CN114507181B - 含5-取代四氢异喹啉的丙酸类化合物、其药物组合物和应用 - Google Patents
含5-取代四氢异喹啉的丙酸类化合物、其药物组合物和应用 Download PDFInfo
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- CN114507181B CN114507181B CN202011286007.6A CN202011286007A CN114507181B CN 114507181 B CN114507181 B CN 114507181B CN 202011286007 A CN202011286007 A CN 202011286007A CN 114507181 B CN114507181 B CN 114507181B
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- tetrahydroisoquinolin
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Abstract
本发明属于药物化学领域,具体公开了一类如通式(I)所示的含四氢异喹啉的丙酸类化合物及其药学上可接受盐、其制备方法、药物组合物,及其在制备治疗与Keap1‑Nrf2靶点功能相关疾病的药物中的应用,在制备氧化应激状态下提高抗氧化能力的药物中的应用,在制备治疗或缓解疾病的炎症的药物中的应用。
Description
技术领域
本发明属于药物化学领域,具体涉及一类含5-取代四氢异喹啉的丙酸类化合物,其制备方法及它们的药物组合物作为Nrf2调节剂的用途。
背景技术
氧化应激(OS)是指体内氧化与抗氧化平衡失衡,导致倾向氧化并产生活性氧(ROS)的过程。活性氧被认为会直接或者间接的导致细胞内蛋白质、核酸等生物大分子的损伤,失去其本身的生理功能,被认为是众多疾病发生的生理基础。机体为了控制活性氧的生成,形成了一套抗氧化防御系统,其中Nrf2(NF-E2相关因子)是含有特征性碱性-亮氨酸拉链的转录因子,由Yamamoto等人首次发现。Nrf2作为转录因子,可以与DNA的抗氧化反应元件(ARE)结合并激活下游一系列细胞保护蛋白的转录翻译过程,从而保护细胞遭受损伤。
除了启动氧化还原酶的表达,Nrf2通路还参与对细胞炎症反应和能量代谢的调控。Nrf2即可通过与NF-κB竞争性结合CBP/p300转录共激活因子而间接抑制炎症反应,也可通过结合到诸如IL-6和IL-1β编码基因的启动子区域而直接抑制炎症因子的表达。而对于能量代谢的调控,Nrf2主要通过调控相关代谢酶的表达来实现,其中包括葡萄糖-6-磷酸-1-脱氢酶(G6PD),6-磷酸葡萄糖脱氢酶(GPD),UDP葡萄糖脱氢酶(UGDH),乙酰辅酶A硫酯酶7(ACOT7),乙酰辅酶A氧化酶1(ACO1),硬脂酰基-辅酶A去饱和酶2(SCD2)。Nrf2通路活化可促进葡糖糖代谢向磷酸戊糖途径进行,并增强脂肪酸β氧化代谢。
许多慢性病,尤其是衰老相关的慢性病(譬如阿尔兹海默病,慢性阻塞性肺病,风湿性关节炎等),具有十分相似的病理因素,即受累器官或组织内存在长期的、低水平的氧化应激和炎症反应。而慢性代谢性疾病(如糖尿病及其并发症和血管粥样硬化等)通常还伴有长期的糖脂代谢异常。已有学者提出,靶向这些共同的疾病驱动因素有望成为治疗诸多慢性病的一种通用策略。鉴于Nrf2对细胞的氧化还原稳态、炎症反应和能量代谢的均具有调控作用,Nrf2有望成为治疗慢性病的潜在通用靶点。与此观点相符的是,在利用系统性或者器官特异性Keap1敲除的转基因小鼠(组成性Nrf2通路活化背景)研究时,已有学者发现该遗传背景小鼠对于II型糖尿病、慢性阻塞性肺炎、非酒精性脂肪肝、急性肝损伤、化学诱导脱髓鞘病、辐射诱导骨髓抑制和败血症等多系统、多种类的急慢性疾病均具有不同程度抵抗作用。以Nrf2为靶点的新药研发工作已在全球范围内开展。
针对该靶点的研究最初的策略是通过模仿亲电试剂与半胱氨酸的共价作用从而抑制Keap1对Nrf2的泛素化作用。针对该策略已经有成功上市的药物富马酸二甲酯(Tecfidera)用于治疗多发性硬化症(MS),还有经过修饰的齐墩果酸类似物甲基巴多索隆也在处于临床研究中。
由于共价作用不可逆并且缺乏选择性,所以现在的研究热门是设计小分子与Keap1高亲和力的结合,从而阻止Keap1和Nrf2的相互作用,这种分子被称为Keap1-Nrf2蛋白-蛋白相互作用抑制剂。虽然PPI抑制剂的设计存在困难,但是其靶向明确且与靶标发生可逆相互作用,所以这种策略在近些年成为该靶点的研究热点。通过高通量筛选及虚拟筛选等方式首先发现了具有微摩尔水平抑制活性的先导化合物,之后包括Biogen、武田等公司及研究机构发现了结构不同的高效Keap1-Nrf2 PPI并在分子水平、细胞动物模型上展现出很好的作用。文献见Kitazaki Tomoyuki等人,WO2018181345;Bin Ma等人,生物有机及药物化学快报(Bioorganic&Medicinal Chemistry Letters),30,126852。但是所有上述文献报道的Keap1-Nrf2衍生物均不同于本发明中所涉及的化合物。
因此,在此基础上继续发现具有优良抑制活性的新结构类型的Keap1-Nrf2 PPI抑制剂,将为Keap-Nrf2 PPI的发展起到启示作用。另外,随着我国人口老龄化日渐加剧,衰老已成为诸多慢性病的首要致病因素。对老龄人口的慢性病管理已对我国医疗资源和医药体系带来严重挑战。如何促进人口健康衰老已成为我国亟待解决的课题。本发明所阐述的Keap-Nrf2 PPI抑制剂将进一步拓展我国在以Nrf2为靶点的针对老年慢性病的新药研发领域的尝试,具有重要的社会价值。
发明内容
本发明解决的技术问题是提供一类含四氢异喹啉的丙酸类化合物及其药学上可接受盐、其制备方法、药物组合物以及其在制备治疗与Keap1-Nrf2靶点功能相关疾病的药物中的应用。
为解决本发明的技术问题,本发明提供如下技术方案:
本发明涉及的化合物是如通式(Ⅰ)所示的化合物、其消旋体或立体异构体及药学上可接受的盐:
其中,
R1选自氢、C1-8直链或者支链烷基、C3-8环烷基;
R2选自氢、氧或者甲基,其为氧时即为羰基;
A为:
苯基,其可被一个、两个或三个独立选自以下的基团取代:氟、氯、溴、硝基、氰基、三氟甲基、三氟甲氧基、二氟甲氧基、甲基、乙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙氧基、甲酰基、乙酰基、丙酰基、异丙酰基、环丙酰基、甲酰胺基、乙酰胺基、丙酰胺基、异丙酰胺基、环丙酰胺基、正丁酰胺基、异丁酰胺基、叔丁酰胺基、氨基乙酰基、氨基丙酰基;
无取代、单取代或多取代的五元或六元芳基、无取代、单取代或多取代的五元或六元芳杂环、无取代、单取代或多取代的五元或六元芳基和/或芳杂环和/或杂环的并环,并且杂环、芳杂环可以含有1-4个杂原子,所含杂原子可以相同或不同,所述的杂原子选自N、S、O;
苯并三氮唑,其可被一个、两个、三个独立选自以下的基团取代:氢、甲基、乙基、丙基、异丙基、环丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙氧基、氟、氯、溴;
–(CH2)m-三唑基,其可被选自以下的基团取代:C1-3烷基;m选自1、2、3、4;
X选自亚甲基、酰基、磺酰基;
Y选自单键、直链或者支链的C1-6烷基或者环烷基,当Y为单键表示X与Z直接相连;
Z选自直链或支链的C1-8烷基、C3-8环烷基、C3-8杂环、单取代或多取代的五元或六元芳基、单取代或多取代的五元或六元芳杂环、单取代或多取代的五元或六元芳基和/或芳杂环和/或杂环的并环,并且杂环可以含有1-5个杂原子,所含杂原子可以相同或不同,所述的杂原子选自N、S、O;
进一步的,Z中所述取代基可被选自以下的基团取代:氢、C1-8直链或者支链烷基、C3-8环烷基、C1-8烷氧基、氟、氯、溴、碘、硝基、氰基、三氟甲基、三氟甲氧基、二氟甲氧基、甲酰胺基、乙酰胺基、丙酰胺基、异丙酰胺基、环丙酰胺基、正丁酰胺基、异丁酰胺基、叔丁酰胺基、氨基乙酰基、氨基丙酰基、氨基异丙酰基、氨基环丙酰基、氨基正丁酰胺基、氨基异丁酰胺基、氨基叔丁酰胺基、叔丁氧羰基。
所述烷基选自C1-8直链或者支链烷基或C3-8环烷基。
或其药学上可接受的盐。
“烷基”是指具有指定碳原子数的单价的饱和的烃链。例如,C1-4烷基是指具有1至4个碳原子的烷基。烷基可以为直链或者支链。代表性支链烷基具有一个、两个或三个支链。烷基包括但不限于甲基、乙基、丙基(正丙基和异丙基)和丁基(正丁基、异丁基、仲丁基和叔丁基)
“环烷基”是指具有指定碳原子数的单价饱和或不饱和烃环。例如,C3-6环烷基是指具有3至6个碳原子的环烷基基团。不饱和环烷基在所述环内具有一个或多个碳-碳双键。环烷基不是芳族的。环烷基包括但不限于环丙基、环丙烯基、环丁基、环丁烯基、环戊环戊烯基、环己基和环己烯基。
术语“独立的”是指当多余一个取代基选自多个可能取代基时,这些取代基可相同或不同。换言之,每个取代基分别选自整个所属可能取代基组。
手性中心也可存在于取代基例如烷基中。当存在于式(I)中或存在于本申请所属的任意化学结构中的手性中心的立体化学未具体说明时,该结构意在涵盖任意立体异构体及其所有混合物。因此,含有一个或多个手性中心的式(I)化合物可作为外消旋混合物、富含对映异构体的混合物或作为对映异构纯的单个立体异构体使用。
技术人员理解的是,可以制备式(I)化合物的药学上可接受的盐。这些药学上可接受的盐可在所述化合物的最终分离和纯化过程中原位制备或分别用适当的碱或酸单独处理游离酸或游离碱形式的经纯化的化合物。
在一些实施方案中,式(I)化合物可含有酸性官能团并因此能够通过用适当的碱处理形成药学上可接受的碱加成盐。适当的碱包括药学上可接受的无机酸和有机酸。代表性的药学上可接受的酸包括a)钠、钾、锂、钙、镁、铝和锌的氢氧化物、碳酸盐和碳酸氢盐;b)伯胺、仲胺和叔胺,包括脂肪族胺、芳族胺、脂肪族二胺和羟基烷基胺如甲胺、乙胺、2-羟基乙胺、二乙胺、三乙胺、乙二胺、乙醇胺、二乙醇胺和环己基胺等。
在一些实施方案中,式(I)化合物可含有碱性官能团并因此能够通过用适当的酸处理形成药学上可接受的酸加成盐。适当的酸包括药学上可接受的无机酸和有机酸。代表性的药学上可接受的酸包括盐酸、氢溴酸、硝酸、硫酸、磺酸、磷酸、乙酸、羟基乙酸、苯基乙酸、丙酸、丁酸、戊酸、马来酸、丙烯酸、富马酸、琥珀酸、苹果酸、丙二酸、酒石酸、枸橼酸、水杨酸、苯甲酸、鞣酸、甲酸、硬脂酸、乳酸、抗坏血酸、甲基磺酸、对甲苯磺酸、油酸、月桂酸等。
作为本发明的优选方案,通式(Ⅰ)的化合物具体是如下的化合物:
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本发明还公开了通式(Ⅰ)化合物的制备方法,其合成路线如下:
其中,A、X、Y、Z、R1的定义同前。
路线(1)
试剂与条件:(a)三乙胺,二氯甲烷,常温;(b)丙烯酸酯,N,N-二异丙基乙胺,三(邻甲基苯基)磷,醋酸钯,N,N-二甲基甲酰胺,95℃;(c)芳基硼酸或芳基硼酸酯,氢氧化钾,(1,5-环辛二烯)氯铑(I)二聚体,1,4-二氧六环,95℃;(d)氢氧化锂,四氢呋喃/水。
路线(2)
试剂与条件:(1)丙烯酸乙酯,N,N-二异丙基乙胺,三(邻甲基苯基)磷,醋酸钯,N,N-二甲基甲酰胺,95℃;(2)芳基硼酸酯,三乙胺,(1,5-环辛二烯)氯铑(I)二聚体,1,4-二氧六环,95℃;(3)三氟乙酸,二氯甲烷;(4)HATU,N,N-二异丙基乙胺,四氢呋喃,常温;(5)氢氧化锂,四氢呋喃/水。
路线(3)
试剂与条件:(1)丙烯酸乙酯,N,N-二异丙基乙胺,三(邻甲基苯基)磷,醋酸钯,N,N-二甲基甲酰胺,95℃;(2)芳基硼酸酯,三乙胺,(1,5-环辛二烯)氯铑(I)二聚体,1,4-二氧六环,95℃;(3)三氟乙酸,二氯甲烷;(4)HATU,N,N-二异丙基乙胺,四氢呋喃,常温;(5)氢氧化锂,四氢呋喃/水。
本发明技术方案的另一方面是提供药物组合物,所述药物组合物中除包含通式(Ⅰ)所示的化合物或其药学上可接受的盐
本发明技术方案的另一方面是提供如通式(Ⅰ)所示的化合物在制备Keap1-Nrf2蛋白-蛋白相互作用抑制剂的用途。
本发明技术方案的另一方面是提供如通式(Ⅰ)所示的化合物在制备氧化应激状态下提高抗氧化能力的药物的用途。
进一步的,所述疾病为炎性疾病或神经退行性疾病,包括慢性阻塞性肺病、阿尔兹海默症、帕金森症、肺动脉高压、动脉粥样硬化、慢性肾脏疾病、类风湿性关节炎等。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚,下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。另外,为了更好的说明本发明,在下文的具体实施方式中给出了众多的具体细节。本领域技术人员应当理解,没有某些具体细节,本发明同样可以实施。在一些实施例中,对于本领域技术人员熟知的原料、元件、方法、手段等未作详细描述,以便于凸显本发明的主旨。
核磁共振仪为Varian-600型、Bruker-500型、Varian Inova-500型、Bruker-400型、Mercury-400型和Mercury-300型。
质谱仪为Thermo Exactive Orbitrap plus spectrometer(ESI-MS)。
熔点仪为Yanaco MP-J3显微熔点仪。
快速制备色谱为Biotage Isolera One。
旋转蒸发仪为EYELA。
薄层层析硅胶板为HSGF254型硅胶板,安徽良辰硅源材料有限公司。柱层析硅胶为GF254型硅胶(300-400目),青岛海洋化工厂。
氘代试剂为北京伊诺凯试剂有限公司。
实验所用溶剂及试剂均为市售,纯度为化学纯或分析纯,未经纯化直接使用。
实施例1
3-(2-苄基-1,2,3,4-四氢异喹啉-5-基)-3-苯丙酸
(1)2-苄基-5-溴-1,2,3,4-四氢异喹啉
将5-溴四氢异喹啉(2000mg,9.5mmol)和三乙胺(2878mg,28.4mmol)溶于无水DCM(20mL)中,在0℃下滴加溴苄(2432mg,14.2mmol)的DCM溶液(20mL),反应液在常温氩气保护下反应3h。加入水(20mL)淬灭反应,用二氯甲烷(20mL)萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得无色油2.7g,收率94.2%。
1H NMR(400MHz,Chloroform-d)δ7.43–7.26(m,6H),6.97(dt,J=7.6,14.6Hz,2H),3.69(s,2H),3.62(s,2H),2.87(t,J=6.0Hz,2H),2.78(t,J=5.7Hz,2H).
(2)(E)-3-(2-苄基-1,2,3,4-四氢异喹啉-5-基)丙烯酸乙酯
将2-苄基5-溴-1,2,3,4-四氢异喹啉(2700mg,9.0mmol)溶于无水DMF(10mL)中,再加入丙烯酸乙酯(4490mg,44.9mmol)、DIPEA(2899mg,22.4mmol)和三邻甲苯基膦(545mg,1.8mmol),然后加入Pd(OAc)2(202mg,0.9mmol)。将反应液混合物在氩气保护下95℃反应10h。将反应液用水(20mL)稀释并用二氯甲烷(20mL)萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得淡黄色固体2.2g,收率76.3%
1H NMR(400MHz,Chloroform-d)δ7.91(d,J=15.9Hz,1H),7.42–7.36(m,3H),7.36–7.30(m,2H),7.30–7.25(m,1H),7.13(t,J=7.7Hz,1H),7.01(d,J=7.4Hz,1H),6.33(d,J=15.8Hz,1H),4.25(q,J=7.1Hz,2H),3.69(s,2H),3.64(s,2H),2.98(t,J=5.8Hz,2H),2.80(t,J=5.7Hz,2H),1.32(t,J=7.1Hz,3H).
(3)3-(2-苄基-1,2,3,4-四氢异喹啉-5-基)3-苯丙酸乙酯
将(E)-3-(2-苄基-1,2,3,4-四氢异喹啉-5-基)丙烯酸乙酯(300mg,1.0mmol)、苯硼酸(353mg,2.9mmol)、氢氧化钾(81mg,1.4mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(24mg,0.05mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得淡黄色油状物200mg,收率51.9%。
1H NMR(400MHz,Chloroform-d)δ7.39–7.26(m,5H),7.26–7.20(m,2H),7.19–7.10(m,5H),6.91–6.86(m,1H),4.68(t,J=7.9Hz,1H),4.03(q,J=7.2Hz,2H),3.65(s,4H),3.08–2.57(m,6H),1.12(t,J=7.1Hz,3H).
(4)标题化合物的制备
将3-(2-苄基-1,2,3,4-四氢异喹啉-5-基)3-苯丙酸乙酯(200mg,0.5mmol)溶于乙醇中,加入1N氢氧化钾溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体135mg,收率72.7%。
1H NMR(400MHz,DMSO-d6)δ7.63–7.36(m,6H),7.32–7.22(m,5H),7.21–7.14(m,1H),7.06(t,J=7.1Hz,1H),4.56(q,J=6.0,6.7Hz,1H),4.46–4.22(m,4H),3.74–3.58(m,1H),3.21–2.72(m,4H).
实施例2
3-(2-苄基-1,2,3,4-四氢异喹啉-5-基)-3-(4-甲氧基苯基)苯丙酸
(1)3-(2-苄基-1,2,3,4-四氢异喹啉-5-基)-3-(4-甲氧基苯基)苯丙酸乙酯
将(E)-3-(2-苄基-1,2,3,4-四氢异喹啉-5-基)丙烯酸乙酯(300mg,1.0mmol)、4-甲氧基苯硼酸(440mg,2.9mmol)、氢氧化钾(81mg,1.4mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(24mg,0.05mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得淡黄色油状物250mg,收率58.2%。
1H NMR(400MHz,Chloroform-d)δ7.40–7.25(m,5H),7.14(s,2H),7.06(d,J=8.7Hz,2H),6.87(d,J=6.7Hz,1H),6.76(d,J=8.7Hz,2H),4.66–4.56(m,1H),4.08–3.96(m,2H),3.74(s,7H),3.02–2.55(m,6H),1.12(t,J=7.1Hz,3H).
(2)标题化合物的的制备
将3-(2-苄基-1,2,3,4-四氢异喹啉-5-基)-3-(4-甲氧基苯基)苯丙酸乙酯(250mg,0.5mmol)溶于乙醇中,加入1N氢氧化钾溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体215mg,收率92.4%
1H NMR(400MHz,DMSO-d6)δ12.22(s,1H),7.63(d,J=21.0Hz,2H),7.45(s,3H),7.39–7.20(m,2H),7.15(d,J=8.4Hz,2H),7.02(t,J=8.4Hz,1H),6.91–6.76(m,2H),4.52(dd,J=7.0,13.6Hz,1H),4.47–4.15(m,4H),3.69(d,J=6.1Hz,3H),3.29(d,J=13.2Hz,2H),3.22–2.82(m,4H).
实施例3
3-(2-苄基-1,2,3,4-四氢异喹啉-5-基)-3-(4-硝基苯基)苯丙酸
(1)3-(2-苄基-1,2,3,4-四氢异喹啉-5-基)-3-(4-硝基苯基)苯丙酸乙酯
将(E)-3-(2-苄基-1,2,3,4-四氢异喹啉-5-基)丙烯酸乙酯(300mg,1.0mmol)、4-硝基苯硼酸(484mg,2.9mmol)、氢氧化钾(81mg,1.4mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(24mg,0.05mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得淡黄色油状物225mg,收率54.6%
1H NMR(400MHz,Chloroform-d)δ8.10(d,J=8.7Hz,2H),7.41–7.25(m,7H),7.20–7.07(m,2H),6.92(d,J=7.4Hz,1H),4.78(t,J=7.8Hz,1H),4.09–3.99(m,2H),3.64(s,4H),3.09–2.46(m,6H),1.13(t,J=7.1Hz,3H).
(2)标题化合物的的制备
将3-(2-苄基-1,2,3,4-四氢异喹啉-5-基)-3-(4-硝基苯基)苯丙酸乙酯(225mg,0.54mmol)溶于乙醇中,加入1N氢氧化钾溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体183mg,收率81.4%
1H NMR(400MHz,DMSO-d6)δ8.19–8.05(m,2H),7.72–7.50(m,4H),7.45(s,3H),7.42–7.31(m,1H),7.26(t,J=7.7Hz,1H),7.06(d,J=7.3Hz,1H),4.72(q,J=7.4Hz,1H),4.52–4.14(m,4H),3.67–3.47(m,2H),3.23–2.85(m,4H).
实施例4
3-(2-(4-甲氧基苄基)-1,2,3,4-四氢异喹啉-5-基)-3-苯丙酸
(1)2-(4-甲氧基苄基)-5-溴-1,2,3,4-四氢异喹啉
将5-溴四氢异喹啉(2000mg,9.5mmol)和三乙胺(2878mg,28.4mmol)溶于无水DCM(20mL)中,在0℃下滴加4-甲氧基溴苄(2859mg,14.2mmol)的DCM溶液(20mL),反应液在常温氩气保护下反应3h。加入水(20mL)淬灭反应,用二氯甲烷(20mL)萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体2.54g,收率80.9%。
1H NMR(400MHz,Chloroform-d)δ7.39(d,J=7.5Hz,1H),7.30(d,J=8.3Hz,2H),7.02–6.86(m,4H),3.82(s,3H),3.63(s,2H),3.60(s,2H),2.86(t,J=5.9Hz,2H),2.76(t,J=6.0Hz,2H).
(2)(E)-3-(2-(4-甲氧基苄基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸乙酯
将2-(4-甲氧基苄基)-5-溴-1,2,3,4-四氢异喹啉(2540mg,7.67mmol)溶于无水DMF(10mL)中,再加入丙烯酸乙酯(3840mg,38.4mmol)、DIPEA(2479mg,19.2mmol)和三邻甲苯基膦(469mg,1.5mmol),然后加入Pd(OAc)2(173mg,0.8mmol)。将反应液混合物在氩气保护下95℃反应10h。将反应液用水(20mL)稀释并用二氯甲烷(20mL)萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体2.4g,收率89.5%
1H NMR(400MHz,Chloroform-d)δ7.90(d,J=15.9Hz,1H),7.39(d,J=7.6Hz,1H),7.30(d,J=8.3Hz,2H),7.12(t,J=7.5Hz,1H),7.00(d,J=7.7Hz,1H),6.87(d,J=8.7Hz,2H),6.32(d,J=15.8Hz,1H),4.25(q,J=7.1Hz,2H),3.80(s,3H),3.62(d,J=4.9Hz,4H),3.01–2.70(m,4H),1.32(t,J=7.1Hz,3H).
(3)3-(2-(4-甲氧基苄基)-1,2,3,4-四氢异喹啉-5-基)3-苯丙酸乙酯
将(E)-3-(2-(4-甲氧基苄基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸乙酯(200mg,0.6mmol)、苯硼酸(209mg,1.7mmol)、氢氧化钾(48mg,0.9mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(15mg,0.03mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得淡黄色油状物200mg,收率81.7%
1H NMR(400MHz,Chloroform-d)δ7.26(s,1H),7.25–7.19(m,3H),7.19–7.08(m,5H),6.89–6.81(m,3H),4.67(t,J=7.9Hz,1H),4.02(q,J=7.1Hz,2H),3.79(s,7H),3.04–2.57(m,6H),1.10(t,J=7.1Hz,3H).
(4)标题化合物的制备
将3-(2-(4-甲氧基苄基)-1,2,3,4-四氢异喹啉-5-基)3-苯丙酸乙酯(200mg,0.5mmol)溶于乙醇中,加入1N氢氧化钾溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体163mg,收率88.1%
1H NMR(400MHz,DMSO-d6)δ12.29(s,1H),7.81–6.78(m,12H),4.59(s,1H),4.26(d,J=12.3Hz,4H),3.80(d,J=11.5Hz,5H),2.98(s,4H).
实施例5
3-(2-(4-甲氧基苄基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-甲氧基苯基)丙酸
(1)3-(2-(4-甲氧基苄基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-甲氧基苯基)苯丙酸乙酯
将(E)-3-(2-(4-甲氧基苄基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸乙酯(200mg,0.6mmol)、4-甲氧基苯硼酸(260mg,1.7mmol)、氢氧化钾(48mg,0.9mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(15mg,0.03mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得黄色油状物180mg,收率68.8%
1H NMR(400MHz,Chloroform-d)δ7.26(d,J=7.5Hz,2H),7.14–7.09(m,2H),7.09–7.04(m,2H),6.85(td,J=2.3,6.0,6.6Hz,3H),6.78–6.73(m,2H),4.61(t,J=7.9Hz,1H),4.02(qd,J=1.4,7.1Hz,2H),3.83–3.51(m,10H),3.04–2.55(m,6H),1.11(t,J=7.1Hz,3H).
(2)标题化合物的制备
将3-(2-(4-甲氧基苄基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-甲氧基苯基)苯丙酸乙酯(180mg,0.4mmol)溶于乙醇中,加入1N氢氧化钾溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体163mg,收率63.6%1H NMR(400MHz,DMSO-d6)δ12.15(s,1H),7.53–7.15(m,4H),7.11(d,J=8.0Hz,2H),7.04–6.85(m,3H),6.77(d,J=7.8Hz,2H),4.46(s,1H),4.38–4.00(m,4H),3.78–3.59(m,6H),3.25–3.17(m,2H),3.19–2.67(m,4H).
实施例6
3-(2-(4-甲氧基苄基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-硝基苯基)丙酸
(1)3-(2-(4-甲氧基苄基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-硝基苯基)苯丙酸乙酯
将(E)-3-(2-(4-甲氧基苄基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸乙酯(200mg,0.6mmol)、4-硝基苯硼酸(286mg,1.7mmol)、氢氧化钾(48mg,0.9mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(15mg,0.03mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得深黄色油状物150mg,收率55.5%
1H NMR(400MHz,Chloroform-d)δ8.13–8.06(m,2H),7.37–7.30(m,2H),7.26(s,2H),7.18–7.05(m,2H),6.92(d,J=7.7Hz,1H),6.85(d,J=8.6Hz,2H),4.77(t,J=7.8Hz,1H),4.04(qd,J=7.1,2.2Hz,2H),3.81–3.45(m,7H),3.06–2.40(m,6H),1.13(t,J=7.1Hz,3H).
(2)标题化合物的制备
将3-(2-(4-甲氧基苄基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-硝基苯基)苯丙酸乙酯(150mg,0.3mmol)溶于乙醇中,加入1N氢氧化钾溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体126mg,收率88.2%1H NMR(400MHz,DMSO-d6)δ12.28(s,1H),8.12(d,J=8.8Hz,2H),7.54(d,J=7.0Hz,4H),7.35(d,J=14.6Hz,1H),7.25(t,J=8.7Hz,1H),7.10–6.90(m,3H),4.71(s,1H),4.42–4.07(m,4H),3.78(s,3H),3.18–2.80(m,4H).
实施例7
3-(2-(4-硝基苄基)-1,2,3,4-四氢异喹啉-5-基)-3-苯丙酸
(1)2-(4-硝基苄基)-5-溴-1,2,3,4-四氢异喹啉
将5-溴四氢异喹啉(2000mg,9.5mmol)溶于无水四氢呋喃(20mL)中,在0℃下加入氢化钠(445mg,11.4mmol)反应30min,接着在0℃下滴加4-硝基溴苄(2859mg,14.2mmol)的四氢呋喃溶液(20mL),反应液在常温氩气保护下反应3h。在0℃下加入水(20mL)淬灭反应,用二氯甲烷(20mL)萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体1.37g,收率41.8%。
1H NMR(400MHz,Chloroform-d)δ8.20(d,J=8.7Hz,2H),7.58(d,J=8.4Hz,2H),7.42(d,J=7.7Hz,1H),7.01(t,J=7.7Hz,1H),6.94(d,J=7.6Hz,1H),3.78(s,2H),3.63(s,2H),2.94–2.85(m,2H),2.81(d,J=5.1Hz,2H).
(2)(E)-3-(2-(4-硝基苄基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸乙酯
将2-(4-硝基苄基)-5-溴-1,2,3,4-四氢异喹啉(1370mg,3.96mmol)溶于无水DMF(6mL)中,再加入丙烯酸乙酯(1982mg,19.8mmol)、DIPEA(1280mg,9.9mmol)和三邻甲苯基膦(241mg,0.8mmol),然后加入Pd(OAc)2(89mg,0.4mmol)。将反应液混合物在氩气保护下95℃反应10h。将反应液用水(20mL)稀释并用二氯甲烷(20mL)萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体1.2g,收率82.7%。
1H NMR(400MHz,Chloroform-d)δ8.20(d,J=8.4Hz,2H),7.90(d,J=15.8Hz,1H),7.59(s,2H),7.43(d,J=7.9Hz,1H),7.16(t,J=8.7Hz,1H),7.01(d,J=7.6Hz,1H),6.35(d,J=15.9Hz,1H),4.25(q,J=7.1Hz,2H),3.89–3.58(m,4H),3.10–2.72(m,4H),1.32(t,J=7.1Hz,3H).
(3)3-(2-(4-硝基苄基)-1,2,3,4-四氢异喹啉-5-基)3-苯丙酸乙酯
将(E)-3-(2-(4-硝基苄基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸乙酯(250mg,0.7mmol)、苯硼酸(252mg,2.1mmol)、氢氧化钾(48mg,0.9mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(15mg,0.03mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得淡黄色油状物200mg,收率81.7%
1H NMR(400MHz,Chloroform-d)δ8.18(d,J=8.7Hz,2H),7.54(d,J=8.4Hz,2H),7.24(d,J=6.4Hz,2H),7.22–7.11(m,5H),6.88(d,J=6.9Hz,1H),4.69(t,J=7.9Hz,1H),4.09–3.99(m,2H),3.76–3.55(m,4H),3.00(dd,J=7.9,4.2Hz,2H),2.75–2.66(m,2H),1.12(t,J=7.1Hz,3H).
(4)标题化合物的制备
将3-(2-(4-硝基苄基)-1,2,3,4-四氢异喹啉-5-基)3-苯丙酸乙酯(250mg,0.6mmol)溶于乙醇中,加入1N氢氧化钾溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得淡黄色固体216mg,收率92.7%
1H NMR(400MHz,Chloroform-d)δ8.12(d,J=8.6Hz,2H),7.47(d,J=8.5Hz,2H),7.21(d,J=7.1Hz,2H),7.17–7.10(m,4H),6.85(d,J=7.3Hz,1H),4.62(t,J=7.8Hz,1H),3.79–3.69(m,2H),3.69–3.54(m,2H),2.97(h,J=8.8Hz,3H),2.78(dd,J=5.7,11.8Hz,1H),2.72–2.52(m,2H).
实施例8
3-(2-(4-硝基苄基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-甲氧基苯基)丙酸
(1)3-(2-(4-硝基苄基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-甲氧基苯基)苯丙酸乙酯
将(E)-3-(2-(4-硝基苄基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸乙酯(250mg,0.7mmol)、4-甲氧基苯硼酸(314mg,2.1mmol)、氢氧化钾(58mg,1.0mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(18mg,0.03mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得深棕色油状物300mg,收率91.7%
1H NMR(400MHz,Chloroform-d)δ8.22–8.12(m,2H),7.53(d,J=8.5Hz,2H),7.22–7.02(m,4H),6.85(dd,J=1.7,7.0Hz,1H),6.80–6.74(m,2H),4.62(t,J=7.9Hz,1H),4.03(q,J=7.2Hz,2H),3.75(s,7H),3.06–2.57(m,6H),1.12(t,J=7.1Hz,3H).
(2)标题化合物的制备
将3-(2-(4-硝基苄基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-甲氧基苯基)苯丙酸乙酯(300mg,0.6mmol)溶于乙醇中,加入1N氢氧化钾溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体248mg,收率88.2%
1H NMR(400MHz,Chloroform-d)δ8.13(d,J=8.7Hz,2H),7.48(d,J=8.6Hz,2H),7.13(dt,J=15.0,7.6Hz,2H),7.05(d,J=8.6Hz,2H),6.83(d,J=7.4Hz,1H),6.75(d,J=8.6Hz,2H),4.58(t,J=7.9Hz,1H),3.72(s,3H),3.62(d,J=7.3Hz,2H),3.05–2.85(m,4H),2.84–2.51(m,4H).
实施例9
3-(2-(4-硝基苄基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-硝基苯基)丙酸
(1)3-(2-(4-硝基苄基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-硝基苯基)苯丙酸乙酯
将(E)-3-(2-(4-硝基苄基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸乙酯(200mg,0.7mmol)、4-甲氧基苯硼酸(346mg,2.1mmol)、氢氧化钾(58mg,1.0mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(17mg,0.04mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得深黄色油状物185mg,收率54.8%
1H NMR(400MHz,Chloroform-d)δ8.18(d,J=7.9Hz,2H),8.11(d,J=8.7Hz,2H),7.54(s,2H),7.35(d,J=8.7Hz,2H),7.16(d,J=14.0Hz,2H),6.92(d,J=7.2Hz,1H),4.79(t,J=7.7Hz,1H),4.05(qd,J=1.1,7.1Hz,2H),3.72(s,2H),3.62(s,2H),3.10–2.47(m,6H),1.14(t,J=7.1Hz,3H).
(2)标题化合物的制备
将3-(2-(4-硝基苄基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-硝基苯基)苯丙酸乙酯(185mg,0.4mmol)溶于乙醇中,加入1N氢氧化钾溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体104mg,收率59.3%
1H NMR(400MHz,Chloroform-d)δ8.13(d,J=8.7Hz,2H),8.06(d,J=8.7Hz,2H),7.48(d,J=8.6Hz,2H),7.29(d,J=8.7Hz,2H),7.16(q,J=7.7Hz,2H),6.90(d,J=7.0Hz,1H),4.71(t,J=7.8Hz,1H),3.89–3.75(m,2H),3.75–3.61(m,2H),3.09–2.87(m,3H),2.88–2.65(m,2H),2.59–2.47(m,1H).
实施例10
3-(2-苯甲酰基-1,2,3,4-四氢异喹啉-5-基)-3-苯丙酸
(1)2-苯甲酰基-5-溴-1,2,3,4-四氢异喹啉
将5-溴四氢异喹啉(1500mg,7.1mmol)和三乙胺(2158mg,21.3mmol)溶于无水DCM(20mL)中,在0℃下滴加苯甲酰氯(1500mg,10.7mmol)的DCM溶液(20mL),反应液在常温氩气保护下反应3h。加入水(20mL)淬灭反应,用二氯甲烷(20mL)萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体2.1g,收率94.2%。
1H NMR(400MHz,Chloroform-d)δ7.46(d,J=11.3Hz,6H),7.22–6.78(m,2H),4.98-4.42(m,2H),4.08-3.48(m,2H),2.90(s,2H).
(2)(E)-3-(2-苯甲酰基-1,2,3,4-四氢异喹啉-5-基)丙烯酸乙酯
将2-苯甲酰基-5-溴-1,2,3,4-四氢异喹啉(2100mg,6.7mmol)溶于无水DMF(10mL)中,再加入丙烯酸乙酯(3354mg,33.5mmol)、DIPEA(2165mg,16.8mmol)和三邻甲苯基膦(408mg,1.3mmol),然后加入Pd(OAc)2(150mg,0.7mmol)。将反应液混合物在氩气保护下95℃反应10h。将反应液用水(20mL)稀释并用二氯甲烷(20mL)萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得淡黄色固体2.2g,收率86.4%
1H NMR(400MHz,Chloroform-d)δ7.90(d,J=15.7Hz,1H),7.38(d,J=76.6Hz,7H),7.21–7.01(m,1H),6.37(d,J=15.8Hz,1H),5.02–4.46(m,2H),4.27(q,J=7.1Hz,2H),4.11–3.50(m,2H),2.99(s,2H),1.34(t,J=7.1Hz,3H).
(3)3-(2-苯甲酰基-1,2,3,4-四氢异喹啉-5-基)3-苯丙酸乙酯
将(E)-3-(2-苯甲酰基-1,2,3,4-四氢异喹啉-5-基)丙烯酸乙酯(160mg,0.5mmol)、苯硼酸(176mg,1.4mmol)、氢氧化钾(40mg,0.7mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(12mg,0.02mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体146mg,收率73.6%
1H NMR(400MHz,Chloroform-d)δ7.47–7.30(m,6H),7.23(d,J=6.0Hz,2H),7.21–7.05(m,5H),5.02–4.44(m,3H),4.04(q,J=7.1Hz,2H),3.98–3.40(m,2H),3.23–2.53(m,4H),1.12(t,J=7.1Hz,3H).
(4)标题化合物的制备
将3-(2-苯甲酰基-1,2,3,4-四氢异喹啉-5-基)3-苯丙酸乙酯(200mg,0.5mmol)溶于乙醇中,加入1N氢氧化钾溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体84mg,收率62.3%
1H NMR(400MHz,Chloroform-d)δ7.40(s,5H),7.29–7.04(m,8H),5.02–4.39(m,3H),4.05–3.33(m,2H),3.20–2.50(m,4H).
实施例11
3-(2-苯甲酰基-1,2,3,4-四氢异喹啉-5-基)-3-(4-甲氧基苯基)苯丙酸
(1)3-(2-苯甲酰基-1,2,3,4-四氢异喹啉-5-基)-3-(4-甲氧基苯基)苯丙酸乙酯
将(E)-3-(2-苯甲酰基-1,2,3,4-四氢异喹啉-5-基)丙烯酸乙酯(300mg,0.9mmol)、4-甲氧基苯硼酸(410mg,2.7mmol)、氢氧化钾(76mg,1.4mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(22mg,0.05mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得透明油状物270mg,收率67.6%
1H NMR(400MHz,Chloroform-d)δ7.40(s,5H),7.20(d,J=6.6Hz,3H),7.05(d,J=8.4Hz,3H),6.78(d,J=8.7Hz,2H),5.00–4.35(m,3H),4.03(q,J=7.1Hz,2H),3.75(s,5H),3.12–2.45(m,4H),1.12(t,J=7.1Hz,3H).
(2)标题化合物的的制备
将3-(2-苯甲酰基-1,2,3,4-四氢异喹啉-5-基)-3-(4-甲氧基苯基)苯丙酸乙酯(270mg,0.6mmol)溶于乙醇中,加入1N氢氧化钾溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体239mg,收率94.4%
1H NMR(400MHz,Chloroform-d)δ7.40(s,5H),7.19(d,J=7.1Hz,3H),7.05(d,J=8.2Hz,2H),6.78(d,J=8.7Hz,2H),5.00–4.45(m,3H),3.75(s,5H),3.14–2.50(m,4H).
实施例12
3-(2-苯甲酰基-1,2,3,4-四氢异喹啉-5-基)-3-(4-硝基苯基)苯丙酸
(1)3-(2-苯甲酰基-1,2,3,4-四氢异喹啉-5-基)-3-(4-硝基苯基)苯丙酸乙酯
将(E)-3-(2-苯甲酰基-1,2,3,4-四氢异喹啉-5-基)丙烯酸乙酯(300mg,0.9mmol)、4-硝基苯硼酸(451mg,2.7mmol)、氢氧化钾(76mg,1.4mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(22mg,0.05mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得淡黄色油状物220mg,收率53.3%
1H NMR(400MHz,Chloroform-d)δ8.13(d,J=8.7Hz,2H),7.41(q,J=1.8,2.4Hz,5H),7.35(d,J=8.4Hz,2H),7.31–7.11(m,3H),5.03–4.46(m,3H),4.07(qd,J=1.3,7.1Hz,2H),4.04–3.42(m,2H),3.18–2.43(m,4H),1.15(t,J=7.1Hz,3H).
(2)标题化合物的的制备
将3-(2-苯甲酰基-1,2,3,4-四氢异喹啉-5-基)-3-(4-硝基苯基)苯丙酸乙酯(225mg,0.54mmol)溶于乙醇中,加入1N氢氧化钾溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得淡黄色固体205mg,收率99.1%
1H NMR(400MHz,Chloroform-d)δ8.11(d,J=8.7Hz,2H),7.46–7.37(m,5H),7.33(d,J=8.4Hz,2H),7.17(d,J=7.2Hz,2H),5.02–4.47(m,3H),4.01–3.41(m,2H),3.17–2.42(m,4H).
实施例13
3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-苯丙酸
(1)2-(4-甲氧基苯甲酰基)-5-溴-1,2,3,4-四氢异喹啉
将5-溴四氢异喹啉(2300mg,10.9mmol)和三乙胺(3308mg,32.7mmol)溶于无水DCM(20mL)中,在0℃下滴加4-甲氧基溴苄(2797mg,16.4mmol)的DCM溶液(20mL),反应液在常温氩气保护下反应3h。加入水(20mL)淬灭反应,用二氯甲烷(20mL)萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得米白色固体3.7g,收率97.9%。
1H NMR(400MHz,Chloroform-d)δ7.50–7.38(m,3H),7.14–7.00(m,2H),6.97–6.87(m,2H),4.76(s,2H),3.83(s,5H),2.91(t,J=5.8Hz,2H).
(2)(E)-3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸乙酯
将2-(4-甲氧基苯甲酰基)-5-溴-1,2,3,4-四氢异喹啉(3680mg,10.7mmol)溶于无水DMF(20mL)中,再加入丙烯酸乙酯(5356mg,53.5mmol)、DIPEA(3463.9mg,26.8mmol)和三邻甲苯基膦(651mg,2.1mmol),然后加入Pd(OAc)2(240mg,1.1mmol)。将反应液混合物在氩气保护下95℃反应10h。将反应液用水(40mL)稀释并用二氯甲烷(40mL)萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得灰色固体3.8g,收率98.3%
1H NMR(400MHz,DMSO-d6)δ7.85(d,J=15.9Hz,1H),7.66–7.60(m,1H),7.45(d,J=8.5Hz,2H),7.24(s,2H),7.00(d,J=8.8Hz,2H),6.51(d,J=15.9Hz,1H),4.71(s,2H),4.20(q,J=7.1Hz,2H),3.81(s,3H),3.68(s,2H),3.04–2.92(m,2H),1.26(t,J=7.1Hz,3H).
(3)3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)3-苯丙酸乙酯
将(E)-3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸乙酯(250mg,0.7mmol)、苯硼酸(252mg,2.1mmol)、氢氧化钾(58mg,1.0mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(23mg,0.04mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得淡黄色油状物191mg,收率62.5%。
1H NMR(400MHz,Chloroform-d)δ7.40(d,J=8.7Hz,2H),7.30–7.10(m,8H),6.91(d,J=8.7Hz,2H),4.71(t,J=7.9Hz,3H),4.04(q,J=7.1Hz,2H),3.84(s,5H),3.13–2.58(m,4H),1.12(t,J=7.1Hz,3H).
(4)标题化合物的制备
将3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)3-苯丙酸乙酯(191mg,0.4mmol)溶于乙醇中,加入1N氢氧化钾溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体120mg,收率67.2%
1H NMR(400MHz,Chloroform-d)δ7.38(d,J=8.7Hz,2H),7.25–7.12(m,7H),6.89(d,J=8.7Hz,2H),4.68(d,J=7.8Hz,3H),3.82(s,5H),3.11–2.55(m,4H).实施例14
3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-甲氧基苯基)丙酸
(1)3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-甲氧基苯基)苯丙酸乙酯
将(E)-3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸乙酯(250mg,0.7mmol)、4-甲氧基苯硼酸(314mg,2.1mmol)、氢氧化钾(58mg,1.0mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(23mg,0.04mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得黄色油状物205mg,收率62.7%
1H NMR(400MHz,Chloroform-d)δ7.40(d,J=8.7Hz,2H),7.21(d,J=3.7Hz,3H),7.07(d,J=8.7Hz,2H),6.91(d,J=8.6Hz,2H),6.79(d,J=8.8Hz,2H),5.00–4.49(m,3H),4.04(q,J=7.1Hz,2H),3.95–3.36(m,8H),3.10–2.57(m,4H),1.13(t,J=7.1Hz,3H).
(2)标题化合物的制备
将3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-甲氧基苯基)苯丙酸乙酯(205mg,0.4mmol)溶于乙醇中,加入1N氢氧化钾溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体110mg,收率57.5%。
1H NMR(400MHz,Chloroform-d)δ7.40(d,J=8.6Hz,2H),7.23(d,J=23.9Hz,3H),7.06(d,J=8.6Hz,2H),6.91(d,J=8.6Hz,2H),6.78(d,J=8.7Hz,2H),4.89–4.53(m,3H),3.95–3.42(m,8H),3.11–2.54(m,4H).
实施例15
3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(2-萘基)丙酸
(1)3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(2-萘基)苯丙酸乙酯
将(E)-3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸乙酯(250mg,0.7mmol)、2-萘硼酸(356mg,2.1mmol)、氢氧化钾(58mg,1.0mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(23mg,0.04mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得透明油状物210mg,收率61.7%
1H NMR(400MHz,Chloroform-d)δ7.76(td,J=6.0,8.4,9.0Hz,3H),7.61(s,1H),7.53–7.33(m,4H),7.33–7.25(m,4H),6.89(d,J=8.4Hz,2H),5.02–4.52(m,3H),4.05(q,J=7.1Hz,2H),3.83(s,5H),3.10(d,J=7.9Hz,4H),1.12(t,J=7.1Hz,3H).
(2)标题化合物的制备
将3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(2-萘基)苯丙酸乙酯(210mg,0.4mmol)溶于乙醇中,加入1N氢氧化钾溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体147mg,收率73.5%
1H NMR(400MHz,Chloroform-d)δ7.78–7.71(m,2H),7.60(s,1H),7.47–7.34(m,3H),7.29–7.23(m,6H),6.87(d,J=8.4Hz,2H),4.90–4.80(m,1H),4.69(s,2H),3.86–3.48(m,5H),3.16–3.01(m,3H),2.76–2.65(m,1H).
实施例16
3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-乙酰氨基苯基)丙酸
(1)3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-乙酰氨基苯基)苯丙酸乙酯
将(E)-3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸乙酯(200mg,0.6mmol)、4-乙酰氨基苯硼酸(115mg,1.6mmol)、氢氧化钾(46mg,0.8mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(14mg,0.03mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得浅黄色油状物210mg,收率76.3%
1H NMR(400MHz,Chloroform-d)δ7.38(t,J=9.0Hz,4H),7.19(d,J=2.8Hz,3H),7.09(d,J=8.3Hz,2H),6.90(d,J=8.7Hz,3H),4.93–4.59(m,3H),4.03(q,J=7.0Hz,2H),3.83(s,5H),3.12–2.57(m,4H),2.13(s,3H),1.12(t,J=7.1Hz,3H).
(2)标题化合物的制备
将3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-乙酰氨基苯基)苯丙酸乙酯(210mg,0.4mmol)溶于乙醇中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体160mg,收率80.7%。
1H NMR(400MHz,Chloroform-d)δ8.14(s,1H),7.41–7.31(m,4H),7.20(d,J=39.0Hz,3H),7.03(d,J=8.4Hz,2H),6.87(d,J=8.7Hz,2H),4.61(t,J=7.5Hz,3H),3.90–3.53(m,5H),3.05–2.51(m,4H),2.04(s,3H).
实施例17
3-(2-(4-硝基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-苯丙酸
(1)2-(4-硝基苯甲酰基)-5-溴-1,2,3,4-四氢异喹啉
将5-溴四氢异喹啉(2000mg,9.5mmol)溶于无水DMF(20mL)中,在0℃下加入氢化钠(445mg,11.4mmol)反应30min,接着在0℃下滴加4-硝基溴苄(2654mg,14.2mmol)的DMF溶液(20mL),反应液在常温氩气保护下反应3h。在0℃下加入水(20mL)淬灭反应,用二氯甲烷(20mL)萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体1.9g,收率55.6%。
1H NMR(400MHz,Chloroform-d)δ8.31(s,2H),7.63(s,2H),7.49(d,J=9.1Hz,1H),7.23–6.79(m,2H),4.99–4.44(m,2H),4.12–3.55(m,2H),3.10–2.84(m,2H).
(2)(E)-3-(2-(4-硝基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸乙酯
将2-(4-硝基苯甲酰基)-5-溴-1,2,3,4-四氢异喹啉(2000mg,5.6mmol)溶于无水DMF(6mL)中,再加入丙烯酸乙酯(2834mg,28.0mmol)、DIPEA(1809mg,14mmol)和三邻甲苯基膦(352mg,1.1mmol),然后加入Pd(OAc)2(130mg,0.6mmol)。将反应液混合物在氩气保护下95℃反应10h。将反应液用水(20mL)稀释并用二氯甲烷(20mL)萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体1.4g,收率65.8%
1H NMR(400MHz,Chloroform-d)δ7.62(d,J=16.0Hz,1H),7.44(d,J=8.8Hz,2H),7.36(d,J=9.2Hz,1H),7.18(d,J=8.0Hz,1H),6.94(d,J=8.8Hz,2H),6.39(d,J=16.0Hz,1H),4.79(s,2H),4.25(q,J=7.1Hz,2H),3.85(s,2H),2.94(s,2H),1.33(t,J=7.1Hz,3H).
(3)3-(2-(4-硝基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)3-苯丙酸乙酯
将(E)-3-(2-(4-硝基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸乙酯(250mg,0.7mmol)、苯硼酸(241mg,2.0mmol)、氢氧化钾(55mg,1.0mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(16mg,0.03mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得棕黄色油状物200mg,收率66.1%
1H NMR(400MHz,Chloroform-d)δ8.28(d,J=8.8Hz,2H),7.57(d,J=8.8Hz,2H),7.29–7.11(m,8H),5.01–4.38(m,3H),4.05(q,J=7.1Hz,4H),3.16–2.51(m,4H),1.13(t,J=7.1Hz,3H).
(4)标题化合物的制备
将3-(2-(4-硝基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)3-苯丙酸乙酯(200mg,0.4mmol)溶于乙醇中,加入1N氢氧化钾溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体145mg,收率76.6%
1H NMR(400MHz,Chloroform-d)δ8.37–8.22(m,2H),7.56(s,2H),7.32–7.05(m,8H),5.02–4.39(m,3H),3.99–3.35(m,2H),3.22–2.49(m,4H).
实施例18
3-(2-(4-硝基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-甲氧基苯基)丙酸
(1)3-(2-(4-硝基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-甲氧基苯基)苯丙酸乙酯
将(E)-3-(2-(4-硝基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸乙酯(250mg,0.7mmol)、4-甲氧基苯硼酸(300mg,2.0mmol)、氢氧化钾(50mg,1.0mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(16mg,0.03mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得棕色油状物250mg,收率77.6%
1H NMR(400MHz,Chloroform-d)δ8.32–8.24(m,2H),7.57(d,J=8.4Hz,2H),7.25–6.99(m,5H),6.83–6.74(m,2H),4.97–4.76(m,1H),4.76–4.36(m,2H),4.03(q,J=7.1Hz,2H),3.75(s,5H),3.22–2.49(m,4H),1.16–1.08(m,3H).
(2)标题化合物的制备
将3-(2-(4-硝基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-甲氧基苯基)苯丙酸乙酯(250mg,0.5mmol)溶于乙醇中,加入1N氢氧化钾溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,用甲醇打浆得白色固体248mg,收率59.6%1H NMR(400MHz,Chloroform-d)δ8.39–8.22(m,2H),7.56(d,J=8.0Hz,2H),7.27–6.71(m,7H),5.04–4.37(m,3H),4.01–3.37(m,5H),3.14–2.52(m,4H).
实施例19
3-(2-(4-硝基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-硝基苯基)丙酸
(1)3-(2-(4-硝基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-硝基苯基)苯丙酸乙酯
将(E)-3-(2-(4-硝基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸乙酯(250mg,0.7mmol)、4-硝基苯硼酸(330mg,2.0mmol)、氢氧化钾(55mg,1.0mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(16mg,0.03mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得深黄色油状物210mg,收率63.2%。
1H NMR(400MHz,Chloroform-d)δ8.28(d,J=8.1Hz,2H),8.12(d,J=7.4Hz,2H),7.60–7.55(m,2H),7.39–7.11(m,5H),5.02–4.72(m,2H),4.49(s,1H),4.13–3.40(m,4H),3.19–2.43(m,4H),1.14(t,J=7.1Hz,3H).
(2)标题化合物的制备
将3-(2-(4-硝基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-硝基苯基)苯丙酸乙酯(185mg,0.4mmol)溶于乙醇中,加入1N氢氧化钾溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体160mg,收率80.2%。1H NMR(400MHz,Chloroform-d)δ8.28(d,J=8.1Hz,2H),8.23–8.07(m,2H),7.58(d,J=8.6Hz,2H),7.45–7.12(m,5H),5.07–4.66(m,2H),4.51(s,1H),3.94(s,1H),3.64–3.42(m,1H),3.20–2.41(m,4H).
实施例20
3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-(3,4-亚甲二氧基)苯基)丙酸
(1)(E)-3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸甲酯
将2-(4-甲氧基苯甲酰基)-5-溴-1,2,3,4-四氢异喹啉(5100mg,14.8mmol)溶于无水DMF(20mL)中,再加入丙烯酸乙酯(6370mg,74mmol)、DIPEA(4782mg,37mmol)和三邻甲苯基膦(901mg,3.0mmol),然后加入Pd(OAc)2(332mg,1.5mmol)。将反应液混合物在氩气保护下95℃反应10h。将反应液用水(60mL)稀释并用二氯甲烷(60mL)萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体4.8g,收率92.0%。
(2)3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-(3,4-亚甲二氧基)苯基)丙酸甲酯
将(E)-3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸甲酯(300mg,0.9mmol)、3,4-亚甲二氧基苯硼酸(425mg,2.6mmol)、氢氧化钾(72mg,1.3mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(21mg,0.04mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得透明油状物270mg,收率66.8%。
1H NMR(400MHz,Chloroform-d)δ7.41(d,J=8.8Hz,2H),7.24–7.15(m,2H),6.92(d,J=8.7Hz,2H),6.69(d,J=8.0Hz,1H),6.66–6.58(m,2H),5.95–5.87(m,2H),5.01–4.45(m,3H),3.60(s,8H),3.05–2.90(m,3H),2.73–2.59(m,1H).
(3)标题化合物的制备
将3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-(3,4-亚甲二氧基)苯基)丙酸甲酯(270mg,0.6mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体210mg,收率80.2%
1H NMR(400MHz,Chloroform-d)δ7.41(d,J=8.5Hz,2H),7.19(d,J=7.2Hz,2H),6.91(d,J=8.4Hz,3H),6.69(d,J=7.9Hz,1H),6.66–6.58(m,2H),5.98–5.86(m,2H),4.93–4.53(m,3H),3.84(s,5H),3.00(qd,J=16.0,7.8Hz,3H),2.77–2.59(m,1H).
实施例21
3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(3,4-二甲氧基苯基)丙酸
(1)3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(3,4-二甲氧基苯基)丙酸甲酯
将(E)-3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸甲酯(300mg,0.9mmol)、3,4-二甲氧基苯硼酸(466mg,2.6mmol)、氢氧化钾(72mg,1.3mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(21mg,0.04mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得透明油状物280mg,收率67.0%。
1H NMR(400MHz,Chloroform-d)δ7.41(d,J=8.3Hz,2H),7.25–7.16(m,2H),6.92(d,J=8.2Hz,3H),6.75(d,J=8.1Hz,1H),6.69–6.61(m,2H),4.93–4.59(m,3H),3.90–3.65(m,12H),3.60(s,4H),3.10–2.91(m,3H),2.76–2.63(m,1H).
(2)标题化合物的制备
将3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(3,4-二甲氧基苯基)丙酸甲酯(280mg,0.6mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体140mg,收率51.7%.
1H NMR(400MHz,Chloroform-d)δ7.39(d,J=8.5Hz,2H),7.19(s,2H),6.90(d,J=8.5Hz,3H),6.78–6.60(m,3H),4.90–4.45(m,3H),3.91–3.41(m,12H),3.12–2.91(m,3H),2.67(d,J=10.5Hz,1H).
实施例22
3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-甲磺酰基苯基)丙酸
(1)3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-甲磺酰基苯基)丙酸甲酯
将(E)-3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸甲酯(200mg,0.6mmol)、4-甲磺酰苯硼酸(342mg,1.7mmol)、氢氧化钾(48mg,0.9mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(15mg,0.03mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得透明油状物100mg,收率34.6%。
1H NMR(400MHz,Chloroform-d)δ7.84(d,J=8.3Hz,2H),7.49–7.34(m,4H),7.25–7.14(m,2H),6.92(d,J=8.5Hz,3H),4.90–4.58(m,3H),3.73(d,J=89.3Hz,8H),3.11–2.97(m,6H),2.66–2.52(m,1H).
(2)标题化合物的制备
将3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-甲磺酰基苯基)丙酸甲酯(100mg,0.6mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体75mg,收率77.2%。
1H NMR(400MHz,Chloroform-d)δ7.84(d,J=8.2Hz,2H),7.39(t,J=6.8Hz,4H),7.26–7.15(m,2H),6.91(d,J=8.1Hz,2H),4.90–4.57(m,3H),3.91–3.55(m,5H),3.16–2.92(m,6H),2.69–2.51(m,1H).
实施例23
3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(3-氟-4-甲氧基苯基)丙酸
(1)3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(3-氟-4-甲氧基苯基)丙酸甲酯
将(E)-3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸甲酯(300mg,0.9mmol)、3-氟-4-二甲氧基苯硼酸(435mg,2.6mmol)、氢氧化钾(72mg,1.3mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(21mg,0.04mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得透明油状物230mg,收率56.4%.
1H NMR(400MHz,Chloroform-d)δ7.41(d,J=8.7Hz,2H),7.26–7.14(m,2H),7.00–6.80(m,6H),5.02–4.52(m,3H),3.92–3.44(m,11H),3.09–2.89(m,3H),2.74–2.55(m,1H).
(2)标题化合物的制备
将3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(3-氟-4-甲氧基苯基)丙酸甲酯(230mg,0.48mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体145mg,收率65.2%。
1H NMR(400MHz,Chloroform-d)δ7.40(d,J=8.4Hz,2H),7.26–7.13(m,2H),7.14–6.76(m,6H),4.93–4.53(m,3H),3.93–3.53(m,8H),3.10–2.90(m,3H),2.73–2.54(m,1H).
实施例24
3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-氰基苯基)丙酸
(1)3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-氰基苯基)丙酸甲酯
将(E)-3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸甲酯(250mg,0.7mmol)、4-氰基苯硼酸(313mg,2.1mmol)、氢氧化钾(62mg,1.1mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(20mg,0.04mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得透明油状物185mg,收率57.4%.
1H NMR(400MHz,Chloroform-d)δ7.56(d,J=8.2Hz,2H),7.40(d,J=8.6Hz,2H),7.28(d,J=8.3Hz,2H),7.22(d,J=7.3Hz,1H),7.15(d,J=7.6Hz,1H),6.92(d,J=8.6Hz,3H),4.77(t,J=7.7Hz,3H),3.97–3.53(m,9H),3.12–2.93(m,3H),2.57(d,J=14.5Hz,1H).
(2)标题化合物的制备
将3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-氰基苯基)丙酸甲酯(185mg,0.40mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体70mg,收率39.1%.
1H NMR(400MHz,Chloroform-d)δ7.55(d,J=8.3Hz,2H),7.39(d,J=8.7Hz,2H),7.27(d,J=8.2Hz,2H),7.14(d,J=7.4Hz,2H),6.91(d,J=8.7Hz,2H),4.75(t,J=7.5Hz,3H),3.11–2.92(m,3H),2.55(s,1H).
实施例25
3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(2,3-二氢苯并呋喃-5-基)丙酸
(1)3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(2,3-二氢苯并呋喃-5-基)丙酸甲酯
将(E)-3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸甲酯(250mg,0.7mmol)、2,3-二氢-1-苯并呋喃-5-基硼酸(350mg,2.1mmol)、氢氧化钾(62mg,1.1mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(20mg,0.04mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得透明油状物185mg,收率55.3%。
1H NMR(400MHz,Chloroform-d)δ7.41(d,J=8.1Hz,2H),7.20(s,2H),7.13–6.87(m,5H),6.66(d,J=8.2Hz,1H),4.96–4.59(m,3H),4.52(t,J=8.7Hz,2H),3.99–3.53(m,8H),3.13(t,J=8.7Hz,2H),3.07–2.90(m,3H),2.68(d,J=11.5Hz,1H).
(2)标题化合物的制备
将3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(2,3-二氢苯并呋喃-5-基)丙酸甲酯(185mg,0.4mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体150mg,收率84.1%.
1H NMR(400MHz,Chloroform-d)δ7.40(d,J=8.4Hz,2H),7.21(s,2H),7.15–6.58(m,6H),4.96–4.45(m,5H),4.01–3.42(m,5H),3.17–2.92(m,5H),2.67(d,J=9.9Hz,1H).
实施例26
3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(1-甲基-1H-吲唑-5-基)丙酸
(1)3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(1-甲基-1H-吲唑-5-基)丙酸甲酯
将(E)-3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸甲酯(230mg,0.7mmol)、1-甲基-1H-吲唑-5-基频哪醇硼酸酯(258mg,1.0mmol)、氢氧化钾(56mg,1.0mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(16mg,0.03mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体170mg,收率53.3%.
1H NMR(400MHz,Chloroform-d)δ7.89(s,1H),7.48(s,1H),7.38(d,J=8.7Hz,2H),7.29(d,J=8.7Hz,1H),7.25–7.18(m,3H),6.90(d,J=8.7Hz,3H),4.97–4.54(m,3H),4.03(s,3H),3.86–3.57(m,8H),3.18–2.96(m,3H),2.65(d,J=17.1Hz,1H).
(2)标题化合物的制备
将3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(1-甲基-1H-吲唑-5-基)丙酸甲酯(185mg,0.4mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体140mg,收率85.3%.
1H NMR(400MHz,Chloroform-d)δ7.85(s,1H),7.47(s,1H),7.35(d,J=8.6Hz,2H),7.26(s,1H),7.20(q,J=8.7,7.7Hz,3H),6.86(d,J=8.7Hz,3H),4.93–4.51(m,3H),3.99(s,3H),3.85–3.47(m,5H),3.18–2.94(m,3H),2.75–2.53(m,1H).
实施例27
3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)5-溴-2-甲氨基苯胺
将4-溴-N-甲基-2-硝基苯胺(1000mg,4.4mmol)溶于20mL二氯甲烷中,加入2mL醋酸,在0℃下分次加入锌粉(1137mg,17.4mmol),常温反应6h。加入饱和氯化铵溶液淬灭反应,用硅藻土抽滤得到滤液。加入DCM/水萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩至固体(830mg)直接投下一步。
(2)5-溴-1-甲基-1H-苯并[d][1,2,3]三唑
将5-溴-2-甲氨基苯胺(830mg,4.2mmol)溶解于5mL 10%H2SO4的水溶液中,在0℃下,逐渐向溶液中缓慢加入NaNO2(400mL,5.8mmol),反应30min后,加入20mL水淬灭反应。过滤,干燥得到黄色固体220mg,收率33.1%.
1H NMR(400MHz,Chloroform-d)δ8.22(d,J=1.6Hz,1H),7.59(dd,J=8.7,1.6Hz,1H),7.41(d,J=8.7Hz,1H),4.30(s,3H).
(3)1-甲基-1H-苯并[d][1,2,3]三唑-5-硼酸频哪醇酯
将5-溴-1-甲基-1H-苯并[d][1,2,3]三唑(100mg,0.5mmol),双联频哪醇硼酸酯(120mg,0.5mmol),醋酸钾(92mg,1.0mmol)和PdCl2(dppf)(25mg,0.03mmol)溶于无水DMF(5mL)中,将反应液混合物在氩气保护下100℃反应6h。将反应液用水(20mL)稀释并用二氯甲烷(60mL)萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得黄色固体90mg,收率90.3%。1H NMR(400MHz,Chloroform-d)δ8.54(s,1H),7.98–7.83(m,1H),7.49(dd,J=8.3,0.8Hz,1H),4.29(s,3H),1.37(s,12H).
(4)3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸甲酯
将(E)-3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸甲酯(150mg,0.4mmol)、1-甲基-1H-苯并[d][1,2,3]三唑-5-硼酸频哪醇酯(334mg,1.3mmol)、氢氧化钾(36mg,0.7mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(11mg,0.01mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得透明油状物140mg,收率67.2%.
1H NMR(400MHz,DMSO-d6)δ7.89(s,1H),7.72(d,J=8.6Hz,1H),7.46(d,J=8.7Hz,1H),7.39(d,J=8.5Hz,2H),7.31(d,J=8.0Hz,1H),7.26–6.94(m,3H),4.83(t,J=8.0Hz,1H),4.76–4.55(m,2H),4.25(s,3H),3.80(s,3H),3.67(s,2H),3.50(s,3H),3.32(s,3H),3.19(d,J=7.8Hz,2H),3.15–2.66(m,2H).
(5)标题化合物的制备
将3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸甲酯(140mg,0.3mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体104mg,收率76.5%.
1H NMR(400MHz,Chloroform-d)δ7.90(s,1H),7.52–7.27(m,5H),7.22(s,1H),6.88(d,J=8.3Hz,3H),4.98–4.53(m,3H),4.24(s,3H),4.02–3.44(m,5H),3.21–2.95(m,3H),2.63(d,J=15.8Hz,1H).
实施例28
3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)2-甲氧基-6-硝基苯胺
将2-羟基-6-硝基苯胺(22g,143.6mmol)溶于100mL DMF中,加入碳酸钾(24g,172.3mmol)和碘甲烷(24g,172.3mmol),将反应液在室温下搅拌6h,然后将其倒入水中,过滤得到红色固体23.2g,收率96.2%。
1H NMR(400MHz,Chloroform-d)δ7.73(dd,J=8.9,1.3Hz,1H),6.89(d,J=9.0Hz,1H),6.66–6.58(m,1H),6.39(s,2H),3.92(s,3H).
(2)4-溴-2-甲氧基-6-硝基苯胺
将2-甲氧基-6-硝基苯胺(23g,138.1mmol)溶于乙酸(200mL)中,加入醋酸钠(30g,221.0mmol)和溴素(24g,152mmol)。将反应液在室温下搅拌1h,然后将其倒入水中,过滤得到红色固体33g,收率97.2%。
1H NMR(400MHz,Chloroform-d)δ7.97–7.85(m,1H),6.94(d,J=1.8Hz,1H),6.48(s,2H),3.93(s,3H).
(3)4-溴-2-甲氧基-N-甲基-6-硝基苯胺
将4-溴-2-甲氧基-6-硝基苯胺(33g,134.1mmol)溶解于DMF(50mL)中,在0℃下加入氢化钠(5.9g,147.5mmol),反应30min后,滴加碘甲烷(20g,140.8mmol)。将反应液在室温下搅拌1h,将其倒入冰水混合物中,过滤得到红色固体30g,收率86.1%。
1H NMR(400MHz,Chloroform-d)δ7.85(d,J=2.6Hz,1H),6.93(d,J=2.2Hz,1H),3.85(s,3H),3.17(s,3H).
(4)4-溴-6-甲氧基-N1-甲基苯-1,2-二胺
将4-溴-2-甲氧基-N-甲基-6-硝基苯胺(30g,115.4mmol)溶解于乙酸中,在0℃下逐渐加入锌粉(28g,346.2mmol)。常温反应过夜后,将反应液用硅藻土过滤并将滤饼用二氯甲烷洗涤,合并滤液并浓缩得深褐色固体13g,直接投下一步。
(5)5-溴-7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑
将4-溴-6-甲氧基-N1-甲基苯-1,2-二胺(13g,56.5mmol)溶解于10%硫酸水溶液中,在0℃下分多次加入NaNO2(6g,84.8mmol)。常温反应30min,加入水淬灭反应,过滤得到黄色固体4g,收率29.4%。
1H NMR(400MHz,Chloroform-d)δ7.75(d,J=1.3Hz,1H),6.84(d,J=1.2Hz,1H),4.43(s,3H),3.98(s,3H).
(6)7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-硼酸频哪醇酯
将5-溴-7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑(720mg,3.0mmol),双联频哪醇硼酸酯(837mg,3.3mmol),醋酸钾(886mg,9.0mmol)和PdCl2(dppf)(147mg,0.2mmol)溶于无水DMF(5mL)中,将反应液混合物在氩气保护下100℃反应6h。将反应液用水(20mL)稀释并用二氯甲烷(60mL)萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得黄色固体610mg,收率70.3%。
1H NMR(400MHz,Chloroform-d)δ8.09(s,1H),7.10(s,1H),4.45(s,3H),4.01(s,3H),1.37(s,12H).
(7)3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸甲酯
将(E)-3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸甲酯(100mg,0.3mmol)、7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-硼酸频哪醇酯(252mg,0.9mmol)、氢氧化钾(24mg,0.4mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(7mg,0.01mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得透明油状物40mg,收率26.8%.
1H NMR(400MHz,Chloroform-d)δ7.39(d,J=8.8Hz,3H),7.21(s,2H),6.90(d,J=8.8Hz,3H),6.57(s,1H),5.01–4.61(m,3H),4.40(s,3H),3.93–3.60(m,11H),3.14–2.96(m,3H),2.66(d,J=16.3Hz,1H).
(8)标题化合物的制备
将3-(2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸甲酯(40mg,0.1mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体25mg,收率78.0%。
1H NMR(400MHz,Chloroform-d)δ7.39(d,J=8.5Hz,4H),7.22(s,1H),6.90(d,J=8.6Hz,3H),6.55(s,1H),4.98–4.53(m,2H),4.40(s,4H),3.95–3.80(m,8H),3.10(d,J=7.7Hz,3H),2.68(d,J=14.2Hz,1H).
实施例29
3-(2-(4-甲氧基苯磺酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-甲氧基苯基)丙酸
(1)2-(4-甲氧基苯磺酰基)-5-溴-1,2,3,4-四氢异喹啉
将5-溴四氢异喹啉(1000mg,4.8mmol)和三乙胺(1446mg,14.3mmol)溶于无水DCM(20mL)中,在0℃下滴加4-甲氧基苯磺酰氯(1182mg,5.7mmol)的DCM溶液(10mL),反应液在常温氩气保护下反应3h。加入水(20mL)淬灭反应,用二氯甲烷(20mL)萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体1.5g,收率82.7%。
1H NMR(400MHz,Chloroform-d)δ7.77(d,J=8.9Hz,2H),7.47–7.37(m,1H),7.09–6.95(m,4H),4.22(s,2H),3.86(s,3H),3.35(t,J=6.1Hz,2H),2.90(t,J=6.0Hz,2H).
(2)(E)-3-(2-(4-甲氧基苯磺酰基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸甲酯
将2-(4-甲氧基苯磺酰基)-5-溴-1,2,3,4-四氢异喹啉(1500mg,3.9mmol)溶于无水DMF(10mL)中,再加入丙烯酸甲酯(1694mg,20.0mmol)、DIPEA(1276mg,9.8mmol)和三邻甲苯基膦(240mg,0.8mmol),然后加入Pd(OAc)2(88mg,0.4mmol)。将反应液混合物在氩气保护下95℃反应10h。将反应液用水(40mL)稀释并用二氯甲烷(40mL)萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得灰色固体1340mg,收率81.3%。
1H NMR(400MHz,Chloroform-d)δ7.84(d,J=15.8Hz,1H),7.78(d,J=8.9Hz,2H),7.41(d,J=7.6Hz,1H),7.18(t,J=7.7Hz,1H),7.07(d,J=7.6Hz,1H),6.99(d,J=8.9Hz,2H),6.32(d,J=15.8Hz,1H),4.24(s,2H),3.86(s,3H),3.80(s,3H),3.36(t,J=6.0Hz,2H),3.00(t,J=5.9Hz,2H).
(3)3-(2-(4-甲氧基苯磺酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-甲氧基苯基)丙酸甲酯
将(E)-3-(2-(4-甲氧基苯磺酰基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸甲酯(250mg,0.7mmol)、4-甲氧基苯硼酸(294mg,1.9mmol)、氢氧化钾(54mg,1.0mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(16mg,0.03mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体260mg,收率80.8%.
1H NMR(400MHz,Chloroform-d)δ7.74(d,J=8.8Hz,2H),7.20–7.11(m,2H),6.98(dd,J=13.8,8.8Hz,4H),6.93–6.89(m,1H),6.76(d,J=8.7Hz,2H),4.57(t,J=7.8Hz,1H),4.19(s,2H),3.85(s,3H),3.75(s,3H),3.57(s,3H),3.25(t,J=6.0Hz,2H),3.05–2.88(m,3H),2.71–2.57(m,1H).
(4)标题化合物的制备
将3-(2-(4-甲氧基苯磺酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(4-甲氧基苯基)丙酸甲酯(260mg,0.5mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体195mg,收率76.5%。
1H NMR(400MHz,Chloroform-d)δ7.73(d,J=8.6Hz,2H),7.23–7.12(m,2H),7.06–6.89(m,5H),6.76(d,J=8.6Hz,2H),4.53(t,J=7.7Hz,1H),4.19(s,2H),3.85(s,3H),3.75(s,3H),3.25(q,J=5.6Hz,2H),3.08–2.88(m,3H),2.70–2.56(m,1H).
实施例30
3-(2-(4-甲氧基苯磺酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-(2-(4-甲氧基苯磺酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸甲酯
将(E)-3-(2-(4-甲氧基苯磺酰基)-1,2,3,4-四氢异喹啉-5-基)丙烯酸甲酯(200mg,0.5mmol)、1-甲基-1H-苯并[d][1,2,3]三唑-5-硼酸频哪醇酯(404mg,1.6mmol)、氢氧化钾(43mg,0.8mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(13mg,0.03mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体70mg,收率25.9%.
1H NMR(400MHz,Chloroform-d)δ7.76(s,1H),7.71(d,J=8.6Hz,2H),7.37(d,J=8.6Hz,1H),7.25(s,1H),7.21–7.14(m,2H),6.93(d,J=8.6Hz,3H),4.79(t,J=7.8Hz,1H),4.32–4.23(m,4H),4.17(s,2H),3.83(s,3H),3.57(s,3H),3.22(t,J=6.0Hz,2H),3.09–2.98(m,3H),2.69–2.52(m,1H).
(2)标题化合物的制备
将3-(2-(4-甲氧基苯磺酰基)-1,2,3,4-四氢异喹啉-5-基)-3-(1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸甲酯(70mg,0.1mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体56mg,收率82.6%.
1H NMR(400MHz,Chloroform-d)δ7.84–7.60(m,3H),7.19(dd,J=37.3,6.2Hz,2H),7.07(s,2H),6.91(d,J=8.8Hz,2H),6.84(s,1H),4.67(s,1H),4.23–3.99(m,5H),3.81(s,3H),3.29–2.71(m,5H),2.50(d,J=15.9Hz,1H).
实施例31
3-(2-(4-甲氧基苄基)-1-氧代-1,2,3,4-四氢异喹啉-5-基)-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)2-(4-甲氧基苄基)-1-氧代-5-溴-1,2,3,4-四氢异喹啉
将5-溴3,4-二氢异喹啉-1(2H)-酮(800mg,3.5mmol)和氢化钠(156mg,3.9mmol)溶于无水DMF(5mL)中,在0℃下滴加4-甲氧基溴苄(854mg,4.3mmol),反应液在常温氩气保护下反应3h。加入冰水(20mL)淬灭反应,用二氯甲烷(20mL)萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体700mg,收率57.3%。
1H NMR(400MHz,Chloroform-d)δ8.18–8.07(m,1H),7.69–7.60(m,1H),7.24(d,J=6.2Hz,3H),6.91–6.83(m,2H),4.71(s,2H),3.80(s,3H),3.47(t,J=6.7Hz,2H),3.01(t,J=6.7Hz,2H).
(2)(E)-3-(2-(4-甲氧基苄基)-1-氧代-1,2,3,4-四氢异喹啉-5-基)丙烯酸甲酯
将2-(4-甲氧基苄基)-1-氧代-5-溴-1,2,3,4-四氢异喹啉(750mg,2.2mmol)溶于无水DMF(20mL)中,再加入丙烯酸甲酯(947mg,1.1mmol)、DIPEA(714mg,5.5mmol)和三邻甲苯基膦(134mg,0.4mmol),然后加入Pd(OAc)2(25mg,0.1mmol)。将反应液混合物在氩气保护下95℃反应10h。将反应液用水(40mL)稀释并用二氯甲烷(40mL)萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体680mg,收率88.0%.
1H NMR(400MHz,Chloroform-d)δ8.21(d,J=7.7Hz,1H),7.87(d,J=15.9Hz,1H),7.72–7.62(m,1H),7.37(t,J=7.8Hz,1H),7.25(d,J=8.6Hz,2H),6.85(d,J=8.6Hz,2H),6.36(d,J=15.8Hz,1H),4.72(s,2H),3.79(s,3H),3.78(s,3H),3.46(t,J=6.6Hz,2H),3.02(t,J=6.6Hz,2H).
(3)3-(2-(4-甲氧基苄基)-1-氧代-1,2,3,4-四氢异喹啉-5-基)-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸甲酯
将(E)-3-(2-(4-甲氧基苄基)-1-氧代-1,2,3,4-四氢异喹啉-5-基)丙烯酸甲酯(100mg,0.3mmol)、7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-硼酸频哪醇酯(252mg,0.9mmol)、氢氧化钾(24mg,0.4mmol)以及(1,5-环辛二烯)氯铑(I)二聚体(7mg,0.01mmol)溶解于6:1的二氧六环水溶液中。氩气保护下100℃反应6h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得透明油状物65mg,收率43.6%.
1H NMR(400MHz,Chloroform-d)δ8.10(dd,J=7.4,1.6Hz,1H),7.47–7.33(m,3H),7.25–7.19(m,2H),6.86–6.80(m,2H),6.43(d,J=1.2Hz,1H),4.82(t,J=7.7Hz,1H),4.73(d,J=14.5Hz,1H),4.61(d,J=14.5Hz,1H),4.40(s,3H),3.84(s,3H),3.77(s,3H),3.60(s,3H),3.45–3.25(m,2H),3.11–2.98(m,3H),2.74–2.62(m,1H).
(4)标题化合物的制备
将3-(2-(4-甲氧基苄基)-1-氧代-1,2,3,4-四氢异喹啉-5-基)-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸甲酯(65mg,0.1mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体50mg,收率76.9%.
1H NMR(400MHz,Chloroform-d)δ8.08(d,J=6.7Hz,1H),7.52–7.29(m,4H),7.20(d,J=7.7Hz,2H),6.80(d,J=7.9Hz,2H),6.41(s,1H),4.89–4.69(m,2H),4.56(d,J=14.4Hz,1H),4.37(s,3H),3.89–3.70(m,6H),3.46–3.21(m,2H),3.18–2.96(m,3H),2.70(s,1H).
实施例32
3-(2-(6-氰基烟酰胺基)-1,2,3,4-四氢异喹啉-5-基)-3-(1,4-二甲基苯并三唑-5-基)丙酸
(1)N,3-二甲基-2-硝基苯胺
将1-氟-3-甲基-2-硝基苯(50g,216.6mmol)和甲胺(60mL,1128.1mmol)溶解于乙醇中,并加入60mL水。将反应液回流16h后冷却至常温,过滤后将滤饼用乙醇(100mL)洗涤三次,干燥得橙色固体36.7g,收率68%。
1H NMR(400MHz,DMSO-d6)δ7.33–7.24(m,1H),6.70(d,J=8.5Hz,1H),6.55(d,J=7.3Hz,1H),6.52–6.46(m,1H),2.77(d,J=4.8Hz,3H),2.29(s,3H).
(2)4-溴-N,3-二甲基-2-硝基苯胺
将N,3-二甲基-2-硝基苯胺(36g,216.6mmol)溶于DMF(300mL)中,在5℃下,加入NBS(47g,266.3mmol)后,将反应液在常温下搅拌16h。加入1L水淬灭反应,并过滤,将滤饼用水(100mL)洗涤三次,干燥得到橙黄色固体52g,收率98%。
1H NMR(400MHz,DMSO-d6)δ7.55(d,J=9.0Hz,1H),6.65(d,J=9.1Hz,1H),6.25(d,J=4.6Hz,1H),2.72(d,J=4.8Hz,3H),2.25(s,3H).
(3)4-溴-N1,3-二甲基苯-1,2-二胺
将4-溴-N,3-二甲基-2-硝基苯胺(40g,163.2mmol)溶于乙酸(300mL)和乙醇(300mL)中,在0℃下分批次加入铁粉(46g,816.0mmol),接下来再加入2N盐酸(250mL)。将反应液在室温下搅拌1h,并过滤。将滤饼用乙酸乙酯(100mL)洗涤三次。合并有机相并浓缩,再加入二氯甲烷(300mL)和水(300mL)萃取。合并有机相,用饱和碳酸氢钠洗涤,再用饱和氯化钠洗涤,无水硫酸钠干燥。浓缩得红色油37g,直接投下一步。
(4)5-溴-1,4-二甲基-1,2,3-苯并三氮唑
将4-溴-N1,3-二甲基苯-1,2-二胺(25g,116.2mmol)和亚硝酸叔丁酯(18g,174.4mmol)溶于乙腈(300mL)中,在0℃下,加入BF3.Et2O(75g,464.0mmol)。将反应液在0℃下反应2h。加入饱和NaOH(1.5L)并过滤。滤饼用水洗涤后,柱层析分离得棕黄色固体20g,收率76%。
1H NMR(400MHz,DMSO-d6)δ7.65(q,J=9.0Hz,2H),4.29(s,3H),2.69(s,3H).
(5)(2E)-3-(1,4-二甲基-1,2,3-苯并三氮唑-5-基)丙烯酸乙酯
将5-溴-1,4-二甲基-1,2,3-苯并三氮唑(20g,88.5mmol)溶于无水DMF(40mL)中,再加入丙烯酸乙酯(18g,177.0mmol)、DIPEA(29g,226.0mmol)和三邻甲苯基膦(5.4g,17.7mmol),然后加入Pd(OAc)2(2g,8.9mmol)。将反应液混合物在氩气保护下95℃反应10h。将反应液用水(500mL)稀释并用二氯甲烷(400mL)萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得黄色固体16g,收率73%.
1H NMR(400MHz,DMSO-d6)δ8.01(d,J=15.9Hz,1H),7.96(d,J=8.8Hz,1H),7.68(d,J=8.8Hz,1H),6.64(d,J=15.9Hz,1H),4.29(s,3H),4.21(q,J=7.1Hz,2H),2.80(s,3H),1.28(t,J=7.1Hz,3H).
(6)5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,4-二氢异喹啉-2(1H)-甲酸叔丁酯
将N-Boc-5-溴-1,2,3,4-四氢异喹啉(60g,192.2mmol),双联频哪醇硼酸酯(97.6g,384.4mmol),醋酸钾(57g,576.5mmol)和PdCl2(dppf)(14g,19mmol)溶于无水1,4-二氧六环(900mL)中,将反应液混合物在氩气保护下100℃反应6h。将反应液用水(3L)稀释并用二氯甲烷(1.5L)萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体60g,收率86%。
1H NMR(400MHz,DMSO-d6)δ7.53(d,J=6.6Hz,1H),7.26(d,J=7.4Hz,1H),7.17(t,J=7.4Hz,1H),4.47(s,2H),3.51(t,J=5.3Hz,2H),3.01(t,J=5.9Hz,2H),1.42(s,9H),1.29(s,12H).
(7)3-(1,4-二甲基苯并三唑-5-基)-3-(N-Boc-1,2,3,4-四氢异喹啉-5-基)丙酸乙酯
将(2E)-3-(1,4-二甲基-1,2,3-苯并三氮唑-5-基)丙烯酸乙酯(10g,40.0mmol),5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,4-二氢异喹啉-2(1H)-甲酸叔丁酯(29.3g,81.0mmol),(1,5-环辛二烯)氯铑(I)二聚体(9g,24.3mmol)和三乙胺(8g,80.9mmol)溶解于1,4-二氧六环(100mL)和水(200mL)。将反应液在氩气保护下95℃反应16h,将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体13.5g,收率69%。
1H NMR(400MHz,DMSO-d6)δ7.52(d,J=8.7Hz,1H),7.29–7.14(m,3H),7.08–6.98(m,1H),4.91(t,J=7.9Hz,1H),4.45(s,2H),4.22(s,3H),3.95(q,J=7.1Hz,2H),3.60–3.40(m,2H),3.12–2.95(m,2H),2.95–2.84(m,1H),2.74(s,3H),2.41–2.24(m,1H),1.36(s,9H),1.03(t,J=7.1Hz,3H).
(8)3-(1,4-二甲基苯并三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯
将3-(1,4-二甲基苯并三唑-5-基)-3-(N-Boc-1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(12g,25.1mmol)溶解于二氯甲烷(120mL)中,加入三氟乙酸(40mL)后常温搅拌2h,将反应液浓缩,并用饱和NaHCO3调pH值,并过滤,滤饼用水洗(50mL),干燥得灰白色固体7g,71%。
1H NMR(400MHz,DMSO-d6)δ9.18–8.74(m,2H),7.54(d,J=8.7Hz,1H),7.41(d,J=7.6Hz,1H),7.31(t,J=7.7Hz,1H),7.21(d,J=8.7Hz,1H),7.12(d,J=7.6Hz,1H),4.88(t,J=7.9Hz,1H),4.23(s,5H),3.96(d,J=7.1Hz,2H),3.19–2.97(m,3H),2.78(s,3H),1.05(t,J=7.1Hz,3H).
(9)标题化合物的制备
将3-(1,4-二甲基苯并三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(900mg,2.4mmol)溶解于四氢呋喃(12mL)和水(3mL)中,并加入氢氧化锂(285mg,12.0mmol),将反应液在常温下搅拌16h,用水稀释,并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩后加入DIPEA(1900mg,14.7mmol)溶于二氯甲烷(20mL),中,在0℃下,滴加6-氰基吡啶-3-碳酰氯(500mg,3mmol)。将反应液在常温下反应16h,将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得淡黄色固体20mg,收率2.8%.
1H NMR(300MHz,DMSO-d6)δ8.77(t,J=1.5Hz,1H),8.08(d,J=1.5Hz,2H),7.52(d,J=8.6Hz,1H),7.47–6.76(m,4H),4.94(t,J=7.7Hz,1H),4.65(s,2H),4.23(s,3H),3.90(s,2H),2.95(dd,J=14.4,7.7Hz,4H),2.73(s,3H),2.56(s,2H).
实施例33
3-[2-(4,5,6,7-四氢-1-苯并噻吩-2-酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(1,4-二甲基苯并三唑-5-基)丙酸
(1)3-[2-(4,5,6,7-四氢-1-苯并噻吩-2-酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(1,4-二甲基苯并三唑-5-基)丙酸乙酯
将4,5,6,7-四氢-1-苯并噻吩-2-羧酸(115mg,0.6mmol),HATU(401mg,1.1mmol)和DIPEA(204mg,1.6mmol)溶于DMF中,再加入3-(1,4-二甲基苯并三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(200mg,0.5mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得黄色固化油后直接投下一步。
(2)标题化合物的制备
将3-[2-(4,5,6,7-四氢-1-苯并噻吩-2-酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(1,4-二甲基苯并三唑-5-基)丙酸乙酯(80mg,0.5mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体52mg,收率68%.
1H NMR(400MHz,DMSO-d6)δ7.54(d,J=8.0Hz,1H),7.26–7.18(m,4H),7.13-7.11(m,1H),4.95-4.91(m,1H),4.85-4.65(m,2H),4.24(s,3H),3.83(s,1H),3.73-3.71(m,2H),3.33-2.89(m,3H),2.75-2.68(m,5H),2.58(s,2H),1.80-1.70(s,4H).
实施例34
3-[2-(4-Boc哌嗪-1-酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(1,4-二甲基苯并三唑-5-基)丙酸
(1)3-[2-(4-Boc哌嗪-1-酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(1,4-二甲基苯并三唑-5-基)丙酸乙酯
将4-Boc哌嗪-1-羧酸(296mg,1.2mmol),HATU(401mg,1.1mmol)和DIPEA(204mg,1.6mmol)溶于DMF中,再加入3-(1,4-二甲基苯并三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(200mg,0.5mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得黄色固化油后直接投下一步。
(2)标题化合物的制备
将3-[2-(4-Boc哌嗪-1-酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(1,4-二甲基苯并三唑-5-基)丙酸乙酯(150mg,0.3mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体70mg,两步收率24%.
1H NMR(400MHz,Methanol-d4)δ7.45(d,J=8.7Hz,1H),7.35-7.19(m,3H),7.07(dd,J=7.5,1.2Hz,1H),5.08(dd,J=8.8,7.0Hz,1H),4.50(d,J=16.3Hz,1H),4.43(d,J=16.3Hz,1H),4.28(s,3H),3.54-3.40(m,6H),3.27-3.20(m,4H),3.06(dd,J=15.8,8.7Hz,2H),2.91(dd,J=15.9,6.9Hz,1H),2.84(s,3H),2.47(dt,J=16.4,6.0Hz,1H),1.48(s,9H).
实施例35
3-[2-(金刚烷-1-酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(1,4-二甲基苯并三唑-5-基)丙酸
(1)3-[2-(金刚烷-1-酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(1,4-二甲基苯并三唑-5-基)丙酸乙酯
将1-金刚烷甲酸(142mg,0.8mmol),HATU(502mg,1.3mmol)和DIPEA(256mg,2.0mmol)溶于DMF(3mL)中,再加入3-(1,4-二甲基苯并三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(250mg,0.7mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得白色固体185mg,收率52%。
1H NMR(400MHz,DMSO-d6)δ7.53(d,J=8.7Hz,1H),7.30–7.07(m,4H),4.89(t,J=7.8Hz,1H),4.81–4.54(m,2H),4.23(s,3H),4.01–3.83(m,3H),3.70–3.57(m,1H),3.12–2.87(m,3H),2.74(s,3H),2.46–2.36(m,1H),1.95(s,3H),1.87(s,6H),1.67(q,J=11.5Hz,6H),1.01(t,J=7.1Hz,3H).
(2)标题化合物的制备
将3-[2-(金刚烷-1-酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(1,4-二甲基苯并三唑-5-基)丙酸乙酯(120mg,0.2mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体100mg,收率88%.
1H NMR(400MHz,DMSO-d6)δ12.27(s,1H),7.54(s,1H),7.32–7.16(m,3H),7.10(d,J=6.4Hz,1H),4.86(t,J=7.8Hz,1H),4.78–4.54(m,2H),4.23(s,3H),3.87(d,J=14.7Hz,1H),3.66(d,J=11.4Hz,1H),3.05–2.83(m,3H),2.73(s,3H),2.41(d,J=17.0Hz,1H),1.95(s,3H),1.87(s,6H),1.67(q,J=12.4Hz,6H).
实施例36
3-[2-(1-苯基环丙酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(1,4-二甲基苯并三唑-5-基)丙酸
(1)3-[2-(1-苯基环丙酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(1,4-二甲基苯并三唑-5-基)丙酸乙酯
将1-苯基环丙基甲酸(128mg,0.8mmol),HATU(502mg,1.3mmol)和DIPEA(256mg,2.0mmol)溶于DMF(3mL)中,再加入3-(1,4-二甲基苯并三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(250mg,0.7mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得白色固体168mg,收率48%。
1H NMR(400MHz,DMSO-d6)δ7.52(t,J=10.3Hz,1H),7.37–6.95(m,8H),6.79(d,J=40.6Hz,1H),5.00–4.62(m,2H),4.49(d,J=15.8Hz,1H),4.24(d,J=7.9Hz,3H),3.94(p,J=6.9Hz,2H),3.74–3.40(m,2H),3.22–2.87(m,3H),2.79–2.55(m,3H),1.42–1.12(m,3H),1.10–0.96(m,4H).
(2)标题化合物的制备
将3-[2-(1-苯基环丙酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(1,4-二甲基苯并三唑-5-基)丙酸乙酯(100mg,0.2mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体77mg,收率81%.
1H NMR(300MHz,DMSO-d6)δ7.61–7.33(m,1H),7.36–6.51(m,8H),4.81(s,1H),4.70–4.43(m,2H),4.23(d,J=9.0Hz,3H),3.77–3.60(m,1H),3.58–3.48(m,1H),2.98–2.77(m,2H),2.64(s,3H),2.06(s,1H),1.37–0.92(m,4H).
实施例37
3-[2-(1-苯基环戊酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(1,4-二甲基苯并三唑-5-基)丙酸
(1)3-[2-(1-苯基环戊酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(1,4-二甲基苯并三唑-5-基)丙酸乙酯
将1-苯基环戊基甲酸(120mg,0.6mmol),HATU(401mg,1.1mmol)和DIPEA(205mg,1.6mmol)溶于DMF(3mL)中,再加入3-(1,4-二甲基苯并三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(200mg,0.5mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得白色固体158mg,收率54%。
1H NMR(400MHz,DMSO-d6)δ7.50(d,J=5.9Hz,1H),7.38–6.76(m,9H),4.95–4.67(m,1H),4.65–4.41(m,1H),4.25(s,4H),3.99–3.43(m,3H),3.31–3.15(m,2H),3.07–2.52(m,5H),2.43–2.08(m,4H),1.88–1.35(m,6H),1.01(t,J=7.1Hz,3H).
(2)标题化合物的制备
将3-[2-(1-苯基环戊酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(1,4-二甲基苯并三唑-5-基)丙酸乙酯(130mg,0.2mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体106mg,收率85%.
1H NMR(300MHz,DMSO-d6)δ7.49(d,J=8.7Hz,1H),7.23–6.54(m,9H),4.73(s,1H),4.40(s,2H),4.24(s,3H),3.39(d,J=22.9Hz,3H),2.95–2.75(m,2H),2.62(s,3H),2.45–2.18(m,3H),2.12–1.96(m,1H),1.94–1.80(m,2H),1.63(d,J=1.9Hz,4H).
实施例38
3-[2-(4-乙基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)(2E)-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙烯酸乙酯
将5-溴-7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-(43g,177.6mmol)溶于无水DMF(100mL)中,再加入丙烯酸乙酯(36g,355.3mmol)、DIPEA(92g,718.2mmol)和三邻甲苯基膦(11g,35.5mmol),然后加入Pd(OAc)2(4g,17.8mmol)。将反应液混合物在氩气保护下95℃反应10h。将反应液用水(500mL)稀释并用二氯甲烷(400mL)萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得黄色固体38g,收率82%.
1H NMR(400MHz,Chloroform-d)δ7.77(d,J=16.0Hz,1H),7.71(s,1H),6.91(s,1H),6.44(d,J=15.9Hz,1H),4.45(s,3H),4.28(q,J=7.1Hz,2H),4.02(s,3H),1.35(t,J=7.1Hz,3H).
(2)3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(N-Boc-1,2,3,4-四氢异喹啉-5-基)丙酸乙酯
将(2E)-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙烯酸乙酯(38g,145.4mmol),5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,4-二氢异喹啉-2(1H)-甲酸叔丁酯(105g,290.9mmol),(1,5-环辛二烯)氯铑(I)二聚体(43g,87.2mmol)和三乙胺(25g,290.9mmol)溶解于1,4-二氧六环(100mL)和水(200mL)。将反应液在氩气保护下95℃反应16h,将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得灰白色固体12g,收率17%。
1H NMR(400MHz,Chloroform-d)δ7.28–7.13(m,2H),7.06–6.95(m,1H),6.57(s,1H),4.80(d,J=36.3Hz,2H),4.54(s,2H),4.39(s,3H),4.17–4.02(m,2H),3.88(s,3H),3.64–3.45(m,2H),3.07–2.93(m,2H),2.68–2.44(m,2H),1.45(s,9H),1.16(t,J=7.0Hz,3H).
(3)3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯
将3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(N-Boc-1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(12g,24.3mmol)溶解于二氯甲烷(120mL)中,加入三氟乙酸(40mL)后常温搅拌2h,将反应液浓缩,并用饱和NaHCO3调pH值,并过滤,滤饼用水洗(50mL),干燥得白色固体7g,68%。
1H NMR(400MHz,Chloroform-d)δ7.37(s,1H),7.16(d,J=4.2Hz,2H),6.92(t,J=4.4Hz,1H),6.57(s,1H),4.81(t,J=7.8Hz,1H),4.40(s,3H),4.13–4.04(m,2H),4.04–3.98(m,2H),3.89(s,3H),3.20–3.07(m,2H),3.04(d,J=7.9Hz,2H),2.97–2.49(m,2H),1.15(t,J=7.1Hz,3H).
(4)3-[2-(4-乙基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将4-乙基苯甲酸(70mg,0.5mmol),HATU(416mg,1.1mmol)和DIPEA(152mg,1.2mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(200mg,0.5mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得白色固体65mg,收率31%。
1H NMR(400MHz,Chloroform-d)δ7.33(d,J=7.4Hz,3H),7.22(d,J=7.1Hz,5H),6.55(d,J=27.8Hz,1H),4.81(s,2H),4.59(s,1H),4.41(s,3H),3.88(s,4H),3.60(d,J=36.5Hz,2H),3.10(d,J=7.1Hz,4H),2.67(q,J=7.6Hz,3H),1.24(t,J=7.6Hz,3H).
(5)标题化合物的制备
将3-[2-(4-乙基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(120mg,0.2mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体61mg,收率53%.
1H NMR(400MHz,Methanol-d4)δ7.30(td,J=18.4,17.9,9.7Hz,8H),6.82(s,1H),4.78(d,J=15.0Hz,1H),4.62(s,1H),4.41(s,3H),3.94(s,4H),3.60(d,J=39.2Hz,1H),3.10(dd,J=7.7,2.3Hz,3H),2.69(q,J=7.6Hz,3H),1.25(t,J=7.6Hz,3H).
实施例39
3-[2-(2,6-二氟-4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(2,6-二氟-4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将2,6-二氟-4-甲氧基苯甲酸(114mg,0.6mmol),HATU(385mg,1.0mmol)和DIPEA(196mg,1.5mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(200mg,0.5mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得白色固体115mg,收率40%。
(2)标题化合物的制备
将3-[2-(2,6-二氟-4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(100mg,0.2mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体53mg,收率56%。
1H NMR(400MHz,Methanol-d4)δ7.48–7.08(m,4H),6.79(d,J=19.6Hz,1H),6.74–6.56(m,2H),4.87(s,3H),4.47(d,J=45.6Hz,4H),3.94(d,J=10.7Hz,4H),3.84(s,3H),3.65–3.49(m,1H),3.10(d,J=7.3Hz,3H),2.89–2.55(m,1H).
实施例40
3-[2-(6-乙基-2-甲基吡啶-3-酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(6-乙基-2-甲基吡啶-3-酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将6-乙基-2-甲基吡啶-3-甲酸(138mg,0.8mmol),HATU(578mg,1.5mmol)和DIPEA(295mg,2.3mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(300mg,0.8mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得灰白色油165mg,收率40%。1H NMR(400MHz,Methanol-d4)δ8.72–8.35(m,1H),7.64–7.29(m,3H),7.25–7.16(m,2H),6.92–6.77(m,1H),4.93(d,J=7.9Hz,2H),4.42(d,J=3.6Hz,3H),4.07–3.90(m,4H),3.78–3.63(m,1H),3.57–3.40(m,1H),3.28–2.92(m,4H),2.71–2.52(m,1H),2.47–2.13(m,3H),1.40–1.34(m,5H),1.34–1.22(m,3H),1.16–1.05(m,3H).
(2)标题化合物的制备
将3-[2-(6-乙基-2-甲基吡啶-3-酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(165mg,0.3mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体81mg,收率52%。
1H NMR(400MHz,Methanol-d4)δ7.53(d,J=7.8Hz,1H),7.44–7.27(m,2H),7.26–7.15(m,3H),6.92–6.78(m,1H),4.95–4.86(m,3H),4.41(d,J=3.5Hz,3H),3.95(d,J=15.4Hz,3H),3.54–3.33(m,2H),3.27–3.15(m,1H),3.13–2.95(m,3H),2.86–2.50(m,3H),2.32(s,3H),1.36–1.18(m,3H).
实施例41
3-[2-(3-甲基-1-苯并呋喃-2-酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(3-甲基-1-苯并呋喃-2-酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将3-甲基-1-苯并呋喃-2-甲酸(107mg,0.6mmol),HATU(386mg,1.0mmol)和DIPEA(196mg,2.3mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(200mg,0.8mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得白色固体145mg,收率51%。
1H NMR(400MHz,DMSO-d6)δ7.71(d,J=7.7Hz,1H),7.59(d,J=8.3Hz,1H),7.51–7.31(m,4H),7.30–6.86(m,3H),4.88–4.65(m,3H),4.33(s,3H),4.05–3.70(m,7H),3.26–3.08(m,3H),2.84(d,J=16.7Hz,1H),2.33(s,3H),1.04(t,J=7.1Hz,3H).
(2)标题化合物的制备
将3-[2-(3-甲基-1-苯并呋喃-2-酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(135mg,0.2mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体79mg,收率61%。
1H NMR(400MHz,Methanol-d4)δ7.72–7.62(m,1H),7.59–6.76(m,8H),4.97–4.88(m,3H),4.40(s,3H),3.97–3.75(m,5H),3.76–3.68(m,1H),3.27–3.06(m,3H),2.92–2.74(m,1H),2.37(s,3H).
实施例42
3-[2-(5-环丙基-3-氧代-4-丙基-2H-1,4-苯并噁嗪-8-酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(5-环丙基-3-氧代-4-丙基-2H-1,4-苯并噁嗪-8-酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将5-环丙基-3-氧代-4-丙基-2H-1,4-苯并噁嗪-8-甲酸(216mg,0.8mmol),HATU(578mg,1.5mmol)和DIPEA(295mg,2.3mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(300mg,0.8mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得白色固体150mg,收率30%。
1H NMR(400MHz,Chloroform-d)δ7.34(s,1H),7.25–7.07(m,3H),6.96(s,1H),6.86–6.45(m,3H),4.94–4.71(m,3H),4.27(d,J=28.5Hz,4H),4.11–4.00(m,3H),3.52–3.34(m,2H),3.12–3.00(m,3H),2.53(s,1H),1.94–1.69(m,4H),1.60–1.43(m,2H),1.19–1.10(m,4H),1.05(d,J=6.2Hz,2H),0.88–0.70(m,6H).
(2)标题化合物的制备
将3-[2-(5-环丙基-3-氧代-4-丙基-2H-1,4-苯并噁嗪-8-酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(140mg,0.2mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体90mg,收率67%。
1H NMR(400MHz,Methanol-d4)δ7.44–6.74(m,7H),5.17–4.86(m,3H),4.67–4.37(m,4H),4.29(s,2H),3.97–3.67(m,4H),3.44(s,1H),3.23–2.66(m,4H),2.66–2.35(m,1H),2.07–1.84(m,1H),1.55–1.22(m,2H),1.15–1.00(m,2H),0.87–0.56(m,5H).
实施例43
3-[2-(4-甲氧基苯乙酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(4-甲氧基苯乙酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将4-甲氧基苯乙酸(92mg,0.6mmol),HATU(385mg,1.0mmol)和DIPEA(196mg,1.5mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(200mg,0.5mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得白色固体230mg,收率83%。
1H NMR(400MHz,Methanol-d4)δ7.32–6.93(m,6H),6.84–6.65(m,3H),4.82–4.58(m,3H),4.42(d,J=7.3Hz,3H),4.09–3.97(m,2H),3.93(d,J=12.3Hz,3H),3.78–3.62(m,6H),3.14–3.05(m,2H),2.91–2.30(m,3H),1.09(t,J=7.1Hz,3H).
(2)标题化合物的制备
将3-[2-(4-甲氧基苯乙酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(200mg,0.4mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体150mg,收率79%。
1H NMR(400MHz,Methanol-d4)δ7.34–7.15(m,3H),7.11–6.65(m,6H),4.82–4.57(m,3H),4.41(d,J=8.5Hz,3H),3.92(d,J=11.6Hz,3H),3.72(d,J=14.2Hz,7H),3.10–2.97(m,2H),2.91–2.28(m,2H).
实施例44
3-[2-(4-甲氧基苯丙酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(4-甲氧基苯丙酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将4-甲氧基苯丙酸(75mg,0.4mmol),HATU(289mg,0.8mmol)和DIPEA(245mg,1.9mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(150mg,0.4mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得白色固体145mg,收率68%。
1H NMR(400MHz,Methanol-d4)δ7.34–7.18(m,3H),7.10–6.91(m,3H),6.85–6.72(m,2H),6.62(d,J=8.6Hz,1H),4.85–4.80(m,1H),4.75–4.46(m,2H),4.40(d,J=7.5Hz,3H),4.03(qd,J=7.1,1.9Hz,2H),3.94(d,J=11.9Hz,3H),3.72–3.47(m,5H),3.12(t,J=7.9Hz,2H),3.07–2.78(m,3H),2.74–2.57(m,3H),1.10(td,J=7.1,3.8Hz,3H).
(2)标题化合物的制备
将3-[2-(4-甲氧基苯丙酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(145mg,0.3mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体104mg,收率75%。
1H NMR(400MHz,Methanol-d4)δ7.36–7.18(m,3H),7.11–6.90(m,3H),6.86–6.72(m,2H),6.66–6.58(m,1H),4.82(t,J=7.5Hz,1H),4.65(q,J=16.9Hz,1H),4.49(s,1H),4.40(d,J=7.6Hz,3H),3.94(d,J=11.7Hz,3H),3.76–3.46(m,5H),3.17–3.06(m,2H),3.05–2.89(m,1H),2.86–2.77(m,2H),2.74–2.53(m,3H).
实施例45
3-(2-环己烷甲酰-1,2,3,4-四氢异喹啉-5-基)-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-(2-环己烷甲酰-1,2,3,4-四氢异喹啉-5-基)-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将环己烷甲酸(71mg,0.6mmol),HATU(385mg,1.0mmol)和DIPEA(196mg,1.5mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(150mg,0.4mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得无色油135mg,收率53%。
(2)标题化合物的制备
将3-(2-环己烷甲酰-1,2,3,4-四氢异喹啉-5-基)-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(135mg,0.3mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体85mg,收率67%。
1H NMR(400MHz,Methanol-d4)δ7.38-7.34(m,1H),7.32-7.20(m,2H),7.17-7.09(m,1H),6.83(d,J=6.4Hz,1H),4.75-4.61(m,3H),4.43(s,3H),3.96(s,3H),3.83-3.65(m,2H),3.15-3.08(m,2H),2.80-2.62(m,2H),1.82-1.61(m,5H),1.48-1.23(m,6H).
实施例46
3-[2-(4-苯氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(4-苯氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将4-苯氧基苯甲酸(119mg,0.6mmol),HATU(385mg,1.0mmol)和DIPEA(196mg,1.5mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(200mg,0.5mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得白色固体145mg,收率48%。1H NMR(400MHz,Methanol-d4)δ7.78–6.75(m,14H),4.82–4.37(m,5H),4.13–3.51(m,8H),3.14(d,J=8.1Hz,3H),2.75(s,1H),1.11(t,J=7.1Hz,3H).
(2)标题化合物的制备
将3-[2-(4-苯氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(300mg,0.5mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得灰白色固体105mg,收率92%。
1H NMR(400MHz,Methanol-d4)δ7.48–6.72(m,14H),4.84–4.52(m,3H),4.40(s,3H),4.01–3.46(m,5H),3.22–3.02(m,3H),2.74(s,1H).
实施例47
3-[2-(3-苯氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(3-苯氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将3-苯氧基苯甲酸(162mg,0.7mmol),HATU(524mg,1.4mmol)和DIPEA(267mg,2.0mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(200mg,0.5mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得黄色固体110mg,收率36%。
1H NMR(400MHz,Chloroform-d)δ7.79–7.27(m,6H),7.25–6.47(m,8H),5.02–4.35(m,6H),4.10–3.83(m,5H),3.69–3.45(m,1H),3.17–2.57(m,4H),1.32–1.23(m,3H).
(2)标题化合物的制备
将3-[2-(3-苯氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(120mg,0.2mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得灰白色固体56mg,收率20%。
1H NMR(400MHz,Methanol-d4)δ7.82–6.75(m,14H),4.90–4.73(m,2H),4.60(s,1H),4.47–4.29(m,3H),3.95(s,5H),3.12(d,J=7.8Hz,3H),2.85–2.59(m,1H).
实施例48
3-[2-(2-氯-4-甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(2-氯-4-甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将2-氯-4-甲氧基苯甲酸(104mg,0.6mmol),HATU(385mg,1.0mmol)和DIPEA(196mg,1.5mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(200mg,0.5mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得白色固体200mg,收率69%。
1H NMR(400MHz,DMSO-d6)δ7.47–6.56(m,8H),4.89–4.64(m,2H),4.34(d,J=3.6Hz,3H),3.99–3.69(m,8H),3.32–3.29(m,2H),3.24–2.60(m,5H),1.03(t,J=6.9Hz,3H).
(2)标题化合物的制备
将3-[2-(2-氯-4-甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(250mg,0.4mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得灰白色固体220mg,收率93%。
1H NMR(400MHz,DMSO-d6)δ12.15(s,1H),7.46–6.63(m,8H),4.95–4.63(m,2H),4.34(d,J=3.1Hz,4H),3.96–3.75(m,6H),3.40(t,J=6.2Hz,1H),3.06(t,J=7.3Hz,3H),2.83–2.62(m,1H).
实施例49
3-[2-(4-二氟甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(4-二氟甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将4-二氟甲氧基苯甲酸(104mg,0.6mmol),HATU(385mg,1.0mmol)和DIPEA(196mg,1.5mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(200mg,0.5mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得灰白色固体148mg,收率52%。1H NMR(400MHz,DMSO-d6)δ7.51(d,J=8.3Hz,2H),7.38–6.81(m,8H),4.90–4.47(m,3H),4.34(s,3H),4.00–3.44(m,7H),3.23–2.70(m,4H),1.04(t,J=7.1Hz,3H).
(2)标题化合物的制备
将3-[2-(4-二氟甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(120mg,0.2mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得灰白色固体75mg,收率66%。
1H NMR(400MHz,Methanol-d4)δ7.50–7.44(m,2H),7.37–6.68(m,8H),4.85–4.54(m,2H),4.40(s,3H),3.95(s,5H),3.26–3.03(m,3H),2.73(s,1H).
实施例50
3-[2-(2-乙基-4-甲基-1,3-噻唑-5-甲酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(2-乙基-4-甲基-1,3-噻唑-5-甲酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将2-乙基-4-甲基-1,3-噻唑-5-甲酸(95mg,0.6mmol),HATU(385mg,1.0mmol)和DIPEA(196mg,1.5mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(200mg,0.5mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得黄色油169mg,收率61%。1H NMR(400MHz,DMSO-d6)δ7.37(d,J=7.6Hz,1H),7.32(s,1H),7.29–7.01(m,2H),6.91(s,1H),4.84–4.56(m,3H),4.33(s,3H),4.00–3.89(m,5H),3.69(d,J=36.4Hz,2H),3.24–2.99(m,3H),2.99–2.87(m,3H),2.83–2.70(m,1H),2.24(s,3H),1.28(t,J=6.4Hz,3H),1.03(t,J=7.1Hz,3H).
(2)标题化合物的制备
将3-[2-(2-乙基-4-甲基-1,3-噻唑-5-甲酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(150mg,0.3mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体85mg,收率60%。
1H NMR(400MHz,Methanol-d4)δ7.37(d,J=7.6Hz,1H),7.35–7.19(m,2H),7.08(s,1H),6.82(s,1H),4.74(s,2H),4.41(s,3H),4.00–3.59(m,5H),3.21–3.05(m,3H),3.01(q,J=7.6Hz,2H),2.73(d,J=16.0Hz,1H),2.27(s,3H),1.37(t,J=7.5Hz,3H).
实施例51
3-[2-(2-氟-4-甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(2-氟-4-甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将2-氟-4-甲氧基苯甲酸(102mg,0.6mmol),HATU(380mg,1.0mmol)和DIPEA(194mg,1.5mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(200mg,0.5mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得白色固体202mg,收率74%。
1H NMR(400MHz,Chloroform-d)δ7.40–7.27(m,2H),7.26–7.09(m,3H),6.88–6.48(m,3H),4.97–4.74(m,2H),4.51(d,J=6.2Hz,1H),4.41(d,J=7.3Hz,3H),4.10–4.00(m,2H),3.94–3.81(m,7H),3.63–3.40(m,1H),3.16–2.95(m,3H),2.75–2.60(m,1H),1.14(t,J=7.1Hz,3H).
(2)标题化合物的制备
将3-[2-(2-氟-4-甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(202mg,0.4mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体110mg,收率57%。
1H NMR(400MHz,Chloroform-d)δ7.45–7.06(m,5H),6.87–6.41(m,3H),4.89–4.74(m,2H),4.49(s,1H),4.38(d,J=6.7Hz,3H),3.91–3.79(m,6H),3.46(s,4H),3.15–2.88(m,3H),2.68(d,J=23.7Hz,1H).
实施例52
3-[2-(2-溴-4-甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(2-溴-4-甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将2-溴-4-甲氧基苯甲酸(210mg,0.9mmol),HATU(578mg,1.5mmol)和DIPEA(295mg,2.2mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(300mg,0.8mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得白色固体150mg,收率33%。
1H NMR(400MHz,Chloroform-d)δ7.31(d,J=22.1Hz,1H),7.26–7.04(m,5H),6.90–6.79(m,1H),6.68–6.47(m,1H),5.08–4.71(m,2H),4.48–4.29(m,4H),4.09–4.03(m,2H),4.00–3.82(m,4H),3.81(s,3H),3.47–3.29(m,1H),3.12–2.83(m,3H),2.76–2.42(m,1H),1.14(t,J=7.2Hz,3H).
(2)标题化合物的制备
将3-[2-(2-溴-4-甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(150mg,0.3mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体100mg,收率69%。
1H NMR(400MHz,Chloroform-d)δ7.42–7.25(m,1H),7.23–6.76(m,6H),6.63–6.36(m,1H),5.10–4.67(m,2H),4.51–4.20(m,4H),4.11–3.73(m,7H),3.44–3.24(m,1H),3.06(t,J=8.2Hz,3H),2.73–2.40(m,1H).
实施例53
3-[2-(2-氯苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(2-氯苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将2-氯苯甲酸(142mg,0.9mmol),HATU(578mg,1.5mmol)和DIPEA(295mg,2.2mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(300mg,0.8mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得白色固体220mg,收率54%。
1H NMR(400MHz,Chloroform-d)δ7.43–7.27(m,4H),7.26–7.09(m,4H),6.84–6.43(m,1H),5.13–4.71(m,2H),4.49–4.24(m,4H),4.09–4.01(m,2H),3.99–3.71(m,3H),3.50–3.27(m,1H),3.14–2.93(m,3H),2.73–2.46(m,1H),1.17–1.09(m,3H).
(2)标题化合物的制备
将3-[2-(2-氯苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(220mg,0.3mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体140mg,收率68%。
1H NMR(400MHz,Chloroform-d)δ7.43–7.06(m,8H),6.82–6.37(m,1H),5.10–4.66(m,2H),4.51–4.20(m,4H),4.06–3.70(m,4H),3.51–3.25(m,1H),3.17–2.81(m,3H),2.78–2.43(m,2H).
实施例54
3-[2-(2-氯-4-乙氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(2-氯-4-乙氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将2-氯-4-乙氧基苯甲酸(183mg,0.9mmol),HATU(578mg,1.5mmol)和DIPEA(295mg,2.2mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(300mg,0.8mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得白色固体280mg,收率65%。
1H NMR(400MHz,Chloroform-d)δ7.32(s,1H),7.29–7.07(m,4H),6.96–6.72(m,2H),6.67–6.45(m,1H),5.09–4.69(m,2H),4.57–4.26(m,4H),4.07–3.97(m,4H),3.95–3.87(m,1H),3.84(s,2H),3.51–3.26(m,1H),3.15–2.79(m,3H),2.75–2.45(m,1H),1.43–1.32(m,3H),1.17–1.03(m,3H).
(2)标题化合物的制备
将3-[2-(2-氯-4-乙氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(280mg,0.5mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体130mg,收率48%.
1H NMR(400MHz,Chloroform-d)δ7.43–7.27(m,1H),7.22–7.02(m,3H),6.96–6.68(m,2H),6.67–6.35(m,1H),5.07–4.67(m,2H),4.38(d,J=8.6Hz,4H),4.11–3.64(m,6H),3.51–3.24(m,1H),3.07(t,J=8.2Hz,3H),2.75–2.37(m,1H),1.40(t,J=7.0Hz,3H).
实施例55
3-[2-(4-乙酰氨基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(4-乙酰氨基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将4-乙酰氨基苯甲酸(163mg,0.9mmol),HATU(434mg,1.1mmol)和DIPEA(295mg,2.2mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(300mg,0.8mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得白色固体200mg,收率47%。
1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),7.64(d,J=8.2Hz,2H),7.50–6.84(m,7H),4.85–4.53(m,3H),4.34(s,3H),4.04–3.87(m,5H),3.83–3.46(m,2H),3.22–3.01(m,3H),2.77(d,J=16.4Hz,1H),2.07(s,3H),1.04(t,J=7.1Hz,3H).
(2)标题化合物的制备
将3-[2-(4-乙酰氨基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(200mg,0.4mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体110mg,收率58%.
1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),10.12(s,1H),7.64(d,J=8.3Hz,2H),7.38(d,J=8.5Hz,2H),7.32(d,J=7.9Hz,2H),7.05(d,J=118.2Hz,3H),4.89–4.55(m,3H),4.34(s,3H),3.92(s,3H),3.84–3.47(m,2H),3.06(d,J=7.8Hz,3H),2.77(d,J=16.3Hz,1H),2.07(s,3H).
实施例56
3-[2-(2-氯-4-氰基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(2-氯-4-氰基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将2-氯-4-氰基苯甲酸(165mg,0.9mmol),HATU(434mg,1.1mmol)和DIPEA(295mg,2.2mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(300mg,0.8mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得白色固体270mg,收率63%。
1H NMR(400MHz,Chloroform-d)δ7.78–7.48(m,2H),7.47–7.06(m,5H),6.87–6.41(m,1H),5.07–4.68(m,2H),4.45–4.18(m,4H),4.12–3.73(m,6H),3.50–3.21(m,1H),3.14–2.83(m,3H),2.74–2.45(m,1H),1.17–1.08(m,3H).
(2)标题化合物的制备
将3-[2-(2-氯-4-氰基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(270mg,0.5mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体180mg,收率71%.
1H NMR(400MHz,Chloroform-d)δ7.81–7.53(m,2H),7.49–7.27(m,2H),7.23–7.06(m,2H),6.86–6.41(m,1H),5.09–4.66(m,2H),4.52–4.15(m,4H),4.05–3.74(m,4H),3.50–3.23(m,1H),3.15–2.82(m,3H),2.76–2.41(m,1H).
实施例57
3-[2-(2-氯-4-三氟甲基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(2-氯-4-三氟甲基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将2-氯-4-三氟甲基苯甲酸(204mg,0.9mmol),HATU(434mg,1.1mmol)和DIPEA(295mg,2.2mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(300mg,0.8mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得白色固体270mg,收率63%。
1H NMR(400MHz,Chloroform-d)δ7.75–7.48(m,2H),7.48–7.25(m,2H),7.24–7.08(m,2H),6.89–6.41(m,1H),5.11–4.70(m,2H),4.51–4.18(m,4H),4.10–3.68(m,6H),3.48–3.22(m,1H),3.16–2.82(m,3H),2.74–2.44(m,1H),1.13(dt,J=11.3,4.5Hz,3H).
(2)标题化合物的制备
将3-[2-(2-氯-4-三氟甲基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(230mg,0.4mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体100mg,收率44%.
1H NMR(400MHz,DMSO-d6)δ12.17(s,1H),8.09–7.92(m,1H),7.86–7.53(m,2H),7.41–6.77(m,5H),4.99–4.63(m,2H),4.34(s,3H),4.03–3.70(m,4H),3.47–3.24(m,3H),3.22–2.91(m,3H),2.89–2.63(m,1H).
实施例58
3-[2-(3-氯-4-甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(3-氯-4-甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将3-氯-4-甲氧基苯甲酸(152mg,0.9mmol),HATU(434mg,1.1mmol)和DIPEA(295mg,2.2mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(300mg,0.8mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得黄色固体220mg,收率51%。
1H NMR(400MHz,DMSO-d6)δ7.75–7.64(m,1H),7.49(d,J=1.9Hz,1H),7.47–7.31(m,3H),7.20(d,J=8.5Hz,2H),6.91(s,1H),4.87–4.57(m,3H),4.34(s,3H),4.22(t,J=6.5Hz,1H),4.00–3.88(m,8H),3.64–3.53(m,1H),3.23–3.01(m,3H),2.82–2.71(m,1H),1.04(t,J=7.0Hz,3H).
(2)标题化合物的制备
将3-[2-(3-氯-4-甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(220mg,0.4mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体160mg,收率77%.
1H NMR(400MHz,DMSO-d6)δ12.20(s,1H),7.49(d,J=2.1Hz,1H),7.41(dd,J=8.5,2.1Hz,1H),7.38–7.29(m,2H),7.29–6.84(m,4H),4.85–4.51(m,3H),4.34(s,3H),3.91(d,J=7.8Hz,6H),3.83–3.45(m,2H),3.12–2.99(m,3H),2.82–2.69(m,1H).
实施例59
3-[2-(2-甲氧基-4-氯苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(2-甲氧基-4-氯苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将2-甲氧基-4-氯苯甲酸(152mg,0.9mmol),HATU(434mg,1.1mmol)和DIPEA(295mg,2.2mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(300mg,0.8mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得白色固体240mg,收率57%。
1H NMR(400MHz,Chloroform-d)δ7.31(s,1H),7.24–7.04(m,4H),7.02–6.76(m,2H),6.69–6.43(m,1H),4.92–4.69(m,2H),4.45–4.23(m,4H),4.11–3.97(m,2H),3.96–3.27(m,8H),3.10–2.84(m,3H),2.73–2.43(m,2H),1.13(q,J=6.9Hz,3H).
(2)标题化合物的制备
将3-[2-(2-甲氧基-4-氯苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(240mg,0.4mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体150mg,收率65%.
1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),7.41–6.99(m,7H),6.94–6.85(m,1H),4.92–4.57(m,2H),4.38–4.26(m,4H),3.92(d,J=10.1Hz,3H),3.88–3.71(m,2H),3.67–3.44(m,2H),3.15–2.85(m,3H),2.79–2.54(m,1H).
实施例60
3-[2-(2-氯-5-甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(2-氯-5-甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将2-氯-5-甲氧基苯甲酸(170mg,0.9mmol),HATU(434mg,1.1mmol)和DIPEA(295mg,2.2mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(300mg,0.8mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得白色固体270mg,收率63%。1H NMR(500MHz,Chloroform-d)δ7.38–7.15(m,4H),6.92–6.43(m,3H),5.09–4.70(m,2H),4.53–4.25(m,4H),4.15–4.00(m,2H),3.98–3.64(m,7H),3.51–3.30(m,1H),3.18–2.87(m,3H),2.78–2.48(m,1H),1.15(t,J=6.7Hz,3H).
(2)标题化合物的制备
将3-[2-(2-氯-5-甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(270mg,0.5mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体220mg,收率86%.
1H NMR(400MHz,DMSO-d6)δ7.50–7.10(m,5H),7.10–6.96(m,1H),6.93–6.81(m,2H),4.93–4.63(m,2H),4.41–4.30(m,4H),3.97–3.87(m,3H),3.87–3.59(m,4H),3.33–3.24(m,1H),3.13–2.59(m,4H).
实施例61
3-[2-(5-甲氧基-2-吡啶苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(5-甲氧基-2-吡啶苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将5-甲氧基-2-吡啶苯甲酸(139mg,0.9mmol),HATU(434mg,1.1mmol)和DIPEA(295mg,2.2mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(300mg,0.8mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得白色固体240mg,收率63%。
1H NMR(400MHz,Chloroform-d)δ8.32–8.20(m,1H),7.67(d,J=8.6Hz,1H),7.39–7.27(m,2H),7.24–7.04(m,2H),6.93–6.48(m,1H),6.08(s,1H),4.99–4.76(m,3H),4.49–4.36(m,4H),4.14–4.00(m,2H),3.83–3.62(m,3H),3.27–2.67(m,9H),1.14(t,J=7.1Hz,3H).
(2)标题化合物的制备
将3-[2-(5-甲氧基-2-吡啶苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(240mg,0.5mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体220mg,收率80%.
1H NMR(400MHz,DMSO-d6)δ12.17(s,1H),8.29(d,J=2.9Hz,1H),7.62(t,J=8.4Hz,1H),7.48(td,J=8.7,3.0Hz,1H),7.43–7.09(m,4H),6.91(d,J=11.8Hz,1H),4.90–4.62(m,3H),4.33(s,3H),3.84–3.51(m,4H),3.22–2.98(m,5H),2.88–2.64(m,1H).
实施例62
3-[2-(7-乙基-2,3-二氢苯并呋喃-4-甲酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(7-乙基-2,3-二氢苯并呋喃-4-甲酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将7-乙基-2,3-二氢苯并呋喃-4-甲酸(107mg,0.6mmol),HATU(385mg,1.0mmol)和DIPEA(196mg,1.5mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(200mg,0.5mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得黄色油180mg,直接投下一步。
(2)标题化合物的制备
将3-[2-(7-乙基-2,3-二氢苯并呋喃-4-甲酰基)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(180mg,0.3mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体110mg,收率64%。
1H NMR(400MHz,Methanol-d4)δ7.40-7.28(m,2H),7.27-7.17(m,2H),7.02-6.97(m,1H),6.86-6.80(m,1H),6.70-6.67(m,1H),4.59-4.37(m,7H),4.00-3.87(m,4H),3.68-3.50(m,1H),3.20-2.95(m,6H),2.78-2.55(m,3H),1.18(t,J=7.2Hz,3H).
实施例63
3-[2-(2-氯-4-异丙氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(2-氯-4-异丙氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将2-氯-4-异丙基苯甲酸(203mg,0.9mmol),HATU(578mg,1.5mmol)和DIPEA(295mg,2.2mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(300mg,0.8mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得白色固体285mg,收率60%。
1H NMR(400MHz,Chloroform-d)δ7.33–6.82(m,8H),4.84–4.73(m,2H),4.55–4.46(m,2H),4.40–4.38(m,3H),4.08–3.84(m,5H),3.44–3.36(m,2H),3.10–3.06(m,4H),1.24–1.10(m,6H),1.00–0.96(m,3H).
(2)标题化合物的制备
将3-[2-(2-氯-4-异丙氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(280mg,0.47mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体132mg,收率50%.
1H NMR(400MHz,Chloroform-d)δ7.41(s,1H),7.26–7.09(m,3H),6.87–6.76(m,3H),6.44(m,1H),4.82–4.75(m,2H),4.55–4.49(m,2H),4.39–4.37(m,3H),3.90–3.82(m,3H),3.37–3.36(m,2H),3.10–3.06(m,4H),1.33–1.24(m,6H).
实施例64
3-[2-(2-氯-4-环丙基甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(2-氯-4-环丙基甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将2-氯-4-环丙基甲氧基苯甲酸(204mg,0.9mmol),HATU(578mg,1.5mmol)和DIPEA(295mg,2.2mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(300mg,0.8mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得白色固体240mg,收率50%。
1H NMR(400MHz,Chloroform-d)δ7.32–6.47(m,8H),4.83–4.72(m,2H),4.40–4.30(m,4H),4.04–4.03(m,2H),3.84–3.77(m,5H),3.44–3.35(m,2H),3.08–2.93(m,2H),2.93–2.68(m,2H),1.29–1.19(m,1H),1.14–1.10(m,3H),0.65–0.62(m,2H),0.35–0.33(m,2H).
(2)标题化合物的制备
将3-[2-(2-氯-4-环丙基甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(170mg,0.28mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体101mg,收率62%.
1H NMR(400MHz,Chloroform-d)δ7.34–6.76(m,8H),4.91–4.80(m,5H),4.37–(s,3H),3.89–3.81(m,5H),3.40–3.38(m,1H),3.31(m,1H),3.10–3.07(m,2H),1.27–1.21(m,2H),0.62–0.6(m,2H),0.35–0.34(m,2H).
实施例65
3-[2-(2-氯-4-环丙基甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(2-氯-4-丁氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将2-氯-4-丁氧基苯甲酸(284mg,1.2mmol),HATU(578mg,1.5mmol)和DIPEA(295mg,2.2mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(394mg,1mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得白色固体420mg,收率69%。
1H NMR(400MHz,Chloroform-d)δ7.32–6.47(m,8H),4.84–4.74(m,2H),4.40–4.38(m,4H),4.04–3.84(m,7H),3.46–3.29(m,1H),3.08–3.01(m,3H),1.76–1.73(m,2H),1.49–1.44(m,2H),1.31–1.23(m,2H),1.13–0.98(m,3H),0.98–0.94(m,3H).
(2)标题化合物的制备
将3-[2-(2-氯-4-丁氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(400mg,0.66mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体260mg,收率68%.
1H NMR(400MHz,Chloroform-d)δ7.39–6.44(m,8H),4.84–4.72(m,2H),4.39–4.33(m,4H),3.94–3.73(m,5H),3.42–3.34(m,1H),3.08–3.04(m,3H),1.76–1.73(m,2H),1.49–1.46(m,2H),1.31–1.23(m,2H),0.98–0.86(m,3H).
实施例66
3-[2-(2-氯-4-庚甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸
(1)3-[2-(2-氯-4-庚氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯
将2-氯-4-庚氧基苯甲酸(325mg,1.2mmol),HATU(578mg,1.5mmol)和DIPEA(295mg,2.2mmol)溶于THF(3mL)中,再加入3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-(1,2,3,4-四氢异喹啉-5-基)丙酸乙酯(394mg,1mmol)后在常温下搅拌2h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,得白色固体430mg,收率66%。
1H NMR(400MHz,Chloroform-d)δ7.32–6.47(m,8H),4.84–4.74(m,2H),4.40–4.38(m,4H),4.04–3.84(m,7H),3.46–3.29(m,1H),3.08–3.01(m,3H),1.76–1.73(m,2H),1.49–1.44(m,2H),1.31–1.23(m,2H),1.13–0.98(m,3H),0.98–0.94(m,3H).
(2)标题化合物的制备
将3-[2-(2-氯-4-庚氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-3-(7-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)丙酸乙酯(400mg,0.62mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体257mg,收率67%.
1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),7.42–7.29(m,4H),7.25–6.87(m,5H),4.85–4.56(m,3H),4.33(s,3H),3.99(t,J=6.5Hz,2H),3.92(s,3H),3.71(d,J=15.4Hz,2H),3.16–3.00(m,3H),2.85–2.70(m,1H),1.77–1.64(m,2H),1.47–1.18(m,8H),0.89–0.78(m,3H)
实施例67
3-[2-(4-甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-5-(1-甲基-1H-1,2,3-三唑-4-基)戊酸
(1)5-(甲氧基(甲基)氨基甲酰)-3-4-二氢异喹啉-2(1H)-甲酸叔丁酯
将N-Boc-四氢异喹啉-5-羧酸(1200mg,4.3mmol)溶于N,N-二甲基甲酰胺(20mL)中,在常温下,分批加入N,N-碳酰二咪唑(1120mg,6.9mmol)搅拌15分钟。在常温下,继续向反应液中加入N,O-二甲基羟胺盐酸盐(1090mg,11.3mmol)和三乙胺(876mg,8.7mmol)。将反应液在50℃中搅拌24h。将反应液用水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得白色固体1.2g,收率87%。
1H NMR(300MHz,Chloroform-d)δ7.25–7.10(m,3H),4.59(s,2H),3.79–3.16(m,8H),2.81(t,J=5.9Hz,2H),1.49(s,9H).
(2)5-(5-(三甲基硅)戊-4-炔酰基)-1,2,3,4-四氢异喹啉-2(1H)-甲酸叔丁酯
将氯化锂(870mg,20.5mmol)溶于四氢呋喃(20mL)中,并在常温氩气保护下加入镁条(540mg,22.3mmol),接着将(4-溴丁基-1-炔-1-基)三甲基硅(3820mg,18.6mmol)溶于四氢呋喃(2mL)并在0℃下加入。将反应液在常温下氮气保护搅拌2h。接着加入碘(62mg,0.2mmol)后接着搅拌30min。将反应液温度降至0℃,接着加入5-(甲氧基(甲基)氨基甲酰)-3-4-二氢异喹啉-2(1H)-甲酸叔丁酯(1200mg,3.7mmol),并常温搅拌12h。将反应液用氯化铵饱和溶液淬灭,加入水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得灰白色油800mg,收率55%。
1H NMR(300MHz,Chloroform-d)δ7.64–7.26(m,3H),4.60(s,2H),3.58(t,J=5.9Hz,2H),3.25–3.01(m,4H),2.63(t,J=7.3Hz,2H),1.51(d,J=15.0Hz,11H),0.13(d,J=0.8Hz,9H).
(3)(Z)-3-(2-Boc-1,2,3,4-四氢异喹啉-5-基)-7-三甲基硅基-2-烯-6-炔庚酸乙酯
将膦酰基乙酸三乙酯(1050mg,4.7mmol)溶于四氢呋喃(5mL)中,在0℃下加入氢化钠(112mg,4.7mmol)并搅拌1h,接着在0℃下加入5-(5-(三甲基硅)戊-4-炔酰基)-1,2,3,4-四氢异喹啉-2(1H)-甲酸叔丁酯(720mg,1.9mmol)。将反应液在常温下16h。加入水稀释并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得灰白色油710mg,收率83%。
1H NMR(300MHz,Chloroform-d)δ7.16(d,J=7.6Hz,1H),7.09(s,1H),6.99(d,J=7.4Hz,1H),5.76(s,1H),4.58(s,2H),4.21(q,J=7.1Hz,2H),3.57(t,J=5.7Hz,2H),3.18(t,J=7.4Hz,2H),2.80(t,J=5.8Hz,2H),2.28(t,J=7.4Hz,2H),1.49(s,9H),1.31(t,J=7.1Hz,3H),0.09(s,9H).
(4)(Z)-3-(2-Boc-1,2,3,4-四氢异喹啉-5-基)-2-烯-6-炔庚酸乙酯
将(Z)-3-(2-Boc-1,2,3,4-四氢异喹啉-5-基)-7-三甲基硅基-2-烯-6-炔庚酸乙酯(710mg,1.6mmol)溶于四氢呋喃(7mL)中并加入四丁基氟化铵(1.5mL,1.6mmol),将反应液在常温下搅拌12h。加入水淬灭反应并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得灰白色油480mg,收率80%。
1H NMR(400MHz,Chloroform-d)δ7.23–6.82(m,3H),5.90(s,1H),4.60(d,J=13.0Hz,2H),4.26–3.93(m,2H),3.75–3.44(m,2H),3.18(t,J=7.5Hz,1H),2.87–2.46(m,3H),2.37–2.20(m,1H),1.58–1.39(m,9H),1.36–1.11(m,3H).
(5)(Z)-3-(2-Boc-1,2,3,4-四氢异喹啉-5-基)-5-(1-甲基-1H-1,2,3-三唑-4-基)-2-烯戊酸乙酯
将叠氮化钠(102mg,1.6mmol),碘甲烷(231mg,1.6mmol)溶解于N,N-二甲基甲酰胺(2.5mL)中,在室温下搅拌16h。接着加入(Z)-3-(2-Boc-1,2,3,4-四氢异喹啉-5-基)-2-烯-6-炔庚酸乙酯(240mg,0.6mmol),水,抗坏血酸钠(249mg,1.3mmol)和硫酸铜(60mg,0.4mmol),将反应液在55℃下搅拌72h。加入水淬灭反应并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得无色油78mg,收率28%。
1H NMR(300MHz,Chloroform-d)δ7.24–6.82(m,4H),5.76(s,1H),4.58(s,2H),4.20(q,J=7.1Hz,2H),4.04(d,J=5.8Hz,3H),3.56(s,2H),3.29(t,J=8.2Hz,2H),2.88–2.66(m,4H),1.49(d,J=1.8Hz,9H),1.31(t,J=7.2Hz,3H).
(6)3-(2-Boc-1,2,3,4-四氢异喹啉-5-基)-5-(1-甲基-1H-1,2,3-三唑-4-基)戊酸乙酯
将(Z)-3-(2-Boc-1,2,3,4-四氢异喹啉-5-基)-5-(1-甲基-1H-1,2,3-三唑-4-基)-2-烯戊酸乙酯(78mg,0.2mmol)溶解于甲醇中加入钯-碳(100mg,10%),将反应液在氢气下反应2h后将过滤,将滤液蒸干得到灰白色油75mg,并直接投下一步。
(7)3-(1,2,3,4-四氢异喹啉-5-基)-5-(1-甲基-1H-1,2,3-三唑-4-基)戊酸乙酯
将3-(2-Boc-1,2,3,4-四氢异喹啉-5-基)-5-(1-甲基-1H-1,2,3-三唑-4-基)戊酸乙酯(75mg,0.2mmol),三氟甲酸(0.4mL)溶解于二氯甲烷中,常温反应2h,浓缩蒸干得到无色油70mg,并直接投下一步。
(8)3-[(2-(4-甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基)]-5-(1-甲基-1H-1,2,3-三唑-4-基)戊酸乙酯
将3-(1,2,3,4-四氢异喹啉-5-基)-5-(1-甲基-1H-1,2,3-三唑-4-基)戊酸乙酯(70mg,0.2mmol)溶于5mL二氯甲烷中,加入三乙胺(103mg,1.0mmol)和4-甲氧基苯甲酰氯(38mg,0.2mmol),在常温下反应2h。加入水稀释,DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得灰白色油70mg,收率72%。
(9)标题化合物的制备
将3-[(2-(4-甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基)]-5-(1-甲基-1H-1,2,3-三唑-4-基)戊酸乙酯(70mg,0.1mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得灰白色固体50mg,收率76%。
1H NMR(300MHz,Methanol-d4)δ7.62(s,1H),7.45(d,J=8.3Hz,2H),7.27–6.65(m,5H),4.74(s,2H),4.03(s,3H),3.96–3.58(m,5H),3.46(s,1H),3.01(s,1H),2.87–2.45(m,5H),2.23–1.88(m,2H).
实施例68
3-[2-(4-甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基]-5-(1-乙基-1H-1,2,3-三唑-4-基)戊酸
(1)(Z)-3-(2-Boc-1,2,3,4-四氢异喹啉-5-基)-5-(1-乙基-1H-1,2,3-三唑-4-基)-2-烯戊酸乙酯
将叠氮化钠(102mg,1.6mmol),碘乙烷(254mg,1.6mmol)溶解于N,N-二甲基甲酰胺(2.5mL)中,在室温下搅拌20h。接着加入(Z)-3-(2-Boc-1,2,3,4-四氢异喹啉-5-基)-2-烯-6-炔庚酸乙酯(240mg,0.6mmol),水,抗坏血酸钠(249mg,1.3mmol)和硫酸铜(60mg,0.4mmol),将反应液在55℃下搅拌72h。加入水淬灭反应并用二氯甲烷萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得灰白色油140mg,收率49%。
1H NMR(300MHz,Chloroform-d)δ7.22–6.80(m,4H),6.02(s,1H),5.76(s,1H),4.58(s,2H),4.36(p,J=7.3Hz,2H),4.29–4.05(m,2H),3.94(q,J=7.1Hz,1H),3.56(s,2H),2.99–2.54(m,6H),1.49(s,9H),1.28(dt,J=14.6,7.1Hz,3H).
(2)3-(2-Boc-1,2,3,4-四氢异喹啉-5-基)-5-(1-乙基-1H-1,2,3-三唑-4-基)戊酸乙酯将(Z)-3-(2-Boc-1,2,3,4-四氢异喹啉-5-基)-5-(1-乙基-1H-1,2,3-三唑-4-基)-2-烯戊酸乙酯(140mg,0.3mmol)溶解于甲醇(2.5mL)中加入钯-碳(100mg,10%),将反应液在氢气下反应2h后将过滤,将滤液蒸干得到无色油135mg,直接投下一步。
(3)3-(1,2,3,4-四氢异喹啉-5-基)-5-(1-乙基-1H-1,2,3-三唑-4-基)戊酸乙酯
将3-(2-Boc-1,2,3,4-四氢异喹啉-5-基)-5-(1-乙基-1H-1,2,3-三唑-4-基)戊酸乙酯(130mg,0.3mmol),三氟甲酸(0.4mL)溶解于二氯甲烷中,常温反应2h,浓缩蒸干得到无色油130mg,并直接投下一步。
(4)3-[(2-(4-甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基)]-5-(1-乙基-1H-1,2,3-三唑-4-基)戊酸乙酯
将3-(1,2,3,4-四氢异喹啉-5-基)-5-(1-乙基-1H-1,2,3-三唑-4-基)戊酸乙酯(125mg,0.4mmol)溶于5mL二氯甲烷中,加入三乙胺(177mg,1.0mmol)和4-甲氧基苯甲酰氯(66mg,0.4mmol),在常温下反应2h。加入水稀释,DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得灰白色油125mg,收率70%。
1H NMR(400MHz,Chloroform-d)δ7.45(d,J=8.3Hz,2H),7.26–6.89(m,6H),4.77(s,2H),4.35(q,J=7.4Hz,2H),4.03(q,J=7.1Hz,2H),3.85(s,4H),3.49(s,2H),3.11–2.80(m,2H),2.68–2.52(m,3H),2.18–1.95(m,2H),1.52(t,J=7.3Hz,3H),1.26–1.07(m,3H).
(5)标题化合物的制备
将3-[(2-(4-甲氧基苯甲酰)-1,2,3,4-四氢异喹啉-5-基)]-5-(1-乙基-1H-1,2,3-三唑-4-基)戊酸乙酯(125mg,0.3mmol)溶于5mL四氢呋喃中,加入1N氢氧化锂溶液3mL,50℃反应6h。加入1N盐酸调pH至2-3,加入DCM萃取三次,合并有机相,用饱和氯化钠洗涤一次,无水硫酸钠干燥。浓缩,柱层析分离得灰白色固体116mg,收率79%。
1H NMR(300MHz,Methanol-d4)δ7.71(s,1H),7.45(d,J=8.6Hz,2H),7.29–6.85(m,5H),4.75(s,2H),4.37(q,J=7.4Hz,2H),3.98–3.61(m,5H),3.46(s,1H),3.06(s,1H),2.84–2.48(m,5H),2.22–1.92(m,2H),1.48(t,J=7.3Hz,3H).
实验例1:Keap1-Nrf2蛋白相互作用抑制活性检测
采用基于Keap1-Nrf2蛋白相互作用的荧光偏振(Fluorescence Polarization,FP)评价体系来测定待测化合物的抑制活性。该方法使用的试剂均以FP检测缓冲液(10mMHEPES,50mM EDTA,150mM NaCl,0.005%Tween-20)进行稀释。具体方法为:取全黑非吸附的384孔板,每孔加入20μL 100μM至1nM的待测化合物溶液、10μL FITC标记的Nrf2寡肽(FITC-AHX/ACP-LDEETGEFL-NH2)溶液和10μL 200nM重组人Keap1(321-609)蛋白溶液。此外,在探针对照孔中加入30μL FP检测缓冲液和10μL FITC标记的Nrf2寡肽溶液,在溶剂对照孔中加入20μL FP检测缓冲液、10μL FITC标记的Nrf2寡肽溶液和10μL 200nM重组人Keap1(321-609)蛋白溶液。将加样完毕的384孔板置于室温、避光环境下孵育30min。使用EnVison仪器(PerkinElmer公司,美国)的荧光偏振模块读取384孔板的荧光偏振值。待测化合物的抑制活性由以下算式得出:抑制率(%)=(溶剂对照-样品)/(溶剂对照-探针对照)*100%。
表A
编号 | IC50(nM) | 编号 | IC50(nM) |
48 | 23.8 | 51 | 132 |
52 | 19.8 | 53 | 123 |
54 | 19.9 | 55 | 508.1 |
56 | 81.5 | 57 | 24.3 |
58 | 707.8 | 59 | 61.0 |
60 | 179.2 | 61 | 3723 |
62 | 49.8 | 63 | 17.1 |
64 | 21.9 | 65 | 24.6 |
66 | 438 | 67 | 1819 |
68 | 999.1 |
实验例2:ARE-luciferase报告细胞活性检测
利用Lipofectamine 3000试剂将pGL4.37质粒转染HEK293细胞,并通过潮霉素筛选得到稳定转染细胞株。该细胞基因组内整合了4xARE启动子控制的luciferase报告基因,可用于评价化合物对Nrf2-ARE通路的激动活性。将细胞接种于96孔板,接种密度为5000cell/well,每孔含90ul DMEM完全培养基(10%胎牛血清+1x青霉素/链霉素混合液),培养24小时。用培养基配制10x待测或对照化合物溶液,每孔加入10ul 10x待测化合物溶液。另外,阴性对照选取加入10ul 10xDMSO溶液,阳性对照孔加入10ul 10xt-BHQ溶液,空白对照孔仅加入10ul培养基。孵育24小时后,取出培养板,小心甩去培养基,每孔加入80ul预冷的FLAR缓冲液(20mM Tricine,1mM MgCO3,2.5mM MgSO4,0.1mM EDTA,15mM DTT,1%Triton X-100,pH=7.8),4℃孵育裂解30min。每孔取40ul裂解液转移至96孔全白酶标仪板,检测前每孔加入40ul FLAR检测液(FLAR缓冲液+0.5mM ATP+0.5mL D-luciferin),使用EnSpire仪器立即读取化学发光信号。待测化合物的激动活性由以下算式得出:以空白对照孔的检测值作为背景,Fold change=检测值/背景。
本申请描述的所有实施例在ARE-luciferase报告细胞活性通过范围表示,其中:EC50<1μM(++++);1μM<EC50<5μM(+++);5μM<EC50<10μM(++);10μM<EC50<20μM(+);EC50>20μM(-)
编号 | EC50 | 编号 | EC50 |
48 | ++++ | 51 | ++ |
52 | +++ | 53 | + |
54 | ++++ | 55 | - |
56 | +++ | 57 | ++++ |
58 | ++ | 59 | ++ |
60 | ++ | 61 | - |
62 | ++ | 63 | ++++ |
64 | ++++ | 65 | +++ |
66 | +++ | 67 | - |
68 | - |
。
Claims (11)
1.如通式(I)所示的化合物或其药学上可接受的盐:
其中,
R1选自氢、C1-8直链或者支链烷基、C3-8环烷基;
R2选自氢或者甲基,或者两个R2与其所连接的碳原子共同形成羰基;A为:
苯基,其可被一个、两个或三个独立选自以下的基团取代:氟、氯、溴、硝基、氰基、三氟甲基、三氟甲氧基、二氟甲氧基、甲基、乙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙氧基、甲酰基、乙酰基、丙酰基、异丙酰基、环丙酰基、甲酰胺基、乙酰胺基、丙酰胺基、异丙酰胺基、环丙酰胺基、正丁酰胺基、异丁酰胺基、叔丁酰胺基、氨基乙酰基、氨基丙酰基;
无取代、单取代或多取代的五元或六元芳杂环,无取代、单取代或多取代的苯环并五元芳杂环,无取代、单取代或多取代的苯环并五元杂环,并且杂环、芳杂环为含有1-4个杂原子,所含杂原子可以相同或不同,所述的杂原子选自N、S、O;
–(CH2)m-三唑基,其可被选自以下的基团取代:C1-3烷基;m选自1、2、3、4;
X选自亚甲基、酰基、磺酰基;
Y选自单键、直链或者支链的C1-6烷基或者C3-6环烷基,当Y为单键表示X与Z直接相连;
Z选自直链或支链的C1-8烷基、C3-8环烷基、C3-8杂环、单取代或多取代的苯基、单取代或多取代的五元或六元芳杂环并且杂环为含有1-5个杂原子,所含杂原子可以相同或不同,所述的杂原子选自N、S、O;
Z中所述取代基可被选自以下的基团取代:C1-8直链或者支链烷基、C3-8环烷基、C1-8烷氧基、氟、氯、溴、碘、硝基、氰基、三氟甲基、三氟甲氧基、二氟甲氧基、甲酰胺基、乙酰胺基、丙酰胺基、异丙酰胺基、环丙酰胺基、正丁酰胺基、异丁酰胺基、叔丁酰胺基、氨基乙酰基、氨基丙酰基、氨基异丙酰基、氨基环丙酰基、氨基正丁酰胺基、氨基异丁酰胺基、氨基叔丁酰胺基、叔丁氧羰基。
2.权利要求1的化合物或其药学上可接受的盐,选自:
R1是氢;
两个R2与其所连接的碳原子共同形成羰基;
A为苯并三氮唑,其可被一个、两个、三个独立选自以下的基团取代:甲基、乙基、甲氧基、乙氧基;
X是酰基;
Y为单键表示X与Z直接相连;
Z是苯环,取代基可被选自以下的基团取代:C1-8直链或者支链烷基、C1-8烷氧基、氟、氯、溴、碘、氰基、三氟甲基、三氟甲氧基、二氟甲氧基、乙酰胺基、氨基乙酰基。
3.根据权利要求1的化合物或其药学上可接受的盐,其特征在于,所述药学上可接受的盐选自有机酸盐、无机酸盐、及金属盐。
4.根据权利要求3的化合物或其药学上可接受的盐,其特征在于,所述的无机酸盐选自盐酸盐、氢溴酸盐,硫酸盐、磷酸盐;有机酸盐选自醋酸盐、柠檬酸盐、苹果酸盐、富马酸盐、酒石酸盐或甲磺酸盐;金属盐选自钾盐、钠盐、钙盐。
5.根据权利要求1的化合物或其药学上可接受的盐,其特征在于,A为:苯并三氮唑,其可被一个、两个、三个独立选自以下的基团取代:甲基、乙基、丙基、异丙基、环丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙氧基、氟、氯、溴。
6.如下化合物或其药学上可接受的盐,其特征在于,所述的化合物选自具有如下结构的化合物:
7.一种药物组合物,其特征在于,所述药物组合物中包含权利要求1-6中任一项所述的化合物或其药学上可接受的盐以及药学上可接受的载体。
8.权利要求1-6中任一项所述的化合物或其药学上可接受的盐或权利要求7中所述的药物组合物在制备Keap1-Nrf2蛋白-蛋白相互作用抑制剂中的应用。
9.权利要求1-6中任一项所述的化合物或其药学上可接受的盐或权利要求7中所述的药物组合物在制备氧化应激状态下提高抗氧化能力的药物中的应用。
10.权利要求1-6中任一项所述的化合物或其药学上可接受的盐或权利要求7中所述的药物组合物在制备治疗或缓解疾病的炎症的药物中的应用。
11.权利要求10的应用,其特征在于,所述疾病为各类人体器官或系统的炎性疾病,其中呼吸系统炎性疾病包括慢性阻塞性肺病、哮喘、慢性哮喘、肺纤维化、继发于环境暴露的肺部疾病、急性肺部感染、慢性肺部感染以及各类呼吸系统肿瘤;泌尿系统炎性疾病包括Alport综合症、肾囊性纤维化、紫癜性肾炎、狼疮性肾炎、IgA肾病、IgM肾病、IgG肾病、糖尿病肾病、慢性肾病、败血症诱导的急性肾损伤、急性肾损伤、肾移植期间肾病或肾功能不全、肾缺血再灌注损伤,尿道感染、炎性尿道狭窄、膀胱炎以及各类泌尿系统肿瘤;循环系统炎性疾病包括肺动脉高压、高血压、动脉粥样硬化、心力衰竭、风湿性心脏病、感染性心内膜炎、心包炎、心肌炎、糖尿病心肌病、动脉炎、败血症、菌血症以及各类循环系统肿瘤;神经系统炎性疾病包括帕金森病、阿尔茨海默病、亨廷顿病、弗里德赖希式共济失调、肌萎缩侧索硬化、多发性硬化、出血性脑卒中、缺血性脑卒中、血管性痴呆、蛛网膜下腔出血、脑水肿、癫痫、糖尿病脑病以及各类神经系统肿瘤;消化系统炎性疾病包括非酒精性脂肪性肝炎、毒素或药物诱导性肝损伤、病毒性肝炎、肝硬化、肝纤维化、炎性肠病、胰腺炎、胆囊炎、糖尿病以及各类消化系统肿瘤;皮肤炎性疾病包括银屑病、皮炎、辐射导致的免疫抑制性皮炎、红斑狼疮、痤疮;眼科疾病包括非新生血管型(干性)黄斑变性、新生血管型(湿性)黄斑变性、眼外伤、富克斯角膜内皮营养不良、葡萄膜炎、糖尿病视网膜病变、白内障和干眼症;运动系统疾病包括类风湿性关节炎、糖尿病足病和肌肉萎缩症。
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