CN108929340B - 脯氨酸硼酸类化合物及其制备方法和用途 - Google Patents

Abstract

本发明提供了具有下述式(I)所示结构的化合物或其盐。该化合物是脯氨酸硼酸类蛋白酶体抑制剂化合物，具有良好的蛋白酶体抑制活性和优异的成药性。

Description

脯氨酸硼酸类化合物及其制备方法和用途

技术领域

本发明涉及一类脯氨酸硼酸类蛋白酶体抑制剂化合物及其制备方法和用途，属于有机医药合成领域。

背景技术

泛素-蛋白酶体途径是真核细胞核内及细胞质内主要的蛋白水解系统，其在许多短寿调节蛋白的降解中起主要作用，这些蛋白控制细胞的分化、生长激活、信号转导和转录。蛋白酶体体系可以通过降解相关蛋白质来影响到多种生理和病理过程。其中最为重要的底物蛋白是细胞周期蛋白cyclin、肿瘤抑制因子p53和转录因子NF-κB的抑制剂IκB，它们同肿瘤的发生、发展息息相关。现在已经证实，蛋白酶体的抑制剂具有优异的抗肿瘤活性。

在临床上已经有数个蛋白酶体抑制剂上市用于肿瘤的治疗。最早且最成功的是一种化学结构为肽硼酸的蛋白酶体抑制剂——硼替佐米(万珂)，其于2003年经美国食品与药物管理局(FDA)快速审批通过了用于多发性骨髓瘤(MM)的临床治疗，目前已经在包括中国在内的全球46个国家上市。

CN101928329A公开了一类三肽硼酸类蛋白酶体抑制剂，具有典型的常规酰胺键结构，获得了同上市药物硼替佐米相似的活性数据，但具有更低的毒性和更好的安全性，代表着一种蛋白酶体抑制剂的发展方向。

发明内容

本发明通过多种合理药物设计方式，发现一类具有全新结构的脯氨酸硼酸类蛋白酶体抑制剂化合物，其具有良好的蛋白酶体抑制活性和优异的成药性。

本发明的脯氨酸硼酸类蛋白酶体抑制剂化合物具有下述结构：

本发明的独立权利要求解决了上述问题并界定了本发明的保护范围。从属权利要求中示出了优选的实施方式，并且各项从属权利要求中不同的技术特征可以互相组合。

药效学试验表明本发明的化合物是哺乳动物细胞中26S蛋白酶体糜蛋白酶样活性的可逆抑制剂。26S蛋白酶体是一种大的蛋白质复合体，可降解泛蛋白。泛蛋白酶体通道在调节特异蛋白在细胞内浓度中起到重要作用，以维持细胞内环境的稳定。蛋白水解会影响细胞内多级信号串联，这种对正常的细胞内环境的破坏会导致细胞的死亡。而对26S蛋白酶体的抑制可防止特异蛋白的水解。体外试验证明本发明的化合物对多种类型的癌细胞具有细胞毒性。临床前肿瘤模型体内试验证明ysy-01A能够延迟包括多发性骨髓瘤在内的多种肿瘤的生长。

具体实施方式

以下对本发明的实施方式进行详细说明。但是，本发明不局限于以下说明，所属技术领域的普通技术人员可以很容易地理解其方式和详细内容可以被变换为各种形式。另外，本发明不应该被解释为仅限定在以下所示的实施方式所记载的内容中。

本发明中使用的术语“烷基”是指仅由碳原子和氢原子组成、且不具有不饱和度(例如双键、三键或环)的基团，其涵盖了各种可能的几何异构基团与立体异构基团。该基团通过单键与分子的其余部分相连。作为烷基的非限制性实例，可以列举以下直链或支链的基团：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基及其另外七种异构体、正己基及其另外十六种异构体、正庚基及其各种异构体、正辛基及其各种异构体、正壬基及其各种异构体、正癸基及其各种异构体。

本发明中使用的术语“环烷基”是指由至少3个碳原子组成的饱和非芳香环系，该环系可以是单环、双环、多环，也可以是稠环、桥环、螺环。作为环烷基的非限制性实例，可以列举以下基团：环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基；以及由两个或多个上述单环通过公共边和公共碳原子形成的稠环、桥环或螺环基团。

本发明中使用的术语“烯基”是指在上述烷基基团中(除甲基外)存在一个或多个双键的情况下所形成的基团。

本发明中使用的术语“环烯基”是指在上述环烷基基团中存在一个或多个双键的情况下所形成的基团。

本发明中使用的术语“炔基”是指在上述烷基基团中(除甲基外)存在一个或多个叁键的情况下所形成的基团。

本发明中使用的术语“烷氧基”是指氧原子与上述烷基相连、并且通过该氧原子以单键连接至分子其余部分的基团，其涵盖了各种可能的几何异构基团与立体异构基团。作为烷氧基的非限制性实例，可以列举以下直链或支链的基团：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基及其另外七种异构体、正己氧基及其另外十六种异构体、正庚氧基及其各种异构体、正辛氧基及其各种异构体、正壬氧基及其各种异构体、正癸氧基及其各种异构体。

本发明中使用的术语“芳基”是指由至少6个碳原子组成的芳香环系，该环系可以是单环、双环、多环，其中双环和多环可以由单环通过单键连接方式或稠合方式形成。作为芳基的非限制性实例，可以列举以下基团：苯基、萘基、蒽基、菲基、茚基、芘基、苝基、薁基、戊搭烯基、庚搭烯基、苊基、芴基、非那烯基、萤蒽基、醋菲烯基、苯并苊基、三亚苯基、基、并四苯基、苉基、戊芬基、并五苯基、四邻亚苯基、己芬基、并六苯基、蔻基、三亚萘基、庚芬基、并七苯基、吡蒽基、卵苯基、联苯基、联萘基。

本发明中使用的术语“杂芳基”是指具有一个或多个独立地选自N、O或S的杂原子的5-14元芳香族杂环环系，该环系可以是单环、双环、多环，其中双环和多环可以由单环通过单键连接方式或稠合方式形成。作为杂芳基的非限制性实例，可以列举以下基团：噁唑基、异噁唑基、咪唑基、呋喃基、吲哚基、异吲哚基、吡咯基、三唑基、三嗪基、四唑基、噻吩基、噻唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并呋喃基、苯并噻唑基、苯并噁唑基、苯并咪唑基、苯并噻吩基、苯并吡喃基、咔唑基、喹啉基、异喹啉基、喹唑啉基、噌啉基、萘啶基、蝶啶基、嘌呤基、喹噁啉基、噻二唑基、吲哚嗪基、吖啶基、吩嗪基、酞嗪基、香豆素基、吡唑并吡啶基、吡啶并哒嗪基、吡咯并吡啶基、咪唑并吡啶基、吡唑并哒嗪基；以及由上述杂芳基通过单键连接方式或稠合方式形成的基团。

本发明中使用的术语“杂环基”是指由碳原子和独立选自N、O或S的杂原子组成的非芳香族3-15元环系，该环系可以是单环、双环或多环，也可以是稠环、桥环、螺环，并且可以任选地包含一个或多个双键。作为杂环基的非限制性实例，可以列举以下基团：氮杂基、吖啶基、苯并间二氧杂环戊烯基、苯并二氧杂环己基、苯并二氢吡喃基、二氧戊环基、二氧磷杂环戊基、十氢异喹啉基、茚满基、吲哚啉基、异吲哚啉基、异苯并二氢吡喃基、异噻唑烷基、异噁唑烷基、吗啉基、噁唑啉基、噁唑烷基、噁二唑基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧代氮杂基、八氢吲哚基、八氢异吲哚基、全氢化氮杂基、哌嗪基、4-哌啶酮基、哌啶基、吩噻嗪基、吩噁嗪基、奎宁环基、四氢异喹啉基、四氢呋喃基、四氢吡喃基、四氢吡咯基、噻唑啉基、噻唑烷基、硫代吗啉基、硫代吗啉基亚砜和硫代吗啉基砜。

本发明中使用的术语“芳基烷基”是指一个或多个氢原子被芳基独立取代的烷基，其中所述的芳基和烷基如上文所定义。

本发明中使用的术语“杂芳基烷基”是指一个或多个氢原子被杂芳基独立取代的烷基，其中所述的杂芳基和烷基如上文所定义。

本发明中使用的术语“卤素”或“卤代”是指氟、氯、溴或碘。

本发明中对于碳原子数的描述包括两个端点以及位于其间的所有整数值，例如：C1-C6烷基包括了甲基、乙基、丙基、丁基、戊基、己基及其全部异构体，C3-C6环烷基包括了环丙基、环丁基、环戊基、环己基。

本发明中的药物组合物含有本发明第一方面所述的化合物作为活性成分。此外，该药物组合物还可包含药学上可接受的载体，包括但不限于：水、盐溶液、醇、聚乙二醇、多羟基乙氧基化的蓖麻油、花生油、橄榄油、明胶、乳糖、石膏粉、蔗糖、糊精、碳酸镁、糖、环糊精、直链淀粉、硬脂酸镁、滑石、明胶、琼脂、果胶、阿拉伯胶、硬脂酸或纤维素低烷基醚、硅酸、脂肪酸、脂肪酸胺、脂肪酸单甘油酯和二甘油酯、季戊四醇脂肪酸醚、聚氧乙烯、羟甲基纤维素和聚乙烯吡咯烷酮。该药物组合物还可包含一种或多种药学上可接受的辅助剂、润湿剂、乳化剂、悬浮剂、防腐剂、渗透压调节剂、缓冲剂、甜味剂、矫味剂、着色剂或上述的任意组合。

本发明的药物组合物可以制成任何形式的制剂，例如胶囊剂、片剂、气雾剂、溶液剂、悬浮剂、糖衣剂、锭剂、糖浆剂、乳剂、软膏剂、膏剂、注射剂、散剂、颗粒剂、糊剂、缓释剂、泡沫剂。根据给药途径，本发明的药物可以制成口服给药制剂、鼻部给药制剂、肺部给药制剂、口腔含化制剂、皮下给药制剂、皮内给药制剂、经皮给药制剂、胃肠外给药制剂、直肠给药制剂、储库式给药制剂、静脉内给药制剂、尿道内给药制剂、肌内给药制剂、鼻内给药制剂、眼部给药制剂、硬膜外给药制剂或局部给药制剂。

本发明中的“癌症”包括本领域中已知的各种癌症，包括但不限于：肺癌、肝癌、胃癌、宫颈癌、结肠癌、乳腺癌、白血病、非小细胞癌、前列腺癌或累色素瘤、脑癌、皮肤癌、骨癌、淋巴癌、鼻咽癌、喉癌、食道癌、十二指肠癌、小肠癌、大肠癌、胰腺癌、肾癌、生殖器官癌、甲状腺癌。

实施例

在以下实施例中，作为原料使用的各试剂均为实验室常用试剂，通过商购得到。本发明实施例中所使用的缩写具有如下含义：

Boc：叔丁氧羰基

THF：四氢呋喃

s-BuLi：仲丁基锂

HOBt：1-羟基苯并三唑

DCC：二环己基碳二亚胺

NMM：N-甲基吗啉

DCM：二氯甲烷

TLC：薄层色谱

equiv：当量

C10：化合物10(以此类推)

Cbz：苄氧羰基

实施例1：(R,S)-N-Boc-脯氨酸硼酸(C1)

在氮气保护下将N-Boc-吡咯烷(2g，11.7mmol)溶于30mL重蒸过的无水THF中，将该溶液冷却到-78℃，并在30min内缓慢加入s-BuLi的己烷溶液(14mmol)。然后，在-78℃下继续搅拌3h；接着，用B(OMe)₃(3.9mL，35mmol)处理，之后缓慢升温至0℃左右，用少量水(约0.5mL)淬灭反应，升至室温后用2N NaOH(25mL)溶液萃取，水相加入2N盐酸将水相调至pH＝3，用乙酸乙酯萃取(3×20mL)，合并有机相，用无水硫酸钠干燥，蒸除溶剂得白色粘稠状固体2.1g，产率84％。粗产物不经纯化直接用于下一步反应。

实施例2：(R,S)-N-Boc-脯氨酸硼酸-(1S,2S,3R,5S)-(+)-2,3-蒎烷二醇酯(C2)

将实施例1的游离硼酸C1(2.1g，9.36mmol)溶于20mL甲基叔丁基醚中，在室温下加入(+)-蒎烷二醇(1.75g，10mmol)并持续搅拌，12h后反应完毕，蒸除溶剂直接进行柱层析(石油醚:乙酸乙酯＝10:1)得到清亮的粘稠油状物2.52g，收率76％。

¹H NMR(400MHz,CDCl₃)δ4.50–4.15(m,1H),3.38(dt,J＝13.8,6.1Hz,2H),3.12(ddd,J＝25.1,15.8,8.4Hz,1H),2.33(dd,J＝12.3,10.3Hz,1H),2.20(s,1H),2.10–1.69(m,7H),1.45(d,J＝7.3Hz,9H),1.41(s,3H),1.28(s,3H),0.84(s,3H).

实施例3：(R,S)-脯氨酸硼酸-(1S,2S,3R,5S)-(+)-2,3-蒎烷二醇酯盐酸盐(C3)

取实施例2的化合物C2 2.52g，溶于少量乙醚中，向该溶液中通HCl气10min。出现白色固体，6h后蒸除溶剂和过量的HCl得到消旋的盐酸盐C3 2.25g，熔点：143-147℃。

¹H NMR(400MHz,CDCl₃)δ4.43(d,J＝8.8Hz,1H),3.37(d,J＝36.9Hz,2H),3.22(s,1H),2.44–2.13(m,3H),2.09–1.90(m,6H),1.46(d,J＝4.0Hz,3H),1.29(s,3H),1.14(d,J＝11.0Hz,1H),0.83(s,3H).

实施例4：L-脯氨酸硼酸-(1S,2S,3R,5S)-(+)-2,3-蒎烷二醇酯盐酸盐(C4)

将盐C3 2.25g溶于适量二氯甲烷(25mL)中同时缓慢加热使之完全溶解，接着搅拌8h以产生蓬松的白色沉淀，抽滤烘干，再溶于适量2-丙醇(20mL)中加热使其溶解，搅拌过夜，抽滤可得白色固态的异构体C4 0.63g，收率28％，熔点：143-147℃。

¹H NMR(400MHz,CDCl₃)δ8.82(s,1H),4.43(d,J＝8.3Hz,1H),3.43(s,2H),3.22(s,1H),2.37–2.18(m,3H),2.09–1.90(m,6H),1.45(s,3H),1.29(s,3H),1.13(d,J＝11.0Hz,1H),0.83(s,3H).

实施例5：N-吡嗪甲酰-L-苯丙氨酸甲酯(C5)

100mL三角瓶内注入50mL无水THF，放入柱形转子，室温下加入吡嗪-2-甲酸(1.24g，10mmol)及HOBt(1.5g，11mmol)，所有固体加入前充分压碎成粉末。5min后加入DCC(2.5g，12mmol)，活化反应40min，加入亮氨酸甲酯盐酸盐(1.8g，10mmol)，10min后加入N-甲基吗啉(1.3mL，12mmol)。继续室温反应18h完全。加入5mL水搅拌10min后进行抽滤，滤饼用THF洗至白色。滤液完全蒸除溶剂得到产物粗品。粗品用80mL THF溶解，经10g硅胶过滤，并用30mL×2THF洗脱，合并THF后蒸除，得红色粘稠液体C5 2.47g，收率98％。

实施例6：N-吡嗪甲酰-L-亮氨酸(C6)

上步所得C5粗品溶于20mL THF后加入20mL蒸馏水，剧烈搅拌下加入25mmol NaOH，0.5h后反应完全。取4N HCl中和至接近中性，蒸除THF，水溶液常压过滤至另一瓶内，搅拌下滴加4N HCl至pH约为1不再析出固体。搅拌过夜，抽滤烘干，得黄白色固体2.36g，收率>99％。熔点：136-138℃。

¹H-NMR(DMSO-d6,400MHz)δ0.88–0.91(t,6H),1.57–1.64(m,2H),1.81–1.91(m,1H),4.48–4.55(m,1H),8.77(q,1H),8.90–8.95(dd,2H),9.19(d,1H),12.81(s,1H).

实施例7：N-吡嗪甲酰-L-亮氨酰-L-萘基丙氨酸甲酯(C10a)

取100mL三角瓶注入50mL THF，放入柱形转子及黄白色固体C62.36g，加入HOBt(1.5g，11mmol)，10min后加入DCC(2.5g，12mmol)，活化反应40min后加入L-萘基丙氨酸甲酯盐酸盐(2.6g，10mmol)，反应10min后加入NMM(1.3mL，12mmol)。继续室温反应18h。加入2mL蒸馏水淬灭10min，抽滤，用THF将滤饼洗至白色。滤液充分蒸除溶剂，用30mL DCM溶解，再次抽滤，20mL DCM洗涤不溶物，合并DCM后用2N Na₂CO₃ 60mL萃洗三次，饱和食盐水50mL萃洗三次。柱层析得产物C10a 3.2g，无色油状物，收率73％。

¹H NMR(400MHz,CDCl₃)δ9.21(d,J＝1.3Hz,1H),8.66(d,J＝2.4Hz,1H),8.36(dd,J＝2.3,1.5Hz,1H),8.04(d,J＝8.7Hz,1H),7.72–7.56(m,3H),7.51(s,1H),7.32(dd,J＝6.2,3.3Hz,2H),7.24–7.05(m,2H),5.02(dd,J＝13.6,6.8Hz,1H),4.76(td,J＝8.6,5.9Hz,1H),3.74(s,3H),3.25(ddd,J＝20.8,14.0,6.2Hz,2H),1.76(dt,J＝15.6,4.9Hz,1H),1.66(dt,J＝12.0,5.5Hz,2H),0.90(t,J＝6.6Hz,6H).¹³C NMR(101MHz,CDCl₃)δ171.85,171.30,162.89,147.33,144.22,143.71,142.57,133.21,132.27,128.08,128.06,127.48,127.15,126.01,125.58,53.10,52.43,51.53,40.88,37.99,24.75,22.87,22.08.

实施例8：N-吡嗪甲酰-L-亮氨酰-L-萘基丙氨酸(C10a-OH)

C10a 3.2g溶于THF20mL后加入20mL蒸馏水及15mmol NaOH，室温下搅拌0.5h，反应完毕。加入4N HCl调pH为8到9，蒸除THF，出现黄色不溶物，常压过滤，静置24h后滤液酸化pH至1，产生大量固体，再次静置24h，抽滤并用大量蒸馏水洗涤滤饼，真空干燥，得泡沫状黄色固体C10a-OH，不经纯化直接投下一步反应。

实施例9：N-吡嗪甲酰-L-亮氨酰-L-萘基丙氨酰-L-脯氨酸硼酸蒎烷二醇酯(C10b)

取N-吡嗪甲酰-L-亮氨酰-L-萘基丙氨酸C10a-OH(0.434g，1mmol)溶于20mL无水二氯甲烷中，加入HOBt(0.15g，1.1mmol)，反应10min后加入DCC(0.25g，1.2mmol)继续反应30min后入a-氨基硼酸的盐酸盐C4(0.31g，1mmol)及DIPEA(0.22mL，1.2mmol)反应过夜，12h后反应完毕，反应液直接用饱和食盐水洗涤2次，有机层用无水Na₂SO₄干燥，过滤，减压蒸除溶剂，经柱层析得白色固体C10b 0.57g，收率86％，熔点：94-97℃。

¹H NMR(400MHz,CDCl₃)δ9.33(s,1H),8.71(d,J＝2.4Hz,1H),8.44(d,J＝1.4Hz,1H),8.05(d,J＝8.8Hz,1H),7.75–7.59(m,4H),7.43(d,J＝8.3Hz,1H),7.34(dd,J＝9.1,5.2Hz,2H),7.02(d,J＝8.0Hz,1H),4.94(dt,J＝13.7,7.0Hz,1H),4.66(dd,J＝15.3,7.7Hz,1H),4.36(d,J＝7.4Hz,1H),3.52–3.39(m,1H),3.29–3.00(m,3H),2.54(dd,J＝17.1,8.8Hz,1H),2.44–2.31(m,1H),2.19(dd,J＝10.9,5.5Hz,1H),2.08(t,J＝5.3Hz,1H),1.97–1.86(m,3H),1.68(dd,J＝16.0,10.9Hz,4H),1.57(ddd,J＝21.5,10.6,4.4Hz,1H),1.47(s,3H),1.42–1.35(m,1H),1.29(s,3H),1.25(dd,J＝8.5,4.7Hz,1H),0.91(t,J＝6.1Hz,6H),0.87(s,3H).¹³C NMR(101MHz,CDCl₃)δ170.87,168.75,162.76,147.30,144.41,143.99,142.59,133.74,133.30,132.24,128.47,128.10,127.76,127.65,127.44,125.69,125.38,85.93,77.79,52.11,51.69,51.34,46.45,41.46,39.61,39.37,38.24,35.56,28.66,27.13,27.04,26.28,24.75,24.07,23.14,21.76.HRMS(ESI)calcd for C₃₈H₄₉BN₅O₅:666.38277[(M+H)⁺],found 666.38192.

实施例10：N-吡嗪甲酰-L-亮氨酰-L-萘基丙氨酰-L-脯氨酸硼酸(C10)

C10b(0.57g，0.86mmol)溶于15mL无水甲醇中，在剧烈搅拌下加入3equiv.PhB(OH)₂后加入15mL正己烷。反应15min后加入15mL2N的HCl水溶液，继续剧烈搅拌。TLC检测反应进程，6h后反应完毕，分液弃去正己烷层，以正己烷15mL×2洗涤。再以二氯甲烷15mL×3从甲醇水混合溶液中萃取，合并有机层后进行柱层析，得白色固体160mg，收率36％，熔点：123-127℃。

¹H NMR(400MHz,DMSO)δ9.25–9.14(m,1H),8.89(d,J＝2.4Hz,1H),8.70(d,J＝1.3Hz,1H),8.65–8.52(m,1H),7.90–7.66(m,4H),7.40(ddd,J＝9.3,7.4,5.3Hz,3H),5.00–4.75(m,1H),4.55(td,J＝9.3,4.8Hz,1H),3.50–3.32(m,1H),3.31–2.92(m,3H),1.92–1.21(m,7H),0.89–0.63(m,6H).¹³C NMR(101MHz,DMSO)δ171.34,168.72,162.61,144.02,143.77,128.49,128.12,127.85,126.29,126.12,125.68,51.90,46.82,41.76,27.45,24.73,23.33,22.07,21.85.HRMS(ESI)calcd for C₂₉H₃₅BN₅O₄:528.27817[(M-H₂O+CH₂+H)⁺],found 528.27799.

实施例11a：N-吡嗪甲酰-L-异亮氨酰-L-萘基丙氨酸甲酯(C11a)

合成方法同化合物C10a，无色油状物，收率77％。

¹H NMR(400MHz,CDCl₃)δ9.23(d,J＝1.3Hz,1H),8.69(d,J＝2.4Hz,1H),8.42(dd,J＝2.4,1.5Hz,1H),8.22(d,J＝9.3Hz,1H),7.73–7.59(m,3H),7.53(s,1H),7.43–7.29(m,2H),7.20(dd,J＝8.4,1.6Hz,1H),6.95(d,J＝8.1Hz,1H),5.07(dd,J＝14.1,6.2Hz,1H),4.62(dd,J＝9.2,7.3Hz,1H),3.76(s,3H),3.26(ddd,J＝20.5,13.9,6.1Hz,2H),2.03–1.94(m,1H),1.53(dtd,J＝11.3,7.4,3.7Hz,1H),1.15(ddd,J＝13.5,9.4,7.3Hz,1H),0.98(d,J＝6.8Hz,3H),0.87(t,J＝7.4Hz,3H).¹³C NMR(101MHz,CDCl₃)δ171.74,170.50,162.82,147.27,144.25,143.86,142.59,133.25,133.11,132.32,128.18,128.08,127.51,127.49,127.17,126.06,125.62,57.63,53.05,52.42,38.13,37.38,24.86,15.43,11.23.

实施例11b：N-吡嗪甲酰-L-异亮氨酰-L-萘基丙氨酰-L-脯氨酸硼酸蒎烷二醇酯(C11b)

合成方法同化合物C10b，白色固体，收率89％，熔点：84-87℃。

¹H NMR(400MHz,CDCl₃)δ9.35(d,J＝1.2Hz,1H),8.72(d,J＝2.4Hz,1H),8.52–8.44(m,1H),8.17(d,J＝9.2Hz,1H),7.74–7.64(m,4H),7.46–7.41(m,1H),7.38–7.31(m,2H),5.05–4.92(m,1H),4.55–4.44(m,1H),4.35(d,J＝7.2Hz,1H),3.45(dd,J＝12.7,5.9Hz,1H),3.22(dd,J＝13.3,8.1Hz,1H),3.18–3.04(m,2H),2.02–1.88(m,4H),1.76–1.63(m,3H),1.46(s,3H),1.29(s,3H),0.93(d,J＝6.8Hz,4H),0.87(s,3H),0.86–0.81(m,3H).¹³CNMR(101MHz,CDCl₃)δ170.00,168.71,162.77,147.26,144.44,144.11,142.60,133.75,133.34,132.27,128.09,127.80,127.65,127.53,127.44,125.69,125.39,85.92,77.80,57.87,52.10,51.36,46.48,39.62,39.37,38.24,38.14,37.51,35.56,28.64,27.12,27.04,26.26,24.65,24.06,15.69,11.22.HRMS(ESI)calcd for C₃₈H₄₉BN₅O₅:666.38277[(M+H)⁺],found 666.38239.

实施例11：N-吡嗪甲酰-L-异亮氨酰-L-萘基丙氨酰-L-脯氨酸硼酸(C11)

合成方法同化合物C10，白色固体，收率39％，熔点：138-141℃。

¹H NMR(400MHz,DMSO)δ9.18(dd,J＝5.6,4.1Hz,1H),8.94–8.85(m,1H),8.71–8.64(m,1H),8.37(d,J＝9.2Hz,1H),7.74(dd,J＝22.8,9.7Hz,4H),7.57–7.04(m,4H),5.00–4.19(m,2H),3.45–2.94(m,4H),1.94–1.47(m,4H),1.42–1.24(m,1H),0.66(dd,J＝38.3,7.1Hz,6H).¹³C NMR(101MHz,DMSO)δ170.38,168.70,162.39,148.24,144.39,143.97,143.75,132.15,128.39,128.26,127.88,127.75,126.11,125.64,57.46,52.24,46.86,37.70,27.24,24.79,15.55,14.54,11.26.HRMS(ESI)calcd for C₂₉H₃₅BN₅O₄:528.27817[(M-H₂O+CH₂+H)⁺],found528.27769.

实施例12a：N-吡嗪甲酰-L-异亮氨酰-L-苯丙氨酸甲酯(C12a)

合成方法同化合物C10a，无色油状物，收率74％。

¹H NMR(400MHz,CDCl₃)δ9.33(d,J＝1.3Hz,1H),8.75(d,J＝2.4Hz,1H),8.54(dd,J＝2.4,1.5Hz,1H),8.31(d,J＝9.3Hz,1H),7.18–7.01(m,5H),6.93(d,J＝8.0Hz,1H),4.94(dt,J＝7.9,6.1Hz,1H),4.65(dd,J＝9.2,7.2Hz,1H),3.73(s,3H),3.18–3.01(m,2H),2.00(ddd,J＝10.2,7.6,4.2Hz,1H),1.56(dqd,J＝14.9,7.4,3.6Hz,1H),1.28–1.10(m,1H),0.98(d,J＝6.8Hz,3H),0.89(t,J＝7.4Hz,3H).¹³C NMR(101MHz,CDCl₃)δ171.68,170.47,162.86,147.38,144.45,144.08,142.66,135.57,129.17,128.44,126.92,57.56,53.12,52.34,37.90,37.55,24.87,15.43,11.29.

实施例12b：N-吡嗪甲酰-L-异亮氨酰-L-苯丙氨酰-L-脯氨酸硼酸蒎烷二醇酯(C12b)

合成方法同化合物C10b，白色固体，收率84％，熔点：81-83℃。

¹H NMR(400MHz,CDCl₃)δ9.34(d,J＝1.2Hz,1H),8.69(d,J＝2.4Hz,1H),8.49–8.40(m,1H),7.84(d,J＝8.2Hz,1H),7.67(d,J＝8.1Hz,1H),7.17(ddd,J＝19.7,14.3,7.2Hz,5H),4.87(ddd,J＝22.6,13.6,8.6Hz,1H),4.59–4.47(m,1H),4.30(dd,J＝15.9,8.4Hz,1H),3.62–3.49(m,1H),3.21–2.89(m,3H),2.11–1.93(m,4H),1.84(dd,J＝9.0,5.3Hz,4H),1.39(s,3H),1.25(s,3H),0.99–0.85(m,7H),0.83(d,J＝4.0Hz,3H).¹³C NMR(101MHz,CDCl₃)δ170.38,169.24,162.93,147.19,144.35,144.16,142.60,136.03,129.89,128.27,126.79,85.92,77.75,57.95,52.32,51.26,46.68,39.52,38.72,38.18,37.39,35.44,28.56,27.09,26.15,24.57,24.01,15.68,11.28.HRMS(ESI)calcd for C₃₄H₄₇BN₅O₅:616.36706[(M+H)⁺],found 616.36700.

实施例12：N-吡嗪甲酰-L-异亮氨酰-L-苯丙氨酰-L-脯氨酸硼酸(C12)

合成方法同化合物C10，白色固体，收率37％，熔点：131-133℃。

¹H NMR(400MHz,DMSO)δ9.21(s,1H),8.91(d,J＝2.3Hz,1H),8.76(s,1H),8.45(d,J＝9.5Hz,1H),7.35–6.86(m,6H),4.80–4.25(m,2H),3.09–2.71(m,3H),2.13–1.31(m,6H),1.16–0.97(m,1H),0.82–0.60(m,6H).¹³C NMR(101MHz,DMSO)δ170.41,162.44,148.33,144.47,143.97,143.85,129.70,128.45,126.55,57.40,52.34,37.76,27.46,27.22,24.78,15.70,11.29.HRMS(ESI)calcd for C₂₅H₃₃BN₅O₄:478.26254[(M-H₂O+CH₂+H)⁺],found478.26226.

实施例13a：N-吡嗪甲酰-L-亮氨酰-L-苯丙氨酸甲酯(C13a)

合成方法同化合物C10a，无色油状物，收率79％。

¹H NMR(400MHz,CDCl₃)δ9.33(d,J＝1.4Hz,1H),8.75(d,J＝2.4Hz,1H),8.52(dd,J＝2.4,1.5Hz,1H),8.14(d,J＝8.8Hz,1H),7.16–6.88(m,6H),4.83(ddt,J＝17.4,8.7,6.0Hz,2H),3.07(ddd,J＝32.4,13.9,6.1Hz,2H),1.86–1.58(m,3H),0.91(t,J＝6.6Hz,6H).¹³C NMR(101MHz,CDCl₃)δ171.77,171.26,162.92,147.46,144.45,143.94,142.68,135.65,129.17,128.36,126.85,53.20,52.37,51.47,40.97,37.82,24.75,22.90,22.08.

实施例13b：N-吡嗪甲酰-L-亮氨酰-L-苯丙氨酰-L-脯氨酸硼酸蒎烷二醇酯(C13b)

合成方法同化合物C10b，白色固体，收率83％，熔点：89-91℃。

¹H NMR(400MHz,CDCl₃)δ9.35(d,J＝1.4Hz,1H),8.70(d,J＝2.4Hz,1H),8.46(dd,J＝2.4,1.5Hz,1H),8.11(d,J＝8.7Hz,1H),7.28–7.09(m,7H),4.98–4.59(m,2H),4.36–4.26(m,1H),3.58–3.44(m,1H),3.19–2.91(m,3H),2.00–1.92(m,1H),1.90–1.77(m,4H),1.74–1.62(m,4H),1.40(s,3H),1.31(d,J＝1.9Hz,1H),1.26(s,3H),1.02–0.92(m,2H),0.95–0.87(m,6H),0.84(s,3H).¹³C NMR(101MHz,CDCl₃)δ171.20,169.20,162.88,147.24,144.38,142.59,136.03,129.92,128.23,126.80,126.70,85.92,77.76,52.35,51.79,51.26,46.62,41.35,39.54,38.84,38.19,35.45,28.58,27.16,27.07,26.18,24.79,24.04,23.12,21.69.HRMS(ESI)calcd for C₃₄H₄₇BN₅O₅:616.36706[(M+H)⁺],found616.36669.

实施例13：N-吡嗪甲酰-L-亮氨酰-L-苯丙氨酰-L-脯氨酸硼酸(C13)

合成方法同化合物C10，白色固体，收率34％，熔点：134-136℃。

¹H NMR(400MHz,DMSO)δ9.19(d,J＝1.2Hz,1H),8.89(dd,J＝5.5,2.4Hz,1H),8.74(dd,J＝5.0,1.5Hz,1H),8.67–8.55(m,1H),7.37–7.03(m,5H),4.81–4.48(m,2H),3.03–2.72(m,3H),1.90–1.41(m,6H),0.94–0.74(m,6H).¹³C NMR(101MHz,DMSO)δ171.34,168.86,162.61,148.23,144.64,144.02,143.81,138.39,129.77,128.43,126.56,51.81,46.77,41.80,37.29,27.42,27.18,24.75,23.37,22.20,22.07.HRMS(ESI)calcd for C₂₅H₃₃BN₅O₄:478.26254[(M-H₂O+CH₂+H)⁺],found 478.26230.

实施例14a：N-吡嗪甲酰-L-苯丙酰-L-苯丙氨酸甲酯(C14a)

合成方法同化合物C10a，无色油状物，收率81％。

¹H NMR(400MHz,CDCl₃)δ9.29(d,J＝1.1Hz,1H),8.75(d,J＝2.4Hz,1H),8.63–8.46(m,1H),8.34(d,J＝8.4Hz,1H),7.27–7.15(m,5H),7.11–6.91(m,5H),6.77(d,J＝7.8Hz,1H),4.92(ddd,J＝19.9,14.5,6.6Hz,2H),3.70(s,3H),3.27–3.13(m,2H),3.05(ddd,J＝30.3,13.8,6.1Hz,2H).¹³C NMR(101MHz,CDCl₃)δ171.36,170.06,162.88,147.50,144.41,143.85,142.71,136.31,135.56,129.38,129.14,128.61,128.40,127.01,126.90,54.23,53.35,52.36,38.23,37.88.

实施例14b：N-吡嗪甲酰-L-苯丙氨酰-L-苯丙氨酰-L-脯氨酸硼酸蒎烷二醇酯(C14b)

合成方法同化合物C10b，白色固体，收率88％，熔点：93-95℃。

¹H NMR(400MHz,CDCl₃)δ9.34(d,J＝1.3Hz,1H),8.74(d,J＝2.4Hz,1H),8.51(dd,J＝2.3,1.5Hz,1H),8.24(d,J＝8.4Hz,1H),7.26–7.08(m,10H),6.76(t,J＝14.5Hz,1H),4.90–4.74(m,2H),4.40–4.29(m,1H),3.22–3.08(m,0H),3.03–2.85(m,0H),2.53(dd,J＝17.6,8.1Hz,1H),2.43–2.30(m,1H),2.20(dd,J＝10.7,6.1Hz,1H),2.06(dd,J＝10.2,4.8Hz,1H),1.98–1.91(m,2H),1.79(dt,J＝16.2,8.1Hz,2H),1.62(ddd,J＝12.1,11.1,5.6Hz,1H),1.44(s,3H),1.30(s,3H),0.87(s,3H).¹³C NMR(101MHz,CDCl₃)δ169.48,168.43,162.71,147.39,144.42,142.66,136.18,129.95,129.46,129.34,128.54,128.19,126.95,126.64,85.88,77.79,54.26,52.40,51.34,46.42,39.17,38.36,38.23,35.49,28.63,27.21,27.12,26.25,24.06.HRMS(ESI)calcd for C₃₇H₄₅BN₅O₅:650.35146[(M+H)⁺],found 650.35123.

实施例14：N-吡嗪甲酰-L-苯丙氨酰-L-苯丙氨酰-L-脯氨酸硼酸(C14)

合成方法同化合物C10，白色固体，收率39％，熔点：174-176℃。

¹H NMR(400MHz,DMSO)δ9.12(dd,J＝9.7,2.5Hz,1H),8.90–8.84(m,1H),8.71(d,J＝2.0Hz,1H),8.57(dd,J＝12.9,8.5Hz,1H),7.31(dd,J＝11.9,5.9Hz,2H),7.26–7.09(m,8H),4.97–4.61(m,2H),3.03(tdd,J＝34.2,16.6,9.4Hz,4H),2.89–2.64(m,2H),1.95–1.45(m,4H).¹³C NMR(101MHz,DMSO)δ170.27,170.09,168.87,162.41,148.29,144.41,143.85,138.42,137.32,129.76,128.52,128.43,126.81,60.20,53.80,52.38,37.36,27.16,21.21.HRMS(ESI)calcd for C₂₈H₃₁BN₅O₄:512.24685[(M-H₂O+CH₂+H)⁺],found 512.24663.

实施例15a：N-吡嗪甲酰-L-苯丙酰-L-萘基丙氨酸甲酯(C15a)

合成方法同化合物C10a，无色油状物，收率83％。

¹H NMR(400MHz,CDCl₃)δ9.17(d,J＝1.3Hz,1H),8.66(d,J＝2.4Hz,1H),8.36(dd,J＝2.2,1.6Hz,1H),8.27(d,J＝8.5Hz,1H),7.76–7.53(m,3H),7.47–7.33(m,3H),7.21–7.09(m,3H),6.88(d,J＝7.7Hz,1H),5.01(dq,J＝14.1,6.9Hz,2H),3.73(s,3H),3.36–3.11(m,4H).¹³C NMR(101MHz,CDCl₃)δ171.45,170.15,162.84,147.36,144.17,143.62,142.62,136.30,133.21,133.07,132.29,129.39,128.59,128.15,128.03,127.51,127.12,127.01,126.05,125.63,54.19,53.22,52.44,38.23,38.08.

实施例15b：N-吡嗪甲酰-L-苯丙氨酰-L-萘基丙氨酰-L-脯氨酸硼酸蒎烷二醇酯(C15b)

合成方法同化合物C10b，白色固体，收率92％，熔点：101-103℃。

¹H NMR(400MHz,CDCl₃)δ9.31(d,J＝1.3Hz,1H),8.71(d,J＝2.2Hz,1H),8.44(dd,J＝2.2,1.5Hz,1H),8.22(d,J＝8.4Hz,1H),7.74(dd,J＝7.0,4.9Hz,3H),7.54–7.34(m,4H),7.25–7.15(m,5H),7.03(d,J＝7.9Hz,1H),4.99–4.80(m,2H),3.41(t,J＝6.9Hz,1H),3.15(ddt,J＝18.7,15.6,4.7Hz,5H),2.55(dd,J＝17.3,8.6Hz,1H),2.46–2.35(m,1H),2.19(dd,J＝10.4,5.9Hz,1H),2.11(s,1H),1.94(dd,J＝10.0,2.0Hz,3H),1.72(dd,J＝14.4,7.6Hz,2H),1.63–1.53(m,1H),1.48(s,3H),1.31(s,3H),0.89(s,3H).¹³C NMR(101MHz,CDCl₃)δ169.70,168.69,162.71,147.32,144.33,143.94,142.66,136.18,133.74,133.36,132.29,129.31,128.55,128.42,127.95,127.71,127.51,126.97,125.75,125.45,85.95,77.78,54.28,52.19,51.35,46.51,39.62,39.28,38.34,38.26,35.58,28.65,27.14,27.07,26.26,24.09.HRMS(ESI)calcd for C₄₁H₄₇BN₅O₅:700.36703[(M+H)⁺],found700.36671.

实施例15：N-吡嗪甲酰-L-苯丙氨酰-L-萘基丙氨酰-L-脯氨酸硼酸(C15)

合成方法同化合物C10，白色固体，收率42％，熔点：197-199℃。

¹H NMR(400MHz,DMSO)δ9.12(s,1H),8.86(s,1H),8.67(d,J＝5.3Hz,1H),8.58(d,J＝8.4Hz,1H),7.78(dd,J＝14.8,7.1Hz,4H),7.51–7.31(m,3H),7.23–6.97(m,5H),4.82(dd,J＝23.9,16.6Hz,2H),3.25(m,2H),3.16–2.85(m,4H),1.75(m,4H).¹³C NMR(101MHz,DMSO)δ170.10,168.74,162.43,148.24,144.35,143.80,137.57,133.41,129.68,128.44,128.08,127.94,127.87,126.82,126.23,125.74,54.08,46.89,38.05,37.62,27.52,27.20.HRMS(ESI)calcd for C₃₂H₃₃BN₅O₄:562.26257[(M-H₂O+CH₂+H)⁺],found 562.26179.

实施例16a：N-吡嗪甲酰-L-苯丙酰-L-亮氨酸甲酯(C16a)

合成方法同化合物C10a，无色油状物，收率71％。

¹H NMR(400MHz,CDCl₃)δ9.32(d,J＝1.3Hz,1H),8.72(d,J＝2.4Hz,1H),8.50(dd,J＝2.2,1.6Hz,1H),8.46(d,J＝8.4Hz,1H),7.26–7.12(m,5H),6.91(d,J＝8.0Hz,1H),5.04(q,J＝7.0Hz,1H),4.56(td,J＝8.3,5.7Hz,1H),3.69(s,3H),3.36–3.04(m,2H),1.65–1.34(m,3H),0.81(t,J＝6.2Hz,6H).¹³C NMR(101MHz,CDCl₃)δ172.78,170.34,162.92,147.51,144.30,143.95,142.81,136.33,129.38,128.52,126.93,54.39,52.27,50.94,41.32,38.66,24.73,22.57,21.93.

实施例16b：N-吡嗪甲酰-L-苯丙氨酰-L-亮氨酰-L-脯氨酸硼酸蒎烷二醇酯(C16b)

合成方法同化合物C10b，白色固体，收率80％，熔点：87-89℃。

¹H NMR(400MHz,CDCl₃)δ9.32(d,J＝1.2Hz,1H),8.70(d,J＝2.4Hz,1H),8.58–8.45(m,1H),8.32(d,J＝8.4Hz,1H),7.24–7.10(m,5H),6.95(d,J＝8.4Hz,1H),5.06–4.70(m,2H),4.33–4.19(m,1H),3.87–3.71(m,1H),3.43(dd,J＝16.2,9.5Hz,1H),3.30–3.11(m,3H),2.29(dd,J＝14.3,8.7Hz,1H),2.16–1.75(m,8H),1.63–1.55(m,1H),1.53–1.41(m,2H),1.36(s,3H),1.25(s,3H),0.88(dd,J＝8.4,6.5Hz,6H),0.81(s,3H).¹³C NMR(101MHz,CDCl₃)δ169.93,169.91,162.72,147.31,144.30,144.07,142.70,136.12,129.35,128.48,126.92,85.81,77.85,54.20,51.20,48.93,46.69,41.47,39.51,38.36,38.16,,35.43(s,9H),28.57,27.34,27.20,27.08,26.15,24.30,24.03,23.08,22.27.HRMS(ESI)calcd forC₃₄H₄₇BN₅O₅:616.36706[(M+H)⁺],found 616.36645.

实施例16：N-吡嗪甲酰-L-苯丙氨酰-L-亮氨酰-L-脯氨酸硼酸(C16)

合成方法同化合物C10，白色固体，收率30％，熔点：152-154℃。

¹H NMR(400MHz,DMSO)δ9.14(d,J＝1.2Hz,1H),8.87(d,J＝2.0Hz,1H),8.72(s,1H),8.70–8.63(m,1H),7.37(s,1H),7.25–7.09(m,5H),4.85(dd,J＝12.6,8.0Hz,1H),4.60(dd,J＝13.7,8.7Hz,1H),3.71–3.45(m,1H),3.20–3.00(m,2H),2.97–2.72(m,1H),2.08–1.33(m,7H),0.87(dt,J＝12.7,6.5Hz,6H).¹³C NMR(101MHz,DMSO)δ170.19,169.45,162.52,148.30,144.47,143.88,137.59,129.78,128.51,128.43,126.82,53.96,48.89,46.71,38.11,27.43,27.28,24.43,23.70,23.63,22.17,21.88.HRMS(ESI)calcd forC₂₅H₃₃BN₅O₄:478.26254[(M-H₂O+CH₂+H)⁺],found 478.26237.

实施例17a：N-吡嗪甲酰-L-亮氨酰-L-亮氨酸甲酯(C17a)

合成方法同化合物C10a，无色油状物，收率68％。

¹H NMR(400MHz,CDCl₃)δ9.37(d,J＝1.2Hz,1H),8.74(d,J＝2.4Hz,1H),8.51(dd,J＝2.3,1.6Hz,1H),8.24(d,J＝8.8Hz,1H),6.97(d,J＝8.1Hz,1H),4.68(dtd,J＝91.7,8.4,5.5Hz,2H),3.71(s,3H),1.97–1.26(m,6H),0.92(t,J＝5.9Hz,6H),0.82(d,J＝6.1Hz,6H).¹³C NMR(101MHz,CDCl₃)δ173.18,171.45,162.96,147.47,144.35,144.04,142.75,52.25,51.59,50.83,41.42,41.24,24.75,24.74,22.87,22.60,22.11,21.86.

实施例17b：N-吡嗪甲酰-L-亮氨酰-L-亮氨酰-L-脯氨酸硼酸蒎烷二醇酯(C17b)

合成方法同化合物C10b，白色固体，收率75％，熔点：75-77℃。

¹H NMR(400MHz,CDCl₃)δ9.37(d,J＝1.3Hz,1H),8.74(d,J＝2.4Hz,1H),8.56–8.51(m,1H),8.16(d,J＝8.8Hz,1H),6.72(d,J＝8.5Hz,1H),4.89–4.50(m,2H),4.32–4.22(m,1H),3.85–3.73(m,1H),3.42(dd,J＝16.1,9.2Hz,1H),3.18(dd,J＝9.9,7.0Hz,1H),2.30(dd,J＝8.2,5.7Hz,1H),2.15–2.00(m,3H),2.00–1.93(m,2H),1.91–1.82(m,2H),1.73–1.61(m,4H),1.56–1.48(m,2H),1.38(s,3H),1.26(s,3H),0.91(ddd,J＝21.7,10.1,6.6Hz,12H),0.82(s,3H).¹³C NMR(101MHz,CDCl₃)δ171.06(s,2H),169.86(s,1H),162.80(s,1H),147.33(s,4H),144.43(s,4H),144.16(s,1H),142.64(s,4H),85.82(s,2H),77.87(s,3H),51.70(s,3H),51.23(s,4H),48.96(s,3H),46.59(s,2H),41.70(d,J＝17.8Hz,6H),39.53(s,4H),38.17(s,4H),35.43(s,3H),28.57(s,4H),27.41–26.76(m,11H),26.19(s,5H),24.78(s,4H),24.34(s,3H),24.02(s,4H),23.17(d,J＝5.9Hz,7H),22.20(s,3H),21.76(s,3H).HRMS(ESI)calcd for C₃₁H₄₉BN₅O₅:582.38266[(M+H)⁺],found 582.38302.

实施例17：N-吡嗪甲酰-L-亮氨酰-L-亮氨酰-L-脯氨酸硼酸(C17)

合成方法同化合物C10，白色固体，收率27％，熔点：102-104℃。

¹H NMR(400MHz,DMSO)δ9.19(d,J＝1.2Hz,1H),8.90(d,J＝2.3Hz,1H),8.76(dd,J＝2.3,1.5Hz,1H),8.70(d,J＝9.0Hz,1H),8.23(d,J＝8.2Hz,1H),4.59(dtd,J＝13.9,8.9,4.9Hz,2H),3.63(m,1H),2.83(m,1H),2.07–1.29(m,10H),1.00–0.77(m,12H).¹³C NMR(101MHz,DMSO)δ171.51,169.47,162.69,148.26,144.67,144.01,143.87,51.71,48.90,46.61,42.00,27.39,27.28,24.84,24.44,23.75,23.52,22.13,22.00.HRMS(ESI)calcdfor C₂₂H₃₅BN₅O₄:444.27805[(M-H₂O+CH₂+H)⁺],found 444.27740.

实施例18a：N-吡嗪甲酰-L-萘基丙氨酰-L-亮氨酸甲酯(C18a)

合成方法同化合物C10a，无色油状物，收率74％。

¹H NMR(400MHz,CDCl₃)δ9.29(d,J＝1.4Hz,1H),8.70(d,J＝2.4Hz,1H),8.54(d,J＝8.4Hz,1H),8.48(dd,J＝2.4,1.5Hz,1H),7.71(dt,J＝21.1,6.5Hz,4H),7.43–7.36(m,3H),6.89(d,J＝8.0Hz,1H),5.14(q,J＝7.0Hz,1H),4.57(td,J＝8.3,5.7Hz,1H),3.55(s,3H),3.38(d,J＝7.0Hz,2H),1.62–1.37(m,3H),0.81(dd,J＝12.5,6.1Hz,6H).¹³C NMR(101MHz,CDCl₃)δ172.64,170.36,163.00,147.48,144.22,143.89,142.81,133.82,133.42,132.42,128.32,128.21,127.58,127.39,126.06,125.70,54.51,52.19,51.02,41.36,38.91,24.73,22.54,21.94.

实施例18b：N-吡嗪甲酰-L-萘基丙氨酰-L-亮氨酰-L-脯氨酸硼酸蒎烷二醇酯(C18b)

合成方法同化合物C10b，白色固体，收率82％，熔点：105-107℃。

¹H NMR(400MHz,CDCl₃)δ9.32(s,1H),8.68(d,J＝2.3Hz,1H),8.44(s,1H),8.39(d,J＝8.3Hz,1H),7.78–7.65(m,4H),7.44–7.34(m,3H),6.98(d,J＝8.3Hz,1H),4.90(ddd,J＝22.3,14.2,7.5Hz,2H),4.25(d,J＝7.7Hz,1H),3.67(dd,J＝12.8,5.5Hz,1H),3.45–3.31(m,3H),3.13(dd,J＝9.2,7.5Hz,1H),2.30(dd,J＝14.1,8.7Hz,1H),2.12–1.94(m,4H),1.88–1.69(m,4H),1.63–1.54(m,1H),1.48(ddd,J＝21.4,9.8,5.3Hz,2H),1.37(s,3H),1.26(s,3H),0.87(dd,J＝16.7,6.3Hz,6H),0.81(s,3H).¹³C NMR(101MHz,CDCl₃)δ169.85,169.79,162.78,147.31,144.32,144.07,142.67,133.70,133.43,132.42,128.20,127.61,127.38,125.93,125.57,85.79,77.87,54.13,51.23,49.04,46.60,41.60,39.54,38.55,38.16,35.43,28.60,27.20,27.14,27.09,26.18,24.31,24.02,23.09,22.26.HRMS(ESI)calcd for C₃₈H₄₉BN₅O₅:666.38277[(M+H)⁺],found 666.38173.

实施例18：N-吡嗪甲酰-L-萘基丙氨酰-L-亮氨酰-L-脯氨酸硼酸(C18)

合成方法同化合物C10，白色固体，收率35％，熔点：188-191℃。

¹H NMR(400MHz,DMSO)δ9.23–9.07(m,1H),8.86(d,J＝2.3Hz,1H),8.74(d,J＝8.4Hz,1H),8.72–8.67(m,1H),7.93–7.62(m,4H),7.47–7.36(m,3H),4.98(td,J＝8.1,4.6Hz,1H),4.61(dd,J＝13.7,8.5Hz,1H),3.40–3.13(m,4H),2.03–1.51(m,6H),0.90(dd,J＝12.2,6.5Hz,6H).¹³C NMR(101MHz,DMSO)δ170.22,169.53,162.59,148.30,144.45,143.87,135.33,133.39,132.30,128.36,128.25,127.88,127.82,126.37,125.91,54.03,49.03,46.69,38.35,27.45,27.27,24.48,23.76,22.09.HRMS(ESI)calcd for C₂₉H₃₅BN₅O₄:528.27817[(M-H₂O+CH₂+H)⁺],found 528.27765.

实施例19b：N-Cbz-L-苯丙氨酰-L-萘丙氨酰-L-脯氨酸硼酸蒎烷二醇酯(C19b)

合成方法同化合物C10b，白色固体，收率92％，熔点：71-73℃。

¹H NMR(400MHz,CDCl₃)δ7.88–7.73(m,4H),7.53–7.42(m,3H),7.38–7.20(m,9H),7.15(d,J＝6.6Hz,2H),6.93(d,J＝7.7Hz,1H),5.35(d,J＝8.3Hz,1H),5.07(q,J＝12.3Hz,2H),4.89(td,J＝8.6,4.8Hz,1H),4.50(d,J＝7.0Hz,1H),4.38(d,J＝7.3Hz,1H),3.39–3.28(m,1H),3.21(dd,J＝12.9,7.9Hz,1H),3.16–3.00(m,4H),2.49–2.36(m,2H),2.23(dt,J＝8.8,5.9Hz,1H),2.12(d,J＝5.2Hz,1H),2.00–1.87(m,3H),1.72–1.60(m,2H),1.51(s,3H),1.33(s,3H),0.91(s,3H).¹³C NMR(101MHz,CDCl₃)δ170.16,168.57,155.80,136.28,133.88,133.47,132.38,129.34,128.57,128.57,128.51,127.59,126.92,125.80,125.52,85.94,77.81,66.96,56.01,52.33,51.40,46.45,39.65,38.28,35.61,28.73,27.17,27.00,26.31,24.10.HRMS(ESI)calcd for C₄₄H₅₁BN₃O₆:728.38728[(M+H)⁺],found728.38555.

实施例19：N-Cbz-L-苯丙氨酰-L-萘丙氨酰-L-脯氨酸硼酸(C19)

合成方法同化合物C10，白色固体，收率47％，熔点：155-157℃。

¹H NMR(400MHz,DMSO)δ7.93–7.70(m,4H),7.46(ddd,J＝19.4,18.7,7.0Hz,4H),7.31(dt,J＝12.9,7.2Hz,3H),7.26–7.11(m,7H),5.11–4.86(m,2H),4.79(dt,J＝24.5,11.4Hz,1H),4.40–4.17(m,1H),3.39–2.57(m,6H),2.01–1.37(m,4H).¹³C NMR(101MHz,DMSO)δ171.69,171.45,168.81,156.11,137.44,133.52,132.29,129.58,128.76,128.47,128.13,127.93,127.86,126.68,65.67,56.54,38.04,37.64,27.47,27.20.HRMS(ESI)calcd for C₃₅H₃₇BN₃O₅:590.28268[(M-H₂O+CH₂+H)⁺],found 590.28150.

实施例20a：N-Cbz-L-亮氨酰-L-萘基丙氨酸甲酯(C20a)

合成方法同化合物C5，起始物为Boc-L-亮氨酸，无色油状物，收率93％。

¹H NMR(400MHz,CDCl₃)δ7.86–7.73(m,3H),7.60(s,1H),7.54–7.44(m,2H),7.41–7.18(m,6H),6.67(d,J＝7.1Hz,1H),5.24(d,J＝8.2Hz,1H),5.17–4.88(m,3H),4.22(d,J＝4.0Hz,1H),3.72(s,3H),3.29(ddd,J＝33.7,13.8,5.9Hz,2H),1.74–1.56(m,2H),1.53–1.41(m,1H),0.90(d,J＝5.5Hz,6H).¹³C NMR(101MHz,CDCl₃)δ171.90,171.95,156.11,136.24,133.45,133.26,132.51,128.52,128.24,128.16,127.99,127.66,127.28,126.16,125.76,67.02,53.54,53.25,52.37,41.25,38.01,24.63,22.85,21.94.

实施例20b：N-Cbz-L-亮氨酰-L-萘丙氨酰-L-脯氨酸硼酸蒎烷二醇酯(C20b)

合成方法同化合物C10b，白色固体，收率90％，熔点：68-71℃。

¹H NMR(400MHz,CDCl₃)δ7.86–7.74(m,4H),7.74(d,J＝8.4Hz,1H),7.51–7.42(m,3H),7.36(t,J＝7.9Hz,5H),7.02(d,J＝7.8Hz,1H),5.36(d,J＝8.5Hz,1H),5.18–5.08(m,2H),4.93(dd,J＝12.8,8.3Hz,1H),4.39(d,J＝7.6Hz,1H),4.34–4.20(m,1H),3.41–3.32(m,1H),3.30–3.21(m,1H),3.18–3.01(m,2H),2.50–2.37(m,2H),2.29–2.19(m,1H),2.13(t,J＝5.4Hz,1H),2.03–1.95(m,2H),1.93–1.86(m,1H),1.64(ddd,J＝18.4,13.6,8.3Hz,4H),1.51(s,3H),1.33(s,3H),0.93(d,J＝7.7Hz,6H),0.90(s,3H).¹³C NMR(101MHz,CDCl₃)δ171.66,168.77,156.06,136.37,133.88,133.45,132.36,128.59,128.53,128.30,128.11,128.07,127.83,127.58,125.78,125.50,85.95,77.81,66.96,53.66,52.27,51.37,46.47,41.88,39.64,38.27,35.61,28.73,27.17,26.99,26.33,24.65,24.12,23.18,21.69.HRMS(ESI)calcd for C₄₁H₅₃BN₃O₆:694.40289[(M+H)⁺],found 694.40212.

实施例20：N-Cbz-L-亮氨酰-L-萘丙氨酰-L-脯氨酸硼酸(C20)

合成方法同化合物C10，白色固体，收率43％，熔点：161-163℃。

¹H NMR(400MHz,DMSO)δ7.92–7.65(m,4H),7.52–7.16(m,9H),5.11–4.92(m,2H),4.91–4.72(m,1H),4.00(dd,J＝13.3,9.7Hz,1H),3.44–2.78(m,4H),1.99–1.02(m,7H),0.89–0.56(m,6H).¹³C NMR(101MHz,DMSO)δ172.48,172.18,170.74,168.82,156.24,137.44,133.40,132.38,128.81,128.19,128.11,128.06,126.37,126.19,65.84,53.60,46.83,41.16,27.48,27.22,24.46,23.30,21.65.HRMS(ESI)calcd for C₃₂H₃₉BN₃O₅:556.29826[(M-H₂O+CH₂+H)⁺],found 556.29727.

实施例21a：N-Boc-L-亮氨酰-L-亮氨酸甲酯(C21a)

合成方法同化合物C5，起始物为Boc-L-亮氨酸，无色油状物，收率88％。

¹H NMR(400MHz,CDCl₃)δ7.48–7.29(m,5H),6.47(s,1H),5.30(s,1H),5.12(s,2H),4.61(td,J＝8.6,5.0Hz,1H),4.25(d,J＝4.8Hz,1H),3.74(s,3H),1.77–1.60(m,4H),1.60–1.45(m,2H),0.94(dd,J＝9.5,5.9Hz,12H).¹³C NMR(101MHz,CDCl₃)δ173.18,171.97,156.19,136.19,128.54,128.20,128.01,67.05,53.40,52.30,50.73,41.44,24.80,24.61,22.90,22.76,22.06,21.90.

实施例21b：N-Cbz-L-亮氨酰-L-亮氨酰-L-脯氨酸硼酸蒎烷二醇酯(C21b)

合成方法同化合物C10b，白色固体，收率85％，熔点：64-67℃。

¹H NMR(400MHz,CDCl₃)δ7.45–7.29(m,5H),6.83(d,J＝8.4Hz,1H),5.46(d,J＝8.8Hz,1H),5.09(dd,J＝31.5,12.3Hz,2H),4.78(dd,J＝13.9,8.4Hz,1H),4.36–4.19(m,2H),3.78(t,J＝7.6Hz,1H),3.42(dd,J＝16.4,9.0Hz,1H),3.18(dd,J＝16.0,8.1Hz,1H),2.32(dd,J＝12.5,10.1Hz,1H),2.15(dd,J＝11.2,5.5Hz,1H),2.09–1.96(m,3H),1.91–1.82(m,3H),1.69–1.48(m,6H),1.39(s,3H),1.27(s,3H),0.92(dd,J＝9.2,5.7Hz,12H),0.83(s,3H).¹³C NMR(101MHz,CDCl₃)δ171.85,169.98,156.02,136.44,128.47,128.03,85.82,77.87,66.85,53.57,51.18,48.75,46.67,41.88,39.52,38.17,35.46,28.62,27.24,27.10,26.24,24.65,24.32,24.07,23.25,23.15,22.31,21.73.HRMS(ESI)calcdfor C₃₄H₅₃BN₃O₆:610.40278[(M+H)⁺],found 610.40249.

实施例21：N-Cbz-L-亮氨酰-L-亮氨酰-L-脯氨酸硼酸(C21)

合成方法同化合物C10，白色固体，收率37％，熔点：138-141℃。

¹H NMR(400MHz,DMSO)δ7.44–7.20(m,6H),5.10–4.93(m,2H),4.74–4.42(m,1H),4.07(d,J＝4.5Hz,1H),3.59(s,1H),3.30(d,J＝7.4Hz,1H),2.07–1.72(m,3H),1.62(d,J＝5.4Hz,3H),1.54–1.26(m,4H),0.93–0.79(m,12H).¹³C NMR(101MHz,DMSO)δ172.59,169.61,156.32,137.54,128.79,127.98,65.79,53.56,48.75,46.61,41.19,27.27,24.66,24.21,23.82,23.53,22.07,21.78.HRMS(ESI)calcd for C₂₅H₃₉BN₃O₅:472.29817[(M-H₂O+CH₂+H)⁺],found 472.29813.

实施例22a：N-L-苯丙氨酸甲酯-N’-1,2,3,4-四氢异喹啉-脲(C22a)

将L-苯丙氨酸甲酯盐酸盐(2.16g，10mmol)和TEA(1.4mL，10mmol)混合加入20mLDCM与5mL THF的混合溶液中，随后加入羰基二咪唑CDI(2.43g，15mmol)，2h后加入饱和食盐水搅拌，分液，除去过量的CDI，水层用DCM萃取三次后合并，有机相用饱和食盐水洗三次。将有机相蒸除，得到中间体，溶于DCM后，加入1,2,3,4-四氢异喹啉反应过夜至中间体消失。反应液经柠檬酸、碳酸氢钠洗后，无水硫酸钠干燥，蒸除溶剂得到白色固体3.3g，收率58％，熔点：119-123℃。

¹H NMR(400MHz,CDCl₃)δ7.36–7.19(m,6H),7.13(dd,J＝12.8,5.1Hz,3H),5.04(d,J＝6.1Hz,1H),4.88(dd,J＝13.2,6.0Hz,1H),4.52(q,J＝15.6Hz,2H),3.74(s,3H),3.69–3.49(m,2H),3.21–3.12(m,2H),2.89–2.78(m,2H).¹³C NMR(101MHz,CDCl₃)δ173.28,156.58,136.36,134.99,133.27,129.32,128.52,128.37,127.02,126.69,126.41,126.35,54.49,52.21,45.40,41.23,38.42,28.92.

实施例22b：N-(L-苯丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-1,2,3,4-四氢异喹啉-脲(C22b)

合成方法同化合物C10b，白色泡沫，收率72％。

¹H NMR(400MHz,Chloroform-d)δ7.36(d,J＝7.2Hz,2H),7.28–7.20(m,3H),7.20–7.05(m,4H),5.70(d,J＝7.9Hz,1H),4.82(q,J＝8.1Hz,1H),4.51(s,2H),4.38(d,J＝8.5Hz,1H),3.65(dt,J＝11.9,5.8Hz,1H),3.54(p,J＝6.7,6.1Hz,2H),3.08(qd,J＝13.4,6.3Hz,3H),2.82(q,J＝5.2Hz,2H),2.43(dq,J＝20.5,11.5,10.0Hz,2H),2.23(dt,J＝11.5,6.3Hz,1H),2.09(t,J＝5.4Hz,1H),1.95(d,J＝11.2Hz,3H),1.77(q,J＝6.7,6.1Hz,2H),1.68–1.57(m,1H),1.48(s,3H),1.40(d,J＝10.6Hz,1H),1.31(s,3H),0.88(s,3H).¹³CNMR(101MHz,CDCl₃)δ170.40,156.73,136.87,135.03,133.33,130.11,128.38,128.20,126.57,126.50,126.37,126.28,85.82,77.73,53.68,51.30,46.40,45.46,41.08,39.91,39.59,38.23,35.54,29.01,28.71,27.35,27.14,27.09,26.30,24.12.

实施例22：N-(L-苯丙氨酰-L-脯氨酸硼酸)-N’-1,2,3,4-四氢异喹啉-脲(C22)

合成方法同化合物C10，白色固体，收率79％，熔点：123-126℃。

¹H NMR(400MHz,CDCl₃)δ7.26–7.01(m,4H),5.23(d,J＝8.2Hz,1H),4.58(dt,J＝8.6,4.4Hz,1H),4.54(d,J＝1.7Hz,2H),3.73(s,3H),3.66(ddd,J＝11.9,6.7,5.0Hz,1H),3.53(ddd,J＝12.2,7.0,5.0Hz,1H),2.93–2.73(m,2H),1.75(dq,J＝8.0,6.3Hz,1H),1.68–1.50(m,2H),0.95(d,J＝6.5Hz,6H).¹³C NMR(101MHz,CDCl₃)δ175.30,157.13,134.98,133.29,128.30,126.57,126.32,52.15,45.37,41.76,41.19,28.95,24.88,22.91,21.92.

实施例23a：N-L-苯丙氨酸甲酯-N’-(6-甲氧基-1,2,3,4-四氢异喹啉)-脲(C23a)

合成方法同化合物C22a，无色油状物，收率65％。

¹H NMR(400MHz,CDCl₃)δ7.30–7.21(m,3H),7.14–7.08(m,2H),6.99(d,J＝8.4Hz,1H),6.74(dd,J＝8.4,2.7Hz,1H),6.67(d,J＝2.6Hz,1H),5.01(d,J＝7.5Hz,1H),4.84(dt,J＝7.5,5.9Hz,1H),4.51–4.34(m,2H),3.77(s,3H),3.72(s,3H),3.60(ddd,J＝11.9,6.5,4.9Hz,1H),3.49(ddd,J＝12.2,6.8,5.1Hz,1H),3.20–3.07(m,2H),2.79(q,J＝5.6Hz,2H).¹³C NMR(101MHz,CDCl₃)δ173.28,158.30,156.57,136.37,136.29,129.33,128.53,127.35,127.02,125.35,113.25,112.49,55.32,54.50,52.25,44.90,41.07,38.42,29.25.

实施例23b：N-(L-苯丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-(6-甲氧基-1,2,3,4-四氢异喹啉)-脲(C23b)

合成方法同C10b，白色泡沫，收率63％。

¹H NMR(400MHz,Chloroform-d)δ7.35(d,J＝6.4Hz,2H),7.31–7.17(m,3H),7.02(d,J＝8.5Hz,1H),6.76(dd,J＝8.4,2.6Hz,1H),6.68(d,J＝2.6Hz,1H),5.52(d,J＝8.0Hz,1H),4.82(q,J＝7.8Hz,1H),4.46(d,J＝3.7Hz,2H),4.38(d,J＝8.0Hz,1H),3.80(s,3H),3.64(dt,J＝11.6,5.5Hz,1H),3.52(dq,J＝16.1,5.7Hz,2H),3.15–2.99(m,3H),2.81(q,J＝5.2Hz,2H),2.52–2.34(m,2H),2.24(dq,J＝12.5,6.3Hz,1H),2.10(t,J＝5.2Hz,1H),2.05(d,J＝10.9Hz,1H),1.99–1.90(m,3H),1.82–1.74(m,2H),1.63(td,J＝10.7,7.7Hz,1H),1.48(s,3H),1.41(d,J＝10.6Hz,1H),1.32(s,3H),1.27(q,J＝7.1,5.4Hz,1H),0.89(s,3H).¹³C NMR(101MHz,CDCl₃)δ170.31,158.15,156.65,136.85,136.32,130.12,128.18,127.34,126.55,125.40,113.15,112.44,85.84,77.75,55.29,53.60,51.31,46.41,44.95,40.92,40.00,39.60,38.24,35.53,29.33,28.70,27.32,27.14,27.08,26.29,24.12.

实施例23：N-(L-苯丙氨酰-L-脯氨酸硼酸)-N’-(6-甲氧基-1,2,3,4-四氢异喹啉)-脲(C23)

合成方法同C10，白色固体，收率77％。熔点：121-124℃。

¹H NMR(400MHz,DMSO-d₆)δ7.32(d,J＝7.5Hz,2H),7.23(t,J＝7.3Hz,2H),7.16(t,J＝7.3Hz,1H),7.00(d,J＝8.4Hz,1H),6.73(d,J＝8.1Hz,1H),6.69(s,1H),4.49–4.40(m,1H),4.35(s,2H),3.70(s,3H),3.56–3.50(m,1H),3.45–3.33(m,2H),3.17(s,1H),3.00(d,J＝11.4Hz,1H),2.94–2.79(m,2H),2.74–2.60(m,2H),2.00–1.84(m,2H),1.82–1.73(m,1H),1.68–1.55(m,1H).¹³C NMR(101MHz,DMSO)δ170.74,158.03,157.44,139.37,136.46,129.79,128.60,128.46,127.55,126.50,113.57,112.72,55.44,54.47,48.94,46.57,45.15,41.36,36.82,28.80,27.40,27.28.

实施例24a：N-L-苯丙氨酸甲酯-N’-(7-硝基-1,2,3,4-四氢异喹啉)-脲(C24a)

合成方法同化合物C22a，黄色固体，收率70％，熔点：105–107℃。

¹H NMR(400MHz,CDCl₃)δ8.00(dd,J＝8.4,2.3Hz,1H),7.93(d,J＝2.3Hz,1H),7.30–7.19(m,4H),7.16–7.09(m,2H),5.26(d,J＝7.7Hz,1H),4.88–4.77(m,1H),4.66–4.49(m,2H),3.74(s,3H),3.64(ddd,J＝12.1,6.6,5.1Hz,1H),3.54(ddd,J＝12.6,6.9,5.1Hz,1H),3.13(qd,J＝13.8,6.1Hz,2H),2.90(q,J＝6.5Hz,2H).¹³C NMR(101MHz,CDCl₃)δ173.28,156.43,146.41,142.58,136.28,134.97,129.52,129.20,128.52,127.03,121.61,121.51,54.59,52.31,45.31,40.81,38.18,28.93.

实施例24b：N-(L-苯丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-(7-硝基-1,2,3,4-四氢异喹啉)-脲(C24b)

合成方法同C10b，白色泡沫，收率72％。

¹H NMR(400MHz,Chloroform-d)δ7.98(d,J＝8.5Hz,1H),7.93(s,1H),7.34(d,J＝6.3Hz,2H),7.27–7.18(m,4H),6.45(d,J＝8.0Hz,1H),4.75(td,J＝9.1,4.9Hz,1H),4.54(q,J＝16.7Hz,2H),4.35(d,J＝8.1Hz,1H),3.72(dt,J＝11.9,5.6Hz,1H),3.65–3.55(m,1H),3.51–3.39(m,1H),3.21(dd,J＝13.0,9.7Hz,1H),3.06(td,J＝12.6,11.8,5.8Hz,2H),2.93–2.73(m,2H),2.41(ddd,J＝23.1,14.3,8.3Hz,2H),2.20(dt,J＝11.0,5.2Hz,1H),2.06(t,J＝5.2Hz,1H),2.01–1.85(m,3H),1.83–1.72(m,2H),1.59(qd,J＝10.5,6.4Hz,1H),1.46(s,3H),1.37(d,J＝10.9Hz,1H),1.28(s,3H),0.86(s,3H).¹³C NMR(101MHz,CDCl₃)δ170.73,156.89,146.39,142.57,136.76,135.18,129.99,129.48,128.25,126.65,121.62,121.38,85.80,77.72,77.30,53.97,51.33,46.38,45.55,40.85,39.62,39.40,38.19,35.52,29.08,28.71,27.40,27.11,27.05,26.30,24.05.

实施例24：N-(L-苯丙氨酰-L-脯氨酸硼酸)-N’-(7-硝基-1,2,3,4-四氢异喹啉)-脲(C24)

合成方法同C10，黄色固体，收率60％。熔点：180-183℃。

¹H NMR(400MHz,DMSO-d₆)δ7.99(d,J＝9.1Hz,2H),7.39(d,J＝8.3Hz,1H),7.29(d,J＝7.5Hz,2H),7.20(t,J＝7.5Hz,2H),7.18–7.09(m,1H),4.53(s,2H),4.45(dd,J＝10.3,3.6Hz,1H),3.72(t,J＝9.1Hz,1H),3.55–3.46(m,1H),3.38(q,J＝8.5Hz,1H),3.00(d,J＝11.4Hz,1H),2.93–2.81(m,2H),2.84–2.71(m,2H),2.01–1.75(m,3H),1.68–1.53(m,1H).¹³CNMR(101MHz,DMSO)δ170.61,157.35,146.08,143.67,139.20,136.46,130.53,129.75,128.46,126.52,121.58,121.49,54.46,46.61,45.60,41.04,36.80,28.52,27.38,27.26.

实施例25a：N-L-苯丙氨酸甲酯-N’-(6,7-二甲氧基-1,2,3,4-四氢异喹啉)-脲(C25a)

合成方法同化合物C22a，白色固体，收率63％，熔点：122–124℃。

¹H NMR(400MHz,CDCl₃)δ7.30–7.22(m,3H),7.15–7.09(m,2H),6.62(s,1H),6.57(s,1H),5.11(d,J＝7.5Hz,1H),4.84(dt,J＝7.6,5.9Hz,1H),4.50–4.33(m,2H),3.83(d,J＝6.7Hz,6H),3.72(s,3H),3.64–3.56(m,1H),3.49(ddd,J＝12.3,6.9,5.0Hz,1H),3.19–3.07(m,2H),2.82–2.66(m,2H).¹³C NMR(101MHz,CDCl₃)δ173.30,156.52,147.65,147.59,136.33,129.26,128.45,126.92,126.68,124.90,111.25,109.17,55.92,55.90,54.48,52.19,45.11,41.27,38.31,28.32.

实施例25b：N-(L-苯丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-(6,7-二甲氧基-1,2,3,4-四氢异喹啉)-脲(C25b)

合成方法同C10b，白色泡沫，收率55％。

¹H NMR(400MHz,Chloroform-d)δ7.34(d,J＝7.1Hz,2H),7.28–7.16(m,3H),6.59(d,J＝11.1Hz,2H),5.77(d,J＝8.0Hz,1H),4.80(td,J＝8.6,5.1Hz,1H),4.42(s,2H),4.37(d,J＝8.2Hz,1H),3.85(d,J＝4.0Hz,6H),3.64(dt,J＝12.0,5.5Hz,1H),3.52(dq,J＝11.8,5.9,5.1Hz,2H),3.16–3.00(m,3H),2.72(q,J＝6.1Hz,2H),2.41(td,J＝17.5,9.9Hz,2H),2.20(ddd,J＝12.7,8.8,4.7Hz,1H),2.08(t,J＝5.1Hz,1H),1.99–1.88(m,3H),1.76(h,J＝7.1,5.6Hz,2H),1.60(dt,J＝19.4,9.5Hz,1H),1.47(s,3H),1.39(d,J＝10.6Hz,1H),1.30(s,3H),0.87(s,3H).¹³C NMR(101MHz,CDCl₃)δ170.44,156.74,147.52,136.87,130.10,128.18,126.74,126.54,125.04,111.20,109.13,85.81,77.73,55.91,53.70,51.32,46.38,45.28,41.17,39.87,39.60,38.22,35.52,28.70,28.43,27.33,27.13,27.07,26.28,24.09.

实施例25：N-(L-苯丙氨酰-L-脯氨酸硼酸)-N’-(6,7-二甲氧基-1,2,3,4-四氢异喹啉)-脲(C25)

合成方法同C10，白色固体，收率63％。熔点：163-166℃。

¹H NMR(400MHz,DMSO-d₆)δ7.33(d,J＝7.3Hz,2H),7.29–7.20(m,4H),6.75–6.59(m,3H),4.49(td,J＝8.6,7.2,3.6Hz,1H),4.35(s,2H),3.71(s,3H),3.64(s,3H),3.52(h,J＝4.9,4.2Hz,1H),3.42(dt,J＝20.5,7.4Hz,2H),3.03(dd,J＝13.7,3.3Hz,1H),2.88(ddd,J＝23.8,11.8,8.5Hz,2H),2.72–2.55(m,2H),2.01–1.74(m,3H),1.63(qd,J＝9.8,5.8Hz,1H).¹³C NMR(101MHz,DMSO)δ170.80,157.47,147.66,147.59,139.22,129.78,128.49,126.85,126.55,126.09,112.37,110.06,55.94,54.49,48.23,46.63,45.38,41.55,36.93,27.95,27.37,27.24,18.81.

实施例26a：N-L-苯丙氨酸甲酯-N’-(4,5,6,7-四氢噻吩[2,3-C]并吡啶)-脲(C26a)

合成方法同化合物C22a，白色泡沫状固体，收率70％。

¹H NMR(400MHz,CDCl₃)δ7.29–7.20(m,3H),7.14–7.08(m,3H),6.74(d,J＝5.2Hz,1H),5.09(d,J＝7.5Hz,1H),4.82(dt,J＝7.5,5.9Hz,1H),4.49–4.29(m,2H),3.77–3.72(m,1H),3.72(s,3H),3.60(ddd,J＝13.3,6.7,4.9Hz,1H),3.20–3.06(m,2H),2.89–2.73(m,2H).¹³C NMR(101MHz,CDCl₃)δ173.27,156.64,136.32,133.65,131.54,129.32,128.54,127.04,124.83,123.28,54.55,52.28,44.23,41.54,38.35,24.98.

实施例26b：N-(L-苯丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-(4,5,6,7-四氢噻吩[2,3-C]并吡啶)-脲(C26b)

合成方法同C10b，白色泡沫，收率70％。

¹H NMR(400MHz,Chloroform-d)δ7.38–7.31(m,3H),7.28–7.17(m,3H),7.11(d,J＝5.1Hz,1H),6.76(d,J＝5.2Hz,1H),5.78(d,J＝8.0Hz,1H),4.80(td,J＝8.6,5.1Hz,1H),4.42(s,2H),4.37(dd,J＝8.7,1.6Hz,1H),3.77(ddd,J＝13.2,6.1,4.9Hz,1H),3.62(ddd,J＝13.1,6.6,5.0Hz,1H),3.52(dt,J＝10.7,6.0Hz,1H),3.16–3.00(m,3H),2.82(q,J＝5.7Hz,2H),2.53–2.34(m,2H),2.26–2.17(m,1H),2.09(t,J＝5.4Hz,1H),2.01–1.89(m,3H),1.82–1.75(m,2H),1.67–1.57(m,1H),1.48(s,3H),1.41(d,J＝10.7Hz,1H),1.31(s,3H),0.89(s,3H).¹³C NMR(101MHz,CDCl₃)δ170.38,156.82,136.85,133.62,131.74,130.10,128.18,126.55,124.88,123.04,85.82,77.76,53.73,51.35,46.40,44.29,41.44,39.83,39.63,38.23,35.53,28.71,27.32,27.14,27.07,26.30,25.03,24.09.

实施例26：N-(L-苯丙氨酰-L-脯氨酸硼酸)-N’-(4,5,6,7-四氢噻吩[2,3-C]并吡啶)-脲(C26)

合成方法同C10，白色固体，收率80％。熔点：142-145℃。

¹H NMR(400MHz,DMSO-d₆)δ7.30(t,J＝7.5Hz,3H),7.23(t,J＝7.3Hz,2H),7.17(d,J＝7.2Hz,1H),6.82(d,J＝5.2Hz,1H),4.46–4.39(m,1H),4.35(s,2H),3.71(t,J＝7.6Hz,1H),3.67–3.59(m,1H),3.57–3.49(m,2H),3.38(q,J＝8.5Hz,1H),2.99(dd,J＝13.9,3.8Hz,1H),2.92–2.79(m,2H),2.74–2.60(m,2H),1.98–1.73(m,3H),1.67–1.55(m,1H).¹³CNMR(101MHz,DMSO)δ170.70,157.55,139.38,133.48,133.33,129.77,128.48,126.52,125.57,123.69,54.57,46.57,44.26,41.80,36.76,27.39,27.29,24.83.

实施例27a：N-L-萘丙氨酸甲酯-N’-1,2,3,4-四氢异喹啉-脲(C27a)

合成方法同化合物C22a，白色泡沫状固体，收率77％。

¹H NMR(400MHz,CDCl₃)δ7.85–7.65(m,3H),7.57(d,J＝1.6Hz,1H),7.44(dt,J＝6.3,3.5Hz,2H),7.27–7.22(m,1H),7.16(dt,J＝7.4,3.8Hz,2H),7.13–7.09(m,1H),7.07–7.02(m,1H),5.02(d,J＝7.5Hz,1H),4.94(dt,J＝7.5,5.8Hz,1H),4.58–4.39(m,2H),3.72(s,3H),3.59(ddd,J＝12.0,6.6,5.1Hz,1H),3.49(ddd,J＝12.2,6.7,5.2Hz,1H),3.37–3.23(m,2H),2.80(q,J＝5.3Hz,2H).¹³C NMR(101MHz,CDCl₃)δ173.30,156.59,135.03,133.95,133.50,133.30,132.51,128.44,128.25,128.11,127.74,127.59,127.53,126.75,126.47,126.41,126.24,125.78,54.55,52.36,45.47,41.30,38.67,28.97.

实施例27b：N-(L-萘丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-1,2,3,4-四氢异喹啉-脲(C27b)

合成方法同C10b，白色泡沫，收率82％。

¹H NMR(400MHz,Chloroform-d)δ7.80(d,J＝9.6Hz,3H),7.73(d,J＝8.4Hz,1H),7.52(d,J＝8.3Hz,1H),7.46–7.38(m,2H),7.19–7.14(m,2H),7.13–7.05(m,2H),5.71(d,J＝8.0Hz,1H),4.90(td,J＝8.6,4.7Hz,1H),4.52(s,2H),4.39(d,J＝8.3Hz,1H),3.65(dt,J＝12.0,5.8Hz,1H),3.54(dt,J＝12.3,5.9Hz,1H),3.52–3.42(m,1H),3.24(qd,J＝13.1,6.9Hz,2H),3.06(dd,J＝10.2,7.1Hz,1H),2.89–2.69(m,2H),2.39(dq,J＝17.8,9.4Hz,2H),2.22(dt,J＝11.7,6.0Hz,1H),2.11(t,J＝5.4Hz,1H),1.93–1.82(m,1H),1.74–1.54(m,2H),1.50(s,3H),1.41(d,J＝10.7Hz,1H),1.30(s,3H),0.88(s,3H).¹³C NMR(101MHz,CDCl₃)δ170.46,156.73,135.03,134.52,133.47,133.34,132.28,128.44,128.39,127.79,127.76,127.55,126.53,126.38,126.31,125.70,125.39,85.86,77.76,77.32,53.59,51.39,46.41,45.50,41.12,40.19,39.66,38.27,35.64,29.01,28.75,27.27,27.17,27.03,26.34,24.13.

实施例27：N-(L-萘丙氨酰-L-脯氨酸硼酸)-N’-1,2,3,4-四氢异喹啉-脲(C27)

合成方法同C10，白色固体，收率68％。熔点：127-130℃。

¹H NMR(400MHz,DMSO-d₆)δ7.88–7.74(m,4H),7.56–7.39(m,3H),7.20–7.03(m,4H),4.59(dd,J＝10.4,3.8Hz,1H),4.42(s,2H),3.76(t,J＝8.3Hz,1H),3.59–3.37(m,3H),3.25–3.15(m,1H),3.06–2.96(m,1H),2.91(t,J＝8.6Hz,1H),2.77–2.60(m,2H),2.00–1.72(m,3H),1.67–1.58(m,1H).¹³C NMR(101MHz,DMSO)δ170.59,157.39,136.89,135.13,134.40,133.41,132.13,128.94,128.55,127.97,127.84,126.68,126.54,126.40,126.34,125.79,54.34,46.65,45.67,41.46,37.07,28.39,27.39,27.26.

实施例28a：N-L-色氨酸甲酯-N’-1,2,3,4-四氢异喹啉-脲(C28a)

合成方法同化合物C22a，白色固体，收率83％，熔点：60–62℃。

¹H NMR(400MHz,CDCl₃)δ8.67(s,1H),7.58–7.50(m,1H),7.32(dd,J＝8.2,0.9Hz,1H),7.19–6.89(m,7H),5.05(d,J＝7.6Hz,1H),4.87(dt,J＝7.6,5.3Hz,1H),4.38(q,J＝15.6Hz,2H),3.67(s,3H),3.52(ddd,J＝12.0,6.8,5.1Hz,1H),3.42(ddd,J＝12.2,6.7,5.1Hz,1H),3.38–3.27(m,2H),2.74(q,J＝5.6Hz,2H).¹³C NMR(101MHz,CDCl₃)δ173.59,156.89,136.29,135.02,133.22,128.38,127.86,126.69,126.40,126.37,122.95,122.17,119.54,118.54,111.53,110.11,54.73,52.31,45.41,41.16,28.93,27.98.

实施例28b：N-(L-色氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-1,2,3,4-四氢异喹啉-脲(C28b)

合成方法同C10b，白色泡沫，收率60％。

¹H NMR(400MHz,Chloroform-d)δ8.45(s,1H),7.77(d,J＝7.8Hz,1H),7.33(d,J＝7.9Hz,1H),7.20(d,J＝2.2Hz,1H),7.18–7.05(m,5H),7.04–6.98(m,1H),5.54(d,J＝7.9Hz,1H),4.96(q,J＝7.5Hz,1H),4.55–4.37(m,2H),4.34(d,J＝8.5Hz,1H),3.57(dt,J＝12.1,5.7Hz,1H),3.52–3.43(m,2H),3.24(dt,J＝14.0,6.9Hz,2H),3.16–3.06(m,1H),2.88–2.67(m,2H),2.63(q,J＝8.5Hz,1H),2.41–2.29(m,1H),2.20(dq,J＝10.8,5.3,4.1Hz,1H),2.06(t,J＝5.1Hz,1H),1.98–1.85(m,3H),1.77–1.69(m,2H),1.68–1.56(m,1H),1.45(s,3H),1.39(d,J＝11.1Hz,1H),1.29(s,3H),0.85(s,3H).¹³C NMR(101MHz,CDCl₃)δ171.06,156.86,135.98,135.06,133.34,128.31,128.01,126.48,126.35,126.26,123.83,121.77,119.44,118.87,111.04,110.65,85.75,77.70,77.29,52.46,51.40,46.39,45.40,41.04,39.61,38.26,35.61,29.07,29.00,28.73,27.29,27.15,26.30,24.09.

实施例28：N-(L-色氨酰-L-脯氨酸硼酸)-N’-1,2,3,4-四氢异喹啉-脲(C28)

合成方法同C10，白色固体，收率80％。熔点：165-168℃。

¹H NMR(400MHz,DMSO-d₆)δ10.76(s,1H),7.63(d,J＝7.8Hz,1H),7.36(dd,J＝8.2,5.1Hz,1H),7.27(s,1H),7.27–7.14(m,4H),7.13–7.03(m,2H),6.99(t,J＝7.4Hz,1H),4.56(dd,J＝9.6,4.2Hz,1H),4.48–4.33(m,2H),3.52(dt,J＝12.1,5.3Hz,1H),3.44(dt,J＝13.9,5.9Hz,2H),3.17(dd,J＝14.6,3.8Hz,1H),3.04–2.87(m,2H),2.81–2.62(m,3H),2.02–1.71(m,3H),1.64(qd,J＝10.4,6.1Hz,1H).¹³C NMR(101MHz,DMSO)δ171.23,157.44,136.42,135.18,134.25,128.89,127.81,126.76,126.55,126.46,124.45,121.32,118.83,118.55,111.86,111.17,53.52,48.23,46.74,45.55,41.38,28.47,27.37,27.28,26.92.

实施例29a：N-L-苯丙氨酸甲酯-N’-吗啉-脲(C29a)

合成方法同化合物C22a，无色油状物，收率75％。

¹H NMR(400MHz,Chloroform-d)δ7.26(dq,J＝14.0,6.9Hz,3H),7.10(d,J＝7.3Hz,2H),4.90(d,J＝7.6Hz,1H),4.79(q,J＝6.3Hz,1H),3.72(s,3H),3.64(t,J＝5.0Hz,4H),3.38–3.22(m,4H),3.17–3.04(m,2H).¹³C NMR(101MHz,CDCl₃)δ173.02,156.68,136.21,129.25,128.50,127.03,66.40,54.33,52.17,43.97,38.31.

实施例29b：N-(L-苯丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-吗啉-脲(C29b)

合成方法同C10b，白色泡沫，收率74％。

¹H NMR(400MHz,Chloroform-d)δ7.34–7.30(m,2H),7.28–7.20(m,3H),5.48(d,J＝7.9Hz,1H),4.76(td,J＝8.2,5.4Hz,1H),4.36(dd,J＝8.7,1.9Hz,1H),3.64(t,J＝4.9Hz,4H),3.48(dt,J＝10.7,5.7Hz,1H),3.40–3.25(m,4H),3.12–2.94(m,3H),2.48(q,J＝8.2Hz,1H),2.44–2.33(m,1H),2.24–2.18(m,1H),2.08(t,J＝5.4Hz,1H),1.99–1.87(m,3H),1.81–1.73(m,2H),1.69–1.54(m,1H),1.46(s,3H),1.38(d,J＝10.8Hz,1H),1.30(s,3H),0.87(s,3H).¹³C NMR(101MHz,CDCl₃)δ170.24,156.90,136.81,130.23,128.31,126.73,85.98,77.90,66.60,53.55,51.47,46.52,44.06,39.98,39.74,38.37,35.65,28.80,27.42,27.26,27.20,26.41,24.21.

实施例29：N-(L-苯丙氨酰-L-脯氨酸硼酸)-N’-吗啉-脲(C29)

合成方法同C10，白色固体，收率77％。熔点：143-146℃。

¹H NMR(400MHz,DMSO-d₆)δ7.32–7.22(m,4H),7.22–7.15(m,1H),4.43(dd,J＝10.2,4.1Hz,1H),3.71(td,J＝9.6,8.8,3.1Hz,1H),3.52–3.41(m,4H),3.37(q,J＝9.1Hz,1H),3.30–3.15(m,5H),2.99(dd,J＝13.9,4.0Hz,1H),2.89(dd,J＝10.0,7.0Hz,1H),2.80(dd,J＝13.8,10.2Hz,1H),2.02–1.70(m,3H),1.68–1.54(m,1H).¹³C NMR(101MHz,DMSO)δ170.63,157.73,139.23,129.78,128.49,126.56,66.32,54.37,46.59,44.31,36.85,27.38,27.26.

实施例30a：N-(L-苯丙氨酰-L-丙氨酸甲酯)-N’-1,2,3,4-四氢喹啉-脲(C30a)

将羧酸C22a-OH(1.68g,5mmol)与HOBt(0.75g,5.5mmol)混悬于20mL DCM中，而后加入EDCI(1.15g,6mmol)活化30分钟，再加入L-丙氨酸甲酯盐酸盐(0.7g,5mmol)反应过夜，反应液经柠檬酸、碳酸氢钠洗后，无水硫酸钠干燥，柱层析后得到白色固体，收率52％。

¹H NMR(400MHz,Chloroform-d)δ7.28–7.16(m,7H),7.13(d,J＝4.7Hz,1H),7.11–7.04(m,1H),6.90(d,J＝6.8Hz,1H),5.30(d,J＝7.4Hz,1H),4.69(q,J＝7.0Hz,1H),4.48(d,J＝8.1Hz,2H),3.71(s,3H),3.60(dt,J＝11.8,5.8Hz,1H),3.50(dt,J＝12.2,5.6Hz,1H),3.11(h,J＝6.8Hz,2H),2.80(s,3H),1.34(d,J＝7.2Hz,3H).¹³C NMR(101MHz,CDCl₃)δ172.93,171.88,156.87,137.00,134.92,133.20,129.45,128.51,128.36,126.84,126.69,126.41,126.33,55.58,52.39,48.21,45.42,41.26,38.84,38.62,28.90,18.00.

实施例30b：N-(L-苯丙氨酰-L-丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-1,2,3,4-四氢喹啉-脲(C30b)

合成方法同C10b，白色泡沫，收率52％。

¹H NMR(400MHz,Chloroform-d)δ7.28–7.20(m,3H),7.20–7.15(m,4H),7.14–7.05(m,2H),6.89(d,J＝7.3Hz,1H),5.04(d,J＝7.4Hz,1H),4.64(dt,J＝10.9,6.7Hz,2H),4.57–4.37(m,2H),4.28(dd,J＝8.8,2.1Hz,1H),3.67–3.54(m,2H),3.53–3.36(m,2H),3.19(dd,J＝9.2,7.2Hz,1H),3.16–3.02(m,2H),2.81(q,J＝6.3Hz,2H),2.32(ddt,J＝13.9,9.1,2.5Hz,1H),2.21–2.09(m,1H),2.09–2.02(m,1H),2.03–1.95(m,2H),1.96(s,2H),1.93–1.77(m,3H),1.40(s,3H),1.30(d,J＝6.5Hz,3H),1.27(s,3H),0.83(s,3H).¹³C NMR(101MHz,CDCl₃)δ171.10,169.76,156.68,136.76,135.00,133.26,129.42,128.49,128.31,126.84,126.63,126.35,85.84,77.87,55.34,51.28,46.71,46.44,45.41,41.24,39.58,38.80,38.21,35.50,28.93,28.55,27.29,27.16,27.10,26.19,24.03,17.86.

实施例30：N-(L-苯丙氨酰-L-丙氨酰-L-脯氨酸硼酸)-N’-1,2,3,4-四氢喹啉-脲(C30)

合成方法同C10b，白色固体，收率81％。熔点：145-148℃。

¹H NMR(400MHz,DMSO-d₆)δ8.09(d,J＝7.5Hz,1H),7.28(d,J＝7.0Hz,2H),7.21(t,J＝7.4Hz,2H),7.17–7.07(m,5H),6.57(d,J＝8.4Hz,1H),4.56–4.33(m,4H),3.61–3.51(m,2H),3.51–3.41(m,1H),3.36(q,J＝9.2Hz,1H),3.01(dd,J＝13.6,4.0Hz,1H),2.92–2.78(m,2H),2.75–2.60(m,2H),1.99–1.65(m,3H),1.64–1.53(m,1H),1.21(d,J＝6.8Hz,3H).¹³CNMR(101MHz,DMSO)δ172.24,169.64,157.33,139.00,135.19,134.43,129.67,128.94,128.38,126.68,126.56,126.53,126.42,56.27,46.54,45.68,41.57,39.82,37.83,28.46,27.32,27.22,17.57.

实施例31a：N-(L-苯丙氨酰-L-亮氨酸甲酯)-N’-1,2,3,4-四氢喹啉-脲(C31a)

合成方法同化合物C30a，白色固体，收率64％。

¹H NMR(400MHz,Chloroform-d)δ7.24–7.08(m,9H),6.85(d,J＝7.9Hz,1H),4.85(dt,J＝20.4,7.3Hz,2H),4.52(s,2H),4.41(td,J＝8.5,5.6Hz,1H),3.70(s,3H),3.63(ddd,J＝11.8,6.5,5.1Hz,1H),3.53(ddd,J＝12.2,6.7,5.3Hz,1H),3.14(dd,J＝13.9,5.8Hz,1H),3.04(dd,J＝13.9,6.8Hz,1H),2.86(td,J＝6.1,3.1Hz,2H),1.75–1.58(m,2H),1.58–1.44(m,1H),0.91(dd,J＝6.3,4.0Hz,6H).¹³C NMR(101MHz,CDCl₃)δ172.95,171.79,157.04,135.89,134.99,133.25,129.24,128.45,128.36,126.96,126.75,126.47,126.36,53.23,52.64,52.27,45.42,41.32,41.27,37.96,29.03,24.77,22.93,22.26.

实施例31b：N-(L-苯丙氨酰-L-亮氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-1,2,3,4-四氢喹啉-脲(C31b)

合成方法同C10b，白色泡沫，收率47％。

¹H NMR(400MHz,Chloroform-d)δ7.30–7.05(m,9H),6.85(d,J＝8.2Hz,1H),5.20(d,J＝7.2Hz,1H),4.71(dq,J＝13.8,7.4,6.9Hz,2H),4.48(q,J＝15.8Hz,2H),4.27(d,J＝8.5Hz,1H),3.74(t,J＝8.7Hz,1H),3.60(dt,J＝12.6,5.8Hz,1H),3.51(p,J＝6.2Hz,1H),3.42(q,J＝9.2,8.6Hz,1H),3.22–3.13(m,1H),3.15–2.95(m,2H),2.81(p,J＝7.8,6.3Hz,2H),2.38–2.25(m,1H),2.17–2.05(m,3H),1.99–1.84(m,4H),1.82–1.72(m,1H),1.68–1.42(m,3H),1.39(s,3H),1.33(d,J＝10.7Hz,1H),1.27(s,3H),0.89(t,J＝6.7Hz,6H),0.83(s,3H).¹³C NMR(101MHz,CDCl₃)δ171.37,169.74,156.65,136.79,134.99,133.28,129.49,128.36,128.33,126.74,126.60,126.35,85.76,77.84,55.17,51.24,48.80,46.55,45.40,41.59,41.20,39.55,38.64,38.19,35.47,28.95,28.62,27.42,27.25,27.12,26.20,24.33,24.07,23.12,22.34.

实施例31：N-(L-苯丙氨酰-L-亮氨酰-L-脯氨酸硼酸)-N’-1,2,3,4-四氢喹啉-脲(C31)

合成方法同C10，白色固体，收率81％。熔点：141-144℃。

¹H NMR(400MHz,DMSO-d₆)δ8.00(d,J＝8.2Hz,1H),7.33–7.06(m,9H),6.57(d,J＝8.4Hz,1H),4.58–4.51(m,1H),4.50–4.35(m,3H),3.67–3.59(m,1H),3.49(dt,J＝10.2,6.6Hz,2H),3.36(q,J＝8.9Hz,1H),3.01(dd,J＝13.6,3.9Hz,1H),2.91–2.78(m,2H),2.75–2.61(m,2H),1.97–1.68(m,3H),1.65–1.38(m,4H),0.86(d,J＝5.2Hz,6H).¹³C NMR(101MHz,DMSO)δ172.49,169.63,157.32,138.96,135.17,134.39,129.70,128.94,128.37,126.68,126.55,126.42,56.02,48.87,48.07,46.63,45.66,41.56,40.81,37.68,28.46,27.34,27.24,24.39,23.71,22.15.

实施例32a：N-(L-苯丙氨酰-L-异亮氨酸甲酯)-N’-1,2,3,4-四氢喹啉-脲(C32a)

合成方法同化合物C30a，白色固体，收率70％。

¹H NMR(400MHz,Chloroform-d)δ7.29–7.06(m,9H),6.61(d,J＝8.1Hz,1H),5.23(d,J＝7.3Hz,1H),4.67(q,J＝7.0Hz,1H),4.57–4.39(m,3H),3.69(s,3H),3.60(dt,J＝11.9,5.8Hz,1H),3.52(dt,J＝12.2,5.8Hz,1H),3.15(dd,J＝13.8,6.4Hz,1H),3.06(dd,J＝13.8,7.5Hz,1H),2.82(q,J＝5.5Hz,2H),1.84–1.74(m,1H),1.33(dtd,J＝14.6,7.4,4.7Hz,1H),1.15–0.99(m,1H),0.89–0.77(m,6H).¹³C NMR(101MHz,CDCl₃)δ171.99,171.82,156.99,137.18,135.04,133.33,129.54,128.71,128.49,126.97,126.82,126.54,126.45,56.85,55.78,52.11,45.58,41.41,38.82,37.79,29.04,25.25,15.49,11.62.

实施例32b：N-(L-苯丙氨酰-L-异亮氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-1,2,3,4-四氢喹啉-脲(C32b)

合成方法同C10b，白色泡沫，收率62％。

¹H NMR(400MHz,Chloroform-d)δ7.28–7.04(m,9H),6.61(d,J＝9.1Hz,1H),5.10(d,J＝7.3Hz,1H),4.66(q,J＝6.2Hz,1H),4.48(q,J＝15.9Hz,2H),4.26(dd,J＝8.8,2.0Hz,1H),3.80–3.69(m,1H),3.60(dt,J＝12.0,5.8Hz,1H),3.56–3.40(m,2H),3.19(dd,J＝10.0,7.1Hz,1H),3.15–3.01(m,2H),2.82(q,J＝5.7Hz,2H),2.37–2.25(m,1H),2.18–2.02(m,3H),1.98(dd,J＝12.5,7.3Hz,3H),1.92–1.82(m,2H),1.83–1.71(m,2H),1.56–1.46(m,1H),1.39(s,3H),1.36(d,J＝10.9Hz,1H),1.27(s,3H),1.07–0.98(m,1H),0.90(d,J＝6.8Hz,3H),0.82(q,J＝7.7,5.6Hz,6H).¹³C NMR(101MHz,CDCl₃)δ171.37,169.30,156.62,136.70,135.00,133.28,129.47,129.38,128.37,128.34,126.76,126.62,126.35,85.85,77.86,55.23,54.77,51.24,46.93,45.42,41.20,39.58,38.56,38.20,37.68,35.45,28.96,28.66,27.40,27.30,27.13,26.23,24.44,24.06,14.92,11.08.

实施例32：N-(L-苯丙氨酰-L-异亮氨酰-L-脯氨酸硼酸)-N’-1,2,3,4-四氢喹啉-脲(C32)

合成方法同C10，白色固体，收率75％。熔点：142-145℃。

¹H NMR(400MHz,DMSO-d₆)δ7.95(d,J＝8.8Hz,1H),7.26–7.07(m,9H),6.55(d,J＝8.3Hz,1H),4.43(d,J＝6.5Hz,2H),4.33(t,J＝8.7Hz,1H),3.71(t,J＝7.5Hz,1H),3.49(dd,J＝10.8,5.1Hz,2H),3.43–3.32(m,1H),2.97(dd,J＝13.4,4.2Hz,1H),2.91–2.79(m,2H),2.75–2.61(m,2H),1.99–1.81(m,2H),1.81–1.55(m,3H),1.55–1.44(m,1H),1.07–0.95(m,1H),0.86(d,J＝6.7Hz,3H),0.77(t,J＝7.4Hz,3H).¹³C NMR(101MHz,DMSO)δ172.30,169.18,157.31,138.90,135.17,134.42,129.73,128.95,128.35,126.67,126.56,126.42,55.84,54.79,47.06,45.68,41.57,40.08,37.53,36.78,28.45,27.46,27.21,24.50,15.46,11.27.

实施例33a：N-(L-苯丙氨酰-L-苯丙氨酸甲酯)-N’-1,2,3,4-四氢喹啉-脲(C33a)

合成方法同化合物C30a，白色固体，收率65％。

¹H NMR(400MHz,Chloroform-d)δ7.27–7.06(m,12H),6.98(d,J＝6.6Hz,2H),6.82(d,J＝7.5Hz,1H),5.15(d,J＝7.4Hz,1H),4.81–4.71(m,1H),4.65(q,J＝6.9Hz,1H),4.43(s,2H),3.66(s,3H),3.54(dt,J＝11.8,5.8Hz,1H),3.45(dt,J＝12.1,5.8Hz,1H),3.15–2.92(m,4H),2.79(d,J＝4.2Hz,2H).¹³C NMR(101MHz,CDCl₃)δ171.75,171.48,156.81,136.88,135.81,134.90,133.12,129.48,129.19,128.56,128.45,128.35,126.96,126.88,126.75,126.47,126.35,55.38,53.45,52.30,45.37,41.27,38.34,37.90,28.90.

实施例33b：N-(L-苯丙氨酰-L-苯丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-1,2,3,4-四氢喹啉-脲(C33b)

合成方法同C10b，白色泡沫，收率50％。

¹H NMR(400MHz,Chloroform-d)δ7.29–7.12(m,14H),7.10(q,J＝4.9Hz,1H),6.80(d,J＝7.9Hz,1H),4.92(d,J＝7.5Hz,1H),4.76(q,J＝8.1Hz,1H),4.63(q,J＝6.5Hz,1H),4.53–4.37(m,2H),4.34(d,J＝8.9Hz,1H),3.60–3.53(m,1H),3.46(dt,J＝12.2,6.5Hz,1H),3.37(dt,J＝10.9,6.1Hz,1H),3.14–3.04(m,3H),2.97(dd,J＝10.0,7.0Hz,2H),2.83(d,J＝5.3Hz,1H),2.56(q,J＝8.2Hz,1H),2.36(dt,J＝8.5,5.1Hz,1H),2.20(dt,J＝10.4,6.1Hz,1H),2.06(t,J＝5.4Hz,1H),1.96–1.91(m,2H),1.83–1.74(m,2H),1.68–1.60(m,1H),1.44(s,3H),1.37(d,J＝10.8Hz,1H),1.30(s,3H),0.86(s,3H).¹³C NMR(101MHz,CDCl₃)δ171.03,168.57,156.61,136.78,136.38,135.01,133.24,130.03,129.48,128.62,128.50,128.33,128.18,126.84,126.64,126.39,126.35,85.87,77.78,55.26,52.31,51.36,46.40,45.38,41.21,39.61,39.13,38.47,38.25,35.51,28.95,28.64,27.22,27.13,26.27,24.08.

实施例33：N-(L-苯丙氨酰-L-苯丙氨酰-L-脯氨酸硼酸)-N’-1,2,3,4-四氢喹啉-脲(C33)

合成方法同C10，白色固体，收率75％。熔点：135-138℃。

¹H NMR(400MHz,DMSO-d₆)δ7.27(d,J＝7.3Hz,2H),7.23–7.07(m,12H),4.75–4.62(m,1H),4.49–4.39(m,2H),4.38–4.32(m,1H),3.52–3.42(m,2H),3.29(q,J＝9.2,8.6Hz,1H),3.07(dd,J＝13.9,4.5Hz,1H),2.96–2.87(m,2H),2.82–2.61(m,4H),1.95–1.68(m,3H),1.66–1.49(m,1H).¹³C NMR(101MHz,DMSO)δ172.32,168.98,157.21,138.86,138.27,135.22,135.20,134.38,129.84,129.78,129.72,129.66,128.91,128.51,128.47,128.38,126.72,126.66,126.57,126.46,56.03,52.29,46.76,45.63,41.54,37.60,37.48,28.49,27.37,27.14.

实施例34a：N-(L-苯丙氨酰-L-萘基丙氨酸甲酯)-N’-1,2,3,4-四氢喹啉-脲(C34a)

合成方法同化合物C30a，白色固体，收率77％。

¹H NMR(400MHz,Chloroform-d)δ7.72–7.66(m,1H),7.63(t,J＝7.8Hz,2H),7.42(s,1H),7.36(dd,J＝6.2,3.2Hz,2H),7.25–7.06(m,9H),7.03–6.93(m,2H),5.05(d,J＝7.4Hz,1H),4.88(q,J＝6.5Hz,1H),4.69(q,J＝6.8Hz,1H),4.32(d,J＝3.6Hz,2H),3.66(s,3H),3.34(ddq,J＝24.0,12.1,5.8Hz,2H),3.22(dd,J＝13.8,5.8Hz,1H),3.13(dt,J＝13.4,6.5Hz,2H),3.02(dd,J＝13.7,6.9Hz,1H),2.67(q,J＝5.7Hz,2H).

实施例34b：N-(L-苯丙氨酰-L-萘基丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-1,2,3,4-四氢喹啉-脲(C34b)

合成方法同C10b，白色泡沫，收率70％。

¹H NMR(400MHz,Chloroform-d)δ7.78–7.72(m,2H),7.70(s,1H),7.68(d,J＝8.4Hz,1H),7.45–7.36(m,3H),7.28–7.06(m,9H),7.08–7.01(m,1H),6.91(d,J＝8.0Hz,1H),4.92(d,J＝7.6Hz,1H),4.86(dt,J＝8.3,4.2Hz,1H),4.66(q,J＝6.6Hz,1H),4.49–4.31(m,3H),3.55–3.45(m,1H),3.46–3.30(m,2H),3.21–3.01(m,5H),2.76(q,J＝5.2Hz,2H),2.53(q,J＝8.7Hz,1H),2.44–2.34(m,1H),2.19(dt,J＝10.9,6.4Hz,1H),1.96–1.90(m,2H),1.75–1.52(m,2H),1.61–1.49(m,1H),1.46(s,3H),1.38(d,J＝10.7Hz,1H),1.30(s,3H),0.87(s,3H).¹³C NMR(101MHz,CDCl₃)δ171.17,168.63,156.64,136.81,135.00,134.02,133.42,133.25,132.32,129.46,128.60,128.50,128.42,128.30,128.24,127.75,127.53,126.84,126.63,126.36,125.73,125.45,85.88,77.77,55.34,52.16,51.42,46.39,45.35,41.19,39.66,39.34,38.51,38.27,35.60,28.92,28.67,27.16,27.08,26.29,24.09.

实施例34：N-(L-苯丙氨酰-L-萘基丙氨酰-L-脯氨酸硼酸)-N’-1,2,3,4-四氢喹啉-脲(C34)

合成方法同C10，白色固体，收率75％。熔点：144-147℃。

¹H NMR(400MHz,DMSO-d₆)δ7.84–7.76(m,3H),7.72(d,J＝8.4Hz,1H),7.46–7.40(m,3H),7.22–7.07(m,9H),4.82–4.75(m,1H),4.42–4.30(m,3H),3.63–3.55(m,1H),3.43(t,J＝6.0Hz,2H),3.33(q,J＝8.4Hz,1H),3.26(dd,J＝14.1,4.6Hz,1H),2.98–2.84(m,3H),2.81–2.75(m,1H),2.72–2.59(m,2H),1.91–1.70(m,3H),1.61(ddd,J＝9.8,6.8,3.1Hz,1H).¹³C NMR(101MHz,DMSO)δ172.32,172.24,168.85,157.23,138.88,135.98,135.22,134.39,133.46,132.23,129.67,129.61,128.92,128.57,128.37,128.04,127.97,127.86,127.80,126.72,126.59,126.52,126.46,126.21,125.77,56.14,52.15,46.81,45.61,41.53,37.57,28.50,27.39,27.15.

实施例35a：N-(L-苯丙氨酰-L-丝氨酸甲酯)-N’-1,2,3,4-四氢喹啉-脲(C35a)

合成方法同化合物C30a，白色固体，收率43％。

¹H NMR(400MHz,Chloroform-d)δ7.62(d,J＝7.9Hz,1H),7.21–7.12(m,7H),7.11–7.07(m,1H),7.05–7.01(m,1H),5.64(d,J＝7.4Hz,1H),4.73–4.58(m,2H),4.48–4.34(m,2H),4.22(s,1H),3.91–3.85(m,2H),3.71(s,3H),3.55(dt,J＝11.8,5.6Hz,1H),3.40(ddd,J＝12.3,7.1,5.0Hz,1H),3.15(dd,J＝13.8,6.0Hz,1H),3.03(dd,J＝13.8,8.2Hz,1H),2.83–2.65(m,J＝5.5Hz,2H),2.37(s,1H).¹³C NMR(101MHz,CDCl₃)δ173.13,170.65,157.44,137.05,134.82,133.11,129.33,128.43,128.32,126.76,126.69,126.40,126.31,62.53,56.32,55.05,52.48,45.41,41.36,38.38,28.78.

实施例35b：N-(L-苯丙氨酰-L-丝氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-1,2,3,4-四氢喹啉-脲(C35b)

合成方法同C10b，白色泡沫，收率51％。

¹H NMR(400MHz,Chloroform-d)δ7.27–7.15(m,7H),7.12(d,J＝4.7Hz,1H),7.08(q,J＝5.0,4.6Hz,1H),7.03(d,J＝7.9Hz,1H),5.10(d,J＝7.3Hz,1H),4.85–4.75(m,1H),4.65(q,J＝6.8Hz,1H),4.56–4.36(m,2H),4.29(dd,J＝8.8,2.1Hz,1H),3.81(dd,J＝11.3,4.8Hz,1H),3.71–3.53(m,4H),3.47(dt,J＝12.1,5.9Hz,1H),3.33–3.24(m,1H),3.10(d,J＝6.6Hz,2H),2.80(q,J＝5.9Hz,2H),2.35–2.28(m,1H),2.20–2.03(m,3H),1.99(t,J＝5.4Hz,1H),1.93–1.73(m,4H),1.38(s,3H),1.30–1.23(m,4H),0.82(s,3H).¹³C NMR(101MHz,CDCl₃)δ172.05,168.23,156.84,136.72,134.94,133.15,129.33,128.57,128.30,126.91,126.67,126.38,126.33,86.31,78.13,63.76,55.69,52.25,51.13,47.00,45.41,41.28,39.51,38.54,38.27,35.37,28.89,28.55,27.21,27.02,26.98,26.12,24.00.

实施例35：N-(L-苯丙氨酰-L-丝氨酰-L-脯氨酸硼酸)-N’-1,2,3,4-四氢喹啉-脲(C35)

合成方法同C10，白色固体，收率59％。熔点：177-179℃。

¹H NMR(400MHz,DMSO-d₆)δ7.35–7.03(m,9H),4.57(t,J＝6.4Hz,1H),4.50–4.32(m,3H),3.62(s,2H),3.57–3.42(m,4H),3.01(dd,J＝13.6,4.0Hz,1H),2.98–2.89(m,1H),2.83(dd,J＝13.4,10.6Hz,1H),2.74–2.60(m,2H),1.97–1.66(m,3H),1.62–1.54(m,1H).¹³CNMR(101MHz,DMSO)δ172.76,168.13,157.33,138.85,135.18,134.33,129.67,128.93,128.40,126.73,126.56,126.45,61.81,56.15,53.09,47.04,45.65,41.55,37.82,28.43,27.36,27.06.

实施例36a：N-(L-苯丙氨酰-L-酪氨酸甲酯)-N’-1,2,3,4-四氢喹啉-脲(C36a)

合成方法同化合物C30a，白色固体，收率77％。¹H NMR(400MHz,Chloroform-d)δ7.22–7.13(m,7H),7.11–7.08(m,1H),7.06–7.01(m,1H),6.87(d,J＝7.9Hz,1H),6.82(d,J＝8.3Hz,2H),6.63(d,J＝8.3Hz,2H),5.25(d,J＝7.8Hz,1H),4.74(q,J＝6.3Hz,1H),4.67(q,J＝7.1Hz,1H),4.42(q,J＝15.6Hz,2H),3.66(s,3H),3.54(dt,J＝11.9,5.7Hz,1H),3.42(dt,J＝12.2,5.9Hz,1H),3.03(d,J＝6.9Hz,2H),2.98(dd,J＝14.0,5.4Hz,1H),2.88(dd,J＝14.0,6.5Hz,1H),2.76(h,J＝10.3Hz,2H).¹³C NMR(101MHz,CDCl₃)δ172.02,171.58,156.90,155.68,136.68,134.91,133.09,130.34,129.41,128.51,128.31,126.86,126.75,126.45,126.35,115.55,55.43,53.66,52.29,45.37,41.33,38.65,37.10,28.82.

实施例36b：N-(L-苯丙氨酰-L-酪氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-1,2,3,4-四氢喹啉-脲(C36b)

合成方法同C10b，白色泡沫，收率77％。

¹H NMR(400MHz,Chloroform-d)δ7.59(s,1H),7.25–7.02(m,12H),6.94(d,J＝8.1Hz,1H),6.68(d,J＝8.3Hz,2H),5.05(d,J＝7.5Hz,1H),4.73(q,J＝7.6Hz,1H),4.62(q,J＝6.8Hz,1H),4.52–4.32(m,2H),4.32(d,J＝7.8Hz,1H),3.54(dd,J＝12.3,5.9Hz,1H),3.48–3.36(m,2H),3.16–3.07(m,1H),3.04(d,J＝6.8Hz,2H),2.95–2.70(m,5H),2.40–2.29(m,1H),2.04(t,J＝5.3Hz,1H),1.96(dd,J＝10.8,4.9Hz,1H),1.94–1.74(m,4H),1.71–1.62(m,1H),1.42(s,3H),1.33(d,J＝10.8Hz,1H),1.28(s,3H),0.84(s,3H).¹³C NMR(101MHz,CDCl₃)δ171.45,168.89,156.73,155.48,136.66,134.98,133.18,131.01,129.41,128.57,128.47,128.28,127.47,126.82,126.66,126.36,115.27,85.89,77.79,55.39,52.51,51.37,46.50,45.35,41.24,39.61,38.50,38.23,38.06,35.50,28.87,28.61,27.13,26.26,24.04.

实施例36：N-(L-苯丙氨酰-L-酪氨酰-L-脯氨酸硼酸)-N’-1,2,3,4-四氢喹啉-脲(C36)

合成方法同C10，白色固体，收率70％。熔点：235-238℃。

¹H NMR(400MHz,DMSO-d₆)δ7.22–7.18(m,3H),7.17–7.09(m,6H),7.07(d,J＝8.3Hz,2H),6.63(d,J＝8.3Hz,2H),4.57(dd,J＝8.6,5.1Hz,1H),4.51–4.28(m,3H),3.59(s,1H),3.47(q,J＝5.7Hz,2H),3.24(q,J＝9.2,8.8Hz,1H),3.00–2.86(m,3H),2.85–2.73(m,2H),3.72–3.61(m,3H),1.93–1.67(m,3H),1.59(ddd,J＝19.7,9.5,4.0Hz,1H).¹³C NMR(101MHz,DMSO)δ172.21,169.19,157.25,155.99,138.88,135.21,134.38,134.34,130.73,129.73,129.67,128.91,128.41,128.39,126.73,126.57,126.46,115.29,56.05,52.58,48.24,46.75,45.64,41.55,37.60,36.72,28.49,27.36,27.13.

实施例37a：N-Cbz-L-萘基丙氨酸甲酯(C37a)

将L-萘基丙氨酸甲酯盐酸盐(0.53g，2mmol)加入8mL甲苯中冰浴，随后加入氯甲酸苄酯(0.35mL，2.4mmol)，剧烈搅拌下滴入碳酸氢钠溶液(1N，2.5mL)，反应过夜，后加入饱和食盐水搅拌，分液，水层用DCM萃取三次后合并，有机相用柠檬酸、碳酸氢钠洗后，无水硫酸钠干燥，蒸除溶剂得到无色油状物0.65g，收率90％。

¹H NMR(400MHz,Chloroform-d)δ7.86–7.68(m,3H),7.55(s,1H),7.49–7.42(m,2H),7.30–7.18(m,6H),5.28(d,J＝7.8Hz,1H),5.14–5.02(m,2H),4.75(q,J＝6.3Hz,1H),3.71(s,3H),3.26(qd,J＝13.9,5.9Hz,2H).¹³C NMR(101MHz,CDCl₃)δ172.05,155.68,136.23,133.42,133.27,132.51,128.52,128.34,128.18,128.10,128.07,127.68,127.64,127.38,127.22,126.20,125.81,66.99,54.86,52.40,38.44.

实施例37b：N-Cbz-L-萘丙氨酰-L-脯氨酸硼酸蒎烷二醇酯(C37b)

合成方法同C10b，白色泡沫，收率77％。直接投入下一步反应。

实施例37：N-Cbz-L-萘丙氨酰-L-脯氨酸硼酸(C37)

合成方法同C10，白色固体，收率80％。熔点：105-108℃。

¹H NMR(400MHz,DMSO-d₆)δ7.87(d,J＝7.4Hz,1H),7.85–7.78(m,3H),7.55–7.42(m,3H),7.28–7.12(m,5H),4.95–4.80(m,2H),4.51(dd,J＝10.5,3.5Hz,1H),3.67(t,J＝8.7Hz,1H),3.47(q,J＝8.5Hz,1H),3.20(dd,J＝13.8,3.4Hz,1H),2.97–2.83(m,2H),1.99–1.73(m,3H),1.69–1.52(m,1H).¹³C NMR(101MHz,DMSO)δ169.41,156.27,137.39,136.43,133.43,132.23,128.68,128.36,128.09,128.00,127.93,127.89,127.77,126.42,125.88,65.62,54.50,46.76,37.10,27.38,27.28.

实施例38a：N-L-萘基丙氨酸甲酯-N’-(N-甲基)-苄胺-脲(C38a)

合成方法同化合物C22a，无色油状物，收率82％。

¹H NMR(400MHz,Chloroform-d)δ7.84–7.65(m,3H),7.56–7.40(m,3H),7.28–7.07(m,6H),4.90(dq,J＝12.8,7.5,7.0Hz,2H),4.51–4.36(m,2H),3.72(s,3H),3.32(dd,J＝13.7,5.2Hz,1H),3.24(dd,J＝13.7,5.6Hz,1H),2.80(s,3H).¹³C NMR(101MHz,CDCl₃)δ173.15,157.41,137.47,133.83,133.42,132.44,128.63,128.20,127.98,127.67,127.56,127.34,127.32,127.17,126.13,125.70,54.50,52.28,52.15,38.53,34.23.

实施例38b：N-(L-萘丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-(N-甲基)-苄胺-脲(C38b)

合成方法同C10b，白色泡沫，收率64％。

¹H NMR(400MHz,Chloroform-d)δ7.84–7.75(m,3H),7.74(d,J＝8.4Hz,1H),7.49(d,J＝8.4Hz,1H),7.47–7.40(m,2H),7.32–7.18(m,4H),7.15(d,J＝6.9Hz,2H),5.44(d,J＝7.9Hz,1H),4.93(q,J＝7.6Hz,1H),4.57–4.38(m,2H),4.38(d,J＝8.7Hz,1H),3.52(t,J＝8.7Hz,1H),3.27–3.10(m,2H),3.13–3.04(m,1H),2.80(s,3H),2.54(q,J＝8.7Hz,1H),2.41(t,J＝11.5Hz,1H),2.20(d,J＝7.8Hz,1H),2.10(t,J＝5.0Hz,1H),1.96(d,J＝12.4Hz,2H),1.78–1.60(m,3H),1.62–1.50(m,1H),1.48(s,3H),1.39(d,J＝10.4Hz,1H),1.31(s,3H),0.89(s,3H).¹³C NMR(101MHz,CDCl₃)δ170.34,157.47,137.83,134.44,133.45,132.29,128.55,128.46,128.40,127.78,127.72,127.56,127.35,127.15,125.70,125.38,53.40,51.98,51.39,46.42,40.03,39.65,38.27,35.61,33.96,28.69,27.22,27.15,27.07,26.30,24.11.

实施例38：N-(L-萘丙氨酰-L-脯氨酸硼酸)-N’-(N-甲基)-苄胺-脲(C38)

合成方法同C10，白色固体，收率66％。熔点：121-124℃。

¹H NMR(400MHz,DMSO-d₆)δ7.91–7.85(m,1H),7.85–7.77(m,3H),7.57–7.42(m,3H),7.18–7.06(m,3H),6.94(d,J＝7.3Hz,2H),4.69(dd,J＝10.1,4.1Hz,1H),4.45–4.17(m,2H),3.75(t,J＝7.4Hz,1H),3.46(q,J＝8.1Hz,1H),3.21(dd,J＝12.4,2.9Hz,1H),3.06–2.88(m,2H),2.67(s,3H),1.99–1.74(m,3H),1.71–1.56(m,1H).¹³C NMR(101MHz,DMSO)δ170.48,157.88,138.75,136.82,133.45,132.18,128.65,128.63,128.02,127.91,127.82,127.51,127.18,126.33,125.79,54.16,51.44,46.72,37.24,34.09,27.40,27.29.

实施例39a：N-L-萘基丙氨酸甲酯-N’-(N-甲基-4-氟)-苄胺-脲(C39a)

合成方法同化合物C22a，无色油状物，收率86％。

¹H NMR(400MHz,Chloroform-d)δ7.84–7.78(m,1H),7.73(dd,J＝12.1,6.9Hz,2H),7.54(s,1H),7.46(dd,J＝6.7,3.2Hz,2H),7.21(d,J＝8.4Hz,1H),7.07(t,J＝6.7Hz,2H),6.88(t,J＝8.4Hz,2H),4.96–4.82(m,2H),4.48–4.31(m,2H),3.74(s,3H),3.33(dd,J＝13.9,5.5Hz,1H),3.23(dd,J＝13.9,6.1Hz,1H),2.77(s,3H).¹³C NMR(101MHz,CDCl₃)δ173.15,163.27,160.83,157.32,133.79,133.40,133.23,132.44,128.88,128.80,128.22,127.96,127.69,127.51,127.30,126.20,125.76,115.55,115.33,54.45,52.31,51.44,38.51,34.07.

实施例39b：N-(L-萘丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-(N-甲基-4-氟)-苄胺-脲(C39b)

合成方法同C10b，白色泡沫，收率60％。

¹H NMR(400MHz,Chloroform-d)δ7.82(dd,J＝10.7,6.4Hz,3H),7.76(d,J＝8.4Hz,1H),7.51(d,J＝9.3Hz,1H),7.49–7.43(m,2H),7.11(dd,J＝8.3,5.5Hz,2H),6.92(t,J＝8.7Hz,2H),5.45(d,J＝8.1Hz,1H),4.95(td,J＝8.2,5.6Hz,1H),4.55–4.34(m,3H),3.54(ddd,J＝10.7,8.0,3.4Hz,1H),3.30–3.06(m,3H),2.80(s,3H),2.58(q,J＝9.1Hz,1H),2.43(ddd,J＝12.2,7.2,2.5Hz,1H),2.26–2.18(m,1H),2.12(t,J＝5.4Hz,1H),2.06–1.87(m,4H),1.78–1.66(m,2H),1.59(td,J＝11.4,11.0,6.3Hz,1H),1.51(s,3H),1.41(d,J＝10.8Hz,1H),1.33(s,3H),0.90(s,3H).¹³C NMR(101MHz,CDCl₃)δ170.25,163.22,160.79,157.36,134.42,133.61,133.58,133.44,132.29,129.03,128.95,128.46,128.38,127.75,127.73,127.58,125.75,125.43,115.46,115.24,85.87,77.77,53.37,51.38,51.30,46.42,40.02,39.64,38.27,35.62,33.85,28.70,27.24,27.15,27.08,26.31,24.11.

实施例39：N-(L-萘丙氨酰-L-脯氨酸硼酸)-N’-(N-甲基-4-氟)-苄胺-脲(C39)

合成方法同C10，白色固体，收率70％。熔点：131-134℃。

¹H NMR(400MHz,DMSO-d₆)δ7.95–7.87(m,1H),7.86–7.77(m,3H),7.54–7.42(m,3H),6.95(t,J＝6.9Hz,2H),6.86(t,J＝8.7Hz,2H),4.69(dd,J＝10.4,3.9Hz,1H),4.40–4.20(m,2H),3.75(t,J＝9.0Hz,1H),3.21(dd,J＝14.1,3.9Hz,1H),3.07–2.90(m,2H),2.67(s,3H),2.02–1.77(m,3H),1.72–1.59(m,1H).¹³C NMR(101MHz,DMSO)δ170.41,162.69,160.28,157.84,136.94,135.00,134.97,133.46,132.19,129.72,129.63,129.51,129.43,128.66,128.03,127.91,127.80,126.31,125.76,115.56,115.37,115.16,54.22,50.72,48.28,46.69,37.21,34.03,27.41,27.31.

实施例40a：N-L-萘基丙氨酸甲酯-N’-(N-甲基-4-甲氧基)-苄胺-脲(C40a)

合成方法同化合物C22a，无色油状物，收率86％。

¹H NMR(400MHz,Chloroform-d)δ7.83–7.76(m,1H),7.72(t,J＝8.0Hz,2H),7.53(s,1H),7.48–7.41(m,2H),7.20(d,J＝8.5Hz,1H),7.02(d,J＝8.0Hz,2H),6.72(dd,J＝8.5,2.0Hz,2H),4.91(s,2H),4.46–4.23(m,2H),3.73(s,3H),3.71(s,3H),3.35–3.27(m,1H),3.21(dd,J＝13.4,4.2Hz,1H),2.77(s,3H).¹³C NMR(101MHz,CDCl₃)δ173.22,158.86,157.41,133.92,133.43,132.43,129.48,128.49,128.18,127.98,127.68,127.57,127.38,126.12,125.68,114.00,55.25,54.52,52.26,51.56,38.51,34.05.

实施例40b：N-(L-萘丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-(N-甲基-4-甲氧基)-苄胺-脲(C40b)

合成方法同C10b，白色泡沫，收率71％。

¹H NMR(400MHz,Chloroform-d)δ7.79(d,J＝8.4Hz,3H),7.74(d,J＝8.6Hz,1H),7.50(d,J＝8.5Hz,1H),7.47–7.40(m,2H),7.26(s,1H),7.07(d,J＝8.1Hz,2H),6.77(d,J＝8.3Hz,2H),5.38(d,J＝8.3Hz,1H),4.93(q,J＝7.4Hz,1H),4.49–4.30(m,3H),3.77(s,3H),3.51(t,J＝8.5Hz,1H),3.24–3.13(m,2H),3.08(t,J＝8.8Hz,1H),2.77(s,3H),2.60–2.49(m,1H),2.41(t,J＝11.5Hz,1H),2.20(q,J＝7.4Hz,1H),2.14–2.06(m,1H),1.96(d,J＝12.9Hz,2H),1.72–1.51(m,3H),1.48(s,3H),1.40(d,J＝10.7Hz,1H),1.31(s,3H),0.88(s,3H).¹³C NMR(101MHz,CDCl₃)δ170.29,158.77,157.40,134.52,133.46,132.29,129.88,128.69,128.46,127.79,127.70,127.56,125.68,125.35,113.92,85.83,77.75,55.27,53.35,51.40,46.39,40.08,39.66,38.26,35.62,33.73,28.71,27.22,27.16,27.08,26.31,24.11.

实施例40：N-(L-萘丙氨酰-L-脯氨酸硼酸)-N’-(N-甲基-4-甲氧基)-苄胺-脲(C40)

合成方法同C10，白色固体，收率66％。熔点：119-122℃。

¹H NMR(400MHz,DMSO-d₆)δ7.94–7.76(m,5H),7.55–7.40(m,4H),6.81(d,J＝8.1Hz,1H),6.61–6.48(m,1H),4.69(dd,J＝10.3,3.9Hz,1H),4.32–4.11(m,2H),3.81–3.72(m,1H),3.67(t,J＝2.3Hz,1H),3.64(s,3H),3.47(q,J＝8.4Hz,1H),3.20(dd,J＝13.9,4.1Hz,1H),3.03–2.89(m,2H),2.61(s,3H),2.00–1.71(m,3H),1.72–1.60(m,1H).¹³C NMR(101MHz,DMSO)δ170.50,158.49,157.81,136.78,133.44,132.18,130.50,128.90,128.60,128.04,127.92,127.85,126.33,125.80,113.96,55.44,55.41,54.05,50.80,46.72,37.23,33.85,27.39,27.29.

实施例41a：N-(L-亮氨酰-L-萘基丙氨酸甲酯)-N’-(N-甲基)-苄胺-脲(C41a)

合成方法同化合物C22a，白色固体，收率77％。

¹H NMR(400MHz,Chloroform-d)δ7.83–7.72(m,3H),7.62(s,1H),7.49–7.41(m,2H),7.35–7.21(m,4H),7.16(d,J＝7.2Hz,2H),4.94(q,J＝6.6Hz,1H),4.75(d,J＝7.6Hz,1H),4.46–4.36(m,2H),4.26(d,J＝16.0Hz,1H),3.71(s,3H),3.34(dd,J＝13.9,5.7Hz,1H),3.23(dd,J＝13.8,6.7Hz,1H),2.77(s,3H),1.62(dt,J＝12.9,6.6Hz,1H),1.53(dt,J＝12.8,6.5Hz,1H),1.49–1.37(m,1H),1.33(dd,J＝19.5,11.1Hz,1H),0.87(d,J＝6.2Hz,6H).¹³C NMR(101MHz,CDCl₃)δ173.10,171.90,157.86,137.59,133.58,133.43,132.44,128.71,128.10,127.70,127.62,127.37,127.32,127.11,126.05,125.67,53.24,52.92,52.31,52.12,40.97,38.04,34.37,24.71,22.95,22.05.

实施例41b：N-(L-亮氨酰-L-萘基丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-(N-甲基)-苄胺-脲(C41b)

合成方法同C10b，白色泡沫，收率63％。

¹H NMR(400MHz,Chloroform-d)δ7.79(d,J＝8.0Hz,3H),7.73(d,J＝8.3Hz,1H),7.49(d,J＝8.4Hz,1H),7.46–7.39(m,2H),7.33(t,J＝7.0Hz,2H),7.29–7.16(m,4H),6.95(d,J＝7.7Hz,1H),4.89(q,J＝7.7Hz,1H),4.69(d,J＝7.7Hz,1H),4.44(s,2H),4.36(dd,J＝16.2,8.5Hz,2H),3.43–3.33(m,1H),3.23(dd,J＝13.5,8.6Hz,1H),3.13(dd,J＝13.5,4.8Hz,1H),3.07(dd,J＝9.9,7.5Hz,1H),2.84(s,3H),2.44(p,J＝10.8,9.8Hz,2H),7.24–2.16(m,1H),2.11(d,J＝5.4Hz,1H),2.05(s,1H),1.97(d,J＝11.6Hz,2H),1.92–1.83(m,1H),1.74–1.60(m,3H),1.50(s,3H),1.44(d,J＝12.8Hz,1H),1.31(s,3H),0.88(d,J＝5.6Hz,6H),0.85(d,J＝6.0Hz,3H).¹³C NMR(101MHz,CDCl₃)δ172.60,168.82,157.77,137.71,134.08,133.43,132.32,128.73,128.55,128.33,127.80,127.73,127.53,127.33,127.20,125.71,125.43,85.91,77.77,77.25,53.16,52.23,52.12,51.40,46.36,41.79,39.65,39.54,38.28,35.61,34.45,33.97,28.69,27.15,27.07,26.31,25.64,24.97,24.73,24.12,23.21,21.80.

实施例41：N-(L-亮氨酰-L-萘基丙氨酰-L-脯氨酸硼酸)-N’-(N-甲基)-苄胺-脲(C41)

合成方法同C10，白色固体，收率50％。熔点：132-135℃。

¹H NMR(400MHz,DMSO-d₆)δ7.90–7.73(m,5H),7.51–7.42(m,3H),7.33(t,J＝7.4Hz,2H),7.27–7.21(m,1H),7.17(d,J＝7.2Hz,2H),4.81(q,J＝6.3,4.8Hz,1H),4.41(q,J＝16.0Hz,2H),4.11(dd,J＝10.6,4.6Hz,1H),3.64(t,J＝7.9Hz,1H),3.37(q,J＝8.1Hz,1H),3.27(dd,J＝14.0,4.6Hz,1H),2.98–2.87(m,2H),2.74(s,3H),1.97–1.68(m,3H),1.67–1.57(m,1H),1.49–1.34(m,2H),1.20–1.13(m,1H),0.74(dd,J＝22.0,6.4Hz,6H).¹³CNMR(101MHz,DMSO)δ173.23,168.82,157.90,138.88,135.85,133.37,132.23,128.89,128.80,128.62,128.17,127.97,127.82,127.55,127.30,126.17,125.76,53.55,51.74,51.52,48.31,46.81,40.96,37.71,34.31,27.40,27.17,24.60,23.42,21.73.

实施例42a：N-(L-亮氨酰-L-萘基丙氨酸甲酯)-N’-1,2,3,4-四氢喹啉-脲(C42a)

合成方法同化合物C22a，白色固体，收率77％。

¹H NMR(400MHz,Chloroform-d)δ7.76–7.63(m,3H),7.59(s,1H),7.41–7.33(m,2H),7.26–7.22(m,1H),7.19(dt,J＝7.3,3.7Hz,2H),7.16–7.11(m,1H),7.08(dd,J＝5.3,3.6Hz,1H),6.99(d,J＝7.8Hz,1H),4.92(q,J＝6.9Hz,1H),4.82(d,J＝8.0Hz,1H),4.46–4.36(m,3H),3.50(dt,J＝11.8,5.8Hz,1H),3.41(dt,J＝12.1,5.9Hz,1H),3.32(dd,J＝13.9,5.7Hz,1H),3.19(dd,J＝13.9,6.9Hz,1H),2.77(t,J＝5.4Hz,2H),1.72–1.60(m,2H),1.50(q,J＝8.7,8.2Hz,1H),0.89(t,J＝5.8Hz,6H).¹³C NMR(101MHz,CDCl₃)δ173.06,171.87,157.03,134.97,133.50,133.39,133.24,132.39,128.35,128.08,128.05,127.64,127.57,127.33,126.71,126.44,126.39,126.04,125.65,53.24,52.70,52.35,45.34,41.23,41.17,38.08,28.97,24.78,22.93,22.22.

实施例42b：N-(L-亮氨酰-L-萘基丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-1,2,3,4-四氢喹啉-脲(C42b)

合成方法同C10b，白色泡沫，收率75％。

¹H NMR(400MHz,Chloroform-d)δ7.81–7.70(m,3H),7.69(d,J＝8.4Hz,1H),7.47(d,J＝8.4Hz,1H),7.40–7.36(m,2H),7.27(s,1H),7.23–7.13(m,3H),7.15–7.08(m,1H),6.91(d,J＝8.0Hz,1H),4.91(dd,J＝15.7,7.7Hz,1H),4.85(d,J＝8.2Hz,1H),4.50(s,2H),4.48–4.29(m,2H),3.74(t,J＝5.0Hz,1H),3.61(dt,J＝11.4,5.6Hz,1H),3.50(dt,J＝12.1,5.9Hz,1H),3.38(t,J＝8.4Hz,1H),3.21(d,J＝8.8Hz,1H),3.13(dd,J＝12.9,4.5Hz,1H),3.11–3.02(m,1H),2.85(q,J＝5.9Hz,2H),2.50–2.38(m,2H),2.27–2.16(m,1H),2.10(t,J＝4.9Hz,1H),2.00–1.92(m,2H),1.89–1.83(m,2H),1.73–1.59(m,3H),1.49(s,3H),1.43(d,J＝7.6Hz,1H),1.31(s,3H),0.95–0.86(m,9H).¹³C NMR(101MHz,CDCl₃)δ172.68,168.80,156.96,135.09,134.03,133.41,133.35,132.29,128.50,128.32,127.76,127.50,126.64,126.38,125.70,125.41,85.91,77.79,77.25,67.97,52.91,52.19,51.38,46.36,45.39,42.19,41.18,39.65,39.56,38.28,35.61,29.05,28.68,27.16,26.92,26.31,25.62,24.77,24.12,23.24,21.95.

实施例42：N-(L-亮氨酰-L-萘基丙氨酰-L-脯氨酸硼酸)-N’-1,2,3,4-四氢喹啉-脲(C42)

合成方法同C10，白色固体，收率63％。熔点：136-139℃。

¹H NMR(400MHz,DMSO-d₆)δ7.86–7.77(m,2H),7.79–7.67(m,2H),7.49–7.40(m,3H),7.21–7.11(m,4H),4.83–4.72(m,1H),4.47(s,2H),4.19–4.10(m,1H),3.53(t,J＝5.3Hz,2H),3.36(q,J＝8.9,8.4Hz,1H),3.28–3.19(m,1H),2.98–2.85(m,2H),2.79–2.69(m,2H),1.95–1.69(m,3H),1.68–1.35(m,4H),0.79(d,J＝6.4Hz,3H),0.72(d,J＝6.5Hz,3H).¹³C NMR(101MHz,DMSO)δ173.27,168.85,157.35,135.88,135.24,134.42,133.37,132.19,128.96,128.60,128.11,127.97,127.77,126.73,126.63,126.48,126.15,125.74,53.30,51.86,46.77,45.67,41.51,40.99,37.53,28.66,27.37,27.16,24.61,23.42,21.84.

实施例43a：N-(L-亮氨酰-L-萘基丙氨酸甲酯)-N’-(N-甲基-4-氟)-苄胺-脲(C43a)

合成方法同化合物C22a，白色固体，收率77％。

¹H NMR(400MHz,Chloroform-d)δ7.82–7.72(m,3H),7.60(s,1H),7.48–7.38(m,2H),7.26(d,J＝2.2Hz,1H),7.11(dd,J＝7.8,4.9Hz,2H),7.01–6.92(m,2H),6.83(d,J＝7.8Hz,1H),4.93(q,J＝6.9Hz,1H),4.61(d,J＝7.8Hz,1H),4.39–4.28(m,2H),4.21(d,J＝15.7Hz,1H),3.72(s,3H),3.34(dd,J＝14.1,5.8Hz,1H),3.22(dd,J＝14.1,6.8Hz,1H),2.71(s,3H),1.58(ddt,J＝33.0,13.4,7.0Hz,2H),1.41(dt,J＝13.8,7.0Hz,1H),0.87(d,J＝6.2Hz,6H).¹³C NMR(101MHz,CDCl₃)δ172.85,171.84,157.73,133.46,133.42,132.45,128.90,128.82,128.12,127.68,127.62,127.27,126.08,125.70,115.62,115.41,53.13,52.93,52.36,51.40,41.01,38.03,34.10,24.77,22.89,22.09.

实施例43b：N-(L-亮氨酰-L-萘基丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-(N-甲基-4-氟)-苄胺-脲(C43b)

合成方法同C10b，白色泡沫，收率80％。

¹H NMR(400MHz,Chloroform-d)δ7.78(d,J＝7.7Hz,3H),7.73(d,J＝8.5Hz,1H),7.49(d,J＝8.3Hz,1H),7.46–7.39(m,2H),7.23–7.12(m,2H),7.01(t,J＝8.1Hz,2H),6.92(d,J＝7.7Hz,1H),4.93–4.86(m,1H),4.70(d,J＝7.6Hz,1H),4.40(s,2H),4.38–4.32(m,1H),3.38(t,J＝8.9Hz,1H),3.26–3.18(m,1H),3.13(dd,J＝13.6,4.0Hz,1H),3.12–3.02(m,1H),2.80(s,3H),2.50–2.39(m,2H),2.21(dt,J＝11.5,6.3Hz,1H),2.11(t,J＝4.7Hz,1H),2.03–1.85(m,4H),1.76–1.60(m,2H),1.56(d,J＝8.2Hz,2H),1.49(s,3H),1.44(d,J＝12.6Hz,2H),1.31(s,3H),0.89(t,J＝7.2Hz,9H).¹³C NMR(101MHz,CDCl₃)δ172.52,168.78,157.67,134.02,133.42,132.32,129.00,128.92,128.56,128.33,127.79,127.74,127.54,125.73,125.45,115.65,115.44,85.94,77.80,53.21,52.14,51.48,51.38,46.39,41.88,39.64,39.55,38.28,35.60,34.14,28.68,27.15,27.06,26.32,24.81,24.12,23.20,21.82.

实施例43：N-(L-亮氨酰-L-萘基丙氨酰-L-脯氨酸硼酸)-N’-(N-甲基-4-氟)-苄胺-脲(C43)

合成方法同C10，白色固体，收率63％。熔点：118-121℃。

¹H NMR(400MHz,DMSO-d₆)δ7.88–7.78(m,3H),7.76(d,J＝7.3Hz,2H),7.45(d,J＝8.2Hz,3H),7.21(q,J＝7.0,6.6Hz,2H),7.20–7.07(m,2H),4.84–4.78(m,1H),4.50–4.27(m,2H),4.08(dd,J＝9.8,4.1Hz,1H),3.40(q,J＝8.9Hz,1H),3.27(dd,J＝14.2,4.5Hz,1H),2.99–2.85(m,2H),2.73(s,3H),1.97–1.72(m,3H),1.67–1.59(m,1H),1.45–1.34(m,2H),1.13(dd,J＝12.6,7.9Hz,1H),0.80–0.66(m,6H).¹³C NMR(101MHz,DMSO)δ173.55,173.21,168.84,168.43,162.88,160.48,157.99,157.83,135.80,135.03,135.00,133.35,132.22,129.64,129.60,129.56,128.61,128.18,127.95,127.82,126.18,125.77,115.70,115.61,115.49,115.40,53.64,51.69,50.78,46.82,40.90,40.34,37.69,34.19,27.40,27.19,24.59,23.37,21.70.

实施例44a：N-(L-亮氨酰-L-萘基丙氨酸甲酯)-N’-(N-甲基-4-甲氧基)-苄胺-脲(C44a)

合成方法同化合物C22a，白色固体，收率66％。

¹H NMR(400MHz,Chloroform-d)δ7.83–7.71(m,3H),7.60(s,1H),7.43(dd,J＝6.5,3.0Hz,2H),7.27(d,J＝7.9Hz,1H),7.07(d,J＝8.1Hz,2H),6.98(d,J＝7.7Hz,1H),6.84–6.78(m,2H),4.92(q,J＝6.5Hz,1H),4.60(d,J＝7.5Hz,1H),4.39–4.25(m,2H),4.17(d,J＝15.8Hz,1H),3.76(s,3H),3.70(s,3H),3.33(dd,J＝13.8,5.7Hz,1H),3.20(dd,J＝13.9,6.7Hz,1H),2.73(s,3H),1.60(dt,J＝13.3,6.6Hz,1H),1.49(dt,J＝12.6,6.1Hz,1H),1.44–1.34(m,1H),0.85(d,J＝6.4Hz,6H).¹³C NMR(101MHz,CDCl₃)δ172.99,171.88,158.95,157.83,133.58,133.43,132.44,129.56,128.44,128.10,127.69,127.61,127.31,126.05,125.67,114.09,55.26,53.18,52.85,52.31,51.57,40.88,38.06,34.24,24.70,22.93,22.05.

实施例44b：N-(L-亮氨酰-L-萘基丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-(N-甲基-4-甲氧基)-苄胺-脲(C44b)

合成方法同C10b，白色泡沫，收率80％。

¹H NMR(400MHz,Chloroform-d)δ7.78(d,J＝7.4Hz,3H),7.72(d,J＝8.4Hz,1H),7.49(d,J＝8.3Hz,1H),7.46–7.38(m,2H),7.14(d,J＝8.0Hz,2H),6.94(d,J＝7.8Hz,1H),6.85(d,J＝7.7Hz,2H),4.90(dt,J＝13.1,7.0Hz,1H),4.66(d,J＝7.6Hz,1H),4.45–4.30(m,4H),3.76(s,3H),3.43–3.33(m,1H),3.21(d,J＝9.3Hz,1H),3.12(dd,J＝12.8,3.2Hz,1H),3.11–3.02(m,1H),2.82(s,3H),2.49–2.38(m,1H),2.21(dt,J＝11.6,6.5Hz,1H),2.09(d,J＝6.5Hz,1H),2.00–1.83(m,3H),1.74–1.61(m,2H),1.59–1.53(m,1H),1.49(s,3H),1.44(d,J＝11.0Hz,1H),1.40(s,1H),1.31(s,3H),1.27(s,1H),0.92–0.82(m,9H).¹³C NMR(101MHz,CDCl₃)δ172.61,168.82,158.93,157.75,134.10,133.43,132.31,129.73,128.54,128.33,127.80,127.73,127.53,125.71,125.42,114.11,85.90,77.77,55.27,53.13,52.11,51.64,51.39,46.35,41.78,39.65,39.55,38.28,35.62,34.29,28.69,27.16,27.07,26.32,24.72,24.12,23.22,21.81.

实施例44：N-(L-亮氨酰-L-萘基丙氨酰-L-脯氨酸硼酸)-N’-(N-甲基-4-甲氧基)-苄胺-脲(C44)

合成方法同C10，白色固体，收率63％。熔点：117-120℃。

¹H NMR(400MHz,DMSO-d₆)δ7.89–7.70(m,5H),7.50–7.38(m,3H),7.10(d,J＝8.2Hz,2H),6.86(d,J＝8.6Hz,2H),4.83–4.78(m,1H),4.31(q,J＝15.8Hz,2H),4.08(dd,J＝10.4,4.6Hz,1H),3.71(s,3H),3.66–3.59(m,1H),3.36(q,J＝8.7Hz,1H),3.24(dd,J＝14.2,4.4Hz,1H),2.98–2.83(m,2H),2.69(s,3H),1.95–1.68(m,3H),1.67–1.55(m,1H),1.43–1.34(m,2H),1.18–1.11(m,1H),0.73(dd,J＝23.2,6.1Hz,6H).¹³C NMR(101MHz,DMSO)δ173.18,168.82,158.70,157.84,135.84,133.36,132.22,130.69,129.01,128.60,128.16,127.96,127.82,126.18,125.77,114.27,114.18,55.48,53.51,51.64,50.88,46.81,40.97,37.69,34.06,27.39,27.17,24.58,23.40,21.74.

实施例中提及的部分化合物结构式如下：

活性试验实施例

酶活性试验测定方法为：37℃下将1μg从大鼠肝脏中提取20S蛋白酶体用含有不同浓度的化合物、50μM的荧光肽和20mM三羟甲基氨基甲烷盐酸盐的100μL溶液分别培养一小时，在380/440nm和335/410nm的激发/发射波长下分别用Fluostar OPTIMA和BMG Germany光谱荧光剂测定AMC及β萘酰胺物质释放的荧光，用0.1％DMSO作为溶剂空白。比较溶剂空白的荧光来计算抑制率。所测定与计算的活性包含蛋白酶体最主要的三个活性位点：类糜蛋白酶活性(chymotrypsin-like，ChTL)、类胰蛋白酶活性(trypsin-like,TL)、肽-谷氨酰肽水解酶活性(PGPH)。所述的试验以抗肿瘤药物硼替佐米(Bortezomib)，即PS-341作为阳性对照的比较化合物。

体外抗肿瘤活性测定方法为：体外培养癌细胞株，当细胞生长至对数生长期后，收集细胞，1000rpm离心5min，弃上清，适量培养基悬浮，调整细胞浓度至3.5×10⁴/mL。将细胞悬液接种到96孔细胞培养板中，每孔100μL，放置细胞培养箱(37℃，5％CO₂)中培养24h后，加入不同终浓度的待测药物，阴性对照组加入终浓度为0.5％DMSO，各组均设3个复孔。培养箱中培养72h后，每孔加入5mg/mL的MTT 20μL，于37℃放置3h。每孔加入150μL DMSO，37℃摇床振荡5min，492nm/620nm测吸光度(OD)。运用Prism Graphpad统计软件计算IC₅₀值。

广泛的抗肿瘤谱筛选实验：用DMSO(Merck)溶解成10mM后，加入PBS(-)配成1000μM的溶液或均匀的混悬液，然后用含DMSO的PBS(-)稀释。样品终浓度100、10、1、0.1、0.01、0.001、0.0001、0.00001、0.000001、……、10^-9μM。96孔板每孔加入浓度为4-5×10⁴个/mL的细胞悬液100μL，置37℃，5％CO₂培养箱内。24h后，加入样品液，10μL/孔，设双复孔，37℃，5％CO₂作用72h。每孔加入5mg/mL的MTT溶液20μL，作用4h后加入溶解液，100μL/孔，置培养箱内，溶解后用全波长多功能酶标仪测570nm OD值。该实验以阿霉素(DOX)作为对照，分别测定了两个化合物对A549(人肺腺癌细胞)、95D(人肺腺癌细胞)、HCT116(人肠癌细胞)、MDA-MB-231(人乳腺癌细胞)、C-3(人前列腺癌细胞)、HL-60(人白血病细胞)、PANC-1(人胰腺癌细胞)、MGC803(人胃癌细胞)在体外的抗肿瘤活性，其半数抑制浓度如表3所示。

表1：本发明实施例化合物的体外酶活性评价结果

注：化合物作用时间为2h

表2：本发明实施例化合物对胃癌细胞MGC-803抗肿瘤活性结果

注：MTT法，作用时间24h

表3：化合物C20对不同肿瘤细胞系的抑制活性(IC₅₀/μM)

Claims (8)

1.具有下述式(I)所示结构的化合物或其盐：

其中，

各基团的定义满足下述(a)至(e)的定义：

(a)n为1或2；

(b)连接基团L为键，或者选自于由-CH₂O-和-CH₂NH-所组成的组，上述-CH₂O-、-CH₂NH-任选被C1-C4烷基取代；

(c)R₁选自于由苯基、吡啶基、吡嗪基、环己基、哌啶基、哌嗪基、吗啉基所组成的组，上述基团任选与另外一个苯基、噻吩基、吡咯基、呋喃基稠合，并且任选被一个或多个独立地选自于由C1-C4烷基、C1-C4烷氧基、卤素、羟基、硝基所组成的组中的取代基取代；

(d)R₂为天然或非天然的氨基酸侧链，n个R₂各自独立地选自于由苄基、萘甲基、吲哚甲基、正丙基、正丁基、仲丁基、异丁基、叔丁基所组成的组，上述基团任选被一个或多个各自独立地选自于由C1-C4烷基、C1-C4烷氧基、卤素、羟基、硝基所组成的组中的取代基取代；

(e)R_a、R_b同时为H，或者R_a、R_b相互连接，连同相邻的两个氧原子以及硼原子共同形成硼酸蒎烷二醇酯基团。

2.如权利要求1所述的化合物或其盐，所述化合物具有下述通式(II)至(V)之一所示的结构：

其中，

m为1、2或3；

R₆对应于通式(I)中R₁上的取代基，m个R₆各自独立地满足权利要求1中对于R₁上取代基的定义。

3.选自于由以下所组成的组的化合物或其盐：

N-吡嗪甲酰-L-亮氨酰-L-萘基丙氨酰-L-脯氨酸硼酸蒎烷二醇酯(化合物10b)

N-吡嗪甲酰-L-亮氨酰-L-萘基丙氨酰-L-脯氨酸硼酸(化合物10)

N-吡嗪甲酰-L-异亮氨酰-L-萘基丙氨酰-L-脯氨酸硼酸蒎烷二醇酯(化合物11b)

N-吡嗪甲酰-L-异亮氨酰-L-萘基丙氨酰-L-脯氨酸硼酸(化合物11)

N-吡嗪甲酰-L-异亮氨酰-L-苯丙氨酰-L-脯氨酸硼酸蒎烷二醇酯(化合物12b)

N-吡嗪甲酰-L-异亮氨酰-L-苯丙氨酰-L-脯氨酸硼酸(化合物12)

N-吡嗪甲酰-L-亮氨酰-L-苯丙氨酰-L-脯氨酸硼酸蒎烷二醇酯(化合物13b)

N-吡嗪甲酰-L-亮氨酰-L-苯丙氨酰-L-脯氨酸硼酸(化合物13)

N-吡嗪甲酰-L-苯丙氨酰-L-苯丙氨酰-L-脯氨酸硼酸蒎烷二醇酯(化合物14b)

N-吡嗪甲酰-L-苯丙氨酰-L-苯丙氨酰-L-脯氨酸硼酸(化合物14)

N-吡嗪甲酰-L-苯丙氨酰-L-萘基丙氨酰-L-脯氨酸硼酸蒎烷二醇酯(化合物15b)

N-吡嗪甲酰-L-苯丙氨酰-L-萘基丙氨酰-L-脯氨酸硼酸(化合物15)

N-吡嗪甲酰-L-苯丙氨酰-L-亮氨酰-L-脯氨酸硼酸蒎烷二醇酯(化合物16b)

N-吡嗪甲酰-L-苯丙氨酰-L-亮氨酰-L-脯氨酸硼酸(化合物16)

N-吡嗪甲酰-L-亮氨酰-L-亮氨酰-L-脯氨酸硼酸蒎烷二醇酯(化合物17b)

N-吡嗪甲酰-L-亮氨酰-L-亮氨酰-L-脯氨酸硼酸(化合物17)

N-吡嗪甲酰-L-萘基丙氨酰-L-亮氨酰-L-脯氨酸硼酸蒎烷二醇酯(化合物18b)

N-吡嗪甲酰-L-萘基丙氨酰-L-亮氨酰-L-脯氨酸硼酸(化合物18)

N-Cbz-L-苯丙氨酰-L-萘丙氨酰-L-脯氨酸硼酸蒎烷二醇酯(化合物19b)

N-Cbz-L-苯丙氨酰-L-萘丙氨酰-L-脯氨酸硼酸(化合物19)

N-Cbz-L-亮氨酰-L-萘丙氨酰-L-脯氨酸硼酸蒎烷二醇酯(化合物20b)

N-Cbz-L-亮氨酰-L-萘丙氨酰-L-脯氨酸硼酸(化合物20)

N-Cbz-L-亮氨酰-L-亮氨酰-L-脯氨酸硼酸蒎烷二醇酯(化合物21b)

N-Cbz-L-亮氨酰-L-亮氨酰-L-脯氨酸硼酸(化合物21)

N-(L-苯丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-1,2,3,4-四氢异喹啉-脲(化合物22b)

N-(L-苯丙氨酰-L-脯氨酸硼酸)-N’-1,2,3,4-四氢异喹啉-脲(化合物22)

N-(L-苯丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-(6-甲氧基-1,2,3,4-四氢异喹啉)-脲(化合物23b)

N-(L-苯丙氨酰-L-脯氨酸硼酸)-N’-(6-甲氧基-1,2,3,4-四氢异喹啉)-脲(化合物23)

N-(L-苯丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-(7-硝基-1,2,3,4-四氢异喹啉)-脲(化合物24b)

N-(L-苯丙氨酰-L-脯氨酸硼酸)-N’-(7-硝基-1,2,3,4-四氢异喹啉)-脲(化合物24)

N-(L-苯丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-(6,7-二甲氧基-1,2,3,4-四氢异喹啉)-脲(化合物25b)

N-(L-苯丙氨酰-L-脯氨酸硼酸)-N’-(6,7-二甲氧基-1,2,3,4-四氢异喹啉)-脲(化合物25)

N-(L-苯丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-(4,5,6,7-四氢噻吩[2,3-C]并吡啶)-脲(化合物26b)

N-(L-苯丙氨酰-L-脯氨酸硼酸)-N’-(4,5,6,7-四氢噻吩[2,3-C]并吡啶)-脲(化合物26)

N-(L-萘丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-1,2,3,4-四氢异喹啉-脲(化合物27b)

N-(L-萘丙氨酰-L-脯氨酸硼酸)-N’-1,2,3,4-四氢异喹啉-脲(化合物27)

N-(L-色氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-1,2,3,4-四氢异喹啉-脲(化合物28b)

N-(L-色氨酰-L-脯氨酸硼酸)-N’-1,2,3,4-四氢异喹啉-脲(化合物28)

N-(L-苯丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-吗啉-脲(化合物29b)

N-(L-苯丙氨酰-L-脯氨酸硼酸)-N’-吗啉-脲(化合物29)

N-(L-苯丙氨酰-L-丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-1,2,3,4-四氢喹啉-脲(化合物30b)

N-(L-苯丙氨酰-L-丙氨酰-L-脯氨酸硼酸)-N’-1,2,3,4-四氢喹啉-脲(化合物30)

N-(L-苯丙氨酰-L-亮氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-1,2,3,4-四氢喹啉-脲(化合物31b)

N-(L-苯丙氨酰-L-亮氨酰-L-脯氨酸硼酸)-N’-1,2,3,4-四氢喹啉-脲(化合物31)

N-(L-苯丙氨酰-L-异亮氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-1,2,3,4-四氢喹啉-脲(化合物32b)

N-(L-苯丙氨酰-L-异亮氨酰-L-脯氨酸硼酸)-N’-1,2,3,4-四氢喹啉-脲(化合物32)

N-(L-苯丙氨酰-L-苯丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-1,2,3,4-四氢喹啉-脲(化合物33b)

N-(L-苯丙氨酰-L-苯丙氨酰-L-脯氨酸硼酸)-N’-1,2,3,4-四氢喹啉-脲(化合物33)

N-(L-苯丙氨酰-L-萘基丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-1,2,3,4-四氢喹啉-脲(化合物34b)

N-(L-苯丙氨酰-L-萘基丙氨酰-L-脯氨酸硼酸)-N’-1,2,3,4-四氢喹啉-脲(化合物34)

N-(L-苯丙氨酰-L-丝氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-1,2,3,4-四氢喹啉-脲(化合物35b)

N-(L-苯丙氨酰-L-丝氨酰-L-脯氨酸硼酸)-N’-1,2,3,4-四氢喹啉-脲(化合物35)

N-(L-苯丙氨酰-L-酪氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-1,2,3,4-四氢喹啉-脲(化合物36b)

N-(L-苯丙氨酰-L-酪氨酰-L-脯氨酸硼酸)-N’-1,2,3,4-四氢喹啉-脲(化合物36)

N-Cbz-L-萘丙氨酰-L-脯氨酸硼酸蒎烷二醇酯(化合物37b)

N-Cbz-L-萘丙氨酰-L-脯氨酸硼酸(化合物37)

N-(L-萘丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-(N-甲基)-苄胺-脲(化合物38b)

N-(L-萘丙氨酰-L-脯氨酸硼酸)-N’-(N-甲基)-苄胺-脲(化合物38)

N-(L-萘丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-(N-甲基-4-氟)-苄胺-脲(化合物39b)

N-(L-萘丙氨酰-L-脯氨酸硼酸)-N’-(N-甲基-4-氟)-苄胺-脲(化合物39)

N-(L-萘丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-(N-甲基-4-甲氧基)-苄胺-脲(化合物40b)

N-(L-萘丙氨酰-L-脯氨酸硼酸)-N’-(N-甲基-4-甲氧基)-苄胺-脲(化合物40)

N-(L-亮氨酰-L-萘基丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-(N-甲基)-苄胺-脲(化合物41b)

N-(L-亮氨酰-L-萘基丙氨酰-L-脯氨酸硼酸)-N’-(N-甲基)-苄胺-脲(化合物41)

N-(L-亮氨酰-L-萘基丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-1,2,3,4-四氢喹啉-脲(化合物42b)

N-(L-亮氨酰-L-萘基丙氨酰-L-脯氨酸硼酸)-N’-1,2,3,4-四氢喹啉-脲(化合物42)

N-(L-亮氨酰-L-萘基丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-(N-甲基-4-氟)-苄胺-脲(化合物43b)

N-(L-亮氨酰-L-萘基丙氨酰-L-脯氨酸硼酸)-N’-(N-甲基-4-氟)-苄胺-脲(化合物43)

N-(L-亮氨酰-L-萘基丙氨酰-L-脯氨酸硼酸蒎烷二醇酯)-N’-(N-甲基-4-甲氧基)-苄胺-脲(化合物44b)

N-(L-亮氨酰-L-萘基丙氨酰-L-脯氨酸硼酸)-N’-(N-甲基-4-甲氧基)-苄胺-脲(化合物44)

4.一种药物组合物，其包含权利要求1-3中任一项所述的化合物或其盐以及一种或多种药用载体。

5.如权利要求4所述的药物组合物，其中，权利要求1-3中任一项所述的化合物或其盐的含量是0.5wt％-99wt％，所述药用载体的含量是1wt％-99.5wt％。

6.权利要求1-3中任一项所述的化合物或其盐在制备蛋白酶体抑制药物方面的用途。

7.如权利要求6所述的用途，其中，所述的蛋白酶体抑制药物是恶性肿瘤、多种神经系统变性疾病、肌肉恶病质或糖尿病的治疗剂。

8.如权利要求7所述的用途，其中，所述的恶性肿瘤选自于由白血病、胃癌、肝癌、乳腺癌和鼻咽癌所组成的组。