CN115304502A - Foxm1抑制剂及其制备方法和应用 - Google Patents

Foxm1抑制剂及其制备方法和应用 Download PDF

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CN115304502A
CN115304502A CN202210929820.3A CN202210929820A CN115304502A CN 115304502 A CN115304502 A CN 115304502A CN 202210929820 A CN202210929820 A CN 202210929820A CN 115304502 A CN115304502 A CN 115304502A
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CN115304502B (zh
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薛司徒
高岩
李卓荣
谢卓松
周子颖
杨鹤显
易红
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Institute of Medicinal Biotechnology of CAMS
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Abstract

本发明涉及一种FOXM1抑制剂，其包括式I所示的化合物、其药用盐或酯、溶剂合物、异构体、多晶型物、同位素标记的化合物、代谢物或前药，并同时提供了其组合物、制备方法和应用，通过大量研究及筛选发现了上述系列化合物能够通过抑制FOXM1下调其下游靶蛋白的水平，从而发挥抗肿瘤活性，因此该系列化合物可用于预防和/或治疗肿瘤疾病。

Description

FOXM1抑制剂及其制备方法和应用
技术领域
本发明属于医药技术领域，具体地说，本发明涉及FOXM1抑制剂及其制备方法，还涉及这类抑制剂在发挥抗肿瘤方面的应用，以及所述化合物作为活性组分的药物组合物及组合物的用途。
背景技术
叉头框(forkhead box，Fox)转录因子，从酵母到人类都广泛存在，属于“翼状螺旋”类蛋白的一个亚群，已拥有超过50个以上的成员，分别参与调节细胞分化、增殖、代谢及细胞凋亡等生理过程。FOXM1(forkhead box protein M1)是该转录因子家族的一员，是细胞周期的主要调节者，越来越多的证据表明FOXM1还通过激活特定的转录途径参与许多其他细胞过程的调控。
FOXM1也被称作为Trident(小鼠)、HFH-11(人类)、WIN或INS-1(大鼠)、MPP-2(部分人类cDNA) 或FKH L-5。人FOXM1基因定位于12p13染色体带，全长约25kb，由10个外显子组成，其中有2 个外显子A1和A2，是选择性连接位点。FOXM1所发挥的主要功能是调节参与细胞周期转变的细胞因子的转录激活，其转录活性具有细胞周期依赖性。FOXM1的转录活性调控机制是在特定的细胞周期调控其磷酸化状态来影响蛋白本身结构域间相互作用。在正常增殖的细胞中，FOXM1能够促进细胞的增殖，在G1/S期及G2/M期转变过程中发挥重要作用。据报道FOXM1通过激活cyclin A/CDK2、 CyclinB1、Cyclin A、Aurora B激酶、Plk1、Cdc25B、p21和p27等促进细胞进入S期和M期。通过调节CENPA，CENPB和CENPF等蛋白质的表达，FOXM1也在染色体分离和纺锤体组装中发挥关键作用。
作为一个刺激增生的转录因子，在肿瘤的发生发展过程中发挥重要作用，参与肿瘤细胞的增殖、侵袭、转移、血管生成及干细胞生成等。尤其是近年来发现FOXM1与化疗药物耐药密切相关，例如 FOXM1在敏感细胞中的过度表达可诱导其对顺铂耐药，沉默FOXM1可显著降低耐药细胞的增殖率，提高药物敏感性，说明靶向FOXM1可使肿瘤细胞对化疗药物增敏。
探索FOXM1蛋白的关键氨基酸位点、结合小分子后对下游通路的影响及肿瘤治疗效果，关键在于寻找特异性结合于FOXM1蛋白的化学分子。目前文献报道的FOXM1相关活性化合物主要分为两种，一种是可以下调FOXM1表达水平，抑制肿瘤增殖的化合物，另一种是结合于FOXM1并抑制其活性的化合物。
近年来研究发现，噻唑类抗生素，如盐屋霉素A和硫链丝菌素，能抑制FOXM1的表达，具有抑制肿瘤细胞增殖和诱导肿瘤细胞凋亡的功效。但由于噻唑类抗生素的蛋白酶体抑制性质，除了抑制 FOXM1之外，这些药物很可能会影响多种信号通路，具有较强的脱靶效应，不适合用于阐明抑制 FOXM1与DNA结合后产生的生物学作用。新型肽类小分子9R-P201也能够显著下调FOXM1在HepG2细胞的表达水平，抑制细胞增殖、血管生成和诱导细胞凋亡。最近，研究人员发现，天然产物芍药苷也能抑制FOXM1的表达，能够在结肠癌细胞中抑制细胞生长，诱导细胞凋亡及抑制细胞侵袭和转移。此外，天然产物槐定碱和白花丹素也通过抑制细胞中FOXM1的表达分别抑制人髓母细胞瘤和神经胶质瘤的细胞增殖。
Figure RE-RE-GDA0003873342650000021
2014年Gormally等通过高通量筛选，发现小分子FDI6能抑制FOXM1活性，通过阻断其与DNA 的结合(IC50＝22.5μM)，从而阻止FOXM1下游靶基因的正常活化，且能诱导喉癌Hep-2细胞凋亡，抑制细胞增殖、侵袭和迁移，这一化合物的发现推进了FOXM1成为肿瘤治疗靶点的进程，近年来 FDI6替代硫链丝菌素成为研究FOXM1的工具分子。最近有学者通过建立分子对接方法发现了能与 FOXM1蛋白结合的降糖药曲格列酮(IC50＝122.4μM)，并且通过化学方法优化，得到能解离 FOXM1-DNA复合物的衍生物，并且能抑制肿瘤细胞集落形成。Sun等也通过高通量筛选确定了一种新型小分子化合物RCM-1，可在体外抑制FOXM1活性，但其研究重点为防止杯状细胞化生，降低肺部炎症等作用，在肿瘤治疗方面的应用尚未开发。和厚朴酚是一种具有广泛抗肿瘤活性的天然产物, 最近Halasi等研究发现，和厚朴酚通过与FOXM1结合，抑制FOXM1活性，从而解释了其在癌细胞中的生物活性。
Figure RE-RE-GDA0003873342650000031
目前与FOXM1相关的活性化合物或抑制剂较少，已发现的有噻唑类抗生素、新型肽9R-P201、 FDI6、曲格列酮、RCM-1以及天然产物芍药苷、槐定碱、白花丹素、和厚朴酚等，均处于早期研究阶段，尚未FOXM1抑制剂进入临床药物研究阶段。鉴于以上原因，系统开展FOXM1的抑制剂研究，发现能确切与FOXM1特异结合的化合物很有必要。
发明内容
本发明的目的之一是提供一组FOXM1抑制剂化合物、其药用盐或酯、溶剂合物、异构体、多晶型物、同位素标记的化合物、代谢物或前药。
本发明的又一目的是提供所述化合物、其药用盐或酯、溶剂合物、异构体、多晶型物、同位素标记的化合物、代谢物或前药在制备抑制FOXM1，抗肿瘤或相关病患方面的药物中的应用。
本发明的另一目的是提供所述化合物、其药用盐或酯、溶剂合物、异构体、多晶型物、同位素标记的化合物、代谢物或前药作为活性成分的药物组合物或药物制剂，以及该药物组合物在治疗或预防肿瘤相关疾病方面的应用。
术语定义
在本文中用于本发明描述中的术语仅是为了描述具体实施方案而不作为对本发明的限制。本文所用命名和在本文所述的有机化学、药物化学、生物学中的实验室操作是本领域熟知的和常用的。除非另外提及，本文所用的全部技术和科学术语与本领域所属技术领域的一般技术人员通常所理解的具有相同的含义。
如在本发明实施方案和所附权利要求的描述中所用，单数形式的“一”、“一种”、“该”“其””用于是指该冠词的单数和复数，除非上下文另外明确提及。例如，一种化合物包括一种或多于一种化合物。
如本文所用，“和/或”是指和包括一或多个相关的所列项目的任意和所有可能的组合。
如本文所用，术语“疾病”或“病患”是指身体状态或一些器官的任意改变，中断或干扰其功能的实施和/或引起症状。
如本文所用，术语“肿瘤”是指机体在各种致病因素作用下,细胞异常增殖而形成的局部肿块，包括良性肿瘤、恶性肿瘤和交界肿瘤。包括但不局限于乳腺癌、卵巢癌、结直肠癌、黑色素瘤、非小细胞肺癌、小细胞肺癌、胃肠道间质瘤、宫颈癌、胰腺癌、前列腺癌、胃癌、慢性髓样白细胞过多症、肝癌、淋巴瘤、腹膜癌和软组织肉瘤。
如本文所用，术语“治疗”目的是减轻或消除所针对的疾病状态或病症。如果受试者按照本文所述方法接受了治疗量的化合物或其药学上可接受的盐、异构体、多晶型物、溶剂合物、同位素标记的化合物、代谢物或前药，或其药物组合物，该受试者一种或多种指征和症状表现出可观察到的和/或可检测出的降低或改善，则受试者被成功地“治疗”了。还应当理解，所述的疾病状态或病症的治疗的不仅包括完全地治疗，还包括未达到完全地治疗，但实现了一些生物学或医学相关的结果。
如本文所用，术语“受试者””可以指患者或者其它接受本发明组合物以治疗、预防、减轻和/或缓解本发明所述疾病或病症的动物，在本发明中尤其指人类和哺乳动物。
技术主题一
FOXM1抑制剂，其包括式I所示的化合物、其药用盐或酯、溶剂合物、异构体、多晶型物、同位素标记的化合物、代谢物或前药：
Figure RE-RE-GDA0003873342650000041
其中，其中，X选自以下基团：―(CH2)n―、―(CH2)mO(CH2)n-m―、―(CH2)kCH(R)(CH2)n-k―；
Ra可以为一个或两个及以上，其独立地选自H、卤素、NO2、CN、OH、C1-C6直链或支链烷基、 C1-C6直链或支链烷氧基、苯氧基、苄氧基、―(CH2)hC(O)Rx、―NRyRz；
Rx选自H、OH、NH2、C1-C6直链或支链烷基、C1-C6直链或支链烷氧基；
Ry、Rz可独立选自H、C1-C6直链或支链烷基、C2-C6直链或支链烯基；
Q代表O、NH或NR5；
R5选自C1-C6直链或支链烷基；
R4选自H、―(CH2)mO(CH2)n-mOH、R取代或未取代的C1-C7直链或支链烷基、R取代或未取代的C3-C7直链或支链环烷基、R取代或未取代的含有1个或2个选自O、S或N的3-6元饱和或不饱和杂烷基、R取代或未取代的芳基、R取代或未取代的5元或6元杂芳基、醛基、C2-C5羰基、C1-C5 羧基、C1-C5羧酸酯基；
R取代基可以为一个或两个及以上，其独立地选自：卤素、OH、C1-C6烃基、C1-C6烃氧基、C1-C5羧基、C2-C5羰基、C1-C5羧酸酯基、C1-C5酰胺基、NH2；
n选自1、2、3、4、5、6、7或8；m选自1、2、3、4、5、6、7或8；k选自0、1、2、3、4、 5、6、7或8；h选自0、1、2或3。
在一些情况下，X选自―(CH2)n―，例如：―(CH2)2―、―(CH2)3―、―(CH2)4―、―(CH2)5―或―(CH2)6―。
在一些情况下，X选自―(CH2)mO(CH2)n-m―，例如：
―CH2OCH2―、―CH2O(CH2)2―、―CH2O(CH2)3―、―CH2O(CH2)4―、―CH2O(CH2)5―、―( CH2)2O―、―(CH2)2OCH2―、―(CH2)2O(CH2)2―、―(CH2)2O(CH2)3―、―(CH2)2O(CH2)4―、―(CH 2)3O―、―(CH2)3OCH2―、―(CH2)3O(CH2)2―、―(CH2)3O(CH2)3―、―(CH2)4O―、―(CH2)4OCH2―、―(CH2)4O(CH2)2―、―(CH2)5O―或―(CH2)5OCH2―。
在一些情况下，X选自―(CH2)kCH(R)(CH2)n-k―，例如：
―CH(R)CH2―、―CH(R)(CH2)2―、―CH(R)(CH2)3―、―CH(R)(CH2)4―、―CH(R)(CH2)5―、―CH2CH(R)CH2―、―CH2CH(R)(CH2)2―、―CH2CH(R)(CH2)3―、―CH2CH(R)(CH2)4―、―CH2C H(R)(CH2)5―、―(CH2)2CH(R)―、―(CH2)2CH(R)CH2―、―(CH2)2CH(R)(CH2)2―、―(CH2)2CH(R)( CH2)3―、―(CH2)2CH(R)(CH2)4―、―(CH2)3CH(R)―、―(CH2)3CH(R)CH2―、―(CH2)3 CH(R)(CH2)2―、―(CH2)3CH(R)(CH2)3―、―(CH2)4CH(R)―、―(CH2)4CH(R)(CH2)2―、―(CH2)5CH (R)―或―(CH2)5CH(R)CH2―。
在一些情况下，Ra可以为一个、两个、三个或四个，当Ra为多个时，可以相同也可以不同。
在一些情况下，Ra选自H、卤素、NO2、CN、苯氧基或苄氧基。
在一些情况下，Ra选自C1-C6直链或支链烷基，例如：
―CH3、―CH2CH3、―CH2CH2CH3、―CH(CH3)CH3-、―C(CH3)3-、―CH2CH2CH2CH3-、―CH(CH3)CH2CH3、―CH(CH3)CH2(CH3)、―CH(CH2CH3)CH3、―C(CH3)2CH3、―CH2CH2CH2CH2CH3或―CH2CH2CH2CH2CH2CH3。
在一些情况下，Ra选自C1-C6直链或支链烷氧基，例如：
―OCH3、―OCH2CH3、―OCH2CH2CH3、―OCH(CH3)CH3-、―OC(CH3)3-、―OCH2CH2CH2CH3-、―OCH(CH3)CH2CH3、―OCH(CH3)CH2(CH3)、―OCH(CH2CH3)CH3、―OC(CH3)2CH3、―OCH2CH2CH2CH2CH3或―OCH2CH2CH2CH2CH2CH3。
在一些情况下，Ra选自C1-C6直链或支链烷氧基，例如：
―C(O)H、―C(O)OH、―C(O)NH2、―C(O)CH3、―C(O)CH2CH3、―C(O)C3H7、―C(O)C4H9、―C(O)C5H11、―C(O)OCH3、―C(O)OC2H5、―C(O)OC3H7、―C(O)OC4H9、―C(O)OC5H11、―CH2C(O)H、―CH2C(O)OH、―CH2C(O)NH2、―CH2C(O)CH3、―CH2C(O)C2H5、―CH2C(O)C3H7、―CH2C(O)C4H9、―CH2C(O)C5H11、―CH2C(O)OCH3、―CH2C(O)OC2H5、―CH2C(O)OC3H7、―C H2C(O)OC4H9或―CH2C(O)OC5H11。
在一些情况下，Ra选自―NRyRz，例如：
―NH2、―NHCH3、―NHC2H5、―NHC3H7、―NHC4H9、―N(CH3)2、―NH(CH3)C2H5、―NH(CH3)C3H7、―NH(CH3)C4H9、―N(C2H5)2、―NH(C2H5)C3H7、―NH(C2H5)C4H9、―N(C3H7)2、―NH(C3H7)C4H9或―N(C4H9)2。
在一些情况下，R4选自―(CH2)mO(CH2)n-mOH，例如：
―CH2OCH2OH、―CH2O(CH2)2OH、―CH2O(CH2)3OH、―CH2O(CH2)4OH、―CH2O(CH2)5OH、―(CH2)2OCH2OH、―(CH2)2O(CH2)2OH、―(CH2)2O(CH2)3OH、―(CH2)2O(CH2)4OH、―(CH2)3OCH2OH、―(CH2)3O(CH2)2OH、―(CH2)3O(CH2)3OH、―(CH2)4O(CH2)2OH或―(CH2)5OCH2OH。
在一些情况下，R4选自：
H、―(CH2)2O(CH2)2OH、―C(O)OH、―CH2C(O)OH、―C(O)OCH3、―CH2C(O)CH3、―C(O)C2H5、甲基、环丙基、环丁基、环戊基、环己基、环庚基、苯基，以上基团可以被一个R或多个R取代。
在一些情况下，R4选自含有1个或2个选自：O、S或N的3-6元饱和或不饱和杂烷基，例如：饱和或不饱和的环氧乙烷基、四氢呋喃基、吡咯烷胺基、哌啶基、吗啉基、哌嗪基四氢吡喃基或吡喃基，以上基团可以被一个R或多个R取代。
在一些情况下，R4选自含有5元或6元杂芳基，例如呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、恶唑基、异恶唑基、噻唑基、三氮唑基、吡啶基、嘧啶基、哒嗪基或吡嗪基，以上基团可以被一个R或多个R取代。
在一些情况下，R4选自醛基，例如：
―C(O)H、―CH2C(O)H、―(CH2)2C(O)H、―(CH2)3C(O)H、―(CH2)4C(O)H。
在一些情况下，R4选自C2-C5羰基选自：―C(O)CH3、―C(O)C2H5、―C(O)C3H7、―C(O)C4H9、 CH2C(O)CH3、―CH2C(O)C2H5、―CH2C(O)C3H7、―(CH2)2C(O)CH3、―(CH2)2C(O)C2H5或―(CH2)3 C(O)CH3；
在一些情况下，R4选自C1-C5羧基，例如：―C(O)OH、―CH2C(O)OH、―(CH2)2C(O)OH、―(CH2)3C(O)OH、―(CH2)4C(O)OH。
在一些情况下，R4选自C1-C5羧酸酯基，例如：
―C(O)OCH3、―C(O)OC2H5、―C(O)OC3H7、―C(O)OC4H9、―CH2C(O)OCH3、―CH2C(O)OC2H5、―CH2C(O)OC3H7、―C2H4C(O)OCH3、―C2H4C(O)OC2H5、―C3H6C(O)O CH3。
在一些情况下，R4选自C1-C5酰胺基，例如：
―C(O)NH2、―CH2C(O)NH2、―(CH2)2C(O)NH2、―(CH2)3C(O)NH2、―(CH2)4C(O)NH2。
本申请及典型实施例中的R可以选自F、Br、Cl、OH、C1-C6烃基、C1-C6烃氧基、C1-C5羧基、C2-C5羰基、C1-C5羧酸酯基、C1-C5酰胺基、NH2，各取代基同前所述，当R基为多个时，R基可以相同或不同。
作为一些特别优选的情况，X选自以下基团：
―(CH2)2O―、―(CH2)2OCH2―、―(CH2)2O(CH2)2―、―(CH2)6―或―CH2CH(OH)CH2―；
Ra可以为一个或两个或三个，其独立地选自H、F、Br、Cl、NO2、CN、OH、甲基、甲氧基、苯氧基、苄氧基、―C(O)H、―C(O)OH、―C(O)NH2、―C(O)CH3、―C(O)OCH3、―C(O)OC2H5、―NH2、―NHCH3或―N(CH3)2；
Q代表O、NH或NCH3；
R4选自：H、―(CH2)2O(CH2)2OH、―C(O)OH、―CH2C(O)OH、―C(O)OCH3、―CH2C(O)CH3、―C(O)C2H5、甲基、环丙基、环丁基、环戊基、环己基、环庚基、环氧乙烷、苯基、四氢呋喃基、四氢吡喃、哌啶基、吗啉基、哌嗪基、吡喃基、哌啶基、吡咯烷胺基、呋喃基、噻唑基、噻吩基、吡咯基、嘧啶基、吡啶基或尿嘧啶基；
R取代基可以为一个或两个，其独立地选自：F、Br、Cl、OH、甲基、甲氧基或―C(O)OC4H9。
最优选的，所述式I化合物选自：
Figure RE-RE-GDA0003873342650000071
Figure RE-RE-GDA0003873342650000081
Figure RE-RE-GDA0003873342650000091
如本文所用，“药用盐”是指保留目标化合物的所需生物活性并表现出最小的不希望的毒理学效应的盐。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与本发明化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱包括无机碱及有机碱制备的盐，所述的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。所述的有机无毒碱的盐，包括伯胺、仲胺和叔胺的盐，包括取取代胺和环状胺。例如：N,N'－二苄基乙二胺、二乙胺、2一二乙基氨基乙醇、2一二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N一乙基吗啉、N一乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪、哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺等。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例盐酸、氢溴酸、氢碘酸、硫酸、磷酸或硝酸等；有机酸例如甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)-苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡萄糖酸、3-羟基 -2-萘甲酸、烟酸、巴莫酸、果胶酯酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、胺基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对-甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、海藻酸、马来酸、富马酸、D-葡萄糖酸、扁桃酸、抗坏血酸、葡庚糖酸、甘油磷酸、天冬胺酸、磺基水杨酸等包括钠、钾、镁、锂、铝、钙、锌、N,N’-二苄基乙二胺、氯代普鲁卡因、胆碱、二乙醇胺、乙二胺、 N-甲基葡糖胺和普鲁卡因等形成的盐。
如本文所用，“药用酯”是指，本发明所提供的化合物中存在的-OH与适当的酸(例如，羧酸或含氧无机酸)形成的酯。适宜的酯基团包括但不限于，甲酸酯、乙酸酯、丙酸酯、丁酸酯、丙烯酸酯、乙基琥珀酸酯、硬脂肪酸酯或棕榈酸酯。
如本文所用，“异构体”是指式I化合物含有一个或多个不对称中心和/或双键的情况下，本发明的化合物能够以外消旋物、外消旋混合物、单一对映异构体、非对映异构体混合物、单一非对映异构体、几何异构体等的形式存在。这些化合物可以由符号“R”或“S”表示，这取决于立体碳原子周围的取代基的构型，还可能由符号“Z”或“E”表示，这取决于碳-碳双键周围的取代基的排列，或者碳-碳双键周围的取代基可被称为“顺式”或“反式”。本文公开的化合物可以互变异构体存在，并且两种互变异构形式均旨在包括在本发明的范围内，即使仅描绘了一种互变异构结构，例如酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。
如本文所用，“多晶型”是指式I化合物也可以各类晶型的形式存在，通过将化合物或其药学上可接受的盐在溶剂中重结晶，得到它们的不同单一晶型以及多晶型混合物。
如本文所用，“溶剂合物”是指式I化合物可以溶剂化物(如水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
如本文所用，“同位素”是指式I化合物也意在包括区别仅在于存在一种或多种同位素富集原子的化合物。例如，具有本发明结构的化合物，但用氘(2H)或氚(3H)代替氢，或用13C-或14C-碳原子代替碳，在本发明的范围内。这种化合物可用作，例如，分析工具、生物测定中的探针或治疗剂。
如本文所用，“前药”是指式I化合物还可以是前药的形式或可在体内代谢变化后释放出所述活性成分的形式。选择和制备适当的前药衍生物是本领域技术人员公知技术。
技术主题二
本发明提供一种药物组合物，其包含式I所示的取代苯并杂环结构的化合物、其药用盐或酯、溶剂合物、异构体、多晶型物、同位素标记的化合物、代谢物或前药，以及药学上可以接受的载体或赋形剂。
如本文所用，“药物组合物”其中含有治疗有效量的所述式I多取代苯并杂环类化合物其药用盐或酯、溶剂合物、异构体、多晶型物、同位素标记的化合物、代谢物或前药，以及一种或多种药学上可接受的载体，制备成片剂、胶囊、颗粒剂、散剂、混悬剂、乳剂、粉剂、溶液、凝胶剂、糖浆剂、丸剂、酊剂、酒剂、煎膏剂、锭剂、合剂、栓剂、注射剂、吸入剂或喷雾剂等形式。该药物组合物优选含有重量比为0.1％-99.5％的本发明的多取代苯并杂环类化合物或其药用盐作为活性成分，更优选含有重量比为0.5％-99.5％的活性成分。
如本文所用，“药学上可接受的载体或赋形剂”包括：稀释剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、粒化剂、包衣剂、润湿剂、溶剂、共溶剂、助悬剂、乳化剂、增甜剂、调味剂、掩味剂、着色剂、防结块剂、保湿剂、螯合剂、增塑剂、增粘剂、抗氧化剂、防腐剂、稳定剂、表面活性剂和缓冲剂，本领域技术人员将理解，某些药学上可接受的赋形剂可以以多于一种功能和以替代性功能来使用，取决于所述赋形剂在制剂中存在多少和在制剂中存在何种其它成分。例如：当用于口服时，可以制成口服制剂，如片剂、胶囊剂、颗粒剂和丸剂等，包含填充剂(例如糖类衍生物如乳糖、蔗糖、葡萄糖、甘露糖醇和山梨糖醇；淀粉衍生物如玉米淀粉、土豆淀粉、糊精和羧甲基淀粉；纤维素衍生物如结晶纤维素、羟丙基纤维素、羧甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠；阿拉伯胶；右旋糖酐；硅酸盐衍生物如偏硅酸镁铝；磷酸盐衍生物如磷酸钙；碳酸盐衍生物如碳酸钙；硫酸盐衍生物如硫酸钙等)、粘合剂(例如明胶、聚乙烯吡咯烃酮和聚乙二醇)、崩解剂(例如纤维素衍生物如羧甲基纤维素钠、聚乙烯吡咯烃酮)、润滑剂(例如滑石、硬脂酸钙、硬脂酸镁、鲸蜡、硼酸、苯甲酸钠、亮氨酸)、稳定剂(对羟基苯甲酸甲酯、对羟基苯甲酸丙酯等)、矫味剂(例如常用的甜味剂、酸味剂和香料等)。当用于肠胃外时，可以制成注射剂，包括注射用无菌粉末与注射用溶剂，所用载体或赋形剂包含无菌水、林格氏液和等渗氯化钠溶液，也可根据药物的性质加入适宜的附加剂例如抗氧化剂、缓冲剂和抑菌剂。当用于直肠给药时，所述药物可以制成栓剂等。用于经肺给药时，所述药物可以制成吸入剂或喷雾剂等。有许多本领域技术人员可用的资源，这些资源描述了药学上可接受的赋形剂且其可用于选择合适的药学上可接受的赋形剂，例如《雷明登药学大全》、《中国药学年鉴》、《药剂学》等书籍。
本发明可以通过本领域已知的任何合适的方法来施用，例如，口服、静脉内、腹膜内、肌肉内、局部、透皮、经眼、经鼻、吸入、皮下、肌内、口含、舌下、直肠给予等方式，可以以1μg～2000mg/kg 受试者体重的任何量施用如上所述的化合物，例如以1μg～1000mg/kg体重/天，50μg～1000mg/kg体重/天，100μg～1000mg/kg体重/天，1～500mg/kg体重/天，2～200mg/kg体重/天，5～100mg/kg体重 /天量施用如上所述的化合物。在本发明的一些的实施方案中，可以以每日4次、每日3次、每日2 次、每日1次、每两日1次、每周1次或其他间隔的方式施用如上所述的化合物，任选地酌情每周或每月重复如上所述的给药方案。在本发明中，所述化合物的给药剂量可根据患者或受试者的病情轻重、年龄、体重、性别、给药方式及疗程等因素进行调整。
本发明化合物可以单独使用，经也可以和另一种或多种其它活性成分联合用于治疗、预防、抑制或者改善疾病或者病状，其中药物的联合使用比任何一种药物的单独使用更为安全或者更为有效。这种其它药物可以以对此通常使用的途径和量与本发明的化合物同时或者依次给药。当本发明的化合物与一种或者多种其它药物同时使用时，在单位剂型中含有该其它药物和本发明的化合物的药物组合物是优选的，特别是与药学可接受的载体联合。然而，联合治疗还可以包括在不同重叠日程中给予本发明的化合物和一种或者多种其它药物的治疗。还可以预期，当与一种或者多种其它活性成分联合使用时，本发明化合物和其它活性成分可以以比各自单独使用时更低的剂量使用。因此，除了本发明的化合物外，本发明药物组合物还包括含有一种或者多种其它活性成分的那些组合物。
技术主题三
本发明还提供了式I所示取代苯并杂环结构的化合物、其药用盐或酯、溶剂合物、异构体、多晶型物、同位素标记的化合物、代谢物或前药在制备FOXM1蛋白抑制剂或抗肿瘤的药物中的应用。
本发明研究了所述式I化合物与FOXM1蛋白的亲和力及抗肿瘤活性。实验证明本发明式I化合物XST20可能通过结合于FOXM1蛋白影响其信号通路，并抑制癌细胞增殖，用于治疗肿瘤相关疾病。
在本发明的一些实施方案中，将式I化合物、其药用盐或酯、溶剂合物、异构体、多晶型物、同位素标记的化合物、代谢物或前药在治疗性治疗中的用途。在本发明的一些实施方案中，所述治疗性治疗用于治疗肿瘤疾病。在一些实施方案中，肿瘤疾病是指机体在各种致病因素作用下,细胞异常增殖而形成的局部肿块，包括良性肿瘤、恶性肿瘤和交界肿瘤。包括但不局限于乳腺癌、卵巢癌、结直肠癌、黑色素瘤、非小细胞肺癌、小细胞肺癌、胃肠道间质瘤、宫颈癌、胰腺癌、前列腺癌、胃癌、慢性髓样白细胞过多症、肝癌、淋巴瘤、腹膜癌和软组织肉瘤。
在本发明的一些实施方案中，涉及到在体内或在体外结合FOXM1蛋白的方法，包括给予受试者、哺乳动物细胞以有效量的本发明中任一所述式I化合物、其药用盐或酯、溶剂合物、异构体、多晶型物、同位素标记的化合物、代谢物或前药的步骤。
在本发明的一些实施方案中，涉及到在体内或在体外抑制FOXM1活性的方法，包括给予受试者、哺乳动物细胞以有效量的本发明中任一所述式I化合物、其药用盐或酯、溶剂合物、异构体、多晶型物、同位素标记的化合物、代谢物或前药的步骤。
发明的有益效果
本申请的发明人通过大量研究及筛选发现了一系列取FOXM1抑制剂，该系列化合物能够通过抑制FOXM1下调其下游靶蛋白的水平，从而发挥抗肿瘤活性。因此该系列化合物可用于预防和/或治疗肿瘤疾病。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案，下面将对具体实施方式描述中所需要使用的附图作简单地介绍。
图1为21天小鼠体重变化图；
图2为21天小鼠肿瘤体积变化图；
图3为小鼠肿瘤荧光面积；
图4为小鼠肿瘤重量；
图5为Western blot检测小鼠肿瘤组织中FOXM1下游靶蛋白的表达水平图。
具体实施方式
以下结合结合具体实施例阐述本发明，这些实施例不旨在限制本发明的范围，而是为本领域技术人员制备和使用本发明化合物、组合物和方法提供指导。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
本申请中描述的化合物的化学名称通常从ChemDraw Ultra(ChambridgeSoft)和生成/或通常遵循 IUPAC命名法的原理。
本发明式I化合物可通过以下制备方法流程制的，本领域技术人员应当知道，为获得本发明中的各种化合物，可适当选择起始原料，致使通过反应方案，有或没有保护，进行最终所需的取代，以产生所需的产物。此外，本领域技术人员应当认识到，下述路线将有助于理解本发明，但并不限制本发明的内容：
路线一：以C系列化合物为代表的合成路线
Figure RE-RE-GDA0003873342650000131
反应条件：a)K2CO3,KI,DMF,90℃；b)CBr4,PPh3,THF,回流；c)K2CO3,KI,THF,回流；d)TFA, DCM,r.t.
路线二：以B和S系列化合物为代表的合成路线
Figure RE-RE-GDA0003873342650000132
反应条件：a)Pd/C,H2,EtOH,50psi,r.t；b)K2CO3,KI,DMF,90℃；c)NaOH,MeOH,回流；d)Pd/C,H2, MeOH,r.t.
路线四：以N系列化合物为代表的合成路线
Figure RE-RE-GDA0003873342650000141
反应条件：a)Cyclopentanol,K2CO3,KI,THF,回流。
路线五：以O系列化合物为代表的合成路线
Figure RE-RE-GDA0003873342650000142
反应条件：a)K2CO3,KI,DMF,90℃；b)CBr4,PPh3,THF,回流；c)环戊烷,K2CO3,KI,THF,回流.
路线八：以O2为代表的合成路线
Figure RE-RE-GDA0003873342650000143
反应条件：a)表氯醇,TBAB,NaOH,H2O,50℃；b)环戊烷,DMF,100℃。
以下通过具体实施例进行说明。
实施例1
Figure RE-RE-GDA0003873342650000144
2-(2-(4-(苄氧基)苯氧基)乙氧基)乙醇(2a)
氮气保护下，将4-苄氧基苯酚(6.06g,30mmol)，K2CO3(16.56g,120mmol)和KI(4.98g,30mmol) 溶于150mL无水DMF中，加热搅拌几分钟。将2-(2-氯乙氧基)乙醇(6.4mL,60mmol)的无水DMF 溶液(30mL)加入上述反应液，加热至90℃反应过夜。TLC检测，反应基本完全。停止加热，使反应液自然冷却至室温。过滤收集滤液，并减压浓缩蒸除DMF。用DCM稀释，分别用蒸馏水(100mL)，饱和食盐水(100mL)洗涤，分离有机层，加入适量无水硫酸钠干燥过夜，抽滤，旋干溶剂。剩余物经硅胶柱层析分离(石油醚：乙酸乙酯＝3:1)后得白色晶体2a 5.18g,收率60％，mp:79.0-80.2℃。1H NMR(400MHz,DMSO-d6)δ:7.43(d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(d,J＝7.2Hz,1H), 6.92(d,J＝9.2Hz,2H),6.86(d,J＝9.2Hz,2H),5.03(s,2H),4.61(t,J＝5.4Hz,1H),4.01(t,J＝5.4Hz, 2H),3.70(t,J＝5.4Hz,2H),3.51-3.47(m,4H).13C NMR(126MHz,CDCl3)δ:153.4,153.1,137.4, 128.8,128.1,127.7,116.0,115.8,72.7,70.8,70.0,68.2,62.0.
实施例2
Figure RE-RE-GDA0003873342650000151
1-(2-(2-溴乙氧基)乙氧基)-4-苄氧基苯(3a)
氮气保护下，将Ca(1.44g,5mmol)和三苯基膦(2.63g,10mmol)溶于40mL无水THF中。将 CBr4(3.4g,10mmol)的无水THF溶液(10mL)加入至上述反应液，室温搅拌反应，立刻有白色沉淀生成，之后变黄再变绿，TLC监测反应，1h反应完全。向反应液中加15mL乙酸乙酯，沉淀杂质，过滤反应液，滤除三苯基氧化膦杂质，收集滤液，蒸除溶剂得粗品。粗品经硅胶柱层析分离(石油醚：乙酸乙酯＝2:1)，得白色晶体3a 1.48g,收率85％，mp:58.5-59.3℃；MS(ESI)m/z:352[M+H]+。
实施例3
Figure RE-RE-GDA0003873342650000152
N-(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)环戊胺(XST20)
氮气保护下，将环戊胺(182μL,2mmol)，K2CO3(1.90g,13.8mmol)和KI(760mg,4.6mmol)溶于70mL无水DMF中。将中间体3a(1.6g,4.6mmol)加入其中，加热至80℃反应。TLC检测，5h 原料未反应完全，18h仍有部分原料剩余。停止加热，使反应液自然冷却至室温。过滤收集滤液，并浓缩蒸除溶剂。剩余物用EA溶解，蒸馏水和饱和食盐水洗涤，无水Na2SO4干燥，过滤，旋干得粗品。经硅胶柱层析分离(乙酸乙酯:乙醇:三乙胺＝10:1:0.001)后得浅棕色固体XST20 1.28g，收率78％， mp:33.1-34.9℃。1H NMR(400MHz,DMSO-d6)δ:7.42(d,J＝6.8Hz,2H),7.37(t,J＝8.0Hz,2H), 7.33-7.29(m,1H),6.92(d,J＝9.2Hz,2H),6.86(d,J＝9.2Hz,2H),5.03(s,2H),4.02-4.00(m,2H), 3.69-3.66(m,2H),3.49(t,J＝6.0Hz,2H),3.00-2.93(m,1H),2.63(t,J＝5.6Hz,2H),1.72-1.53(m,4H), 1.48-1.39(m,2H),1.28-1.19(m,2H).13C NMR(101MHz,DMSO-d6)δ:152.6,152.4,137.4,128.4, 127.7,127.6,115.6,115.3,70.3,69.6,68.8,67.4,59.2,47.4,32.6,23.6.
实施例4
Figure RE-RE-GDA0003873342650000161
N-(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)环丙胺(C1)
以环丙胺为原料，按照化合物XST20的制备方法得到棕色油状物C1，收率18％。1HNMR(500 MHz,DMSO-d6)δ:7.42(d,J＝7.5Hz,2H),7.38(t,J＝7.5Hz,2H),7.31(t,J＝7.5Hz,1H),6.92(d,J＝ 9.0Hz,2H),6.86(d,J＝9.0Hz,2H),5.03(s,2H),4.01(t,J＝4.5Hz,2H),3.68(t,J＝4.5Hz,2H),3.49(t,J ＝5.5Hz,2H),2.71(t,J＝5.5Hz,2H),2.09-2.05(m,1H),0.35-0.31(m,2H),0.18-0.16(m,2H).13C NMR(105MHz,DMSO-d6)δ:152.6,152.4,137.4,128.4,127.7,127.6,115.7,115.3,70.0,69.6,68.8,67.5, 48.4,30.0,6.1.
实施例5
Figure RE-RE-GDA0003873342650000162
N-(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)环丁胺(C2)
以环丁胺为原料，按照化合物XST20的制备方法得到棕色固体C2，收率35％，mp:37.2-38.5℃。 1H NMR(500MHz,DMSO-d6)δ:7.42(d,J＝7.0Hz,2H),7.38(t,J＝7.0Hz,2H),7.31(t,J＝7.0Hz,1H), 6.93(d,J＝9.0Hz,2H),6.86(d,J＝9.0Hz,2H),5.03(s,2H),4.01(t,J＝4.5Hz,2H),3.67(t,J＝4.5Hz, 2H),3.46(t,J＝6.0Hz,2H),3.17-3.11(m,1H),2.58(t,J＝6.0Hz,2H),2.09-2.03(m,2H),1.64-1.50(m, 4H).13C NMR(101MHz,DMSO-d6)δ:152.7,152.4,137.4,128.4,127.8,127.7,115.7,115.3,70.2,69.6, 68.9,67.4,53.7,45.8,30.5,14.4.
实施例6
Figure RE-RE-GDA0003873342650000163
N-(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)环己胺(C3)
以环己胺为原料，按照化合物XST20的制备方法得到淡黄色固体C3，收率53％，mp:58.7-59.8℃。 1H NMR(400MHz,DMSO-d6)δ:7.43(d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H), 6.92(d,J＝9.2Hz,2H),6.86(d,J＝9.2Hz,2H),5.03(s,2H),4.01(t,J＝4.8Hz,2H),3.68(t,J＝4.8Hz, 2H),3.49(t,J＝5.6Hz,2H),2.67(t,J＝5.6Hz,2H),2.36-2.29(m,1H),1.78-1.74(m,2H),1.66-1.61(m, 2H),1.54-1.50(m,1H),1.23-1.08(m,3H),1.00-0.94(m,2H).13C NMR(101MHz,DMSO-d6)δ:152.6, 152.4,137.4,128.4,127.7,127.6,115.7,115.3,70.4,69.6,68.8,67.5,56.0,45.8,33.0,25.9,24.4.HRMS (ESI):calcd for C23H32O3N[M+H]+,370.2377,found 370.2371.
实施例7
Figure RE-RE-GDA0003873342650000171
N-(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)环庚胺(C4)
以环庚胺为原料，按照化合物XST20的制备方法得到棕色油状物C4，收率23％。1HNMR(400 MHz,DMSO-d6)δ:7.42(d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.92(d,J＝ 9.2Hz,2H),6.86(d,J＝9.2Hz,2H),5.03(s,2H),4.02-4.00(m,2H),3.69-3.66(m,2H),3.49(t,J＝5.6Hz, 2H),2.64(t,J＝5.6Hz,2H),2.58-2.52(m,1H),1.74-1.68(m,2H),1.60-1.53(m,2H),1.51-1.42(m,4H), 1.38-1.22(m,4H).13C NMR(105MHz,DMSO-d6)δ:152.6,152.4,137.4,128.4,127.7,127.6,115.7, 115.3,70.3,69.6,68.8,67.5,58.0,46.3,34.2,28.0,23.7.
实施例8
Figure RE-RE-GDA0003873342650000172
N-(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)苯胺(C5)
以苯胺为原料，按照化合物XST20的制备方法得到棕色固体C5，收率46％。mp:47.9-49.1℃。1H NMR(400MHz,DMSO-d6)δ:7.42(d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H), 7.05(t,J＝7.2Hz,2H),6.92(d,J＝9.2Hz,2H),6.86(d,J＝9.2Hz,2H),6.57(d,J＝7.6Hz,2H),6.52(t,J ＝7.2Hz,1H),5.49(s,1H),5.03(s,2H),4.03(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.61(t,J＝5.6Hz, 2H),3.19(t,J＝5.6Hz,2H).13CNMR(101MHz,DMSO-d6)δ:153.1,152.9,149.1,137.8,129.4(2), 128.8(2),128.2,128.1(2),116.2,116.1(2),115.8(2),112.5(2),70.1,69.6,69.4,68.0,43.1.
实施例9
Figure RE-RE-GDA0003873342650000181
N-2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基-4-吡啶胺(C6)
以化合物4-氨基吡啶为原料，按照化合物XST20的制备方法得到淡黄色固体C6，收率22％， mp:120.7-122.3℃。1H NMR(400MHz,DMSO-d6)δ:7.24-1.18(m,2H),6.62-6.49(m,5H),6.11-6.09 (m,2H),6.00-5.93(m,4H),4.21(s,2H),3.50-3.48(m,2H),3.20-3.19(m,2H),3.08-3.06(m,2H),2.98- 2.96(m,2H).13C NMR(105MHz,DMSO-d6)δ:151.3,145.1,144.9,135.0,129.4,120.0,119.3,119.1, 107.4,107.0,100.9,62.1,61.4,61.2,59.6,49.4.
实施例10
Figure RE-RE-GDA0003873342650000182
3-(N-(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)氨基)四氢呋喃(C7)
以化合物3-氨基四氢呋喃为原料，按照化合物XST20的制备方法得到淡黄色油状物C7，收率 39％。1H NMR(500MHz,DMSO-d6)δ:7.42(d,J＝7.0Hz,2H),7.38(t,J＝7.0Hz,2H),7.31(t,J＝7.0 Hz,1H),6.92(d,J＝9.0Hz,2H),6.86(d,J＝9.0Hz,2H),5.03(s,2H),4.01(t,J＝4.5Hz,2H),3.68(m, 4H),3.62(dd,J＝5.5,8.0Hz,1H),3.49(t,J＝5.5Hz,2H),3.36(dd,J＝4.0,4.5Hz,1H),3.26(m,1H), 2.65(m,2H),1.91(m,1H),1.59(m,1H).13C NMR(101MHz,DMSO-d6)δ:152.6,152.4,137.4,128.4(2), 127.7,127.6(2),115.7(2),115.3(2),72.6,70.3,69.6,68.9,67.4,66.4,58.1,47.3,32.6.
实施例11
Figure RE-RE-GDA0003873342650000183
3-((2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)氨基)-1-吡咯烷甲酸叔丁酯(C8)
以化合物3-氨基吡咯烷-1-甲酸叔丁酯为原料，按照化合物XST20的制备方法得到淡黄色油状物 C8，收率76％。1H NMR(500MHz,DMSO-d6)δ:7.42(d,J＝9.5Hz,2H),7.38(t,J＝9.0Hz,2H),7.31(t, J＝9.0Hz,1H),6.92(d,J＝10.0Hz,2H),6.86(d,J＝10.0Hz,2H),5.03(s,2H),4.02(m,2H),3.69-3.68 (m,2H),3.49(t,J＝6.5Hz,2H),3.28-3.24(m,1H),3.19-3.13(m,2H),2.94(dd,J＝5.5,13.5Hz,1H), 2.70-2.62(m,2H),1.90-1.86(m,2H),1.64-1.56(m,1H),1.38(s,11H).13C NMR(101MHz,DMSO-d6) δ:152.6,152.4,137.4,128.4,127.7,127.6,115.6,115.3,78.0,70.3,69.6,68.8,67.4,57.2,56.4,51.6,51.4,46.9,44.2,44.0,31.3,30.6,28.2.
实施例12
Figure RE-RE-GDA0003873342650000191
N-(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)-3-吡咯烷胺(C9)
将C8(250mg,0.55mmol)加入至DCM(5mL)中，再加入三氟醋酸(340μL,4.4mmol)室温搅拌反应。TLC监测反应，6h反应完全，蒸干反应液。用DCM(10mL)稀释后，再次蒸干，重复此过程一次。随后加DCM(4mL)和1N HCl(4mL)搅拌，用1N NaOH调节pH至9左右，出现固体。旋干溶剂，用甲醇溶解稀释后过滤，收集滤液，旋干甲醇，剩余物用真空干燥箱干燥得棕黄色油状物C9 52mg，收率26％。1H NMR(500MHz,CD3OD)δ:7.41(d,J＝7.5Hz,2H),7.36(t,J＝7.5Hz,2H),7.30(t,J＝ 7.5Hz,1H),6.92(d,J＝9.0Hz,2H),6.87(d,J＝9.0Hz,2H),5.02(s,2H),4.11(t,J＝4.5Hz,2H),3.86(t, J＝4.5Hz,2H),3.80(t,J＝5.0Hz,2H),3.24(t,J＝5.0Hz,2H),3.10-3.05(m,1H),2.10-2.05(m,2H), 1.90-1.84(m,2H),1.34-1.31(m,2H).13C NMR(126MHz,CD3OD)δ:154.8,154.4,139.1,129.6,129.0, 128.7,117.2,116.6,71.7,71.2,69.3,67.5,58.4,45.6,30.4,26.2,25.6.
实施例13
Figure RE-RE-GDA0003873342650000192
2-(2-((2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)氨基)乙氧基)乙醇(C10)
以化合物2-氨基乙氧基乙醇为原料，按照化合物XST20的制备方法得到淡黄色油状物C10，收率10％。1H NMR(500MHz,DMSO-d6)δ:7.43(d,J＝7.0Hz,2H),7.38(t,J＝7.0Hz,2H),7.31(t,J＝7.0 Hz,1H),6.92(d,J＝9.0Hz,2H),6.86(d,J＝9.0Hz,2H),5.03(s,2H),4.01(t,J＝4.5Hz,2H),3.68(t,J＝ 4.5Hz,2H),3.50(t,J＝5.5Hz,2H),3.47(t,J＝5.0Hz,2H),3.44(t,J＝5.5Hz,2H),3.38(t,J＝5.0Hz, 2H),2.68-2.64(m,4H).13C NMR(101MHz,DMSO-d6)δ:152.6,152.4,137.4,128.4,127.7,127.6,115.7, 115.3,72.2,69.6,69.6,69.4,68.9,67.4,60.2,48.5,48.4.
实施例14
Figure RE-RE-GDA0003873342650000201
2-(2-(4-(苄氧基)苯氧基)乙氧基)-N,N-二甲基乙胺(C11)
以化合物二甲胺为原料，按照化合物XST20的制备方法得到无色油状物C11，收率35％。1H NMR (500MHz,DMSO-d6)δ:7.42(d,J＝7.0Hz,2H),7.38(t,J＝7.0Hz,2H),7.31(t,J＝7.0Hz,1H),6.92(d, J＝9.0Hz,2H),6.86(d,J＝9.0Hz,2H),5.03(s,2H),4.00(t,J＝4.5Hz,2H),3.68(t,J＝4.5Hz,2H),3.53 (t,J＝6.0Hz,2H),2.43(t,J＝6.0Hz,2H),2.16(s,6H).13C NMR(126MHz,DMSO-d6)δ:152.6,152.4, 137.4,128.4,127.8,127.7,115.7,115.3,69.6,68.9,68.6,67.5,58.3,45.6.
实施例15
Figure RE-RE-GDA0003873342650000202
4-(2-(2-(环戊基氨基)乙氧基)乙氧基)苯酚(4a)
将化合物XST20(1.85g,5mmol)溶于无水甲醇(100mL)中，配成流动氢化的黄金浓度0.05M，用流动加氢装置进行反应(设置常温常压全H2模式，流速为1mL/min，Pd/C柱催化)。TLC监测反应，一次性反应完全，旋干溶剂得白色固体4a 1.3g，收率98％,mp:106.3-107.5℃。1H NMR(400MHz, DMSO-d6)δ:8.90(s,1H),6.74(d,J＝9.2Hz,2H),6.65(d,J＝9.2Hz,2H),3.96(t,J＝4.8Hz,2H),3.66(t, J＝4.8Hz,2H),3.48(t,J＝6.4Hz,2H),2.96(m,1H),2.63(t,J＝4.8Hz,2H),1.67(m,2H),1.58(m,2H), 1.44(m,2H),1.24(m,2H).13CNMR(126MHz,CDCl3)δ:152.2,151.3,116.4,116.0,70.1,69.9,67.9, 60.1,48.06,32.7,24.2.
实施例16
Figure RE-RE-GDA0003873342650000203
N-(2-(2-(4-((4-甲氧基苄基)氧基)苯氧基)乙氧基)乙基)环戊胺(B1)
氮气保护下，将4a(100mg,0.38mmol)，K2CO3(159mg,1.14mmol)和KI(63mg,0.38mmol)溶于 5mL无水DMF中，加热搅拌几分钟。将4-甲氧基溴苄(89μL,0.57mmol)的无水DMF溶液(2mL)加入上述反应液，室温搅拌反应。TLC检测，12h反应完全。过滤反应液，收集滤液，分别用蒸馏水(20 mL)，饱和食盐水(20mL)洗涤，分离有机层，加入适量无水硫酸钠干燥过夜，抽滤，旋干溶剂。剩余物经硅胶柱层析分离(石油醚:乙酸乙酯:三乙胺＝3:1:0.001)后得淡黄色油状物B1 120mg，收率82％。1H NMR(400MHz,DMSO-d6)δ:8.89(s,1H),7.21(d,J＝8.4Hz,2H),6.83(d,J＝8.4Hz,2H),6.72(d,J ＝9.2Hz,2H),6.64(d,J＝9.2Hz,2H),3.92(t,J＝4.4Hz,2H),3.71(s,3H),3.59(t,J＝4.8Hz,2H),3.54 (s,2H),3.42(t,J＝6.4Hz,2H),3.06(m,1H),2.58(t,J＝6.4Hz,2H),1.70(m,2H),1.57(m,2H),1.41(m, 4H).13C NMR(101MHz,DMSO-d6)δ:158.1,151.4,151.3,132.4,129.6,115.7,115.4,113.5,69.3,69.0,67.6,63.1,55.6,55.0,50.1,28.9,23.9.
实施例17
Figure RE-RE-GDA0003873342650000211
N-(2-(2-(4-((4-甲基苄基)氧基)苯氧基)乙氧基)乙基)环戊胺(B2)
以化合物4-甲基溴苄为原料，按照化合物B1的制备方法得到白色油状物B2，收率42％。1H NMR (400MHz,DMSO-d6)δ:8.88(s,1H),7.18(d,J＝7.6Hz,2H),7.07(d,J＝7.6Hz,2H),6.71(d,J＝9.2Hz, 2H),6.65(d,J＝9.2Hz,2H),3.90(t,J＝4.8Hz,2H),3.58(t,J＝4.8Hz,2H),3.57(s,2H),3.43(t,J＝6.4 Hz,2H),3.07(m,1H),2.58(t,J＝6.4Hz,2H),2.26(s,3H),1.70(m,2H),1.57(m,2H),1.38(m,4H).13C NMR(101MHz,DMSO-d6)δ:151.3,151.2,137.5,135.4,128.6,128.4,115.7,115.34,69.3,69.0,67.6, 63.2,55.9,50.2,28.8,23.8,20.7.。
实施例18
Figure RE-RE-GDA0003873342650000212
N-(2-(2-(4-((4-(苄氧基)苄基)氧基)苯氧基)乙氧基)乙基)环戊胺(B3)
以化合物4-苄氧基溴苄为原料，按照化合物B1的制备方法得到淡黄色油状物B3，收率48％。1H NMR(400MHz,DMSO-d6)δ:8.89(s,1H),7.43(d,J＝6.8Hz,2H),7.38(t,J＝6.8Hz,2H),7.31(t,J＝ 7.6Hz,1H),7.21(d,J＝8.8Hz,2H),6.91(d,J＝8.8Hz,2H),6.72(d,J＝9.2Hz,2H),6.65(d,J＝9.2Hz, 2H),5.05(s,2H),3.91(t,J＝4.8Hz,2H),3.59(t,J＝4.8Hz,2H),3.54(s,2H),3.42(t,J＝6.4Hz,2H), 3.07(m,1H),2.58(t,J＝6.4Hz,2H),1.70(m,2H),1.56(m,2H),1.40(m,4H).13C NMR(101MHz, DMSO-d6)δ:157.1,151.3,151.2,137.2,132.6,129.5,128.4,127.8,127.7,115.7,115.4,114.3,69.3,69.1, 69.0,67.6,63.1,55.5,50.1,28.8,23.8.1-67。
实施例19
Figure RE-RE-GDA0003873342650000221
N-(2-(2-(4-((4-氯苄基)氧基)苯氧基)乙氧基)乙基)环戊胺(B4)
以化合物4-氯溴苄为原料，按照化合物B1的制备方法得到棕黄色油状物B4，收率30％。1H NMR (400MHz,DMSO-d6)δ:8.89(s,1H),7.35-7.30(m,4H),6.72-6.69(m,2H),6.67-6.64(m,2H),3.92-3.90 (m,2H),3.61(s,2H),3.60-3.58(m,2H),3.44(t,J＝6.4Hz,2H),3.11-3.03(m,1H),2.60(t,J＝6.4Hz, 2H),1.74-1.67(m,2H),1.58-1.53(m,2H),1.45-1.32(m,4H).13C NMR(101MHz,DMSO-d6)δ:151.3, 151.2,140.0,130.9,130.0,127.9,115.7,115.4,69.3,69.0,67.6,63.4,55.3,50.6,28.8,23.8.
实施例20
Figure RE-RE-GDA0003873342650000222
4-((4-(2-(2-(2-(环戊基氨基)乙氧基)乙氧基)苯氧基)甲基)苯甲酸甲酯(B5)
以化合物4-溴甲基苯甲酸甲酯为原料，按照化合物B1的制备方法得到棕色油状物B5，收率55％。1H NMR(400MHz,DMSO-d6)δ:8.89(s,1H),7.87(d,J＝8.0Hz,2H),7.47(d,J＝8.0Hz,2H),6.70(d,J ＝8.8Hz,2H),6.64(d,J＝8.8Hz,2H),3.90(t,J＝4.4Hz,2H),3.83(s,3H),3.71(s,2H),3.58(t,J＝4.4Hz, 2H),3.45(t,J＝6.4Hz,2H),3.09(m,1H),2.63(t,J＝6.4Hz,2H),1.71(m,2H),1.57(m,2H),1.39(m, 4H).13C NMR(101MHz,DMSO-d6)δ:166.3,151.3,151.3,147.2,129.0,128.5,128.0,115.7,115.4,69.3, 69.0,67.6,63.8,55.9,52.1,51.1,28.9,23.8.
实施例21
Figure RE-RE-GDA0003873342650000223
4-((4-(2-(2-(2-(环戊基氨基)乙氧基)乙氧基)苯氧基)甲基)苯甲酸(B6)
将B5(300mg,0.74mmol)溶于甲醇(15mL)中，加入1N NaOH溶液(1.5mL,1.5mmol)加热回流反应。TLC监测，20h反应完全。停止加热，自然冷却反应液至室温，过滤反应液，收集滤液并旋干。剩余物用少量蒸馏水溶解，再用1N HCl溶液调节pH至2-3，直到有固体析出。蒸除溶剂，甲醇溶解后过滤，收集滤液，旋干，剩余物用真空干燥箱干燥得淡粉色固体B6110mg，收率30％，mp:199.1- 201.9℃。1H NMR(400MHz,CD3OD)δ:8.08(d,J＝8.0Hz,2H),7.71(d,J＝8.0Hz,2H),6.79(d,J＝4.8 Hz,2H),6.71(d,J＝4.8Hz,2H),4.57(s,2H),4.10(t,J＝4.4Hz,2H),3.92-3.87(m,1H),3.84-3.82(m, 4H),3.39(t,J＝4.4Hz,2H),2.20-2.18(m,2H),1.93-1.85(m,4H),1.69-1.66(m,2H).13C NMR(101 MHz,CD3OD)δ:169.0,153.4,152.9,136.1,133.6,132.8,131.6,117.1,116.8,71.3,69.3,67.1,66.3,57.7,51.5,29.1,25.3.
实施例22
Figure RE-RE-GDA0003873342650000231
3-((4-(2-(2-(2-(环戊基氨基)乙氧基)乙氧基)苯氧基)甲基)苯甲酸甲酯(B7)
以化合物3-溴甲基苯甲酸甲酯为原料，按照化合物B1的制备方法得到淡黄色固体B7，收率96％， mp:73.6-75.0℃。1H NMR(500MHz,DMSO-d6)δ:8.87(s,1H),7.93(s,1H),7.80(d,J＝7.5Hz,1H), 7.60(d,J＝7.5Hz,1H),7.43(t,J＝7.5Hz,1H),6.70(d,J＝9.0Hz,2H),6.64(d,J＝9.0Hz,2H),3.90(t,J ＝4.5Hz,2H),3.83(s,2H),3.57(t,J＝4.5Hz,2H),3.45(t,J＝6.0Hz,2H),3.10(m,1H),2.63(t,J＝6.0 Hz,2H),1.72(m,2H),1.58(m,2H),1.40(m,4H).13C NMR(101MHz,DMSO-d6)δ:166.4,151.2,151.2, 141.9,133.2,129.4,128.9,128.4,127.4,115.6,115.4,69.2,68.9,67.5,63.5,55.6,52.1,50.7,28.9,23.8.
实施例23
Figure RE-RE-GDA0003873342650000232
3-((4-(2-(2-(2-(环戊基氨基)乙氧基)乙氧基)苯氧基)甲基)苯甲酸(B8)
以化合物B7为原料，按照化合物B6的制备方法得到粉色固体B8，收率30％，mp:209.1-211.7℃。1H NMR(400MHz,CD3OD)δ:8.21(s,1H),8.09(d,J＝7.6Hz,1H),7.78(d,J＝7.6Hz,1H),7.53(t,J＝ 7.6Hz,1H),6.76(d,J＝9.2Hz,2H),6.68(d,J＝9.2Hz,2H),4.54(s,2H),4.10-4.07(m,2H),3.89-3.86(m, 1H),3.83-3.79(m,4H),3.37-3.34(m,2H),2.20-2.15(m,2H),1.89-1.79(m,4H),1.71-1.60(m,2H).13C NMR(101MHz,CD3OD)δ:169.42,153.41,152.91,136.72,133.95,133.57,132.25,131.86,130.64, 117.05,116.91,71.31,69.32,66.96,66.38,57.82,51.46,29.26,25.35.
实施例24
Figure RE-RE-GDA0003873342650000241
2-((4-(2-(2-(环戊基氨基)乙氧基)乙氧基)苯氧基)甲基)苯甲酸甲酯(B9)
以化合物2-溴甲基苯甲酸甲酯为原料，按照化合物B1的制备方法得到淡黄色油状物B9，收率 98％。1H NMR(500MHz,CD3OD)δ:8.91(s,1H),7.62(t,J＝9.0Hz,2H),7.46(t,J＝7.5Hz,1H),7.31 (t,J＝7.5Hz,1H),6.70(d,J＝9.0Hz,2H),6.64(d,J＝9.0Hz,2H),3.89-3.87(m,4H),3.78(s,3H),3.53 (t,J＝4.5Hz,2H),3.34-3.32(m,2H),3.08-3.02(m,1H),2.57(t,J＝6.5Hz,2H),1.68-1.65(m,2H), 1.58-1.52(m,2H),1.43-1.39(m,2H),1.36-1.29(m,2H).13C NMR(101MHz,DMSO-d6)δ:168.2,151.2, 151.2,141.3,131.1,130.7,129.6,128.9,126.6,115.6,115.4,69.1,68.9,67.5,63.8,54.6,51.9,50.8,28.4, 23.7.
实施例25
Figure RE-RE-GDA0003873342650000242
2-((4-(2-(2-(环戊基氨基)乙氧基)乙氧基)苯氧基)甲基)苯甲酸(B10)
以化合物B9为原料，按照化合物B6的制备方法得到粉色固体B10，收率38％，mp:221.3-224.7℃。1H NMR(400MHz,CD3OD)δ:8.08(d,J＝8.0Hz,2H),7.71(d,J＝8.0Hz,2H),6.79(d,J＝4.8Hz,2H), 6.71(d,J＝4.8Hz,2H),4.57(s,2H),4.10(t,J＝4.4Hz,2H),3.92-3.87(m,1H),3.84-3.82(m,4H),3.39 (t,J＝4.4Hz,2H),2.20-2.18(m,2H),1.93-1.85(m,4H),1.69-1.66(m,2H).13C NMR(101MHz, CD3OD)δ:174.6,153.6,152.7,139.5,134.2,133.0,132.3,131.3,131.2,117.0,116.9,71.2,69.3,66.7,66.5, 58.8,51.2,28.9,25.1.
实施例26
Figure RE-RE-GDA0003873342650000251
4-((4-(2-(2-(环戊基氨基)乙氧基)乙氧基)苯氧基)甲基)苯甲醛(B11)
以化合物4-溴甲基苯甲醛为原料，按照化合物B1的制备方法得到淡黄色油状物B11，收率75％。1H NMR(500MHz,DMSO-d6)δ:9.95(s,1H),8.88(s,1H),7.82(d,J＝8.0Hz,2H),7.56(d,J＝8.0Hz, 2H),6.70(d,J＝9.0Hz,2H),6.64(d,J＝9.0Hz,2H),3.91(t,J＝4.5Hz,2H),3.74(s,2H),3.58(t,J＝4.5 Hz,2H),3.47(t,J＝6.0Hz,2H),3.10(m,1H),2.64(t,J＝6.0Hz,2H),1.72(m,2H),1.57(m,2H),1.40(m, 4H).13C NMR(126MHz,DMSO-d6)δ:151.3,151.3,148.8,135.0,129.4,128.8,115.7,115.4,69.5,69.0, 67.6,63.8,56.0,51.1,28.9,23.8.
实施例27
Figure RE-RE-GDA0003873342650000252
N-(2-(2-(4-((4-硝基苄基)氧基)苯氧基)乙氧基)乙基)环戊胺(B12)
以化合物对硝基溴化苄为原料，按照化合物B1的制备方法得到淡黄色油状物B12，收率49％。1H NMR(500MHz,DMSO-d6)δ:8.88(s,1H),8.13(d,J＝8.5Hz,2H),7.61(d,J＝8.5Hz,2H),6.70(d,J ＝8.5Hz,2H),6.64(d,J＝8.5Hz,2H),3.91(t,J＝4.5Hz,2H),3.77(s,2H),3.58(t,J＝4.5Hz,2H),3.47(t, J＝6.0Hz,2H),3.10(m,1H),2.65(t,J＝6.0Hz,2H),1.72(m,2H),1.57(m,2H),1.43(m,2H),1.34(m, 2H).13C NMR(101MHz,DMSO-d6)δ:151.3,151.3,150.1,146.3,129.2,123.2,115.7,115.4,69.4,69.1, 67.6,64.0,55.6,51.4,29.0,23.8.
实施例28
Figure RE-RE-GDA0003873342650000253
4-((4-(2-(2-(环戊基氨基)乙氧基)乙氧基)苯氧基)甲基)苯胺(B13)
将化合物B12(150mg,0.39mmol)溶于甲醇(9.5mL)中，配成流动氢化的黄金浓度0.05M，用流动加氢装置进行反应(设置常温常压全H2模式，流速为1mL/min，Pd/C柱催化)。TLC监测反应，一次性反应完全，旋干溶剂。剩余物经硅胶柱层析分离得棕色固体B13 65mg，收率45％，mp:110.0- 112.2℃。1H NMR(400MHz,DMSO-d6)δ:8.88(s,1H),6.93(d,J＝7.6Hz,2H),6.72(d,J＝8.8Hz,2H), 6.64(d,J＝8.8Hz,2H),6.48(d,J＝7.6Hz,2H),4.87(s,2H),3.91(s,2H),3.59(s,2H),3.41(m,4H),3.05 (m,1H),2.55(t,J＝6.4Hz,2H),1.70(m,2H),1.56(m,2H),1.39(m,4H).
实施例29
Figure RE-RE-GDA0003873342650000261
N-(2-(2-(4-((3-硝基苄基)氧基)苯氧基)乙氧基)乙基)环戊胺(B14)
以化合物3-硝基溴苄为原料，按照化合物B1的制备方法得到淡黄色油状物B14，收率82％。1H NMR(500MHz,DMSO-d6)δ:8.87(s,1H),8.20(s,1H),8.06(d,J＝8.0Hz,1H),7.78(d,J＝8.0Hz,1H), 7.57(t,J＝8.0Hz,1H),6.69(d,J＝9.0Hz,2H),6.63(d,J＝9.0Hz,2H),3.91(t,J＝4.5Hz,2H),3.78(s, 2H),3.58(t,J＝4.5Hz,2H),3.48(t,J＝6.0Hz,2H),3.12(m,1H),2.66(t,J＝6.0Hz,2H),1.73(m,2H), 1.58(m,2H),1.44(m,2H),1.36(m,2H).13CNMR(101MHz,DMSO-d6)δ:151.2,151.2,147.8,144.0, 134.8,129.4,122.5,121.5,115.6,115.3,69.2,69.0,67.5,63.7,55.0,51.1,28.9,23.7.
实施例30
Figure RE-RE-GDA0003873342650000262
3-((4-(2-(2-(环戊基氨基)乙氧基)乙氧基)苯氧基)甲基)苯胺(B15)
以化合物B14为原料，按照化合物B13的制备方法得到淡黄色油状物B15，收率27％。1H NMR (400MHz,DMSO-d6)δ:8.88(s,1H),6.90(t,J＝7.6Hz,1H),6.72(d,J＝7.6Hz,2H),6.65(d,J＝7.6Hz, 2H),6.55(s,1H),6.44(d,J＝7.6Hz,1H),6.39(d,J＝7.6Hz,1H),4.93(s,2H),3.92(s,2H),3.60(s,2H), 3.44(m,4H),3.08(m,1H),2.58(t,J＝7.0Hz,2H),1.72(m,2H),1.57(m,2H),1.40(m,4H).13C NMR (101MHz,DMSO-d6)δ:151.4,151.3,148.5,141.2,128.5,116.2,115.8,115.5,114.0,112.4,69.3,69.1, 67.7,63.2,56.6,50.3,28.8,23.9.
实施例31
Figure RE-RE-GDA0003873342650000271
N-(2-(2-(4-((2-硝基苄基)氧基)苯氧基)乙氧基)乙基)环戊胺(B16)
以化合物2-硝基溴苄为原料，按照化合物B1的制备方法得到淡黄色油状物B16，收率93％。1H NMR(500MHz,DMSO-d6)δ:8.88(s,1H),7.83(d,J＝8.0Hz,1H),7.78(d,J＝7.5Hz,1H),7.62(t,J＝8.0Hz,1H),7.47(t,J＝7.5Hz,1H),6.70(d,J＝9.0Hz,2H),6.63(d,J＝9.0Hz,2H),3.91(s,2H),3.88(t, J＝4.5Hz,2H),3.53(m,J＝4.5Hz,2H),3.36(t,J＝6.0Hz,2H),3.04(m,1H),2.60(t,J＝6.0Hz,2H), 1.66(m,2H),1.55(m,2H),1.42(m,2H),1.30(m,2H).13C NMR(101MHz,DMSO-d6)δ:151.3,151.3, 149.4,135.5,132.6,131.1,128.1,123.9,115.7,115.4,69.1,69.0,67.6,64.0,53.3,51.1,28.5,23.6.
实施例32
Figure RE-RE-GDA0003873342650000272
2-((4-(2-(2-(环戊基氨基)乙氧基)乙氧基)苯氧基)甲基)苯胺(B17)
以化合物B16为原料，按照化合物B13的制备方法得到黄色油状物B17，收率10％。1H NMR(500 MHz,DMSO-d6)δ:8.91(s,1H),6.95(t,J＝7.0Hz,2H),6.73(d,J＝9.0Hz,2H),6.65(d,J＝9.0Hz,2H), 6.57(d,J＝8.5Hz,1H),6.47(t,J＝7.0Hz,1H),5.28(s,2H),3.92(t,J＝4.5Hz,2H),3.58(t,J＝4.5Hz, 2H),3.54(s,2H),3.46(t,J＝6.0Hz,2H),3.07-3.04(m,1H),2.56(t,J＝6.0Hz,2H),1.74-1.64(m,2H), 1.60-1.52(m,2H),1.47-1.37(m,4H).13C NMR(126MHz,DMSO-d6)δ:151.3,151.2,147.9,129.9,127.8, 122.3,115.8,115.7,115.4,114.5,68.9,68.7,67.5,62.5,55.8,49.1,27.9,23.8.
实施例33
Figure RE-RE-GDA0003873342650000281
1-(苄氧基)-4-(2-(2-(环戊氧基)乙氧基)乙氧基)苯(N1)
以化合物环戊醇为原料，按照化合物XST20的制备方法得到淡黄色油状物N1，收率15％。1H NMR (500MHz,DMSO-d6)δ:7.42(d,J＝7.0Hz,2H),7.38(t,J＝7.0Hz,2H),7.31(t,J＝7.0Hz,1H),6.92(d, J＝9.0Hz,2H),6.86(d,J＝9.0Hz,2H),5.03(s,2H),4.00(t,J＝4.5Hz,2H),3.88-3.87(m,1H),3.69(t,J ＝4.5Hz,2H),3.54(t,J＝5.0Hz,2H),3.45(t,J＝5.0Hz,2H),1.66-1.62(m,2H),1.59-1.54(m,4H), 1.48-1.44(m,2H).13C NMR(105MHz,DMSO-d6)δ:152.6,152.4,137.4,128.4,127.7,127.6,115.7,115.3, 80.7,70.1,69.6,69.0,67.5,31.8,23.1.
实施例34
Figure RE-RE-GDA0003873342650000282
6-(4-(苄氧基)苯氧基)-1-己醇(2m)
以化合物4-苄氧基苯酚和6-氯-1-己醇为原料，按照化合物2a的制备方法得到淡黄色固体2m，收率55％，mp:94.9-96.8℃。MS(ESI)m/z:301[M+H]+。1H NMR(400MHz,DMSO-d6)δ:7.44-7.41(m, 2H),7.40-7.36(m,2H),7.33-7.29(m,1H),6.93-6.90(m,2H),6.85-6.82(m,2H),5.03(s,2H),4.33(t,J＝ 5.2Hz,1H),3.87(t,J＝6.8Hz,2H),3.40-3.36(m,2H),1.70-1.63(m,2H),1.46-1.30(m,6H).
实施例35
Figure RE-RE-GDA0003873342650000283
1-苄氧基-4-((6-溴己基)氧基)苯(3m)
以化合物2m为原料，按照化合物3a的制备方法得到淡黄色固体3m，收率99％，mp:78.1-79.4℃。 MS(ESI)m/z:364[M+H]+。1H NMR(400MHz,DMSO-d6)δ:7.44-7.41(m,2H),7.40-7.36(m,2H), 7.33-7.29(m,1H),6.93-6.90(m,2H),6.85-6.83(m,2H),5.03(s,2H),3.88(t,J＝6.4Hz,2H),3.53(t,J＝ 6.4Hz,2H),1.85-1.78(m,2H),1.71-1.64(m,2H),1.43-1.41(m,4H).
实施例36
Figure RE-RE-GDA0003873342650000291
N-(6-(4-(苄氧基)苯氧基)己基)环戊胺(O1)
以化合物3m和环戊胺为原料，按照化合物XST20的制备方法得到淡黄色固体O1，收率52％， mp:51.2-53.3℃。1H NMR(500MHz,DMSO-d6)δ:7.42(d,J＝7.0Hz,2H),7.38(t,J＝7.0Hz,2H),7.31 (t,J＝7.0Hz,1H),6.91(d,J＝9.0Hz,2H),6.83(d,J＝9.0Hz,2H),5.03(s,2H),3.87(t,J＝6.5Hz,2H), 2.97-2.93(m,1H),2.45(t,J＝6.5Hz,2H),1.66-1.65(m,4H),1.58-1.58(m,2H),1.44-1.32(m,8H), 1.26-1.23(m,2H).13C NMR(105MHz,DMSO-d6)δ:152.9,152.3,137.4,128.4,127.7,127.6,115.7, 115.2,69.6,67.8,59.3,47.8,32.3,29.5,28.8,26.6,25.5,23.6.HRMS(ESI):calcd for C24H34O2N[M+H]+, 368.2584,found368.2581.
实施例37
Figure RE-RE-GDA0003873342650000292
2-((4-(苄氧基)苯氧基)甲基)环氧乙烷(5)
将4-苄氧基苯酚(1.45g,7mmol)和NaOH(0.84g,21mmol)溶于30mL H2O中，室温搅拌0.5h。将上述反应液滴加到含有表氯醇(1.64mL，21mmol)和四丁基溴化铵(112mg，0.35mmol)的50mL圆底烧瓶中，加热至50℃反应过夜。TLC检测，反应基本完全。停止加热，使反应液自然冷却至室温。用EA萃取(20mL×3)，合并有机相，加入适量无水硫酸钠干燥过夜，抽滤，旋干溶剂。剩余物经硅胶柱层析分离(石油醚：乙酸乙酯＝3:1)后得白色固体化合物51.05g,收率59％，mp:69.5-71.0℃。 MS(ESI)m/z:256[M+H]+。1H NMR(400MHz,DMSO-d6)δ:7.43-7.42(m,2H),7.39-7.36(m,2H), 7.32-7.30(m,1H),6.94-6.92(m,2H),6.90-6.88(m,2H),5.03(s,2H),4.23(dd,J＝1.6,7.6Hz,1H),3.76 (q,J＝4.4Hz,1H),3.30-3.27(m,1H),2.82-2.81(m,1H),2.68-2.67(m,1H).
实施例38
Figure RE-RE-GDA0003873342650000293
N-(3-(4-苄氧基基苯氧基)-2-羟基丙基)环戊胺(O2)
将环氧化物5(450mg，1.6mmol)和环戊胺(0.25mL，2.5mmol)溶于15mL DMF中。加热至100℃下搅拌60h。反应完成后，将反应液用乙酸乙酯(25mL×3)萃取。合并有机相，用无水Na2SO4干燥，浓缩，得到粗产物。粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝2:1)得到白色固体O2，收率10％， mp:151.6-154.9℃。1H NMR(500MHz,DMSO-d6)δ:7.42(d,J＝7.0Hz,2H),7.38(t,J＝7.0Hz,2H), 7.31(t,J＝7.0Hz,1H),6.92(d,J＝9.0Hz,2H),6.86(d,J＝9.0Hz,2H),5.03(s,2H),3.89-3.86(m,2H), 3.84-3.81(m,1H),3.12-3.10(m,1H),2.77-2.74(m,1H),2.65-2.61(m,1H),1.79-1.74(m,2H),1.62-1.59 (m,2H),1.51-1.42(m,2H),1.39-1.34(m,2H).13C NMR(105MHz,DMSO-d6)δ:152.8,152.4,137.4, 128.4,127.7,127.6,115.7,115.4,71.0,69.6,67.5,59.1,50.6,31.7,23.6.HRMS(ESI):calcd for C21H28O3N [M+H]+,342.2064,found 342.2059.
实施例39
Figure RE-RE-GDA0003873342650000301
4-(2-(2-(环己基氨基)乙氧基)乙氧基)苯酚(4b)
以化合物C3为原料，按照化合物4a的制备方法得到白色油状物4b，收率92％，mp:106.4-107.4℃。 MS(ESI)m/z:280[M+H]+。1H NMR(500MHz,DMSO-d6)δ:8.89(s,1H),6.74(d,J＝8.5Hz,2H),6.65 (d,J＝8.5Hz,2H),3.96(t,J＝4.5Hz,2H),3.65(t,J＝4.5Hz,2H),3.48(t,J＝5.5Hz,2H),2.67(t,J＝5.5 Hz,2H),2.35-2.31(m,1H),1.78-1.76(m,2H),1.65-1.63(m,2H),1.55-1.52(m,1H),1.22-1.09(m,3H), 0.97-0.93(m,2H).
实施例40
Figure RE-RE-GDA0003873342650000302
N-(2-(2-(4-(2-硝基苄氧基)苯氧基)乙氧基)乙基)环己胺(S1)
以化合物4-硝基溴苄和4b为原料，按照化合物B1的制备方法得到白色油状物S1，收率75％。1H NMR(500MHz,DMSO-d6)δ:8.88(s,1H),7.82(d,J＝8.0Hz,1H),7.77(d,J＝8.0Hz,1H),7.61(t,J ＝7.5Hz,1H),7.46(t,J＝7.5Hz,1H),6.69(d,J＝9.0Hz,2H),6.64(d,J＝9.0Hz,2H),3.92(s,2H),3.87 (t,J＝4.5Hz,2H),3.51(t,J＝4.5Hz,2H),3.27(t,J＝6.5Hz,2H),2.59(t,J＝6.5Hz,2H),2.36-2.32(m, 1H),1.70-1.68(m,4H),1.53-1.51(m,1H),1.17-1.03(m,5H).13C NMR(105MHz,DMSO-d6)δ:151.2, 151.1,149.4,135.7,132.5,130.9,128.0,123.8,115.6,115.3,70.1,68.9,67.5,60.8,52.1,49.6,28.4,25.7, 25.6.
实施例41
Figure RE-RE-GDA0003873342650000311
N-(2-(2-(4-(2-氯苄氧基)苯氧基)乙氧基)乙基)环己胺(S2)
以化合物4-氯溴苄和4b为原料，按照化合物B1的制备方法得到白色固体S2，收率60％，mp: 100.1-102.3℃。。1H NMR(500MHz,DMSO-d6)δ:8.88(s,1H),7.34(d,J＝8.5Hz,2H),7.31(d,J＝8.5 Hz,2H),6.70(d,J＝8.5Hz,2H),6.65(d,J＝8.5Hz,2H),3.90(t,J＝4.5Hz,2H),3.62(s,2H),3.58(t,J＝ 4.5Hz,2H),3.38(t,J＝6.5Hz,2H),2.62(t,J＝6.5Hz,2H),2.42-2.38(m,1H),1.74-1.69(m,4H),1.54- 1.52(m,1H),1.21-1.01(m,5H).13CNMR(105MHz,DMSO-d6)δ:151.3,151.2,140.7,130.8,129.8, 127.9,115.6,115.3,70.3,68.9,67.5,59.8,53.7,49.6,28.5,25.8,25.7.
实施例42
Figure RE-RE-GDA0003873342650000312
4-((4-(2-(2-环己氨基)乙氧基)乙氧基)苯氧基)甲基)苯甲酸甲酯(S3)
以化合物4-溴甲基苯甲酸甲酯和4b为原料，按照化合物B1的制备方法得到白色油状物S3，收率23％。1H NMR(500MHz,DMSO-d6)δ:8.88(s,1H),7.87(d,J＝8.0Hz,2H),7.47(d,J＝8.0Hz,2H), 6.69(d,J＝9.0Hz,2H),6.64(d,J＝9.0Hz,2H),3.89(t,J＝4.5Hz,2H),3.83(s,3H),3.72(s,2H),3.57(t, J＝4.5Hz,2H),3.39(t,J＝6.5Hz,2H),2.64(t,J＝6.5Hz,2H),2.44-2.39(m,1H),1.76-1.69(m,4H), 1.54-1.52(m,1H),1.24-1.02(m,5H).13CNMR(105MHz,DMSO-d6)δ:166.2,151.3,151.2,147.8,129.0, 128.2,127.8,115.6,115.3,70.3,68.9,67.5,60.1,54.3,52.0,49.9,28.6,25.8,25.6.
实施例43
Figure RE-RE-GDA0003873342650000313
N-(2-(2-(4-((4-(苄氧基)苄基)氧基)苯氧基)乙氧基)乙基)环己胺(S4)
以化合物4-苄氧基溴苄和4b为原料，按照化合物B1的制备方法得到淡黄色油状物S4，收率65％。1H NMR(400MHz,DMSO-d6)δ:8.89(s,1H),7.43(d,J＝6.8Hz,2H),7.38(t,J＝7.2Hz,2H),7.32(t,J ＝7.2Hz,1H),7.21(d,J＝8.8Hz,2H),6.91(d,J＝8.8Hz,2H),6.73-6.70(m,2H),6.66-6.64(m,2H), 5.05(s,2H),3.91-3.89(m,2H),3.59-3.57(m,2H),3.55(s,2H),3.36(t,J＝6.4Hz,2H),2.59(t,J＝6.4Hz, 2H),2.44-2.38(m,1H),1.74-1.69(m,4H),1.55-1.52(m,1H),1.25-1.01(m,5H).13C NMR(105MHz, DMSO-d6)δ:157.0,151.3,151.2,137.2,133.3,129.2,128.4,127.7,127.6,115.7,115.3,114.3,70.4,69.1, 68.9,67.5,59.4,53.9,49.2,28.5,25.9,25.7.
实施例44
Figure RE-RE-GDA0003873342650000321
1-(苄氧基)-4-(2-(2-(环己氧基)乙氧基)乙氧基)苯(S5)
以化合物环己醇为原料，按照化合物XST20的制备方法得到淡黄色油状物S5，收率19％。1H NMR (500MHz,DMSO-d6)δ:7.42(d,J＝7.0Hz,2H),7.38(t,J＝7.0Hz,2H),7.31(t,J＝7.0Hz,1H),6.92(d, J＝9.0Hz,2H),6.86(d,J＝9.0Hz,2H),5.03(s,2H),4.00(t,J＝4.5Hz,2H),3.70(t,J＝4.5Hz,2H), 3.55-3.51(m,4H),3.24-3.22(m,1H),1.81-1.80(m,2H),1.65-1.63(m,2H),1.47-1.46(m,1H),1.22-1.15 (m,5H).13C NMR(105MHz,DMSO-d6)δ:152.6,152.4,137.4,128.4,127.7,127.6,115.7,115.3,76.7, 70.3,69.6,69.1,67.5,66.6,31.8,25.4,23.5.
实施例45
Figure RE-RE-GDA0003873342650000322
N-(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)-2-呋喃胺(CC1)
按照化合物XST20的制备方法得到类白色固体，收率70％。1H NMR(400MHz,DMSO-d6)δ:7.88 (d,J＝7.2Hz,1H),7.47(d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),7.00(d,J＝ 7.2Hz,1H),6.88(d,J＝9.2Hz,2H),6.83(d,J＝9.2Hz,2H),6.68(t,J＝7.2Hz,1H),5.16(s,2H),4.31(t, J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.73(t,J＝5.6Hz,2H),3.46(t,J＝5.6Hz,2H).
实施例46
Figure RE-RE-GDA0003873342650000331
N-(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)-2-噻唑胺(CC2)
按照化合物XST20的制备方法得到类白色固体，收率57％。1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),7.22(d,J＝7.2Hz,1H),6.88(d,J＝ 9.2Hz,2H),6.83(d,J＝9.2Hz,2H),6.75(d,J＝7.2Hz,1H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t, J＝4.4Hz,2H),3.73(t,J＝5.6Hz,2H),3.46(t,J＝5.6Hz,2H).
实施例47
Figure RE-RE-GDA0003873342650000332
6-((2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)氨基)-1,3-二甲基尿嘧啶(CC3)
按照化合物XST20的制备方法得到类白色固体，收率35％。1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.88(d,J＝9.2Hz,2H),6.83(d,J＝ 9.2Hz,2H),5.16(s,2H),4.50(s,1H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.76(t,J＝5.6Hz, 2H),3.16(s,3H),3.01(s,3H),2.73(t,J＝5.6Hz,2H).
实施例48
Figure RE-RE-GDA0003873342650000333
N-(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)-4-氯苯胺(CC4)
按照化合物XST20的制备方法得到类白色固体，收率75％。1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),7.27(d,J＝7.2Hz,2H),6.88(d,J＝ 9.2Hz,2H),6.84(d,J＝9.2Hz,2H),6.54(d,J＝7.2Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t, J＝4.4Hz,2H),3.73(t,J＝5.6Hz,2H),3.46(t,J＝5.6Hz,2H).
实施例49
Figure RE-RE-GDA0003873342650000341
N-2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基-2-吡啶胺(CC5)
按照化合物XST20的制备方法得到类白色固体，收率52％。1H NMR(400MHz,DMSO-d6)δ:8.07 (d,J＝7.0Hz,1H),7.86(t,J＝7.0Hz,1H),7.47(d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝ 7.2Hz,1H),7.13(d,J＝7.0Hz,1H),6.88(d,J＝9.2Hz,2H),6.84(d,J＝9.2Hz,2H),6.62(t,J＝7.0Hz, 1H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.73(t,J＝5.6Hz,2H),3.46(t,J＝5.6 Hz,2H).
实施例50
Figure RE-RE-GDA0003873342650000342
2-(2-(4-(苄氧基)苯氧基)乙氧基)-N-甲基乙胺(CC6)
按照化合物XST20的制备方法得到类白色固体，收率63％。1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.88(d,J＝9.2Hz,2H),6.83(d,J＝ 9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝5.6Hz,2H),3.26(s, 3H),2.72(t,J＝5.6Hz,2H).
实施例51
Figure RE-RE-GDA0003873342650000343
2-(2-(4-(苄氧基)苯氧基)乙氧基)乙胺(CC7)
按照化合物XST20的制备方法得到类白色固体，收率47％。1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.88(d,J＝9.2Hz,2H),6.82(d,J＝ 9.2Hz,2H),5.16(s,2H),5.11(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.76(t,J＝5.6Hz, 2H),3.07(t,J＝5.6Hz,2H).
实施例52
Figure RE-RE-GDA0003873342650000351
2-(2-(2-(4-(苄氧基)苯氧基)乙氧基)氨基)乙酸(CC8)
按照化合物XST20的制备方法得到类白色固体，收率48％。1H NMR(400MHz,DMSO-d6)δ:10.8 (s,1H),7.47(d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.88(d,J＝9.2Hz,2H), 6.82(d,J＝9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝5.6Hz, 2H),3.49(s,2H),2.72(t,J＝5.6Hz,2H).
实施例53
Figure RE-RE-GDA0003873342650000352
2-(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)氨基四氢呋喃(CC10)
按照化合物XST20的制备方法得到类白色固体，收率51％。1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.92(d,J＝9.2Hz,2H),6.86(d,J＝9.2Hz,2H),5.16(s,2H),4.88(t,J＝4.4Hz,1H),4.31(t,J＝4.8Hz,2H),3.78(t,J＝4.8Hz,2H),3.49(t,J ＝5.6Hz,2H),3.80-3.70(m,2H),2.72(t,J＝5.6Hz,2H),2.05-1.90(m,2H),1.90-1.80(m,2H).
实施例54
Figure RE-RE-GDA0003873342650000353
N-(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)氨基吗啉(CC11)
按照化合物XST20的制备方法得到类白色固体，收率60％。1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.88(d,J＝9.2Hz,2H),6.84(d,J＝ 9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.76(t,J＝5.6Hz,2H), 3.68-3.60(m,4H),3.11-2.87(m,4H),2.82(t,J＝5.6Hz,2H).
实施例55
Figure RE-RE-GDA0003873342650000361
1-甲基-4-(2-(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)氨基)哌嗪(CC12)
按照化合物XST20的制备方法得到类白色固体，收率51％。1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.88(d,J＝9.2Hz,2H),6.84(d,J＝ 9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.76(t,J＝5.6Hz,2H),2.82(t,J ＝5.6Hz,2H),2.95-2.60(m,4H),2.40-2.30(m,4H),2.26(s,3H).
实施例56
Figure RE-RE-GDA0003873342650000362
N-(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)四氢-2H-吡喃-2-胺(CC14)
按照化合物XST20的制备方法得到类白色固体，收率63％。1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.92(d,J＝9.2Hz,2H),6.88(d,J＝ 9.2Hz,2H),5.16(s,2H),4.73(t,J＝4.4Hz,1H),4.31(t,J＝4.8Hz,2H),3.79(t,J＝4.8Hz,2H),3.49(t,J ＝5.6Hz,2H),3.65-3.55(m,2H),2.72(t,J＝5.6Hz,2H),1.90-1.65(m,2H),1.65-1.55(m,4H).
实施例57
Figure RE-RE-GDA0003873342650000363
N-(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)哌啶-2-胺(CC15)
按照化合物XST20的制备方法得到类白色固体，收率47％。1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.92(d,J＝9.2Hz,2H),6.88(d,J＝ 9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.8Hz,2H),3.87(t,J＝4.4Hz,1H),3.79(t,J＝4.8Hz,2H),3.49(t,J ＝5.6Hz,2H),2.72(t,J＝5.6Hz,2H),2.71-2.69(m,2H),1.71-1.60(m,2H),1.55-1.40(m,4H).
实施例58
Figure RE-RE-GDA0003873342650000371
(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)氨基甲酸(CC16)
按照化合物XST20的制备方法得到类白色固体，收率64％。1H NMR(400MHz,DMSO-d6)δ:10.8 (s,1H),7.47(d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.92(d,J＝9.2Hz,2H), 6.88(d,J＝9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.8Hz,2H),3.79(t,J＝4.8Hz,2H),3.76(t,J＝5.6Hz, 2H),3.04(t,J＝5.6Hz,2H).
实施例59
Figure RE-RE-GDA0003873342650000372
(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)氨基甲酸甲酯(CC17)
按照化合物XST20的制备方法得到淡黄色液体，收率27％。1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.92(d,J＝9.2Hz,2H),6.88(d,J＝ 9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.8Hz,2H),3.79(t,J＝4.8Hz,2H),3.76(t,J＝5.6Hz,2H),3.04(t,J ＝5.6Hz,2H),3.68(s,1H).
实施例60
Figure RE-RE-GDA0003873342650000373
N-(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)丙酰胺(CC18)
按照化合物XST20的制备方法得到类白色固体，收率66％。1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.92(d,J＝9.2Hz,2H),6.88(d,J＝ 9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.8Hz,2H),3.79(t,J＝4.8Hz,2H),3.76(t,J＝5.6Hz,2H),3.28(t,J ＝5.6Hz,2H),2.27(m,2H),1.02(m,3H).
实施例61
Figure RE-RE-GDA0003873342650000381
2-(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)氨基乙酸甲酯(CC19)
按照化合物XST20的制备方法得到类白色固体，收率40％。1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.92(d,J＝9.2Hz,2H),6.88(d,J＝ 9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.8Hz,2H),3.79(t,J＝4.8Hz,2H),3.68(s,3H),3.62(t,J＝5.6Hz, 2H),3.51(m,2H),2.72(t,J＝5.6Hz,2H).
实施例62
Figure RE-RE-GDA0003873342650000382
N-(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)-1H-吡咯-2-胺(CC21)
按照化合物XST20的制备方法得到白色固体，收率75％。1H NMR(400MHz,DMSO-d6)δ:7.47(d, J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.95(d,J＝7.0Hz,1H),6.88(d,J＝9.2 Hz,2H),6.84(d,J＝9.2Hz,2H),6.40(d,J＝7.0Hz,1H),6.15(t,J＝7.0Hz,1H),5.16(s,2H),5.00(s, 1H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.73(t,J＝5.6Hz,2H),3.46(t,J＝5.6Hz,2H).
实施例63
Figure RE-RE-GDA0003873342650000383
N-(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)噻吩-2-胺(CC22)
按照化合物XST20的制备方法得到类白色固体，收率64％。1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.92(d,J＝9.2Hz,2H),6.87(d,J＝9.2Hz,2H),6.84(d,J＝7.0Hz,1H),6.72(t,J＝7.0Hz,1H),6.01(d,J＝7.0Hz,1H),5.16(s,2H),4.31(t, J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.73(t,J＝5.6Hz,2H),3.46(t,J＝5.6Hz,2H).
实施例64
Figure RE-RE-GDA0003873342650000391
N-(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)嘧啶-4-胺(CC23)
按照化合物XST20的制备方法得到类白色固体，收率52％。1H NMR(400MHz,DMSO-d6)δ:8.43 (s,1H),8.40(d,J＝7.0Hz,1H),7.47(d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H), 6.92(d,J＝9.2Hz,2H),6.87(d,J＝9.2Hz,2H),6.44(d,J＝7.0Hz,1H),5.16(s,2H),4.31(t,J＝4.4Hz, 2H),3.79(t,J＝4.4Hz,2H),3.73(t,J＝5.6Hz,2H),3.46(t,J＝5.6Hz,2H).
实施例65
Figure RE-RE-GDA0003873342650000392
N-(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)-4-甲氧基苯胺(CC24)
按照化合物XST20的制备方法得到白色固体，收率66％。1H NMR(500MHz,DMSO-d6)δ:7.47(d, J＝7.0Hz,2H),7.38(t,J＝7.0Hz,2H),7.31(t,J＝7.0Hz,1H),6.92(d,J＝9.0Hz,2H),6.86(d,J＝9.0 Hz,2H),6.77(d,J＝9.0Hz,2H),6.70(d,J＝9.0Hz,2H),5.16(s,2H),4.31(t,J＝4.5Hz,2H),3.83(s, 3H),3.79(t,J＝4.5Hz,2H),3.73(t,J＝6.0Hz,2H),3.46(t,J＝6.0Hz,2H).
实施例66
Figure RE-RE-GDA0003873342650000393
N-(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)-1-甲基-1,4,5,6-四氢吡啶-2-胺(CC25)
按照化合物XST20的制备方法得到类白色固体，收率59％。1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.92(d,J＝9.2Hz,2H),6.88(d,J＝ 9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.8Hz,2H),3.79(t,J＝4.8Hz,2H),3.76(t,J＝5.6Hz,2H),3.23(t,J ＝4.4Hz,1H),3.04(s,3H),2.73(t,J＝5.6Hz,2H),2.55-1.96(m,4H),1.71-1.45(m,2H).
实施例67
Figure RE-RE-GDA0003873342650000401
N-(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙基)-2-吡咯烷胺(CC26)
按照化合物XST20的制备方法得到白色固体，收率59％。1H NMR(400MHz,DMSO-d6)δ:7.47(d, J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.92(d,J＝9.2Hz,2H),6.88(d,J＝9.2 Hz,2H),5.16(s,2H),4.31(t,J＝4.8Hz,2H),3.90-3.80(m,1H),3.79(t,J＝4.8Hz,2H),3.49(t,J＝5.6 Hz,2H),3.23(t,J＝4.4Hz,1H),3.04(s,3H),2.90-2.75(m,2H),2.72(t,J＝5.6Hz,2H),1.79-1.54(m, 4H).
实施例68
Figure RE-RE-GDA0003873342650000402
N-(2-(2-(4-(3-甲氧基苄氧基)苯氧基)乙氧基)乙基)环戊胺(BD2)
按照化合物B1的制备方法得到淡黄色固体，收率47％。1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),7.27(t,J＝8.4Hz,1H),7.14(s,1H),7.03(d,J＝8.4Hz,2H),6.92(d,J＝8.4Hz,2H),6.88(d,J＝8.4 Hz,2H),6.83(d,J＝8.4Hz,2H),4.31(t,J＝4.4Hz,2H),3.83(s,3H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝ 4.8Hz,2H),3.54(s,2H),2.72(t,J＝6.4Hz,2H),2.64-2.60(m,1H),1.72-1.56(m,4H),1.57-1.46(m,4H).
实施例69
Figure RE-RE-GDA0003873342650000403
N-(2-(2-(4-(3,4-二甲氧基苄氧基)苯氧基)乙氧基)乙基)环戊胺(BD3)
按照化合物B1的制备方法得到淡黄色固体，收率41％。1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),7.03(s,1H),6.90(d,J＝8.4Hz,2H),6.88(d,J＝8.4Hz,2H),6.81(d,J＝8.0Hz,1H),6.55(d,J＝ 8.0Hz,1H),4.31(t,J＝4.4Hz,2H),3.83(s,6H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝4.8Hz,2H),3.54(s, 2H),2.72(t,J＝6.4Hz,2H),2.64-2.60(m,1H),1.72-1.56(m,4H),1.57-1.46(m,4H).
实施例70
Figure RE-RE-GDA0003873342650000411
N-(2-(2-(4-(2,6-二甲氧基苄氧基)苯氧基)乙氧基)乙基)环戊胺(BD4)
按照化合物B1的制备方法得到淡黄色固体，收率30％。1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),7.16(t,J＝8.0Hz,,1H),6.90(d,J＝8.4Hz,2H),6.88(d,J＝8.4Hz,2H),6.48(d,J＝8.0Hz,2H), 4.31(t,J＝4.4Hz,2H),3.83(s,6H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝4.8Hz,2H),3.54(s,2H),2.72(t, J＝6.4Hz,2H),2.64-2.60(m,1H),1.72-1.56(m,4H),1.57-1.46(m,4H).
实施例71
Figure RE-RE-GDA0003873342650000412
N-(2-(2-(4-(2-甲氧基苄氧基)苯氧基)乙氧基)乙基)环戊胺(BD5)
按照化合物B1的制备方法得到淡黄色固体，收率32％。1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),7.25(d,J＝8.4Hz,1H),6.94(t,J＝8.4Hz,2H),6.92(d,J＝8.4Hz,1H),6.88(d,J＝8.4Hz,2H), 6.83(d,J＝8.4Hz,2H),4.31(t,J＝4.4Hz,2H),3.83(s,3H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝4.8Hz, 2H),3.54(s,2H),3.10-3.00(m,1H),2.72(t,J＝4.8Hz,2H),1.72-1.70(m,2H),1.60-1.50(m,2H), 1.49-1.40(m,4H).
实施例72
Figure RE-RE-GDA0003873342650000413
4-((4-(2-(2-(环戊氨基)乙氧基)乙氧基)苯氧基)甲基)-2-甲氧基苯酚(BD6)
按照化合物B1的制备方法得到淡黄色固体，收率45％。1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),6.97(s,1H),6.90(d,J＝8.4Hz,2H),6.88(d,J＝8.4Hz,2H),6.77(d,J＝8.0Hz,1H),6.49(d,J＝8.0Hz,1H),4.31(t,J＝4.4Hz,2H),3.83(s,6H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝4.8Hz,2H),3.54(s, 2H),2.72(t,J＝6.4Hz,2H),2.64-2.60(m,1H),1.72-1.56(m,4H),1.57-1.46(m,4H).
实施例73
Figure RE-RE-GDA0003873342650000421
N-(2-(2-(4-(3,4,5-三甲氧基苄氧基)苯氧基)乙氧基)乙基)环戊胺(BD7)
按照化合物B1的制备方法得到淡黄色固体，收率35％。1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),6.90(d,J＝8.4Hz,2H),6.88(d,J＝8.4Hz,2H),6.59(s,2H),4.31(t,J＝4.4Hz,2H),3.83(s,9H), 3.79(t,J＝4.4Hz,2H),3.62(t,J＝4.8Hz,2H),3.54(s,2H),2.72(t,J＝6.4Hz,2H),2.64-2.60(m,1H), 1.72-1.56(m,4H),1.57-1.46(m,4H).
实施例74
Figure RE-RE-GDA0003873342650000422
4-((4-(2-(2-(环戊基氨基)乙氧基)乙氧基)苯氧基)甲基)-1,2-苯二酚(BD8)
按照化合物B1的制备方法得到淡黄色固体，收率51％。1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),6.93(s,1H),6.90(d,J＝8.4Hz,2H),6.88(d,J＝8.4Hz,2H),6.71(d,J＝8.0Hz,1H),6.49(d,J＝ 8.0Hz,1H),5.35(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝4.8Hz,2H),3.54(s, 2H),2.72(t,J＝6.4Hz,2H),2.64-2.60(m,1H),1.72-1.56(m,4H),1.57-1.46(m,4H).
实施例75
Figure RE-RE-GDA0003873342650000423
4-((4-(2-(2-(环戊氨基)乙氧基)乙氧基)苯氧基)甲基)苯酚(BD9)
按照化合物B1的制备方法得到淡黄色固体，收率40％。1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),6.93(d,J＝9.2Hz,2H),6.88(d,J＝8.4Hz,2H),6.83(d,J＝8.4Hz,2H),6.68(d,J＝9.2Hz,2H), 5.35(s,1H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.8Hz,2H),3.62(t,J＝6.4Hz,2H),3.54(s,2H), 3.10-3.00(m,1H),2.72(t,J＝6.4Hz,2H),1.71-1.70(m,2H),1.60-1.50(m,2H),1.49-1.40(m,4H).
实施例76
Figure RE-RE-GDA0003873342650000431
4-((4-(2-(2-(环戊氨基)乙氧基)乙氧基)苯氧基)甲基)-N-甲基苯胺(BD12)
按照化合物B1的制备方法得到淡黄色固体，收率60％。1H NMR(400MHz,DMSO-d6)δ:8.88(s, 1H),7.14(d,J＝8.8Hz,2H),6.93(d,J＝7.6Hz,2H),6.88(d,J＝7.6Hz,2H),6.53(d,J＝8.8Hz,2H), 4.31(t,J＝6.4Hz,2H),4.00(s,1H),3.91(s,2H),3.79(t,J＝6.4Hz,2H),3.62(t,J＝6.4Hz,2H), 3.10-3.00(m,1H),2.72(t,J＝6.4Hz,2H),2.68(s,3H),1.72-1.68(m,2H),1.60-1.50(m,2H),1.45-1.35(m, 4H).
实施例77
Figure RE-RE-GDA0003873342650000432
3-((4-(2-(2-(环戊氨基)乙氧基)乙氧基)苯氧基)甲基)苯酚(BD13)
按照化合物B1的制备方法得到淡黄色固体，收率43％。1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),7.21(t,J＝7.0Hz,1H),7.10(s,1H),7.03(d,J＝7.0Hz,2H),6.92(d,J＝8.4Hz,2H),6.89(d,J＝8.4 Hz,2H),6.88(d,J＝7.0Hz,2H),5.35(s,1H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝ 4.8Hz,2H),3.54(s,2H),2.72(t,J＝6.4Hz,2H),2.64-2.60(m,1H),1.72-1.56(m,4H),1.57-1.46(m,4H).
实施例78
Figure RE-RE-GDA0003873342650000433
2-((4-(2-(2-(环戊氨基)乙氧基)乙氧基)苯氧基)甲基)苯酚(BD14)
按照化合物B1的制备方法得到淡黄色固体，收率47％。1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),7.21(t,J＝8.4Hz,1H),7.19(d,J＝8.4Hz,1H),6.94(t,J＝8.4Hz,1H),6.92(d,J＝8.4Hz,1H), 6.88(d,J＝8.4Hz,2H),6.83(d,J＝8.4Hz,2H),5.34(s,1H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz, 2H),3.62(t,J＝4.8Hz,2H),3.54(s,2H),3.10-3.00(m,1H),2.72(t,J＝4.8Hz,2H),1.72-1.70(m,2H), 1.60-1.50(m,2H),1.49-1.40(m,4H).
实施例79
Figure RE-RE-GDA0003873342650000441
N-(2-(2-(4-(2-甲基苄氧基)苯氧基)乙氧基)乙基)环戊胺(BD17)
按照化合物B1的制备方法得到淡黄色固体，收率55％。1H NMR(500MHz,DMSO-d6)δ:8.91(s, 1H),7.39(d,J＝7.0Hz,1H),7.26(t,J＝7.0Hz,1H),7.24(d,J＝7.0Hz,1H),7.19(t,J＝7.0Hz,1H),6.93 (d,J＝9.0Hz,2H),6.88(d,J＝9.0Hz,2H),5.28(s,2H),4.31(t,J＝4.5Hz,2H),3.79(t,J＝4.5Hz,2H), 3.62(t,J＝6.0Hz,2H),3.07-3.04(m,1H),2.72(t,J＝6.0Hz,2H),2.34(s,3H),1.74-1.64(m,2H), 1.60-1.52(m,2H),1.47-1.37(m,4H).
实施例80
Figure RE-RE-GDA0003873342650000442
N-(2-(2-(4-(3-甲基苄氧基)苯氧基)乙氧基)乙基)环戊胺(BD18)
按照化合物B1的制备方法得到淡黄色固体，收率62％。1H NMR(400MHz,DMSO-d6)δ:8.88(s, 1H),7.48(t,J＝7.6Hz,1H),7.28(d,J＝7.6Hz,1H),7.23(s,1H),7.16(d,J＝7.6Hz,1H),6.90(d,J＝7.6 Hz,2H),6.88(d,J＝7.6Hz,2H),4.93(s,2H),4.31(t,J＝7.0Hz,2H),3.79-3.60(m,4H),3.10-3.05(m, 1H),2.72(t,J＝7.0Hz,2H),2.34(s,3H),1.78-1.68(m,2H),1.60-1.55(m,2H),1.45-1.37(m,4H).
实施例81
Figure RE-RE-GDA0003873342650000451
N-(2-(2-(4-(2,4-二甲氧基苄氧基)苯氧基)乙氧基)乙基)环戊胺(BD19)
按照化合物B1的制备方法得到淡黄色固体，收率50％。1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),7.14(d,J＝8.0Hz,1H),6.62(s,1H),6.90(d,J＝8.4Hz,2H),6.88(d,J＝8.4Hz,2H),6.48(d,J＝8.0 Hz,1H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.83(s,6H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝4.8Hz,2H), 2.72(t,J＝6.4Hz,2H),2.64-2.60(m,1H),1.72-1.56(m,4H),1.57-1.46(m,4H).
实施例82
Figure RE-RE-GDA0003873342650000452
4-((4-(2-(2-(环戊氨基)乙氧基)乙氧基)苯氧基)甲基)-N，N-二甲基苯胺(BD20)
按照化合物B1的制备方法得到淡黄色固体，收率52％。1H NMR(400MHz,DMSO-d6)δ:8.88(s, 1H),7.18(d,J＝8.8Hz,2H),6.93(d,J＝7.6Hz,2H),6.88(d,J＝7.6Hz,2H),6.69(d,J＝8.8Hz,2H), 4.31(t,J＝6.4Hz,2H),3.91(s,2H),3.79(t,J＝6.4Hz,2H),3.62(t,J＝6.4Hz,2H),3.06(s,6H), 3.05-3.00(m,1H),2.72(t,J＝6.4Hz,2H),1.72-1.68(m,2H),1.60-1.50(m,2H),1.45-1.35(m,4H).
实施例83
Figure RE-RE-GDA0003873342650000453
2-((4-(2-(2-(环戊氨基)乙氧基)乙氧基)苯氧基)甲基)-N-甲基苯胺(BD21)
按照化合物B1的制备方法得到淡黄色固体，收率47％。1H NMR(500MHz,DMSO-d6)δ:8.91(s, 1H),7.16(t,J＝7.0Hz,1H),7.14(d,J＝7.0Hz,1H),6.92(d,J＝9.0Hz,2H),6.88(d,J＝9.0Hz,2H), 6.70(t,J＝7.0Hz,1H),6.68(d,J＝7.0Hz,1H),5.16(s,2H),4.31(t,J＝4.5Hz,2H),3.79(t,J＝4.5Hz, 2H),3.62(t,J＝6.0Hz,2H),3.09(s,3H),3.07-3.04(m,1H),2.72(t,J＝6.0Hz,2H),1.74-1.64(m,2H), 1.60-1.52(m,2H),1.47-1.37(m,4H).
实施例84
Figure RE-RE-GDA0003873342650000461
3-((4-(2-(2-(环戊氨基)乙氧基)乙氧基)苯氧基)甲基)-N-甲基苯胺(BD22)
按照化合物B1的制备方法得到淡黄色固体，收率63％。1H NMR(400MHz,DMSO-d6)δ:8.88(s, 1H),7.16(t,J＝7.6Hz,1H),6.90(d,J＝7.6Hz,2H),6.88(d,J＝7.6Hz,2H),6.79(d,J＝7.6Hz,1H), 6.76(d,J＝7.6Hz,1H),6.65(s,1H),5.16(s,2H),4.31(t,J＝7.0Hz,2H),3.79-3.60(m,4H),3.10-3.05(m, 1H),2.72(t,J＝7.0Hz,2H),2.68(s,3H),1.78-1.68(m,2H),1.60-1.55(m,2H),1.45-1.37(m,4H).
实施例85
Figure RE-RE-GDA0003873342650000462
N-(2-(2-(4-(3-氯苄氧基)苯氧基)乙氧基)乙基)环戊胺(BD23)
按照化合物B1的制备方法得到白色固体，收率53％。1H NMR(400MHz,DMSO-d6)δ:8.91(s,1H), 7.56(s,1H),7.42(d,J＝7.2Hz,1H),7.35(d,J＝7.2Hz,1H),7.32(t,J＝7.2Hz,1H),6.93(d,J＝9.0Hz, 2H),6.88(d,J＝9.0Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝6.0 Hz,2H),3.07-3.04(m,1H),2.72(t,J＝6.0Hz,2H),1.74-1.64(m,2H),1.60-1.52(m,2H),1.47-1.37(m, 4H).
实施例86
Figure RE-RE-GDA0003873342650000463
N-(2-(2-(4-(2,4-二氯苄氧基)苯氧基)乙氧基)乙基)环戊胺(BD25)
按照化合物B1的制备方法得到淡黄色固体，收率41％。1H NMR(400MHz,DMSO-d6)δ:8.91(s, 1H),7.73(s,1H),7.30(d,J＝7.2Hz,1H),7.24(d,J＝7.2Hz,1H),6.93(d,J＝9.0Hz,2H),6.88(d,J＝9.0Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝6.0Hz,2H), 3.07-3.04(m,1H),2.72(t,J＝6.0Hz,2H),1.74-1.64(m,2H),1.60-1.52(m,2H),1.47-1.37(m,4H).
实施例87
Figure RE-RE-GDA0003873342650000471
N-(2-(2-(4-(3,4-二氯苄氧基)苯氧基)乙氧基)乙基)环戊胺(BD26)
按照化合物B1的制备方法得到淡黄色固体，收率40％。1H NMR(400MHz,DMSO-d6)δ:8.91(s, 1H),7.50(s,1H),7.66(d,J＝7.2Hz,1H),7.18(d,J＝7.2Hz,1H),6.93(d,J＝9.0Hz,2H),6.88(d,J＝ 9.0Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝6.0Hz,2H), 3.07-3.04(m,1H),2.72(t,J＝6.0Hz,2H),1.74-1.64(m,2H),1.60-1.52(m,2H),1.47-1.37(m,4H).
实施例88
Figure RE-RE-GDA0003873342650000472
N-(2-(2-(4-(2,5-二氯苄氧基)苯氧基)乙氧基)乙基)环戊胺(BD27)
按照化合物B1的制备方法得到类白色固体，收率61％。1H NMR(400MHz,DMSO-d6)δ:8.91(s, 1H),7.50(s,1H),7.66(d,J＝7.2Hz,1H),7.36(d,J＝7.2Hz,1H),6.93(d,J＝9.0Hz,2H),6.88(d,J＝ 9.0Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝6.0Hz,2H), 3.07-3.04(m,1H),2.72(t,J＝6.0Hz,2H),1.74-1.64(m,2H),1.60-1.52(m,2H),1.47-1.37(m,4H).
实施例89
Figure RE-RE-GDA0003873342650000473
N-(2-(2-(4-(4-氟苄氧基)苯氧基)乙氧基)乙基)环戊胺(BD28)
按照化合物B1的制备方法得到类白色固体，收率51％。1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),7.34(d,J＝7.2Hz,2H),7.17(d,J＝7.2Hz,2H),6.88(d,J＝9.2Hz,2H),6.71(d,J＝9.2Hz,2H), 5.16(s,2H),3.91(t,J＝4.8Hz,2H),3.58(t,J＝4.8Hz,2H),3.44(t,J＝6.4Hz,2H),3.11-3.05(m,1H), 2.60(t,J＝6.4Hz,2H),1.71-1.68(m,2H),1.57-1.55(m,2H),1.43-1.34(m,4H).
实施例90
Figure RE-RE-GDA0003873342650000481
N-(2-(2-(4-(2,4-二氟苄氧基)苯氧基)乙氧基)乙基)环戊胺(BD29)
按照化合物B1的制备方法得到类白色固体，收率50％。1H NMR(400MHz,DMSO-d6)δ:8.91(s, 1H),7.32(d,J＝7.2Hz,1H),6.94(d,J＝7.2Hz,1H),6.90(d,J＝9.0Hz,2H),6.88(d,J＝9.0Hz,2H), 6.61(s,1H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝6.0Hz,2H), 3.07-3.04(m,1H),2.72(t,J＝6.0Hz,2H),1.74-1.64(m,2H),1.60-1.52(m,2H),1.47-1.37(m,4H).
实施例91
Figure RE-RE-GDA0003873342650000482
N-(2-(2-(4-(2,5-二氟苄氧基)苯氧基)乙氧基)乙基)环戊胺(BD30)
按照化合物B1的制备方法得到类白色固体，收率57％。1H NMR(400MHz,DMSO-d6)δ:8.91(s, 1H),7.15(d,J＝7.2Hz,2H),6.93(d,J＝9.0Hz,2H),6.88(d,J＝9.0Hz,2H),6.80(s,1H),5.16(s,2H), 4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝6.0Hz,2H),3.07-3.04(m,1H),2.72(t,J＝6.0 Hz,2H),1.74-1.64(m,2H),1.60-1.52(m,2H),1.47-1.37(m,4H).
实施例92
Figure RE-RE-GDA0003873342650000483
N-(2-(2-(4-(3-氟苄氧基)苯氧基)乙氧基)乙基)环戊胺(BD31)
按照化合物B1的制备方法得到类白色固体，收率63％。1H NMR(400MHz,DMSO-d6)δ:8.91(s, 1H),7.36(t,J＝7.2Hz,1H),7.24(d,J＝7.2Hz,1H),7.17(d,J＝7.2Hz,1H),6.93(d,J＝9.0Hz,2H), 6.90(s,1H),6.88(d,J＝9.0Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t, J＝6.0Hz,2H),3.07-3.04(m,1H),2.72(t,J＝6.0Hz,2H),1.74-1.64(m,2H),1.60-1.52(m,2H), 1.47-1.37(m,4H).
实施例93
Figure RE-RE-GDA0003873342650000491
3-((4-(2-(2-(环戊氨基)乙氧基)乙氧基)苯氧基)甲基)苯甲酸乙酯(BD32)
按照化合物B7的制备方法得到类白色固体，收率51％。1H NMR(400MHz,DMSO-d6)δ:8.91(s, 1H),7.98(d,J＝7.2Hz,1H),7.89(s,1H),7.68(d,J＝7.2Hz,1H),7.35(t,J＝7.2Hz,1H),6.93(d,J＝9.0 Hz,2H),6.88(d,J＝9.0Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝ 6.0Hz,2H),3.07-3.04(m,1H),2.72(t,J＝6.0Hz,2H),1.74-1.64(m,2H),1.60-1.52(m,2H),1.47-1.37(m, 4H).
实施例94
Figure RE-RE-GDA0003873342650000492
3-((4-(2-(2-(环戊氨基)乙氧基)乙氧基)苯氧基)甲基)苯甲酰胺(BD34)
按照化合物B1的制备方法得到类白色固体，收率56％。1H NMR(400MHz,CD3OD)δ:7.96(d,J ＝7.6Hz,1H),7.87(s,1H),7.72(d,J＝7.6Hz,1H),7.42(t,J＝7.6Hz,1H),6.76(d,J＝9.2Hz,2H),6.68 (d,J＝9.2Hz,2H),5.16(s,2H),4.33-4.30(m,2H),3.89-3.86(m,1H),3.83-3.79(m,4H),3.37-3.34(m, 2H),2.20-2.15(m,2H),1.89-1.79(m,4H),1.71-1.60(m,2H).
实施例95
Figure RE-RE-GDA0003873342650000493
N-(2-(2-(4-(4-溴苄氧基)苯氧基)乙氧基)乙基)环戊胺(BD35)
按照化合物B1的制备方法得到类白色固体，收率60％。1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),7.90(d,J＝7.2Hz,2H),7.25(d,J＝7.2Hz,2H),6.88(d,J＝9.2Hz,2H),6.71(d,J＝9.2Hz,2H), 5.16(s,2H),4.31(t,J＝4.8Hz,2H),3.79(t,J＝4.8Hz,2H),3.62(t,J＝6.4Hz,2H),3.11-3.05(m,1H), 2.72(t,J＝6.4Hz,2H),1.71-1.68(m,2H),1.57-1.55(m,2H),1.43-1.34(m,4H).
实施例96
Figure RE-RE-GDA0003873342650000501
4-((4-(2-(2-(环戊氨基)乙氧基)乙氧基)苯氧基)甲基)苄腈(BD36)
按照化合物B1的制备方法得到类白色固体，收率52％。1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),7.57(d,J＝7.2Hz,2H),7.54(d,J＝7.2Hz,2H),6.88(d,J＝9.2Hz,2H),6.71(d,J＝9.2Hz,2H), 5.16(s,2H),4.31(t,J＝4.8Hz,2H),3.79(t,J＝4.8Hz,2H),3.62(t,J＝6.4Hz,2H),3.11-3.05(m,1H), 2.72(t,J＝6.4Hz,2H),1.71-1.68(m,2H),1.57-1.55(m,2H),1.43-1.34(m,4H).
实施例97
Figure RE-RE-GDA0003873342650000502
N-(2-(2-(4-(2-氯苄氧基)苯氧基)乙氧基)乙基)环戊胺(BD37)
按照化合物B1的制备方法得到类白色固体，收率59％。1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),7.70(d,J＝7.2Hz,1H),7.32(t,J＝7.2Hz,1H),7.30(d,J＝7.2Hz,1H),7.26(t,J＝7.2Hz,1H), 6.88(d,J＝9.2Hz,2H),6.71(d,J＝9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.8Hz,2H),3.79(t,J＝4.8Hz, 2H),3.58(t,J＝6.4Hz,2H),3.11-3.05(m,1H),2.60(t,J＝6.4Hz,2H),1.71-1.68(m,2H),1.57-1.55(m, 2H),1.43-1.34(m,4H).
实施例98
Figure RE-RE-GDA0003873342650000503
N-(2-(2-(4-(2-氟苄氧基)苯氧基)乙氧基)乙基)环戊胺(BD38)
按照化合物B1的制备方法得到类白色固体，收率53％。1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),7.68(t,J＝7.2Hz,1H),7.53(d,J＝7.2Hz,1H),7.34(d,J＝7.2Hz,1H),7.15(d,J＝7.2Hz,1H), 6.88(d,J＝9.2Hz,2H),6.71(d,J＝9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.8Hz,2H),3.79(t,J＝4.8Hz, 2H),3.58(t,J＝6.4Hz,2H),3.11-3.05(m,1H),2.60(t,J＝6.4Hz,2H),1.71-1.68(m,2H),1.57-1.55(m, 2H),1.43-1.34(m,4H).
实施例99
Figure RE-RE-GDA0003873342650000511
N-(2-(2-(4-(3,4-二氟苄氧基)苯氧基)乙氧基)乙基)环戊胺(BD39)
按照化合物B1的制备方法得到类白色固体，收率37％。1H NMR(400MHz,DMSO-d6)δ:8.91(s, 1H),7.15(d,J＝7.2Hz,1H),7.11(d,J＝7.2Hz,1H),6.93(d,J＝9.0Hz,2H),6.90(s,1H),6.88(d,J＝9.0 Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝6.0Hz,2H),3.07-3.04 (m,1H),2.72(t,J＝6.0Hz,2H),1.74-1.64(m,2H),1.60-1.52(m,2H),1.47-1.37(m,4H).
实施例100
Figure RE-RE-GDA0003873342650000512
4-((4-(2-(2-(环戊氨基)乙氧基)乙氧基)苯氧基)甲基)苯甲酰胺(BD41)
按照化合物B1的制备方法得到类白色固体，收率48％。1H NMR(400MHz,CD3OD)δ:7.96(d,J ＝8.0Hz,2H),7.54(d,J＝8.0Hz,2H),6.79(d,J＝4.8Hz,2H),6.71(d,J＝4.8Hz,2H),5.16(s,2H),4.31 (t,J＝4.4Hz,2H),3.92-3.87(m,1H),3.84-3.82(m,4H),3.39(t,J＝4.4Hz,2H),2.20-2.18(m,2H), 1.93-1.85(m,4H),1.69-1.66(m,2H).
实施例101
Figure RE-RE-GDA0003873342650000521
2-((4-(2-(2-(环戊氨基)乙氧基)乙氧基)苯氧基)甲基)苯甲酰胺(BD43)
按照化合物B1的制备方法得到类白色固体，收率53％。1H NMR(400MHz,CD3OD)δ:7.96(d,J ＝8.0Hz,1H),7.63(t,J＝8.0Hz,1H),7.54(d,J＝8.0Hz,1H),7.30(t,J＝8.0Hz,1H),6.88(d,J＝4.8Hz, 2H),6.81(d,J＝4.8Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.92-3.87(m,1H),3.84-3.82(m,4H), 3.39(t,J＝4.4Hz,2H),2.20-2.18(m,2H),1.93-1.85(m,4H),1.69-1.66(m,2H).
实施例102
Figure RE-RE-GDA0003873342650000522
3-((4-(2-(2-(环戊氨基)乙氧基)乙氧基)苯氧基)甲基)苯甲醛(BD46)
按照化合物B1的制备方法得到类白色固体，收率36％。1H NMR(400MHz,CD3OD)δ:9.88(s,1H), 7.82(d,J＝7.6Hz,1H),7.75(d,J＝7.6Hz,1H),7.73(s,1H),7.43(t,J＝7.6Hz,1H),6.88(d,J＝9.2Hz, 2H),6.82(d,J＝9.2Hz,2H),5.16(s,2H),4.33-4.30(m,2H),3.89-3.86(m,1H),3.83-3.79(m,4H), 3.37-3.34(m,2H),2.20-2.15(m,2H),1.89-1.79(m,4H),1.71-1.60(m,2H).
实施例103
Figure RE-RE-GDA0003873342650000523
2-((4-(2-(2-(环戊氨基)乙氧基)乙氧基)苯氧基)甲基)苯甲醛(BD47)
按照化合物B1的制备方法得到类白色固体，收率43％。1H NMR(500MHz,CD3OD)δ:10.36(s, 1H),8.91(s,1H),7.82(d,J＝7.5Hz,1H),7.66(t,J＝7.5Hz,1H),7.57(t,J＝7.5Hz,1H),7.55(d,J＝7.5 Hz,1H),6.88(d,J＝9.0Hz,2H),6.84(d,J＝9.0Hz,2H),5.16(s,2H),4.35-4.30(m,4H),3.53(t,J＝4.5 Hz,2H),3.08-3.02(m,1H),2.57(t,J＝6.5Hz,2H),1.68-1.65(m,2H),1.58-1.52(m,2H),1.43-1.39(m, 2H),1.36-1.29(m,2H).
实施例104
Figure RE-RE-GDA0003873342650000531
O-(2-(4-(苄氧基)苯氧基)乙基)-N-环戊基羟胺(BD53)
按照化合物XST20的制备方法得到类白色固体，收率57％。1H NMR(400MHz,DMSO-d6)δ:8.89 (s,1H),7.47(d,J＝8.0Hz,2H),7.38(t,J＝8.0Hz,2H),7.34(t,J＝8.0Hz,1H),6.92(d,J＝8.4Hz,2H), 6.88(d,J＝8.4Hz,2H),5.16(s,2H),4.33(t,J＝4.4Hz,2H),3.95(t,J＝4.4Hz,2H),2.67-2.62(m,1H), 1.72-1.70(m,2H),1.60-1.50(m,2H),1.49-1.40(m,4H).
实施例105
Figure RE-RE-GDA0003873342650000532
N-(2-(4-(苄氧基)苯氧基)乙基)环戊胺(BD55)
按照化合物XST20的制备方法得到类白色固体，收率62％。1H NMR(400MHz,DMSO-d6)δ:8.89 (s,1H),7.47(d,J＝8.0Hz,2H),7.38(t,J＝8.0Hz,2H),7.34(t,J＝8.0Hz,1H),6.92(d,J＝8.4Hz,2H), 6.88(d,J＝8.4Hz,2H),5.16(s,2H),4.13(t,J＝4.4Hz,2H),2.97(t,J＝4.4Hz,2H),2.67-2.62(m,1H), 1.72-1.70(m,2H),1.60-1.50(m,2H),1.49-1.40(m,4H).
实施例106
Figure RE-RE-GDA0003873342650000533
N-((2-(4-(苄氧基)苯氧基)乙氧基)甲基)环戊胺(BD56)
按照化合物XST20的制备方法得到类白色固体，收率42％。1H NMR(400MHz,DMSO-d6)δ:8.89 (s,1H),7.47(d,J＝8.0Hz,2H),7.38(t,J＝8.0Hz,2H),7.34(t,J＝8.0Hz,1H),6.92(d,J＝8.4Hz,2H), 6.88(d,J＝8.4Hz,2H),5.16(s,2H),4.63(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H), 2.67-2.62(m,1H),1.72-1.70(m,2H),1.60-1.50(m,2H),1.49-1.40(m,4H).
实验例1体外抗肿瘤活性测定。
细胞株为人卵巢癌细胞SKOV3、人结肠癌细胞HCT116、人肝癌细胞HepG2，对化合物进行抑制肿瘤增殖的IC50值检测，采用CCK8方法进行实验，以顺铂为阳性参照药，结果为3次测试的平均值，IC50 值以平均值±SD表示。结果见表1。
表1化合物对三株肿瘤细胞的体外抑制IC50
Figure RE-RE-GDA0003873342650000541
Figure RE-RE-GDA0003873342650000551
Figure RE-RE-GDA0003873342650000561
Figure RE-RE-GDA0003873342650000571
实验例2化合物与FOXM1的亲和力测定
利用表面等离子共振(SPR)技术，建立了小分子与FOXM1亲和力测定方法。设计表达了截短的FOXM1b蛋白，氨基酸序列为222-360，该部分包括了FOXM1的DNA结合域，带有His标签，以FD16为阳性对照物，检测了部分化合物与FOXM1的亲和力，根据BIAevaluation软件计算解离常数(KD)，结果见表2。
表2化合物与FOXM1的亲和力KD(μM)
Figure RE-RE-GDA0003873342650000572
Figure RE-RE-GDA0003873342650000581
实验例3体内活性研究
3.1化合物S2的溶解处方摸索
实验中观察到化合物S2的脂溶性较强，为进行体内活性研究先进行化合物溶解处方的摸索。体内急性毒性的剂量设置为500mg/kg，每只小鼠给药体积为100μL～200μL，初步计算后，化合物的溶解度应达到50～100mg/kg，经实验，最终确定化合物体内活性实验的溶解处方为 5％DMSO+5％EtOH+20％HS15+70％H2O，在该处方中溶解度可以达到51.1mg/mL。
3.2化合物S2的初步急性毒性测定
初步考察化合物S2以腹腔注射方式给药对BALB/c小鼠的毒性，给药组剂量分别为500mg/kg、 750mg/kg，给药体积分别为0.2mL和0.3mL，每组3只小鼠。一次性给药后，观察7天。500mg/kg 剂量组小鼠无死亡，活动无异常；750mg/kg剂量组小鼠全部死亡。初步急毒结果提示，化合物S2 毒性低，LD50大于500mg/kg，远远低于与文献所报道顺铂的急毒(LD50＝12.6mg/kg)。
3.3化合物S2的体内抗肿瘤活性研究
化合物S2对SKOV3细胞和HCT116细胞的体外抑制活性水平相当，本次采用卵巢癌SKOV3细胞株进行活性研究。以卵巢癌治疗的临床一线药物顺铂为阳性对照，以溶剂为空白对照。
以8周龄的雌性BALB/c裸鼠为实验对象，应用人SKOV3-GFP卵巢癌模型进行研究。体外培养细胞，接种至小鼠右腋皮下，肿瘤自然生长14天，体积在90-100mm3。将化合物溶解于含5％DMSO+20 Solutol HS15的水溶液中，溶液澄清。化合物S2设置25mg/kg/天和50mg/kg/天两个剂量组，腹腔注射给药，1次/天，共给药21天；阳性对照药物顺铂设置3mg/kg/周剂量组，腹腔注射给药，1次/周， 21天共给药3次。每天观察动物的状况，每周两次称重，记录小鼠肿瘤面积及体积。给药21天后，取材并记录肿瘤重量。小鼠体重变化见表3和图1。
表3给药前后小鼠体重变化
分组 给药前体重/g 给药前体重/g 体重增长率
空白溶剂组 16.7±0.8 16.2±1.7 -3.0％
S2(25mg/kg) 17.4±1.0 16.7±1.2 -3.7％
S2(50mg/kg) 17.1±1.3 15.5±1.9 -9.5％
顺铂 16.9±0.9 13.7±2.7 -20.0％
如图1和表3所示，整体上各组小鼠的体重均有不同程度的下降趋势。实验结束时，空白溶剂组小鼠平均体重下降3％；顺铂组小鼠死亡1只，给药7天后小鼠状态变差，结束时平均体重下降20％；S2(50mg/kg)组小鼠平均体重下降9.5％；S2(25mg/kg)组小鼠平均体重下降3.7％。由此可知，顺铂对小鼠有一定的毒性，而化合物S2对小鼠的毒性较小。
小鼠肿瘤体积变化见图2，空白溶剂组小鼠肿瘤体积明显增加，其他各组肿瘤体积增加趋势与空白溶剂组比均变缓。化合物S2在高低两个剂量下，小鼠肿瘤体积相当；与空白溶剂组相比，化合物 S2能够抑制肿瘤体积的增长。结束实验时，与顺铂组比较，化合物S2组的小鼠肿瘤体积均比顺铂组大，但S2(50mg/kg)组与顺铂组无显著性差异(P>0.05)。
通过FluorVivo成像系统无侵袭地观察实验小鼠的肿瘤负荷情况并荧光成像，依据影像结果记录各组小鼠的肿瘤面积，计算平均值。如图3所示，与空白溶剂组比较，各给药组肿瘤荧光成像面积均减小。化合物S2在高低两个剂量下，小鼠肿瘤面积相当；S2高低剂量组与空白溶剂组相比较，肿瘤荧光面积具有显著性差异(P<0.01)，提示化合物S2在高低两个剂量下对人卵巢癌模型有抑制作用。
给药结束后，通过解剖剥离所有的肿瘤，称重，记录并计算平均值，结果如图4。S2(50mg/kg) 组和S2(25mg/kg)组与空白溶剂组相比，肿瘤重量具有显著性差异(P<0.01)，提示化合物S2在高低两个剂量下对人卵巢癌模型有抑制作用，且S2(50mg/kg)组肿瘤重量略小于低剂量组。与顺铂组比较，化合物S2组的肿瘤重量稍大于阳性药物。通过公式IR(％)＝(1-给药组平均瘤重/空白溶剂组平均瘤重)×100％计算抑瘤率，结果见表4。S2(25mg/kg)组、S2(50mg/kg)组、顺铂组肿瘤抑制率分别为35.2％、 37.6％和51.8％。在本次实验中，顺铂对人卵巢癌小鼠模型具有较强的抑制作用；化合物S2高低剂量组均具有明显抑制作用，但弱于阳性药物顺铂，且未表现出明显的剂量依赖型抑制作用。
表4.小鼠瘤重及肿瘤抑制率
Figure RE-RE-GDA0003873342650000591
Figure RE-RE-GDA0003873342650000601
综上所述，阳性药物顺铂(3mg/kg)在本次小鼠实验模型中具有较强的抑制作用，但该组小鼠出现 1只死亡，说明在现有剂量下顺铂对小鼠有明显的毒副作用。S2(25mg/kg)组和S2(50mg/kg)组在本次小鼠实验模型中表现出了一定的肿瘤抑制作用，且在高低剂量下对小鼠没有明显的毒副作用。化合物 S2对人卵巢癌小鼠模型的抑制作用稍弱于阳性药物顺铂，但却表现出小于顺铂的毒性。
将采集的小鼠肿瘤组织进行切片，采用Western blot手段检测空白溶剂组和化合物S2高剂量组肿瘤组织中FOXM1下游靶蛋白的表达水平，结果如图5所示，与空白溶剂组蛋白的表达水平相比，高剂量组的小鼠肿瘤中，肿瘤血管生成相关的CD31、CD34表达被明显下调；促进细胞周期相关的 CDC25B、CENP-A、CyclinB1、CyclinF、PLK1表达被明显下调；存活蛋白表达水平也被下调。结果表明在肿瘤组织中，化合物S2通过抑制FOXM1下调了其下游靶蛋白的水平。
最后应说明的是：以上实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明实施例技术方案的精神和范围。

Claims (8)

1.一种式I所示的化合物、其药用盐或酯、溶剂合物、异构体、多晶型物、同位素标记的化合物、代谢物或前药：
Figure FDA0003779451240000011
其中，X选自以下基团：―(CH2)n―、―(CH2)mO(CH2)n-m―或―(CH2)kCH(R)(CH2)n-k―；
Ra可以为一个或两个及以上，其独立地选自H、卤素、NO2、CN、OH、C1-C6直链或支链烷基、C1-C6直链或支链烷氧基、苯氧基、苄氧基、―(CH2)hC(O)Rx或―NRyRz；
Rx选自H、OH、NH2、C1-C6直链或支链烷基、C1-C6直链或支链烷氧基；
Ry、Rz可独立选自H、C1-C6直链或支链烷基、C2-C6直链或支链烯基；
Q代表O、NH或NR5；
R5选自C1-C6直链或支链烷基；
R4选自H、―(CH2)mO(CH2)n-mOH、R取代或未取代的C1-C7直链或支链烷基、R取代或未取代的C3-C7直链或支链环烷基、R取代或未取代的含有1个或2个选自O、S或N的3-6元饱和或不饱和杂烷基、R取代或未取代的芳基、R取代或未取代的5元或6元杂芳基、醛基、C2-C5羰基、C1-C5羧基或C1-C5羧酸酯基；
R取代基可以为一个或两个及以上，其独立地选自：卤素、OH、C1-C6烃基、C1-C6烃氧基、C1-C5羧基、C2-C5羰基、C1-C5羧酸酯基、C1-C5酰胺基、NH2；
n选自1、2、3、4、5、6、7或8；m选自1、2、3、4、5、6、7或8；k选自0、1、2、3、4、5、6、7或8；h选自0、1、2或3。
2.根据权利要求1所述的式I所示的化合物、其药用盐或酯、溶剂合物、异构体、多晶型物、同位素标记的化合物、代谢物或前药，其特征在于：
其中，卤素选自F、Br和Cl；
―(CH2)mO(CH2)n-m―选自：
―CH2OCH2―、―CH2O(CH2)2―、―CH2O(CH2)3―、―CH2O(CH2)4―、―CH2O(CH2)5―、―(CH2)2O―、―(CH2)2OCH2―、―(CH2)2O(CH2)2―、―(CH2)2O(CH2)3―、―(CH2)2O(CH2)4―、―(CH2)3O―、―(CH2)3OCH2―、―(CH2)3O(CH2)2―、―(CH2)3O(CH2)3―、―(CH2)4O―、―(CH2)4O(CH2)2―、―(CH2)5O―或―(CH2)5OCH2―；
―(CH2)kCH(R)(CH2)n-k―选自：
―CH(R)CH2―、―CH(R)(CH2)2―、―CH(R)(CH2)3―、―CH(R)(CH2)4―、―CH(R)(CH2)5―、―CH2CH(R)CH2―、―CH2CH(R)(CH2)2―、―CH2CH(R)(CH2)3―、―CH2CH(R)(CH2)4―、―CH2CH(R)(CH2)5―、―(CH2)2CH(R)―、―(CH2)2CH(R)CH2―、―(CH2)2CH(R)(CH2)2―、―(CH2)2CH(R)(CH2)3―、―(CH2)2CH(R)(CH2)4―、―(CH2)3CH(R)―、―(CH2)3CH(R)CH2―、―(CH2)3CH(R)(CH2)2―、―(CH2)3CH(R)(CH2)3―、―(CH2)4CH(R)―、―(CH2)4CH(R)CH2―、―(CH2)4CH(R)(CH2)2―、―(CH2)5CH(R)―或―(CH2)5CH(R)CH2―；
―(CH2)hC(O)Rx选自：
―C(O)H、―C(O)OH、―C(O)NH2、―C(O)CH3、―C(O)CH2CH3、―C(O)C3H7、―C(O)C4H9、―C(O)C5H11、―C(O)OCH3、―C(O)OC2H5、―C(O)OC3H7、―C(O)OC4H9、―C(O)OC5H11、―CH2C(O)H、―CH2C(O)OH、―CH2C(O)NH2、―CH2C(O)CH3、―CH2C(O)C2H5、―CH2C(O)C3H7、―CH2C(O)C4H9、―CH2C(O)C5H11、―CH2C(O)OCH3、―CH2C(O)OC2H5、―CH2C(O)OC3H7、―CH2C(O)OC4H9或―CH2C(O)OC5H11；
―NRyRz选自：
―NH2、―NHCH3、―NHC2H5、―NHC3H7、―NHC4H9、―N(CH3)2、―NH(CH3)C2H5、―NH(CH3)C3H7、―NH(CH3)C4H9、―N(C2H5)2、―NH(C2H5)C3H7、―NH(C2H5)C4H9、―N(C3H7)2、―NH(C3H7)C4H9或―N(C4H9)2；
―(CH2)mO(CH2)n-mOH选自：
―CH2OCH2OH、―CH2O(CH2)2OH、―CH2O(CH2)3OH、―CH2O(CH2)4OH、―CH2O(CH2)5OH、―(CH2)2OCH2OH、―(CH2)2O(CH2)2OH、―(CH2)2O(CH2)3OH、―(CH2)2O(CH2)4OH、―(CH2)3OCH2OH、―(CH2)3O(CH2)2OH、―(CH2)3O(CH2)3OH、―(CH2)4O(CH2)2OH或―(CH2)5OCH2OH；
含有1个或2个选自：O、S或N的3-6元饱和或不饱和杂烷基选自：饱和或不饱和的环氧乙烷基、四氢呋喃基、吡咯烷胺基、哌啶基、吗啉基、哌嗪基、吡喃基或四氢吡喃基；
5元或6元杂芳基选自：呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、恶唑基、异恶唑基、噻唑基、三氮唑基、吡啶基、嘧啶基、哒嗪基或吡嗪基；
醛基选自：―C(O)H、―CH2C(O)H、―(CH2)2C(O)H、―(CH2)3C(O)H或―(CH2)4C(O)H；
C2-C5羰基选自：
―C(O)CH3、―C(O)C2H5、―C(O)C3H7、―C(O)C4H9、―CH2C(O)CH3、―CH2C(O)C2H5、―CH2C(O)C3H7、―(CH2)2C(O)CH3、―(CH2)2C(O)C2H5或―(CH2)3C(O)CH3；
C1-C5羧基选自：―C(O)OH、―CH2C(O)OH、―(CH2)2C(O)OH、―(CH2)3C(O)OH或―(CH2)4C(O)OH；
C1-C5羧酸酯基选自：
―C(O)OCH3、―C(O)OC2H5、―C(O)OC3H7、―C(O)OC4H9、―CH2C(O)OCH3、―CH2C(O)OC2H5、―CH2C(O)OC3H7、―C2H4C(O)OCH3、―C2H4C(O)OC2H5或―C3H6C(O)OCH3；
C1-C5酰胺基选自：
―C(O)NH2、―CH2C(O)NH2、―(CH2)2C(O)NH2、―(CH2)3C(O)NH2或―(CH2)4C(O)NH2。
3.根据权利要求1所述的式I所示的化合物、其药用盐或酯、溶剂合物、异构体、多晶型物、同位素标记的化合物、代谢物或前药，其特征在于：
X选自以下基团：
―(CH2)2O―、―(CH2)2OCH2―、―(CH2)2O(CH2)2―、―(CH2)6―或―CH2CH(OH)CH2―；
Ra可以为一个或两个或三个，其独立地选自H、F、Br、Cl、NO2、CN、OH、甲基、甲氧基、苯氧基、苄氧基、―C(O)H、―C(O)OH、―C(O)NH2、―C(O)CH3、―C(O)OCH3、―C(O)OC2H5、―NH2、―NHCH3或―N(CH3)2；
Q代表O、NH或NCH3；
R4选自H、―(CH2)2O(CH2)2OH、―C(O)OH、―CH2C(O)OH、―C(O)OCH3、―CH2C(O)CH3、―C(O)C2H5、甲基、环丙基、环丁基、环戊基、环己基、环庚基、苯基、环氧丙烷基、四氢呋喃基、四氢吡喃基、哌啶基、吗啉基、哌嗪基、吡喃基、哌啶基、吡咯烷胺基、呋喃基、噻唑基、噻吩基、吡咯基、嘧啶基、吡啶基或尿嘧啶基；
R取代基可以为一个或两个，其独立地选自：F、Br、Cl、OH、甲基、甲氧基或―C(O)OC4H9。
4.根据权利要求1所述的式I所示的化合物选自如下：
Figure FDA0003779451240000031
Figure FDA0003779451240000041
Figure FDA0003779451240000051
5.药物组合物，其包含权利要求1-4任一项所述的式I所示结构的化合物、其药用盐或酯、溶剂合物、异构体、多晶型物、同位素标记的化合物、代谢物或前药，以及任选地，一种或多种药学上可接受的载体或赋形剂。
6.一种权利要求1-4任一项所述的式I所示的化合物、其药用盐或酯、溶剂合物、异构体、多晶型物、同位素标记的化合物、代谢物或前药在制备抑制FOXM1药物中的应用。
7.一种权利要求1-4任一项所述的式I所示结构的化合物、其药用盐或酯、溶剂合物、异构体、多晶型物、同位素标记的化合物、代谢物或前药在制备抗肿瘤药物中的应用。
8.根据权利要求7所述的应用，其特征在于，所述肿瘤包括但不限于乳腺癌、卵巢癌、结直肠癌、黑色素瘤、非小细胞肺癌、小细胞肺癌、胃肠道间质瘤、宫颈癌、胰腺癌、前列腺癌、胃癌、慢性髓样白细胞过多症、肝癌、淋巴瘤、腹膜癌和软组织肉瘤。
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