CN105131082A - 环肽类化合物及其应用 - Google Patents
环肽类化合物及其应用 Download PDFInfo
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- CN105131082A CN105131082A CN201510594931.3A CN201510594931A CN105131082A CN 105131082 A CN105131082 A CN 105131082A CN 201510594931 A CN201510594931 A CN 201510594931A CN 105131082 A CN105131082 A CN 105131082A
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- alkyl
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- pharmaceutically acceptable
- hydrogen
- cancer
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Abstract
本发明公开了具有通式Ⅰ所示的化学结构的环肽类化合物，或其药物上可接受的盐、异构体、外消旋体、前体药物或溶剂合物。该化合物与阳性对照(SAHA)相比，具有显著的抑制与肿瘤增殖及转移密切相关的HDAC酶(主要为HDAC1，HDAC2，HDAC3，HDAC8，HDAC11)的去乙酰化作用的活性；与阳性对照(SAHA)相比，具有显著的抑制肿瘤细胞生长的活性。
Description
技术领域
本发明涉及医药化学技术领域，特别是涉及一种环肽类化合物及其应用。
背景技术
组蛋白乙酰化作用在染色体的DNA转录，复制和修复过程中起着非常重要的作用。染色质的组蛋白乙酰化和去乙酰化是调节基因表达的关键环节之一，而异常的基因表达是肿瘤及一些遗传和代谢疾病发生的分子生物学基础。组蛋白的乙酰化程度，有组蛋白乙酰化酶(HAT)和组蛋白去乙酰化酶(HDAC)协调控制的。组蛋白去乙酰化酶(HDACs)是一组在细胞染色质水平、通过诱导组蛋白去乙酰化来调控包括染色质重组、转录活化或抑制、细胞周期、细胞分化及细胞凋亡等一系列生物学效应的酶，特别是与细胞活化后的基因转录表达调控有关。目前已知组蛋白去乙酰化酶有18个不同的亚型，按种系分为4大类：Ⅰ(HDAC1、2、3、8)、Ⅱ(HDAC4、5、6、7、9、10)、III(SIRT1-SIRT7)和Ⅳ(HDAC11)。其中Ⅰ、Ⅱ、Ⅳ为经典家族，是Zn2+依赖性的HDAC。
组蛋白去乙酰化酶抑制剂可以抑制细胞内HDAC的活性，使细胞内组蛋白的乙酰化程度增加，提高p21、p53等基因的表达，进而抑制肿瘤细胞的增殖，诱导其分化、凋亡。组蛋白去乙酰化酶抑制剂一般包括锌离子结合区，连接区和表面识别区三个部分。抑制剂与锌离子的直接作用是产生抑制活性所必须的。HDAC抑制剂主要包括以下四类：(1)短链脂肪酸，如丁酸，苯丁酸及其盐类化合物；(2)羟肟酸类，这是迄今研究最广泛的一类HDAC抑制剂，如辛二酰苯胺异羟肟酸(suberoylanilidehydroxamicacid，SAHA)和曲古抑菌素A(trichostatinA，TSA)；(3)环四肽类，环肽类化合物是结构最为复杂的一类抑制剂，环肽类抑制剂的分子中氨基酸大环作为疏水的表面识别区，烷基链作为连接区，烷基链末端连接着一个锌离子结合基团，如trapoxin，HC-toxon，Apicidin，FK228和Largazole等；(4)苯甲酰胺类化合物，这类化合物的活性比一般的羟肟酸类和环肽类化合物低，但是对Ⅰ类HDAC具有较高的选择性。如MS-275，CI-994等。2006年，美国FDA批准默克公司的辛二酰苯胺异羟肟酸(suberoylanilidehydroxamicacid，SAHA)上市，用于治疗转移性皮肤T细胞淋巴瘤(CTCL)，这是第一个面世的组蛋白去乙酰化酶抑制剂类抗肿瘤药物。
目前临床研究的绝大多数HDAC抑制剂是组蛋白去乙酰化酶广谱抑制剂。由于该类广谱抑制剂抑制大多数组蛋白去乙酰化酶,它们存在毒副作用较大的缺点。研究发现组蛋白去乙酰化I型酶在胰腺癌,胃癌,肺癌,前列腺癌,直肠癌,乳腺癌,淋巴癌等多种癌细胞中高表达。实验证明，组蛋白去乙酰化I型酶选择性抑制剂会使染色质组蛋白乙酰化水平提高，因此导致特定基因激活表达，相应的导致细胞的末端分化或癌细胞的凋亡。因此，组蛋白去乙酰化I型酶已成为目前肿瘤化疗药物研发领域最热门的靶标之一。组蛋白去乙酰化I型酶选择性抑制剂具有高效,低毒等优点,本发明因此而来。
发明内容
基于此，本发明的目的是提供一种环肽类化合物，可作为组蛋白去乙酰化I型酶选择性抑制剂。
具体的技术方案如下：
具有通式Ⅰ所示的化学结构的环肽类化合物，或其药物上可接受的盐、异构体、外消旋体、前体药物或溶剂合物：
其中，
X为O或NH；
R1基团为氢，C1-12烷基，C1-12烷基氨基、-CH2-O-(C1-12烷基)，-CH2-NH-(C1-12烷基)，-CH2-S-(C1-12烷基)，C6-12芳基，杂芳基，-CH2-(C6-12芳基)或-CH2-杂芳基；上述的C6-12芳基，杂芳基，-CH2-C6-12芳基，-CH2-杂芳基，含有1个或多个取代基，其取代基选自卤素、氨基、羟基、硝基、氰基、C1-12烷基、C1-12烷氧基、氨基C1-12烷基、酰基、酰氧基、硫代C1-12烷基、羧基或苯基；
R2和R3基团独立地选自氢，C1-12烷基，-O-(C1-12烷基)，-NH-(C1-12烷基)，-S-(C1-12烷基)，C6-12芳基或杂芳基；R2和R3成三到七元环；
R4基团为氢，C1-12烷基，-O-(C1-12烷基)，-NH-(C1-12烷基)，-S-(C1-12烷基)，羟乙基，C6-12芳基或杂芳基；
Y为 或其中R9基团是氢，C1-12烷基，-O-(C1-12烷基)，-NH-(C1-12烷基)，-S-(C1-12烷基)，C6-12芳基，杂芳基，卤素，氨基，羟基，硝基，氰基或羧基。
在其中一些实施例中，R1基团为氢，甲基,异丙基,丁氨基。
在其中一些实施例中，R2和R3基团独立地选自氢，C1-12烷基。
在其中一些实施例中，R2为氢，R3为CH3。
在其中一些实施例中，R4基团为氢，C1-12烷基。
在其中一些实施例中，Y选自 或其中R9基团为氢。
在其中一些实施例中，R1基团为氢，甲基,异丙基,丁氨基；R2为氢，R3为CH3；R4基团为氢，C1-12烷基；Y选自 或其中R9基团为氢。
本发明的另一目的是提供一种治疗肿瘤的药用组合物。
具体的技术方案如下：
一种治疗肿瘤的药用组合物,其包括上述环肽类化合物或其药物上可接受的盐、异构体、外消旋体、前体药物或溶剂合物与药学上可接受的载体。
本发明的另一目的是提供上述化合物的应用。
具体的技术方案如下：
上述环肽类化合物或其药物上可接受的盐、异构体、外消旋体、前体药物或溶剂合物在制备预防或治疗肿瘤的药物中的应用。
本发明的另一目的是提供上述化合物的另一应用。
具体的技术方案如下：
上述环肽类化合物或其药物上可接受的盐、异构体、外消旋体、前体药物或溶剂合物在制备预防或者治疗与组蛋白去乙酰化酶调节异常有关的哺乳动物疾病药物中的应用。
在其中一些实施例中，所述与组蛋白去乙酰化酶调节异常有关的哺乳动物疾病包括癌症、神经变性疾病、艾滋病、老年痴呆、疟疾或糖尿病。
在其中一些实施例中，所述癌症包括淋巴瘤、非小细胞肺癌、小细胞肺癌、胃癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、白血病、宫颈癌中的任一种。
本发明的有益效果：
本发明具有式I结构的化合物与阳性对照(SAHA)相比，具有显著的抑制与肿瘤增殖及转移密切相关的HDAC酶(主要为HDAC1，HDAC2，HDAC3，HDAC8，HDAC11)的去乙酰化作用的活性；与阳性对照(SAHA)相比，具有显著的抑制肿瘤细胞生长的活性。
具体实施方式
本发明制备式I所示的环肽化合物的方法，包括如下步骤：
(1)将式II化合物、式III化合物和有机碱在缩合剂的作用下进行缩合反应，并脱保护基得到式IV化合物；反应过程如下所示：
(2)将式IV化合物、式V化合物和有机碱在缩合剂的作用下进行缩合反应，得到式VI化合物；反应过程如下所示：
(3)脱去VI化合物上的氨基保护基P，然后在缩合剂和有机碱的作用下，分子内关环得到式VII化合物；反应过程如下所示：
(4)化合物VII在有机碱或碘的作用下得到式I化合物；反应过程如下所示：
其中，
R1、R2、R3、R4同权利要求1中所述；
P为氨基保护基团,T为巯基保护基团如Trt等。
进一步地，所述的缩合剂可以为DCC、EDC、HATU、HOAt、HOBt、DEAD、HBTU或PyBOP；所述的有机碱选自咪唑、三乙胺、二异丙基乙胺、哌啶、二甲基吡啶、LiHMDS、NaHMDS、KHMDS、N-甲基吗啉、DABCO或吡啶；所述的氨基保护基团P选自Boc、Cbz、Bn、Fmoc、Alloc、Tos、Tfa、Trt或Bn。；所述的巯基保护基团T选自Trt、Tmob、Qm、Xan、DMTr、t-Bu或Acm。
上述的合成反应过程中，必要的有机溶剂可以选自二氯甲烷、四氢呋喃(THF)、二甲基甲酰胺(DMF)、乙二醇二甲醚、1,2-二氯乙烷、邻苯二甲酸二甲酯(DMP)、甲醇、乙醇、石油醚、正己烷或乙醚；必要的无机碱可以选自氢氧化钠、氢氧化锂、碳酸钾、碳酸钠、碳酸氢钠、碳酸钙；必要的酸可以选自三氟乙酸、盐酸、硫酸或硝酸。所述的氧化剂可以是Dess-Martin氧化剂、Swern氧化剂、间氯过氧苯甲酸、氯重铬酸吡啶(PDC)或氯铬酸吡啶(PCC)。
应当说明的是，本文所使用相关术语诸如“烷基”“芳基”“杂芳基”“卤素”“酰基”等等与所属领域中所述术语的一般含义无明显不同。
例如，术语“烷基”指直链或支链，C1～n烷基则表示1～n个碳原子的饱和的脂烃基，包括直链和支链，例如“C1～12烷基”指的是该基团为烷基，且烷基的碳链上碳原子的数量在1～12之间。应当说明的是，当没有特别限制其碳原子数时，仅指其中指明的烷基部分的碳原子数，而并不包括烷基的取代基上碳原子数。
本领域的普通技术人员应当知道下列术语或缩写的含义。
术语“药物上可接受的盐”是指在合理医学判断范围内适用于与哺乳动物特别是人的组织接触而无过度毒性、刺激、过敏反应等并与合理的效益/风险比相称的盐，比如胺、羧酸和其它类型化合物的医学上可接受的盐在所属领域中是被熟知的。
术语“异构体”是指分子组成相同、但结构和性质不同的两种或多种化合物。
术语“外消旋体”是指一种具有旋光性的手性分子与其对映体的等摩尔混合物，它由旋光方向相反、旋光能力相同的分子等量混合而成，其旋光性因这些分子间的作用而相互抵消，因而是不旋光的。
术语“溶剂合物”是指化合物与溶剂组成的混合物，例如结晶体即是一种溶剂合物。
术语“前体药物”指通过在血液中水解而活体内快速转化产生具有上述化学式的母体化合物的化合物。
权利要求书或说明书中所用的英文缩写所对应的物质分别是：
DCC(N,N'-二环己基碳二亚胺,CasNo.:538-75-0)、EDCI[1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐,CasNo.:25952-53-8]、HATU(CasNo.:148893-10-1)、HOAt(CasNo.:39968-33-7)、HOBt(1-羟基-苯并-三氮唑,CasNo.:2592-95-2)、DEAD(偶氮二甲酸二乙酯，CasNo.:1972-28-7)、HBTU(CasNo.:94790-37-1),PyBOP(六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷,CasNo.:132705-51-2),DIPEA(N，N-二异丙基乙胺,CAS:7087-68-5)；LiHMDS[二(三甲基硅基)氨基锂]、NaHMDS(六甲基二硅基胺基钠)、KHMDS(六甲基二硅基胺基钾)、DABCO(1,4-二氮杂二环[2.2.2]辛烷)；所述的氨基保护基团P选自Boc(叔丁氧羰基)、Cbz(苄氧羰基)、Bn(苄基)、Fmoc(笏甲氧羰基)、Alloc(丙氧羰基)、Tos(对甲苯磺酰基)、Tfa(三氟乙酰基)或Trt(三苯甲基)。所述的巯基保护基团T选自Trt(三苯甲基)、Tmob(三甲氧基苯甲基)、Qm(2-喹啉甲基)、Xan(夹氧蒽基)、DMTr(双4-甲氧基苯甲基)、t-Bu(叔丁基)或Acm(乙酰氨基甲基)。
本发明所述化合物中,当任何变量(例如R1,R2等)在任何组分中出现超过一次,则其每次出现的定义独立于其它每次出现的定义。同样,允许取代基及变量的组合,只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环,其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域的普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料,容易的合成目标化合物。如果取代基自身被超过一个基团取代,应理解这些基团可在相同碳原子上或不同碳原子上,只要使结构稳定。
应当说明的是，本文所使用相关术语诸如“烷基”“芳基”“杂芳基”“卤素”“酰基”等等与所属领域中所述术语的一般含义无明显不同。
除非另有定义,烷基,环烷基,芳基,杂芳基和杂环基取代基可为未被取代的或取代的.例如,(C1-C6)烷基可被一个,两个,或三个选自OH,卤素,烷氧基,二烷基氨基或杂环基例如吗啉基,哌啶基等取代基取代。
本发明包括式I的游离形式,也包括药学上可接受的盐及立体异构体。文中一些特定的示例性化合物为胺类化合物的质子化了的盐。术语“游离形式”指以非盐形式的胺类化合物。包括药学上可接受的盐不仅包括本文所述特定化合物的示例性盐,也包括所有式I化合物游离形式的典型的药学上可接收的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如,通过适当的碱稀水溶液如氢氧化钠稀水溶液,碳酸钠稀水溶液,,稀氨水溶液及碳酸氢钾稀水溶液处理该盐使游离形式再生.游离形式在某些物理性质如在极性溶剂中的溶解度上与其各自盐形式多少有些区别,但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常,通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的,通过和适当的无机或有机碱反应形成化合物的盐。
因此,本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如,常规无毒盐包括得自无机酸例如盐酸、硫酸、氢溴酸、氨基磺酸、磷酸、硝酸等的盐,也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、乙酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、富马酸、2-乙酰氧基-苯甲酸、富马酸、对甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。
如果本发明的化合物为酸性的,则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐。得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。药学上可接受的有机无毒碱的盐,所述碱包括伯胺、仲胺和叔胺的盐,取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂,例如精氨酸、甜菜、咖啡因、胆碱、N,N’-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡萄糖、甲基葡萄糖胺、组氨酸、赖氨酸、异丙基胺、吗啉、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
在一个实施方案中,本申请所设计的化合物及其药学可接受的盐可以与目前应用的或处于开发阶段的细胞毒素/细胞抑制剂、雌激素受体调节剂、雄激素受体调节剂、视网膜样受体调节剂、抗增殖剂、蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白酶抑制剂、逆转录酶抑制剂、血管生成抑制剂、细胞增殖及生存信号抑制剂、干扰细胞周期关卡的药物和细胞凋亡诱导剂、细胞毒类药物、酪氨酸蛋白抑制剂、EGFR抑制剂、VEGFR抑制剂、丝氨酸/苏氨酸蛋白抑制剂、Bcr-Abl抑制剂、c-Kit抑制剂、Met抑制剂、Raf抑制剂、MEK抑制剂、MMP抑制剂、拓扑异构酶抑制剂、组蛋白去乙酰化酶抑制剂、蛋白酶体抑制剂、CDK抑制剂、Bcl-2家族蛋白抑制剂、MDM2家族蛋白抑制剂、IAP家族蛋白抑制剂、STAT家族蛋白抑制剂、PI3K抑制剂、AKT抑制剂、COX-2抑制剂、整联蛋白阻滞剂、P53激活剂、VEGF抗体、EGF抗体等药物联合用药增加其临床效果。
本申请所涉及的化合物及其药学可接受的盐可根据下面的方法用于治疗下列的疾病以及下面没有列出的其它疾病:
1)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的乳腺癌的方法。包括但不局限于侵袭性导管癌、侵袭性小叶癌、原位管癌和原位小叶癌。
2)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的呼吸道癌的方法。包括但不局限于小细胞&非小细胞肺癌、支气管腺癌和胸膜肺母细胞瘤。
3)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的脑癌的方法。包括但不局限于脑干和眼下神经胶质瘤、小脑和大脑星形细胞瘤、室管膜细胞瘤以及神经外胚层和松果体瘤。
4)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的雌、雄性生殖器官的肿瘤的方法。雄性生殖器官的肿瘤包括但不局限于前列腺和睾丸癌。雌性生殖器官的肿瘤包括但不局限于宫颈癌、子宫内膜癌、卵巢癌、阴道癌和外阴癌以及子宫内瘤。
5)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的消化道癌的方法。包括但不局限于肛门癌、结肠癌、结肠直道癌、食道癌、胃癌、胰腺癌、直肠癌、小肠癌、和唾腺癌。
6)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的尿道癌的方法。包括但不局限于膀胱癌、阴茎癌、肾癌、肾盂癌、输尿管癌、和尿道癌。
7)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的眼癌的方法。包括但不局限于眼内黑素瘤和视网膜细胞瘤。
8)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的肝癌的方法。包括但不局限于肝细胞瘤(具有或不具有纤维板变化的肝细胞癌)、胆管癌(肝内胆管癌)和混合的肝细胞性胆管癌。
9)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的皮肤癌的方法。包括但不局限于扁平细胞癌、卡波济氏肉瘤、恶性黑色素瘤、默克氏细胞皮肤癌、和非黑素瘤细胞癌。
10)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的头颈癌的方法。包括但不局限于喉、下咽、鼻咽、口咽癌以及唇和口腔癌。
11)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的淋巴瘤的方法。包括但不局限于AIDS相关的淋巴瘤、非何杰金淋巴瘤、皮肤T细胞淋巴瘤、全身T细胞淋巴瘤、何杰金淋巴瘤和中枢神经系统淋巴瘤。
12)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的肉瘤的方法。包括但不局限于软组织肉瘤、骨肉瘤、恶性纤维性组织细胞瘤、淋巴肉瘤和横纹肌肉瘤。
13)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的白血病的方法。包括但不局限于急性骨髓性白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、慢性骨髓性白血病以及多毛细胞白血病。
服用方式与剂量范围
根据标准药学技术,本发明化合物可单独偶或在药用组合物中与药学上可接受的受体、辅料或稀释剂组合给予哺乳动物,优选人。可口服或皮下、肌注、腹膜内、静脉、直肠及局部、眼睛、肺部、鼻腔、胃肠外给予化合物。
在一个实施方案中,利用式(I)化合物治疗或控制癌症等患者时,服用剂量范围为在静脉注射0.1～500毫克/天/公斤体重。适当的给药方式为每日单剂量给药或每日两次、三次、四次等多次给药或利用缓释技术给药。对于大型哺乳动物,其优选剂量范围为0.1～1500毫克/天/公斤体重。对于平均体重为70公斤的病人,其剂量为1～500毫克。对于一些特别高活性化合物,成年病人每日剂量可低达0.1毫克/天。
为了更好的说明本发明的技术内容，下面结合具体实例对本发明作进一步阐述,但该实施例并非用于限制本发明的保护范围。
应当说明的是，下述实施例中，常规后处理方法是：反应完成后，在反应液中加入适量的水，分离有机相和水相，合并有机相；如有需要，依次使用5％HCl溶液和/或饱和NaSO4干燥，过滤之后减压选干，得到粗产物，再经过柱层析分离纯化之后得到最终产物。
实施例1
步骤1.化合物b的合成
将Fmoc-L-Ala(3.11g，10.0mmol)，EDCI(1.91g，10.0mmol)和DMAP(50mg，0.406mmol)溶于无水二氯甲烷(38mL)，在0℃下加入DIPEA(1.6mL，10.0mmol)和化合物a(3.18g，6.15mmol)，室温下搅拌12h，加二氯甲烷稀释，反应液用碳酸氢钠溶液洗涤(70mLx3)，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，残留物用硅胶柱层析得淡黄色固体化合物9(4.49g，90％)。[α]20 D:-15.0(c1.10,CHCl3).1HNMR(400MHz,CDCl3):δ7.73(d,J＝7.6Hz,2H),7.57(m,2H),7.38(dd,J＝7.4Hz,2H),7.30(dd,J＝7.4Hz,2H),7.37-7.13(m,15H),5.82and5.73(m,1H),5.65(dd,J＝13.6,7.2Hz,1H),5.50(dd,J＝15.2,7.2Hz,1H),5.31(d,J＝8.8Hz,1H),4.36(t,J＝6.8Hz,2H),4.25(dd,J＝9.2,4.6Hz,1H),4.21(t,J＝7.2,1H),4.12(t,J＝8.4Hz,2H),2.86(t,J＝7.2Hz,2H),2.68(dd,J＝15.6,7.6Hz,1H),2.58(dd,J＝15.6,5.6Hz,1H),2.50(t,J＝7.2Hz,2H),2.26(dt,J＝13.6,6.8Hz,2H),2.19(m,1H),1.60(d,J＝6.8Hz,3H),0.01(s,9H)ppm.13CNMR(100MHz,CDCl3):δ199.1,170.5,169.0,155.8,143.9,141.0,133.0,127.9,127.2,127.1,126.9,124.8,119.7,71.6,67.0,63.0,58.6,46.8,43.9,39.5,32.0,31.3,28.6,-1.30ppm.MS(EI,m/z):812(M++1).
步骤2.化合物c的合成
将化合物b(1.62g，2.00mmol)溶于乙腈(18mL)，加入二乙胺(0.50mL，4.88mmol)，搅拌2h，减压旋走乙腈，残留物用硅胶柱层析得无水油状化合物c(1.12g，95％)。[α]20 D:-10.8(c1.30,CHCl3).1HNMR(400MHz,CDCl3):δ7.39-7.37(m,6H),7.27-7.23(m,6H),7.20-7.15(m,3H),5.67-5.56(m,2H),5.33(dd,J＝15.4Hz,7.4Hz,1H),4.15-4.08(m,2H),3.19(d,J＝4.8Hz,1H),2.62(dd,J＝15.6Hz,8.2Hz,1H),2.51(dd,J＝15.6Hz,5.2Hz,1H),2.16(m,2H),2.05-1.98(m,2H),1.96(d,J＝6.8Hz,3H),0.93(m,2H),0.02(s,9H).MS(EI,m/z):590(M++1).
步骤3.化合物e的合成
将化合物c(2.95g，5.0mmol)溶于无水二氯甲烷(36mL)，0℃下依次加入HATU(2.09g，5.50mmol)，HOAt(0.748g，5.50mmol)，化合物d(3.08g，5.0mmol)的二氯甲烷溶液(30mL)和DIPEA(1.48mL，9.0mmol)。室温下搅拌12h，减压旋走二氯甲烷，残留物用乙酸乙酯(100mL)溶解，依次用饱和碳酸氢钠溶液，饱和氯化铵溶液和饱和食盐水洗涤有机相，有机相用无水硫酸钠干燥，浓缩，残留物用硅胶柱层析得淡黄色油状化合物e(4.11g，90％)。[α]20 D:-6.80(c1.5,CHCl3).1HNMR(400MHz,CDCl3,ppm):δ8.58(s,1H),8.09(s,1H),7.39-7.36(m,6H),7.28-7.24(m,6H),7.20-7.16(m,3H),6.58(m,2H),5.75(m,1H),5.60(dd,J＝13.8,7.2Hz,1H),5.46(dd,J＝13.8,7.5Hz,1H),5.40(m,1H),4.55(m,3H),4.12(t,J＝8.6Hz,2H),2.83(t,J＝7.2Hz,2H),2.65(dd,J＝15.7,7.7Hz,2H),2.47(t,J＝7.5Hz,2H),2.23(q,J＝7.2Hz,2H),2.19(d,J＝6.8Hz,1H),1.82(d,J＝7.2Hz,3H),1.57(m,2H),1.43(m,5H),0.01(s,9H).13CNMR(125MHz,CDCl3):δ199.0,170.3,169.36,164.0,159.0,148.6,133.0,129.1,128.9,128.0,124.6,71.6,63.0,57.0,44.0,39.3,27.5,0.93,-1.58.MS(EI,m/z):913[M+H]+.HRMS(ESI):calcdm/zforC48H60N4O8S2Si[M+H]+913.3622,found913.3625.
步骤4.化合物f的合成
化合物e(1.37g，1.5mmol)溶于无水二氯甲烷(30mL)，0℃下加入三氟醋酸(3.0mL)，搅拌24h，减压旋走二氯甲烷和三氟醋酸，加甲苯(3mLx2)在真空下带走残余的三氟醋酸，将所得氨基酸溶于乙腈(220mL)后滴入乙腈(400mL)和HATU(833mg，2.193mmol)、DIPEA(1.09mL，6.58mmol)的混合物中，室温下搅拌24h，减压旋走乙腈，残留物用乙酸乙酯(100mL)溶解，有机相依次用饱和碳酸氢钠溶液、稀盐酸和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，残留物用硅胶柱层析白色固体化合物f(0.687g，66％)。[α]23 D:16.1(c0.8,CHCl3).1HNMR(CDCl3,400MHz,ppm):δ8.50(s,1H),8.13(s,1H),7.39-7.36(m,6H),7.28-7.25(m,6H),7.21-7.17(m,3H),7.05(q,J＝7.2Hz,1H),6.40(d,J＝10.4Hz,1H),6.26(s,1H),5.76-5.66(m,2H),5.53(dd,J＝15.6,7.2Hz,1H),5.23(dd,J＝15.6,7.2Hz,1H),4.81(dd,J＝10.4,3.2Hz,1H),4.36(dd,J＝17.6,4.0Hz,1H),2.89(t,J＝7.2Hz,2H),2.70(d,J＝6.4Hz,2H),2.28(m,8H)；13CNMR(125MHz,CDCl3):δ195.3,169.5,170.1,167.2,163.0,158.2,147.8,134.3,132.2,128.1,126.7,123.9,71.5,56.8,40.6,40.1,32.0,31.3,30.5,28.0,18.8ppm；HRMS(ESI)Calcdm/zforC38H38N4O5S2[(M+H)+]695.2362,found695.2360.
步骤5.化合物1-1的合成
将化合物6(627mg,0.87mmol)溶于甲醇(5mL)，0℃下加入I2(440mg,1.74mmol)的甲醇溶液(5ml)，搅拌2h，加入硫代硫酸钠饱和溶液(10ml)，用乙酸乙酯萃取(10mlx3)，无水硫酸钠干燥，浓缩，残留物用硅胶柱层析白色固体化合物7(375mg，90％)。[α]20 D＝18.1(c0.30,CHCl3).1HNMR(400MHz,CDCl3)δ8.58(s,1H),8.13(s,1H),6.95(q,J＝7.1Hz,2H),6.52(d,J＝10.2Hz,1H),5.85–5.64(m,2H),5.55(dd,J＝15.6,6.8Hz,1H),5.22(dd,J＝17.6,8.2Hz,1H),4.75(dd,J＝10.2,3.8Hz,1H),4.34(dd,J＝17.7,4.1Hz,1H),2.92–2.76(m,1H),2.76–2.62(m,3H),2.49–2.36(m,2H),2.31(d,J＝6.7Hz,3H),1.83(d,J＝7.1Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.8,169.1,167.5,163.6,158.5,148.0,134.5,132.2,128.8,127.1,124.4,72.0,57.2,40.8,40.4,37.5,31.6,31.3,19.0ppm.HRMS(ESI)Calcdm/zforC38H47N8O10S4[(M+H)+]903.2298,found903.2297.
实施例2,化合物1-2的合成
合成方法如实施例1。
[α]20 D＝8.6(c0.20,CHCl3).1HNMR(400MHz,CDCl3)δ8.55(s,1H),8.10(s,1H),6.92(q,J＝7.0Hz,2H),6.51(d,J＝10.0Hz,1H),5.82–5.61(m,2H),5.53(dd,J＝15.6,6.8Hz,1H),5.20(dd,J＝17.4,8.0Hz,1H),4.73(dd,J＝10.2,3.8Hz,1H),4.32(dd,J＝17.7,4.1Hz,1H),2.88–2.76(m,2H),2.73–2.60(m,3H),2.47–2.33(m,2H),2.30(d,J＝6.7Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.5,168.8,167.2,163.2,158.1,148.0,134.2,132.0,128.5,127.0,124.2,71.8,40.6,40.2,37.2,31.3,31.0ppm.HRMS(ESI)Calcdm/zforC36H43N8O10S4[(M+H)+]875.1985,found875.1986.
实施例3,化合物1-3的合成
合成方法如实施例1。
[α]20 D＝11.6(c0.20,CHCl3).1HNMR(400MHz,CDCl3)δ8.57(s,1H),8.13(s,1H),6.94(q,J＝7.1Hz,2H),6.51(d,J＝10.2Hz,1H),5.85–5.65(m,2H),5.54(dd,J＝15.6,6.8Hz,1H),5.20(dd,J＝17.6,8.2Hz,1H),4.75(dd,J＝10.2,3.8Hz,1H),4.33(dd,J＝17.7,4.1Hz,1H),2.90–2.75(m,1H),2.70–2.60(m,3H),2.48–2.35(m,2H),2.29(m,1H),1.82(d,J＝7.1Hz,3H),0.80(t,J＝6.8Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.7,169.1,167.3,163.5,158.3,148.0,134.4,132.1,128.6,127.0,124.2,71.8,57.0,40.7,40.2,37.3,31.5,31.2,19.0,16.3,ppm.HRMS(ESI)Calcdm/zforC40H51N8O10S4[(M+H)+]931.2611,found931.2612.
实施例4,化合物1-4的合成
合成方法如实施例1。
[α]20 D＝10.1(c0.20,CHCl3).1HNMR(400MHz,CDCl3)δ8.56(s,1H),8.13(s,1H),6.93(q,J＝7.0Hz,2H),6.50(d,J＝10.2Hz,1H),5.85–5.64(m,2H),5.53(dd,J＝15.6,6.8Hz,1H),5.19(dd,J＝17.6,8.2Hz,1H),4.73(dd,J＝10.2,3.8Hz,1H),4.32(dd,J＝17.7,4.1Hz,1H),2.90–2.75(m,1H),2.70–2.60(m,3H),2.48–2.35(m,2H),1.95(m,2H),1.82(d,J＝7.1Hz,3H),1.30(m,2H),0.79(t,J＝6.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,169.1,167.4,163.3,158.3,148.1,134.5,132.0,128.5,127.1,124.1,71.7,57.1,40.6,40.2,37.2,31.4,31.1,19.1,16.2,14.0ppm.HRMS(ESI)Calcdm/zforC42H55N8O10S4[(M+H)+]959.2924,found959.2926.
实施例5,化合物1-5的合成
合成方法如实施例1。
[α]23 D:15.9(c0.26,CHCl3).1HNMR(400MHz,CDCl3)δ8.58(s,1H),8.13(s,1H),6.95(q,J＝7.1Hz,2H),6.52(d,J＝10.2Hz,1H),5.85–5.64(m,2H),5.55(dd,J＝15.6,6.8Hz,1H),5.22(dd,J＝17.6,8.2Hz,1H),4.75(dd,J＝10.2,3.8Hz,1H),4.34(dd,J＝17.7,4.1Hz,1H),2.92–2.76(m,1H),2.76–2.62(m,3H),2.49–2.36(m,2H),2.31(q,J＝6.7,6.3Hz,1H),1.83(d,J＝7.1Hz,3H),0.81(d,J＝6.8Hz,3H),0.63(d,J＝6.7Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.8,169.1,167.5,163.6,158.5,148.0,134.5,132.2,128.8,127.1,124.4,72.0,57.2,40.8,40.4,37.5,31.6,31.3,19.0,16.6,14.8ppm.
实施例6,化合物1-6的合成
合成方法如实施例1。
[α]20 D:-18.0(c0.20,CHCl3).1HNMR(400MHz,CDCl3)δ8.58(s,1H),8.13(s,1H),6.95(q,J＝7.1Hz,2H),6.52(d,J＝10.2Hz,1H),5.85–5.64(m,2H),5.55(dd,J＝15.6,6.8Hz,1H),5.22(dd,J＝17.6,8.2Hz,1H),4.75(dd,J＝10.2,3.8Hz,1H),4.34(dd,J＝17.7,4.1Hz,1H),2.92–2.76(m,1H),2.76–2.62(m,3H),2.49–2.36(m,2H),2.31(d,J＝6.7Hz,3H),1.83(d,J＝7.1Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.8,169.1,167.5,163.6,158.5,148.0,134.5,132.2,128.8,127.1,124.4,72.0,57.2,40.8,40.4,37.5,31.6,31.3,19.0ppm.HRMS(ESI)Calcdm/zforC38H47N8O10S4[(M+H)+]903.2298,found903.2299.
实施例7,化合物1-7的合成
合成方法如实施例1。
[α]23 D:14.8(c0.36,CHCl3).1HNMR(400MHz,CDCl3)δ8.59(s,1H),8.15(s,1H),6.97(q,J＝7.2Hz,2H),6.53(d,J＝10.2Hz,1H),5.87–5.65(m,2H),5.56(dd,J＝15.6,6.8Hz,1H),5.23(dd,J＝17.6,8.2Hz,1H),4.76(dd,J＝10.2,3.8Hz,1H),4.36(dd,J＝17.6,4.0Hz,1H),2.93(m,1H),2.76–2.63(m,3H),2.49–2.36(m,2H),2.32(m,2H),1.85(d,J＝7.1Hz,3H),1.70(m,1H),0.79(d,J＝6.8Hz,3H),0.61(d,J＝6.7Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.9,169.2,167.6,163.7,158.5,148.0,134.6,132.2,128.9,127.1,124.6,72.1,57.3,40.9,40.5,37.5,31.7,31.5,30.1,19.2,16.3,14.6ppm.HRMS(ESI)Calcdm/zforC44H59N8O10S4[(M+H)+]987.3237,found987.3238.
实施例8,化合物1-8的合成
合成方法如实施例1。
[α]23 D:20.8(c0.38,CHCl3).1HNMR(400MHz,CDCl3)δ8.59(s,1H),8.16(s,1H),6.97(q,J＝7.2Hz,2H),6.54(d,J＝10.2Hz,1H),5.88–5.67(m,2H),5.58(dd,J＝15.6,6.8Hz,1H),5.25(dd,J＝17.6,8.2Hz,1H),4.77(dd,J＝10.2,3.8Hz,1H),4.36(dd,J＝17.7,4.1Hz,1H),2.95(m,1H),2.78–2.66(m,3H),2.52–2.38(m,2H),1.85(d,J＝7.1Hz,3H),0.92(s,9H)ppm.13CNMR(125MHz,CDCl3)δ169.9,169.4,167.6,163.6,158.8,148.3,134.3,132.2,128.9,127.1,124.6,72.2,57.3,40.9,40.5,37.8,31.7,31.6,29.6,16.0ppm.HRMS(ESI)Calcdm/zforC44H59N8O10S4[(M+H)+]987.3237,found987.3239.
实施例9,化合物1-9的合成
合成方法如实施例1。
[α]23 D:11.3(c0.50,CHCl3).1HNMR(400MHz,CDCl3)δ8.59(s,1H),8.14(s,1H),7.15-7.08(m,5H),6.96(q,J＝7.1Hz,2H),6.53(d,J＝10.2Hz,1H),5.89–5.66(m,2H),5.57(dd,J＝15.6,6.8Hz,1H),5.26(dd,J＝17.6,8.2Hz,1H),4.78(dd,J＝10.2,3.8Hz,1H),4.35(dd,J＝17.7,4.1Hz,1H),3.28-3.03(m,2H),2.93(m,1H),2.77–2.63(m,3H),2.49–2.36(m,2H),1.83(d,J＝7.1Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.8,169.2,167.8,163.7,158.6,148.1,134.6,134.3,132.3,128.9,128.7,127.2,126.0,124.6,72.1,57.3,40.9,40.6,37.6,36.2,31.5,19.2ppm.HRMS(ESI)Calcdm/zforC50H55N8O10S4[(M+H)+]1055.2924,found1055.2926.
实施例10,化合物1-10的合成
合成方法如实施例1。
[α]23 D:12.6(c1.0,CHCl3).1HNMR(400MHz,CDCl3)δ8.59(s,1H),8.15(s,1H),7.09-7.03(m,4H),6.97(q,J＝7.1Hz,2H),6.55(d,J＝10.2Hz,1H),5.89–5.67(m,2H),5.58(dd,J＝15.6,6.8Hz,1H),5.27(dd,J＝17.6,8.2Hz,1H),4.79(dd,J＝10.2,3.8Hz,1H),4.37(dd,J＝17.6,4.1Hz,1H),3.29-3.05(m,2H),2.94(m,1H),2.78–2.65(m,3H),2.49–2.36(m,2H),1.83(d,J＝7.1Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.8,169.3,167.8,163.8,158.7,153.7,148.2,134.3,132.3,131.8,129.3,128.9,127.2,126.1,124.6,116.5,72.2,57.3,40.9,40.6,37.6,36.6,31.5,19.2ppm.HRMS(ESI)Calcdm/zforC50H55N8O12S4[(M+H)+]1087.2822,found1087.2825.
实施例11,化合物1-11的合成
合成方法如实施例1。
[α]23 D:8.6(c0.20,CHCl3).1HNMR(400MHz,CDCl3)δ8.59(s,1H),8.16(s,1H),7.69-7.23(m,7H),6.98(q,J＝7.1Hz,2H),6.57(d,J＝10.2Hz,1H),5.89–5.67(m,2H),5.59(dd,J＝15.6,6.8Hz,1H),5.29(dd,J＝17.6,8.2Hz,1H),4.79(dd,J＝10.2,3.8Hz,1H),4.38(dd,J＝17.6,4.1Hz,1H),3.29-3.06(m,2H),2.94(m,1H),2.78–2.65(m,3H),2.49–2.36(m,2H),1.83(d,J＝7.1Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.8,169.2,167.9,163.8,158.7,148.1,135.3,134.6,133.5,132.7,132.3,128.9,127.2,126.9,126.5,125.8,125.6,124.6,124.3,124.2,72.1,57.3,41.2,40.8,37.6,36.7,31.6,19.2ppm.HRMS(ESI)Calcdm/zforC58H59N8O10S4[(M+H)+]1155.3237,found1155.3239.
实施例12,化合物1-12的合成
合成方法如实施例1。
[α]23 D:16.1(c0.52,CHCl3).1HNMR(400MHz,CDCl3)δ8.59(s,1H),8.15(s,1H),6.97(q,J＝7.2Hz,2H),6.55(d,J＝10.2Hz,1H),5.88–5.66(m,2H),5.56(dd,J＝15.6,6.8Hz,1H),5.25(dd,J＝17.6,8.2Hz,1H),4.77(dd,J＝10.2,3.8Hz,1H),4.36(dd,J＝17.6,4.0Hz,1H),2.93(m,1H),2.76–2.63(m,3H),2.49–2.36(m,2H),2.32-2.28(m,4H),2.05(s3H),1.85(d,J＝7.1Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.7,169.1,167.6,163.5,158.5,148.1,134.3,132.1,128.9,127.1,124.5,72.0,57.2,40.9,40.5,37.3,35.2,31.6,24.7,19.2,17.4ppm.HRMS(ESI)Calcdm/zforC43H57N8O10S6[(M+H)+]1037.2522,found1037.2525.
实施例13,化合物1-13的合成
合成方法如实施例1。
[α]23 D:16.6(c0.41,CHCl3).1HNMR(400MHz,CDCl3)δ8.59(s,1H),8.16(s,1H),6.96(q,J＝7.2Hz,2H),6.51(d,J＝10.2Hz,1H),5.86–5.63(m,2H),5.55(dd,J＝15.6,6.8Hz,1H),5.21(dd,J＝17.6,8.2Hz,1H),4.74(dd,J＝10.2,3.8Hz,1H),4.35(dd,J＝17.6,4.0Hz,1H),2.92(m,1H),2.76–2.63(m,3H),2.60(t,J＝6.8Hz,2H),2.49–2.35(m,2H),2.31(m,2H),1.86(d,J＝7.1Hz,3H),1.59(m,2H),1.29-1.36(m,4H)ppm.13CNMR(125MHz,CDCl3)δ169.9,169.1,167.5,163.7,158.6,148.0,134.8,132.1,128.9,127.3,124.6,72.2,57.3,41.8,40.8,40.3,37.6,32.9,31.7,31.5,31.2,26.6,23.5,19.2ppm.HRMS(ESI)Calcdm/zforC45H63N10O10S4[(M+H)+]1031.3611,found1031.3613.
实施例14,化合物1-14的合成
合成方法如实施例1。
[α]23 D:6.3(c0.22,CHCl3).1HNMR(400MHz,CDCl3)δ8.59(s,1H),8.16(s,1H),6.95(q,J＝7.2Hz,2H),6.53(d,J＝10.2Hz,1H),5.87–5.65(m,2H),5.55(dd,J＝15.6,6.8Hz,1H),5.22(dd,J＝17.6,8.2Hz,1H),4.75(dd,J＝10.2,3.8Hz,1H),4.33(dd,J＝17.6,4.0Hz,1H),2.93-2.90(m,2H),2.76–2.63(m,2H),2.49–2.36(m,2H),2.32(m,2H),1.83(d,J＝7.1Hz,3H),1.70(m,1H),1.02(d,J＝6.7Hz,3H),0.76(d,J＝6.8Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.9,169.1,167.6,163.6,158.5,148.0,134.5,132.2,128.9,127.0,124.6,72.0,57.3,40.9,40.5,37.6,36.1,31.4,30.1,19.5,15.3,12.6ppm.HRMS(ESI)Calcdm/zforC44H59N8O10S4[(M+H)+]987.3237,found987.3235.
实施例15,化合物1-15的合成
合成方法如实施例1。
[α]23 D:20.2(c0.31,CHCl3).1HNMR(400MHz,CDCl3)δ8.59(s,1H),8.16(s,1H),6.96(q,J＝7.2Hz,2H),6.51(d,J＝10.2Hz,1H),5.86–5.62(m,2H),5.54(dd,J＝15.6,6.8Hz,1H),5.21(dd,J＝17.6,8.2Hz,1H),4.73(dd,J＝10.2,3.8Hz,1H),4.33(dd,J＝17.6,4.0Hz,1H),2.93(m,1H),2.76–2.65(m,3H),2.63(t,J＝6.8Hz,2H),2.49–2.35(m,2H),2.31(m,2H),1.86(d,J＝7.1Hz,3H),1.59-1.30(m,4H)ppm.13CNMR(125MHz,CDCl3)δ169.9,169.1,167.3,163.7,158.5,148.0,134.7,132.0,128.9,127.3,124.5,72.1,57.3,42.0,40.7,40.2,37.5,32.6,31.7,31.5,31.0,21.1,19.2ppm.HRMS(ESI)Calcdm/zforC43H59N10O10S4[(M+H)+]1003.3298,found1003.3296.
实施例16,化合物1-16的合成
合成方法如实施例1。
[α]23 D:23.1(c0.23,CHCl3).1HNMR(400MHz,CDCl3)δ8.59(s,1H),8.18(s,1H),6.98(q,J＝7.2Hz,2H),6.52(d,J＝10.2Hz,1H),5.87–5.63(m,2H),5.55(dd,J＝15.6,6.8Hz,1H),5.23(dd,J＝17.6,8.2Hz,1H),4.74(dd,J＝10.2,3.8Hz,1H),4.35(dd,J＝17.6,4.0Hz,1H),2.95(m,1H),2.77–2.67(m,3H),2.64(t,J＝6.8Hz,2H),2.49–2.37(m,2H),2.32(m,2H),2.12(m,2H),1.85(d,J＝7.1Hz,3H),ppm.13CNMR(125MHz,CDCl3)δ169.9,169.0,167.2,163.7,158.5,148.1,134.6,132.0,128.8,127.4,124.6,72.0,57.2,42.1,40.7,40.1,36.2,32.6,31.6,30.8,21.1,19.2ppm.HRMS(ESI)Calcdm/zforC40H53N10O10S4[(M+H)+]961.2829,found961.2827.
实施例17,化合物2-1的合成
合成方法如实施例1。
[α]20 D＝17.2(c0.37,CHCl3).1HNMR(400MHz,CDCl3)δ8.58(s,1H),8.13(s,1H),6.97(q,J＝7.6Hz,2H),6.52(d,J＝10.2Hz,1H),5.86–5.66(m,2H),5.56(dd,J＝15.6,6.8Hz,1H),5.23(dd,J＝17.6,8.2Hz,1H),4.76(dd,J＝10.2,4.0Hz,1H),4.34(dd,J＝17.6,4.0Hz,1H),2.92–2.76(m,1H),2.76–2.62(m,3H),2.49–2.36(m,2H),2.31(d,J＝6.7Hz,3H),1.86(d,J＝7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.8,169.1,167.8,163.9,158.6,148.0,134.5,132.2,128.8,127.1,124.4,72.0,57.2,40.8,40.4,37.5,31.6,31.3,19.5ppm.HRMS(ESI)Calcdm/zforC38H47N8O10S4[(M+H)+]903.2298,found903.2296.
实施例18,化合物2-2的合成
合成方法如实施例1。
[α]23 D:18.9(c0.38,CHCl3).1HNMR(400MHz,CDCl3)δ8.58(s,1H),8.13(s,1H),6.98(q,J＝7.2Hz,2H),6.53(d,J＝10.2Hz,1H),5.85–5.66(m,2H),5.55(dd,J＝15.6,6.8Hz,1H),5.24(dd,J＝17.6,8.2Hz,1H),4.77(dd,J＝10.2,3.8Hz,1H),4.35(dd,J＝17.7,4.1Hz,1H),2.93–2.78(m,1H),2.75–2.62(m,3H),2.49–2.36(m,2H),2.33(q,J＝6.7,6.3Hz,1H),1.85(d,J＝7.2Hz,3H),0.82(d,J＝6.8Hz,3H),0.65(d,J＝6.7Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.8,169.1,167.6,163.6,158.6,148.1,134.5,132.2,128.9,127.1,124.4,72.1,57.2,40.8,40.5,37.5,31.7,31.3,19.6,16.6,14.8ppm.HRMS(ESI)Calcdm/zforC42H55N8O10S4[(M+H)+]959.2924,found959.2927.
实施例19,化合物2-3的合成
合成方法如实施例1。
[α]20 D＝12.3(c0.41,CHCl3).1HNMR(400MHz,CDCl3)δ8.58(s,1H),8.15(s,1H),6.97(t,J＝6.8Hz,2H),6.53(d,J＝10.2Hz,1H),5.86–5.66(m,2H),5.55(dd,J＝15.6,6.8Hz,1H),5.22(dd,J＝17.6,8.2Hz,1H),4.76(dd,J＝10.2,3.8Hz,1H),4.35(dd,J＝17.7,4.1Hz,1H),2.92–2.76(m,1H),2.76–2.62(m,3H),2.49–2.36(m,2H),2.32(d,J＝6.6Hz,3H),1.88(m,2H),1.01(t,J＝5.8Hz,3H)ppm.13CNMR(100MHz,CDCl3)δ169.8,169.1,167.6,163.6,158.5,148.1,134.8,132.2,128.8,127.1,124.3,72.2,57.2,40.8,40.2,37.6,31.8,31.3,19.2,14.9ppm.HRMS(ESI)Calcdm/zforC40H51N8O10S4[(M+H)+]931.2611,found931.2613.
实施例20,化合物2-4的合成
合成方法如实施例1。
[α]23 D:12.9(c0.33,CHCl3).1HNMR(400MHz,CDCl3)δ8.58(s,1H),8.13(s,1H),6.95(t,J＝7.2Hz,2H),6.53(d,J＝10.2Hz,1H),5.88–5.67(m,2H),5.57(dd,J＝15.6,6.8Hz,1H),5.22(dd,J＝17.6,8.2Hz,1H),4.75(dd,J＝10.2,3.8Hz,1H),4.35(dd,J＝17.6,4.0Hz,1H),2.92–2.76(m,1H),2.76–2.62(m,3H),2.49–2.36(m,2H),2.32(q,J＝6.7,6.3Hz,1H),1.89(m,2H),1.00(t,J＝5.6Hz,3H),0.81(d,J＝6.8Hz,3H),0.63(d,J＝6.7Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.8,169.2,167.6,163.6,158.3,148.0,134.5,132.5,128.8,127.1,124.5,72.0,57.3,40.8,40.5,37.5,31.7,31.2,19.5,16.5,15.0,14.8ppm.HRMS(ESI)Calcdm/zforC44H59N8O10S4[(M+H)+]987.3237,found987.3239.
实施例21,化合物2-5的合成
合成方法如实施例1。
[α]20 D＝13.7(c0.35,CHCl3).1HNMR(400MHz,CDCl3)δ8.58(s,1H),8.15(s,1H),6.98(d,J＝6.8Hz,2H),6.53(d,J＝10.2Hz,1H),5.87–5.65(m,2H),5.56(dd,J＝15.6,6.8Hz,1H),5.23(dd,J＝17.6,8.2Hz,1H),4.76(dd,J＝10.2,3.8Hz,1H),4.37(dd,J＝17.7,4.1Hz,1H),2.93–2.77(m,1H),2.75–2.62(m,3H),2.49–2.36(m,2H),2.33(d,J＝6.6Hz,3H),1.98(m,1H),1.05(t,J＝5.8Hz,6H)ppm.HRMS(ESI)Calcdm/zforC42H55N8O10S4[(M+H)+]959.2924,found959.2927.
实施例22,化合物2-6的合成
合成方法如实施例1。
[α]23 D:12.9(c0.33,CHCl3).1HNMR(400MHz,CDCl3)δ8.58(s,1H),8.15(s,1H),6.98(d,J＝7.2Hz,2H),6.53(d,J＝10.2Hz,1H),5.89–5.67(m,2H),5.58(dd,J＝15.6,6.8Hz,1H),5.25(dd,J＝17.6,8.2Hz,1H),4.75(dd,J＝10.2,3.8Hz,1H),4.36(dd,J＝17.6,4.0Hz,1H),2.95–2.77(m,1H),2.75–2.62(m,3H),2.49–2.36(m,2H),2.33(q,J＝6.7,6.3Hz,1H),1.98(m,1H),1.05(t,J＝5.8Hz,6H),0.82(d,J＝6.8Hz,3H),0.65(d,J＝6.7Hz,3H)ppm.HRMS(ESI)Calcdm/zforC46H63N8O10S4[(M+H)+]1015.3550,found1015.3551.
实施例23,化合物2-7的合成
合成方法如实施例1。
[α]20 D＝16.1(c0.39,CHCl3).1HNMR(400MHz,CDCl3)δ8.58(s,1H),8.13(s,1H),6.98(q,J＝7.6Hz,2H),6.56(s,2H),5.86–5.66(m,2H),5.58(dd,J＝15.6,6.8Hz,1H),5.26(dd,J＝17.6,8.2Hz,1H),4.78(dd,J＝10.2,4.0Hz,1H),4.36(dd,J＝17.6,4.0Hz,1H),2.96–2.78(m,1H),2.75–2.62(m,3H),2.49–2.36(m,2H),2.32(d,J＝6.7Hz,3H)ppm.HRMS(ESI)Calcdm/zforC36H43N8O10S4[(M+H)+]875.1985,found875.1987.
实施例24,化合物2-8的合成
合成方法如实施例1。
[α]23 D:15.1(c0.42,CHCl3).1HNMR(400MHz,CDCl3)δ8.58(s,1H),8.13(s,1H),6.99(q,J＝7.2Hz,2H),6.57(s,2H),5.85–5.66(m,2H),5.55(dd,J＝15.6,6.8Hz,1H),5.26(dd,J＝17.6,8.2Hz,1H),4.78(dd,J＝10.2,3.8Hz,1H),4.36(dd,J＝17.7,4.1Hz,1H),2.96–2.79(m,1H),2.75–2.63(m,3H),2.49–2.37(m,2H),2.33(q,J＝6.7,6.3Hz,1H),0.83(d,J＝6.8Hz,3H),0.66(d,J＝6.7Hz,3H)ppm.HRMS(ESI)Calcdm/zforC40H51N8O10S4[(M+H)+]931.2611,found931.2612.
实施例25,化合物2-9的合成
合成方法如实施例1。
[α]20 D＝17.2(c0.36,CHCl3).1HNMR(400MHz,CDCl3)δ8.58(s,1H),8.13(s,1H),6.96(q,J＝7.6Hz,2H),5.86–5.67(m,2H),5.57(dd,J＝15.6,6.8Hz,1H),5.27(dd,J＝17.6,8.2Hz,1H),4.77(dd,J＝10.2,4.0Hz,1H),4.35(dd,J＝17.6,4.0Hz,1H),2.97–2.77(m,1H),2.74–2.63(m,3H),2.49–2.37(m,2H),2.32(d,J＝6.7Hz,3H),1.99(s,3H),1.95(s,3H)ppm.HRMS(ESI)Calcdm/zforC40H51N8O10S4[(M+H)+]931.2611,found931.2613.
实施例26,化合物2-10的合成
合成方法如实施例1。
[α]23 D:15.9(c0.33,CHCl3).1HNMR(400MHz,CDCl3)δ8.58(s,1H),8.15(s,1H),6.98(q,J＝7.2Hz,2H),5.85–5.66(m,2H),5.56(dd,J＝15.6,6.8Hz,1H),5.27(dd,J＝17.6,8.2Hz,1H),4.77(dd,J＝10.2,3.8Hz,1H),4.36(dd,J＝17.7,4.1Hz,1H),2.97–2.79(m,1H),2.75–2.64(m,3H),2.49–2.38(m,2H),2.33(d,J＝6.6Hz,1H),1.99(s,3H),1.95(s,3H),0.83(d,J＝6.8Hz,3H),0.66(d,J＝6.7Hz,3H)ppm.HRMS(ESI)Calcdm/zforC44H59N8O10S4[(M+H)+]987.3237,found987.3239.
实施例27,化合物2-11的合成
合成方法如实施例1。
[α]20 D＝22.1(c0.58,CHCl3).1HNMR(400MHz,CDCl3)δ8.59(s,1H),8.16(s,1H),6.98(q,J＝7.6Hz,2H),5.86–5.66(m,2H),5.57(dd,J＝15.6,6.8Hz,1H),5.28(dd,J＝17.6,8.2Hz,1H),4.79(dd,J＝10.2,4.0Hz,1H),4.37(dd,J＝17.6,4.0Hz,1H),2.99–2.79(m,1H),2.75–2.65(m,3H),2.49–2.38(m,2H),2.33(d,J＝6.7Hz,3H),1.96(m,4H),1.38(m,4H),1.28(m,2H)ppm.HRMS(ESI)Calcdm/zforC46H59N8O10S4[(M+H)+]1011.3237,found1011.3239.
实施例28,化合物2-12的合成
合成方法如实施例1。
[α]23 D:17.2(c0.30,CHCl3).1HNMR(400MHz,CDCl3)δ8.59(s,1H),8.13(s,1H),6.99(q,J＝7.2Hz,2H),5.88–5.66(m,2H),5.56(dd,J＝15.6,6.8Hz,1H),5.29(dd,J＝17.6,8.2Hz,1H),4.78(dd,J＝10.2,3.8Hz,1H),4.39(dd,J＝17.7,4.1Hz,1H),2.97–2.79(m,1H),2.75–2.65(m,3H),2.49–2.38(m,2H),2.32(d,J＝6.6Hz,1H),1.97(m,4H),1.39(m,4H),0.83(d,J＝6.8Hz,3H),0.66(d,J＝6.7Hz,3H)ppm.HRMS(ESI)Calcdm/zforC48H63N8O10S4[(M+H)+]1039.3550,found1039.3552.
实施例29,化合物2-13的合成
合成方法如实施例1。
[α]20 D＝16.3(c0.26,CHCl3).1HNMR(400MHz,CDCl3)δ8.57(s,1H),8.15(s,1H),6.97(q,J＝7.6Hz,2H),5.88–5.68(m,2H),5.58(dd,J＝15.6,6.8Hz,1H),5.29(dd,J＝17.6,8.2Hz,1H),4.79(dd,J＝10.2,4.0Hz,1H),4.38(dd,J＝17.6,4.0Hz,1H),2.99–2.79(m,1H),2.75–2.66(m,3H),2.49–2.38(m,2H),2.32(d,J＝6.7Hz,3H),1.99(t,J＝7.2Hz,4H),1.08(t,J＝7.2Hz,,4H)ppm.HRMS(ESI)Calcdm/zforC44H59N8O10S4[(M+H)+]987.3237,found987.3236.
实施例30,化合物2-14的合成
合成方法如实施例1。
[α]23 D:12.6(c0.13,CHCl3).1HNMR(400MHz,CDCl3)δ8.58(s,1H),8.15(s,1H),6.98(t,J＝7.2Hz,2H),6.56(d,J＝10.2Hz,1H),5.89–5.67(m,2H),5.58(dd,J＝15.6,6.8Hz,1H),5.23(dd,J＝17.6,8.2Hz,1H),4.76(dd,J＝10.2,3.8Hz,1H),4.37(dd,J＝17.6,4.0Hz,1H),3.57(d,J＝6.6Hz,3H),2.95–2.78(m,1H),2.75–2.63(m,3H),2.49–2.38(m,2H),2.32(q,J＝6.7,6.3Hz,1H),2.15(m,2H),0.81(d,J＝6.8Hz,3H),0.63(d,J＝6.7Hz,3H)ppm.HRMS(ESI)Calcdm/zforC44H59N8O12S4[(M+H)+]1019.3135,found1019.3137.
实施例31,化合物3-1的合成
合成方法如实施例1。
[α]20 D＝19.8(c0.28,CHCl3).1HNMR(400MHz,CDCl3)δ8.59(s,1H),8.14(s,1H),6.98(q,J＝7.0Hz,2H),6.52(d,J＝10.2Hz,1H),5.76(m,1H),5.57(dd,J＝15.6,6.8Hz,1H),5.26(dd,J＝17.6,8.2Hz,1H),4.77(dd,J＝10.2,3.8Hz,1H),4.36(dd,J＝17.7,4.1Hz,1H),2.95–2.77(m,1H),2.75–2.63(m,3H),2.49–2.39(m,2H),2.36(s,3H),2.33(d,J＝6.7Hz,3H),1.85(d,J＝7.1Hz,3H)ppm.HRMS(ESI)Calcdm/zforC40H51N8O10S4[(M+H)+]931.2611,found931.2613.
实施例32,化合物3-2的合成
合成方法如实施例1。
[α]23 D:18.8(c0.35,CHCl3).1HNMR(400MHz,CDCl3)δ8.58(s,1H),8.13(s,1H),6.97(q,J＝7.1Hz,2H),6.52(d,J＝10.2Hz,1H),5.80(m,1H),5.56(dd,J＝15.6,6.8Hz,1H),5.26(dd,J＝17.6,8.2Hz,1H),4.77(dd,J＝10.2,3.8Hz,1H),4.36(dd,J＝17.7,4.1Hz,1H),2.95–2.78(m,1H),2.76–2.66(m,3H),2.49–2.38(m,2H),2.35(s,3H),2.31(q,J＝6.7,6.3Hz,1H),1.85(d,J＝7.1Hz,3H),0.82(d,J＝6.8Hz,3H),0.65(d,J＝6.7Hz,3H)ppm.HRMS(ESI)Calcdm/zforC44H59N8O10S4[(M+H)+]987.3237,found987.3238.
实施例33,化合物3-3的合成
合成方法如实施例1。
[α]20 D＝13.2(c0.41,CHCl3).1HNMR(400MHz,CDCl3)δ8.55(s,1H),8.10(s,1H),6.93(q,J＝6.8Hz,2H),6.50(d,J＝10.2Hz,1H),5.82–5.60(m,2H),5.52(dd,J＝15.6,6.8Hz,1H),5.20(dd,J＝17.6,8.2Hz,1H),4.72(dd,J＝10.2,3.8Hz,1H),4.30(dd,J＝17.7,4.1Hz,1H),2.92–2.76(m,1H),2.70–2.61(m,3H),2.45–2.33(m,2H),2.30(d,J＝6.7Hz,3H),1.80(d,J＝7.1Hz,3H)ppm.HRMS(ESI)Calcdm/zforC38H47N8O12S2[(M+H)+]871.2755,found871.2756.
实施例34,化合物3-4的合成
合成方法如实施例1。
[α]23 D:10.1(c0.31,CHCl3).1HNMR(400MHz,CDCl3)δ8.56(s,1H),8.11(s,1H),6.93(q,J＝7.0Hz,2H),6.50(d,J＝10.2Hz,1H),5.82–5.62(m,2H),5.53(dd,J＝15.6,6.8Hz,1H),5.20(dd,J＝17.6,8.2Hz,1H),4.72(dd,J＝10.2,4.0Hz,1H),4.31(dd,J＝17.6,4.0Hz,1H),2.91–2.76(m,1H),2.72–2.60(m,3H),2.49–2.33(m,2H),2.31(q,J＝6.7,6.3Hz,1H),1.82(d,J＝7.0Hz,3H),0.80(d,J＝6.8Hz,3H),0.62(d,J＝6.7Hz,3H)ppm.HRMS(ESI)Calcdm/zforC42H55N8O12S2[(M+H)+]927.3381,found927.3382.
实施例35,化合物3-5的合成
合成方法如实施例1。
[α]20 D＝15.3(c0.22,CHCl3).1HNMR(400MHz,CDCl3)δ8.56(s,1H),8.12(s,1H),6.96(q,J＝7.2Hz,2H),6.51(d,J＝10.6Hz,1H),5.76(m,1H),5.53(dd,J＝15.2,6.6Hz,1H),5.23(dd,J＝17.2,8.2Hz,1H),4.75(dd,J＝10.6,4.0Hz,1H),4.33(dd,J＝17.2,4.2Hz,1H),2.95–2.76(m,1H),2.74–2.65(m,3H),2.48–2.39(m,2H),2.35(s,3H),2.32(d,J＝6.7Hz,3H),1.83(d,J＝7.1Hz,3H)ppm.HRMS(ESI)Calcdm/zforC40H51N8O12S2[(M+H)+]899.3068,found899.3069.
实施例36,化合物3-6的合成
合成方法如实施例1。
[α]23 D:16.1(c0.51,CHCl3).1HNMR(400MHz,CDCl3)δ8.56(s,1H),8.12(s,1H),6.93(q,J＝7.0Hz,2H),6.51(d,J＝10.0Hz,1H),5.80(m,1H),5.55(dd,J＝15.4,6.8Hz,1H),5.26(dd,J＝17.2,8.2Hz,1H),4.77(dd,J＝10.0,3.8Hz,1H),4.35(dd,J＝17.2,4.0Hz,1H),2.94–2.77(m,1H),2.75–2.65(m,3H),2.49–2.38(m,2H),2.34(s,3H),2.30(q,J＝6.6,6.2Hz,1H),1.84(d,J＝7.0Hz,3H),0.82(d,J＝6.8Hz,3H),0.65(d,J＝6.8Hz,3H)ppm.HRMS(ESI)Calcdm/zforC44H59N8O12S2[(M+H)+]955.3694,found955.3696.
实施例37,化合物3-7的合成
合成方法如实施例1。
[α]20 D＝10.1(c0.21,CHCl3).1HNMR(400MHz,CDCl3)δ8.52(s,1H),8.10(s,1H),6.94(q,J＝7.0Hz,2H),6.50(d,J＝10.2Hz,1H),5.73(m,1H),5.50(dd,J＝15.2,6.6Hz,1H),5.23(dd,J＝17.2,8.0Hz,1H),4.75(dd,J＝10.2,4.0Hz,1H),4.31(dd,J＝17.2,4.0Hz,1H),3.60(m,1H),2.95–2.76(m,1H),2.73–2.63(m,3H),2.48–2.38(m,2H),2.35(s,3H),2.31(d,J＝6.7Hz,3H),1.21(m,3H)ppm.HRMS(ESI)Calcdm/zforC40H55N8O12S2[(M+H)+]903.3381,found903.3382.
实施例38,化合物3-8的合成
合成方法如实施例1。
[α]23 D:10.8(c0.11,CHCl3).1HNMR(400MHz,CDCl3)δ8.55(s,1H),8.10(s,1H),6.92(q,J＝7.2Hz,2H),6.50(d,J＝10.2Hz,1H),5.80(m,1H),5.53(dd,J＝15.6,6.6Hz,1H),5.25(dd,J＝17.4,8.0Hz,1H),4.77(dd,J＝10.2,3.8Hz,1H),4.35(dd,J＝17.4,4.0Hz,1H),3.55(m,1H),2.94–2.76(m,1H),2.73–2.65(m,3H),2.49–2.38(m,2H),2.33(s,3H),2.30(q,J＝6.6,6.2Hz,1H),1.22(m,3H),0.81(d,J＝6.8Hz,3H),0.63(d,J＝6.8Hz,3H)ppm.HRMS(ESI)Calcdm/zforC44H63N8O12S2[(M+H)+]959.4007,found959.4009.
实施例39,化合物3-9的合成
合成方法如实施例1。
[α]20 D＝16.3(c0.21,CHCl3).1HNMR(400MHz,CDCl3)δ12.3(s,1H),8.59(s,1H),8.18(s,1H),6.96(q,J＝7.6Hz,2H),6.55(d,J＝10.2Hz,1H),5.89–5.69(m,2H),5.58(dd,J＝15.8,6.8Hz,1H),5.26(dd,J＝17.8,8.2Hz,1H),4.78(dd,J＝10.2,4.2Hz,1H),4.34(dd,J＝17.8,4.2Hz,1H),2.98–2.78(m,1H),2.76–2.65(m,3H),2.49–2.38(m,2H),2.33(d,J＝6.7Hz,3H),1.85(d,J＝7.1Hz,3H)ppm.HRMS(ESI)Calcdm/zforC38H49N10O10S2[(M+H)+]869.3075,found869.3077.
实施例40,化合物3-10的合成
合成方法如实施例1。
[α]23 D:13.6(c0.11,CHCl3).1HNMR(400MHz,CDCl3)δ13.5(s,1H),8.59(s,1H),8.18(s,1H),6.98(q,J＝7.2Hz,2H),6.57(d,J＝10.2Hz,1H),5.89–5.68(m,2H),5.59(dd,J＝15.6,6.8Hz,1H),5.28(dd,J＝17.6,8.2Hz,1H),4.78(dd,J＝10.2,4.2Hz,1H),4.38(dd,J＝17.6,4.2Hz,1H),2.96–2.76(m,1H),2.75–2.65(m,3H),2.49–2.38(m,2H),2.33(q,J＝6.7,6.3Hz,1H),1.85(d,J＝7.1Hz,3H),0.83(d,J＝6.8Hz,3H),0.66(d,J＝6.7Hz,3H)ppm.HRMS(ESI)Calcdm/zforC42H57N10O10S2[(M+H)+]925.3701,found925.3703.
实施例41,化合物3-11的合成
合成方法如实施例1。
[α]20 D＝15.1(c0.18,CHCl3).1HNMR(400MHz,CDCl3)δ8.57(s,1H),8.15(s,1H),6.95(q,J＝7.4Hz,2H),6.83(d,J＝6.0Hz,1H),6.53(d,J＝10.2Hz,1H),5.99(d,J＝6.0Hz,1H),5.88–5.67(m,2H),5.56(dd,J＝15.6,6.6Hz,1H),5.23(dd,J＝17.6,8.0Hz,1H),4.76(dd,J＝10.2,4.0Hz,1H),4.34(dd,J＝17.6,4.0Hz,1H),2.97–2.77(m,1H),2.75–2.65(m,3H),2.49–2.38(m,2H),2.32(d,J＝6.7Hz,3H),1.84(d,J＝7.1Hz,3H)ppm.HRMS(ESI)Calcdm/zforC40H51N8O10S2[(M+H)+]867.3170,found867.3169.
实施例42,化合物3-12的合成
合成方法如实施例1。
[α]23 D＝12.1(c0.16,CHCl3).1HNMR(400MHz,CDCl3)δ8.59(s,1H),8.16(s,1H),6.97(q,J＝7.0Hz,2H),6.83(d,J＝6.0Hz,1H),6.56(d,J＝10.2Hz,1H),5.99(d,J＝6.0Hz,1H),5.89–5.68(m,2H),5.57(dd,J＝15.6,6.8Hz,1H),5.26(dd,J＝17.2,8.2Hz,1H),4.77(dd,J＝10.0,4.2Hz,1H),4.38(dd,J＝17.2,4.2Hz,1H),2.96–2.77(m,1H),2.75–2.65(m,3H),2.49–2.39(m,2H),2.35(q,J＝6.7,6.3Hz,1H),1.86(d,J＝7.1Hz,3H),0.83(d,J＝6.6Hz,3H),0.66(d,J＝6.6Hz,3H)ppm.HRMS(ESI)Calcdm/zforC44H59N8O10S2[(M+H)+]923.3796,found923.3793.
实施例43,化合物3-13的合成
合成方法如实施例1。
[α]20 D＝13.2(c0.43,CHCl3).1HNMR(400MHz,CDCl3)δ8.59(s,1H),8.15(s,1H),7.76(s,1H),7.32-7.39(m,3H),6.97(q,J＝7.0Hz,2H),6.53(d,J＝10.2Hz,1H),5.87–5.65(m,2H),5.57(dd,J＝15.6,6.8Hz,1H),5.25(dd,J＝17.2,8.0Hz,1H),4.77(dd,J＝10.2,4.0Hz,1H),4.36(dd,J＝17.2,4.1Hz,1H),2.95–2.77(m,1H),2.76–2.63(m,3H),2.49–2.37(m,2H),2.32(d,J＝6.6Hz,3H),1.83(d,J＝6.6Hz,3H)ppm.HRMS(ESI)Calcdm/zforC44H53N6O10S2[(M+H)+]889.3265,found889.3267.
实施例44,化合物3-14的合成
合成方法如实施例1。
[α]23 D:12.6(c0.36,CHCl3).1HNMR(400MHz,CDCl3)δ8.57(s,1H),8.15(s,1H),7.75(s,1H),7.33-7.39(m,3H),6.96(q,J＝7.4Hz,2H),6.53(d,J＝10.2Hz,1H),5.87–5.65(m,2H),5.57(dd,J＝15.6,6.8Hz,1H),5.25(dd,J＝17.2,8.0Hz,1H),4.75(dd,J＝10.2,4.0Hz,1H),4.34(dd,J＝17.2,4.0Hz,1H),2.95–2.78(m,1H),2.76–2.63(m,3H),2.49–2.37(m,2H),2.32(q,J＝6.8,6.3Hz,1H),1.83(d,J＝7.4Hz,3H),0.83(d,J＝6.8Hz,3H),0.62(d,J＝6.8Hz,3H)ppm.HRMS(ESI)Calcdm/zforC48H61N6O10S2[(M+H)+]945.3891,found945.3893.
实施例45,化合物3-15的合成
合成方法如实施例1。[α]20 D＝15.3(c0.30,CHCl3).1HNMR(400MHz,CDCl3)δ8.59(s,1H),8.13(s,1H),8.01-8.08(m,3H),6.96(q,J＝7.2Hz,2H),6.53(d,J＝10.2Hz,1H),5.87–5.65(m,2H),5.57(dd,J＝15.4,6.6Hz,1H),5.24(dd,J＝17.6,8.0Hz,1H),4.76(dd,J＝10.2,3.8Hz,1H),4.35(dd,J＝17.6,4.0Hz,1H),2.93–2.77(m,1H),2.75–2.63(m,3H),2.49–2.38(m,2H),2.32(d,J＝6.6Hz,3H),1.83(d,J＝7.2Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.8,169.1,167.5,163.6,158.5,148.0,134.5,132.2,128.8,127.1,124.4,72.0,57.2,40.8,40.4,37.5,31.6,31.3,19.0ppm.HRMS(ESI)Calcdm/zforC42H51N8O10S2[(M+H)+]891.3170,found891.3172.
实施例46,化合物3-16的合成
合成方法如实施例1。
[α]23 D:15.8(c0.26,CHCl3).1HNMR(400MHz,CDCl3)δ8.57(s,1H),8.15(s,1H),8.03-8.10(m,3H),6.96(q,J＝7.1Hz,2H),6.55(d,J＝10.2Hz,1H),5.85–5.65(m,2H),5.56(dd,J＝15.6,6.8Hz,1H),5.22(dd,J＝17.2,8.2Hz,1H),4.76(dd,J＝10.2,4.1Hz,1H),4.36(dd,J＝17.2,4.1Hz,1H),2.93–2.78(m,1H),2.75–2.63(m,3H),2.49–2.36(m,2H),2.31(q,J＝6.7,6.3Hz,1H),1.84(d,J＝7.1Hz,3H),0.82(d,J＝6.8Hz,3H),0.63(d,J＝6.7Hz,3H)ppm.HRMS(ESI)Calcdm/zforC46H59N8O10S2[(M+H)+]947.3796,found947.3797.
实施例47,化合物3-17的合成
合成方法如实施例1。
[α]23 D:12.6(c0.21,CHCl3).1HNMR(400MHz,CDCl3)δ8.59(s,1H),8.16(s,1H),8.06(s,1H),7.73(s,1H),6.99(q,J＝7.1Hz,2H),6.57(d,J＝10.2Hz,1H),5.89–5.69(m,2H),5.58(dd,J＝15.6,6.8Hz,1H),5.25(dd,J＝17.2,8.2Hz,1H),4.78(dd,J＝10.2,4.1Hz,1H),4.39(dd,J＝17.2,4.1Hz,1H),2.99–2.79(m,1H),2.75–2.65(m,3H),2.49–2.37(m,2H),2.32(q,J＝6.7,6.3Hz,1H),1.86(d,J＝7.1Hz,3H),0.83(d,J＝6.8Hz,3H),0.65(d,J＝6.7Hz,3H)ppm.HRMS(ESI)Calcdm/zforC46H57F2N8O10S2[(M+H)+]983.3607,found983.3606.
实施例48,化合物3-18的合成
合成方法如实施例1。
[α]23 D:20.3(c0.18,CHCl3).1HNMR(400MHz,CDCl3)δ8.63(s,1H),8.26(s,1H),8.19(s,1H),8.02(s,1H),6.99(q,J＝7.1Hz,2H),6.58(d,J＝10.2Hz,1H),5.89–5.69(m,2H),5.59(dd,J＝15.6,6.8Hz,1H),5.28(dd,J＝17.2,8.2Hz,1H),4.79(dd,J＝10.2,4.1Hz,1H),4.39(dd,J＝17.2,4.1Hz,1H),2.99–2.79(m,1H),2.79–2.69(m,3H),2.49–2.36(m,2H),2.36(q,J＝6.7,6.3Hz,1H),1.88(d,J＝7.1Hz,3H),0.86(d,J＝6.8Hz,3H),0.67(d,J＝6.7Hz,3H)ppm.HRMS(ESI)Calcdm/zforC48H57F6N8O10S2[(M+H)+]1083.3543,found1083.3546.
实施例49,化合物3-19的合成
合成方法如实施例1。
[α]23 D:13.1(c0.17,CHCl3).1HNMR(400MHz,CDCl3)δ8.59(s,1H),8.21(d,J＝7.8Hz,1H),8.16(s,1H),7.61(d,J＝7.8Hz,1H),6.98(q,J＝7.1Hz,2H),6.58(d,J＝10.2Hz,1H),5.89–5.65(m,2H),5.58(dd,J＝15.6,6.8Hz,1H),5.25(dd,J＝17.2,8.2Hz,1H),4.79(dd,J＝10.2,4.1Hz,1H),4.39(dd,J＝17.2,4.1Hz,1H),2.99–2.79(m,1H),2.75–2.64(m,3H),2.49–2.39(m,2H),2.31(q,J＝6.7,6.3Hz,1H),1.83(d,J＝7.1Hz,3H),0.86(d,J＝6.8Hz,3H),0.66(d,J＝6.7Hz,3H)ppm.HRMS(ESI)Calcdm/zforC44H57N10O10S2[(M+H)+]949.3701,found949.3705.
实施例50,化合物3-20的合成
合成方法如实施例1。
[α]23 D:16.1(c0.22,CHCl3).1HNMR(400MHz,CDCl3)δ8.81(d,J＝8.2Hz,1H),8.59(s,1H),8.19(s,1H),8.06(d,J＝8.2Hz,1H),6.99(q,J＝7.1Hz,2H),6.57(d,J＝10.2Hz,1H),5.88–5.65(m,2H),5.58(dd,J＝15.6,6.8Hz,1H),5.27(dd,J＝17.2,8.2Hz,1H),4.79(dd,J＝10.2,4.1Hz,1H),4.39(dd,J＝17.2,4.1Hz,1H),2.99–2.79(m,1H),2.75–2.64(m,3H),2.49–2.39(m,2H),2.32(q,J＝6.7,6.3Hz,1H),1.85(d,J＝7.1Hz,3H),0.87(d,J＝6.8Hz,3H),0.67(d,J＝6.7Hz,3H)ppm.HRMS(ESI)Calcdm/zforC44H57N10O10S2[(M+H)+]949.3701,found949.3700.
实施例51,化合物4-1的合成
合成方法如实施例1。
[α]23 D:7.3(c0.31,CHCl3).1HNMR(400MHz,CDCl3):δ8.48(s,1H),8.19(s,1H),7.07(q,J＝7.2Hz,1H),6.37(d,J＝10.0Hz,1H),5.98(d,J＝9.2Hz,1H),5.83-5.69(m,2H),5.55(dd,J＝15.6,6.8Hz,1H),4.80(dd,J＝10.2,3.6Hz,1H),4.78(dd,J＝10.2,3.6Hz,1H),2.77(s,1H),2.77(d,J＝2.6Hz,1H),2.57(q,J＝7.2Hz,2H),2.38-2.28(m,5H),1.91(d,J＝7.2Hz,3H),1.83(d,J＝6.8Hz,3H),0.83(d,J＝6.8Hz,3H),0.62(d,J＝6.8Hz,3H)ppm.HRMS(ESI)Calcdm/zforC44H59N8O10S4[(M+H)+]987.3237,found987.3236.
实施例52,化合物4-2的合成
合成方法如实施例1。
[α]23 D:15.6(c0.28,CHCl3).1HNMR(400MHz,CDCl3):δ8.47(s,1H),8.17(s,1H),7.06(q,J＝7.2Hz,1H),6.36(d,J＝10.0Hz,1H),5.97(d,J＝9.2Hz,1H),5.82-5.69(m,2H),5.55(dd,J＝15.6,6.8Hz,1H),4.80(dd,J＝10.2,3.6Hz,1H),4.78(dd,J＝10.2,3.6Hz,1H),2.77(s,1H),2.77(d,J＝2.6Hz,1H),2.57(q,J＝7.2Hz,2H),2.38-2.28(m,5H),1.90(d,J＝7.2Hz,3H),1.81(d,J＝6.8Hz,3H),0.81(d,J＝6.8Hz,3H),0.60(d,J＝6.8Hz,3H)ppm.HRMS(ESI)Calcdm/zforC44H59N8O10S4[(M+H)+]987.3237,found987.3239.
实施例53,化合物4-3的合成
合成方法如实施例1。
[α]23 D:-3.9(c0.32,CHCl3).1HNMR(400MHz,CDCl3):δ8.49(s,1H),8.20(s,1H),7.09(q,J＝7.2Hz,1H),6.37(d,J＝10.0Hz,1H),5.99(d,J＝9.2Hz,1H),5.83-5.69(m,2H),5.57(dd,J＝15.6,6.8Hz,1H),4.79(dd,J＝10.4,3.6Hz,1H),4.81(dd,J＝10.4,3.6Hz,1H),2.79(s,1H),2.76(d,J＝2.4Hz,1H),2.58(q,J＝7.2Hz,2H),2.38-2.28(m,5H),1.93(d,J＝7.2Hz,3H),1.38(t,J＝8.0Hz,1H),1.12(d,J＝6.8Hz,3H),0.93(d,J＝6.8Hz,3H),0.80(d,J＝6.8Hz,3H),0.55(d,J＝6.8Hz,3H)ppm.HRMS(ESI)Calcdm/zforC48H67N8O10S4[(M+H)+]1043.3863,found1043.3862.
实施例54,化合物4-4的合成
合成方法如实施例1。
[α]23 D:19.9(c0.25,CHCl3).1HNMR(400MHz,CDCl3):δ8.49(s,1H),8.20(s,1H),7.09(q,J＝7.2Hz,1H),6.37(d,J＝10.0Hz,1H),5.99(d,J＝9.2Hz,1H),5.83-5.69(m,2H),5.56(dd,J＝15.6,6.8Hz,1H),4.79(dd,J＝10.4,3.6Hz,1H),4.80(dd,J＝10.4,3.6Hz,1H),2.77(s,1H),2.75(d,J＝2.4Hz,1H),2.57(q,J＝7.2Hz,2H),2.38-2.28(m,5H),1.93(d,J＝7.2Hz,3H),1.38(t,J＝8.0Hz,1H),1.11(d,J＝6.8Hz,3H),0.92(d,J＝6.8Hz,3H),0.80(d,J＝6.8Hz,3H),0.55(d,J＝6.8Hz,3H)ppm.HRMS(ESI)Calcdm/zforC48H67N8O10S4[(M+H)+]1043.3863,found1043.3865.
实施例55,化合物4-5的合成
合成方法如实施例1。
[α]23 D:-2.8(c0.25,CHCl3).1HNMR(400MHz,CDCl3):δ8.46(s,1H),8.18(s,1H),7.07(q,J＝7.2Hz,1H),6.35(d,J＝10.0Hz,1H),5.97(d,J＝9.2Hz,1H),5.83-5.67(m,2H),5.56(dd,J＝15.6,6.8Hz,1H),4.78(dd,J＝10.2,3.6Hz,1H),4.80(dd,J＝10.2,3.6Hz,1H),2.78(s,1H),2.75(d,J＝2.4Hz,1H),2.56(q,J＝7.2Hz,2H),2.38-2.28(m,5H),1.93(d,J＝7.2Hz,3H),0.93(t,J＝6.6Hz,3H),0.80(d,J＝6.8Hz,3H),0.56(d,J＝6.8Hz,3H)ppm.HRMS(ESI)Calcdm/zforC46H63N8O10S4[(M+H)+]1015.3550,found1015.3550.
实施例56,化合物4-6的合成
合成方法如实施例1。
[α]23 D:12.3(c0.11,CHCl3).1HNMR(400MHz,CDCl3):δ8.46(s,1H),8.19(s,1H),7.07(q,J＝7.2Hz,1H),6.37(d,J＝10.0Hz,1H),5.97(d,J＝9.2Hz,1H),5.83-5.69(m,2H),5.55(dd,J＝15.6,6.8Hz,1H),4.80(dd,J＝10.2,3.6Hz,1H),4.79(dd,J＝10.2,3.6Hz,1H),2.77(s,1H),2.75(d,J＝2.4Hz,1H),2.57(q,J＝7.2Hz,2H),2.38-2.28(m,5H),1.93(d,J＝7.2Hz,3H),0.94(d,J＝6.8Hz,3H),0.80(d,J＝6.8Hz,3H),0.56(d,J＝6.8Hz,3H)ppm.HRMS(ESI)Calcdm/zforC46H63N8O10S4[(M+H)+]1015.3550,found1015.3548.
实施例57,化合物4-7的合成
合成方法如实施例1。
[α]23 D:5.1(c0.27,CHCl3).1HNMR(400MHz,CDCl3):δ8.49(s,1H),8.21(s,1H),7.20-7.13(m,5H),7.08(q,J＝7.2Hz,1H),6.38(d,J＝10.0Hz,1H),5.99(d,J＝9.2Hz,1H),5.83-5.69(m,2H),5.58(dd,J＝15.6,6.8Hz,1H),4.82(dd,J＝10.2,3.6Hz,1H),4.80(dd,J＝10.2,3.6Hz,1H),2.77(s,1H),2.76(d,J＝2.6Hz,1H),2.57(q,J＝7.2Hz,2H),2.38-2.28(m,5H),1.91(d,J＝7.2Hz,3H),0.83(d,J＝6.8Hz,3H),0.62(d,J＝6.8Hz,3H)ppm.HRMS(ESI)Calcdm/zforC56H67N8O10S4[(M+H)+]1139.3863,found1139.3862.
实施例58,化合物4-8的合成
合成方法如实施例1。
[α]23 D:13.2(c0.22,CHCl3).1HNMR(400MHz,CDCl3):δ8.47(s,1H),8.20(s,1H),7.19-7.13(m,5H),7.07(q,J＝7.0Hz,1H),6.37(d,J＝10.0Hz,1H),5.98(d,J＝8.8Hz,1H),5.83-5.69(m,2H),5.58(dd,J＝15.6,6.8Hz,1H),4.81(dd,J＝10.2,3.6Hz,1H),4.80(dd,J＝10.2,3.6Hz,1H),2.77(s,1H),2.73(d,J＝2.6Hz,1H),2.56(q,J＝7.2Hz,2H),2.39-2.29(m,5H),1.92(d,J＝7.2Hz,3H),0.84(d,J＝6.8Hz,3H),0.63(d,J＝6.8Hz,3H)ppm.HRMS(ESI)Calcdm/zforC56H67N8O10S4[(M+H)+]1139.3863,found1139.3861.
实施例59,化合物4-9的合成
合成方法如实施例1。
[α]23 D:-3.2(c0.16,CHCl3).1HNMR(400MHz,CDCl3):δ8.48(s,1H),8.19(s,1H),7.09(q,J＝7.2Hz,1H),6.38(d,J＝10.0Hz,1H),5.99(d,J＝9.2Hz,1H),5.86-5.69(m,2H),5.58(dd,J＝15.6,6.6Hz,1H),4.80(dd,J＝10.2,3.6Hz,1H),4.79(dd,J＝10.2,3.6Hz,1H),3.50(d,J＝6.6Hz,2H),2.79(s,1H),2.76(d,J＝2.2Hz,1H),2.59(q,J＝7.2Hz,2H),2.38-2.28(m,5H),1.93(d,J＝7.2Hz,3H),0.82(d,J＝6.8Hz,3H),0.62(d,J＝6.8Hz,3H)ppm.HRMS(ESI)Calcdm/zforC46H63N8O12S4[(M+H)+]1047.3448,found1047.3446.
实施例60,化合物4-10的合成
合成方法如实施例1。
[α]23 D:11.5(c0.17,CHCl3).1HNMR(400MHz,CDCl3):δ8.47(s,1H),8.21(s,1H),7.09(q,J＝7.2Hz,1H),6.39(d,J＝10.0Hz,1H),5.99(d,J＝9.2Hz,1H),5.86-5.69(m,2H),5.57(dd,J＝15.6,6.8Hz,1H),4.80(dd,J＝10.2,3.6Hz,1H),4.79(dd,J＝10.2,3.6Hz,1H),3.53(d,J＝6.6Hz,2H),2.79(s,1H),2.76(d,J＝2.2Hz,1H),2.57(q,J＝7.2Hz,2H),2.39-2.29(m,5H),1.93(d,J＝7.2Hz,3H),0.82(d,J＝6.8Hz,3H),0.57(d,J＝6.8Hz,3H)ppm.HRMS(ESI)Calcdm/zforC46H63N8O12S4[(M+H)+]1047.3448,found1047.3449.
实施例61,化合物5-1的合成
合成方法如实施例1。[α]20 D＝28.1(c0.26,CHCl3).1HNMR(400MHz,CDCl3)δ8.59(s,1H),8.16(s,1H),8.03(s,1H),6.98(q,J＝7.2Hz,2H),6.55(d,J＝10.2Hz,1H),5.88–5.67(m,2H),5.58(dd,J＝15.6,6.8Hz,1H),5.25(dd,J＝17.6,8.2Hz,1H),4.76(dd,J＝10.2,3.8Hz,1H),4.36(dd,J＝17.7,4.1Hz,1H),2.97–2.78(m,1H),2.76–2.62(m,3H),2.49–2.35(m,2H),2.32(d,J＝6.6Hz,3H),1.83(d,J＝7.1Hz,3H)ppm.HRMS(ESI)Calcdm/zforC38H49N10O8S4[(M+H)+]901.2618,found901.2616.
实施例62,化合物5-2的合成
合成方法如实施例1。
[α]20 D:-6.1(c0.16,CHCl3).1HNMR(400MHz,CDCl3)δ8.58(s,1H),8.16(s,1H),8.03(s,1H),6.97(q,J＝7.1Hz,2H),6.52(d,J＝10.2Hz,1H),5.89–5.66(m,2H),5.56(dd,J＝15.6,6.8Hz,1H),5.25(dd,J＝17.6,8.2Hz,1H),4.77(dd,J＝10.2,4.0Hz,1H),4.36(dd,J＝17.7,4.0Hz,1H),2.98–2.78(m,1H),2.76–2.62(m,3H),2.49–2.37(m,2H),2.31(d,J＝6.7Hz,3H),1.83(d,J＝7.1Hz,3H)ppm.HRMS(ESI)Calcdm/zforC38H49N10O8S4[(M+H)+]901.2618,found901.2619.
实施例63,化合物5-3的合成
合成方法如实施例1。
[α]20 D＝16.1(c0.23,CHCl3).1HNMR(400MHz,CDCl3)δ8.59(s,1H),8.16(s,1H),8.07(s,1H),6.96(q,J＝7.2Hz,2H),6.53(d,J＝10.2Hz,1H),5.86–5.65(m,2H),5.57(dd,J＝15.6,6.8Hz,1H),5.20(dd,J＝17.6,8.2Hz,1H),4.75(dd,J＝10.2,4.0Hz,1H),4.38(dd,J＝17.6,4.0Hz,1H),2.96–2.79(m,1H),2.72–2.62(m,3H),2.48–2.35(m,2H),2.29(m,1H),1.86(d,J＝7.1Hz,3H),0.83(t,J＝6.8Hz,3H)ppm.HRMS(ESI)Calcdm/zforC40H53N10O8S4[(M+H)+]929.2931,found929.2933.
实施例64,化合物5-4的合成
合成方法如实施例1。
[α]23 D:27.5(c0.31,CHCl3).1HNMR(400MHz,CDCl3)δ8.59(s,1H),8.19(s,1H),6.97(q,J＝7.0Hz,2H),6.55(d,J＝10.2Hz,1H),5.89–5.66(m,2H),5.57(dd,J＝15.6,6.8Hz,1H),5.26(dd,J＝17.6,8.2Hz,1H),4.77(dd,J＝10.2,3.8Hz,1H),4.35(dd,J＝17.6,4.1Hz,1H),2.93–2.76(m,1H),2.75–2.62(m,3H),2.49–2.36(m,2H),2.32(q,J＝6.8,6.3Hz,1H),1.83(d,J＝7.1Hz,3H),0.81(d,J＝6.8Hz,3H),0.63(d,J＝6.7Hz,3H)ppm.HRMS(ESI)Calcdm/zforC42H57N10O8S4[(M+H)+]957.3244,found957.3246.
实施例65,化合物5-5的合成
合成方法如实施例1。[α]23 D:19.3(c0.23,CHCl3).1HNMR(400MHz,CDCl3)δ8.58(s,1H),8.18(s,1H),7.17-7.09(m,5H),6.97(q,J＝7.1Hz,2H),6.54(d,J＝10.2Hz,1H),5.89–5.67(m,2H),5.59(dd,J＝15.6,6.8Hz,1H),5.27(dd,J＝17.6,8.2Hz,1H),4.79(dd,J＝10.2,3.8Hz,1H),4.38(dd,J＝17.7,4.1Hz,1H),3.29-3.06(m,2H),2.95(m,1H),2.79–2.66(m,3H),2.49–2.38(m,2H),1.85(d,J＝7.1Hz,3H)ppm.HRMS(ESI)Calcdm/zforC50H57N10O8S4[(M+H)+]1053.3244,found1053.3246.
实施例66,化合物5-6的合成
合成方法如实施例1。[α]23 D:23.1(c0.52,CHCl3).1HNMR(400MHz,CDCl3)δ8.59(s,1H),8.18(s,1H),6.98(q,J＝7.2Hz,2H),6.58(d,J＝10.2Hz,1H),5.89–5.67(m,2H),5.58(dd,J＝15.6,6.8Hz,1H),5.28(dd,J＝17.6,8.2Hz,1H),4.78(dd,J＝10.2,3.8Hz,1H),4.38(dd,J＝17.6,4.0Hz,1H),2.96(m,1H),2.78–2.63(m,3H),2.49–2.36(m,2H),2.33-2.29(m,4H),2.06(s3H),1.86(d,J＝7.2Hz,3H)ppm.HRMS(ESI)Calcdm/zforC43H59N10O8S6[(M+H)+]1035.2842,found1035.2843.
实施例67,化合物5-7的合成
合成方法如实施例1。
[α]23 D:25.1(c0.32,CHCl3).1HNMR(400MHz,CDCl3)δ8.59(s,1H),8.16(s,1H),6.96(q,J＝7.2Hz,2H),6.51(d,J＝10.2Hz,1H),5.86–5.63(m,2H),5.55(dd,J＝15.6,6.8Hz,1H),5.21(dd,J＝17.6,8.2Hz,1H),4.74(dd,J＝10.2,3.8Hz,1H),4.35(dd,J＝17.6,4.0Hz,1H),2.92(m,1H),2.76–2.63(m,3H),2.60(t,J＝6.8Hz,2H),2.49–2.35(m,2H),2.31(m,2H),1.86(d,J＝7.2Hz,3H),1.59(m,2H),1.30-1.38(m,4H)ppm.HRMS(ESI)Calcdm/zforC45H65N12O8S4[(M+H)+]1029.3931,found1029.3933.
实施例68,化合物5-8的合成
合成方法如实施例1。
[α]23 D:28.2(c0.36,CHCl3).1HNMR(400MHz,CDCl3)δ8.58(s,1H),8.17(s,1H),6.97(q,J＝7.1Hz,2H),6.51(d,J＝10.2Hz,1H),5.86–5.62(m,2H),5.53(dd,J＝15.6,6.8Hz,1H),5.21(dd,J＝17.6,8.2Hz,1H),4.72(dd,J＝10.2,3.8Hz,1H),4.33(dd,J＝17.6,4.0Hz,1H),2.95(m,1H),2.79–2.67(m,3H),2.63(t,J＝6.8Hz,2H),2.49–2.38(m,2H),2.31(m,2H),2.11(m,2H),1.83(d,J＝7.1Hz,3H),ppm.HRMS(ESI)Calcdm/zforC40H55N12O8S4[(M+H)+]959.3149,found959.3148.
实施例69HDAC生化活性的测定
1.测定原理：化合物生化活的性测定是根据其抑制HDAC酶的去乙酰化作用程度来确定的。用荧光标记的含有乙酰化的赖氨酸侧链的底物和HDAC酶作用之后，该荧光底物被去乙酰化。去乙酰化后的荧光标记底物被酶裂解后，释放出荧光物质，该荧光物质在360nm光的激发下产生460nm的发射光。
2.具体步骤：HDAC的底物用反应缓冲液稀释至200M(反应浓度为20M)，将HDAC酶稀释至适当浓度，加入不同浓度待测化合物，37℃反应30分钟，然后加入相同体积的2倍浓度底物发展液(developer)，室温孵育15分钟，最后用微孔板读板仪测定读数，激发光为360nm，发射光为460nm，数据用Prime4软件处理。
3.检测结果与分析：
从上表中结果可以看出：上表中IC50是指被抑制一半时抑制剂的浓度(50％inhibitoryconcentration)。从上表中结果可以看出：上述的化合物与阳性对照(SAHA)相比，具有显著的抑制与肿瘤增殖及转移密切相关的HDAC酶(主要为HDAC1，HDAC2，HDAC3，HDAC8，HDAC11)的去乙酰化作用的活性。而与肿瘤增殖及转移关系不大的HDAC7却没有作用。
实施例70检测化合物对癌细胞活性实验
1.实验原理：化合物抑制癌细胞生长用MTT方法来检测。MTT法的原理是，黄色的噻唑兰可透过细胞膜进入细胞内，活细胞线粒体中的琥珀脱氢酶能使外源性MTT还原为难溶于水的蓝紫色的针状Formazan结晶并沉积在细胞中，结晶能被二甲基亚砜(DMSO)溶解，用酶联免疫检测仪在490nm/570nm波长处检测其光吸收值，可间接反映细胞数量。
2.实验材料：所使用的癌细胞系为Hela(人宫颈癌细胞)，MCF-7(人乳腺癌细胞)，BGC-823(人胃癌细胞)，A549(人肺癌细胞)，HT1080(人纤维肉瘤细胞)，A431(人表皮鳞状细胞癌细胞)，DU145(人前列腺癌细胞)，U937(人白血病细胞)，Pac-1(人胰腺癌细胞)，MOLT-4(人急性淋巴母细胞白血病细胞)；分别用DMEM+10％FBS培养基培养或者使用1640+10％FBS培养。
3.实验方法与结果分析：
实验组：190μl细胞悬液+10μl不同浓度的药物(终浓度为10-5～10-10M)
空白对照组：200μlPBS
阴性对照组：190μl细胞悬液+10μl2％DMSO(DMSO终浓度为0.1％)
阳性对照组：190μl细胞悬液+10μl不同浓度的化合物
a).细胞接种于96孔板，接种量为1500个/孔，190μl/孔，37℃5％的CO2培养箱培养过夜；
b).次日每孔加入10μl不同药物，药物终浓度为10-5～10-10M，设三个平行孔；37℃、5％的CO2培养箱孵育72小时；
c).每孔加入20μl5mg/ml的MTT，37℃5％的CO2培养箱孵育4小时；
d).弃上清，每孔加入100μl的DMSO，振荡；
e).570nm读数，计算细胞存活率，根据结果计算GI50，得下表。
上表中GI50表示的是细胞50％生长抑制所需的药物浓度(50％growthinhibition)。
从上表中结果可以看出：上述的药物与阳性对照(SAHA)相比，具有显著的抑制所列肿瘤细胞生长的活性。
应当说明的是，上述的实施例仅用于说明而不是限制本发明的技术方案，任何等同的替换或更改，均应当视为包含在本发明的范围之内。
实施例71检测化合物1-1对裸鼠体内肿瘤的抑制实验
5×106个HCT116细胞接种到BALB/C裸鼠的右前腋下,待瘤体增长至100-200mm3大小时分组口服给药,设3个剂量组,10mg/kg,20mg/kg,和40mg/kg,iv,qd,8～10只/组,每两天称取一次动物体重,量取瘤体积(分组当天记录初始瘤体积和体重)。瘤体积计算公式为:V＝π/6*a*b*b.结果发现化合物1-1对动物体重无明显影响,均表现出良好的体内抑制肿瘤生长活性。该化合物均能完全抑制肿瘤的生长。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
Claims (13)
1.具有通式Ⅰ所示的化学结构的环肽类化合物，或其药物上可接受的盐、异构体、外消旋体、前体药物或溶剂合物：
其中，
X为O或NH；
R1基团为氢，C1-12烷基，C1-12烷基氨基、-CH2-O-(C1-12烷基)，-CH2-NH-(C1-12烷基)，-CH2-S-(C1-12烷基)，C6-12芳基，杂芳基，-CH2-(C6-12芳基)或-CH2-杂芳基；上述的C6-12芳基，杂芳基，-CH2-C6-12芳基及-CH2-杂芳基含有1个或多个取代基，其取代基选自卤素、氨基、羟基、硝基、氰基、C1-12烷基、C1-12烷氧基、氨基C1-12烷基、酰基、酰氧基、硫代C1-12烷基、羧基或苯基；
R2、R3、R4基团分别独立地选自氢，C1-12烷基，-O-(C1-12烷基)，-NH-(C1-12烷基)，-S-(C1-12烷基)，C6-12芳基或杂芳基；或R2和R3成三到七元环；
Y为 其中R9基团是氢，C1-12烷基，-O-(C1-12烷基)，-NH-(C1-12烷基)，-S-(C1-12烷基)，C6-12芳基，杂芳基，卤素，氨基，羟基，硝基，氰基或羧基。
2.根据权利要求1所述的环肽类化合物或其药物上可接受的盐、异构体、外消旋体、前体药物或溶剂合物，其特征在于，R1基团为氢，甲基,异丙基或丁氨基。
3.根据权利要求1所述的环肽类化合物或其药物上可接受的盐、异构体、外消旋体、前体药物或溶剂合物，其特征在于，R2和R3基团独立地选自氢，C1-12烷基。
4.根据权利要求3所述的环肽类化合物或其药物上可接受的盐、异构体、外消旋体、前体药物或溶剂合物，其特征在于，R2为氢，R3为CH3。
5.根据权利要求1所述的环肽类化合物或其药物上可接受的盐、异构体、外消旋体、前体药物或溶剂合物，其特征在于，R4基团为氢，C1-12烷基。
6.根据权利要求1所述的环肽类化合物或其药物上可接受的盐、异构体、外消旋体、前体药物或溶剂合物，其特征在于，Y选自 其中R9基团为氢。
7.根据权利要求1-6任一项所述的环肽类化合物或其药物上可接受的盐、异构体、外消旋体、前体药物或溶剂合物，其特征在于，R1基团为氢，甲基,异丙基,丁氨基；R2为氢，R3为CH3；R4基团为氢，C1-12烷基；Y选自 其中R9基团为氢。
8.根据权利要求1所述的环肽类化合物或其药物上可接受的盐、异构体、外消旋体、前体药物或溶剂合物，其特征在于，该化合物选自：
9.一种治疗肿瘤的药用组合物,其包括权利要求1-8任一项所述的环肽类化合物或其药物上可接受的盐、异构体、外消旋体、前体药物或溶剂合物与药学上可接受的载体。
10.权利要求1-8任一项所述的环肽类化合物或其药物上可接受的盐、异构体、外消旋体、前体药物或溶剂合物在制备预防或治疗肿瘤的药物中的应用。
11.权利要求1-8任一项所述的环肽类化合物或其药物上可接受的盐、异构体、外消旋体、前体药物或溶剂合物在制备预防或者治疗与组蛋白去乙酰化酶调节异常有关的哺乳动物疾病药物中的应用。
12.根据权利要求11所述的应用，其特征在于，所述与组蛋白去乙酰化酶调节异常有关的哺乳动物疾病包括癌症、神经变性疾病、艾滋病、老年痴呆、疟疾或糖尿病。
13.根据权利要求12所述的应用，其特征在于，所述癌症包括淋巴瘤、非小细胞肺癌、小细胞肺癌、胃癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、白血病及宫颈癌中的任一种。
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