CN107531589A - TrkA激酶抑制剂 - Google Patents
TrkA激酶抑制剂 Download PDFInfo
- Publication number
- CN107531589A CN107531589A CN201680017646.8A CN201680017646A CN107531589A CN 107531589 A CN107531589 A CN 107531589A CN 201680017646 A CN201680017646 A CN 201680017646A CN 107531589 A CN107531589 A CN 107531589A
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- CN
- China
- Prior art keywords
- bases
- urea
- methoxy ethyls
- phenylpyrrolidine
- quinoline
- Prior art date
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Abstract
本发明涉及作为原肌球蛋白相关激酶A TrkA的抑制剂的式I化合物：式(I)，或其立体异构体、互变异构体，或医药上可接受的盐、代谢物、同位素、溶剂合物或前药，其中Ra、Rb、Rc、Rd、R1、R2、L和Het‑Ar如本文中所定义。这些化合物可用于预防性和/或治疗性治疗与神经生长因子NGF受体TrkA的异常活性相关的疾病或病症，例如疼痛、炎症或炎症性疾病、癌症、动脉粥样硬化、再狭窄、血栓形成、神经退化性疾病、勃起功能障碍ED、皮肤病症；自体免疫疾病，例如多发性硬化；斯耶格伦综合症、子宫内膜异位症、糖尿病性周围神经病变、前列腺炎、传染病、与骨重塑的调节失衡有关的疾病、子宫内膜异位症、骨盆疼痛综合症和由异常组织重塑和纤维变性病症导致的疾病；或与髓鞘形成障碍或脱髓鞘有关的疾病、病症、损伤或功能失常。
Description
技术领域
本发明涉及用作Trk家族蛋白激酶的成员的抑制剂的新颖化合物。具体来说，本发明揭示具有针对TrkA的抑制活性的化合物。
背景技术
目前可用于治疗疼痛的疗法利用若干种类的化合物，如非类固醇消炎药(NSAID)和类鸦片。大多数NSAID具有一或多种副作用，例如刺激胃肠(GI)道而导致恶心/呕吐、胃溃疡/出血、消化不良、炎症性肠病、肾功能改变、对心血管系统的有害作用和更多的副作用。类鸦片引起催吐、便秘和负性呼吸作用以及成瘾的潜能。因此，对缓和疼痛而无由当前疼痛疗法引起的不良效应具有很大的未满足的需求。
Trks和神经营养因子通过调节中枢和周围神经系统中神经元的细胞增殖、分化、细胞凋亡和存活而对神经元生长和存活的作用是众所周知的。具有三种高度同源同种型TrkA、TrkB和TrkC的Trk激酶是由高亲和力生长因子活化，所述高亲和力生长因子是由以下命名之神经营养因子：神经生长因子(NGF)，其活化TrkA；脑源性神经营养因子(BDNF)和NT-4/5，其活化TrkB；和NT-3，其活化TrkC。神经营养因子与Trk的细胞外结构域的结合引起Trk激酶在若干细胞内酪胺酸位点自体磷酸化并且触发下游信号转导路径，例如PI3K、Ras和PLC-γ路径(分子(Molecules)2015，20(6)，10657-10688)。
认识到通过TrkA的NGF信号传导在疼痛感觉中起重要作用。具有功能突变的TrkA损失的人类中的遗传研究已经证明NGF信号传导在疼痛感觉中的显著作用(临床自体研究(ClinAuton Res)2002；12增刊1:120-32)。当前，由于NSAIDS和鸦片剂的低效能和/或不希望的胃肠、肾和精神副作用，高度需要新颖疼痛治疗。NGF表达在各种疼痛病况中增加并且投与NGF增加疼痛敏感性。已显示使用各种基于抗体和小分子的方法抑制通过TrkA的NGF信号传导在临床前动物模型中对于疼痛有效(麻醉学(Anesthesiology).2011年7月；115(1):189-204)。选择性TrkA抑制展现与非选择性Trk抑制剂等效的效能。在疼痛模型中，使用小分子的间歇TrkA抑制产生与NGF抗体相当的效能(安德鲁斯(Andrews)IASP，2012)。NGFmab、他尼珠单抗(Tanezumab)在骨关节炎、慢性下背疼痛和糖尿病性周围神经病变中展现优良临床效能。TrkA选择性小分子抑制剂对于各种疼痛病况具有治疗效用。抗TrkA抗体和抗NGF抗体用于治疗炎症性和神经性疼痛的效能已展现于WO2006/131952和WO2005/061540中的活体内模型中。
Trk在人类肿瘤中的恶性转变、趋化性、转移及存活信号传导中起重要作用(癌症通讯(Cancer Lett)2001；169:107-14)。TRKA的致癌活化通过基因组重排以及基因融合物的产生而发生，其中TrkA的细胞外结构域通过与具有完整激酶结构域的另一基因融合而被替代，此导致TrkA路径的组成型活化。已在多种癌症、例如NSCLC、斯皮茨黑色素瘤(spitzmelanoma)、结肠直肠癌、胆管癌、软组织肉瘤、神经胶质母细胞瘤和和乳头状甲状腺癌中报告多种NTRK1基因融合物(癌症发现(Cancer Discovery)，2015年1月1日，5；25)，其中更多新的融合物是基于患者DNA的NGS测序报告。Trk抑制剂(例如恩曲替尼(Entrectinib)和LOXO-101)已在具有Trk融合物的患者中展现显著肿瘤消退(癌症发现，2015年10月；5(10):1049-57，美国国立癌症研究所杂志(J Natl Cancer Inst.)2015年11月12日；108(1))。
除基因融合外，分子改变(例如急性骨髓性白血病(AML)中的NTRK1(ΔTRKA)的框内缺失和神经胚细胞瘤中的NTRK1(TRKAIII)的剪接变体)已在功能上表征为致癌。由Trk受体的自分泌和旁分泌信号传导已在若干不同肿瘤类型中参与原致瘤。涉及TrkA和NGF的自分泌环与乳癌和前列腺癌二者中的原致瘤活性相关(分子细胞生物学(Mol Cell Biol.)2000年12月；20(23):8655-66，临床癌症研究(Clin Cancer Res)2001；7:2237-45)。TrkA和TrkC野生型受体的表达与具有神经胚细胞瘤的患者的正性预后相关(排除剪接变体TRKAIII的表达)(新英格兰医学杂志(N Engl J Med.)1993年3月25日；328(12):847-54)。因此，TrkA抑制剂对于由于分子改变由活化TrkA信号传导驱动或由于TrkA和/或NGF的表达增加由从分泌/旁分泌信号传导驱动的癌症具有潜能。
在骨折的小鼠模型中，TrkA在骨形成区域中表现(骨(Bone.)2000年1月；26(6):625-33)并且Trk抑制剂诱导增殖成骨细胞的细胞凋亡(癌症研究2002年2月15日；62(4):986-9)，此表明Trk抑制剂在癌症患者中用于骨重塑疾病(例如骨转移)的用途。
NGF和TrkA在免疫细胞中表达并且在炎症过程期间观察到炎症位点的NGF的局部增加。炎症性细胞因子(例如IL-1β、TNF-α和IL-6)能够改良生物体中NGF的基础产生并诱导多种细胞类型和组织中NGF的合成。TrkA-NGF路径还参与多种病症，例如骨关节炎、多发性硬化(临床免疫学杂志(J Clinlmmunol.)2011年12月；31(6):1010-1020)，以及炎症性疾病，包括气喘(药理学与疗法(Pharmacology&Therapeutics)2008，117(1)，52-76)、间质性膀胱炎(泌尿外科学杂志(The Journal of Urology)2005，173(3)，1016-21)、炎症性肠病(包括溃疡性结肠炎和克罗恩氏病(Crohn's disease))(肠(Gut)2000，46(5)，670-678)、神经退化性疾病(如阿兹海默氏病(Alzheimer's disease)、亨廷顿氏病(Huntington'sdisease)、进行性核上性麻痺(阿兹海默氏病杂志(J Alzheimers Dis.)2014；40(3):605-617，神经病理性学报(ActaNeuropathol.)1998年11月；96(5):495-501)和神经性勃起功能障碍(欧洲泌尿外科学(European Urology)，2014年11月)。已显示Trk路径的抑制在炎症性疾病的临床前模型中有效。
因此，TrkA激酶抑制可用作用于治疗这些疾病的新方法。
Trk激酶还参与皮肤病，如异位性皮肤炎(皮肤病学研究档案(Archives ofDermatological Research)，2006，298(1)，31-37)、湿疹、牛皮癣(皮肤病学研究杂志(J.Investigative Dermatology)，2004，122(3)，812-819)、瘙痒症(皮肤病学与性病学学报(Acta Derm Venereol)，2015；95：542-548)、再狭窄和动脉粥样硬化。TrkA抑制还基于结缔组织生长因子(CTGF)活化TrkA信号传导的能力参与治疗纤维变性病症(纤维发生组织修复(Fibrogenesis Tissue Repair.)2012年6月6日；5(增刊1):S24)。TrkA抑制剂还可用于治疗子宫内膜异位症(生殖科学(Reprod Sci.)2011年12月；18(12):1202-10，人类生殖(Hum Reprod.)2009年4月；24(4):827-34)、糖尿病性周围神经病变(脑研究(Brain Res.)2000年6月9日；867(1-2):149-56，糖尿病医学(Diabet Med.)2009年12月；26(12):1228-34.)、慢性前列腺炎/慢性骨盆疼痛综合症(泌尿外科学(Urology.)2002年4月；59(4):603-8，国际泌尿外科学杂志(BJU Int.)2011年7月；108(2):248-51)和查加斯氏病(Chagas'disease)(细胞宿主微生物(Cell Host Microbe.)2007年6月14日；1(4):251-61)。
已知若干种类的Trk激酶的小分子抑制剂可用于治疗疼痛或癌症。国际公开案第WO2014/078378号、第WO2012/125668号、专利公开案第US20150336970号、第AU2015200511号和治疗术专利专家评述(Expert Opinion on Therapeutic Patents)(2009)19，305-19和治疗术专利专家评述(2014)，24(7):731-744揭示据称为Trk激酶抑制剂的化合物种类，其可用于治疗疾病，例如疼痛、癌症、再狭窄、牛皮癣、血栓形成、动脉粥样硬化、炎症性疾病、神经退化性疾病或诸如此类。
因此，TrkA路径的药理学抑制提供用于治疗依赖于TrkA路径的超活化的各种疾病的有前景的方法。
发明内容
本发明提供式I化合物，其是原肌球蛋白有关激酶A(TrkA)的抑制剂：
其中Ra、Rb、Rc、Rd、R1、R2、L和Het-Ar如本文所定义。
本发明进一步提供医药组合物，其包括有效量的式I化合物或其立体异构体、互变异构体或医药上可接受的盐、溶剂合物、代谢物、同位素或前药以及医药上可接受的载剂。
本发明进一步提供医药组合物的用途，其用于治疗和/或预防有需要的患者中与异常或失调TrkA激酶活性相关的疾病，如疼痛、炎症或炎症性疾病、癌症、动脉粥样硬化、再狭窄、血栓形成、神经退化性疾病(如阿兹海默氏病(Alzheimer's Disease)、亨廷顿氏病(Huntington's disease)或进行性核上性麻痺)、勃起功能障碍(ED)、皮肤病症(如异位性皮肤炎、湿疹、瘙痒症或牛皮癣)、自体免疫疾病(如多发性硬化)、斯耶格伦综合症( syndrome)、子宫内膜异位症、糖尿病性周围神经病变、前列腺炎、传染病、与骨重塑的调节失衡有关的疾病、子宫内膜异位症、骨盆疼痛综合症和由异常组织重塑和纤维变性病症导致的疾病；或与髓鞘形成障碍或脱髓鞘有关的疾病、病症、损伤或功能失常或与神经生长因子(NGF)受体TrkA的异常活性相关的疾病或病症。
本发明进一步提供治疗有需要的患者中由Trk受体介导或与异常或失调TrkA激酶活性相关的疾病或病症的方法，其中所述疾病或病症是选自由以下组成的群组：疼痛、炎症或炎症性疾病、癌症、动脉粥样硬化、再狭窄、血栓形成、神经退化性疾病、勃起功能障碍(ED)、皮肤病症、自体免疫疾病、斯耶格伦综合症、子宫内膜异位症、糖尿病性周围神经病变、前列腺炎、传染病、与骨重塑的调节失衡有关的疾病、子宫内膜异位症、骨盆疼痛综合症和由异常组织重塑和纤维变性病症导致的疾病；或与髓鞘形成障碍或脱髓鞘有关的疾病、病症、损伤，或功能失常或与神经生长因子(NGF)受体Trk A的异常活性相关的疾病或病症，所述方法包含向患者投与治疗有效量的式I化合物或其医药上可接受的盐以及医药上可接受的载剂。
本发明进一步提供治疗由TrkA调节或NGF受体TrkA激酶所参与的疾病或病症的方法。所述方法进一步包含向有需要的患者投与治疗有效量的本发明化合物或其立体异构体、互变异构体或医药上可接受的盐、同位素、代谢物、溶剂合物或前药。
本发明进一步提供式I化合物的合成所需的中间体，
本发明进一步提供本发明化合物的合成、分离和纯化方法。
本发明进一步提供用作TrkA抑制剂和/或拮抗剂的新颖式I化合物的用途，其用于制备可用于治疗以下病症的药剂：如疼痛、炎症或炎症性疾病、癌症、动脉粥样硬化、再狭窄、血栓形成、神经退化性疾病(如阿兹海默氏病、帕金森氏病(Parkinson's disease)、亨廷顿氏病或进行性核上性麻痺)、勃起功能障碍(ED)、皮肤病症(如异位性皮肤炎、湿疹、瘙痒症或牛皮癣)、自体免疫疾病(如多发性硬化)、斯耶格伦综合症、子宫内膜异位症、糖尿病性周围神经病变、前列腺炎、传染病、与骨重塑的调节失衡有关的疾病、子宫内膜异位症、骨盆疼痛综合症和由异常组织重塑和纤维变性病症导致的疾病；或与髓鞘形成障碍或脱髓鞘有关的疾病、病症、损伤，或功能失常或与神经生长因子(NGF)受体Trk-A的异常活性相关的疾病或病症。
根据以下详细说明，通过结合本发明的特征，将明了本发明的额外特征和优点。
具体实施方式
通过某些实施例的上述详细说明，现在将参照实例性实施例和实例，显而易见的是，在不脱离本发明的真实范畴和精神的情况下，可以进行各种修改、添加和其它替代实施例、实例。所论述的实施例和实例经选择和描述以提供对本发明的原理和其实际应用的最优说明，使得所属领域的技术人员能够在各种实施例中且以适于所涵盖的特定用途的各种修改来利用本发明。所有这些修改和变化都在本发明的范畴内。
定义：
如本文所用术语“烷基”自身或作为另一取代基的一部分是指具有1到10个碳原子的直链或具支链烷基。
如本文所用术语“烯基”自身或作为另一取代基的一部分意指具有单一碳-碳双键的直链或具支链烃基团。
如本文所用术语“烷氧基”是指—O(烷基)，其中烷基是如上文所定义。
如本文所用术语“炔基”是指是直链或具支链并且含有至少一个不饱和度，也就是至少一个碳-碳三键的烃链。
如本文所用术语“卤素或卤基”代表氟、氯、溴或碘。
如本文所用术语“卤代烷基”意指在烷基上经至少一个卤素原子取代。卤素和烷基二者都具有如上文所定义的含义。
如本文所用术语“羟基”(“Hydroxy”或“Hydroxyl”)代表—OH。
如本文所用术语“羟基烷基”意指烷基的至少一个氢原子由羟基替代。烷基是如上文所定义。
如本文所用术语“卤代烷氧基”意指在烷氧基上经至少一个卤素取代，其中烷氧基及卤素基团是如上文所定义。
如本文所用术语“烷氧基羰基”并且如本文所用表示式—C(＝O)OR的基团，其中R是烷基；烷基如本文所定义。
如本文所用术语“3到10元杂环”是指单环或多环系统、饱和或不饱和或芳香族；含有一个氮原子和任选地1到3个独立地选自O、S、N、CO、SO或SO2的额外杂原子或杂基团。
如本文所用术语“杂芳香族环”或“Het-Ar环”应理解为涵盖具有5或6个原子、含有一或多个选自氮、氧和硫的独立杂原子的任何杂环芳香族环。应注意，杂原子可位于所形成稠合5到6元杂芳香族环上的任何位置。
如本文所用术语“环烷基”表示含有3到6个碳原子的饱和碳环。
如本文所用术语“杂原子”是指硫、氮或氧原子。
如本文所用术语“氨基羰基”是指式-(CO)N(R2)2的单价基团，其中每一R2都独立地是氢或烷基。
如本文所用术语“芳基”是指单环或多环芳香族环系统。实例性芳基包括(但不限于)苯基、萘基等等。
如本文所用术语“杂环基”、“杂环”(“heterocycle”或“heterocyclic”)代表稳定5到7元单环或稳定8到11元二环杂环，其是饱和或不饱和的，并且其由碳原子和1到4个选自由N、O或S组成的群组的杂原子组成，并且包括上文定义的杂环中的任一者稠合到苯环的任何二环基团。
如本文所用术语“碳环”是指饱和或非芳香族不饱和环。术语“3到6元碳环”是指其中环碳原子数是3到6的碳环。
如本文所用术语“氰基”是指碳原子由三键接合到氮原子的的取代基。
如本文所用术语“硝基”是指基团—NO2。
如本文所用术语“氨基”是指基团—NH2。
如本文所用术语“羰基”是指二价基团—C(O)-。
如本文所用术语“氰基(1-3C烷基)”表示其中烷基的氢原子由氰基(-CN)替代的如上文所定义的烷基。
如本文所用术语“配体”或“L”表示连接体分子或配体分子。实例性配体或连接体分子包括(但不限于)—O—、—NH—、—SO2N(R')—、—C(O)N(R')—；—N(R')C(O)—、—C(O)N(R')C(O)—、—N(R')SO2—、—N(R')SO2N(R')—、—NR'C(O)N(R')—、—NR'C(S)N(R')—或—N(R')C(O)O—。
如本文所用术语“杂芳基”，如本文所用，除非另有说明，否则代表稳定5到7元单环-或稳定9到10元稠合二环杂环系统，其含有芳香族环，其中的任一环都可为饱和、部分饱和或不饱和的，并且其由碳原子和1到4个选自由N、O和S组成的群组的杂原子组成。
如本文所用，除非另外明确定义，否则经取代的烷基、经取代的芳基、经取代的杂芳基和经取代的杂环包括除化合物的其余部分的附接点外还含有1到3个取代基的部分。
如本文所用术语“任选地经取代”意指取代是可选的并且因此指定原子或基团可未经取代。在原子或基团上存在一个以上取代基时，所选取代基彼此独立(也就是相同或不同)。
如本文所用术语“立体异构体”是用于个别分子中仅在空间中其原子的取向不同的所有异构体的一般术语。应理解，本发明化合物的所有立体异构形式(包括但不限于非对映异构体、对映异构体和阻转异构体，以及其混合物，例如形式)都包括在本申请案的范畴内。
如本文所用术语“互变异构体”是指共存两种(或更多种)仅一个(或多个)可移动原子的位置以及电子分布彼此不同的化合物，例如酮-烯醇互变异构体。
如本文所用术语“医药上可接受的”是指载剂、稀释剂、盐、溶剂合物或赋形剂必须与调配物的其它成分相容并且对其接受者无害。
如本文所用，如本文所用术语“代谢物”是指在投与母化合物后在个体中产生的任何衍生物的式。衍生物可通过个体中的各种生物化学转变(例如氧化、还原、水解或偶联)从母化合物产生并且包括(例如)氧化物和去甲基化衍生物。
如本文所用术语“前药”是指通过(例如)在血液中水解在活体内快速转变以得到上式的母化合物的化合物以及本发明化合物的两性离子形式。
如本文所用术语‘治疗有效量’是指在投与个体时有效用于以下的本发明化合物的量：(i)至少部分缓和、抑制、预防和/或改善由TrkA、TrkB和/或TrkC介导、与TrkA、TrkB和/或TrkC活性相关或特征在于TrkA、TrkB和/或TrkC的活性(正常或异常)的病况或病症或疾病；(ii)降低或抑制TrkA、TrkB和/或TrkC的活性；或(iii)降低或抑制TrkA、TrkB和/或TrkC的表达。
如本文所用术语“融合物”或“融合蛋白”是指两种或更多种蛋白质或其片段通过其个别肽主链、最优选地通过编码那些蛋白质的多核苷酸分子的基因表达的共线、共价链接。
如本文所用术语“TrkA”是指由神经营养因子(NT)(一组可溶性生长因子神经生长因子(NGF)、脑源神经营养因子(BDNF)和神经营养因子3-5(NT 3-5))活化的Trk的高亲和力结合蛋白激酶受体之一。Trk是由结合并介导源自神经营养物的信号转导的TrkA、TrkB和TrkC的三个家族成员构成。已展现，Trk/神经营养因子路径的抑制剂在众多临床前动物疼痛模型中高度有效。本发明化合物是Trk受体、具体来说TrkA的调节剂。
本发明涉及用作Trk家族蛋白激酶的成员的抑制剂的新颖化合物。具体来说，本发明揭示具有针对TrkA的抑制活性的化合物。本发明化合物可用作用于预防性和/或治疗性治疗上文所提到的疾病的药剂的活性成分。
根据本发明的实施例，化合物是由通式I代表：
或其立体异构体、互变异构体，或医药上可接受的盐、溶剂合物、代谢物、同位素或前药，其中：
Ra和Rb各自独立地选自H、烷基、烯基、炔基、卤代烷基、卤素、羟基、羟基烷基、烷氧基、卤代烷氧基、任选经取代的苯基、具有1到3个选自O、N和S的杂原子的任选经取代的5到6元芳香族环，或Ra和Rb一起形成羰基、进一步任选地经卤素取代的任选经取代的苯基；
Rc和Rd是H、烷基、烯基、炔基、卤代烷基、羟基、烷氧基、卤代烷氧基、任选经取代的苯基、具有1到3个选自O、N和S的杂原子的任选经取代的5到6元芳香族环，或Rc和Rd一起形成具有或无杂原子的环(4到6元)；
R1是H、烷基、烯基、炔基、卤代烷基、羟基、烷氧基、卤代烷氧基、(1-3C烷氧基)(1-3C)烷基、(1-4C烷氧基羰基)(1-6C烷基)、单、二、三卤代(1-4C烷基)、(1-3C烷基)氨基羰基、氰基(1-3C烷基)、(1-3C卤代烷氧基)(1-3C)烷基、任选经取代的苯基；3到6元碳环或杂环，其具有一或多个选自O、N或S的杂原子且任选地经一或多个独立地选自以下的取代基取代：H、烷基、烯基、炔基、卤代烷基、卤素、羟基、烷氧基、卤代烷氧基、硝基或氨基；具有1到3个环氮原子的9到10元二环杂芳基；
R2和R3独立地选自H、烷基、烯基、炔基、异丙基、叔丁基、卤代烷基、卤素、羟基、烷氧基、卤代烷氧基、任选经取代的苯基，或具有1到3个选自O、N或S的杂原子的任选经取代的5到6元芳香族环，或R2与R3能够组合以形成具有1到2个杂原子的环(5/6元)。
L是选自—O—、—NH—、—SO2N(R')—、—C(O)N(R')—；—N(R')C(O)—、—C(O)N(R')C(O)—、—N(R')SO2—、—N(R')SO2N(R')-、—NR'C(O)N(R')—、—NR'C(S)N(R')—或—N(R')C(O)O-的配体；
每一R'都独立地选自H或烷基；
Het-Ar环是选自H1或H2；
X1到X7在每次出现时是键、-CR5-、-CH2-或选自N、O或S的杂原子；
X8是选自O、S、NH、N-烷基、SO、SO2或C＝O。
R4、R5和R6各自独立地选自由以下组成的群组：H、烷基、烯基、炔基、异丙基、叔丁基、卤代烷基、卤素、单、二、三卤代(1-4C烷基)羟基、烷氧基、卤代烷氧基、氰基、环烷基(3到7个碳)、任选经取代的苯基、具有1到3个选自O、N或S的杂原子的任选经取代的5到6元杂环或具有一或多个选自O、N或S的杂原子的3到6元碳环、—NH2、—N(H)(烷基)、—N(烷基)2、—N(H)C(O)烷基、—N(烷基)C(O)烷基、—N(H)C(O)O烷基、—N(烷基)C(O)O烷基、—N(H)SO2(烷基)、—N(烷基)SO2(烷基)、—C(O)烷基、—C(O)OH、—C(O)O烷基、—C(O)NH2、—C(O)N(H)(烷基)、—C(O)N(烷基)2、—S(烷基)、—S(O)烷基、—S(O)2烷基、—S(O)2N(H)2、—S(O)2N(H)(烷基)和—S(O)2N(烷基)2。
在另一实例性实施例中，其中L是脲或任选经取代的脲。
在另一实例性实施例中，其中L是经取代的脲并且每一R'可接合在一起以形成5到6元环结构。
根据实例性实施例，其中H1是选自由以下组成的群组，但不限于其：
并且R4、R5各自独立地选自由以下组成的群组：H、烷基、烯基、炔基、异丙基、叔丁基、卤代烷基、卤素、单、二、三卤代(1-4C烷基)羟基、烷氧基、卤代烷氧基、氰基、环烷基(3到7个碳)、任选经取代的苯基、具有1到3个选自O、N或S的杂原子的任选经取代的5到6元杂环或具有一或多个选自O、N或S的杂原子的3到6元碳环、—NH2、—N(H)(烷基)、—N(烷基)2、—N(H)C(O)烷基、—N(烷基)C(O)烷基、—N(H)C(O)O烷基、—N(烷基)C(O)O烷基、—N(H)SO2(烷基)、—N(烷基)SO2(烷基)、—C(O)烷基、—C(O)OH、—C(O)O烷基、—C(O)NH2、—C(O)N(H)(烷基)、—C(O)N(烷基)2、—S(烷基)、—S(O)烷基、—S(O)2烷基、—S(O)2N(H)2、—S(O)2N(H)(烷基)和—S(O)2N(烷基)2。
根据另一实例性实施例，其中H2是选自由以下组成的群组，但不限于其：
并且每一R6都独立地选自由以下组成的群组：H、烷基、烯基、炔基、异丙基、叔丁基、卤代烷基、卤素、单、二、三卤代(1-4C烷基)羟基、烷氧基、卤代烷氧基、氰基、环烷基(3到7个碳)、任选经取代的苯基、具有1到3个选自O、N或S的杂原子的任选经取代的5到6元杂环或具有一或多个选自O、N或S的杂原子的3到6元碳环、—NH2、—N(H)(烷基)、—N(烷基)2、—N(H)C(O)烷基、—N(烷基)C(O)烷基、—N(H)C(O)O烷基、—N(烷基)C(O)O烷基、—N(H)SO2(烷基)、—N(烷基)SO2(烷基)、—C(O)烷基、—C(O)OH、—C(O)O烷基、—C(O)NH2、—C(O)N(H)(烷基)、—C(O)N(烷基)2、—S(烷基)、—S(O)烷基、—S(O)2烷基、—S(O)2N(H)2、—S(O)2N(H)(烷基)和—S(O)2N(烷基)2。
根据实施例，本发明提供医药组合物，其包含治疗有效量的所选式I化合物或其生理上可接受的盐、其立体异构体、其溶剂合物或其水合物，或其代谢物或同位素作为活性成分。上文所提到的医药组合物用于预防性和/或治疗性治疗由异常或失调TrkA活性引起的疾病。涉及异常TrkA活性的疾病可为以下中的一或多者，但不限于其：疼痛、炎症或炎症性疾病、癌症、动脉粥样硬化、再狭窄、血栓形成、神经退化性疾病、勃起功能障碍(ED)、皮肤病症、自体免疫疾病(如多发性硬化)、斯耶格伦综合症、子宫内膜异位症、糖尿病性周围神经病变、前列腺炎、传染病、与骨重塑的调节失衡有关的疾病、子宫内膜异位症、骨盆疼痛综合症和由异常组织重塑和纤维变性病症导致的疾病；或与髓鞘形成障碍或脱髓鞘有关的疾病、病症、损伤，或功能失常，或与神经生长因子(NGF)受体TrkA的异常活性相关的疾病或病症。
根据本发明的另一实施例，提供预防和/或治疗性治疗选自包含以下的群组的疾病或病症的方法：疼痛、炎症或炎症性疾病、癌症、动脉粥样硬化、再狭窄、血栓形成、神经退化性疾病、勃起功能障碍(ED)、皮肤病症、自体免疫疾病(如多发性硬化)、斯耶格伦综合症、子宫内膜异位症、糖尿病性周围神经病变、前列腺炎、传染病、与骨重塑的调节失衡有关的疾病、子宫内膜异位症、骨盆疼痛综合症和由异常组织重塑和纤维变性病症导致的疾病；或与髓鞘形成障碍或脱髓鞘有关的疾病、病症、损伤，或功能失常，或与神经生长因子(NGF)受体Trk A的异常活性相关的疾病或病症。
根据本发明的另一实施例，提供通过向患者投与治疗有效量的式I化合物来抑制患者的原肌球蛋白受体激酶A(TrkA)的方法。
根据本发明的又一实施例，通过向患者投与治疗有效量的式I化合物或医药上可接受的盐和医药上可接受的载剂来预防和/或治疗性治疗上文所提到的疾病或病症的方法。
根据本发明的又一实施例，提供可用于预防性和/或治疗性治疗炎症性疾病的药剂。特定来说，本发明化合物用于预防性和/或治疗性治疗选自肺病、肠病、间质性膀胱炎和疼痛性膀胱综合症的炎症性疾病。
炎症性肺病是气喘或间质性膀胱炎，并且炎症性肠病是溃疡性结肠炎、克罗恩氏病或尿失禁。
根据本发明的又一实施例，提供预防性和/或治疗性治疗急性或慢性疼痛的方法。特定来说，本发明化合物用于预防性和/或治疗性治疗选自以下的急性疼痛和慢性疼痛：癌症诱导的疼痛、骨折疼痛、炎症性疼痛、神经性疼痛、手术、骨折、由肿瘤转移引起的骨骼疼痛、骨关节炎、牛皮癣关节炎、类风湿性关节炎、间质性膀胱炎、慢性胰脏炎、内脏疼痛、炎症性疼痛、偏头痛、慢性下背疼痛、膀胱疼痛综合症、股骨破裂疼痛、痛觉过敏、反复运动疼痛、牙痛、肌筋膜疼痛、痛经、以及与绞痛相关的疼痛。
根据本发明的又一实施例，提供预防性和/或治疗性治疗骨重塑调节失衡的方法。特定来说，本发明化合物用于预防性和/或治疗性治疗骨质疏松症、类风湿性关节炎、和骨转移、溶骨性转移、威胁生命的高钙血症、脊髓压迫症、关节粘连性脊椎炎、肿瘤诱导的骨质溶解、牙周病。
根据本发明的又一实施例，本发明化合物可用于降低对疼痛的类鸦片治疗和(例如)酒精、类鸦片和古柯碱(cocaine)的戒断综合症治疗的耐受性和/或依赖性。
根据本发明的又一实施例，提供预防性和/或治疗性治疗异常组织重塑和纤维变性病症的方法。特定来说，本发明化合物用于预防性和/或治疗性治疗异常组织重塑和纤维变性病症，其选自特发性肺纤维化、雷诺氏综合症(Raynaud's syndrome)、子宫内膜纤维化、心房纤维化、骨髓纤维化、进行性大块纤维化、肾源性系统性纤维化、硬皮症、全身性硬化、关节纤维化、眼纤维化、结瘢和硬化。
根据本发明的又一实施例，提供可用于预防性和/或治疗性治疗与TrkA失调有关的癌症的药剂。TrkA的失调是由于染色体重排，如TrkA蛋白中的一或多个染色体易位、过表达、转化、插入、缺失或突变。已显示这些重排是多种癌症(如非小细胞肺癌、结肠直肠癌、乳头状甲状腺癌、神经胶质母细胞瘤、黑色素瘤、急性骨髓性白血病、大细胞神经内分泌癌、胃癌、胰脏癌、前列腺癌、头颈部鳞状细胞癌)中的致癌驱动。
由于一或多个染色体易位或转化的TrkA失调导致形成TrkA基因融合物。TrkA基因融合物可为LMNA-TrkA、TFG-TrkA、TPM3-TrkA、CD74-TrkA、NFASC-TrkA、MPRIP-TrkA、BCAN-TrkA、TP53-TrkA、RNF213-TrkA、RABGAP1L-TrkA、IRF2BP2-TrkA、SQSTMI-TrkA、SSBP2-TrkA或TPR-TrkA。
根据本发明的又一实施例，提供可用于预防性和/或治疗性治疗癌症的药剂。特定来说，本发明化合物用于预防性和/或治疗性治疗选自以下的癌症：肺腺癌、乳癌、甲状腺癌、胰脏癌、卵巢癌、胃癌(gastric carcinoma)、恶性间皮瘤、前列腺癌、神经胚细胞瘤、结肠直肠癌、斯皮茨样黑色素瘤、唾液腺样囊性癌、胃癌(stomach cancer)、肾癌、尿道癌、多形性神经胶质母细胞瘤、口腔鳞状细胞癌、急性骨髓性白血病、胆管癌、肥大细胞增多症或乳房外佩吉特病(Paget's disease)。
根据本发明的又一实施例，根据待治疗或预防的特定病况，可将额外治疗剂与本发明化合物一起投与。在一些情形下，通常投与这些额外治疗剂以治疗或预防相同病况。例如，可组合甲氨蝶呤与本发明化合物以治疗白血病。
根据一实施例，额外治疗剂是选自抗TNF药物，或其与循环受体融合蛋白(例如依那西普(etanercept)(恩博(Enbrel))一起、靶向激酶抑制剂，这些额外治疗剂可与式I化合物或其医药上可接受的盐一起作为相同或单独剂型的部分、通过相同或不同投与途径、并以相同或不同投与时间表根据所属领域技术人员已知的标准医药实践投与。
根据另一实施例，额外治疗剂是选自抗炎症性化合物、类固醇、止痛药、类鸦片、降钙素基因有关的肽受体拮抗剂、亚型选择性离子通过调节剂、抗痉挛剂、双重血清素-去甲肾上腺素再摄取抑制剂、KSP(纺锤体驱动蛋白)抑制剂、JAK家族激酶抑制剂、和三环抗抑郁药、卡博替尼(cabozantinib)、克唑替尼(crizotinib)、厄洛替尼(erlotinib)、吉非替尼(gefitinib)、伊马替尼(imatinib)、拉帕替尼(lapatinib)、尼罗替尼(nilotinib)、帕唑帕尼(pazopanib)、帕妥珠单抗(pertuzumab)、瑞格菲尼(regorafenib)、舒尼替尼(sunitinib)、和曲妥珠单抗(trastuzumab)、索拉菲尼(sorafenib)、曲美替尼(trametinib)、威罗菲尼三氧化砷(vemurafenib arsenic trioxide)、博来霉素(bleomycin)、卡巴他赛(cabazitaxel)、卡培他滨(capecitabine)、卡铂(carboplatin)、顺铂(cisplatin)、环磷酰胺(cyclophosphamide)、阿糖胞苷(cytarabine)、达卡巴嗪(dacarbazine)、道诺霉素(daunorubicin)、多西他赛(docetaxel)、多柔比星(doxorubicin)、依托泊苷(etoposide)、氟尿嘧啶(fluorouracil)、吉西他滨(gemcitabine)、伊立替康(irinotecan)、洛莫司汀(lomustine)、甲氨蝶呤(methotrexate)、丝裂霉素C(mitomycin C)、奥沙利铂(oxaliplatin)、太平洋紫杉醇(paclitaxel)、培美曲塞(pemetrexed)、替莫唑胺(temozolomide)、长春新碱(vincristine)、阿柏西普(Aflibercept)、贝伐珠单抗(bevacizumab)、阿地白介素(aldesleukin)、伊匹单抗(ipilimumab)、兰布鲁珠单抗(lambrolizumab)、尼沃鲁单抗(nivolumab)和西普鲁塞-T(sipuleucel-T)。
一或多种式I化合物可以在本申请案的范畴内的治疗组合物形式供应。
除非另有定义，否则本文所使用的所有技术和科学术语具有与所属领域技术人员通常所理解的含义相同的含义。
实例
本发明化合物的实例示于表1中。
表1：式I的实例性化合物(实例1到202)
上文提及的化合物仅用于实例性目的并且不限制本发明的范畴。
制备本发明化合物的若干方法阐释于以下反应方案和实例中。起始材料和必需中间体在一些情形下有市售，或可根据文献程序或如本文所阐释制备。
除在文献中得知或在实验程序中所例示的其它标准操作以外，本发明化合物还可通过利用如以下方案中所示反应来制备。如这些方案中所示的取代基编号并非必须与权利要求书中所用者相关，且通常为简便起见，当在上文定义中允许有多个取代基时，显示附接到所述化合物的单一取代基。除如在文献中可知或在实验程序中所例示的其它标准操作(例如酯水解、保护基团解离等)以外，用于产生本发明化合物的反应是通过利用如本文方案和实例中所示的反应制备。
反应方案：本发明化合物可根据以下方案和具体实例或其修改形式、使用容易获得的起始材料、试剂和常规合成程序容易地制得。在这些反应中，还可利用自身为所述领域的技术人员已知但未更详细提及的变化形式。所述领域的技术人员参阅以下方案可容易地理解并了解制备本发明中所主张的化合物的一般程序。
方法1
方法2
方法3
实验部分：
所有市售试剂和溶剂都是从柯姆比-布劳科斯(combi-blocks)、奥德里奇(Aldrich)、阿瓦拉(Avra)等购得，并且按原样使用。使用空气或水分敏感性试剂的反应是在氮气氛下使用新打开的缀萨瓦(drySolv)溶剂进行。通过TLC和/或LCMS监测反应进展。急速管柱色谱是利用格拉斯(Grace)纯化系统或艾斯卡柯姆比急速伴侣系统(Isco CombiFlash Companion System)使用预填充的硅胶管柱(40-60μm粒径瑞迪赛普(RediSep)或20-40μm球形硅胶瑞迪赛普古德(RediSep Gold)管柱或瑞瓦乐瑞斯(reveleris)管柱或来自其它供应商的类似管柱)进行。利用鲁道夫(Rudolph)记录比旋度并利用布奇(Buchi)仪器记录熔点。利用安捷伦(Agilent)或沃特世(Waters)仪器进行制备型反相HPLC纯化。利用安捷伦300或400MHz光谱仪测量NMR谱，并且使用残余非氘化溶剂作为内標準品(CHCl3，7.26ppm；DMSO，2.50ppm；MeOH，3.31ppm)以距TMS的低场的ppm报告化学位移。使用以下缩写：br＝宽，s＝单峰，d＝双重峰，dd＝双重峰的双重峰，t＝三重峰，q＝四重峰，m＝多重峰。在所有情形下通过HPLC使用固定相和水/乙腈的梯度(5-95％经10min，两个相中0.05％TFA)以0.4mL/min的流速检验最终化合物的纯度。
下文描述的式I化合物的合成所需的中间体的清单.
中间体的制备
某些中间体直接购自商业供应商并且原样用于式I的实例的相应合成。其它中间体是通过以下所报道的文献程序或根据需要修改或应用利用适当取代衍生化中的技能来制备。
中间体A：喹啉中间体(A1到A72)
方案1(所述方案描述于欧洲化学杂志(Chemistry-A European Journal)，2012，18，5530-5535；四面体(Tetrahedron)，2004，60，2937-2942中)。
方案2(所述方案描述于有机化学杂志(J.Org.Chem.)2004，69，1565-1570中)
方案3(所述方案描述于WO2014062667A1中)
方案4
方案5(所述方案的部分描述于US2008/161340A1中)
例如A1-A5等中间体是购自商业供应商并且其它中间体A6-A72是基于上文一般方案1-5合成并且下文显示分析型数据。
中间体A1：喹啉-3-胺
中间体A2：2-氯喹啉-3-胺
中间体A3：喹啉-4-胺
中间体A4：喹唑啉-4-胺
中间体A5：喹喏啉-2-胺
中间体A6：2-苯基喹啉-3-胺。LCMS(M+H):221.10
中间体A7：2-甲基喹啉-3-胺。LCMS(M+H):158.95。
中间体A8：2-乙基喹啉-3-胺。LCMS(M+H):173.12。
中间体A9：2-(环丙基)-喹啉-3-胺。LCMS(M+H):185.28。
中间体A10：2-(三氟甲基)-喹啉-3-胺。LCMS(M+H):213.10。
中间体A11：6-氟-2-苯基喹啉-3-胺。LCMS(M+H):238.95。
中间体A12：7-氟-2-苯基喹啉-3-胺。1H NMR(DMSO-d6,300MHz):δ7.77-7.72(m,3H),7.60-7.37(m,5H),7.40-7.30(m,1H),5.24(s,2H)。
中间体A13：6-甲氧基-2-苯基喹啉-3-胺。1H NMR(DMSO-d6,300MHz):δ7.72-7.66(m,3H),7.53-7.44(m,3H),7.30(s,1H),7.03-6.97(m,2H),5.22(s,2H),3.87(s,3H)。
中间体A14：6,7-二甲氧基-2-苯基喹啉-3-胺。LCMS(M+H):281.19。
中间体A15：6,7-二甲氧基-2-甲基喹啉-3-胺。LCMS(M+H):219.24。
中间体A16：6-氟-2-甲基喹啉-3-胺。LCMS(M+H):177.08。
中间体A17：6-甲基-2-甲基喹啉-3-胺。LCMS(M+H):173.12。
中间体A18：7-甲基-2-甲基喹啉-3-胺。LCMS(M+H):173.12。
中间体A19：5-甲基-2-甲基喹啉-3-胺。LCMS(M+H):173.05
中间体A20：5-氟-2-甲基喹啉-3-胺。LCMS(M+H):177.04。
中间体A21：8-甲基-2-甲基喹啉-3-胺。LCMS(M+H):173.30。
中间体A22：8-氟-2-甲基喹啉-3-胺。LCMS(M+H):177.25。
中间体A23：5-甲氧基-2-甲基喹啉-3-胺。LCMS(M+H):189.29。
中间体A24：6-甲氧基-2-甲基喹啉-3-胺。LCMS(M+H):189.29。
中间体A25：7-甲氧基-2-甲基喹啉-3-胺。LCMS(M+H):189.03。
中间体A26：8-甲氧基-2-甲基喹啉-3-胺。LCMS(M+H):189.10。
中间体A27：7-氟-2-甲基喹啉-3-胺。LCMS(M+H):177.08。
中间体A28：6-甲氧基-2-甲基-7-吗啉基喹啉-3-胺。LCMS(M+H):274.10。
中间体A29：6-氟-7-甲基-2-苯基喹啉-3-胺。LCMS(M+H):253.31。
中间体A30：6-溴-8-甲氧基-2-甲基喹啉-3-胺。
中间体A31：8-甲氧基-2,7-二甲基喹啉-3-胺。LCMS(M+H):265.46。
中间体A32：6-苯基-[1,3]二氧杂环戊烯并[4,5-g]喹啉-7-胺。LCMS(M+H):265.25。
中间体A33：N-(3-氨基-7-甲氧基-2-苯基喹啉-6-基)乙酰胺。LCMS(M+H):308.16。
中间体A34：8-溴-2-甲基喹啉-3-胺。LCMS(M+H+2H):238.93。
中间体A35：6-甲基-[1,3]二氧杂环戊烯并[4,5-g]喹啉-7-胺。LCMS(M+H):203.07。
中间体A36：7-甲基-2,3-二氢-[1,4]二氧杂环己烯并[2,3-g]喹啉-8-胺。LCMS(M+H):217.11。
中间体A37：7-苯基-2,3-二氢-[1,4]二氧杂环己烯并[2,3-g]喹啉-8-胺。LCMS(M+H):279.11。
中间体A38：N-(3-氨基-6-甲氧基-2-苯基喹啉-7-基)乙酰胺。LCMS(M+H):308.16。
中间体A39：N-(3-氨基-6-甲氧基-2-甲基喹啉-7-基)乙酰胺。LCMS(M+H):246.13。
中间体A40：6-甲氧基-7-甲基-2-苯基喹啉-3-胺。LCMS(M+H):265.16。
中间体A41：3-氨基-7-氟-2-甲基喹啉-6-甲腈。LCMS(M+H):202.06。
中间体A42：3-氨基-7-甲氧基-2-甲基喹啉-6-甲腈。
中间体A43：3-氨基-6-氟-2-甲基喹啉-7-甲腈。LCMS(M+H):202.03。
中间体A44：3-氨基-6-氟-2-苯基喹啉-7-甲腈。LCMS(M+H):264.13。
中间体A45：3-氨基-6-甲氧基-2-苯基喹啉-7-甲腈。1H NMR(DMSO-d6,300MHz):δ8.17(s,1H),7.70-7.67(m,2H),7.55-7.48(m,3H),7.28(d,J＝13.2Hz,2H),5.81(b s,2H),3.97(s,3H)。
中间体A46：6-(二氟甲氧基)-7-甲氧基-2-甲基喹啉-3-胺。LCMS(M+H):255.05。
中间体A47：2,2-二氟-6-甲基-[1,3]二氧杂环戊烯并[4,5-g]喹啉-7-胺。LCMS(M+H):239.20。
中间体A48：2-环己基喹啉-3-胺。LCMS(M+H):227.42。
中间体A49：6-(三氟甲基)-[1,3]二氧杂环戊烯并[4,5-g]喹啉-7-胺。LCMS(M+H):257.19。
中间体A50：7-甲基-2-苯基-1,8-萘啶-3-胺。LCMS(M+H):236.22。
中间体A51：6,7-二甲氧基喹啉-3-胺。LCMS(M+H):205.04。
中间体A52：[1,3]二氧杂环戊烯并[4,5-g]喹啉-7-胺。LCMS(M+H):189.07。
中间体A53：6-甲基-2-苯基喹啉-3-胺。LCMS(M+H):235.1。
中间体A54：6-氟-3-氨基-2-苯基喹啉。LCMS(M+H):238.95。
中间体A55：7-甲基-3-氨基-2-苯基喹啉。LCMS-(M+H):234.99。
中间体A56：7-甲氧基-2-苯基喹啉-3-胺。LCMS(M+H):251.10。
中间体A57：7-氟-6-甲氧基-2-苯基喹啉-3-胺。LCMS(M+H):269.13。
中间体A58：7-氟-6-甲基-2-苯基喹啉-3-胺。LCMS(M+H):253.08。
中间体A59：N-(3-氨基-7-氟-2-苯基喹啉-6-基)乙酰胺。
中间体A60：6-甲氧基-7-甲基-2-甲基喹啉-3-胺。LCMS(M+H):203.20。
中间体A61：6-甲氧基-7-氟-2-甲基喹啉-3-胺。LCMS(M+H):207.03。
中间体A62：(3-氨基-7-甲氧基-2-甲基喹啉-6-基)(甲基)氨基甲酸叔丁基酯。LCMS(M+H):380.24。
中间体A63：2-(1-甲基-1H-吡唑-4-基)喹啉-3-胺。LCMS(M+H):224.94。
中间体A64：2-(吡啶-3-基)喹啉-3-胺。LCMS(M+H):222.23。
中间体A65：2-(吡啶-4-基)喹啉-3-胺。LCMS(M+H):222.23。
中间体A66：2-(嘧啶-5-基)喹啉-3-胺。LCMS(M+H):223.12。
中间体A67：2-(噻唑-5-基)喹啉-3-胺。LCMS(M+H):228.17。
中间体A68：2-(2,4-二氟苯基)喹啉-3-胺。LCMS(M+H):257.15。
中间体A69：2-(3,5-二氟苯基)喹啉-3-胺。LCMS(M+H):257.15。
中间体A70：2-吗啉基喹啉-3-胺。LCMS(M+H):230.29。
中间体A71：2-苯基-5,6,7,8-四氢喹啉-3-胺。LCMS:(M+H):225.04。
中间体A72：6-(二氟甲基)-[1,3]二氧杂环戊烯并[4,5-g]喹啉-7-胺。LCMS(M+H):239.01。
中间体D：二苯并呋喃和二苯并噻吩中间体(D1-D10)
中间体D1-D10是基于方案6-8合成并且下文显示每一中间体的分析型数据。
方案6(所述方案描述于合成(Synthesis)，1983，234-235中)
方案7(所述方案描述于医药化学杂志(J.Med.Chem.)2010,53，8498-8507中)
方案8(所述方案描述于美国化学学会杂志(J.Am.Chem.Soc)，1954，76，2906-2908中)
D1-D10的分析型数据
中间体D1：6-甲氧基二苯并[b,d]呋喃-1-胺。LCMS(M+H):214.10。
中间体D2：二苯并[b,d]呋喃-1-胺。LCMS(M+H):184.10。
中间体D3：8-甲基二苯并[b,d]呋喃-1-胺。LCMS(M+H):198.00。
中间体D4：8-甲氧基二苯并[b,d]呋喃-1-胺。1H NMR(CDCl3,300MHz):δ8.44(s,1H),8.28-8.25(m,1H),8.03-8.00(m,1H),7.57-7.54(m,1H),7.45(m,1H),7.21-7.18(m,1H),3.94(s,3H)。
中间体D5：8-氟二苯并[b,d]呋喃-1-胺。1H NMR(CDCl3,300MHz):δ7.51-7.45(m,2H),7.30-7.28(m,1H),7.15(dt,J＝2.4,9.0Hz,1H),7.01(d,J＝8.4Hz,1H),6.63(d,J＝8.4Hz,1H)。
中间体D6：7-氟二苯并[b,d]呋喃-1-胺。LCMS(M+H):202.20。
中间体D7：7-甲氧基二苯并[b,d]呋喃-1-胺。LCMS(M+H):214.20。
中间体D8：6-甲基二苯并[b,d]呋喃-1-胺。
中间体D9：4-甲氧基-5,5-二氧代-二苯并[b,d]噻吩-1-基胺。LCMS(M+H):262.03。
中间体D10：5,5-二氧代-二苯并[b,d]噻吩-1-基胺。LCMS(M+H):231.95。
中间体I：异喹啉中间体(I1-I30)
中间体I1-I30是基于一般方案9-12合成并且下文显示每一中间体的分析型数据。
方案9(方案的部分描述于WO 2007/53346A1和欧洲化学杂志，2013，19，11553-11557中)
方案10(所述方案描述于WO 2007/53346A1中)
方案11(方案的部分描述于有机化学通讯(Org.Lett.)2009，11，2469-2472中)
方案12(方案的部分描述于杂环(Heterocycles)，2000，52，1371-1383中)
I1-I30d分析型数据
中间体I1：7-氟-1-甲基-3-苯基异喹啉-4-胺。LCMS:(M+H)＝253.10。
中间体I2：1-(1-甲基-1H-吡唑-4-基)-3-苯基异喹啉-4-胺。LCMS(M+H):301.34。
中间体I3：7-甲氧基-1-甲基-3-苯基异喹啉-4-胺。LCMS:(M+H)＝265.31。
中间体I4：1-甲基-3-苯基异喹啉-4-胺。LCMS:(M+H):235.09。
中间体I5：1,7-二甲基-3-苯基异喹啉-4-胺。LCMS:(M+H):249.41。
中间体I6：3-苯基-1-(吡啶-3-基)异喹啉-4-胺。LCMS:(M+H):298.41。
中间体I7：8-甲氧基-1-甲基-3-苯基异喹啉-4-胺。LCMS:(M+H):265.08。
中间体I8：1,3-二苯基异喹啉-4-胺。
中间体I9：6-甲氧基-1-甲基-3-苯基异喹啉-4-胺。LCMS:(M+H):265.25。
中间体I10：1,6-二甲基-3-苯基异喹啉-4-胺。LCMS:(M+H):249.23。
中间体I11：6,7-二甲氧基-1-甲基-3-苯基异喹啉-4-胺。LCMS:(M+H):295.39。
中间体I12：6-氟-1-甲基-3-苯基异喹啉-4-胺。LCMS:(M+H)＝295.39。
中间体I13：1-氯-3-苯基异喹啉-4-胺。ESI-MS m/z:255.34(M+H)+。
中间体I14：5-甲氧基-3-苯基异喹啉-4-胺。LCMS:(M+H):251.07。
中间体I15：8-氟-3-苯基异喹啉-4-胺。LCMS:(M+H):239.09。
中间体I16：7-氟-3-苯基异喹啉-4-胺。LCMS:(M+H)＝239.07。
中间体I17：1-(1-甲基-1H-吡唑-4-基)异喹啉-4-胺。LCMS:(M+H)＝225.28。
中间体I18：3-甲基-1-(1-甲基-1H-吡唑-4-基)异喹啉-4-胺。ESI-MS m/z:239.36(M+H)+。
中间体I19：3-苯基异喹啉-4-胺。ESI-MS m/z:221.08(M+H)+。
中间体I20：3-甲基异喹啉-4-胺。ESI-MS m/z:159.24(M+H)+。
中间体I21：4-氨基异喹啉-3-甲腈。ESI-MS m/z:170.05(M+H)+。
中间体I22：3-(3-氟苯基)-1-甲基异喹啉-4-胺。LC-MS(M+H)+:253.23。
中间体I23：3-(2-氟苯基)-1-甲基异喹啉-4-胺。LC-MS(M+H):253.32。
中间体I24：1-甲氧基-3-苯基异喹啉-4-胺。LCMS:(M+H):251.03
中间体I25：(4-氨基-3-苯基异喹啉-1-基)氨基甲酸叔丁基酯。LCMS:(M+H):336.24。
中间体I26：1-氟-3-苯基异喹啉-4-胺。ESI-MS m/z:239.29(M+H)+。
中间体I27：4-氨基-3-苯基异喹啉-1-甲腈。ESI-MS m/z:246.21(M+H)+。
中间体I28：1-吗啉基-3-苯基异喹啉-4-胺。LCMS:(M+H)＝306.42。
中间体I29：1-(4-氨基-3-苯基异喹啉-1-基)哌啶-4-醇。LCMS:(M+H)＝320.26。
中间体I30：4-氨基-7-氟-3-苯基异喹啉-1-羧酸甲基酯。LCMS:(M+H)＝296.94。
中间体B：吡咯烷-3-胺(B1-B21)
经取代的吡咯烷-3-胺中间体是通过使用适当起始材料基于所报道文献方法(WO2012/125668，WO2014/078378，治疗术专利专家评述，2014，24(7)，731-744，医药化学杂志，2012，55，8903-8925，WO2011/147951，化学学会化学通讯杂志(J.Chem.Soc,Chem.Commun.)1985，1566-1567和有机化学杂志(Journal of Organic Chemistry)，1992，57，4404-4414)来合成。本文中的中间体B1-B21用于合成式I中所描述的实例。
中间体B1：(3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺。LCMS(M+H):221.10。
中间体B2：(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺.HCl。LCMS-(M+H):257.20。
中间体B3：(3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺.HCl。LCMS(M+H):239.40。
中间体B4：3-((3R,4S)-4-氨基-1-(2-甲氧基乙基)吡咯烷-3-基)苯甲腈.HCl。LCMS(M+H):245.98。
中间体B5：(3S,4R)-1-(2-甲氧基乙基)-4-(吡啶-3-基)吡咯烷-3-胺.HCl。LCMS(M+H):221.98。
中间体B6：(3S,4R)-1-(2-甲氧基乙基)-4-(1-甲基-1H-吡唑-4-基)吡咯烷-3-胺.HCl。LCMS(M+H):225.20。
中间体B7：(3S,4R)-4-(叔丁基)-1-(2-甲氧基乙基)吡咯烷-3-胺.HCl。LCMS(M+H):201.41
中间体B8：2-((3S,4R)-3-氨基-4-苯基吡咯烷-1-基)乙酸甲基酯。LCMS(M+H)+:235.19。
中间体B9：2-((3R,4S)-3-氨基-4-苯基吡咯烷-1-基)乙酸甲基酯盐酸盐。
中间体B10：(3R,4S)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺盐酸盐。1HNMR(CD3OD,300MHz):δ7.48-7.39(m,5H),4.29-4.24(m,1H),4.08-4.05(m,2H),3.78-3.75(m,2H),3.65-3.59(m,4H),3.58(m,1H),3.43(s,3H)。
中间体B11：(3S,4R)-1-(2-氟乙基)-4-苯基吡咯烷-3-胺盐酸盐。LCMS(M+H):209.10。
中间体B12：(3R,4S)-1-(2-氟乙基)-4-苯基吡咯烷-3-胺盐酸盐。LCMS(M+H):209.10。
中间体B13：2-((3S,4R)-3-氨基-4-苯基吡咯烷-1-基)乙腈盐酸盐。LCMS(M+H):202.31。
中间体B14：2-((3S,4R)-3-氨基-4-苯基吡咯烷-1-基)乙酰胺盐酸盐。LCMS(M+H):220.00。
中间体B15：(3S,4R)-4-苯基-1-(2,2,2-三氟乙基)吡咯烷-3-胺盐酸盐。LCMS(M+H)+:244.92。
中间体B16：(3R,4S)-4-苯基-1-(2,2,2-三氟乙基)吡咯烷-3-胺盐酸盐。LCMS(M+H):245.43。
中间体B17：(3S,4R)-1-(2,2-二氟乙基)-4-苯基吡咯烷-3-胺盐酸盐。LCMS(M+H):227.34。
中间体B18：1-((3S,4R)-3-氨基-4-苯基吡咯烷-1-基)-2-甲氧基乙-1-酮盐酸盐。LCMS(M+H):235.33。
中间体B19：(3S,4R)-1-(氧杂环丁-3-基)-4-苯基吡咯烷-3-胺盐酸盐。1HNMR(DMSO-d6,300MHz):δ8.22(br s,2H),7.42-7.31(m,5H),4.67-4.64(m,2H),4.57-4.51(m,2H),4.02(m,1H),3.92-3.74(m,2H),3.41-3.34(m,2H),3.28-2.96(m,2H)。
中间体B20：3-氨基-1-(2-甲氧基乙基)-4-苯基吡咯烷-2-酮。
中间体B21：4-氨基-1-(2-甲氧基乙基)-3-苯基吡咯烷-3-醇二盐酸盐。LCMS:(M+1)＝237.17。
现将参照实例更详细地阐释本发明，但本发明不应解释为对其具有限制性。
实例1-202的制备
实例1：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(喹啉-3-基)脲
所述化合物是使用如一般方案中所提到的方法3来合成。
向(3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-羧酸(0.15g,0.6mmol)于甲苯(10mL)中的溶液中添加二苯基磷酰基叠氮化物(0.24g,0.96mmol)、二异丙基乙胺(0.32mL,1.80mmol)并将所得混合物加热到回流温度保持1h。然后将反应混合物冷却到室温，之后添加3-氨基喹啉(中间体A1)(0.1g,0.72mmol)并将其加热回流24h。使反应混合物冷却到室温并在减压下浓缩。将由此获得的残余物用10％MeOH/二氯甲烷稀释，用水(10mL)、盐水(10mL)洗涤，经无水硫酸钠干燥，过滤并在减压下浓缩。通过急速管柱色谱通过用2％MeOH/二氯甲烷溶析纯化粗产物，从而获得呈浅褐色胶状物质形式的期望产物。产率：0.035g(6％)；(1HNMR CDCl3,300M Hz):δ8.69(br s,1H),8.59(br s,1H),8.01(d,J＝8.4Hz,1H),7.75(d,J＝8.0Hz,1H),7.56(t,J＝7.6Hz,1H),7.48(t,J＝7.6Hz,1H),7.35-7.31(m,2H),7.28-7.24(m,3H),4.22-4.13(m,1H),3.58(m,3H),3.50-3.45(m,1H),3.33(s,3H),3.28-3.26(m,1H),2.92-2.84(m,2H),2.79-2.75(m,1H),2.46(t,J＝9.0Hz,1H)；LCMS(M+H):391.20。
实例2：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-苯基喹啉-3-基)脲。所述化合物是根据上文所提到的方案使用中间体A6和(3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-羧酸来制备。1HNMR(CD3OD,300M Hz):δ8.64(s,1H),7.98(d,J＝8.4Hz,1H),7.87(d,J＝7.8Hz,1H),7.68-7.52(m,7H),7.33-7.24(m,5H),4.30-4.26(m,1H),3.56(t,J＝5.1Hz,2H),3.35(s,3H),3.19-3.16(m,3H),2.90-2.66(m,4H)；LCMS(M+H):467.4。
实例3：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-甲基喹啉-3-基)脲
所述化合物是使用如一般方案中所提到的方法1来合成。
步骤1：2-甲基喹啉-3-基氨基甲酸苯基酯的制备：在0℃下向2-甲基喹啉-3-胺(中间体A7)(0.05g,0.31mmol)和吡啶(0.076mL,0.94mmol)于THF(5mL)中的溶液中逐滴添加氯甲酸苯基酯(0.076g,0.47mmol)，并且将所得混合物在室温下搅拌2h。向反应混合物中添加冰冷水并将其用乙酸乙酯(2×25mL)催化。将合并的有机层用水(10mL)、盐水(10mL)洗涤并经硫酸钠干燥。过滤有机层并在减压下浓缩，从而获得浅褐色固体状标题化合物。产率：0.24g(29％)；LCMS(M+H):278.91。
步骤2：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-甲基喹啉-3-基)脲的制备：在0℃下向(3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺二盐酸盐(0.18g,0.64mmol)和二异丙基乙胺(0.32mL,1.92mmol)于DMF(5mL)中的溶液中缓慢添加2-甲基喹啉-3-基氨基甲酸苯基酯(0.18g.0.64mmol)，并将所得混合物在室温下搅拌12h。将反应混合物用水(10mL)稀释并用乙酸乙酯(25mL)萃取。将萃取物用水(10mL)、盐水(10mL)洗涤，并经硫酸钠干燥。过滤有机层，在减压下浓缩，并且通过急速管柱色谱用2％MeOH/CHCl3溶析来纯化残余物，从而获得灰白色固体状标题化合物。产率：0.045g(10％)；1HNMR(CD3OD,400MHz):δ8.51(s,1H),7.90(d,J＝8.4Hz,1H),7.80(d,J＝7.6Hz,1H),7.62(dt,J＝0.8Hz和6.8Hz,1H),7.51(t,J＝6.8Hz,1H),7.43-7.33(m,4H),7.26(t,J＝7.2Hz,1H),4.45-4.40(m,1H),3.59(t,J＝5.6Hz,2H),3.37(s,3H),3.36-3.34(m,1H),3.33-3.23(m,1H),3.13-2.97(m,1H),2.96-2.94(m,1H),2.88-2.77(m,2H),2.70-2.68(m,1H),2.65(s,3H)，LCMS(M+H):404.87。
以下实例是根据上文所提到的程序通过使用适当中间体来制备。
实例4：1-(2-乙基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,400MHz):δ8.45(s,1H),7.91(d,J＝8.0Hz,1H),7.77(d,J＝8.4Hz,1H),7.60(dt,J＝1.2Hz和8.4Hz,1H),7.48(t,J＝7.2Hz,1H),7.37-7.32(m,4H),7.30-7.23(m,1H),4.41-4.39(m,1H),3.57(t,J＝5.2Hz,2H),3.35(s,3H),3.26-3.21(m,1H),3.11-3.07(m,1H),2.99-2.91(m,3H),2.83-2.76(m,3H),2.67-2.65(m,1H),1.30(t,J＝8.0Hz,3H)。LCMS(M+H):419.22。
实例5：1-(2-环丙基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,300MHz):δ8.38(s,1H),7.83(d,J＝8.4Hz,1H),7.72(d,J＝7.2Hz,1H),7.56-7.51(m,1H),7.44-7.29(m,5H),7.25-7.22(m,1H),4.43-4.38(m,1H),3.56(t,J＝5.4Hz,2H),3.35(s,3H),3.23-3.08(m,1H),3.08-3.05(m,1H),2.93-2.88(m,1H),2.83-2.71(m,3H),2.65-2.59(m,1H),2.23-2.18(m,1H),1.15-1.09(m,2H),1.07-1.01(m,2H)。LCMS(M+H):431.0。
实例6：1-(2-(三氟甲基)喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(DMSO-d6,400MHz):δ8.87(s,1H),8.05-7.99(m,3H),7.76-7.70(m,2H),7.59(d,J＝7.6Hz,1H),7.33-7.30(m,4H),7.24-7.22(m,1H),4.20-4.17(m,1H),3.47(t,J＝5.6Hz,2H),3.26(s,3H),3.22-3.18(m,1H),3.13-3.08(m,1H),2.93-2.89(m,1H),2.71-2.60(m,3H),2.45-2.43(m,1H)。LCMS(M+H):459.2。
实例7：1-(6-氟-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(DMSO-d6,300MHz):δ8.81(s,1H),7.96-7.91(m,1H),7.73-7.70(m,1H),7.69-7.65(m,1H),7.60-7.53(m,5H),7.50-7.44(m,1H),7.39-7.36(m,1H),7.34-7.31(m,4H),7.23-7.20(m,1H),4.18-4.15(m,1H),3.43(t,J＝6.0Hz,2H),3.23(s,3H),3.17-3.11(m,1H),3.05-3.00(m,1H),2.88-2.82(m,1H),2.62-2.59(m,3H),2.43-2.37(m,1H)。LCMS(M+H):484.86。
实例8：1-(6-氟-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(DMSO-d6,300MHz):δ8.62(s,1H),8.32(br s,1H)7.88-7.83(m,1H),7.59-7.55(m,2H),7.43-7.32(m,6H),4.52-4.48(m,1H),4.04-4.01(m,1H),3.82-3.67(m,4H),3.58-3.45(m,4H),3.31(s,3H),2.57(s,3H)。LCMS(M+H):423.25。
实例9：1-(5-氟-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,400MHz):δ8.76(s,1H),7.70(d,J＝8.8Hz,1H),7.56-7.50(m,1H),7.38-7.31(m,4H),7.25-7.17(m,2H),4.40-4.39(m,1H),3.56(t,J＝6.0Hz,2H),3.36(s,3H),3.34-3.33(m,1H),3.26-3.22(m,1H),3.12-3.07(m,1H),2.95-2.91(m,1H),2.85-2.74(m,2H),2.74-2.62(m,4H)。LCMS(M+H):423.33。
实例10：1-(8-氟-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(DMSO-d6,300MHz):δ8.74(s,1H),8.08(br s,1H),7.59(d,J＝7.8Hz,1H),7.43-7.23(m,8H),4.25-4.18(m,1H),3.58-3.40(m,2H),3.34-3.33(m,1H),3.26(s,3H),3.18-3.04(m,2H),2.90-2.86(m,2H),2.74-2.70(m,2H),2.61(s,3H)。LCMS(M+H):423.36。
实例11：1-(7-氟-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,400MHz):δ8.65(s,1H),7.96-7.92(m,1H),7.64-7.60(m,3H),7.59-7.54(m,3H),7.43(dt,J＝2.8Hz和8.8Hz,1H),7.35-7.30(m,4H),7.26-7.22(m,1H),4.33-4.29(m,1H),3.54(t,J＝5.6Hz,2H),3.33(s,3H),3.24-3.21(m,1H),3.15-3.08(m,1H),3.04-2.99(m,1H),2.82-2.70(m,3H),2.62-2.57(m,1H)。LCMS(M+H):484.80。
实例12：1-(7-氟-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,300MHz):δ8.51(br s,1H),7.85-7.81(m,1H),7.53-7.35(m,7H),4.59-4.52(m,1H),4.08-3.65(m,5H),3.64-3.56(m,2H),3.44(s,3H),3.38-3.35(m,1H),3.30-3.18(m,1H),2.61(s,3H)。LCMS(M+H):423.11。
实例13：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(6-甲氧基-2-苯基喹啉-3-基)脲。1HNMR(CD3OD,300MHz):δ8.53(s,1H),7.84(d,J＝9.3Hz,1H),7.56-7.50(m,5H),7.31-7.19(m,7H),4.30-4.28(m,1H),3.92(s,3H),3.51(t,J＝5.7Hz,2H),3.23-3.12(m,2H),3.09-3.02(m,2H),2.98-2.96(m,1H),2.80-2.65(m,4H),2.59-2.53(m,1H)。LCMS(M+H):496.83。
实例14：1-(7-甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(DMSO-d6,400MHz):δ8.60(s,1H),7.79(d,J＝9.2Hz,1H),7.64-7.60(m,3H),7.55-7.50(m,3H),7.33-7.28(m,5H),7.23-7.13(m,3H),4.15-4.10(m,1H),3.87(s,3H),3.43(t,J＝6.0Hz,2H),3.23(s,3H),3.14-3.10(m,1H),3.04-2.98(m,1H),2.85(t,J＝8.0Hz,1H),2.67-2.55(m,3H),2.44-2.40(m,1H)。LCMS(M+H):497.10。
实例15：1-(8-甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(DMSO-d6,300MHz):δ8.72(s,1H),7.68(br s,1H),7.56-7.54(m,4H),7.45-7.21(m,9H),7.03(d,J＝7.8Hz,1H),4.23-4.14(m,1H),3.91(s,3H),3.49-3.34(m,2H),3.24(s,3H),3.14-3.13(m,1H),3.03-3.00(m,2H),2.62-2.60(m,3H),2.49-2.48(m,1H)。LCMS(M+H):497.62。
实例16：1-(5-甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,300MHz):δ8.92(s,1H),7.60-7.50(m,7H),7.31-7.22(m,5H),6.98(dd,J＝2.1Hz和6.6Hz,1H),4.31-4.28(m,1H),4.02(s,3H),3.54-3.50(m,2H),3.31(s,3H),3.23-3.18(m,1H),3.11-3.00(m,2H),2.84-2.72(m,3H),2.60-2.58(m,1H)。LCMS(M+H):497.55。
实例17：1-(5-甲氧基-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,300MHz):δ8.77(s,1H),7.51-7.44(m,2H),7.38-7.21(m,5H),6.92(d,J＝6.9Hz,1H),4.40-4.38(m,1H),3.98(s,3H),3.57(t,J＝5.4Hz,2H),3.36(s,3H),3.39-3.24(m,2H),3.16-3.10(m,1H),2.98-2.97(m,1H),2.86-2.79(m,2H),2.71-2.68(m,1H),2.59(s,3H)。LCMS(M+H):435.39
实例18：1-(6-甲氧基-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,400MHz):δ8.40(s,1H),7.75(d,J＝9.2Hz,1H),7.37-7.31(m,4H),7.25-7.21(m,2H),7.13(d,J＝2.4Hz,1H),4.41-4.40(m,1H),3.89(s,3H),3.57(t,J＝6.0Hz,2H),3.36(s,3H),3.34-3.31(m,1H),3.26-3.22(m,1H),3.13-3.08(m,1H),2.95-2.91(m,1H),2.86-2.72(m,2H),2.68-2.62(m,1H),2.57(s,3H)。LCMS(M+H):435.35。
实例19：1-(7-甲氧基-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,400MHz):δ8.30(s,1H),7.69(d,J＝9.6Hz,1H),7.38-7.31(m,4H),7.26-7.24(m,2H),7.16(dd,J＝2.4Hz和8.8Hz,1H),4.41-4.40(m,1H),3.94(s,3H),3.58(t,J＝5.6Hz,2H),3.36(s,3H),3.41-3.26(m,2H),3.21-3.17(m,1H),3.01-2.99(m,1H),2.90-2.86(m,2H),2.72-2.70(m,1H),2.58(s,3H)。LCMS(M+H):435.39。
实例20：1-(8-甲氧基-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,300MHz):δ8.45(s,1H),7.41-7.22(m,7H),7.03(d,J＝7.2Hz,1H),4.40-4.38(m,1H),4.02(s,3H),3.56(t,J＝5.7Hz,2H),3.35(s,3H),3.31-3.29(m,1H),3.25-3.20(m,1H),3.10-3.04(m,1H),2.92-2.87(m,1H),2.84-2.71(m,2H),2.62(s,3H),2.61-2.59(m,1H)。LCMS(M+H):435.12。
实例21：1-(6,7-二甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(DMSO d6,300MHz):δ8.53(s,1H),7.60-7.58(m,3H),7.53-7.47(m,3H),7.31-7.19(m,7H),7.12(d,J＝7.8Hz,1H),4.17-4.28(m,1H),3.88(s,6H),3.43(t,J＝6.0Hz,2H),3.24(s,3H),3.09(t,J＝8.1Hz,1H),3.02(q,J＝6.9Hz,1H),2.85(t,J＝7.8Hz,1H),2.60-2.57(m,3H),2.42(t,J＝8.4Hz,1H)。LCMS(M+H):527.72。
实例22：1-(6,7-二甲氧基-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,300MHz):δ8.24(s,1H),7.37-7.29(m,4H),7.25-7.20(m,2H),7.13(s,1H),4.42-4.37(m,1H),3.95(s,3H),3.93(s,3H),3.55(t,J＝5.4Hz,2H),3.31(s,3H),3.30-3.19(m,2H),3.09-2.92(m,1H),2.90-2.83(m,1H),2.81-2.70(m,2H),2.62(t,J＝9.0Hz,1H),2.54(s,3H)。LCMS(M+H):464.91。
实例23：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(6,7-二甲氧基喹啉-3-基)脲。1H NMR(CD3OD,400MHz):δ8.51(d,J＝2.4Hz,1H),8.22(d,J＝1.6Hz,1H),7.37-7.30(m,4H),7.25-7.23(m,2H),7.15(s,1H),4.43-4.37(m,1H),3.95(s,6H),3.58(t,J＝5.6Hz,2H),3.40-3.37(m,4H),3.31-3.24(m,1H),3.11-3.09(m,1H),2.97-2.95(m,1H),2.87-2.80(m,2H),2.68-2.65(m,1H)。LCMS(M+H):450.81。
实例24：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(6-甲基-2-苯基喹啉-3-基)脲。1HNMR(CD3OD,300MHz):δ8.53(s,1H),7.86(d,J＝9.0Hz,1H),7.63-7.48(m,7H),7.35-7.22(m,5H),4.31-4.28(m,1H),3.53(t,J＝5.4Hz,2H),3.32(s,3H),3.23-2.98(m,3H),2.82-2.71(m,3H),2.61-2.58(m,1H),2.53(s,3H)。LCMS(M+H):480.90。
实例25：1-(2,6-二甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,400MHz):δ8.38(s,1H),7.77(d,J＝8.4Hz,1H),7.54(s,1H),7.45-7.43(m,1H),7.37-7.30(m,4H),7.24-7.21(m,1H),4.42-4.37(m,1H),3.56(t,J＝5.6Hz,2H),3.35(s,3H),3.24-3.18(m,2H),3.09-3.04(m,1H),2.90-2.88(m,1H),2.84-2.70(m,2H),2.64-2.62(m,1H),2.59(s,3H),2.48(s,3H)。LCMS(M+H):419.33。
实例26：1-(2,7-二甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,300MHz):δ8.38(s,1H),7.68-7.65(m,2H),7.38-7.30(m,5H),7.26-7.21(m,1H),4.43-4.36(m,1H),3.57(t,J＝5.4Hz,2H),3.38-3.31(m,1H),3.36(s,3H),3.25-3.20(m,1H),3.15-3.09(m,1H),2.97-2.92(m,1H),2.90-2.74(m,2H),2.70-2.64(m,1H),2.59(s,3H),2.51(s,3H)。LCMS(M+H):419.37。
实例27：1-(2,5-二甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,400MHz):δ8.68(s,1H),7.73(d,J＝8.8Hz,1H),7.47(t,J＝8.4Hz,1H),7.38-7.29(m,5H),7.25-7.21(m,1H),4.40-4.38(m,1H),3.56(t,J＝5.2Hz,2H),3.36(s,3H),3.35-3.33(m,1H),3.26-3.20(m,1H),3.11-3.07(m,1H),2.94-2.90(m,1H),2.85-2.72(m,2H),2.66-2.64(m,1H),2.62(s,6H)。LCMS(M+H):419.33。
实例28：1-(2,8-二甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(DMSO-d6,300MHz):δ8.62(s,1H),7.97(br s,1H),7.58(d,J＝7.8Hz,1H),7.38-7.20(m,8H),4.22-4.18(m,1H),3.47(t,J＝5.7Hz,2H),3.26(s,3H),3.22-3.19(m,1H),3.14-3.09(m,1H),2.94-2.88(m,1H),2.75-2.67(m,3H),2.64(s,3H),2.60(s,3H),2.44-2.42(m,1H)。LCMS(M+H):419.37。
实例29：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(7-甲基-2-苯基喹啉-3-基)脲。1H NMR(DMSO-d6,300MHz):δ8.66(s,1H),7.76(d,J＝8.7Hz,1H),7.69-7.59(m,2H),7.54-7.52(m,5H),7.38-7.21(m,7H),4.15-4.10(m,1H),3.43(t,J＝6.0Hz,2H),3.23(s,3H),3.13-3.10(m,1H),3.02-3.00(m,1H),2.85-2.84(m,1H),2.60-2.59(m,3H),2.50(s,3H),2.44-2.39(m,1H)。LCMS(M+H):480.83。
实例30：1-(2-氯喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1HNMR(CD3OD 300MHz):δ8.81(s,1H),7.84-7.79(m,2H),7.65-7.51(m,2H),7.38-7.29(m,4H),7.25-7.22(m,1H),4.39-4.38(m,1H),3.56(t,J＝5.4Hz,2H),3.34(s,3H),3.30-3.20(m,1H),3.13-3.08(m,1H),2.92-2.74(m,4H),2.69-2.63(m,1H)。LCMS(M+H):425.30。
实例31：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-(1-甲基-1H-吡唑-4-基)喹啉-3-基)脲。1HNMR(CD3OD,300MHz):δ8.38(s,1H),8.08(s,1H),8.00(s,1H),7.96(d,J＝8.4Hz,1H),7.83(d,J＝8.4Hz,1H),7.68-7.62(m,1H),7.53-7.49(m,1H),7.32-7.31(m,4H),7.25-7.22(m,1H),4.42-4.35(m,1H),3.94(s,3H),3.54(t,J＝5.4Hz,2H),3.34(s,3H),3.31-3.30(m,1H),3.23-3.13(m,1H),3.07-3.01(m,1H),2.89-2.84(m,1H),2.80-2.75(m,2H),2.63-2.57(m,1H)。LCMS(M+H):470.82。
实例32：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-(吡啶-3-基)喹啉-3-基)脲。1H NMR(CD3OD,300MHz):δ8.83(s,1H),8.64(d,J＝5.1Hz,1H),8.53(s,1H),8.12-8.09(m,1H),8.03(d,J＝8.4Hz,1H),7.90(d,J＝7.8Hz,1H),7.72-7.67(m,1H),7.62-7.53(m,2H),7.34-7.22(m,5H),4.28-4.26(m,1H),3.52(t,J＝5.4Hz,2H),3.32(s,3H),3.24-3.21(m,1H),3.11-3.08(m,1H),2.96-2.95(m,1H),2.80-2.71(m,3H),2.56-2.55(m,1H)。LCMS(M+H):467.87。
实例33：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-(吡啶-4-基)喹啉-3-基)脲。1H NMR(CD3OD,300MHz):δ8.67-8.65(m,2H),8.53(s,1H),8.03(d,J＝8.4Hz,1H),7.91(d,J＝8.1Hz,1H),7.74-7.69(m,3H),7.64-7.59(m,1H),7.36-7.23(m,5H),4.30-4.29(m,1H),3.56(t,J＝5.4Hz,2H),3.38-3.37(m,1H),3.35(s,3H),3.24-3.16(m,2H),2.91-2.90(m,3H),2.75-2.74(m,1H)。LCMS(M-H):465.85。
实例34：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-(嘧啶-5-基)喹啉-3-基)脲。1H NMR(CD3OD,400MHz):δ9.22(s,1H),9.11(s,2H),8.44(s,1H),8.05(d,J＝8.8Hz,1H),7.92(d,J＝8.4Hz,1H),7.74-7.71(m,1H),7.64-7.60(m,1H),7.32-7.21(m,5H),4.32-4.29(m,1H),3.53(t,J＝5.2,2H),3.32(s,3H),3.12-3.10(m,1H),2.93-2.91(m,1H),2.76-2.75(m,4H),2.55-2.54(m,1H)。LCMS(M+H):469.60。
实例35：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-吗啉基喹啉-3-基)脲。1H NMR(CD3OD,300MHz):δ8.48(s,1H),7.80(d,J＝8.4Hz,1H),7.68(d,J＝8.4Hz,1H),7.53-7.47(m,1H),7.40-7.29(m,5H),7.25-7.22(m,1H),4.41-4.40(m,1H),3.90(t,J＝4.8Hz,4H),3.56(t,J＝5.7Hz,2H),3.36(s,3H),3.22-3.16(m,5H),3.12-3.06(m,1H),2.90-2.71(m,4H),2.67-2.61(m,1H)。LCMS(M+H):476.21。
实例36：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(喹啉-4-基)脲。1H NMR(DMSO-d6,300MHz):δ8.98(s,1H),8.62(d,J＝5.1Hz,1H),8.16-8.13(m,2H),7.94(d,J＝8.1Hz,1H),7.72(t,J＝7.2Hz,1H),7.61(t,J＝7.8Hz,1H),7.39-7.23(m,6H),4.25-4.23(m,1H),3.49-3.47(m,2H),3.31-3.28(m,1H),3.26(s,3H),3.15-3.12(m,2H),2.93-2.91(m,1H),2.72-2.69(m,3H)。LCMS(M+H):391.10。
实例37：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(喹唑啉-4-基)脲。1H NMR(CD3OD,400MHz):δ8.80(s,1H),8.36(d,J＝8.0Hz,1H),7.95-7.87(m,2H),7.69-7.65(m,1H),7.45-7.38(m,2H),7.32-7.29(m,2H),7.23-7.17(m,1H),4.85-4.52(m,1H),3.60-3.58(m,2H),3.46-3.37(m,2H),3.30(s,3H),3.18-3.13(m,1H),3.08-3.04(m,1H),2.92-2.71(m,3H)。LCMS(M+H):391.84。
实例38：1-(2-氯-6,7-二甲氧基喹唑啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,300MHz):δ7.71(s,1H),7.42-7.40(m,2H),7.34-7.29(m,2H),7.24-7.22(m,1H),7.15(s,1H),4.41-4.39(m,1H),3.99(s,3H),3.97(s,3H)3.58(t,J＝5.7Hz,2H),3.36(s,3H),3.34-3.30(m,2H),3.22-3.16(m,1H),3.02-2.98(m,1H),2.85-2.76(m,3H)。LCMS(M+H):485.81。
实例39：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(喹喏啉-2-基)脲。1H NMR:(DMSO-d6,300MHz):δ10.05(s,1H),9.07(d,J＝6.9Hz,1H),8.85(s,1H),7.96(d,J＝8.4Hz,1H),7.88(d,J＝8.4Hz,1H),7.80-7.74(m,1H),7.65-7.59(m,1H),7.39-7.29(m,4H),7.24-7.21(m,1H),4.27-4.25(m,1H),3.49(t,J＝5.4Hz,2H),3.31(s,3H),3.27-3.25(m,2H)2.99-2.98(m,1H),2.80-2.69(m,3H),2.50-2.49(m,1H)。LCMS(M+H):392.20。
实例40：1-(2-异丙基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR:(CDCl3,400MHz):δ8.31(s,1H),8.01(d,J＝8.4Hz,1H),7.72(d,J＝8.4Hz,1H),7.62-7.57(m,1H),7.46-7.43(m,1H),7.35-7.23(m,5H),5.25(br s,1H),4.43-4.34(m,1H),3.51-3.48(m,2H),3.47-3.44(m,1H),3.34-3.29(m,2H),3.26(s,3H),3.14-3.12(m,1H),2.91-2.87(m,1H),2.81-2.79(m,1H),2.71-2.70(m,1H),2.49-2.47(m,1H),1.35(d,J＝2.0Hz,3H),1.33(d,J＝1.6Hz,3H)。LCMS(M+H):433.14。
实例41：1-(2-叔丁基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR:(CDCl3,300MHz):δ8.14(s,1H),8.01(d,J＝8.7Hz,1H),7.71-7.60(m,2H),7.49-7.44(m,1H),7.35-7.26(m,5H),6.59(br s,1H),4.58-4.50(m,1H),3.58-3.52(m,3H),3.37-3.31(m,1H),3.31(s,3H),3.23-3.19(m,1H),3.04-3.02(m,1H),2.82-2.79(m,2H),2.63-2.59(m,1H),1.50(s,9H)。LCMS(M+H):447.13。
实例42：1-(6-甲氧基-2-甲基-7-吗啉基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR:(CDCl3,300MHz):δ8.37(s,1H),7.36-7.26(m,6H),6.98(s,1H),6.79(br s,1H),4.49-4.42(m,1H),3.95(s,3H),3.92-3.91(m,4H),3.73-3.70(m,1H),3.67-3.59(m,2H),3.58-3.49(m,1H),3.35-3.34(m,1H),3.30(s,3H),3.20-3.19(m,4H),3.04-2.91(m,3H),2.74-2.68(m,1H),2.61(s,3H)。LCMS(M+H):520.42。
实例43：1-(6-氟-7-甲基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CDCl3,300MHz):δ8.76(s,1H),7.86(d,J＝7.5Hz,1H),7.63-7.60(m,2H),7.56-7.48(m,3H),7.35-7.26(m,4H),7.23-7.22(m,2H),5.16-5.10(br m,1H),4.26-4.23(m,1H),3.44-3.37(m,2H),3.24(s,3H),3.21-3.17(m,2H),3.05-3.02(m,1H),2.73-2.52(m,3H),2.44(s,3H),2.31-2.25(m,1H)。LCMS(M+H):499.44。
实例44：1-(6-溴-8-甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CDCl3,400MHz):δ8.51(s,1H),7.45(d,J＝1.2Hz,1H),7.33-7.29(m,2H),7.24-7.22(m,3H),6.98(d,J＝2.0Hz,1H),6.04(br s,1H)4.34-4.31(m,1H),4.01(s,3H),3.53-3.46(m,3H),3.30-3.20(m,5H),2.90-2.84(m,2H),2.74-2.68(m,1H),2.63(s,3H),2.49(t,J＝9.2Hz,1H)。LCMS(M+H):513.33。
实例45：1-(7-氟-6-甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CDCl3,400MHz):δ8.76(s,1H),7.69-7.61(m,3H),7.55-7.48(m,3H),7.34-7.30(m,3H),7.26-7.24(m,2H),7.13(d,J＝8.8Hz,1H),5.22(brs,1H),4.26-4.20(m,1H),3.99(s,3H),3.44-3.40(m,2H),3.24(s,3H),3.21-3.17(m,2H),3.08-3.04(m,1H),2.79-2.52(m,3H),2.32-2.28(m,1H)。LCMS(M+H):515.35。
实例46：1-(7-氟-6-甲氧基-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,300MHz):δ8.41(s,1H),7.49(d,J＝12.0Hz,1H),7.37-7.23(m,6H),4.42-4,38(m,1H),3.97(s,3H),3.56(t,J＝5.4Hz,2H),3.36(s,3H),3.24-3.21(m,2H),3.09-2.94(m,1H),2.94-2.72(m,4H),2.57(s,3H)。LCMS(M+H):453.26。
实例47：1-(8-甲氧基-7-甲基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CDCl3,400MHz):δ8.73(s,1H),7.70-7.68(m,2H),7.54-7.43(m,4H),7.33-7.29(m,3H),7.23-7.21(m,3H),5.09-5.07(d,J＝8.0Hz,1H),4.26-4.20(m,1H),4.11(s,3H),3.41(t,J＝5.2Hz,2H),3.24(s,3H),3.21-3.17(m,2H),3.03-3.00(m,1H),2.73-2.62(m,2H),2.57-2.53(m,1H),2.45(s,3H),2.28(t,J＝8.8Hz,1H)。LCMS(M+H):511.39。
实例48：1-(6-甲氧基-2,7-二甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,300MHz):δ8.33(s,1H),7.61(s,1H),7.38-7.30(m,4H),7.26-7.23(m,1H),7.08(s,1H),4.45-4.36(m,1H),3.93(s,3H),3.57(t,J＝5.4Hz,2H),3.36(s,3H),3.25-3.09(m,2H),2.96-2.78(m,4H),2.70-2.64(m,1H),2.55(s,3H),2.34(s,3H)。LCMS(M+H):449.26。
实例49：1-(7-氟-6-甲基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CDCl3,400MHz):δ8.73(s,1H),7.64-7.61(m,3H),7.58-7.46(m,4H),7.33-7.30(m,2H),7.24-7.22(m,3H),5.06(br s,1H),4.25-4.21(m,1H),3.41-3.40(m,2H),3.22(s,3H),3.20-3.17(m,2H),3.05-3.02(m,1H),2.73-2.64(m,2H),2.57-2.48(m,1H),2.45(s,3H),2.29-2.26(m,1H)。LCMS(M+H):499.33。
实例50：1-(7-氟-2,6-二甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(DMSO-d6,300MHz):δ8.62(s,1H),7.97(s,1H),7.71(d,J＝7.8Hz,1H),7.51(d,J＝10.8Hz,1H),7.34-7.20(m,6H),4.22-4.16(m,1H),3.47(t,J＝5.7Hz，，2H),3.25(s,3H),3.21-3.18(m,1H),3.13-3.09(m,1H),2.93-2.87(m,1H),2.72-2.59(m,3H),2.55(s,3H),2.44-2.41(m,1H),2.37(s,3H)。LCMS(M+H):437.28。
实例51：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(6-苯基-[1,3]二氧杂环戊烯并[4,5-g]喹啉-7-基)脲。1H NMR(CDCl3,300MHz):δ8.61(s,1H),7.63-7.60(m,2H),7.54-7.45(m,3H),7.34-7.29(m,3H),7.27-7.22(m,3H),7.04(s,1H),6.08(s,2H),5.07(br s,1H),4.24-4.22(m,1H),3.41(t,J＝5.4Hz,2H),3.24(s,3H),3.20-3.16(m,2H),3.04-3.01(m,1H),2.74-2.56(m,3H),2.32-2.26(m,1H)。LCMS(M+H):511.39。
实例52：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(6-甲基-[1,3]二氧杂环戊烯并[4,5-g]喹啉-7-基)脲。1H NMR(CD3OD,300MHz):δ8.23(s,1H),7.39-7.32(m,4H),7.29-7.26(m,1H),7.16(s,1H),7.05(s,1H),6.08(s,2H),4.42-4.39(m,1H),3.61(t,J＝5.4Hz,2H),3.55-3.49(m,1H),3.38(s,3H),3.36-3.32(m,1H),3.14-3.00(m,3H),2.93-2.80(m,2H),2.51(s,3H)。LCMS(M+H):449.36。
实例53：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(7-甲基-2,3-二氢-[1,4]二氧杂环己烯并[2,3-g]喹啉-8-基)脲。1H NMR(CD3OD,400MHz):δ8.18(s,1H),7.36-7.30(m,4H),7.27-7.23(m,2H),7.14(s,1H),4.42-4.37(m,1H),4.33(s,4H),3.56(t,J＝5.6Hz,2H),3.35(s,3H),3.34-3.32(m,1H),3.25-3.21(m,1H),3.09-3.06(m,1H),2.93-2.90(m,1H),2.85-2.75(m,2H),2.65(t,J＝9.6Hz,1H),2.52(s,3H)。LCMS M+H):463.25。
实例54：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(7-苯基-2,3-二氢-[1,4]二氧杂环己烯并[2,3-g]喹啉-8-基)脲。1H NMR(CDCl3,400MHz):δ8.57(s,1H),7.61-7.59(m,2H),7.51-7.45(m,4H),7.33-7.29(m,2H),7.24-7.22(m,3H),7.17(s,1H),5.22(br s,1H),4.36(s,4H),4.26-4.22(m,1H),3.42-3.36(m,2H),3.24(s,3H),3.19-3.16(m,2H),3.04-3.01(m,1H),2.75-2.65(m,2H),2.59-2.56(m,1H),2.32-2.28(m,1H)。LCMS(M+H):525.32。
实例55：1-(6-氨基-7-甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CDCl3,400MHz):δ8.46(s,1H),7.61-7.59(m,2H),7.52-7.48(m,3H),7.45-7.43(m,2H),7.35-7.23(m,4H),6.88(s,1H),4.56-4.49(m,1H),4.19(br s,2H),3.96(s,3H),3.66-3.60(m,3H),3.46-3.44(m,2H),3.32(s,3H),3.16-2.98(m,3H),2.78-2.52(m,1H)。LCMS(M+H):512.32。
实例56：1-(7-甲氧基-6-(甲基氨基)-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,400MHz):δ8.18(s,1H),7.55-7.53(m,2H),7.48-7.44(m,3H),7.33-7.27(m,4H),7.24-7.20(m,2H),6.64(s,1H),4.29-4.21(m,1H),3.98(s,3H),3.52(t,J＝5.6Hz,2H),3.33(s,3H),3.12-2.98(m,2H),2.93(s,3H),2.82-2.72(m,4H),2.62-2.52(m,1H)。LCMS(M+H):526.37。
实例57：N-(7-甲氧基-3-(3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)-2-苯基喹啉-6-基)乙酰胺。1H NMR(CDCl3,300MHz):δ8.78(s,1H),8.61(s,1H),7.99(br s,1H),7.60-7.58(m,2H),7.52-7.43(m,3H),7.39(s,1H),7.34-7.29(m,2H),7.23-7.19(m,2H),5.22(br s,1H),4.29-4.21(m,1H),4.00(s,3H),3.42(t,J＝5.7Hz,2H),3.24(s,3H),3.21-3.17(m,2H),3.04-3.02(m,1H),2.75-2.58(m,3H),2.32-2.28(m,1H),2.26(s,3H)。LCMS(M+H):554.41。
实例58：N-(7-甲氧基-3-(3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)-2-甲基喹啉-6-基)乙酰胺。1H NMR(CD3OD,300MHz):δ8.71(s,1H),8.34(s,1H),7.38-7.31(m,4H),7.27-7.20(m,1H),7.19(s,1H),4.44-4.39(m,1H),4.01(s,3H),3.58(t,J＝5.4Hz，，2H),3.37(s,3H),3.24-3.13(m,2H),3.00-2.84(m,3H),2.72-2.54(m,2H),2.54(s,3H),2.23(s,3H)。LCMS(M+H):492.31。
实例59：N-(6-甲氧基-3-(3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)-2-苯基喹啉-7-基)乙酰胺。1H NMR(CD3OD,400MHz):δ8.76(s,1H),8.45(s,1H),7.57-7.48(m,5H),7.32-7.23(m,6H),4.29-4.24(m,1H),4.04(s,3H),3.53(t,J＝4.8Hz,2H),3.33(s,3H),3.14-3.03(m,3H),2.85-2.61(m,4H),2.23(s,3H)。LCMS(M+H):554.30。
实例60：N-(6-甲氧基-3-(3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)-2-甲基喹啉-7-基)乙酰胺。1H NMR(CD3OD,300MHz):δ8.71(s,1H),8.33(s,1H),7.39-7.30(m,4H),7.26-7.19(m,2H),4.45-4.38(m,1H),4.00(s,3H),3.58(t,J＝5.4Hz,2H),3.36(s,3H),3.24-3.13(m,3H),3.00-2.82(m,3H),2.72-2.54(m,1H),2.54(s,3H),2.23(s,3H)。LCMS(M+H):492.21。
实例61：1-(8-甲氧基-6-(1-甲基-1H-吡唑-4-基)-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CDCl3,300MHz):δ8.51(s,1H),7.84(s,1H),7.70(s,1H),7.39-7.38(m,2H),7.33-7.30(m,4H),7.03-7.00(m,1H),5.51(brs,1H),4.36-4.25(m,1H),4.10(s,3H),3.98(s,3H),3.68-3.64(m,1H),3.52-3.49(m,2H),3.42-3.33(m,1H),3.26(s,3H),3.18-3.10(m,2H),2.89-2.81(m,2H),2.67(s,3H),2.48-2.42(m,1H)。LCMS(M+H):515.35。
实例62：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-甲基-8-(1-甲基-1H-吡唑-4-基)喹啉-3-基)脲。1H NMR(CDCl3,300MHz):δ8.48(s,1H),8.42(s,1H),8.13(s,1H),7.78(dd,J＝1.2Hz和7.2Hz,1H),7.61-7.58(m,1H),7.43(t,J＝7.2Hz,1H),7.34-7.28(m,6H),5.66(br s,1H),4.36-4.32(m,1H),4.00(s,3H),3.52-3.50(m,3H),3.38-3.26(m,1H),3.26(s,3H),3.22-3.19(m,1H),2.92-2.82(m,2H),2.76-2.70(m,1H),2.67(s,3H),2.57-2.50(m,1H)。LCMS(M+H):485.30。
实例63：1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(喹啉-3-基)脲。1H NMR:(CD3OD,300MHz):δ8.73(d,J＝2.4Hz,1H),8.39(d,J＝2.1Hz,1H),7.93(d,J＝8.4Hz,1H),7.81(d,J＝7.8Hz,1H),7.63-7.50(m,2H),7.35-7.31(m,1H),7.25-7.16(m,2H),4.39-4.32(m,1H),3.58-3.54(m,2H),3.37(s,3H),3.27-3.22(m,3H),3.13-3.07(m,1H),2.85-2.72(m,2H),2.66-2.61(m,1H)。LCMS:M+H):426.85。
实例64：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(萘-2-基)脲。1H NMR(DMSO-d6,300MHz):δ10.21(br s,1H),8.93-8.85(m,1H),7.96(s,1H),7.78-7.69(m,3H),7.41-7.32(m,7H),6.82-6.80(m,1H),4.56-4.54(m,1H),3.93(s,1H),3.75-3.67(m,3H),3.49-3.47(m,4H),3.34-3.31(m,4H)。LCMS(M+H):390.10。
实例65：1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(2-苯基喹啉-3-基)脲。1H NMR(CD3OD 300MHz):δ8.63(s,1H),7.97(d,J＝8.4Hz,1H),7.87(d,J＝8.1Hz,1H),7.68-7.53(m,7H),7.28-7.06(m,3H),4.26-4.22(m,1H),3.51(t,J＝5.7Hz,2H),3.31(s,3H),3.29-3.05(m,3H),2.79-2.73(m,3H),2.67-2.54(m,1H)。LCMS(M+H):502.50。
实例66：1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(2-(吡啶-3-基)喹啉-3-基)脲。1H NMR(CD3OD,300MHz):δ8.85(d,J＝1.5Hz,1H),8.65(dd,J＝1.2Hz和5.4Hz,1H),8.52(s,1H),8.15-8.11(m,1H),8.02(d,J＝8.4Hz,1H),7.91(d,J＝8.1Hz,1H),7.73-7.67(m,1H),7.62-7.55(m,2H),7.26-7.17(m,2H),7.08-7.05(m,1H),4.21-4.19(m,1H),3.51(t,J＝5.4Hz,2H),3.30(s,3H),3.21-3.15(m,1H),3.10-2.94(m,2H),2.76-2.65(m,3H),2.58-2.52(m,1H)。LCMS(M+H):504.76。
实例67：1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(2-甲基喹啉-3-基)脲。1H NMR(CD3OD 300MHz):δ8.49(s,1H),7.89(d,J＝8.4Hz,1H),7.78(d,J＝8.1Hz,1H),7.62-7.57(m,1H),7.51-7.46(m,1H),7.35-7.29(m,1H),7.22-7.17(m,2H),4.36-4.32(m,1H),3.55(t,J＝5.4Hz,2H),3.36(s,3H),3.22-3.17(m,3H),3.13-3.07(m,1H),2.84-2.73(m,3H),2.63(s,3H)。LCMS(M+H):440.90。
实例：68：1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(6,7-二甲氧基-2-甲基喹啉-3-基)脲。1H NMR(CD3OD 400MHz):δ8.25(s,1H),7.34-7.29(m,1H),7.22-7.14(m,4H),4.37-4.32(m,1H),3.95(s,3H),3.93(s,3H),3.55(t,J＝5.2Hz,2H),3.35(s,3H),3.25-3.11(m,2H),3.09-3.07(m,1H),2.82-2.70(m,3H),2.65-2.61(m,1H),2.55(s,3H)。LCMS(M+H):501.40。
实例：69：1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(6,7-二甲氧基喹啉-3-基)脲。1H NMR(CD3OD,400MHz):δ8.51(d,J＝2.4Hz,1H),8.23(d,J＝2.4Hz,1H),7.34-7.29(m,1H),7.25(s,1H),7.21-7.14(m,3H),4.34-4.32(m,1H),3.95(s,6H),3.56(t,J＝5.2Hz,2H),3.37(s,3H),3.27-3.19(m,2H),3.09-3.06(m,1H),2.85-2.72(m,3H),2.63(t,J＝8.8Hz,1H)。LCMS(M+H):487.40。
实例：70：1-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(喹啉-3-基)脲。1H NMR(DMSO-d6,300MHz):δ8.86(s,1H),8.71(d,J＝2.7Hz,1H),8.41(d,J＝2.7Hz,1H),7.88(d,J＝7.8Hz,1H),7.80(d,J＝8.4Hz,1H),7.57-7.47(m,2H),7.40-7.32(m,1H),7.19(d,J＝7.8Hz,2H),7.07-7.02(m,1H),6.82(d,J＝8.1Hz,1H),4.21-4.18(m,1H),3.47(t,J＝5.7Hz,2H),3.26(s,3H),3.22-3.15(m,2H),3.00-2.94(m,1H),2.72-2.64(m,3H),2.50-2.49(m,1H)。LCMS(M+H):409.40。
实例：71：1-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(2-甲基喹啉-3-基)脲。1H NMR(DMSO-d6,300MHz):δ8.49(s,1H),7.88(d,J＝8.4Hz,1H),7.78(d,J＝8.4Hz,1H),7.60(t,J＝6.9Hz,1H),7.49(t,J＝7.5Hz,1H),7.40-7.33(m,1H),7.21-7.15(m,2H),7.03-6.97(m,1H),6.70-6.68(d,J＝7.8Hz,1H),6.61(d,J＝7.8Hz,1H),4.47-4.40(m,1H),3.74-3.70(m,1H),3.62(t,J＝5.4Hz,2H),3.55-3.42(m,1H),3.38(s,3H),3.34-3.30(m,1H),3.26-3.18(m,1H),3.12-2.88(m,3H),2.62(s,3H)。LCMS(M+H):423.33。
实例：72：1-(6-氟-2-甲基喹啉-3-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲。1H NMR(CD3OD,300MHz):δ8.52(s,1H),7.91-7.86(m,1H),7.45-7.29(m,3H),7.19-7.12(m,2H),6.98-6.92(m,1H),4.39-4.37(m,1H),3.56(t,J＝5.4Hz,2H),3.36(s,3H),3.31-3.22(m,2H),3.12-3.06(m,1H),2.87-2.64(m,4H),2.62(s,3H)。LCMS(M+H):441.05。
实例：73：1-(7-氟-2-甲基喹啉-3-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲。1H NMR(CD3OD,400MHz):δ8.49(s,1H),7.85-7.81(m,1H),7.51(dd,J＝2.4Hz和10.0Hz,1H),7.36-7.30(m,2H),7.19-7.12(m,2H),6.99-6.94(m,1H),4.39-4.37(m,1H),3.56(t,J＝5.2Hz,2H),3.36(s,3H),3.27-3.23(m,1H),3.13-3.08(m,1H),2.89-2.73(m,4H),2.68-2.64(m,1H),2.62(s,3H)。LCMS(M+H):441.37。
实例：74：1-(6,7-二甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲。1H NMR(DMSO-d6,400MHz):δ8.52(s,1H),7.63-7.58(m,3H),7.53-7.45(m,3H),7.38-7.32(m,1H),7.27(d,J＝7.2Hz,2H),7.16-7.11(m,3H),7.06-7.02(m,1H),4.16-4.10(m,1H),3.89(s,3H),3.88(s,3H),3.44(t,J＝5.6Hz,2H),3.24(s,3H),3.12-3.04(m,2H),2.91-2.87(m,1H),2.62-2.51(m,3H),2.50-2.45(m,1H)。LCMS(M+H):545.30。
实例：75：1-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(6-苯基-[1,3]二氧杂环戊烯并[4,5-g]喹啉-7-基)脲。1H NMR(CD3OD,400MHz):δ8.37(s,1H),7.57-7.48(m,5H),7.34-7.29(m,1H),7.24(s,1H),7.14-7.04(m,3H),6.98-6.94(m,1H),6.11(s,2H),4.24-4.22(m,1H),3.51(t,J＝6.0Hz,2H),3.33(s,3H),3.18-3.16(m,1H),3.13-3.07(m,1H),3.02-2.96(m,1H),2.76-2.68(m,3H),2.59-2.57(m,1H)。LCMS(M+H):529.29。
实例：76：1-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(6-甲基-[1,3]二氧杂环戊烯并[4,5-g]喹啉-7-基)脲。1H NMR(CD3OD,300MHz):δ8.23(s,1H),7.37-7.29(m,1H),7.18-7.11(m,3H),7.06(s,1H),6.99-6.93(m,1H),6.08(s,2H),4.40-4.34(m,1H),3.55(t,J＝5.7Hz,2H),3.35(s,3H),3.26-3.18(m,2H),3.10-3.04(m,1H),2.86-2.70(m,3H),2.66-2.60(m,1H),2.53(s,3H)。LCMS(M+H):467.30。
实例：77：1-((3S,4R)-4-(3-氰基苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(喹啉-3-基)脲。1H NMR(CD3OD,400MHz):δ8.72(s,1H),8.38(s,1H),7.91(d,J＝8.4Hz,1H),7.81-7.74(m,2H),7.71(d,J＝7.6Hz,1H),7.61-7.58(m,2H),7.55-7.49(m,2H),4.41-4.38(m,1H),3.58-3.51(m,2H),3.49-3.45(m,1H),3.39-3.35(m,3H),3.15-3.11(m,1H),2.84-2.68(m,5H)。LCMS(M+H):416.00。
实例：78：1-((3S,4R)-4-(3-氰基苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(6,7-二甲氧基-2-苯基喹啉-3-基)脲。1H NMR(CD3OD,300MHz):δ8.38(s,1H),7.67-7.59(m,5H),7.54-7.47(m,4H),7.33(s,1H),7.23(s,1H),4.25-4.23(m,1H),3.98(s,3H),3.96(s,3H),3.57-3.50(m,2H),3.37(s,3H),3.25-3.09(m,3H),2.78-2.59(m,4H)。LCMS(M+H):551.70。
实例：79：1-((3S,4R)-1-(2-甲氧基乙基)-4-(吡啶-3-基)吡咯烷-3-基)-3-(喹啉-3-基)脲。1H NMR(CD3OD,400MHz):δ8.73(d,J＝2.4Hz,1H),8.54(d,J＝2.0Hz,1H),8.42(dd,J＝1.6Hz和8.4Hz,1H),8.38(d,J＝2.4Hz,1H),7.94-7.90(m,2H),7.80(d,J＝7.6Hz,1H),7.62-7.51(m,2H),7.44-7.41(m,1H),4.42-4.41(m,1H),3.58(t,J＝5.2Hz,2H),3.38(s,3H),3.35-3.31(m,2H),3.21-3.16(m,1H),2.92-2.73(m,4H)。LCMS(M+H):392.48。
实例：80：1-(6,7-二甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-(吡啶-3-基)吡咯烷-3-基)脲。1H NMR(CD3OD,300MHz):δ8.46(d,J＝1.5Hz,1H),8.42(d,J＝4.8Hz,1H),8.38(s,1H),7.86-7.83(m,1H),7.59-7.48(m,5H),7.43-7.39(m,1H),7.33(s,1H),7.22(s,1H),4.29-4.27(m,1H),3.97(s,3H),3.96(s,3H),3.54-3.51(m,2H),3.34(s,3H),3.24-3.15(m,1H),3.13-3.03(m,2H),2.82-2.62(m,4H)。LCMS(M+H):528.55。
实例：81：1-((3S,4R)-4-叔丁基-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(喹啉-3-基)脲。1H NMR(CDCl3,400MHz):δ8.79(s,1H),8.50(brs,1H),8.01(d,J＝8.0Hz,1H),7.75(d,J＝8.4Hz,1H),7.55-7.47(m,2H),6.86-6.82(m,1H),3.76-3.72(m,2H),3.58-3.42(m,4H),3.35(s,3H),3.02-2.98(m,2H),2.38-2.24(m,2H),0.97(s,9H)。LCMS(M+H):371.34。
实例：82：1-(6,7-二甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-(1-甲基-1H-吡唑-4-基)吡咯烷-3-基)脲。
1H NMR(CD3OD,300MHz):δ8.43(s,1H),7.60-7.57(m,2H),7.54-7.48(m,4H),7.38(s,1H),7.34(s,1H),7.24(s,1H),4.18-4.14(m,1H),3.98(s,3H),3.96(s,3H),3.84(s,3H),3.51(t,J＝5.4Hz,2H),3.33(s,3H),3.30-3.20(m,1H),3.07-2.90(m,2H),2.77-2.71(m,3H),2.52-2.49(m,1H)。LCMS(M+H):538.41。
实例：83：1-((3S,4R)-1-(2-甲氧基乙基)-4-(1-甲基-1H-吡唑-4-基)吡咯烷-3-基)-3-(喹啉-3-基)脲。1H NMR(CD3OD,300MHz):δ8.75(d,J＝2.4Hz,1H),8.42(d,J＝2.4Hz,1H),7.93(d,J＝8.1Hz,1H),7.82(d,J＝7.8Hz,1H),7.63-7.51(m,3H),7.44(s,1H),4.28-4.26(m,1H),3.84(s,3H),3.55(t,J＝5.4Hz,2H),3.36(s,3H),3.22-3.16(m,1H),3.01-2.95(m,1H),2.88-2.73(m,4H),2.52(t,J＝9.0Hz,1H)。LCMS(M+H):395.14。
实例84：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-苯基-1,8-萘啶-3-基)脲
步骤1：2-苯基-1,8-萘啶-3-羧酸乙基酯的合成：向2-氨基烟碱醛(1.5g,12.29mmol)于哌啶(7.5mL)中的溶液中添加3-氧代基-3-苯基丙酸乙基酯(2.59g,13.52mmol)并在90℃下搅拌3h。将反应混合物冷却到环境温度并倾倒于冰水中。过滤所得固体并用醚洗涤洗涤以得到灰白色固体状所需化合物。产率：2.87g(84％)；1H NMR(DMSO-d6,400MHz):δ9.21-9.2(m,1H),8.95(s,1H),8.65(dd,J＝8.4和2.0Hz,1H),7.75-7.72(m,2H),7.65-7.63(m,2H),7.54-7.52(m,2H),4.21-4.16(m,2H),1.07(t,J＝6.8Hz,3H)。
步骤2：2-苯基-1,8-萘啶-3-羧酸的合成：向2-苯基-1,8-萘啶-3-羧酸乙基酯(1g,3.59mmol)于EtOH(10mL)中的溶液中添加H2O(10mL)，之后添加NaOH(0.79g,17.9mmol)。然后将反应混合物回流4小时，冷却到室温并且在减压下蒸发溶剂。在0℃下将由此获得的残余物用2N HCl(pH约3到4)中和并将所得固体过滤，用戊烷洗涤并且在真空中干燥，从而得到白色固体状所需化合物。产率：0.81g(89％)。1H NMR(DMSO-d6,300MHz):δ13.5(s,1H),9.19-9.17(m,1H),8.62(dd,J＝8.1和1.8Hz,1H),7.74-7.69(m,4H),7.54-7.5(m,3H)。
步骤3：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-苯基-1,8-萘啶-3-基)脲的合成：向2-苯基-1,8-萘啶-3-羧酸(0.2g,0.8mmol)于甲苯(4mL)中的溶液中添加DPPA(0.261g,0.96mmol)，之后添加TEA(0.57mL,4mmol)。将反应混合物在室温下搅拌16小时。然后向反应混合物中添加(3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺(中间体B1)(0.22g,1.03mmol)并且回流2小时。在真空下蒸发反应混合物并且将所得残余物用EtOAc(2×25mL)萃取两次。将合并的有机层用水(25mL)、盐水(25mL)洗涤，经硫酸钠干燥，过滤并在减压下浓缩。通过管柱色谱(2％MeOH/DCM)纯化粗产物，从而得到无色半固体状标题化合物。产率：0.033g。1H NMR(DMSO-d6,300MHz):δ8.97-8.89(m,1H),8.75(S,1H),8.35(dd,J＝1.2Hz和8.1Hz,1H),7.68-7.60(m,2H),7.59-7.47(m,5H),7.37-7.32(m,4H),7.26-7.17(m,2H),4.35-4.33(m,1H),3.55(t,J＝5.4Hz,2H),3.37-3.31(m,4H),3.22-3.14(m,2H),2.95-2.84(m,3H),2.77-2.70(m,1H)。LCMS(M+H):468.1。
实例85：2-((3S,4R)-3-(3-(6,7-二甲氧基-2-苯基喹啉-3-基)脲基)-4-苯基吡咯烷-1-基)乙酸甲基酯。1H NMR(DMSO-d6,300MHz):δ8.52(s,1H),7.62-7.57(m,3H),7.53-7.48(m,3H),7.32-7.22(m,7H),7.12(d,J＝7.5Hz,1H),4.22-4.18(m,1H),3.88(s,6H),3.63(s,3H),3.41-3.38(m,2H),3.18-2.98(m,3H),2.72-2.60(m,2H)。(M+H)+＝540.71。
实例86：甲基2-((3R,4S)-3-苯基-4-(3-(喹啉-3-基)脲基)吡咯烷-1-基)乙酸酯.1H NMR(DMSO-d6,300MHz):δ8.86(s,1H),8.71(d,J＝2.4Hz,1H),8.40(d,J＝2.1Hz,1H),7.88(d,J＝7.8Hz,1H),7.81(d,J＝7.5Hz,1H),7.55-7.49(m,2H),7.37-7.30(m,4H),7.24-7.22(m,1H),6.81(d,J＝7.8Hz,1H),4.28-4.23(m,1H),3.64(s,3H),3.51-3.36(m,2H),3.23-3.19(m,2H),3.11-3.06(m,1H),2.80-2.69(m,2H)。LCMS(M+H):405.29。
实例87：1-((3S,4R)-1-(2-氟乙基)-4-苯基吡咯烷-3-基)-3-(6,7-二甲氧基-2-苯基喹啉-3-基)脲。1H NMR(DMSO-d6,300MHz):δ8.53(s,1H),7.60-7.57(m,3H),7.53-7.49(m,3H),7.32-7.25(m,7H),7.14(d,J＝7.5Hz,1H),4.62(t,J＝5.1Hz,1H),4.46(t,J＝4.8Hz,1H),4.19-4.15(m,1H),3.89(s,3H),3.88(s,3H),3.31-3.16(m,1H),3.05-3.03(m,1H),2.90-2.88(m,1H),2.81-2.79(m,1H),2.71-2.61(m,3H)。LCMS(M+H):515.52。
实例88：1-((3R,4S)-1-(2-氟乙基)-4-苯基吡咯烷-3-基)-3-(6,7-二甲氧基-2-苯基喹啉-3-基)脲。1H NMR(DMSO-d6,300MHz):δ8.53(s,1H),7.61-7.58(m,3H),7.53-7.49(m,3H),7.32-7.22(m,7H),7.14-7.12(m,1H),4.62(t,J＝5.1Hz,1H),4.46(t,J＝5.1Hz,1H),4.17-4.16(m,1H),3.88(s,6H),3.19-3.13(m,1H),3.08-3.03(m,1H),2.93-2.88(m,1H),2.81-2.79(m,1H),2.71-2.61(m,3H)。LCMS(M+H):514.76。
实例89：1-((3S,4R)-1-(2-氟乙基)-4-苯基吡咯烷-3-基)-3-(2-苯基喹啉-3-基)脲。1H NMR(CD3OD,300MHz):δ8.64(s,1H),7.96(d,J＝8.4Hz,1H),7.86(d,J＝8.1Hz,1H),7.67-7.52(m,7H),7.31-7.30(m,4H),7.25-7.22(m,1H),4.63(t,J＝4.8Hz,1H),4.47(t,J＝5.1Hz,1H),4.32-4.30(m,1H),3.24-3.21(m,1H),3.15-3.04(m,2H),2.91-2.77(m,3H),2.63(t,J＝9.0Hz,1H)。SOR：-33.636°(c＝1,MeOH)。LCMS(M+H):454.82。
实例90：1-((3S,4R)-1-(2-氟乙基)-4-苯基吡咯烷-3-基)-3-(喹啉-3-基)脲。1HNMR(CD3OD,300MHz):δ8.72(d,J＝2.7Hz,1H),8.38(d,J＝2.4Hz,1H),7.92(d,J＝8.4Hz,1H),7.80(d,J＝8.4Hz,1H),7.62-7.50(m,2H),7.38-7.29(m,4H),7.24-7.20(m,1H),4.68(t,J＝4.8Hz,1H),4.52(t,J＝5.1Hz,1H),4.45-4.38(m,1H),3.38-3.35(m,1H),3.26-3.20(m,1H),3.13-3.07(m,1H),2.97-2.81(m,3H),2.67(t,J＝8.7Hz,1H)。SOR：-28.000°(c＝1,MeOH)。LCMS(M+H):379.76。
实例91：1-((3S,4R)-1-(2,2,2-三氟乙基)-4-苯基吡咯烷-3-基)-3-(6,7-二甲氧基-2-苯基喹啉-3-基)脲。1H NMR(DMSO-d6,300MHz):δ8.49(s,1H),7.61-7.57(m,3H),7.51-7.47(m,3H),7.33-7.23(m,7H),7.09(d,J＝7.8Hz,1H),4.24-4.20(m,1H),3.88(s,6H),3.37-3.32(m,1H),3.31-3.22(m,2H),3.14-3.09(m,2H),2.77-2.70(m,2H)。LCMS(M+H):550.73。
实例92：1-((3R,4S)-1-(2,2,2-三氟乙基)-4-苯基吡咯烷-3-基)-3-(6,7-二甲氧基-2-苯基喹啉-3-基)脲。1H NMR(DMSO-d6,300MHz):δ8.50(s,1H),7.61-7.57(m,3H),7.51-7.47(m,3H),7.33-7.23(m,7H),7.09(d,J＝7.5Hz,1H),4.24-4.20(m,1H),3.89(s,3H),3.88(s,3H),3.37-3.34(m,1H),3.28-3.23(m,2H),3.14-3.09(m,2H)2.77-2.70(m,2H)。LCMS(M+H):551.53。
实例93：1-((3S,4R)-1-(2,2,2-三氟乙基)-4-苯基吡咯烷-3-基)-3-(喹啉-3-基)脲。1H NMR(DMSO-d6,300MHz):δ8.85(s,1H),8.71(d,J＝2.4Hz,1H),8.40(d,J＝2.7Hz,1H),7.88(d,J＝7.8Hz,1H),7.81(d,J＝7.8Hz,1H),7.56-7.47(m,2H),7.37-7.30(m,4H),7.26-7.21(m,1H),6.81(d,J＝7.8Hz,1H),4.31-4.22(m,1H),3.46-3.33(m,2H),3.28-3.16(m,3H),2.86-2.72(m,2H)。LCMS(M+H):415.35。
实例94：1-((3S,4R)-1-(2,2-二氟乙基)-4-苯基吡咯烷-3-基)-3-(6,7-二甲氧基-2-苯基喹啉-3-基)脲。1H NMR(CD3OD,400MHz):δ8.40(s,1H),7.56-7.48(m,5H),7.33-7.30(m,5H),7.28-7.21(m,2H),6.08-5.80(m,1H),4.30-4.27(m,1H),3.97(s,3H),3.95(s,3H),3.26-3.21(m,1H),3.11-3.06(m,2H),2.97-2.65(m,4H)。LCMS(M+H):533.79。
实例95：1-((3S,4R)-1-(2,2-二氟乙基)-4-苯基吡咯烷-3-基)-3-(喹啉-3-基)脲。1H NMR(DMSO-d6,400MHz):δ8.85(s,1H),8.71(d,J＝2.4Hz,1H),8.40(d,J＝2.4Hz,1H),7.88(d,J＝7.6Hz,1H),7.82(dd,J＝1.2Hz和8.0Hz,1H),7.56-7.48(m,2H),7.36-7.30(m,4H),7.25-7.20(m,1H),6.82(d,J＝8.0Hz,1H),6.29-6.60(m,1H),4.27-4.20(m,1H),3.26-3.16(m,2H),3.10-3.03(m,1H),3.01-2.83(m,2H),2.79-2.75(m,1H),2.68-2.64(m,1H)。LCMS(M+H):397.45。
实例96：1-(6,7-二甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙酰基)-4-苯基吡咯烷-3-基)脲。1H NMR(DMSO-d6,400MHz):δ8.46(br s,1H),7.65-7.62(m,1H),7.56-7.54(m,2H),7.46-7.45(m,3H),7.35-7.27(m,7H),7.00-6.95(m,1H),4.37-4.28(m,1H),4.03(s,2H),3.90(s,6H),3.85-3.80(m,2H),3.37-3.35(m,1H),3.31(s,3H),3.20-3.17(m,1H),3.13-3.10(m,1H)。LCMS(M+H):540.78。
实例97：1-((3S,4R)-1-(2-甲氧基乙酰基)-4-苯基吡咯烷-3-基)-3-(喹啉-3-基)脲。1H NMR(DMSO-d6,400MHz):δ8.91(d,J＝9.2Hz,1H),8.71-8.69(m,1H),8.41(br s,1H),7.88(d,J＝8.4Hz,1H),7.82(d,J＝8.0Hz,1H),7.57-7.49(m,2H),7.40-7.35(m,4H),7.28-7.25(m,1H),6.78-6.72(m,1H),4.44-4.34(m,1H),4.05(s,2H),3.99-3.89(m,2H),3.88-3.46(m,1H),3.36-3.35(m,1H),3.32(s,3H),3.28-3.17(m,1H)。LCMS(M+H):405.50。
实例98：1-(6,7-二甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(氧杂环丁-3-基)-4-苯基吡咯烷-3-基)脲。1H NMR(DMSO-d6,300MHz):δ8.51(s,1H),7.62-7.58(m,3H),7.53-7.47(m,3H),7.33-7.31(m,4H),7.28-7.22(m,3H),7.14(d,J＝7.8Hz,1H),4.59(t,J＝6.3Hz,2H),4.50-4.45(m,2H),4.20-4.18(m,1H),3.88(s,6H),3.66-3.62(m,1H),3.12-3.06(m,2H),2.88-2.82(m,1H),2.55-2.53(m,1H),2.45-2.41(m,1H)。LCMS(M+H):524.53。
实例99：2-((3S,4R)-3-(3-(6,7-二甲氧基-2-苯基喹啉-3-基)脲基)-4-苯基吡咯烷-1-基)乙酰胺。1H NMR(DMSO-d6,300MHz):δ8.50(br s,1H),7.61-7.58(m,3H),7.51-7.48(m,3H),7.33-7.31(m,4H),7.28(d,J＝6.0Hz,2H),7.25-7.21(m,2H),7.10-7.07(m,2H),4.20-4.18(m,1H),3.88(s,6H),3.15-2.97(m,5H),2.60-2.57(m,2H)。LCMS(M+H):526.54。
实例100：1-((3S,4R)-1-(氰基甲基)-4-苯基吡咯烷-3-基)-3-(6,7-二甲氧基-2-苯基喹啉-3-基)脲。1H NMR(DMSO-d6,400MHz):δ8.52(br s,1H),7.62-7.58(m,3H),7.58-7.45(m,3H),7.35-7.22(m,7H),7.15(d,J＝7.2Hz,1H),4.23-4.19(m,1H),3.88(s,6H),3.40-3.31(m,1H),3.17-3.08(m,3H),3.05-3.01(m,1H)2.63-2.45(m,2H)。LCMS(M+H):508.57。
实例101：1-((3S,4R)-1-(氰基甲基)-4-苯基吡咯烷-3-基)-3-(喹啉-3-基)脲。1HNMR(DMSO-d6,400MHz):δ8.85(br s,1H),8.71(d,J＝2.4Hz,1H),8.40(d,J＝2.4Hz,1H),7.88(d,J＝8.4Hz,1H),7.82(dd,1.2Hz和8.0Hz,1H),7.56-7.48(m,2H),7.34-7.32(m,4H),7.26-7.22(m,1H),6.88(d,J＝8.0Hz,1H),4.23-4.19(m,1H),3.90(s,2H),3.31-3.17(m,2H),3.13-3.09(m,1H),2.70-2.64(m,2H)。LCMS(M+H):371.76。
实例102：2-((3R,4S)-3-苯基-4-(3-(喹啉-3-基)脲基)吡咯烷-1-基)乙酰胺。1HNMR(DMSO-d6,400MHz):δ8.85(br s,1H),8.72(d,J＝2.8Hz,1H),8.40(d,J＝2.4Hz,1H),7.88(d,J＝8.0Hz,1H),7.81(d,8.0Hz,1H),7.54-7.50(m,2H),7.37-7.22(m,6H),7.16(brs,1H),6.85(d,J＝8.0Hz,1H),4.25-4.24(m,1H),3.31-3.12(m,3H),3.05-3.00(m,2H),2.73-2.64(m,1H)2.61-2.55(m,1H)。LCMS(M+H):389.87。
实例103：1-(1-(2-甲氧基乙基)-2-氧代基-4-苯基吡咯烷-3-基)-3-(喹啉-3-基)脲。1H NMR(CD3OD,400MHz):δ8.74(d,J＝3.2Hz,1H),8.40(d,J＝2.4Hz,1H),7.92(d,J＝8.0Hz,1H),7.80(d,J＝8.4Hz,1H),7.62-7.58(m,1H),7.55-7.51(m,1H),7.43-7.41(m,2H),7.37-7.33(m,2H),7.29-7.25(m,1H),4.71(d,J＝10.8Hz,1H),3.84-3.82(m,1H),3.73-3.46(m,6H),3.38(s,3H)。LCMS(M+H):405.2。
实例104：1-(二苯并[b,d]呋喃-1-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
步骤1：二苯并[b,d]呋喃-1-基氨基甲酸苯基酯的制备：
在0℃下向二苯并[b,d]呋喃-1-胺(0.2g,1.09mmol)和吡啶(0.17g,2.18mmol)于THF(20mL)中的溶液中逐滴添加氯甲酸苯基酯(0.17g,1.09mmol)，并且将所得混合物在室温下搅拌2h。向反应混合物中添加冷水并将其用乙酸乙酯(2×25mL)萃取。将合并的有机层用水(10mL)、盐水(10mL)洗涤并且经硫酸钠干燥。过滤有机层并在减压下浓缩，从而获得浅褐色固体状标题化合物。产率：0.2g(61％)；LCMS(M+H):304.27。
步骤2：1-(二苯并[b,d]呋喃-1-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲的制备：在0℃下向(3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺二盐酸盐(0.2g,0.78mmol)和二异丙基乙胺(0.30g,2.34mmol)于DMF(4mL)中的溶液中缓慢添加二苯并[b,d]呋喃-1-基氨基甲酸苯基酯(0.23g,0.78mmol)，并将所得混合物在室温下搅拌12h。将反应混合物用水(10mL)稀释并用乙酸乙酯(25mL)萃取。将有机层用水(10mL)、盐水(10mL)洗涤并经硫酸钠干燥。过滤有机层，在减压下浓缩，并通过急速管柱色谱用2％MeOH/CHCl3溶析来纯化残余物，从而获得灰白色固体状标题化合物。产率：0.03g(9％)；1H NMR(CDCl3,300MHz):δ8.01(d,J＝8.1Hz,1H),7.93(d,J＝7.2Hz,1H),7.61(d,J＝8.1Hz,1H),7.51(d,J＝8.1Hz,1H),7.44(dt,J＝1.2和8.4Hz,1H),7.36(d,J＝8.4Hz,1H),7.31-7.25(m,5H),7.22-7.20(m,1H),5.35(d,J＝7.8Hz,1H),4.36-4.32(m,1H),3.52(t,J＝6.0Hz,2H),3.49-3.46(m,1H),3.38-3.33(m,1H),3.30(s,3H),3.14-3.11(m,1H),2.92-2.70(m,3H),2.46(t,J＝9.0Hz,1H)。(M+H):430.35。
以下实例是根据上文所提到的程序通过使用适当中间体来制备。
实例105：1-(二苯并[b,d]呋喃-1-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲。1H NMR(DMSO-d6,300MHz):δ8.68(br s,1H),8.10(t,J＝7.5Hz,2H),7.70(d,J＝6.6Hz,1H),7.66(dd,J＝1.2和7.8Hz,1H),7.53(dt,J＝1.2和7.8Hz,1H),7.42(d,J＝7.2Hz,1H),7.40-7.32(m,1H),7.26(d,J＝7.8Hz,1H),7.21-7.17(m,3H),7.09-7.01(m,1H),4.22-4.16(m,1H),3.47(t,J＝6.0Hz,2H),3.26(s,3H),3.16-3.11(m,2H),2.98(t,J＝7.5Hz,1H),2.74-2.60(m,4H)。LCMS(M+H):448.24。
实例106：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(8-甲基二苯并[b,d]呋喃-1-基)脲。1H NMR(CD3OD,300MHz):δ7.71(s,1H),7.43(d,J＝8.4Hz,1H),7.39-7.22(m,9H),4.48-4.40(m,1H),3.95-3.90(m,1H),3.54(t,J＝5.4Hz,2H),3.34(s,3H),3.25-3.20(m,1H),3.10-3.05(m,1H),2.98-2.92(m,1H),2.85-2.75(m,2H),2.61(t,J＝9.0Hz,1H),2.41(s,3H)。LCMS(M+H):444.26。
实例107：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(8-甲氧基二苯并[b,d]呋喃-1-基)脲。1H NMR(CD3OD,300MHz):δ7.46(d,J＝9.0Hz,1H),7.40-7.35(m,3H),7.31-7.22(m,6H),7.06(dd,J＝3.0和9.0Hz,1H),4.46-4.42(m,1H),3.72(s,3H),3.54(t,J＝5.4Hz,2H),3.38-3.36(m,1H),3.34(s,3H),3.24-3.20(m,1H),3.12-3.07(m,1H),3.02-2.96(m,1H),2.87-2.80(m,2H),2.63(t,J＝9.0Hz,1H)。LCMS(M+H):460.28。
实例108：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(8-氟二苯并[b,d]呋喃-1-基)脲。1H NMR(CDCl3,300MHz):δ7.58(dd,J＝2.7和8.4Hz,1H),7.46-7.29(m,5H),7.25-7.18(m,5H),7.10(dt,J＝2.1和9.0Hz,1H),5.71(brs,1H),4.45-4.35(m,1H),3.40(t,J＝5.4Hz,2H),3.37-3.33(m,1H),3.21(s,3H),3.20-3.19(m,1H),3.07(d,J＝10.2Hz,1H),2.83(t,J＝7.5Hz,1H),2.73-2.59(m,2H),2.37(t,J＝9.6Hz,1H)。LCMS(M+H):448.25。
实例109：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(7-甲氧基二苯并[b,d]呋喃-1-基)脲。1H NMR(CD3OD,400MHz):δ7.66(d,J＝8.8Hz,1H),7.36-7.22(m,8H),7.13(d,J＝2.0Hz,1H),6.82(dd,J＝2.4和8.8Hz,1H),4.50-4.40(m,1H),3.88(s,3H),3.53(t,J＝5.2Hz,2H),3.34(s,3H),3.22-3.18(m,1H),3.03(t,J＝7.6Hz,1H),2.91-2.87(m,1H),2.80-2.72(m,3H),2.58(t,J＝9.2Hz,1H)。LCMS(M+H):460.28。
实例110：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(7-氟二苯并[b,d]呋喃-1-基)脲。1H NMR(DMSO-d6,300MHz):δ8.24(br s,1H),8.14-8.09(m,1H),7.68-7.63(m,2H),7.40-7.28(m,7H),7.25-7.20(m,2H),4.32-4.20(m,1H),3.48(t,J＝5.7Hz,2H),3.26(s,3H),3.22-3.13(m,2H),3.00-2.90(m,1H),2.80-2.60(m,3H),2.43-2.40(m,1H)。LCMS(M+H):448.29。
实例111：1-(二苯并[b,d]噻吩-1-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(DMSO-d6,400MHz):δ8.32(d,J＝6.8Hz,2H),8.01(d,J＝7.2Hz,1H),7.78-7.76(m,1H),7.50(t,J＝7.2Hz,1H),7.45-7.41(m,3H),7.36-7.29(m,4H),7.23-7.20(m,1H),7.07(d,J＝7.6Hz,1H),4.25-4.16(m,1H),3.47(t,J＝6.0Hz,2H),3.26(s,3H),3.19-3.15(m,2H),2.93(t,J＝7.6Hz,1H),2.72-2.60(m,3H),2.54-2.50(m,1H)。LCMS(M+H):446.20。
实例112：1-(5,5-二氧代二苯并[b,d]]噻吩-1-基)-3-[1-(2-甲氧基-乙基)-4-苯基-吡咯烷-3-基]-脲。1H NMR(CDCl3,300MHz):δ8.07-8.04(m,1H),7.82-7.79(m,1H),7.66(t,J＝7.5Hz,2H),7.48-7.42(m,3H),7.34-7.28(m,2H),7.23-7.20(m,3H),7.05-7.01(m,1H),6.40(br s,1H),4.50-4.35(m,1H),3.56(t,J＝8.1Hz,2H),3.48-3.44(m,2H),3.35-3.32(m,1H),3.22(s,3H),2.95(t,J＝7.8Hz,1H),2.81-2.77(m,2H),2.56(t,J＝9.6Hz,1H)。LCMS(M+H):478.13。
实例113：1-(4-甲氧基二苯并[b,d]噻吩-1-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(DMSO-d6,300MHz):δ8.29(d,J＝8.1Hz,1H),8.12(br s,1H),8.02(d,J＝7.8Hz,1H),7.50(t,J＝7.2Hz,1H),7.39(t,J＝7.2Hz,1H),7.32-7.19(m,6H),7.06(d,J＝8.4Hz,1H),6.84(d,J＝8.1Hz,1H),4.25-4.15(m,1H),3.97(s,3H),3.46(t,J＝6.0Hz,2H),3.25(s,3H),3.21-3.11(m,2H),2.93-2.89(m,2H),2.67-2.57(m,3H)。LCMS(M+H):476.15。
实例114:1-(4-甲氧基-5,5-二氧代二苯并[b,d]噻吩-1-基)-3-[1-(2-甲氧基-乙基)-4-苯基-吡咯烷-3-基]-脲。1H NMR(DMSO-d6,300MHz):δ8.16(br s,1H),7.98(d,J＝8.1Hz,1H),7.91-7.88(m,1H),7.63-7.61(m,2H),7.50(d,J＝8.7Hz,1H),7.32-7.28(m,4H),7.23(d,J＝9.0Hz,2H),7.01(d,J＝7.8Hz,1H),4.20-4.10(m,1H),3.95(s,3H),3.46(t,J＝5.1Hz,2H),3.25(s,3H),3.18-3.14(m,2H),2.96-2.85(m,1H),2.70-2.62(m,3H),2.58-2.54(m,1H)。LCMS(M+H):508.26。
实例115：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(9-氧代基-9H-芴-4-基)脲。1H NMR(DMSO-d6,300MHz):δ8.13(br s,1H),7.73-7.54(m,4H),7.38-7.21(m,9H),4.22-4.18(m,1H),3.47(t,J＝6.0Hz,2H),3.26(s,3H),3.21-3.15(m,2H),2.95-2.89(m,1H),2.72-2.61(m,3H),2.43-2.41(m,1H)。LCMS(M+H):442.21。
实例116：1-(6-甲氧基二苯并[b,d]呋喃-1-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,400MHz):δ7.46(d,J＝8.0Hz,1H),7.42(d,J＝8.4Hz,1H),7.40-7.30(m,6H),7.26-7.23(m,1H),7.19(t,J＝8.8Hz,1H),7.08(d,J＝7.2Hz,1H),4.46-4.43(m,1H),4.02(s,3H),3.54(t,J＝5.2Hz,2H),3.38-3.36(m,1H),3.35(s,3H),3.26-3.22(m,1H),3.07(t,J＝8.4Hz,1H),2.95-2.91(m,1H),2.85-2.76(m,2H),2.63(t,J＝9.2Hz,1H)。LCMS(M+H):460.24。
实例117：1-(6-甲基二苯并[b,d]呋喃-1-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,300MHz):δ7.71(s,1H),7.43(d,J＝8.4Hz,1H),7.39-7.20(m,9H),4.48-4.40(m,1H),3.54(t,J＝5.4Hz,2H),3.38-3.36(m,1H),3.34(s,3H),3.25-3.20(m,1H),3.08-3.03(m,1H),2.95-2.92(m,1H),2.80-2.74(m,2H),2.59(t,J＝9.3Hz,1H),2.41(s,3H)。LCMS(M+H):444.21。
以下化合物是通过以下合成方法1和实例3中描述的程序通过使用适当起始材料来合成。
实例118：1-(6-甲氧基-7-甲基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,300MHz):δ8.46(s,1H),7.70(br s,1H),7.56-7.49(m,5H),7.31-7.30(m,5H),7.16(s,1H),4.36-4.30(m,1H),3.97(s,3H),3.52(t,J＝4.8Hz,2H),3.31(s,3H),3.12-3.02(m,2H),2.82-2.74(m,5H),2.36(s,3H)。LCMS(M+H):511.39。
实例119：1-(6-氰基-7-氟-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(DMSO d6,400MHz):δ8.85(s,1H),8.60(d,J＝7.6Hz,1H),8.13(s,1H),7.84(d,J＝10.8Hz,1H),7.63-7.52(m,1H),7.38-7.30(m,5H),7.24-7.21(m,1H),4.25-4.22(m,1H),3.47(t,J＝6.0Hz,2H),3.26(s,3H),3.23-3.22(m,2H),3.12-3.10(m,1H),2.93-2.90(m,1H),2.72-2.66(m,2H),2.64(s,3H),2.44-2.43(m,1H)。LCMS(M+H):448.21。
实例120：1-(6-氰基-7-甲氧基-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(DMSO d6,400MHz):δ8.67(s,1H),8.39(s,1H),8.03(s,1H),7.43(s,1H),7.35-7.22(m,6H),4.25-4.22(m,1H),3.98(s,3H),3.47(t,J＝6.4Hz,2H),3.26(s,3H),3.23-3.21(m,1H),3.14-3.10(m,1H),2.94-2.88(m,1H),2.75-2.65(m,3H),2.59(s,3H),2.50-2.49(m,1H)。LCMS(M+H):460.25。
实例121：1-(7-氰基-6-氟-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,400MHz):δ8.73(s,1H),8.26(d,J＝6.0Hz,1H),7.66(d,J＝9.6Hz,1H),7.38-7.31(m,4H),7.25-7.23(m,1H),4.42-4.40(m,1H),3.58(t,J＝6.4Hz,2H),3.37(s,3H),3.26-3.21(m,2H),3.18-3.13(m,1H),2.98-2.94(m,1H),2.90-2.78(m,2H),2.73-2.68(m,1H),2.65(s,3H)。LCMS(M+H):448.29。
实例122：1-(7-氰基-6-氟-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,400MHz):δ8.85(s,1H),8.37(d,J＝6.0Hz,1H),7.75(d,J＝10.0Hz,1H),7.62-7.56(m,5H),7.34-7.30(m,4H),7.24-7.20(m,1H),4.40-4.38(m,1H),3.53(t,J＝5.6Hz,2H),3.31(s,3H),3.13-3.05(m,2H),2.84-2.71(m,4H),2.62-2.60(m,1H)。LCMS(M+H):510.30。
实例123：1-(7-氰基-6-甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,400MHz):δ8.75(s,1H),8.22(s,1H),7.59-7.54(m,5H),7.39(s,1H),7.31-7.30(m,4H),7.24-7.21(m,1H),4.38-4.36(m,1H),4.05(s,3H),3.53(t,J＝6.0Hz,2H),3.33(s,3H),3.15-3.07(m,2H),2.84-2.74(m,4H),2.62-2.60(m,1H)。LCMS(M+H):522.30。
实例124：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-(噻唑-5-基)喹啉-3-基)脲。1H NMR(CD3OD,400MHz):δ9.08(s,1H),8.49(s,1H),8.31(s,1H),8.01(d,J＝8.8Hz,1H),7.86(d,J＝8.0Hz,1H),7.73-7.68(m,1H),7.58-7.54(m,1H),7.32-7.24(m,4H),7.23-7.21(m,1H),4.40-4.35(m,1H),3.54(t,J＝5.6Hz,2H),3.38-3.35(m,1H),3.35(s,3H),3.24-3.13(m,1H),3.12-3.06(m,1H),2.93-2.77(m,3H),2.69-2.64(m,1H)。LCMS(M+H):474.37。
实例125：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-苯基-5,6,7,8-四氢喹啉-3-基)脲。1H NMR(CDCl3,400MHz):δ7.94(s,1H),7.52(s,1H),7.50(s,1H),7.44(t,J＝7.2Hz,2H),7.39(d,J＝6.8Hz,1H),7.32-7.29(m,2H),7.22-7.21(m,3H),5.32(br s,1H),4.28(br s,1H),3.48-3.44(m,2H),3.31-3.30(m,1H),3.28(s,3H),3.20-3.18(m,1H),3.04-3.02(m,1H),2.90(t,J＝6.4Hz,2H),2.82-2.61(m,5H),2.35-2.33(m,1H),1.89-1.88(m,2H),1.82-1.80(m,2H)。LCMS(M+H):471.33。
实例126：1-(6,7-二甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-1,3-二甲脲。LCMS(M+H):555.39。
实例127：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-1-甲基-3-(2-苯基喹啉-3-基)脲。1H NMR(CDCl3,400MHz):δ9.20(br s,1H),8.71(s,1H),8.06(d,J＝8.4Hz,1H),7.80(d,J＝8.4Hz,1H),7.74(d,J＝7.2Hz,2H),7.60(t,J＝6.8Hz,1H),7.53-7.42(m,4H),7.34-7.30(m,2H),7.24-7.19(m,2H),4.28-4.25(m,1H),3.50(br s,1H),3.34-3.17(m,4H),2.98(s,3H),2.93(s,3H),2.76-2.74(m,1H),2.57-2.49(m,2H),2.25-2.22(m,1H),2.13(t,J＝10.0Hz,1H)。LCMS(M+H):481.47。
实例128：1-(6-(二氟甲氧基)-7-甲氧基-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,300MHz):δ8.33(s,1H),7.49(s,1H),7.37-7.33(m,5H),7.28-7.25(m,1H),7.10-6.66(m,1H),4.40-4.39(m,1H),3.99(s,3H),3.57(t,J＝5.4Hz,2H),3.38-3.37(m,1H),3.36(s,3H),3.26-3.23(m,1H),3.13-3.10(m,1H),2.98-2.82(m,3H),2.72-2.69(m,1H),2.58(s,3H)。LCMS(M+H):501.25
实例129：1-(2,2-二氟-6-甲基-[1,3]二氧杂环戊烯并[4,5-g]喹啉-7-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CDCl3,400MHz):δ8.48(s,1H),7.50(s,1H),7.35-7.31(m,5H),7.25-7.23(m,2H),5.79-5.78(m,1H),4.26-4.24(m,1H),3.53-3.50(m,4H),3.22-3.20(m,1H),3.19(s,3H),2.86-2.80(m,2H),2.70-2.64(m,1H),2.57(s,3H),2.45-2.40(m,1H)。LCMS(M+H):485.01。
实例130：1-(6-(二氟甲基)-[1,3]二氧杂环戊烯并[4,5-g]喹啉-7-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,400MHz):δ8.39(s,1H),7.36-7.20(m,6H),7.12(s,1H),6.96-6.69(m,1H),6.13(s,2H),4.37-4.34(m,1H),3.55(t,J＝4.4Hz,2H),3.35(s,3H),3.24-3.18(m,2H),3.07-3.03(m,1H),2.88-2.86(m,1H),2.85-2.70(m,2H),2.65-2.60(m,1H)。LCMS(M+H):484.94。
实例131：1-([1,3]二氧杂环戊烯并[4,5-g]喹啉-7-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CDCl3,400MHz):δ8.46(s,1H),8.39(s,1H),7.35-7.32(m,2H),7.29-7.26(m,5H),6.99(s,1H),6.07(s,2H),5.48-5.46(m,1H),4.15-4.12(m,1H),3.59-3.56(m,3H),3.45-3.42(m,1H),3.32(s,3H),3.26-3.23(m,1H),2.89-2.84(m,2H),2.79-2.74(m,1H),2.49-2.45(m,1H)。LCMS(M+H):435.39。
实例132：1-(2-环己基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,400MHz):δ8.25(s,1H),7.96(d,J＝8.4Hz,1H),7.75(d,J＝7.2Hz,1H),7.60(t,J＝7.2Hz 1H),7.46(t,J＝7.2Hz,1H),7.37-7.29(m,4H),7.25-7.22(m,1H),4.40-4.39(m,1H),3.56(t,J＝5.6Hz,2H),3.35(s,3H),3.12-3.05(m,2H),3.02-2.96(m,1H),2.84-2.77(m,3H),2.70-2.69(m,1H),2.66(t,J＝8.8Hz,1H),1.86-1.73(m,7H),1.48-1.35(m,3H)。LCMS(M+H):473.45。
实例133：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(6-(三氟甲基)-[1,3]二氧杂环戊烯并[4,5-g]喹啉-7-基)脲。1H NMR(CDCl3,400MHz):δ8.57(s,1H),7.35-7.30(m,5H),7.24-7.22(m,1H),7.02(s,1H),6.12(s,2H),5.68-5.66(m,1H),4.35-4.30(m,1H),3.53-3.49(m,3H),3.39-3.27(m,1H)3.26(s,3H),3.18-3.16(m,1H),2.88-2.69(m,3H),2.46-2.42(m,1H)。LCMS(M+H):503.35。
实例134：1-(6-(二氟甲基)-[1,3]二氧杂环戊烯并[4,5-g]喹啉-7-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲。1H NMR(DMSO-d6,300MHz):δ8.58(s,1H),8.00(s,1H),7.45-7.31(m,4H),7.21-7.17(m,2H),7.07-7.02(m,2H),6.21(s,2H),4.19-4.16(m,1H),3.46(t,J＝5.7Hz,2H),3.25(s,3H),3.16-3.14(m,2H),2.98-2.92(m,1H),2.72-2.63(m,4H)。LCMS(M+H):503.35。
实例135：1-([1,3]二氧杂环戊烯并[4,5-g]喹啉-7-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲。1H NMR(CDCl3,400MHz):δ8.51(s,1H),8.36(s,1H),7.29(s,1H),7.14-7.08(m,2H),7.07-7.00(m,2H),6.07(s,2H),5.48-5.46(m,1H),4.15-4.12(m,1H),3.59-3.56(m,2H),3.45-3.42(m,2H),3.34(s,3H),3.26-3.23(m,1H),2.91-2.86(m,2H),2.82-2.78(m,1H),2.49-2.44(m,1H)。LCMS(M+H):471.34。
实例136：1-(6-氟-2-苯基喹啉-3-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲。1HNMR(CD3OD,300MHz):8.65(s,1H),8.00-7.95(m,1H),7.61-7.41(m,7H),7.35-7.28(m,1H),7.13-7.05(m,2H),6.99-6.93(m,1H),4.32-4.26(m,1H),3.54(t,J＝5.7Hz,2H),3.32(s,3H),3.23-3.00(m,3H),2.79-2.58(m,4H)。LCMS(M+H):503.48。
实例137：1-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(2-苯基-5,6,7,8-四氢喹啉-3-基)脲。1HNMR(CD3OD,300MHz):7.77(s,1H),7.48-7.41(m,5H),7.35-7.28(m,1H),7.10-7.03(m,2H),6.98-6.92(m,1H),4.27-4.22(m,1H),3.53(t,J＝5.7Hz,2H),3.33(s,3H),3.24-3.18(m,1H),3.12-2.97(m,2H),2.85-2.71(m,7H),2.67-2.57(m,1H),1.90-1.82(m,4H)。LCMS(M+H):489.48。
实例138：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(7-甲基-2-苯基-1,8-萘啶-3-基)脲。1HNMR(CDCl3,300MHz):δ8.89-8.88(m,1H),8.05(d,J＝8.1Hz,1H),7.74(d,J＝6.0Hz,2H),7.54-7.47(m,3H),7.35-7.30(m,3H),7.26-7.24(m,3H),4.30-4.28(m,1H),3.48-3.44(m,2H),3.33-3.28(m,1H),3.24(s,3H),3.22-3.13(m,2H),2.76(s,3H),2.54-2.50(m,3H),2.48-2.30(m,1H)。LCMS(M+H):482.46。
实例139：1-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(2-苯基喹啉-3-基)脲。1HNMR(CDCl3,400MHz):δ8.85(s,1H),8.05(d,J＝8.8Hz,1H),7.81(d,J＝8.0Hz,1H),7.64-7.49(m,7H),7.30-7.26(m,1H),7.04(d,J＝8.0Hz,1H),6.97-6.90(m,2H),5.22-5.21(m,1H),4.26-4.24(m,1H),3.47-3.37(m,2H),3.26(s,3H),3.20-3.15(m,2H)3.01-2.98(m,1H),2.73-2.65(m,2H),2.59-2.56(m,1H),2.31-2.37(m,1H)。LCMS(M+H):485.47。
实例140：1-([1,3]二氧杂环戊烯并[4,5-g]喹啉-7-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲。1HNMR(CDCl3,300MHz):δ8.49(s,1H),8.38(s,1H),7.32-7.27(m,3H),7.07(d,J＝7.5Hz,1H),6.97-6.92(m,3H),6.07(s,2H),5.48-5.46(m,1H),4.18-4.15(m,1H),3.58-3.52(m,3H),3.42-3.40(m,1H),3.33(s,3H),3.21-3.18(m,1H),2.87-2.72(m,3H),2.45-2.39(m,1H)。LCMS(M+H):453.38。
实例141：1-(2-(2,4-二氟苯基)喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1HNMR(CDCl3,400MHz):δ8.70(s,1H),8.05(d,J＝8.8Hz,1H),7.82(d,J＝7.6Hz,1H),7.65-7.51(m,3H),7.34-7.30(m,2H),7.26-7.22(m,4H),7.08-7.04(m,1H),6.99-6.94(m,1H),5.32-5.29(m,1H),4.28-4.25(m,1H),3.45(t,J＝4.8Hz,2H),3.36-3.29(m,2H),3.23(s,3H),3.09-3.06(m,1H),2.76-2.69(m,2H),2.63-2.59(m,1H),2.36-2.32(m,1H)。LCMS(M+H):503.48。
实例142：1-(2-(3,5-二氟苯基)喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1HNMR(CDCl3,300MHz):δ8.75(s,1H),8.05(d,J＝8.4Hz,1H),7.82(d,J＝8.1Hz,1H),7.65-7.60(m,1H),7.55-7.50(m,1H),7.35-7.30(m,8H),6.96-6.90(m,1H),5.40-5.38(m,1H),4.19-4.16(m,1H),3.38(t,J＝5.4Hz,2H),3.24-3.21(m,3H),3.13(s,3H),2.73-2.67(m,2H),2.60-2.55(m,1H),2.30-2.28(m,1H)。LCMS(M+H):502.99。
实例143：1-(4-(苄基氧基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(6-甲基-[1,3]二氧杂环戊烯并[4,5-g]喹啉-7-基)脲。1H NMR(CD3OD,300MHz):δ8.29(s,1H),7.38-7.25(m,5H),7.17(s,1H),7.09(s,1H),6.09(s,2H),4.70(d,J＝10.4Hz,1H),4.59(d,J＝12.0Hz,1H),4.28-4.25(m,1H),3.98-3.94(m,1H),3.52(t,J＝5.4Hz,2H),3.33(s,3H),3.16-3.10(m,1H),3.04-2.99(m,1H),2.74-2.60(m,4H),2.56(s,3H)。LCMS(M+H)+:479.15。
实例144：1-(1-氯-3-甲基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,400MHz):δ8.31(d,J＝8.4Hz,1H),7.87-7.85(m,1H),7.80-7.77(m,1H),7.72-7.68(m,1H),7.33-7.32(m,4H),7.26-7.22(m,1H),4.45-4.41(m,1H),3.55-3.47(m,2H),3.33(s,3H),3.20-3.06(m,2H),2.90-2.64(m,5H),2.48(s,3H)。LCMS439.08。
实例145：1-(1,3-二苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,400MHz):δ8.04(d,J＝8.4Hz,2H),7.78(t,J＝6.8Hz,1H),7.68-7.67(m,4H),7.62-7.54(m,5H),7.38-7.24(m,7H),4.40-4.36(m,1H),3.50-3.47(m,2H),3.30(s,3H),3.25-3.24(m,1H),2.80-2.68(m,5H),2.50-2.48(m,1H)。LCMS(M+H):543.99。
实例146：1-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-甲基-1-(1-甲基-1H-吡唑-4-基)异喹啉-4-基)脲。1H NMR(CD3OD,400MHz):δ8.29(d,J＝8.8Hz,1H),8.12(s,1H),7.93(s,1H),7.89(d,J＝7.6Hz,1H),7.75-7.71(m,1H),7.62-7.58(m,1H),7.36-7.31(m,1H),7.15-7.09(m,2H),6.99-6.95(m,1H),4.45-4.40(m,1H),4.03(s,3H)3.54-3.51(m,3H),3.33(s,3H),3.12-3.05(m,1H),2.77-2.64(m,5H),2.55(s,3H)。LCMS(M+H):503.44。
实例147：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(1-(1-甲基-1H-吡唑-4-基)-3-苯基异喹啉-4-基)脲。1H NMR(DMSO d6,300MHz):δ8.41(s,1H),8.38-8.37(m,1H),8.00(s,1H),7.91(d,J＝8.1Hz,2H),7.80-7.64(m,4H),7.40-7.39(m,3H),7.34-7.22(m,5H),6.70(br s,1H),4.19-4.11(m,1H),3.96(s,3H)3.46-3.43(m,2H),3.25(s,3H),3.19-3.12(m,2H),2.91-2.75(m,1H),2.71-2.54(m,4H)。LCMS(M+H):547.12。
实例148：1-(异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(DMSO d6,300MHz):δ9.07(d,J＝9.9Hz 1H),8.96(d,J＝6.9Hz,1H),8.54(brs1H),8.25-8.16(m,1H),8.07(t,J＝9.0Hz,2H),7.84-7.66(m,2H),7.37-7.22(m,4H),7.07(d,J＝7.5Hz 1H),4.25-4.20(m,1H),3.48(t,J＝5.4Hz,2H),3.26(s,3H),3.18-3.08(m,2H),2.98-2.85(m,1H),2.78-2.60(m,3H),2.48-2.39(m,1H)。LCMS(M+H):391.47。
实例149：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(3-苯基异喹啉-4-基)脲。1H NMR(DMSO d6,300MHz):δ9.29(s,1H),8.15(d,J＝8.1Hz,1H),7.95(br s,1H),7.86-7.75(m,2H),7.70.-7.65(m,3H),7.41-7.20(m,8H),6.67(br s,1H),4.20-4.08(m,1H),3.44(t,J＝5.7Hz,2H),3.25(s,3H),3.13-3.06(m,2H),2.84(t,J＝8.7Hz,1H),2.65-2.58(m,3H),2.46-2.42(m,1H)。LCMS(M+H):467.03。
实例150：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(3-甲基异喹啉-4-基)脲。1H NMR(DMSO d6,300MHz):δ9.09(s,1H),8.08(s,1H),8.05-8.02(m,1H),7.80-7.69(m,2H),7.58(t,J＝7.8Hz,1H),7.33-7.31(m,5H),7.24-7.23(m,1H),6.70(d,J＝8.1Hz,1H),4.32-4.11(m,1H),3.48-3.45(m,2H),3.25(s,3H),3.21-3.11(m,2H),2.98-2.91(m,1H),2.68-2.62(m,4H),2.46(s,3H)。LCMS(M+H):405.02。
实例151：1-(1-氰基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(DMSO d6,300MHz):δ8.52-8.39(m,1H),8.27-8.24(m,1H),8.04-8.02(m,1H),7.97-7.91(m,2H),7.65-7.62(m,2H),7.46-7.44(m,3H),7.33-7.19(m,5H),6.88(d,J＝8.4Hz,1H),4.09-4.07(m,1H),3.45-3.41(m,2H),3.24(s,3H),3.17-3.05(m,3H),2.82-2.76(m,1H),2.63-2.56(m,3H)。LCMS(M+H):492.25。
实例152：1-(1-氯-3-苯基异喹啉-4-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲。1H NMR(DMSO d6,400MHz):δ8.30(d,J＝8.4Hz,1H),8.15-8.02(m,1H),7.95-7.88(m,2H),7.85-7.80(m,1H),7.66-7.65(m,2H),7.42-7.41(m,3H),7.37-7.31(m,1H),7.09-7.02(m,3H),6.78-6.65(m,1H),4.19-4.05(m,1H),3.45-3.41(m,2H),3.24(s,3H),3.17-3.05(m,3H),2.92-2.83(m,1H),2.66-2.56(m,3H)。LCMS(M+H):519.38。
实例153：1-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-苯基异喹啉-4-基)脲。1H NMR(CD3OD,300MHz):δ9.22(s,1H),8.17(d,J＝8.4Hz,1H),7.98(d,J＝8.1Hz,1H),7.84-7.79(m,1H),7.73-7.67(m,1H),7.62-7.61(m,2H),7.42-7.40(m,3H),7.36-7.29(m,1H),7.08-6.95(m,3H),4.22-4.32(m,1H),3.51-3.48(m,2H),3.29(s,3H),3.22-3.19(m,1H),3.08-3.02(m,1H),2.95-2.85(m,1H),2.72-2.67(m,3H),2.55-2.48(m,1H)。LCMS(M+H):485.38。
实例154：1-(1-氰基-3-苯基异喹啉-4-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲。1H NMR(CD3OD,400MHz):δ8.35-8.32(m,1H),8.09(d,J＝7.2Hz,1H),7.91-7.87(m,2H),7.67-7.64(m,2H),7.44-7.43(m,3H),7.33-7.30(m,1H),7.09-6.97(m,3H),4.32-4.21(m,1H),3.50-3.47(m,2H),3.30(s,3H),3.22-3.20(m,1H),3.13-3.08(m,2H),2.92-2.90(m,1H),2.74-2.69(m,2H),2.52-2.50(m,1H)。LCMS(M+H):510.41。
实例155：1-(1-羟基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(DMSO d6,300MHz):δ11.38(s,1H),8.21(d,J＝9.0Hz,1H),7.72(t,J＝7.2Hz,1H),7.53-7.48(m,4H),7.42-7.38(m,3H),7.30-7.21(m,6H),6.50(brs,1H),4.10-4.06(m,1H),3.43-3.39(m,2H),3.23(s,3H),3.08-3.02(m,2H),2.83-2.78(m,1H),2.66-2.52(m,3H),2.47-2.43(m,1H)。LCMS(M+H):483.49。
实例156：1-(1-氨基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,300MHz):δ8.13(d,J＝8.1Hz,1H),7.77-7.73(m,1H),7.71-7.64(m,1H),7.62-7.48(m,3H),7.42-7.30(m,3H),7.29-7.18(m,5H),4.34-4.28(m,1H),3.50-3.46(m,2H),3.31(s,3H),3.28-3.22(m,1H),2.94-2.90(m,2H),2.64-2.59(m,3H),2.54-2.48(m,1H)。LCMS(M+H):482.07。
实例157：1-(1-甲氧基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(DMSO d6,300MHz):δ8.19(d,J＝8.1Hz,1H),7.75-7.59(m,6H),7.39-7.22(m,8H),6.66(brs,1H),4.22-4.10(m,1H),4.09(s,3H),3.45-3.42(m,2H),3.25(s,3H),3.08-3.06(m,2H),2.84-2.80(m,1H),2.62-2.54(m,4H)。LCMS(M+H):497.49。
实例158：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(1-甲基-3-苯基异喹啉-4-基)脲。1H NMR(CD3OD,300MHz):δ8.25(d,J＝8.4Hz,1H),7.95(d,J＝7.8Hz,1H),7.77(t,J＝8.1Hz,1H),7.68(t,J＝7.2Hz,1H),7.62-7.56(m,2H),7.42-7.36(m,3H),7.34-7.23(m,5H),4.33-4.28(m,1H),3.49(t,J＝5.7Hz,2H),3.30(s,3H),3.26-3.23(m,1H),3.10-3.05(m,1H),2.97(s,3H),2.93-2.90(m,1H),2.74-2.64(m,2H),2.54-2.47(m,1H)。LCMS(M+H):481.42。
实例159：1-(7-氟-1-甲基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(DMSO d6,400MHz):δ7.95(dd,J＝2.0和9.6Hz,1H),7.92-7.88(m,2H),7.68(dd,J＝2.4和9.2Hz,1H),7.64-7.62(m,2H),7.39-7.38(m,3H),7.33-7.26(m,4H),7.23(d,J＝6.8Hz 1H),6.65(br s,1H),4.14-4.10(m,1H),3.44(t,J＝5.6Hz,2H),3.25(s,3H),3.11-3.05(m,2H),2.87(s,3H),2.84-2.82(m,1H),2.65-2.55(m,3H),2.46(t,J＝7.2Hz,1H)。LCMS(M+H):499.38。
实例160：1-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1-(1-甲基-1H-吡唑-4-基)-3-苯基异喹啉-4-基)脲。1H NMR(CD3OD,300MHz):δ8.41(d,J＝8.4Hz,1H),8.19(s,1H),8.05-7.98(m,2H),7.79(t,J＝8.1Hz 1H),7.70-7.66(m,3H),7.41-7.28(m,4H),7.03-6.94(m,3H),4.33-4.26(m,1H),4.02(s,3H),3.49(t,J＝5.4Hz 2H),3.29(s,3H),3.22-3.18(m,2H),2.94-2.88(m,1H),2.71-2.64(m,3H),2.53-2.48(m,1H)。LCMS(M+H):565.18。
实例161：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(3-甲基-1-(1-甲基-1H-吡唑-4-基)异喹啉-4-基)脲。1H NMR(CD3OD,300MHz):δ8.29(d,J＝8.4Hz,1H),8.12(s,1H),7.93(s,1H),7.87(d,J＝8.1Hz,1H),7.72(t,J＝8.1Hz,1H),7.59(t,J＝6.9Hz,1H),7.41-7.32(m,4H),7.27-7.22(m,1H),4.46-4.43(m,1H),4.03(s,3H),3.54(t,J＝5.1Hz,2H),3.33(s,3H),3.23-3.19(m,2H),3.09-3.06(m,1H),2.95-2.92(m,1H),2.82-2.78(m,2H),2.54(s,3H)。LCMS(M+H):485.20。
实例162：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(1-(1-甲基-1H-吡唑-4-基)异喹啉-4-基)脲。1H NMR(CDCl3,300MHz):δ8.60(s,1H),8.37(d,J＝8.4Hz,1H),7.96-7.90(m,3H),7.70-7.57(m,2H),7.34-7.29(m,2H),7.23-7.21(m,3H),5.57(brs,1H),4.48-4.46(m,1H),4.03(s,3H),3.46(t,J＝5.4Hz,2H),3.41-3.38(m,1H),3.31-3.27(m,1H),3.24(s,3H),3.14-3.10(m,1H),2.94-2.88(m,1H),2.77-2.70(m,2H),2.47(t,J＝9.3Hz,1H)。LCMS(M+H):471.38。
实例163：1-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1-(1-甲基-1H-吡唑-4-基)异喹啉-4-基)脲。1H NMR(CDCl3,400MHz):δ8.58(s,1H),8.39(d,J＝8.8Hz,1H),7.98-7.92(m,3H),7.71(t,J＝7.2Hz,1H),7.63(t,J＝7.2Hz,1H),7.29-7.27(m,2H),7.03(d,J＝8.0Hz,1H),6.95-6.91(m,2H),5.25(br s,1H),4.44-4.41(m,1H),4.04(s,3H),3.43(t,J＝5.2Hz,2H),3.34(t,J＝8.8Hz,1H),3.25(s,3H),3.17-3.14(m,1H),2.99-2.97(m,1H),2.86(t,J＝8.0Hz,1H),2.73-2.62(m,2H),2.40(t,J＝9.2Hz,1H)。LCMS(M+H):489.48。
实例164：1-(3-(叔丁基)-1-(1-甲基-1H-吡唑-4-基)异喹啉-4-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲。1H NMR(CD3OD 300MHz):8.43-8.40(m,1H),8.33(d,J＝7.5Hz,1H),8.08-8.01(m,1H),7.91-7.78(m,1H),7.72-7.48(m,2H),7.42-7.24(m,1H),7.22-7.14(m,1H),7.08-6.82(m,2H),4.48-4.40(m,1H),4.01(s,3H),3.57(t,J＝5.7Hz,2H),3.37(s,3H),3.26-3.21(m,1H),3.11-3.05(m,1H),2.94-2.78(m,2H),2.76-2.68(m,1H),2.63-2.59(m,1H),2.48-2.33(m,1H),1.49(s,9H)。LCMS(M+H):545.53。
实例165：1-(3-(叔丁基)-1-(1-甲基-1H-吡唑-4-基)异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,300MHz):δ8.42-8.01(m,3H),7.79-7.55(m,3H),7.35-7.10(m,5H),4.48-4.44(m,1H),4.01(s,3H),3.57-3.53(m,2H),3.37(s,3H),3.22-3.08(m,2H),2.83-2.70(m,4H),2.37-2.32(m,1H),1.48(s,9H)。LCMS(M+H):527.52。
实例166：1-(1-氟-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(DMSO d6 400MHz):8.17(d,J＝8.4Hz,1H),7.96(brs,1H),7.99-7.89(m,2H),7.78(t,J＝8.0Hz,1H),7.68-7.64(m,2H),7.44-7.39(m,3H),7.33-7.20(m,5H),6.71(brs,1H),4.15-4.10(m,1H),3.44(t,J＝4.8Hz,2H),3.38-3.34(m,1H),3.24(s,3H),3.14-3.05(m,2H),2.86-2.80(m,1H),2.69-2.58(m,3H)。LCMS(M+H):485.40。
实例167：1-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1-甲基-3-苯基异喹啉-4-基)脲。1H NMR(CD3OD,300MHz):8.27(d,J＝8.4Hz,1H),7.96(d,J＝7.5Hz,1H),7.79(t,J＝5.1Hz,1H),7.69(t,J＝7.2Hz,1H),7.62-7.56(m,2H),7.41-7.28(m,4H),7.03-6.94(m,3H),4.29-4.25(m,1H),3.49(t,J＝5.4Hz,2H),3.34(s,3H),3.28-3.16(m,2H),3.09-3.04(m,1H),2.97(s,3H),2.92-2.86(m,1H),2.68-2.64(m,2H),2.53-2.48(m,1H)。LCMS(M+H):499.43。
实例168：1-(7-甲氧基-1-甲基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD 400MHz):7.85(d,J＝8.4Hz,1H),7.58-7.54(m,2H),7.46(d,J＝2.0Hz,1H),7.41-7.37(m,4H),7.31(d,J＝6.8Hz,2H),7.25(J＝6.8Hz,2H),7.23-7.19(m,1H),4.31-4.26(m,1H),3.99(s,3H),3.52-3.48(m,2H),3.42-3.38(m,1H),3.30(s,3H),3.28-3.20(m,1H),3.12-3.06(m,1H),2.93(s,3H),2.78-2.74(m,3H),2.58-2.54(m,1H)。LCMS(M+H):511.45。
实例169：1-(6-甲氧基-1-甲基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CDCl3,400MHz):δ8.07(d,J＝9.6Hz,1H),7.65(d,J＝7.2Hz,2H),7.42-7.35(m,3H),7.28-7.25(m,1H),7.22-7.19(m,4H),7.09(d,J＝6.8Hz,2H),4.86(br s,1H),4.38-4.33(m,1H),3.78(s,3H),3.37-3.35(m,2H),3.23(s,3H),3.18-3.16(m,1H),2.98(s,3H),2.89-2.87(m,1H),2.82-2.76(m,2H),2.63-2.55(m,2H),2.29(t,J＝9.6Hz,1H)。LCMS(M+H):511.45。
实例170：1-(1,6-二甲基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CDCl3 400MHz):8.05(d,J＝8.4Hz,1H),7.79(s,1H),7.67(d,J＝7.2Hz,2H),7.46-7.34(m,5H),7.29-7.26(m,2H),7.22(d,J＝7.2Hz,1H),7.12(d,J＝7.2Hz,2H),4.85(br s,1H),4.42-4.28(m,1H),3.39-3.35(m,2H),3.21(s,3H),2.99(s,3H),2.92-2.85(m,1H),2.83-2.74(m,2H),2.64-2.60(m,2H),2.51(s,3H),2.33-2.29(m,2H)。LCMS(M+H):495.47。
实例171：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(3-苯基-1-(吡啶-3-基)异喹啉-4-基)脲。1H NMR(DMSO d6,300MHz):δ8.91(d,J＝1.5Hz,1H),8.75(dd,J＝1.5和4.8Hz,1H),8.15(dt,J＝1.8和3.6Hz,1H),8.00-7.96(m,3H),7.83(t,J＝6.9Hz,1H),7.73-7.59(m,4H),7.42-7.21(m,8H),6.73(br s,1H),4.22-4.13(m,1H),3.45(t,J＝5.7Hz,2H),3.26(s,3H),3.17-3.12(m,2H),2.86-2.83(m,1H),2.70-2.55(m,3H),2.49-2.47(m,1H)。LCMS(M+H):544.51。
实例172：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(1-吗啉基-3-苯基异喹啉-4-基)脲。1H NMR(CD3OD,400MHz):8.19(d,J＝7.6Hz,1H),7.88-7.82(m,3H),7.69(d,J＝6.4Hz,1H),7.57(t,J＝7.2Hz,1H),7.36-7.28(m,4H),7.30-7.25(m,2H),7.23(d,J＝7.2Hz,2H),4.33-4.28(m,1H),3.96(t,J＝4.4Hz,4H),3.68-3.52(m,2H),3.55-3.44(m,4H),3.30(s,3H),3.27-3.18(m,2H),2.96-2.82(m,2H),2.74-2.63(m,2H),2.53-2.48(m,1H)。LCMS(M+H):552.52。
实例173：1-(1-(4-羟基哌啶-1-基)-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD 400MHz):8.13(d,J＝8.0Hz,1H),7.88-7.82(m,1H),7.74-7.63(m,3H),7.56(t,J＝8.4Hz,1H),7.42-7.28(m,5H),7.25-7.19(m,3H),4.33-4.29(m,1H),3.86-3.79(m,3H),3.52-3.46(m,2H),3.30(s,3H),3.15(t,J＝9.6Hz,4H),2.96-2.88(m,2H),2.74-2.65(m,2H),2.53-2.47(m,1H),2.07-2.05(m,2H),1.86-1.79(m,2H)。LCMS(M+H):566.56。
实例174：1-(3-(3-氟苯基)-1-甲基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,400MHz):δ8.27(d,J＝8.4Hz,1H),7.97-7.95(m,1H),7.79(t,J＝7.2Hz,1H),7.70(t,J＝8.0Hz,1H),7.44-7.38(m,3H),7.32-7.20(m,5H),7.12(t,J＝6.8Hz,1H),4.31-4.26(m,1H),3.52-3.47(m,2H),3.30(s,3H),3.25-3.14(m,2H),2.98(s,3H),2.88-2.82(m,1H),2.78-2.62(m,3H),2.52-2.47(m,1H)。LCMS(M+H):499.47。
实例175：1-(3-(2-氟苯基)-1-甲基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CDCl3,400MHz):δ8.18(d,J＝8.4Hz,1H),8.03(d,J＝8.4Hz,1H),7.73-7.64(m,2H),7.57-7.51(m,1H),7.39-7.35(m,1H),7.29-7.28(m,2H),7.23-7.20(m,2H),7.16-7.08(m,3H),4.82(br s,1H),4.25-4.22(m,1H),3.41-3.43(m,2H),3.28-3.26(m,1H),3.21(s,3H),3.03(s,3H),2.94-2.90(m,2H),2.71-2.54(m,3H),2.33-2.30(m,1H)。LCMS(M+H):499.47。
实例176：1-(6,7-二甲氧基-1-甲基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CDCl3,300MHz):δ7.63(d,J＝6.9Hz,2H),7.42-7.32(m,5H),7.23-7.19(m,3H),7.09(d,J＝6.6Hz,2H),4.85(br s,1H),4.45-4.37(m,1H),4.08(s,3H),3.83(s,3H),3.40-3.36(m,2H),3.24(s,3H),3.23-3.22(m,1H),2.96(s,3H),2.87-2.77(m,3H),2.61-2.56(m,2H),2.30(t,J＝8.4Hz,1H)。LCMS(M+H):541.50。
实例177：1-(6-氟-1-甲基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,400MHz):δ8.36-8.32(m,1H),7.57-7.45(m,4H),7.39-7.38(m,3H),7.33-7.22(m,5H),4.30-4.28(m,1H),3.52-3.51(m,2H),3.31(s,3H),3.31-3.30(m,2H),3.11-3.09(m,1H),2.96(s,3H),2.79-2.73(m,3H),2.57-2.55(m,1H)。LCMS(M+H):499.51。
实例178：1-(1,7-二甲基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,400MHz):δ8.03(s,1H),7.84(d,J＝8.0Hz,1H),7.62(d,J＝8.8Hz 1H),7.58-7.56(m,2H),7.39-7.36(m,3H),7.33-7.29(m,2H),7.25-7.21(m,3H),4.32-4.27(m,1H),3.52-3.48(m,2H),3.30(s,3H),3.24-3.22(m,1H),3.12-2.99(m,1H),2.95-2.93(m,1H),2.92(s,3H),2.80-2.70(m,3H),2.59(s,3H),2.53-2.48(m,1H)。LCMS(M+H):495.55。
实例179：4-(3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)-3-苯基异喹啉-1-甲酰胺。1H NMR(CD3OD,300MHz):δ8.95(dd,J＝2.7Hz和10.8Hz,1H),8.08-8.03(m,1H),7.71-7.69(m,3H),7.63-7.56(m,2H),7.41-7.33(m,5H),7.31-7.25(m,2H),4.32-4.27(m,1H),3.52(t,J＝4.5Hz,2H),3.31(s,3H),3.17-3.11(m,2H),2.97(t,J＝8.1Hz,1H),2.82-2.74(m,3H),2.59(t,J＝9.3Hz,1H)。LCMS(M+H):510.54。
实例180：1-(8-甲氧基-1-甲基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,400MHz):δ8.00(d,J＝8.4Hz,2H),7.91(s,1H),7.60(d,J＝8.4Hz,1H),7.49-7.42(m,3H),7.29-7.26(m,3H),7.23(d,J＝8.0Hz,1H),7.20(d,J＝6.8Hz 1H),7.03(d,J＝8.4Hz 1H),4.44-4.39(m,1H),4.02(s,3H),3.54(t,J＝5.6Hz,2H),3.48-3.46(m,1H),3.33(s,3H),3.14(s,3H),3.08-3.02(m,1H),2.91-2.87(m,3H),2.80-2.71(m,2H)。LCMS(M+H):510.94。
实例181：1-(8-氟-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,400MHz):δ9.22(s,1H),8.15(d,J＝8.0Hz,1H),7.98-7.86(m,1H),7.82-7.78(m,1H),7.70-7.68(m,1H),7.62-7.58(m,1H),7.45-7.39(m,3H),7.34-7.29(m,1H),7.26-7.15(m,3H)7.02-6.94(m,1H),4.35-4.22(m,1H),3.50(t,J＝4.4Hz,2H),3.37-3.35(m,1H),3.30(s,3H),3.26-3.22(m,1H),3.12-3.08(m,1H),2.95-2.92(m,1H),2.78-2.66(m,2H),2.56(t,J＝7.6Hz,1H)。LCMS(M+H):485.35。
实例182：1-(7-氟-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,300MHz):δ9.20(s,1H),8.01-7.96(m,1H),7.84(dd,J＝2.4和9.0Hz,1H),7.64-7.57(m,3H),7.41-7.39(m,3H),7.35-7.23(m,5H),4.32-4.28(m,1H),3.53-3.50(m,2H),3.33(s,3H),3.24-3.22(m,1H),3.12-3.07(m,1H),2.98-2.94(m,1H),2.80-2.74(m,3H),2.56-2.54(m,1H)。LCMS(M+H):484.88。
实例183：1-(7-氟-3-苯基异喹啉-4-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲。1H NMR(CD3OD,300MHz):δ9.21(s,1H),8.04-7.99(m,1H),7.84(dd,J＝2.4和9.0Hz,1H),7.65-7.58(m,3H),7.42-7.29(m,4H),7.09-6.95(m,3H),4.32-4.28(m,1H),3.50(t,J＝5.7Hz,2H),3.31(s,3H),3.24-3.19(m,1H),3.10-3.07(m,1H),2.95-2.90(m,1H),2.79-2.65(m,3H),2.56-2.54(m,1H)。LCMS(M+H):502.82。
实例184：1-(5-甲氧基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,400MHz):δ8.99(s,1H),7.58(d,J＝8.0Hz,1H),7.53-7.52(m,2H),7.48(d,J＝8.0Hz,1H),7.28-7.26(m,3H),7.19(d,J＝7.2Hz,2H),7.15-7.10(m,4H),4.07-4.09(m,1H),3.69(s,3H),3.42-3.41(m,2H),3.31-3.29(m,1H),3.21(s,3H),3.04-3.02(m,1H),2.86-2.82(m,1H),2.72-2.64(m,3H),2.50-2.48(m,1H)。LCMS(M+H):497.39。
实例185：1-(7-氟-1-甲基-3-苯基异喹啉-4-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲。1H NMR(CD3OD,300MHz):δ8.03-7.98(m,1H),7.91(dd,J＝2.4和9.9Hz,1H),7.61-7.57(m,3H),7.40-7.28(m,4H),7.07-6.94(m,3H),4.27-4.24(m,1H),3.49(m,J＝5.1Hz,2H),3.31(s,3H),3.29-3.21(m,2H),3.20-3.05(m,1H),2.93(s,3H),2.75-2.65(m,3H),2.54-2.50(m,1H)。LCMS(M+H):517.10。
实例186：1-(3-氰基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,300MHz):δ8.83(s,1H),8.68-8.65(m,1H),8.06-8.03(m,1H),7.84-7.80(m,2H),7.37-7.19(m,4H),6.46-6.41(m,1H),3.90-3.84(m,1H),3.82-3.76(m,1H),3.64(t,J＝5.1Hz,2H),3.56(d，，J＝8.7Hz 1H),3.42(s,3H),3.35-3.31(m,1H),3.07-2.94(m,2H),2.87-2.79(m,1H),2.58(t,J＝9.6Hz,1H)。LCMS(M+H):415.91。
实例187：1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(3-苯基-1-(哌嗪-1-基)异喹啉-4-基)脲。1H NMR(CD3OD,400MHz):δ8.16(d,J＝8.0Hz,1H),7.89-7.85(m,1H),7.70-7.66(m,3H),7.58(t,J＝8.0Hz,1H),7.33-7.22(m,8H),4.33-4.29(m,1H),3.52-3.49(m,6H),3.35-3.50(m,4H),3.25-3.12(m,5H),2.91-2.68(m,5H)。LCMS(M+H):551.39。
实例188：1-(1-氰基-7-氟-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(DMSO d6,400MHz):δ8.40(br s,1H),8.12-8.09(m,1H),7.93-7.85(m,2H),7.63-7.61(m,2H),7.52-7.45(m,3H),7.33-7.20(m,5H),6.90(d,J＝8.0Hz,1H),4.09-4.04(m,1H),3.43(t,J＝5.6Hz,2H),3.24(s,3H),3.13-3.04(m,2H),2.80(t,J＝8.0Hz,1H),2.65-2.55(m,3H),2.44(t,J＝8.4Hz,1H)。LCMS(M+H):510.36。
实例189：1-(1-(二氟甲基)-3-苯基异喹啉-4-基)-3-(4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲
步骤1：1-(4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1-甲酰基-3-苯基异喹啉-4-基)脲的合成：向1-(4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1-甲基-3-苯基异喹啉-4-基)脲(0.1g,0.200mmol)于1,4二噁烷(30mL)中的搅拌溶液中添加二氧化硒(0.033g,0.301mmol)并且将反应混合物回流4h。使反应混合物达到室温，在减压下浓缩，并通过急速色谱使用二氯甲烷中的5％甲醇作为洗脱液纯化所得粗制化合物，从而获得白色固体状中间体1-(4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1-甲酰基-3-苯基异喹啉-4-基)脲(0.05g,49％)。ESI-MS m/z:513.47(M+H)+。
步骤2：1-(1-(二氟甲基)-3-苯基异喹啉-4-基)-3-(4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲的合成：在0℃下向1-(4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1-甲酰基-3-苯基异喹啉-4-基)脲(0.05g,0.097mmol)于DCM(20mL)中的溶液中添加THF中的50％溶液(0.064g,0.292mmol)并且在室温下搅拌12h。将反应混合物用二氯甲烷稀释并用水洗涤。将分离的有机层经污水Na2SO4干燥，过滤，并且在减压下蒸发滤液。通过急速色谱使用二氯甲烷中的5％甲醇作为洗脱液纯化粗制化合物，从而获得灰白色固体状标题化合物(0.01g,19％)。1H NMR(DMSO d6 300MHz):8.41(d,J＝8.4Hz,1H),8.17(br s,1H),8.00(d,J＝7.5Hz,1H),7.90-7.77(m,2H),7.69-7.65(m,2H),7.58-7.38(m,4H),7.35-7.31(m,1H),7.11-7.01(m,3H),6.79(d,J＝7.8Hz,1H),4.15-4.03(m,1H),3.44(t,J＝5.7Hz,2H),3.24(s,3H),3.09-3.05(m,2H),2.86(t,J＝7.5Hz,1H),2.74-2.71(m,1H),2.66-2.57(m,2H),2.28-2.24(m,1H)。ESI-MS m/z:535.49(M+H)+。
实例190：7-氟-4-(3-(1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)-3-苯基异喹啉-1-羧酸
向7-氟-4-(3-(1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)-3-苯基异喹啉-1-羧酸甲基酯(0.02g,0.036mmol)于THF:MeOH(1:1)(6mL)中的搅拌溶液中添加LiOH.H2O(0.003g 0.073mmol)并且将反应混合物在室温下搅拌2h。然而，将其在真空下浓缩并将所得残余物用2N HCl中和，将所形成固体过滤并在减压下干燥，从而得到灰色固体状标题化合物。产率：0.010g(53％)。1H NMR(CD3OD,400MHz):δ8.22-8.14(m,1H),8.02-7.94(m,1H),7.65-7.53(m,3H),7.36-7.29(m,8H),4.42-4.36(m,1H),3.89-3.85(m,1H),3.66-3.63(m,2H),3.59-3.47(m,2H),3.38(s,3H),3.35-3.31(m,3H),3.28-3.21(m,1H)。LC-MS(M+H):529.69。
实例191：7-氟-4-(3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)-3-苯基异喹啉-1-甲酰胺
向7-氟-4-(3-(1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)-3-苯基异喹啉-1-羧酸(实例190,0.075g,0.142mmol)于DMF(5mL)中的搅拌溶液中添加HATU(0.081g0.213mmol)、DIPEA(0.075mL,0.426mmol)和氨的THF溶液(5mL)并将其在室温下搅拌1h。将反应混合物用水(10mL)稀释并用乙酸乙酯(2×20mL)萃取。将合并的有机层用水(10mL)、盐水(10mL)洗涤并经硫酸钠干燥。过滤溶剂，在减压下浓缩，并通过急速管柱色谱用3％甲醇/二氯甲烷溶析纯化残余物，从而获得黄色固体状标题化合物。产率：0.008g(11％)。1H NMR(CD3OD,300MHz):δ8.95(dd,J＝2.7Hz和10.8Hz,1H),8.08-8.03(m,1H),7.71-7.69(m,2H),7.63-7.56(m,2H),7.41-7.33(m,5H),7.31-7.25(m,2H),4.32-4.27(m,1H),3.52(t,J＝4.5Hz,2H),3.31(s,3H),3.17-3.11(m,2H),2.97(t,J＝8.1Hz,1H),2.82-2.74(m,3H),2.59(t,J＝9.3Hz,1H)。LC-MS(M+H):528.38。
实例192：4-(3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)异喹啉-3-甲酰胺。1H NMR(CD3OD,400MHz):δ8.98(s,1H),8.65(d,J＝8.0Hz 1H),7.80(d,J＝8.4Hz,1H),7.72-7.64(m,2H),7.40-7.33(m,4H),7.25(t,J＝6.8Hz,1H),4.44-4.38(m,1H),3.58(t,J＝5.4Hz 2H),3.37(s,3H),3.35-3.34(m,2H),3.18(t,J＝9.2Hz,1H),2.99-2.95(m,1H),2.91-2.80(m,3H)。LC-MS(M+H):434.24。
实例193：2-((7-氟-4-(3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)-3-苯基异喹啉-1-基)(甲基)氨基)乙酸甲基酯。1H NMR(DMSO-d6,300MHz):δ7.84(dd,J＝2.4,10.2Hz,1H),7.80-7.78(m,1H),7.73-7.68(m,1H),7.65-7.58(m,3H),7.36-7.21(m,8H),6.63(brs,1H),4.21-4.16(m,1H),4.13(s,2H),3.64(s,3H),3.44(t,J＝5.4Hz,2H),3.31(s,3H),3.25(s,3H),3.11-3.04(m,2H),2.88-2.85(m,1H),2.67-2.58(m,3H),2.49(t,J＝1.8Hz,1H)。LC-MS(M+H):586.08。
实例194：2-((7-氟-4-(3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)-3-苯基异喹啉-1-基)(甲基)氨基)乙酸。1H NMR(DMSO-d6,300MHz):δ7.85-7.82(m,1H),7.78(d,J＝8.0Hz,1H),7.62-7.55(m,3H),7.34-7.32(m,9H),6.62(br s,1H),4.16-4.10(m,1H),4.04(s,2H),3.44(t,J＝5.7Hz,2H),3.32(s,3H),3.24(s,3H),3.13-3.02(m,2H),2.88-2.85(m,1H),2.66-2.55(m,3H)。LC-MS(M+H):572.35。
实例195：1-(7-氟-1-((2-羟基乙基)(甲基)氨基)-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,400MHz):δ8.06(d,J＝9.6Hz,1H),7.93-7.88(m,1H),7.86-7.79(m,1H),7.66-7.60(m,2H),7.48-7.42(m,1H),7.36-7.28(m,7H),4.68-4.59(m,1H),3.92-3.89(m,4H),3.78-3.72(m,1H),3.70-3.61(m,3H),3.59(s,3H),3.52-3.45(m,2H),3.38-3.34(m,3H),3.12(s,3H)。LC-MS(M+H):558.45。
实例196：2-((4-(3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)-3-苯基异喹啉-7-基)氧基)乙酸乙基酯。1H NMR(CD3OD,400MHz):8 9.10(s,1H),7.87(d,J＝9.2Hz,1H),7.57-7.56(m,2H),7.48(d,J＝9.6Hz,2H),7.39-7.21(m,8H),4.91(s,2H),4.35-4.32(m,1H)4.28(q,J＝7.2Hz,2H),3.50(t,J＝10.8Hz,2H),3.30(s,3H),3.24-3.19(m,1H),3.12-3.04(m,1H),2.92-2.90(m,1H),2.76-2.70(m,3H),2.53(t,J＝10.8Hz,1H),1.30(t,J＝6.8Hz,3H)。LC-MS:(M+H):569.31。
实例197：2-((4-(3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)-3-苯基异喹啉-7-基)氧基)乙酸。1H NMR(CD3OD,300MHz):δ9.09(s,1H),7.82-7.76(m,1H),7.60-7.54(m,1H),7.50-7.45(m,3H),7.42-7.36(m,5H),7.32-7.28(m,3H),4.58(s,2H),4.42-4.34(m,1H),3.75-3.71(m,1H),3.62(t,J＝4.8Hz,2H),3.52-3.44(m,2H),3.38(s,3H),3.23-3.18(m,1H),3.12-3.05(m,3H)。LC-MS(M+H):541.35。
实例198：1-(7-(2-羟基乙氧基)-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(CD3OD,300MHz):9.10(s,1H),7.84(d,J＝9.3Hz,1H),7.57-7.51(m,3H),7.47(dd,J＝2.4和9.3Hz,1H),7.39-7.24(m,8H),4.32-4.28(m,1H),4.24(t,J＝4.2Hz,2H),3.96(t,J＝4.8Hz,2H),3.50(t,J＝5.4Hz,2H),3.31(s,3H),3.26-3.22(m,1H),3.12-3.05(m,1H),2.93(t,J＝6.9Hz,1H),2.76-2.71(m,3H),2.54(t,J＝9.3Hz,1H)。LC-MS(M+H):527.46。
实例199：1-(4-(苄基氧基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(7-氟-1-甲基-3-苯基异喹啉-4-基)脲。1H NMR(CD3OD,400MHz):δ8.13-8.09(m,1H),7.94(dd,J＝2.4和9.6Hz,1H),7.64-7.59(m,3H),7.42-7.33(m,3H),7.28-7.25(m,5H),4.57-4.54(m,1H),4.44-4.40(m,1H),4.34-4.10(m,1H),3.78-3.60(m,2H),3.44(s,3H),3.30-3.25(m,1H),3.10-2.98(m,1H),2.94(s,3H),2.87-2.78(m,1H),2.68-2.57(m,2H),2.49-2.42(m,2H)。LCMS(M+H):529.08。
实例200：1-(7-氟-1-甲基-3-苯基异喹啉-4-基)-3-(4-羟基-1-(2-甲氧基乙基)吡咯烷-3-基)脲。1H NMR(DMSO-d6,400MHz):δ8.50-7.79(m,2H),7.76-7.67(m,3H),7.45(t,＝7.2Hz,2H),7.39(t,J＝7.6Hz,1H),6.54-6.48(m,2H),4.00-3.89(m,1H),3.87-3.79(m,2H),3.51-3.42(m,3H),3.25(s,3H),3.23-3.20(m,1H),3.10-3.00(m,2H),2.89(s,3H),2.64-2.58(m,1H)。LCMS(M+H):439.25。
实例201：1-(7-氟-1-甲基-3-苯基异喹啉-4-基)-3-(4-羟基-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲。1H NMR(DMSO-d6,300MHz):δ7.91(dd,J＝2.1和9.9Hz,1H),7.69(brs,1H),7.53-7.50(m,5H),7.41-7.35(m,7H),6.28(brs,1H),5.44(brs,1H),4.30-4.23(m,1H),3.51-3.47(m,2H),3.28(s,3H),3.24-3.15(m,3H),2.84(s,3H),2.80-2.75(m,3H),2.61-2.58(m,1H)。LCMS(M+H):515.35。
实例202：1-(4-氟-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(7-氟-1-甲基-3-苯基异喹啉-4-基)脲。1H NMR(CDCl3,300MHz):δ7.67(d,J＝7.5Hz,2H),7.50-7.42(m,4H),7.40-7.33(m,5H),7.22-7.17(m,3H),5.91(br s,1H),4.63-4.53(m,1H),3.46(t,J＝5.4Hz,2H),3.32(s,3H),3.16-3.06(m,2H),3.01-2.97(m,1H),2.93(s,3H),2.75-2.73(m,2H),2.63-2.61(m,1H)。LCMS(M+H):517.33。
生物活性
实例A：基于TrkA细胞的磷酸化分析
使用过表达人类TrkA的重组AD293细胞以测定在NGF刺激时的TrkA Y490磷酸化。在37℃下在5％CO2培育器中将平铺于96孔板中的无血清的DMEM培养基中的25000个细胞血清饥饿2小时。将测试化合物以2.5％DMSO的最终浓度添加到板中并在37℃下培育20min。添加6nM NGF并在37℃下培育5min。立刻将板以2000rpm离心1min并去除培养基。添加含有1％NP-40替代品、20mM Tris(pH 8.0)、137mM NaCl最终浓度的溶解缓冲液，混合1分钟并且在冰上保持15min，同时每5分钟振荡。将100ul细胞溶解物添加到具有预涂布孔的磷酸化-TrkA(Tyr490)夹心式ELISA板中并且根据制造商的说明书进行ELISA用于显色。在格莱夫帕德匹瑞泽(Graph Pad Prism)软件中以非线性回归格式生成IC50。
本发明的代表性化合物的IC50提供于下表2中。
表2：代表性化合物的基于TrkA细胞的活性
+++代表IC50<100nM，++代表IC50介于100nM到1000nM的范围内并且+代表IC50>1000nM。
Claims (18)
1.一种式I化合物：
或其立体异构体、互变异构体，或医药上可接受的盐、同位素、溶剂合物、前药或代谢物，其中：
Ra和Rb各自独立地选自H、烷基、烯基、炔基、卤代烷基、卤素、羟基、羟基烷基、烷氧基、卤代烷氧基、任选经取代的苯基、具有1到3个选自O、N和S的杂原子的任选经取代的5到6元芳香族环，或Ra和Rb一起形成羰基、进一步任选地经卤素取代的任选经取代的苯基；
Rc和Rd是H、烷基、烯基、炔基、卤代烷基、羟基、烷氧基、卤代烷氧基、任选经取代的苯基、具有1到3个选自O、N或S的杂原子的任选经取代的5到6元芳香族环，或Rc和Rd一起形成有或没有杂原子的环(4到6元)；
R1是H、烷基、烯基、炔基、卤代烷基、羟基、烷氧基、卤代烷氧基、(1-3C烷氧基)(1-3C)烷基、(1-4C烷氧基羰基)(1-6C烷基)、单、二、三卤代(1-4C烷基)、(1-3C烷基)氨基羰基、氰基(1-3C烷基)、(1-3C卤代烷氧基)(1-3C)烷基、任选经取代的苯基；3到6元碳环或杂环，其具有一或多个选自O、N或S的杂原子且任选地经一或多个独立地选自以下的取代基取代：H、烷基、烯基、炔基、卤代烷基、卤素、羟基、烷氧基、卤代烷氧基、硝基或氨基；具有1到3个环氮原子的9到10元二环杂芳基；
R2和R3独立地选自H、烷基、烯基、炔基、异丙基、叔丁基、卤代烷基、卤素、羟基、烷氧基、卤代烷氧基、任选经取代的苯基，或具有1到3个选自O、N或S的杂原子的任选经取代的5到6元芳香族环，或R2与R3能够组合以形成具有1到2个杂原子的环(5/6元)；
L是选自以下的配体：—O—、—NH—、—SO2N(R')—、—C(O)N(R')—、—N(R')C(O)—、—C(O)N(R')C(O)—、—N(R')SO2—、—N(R')SO2N(R')—、—NR'C(O)N(R')—、—NR'C(S)N(R')—或—N(R')C(O)O—；每一R'均独立地选自H或烷基；
Het-Ar环是选自H1或H2；
X1到X7在每次出现时是键、-CR5-、-CH2或选自N、O或S的杂原子；
X8选自O、S、NH、N-烷基、SO、SO2或C＝O；
R4、R5和R6各自独立地选自由以下组成的群组：H、烷基、烯基、炔基、异丙基、叔丁基、卤代烷基、卤素、单、二、三卤代(1-4C烷基)羟基、烷氧基、卤代烷氧基、氰基、环烷基(3到7个碳)、任选经取代的苯基、具有1到3个选自O、N或S的杂原子的任选经取代的5到6元杂环或具有一或多个选自O、N或S的杂原子的3到6元碳环、—NH2、—N(H)(烷基)、—N(烷基)2、—N(H)C(O)烷基、—N(烷基)C(O)烷基、—N(H)C(O)O烷基、—N(烷基)C(O)O烷基、—N(H)SO2(烷基)、—N(烷基)SO2(烷基)、—C(O)烷基、—C(O)OH、—C(O)O烷基、—C(O)NH2、—C(O)N(H)(烷基)、—C(O)N(烷基)2、—S(烷基)、—S(O)烷基、—S(O)2烷基、—S(O)2N(H)2、—S(O)2N(H)(烷基)和—S(O)2N(烷基)2。
2.根据权利要求1所述的化合物，其中L选自脲或任选经取代的脲。
3.根据权利要求1所述的化合物，其中H1选自由以下组成的群组：
并且R4、R5各自独立地选自由以下组成的群组：H、烷基、烯基、炔基、异丙基、叔丁基、卤代烷基、卤素、单、二、三卤代(1-4C烷基)羟基、烷氧基、卤代烷氧基、氰基、环烷基(3到7个碳)、任选经取代的苯基、具有1到3个选自O、N或S的杂原子的任选经取代的5到6元杂环或具有一或多个选自O、N或S的杂原子的3到6元碳环、—NH2、—N(H)(烷基)、—N(烷基)2、—N(H)C(O)烷基、—N(烷基)C(O)烷基、—N(H)C(O)O烷基、—N(烷基)C(O)O烷基、—N(H)SO2(烷基)、—N(烷基)SO2(烷基)、—C(O)烷基、—C(O)OH、—C(O)O烷基、—C(O)NH2、—C(O)N(H)(烷基)、—C(O)N(烷基)2、—S(烷基)、—S(O)烷基、—S(O)2烷基、—S(O)2N(H)2、—S(O)2N(H)(烷基)和—S(O)2N(烷基)2。
4.根据权利要求1所述的化合物，其中H2选自由以下组成的群组：
并且每一R6均独立地选自由以下组成的群组：H、烷基、烯基、炔基、异丙基、叔丁基、卤代烷基、卤素、单、二、三卤代(1-4C烷基)羟基、烷氧基、卤代烷氧基、氰基、环烷基(3到7个碳)、任选经取代的苯基、具有1到3个选自O、N或S的杂原子的任选经取代的5到6元杂环或具有一或多个选自O、N或S的杂原子的3到6元碳环、—NH2、—N(H)(烷基)、—N(烷基)2、—N(H)C(O)烷基、—N(烷基)C(O)烷基、—N(H)C(O)O烷基、—N(烷基)C(O)O烷基、—N(H)SO2(烷基)、—N(烷基)SO2(烷基)、—C(O)烷基、—C(O)OH、—C(O)O烷基、—C(O)NH2、—C(O)N(H)(烷基)、—C(O)N(烷基)2、—S(烷基)、—S(O)烷基、—S(O)2烷基、—S(O)2N(H)2、—S(O)2N(H)(烷基)和—S(O)2N(烷基)2。
5.一种医药组合物，其包含治疗有效量的根据权利要求1所述的式I化合物或其医药上可接受的盐。
6.根据权利要求5所述的医药组合物，其中所述组合物用于治疗或预防由异常或失调TrkA活性引起的病症或疾病。
7.根据权利要求6所述的医药组合物，其中所述疾病或病症选自由以下组成的群组：疼痛、炎症或炎症性疾病、癌症、动脉粥样硬化、再狭窄、血栓形成、神经退化性疾病、勃起功能障碍ED、皮肤病症、自体免疫疾病、斯耶格伦综合症、子宫内膜异位症、糖尿病性周围神经病变、前列腺炎、传染病、与骨重塑的调节失衡有关的疾病、子宫内膜异位症、骨盆疼痛综合症和由异常组织重塑和纤维变性病症导致的疾病；或与髓鞘形成障碍或脱髓鞘有关的疾病、病症、损伤或功能失常或与神经生长因子NGF受体TrkA的异常活性相关的疾病或病症。
8.一种治疗有需要的患者的由Trk受体介导或与异常或失调TrkA激酶活性相关的疾病或病症的方法，其中所述疾病或病症选自由以下组成的群组：疼痛、炎症或炎症性疾病、癌症、动脉粥样硬化、再狭窄、血栓形成、神经退化性疾病、勃起功能障碍ED、皮肤病症、自体免疫疾病、斯耶格伦综合症、子宫内膜异位症、糖尿病性周围神经病变、前列腺炎、传染病、与骨重塑的调节失衡有关的疾病、子宫内膜异位症、骨盆疼痛综合症和由异常组织重塑和纤维变性病症导致的疾病；或与髓鞘形成障碍或脱髓鞘有关的疾病、病症、损伤或功能失常或与神经生长因子NGF受体Trk-A的异常活性相关的疾病或病症，所述方法包含向所述患者投与治疗有效量的根据权利要求1所述的化合物或其医药上可接受的盐以及医药上可接受的载剂。
9.根据权利要求8所述的方法，其中所述炎症性疾病选自由以下组成的群组：肺病、肠病、间质性膀胱炎或疼痛性膀胱综合症。
10.根据权利要求8所述的方法，其中所述疼痛包括慢性和急性疼痛。
11.根据权利要求10所述的方法，其中所述疼痛与以下有关：癌症诱导的疼痛、骨折疼痛、炎症性疼痛、神经性疼痛、手术、骨折、由肿瘤转移引起的骨骼疼痛、骨关节炎、牛皮癣关节炎、类风湿性关节炎、间质性膀胱炎、慢性胰脏炎、内脏疼痛、炎症性疼痛、偏头痛、慢性下背疼痛、膀胱疼痛综合症。
12.根据权利要求8所述的方法，其中由异常组织重塑和纤维变性病症导致的所述疾病选自包含以下的群组：特发性肺纤维化、雷诺氏综合症、子宫内膜纤维化、心房纤维化、骨髓纤维化、进行性大块纤维化、肾源性系统性纤维化、硬皮症、全身性硬化、关节纤维化、眼纤维化、结瘢和硬化。
13.根据权利要求8所述的方法，其中所述癌症与TrkA失调有关。
14.根据权利要求13所述的方法，其中所述TrkA失调包含一或多个染色体易位或转化，从而产生TrkA基因融合物。
15.根据权利要求14所述的方法，其中所述TrkA基因融合物是LMNA-TrkA、TFG-TrkA、TPM3-TrkA、CD74-TrkA、NFASC-TrkA、MPRIP-TrkA、BCAN-TrkA、TP53-TrkA、RNF213-TrkA、RABGAP1L-TrkA、IRF2BP2-TrkA、SQSTMI-TrkA、SSBP2-TrkA或TPR-TrkA。
16.根据权利要求8和13所述的方法，其中所述TrkA失调包含TrkA蛋白中的一或多个缺失、插入或突变。
17.根据权利要求8所述的方法，其中所述癌症选自包含以下的群组：肺腺癌、乳癌、甲状腺癌、胰脏癌、乳头状甲状腺癌、卵巢癌、胃癌(gastric carcinoma)、恶性间皮瘤、前列腺癌、神经胚细胞瘤、结肠直肠癌、斯皮茨样黑色素瘤、唾液腺样囊性癌、多形性神经胶质母细胞瘤、胃癌(stomach cancer)、肾癌、尿道癌、口腔鳞状细胞癌、肥大细胞增多症、乳房外佩吉特病、急性骨髓性白血病、胆管癌或肉瘤。
18.一种化合物，其为：
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(喹啉-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-苯基喹啉-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-甲基喹啉-3-基)脲
●1-(2-乙基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(2-环丙基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(2-(三氟甲基)喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(6-氟-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(6-氟-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(5-氟-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(8-氟-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(7-氟-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(7-氟-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(6-甲氧基-2-苯基喹啉-3-基)脲
●1-(7-甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(8-甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(5-甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(5-甲氧基-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(6-甲氧基-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(7-甲氧基-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(8-甲氧基-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(6,7-二甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(6,7-二甲氧基-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(6,7-二甲氧基喹啉-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(6-甲基-2-苯基喹啉-3-基)脲
●1-(2,6-二甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(2,7-二甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(2,5-二甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(2,8-二甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(7-甲基-2-苯基喹啉-3-基)脲
●1-(2-氯喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-(1-甲基-1H-吡唑-4-基)喹啉-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-(吡啶-3-基)喹啉-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-(吡啶-4-基)喹啉-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-(嘧啶-5-基)喹啉-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-吗啉基喹啉-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(喹啉-4-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(喹唑啉-4-基)脲
●1-(2-氯-6,7-二甲氧基喹唑啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(喹喏啉-2-基)脲
●1-(2-异丙基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(2-叔丁基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(6-甲氧基-2-甲基-7-吗啉基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(6-氟-7-甲基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(6-溴-8-甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(7-氟-6-甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(7-氟-6-甲氧基-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(8-甲氧基-7-甲基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(6-甲氧基-2,7-二甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(7-氟-6-甲基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(7-氟-2,6-二甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(6-苯基-[1,3]二氧杂环戊烯并[4,5-g]喹啉-7-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(6-甲基-[1,3]二氧杂环戊烯并[4,5-g]喹啉-7-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(7-甲基-2,3-二氢-[1,4]二氧杂环己烯并[2,3-g]喹啉-8-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(7-苯基-2,3-二氢-[1,4]二氧杂环己烯并[2,3-g]喹啉-8-基)脲
●1-(6-氨基-7-甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(7-甲氧基-6-(甲基氨基)-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●N-(7-甲氧基-3-(3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)-2-苯基喹啉-6-基)乙酰胺
●N-(7-甲氧基-3-(3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)-2-甲基喹啉-6-基)乙酰胺
●N-(6-甲氧基-3-(3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)-2-苯基喹啉-7-基)乙酰胺
●N-(6-甲氧基-3-(3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)-2-甲基喹啉-7-基)乙酰胺
●1-(8-甲氧基-6-(1-甲基-1H-吡唑-4-基)-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-甲基-8-(1-甲基-1H-吡唑-4-基)喹啉-3-基)脲
●1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(喹啉-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(萘-2-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(萘-2-基)脲
●1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(2-(吡啶-3-基)喹啉-3-基)脲
●1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(2-甲基喹啉-3-基)脲
●1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(6,7-二甲氧基-2-甲基喹啉-3-基)脲
●1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(6,7-二甲氧基喹啉-3-基)脲
●1-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(喹啉-3-基)脲
●1-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(2-甲基喹啉-3-基)脲
●1-(6-氟-2-甲基喹啉-3-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲
●1-(7-氟-2-甲基喹啉-3-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲
●1-(6,7-二甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲
●1-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(6-苯基-[1,3]二氧杂环戊烯并[4,5-g]喹啉-7-基)脲
●1-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(6-甲基-[1,3]二氧杂环戊烯并[4,5-g]喹啉-7-基)脲
●1-((3S,4R)-4-(3-氰基苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(喹啉-3-基)脲
●1-((3S,4R)-4-(3-氰基苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(6,7-二甲氧基-2-苯基喹啉-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-(吡啶-3-基)吡咯烷-3-基)-3-(喹啉-3-基)脲
●1-(6,7-二甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-(吡啶-3-基)吡咯烷-3-基)脲
●1-((3S,4R)-4-叔丁基-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(喹啉-3-基)脲
●1-(6,7-二甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-(1-甲基-1H-吡唑-4-基)吡咯烷-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-(1-甲基-1H-吡唑-4-基)吡咯烷-3-基)-3-(喹啉-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-苯基-1,8-萘啶-3-基)脲
●2-((3S,4R)-3-(3-(6,7-二甲氧基-2-苯基喹啉-3-基)脲基)-4-苯基吡咯烷-1-基)乙酸甲基酯
●2-((3R,4S)-3-苯基-4-(3-(喹啉-3-基)脲基)吡咯烷-1-基)乙酸甲基酯
●1-((3S,4R)-1-(2-氟乙基)-4-苯基吡咯烷-3-基)-3-(6,7-二甲氧基-2-苯基喹啉-3-基)脲
●1-((3R,4S)-1-(2-氟乙基)-4-苯基吡咯烷-3-基)-3-(6,7-二甲氧基-2-苯基喹啉-3-基)脲
●1-((3S,4R)-1-(2-氟乙基)-4-苯基吡咯烷-3-基)-3-(2-苯基喹啉-3-基)脲
●1-((3S,4R)-1-(2-氟乙基)-4-苯基吡咯烷-3-基)-3-(喹啉-3-基)脲
●1-((3S,4R)-1-(2,2,2-三氟乙基)-4-苯基吡咯烷-3-基)-3-(6,7-二甲氧基-2-苯基喹啉-3-基)脲
●1-((3R,4S)-1-(2,2,2-三氟乙基)-4-苯基吡咯烷-3-基)-3-(6,7-二甲氧基-2-苯基喹啉-3-基)脲
●1-((3S,4R)-1-(2,2,2-三氟乙基)-4-苯基吡咯烷-3-基)-3-(喹啉-3-基)脲
●1-((3S,4R)-1-(2,2-二氟乙基)-4-苯基吡咯烷-3-基)-3-(6,7-二甲氧基-2-苯基喹啉-3-基)脲
●1-((3S,4R)-1-(2,2-二氟乙基)-4-苯基吡咯烷-3-基)-3-(喹啉-3-基)脲
●1-(6,7-二甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙酰基)-4-苯基吡咯烷-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙酰基)-4-苯基吡咯烷-3-基)-3-(喹啉-3-基)脲
●1-(6,7-二甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(氧杂环丁-3-基)-4-苯基吡咯烷-3-基)脲
●2-((3S,4R)-3-(3-(6,7-二甲氧基-2-苯基喹啉-3-基)脲基)-4-苯基吡咯烷-1-基)乙酰胺
●1-((3S,4R)-1-(氰基甲基)-4-苯基吡咯烷-3-基)-3-(6,7-二甲氧基-2-苯基喹啉-3-基)脲
●1-((3S,4R)-1-(氰基甲基)-4-苯基吡咯烷-3-基)-3-(喹啉-3-基)脲
●2-((3R,4S)-3-苯基-4-(3-(喹啉-3-基)脲基)吡咯烷-1-基)乙酰胺
●1-(1-(2-甲氧基乙基)-2-氧代基-4-苯基吡咯烷-3-基)-3-(喹啉-3-基)脲
●1-(二苯并[b,d]呋喃-1-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(二苯并[b,d]呋喃-1-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(8-甲基二苯并[b,d]呋喃-1-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(8-甲氧基二苯并[b,d]呋喃-1-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(8-氟二苯并[b,d]呋喃-1-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(7-甲氧基二苯并[b,d]呋喃-1-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(7-氟二苯并[b,d]呋喃-1-基)脲
●1-(二苯并[b,d]噻吩-1-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(5,5-二氧代二苯并[b,d]噻吩-1-基)-3-[1-(2-甲氧基-乙基)-4-苯基-吡咯烷-3-基]-脲
●1-(4-甲氧基二苯并[b,d]噻吩-1-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(4-甲氧基-5,5-二氧代二苯并[b,d]噻吩-1-基)-3-[1-(2-甲氧基-乙基)-4-苯基-吡咯烷-3-基]-脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(9-氧代基-9H-芴-4-基)脲
●1-(6-甲氧基二苯并[b,d]呋喃-1-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(6-甲基二苯并[b,d]呋喃-1-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(6-甲氧基-7-甲基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(6-氰基-7-氟-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(6-氰基-7-甲氧基-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(7-氰基-6-氟-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(7-氰基-6-氟-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(7-氰基-6-甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-(噻唑-5-基)喹啉-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-苯基-5,6,7,8-四氢喹啉-3-基)脲
●1-(6,7-二甲氧基-2-苯基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-1,3-二甲基脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-1-甲基-3-(2-苯基喹啉-3-基)脲
●1-(6-(二氟甲氧基)-7-甲氧基-2-甲基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(2,2-二氟-6-甲基-[1,3]二氧杂环戊烯并[4,5-g]喹啉-7-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(6-(二氟甲基)-[1,3]二氧杂环戊烯并[4,5-g]喹啉-7-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-([1,3]二氧杂环戊烯并[4,5-g]喹啉-7-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(2-环己基喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(6-(三氟甲基)-[1,3]二氧杂环戊烯并[4,5-g]喹啉-7-基)脲
●1-(6-(二氟甲基)-[1,3]二氧杂环戊烯并[4,5-g]喹啉-7-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲
●1-([1,3]二氧杂环戊烯并[4,5-g]喹啉-7-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲
●1-(6-氟-2-苯基喹啉-3-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲
●1-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(2-苯基-5,6,7,8-四氢喹啉-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(7-甲基-2-苯基-1,8-萘啶-3-基)脲
●1-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(2-苯基喹啉-3-基)脲
●1-([1,3]二氧杂环戊烯并[4,5-g]喹啉-7-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲
●1-(2-(2,4-二氟苯基)喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(2-(3,5-二氟苯基)喹啉-3-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(4-(苄基氧基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(6-甲基-[1,3]二氧杂环戊烯并[4,5-g]喹啉-7-基)脲
●1-(1-氯-3-甲基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(1,3-二苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-甲基-1-(1-甲基-1H-吡唑-4-基)异喹啉-4-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(1-(1-甲基-1H-吡唑-4-基)-3-苯基异喹啉-4-基)脲
●1-(异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(3-苯基异喹啉-4-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(3-甲基异喹啉-4-基)脲
●1-(1-氰基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(1-氯-3-苯基异喹啉-4-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲
●1-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-苯基异喹啉-4-基)脲
●1-(1-氰基-3-苯基异喹啉-4-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲
●1-(1-羟基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(1-氨基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(1-甲氧基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(1-甲基-3-苯基异喹啉-4-基)脲
●1-(7-氟-1-甲基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1-(1-甲基-1H-吡唑-4-基)-3-苯基异喹啉-4-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(3-甲基-1-(1-甲基-1H-吡唑-4-基)异喹啉-4-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(1-(1-甲基-1H-吡唑-4-基)异喹啉-4-基)脲
●1-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1-(1-甲基-1H-吡唑-4-基)异喹啉-4-基)脲
●1-(3-(叔丁基)-1-(1-甲基-1H-吡唑-4-基)异喹啉-4-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲
●1-(3-(叔丁基)-1-(1-甲基-1H-吡唑-4-基)异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(1-氟-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1-甲基-3-苯基异喹啉-4-基)脲
●1-(7-甲氧基-1-甲基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(6-甲氧基-1-甲基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(1,6-二甲基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(3-苯基-1-(吡啶-3-基)异喹啉-4-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(1-吗啉基-3-苯基异喹啉-4-基)脲
●1-(1-(4-羟基哌啶-1-基)-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(3-(3-氟苯基)-1-甲基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(3-(2-氟苯基)-1-甲基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(6,7-二甲氧基-1-甲基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(6-氟-1-甲基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(1,7-二甲基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●4-(3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)-3-苯基异喹啉-1-甲酰胺
●1-(8-甲氧基-1-甲基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(8-氟-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(7-氟-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(7-氟-3-苯基异喹啉-4-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲
●1-(5-甲氧基-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(7-氟-1-甲基-3-苯基异喹啉-4-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲
●1-(3-氰基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(3-苯基-1-(哌嗪-1-基)异喹啉-4-基)脲
●1-(1-氰基-7-氟-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(1-(二氟甲基)-3-苯基异喹啉-4-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲
●7-氟-4-(3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)-3-苯基异喹啉-1-羧酸
●7-氟-4-(3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)-3-苯基异喹啉-1-甲酰胺
●4-(3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)异喹啉-3-甲酰胺
●2-((7-氟-4-(3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)-3-苯基异喹啉-1-基)(甲基)氨基)乙酸甲基酯
●2-((7-氟-4-(3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)-3-苯基异喹啉-1-基)(甲基)氨基)乙酸
●1-(7-氟-1-((2-羟基乙基)(甲基)氨基)-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●2-((4-(3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)-3-苯基异喹啉-7-基)氧基)乙酸乙基酯
●2-((4-(3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)-3-苯基异喹啉-7-基)氧基)乙酸
●1-(7-(2-羟基乙氧基)-3-苯基异喹啉-4-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(4-(苄基氧基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(7-氟-1-甲基-3-苯基异喹啉-4-基)脲
●1-(7-氟-1-甲基-3-苯基异喹啉-4-基)-3-(4-羟基-1-(2-甲氧基乙基)吡咯烷-3-基)脲
●1-(7-氟-1-甲基-3-苯基异喹啉-4-基)-3-(4-羟基-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲
●1-(4-氟-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(7-氟-1-甲基-3-苯基异喹啉-4-基)脲
或其立体异构体、互变异构体，或医药上可接受的盐、同位素、溶剂合物、前药或代谢物。
Applications Claiming Priority (3)
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| IN362/CHE/2015 | 2015-01-23 | ||
| IN362CH2015 | 2015-01-23 | ||
| PCT/IB2016/050328 WO2016116900A1 (en) | 2015-01-23 | 2016-01-22 | Inhibitors of trka kinase |
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| CN107531589A true CN107531589A (zh) | 2018-01-02 |
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| US (1) | US10336723B2 (zh) |
| EP (1) | EP3247692B1 (zh) |
| JP (1) | JP6706630B2 (zh) |
| CN (1) | CN107531589A (zh) |
| AU (2) | AU2016210544B2 (zh) |
| BR (1) | BR112017015760A2 (zh) |
| CA (1) | CA2974784A1 (zh) |
| RU (1) | RU2017129757A (zh) |
| WO (1) | WO2016116900A1 (zh) |
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| CN108947900A (zh) * | 2018-08-06 | 2018-12-07 | 河南大学 | 光诱导无金属催化的碳芳基化串联反应合成杂环化合物的方法 |
| CN112424189A (zh) * | 2018-07-12 | 2021-02-26 | 漳州片仔癀药业股份有限公司 | 吡咯烷基脲衍生物及其在TrkA相关疾病的应用 |
| CN112979615A (zh) * | 2019-12-17 | 2021-06-18 | 上海医药集团股份有限公司 | 一种喹唑啉脲类化合物、其制备方法、制备中间体、药物组合物及应用 |
| CN116217458A (zh) * | 2023-02-13 | 2023-06-06 | 湖北民族大学 | 2-羰基-5-苯基吡咯类化合物及其制备方法、应用和衍生物、药物组合物 |
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| CA3129665A1 (en) | 2019-03-21 | 2020-09-24 | Onxeo | A dbait molecule in combination with kinase inhibitor for the treatment of cancer |
| JP2023500906A (ja) | 2019-11-08 | 2023-01-11 | インサーム（インスティテュ ナシオナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシェ メディカル） | キナーゼ阻害剤に対する獲得抵抗性を有するがんの処置方法 |
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- 2016-01-22 AU AU2016210544A patent/AU2016210544B2/en not_active Expired - Fee Related
- 2016-01-22 JP JP2017557507A patent/JP6706630B2/ja not_active Expired - Fee Related
- 2016-01-22 CA CA2974784A patent/CA2974784A1/en not_active Abandoned
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- 2016-01-22 CN CN201680017646.8A patent/CN107531589A/zh active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108314648A (zh) * | 2018-04-12 | 2018-07-24 | 苏州康润医药有限公司 | 4-溴-7-氟异喹啉的合成方法 |
| CN112424189A (zh) * | 2018-07-12 | 2021-02-26 | 漳州片仔癀药业股份有限公司 | 吡咯烷基脲衍生物及其在TrkA相关疾病的应用 |
| CN112424189B (zh) * | 2018-07-12 | 2023-07-07 | 漳州片仔癀药业股份有限公司 | 吡咯烷基脲衍生物及其在TrkA相关疾病的应用 |
| US11932652B2 (en) | 2018-07-12 | 2024-03-19 | Zhangzhou Pien Tze Huang Pharmaceutical Co., Ltd. | Pyrrolidinyl urea derivatives and application thereof in TrkA-related diseases |
| CN108947900A (zh) * | 2018-08-06 | 2018-12-07 | 河南大学 | 光诱导无金属催化的碳芳基化串联反应合成杂环化合物的方法 |
| CN108947900B (zh) * | 2018-08-06 | 2021-07-30 | 河南大学 | 光诱导无金属催化的碳芳基化串联反应合成杂环化合物的方法 |
| CN112979615A (zh) * | 2019-12-17 | 2021-06-18 | 上海医药集团股份有限公司 | 一种喹唑啉脲类化合物、其制备方法、制备中间体、药物组合物及应用 |
| CN112979615B (zh) * | 2019-12-17 | 2024-08-09 | 上海医药集团股份有限公司 | 一种喹唑啉脲类化合物、其制备方法、制备中间体、药物组合物及应用 |
| CN116217458A (zh) * | 2023-02-13 | 2023-06-06 | 湖北民族大学 | 2-羰基-5-苯基吡咯类化合物及其制备方法、应用和衍生物、药物组合物 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP3247692B1 (en) | 2022-09-07 |
| JP2018502930A (ja) | 2018-02-01 |
| US10336723B2 (en) | 2019-07-02 |
| AU2016210544B2 (en) | 2020-12-10 |
| CA2974784A1 (en) | 2016-07-28 |
| AU2016210544A1 (en) | 2017-08-31 |
| RU2017129757A (ru) | 2019-02-25 |
| WO2016116900A1 (en) | 2016-07-28 |
| RU2017129757A3 (zh) | 2019-06-06 |
| US20180009781A1 (en) | 2018-01-11 |
| JP6706630B2 (ja) | 2020-06-10 |
| BR112017015760A2 (pt) | 2018-03-27 |
| AU2020223776A1 (en) | 2020-10-01 |
| EP3247692A1 (en) | 2017-11-29 |
| EP3247692A4 (en) | 2019-01-16 |
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