,Ph),7.12(d,J＝8.4Hz,2H,Ph),7.25(d,J＝8.4Hz,2H,Ph),7.32(d,J＝8.4Hz,2H,Ph),8.30ppm(d,J＝7.8Hz,1H,NH)；MS(ESI):m/z513.39(M+Na+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为77.46％。mp:176-177℃；1HNMR(400MHz,DMSO-d6):δ＝0.89-0.92(m,6H,CH3),1.28(s,9H,Boc),1.49-1.55(m,2H,CH2),1.64-1.67(m,1H,CH),2.54-2.60(m,1H,CH2Ph),2.75-2.78(m,2H,CH2Ph),2.94-2.98(m,1H,CH2Ph),3.70(s,3H,OCH3),4.01-4.06(m,1H,CH),4.57-4.62(m,1H,CH),5.00-5.06(m,1H,CH),6.74(dd,J＝1.4,3.4Hz,1H,F-4),6.78-6.82(m,3H,Ph,NH),7.08(d,J＝8.4Hz,2H,Ph),7.19-7.26(m,4H,Ph),7.47(d,J＝3.6Hz,1H,F-3),7.95(d,J＝8.6Hz,1H,NH),8.05(s,1H,F-5),8.50ppm(d,J＝7.6Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.5,24.9,28.6,37.1,37.6,39.4,39.6,39.8,40.0,40.2,40.4,40.6,52.9,53.5,55.4,56.5,78.6,113.1,113.9,119.5,128.3,130.3,130.6,131.5,131.6,136,148.7,150.8,155.5,158.2,171.1,171.9,187.5ppm；HRMS(ESI):m/z640.27683(M+H+).15.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-3-(4-氯苯基)-1-氧代丙-2-基氨基)-1-氧代-3-苯基丙-2-基氨基甲酸苄酯(化合物PS-46)的合成第一步以Cbz-Phe-OH和H-(4-Cl)Phe-OMe为原料，制备方法同化合物1，得到的2-(2-(苄氧羰酰氨)-3-苯基丙酰氨)-3-(4-氯苯基)丙酸甲酯为白色固体，产率为95.23％。mp:164-165℃；1HNMR(400MHz,DMSO-d6):δ＝2.66-2.72(m,1H,CH2Ph),2.90-2.98(m,2H,CH2Ph),3.02-3.07(m,1H,CH2Ph),3.59(s,3H,OCH3),4.24-4.30(m,1H,CH),4.48-4.54(m,1H,CH),4.93(s,2H,OCH2Ph),7.19-7.34(m,14H,Ph),7.46(d,J＝8.8Hz,1H,NH),8.48ppm(d,J＝7.6Hz,1H,NH)；MS(ESI):m/z517.37(M+Na+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为67.15％。mp:184-185℃；1HNMR(400MHz,DMSO-d6):δ＝0.90-0.93(m,6H,CH3),1.46-1.58(m,2H,CH2),1.60-1.67(m,1H,CH),2.65(dd,J＝11.1,13.6Hz,1H,CH2Ph),2.77(dd,J＝9.0,22.7Hz,1H,CH2Ph),2.90(dd,J＝3.8,14.0Hz,1H,CH2Ph),2.98(dd,J＝4.8,18.6Hz,1H,CH2Ph),4.20-4.25(m,1H,CH),4.57-4.62(m,1H,CH),4.93(s,2H,OCH2Ph),5.01-5.06(m,1H,CH),6.73-6.74(dd,J＝1.5,3.4Hz,1H,F-4),7.18-7.33(m,14H,Ph),7.44(d,J＝8.8Hz,1H,NH),7.47(d,J＝3.5Hz,1H,F-3),8.05(s,1H,F-5),8.13(d,J＝8.2Hz,1H,NH),8.48ppm(d,J＝7.6Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.5,24.9,37.4,37.9,39.4,39.6,39.8,40.0,40.2,40.4,40.6,53.0,53.7,56.5,65.7,113.1,119.5,126.7,127.9,128.1,128.4,128.5,128.7,129.6,131.5,131.6,136.9,137.4,138.5,148.7,150.8,156.2,171.1,171.7,187.5ppm；HRMS(ESI):m/z644.25203(M+H+).16.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-3-(4-羟基苯基)-1-氧代丙-2-基氨基)-3-(4-氯苯基)-1-氧代丙-2-基氨基甲酸叔丁酯(化合物PS-47)的合成第一步以Boc-(4-Cl)Phe-OH和H-Tyr-OMe为原料，制备方法同化合物1，得到的2-(2-叔丁氧羰酰氨-3-(4-氯苯基)-丙酰氨)-3-(4-羟基-苯基)-丙酸甲酯为白色固体，产率为78.78％。mp:171-172℃；1HNMR(400MHz,DMSO-d6):δ＝1.29(s,9H,Boc),2.63-2.69(m,1H,CH2Ph),2.82-2.93(m,3H,CH2Ph),3.57(s,3H,OCH3),4.13-4.19(m,1H,CH),4.38-4.43(m,1H,CH),6.66(d,J＝8.4Hz,2H,Ph),6.89(d,J＝8.8Hz,1H,NH),7.00(d,J＝8.3Hz,2H,Ph),7.23(d,J＝8.3Hz,2H,Ph),7.31(d,J＝8.3Hz,2H,Ph),8.25(d,J＝7.4Hz,1H,NH),9.23ppm(s,1H,OH)；MS(ESI):m/z499.34(M+Na+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为76.42％。mp:127℃；1HNMR(400MHz,DMSO-d6):δ＝0.89-0.92(m,6H,CH3),1.28(s,9H,Boc),1.45-1.57(m,2H,CH2),1.62-1.67(m,1H,CH),2.62-2.68(m,2H,CH2Ph),2.83-2.88(m,2H,CH2Ph),4.02-4.11(m,1H,CH),4.48-4.53(m,1H,CH),5.00-5.05(m,1H,CH),6.59(d,J＝8.3Hz,2H,Ph),6.73(dd,J＝1.5,3.5Hz,1H,F-4),6.90(d,J＝8.9Hz,1H,NH),6.97(d,J＝8.2Hz,2H,Ph),7.18(d,J＝8.3Hz,2H,Ph),7.28(d,J＝8.2Hz,2H,Ph),7.46(d,J＝3.6Hz,1H,F-3),7.88(d,J＝8.2Hz,1H,NH),8.04(s,1H,F-5),8.45(d,J＝7.7Hz,1H,NH),9.13ppm(s,1H,OH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.5,24.8,28.5,31.4,37.4,39.4,39.6,39.8,40.0,40.2,40.4,40.6,52.9,54.1,56.1,78.6,113.1,115.3,119.5,127.8,128.3,130.6,131.3,131.5,137.6,148.6,150.9,155.5,156.3,171.4,187.5ppm；HRMS(ESI):m/z626.26338(M+H+).17.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-3-(4-羟基苯基)-1-氧代丙-2-基氨基)-3-(4-羟基苯基)-1-氧代丙-2-基氨基甲酸-4-羟甲基苯甲酯(化合物PS-48)的合成第一步以4-羟甲基苯甲酸和H-Tyr-OMe为原料，制备方法同化合物1，得到的2-(4-羟甲基苯甲酰胺)-3-(4-羟基苯基)丙酸甲酯为白色固体，产率为75.13％。mp:160-161℃；1HNMR(400MHz,DMSO-d6):δ＝3.00(dq,J＝5.6,13.8Hz,2H,CH2Ph),3.62(s,3H,OCH3),4.53-4.58(m,3H,CH2,CH),5.30(t,J＝5.8,11.4Hz,1H,NH),6.64(d,J＝8.4Hz,2H,Ph),7.07(d,J＝8.4Hz,2H,Ph),7.38(d,J＝8.2Hz,2H,Ph),7.77(d,J＝8.2Hz,2H,Ph),8.72(d,J＝7.7Hz,1H,OH),9.20ppm(s,1H,OH)；MS(ESI):m/z330.1319(M+H+),352.1140(M+Na+).第二步将上述的中间体溶于适量THF中，加入1NNaOH调节pH到12-13，室温搅拌反应2小时。减压蒸干溶剂，用少量EA溶解之后滴加1NHCl溶液调节pH到2-3，继续搅拌反应5min。用乙酸乙酯萃取3次，合并有机相，无水Na2SO4干燥，蒸除溶剂，得到的2-(4-羟甲基苯甲酰胺)-3-(4-羟基苯基)丙酸为白色固体，直接用于缩合反应。第三步以上述的中间体和H-Tyr-OMe为原料，制备方法同化合物1，得到的甲基-2-(2-(4-羟甲基苯甲酰氨)-3-(4-羟基苯基)丙酰氨)-3-(4-羟基苯基)丙酸甲酯为白色固体，产率为39.87％。第四步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为48.94％。mp:161℃；1HNMR(400MHz,DMSO-d6):δ＝0.90(dd,J＝4.7,10.0Hz,6H,CH3),1.45-1.68(m,3H,CH2,CH),2.62-2.70(m,2H,CH2),2.76-2.92(m,2H,CH2),4.48-4.54(m,4H,CH2,CH),4.96-5.06(m,1H,CH),5.28(s,1H,NH),6.55(dd,J＝3.6,8.1Hz,2H,Ph),6.59(dd,J＝3.7,8.1Hz,2H,Ph),6.72(s,1H,F-4),6.96-7.07(m,4H,Ph),7.36(t,J＝5.6Hz,2H,Ph),7.47(t,J＝3.6Hz,1H,F-3),7.73(d,J＝7.3Hz,2H,Ph),8.03(s,2H,F-5,NH),8.30-8.41(m,2H,NH,OH),9.10(d,J＝4.7Hz,2H,OH)；HRMS(ESI):m/z642.27997(M+H+),664.26175(M+Na+),680.23547(M+K+).18.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-3-(4-甲氧基苯基)-1-氧代丙-2-基氨基)-1-氧代-3-苯基丙-2-基氨基甲酸吡嗪-2-甲酯(化合物PS-49)的合成第一步以2-甲酸吡嗪和H-Phe-OMe为原料，制备方法同化合物1，得到的3-苯基-2-(吡嗪-2-甲酰胺)丙酸甲酯为白色针状固体，产率为89.82％。mp:64-65℃；1HNMR(400MHz,DMSO-d6):δ＝3.24(d,J＝7.2Hz,2H,CH2),3.67(s,3H,OCH3),4.83(m,1H,CH),7.18-7.26(m,5H,Ph),8.76(dd,J＝1.5,2.4Hz,1H,Pz-5),8.89(d,J＝2.5Hz,1H,NH),9.12(d,J＝8.2Hz,1H,Pz-6),9.14ppm(d,J＝1.4Hz,1H,Pz-3)；MS(ESI):m/z286.14(M+H+),308.22(M+Na+).第二步将上述的中间体溶于适量THF中，加入1NNaOH调节pH到12-13，室温搅拌反应2小时。减压蒸干溶剂，用少量EA溶解之后滴加1NHCl溶液调节pH到2-3，继续搅拌反应5min。用乙酸乙酯萃取3次，合并有机相，无水Na2SO4干燥，蒸除溶剂，得到的3-苯基-2-(吡嗪-2-甲酰胺)丙酸为白色固体，直接用于缩合反应。第三步以上述的中间体和H-(4-OMe)Phe-OMe为原料，制备方法同化合物1，得到的甲基-3-(4-甲氧基苯基)-2-(3-苯基-2-(吡嗪-2-酰氨)丙酰氨)丙酸甲酯为白色固体，产率为52.21％。mp:123-124℃；1HNMR(400MHz,DMSO-d6):δ＝2.86-2.91(m,1H,CH2Ph),2.97-3.13(m,3H,CH2Ph),3.61(s,3H,OCH3),3.65(s,3H,OCH3),4.46-4.51(m,1H,CH),4.78-4.84(m,1H,CH),6.77(d,J＝8.6Hz,2H,Ph),7.12(d,J＝8.6Hz,2H,Ph),7.14-7.21(m,5H,Ph),8.63(d,J＝8.8Hz,1H,NH),8.66(d,J＝7.8Hz,1H,NH),8.73(dd,J＝1.6,2.4Hz,1H,P-5),8.88(d,J＝2.5Hz,1H,P-6),9.12ppm(d,J＝1.4Hz,1H,P-3)；MS(ESI):m/z485.36(M+Na+).第四步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为69.48％。mp:165-166℃；1HNMR(400MHz,DMSO-d6):δ＝0.90(d,J＝6.6Hz,3H,CH3),0.93(d,J＝6.5Hz,3H,CH3),1.47-1.61(m,2H,CH2),1.63-1.72(m,1H,CH),2.67-2.72(m,1H,CH2Ph),2.91-2.95(m,1H,CH2Ph),3.01-3.10(m,2H,CH2Ph),3.64(s,3H,OCH3),4.56-4.62(m,1H,CH),4.74-4.79(m,1H,CH),5.04-5.09(m,1H,CH),6.70(d,J＝8.5Hz,2H,Ph),6.74(dd,J＝1.6,3.5Hz,1H,F-4),7.11-7.17(m,7H,Ph),7.49(d,J＝3.5Hz,1H,F-3),8.05(d,J＝0.8Hz,1H,F-5),8.40(d,J＝8.5Hz,1H,NH),8.52(d,J＝7.7Hz,1H,NH),8.63(d,J＝8.6Hz,1H,NH),8.72(d,J＝1.5Hz,1H,P-5),8.87(d,J＝2.2Hz,1H,P-6),9.12ppm(d,J＝1.0Hz,1H,P-3)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.5,24.9,37.4,37.9,39.4,39.6,39.8,40.0,40.2,40.4,40.6,52.9,54.1,54.3,55.3,113.1,113.8,119.5,126.8,128.4,129.7,130.6,137.7,143.8,143.9,144.4,148.3,148.7,150.8,158.2,162.5,170.4,171.4,187.5ppm；HRMS(ESI):m/z612.28120(M+H+).19.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-3-(4-羟基苯基)-1-氧代丙-2-基氨基)-3-(4-甲氧基苯基)-1-氧代丙-2-基氨基吡嗪-2-甲酯(化合物PS-50)的合成第一步以2-甲酸吡嗪和H-(4-OMe)Phe-OMe为原料，制备方法同化合物1，得到的3-(4-甲氧基苯基)-2-(吡嗪-2-甲酰胺)丙酸甲酯为无色透明油状物，产率为63.81％。mp:86-87℃；1HNMR(400MHz,DMSO-d6):δ＝3.16(d,J＝7.1Hz,2H,CH2),3.67(s,3H,OCH3),3.69(s,3H,OCH3),4.74-4.80(m,1H,CH),6.81(d,J＝8.6Hz,2H,Ph),7.16(d,J＝8.6Hz,2H,Ph),8.75(dd,J＝2.3,1.5Hz,1H,P-5),8.89(d,J＝2.5Hz,1H,P-6),9.05(d,J＝8.1Hz,1H,NH),9.14ppm(d,J＝1.4Hz,1H,P-3)；MS(ESI):m/z338.27(M+Na+).第二步将上述的中间体溶于适量THF中，加入1NNaOH调节pH到12-13，室温搅拌反应2小时。减压蒸干溶剂，用少量EA溶解之后滴加1NHCl溶液调节pH到2-3，继续搅拌反应5min。用乙酸乙酯萃取3次，合并有机相，无水Na2SO4干燥，蒸除溶剂，得到的3-(4-甲氧基苯基)-2-(吡嗪-2-甲酰胺)丙酸为无色油状物，直接用于缩合反应。第三步以上述的中间体和H-Tyr-OMe为原料，制备方法同化合物1，得到的甲基-3-(4-羟基苯基)-2-(3-(4-甲氧基苯基)-2-(吡嗪-2-酰氨)丙酰氨)丙酸甲酯为无色油状物，产率为53.01％。1HNMR(400MHz,DMSO-d6):δ＝2.82-2.88(m,1H,CH2Ph),2.93-3.08(m,3H,CH2Ph),3.61(s,3H,OCH3),3.68(s,3H,OCH3),4.44-4.50(m,1H,CH),4.75-4.80(m,1H,CH),6.62(d,J＝8.4Hz,2H,Ph),6.76(d,J＝8.6Hz,2H,Ph),7.00(d,J＝8.4Hz,2H,Ph),7.11(d,J＝8.6Hz,2H,Ph),8.61(d,J＝8.8Hz,1H,NH),8.63(d,J＝7.9Hz,1H,NH),8.72(dd,J＝1.5,2.4Hz,1H,P-5),8.87(d,J＝2.5Hz,1H,P-6),9.13(d,J＝1.4Hz,1H,P-3),9.22ppm(s,1H,OH)；MS(ESI):m/z501.39(M+Na+).第四步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为59.31％。mp:115-116℃；1HNMR(400MHz,DMSO-d6):δ＝0.83-0.95(m,6H,CH3),1.49-1.59(m,2H,CH2),1.64-1.73(m,1H,CH),2.66(dd,J＝9.6,13.8Hz,1H,CH2),2.87-3.02(m,3H,CH2),3.67(s,3H,CH3),4.54-4.61(m,1H,CH),4.69-4.76(m,1H,CH),5.05-5.11(m,1H,CH),6.55-6.64(m,2H,Ph),6.68-6.79(m,3H,Ph,F-4),7.04(dd,J＝8.6,16.7Hz,4H,Ph),7.49(d,J＝3.5Hz,1H,F-3),8.04(d,J＝0.8Hz,1H,F-5),8.38(d,J＝8.4Hz,1H,NH),7.51(d,J＝7.6Hz,1H,NH),8.61(d,J＝8.5Hz,1H,NH),8.72(s,1H,OH),8.88(d,J＝2.4Hz,1H,P-5),9.12ppm(d,J＝7.2Hz,2H,P-6,P-3)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.5,24.9,37.1,37.4,53.0,54.3,55.3,113.1,113.9,115.3,119.5,128.0,129.4,130.5,130.8,143.8,143.9,144.5,148.3,148.6,148.7,150.8,156.2,158.3,162.5,170.4,171.6,187.6ppm；HRMS(ESI):m/z628.2781(M+H+).20.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-3-(4-甲氧基苯基)-1-氧代丙-2-基氨基)-1-氧代-3-苯基丙-2-基氨基甲酸-2-甲基苯甲酯(化合物PS-51)的合成第一步以2-甲基苯甲酸和H-Phe-OMe为原料，制备方法同化合物1，得到的2-(2-甲基苯甲酰胺)-3-苯基丙酸甲酯为白色固体，产率为74.12％。mp:91-92℃；1HNMR(400MHz,DMSO-d6):δ＝2.14(s,3H,CH3),3.08(dq,J＝4.9,13.8Hz,2H,CH2Ph),3.67(s,3H,OCH3),4.63-4.69(m,1H,CH),7.13-7.15(m,1H,Ph),7.18-7.25(m,3H,Ph),7.28-7.32(m,5H,Ph),8.68ppm(d,J＝7.9Hz,1H,NH)；MS(ESI):m/z298.1(M+H+),320.1(M+Na+),336.1(M+K+).第二步将上述的中间体溶于适量THF中，加入1NNaOH调节pH到12-13，室温搅拌反应2小时。减压蒸干溶剂，用少量EA溶解之后滴加1NHCl溶液调节pH到2-3，继续搅拌反应5min。用乙酸乙酯萃取3次，合并有机相，无水Na2SO4干燥，蒸除溶剂，得到的2-(2-甲基苯甲酰胺)-3-苯基丙酸为无色油状物，直接用于缩合反应。第三步以上述的中间体和H-(4-OMe)Phe-OMe为原料，制备方法同化合物1，得到的甲基-3-(4-甲氧基苯基-2-(2-(2-甲基苯酰氨)-3-苯基丙酰氨)丙酸甲酯为白色固体，产率为74.89％。mp:160-161℃；1HNMR(400MHz,DMSO-d6):δ＝2.05(s,3H,CH3),2.78-3.08(m,4H,CH2Ph),3.63(s,3H,OCH3),3.68(s,3H,OCH3),4.48-4.56(m,1H,CH),4.73-4.77(m,1H,CH),6.82(dd,J＝3.4,7.3Hz,2H,Ph),7.08(d,J＝7.7Hz,1H,Ph),7.15-7.30(m,10H,Ph),8.29(d,J＝8.8Hz,1H,NH),8.40ppm(d,J＝7.8Hz,1H,NH)；MS(ESI):m/z475.2(M+H+),497.2(M+Na+),513.2(M+K+).第四步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为84.27％。mp:152-154℃；1HNMR(400MHz,DMSO-d6):δ＝0.91(dd,J＝6.6,10.0Hz,6H,CH3),1.50-1.70(m,3H,CH2,CH),2.04(d,J＝5.0Hz,3H,CH3),2.62-3.05(m,4H,CH2),3.66(d,J＝8.3Hz,3H,OCH3),4.62-4.71(m,2H,CH),5.07(s,1H,CH),6.75(s,3H,Ph,F-4),7.06-7.29(m,11H,Ph),7.50(s,1H,F-4),8.00-8.39(m,3H,F-3,NH),8.51ppm(t,J＝7.2,14.2Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝19.5,21.9,23.5,24.9,37.4,52.9,53.2,54.1,54.8,55.3,113.1,113.9,119.6,125.7,126.7,127.3,128.5,129.6,129.7,129.7,130.7,135.8,137.1,138.6,148.7,150.9,158.3,169.3,171.4,171.6,187.5,187.7ppm；HRMS(ESI):m/z624.3079(M+H+).21.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-3-(4-甲氧基苯基)-1-氧代丙-2-基氨基)-1-氧代-3-苯基丙-2-基氨基甲酸-2-甲氧基苯甲酯(化合物PS-52)的合成第一步以2-甲氧基苯甲酸和H-Phe-OMe为原料，制备方法同化合物1，得到的2-(2-甲氧基苯甲酰胺)-3-苯基丙酸甲酯为无色油状物，产率为93.61％。1HNMR(400MHz,CD3OD):δ＝3.15-3.25(m,2H,CH2Ph),3.73(s,3H,OCH3),3.80(s,3H,OCH3),4.90-4.95(m,1H,CH),7.01-7.08(m,2H,Ph),7.18-7.31(m,5H,Ph),7.45-7.49(m,1H,Ph),7.95ppm(dd,J＝1.7,7.8Hz,1H,Ph)；MS(ESI):m/z314.1(M+H+),336.1(M+Na+),352.1(M+K+).第二步将上述的中间体溶于适量THF中，加入1NNaOH调节pH到12-13，室温搅拌反应2小时。减压蒸干溶剂，用少量EA溶解之后滴加1NHCl溶液调节pH到2-3，继续搅拌反应5min。用乙酸乙酯萃取3次，合并有机相，无水Na2SO4干燥，蒸除溶剂，得到的2-(2-甲氧基苯甲酰胺)-3-苯基丙酸为无色油状物，直接用于缩合反应。第三步以上述的中间体和H-(4-OMe)Phe-OMe为原料，制备方法同化合物1，得到的甲基-3-(4-甲氧基苯基-2-(2-(2-甲氧基苯酰氨)-3-苯基丙酰氨)丙酸甲酯为无色油状物，产率为63.01％。1HNMR(400MHz,DMSO-d6):δ＝2.87-3.11(m,4H,CH2Ph),3.61(s,3H,OCH3),3.67(s,3H,OCH3),3.79(s,3H,OCH3),4.45-4.51(m,1H,CH),4.76-4.81(m,1H,CH),6.79(d,J＝8.6Hz,2H,Ph),7.08(t,J＝7.4,15.0Hz,1H,Ph),7.11-7.17(m,3H,Ph),7.19-7.28(m,5H,Ph),7.46-7.50(m,1H,Ph),7.78(dd,J＝7.7,1.6Hz,1H,Ph),8.25(d,J＝7.7Hz,1H,NH),8.54ppm(d,J＝7.6Hz,1H,NH).第四步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为75.21％。mp:103-105℃；1HNMR(400MHz,DMSO-d6):δ＝0.86-0.95(m,6H,CH3),1.49-1.69(m,3H,CH2,CH),2.04(d,J＝5.0Hz,3H,CH3),2.64-3.10(m,4H,CH2),3.66(s,3H,CH3),3.77(s,3H,OCH3),4.51-4.62(m,1H,CH),4.71-4.80(m,1H,CH),5.00-5.11(m,1H,CH),6.71-6.82(m,4H,Ph),7.01-7.23(m,8H,Ph),7.46-7.49(m,2H,F-4,Ph),7.78-7.83(m,1H,F-3),7.78-7.83(m,1H,F-3),8.04(d,J＝8.4Hz,1H,NH),8.22-8.29(m,1H,F-5),8.45-8.49ppm(m,2H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.4,24.9,37.1,38.1,53.2,54.2,54.5,55.4,56.4,112.7,113.1,114.0,119.4,121.1,121.9,126.7,128.3,129.8,130.1,130.6,131.3,133.3,137.4,148.6,150.9,157.7,158.2,164.3,170.9,171.7,187.7ppm；HRMS(ESI):m/z640.3018(M+H+).22.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-3-(4-甲氧基苯基)-1-氧代丙-2-基氨基)-1-氧代-3-苯基丙-2-基氨基甲酸-2-硝基基苯甲酯(化合物PS-53)的合成第一步以2-硝基苯甲酸和H-Phe-OMe为原料，制备方法同化合物1，得到的2-(2-硝基苯甲酰胺)-3-苯基丙酸甲酯为白色固体，产率为68.94％。mp:97℃；1HNMR(400MHz,CDCl3):δ＝3.25-3.35(m,2H,CH2Ph),3.78(s,3H,OCH3),5.12-5.16(m,1H,CH),6.33(d,J＝7.6Hz,1H,NH),7.18-7.20(m,2H,Ph),7.23-7.32(m,3H,Ph),7.42(dd,J＝7.4,1.4Hz,1H,Ph),7.56-7.67(m,2H,Ph),8.05ppm(dd,J＝0.9,8.0Hz,1H,Ph)；MS(ESI):m/z329.1(M+H+),351.1(M+Na+),367.1(M+K+).第二步将上述的中间体溶于适量THF中，加入1NNaOH调节pH到12-13，室温搅拌反应2小时。减压蒸干溶剂，用少量EA溶解之后滴加1NHCl溶液调节pH到2-3，继续搅拌反应5min。用乙酸乙酯萃取3次，合并有机相，无水Na2SO4干燥，蒸除溶剂，得到的2-(2-硝基苯甲酰胺)-3-苯基丙酸为无色油状物，直接用于缩合反应。第三步以上述的中间体和H-(4-OMe)Phe-OMe为原料，制备方法同化合物1，得到的甲基-3-(4-甲氧基苯基-2-(2-(2-硝基苯酰氨)-3-苯基丙酰氨)丙酸甲酯为白色固体，产率为65.74％。mp:155-156℃；1HNMR(400MHz,DMSO-d6):δ＝2.83-3.09(m,4H,CH2Ph),3.59(s,3H,OCH3),3.70(s,3H,OCH3),4.46-4.51(m,1H,CH),4.73-4.78(m,1H,CH),6.82(d,J＝8.4Hz,2H,Ph),7.14(d,J＝8.3Hz,2H,Ph),7.19-7.33(m,6H,Ph),7.66(t,J＝7.9,15.4Hz,1H,Ph),7.73(t,J＝7.0,14.4Hz,1H,Ph),7.98(d,J＝7.9Hz,1H,Ph),8.44(d,J＝7.4Hz,1H,NH),8.90ppm(d,J＝8.5Hz,1H,NH)；MS(ESI):m/z506.2(M+H+),528.2(M+Na+),544.1(M+K+).第四步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为88.84％。mp:193-195℃；1HNMR(400MHz,DMSO-d6):δ＝0.89(d,J＝6.6Hz,3H,CH3),0.92(d,J＝6.5Hz,3H,CH3),1.45-1.59(m,2H,CH2),1.63-1.67(m,1H,CH),2.72-2.86(m,2H,CH2),2.95(dd,J＝4.9,14.0Hz,1H,CH),3.00(dd,J＝4.0,14.0Hz,1H,CH),3.68(s,3H,CH3),4.54-4.61(m,1H,CH),4.67-4.73(m,1H,CH),5.02-5.08(m,1H,CH),6.73-6.76(m,3H,Ph,F-4),7.12(d,J＝8.4Hz,2H,Ph),7.18-7.22(m,1H,Ph),7.26-7.33(m,5H,Ph),7.48(d,J＝3.4Hz,1H,F-3),7.66(t,J＝7.8Hz,1H,Ph),7.74(t,J＝7.3,14.7Hz,1H,Ph),7.98(d,J＝7.9,15.3Hz,1H,Ph),8.06(s,1H,F-5),8.12(d,J＝8.1Hz,1H,NH),8.43(d,J＝7.6Hz,1H,NH),8.90ppm(d,J＝8.4Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.5,24.8,37.2,37.7,52.9,54.3,54.6,55.3,113.1,113.9,119.6,124.4,126.7,128.5,129.5,129.6,129.7,130.6,131.3,132.3,133.7,138.2,147.6,148.7,150.8,158.2,165.5,170.9,171.3,187.5ppm；HRMS(ESI):m/z655.2769(M+H+).23.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-3-(4-甲氧基苯基)-1-氧代丙-2-基氨基)-1-氧代-3-苯基丙-2-基氨基甲酸-2-溴苯甲酯(化合物PS-54)的合成第一步以2-溴苯甲酸和H-Phe-OMe为原料，制备方法同化合物1，得到的2-(2-溴苯甲酰胺)-3-苯基丙酸甲酯为白色固体，产率为85.46％。mp:83-84℃；1HNMR(400MHz,DMSO-d6):δ＝3.08(dq,J＝5.2,13.8Hz,2H,CH2Ph),3.66(s,3H,OCH3),4.63-4.68(m,1H,CH),7.17(dd,J＝1.8,7.4Hz,1H,Ph),7.22-7.25(m,1H,Ph),7.28-7.37(m,5H,Ph),7.42(dd,J＝7.4,14.8Hz,1H,Ph),7.62(d,J＝7.8Hz,1H,Ph),8.93ppm(d,J＝7.9Hz,1H,NH)；MS(ESI):m/z362.0(M+H+),390.0(M+K+).第二步将上述的中间体溶于适量THF中，加入1NNaOH调节pH到12-13，室温搅拌反应2小时。减压蒸干溶剂，用少量EA溶解之后滴加1NHCl溶液调节pH到2-3，继续搅拌反应5min。用乙酸乙酯萃取3次，合并有机相，无水Na2SO4干燥，蒸除溶剂，得到的2-(2-溴苯甲酰胺)-3-苯基丙酸为无色油状物，直接用于缩合反应。第三步以上述的中间体和H-(4-OMe)Phe-OMe为原料，制备方法同化合物1，得到的甲基-3-(4-甲氧基苯基-2-(2-(2-溴苯酰氨)-3-苯基丙酰氨)丙酸甲酯为白色固体，产率为67.23％。mp:169-170℃；1HNMR(400MHz,DMSO-d6):δ＝2.79-3.08(m,4H,CH2Ph),3.60(s,3H,OCH3),3.70(s,3H,OCH3),4.47-4.53(m,1H,CH),4.72-4.77(m,1H,CH),6.83(d,J＝8.2Hz,2H,Ph),7.08(d,J＝7.2Hz,1H,Ph),7.15-7.40(m,9H,Ph),7.58(d,J＝7.8Hz,1H,Ph),8.37(d,J＝7.4Hz,1H,NH),8.55ppm(d,J＝8.6Hz,1H,NH)；MS(ESI):m/z538.1(M+H+),561.1(M+Na+).第四步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为84.13％。mp:183-185℃；1HNMR(400MHz,DMSO-d6):δ＝0.91(dd,J＝6.5,11.3Hz,6H,CH3),1.45-1.60(m,2H,CH2),1.63-1.68(m,1H,CH),2.70-2.82(m,2H,CH2),2.94(dd,J＝5.0,13.9Hz,1H,CH2),3.04(dd,J＝3.9,14.0Hz,1H,CH2),3.69(s,3H,OCH3),4.56-4.63(m,1H,CH),4.64-4.71(m,1H,CH),5.02-5.09(m,1H,CH),6.75(t,J＝1.9Hz,2H,Ph),6.77(s,1H,F-4),7.06(dd,J＝1.8,7.4Hz,1H,Ph),7.12(d,J＝8.6Hz,2H,Ph),7.18-7.22(m,1H,Ph),7.26-7.40(m,6H,Ph),7.49(d,J＝3.5Hz,1H,F-3),7.59(d,J＝7.6Hz,1H,Ph),8.01(d,J＝8.2Hz,1H,NH),8.05(d,J＝1.04Hz,1H,F-5),8.48(d,J＝7.8Hz,1H,NH),8.57ppm(d,J＝8.5Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.5,24.8,37.4,37.7,52.9,54.2,54.7,55.4,113.1,113.9,119.3,119.6,126.7,127.8,128.5,129.2,129.6,129.7,130.7,131.4,133.1,138.3,139.0,148.7,150.8,158.3,167.3,171.0,171.3,187.5ppm；HRMS(ESI):m/z688.2027(M+H+).三、式I中n为0的化合物(式I/B)的制备及式I/A中部分化合物的制备方法1.(S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-1-氧代丙-2-基氨基甲酸叔丁酯(化合物PS-1)的合成以Boc-Ala-OH和3为原料，制备方法同化合物1，得白色针状固体，产率为75.31％。mp:118-119℃；1HNMR(400MHz,CDCl3):δ＝0.91(d,J＝6.4Hz,3H,CH3),1.03(d,J＝6.2Hz,3H,CH3),1.35(d,J＝7.0Hz,CH3),1.45(s,9H,Boc),1.52-1.57(m,1H,CH),1.61-1.72(m,2H,CH2),4.19(s,1H,CH),5.01(s,1H,CH),5.36-5.42(m,1H,NH),6.57(dd,J＝1.6,3.5Hz,1H,F-4),6.69(d,J＝8.1Hz,1H,NH),7.34(d,J＝3.5Hz,1H,F-3),7.64ppm(d,J＝0.8Hz,1H,F-5)；13CNMR(100MHz,CDCl3):δ＝18.4,21.7,23.1,24.8,28.2,41.5,49.8,52.5,79.5,112.5,119.0,147.2,150.8,155.3,172.8,187.6ppm；HRMS(ESI):m/z353.2074(M+H+),375.1894(M+Na+),391.1635(M+K+).2.(S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-3-甲氧基-1-氧代丙-2-基氨基甲酸叔丁酯(化合物PS-2)的合成以Boc-Ser(OMe)-OH和3为原料，制备方法同化合物1，得白色针状固体，产率为75.31％。mp:80-82℃；1HNMR(400MHz,DMSO-d6):δ＝0.90(t,J＝6.0,6,4Hz,6H,CH3),1.38(s,9H,CH3),1.48-1.59(m,2H,CH2),1.66-1.69(m,1H,CH),3.19(s,3H,OCH3),3.39-3.46(m,2H,CH2),4.16-4.21(m,1H,CH),5.00-5.05(m,1H,CH),6.73(dd,J＝1.4,3.4Hz,1H,F-4),6.86(d,J＝8.2Hz,1H,NH),7.47(d,J＝3.6Hz,1H,F-3),8.03(s,1H,F-5),8.28ppm(d,J＝7.7Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.8,23.6,24.7,28.6,53.0,54.6,58.5,72.3,78.7,113.1,119.5,148.6,150.7,155.6,170.4,187.6ppm；HRMS(ESI):m/z383.2180(M+H+),405.1999(M+Na+),421.1739(M+K+).3.(S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-4-甲基-1-氧代丙-2-基氨基甲酸叔丁酯(化合物PS-3)的合成以Boc-Leu-OH和3为原料，制备方法同化合物1，得白色固体，产率为87.59％。mp:188℃；1HNMR(400MHz,DMSO-d6):δ＝0.84(dd,J＝6.6,8.8Hz,6H,CH3),0.90(dd,J＝3.2,6.4Hz,6H,CH3),1.30-1.49(m,12H,CH,CH2,Boc),1.51-1.60(m,2H,CH2),1.68-1.75(m,1H,CH),3.96-4.02(m,1H,CH),5.00-5.06(m,1H,CH),6.73(dd,J＝1.5,3.5Hz,1H,F-4),6.85(d,J＝8.4Hz,1H,NH),7.47(d,J＝3.5Hz,1H,F-3),8.03(s,1H,F-5),8.17ppm(d,J＝7.8Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.8,22.1,23.3,23.6,24.6,24.7,28.6,41.1,52.8,53.0,78.4,113.0,119.4,148.6,150.8,155.7,173.0,187.8ppm；HRMS(ESI):m/z395.2545(M+H+),417.2365(M+Na+),433.2104(M+K+).4.(S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-1-氧代-3-苯基丙基-2-基氨基甲酸叔丁酯(化合物PS-4)的合成以Boc-Phe-OH和3为原料，制备方法同化合物1，得白色固体，产率为75％。mp:151-152℃；1HNMR(400MHz,DMSO-d6):δ＝0.90-0.93(m,6H,CH3),1.30(s,9H,Boc),1.45-1.61(m,2H,CH2),1.69-1.72(m,1H,CH),2.66-2.92(m,2H,CH2Ph),4.17-4.23(m,1H,CH),5.04-5.09(m,1H,CH),6.74(s,1H,F-4),6.92(d,J＝8.7Hz,1H,NH),7.16-7.29(m,5H,Ph),7.49(d,J＝3.5Hz,1H,F-3),8.04(s,1H,F-5),8.32ppm(d,J＝7.8Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.8,23.6,24.7,28.6,37.7,52.8,56.0,78.5,113.1,119.5,126.6,128.4,129.6,138.5,148.7,150.8,155.6,172.2,187.8ppm；HRMS(ESI):m/z429.2387(M+H+),451.2214(M+Na+).5.(S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-3-(4-羟基苯基)-1-氧代丙-2-基氨基甲酸叔丁酯(化合物PS-5)的合成以Boc-Tyr-OH和3为原料，制备方法同化合物1，得白色固体，产率为63％。mp:76-78℃；1HNMR(400MHz,DMSO-d6):δ＝0.90-0.92(m,6H,CH3),1.31(s,9H,Boc),1.48-1.61(m,2H,CH2),1.69-1.71(m,1H,CH),2.54-2.80(m,2H,CH2Ph),4.04-4.13(m,1H,CH),5.03-5.08(m,1H,CH),6.61(d,J＝8.1Hz,2H,Ph),6.74(s,1H,F-4),6.81(d,J＝8.5Hz,1H,NH),7.01(d,J＝8.1Hz,2H,Ph),7.47(d,J＝3.3Hz,1H,F-3),8.04(s,1H,F-5),8.26(d,J＝7.7Hz,1H,NH),9.14ppm(s,1H,OH)；13CNMR(100MHz,DMSO-d6):δ＝21.8,23.6,24.7,28.6,36.9,52.8,56.3,78.4,113.1,115.2,119.5,128.5,130.5,148.6,150.8,155.6,156.2,172.4,187.8ppm；HRMS(ESI):m/z445.2336(M+H+),467.2152(M+Na+).6.(S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-3-(4-甲氧基苯基)-1-氧代丙-2-基氨基甲酸叔丁酯(化合物PS-6)的合成以13和3为原料，制备方法同化合物1，得白色固体，产率为83.26％。mp:171-172℃；1HNMR(400MHz,DMSO-d6):δ＝0.91(m,6H,CH3),1.31(s,9H,Boc),1.44-1.61(m,2H,CH2),1.62-1.80(m,1H,CH),2.62(dd,J＝10.4,13.6Hz,1H,CH2),2.82(dd,J＝4.0,14.0Hz,1H,CH2),3.70(s,3H,OCH3),4.10-4.16(m,1H,CH),5.03-5.09(m,1H,CH),6.74(s,1H,F-4),6.80(d,J＝8.4Hz,2H,Ph),6.87(d,J＝8.6Hz,1H,NH),7.14(d,J＝8.3Hz,2H,Ph),7.49(d,J＝3.4Hz,1H,F-3),8.05(s,1H,F-5),8.29ppm(d,J＝7.8Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.8,23.6,24.7,28.6,36.9,52.8,55.4,56.3,78.5,113.1,113.9,119.5,130.3,130.6,148.7,150.8,155.6,158.2,172.3,187.7ppm；HRMS(ESI):m/z459.2493(M+H+),481.2312(M+Na+),497.2052(M+K+).7.(S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-1-氧代-3-苯基丙-2-基氨基甲酸苄酯(化合物PS-7)的合成以Cbz-Phe-OH和3为原料，制备方法同化合物1，得白色固体，产率为87％。mp:123-124℃；1HNMR(400MHz,DMSO-d6):δ＝0.87-0.92(m,6H,CH3),1.48-1.58(m,2H,CH2),1.68-1.70(m,1H,CH),2.65-2.96(m,2H,CH2Ph),4.28-4.34(m,1H,CH),4.92(s,2H,OCH2Ph),5.02-5.07(m,1H,CH),6.74(dd,J＝1.6,3.6Hz,1H,F-4),7.19-7.33(m,10H,Ph),7.48-7.50(m,2H,NH,F-3),8.05(d,J＝0.9Hz,1H,F-5),8.46ppm(d,J＝7.6Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.5,24.9,37.8,53.1,56.3,65.6,113.1,119.5,126.7,127.9,128.1,128.5,128.7,129.6,137.5,138.4,148.7,150.8,156.3,172.1,187.8ppm；HRMS(ESI):m/z463.2235(M+H+),485.2053(M+Na+).8.(S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-3-(4-羟基苯基)-1-氧代丙-2-基氨基甲酸苄酯(化合物PS-8)的合成以Cbz-Tyr-OH和3为原料，制备方法同化合物1，得白色固体，产率为69％。mp:57-58℃；1HNMR(400MHz,DMSO-d6):δ＝0.91-0.94(m,6H,CH3),1.46-1.58(m,2H,CH2),1.60-1.70(m,1H,CH),2.54-2.85(m,2H,CH2Ph),4.20-4.26(m,1H,CH),4.95(s,2H,OCH2Ph),5.02-5.07(m,1H,CH),6.63(d,J＝8.2Hz,2H,Ph),6.74(dd,J＝1.5,3.5Hz,1H,F-4),7.06(d,J＝8.3Hz,2H,Ph),7.23-7.35(m,5H,Ph),7.40(d,J＝8.7Hz,1H,NH),8.48(d,J＝3.6Hz,1H,F-3),8.04(s,1H,F-5),8.41(d,J＝7.6Hz,1H,NH),9.18ppm(s,1H,OH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.5,24.9,37.1,53.0,56.7,65.6,113.1,115.3,119.4,127.2,127.8,128.1,128.4,128.7,130.6,137.5,148.6,150.9,156.2,172.2,187.8ppm；HRMS(ESI):m/z479.2186(M+H+),501.2003(M+Na+).9.N-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-1-氧代-3-苯基丙-2-基)吡嗪-2-氨基(化合物PS-9)的合成第一步以2-甲酸吡嗪和H-Phe-OMe为原料，制备方法同化合物1，得到的3-苯基-2-(吡嗪-2-甲酰胺)丙酸甲酯为白色针状固体，产率为89.82％。mp:64-65℃；1HNMR(400MHz,DMSO-d6):δ＝3.24(d,J＝7.2Hz,2H,CH2),3.67(s,3H,OCH3),4.83(m,1H,CH),7.18-7.26(m,5H,Ph),8.76(dd,J＝1.5,2.4Hz,1H,Pz-5),8.89(d,J＝2.5Hz,1H,NH),9.12(d,J＝8.2Hz,1H,Pz-6),9.14ppm(d,J＝1.4Hz,1H,Pz-3)；MS(ESI):m/z286.14(M+H+),308.22(M+Na+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为87.32％。mp:129-130℃；1HNMR(400MHz,CDCl3):δ＝0.83(d,J＝2.8Hz,3H,CH3),0.95(d,J＝2.4Hz,3H,CH3),1.43-1.47(m,1H,CH),1.58(s,2H,CH2),3.13-3.24(m,2H,CH2),4.92(t,J＝8.0,16.0Hz,1H,CH),5.35(d,J＝8.0Hz,1H,CH),6.53(d,J＝8.0Hz,1H,NH),6.59(s,1H,F-4),7.21(s,5H,Ph),7.34(s,1H,F-3),7.65(s,1H,F-5),8.40(d,J＝8.0Hz,1H,NH),8.53(s,1H,Pz-5),8.75(s,1H,Pz-6),9.37ppm(s,1H,Pz-3)；13CNMR(100MHz,CDCl3):δ＝21.9,23.1,24.9,38.6,42.0,52.7,54.6,76.7,77.0,77.4,112.6,119.0,127.1,128.6,129.3,136.2,142.7,144.0,144.4,147.3,147.5,150.9,162.9,170.0,186.9ppm；HRMS(ESI):m/z435.20315(M+H+),457.18499(M+Na+),473.15919(M+K+).10.N-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代-3-苯基丙-2-基)呋喃-2-甲氨基(化合物PS-10)的合成第一步以2-呋喃甲酸和H-Phe-OMe为原料，制备方法同化合物1，得到的2-(呋喃-2-甲酰胺)-3-苯基丙酸甲酯为白色柱状晶体，产率为68.32％。mp:65-66℃；1HNMR(400MHz,CDCl3):δ＝3.22(dd,J＝4.0Hz,2H,CH2),3.74(s,3H,OCH3),5.06(dd,J＝8.0Hz,1H,CH),6.50(dd,J＝4.0Hz,1H,F-4),6.77(dd,J＝8.0Hz,1H,NH),7.12(dd,J＝8.0Hz,3H,F-3,Ph),7.25-7.26(m,3H,Ph),7.43ppm(s,1H,F-5)；MS(ESI):m/z274.0911(M+H+),296.0681(M+Na+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为68.33％。mp:151-153℃；1HNMR(400MHz,DMSO-d6):δ＝0.91(d,J＝3.4Hz,3H,CH3),0.93(d,J＝3.2Hz,3H,CH3),1.48-1.74(m,3H,CH,CH2),2.90-3.05(m,2H,CH2),4.70-4.76(m,1H,CH),5.03-5.08(m,1H,CH),6.59(dd,J＝1.7,3.4Hz,1H,F-4),6.73(dd,J＝1.6,3.6Hz,1H,F-4’),7.10(d,J＝3.4Hz,1H,F-3),7.15(t,J＝7.2,14.4Hz,1H,Ph),7.22(t,J＝7.2,14.8Hz,2H,Ph),7.28(d,J＝7.1Hz,2H,Ph),7.49(d,J＝3.4Hz,1H,F-3’),7.81(d,J＝0.9Hz,1H,F-5),8.04(d,J＝1.0Hz,1H,F-5’),8.28(d,J＝8.6Hz,1H,NH),8.56ppm(d,J＝7.6Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.5,24.9,37.6,53.1,54.1,112.3,113.1,114.2,119.4,126.7,128.5,129.6,138.4,145.6,147.9,148.6,150.9,157.9,171.6,187.7ppm；HRMS(ESI):m/z423.19177(M+H+),461.14869(M+K+).11.N-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-4-甲基-1-氧代丙-2-基)呋喃-2-氨基(化合物PS-11)的合成第一步以2-呋喃甲酸和H-Leu-OMe为原料，制备方法同化合物1，得到的2-(呋喃-2-甲酰胺)-4-甲基丙酸甲酯为白色固体，产率为66.60％。mp:77-78℃；1HNMR(400MHz,CDCl3):δ＝0.98(t,J＝6.4,12.9Hz,6H,CH3),1.65-1.78(m,3H,CH,CH2),3.78(s,3H,OCH3),4.81-4.86(m,1H,CH),6.52(dd,J＝1.6,3.3Hz,1H,F-4),6.71(d,J＝8.1Hz,1H,NH),7.15(d,J＝3.4Hz,1H,F-3),7.48ppm(d,J＝0.6Hz,1H,F-5)；MS(ESI):m/z240.1075(M+H+),262.0861(M+Na+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为66.76％。mp:169-170℃；1HNMR(400MHz,DMSO-d6):δ＝0.85-0.92(m,12H,CH3),1.44-1.51(m,2H,CH2),1.53-1.63(m,3H,CH,CH2),1.66-1.71(m,1H,CH),4.49-4.55(m,1H,CH),4.99-5.04(m,1H,CH),6.62(dd,J＝1.7,3.4Hz,1H,F-4),6.72(dd,J＝1.6,3.6Hz,1H,F-4’),7.18(d,J＝3.4Hz,1H,F-3),7.46(d,J＝3.4Hz,1H,F-3’),7.84(d,J＝0.9Hz,1H,F-5),8.02(d,J＝1.0Hz,1H,F-5’),8.17(d,J＝8.4Hz,1H,NH),8.40ppm(d,J＝7.4Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.8,21.9,23.5,24.7,24.9,41.0,51.2,53.1,112.3,113.0,114.2,119.3,145.5,148.0,148.5,150.9,158.0,172.4,187.8ppm；HRMS(ESI):m/z389.20741(M+H+),411.18915(M+Na+),427.16322(M+K+).12.N-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代-3-苯基丙-2-基)亚甲二氧基苯基-5-氨基(化合物PS-12)的合成第一步以胡椒酸和H-Phe-OMe为原料，制备方法同化合物1，得到的2-(苯并-1,3-亚基二氧基-5-甲酰胺)-3-苯基丙酸甲酯为白色固体，产率为61.16％。mp:87-88℃；1HNMR(400MHz,CDCl3):δ＝3.20(dd,J＝5.4,13.8Hz,1H,CH2),3.27(dd,J＝5.8,13.8Hz,1H,CH2),3.76(s,3H,OCH3),5.03-5.08(m,1H,CH),6.02(s,2H,OCH2O),6.43(d,J＝7.4Hz,1H,Ph),6.81(d,J＝8.0Hz,1H,NH),7.11-7.13(m,2H,Ph),7.22-7.32ppm(m,5H,Ph)；MS(ESI):m/z328.11788(M+H+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为79.43％。mp:171-173℃；1HNMR(400MHz,DMSO-d6):δ＝0.86(d,J＝6.6Hz,3H,CH3),0.88(d,J＝6.6Hz,3H,CH3),1.45-1.56(m,3H,CH,CH2),2.93-3.07(m,2H,CH2),4.76-4.81(m,1H,CH),5.03-5.08(m,1H,CH),6.07(d,J＝1.8Hz,2H,OCH2O),6.72(dd,J＝1.6,3.6Hz,1H,F-4),6.94(d,J＝8.2Hz,1H,Ph),7.16(t,J＝7.3,14.4Hz,1H,Ph),7.24(t,J＝7.3,14.9Hz,2H,Ph),7.32-7.39(m,4H,Ph),7.50(d,J＝3.5Hz,1H,F-3),8.03(d,J＝1.1Hz,1H,F-5),8.34(d,J＝8.6Hz,1H,NH),8.58ppm(d,J＝8.0Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.8,23.5,24.9,38.1,52.9,55.1,102.1,107.9,108.2,113.1,119.6,122.9,126.7,128.5,129.6,138.6,147.6,148.7,150.2,150.8,165.6,171.8,187.9ppm；HRMS(ESI):m/z477.20239(M+H+),499.18510(M+Na+),515.15928(M+K+).13.N-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代-3-苯基丙-2-基)苯基氨基(化合物PS-13)的合成第一步以苯甲酸和H-Phe-OMe为原料，制备方法同化合物1，得到的2-苯甲酰胺-3-苯基丙酸甲酯为白色针状固体，产率为71.57％。mp:77℃；1HNMR(400MHz,CDCl3):δ＝3.27(dq,J＝5.6,14.0,19.6Hz,2H,CH2),3.77(s,3H,OCH3),5.10(dd,J＝6.0,12.4Hz,1H,CH),6.57(d,J＝6.4Hz,1H,NH),7.14(d,J＝6.8Hz,2H,Ph),7.26-7.31(m,3H,Ph),7.42(t,J＝7.2,7.6Hz,2H,Ph-3,5),7.51(t,J＝7.2Hz,1H,Ph-4),7.72ppm(d,J＝7.6Hz,2H,Ph-2,6)；MS(ESI):m/z284.1(M+H+),306.1(M+Na+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为49.83％。mp:115-116℃；1HNMR(400MHz,DMSO-d6)：δ＝0.86-0.94(dq,J＝4.1,6.5,9.1Hz,6H,CH3),1.40-1.71(m,3H,CH,CH2),2.92-3.11(m,2H,CH2),4.74-4.86(m,1H,CH),5.04-5.07(m,1H,CH),6.72-6.75(m,1H,NH),7.13-7.18(m,1H,NH),7.22-7.27(m,2H,Ph),7.34-7.37(m,2H,Ph),7.41-7.45(m,2H,Ph),7.48-7.49(m,2H,Ph),7.76(d,J＝1.2Hz,1H,F-4),7.78(s,1H,F-3),8.04(t,J＝1.2,2.8Hz,1H,F-5),8.50-8.63ppm(m,2H,Ph)；13CNMR(400MHz,DMSO-d6):δ＝21.8,23.5,24.9,37.5,38.1,52.9,55.1,113.2,119.4,119.6,126.7,127.8,128.5,129.6,131.7,134.5,138.5,148.6,150.8,166.6,171.8,187.8ppm；HRMS(ESI):m/z433.21284(M+H+),471.16943(M+K+).14.N-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4-甲基苯基氨基(化合物PS-14)的合成第一步以4-甲基苯甲酸和H-Phe-OMe为原料，制备方法同化合物1，得到的2-(4-甲基苯甲酰胺)-3-苯基丙酸甲酯为白色针状固体，产率为75.46％。mp:113-114℃；1HNMR(400MHz,CDCl3):δ＝2.39(s,3H,CH3),3.26(dq,J＝5.6,13.6,19.6Hz,2H,CH2),3.76(s,3H,OCH3),5.08(dd,J＝5.6,12.8Hz,1H,CH),6.52(d,J＝6.8Hz,1H,NH),7.13(d,J＝8.0Hz,2H,Ph),7.21-7.29(m,5H,Ph),7.62ppm(d,J＝8.0Hz,2H,Ph)；MS(ESI):m/z298.1(M+H+),320.1(M+Na+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为68.80％。mp:94-95℃；1HNMR(400MHz,DMSO-d6)：δ＝0.86-0.94(m,6H,CH3),1.53-1.56(m,3H,CH,CH2),2.33(s,3H,CH3),2.91-3.09(m,2H,CH2),4.73-4.85(m,1H,CH),5.03-5.08(m,1H,CH),6.71-6.74(m,1H,F-4),7.14-7.18(m,1H,F-3),7.22-7.27(m,4H,Ph),7.34(dd,J＝4.0,8.0Hz,2H,Ph),7.50(t,J＝3.2,6.4Hz,1H,Ph),7.69(d,J＝8.0Hz,2H,Ph),8.03(t,J＝1.6,3.0Hz,1H,F-5),8.42(t,J＝8.3,16.7Hz,1H,NH),8.56ppm(d,J＝7.6Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.4,21.9,23.5,24.9,37.5,38.1,52.9,55.1,113.1,119.4,126.7,127.8,128.5,129.1,129.7,131.7,138.8,141.6,148.7,150.8,166.6,171.8,187.9ppm；HRMS(ESI):m/z447.22780(M+H+),469.20989(M+Na+),485.18355(M+K+).15.N-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代-3-苯基丙-2-基)-2-萘基氨基(化合物PS-15)的合成第一步以2-萘甲酸和H-Phe-OMe为原料，制备方法同化合物1，得到的2-(2-萘基甲酰胺)-3-苯基丙酸甲酯为白色固体，产率为59.91％。mp:99-100℃；1HNMR(400MHz,CDCl3):δ＝3.21(dd,J＝6.3,14.0Hz,1H,CH2),3.40(dd,J＝5.5,13.9Hz,1H,CH2),3.81(s,3H,OCH3),5.23(dd,J＝6.4,13.1Hz,1H,CH),6.41(d,J＝6.9Hz,1H,NH),7.19-7.31(m,5H,Ph),7.41-7.54(m,4H,Ph),7.84-7.92(m,2H,Ph),8.16-8.19(m,1H,Ph)；MS(ESI):m/z334.14403(M+H+),356.12585(M+Na+),372.09998(M+K+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为81.69％。mp:173-175℃；1HNMR(400MHz,DMSO-d6)：δ＝0.95(d,J＝6.6Hz,3H,CH3),0.98(d,J＝6.6Hz,3H,CH3),1.52-1.83(m,3H,CH,CH2),2.84-3.13(m,2H,CH2),4.88-4.94(m,1H,CH),5.12-5.17(m,1H,CH),6.76(dd,J＝1.7,3.6Hz,1H,F-4),7.23-7.32(m,3H,Ph),7.36-7.44(m,4H,Ph,F-3),7.48-7.54(m,3H,Ph),7.79(d,J＝8.5Hz,1H,Ph),7.93(d,J＝8.1Hz,1H,Ph),7.97(d,J＝7.2Hz,1H,Ph),8.06(d,J＝1.2Hz,1H,F-5),8.55(d,J＝7.7Hz,1H,NH),8.69ppm(d,J＝8.6Hz,1H,NH)；13CNMR(400MHz,DMSO-d6):δ＝21.9,23.6,24.9,37.6,53.1,54.8,113.2,119.5,125.3,125.5,125.9,126.6,126.8,126.9,128.5,128.6,129.7,130.1,130.2,133.5,135.1,138.6,148.7,150.9,168.9,171.9,187.8ppm；HRMS(ESI):m/z483.22727(M+H+),505.20907(M+Na+),521.18329(M+K+).16.N-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代-3-苯基丙-2-基)-2-吡啶氨基(化合物PS-16)的合成第一步以2-吡啶甲酸和H-Phe-OMe为原料，制备方法同化合物1，得到的3-苯基-2-(吡啶甲酰胺)丙酸甲酯为白色固体，产率为74.79％。mp:79-80℃；1HNMR(400MHz,CDCl3):δ＝3.23(dd,J＝5.7,13.9Hz,1H,CH2),3.30(dd,J＝5.7,13.9Hz,1H,CH2),3.78(s,3H,OCH3),5.09(dd,J＝5.8,13.2Hz,1H,CH),6.70(d,J＝7.0Hz,1H,NH),7.13(d,J＝7.5Hz,2H,Ph),7.25-7.31(m,3H,Ph),7.36(dd,J＝5.0,7.8Hz,1H,P-5),8.04(d,J＝7.9Hz,1H,P-4),8.71(d,J＝4.6Hz,1H,P-3),8.91ppm(s,1H,P-6).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为64.79％。mp:115-116℃；1HNMR(400MHz,DMSO-d6)：δ＝0.90(d,J＝2.5Hz,3H,CH3),0.92(d,J＝2.6Hz,3H,CH3),1.50-1.71(m,3H,CH,CH2),3.00-3.15(m,2H,CH2),4.84-4.89(m,1H,CH),5.07-5.12(m,1H,CH),6.74(dd,J＝1.7,3.6Hz,1H,F-4),7.12-7.17(m,5H,Ph),7.50(d,J＝3.6Hz,1H,F-3),7.59(dd,J＝4.8,20.8Hz,1H,Ph),7.98(d,J＝4.7Hz,2H,Ph),8.05(d,J＝1.4Hz,1H,F-5),8.62(t,J＝4.5,12.6Hz,1H,NH),8.70ppm(d,J＝7.7Hz,1H,NH)；13CNMR(400MHz,DMSO-d6):δ＝21.9,23.4,24.9,38.3,52.9,53.9,113.2,119.7,122.3,126.8,127.2,128.5,129.7,137.6,138.4,148.8,149.0,149.7,150.9,163.5,171.0,187.6ppm；HRMS(ESI):m/z434.20803(M+H+),456.19088(M+Na+),472.16492(M+K+).17.4-氯-N-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代-3-苯基丙-2-基)-苯基氨基(化合物PS-17)的合成第一步以4-氯苯甲酸和H-Phe-OMe为原料，制备方法同化合物1，得到的2-(4-氯苯甲酰胺)-3-苯基丙酸甲酯为白色固体，产率为69.36％。mp:99-100℃；1HNMR(400MHz,CDCl3):δ＝3.26(dq,J＝5.5,13.9Hz,2H,CH2),3.80(s,3H,CH3),5.07(dd,J＝5.9,12.9Hz,1H,CH),6.51(d,J＝6.5Hz,1H,NH),7.11(d,J＝7.3Hz,2H,Ph),7.26-7.30(m,3H,Ph),7.40(d,J＝8.4Hz,2H,Ph-3,5),7.66ppm(d,J＝8.4Hz,2H,Ph-2,6)；HRMS(ESI):m/z318.08909(M+H+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为67.98％。mp:147-148℃；1HNMR(400MHz,DMSO-d6):δ＝0.87-0.93(m,6H,CH3),1.24-1.72(m,3H,CH,CH2),2.89-3.08(m,2H,CH2),4.76-4.82(m,1H,CH),5.06(s,1H,CH),6.73(s,1H,NH),7.16(s,1H,NH),7.24(d,J＝5.6Hz,2H,Ph),7.34(s,2H,Ph),7.50(s,3H,Ph),7.80(d,J＝7.2Hz,2H,Ph),8.03(s,1H,F-4),8.55(d,J＝7.2Hz,1H,F-3),8.64(d,J＝5.6Hz,1H,F-5)；13CNMR(400MHz,DMSO-d6):δ＝21.9,23.5,24.9,37.5,38.1,52.9,55.1,113.1,119.6,126.7,128.5,128.7,129.6,129.8,133.2,136.6,138.5,148.6,150.8,165.5,171.9,187.8ppm；HRMS(ESI):m/z467.17407(M+H+),489.15616(M+Na+),505.12995(M+K+).18.N-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4-硝基苯基氨基(化合物PS-18)的合成第一步以4-硝基苯甲酸和H-Phe-OMe为原料，制备方法同化合物1，得到的2-(4-硝基苯甲酰胺)-3-苯基丙酸甲酯为白色固体，产率为90.18％。mp:101-102℃；1HNMR(400MHz,CDCl3):δ＝3.29(dq,J＝5.5,13.9Hz,2H,CH2),3.81(s,3H,OCH3),5.09(dd,J＝5.5,13.0Hz,1H,CH),6.60(d,J＝7.1Hz,1H,NH),7.11-7.13(m,2H,Ph),7.26-7.31(m,3H,Ph),7.87(d,J＝8.8Hz,2H,Ph-3,5),8.29ppm(d,J＝8.8Hz,2H,Ph-2,6)；HRMS(ESI):m/z329.11347(M+H+),351.09533(M+Na+),367.06923(M+K+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为52.07％。mp:203-205℃；1HNMR(400MHz,DMSO-d6):δ＝0.86-0.94(m,6H,CH3),1.48-1.60(m,3H,CH,CH2),2.92-3.11(m,2H,CH2),4.77-4.86(m,1H,CH),5.06(s,1H,CH),6.74(s,1H,F-4),7.15-7.18(m,1H,F-3),7.25(dd,J＝7.1,13.8Hz,2H,Ph),7.34(s,2H,Ph),7.50(s,1H,Ph),7.99(d,J＝8.3Hz,2H,Ph),8.04(s,1H,F-5),8.29(t,J＝5.7,7.9Hz,2H,Ph),8.66(dd,J＝7.7,8.2Hz,1H,NH),8.94ppm(d,J＝8.4Hz,1H,NH)；13CNMR(400MHz,DMSO-d6):δ＝21.8,23.5,24.9,37.5,38.1,53.2,55.2,79.1,113.1,119.4,123.9,126.7,128.5,129.3,129.6,138.5,140.1,148.6,149.5,150.9,165.1,171.6,187.7ppm；HRMS(ESI):m/z478.19781(M+H+),500.17870(M+Na+),516.15239(M+K+).19.N-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4-甲氧基苯基氨基(化合物PS-19)的合成第一步以4-甲氧基苯甲酸和H-Phe-OMe为原料，制备方法同化合物1，得到的2-(4-甲氧基苯甲酰胺)-3-苯基丙酸甲酯为白色固体，产率为74.92％。mp:110-111℃；1HNMR(400MHz,CDCl3):δ＝3.20-3.31(m,2H,CH2),3.76(s,3H,CH3),3.85(s,3H,OCH3),5.08(dd,J＝6.4,7.2Hz,1H,CH),6.46(d,J＝7.2Hz,1H,NH),6.91(d,J＝8.4Hz,2H,Ph-3,5),7.13(d,J＝6.8Hz,2H,Ph),7.26-7.31(m,3H,Ph),7.70ppm(d,J＝8.4Hz,2H,Ph-2,6)；MS(ESI):m/z314.1226(M+H+),336.1019(M+Na+),352.0842(M+K+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为45.67％。mp:144-145℃；1HNMR(400MHz,DMSO-d6):δ＝0.87(dd,J＝6.4,8.4Hz,3H,CH3),0.92(dd,J＝3.8,6.4Hz,3H,CH3),1.42-1.73(m,3H,CH2,CH),2.90-3.08(m,2H,CH2),3.79(s,3H,OCH3),4.70-4.83(m,1H,CH),5.02-5.08(m,1H,CH),6.71-6.74(m,1H,Ph),6.96(dd,J＝3.6,8.8Hz,2H,Ph),7.12-7.17(m,1H,F-4),7.24(dd,J＝7.2,13.2Hz,2H,Ph),7.33-7.35(m,2H,Ph),7.50(t,J＝3.6,7.1Hz,1H,F-3),7.76(d,J＝8.7Hz,2H,Ph),8.03(s,1H,F-5),8.35(t,J＝8.3,16.7Hz,1H,NH),8.54ppm(d,J＝7.8Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.8,23.5,24.9,37.5,38.1,52.9,55.1,55.8,113.1,113.8,119.4,119.6,126.7,128.5,129.6,129.7,138.6,148.7,150.8,162.1,166.2,171.9,187.9ppm；HRMS(ESI):m/z463.22345(M+H+),485.20554(M+Na+),501.18005(M+K+).20.N-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代-3-苯基丙-2-基)-3,4-二甲氧基苯基氨基(化合物PS-20)的合成第一步以3,4-二甲氧基苯甲酸和H-Phe-OMe为原料，制备方法同化合物1，得到的2-(3,4-二甲氧基苯甲酰胺)-3-苯基丙酸甲酯为白色固体，产率为64.61％。mp:117-118℃；1HNMR(400MHz,CDCl3):δ＝3.26(dq,J＝5.6,13.8Hz,2H,CH2),3.77(s,3H,OCH3),3.92(s,6H,OCH3),5.08(dd,J＝6.1,12.2Hz,1H,CH),6.50(d,J＝7.1Hz,1H,NH),6.84(d,J＝8.3Hz,1H,Ph),7.13(d,J＝7.0Hz,2H,Ph),7.20-7.32(m,4H,Ph),7.37ppm(s,1H,Ph)；MS(ESI):m/z344.1361(M+H+),366.1125(M+Na+),382.0882(M+K+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为81.69％。mp:152-154℃；1HNMR(400MHz,DMSO-d6):δ＝0.88(dd,J＝6.5,8.2Hz,6H,CH3),1.42-1.60(m,3H,CH2,CH),2.95-3.09(m,2H,CH2),3.77(s,3H,OCH3),3.78(s,3H,OCH3),4.79-4.85(m,1H,CH),5.04-5.09(m,1H,CH),6.72(dd,J＝1.7,3.6Hz,1H,F-4),6.98(d,J＝8.5Hz,1H,Ph),7.16(t,J＝7.3,14.5Hz,1H,Ph),7.25(t,J＝7.3,14.9Hz,2H,Ph),7.34-7.37(m,3H,Ph),7.41(dd,J＝1.9,8.4Hz,1H,Ph),7.50(d,J＝3.6Hz,1H,F-3),8.03(d,J＝1.0Hz,1H,F-5),8.37(d,J＝8.6Hz,1H,NH),8.60ppm(d,J＝7.9Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.8,23.5,24.9,38.2,52.9,55.1,56.0,56.1,111.2,111.3,113.1,119.6,121.1,126.7,126.8,128.5,129.7,138.6,148.6,148.7,150.8,151.8,166.1,171.9,187.9ppm；HRMS(ESI):m/z493.23377(M+H+),515.21628(M+Na+),531.18967(M+K+).21.N-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代-3-苯基丙-2-基)-3-硝基苯基氨基(化合物PS-21)的合成第一步以3-硝基苯甲酸和H-Phe-OMe为原料，制备方法同化合物1，得到的2-(3-硝基苯甲酰胺)-3-苯基丙酸甲酯为白色固体，产率为58.36％。1HNMR(400MHz,CDCl3):δ＝3.28(dq,J＝5.6,13.6Hz,2H,CH2),3.80(s,3H,OCH3),5.10(dd,J＝6.4,12.8Hz,1H,CH),6.72(d,J＝7.0Hz,1H,NH),7.14(d,J＝6.8Hz,2H,Ph),7.27-7.33(m,3H,Ph),7.62(t,J＝8.0,15.9Hz,1H,Ph),8.04(d,J＝8.0Hz,1H,Ph),8.35(d,J＝8.2,1H,Ph),8.54ppm(s,1H,Ph).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为42.41％。mp:162-163℃；1HNMR(400MHz,DMSO-d6):δ＝0.86-0.95(m,6H,CH3),1.46-1.76(m,3H,CH,CH2),2.92-3.14(m,2H,CH2),4.81-4.93(m,1H,CH),5.05-5.10(m,1H,CH),6.74(ddd,J＝1.7,3.6Hz,1H,F-4),7.14-7.19(m,1H,Ph),7.25(dd,J＝7.0,14.0Hz,2H,Ph),7.35-7.38(m,2H,Ph),7.50(d,J＝3.6Hz,1H,F-3),7.73-7.77(m,1H,Ph),8.04(dd,J＝1.2,3.8Hz,1H,F-5),8.21(d,J＝7.7Hz,1H,Ph),8.36(d,J＝8.1Hz,1H,NH),8.63-8.72(m,2H,Ph),9.02ppm(d,J＝8.5Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.6,24.9,37.6,53.1,54.9,113.1,119.5,125.3,125.5,125.9,126.9,128.5,129.7,130.2,133.5,135.0,138.6,148.7,150.9,168.9,171.9,187.8ppm；HRMS(ESI):m/z478.19693(M+H+),500.17830(M+Na+),516.15276(M+K+).22.2-氯-N-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代-3-苯基丙-2-基)苯基氨基(化合物PS-22)的合成第一步以2-氯苯甲酸和H-Phe-OMe为原料，制备方法同化合物1，得到的2-(2-氯基苯甲酰胺)-3-苯基丙酸甲酯为白色固体，产率为79.73％。mp:60-61℃；1HNMR(400MHz,CDCl3):δ＝3.27(dq,J＝5.8,13.9Hz,2H,CH2),3.77(s,3H,OCH3),5.10(dd,J＝5.8,13.2Hz,1H,CH),6.70(d,J＝7.2Hz,1H,NH),7.16-7.18(m,2H,Ph),7.24-7.39(m,6H,Ph),7.61ppm(d,J＝7.2Hz,1H,Ph)；MS(ESI):m/z318.1(M+H+),340.1(M+Na+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为87.69％。mp:125-126℃；1HNMR(400MHz,DMSO-d6):δ＝0.93(dd,J＝6.6,9.6Hz,6H,CH3),1.47-1.77(m,3H,CH,CH2),2.82(dd,J＝10.6,13.8Hz,1H,CH2),3.05(dd,J＝4.2,14.0Hz,1H,CH2),4.73-4.79(m,1H,CH),5.07-5.12(m,1H,CH),6.75(dd,J＝1.7,3.6Hz,1H,F-4),7.16-7.21(m,2H,Ph),7.25-7.37(m,5H,Ph),7.39-7.45(m,2H,Ph),7.51(d,J＝3.4Hz,1H,F-3),8.05(d,J＝1.1Hz,1H,F-5),8.42(d,J＝7.7Hz,1H,NH),8.63ppm(d,J＝8.5Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.6,24.9,37.6,53.0,54.5,113.2,119.5,126.7,127.3,128.5,129.3,129.7,130.0,130.4,131.3,136.9,138.3,148.7,150.8,166.5,171.4,187.7ppm；HRMS(ESI):m/z467.17363(M+H+),489.15649(M+Na+),505.12973(M+K+).23.3-氯-N-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代-3-苯基丙-2-基)苯基氨基(化合物PS-23)的合成第一步以3-氯苯甲酸和H-Phe-OMe为原料，制备方法同化合物1，得到的2-(3-氯基苯甲酰胺)-3-苯基丙酸甲酯为白色固体，产率为86.28％。1HNMR(400MHz,CDCl3):δ＝3.26(dq,J＝5.6,13.6Hz,2H,CH2),3.78(s,3H,OCH3),5.07(dd,J＝6.0,13.2Hz,1H,CH),6.52(d,J＝6.0Hz,1H,NH),7.12(d,J＝6.8Hz,2H,Ph),7.26-7.38(m,3H,Ph),7.48(d,J＝7.7Hz,1H,Ph),7.57(d,J＝7.6Hz,1H,Ph),7.72ppm(s,1H,Ph).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为59.74％。mp:106-108℃；1HNMR(400MHz,DMSO-d6):δ＝0.87-0.93(m,6H,CH3),1.46-1.72(m,3H,CH,CH2),2.89-3.09(m,2H,CH2),4.77-4.83(m,1H,CH),5.06(s,1H,CH),6.73(s,1H,F-4),7.17(s,1H,F-3),7.25(d,J＝5.6Hz,2H,Ph),7.34(s,2H,Ph),7.47-7.50(m,2H,Ph),7.57(d,J＝5.9Hz,1H,Ph),7.73(d,J＝7.1Hz,1H,Ph),7.83(s,1H,Ph),8.04(s,1H,F-5),8.61(d,J＝7.6Hz,1H,NH),8.69ppm(d,J＝6.7Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.5,24.9,37.5,38.1,52.9,53.2,55.1,113.1,119.5,126.7,127.7,128.5,129.6,130.7,131.5,133.5,136.5,138.5,148.6,150.9,165.3,171.7,187.8ppm；HRMS(ESI):m/z467.17387(M+H+),489.15570(M+Na+),505.12917(M+K+).24.2,4-二氯-N-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代-3-苯基丙-2-基)苯基氨基(化合物PS-24)的合成第一步以2,4-二氯苯甲酸和H-Phe-OMe为原料，制备方法同化合物1，得到的2-(2,4-二氯苯甲酰胺)-3-苯基丙酸甲酯为白色固体，产率为80.48％。mp:87-88℃；1HNMR(400MHz,CDCl3):δ＝3.26(dq,J＝5.6,13.9Hz,2H,CH2),3.78(s,3H,OCH3),5.08(dt,J＝4.0,8.0,12.0Hz,1H,CH),6.73-6.71(d,J＝8.0Hz,1H,NH),7.16-7.14(m,2H,Ph,Ph-6),7.32-7.25(m,4H,Ph),7.41(d,J＝4.0Hz,1H,Ph-5),7.58ppm(d,J＝8.0Hz,1H,Ph-3).MS(ESI):m/z352.05034(M+H+),374.03248(M+Na+),390.00650(M+K+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为37.36％。mp:102-103℃；1HNMR(400MHz,DMSO-d6):δ＝0.86(m,3H,CH3),0.93(m,3H,CH3),1.40-1.73(m,3H,CH,CH2),2.77-3.07(m,2H,CH2),4.76-4.83(m,1H,CH),5.06-5.08(m,1H,CH),6.74(s,1H,F-4),7.17-7.28(m,6H,Ph,F-3),7.46-7.51(m,2H,Ph),7.62(s,1H,Ph),8.05(s,1H,F-5),8.51(d,J＝7.0Hz,1H,NH),8.69ppm(d,J＝8.2Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.5,24.9,37.6,38.3,53.1,54.7,113.1,119.5,126.8,127.6,128.5,129.6,130.7,131.7,135.0,135.7,138.2,148.7,150.9,165.5,171.3,187.6ppm；HRMS(ESI):m/z501.13469(M+H+),523.11617(M+Na+),539.08979(M+K+).25.2-氯-4-氟-N-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代-3-苯基丙-2-基)苯基氨基(化合物PS-25)的合成第一步以2-氯-4-氟苯甲酸和H-Phe-OMe为原料，制备方法同化合物1，得到的2-(2-氯-4-氟苯甲酰胺)-3-苯基丙酸甲酯为白色固体，产率为30.45％。mp:59-60℃；1HNMR(400MHz,CDCl3):δ＝3.6(dq,J＝5.9,13.9Hz,2H,CH2),3.78(s,3H,CH3),5.08(dd,J＝5.9,13.1Hz,1H,CH),6.73(d,J＝6.6Hz,1H,NH),7.01-7.05(m,1H,Ph),7.12-7.17(m,3H,Ph),7.20-7.36(m,2H,Ph),7.67ppm(dd,J＝6.1,8.7Hz,1H,Ph).MS(ESI):m/z336.08000(M+H+),358.06199(M+Na+),374.03600(M+K+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为56.75％。mp:103-104℃；1HNMR(400MHz,CDCl3):δ＝0.87(t,J＝5.5,11.0Hz,3H,CH3),0.99(d,J＝5.6Hz,3H,CH3),1.31-1.61(m,3H,CH,CH2),3.13-3.29(m,2H,CH2),4.87-4.98(m,1H,CH),5.30-5.37(m,1H,CH),6.39(t,J＝5.6,13.5Hz,1H,Ph),6.58(ddd,J＝1.6,5.2Hz,1H,F-4),6.85(t,J＝7.9,16.8Hz,1H,Ph),7.01-7.03(m,1H,Ph),7.10-7.14(m,1H,Ph),7.24-7.33(m,6H,Ph,F-5),7.59-7.66ppm(m,2H,NH)；13CNMR(100MHz,CDCl3):δ＝20.7,22.1,23.9,37.2,41.0,51.7,54.1,111.5,113.5,116.5,117.9,126.1,127.6,128.3,129.5,130.9,131.0,135.1,146.2,149.7,161.0,163.5,164.1,169.0,185.8ppm；HRMS(ESI):m/z485.16365(M+H+),507.14538(M+Na+),523.11821(M+K+).26.2-碘-N-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代-3-苯基丙-2-基)苯基氨基(化合物PS-26)的合成第一步以2-碘苯甲酸和H-Phe-OMe为原料，制备方法同化合物1，得到的2-(2-碘苯甲酰胺)-3-苯基丙酸甲酯为白色固体，产率为83.28％。mp:86-87℃；1HNMR(400MHz,CDCl3):δ＝3.29(dq,J＝6.0,13.9Hz,2H,CH2),3.78(s,3H,OCH3),5.09(dd,J＝5.6,12.0Hz,1H,CH),6.25(d,J＝7.2Hz,1H,NH),7.08-7.37(m,8H,Ph),7.86ppm(d,J＝7.6Hz,1H,Ph)；MS(ESI):m/z410.0013(M+H+),431.9810(M+Na+),447.9608(M+K+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为49.62％。mp:99-100℃；1HNMR(400MHz,DMSO-d6):δ＝0.87(s,6H,CH3),1.50-1.52(m,3H,CH,CH2),2.91-3.07(m,2H,CH2),4.82(s,1H,CH),5.06(s,1H,CH),6.74(s,1H,F-4),7.08-7.39(m,8H,Ph),7.53(s,1H,F-3),7.83(d,J＝6.8Hz,1H,Ph),8.04(s,1H,F-5),8.47(d,J＝6.6Hz,1H,NH),8.55ppm(d,J＝7.4Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.8,23.6,24.7,38.2,52.7,54.6,93.6,113.2,119.7,126.8,128.3,128.5,129.7,131.3,138.1,139.6,142.7,148.7,150.8,168.8,171.0,187.6ppm；HRMS(ESI):m/z559.10794(M+H+),581.09011(M+Na+),597.06438(M+K+).27.2-氟-N-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代-3-苯基丙-2-基)苯基氨基(化合物PS-27)的合成第一步以2-氟苯甲酸和H-Phe-OMe为原料，制备方法同化合物1，得到的2-(2-氟苯甲酰胺)-3-苯基丙酸甲酯为白色固体，产率为92.43％。mp:146-147℃；1HNMR(400MHz,CDCl3):δ＝3.18-3.30(m,2H,CH2Ph),3.73(s,3H,OCH3),5.05-5.11(m,1H,CH),7.08(dd,J＝8.3,12.0Hz,1H,Ph),7.15-7.30(m,7H,Ph),7.41-7.46(m,1H,Ph),8.02-8.06ppm(m,1H,NH)；MS(ESI):m/z324.23(M+Na+).第二步以上述得到的甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为77.03％。mp:132-133℃；1HNMR(400MHz,DMSO-d6):δ＝0.93(t,J＝6.6,13.2Hz,6H,CH3),1.49-1.73(m,3H,CH,CH2),2.87(dd,J＝9.8,13.8Hz,1H,CH2),3.07(dd,J＝4.2,13.8Hz,1H,CH2),4.74-4.79(m,1H,CH),5.05-5.11(m,1H,CH),6.74(dd,J＝1.6,3.6Hz1H,F-4),7.18-7.28(m,7H,Ph),7.47-7.53(m,3H,F-3,Ph),8.05(d,J＝1.0Hz,1H,F-5),8.29(dd,J＝3.2,8.2Hz,1H,NH),8.53ppm(d,J＝7.6Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.5,24.9,37.7,53.1,54.7,113.1,116.5,116.7,119.6,123.7,123.8,124.9,126.8,128.5,129.7,130.6,133.1,133.2,138.1,148.7,150.9,163.8,171.3,187.7ppm；HRMS(ESI):m/z451.2029(M+H+),473.1850(M+Na+).28.2-甲基-N-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代-3-苯基丙-2-基)苯基氨基(化合物PS-28)的合成以前面叙述得到的2-(2-甲基苯甲酰胺)-3-苯基丙酸甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为83.06％。mp:143-145℃；1HNMR(400MHz,CD3OD):δ＝0.88(d,J＝6.3Hz,3H,CH3),0.93(d,J＝6.2Hz,3H,CH3),1.44-1.54(m,3H,CH,CH2),2.17(s,3H,CH3),2.98(dd,J＝8.8,13.5Hz,1H,CH2),3.17(dd,J＝6.9,13.6Hz,1H,CH2),4.96(t,J＝7.6,15.6Hz,1H,CH),5.18(t,J＝7.0,14.1Hz,1H,CH),6.65(d,J＝1.8Hz,1H,F-4),7.16-7.17(m,3H,Ph),7.23-7.31(m,6H,Ph,NH),7.42(d,J＝3.4Hz,1H,F-3),7.81ppm(s,1H,F-5)；13CNMR(100MHz,CD3OD):δ＝18.1,20.5,22.2,24.6,37.7,40.2,53.0,54.8,112.3,118.8,125.2,126.5,126.6,128.1,129.0,129.5,130.2,135.5,136.0,137.0,147.6,150.9,171.3,171.9,187.5ppm；HRMS(ESI):m/z447.2277(M+H+),469.2097(M+Na+).29.2-甲氧基-N-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代-3-苯基丙-2-基)苯基氨基(化合物PS-29)的合成以前面叙述得到的2-(2-甲氧基苯甲酰胺)-3-苯基丙酸甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为78.23％。mp:122-123℃；1HNMR(400MHz,DMSO-d6):δ＝0.91(d,J＝5.3Hz,3H,CH3),0.93(d,J＝5.2Hz,3H,CH3),1.48-1.72(m,3H,CH,CH2),2.93(dd,J＝8.1,13.8Hz,1H,CH2),3.08(dd,J＝4.8,13.9Hz,1H,CH2),3.80(s,3H,CH3),4.80-4.85(m,1H,CH),5.06-5.11(m,1H,CH),6.75(d,J＝1.7,3.6Hz,1H,F-4),7.03(t,J＝7.7,14.9Hz,1H,Ph),7.12-7.24(m,6H,Ph),7.46-7.50(m,1H,Ph),7.51(d,J＝3.4Hz,1H,F-3),7.77(dd,J＝1.8,7.8Hz,1H,Ph),8.06(d,J＝1.0Hz,1H,F-5),8.27(d,J＝7.7Hz,1H,NH),8.57ppm(d,J＝7.7Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.5,24.9,38.2,52.9,54.3,56.4,112.7,113.2,119.7,121.1,122.0,126.9,128.5,129.8,131.3,133.2,137.6,148.8,150.9,157.7,164.5,171.3,187.7ppm；HRMS(ESI):m/z463.2231(M+H+).30.2-硝基-N-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代-3-苯基丙-2-基)苯基氨基(化合物PS-30)的合成以前面叙述得到的2-(2-硝基苯甲酰胺)-3-苯基丙酸甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为69.05％。mp:164-165℃；1HNMR(400MHz,DMSO-d6):δ＝0.92(d,J＝6.6Hz,3H,CH3),0.94(d,J＝6.6Hz,3H,CH3),1.48-1.73(m,3H,CH2,CH),2.82-3.09(m,2H,CH2Ph),4.75-4.80(m,1H,CH),5.05-5.11(m,1H,CH),6.74(d,J＝2.0Hz,1H,F-4),7.18-7.35(m,6H,Ph),7.50(d,J＝3.4Hz,1H,F-3),7.66(t,J＝7.8,15.5Hz,1H,Ph),7.75(t,J＝7.4,14.9Hz,1H,Ph),7.98(d,J＝8.0Hz,1H,Ph),8.05(s,1H,F-5),8.43(d,J＝7.6Hz,1H,NH),8.94ppm(d,J＝8.4Hz,1H,NH)；13CNMR(100MHz,CD3OD):δ＝20.6,22.2,24.7,37.2,40.3,53.0,54.7,112.3,118.9,124.1,126.4,128.0,128.7,129.0,130.5,132.2,133.5,136.9,146.4,147.7,151.0,167.6,171.5,187.5ppm；HRMS(ESI):m/z478.1980(M+H+),500.1801(M+Na+).31.2-溴-N-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代-3-苯基丙-2-基)苯基氨基(化合物PS-31)的合成以前面叙述得到的2-(2-溴苯甲酰胺)-3-苯基丙酸甲酯中间体和化合物3为原料，制备方法同化合物PS-32，得到白色固体，产率为71.51％。mp:151-152℃；1HNMR(400MHz,DMSO-d6):δ＝0.93(d,J＝6.7Hz,3H,CH3),0.95(d,J＝6.8Hz,3H,CH3),1.49-1.78(m,3H,CH2,CH),2.83(t,J＝10.6,13.7Hz,1H,CH2Ph),3.06(dd,J＝4.2,14.0Hz,1H,CH2Ph),4.74-4.80(m,1H,CH),5.07-5.13(m,1H,CH),6.75(t,J＝1.9,3.4Hz,1H,F-4),7.13(d,J＝7.4Hz,1H,Ph),7.20(t,J＝6.8,13.3Hz,1H,Ph),7.25-7.35(m,5H,Ph),7.40(t,J＝7.4,14.8Hz,1H,Ph),7.51(d,J＝3.4Hz,1H,F-3),7.60(d,J＝7.9Hz,1H,Ph),8.05(s,1H,F-5),8.40(d,J＝7.6Hz,1H,NH),8.62ppm(d,J＝8.4Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝22.0,23.6,24.9,37.6,53.0,54.5,113.2,119.3,119.5,126.7,127.8,128.5,129.2,129.7,131.4,133.1,138.3,139.1,148.7,150.8,167.3,171.4,187.7ppm；HRMS(ESI):m/z511.1233(M+H+).32.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-3-(4-甲氧基苯基)-1-氧代丙-2-基氨基)-1-氧代-3-苯基丙-2-基氨基甲酸乙酯(化合物PS-55)的合成第一步以前面叙述过的PS-5为原料，制备方法同化合物3，得到白色固体，直接用于下一步反应。第二步以Ac-Phe-OH和上述中间体为原料，制备方法同化合物1，得到白色固体，产率为74.88％。mp:197-199℃；1HNMR(400MHz,DMSO-d6):δ＝0.90(d,J＝6.8Hz,3H,CH3),0.92(d,J＝6.7Hz,3H,CH3),1.48-1.57(m,2H,CH2),1.66-1.67(m,1H,CH),1.72(s,3H,CH3),2.62-2.68(m,2H,CH2),2.85-2.95(m,2H,CH2),4.43-4.49(m,2H,CH),5.01-5.06(m,1H,CH),6.60(d,J＝8.4Hz,2H,Ph),6.73(q,J＝1.6,3.5Hz,1H,F-4),6.98(d,J＝8.4Hz,2H,Ph),7.16-7.23(m,5H,Ph),7.47(d,J＝3.5Hz,1H,F-3),8.02(m,3H,NH,F-5),8.35(d,J＝7.7Hz,1H,NH),9.15ppm(s,1H,OH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,22.9,23.5,24.8,37.1,37.8,52.9,54.2,54.4,113.1,115.3,119.5,126.6,128.0,128.4,129.6,130.6,138.5,148.7,150.8,156.3,169.5,171.5,171.6,187.6ppm；HRMS(ESI):m/z534.25893(M+H+),556.24098(M+Na+),572.21470(M+K+).33.(S)-N-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)-3-(4-羟基苯基)-2-((S)-2-(4-甲基苯磺酰胺)-3-苯基丙酰氨基)丙酰胺(化合物PS-56)的合成第一步以前面叙述过的PS-5为原料，制备方法同化合物3，得到氨基中间体，直接用于缩合反应。第二步将L-Phe-OH(1.65g,10mmol)溶于24mLTHF，加入12mL1NNaOH溶液，随后在冰浴、剧烈搅拌的条件下分批加入对甲苯磺酰氯(1.9g,10mmol)。反应过程中通过加入4NNaOH溶液调节pH保持大于8，2小时后反应结束，加入6MHCl溶液直至pH＝2，乙酸乙酯萃取3次后合并有机相，分别用1MHCl溶液，H2O，饱和NaCl溶液洗涤，无水Na2SO4干燥。滤除干燥剂，有机相减压蒸干，得到的2-(4-甲基苯磺酰胺)-3-苯基丙酸(羧基中间体)为白色固体2.86g，产率为89.74％。第三步以上述的氨基中间体和羧基中间体为原料，制备方法同化合物1，得到白色固体，产率为80.81％。mp:227-229℃；1HNMR(400MHz,DMSO-d6):δ＝0.88(d,J＝6.8Hz,3H,CH3),0.89(d,J＝6.7Hz,3H,CH3),1.43-1.53(m,2H,CH2),1.61-1.66(m,1H,CH),2.29(s,3H,CH3),2.54-2.58(m,2H,CH2),2.74-2.82(m,2H,CH2),3.95-4.01(m,1H,CH),4.23-4.29(m,1H,CH),4.97-5.03(m,1H,CH),6.63(d,J＝8.4Hz,2H,Ph),6.71(dd,J＝1.6,3.6Hz,1H,F-4),6.96(d,J＝8.4Hz,2H,Ph),7.05(d,J＝8.2Hz,2H,Ph),7.10-7.18(m,5H,Ph),7.30(d,J＝8.2Hz,2H,Ph),7.45(d,J＝3.6Hz,1H,F-3),7.89(d,J＝9.1Hz,1H,NH),8.03(d,J＝1.1Hz,1H,F-5),8.16(d,J＝8.0Hz,1H,NH),8.34(d,J＝7.7Hz,1H,NH),9.19ppm(s,1H,OH)；13CNMR(100MHz,DMSO-d6):δ＝21.4,21.9,23.5,24.8,37.0,38.8,52.9,54.4,57.9,113.1,115.3,119.5,126.6,126.7,128.0,128.4,129.5,129.7,130.6,137.7,138.5,142.4,148.6,150.8,156.3,170.8,171.4,187.5ppm；HRMS(ESI):m/z646.25615(M+H+),668.23801(M+Na+),684.21170(M+K+).34.(S)-N-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)-3-(4-羟基苯基)-2-((S)-3-(4-甲氧基苯基)-2-(4-甲基苯磺酰胺)丙酰氨基)丙酰胺(化合物PS-57)的合成第一步以前面叙述过的PS-5为原料，制备方法同化合物3，得到氨基中间体，直接用于缩合反应。第二步以L-(4-OMe)Phe-OH为原料，制备方法同化合物PS-56的第二步，得到的3-(4-甲氧基苯基)-2-(4-甲基苯磺酰胺)丙酸(羧基中间体)为白色固体，产率为89.6％。第三步以上述的氨基中间体和羧基中间体为原料，制备方法同化合物1，得到白色固体，产率为82.03％。mp:174-175℃；1HNMR(400MHz,DMSO-d6):δ＝0.89(t,J＝6.9Hz,6H,CH3),1.42-1.57(m,2H,CH2),1.61-1.67(m,1H,CH),2.29(s,3H,CH3),2.44-2.48(m,1H,CH2),2.53-2.58(m,1H,CH2),2.70-2.81(m,2H,CH2),3.72(s,3H,OCH3),3.86-3.93(m,1H,CH),4.26-4.32(m,1H,CH),4.97-5.04(m,1H,CH),6.62(d,J＝8.4Hz,2H,Ph),6.69(s,1H,F-4),6.71-6.73(m,2H,Ph),6.94-7.06(m,4H,Ph),7.30(d,J＝8.2Hz,2H,Ph),7.45(d,J＝3.5Hz,1H,F-3),7.84(d,J＝9.0Hz,1H,NH),8.02(d,J＝1.0Hz,1H,F-5),8.12(d,J＝8.0Hz,1H,NH),8.33(d,J＝7.7Hz,1H,NH),9.17ppm(s,1H,OH)；13CNMR(100MHz,DMSO-d6):δ＝21.4,21.9,23.5,24.8,37.1,38.0,52.9,54.4,55.3,58.3,113.1,113.7,115.3,119.5,126.7,127.9,129.4,129.5,130.6,130.7,138.5,142.3,148.6,150.8,156.3,158.2,170.9,171.3,187.5ppm；HRMS(ESI):m/z676.2684(M+H+).35.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-1-氧代-2-基氨基)-1-氧代-3-苯基丙-2-基氨基甲酸叔丁酯(化合物PS-58)的合成第一步以前面叙述过的PS-1为原料，制备方法同化合物3，得到氨基中间体，直接用于下一步反应。第二步以Boc-Phe-OH和上述的氨基中间体为原料，制备方法同化合物1，得到白色固体，产率为81.43％。mp:97-98℃；1HNMR(400MHz,DMSO-d6):δ＝0.89(d,J＝7.5Hz,3H,CH3),0.92(d,J＝7.2Hz,3H,CH3),1.18(d,J＝6.9Hz,3H,CH3),1.29(s,9H,Boc),1.44-1.57(m,2H,CH2),1.66-1.69(m,1H,CH),2.66-2.99(m,2H,CH2),4.12-4.17(m,1H,CH),4.33-4.37(m,1H,CH),4.99-5.05(m,1H,CH),6.74(t,J＝1.5,3.5Hz,1H,F-4),6.94(d,J＝8.5Hz,1H,NH),7.18-7.26(m,5H,Ph),7.47(d,J＝3.5Hz,1H,F-3),7.99(d,J＝7.3Hz,1H,NH),8.04(s,1H,F-5),8.35ppm(d,J＝7.6Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝18.8,21.8,23.5,24.9,28.6,37.7,48.2,53.0,56.1,78.5,113.1,119.3,126.6,128.4,129.6,138.7,148.6,150.8,155.7,171.8,172.6,187.8ppm；HRMS(ESI):m/z500.27585(M+H+),522.25768(M+Na+),538.23148(M+K+).36.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-1-氧代-2-基氨基)-1-氧代-3-苯基丙-2-基氨基甲酸苄酯(化合物PS-59)的合成第一步以前面叙述过的PS-1为原料，制备方法同化合物3，得到氨基中间体，直接用于下一步反应。第二步以Cbz-Phe-OH和上述的氨基中间体为原料，制备方法同化合物1，得到白色固体，产率为80.7％。mp:190-191℃；1HNMR(400MHz,DMSO-d6):δ＝0.90(d,J＝7.1Hz,3H,CH3),0.92(d,J＝7.2Hz,3H,CH3),1.20(d,J＝7.0Hz,3H,CH3),1.46-1.59(m,2H,CH2),1.67-1.72(m,1H,CH),2.70-3.03(m,2H,CH2),4.24-4.30(m,1H,CH),4.33-4.37(m,1H,CH),4.93(s,2H,CH2),5.00-5.04(m,1H,CH),6.74(dd,J＝1.6,3.6Hz,1H,F-4),7.19-7.34(m,10H,Ph),7.48(d,J＝3.2Hz,1H,F-3),7.50(s,1H,NH),8.04(d,J＝1.0Hz,1H,F-5),8.17(d,J＝7.4Hz,1H,NH),8.33ppm(d,J＝7.5Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝18.6,21.9,23.5,24.9,37.8,48.4,53.1,56.5,65.6,113.1,119.3,126.7,127.8,128.1,128.5,128.7,129.7,137.5,138.6,148.6,150.8,156.3,171.6,172.6,187.8ppm；HRMS(ESI):m/z534.25955(M+H+),556.24169(M+Na+),572.21525(M+K+).37.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-1-氧代-2-基氨基)-1-氧代-3-(4-甲氧基苯基)丙-2-基氨基甲酸叔丁酯(化合物PS-60)的合成第一步以前面叙述过的PS-1为原料，制备方法同化合物3，得到氨基中间体，直接用于下一步反应。第二步以Boc-(4-OMe)Phe-OH和上述的氨基中间体为原料，制备方法同化合物1，得到白色固体，产率为72.7％。mp:97-99℃；1HNMR(400MHz,DMSO-d6):δ＝0.89(d,J＝7.3Hz,3H,CH3),0.92(d,J＝7.4Hz,3H,CH3),1.18(d,J＝6.9Hz,3H,CH3),1.29(s,9H,Boc),1.44-1.57(m,2H,CH2),1.65-1.68(m,1H,CH),2.59-2.91(m,2H,CH2),3.71(s,3H,OCH3),4.04-4.10(m,1H,CH),4.31-4.37(m,1H,CH),4.99-5.05(m,1H,CH),6.74(dd,J＝1.5,4.9Hz,1H,F-4),6.82(d,J＝8.3Hz,2H,Ph),6.88(d,J＝8.5Hz,1H,NH),7.17(d,J＝8.3Hz,2H,Ph),7.47(d,J＝3.5Hz,1H,F-3),7.97(d,J＝7.4Hz,1H,NH),8.04(s,1H,F-5),8.34ppm(d,J＝7.6Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝18.8,21.8,23.5,24.9,28.6,36.9,48.2,53.0,55.4,56.4,78.5,113.1,113.9,119.3,130.5,130.6,148.6,150.8,155.7,158.2,171.8,172.6,187.8ppm；HRMS(ESI):m/z530.28602(M+H+),552.26800(M+Na+),568.24190(M+K+).38.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-1-氧代-3-甲氧基-2-基氨基)-1-氧代-3-苯基丙-2-基氨基甲酸叔丁酯(化合物PS-61)的合成第一步以前面叙述过的PS-2为原料，制备方法同化合物3，得到氨基中间体，直接用于下一步反应。第二步以Boc-Phe-OH和上述的氨基中间体为原料，制备方法同化合物1，得到白色固体，产率为79.69％。mp:104-105℃；1HNMR(400MHz,DMSO-d6):δ＝0.89(d,J＝6.9Hz,3H,CH3),0.92(d,J＝7.0Hz,3H,CH3),1.29(s,9H,Boc),1.45-1.58(m,2H,CH2),1.64-1.69(m,1H,CH),2.66-2.97(m,2H,CH2),3.21(s,3H,OCH3),3.47(d,J＝5.6Hz,2H,CH2),4.17-4.22(m,1H,CH),4.52-4.55(m,1H,CH),5.01-5.07(m,1H,CH),6.73(dd,J＝1.7,3.6Hz,1H,F-4),6.94(d,J＝8.5Hz,1H,NH),7.18-7.27(m,5H,Ph),7.47(d,J＝3.4Hz,1H,F-3),8.03(d,J＝1.1Hz,1H,F-5),8.05(s,1H,NH),8.41ppm(d,J＝7.8Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.5,24.8,28.6,37.7,52.8,53.0,56.1,58.7,72.5,78.5,113.1,119.5,126.6,128.4,129.7,138.7,148.6,150.7,155.7,169.8,172.1,187.5ppm；HRMS(ESI):m/z530.28656(M+H+),552.26843(M+Na+),568.24223(M+K+).39.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-1-氧代-3-甲氧基-2-基氨基)-1-氧代-3-苯基丙-2-基氨基甲酸苄酯(化合物PS-62)的合成第一步以前面叙述过的PS-2为原料，制备方法同化合物3，得到氨基中间体，直接用于下一步反应。第二步以Cbz-Phe-OH和上述的氨基中间体为原料，制备方法同化合物1，得到白色固体，产率为72.84％。mp:113℃；1HNMR(400MHz,DMSO-d6):δ＝0.89(d,J＝7.0Hz,3H,CH3),0.92(d,J＝6.8Hz,3H,CH3),1.49-1.55(m,2H,CH2),1.67-1.68(m,1H,CH),2.67-3.03(m,2H,CH2),3.22(s,3H,OCH3),3.49(d,J＝5.6Hz,2H,CH2),4.30-4.36(m,1H,CH),4.61-4.66(m,1H,CH),4.93(s,2H,CH2),5.01-5.07(m,1H,CH),6.73(dd,J＝1.6,3.5Hz,1H,F-4),7.18-7.34(m,10H,Ph),7.48(d,J＝3.4Hz,1H,F-3),7.51(s,1H,NH),8.03(d,J＝0.9Hz,1H,F-5),8.23(d,J＝7.8Hz,1H,NH),8.38ppm(d,J＝7.6Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.5,24.8,37.9,53.0,53.1,56.4,58.7,65.6,72.4,113.1,119.5,126.7,127.8,128.1,128.4,128.7,129.7,137.5,138.6,148.6,150.7,156.3,169.8,172.1,187.5ppm；HRMS(ESI):m/z564.26897(M+H+),586.25096(M+Na+),602.22489(M+K+).40.(S)-1-((S)-1-((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基氨基)-1-氧代-3-甲氧基-2-基氨基)-1-氧代-3-(4-甲氧基苯基)丙-2-基氨基甲酸叔丁酯(化合物PS-63)的合成第一步以前面叙述过的PS-2为原料，制备方法同化合物3，得到氨基中间体，直接用于下一步反应。第二步以Boc-(4-OMe)Phe-OH和上述的氨基中间体为原料，制备方法同化合物1，得到白色固体，产率为70.08％。mp:75-76℃；1HNMR(400MHz,DMSO-d6):δ＝0.89(d,J＝7.1Hz,3H,CH3),0.92(d,J＝7.1Hz,3H,CH3),1.30(s,9H,Boc),1.46-1.58(m,2H,CH2),1.64-1.67(m,1H,CH),2.59-2.93(m,2H,CH2),3.21(s,3H,OCH3),3.46(d,J＝5.4Hz,2H,CH2),3.71(s,3H,OCH3),4.10-4.15(m,1H,CH),4.50-4.55(m,1H,CH),5.01-5.07(m,1H,CH),6.74(dd,J＝1.3,3.3Hz,1H,F-4),6.82(d,J＝8.2Hz,2H,Ph),6.90(d,J＝8.6Hz,1H,NH),7.18(d,J＝8.4Hz,2H,Ph),7.48(d,J＝3.5Hz,1H,F-3),8.04(s,1H,F-5),8.06(s,1H,NH),8.42ppm(d,J＝7.7Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.9,23.5,24.8,28.6,36.9,52.8,53.0,55.4,56.4,58.7,72.5,78.5,113.1,113.9,119.5,130.5,130.7,148.7,150.7,155.7,158.2,169.9,172.2,187.5ppm；HRMS(ESI):m/z560.29613(M+H+),582.27862(M+Na+),598.25222(M+K+).41.(S)-N1-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代丙-2-基)-2-(4-甲基苯磺酰胺)-N4-新戊基琥珀酰胺(化合物PS-64)的合成第一步以前面叙述过的PS-1为原料，制备方法同化合物3，得到氨基中间体，直接用于缩合反应。第二步以Boc-Asp-OtBu和新戊胺为原料，制备方法同化合物1，得到的2-叔丁氧羰酰氨-4-(新戊胺-4-羰基)-丁酸叔丁酯为白色固体，产率为96.83％。mp:115℃；1HNMR(400MHz,CDCl3):δ＝0.82(s,9H,CH3),1.37(s,18H,CH3),2.43-2.56(m,2H,CH2),2.80(dd,J＝5.9,13.1Hz,1H,CH2),2.92(dd,J＝6.6,13.1Hz,1H,CH2),4.17(dd,J＝7.7,13.6Hz,1H,CH),6.93(d,J＝8.2Hz,1H,CH2),7.73ppm(t,J＝6.1,12.2Hz,1H,CH)；MS(ESI):m/z381.50(M+Na+).第三步以上述的叔丁酯为原料，制备方法同化合物3，得到的2-氨基-4-(新戊胺-4-羰基)-丁酸盐酸盐，直接用于下一步反应。第四步以上述的盐酸盐中间体为原料，制备方法同化合物PS-56第二步，得到的2-(4-甲基苯磺酰胺)-4-(新戊胺)-4-羰基丁酸(羧基中间体)为白色固体，产率为75.06％。第五步以上述的氨基中间体和羧基中间体为原料，制备方法同化合物1，得到白色固体，产率为79.32％。mp:209-210℃；1HNMR(400MHz,DMSO-d6):δ＝0.79(s,9H,CH3),0.88(d,J＝3.5Hz,3H,CH3),0.89(d,J＝3.5Hz,3H,CH3),1.00(d,J＝7.1Hz,3H,CH3),1.43-1.49(m,1H,CH),1.59-1.68(m,2H,CH2),2.23-2.55(m,2H,CH2),2.36(s,3H,CH3),2.75-2.86(m,2H,CH2),3.92-3.96(m,1H,CH),4.04-4.09(m,1H,CH),4.83-4.89(m,1H,CH),6.69(dd,J＝1.6,3.6Hz,1H,F-4),7.32(d,J＝8.2Hz,2H,Ph),7.41(d,J＝3.5Hz,1H,F-3),7.65(d,J＝8.2Hz,2H,Ph),7.79(t,J＝6.0,12.0Hz,1H,NH),7.97(s,1H,NH),7.99(d,J＝1.2Hz,1H,F-5),8.09(d,J＝7.6Hz,1H,NH),8.22ppm(d,J＝7.3Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝18.0,21.4,21.9,23.4,24.8,27.6,32.2,38.9,48.3,50.2,53.5,112.9,119.2,127.1,129.7,138.7,142.9,148.4,150.7,169.6,170.0,172.4,187.7ppm；HRMS(ESI):m/z591.28308(M+H+),613.26508(M+Na+),629.23905(M+K+).42.(S)-N1-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代丙-2-基)-2-(4-甲基苯磺酰胺)-N4-异戊基琥珀酰胺(化合物PS-65)的合成第一步以前面叙述过的PS-1为原料，制备方法同化合物3，得到氨基中间体，直接用于缩合反应。第二步以Boc-Asp-OtBu和异戊胺为原料，制备方法同化合物1，得到的2-叔丁氧羰酰氨-4-(异戊胺-4-羰基)-丁酸叔丁酯为白色固体，产率为87.33％。mp:107-108℃；1HNMR(400MHz,CDCl3):δ＝0.90(s,3H,CH3),0.91(s,3H,CH3),1.38(dd,J＝7.1,14.8Hz,2H,CH2),1.44(s,9H,CH3),1.46(s,9H,CH3),1.59-1.64(m,1H,CH),2.65(dd,J＝3.8,15.0Hz,1H,CH2),2.76(dd,J＝4.9,15.6Hz,1H,CH2),3.25(dd,J＝6.8,13.6Hz,2H,NCH2),4.35(t,J＝4.3,7.2Hz,1H,CH),5.66ppm(s,2H,NH)；MS(ESI):m/z359.3(M+H+),381.2(M+Na+),397.2(M+K+).第三步以上述的叔丁酯为原料，制备方法同化合物3，得到的2-氨基-4-(异戊胺-4-羰基)-丁酸盐酸盐，直接用于下一步反应。第四步以上述的盐酸盐中间体为原料，制备方法同化合物PS-56第二步，得到的4-(异戊胺)-2-(4-甲基苯磺酰胺)-4-羰基丁酸(羧基中间体)为白色固体，产率为84.62％。第五步以上述的氨基中间体和羧基中间体为原料，制备方法同化合物1，得到白色固体，产率为81.29％。mp:210℃；1HNMR(400MHz,DMSO-d6):δ＝0.81(d,J＝6.5Hz,6H,CH3),0.88(d,J＝6.2Hz,6H,CH3),1.01(d,J＝7.1Hz,3H,CH3),1.19-1.25(m,2H,CH2),1.41-1.54(m,2H,CH2),1.61-1.73(m,2H,CH),2.23-2.47(m,2H,CH2),2.36(s,3H,CH3),2.95-2.97(m,2H,CH2),3.93-3.97(m,1H,CH),4.03-4.08(m,1H,CH),4.84-4.89(m,1H,CH),6.69(dd,J＝1.6,3.4Hz,1H,F-4),7.32(d,J＝8.1Hz,2H,Ph),7.41(d,J＝3.6Hz,1H,F-3),7.65(d,J＝8.2Hz,2H,Ph),7.86(t,J＝5.3,10.6Hz,1H,NH),7.97(s,1H,NH),7.99(s,1H,F-5),8.13(d,J＝7.6Hz,1H,NH),8.21ppm(d,J＝7.4Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝17.9,21.4,21.8,22.7,22.8,23.4,24.8,25.6,37.3,38.2,38.9,48.3,53.4,53.5,112.9,119.2,127.1,129.7,138.8,142.9,148.4,150.7,169.2,170.0,172.4,187.7ppm；HRMS(ESI):m/z591.28302(M+H+),613.26521(M+Na+),629.23900(M+K+).43.(S)-N1-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代丙-2-基)-2-(4-甲基苯磺酰胺)-N4-异丁基琥珀酰胺(化合物PS-66)的合成第一步以前面叙述过的PS-1为原料，制备方法同化合物3，得到氨基中间体，直接用于缩合反应。第二步以Boc-Asp-OtBu和异丁胺为原料，制备方法同化合物1，得到的2-叔丁氧羰酰氨-4-(异丁胺-4-羰基)-丁酸叔丁酯为白色固体，产率为93.61％。mp:142℃；1HNMR(400MHz,CDCl3):δ＝0.89(s,3H,CH3),0.91(s,3H,CH3),1.44(s,9H,CH3),1.46(s,9H,CH3),1.70-1.80(m,1H,CH),2.68(dd,J＝3.8,15.6Hz,1H,CH2),2.80(dd,J＝4.1,16.1Hz,1H,CH2),3.06(t,J＝6.5,12.8Hz,2H,NCH2),4.35(t,J＝4.3,7.3Hz,1H,CH),5.72ppm(s,2H,NH)；MS(ESI):m/z345.2(M+H+),367.2(M+Na+),383.2(M+K+).第三步以上述的叔丁酯为原料，制备方法同化合物3，得到的2-氨基-4-(异丁胺-4-羰基)-丁酸盐酸盐，直接用于下一步反应。第四步以上述的盐酸盐中间体为原料，制备方法同化合物PS-56第二步，得到的4-(异丁胺)-2-(4-甲基苯磺酰胺)-4-羰基丁酸(羧基中间体)为白色固体，产率为84.55％。第五步以上述的氨基中间体和羧基中间体为原料，制备方法同化合物1，得到白色固体，产率为78.65％。mp:233-234℃；1HNMR(400MHz,DMSO-d6):δ＝0.77(d,J＝3.5Hz,3H,CH3),0.78(d,J＝3.5Hz,3H,CH3),0.88(d,J＝1.4Hz,3H,CH3),0.89(d,J＝1.3Hz,3H,CH3),1.01(d,J＝7.1Hz,3H,CH3),1.42-1.48(m,1H,CH),1.56-1.70(m,3H,CH,CH2),2.27-2.53(m,2H,CH2),2.36(s,3H,CH3),2.76-2.80(m,2H,CH2),3.95-3.97(m,1H,CH),4.03-4.09(m,1H,CH),4.84-4.89(m,1H,CH),6.69(dd,J＝1.6,3.5Hz,1H,F-4),7.32(d,J＝8.1Hz,2H,Ph),7.41(d,J＝3.5Hz,1H,F-3),7.65(d,J＝8.2Hz,2H,Ph),7.89(t,J＝5.6,11.3Hz,1H,NH),7.96(s,1H,NH),7.99(d,J＝1.2Hz,1H,F-5),8.09(d,J＝7.6Hz,1H,NH),8.22ppm(d,J＝7.3Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝18.0,20.5,21.4,21.8,23.4,24.8,28.3,38.9,46.6,48.3,53.4,53.5,113.0,119.2,127.1,129.7,138.8,142.9,148.4,150.7,169.4,170.0,172.4,187.7ppm；HRMS(ESI):m/z577.26793(M+H+),599.24946(M+Na+),615.22352(M+K+).44.(S)-N1-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代丙-3-甲氧基-2-基)-2-(4-甲基苯磺酰胺)-N4-新戊基琥珀酰胺(化合物PS-67)的合成第一步以前面叙述过的PS-2为原料，制备方法同化合物3，得到氨基中间体，直接用于缩合反应。第二步以上述的氨基中间体和前面叙述过的2-(4-甲基苯磺酰胺)-4-(新戊胺)-4-羰基丁酸(羧基中间体)为原料，制备方法同化合物1，得到白色固体，产率为81.36％。mp:156-157℃；1HNMR(400MHz,DMSO-d6):δ＝0.79(s,9H,CH3),0.87(d,J＝3.7Hz,3H,CH3),0.89(d,J＝3.7Hz,3H,CH3),1.43-1.49(m,1H,CH),1.59-1.69(m,2H,CH2),2.30-2.50(m,2H,CH2),2.37(s,3H,CH3),2.80(dd,J＝1.9,6.1Hz,2H,CH2),3.17(s,3H,OCH3),3.27(dd,J＝4.4,9.7Hz,1H,CH2),3.44(dd,J＝5.5,9.8Hz,1H,CH2),4.14-4.22(m,2H,CH),4.86-4.91(m,1H,CH),6.69(dd,J＝1.6,3.6Hz,1H,F-4),7.32(d,J＝8.2Hz,2H,Ph),7.43(d,J＝3.6Hz,1H,F-3),7.65(d,J＝8.2Hz,2H,Ph),7.77(t,J＝6.0,12.2Hz,1H,NH),7.95(d,J＝8.8Hz,1H,NH),7.99(d,J＝1.2Hz,1H,F-5),8.13(d,J＝7.9Hz,1H,NH),8.32ppm(d,J＝7.5Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.4,21.9,23.4,24.7,27.7,32.2,39.0,50.2,53.1,53.4,53.6,58.7,72.0,112.9,119.4,127.1,129.8,138.7,142.9,148.4,150.6,169.5,169.8,170.6,187.5ppm；HRMS(ESI):m/z621.29429(M+H+),643.27633(M+Na+),659.24997(M+K+).45.(S)-N1-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代丙-3-甲氧基-2-基)-2-(4-甲基苯磺酰胺)-N4-异戊基琥珀酰胺(化合物PS-68)的合成第一步以前面叙述过的PS-2为原料，制备方法同化合物3，得到氨基中间体，直接用于缩合反应。第二步以上述的氨基中间体和前面叙述过的4-(异戊胺)-2-(4-甲基苯磺酰胺)-4-羰基丁酸(羧基中间体)为原料，制备方法同化合物1，得到白色固体，产率为80.65％。mp:194-195℃；1HNMR(400MHz,DMSO-d6):δ＝0.81(d,J＝6.6Hz,6H,CH3),0.88(d,J＝6.1Hz,6H,CH3),1.19-1.24(m,2H,CH),1.41-1.54(m,2H,CH2),1.61-1.69(m,2H,CH2),2.22-2.50(m,2H,CH2),2.37(s,3H,CH3),2.96(dd,J＝6.6,13.6Hz,2H,CH2),3.18(s,3H,OCH3),3.28(dd,J＝4.1,9.7Hz,1H,CH2),3.47(dd,J＝5.5,9.7Hz,1H,CH2),4.16-4.18(m,2H,CH),4.86-4.91(m,1H,CH),6.69(d,J＝1.9Hz,1H,F-4),7.33(d,J＝8.0Hz,2H,Ph),7.43(d,J＝3.5Hz,1H,F-3),7.66(d,J＝8.0Hz,2H,Ph),7.85(t,J＝5.1,10.4Hz,1H,NH),7.99(s,2H,NH,F-5),8.18(d,J＝8.0Hz,1H,NH),8.33ppm(d,J＝7.3Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝21.4,21.8,22.8,23.5,24.7,25.7,37.3,38.2,39.0,53.1,53.3,53.6,58.8,72.0,112.9,119.4,127.0,129.8,138.8,142.8,148.4,150.6,169.2,169.8,170.6,187.5ppm；HRMS(ESI):m/z621.29436(M+H+),643.27622(M+Na+),659.24983(M+K+).46.(S)-N1-((S)-1-(((S)-1-(呋喃-2-基)-4-甲基-1-氧代戊-2-基)氨基)-1-氧代丙-3-甲氧基-2-基)-2-(4-甲基苯磺酰胺)-N4-异丁基琥珀酰胺(化合物PS-69)的合成第一步以前面叙述过的PS-2为原料，制备方法同化合物3，得到氨基中间体，直接用于缩合反应。第二步以上述的氨基中间体和前面叙述过的4-(异丁胺)-2-(4-甲基苯磺酰胺)-4-羰基丁酸(羧基中间体)为原料，制备方法同化合物1，得到白色固体，产率为75.26％。mp:194-195℃；1HNMR(400MHz,DMSO-d6):δ＝0.78(dd,J＝3.4,6.5Hz,6H,CH3),0.88(d,J＝4.6Hz,6H,CH3),1.41-1.48(m,1H,CH),1.56-1.69(m,3H,CH2,CH),2.28(dd,J＝5.9,15.1Hz,1H,CH2),2.37(s,3H,CH3),2.78(t,J＝6.2Hz,2H,CH2),3.18(s,3H,OCH3),3.26-3.33(m,2H,CH2),3.43-3.48(m,1H,CH2),4.14-4.22(m,2H,CH),4.85-4.92(m,1H,CH),6.69(dd,J＝1.5,3.4Hz,1H,F-4),7.33(d,J＝8.0Hz,2H,Ph),7.43(d,J＝3.5Hz,1H,F-3),7.65(d,J＝8.1Hz,1H,Ph),7.87(t,J＝5.5Hz,1H,Ph),7.95-8.00(m,2H,F-5,NH),8.15(d,J＝7.9Hz,1H,NH),8.33ppm(d,J＝7.4Hz,1H,NH)；13CNMR(100MHz,DMSO-d6):δ＝20.6,21.4,21.9,23.4,24.7,28.3,39.0,46.6,53.1,53.4,53.6,58.7,72.0,112.9,119.4,127.1,129.8,138.8,142.9,148.4,150.7,169.3,169.8,170.6,187.5ppm；HRMS(ESI):m/z607.27840(M+H+),629.26037(M+Na+),645.23397(M+K+).四、式I中X为4-甲基苄胺化合物(式I/C)的制备：1.((S)-1-(((S)-3-(4-羟基苯基)-1-((4-甲基苄基)氨基)-1-氧代丙-2-基)氨基)-1-氧代-3-苯基丙-2-基)氨基甲酸苄酯(化合物PS-70)的合成第一步将Boc-Tyr-OH(2.25g,8mmol)和4-甲基苄胺(1.08mL,8.5mmol)溶于50mLDMF中，随后加入HBTU(3.48g,9.2mmol)和NMM(1.77mL,16mmol)。室温下搅拌反应过夜，反应结束后加入乙酸乙酯稀释反应液，饱和NaHCO3溶液洗涤，无水Na2SO4干燥。滤除干燥剂，浓缩后将得到的粗品采用乙酸乙酯/石油醚重结晶，得到浅黄色固体，产率为93.16％。第二步以上述的中间体为原料，制备方法同化合物3，得到2-氨基-3-(4-羟基苯基)-N-(4-甲基苄基)丙酰胺(氨基中间体)，直接用于缩合反应。第三步以Cbz-Phe-OH和上述氨基中间体为原料，制备方法同化合物1，得白色固体，产率为46.87％。mp:182-183℃；1HNMR(400MHz,DMSO-d6):δ＝2.25(s,3H,CH3),2.65-2.80(m,2H,CH2),2.85-2.95(m,2H,CH2),4.16-4.28(m,3H,CH2,CH),4.48(dd,J＝7.6,14.2Hz,1H,CH),4.92(dd,J＝12.7,20.1Hz,2H,CH2),6.65(d,J＝8.3Hz,2H,Ph),7.01(d,J＝8.3Hz,4H,Ph),7.08(d,J＝7.9Hz,2H,Ph),7.16-7.36(m,10H,Ph),7.47(d,J＝8.6Hz,1H,NH),8.09(d,J＝8.1Hz,1H,NH),8.34(t,J＝5.8Hz,1H,NH),9.18ppm(s,1H,OH)；13CNMR(100MHz,DMSO-d6):δ＝21.1,37.6,37.9,42.2,54.9,56.6,65.7,115.4,126.7,127.5,127.9,128.0,128.1,128.5,128.7,129.2,129.6,130.6,136.1,136.5,137.4,138.5,156.2,156.3,171.2,171.6ppm；HRMS(ESI):m/z566.26334(M+H+),588.24637(M+Na+),604.22019(M+K+).2.4-(羟甲基)-N-((S)-3-(4-羟基苯基)-1-(((S)-3-(4-羟基苯基)-1-((4-甲基苄基)氨基)-1-氧代丙-2-基)氨基)-1-氧代丙-2-基)苯甲酰胺(化合物PS-71)的合成第一步以4-羟甲基苯甲酸和L-Tyr-OMe为原料，制备方法同化合物1，得到的2-(4-羟甲基苯甲酰胺)-3-(4-羟基苯基)丙酸甲酯为白色固体，产率为75.13％。mp:160-161℃；1HNMR(400MHz,DMSO-d6):δ＝3.00(dq,J＝5.6,13.8Hz,2H,CH2Ph),3.62(s,3H,OCH3),4.53-4.58(m,3H,CH2,CH),5.30(t,J＝5.8,11.4Hz,1H,NH),6.64(d,J＝8.4Hz,2H,Ph),7.07(d,J＝8.4Hz,2H,Ph),7.38(d,J＝8.2Hz,2H,Ph),7.77(d,J＝8.2Hz,2H,Ph),8.72(d,J＝7.7Hz,1H,OH),9.20ppm(s,1H,OH)；MS(ESI):m/z330.1319(M+H+),352.1140(M+Na+).第二步将上述甲酯中间体溶于适量THF中，加入1NNaOH调节pH到12-13，室温搅拌反应2小时。减压蒸干溶剂，用少量EA溶解之后滴加1NHCl溶液调节pH到2-3，继续搅拌反应5min。用乙酸乙酯萃取3次，合并有机相，无水Na2SO4干燥，蒸除溶剂，得到的2-(4-羟甲基苯甲酰胺)-3-(4-羟基苯基)丙酸(甲酯中间体)为白色固体，直接用于缩合反应。第三步以上述的羧酸中间体和前面叙述过的2-氨基-3-(4-羟基苯基)-N-(4-甲基苄基)丙酰胺(氨基中间体)为原料，制备方法同化合物1，得到白色固体，产率为56.13％。mp:244-245℃；1HNMR(400MHz,DMSO-d6):δ＝2.26(s,3H,CH3),2.73-2.94(m,4H,CH2),4.19-4.20(m,2H,CH2),4.44-4.61(m,4H,CH2,CH),5.29(t,J＝5.8Hz,1H,OH),6.59(dd,J＝5.6,8.4Hz,4H,Ph),6.99(t,J＝7.4Hz,4H,Ph),7.06(d,J＝6.4Hz,4H,Ph),7.37(d,J＝8.2Hz,2H,Ph),7.73(d,J＝8.2Hz,2H,Ph),8.06(d,J＝8.2Hz,1H,NH),8.32(d,J＝5.8Hz,1H,NH),8.39(d,J＝8.3Hz,1H,NH),9.11(s,1H,OH),9.15ppm(s,1H,OH)；HRMS(ESI):m/z582.25811(M+H+).3.N-((S)-3-(4-羟基苯基)-1-(((S)-3-(4-羟基苯基)-1-((4-甲基苄基)氨基)-1-氧代丙-2-基)氨基)-1-氧代丙-2-基)吡嗪-2-甲酰胺(化合物PS-72)的合成第一步以2-吡嗪甲酸和L-Tyr-OMe为原料，制备方法同化合物1，得到的3-(4-羟基苯基)-2-(吡嗪-2-甲酰胺)丙酸甲酯为白色固体，产率为58.40％。1HNMR(400MHz,CDCl3):δ＝3.16(dq,J＝5.6,14.1Hz,2H,CH2Ph),3.74(s,3H,OCH3),5.01-5.03(m,1H,CH),6.74(d,J＝8.4Hz,2H,Ph),6.98(d,J＝8.4Hz,2H,Ph),7.50(s,1H,OH),8.30(d,J＝8.3Hz,1H,NH),8.51(dd,J＝1.6,2.2Hz,1H,Pz-5),8.72(d,J＝2.4Hz,1H,Pz-6),9.33ppm(d,J＝1.6Hz,1H,Pz-3)；MS(ESI):m/z302.1(M+H+),340.1(M+K+).第二步将上述甲酯中间体溶于适量THF中，加入1NNaOH调节pH到12-13，室温搅拌反应2小时。减压蒸干溶剂，用少量EA溶解之后滴加1NHCl溶液调节pH到2-3，继续搅拌反应5min。用乙酸乙酯萃取3次，合并有机相，无水Na2SO4干燥，蒸除溶剂，得到的3-(4-羟基苯基)-2-(吡嗪-2-甲酰胺)丙酸(甲酯中间体)为白色固体，直接用于缩合反应。第三步以上述的羧酸中间体和前面叙述过的2-氨基-3-(4-羟基苯基)-N-(4-甲基苄基)丙酰胺(氨基中间体)为原料，制备方法同化合物1，得到白色固体，产率为59.01％。mp:171-172℃；1HNMR(400MHz,DMSO-d6):δ＝2.26(s,3H,CH3),2.69-2.77(m,1H,CH2),2.82-2.99(m,3H,CH2),4.22(d,J＝5.7Hz,2H,CH2),4.47-4.54(m,1H,CH),4.66-4.73(m,1H,CH),6.54-6.64(m,4H,Ph),6.93(d,J＝8.4Hz,2H,Ph),7.01(dd,J＝3.8,7.8Hz,3H,Ph),7.06(s,3H,Ph),8.37-8.46(m,2H,NH),8.59(d,J＝8.5Hz,1H,NH),8.72(dd,J＝1.5,2.2Hz,1H,P-5),8.88(d,J＝2.4Hz,1H,P-6),9.08-9.16ppm(m,3H,P-2,OH)；HRMS(ESI):m/z554.23821(M+H+),576.22040(M+Na+),592.19421(M+K+).第二部分化合物生物活性评价1.蛋白酶体活性测定Proteasome-GloTM检测试剂盒是一种均质的发光检测方法，能够分别检测蛋白酶体相关的类糜蛋白酶(CT-L，β5亚基)、类胰蛋白酶(T-L，β2亚基)和类半胱氨酸蛋白酶(C-L，β1亚基)的活性。用于监测三种特异蛋白酶活性的发光前体底物包括：用于检测类糜蛋白酶活性的Suc-LLVY-氨基萤光素、用于检测类胰蛋白酶活性的Z-LRR-氨基萤光素以及用于检测类半胱氨酸蛋白酶活性的Z-nLPnLD-氨基萤光素。将试剂加入到包含蛋白酶体的测试样品中，就能剪切底物、释放萤光素，后者经萤光素酶的作用，产生\辉光型\发光信号，发光强度与酶的活性或抑制性相关。将表1所示的化合物分别配成10mM的DMSO溶液，再用缓冲液10mMHEPES(pH7.6)稀释成所需浓度，保证所有测试浓度的DMSO含量均为1％，排除DMSO对实验的影响。在白色的384平板(Greiner781080)中分别加入10μl化合物，10μl酶，于25℃下培养2个小时后，再加入20μlGlo试剂，于25℃下培养10min，读取发光值，计算抑制率，结果如表2所示。表1.本发明化合物结构实例表2.本发明化合物对20S蛋白酶体的抑制活性2.蛋白激酶活性测定将蛋白激酶分别加入含有50mMHEPES、0.0015％的Brij-35、10mMMgCl2和2mMDTT，pH为7.5的缓冲液中，配成酶原液。取20μl相应浓度的待测样品、20μl酶原液、加入10mM有FAM(羧基荧光素)标记的多肽底物和10mMATP的缓冲液，室温下孵育5h，加入终止液(pH为7.5的50mMHEPES、0.0015％的Brij-35、0.2％的封闭剂、50mMEDTA的混合液)终止反应，酶标仪读取数据，计算抑制率，结果如表3、表4所示。表3部分化合物对多种蛋白激酶的抑制作用表4部分化合物对多种蛋白激酶的抑制作用3.抗肿瘤细胞增殖作用我们采用CellTiter-Glo冷光细胞活力检测法，考察活性化合物对细胞增殖的抑制作用，涵盖了恶性肿瘤，包括有BGC-823人胃癌、A549人肺癌、Hela人子宫癌、SW480人结肠癌、DU145人前列腺癌、A375人黑色素瘤、PC3M1E8人前列腺癌、HCT-116人结肠癌和HT-29人结肠癌细胞和正常的人胚肾HEK293细胞系。CellTiter-Glo是通过对ATP进行定量测定来检测培养物中活细胞数目的一种均质检测方法。甲虫萤光素、ATP、氧气在重组荧光素酶和Mg2+催化下，形成氧合荧光素，其释放出的冷光光强度与ATP浓度成正比，ATP浓度又与细胞活力成正比，因此可以通过吸光度判断细胞存活量。部分化合物测试结果如下表5所示。表5部分化合物对多种肿瘤细胞系的抗增殖作用其中，n.i.代表化合物在50μM浓度下抑制率低于50％，n.d.表示没有进行相应的测定。结果：本发明中的化合物对多种肿瘤细胞系的增殖具有较好的抑制活性，而对正常细胞系HEK293在50μM浓度下并没有表现出明显的抑制作用，说明本发明中的化合物对肿瘤细胞具有很好的选择性。以上所述仅为本发明的优选实施例，对本发明而言仅是说明性的，而非限制性的；本领域普通技术人员理解，在本发明权利要求所限定的精神和范围内可对其进行许多改变，修改，甚至等效变更，但都将落入本发明的保护范围内。