CN113387934B - 一种多芳基取代咪唑衍生物及其制备方法与应用 - Google Patents

一种多芳基取代咪唑衍生物及其制备方法与应用 Download PDF

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CN113387934B
CN113387934B CN202110628700.5A CN202110628700A CN113387934B CN 113387934 B CN113387934 B CN 113387934B CN 202110628700 A CN202110628700 A CN 202110628700A CN 113387934 B CN113387934 B CN 113387934B
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黄志纾
李茂林
谭嘉恒
陈硕斌
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Sun Yat Sen University
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Abstract

本发明公开了一种多芳基取代咪唑衍生物及其制备方法与应用。该多芳基取代咪唑衍生物的结构式如下式(I)、(Ⅱ)、(Ⅲ)、(Ⅳ)所示
Figure DDA0003102834380000011
。多芳基取代咪唑衍生物作为c‑MYC G‑四链体的特异性配体，其结构中的中心咪唑结构有利于与G四链体的负电中心结合，整个分子的平面结构通过Π‑Π堆叠于G‑四链体平面，甲基哌嗪部分可以与G‑四链体的沟槽中的磷酸骨架结合，咔唑部分据研究报道有利于结合c‑MYC G‑四链体，其中，糖部分可以作为癌细胞的靶向支架以及助溶剂。本发明提供的多芳基取代咪唑衍生物能够增加对肿瘤细胞的选择性，同时能够下调原癌基因c‑MYC和抑制c‑MYC的转录，在制备抗肿瘤药物上具有广泛的应用前景。

Description

一种多芳基取代咪唑衍生物及其制备方法与应用
技术领域
本发明属于药物化学领域，具体涉及一种多芳基取代咪唑衍生物及其制备方法与应用。
背景技术
癌症现已成为中国高发疾病之一。随着我国的科研水平与医疗水平不断地发展，抗肿瘤的药物研发取得了重大突破，某些肿瘤疾病可以通过药物与手术治疗达到完全恢复。但是仍面临着许多科研挑战。药物的毒副作用、溶解性、生物利用度、耐药等问题仍然是开发临床新药需面临的一大阻碍。
G-四链体是一种特殊的二级结构DNA，广泛分布于基因组，转录组，参与重要的调控过程。G-四链体的折叠与去折叠在体内处于一个动态平衡。当G-四链体被G-四链体配体稳定时，会诱导DNA损伤积累，从而导致细胞的衰老与凋亡。原癌基因c-MYC在癌细胞会异常高表达，会激活c-MYC的转录，调控着癌细胞的分化、增殖等生命过程。综上所述，特异性稳定c-MYC G-四链体，可以下调c-MYC，进而抑制c-MYC的转录，诱导癌细胞的凋亡。因此，原癌基因c-MYC G-四链体可以作为潜在的癌症治疗靶点。
c-MYC基因的转录调节十分复杂，涉及多个启动元件。尽管目前国内外研究人员发现了一些靶点c-MYC G-四链体的小分子配体，且部分以c-MYC G-四链体为靶点而设计的小分子化合物已经进入了二期临床阶段，然而，这些小分子配体由于毒性、选择性等原因，距离走向临床仍存在一定的距离，仍需要不断进行新的小分子配体结构设计。
本背景技术中所陈述内容并不代表承认其属于已公开的现有技术。
发明内容
本发明旨在至少解决上述现有技术中存在的技术问题之一。为此，本发明提出一种新的多芳基取代咪唑衍生物，该化合物能够对c-MYC转录有效调控阻断。
本发明还提出一种上述多芳基取代咪唑衍生物的制备方法。
本发明还提出一种上述多芳基取代咪唑衍生物的应用。
根据本发明的一个方面，提出了多芳基取代咪唑衍生物，所述衍生物的结构式如式(I)、(Ⅱ)、(Ⅲ)或(Ⅳ)所示：
Figure BDA0003102834360000011
所述R1选自H、Me、OBn、(CH2)nOR6、(CH2O)nR6或R6中的任意一种；
所述R2选自(CH2)nR6、(CH2)nOR6或(CH2O)nR6中的任意一种；
所述R3选自(CH2)nOR6、(CH2O)nR6或R6中的任意一种；
所述R4选自H、NO2、NH2、卤素、(CH2)nNH2或(CH2O)nNH2中的任意一种；
所述R5选自(CH2)nOR6、(CH2O)nR6或R6中的任意一种；
其中，所述R1为OBn、(CH2)nOR6、(CH2O)nR6或R6中的任意一种时，所述R4为H；所述R1为Me时，所述R4为NO2、NH2、卤素、(CH2)nNH2或(CH2O)nNH2；
所述R6选自H、NH2、卤素、五元环或六元杂环基、单糖或乙酰化单糖中的任意一种；
n选自1-10任意一个整数。
在本发明的一些实施方式中，所述单糖选自六碳单糖、五碳单糖、1,2-原酸酯单糖、氨基六碳单糖或氨基五碳单糖中的任意一种；优选地，所述单糖选自葡萄糖、半乳糖、氨基葡萄糖、2-三氟乙酰氨基葡萄糖、甘露糖或1,2-原酸酯葡萄糖中的任意一种。
在本发明的一些实施方式中，所述乙酰化单糖选自氨基乙酰单糖、乙酰化六碳糖或乙酰化五碳糖中的任意一种；所述乙酰化单糖选自乙酰化葡萄糖、乙酰化半乳糖、乙酰化的2-三氟乙酰氨基葡萄糖、乙酰化甘露糖、1,2-原酸酯乙酰化葡萄糖或2-三氟乙酰氨基葡萄糖中的任意一种。
根据本发明的一种优选的实施方式的衍生物，至少具有以下有益效果：该衍生物为多芳基取代咪唑与糖类偶联衍生物，多芳基取代咪唑化合物作为c-MYC G-四链体的特异性配体，其结构中的中心咪唑结构有利于与G四链体的负电中心结合，整个分子的平面结构通过Π-Π堆叠于G-四链体平面，甲基哌嗪部分可以与G-四链体的沟槽中的磷酸骨架结合，咔唑部分据研究报道有利于结合c-MYC G-四链体，其中，糖部分可以作为癌细胞的靶向支架以及助溶剂，同时能够降低体内毒性。
根据本发明的另一个方面，提出了上述多芳基取代咪唑衍生物的制备方法，所述制备方法包括如下步骤：
利用4,4'-二氟苯偶酰与甲基哌嗪的反应产物制备所述多芳基取代咪唑衍生物。
在本发明的一些实施方式中，所述4,4'-二氟苯偶酰与甲基哌嗪的反应产物
Figure BDA0003102834360000021
和/或
Figure BDA0003102834360000022
在本发明的一些实施方式中，所述衍生物的结构式如式(I)或(Ⅱ)所示，利用化合物
Figure BDA0003102834360000023
与胺类化合物、3-甲醛N-乙基咔唑或衍生物以及乙酸铵得到结构式如式(I)或(Ⅱ)所示的衍生物。
在本发明的一些实施方式中，所述衍生物的结构式如式(I)或(Ⅱ)所示，若所述衍生物的结构式如式(I)所示，所述制备方法包括如下步骤：S1、利用化合物
Figure BDA0003102834360000024
与苯胺类化合物、3-甲醛N-乙基咔唑以及乙酸铵制备结构式如式(I)
Figure BDA0003102834360000025
其中R1选自H、Me、OBn、(CH2)nOR6、(CH2O)nR6或R6中的任意一种；R6选自H、NH2、卤素、五元环或六元杂环基、单糖或乙酰化单糖中的任意一种；n选自1-10任意一个整数；R4选自H；
S2、利用4,4'-二氟苯偶酰与甲基哌嗪的反应产物制备
Figure BDA0003102834360000026
利用
Figure BDA0003102834360000027
制备结构式如式(I)所示的衍生物；
其中，R7为Me、(CH2)2OH或(CH2)2O(CH2)2OH。
在本发明的一些实施方式中，所述步骤S2包括利用溴糖与
Figure BDA0003102834360000031
反应制备式如式(I)所示的衍生物；其中，R7为(CH2)2OH或(CH2)2O(CH2)2OH。
在本发明的一些实施方式中，若所述R4为NH2，则所述步骤S2还包括将式中NO2还原的步骤。
在本发明的一些实施方式中，所述步骤S1包括由
Figure BDA0003102834360000032
与胺类化合物、3-甲醛N-乙基咔唑或衍生物以及乙酸铵反应制备目标产物结构式如式(Ⅱ)所示的衍生物。
在本发明的一些实施方式中，所述衍生物的结构式如式(III)或(IV)所示，若所述衍生物的结构式如式(III)所示，则所述制备方法包括如下步骤：
i、利用
Figure BDA0003102834360000033
与对甲氧基苯胺，3-甲醛N-丙炔基咔唑，乙酸铵反应制备
Figure BDA0003102834360000034
ii、由
Figure BDA0003102834360000035
与叠氮化合物反应制备结构式如式(III)所示的衍生物；
若所述衍生物的结构式如式(IV)所示，所述制备方法包括如下步骤：
i、利用
Figure BDA0003102834360000036
与
Figure BDA0003102834360000037
反应制备得
Figure BDA0003102834360000038
ii、由
Figure BDA0003102834360000039
与3-甲醛N-乙基咔唑，乙酸铵反应制备
Figure BDA00031028343600000310
iii、由
Figure BDA00031028343600000311
与叠氮化合物反应制备结构式如式(Ⅳ)所示的衍生物。
根据本发明的一种优选的实施方式的制备方法，至少具有以下有益效果：本发明的制备方法操作简便，产率高，具有良好的工业应用前景。
根据本发明的再一个方面，提出了上述多芳基取代咪唑衍生物或其类似物在制备抗肿瘤药物中的应用。
在本发明的一些实施方式中，所述类似物包括其药学上可接受的盐、酯、水合物、溶剂化物、结晶形式、对映异构体、立体异构体、醚、代谢物和前药分子中的至少一种。
在本发明的一些实施方式中，所述药学上可接受的盐包括但不仅限于无机酸盐，有机酸盐，烷基磺酸盐和芳基磺酸盐中的至少一种；优选地，所述无机酸盐包括但不仅限于盐酸盐、氢溴酸盐、硝酸盐、硫酸盐和磷酸盐中的至少一种；优选地，所述有机酸盐包括但不仅限于甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐和柠檬酸盐中的至少一种；优选地，所述烷基磺酸盐包括但不仅限于甲基磺酸盐和乙基磺酸盐中的至少一种；所述芳基磺酸盐包括但不仅限于苯磺酸盐和对甲苯磺酸盐中的至少一种。
在本发明的一些实施方式中，所述药物的制备原料还包括载体。可采用常用载体即可，以便于制备成不同剂型。
在本发明的一些实施方式中，所述药物的剂型选自注射剂、片剂、丸剂、胶囊剂、颗粒剂、乳剂或悬浮剂。
在本发明的一些实施方式中，所述肿瘤选自乳腺癌、肝癌、结肠癌、肺癌、上皮细胞癌、宫颈癌、前列腺癌、鼻咽癌、卵巢癌、恶性胶质瘤、淋巴瘤或黑色素瘤的一种或多种。本发明所提供的多芳基取代咪唑与糖类偶联衍生物能够抑制c-MYC的表达与转录，从而抑制多种类型的肿瘤细胞株增殖，具有广谱抗肿瘤的活性。
在本发明的一些实施方式中，所述肺癌选自小细胞肺癌或非小细胞肺癌。
本发明还提出了一种抗肿瘤药物，包括上述多芳基取代咪唑衍生物或其类似物。
本发明还提出了上述多芳基取代咪唑衍生物或其类似物在制备c-MYC转录调控阻断剂中的应用。
本发明还提出了一种c-MYC转录调控阻断剂，包括上述多芳基取代咪唑衍生物或其类似物。
根据本发明的一种优选的实施方式的应用，至少具有以下有益效果：本发明涉及具有通式(I)、(Ⅱ)、(Ⅲ)、(Ⅳ)结构特征的衍生物可以特异性结合和稳定平行型c-MYC G-四链体，并能显著下调c-MYC水平和抑制c-MYC转录，从而抑制多种癌细胞的生长，在制备抗肿瘤药物上具有广泛的应用前景。
附图说明
下面结合附图和实施例对本发明做进一步的说明，其中：
图1为本发明实施例制得的化合物3a、16a、17a、空白对照及其他阳性对照化合物对c-MYC转录水平的影响效果图；
图2为本发明实施例制得的化合物3a、4a、9a、16a、空白对照及其他阳性对照化合物对c-MYC表达水平的影响效果图。
具体实施方式
以下将结合实施例对本发明的构思及产生的技术效果进行清楚、完整地描述，以充分地理解本发明的目的、特征和效果。实施例中所使用的试验方法如无特殊说明，均为常规方法；所使用的材料、试剂等，如无特殊说明，均可从商业途径得到的试剂和材料。
本发明实施例所述衍生物合成路线如下：
Figure BDA0003102834360000051
Figure BDA0003102834360000061
上述实施例中衍生物合成路线具体如下：
4,4'-二氟苯偶酰与甲基哌嗪反在应得到化合物C1-1或D1-1；化合物C1-1与
Figure BDA0003102834360000062
以及对甲氧基苯胺反应得到化合物1c；化合物D1-1与
Figure BDA0003102834360000063
反应得到化合物D1-2；化合物D1-2与3-甲醛-N-乙基咔唑以及乙酸铵反应得到化合物1d；化合物C1-1与胺类化合物、3-甲醛N-乙基咔唑或衍生物以及乙酸铵得到化合物2c或结构通式式(I)或式(II)的其他目标衍生物；或者通过化合物溴糖与1a或3a得到结构通式式(I)或式(II)的其他目标衍生物；化合物2c还原反应得到化合物3c；将化合物1c或1d与叠氮化合物反应得到结构通式式(III)或式(IV)的目标衍生物。
制备结构通式式(I)或式(II)的目标衍生物过程中，若使用C1-1、胺类化合物、3-甲醛N-乙基咔唑或衍生物以及乙酸铵进行制备，则其摩尔比例为1：3～6：1.2：15～20；反应温度为100～150℃，反应时间为3h～12h。或者使用溴糖与1a(或3a)，则还需添加K2CO3及TABA，四者的摩尔比例为1：0.5～0.8：1.5～3：0.2；反应温度为室温，反应时间为6h～48h。
制备结构通式式(III)或式(IV)的目标衍生物过程中，若使用1c或1d与叠氮化合物反应制备，则还需添加无水硫酸铜和抗坏血酸钠的摩尔比例为1：2：0.05～0.1：0.15～0.3；反应温度为70～100℃，反应时间为10h～48h。
实施例中间体的制备：
(1)化合物C1-1的制备
将二氟苯偶酰(490mg,2mmol)与碳酸钾(829mg,6mmol)混溶于6mL DMF中，滴加入N-甲基哌秦(1g,10mmol)。混合物在80℃下反应过夜。反应结束后，将反应液倒入冰水中，用乙酸乙酯萃取，加饱和食盐水洗涤，浓缩干燥，经柱层析分离纯化，得黄色固体化合物C1-1(818mg,99％),1H NMR(400MHz,CDCl3)δ7.85(d,J＝9.0Hz,4H),6.85(d,J＝9.1Hz,4H),3.41(t,J＝5.2Hz,8H),2.54(t,J＝5.1Hz,8H),2.34(s,6H).
(2)化合物D1-1的制备
将二氟苯偶酰(490mg,2mmol)与碳酸钾(829mg,6mmol)混溶于6mL DMF中，滴加入N-甲基哌秦(300mg,3mmol)。混合物在80℃下反应过夜。反应结束后，将反应液倒入冰水中，用乙酸乙酯萃取，加饱和食盐水洗涤，浓缩干燥，经柱层析分离纯化，得黄色固体化合物D1-1(550mg,85％),1H NMR(400MHz,CDCl3)δ8.01(dd,J＝8.9,5.4Hz,2H),7.85(d,J＝9.0Hz,2H),7.16(t,J＝8.6Hz,2H),6.87(d,J＝9.1Hz,2H),3.45(t,J＝5.1Hz,4H),2.55(t,J＝5.1Hz,4H),2.36(s,3H).
(3)化合物D1-2的制备
将D1-1(500mg,1.53mmol)与碳酸钾(635mg,4.6mmol)混溶于6mL DMF中，滴加入1-(丙-2-炔-1-基)哌嗪(372mg,3mmol)。混合物在80℃下反应过夜。反应结束后，将反应液倒入冰水中，用乙酸乙酯萃取，加饱和食盐水洗涤，浓缩干燥，经柱层析分离纯化，得黄色固体化合物D1-2(570mg,86％),1H NMR(400MHz,CDCl3)δ7.84(d,J＝8.8Hz,4H),6.84(dd,J＝9.1,1.9Hz,4H),3.42(td,J＝7.0,4.6Hz,9H),3.35(d,J＝2.4Hz,2H),2.68(t,J＝5.1Hz,4H),2.54(t,J＝5.1Hz,4H),2.34(s,3H),2.27(t,J＝2.4Hz,1H).13C NMR(100MHz,CDCl3)δ193.7,154.9,154.9,132.2,123.5,123.4,113.4,113.3,78.8,73.8,54.6,51.4,46.9,46.9,46.1.
(4)化合物1c、1d的制备
C1-1或D1-2(1.0mmol)，苯胺衍生物(6.0mmol)或不加，N-乙基咔唑-3-甲醛或它的衍生物(1.2mmol)，NH4OAc(20.0mmol)和AcOH(5mL)的混合物于115℃搅拌5小时。冷却后，将混合物用饱和碳酸氢钠溶液调节至pH＝8，并将产物用CH2Cl2(20mL×3)萃取。合并的有机层经无水Na2SO4干燥，并在减压下浓缩溶剂，得到残余物。残留物用快速柱色谱纯化，得到最终产物1c或1d。
1c:浅黄色固体(产率82％).1H NMR(400MHz,CDCl3)δ8.24(d,J＝1.7Hz,1H),7.91(d,J＝7.8Hz,1H),7.58(d,J＝8.7Hz,2H),7.45(dd,J＝8.5,1.7Hz,1H),7.43–7.37(m,2H),7.23(d,J＝8.4Hz,1H),7.19(d,J＝7.2Hz,1H),6.99(dd,J＝14.4,8.7Hz,4H),6.84(d,J＝8.8Hz,2H),6.73(t,J＝8.5Hz,4H),4.89(d,J＝2.5Hz,2H),3.70(s,3H),3.19(dt,J＝9.9,4.8Hz,8H),2.54(dt,J＝9.9,4.8Hz,8H),2.33(s,3H),2.32(s,3H),2.21(t,J＝2.5Hz,1H).13C NMR(125MHz,CDCl3)δ158.8,150.1,149.6,147.3,140.1,139.4,137.6,132.0,130.6,129.8,129.7,128.1,127.0,126.6,126.0,123.4,123.0,122.7,121.8,121.4,120.6,119.8,115.7,115.1,114.1,108.7,108.2,77.7,72.5,55.3,55.2,55.11,49.0,48.3,46.2,32.3.HRMS(ESI)m/z:calcd for C47H47N7O:[M+2H]2+.Found[M+2H]2+.
1d:棕色固体(产率77％).1H NMR(500MHz,CDCl3)δ8.61(s,1H),8.00(d,J＝8.5Hz,1H),7.96(d,J＝7.7Hz,1H),7.44(dd,J＝8.2,3.0Hz,4H),7.40(t,J＝7.6Hz,1H),7.31(d,J＝8.2Hz,1H),7.23(d,J＝8.5Hz,1H),7.14(t,J＝7.4Hz,1H),6.78(dd,J＝8.4,4.9Hz,4H),4.20(q,J＝7.2Hz,2H),3.32(d,J＝2.3Hz,2H),3.15(dt,J＝15.5,4.8Hz,8H),2.66(t,J＝4.8Hz,4H),2.50(t,J＝4.8Hz,4H),2.30(s,3H),2.28(t,J＝2.3Hz 1H),1.31(t,J＝7.2Hz,3H).13C NMR(125MHz,CDCl3)δ173.0,149.9,149.9,147.0,140.3,140.0,128.7,125.9,123.7,123.0,121.3,120.7,119.1,117.9,115.8,115.7,108.6,108.6,78.7,73.5,55.0,51.8,48.7,48.7,46.9,46.1,37.6,22.6,13.8.HRMS(ESI)m/z:calcd for C47H47N7O:[M+2H]2+.Found[M+2H]2+.
(5)通用方法A的步骤
C1-1或D1-2(1.0mmol)，苯胺衍生物(6.0mmol)或不加，N-乙基咔唑-3-甲醛或它的衍生物(1.2mmol)，NH4OAc(20mmol)和AcOH(5mL)的混合物于115℃搅拌5小时。冷却后，将混合物用饱和碳酸氢钠溶液调节至pH＝8，并将产物用CH2Cl2(20mL×3)萃取。合并的有机层经无水Na2SO4干燥，并在减压下浓缩溶剂，得到残余物。残留物用快速柱色谱纯化，得到最终对应的产物。
(6)通用方法B的步骤
向化合物(1c或1d)(0.1mmol)，叠氮基化合物(0.2mmol)溶于t-BuOH/H2O(1.5mL，V/V＝2：1)的混合物中加入CuSO4溶液(0.3mL，100mM)和抗坏血酸钠盐溶液(0.9mL，100mM)。将混合物在70℃下搅拌19小时。冷却后，将所得混合物倒入CH2Cl2和水的混合物中。减压浓缩有机相，得到粗产物，将其通过快速柱色谱法纯化，得到相应的产物。
(7)通用方法C的步骤
将来自通用方法A或通用方法B的产物(0.1mmol)溶于无水MeOH(5mL)，加入催化量的甲醇钠。将混合物在室温搅拌2小时，并加入过量的Dowex H+树脂以中和所得溶液，并再搅拌20分钟。将溶液过滤并在减压下浓缩以提供相应的目标产物。
实施例1
化合物1a的制备
Figure BDA0003102834360000071
通过通用方法C合成化合物1a。浅黄色固体(产率为98％)。1H NMR(400MHz,CDCl3)δ8.21(s,1H),7.93(d,J＝7.7Hz,1H),7.56(d,J＝8.4Hz,2H),7.44(dd,J＝12.8,8.1Hz,2H),7.37(d,J＝8.1Hz,1H),7.23(d,J＝8.7Hz,1H),7.18(t,J＝7.4Hz,1H),7.00(dd,J＝14.1,8.5Hz,4H),6.84(d,J＝8.4Hz,2H),6.75(t,J＝8.9Hz,4H),4.31(q,J＝7.2Hz,2H),4.05(t,J＝5.9Hz,2H),3.83(t,J＝5.9Hz,2H),3.25(q,J＝5.0Hz,8H),2.66(dt,J＝13.2,4.9Hz,8H),2.41(s,3H),2.39(s,3H),2.00(p,J＝5.9Hz,2H),1.40(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ158.2,150.1,149.4,140.4,139.7,137.6,132.1,130.8,129.9,129.8,128.3,127.0,125.9,123.2,122.8,122.2,121.7,121.7,120.7,119.1,116.0,115.5,114.8,108.7,108.1,65.7,60.2,55.0,54.9,48.8,48.3,45.9,45.8,37.7,32.1,14.0.HRMS(ESI)m/z:calcd for C48H53N7O2:380.7203[M+2H]2+.Found 380.7203[M+2H]2+.
实施例2
化合物2a的制备
Figure BDA0003102834360000081
通过通用方法A合成化合物2a。浅黄色固体(收率72％)。1H NMR(500MHz,CDCl3)δ8.21(s,1H),7.93(d,J＝7.8Hz,1H),7.57(d,J＝8.3Hz,2H),7.50–7.40(m,2H),7.36(d,J＝8.1Hz,1H),7.22(d,J＝8.6Hz,1H),7.18(t,J＝7.4Hz,1H),7.01(dd,J＝16.4,8.3Hz,4H),6.84(d,J＝8.4Hz,2H),6.75(dd,J＝18.0,8.4Hz,4H),4.30(q,J＝7.2Hz,2H),4.23(t,J＝6.2Hz,2H),3.96(t,J＝6.2Hz,2H),3.21(t,J＝5.0Hz,8H),2.56(q,J＝4.9Hz,8H),2.34(s,6H),2.08(p,J＝6.2Hz,2H),2.03(s,3H),1.39(t,J＝7.2Hz,3H).13C NMR(125MHz,CDCl3)δ171.1,158.1,150.2,149.6,147.7,140.3,139.6,137.7,132.1,130.8,129.8,129.7,128.2,126.9,126.7,125.8,123.2,122.7,122.0,121.7,121.6,120.6,119.1,115.8,115.3,114.7,108.6,108.0,64.6,61.4,55.3,55.2,49.1,48.5,46.3,37.7,28.6,21.0,13.9.HRMS(ESI)m/z:calcd for C50H55N7O3:401.7256[M+2H]2+.Found 401.7253[M+2H]2+.
实施例3
化合物3a的制备
Figure BDA0003102834360000082
通过通用方法C合成化合物3a。浅黄色固体(产率为98％)。1H NMR(500MHz,CDCl3)δ8.42(s,1H),8.10(d,J＝7.8Hz,1H),7.78(d,J＝8.3Hz,1H),7.52–7.39(m,5H),7.29(d,J＝8.2Hz,2H),7.23(t,J＝7.4Hz,1H),6.96(d,J＝8.3Hz,2H),6.76(d,J＝8.5Hz,2H),4.37(q,J＝7.2Hz,2H),4.14(t,J＝6.2Hz,2H),3.45(t,J＝4.6Hz,2H),3.30(q,J＝6.2,5.4Hz,6H),3.18(dt,J＝9.0,4.6Hz,6H),2.64(t,J＝4.9Hz,4H),2.61(t,J＝4.9Hz,4H),2.38(s,2H),2.35(s,3H),1.43(t,J＝7.2Hz,3H).13C NMR(125MHz,CDCl3)δ150.8,149.2,148.9,140.4,140.1,137.3,132.1,128.4,127.6,127.1,126.7,126.1,123.1,122.9,122.2,121.9,121.8,120.7,119.3,116.0,115.8,108.8,108.6,72.3,69.6,61.4,54.9,54.8,48.6,48.1,45.9,45.6,44.3,37.8,13.9.HRMS(ESI)m/z:calcd for C49H55N7O3:395.7256[M+2H]2+.Found 395.7253[M+2H]2+.
实施例4
化合物4a的制备
Figure BDA0003102834360000083
通过通用方法A合成化合物4a。粉红色固体(收率62％)。1H NMR(400MHz,CDCl3)δ8.45(d,J＝1.6Hz,1H),8.12(d,J＝7.7Hz,1H),7.81(dd,J＝8.5,1.7Hz,1H),7.54–7.41(m,5H),7.33(d,J＝8.4Hz,2H),7.25(t,J＝7.5Hz,1H),7.01(d,J＝8.4Hz,2H),6.79(d,J＝8.6Hz,2H),4.41(q,J＝7.2Hz,2H),4.16(t,J＝6.3Hz,2H),4.00(t,J＝4.8Hz,2H),3.39–3.26(m,8H),3.18(t,J＝5.1Hz,4H),2.62(t,J＝5.0Hz,4H),2.56(t,J＝5.0Hz,4H),2.39(s,3H),2.34(s,3H),1.93(s,3H),1.47(t,J＝7.2Hz,3H).13C NMR(125MHz,CDCl3)δ171.1,151.1,149.5,148.7,140.5,140.2,137.6,132.2,128.3,127.6,127.3,126.8,126.1,123.2,123.1,122.3,122.2,122.0,120.8,119.3,116.0,115.7,108.8,108.6,69.7,69.0,63.4,55.3,55.2,49.1,48.6,46.3,46.3,44.1,37.84,21.0,14.0.HRMS(ESI)m/z:calcdfor C51H57N7O4:416.7309[M+2H]2+.Found 416.7301[M+2H]2+.
实施例5
化合物5a的制备
Figure BDA0003102834360000091
通过通用方法A合成化合物5a。浅黄色固体(收率21％)。1H NMR(500MHz,CDCl3)δ8.20(d,J＝1.6Hz,1H),7.92(d,J＝7.7Hz,1H),7.54(d,J＝8.4Hz,2H),7.47–7.41(m,2H),7.37(d,J＝8.1Hz,1H),7.23(d,J＝8.6Hz,1H),7.18(t,J＝7.4Hz,1H),7.00(dd,J＝15.1,8.4Hz,4H),6.83(d,J＝8.5Hz,2H),6.74(dd,J＝21.0,8.5Hz,4H),5.17(t,J＝9.5Hz,1H),5.06(t,J＝9.7Hz,1H),4.96(t,J＝8.8Hz,1H),4.48(d,J＝8.0Hz,1H),4.31(q,J＝7.2Hz,2H),4.24(dd,J＝12.3,4.7Hz,1H),4.11(dd,J＝12.4,2.4Hz,1H),4.02–3.90(m,3H),3.22(q,J＝4.8Hz,8H),2.60(dt,J＝10.4,4.7Hz,8H),2.37(s,3H),2.36(s,3H),2.05(s,3H),2.02(s,3H),1.99(s,3H),1.82(s,3H),1.40(t,J＝7.2Hz,3H).13C NMR(125MHz,CDCl3)δ170.8,170.4,169.6,169.4,158.2,150.2,149.5,147.9,140.4,139.7,137.7,132.1,130.8,129.9,129.8,128.3,127.0,126.9,125.8,123.2,122.7,122.1,121.9,121.7,120.7,119.1,115.9,115.4,114.7,108.7,108.0,101.1,72.9,71.9,71.4,68.5,66.7,64.5,62.0,55.1,49.0,48.4,46.1,46.1,37.7,29.5,20.9,20.7,20.7,20.6,13.9.HRMS(ESI)m/z:calcd for C62H71N7O11:545.7679[M+2H]2+.Found 545.7672[M+2H]2+.
实施例6
化合物6a的制备
Figure BDA0003102834360000092
通过通用方法A合成化合物6a。浅黄色固体(产率18％)。1H NMR(500MHz,CDCl3)δ8.19(s,1H),7.91(d,J＝7.8Hz,1H),7.54(d,J＝8.3Hz,2H),7.44(dd,J＝19.7,8.1Hz,2H),7.36(d,J＝8.3Hz,1H),7.23(d,J＝8.6Hz,1H),7.18(t,J＝7.5Hz,1H),7.00(dd,J＝13.1,8.2Hz,4H),6.83(d,J＝8.6Hz,2H),6.74(dd,J＝16.6,8.3Hz,4H),5.37(d,J＝3.4Hz,1H),5.17(dd,J＝10.4,7.9Hz,1H),4.98(dd,J＝10.4,3.5Hz,1H),4.44(d,J＝8.0Hz,1H),4.31(q,J＝7.2Hz,3H),4.13(dq,J＝17.9,7.0,5.9Hz,2H),4.01(dt,J＝10.4,5.6Hz,1H),3.94(tt,J＝9.6,4.9Hz,2H),3.88(t,J＝6.7Hz,1H),3.68(dt,J＝14.3,6.9Hz,2H),3.23(q,J＝5.0Hz,8H),2.62(dt,J＝16.9,5.0Hz,8H),2.39(s,3H),2.37(s,3H),2.13(s,3H),2.05–2.00(m,2H)2.02(s,3H),1.97(s,3H),1.80(s,3H),1.39(t,J＝7.2Hz,3H).13C NMR(125MHz,CDCl3)δ170.5,170.4,170.2,169.5,158.2,150.1,149.4,147.8,140.4,139.7,137.6,132.1,130.7,129.9,129.8,128.3,127.0,126.9,125.9,123.2,122.7,122.1,121.8,121.6,120.6,119.1,115.9,115.4,114.7,108.7,108.0,101.6,70.9,70.8,68.9,67.1,66.7,64.4,61.3,55.1,55.1,48.8,48.3,46.1,46.0,37.7,29.5,20.8,20.7,13.9.HRMS(ESI)m/z:calcd for C62H71N7O11:545.7679[M+2H]2+.Found 545.7680[M+2H]2+.
实施例7
化合物7a的制备
Figure BDA0003102834360000101
通过通用方法C合成化合物7a。浅黄色固体(产率为97％)。HRMS(ESI)m/z:calcdfor C54H63N7O7:461.7467[M+2H]2+.Found 461.7470[M+2H]2+.
实施例8
化合物8a的制备
Figure BDA0003102834360000102
通过通用方法A合成化合物8a。浅黄色固体(产率19％)。1H NMR(500MHz,CDCl3)δ8.23(s,1H),7.92(d,J＝7.7Hz,1H),7.55(d,J＝8.4Hz,2H),7.42(d,J＝7.9Hz,2H),7.36(d,J＝8.2Hz,1H),7.21(d,J＝8.6Hz,1H),7.17(t,J＝7.5Hz,1H),6.99(dd,J＝11.8,8.4Hz,4H),6.83(d,J＝8.4Hz,2H),6.75(d,J＝8.3Hz,4H),5.19(t,J＝9.5Hz,1H),5.07(t,J＝9.7Hz,1H),4.99(t,J＝8.8Hz,1H),4.57(d,J＝7.9Hz,1H),4.30(q,J＝7.2Hz,2H),4.23(dd,J＝12.3,4.7Hz,1H),4.12(dd,J＝12.3,2.4Hz,1H),4.01(t,J＝4.7Hz,2H),3.96(dt,J＝10.8,4.2Hz,1H),3.79(q,J＝3.8Hz,2H),3.76–3.63(m,4H),3.23(q,J＝4.6Hz,8H),2.62(dt,J＝13.3,4.9Hz,8H),2.39(s,3H),2.38(s,3H),2.06(s,3H),2.00(s,3H),1.99(s,3H),1.98(s,3H),1.39(t,J＝7.2Hz,3H).13C NMR(126MHz,CDCl3)δ170.7,170.4,169.5,169.5,158.1,150.1,149.4,147.8,140.3,139.7,137.6,132.1,130.9,129.8,129.8,128.3,126.9,126.9,125.8,123.1,122.7,122.0,121.7,121.6,120.7,119.1,115.9,115.4,114.8,108.6,108.0,100.9,72.9,71.9,71.3,70.5,69.9,69.3,68.5,67.6,62.0,55.1,55.0,48.8,48.3,46.0,45.9,37.7,20.8,20.8,20.7,20.7,13.9.HRMS(ESI)m/z:calcd forC63H73N7O12:560.7731[M+2H]2+.Found 560.7742[M+2H]2+.
实施例9
化合物9a的制备
Figure BDA0003102834360000103
通过通用方法C.合成化合物9a。浅黄色固体(产率99％)。1H NMR(400MHz,CD3OD)δ8.14(s,1H),7.85(d,J＝7.8Hz,1H),7.50–7.36(m,5H),7.24(d,J＝8.6Hz,1H),7.14(t,J＝7.2Hz,1H),6.91(dd,J＝8.6,3.6Hz,4H),6.78(d,J＝8.4Hz,2H),6.65(t,J＝8.2Hz,4H),4.32–4.22(m,3H),3.96(t,J＝7.5Hz,1H),3.90–3.80(m,3H),3.72–3.59(m,6H),3.33(d,J＝7.9Hz,1H),3.29–3.22(m,2H),3.18(t,J＝8.4Hz,1H),3.11(t,J＝4.9Hz,4H),3.02(t,J＝5.1Hz,4H),2.55(t,J＝4.9Hz,4H),2.45(t,J＝5.1Hz,4H),2.31(s,3H),2.27(s,3H),1.28(t,J＝7.2Hz,3H).13C NMR(100MHz,CD3OD)δ159.8,151.7,151.0,149.3,141.7,141.0,138.3,133.3,131.7,131.5,131.2,129.3,127.9,127.5,127.3,124.0,123.8,122.6,122.4,122.2,121.3,120.4,116.9,116.3,115.8,110.0,109.4,104.4,78.0,77.9,75.0,71.6,70.6,69.6,68.6,62.7,55.9,55.8,46.1,46.0,38.4,14.2.HRMS(ESI)m/z:calcd forC55H65N7O8:476.7520[M+2H]2+.Found 476.7533[M+2H]2+.
实施例10
化合物10a的制备
Figure BDA0003102834360000111
通过通用方法A合成化合物10a。浅黄色固体(产率15％)。1H NMR(500MHz,CDCl3)δ8.22(d,J＝1.7Hz,1H),7.92(d,J＝7.7Hz,1H),7.54(d,J＝8.6Hz,2H),7.43(t,J＝7.7Hz,2H),7.36(d,J＝8.2Hz,1H),7.21(d,J＝8.7Hz,1H),7.17(t,J＝7.4Hz,1H),7.00(t,J＝8.9Hz,4H),6.83(d,J＝8.6Hz,2H),6.75(d,J＝8.5Hz,4H),5.24(t,J＝10.0Hz,1H),5.08(t,J＝9.7Hz,1H),4.76(d,J＝8.4Hz,1H),4.30(q,J＝7.2Hz,2H),4.24(dd,J＝12.3,4.6Hz,1H),4.10(dd,J＝12.3,2.4Hz,1H),4.05–3.97(m,3H),3.94(dt,J＝11.4,3.6Hz,1H),3.78–3.71(m,3H),3.69–3.63(m,3H),3.21(q,J＝4.7Hz,8H),2.59(q,J＝4.6Hz,8H),2.36(s,6H),2.06(s,3H),1.99(s,3H),1.97(s,3H),1.38(t,J＝7.2Hz,3H).13C NMR(125MHz,CDCl3)δ13C NMR(125MHz,CDCl3)δ170.8,169.4,158.0,157.38(q,J＝37.5Hz),150.1,149.5,147.8,140.3,139.7,137.6,132.1,131.0,129.9,129.8,128.3,126.9,126.7,125.9,123.1,122.7,121.9,121.7,121.6,120.6,119.1,115.8,115.7(q,J＝288.2Hz),115.3,114.8,108.7,108.0,100.6,72.1,72.0,70.8,69.7,69.2,68.4,67.6,62.0,55.1,55.1,54.9,48.9,48.3,46.1,37.7,20.8,20.7,20.5,13.9.19F NMR(470MHz,CDCl3)δ-75.65.HRMS(ESI)m/z:calcd for C63H71N8O11F3:587.2670[M+2H]2+.Found587.2660[M+2H]2+.
实施例11
化合物11a的制备
Figure BDA0003102834360000112
通过通用方法C合成化合物11a。浅黄色固体(收率97％)。1H NMR(500MHz,CD3OD)δ8.16(d,J＝1.7Hz,1H),7.88(d,J＝7.7Hz,1H),7.49–7.38(m,5H),7.29(d,J＝8.6Hz,1H),7.16(t,J＝7.3Hz,1H),6.95(t,J＝8.1Hz,4H),6.81(d,J＝8.7Hz,2H),6.71(dd,J＝8.6,5.5Hz,4H),4.52(d,J＝8.4Hz,1H),4.33(q,J＝7.1Hz,2H),3.96–3.84(m,4H),3.73–3.62(m,6H),3.59(t,J＝4.6Hz,2H),3.54(dd,J＝10.4,8.5Hz,1H),3.34(d,J＝9.5Hz,1H),3.30–3.25(m,1H),3.17(t,J＝5.0Hz,4H),3.10(t,J＝5.0Hz,4H),2.68(t,J＝5.0Hz,4H),2.58(t,J＝5.0Hz,4H),2.42(s,3H),2.36(s,3H),1.32(t,J＝7.1Hz,3H).13C NMR(125MHz,CD3OD)δ159.9,159.3(q,J＝36.4Hz),151.6,150.8,149.4,141.7,141.1,138.2,133.3,131.7,131.4,131.2,130.8,129.4,127.9,127.6,127.3,124.0,123.8,122.7,122.4,122.0,121.3,120.4,117.6(q,J＝287.2Hz),117.0,116.4,115.8,110.0,109.4,102.1,78.1,75.2,72.1,71.5,70.7,70.0,68.7,62.7,57.7,55.7,55.7,45.8,45.7,38.4,14.1.19FNMR(470MHz,CD3OD)δ-76.99.HRMS(ESI)m/z:calcd for C57H65N8O8F3:524.2511[M+2H]2+.Found 524.2508[M+2H]2+.
实施例12
化合物12a的制备
Figure BDA0003102834360000121
向溶于干燥MeOH(3mL)中的化合物11a(100mg，0.1mmol)的溶液中加入LiOH(6mg，2当量)。在除去溶剂之前，将混合物在60℃搅拌6小时，然后通过快速柱色谱纯化粗产物，使用MeOH和CH2Cl2(V/V/V＝1：10：1％NH3·H2O)作为洗脱剂。洗脱得到化合物12a，为棕黄色固体(收率66％)。1H NMR(500MHz,CD3OD)δ8.15(s,1H),7.84(d,J＝7.7Hz,1H),7.43(q,J＝7.5,6.8Hz,4H),7.37(d,J＝8.6Hz,1H),7.20(d,J＝8.6Hz,1H),7.13(t,J＝7.2Hz,1H),6.87(t,J＝9.1Hz,4H),6.75(d,J＝8.6Hz,2H),6.61(t,J＝7.1Hz,4H),4.23(dd,J＝11.9,7.4Hz,3H),3.96(dt,J＝9.6,4.4Hz,1H),3.84(d,J＝11.9Hz,1H),3.80(t,J＝4.5Hz,2H),3.68–3.57(m,6H),3.28–3.20(m,3H),3.08(t,J＝5.0Hz,4H),2.98(t,J＝5.0Hz,4H),2.56(t,J＝8.6Hz,1H),2.49(t,J＝5.0Hz,4H),2.40(t,J＝5.0Hz,4H),2.27(s,3H),2.23(s,3H),1.25(t,J＝7.4Hz,3H).13C NMR(125MHz,CD3OD)δ159.8,151.7,151.0,149.2,141.7,141.0,138.3,133.3,131.7,131.5,131.2,129.3,127.9,127.4,127.2,124.0,123.8,122.5,122.4,122.2,121.3,120.4,116.8,116.3,115.8,110.0,109.4,104.7,78.2,77.6,71.8,71.4,70.5,69.7,68.6,62.7,58.3,55.9,55.8,49.6,46.2,46.1,38.4,14.2.HRMS(ESI)m/z:calcd for C55H66N8O7:476.2600[M+2H]2+.Found 476.2608[M+2H]2+.
实施例13
化合物13a的制备
Figure BDA0003102834360000122
通过通用方法A合成化合物13a。浅黄色固体(收率22％)。1H NMR(500MHz,CDCl3)δ8.23(d,J＝1.6Hz,1H),7.92(d,J＝7.7Hz,1H),7.55(d,J＝8.4Hz,2H),7.42(dd,J＝7.1,2.7Hz,2H),7.36(d,J＝8.2Hz,1H),7.21(d,J＝8.6Hz,1H),7.17(t,J＝7.4Hz,1H),6.99(dd,J＝11.4,8.4Hz,4H),6.83(d,J＝8.6Hz,3H),6.75(d,J＝8.4Hz,4H),5.37(d,J＝3.5Hz,1H),5.20(dd,J＝10.5,7.8Hz,1H),5.00(dd,J＝10.5,3.5Hz,1H),4.53(d,J＝8.0Hz,1H),4.31(q,J＝7.2Hz,2H),4.19–4.07(m,3H),4.02(t,J＝4.7Hz,2H),3.98(dt,J＝10.3,4.1Hz,1H),3.89(t,J＝6.7Hz,1H),3.80(q,J＝4.3Hz,2H),3.76–3.67(m,4H),3.24(q,J＝5.1Hz,8H),2.68–2.59(m,8H),2.39(s,3H),2.38(s,3H),2.13(s,3H),2.02(s,3H),2.00(s,3H),1.97(s,3H),1.39(t,J＝7.2Hz,3H).13C NMR(125MHz,CDCl3)δ170.5,170.4,170.3,169.6,158.1,150.0,149.4,147.8,140.3,139.7,137.6,132.1,130.9,129.8,129.8,128.3,126.9,125.8,123.2,122.7,122.1,121.8,121.6,120.7,119.1,115.9,115.4,114.8,108.6,108.0,101.5,71.0,70.8,70.5,69.9,69.3,68.9,67.6,67.1,61.4,55.1,55.0,48.8,48.3,46.0,45.9,37.7,20.9,20.8,20.7,13.9.HRMS(ESI)m/z:calcd forC63H73N7O12:560.7731[M+2H]2+.Found 560.7735[M+2H]2+.
实施例14
化合物14a的制备
Figure BDA0003102834360000131
通过通用方法C合成化合物14a。浅黄色固体(产率98％)。1H NMR(500MHz,CD3OD)δ8.16(s,1H),7.88(d,J＝7.8Hz,1H),7.50–7.38(m,5H),7.29(d,J＝8.6Hz,1H),7.16(t,J＝7.4Hz,1H),6.96(d,J＝8.1Hz,4H),6.81(d,J＝8.3Hz,2H),6.72(dd,J＝8.4,3.9Hz,4H),4.33(q,J＝7.1Hz,2H),4.21(d,J＝7.6Hz,1H),3.98(t,J＝7.7Hz,1H),3.91(t,J＝4.6Hz,2H),3.81(d,J＝3.3Hz,1H),3.75–3.62(m,7H),3.54–3.43(m,3H),3.17(t,J＝5.0Hz,4H),3.09(t,J＝5.1Hz,4H),2.66(t,J＝5.1Hz,4H),2.58(t,J＝5.0Hz,4H),2.40(s,3H),2.35(s,3H),1.32(t,J＝7.1Hz,3H).13C NMR(125MHz,CD3OD)δ159.9,151.7,150.9,149.4,141.7,141.1,138.2,133.3,131.7,131.4,131.2,129.4,128.0,127.6,127.3,124.0,123.8,122.7,122.1,121.3,120.4,117.0,116.4,115.7,110.0,109.4,105.1,76.7,74.9,72.5,71.6,70.6,70.3,69.6,68.7,62.5,55.8,55.7,45.8,45.8,38.4,14.1.HRMS(ESI)m/z:calcd for C55H65N7O8:476.7520[M+2H]2+.Found 476.7525[M+2H]2+.
实施例15
化合物15a的制备
Figure BDA0003102834360000132
向溶于DMF(3mL)中的化合物1a(300mg，0.4mmol)的溶液中加入K2CO3(165mg，1.2mmol)和TBAB(33mg，0.1mmol)，并在0℃下将溴乙酰葡萄糖(288mg，0.7mmol)逐滴加入。随后，使反应升温至室温，再搅拌24小时。完成后，将溶液用乙酸乙酯萃取，并用Na2SO4干燥，然后在减压下浓缩以获得残余物，将其通过硅胶柱色谱法纯化，以获得为浅白色固体的化合物15a(收率16％)。1H NMR(500MHz,CDCl3)δ8.20(s,1H),7.92(d,J＝7.7Hz,1H),7.55(d,J＝8.3Hz,2H),7.J44(dd,＝19.9,8.1Hz,2H),7.37(d,J＝8.2Hz,1H),7.23(d,J＝8.7Hz,1H),7.18(t,J＝7.5Hz,1H),7.00(dd,J＝16.5,8.2Hz,4H),6.84(d,J＝8.4Hz,2H),6.74(dd,J＝18.1,8.3Hz,4H),5.69(d,J＝5.2Hz,1H),5.18(d,J＝3.3Hz,1H),4.92–4.86(m,1H),4.35–4.27(m,3H),4.19(t,J＝4.2Hz,2H),3.95(q,J＝5.7,5.0Hz,3H),3.64(q,J＝5.7Hz,2H),3.22(t,J＝4.7Hz,8H),2.59(dd,J＝8.8,4.6Hz,8H),2.36(s,6H),2.08(s,6H),2.07(s,3H),2.03–1.95(m,2H),1.70(s,3H),1.40(t,J＝7.2Hz,3H).13C NMR(125MHz,CDCl3)δ170.8,169.8,169.3,158.2,150.1,149.5,147.8,140.3,139.7,137.7,132.1,130.7,129.8,129.7,128.3,127.0,126.8,125.8,123.2,122.7,122.0,121.8,121.6,121.5,120.6,119.1,115.8,115.3,114.7,108.6,108.0,97.0,73.3,70.2,68.3,67.1,64.8,63.1,60.3,55.2,49.0,48.4,46.2,46.1,37.7,29.5,20.9,20.9,13.9.HRMS(ESI)m/z:calcd for C62H71N7O11:545.7679[M+2H]2+.Found 545.7678[M+2H]2+.
实施例16
化合物16a的制备
Figure BDA0003102834360000141
化合物16a的合成与化合物15a的步骤相似，只是起始原料1a被3a代替(收率16％)。1H NMR(500MHz,CDCl3)δ8.24(d,J＝1.7Hz,1H),7.94(d,J＝7.7Hz,1H),7.56(d,J＝8.7Hz,2H),7.43(dd,J＝8.6,1.7Hz,2H),7.37(d,J＝8.2Hz,1H),7.22(d,J＝8.6Hz,1H),7.19(t,J＝7.4Hz,1H),7.00(dd,J＝13.1,8.8Hz,4H),6.85(d,J＝8.8Hz,2H),6.76(dd,J＝8.8,4.1Hz,4H),5.73(d,J＝5.2Hz,1H),5.18(t,J＝2.8Hz,1H),4.89(dd,J＝9.6,2.6Hz,1H),4.36(dd,J＝5.5,2.9Hz,1H),4.32(q,J＝7.2Hz,2H),4.19(t,J＝3.7Hz,2H),4.04(t,J＝4.7Hz,2H),3.94(ddd,J＝8.8,5.0,3.2Hz,1H),3.80(dd,J＝5.9,3.8Hz,2H),3.67–3.64(m,4H),3.22(t,J＝5.0Hz,8H),2.61–2.54(m,8H),2.35(s,6H),2.08(s,6H),2.02(s,3H),1.72(s,3H),1.41(t,J＝7.2Hz,3H).13C NMR(125MHz,CDCl3)δ170.8,169.8,169.3,158.1,150.2,149.6,147.8,140.4,139.7,137.7,132.1,131.0,129.8,129.7,128.3,127.0,126.7,125.8,123.2,122.7,121.9,121.8,121.7,121.4,120.7,119.1,115.8,115.3,114.8,108.6,108.0,97.0,73.1,70.4,70.2,69.7,68.4,67.6,67.0,63.2,63.0,55.3,55.2,49.1,48.5,46.3,37.7,20.9,20.9,20.9,20.8,14.0.HRMS(ESI)m/z:calcd forC63H73N7O12:560.7731[M+2H]2+.Found 560.7733[M+2H]2+.
实施例17
化合物17a的制备
Figure BDA0003102834360000142
通过通用方法C合成化合物17a。浅黄色固体(收率96％)。1H NMR(500MHz,CD3OD)δ8.14(d,J＝1.7Hz,1H),7.88(d,J＝7.7Hz,1H),7.49–7.40(m,5H),7.29(d,J＝8.6Hz,1H),7.16(t,J＝7.3Hz,1H),6.96(d,J＝8.7Hz,4H),6.81(d,J＝8.6Hz,2H),6.72(dd,J＝8.7,6.7Hz,4H),5.68(d,J＝5.2Hz,1H),4.32(q,J＝7.1Hz,2H),4.23(t,J＝4.7Hz,1H),3.91(t,J＝4.6Hz,2H),3.82(t,J＝4.6Hz,1H),3.78(dd,J＝12.0,2.5Hz,1H),3.70–3.63(m,3H),3.60–3.53(m,5H),3.47(dd,J＝9.3,5.0Hz,1H),3.15(t,J＝5.0Hz,4H),3.09(t,J＝5.0Hz,4H),2.60(t,J＝5.0Hz,4H),2.51(t,J＝5.0Hz,4H),2.35(s,3H),2.30(s,3H),1.61(s,3H),1.32(t,J＝7.1Hz,3H).13C NMR(125MHz,CD3OD)δ159.9,151.7,151.0,149.4,141.7,141.1,138.3,133.3,131.7,131.5,131.2,129.4,128.0,127.2,123.8,122.7,122.4,122.1,121.3,120.4,116.9,116.4,115.9,110.0,109.4,99.0,78.7,74.8,74.5,71.4,70.5,70.3,68.7,63.4,63.2,55.9,55.8,46.0,38.4,22.5,14.1.
实施例18
化合物18a的制备
Figure BDA0003102834360000151
通过通用方法A合成化合物18a。浅黄色固体(产率16％)。1H NMR(400MHz,CDCl3)δ8.19(d,J＝1.7Hz,1H),7.92(d,J＝7.7Hz,1H),7.58(d,J＝8.4Hz,2H),7.51(dd,J＝8.6,1.7Hz,1H),7.47–7.28(m,7H),7.23(d,J＝8.6Hz,1H),7.19(t,J＝7.4Hz,1H),7.02(t,J＝8.9Hz,4H),6.84(dd,J＝8.7,5.8Hz,4H),6.77(d,J＝8.6Hz,2H),5.00(s,2H),4.32(q,J＝7.2Hz,2H),3.22(t,J＝5.1Hz,8H),2.58(dq,J＝5.1,2.5Hz,8H),2.36(s,3H),2.35(s,3H),1.41(t,J＝7.2Hz,3H).13C NMR(125MHz,CDCl3)δ158.2,150.2,149.7,147.8,140.4,139.7,137.7,136.6,132.1,131.1,129.9,129.8,128.7,128.3,128.2,127.6,127.0,126.8,125.8,123.3,122.7,122.0,121.9,121.6,120.7,119.1,115.8,115.3,115.2,108.6,108.0,70.3,55.3,55.3,49.1,48.6,46.3,46.3,37.7,14.0.HRMS(ESI)m/z:calcd forC52H53N7O:396.7229[M+2H]2+.Found 396.7222[M+2H]2+.
实施例19
化合物19a的制备
Figure BDA0003102834360000152
向化合物18a(400mg，0.5mmol)的乙酸乙酯(10mL)溶液中加入催化量为5％的Pd/C。将反应混合物在室温在H2气氛下搅拌过夜。整个过程由TLC监控。完成后，将所得混合物过滤以除去Pd/C，并在减压下浓缩，得到浅黄色固体形式的化合物19a(收率99％)。1H NMR(500MHz,CDCl3)δ8.17(d,J＝1.7Hz,1H),7.89(d,J＝7.7Hz,1H),7.53(d,J＝8.5Hz,2H),7.47(dd,J＝8.4,1.7Hz,1H),7.40(t,J＝7.6Hz,1H),7.34(d,J＝8.2Hz,1H),7.16–7.11(m,2H),7.01(d,J＝8.3Hz,2H),6.87(d,J＝8.3Hz,2H),6.81(d,J＝8.5Hz,2H),6.71(d,J＝8.4Hz,2H),6.58(d,J＝8.3Hz,2H),4.25(q,J＝7.2Hz,2H),3.18(q,J＝4.9Hz,8H),2.57(dt,J＝9.9,4.9Hz,8H),2.33(s,6H),1.35(t,J＝7.2Hz,3H).13C NMR(125MHz,CDCl3)δ156.7,150.0,149.6,147.8,140.3,139.7,137.5,132.1,129.9,129.9,129.6,128.3,127.0,126.7,125.8,123.2,122.7,122.2,121.7,121.5,120.7,119.1,116.2,115.8,115.4,108.6,108.0,55.2,55.1,48.9,48.2,46.2,46.0,37.7,29.8,14.0.HRMS(ESI)m/z:calcd for C45H47N7O:351.6994[M+2H]2+.Found 351.6989[M+2H]2+.
实施例20
化合物20a的制备
Figure BDA0003102834360000153
通过通用方法A合成化合物20a。浅黄色固体(收率16％)。1H NMR(500MHz,CDCl3)δ8.15(d,J＝1.7Hz,1H),7.90(d,J＝7.7Hz,1H),7.55(d,J＝8.8Hz,2H),7.44(dd,J＝8.6,1.7Hz,2H),7.38(d,J＝8.1Hz,1H),7.24(d,J＝8.6Hz,1H),7.19(t,J＝7.4Hz,1H),7.03–6.99(m,4H),6.85(t,J＝8.5Hz,4H),6.77(d,J＝8.8Hz,2H),5.28–5.21(m,2H),5.14(t,J＝9.2Hz,1H),5.02(d,J＝7.1Hz,1H),4.32(q,J＝7.2Hz,2H),4.25(dd,J＝12.3,5.4Hz,1H),4.06(dd,J＝12.3,2.4Hz,1H),3.78(ddd,J＝10.0,5.4,2.4Hz,1H),3.24(t,J＝4.8Hz,8H),2.61(dt,J＝10.3,4.8Hz,8H),2.38(s,3H),2.37(s,3H),2.03(s,3H),2.02(s,3H),2.02(s,3H),1.94(s,3H),1.41(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ170.6,170.3,169.5,169.3,156.1,150.2,149.6,147.8,140.4,139.7,137.9,133.2,132.1,130.0,129.5,128.3,127.0,126.7,126.0,123.1,122.7,121.7,121.6,120.6,119.2,117.3,115.9,115.4,108.7,108.1,99.2,72.7,72.2,71.2,68.2,61.9,55.1,48.9,48.3,46.1,46.1,37.7,29.8,20.8,20.7,20.7,14.0.HRMS(ESI)m/z:calcd for C59H65N7O10:516.7469[M+2H]2+.Found 516.7465[M+2H]2+.
实施例21
化合物21a的制备
Figure BDA0003102834360000161
通过通用方法C合成化合物21a。浅黄色固体(收率98％)。1H NMR(500MHz,CD3OD)δ8.16(d,J＝1.7Hz,1H),7.91(d,J＝7.7Hz,1H),7.50–7.42(m,4H),7.39(dd,J＝8.5,1.7Hz,1H),7.28(d,J＝8.6Hz,1H),7.17(t,J＝7.3Hz,1H),7.00–6.89(m,6H),6.80(d,J＝8.7Hz,2H),6.68(d,J＝8.6Hz,2H),4.79(d,J＝7.1Hz,1H),4.32(q,J＝7.2Hz,2H),3.77(dd,J＝12.2,1.9Hz,1H),3.63(dd,J＝12.2,4.7Hz,1H),3.42–3.33(m,4H),3.16(t,J＝5.0Hz,4H),3.07(t,J＝5.0Hz,4H),2.69(t,J＝5.0Hz,4H),2.55(t,J＝5.0Hz,4H),2.42(s,3H),2.34(s,3H),1.32(t,J＝7.2Hz,3H).13C NMR(125MHz,CD3OD)δ158.8,151.6,150.8,149.4,141.7,141.1,138.3,133.4,132.7,131.7,131.2,129.4,128.0,127.6,127.3,124.0,123.9,122.6,122.5,122.0,121.4,120.5,117.9,117.0,116.4,110.0,109.4,102.1,78.1,77.8,74.8,71.1,62.3,55.6,55.6,45.7,45.6,38.4,14.2.HRMS(ESI)m/z:calcd forC51H57N7O6:432.7258[M+2H]2+.Found 432.7260[M+2H]2+.
实施例22
化合物22a的制备
Figure BDA0003102834360000162
通过通用方法A合成化合物22a。浅黄色固体(收率76％)。1H NMR(400MHz,CDCl3)δ8.20(s,1H),7.92(d,J＝7.6Hz,1H),7.56(d,J＝8.3Hz,2H),7.44(dd,J＝16.3,8.1Hz,2H),7.36(d,J＝8.2Hz,1H),7.22(d,J＝8.6Hz,1H),7.18(t,J＝7.4Hz,1H),7.00(t,J＝7.8Hz,4H),6.84(d,J＝8.4Hz,2H),6.75(t,J＝7.1Hz,4H),4.29(q,J＝7.6,7.1Hz,2H),4.12(t,J＝5.6Hz,2H),3.76(dt,J＝7.7,4.0Hz,2H),3.21(t,J＝4.8Hz,8H),2.57(t,J＝5.1Hz,8H),2.34(s,6H),1.38(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ157.5,150.2,149.6,147.7,140.3,139.7,137.7,132.0,131.4,129.9,129.9,129.7,128.2,126.9,126.7,125.8,123.1,122.7,121.8,121.6,121.5,120.6,119.1,119.1,115.8,115.3,114.9,114.8,108.6,108.0,68.7,55.2,55.2,49.0,48.4,46.2,41.9,37.7,13.9.
实施例23
化合物23a的制备
Figure BDA0003102834360000163
向化合物22a(400mg，0.5mmol)的DMF(10mL)溶液中，加入叠氮化钠(5mmol)。将反应混合物在70℃反应过夜。反应完之后，用乙酸乙酯萃取，干燥，浓缩得中间体，直接用于下一步。将中间体溶于乙酸乙酯(10mL)溶液中，加入催化量为5％的Pd/C。将反应混合物在室温在H2气氛下搅拌过夜。整个过程由TLC监控。完成后，将所得混合物过滤以除去Pd/C，并在减压下浓缩，得到浅黄色固体形式的化合物23a(收率92％)。1H NMR(500MHz,CDCl3)δ8.23(s,1H),7.93(d,J＝7.8Hz,1H),7.57(d,J＝8.2Hz,2H),7.44(dd,J＝14.3,7.8Hz,2H),7.36(d,J＝8.1Hz,1H),7.22(d,J＝8.6Hz,1H),7.18(t,J＝7.4Hz,1H),7.00(dd,J＝16.4,8.3Hz,4H),6.84(d,J＝8.4Hz,2H),6.75(t,J＝9.2Hz,5H),4.30(q,J＝7.2Hz,2H),3.91(t,J＝5.1Hz,2H),3.21(t,J＝4.9Hz,8H),3.04(t,J＝5.1Hz,2H),2.56(q,J＝5.0Hz,9H),2.34(s,6H),1.76(s,3H),1.39(t,J＝7.2Hz,3H).13C NMR(125MHz,CDCl3)δ158.3,150.2,149.6,147.8,140.4,139.7,137.7,132.1,130.9,129.8,129.7,128.2,126.9,126.8,125.8,123.2,122.7,122.0,121.9,121.6,120.7,119.1,115.8,115.3,114.7,108.6,108.0,70.3,55.3,55.2,49.1,48.5,46.3,41.5,37.7,13.9.
实施例24
化合物1b的制备
Figure BDA0003102834360000171
通过通用方法A和C合成化合物1b。浅黄色固体。(两步总产率为70％)1H NMR(400MHz,CDCl3)δ8.39(d,J＝1.6Hz,1H),8.08(d,J＝7.7Hz,1H),7.72(dd,J＝8.4,1.7Hz,1H),7.48(d,J＝8.3Hz,2H),7.45(d,J＝7.5Hz,1H),7.39(d,J＝8.4Hz,2H),7.22(d,J＝7.9Hz,2H),7.21(t,J＝7.5Hz,1H),6.90(d,J＝8.3Hz,2H),6.74(d,J＝8.5Hz,2H),4.31(q,J＝7.2Hz,2H),3.98(t,J＝7.3Hz,2H),3.23(t,J＝5.0Hz,4H),3.18(t,J＝6.1Hz,2H),3.12(t,J＝5.0Hz,4H),3.06(brs,1H),2.55(t,J＝5.0Hz,4H),2.50(t,J＝5.0Hz,4H),2.32(s,3H),2.28(s,3H),1.55–1.45(m,2H),1.39(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ150.8,149.2,148.1,140.4,140.0,137.3,131.9,128.3,127.5,126.9,126.6,126.1,123.0,122.9,122.1,121.9,121.5,120.8,119.2,115.8,115.6,108.7,108.6,59.1,55.0,48.8,48.2,46.1,46.0,41.7,37.7,33.6,13.9.HRMS(ESI)m/z:calcd for C42H49N7O:334.7072[M+2H]2+.Found 334.7063[M+2H]2+.
实施例25
化合物2b的制备方法
Figure BDA0003102834360000172
通过通用方法A合成化合物2b。浅黄色固体(收率72％)。1H NMR(400MHz,CDCl3)δ8.37(d,J＝1.7Hz,1H),8.12(d,J＝7.7Hz,1H),7.74(dd,J＝8.4,1.7Hz,1H),7.53–7.41(m,5H),7.30(d,J＝8.7Hz,1H),7.25(t,J＝7.5Hz,1H),7.00(d,J＝8.8Hz,2H),6.79(d,J＝9.0Hz,2H),4.39(q,J＝7.2Hz,2H),4.06(dd,J＝8.2,6.3Hz,2H),3.70(t,J＝5.9Hz,2H),3.30(t,J＝5.0Hz,4H),3.17(t,J＝5.0Hz,4H),2.60(t,J＝5.0Hz,4H),2.54(t,J＝5.0Hz,4H),2.37(s,3H),2.32(s,3H),1.69–1.62(m,2H),1.60(s,3H),1.44(t,J＝7.1Hz,3H).13CNMR(100MHz,CDCl3)δ170.7,150.9,149.4,148.4,140.4,140.1,137.6,132.0,128.3,127.6,127.0,126.7,126.1,123.1,123.0,122.2,121.6,120.8,119.3,115.9,115.7,108.8,108.6,61.2,55.2,55.2,49.0,48.5,46.2,46.2,41.8,37.8,29.5,20.6,13.9.HRMS(ESI)m/z:calcd for C44H51N7O2:355.7125[M+2H]2+.Found 355.7121[M+2H]2+.
实施例26
化合物3b的制备方法
Figure BDA0003102834360000181
通过通用方法A和C合成化合物3b。浅黄色固体(两步产率总68％)。1H NMR(500MHz,CDCl3)δ8.42(s,1H),8.10(d,J＝7.8Hz,1H),7.78(d,J＝8.3Hz,1H),7.52–7.39(m,5H),7.29(d,J＝8.2Hz,2H),7.23(t,J＝7.4Hz,1H),6.96(d,J＝8.3Hz,2H),6.76(d,J＝8.5Hz,2H),4.37(q,J＝7.2Hz,2H),4.14(t,J＝6.2Hz,2H),3.45(t,J＝4.6Hz,2H),3.30(q,J＝6.2,5.4Hz,6H),3.18(dt,J＝9.0,4.6Hz,6H),2.64(t,J＝4.9Hz,4H),2.61(t,J＝4.9Hz,4H),2.38(s,2H),2.35(s,3H),1.43(t,J＝7.2Hz,3H).13C NMR(125MHz,CDCl3)δ150.8,149.2,148.9,140.4,140.1,137.3,132.1,128.4,127.6,127.1,126.7,126.1,123.1,122.9,122.2,121.9,121.8,120.7,119.3,116.0,115.8,108.8,108.6,72.3,69.6,61.4,54.9,54.8,48.6,48.1,45.9,45.6,44.3,37.8,13.9.HRMS(ESI)m/z:calcd forC43H51N7O2:349.7125[M+2H]2+.Found 349.7124[M+2H]2+.
实施例27
化合物4b的制备方法
Figure BDA0003102834360000182
通过通用方法A合成化合物4b。浅黄色固体(收率70％)。1H NMR(400MHz,CDCl3)δ8.45(d,J＝1.6Hz,1H),8.12(d,J＝7.7Hz,1H),7.81(dd,J＝8.5,1.7Hz,1H),7.54–7.41(m,5H),7.33(d,J＝8.4Hz,2H),7.25(t,J＝7.5Hz,1H),7.01(d,J＝8.4Hz,2H),6.79(d,J＝8.6Hz,2H),4.41(q,J＝7.2Hz,2H),4.16(t,J＝6.3Hz,2H),4.00(t,J＝4.8Hz,2H),3.39–3.26(m,8H),3.18(t,J＝5.1Hz,4H),2.62(t,J＝5.0Hz,4H),2.56(t,J＝5.0Hz,4H),2.39(s,3H),2.34(s,3H),1.93(s,3H),1.47(t,J＝7.2Hz,3H).13C NMR(125MHz,CDCl3)δ171.1,151.1,149.5,148.7,140.5,140.2,137.6,132.2,128.3,127.6,127.3,126.8,126.1,123.2,123.1,122.3,122.2,122.0,120.8,119.3,116.0,115.7,108.8,108.6,69.7,69.0,63.4,55.3,55.2,49.1,48.6,46.3,46.3,44.1,37.84,21.0,14.0.HRMS(ESI)m/z:calcdfor C45H53N7O3:370.7178[M+2H]2+.Found 370.7178[M+2H]2+.
实施例28
化合物5b的制备方法
Figure BDA0003102834360000183
通过通用方法A合成化合物5b。浅黄色固体(收率16％)。1H NMR(500MHz,CDCl3)δ8.47(d,J＝1.6Hz,1H),8.12(d,J＝7.7Hz,1H),7.81(dd,J＝8.4,1.7Hz,1H),7.54–7.44(m,6H),7.33(d,J＝8.3Hz,2H),7.26(t,J＝7.5Hz,1H),7.02(d,J＝8.4Hz,2H),6.79(d,J＝8.7Hz,2H),5.26(d,J＝3.4Hz,1H),5.06(dd,J＝10.5,7.9Hz,1H),4.86(dd,J＝10.5,3.4Hz,1H),4.43(q,J＝7.2Hz,2H),4.20(d,J＝8.0Hz,1H),4.15(t,J＝6.3Hz,2H),4.00(d,J＝6.7Hz,2H),3.70(dt,J＝11.2,4.2Hz,1H),3.57(t,J＝6.7Hz,1H),3.43(dq,J＝15.2,5.3Hz,2H),3.35–3.29(m,6H),3.25(t,J＝5.0Hz,2H),3.19(t,J＝5.0Hz,4H),2.64(t,J＝5.0Hz,4H),2.57(t,J＝5.0Hz,4H),2.40(s,3H),2.35(s,3H),2.08(s,3H),1.98(s,3H),1.96(s,3H),1.81(s,3H),1.46(t,J＝7.2Hz,3H).HRMS(ESI)m/z:calcd for C57H69N7O11:514.7600[M+2H]2+.Found 514.7601[M+2H]2+.
实施例29
化合物6b的制备方法
Figure BDA0003102834360000191
通过通用方法A合成化合物6b。浅黄色固体(收率16％)。1H NMR(400MHz,CDCl3)δ8.37(d,J＝1.6Hz,1H),8.13(d,J＝7.7Hz,1H),7.73(dd,J＝8.4,1.7Hz,1H),7.53–7.42(m,5H),7.31(d,J＝8.7Hz,2H),7.26(t,J＝7.5Hz,1H),7.01(d,J＝8.8Hz,2H),6.78(d,J＝8.9Hz,2H),5.00(t,J＝9.4Hz,1H),4.93(t,J＝9.6Hz,1H),4.82(dd,J＝9.5,8.0Hz,1H),4.42(q,J＝7.2Hz,2H),4.19–4.12(m,2H),4.06(dd,J＝12.4,4.5Hz,1H),4.00(d,J＝8.0Hz,1H),3.87(dd,J＝12.4,2.4Hz,1H),3.72–3.63(m,2H),3.35(t,J＝5.1Hz,4H),3.32(dd,J＝4.4,2.4Hz,1H),3.21(t,J＝5.1Hz,4H),2.67(t,J＝5.0Hz,4H),2.64(d,J＝5.0Hz,4H),2.41(s,3H),2.38(s,3H),1.97(s,3H),1.96(s,3H),1.94(s,3H),1.84(s,3H),1.47(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ170.7,170.3,169.5,169.4,151.0,149.2,148.6,140.5,140.2,137.3,132.2,128.3,127.6,127.1,126.7,126.3,123.2,122.9,122.1,121.9,121.8,120.9,119.4,116.0,115.9,108.8,108.7,101.0,72.8,71.7,70.9,68.1,61.7,55.1,55.0,48.7,48.3,46.1,45.9,43.8,37.9,20.8,20.7,20.6,14.0.HRMS(ESI)m/z:calcd for C55H65N7O10:492.7469[M+2H]2+.Found 492.7478[M+2H]2+.
实施例30
化合物7b的制备方法
Figure BDA0003102834360000192
通过通用方法A合成化合物7b。浅黄色固体(收率16％)。1H NMR(400MHz,CDCl3)δ8.40(d,J＝1.6Hz,1H),8.13(d,J＝7.7Hz,1H),7.74(dd,J＝8.4,1.7Hz,1H),7.53–7.41(m,5H),7.31(d,J＝8.6Hz,2H),,7.25(t,J＝7.5Hz,1H),7.02(d,J＝8.8Hz,2H),6.78(d,J＝8.9Hz,2H),5.24(d,J＝3.6Hz,1H),5.06(dd,J＝10.5,7.9Hz,1H),4.82(dd,J＝10.5,3.4Hz,1H),4.41(q,J＝7.2Hz,2H),4.21–4.12(m,2H),4.02–3.90(m,3H),3.75–3.68(m,1H),3.59(t,J＝6.8Hz,1H),3.39–3.28(m,5H),3.19(t,J＝5.0Hz,4H),2.64(t,J＝5.0Hz,4H),2.59(t,J＝5.0Hz,4H),2.39(s,3H),2.35(s,3H),2.08(s,3H),1.96(s,3H),1.92(s,3H),1.83(s,3H),1.46(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ170.3,170.3,170.2,169.5,151.0,149.3,148.5,140.5,140.2,137.3,132.2,128.3,127.6,127.0,126.7,126.2,123.2,123.0,122.1,122.0,121.9,120.8,119.3,115.9,115.7,108.8,108.7,101.5,70.9,70.5,68.4,68.0,66.9,61.0,55.2,55.1,48.9,48.4,46.2,46.1,43.8,37.8,20.7,20.7,20.6,13.9.HRMS(ESI)m/z:calcd for C55H65N7O10:492.7469[M+2H]2+.Found492.7462[M+2H]2+.
实施例31
化合物8b的制备方法
Figure BDA0003102834360000201
通过通用方法A合成化合物9b。浅黄色固体(收率62％)。HRMS(ESI)m/z:calcd forC47H57N7O6:408.7258[M+2H]2+.Found 408.7264[M+2H]2+.
实施例32
化合物9b的制备方法
Figure BDA0003102834360000202
通过通用方法A合成化合物9b。浅黄色固体(收率68％)。1H NMR(500MHz,CDCl3)δ8.39(s,1H),8.11(d,J＝7.8Hz,1H),7.75(d,J＝8.4Hz,1H),7.55–7.41(m,5H),7.32(d,J＝8.2Hz,2H),7.24(t,J＝7.5Hz,1H),7.00(d,J＝8.2Hz,2H),6.79(d,J＝8.4Hz,2H),4.39(q,J＝7.3Hz,2H),4.00(t,J＝7.8Hz,2H),3.29(t,J＝4.9Hz,4H),3.16(t,J＝4.9Hz,4H),2.61(t,J＝5.0Hz,4H),2.53(t,J＝5.0Hz,4H),2.37(s,3H),2.32(s,3H),2.13–2.05(m,6H),1.61–1.49(m,6H),1.44(t,J＝7.3Hz,3H).13C NMR(125MHz,CDCl3)δ151.0,149.4,148.2,140.4,140.1,137.3,132.1,128.3,127.5,127.0,126.8,126.0,123.1,123.0,122.5,122.3,121.6,120.7,119.1,116.0,115.7,108.7,108.5,55.2,55.2,53.7,53.2,49.1,48.6,46.2,46.2,43.2,37.8,29.7,23.3,13.9.HRMS(ESI)m/z:calcd for C46H56N8:361.2387[M+2H]2+.Found 361.2382[M+2H]2+.
实施例33
化合物1c的制备方法
Figure BDA0003102834360000203
通过通用方法A合成化合物1c。浅黄色固体(收率82％)。1H NMR(400MHz,CDCl3)δ8.24(d,J＝1.7Hz,1H),7.91(d,J＝7.8Hz,1H),7.58(d,J＝8.7Hz,2H),7.45(dd,J＝8.5,1.7Hz,1H),7.43–7.37(m,2H),7.23(d,J＝8.4Hz,1H),7.19(d,J＝7.2Hz,1H),6.99(dd,J＝14.4,8.7Hz,4H),6.84(d,J＝8.8Hz,2H),6.73(t,J＝8.5Hz,4H),4.89(d,J＝2.5Hz,2H),3.70(s,3H),3.19(dt,J＝9.9,4.8Hz,8H),2.54(dt,J＝9.9,4.8Hz,8H),2.33(s,3H),2.32(s,3H),2.21(t,J＝2.5Hz,1H).13C NMR(125MHz,CDCl3)δ158.8,150.1,149.6,147.3,140.1,139.4,137.6,132.0,130.6,129.8,129.7,128.1,127.0,126.6,126.0,123.4,123.0,122.7,121.8,121.4,120.6,119.8,115.7,115.1,114.1,108.7,108.2,77.7,72.5,55.3,55.2,55.11,49.0,48.3,46.2,32.3.HRMS(ESI)m/z:calcd for C47H47N7O:363.6994[M+2H]2+.Found 363.6988[M+2H]2+.
实施例34
化合物2c的制备方法
Figure BDA0003102834360000211
通过通用方法A合成化合物2c。黄色固体(收率86％)。1H NMR(500MHz,CDCl3)δ8.76(d,J＝2.3Hz,1H),8.31(dd,J＝9.0,2.3Hz,1H),8.16(d,J＝1.7Hz,1H),7.63(dd,J＝8.6,1.7Hz,1H),7.56(d,J＝8.8Hz,2H),7.33(d,J＝9.1Hz,1H),7.28(d,J＝8.7Hz,1H),7.02(t,J＝8.5Hz,4H),6.84(d,J＝8.9Hz,2H),6.77(t,J＝9.1Hz,4H),4.32(q,J＝7.2Hz,2H),3.77(s,3H),3.21(t,J＝5.0Hz,8H),2.62–2.51(m,8H),2.34(s,6H),1.41(t,J＝7.2Hz,3H).13CNMR(125MHz,CDCl3)δ159.2,150.2,149.7,146.7,143.4,140.8,140.7,137.8,132.0,130.4,130.2,129.8,128.5,128.1,126.5,123.9,122.8,122.6,121.8,121.6,121.6,117.4,115.7,115.3,114.4,109.1,108.2,55.5,55.2,55.1,49.0,48.4,46.2,46.2,38.3,13.9.HRMS(ESI)m/z:calcd for C46H48N8O3:381.1997[M+2H]2+.Found 381.1999[M+2H]2+.
实施例35
化合物3c的制备方法
Figure BDA0003102834360000212
化合物3c的合成与化合物19a的步骤相似，只是起始原料18a被2c代替(产率98％)。1H NMR(500MHz,CDCl3)δ8.11(s,1H),7.56(d,J＝8.3Hz,2H),7.40(d,J＝8.6Hz,1H),7.24(d,J＝2.3Hz,1H),7.15(t,J＝9.7Hz,2H),7.00(dd,J＝13.5,8.6Hz,4H),6.85(dd,J＝13.2,8.5Hz,3H),6.75(t,J＝8.8Hz,4H),4.22(q,J＝7.1Hz,2H),3.75(s,3H),3.21(t,J＝5.0Hz,8H),2.56(q,J＝5.0Hz,8H),2.34(s,6H),1.35(t,J＝7.1Hz,3H).13C NMR(125MHz,CDCl3)δ158.9,150.2,149.6,147.9,140.1,139.2,137.6,134.9,132.1,130.8,129.8,129.7,128.3,126.8,124.0,122.2,122.1,121.7,121.1,115.8,115.7,115.3,114.2,109.2,107.9,106.6,55.5,55.2,55.2,49.1,48.5,46.2,37.7,14.0.HRMS(ESI)m/z:calcdfor C46H50N8O:366.2127[M+2H]2+.Found 366.2116[M+2H]2+.
实施例36
化合物4c的制备方法
Figure BDA0003102834360000213
通过通用方法B合成化合物4c。黄色固体(收率76％)。1H NMR(500MHz,CDCl3)δ8.21(s,1H),7.92(d,J＝7.8Hz,1H),7.54(d,J＝8.2Hz,2H),7.45–7.39(m,3H),7.26(d,J＝7.6Hz,1H),7.20(t,J＝7.0Hz,1H),7.04–6.95(m,5H),6.82(d,J＝8.3Hz,2H),6.74(t,J＝9.4Hz,4H),5.54(s,2H),4.28(t,J＝6.8Hz,2H),3.75(s,3H),3.47(t,J＝5.7Hz,2H),3.23(t,J＝4.8Hz,8H),2.64–2.58(m,8H),2.38(s,3H),2.37(s,3H),1.94(q,J＝6.5Hz,2H).13CNMR(125MHz,CDCl3)δ159.0,150.2,149.5,147.6,144.2,140.6,139.8,137.6,132.1,130.5,129.9,129.8,128.3,127.3,126.7,126.3,123.3,123.0,122.5,122.1,121.9,121.7,120.7,119.9,115.9,115.4,114.3,109.1,108.5,58.6,55.5,55.1,55.1,48.9,48.4,47.1,46.1,46.0,39.1,32.5.HRMS(ESI)m/z:calcd for C50H54N10O2:414.2288[M+2H]2+.Found 414.2296[M+2H]2+.
实施例37
化合物5c的制备方法
Figure BDA0003102834360000221
通过通用方法B合成化合物5c。黄色固体(收率70％)。1H NMR(500MHz,CDCl3)δ8.07(s,1H),7.90(d,J＝7.8Hz,1H),7.58–7.41(m,5H),7.30(d,J＝8.6Hz,1H),7.21(t,J＝7.6Hz,1H),7.08–6.98(m,5H),6.83(d,J＝8.4Hz,2H),6.75(dd,J＝13.0,8.4Hz,4H),5.61(s,2H),4.33(t,J＝4.8Hz,2H),3.74(s,3H),3.63(t,J＝4.8Hz,2H),3.31–3.19(m,12H),2.62(dt,J＝10.7,4.9Hz,8H),2.39(s,3H),2.38(s,3H).13C NMR(100MHz,CDCl3)δ159.0,150.2,149.5,147.8,144.1,140.7,139.9,137.5,132.1,130.3,130.0,129.9,129.8,128.3,127.6,126.5,126.3,123.3,123.1,122.4,121.8,121.7,120.6,119.9,115.9,115.4,114.3,109.2,109.0,72.2,69.2,60.8,55.5,55.1,55.1,50.3,48.8,48.3,46.1,46.0,39.1.HRMS(ESI)m/z:calcd for C51H56N10O3:429.2341[M+2H]2+.Found 429.2350[M+2H]2+.
实施例39
化合物6c的制备方法
Figure BDA0003102834360000222
通过通用方法B合成化合物6c。黄色固体(收率64％)。1H NMR(400MHz,CDCl3)δ8.22(d,J＝1.7Hz,1H),7.92(d,J＝7.7Hz,1H),7.54(d,J＝8.8Hz,2H),7.50–7.40(m,3H),7.33(d,J＝8.6Hz,1H),7.22(s,1H),7.20(t,J＝7.2Hz,1H),7.01(dd,J＝8.7,4.2Hz,4H),6.83(d,J＝8.6Hz,2H),6.75(dd,J＝8.9,4.5Hz,4H),5.58(s,2H),5.15(t,J＝9.5Hz,1H),5.04(t,J＝9.6Hz,1H),4.91(dd,J＝9.6,7.9Hz,1H),4.36–4.31(m,3H),4.19(dd,J＝12.4,4.4Hz,1H),4.05(dd,J＝12.4,2.4Hz,1H),3.75(s,3H),3.71(q,J＝5.2,4.8Hz,3H),3.61(ddd,J＝9.9,4.5,2.4Hz,1H),3.48–3.40(m,3H),3.20(t,J＝5.0Hz,8H),2.56(q,J＝5.0Hz,8H),2.34(s,6H),2.02(s,3H),2.00(s,3H),1.99(s,3H),1.86(s,3H).13C NMR(100MHz,CDCl3)δ170.7,170.3,169.5,169.4,159.0,150.2,149.6,147.5,144.1,140.5,139.8,137.6,132.0,130.6,129.9,129.8,128.1,127.1,126.6,126.1,123.3,122.9,122.7,122.6,121.8,121.5,120.7,119.7,115.8,115.3,114.2,109.1,108.5,100.7,72.8,71.8,71.2,70.2,69.4,69.0,68.3,61.8,55.4,55.2,55.2,50.4,49.0,48.4,46.2,46.2,38.9,20.8,20.7,20.6.HRMS(ESI)m/z:calcd for C65H74N10O12:594.2817[M+2H]2+.Found594.2812[M+2H]2+.
实施例40
化合物7c的制备方法
Figure BDA0003102834360000223
通过通用方法C合成化合物7c。黄色固体(产率99％)。1H NMR(500MHz,DMSO-d6)δ8.11(d,J＝4.6Hz,2H),7.93(d,J＝7.8Hz,1H),7.77(d,J＝8.3Hz,1H),7.67(d,J＝8.6Hz,1H),7.46(d,J＝7.7Hz,2H),7.41(d,J＝8.3Hz,2H),7.19(d,J＝7.8Hz,3H),7.05(d,J＝8.2Hz,2H),6.87(d,J＝8.3Hz,2H),6.81(d,J＝8.4Hz,4H),5.63(s,2H),5.15(brs,2H),5.09(brs,1H),4.58(brs,1H),4.43(t,J＝5.2Hz,2H),4.15(d,J＝7.8Hz,1H),3.77(dt,J＝21.8,6.5Hz,3H),3.70(s,3H),3.67(d,J＝10.8Hz,1H),3.56–3.49(m,3H),3.46(dd,J＝11.9,4.9Hz,1H),3.20–3.04(m,11H),2.99(t,J＝8.4Hz,1H),2.41(q,J＝6.6,5.8Hz,8H),2.20(s,6H).13C NMR(125MHz,DMSO-d6)δ158.7,149.9,149.2,146.6,142.8,140.2,139.3,136.5,131.8,130.1,129.9,129.7,127.1,126.1,126.0,125.7,123.8,122.1,122.0,121.8,120.4,120.2,119.9,119.4,114.8,114.3,114.2,110.0,109.2,103.0,76.9,76.8,73.4,70.1,69.4,68.6,67.8,61.1,55.3,54.7,54.6,49.3,47.9,47.1,45.8,45.8,37.6.HRMS(ESI)m/z:calcd for C57H66N10O8:510.2605[M+2H]2+.Found 510.2612[M+2H]2+.
实施例41
化合物8c的制备方法
Figure BDA0003102834360000231
通过通用方法B合成化合物8c。黄色固体(产率77％)。1H NMR(500MHz,CDCl3)δ8.21(s,1H),7.92(d,J＝7.8Hz,1H),7.55(d,J＝8.4Hz,2H),7.49(d,J＝8.5Hz,1H),7.45–7.39(m,2H),7.33(s,1H),7.29(d,J＝8.5Hz,1H),7.21(t,J＝7.0Hz,1H),7.00(t,J＝8.9Hz,4H),6.83(d,J＝8.5Hz,2H),6.75(t,J＝7.8Hz,4H),5.71(d,J＝8.9Hz,1H),5.60–5.49(m,2H),5.35–5.25(m,2H),5.14(t,J＝9.5Hz,1H),4.20(dd,J＝12.6,5.0Hz,1H),4.05(dd,J＝12.6,2.0Hz,1H),3.89(dt,J＝10.3,3.0Hz,1H),3.75(s,3H),3.21(t,J＝4.9Hz,8H),2.57(q,J＝4.9Hz,8H),2.34(s,6H),2.01(s,3H),1.99(s,3H),1.97(s,3H),1.72(s,3H).13C NMR(125MHz,CDCl3)δ170.6,170.0,169.3,168.7,158.9,150.2,149.6,147.4,144.9,140.4,139.7,137.7,132.0,130.6,129.9,129.8,128.2,127.3,126.7,126.2,123.4,123.0,122.8,121.9,121.6,120.7,120.4,119.9,115.8,115.3,114.2,109.0,108.3,85.8,75.2,72.6,70.2,67.7,61.5,55.4,55.2,55.2,49.0,48.4,46.2,46.2,38.9,20.8,20.6,20.6,20.1.HRMS(ESI)m/z:calcd for C61H66N10O10:550.2554[M+2H]2+.Found 550.2564[M+2H]2+.
实施例42
化合物9c的制备方法
Figure BDA0003102834360000232
通过通用方法C合成化合物9c。黄色固体(收率97％)。1H NMR(500MHz,DMSO-d6)δ8.31(s,1H),8.11(s,1H),7.94(d,J＝7.8Hz,1H),7.80(d,J＝8.2Hz,1H),7.69(d,J＝8.7Hz,1H),7.47(d,J＝8.3Hz,2H),7.41(d,J＝8.4Hz,2H),7.20(d,J＝8.1Hz,3H),7.05(d,J＝8.1Hz,2H),6.87(d,J＝8.3Hz,2H),6.82(d,J＝8.4Hz,4H),5.64(s,2H),5.46(d,J＝9.3Hz,1H),5.39–5.25(m,1H),5.16(brs,1H),4.58(brs,1H),3.71(s,3H),3.69(d,J＝12.1Hz,1H),3.62(d,J＝10.9Hz,1H),3.36–3.29(m,4H),3.18(d,J＝9.5Hz,1H),3.11(dt,J＝10.6,4.7Hz,8H),2.44–2.38(m,8H),2.20(s,6H).13C NMR(125MHz,DMSO-d6)δ158.7,150.0,149.2,146.6,142.8,140.1,139.2,136.5,131.8,130.2,129.9,127.1,126.2,125.7,122.7,122.1,121.8,120.4,120.2,119.9,119.5,114.8,114.3,114.2,110.0,109.3,87.4,80.0,77.0,72.0,69.5,60.6,55.3,54.7,54.6,47.9,47.1,45.8,45.8,37.5.HRMS(ESI)m/z:calcd for C53H58N10O6:466.2343[M+2H]2+.Found 466.2347[M+2H]2+.
实施例43
化合物10c的制备方法
Figure BDA0003102834360000241
通过通用方法B合成化合物10c。黄色固体(收率75％)。1H NMR(400MHz,CDCl3)δ8.22(d,J＝1.7Hz,1H),7.93(d,J＝7.8Hz,1H),7.55(d,J＝8.4Hz,2H),7.49(dd,J＝8.5,1.8Hz,1H),7.45–7.40(m,2H),7.37(s,1H),7.29(d,J＝8.6Hz,1H),7.21(ddd,J＝8.0,5.2,2.9Hz,1H),7.00(dd,J＝8.6,5.8Hz,4H),6.83(d,J＝8.5Hz,2H),6.75(dd,J＝8.6,5.0Hz,4H),5.69(d,J＝9.2Hz,1H),5.61–5.50(m,2H),5.46(d,J＝3.4Hz,1H),5.36(t,J＝9.8Hz,1H),5.15(dd,J＝10.3,3.4Hz,1H),4.14–4.08(m,2H),4.02(dd,J＝13.0,8.8Hz,1H),3.74(s,3H),3.20(t,J＝4.9Hz,8H),2.56(q,J＝4.9Hz,8H),2.34(s,6H),2.15(s,3H),1.98(s,3H),1.95(s,3H),1.75(s,3H).13C NMR(100MHz,CDCl3)δ170.3,170.2,169.8,168.8,158.9,150.2,149.6,147.4,144.9,140.5,139.8,137.7,132.0,130.6,129.9,129.8,128.2,127.3,126.7,126.2,123.4,123.0,122.7,121.8,121.5,120.6,120.3,119.8,115.8,115.3,114.2,109.0,108.3,86.3,74.2,70.7,67.8,66.8,61.17,55.4,55.2,55.2,49.0,48.4,46.2,46.2,39.0,20.8,20.7,20.5,20.2.HRMS(ESI)m/z:calcd for C61H66N10O10:550.2554[M+2H]2+.Found 550.2574[M+2H]2+.
实施例44
化合物11c的制备方法
Figure BDA0003102834360000242
通过通用方法C合成化合物11c。黄色固体(收率98％)。1H NMR(400MHz,DMSO-d6)δ8.24(s,1H),8.11(s,1H),7.94(d,J＝7.9Hz,1H),7.81(d,J＝8.3Hz,1H),7.70(d,J＝8.7Hz,1H),7.48(t,J＝7.0Hz,2H),7.41(d,J＝8.5Hz,2H),7.25–7.17(m,3H),7.05(d,J＝8.3Hz,2H),6.88(d,J＝8.5Hz,2H),6.85–6.80(m,4H),5.64(s,2H),5.41(d,J＝9.2Hz,1H),5.14(d,J＝5.5Hz,1H),4.96(brs,1H),4.68–4.55(m,2H),3.99–3.88(m,1H),3.71(s,3H),3.64(t,J＝5.8Hz,1H),3.51–3.39(m,4H),3.12(dt,J＝9.8,4.8Hz,8H),2.42(q,J＝4.8Hz,8H),2.21(s,6H).13C NMR(125MHz,DMSO-d6)δ158.7,150.0,149.2,146.6,143.0,140.1,139.2,136.5,131.8,130.2,129.9,127.1,126.2,125.7,122.1,121.7,120.4,120.2,119.9,119.4,114.8,114.3,114.2,110.0,109.2,88.0,78.5,73.6,69.3,68.4,60.4,55.3,54.7,54.6,47.9,47.1,45.8,45.8,37.5.HRMS(ESI)m/z:calcd for C53H58N10O6:466.2342[M+2H]2+.Found 466.2344[M+2H]2+.
实施例45
化合物1d的制备方法
Figure BDA0003102834360000243
通过通用方法A.合成化合物1d。棕色固体(产率77％)。1H NMR(500MHz,CDCl3)δ8.61(s,1H),8.00(d,J＝8.5Hz,1H),7.96(d,J＝7.7Hz,1H),7.44(dd,J＝8.2,3.0Hz,4H),7.40(t,J＝7.6Hz,1H),7.31(d,J＝8.2Hz,1H),7.23(d,J＝8.5Hz,1H),7.14(t,J＝7.4Hz,1H),6.78(dd,J＝8.4,4.9Hz,4H),4.20(q,J＝7.2Hz,2H),3.32(d,J＝2.3Hz,2H),3.15(dt,J＝15.5,4.8Hz,8H),2.66(t,J＝4.8Hz,4H),2.50(t,J＝4.8Hz,4H),2.30(s,3H),2.28(t,J＝2.3Hz 1H),1.31(t,J＝7.2Hz,3H).13C NMR(125MHz,CDCl3)δ173.0,149.9,149.9,147.0,140.3,140.0,128.7,125.9,123.7,123.0,121.3,120.7,119.1,117.9,115.8,115.7,108.6,108.6,78.7,73.5,55.0,51.8,48.7,48.7,46.9,46.1,37.6,22.6,13.8.HRMS(ESI)m/z:calcd for C41H43N7O:317.6863[M+2H]2+.Found 317.6850[M+2H]2+.
实施例46
化合物2d的制备方法
Figure BDA0003102834360000251
通过通用方法B合成化合物2d。黄色固体(收率72％)。1H NMR(500MHz,CDCl3)δ8.65(s,1H),8.04(d,J＝8.5Hz,1H),7.95(d,J＝7.6Hz,1H),7.46–7.27(m,8H),7.11(t,J＝7.5Hz,1H),6.75(d,J＝8.2Hz,2H),6.67(d,J＝8.2Hz,2H),4.31(q,J＝7.2Hz,2H),4.25–4.15(m,2H),3.52(s,2H),3.48–3.40(m,2H),3.17–2.90(m,8H),2.53–2.37(m,8H),2.27(s,3H),1.98–1.90(m,2H),1.30(t,J＝7.2Hz,3H).13C NMR(125MHz,CDCl3)δ150.0,147.0,143.7,140.4,140.1,128.9,128.8,126.1,123.8,123.6,123.1,123.0,121.2,120.8,119.3,118.1,115.7,115.6,108.8,58.3,55.0,53.0,52.6,48.6,48.5,47.0,46.1,37.7,32.7,13.9.HRMS(ESI)m/z:calcd for C44H50N10O:368.2157[M+2H]2+.Found 368.2160[M+2H]2+.
实施例47
化合物3d的制备方法
Figure BDA0003102834360000252
通过通用方法B合成化合物3d。黄色固体(收率66％)。1H NMR(500MHz,CDCl3)δ8.66(s,1H),8.03(dd,J＝14.1,7.9Hz,2H),7.63(s,1H),7.49–7.38(m,5H),7.32(dd,J＝15.2,8.1Hz,2H),7.16(t,J＝6.9Hz,1H),6.78(d,J＝8.3Hz,4H),5.14(t,J＝9.5Hz,1H),5.02(t,J＝9.8Hz,1H),4.95(t,J＝8.7Hz,1H),4.51–4.40(m,3H),4.28(t,J＝8.2Hz,2H),4.18(dd,J＝12.2,4.0Hz,1H),4.07(d,J＝12.2Hz,1H),3.87(dd,J＝9.8,5.0Hz,1H),3.79(q,J＝5.0Hz,2H),3.71(s,2H),3.66–3.50(m,4H),3.22–3.09(m,8H),2.62(t,J＝4.7Hz,4H),2.54(t,J＝4.7Hz,4H),2.32(s,3H),2.03(s,3H),1.98(s,3H),1.96(s,3H),1.95(s,3H),1.38(t,J＝7.2Hz,3H).13C NMR(125MHz,CDCl3)δ170.8,170.4,169.5,169.4,150.1,149.9,146.7,144.0,140.4,140.1,128.8,128.7,126.0,124.0,123.7,123.1,123.0,120.8,119.2,118.0,115.7,115.7,108.7,100.8,72.8,71.8,71.3,70.2,69.6,68.9,68.4,61.9,55.0,53.1,52.7,50.3,48.7,48.6,46.0,37.7,20.8,20.7,20.7,20.6,13.9.HRMS(ESI)m/z:calcd for C59H70N10O11:548.2686[M+2H]2+.Found 548.2694[M+2H]2+.
实施例48
化合物4d的制备方法
Figure BDA0003102834360000253
通过通用方法C合成化合物4d。黄色固体(收率97％)。1H NMR(500MHz,DMSO-d6)δ12.30(s,1H),8.82(s,1H),8.20(d,J＝8.6Hz,1H),8.16(d,J＝7.6Hz,1H),8.06(s,1H),7.68(d,J＝8.6Hz,1H),7.63(d,J＝8.2Hz,1H),7.48(t,J＝7.6Hz,1H),7.46–7.36(m,4H),7.24(t,J＝7.5Hz,1H),7.02–6.82(m,4H),4.94(brs,2H),4.52(t,J＝5.3Hz,2H),4.47(q,J＝7.1Hz,2H),4.17(d,J＝7.8Hz,1H),3.84(t,J＝5.2Hz,3H),3.68(d,J＝11.6Hz,1H),3.62(s,2H),3.61–3.57(m,3H),3.44(dd,J＝11.8,5.7Hz,1H),3.23–3.02(m,13H),2.98(t,J＝8.4Hz,1H),2.56(t,J＝4.9Hz,4H),2.50(t,J＝4.9Hz,4H),2.25(s,3H),1.35(t,J＝7.1Hz,3H).13C NMR(125MHz,DMSO-d6)δ145.8,143.0,140.0,139.3,126.0,124.4,123.5,122.3,122.2,122.0,120.3,119.1,117.0,114.9,109.4,109.2,103.0,76.9,76.8,73.4,70.1,69.4,68.7,67.8,61.1,54.5,52.6,52.3,49.3,48.6,47.7,47.7,45.6,37.1,13.8.HRMS(ESI)m/z:calcd for C51H62N10O7:464.2474[M+2H]2+.Found 464.2465[M+2H]2+.
实施例49
化合物5d的制备方法
Figure BDA0003102834360000261
通过通用方法B合成化合物5d。黄色固体(收率76％)。1H NMR(400MHz,CDCl3)δ8.63(s,1H),8.02(d,J＝7.9Hz,2H),7.73(s,1H),7.47–7.39(m,5H),7.32(dd,J＝14.9,8.4Hz,2H),7.16(t,J＝7.4Hz,1H),6.79(d,J＝8.3Hz,4H),5.76(d,J＝8.3Hz,1H),5.36(q,J＝9.5,7.7Hz,2H),5.20(t,J＝9.3Hz,1H),4.33–4.20(m,3H),4.09(d,J＝12.5Hz,1H),3.92–3.85(m,1H),3.68(s,2H),3.22–3.06(m,8H),2.57(t,J＝5.0Hz,4H),2.53(t,J＝5.0Hz,4H),2.31(s,3H),2.05(s,3H),2.03(s,3H),2.00(s,3H),1.81(s,3H),1.36(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ170.6,170.0,169.5,169.0,150.0,150.0,146.8,145.2,140.4,140.1,128.7,126.0,123.8,123.1,123.0,121.3,120.8,119.2,118.0,115.7,108.7,85.7,75.1,72.6,70.4,67.7,61.6,55.0,53.2,52.8,48.7,48.6,46.1,37.7,20.8,20.6,20.2,13.9.HRMS(ESI)m/z:calcd for C55H62N10O9:504.2423[M+2H]2+.Found504.2436[M+2H]2+.
实施例50
化合物6d的制备方法
Figure BDA0003102834360000262
通过通用方法C合成化合物6d。黄色固体(产率99％)。1H NMR(500MHz,DMSO-d6)δ12.31(s,1H),8.82(s,1H),8.23–8.15(m,3H),7.68(d,J＝8.6Hz,1H),7.63(d,J＝8.2Hz,1H),7.48(t,J＝7.7Hz,1H),7.43(d,J＝8.3Hz,4H),7.24(t,J＝7.5Hz,1H),6.93(d,J＝8.2Hz,4H),5.52(d,J＝9.2Hz,1H),5.39(brs,1H),5.31(brs,1H),5.18(brs,1H),4.66(brs,1H),4.47(q,J＝7.2Hz,2H),3.79(t,J＝9.1Hz,1H),3.72(d,J＝10.8Hz,1H),3.64(s,2H),3.47–3.44(m,2H),3.40(t,J＝8.9Hz,1H),3.25(t,J＝9.2Hz,1H),3.20–3.14(m,8H),2.58(t,J＝4.9Hz,4H),2.48(t,J＝4.9Hz,4H),2.25(s,3H),1.35(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)δ145.8,143.1,140.0,139.3,128.3,126.0,123.5,123.1,122.3,122.2,122.0,120.3,119.1,117.0,114.9,109.4,109.2,87.5,80.0,77.0,72.1,69.6,60.8,54.5,52.5,52.3,47.9,47.7,45.6,37.1,35.8,30.8,13.8.HRMS(ESI)m/z:calcd forC47H54N10O5:420.2212[M+2H]2+.Found 420.2213[M+2H]2+.
实施例51
化合物7d的制备方法
Figure BDA0003102834360000263
通过通用方法B合成化合物7d。黄色固体(收率72％)。1H NMR(500MHz,CDCl3)δ8.64(s,1H),8.05(d,J＝7.8Hz,1H),8.02(d,J＝8.3Hz,1H),7.80(s,1H),7.50–7.40(m,5H),7.38–7.32(m,2H),7.18(t,J＝7.5Hz,1H),6.81(d,J＝8.2Hz,4H),5.78(d,J＝9.3Hz,1H),5.56–5.47(m,2H),5.21(dd,J＝10.3,3.4Hz,1H),4.30(q,J＝7.2Hz,2H),4.20–4.06(m,3H),3.71(s,2H),3.22–3.09(m,8H),2.61(t,J＝5.0Hz,4H),2.56(t,J＝5.0Hz,4H),2.33(s,3H),2.20(s,3H),2.02(s,3H),2.00(s,3H),1.85(s,3H),1.39(t,J＝7.2Hz,3H).13C NMR(125MHz,CDCl3)δ170.5,170.1,169.9,169.3,150.1,150.0,146.7,145.1,140.4,140.2,128.8,126.1,123.7,123.2,123.1,121.4,120.9,119.3,118.0,115.8,108.8,86.3,74.1,70.8,68.1,66.9,61.3,55.0,53.3,52.9,48.7,48.6,46.1,37.8,20.8,20.7,20.6,20.3,14.0.HRMS(ESI)m/z:calcd for C55H62N10O9:504.2423[M+2H]2+.Found 504.2420[M+2H]2+.
实施例52
化合物8d的制备方法
Figure BDA0003102834360000271
通过通用方法C合成化合物8d。黄色固体(产率99％)1H NMR(500MHz,DMSO-d6)δ12.30(s,1H),8.81(s,1H),8.20(d,J＝8.6Hz,1H),8.17(d,J＝9.1Hz,1H),8.16(s,1H),7.69(d,J＝8.6Hz,1H),7.64(d,J＝8.2Hz,1H),7.48(t,J＝7.7Hz,1H),7.43(t,J＝7.1Hz,4H),7.24(t,J＝7.4Hz,1H),6.94(d,J＝7.9Hz,4H),5.47(d,J＝9.1Hz,1H),5.24(brs,1H),5.03(brs,1H),4.72(brs,1H),4.63(brs,1H),4.48(q,J＝7.2Hz,2H),4.05(t,J＝9.3Hz,1H),3.80–3.75(m,1H),3.72(t,J＝6.1Hz,1H),3.65(s,2H),3.58–3.48(m,3H),3.24–3.14(m,8H),2.59(q,J＝7.4,6.0Hz,8H),2.31(s,3H),1.35(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)δ145.8,143.2,140.0,139.3,126.0,123.5,122.7,122.3,122.2,121.9,120.3,119.1,117.0,115.0,114.9,109.4,109.2,88.1,78.4,73.7,69.4,68.5,60.4,54.3,52.5,52.3,47.9,47.5,45.3,37.1,13.8.HRMS(ESI)m/z:calcd for C47H54N10O5:420.2212[M+2H]2+.Found 420.2216[M+2H]2+.
试验例
本试验例测试了实施例和对比例制备的产物对肿瘤细胞生长的抑制作用性能及化合物3a,16a,17a对细胞内c-MYC基因的转录与表达的影响。其中：
1、对肿瘤细胞生长的抑制作用性能
选取上述实施例制得的多芳基取代咪唑与糖类偶联衍生物，对不同种类肿瘤细胞株(市购所得)采用噻唑蓝(MTT)法进行体外细胞毒测定。对数生长期的细胞加入不同浓度的衍生物，作用48h后，加入MTT，测定其吸光度。分别计算出抑制细胞生长50％时是化合物浓度，以IC50值表示，结果如表1所示。化合物16a对不同肿瘤细胞的抑制作用如表2所示。
表1多芳基取代咪唑与糖类偶联衍生物对肿瘤细胞株生长的抑制作用(IC50值/μM)
Figure BDA0003102834360000272
表2化合物16a对不同肿瘤细胞株与正常细胞生长的抑制作用(IC50值/μM)
Figure BDA0003102834360000281
结果表明多芳基取代咪唑与糖类偶联衍生物在体外对肿瘤细胞株有较强的抑制作用，尤其是化合物16a对肿瘤细胞具有选择性抑制，可用于制备抗肿瘤药物。
2、对细胞内c-MYC基因的转录与表达的影响
取部分代表性化合物测试其对细胞内c-MYC基因的转录与表达的影响。具体操作如下：
(1)对转录的影响：
细胞培养：将细胞接种到6孔板中，200 000个/孔，待24小时细胞贴壁后，加入等量化合物(3a、16a、17a)2.5μM，培养24小时后(可以为3～24小时)，收集细胞，提取RNA，检测RNA浓度，后按照下面体系进行逆转录实验及PCR实验。设置两个对照组：空白对照组(Ctrl)和阳性对照组，其中，其他操作相同，仅添加的物质不同，空白对照组不加任何物质，阳性对照组加入IZCZ-3
Figure BDA0003102834360000282
2.5μM。
使用的PCR产物、引物、配制体系如下：10×Dream Taq Green buffer，2.5μL；dNTPmixture(2.5mM)，0.5μL；CDNA，1μL；引物(sense)，0.5μL；引物(antisense)，0.5μL；DreamTaqDNA聚合酶，0.25μL；ddH2O，20.25μL；total，25μL。
程序：95℃变性，5min；95℃变性，30s；58℃退火，30s；72℃延伸，60s(30cycles)；72℃，10min；最终降温至10℃。
1.5％琼脂糖电泳120V，0.5h，电泳结束后，凝胶成像。结果如图1所示，多芳基取代咪唑与糖类偶联衍生物16a，3a，17a能够降低c-MYC的转录水平。
(2)对表达的影响：
Western blot实验方法：细胞培养：细胞计数，接种，加入化合物(3a、4a、9a、16a)2.5μM后，培养在六孔板中，长至500万个细胞后，取出，裂解。细胞被收集后，加入50μL细胞裂解液，提取上清总蛋白液。使用CBA法检测总蛋白浓度，后变性蛋白样品，取相同质量的蛋白上样，SDS-PAGE胶电泳分离蛋白条带。根据目标蛋白计算分子量，将相应位置的电泳条带切下，湿转发将蛋白条带转到PVDF膜上。设置两个对照组：空白对照组(Ctrl)和阳性对照组，其中，其他操作相同，仅添加的物质不同，空白对照组不加任何物质，阳性对照组加入IZCZ-3 2.5μM。
配制洗涤缓冲液(TBST)缓冲液(25mM NaCl，100Tris，0.2％Tween-20，pH7.4)：BST缓冲液溶解的5％脱脂奶粉溶液(w/v)封闭PVDF膜。分别相应用一抗(c-MYC)和二抗(山羊抗兔)孵育PVDF膜，TBST缓冲液漂洗适当次数后，使用SuperECL Plus超敏发光试剂盒显色成像。结果如图2所示，多芳基取代咪唑与糖类偶联衍生物16a能够降低c-MYC的表达水平。
通过将其应用于靶向c-MYC G-四链体，抑制c-MYC基因的转录，从而抑制癌细胞的增殖的实验，发现本发明实施例方案制得的化合物均具备显著的抗肿瘤效果。
3、体内安全性评价：
动物对象为昆明小鼠(20g)，每组为2只雄鼠，2只雌鼠。分为3组，IZCZ-3组，化合物16a组，对照组。单剂量给药200mg/kg,给药一天后，观察给药IZCZ-3组4只小鼠全部死亡，而给药16a组和对照组的小鼠仍然全部存活。结果表明制备新型的多芳基取代咪唑衍生物同时能够降低体内毒性。
综上所述，本发明方案设计了一类新的多芳基取代咪唑衍生物，该类衍生物通过多芳基取代咪唑与糖类化合物偶联制得，其以多芳基取代咪唑作为c-MYC G-四链体的特异性配体，糖部分可以作为癌细胞的靶向支架以及助溶剂，同时能够降低体内毒性。该衍生物可以选择性结合和稳定平行型c-MYC G-四链体，而对启动子区域其他G-四链体以及双链DNA几乎没有作用，其中上述所制备多芳基取代咪唑与糖类偶联衍生物能够明显增加对肿瘤细胞的选择性，同时能够下调原癌基因c-MYC和抑制c-MYC的转录。因此，本发明多芳基取代咪唑与糖类偶联衍生物可作为新型特异性靶向c-MYC G-四链体配体，在制备抗肿瘤药物上具有广泛的应用前景。
上面结合附图对本发明实施例作了详细说明，但是本发明不限于上述实施例，在所属技术领域普通技术人员所具备的知识范围内，还可以在不脱离本发明宗旨的前提下作出各种变化。此外，在不冲突的情况下，本发明的实施例及实施例中的特征可以相互组合。

Claims (10)

1.一种多芳基取代咪唑衍生物，其特征在于：所述衍生物的结构式如式(I)、(Ⅱ)、(Ⅲ)或(Ⅳ)所示：
Figure FDA0003791705430000011
所述R1选自H、Me、OBn、(CH2)nOR6、(CH2O)nR6或R6中的任意一种；
所述R2选自(CH2)nR6、(CH2)nOR6或(CH2O)nR6中的任意一种；
所述R3选自(CH2)nOR6、(CH2O)nR6或R6中的任意一种；
所述R4选自H、NO2、NH2、卤素、(CH2)nNH2或(CH2O)nNH2中的任意一种；
所述R5选自(CH2)nOR6、(CH2O)nR6或R6中的任意一种；
其中，所述R1为OBn、(CH2)nOR6、(CH2O)nR6或R6中的任意一种时，所述R4为H；所述R1为Me时，所述R4为NO2、NH2、卤素、(CH2)nNH2或(CH2O)nNH2；
所述R6选自H、NH2、卤素、五元环或六元杂环基、1,2-原酸酯单糖、氨基六碳单糖、氨基五碳单糖、2-三氟乙酰氨基葡萄糖、乙酰化的2-三氟乙酰氨基葡萄糖、1,2-原酸酯乙酰化葡萄糖、2-三氟乙酰氨基葡萄糖、单糖或乙酰化单糖中的任意一种；
n选自1-10任意一个整数。
2.根据权利要求1所述的多芳基取代咪唑衍生物，其特征在于：所述单糖选自六碳单糖、五碳单糖中的任意一种。
3.根据权利要求1所述的多芳基取代咪唑衍生物，其特征在于：所述单糖选自葡萄糖、半乳糖、或甘露糖中的任意一种；所述氨基六碳单糖选自氨基葡萄糖；所述1,2-原酸酯单糖选自1,2-原酸酯葡萄糖。
4.根据权利要求1所述的多芳基取代咪唑衍生物，其特征在于：所述乙酰化单糖选自乙酰化葡萄糖、乙酰化半乳糖或乙酰化甘露糖中的任意一种。
5.一种如权利要求1至4任一项所述的多芳基取代咪唑衍生物的制备方法，其特征在于：所述衍生物的结构式如式(I)或(Ⅱ)所示，所述制备方法包括如下步骤：
利用4,4'-二氟苯偶酰与甲基哌嗪的反应产物制备所述多芳基取代咪唑衍生物；其中，所述4,4'-二氟苯偶酰与甲基哌嗪的反应产物为
Figure FDA0003791705430000012
利用化合物
Figure FDA0003791705430000013
与胺类化合物、3-甲醛N-乙基咔唑或衍生物以及乙酸铵得到结构式如式(I)或(Ⅱ)所示的衍生物。
6.一种如权利要求1至4任一项所述的多芳基取代咪唑衍生物的制备方法，其特征在于：所述衍生物的结构式如式(IV)所示，所述制备方法包括如下步骤：
利用4,4'-二氟苯偶酰与甲基哌嗪的反应产物制备所述多芳基取代咪唑衍生物；其中，所述4,4'-二氟苯偶酰与甲基哌嗪的反应产物为
Figure FDA0003791705430000014
再利用
Figure FDA0003791705430000021
制备如(IV)所示的多芳基取代咪唑衍生物：
i、利用
Figure FDA0003791705430000022
与
Figure FDA0003791705430000023
反应制备得
Figure FDA0003791705430000024
ii、由
Figure FDA0003791705430000025
与3-甲酰-N-乙基咔唑，乙酸铵反应制备
Figure FDA0003791705430000026
iii、由
Figure FDA0003791705430000027
与叠氮化合物反应制备结构式如式(Ⅳ)所示的衍生物。
7.如权利要求1至4任一项所述的多芳基取代咪唑衍生物或其类似物在制备抗肿瘤药物中的应用，其特征在于：所述类似物选自其药学上可接受的盐中的至少一种；所述肿瘤选自乳腺癌、肝癌、宫颈癌或黑色素瘤的一种或多种。
8.一种抗肿瘤药物，其特征在于：包括如权利要求1至4任一项所述的多芳基取代咪唑衍生物或其类似物；所述类似物选自其药学上可接受的盐中的至少一种。
9.如权利要求1至4任一项所述的多芳基取代咪唑衍生物或其类似物在制备c-MYC转录调控阻断剂中的应用，其特征在于：所述类似物选自其药学上可接受的盐中的至少一种。
10.一种c-MYC转录调控阻断剂，其特征在于：包括如权利要求1至4任一项所述的多芳基取代咪唑衍生物或其类似物；所述类似物选自其药学上可接受的盐中的至少一种。
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