CN110423265A - 一种环肽类trf2抑制剂的制备方法和用途 - Google Patents
一种环肽类trf2抑制剂的制备方法和用途 Download PDFInfo
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Abstract
本发明涉及一类阻断端粒结合蛋白TRF2与其它蛋白的相互作用的环肽类化合物(I)的制备方法,采用化学方法将十肽C端五肽末端两个氨基酸侧链相连,构建环肽以控制其构象;用非肽类小分子对N端五肽进行替代模拟其与TRF2的疏水作用,设计并合成了一类环肽类化合物(I),本发明进一步涉及其作为TRF2抑制剂的医疗用途。
Description
技术领域
本发明涉及一类阻断端粒结合蛋白TRF2与其它蛋白的相互作用的拟肽类小分子化合物及它们的制备方法和用途。
背景技术
Shelterin是端粒末端由六个端粒结合蛋白形成的蛋白复合物,其主要功能是保护染色体末端,避免它被DNA修复机制识别为DNA断裂并防止染色体末端偶联。TRF2是Shelterin的重要组成部分,在保持端粒稳定所需要的两个重要结构3’末端DNA单链及T-Loop的形成中有重要作用。另外,TRF2在DNA损伤修复中也有重要作用。TRF2可以与端粒的双链DNA结合并将很多其它蛋白招募到端粒上,它的功能主要是通过它招募的这些蛋白来实现。TRFH结构域是TRF2中的一个重要的结构域,很多被TRF2招募的蛋白是通过与TRF2的TRFH结构域结合而被招募,因此研发阻断TRF2的TRFH结构域与其它蛋白结合的小分子化合物在TRF2及其它端粒结合蛋白的生物学作用机制研究中有重要意义。
本发明中我们公开了一类拟肽类TRF2抑制剂,这类化合物可以用于TRF2及其它端粒结合蛋白的生物学作用机制研究,并有可能用于以端粒结合蛋白为靶点的新药研发。
发明内容
本发明公开了如式I所示的拟肽类化合物,所述式(I)化合物具有如下结构:
其中L为-(CH2)6-10-,其中一个或多个亚甲基可以被氧原子替换;X为-CH2-或-CH2CH2-;R1选自酰胺基、任意取代的芳基、任意取代的杂环芳基;R2为C1-C6的烷基、环烷基或取代的环烷基,上述基团中一个或多个氢原子可以被羟基、氨基、烷氧基、烷氨基、烷巯基取代;R3为C1-C8的烷基、任意取代的烷基、环烷基、取代的环烷基;R4和R5为C1-C8的烷基、任意取代的烷基、环烷基、任意取代的环烷基、烷氧基、烷氨基、烷巯基、任意取代的芳基、任意取代的杂芳基。
本发明中的化合物进一步优选式II的结构:
其中L为-(CH2)6-10-,其中一个或多个亚甲基可以被氧原子替换;R1为C1-C6的烷基、环烷基或取代的环烷基,上述基团中一个或多个氢原子可以被羟基、氨基、烷氧基、烷氨基取代;R2为C1-C8的烷基、任意取代的烷基、环烷基、取代的环烷基;R3为C1-C8的烷基、任意取代的烷基、环烷基、任意取代的环烷基、任意取代的芳基、任意取代的杂芳基;R4为-OR5或选自氢、烷基、任意取代的烷基、环烷基、任意取代的环烷基;R5为C1-C8的烷基、任意取代的烷基、环烷基、任意取代的环烷基、任意取代的芳基、任意取代的杂芳基。
式I中的化合物采用如下方法合成:
具体包括以下步骤:
氨基酸衍生物1和2缩合制备二肽衍生物3;
3脱除保护基后与氨基酸衍生物缩合制备三肽衍生物4;
4脱除保护基后与氨基酸衍生物缩合制备四肽衍生物5;
5保护基后与氨基酸衍生物缩合制备四肽衍生物6;
6过烯烃复分解反应关环得到环肽中间体7;
还原7中的双键并脱除保护基制备中间体8;
8与取代的苯甲酸反应,并在需要的情况下脱除保护基得到式I代表的化合物9;
上述结构式中P为保护基,根据需要从Boc、Cbz或Fmoc中选择。
式(I)和式II所代表的部分化合物结构及命名如下:
(3S,12S,15S,18S,23aS,E)-12-(3-甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-1);
(3S,12S,15S,18S,23aS,E)-12-(3-异丙氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-2);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-3);
(3S,12S,15S,18S,23aS,E)-12-(3-环丙甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-4);
(3S,12S,15S,18S,23aS,E)-12-(3-环戊氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-5);
(3S,12S,15S,18S,23aS,E)-12-(3-苯丙氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-6);
(3S,12S,15S,18S,23aS,E)-12-(3-苯乙氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-7);
(3S,12S,15S,18S,23aS,E)-12-(3-环己甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-8);
(3S,12S,15S,18S,23aS,E)-12-(3-异丁氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-9);
(3S,12S,15S,18S,23aS,E)-12-(3-(2-萘甲基)氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-10);
(3S,12S,15S,18S,23aS,E)-12-(3-异戊氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-11);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-12);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二邻甲基苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-13);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二间甲基苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-14);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二对甲基苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-15);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二间氯苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-16);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二对氯苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-17);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二间溴苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-18);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二对氯苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-19);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二间氟苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-20);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二对氟苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-21);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二(1-萘甲氧基)苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-22);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二(2-萘甲氧基)苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-23);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二邻溴苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-24);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二邻氯苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-25);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二间甲基苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-26);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二邻氟苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-27);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二环戊氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-28);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二环己甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-29);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二正己氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-30);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二环丙甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-31);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二苯丙氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-32);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-异戊氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-33);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-异丁氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-34);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-异丙氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-35);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-环丁氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-36);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-环戊氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-37);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-环丙甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-38);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-环己甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-39);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-正己氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-40);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-羟基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-41);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-42);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-乙氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-43);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-乙氨基氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-44);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-丙氨基氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-45);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-丁氨基氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-46);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-戊氨基氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-47);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-乙羧基氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-48);
实施方式
方法1--缩合反应:
将1eq的酸和1eq的胺或铵盐溶于DMF或二氯甲烷中,在搅拌下于0度加入1.1eqEDC或HBTU、1.1eq HOBt和3.5eq DIEA。反应液升至室温后搅拌至TLC显示反应完全。减压下蒸除大部分溶剂后,残余物用1N的盐酸稀释,水相用乙酸乙酯或二氯甲烷萃取三次,萃取液合并后用饱和碳酸氢钠溶液和饱和氯化钠溶液各洗一次,有机相用无水硫酸钠干燥后过滤、浓缩,粗品用柱层析纯化得到缩合产物。
通用合成方法2-Boc保护基的脱除:
方法1:将带有Boc保护基的底物溶于二氯甲烷中,在搅拌下于室温加入三氟醋酸,根据反应情况决定三氟醋酸的用量,待TLC显示反应完全后,蒸除溶剂和过量的三氟醋酸,残余物用水稀释,用饱和碳酸氢钠溶液中和至中性,用乙酸乙酯或二氯甲烷萃取三次,有机相合并,用饱和氯化钠溶液洗一次,有机相用无水硫酸钠干燥、过滤、浓缩后直接用于下面的反应。
方法2:将带有Boc保护基的底物溶于甲醇中,在室温下加入4N的HCl在1,4-二氧六环中的溶液,反应液搅拌至TLC显示反应完全后蒸除溶剂,得到的盐酸盐直接用于下面的反应。
通用合成方法3-Cbz的脱除:
将带有Cbz的底物溶于甲醇中,反应瓶中的空气用氮气置换后在反应液中加入10%的Pd-C,在氢气下反应至TLC显示反应完全。滤除催化剂后,滤液浓缩,所得的粗品直接用于下面的反应。
通用合成方法4-Fmoc保护基的脱除:
将带有Fmoc保护基的底物溶于二氯甲烷中,在室温下加入等体积的哌啶,搅拌至TLC显示反应完全。反应液浓缩后粗产品可以直接用于下面的反应或在有必要的情况下用柱层析纯化。
烯烃复分解反应:
将关环前体溶于二氯甲烷或1,2-二氯乙烷中,在反应液中加入Grubbs催化剂。反应液在氮气保护下回流至TLC显示反应完全,蒸除溶剂后粗品用柱层析纯化得到关环产物(化合物7)。1H NMR(300MHz,CDCl3)δ7.80-7.60(m,1H),7.55-7.20(m,2H),5.95-5.70(m,3H),5.30-5.02(m,5H),4.80-4.55(m,3H),4.30(m,1H),4.15-3.40(m,10H),3.10(brs,3H),2.95(brs,3H),2.20-1.80(m,4H),1.65-120(m,15H),0.90-0.80(m,6H);ESI-MS m/z calc’d for C33H57N6O9[M+H]+681.41,found 681.55.
双键的氢化及脱除保护基:
将带有双键的底物溶于甲醇中,反应瓶中的空气用氮气置换后在反应液中加入10%的Pd-C,在氢气下反应至TLC显示反应完全。滤除催化剂后,滤液浓缩,粗品直接用于下面的反应。
部分关键氨基酸衍生物的合成
N-Boc-O-烯丙基-丝氨酸的制备
将S-丝氨酸(1)溶于二氧六环∶水=1∶1混合溶液中,依次加入1eq NaOH、2eqNaHCO3、1.1eq Boc2O室温搅拌过夜,反应完全后,用3N盐酸调PH为酸性,EA萃取,饱和食盐水洗一次,无水硫酸钠干燥,浓缩,得到S-N-Boc-丝氨酸粗品。将S-N-Boc-丝氨酸粗品溶于适量DMF中,0℃下缓慢分批加入3.1eq 60%NaH。反应液在0℃下搅拌30min后,缓慢滴加1.05eq 3-溴丙烯的DMF溶液,加毕,反应液缓慢升至室温搅拌3h,TLC检测反应完全后,用3N盐酸调PH至酸性,EA萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,浓缩,得到S-N-Boc-O-烯丙基-丝氨酸,收率约为68%。
S-N-Boc-O-烯丙基-丝氨酸-N,N-二甲基酰胺的制备
将S-N-Boc-O-烯丙基-丝氨酸溶于适量DMF中,0℃条件下,加入1.1eq HBTU、1.5eqHOBT、3eq DIEA,缓慢分批加入1.2eq盐酸二甲胺,提至室温反应4-5h,TLC检测反应完全后,用水稀释,用乙酸乙酯萃取三次,有机相合并后分别用1N盐酸、饱和碳酸氢钠水溶液、饱和食盐水洗,无水硫酸钠干燥,浓缩,柱分离得S-N-Boc-O-烯丙基-丝氨酸-N,N-二甲基酰胺,收率约为81%。
S-2-Cbz-氨基-3-氨基丙酸的制备
将N-Cbz保护的S-天冬酰胺溶于水∶乙腈∶乙酸乙酯=1∶2∶2的混合溶液中,在0℃的条件下,加入1.5eq碘苯二乙酯,缓慢升至室温搅拌5h,TLC检测反应完全后,硅藻土抽滤,滤饼用少量EA洗涤3次,干燥,得S-2-Cbz-氨基-3-氨基丙酸粗品,收率约为62%。
S-2-Cbz-氨基-3-Boc-氨基丙酸的制备
将S-2-Cbz-氨基-3-氨基丙酸溶于二氧六环∶水=1∶1的混合溶液中,依次加入1eqNaOH、2eq NaHCO3、1.1eq Boc2O室温搅拌过夜,反应完全后,用石油醚萃取除去多余的Boc2O后水相用3N盐酸调PH为5,用乙酸乙酯萃取三次,合并有机相,饱和食盐水洗一次,无水硫酸钠干燥,浓缩,得到S-2-Cbz-氨基-3-Boc-氨基丙酸,收率约为85%。
终产物根据[0008]所示的合成路线利用[0068]-[0079]所示的通用合成方法合成。
(3S,12S,15S,18S,23aS,E)-12-(3-甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-1):1H NMR(300MHz,CDCl3)δ7.70(brd,J=6.5Hz,1H),7.48-7.30(m,4H),7.20-7.05(m,2H),6.45(brd,J=6.5Hz,1H),5.10-4.95(m,1H),4.85-4.40(m,4H),4.05-3.40(m,10H),3.35(s,3H),3.20-3.15(brs,3H),2.95-2.85(brs,3H),2.30-1.40(m,11H),1.40-1.05(brd,J=7.2Hz,3H),1.05-0.80(m,6H);ESI-MS m/z calc’d for C34H53N6O9[M+H]+689.38,found 689.50.
(3S,12S,15S,18S,23aS,E)-12-(3-异丙氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-2):1H NMR(300MHz,CDCl3)δ7.70(brd,J=6.5Hz,1H),7.48-7.30(m,4H),7.20-7.05(m,2H),6.45(brd,J=6.5Hz,1H),5.10-4.95(m,1H),4.85-4.40(m,4H),4.05-3.40(m,11H),3.20-3.15(brs,3H),2.95-2.85(brs,3H),2.30-1.40(m,11H),1.40-1.05(m,9H),1.05-0.80(m,6H);ESI-MS m/z calc’d for C36H57N6O9[M+H]+717.41,found 717.60.
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-3):1H NMR(300MHz,CDCl3)δ7.70(brd,J=6.5Hz,1H),7.48-7.30(m,9H),7.20-7.05(m,2H),6.45(brd,J=6.5Hz,1H),5.20(brs,2H),5.10-4.95(m,1H),4.85-4.40(m,4H),4.05-3.40(m,10H),3.20-3.15(brs,3H),2.95-2.85(brs,3H),2.30-1.40(m,11H),1.40-1.05(brd,J=7.2Hz,3H),1.05-0.80(m,6H);ESI-MS m/z calc’d for C40H57N6O9[M+H]+765.41,found 765.60.
(3S,12S,15S,18S,23aS,E)-12-(3-环丙甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-4):1H NMR(300MHz,CDCl3)δ7.70(brd,J=6.5Hz,1H),7.48-7.30(m,4H),7.15-6.95(m,2H),6.45(brd,J=6.5Hz,1H),4.90-4.85(m,1H),4.75-4.25(m,4H),4.05-3.40(m,12H),3.10-3.04(brs,3H),2.85-2.75(brs,3H),2.30-1.40(m,12H),1.40-1.05(brd,J=7.2Hz,3H),1.05-0.80(m,6H),0.51(m,2H),0.30(m,2H);ESI-MS m/z calc’d forC37H57N6O9[M+H]+729.41,found 729.60.
(3S,12S,15S,18S,23aS,E)-12-(3-环戊氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-5):1H NMR(300MHz,CDCl3)δ7.70(brd,J=6.5Hz,1H),7.48-7.30(m,4H),7.15-7.02(m,2H),6.45(brd,J=6.5Hz,1H),5.05-4.94(m,1H),4.85-4.40(m,4H),4.05-3.40(m,11H),3.20-3.04(brs,3H),3.04-2.85(brs,3H),2.40-1.40(m,19H),1.40-1.05(brd,J=7.2Hz,3H),1.05-0.80(m,6H);ESI-MS m/z calc’d for C38H59N6O9[M+H]+743.43,found743.60.
(3S,12S,15S,18S,23aS,E)-12-(3-苯丙氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-6):1H NMR(300MHz,CDCl3)δ7.70(brd,J=6.5Hz,1H),7.48-7.30(m,4H),7.30-7.05(m,7H),6.45(brd,J=6.5Hz,1H),5.05-4.94(m,1H),4.85-4.40(m,4H),4.05-3.40(m,12H),3.20-3.04(brs,3H),3.04-2.85(brs,3H),2.85-2.78(m,2H),2.40-1.40(m,13H),1.40-1.05(brd,J=7.2Hz,3H),1.05-0.80(m,6H);ESI-MS m/z calc’d for C42H61N6O9[M+H]+793.44,found 793.60.
(3S,12S,15S,18S,23aS,E)-12-(3-苯乙氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-7):1H NMR(300MHz,CDCl3)δ7.70(brd,J=6.5Hz,1H),7.48-7.05(m,11H),6.45(brd,J=6.5Hz,1H),5.05-4.94(m,1H),4.85-4.40(m,4H),4.05-3.40(m,12H),3.20-3.04(brs,3H),3.04-2.85(brs,3H),2.85-2.78(m,2H),2.40-1.40(m,11H),1.40-1.05(brd,J=7.2Hz,3H),1.05-0.80(m,6H);ESI-MS m/z calc’d for C41H59N6O9[M+H]+779.43,fbund779.60.
(3S,12S,15S,18S,23aS,E)-12-(3-环己甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-8):1H NMR(300MHz,CDCl3)δ7.70(brd,J=6.5Hz,1H),7.48-7.30(m,4H),7.20-7.05(m,2H),6.45(brd,J=6.5Hz,1H),5.05-4.94(m,1H),4.85-4.40(m,4H),4.05-3.40(m,12H),3.20-3.04(brs,3H),3.04-2.85(brs,3H),2.40-1.40(m,18H),1.40-1.05(m,7H),1.05-0.80(m,6H);ESI-MS m/z calc’d for C40H63N6O9[M+H]+771.46,found 771.60.
(3S,12S,15S,18S,23aS,E)-12-(3-异丁氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-9):1H NMR(300MHz,CDCl3)δ7.70(brd,J=6.5Hz,1H),7.48-7.30(m,4H),7.20-7.05(m,2H),6.45(brd,J=6.5Hz,1H),5.05-4.94(m,1H),4.85-4.45(m,4H),4.05-3.40(m,12H),3.20-3.04(brs,3H),3.04-2.85(brs,3H),2.40-1.40(m,12H),1.35(brd,J=7.2Hz,3H),1.05-0.80(m,12H);ESI-MS m/z calc’d for C37H59N6O9[M+H]+731.43,found 745.60.
(3S,12S,15S,18S,23aS,E)-12-(3-(2-萘甲基)氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-10):1H NMR(300MHz,CDCl3)δ7.70(brd,J=6.5Hz,1H),7.48-7.05(m,13H),6.50(brd,J=6.5Hz,1H),5.10(brs,1H),5.02-4.95(m,1H),4.82-4.45(m,4H),3.95-3.40(m,10H),3.20-3.05(brs,3H),3.04-2.85(brs,3H),2.40-1.45(m,11H),1.35(brd,J=7.2Hz,3H),1.05-0.80(m,6H);ESI-MS m/z calc’d for C44H58N6O9[M+H]+815.43,found815.60
(3S,12S,15S,18S,23aS,E)-12-(3-异戊氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-11):1H NMR(300MHz,CDCl3)δ7.70(brd,J=6.5Hz,1H),7.48-7.30(m,4H),7.20-7.05(m,2H),6.45(brd,J=6.5Hz,1H),5.01-4.84(m,1H),4.80-4.45(m,4H),3.95-3.40(m,12H),3.20-3.04(brs,3H),3.04-2.85(brs,3H),2.40-1.40(m,14H),1.35(brd,J=7.2Hz,3H),1.05-0.80(m,12H);ESI-MS m/z calc’d for C38H61N6O9[M+H]+745.44,found745.60.
(3S,12S,15S,18S,23aS,E)-12-(3,5-二苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-12):1H NMR(300MHz,CDCl3)δ7.66(brd,J=6.5Hz,1H),7.51(m,1H),7.48-7.29(m,10H),7.21(m,1H),7.14-7.04(m,2H),6.78(m,1H),6.75(m,1H),5.08(brs,4H),4.94(m,1H),4.87-4.65(m,3H),4.54(m,1H),3.86-3.32(m,10H),3.11(brs,3H),2.94(brs,3H),2.23-1.48(m,11H),1.40(brd,J=7.2Hz,3H),1.05-0.80(m,6H).ESI-MS m/z calc’dfor C47H63N6O10[M+H]+871.46,found 871.54.
(3S,12S,15S,18S,23aS,E)-12-(3,5-二邻甲基苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-13):1H NMR(300MHz,CDCl3)δ7.67(m,1H),7.54(m,1H),7.49(m,1H),7.47-7.36(m,2H),7.33-7.15(m,7H),7.15-7.07(m,2H),6.81-6.70(m,2H),5.07(m,4H),4.94(m,1H),4.87-4.74(m,1H),4.74-4.67(m,1H),4.67-4.62(m,1H),4.53(m,1H),3.99-3.74(m,3H),3.73-3.48(m,5H),3.39(m,2H),3.18-3.05(m,3H),3.04-2.89(m,3H),2.39(m,6H),2.11-1.96(m,2H),1.95-1.78(m,3H),1.76-1.60(m,3H),1.55(m,2H),1.35(d,J=6.8Hz,3H),1.04-0.88(m,7H).ESI-MS m/z calc’d for C49H66N6O10[M+Na]+922.1,found922.3.
(3S,12S,15S,18S,23aS,E)-12-(3,5-二间甲基苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-14):1H NMR(300MHz,CDCl3)δ7.63(m,1H),7.52(m,1H),7.32(m,4H),7.20(m,5H),7.08(m,2H),6.80-6.65(m,2H),5.05(m,4H),4.95(m,1H),4.80(m,1H),4.71(m,1H),4.65(m,1H),4.62-4.48(m,1H),3.97-3.79(m,2H),3.77-3.49(m,5H),3.50-3.30(m,2H),3.09(m,3H),3.04-2.89(m,3H),2.38(s,6H),2.33-2.23(m,1H),2.09-1.93(m,2H),1.85(m,3H),1.76-1.60(m,3H),1.60-1.44(m,2H),1.36(m,3H),1.04-0.81(m,7H).ESI-MSm/z calc’d for C49H66N6O10[M+Na]+922.1,found 922.5.
(3S,12S,15S,18S,23aS,E)-12-(3,5-二对甲基苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-15):1H NMR(300MHz,CDCl3)δ7.63(m,1H),7.52(m,1H),7.32(m,4H),7.20(m,5H),7.08(m,2H),6.80-6.65(m,2H),5.05(m,4H),4.95(m,1H),4.80(m,1H),4.71(m,1H),4.65(m,1H),4.62-4.48(m,1H),3.97-3.79(m,2H),3.77-3.49(m,5H),3.50-3.30(m,2H),3.09(m,3H),3.04-2.89(m,3H),2.38(s,6H),2.33-2.23(m,1H),2.09-1.93(m,2H),1.85(m,3H),1.76-1.60(m,3H),1.60-1.44(m,2H),1.36(m,3H),1.04-0.81(m,7H).ESI-MSm/z calc’d for C49H66N6O10[M+Na]+922.1,found 922.5.
(3S,12S,15S,18S,23aS,E)-12-(3,5-二间氯苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-16):1H NMR(300MHz,CDCl3)δ7.67(m,1H),7.50(m,1H),7.47-7.42(m,2H),7.40-7.30(m,5H),7.26-7.20(m,1H),7.09(m,2H),6.77-6.68(m,2H),5.18-5.01(m,4H),4.96(m,1H),4.80(m,1H),4.74-4.61(m,2H),4.59-4.46(m,1H),3.99-3.91(m,1H),3.84(m,1H),3.74-3.48(m,5H),3.47-3.35(m,2H),3.12(m,3H),2.95(m,3H),2.36-2.21(m,1H),2.10-1.95(m,1H),1.94-1.80(m,3H),1.79-1.63(m,3H),1.56(m,2H),1.34(m,3H),1.05-0.86(m,6H).ESI-MS m/z calc’d for C47H60Cl2N6O10[M+Na]+962.9,found 963.2.
(3S,12S,15S,18S,23aS,E)-12-(3,5-二对氯苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-17):1H NMR(300MHz,CDCl3)δ7.67(m,1H),7.48(m,1H),7.43-7.30(m,8H),7.21(m,1H),7.12-7.02(m,2H),6.77-6.64(m,2H),5.11-5.01(m,4H),4.96(m,1H),4.80(m,1H),4.74-4.61(m,2H),4.59-4.47(m,1H),3.96-3.79(m,3H),3.73-3.48(m,5H),3.47-3.36(m,2H),3.12(m,3H),2.95(m,3H),2.30(m,1H),1.99(m,1H),1.93-1.79(m,3H),1.78-1.62(m,3H),1.62-1.49(m,2H),1.34(m,3H),0.95(m,6H).ESI-MS m/z calc’d forC47H60Cl2N6O10[M+Na]+962.9,found 963.3.
(3S,12S,15S,18S,23aS,E)-12-(3,5-二间溴苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-18):1H NMR(300MHz,CDCl3)δ7.67(m,1H),7.65-7.58(m,2H),7.54-7.44(m,3H),7.41-7.33(m,2H),7.34-7.21(m,4H),7.13-7.06(m,2H),6.73(m,2H),5.19-5.01(m,4H),5.00-4.90(m,1H),4.85-4.77(m,1H),4.77-4.60(m,2H),4.53(m,1H),4.02-3.89(m,2H),3.87-3.77(m,1H),3.59(m,5H),3.48-3.35(m,2H),3.17-3.05(m,3H),3.05-2.90(m,3H),2.36-2.22(m,1H),2.06-1.92(m,2H),1.90-1.78(m,3H),1.77-1.63(m,3H),1.62-1.50(m,2H),1.34(m,3H),1.02-0.91(m,6H).ESI-MS m/z calc’d for C47H60Br2N6O10[M+Na]+1051.8,found 1051.9.
(3S,12S,15S,18S,23aS,E)-12-(3,5-二对溴苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-19):1H NMR(300MHz,CDCl3)δ7.67(m,1H),7.58-7.43(m,5H),7.36-7.27(m,4H),7.21(m,1H),7.13-7.05(m,2H),6.79-6.66(m,2H),5.11-5.00(m,4H),4.99-4.90(m,1H),4.80(m,1H),4.69(m,2H),4.60-4.47(m,1H),3.94(m,1H),3.90-3.78(m,1H),3.74-3.48(m,5H),3.48-3.36(m,2H),3.12(m,3H),2.96(m,3H),2.36-2.22(m,1H),2.07-1.94(m,1H),1.93-1.79(m,3H),1.79-1.61(m,3H),1.61-1.49(m,2H),1.34(m,3H),1.04-0.87(m,6H).ESI-MS m/z calc’d for C47H60Cl2N6O10[M+Na]+962.9,found 963.3.
(3S,12S,15S,18S,23aS,E)-12-(3,5-二间氟苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-20):1H NMR(300MHz,CDCl3)δ7.67(m,1H),7.50(m,1H),7.42-7.31(m,2H),7.27-7.12(m,5H),7.09(m,2H),7.08-6.98(m,2H),6.78-6.68(m,2H),5.14-5.02(m,4H),4.96(m,1H),4.86-4.76(m,1H),4.67(m,2H),4.54(m,1H),3.99-3.76(m,2H),3.74-3.48(m,5H),3.47-3.36(m,2H),3.12(m,3H),2.95(m,3H),2.34-1.97(m,3H),1.80-1.97(m,3H),1.80-1.62(m,3H),1.62-1.46(m,2H),1.43-1.30(m,3H),1.02-0.87(m,6H).ESI-MS m/z calc’d for C47H60F2N6O10[M+Na]+940.0,found 940.2.
(3S,12S,15S,18S,23aS,E)-12-(3,5-二对氟苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-21):1H NMR(300MHz,CDCl3)δ7.67(m,1H),7.49(m,1H),7.47-7.32(m,4H),7.22(m,1H),7.16-7.01(m,6H),6.79-6.69(m,2H),5.12-5.01(m,4H),5.01-4.90(m,1H),4.86-4.76(m,1H),4.75-4.62(m,2H),4.60-4.47(m,1H),3.97-3.79(m,3H),3.73-3.48(m,5H),3.43(m,2H),3.17-3.04(m,3H),2.96(m,3H),2.36-2.23(m,1H),2.05-1.96(m,1H),1.94-1.80(m,3H),1.79-1.62(m,3H),1.61-1.47(m,2H),1.34(d,J=6.8Hz,3H),1.05-0.88(m,6H).ESI-MS m/z calc’d for C47H60F2N6O10[M+Na]+940.0,found 940.2.
(3S,12S,15S,18S,23aS,E)-12-(3,5-二-(1-萘甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-22):1H NMR(300MHz,CDCl3)δ7.95-7.75(m,8H),7.67(m,1H),7.60-7.44(m,7H),7.22-7.12(m,2H),6.86(m,1H),6.74(m,1H),5.33-5.17(m,4H),5.02-4.90(m,1H),4.82(m,1H),4.69(m,2H),4.55(m,1H),3.97(m,1H),3.90-3.79(m,1H),3.75-3.47(m,6H),3.47-3.36(m,2H),3.11(m,3H),2.95(m,3H),2.34-2.24(m,1H),2.01-1.94(m,1H),1.92-1.78(m,3H),1.76-1.63(m,3H),1.62-1.49(m,2H),1.36(s,3H),1.04-0.91(m,6H).ESI-MS m/z calc’d for C55H66N6O10[M+Na]+994.1,found 994.2.
(3S,12S,15S,18S,23aS,E)-12-(3,5-二-(2-萘甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-23):1H NMR(300MHz,CDCl3)δ8.20-8.00(m,2H),7.99-7.81(m,4H),7.75-7.42(m,9H),7.38-7.15(m,4H),7.03-6.85(m,1H),6.77(m,1H),5.67-5.33(m,4H),5.01-4.92(m,1H),4.85(m,1H),4.74-4.65(m,1H),4.63(m,1H),4.58-4.45(m,1H),4.02-3.90(m,1H),3.85(m,1H),3.76-3.47(m,5H),3.47-3.34(m,2H),3.07(m,3H),2.94(d,J=18.2Hz,3H),2.19-1.99(m,2H),1.97-1.80(m,3H),1.71(m,3H),1.62-1.50(m,2H),1.44-1.32(m,3H),0.93(m,6H).ESI-MS m/z calc’d for C55H66N6O10[M+Na]+994.1,found 994.2.
(3S,12S,15S,18S,23aS,E)-12-(3,5-二邻溴苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-24):1H NMR(300MHz,CDCl3)δ7.67(m,1H),7.63-7.47(m,5H),7.41-7.31(m,2H),7.26-7.16(m,3H),7.15-7.10(m,2H),6.81-6.70(m,2H),5.23-5.12(m,4H),4.96(m,1H),4.89-4.76(m,1H),4.76-4.62(m,2H),4.62-4.47(m,1H),3.98-3.79(m,2H),3.74-3.51(m,5H),3.50-3.32(m,2H),3.17-3.03(m,3H),2.99(m,3H),2.36-2.22(m,1H),2.04(m,1H),1.94-1.81(m,3H),1.77-1.63(m,3H),1.61-1.50(m,2H),1.35(d,J=6.8Hz,3H),0.96(m,6H).ESI-MS m/z calc’d for C47H60Br2N6O10[M+Na]+1051.8,found 1051.9.
(3S,12S,15S,18S,23aS,E)-12-(3,5-二邻氯苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-25):1H NMR(300MHz,CDCl3)δ7.72-7.65(m,1H),7.61-7.47(m,4H),7.45-7.35(m,3H),7.35-7.20(m,7H),7.17-7.08(m,2H),6.86-6.71(m,2H),5.27-5.12(m,5H),5.02-4.92(m,1H),4.90-4.76(m,1H),4.77-4.60(m,2H),4.62-4.45(m,1H),3.99-3.78(m,2H),3.76-3.49(m,5H),3.48-3.31(m,2H),3.20-3.04(m,3H),3.03-2.84(m,3H),2.35-2.24(m,1H),2.09-1.98(m,1H),1.97-1.79(m,3H),1.77-1.60(m,3H),1.60-1.46(m,2H),1.35(d,J=6.7Hz,3H),1.02-0.90(m,6H).ESI-MS m/z calc’d for C47H60Cl2N6O10[M+Na]+962.9,found 963.3.
(3S,12S,15S,18S,23aS,E)-12-(3,5-二间甲氧基苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-26):1H NMR(300MHz,CDCl3)δ7.70-7.59(m,1H),7.55-7.43(m,1H),7.37-7.29(m,2H),7.26-7.18(m,1H),7.15-7.06(m,2H),7.06-6.95(m,3H),6.93-6.85(m,2H),6.81-6.70(m,2H),5.19-5.02(m,4H),5.01-4.89(m,1H),4.86-4.77(m,1H),4.76-4.61(m,2H),4.53(m,1H),3.99-3.89(m,1H),3.89-3.77(m,6H),3.76-3.48(m,5H),3.49-3.33(m,2H),3.17-3.05(m,3H),3.04-2.90(m,3H),2.34-2.22(m,1H),2.07-1.96(m,1H),1.93-1.78(m,3H),1.76-1.61(m,3H),1.61-1.48(m,2H),1.34(d,J=6.8Hz,3H),1.04-0.89(m,6H).ESI-MS m/z calc’d for C49H66N6O12[M+Na]+954.1,found 954.3.
(3S,12S,15S,18S,23aS,E)-12-(3,5-二邻氟苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-27):1H NMR(300MHz,CDCl3)δ7.77-7.61(m,1H),7.63-7.43(m,3H),7.33(tdd,J=13.9,11.6,6.4Hz,4H),7.16(m,5H),6.93-6.69(m,2H),5.30-5.06(m,3H),5.04-4.92(m,1H),4.87-4.76(m,1H),4.75-4.60(m,1H),4.51(m,1H),3.98-3.78(m,2H),3.77-3.51(m,5H),3.49-3.33(m,2H),3.20-3.04(m,3H),3.04-2.89(m,3H),2.36-2.22(m,1H),2.09-2.00(m,1H),1.98-1.81(m,3H),1.80-1.63(m,3H),1.62-1.49(m,2H),1.46-1.33(m,3H),1.06-0.87(m,6H).ESI-MS m/z calc’d for C47H60F2N6O10[M+Na]+940.0,found940.2.
(3S,12S,15S,18S,23aS,E)-12-(3,5-二环戊氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-28):1H NMR(300MHz,CDCl3)δ7.77-7.59(m,1H),7.38(m,1H),7.17(m,1H),6.94-6.80(m,2H),6.52(m,1H),5.04-4.90(m,1H),4.90-4.70(m,3H),4.69-4.50(m,2H),4.50-4.42(m,1H),3.98(m,1H),3.91-3.81(m,1H),3.81-3.69(m,1H),3.70-3.44(m,5H),3.43-3.28(m,1H),3.17-3.04(m,2H),3.02-2.87(m,3H),2.30(m,1H),2.00-1.71(m,17H),1.69-1.53(m,8H),1.34(m,=3H),0.98-0.83(m,6H).ESI-MS m/z calc’d forC43H66N6O10[M+Na]+840.0,found 840.2.
(3S,12S,15S,18S,23aS,E)-12-(3,5-二环己甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-29):1H NMR(300MHz,CDCl3)δ7.77-7.59(m,1H),7.38(m,1H),7.17(m,1H),6.94-6.80(m,2H),6.52(m,1H),5.04-4.90(m,1H),4.90-4.70(m,3H),4.69-4.50(m,2H),4.50-4.42(m,1H),3.98(m,1H),3.91-3.81(m,1H),3.81-3.69(m,1H),3.70-3.44(m,5H),3.43-3.28(m,1H),3.17-3.04(m,2H),3.02-2.87(m,3H),2.30(m,1H),2.00-1.71(m,17H),1.69-1.53(m,8H),1.34(m,=3H),0.98-0.83(m,6H).ESI-MS m/z calc’d forC43H66N6O10[M+Na]+840.0,found 840.2.
(3S,12S,15S,18S,23aS,E)-12-(3,5-二正己氧基苯甲酰基氨基)-15-异丁基.N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-30):1H NMR(300MHz,CDCl3)δ7.74-7.64(m,1H),7.48-7.39(m,1H),7.24-7.19(m,2H),6.93(m,2H),6.68(m,1H),6.63-6.55(m,1H),5.03-4.93(m,1H),4.88-4.77(m,1H),4.74-4.59(m,2H),4.55-4.43(m,1H),4.00-3.86(m,2H),3.83-3.74(m,6H),3.70-3.50(m,5H),3.45(m,2H),3.18-3.06(m,3H),3.01-2.90(m,3H),1.92-1.67(m,23H),1.65-1.52(m,4H),1.38-1.23(m,17H),1.07(m,3H),0.99-0.90(m,6H).ESI-MS m/z calc’dfor C47H74N6O10[M+Na]+906.1,found 906.3.
(3S,12S,15S,18S,23aS,E)-12-(3,5-二环丙甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-31):1H NMR(300MHz,CDCl3)δ7.70(brd,J=6.5Hz,1H),7.48(brd,J=6.4Hz,1H),7.20(brd,J=6.5Hz,1H),6.95-6.90(m,2H),6.45(brd,J=6.5Hz,1H),6.65-6.60(m,1H),5.01-4.84(m,1H),4.80-4.60(m,3H),4.60-4.45(m,1H),3.95-3.75(m,7H),3.65-3.30(m,7H),3.20-3.04(brs,3H),3.04-2.85(brs,3H),2.40-1.40(m,12H),1.35(brd,J=7.2Hz,3H),1.05-0.80(m,6H),0.70-0.55(m,4H),0.40-0.30(m,4H).ESI-MS m/zcalc’d for C41H63N6O10[M+H]+799.45.44,found 799.60.
(3S,12S,15S,18S,23aS,E)-12-(3,5-二苯丙氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-32):1H NMR(300MHz,CDCl3)δ7.68(d,J=7.2Hz,1H),7.48(d,J=6.9Hz,1H),7.34-7.26(m,6H),7.25-7.15(m,8H),6.95(dd,J=5.7,2.3Hz,2H),6.75(d,J=8.5Hz,1H),6.58(dt,J=4.2,2.1Hz,1H),4.96(ddd,J=7.6,6.1,3.1Hz,1H),4.86-4.75(m,1H),4.74-4.62(m,2H),4.60-4.48(m,1H),4.00(t,J=6.2Hz,5H),3.93-3.79(m,2H),3.73-3.50(m,5H),3.50-3.36(m,2H),3.16-3.04(m,3H),2.95(d,J=14.3Hz,3H),2.82(t,J=7.6Hz,5H),2.38-2.25(m,1H),2.17-1.98(m,7H),1.96-1.79(m,4H),1.79-1.64(m,3H),1.62-1.46(m,3H),1.35(d,J=6.8Hz,3H),1.02-0.91(m,6H).
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-异戊氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-33):1H NMR(300MHz,CDCl3)δ7.71(brd,J=6.5Hz,1H),7.60-7.48(m,1H),7.48-7.30(m,5H),7.25-7.20(brd,J=6.5Hz,1H),7.10-7.05(m,1H),7.01-6.94(m,1H),6.85-6.60(m,2H),5.13-5.02(brs,2H),4.95-4.85(m,1H),4.79-4.49(m,4H),4.10-3.30(m,12H),3.17-3.04(brs,3H),3.02-2.80(brs,3H),2.30-1.45(m,14H),1.40(brd,J=7.2Hz,3H),1.10-0.70(m,12H).ESI-MS m/z calc’d for C45H67N6O10[M+H]+851.48,fourd 851.60.
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-异丁氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-34):1H NMR(300MHz,CDCl3)δ7.71(brd,J=6.5Hz,1H),7.60-7.49(m,1H),7.48-7.30(m,5H),7.30-7.20(m,1H),7.09-7.01(m,1H),7.01-6.94(m,1H),6.85-6.60(m,2H),5.13-5.02(brs,2H),4.95-4.85(m,1H),4.79-4.49(m,4H),4.05-3.30(m,12H),3.17-3.04(brs,3H),2.97-2.85(brs,3H),2.30-1.45(m,12H),1.40(brd,J=7.2Hz,3H),1.10-0.70(m,12H).ESI-MS m/z calc’d for C44H65N6O10[M+H]+837.47,found 837.60.
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-异丙氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-35):1H NMR(300MHz,CDCl3)δ7.71(brd,J=6.5Hz,1H),7.58-7.49(m,1H),7.48-7.25(m,5H),7.20(brd,J=6.5Hz,1H),7.09-7.01(m,1H),7.01-6.94(m,1H),6.80-6.60(m,2H),5.13-5.02(brs,2H),4.95-4.85(m,1H),4.79-4.49(m,4H),3.95-3.34(m,11H),3.17-3.04(brs,3H),2.97-2.85(brs,3H),2.36-1.45(m,11H),1.40-1.25(m,9H),0.95-0.70(m,6H).ESI-MS m/z calc’d for C43H63N6O10[M+H]+823.46,found 823.67.
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-环丁氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-36):1H NMR(300MHz,CDCl3)δ7.71(brd,J=6.5Hz,1H),7.58-7.49(m,1H),7.48-7.30(m,5H),7.20(brd,J=6.5Hz,1H),7.10-7.01(m,1H),7.01-6.94(m,1H),6.70-6.60(m,1H),6.60-6.55(m,1H),5.13-5.02(brs,2H),4.95-4.84(m,1H),4.79-4.49(m,4H),3.95-3.34(m,11H),3.17-3.04(brs,3H),3.04-2.85(brs,3H),2.36-1.45(m,17H),1.35(brd,J=7.2Hz,3H),0.95-0.70(m,6H).ESI-MS m/z calc’d for C44H63N6O10[M+H]+835.45,found 835.58.
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-环戊氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-37):1H NMR(300MHz,CDCl3)δ7.75-7.60(m,1H),7.58-7.49(m,1H),7.48-7.30(m,5H),7.24(brd,J=6.5Hz,1H),7.10-6.99(m,1H),6.98-6.94(m,1H),6.70-6.60(m,1H),6.60-6.55(m,1H),5.13-5.02(brs,2H),4.95-4.84(m,1H),4.79-4.49(m,4H),4.35-4.30(m,1H),3.95-3.34(m,10H),3.20-3.04(brs,3H),3.04-2.85(brs,3H),2.30-1.40(m,19H),1.35(brd,J=7.2Hz,3H),0.95-0.70(m,6H).ESI-MS m/z calc’d forC45H65N6O10[M+H]+849.47,found 849.60.
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-环丙甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-38):1H NMR(300MHz,CDCl3)δ7.70(brd,J=6.5Hz,1H),7.58-7.30(m,5H),7.20(brd,J=6.5Hz,1H),7.10-7.02(m,1H),6.98-6.94(m,1H),6.50-6.30(m,2H),5.15-5.02(brs,2H),4.95-4.84(m,1H),4.79-4.49(m,4H),3.95-3.75(m,5H),3.65-3.30(m,7H),3.20-3.04(brs,3H),3.04-2.85(brs,3H),2.35-1.40(m,12H),1.35(brd,J=7.2Hz,3H),0.95-0.80(m,6H),0.70-0.55(m,2H),0.40-0.30(m,2H).ESI-MS m/z calc’dfor C44H63N6O10[M+H]+835.45,found 835.61.
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-环己甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-39):1H NMR(300MHz,CDCl3)δ7.66(m,1H),7.56-7.31(m,7H),7.19(m,1H),7.11-7.01(m,1H),7.01-6.91(m,1H),6.68(m,2H),5.16-5.02(m,2H),4.96(m,1H),4.81(m,1H),4.68(m,2H),4.57(m,1H),3.99-3.84(m,3H),3.78(m,3H),3.74-3.51(m,5H),3.51-3.39(m,2H),3.19-3.06(m,3H),3.06-2.90(m,3H),2.33(m,1H),2.07-1.88(m,5H),1.87-1.68(m,9H),1.66-1.49(m,4H),1.36m,5H),1.17-1.02(m,4H),1.03-0.83(m,6H).
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-正己氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-40):1H NMR(300MHz,CDCl3)δ7.67(d,J=7.1Hz,1H),7.54-7.31(m,7H),7.21(m,1H),7.06(m,1H),6.98(m,1H),6.77-6.59(m,2H),5.15-5.05(m,2H),4.95(m,1H),4.87-4.77(m,1H),4.76-4.63(m,2H),4.62-4.47(m,1H),4.03-3.90(m,4H),3.89-3.78(m,1H),3.76-3.50(m,6H),3.43(m,2H),3.18-3.05(m,3H),2.97(m,3H),2.32(m,1H),2.04(m,1H),1.98-1.84(m,3H),1.84-1.64(m,6H),1.63-1.53(m,2H),1.53-1.42(m,3H),1.41-1.25(m,9H),1.02-0.89(m,10H).
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-羟基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-41):1H NMR(300MHz,CDC13)δ7.70(brd,J=6.5Hz,1H),7.55-7.45(m,1H),7.48-7.25(m,5H),7.20(brd,J=6.5Hz,1H),7.09-7.01(m,1H),7.01-6.94(m,1H),6.80-6.60(m,2H),5.13-5.02(brs,2H),4.95-4.85(m,1H),4.79-4.49(m,4H),3.95-3.34(m,13H),3.15-3.05(brs,3H),2.95-2.83(brs,3H),2.35-1.45(m,11H),0.95-0.70(m,6H).
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-42):1H NMR(300MHz,CDC13)δ7.71(brd,J=6.5Hz,1H),7.55-7.45(m,1H),7.48-7.25(m,5H),7.20(brd,J=6.5Hz,1H),7.09-7.01(m,1H),7.01-6.94(m,1H),6.80-6.60(m,2H),5.13-5.02(brs,2H),4.95-4.85(m,1H),4.79-4.49(m,4H),3.95-3.34(m,13H),3.15-3.05(brs,3H),2.95-2.83(brs,3H),2.35-1.45(m,11H),1.40-1.25(brd,J=7.2Hz,3H),0.95-0.70(m,6H).ESI-MS m/z calc’d for C41H59N6O10[M+H]+795.42,found795.61.
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-乙氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-43):1H NMR(300MHz,CDCl3)δ7.70(brd,J=6.5Hz,1H),7.55-7.45(m,1H),7.48-7.25(m,5H),7.20(brd,J=6.5Hz,1H),7.09-7.01(m,1H),7.01-6.94(m,1H),6.80-6.60(m,2H),5.13-5.02(brs,2H),4.95-4.85(m,1H),4.79-4.49(m,4H),3.95-3.30(m,12H),3.15-3.05(brs,3H),2.95-2.83(brs,3H),2.35-1.45(m,11H),1.40-1.20(m,,6H),0.95-0.80(m,6H).ESI-MS m/z calc’d for C42H61N6O10[M+H]+809.44,found 809.65.
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-乙氨基氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-44):1H NMR(300MHz,CD3OD)δ7.50-7.45(m,2H),7.45-7.30(m,3H),7.25(m,1H),7.16(m,1H),6.60(m,1H),5.20(brs,2H),5.02(m,1H),4.80-4.35(m,4H),4.30-4.20(m,2H),4.02(m,1H),3.75-3.45(m,9H),3.35-3.30(m,2H),3.20(brs,3H),2.95(brs,3H),2.25-1.55(m,11H),1.40-1.30(brd,J=7.2Hz,3H),1.05-0.80(m,6H);ESI-MSm/z calc’d for C42H62N7O10[M+H]+824.45,found 824.7.
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-丙氨基氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-45):ESI-MS m/z calc’d for C43H64N7O10[M+H]+838.46,found838.7.
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-戊氨基氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-47):ESI-MS m/z calc’d for C45H68N7O10[M+H]+866.50,found866.8.
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-乙羧基氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-48):1H NMR(300MHz,CD3OD)δ7.50-7.45(m,2H),7.45-7.30(m,3H),7.25(m,1H),7.16(m,1H),6.60(m,1H),5.20-5.15(m,4H),5.02(m,1H),4.80-4.35(m,4H),3.98(m,1H),3.80-3.40(m,7H),3.35-3.30(m,2H),3.20(brs,3H),2.95(brs,3H),2.25-1.55(m,11H),1.40-1.30(brd,J=7.2Hz,3H),1.05-0.80(m,6H);ESI-MS m/z calc’dfor C44H59N6O12[M+H]+839.41,found 839.7.
化合物与TRF2的TRFH结构域结合的Ki按照已发表的方法测定(ACSMed.Chem.Lett.2018,9(5),507-511)
Claims (6)
1.一种通式(I)的化合物或其药学上可接受的盐:
其中L为-(CH2)6-10-,其中一个或多个亚甲基可以被氧原子替换;X为-CH2-或-CH2CH2-;R1选自酰胺基、任意取代的芳基、任意取代的杂环芳基;R2为C1-C6的烷基、环烷基或取代的环烷基,上述基团中一个或多个氢原子可以被羟基、氨基、烷氧基、烷氨基、烷巯基取代;R3为C1-C8的烷基、任意取代的烷基、环烷基、取代的环烷基;R4和R5为C1-C8的烷基、任意取代的烷基、环烷基、任意取代的环烷基、烷氧基、烷氨基、烷巯基、任意取代的芳基、任意取代的杂芳基。
2.本发明中的化合物进一步优选式II的结构:
其中L为-(CH2)6-10-,其中一个或多个亚甲基可以被氧原子替换;R1为C1-C6的烷基、环烷基或取代的环烷基,上述基团中一个或多个氢原子可以被羟基、氨基、烷氧基、烷氨基取代;R2为C1-C8的烷基、任意取代的烷基、环烷基、取代的环烷基;R3为C1-C8的烷基、任意取代的烷基、环烷基、任意取代的环烷基、任意取代的芳基、任意取代的杂芳基;R4为-OR5或选自氢、烷基、任意取代的烷基、环烷基、任意取代的环烷基;R5为C1-C8的烷基、任意取代的烷基、环烷基、任意取代的环烷基、任意取代的芳基、任意取代的杂芳基。
3.式(I)和式II所代表的部分化合物如下:
(3S,12S,15S,18S,23aS,E)-12-(3-甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-1);
(3S,12S,15S,18S,23aS,E)-12-(3-异丙氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-2);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-3);
(3S,12S,15S,18S,23aS,E)-12-(3-环丙甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-4);
(3S,12S,15S,18S,23aS,E)-12-(3-环戊氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-5);
(3S,12S,15S,18S,23aS,E)-12-(3-苯丙氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-6);
(3S,12S,15S,18S,23aS,E)-12-(3-苯乙氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-7);
(3S,12S,15S,18S,23aS,E)-12-(3-环己甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-8);
(3S,12S,15S,18S,23aS,E)-12-(3-异丁氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-9);
(3S,12S,15S,18S,23aS,E)-12-(3-(2-萘甲基)氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-10);
(3S,12S,15S,18S,23aS,E)-12-(3-异戊氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-11);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-12);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二邻甲基苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-13);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二间甲基苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-14);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二对甲基苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-15);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二间氯苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-16);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二对氯苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-17);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二间溴苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-18);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二对氯苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-19);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二间氟苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-20);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二对氟苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-21);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二(1-萘甲氧基)苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-22);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二(2-萘甲氧基)苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-23);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二邻溴苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-24);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二邻氯苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-25);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二间甲基苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-26);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二邻氟苄氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-27);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二环戊氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-28);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二环己甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-29);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二正己氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-30);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二环丙甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-31);
(3S,12S,15S,18S,23aS,E)-12-(3,5-二苯丙氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-32);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-异戊氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-33);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-异丁氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-34);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-异丙氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-35);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-环丁氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-36);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-环戊氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-37);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-环丙甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-38);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-环己甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-39);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-正己氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-40);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-羟基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-41);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-甲氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-42);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-乙氧基苯甲酰基氨基)-15-异丁基-N,N,18- 三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-43);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-乙氨基氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-44);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-丙氨基氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-45);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-丁氨基氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-46);
(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-戊氨基氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-47);(3S,12S,15S,18S,23aS,E)-12-(3-苄氧基-5-乙羧基氧基苯甲酰基氨基)-15-异丁基-N,N,18-三甲基-1,13,16,19-四氧代-吡咯[2,1-f]并[1,17]二氧杂[4,7,10,13]四氮杂二十一环-3-甲酰胺(I-48)。
4.式I中的化合物采用如下方法合成:
5.具体包括以下步骤:氨基酸衍生物1和2缩合制备二肽衍生物3;3脱除保护基后与氨基酸衍生物缩合制备三肽衍生物4;4脱除保护基后与氨基酸衍生物缩合制备四肽衍生物5;5保护基后与氨基酸衍生物缩合制备四肽衍生物6;6过烯烃复分解反应关环得到环肽中间体7;还原7中的双键并脱除保护基制备中间体8;8与取代的苯甲酸反应,并在需要的情况下脱除保护基得到式I代表的化合物9。
6.根据权利要求任意一项所述的式I化合物或其药学上可接受的盐作为TRF2抑制剂在治疗癌症方面的用途。
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