CN111793025A - 一种唑啉季铵盐修饰分子中氨基的方法及其用途 - Google Patents

一种唑啉季铵盐修饰分子中氨基的方法及其用途 Download PDF

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CN111793025A
CN111793025A CN202010236788.1A CN202010236788A CN111793025A CN 111793025 A CN111793025 A CN 111793025A CN 202010236788 A CN202010236788 A CN 202010236788A CN 111793025 A CN111793025 A CN 111793025A
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李波
刘鹏
孙海国
奚萌宇
徐志建
张勇
朱维良
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Abstract

本发明涉及一种修饰或标记分子中的氨基的方法，其中，使用由下式1表示的唑啉季铵盐来修饰或标记分子中的氨基，其中，所述分子包括氨基酸酯、氨基酰胺，或肽/蛋白。本发明的方法具有经济性和位点选择性优势，在药物分子合成、探针分子及诊断标记试剂开发等领域具有巨大的潜在应用价值。

Description

一种唑啉季铵盐修饰分子中氨基的方法及其用途
技术领域
本申请属于生物化学领域，具体地，涉及一种使用唑啉季铵盐(或唑啉鎓，zolinium)修饰或标记分子中的氨基的方法及用途。
背景技术
季铵盐(四级铵盐)为铵离子中的四个氢原子都被烃基取代而生成的化合物。其中四个烃基可以相同，也可以不同；阴离子多是卤素负离子(F、Cl、Br、I)，也可是酸根(如HSO4 -、RCOO-等)。季铵盐类化合物在医药、化工等领域都有着极其广泛的应用，如用于杀菌剂、消毒剂、柔软抗静电剂、絮凝剂破乳剂、钻井液、VES压裂液、减阻剂、增稠剂、阴离子增效剂、相转移催化剂等。
在季铵盐中，唑类季铵盐是一种很重要的有机合成试剂，它可以发生1,3-偶极环加成反应、可以用来制备氮杂卡宾化合物、可以用作制备药物活性分子中间体等。吡啶季铵盐除了本身是一种很重要的有机合成试剂，可以发生亲核加成、Michael加成、1,3-偶极加成、亲核取代和σ-迁移重排等反应外，该类化合物还具有不同的生理活性，如甲基丙烯酰氧十二烷基溴吡啶(12-methacryloyloxydodecylpyridinium bromide,MDPB)和氯化十六烷吡啶(Cetylpyridinium chloride,CPC)可以用于口腔消毒剂；来自于海洋生物的3-烷基吡啶季铵盐多聚物具有抗肺癌活性。来自于传统中药活性成分的盐酸小檗碱(又名黄连素)为异喹啉类生物碱，分子结构中具有异喹啉季铵盐(也即苯并吡啶季铵盐)片段，临床广泛用于治疗肠炎菌痢等，现代研究表明，其还具有抗肿瘤、糖尿病、心血管病、中枢神经系统疾病等药理作用。
李波等人前期在进行中药活性成分黄连素的结构优化设计与合成的研究过程中(Eur.J.Med.Chem.,2013,70,677)，首次发现了一类新型的缩醛重排反应及其生成的具有良好抗肿瘤活性的新型N-取代芳基异喹啉酮类化合物(Eur.J.Med.Chem.，2014，77：204-210)，通过深入研究该缩醛重排反应的机制，又发现了一类新型噁唑啉并吡啶季铵盐核心骨架，并首次将该核心骨架应用于氨基化合物的点击化学偶联反应中，获得了由不同亲核试剂控制的区域选择性反应产物(Sci Rep.2017,7,41287；CN107759614A)，在此过程中还发现了具有良好体内外抗血液肿瘤活性的噁唑啉并芳基异喹啉季铵盐类化合物DCZ0358(Cancer Lett.2018,421:135-144)。但这些研究均未涉及到该类唑啉季铵盐与氨基酸残基的偶联反应。
发明内容
本发明的技术目的是提供一种可用于修饰或标记分子中的氨基的方法。
一方面，本发明提供一种修饰或标记分子中的氨基的方法，其中，使用由下式1表示的唑啉季铵盐来修饰或标记分子中的氨基，
Figure BDA0002431269780000021
在式1中，
B环代表取代或未取代的五元、六元或七元含氮杂环；
Q、U各自独立地代表氧(O)、硫(S)、硒(Se)、碲(Te)、钋(Po)、氮(N)、磷(P)、硼(B)或硅(Si)；
R1为位于B环上的1-5个取代基，其各自独立地选自氢、羟基、氨基、巯基、硝基、氰基、取代或未取代的酰胺基、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的烷硫基、取代或未取代的烷氨基、取代或未取代的芳基、取代或未取代的芳氧基、取代或未取代的芳硫基、取代或未取代的芳氨基或卤素；或者，当R1为B环上的2个或2个以上取代基时，其中两个相邻的取代基可彼此连接与B环上的原子共同形成取代或未取代的芳基，取代或未取代的5-7元环烷基，取代或未取代的含有1-5个独立选自氧(O)、硫(S)、硒(Se)、碲(Te)、钋(Po)、氮(N)、磷(P)、硼(B)或硅(Si)原子的5-7元杂环烷基，或取代或未取代的含有1-5个独立选自氧(O)、硫(S)、硒(Se)、碲(Te)、钋(Po)、氮(N)、磷(P)、硼(B)或硅(Si)原子的5-7元杂芳基；
R2、R3各自独立地代表氢、羟基、氨基、巯基、硝基、氰基、取代或未取代的酰胺基、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的烷硫基、取代或未取代的烷氨基、取代或未取代的芳基、取代或未取代的芳氧基、取代或未取代的芳硫基、取代或未取代的芳氨基或卤素；
R4代表氢、取代或未取代的烷基、取代或未取代的芳基；
Y为酸根阴离子，其选自无机酸根离子、有机酸根离子和卤素离子，包括但不限于硝酸根离子、硫酸根离子、磷酸根离子、甲磺酸根离子、苯磺酸根离子、醋酸根离子、酒石酸根离子、枸橼酸根离子、马来酸根离子、琥珀酸根离子、柠檬酸根离子、水杨酸根离子、甘油酸根离子、抗坏血酸根离子、氟离子、氯离子、溴离子或碘离子。
优选地，在式1中，B环为五元环或六元环；Q、U各自独立地选自氧、硫或硒；R1为B环上的2个或2个以上取代基，其中2个相邻的取代基可彼此连接与B环上的碳原子共同形成取代或未取代的芳环；R2、R3各自独立地选自氢、取代或未取代的烷基、取代或未取代的芳基；R4为取代或未取代的烷基。
具体地，在所述方法中，所述分子包括氨基酸酯、氨基酰胺，或肽/蛋白。
具体地，所述方法包括，在有或没有添加剂的情况下，使式1表示的唑啉季铵盐与包含氨基的分子在溶剂中反应，制备得到氨基经标记或修饰的产物。
在一个具体实施方式中，所述方法通过由以下反应式I表示的反应来进行：
Figure BDA0002431269780000031
反应式I
在反应式I中，在有或没有添加剂的情况下，式1表示的唑啉季铵盐与由式3表示的化合物在溶剂中反应，制备得到由式2表示的氨基经修饰的产物，
其中，在式3中，
n代表1-6的整数；
R5代表氢、取代或未取代的烷基、取代或未取代的芳基；
R6各自独立地代表氢、羟基、氨基、巯基、硝基、氰基、取代或未取代的酰胺基、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的烷硫基、取代或未取代的烷氨基、取代或未取代的芳基、取代或未取代的芳氧基、取代或未取代的芳硫基、取代或未取代的芳氨基或卤素；或者
R5和R6彼此连接形成包含1-3个选自氧(O)、硫(S)、硒(Se)、碲(Te)、钋(Po)、氮(N)、磷(P)、硼(B)或硅(Si)中的杂原子的5-7元杂环；
W代表氧(O)、硫(S)、硒(Se)、碲(Te)、钋(Po)、氮(N)、磷(P)、硼(B)或硅(Si)。
其中，在式2中，B环、R1、R5、R6、W和n的定义与前述定义相同。
优选地，在式3中，n为1或5；W选自氧或氮；R5选自氢、取代或未取代的烷基；R6选自氨基、取代或未取代的酰氨基、取代或未取代的烷基，或取代或未取代的苯基。
具体地，在上述方法中，所述溶剂包括但不限于非质子性溶剂或质子性溶剂中的任一种或两种以上组合溶剂。其中，所述非质子性溶剂优选自能与水互溶比例达到10％(水/溶剂)以上的溶剂，包括但不限于甲苯、丙酮、二氯甲烷、1,2-二氯乙烷、四氢呋喃、乙腈、二甲苯、氯苯、二氧六环、二甲基亚砜、二甲基甲酰胺、二甲基乙酰胺等；所述质子性溶剂包括但不限于正丁醇、正丙醇、乙醇、甲醇、丙三醇、乙二醇、水等，优选地，所述溶剂选自正丁醇或水。
具体地，在上述方法中，所述添加剂包括但不限于有机碱或无机碱，所述有机碱包括但不限于三乙胺、DMAP(N，N-二甲基苯胺)、DBU(1,8-二氮杂二环十一碳-7-烯)、咪唑、吡啶等，最优选为三乙胺；所述无机碱包括但不限于碳酸钾、碳酸钠、碳酸铯、碳酸氢钠、氢氧化钠、氢氧化钾、磷酸钾、磷酸钠等，最优选为磷酸钾。
具体地，在上述方法中，所述反应的反应温度范围可为-80℃～200℃，优选0℃～50℃，反应时间为0.1分钟～72小时。
另一方面，本发明提供如下式1表示的唑啉季铵盐在修饰或标记分子中的氨基中的用途，
Figure BDA0002431269780000041
其中，式1中各取代基的定义如上文所述。
具体地，在所述方法中，所述分子包括氨基酸酯、氨基酰胺、肽或蛋白。其中，在肽/蛋白的情况下，所述修饰或标记具体指修饰或标记肽/蛋白的氨基酸残基的α-氨基，或修饰或标记赖氨酸残基的ε-氨基。
在具体实施方式中，所述修饰或标记用于药物分子合成、探针分子及诊断标记试剂开发等领域。
有益效果
本领域中常见的季铵盐，如吡啶氮酰基季铵盐、吡啶氮氧化物、吡啶氮烷基季铵盐等在本发明方法的反应条件下均不易与氨基酸残基反应，而与其不同，本发明描述的唑啉季铵盐则能特异性地与氨基酸残基反应获得N-邻位氨基偶联产物。此外，本发明的唑啉季铵盐与复杂肽类分子的氨基反应时，不与复杂肽类分子结构中的醇羟基、酚羟基、酰氨基、二硫键、氰基、酯基等活性基团反应，由此，具有良好的基团相容性。因此，本发明涉及的唑啉季铵盐与氨基酸残基偶联的方法具有经济性和位点选择性优势，在药物分子合成、探针分子及诊断标记试剂开发等领域具有巨大的潜在应用价值。
附图说明
图1显示出化合物2-68的质谱图。
图2显示出化合物2-69的质谱图。
图3显示出化合物2-40在肝组织中的浓度随时间的变化。
具体实施方式
术语
在本文中，术语“取代或未取代”中的“取代”是指被选自卤素、芳基、杂芳基、烷基、羟基、巯基、氢硒基、氨基、酰胺基中的一种或多种取代基所取代。
在本文中，术语“卤素”是指氟、氯、溴或碘。
在本文中，术语“烷基”是指C1至C20的直链或支链烷基，优选C1至C10的直链或支链烷基，再优选C1至C6的直链或支链烷基，更优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基。
在本文中，术语“环烷基”指具有3-7个环原子的饱和环体系基团。
在本文中，术语“杂环烷基”指含有1-5个独立选自氧(O)、硫(S)、硒(Se)、碲(Te)、钋(Po)、氮(N)、磷(P)、硼(B)或硅(Si)原子的饱和或部分不饱和环体系基团。
在本文中，术语“酰胺基”是指C1至C4酰胺基，优选甲酰基。
在本文中，术语“芳基”是指5-7元芳基，优选为苯基、呋喃基、噻吩基、吡咯基、吡啶基、吲哚基、喹啉基、异喹啉基、咪唑基、噁唑基、噻唑基、萘基、蒽基、菲基。
在本文中，术语“杂芳基”是指包含1-5个选自氧(O)、硫(S)、硒(Se)、碲(Te)、钋(Po)、氮(N)、磷(P)、硼(B)或硅(Si)中的杂原子的5-7元杂芳基。
在B环定义中，术语“五元、六元或七元含氮杂环”包括含氮饱和或不饱和杂环，如吡啶环、吡嗪环、三嗪环、噁唑环、噻唑环、硒唑环、咪唑环、氮杂卓环、二氮杂卓环、氮氧杂卓环、氮硫杂卓环、氮硒杂卓环。
下面结合具体实施例对本发明作进一步阐述，但不意图限制本发明。
制备实施实例
Figure BDA0002431269780000051
在以上反应式中，各取代基的定义如上文所述。另外，R7代表氢、取代或未取代的烷基、取代或未取代的芳基；或R7与R4连接在一起；U’代表氧(O)、硫(S)、硒(Se)、碲(Te)、钋(Po)、氮(N)、磷(P)、硼(B)或硅(Si)。
化合物4可参考文献的方法(李波(Li Bo)等人，Discovery of N-substituted3-arylisoquinolone derivatives as antitumor agents originating from O-substituted3-arylisoquinolines via[2,3]or[3,3]rearrangement，Eur.J.Med.Chem.，2014，77：204-210)制备。具体地，将化合物4溶于酸，如干燥的盐酸乙醚中，保持干燥，反应过夜，将过量的酸，如盐酸乙醚旋干，得到化合物1。接着，在室温下，将化合物1加入到化合物3的正丁醇或水溶液中，或者将化合物1溶解于正丁醇或水中，向其中加入化合物3，再加入或不加入添加剂，如三乙胺或磷酸钾等，搅拌过夜。反应完毕，通过溶剂萃取、分离等后处理步骤得到产物2。
唑啉季铵盐与各种简单氨基酸酯或氨基酰胺反应的制备实例：
实施例1化合物2-1的制备
Figure BDA0002431269780000061
以取代或未取代的2-氯喹啉或2-氯异喹啉类化合物为原料，参照文献(李波(LiBo)等人，Discovery of N-substituted 3-arylisoquinolone derivatives asantitumor agents originating from O-substituted 3-arylisoquinolines via[2,3]or[3,3]rearrangement，Eur.J.Med.Chem.，2014，77：204-210)的方法制得2-(2,2-二甲氧基乙氧基)喹啉、2-(2,2-二甲氧基乙硫基)喹啉或2-(2,2-二甲氧基乙硒基)喹啉(0.13mmol)，然后溶于干燥的盐酸乙醚(5ml)中，保持干燥，反应过夜，将过量的盐酸乙醚旋干，得到中间体1。a)将所得中间体1直接溶解于正丁醇或者水(10ml)中，向其中加入胺亲核试剂2-氨基-N-甲基乙酰胺盐酸盐(0.26mmol)；或者b)将所得中间体1加入到胺亲核试剂2-氨基-N-甲基乙酰胺盐酸盐(0.26mmol)的正丁醇或者水溶液中。再加入或不加入三乙胺或者磷酸钾(0.26mmol)，搅拌反应完毕，直接减压蒸干溶剂得到残余物或者用正丁醇萃取后再减压蒸干溶剂，残余物经过反相硅胶柱层析分离得到产物2-1，收率95％。1H NMR(400MHz,CDCl3)δ7.86(d,J＝8.9Hz,1H),7.72(d,J＝8.4Hz,1H),7.63(d,J＝8.0Hz,1H),7.57(t,J＝7.5Hz,1H),7.31–7.25(m,1H),6.96(s,1H),6.71(d,J＝8.9Hz,1H),5.67(s,1H),4.24(s,2H),2.84(d,J＝4.9Hz,3H),2.24(s,1H).13C NMR(125MHz,CDCl3)δ171.3,156.0,147.4,137.8,129.8,127.5,126.2,123.7,122.8,111.9,45.9,26.2。HRMS(ESI)：C12H14N3O[M+H]+计算值：216.1060，实测值：216.1060。
实施例2化合物2-2的制备
Figure BDA0002431269780000062
除将亲核试剂换成(S)-2-氨基-N-甲基丙酰胺盐酸盐之外，制备方法同实施例1，得化合物2-2，收率92％。1H NMR(600MHz,CDCl3)δ7.80(d,J＝8.8Hz,1H),7.67(d,J＝8.3Hz,1H),7.59(d,J＝7.9Hz,1H),7.53(t,J＝7.3Hz,1H),7.27–7.21(m,1H),7.10(s,1H),6.61(d,J＝8.8Hz,1H),5.28(d,J＝5.9Hz,1H),4.72(p,J＝6.7Hz,1H),2.78(d,J＝4.9Hz,3H),1.52(d,J＝7.0Hz,3H).13C NMR(150MHz,CDCl3)δ174.3,155.8,147.4,137.6,129.7,127.5,126.1,123.6,122.6,112.0,50.7,26.1,18.1。HRMS(ESI)：C13H16N3O[M+H]+计算值：230.1288，实测值：230.1288。
实施例3化合物2-3的制备
Figure BDA0002431269780000071
除将亲核试剂换成2-氨基-N,3,3-三甲基丁酰胺盐酸盐之外，制备方法同实施例1，得化合物2-3，收率66％。1H NMR(400MHz,CDCl3)δ7.82(d,J＝8.9Hz,1H),7.69(d,J＝8.4Hz,1H),7.61(s,1H),7.57–7.52(m,1H),7.25(t,J＝8.0Hz,1H),6.70(d,J＝8.9Hz,1H),6.44(s,1H),5.68(s,1H),4.50(d,J＝7.8Hz,1H),2.80(d,J＝4.9Hz,3H),1.14(s,9H).13CNMR(125MHz,CDCl3)δ172.6,156.3,147.1,137.8,129.7,127.5,125.7,123.6,122.5,112.0,34.4,27.0,26.1。HRMS(ESI)：C16H22N3O[M+H]+计算值：272.1757，实测值：272.1756。
实施例4化合物2-4的制备
Figure BDA0002431269780000072
除将亲核试剂换成(S)-2-氨基-N-甲基-2-苯基乙酰胺盐酸盐之外，制备方法同实施例1，得化合物2-4，收率63％。1H NMR(400MHz,MeOD4)δ7.88(d,J＝8.9Hz,1H),7.66–7.60(m,2H),7.57–7.47(m,3H),7.42–7.36(m,2H),7.36–7.30(m,1H),5.69(s,1H),2.77(s,3H).13C NMR(125MHz,MeOD4)δ173.8,156.1,147.5,138.6,136.8,128.9,128.3,127.7,127.5,127.1,125.6,123.7,122.0,112.4,59.7,25.1。HRMS(ESI)：C18H18N3O[M+H]+计算值：292.144，实测值：292.145。
实施例5化合物2-5的制备
Figure BDA0002431269780000073
除将亲核试剂换成(S)-2-氨基-N-甲基-3-苯基丙酰胺盐酸盐之外，制备方法同实施例1，得化合物2-5，收率72％。1H NMR(400MHz,Acetone-d6)δ7.86(s,1H),7.63(d,J＝8.3Hz,2H),7.50(t,J＝7.5Hz,1H),7.41(s,1H),7.33(d,J＝7.5Hz,2H),7.25(t,J＝7.5Hz,2H),7.17(s,2H),6.88(d,J＝8.9Hz,1H),6.50(s,1H),5.11–5.02(m,1H),3.30(dd,J＝13.8,5.9Hz,1H),3.13(dd,J＝13.7,7.8Hz,1H),2.70(d,J＝4.7Hz,3H).13C NMR(125MHz,Acetone-d6)δ205.2,172.3,156.2,147.8,138.5,136.7,129.3,129.0,128.1,127.4,126.2,126.1,123.6,121.8,113.1,56.0,38.0,25.2。HRMS(ESI)：C19H20N3O[M+H]+计算值：306.1601，实测值：306.1597。
实施例6化合物2-6的制备
Figure BDA0002431269780000081
除将亲核试剂换成3-氨基哌啶-2-酮盐酸盐之外，制备方法同实施例1，得化合物2-6，收率28％。1H NMR(500MHz,CDCl3)δ7.76(d,J＝8.8Hz,1H),7.69(d,J＝8.3Hz,1H),7.57(d,J＝7.9Hz,1H),7.55–7.49(m,1H),7.21(t,J＝7.4Hz,1H),6.71(d,J＝8.8Hz,1H),6.34(s,0H),5.86(s,0H),4.60(dt,J＝11.3,6.0Hz,2H),3.39(dd,J＝7.3,4.2Hz,2H),2.90(dd,J＝12.4,5.0Hz,2H),2.02(dddt,J＝33.9,13.7,9.0,4.5Hz,2H),1.66(qd,J＝11.7,3.4Hz,1H).13C NMR(125MHz,CDCl3)δ173.2,156.1,147.8,136.8,129.2,127.4,126.5,123.6,122.2,113.1,52.0,41.8,27.5,21.2。HRMS(ESI)：C14H16N3O[M+H]+计算值：242.1288，实测值：242.1286。
实施例7化合物2-7的制备
Figure BDA0002431269780000082
除将亲核试剂换成2-氨基丁酰胺盐酸盐之外，制备方法同实施例1，得化合物2-7，收率85％。1H NMR(400MHz,DMSO-d6)δ7.85(d,J＝8.9Hz,1H),7.62(d,J＝7.9Hz,1H),7.48–7.43(m,3H),7.15(ddd,J＝8.1,4.8,3.2Hz,1H),7.06(d,J＝7.8Hz,1H),6.99(s,1H),6.93(d,J＝8.9Hz,1H),4.54(q,J＝6.9Hz,1H),1.90–1.76(m,1H),1.76–1.63(m,1H),0.94(t,J＝7.4Hz,3H).13C NMR(125MHz,DMSO-d6)δ175.1,157.0,148.0,136.6,129.4,127.9,126.0,123.5,121.7,113.9,55.4,25.8,10.8。HRMS(ESI)：C13H16N3O[M+H]+计算值：230.1288，实测值：230.1288。
实施例8化合物2-8的制备
Figure BDA0002431269780000083
除将亲核试剂换成甘氨酸甲酯盐酸盐之外，制备方法同实施例1，得化合物2-8，收率95％。1H NMR(400MHz,CDCl3)δ7.83(d,J＝8.9Hz,1H),7.71(d,J＝8.4Hz,1H),7.60(d,J＝7.9Hz,1H),7.57–7.51(m,1H),7.23(t,1H),6.72(d,1H),5.24(s,1H),4.38(d,J＝5.1Hz,2H),3.80(s,3H).13C NMR(125MHz,CDCl3)δ171.8,155.7,147.6,137.4,129.5,127.4,126.4,123.7,122.5,112.1,52.3,43.3,29.7。HRMS(ESI)：C12H13N2O2[M+H]+计算值：217.0973，实测值：217.0972。
实施例9化合物2-9的制备
Figure BDA0002431269780000091
除将亲核试剂换成D-丙氨酸甲酯盐酸盐之外，制备方法同实施例1，得化合物2-9，收率93％。1H NMR(400MHz,CDCl3)δ7.81(d,J＝8.8Hz,1H),7.68(d,J＝8.3Hz,1H),7.59(d,J＝8.8Hz,1H),7.53(t,J＝7.7Hz,1H),7.25–7.21(m,1H),6.67(d,J＝8.8Hz,1H),5.27(s,1H),4.90(p,J＝7.1Hz,1H),3.77(s,3H),1.56(d,J＝7.1Hz,3H).13C NMR(125MHz,CDCl3)δ175.0,155.3,147.4,137.4,129.5,127.4,126.4,123.6,122.5,112.0,52.3,49.7,18.6。HRMS(ESI)：C13H15N2O2[M+H]+计算值：231.1128，实测值：231.1129。
实施例10化合物2-10的制备
Figure BDA0002431269780000092
除将亲核试剂换成L-缬氨酸甲酯盐酸盐之外，制备方法同实施例1，得化合物2-10，收率91％。1H NMR(400MHz,CDCl3)δ7.76(d,J＝8.8Hz,1H),7.67(d,J＝8.4Hz,1H),7.56(d,J＝8.8Hz,1H),7.54–7.49(m,1H),7.24–7.19(m,1H),6.67(d,J＝8.8Hz,1H),5.21(d,J＝7.5Hz,1H),4.87(dd,J＝8.3,5.4Hz,1H),3.75(s,3H),1.05(dd,J＝6.8,3.4Hz,6H).13CNMR(125MHz,CDCl3)δ174.1,156.1,147.7,137.2,129.4,127.3,126.5,123.7,122.3,112.1,59.0,51.9,31.3,19.1,18.5。HRMS(ESI)：C13H15N2O2[M+H]+计算值：231.1128，实测值：231.1129。
实施例11化合物2-11的制备
Figure BDA0002431269780000093
除将亲核试剂换成L-异亮氨酸氨酸甲酯盐酸盐之外，制备方法同实施例1，得化合物2-11，收率82％。1H NMR(400MHz,CDCl3)δ7.83(d,J＝8.8Hz,1H),7.69(d,J＝8.4Hz,1H),7.60(d,J＝7.9Hz,1H),7.54(t,J＝7.1Hz,1H),7.24(t,J＝7.4Hz,1H),6.70(dd,J＝8.9,4.5Hz,1H),5.11(s,1H),4.93(dd,J＝8.3,5.5Hz,1H),3.77(s,3H),2.10–2.00(m,1H),1.71–1.54(m,2H),1.05–1.00(m,6H)。HRMS(ESI)：C16H21N2O2[M+H]+计算值：273.1598，实测值：273.1603。
实施例12化合物2-12的制备
Figure BDA0002431269780000101
除将亲核试剂换成L-丝氨酸甲酯盐酸盐之外，制备方法同实施例1，得化合物2-12，收率88％。1H NMR(400MHz,CDCl3)δ7.86(d,J＝8.9Hz,1H),7.68(d,J＝8.4Hz,1H),7.62(d,J＝7.9Hz,1H),7.59–7.53(m,1H),7.28–7.25(m,1H),6.77(d,J＝8.9Hz,1H),5.87(s,1H),4.97(s,1H),4.26(dd,J＝10.9,2.6Hz,1H),3.98(dd,J＝10.9,6.2Hz,1H),3.85(s,3H).13C NMR(150MHz,CDCl3)δ171.8,155.6,146.2,138.2,130.0,127.5,125.6,123.5,123.0,112.5,65.5,58.0,52.9。HRMS(ESI)：C13H15N2O3[M+H]+计算值：247.1081，实测值：247.1077。
实施例13化合物2-13的制备
Figure BDA0002431269780000102
除将亲核试剂换成D-苏氨酸甲酯盐酸盐之外，制备方法同实施例1，得化合物2-13，收率66％。1H NMR(400MHz,CDCl3)δ7.86(d,J＝8.8Hz,1H),7.68(d,J＝8.3Hz,1H),7.62(dd,J＝8.0,1.2Hz,1H),7.55(ddd,J＝8.4,7.0,1.5Hz,1H),7.28–7.24(m,1H),6.77(d,J＝8.8Hz,1H),5.51(s,1H),4.96(dd,J＝7.3,3.8Hz,1H),4.40(qd,J＝6.4,3.7Hz,1H),3.82(s,3H),1.35(d,J＝6.4Hz,3H).13C NMR(150MHz,CDCl3)δ172.8,156.0,147.1,137.6,129.6,127.4,126.3,123.8,122.7,112.4,69.3,59.9,52.5,20.4。HRMS(ESI)：C14H17N2O3[M+H]+计算值：261.1234，实测值：261.1228。
实施例14化合物2-14的制备
Figure BDA0002431269780000103
除将亲核试剂换成L-蛋氨酸甲酯盐酸盐之外，制备方法同实施例1，得化合物2-14，收率96％。1H NMR(400MHz,CDCl3)δ7.82(d,J＝8.8Hz,1H),7.68(d,J＝8.4Hz,1H),7.59(d,J＝7.9Hz,1H),7.53(t,J＝7.7Hz,1H),7.24(t,J＝7.4Hz,1H),6.70(d,J＝8.8Hz,1H),5.42(s,1H),5.06(q,J＝7.2Hz,1H),3.78(s,3H),2.65(td,J＝7.9,3.4Hz,2H),2.35(dq,J＝13.5,7.4Hz,1H),2.16(dd,J＝14.3,7.5Hz,1H).13C NMR(125MHz,CDCl3)δ173.9,155.4,147.3,137.5,129.6,127.4,126.4,123.7,122.6,112.0,53.2,52.4,32.0,30.3,15.5。HRMS(ESI)：C15H19N2O2S[M+H]+计算值：291.1162，实测值：291.1167。
实施例15化合物2-15的制备
Figure BDA0002431269780000111
除将亲核试剂换成L-苯丙氨酸甲酯盐酸盐之外，制备方法同实施例1，得化合物2-15，收率61％。1H NMR(400MHz,CDCl3)δ7.82(dd,J＝8.8,2.4Hz,1H),7.75(d,J＝8.1Hz,1H),7.62(d,J＝7.7Hz,1H),7.60–7.54(m,1H),7.35–7.26(m,4H),7.21(d,J＝7.3Hz,2H),6.65(dd,J＝8.8,2.7Hz,1H),5.27–5.21(m,1H),5.19(s,1H),3.77(d,J＝2.8Hz,3H),3.39(ddd,J＝13.7,5.5,2.4Hz,1H),3.27(ddd,J＝13.9,5.7,2.5Hz,1H).13C NMR(125MHz,CDCl3)δ173.3,155.1,147.1,137.6,136.6,130.4,129.6,129.4,128.5,127.4,126.9,126.2,123.6,122.6,112.1,55.1,52.2。HRMS(ESI)：C19H19N2O2[M+H]+计算值：307.1441，实测值：307.1437。
实施例16化合物2-16的制备
Figure BDA0002431269780000112
除将亲核试剂换成L-酪氨酸甲酯盐酸盐之外，制备方法同实施例1，得化合物2-16，收率63％。1H NMR(400MHz,CDCl3)δ7.85(d,J＝8.9Hz,1H),7.73(d,J＝8.5Hz,1H),7.61(dd,J＝8.0,1.2Hz,1H),7.54(ddd,J＝8.4,7.0,1.5Hz,1H),7.26(ddd,J＝8.0,7.0,1.1Hz,1H),6.97(d,J＝8.5Hz,2H),6.68(d,J＝8.5Hz,2H),6.64(d,J＝8.9Hz,1H),5.47(s,1H),5.03(s,1H),3.75(s,3H),3.25(dd,J＝13.9,5.3Hz,1H),3.13(dd,J＝13.9,6.4Hz,1H).13CNMR(125MHz,CDCl3)δ173.6,155.5,155.5,147.0,138.1,130.4,129.9,127.5,127.3,125.8,123.6,122.7,115.6,111.5,55.5,52.3,37.2。HRMS(ESI)：C19H19N2O3[M+H]+计算值：323.139，实测值：323.1388。
实施例17化合物2-17的制备
Figure BDA0002431269780000121
除将亲核试剂换成L-色氨酸甲酯盐酸盐之外，制备方法同实施例1，得化合物2-17，收率70％。1H NMR(400MHz,CDCl3)δ8.27(s,1H),7.80(d,J＝8.9Hz,1H),7.76(d,J＝8.4Hz,1H),7.61(d,J＝7.9Hz,2H),7.59–7.54(m,1H),7.35(d,J＝8.1Hz,1H),7.28–7.24(m,1H),7.20(t,J＝7.1Hz,1H),7.13(t,J＝7.5Hz,1H),7.01(d,J＝2.1Hz,1H),6.57(d,J＝8.8Hz,1H),5.34–5.29(m,1H),5.27(d,J＝8.2Hz,1H),3.73(s,3H),3.54(dd,J＝14.6,5.2Hz,1H),3.45(dd,J＝14.6,5.6Hz,1H).13C NMR(125MHz,CDCl3)δ173.9,155.4,147.5,137.4,136.2,129.5,127.8,127.4,126.4,123.6,122.9,122.5,122.1,119.6,118.8,112.2,111.2,110.7,54.6,52.2,27.9。HRMS(ESI)：C21H20N3O2[M+H]+计算值：346.155，实测值：346.156。
实施例18化合物2-18的制备
Figure BDA0002431269780000122
除将亲核试剂换成赖氨酸甲酯盐酸盐之外，制备方法同实施例1，得化合物2-18，收率53％。1H NMR(400MHz,D2O)δ7.94(s,1H),7.63(t,1H),7.59(d,J＝7.5Hz,1H),7.53(s,1H),7.35(t,J＝7.6Hz,1H),6.76(s,1H),4.06(t,J＝6.4Hz,1H),3.70(s,3H),3.33(t,J＝6.7Hz,2H),2.00–1.80(m,2H),1.67(p,J＝7.2Hz,2H),1.55–1.34(m,2H).13C NMR(125MHz,D2O)δ170.6,152.5,141.9,135.6,132.5,128.7,125.4,121.1,117.0,113.8,53.6,52.7,41.6,29.4,26.9,21.7。HRMS(ESI)：C16H22N3O2[M+H]+计算值：288.1707，实测值：288.17。
实施例19化合物2-19的制备
Figure BDA0002431269780000123
除将亲核试剂换成赖氨酸甲酰胺之外，制备方法同实施例1，得化合物2-19，收率80％。1H NMR(500MHz,Chloroform-d)δ7.80(d,J＝8.8Hz,1H),7.65(d,J＝8.2Hz,1H),7.57(dd,J＝8.0,1.4Hz,1H),7.51(ddd,J＝8.4,6.9,1.5Hz,1H),7.22–7.17(m,1H),6.63(d,J＝8.9Hz,1H),3.56–3.49(m,2H),3.40–3.33(m,1H),2.80(d,J＝4.9Hz,3H),1.73–1.58(m,6H).
实施例20化合物2-20的制备
Figure BDA0002431269780000131
除将2-(2,2-二甲氧基乙氧基)喹啉换成2-(2,2-二甲氧基乙氧基)-8-甲基喹啉、亲核试剂换成赖氨酸甲酯盐酸盐之外，制备方法同实施例1，得化合物2-20，收率56％。1HNMR(400MHz,MeOD4)δ8.44(s,1H),7.77(d,J＝7.9Hz,1H),7.68(d,J＝7.5Hz,1H),7.44(t,J＝7.7Hz,1H),7.31(s,1H),4.10(t,J＝6.4Hz,1H),3.86(s,3H),3.63(t,J＝8.1Hz,2H),2.65(s,3H),2.11–1.93(m,2H),1.81(ddd,J＝28.3,14.9,6.4Hz,2H),1.71–1.55(m,2H).13CNMR(125MHz,MeOD4)δ169.2,161.5,153.5,144.8,134.0,126.5,124.7,121.0,108.7,52.0,52.0,41.6,29.4,21.5,15.1。HRMS(ESI)：C17H24N3O2[M+H]+计算值：302.1863，实测值：302.1867。
实施例21化合物2-21的制备
Figure BDA0002431269780000132
除将2-(2,2-二甲氧基乙氧基)喹啉换成2-(2,2-二甲氧基乙氧基)-7-苯基喹啉、亲核试剂换成赖氨酸甲酯盐酸盐之外，制备方法同实施例1，得化合物2-21，收率40％。1HNMR(400MHz,MeOD4)δ8.42(s,1H),8.15(s,1H),8.10(d,J＝9.5Hz,1H),7.95(s,1H),7.73(d,J＝7.3Hz,2H),7.51(t,J＝7.6Hz,2H),7.42(t,J＝7.4Hz,1H),7.25(d,J＝9.4Hz,1H),3.84(s,3H),2.99(t,J＝7.4Hz,2H),2.28–2.16(m,1H),2.10–1.97(m,1H),1.84–1.72(m,2H),1.64(dt,J＝16.6,8.5Hz,2H).13C NMR(125MHz,MeOD4)δ170.2,161.2,153.0,138.5,135.2,131.3,128.5,127.5,126.4,125.8,121.8,117.6,54.6,51.8,38.6,30.3,26.3,22.0。HRMS(ESI)：C22H26N3O2[M+H]+计算值：364.202，实测值：364.2024。
实施例22化合物2-22的制备
Figure BDA0002431269780000133
除将2-(2,2-二甲氧基乙氧基)喹啉换成2-(2,2-二甲氧基乙氧基)-6-(4-甲氧基苯基)喹啉、亲核试剂换成赖氨酸甲酯盐酸盐之外，制备方法同实施例1，得化合物2-22，收率42％。1H NMR(400MHz,MeOD4)δ8.39(s,1H),8.05(d,J＝11.0Hz,2H),7.91(s,1H),7.66(d,J＝8.8Hz,2H),7.23(d,J＝9.4Hz,1H),7.05(d,J＝8.8Hz,2H),3.86(s,3H),3.84(s,3H),2.98(t,J＝7.5Hz,2H),2.20(s,1H),2.02(s,1H),1.82–1.73(m,2H),1.63(dt,J＝14.2,7.2Hz,2H).13C NMR(125MHz,MeOD4)δ170.2,159.7,152.8,138.2,134.7,130.9,130.8,127.5,127.4,124.9,121.8,117.5,113.9,54.6,54.1,51.8,38.6,30.3,26.3,22.0。HRMS(ESI)：C23H28N3O3[M+H]+计算值：394.2125，实测值：394.2122。
实施例23化合物2-23的制备
Figure BDA0002431269780000141
除将2-(2,2-二甲氧基乙氧基)喹啉或2-(2,2-二甲氧基乙硫基)喹啉换成2-(2,2-二甲氧基乙氧基)-4-甲基喹啉或2-(2,2-二甲氧基乙硫基)-4-甲基喹啉之外，制备方法同实施例1，得化合物2-23，收率91％。1H NMR(400MHz,CDCl3)δ7.81(s,1H),7.73(s,1H),7.58(s,1H),7.30(s,1H),7.05(s,1H),6.55(s,1H),5.63(s,1H),4.21(s,2H),2.83(d,J＝4.5Hz,3H),2.56(s,3H).13C NMR(125MHz,DMSO-d6)δ170.9,156.7,147.8,144.1,129.3,126.4,124.2,123.8,121.9,113.5,44.3,26.0,18.7。HRMS(ESI)：C13H16N3O[M+H]+计算值：230.1288，实测值：230.1291。
实施例24化合物2-24的制备
Figure BDA0002431269780000142
除将2-(2,2-二甲氧基乙氧基)喹啉或2-(2,2-二甲氧基乙硫基)喹啉换成2-(2,2-二甲氧基乙氧基)-8-甲基喹啉或2-(2,2-二甲氧基乙硫基)-8-甲基喹啉之外，制备方法同实施例1，得化合物2-24，收率45％。1H NMR(400MHz,CDCl3)δ7.85(d,J＝8.8Hz,1H),7.50(dd,J＝8.0,1.4Hz,1H),7.46(d,J＝7.1Hz,0H),7.24(s,2H),7.19(dd,J＝7.9,7.1Hz,1H),6.72(d,J＝8.8Hz,1H),5.50(s,1H),4.22(d,J＝5.2Hz,2H),2.83(d,J＝4.9Hz,3H),2.65(s,3H).13C NMR(125MHz,CDCl3)δ171.9,155.2,146.1,138.0,134.0,130.1,125.5,123.4,122.5,111.6,46.5,26.0,17.9。HRMS(ESI)：C13H16N3O[M+H]+计算值：230.1288，实测值：230.1291。
实施例25化合物2-25的制备
Figure BDA0002431269780000151
除将2-(2,2-二甲氧基乙氧基)喹啉或2-(2,2-二甲氧基乙硫基)喹啉换成2-(2,2-二甲氧基乙氧基)-6-氯喹啉2-(2,2-二甲氧基乙硫基)-6-氯喹啉之外，制备方法同实施例1，得化合物2-25，收率53％。1H NMR(400MHz,MeOD4)δ7.86(d,J＝9.0Hz,1H),7.65(s,1H),7.59(d,J＝9.0Hz,1H),7.46(d,J＝8.9Hz,1H),6.88(d,J＝8.8Hz,1H),4.13(s,2H),2.76(s,3H).13C NMR(125MHz,DMSO-d6)δ170.6,157.3,146.6,135.9,129.6,128.0,126.6,125.6,124.4,114.9,44.3,26.0。HRMS(ESI)：C12H13ClN3O[M+H]+计算值：250.0742，实测值：250.0739。
实施例26化合物2-26的制备
Figure BDA0002431269780000152
除将2-(2,2-二甲氧基乙氧基)喹啉或2-(2,2-二甲氧基乙硫基)喹啉换成2-(2,2-二甲氧基乙氧基)-8-溴喹啉或2-(2,2-二甲氧基乙硫基)-8-溴喹啉之外，制备方法同实施例1，得化合物2-26，收率42％。1H NMR(400MHz,CDCl3)δ7.90(dd,J＝7.6,1.2Hz,1H),7.81(d,J＝8.9Hz,1H),7.59(dd,J＝7.9,1.1Hz,1H),7.13(t,J＝7.8Hz,1H),6.76(d,J＝8.9Hz,1H),6.10(s,1H),4.23(d,J＝6.0Hz,2H),2.85(d,J＝4.9Hz,3H).13C NMR(125MHz,CDCl3)δ171.5,156.7,144.4,137.9,133.1,127.3,124.8,123.0,121.2,113.2,46.8,26.0。HRMS(ESI)：C12H13BrN3O[M+H]+计算值：294.0237，实测值：294.0245。
实施例27化合物2-27的制备
Figure BDA0002431269780000153
除将2-(2,2-二甲氧基乙氧基)喹啉或2-(2,2-二甲氧基乙硫基)喹啉换成3-氯-1-(2,2-二甲氧基乙氧基)异喹啉或3-氯-1-(2,2-二甲氧基乙硫基)异喹啉之外，制备方法同实施例1，得化合物2-27，收率52％。1H NMR(400MHz,CDCl3)δ7.86(d,J＝8.4Hz,1H),7.65–7.58(m,2H),7.50–7.42(m,1H),7.01(s,1H),6.49(s,1H),6.39(s,1H),4.29(d,J＝5.0Hz,2H),2.91(d,J＝4.8Hz,3H).13C NMR(125MHz,CDCl3)δ170.5,154.7,143.8,138.7,130.8,126.4,126.2,122.0,116.6,109.4,45.4,26.3。HRMS(ESI)C12H13ClN3O[M+H]+计算值：250.0742，实测值：250.0739。
实施例28化合物2-28的制备
Figure BDA0002431269780000161
除将2-(2,2-二甲氧基乙氧基)喹啉或2-(2,2-二甲氧基乙硫基)喹啉换成2-(2,2-二甲氧基乙氧基)-7-苯基喹啉或2-(2,2-二甲氧基乙硫基)-7-苯基喹啉之外，制备方法同实施例1，得化合物2-28，收率75％。1H NMR(400MHz,CDCl3)δ7.90(d,J＝8.8Hz,1H),7.82(t,2H),7.76(d,J＝9.1Hz,1H),7.67(d,J＝8.0Hz,2H),7.47(t,J＝7.6Hz,2H),7.36(t,J＝7.4Hz,1H),6.83(s,1H),6.72(d,J＝8.8Hz,1H),5.50(s,1H),4.23(d,J＝5.1Hz,2H),2.84(d,J＝4.9Hz,2H).13C NMR(125MHz,CDCl3)δ171.2,156.0,146.7,140.7,138.0,135.7,129.3,128.9,127.1,127.1,126.5,125.4,123.9,112.3,45.9,26.2。HRMS(ESI)：C18H18N3O[M+H]+计算值：292.1444，实测值：292.1449。
实施例29化合物2-29的制备
Figure BDA0002431269780000162
除将2-(2,2-二甲氧基乙氧基)喹啉或2-(2,2-二甲氧基乙硫基)喹啉换成2-(2,2-二甲氧基乙氧基)-6-(4-甲氧基苯基)喹啉或2-(2,2-二甲氧基乙硫基)-6-(4-甲氧基苯基)喹啉之外，制备方法同实施例1，得化合物2-29，收率54％。1H NMR(400MHz,DMSO-d6)δ7.91(d,J＝9.0Hz,1H),7.87(d,J＝1.9Hz,1H),7.75(dd,J＝8.7,2.0Hz,1H),7.65(d,J＝8.7Hz,2H),7.51(d,1H),7.28(t,J＝5.5Hz,1H),7.01(d,J＝8.7Hz,2H),6.89(d,J＝8.9Hz,1H),4.00(d,J＝5.5Hz,2H),3.78(s,3H),2.60(d,J＝4.0Hz,3H).13C NMR(125MHz,DMSO-d6)δ170.8,159.0,157.0,147.1,136.9,133.3,132.8,128.1,128.0,126.6,124.7,123.8,114.8,114.1,55.6,44.5,26.0。HRMS(ESI)：C19H20N3O2[M+H]+计算值：322.155，实测值：322.1549。
实施例30化合物2-30的制备
Figure BDA0002431269780000163
除将2-(2,2-二甲氧基乙氧基)喹啉或2-(2,2-二甲氧基乙硫基)喹啉换成2-(2,2-二甲氧基乙氧基)-6-(4-三氟甲基苯基)喹啉或2-(2,2-二甲氧基乙硫基)-6-(4-三氟甲基苯基)喹啉之外，制备方法同实施例1，得化合物2-30，收率65％。1H NMR(400MHz,DMSO-d6)δ8.06(d,J＝1.8Hz,1H),7.96(t,3H),7.86(dd,J＝8.7,2.0Hz,1H),7.80(d,J＝8.3Hz,2H),7.57(d,1H),7.41(t,J＝5.8Hz,1H),6.93(d,J＝8.9Hz,1H),4.02(d,J＝5.4Hz,2H),2.60(d,J＝3.9Hz,3H).13C NMR(125MHz,DMSO-d6)δ170.6,157.5,148.1,144.4,137.1,131.7,128.3,127.5,126.8,126.3,126.2,126.2,126.2,123.8,114.5,44.4,26.0。HRMS(ESI)：C19H17FN3O[M+H]+计算值：360.1318，实测值：360.1317。
实施例31化合物2-31的制备
Figure BDA0002431269780000171
除将2-(2,2-二甲氧基乙氧基)喹啉或2-(2,2-二甲氧基乙硫基)喹啉换成2-(2,2-二甲氧基乙氧基)-6-(4-氰基苯基)喹啉或2-(2,2-二甲氧基乙硫基)-6-(4-氰基苯基)喹啉之外，制备方法同实施例1，得化合物2-31，收率78％。1H NMR(400MHz,DMSO-d6)δ8.11(s,1H),7.94(dt,J＝19.1,9.6Hz,7H),7.59(d,J＝8.8Hz,1H),7.49(t,J＝5.6Hz,1H),6.96(d,J＝9.1Hz,1H),4.04(d,J＝5.2Hz,2H),2.62(d,J＝4.4Hz,3H).13C NMR(125MHz,DMSO-d6)δ170.6,157.6,148.3,144.9,137.1,133.3,131.3,128.2,127.6,126.9,126.5,123.7,119.5,114.5,109.7,44.4,26.0。HRMS(ESI)：C19H17N4O[M+H]+计算值：317.1397，实测值：317.1401。
实施例32化合物2-32的制备
Figure BDA0002431269780000172
除将2-(2,2-二甲氧基乙氧基)喹啉或2-(2,2-二甲氧基乙硫基)喹啉换成4-(2-(2,2-二甲氧基乙氧基)喹啉-6-基)苯甲酸甲酯或者4-(2-(2,2-二甲氧基乙硫基)喹啉-6-基)苯甲酸甲酯之外，制备方法同实施例1，得化合物2-32，收率57％。1H NMR(400MHz,DMSO-d6)δ8.09(d,J＝2.0Hz,1H),8.05(d,J＝8.4Hz,2H),7.98(d,J＝8.9Hz,1H),7.94–7.88(m,4H),7.59(d,J＝8.7Hz,1H),7.44(t,J＝5.5Hz,1H),6.95(d,J＝8.9Hz,1H),4.04(d,J＝5.6Hz,2H),3.88(s,3H),2.62(d,J＝4.6Hz,3H).13C NMR(125MHz,DMSO-d6)δ170.7,166.6,157.5,148.1,145.0,137.1,131.9,130.3,128.3,128.2,127.0,126.8,126.3,123.8,114.4,56.5,52.6,26.0。HRMS(ESI)：C20H20N3O3[M+H]+计算值：350.1499，实测值：350.1501。
实施例33化合物2-33的制备
Figure BDA0002431269780000181
除将2-(2,2-二甲氧基乙氧基)喹啉或2-(2,2-二甲氧基乙硫基)喹啉换成2-(2,2-二甲氧基乙氧基)-7-(2-氟苯基)-4-甲基喹啉或2-(2,2-二甲氧基乙硫基)-7-(2-氟苯基)-4-甲基喹啉之外，制备方法同实施例1，得化合物2-33，收率70％。1H NMR(400MHz,CDCl3)δ7.86(d,J＝8.9Hz,1H),7.68(d,J＝8.4Hz,1H),7.62(d,J＝7.9Hz,1H),7.59–7.53(m,1H),7.28–7.25(m,1H),6.77(d,J＝8.9Hz,1H),5.87(s,1H),4.97(s,1H),4.26(dd,J＝10.9,2.6Hz,1H),3.98(dd,J＝10.9,6.2Hz,1H),3.85(s,3H).13C NMR(125MHz,CDCl3)δ171.8,155.6,146.2,138.2,130.0,127.5,125.6,123.5,123.0,112.5,65.5,58.0,52.9.HRMS(ESI)：C13H15N2O3[M+H]+计算值：247.1077，实测值：247.1081。
唑啉季铵盐与各种含氨基酸残基的复杂分子反应的制备实例：
通过以下各种含氨基酸残基的复杂分子与唑啉季铵盐反应的制备实例说明本方法可用于各种含氨基酸残基的复杂分子化学修饰，且选择性良好。
实施例34化合物2-34的制备
Figure BDA0002431269780000182
除将亲核试剂换成2-氨基-N-(2-(2,5-二甲氧基苯基)-2-羟基乙基)乙酰胺盐酸盐之外，制备方法同实施例1，得化合物2-34，收率72％。1H NMR(500MHz,MeOD4)δ7.88(d,J＝8.9Hz,1H),7.62(t,J＝8.0Hz,2H),7.53–7.48(m,1H),7.24(t,1H),7.00(d,1H),6.81(d,1H),6.75(d,1H),6.70(dd,J＝8.9,3.1Hz,1H),5.08(dd,J＝7.1,4.3Hz,1H),4.12(s,2H),3.72(s,3H),3.68(s,3H),3.56(dd,1H),3.39(dd,1H).13C NMR(126MHz,MeOD4)δ172.5,156.8,153.8,150.3,147.3,137.2,131.1,129.1,127.2,125.4,123.7,122.0,112.5,112.3,111.1,66.7,54.9,54.6,45.1,44.6。HRMS(ESI)：C21H24N3O4[M+H]+计算值：382.1761，实测值：382.1761。
实施例35化合物2-35的制备
Figure BDA0002431269780000191
除将亲核试剂换成沙格列汀盐酸盐之外，制备方法同实施例1，得化合物2-35，收率46％。1H NMR(400MHz,CDCl3)δ7.58–7.46(m,5H),7.22(t,J＝7.3Hz,1H),6.65(d,J＝8.7Hz,1H),5.94(d,J＝9.5Hz,1H),5.27(d,J＝9.4Hz,1H),5.00(dd,J＝10.6,2.4Hz,1H),4.63(td,J＝6.2,2.6Hz,1H),2.75(s,1H),2.51(ddd,J＝13.8,10.7,5.8Hz,1H),2.36(dd,J＝13.7,2.4Hz,1H),2.32–2.23(m,3H),2.07(d,J＝11.6Hz,1H),2.00–1.92(m,2H),1.86(dd,J＝25.7,12.0Hz,2H),1.73(q,J＝14.1Hz,6H),1.59(d,J＝14.3Hz,3H),1.28(s,2H),1.18(s,1H),1.17–1.11(m,1H).13C NMR(126MHz,CDCl3)δ171.7,156.6,147.5,136.9,129.2,127.5,126.1,123.8,122.2,119.5,113.2,68.7,58.9,46.2,45.3,44.6,44.2,40.7,38.3,38.0,37.7,35.5,30.6,30.4,30.3,17.5,13.7。HRMS(ESI)：C27H31N4O2[M+H]+计算值：443.2432，实测值：443.2442。
实施例36化合物2-36的制备
Figure BDA0002431269780000192
除将亲核试剂换成(S)-2-((S)-2-氨基-3-甲基丁酰氨基)-N-(4-(羟基甲基)苯基)-5-脲基戊酰胺盐酸盐之外，制备方法同实施例1，得化合物2-36，收率56％。1H NMR(400MHz,MeOD4)δ7.87(d,J＝8.9Hz,1H),7.63–7.58(m,2H),7.47(ddd,J＝8.4,7.0,1.4Hz,1H),7.39(d,J＝8.5Hz,2H),7.25(d,J＝8.6Hz,2H),7.22–7.17(m,1H),6.91(d,J＝8.9Hz,1H),4.58–4.53(m,3H),4.49(d,J＝7.5Hz,1H),3.37(s,2H),3.09(dt,J＝13.3,6.7Hz,1H),2.99(dt,J＝13.5,6.7Hz,1H),2.30–2.19(m,1H),1.94–1.84(m,1H),1.80–1.68(m,1H),1.60–1.43(m,2H),1.11(d,J＝6.9Hz,3H),1.09(d,J＝6.8Hz,3H).13C NMR(126MHz,MeOD4)δ174.4,170.9,160.8,157.0,147.4,137.4,137.0,136.9,129.0,127.1,127.1,125.4,123.6,121.9,120.0,112.6,63.4,60.9,53.4,48.4,30.4,29.3,26.3,18.7,17.9。HRMS(ESI)：C27H35N6O4[M+H]+计算值：507.2724，实测值：507.2714。
实施例37化合物2-37的制备
Figure BDA0002431269780000201
除将亲核试剂换成缩宫素之外，制备方法同实施例1，得化合物2-37，收率42％。1HNMR(400MHz,MeOD4-d4)δ8.36(d,J＝9.2Hz,1H),7.96(d,J＝7.8Hz,1H),7.89(t,J＝7.8Hz,1H),7.74(d,J＝8.3Hz,1H),7.61(t,J＝7.4Hz,1H),7.00(d,4H),6.18(s,1H),5.17(s,1H),4.87(d,J＝6.8Hz,2H),4.50–4.42(m,1H),4.31(dd,J＝9.4,5.4Hz,1H),4.07(d,J＝6.5Hz,1H),3.95(d,J＝7.6Hz,1H),3.91(d,J＝17.1Hz,1H),3.81(d,J＝8.4Hz,1H),3.76(d,J＝17.0Hz,1H),3.68(dt,J＝10.4,5.7Hz,1H),3.42(dt,J＝13.6,4.3Hz,2H),3.37(s,4H),2.91(s,1H),2.71(s,1H),2.39(t,J＝6.9Hz,2H),2.31–2.14(m,3H),2.03–1.83(m,4H),1.68(qd,J＝9.7,9.3,5.1Hz,4H),1.37–1.24(m,1H),1.05(d,J＝6.7Hz,3H),1.00(t,J＝7.4Hz,3H),0.94(d,J＝6.3Hz,3H),0.91(d,J＝6.1Hz,3H).13C NMR(125MHz,MeOD4)δ176.6,173.7,173.5,173.2,172.9,172.1,168.4,167.7,157.7,157.4,155.6,133.1,129.8,128.7,127.2,125.9,121.8,117.7,115.8,114.4,113.5,61.0,60.8,55.8,54.9,53.6,53.0,52.3,50.6,48.5,48.2,41.9,39.7,37.7,35.7,31.4,29.0,25.6,24.5,24.5,22.1,20.5,14.6,10.2。HRMS(ESI)：C52H70N13O12S2[M+H]+计算值：1132.4742，实测值：1132.4742。
实施例38化合物2-38的制备
Figure BDA0002431269780000202
除将亲核试剂换成皮啡肽之外，制备方法同实施例1，得化合物2-38，收率47％。1HNMR(400MHz,DMSO-d6)δ9.25(s,1H),9.17(s,1H),8.27(d,J＝8.0Hz,1H),8.20(s,1H),8.12(d,J＝8.6Hz,1H),8.00(d,J＝6.9Hz,1H),7.82(d,J＝8.9Hz,1H),7.75(d,J＝7.4Hz,1H),7.59(d,J＝7.6Hz,1H),7.49(d,J＝7.8Hz,1H),7.46–7.38(m,1H),7.18(dd,J＝13.4,5.1Hz,5H),7.12(d,J＝7.5Hz,3H),7.10–7.05(m,3H),6.85(d,J＝8.9Hz,1H),6.66(d,J＝8.2Hz,2H),6.62(d,J＝8.0Hz,2H),4.91(t,J＝5.3Hz,1H),4.74(d,J＝4.4Hz,1H),4.60(s,1H),4.47(s,1H),4.35(d,J＝6.0Hz,1H),4.26–4.04(m,2H),3.78–3.69(m,1H),3.68–3.54(m,4H),2.97(d,J＝10.9Hz,3H),2.87–2.76(m,1H),2.69–2.60(m,1H),2.57(d,J＝12.8Hz,1H),1.93(d,J＝51.9Hz,4H),0.82(d,J＝6.9Hz,3H).13C NMR(125MHz,DMSO-d6)δ172.5,172.3,172.3,171.6,171.6,171.0,168.8,156.6,156.3,156.1,147.9,138.2,136.8,130.7,130.6,129.6,129.5,128.8,128.4,128.1,127.8,126.6,126.2,123.5,121.9,115.5,115.3,113.6,62.0,60.4,56.5,55.5,54.1,53.1,48.5,47.4,42.0,38.1,37.5,36.7,29.3,24.9,18.8。HRMS(ESI)：C49H54N9O10[M+H]+计算值：928.3999，实测值：928.3993。
实施例39化合物2-39的制备
Figure BDA0002431269780000211
除将亲核试剂换成酪丝亮肽之外，制备方法同实施例1，得化合物2-39，收率56％。1HNMR(400MHz,DMSO-d6)δ9.16(s,1H),8.20(d,J＝7.9Hz,1H),7.98(d,J＝7.9Hz,1H),7.84(d,J＝8.9Hz,1H),7.60(d,J＝7.9Hz,1H),7.50–7.42(m,2H),7.21(d,J＝7.6Hz,1H),7.17(s,1H),7.13(d,J＝7.6Hz,2H),6.85(d,J＝8.9Hz,1H),6.62(d,J＝7.6Hz,2H),4.84(t,J＝5.0Hz,1H),4.76(s,1H),4.31(dd,J＝14.0,7.0Hz,2H),4.15(d,J＝5.0Hz,1H),3.61(s,3H),3.19–3.17(m,3H),1.58–1.44(m,2H),1.41–1.35(m,2H),0.81–0.75(m,6H).13C NMR(125MHz,DMSO-d6)δ173.1,173.1,170.5,156.8,156.1,147.9,136.8,130.6,129.4,129.0,127.9,126.2,123.5,121.9,115.3,113.6,62.1,56.7,55.3,52.3,50.6,49.1,37.2,24.5,23.1,21.7。HRMS(ESI)：C28H35N4O6[M+H]+计算值：523.2551，实测值：523.2554。
实施例40化合物2-40的制备
Figure BDA0002431269780000212
除将2-(2,2-二甲氧基乙氧基)喹啉或2-(2,2-二甲氧基乙硫基)喹啉换成2-(2,2-二甲氧基乙氧基)-7-(2-氟苯基)-4-甲基喹啉或2-(2,2-二甲氧基乙硫基)-7-(2-氟苯基)-4-甲基喹啉、将亲核试剂换成(S)-2-((S)-2-氨基-3-甲基丁酰氨基)-N-(4-(羟基甲基)苯基)-5-脲基戊酰胺盐酸盐之外，制备方法同实施例1，得化合物2-40，收率52％。1H NMR(500MHz,MeOD-d4)δ7.88(d,J＝8.4Hz,1H),7.80(s,1H),7.51(t,J＝7.8Hz,1H),7.44(d,J＝8.4Hz,1H),7.42–7.37(m,1H),7.33(d,J＝8.5Hz,2H),7.28(t,J＝7.5Hz,1H),7.24–7.21(m,1H),7.20(d,J＝8.4Hz,2H),6.82(s,1H),4.56(dd,J＝9.0,5.1Hz,1H),4.52(s,2H),4.48(d,J＝7.4Hz,1H),3.11–3.04(m,1H),3.01–2.94(m,1H),2.61(s,3H),2.31–2.22(m,1H),1.89(dt,J＝14.3,6.6Hz,1H),1.78–1.68(m,1H),1.57–1.47(m,2H),1.13(d,J＝6.8Hz,3H),1.11(d,J＝6.8Hz,3H).13C NMR(125MHz,MeOD4-d4)δ175.8,172.3,162.2,160.3,158.7,148.8,146.2,138.8,138.3,137.9,132.1,130.5,130.4,128.4,127.4,125.7,124.8,124.6,124.1,121.5,117.2,117.0,114.2,64.8,62.4,54.8,31.7,30.7,27.7,20.1,19.3,18.7.HRMS(ESI)：C34H40FN6O4[M+H]+计算值：615.309，实测值：615.3081。
实施例41化合物2-41的制备
Figure BDA0002431269780000221
用2-(2,2-二甲氧基乙氧基)喹啉，将亲核试剂换成醋酸奥曲肽盐酸盐，其余制备方法同实施例1，得化合物2-41，收率41％。1H NMR(500MHz,Methanol-d4)δ8.27(d,J＝9.4Hz,1H),7.85(d,J＝7.9Hz,1H),7.78(dd,J＝14.4,7.1Hz,2H),7.53(d,J＝7.8Hz,1H),7.48(d,J＝7.9Hz,1H),7.40–7.36(m,3H),7.27–7.22(m,3H),7.19(t,J＝7.9Hz,4H),7.16–7.10(m,3H),7.04(t,J＝7.4Hz,1H),7.00(s,1H),5.25(d,J＝9.4Hz,2H),4.68(dd,J＝8.8,6.2Hz,1H),4.49(d,J＝5.6Hz,1H),4.40–4.31(m,1H),4.23(dd,J＝11.0,5.3Hz,1H),4.17(dd,J＝6.4,2.8Hz,1H),4.02(dd,J＝10.9,3.2Hz,1H),3.89–3.85(m,1H),3.74(s,2H),3.50(d,J＝9.2Hz,1H),3.33(s,2H),3.18–2.90(m,8H),2.86(dd,J＝13.8,5.2Hz,1H),2.61(dq,J＝18.7,12.4,9.4Hz,2H),1.35–1.23(m,9H),0.64–0.43(m,2H).HRMS(ESI)：C58H72N11O10S2[M+H]+计算值：1146.49，实测值：1146.4891。
实施例42化合物2-42的制备
Figure BDA0002431269780000231
用2-(2,2-二甲氧基乙氧基)-6-(4-甲氧基苯基)喹啉、亲核试剂换成醋酸奥曲肽盐酸盐，其余制备方法同实施例1，得化合物2-42，收率40％。1H NMR(500MHz,Methanol-d4)δ8.35(d,J＝9.4Hz,1H),8.23(d,J＝8.7Hz,1H),8.14–8.00(m,2H),7.81(d,J＝9.0Hz,1H),7.71–7.64(m,2H),7.51(d,J＝8.0Hz,1H),7.42(d,J＝7.6Hz,2H),7.39(d,J＝8.1Hz,1H),7.31(t,J＝7.5Hz,2H),7.27–7.19(m,5H),7.18–7.13(m,2H),7.08(dd,J＝8.4,6.7Hz,3H),7.02(s,1H),5.30(t,J＝12.2Hz,2H),4.71(dd,J＝8.9,6.0Hz,1H),4.54–4.47(m,1H),4.44–4.33(m,1H),4.25(dd,J＝10.9,5.4Hz,1H),4.23–4.16(m,1H),4.06(dd,J＝11.0,3.5Hz,1H),3.89(s,4H),3.77(d,J＝5.2Hz,2H),3.54(dd,J＝14.0,5.0Hz,1H),3.39(s,2H),3.23–2.94(m,8H),2.89(dd,J＝13.8,5.3Hz,1H),2.65(tt,J＝20.1,10.6Hz,2H),1.28(m,9H),0.69–0.50(m,2H).HRMS(ESI)：C65H78N11O11S2[M+H]+计算值：1252.5318，实测值：1252.5299。
实施例43化合物2-43的制备
Figure BDA0002431269780000232
用2-(2,2-二甲氧基乙硫基)喹啉或者2-(2,2-二甲氧基乙硒基)喹啉，亲核试剂换成醋酸奥曲肽盐酸盐，其余制备方法同实施例1，得化合物2-43，收率33％-41％。1H NMR(500MHz,Methanol-d4)δ7.84(d,J＝9.1Hz,1H),7.68(d,J＝8.4Hz,1H),7.61(dd,J＝8.0,1.5Hz,1H),7.53–7.49(m,1H),7.48–7.42(m,1H),7.36–7.24(m,11H),7.20(m,1H),7.05(m,2H),6.95(s,1H),6.74(d,J＝9.0Hz,1H),5.19(m,1H),5.13(m,1H),4.69(m,1H),4.47(d,J＝5.2Hz,1H),4.43–4.34(m,1H),4.17(m,1H),4.08(m,1H),4.01(m,1H),3.86(m,1H),3.82–3.76(m,1H),3.73(m,1H),3.67(m,1H),3.32–3.25(m,2H),3.16–3.09(m,2H),3.07–2.85(m,7H),2.83–2.76(m,1H),1.78(m,1H),1.42–1.31(m,3H),1.28(d,J＝6.4Hz,3H),1.21(d,J＝6.4Hz,3H),0.80–0.60(m,2H).13C NMR(125MHz,Methanol-d4)δ174.44,174.20,173.98,171.47,171.41,169.10,157.46,147.27,137.07,136.87,136.66,136.57,129.24,129.15,129.08,128.33,128.08,127.32,127.04,126.64,126.52,124.11,123.13,121.56,121.16,118.53,117.82,112.71,111.12,108.59,67.02,65.79,61.31,59.77,56.37,56.27,55.80,54.97,54.26,52.64,52.46,44.38,42.03,40.71,40.43,39.29,30.40,28.48,25.87,22.70,19.02,18.81.HRMS(ESI)：C58H72N11O10S2[M+H]+计算值：1146.4900，实测值：1146.4894。
实施例44化合物2-44的制备
Figure BDA0002431269780000241
用6-氟-2-(2,2-二甲氧基乙硫基)喹啉或6-氟-2-(2,2-二甲氧基乙硒基)喹啉，亲核试剂换成醋酸奥曲肽盐酸盐，其余制备方法同实施例1，得化合物2-44，收率47％-52％。1H NMR(600MHz,Methanol-d4)δ7.79(d,J＝9.0Hz,1H),7.68–7.62(m,1H),7.42(dd,J＝7.4,1.3Hz,1H),7.34–7.26(m,11H),7.22(dd,J＝8.0,1.6Hz,2H),7.02(m,2H),6.92(s,1H),6.75(d,J＝9.0Hz,1H),5.14(m,2H),4.65(m,1H),4.44(d,J＝5.3Hz,1H),4.41–4.32(m,1H),4.14(m,1H),4.09–4.05(m,1H),4.02–3.93(m,2H),3.81(m,1H),3.72–3.61(m,2H),3.26(m,2H),3.16(m,1H),3.09(m,1H),3.03–2.85(m,7H),2.77(m,1H),1.75(m,1H),1.43–1.30(m,3H),1.25(d,J＝6.4Hz,3H),1.18(d,J＝6.5Hz,3H),0.65(m,2H).13C NMR(150MHz,Methanol-d4)δ174.35,174.07,171.69,171.36,171.33,171.22,168.85,158.44,157.01,156.86,144.04,136.54,136.41,136.17,135.57,129.09,128.93,128.41,127.97,126.94,126.43,126.02,125.96,123.22,123.16,123.02,121.04,118.40,117.87,117.70,113.76,110.99,110.74,110.60,108.46,66.89,65.68,61.12,59.63,56.17,55.05,54.86,54.11,52.73,52.29,44.21,42.02,40.52,39.16,39.09,30.25,28.31,25.72,22.58,18.86,18.68.HRMS(ESI)：C58H71FN11O10S2[M+H]+计算值：1164.4805，实测值：1164.482。
实施例45化合物2-45的制备
Figure BDA0002431269780000251
用6-炔基-3-苄基-2-(2,2-二甲氧基乙硫基)喹啉或6-炔基-3-苄基-2-(2,2-二甲氧基乙硒基)喹啉，亲核试剂换成醋酸奥曲肽盐酸盐，其余制备方法同实施例1，得化合物2-45，收率40％。1H NMR(600MHz,Methanol-d4)δ7.66(d,J＝1.9Hz,1H),7.62(d,J＝8.6Hz,1H),7.52–7.46(m,2H),7.44–7.38(m,1H),7.36–7.17(m,16H),7.04–6.96(m,2H),6.88(s,1H),5.21–5.09(m,2H),4.71–4.60(m,1H),4.43(d,J＝5.4Hz,1H),4.38–4.31(m,1H),4.16–4.11(m,1H),4.08–4.04(m,1H),3.98–3.90(m,4H),3.83–3.78(m,1H),3.71–3.61(m,2H),3.41(s,1H),3.34(t,J＝3.7Hz,2H),3.18–3.12(m,1H),3.11–3.06(m,1H),3.03–2.85(m,7H),2.79–2.72(m,1H),1.74–1.63(m,1H),1.34–1.28(m,1H),1.27–1.25(m,2H),1.23(d,J＝6.4Hz,3H),1.18(d,J＝6.5Hz,3H),0.65–0.45(m,2H).HRMS(ESI)：C67H78N11O10S2[M+H]+计算值：1260.5369，实测值：1260.5374。
实施例46化合物2-46的制备
Figure BDA0002431269780000252
用6-炔基-2-(2,2-二甲氧基乙硫基)喹啉或6-炔基-2-(2,2-二甲氧基乙硒基)喹啉，亲核试剂换成醋酸奥曲肽盐酸盐，其余制备方法同实施例1，得化合物2-46，收率45％-78％。1H NMR(600MHz,Methanol-d4)δ7.77(d,J＝9.0Hz,1H),7.72(d,J＝1.9Hz,1H),7.59(d,J＝8.6Hz,1H),7.52(dd,J＝8.7,1.9Hz,1H),7.42(dd,J＝7.7,1.3Hz,1H),7.34–7.22(m,11H),7.03(m,2H),6.93(s,1H),6.73(d,J＝9.0Hz,1H),5.13(m,2H),4.65(m,1H),4.43(d,J＝5.3Hz,1H),4.40–4.32(m,1H),4.14(m,1H),4.06(m,1H),3.98(m,1H),3.89(t,J＝7.1Hz,1H),3.81(m,1H),3.69(m,1H),3.64(m,1H),3.43(s,1H),3.27(m,2H),3.12(m,2H),3.03–2.89(m,7H),2.77(m,1H),1.75(m,1H),1.43–1.30(m,3H),1.25(d,J＝6.4Hz,3H),1.18(d,J＝6.5Hz,3H),0.81–0.58(m,2H).13C NMR(125MHz,Methanol-d4)δ174.02,173.75,172.10,171.02,170.99,170.90,168.55,157.54,147.13,136.20,136.08,135.98,135.65,131.67,130.82,128.71,128.59,128.00,127.61,126.58,126.45,126.07,124.06,122.67,122.27,120.70,118.06,117.35,114.79,110.64,108.13,82.82,75.87,66.51,65.32,60.79,59.30,55.84,54.94,54.52,53.78,52.31,51.94,43.87,41.55,40.12,39.17,38.82,29.89,27.94,25.37,22.22,18.52,18.32.HRMS(ESI)：C60H72N11O10S2[M+H]+计算值：1170.49，实测值：1170.4902。
实施例47化合物2-47的制备
Figure BDA0002431269780000261
用2-(2,2-二甲氧基乙硫基)喹啉或2-(2,2-二甲氧基乙硒基)喹啉，亲核试剂换成促生长激素释放肽，其余制备方法同实施例1，得化合物2-47，收率50％-93％。1H NMR(600MHz,Methanol-d4)δ7.72(d,J＝9.0Hz,1H),7.69–7.65(m,1H),7.60–7.51(m,3H),7.49(dd,J＝8.0,1.4Hz,1H),7.43(s,1H),7.42–7.37(m,1H),7.35(d,J＝7.9Hz,1H),7.33–7.28(m,2H),7.23(d,J＝8.2Hz,1H),7.16–6.99(m,8H),6.96–6.89(m,1H),6.81(s,1H),6.65(d,J＝9.0Hz,1H),4.54–4.50(m,1H),4.49–4.44(m,1H),4.31–4.26(m,1H),4.03–3.98(m,1H),3.52(q,J＝7.0Hz,1H),3.33–3.21(m,2H),3.04–2.97(m,1H),2.97–2.92(m,1H),2.90–2.85(m,1H),2.84–2.77(m,2H),2.66–2.61(m,1H),1.74–1.63(m,1H),1.52–1.37(m,3H),1.18(d,J＝7.1Hz,3H),1.07–0.98(m,2H).13C NMR(125MHz,Methanol-d4)δ176.63,175.74,172.74,172.29,171.88,157.58,147.59,136.83,136.60,134.18,133.43,132.46,129.06,128.95,128.18,128.13,127.62,127.58,127.36,127.21,127.14,127.06,126.55,125.64,125.23,124.43,123.28,123.15,121.38,121.10,118.56,117.82,112.61,111.05,109.18,55.66,54.66,54.39,53.23,49.88,40.64,37.28,36.64,30.89,28.45,27.01,22.99,19.63.HRMS(ESI)：C51H56N9O5[M+H]+计算值：874.4399，实测值：874.4393。
实施例48化合物2-48的制备
Figure BDA0002431269780000271
用6-炔基-2-(2,2-二甲氧基乙硫基)喹啉或6-炔基-2-(2,2-二甲氧基乙硒基)喹啉，亲核试剂换成促生长激素释放肽，其余制备方法同实施例1，得化合物2-48，收率48％-90％。1H NMR(600MHz,Methanol-d4)δ7.76(dd,J＝9.1,3.6Hz,2H),7.71(d,J＝1.9Hz,1H),7.69–7.65(m,2H),7.57–7.53(m,2H),7.51(dd,J＝8.6,1.9Hz,1H),7.45(m,1H),7.43–7.39(m,2H),7.32(m,1H),7.24–7.20(m,3H),7.17–7.14(m,1H),7.11(m,3H),7.02(m,1H),6.92(s,1H),6.76(d,J＝9.0Hz,1H),4.61(dd,J＝8.8,5.9Hz,1H),4.57(dd,J＝7.9,6.4Hz,1H),4.38(dd,J＝8.7,7.0Hz,1H),4.10(m,1H),3.80–3.75(m,1H),3.45(s,1H),3.42–3.32(m,2H),3.07(m,2H),2.98(m,1H),2.90(m,2H),2.72(m,1H),1.82–1.74(m,1H),1.62–1.49(m,3H),1.34(d,J＝7.0Hz,3H),1.17–1.08(m,2H).13C NMR(150MHz,Methanol-d4)δ176.09,172.84,172.53,171.20,170.31,157.51,146.48,136.85,136.58,136.48,134.21,133.47,132.50,132.37,131.33,128.97,128.20,127.74,127.56,127.39,127.21,127.19,126.96,126.60,125.75,125.34,123.93,123.25,122.56,121.08,118.53,117.89,115.62,111.04,109.34,83.12,76.61,55.85,55.09,54.16,53.33,48.73,40.70,36.95,36.49,30.69,28.20,27.37,23.01,16.30.HRMS(ESI)：C53H55N9NaO5[M+Na]+计算值：920.4218，实测值：920.4221。
实施例49化合物2-49的制备
Figure BDA0002431269780000272
用2-(2,2-二甲氧基乙硫基)喹啉或2-(2,2-二甲氧基乙硒基)喹啉，亲核试剂换成六肽-10，其余制备方法同实施例1，得化合物2-49，收率40％-83％。1H NMR(500MHz,Methanol-d4)δ7.82(d,J＝9.0Hz,1H),7.63(d,J＝8.4Hz,1H),7.59(dd,J＝7.9,1.5Hz,1H),7.49(m,1H),7.20–7.14(m,1H),6.78(d,J＝9.0Hz,1H),4.48(d,J＝7.1Hz,1H),4.43(dd,J＝9.3,5.3Hz,1H),4.31(d,J＝6.3Hz,1H),4.26(d,J＝7.0Hz,1H),4.18(d,J＝5.1Hz,1H),3.74(m,1H),3.66(m,1H),3.55(m,1H),3.46(m,2H),2.16(m,2H),1.97–1.84(m,2H),1.80–1.65(m,3H),1.55(m,3H),1.38(d,J＝7.1Hz,3H),1.23(m,1H),1.01–0.88(m,18H).13CNMR(125MHz,Methanol-d4)δ176.80,174.98,172.87,172.40,171.65,157.62,147.62,136.81,129.01,127.21,124.45,123.16,121.34,112.72,64.50,60.12,58.63,58.29,55.93,53.59,49.22,40.66,39.06,36.62,31.29,30.61,28.49,24.58,23.24,18.82,18.55,17.32,17.10,16.67,14.70,10.36.HRMS(ESI)：C37H59N8O8[M+H]+计算值：743.445，实测值：743.4437。
实施例50化合物2-50的制备
Figure BDA0002431269780000281
用6-炔基-2-(2,2-二甲氧基乙硫基)喹啉或6-炔基-2-(2,2-二甲氧基乙硒基)喹啉，亲核试剂换成六肽-10，其余制备方法同实施例1，得化合物2-50，收率40％-90％。1HNMR(600MHz,Methanol-d4)δ7.79–7.76(m,1H),7.71(d,J＝1.8Hz,1H),7.54(d,J＝8.6Hz,1H),7.50(dd,J＝8.6,1.9Hz,1H),6.78(d,J＝9.0Hz,1H),4.49–4.39(m,2H),4.28(d,J＝6.7Hz,1H),4.21(d,J＝7.0Hz,1H),4.18(d,J＝4.9Hz,1H),3.72–3.67(m,1H),3.59(s,1H),3.55–3.54(m,1H),3.47–3.43(m,2H),3.43–3.42(m,1H),2.17–2.09(m,2H),1.86(m,2H),1.69(m,3H),1.55–1.50(m,2H),1.47(d,J＝9.1Hz,1H),1.34(d,J＝7.1Hz,3H),1.22–1.16(m,1H),0.96–0.90(m,18H).HRMS(ESI)：C39H59N8O8[M+H]+计算值：767.445，实测值：767.4458。
实施例51化合物2-51的制备
Figure BDA0002431269780000291
用2-(2,2-二甲氧基乙硫基)喹啉或2-(2,2-二甲氧基乙硒基)喹啉，亲核试剂换成精氨酸-促生长激素释放肽，其余制备方法同实施例1，得化合物2-51，收率45％-57％。1HNMR(600MHz,Methanol-d4)δ7.83(d,J＝9.0Hz,1H),7.77(dd,J＝7.5,1.9Hz,1H),7.71(d,J＝8.5Hz,2H),7.67–7.63(m,1H),7.62–7.58(m,2H),7.50(m,1H),7.45–7.39(m,3H),7.35–7.31(m,1H),7.28(dd,J＝8.5,1.7Hz,1H),7.24–7.18(m,3H),7.15(d,J＝7.4Hz,1H),7.12–7.08(m,3H),7.03(m,1H),6.89(s,1H),6.77(d,J＝9.0Hz,1H),4.70(m,1H),4.55(m,1H),4.34(m,1H),4.03(m,1H),3.57(m,1H),3.36(qm,J＝7.3Hz,2H),3.14–2.94(m,5H),2.92–2.81(m,2H),2.64(m,1H),1.85–1.74(m,1H),1.64(m,2H),1.54(m,3H),1.47–1.35(m,2H),1.17–1.05(m,2H).13C NMR(125MHz,Methanol-d4)δ175.71,172.51,172.38,171.97,171.05,156.69,156.45,145.54,137.12,136.05,135.85,133.75,132.97,132.00,129.05,128.43,127.72,127.24,127.06,126.94,126.73,126.70,126.50,126.15,125.27,124.86,122.89,122.87,122.40,121.43,120.58,118.06,117.41,112.13,110.55,108.75,55.55,54.29,53.66,53.14,52.52,40.33,40.01,36.72,35.93,30.12,29.30,27.75,27.06,23.16,22.62HRMS(ESI)：C54H63N12O5[M+H]+计算值：959.5039，实测值：959.5025。
实施例52化合物2-52的制备
Figure BDA0002431269780000292
用2-(2,2-二甲氧基乙硫基)喹啉或2-(2,2-二甲氧基乙硒基)喹啉，亲核试剂换成组氨酸-促生长激素释放肽，其余制备方法同实施例1，得化合物2-52，收率42％-91％。1HNMR(600MHz,Methanol-d4)δ7.84(d,J＝9.0Hz,1H),7.77–7.72(m,1H),7.65(dd,J＝8.3,3.0Hz,3H),7.60(dd,J＝7.9,1.4Hz,1H),7.57(s,1H),7.55–7.49(m,2H),7.45(d,J＝7.9Hz,1H),7.42–7.36(m,2H),7.32(d,J＝8.1Hz,1H),7.21(m,4H),7.16–7.06(m,4H),7.03(m,1H),6.92(s,1H),6.81(s,1H),6.77(d,J＝9.0Hz,1H),4.65(dd,J＝8.5,6.0Hz,1H),4.60–4.52(m,1H),4.37(m,1H),4.10(m,1H),3.79(m,1H),3.34(m,2H),3.10(m,1H),3.04(m,1H),3.00–2.81(m,5H),2.66(m,1H),1.82–1.72(m,1H),1.54(m,3H),1.11(m,2H).13CNMR(125MHz,Methanol-d4)δ175.74,175.43,172.37,172.17,171.07,170.56,155.86,144.10,137.77,136.08,135.96,134.90,133.60,132.95,131.99,131.33,129.45,128.46,127.67,127.21,127.07,127.04,126.90,126.73,126.67,126.48,126.07,125.22,124.82,122.79,122.15,121.96,121.89,120.60,118.05,117.40,116.44,112.15,110.56,108.90,55.36,54.39,53.82,52.90,47.95,40.47,36.78,35.93,30.10,29.28,27.58,26.88,22.48.HRMS(ESI)：C54H58N11O5[M+H]+计算值：940.4617，实测值：940.4643。
实施例53化合物2-53的制备
Figure BDA0002431269780000301
用2-(2,2-二甲氧基乙硫基)喹啉或2-(2,2-二甲氧基乙硒基)喹啉，亲核试剂换成苯丙氨酸-促生长激素释放肽，其余制备方法同实施例1，得化合物2-53，收率43％-47％。1HNMR(600MHz,Methanol-d4)δ7.79(d,J＝9.1Hz,1H),7.72–7.67(m,1H),7.61–7.52(m,4H),7.45(m,2H),7.37(d,J＝7.9Hz,1H),7.35–7.31(m,2H),7.25(d,J＝8.1Hz,1H),7.16(m,6H),7.11–7.05(m,4H),7.03(dd,J＝7.6,5.9Hz,3H),6.96(m,1H),6.81(s,1H),6.70(d,J＝9.0Hz,1H),4.59(m,1H),4.47m,1H),4.30(dd,J＝8.5,7.0Hz,1H),4.05(m,1H),3.66(dd,J＝8.6,4.9Hz,1H),3.32–3.28(m,1H),3.27–3.25(m,1H),3.06–2.79(m,6H),2.63(m,2H),1.75–1.65(m,1H),1.46(m,3H),1.09–0.99(m,2H).13C NMR(150MHz,Methanol-d4)δ176.01,172.86,172.44,171.20,156.34,138.20,136.57,136.50,135.15,134.05,133.46,132.51,129.96,129.07,128.96,128.54,128.18,127.74,127.60,127.41,127.23,127.18,127.09,127.00,126.57,125.75,125.34,123.28,122.69,122.48,122.43,121.08,118.53,117.87,112.83,111.05,109.23,55.86,54.81,54.69,54.28,53.17,40.96,38.35,37.27,36.32,30.63,27.99,27.39,22.91.HRMS(ESI)：C57H60N9O5[M+H]+计算值：950.4712，实测值：950.4708。
实施例54化合物2-54的制备
Figure BDA0002431269780000311
用2-(2,2-二甲氧基乙硫基)喹啉或2-(2,2-二甲氧基乙硒基)喹啉，亲核试剂换成丝氨酸-促生长激素释放肽，其余制备方法同实施例1，得化合物2-54，收率40％-86％。1HNMR(600MHz,Methanol-d4)δ7.82(d,J＝9.0Hz,1H),7.75(dd,J＝6.1,3.4Hz,1H),7.66–7.58(m,4H),7.53–7.49(m,2H),7.46(m,1H),7.40(m,2H),7.33(m,1H),7.23–7.10(m,6H),7.09–7.05(m,2H),7.04(m,1H),6.94(s,1H),6.75(d,J＝9.0Hz,1H),4.66(m,1H),4.51(m,1H),4.41(m,1H),4.14(m,1H),3.68(d,J＝5.5Hz,2H),3.57(m,1H),3.36(m,2H),3.15(m,1H),3.07–3.00(m,1H),2.99–2.84(m,3H),2.74(m,1H),1.79(m,1H),1.63–1.50(m,3H),1.16(m,2H).13C NMR(125MHz,Methanol-d4)δ175.84,172.82,172.31,171.58,170.76,156.82,137.66,136.62,136.53,134.13,133.46,132.48,129.59,128.96,128.17,127.66,127.51,127.44,127.34,127.23,127.14,126.98,126.54,125.66,125.27,123.26,122.87,122.01,121.12,118.54,117.87,112.71,111.07,109.30,56.92,55.53,55.36,54.82,54.57,53.22,40.84,37.15,36.49,30.79,28.22,27.12,22.95.HRMS(ESI)：C51H56N9O6[M+H]+计算值：890.4348，实测值：890.4356。
实施例55化合物2-55的制备
Figure BDA0002431269780000312
用2-(2,2-二甲氧基乙硫基)喹啉或2-(2,2-二甲氧基乙硒基)喹啉，亲核试剂换成色氨酸-促生长激素释放肽，其余制备方法同实施例1，得化合物2-55，收率41％-98％。1HNMR(600MHz,Methanol-d4)δ7.81(d,J＝9.1Hz,1H),7.73(dd,J＝6.2,3.4Hz,1H),7.65–7.61(m,1H),7.61–7.57(m,2H),7.57–7.53(m,2H),7.50(m,1H),7.45(m,1H),7.38(m,3H),7.33(m,2H),7.24–7.17(m,3H),7.16–7.02(m,8H),6.99(m,1H),6.90(s,1H),6.73(d,J＝9.0Hz,1H),4.66(dd,J＝7.8,6.3Hz,1H),4.53(dd,J＝7.8,6.4Hz,1H),4.38(dd,J＝8.5,7.0Hz,1H),4.12(m,1H),3.82(dd,J＝7.6,5.3Hz,1H),3.36–3.31(m,1H),3.28(m,1H),3.17(m,1H),3.05–2.97(m,3H),2.96–2.88(m,3H),2.69(m,1H),1.80–1.71(m,1H),1.50(m,3H),1.15–1.02(m,2H).13C NMR(125MHz,Methanol-d4)δ175.85,172.90,172.51,171.38,156.89,145.98,137.57,136.75,136.60,136.51,133.95,133.41,132.46,129.54,128.95,128.18,127.64,127.57,127.42,127.38,127.25,127.20,127.13,127.03,126.56,125.66,125.27,124.13,123.38,123.29,122.90,121.94,121.30,121.11,118.71,118.56,117.87,117.84,112.68,111.14,111.08,109.28,107.60,55.78,54.65,54.40,54.03,53.27,40.80,37.35,36.41,30.68,28.55,28.16,27.29,22.95.HRMS(ESI)：C59H61N10O5[M+H]+计算值：989.4821，实测值：989.4829。
实施例56化合物2-56的制备
Figure BDA0002431269780000321
用2-(2,2-二甲氧基乙硫基)喹啉或2-(2,2-二甲氧基乙硒基)喹啉，亲核试剂换成甘氨酸-促生长激素释放肽，其余制备方法同实施例1，得化合物2-56，收率35％-83％。1HNMR(600MHz,Methanol-d4)δ7.96(d,J＝9.2Hz,1H),7.78–7.75(m,1H),7.72(d,J＝8.4Hz,1H),7.70–7.65(m,3H),7.60(m,1H),7.54(d,J＝1.6Hz,1H),7.45(m,1H),7.43–7.39(m,2H),7.34–7.31(m,2H),7.24–7.20(m,3H),7.15(m,1H),7.11(m,3H),7.03(m,1H),6.91(s,1H),6.87(d,J＝9.2Hz,1H),4.68(dd,J＝8.5,6.0Hz,1H),4.55(dd,J＝7.8,6.7Hz,1H),4.38(dd,J＝8.5,6.9Hz,1H),4.13(m,1H),3.60–3.48(m,2H),3.39(m,2H),3.06(m,2H),2.92(m,3H),2.71(m,1H),1.85–1.76(m,1H),1.58(m,3H),1.19–1.11(m,2H).13C NMR(125MHz,Methanol-d4)δ175.93,172.88,172.43,171.37,166.52,139.37,138.65,136.58,136.53,134.03,133.47,132.50,130.68,128.96,128.17,127.87,127.70,127.51,127.37,127.22,127.16,126.95,126.53,125.73,125.34,123.26,122.30,121.09,118.52,117.86,113.04,111.06,109.26,55.77,54.85,54.35,53.15,41.27,40.21,37.37,36.40,30.54,27.73,27.29,22.83.HRMS(ESI)：C50H53N9NaO5[M+Na]+计算值：882.4062，实测值：882.4056。
实施例57化合物2-57的制备
Figure BDA0002431269780000331
用2-(2,2-二甲氧基乙硫基)喹啉或2-(2,2-二甲氧基乙硒基)喹啉，亲核试剂换成半胱氨酸-促生长激素释放肽，其余制备方法同实施例1，得化合物2-57，收率55％。1H NMR(600MHz,Methanol-d4)δ8.31–8.15(m,1H),8.06(d,J＝9.4Hz,1H),7.88(d,J＝8.5Hz,1H),7.81–7.68(m,3H),7.68–7.62(m,2H),7.56(s,1H),7.49–7.42(m,2H),7.39(m,2H),7.30(d,J＝8.2Hz,1H),7.22(m,3H),7.14(d,J＝7.8Hz,3H),7.07(t,J＝7.6Hz,1H),7.00(d,J＝7.4Hz,1H),6.94(s,1H),4.64(dd,J＝9.0,5.8Hz,1H),4.55(dd,J＝8.3,6.2Hz,1H),4.42(t,J＝7.8Hz,1H),4.19(m,1H),4.00(m,1H),3.52–3.36(m,2H),3.09(m,2H),3.02–2.83(m,5H),2.78(m,1H),1.81(m,1H),1.65(m,3H),1.31–1.18(m,2H).13C NMR(125MHz,Methanol-d4)δ175.46,172.51,172.03,170.89,167.01,152.28,141.24,136.22,136.10,135.59,133.68,132.98,132.01,131.79,128.58,128.03,127.72,127.31,127.08,126.86,126.78,126.71,126.45,126.00,125.30,124.90,124.84,122.85,120.87,120.63,118.08,117.45,116.70,113.38,110.61,108.92,55.39,54.84,53.98,52.57,41.59,36.41,36.02,29.94,26.78,26.50,24.70,22.23.HRMS(ESI)：C51H56N9O5S[M+H]+计算值：906.4120，实测值：906.4116。
实施例58化合物2-58的制备
Figure BDA0002431269780000332
用2-(2,2-二甲氧基乙硫基)喹啉或2-(2,2-二甲氧基乙硒基)喹啉，亲核试剂换成天冬氨酸-促生长激素释放肽，其余制备方法同实施例1，得化合物2-58，收率93％-97％。1HNMR(500MHz,Methanol-d4)δ7.76(dd,J＝9.2,3.6Hz,2H),7.71–7.60(m,3H),7.57(dd,J＝7.9,1.5Hz,1H),7.52(s,1H),7.48(t,J＝7.9Hz,2H),7.40(m,2H),7.35(d,J＝8.1Hz,1H),7.33–7.13(m,6H),7.13–7.09(m,2H),7.04(t,J＝7.5Hz,1H),6.99(s,1H),6.73(d,J＝9.0Hz,1H),4.56(dd,J＝8.1,5.9Hz,1H),4.52–4.41(m,2H),4.18(m,1H),3.57(dd,J＝7.6,5.4Hz,1H),3.37(m,2H),3.19(m,1H),3.11(m,1H),3.08–2.92(m,3H),2.90–2.82(m,1H),2.56(m,1H),2.35(m,1H),1.80(m,1H),1.58(m,3H),1.26–1.14(m,2H).13C NMR(125MHz,Methanol-d4)δ177.48,176.00,175.80,172.85,172.32,172.16,157.59,147.62,136.78,136.62,134.30,133.48,132.45,129.00,128.15,127.64,127.52,127.36,127.31,127.21,127.11,126.48,125.58,125.17,124.44,123.33,123.15,121.32,121.07,118.50,117.91,112.66,111.04,109.49,55.53,55.04,54.78,53.42,52.56,42.65,40.65,37.26,36.66,30.96,28.48,26.86,23.05.HRMS(ESI)：C52H54N9O7[M-H]-计算值：916.4152，实测值：916.4158。
实施例59化合物2-59的制备
Figure BDA0002431269780000341
用2-(2,2-二甲氧基乙硫基)喹啉或2-(2,2-二甲氧基乙硒基)喹啉，亲核试剂换成酪氨酸-促生长激素释放肽，其余制备方法同实施例1，得化合物2-59，收率69％-90％。1HNMR(500MHz,DMSO-d6)δ10.83(d,J＝2.4Hz,1H),9.18(s,1H),8.57(d,J＝8.0Hz,1H),8.44(d,J＝8.1Hz,1H),8.14(d,J＝8.4Hz,1H),7.93(d,J＝8.2Hz,1H),7.82–7.69(m,3H),7.58(dd,J＝7.9,1.4Hz,1H),7.49(d,J＝8.2Hz,1H),7.47–7.42(m,1H),7.41–7.36(m,2H),7.36–7.30(m,5H),7.29–7.23(m,3H),7.21(d,J＝2.4Hz,1H),7.19–7.06(m,4H),7.00(s,2H),6.95–6.88(m,3H),6.74(d,J＝8.9Hz,1H),6.66(m,3H),4.71(m,1H),4.62(m,1H),4.52(m,1H),4.19(m,1H),4.11(m,1H),3.19(d,J＝3.8Hz,2H),3.01(m,1H),2.89–2.76(m,3H),2.75–2.65(m,3H),2.39(m,1H),1.67(m,1H),1.52(m,3H),1.24(m,2H).13C NMR(125MHz,Methanol-d4)δ174.03,173.61,172.24,171.30,170.49,157.45,156.33,148.43,138.19,136.66,136.45,135.01,133.10,132.09,130.66,129.88,129.35,128.55,128.42,128.01,127.86,127.70,127.61,127.31,126.74,126.01,125.65,124.71,123.23,121.37,119.34,118.73,115.51,113.57,111.82,110.54,56.34,54.73,53.97,53.05,52.60,40.76,38.75,38.43,32.21,28.95,28.45,23.34.HRMS(ESI)：C57H60N9O6[M+H]+计算值：966.4661，实测值：966.4668。
实施例60化合物2-60的制备
Figure BDA0002431269780000351
用6-对甲氧基苯基-2-(2,2-二甲氧基乙硫基)喹啉或6-对甲氧基苯基-2-(2,2-二甲氧基乙硒基)喹啉，亲核试剂换成醋酸奥曲肽盐酸盐，其余制备方法同实施例1，得化合物2-60，收率39％-46％。1H NMR(600MHz,Methanol-d4)δ7.87(d,J＝8.9Hz,1H),7.77(d,J＝2.2Hz,1H),7.76–7.72(m,1H),7.70(d,J＝8.6Hz,1H),7.63–7.58(m,2H),7.43(dd,J＝7.7,1.3Hz,1H),7.34(d,J＝8.1Hz,1H),7.32–7.28(m,4H),7.26(m,3H),7.24–7.21(m,3H),7.04(m,2H),7.01–6.99(m,2H),6.93(s,1H),6.74(m,1H),5.19–5.12(m,1H),5.11–5.05(m,1H),4.64(m,1H),4.43(d,J＝5.2Hz,1H),4.39–4.35(m,1H),4.14(m,1H),4.05(dd,J＝6.5,3.3Hz,1H),3.99(m,1H),3.85–3.81(m,4H),3.74–3.62(m,3H),3.12–2.75(m,10H),1.76(m,1H),1.48–1.32(m,3H),1.26(d,J＝6.4Hz,3H),1.18(d,J＝6.5Hz,3H),0.79–0.62(m,2H).13C NMR(150MHz,Methanol-d4)δ174.82,174.40,174.16,171.44,171.37,171.33,169.01,158.98,157.40,146.50,137.27,136.99,136.55,136.46,134.12,133.04,129.02,128.96,128.13,128.02,127.95,127.34,126.93,126.39,126.35,124.56,124.25,123.25,123.02,121.05,118.41,117.71,113.79,112.98,111.01,108.47,66.86,65.62,61.18,59.69,56.28,56.16,55.96,54.85,54.24,54.18,52.41,52.33,44.23,41.78,40.82,40.58,39.17,30.27,28.43,25.72,22.61,18.90,18.69.HRMS(ESI)：C65H78N11O11S2[M+H]+计算值：1252.5318，实测值：1252.5313。
实施例61化合物2-61的制备
Figure BDA0002431269780000352
用6-氰基-2-(2,2-二甲氧基乙硫基)喹啉或6-氰基-2-(2,2-二甲氧基乙硒基)喹啉，亲核试剂换成醋酸奥曲肽盐酸盐，其余制备方法同实施例1，得化合物2-61，收率58％。1H NMR(500MHz,Methanol-d4)δ8.01(d,J＝1.8Hz,1H),7.85(d,J＝9.3Hz,1H),7.71–7.66(m,2H),7.46–7.43(m,1H),7.34–7.25(m,11H),7.10–7.02(m,2H),6.95(s,1H),6.82(d,J＝9.1Hz,1H),5.16(m,2H),4.67(m,1H),4.46(d,J＝5.3Hz,1H),4.42–4.35(m,1H),4.17(m,1H),4.08(dd,J＝6.5,3.2Hz,1H),4.02(m,1H),3.84(dd,J＝6.1,3.3Hz,1H),3.81(m,1H),3.73(m,1H),3.67(m,1H),3.13(m,2H),3.07–2.85(m,7H),2.80(m,1H),1.79(m,1H),1.50–1.36(m,3H),1.28(d,J＝6.3Hz,3H),1.21(d,J＝6.5Hz,3H),0.81–0.68(m,2H).13C NMR(125MHz,Methanol-d4)δ174.45,174.15,173.81,171.49,171.43,171.38,169.11,158.99,150.30,140.19,136.76,136.65,136.54,136.37,133.04,130.53,129.15,129.04,128.35,128.05,127.04,126.68,126.51,125.77,123.15,122.75,121.16,119.09,118.53,117.83,116.37,111.09,108.63,103.50,67.00,65.79,61.30,59.75,56.35,56.25,55.75,54.96,54.18,52.67,44.36,42.08,40.45,40.32,39.24,30.31,28.29,25.85,22.64,19.00,18.79.HRMS(ESI)：C59H71N12O10S2[M+H]+计算值：1171.4852，实测值：1171.4837。
实施例62化合物2-62的制备
Figure BDA0002431269780000361
用6-羧基-2-(2,2-二甲氧基乙硫基)喹啉，亲核试剂换成醋酸奥曲肽盐酸盐，其余制备方法同实施例1，得化合物2-62，收率60％。1H NMR(500MHz,Methanol-d4)δ8.22(d,J＝2.0Hz,1H),8.10(dd,J＝8.6,2.1Hz,1H),7.87(d,J＝9.0Hz,1H),7.61(d,J＝8.7Hz,1H),7.43(d,J＝7.6Hz,1H),7.28(m,11H),7.07–7.00(m,2H),6.94(s,1H),6.73(d,J＝9.0Hz,1H),5.12(m,1H),5.05(dd,J＝7.4,3.5Hz,1H),4.65(m,1H),4.43(d,J＝5.0Hz,1H),4.42–4.36(m,1H),4.14(m,1H),4.05(dd,J＝6.5,3.3Hz,1H),3.96(m,1H),3.83(dd,J＝6.2,3.3Hz,1H),3.72(m,1H),3.69–3.61(m,2H),3.21–2.72(m,10H),1.74(m,1H),1.38(m,3H),1.26(d,J＝6.3Hz,3H),1.19(d,J＝6.5Hz,3H),0.78–0.59(m,2H).13C NMR(125MHz,Methanol-d4)δ175.10,174.54,174.33,173.93,171.50,171.43,169.02,158.13,149.03,137.65,137.46,136.60,136.52,130.94,130.09,129.07,129.03,128.96,128.17,128.03,126.99,126.47,126.36,123.40,123.08,122.12,121.11,118.46,117.75,112.78,111.09,108.51,66.88,65.70,61.25,59.81,56.37,56.27,56.10,54.94,54.36,52.40,52.38,44.17,41.59,41.00,40.62,39.28,30.32,28.43,25.81,22.69,18.97,18.76.HRMS(ESI)：C59H72N11O12S2[M+H]+计算值：1190.4798，实测值：1190.4801。
实施例63化合物2-63的制备
Figure BDA0002431269780000371
用5-羧基-2-(2,2-二甲氧基乙硫基)喹啉，亲核试剂换成醋酸奥曲肽盐酸盐，其余制备方法同实施例1，得化合物2-63，收率12％。1H NMR(600MHz,Methanol-d4)δ8.55(m,1H),7.66–7.63(m,1H),7.44(d,J＝4.8Hz,2H),7.42(d,J＝7.7Hz,1H),7.30(m,7H),7.26–7.23(m,4H),7.07–7.00(m,2H),6.93(s,1H),6.72(d,J＝9.3Hz,1H),5.11(m,1H),5.04(m,1H),4.65(m,1H),4.42(d,J＝5.1Hz,1H),4.40–4.35(m,1H),4.12(m,1H),4.04(m,1H),3.94(m,1H),3.83(m,1H),3.71(m,1H),3.65(m,2H),3.26(m,2H),3.11(m,1H),3.05–2.89(m,7H),2.83–2.75(m,2H),1.78–1.66(m,1H),1.43–1.31(m,3H),1.26(d,J＝6.4Hz,3H),1.18(d,J＝6.4Hz,3H),0.73–0.57(m,2H).13C NMR(150MHz,Methanol-d4)δ175.38,174.65,174.11,173.93,171.09,171.02,170.99,168.58,156.77,151.77,147.20,138.14,137.03,136.18,136.12,135.48,128.65,128.63,127.75,127.61,126.57,126.05,125.95,124.64,122.67,120.69,120.60,119.83,118.05,117.32,111.98,110.68,108.08,66.45,65.27,60.82,59.39,55.95,55.88,55.67,54.52,53.99,51.99,51.95,43.77,41.15,40.57,40.19,38.88,29.91,28.09,25.40,22.28,18.55,18.34.HRMS(ESI)：C59H72N11O12S2[M+H]+计算值：1190.4798，实测值：1190.4831。
实施例64化合物2-64的制备
Figure BDA0002431269780000372
用8-羧基-2-(2,2-二甲氧基乙硫基)喹啉，亲核试剂换成醋酸奥曲肽盐酸盐，其余制备方法同实施例1，得化合物2-64，收率59％。1H NMR(500MHz,Methanol-d4)δ8.32(d,J＝1.5Hz,1H),7.84(d,J＝9.0Hz,1H),7.77(dd,J＝8.2,1.7Hz,1H),7.58(d,J＝8.2Hz,1H),7.43(d,J＝7.9Hz,1H),7.35–7.24(m,11H),7.08–7.00(m,2H),6.98(s,1H),6.75(d,J＝9.0Hz,1H),5.12(m,1H),5.05(m,1H),4.70–4.67(m,1H),4.46–4.39(m,2H),4.15(m,1H),4.07(m,1H),3.95(m,1H),3.86(m,1H),3.74(m,1H),3.71–3.64(m,2H),3.31(d,J＝7.2Hz,2H),3.15(m,1H),3.07–2.81(m,9H),1.73(m,1H),1.45–1.36(m,3H),1.29(d,J＝6.2Hz,3H),1.21(d,J＝6.4Hz,3H),0.77–0.60(m,2H).13C NMR(125MHz,Methanol-d4)δ175.04,174.59,174.45,174.23,171.59,171.48,171.45,169.00,157.69,147.25,139.06,137.44,136.63,136.53,136.45,129.08,128.20,128.06,127.04,126.50,126.45,126.41,125.68,124.30,123.17,122.14,121.12,118.47,117.75,113.28,111.20,108.51,66.87,65.76,61.28,59.89,56.42,56.37,56.11,54.97,54.53,52.41,44.13,41.44,40.98,40.67,39.32,30.37,28.49,25.88,22.73,19.01,18.81.HRMS(ESI)：C59H72N11O12S2[M+H]+计算值：1190.4798，实测值：1190.4814。
实施例65化合物2-65的制备
Figure BDA0002431269780000381
用7-炔基-2-(2,2-二甲氧基乙硫基)喹啉，亲核试剂换成醋酸奥曲肽盐酸盐，其余制备方法同实施例1，得化合物2-65，收率32％。1H NMR(500MHz,Methanol-d4)δ7.81(d,J＝9.0Hz,1H),7.79(d,J＝1.4Hz,1H),7.57(d,J＝8.1Hz,1H),7.47–7.43(m,1H),7.34–7.25(m,12H),7.06(m,2H),6.96(s,1H),6.75(d,J＝9.0Hz,1H),5.18(m,1H),5.11(m,1H),4.70–4.67(m,1H),4.46(d,J＝5.2Hz,1H),4.40(d,J＝6.0Hz,1H),4.20–4.16(m,1H),4.07(dd,J＝6.5,3.3Hz,1H),4.00(m,1H),3.86(m,1H),3.76–3.70(m,2H),3.67(d,J＝5.0Hz,1H),3.57(s,1H),3.29(m,2H),3.12–2.85(m,10H),1.77(m,1H),1.49–1.35(m,3H),1.28(d,J＝6.3Hz,3H),1.21(d,J＝6.5Hz,3H),0.81–0.64(m,2H).13C NMR(125MHz,Methanol-d4)δ174.72,174.47,174.23,171.46,171.42,169.09,157.96,147.25,137.26,136.64,136.55,136.37,129.11,129.06,128.23,128.09,128.05,127.42,127.02,126.48,124.27,123.25,123.13,121.15,118.51,117.80,113.68,111.09,108.58,83.34,77.89,66.95,65.75,61.29,59.77,56.38,56.27,56.01,54.95,54.28,52.53,52.43,44.33,41.88,40.82,40.58,39.27,30.36,28.37,25.84,22.69,18.99,18.79.HRMS(ESI)：C60H72N11O10S2[M+H]+计算值：1170.49，实测值：1170.4897。
实施例66化合物2-66的制备
Figure BDA0002431269780000391
用7-碘-2-(2,2-二甲氧基乙硫基)喹啉或7-碘-2-(2,2-二甲氧基乙硒基)喹啉，亲核试剂换成促生长激素释放肽，其余制备方法同实施例1，得化合物2-66，收率27％-36％。1H NMR(500MHz,Methanol-d4)δ7.94(d,J＝2.1Hz,1H),7.83–7.75(m,1H),7.73–7.65(m,4H),7.54(d,J＝1.6Hz,1H),7.48–7.45(m,1H),7.45–7.42(m,2H),7.39(d,J＝8.8Hz,1H),7.35(d,J＝8.1Hz,1H),7.28–7.21(m,3H),7.20–7.16(m,1H),7.13(m,3H),7.05(m,1H),6.93(s,1H),6.74(d,J＝9.0Hz,1H),4.63(dd,J＝8.6,6.0Hz,1H),4.58(dd,J＝7.8,6.3Hz,1H),4.41(dd,J＝8.5,7.0Hz,1H),4.19–4.10(m,1H),3.61(q,J＝7.0Hz,1H),3.39(dd,J＝14.5,7.2Hz,2H),3.10(,m 2H),2.99(dd,J＝13.8,8.5Hz,1H),2.93(dd,J＝14.1,8.1Hz,2H),2.76(dd,J＝13.4,7.1Hz,1H),1.87–1.75(m,1H),1.63–1.48(m,3H),1.28(d,J＝7.0Hz,3H),1.21–1.10(m,2H).13C NMR(125MHz,Methanol-d4)δ175.97,172.77,172.56,172.40,171.42,157.74,146.87,137.52,136.59,136.49,135.82,135.56,134.16,133.45,132.49,128.94,128.18,127.68,127.53,127.38,127.19,127.17,126.97,126.56,125.71,125.30,125.19,123.24,121.09,118.54,117.85,113.53,111.03,109.26,55.73,54.88,54.23,53.30,49.14,40.52,37.11,36.53,30.77,28.35,27.25,22.99,17.50.HRMS(ESI)：C51H55IN9O5[M+H]+计算值：1000.3365，实测值：1000.3354。
实施例67化合物2-67的制备
Figure BDA0002431269780000392
用7-羧基-2-(2,2-二甲氧基乙硫基)喹啉，亲核试剂换成促生长激素释放肽，其余制备方法同实施例1，得化合物2-67，收率77％。1H NMR(500MHz,Methanol-d4)δ8.32(s,1H),8.13(d,J＝8.8Hz,1H),7.94(d,J＝9.1Hz,1H),7.83–7.76(m,1H),7.74–7.65(m,3H),7.57(s,1H),7.48(d,J＝7.9Hz,1H),7.44(p,J＝5.4Hz,2H),7.34(d,J＝8.1Hz,1H),7.26(m,3H),7.19(d,J＝7.3Hz,1H),7.14(d,J＝7.5Hz,3H),7.04(d,J＝7.4Hz,1H),6.94(s,1H),6.85(d,J＝9.1Hz,1H),4.68–4.64(m,1H),4.60(dd,J＝7.9,6.5Hz,1H),4.41(dd,J＝8.6,7.0Hz,1H),4.15(dd,J＝10.2,4.2Hz,1H),3.81(q,J＝7.1Hz,1H),3.43(m2H),3.10(m,2H),3.03–2.98(m,1H),2.97–2.89(m,2H),2.78–2.71(m,1H),1.89–1.75(m,1H),1.59(m,3H),1.38(d,J＝7.1Hz,3H),1.17(m,2H).13C NMR(125MHz,Methanol-d4)δ176.01,172.81,172.46,171.14,170.02,136.57,136.46,134.15,133.45,132.49,130.21,128.93,128.17,127.72,127.51,127.36,127.16,126.91,126.57,125.74,125.33,123.21,121.86,121.07,118.51,117.86,111.02,109.31,55.78,55.05,54.15,53.22,48.68,40.80,36.96,36.45,30.61,28.01,27.34,22.90,16.15.HRMS(ESI)：C52H56N9O7[M+H]+计算值：918.4297，实测值：918.4318。
实施例68
化合物2-68(H-His7-Aib8-Glu9-Gly10-Thr11-Phe12-Thr13-Ser14-Asp15-Val16-Ser17-Ser18-Tyr19-Leu20-Glu21-Gly22-Gln23-Ala24-Ala25-Lys26(喹啉基)-Glu27-Phe28-Ile29-Ala30-Trp31-Leu32-Val33-Arg34-Gly35-Arg36-Gly37-OH)的制备：
用2-(2,2-二甲氧基乙硫基)喹啉或者2-(2,2-二甲氧基乙硒基)喹啉，亲核试剂换成索玛鲁肽主链(H-His7-Aib8-Glu9-Gly10-Thr11-Phe12-Thr13-Ser14-Asp15-Val16-Ser17-Ser18-Tyr19-Leu20-Glu21-Gly22-Gln23-Ala24-Ala25-Lys26-Glu27-Phe28-Ile29-Ala30-Trp31-Leu32-Val33-Arg34-Gly35-Arg36-Gly37-OH)，其余制备方法同实施例1，得化合物2-68。产物的结构鉴定由生物质谱图(图1)确定。分子量3522.7392为喹啉计划索玛鲁肽主链产物的分子量。
实施例69
化合物2-69(喹啉基化胰岛素)的制备：
用2-(2,2-二甲氧基乙硫基)喹啉或者2-(2,2-二甲氧基乙硒基)喹啉，亲核试剂换成胰岛素，其余制备方法同实施例1，得化合物2-69。产物的结构鉴定由生物质谱图(图2)确定。分子量5930.6892为喹啉基化胰岛素产物的分子量。
生物测试例1(细胞增殖抑制实验)：
肝癌细胞BEL-7402和SMMC-7721购自美国标准菌库。将所有细胞系在37℃和5％CO2的潮湿环境下保存在含有10％胎牛血清的细胞培养基中。将两种肝癌细胞接种在96孔板中过夜，实验采取最终最高浓度100μM，10倍稀释，6个梯度，设3复孔，处理细胞72小时，进行三次独立重复实验。通过甲磺酰罗丹明B(Sulforhodamine B，SRB)法测定化合物的抗增殖活性。然后使用Synergy H4 Hybrid读数器(BioTek，Winooski，VT，USA)，使用Gen5.0软件(BioTek)在510nm波长下测量吸光度OD值。使用软件Prism 5(GraphPad Software，Inc)计算IC50值。测试结果如表1所示。
表1 所选化合物的肝癌细胞增殖抑制实验
Figure BDA0002431269780000411
酪丝亮肽(tyroserleutide,YSL)已经处于III期临床试验中用于治疗肝癌。通过测试YSL、YSL-M(酪丝亮肽甲酯)和经喹啉基修饰得到的化合物2-39对肝癌BEL-7402和SMMC-7721细胞的抗癌活性，结果显示，化合物2-39对BEL-7402和SMMC-7721细胞均表现出较原药更优的细胞毒性，这表明在肽中引入喹啉基可以增强其活性。
生物测试例2([35S]GTPγS结合分析)：
BCA蛋白浓度测定试剂盒检测蛋白浓度：取蛋白标准品10μl，使终浓度为0.5mg/ml；分别取BSA标准蛋白0、1、2、4、8、12、16、20μl以及待测样品分别加到96孔板中，并用稀释标准品的溶液补足到20μl；各孔加200μl BCA工作液，37℃放置30min。用酶标仪测定A562波长的吸光度。根据标准曲线计算出蛋白浓度。
制备的膜受体用反应缓冲液(R.B)稀释到所需浓度，按下表2加样(单位：μl)。
表2
Figure BDA0002431269780000412
将反应管于27℃水浴中孵育1小时，以玻璃纤维膜进行减压过滤并液闪计数。按下列公式进行计算：
[35S]GTPγS结合率＝100×(cpmsample-cpmnon-specific)/(cpmbasal-cpmnon-specific)
在以下表3中示出皮啡肽和其喹啉基化后的化合物2-38的μ-阿片受体(MOR)激动剂活性。
表3 μ-阿片受体(MOR)激动剂活性测定
Figure BDA0002431269780000421
皮啡肽是临床上使用的μ-阿片受体(MOR)激动剂，从上表3结果可以看出，其喹啉基化后的化合物2-38具有与皮啡肽相当的活性。
生物测试例3(肝组织代谢评价)：
从5g新鲜猪肝中除去粘附的脂肪和结缔组织。用冷盐水洗净，用滤纸在表面上吸水并称重。加入适当的PBS缓冲液，用剪刀剪碎猪肝，用频率为30/s的匀浆机匀浆4分钟制备20ml匀浆。将待测试的化合物物2-40(终浓度1mg/ml和共溶剂(1％DMSO))加入20ml猪肝匀浆中，充分搅拌并静置。分别在0.25小时，0.5小时，1小时，1.5小时，2小时和3小时的六个时间段内取1ml样品两次，并加入甲醇(500μl)终止反应。离心(1000rpm，6分钟)后，分离上清液，用750μl水饱和的正丁醇萃取两次。然后通过HPLC分析提取的样品。HPLC分析在AgilentZorbax SB-C18柱(5μm，4.6×250mm)上进行，流速为1mL/min，温度为25℃。使用的梯度条件是在16分钟内从50％A(MeOH)和50％B(H2O+0.2％CH3COOH)，到95％A和5％B。使用UV-DAD检测器的采集210，254和280nm下的吸光度值。在图3中示出化合物2-40在肝组织中的浓度随时间的变化。
7-(2-氟苯基)-4-甲基喹啉-2(1H)-酮是一种端锚聚合酶(tankyrase,TNKS)抑制剂，IC50值为0.052μM，采用本申请开发的方法可以很方便地将其与(S)-2-((S)-2-氨基-3-甲基丁酰氨基)-N-(4-(羟基甲基)苯基)-5-脲基戊酰胺(Val-Cit-PAB-OH)偶联得到化合物2-40。图3示出化合物2-40的体外肝组织代谢稳定性评估表现出良好的代谢稳定性。
从上述内容看出，本申请中的方法为小分子-肽偶联药物的制备提供了一种新的化学链接方法，该方法在药物，特别是药物肽的修饰方面具有非常广泛的用途和应用潜力。

Claims (10)

1.一种修饰或标记分子中的氨基的方法，其中，使用由下式1表示的唑啉季铵盐来修饰或标记分子中的氨基，
Figure FDA0002431269770000011
在上式1中，
B环代表取代或未取代的五元、六元或七元含氮杂环；
Q、U各自独立地代表氧(O)、硫(S)、硒(Se)、碲(Te)、钋(Po)、氮(N)、磷(P)、硼(B)或硅(Si)；
R1为位于B环上的1-5个取代基，其各自独立地选自氢、羟基、氨基、巯基、硝基、氰基、取代或未取代的酰胺基、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的烷硫基、取代或未取代的烷氨基、取代或未取代的芳基、取代或未取代的芳氧基、取代或未取代的芳硫基、取代或未取代的芳氨基或卤素；或者，当R1为B环上的2个或2个以上取代基时，其中两个相邻的取代基可彼此连接与B环上的原子共同形成取代或未取代的芳基，取代或未取代的3-7元环烷基，取代或未取代的含有1-5个独立选自氧(O)、硫(S)、硒(Se)、碲(Te)、钋(Po)、氮(N)、磷(P)、硼(B)或硅(Si)原子的5-7元杂环烷基，或取代或未取代的含有1-5个独立选自氧(O)、硫(S)、硒(Se)、碲(Te)、钋(Po)、氮(N)、磷(P)、硼(B)或硅(Si)原子的5-7元杂芳基；
R2、R3各自独立地代表氢、羟基、氨基、巯基、硝基、氰基、取代或未取代的酰胺基、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的烷硫基、取代或未取代的烷氨基、取代或未取代的芳基、取代或未取代的芳氧基、取代或未取代的芳硫基、取代或未取代的芳氨基或卤素；
R4代表氢、取代或未取代的烷基、取代或未取代的芳基；以及
Y为酸根阴离子，其选自无机酸根离子、有机酸根离子和卤素离子。
2.根据权利要求1所述的方法，其中，
在式1中，
B环为五元环或六元环；
Q、U各自独立地选自氧、硫或硒；
R1为B环上的2个或2个以上取代基，其中两个相邻的取代基可彼此连接与B环上的碳原子共同形成取代或未取代的芳环；
R2、R3各自独立地选自氢、取代或未取代的烷基、取代或未取代的芳基；以及
R4为取代或未取代的烷基。
3.根据权利要求1所述的方法，其中，所述分子包括氨基酸酯、氨基酰胺、肽或蛋白。
4.根据权利要求1所述的方法，其中，在有或没有添加剂的情况下，使式1表示的唑啉季铵盐与包含氨基的分子在溶剂中反应，制备得到氨基经标记或修饰的产物。
5.根据权利要求4所述的方法，其中，所述方法通过由以下反应式I表示的反应来进行：
Figure FDA0002431269770000021
反应式I
在反应式I中，在有或没有添加剂的情况下，由式1表示的唑啉季铵盐与由式3表示的化合物在溶剂中反应，制备得到由式2表示的氨基经修饰的产物，
其中，在式3中，
n代表1-6的整数；
R5代表氢、取代或未取代的烷基、取代或未取代的芳基；
R6各自独立地代表氢、羟基、氨基、巯基、硝基、氰基、取代或未取代的酰胺基、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的烷硫基、取代或未取代的烷氨基、取代或未取代的芳基、取代或未取代的芳氧基、取代或未取代的芳硫基、取代或未取代的芳氨基或卤素；或者
R5和R6彼此连接形成包含1-3个选自氧(O)、硫(S)、硒(Se)、碲(Te)、钋(Po)、氮(N)、磷(P)、硼(B)或硅(Si)中的杂原子的5-7元杂环；
W代表氧(O)、硫(S)、硒(Se)、碲(Te)、钋(Po)、氮(N)、磷(P)、硼(B)或硅(Si)，
在式2中，B环、R1、R5、R6、W和n的定义与式1和式3中的定义相同。
6.根据权利要求5所述的方法，其中，
n为1或5；
W选自氧或氮；
R5选自氢、取代或未取代的烷基；以及
R6选自氨基、取代或未取代的酰氨基、取代或未取代的烷基，或取代或未取代的苯基。
7.根据权利要求5所述的方法，其中，所述溶剂包括非质子性溶剂或质子性溶剂中的任一种或两种以上组合溶剂，优选地，所述溶剂为正丁醇或水，和/或
所述添加剂包括有机碱或无机碱。
8.一种由下式1表示的唑啉季铵盐在修饰或标记分子中的氨基中的用途，
Figure FDA0002431269770000031
在上式1中，
B环代表取代或未取代的五元、六元或七元含氮杂环；
Q、U各自独立地代表氧(O)、硫(S)、硒(Se)、碲(Te)、钋(Po)、氮(N)、磷(P)、硼(B)或硅(Si)；
R1为位于B环上的1-5个取代基，其各自独立地选自氢、羟基、氨基、巯基、硝基、氰基、取代或未取代的酰胺基、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的烷硫基、取代或未取代的烷氨基、取代或未取代的芳基、取代或未取代的芳氧基、取代或未取代的芳硫基、取代或未取代的芳氨基或卤素；或者，当R1为B环上的2个或2个以上取代基时，其中两个相邻的取代基可彼此连接与B环上的原子共同形成取代或未取代的芳基，取代或未取代的3-7元环烷基，取代或未取代的含有1-5个独立选自氧(O)、硫(S)、硒(Se)、碲(Te)、钋(Po)、氮(N)、磷(P)、硼(B)或硅(Si)原子的5-7元杂环烷基，或取代或未取代的含有1-5个独立选自氧(O)、硫(S)、硒(Se)、碲(Te)、钋(Po)、氮(N)、磷(P)、硼(B)或硅(Si)原子的5-7元杂芳基；
R2、R3各自独立地代表氢、羟基、氨基、巯基、硝基、氰基、取代或未取代的酰胺基、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的烷硫基、取代或未取代的烷氨基、取代或未取代的芳基、取代或未取代的芳氧基、取代或未取代的芳硫基、取代或未取代的芳氨基或卤素；
R4代表氢、取代或未取代的烷基、取代或未取代的芳基；
Y为酸根阴离子，其选自无机酸根离子、有机酸根离子和卤素离子。
9.根据权利要求8所述的用途，其中，所述分子包括氨基酸酯、氨基酰胺、肽或蛋白。
10.根据权利要求8所述的用途，其中，所述修饰或标记用于药物分子合成、探针分子及诊断标记试剂开发领域。
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