CN114751874A - 作为TRPV4-KCa2.3促耦联剂的1-苄基-4-乙基哌嗪衍生物及其应用 - Google Patents
作为TRPV4-KCa2.3促耦联剂的1-苄基-4-乙基哌嗪衍生物及其应用 Download PDFInfo
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- CN114751874A CN114751874A CN202210602380.0A CN202210602380A CN114751874A CN 114751874 A CN114751874 A CN 114751874A CN 202210602380 A CN202210602380 A CN 202210602380A CN 114751874 A CN114751874 A CN 114751874A
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Abstract
本发明涉及作为TRPV4‑KCa2.3促耦联剂的1‑苄基‑4‑乙基哌嗪衍生物及其应用，属于化学医药领域。本发明提供了如通式I所示化合物或其药学上可接受的盐，该化合物或其药学上可接受的盐能够选择性的增强TRPV4与KCa2.3的空间耦联度，从而可用于治疗或改善TRPV4‑KCa2.3耦联作用异常导致的病症。
Description
技术领域
本发明属于化学医药领域，具体涉及作为TRPV4-KCa2.3促耦联剂的1-苄基-4-乙基哌嗪衍生物及其应用。
背景技术
肺动脉高压(pulmonary artery hypertension，PAH)是一种较难治愈的恶性肺部血管疾病，其定义为静息状态下平均肺动脉压≧25mmHg，其病理特征是肺血管阻力(pulmonary vascular resistance，PVR)和肺动脉压(pulmonary artery pressure，PAP)进行性升高和重塑性病变，并导致其他并发症，如右心衰竭、动脉粥样硬化、外周动脉疾病等。我国肺动脉高压患者的3年生存率为39％，5年生存率仅为21％。全球约有1％的人口受肺动脉高压影响，65岁以上人群发病率可达5％～10％。该病发病机制复杂，其病因除了肺血管本身的疾病外，左右心及肺实质等器质性病变及功能性改变都可对肺血管产生明显的影响。多种血管活性介质(血管生长素Ⅱ、内皮素等)、生长因子(血小板衍生因子、成纤维细胞生长因子等)和离子通道(K+通道和Ca2+通道)介导其病理发展进程。目前已上市的抗肺动脉高压药物主要有以下几类：(1)前列环素类似物和前列环素受体激动剂，如依前列醇、贝前列环素、伊洛前列素：(2)内皮素受体拮抗剂，如波生坦、安贝生坦、马西替坦；(3)磷酸二酯酶-5抑制剂，如西地那非、他达拉非、伐地那非；(4)可溶性鸟苷酸环化酶受体激活剂：如利奥西呱。已有的临床治疗药物主要作用于血管舒张，仅能减轻症状，不能降低患者的死亡率，且各自存在不同程度的不良临床表现。因此，迫切需要针对新的药理学靶点开发疗效更佳、副作用更小、代谢稳定性高、生物利用度好的新药来提高肺动脉高压患者的生存率。
基础研究发现肺动脉高压患者中存在细胞特异性离子通道调节失衡，包括K+通道、不同类型的瞬时受体电位通道、钙感受器蛋白等(Int J Mol Sci.2018,19(10):3162)。其中，瞬时受体电位香草素亚型4(transient receptor potential vanilloid 4，TRPV4)是存在于细胞膜或细胞内细胞器膜上的非选择性阳离子钙通道蛋白，TRPV4调节人体一系列重要的生理功能，包括调节钙信号、保护内皮细胞屏障完整性等。TRPV4通道通过一氧化氮、前列环素和中/小电导钾通道依赖途径，介导钙离子内流。TRPV4介导的Ca2+内流在血流诱导的血管舒张中起重要作用，TRPV4敲除后剪切力诱导的血管舒张反应受损。在血管内皮细胞中，TRPV4已被证明有助于对5-羟色胺诱导的肺血管收缩和慢性缺氧性肺动脉高压中血管反应性的增强(AM J Physiol-Cell Ph.2013,305(7):C704-C715.)。
Ca2+是细胞内重要的信使物质之一，胞内的游离Ca2+浓度([Ca2+]i)的变化是促发细胞相关信号转导的关键因素，如增殖、基因表达和调亡等，与心血管疾病的发生、发展密切相关。KCa2.3是小电导Ca2+激活的钾通道，细胞内Ca2+静息浓度(约100nM)下KCa2.3通道处于静止状态，增加[Ca2+]i通过钙调蛋白激活KCa2.3通道(Nature.2010,14(8):825-837.)。在KCa2.3过表达小鼠中检测到肠系膜脉管系统的动脉直径明显扩大，较大的血管直径伴随着肠系膜内皮的连续超极化，导致肌源性和去氧肾上腺素诱导的张力降低，表明KCa2.3对血管张力具有扩张作用。研究表明，肺微血管内皮细胞(Pulmonarymicrovascular endothelial cells，PMVEC)和肺动脉内皮细胞(Pulmonary ArteryEndothelial Cells，PAEC)表达TRPV4、BK、IK和SK3离子通道，通过TRPV4通道流入的Ca2+选择性激活IK和SK通道，而IK和SK3通道活性的抑制会减弱TRPV4诱导的肺内皮通透性，电生理结果表明TRPV4通道在功能上与IK、SK耦合(Pulm Circ.2016,5(2):279-290.)。肺血管系统的低血管张力主要由肺动脉平滑肌细胞(Pulmonary arterial smooth muscle cells，PASMCs)的静息膜电位维持，其中主要由KCa诱导。在特发性肺动脉高压中，KCa通道及其亚基被上调，导致PASMCs具有更多的去极化膜电位(Circulation.1998,98(14):1400-1406.)。肺动脉的内皮依赖性血管舒张功能丧失是肺动脉压升高的重要原因，二十二碳六烯酸(docosahexaenoic acid,DHA)可以激活这些PASMCs中的KCa通道，并使特发性肺动脉高压PASMCs的膜电位超极化至健康供体的PASMCs的膜电位，导致血管舒张(Eur RespirJ.2016,48(4):1127-1136.)。
近年来研究认为，肺血管收缩、重构和原位血栓形成是肺动脉高压发生发展的重要病理生理基础，内皮功能障碍在其中起着关键作用。过去人们将研究重点放在大动脉系统产生的血管活性因子一氧化氮和血管收缩因子内皮素-1上，而忽略了小动脉系统产生的内皮依赖性超极化因子(Endothelium Derived Hyperpolarizing Factor，EDHF)的重要作用。已有研究表明血管内皮细胞中TRPV4和KCa2.3离子通道形成TRPV4-KCa2.3物理和功能耦联作用，是内皮细胞中发生EDHF反应的原因(Hypertension.2013,62(1):134-139.)。当TRPV4-KCa2.3蛋白处于解耦联状态时，内皮细胞诱导的超极化因子减少，是导致高血压患者血管舒张机制受损的重要原因。已有化合物JNC-440可以恢复高血压模型鼠血管内皮中TRPV4-KCa2.3蛋白的重新耦联，从而发挥降低血压的作用(EMBO Mol Med.2017,9(11):1491-1503.)，又在肺动脉高压模型中发现JNC-440具有良好的调控效果。
JNC-440的结构如下所示：
因此，TRPV4-KCa2.3复合体是肺动脉高压治疗干预的有吸引力的分子靶标，目前仍无针对TRPV4-KCa2.3复合体的靶向药物。
发明内容
技术问题：
为了解决现有技术存在的上述问题，本发明提供一类新型1-苄基-4-乙基哌嗪衍生物，该结构化合物体外促TRPV4-KCa2.3耦联活性更高，预期此类促耦联剂将会有好的疗效，有望克服毒副作用问题，具有良好的开发前景。
技术方案：
本发明提供以下通式(I)化合物，或其药学上可接受的盐：
在本发明式(I)化合物或其药学上可接受的盐的一个优选的实施方案中，X，Y独立选自NH、O、CO或CH2；
在本发明式(I)化合物或其药学上可接受的盐的一个更优的实施方案中，X，Y独立选自NH或CO；
在本发明式(I)化合物或其药学上可接受的盐的一个优选的实施方案中，R1选自氢、C1-C4烷基、苯基，其中所述烷基、苯基可任选地被下述相同或不相同的取代基单取代至五取代，所述的取代基选自：卤素、三氟甲基、氰基、硝基、羟基或C1-C4烷基；
在本发明式(I)化合物或其药学上可接受的盐的一个更优的实施方案中，R1选自取代基取代的苯基，所述的取代基优选自：氟、氯、三氟甲基或氰基中的单取代至五取代；
在本发明式(I)化合物或其药学上可接受的盐的一个优选的实施方案中，R2选自
C1-C4烷基或空；
其中R4选自-CH-、-C2H3-、-C3H5-或-C4H7-；
Z选自C、N、O或S；
在本发明式(I)化合物或其药学上可接受的盐的一个更优的实施方案中，R2选自
或空；
其中R4优选自-CH-或-C3H5-；
Z优选自N；
在本发明式(I)化合物或其药学上可接受的盐的一个优选的实施方案中，R3选自
取代基取代或未取代的苯基，其中所述苯基可任选地被下述相同或不相同的取代基单取代至五取代，所述的取代基选自：卤素、三氟甲基、氰基、硝基、羟基或C1-C4烷基；
其中R5选自氢、C1-C4烷基或CONHR6、取代基取代或未取代的苯基，其中所述烷基、苯基可任选地被下述相同或不相同的取代基单取代至五取代，所述的取代基选自：卤素、三氟甲基、氰基、硝基、羟基或C1-C4烷基；
R6选自氢、C1-C4烷基、取代基取代或未取代的苯基，其中所述烷基、苯基可任选地被下述相同或不相同的取代基单取代至五取代，所述的取代基选自：卤素、三氟甲基、氰基、硝基、羟基或C1-C4烷基；
在本发明式(I)化合物或其药学上可接受的盐的一个更优的实施方案中，R3选自
C4烷基氨基-(CH2)4-NH-；
其中R5优选自氢或CONHR6；
R6优选自取代基取代或未取代的苯基，所述的取代基优选自：氟、氯中的单取代至五取代。
在本发明式(I)所示的化合物或其药学上可接受的盐，其特征在于，R2为空时，相应的结构式为：
在本发明式(I)所示的化合物或其药学上可接受的盐，其特征在于，化合物的结构如下所示：
其中，R’、R”分别独立地选自：卤素(F、Cl、Br)，硝基、氰基、三氟甲基、C1-4烷基。
本发明中，具体优选的通式(I)化合物或其药学上可接受的盐选自：
本发明通式(I)化合物或其药学上可接受的盐，其中所述的药学上可接受的盐为无机盐或有机盐，无机盐包括盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、酸式磷酸盐；所述有机盐选自乙酸盐、三氟乙酸盐、丙酸盐、丙酮酸盐、羟乙酸盐、乙二酸盐、丙二酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、以磺酸盐、苯磺酸盐、水杨酸盐。
<药物组合物>
本发明还提供药物组合物，包括上述本发明通式(I)化合物或其药学上可接受的盐、以及药学上可接受的载体、赋形剂或稀释剂。
通式(Ⅰ)化合物或它们的盐可以溶剂合物的形式分离，且因此任何这种溶剂合物都属于本发明的范围。
本发明化合物或其药学上可接受的盐可以配制为用于口服给药的固体制剂，包括，但不限于胶囊剂、片剂、丸剂、散剂、颗粒剂等。在这些固体剂型中，本发明通式(I)化合物作为活性成分与至少一种常规惰性赋形剂(或载体)混合，例如与柠檬酸钠或磷酸二钙。或与下属成分混合：(1)填料或增溶剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸等；(2)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖、阿拉伯胶等；(3)保湿剂，例如，甘油等；(4)崩解剂、例如琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些符合硅酸盐和碳酸钠等；(5)缓溶剂，例如石蜡等；(6)吸收加速剂，例如季铵化合物等；(7)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯等；(8)吸附剂，例如，高岭土等；(9)润滑剂，例如，滑石、硬脂酸钙、固体聚乙二醇、十二烷基硫酸钠等，或其混合物。胶囊剂、片剂、丸剂中也可包含缓冲剂。
所述固体剂型例如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材料如肠溶衣和其他本领域公知的材料晶型包衣或微囊化。他们可包含不透明剂，并且，这种组合物中活性成分的释放可以延迟的方式在消化道的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性成分也可与上述赋形剂中的一种或者多种形成微胶囊形式。
本发明化合物或其药学上可接受的盐可以配制为用于口服给药的液体剂型，包括，但不限于药学上可接受的乳液、溶液、悬浮液、糖浆、酊剂等。除了作为活性成分的通式(I)化合物或其药学上可接受的盐外，液体剂型可包含本领域中常规采用的惰性稀释剂，例如水和其他溶剂，增溶剂和乳化剂、例如，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1，3-丁二醇、二甲基甲酰胺以及油类，特别是棉籽油、花生油、玉米油、橄榄油、蓖麻油、芝麻油等或这些物质的混合物等。除了这些惰性稀释剂外，本发明液体剂型也可包括常规助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料等。
所述悬浮剂包括，例如，乙氧基化十八烷醇、聚氧乙烯山梨醇、和脱水山梨醇、微晶纤维素、琼脂等或这些物质的混合物。
本发明化合物和其药学上可接受的盐可以配置为用于胃肠外注射的剂型，包括，但不限于生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，以及用于重新溶解成无菌的可注射溶液和分散液的无菌粉末。适宜的载体、稀释剂、溶剂、赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物或其药学上可接受的盐可以配置为用于局部给药的剂型，包括如软膏剂、散剂、栓剂、滴剂、喷射剂和吸入剂等。作为活性成分的本发明通式(I)化合物或其药学上可接受的盐在无菌条件下和生理上可接受的载体及任选的防腐剂、缓冲剂，和必要时可能需要的推进剂一起混合。
本发明的药物组合物包括通式(I)化合物或其药学上可接受的盐作为活性成分，以及药学上可接受载体、赋形剂、稀释剂。在制备药物组合物时，通常是将本发明通式(I)化合物或其药学上可接受的盐与药学上可接受载体、赋形剂或稀释剂混合。其中通式(I)化合物或其药学上可接受的盐的含量可以为0.01-1000mg，例如0.05-800mg、0.1-500mg、0.01-300mg、0.01-200mg、0.05-150mg、0.05-50mg等。
<用途>
本发明还提供通式(I)化合物或其药学上可接受的盐在制备TRPV4-KCa2.3促耦联剂中的用途。
本发明还提供通式(I)化合物或其药学上可接受的盐在制备用于治疗哺乳动物包括人的肺动脉高压药物中的用途。
本发明还提供通式(I)化合物或其药学上可接受的盐在制备肺动脉高压(PAH)调节剂中的用途。
本发明还提供通式(I)化合物或其药学上可接受的盐在制备用于治疗人类TRPV4-KCa2.3耦联作用异常所介导的恶性肺部疾病，心血管疾病的药物中的用途。
通式(I)化合物或其药学上可接受的盐，通过促进TRPV4-KCa2.3的偶联作用，用于治疗哺乳动物包括人的肺动脉高压疾病的方法，所述方法包括向所述哺乳动物包括人施用治疗有效量的上述式I的化合物或其药学上可接受的盐。
“治疗有效量”为个体中有效产生生物或医学应答(例如增强蛋白耦联活性，或者改善症状、减轻病况、减缓或延迟疾病进展或者预防疾病)的本发明的化合物的量。
本发明所提及的肺动脉高压，包括遗传性肺动脉高压(heritable pulmonaryarterial hypertension，HPAH)、药物和毒素诱导肺动脉高压(drug-induced pulmonaryhypertension，DPAH)、特发性肺动脉高压(idiopathic pulmonary arterialhypertension，IPAH)、门静脉高压相关性肺动脉高压(Portopulmoanry hypertension，PoPH)、结缔组织病相关性肺动脉高压(connective tissue disease-associatedpulmonary arterial hypertension，PAH-CTD)、慢性血栓栓塞性肺动脉高压(chronicthromboembolic pulmonary hypertension,CTEPH)、新生儿持续性肺动脉高压(Persistent PH of the newborn，PPHN)、孤立的毛细血管后肺动脉高压(isolated post-capillary pulmonary hypertension，Ipc-PH)、慢性阻塞性肺病(COPD)所致肺动脉高压、先天性心脏病(CHD)所致肺动脉高压等。
本发明所提及的恶性肺部疾病，包括肺动脉栓塞(pulmonary embolism，PE)、急性肺血栓栓塞症(acute pulmonary thromboembolism，APTE)、肺血管炎、肺血管肿瘤、肺水肿、急性肺损伤(acute lung injury，ALI)等。
本发明所提及的心血管疾病，包括高血压、高血脂、高血压心脏病、肺源性心脏病、瓣膜性心脏病、先天性心脏病、冠心病、心肌病、心力衰竭、动脉粥样硬化(AS)、糖尿病、慢性肾脏病、静脉血栓栓塞症(VTE)、代谢综合征、心律失常、主动脉疾病、外周动脉疾病、脑卒中等。
本发明的化合物或其药学上可接受的盐可给药于哺乳动物包括人，可以口服、直肠、胃肠外(静脉内、肌肉内或皮下)、局部给药(粉剂、软膏剂、滴剂)或瘤内给药。
本发明所述的化合物或其药学上可接受的盐可以单独给药，或者与其他药学上可接受的治疗剂联合给药，与其他治疗肺动脉高压药物组合。此联合治疗可通过同时、顺序或分开使用治疗的各个组分来实现。所述治疗剂包括但不限于：钙拮抗剂如长效硝苯地平、地尔硫卓、氨氯地平等，前列腺素类药物如前列环素、曲罗尼尔、伊洛前列素等，内皮素受体抑制剂如波生坦、安贝生坦、西他生坦等，磷酸二酯酶抑制剂如西地那非、伐地那非、他达拉非等，可溶性鸟苷酸环化酶激动剂如利奥西呱等，酪氨酸激酶抑制剂如伊马替尼、索拉非尼等，Rho激酶抑制剂如法舒地尔等。待组合的各成分可同时或顺序的给予，以单一制剂形式或者以不同制剂的形式给予。所述组合不仅包括本发明化合物的一种或其他活性剂的组合，而且也包括本发明化合物的两种或更多的其他活性剂的组合。
有益效果：
本发明一类新型1-苄基-4-乙基哌嗪衍生物具有促进TRPV4-KCa2.3耦联的生物学功能，用于肺动脉高压的研究性治疗，从而为寻找新的治疗恶性肺部疾病、心血管疾病以及循环系统疾病等提供新手段。本发明提供的具有通式(I)所示结构的一类1-苄基-4-乙基哌嗪衍生物具有较为便捷的合成方法、较高的纯度(>95％)以及良好的体外耦联活性。
附图说明
图1为TRPV4-KCa2.3在肺动脉高压模型小鼠原代肺动脉内皮细胞中的亚细胞共定位图。
具体实施方式
下面将结合实施例对本发明的技术方案进行详细的描述。
在本发明中“C1-C8烷基”是指分别为1至8个碳原子的饱和的直链或支链的单价烃基。实例包括，但不限于戊基。
在本发明中“药学上可接受的盐”是指表示保留母体化合物的生物有效性和性质的那些盐。术语“盐”是指由无机或有机酸或碱和内部形成的盐制备的根据本发明的化合物的任何盐。通常，这种盐具有生理上可接受的阴离子或阳离子。
在本发明中“给药”或“给予”个体化合物是指向需要治疗的个体提供本发明的化合物。
在整个本说明书中提到的“实施方式”或“实施方案”或“在另一实施方案中”或“在某些实施方案中”或“在本申请的部分实施方式中”意指在至少一实施方案中包括与该实施方案所述的相关的具体参考要素、结构或特征。因此，在整个说明书中不同位置出现的短语“在一实施方案中”或“在实施方案中”或“在另一实施方案中”或“在某些实施方案中”或“在本申请的部分实施方式中”不必全部指同一实施方案。此外，具体要素、结构或特征可以任何适当的方式在一个或多个实施方案中结合。
除非本申请中另外要求，在整个说明书和其后的权利要求书中，词语“包括”应解释为开放式的、含括式的意义，即“包括但不限于”。
本发明包括通式(I)化合物的全部药学上可接受的同位素标记化合物，其中一个或多个原子被有相同原子数的原子替换，但原子质量或质量数与通常见于自然中的原子质量或质量数不同。
适于包含在本发明化合物中的同位素实例包括氢的同位素，例如2H和3H，碳的同位素例如11C、13C和14C，氮的同位素例如13N和15N，氧的同位素例如15O、17O和18O。
下面结合具体实施例，进一步阐述化合物1-20的合成方法。应理解为这些实施例仅用于举例说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件。
下列实施例中涉及的中间体化合物通过如下过程制备得到：
中间体M-3：(4-(4-乙基哌嗪-1-基)甲基苯基)氨基甲酸酯的制备
步骤a：1-乙基-4-(4-硝基苄基)哌嗪(M-1)的制备
将4-硝基苄氯(7.00g，40.80mmol)溶于丙酮(100mL)中，加入N-乙基哌嗪(5.59g，48.96mmol)和碳酸钾(11.28g，81.59mmol)，升温至45℃回流反应过夜。次日，TLC监测反应完全。停止加热和搅拌，经硅藻土助滤得滤液，滤液减压浓缩得褐色液体。粗品用乙酸乙酯重结晶得黄色固体M-1(9.50g，93.5％)。HRMS-ESI(m/z):251.0444[M+H]+；1H NMR(400MHz,DMSO-d6)δ8.53(td,J＝6.0,2.0Hz,2H),8.19(dd,J＝9.5,6.2Hz,2H),6.82(dd,J＝12.1,2.6Hz,2H),6.59(ddd,J＝9.9,7.5,2.6Hz,2H),4.29(d,J＝5.8Hz,4H),3.73(s,7H)。
步骤b：4-(4-乙基哌嗪-1-基)甲基苯胺(M-2)的制备
将M-1(9.00g，36.14mmol)溶于甲醇(90mL)中,加入雷尼镍(0.9g，15.25mmol),H2氛围下升温至45℃反应24h，TLC监测反应完全。待反应液冷却至室温后，经硅藻土助滤得滤液，滤液减压浓缩得褐色液体M-2(6.69g，84.6％)，无需纯化直接用于下一步反应。
步骤c：(4-(4-乙基哌嗪-1-基)甲基苯基)氨基甲酸酯(M-3)的制备
将化合物M-2(6.69g,30.55mmol)溶于二氯甲烷(60mL)中，再加入吡啶(7mL)，反应瓶置于-10℃低温反应釜中，向其中恒压滴加氯甲酸苯酯(5.74g，36.66mmol)，反应体系于-10℃下反应0.5h后移至室温反应0.5h，TLC监测反应完全。反应液减压浓缩，加入水稀释，用乙酸乙酯萃取(15mL×3)，合并有机相，依次用水洗、饱和NaCl溶液洗涤，无水硫酸钠干燥，抽滤，滤液经减压浓缩得M-3粗品，经硅胶柱层析[洗脱剂：二氯甲烷/甲醇＝30/1(v/v)]纯化得白色固体M-3(7.79g，75.2％)。HRMS-ESI(m/z):340.1985[M+H]+；1H-NMR(400MHz,DMSO-d6)δ8.65(s,1H),7.39(d,J＝8.6Hz,3H),7.28–7.01(m,5H),6.77–6.74(m,1H),3.36(s,2H),2.36–2.25(m,10H),0.96(d,J＝1.9Hz,3H)。
中间体M-5a：5-氨基-N-(4-氰基苯基)戊酰胺的制备
步骤d：叔丁基(5-(4-氰基苯基)氨基)-5-氧代戊基氨基甲酸酯(M-4a)的制备
将Boc-5-氨基戊酸(2.17g，10.0mmol)溶于N,N-二甲基甲酰胺(30mL)中，加入缩合剂HATU(4.18g，11mmol)，在N2保护下搅拌10min，活化羧基；搅拌状态下依次加入对氨基苯腈(1.18g，10mmol)，DIPEA(3.88g，30mmol)，加毕，N2保护，室温反应6h，TLC监测反应完全。反应液加水稀释，用乙酸乙酯萃取(20mL×3)，合并有机相，水洗有机相除去残余的N,N-二甲基甲酰胺溶液(20mL×6)，再用饱和NaCl溶液洗涤，无水硫酸钠干燥，抽滤，滤液经减压浓缩得褐色油状物M-4a粗品，硅胶柱层析[洗脱剂：石油醚/乙酸乙酯＝10/1(v/v)]纯化得白色固体M-4a(2.62g，82.6％)。HRMS-ESI(m/z):340.1632[M+Na]+；1H-NMR(400MHz,DMSO-d6)δ10.32(s,1H),7.82–7.74(m,4H),6.82(t,J＝5.7Hz,1H),2.96(q,J＝6.6Hz,2H),2.38(t,J＝7.4Hz,2H),1.60(p,J＝7.4Hz,2H),1.45(dd,J＝10.2,5.0Hz,2H),1.39(s,9H)。
步骤e：5-氨基-N-(4-氰基苯基)戊酰胺(M-5a)的制备
将M-4a(1g,3.15mol)溶于盐酸-甲醇(10mL)溶液中，室温下搅拌反应2h，反应完全。旋蒸除去反应液中的甲醇，在冰浴下用饱和NaHCO3溶液调节pH至8～9；用乙酸乙酯萃取(10mL×3)，合并有机相，经饱和NaCl溶液洗涤，无水硫酸钠干燥，抽滤，滤液经减压浓缩得棕色油状物M-5a(590.91m g，86.4％)。HRMS-ESI(m/z):218.1288[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.05(s,1H),7.83–7.62(m,4H),2.69(q,J＝6.6Hz,2H),2.35(t,J＝7.4Hz,2H),1.52(p,J＝7.4Hz,2H),1.5(t,2H)1.63(dd,J＝10.2,5.0Hz,2H)。
中间体M-5b：叔丁基(5-(3-氰基-4-氟苯基)氨基)-5-氧代戊基)氨基甲酸酯的制备
以化合物5-氨基-2-氟苯腈为原料合成M-5b，合成方法参照中间体M-5a。褐色油状液体243mg，收率87.1％。HRMS-ESI(m/z):236.1197[M+H]+。
中间体M-5c：5-氨基-N-(4-三氟甲基苯基)戊酰胺的制备
以化合物对三氟甲基苯胺为原料合成M-5c，合成方法参照中间体M-5a。黄色油状物265mg，收率90.0％。HRMS-ESI(m/z):261.1213[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.56(s,1H),7.86(d,J＝8.4Hz,4H),7.66(d,J＝8.5Hz,2H),2.82(t,J＝7.1Hz,2H),2.43(t,J＝6.9Hz,2H),1.70–1.58(m,4H)。
中间体M-7：4-氟-N-(1,2,3,4-四氢异喹啉-6-基)苯甲酰胺的制备
步骤f：6-(4-氟苯甲酰胺)-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯(M-6)的制备
以对氟苯甲酸和6-氨基-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯为原料合成M-6，合成方法参照中间体M-4a。白色固体2.98g，收率85.0％。
步骤g：4-氟-N-(1,2,3,4-四氢异喹啉-6-基)苯甲酰胺盐酸盐(M-7)的制备
将M-6(1g，2.70mmol)溶于盐酸-甲醇混合溶液中(10mL)，室温下搅拌反应2h，TLC监测反应完全。旋蒸除去甲醇，即得白色固体M-12a(658.21mg，90.2％)，无需纯化直接用于下一步。1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),9.73(s,1H),8.10(dd,J＝8.6,5.4Hz,2H),7.75–7.61(m,2H),7.37(t,J＝8.7Hz,2H),7.20(d,J＝8.4Hz,1H),4.21(s,2H),3.35(d,J＝6.9Hz,2H),3.03(d,J＝6.3Hz,2H),1.32(d,J＝6.4Hz,1H)。
中间体M-9a：N-(4-氟苯基)-4-哌嗪-1-基苯甲酰胺的制备
步骤h：4-(4-(4-氟苯基)氨基甲酰基)苯基)哌嗪-1-羧酸叔丁酯(M-8a)的制备
以对氟苯胺和4-(4-羧基苯基)哌嗪-1-羧酸叔丁酯为原料合成M-8a，合成方法参照中间体M-4a。白色固体3.53g，收率88.5％。HRMS-ESI(m/z):400.2031[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),7.89(d,J＝8.4Hz,2H),7.80(dd,J＝8.9,5.0Hz,2H),7.17(t,J＝8.7Hz,2H),7.03(d,J＝8.5Hz,2H),3.51–3.44(m,4H),3.28(t,J＝5.2Hz,4H),1.43(s,9H)。
步骤i：N-(4-氟苯基)-4-哌嗪-1-基苯甲酰胺(M-9a)的制备
M-8a(1g，2.51mmol)溶于三氟乙酸/二氯甲烷(v/v＝1/4，10mL)混合溶液中，室温下搅拌反应1h，TLC监测反应完全。旋蒸除去二氯甲烷，在冰浴下用饱和NaHCO3溶液调节pH至8～9，固体析出，抽滤得M-9a。白色固体693.45mg，收率92.4％。HRMS-ESI(m/z):300.1514[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.05(s,1H),7.90(d,J＝8.8Hz,2H),7.80(dd,J＝9.1,5.0Hz,2H),7.17(t,J＝8.9Hz,2H),7.02(d,J＝8.7Hz,2H),4.81(s,1H),3.29(t,J＝4.9Hz,4H),2.96(s,4H)。
中间体M-9b：N-(4-氟苯基)-4-(哌啶-4-基)苯甲酰胺的制备
步骤j：4-(4-(4-(4-氟苯基)氨基甲酰基)苯基)哌啶-1-羧酸叔丁酯(M-8b)的制备
以对氟苯胺和4-(4-羧基苯基)哌啶-1-羧酸叔丁酯为原料合成M-8b，合成方法参照中间体M-4a。白色固体3.31g，收率83.1％。HRMS-ESI(m/z):421.1907[M+Na]+；1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),7.89(d,J＝8.1Hz,2H),7.80(dd,J＝9.1,5.0Hz,2H),7.40(d,J＝8.1Hz,2H),7.19(t,J＝8.9Hz,2H),4.10(d,J＝10.3Hz,2H),2.77(t,J＝12.1Hz,3H),1.78(d,J＝14.7Hz,2H),1.58–1.48(m,2H),1.43(s,9H)。
步骤k：N-(4-氟苯基)-4-(哌啶-4-基)苯甲酰胺盐酸盐(M-9b)的制备
以M-8b为原料合成M-9b，合成方法参照中间体M-7。白色固体739.68mg，收率88.2％。1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),9.28–9.10(m,2H),7.96(d,J＝8.1Hz,2H),7.82(dd,J＝9.1,5.1Hz,2H),7.38(d,J＝8.1Hz,2H),7.19(t,J＝8.9Hz,2H),3.39(s,2H),2.98(dt,J＝16.6,8.3Hz,3H),1.95(q,J＝5.8Hz,4H)。
中间体M-9c：N-(4-氟苯基)-3-(哌啶-4-基)苯甲酰胺的制备
步骤l：4-(3-(4-氟苯基)氨基甲酰基)苯基)哌啶-1-羧酸叔丁酯(M-8c)的制备
以对氟苯胺和4-(3-羧基苯基)哌啶-1-羧酸叔丁酯为原料合成M-8c，合成方法参照中间体M-4a。白色固体3.16g，收率79.3％。HRMS-ESI(m/z):421.1898[M+Na]+；1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),7.84–7.73(m,3H),7.57(d,J＝8.1Hz,1H),7.50–7.36(m,3H),6.94(t,J＝7.2Hz,1H),4.11(d,J＝12.5Hz,1H),3.35(s,1H),2.79(t,J＝12.1Hz,3H),1.80(d,J＝11.0Hz,2H),1.62–1.52(m,2H),1.43(s,9H)。
步骤m：N-(4-氟苯基)-3-(哌啶-4-基)苯甲酰胺盐酸盐(M-9c)的制备
以M-8c为原料合成M-9c，合成方法参照中间体M-7。白色固体725.42mg，收率86.5％。无需纯化直接用于下一步反应。
中间体M-9d：3-哌啶-4-基-N-三氟甲基苯甲酰胺的制备
以对三氟甲基苯胺和4-(3-羧基苯基)哌啶-1-羧酸叔丁酯为原料合成M-9d，合成方法参照中间体M-9c。白色固体715.79mg，收率92.2％。HRMS-ESI(m/z):349.1536[M+H]+；1HNMR(400MHz,DMSO-d6)δ10.65(s,1H),8.04(d,J＝8.5Hz,2H),7.86(d,J＝10.9Hz,2H),7.74(d,J＝8.5Hz,2H),7.51(d,J＝7.6Hz,2H),5.59(s,1H),3.35(d,J＝12.2Hz,2H),2.94(dd,J＝27.8,15.1Hz,3H),1.95(d,J＝13.2Hz,2H),1.83(q,J＝13.3,12.8Hz,2H)。
中间体M-9e：N-4-氯苯基-3-哌啶-4-基苯甲酰胺的制备
以对氯苯胺和4-(3-羧基苯基)哌啶-1-羧酸叔丁酯为原料合成M-9e，合成方法参照中间体M-9c。白色固体662.66mg，收率94.6％。HRMS-ESI(m/z):315.1258[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),7.94–7.84(m,4H),7.52–7.40(m,4H),3.36(d,J＝12.3Hz,3H),3.04–2.94(m,3H),2.06–1.95(m,4H)。
中间体M-9f：N-3-氯苯基-3-哌啶-4-基苯甲酰胺的制备的制备
以3-氯苯胺和4-(3-羧基苯基)哌啶-1-羧酸叔丁酯为原料合成M-9f，合成方法参照中间体M-9c。白色固体668.27mg，收率95.4％，直接用于下一步反应。
中间体M-9g：3-氯-4-氟苯基-3-哌啶-4-基苯甲酰胺的制备
以3-氯-4-氟苯胺和4-(3-羧基苯基)哌啶-1-羧酸叔丁酯为原料合成M-9g，合成方法参照中间体M-9c。白色固体668.76mg，收率93.0％。HRMS-ESI(m/z):333.1164[M+H]+；1HNMR(400MHz,DMSO-d6)δ10.52(s,1H),8.10(dd,J＝6.9,2.6Hz,1H),7.87–7.79(m,2H),7.75(ddd,J＝9.1,4.3,2.6Hz,1H),7.54–7.41(m,3H),3.43(d,J＝13.2Hz,3H),3.10–2.92(m,3H),2.00(d,J＝11.2Hz,2H),1.88(qd,J＝13.0,4.0Hz,2H)。
中间体M-9h：N-(3-氟苯基)-3-哌啶-4-基苯甲酰胺的制备
以3-氟苯胺和4-(3-羧基苯基)哌啶-1-羧酸叔丁酯为原料合成M-9h，合成方法参照中间体M-9c。白色固体625.65mg，收率94.1％，直接用于下一步反应。
中间体M-9i：N-(3-氟苯基)-4-哌啶-4-基苯甲酰胺的制备
以3-氟苯胺和4-(4-羧基苯基)哌啶-1-羧酸叔丁酯为原料合成M-9i，合成方法参照中间体M-9b。白色固体604.37mg，收率90.9％。HRMS-ESI(m/z):299.1545[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),8.66(s,1H),7.94(d,J＝8.4Hz,2H),7.76(dt,J＝11.9,2.3Hz,1H),7.57(dd,J＝8.1,1.9Hz,1H),7.39(dd,J＝7.6,5.8Hz,3H),6.93(td,J＝8.5,2.6Hz,1H),3.08–2.92(m,3H),2.51(t,J＝1.9Hz,2H),1.97(d,J＝13.3Hz,2H),1.89–1.78(m,2H)。
中间体M-9j：N-(4-氯苯基)-4-哌啶-4-基苯甲酰胺的制备
以4-氯苯胺和4-(4-羧基苯基)哌啶-1-羧酸叔丁酯为原料合成M-9j，合成方法参照中间体M-9b。白色固体624.13mg，收率89.1％。HRMS-ESI(m/z):315.1249[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),7.95(d,J＝8.1Hz,2H),7.84(d,J＝8.9Hz,2H),7.40(dd,J＝8.4,5.4Hz,4H),3.00(dt,J＝34.3,10.9Hz,3H),1.99–1.85(m,4H),1.30–1.22(m,3H)。
中间体M-9k：N-(3-氯苯基)-4-哌啶-4-基苯甲酰胺的制备
以3-氯苯胺和4-(4-羧基苯基)哌啶-1-羧酸叔丁酯为原料合成M-9k，合成方法参照中间体M-9b。白色固体617.83mg，收率88.2％。HRMS-ESI(m/z):315.1267[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),7.98(t,J＝2.0Hz,1H),7.93(d,J＝8.3Hz,2H),7.72(dd,J＝8.3,2.1Hz,1H),7.42–7.35(m,3H),7.16(dd,J＝8.3,2.1Hz,1H),3.28(d,J＝12.9Hz,2H),2.89(td,J＝12.6,3.0Hz,3H),1.88(dd,J＝14.0,3.4Hz,2H),1.74(qd,J＝12.8,3.9Hz,2H),1.35–1.15(m,1H)。
中间体M-9l：N-(3-氯苯基)-4-哌嗪-1-基苯甲酰胺的制备
以3-氯苯胺和4-(4-羧基苯基)哌嗪-1-羧酸叔丁酯为原料合成M-9l，合成方法参照中间体M-9a。白色固体623.29mg，收率88.7％。HRMS-ESI(m/z):316.1210[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),8.00(d,J＝2.1Hz,1H),7.93(d,J＝8.7Hz,2H),7.73(dd,J＝8.2,2.0Hz,1H),7.36(t,J＝8.1Hz,1H),7.16–7.04(m,3H),3.48(t,J＝5.3Hz,4H),3.19(t,J＝5.1Hz,4H),1.27(dd,J＝19.6,12.8Hz,1H)。
中间体M-13a：N-(4-氟苯基)-1-(4-哌嗪-1-基)苯甲酰基氮杂环丁烷-3-甲酰胺的制备
步骤n：3-((4-氟苯基)氨基甲酰基)氮杂环丁烷-1-羧酸叔丁酯(M-10a)的制备
以对氟苯胺(2.22g，20mmol)和1-Boc-氮杂环丁烷-3-羧酸(4.02g，20mmol)为原料合成M-10a，合成方法参照中间体M-4a。淡黄色固体4.85g，收率82.4％。HRMS-ESI(m/z):317.1278[M+Na]+；1H NMR(400MHz,DMSO-d6)δ10.10(s,1H),7.71–7.59(m,2H),7.15(t,J＝8.9Hz,2H),4.02(dq,J＝19.2,10.9,9.1Hz,4H),3.47(ddd,J＝14.4,8.6,5.8Hz,1H),1.40(s,9H)。
步骤o：N-(4-氟苯基)氮杂环丁烷-3-甲酰胺(M-11a)的制备
以M-10a(3g，10.20mmol)为原料合成M-11a，合成方法参照中间体M-9a。白色固体1.85g，收率93.4％。HRMS-ESI(m/z):195.0934[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),7.68–7.64(m,2H),7.17(t,J＝8.9Hz,2H),4.25–3.93(m,5H),3.80(t,J＝8.3Hz,1H)。
步骤p：4-(4-(3-((4-氟苯基)氨基甲酰基)氮杂环丁烷-1-羰基)苯基)哌嗪-1-羧酸叔丁酯(M-12a)的制备
以化合物M-11a(2g，10.30mmol)与4-(4-羧基苯基)哌嗪-1-羧酸叔丁酯为原料(3.15g，10.30mmol)为原料合成M-12a，合成方法参照化合物M-9a。白色固体3.59g，收率72.4％。HRMS-ESI(m/z):483.2405[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),7.64(dd,J＝9.1,5.0Hz,2H),7.55(d,J＝8.8Hz,2H),7.16(t,J＝8.9Hz,2H),6.96(d,J＝8.9Hz,2H),4.46(d,J＝30.8Hz,2H),4.20(s,1H),3.62–3.55(m,1H),3.46(t,J＝5.1Hz,4H),3.36(s,1H),3.27–3.21(m,4H),1.43(s,9H)。
步骤q：N-(4-氟苯基)-1-(4-哌嗪-1-基)苯甲酰基氮杂环丁烷-3-甲酰胺(M-13a)的制备
以中间体M-12a(1g，2.07mmol)为原料合成M-13a，合成方法参照中间体M-9a。白色固体704.88mg，收率89.1％。HRMS-ESI(m/z):383.21[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),7.65(dd,J＝8.8,5.0Hz,2H),7.53(d,J＝8.5Hz,2H),7.15(t,J＝8.7Hz,2H),6.93(d,J＝8.5Hz,2H),4.45(d,J＝33.4Hz,2H),4.14(d,J＝33.3Hz,2H),3.43(s,1H),3.17(s,5H),2.80(d,J＝18.8Hz,3H),2.51(s,1H)。
中间体M-13b：N-(4-氟苯基)-1-(4-哌嗪-1-基)苯甲酰基哌啶-4-甲酰胺的制备
以对氟苯胺(2.22g，20mmol)和1-Boc-4-哌啶甲酸(4.58g，20mmol)为原料合成M-13b，合成方法参照中间体M-13a。白色固体750.95mg，收率93.4％。HRMS-ESI(m/z):411.2191[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),7.67(dd,J＝9.1,5.0Hz,2H),7.30(d,J＝8.7Hz,2H),7.13(t,J＝8.9Hz,2H),6.95(d,J＝8.8Hz,2H),4.04(d,J＝7.1Hz,1H),3.89(s,2H),3.19(t,J＝5.1Hz,4H),2.92(s,4H),2.67(t,J＝11.2Hz,1H),1.83(d,J＝14.0Hz,2H),1.59(qd,J＝12.3,4.2Hz,2H),1.18(t,J＝7.1Hz,2H)。
中间体M-17a：N1，N3-双(4-氟苯基)-5-(哌啶-4-基)间苯胺的制备
步骤r：5-溴-N1，N3-双(4-氟苯基)间苯胺(M-14a)的制备
将5-溴间苯二甲酸(2.77g，10.0mmol)溶于N，N-二甲基甲酰胺(30mL)中，向其中加入缩合剂HATU(4.18g，11mmol)，搅拌10min后，再加入2倍当量的对氟苯胺(1.11g，20.0mmol)，4倍当量的DIPEA(5.17g，40mmol)，加毕，N2保护，室温反应4h，TLC监测反应完全。反应液加入碎冰中，淡黄色固体析出，抽滤，滤饼用水洗多次，后于真空干燥箱35℃烘干得淡黄色粉末状固体M-14a(3.24g，75.4％)。HRMS-ESI(m/z):431.0325[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.58(s,2H),8.53(s,1H),8.35(d,J＝1.4Hz,2H),7.82(dd,J＝9.1,5.0Hz,4H),7.23(t,J＝8.9Hz,4H)。
步骤s：4-(3，5-双(4-氟苯基)氨基甲酰基)-3，6-二氢吡啶-1(2H)-羧酸叔丁酯(M-15a)的制备
向反应瓶中依次加入M-14a(3.00g，6.98mmol)，N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(3.24g，10.47mmol)，四(三苯基)膦钯(0.69g，0.6mmol)，碳酸钾(1.93g，13.96mmol)，再加入1,4-二氧六环/水(v/v＝5/1，60mL)混合溶剂，搅拌溶解。N2保护，升温至100℃，回流反应过夜。次日TLC监测反应完全。停止反应，待反应液冷却至室温，经硅藻土助滤抽滤得滤液，滤液减压浓缩后，用乙酸乙酯萃取(20mL×3)，饱和NaCl溶液洗涤，无水硫酸钠干燥，抽滤，滤液经减压浓缩，硅胶柱层析[洗脱剂：二氯甲烷/甲醇＝200/1(v/v)]纯化得黄色固体M-15a(2.12g，56.9％)。1H NMR(400MHz,DMSO-d6)δ10.54(d,J＝28.4Hz,2H),8.39(d,J＝32.9Hz,1H),8.18(s,1H),7.83(s,4H),7.65–7.54(m,1H),7.23(t,J＝8.7Hz,4H),6.41(s,1H),3.98(d,J＝86.6Hz,2H),3.59(d,J＝17.3Hz,2H),2.61(s,1H),2.04(d,J＝36.6Hz,1H),1.43(d,J＝19.2Hz,9H)。
步骤t：4-(3，5-双(4-氟苯基)氨基甲酰基)苯基)哌啶-1-羧酸叔丁酯(M-16a)的制备
将M-15a(2.00g，3.75mmol)溶于无水甲醇溶液(20mL)中，加入钯碳/氢氧化钯碳(m/m＝1/1，200mg)混合物，H2氛围下升温至50℃，反应48h，LC-MS监测反应完全。停止加热，待反应液冷却至室温，在硅藻土助滤下抽滤，滤液经减压浓缩得淡黄色固体M-16a(967.43mg，48.2％)。无需纯化直接用于下一步反应。1H NMR(400MHz,DMSO-d6)δ10.43(s,2H),8.38(s,1H),8.02(d,J＝1.6Hz,2H),7.80(dd,J＝9.1,5.0Hz,4H),7.22(t,J＝8.9Hz,4H),3.93(s,2H),2.90(t,J＝12.1Hz,2H),2.69(s,1H),1.86(d,J＝12.8Hz,2H),1.69–1.59(m,2H),1.43(s,9H)。
步骤u：N1，N3-双(4-氟苯基)-5-(哌啶-4-基)间苯胺(M-17a)的制备
以中间体M-16a(900mg，1.68mmol)为原料合成M-17a，合成方法参照中间体M-9a。白色固体644.83mg，收率88.2％。HRMS-ESI(m/z):436.1838[M+H]+。
中间体M-17b：N1，N3-双(3-氯苯基)-5-(哌啶-4-基)间苯胺的制备
以3-氯苯胺(2.54g，20.0mmol)与5-溴间苯二甲酸(2.77g，10.0mmol)为原料合成M-17b，合成方法参照中间体M-17a。白色固体678.85mg，收率91.4％。
实施例1：N-(4-氰基苯基)-5-(4-(4-乙基哌嗪-1-基)甲基苯基)脲基)戊酰胺(化合物1)
将中间体M-5a(150mg，0.69mmol)，中间体M-3(281.37mg，0.83mmol)，三乙胺(104.03mg，1.03mmol)，N,N-二甲基甲酰胺(4mL)依次加入反应瓶中，60℃反应8h，TLC监测反应完全。向反应液中加入水(4mL)稀释，用乙酸乙酯萃取(4mL×3)，合并有机相，有机相用水洗除去残留的N,N-二甲基甲酰胺溶液，再用饱和NaCl溶液洗涤，无水硫酸钠干燥，抽滤，滤液经减压浓缩，硅胶柱层析[洗脱剂：二氯甲烷/甲醇/氨水＝200/10/1(v/v)]纯化得淡黄色固体化合物1(252.47mg，79.2％)。HRMS-ESI(m/z):463.2817[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.39(s,1H),7.80(d,J＝8.9Hz,2H),7.75(d,J＝8.8Hz,2H),7.33(d,J＝8.5Hz,2H),7.11(d,J＝8.5Hz,2H),6.15(t,J＝5.7Hz,1H),3.34(s,2H),3.12(q,J＝6.5Hz,2H),2.40(t,J＝7.4Hz,4H),2.33(s,2H),2.31(s,2H),2.27(d,J＝7.2Hz,4H),1.64(dt,J＝14.8,7.3Hz,2H),1.48(dd,J＝8.9,6.0Hz,2H),0.97(t,J＝7.2Hz,3H)；13C NMR(101MHz,DMSO-d6)δ172.47,155.72,143.92,139.80,133.67,131.02,129.80,129.64,119.55,119.43,117.87,115.67,105.12,62.22,53.00,52.84,52.07,39.16,36.65,31.60,30.29,29.87,29.44,29.42,22.76,12.46。
实施例2：N-(3-氰基-4-氟苯基)-5-(4-(4-乙基哌嗪-1-基)甲基苯基)脲基)戊酰胺(化合物2)
以中间体M-5b和M-3为原料合成化合物2，合成方法参照化合物1。淡黄色固体259.99mg，收率78.5％。HRMS-ESI(m/z):481.1764[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.42(s,1H),8.13(dd,J＝5.9,2.7Hz,1H),7.85–7.80(m,1H),7.47(t,J＝9.1Hz,1H),7.32(d,J＝8.2Hz,2H),7.10(d,J＝8.2Hz,2H),6.17(t,J＝5.7Hz,1H),3.32(s,2H),3.10(q,J＝6.5Hz,2H),2.52–2.36(m,4H),2.33(d,J＝5.2Hz,2H),2.32–2.28(m,2H),2.26(t,J＝7.2Hz,4H),1.66–1.59(m,2H),1.50–1.43(m,2H),0.96(t,J＝7.1Hz,3H)。13C NMR(101MHz,Methanol-d4)δ172.97,160.18,157.67,156.91,138.94,130.49,129.86,126.33(d,J＝8.0Hz),123.50,118.58,116.41(d,J＝20.9Hz),113.29,100.53(d,J＝16.4Hz),61.92,51.88(d,J＝10.6Hz),38.91,35.93,29.38,27.57,22.42,10.35。
实施例3：5-(4-(4-乙基哌嗪-1-甲基)苯基脲基)-N-(4-三氟甲基苯基)戊酰胺(化合物3)
以中间体M-5c和M-3为原料合成化合物3，合成方法参照化合物1。淡黄色固体259.99mg，收率78.5％。HRMS-ESI(m/z):506.2764[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.42(s,1H),8.13(dd,J＝5.9,2.7Hz,1H),7.85–7.80(m,1H),7.47(t,J＝9.1Hz,1H),7.32(d,J＝8.2Hz,2H),7.10(d,J＝8.2Hz,2H),6.17(t,J＝5.7Hz,1H),3.32(s,2H),3.10(q,J＝6.5Hz,2H),2.52–2.36(m,4H),2.33(d,J＝5.2Hz,2H),2.32–2.28(m,2H),2.26(t,J＝7.2Hz,4H),1.66–1.59(m,2H),1.50–1.43(m,2H),0.96(t,J＝7.1Hz,3H)。13C NMR(101MHz,Methanol-d4)δ172.97,160.18,157.67,156.91,138.94,130.49,129.86,126.33(d,J＝8.0Hz),123.50,118.58,116.41(d,J＝20.9Hz),113.29,100.53(d,J＝16.4Hz),61.92,51.88(d,J＝10.6Hz),38.91,35.93,29.38,27.57,22.42,10.35。
实施例4：N-(4-(4-乙基哌嗪-1-基)甲基苯基)-6-(4-氟苯甲酰胺基)-3，4-二氢异喹啉-2(1H)-甲酰胺(化合物4)
以中间体M-7和M-3为原料合成化合物4，合成方法参照化合物1。白色固体127.09mg，收率66.7％。HRMS-ESI(m/z):516.2769[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.20(s,1H),8.53(s,1H),8.01(s,1H),7.58(d,J＝33.6Hz,2H),7.36(d,J＝21.0Hz,4H),7.12(s,4H),4.58(s,2H),3.68(t,J＝15.3Hz,2H),3.48(s,2H),3.14–2.94(m,2H),2.92–2.57(m,4H),2.48(s,2H),2.32–2.24(m,4H),0.94(t,3H)；13C NMR(101MHz,DMSO-d6)δ165.74,164.74,163.27,155.51,139.74,137.73,135.41,131.94,131.81,130.84,130.75,129.79,129.28,126.85,120.72,120.07,118.98,115.87,115.66,62.24,53.07,52.87,52.08,45.84,41.83,40.60,40.39,39.35,29.08,12.49。
实施例5：N-(4-(4-乙基哌嗪-1-基)甲基苯基)-4-(4-(4-氟苯基)氨基甲酰基)哌嗪-1-甲酰胺(化合物5)
以中间体M-9a和M-3为原料合成化合物5，合成方法参照化合物1。白色固体131.95mg，收率73.5％。HRMS-ESI(m/z):545.3035[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),8.62(s,1H),7.90(d,J＝8.7Hz,2H),7.79(dd,J＝9.0,5.0Hz,2H),7.42(d,J＝8.1Hz,2H),7.18(d,J＝9.0Hz,2H),7.15(d,J＝8.2Hz,2H),7.07(d,J＝8.6Hz,2H),3.62(t,J＝5.0Hz,4H),3.36(s,4H),3.23(t,J＝4.9Hz,1H),2.87(t,J＝4.9Hz,1H),2.33(s,4H),2.28(t,J＝7.2Hz,4H),1.23(d,J＝3.9Hz,2H),0.97(t,J＝7.1Hz,3H)。13C NMR(101MHz,DMSO-d6)δ165.37,159.68,157.30,153.99,155.52,153.37,139.65,136.36,131.99,129.52,129.33,124.19,122.50,122.43,119.94,115.61,115.39,114.61,114.19,113.84,62.22,53.05,52.86,52.08,48.28,47.46,45.64,43.85,40.61,39.36,12.48。
实施例6：N-(4-(4-乙基哌嗪-1-基)甲基苯基)-4-(4-(4-氟苯基)氨基甲酰基)哌啶-1-甲酰胺(化合物6)
以中间体M-9b和M-3为原料合成化合物6，合成方法参照化合物1。白色固体129.34mg，收率79.4％。HRMS-ESI(m/z):544.3108[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),8.53(s,1H),7.91(d,J＝7.8Hz,2H),7.80(dd,J＝8.8,5.0Hz,2H),7.43(d,J＝8.1Hz,4H),7.19(t,J＝8.6Hz,2H),7.14(d,J＝8.1Hz,2H),4.30(d,J＝12.9Hz,2H),3.37(s,4H),2.94–2.81(m,3H),2.51(s,2H),2.43–2.37(m,2H),2.29(t,J＝7.1Hz,4H),1.83(t,J＝12.7Hz,2H),1.61(q,J＝13.0,12.1Hz,2H),0.98(t,J＝7.1Hz,3H)；13C NMR(101MHz,DMSO-d6)δ165.77,157.49,155.36,150.10,139.96,133.25,131.71,129.27,128.32,127.25,122.52(d,J＝7.9Hz),119.89,115.70,115.48,62.25,55.37,52.95(d,J＝18.3Hz),52.08,44.78,42.30,40.63,39.38,33.17,12.47。
实施例7：N-(4-(4-乙基哌嗪-1-基)甲基苯基)-4-(3-(4-氟苯基)氨基甲酰基)哌啶-1-甲酰胺(化合物7)
以中间体M-9c和M-3为原料合成化合物7，合成方法参照化合物1。白色固体111.09mg，收率68.2％。HRMS-ESI(m/z):544.3031[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),8.54(s,1H),7.85(s,1H),7.81(d,J＝5.1Hz,1H),7.78(dd,J＝8.1,3.9Hz,2H),7.52–7.45(m,2H),7.43(d,J＝8.4Hz,2H),7.20(t,J＝8.9Hz,2H),7.14(d,J＝8.2Hz,2H),4.35–4.27(m,2H),3.44(s,4H),2.93–2.82(m,3H),2.51(t,J＝1.9Hz,4H),2.35(t,J＝7.2Hz,4H),1.85(dd,J＝13.2,3.3Hz,2H),1.69–1.59(m,2H),0.99(t,J＝7.1Hz,3H)；13CNMR(101MHz,DMSO-d6)δ165.92,155.36,146.60,140.00,135.94,135.29,131.55,130.60,129.32,129.01,126.36,126.11,122.81(d,J＝7.8Hz),119.92,115.73,115.51,62.13,52.73(d,J＝8.4Hz),52.00,44.82,42.33,40.50(d,J＝21.0Hz),39.46(d,J＝21.1Hz),33.30,12.26。
实施例8：4-(4-(三氟甲基苯基)氨基甲酰基)-N-(4-(4-乙基哌嗪-1-基)甲基苯基)哌啶-1-甲酰胺(化合物8)
以中间体M-9d和M-3为原料合成化合物8，合成方法参照化合物1。白色固体120.72mg，收率70.2％。HRMS-ESI(m/z):594.3050[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),8.56(s,1H),8.07(s,1H),8.05(s,1H),7.91(d,J＝1.8Hz,1H),7.86(d,J＝7.1Hz,1H),7.73(d,J＝8.6Hz,2H),7.51(d,J＝7.7Hz,1H),7.50–7.47(m,2H),7.46(s,1H),7.15(d,J＝8.4Hz,2H),4.41–4.29(m,2H),3.36(s,2H),2.95–2.82(m,3H),2.52(t,J＝1.9Hz,4H),2.35–2.32(m,2H),2.29(q,J＝7.2Hz,4H),1.87(dd,J＝13.2,3.6Hz,2H),1.67(qd,J＝12.7,3.9Hz,2H),0.96(t,J＝7.1Hz,3H)；13C NMR(101MHz,DMSO-d6)δ166.49,155.39,146.64,143.31,139.97,135.04,131.72,130.86,129.77,129.13(d,J＝23.3Hz),126.80–125.97(m),124.59,124.27,123.96,123.58(d,J＝12.7Hz),120.66,119.93,62.27,60.19,52.93(d,J＝17.6Hz),52.07,44.83,42.36,33.30,12.41。
实施例9：4-(3-(4-氯苯基)氨基甲酰基)-N-(4-(4-乙基哌嗪-1-基)甲基苯基)哌啶-1-甲酰胺(化合物9)
以中间体M-9e和M-3为原料合成化合物9，合成方法参照化合物1。白色固体136.66mg，收率76.4％。HRMS-ESI(m/z):560.2787[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.53(s,1H),7.86(s,1H),7.84(d,J＝2.1Hz,1H),7.82(d,J＝5.2Hz,2H),7.48(s,2H),7.46–7.41(m,3H),7.41(d,J＝2.2Hz,1H),7.14(d,J＝8.4Hz,2H),4.32(d,J＝13.8Hz,2H),3.36(s,2H),2.93–2.81(m,3H),2.36(d,J＝18.7Hz,4H),2.31(s,2H),2.28(t,J＝7.2Hz,4H),1.88–1.82(m,2H),1.65(qd,J＝12.7,4.0Hz,2H),0.96(t,J＝7.1Hz,3H)；13CNMR(101MHz,DMSO-d6)δ166.09,155.36,146.61,139.96,138.60,135.23,131.72,130.68,129.26,128.98(d,J＝5.2Hz),127.74,126.29(d,J＝25.5Hz),122.42,119.92,62.26,52.96(d,J＝18.3Hz),52.09,44.82,42.35,33.30,29.51,12.48。
实施例10：4-(3-(3-氯苯基)氨基甲酰基)-N-(4-(4-乙基哌嗪-1-基)甲基苯基)哌啶-1-甲酰胺(化合物10)
以中间体M-9f和M-3为原料合成化合物10，合成方法参照化合物1。白色固体135.77mg，收率75.9％。HRMS-ESI(m/z):560.2787[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.53(s,1H),7.98(t,J＝2.1Hz,1H),7.86(s,1H),7.82(d,J＝7.2Hz,1H),7.73(dd,J＝8.2,1.9Hz,1H),7.57–7.46(m,2H),7.45(d,J＝2.2Hz,1H),7.43(d,J＝2.0Hz,1H),7.39(t,J＝8.1Hz,1H),7.19–7.14(m,2H),7.13(s,1H),4.38–4.26(m,2H),3.40(s,2H),2.94–2.81(m,3H),2.50–2.33(m,4H),2.30(s,2H),2.27(t,J＝7.2Hz,4H),1.89–1.80(m,2H),1.65(qd,J＝12.6,3.9Hz,2H),0.96(t,J＝7.2Hz,3H)；13C NMR(101MHz,DMSO-d6)δ166.24,155.37,146.65,141.11,139.94,135.07,133.40,131.74,130.77(d,J＝7.9Hz),129.16(d,J＝21.8Hz),126.31(d,J＝22.0Hz),123.79,120.29,119.92,119.17,62.27,52.98(d,J＝19.7Hz),52.09,44.81,42.34,40.61,39.36,33.29,12.51。
实施例11：4-(3-氯-4-氟苯基)氨基甲酰基)-N-(4-(4-乙基哌嗪-1-基)甲基苯基)哌啶-1-甲酰胺(化合物11)
以中间体M-9g和M-3为原料合成化合物11，合成方法参照化合物1。白色固体120.82mg，收率69.8％。HRMS-ESI(m/z):578.2686[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),8.53(s,1H),8.07(dd,J＝7.0,2.6Hz,1H),7.85(s,1H),7.80(d,J＝7.4Hz,1H),7.75–7.70(m,1H),7.48(dd,J＝14.8,7.5Hz,3H),7.42(d,J＝8.3Hz,2H),7.13(d,J＝8.2Hz,2H),4.31(d,J＝13.0Hz,2H),3.38(s,2H),2.90(t,J＝12.8Hz,3H),2.50–2.33(m,4H),2.30(d,J＝7.1Hz,2H),2.26(d,J＝7.2Hz,4H),1.85(d,J＝12.0Hz,2H),1.64(qd,J＝12.6,3.9Hz,2H),0.97(t,J＝7.1Hz,3H)；13C NMR(101MHz,Methanol-d4)δ167.33,156.36,155.75,153.32,146.27,139.04,135.69,134.59,131.25,130.37,129.60,128.51,125.80,125.34,122.63,120.98–120.33(m),120.06(d,J＝18.7Hz),116.22,116.00,61.99,52.28–51.62(m),48.28,47.00,44.54,42.40,32.93,10.40。
实施例12：4-(3-(3-氟苯基)氨基甲酰基)-N-(4-(4-乙基哌嗪-1-基)甲基苯基)哌啶-1-甲酰胺(化合物12)
以中间体M-9h和M-3为原料合成化合物12，合成方法参照化合物1。白色固体134.96mg，收率73.1％。HRMS-ESI(m/z):544.3162[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),8.54(s,1H),7.86(s,1H),7.81(d,J＝10.4Hz,1H),7.76(s,1H),7.67–7.46(m,3H),7.46–7.37(m,3H),7.14(d,J＝7.1Hz,2H),6.94(s,1H),4.32(d,J＝13.2Hz,2H),3.50(s,2H),2.96–2.80(m,3H),2.51(s,2H),2.41–2.30(m,4H),2.30–2.14(m,4H),1.85(q,J＝12.7Hz,2H),1.66(dd,J＝25.3,11.2Hz,2H),0.96(t,J＝7.7Hz,3H)；13C NMR(101MHz,Methanol-d4)δ167.51,164.05,161.64,156.38,146.27,140.41(d,J＝10.9Hz),139.06,134.83,131.23,130.30,130.00–129.40(m),128.49,125.82,125.34,120.51,116.04(d,J＝3.0Hz),110.40(d,J＝21.4Hz),107.72,107.46,61.97,52.24–51.62(m),44.54,42.42,32.93,10.36。
实施例13：4-(4-(3-氟苯基)氨基甲酰基)-N-(4-(4-乙基哌嗪-1-基)甲基苯基)哌啶-1-甲酰胺(化合物13)
以中间体M-9i和M-3为原料合成化合物13，合成方法参照化合物1。白色固体151.20mg，收率81.9％。HRMS-ESI(m/z):544.3126[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.56(s,1H),7.91(d,J＝7.9Hz,2H),7.79(d,J＝11.9Hz,1H),7.58(d,J＝8.2Hz,1H),7.45(s,2H),7.43(s,2H),7.41–7.34(m,1H),7.14(d,J＝8.1Hz,2H),6.92(td,J＝8.5,2.6Hz,1H),4.31(d,J＝13.0Hz,2H),3.40(s,2H),2.89(t,J＝12.6Hz,3H),2.54–2.35(m,4H),2.34–2.30(m,2H),2.27(t,J＝7.2Hz,4H),1.83(dd,J＝13.3,3.6Hz,2H),1.61(qd,J＝12.5,3.9Hz,2H),0.96(t,J＝7.1Hz,3H)；13C NMR(101MHz,DMSO-d6)δ166.10(d,J＝8.8Hz),163.72,161.33,155.35,150.35,141.45,139.89(d,J＝9.5Hz),133.07,131.74,130.67(d,J＝9.4Hz),129.28,128.39,127.33,119.83(d,J＝10.6Hz),116.33,110.43(d,J＝20.7Hz),107.43,107.17,62.25,52.98(d,J＝19.7Hz),52.09,44.76,42.31,33.15,12.52。
实施例14：4-(4-(4-氯苯基)氨基甲酰基)-N-(4-(4-乙基哌嗪-1-基)甲基苯基)哌啶-1-甲酰胺(化合物14)
以中间体M-9j和M-3为原料合成化合物14，合成方法参照化合物1。白色固体144.18mg，收率80.6％。HRMS-ESI(m/z):560.2787[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.54(s,1H),7.90(d,J＝7.9Hz,2H),7.83(d,J＝8.5Hz,2H),7.44(d,J＝2.5Hz,2H),7.42(s,3H),7.40(s,1H),7.14(d,J＝8.1Hz,2H),4.30(d,J＝13.0Hz,2H),3.36(s,2H),2.93–2.81(m,3H),2.51–2.34(m,4H),2.31(s,2H),2.28(t,J＝7.2Hz,4H),1.86–1.79(m,2H),1.61(td,J＝12.4,8.6Hz,2H),0.97(t,J＝7.1Hz,3H)；13C NMR(101MHz,DMSO-d6)δ165.92(d,J＝8.4Hz),155.32(d,J＝6.6Hz),150.25,139.90(d,J＝9.2Hz),138.65(d,J＝10.2Hz),133.15,131.73,129.28,128.96,128.37,127.59,127.30,122.16(d,J＝9.6Hz),119.84(d,J＝10.6Hz),62.25,52.97(d,J＝19.4Hz),52.08,44.77,42.30,33.16,12.51。
实施例15：4-(4-(3-氯苯基)氨基甲酰基)-N-(4-(4-乙基哌嗪-1-基)甲基苯基)哌啶-1-甲酰胺(化合物15)
以中间体M-9k和M-3为原料合成化合物15，合成方法参照化合物1。白色固体140.24mg，收率78.4％。HRMS-ESI(m/z):560.4980[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.53(s,1H),7.99(s,1H),7.91(d,J＝7.9Hz,2H),7.72(d,J＝8.2Hz,1H),7.46(s,1H),7.44(s,2H),7.42–7.40(m,1H),7.37(d,J＝8.1Hz,1H),7.15(t,J＝8.3Hz,3H),4.30(d,J＝13.0Hz,2H),2.89(t,J＝12.7Hz,3H),2.51–2.35(m,4H),2.35–2.30(m,2H),2.28(t,J＝7.2Hz,4H),1.86–1.79(m,2H),1.62(tt,J＝12.3,6.2Hz,2H),0.97(t,J＝7.1Hz,3H)；13CNMR(101MHz,DMSO-d6)δ166.12,155.37,150.35,141.24,139.96,133.41,133.01,131.71,130.71,129.27,128.41,127.30,123.65,119.99(d,J＝18.3Hz),118.98,62.26,52.95(d,J＝18.0Hz),52.08,49.08,44.78,42.32,40.63,39.38,33.16,12.47。
实施例16：4-(4-(3-氯苯基)氨基甲酰基)-N-(4-(4-乙基哌嗪-1-基)甲基苯基)哌嗪-1-甲酰胺(化合物16)
以中间体M-9l和M-3为原料合成化合物16，合成方法参照化合物1。白色固体135.47mg，收率75.6％。HRMS-ESI(m/z):561.2656[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),8.63(s,1H),7.98(s,1H),7.90(d,J＝8.5Hz,2H),7.71(d,J＝7.5Hz,1H),7.41(d,J＝8.1Hz,2H),7.36(t,J＝8.1Hz,1H),7.13(t,J＝8.3Hz,3H),7.08(d,J＝8.6Hz,2H),3.61(t,J＝4.9Hz,4H),3.36(s,6H),2.48(d,J＝18.3Hz,4H),2.34–2.29(m,2H),2.27(t,J＝7.2Hz,4H),0.96(t,J＝7.1Hz,3H)；13C NMR(101MHz,DMSO-d6)δ170.77,165.62(d,J＝8.0Hz),155.49(d,J＝7.2Hz),153.50,141.56,139.67,133.34,131.93,130.63,129.67,129.33,123.82,123.24,119.92(dd,J＝9.9,5.6Hz),118.85(d,J＝9.7Hz),114.13,62.19,60.22,52.88(d,J＝15.9Hz),52.05,47.39,43.84,21.23,14.56,12.41。
实施例17：N-(4-(4-乙基哌嗪-1-基)甲基苯基)-4-(4-(3-(4-氟苯基)氨基甲酰基)氮杂环丁烷-1-羰基)苯基)哌嗪-1-甲酰胺(化合物17)
以中间体M-13a和M-3为原料合成化合物17，合成方法参照化合物1。白色固体119.33mg，收率73.2％。HRMS-ESI(m/z):628.3484[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),8.63(s,1H),7.65(dd,J＝8.7,5.0Hz,2H),7.56(d,J＝8.3Hz,2H),7.43(d,J＝8.1Hz,2H),7.16(t,J＝9.4Hz,4H),7.00(d,J＝8.5Hz,2H),4.47(d,J＝32.0Hz,2H),4.16(d,J＝35.9Hz,2H),3.59(q,J＝7.9,6.3Hz,5H),3.42(s,3H),3.35(s,3H),2.51(s,2H),2.40–2.30(m,4H),2.29–2.13(m,4H),0.96(t,J＝7.2Hz,3H)；13C NMR(101MHz,DMSO-d6)δ170.69(d,J＝8.8Hz),169.36,159.70,157.32,155.47(d,J＝7.2Hz),152.86,139.68(d,J＝9.5Hz),135.78(d,J＝10.4Hz),131.75,129.74,129.36,122.55,121.45(t,J＝8.7Hz),119.87(d,J＝10.5Hz),115.76(d,J＝22.2Hz),114.32,62.09,55.60(d,J＝44.6Hz),52.66,51.74(d,J＝47.6Hz),47.44,43.88,34.71–33.84(m),12.21.
实施例18：N-(4-(4-乙基哌嗪-1-基)甲基苯基)-4-(4-(4-(4-氟苯基)氨基甲酰基)哌啶-1-羰基)苯基)哌嗪-1-甲酰胺(化合物18)
以中间体M-13b和M-3为原料合成化合物18，合成方法参照化合物1。白色固体120.88mg，收率76.9％。HRMS-ESI(m/z):656.3712[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),8.63(s,1H),7.64(dd,J＝8.8,5.0Hz,2H),7.43(d,J＝8.1Hz,2H),7.32(d,J＝8.2Hz,2H),7.13(t,J＝8.5Hz,4H),7.01(d,J＝8.5Hz,2H),3.60(t,J＝4.9Hz,4H),3.39(d,J＝29.6Hz,4H),3.26(t,J＝5.0Hz,4H),2.96(s,2H),2.64–2.57(m,1H),2.37(d,J＝27.5Hz,4H),2.30(s,2H),2.27(t,J＝7.1Hz,4H),1.83(d,J＝12.5Hz,2H),1.65–1.55(m,2H),0.96(t,J＝7.1Hz,3H)；13C NMR(101MHz,Methanol-d4)δ173.97,171.49,160.44,158.04,156.41,152.38,138.88,134.68,131.33,129.62,128.40,125.49,121.72(d,J＝7.9Hz),120.49,114.86(d,J＝22.3Hz),61.86,53.44,51.85(d,J＝7.3Hz),48.27,46.99,46.34,43.58,43.25,28.95(d,J＝78.9Hz),10.20,8.19。
实施例19：N1，N3-双(4-氟苯基)-5-(4-(4-(4-乙基哌嗪-1-基)甲基苯基)氨基甲酰基哌啶-4-基)-间苯胺(化合物19)
以中间体M-17a和M-3为原料合成化合物19，合成方法参照化合物1。白色固体107.13mg，收率68.5％。HRMS-ESI(m/z):681.3330[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.48(s,2H),8.56(s,1H),8.42(s,1H),8.06(s,2H),7.82(dd,J＝8.9,5.0Hz,4H),7.44(d,J＝8.1Hz,2H),7.23(t,J＝8.7Hz,4H),7.14(d,J＝8.1Hz,2H),4.35(d,J＝12.9Hz,2H),3.36(s,2H),3.01–2.90(m,3H),2.63–2.48(m,2H),2.48–2.33(m,4H),2.30(q,J＝7.2Hz,4H),1.92(d,J＝12.4Hz,2H),1.73(tt,J＝12.7,6.4Hz,2H),0.97(t,J＝7.1Hz,3H)；13C NMR(101MHz,DMSO-d6)δ165.34(d,J＝8.7Hz),160.06,157.67,155.32(d,J＝6.9Hz),147.00,139.89(d,J＝9.3Hz),135.67(dd,J＝21.3,7.3Hz),131.73,129.39(d,J＝21.9Hz),125.66,122.80(t,J＝9.1Hz),119.91(d,J＝10.4Hz),115.80,115.58,62.23,52.92(d,J＝17.2Hz),52.06,46.17,44.78,42.35,40.61,39.36,33.19,12.43,11.13。
实施例20：N1，N3-双(3-氯苯基)-5-(4-(4-乙基哌嗪-1-基)甲基苯基)氨基甲酰基哌啶-4-基)-间苯胺(化合物20)
以中间体M-17b和M-3为原料合成化合物20，合成方法参照化合物1。白色固体89.41mg，收率59.8％。HRMS-ESI(m/z):713.2800[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.59(s,2H),8.57(s,1H),8.44(s,1H),8.08(s,2H),8.00(s,2H),7.77(d,J＝8.2Hz,2H),7.45–7.39(m,4H),7.19(d,J＝7.8Hz,2H),7.14(d,J＝8.1Hz,2H),4.36(d,J＝12.9Hz,2H),3.36(s,2H),2.94(t,J＝12.5Hz,3H),2.51(t,J＝2.6Hz,4H),2.34(s,2H),2.29(q,J＝7.2Hz,4H),1.92(d,J＝12.4Hz,2H),1.78–1.68(m,2H),0.96(t,J＝7.1Hz,3H)；13C NMR(101MHz,DMSO-d6)δ165.65,155.36,147.13,140.96,139.95,135.38,133.44,131.69,130.84,129.77,129.30,125.79,124.02,120.35,119.95,119.25,62.19,52.87(d,J＝14.3Hz),52.05,44.77,42.32,40.63,39.38,33.16,12.40。
对比例1：5-(3-(4-((4-乙基哌嗪-1-基)甲基)苯基)脲基)-N-苯基戊酰胺
合成方法如下：
(5-氧代-5-(苯基氨基)戊基)氨基甲酸叔丁酯的制备：
将苯胺(689mg，7.41mmol，1.0eq)溶于DMF(20mL)中，依次加入Boc-5-氨基戊酸(1930mg，8.89mmol，1.2eq)，EDCI(2122mg，11mmol，1.5eq)，HOBT(1490mg，11mmol，1.5eq)，室温搅拌18h。反应液经乙酸乙酯稀释，水洗，饱和氯化钠洗，无水硫酸钠干燥，浓缩得到1.8g，收率83％。
5-氨基-N-苯基戊酰胺盐酸盐的制备：
将(5-氧代-5-(苯基氨基)戊基)氨基甲酸叔丁酯(1g，3.42mmol)溶于盐酸-甲醇(10mL)溶液中，室温下搅拌3h，浓缩，得到650mg，收率83％。
5-(3-(4-((4-乙基哌嗪-1-基)甲基)苯基)脲基)-N-苯基戊酰胺的制备：
将5-氨基-N-苯基戊酰胺盐酸盐的制备(100mg，0.438mmol，1.0eq)溶于DMF(2cmL)中，依次加入三乙胺(132.9mg，1.316mmol，3.0eq)和苯基(4-((4-乙基哌嗪-1-基)甲基)苯基)氨基甲酸酯(178.2mg，0.525mmol，1.2eq)，室温反应18h，将反应液经乙酸乙酯稀释，水洗3次，饱和氯化钠洗涤1次，无水硫酸钠干燥，浓缩，柱纯化得白色固体23mg(5-(3-(4-((4-乙基哌嗪-1-基)甲基)苯基)脲基)-N-苯基戊酰胺)，收率12％。
ESI-MS m/z:438.3[M+H]+；1H NMR(400MHz,Chloroform-d)δ8.20(s,1H),7.53(d,J＝8.0Hz,2H),7.27-7.25(m,3H),7.18(t,J＝8.0Hz,3H),7.07(q,J＝8.0Hz,2H),5.42(s,1H),3.45(s,2H),3.24(d,J＝4.0Hz,2H),2.50-2.36(m,12H),1.71(t,J＝8.0Hz,2H),1.52(t,J＝8.0Hz,2H),1.09(t,J＝8.0Hz,3H).
对比例2：5-(3-(4-((4-乙基哌嗪-1-基)甲基)苯基)脲基)-N-(4-氟苯基)戊酰胺
合成方法参见对比例1的制备，区别在于，把苯胺替换成对氟苯胺。
ESI-MS m/z:456.3[M+H]+,1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),8.34(s,1H),7.61-7.58(m,2H),7.30(d,J＝8.0Hz,2H),7.13–7.09(m,4H),6.11(t,J＝4.0Hz,1H),3.34(s,2H),3.10(q,J＝6.0Hz,2H),2.51-2.21(m,12H),1.61(t,J＝8.0Hz,2H),1.45(t,J＝8.0Hz,2H),0.97(t,J＝8.0Hz,3H).
实施例21：化合物体外耦联活性的测定
1.肺动脉高压小鼠造模
实验用C57BL/6雄性小鼠50只，并对小鼠编号，适应性饲养7天后置于低氧舱中培养3周，通过压力调节阀控制维持压力平衡，舱内氧浓度氧浓度(10±0.2)％，温度(22～25)℃，湿度(60～70)％。
2.体外耦联活性评价
(1)细胞培养
从低氧应激的肺动脉高压模型小鼠中分离原代肺动脉血管内皮细胞，于细胞培养箱中培养3-5天。
(2)免疫荧光染色
1)接种：将细胞接种到共聚焦小皿中，于显微镜下观察，待贴壁后，用实施例1-20和对比例1-2以10μMol/L的浓度进行预处理；
2)孵育：处理后继续置于5％CO2，37℃细胞培养箱中培养24h；
3)固定：弃去旧培养基，PBS缓冲液洗两次，加4％多聚甲醛室温固定；
4)通透：PBS缓冲液洗两次，0.1％triton X-100(in PBS)每孔加500μL，室温15min；
5)封闭：PBS缓冲液洗两次，5mg/mL牛血清蛋白(in PBS)每孔加500μL，室温1h；
6)孵育荧光一抗和二抗：将细胞用TRPV4-550和KCa2.3作为一抗和耦联的二抗进行孵育；
7)Fret图像采集：4',6-二脒基-2-苯基吲哚(4',6-diamidino-2-phenylindole，DAPI)染色10min，激光共聚焦显微镜采集荧光照片，并计算Fret效率值。
表1化合物体外耦联活性数据
表1为各实施例化合物免疫Fret的效率测定值，该值越高表明TRPV4与KCa2.3的耦联程度越高。其中，JNC-440为对照组，PAH指未经实施例处理的肺动脉高压模型小鼠，WT指正常的野生型小鼠，M表示平均值，a表示三次重复的数据标准差。
体外耦联活性测定试验证明，在低氧应激下，肺动脉高压模型小鼠的肺动脉内皮细胞中TRPV4与KCa2.3的耦联下降，但在给药后，耦联程度总体提高。化合物10、12、14、15、16和20与PAH组比较，其Fret效率值几乎提高了2倍。其中，化合物14、化合物15和化合物16均优于对比例1和对比例2，表明实施例可以促进肺动脉高压模型小鼠肺动脉内皮细胞中的TRPV4-KCa2.3蛋白复合体的耦联。
实施例22：亚细胞共定位分析
以化合物14为代表性化合物，以10μMol/L的浓度对肺动脉高压模型小鼠肺动脉内皮细胞孵育24h，使用抗TRPV4抗体和抗KCa2.3抗体进行双重免疫标记，采集双重免疫荧光染色共聚焦图像，进行亚细胞共定位分析。绿色为荧光二抗标记的KCa2.3蛋白，红色为荧光二抗标记的TRPV4蛋白，DAPI染色定位细胞核位置，Merged为叠加图像，Fret用于标记细胞膜得出效率值。
图1 TRPV4-KCa2.3在肺动脉高压模型小鼠原代肺动脉内皮细胞中的亚细胞共定位
TRPV4与KCa2.3在耦联情况下，绿色荧光与红色荧光荧光重合Merged得到黄色荧光，黄色荧光强弱可以直观表示TRPV4蛋白与KCa2.3蛋白的耦联程度。分析上述结果可知：空白对照组的Merged图几乎无黄色荧光，表明TRPV4与KCa2.3耦联程度较弱；经化合物14给药后其TRPV4与KCa2.3的Merged黄色荧光强度明显大于空白对照组，表明TRPV4与KCa2.3的耦联作用得到增强，且高于阳性化合物JNC-440，与Fret效率值测定结果一致。
实施例21-22表明本发明化合物在肺动脉高压模型小鼠的肺动脉内皮细胞中对TRPV4与KCa2.3具有体外耦联活性，并且明显高于已有化合物JNC-440，化合物14、15和16具有进一步开发为肺动脉高压调节剂的潜力。
由化合物1-20的体外耦联活性数据及亚细胞共定位图可知，对于通式(I)类的化合物而言，连接基团和取代基团对于化合物的体外耦联活性有着重要的影响。
尽管本发明通过之前的特定实施例说明，但不应将其解释为受此限制；而是本发明涵盖之前公开的一般方面，可在不背离本发明的精神和范围下进行多种修饰并具有多种实施方案。
Claims (10)
1.通式(I)所示结构的化合物或其药学上可接受的盐：
其中：
X，Y独立选自NH、O、CO或CH2；
R1选自氢、C1-C4烷基、苯基，其中所述烷基、苯基可任选地被下述相同或不相同的取代基单取代至五取代，所述的取代基选自:卤素、三氟甲基、氰基、硝基、羟基或C1-C4烷基；
R2选自
C1-C4烷基或空；
R3选自
取代基取代或未取代的苯基，其中苯基可任选地被下述相同或不相同的取代基单取代至五取代：卤素、三氟甲基、氰基、硝基、羟基或C1-C4烷基；
R4选自-CH-、-C2H3-、-C3H5-或-C4H7-；Z选自CH、N；
R5选自氢、C1-C4烷基、-CONHR6、取代基取代或未取代的苯基，其中所述烷基、苯基可任选地被下述相同或不相同的取代基单取代至五取代，所述的取代基选自：卤素、三氟甲基、氰基、硝基、羟基或C1-C4烷基；R6选自氢、C1-C4烷基、苯基，其中烷基、苯基可任选地被下述相同或不相同的取代基单取代至五取代：卤素、三氟甲基、氰基、硝基、羟基或C1-C4烷基。
2.如权利要求1所述的化合物或其药学上可接受的盐，其特征在于，R2为空时，相应的结构式为：
3.如权利要求1所述的化合物或其药学上可接受的盐，其特征在于，化合物的结构如下所示：
其中，R’、R”分别独立地选自：卤素(F、Cl、Br)，硝基、氰基、三氟甲基、C1-4烷基。
4.权利要求1-3任一项所述的化合物或其药学上可接受的盐，其特征在于，其药学上可接受的盐为无机盐或有机盐；无机盐包括盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、酸式磷酸盐；有机盐选自乙酸盐、三氟乙酸盐、丙酸盐、丙酮酸盐、羟乙酸盐、乙二酸盐、丙二酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、以磺酸盐、苯磺酸盐、水杨酸盐。
5.权利要求1-3任一项所述的化合物或其药学上可接受的盐在制备TRPV4-KCa2.3促耦联剂中的用途。
6.一种包含权利要求1-3任一项所述的化合物或其药学上可接受的盐的药物组合物。
7.根据权利要求6所述的药物组合物，其特征在于，包括药物可接受载体、赋形剂或稀释剂。
8.权利要求1-3任一项所述的化合物或其药学上可接受的盐在制备用于治疗人类TRPV4-KCa2.3耦联作用异常所介导的恶性肺部疾病，心血管疾病的药物中的用途。
9.根据权利要求8所述的用途，其特征在于，恶性肺部疾病包括：肺动脉栓塞、急性肺血栓栓塞症、肺血管炎、肺血管肿瘤、肺水肿、急性肺损伤；,心血管疾病包括：高血压、高血脂、高血压心脏病、肺源性心脏病、瓣膜性心脏病、先天性心脏病、冠心病、心肌病、心力衰竭、动脉粥样硬化、糖尿病、慢性肾脏病、静脉血栓栓塞症、代谢综合征、心律失常、主动脉疾病、外周动脉疾病、脑卒中。
10.根据权利要求8所述的用途，其特征在于，心血管疾病为肺动脉高压，具体包括：遗传性肺动脉高压、药物和毒素诱导肺动脉高压、特发性肺动脉高压、门静脉高压相关性肺动脉高压、结缔组织病相关性肺动脉高压、慢性血栓栓塞性肺动脉高压、新生儿持续性肺动脉高压、孤立的毛细血管后肺动脉高压、慢性阻塞性肺病所致肺动脉高压、先天性心脏病所致肺动脉高压。
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| CN101291917A (zh) * | 2003-11-28 | 2008-10-22 | 诺瓦提斯公司 | 治疗蛋白激酶依赖性疾病的二芳基脲衍生物 |
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| US11161852B1 (en) * | 2020-05-08 | 2021-11-02 | Halia Therapeutics, Inc. | Inhibitors of NEK7 kinase |
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