具体实施方式
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。
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。“环烷基”指的是具有特定碳原子数的单环饱和的脂烃基。例如“环烷基”包括环丙基,甲基-环丙基,2,2-二甲基-环丁基,2-乙基-环戊基,环己基等。
本文所使用术语“杂芳基”代表环中多达6个原子的稳定的单环或每个环中多达6个原子双环碳环,其中至少一个环为芳香环且含有1-4个选自O,N和S的杂原子。本定义范围内的杂芳基包括但不限于:咪唑基、噻唑基、吡唑基、呋喃基、噻吩基、噁唑基、异噁唑基、吡嗪基、哒嗪基、嘧啶基、吡咯基、吡啶基。对于于“杂芳基”也理解为包括任何含有氮的杂芳基的N-氧化物衍生物。在杂芳基取代基是双环的且含有一个环为非芳香性或不含有杂原子的例子中,应理解各自经芳香环或含杂原子环连接。
正如本领域技术人员所理解的,本文中所用“卤素”意指包括氯,氟,溴和碘。
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,本申请提供了一种利用具有式(I)的化合物及其药学可接受的盐治疗人或其它哺乳动物肿瘤等过渡增殖性疾病或症状。
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用于治疗或控制淋巴瘤、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胃癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、白血病和宫颈癌等过渡增殖性疾病。
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,服用剂量范围为在口服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。
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。
剂型
这种含有活性成分的药用组合物可制成适于口服给药形式,例如片剂、含片、锭剂、水或油混悬液、可分散粉剂或颗粒剂、乳剂、硬胶囊剂或软胶囊剂、或糖浆剂或酊剂。可根据药用组合物制造领域中任何已知方法制备预期口服给以予的组合物,并且为提供药学上精制的及适口的制剂,这种组合物可含有一种或多种选自甜味剂、调味剂、着色剂和防腐剂的药剂。片剂含有活性成分与无毒的适用于制造片剂的药学上可接受的辅料。这些辅料可为例如,惰性稀释剂如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;制粒剂(granulating)和崩解剂如微晶纤维素、交联羧甲纤维素钠、玉米淀粉或海藻酸;粘合剂例如淀粉、明胶、聚乙烯吡咯烷酮或阿拉伯胶;及润滑剂例如硬脂酸镁、硬脂酸或滑石粉。片剂可不包衣或通过已知技术包衣从而掩盖药物的不良味道或延长在胃肠道中崩解和吸收且因而提供持续更长时间的药物效应。例如,可采用水溶性掩盖味道的原料例如羟丙基-甲基纤维素或羟丙纤维素,或采用延时原料例如乙基纤维素、醋酸丁酸纤维素。片剂剂型可为0.1毫克/片、0.2毫克/片、0.25毫克/片、0.5毫克/片、1毫克/片、2毫克/片、5毫克/片、10毫克/片、25毫克/片、50毫克/片、100毫克/片、和250毫克/片。其它剂型如胶囊等可作相似剂量参考。
口服使用的制剂也可制成硬明胶胶囊剂,其中活性成分混合于惰性固体稀释剂,例如碳酸钙、碳酸钠或白陶土中;或制成软明胶胶囊剂,其中活性成分混合于水溶性载体例如聚乙烯二醇或油性介质如花生油、液体石蜡或橄榄油中。
水混悬液含有与适于制造水混悬液的辅料混合的活性材料。这种辅料为助悬剂例如羧甲纤维素钠、甲基纤维素、羟丙基-甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、或阿拉伯胶;此水混悬液也可含有一种或多种防腐剂例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯,一种或多种着色剂,一种或多种调味剂,和一种或多种甜味剂例如蔗糖、糖精或阿司帕坦。
可通过将活性成分混悬与植物油例如,花生油、麻油、椰子油、或橄榄油中,矿物油例如液体石蜡制备油性混悬液。这种油性混悬液可含有增稠剂例如蜂蜡、固体石蜡或鲸蜡醇。可加入上文所述的甜味剂和调味剂以提供适合口服的制剂。可通过加入抗氧化剂例如丁羟茴醚或a生育酚储存这些组合物。
可分散粉剂或颗粒剂适于通过加入水制备水混悬液而提供与分散剂或湿润剂、助悬剂和一种或多种防腐剂混合的活性成分。适当的分散剂或湿润剂及助悬剂已通过上文涉及的例子说明。也可存在其他辅料例如甜味剂、调味剂和着色剂。这些组合物可通过加入抗氧化剂例如抗坏血酸而储存。
本发明组合物可制成水包油乳状液的形式。油相可为植物油例如花生油或橄榄油,或矿物油例如液体石蜡或其混合物。适当的乳化剂可为天然存在的磷脂例如大豆卵磷脂及酯类或得自脂肪酸和己糖醇酐混合的偏脂例如脱水山梨糖醇单油酸酯,及所述偏酯和烯化氧的缩合产物例如聚氧乙烯脱水山梨糖醇单油酸酯。此乳剂也可含甜味剂、调味剂、抗氧化剂和防腐剂。
可使用甜味剂例如甘油、丙二醇、山梨醇、或蔗糖制备糖浆剂和酊剂。这种制剂也可含有湿润剂、调味剂、着色剂、抗氧化剂和防腐剂。
本发明组合物可制成无菌注射的水溶液。在可接受的载体和溶剂中可采用水、林格氏液和等渗氯化钠溶液。
这种无菌可注射剂也可制成活性成分溶于油相中的无菌可注射水包油微乳剂。例如,首先将活性成分溶于豆油和卵磷脂的混合物中,然后将油溶液放入水和甘油的混合物中并处理而制成微乳剂。
这种药用组合物可制成用于肌内或皮下给药的无菌可注射溶液或油状混悬液形式。可根据已知技术使用上文中提到的分散剂或湿润剂及助悬剂制备这种混悬液。无菌可注射制剂也可制成在无毒胃肠外可接受的稀释剂或溶剂中的无菌可注射溶液或混悬液,例如作为在1,3-丁二醇中的溶液。另外,常规采用非挥发油作为溶剂或混悬介质。为此目的,可采用任何无刺激性的非挥发油包括合成的甘油一酯或甘油二酯。另外,发现在可注射制剂中使用脂肪酸例如油酸。
药物代谢物及前药
本申请所涉及的化合物及其药学上可接受的盐的代谢产物,以及可以在体内转变为本申请所涉及的化合物及其药学上可接受的盐的结构的前药,也包括本申请的专利要求中。
联合用药
式(I)化合物可以与已知的治疗或改进相似病状的其它药物联用。联合给药时,原来药物的给药方式&剂量保持不变,而同时或随后服用式(I)化合物。当式I化合物与其它一种或几种药物同时服用时,优选使用同时含有一种或几种已知药物和式(I)化合物的药用组合物。药物联用也包括在重叠的时间段服用式(I)化合物与其它一种或几种已知药物。当式(I)化合物与其它其它一种或几种药物进行联用时,式(I)化合物或已知药物的剂量可能比它们单独用药时的剂量较低。
可以与式I化合物进行药物联用的药物或活性成分包括但不局限为:
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。
在一个实施方案中,可以与式(I)化合物进行药物联用的药物包括但不局限为:阿地白介素、阿仑瞵酸、干扰素、阿曲诺英、别嘌醇、别嘌醇钠、帕洛诺司琼盐酸盐、六甲蜜胺、氨基格鲁米特、氨磷汀、氨柔比星、安丫啶、阿纳托唑、多拉司琼、aranesp、arglabin、三氧化二砷、阿诺新、5-氮胞苷、硫唑嘌呤、卡介苗、贝他定、醋酸倍他米松、倍他米松磷酸钠、贝沙罗汀、硫酸博来霉素、溴尿甘、bortezomib、白消安、降钙素、阿来佐单抗注射液、卡培他滨、卡铂、顺铂、康士德、cefesone、西莫白介素、柔红霉素、苯丁酸氮芥、克拉屈滨、氯屈磷酸、环磷酰胺、阿糖胞昔、达卡巴嗪、放线菌素D、柔红霉素脂质体、地塞米送、磷酸地塞米送、戊酸雌二醇、地尼白介素2、地洛瑞林、地拉佐生、己烯雌酚、大扶康、多西他奇、去氧氟尿苷、阿霉素、屈大麻酚、壳聚糖复合物、拉步立酶、盐酸表柔比星、阿瑞吡坦、表阿霉素、阿法依伯汀、红细胞生成素、依铂、左旋咪唑片、雌二醇制剂、17-β-雌二醇、雌莫司汀磷酸钠、炔雌醇、羟磷酸、凡毕复、依托泊甙、法倔唑、他莫昔芬制剂、非格司亭、非雷司替、氟尿苷、氟康唑、氟达拉滨、5-氟脱氧尿嘧啶核苷磷酸盐、5-氟尿嘧啶、氟甲睾酮、氟他胺、福麦斯坦、1-β-D-阿糖呋喃胞塞啶-5’-硬脂磷酸酯、福莫司汀、氟维司群、丙钟球蛋白、吉西他滨、吉妥单抗、伊马替尼、卡氮芥糯米纸胶囊剂、戈舍瑞林、盐酸格拉尼西隆、组氨瑞林、和美新、氢化可的松、赤型-羟基壬基腺嘌呤、羟基脲、替坦异贝莫单抗、伊达比星、异环磷酰胺、干扰素α、干扰素α2、干扰素α-2A、干扰素α-2B、干扰素α-n1、干扰素α-n3、干扰素β、干扰素γ-1a、白细胞介素-2、内含子A、易瑞沙、依立替康凯特瑞、硫酸香菇多糖、来曲唑、甲酰四氢叶酸、亮丙瑞林、亮丙瑞林醋酸盐、左旋四咪唑、左旋亚叶酸钙盐、左甲状腺素钠、左甲状腺素钠制剂、洛莫司汀、氯尼达明、屈大麻酚、甲钴胺、甲羟孕酮醋酸酯、醋酸甲地孕酮、美法仑、酯化雌激素、6-巯基嘌呤、美司钠、氨甲蝶呤、氨基乙酰丙酸酯、米替福新、美满霉素、丝裂霉素C、米托坦、米托葱醌、曲洛司坦、柠檬酸阿霉素脂质体、奈达铂、聚乙二醇化非格司亭、奥普瑞白介素、neupogen、尼鲁米特、三苯氧胺、NSC-631570、重组人白细胞介素1-β、奥曲肽、盐酸奥丹西隆、去氢化可的松口服溶液剂、奥沙利铂、紫杉醇、多西他塞、卡巴他塞、泼尼松磷酸钠、培门冬酶、派罗欣、喷司他丁、溶链菌制剂、盐酸皮鲁卡品、毗柔比星、普卡霉素、卜吩姆钠、泼尼莫司汀、泼尼松、司替泼尼松龙、倍美力、丙卡巴齐、重组人类红细胞生成素、雷替曲塞、利比、依替瞵酸铼-186、美罗华、力度伸-A、罗莫肽、盐酸毛果芸香碱片剂、沙莫司亭、司莫司汀、西佐喃、奥布佐生、唬钠甲强龙、帕福斯酸、链佐星、氯化锶-89、左旋甲状腺素钠、他莫昔芬、坦舒洛辛、他索那明、tastolactone、泰索帝、替西硫津、替莫唑胺、替尼泊苷、丙酸睾酮、甲睾酮、硫鸟嘌呤、噻替哌、促甲状腺激素、替鲁瞵酸、拓扑替康、托瑞米芬、托西莫单抗、曲瑞妥珠单抗、曲奥舒凡、维甲酸、甲氨喋呤片剂、三甲基密胺、三甲曲沙、
乙酸曲普瑞林、双羟萘酸曲普瑞林、优福定、尿苷、戊柔比星、维司力农、长春碱、长春新碱、长春酰胺、长春瑞滨、维鲁利秦、右旋丙亚胺、净司他丁斯酯、枢复宁、紫杉醇蛋白质稳定制剂、acolbifene、affinitak、氨基喋呤、阿佐昔芬、asoprisnil、阿他美坦、阿曲生坦、阿瓦斯丁、CCI-779、CDC-501、西乐葆、西妥昔单抗、克立那托、环丙孕酮醋酸酯、吉西他滨、阿霉素-MTC、伊班瞵酸、兰乐肽、拉索昔芬、米泼昔芬、米诺屈酸酯、脂质体MTP-PE、那法瑞林、诺拉曲特、紫杉醇聚谷氨酸酯、西奥骨化醇、埃罗替尼、紫杉醇脂质体、tipifarnib、SAHA、替拉扎明、伐普肽、vatalanib、维替泊芬、长春氟宁或它们的组合。
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.(E)-4-(2-硝基乙烯基)-1H-吲哚
吲哚-4-甲醛(1g,6.89mmol)和(NH4)2OAc(266mg,3.44mmol)溶于硝基甲烷(16ml)中,然后向溶液中加入乙酸楚(6.9ml,6.9mmol).在110oC条件下,反应12h,旋干反应液,剩余物用水稀释,然后加入乙酸乙酯(30mL×3)萃取,有机相依次用水,饱和食盐水洗涤。有机层用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析得到桔红色固体600mg,产率60%。1H NMR(400MHz,CDCl3),δ8.51(br,1H),8.21(d,J=15.6Hz,1H),7.89(s,1H),7.70(d,J=15.2Hz,1H),7.49(d,J=8.4Hz,1H),7.44(dd,J=1.6,8.4Hz,1H),7.35(t,J=2.8Hz,1H),6.68(t,J=2.2Hz,1H)ppm.MS(EI,m/z):189(M++1).步骤2.4-(2-硝乙基)-1H-吲哚
(E)-4-(2-硝基乙烯基)-1H-吲哚(988mg,5.25mmol)溶于MeOH/THF(1:1,20mL)中,0℃时分批加入NaBH4(875mg,23.09mmol).加完后,移去冰浴,反应液在室温下搅拌半小时。蒸干溶剂,硅胶柱层析得到黄色油状液体体798mg,产率80%。1HNMR(400MHz,CDCl3):δ8.28(br,1H),7.34(d,J=8.0Hz,1H),7.27-7.25(m,1H),7.16(t,J=7.6Hz,1H),6.96(d,J=7.2Hz,1H),6.59(s,1H),4.72(t,J=7.6Hz,2H),3.63(t,J=7.8Hz,2H)ppm.MS(EI,m/z):191(M++1).
步骤3.4-(2-氨乙基)-1H-吲哚
将催化量的Raney-Ni在95%乙醇(6ml)加入到4-(2-硝乙基)-1H-吲哚(500mg,2.63mmol)和水合肼(0.38ml,7.89mmo)在95%乙醇(7ml)的溶液中。回流12h后,过滤除去固体,蒸干溶剂,硅胶柱层析得到棕色固体331mg,产率78%。1H NMR(400MHz,CDCl3):δ8.59(br,1H),7.27(d,J=8.8Hz,1H),7.19(t,J=2.6Hz,1H),7.14(t,J=7.6Hz,1H),6.95(d,J=7.2Hz,1H),6.59(s,1H),3.13-3.04(m,4H)ppm.MS(EI,m/z):161(M++1).
步骤4.(E)-3-(4-(((2-(1H-吲哚-4-取代)乙基)氨基)甲基)苯基)丙烯酸甲酯
向4-(2-氨乙基)-1H-吲哚(393mg,2.45mmol)甲醇溶液中(20ml)分批慢慢加入(E)-3-(4-甲醛基苯基)丙烯酸甲酯(389mg,2.04mmol)和醋酸(0.12ml,2.04mmol)。五分钟后,加入NaBH3CN(257mg,4.08mmol)。反应2h后,用饱和NaHCO3淬灭反应液,然后加入乙酸乙酯(30mL×3)萃取,有机相依次用水,饱和食盐水洗涤。有机层用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析得到黄色液体(698mg,85%)。1H NMR(400MHz,CDCl3):δ8.26(br,1H),7.67(d,J=16.0Hz,1H),7.44(d,J=8.0Hz,2H),7.29-7.26(m,3H),7.20(t,J=2.8Hz,1H),7.13(t,J=7.6Hz,1H),6.95(d,J=6.8Hz,1H),6.59(s,1H),6.41(d,J=16.0Hz,1H),3.83(s,2H),3.80(s,3H),3.14(t,J=7.0Hz,2H),3.04(t,J=6.8Hz,2H)ppm.MS(EI,m/z):335(M++1).HRMS(ESI):calcdforC21H22N2O2[MH+]335.1681,found335.1682.
步骤5.(E)-3-(4-(((2-(1H-吲哚-4-取代)乙基)氨基)甲基)苯基)-N-羟基-丙烯酰胺
在冰浴条件下,向(E)-3-(4-(((2-(1H-吲哚-4-取代)乙基)氨基)甲基)苯基)丙烯酸甲酯(202mg,0.6mmol)的甲醇(1.5ml)溶液中加入新制的2M NH2OH甲醇溶液(3ml,6mmol)和KOH(58mg,0.91mmol,87%w/w)甲醇溶液(1.5ml).室温反应12h后,蒸干溶剂,硅胶柱层析得到淡黄色固体141mg,产率70%。1H NMR(400MHz,MeOD):δ7.56-7.52(m,3H),7.35(d,J=8.0Hz,2H),7.27(d,J=8.4Hz,1H),7.22(d,J=3.2Hz,1H),7.03(t,J=7.6Hz,1H),6.85(d,J=7.2Hz,1H),6.50-6.44(m,2H),3.93(s,2H),3.31-3.09(m,4H)ppm.13CNMR(125MHz,MeOD):δ162.1,136.9,135.4,133.8,132.0,126.8,126.6,125.1,124.7,121.5,118.4,116.0,114.8,107.0,96.3,49.2,45.9,29.2ppm.HRMS(ESI):calcd for C20H22N3O2[MH+]336.1634,found336.1635.
实施例2
(E)-3-(4-(((2-(1H-吲哚-4-取代)乙基)氨基)甲基)苯基)-N-羟基-丁烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.0(s,NH),8.0(brs,NH),7.66-7.50(m,4H),7.37(d,J=8.0Hz,2H),7.28(d,J=8.0Hz,2H),7.25(d,J=3.2Hz,1H),7.03(t,J=7.6Hz,1H),3.93(s,2H),3.31-3.09(m,4H),1.71(s,3H)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found350.1792.
实施例3
(E)-3-(4-(((2-(1H-吲哚-4-取代)乙基)甲氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.0(brs,NH),8.01(brs,NH),7.56-7.52(m,3H),7.35(d,J=8.0Hz,2H),7.27(d,J=8.4Hz,1H),7.22(d,J=3.2Hz,1H),7.03(t,J=7.6Hz,1H),6.85(d,J=7.2Hz,1H),6.50-6.44(m,2H),3.93(s,2H),3.11-3.02(m,4H),2.30(s,3H)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found350.1792.
实施例4
(E)-3-(4-(((2-(1H-吲哚-4-取代)乙基)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.1(brs,NH),8.03(brs,NH),7.59-7.55(m,3H),7.38(d,J=8.2Hz,2H),7.29(d,J=8.2Hz,2H),7.25(d,J=7.2Hz,1H),7.03(d,J=15.6Hz,1H),6.85(d,J=7.2Hz,1H),6.53(d,J=15.6Hz,1H),3.96(s,2H),3.19-3.12(m,4H),2.41(q,J=6.8Hz,2H),1.08(t,J=6.8Hz,2H)ppm.HRMS(ESI):calcd for C22H26N3O2[MH+]364.1947,found364.1948.
实施例5
(E)-3-(4-(((2-(1H-吲哚-4-取代)乙基)2-羟乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,CDCl3):δ8.24(br,1H),7.69(d,J=16.0Hz,1H),7.45(d,J=8.0Hz,2H),7.30-7.26(m,3H),7.18-7.12(m,2H),6.91(d,J=6.8Hz,1H),6.46-6.42(m,2H),3.84(s,3H),3.76(s,2H),3.54(t,J=5.2Hz,2H),3.12-3.08(m,2H),2.95-2.91(m,2H),2.75(t,J=5,2Hz,2H)ppm.HRMS(ESI):calcd for C22H26N3O3[MH+]380.1896,found380.1896.
实施例6(E)-3-(4-((2-(2-甲基-1H-吲哚-4-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ9.99(brs,NH),8.00(brs,NH),7.55-7.53(m,3H),7.37(d,J=8.0Hz,2H),7.22(d,J=8.0Hz,2H),7.12(d,J=3.2Hz,1H),7.00(t,J=13.6Hz,1H),6.93(d,J=3.2Hz,1H),6.52(t,J=13.6Hz,1H),3.97(s,2H),3.35-3.19(m,4H)2.89(s,3H)ppm.13CNMR(125MHz,MeOD):δ162.2,136.7,135.7,133.9,132.3,126.9,126.6,125.6,124.8,121.7,118.6,116.2,114.9,107.1,49.5,45.8,29.5,18.9ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found350.1789.
实施例7(E)-3-(4-((2-(2-甲基-1H-吲哚-4-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ9.98(brs,NH),8.01(brs,NH),7.56-7.52(m,3H),7.36(d,J=8.0Hz,2H),7.23(d,J=8.0Hz,2H),7.12(s,1H),7.00(d,J=13.6Hz,1H),6.52(d,J=13.6Hz,1H),3.98(s,2H),3.36-3.20(m,4H)2.88(s,3H)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found350.1789.
实施例8(E)-N-羟基-3-(4-((2-(1,2,3,4-四氢环戊烷并[b]吲哚-8-取代)乙氨基)甲基)苯基)-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.03(brs,NH),7.59-7.55(m,3H),7.38(d,J=8.2Hz,2H),7.25(d,J=8.2Hz,2H),7.33(d,J=15.6Hz,1H),6.55(d,J=15.6Hz,1H),3.95(s,2H),3.16-3.05(m,4H),2.45-2.60(m,4H),2.06(brs,OH),1.88(m,2H)ppm.HRMS(ESI):calcd for C23H26N3O2[MH+]376.1947,found376.1948.
实施例9(E)-3-(4-((2-(苯并呋喃-4-取代)乙氨基)甲基)苯基)-N-羟基丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.01(brs,NH),8.02(brs,NH),7.53(d,J=13.6Hz,1H),7.49-7.35(m,3H),7.28(d,J=8.0Hz,2H),7.15(d,J=8.0Hz,2H),6.55(d,J=13.6Hz,1H),4.01(brs,NH),3.93(s,2H),3.15-3.04(m,4H),3.01(t,J=6.6Hz,2H),2.45(t,J=6.6Hz,2H),2.02(brs,OH)ppm.HRMS(ESI):calcd for C22H25N4O2[MH+]337.1474,found337.1476.
实施例10(E)-3-(4-((2-(苯并噻吩-4-取代)乙氨基)甲基)苯基)-N-羟基丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.00(brs,NH),8.00(brs,NH),7.55(d,J=13.8Hz,1H),7.28(d,J=8.2Hz,2H),7.13-7.07(m,3H),7.05(d,J=8.2Hz,2H),6.88(d,J=13.8Hz,1H),3.93(s,2H),3.86(s,2H),3.70(s,2H),3.00(t,J=6.8Hz,2H),2.72(t,J=6.8Hz,2H),2.01(brs,OH)ppm.HRMS(ESI):calcd for C20H20N2O2S[MH+]353.1245,found353.1246.
实施例11(E)-3-(4-(((2-(苯并呋喃-4-取代)乙基(甲基)氨基)甲基)苯基)-N-羟基丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.01(brs,NH),8.00(brs,NH),7.54(d,J=13.8Hz,1H),7.26(d,J=8.2Hz,2H),7.15-7.08(m,3H),7.06(d,J=8.2Hz,2H),6.85(d,J=13.8Hz,1H),3.85(s,2H),3.33(t,J=7.6Hz,2H),3.00(t,J=7.8Hz,2H),2.92(t,J=6.8Hz,2H),2.70(t,J=6.8Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H23N2O3[MH+]351.1630,found351.1629.
实施例12(E)-3-(4-(((2-(苯并噻吩-4-取代)乙基(甲基)氨基)甲基)苯基)-N-羟基丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.01(brs,NH),8.00(brs,NH),7.55(d,J=13.8Hz,1H),7.25(d,J=8.0Hz,2H),7.20-7.00(m,5H),7.06(d,J=8.0Hz,2H),6.85(d,J=13.8Hz,1H),3.81(s,2H),2.89(t,J=6.8Hz,2H),2.71(t,J=6.8Hz,2H),2.02(brs,OH)ppm.HRMS(ESI):calcd for C21H23N2O2S[MH+]367.1402,found367.1401.
实施例13(E)-3-(4-(((2-(苯并呋喃-4-取代)乙基(2-羟乙基)氨基)甲基)苯基)-N-羟基丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.01(brs,NH),7.56(d,J=13.8Hz,1H),7.26(d,J=8.0Hz,2H),7.21-7.03(m,5H),7.05(d,J=8.0Hz,2H),6.85(d,J=13.8Hz,1H),3.85(s,2H),2.88(t,J=6.8Hz,2H),2.70(t,J=6.8Hz,2H),2.01(brs,OH)ppm.HRMS(ESI):calcd for C22H25N2O4[MH+]381.1736,found381.1735.
实施例14(E)-3-(4-(((2-(苯并噻吩-4-取代)乙基(2-羟乙基)氨基)甲基)苯基)-N-羟基丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.00(brs,NH),8.00(brs,NH),7.55(d,J=13.6Hz,1H),7.20(d,J=8.0Hz,2H),7.11-7.03(m,3H),7.01(d,J=8.0Hz,2H),6.84(d,J=13.6Hz,1H),4.21(t,J=6.6Hz,2H),3.83(s,2H),2.89(m2H),2.85(t,J=6.6Hz,2H),2.67(m,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H24N2O3S[MH+]397.1580,found397.1581.
实施例15(E)-3-(4-((2-(3,8-二氢噻吩并[2,3-b]吲哚-4-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.01(brs,NH),7.55(d,J=13.6Hz,1H),7.18(d,J=8.0Hz,2H),7.13-7.01(m,3H),7.01(d,J=8.0Hz,2H),6.84(d,J=13.6Hz,1H),3.83(s,2H),3.21(t,J=6.6Hz,2H),2.89(m2H),2.85(t,J=6.6Hz,2H),2.67(m,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H24N3O2S[MH+]394.1511,found394.1511.
实施例16(E)-N-羟基-3-(4-((2-(2,3,4,9-四氢-1H-吡啶并[2,3-b]吲哚-5-取代)乙氨基)甲基)苯基)-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.01(brs,NH),7.55(d,J=13.6Hz,1H),7.20(d,J=8.0Hz,2H),7.10-7.05(m,3H),7.07(d,J=8.0Hz,2H),6.85(d,J=13.6Hz,1H),4.00(brs,NH),3.90(s,2H),3.06(t,J=6.8Hz,2H),2.88(t,J=6.6Hz,2H),2.67(t,J=6.6Hz,2H),2.43(m,2H),2.02(brs,OH),1.79(m,2H)ppm.HRMS(ESI):calcd for C23H27N4O2[MH+]391.2056,found391.2057.
实施例17(E)-N-羟基-3-(4-((2-(2,3,4,5-四氢-1H-吡啶并[3,4-b]吲哚-9-取代)乙氨基)甲基)苯基)-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.01(brs,NH),7.55(d,J=13.6Hz,1H),7.19(d,J=8.0Hz,2H),7.01(d,J=8.0Hz,2H),7.00-6.91(m,3H),6.84(d,J=13.6Hz,1H),4.00(brs,2H),3.85(s,2H),3.08(t,J=6.8Hz,2H),2.88(t,J=6.6Hz,2H),2.67(t,J=6.6Hz,2H),2.59(m,2H),2.00(brs,OH),1.80(m,2H)ppm.HRMS(ESI):calcd for C23H27N4O2[MH+]391.2056,found391.2055.
实施例18(E)-N-羟基-3-(4-((2-(2,3,4,9-四氢吡喃并[2,3-b]吲哚-5-取代)乙氨基)甲基)苯基)-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.03(brs,NH),7.57(d,J=13.6Hz,1H),7.22(d,J=8.0Hz,2H),7.15-7.10(m,3H),7.10(d,J=8.0Hz,2H),6.88(d,J=13.6Hz,1H),4.01(t,J=7.2Hz,2H),3.88(s,2H),2.88(t,J=6.6Hz,2H),2.67(t,J=6.6Hz,2H),2.43(m,2H),2.01(brs,OH),1.98(m,2H)ppm.HRMS(ESI):calcd for C23H26N3O3[MH+]392.1896,found392.1897.
实施例19(E)-N-羟基-3-(4-((2-(2,3,4,5-四氢吡喃并[3,2-b]吲哚-9-取代)乙氨基)甲基)苯基)-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.01(brs,NH),7.55(d,J=13.6Hz,1H),7.23(d,J=8.0Hz,2H),7.10(d,J=8.0Hz,2H),7.00-6.90(m,3H),6.85(d,J=13.6Hz,1H),4.00(t,J=7.2Hz,2H),3.85(s,2H),2.88(t,J=6.6Hz,2H),2.67(t,J=6.6Hz,2H),2.59(m,2H),2.01(brs,OH),1.98(m,2H)ppm.HRMS(ESI):calcd for C23H26N3O3[MH+]392.1896,found392.1896.
实施例20(E)-N-羟基-3-(4-((2-(2,3,4,9-四氢硫代吡喃并[2,3-b]吲哚-5-取代)乙氨基)甲基)苯基)-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.01(brs,NH),8.00(brs,NH),7.53(d,J=13.6Hz,1H),7.18(d,J=8.0Hz,2H),7.13-7.05(m,3H),7.01(d,J=8.0Hz,2H),6.85(d,J=13.6Hz,1H),3.81(s,2H),2.98(t,J=7.0Hz,2H),2.88(t,J=6.6Hz,2H),2.67(t,J=6.6Hz,2H),2.43(m,2H),2.01(brs,OH),1.96(m,2H)ppm.HRMS(ESI):calcd for C23H26N3O2S[MH+]408.1667,found408.1668.
实施例21(E)-3-(4-((2-(9H-咔唑胺-4-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.05(brs,NH),7.55(d,J=13.6Hz,1H),7.52(d,J=7.6Hz,1H),7.42(d,J=7.2Hz,1H),7.19(d,J=8.2Hz,2H),7.17-7.00(m,5H),7.01(d,J=8.2Hz,2H),6.85(d,J=13.6Hz,1H),3.86(s,2H),2.89(t,J=6.2Hz,2H),2.67(t,J=6.2Hz,2H)ppm.HRMS(ESI):calcd for C24H24N3O2[MH+]386.1790,found386.1791.
实施例22(E)-3-(4-((2-(9H-吡啶并[2,3-b]吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.09(brs,NH),8.57(d,J=7.0Hz,1H),8.03(brs,NH),7.75(d,J=7.2Hz,1H),7.55(d,J=13.6Hz,1H),7.38(m,1H),7.18(d,J=8.2Hz,2H),7.22-7.05(m,3H),7.01(d,J=8.2Hz,2H),6.85(d,J=13.6Hz,1H),3.81(s,2H),2.83(t,J=6.2Hz,2H),2.66(t,J=6.2Hz,2H)ppm.HRMS(ESI):calcdfor C23H23N4O2[MH+]387.1743,found387.1742.
实施例23(E)-3-(4-((2-(2-(2-羟乙基)-3-甲基-1H-吲哚-4-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ9.98(brs,NH),8.00(brs,NH),7.53(t,J=13.6Hz,1H),7.20(d,J=8.0Hz,2H),7.13-7.07(m,3H),7.02(d,J=8.0Hz,2H),6.83(t,J=13.6Hz,1H),3.90(s,2H),3.80(m,2H),2.88(t,J=6.2Hz,2H),2.78(t,J=6.6Hz,2H),2.67(t,J=6.2Hz,2H)2.30(s,3H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C23H28N3O3[MH+]394.2052,found394.2053.
实施例24(E)-3-(4-((2-(2,3-二氢-1H-吡咯并[1,2-a]吲哚-8-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ8.05(brs,NH),7.55(t,J=13.6Hz,1H),7.18(d,J=8.0Hz,2H),7.13-7.11(m,2H),7.02(d,J=8.0Hz,2H),6.85(t,J=13.6Hz,1H),6.67(d,J=8.6Hz,1H),6.16(s,1H),3.88(m,2H),3.82(s,2H),2.88(t,J=6.2Hz,2H),2.67(t,J=6.2Hz,2H),2.59(m,2H),2.04(m,2H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C23H26N3O2[MH+]376.1947,found376.1948.
实施例25(E)-3-(4-((2-(1,2-二甲基-1H-吲哚-4-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ8.00(brs,NH),7.55(t,J=13.6Hz,1H),7.18(d,J=8.0Hz,2H),7.12-7.10(m,2H),7.01(d,J=8.0Hz,2H),6.89(t,J=13.6Hz,1H),6.67(d,J=7.2Hz,1H),6.16(s,1H),3.87(s,2H),3.61(s,3H),2.89-2.67(m,4H),2.30(s,3H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C22H26N3O2[MH+]364.1947found364.1948.
实施例26(E)-3-(4-((2-(1-甲基-1H-吲哚-4-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ8.00(brs,NH),7.53(t,J=13.6Hz,1H),7.17(d,J=8.0Hz,2H),7.12-7.00(m,3H),7.01(d,J=8.0Hz,2H),6.85(t,J=13.6Hz,1H),6.82(d,J=7.2Hz,1H),6.48(d,J=7.2Hz,1H),3.81(s,2H),3.60(s,3H),2.88-2.67(m,4H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790found350.1791.
实施例27(E)-3-(4-((2-(2-叔丁基-1H-吲哚-4-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.02(brs,NH),7.55(t,J=13.6Hz,1H),7.19(d,J=8.0Hz,2H),7.03-6.93(m,3H),7.03(d,J=8.0Hz,2H),6.86(t,J=13.6Hz,1H),6.27(s,1H),3.87(s,2H),2.89-2.67(m,4H),2.00(brs,NH),1.38(s,9H)ppm.HRMS(ESI):calcd for C24H30N3O2[MH+]392.2260found392.2261.
实施例28(E)-3-(4-((2-(2-羟乙基-1H-吲哚-4-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.03(brs,NH),7.55(t,J=13.6Hz,1H),7.18(d,J=8.0Hz,2H),7.03-6.93(m,3H),7.01(d,J=8.0Hz,2H),6.84(t,J=13.6Hz,1H),6.13(s,1H),3.85(s,2H),3.80(m,2H),2.88-2.67(m,4H),2.78(t,J=6.6Hz,1H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C22H26N3O3[MH+]380.1896found380.1897.
实施例29(E)-3-(4-((2,3-二甲基-1H-吲哚-4-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.02(brs,NH),7.55(t,J=13.6Hz,1H),7.18(d,J=8.0Hz,2H),7.13-7.10(m,2H),7.01(d,J=8.0Hz,2H),6.84(t,J=13.6Hz,1H),6.68(d,J=8.6Hz,1H),3.83(s,2H),2.88-2.67(m,4H),2.38(s,3H),2.35(s,3H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C22H26N3O2[MH+]364.1947found364.1948.
实施例30(E)-3-(4-((2-(2-苯基-1H-吲哚-4-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.05(brs,NH),7.55(t,J=13.6Hz,1H),7.48-7.25(m,5H),7.20(d,J=8.0Hz,2H),7.19-7.08(m,3H),7.06(d,J=8.0Hz,2H),6.86(t,J=13.6Hz,1H),6.46(s,1H),3.85(s,2H),2.89-2.67(m,4H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C26H26N3O2[MH+]412.1947found412.1948.
实施例31(E)-3-(4-((2-(2-(2-羟丙基-2取代)-1H-吲哚-4-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.05(brs,NH),8.06(brs,NH),7.55(t,J=13.6Hz,1H),7.19(d,J=8.0Hz,2H),7.03-6.93(m,3H),7.01(d,J=8.0Hz,2H),6.84(t,J=13.6Hz,1H),6.15(s,1H),3.82(s,2H),2.86-2.67(m,4H),2.00(brs,NH),1.58(s,6H)ppm.HRMS(ESI):calcd for C23H28N3O3[MH+]394.2052found394.2053.
实施例32(E)-3-(4-((2-(1H-吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺]
1H NMR(400MHz,MeOD):δ7.60(d,J=8.0Hz,2H),7.56(d,J=15.5Hz,1H),7.46-7.42(m,3H),7.34(d,J=8.5Hz,1H),7.22(d,J=2.5Hz,1H),6.98(d,J=8.5Hz,1H),6.50(d,J=16.0Hz,1H),6.39(s,1H),4.12(s,2H),3.20(t,J=7.8Hz,2H),3.03(t,J=7.8Hz,2H)ppm.13CNMR(125MHz,MeOD):δ164.5,139.1,135.6,135.4,134.3,129.8,128.5,127.9,126.9,124.8,121.5,119.6,118.1,111.1,100.6,50.8,49.4,32.7ppm.HRMS(ESI):calcd for C20H22N3O2[MH+]336.1634,found336.1633.
实施例33(E)-3-(4-(((2-(1H-吲哚-5-取代)乙基)氨基)甲基)苯基)-N-羟基-丁烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.01(s,NH),8.01(brs,NH),7.62-7.46(m,3H),7.31(d,J=8.0Hz,1H),7.28(d,J=7.6Hz,2H),7.07(d,J=8.0Hz,1H),7.03(d,J=7.6Hz,2H),6.78(s,1H),3.93(s,2H),3.30-3.07(m,4H),1.72(s,3H)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found350.1791.
实施例34(E)-3-(4-(((2-(1H-吲哚-5-取代)乙基)甲氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.03(brs,NH),7.55-7.50(m,3H),7.36(d,J=8.0Hz,2H),7.28(d,J=8.4Hz,1H),7.23(s,1H),7.05(t,J=7.6Hz,1H),6.86(d,J=7.2Hz,1H),6.50-6.44(m,2H),3.92(s,2H),3.10-3.01(m,4H),2.31(s,3H)ppm.13CNMR(125MHz,MeOD):δ162.7,136.6,135.9,133.7,132.3,126.8,126.7,125.5,124.9,121.8,118.8,116.3,114.7,107.1,51.2,49.5,45.5,29.6ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found350.1791.
实施例35(E)-3-(4-(((2-(1H-吲哚-5-取代)乙基)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.02(brs,NH),7.59-7.53(m,3H),7.37(d,J=8.2Hz,2H),7.27(d,J=8.2Hz,2H),7.25(s,1H),7.13(d,J=15.6Hz,1H),6.85(d,J=7.2Hz,1H),6.53(d,J=15.6Hz,1H),3.96(s,2H),3.19-3.12(m,4H),2.42(q,J=6.8Hz,2H),1.09(t,J=6.8Hz,2H)ppm.HRMS(ESI):calcd forC22H26N3O2[MH+]364.1947,found364.1946.
实施例36(E)-3-(4-(((2-(1H-吲哚-5-取代)乙基)2-羟乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,CDCl3):δ8.12(br,1H),7.68(d,J=16.0Hz.1H),7.42(d,J=8.0Hz,2H),7.37(s,1H),7.30-7.24(m,2H),7.19(t,J=2.6Hz,1H),6.96(dd,J=1.2,8.4Hz,1H),6.46(d,J=2.0Hz,1H),6.41(d,J=16.0Hz,1H),3,81(s,3H),3.72(s,2H),3.54(t,J=5.4Hz,2H),2.91-2.87(m,2H),2.84-2.80(m,2H),2.72(t,J=5.2Hz,2H)ppm.HRMS(ESI):calcd for C22H26N3O3[MH+]380.1896,found380.1896.
实施例37(E)-3-(4-((2-(2-甲基-1H-吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ9.98(brs,NH),8.00(brs,NH),7.54-7.52(m,3H),7.38(d,J=8.0Hz,2H),7.20(d,J=8.0Hz,2H),7.12(s,1H),7.00(t,J=13.6Hz,1H),6.93(d,J=3.2Hz,1H),6.52(t,J=13.6Hz,1H),3.90(s,2H),3.35-3.19(m,4H)2.88(s,3H)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found350.1789.
实施例38(E)-3-(4-((2-(2-甲基-1H-吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ9.97(brs,NH),8.00(brs,NH),7.55-7.50(m,3H),7.33(d,J=8.0Hz,2H),7.20(d,J=8.0Hz,2H),7.12(s,1H),7.10(d,J=13.6Hz,1H),6.52(d,J=13.6Hz,1H),3.98(s,2H),3.36-3.20(m,4H)2.88(s,3H)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found350.1788.
实施例39(E)-N-羟基-3-(4-((2-(1,2,3,4-四氢环戊烷并[b]吲哚-9-取代)乙氨基)甲基)苯基)-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.03(brs,NH),7.59-7.52(m,3H),7.38(d,J=8.2Hz,2H),7.25(d,J=8.2Hz,2H),7.33(d,J=15.6Hz,1H),6.55(d,J=15.6Hz,1H),3.93(s,2H),3.15-3.03(m,4H),2.61-2.43(m,4H),2.02(brs,OH),1.89(m,2H)ppm.HRMS(ESI):calcd for C23H26N3O2[MH+]376.1947,found376.1946.
实施例40(E)-3-(4-((2-(苯并呋喃-5-取代)乙氨基)甲基)苯基)-N-羟基丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.03(brs,NH),7.54(d,J=13.6Hz,1H),7.48-7.35(m,3H),7.27(d,J=8.0Hz,2H),7.13(d,J=8.0Hz,2H),6.58(d,J=13.6Hz,1H),4.02(brs,NH),3.92(s,2H),3.15-3.06(m,4H),3.02(t,J=6.6Hz,2H),2.47(t,J=6.6Hz,2H),2.01(brs,OH)ppm.HRMS(ESI):calcd for C20H21N2O3[MH+]337.1474,found337.1475.
实施例41(E)-3-(4-((2-(苯并噻吩-5-取代)乙氨基)甲基)苯基)-N-羟基丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.00(brs,NH),7.55(d,J=13.8Hz,1H),7.28(d,J=8.2Hz,2H),7.15-7.07(m,3H),7.03(d,J=8.2Hz,2H),6.89(d,J=13.8Hz,1H),3.93(s,2H),3.86(s,2H),3.70(s,2H),3.01(t,J=6.8Hz,2H),2.73(t,J=6.8Hz,2H),2.00(brs,OH)ppm.13CNMR(125MHz,MeOD):δ161.7,144.1,136.1,135.6,133.3,132.3,127.6,126.3,125.9,123.2,120.1,119.7,118.9,114.2,107.8,54.8,49.5,47.2,34.2ppm.HRMS(ESI):calcd for C20H21N2O2S[MH+]353.1245,found353.1243.
实施例41(E)-3-(4-(((2-(苯并呋喃-5-取代)乙基(甲基)氨基)甲基)苯基)-N-羟基丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.01(brs,NH),7.53(d,J=13.8Hz,1H),7.26(d,J=8.2Hz,2H),7.15-7.07(m,3H),7.05(d,J=8.2Hz,2H),6.87(d,J=13.8Hz,1H),3.85(s,2H),3.32(t,J=7.6Hz,2H),3.01(t,J=7.8Hz,2H),2.92(t,J=6.8Hz,2H),2.71(t,J=6.8Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25N4O2[MH+]351.1630,found351.1633.
实施例42(E)-3-(4-(((2-(苯并噻吩-5-取代)乙基(甲基)氨基)甲基)苯基)-N-羟基丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.01(brs,NH),7.55(d,J=13.8Hz,1H),7.26(d,J=8.2Hz,2H),7.20-7.00(m,5H),7.07(d,J=8.2Hz,2H),6.86(d,J=13.8Hz,1H),3.82(s,2H),2.88(t,J=6.8Hz,2H),2.70(t,J=6.8Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H22N2O2S[MH+]367.1402,found367.1400.
实施例43(E)-3-(4-(((2-(苯并呋喃-5-取代)乙基(2-羟乙基)氨基)甲基)苯基)-N-羟基丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.07(brs,NH),8.02(brs,NH),7.55(d,J=13.8Hz,1H),7.25(d,J=8.0Hz,2H),7.22-7.03(m,5H),7.07(d,J=8.0Hz,2H),6.86(d,J=13.8Hz,1H),3.86(s,2H),2.89(t,J=6.8Hz,2H),2.71(t,J=6.8Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25N2O4[MH+]381.1736,found381.1733.
实施例44(E)-3-(4-(((2-(苯并噻吩-5-取代)乙基(2-羟乙基)氨基)甲基)苯基)-N-羟基丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.02(brs,NH),7.57(d,J=13.6Hz,1H),7.23(d,J=8.0Hz,2H),7.15-7.03(m,3H),7.04(d,J=8.0Hz,2H),6.88(d,J=13.6Hz,1H),4.23(t,J=6.6Hz,2H),3.85(s,2H),2.89(m2H),2.86(t,J=6.6Hz,2H),2.68(m,2H),2.00(brs,OH)ppm.HRMS(ESI):calcdfor C22H24N2O3S[MH+]397.1580,found397.1580.
实施例45(E)-3-(4-((2-(8H-呋喃并[2,3-b]吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.07(brs,NH),8.00(brs,NH),7.55(d,J=13.6Hz,1H),7.41(s,1H),7.37(d,J=7.2Hz,1H),7.18(d,J=8.0Hz,2H),7.13-7.03(m,2H),7.01(d,J=8.0Hz,2H),6.85(d,J=13.6Hz,1H),6.38(d,J=7.2Hz,1H),3.82(s,2H),2.87(m2H),2.66(m,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H21N3O3[MH+]375.1505,found375.1504.
实施例46(E)-3-(4-((2-(3,8-二氢噻吩并[2,3-b]吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.00(brs,NH),7.55(d,J=13.6Hz,1H),7.18(d,J=8.0Hz,2H),7.13-7.06(m,3H),7.03(s,1H),7.01(d,J=8.0Hz,2H),6.85(d,J=13.6Hz,1H),3.82(s,2H),3.20(t,J=6.6Hz,2H),2.90(m2H),2.88(t,J=6.6Hz,2H),2.67(m,2H),2.00(brs,OH)ppm.13CNMR(125MHz,MeOD):δ161.1,143.9,136.2,135.6,133.3,132.6,127.9,126.2,126.0,123.2,120.0,119.3118.9,108.3,72.3,54.8,48.6,36.6,34.2,31.6ppm.HRMS(ESI):calcd for C22H24N3O2S[MH+]394.1511,found394.1510.
实施例47(E)-N-羟基-3-(4-((2-(6,7,8,9-四氢-5H-咔唑胺-5-取代)乙氨基)甲基)苯基)-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ9.99(brs,NH),8.00(brs,NH),7.55(d,J=15.6Hz,1H),7.18(d,J=8.2Hz,2H),7.05-7.00(m,2H),7.01(d,J=8.2Hz,2H),6.85(d,J=15.6Hz,1H),6.57(s,1H),3.86(s,2H),2.88(m,2H),2.67(m,2H),2.59(t,J=6.2Hz,2H),2.43(t,J=6.2Hz,2H),1.56-1.58(m,4H)ppm.HRMS(ESI):calcd for C24H28N3O2[MH+]390.2103,found390.2104.
实施例48(E)-N-羟基-3-(4-((2-(2,3,4,9-四氢-1H-吡啶并[2,3-b]吲哚-5-取代)乙氨基)甲基)苯基)-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.01(brs,NH),8.00(brs,NH),7.55(d,J=13.6Hz,1H),7.20(d,J=8.0Hz,2H),7.10-7.05(m,2H),7.07(d,J=8.0Hz,2H),7.03(s,1H),6.85(d,J=13.6Hz,1H),4.00(brs,NH),3.82(s,2H),3.06(t,J=6.8Hz,2H),2.88(t,J=6.6Hz,2H),2.67(t,J=6.6Hz,2H),2.43(m,2H),2.01(brs,OH),1.79(m,2H)ppm.HRMS(ESI):calcd for C23H27N4O2[MH+]391.2056,found391.2056.
实施例49(E)-N-羟基-3-(4-((2-(2,3,4,9-四氢吡喃并[2,3-b]吲哚-6-取代)乙氨基)甲基)苯基)-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.02(brs,NH),7.56(d,J=13.6Hz,1H),7.22(d,J=8.0Hz,2H),7.17-7.13(m,3H),7.10(s,1H),7.08(d,J=8.0Hz,2H),6.88(d,J=13.6Hz,1H),3.96(t,J=7.2Hz,2H),3.83(s,2H),2.88(t,J=6.6Hz,2H),2.67(t,J=6.6Hz,2H),2.43(m,2H),2.01(brs,OH),1.98(m,2H)ppm.HRMS(ESI):calcd for C23H26N3O3[MH+]392.1896,found392.1897.
实施例50(E)-N-羟基-3-(4-((2-(2,3,4,9-四氢硫代吡喃并[2,3-b]吲哚-6-取代)乙氨基)甲基)苯基)-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.03(brs,NH),7.55(d,J=13.6Hz,1H),7.18(d,J=8.0Hz,2H),7.13-7.08(m,2H),7.05(s,1H),7.01(d,J=8.0Hz,2H),6.86(d,J=13.6Hz,1H),3.82(s,2H),2.93(t,J=7.0Hz,2H),2.88(t,J=6.6Hz,2H),2.66(t,J=6.6Hz,2H),2.43(m,2H),2.00(brs,OH),1.95(m,2H)ppm.HRMS(ESI):calcd for C23H26N3O2S[MH+]408.1667,found408.1666.
实施例51(E)-3-(4-((2-(9H-咔唑胺-3-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.09(brs,NH),8.06(brs,NH),7.58(d,J=7.6Hz,1H),7.55(d,J=13.6Hz,1H),7.42(s,1H),7.40(d,J=7.2Hz,1H),7.19(d,J=8.2Hz,2H),7.17-7.00(m,4H),7.01(d,J=8.2Hz,2H),6.85(d,J=13.6Hz,1H),3.85(s,2H),2.88(t,J=6.2Hz,2H),2.67(t,J=6.2Hz,2H)ppm.HRMS(ESI):calcdfor C24H24N3O2[MH+]386.1790,found386.1791.
实施例52(E)-3-(4-((2-(2-(2-羟乙基)-3-甲基-1H-吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ9.99(brs,NH),8.00(brs,NH),7.54(t,J=13.6Hz,1H),7.20(d,J=8.0Hz,2H),7.05-7.03(m,2H),7.01(d,J=8.0Hz,2H),6.83(t,J=13.6Hz,1H),6.57(s,1H),3.88(s,2H),3.81(m,2H),2.88(t,J=6.2Hz,2H),2.78(t,J=6.6Hz,2H),2.67(t,J=6.2Hz,2H)2.31(s,3H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C23H28N3O3[MH+]394.2052,found394.2053.
实施例53(E)-3-(4-((2-(2,3-二氢-1H-吡咯并[1,2-a]吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.03(brs,NH),7.55(t,J=13.6Hz,1H),7.18(d,J=8.0Hz,2H),7.03(d,J=8.0Hz,2H),7.01-6.95(m,2H),6.85(t,J=13.6Hz,1H),6.56(s,1H),6.16(s,1H),3.85(m,2H),3.81(s,2H),2.88(t,J=6.2Hz,2H),2.67(t,J=6.2Hz,2H),2.59(m,2H),2.04(m,2H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C23H26N3O2[MH+]376.1947,found376.1948.
实施例54(E)-3-(4-((2-(1,2-二甲基-1H-吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.01(brs,NH),7.56(t,J=13.6Hz,1H),7.18(d,J=8.0Hz,2H),7.03(d,J=8.0Hz,2H),7.00-6.91(m,2H),6.89(t,J=13.6Hz,1H),6.56(s,1H),6.16(s,1H),3.86(s,2H),3.60(s,3H),2.88-2.67(m,4H),2.30(s,3H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C22H26N3O2[MH+]364.1947found364.1948.
实施例55(E)-3-(4-((2-(1-甲基-1H-吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.01(brs,NH),7.55(t,J=13.6Hz,1H),7.18(d,J=8.0Hz,2H),7.12-7.05(m,2H),7.03(s,1H),7.01(d,J=8.0Hz,2H),6.85(t,J=13.6Hz,1H),6.82(d,J=7.2Hz,1H),6.48(d,J=7.2Hz,1H),3.81(s,2H),3.60(s,3H),2.88-2.67(m,4H),2.00(brs,NH)ppm.HRMS(ESI):calcdfor C21H24N3O2[MH+]350.1790found350.1791.
实施例56(E)-3-(4-((2-(2-叔丁基-1H-吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.05(brs,NH),8.01(brs,NH),7.55(t,J=13.6Hz,1H),7.19(d,J=8.0Hz,2H),7.03(d,J=8.0Hz,2H),7.01-6.95(m,2H),6.93(s,1H),6.86(t,J=13.6Hz,1H),6.13(s,1H),3.83(s,2H),2.89-2.67(m,4H),2.00(brs,NH),1.35(s,9H)ppm.HRMS(ESI):calcd for C24H30N3O2[MH+]392.2260found392.2261.
实施例57(E)-3-(4-((2-(2-羟乙基-1H-吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.02(brs,NH),7.55(t,J=13.6Hz,1H),7.18(d,J=8.0Hz,2H),7.03-6.98(m,3H),7.01(d,J=8.0Hz,2H),6.94(s,1H),6.84(t,J=13.6Hz,1H),6.13(s,1H),3.85(s,2H),3.80(m,2H),2.88-2.67(m,4H),2.78(t,J=6.6Hz,1H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C22H26N3O3[MH+]380.1896found380.1895.
实施例58(E)-3-(4-((2,3-二甲基-1H-吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.02(brs,NH),7.55(t,J=13.6Hz,1H),7.18(d,J=8.0Hz,2H),7.03(d,J=8.0Hz,2H),7.01-6.97(m,2H),6.84(t,J=13.6Hz,1H),6.57(s,1H),3.83(s,2H),2.88-2.67(m,4H),2.37(s,3H),2.34(s,3H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C22H26N3O2[MH+]364.1947found364.1948.
实施例59(E)-3-(4-((2-(2-苯基-1H-吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.05(brs,NH),7.55(t,J=13.6Hz,1H),7.48-7.22(m,5H),7.40(s,1H),7.19(d,J=8.0Hz,2H),7.30-7.10(m,2H),7.05(d,J=8.0Hz,2H),6.86(t,J=13.6Hz,1H),6.43(s,1H),3.85(s,2H),2.89-2.67(m,4H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C26H26N3O2[MH+]412.1947found412.1948.
实施例60(E)-3-(4-((2-(2-(2-羟丙基-2取代)-1H-吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.05(brs,NH),8.06(brs,NH),7.55(t,J=13.6Hz,1H),7.19(d,J=8.0Hz,2H),7.06-7.02(m,2H),7.01(d,J=8.0Hz,2H),6.94(s,1H),6.83(t,J=13.6Hz,1H),6.13(s,1H),3.82(s,2H),2.86-2.67(m,4H),2.00(brs,NH),1.54(s,6H)ppm.HRMS(ESI):calcd for C23H28N3O3[MH+]394.2052found394.2051.
实施例61(E)-3-(4-((2-(1H-吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ7.56(d,J=15.6Hz,1H),7.50(d,J=8.2Hz,1H),7.26(s,1H),7.25-7.19(m,3H),7.18(d,J=8.0Hz,2H),7.01(d,J=8.0Hz,1H),6.84(d,J=15.6Hz,1H),4.10(s,2H),3.18(t,J=7.8Hz,2H),3.00(t,J=7.8Hz,2H)ppm.13CNMR(125MHz,MeOD):δ164.3,139.1,135.6,135.4,134.1,129.8,128.7,127.9,126.9,124.8,121.6,119.6,118.3,111.1,100.6,50.9,49.6,32.9ppm.HRMS(ESI):calcd for C20H22N3O2[MH+]336.1634,found336.1634.
实施例62(E)-3-(4-(((2-(1H-吲哚-6-取代)乙基)氨基)甲基)苯基)-N-羟基-丁烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.02(s,NH),8.04(brs,NH),7.50-7.27(m,3H),7.18(d,J=8.0Hz,2H),7.01(d,J=8.0Hz,2H),6.86(m,1H),6.56(s,1H),6.45(d,J=7.6Hz,1H),3.89(s,2H),2.88-2.68(m,4H),1.72(s,3H)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found350.1790.
实施例63(E)-3-(4-(((2-(1H-吲哚-6-取代)乙基)甲氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.02(brs,NH),7.55(d,J=13.8Hz,1H),7.50(d,J=8.2Hz,1H),7.28(d,J=7.8Hz,1H),7.26(s,1H),7.22(d,J=7.2Hz,2H),7.06(d,J=7.2Hz,2H),6.86(d,J=8.2Hz,1H),6.84(d,J=13.8Hz,1H),6.45(d,d,J=7.8Hz,1H),3.62(s,2H),2.69-2.65(m,4H),2.27(s,3H)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found350.1792.
实施例64(E)-3-(4-(((2-(1H-吲哚-6-取代)乙基)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.06(brs,NH),7.57(d,J=8.6Hz,1H),7.53(d,J=15.6Hz,1H),7.28(d,J=7.8Hz,2H),7.25(s,1H),7.20(d,J=8.2Hz,2H),7.08(d,J=8.2Hz,2H),6.86(d,J=8.6Hz,1H),6.83(d,J=15.6Hz,1H),3.62(s,2H),2.89-2.78(m,4H),2.40(q,J=6.8Hz,2H),1.00(t,J=6.8Hz,2H)ppm.HRMS(ESI):calcd for C22H26N3O2[MH+]364.1947,found364.1948.
实施例65(E)-3-(4-(((2-(1H-吲哚-6-取代)乙基)2-羟乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,CDCl3):δ8.12(br,1H),7.66(d,J=16.0Hz.1H),7.40(d,J=8.0Hz,2H),7.27(d,J=7.2Hz,2H),7.26(s,1H),7.19(d,J=8.0Hz,2H),6.86(d,J=8.0Hz,1H),6.45(d,J=7.2Hz,1H),6.42(d,J=16.0Hz,1H),3.72(s,2H),3.56(t,J=5.4Hz,2H),2.89(m,2H),2.80(m,2H),2.70(t,J=5.2Hz,2H)ppm.HRMS(ESI):calcd for C22H26N3O3[MH+]380.1896,found380.1895.
实施例66(E)-3-(4-((2-(2-甲基-1H-吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ9.99(brs,NH),8.01(brs,NH),7.56-7.50(m,3H),7.38(d,J=8.2Hz,2H),7.19(d,J=8.0Hz,2H),7.10(s,1H),7.05(t,J=13.6Hz,1H),6.90(m,1H),6.52(t,J=13.6Hz,1H),3.88(s,2H),3.30-3.15(m,4H)2.80(s,3H)ppm.13CNMR(125MHz,MeOD):δ162.0,136.5,135.5,133.6,132.1,126.9,126.2,125.6,124.6,121.6,118.7,116.2,114.8,107.0,49.9,45.6,29.6,18.9ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found350.1788.
实施例67(E)-3-(4-((2-(2-甲基-1H-吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ9.98(brs,NH),8.01(brs,NH),7.52-7.48(m,3H),7.32(d,J=8.0Hz,2H),7.20(d,J=8.0Hz,2H),7.13(s,1H),7.11(d,J=13.6Hz,1H),6.58(d,J=13.6Hz,1H),3.96(s,2H),3.33-3.20(m,4H)2.80(s,3H)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found350.1789.
实施例68(E)-N-羟基-3-(4-((2-(1,2,3,4-四氢环戊烷并吲哚-6-取代)乙氨基)甲基)苯基)-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.01(brs,NH),7.57-7.50(m,3H),7.36(d,J=8.2Hz,2H),7.22(d,J=8.2Hz,2H),7.31(d,J=15.6Hz,1H),6.58(d,J=15.6Hz,1H),3.90(s,2H),3.10-3.03(m,4H),2.60-2.41(m,4H),2.01(brs,OH),1.88(m,2H)ppm.HRMS(ESI):calcd for C23H26N3O2[MH+]376.1947,found376.1948.
实施例69(E)-3-(4-((2-(苯并呋喃-6-取代)乙氨基)甲基)苯基)-N-羟基丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.08(brs,NH),7.57(d,J=13.6Hz,1H),7.49-7.36(m,3H),7.29(d,J=8.0Hz,2H),7.15(d,J=8.0Hz,2H),6.59(d,J=13.6Hz,1H),4.03(brs,NH),3.93(s,2H),3.15-3.05(m,4H),3.00(t,J=6.6Hz,2H),2.48(t,J=6.6Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H21N2O3[MH+]337.1474,found337.1475.
实施例70(E)-3-(4-((2-(苯并噻吩-6-取代)乙氨基)甲基)苯基)-N-羟基丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.00(brs,NH),7.54(d,J=13.8Hz,1H),7.26(d,J=8.2Hz,2H),7.17-7.09(m,3H),7.04(d,J=8.2Hz,2H),6.88(d,J=13.8Hz,1H),3.91(s,2H),3.80(s,2H),3.70(s,2H),3.00(t,J=6.8Hz,2H),2.71(t,J=6.8Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcdfor C20H21N2O2S[MH+]353.1245,found353.1246.
实施例71(E)-3-(4-(((2-(苯并呋喃-6-取代)乙基(甲基)氨基)甲基)苯基)-N-羟基丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.00(brs,NH),7.55(d,J=13.8Hz,1H),7.28(d,J=8.2Hz,2H),7.18-7.07(m,3H),7.04(d,J=8.2Hz,2H),6.85(d,J=13.8Hz,1H),3.82(s,2H),3.30(t,J=7.6Hz,2H),3.00(t,J=7.8Hz,2H),2.92(t,J=6.8Hz,2H),2.70(t,J=6.8Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25N4O2[MH+]351.1630,found351.1631.
实施例72(E)-3-(4-(((2-(苯并噻吩-6-取代)乙基(甲基)氨基)甲基)苯基)-N-羟基丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.05(brs,NH),8.00(brs,NH),7.56(d,J=13.8Hz,1H),7.23(d,J=8.2Hz,2H),7.21-7.03(m,5H),7.07(d,J=8.2Hz,2H),6.85(d,J=13.8Hz,1H),3.80(s,2H),2.89(t,J=6.8Hz,2H),2.71(t,J=6.8Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H22N2O2S[MH+]367.1402,found367.1401.
实施例73(E)-3-(4-(((2-(苯并呋喃-6-取代)乙基(2-羟乙基)氨基)甲基)苯基)-N-羟基丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.05(brs,NH),8.01(brs,NH),7.55(d,J=13.8Hz,1H),7.27(d,J=8.0Hz,2H),7.23-7.04(m,5H),7.05(d,J=8.0Hz,2H),6.85(d,J=13.8Hz,1H),3.85(s,2H),2.88(t,J=6.8Hz,2H),2.72(t,J=6.8Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25N2O4[MH+]381.1736,found381.1735.
实施例74(E)-3-(4-(((2-(苯并噻吩-6-取代)乙基(2-羟乙基)氨基)甲基)苯基)-N-羟基丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.05(brs,NH),7.56(d,J=13.6Hz,1H),7.23(d,J=8.0Hz,2H),7.16-7.03(m,3H),7.05(d,J=8.0Hz,2H),6.87(d,J=13.6Hz,1H),4.22(t,J=6.6Hz,2H),3.85(s,2H),2.88(m2H),2.85(t,J=6.6Hz,2H),2.66(m,2H),2.01(brs,OH)ppm.HRMS(ESI):calcdfor C22H24N2O3S[MH+]397.1580,found397.1581.
实施例75(E)-3-(4-((2-(8H-呋喃并[2,3-b]吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.05(brs,NH),7.98(brs,NH),7.54(d,J=13.6Hz,1H),7.40(s,1H),7.36(d,J=7.2Hz,1H),7.17(d,J=8.0Hz,2H),7.15-7.03(m,2H),7.00(d,J=8.0Hz,2H),6.84(d,J=13.6Hz,1H),6.38(d,J=7.2Hz,1H),3.81(s,2H),2.87(m2H),2.64(m,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H21N3O3[MH+]375.1505,found375.1504.
实施例76(E)-3-(4-((2-(3,8-二氢噻吩并[2,3-b]吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.01(brs,NH),7.53(d,J=13.6Hz,1H),7.17(d,J=8.0Hz,2H),7.15-7.06(m,3H),7.02(s,1H),7.00(d,J=8.0Hz,2H),6.86(d,J=13.6Hz,1H),3.81(s,2H),3.21(t,J=6.6Hz,2H),2.90(m2H),2.83(t,J=6.6Hz,2H),2.62(m,2H),2.00(brs,OH)ppm.HRMS(ESI):calcdfor C22H24N3O2S[MH+]394.1511,found394.1511.
实施例77(E)-N-羟基-3-(4-((2-(6,7,8,9-四氢-5H-咔唑胺-6-取代)乙氨基)甲基)苯基)-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ9.99(brs,NH),8.00(brs,NH),7.55(d,J=15.6Hz,1H),7.18(d,J=8.2Hz,2H),7.05-7.00(m,2H),7.01(d,J=8.2Hz,2H),6.85(d,J=15.6Hz,1H),6.57(s,1H),3.86(s,2H),2.88(m,2H),2.67(m,2H),2.59(t,J=6.2Hz,2H),2.43(t,J=6.2Hz,2H),1.56-1.58(m,4H)ppm.HRMS(ESI):calcdfor C24H28N3O2[MH+]390.2103,found390.2105.
实施例78(E)-N-羟基-3-(4-((2-(2,3,4,9-四氢-1H-吡啶并[2,3-b]吲哚-6-取代)乙氨基)甲基)苯基)-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.01(brs,NH),7.55(d,J=13.6Hz,1H),7.22(d,J=8.0Hz,2H),7.13-7.09(m,2H),7.06(d,J=8.0Hz,2H),7.02(s,1H),6.85(d,J=13.6Hz,1H),4.01(brs,NH),3.81(s,2H),3.08(t,J=6.8Hz,2H),2.87(t,J=6.6Hz,2H),2.66(t,J=6.6Hz,2H),2.42(m,2H),2.00(brs,OH),1.77(m,2H)ppm.HRMS(ESI):calcd for C23H27N4O2[MH+]391.2056,found391.2055.
实施例79(E)-N-羟基-3-(4-((2-(2,3,4,9-四氢吡喃并[2,3-b]吲哚-7-取代)乙氨基)甲基)苯基)-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.01(brs,NH),8.03(brs,NH),7.55(d,J=13.6Hz,1H),7.23(d,J=8.0Hz,2H),7.17-7.12(m,3H),7.10(s,1H),7.08(d,J=8.0Hz,2H),6.86(d,J=13.6Hz,1H),3.93(t,J=7.2Hz,2H),3.82(s,2H),2.87(t,J=6.6Hz,2H),2.66(t,J=6.6Hz,2H),2.42(m,2H),2.00(brs,OH),1.97(m,2H)ppm.HRMS(ESI):calcd for C23H26N3O3[MH+]392.1896,found392.1895.
实施例80(E)-N-羟基-3-(4-((2-(2,3,4,9-四氢硫代吡喃并[2,3-b]吲哚-7-取代)乙氨基)甲基)苯基)-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.01(brs,NH),7.55(d,J=13.6Hz,1H),7.18(d,J=8.0Hz,2H),7.16-7.09(m,2H),7.06(s,1H),7.02(d,J=8.0Hz,2H),6.85(d,J=13.6Hz,1H),3.82(s,2H),2.93(t,J=7.0Hz,2H),2.88(t,J=6.6Hz,2H),2.66(t,J=6.6Hz,2H),2.46(m,2H),2.00(brs,OH),1.95(m,2H)ppm.HRMS(ESI):calcd for C23H26N3O2S[MH+]408.1667,found408.1668.
实施例81(E)-3-(4-((2-(9H-咔唑胺-2-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.05(brs,NH),7.59(d,J=7.6Hz,1H),7.54(d,J=13.6Hz,1H),7.43(s,1H),7.40(d,J=7.2Hz,1H),7.18(d,J=8.2Hz,2H),7.16-7.00(m,4H),7.03(d,J=8.2Hz,2H),6.86(d,J=13.6Hz,1H),3.81(s,2H),2.85(t,J=6.2Hz,2H),2.66(t,J=6.2Hz,2H)ppm.HRMS(ESI):calcd for C24H24N3O2[MH+]386.1790,found386.1791.
实施例82(E)-3-(4-((2-(2-(2-羟乙基)-3-甲基-1H-吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1HNMR(400MHz,MeOD):δ9.98(brs,NH),8.02(brs,NH),7.55(t,J=13.6Hz,1H),7.21(d,J=8.0Hz,2H),7.07-7.05(m,2H),7.02(d,J=8.0Hz,2H),6.86(t,J=13.6Hz,1H),6.58(s,1H),3.88(s,2H),3.82(m,2H),2.87(t,J=6.2Hz,2H),2.77(t,J=6.6Hz,2H),2.66(t,J=6.2Hz,2H)2.31(s,3H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C23H28N3O3[MH+]394.2052,found394.2050.
实施例83(E)-3-(4-((2-(2,3-二氢-1H-吡咯并[1,2-a]吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ8.08(brs,NH),7.55(t,J=13.6Hz,1H),7.19(d,J=8.0Hz,2H),7.06(d,J=8.0Hz,2H),7.02-6.97(m,2H),6.85(t,J=13.6Hz,1H),6.58(s,1H),6.19(s,1H),3.83(m,2H),3.80(s,2H),2.86(t,J=6.2Hz,2H),2.65(t,J=6.2Hz,2H),2.58(m,2H),2.03(m,2H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C23H26N3O2[MH+]376.1947,found376.1946.
实施例84(E)-3-(4-((2-(1,2-二甲基-1H-吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.03(brs,NH),7.58(t,J=13.6Hz,1H),7.19(d,J=8.0Hz,2H),7.06(d,J=8.0Hz,2H),7.03-6.93(m,2H),6.88(t,J=13.6Hz,1H),6.57(s,1H),6.18(s,1H),3.86(s,2H),3.61(s,3H),2.89-2.68(m,4H),2.31(s,3H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C22H26N3O2[MH+]364.1947found364.1949.
实施例85(E)-3-(4-((2-(1-甲基-1H-吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ8.03(brs,NH),7.56(t,J=13.6Hz,1H),7.18(d,J=8.0Hz,2H),7.14-7.06(m,2H),7.04(s,1H),7.02(d,J=8.0Hz,2H),6.85(t,J=13.6Hz,1H),6.81(d,J=7.2Hz,1H),6.48(d,J=7.2Hz,1H),3.81(s,2H),3.61(s,3H),2.88-2.66(m,4H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790found350.1791.
实施例86(E)-3-(4-((2-(2-叔丁基-1H-吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.07(brs,NH),8.00(brs,NH),7.55(t,J=13.6Hz,1H),7.19(d,J=8.0Hz,2H),7.05(d,J=8.0Hz,2H),7.02-6.97(m,2H),6.91(s,1H),6.85(t,J=13.6Hz,1H),6.13(s,1H),3.83(s,2H),2.89-2.64(m,4H),2.00(brs,NH),1.33(s,9H)ppm.HRMS(ESI):calcd for C24H30N3O2[MH+]392.2260found392.2262.
实施例87(E)-3-(4-((2-(2-羟乙基-1H-吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.05(brs,NH),8.03(brs,NH),7.55(t,J=13.6Hz,1H),7.19(d,J=8.0Hz,2H),7.08-7.04(m,3H),7.00(d,J=8.0Hz,2H),6.94(s,1H),6.84(t,J=13.6Hz,1H),6.16(s,1H),3.83(s,2H),3.80(m,2H),2.88-2.67(m,4H),2.76(t,J=6.6Hz,1H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C22H26N3O3[MH+]380.1896found380.1897.
实施例88(E)-3-(4-((2,3-二甲基-1H-吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.05(brs,NH),8.03(brs,NH),7.55(t,J=13.6Hz,1H),7.18(d,J=8.0Hz,2H),7.03(d,J=8.0Hz,2H),7.00-6.96(m,2H),6.83(t,J=13.6Hz,1H),6.58(s,1H),3.83(s,2H),2.88-2.65(m,4H),2.37(s,3H),2.32(s,3H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C22H26N3O2[MH+]364.1947found364.1946.
实施例89(E)-3-(4-((2-(2-苯基-1H-吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.03(brs,NH),7.55(t,J=13.6Hz,1H),7.48-7.21(m,5H),7.42(s,1H),7.17(d,J=8.0Hz,2H),7.31-7.11(m,2H),7.04(d,J=8.0Hz,2H),6.88(t,J=13.6Hz,1H),6.45(s,1H),3.85(s,2H),2.89-2.67(m,4H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C26H26N3O2[MH+]412.1947found412.1947.
实施例90(E)-3-(4-((2-(2-(2-羟丙基-2取代)-1H-吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.07(brs,NH),8.03(brs,NH),7.55(t,J=13.6Hz,1H),7.18(d,J=8.0Hz,2H),7.07-7.03(m,2H),7.01(d,J=8.0Hz,2H),6.96(s,1H),6.82(t,J=13.6Hz,1H),6.13(s,1H),3.81(s,2H),2.87-2.66(m,4H),2.00(brs,NH),1.54(s,6H)ppm.HRMS(ESI):calcd for C23H28N3O3[MH+]394.2052found394.2053.
实施例91(E)-3-(4-(((2-(1H-吲哚-7-取代)乙基)氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ7.66-7.55(m,3H),7.36(d,J=8.0Hz,2H),7.28(d,J=8.4Hz,1H),7.24(d,J=3.2Hz,1H),7.05(t,J=7.6Hz,1H),6.86(d,J=7.2Hz,1H),6.53-6.45(m,2H),3.95(s,2H),3.32-3.08(m,4H)ppm.13CNMR(125MHz,MeOD):δ162.3,136.9,135.3,133.8,132.0,126.9,126.5,125.1,124.9,121.5,118.5,116.1,114.3,107.0,96.3,49.3,45.8,29.3ppm.HRMS(ESI):calcd forC20H22N3O2[MH+]336.1634,found336.1633.
实施例92(E)-3-(4-(((2-(1H-吲哚-7-取代)乙基)氨基)甲基)苯基)-N-羟基-丁烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.02(s,NH),8.03(brs,NH),7.68-7.53(m,4H),7.38(d,J=8.0Hz,2H),7.27(d,J=8.0Hz,2H),7.23(d,J=3.2Hz,1H),7.02(t,J=7.6Hz,1H),3.91(s,2H),3.30-3.07(m,4H),1.71(s,3H)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found350.1790.
实施例93
(E)-3-(4-(((2-(1H-吲哚-7-取代)乙基)甲氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.02(brs,NH),7.58-7.52(m,3H),7.37(d,J=8.0Hz,2H),7.27(d,J=8.4Hz,1H),7.23(d,J=3.2Hz,1H),7.02(t,J=7.6Hz,1H),6.86(d,J=7.2Hz,1H),6.51-6.45(m,2H),3.95(s,2H),3.11-3.02(m,4H),2.32(s,3H)ppm.13CNMR(125MHz,MeOD):δ162.5,136.6,135.9,133.8,132.4,126.9,126.7,125.4,124.9,121.6,118.7,116.5,114.9,107.3,51.5,49.6,45.6,29.6ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found350.1791.
实施例94(E)-3-(4-(((2-(1H-吲哚-7-取代)乙基)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.09(brs,NH),8.01(brs,NH),7.58-7.53(m,3H),7.38(d,J=8.2Hz,2H),7.29(d,J=8.2Hz,2H),7.26(d,J=7.2Hz,1H),7.06(d,J=15.6Hz,1H),6.85(d,J=7.2Hz,1H),6.56(d,J=15.6Hz,1H),3.93(s,2H),3.19-3.12(m,4H),2.45(q,J=6.8Hz,2H),1.09(t,J=6.8Hz,2H)ppm.HRMS(ESI):calcd for C22H26N3O2[MH+]364.1947,found364.1946.
实施例95(E)-3-(4-(((2-(1H-吲哚-7-取代)乙基)2-羟乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,CDCl3):δ8.27(br,1H),7.68(d,J=16.0Hz,1H),7.46(d,J=8.0Hz,2H),7.30-7.26(m,3H),7.19-7.13(m,2H),6.92(d,J=6.8Hz,1H),6.48-6.40(m,2H),3.83(s,3H),3.76(s,2H),3.52(t,J=5.2Hz,2H),3.12-3.06(m,2H),2.95-2.90(m,2H),2.75(t,J=5.2Hz,2H)ppm.HRMS(ESI):calcdfor C22H26N3O3[MH+]380.1896,found380.1895.
实施例96(E)-3-(4-((2-(2-甲基-1H-吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.00(brs,NH),7.99(brs,NH),7.56-7.52(m,3H),7.38(d,J=8.0Hz,2H),7.23(d,J=8.0Hz,2H),7.15(d,J=3.2Hz,1H),7.02(t,J=13.6Hz,1H),6.92(d,J=3.2Hz,1H),6.53(t,J=13.6Hz,1H),3.92(s,2H),3.36-3.20(m,4H)2.88(s,3H)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found350.1788.
实施例97(E)-3-(4-((2-(2-甲基-1H-吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ9.96(brs,NH),8.00(brs,NH),7.58-7.52(m,3H),7.37(d,J=8.0Hz,2H),7.23(d,J=8.0Hz,2H),7.10(s,1H),7.01(d,J=13.6Hz,1H),6.53(d,J=13.6Hz,1H),3.98(s,2H),3.36-3.20(m,4H)2.90(s,3H)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found350.1791.
实施例98(E)-3-(4-((2-(苯并呋喃-7-取代)乙氨基)甲基)苯基)-N-羟基丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.01(brs,NH),7.55(d,J=13.6Hz,1H),7.49-7.37(m,3H),7.29(d,J=8.0Hz,2H),7.13(d,J=8.0Hz,2H),6.56(d,J=13.6Hz,1H),4.00(brs,NH),3.92(s,2H),3.16-3.07(m,4H),3.02(t,J=6.6Hz,2H),2.46(t,J=6.6Hz,2H),2.01(brs,OH)ppm.HRMS(ESI):calcd for C20H21N2O3[MH+]337.1474,found337.1474.
实施例99(E)-3-(4-((2-(苯并噻吩-7-取代)乙氨基)甲基)苯基)-N-羟基丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.00(brs,NH),8.00(brs,NH),7.55(d,J=13.8Hz,1H),7.28(d,J=8.2Hz,2H),7.13-7.07(m,3H),7.05(d,J=8.2Hz,2H),6.88(d,J=13.8Hz,1H),3.93(s,2H),3.86(s,2H),3.70(s,2H),3.00(t,J=6.8Hz,2H),2.72(t,J=6.8Hz,2H),2.01(brs,OH)ppm.HRMS(ESI):calcdfor C20H21N2O2S[MH+]353.1245,found353.1244.
实施例100(E)-3-(4-(((2-(苯并呋喃-7-取代)乙基(甲基)氨基)甲基)苯基)-N-羟基丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.01(brs,NH),7.55(d,J=13.8Hz,1H),7.26(d,J=8.2Hz,2H),7.17-7.09(m,3H),7.08(d,J=8.2Hz,2H),6.87(d,J=13.8Hz,1H),3.85(s,2H),3.33(t,J=7.6Hz,2H),3.00(t,J=7.8Hz,2H),2.92(t,J=6.8Hz,2H),2.72(t,J=6.8Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25N4O2[MH+]351.1630,found351.1629.
实施例101(E)-3-(4-(((2-(苯并噻吩-7-取代)乙基(甲基)氨基)甲基)苯基)-N-羟基丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.00(brs,NH),7.56(d,J=13.8Hz,1H),7.25(d,J=8.0Hz,2H),7.23-7.06(m,5H),7.03(d,J=8.0Hz,2H),6.85(d,J=13.8Hz,1H),3.81(s,2H),2.89(t,J=6.8Hz,2H),2.71(t,J=6.8Hz,2H),2.01(brs,OH)ppm.HRMS(ESI):calcd for C21H22N2O2S[MH+]367.1402,found367.1402.
实施例102(E)-3-(4-(((2-(苯并呋喃-6-取代)乙基(2-羟乙基)氨基)甲基)苯基)-N-羟基丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.01(brs,NH),7.56(d,J=13.8Hz,1H),7.27(d,J=8.0Hz,2H),7.24-7.07(m,5H),7.03(d,J=8.0Hz,2H),6.86(d,J=13.8Hz,1H),3.85(s,2H),2.88(t,J=6.8Hz,2H),2.70(t,J=6.8Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25N2O4[MH+]381.1736,found381.1733.
实施例103(E)-3-(4-(((2-(苯并噻吩-7-取代)乙基(2-羟乙基)氨基)甲基)苯基)-N-羟基丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.01(brs,NH),8.03(brs,NH),7.55(d,J=13.6Hz,1H),7.22(d,J=8.0Hz,2H),7.13-7.06(m,3H),7.02(d,J=8.0Hz,2H),6.86(d,J=13.6Hz,1H),4.23(t,J=6.6Hz,2H),3.82(s,2H),2.87(m2H),2.83(t,J=6.6Hz,2H),2.66(m,2H),2.00(brs,OH)ppm.HRMS(ESI):calcdfor C22H24N2O3S[MH+]397.1580,found397.1580.
实施例104(E)-3-(4-((2-(3,8-呋喃并[2,3-b]吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.00(brs,NH),7.55(d,J=13.6Hz,1H),7.38(d,J=7.2Hz,1H),7.18(d,J=8.0Hz,2H),7.06-6.91(m,3H),7.00(d,J=8.0Hz,2H),6.86(d,J=13.6Hz,1H),6.32(d,J=7.2Hz,1H),3.81(s,2H),2.88(m2H),2.68(m,2H),2.05(brs,OH)ppm.HRMS(ESI):calcdfor C22H21N3O3[MH+]375.1505,found375.1505.
实施例105(E)-3-(4-((2-(3,8-二氢噻吩并[2,3-b]吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.05(brs,NH),8.00(brs,NH),7.55(d,J=13.6Hz,1H),7.19(d,J=8.0Hz,2H),7.16-7.03(m,3H),7.01(d,J=8.0Hz,2H),6.85(d,J=13.6Hz,1H),3.83(s,2H),3.21(t,J=6.6Hz,2H),2.89(m2H),2.83(t,J=6.6Hz,2H),2.66(m,2H),2.00(brs,OH)ppm.HRMS(ESI):calcdfor C22H24N3O2S[MH+]394.1511,found394.1512.
实施例107(E)-N-羟基-3-(4-((2-(6,7,8,9-四氢-5H-咔唑胺-7-取代)乙氨基)甲基)苯基)-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ9.97(brs,NH),8.01(brs,NH),7.55(d,J=15.6Hz,1H),7.18(d,J=8.2Hz,2H),7.13-7.05(m,3H),7.00(d,J=8.2Hz,2H),6.85(d,J=15.6Hz,1H),3.91(s,2H),2.89(m,2H),2.67(m,2H),2.58(t,J=6.2Hz,2H),2.42(t,J=6.2Hz,2H),1.58(m,4H)ppm.HRMS(ESI):calcdfor C24H28N3O2[MH+]390.2103,found390.2102.
实施例108(E)-N-羟基-3-(4-((2-(2,3,4,9-四氢-1H-吡啶并[2,3-b]吲哚-8-取代)乙氨基)甲基)苯基)-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.05(brs,NH),8.03(brs,NH),7.55(d,J=13.6Hz,1H),7.22(d,J=8.0Hz,2H),7.17-7.08(m,3H),7.05(d,J=8.0Hz,2H),6.85(d,J=13.6Hz,1H),4.00(brs,NH),3.90(s,2H),3.08(t,J=6.8Hz,2H),2.89(t,J=6.6Hz,2H),2.65(t,J=6.6Hz,2H),2.43(m,2H),2.01(brs,OH),1.78(m,2H)ppm.HRMS(ESI):calcd for C23H27N4O2[MH+]391.2056,found391.2055.
实施例109(E)-N-羟基-3-(4-((2-(2,3,4,9-四氢吡喃并[2,3-b]吲哚-8-取代)乙氨基)甲基)苯基)-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.03(brs,NH),7.56(d,J=13.6Hz,1H),7.22(d,J=8.0Hz,2H),7.15-7.10(m,3H),7.07(d,J=8.0Hz,2H),6.87(d,J=13.6Hz,1H),4.01(t,J=7.2Hz,2H),3.88(s,2H),2.86(t,J=6.6Hz,2H),2.67(t,J=6.6Hz,2H),2.43(m,2H),2.00(brs,OH),1.96(m,2H)ppm.HRMS(ESI):calcd for C23H26N3O3[MH+]392.1896,found392.1896.
实施例110(E)-N-羟基-3-(4-((2-(2,3,4,9-四氢硫代吡喃并[2,3-b]吲哚-8-取代)乙氨基)甲基)苯基)-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.01(brs,NH),7.55(d,J=13.6Hz,1H),7.19(d,J=8.0Hz,2H),7.15-7.07(m,3H),7.02(d,J=8.0Hz,2H),6.86(d,J=13.6Hz,1H),3.81(s,2H),2.98(t,J=7.0Hz,2H),2.86(t,J=6.6Hz,2H),2.66(t,J=6.6Hz,2H),2.42(m,2H),2.00(brs,OH),1.95(m,2H)ppm.HRMS(ESI):calcd for C23H26N3O2S[MH+]408.1667,found408.1667.
实施例111(E)-3-(4-((2-(9H-咔唑胺-1-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.03(brs,NH),7.56(d,J=13.6Hz,1H),7.52(d,J=7.6Hz,1H),7.41(d,J=7.2Hz,1H),7.21(d,J=8.2Hz,2H),7.19-7.05(m,5H),7.01(d,J=8.2Hz,2H),6.85(d,J=13.6Hz,1H),3.86(s,2H),2.89(t,J=6.2Hz,2H),2.67(t,J=6.2Hz,2H)ppm.HRMS(ESI):calcd for C24H24N3O2[MH+]386.1790,found386.1791.
实施例112(E)-3-(4-((2-(2-(2-羟乙基)-3-甲基-1H-吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ9.99(brs,NH),8.01(brs,NH),7.55(t,J=13.6Hz,1H),7.21(d,J=8.0Hz,2H),7.13-7.07(m,3H),7.02(d,J=8.0Hz,2H),6.85(t,J=13.6Hz,1H),3.90(s,2H),3.81(m,2H),2.88(t,J=6.2Hz,2H),2.78(t,J=6.6Hz,2H),2.66(t,J=6.2Hz,2H)2.30(s,3H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C23H28N3O3[MH+]394.2052,found394.2052.
实施例113(E)-3-(4-((2-(2,3-二氢-1H-吡咯并[1,2-a]吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.08(brs,NH),7.56(t,J=13.6Hz,1H),7.19(d,J=8.0Hz,2H),7.14-7.11(m,2H),7.02(d,J=8.0Hz,2H),6.85(t,J=13.6Hz,1H),6.67(d,J=8.6Hz,1H),6.16(s,1H),3.88(m,2H),3.82(s,2H),2.88(t,J=6.2Hz,2H),2.67(t,J=6.2Hz,2H),2.59(m,2H),2.04(m,2H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C23H26N3O2[MH+]376.1947,found376.1948.
实施例114(E)-3-(4-((2-(1,2-二甲基-1H-吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.03(brs,NH),7.55(t,J=13.6Hz,1H),7.18(d,J=8.0Hz,2H),7.13-7.09(m,2H),7.01(d,J=8.0Hz,2H),6.88(t,J=13.6Hz,1H),6.65(d,J=7.2Hz,1H),6.16(s,1H),3.87(s,2H),3.60(s,3H),2.89-2.67(m,4H),2.30(s,3H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C22H26N3O2[MH+]364.1947found364.1947.
实施例115(E)-3-(4-((2-(1-甲基-1H-吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.03(brs,NH),7.55(t,J=13.6Hz,1H),7.19(d,J=8.0Hz,2H),7.13-7.00(m,3H),7.01(d,J=8.0Hz,2H),6.85(t,J=13.6Hz,1H),6.81(d,J=7.2Hz,1H),6.46(d,J=7.2Hz,1H),3.81(s,2H),3.60(s,3H),2.88-2.65(m,4H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790found350.1792.
实施例116(E)-3-(4-((2-(2-叔丁基-1H-吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.03(brs,NH),7.55(t,J=13.6Hz,1H),7.19(d,J=8.0Hz,2H),7.05-6.95(m,3H),7.02(d,J=8.0Hz,2H),6.86(t,J=13.6Hz,1H),6.25(s,1H),3.87(s,2H),2.89-2.67(m,4H),2.00(brs,NH),1.39(s,9H)ppm.HRMS(ESI):calcd for C24H30N3O2[MH+]392.2260found392.2260.
实施例117(E)-3-(4-((2-(2-羟乙基-1H-吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.05(brs,NH),7.55(t,J=13.6Hz,1H),7.18(d,J=8.0Hz,2H),7.05-6.96(m,3H),7.01(d,J=8.0Hz,2H),6.85(t,J=13.6Hz,1H),6.15(s,1H),3.85(s,2H),3.80(m,2H),2.88-2.67(m,4H),2.79(t,J=6.6Hz,1H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C22H26N3O3[MH+]380.1896found380.1895.
实施例118(E)-3-(4-((2,3-二甲基-1H-吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.05(brs,NH),8.03(brs,NH),7.55(t,J=13.6Hz,1H),7.18(d,J=8.0Hz,2H),7.15-7.11(m,2H),7.01(d,J=8.0Hz,2H),6.85(t,J=13.6Hz,1H),6.67(d,J=8.6Hz,1H),3.83(s,2H),2.88-2.67(m,4H),2.39(s,3H),2.35(s,3H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C22H26N3O2[MH+]364.1947found364.1947.
实施例119(E)-3-(4-((2-(2-苯基-1H-吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.07(brs,NH),8.03(brs,NH),7.56(t,J=13.6Hz,1H),7.49-7.27(m,5H),7.22(d,J=8.0Hz,2H),7.20-7.10(m,3H),7.05(d,J=8.0Hz,2H),6.87(t,J=13.6Hz,1H),6.45(s,1H),3.85(s,2H),2.87-2.66(m,4H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C26H26N3O2[MH+]412.1947found412.1946.
实施例120(E)-3-(4-((2-(2-(2-羟丙基-2取代)-1H-吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.05(brs,NH),7.55(t,J=13.6Hz,1H),7.19(d,J=8.0Hz,2H),7.06-6.96(m,3H),7.01(d,J=8.0Hz,2H),6.85(t,J=13.6Hz,1H),6.15(s,1H),3.82(s,2H),2.86-2.67(m,4H),2.00(brs,NH),1.59(s,6H)ppm.HRMS(ESI):calcd for C23H28N3O3[MH+]394.2052found394.2051.
实施例121(E)-3-(5-((2-(1H-吲哚-4-取代)乙氨基)甲基)吡啶基-2-取代)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.79(s,1H),8.03(brs,NH),7.77(d,J=13.6Hz,1H),7.73(d,J=7.8Hz,1H),7.53(d,J=7.8Hz,1H),7.45(d,J=13.6Hz,1H),7.27(d,J=6.0Hz,1H),7.22(d,J=7.4Hz,1H),7.03(m,1H),6.86(d,J=6.6Hz,1H),6.45(d,J=6.0Hz,1H),3.89(s,2H),2.96-2.77(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C19H21N4O2[MH+]337.1586found337.1587.
实施例123(E)-3-(4-((2-(1H-吲哚-4-取代)乙氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.01(brs,NH),7.82(d,J=13.8Hz,1H),7.27(d,J=6.0Hz,1H),7.22(d,J=8.6Hz,1H),7.16(d,J=8.8Hz,1H),7.03(m,1H),6.86(d,J=7.8Hz,1H),6.78(d,J=8.8Hz,1H),6.72(s,1H),6.67(d,J=13.8Hz,1H),6.45(d,J=6.0Hz,1H),3.82(s,2H),2.88-2.68(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H21FN3O2[MH+]354.1540found354.1541.
实施例124(E)-3-(4-((2-(1H-吲哚-4-取代)乙氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.00(brs,NH),7.55(d,J=13.6Hz,1H),7.27(d,J=6.0Hz,1H),7.22(d,J=8.6Hz,1H),7.03(m,1H),6.99(d,J=8.8Hz,1H),6.95(d,J=8.6Hz,1H),6.89(s,1H),6.86(d,J=8.4Hz,1H),6.84(d,J=13.6Hz,1H),6.45(d,J=6.0Hz,1H),3.86(s,2H),2.92-2.75(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H21FN3O2[MH+]354.1540found354.1542.
实施例125(E)-3-(5-(((2-(1H-吲哚-4-取代)乙基)(2-羟乙基)氨基)甲基)吡啶基-2-取代)-N-羟基
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.09(brs,NH),8.79(s,1H),8.03(brs,NH),7.78(d,J=14.6Hz,1H),7.74(d,J=7.8Hz,1H),7.53(d,J=7.8Hz,1H),7.45(d,J=14.6Hz,1H),7.27(d,J=6.0Hz,1H),7.22(d,J=7.4Hz,1H),7.03(m,1H),6.86(d,J=6.6Hz,1H),6.45(d,J=6.0Hz,1H),3.68(t,J=6.6Hz,2H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J=6.2Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H25N4O3[MH+]381.1848found381.1849.
实施例126(E)-3-(4-(((2-(1H-吲哚-4-取代)乙基)(2-羟乙基)氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.01(brs,NH),7.83(d,J=13.8Hz,1H),7.26(d,J=6.0Hz,1H),7.21(d,J=8.6Hz,1H),7.15(d,J=8.8Hz,1H),7.03(m,1H),6.86(d,J=7.8Hz,1H),6.79(d,J=8.8Hz,1H),6.73(s,1H),6.69(d,J=13.8Hz,1H),6.46(d,J=6.0Hz,1H),3.65(t,J=6.6Hz,2H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J=6.2Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25FN3O3[MH+]398.1802found398.1803.
实施例127(E)-3-(4-(((2-(1H-吲哚-4-取代)乙基)(2-羟乙基)氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.11(brs,NH),8.00(brs,NH),7.55(d,J=13.2Hz,1H),7.27(d,J=6.0Hz,1H),7.22(d,J=8.6Hz,1H),7.03(m,1H),6.99(d,J=7.8Hz,1H),6.95(d,J=7.8Hz,1H),6.89(s,1H),6.86(d,J=7.8Hz,1H),6.84(d,J=13.2Hz,1H),6.45(d,J=6.0Hz,1H),3.65(t,J=6.6Hz,2H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J=6.2Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25FN3O3[MH+]398.1802found398.1801.
实施例128(E)-3-(4-((2-(1H吡咯并[2,3-b]吡啶-4-取代)乙基氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.09(brs,NH),8.60(d,J=8.6Hz,1H),8.28(brs,NH),7.55(d,J=13.6Hz,1H),7.28(d,J=8.6Hz,1H),7.18(d,J=8.0Hz,2H),7.01(d,J=8.0Hz,2H),6.96(d,J=6.6Hz,2H),6.84(d,J=13.6Hz,1H),6.73(d,J=6.6Hz,2H),3.90(s,2H),2.88-2.67(m,4H),2.01(brs,OH)ppm.HRMS(ESI):calcd for C19H21N4O2[MH+]337.1586,found337.1587.
实施例129(E)-3-(4-((2-(1H吡咯并[2,3-b]吡啶-4-取代)乙基氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.61(d,J=8.0Hz,1H),8.01(brs,NH),7.82(d,J=14.6Hz,1H),7.28(d,J=8.0Hz,1H),7.22(d,J=6.6Hz,1H),7.16(d,J=7.6Hz,1H),6.78(d,J=7.6Hz,1H),6.72(s,1H),6.67(d,J=14.6Hz,1H),6.45(d,J=6.6Hz,1H),3.83(s,2H),2.90-2.69(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C19H20FN4O2[MH+]355.1492found355.1493.
实施例130(E)-3-(4-((2-(1H吡咯并[2,3-b]吡啶-4-取代)乙基)(2-羟乙基)氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.11(brs,NH),8.60(d,J=8.8Hz,1H),8.02(brs,NH),7.55(d,J=13.6Hz,1H),7.28(d,J=8.8Hz,1H),7.18(d,J=8.0Hz,2H),7.01(d,J=8.0Hz,2H),6.96(d,J=6.6Hz,2H),6.84(d,J=13.6Hz,1H),6.73(d,J=6.6Hz,1H),3.63(t,J=5.6Hz,1H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J=5.6Hz,2H),2.00(brs,OH)ppmHRMS(ESI):calcd for C21H25N4O3[MH+]381.1848,found381.1849.
实施例131(E)-3-(4-(((2-(1H吡咯并[2,3-b]吡啶-4-取代)乙基(2--羟乙基)氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.60(d,J=8.0Hz,1H),8.00(brs,NH),7.82(d,J=13.6Hz,1H),7.28(d,J=8.0Hz,1H),7.16(d,J=7.6Hz,1H),6.90(d,J=6.6Hz,1H),6.78(d,J=7.6Hz,1H),6.72(s,1H),6.67(d,J=13.6Hz,1H),6.48(d,J=6.6Hz,1H),3.63(t,J=5.6Hz,2H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J=5.6Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H24FN4O3[MH+]399.1754found399.1755.
实施例132(E)-3-(4-((2-(苯并呋喃-4-取代)乙氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.00(brs,NH),7.84(d,J=13.6Hz,1H),7.52(d,J=6.2Hz,1H),7.24(d,J=8.0Hz,1H),7.16(d,J=6.8Hz,1H),7.14(m,1H),6.99(d,J=7.0Hz,1H),6.78(d,J=8.8Hz,1H),6.72(s,1H),6.67(d,J=13.6Hz,1H),6.60(d,J=7.2Hz,1H),3.81(s,2H),2.88-2.67(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O3[MH+]355.1380found355.1381.
实施例133(E)-3-(4-((2-(苯并噻吩-3-取代)乙氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.02(brs,NH),7.68(d,J=6.0Hz,1H),7.55(d,J=13.6Hz,1H),7.40(d,J=6.6Hz,1H),7.29(d,J=6.6Hz,1H),7.26(m,1H),7.19(d,J=5.6Hz,1H),6.99(d,J=6.8Hz,1H),6.95(d,J=6.8Hz,1H),6.89(s,1H),6.82(d,J=13.6Hz,1H),3.81(s,2H),2.88-2.67(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O2S[MH+]371.1151found371.1152.
实施例134(E)-3-(5-((2-(1H-吲哚-5-取代)乙氨基)甲基)吡啶基-2-取代)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.07(brs,NH),8.76(s,1H),8.01(brs,NH),7.76(d,J=13.6Hz,1H),7.72(d,J=7.8Hz,1H),7.52(d,J=7.8Hz,1H),7.46(d,J=13.6Hz,1H),7.26(d,J=6.0Hz,1H),7.21(d,J=7.4Hz,1H),7.02(m,1H),6.85(d,J=6.6Hz,1H),6.43(d,J=6.0Hz,1H),3.88(s,2H),2.97-2.76(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C19H21N4O2[MH+]337.1586found337.1585.
实施例135(E)-3-(4-((2-(1H-吲哚-5-取代)乙氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.01(brs,NH),7.82(d,J=13.8Hz,1H),7.27(d,J=6.0Hz,1H),7.22(d,J=8.6Hz,1H),7.16(d,J=8.8Hz,1H),7.03(m,1H),6.86(d,J=7.8Hz,1H),6.78(d,J=8.8Hz,1H),6.72(s,1H),6.67(d,J=13.8Hz,1H),6.45(d,J=6.0Hz,1H),3.82(s,2H),2.88-2.68(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H21FN3O2[MH+]354.1540found354.1540.
实施例136(E)-3-(4-((2-(1H-吲哚-5-取代)乙氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.07(brs,NH),8.00(brs,NH),7.56(d,J=13.6Hz,1H),7.28(d,J=6.0Hz,1H),7.23(d,J=8.6Hz,1H),7.03(m,1H),6.99(d,J=8.8Hz,1H),6.93(d,J=8.6Hz,1H),6.89(s,1H),6.85(d,J=8.4Hz,1H),6.80(d,J=13.6Hz,1H),6.46(d,J=6.0Hz,1H),3.83(s,2H),2.90-2.77(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H21FN3O2[MH+]354.1540found354.1541.
实施例137(E)-3-(5-(((2-(1H-吲哚-5-取代)乙基)(2-羟乙基)氨基)甲基)吡啶基-2-取代)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.76(s,1H),8.02(brs,NH),7.75(d,J=14.6Hz,1H),7.70(d,J=7.8Hz,1H),7.51(d,J=7.8Hz,1H),7.45(d,J=14.6Hz,1H),7.26(d,J=6.0Hz,1H),7.22(d,J=7.4Hz,1H),7.01(m,1H),6.83(d,J=6.6Hz,1H),6.47(d,J=6.0Hz,1H),3.67(t,J=6.6Hz,2H),3.61(s,2H),2.69-2.65(m,4H),2.53(t,J=6.2Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H25N4O3[MH+]381.1848found381.1847.
实施例138(E)-3-(4-(((2-(1H-吲哚-5-取代)乙基)(2-羟乙基)氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.00(brs,NH),7.82(d,J=13.8Hz,1H),7.27(d,J=6.0Hz,1H),7.20(d,J=8.6Hz,1H),7.16(d,J=8.8Hz,1H),7.01(m,1H),6.87(d,J=7.8Hz,1H),6.77(d,J=8.8Hz,1H),6.73(s,1H),6.66(d,J=13.8Hz,1H),6.42(d,J=6.0Hz,1H),3.63(t,J=6.6Hz,2H),3.60(s,2H),2.69-2.65(m,4H),2.53(t,J=6.2Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25FN3O3[MH+]398.1802found398.1802.
实施例139(E)-3-(4-(((2-(1H-吲哚-5-取代)乙基)(2-羟乙基)氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.05(brs,NH),7.56(d,J=13.2Hz,1H),7.27(d,J=6.0Hz,1H),7.23(d,J=8.6Hz,1H),7.05(m,1H),6.97(d,J=7.8Hz,1H),6.93(d,J=7.8Hz,1H),6.88(s,1H),6.83(d,J=7.8Hz,1H),6.81(d,J=13.2Hz,1H),6.48(d,J=6.0Hz,1H),3.62(t,J=6.6Hz,2H),3.60(s,2H),2.69-2.65(m,4H),2.57(t,J=6.2Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25FN3O3[MH+]398.1802found398.1802.
实施例140(E)-3-(4-((2-(1H吡咯并[2,3-b]吡啶-5-取代)乙基氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.58(s,1H),8.26(brs,NH),7.55(d,J=13.6Hz,1H),7.28(s,1H),7.19(d,J=8.0Hz,2H),7.01(d,J=8.0Hz,2H),6.96(d,J=6.6Hz,2H),6.86(d,J=13.6Hz,1H),6.73(d,J=6.6Hz,2H),3.91(s,2H),2.88-2.67(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C19H21N4O2[MH+]337.1586,found337.1586.
实施例141(E)-3-(4-((2-(1H吡咯并[2,3-b]吡啶-5-取代)乙基氨基)甲基)吡啶-3-取代)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.69(s,1H),8.58(s,1H),7.86(d,J=8.2Hz,1H),7.56(d,J=13.6Hz,1H),7.50(d,J=8.2Hz,1H),7.28(s,1H),6.96(d,J=6.6Hz,2H),6.83(d,J=13.6Hz,1H),6.72(d,J=6.6Hz,2H),4.12(s,2H),2.88-2.67(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcdfor C18H20N5O2[MH+]338.1539,found338.1537.
实施例142(E)-3-(4-((2-(1H吡咯并[2,3-b]吡啶-5-取代)乙基氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.12(brs,NH),8.60(s,1H),8.00(brs,NH),7.81(d,J=14.6Hz,1H),7.29(s,1H),7.23(d,J=6.6Hz,1H),7.18(d,J=7.6Hz,1H),6.81(d,J=7.6Hz,1H),6.73(s,1H),6.67(d,J=14.6Hz,1H),6.43(d,J=6.6Hz,1H),3.82(s,2H),2.90-2.69(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C19H20FN4O2[MH+]355.1492found355.1491.
实施例143(E)-3-(4-((2-(1H吡咯并[2,3-b]吡啶-5-取代)乙基)(2-羟乙基)氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.61(s,,1H),8.00(brs,NH),7.55(d,J=13.6Hz,1H),7.28(s,,1H),7.19(d,J=8.0Hz,2H),7.01(d,J=8.0Hz,2H),6.97(d,J=6.6Hz,2H),6.84(d,J=13.6Hz,1H),6.73(d,J=6.6Hz,1H),3.63(t,J=5.6Hz,1H),3.62(s,2H),2.69-2.65(m,4H),2.53(t,J=5.6Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H25N4O3[MH+]381.1848,found381.1847.
实施例144(E)-3-(4-(((2-(1H吡咯并[2,3-b]吡啶-5-取代)乙基)(2-羟乙基)氨基)甲基)吡啶基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.75(s,1H),8.56(s,1H),8.01(brs,NH),7.78(d,J=13.6Hz,1H),7.72(d,J=8.0Hz,1H),7.53(d,J=8.0Hz,1H),7.47(d,J=13.6Hz,1H),7.28(s,1H),7.02(d,J=6.6Hz,1H),6.75(d,J=6.6Hz,1H),3.60(t,J=5.6Hz,2H),3.58(s,2H),2.69-2.65(m,4H),2.53(t,J=5.6Hz,2H),2.00(brs,OH)ppmHRMS(ESI):calcd for C20H24N5O3[MH+]382.1801,found382.1802.
实施例145(E)-3-(4-(((2-(1H吡咯并[2,3-b]吡啶-5-取代)乙基(2--羟乙基)氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.61(s,1H),8.00(brs,NH),7.82(d,J=13.6Hz,1H),7.28(d,J=8.0Hz,1H),7.16(d,J=7.6Hz,1H),6.92(d,J=6.6Hz,1H),6.78(d,J=7.6Hz,1H),6.72(s,1H),6.67(d,J=13.6Hz,1H),6.47(d,J=6.6Hz,1H),3.65(t,J=5.6Hz,2H),3.62(s,2H),2.69-2.65(m,4H),2.53(t,J=5.6Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcdfor C21H24FN4O3[MH+]399.1754found399.1753.
实施例146(E)-3-(4-(((2-(1H吡咯并[2,3-b]吡啶-5-取代)乙基(2--羟乙基)氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.09(brs,NH),8.62(s,1H),8.00(brs,NH),7.56(d,J=13.6Hz,1H),7.28(s,1H),7.05(d,J=6.6Hz,1H),6.98(d,J=7.6Hz,1H),6.93(d,J=7.6Hz,1H),6.88(s,1H),6.82(d,J=13.6Hz,1H),6.49(d,J=6.6Hz,1H),3.62(t,J=5.6Hz,2H),3.60(s,2H),2.69-2.65(m,4H),2.57(t,J=5.6Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H24FN4O3[MH+]399.1754found399.1753.
实施例147(E)-3-(4-((2-(苯并呋喃-5-取代)乙氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.03(brs,NH),7.82(d,J=13.6Hz,1H),7.52(d,J=6.2Hz,1H),7.37(d,J=8.2Hz,1H),7.35(s,1H),7.16(d,J=6.8Hz,1H),7.05(d,J=7.0Hz,1H),6.78(d,J=8.2Hz,1H),6.72(s,1H),6.67(d,J=13.6Hz,1H),6.62(d,J=7.2Hz,1H),3.81(s,2H),2.88-2.67(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O3[MH+]355.1380found355.1383.
实施例148(E)-3-(4-((2-(苯并呋喃-5-取代)乙氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):1HNMR(400MHz,MeOD):δ8.03(brs,NH),7.55(d,J=13.6Hz,1H),7.52(d,J=6.2Hz,1H),7.37(d,J=7.6Hz,1H),7.33(s,1H),7.06(d,J=7.3Hz,1H),6.99(d,J=7.0Hz,1H),6.96(d,J=7.0Hz,1H),6.89(s,1H),6.83(d,J=13.6Hz,1H),6.67(d,J=7.2Hz,1H),3.82(s,2H),2.88-2.68(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O3[MH+]355.1380found355.1382.
实施例149(E)-3-(4-((2-(苯并噻吩-5-取代)乙氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.01(brs,NH),7.82(d,J=13.6Hz,1H),7.80(d,J=6.6Hz,1H),7.66(s,1H),7.40(d,J=6.2Hz,1H),7.29(d,J=6.2Hz,1H),7.18(d,J=6.6Hz,1H),7.16(d,J=6.8Hz,1H),6.79(d,J=6.8Hz,1H),6.73(s,1H),6.65(d,J=13.6Hz,1H),3.81(s,2H),2.89-2.68(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O2S[MH+]371.1151found371.1150.
实施例150(E)-3-(4-((2-(苯并噻吩-5-取代)乙氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):1HNMR(400MHz,MeOD):δ8.03(brs,NH),7.81(d,J=8.0Hz,1H),7.64(s,1H),7.56(d,J=13.8Hz,1H),7.41(d,J=6.0Hz,1H),7.29(d,J=6.2Hz,1H),7.17(d,J=8.2Hz,1H),6.99(d,J=7.0Hz,1H),6.96(d,J=7.0Hz,1H),6.89(s,1H),6.83(d,J=13.8Hz,1H),3.83(s,2H),2.89-2.68(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O3[MH+]371.1151found371.1149.
实施例151(E)-3-(5-((2-(1H-吲哚-6-取代)乙氨基)甲基)吡啶基-2-取代)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.07(brs,NH),8.78(s,1H),8.05(brs,NH),7.76(d,J=13.6Hz,1H),7.72(d,J=7.8Hz,1H),7.53(d,J=7.8Hz,1H),7.46(d,J=13.6Hz,1H),7.27(d,J=6.0Hz,1H),7.20(d,J=7.4Hz,1H),7.05(m,1H),6.89(d,J=6.6Hz,1H),6.47(d,J=6.0Hz,1H),3.89(s,2H),2.96-2.77(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C19H21N4O2[MH+]337.1586found337.1586.
实施例152(E)-3-(6-((2-(1H-吲哚-6-取代)乙氨基)甲基)吡啶基-3-取代)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.09(brs,NH),8.67(s,1H),8.01(brs,NH),7.87(d,J=7.8Hz,1H),7.53(d,J=13.6Hz,1H),7.48(d,J=7.8Hz,1H),7.27(d,J=6.2Hz,1H),7.20(d,J=7.8Hz,1H),7.03(m,1H),6.87(d,J=6.8Hz,1H),6.82(d,J=13.6Hz,1H),6.46(d,J=6.0Hz,1H),4.13(s,2H),2.98-2.78(m,4H),2.00(brs,OH)ppmHRMS(ESI):calcd for C19H21N4O2[MH+]337.1586found337.1585.
实施例153(E)-3-(4-((2-(1H-吲哚-6-取代)乙氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.07(brs,NH),8.00(brs,NH),7.80(d,J=13.8Hz,1H),7.25(d,J=6.0Hz,1H),7.21(d,J=8.6Hz,1H),7.15(d,J=8.8Hz,1H),7.00(m,1H),6.85(d,J=7.8Hz,1H),6.76(d,J=8.8Hz,1H),6.70(s,1H),6.65(d,J=13.8Hz,1H),6.45(d,J=6.0Hz,1H),3.81(s,2H),2.88-2.68(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H21FN3O2[MH+]354.1540found354.1542.
实施例154(E)-3-(4-((2-(1H-吲哚-6-取代)乙氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.00(brs,NH),7.53(d,J=13.6Hz,1H),7.26(d,J=6.0Hz,1H),7.21(d,J=8.6Hz,1H),7.03(m,1H),6.99(d,J=8.8Hz,1H),6.93(d,J=8.6Hz,1H),6.89(s,1H),6.86(d,J=8.4Hz,1H),6.81(d,J=13.6Hz,1H),6.42(d,J=6.0Hz,1H),3.83(s,2H),2.92-2.75(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H21FN3O2[MH+]354.1540found354.1542.
实施例155(E)-3-(5-(((2-(1H-吲哚-6-取代)乙基)(2-羟乙基)氨基)甲基)吡啶基-2-取代)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.79(s,1H),8.02(brs,NH),7.76(d,J=14.6Hz,1H),7.72(d,J=7.8Hz,1H),7.53(d,J=7.8Hz,1H),7.42(d,J=14.6Hz,1H),7.27(d,J=6.0Hz,1H),7.20(d,J=7.4Hz,1H),7.03(m,1H),6.86(d,J=6.6Hz,1H),6.45(d,J=6.0Hz,1H),3.68(t,J=6.6Hz,2H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J=6.2Hz,2H),2.00(brs,OH)ppmHRMS(ESI):calcd for C21H25N4O3[MH+]381.1848found381.1848.
实施例156(E)-3-(4-(((2-(1H-吲哚-6-取代)乙基)(2-羟乙基)氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.12(brs,NH),8.01(brs,NH),7.85(d,J=13.8Hz,1H),7.28(d,J=6.0Hz,1H),7.21(d,J=8.6Hz,1H),7.13(d,J=8.8Hz,1H),7.00(m,1H),6.86(d,J=7.8Hz,1H),6.79(d,J=8.8Hz,1H),6.72(s,1H),6.66(d,J=13.8Hz,1H),6.48(d,J=6.0Hz,1H),3.63(t,J=6.6Hz,2H),3.60(s,2H),2.69-2.65(m,4H),2.53(t,J=6.2Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25FN3O3[MH+]398.1802found398.1801.
实施例157(E)-3-(4-(((2-(1H-吲哚-4-取代)乙基)(2-羟乙基)氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.11(brs,NH),8.00(brs,NH),7.55(d,J=13.2Hz,1H),7.27(d,J=6.0Hz,1H),7.22(d,J=8.6Hz,1H),7.03(m,1H),6.99(d,J=7.8Hz,1H),6.95(d,J=7.8Hz,1H),6.89(s,1H),6.86(d,J=7.8Hz,1H),6.84(d,J=13.2Hz,1H),6.45(d,J=6.0Hz,1H),3.65(t,J=6.6Hz,2H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J=6.2Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25FN3O3[MH+]398.1802found398.1801.
实施例158(E)-3-(4-((2-(1H吡咯并[2,3-b]吡啶-6-取代)乙基氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.07(brs,NH),8.61(d,J=8.6Hz,1H),8.29(brs,NH),7.55(d,J=13.6Hz,1H),7.28(d,J=8.6Hz,1H),7.19(d,J=8.0Hz,2H),7.01(d,J=8.0Hz,2H),6.96(d,J=6.6Hz,2H),6.85(d,J=13.6Hz,1H),6.75(d,J=6.6Hz,2H),3.88(s,2H),2.88-2.67(m,4H),2.01(brs,OH)ppm.HRMS(ESI):calcd for C19H21N4O2[MH+]337.1586,found337.1585.
实施例159(E)-3-(4-((2-(1H吡咯并[2,3-b]吡啶-6-取代)乙基氨基)甲基)吡啶-3-取代)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.66(s,1H),8.61(d,J=8.6Hz,1H),7.82(d,J=8.2Hz,1H),7.57(d,J=13.6Hz,1H),7.52(d,J=8.2Hz,1H),7.28(d,J=8.6Hz,1H),6.96(d,J=6.6Hz,2H),6.86(d,J=13.6Hz,1H),6.75(d,J=6.6Hz,2H),4.12(s,2H),2.88-2.67(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C18H20N5O2[MH+]338.1539,found338.1537.
实施例160(E)-3-(4-((2-(1H吡咯并[2,3-b]吡啶-6-取代)乙基氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.09(brs,NH),8.60(d,J=8.0Hz,1H),8.00(brs,NH),7.80(d,J=14.6Hz,1H),7.26(d,J=8.0Hz,1H),7.20(d,J=6.6Hz,1H),7.16(d,J=7.6Hz,1H),6.79(d,J=7.6Hz,1H),6.72(s,1H),6.65(d,J=14.6Hz,1H),6.46(d,J=6.6Hz,1H),3.82(s,2H),2.90-2.69(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C19H20FN4O2[MH+]355.1492found355.1492.
实施例161(E)-3-(4-((2-(1H吡咯并[2,3-b]吡啶-6-取代)乙基)(2-羟乙基)氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.61(d,J=8.8Hz,1H),8.00(brs,NH),7.55(d,J=13.6Hz,1H),7.28(d,J=8.8Hz,1H),7.19(d,J=8.0Hz,2H),7.01(d,J=8.0Hz,2H),6.96(d,J=6.6Hz,2H),6.82(d,J=13.6Hz,1H),6.71(d,J=6.6Hz,1H),3.62(t,J=5.6Hz,1H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J=5.6Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H25N4O3[MH+]381.1848,found381.1849.
实施例212(E)-3-(4-(((2-(1H吡咯并[2,3-b]吡啶-6-取代)乙基)(2-羟乙基)氨基)甲基)吡啶基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.11(brs,NH),8.76(s,1H),8.58(d,J=8.8Hz,1H),8.01(brs,NH),7.73(d,J=13.6Hz,1H),7.70(d,J=8.0Hz,1H),7.51(d,J=8.0Hz,1H),7.43(d,J=13.6Hz,1H),7.24(d,J=8.8Hz,1H),7.02(d,J=6.6Hz,1H),6.71(d,J=6.6Hz,1H),3.63(t,J=5.6Hz,2H),3.60(s,2H),2.69-2.65(m,4H),2.56(t,J=5.6Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H24N5O3[MH+]382.1801,found382.1801.
实施例162(E)-3-(4-(((2-(1H吡咯并[2,3-b]吡啶-6-取代)乙基(2--羟乙基)氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.61(d,J=8.0Hz,1H),8.03(brs,NH),7.81(d,J=13.6Hz,1H),7.27(d,J=8.0Hz,1H),7.16(d,J=7.6Hz,1H),6.90(d,J=6.6Hz,1H),6.78(d,J=7.6Hz,1H),6.72(s,1H),6.67(d,J=13.6Hz,1H),6.48(d,J=6.6Hz,1H),3.64(t,J=5.6Hz,2H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J=5.6Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H24FN4O3[MH+]399.1754found399.1753.
实施例163(E)-3-(4-(((2-(1H吡咯并[2,3-b]吡啶-6-取代)乙基(2--羟乙基)氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.09(brs,NH),8.62(d,J=8.0Hz,1H),8.00(brs,NH),7.56(d,J=13.6Hz,1H),7.21(d,J=8.0Hz,1H),7.03(d,J=6.6Hz,1H),6.99(d,J=7.6Hz,1H),6.93(d,J=7.6Hz,1H),6.85(s,1H),6.80(d,J=13.6Hz,1H),6.48(d,J=6.6Hz,1H),3.63(t,J=5.6Hz,2H),3.62(s,2H),2.69-2.65(m,4H),2.52(t,J=5.6Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H24FN4O3[MH+]399.1754found399.1753.
实施例164(E)-3-(4-((2-(苯并呋喃-6-取代)乙氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.02(brs,NH),7.83(d,J=13.6Hz,1H),7.51(d,J=6.2Hz,1H),7.45(d,J=8.2Hz,1H),7.28(s,1H),7.17(d,J=6.8Hz,1H),6.99(d,J=8.2Hz,1H),6.78(d,J=7.0Hz,1H),6.72(s,1H),6.69(d,J=13.6Hz,1H),6.65(d,J=6.2Hz,1H),3.82(s,2H),2.89-2.67(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O3[MH+]355.1380found355.1382.
实施例165(E)-3-(4-((2-(苯并呋喃-6-取代)乙氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.05(brs,NH),7.59(d,J=13.8Hz,1H),7.53(d,J=6.6Hz,1H),7.45(d,J=7.6Hz,1H),7.29(s,1H),7.06(d,J=7.6Hz,1H),6.99(d,J=6.2Hz,1H),6.96(d,J=6.2Hz,1H),6.89(s,1H),6.83(d,J=13.8Hz,1H),6.66(d,J=7.2Hz,1H),3.83(s,2H),2.90-2.68(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O3[MH+]355.1380found355.1381.
实施例166(E)-3-(4-((2-(苯并噻吩-6-取代)乙氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.03(brs,NH),7.83(d,J=13.6Hz,1H),7.75(d,J=6.6Hz,1H),7.72(s,1H),7.41(d,J=6.2Hz,1H),7.29(d,J=6.2Hz,1H),7.19(d,J=6.6Hz,1H),7.15(d,J=6.8Hz,1H),6.80(d,J=6.8Hz,1H),6.72(s,1H),6.66(d,J=13.6Hz,1H),3.80(s,2H),2.85-2.63(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O2S[MH+]371.1151found371.1151.
实施例167(E)-3-(4-((2-(苯并噻吩-6-取代)乙氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):1HNMR(400MHz,MeOD):δ8.01(brs,NH),7.75(d,J=8.0Hz,1H),7.72(s,1H),7.55(d,J=13.8Hz,1H),7.40(d,J=6.2Hz,1H),7.29(d,J=6.2Hz,1H),7.19(d,J=8.2Hz,1H),7.03(d,J=7.0Hz,1H),6.98(d,J=7.0Hz,1H),6.89(s,1H),6.84(d,J=13.8Hz,1H),3.82(s,2H),2.89-2.67(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O3[MH+]371.1151found371.1148.
实施例168(E)-3-(5-((2-(1H-吲哚-7-取代)乙氨基)甲基)吡啶基-2-取代)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.09(brs,NH),8.79(s,1H),8.03(brs,NH),7.77(d,J=13.6Hz,1H),7.73(d,J=7.8Hz,1H),7.53(d,J=7.8Hz,1H),7.45(d,J=13.6Hz,1H),7.27(d,J=6.0Hz,1H),7.22(d,J=7.4Hz,1H),7.03(m,1H),6.86(d,J=6.6Hz,1H),6.45(d,J=6.0Hz,1H),3.89(s,2H),2.96-2.77(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C19H21N4O2[MH+]337.1586found337.1587.
实施例169(E)-3-(4-((2-(1H-吲哚-7-取代)乙氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.12(brs,NH),8.00(brs,NH),7.83(d,J=13.8Hz,1H),7.27(d,J=6.0Hz,1H),7.21(d,J=8.6Hz,1H),7.16(d,J=8.8Hz,1H),7.03(m,1H),6.88(d,J=7.8Hz,1H),6.75(d,J=8.8Hz,1H),6.70(s,1H),6.63(d,J=13.8Hz,1H),6.49(d,J=6.0Hz,1H),3.82(s,2H),2.89-2.68(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H21FN3O2[MH+]354.1540found354.1542.
实施例170(E)-3-(4-((2-(1H-吲哚-7-取代)乙氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.09(brs,NH),8.01(brs,NH),7.57(d,J=13.6Hz,1H),7.23(d,J=6.0Hz,1H),7.20(d,J=8.6Hz,1H),7.01(m,1H),6.99(d,J=8.8Hz,1H),6.93(d,J=8.6Hz,1H),6.89(s,1H),6.85(d,J=8.4Hz,1H),6.81(d,J=13.6Hz,1H),6.45(d,J=6.0Hz,1H),3.85(s,2H),2.92-2.75(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H21FN3O2[MH+]354.1540found354.1542.
实施例171(E)-3-(5-(((2-(1H-吲哚-7-取代)乙基)(2-羟乙基)氨基)甲基)吡啶基-2-取代)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.78(s,1H),8.05(brs,NH),7.78(d,J=14.6Hz,1H),7.72(d,J=7.8Hz,1H),7.50(d,J=7.8Hz,1H),7.46(d,J=14.6Hz,1H),7.27(d,J=6.0Hz,1H),7.21(d,J=7.4Hz,1H),7.03(m,1H),6.86(d,J=6.6Hz,1H),6.45(d,J=6.0Hz,1H),3.66(t,J=6.6Hz,2H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J=6.2Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H25N4O3[MH+]381.1848found381.1847.
实施例172(E)-3-(4-(((2-(1H-吲哚-7-取代)乙基)(2-羟乙基)氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.11(brs,NH),8.02(brs,NH),7.85(d,J=13.8Hz,1H),7.27(d,J=6.0Hz,1H),7.21(d,J=8.6Hz,1H),7.13(d,J=8.8Hz,1H),7.03(m,1H),6.86(d,J=7.8Hz,1H),6.75(d,J=8.8Hz,1H),6.70(s,1H),6.67(d,J=13.8Hz,1H),6.46(d,J=6.0Hz,1H),3.63(t,J=6.6Hz,2H),3.61(s,2H),2.69-2.65(m,4H),2.53(t,J=6.2Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25FN3O3[MH+]398.1802found398.1802.
实施例173(E)-3-(4-(((2-(1H-吲哚-7-取代)乙基)(2-羟乙基)氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.12(brs,NH),8.01(brs,NH),7.55(d,J=13.2Hz,1H),7.27(d,J=6.0Hz,1H),7.22(d,J=8.6Hz,1H),7.05(m,1H),6.99(d,J=7.8Hz,1H),6.93(d,J=7.8Hz,1H),6.89(s,1H),6.85(d,J=7.8Hz,1H),6.80(d,J=13.2Hz,1H),6.45(d,J=6.0Hz,1H),3.66(t,J=6.6Hz,2H),3.60(s,2H),2.69-2.65(m,4H),2.55(t,J=6.2Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25FN3O3[MH+]398.1802found398.1801.
实施例174(E)-3-(4-((2-(1H吡咯并[2,3-c]吡啶-4-取代)乙基氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.59(s,1H),8.52(s,1H),8.09(brs,NH),7.55(d,J=13.6Hz,1H),7.19(d,J=8.0Hz,2H),7.01(d,J=8.0Hz,2H),6.99(d,J=6.6Hz,2H),6.85(d,J=13.6Hz,1H),6.78(d,J=6.6Hz,2H),3.83(s,2H),2.88-2.67(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C19H21N4O2[MH+]337.1586,found337.1588.
实施例175(E)-3-(4-((2-(1H吡咯并[2,3-c]吡啶-5-取代)乙基氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.09(brs,NH),8.62(s,1H),8.09(brs,NH),7.55(d,J=13.6Hz,1H),7.29(s,1H),7.18(d,J=8.0Hz,2H),7.01(d,J=8.0Hz,2H),6.93(d,J=6.6Hz,2H),6.85(d,J=13.6Hz,1H),6.78(d,J=6.6Hz,2H),3.88(s,2H),2.88-2.67(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C19H21N4O2[MH+]337.1586,found337.1586.
实施例176(E)-3-(4-((2-(1H吡咯并[3,2-b]吡啶-7-取代)乙基)(2-羟乙基)氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.60(d,J=8.2Hz,1H),8.20(brs,NH),7.28(d,J=8.2Hz,1H),7.55(d,J=13.6Hz,1H),7.18(d,J=8.0Hz,2H),7.01(d,J=8.0Hz,2H),6.98(d,J=6.6Hz,2H),6.83(d,J=13.6Hz,1H),6.79(d,J=6.6Hz,2H),3.83(s,2H),2.88-2.67(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C19H21N4O2[MH+]337.1586,found337.1584.
实施例177(E)-3-(4-((2-(1H吡咯并[2,3-c]吡啶-4-取代)乙基)(2-羟乙基)氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.60(s,1H),8.57(s,1H),8.00(brs,NH),7.55(d,J=13.6Hz,1H),7.18(d,J=8.0Hz,2H),7.01(d,J=8.0Hz,2H),6.96(d,J=6.6Hz,2H),6.84(d,J=13.6Hz,1H),6.71(d,J=6.6Hz,1H),3.63(t,J=5.6Hz,1H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J=5.6Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H25N4O3[MH+]381.1848,found381.1847.
实施例178(E)-3-(4-((2-(1H吡咯并[2,3-c]吡啶-5-取代)乙基)(2-羟乙基)氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.62(s,1H),8.00(brs,NH),7.55(d,J=13.6Hz,1H),7.29(s,1H),7.18(d,J=8.0Hz,2H),7.01(d,J=8.0Hz,2H),6.95(d,J=6.6Hz,2H),6.83(d,J=13.6Hz,1H),6.70(d,J=6.6Hz,1H),3.65(t,J=5.6Hz,1H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J=5.6Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H25N4O3[MH+]381.1848,found381.1848.
实施例178(E)-3-(4-((2-(1H吡咯并[3,2-b]吡啶-7-取代)乙基)(2-羟乙基)氨基)甲基)苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.11(brs,NH),8.60(d,J=8.6Hz,1H),8.06(brs,NH),7.55(d,J=13.6Hz,1H),7.28(d,J=8.6Hz,1H),7.18(d,J=8.0Hz,2H),7.01(d,J=8.0Hz,2H),6.97(d,J=6.6Hz,2H),6.82(d,J=13.6Hz,1H),6.75(d,J=6.6Hz,1H),3.67(t,J=5.6Hz,1H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J=5.6Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H25N4O3[MH+]381.1848,found381.1849.
实施例179(E)-3-(4-((2-(苯并呋喃-7-取代)乙氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.01(brs,NH),7.83(d,J=13.6Hz,1H),7.53(d,J=6.2Hz,1H),7.32(d,J=8.2Hz,1H),7.19(d,J=6.8Hz,1H),7.09(m,1H),7.05(d,J=8.0Hz,1H),6.80(d,J=8.2Hz,1H),6.77(s,1H),6.70(d,J=13.6Hz,1H),6.66(d,J=7.2Hz,1H),3.80(s,2H),2.87-2.66(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O3[MH+]355.1380found355.1380.
实施例180(E)-3-(4-((2-(苯并呋喃-7-取代)乙氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):1HNMR(400MHz,MeOD):δ8.02(brs,NH),7.57(d,J=13.6Hz,1H),7.52(d,J=6.6Hz,1H),7.32(d,J=7.6Hz,1H),7.09(m,1H),7.05(d,J=7.2Hz,1H),6.99(d,J=7.0Hz,1H),6.96(d,J=7.0Hz,1H),6.89(s,1H),6.83(d,J=13.6Hz,1H),6.65(d,J=6.6Hz,1H),3.82(s,2H),2.88-2.68(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O3[MH+]355.1380found355.1383.
实施例181(E)-3-(4-((2-(苯并噻吩-7-取代)乙氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.06(brs,NH),7.83(d,J=13.6Hz,1H),7.62(d,J=6.6Hz,1H),7.40(d,J=6.6Hz,1H),7.29(d,J=6.6Hz,1H),7.27(m,1H),7.19(d,J=6.2Hz,1H),7.18(d,J=6.6Hz,1H),7.16(d,J=6.2Hz,1H),6.79(d,J=6.2Hz,1H),6.72(s,1H),6.67(d,J=13.6Hz,1H),3.83(s,2H),2.89-2.66(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O2S[MH+]371.1151found371.1153.
实施例182(E)-3-(4-((2-(苯并噻吩-7-取代)乙氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):1HNMR(400MHz,MeOD):δ8.02(brs,NH),7.63(d,J=8.0Hz,1H),7.55(d,J=13.8Hz,1H),7.40(d,J=6.0Hz,1H),7.29(d,J=6.2Hz,1H),7.27(m,1H),7.17(d,J=8.2Hz,1H),7.00(d,J=7.0Hz,1H),6.95(d,J=7.0Hz,1H),6.89(s,1H),6.84(d,J=13.8Hz,1H),3.82(s,2H),2.89-2.67(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O3[MH+]371.1151found371.1150.
实施例183HDAC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(如表1所示)与分析:
表1
上表中IC50是指被抑制一半时抑制剂的浓度(50%inhibitory concentration)。
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HDAC酶的去乙酰化作用的活性。
本发明化合物结构与现有的相关化合物相比,酶活性结果见表2,显示出显著优势,相差几倍到数十倍。
表2酶活性结果比较表
在吲哚的4,5,6,7位引入侧链可以很好的提高其对组蛋白去乙酰化酶的活性。与现有化合物相比,其活性可以提高10倍以上。吲哚环的1,2及3位上可以引入烷基或烷烃基取代基,其对组蛋白去乙酰化酶的活性与母体化合物基本相当或更好。在吲哚环的2,3位上引入引入其它环状结构,其对组蛋白去乙酰化酶的活性与母体化合物基本相当。双键上引入取代基其对组蛋白去乙酰化酶的活性比母体化合物稍弱。中间苯环引入氟或含氮杂原子,其对组蛋白去乙酰化酶的活性与母体化合物基本相当。吲哚环可以被苯并呋喃或苯并噻吩取代,其对组蛋白去乙酰化酶的活性与母体化合物基本相当。
实施例184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3。
表3
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。
本发明化合物与现有的化合物相比,显示出显著优势,对肿瘤细胞活性结果见表4。
表4
在吲哚的4,5,6,7位引入侧链可以很好的提高其抗肿瘤细胞的的活性。与现有化合物相比,其活性可以提高10到100倍以上。吲哚环的1,2及3位上可以引入烷基或烷烃基取代基,其抗肿瘤细胞的活性与母体化合物基本相当或更好。在吲哚环的2,3位上引入引入其它环状结构,其对抗肿瘤细胞的活性与母体化合物基本相当。双键上引入取代基其对抗肿瘤细胞的活性比母体化合物稍弱。中间苯环引入氟或含氮杂原子,其对抗肿瘤细胞的活性与母体化合物基本相当。吲哚环可以被苯并呋喃或苯并噻吩取代,其对抗肿瘤细胞的活性与母体化合物基本相当。
实施例185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本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。