CN101686979A - 脂肪酸酰胺水解酶的杂芳基取代的脲调节剂 - Google Patents
脂肪酸酰胺水解酶的杂芳基取代的脲调节剂 Download PDFInfo
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- CN101686979A CN101686979A CN200880017537A CN200880017537A CN101686979A CN 101686979 A CN101686979 A CN 101686979A CN 200880017537 A CN200880017537 A CN 200880017537A CN 200880017537 A CN200880017537 A CN 200880017537A CN 101686979 A CN101686979 A CN 101686979A
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- piperazine
- benzyl
- methanamide
- amide
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Classifications
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Abstract
本发明描述了某些杂芳基-取代的哌啶基和哌嗪基脲化合物,所述化合物可用作FAAH抑制剂。这种化合物可以在用于治疗由脂肪酸酰胺水解酶(FAAH)活性介导的疾病状态、障碍和病症的药物组合物和方法中使用,所述疾病状态、障碍和病症例如为焦虑、疼痛、炎症、睡眠障碍、进食障碍、胰岛素耐受、糖尿病、骨质疏松和移动障碍(如多发性硬化症)。
Description
技术领域
本发明涉及某些杂芳基-取代的哌啶脲(piperidinyl urea)化合物和哌嗪脲(piperazinyl urea)化合物、含有它们的药物组合物以及使用它们治疗由脂肪酸酰胺水解酶(FAAH)活性介导的疾病状态、障碍和病症的方法。
背景技术
大麻属植物的医用益处为人所知已经有几个世纪了。大麻的主要生物活性组分是Δ9-四氢-大麻酚(THC)。THC的发现最终导致鉴定出两种对其药理学作用负责的内源性大麻素受体,称为CB1和CB2(Goya,Exp.Opin.Ther.Patents 2000,10,1529)。这些发现不仅确立了THC的作用位点,还启发人们对这些受体的内源性激动剂或“内源性大麻素”进行了探询。所鉴定的第一种内源性大麻素是脂肪酸酰胺花生四烯酸乙醇胺(anandamide,AEA)。AEA自身引起许多外源性大麻素的药理学效果(Piomelli,Nat.Rev.Neurosci.2003,4(11),873)。
AEA的分解代谢主要归因于整合的膜结合蛋白脂肪酸酰胺水解酶(FAAH),其将AEA水解成花生四烯酸。FAAH于1996年被Cravatt及其合作者所表征(Cravatt,Nature 1996,384,83)。随后确定FAAH还对大量重要的脂质信号脂肪酸酰胺的分解代谢负责:这些脂肪酸酰胺包括另一种主要的内源性大麻素,2-花生四烯酰丙三醇(2-AG)(Science 1992,258,1946-1949);睡眠诱导物质,油酰胺(OEA)(Science 1995,268,1506);食欲抑制剂,N-油酰乙醇胺(Rodriguez de Fonesca,Nature 2001,414,209);以及消炎药,棕榈酰乙醇酰胺(PEA)(Lambert,Curr.Med.Chem.2002,9(6),663)。
FAAH的小分子抑制剂应该可以提高这些内源性信号脂质的浓度,从而产生其相关的有益药理学效果。已经有一些关于各种FAAH抑制剂在预临床模型中的效果的报道。
特别是,据报道两种氨基甲酸酯基FAAH抑制剂在动物模型中具有止痛效果。据报道,在大鼠中,结构如下所示的BMS-1(参见WO02/087569)在神经性疼痛的Chung脊神经结扎模型中和灵敏热伤害感受的Hargraves试验中具有止痛效果。据报道,URB-597在大鼠焦虑的零加迷宫模型(zero plus maze model)中有效,并且在大鼠的热板和福尔马林试验中具有止痛效果(Kathuria,Nat.Med.2003,9(1),76)。磺酰氟化物AM374也显示在慢性复发性实验性自身免疫性脑脊髓炎(CREAE)小鼠(一种多发性硬化症的动物模型)中显著减轻了痉挛(Baker,FASEB J.2001,15(2),300)。
此外,据报道,噁唑吡啶酮OL-135是FAAH的有效抑制剂,并且在大鼠的热伤害感受的热板和尾部浸水试验中都具有止痛活性(WO04/033652)。
对某些外源性大麻素效果的研究结果说明,FAAH抑制剂可用于治疗各种病症、疾病、障碍或症状。这些包括疼痛、恶心/呕吐、厌食、痉挛、移动障碍、癫痫和青光眼。迄今为止,已经证实的大麻素的治疗用途包括减轻癌症患者因化疗剂诱发的恶心和呕吐,以及增进因衰竭综合征而经历厌食的HIV/AID患者的食欲。对于这些适应症,在一些国家中两种产品是市售的,即屈大麻酚()和大麻隆。
除了已批准的适应症之外,大麻素的使用受到很多关注的治疗领域是止痛,即治疗疼痛。五个小型随机控制实验显示,THC在产生剂量相关的止痛效果时优于安慰剂(Robson,Br.J.Psychiatry 2001,178,107-115)。据报道,Atlantic Pharmaceuticals公司正在开发一种合成的大麻素CT-3(一种四氢大麻酚的羧酸代谢物的1,1-二甲基庚基衍生物)作为口服的活性止痛和消炎药。据报道,CT-3在慢性神经痛方面的先导性二期实验已经于2002年5月在德国启动。
小型控制实验证明,多个患有活动能力-相关的疾病(例如多发性硬化症)的个体已经从大麻中得到了在与疾病相关的疼痛和痉挛状态两个方面的好处(Croxford等人,J.Neuroimmunol,2008,193,120-9;Svendsen,Br.Med.J.2004,329,253)。类似地,据报道,在吸食大麻烟之后,多个脊髓损伤(例如截瘫)患者已经减轻了其疼痛痉挛。报道显示,大麻素看来在多发性硬化症的CREAE模型中控制痉挛状态和震颤,这证实了这些效果是由CB1和CB2受体介导的(Baker,Nature 2000,404,84-87)。已经用四氢大麻酚/大麻酚(THC/CBD)的窄比率混合物在多发性硬化症患者和脊髓损伤患者中进行了三期临床试验。
进行小规模控制实验以调查大麻素的其他潜在商业用途已有报道。据报道,在志愿者中的试验已经证实,口服、注射和吸食大麻素能够与剂量相关地减轻眼内压(IOP),因此可以减轻青光眼症状。眼科医师已经为其他药物不足以控制眼内压的青光眼患者开出大麻处方(Robson,2001,同上)。
与用直接作用的CB1激动剂治疗相比,使用小分子抑制剂来抑制FAAH是有优势的。外源性CB1激动剂的施用可以产生一系列响应,包括减轻伤害感受、强直性昏厥、体温过低和增强进食行为。具体地讲,这四项被称为“大麻素四连法(cannabinoid tetrad)”。用FAAH-/-小鼠进行的实验显示在伤害感受实验中具有减轻的反应,但是未显示强直性昏厥、体温过低或增强进食行为(Cravatt,Proc.Natl.Acad.Sci.USA 2001,98(16),9371)。禁食导致大鼠边缘前脑中的AEA水平升高,但是在其他脑部区域未升高,这提供了AEA生物合成刺激可以在解剖学上区域化到目标CNS通道的证据(Kirkham,Br.J.Pharmacol.2002,136,550)。AEA升高在大脑内局部发生而不是系统性发生的发现暗示,用小分子抑制FAAH能够增强AEA和其他脂肪酸酰胺在下述组织区域中的作用:在该组织区域中,在特定病理学条件下发生这些信号分子的合成和释放(Piomelli,2003,同上)。
除了FAAH抑制剂对AEA和其他内源性大麻素的效果之外,其他脂质介质的FAAH分解代谢的抑制剂可以用于处理一些其他治疗征兆。例如,PEA已显示在炎症(Holt等人,Br.J.Pharmacol.2005,146,467-476)、免疫抑制、止痛和神经保护(Ueda,J.Biol.Chem.2001,276(38),35552)的动物模型中具有生物学效果。油酰胺(另一种FAAH底物)可诱导睡眠(Boger,Proc.Natl.Acad.Sci.USA 2000,97(10),5044;Mendelson,Neuropsychopharmacology 2001,25,S36)。FAAH的抑制还涉及认知(Varvel等人,J.Pharmacol.Exp.Ther.2006,317(1),251-257)和抑郁(Gobbi等人,Proc.Natl.Acad.Sci.USA 2005,102(51),18620-18625)。
FAAH的另外两种适应症得到了最近的数据的支持,这些数据表明FAAH底物激活受体在能量代谢和骨内环境稳定方面很重要(Overton等人,Br.J.Pharmacol.2008(已付印);和Plutzky,Diab.Vasc.Dis.Res.2007,4Suppl 3,S12-4)。已显示,此前提及的由FAAH分解代谢的脂质信号脂肪酸酰胺油酰乙醇胺(OEA)是最近找到的GPCR 119(GPR119)(也称为葡萄糖依赖性促胰岛素受体)的最具活性的激动剂中的其中一种。该受体主要在人的胰腺中表达,并且其激活可通过胰β-细胞中的葡萄糖-依赖性胰岛素释放来改善葡萄糖内环境稳定。GPR119激动剂在口服葡萄糖耐量试验过程中施用时可以抑制葡萄糖波动,并且已经独立地显示,OEA在施用给啮齿类动物时可调节食物摄取和体重增加,表明可能对能量代谢障碍例如胰岛素耐受和糖尿病有益。FAAH底物棕榈酰乙醇酰胺(PEA)是PPARα受体的激动剂。从用PPARα激动剂非诺贝特进行的人体研究中的代用标志物获得的证据支持这样一种观点:PPARα激动剂提供了诱导协同的PPARα响应的潜能,在患有代谢综合征或2型糖尿病的患者中该响应可改善血脂异常、抑制炎症和减少动脉硬化症。FAAH底物花生四烯酸乙醇胺(AEA)是PPARγ受体的激动剂。花生四烯酸乙醇胺处理诱导3T3-L1分化成脂细胞,以及诱导甘油三酯小滴积聚和脂联素的表达(Bouaboula等人,E.J.Pharmacol.2005,517,174-181)。已经显示低剂量的大麻素治疗可减少小鼠中的动脉硬化症,进一步表明了FAAH抑制在血脂障碍、肝脂肪变性、脂肪性肝炎、肥胖症和代谢综合征中的治疗有益效果(Steffens等人,Nature,2005,434,782-6)。
骨质疏松是一种最常见的退行性疾病。该疾病表征为骨矿物质密度(BMD)减小,骨折的风险增加。CB2-缺陷型小鼠具有显著增加的年龄相关的骨小梁缺失和皮质扩张。CB2-选择性激动剂可增加皮质内成骨细胞的数目和活性,并抑制小梁破骨细胞形成和减弱卵巢切除术引起的骨丢失(Ofek等人,Proc.Natl.Acad.Sci.U.S.A.2006,103,696-701)。遗传对BMD有相当大的作用,但涉及人骨质疏松的遗传因素在很大程度上是未知的。可通过遗传研究来说明对人BMD的适用性,在该研究中,找到了单核苷酸多态性和单元型的显著关联,包括人染色体1p36上的CNR2基因,表明了在外周表达的CB2受体在骨质疏松的病因学中的作用(Karsak等人,Hum.Mol.Genet,2005,14,3389-96)。
因此,小分子FAAH抑制剂应该可用于治疗多种病因的疼痛、焦虑、多发性硬化症和其他行动障碍、恶心/呕吐、进食障碍、癫痫、青光眼、炎症、免疫抑制、神经保护、抑郁、认知增强和睡眠障碍,并且潜在地比用外源性大麻素治疗的副作用小。
多种杂芳基-取代的脲已经在多个出版物中报道。某些取代的噻吩脲在美国专利No.6,881,741中有所描述。某些脲基-吡唑在美国专利No.6,387,900中有所描述。某些苯并噻唑酰胺衍生物在美国专利公布US2003/149036中有所描述。在WO 2003/047569中,报道了作为异戊烯转移酶抑制剂的某些脲。在美国专利No.6,100,279中将哌啶脲描述为组胺H3受体拮抗剂。在美国专利No.6,124,299和6,395,740中公开了作为降钙素模拟剂的哌嗪脲。在美国专利公布No.US 2006/173184和US2007/0004741、国际专利申请No.WO 2008/023720、WO 2008/047229和WO 2008/024139,以及Cravatt等人,(Biochemistry 2007,46(45),13019)中报道了作为小分子FAAH调节剂的多种脲。在美国专利申请公布US2007/270433以及国际专利申请公布No.WO 2007/096251和WO2006/085108中描述了作为其他靶标的调节剂的脲。然而,仍然需要具有合适药学性质的有效FAAH调节剂。
发明内容
现在,已经发现了某些杂芳基-取代的哌啶脲和哌嗪脲衍生物具有FAAH-调节活性。因此,本发明涉及分别由所附的独立权利要求和从属权利要求限定的一般实施例和优选实施例,将其以引用方式并入本文中。
在一个一般方面,本发明涉及式(I)化合物以及所述化合物的可药用盐、可药用前药和药学活性代谢物:
其中:
Ar1是苯并[d]异噁唑-3-基、6-氟苯并[d]异噁唑-3-基、3-苯基-[1,2,4]噻二唑-5-基、1H-四唑-5-基、苯并[1,2,5]噻二唑-4-基、苯并[1,2,5]噁二唑-4-基、噻吩-2-基、噻吩-3-基、6-氯-哒嗪-3-基、吡嗪-2-基、异噁唑-3-基、1H-苯并三唑-5-基、[1,5]萘啶-2-基、喹啉-2-基、苯并噻唑-6-基、喹啉-5-基、1H-吡唑-3-基、5-甲基吡嗪-2-基、3-氯吡嗪-2-基、哒嗪-3-基、6-甲氧基哒嗪-3-基、5-甲基异噁唑-3-基、1,5-二甲基-1H-吡唑-3-基、4-溴-1-甲基-1H-吡唑-3-基、2-乙基-2H-吡唑-3-基、5-甲基-1H-吡唑-3-基或5-苯基-1H-吡唑-3-基;
Z是-N-或>CH;并且
Ar2是:
(i)未被Ra部分取代或被一个或两个Ra部分取代的苯基;
其中每个Ra部分独立地是-C1-4烷基、-C≡C-Rd、-OC1-4烷基、卤素、-CF3、-OCF3、-OCH2CF3、-SCF3、-S(O)0-2C1-4烷基、-SO2CF3、-OSO2C1-4烷基、-(CH2)0-1CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(O)NRbRc、-NO2或-(CH2)0-1CN;
或者两个相邻的Ra部分合在一起形成-O(CH2)1-2O-或-OCF2O-;
其中Rb和Rc各自独立地是-H或-C1-4烷基;并且
Rd是H、C3-6环烷基或-CH2NReRf;
其中Re和Rf各自独立地是H或C1-4烷基;
(ii)在3-位置或4-位置处被-L-Ar3取代、未被Ra部分取代或被一个或两个Ra部分取代的苯基,其中:
L是选自由以下连接基组成的组的连接基:-(CH2)1-3-、-CH=CH-、-O-、-OCH2-、-CH2O-、-NH-、>NC1-4烷基、-S-、-C≡C-、-C(=O)-和共价键;并且
Ar3是:
(a)苯基;
(b)萘基;或
(c)单环杂芳基或双环杂芳基;或
(iii)9元或10元稠合双环杂芳基;
其中当Ar1为6-氯-哒嗪-3-基、异噁唑-3-基或1H-吡唑-3-基时,Ar2不是苯并[1,3]二氧杂环戊烯-5-基或2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基。
在另一个一般方面,本发明涉及式(Ia)化合物以及这种化合物的可药用盐、可药用前药和药学活性代谢物:
其中:
Ar1是苯并[d]异噁唑-3-基、6-氟苯并[d]异噁唑-3-基、3-苯基-[1,2,4]噻二唑-5-基、1H-四唑-5-基、苯并[1,2,5]噻二唑-4-基、苯并[1,2,5]噁二唑-4-基、噻吩-2-基、噻吩-3-基、6-氯-哒嗪-3-基、吡嗪-2-基、异噁唑-3-基、1H-苯并三唑-5-基、[1,5]萘啶-2-基、喹啉-2-基、苯并噻唑-6-基、喹啉-5-基或1H-吡唑-3-基;
Z是-N-或>CH;并且
Ar2是:
(i)被一个或两个Ra部分取代的苯基或3-苯氧基苯基;
其中每个Ra部分独立地是-C1-4烷基、-OC1-4烷基、卤素、-CF3、-OCF3、-OCH2CF3、-SCF3、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(O)NRbRc、-NO2或-CN;
其中Rb和Rc各自独立地是-H或-C1-4烷基;或者
(ii)苯并[1,3]二氧杂环戊烯-5-基、2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基或萘基;
其中当Ar1为6-氯-哒嗪-3-基、异噁唑-3-基或1H-吡唑-3-基时,Ar2不是苯并[1,3]二氧杂环戊烯-5-基或2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基。
在尤其优选的实施例中,本发明涉及在下面具体描述中所描述或示例的化合物以及它们的可药用盐。
本领域技术人员将认识到式(Ia)化合物是式(I)化合物的实施例。因此,本文中提及式(I)化合物也涵盖式(Ia)化合物。
在又一个一般方面,本发明涉及各自包含下述成分的药物组合物:(a)有效量的至少一种选自式(I)化合物、式(I)化合物的可药用盐、式(I)化合物的可药用前药和式(I)化合物的药学活性代谢物的制剂;以及(b)可药用赋形剂。
在另一个一般方面,本发明涉及治疗患有或被诊断患有由FAAH活性介导的疾病、障碍或医学病症的方法,该方法包括向需要这种治疗的受试者施用有效量的至少一种选自式(I)化合物和它们的可药用盐、药学活性前药和药学活性代谢物的制剂。在本发明方法的优选实施例中,疾病、障碍或医学病症选自:焦虑、抑郁、疼痛、睡眠障碍、进食障碍、炎症、多发性硬化症和其他移动障碍、HIV衰竭综合征、封闭型颅脑损伤、中风、学习记忆障碍、阿尔茨海默病、癫痫、图雷特综合征、尼曼-匹克病、帕金森病、亨廷顿舞蹈病、视神经炎、自身免疫性葡萄膜炎、药物戒断的症状、恶心、呕吐、性功能障碍、创伤后应激障碍、脑血管痉挛、青光眼、过敏性肠综合征、炎性肠疾病、免疫抑制、胃食管反流性疾病、麻痹性肠梗阻、分泌性腹泻、胃溃疡、类风湿性关节炎、意外妊娠、高血压、癌、肝炎、过敏性气管病、自身免疫性糖尿病、顽固性瘙痒以及神经炎。
通过以下详细描述和本发明的实践,本发明的其他实施例、特征和优点将会是显而易见的。
本发明的具体实施方式及其优选的实施例
参考以下详细说明,包括以下术语词汇表和所包含的实例,可以更全面地理解本发明。为简单起见,将本说明书所引用的出版物(包括专利)的公开内容以引用的方式并入本文中。
如本文所用,术语“包括”、“含有”和“包含”以其开放的、非限制性意义使用。
术语“烷基”指链中具有1至12个碳原子的直链或支链烷基。烷基的实例包括甲基(Me,其在结构上也可以用符号“/”描述)、乙基(Et)、正丙基、异丙基、丁基、异丁基、仲丁基、叔丁基(tBu)、戊基、异戊基、叔戊基、己基、异己基等。
术语“链烯基”指链中具有2至12个碳原子的直链或支链的链烯基。(链烯基的双键由两个sp2杂化的碳原子形成。)示例性的链烯基包括丙-2-烯基、丁-2-烯基、丁-3-烯基、2-甲基丙-2-烯基、己-2-烯基等。
术语“环烷基”指每个碳环具有3至12个环原子的饱和或部分饱和的单环、稠合多环或螺多环的碳环。示例性的环烷基例子包括正确键合部分形式的下述实体:
“杂环烷基”指每个环结构具有3至12个环原子的饱和或部分饱和的单环或者稠合多环、桥环或螺多环的环结构,其中环原子选自碳原子以及最多三个选自氮、氧和硫的杂原子。环结构的碳或硫环部分上可任选含有最多两个氧基团。示例性的杂环烷基例子包括正确键合部分形式的以下实体:
术语“杂芳基”指每个杂环具有3至12个环原子的单环、稠双环或稠合多环的芳族杂环(环结构具有选自碳原子和最多四个选自氮、氧和硫的杂原子的环原子)。示例性的杂芳基例子包括正确结合部分形式的以下实体:
术语“卤素”表示氯、氟、溴或碘。术语“卤代”表示氯代、氟代、溴代或碘代。
术语“取代”指特定基团或部分带有一个或多个取代基。术语“未取代”表示特定基团不带有取代基。术语“任选取代”表示特定基团是未被取代基取代或被一个或多个取代基取代。当术语“取代”用于描述结构系统时,可以在系统上任何化合价允许的位置发生取代。在未明确地指明特定部分或基团是被任选取代或被任何特定取代基取代的情况下,应该理解这样的部分或基团旨在为未取代的。
本文所给定的结构式旨在表示具有该式所描绘的结构的化合物以及等同的变体或形式。例如,式(I)包含的化合物可以具有不对称中心,因此存在不同的对映异构形式。该通式的化合物的所有光学异构体和立体异构体及其混合物均被视为处于该式的范围内。因此,本文给定的通式旨在表示外消旋体、一种或多种对映体形式、一种或多种非对映体形式、一种或多种阻转异构体形式以及它们的混合物。此外,某些结构可以作为几何异构体(即顺式和反式异构体)存在、作为互变异构体(例如,吡唑、苯并咪唑、四唑或苯并三唑互变异构体)存在,或者作为阻转异构体存在,其旨在由结构式表示。另外,本文给定的式子旨在包含这种化合物的水合物、溶剂化物和多晶型物,以及它们的混合物。
本文给定的结构式还旨在表示该化合物的未标记形式以及同位素标记形式。除了一个或多个原子被具有所选原子量或质量数的原子代替之外,同位素标记的化合物具有本文给定的式子所描绘的结构。可以整合进本发明化合物中的同位素的例子分别包括氢、碳、氮、氧、磷、氟和氯的同位素,例如2H、3H、11C、13C、14C、15N、18O、17O、32p、33p、35S、18F、36C1和125I。这种同位素标记的化合物可用于代谢研究(优选使用14C)、反应动力学研究(使用例如2H或3H)、检测或显像技术[例如正电子发射断层扫描术(PET)或单光子发射电子计算机断层扫描(SPECT)],包括药物或底物的组织分布测定,或者可用于患者的放射治疗。对于PET或SPECT研究而言,特别优选的是18F-或11C-标记的化合物。此外,用较重的同位素如氘(即2H)取代可以提供由更大的代谢稳定性所带来的某些治疗优势,例如体内半衰期延长或需要的剂量减少。同位素标记的本发明化合物及其前药通常可通过执行下面描述的“方案”或“实例”中所公开的过程和制备,通过用容易获得的同位素标记试剂代替非同位素标记试剂来制备。
当提及考本文给定的任何式子时,针对具体变量,从可能物种的列表中选择具体部分并非意图限定出现在其他位置的变量的部分。换句话讲,当式子变量出现多于一次时,从指定列表选择物种与针对式中其他位置的相同变量选择物种无关。
在式(I)的优选实施例中,Ar1是苯并[d]异噁唑-3-基、6-氟苯并[d]异噁唑-3-基、苯并[1,2,5]噻二唑-4-基、苯并[1,2,5]噁二唑-4-基、6-氯-哒嗪-3-基、吡嗪-2-基、异噁唑-3-基、1H-苯并三唑-5-基、苯并噻唑-6-基或1H-吡唑-3-基。在另外的优选实施例中,Ar1是苯并[d]异噁唑-3-基。在又一优选的实施例中,Ar1是吡嗪-2-基。在又一优选的实施例中,Ar1是异噁唑-3-基。在又一优选的实施例中,Ar1是哒嗪-3-基。
在优选的实施例中,Z是-N-。在其他优选的实施例中,Z是>CH。
在优选的实施例中,Ar2是被一个或两个Ra部分取代的苯基。
在优选的实施例中,Ar2是被一个或两个Ra部分取代的苯基,并且每个Ra部分独立地选自由以下基团组成的组:氯、氰基、异丁基、甲硫基、甲磺酰基、三氟甲基、三氟甲氧基、2,2,2-三氟乙氧基、氟、甲基、甲氧基、叔丁基、溴、甲氧羰基、氰甲基、甲氧羰基甲基、三氟甲烷磺酰基、三氟甲硫基和丁基;或者两个相邻的Ra部分合在一起形成-OCH2O-或-OCF2O-。
在另外的优选实施例中,Ar2是在3-位置或4-位置处被-L-Ar3取代的苯基,以形成-苯基-L-Ar3基团,该基团是未被Ra部分取代或被一个或两个Ra部分取代。在另外的优选实施例中,L是-CH2CH2-、-O-、-OCH2-或-C≡C-。在又一优选的实施例中,Ar3是苯基。在又一优选的实施例中,Ar3是苯基并且每个Ra部分独立地选自由以下基团组成的组:氯、氰基、异丁基、甲硫基、甲磺酰基、三氟甲基、三氟甲氧基、2,2,2-三氟乙氧基、氟、甲基、甲氧基、叔丁基、溴、甲氧羰基、氰甲基、甲氧羰基甲基、三氟甲烷磺酰基、三氟甲硫基和丁基;或者两个相邻的Ra部分合在一起形成-OCH2O-或-OCF2O-。
在又一优选的实施例中,Ar3是萘基。在又一优选的实施例中,Ar3是单环或双环杂芳基。在又一优选的实施例中,Ar3是噻吩基、嘧啶基、吡啶基、吡嗪基或喹啉基。在又一优选的实施例中,Ar3是萘基或单环或双环杂芳基并且每个Ra部分独立地选自由以下基团组成的组:氯、氰基、异丁基、甲硫基、甲磺酰基、三氟甲基、三氟甲氧基、2,2,2-三氟乙氧基、氟、甲基、甲氧基、叔丁基、溴、甲氧羰基、氰甲基、甲氧羰基甲基、三氟甲烷磺酰基、三氟甲硫基和丁基;或者两个相邻的Ra部分合在一起形成-OCH2O-或-OCF2O-。
在另外的优选实施例中,Ar2是9元或10元稠合双环杂芳基。在又一优选的实施例中,Ar2是苯并咪唑基、吲唑基、苯并噻吩基、喹啉基、吲哚基或苯并呋喃基。
在式(I)或式(Ia)的优选实施例中,Ar1是苯并[d]异噁唑-3-基、6-氟苯并[d]异噁唑-3-基、苯并[1,2,5]噻二唑-4-基、苯并[1,2,5]噁二唑-4-基、6-氯-哒嗪-3-基、吡嗪-2-基、异噁唑-3-基、1H-苯并三唑-5-基、苯并噻唑-6-基或1H-吡唑-3-基。在另外的优选实施例中,Ar1是苯并[d]异噁唑-3-基。在又一优选的实施例中,Ar1是吡嗪-2-基。在又一优选的实施例中,Ar1是异噁唑-3-基。在又一优选的实施例中,Ar1是哒嗪-3-基。
在优选的实施例中,Ar2是被一个或两个Ra部分取代的3-苯氧基苯基,该部分独立地选自由以下基团组成的组:氟、氯、溴、-CF3、-OCF3或-OCH2CF3。在其他优选的实施例中,Ar2是萘基。
本发明还涉及式(I)表示的游离酸或碱的可药用盐,优选为上述优选实施例的可药用盐,以及本文示例的具体化合物的可药用盐。本发明的治疗性组合物和方法可采用式(I)表示的游离酸或碱的可药用盐,优选上述优选实施例的可药用盐,以及本文示例的具体化合物的可药用盐。“可药用盐”旨在表示式(I)表示的化合物的游离酸或碱的盐,其是无毒的、生物学耐受的或在生物学上适用于施用给受试者。一般参见S.M.Berge等人,“Pharmaceutical Salts”,J.Pharm.Sci.,1977,66:1-19,以及Handbook of Pharmaceutical Salts,Properties,Selection,and Use,Stahland Wermuth,Eds.,Wiley-VCH and VHCA,Zurich,2002(《药用盐、性质、选择和用途手册》,Stahl和Wermuth编辑,2002年)。
优选的可药用盐是那些在药理学上有效且适于与患者组织接触而不会有不当毒性、刺激或变态性反应的盐。式(I)化合物可具有足够酸性的基团、足够碱性的基团或这两种类型的官能团,从而与多种无机碱或有机碱,以及无机酸和有机酸反应,形成可药用盐。可药用盐的例子包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、己酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、丁炔-1,4-二酸盐、己炔-1,6-二酸盐、苯甲酸盐、氯代苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、磺酸盐、二甲苯磺酸盐、苯乙酸盐、苯丙酸盐、苯丁酸盐、柠檬酸盐、乳酸盐、γ-羟丁酸盐、乙醇酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐和扁桃酸盐。
如果式(I)化合物含有碱性氮,则理想的可药用盐可以通过本领域可用的任何合适方法制备,例如,用下述酸处理游离碱:无机酸,例如盐酸、氢溴酸、硫酸、氨基磺酸、硝酸、硼酸、磷酸等;或有机酸,例如乙酸、苯乙酸、丙酸、硬脂酸、乳酸、抗坏血酸、马来酸、羟基马来酸、羟基乙磺酸、琥珀酸、戊酸、富马酸、丙二酸、丙酮酸、草酸、乙醇酸、水杨酸、油酸、棕榈酸、月桂酸、吡喃糖苷酸(pyranosidyl acid),例如葡糖醛酸或半乳糖醛酸;α-羟基酸,例如扁桃酸、柠檬酸或酒石酸;氨基酸,例如天冬氨酸或谷氨酸;芳香酸,例如苯甲酸、2-乙酰氧基苯甲酸、萘甲酸或肉桂酸;磺酸,例如月桂基磺酸、对-甲苯璜酸、甲磺酸或乙磺酸,或者酸的任何相容混合物,例如在本文实例中给出的那些。
如果式(I)化合物是酸,例如羧酸或磺酸,则理想的可药用盐可以通过任何合适的方法制备,例如用无机碱或有机碱来处理游离酸,例如胺(伯胺、仲胺或叔胺)、碱金属氢氧化物或碱土金属氢氧化物或碱的任何相容混合物,例如在本文实例中给出的那些。合适的盐的示例性例子包括衍生自下述物质的有机盐:氨基酸如甘氨酸和精氨酸、氨、碳酸盐、碳酸氢盐、伯胺、仲胺、叔胺以及环胺如苄胺、吡咯烷、哌啶、吗啉和哌嗪;以及衍生自下列物质的无机盐:钠、钙、钾、镁、锰、铁、铜、锌、铝和锂。
本发明还涉及式(I)化合物的可药用前药。术语“前药”表示指定化合物的前体,其施用给受试者后,在体内经由诸如溶剂分解或酶裂解之类的化学或生理学过程或在生理学条件下而得到该化合物(例如,前药在生理pH下转化为(I)化合物)。“可药用前药”指这样的前药,其是无毒的、生物学耐受的或在生物学上适用于施用给受试者。用于选择和制备合适的前药衍生物的示例性方法在(例如)“Design of Prodrugs”,H.Bundgaard ed.,Elsevier,1985(《前药的设计》,H.Bundgaard编辑,1985)中有描述。
前药的例子包括具有通过酰胺或酯键共价连接至式(I)化合物的游离氨基、羟基或羧酸基团的氨基酸残基、或者两个或更多个(例如两个、三个或四个)氨基酸残基的多肽链的化合物。氨基酸残基的例子包括通常用三个字母符号标识的二十种天然存在的氨基酸以及4-羟脯氨酸、羟基赖氨酸、锁链素(demosine)、异锁链素(isodemosine)、3-甲基组氨酸、正缬氨酸、β-丙氨酸、γ-氨基丁酸、瓜氨酸高半胱氨酸、高丝氨酸、鸟氨酸和甲硫氨酸砜。
其他类型的前药可以通过(例如)将式(I)结构的游离羧酸衍生为酰胺或烷基酯来制备。酰胺的例子包括衍生自氨、C1-6烷基伯胺和二(C1-6烷基)仲胺的那些。仲胺包括5-元或6-元杂环烷基或杂芳基环部分。酰胺的例子包括衍生自氨、C1-3烷基伯胺和二(C1-2烷基)胺的那些。本发明的酯的例子包括C1-7烷基酯、C5-7环烷基酯、苯酯和(C1-6烷基)苯酯。优选的酯包括甲酯。前药还可以通过下述方式制备:按照在(例如)Fleisher等人,Adv.Drug Delivery Rev.1996,19,115-130中列出的那些方法,使用包括半琥珀酸酯、磷酸酯、二甲基氨基乙酸酯和磷酰氧基甲氧基羰基的基团来衍生游离羟基。羟基和氨基的氨基甲酸衍生物也可以得到前药。羟基的碳酸酯衍生物、磺酸酯和硫酸酯也可以提供前药。羟基的下述衍生物也可以用于得到前药:如(酰氧基)甲基醚和(酰氧基)乙基醚,其中酰基可以是任选被一个或更多个醚、胺或羧酸官能团取代的烷基酯,或者其中酰基是如上所述的氨基酸酯。这种类型的前药可以如Robinson等人,J.Med.Chem.1996,39,10-18中所述制备。游离胺也可以衍生为酰胺、磺酰胺或磷酰胺。所有这些前药部分可以加入包括醚、胺和羧酸官能团的基团。
本发明还涉及式(I)化合物的药学活性代谢物。“药学活性代谢物”指式(I)化合物或其盐的体内代谢的药学活性产物。化合物的前药和活性代谢物可以使用本领域已知或可用的常规技术确定。参见,例如,Bertolini等人,J.Med.Chem.1997,40,2011-2016;Shan等人,J.Pharm.Sci.1997,86(7),765-767;Bagshawe,Drug Dev.Res.1995,34,220-230;Bodor,Adv.Drug Res.1984,13,255-331;Bundgaard,Design of Prodrugs(Elsevier Press,1985);以及Larsen,Design and Application of Prodrugs,Drug Design and Development(Krogsgaard-Larsen等人编辑,HarwoodAcademic Publishers,1991)。
本发明的式(I)化合物及其可药用盐、可药用前药和药学活性代谢物(统称为“活性剂”)在本发明方法中可用作FAAH抑制剂。活性剂可以在本发明方法中使用,用于治疗通过抑制或调节FAAH而介导的医学病症、疾病或障碍,例如本文所描述的那些。因此,根据本发明的活性剂可以用作止痛药、抗抑郁药、认知增强药、神经保护药、镇静药、食欲刺激剂或避孕药。
示例性的由FAAH活性介导的医学病症、疾病和障碍包括:焦虑、抑郁、疼痛、睡眠障碍、进食障碍、炎症、多发性硬化症和其他移动障碍、HIV衰竭综合征、封闭型颅脑损伤、中风、学习记忆障碍、阿尔茨海默病、癫痫、图雷特综合征、癫痫、尼曼-匹克病、帕金森病、亨廷顿舞蹈病、视神经炎、自身免疫性葡萄膜炎、药物戒断的症状、恶心、呕吐、性功能障碍、创伤后应激障碍、脑血管痉挛、糖尿病、代谢综合征和骨质疏松。
因此,活性剂可用于治疗被诊断有或患有这类疾病、障碍或病症的受试者。如本文所用,术语“处理”或“治疗”意指为了通过调节FAAH活性而得到治疗益处的目的而施用给受试者本发明的药剂或组合物。治疗包括恢复、改善、减轻、抑制进展、降低严重程度、减少发病率或预防通过调节FAAH活性而介导的疾病、障碍或病症或者这些疾病、障碍或病症的一种或多种症状。术语“受试者”指需要这种治疗的哺乳动物患者,例如人。“调节剂”包括抑制剂和活化剂,其中“抑制剂”指降低、阻止、灭活、减敏或下调FAAH表达或活性的化合物,而“活化剂”是提高、激活、促进、敏化或上调FAAH表达或活性的化合物。
因此,本发明涉及使用本文所述活性剂来治疗被诊断有或患有通过FAAH活性介导的疾病、障碍或病症的受试者的方法,这些疾病、障碍或病症例如为:焦虑、疼痛、睡眠障碍、进食障碍、炎症、移动障碍(例如,多发性硬化)、能量代谢疾病(如胰岛素耐受、糖尿病、血脂障碍、肝脂肪变性、脂肪性肝炎、肥胖症和代谢综合征)和骨内环境稳定(如骨质疏松)。
症状或疾病状态旨在包含于“医学病症、障碍或疾病”的范围内。例如,疼痛可能与多种疾病、障碍或病症有关,并且可能包括多种病因。可用根据本发明的FAAH调节剂(在本文的一个实例中为FAAH抑制剂)治疗的示例性疼痛类型包括癌痛、手术后疼痛、胃肠道疼痛、脊髓损伤痛、内脏痛觉过敏、丘脑性疼痛、头痛(包括应激性头痛和偏头痛)、腰背痛、颈痛、肌肉骨骼痛、周围神经痛、中枢神经痛、神经发生障碍相关的疼痛、以及痛经。HIV衰竭综合征包括诸如食欲丧失和恶心之类的相关症状。帕金森病包括(例如)左旋多巴诱导的运动障碍。多发性硬化症的治疗可以包括对下述症状的治疗:例如痉挛、神经性疼痛、中枢性疼痛或膀胱功能障碍。药物戒断的症状可以由(例如)鸦片或尼古丁成瘾导致。恶心或呕吐可归因于化学疗法、术后或与阿片相关的诱因。性功能障碍的治疗可以包括改善性欲或延迟射精。癌症的治疗可以包括治疗神经胶质瘤。睡眠障碍包括(例如)睡眠呼吸暂停、失眠和因使用具有镇静或麻醉型作用的药剂进行治疗而导致的障碍。进食障碍包括(例如)厌食症或与诸如癌症或HIV感染/AIDS之类的疾病相关的食欲丧失。
在根据本发明的治疗方法中,对患有或被诊断患有这样的疾病、障碍或病症的受试者施用有效量的至少一种根据本发明的活性剂。“治疗有效量”或“有效量”指足以为需要治疗由FAAH活性介导的疾病、障碍或病症的患者大致带来治疗益处的FAAH-调节剂的量或剂量。本发明活性剂的有效量或剂量可以通过常规方法(例如建模、剂量升级研究或临床实验)并考虑常规因素(例如,施用或药物递送的模式或途径、药剂的药代动力学、疾病、障碍或病症的严重程度和进程、受试者先前或正在进行的治疗、受试者的健康状况和对药物的响应,以及治疗医生的判断)来确定。示例性的剂量范围是每天每千克受试者体重为约0.0001至约200mg活性剂,优选约0.001至100mg/kg/天,或者约0.01至35mg/kg/天,或者约0.1至10mg/kg/天,为单次剂量单位或分份剂量单位(例如BID、TID、QID)。对于70kg的人,合适剂量的示例性范围是约0.05至约7g/天,或者约0.2至约5g/天。一旦患者的疾病、障碍或病症有所改善,可以将剂量调整为维持治疗性的。例如,施用的剂量或频率或者这两者都可以随症状的变化减小至维持所需治疗效果的水平。当然,如果症状已经减轻到合适水平,可以停止治疗。然而,患者可能因病征的任何复发而需要长期的间歇性治疗。
另外,在上述病症的治疗中,本发明的活性剂可以与另外的活性成分联合使用。另外的活性成分可以与式(I)活性剂一起独立地同时施用,或者与这类药剂一起包含在根据本发明的药物组合物中。在一个示例性的实施例中,另外的活性成分是已知或发现在由FAAH活性介导的病症、障碍或疾病的治疗中有效的那些,例如另一种FAAH调节剂或积极对抗与特定病症、障碍或疾病有关的另一靶标的化合物。组合给药可用于提高效力(例如,通过在组合中包括强化根据本发明的活性剂的效能或有效性的化合物来实现)、减小一种或多种副作用、或者减少根据本发明的活性剂的所需剂量。在一个示例性实施例中,根据本发明的组合物可以含有一种或多种选自阿片、NSAID(例如,布洛芬、环氧合酶-2(COx-2)抑制剂和萘普生)、加巴喷丁、普瑞巴林、曲马多、对乙酰氨基酚和阿司匹林的其它活性成分。
本发明的活性剂可以单独使用或者与一种或多种其它活性成分联合使用,以配制本发明的药物组合物。本发明的药物组合物包含:(a)有效量的至少一种根据本发明的活性剂;以及(b)可药用赋形剂。
“可药用赋形剂”指这样的物质:其是无毒的、生物学耐受的,或者在生物学上适用于施用给受试者,例如被加入药物组合物中或以其它方式用作媒介物、载体或稀释剂以促进药剂的施用并与药剂相容的惰性物质。赋形剂的例子包括碳酸钙、磷酸钙、多种糖和多类淀粉、纤维素衍生物、明胶、植物油和聚乙二醇。
含有一个或多个剂量单位活性剂的药物组合物的递送形式可以使用本领域技术人员已知或会变得可用的合适药物赋形剂和配合技术来制备。在本发明方法中组合物可以通过诸如口部、肠胃外、直肠、局部或眼部途径之类的合适递送途经施用,或者通过吸入施用。
制剂可以是片剂、胶囊、小药囊、糖衣丸、粉剂、颗粒剂、锭剂、用于重构的粉剂、液体制剂或栓剂的形式。优选将该组合物配制成用于静脉输注、局部施用或口服施用。
对于口服施用,本发明的活性剂可以以片剂或胶囊的形式提供,或者作为溶液剂、乳剂或混悬剂提供。为制备口服组合物,活性剂可以配制成(例如)每天约5mg至5g的剂量,或者每天约50mg至5g的剂量,为单次剂量或分份剂量。例如,每天约5mg至5g的总日剂量可以通过每天定量给药一次、两次、三次或四次来完成。
口服片剂可以包含与相容的可药用赋形剂混合的活性成分,该赋形剂例如为稀释剂、崩解剂、粘合剂、润滑剂、甜味剂、调味剂、着色剂和防腐剂。合适的惰性填料包括碳酸钠和碳酸钙、磷酸钠和磷酸钙、乳糖、淀粉、糖、葡萄糖、甲基纤维素、硬脂酸镁、甘露醇、山梨醇等。示例性的液体口服赋形剂包括乙醇、甘油、水等。淀粉、聚乙烯吡咯烷酮(PVP)、羟乙酸淀粉钠、微晶纤维素和藻酸是示例性的崩解剂。粘合剂可以包括淀粉和明胶。润滑剂(如果存在)可以是硬脂酸镁、硬脂酸或滑石。如果需要,片剂可以用(例如)甘油单硬脂酸酯或甘油二硬脂酸酯包被,以延迟在胃肠道中的吸收,或者可以用肠溶衣包被。
用于口服施用的胶囊包括硬明胶胶囊和软明胶胶囊。为制备硬明胶胶囊,可以将活性成分与固体、半固体或液体稀释剂混合。软明胶胶囊可以通过将活性成分与下述物质混合而制备:水、油例如花生油或橄榄油、液体石蜡、短链脂肪酸的单甘油酯和二甘油酯的混合物、聚乙二醇400或丙二醇。
用于口服施用的液体剂可以是混悬剂、溶液剂、乳剂或糖浆的形式,或者可以被冻干或作为可在使用前用水或其它合适媒介物重构的干的产品存在。这种液体组合物可以任选含有:可药用赋形剂如助悬剂(例如,山梨醇、甲基纤维素、藻酸钠、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶等);非水媒介物,例如,油(例如,杏仁油或分级椰子油)、丙二醇、乙醇或水;防腐剂(例如,对羟基苯甲酸甲酯或对羟基苯甲酸丙酯或山梨酸);湿润剂,例如卵磷脂;以及,如果需要,调味剂或着色剂。
本发明的活性剂还可以通过非口服途径施用。例如,组合物可以配制成栓剂用于直肠施用。对于肠胃外使用(包括静脉、肌内、腹膜内或皮下途径)来说,本发明的药剂可以以被缓冲至合适pH和等渗性的无菌水溶液或混悬剂提供,或者以肠胃外可接受的油提供。合适的水性媒介物包括林格溶液和等渗氯化钠。这种形式将以单剂量形式如安瓿或一次性注射装置存在,或者以多剂量形式如可以从其中抽出合适剂量的小瓶存在,或者以可用于制备注射制剂的固体形式或预浓缩液存在。示例性的输注剂量范围是约1至1000μg/kg/分钟的药剂,该药剂与药物载体在几分钟至几天的时间范围内混合。
对于局部施用,可以将药剂与药物载体混合,浓度为约0.1%至约10%的药物/媒介物。本发明的药剂的另一种施用模式可以利用贴剂来进行透皮递送。
或者,在本发明的方法中活性剂可以(例如)以还含有合适载体的喷雾剂经由鼻或口腔途径通过吸入施用。
现在将参考下面的有关它们的一般制备的示例性合成方案以及随后的具体实例来描述可用于本发明方法的示例性活性剂。技术人员将认识到,为获得本文中的各种化合物,可以适当地选择起始物质,从而通过反应方案(视情况而定,采用或不采用保护)可携带最终所需的取代基来得到所需产物。或者,可能需要或希望采用合适的基团来代替最终所需的取代基,这种合适的基团可以通过反应方案获得并且可合适地用所需取代基取代。除非另外指明,否则变量如上述对式(I)的定义。
方案A:
参考方案A,式(IV)的氨基甲酸酯化合物可以通过使式(II)化合物与式(III)化合物在氯甲酸酯缩合条件下反应而获得,其中Q1表示芳基。优选Q1为取代或未取代的苯基,并且该反应在约0℃至约80℃的温度、有碱或无碱的情况下在溶剂如乙腈中进行。更优选地,Q1是苯基,并且该反应在约70℃下在乙腈中进行,或者在存在诸如吡啶、三乙胺或二异丙基乙胺之类的碱的情况下在二氯甲烷中于0℃然后升温至室温的温度下进行。
方案B:
参见方案B,式(VII)化合物由式(V)化合物制备。基团Q2是CH2Ar2或者当Z是N时,Q2也可以是合适的氮保护基团Q3。式(VII)化合物可通过使式(V)化合物与式(VI)化合物在异氰酸酯加成条件下反应而获得。在一个优选的实施例中,反应在0℃至100℃的温度下在溶剂中进行。优选的条件采用室温下的二氯甲烷(DCM)。或者,式(VII)化合物通过使式(V)化合物与式(IV)化合物在氨基甲酸芳基酯缩合条件下反应而获得。该反应优选在约室温至约120℃的温度下在溶剂中发生。优选Q1为苯基,并且该反应在约100℃下在微波反应器中的二甲基亚砜(DMSO)中进行或者通过从约室温常规加热至约50℃来进行。其中Q2是CH2Ar2,式(VII)化合物是属于式(I)的范围内。
方案C:
参见方案C,式(I)化合物是由式(XI)化合物制备。在方案C中选择与转化相容的合适保护基团Q3。优选Q3为叔丁基-氨基甲酰基(Boc)。式(X)化合物可通过使式(XI)化合物在存在二-(N-琥珀酰亚胺基)碳酸酯的情况下与以下化合物反应获得:(a)式(VI)化合物;(b)式(IV)化合物;或(c)化合物Ar1NH2。式(XIV)的胺可通过在合适的Q3去保护条件下用试剂对式(x)化合物进行去保护而获得。优选用诸如二乙醚(Et2O)、DCM或1,4-二噁烷之类的溶剂中的HCl或三氟乙酸(TFA)来实现Boc去保护。式(I)化合物可通过使式(XIV)化合物与醛(XII)在存在还原剂的还原性胺化条件下、在溶剂中于约0℃至80℃的温度下反应而获得,该还原剂例如为三乙酰氧基硼氢化钠、树脂负载的三乙酰氧基硼氢化物(如MP-B(OAc)3H)、氰基硼氢化钠或苯基硅烷,该溶剂例如为四氢呋喃(THF)、1,2-二氯乙烷(DCE)、DCM、甲醇(MeOH)、乙醇(EtOH)或Et2O。使用具有酸性特性的促进剂或催化剂如有机金属络合物或羧酸可以提高反应速度和/或减少副产品的形成。优选地,在室温下采用DCE中的三乙酰氧基硼氢化钠。还原胺化也可以在存在四氢呋喃(THF)中的Et3N的情况下使用固体负载的三乙酰氧基硼氢化物来进行。
或者,式(XIII)化合物可通过使醛(XI)与受保护的哌嗪(XII)在上述还原胺化条件下反应而获得。在一般的去保护条件下使式(XIII)化合物的Q3去保护得到哌嗪(XVI)。式(I)化合物可如前面的方案中所述通过使式(XVI)化合物与式(IV)化合物或者与式(VI)化合物反应而获得。
方案D:
参见方案D,如前面的方案中所述制备式(XVII)化合物,其中Q4是-CONR1Ar1或氮保护基团Q3。将式(XVII)化合物通过在存在诸如粉末状分子筛之类的干燥剂、诸如乙酸铜(II)之类的促进剂的情况下,可任选地在存在空气气氛或纯氧气氛的情况下,可任选地在存在诸如吡啶或三乙胺之类的碱的情况下,在诸如DCM或DCE之类的溶剂中与合适的硼酸(XVIIIa)反应而转化成式(XIX)化合物。其中Q4是-CONR1Ar1,式(XIX)化合物属于式(I)的范围内。或者,式(XIX)化合物(其中Q4是氮保护基团Q3)是通过在约室温至约120℃范围内的温度下,在诸如DMSO之类的溶剂中用合适的芳基卤(XVIIIb,其中HAL是氯、溴或碘)和碱如Cs2CO3进行处理而从式(XVII)制备。
方案E:
也可以根据方案E制备式(I)化合物。将Wittig试剂(XXI;可购自商业来源或由合适的溴、醇、醛或其他前体按照本领域已知的一般技术制备)在溶剂如DMSO中用碱如NaH去保护,随后用哌啶酮(XX)处理而产生式(XXII)化合物,其中Q3是氮保护基团(例如Boc或苄基)。在存在诸如钯碳或氧化铂(II)之类的催化剂的情况下,在诸如MeOH或EtOH之类的溶剂中用氢(约10至100psi)还原双键而产生式(XXIII)化合物。Q3的去保护可利用常规条件来完成以产生哌啶(XXIV)。式(I)化合物可如前面方案中所述通过将式(XXIV)化合物与式(IV)化合物或式(VI)化合物反应而制备。
方案F:
也可根据方案F制备式(XXIII)中间化合物。链烯基化合物(XXV)的氢金属化产生了活化物质,该活化物质随后与合适试剂Ar2-HAL(其中HAL是氯化物、溴化物或碘化物)反应而产生化合物(XXIII)。优选地,氢金属化可使用合适的二烷基硼烷制剂如9-硼双环[3.3.1]壬烷(9-BBN)或二异松蒎基硼烷在诸如THF之类的溶剂中进行硼氢化反应来完成。所得硼加成物优选在存在合适的钯(II)催化剂、诸如K2CO3或Cs2CO3之类的碱的情况下,在诸如N,N-二甲基甲酰胺(DMF)或其水性混合物之类的溶剂中与Ar2-HAL反应。用前面方案中所述方法将式(XXIII)化合物转化成式(I)化合物。
方案G:
如方案G所述制备式(I)化合物的其他实施例,例如化合物(XXIX)或(XXXI)。钯-催化的化合物(XXVII,如前面方案中所述制备)与炔烃(XXVIIIa/b)的偶联提供了化合物(XXIX)。优选地,该反应在存在钯(II)催化剂如Pd(PPh3)2Cl2、铜(I)催化剂如CuI、碱如三乙胺的情况下,在有或无另外的膦配体如三苯膦的情况下,在溶剂如THF中于约室温至约50℃的温度下进行。或者,使碘化物(XXVII)与受保护的炔烃试剂偶联,其中PG是合适的保护基团例如三甲基甲硅烷基,以产生化合物(XXX)。移除保护基团得到化合物(XXXI)。另外的与合适的卤化物Ar2-HAL或Rd-HAL(其中HAL是氯化物、溴化物或碘化物)进行的钯-催化偶联反应得到化合物(XXIX)。
方案H:
可任选用标准的氢化方法将炔烃(XXIX)还原成化合物(XXXII)。优选的是,用氢气和诸如钯碳之类的催化剂在诸如EtOH之类的溶剂中完成该反应。
方案I:
如方案I中所示制备式(I)的其他实施例。在约室温至约50℃的温度下,酚(XVII)与合适的苄基卤(XXXIII)和碱如K2CO3在溶剂如乙腈中的烷化反应产生了化合物(XXXIV)。
式(I)化合物可以通过应用本领域描述的一般技术来转化成它们相应的盐。例如,式(I)化合物可以用诸如Et2O、1,4-二噁烷、DCM、THF或MeOH之类的溶剂中的三氟乙酸、HCl或柠檬酸处理而产生相应的盐形式。
根据上述方案制备的化合物可以通过对映特异性合成、非对映特异性合成或区位特异性合成或者通过分解来作为单一对映体、非对映体或区域异构体获得。或者,根据上面方案制备的化合物可以作为外消旋混合物(1∶1)或非外消旋混合物(非1∶1)或者作为非对映体或区域异构体的混合物获得。如果获得对映体的外消旋混合物和非外消旋混合物,可以使用常规分离方法例如手性色谱、重结晶、非对映体盐形成法、衍生成非对映体加成物、生物转化或酶促转化来分离单一对映体。如果获得区域异构体混合物或非对映体混合物,可以使用常规方法例如色谱法或结晶来分离单一异构体。
提供如下具体实例来进一步说明本发明和各种优选实施例。
实例
化学:
在制备下面列出的实例中,使用了如下一般实验方法和分析方法。
除非另外说指明,否则将反应混合物在室温(rt)下于氮气氛中搅拌。如果溶液或混合物是浓缩过的,则它们通常是用旋转蒸发仪在减压下进行浓缩。如果溶液是干燥的,则它们通常是在诸如MgSO4或Na2SO4之类的干燥剂上进行干燥。
除非另外指明,否则在硅胶柱上进行正相快速柱色谱(FCC),将乙酸乙酯(EtOAc)/己烷用作洗脱液。
使用如下仪器进行反相高效液相色谱(HPLC):1)具有YMC-PackODS-A柱(5μm,75×30mm)的仪器,流速为25mL/分钟,在220nm和254nm处检测,采用15%至99%的乙腈/水/0.05%TFA梯度;或2)装配有Phenomenex Gemini柱(5μm C18(150×21.2mm))的Shimadzu仪器,或装配有Waters Xterra RP18 OBD柱(5μm,100×30mm)的Shimadzu仪器,采用95∶5至0∶100的水(0.05%TFA)/CH3CN(0.05%TFA)梯度,流速为30mL/分钟,在254nm处检测。
除非另外指明,否则质谱在Agilent系列1100MSD上使用电喷射离子化(ESI)在正模式中获得。
NMR谱在Bruker DPX400(400MHz)型、DPX500(500MHz)型、DRX600(600MHz)型光谱仪上获得。以下1H NMR数据的格式是:以四甲基硅烷为参照的低场化学位移(单位为ppm)(多重度,耦合常数J(单位为Hz),积分)。
用ChemDraw Ultra 6.0.2(CambridgeSoft Corp.,Cambridge,MA)或ACD/Name第9版(Advanced Chemistry Development,Toronto,Ontario,Canada)产生化学名。
实例1:4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸 苯并[d]异噁唑-3-基酰胺三氟乙酸盐
步骤A:苯并[d]异噁唑-3-基-氨基甲酸苯酯将苯并[d]异噁唑-3-基酰胺(3.0g)和ClCO2Ph(0.94mL)在干CH3CN(30mL)中的混合物在70℃下搅拌23小时。将反应混合物倾注至去离子水中,搅拌30分钟并过滤。将分离出的固体用水冲洗彻底,然后在高度真空下干燥获得1.90g(100%)标题化合物。MS:255.1.
步骤B:1-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪将哌嗪-1-羧酸叔丁酯(20.0g)和2,2-二氟-苯并[1,3]二氧杂环戊烯-5-甲醛(14.8mL)在DCE(208mL)中的0℃溶液用NaB(OAc)3H(31.8g)处理。使该混合物升温至室温并搅拌16小时。将所得混合物在冰浴中冷却并用10%的含水KOH(200mL)进行处理。1小时后,将所得混合物用DCM(3×200mL)萃取。将合并的有机萃取物干燥并浓缩,得到白色固体物质(37.6g)。将该固体物质溶解于MeOH(850mL)中并用HCl(在Et2O中为2M;159mL)处理。16小时后,将所得混合物用Et2O(850mL)处理。过滤出白色沉淀物并用Et2O(2×140mL)洗涤,得到白色固体物质(27.6g)。将该固体物质(27.5g)悬浮于DCM(200mL)中并用10%的含水KOH(200mL)处理。用DCM(2×150mL)萃取有机相。将合并的有机萃取物干燥并浓缩,得到白色固体状的标题化合物(20.8g)。MS:257.1.
步骤C:4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸 苯并[d]异噁唑-3-基酰胺三氟乙酸盐向史密斯反应瓶(Smith Process vial)中装入旋转叶片,加入苯并[d]异噁唑-3-基-氨基甲酸苯酯(51.2mg)、1-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪(76.5mg)和DMSO(0.5mL)。将瓶用N2吹扫、封盖并通过微波辐射在100℃下加热15分钟。然后将反应混合物通过反相HPLC直接纯化得到62.4mg(58%)作为TFA盐的所需产物。MS:417.2.1H NMR(d4-MeOH):7.88(d,J=7.8,1H),7.60-7.57(m,1H),7.52(d,J=8.4,1H),7.43(d,J=1.8,1H),7.35-7.34(dd,J=1.5,8.1,1H),7.32-7.30(m,2H),4.53-3.54(br hump,4H),4.43(s,2H),3.40(br s,4H)。
使用与实例1中所述的那些类似的方法制备实例2-8中的化合物。
实例2:4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸
(3-苯基-[1,2,4]噻二唑-5-基)-酰胺三氟乙酸盐
MS:460.5.1H NMR(CDCl3):10.66(br s,1H),8.10-8.08(m,2H),7.46-7.43(m,3H),7.00(s,1H),6.96(d,J=8.4,1H),6.91-6.89(dd,J=1.2,7.8,1H),3.33(br s,6H),2.15(br s,4H)。
实例3:4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸
(1H-四唑-5-基)-酰胺三氟乙酸盐
MS:368.5.1H NMR(d6-DMSO):15.51(s,1H),10.98(s,1H),7.54(s,2H),7.33-7.32(m,1H),4.29(br s,4H),3.58-2.86(m,6H)。
实例4:4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸
苯并[1,2,5]噻二唑-4-基酰胺三氟乙酸盐
MS:434.5.1H NMR(d4-MeOH):7.94-7.93(dd,J=1.2,7.2,1H),7.63-7.57(m,2H),7.26(s,1H),7.14(d,J=0.6,2H),3.64(t,J=4.8,4H),2.54(t,J=4.8,4H)。
实例5:4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸 苯并[1,2,5]噁二唑-4-基酰胺三氟乙酸盐
MS:418.2.1H NMR(d4-MeOH):7.62(d,J=7.2,1H),7.57(d,J=9.0,1H),7.48-7.45(m,2H),7.38-7.34(m,2H),4.44(s,2H),4.28-3.63(br hump,4H),3.39(br s,4H)。
实例6:4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸
(3H-苯并三唑-5-基)-酰胺三氟乙酸盐
MS:417.2.1H NMR(d4-MeOH):8.00(s,1H),7.79(d,J=9.0,1H),7.44(s,1H),7.42-7.40(dd,J=1.8,9.0,1H),7.37-7.33(m,2H),4.44(s,2H),4.50-3.20(br hump,4H),3.37(br s,4H)。
实例7:4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸
噻吩-2-基酰胺
MS:382.1.1H NMR(CDCl3):7.11(s,1H),7.05(s,1H),7.02-6.97(m,2H),6.83-6.77(m,2H),6.54-6.51(m,1H),3.52-3.48(m,6H),2.49-2.43(m,4H)。
实例8:4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸
噻吩-3-基酰胺
MS:382.1.1H NMR(CDCl3):7.27-7.25(m,1H),7.21-7.17(m,1H),7.11(s,1H),7.01-6.94(m,3H),6.69(s,1H),3.51-3.45(m,6H),2.48-2.42(m,4H)。
实例9:4-萘-2-基甲基-哌啶-1-羧酸(6-氯-哒嗪-3-基)-酰胺
步骤A:萘-2-基甲基-三苯基-溴化磷将装有二甲苯(230mL)中的2-溴甲基-萘(25.0g)和三苯膦(31.3g)的混合物的烧瓶配备回流冷凝器,用N2吹扫并加热至135℃24小时。通过过滤分离所得白色固体物质,将其用甲苯洗涤并在高度真空下干燥。
步骤B:4-萘-2-基亚甲基-哌啶-1-羧酸叔丁酯将干DMSO(300mL)中的NaH(95%,3.30g)的0℃混悬液搅拌10分钟,然后通过插管用热的DMSO(100mL)中的萘-2-基甲基-三苯基-溴化磷(52.4g)溶液处理20分钟(需要加热该DMSO溶液来溶解磷鎓盐)。让所得鲜红色混合物在0℃下搅拌10分钟,然后通过插管在20分钟内加入DMSO(100mL)中的N-Boc-哌啶酮(26.3g)溶液。在0℃下搅拌1小时,在室温下搅拌3小时并在50℃下搅拌18小时后,将该混合物用1-L水稀释并用Et2O(500mL×4)萃取。将有机萃取物用水(×2)洗涤、干燥并浓缩得到黄色异质混合物。将该粗物质悬浮于热己烷(700mL)中并通过过滤移除固体物质。浓缩滤液得到油状残余物,该油状残余物通过FCC纯化得到28.1g(80%)无色油状标题化合物。
步骤C:4-萘-2-基甲基-哌啶-1-羧酸叔丁酯将装有EtOH(350mL)中的4-萘-2-基亚甲基-哌啶-1-羧酸叔丁酯(22.7g)和10%Pd/C(6.3g)的混悬液的烧瓶抽真空,然后配备H2球。18小时后,抽空烧瓶中的H2并替换为N2。使反应混合物滤过硅藻土两次,然后滤过Zapcap。将滤液浓缩得到21.9g(96%)淡黄色油状标题化合物。MS:348.5(M+Na)+.
步骤D:4-萘-2-基甲基-哌啶将4-萘-2-基甲基-哌啶-1-羧酸叔丁酯(21.4g)和TFA(75mL)的混合物在室温下搅拌18小时。将该混合物浓缩、用DCM稀释并用1N NaOH洗涤。将有机层干燥并浓缩得到14.8g(100%)淡黄色油状标题化合物,该标题化合物在静置时会结晶。MS:226.2.
步骤E:4-萘-2-基甲基-哌啶-1-羧酸(6-氯-哒嗪-3-基)-酰胺使用与实例1中步骤C所述的那些类似的方法制备该标题化合物。MS:481.5.1HNMR(CDCl3):8.46(br s,1H),8.31(br s,1H),7.81(d,J=7.5,1H),7.78(d,J=8.5,2H),7.58(s,1H),7.48-7.39(m,3H),7.30-7.28(dd,J=1.5,8.5,1H),4.17(d,J=13.5,2H),2.87(t,J=12.5,2H),2.73(d,J=7.0,2H),1.94-1.83(m,1H),1.76(d,J=13,2H),1.36-1.25(m,2H)。
使用与实例9中所述的那些类似的方法制备实例10-27中的化合物。
实例10:4-萘-2-基甲基-哌啶-1-羧酸吡嗪-2-基酰胺三氟乙酸盐
MS:347.5.1H NMR(CDCl3):9.42(d,J=1.5,1H),8.27(d,J=2.5,1H),8.15-8.14(dd,J=1.5,2.5,1H),7.84-7.79(m,3H),7.60(s,1H),7.48-7.43(m,2H),7.32-7.30(m,1H),4.13(d,J=13,2H),2.94-2.88(dt,J=3.0,12.5,2H),2.76(d,J=7.5,2H),1.92-1.87(m,1H),1.81(d,J=13.0,2H),1.39-1.30(m,2H)。
实例11:4-萘-2-基甲基-哌啶-1-羧酸异噁唑-3-基酰胺
MS:336.5.1H NMR(d6-acetone):8.71(s,1H),8.16(s,1H),7.81(d,J=8.4,1H),7.78(d,J=8.4,2H),7.58(s,1H),7.48-7.42(m,2H),7.30-7.28(dd,J=1.8,9,1H),7.00(s,1H),4.17(d,J=13.2,2H),2.86(t,J=12.6,2H),2.72(d,J=7.2,2H),1.90-1.83(m,1H),1.75(d,J=12.6,2H),1.33-1.25(m,2H)。
实例12:4-萘-2-基甲基-哌啶-1-羧酸(3-苯基-[1,2,4]噻二唑-5-基)-酰
胺
MS:429.5.1H NMR(CDCl3):8.13-8.12(m,2H),7.82(d,J=7.8,1H),7.79(d,J=8.4,2H),7.56(s,1H),7.50-7.43(m,5H),7.28-7.26(m,1H),4.16(br s,1H),2.86(t,J=12.6,2H),2.70(d,J=7.2,2H),1.90-1.83(m,1H),1.76(d,J=13.2,2H),1.28-1.21(m,2H)。
实例13:4-萘-2-基甲基-哌啶-1-羧酸(1H-四唑-5-基)-酰胺
MS:337.5.1H NMR(d6-DMSO):15.36(s,1H),10.67(s,1H),7.88-7.84(m,3H),7.68(s,1H),7.50-7.44(m,2H),7.38-7.37(dd,J=1.8,8.4,1H),4.15(d,J=13.2,2H),2.83-2.79(m,2H),2.70(d,J=7.2,2H),1.91-1.85(m,1H),1.64-1.61(m,2H),1.20-1.13(m,3H)。
实例14:4-萘-2-基甲基-哌啶-1-羧酸(2H-吡唑-3-基)-酰胺
MS:335.5.1H NMR(CDCl3):7.79(d,J=7.8,1H),7.76(d,J=7.8,2H),7.63(br s,1H),7.56(s,1H),7.46-7.40(m,2H),7.37(s,1H),7.28-7.26(m,1H),6.37(br s 1H),4.05(d,J=12.6,2H),2.78-2.74(m,2H),2.68(d,J=7.2,2H),1.83-1.77(m,1H),1.68(d,J=12.6,2H),1.29-1.21(m,2H)。
实例15:4-萘-2-基甲基-哌啶-1-羧酸苯并[1,2,5]噁二唑-4-基酰胺
MS:387.3.1H NMR(CDCl3):7.97-7.96(m,1H),7.82(d,J=15.6,1H),7.80-7.81(m,2H),7.60(s,1H),7.49-7.43(m,2H),7.40-7.39(m,2H),7.36(s,1H),7.30(d,J=8.4,1H),4.13(d,J=13.2,2H),2.98-2.94(m,2H),2.76(d,J=7.2,2H),1.96-1.88(m,1H),1.85-1.82(m,2H),1.40-1.33(m,2H)。
实例16:4-萘-2-基甲基-哌啶-1-羧酸(1H-苯并三唑-5-基)-酰胺
MS:386.3.1H NMR(CDCl3):8.19(br s,1H),7.80-7.76(m,3H),7.64(br s,1H),7.56(s,1H),7.46-7.40(m,2H),7.36(br s,1H),6.91(br s,1H),4.14(d,J=11.4,2H),2.91-2.87(m,2H),2.69(d,J=6.6,2H),1.90(br s,1H),1.77(d,J=12.6,2H),1.34-1.28(m,2H)。
实例17:4-萘-2-基甲基-哌啶-1-羧酸[1,5]萘啶-2-基酰胺三氟乙酸盐
MS:397.3.1H NMR(CDCl3):9.00(d,J=3.6,1H),8.65(d,J=9.6,1H),8.49(d,J=9.6,1H),8.41(d,J=8.4,1H),7.82-7.78(m,4H),7.59(s,1H),7.48-7.42(m,2H),7.31-7.29(dd,J=1.2,8.4,1H),4.32-4.30(m,2H),2.96(br s,2H),2.76(d,J=7.2,2H),1.96-1.88(m,1H),1.84(d,J=13.2,2H),1.41-1.34(m,2H)。
实例18:4-萘-2-基甲基-哌啶-1-羧酸喹啉-2-基酰胺三氟乙酸盐
MS:396.3.1H NMR(d6-acetone):8.72(d,J=9.6,1H),8.23(d,J=9.0,1H),8.12-8.09(m,2H),7.99-7.96(m,1H),7.87-7.83(m,3H),7.73-7.70(m,2H),7.49-7.43(m,2H),7.41-7.40(dd,J=1.2,8.4,1H),4.35(d,J=13.8,2H),2.99(br s,2H),2.78(d,J=7.2,2H),2.09-1.98(m,1H),1.80-1.77(m,2H),1.41-1.34(m,2H)。
实例19:4-萘-2-基甲基-哌啶-1-羧酸苯并噻唑-6-基酰胺
MS:402.2.1H NMR(CDCl3):9.01(s,1H),8.31(s,1H),8.03(d,J=8.4,1H),7.83-7.78(m,3H),7.59(s,1H),7.49-7.43(m,2H),7.30(d,J=8.4,1H),7.25-7.23(m,1H),6.70(s,1H),4.08(d,J=13.8,2H),2.91-2.86(m,2H),2.75(d,J=7.2,2H),1.93-1.85(m,1H),1.78(d,J=12.6,2H),1.37-1.30(m,2H)。
实例20:4-萘-2-基甲基-哌啶-1-羧酸喹啉-5-基酰胺三氟乙酸盐
MS:396.3.1H NMR(CDCl3):8.72(d,J=7.8,2H),7.95(s,1H),7.85-7.80(m,4H),7.66-7.62(m,3H),7.52-7.44(m,3H),7.32(d,J=8.4,1H),4.24(d,J=13.8,2H),2.93(t,J=12.6,2H),2.78(d,J=6.6,2H),1.96-1.87(m,1H),1.82(d,J=12.6,2H),1.41-1.34(m,2H)。
实例21:4-萘-2-基甲基-哌啶-1-羧酸苯并[d]异噁唑-3-基酰胺
MS:386.3.1H NMR(CDCl3/d4-Me0H mix):7.84(d,J=7.8,1H),7.79-7.75(m,3H),7.58(s,1H),7.52-7.49(m,1H),7.44-7.38(m,3H),7.31-7.29(dd,J=1.5,15.9,1H),7.24(br t,J=7.5,1H),4.18(d,J=13.2,2H),2.91-2.87(m,2H),2.73(d,J=7.2,2H),1.95-1.85(m,1H),1.75(d,J=12.6,2H),1.36-1.29(m,2H)。
实例22:4-(4-氟-苄基)-哌啶-1-羧酸苯并[d]异噁唑-3-基酰胺
MS:354.2.1H NMR(CDCl3):8.79(s,1H),8.06(d,J=8.5,1H),7.54-7.51(m,1H),7.43-7.42(m,1H),7.29-7.26(m,1H),7.11-7.08(m,2H),7.00-6.96(m,2H),4.27(d,J=13.0,2H),2.93(t,J=12.0,2H),2.55(d,J=7.0,2H),1.74(d,J=9.5,3H),1.33-1.24(m,2H)。
实例23:4-(4-氟-苄基)-哌啶-1-羧酸(6-氯-哒嗪-3-基)-酰胺
MS:349.2.1H NMR(CDCl3):8.45(s,1H),8.29(d,J=9.5,1H),7.42(d,J=9.5,1H),7.11-7.08(m,2H),6.99-6.96(m,2H),4.18(d,J=13.5,2H),2.90-2.89(m,2H),2.55(d,J=6.5,2H),1.77-1.71(m,3H),1.29-1.21(m,2H)。
实例24:4-(4-氟-苄基)-哌啶-1-羧酸异噁唑-3-基酰胺
MS:304.2.1H NMR(CDCl3):9.04(s,1H),8.17(d,J=1.5,1H),7.10-7.08(m,2H),7.01(d,J=2.0,1H),6.99-6.96(m,2H),4.21(m,J=13.5,2H),2.88-2.83(m,2H),2.33(d,J=7.0,2H),1.74-1.70(m,3H),1.28-1.93(m,2H)。
实例25:4-(3-三氟甲基-苄基)-哌啶-1-羧酸(6-氯-哒嗪-3-基)-酰胺
MS:399.1.1H NMR(CDCl3):8.46(d,J=9.5,1H),7.57(d,J=9.5,1H),7.48(d,J=8.0,1H),7.43-7.40(m,2H),7.33(d,J=7.5,1H),4.22(d,J=13.5,2H),2.90(t,J=12.0,2H),2.64(d,J=7.0,2H),1.86-1.74(m,3H),1.33-1.25(m,2H)。
实例26:4-(3-三氟甲基-苄基)-哌啶-1-羧酸异噁唑-3-基酰胺
MS:354.2.1H NMR(CDCl3):9.11(s,1H),8.17(d,J=2.0,1H),7.48(d,J=7.5,1H),7.43-7.40(m,2H),7.33(d,J=7.5,1H),7.02(d,J=2.0,1H),4.22(d,J=13.5,2H),2.90-2.84(m,2H),2.63(d,J=7.0,2H),1.82-1.76(m,1H),1.72(d,J=13.5,2H),1.27(m,2H)。
实例27:4-(3-三氟甲基-苄基)-哌啶-1-羧酸苯并[d]异噁唑-3-基酰胺
MS:404.2.1H NMR(CDCl3):9.09(s,1H),8.06(d,J=8.0,1H),7.54-7.48(m,2H),7.42-7.39(m,3H),7.32(d,J=7.5,1H),7.29-7.26(m,1H),4.30(d,J=13.0,2H),2.93(t,J=12.5,2H),2.63(d,J=7.0,2H),1.84-1.78(m,1H),1.74(d,J=14.0,2H),1.35-1.27(m,2H)。
实例28:4-[3-(4-氟-3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d] 异噁唑-3-基酰胺三氟乙酸盐
步骤A:4-(3-羟基-苄基)-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺使用与实例1中所述的那些类似的方法制备该标题化合物。MS:353.2.1H NMR(d4-MeOH):7.84-7.81(m,1H),7.59-7.54(m,1H),7.53-7.50(m,1H),7.32-7.27(m,1H),7.16-7.11(m,1H),6.82-6.80(m,2H),6.71-6.68(m,1H),3.64-3.61(m,4H),3.52-3.50(m,2H),2.55-2.51(m,4H)。
步骤B:4-[3-(4-氟-3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d] 异噁唑-3-基酰胺三氟乙酸盐将DCM(3mL)中的4-氟-3-(三氟甲基)苯基硼酸(124.7mg)、吡啶(122mL)、粉末分子筛(181mg)和Cu(OAc)2(51.5mg)的混合物在室温下的非密封空气中搅拌48小时。当混合物干涸时,另外加入DCM。让该反应混合物滤过硅藻土垫并滤过硅胶垫(NH3/MeOH/DCM)。浓缩滤液并将残余物通过反相HPLC纯化得到45.1mg(24%)作为TFA盐的所需产物。MS:515.2.1H NMR(CDCl3):9.75(s,1H),7.93(d,J=8.0,1H),7.51-7.48(m,1H),7.35-7.32(m,2H),7.24(t,J=8.0,1H),7.19-7.17(m,1H),7.15-7.10(m,3H),7.03(t,J=2.0,1H),6.99-6.97(m,1H),4.17(s,2H),4.39-3.50(br s,4H),3.45-2.82(br s,4H)。
使用与实例28中所述的那些类似的方法制备实例29-35中的化合物。
实例29:4-[3-(3-三氟甲氧基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺三氟乙酸盐
MS:513.2.1H NMR(d4-MeOH):7.87(d,J=8.0,1H),7.62-7.59(m,1H),7.56-7.52(m,2H),7.47(t,J=8.0,1H),7.36-7.30(m,2H),7.27(s,1H),7.21-7.18(m,1H),7.08-7.07(m,1H),7.04-7.01(m,1H),6.94(s,1H),4.42(s,2H),4.09-3.50(br s,4H),3.39(s,4H)。
实例30:4-[3-(4-三氟甲氧基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺三氟乙酸盐
MS:513.2.1H NMR(d4-MeOH):7.87(d,J=8.0,1H),7.61-7.58(m,1H),7.55-7.52(m,2H),7.33-7.30(m,4H),7.24-7.23(m,1H),7.19-7.17(m,1H),7.14-7.11(m,2H),4.41(s,2H),4.15-3.55(br s,4H),3.38(s,4H)。
实例31:4-[3-(3-溴-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰 胺三氟乙酸盐
MS:507.1.1H NMR(CDCl3):9.72(s,1H),7.93(d,J=8.0,1H),7.52-7.49(m,1H),7.36-7.32(m,2H),7.26-7.23(m,2H),7.17(t,J=8.0,1H),7.12(d,J=8.0,1H),7.10(t,J=2.0,1H),7.02-7.01(m,2H),6.90-6.88(m,1H),4.15(s,2H),4.35-3.55(br s,4H),3.55-2.89(br s,4H)。
实例32:4-[3-(4-溴-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰 胺三氟乙酸盐
MS:507.1.1H NMR(CDCl3):9.70(s,1H),7.93(d,J=8.0,1H),7.50(t,J=8.0,1H),7.43-7.40(m,2H),7.36-7.31(m,2H),7.27-7.24(m,1H),7.09(d,J=7.5,1H),7.00-6.99(m,2H),6.85-6.82(m,2H),4.15(s,2H),4.31-3.35(br s,4H),3.45-2.70(br s,4H)。
实例33:4-[3-(3,4-二氟-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3- 基酰胺
MS:465.2.1H NMR(d4-MeOH):9.78(s,1H),7.92(d,J=6.8,1H),7.49(t,J=6.4,1H),7.34-7.31(m,2H),7.23(t,J=6.0,1H),7.11-7.07(m,2H),7.01-6.98(m,2H),6.80-6.76(m,1H),6.70-6.67(m,1H),4.14(s,2H),4.30-3.50(br s,4H),3.35-2.85(br s,4H)。
实例34:4-[3-(3,5-二氟-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3- 基酰胺三氟乙酸盐
MS:465.2.1H NMR(CDCl3):9.75(s,1H),7.92(d,J=8.0,1H),7.51-7.47(m,1H),7.38-7.33(m,2H),7.24(t,J=8.0,1H),7.17(d,J=7.5,1H),7.07-7.05(m,2H),6.56-6.51(m,1H),6.46-6.41(m,2H),4.147(s,2H),4.28-3.55(br s,4H),3.40-2.90(br s,4H)。
实例35:4-{3-[4-(2,2,2-三氟-乙氧基)-苯氧基]-苄基}-哌嗪-1-羧酸苯 并[d]异噁唑-3-基酰胺
MS:527.2.1H NMR(CDCl3):8.41(s,1H),8.07(d,J=8.0,1H),7.54-7.50(m,1H),7.44(d,J=8.5,1H),7.28(d,J=8.0,2H),7.06(d,J=7.5,1H),7.01-6.98(m,3H),6.95-6.92(m,2H),6.87-6.85(m,1H),4.36-4.31(m,2H),3.66-3.64(m,4H),3.54(s,2H),2.55-2.53(m,4H)。
实例36:4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰 胺三氟乙酸盐
步骤A:4-(苯并[d]异噁唑-3-基氨基甲酰基)-哌嗪-1-羧酸叔丁酯将DMSO(8mL)中的苯并[d]异噁唑-3-基-氨基甲酸苯酯(1.072g)和哌嗪-1-羧酸叔丁酯(942mg)的混合物在50℃下搅拌20小时,然后用水(400mL)稀释、彻底混合并过滤。将收集的固体溶解于DCM中并用水(×1)和饱和的含水NaHCO3(×1)洗涤、干燥并浓缩得到褐色固体。通过FCC纯化得到1.10g(79%)作为结晶固体的产物。
步骤B:哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺将DCM(32mL)中的4-(苯并[d]异噁唑-3-基氨基甲酰基)-哌嗪-1-羧酸叔丁酯(1.10g)和TFA(2.5mL)的混合物搅拌2.5小时,然后将其浓缩得到1.15g(100%)淡黄色粘性油状标题化合物。MS:247.2.
步骤C:4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰 胺将THF(2.0mL)中的哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺(60.5mg)、3-(4-氯苯氧基)-苯甲醛(88.4mg)、Et3N(0.1mL)和MP-B(OAc)3H(235mg;树脂载荷=2.33mmol/g)的混合物在振动台上混合19小时。将该混合物过滤并将滤液浓缩。通过反相HPLC纯化残余物得到44.6mg(46%)作为TFA盐的标题化合物。MS:463.2.1H NMR(d4-MeOH):7.88(d,J=7.8,1H),7.60-7.58(m,1H),7.54-7.48(m,2H),7.38-7.35(m,2H),7.33-7.28(m,2H),7.202-7.196(m,1H),7.14-7.12(dd,J=1.8,8.4,1H),7.03-7.01(m,2H),4.66-2.69(br hump,4H),4.40(s,2H),3.38(br hump,4H)。
使用与实例36中所述的那些类似的方法制备实例37-57中的化合物。
实例37:4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸苯并[1,2,5]噻二唑-4-
基酰胺三氟乙酸盐
MS:480.2.1H NMR(d4-MeOH):7.92-7.90(dd,J=0.6,7.2,1H),7.66-7.65(d,J=9.0,1H),7.60-7.57(dd,J=9.0,7.8,1H),7.51-7.48(t,J=8.4,1H),7.38-7.36(m,2H),7.29(br d,J=7.8,1H),7.21-7.20(br m,1H),7.14-7.12(dd,J=1.8,7.8,1H),7.04-7.02(m,2H),4.40(s,2H),3.80-3.01(br hump,8H)。
实例38:4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯并[1,2,5]噻二
唑-4-基酰胺三氟乙酸盐
MS:514.1.1H NMR(d4-MeOH):7.92-7.91(dd,J=1.2,7.8,1H),7.67-7.65(dd,J=1.2,9.0,1H),7.61-7.58(dd,J=7.2,9.0,1H),7.55-7.52(t,J=7.8,1H),7.50(d,J=9.0,1H),7.35(d,J=7.2,1H),7.25(br m,1H),7.21(d,J=2.4,1H),7.20-7.18(dd,J=2.4,8.4,1H),6.99-6.97(dd,J=3.0,9.0,1H),4.58-4.22(br hump,4H),4.42(s,2H),3.72-3.01(br hump,4H)。
实例39:4-[3-(3,5-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯并[1,2,5]噻二
唑-4-基酰胺三氟乙酸盐
MS:514.1.1H NMR(d4-MeOH):7.94-7.93(dd,J=0.6,7.2,1H),7.70-7.68(dd,J=1.2,9.0,1H),7.63-7.56(m,2H),7.40(d,J=7.8,1H),7.30-7.29(m,1H),7.24-7.23(m,2H),7.02(d,J=1.8,2H),4.83-2.94(brhump,4H),4.40(s,2H),3.41(br s,4H)。
实例40:4-[3-(3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[1,2,5]噻
二唑-4-基酰胺三氟乙酸盐
MS:514.2.1H NMR(d4-MeOH):7.92-7.91(dd,J=1.2,7.2,1H),7.67-7.65(dd,J=1.2,9.0,1H),7.61-7.53(m,3H),7.45(d,J=7.8,1H),7.36(d,J=7.8,1H),7.31-7.28(m,3H),7.20-7.18(m,1H),4.85-2.94(brhump,4H),4.43(s,2H),3.41(br hump,4H)。
实例41:4-(3-三氟甲氧基-苄基)-哌嗪-1-羧酸苯并[1,2,5]噻二唑-4-
基酰胺三氟乙酸盐
MS:438.2.1H NMR(d4-MeOH):7.93-7.92(dd,J=7.2,0.6,1H),7.69-7.67(1.2,9.0,1H),7.64-7.60(m,2H),7.57-7.55(m,2H),7.47-7.45(m,1H),4.48(s,2H),4.33-3.66(br hump,4H),3.42(br s,4H)。
实例42:4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(6-氯-哒嗪-3-基)-酰
胺三氟乙酸盐
MS:413.2.1H NMR(d4-MeOH):8.47(s,1H),7.48(t,J=8.4,1H),7.38-7.36(m,2H),7.28(d,J=7.2,1H),7.18(t,J=1.8,1H),7.14-7.12(dd,J=2.4,7.8,1H),7.03-7.01(m,2H),6.73(s,1H),4.70-2.85(br hump,4H),4.37(s,2H),3.36(br hump,4H)。
实例43:4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸(6-氯-哒嗪-3-基)-
酰胺三氟乙酸盐
MS:447.1.1H NMR(d4-MeOH):8.46(s,1H),7.53-7.50(s,2H),7.33(d,J=7.8,1H),7.23(t,J=1.8,1H),7.20(d,J=3.0,1H),7.19-7.17(m,1H),6.98-6.96(dd,J=2.4,8.4,1H),6.73(s,1H),4.74-2.66(br hump,4H),4.39(s,2H),3.36(br hump,4H)。
实例44:4-[3-(3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸(6-氯-哒嗪-3-
基)-酰胺三氟乙酸盐
MS:447.2.1H NMR(d4-MeOH):8.61(br s,1H),7.57(t,J=8.4,1H),7.53(t,J=7.8,1H),7.45(d,J=7.8,1H),7.34(d,J=7.8,1H),7.29-7.25(m,3H),7.18-7.17(dd,J=1.8,7.8,1H),6.84(br s,1H),4.77-2.89(brhump,4H),4.40(s,2H),3.35(br hump,4H)。
实例45:4-(4-氟-3-苯氧基-苄基)-哌嗪-1-羧酸(6-氯-哒嗪-3-基)-酰胺
三氟乙酸盐
MS:397.2.1H NMR(d4-MeOH):8.44(d,J=1.8,1H),7.38-7.31(m,4H),7.28-7.27(dd,J=1.8,7.8,1H),7.15-7.12(m,1H),7.009-6.995(m,1H),6.71(d,J=1.8,1H),4.75-2.84(br hump,4H),4.34(s,2H),3.33(brhump,4H)。
实例46:4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸异噁唑-3-基酰胺三氟 乙酸盐
MS:458.1.1H NMR(d4-MeOH):8.12(d,J=9.0,1H),7.67(d,J=9.6,1H),7.49(t,J=7.8,1H),7.38-7.35(m,2H),7.28(d,J=7.8,1H),7.19(t,J=1.8,1H),7.14-7.12(dd,J=1.8,7.8,1H),7.03-7.01(m,2H),4.79-2.86(brhump,4H),4.39(s,2H),3.38(br hump,4H)。
实例47:4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸异噁唑-3-基酰胺 三氟乙酸盐
MS:490.1.1H NMR(d4-MeOH):8.14(d,J=9.6,1H),7.68(d,J=9.0,1H),7.55-7.51(m,2H),7.34(d,J=7.8,1H),7.24(t,J=2.4,1H),7.21(d,J=2.4,1H),7.20-7.18(m,1H),7.00-6.98(dd,J=3.0,9.0,1H),4.72-2.72(brhump,4H),4.40(s,2H),3.38(br hump,4H)。
实例48:4-[3-(3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸异噁唑-3-基酰 胺三氟乙酸盐
MS:492.2.1H NMR(d4-MeOH):8.21(br s,1H),7.72(br s,1H),7.59-7.53(m,2H),7.45(d,J=7.8,1H),7.35(d,J=7.8,1H),7.30-7.27(m,3H),7.20-7.18(dd,J=1.8,7.8,1H),4.70-2.82(br hump,4H),4.41(s,2H),3.39(br hump,4H)。
实例49:4-(4-氟-3-苯氧基-苄基)-哌嗪-1-羧酸异噁唑-3-基酰胺三氟 乙酸盐
MS:442.2.1H NMR(d4-MeOH):8.13(br s,1H),7.67(d,J=9.0,1H),7.39-7.32(m,4H),7.30-7.28(dd,J=2.4,7.8,1H),7.15-7.12(m,1H),7.02-7.00(dd,J=1.2,9.0,1H),4.76-2.55(br hump,4H),4.35(s,2H),3.34(br hump,4H)。
实例50:4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3- 基酰胺三氟乙酸盐
MS:497.1.1H NMR(d4-MeOH):7.87(d,J=2.4,1H),7.61-7.59(m,1H),7.55-7.50(m,3H),7.35-7.30(m,2H),7.25-7.24(m,1H),7.21(d,J=3.0,1H),7.20-7.18(m,1H),6.99-6.97(dd,J=2.4,8.4,1H),4.55-2.93(brhump,4H),4.42(s,2H),340(br hump,4H)。
实例51:4-[3-(3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑 -3-基酰胺三氟乙酸盐
MS:497.2.1H NMR(d4-MeOH):7.88(d,J=7.8,1H),7.60-7.52(m,4H),7.45(d,J=7.8,1H),7.35(d,J=7.8,1H),7.32-7.27(m,4H),7.19-7.17(dd,J=2.4,7.8,1H),4.69-2.98(br hump,4H),4.42(s,2H),3.40(br hump,4H)。
实例52:4-(3-三氟甲氧基-苄基)-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰 胺三氟乙酸盐
MS:421.2.1H NMR(d4-MeOH):7.88(d,J=7.8,1H),7.63-7.58(m,2H),7.55-7.50(m,3H),7.43(d,J=7.2,1H),7.32(t,J=7.8,1H),4.61-2.99(br hump,4H),4.47(s,2H),3.42(br hump,4H)。
实例53:4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(1H-吡唑-3-基)-酰胺
三氟乙酸盐
MS:412.2.1H NMR(d4-MeOH):7.89(br hump,1H),7.50(t,J=7.8Hz,1H),7.39-7.36(m,2H),7.28(d,J=7.8,1H),7.19(t,J=1.8,1H),7.15-7.13(dd,J=1.8,7.8,1H),7.04-7.02(m,2H),6.38(br hump,1H),4.50-2.95(br hump,4H),3.35(br hump,4H)。
实例54:4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸(1H-吡唑-3-基)-
酰胺三氟乙酸盐
MS:446.1.1H NMR(d4-MeOH):7.91(br hump,1H),7.55-7.52(m,2H),7.34(d,J=7.8,1H),7.25(t,J=1.8,1H),7.22(d,J=3.0,1H),7.20-7.18(dd,J=2.4,7.8,1H),7.01-6.99(dd,J=3.0,9.0,1H),6.44(brhump,1H),4.6-2.85(br hump,4H),4.40(s,2H),3.37(br hump,4H)。
实例55:4-[3-(3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸(1H-吡唑-3-
基)-酰胺三氟乙酸盐
MS:446.2.1H NMR(d4-MeOH):7.98(br hump,1H),7.61-7.55(m,2H),7.47(d,J=7.8,1H),7.36(d,J=7.8,1H),7.31-7.27(m,3H),7.22-7.20(dd,J=2.4,7.8,1H),4.60-2.89(br hump,4H),4.41(s,2H),3.36(br hump,4H)。
实例56:4-(4-氟-3-苯氧基-苄基)-哌嗪-1-羧酸(1H-吡唑-3-基)-酰胺三
氟乙酸盐
MS:396.2.1H NMR(d4-MeOH):7.89(br hump,1H),7.41-7.33(m,4H),7.31-7.29(dd,J=1.8,7.8,1H),7.16(t,J=7.2,1H),7.03(d,J=7.8,1H),6.43(br hump,1H),4.60-2.71(br hump,4H),4.35(s,2H),3.35(brhump,4H)。
实例57:4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(1H-四唑-5-基)-酰胺
三氟乙酸盐
MS:414.2.1H NMR(d4-MeOH):7.51(t,J=7.8,1H),7.40-7.39(m,2H),7.28(d,J=7.8,1H),7.19(br s,1H),7.16-7.14(dd,J=1.8,7.8,1H),7.05-7.03(m,2H),4.36(s,2H),4.10-3.60(br hump,4H),3.44-3.21(brhump,4H)。
实例58:4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸吡嗪-2-基酰胺三氟乙
酸盐
步骤A:4-(吡嗪-2-基氨基甲酰基)-哌嗪-1-羧酸叔丁酯向DCM(52mL)中的氨基吡嗪(530mg)混合物中加入二(N-琥珀酰亚胺基)碳酸酯(1.43g)。将该异质混合物搅拌21小时,然后用N-Boc-哌嗪(1.62g)处理。8小时后,将混合物浓缩并通过FCC(NH3/MeOH/DCM)纯化残余物得到1.07g(63%)作为白色固体的标题化合物。MS:308.2.
步骤B:哌嗪-1-羧酸吡嗪-2-基酰胺使用与实例36中步骤B所述的那些类似的方法制备该标题化合物。MS:208.2.
步骤C:4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸吡嗪-2-基酰胺使用与实例36中步骤C所述的那些类似的方法制备该标题化合物。MS:424.2.1H NMR(d4-MeOH):9.18(br s,1H),8.34(br s,2H),7.50(t,J=7.8,1H),7.39-7.36(m,2H),7.29(d,J=7.2,1H),7.201-7.195(m,1H),7.15-7.13(m,1H),7.04-7.02(m,2H),4.58-2.83(br hump,4H),4.38(s,2H),3.37(brhump,4H)。
使用与实例58中所述的那些类似的方法制备实例59-61中的化合物。
实例59:4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸吡嗪-2-基酰胺三
氟乙酸盐
MS:458.1.1H NMR(d4-MeOH):9.06(s,1H),8.31(s,1H),8.21(s,1H),7.55-7.51(m,2H),7.34(d,1H),7.24-7.18(m,3H),7.00-6.98(dd,J=2.4,8.4,1H),4.57-2.85(br hump,4H),4.40(s,2H),3.36(br hump,4H)。
实例60:4-[3-(3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸吡嗪-2-基酰胺
三氟乙酸盐
MS:458.2.1H NMR(d4-MeOH):9.22(br s,1H),8.36(br s,2H),7.59-7.53(m,2H),7.45(d,J=7.8,1H),7.35(d,J=7.8,1H),7.30-7.26(m,3H),7.20-7.18(m,1H),4.80-2.94(br hump,4H),4.41(s,2H),3.37(brhump,4H)。
实例61:4-(3-三氟甲氧基-苄基)-哌嗪-1-羧酸吡嗪-2-基酰胺三氟乙
酸盐
MS:382.2.1H NMR(d4-MeOH):9.06(s,1H),8.32(s,1H),8.21(s,1H),7.61(t,J=7.8,1H),7.56-7.53(m,2H),7.45-7.44(m,1H),4.62-2.89(br hump,4H),4.46(s,2H),3.38(br hump,4H)。
实例62:N-1,2-苯并异噁唑-3-基-4-[(2,2-二氟-1,3-苯并二氧杂环戊烯 -5-基)甲基]哌啶-1-甲酰胺
步骤A:4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌啶-1-羧酸 叔丁酯将1-Boc-4-亚甲基哌啶(454.6mg)除气(净物质)15分钟,然后用9-硼双环[3.3.1]壬烷(BBN;在THF中为0.5M,4.7mL)的THF溶液进行处理。将反应混合物回流3.5小时,然后冷却至室温。然后将该反应混合物通过插管加至由如下化合物组成的预先形成的溶液中:DMF/H2O(10mL/1mL)中的5-溴-2,2-二氟-1,3-苯并二氧杂环戊烯(502.3mg)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)(Pd(dppf)Cl2)(其为与DCM的络合物,45.9mg)和碳酸钾(369.6mg)。将所得混合物在60℃下加热18小时,冷却至室温,倾注入水中,用10%的NaOH碱化至pH 11,并用EtOAc(3x)萃取。合并有机相,将其干燥(Na2S04)并浓缩。纯化(FCC)粗残余物得到4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌啶-1-羧酸叔丁酯(608.2mg,81%)。
步骤B:4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌啶使用与实例9中步骤D所述的那些类似的方法制备该标题化合物。
步骤C:N-1,2-苯并异噁唑-3-基-4-[(2,2-二氟-1,3-苯并二氧杂环戊烯 -5-基)甲基]哌啶-1-甲酰胺使用与实例1中步骤C所述的那些类似的方法制备该标题化合物。MS:414.4.1H NMR(d4-MeOH):7.83-7.80(m,1H),7.59-7.54(m,1H),7.53-7.50(m,1H),7.31-7.27(m,1H),7.11-7.07(m,2H),7.00-6.97(m,1H),4.24-4.17(m,2H),2.98-2.90(m,2H),2.64(d,J=7.2,2H),1.89-1.81(m,1H),1.75-1.70(m,2H),1.33-1.24(m,2H)。
实例63:4-(3-邻甲苯基乙炔基-苄基)-哌嗪-1-羧酸苯并[d]异噁唑-3- 基酰胺
步骤A:1-(3-碘-苄基)-哌嗪使用与实例1中步骤B所述的那些类似的方法制备该标题化合物。MS:403.1.
步骤B:4-(3-碘-苄基)-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺使用与实例1中步骤C所述的那些类似的方法制备该标题化合物。MS:463.1.
步骤C:4-(3-邻甲苯基乙炔基-苄基)-哌嗪-1-羧酸苯并[d]异噁唑-3- 基酰胺向THF/Et3N(各为1mL)中的Pd(PPh3)2Cl2(7.2mg)溶液中加入4-(3-碘-苄基)-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺(100.0mg)。将该溶液除气15分钟,然后加入碘化铜(I)(4.6mg)和2-乙炔基甲苯(37.8mg)。将反应混合物在室温下搅拌10分钟,然后倾注入水中并用EtOAc(3x)萃取。合并有机相,将其用NH4OH洗涤、干燥(Na2SO4)并浓缩。将粗残余物纯化(FCC)得到标题化合物(89.3mg,92%)。MS:451.2.1H NMR(d4-MeOH):7.88-7.83(m,1H),7.62-7.51(m,3H),7.50-7.44(m,2H),7.42-7.36(m,2H),7.34-7.24(m,3H),7.22-7.17(m,1H),3.71-3.60(m,6H),2.61-2.55(m,4H),2.53(s,3H)。
使用与实例63中所述的那些类似的方法制备实例64-80中的化合物。
实例64:N-1,2-苯并异噁唑-3-基-4-(3-{[2-(三氟甲基)-苯基]-乙炔基} 苄基)-哌嗪-1-甲酰胺
MS:505.2.1H NMR(d4-MeOH):7.86(d,J=8.1,1H),7.78-7.72(m,2H),7.67-7.62(m,1H),7.61-7.52(m,4H),7.49-7.39(m,3H),7.34-7.29(m,1H),3.71-3.60(m,6H),2.62-2.52(m,4H)。
实例65:N-1,2-苯并异噁唑-3-基-4-{3-[(2-甲氧苯基)-乙炔基]-苄基}- 哌嗪-1-甲酰胺
MS:467.2.1H NMR(d4-MeOH):7.88-7.83(m,1H),7.61-7.51(m,3H),7.47-7.42(m,2H),7.39-7.29(m,4H),7.04(d,J=8.4,1H),6.98-6.93(m,1H),3.93(s,3H),3.69-3.64(m,4H),3.62(s,2H),2.61-2.55(m,4H)。
实例66:N-1,2-苯并异噁唑-3-基-4-{3-[(2-氟代苯基)乙炔基]-苄基}- 哌嗪-1-甲酰胺
MS:455.2.1H NMR(d4-MeOH):7.88-7.83(m,1H),7.62-7.51(m,4H),7.50-7.46(m,1H),7.45-7.37(m,3H),7.34-7.29(m,1H),7.24-7.15(m,2H),3.71-3.59(m,6H),2.61-2.54(m,4H)。
实例67:N-1,2-苯并异噁唑-3-基-4-{3-[(2-溴代苯基)-乙炔基]苄基}- 哌嗪-1-甲酰胺
MS:515.1.1H NMR(CDCl3):8.11-8.07(m,1H),7.66-7.63(m,1H),7.60-7.57(m,2H),7.56-7.51(m,2H),7.50-7.47(m,1H),7.42-7.28(m,5H),7.23-7.19(m,1H),3.66-3.62(m,4H),3.60(s,2H),2.60-2.55(m,4H)。
实例68:4-(3-乙炔基-苄基)-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺
步骤A:4-(3-三甲基甲硅烷基乙炔基-苄基)-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺使用与实例63中步骤C所述的那些类似的方法制备该标题化合物。MS:433.2.
步骤B:4-(3-乙炔基-苄基)-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺向MeOH(10mL)中的4-(3-三甲基甲硅烷基乙炔基-苄基)-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺(396.2mg)溶液中加入碳酸钾(500mg)。将反应混合物在室温下搅拌2小时,然后滤过硅藻土并浓缩。将粗残余物纯化(FCC)得到标题化合物(291.7mg,88%)。MS:361.2.1H NMR(CDCl3):8.11-8.08(m,1H),7.88(s,1H),7.57-7.50(m,2H),7.49-7.46(m,1H),7.45-7.42(m,1H),7.37-7.29(m,3H),3.68-3.62(m,4H),3.56(s,2H),3.10(s,1H),2.58-2.53(m,4H)。
实例69:N-1,2-苯并异噁唑-3-基-4-{3-[3-(二甲基氨基)丙-1-炔-1-基] 苄基}-哌嗪-1-甲酰胺
MS:418.2.1H NMR(d4-MeOH):7.87-7.83(m,1H),7.61-7.56(m,1H),7.56-7.52(m,1H),7.49-7.46(m,1H),7.39-7.29(m,4H),3.67-3.62(m,4H),3.59(s,2H),3.51(s,2H),2.58-2.51(m,4H),2.40(s,6H)。
实例70:N-1,2-苯并异噁唑-3-基-4-[3-(环己基乙炔基)苄基]-哌嗪-1- 甲酰胺
MS:443.2.1H NMR(d6-DMSO):8.00-7.96(m,1H),7.60-7.55(m,1H),7.53-7.51(m,1H),7.41-7.38(m,1H),7.34-7.26(m,4H),3.70-3.64(m,4H),3.55(s,2H),2.65-2.60(m,1H),2.54-2.49(m,4H),1.91-1.85(m,2H),1.79-1.72(m,2H),1.58-1.48(m,3H),1.43-1.35(m,3H)。
实例71:N-1,2-苯并异噁唑-3-基-4-[3-(环戊基乙炔基)苄基]-哌嗪-1- 甲酰胺
MS:429.2.1H NMR(d4-MeOH):7.87-7.83(m,1H),7.61-7.57(m,1H),7.55-7.52(m,1H),7.40-7.37(m,1H),7.34-7.26(m,4H),3.68-3.62(m,4H),3.57(s,2H),2.90-2.83(m,1H),2.57-2.52(m,4H),2.07-1.98(m,2H),1.84-1.77(m,2H),1.74-1.62(m,4H)。
实例72:N-1,2-苯并异噁唑-3-基-4-{3-[(2-氯苯基)-乙炔基]苄基}-哌 嗪-1-甲酰胺
MS:471.2.1H NMR(d4-MeOH):7.87-7.84(m,1H),7.63-7.56(m,3H),7.55-7.47(m,3H),7.45-7.29(m,5H),3.69-3.61(m,6H),2.61-2.55(m,4H)。
实例73:N-1,2-苯并异噁唑-3-基-4-{3-[(3-氯苯基)乙炔基]苄基}-哌嗪 -1-甲酰胺
MS:471.2.1H NMR(CDCl3):8.12-8.08(m,1H),7.69(s,1H),7.57-7.51(m,3H),7.50-7.45(m,2H),7.45-7.42(m,1H),7.37-7.28(m,5H),3.68-3.63(m,4H),3.59(s,2H),2.60-2.54(m,4H)。
实例74:N-1,2-苯并异噁唑-3-基-4-{3-[(4-氯苯基)乙炔基]苄基}-哌嗪 -1-甲酰胺
MS:471.2.1H NMR(CDCl3):8.11-8.08(m,1H),7.76(s,1H),7.57-7.51(m,2H),7.50-7.45(m,4H),7.38-7.33(m,4H),7.31-7.28(m,1H),3.68-3.63(m,4H),3.59(s,2H),2.61-2.52(m,4H)。
实例75:N-1,2-苯并异噁唑-3-基-4-{3-[(3,4-二氯苯基)乙炔基]-苄基}- 哌嗪-1-甲酰胺
MS:505.1.1H NMR(CDCl3):8.11-8.08(m,1H),7.69(s,1H),7.65(d,J=1.9,1H),7.56-7.52(m,2H),7.49-7.43(m,3H),7.39-7.35(m,3H),7.32-7.28(m,1H),3.67-3.64(m,4H),3.59(s,2H),2.60-2.55(m,4H)。
实例76:N-1,2-苯并异噁唑-3-基-4-[3-(环丙基乙炔基)苄基]-哌嗪-1- 甲酰胺
MS:401.2.1H NMR(CDCl3):8.09(d,J=8.1,1H),7.57-7.51(m,1H),7.49-7.46(m,1H),7.40-7.38(m,1H),7.33-7.23(m,5H),3.66-3.60(m,4H),3.53(s,2H),2.57-2.51(m,4H),1.51-1.44(m,1H),0.92-0.87(m,2H),0.85-0.81(m,2H)。
实例77:N-1,2-苯并异噁唑-3-基-4-[3-(噻吩-3-基乙炔基)苄基]-哌嗪 -1-甲酰胺
MS:443.2.1H NMR(d4-MeOH):7.86-7.81(m,1H),7.64-7.49(m,4H),7.46-7.27(m,5H),7.21-7.16(m,1H),3.69-3.56(m,6H),2.60-2.50(m,4H)。
实例78:4-{3-[(2-氯苯基)乙炔基]苄基}-N-吡嗪-2-基哌嗪-1-甲酰胺
盐酸盐
MS:431.2.1H NMR(d6-DMS0):9.83-9.82(m,1H),9.03-9.02(m,1H),8.34-8.32(m,1H),8.25(d,J=2.6,1H),7.84-7.82(m,1H),7.71-7.65(m,3H),7.64-7.61(m,1H),7.60-7.55(m,1H),7.50-7.41(m,2H),4.43-4.39(m,2H),4.32-4.25(m,2H),3.41-3.25(m,4H),3.14-3.03(m,2H)。
实例79:4-{3-[(2-氯苯基)乙炔基]苄基}-N-哒嗪-3-基哌嗪-1-甲酰胺
MS:432.2.1H NMR(d4-MeOH):8.82-8.76(m,1H),8.15-8.08(m,1H),7.62-7.56(m,3H),7.50-7.46(m,2H),7.43-7.29(m,4H),3.67-3.58(m,6H),2.60-2.50(m,4H)。
实例80:4-{3-[(2-氯苯基)乙炔基]苄基}-N-(5-甲基吡嗪-2-基)哌嗪-1-
甲酰胺
MS:446.2.1H NMR(d4-MeOH):8.89(d,J=1.5,1H),8.19-8.16(m,1H),7.61-7.56(m,2H),7.50-7.45(m,2H),7.42-7.29(m,4H),3.62-3.56(m,6H),2.55-2.50(m,4H),2.46(s,3H)。
实例81:N-1,2-苯并异噁唑-3-基-4-{3-[(2,4-二氯苯基)-乙炔基]苄基}- 哌嗪-1-甲酰胺
向THF/Et3N(各为1mL)中的Pd(PPh3)2Cl2(7.2mg)溶液中加入1,3-二氯-4-碘苯(60.3mg)。将该溶液除气15分钟,然后加入碘化铜(I)(4.3mg)和4-(3-乙炔基-苄基)-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺(75.6mg)。将反应混合物在室温下搅拌3小时,然后将其倾注入水中,并用EtOAc(3x)萃取。合并有机层,将其用NH4OH洗涤、干燥(Na2SO4)并浓缩。将粗残余物纯化(FCC)得到标题化合物(70.8mg,67%)。MS:505.1.1H NMR(d4-MeOH):7.87-7.83(m,1H),7.61-7.56(m,4H),7.55-7.52(m,1H),7.51-7.47(m,1H),7.46-7.36(m,3H),7.34-7.29(m,1H),3.69-3.60(m,6H),2.61-2.53(m,4H)。
使用与实例81中所述的那些类似的方法制备实例82-93中的化合物。
实例82:N-1,2-苯并异噁唑-3-基-4-(3-{[2-(三氟甲氧基)苯基]-乙炔基} 苄基)-哌嗪-1-甲酰胺
MS:521.2.1H NMR(CDCl3):8.12-8.08(m,1H),7.64-7.59(m,1H),7.57-7.52(m,2H),7.51-7.47(m,2H),7.43-7.35(m,4H),7.34-7.29(m,3H),3.66-3.61(m,4H),3.60(s,2H),2.62-2.53(m,4H)。
实例83:N-1,2-苯并异噁唑-3-基-4-{3-[(3,5-二氯苯基)乙炔基]苄基}- 哌嗪-1-甲酰胺
MS:505.1.1H NMR(d4-MeOH):7.87-7.83(m,1H),7.62-7.56(m,2H),7.56-7.52(m,1H),7.52-7.47(m,4H),7.46-7.43(m,1H),7.43-7.38(m,1H),7.34-7.29(m,1H),3.69-3.64(m,4H),3.63(s,2H),2.60-2.54(m,4H)。
实例84:N-1,2-苯并异噁唑-3-基-4-{3-[(2,5-二氯苯基)乙炔基]苄基}- 哌嗪-1-甲酰胺
MS:505.1.1H NMR(CDCl3):8.11-8.08(m,1H),7.59-7.56(m,2H),7.56-7.47(m,4H),7.40-7.36(m,3H),7.32-7.24(m,2H),3.67-3.62(m,4H),3.60(s,2H),2.62-2.55(m,4H)。
实例85:N-1,2-苯并异噁唑-3-基-4-{3-[(2-氰基苯基)乙炔基]苄基}- 哌嗪-1-甲酰胺
MS:462.2.1H NMR(d4-MeOH):7.87-7.84(m,1H),7.82-7.79(m,1H),7.75-7.68(m,2H),7.67-7.63(m,1H),7.61-7.51(m,4H),7.49-7.41(m,2H),7.34-7.29(m,1H),3.70-3.60(m,6H),2.63-2.52(m,4H)。
实例86:N-1,2-苯并异噁唑-3-基-4-[3-(萘-1-基乙炔基)苄基]哌嗪-1- 甲酰胺
MS:487.2.1H NMR(CDCl3):8.48-8.43(m,1H),8.10-8.06(m,1H),7.90-7.84(m,2H),7.79-7.76(m,1H),7.66-7.44(m,8H),7.42-7.36(m,2H),7.30-7.27(m,1H),3.67-3.59(m,6H),2.62-2.54(m,4H)。
实例87:2-[(3-{[4-(1,2-苯并异噁唑-3-基氨基甲酰基)哌嗪-1-基]甲基} 苯基)乙炔基]苯甲酸甲酯
MS:495.2.1H NMR(d4-MeOH):7.99-7.95(m,1H),7.87-7.84(m,1H),7.70-7.66(m,1H),7.62-7.57(m,3H),7.56-7.45(m,3H),7.44-7.38(m,2H),7.34-7.30(m,1H),3.98(s,3H),3.69-3.62(m,6H),2.61-2.56(m,4H)。
实例88:N-1,2-苯并异噁唑-3-基-4-{3-[(3-氰基苯基)乙炔基]苄基}哌 嗪-1-甲酰胺
MS:462.2.1H NMR(d4-MeOH):7.90-7.88(m,1H),7.85-7.80(m,2H),7.74-7.71(m,1H),7.60-7.55(m,3H),7.52(d,J=8.5,1H),7.49-7.47(m,1H),7.44-7.42(m,1H),7.39(t,J=7.6,1H),7.30(t,J=7.5,1H),3.66-3.63(m,4H),3.62(s,2H),2.58-2.54(m,4H)。
实例89:N-1,2-苯并异噁唑-3-基-4-[3-(1,3-苯并二氧杂环戊烯-5-基乙 炔基)苄基]-哌嗪-1-甲酰胺
MS:481.2.1H NMR(d4-MeOH):7.88-7.84(m,1H),7.63-7.53(m,3H),7.45-7.30(m,4H),7.09-7.05(dd,J=8.0,1.6,1H),6.99-6.98(m,1H),6.87-6.84(m,1H),6.01(s,2H),3.69-3.65(m,4H),3.62(s,2H),2.61-2.55(m,4H)。
实例90:N-1,2-苯并异噁唑-3-基-4-{3-[(2,3-二氯苯基)乙炔基]苄基}- 哌嗪-1-甲酰胺
MS:505.1.1H NMR(d4-MeOH):7.87-7.84(m,1H),7.64-7.50(m,6H),7.48-7.40(m,2H),7.36-7.30(m,2H),3.71-3.62(m,6H),2.63-2.54(m,4H)。
实例91:N-1,2-苯并异噁唑-3-基-4-{3-[(2-氰基-3-氟代苯基)乙炔基]- 苄基}哌嗪-1-甲酰胺
MS:480.2.1H NMR(d4-MeOH):7.85-7.82(m,1H),7.76-7.69(m,1H),7.67-7.64(m,1H),7.60-7.35(m,7H),7.33-7.27(m,1H),3.68-3.62(m,6H),2.61-2.53(m,4H)。
实例92:N-1,2-苯并异噁唑-3-基-4-(3-{[2-(氰甲基)苯基]乙炔基}-苄 基)哌嗪-1-甲酰胺
MS:476.2.1H NMR(d6-DMSO):9.89(s,1H),7.82-7.79(m,1H),7.65-7.61(m,2H),7.61-7.58(m,2H),7.56-7.53(m,2H),7.50-7.46(m,1H),7.46-7.41(m,3H),7.32-7.29(m,1H),4.21(s,2H),3.60-3.51(m,6H),2.46-2.42(m,4H)。
实例93:{2-[(3-{[4-(1,2-苯并异噁唑-3-基氨基甲酰基)哌嗪-1-基]甲 基}苯基)乙炔基]苯基}乙酸甲酯
MS:509.2.1H NMR(d6-DMSO):9.88(s,1H),7.82-7.79(m,1H),7.65-7.53(m,3H),7.51-7.48(m,1H),7.45-7.27(m,7H),3.93(s,2H),3.63(s,3H),3.58-3.52(m,6H),2.47-2.41(m,4H)。
实例94:4-[3-(2-邻甲苯基-乙基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3- 基酰胺盐酸盐
步骤A:4-(3-邻甲苯基乙炔基-苄基)-哌嗪-1-羧酸叔丁酯使用与实例63中步骤C所述的那些类似的方法制备该标题化合物。MS:391.3.
步骤B:4-[3-(2-邻甲苯基-乙基)-苄基]-哌嗪-1-羧酸叔丁酯向EtOH(20mL)中的4-(3-邻甲苯基乙炔基-苄基)-哌嗪-1-羧酸叔丁酯(489.4mg)溶液中加入10%Pd/C(139mg)。将烧瓶用N2吹扫,然后配备H2球。在1大气压的H2下将混合物在室温下搅拌2小时,然后滤过硅藻土并浓缩而得到4-[3-(2-邻甲苯基-乙基)-苄基]-哌嗪-1-羧酸叔丁酯(480.2mg,97%)。MS:395.3.
步骤C:1-[3-(2-邻甲苯基-乙基)-苄基]-哌嗪使用与实例1中步骤B所述的那些类似的方法制备该标题化合物。MS:295.2.
步骤D:4-[3-(2-邻甲苯基-乙基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3- 基酰胺盐酸盐使用与实例1中步骤C所述的那些类似的方法制备该标题化合物。MS:455.3.1H NMR(d6-DMSO):7.87-7.83(m,1H),7.68-7.60(m,2H),7.46-7.30(m,5H),7.16-7.07(m,4H),4.37-4.25(m,4H),3.47-3.25(brhump,2H),3.13-3.02(m,2H),2.90-2.85(m,4H),2.27(s,3H)。
实例95:4-[3-(嘧啶-2-基氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3- 基酰胺
步骤A:4-[3-(嘧啶-2-基氧基)-苄基]-哌嗪-1-羧酸叔丁酯向DMSO(5mL)中的4-(3-羟基-苄基)-哌嗪-1-羧酸叔丁酯(500.2mg)溶液中加入碳酸铯(1.10g)和2-氯嘧啶(236.2mg)。将反应混合物在60℃下加热18小时,然后冷却至室温,倾注入H2O中,并用EtOAc(3x)萃取。合并有机层,将其干燥(Na2SO4)并浓缩。将粗残余物纯化(FCC)得到4-[3-(嘧啶-2-基氧基)-苄基]-哌嗪-1-羧酸叔丁酯(452.8mg,71%)。MS:371.5.
步骤B:2-(3-哌嗪-1-基甲基-苯氧基)-嘧啶使用与实例1中步骤B所述的那些类似的方法制备该标题化合物。MS:271.2.
步骤C:4-[3-(嘧啶-2-基氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基 酰胺使用与实例1中步骤C所述的那些类似的方法制备该标题化合物。MS:431.5.1H NMR(d4-MeOH):8.61(d,J=4.8,2H),7.87-7.82(m,1H),7.62-7.57(m,1H),7.55-7.53(m,1H),7.43(t,J=7.8,1H),7.34-7.28(m,2H),7.25-7.22(m,2H),7.14-7.10(m,1H),3.69-3.63(m,6H),2.64-2.54(m,4H)。
使用与实例95中所述的那些类似的方法制备实例96-97中的化合物。
实例96:N-1,2-苯并异噁唑-3-基-4-[3-(吡啶-2-基氧基)苄基]哌嗪-1- 甲酰胺
MS:430.5.1H NMR(d4-MeOH):8.19-8.14(m,1H),7.88-7.83(m,2H),7.62-7.57(m,1H),7.56-7.53(m,1H),7.43-7.39(m,1H),7.34-7.30(m,1H),7.27-7.24(m,1H),7.19-7.13(m,2H),7.07-7.03(m,1H),6.99-6.95(m,1H),3.69-3.61(m,6H),2.63-2.54(m,4H)。
实例97:N-1,2-苯并异噁唑-3-基-4-[3-(吡嗪-2-基氧基)苄基]哌嗪-1- 甲酰胺
MS:431.5.1H NMR(d4-MeOH):8.42(d,J=1.3,1H),8.29(d,J=2.7,1H),8.15-8.14(m,1H),7.85-7.82(m,1H),7.59-7.55(m,1H),7.53-7.51(m,1H),7.42(t,J=7.9,1H),7.32-7.26(m,2H),7.23-7.21(m,1H),7.11-7.08(m,1H),3.67-3.60(m,6H),2.60-2.54(m,4H)。
实例98:4-[3-(2-氰基-苄氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3- 基酰胺
向乙腈(1mL)中的4-(3-羟基-苄基)-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺(100.2mg)溶液中加入碳酸钾(75.6mg)和α-溴-邻甲苯腈(62.9mg)。将反应混合物在50℃下加热18小时,然后冷却至室温,倾注入H2O中,并用EtOAc(3x)萃取。合并有机层,将其干燥(Na2SO4)并浓缩。将粗残余物纯化(FCC)得到标题化合物(41.3mg,31%)。MS:468.2.1H NMR(d4-MeOH):7.84-7.81(m,1H),7.80-7.78(m,1H),7.72-7.68(m,2H),7.60-7.56(m,1H),7.54-7.50(m,2H),7.32-7.26(m,2H),7.09-7.07(m,1H),7.00-6.95(m,2H),5.29-5.26(m,2H),3.64-3.60(m,4H),3.59-3.57(m,2H),2.55-2.50(m,4H)。
实例99:N-1,2-苯并异噁唑-3-基-4-[3-(苄氧基)苄基]哌嗪-1-甲酰胺
使用与实例98中所述的那些类似的方法制备该标题化合物。MS:443.2.1H NMR(d4-MeOH):7.84-7.81(m,1H),7.59-7.56(m,1H),7.54-7.51(m,1H),7.45-7.42(m,2H),7.38-7.34(m,2H),7.32-7.28(m,2H),7.26-7.23(m,1H),7.03-7.01(m,1H),6.95-6.90(m,2H),5.10(s,2H),3.63-3.59(m,4H),3.56(s,2H),2.54-2.47(m,4H)。
使用与实例1中所述的那些类似的方法制备实例100-203中的化合物。
实例100:4-(1H-苯并咪唑-6-基甲基)-N-1,2-苯并异噁唑-3-基哌嗪-1- 甲酰胺
MS:377.5.1H NMR(d6-DMSO):8.18(s,1H),7.81-7.78(td,J=8.0,1.0,1H),7.61-7.50(m,4H),7.28-7.24(m,1H),7.19-7.16(dd,J=8.2,1.4,1H),3.62(s,2H),3.55-3.50(m,4H),2.44-2.40(m,4H)。
实例101:N-1,2-苯并异噁唑-3-基-4-(1H-吲唑-6-基甲基)哌嗪-1-甲酰 胺
MS:377.4.1H NMR(d6-DMSO):13.00(s,1H),9.85(s,1H),8.03(d,J=0.8,1H),7.79(d,J=8.0,1H),7.66(s,1H),7.61-7.55(m,2H),7.50(d,J=8.5,1H),7.37-7.33(dd,J=8.6,1.4,1H),7.27(t,J=7.9,1H),3.61(s,2H),3.55-3.50(m,4H),2.45-2.40(m,4H)。
实例102:N-1,2-苯并异噁唑-3-基-4-[4-(甲磺酰)苄基]哌嗪-1-甲酰胺
MS:415.4.1H NMR(d6-DMSO):9.88(s,1H),7.91(d,J=8.4,1H),7.81(d,J=8.0,1H),7.64-7.56(m,4H),7.31-7.27(m,1H),3.65(s,2H),3.57-3.53(m,4H),3.22(s,3H),2.46-2.41(m,4H)。
实例103:N-1,2-苯并异噁唑-3-基-4-[4-(三氟甲氧基)苄基]哌嗪-1-甲 酰胺
MS:421.4.1H NMR(d6-DMSO):9.83(s,1H),7.82-7.79(td,J=8.1,0.9,2H),7.63-7.56(m,2H),7.47(d,J=8.7,1H),7.35-7.27(m,3H),3.56(s,2H),3.55-3.51(m,4H),2.44-2.40(m,4H)。
实例104:4-[3-(4-氯苯氧基)苄基]-N-(6-甲氧基哒嗪-3-基)哌嗪-1-甲
酰胺
MS:454.2.1H NMR(d6-DMSO):8.10(d,J=9.6,1H),7.41(d,J=8.9,2H),7.38(t,J=7.8,1H),7.19(d,J=7.5,1H),7.11-7.09(m,1H),7.06-7.03(m,3H),6.96-6.93(dd,J=7.9,2.3,1H),3.99(s,3H),3.63-3.59(m,4H),3.58(s,2H),2.52-2.47(m,4H)。
实例105:N-1,2-苯并异噁唑-3-基-4-[4-氯-3-(三氟甲氧基)苄基]-哌嗪 -1-甲酰胺
MS:455.4.1H NMR(d6-DMSO):9.87(s,1H),7.80(d,J=8.0,1H),7.67(d,J=8.2,1H),7.64-7.57(m,2H),7.52(s,1H),7.44-7.41(dd,J=8.3,1.8,1H),7.31-7.27(m,1H),3.60(s,2H),3.56-3.52(m,4H),2.46-2.40(m,4H)。
实例106:N-1,2-苯并异噁唑-3-基-4-[4-氟-3-(三氟甲氧基)苄基]-哌嗪 -1-甲酰胺
MS:439.4.1H NMR(d6-DMSO):9.83(s,1H),7.82-7.79(td,J=8.1,1.0,1H),7.64-7.56(m,2H),7.52-7.40(m,3H),7.32-7.27(m,1H),3.57(s,2H),3.56-3.51(m,4H),2.46-2.40(m,4H)。
实例107:N-1,2-苯并异噁唑-3-基-4-[3-氯-4-(三氟甲氧基)苄基]-哌嗪 -1-甲酰胺
MS:455.4.1H NMR(d6-DMSO):9.88(s,1H),7.81(d,J=8.0,1H),7.67-7.52(m,4H),7.47-7.43(dd,J=8.4,2.0,1H),7.32-7.28(m,1H),3.58(s,2H),3.57-3.51(m,4H),2.46-2.41(m,4H)。
实例108:N-1,2-苯并异噁唑-3-基-4-[3-氟-4-(三氟甲氧基)苄基]-哌嗪 -1-甲酰胺
MS:439.4.1H NMR(d6-DMSO):9.88(s,1H),7.81(d,J=8.0,1H),7.64-7.58(m,2H),7.54(t,J=8.2,1H),7.49-7.45(dd,J=11.4,1.8,1H),7.33-7.28(m,2H),3.58(s,2H),3.57-3.51(m,4H),2.45-2.42(m,4H)。
实例109:N-1,2-苯并异噁唑-3-基-4-{3-[4-(三氟甲基)苯氧基]苄基}- 哌嗪-1-甲酰胺
MS:497.5.1H NMR(CDCl3):8.08(d,J=8.1,1H),7.87(s,1H),7.60(d,J=8.9,2H),7.56-7.52(m,1H),7.47(d,J=8.5,1H),7.37(t,J=7.9,1H),7.32-7.28(m,1H),7.19(d,J=7.4,1H),7.12-7.10(m,1H),7.07(d,J=8.4,2H),7.00-6.97(m,1H),3.69-3.62(m,4H),3.59(s,2H),2.60-2.53(m,4H)。
实例110:N-1,2-苯并异噁唑-3-基-4-(3-苯氧基苄基)哌嗪-1-甲酰胺
MS:429.5.1H NMR(CDCl3):8.09(d,J=8.1,1H),7.80(s,1H),7.57-7.52(m,1H),7.48(d,J=8.5,1H),7.39-7.29(m,4H),7.16-7.01(m,5H),6.96-6.92(m,1H),3.67-3.60(m,4H),3.57(s,2H),2.60-2.51(m,4H)。
实例111:N-1,2-苯并异噁唑-3-基-4-(3,4-二氯苄基)哌嗪-1-甲酰胺
MS:405.4.1H NMR(CDCl3):8.08(d,J=8.0,1H),7.94(s,1H),7.57-7.53(m,1H),7.50-7.46(m,2H),7.43(d,J=8.2,1H),7.32-7.28(m,1H),7.22-7.19(dd,J=8.2,2.0,1H),3.68-3.63(m,4H),3.53(s,2H),2.59-2.52(m,4H)。
实例112:N-1,2-苯并异噁唑-3-基-4-[4-(苄氧基)苄基]哌嗪-1-甲酰胺
MS:443.5.1H NMR(CDCl3):8.09(d,J=8.1,1H),7.80(s,1H),7.57-7.52(m,1H),7.50-7.25(m,9H),6.97(d,J=8.6,2H),5.09(s,2H),3.66-3.61(m,4H),3.52(s,2H),2.58-2.50(m,4H)。
实例113:N-1,2-苯并异噁唑-3-基-4-(1-苯并噻吩-2-基甲基)哌嗪-1- 甲酰胺
MS:393.4.1H NMR(CDCl3):8.08(d,J=8.1,1H),7.83(d,J=8.1,1H),7.77(s,1H),7.73(d,J=8.0,1H),7.56-7.52(m,1H),7.47(d,J=8.5,1H),7.38-7.29(m,3H),7.20(s,1H),3.88(s,2H),3.71-3.63(m,4H),2.69-2.62(m,4H)。
实例114:N-1,2-苯并异噁唑-3-基-4-[3-(喹啉-6-基氧基)苄基]哌嗪-1- 甲酰胺
MS:480.5.1H NMR(CDCl3):8.88-8.85(dd,J=4.2,1.7,1H),8.12(d,J=9.2,1H),8.08(d,J=8.1,1H),8.04(d,J=8.2,1H),7.64(s,1H),7.56-7.50(m,2H),7.48(d,J=8.5,1H),7.42-7.35(m,2H),7.31-7.26(m,2H),7.18(d,J=7.7,1H),7.16-7.13(m,1H),7.05-7.01(m,1H),3.66-3.58(m,6H),2.62-2.53(m,4H)。
实例115:N-1,2-苯并异噁唑-3-基-4-(4-溴-3-氟苄基)哌嗪-1-甲酰胺
MS:433.4.1H NMR(CDCl3):8.08(d,J=8.0,1H),7.91(s,1H),7.58-7.46(m,3H),7.32-7.29(m,1H),7.21-7.17(dd,J=9.4,1.8,1H),7.05-7.02(dd,J=8.1,1.4,1H),3.69-3.61(m,4H),3.54(s,2H),2.59-2.51(m,4H)。
实例116:N-1,2-苯并异噁唑-3-基-4-(1,3-苯并二氧杂环戊烯-5-基甲 基)哌嗪-1-甲酰胺
MS:381.4.1H NMR(CDCl3):8.13-8.06(m,2H),7.57-7.52(m,1H),7.47(d,J=8.5,1H),7.32-7.28(m,1H),6.90(s,1H),6.80-6.76(m,2H),5.98(s,2H),3.69-3.62(m,4H),3.49(s,2H),2.57-2.50(m,4H)。
实例117:N-1,2-苯并异噁唑-3-基-4-(喹啉-3-基甲基)哌嗪-1-甲酰胺
MS:388.5.1H NMR(CDCl3):8.94(d,J=2.1,1H),8.62(s,1H),8.15-8.04(m,3H),7.82(d,J=9.2,1H),7.74-7.69(m,1H),7.59-7.48(m,2H),7.41(d,J=8.5,1H),7.29-7.24(m,1H),3.75(s,2H),3.72-3.67(m,4H),2.65-2.56(m,4H)。
实例118:N-1,2-苯并异噁唑-3-基-4-(1H-吲哚-5-基甲基)哌嗪-1-甲酰 胺
MS:376.5.1H NMR(CDCl3):8.18(s,1H),8.08(d,J=8.0,1H),7.99(s,1H),7.58(s,1H),7.54-7.49(m,1H),7.44(d,J=8.5,1H),7.37(d,J=8.3,1H),7.29-7.24(m,1H),7.23-7.17(m,2H),6.56-6.51(m,1H),3.67(s,2H),3.65-3.60(m,4H),2.61-2.53(m,4H)。
实例119:N-1,2-苯并异噁唑-3-基-4-[3-(萘-2-基氧基)苄基]哌嗪-1-甲 酰胺
MS:479.5.1H NMR(CDCl3):8.11-8.04(m,2H),7.85-7.80(m,2H),7.70(d,J=8.1,1H),7.53-7.38(m,4H),7.35-7.24(m,4H),7.11(d,J=7.5,1H),7.00-6.96(m,1H),3.66-3.60(m,4H),3.56(s,2H),2.58-2.51(m,4H)。
实例120:N-1,2-苯并异噁唑-3-基-4-(4-溴苄基)哌嗪-1-甲酰胺
MS:415.4.1H NMR(CDCl3):8.68(s,1H),8.07(d,J=8.0,1H),7.55-7.40(m,4H),7.30-7.20(m,3H),3.70-3.62(m,4H),3.50(s,2H),2.56-2.47(m,4H)。
实例121:N-1,2-苯并异噁唑-3-基-4-(3,4-二溴苄基)哌嗪-1-甲酰胺
MS:493.3.1H NMR(CDCl3):8.73(s,1H),8.07(d,J=8.1,1H),7.63(d,J=2.0,1H),7.57(d,J=8.2,1H),7.55-7.50(m,1H),7.43(d,J=8.5,1H),7.30-7.25(m,1H),7.17-7.13(m,1H),3.71-3.64(m,4H),3.48(s,2H),2.56-2.48(m,4H)。
实例122:N-1,2-苯并异噁唑-3-基-4-[3-(2-氯苯氧基)苄基]哌嗪-1-甲 酰胺
MS:463.5.1H NMR(d6-DMSO):9.86(s,1H),7.80(d,J=8.0,1H),7.65-7.57(m,3H),7.40-7.28(m,3H),7.26-7.21(m,1H),7.13-7.09(m,2H),6.94(s,1H),6.86-6.83(m,1H),3.55-3.47(m,6H),2.44-2.37(m,4H)。
实例123:4-萘-2-基甲基-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺
MS:387.5.1H NMR(CDCl3):8.07(d,J=8.4,1H),7.85-7.82(m,3H),7.76(s,1H),7.53-7.45(m,6H),7.28-7.26(m,1H),3.73(s,2H),3.63(t,J=4.8,4H),2.59(t,J=4.8,4H)。
实例124:4-喹啉-2-基甲基-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺
MS:388.5.1H NMR(CDCl3):8.17(d,J=8.4,1H),8.10-8.07(m,2H),7.83(d,J=7.8,1H),7.74-7.71(m,1H),7.64(d,J=8.4,1H),7.56-7.51(m,3H),7.46(d,J=7.8,1H),7.29-7.26(m,1H),3.92(s,2H),3.66(t,J=4.8,4H),2.67(t,J=4.8,4H)。
实例125:4-[3-(4-氰基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3- 基酰胺
MS:454.5.1H NMR(CDCl3):8.07(d,J=7.8,1H),7.91(s,1H),7.62-7.60(m,2H),7.54-7.51(m,1H),7.45(d,J=8.4,1H),7.38(t,J=7.8,1H),7.29-7.26(m,1H),7.21(d,J=7.2,1H),7.10-7.09(m,1H),7.03-7.01(m,2H),6.99-6.97(dd,J=1.8,7.2,1H),3.64(t,J=4.8,4H),3.58(s,2H),2.55(t,J=4.8,4H)。
实例126:4-苯并呋喃-2-基甲基-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺
MS:377.4.1H NMR(CDCl3):8.07(d,J=7.8,1H),8.05(s,1H),7.56-7.50(m,3H),7.45(d,J=8.4,1H),7.30-7.27(m,2H),7.25-7.22(m,1H),6.65(s,1H),3.78(s,2H),3.70(t,J=4.8,4H),2.67(t,J=4.8,4H)。
实例127:N-1,2-苯并异噁唑-3-基-4-[3-(3-氯苯氧基)苄基]哌嗪-1-甲 酰胺.
MS:463.5.1H NMR(d4-MeOH):7.85-7.82(m,1H),7.59-7.55(m,1H),7.53-7.51(m,1H),7.39-7.35(m,1H),7.34-7.28(m,2H),7.19-7.17(m,1H),7.12-7.07(m,2H),6.97-6.94(m,2H),6.93-6.91(m,1H),3.65-3.58(m,6H),2.57-2.51(m,4H)。
实例128:N-1,2-苯并异噁唑-3-基-4-{3-[4-氰基-3-(三氟甲基)苯氧基] 苄基}哌嗪-1-甲酰胺
MS:522.2.1H NMR(d4-MeOH):7.94(d,J=8.6,1H),7.84-7.82(m,1H),7.59-7.55(m,1H),7.53-7.51(m,1H),7.48(t,J=7.9,1H),7.42(d,J=2.4,1H),7.35-7.26(m,3H),7.22-7.20(m,1H),7.10-7.07(m,1H),3.65-3.61(m,6H),2.58-2.53(m,4H)。
实例129:N-1,2-苯并异噁唑-3-基-4-[3-(3-氰基苯氧基)苄基]哌嗪-1- 甲酰胺
1H NMR(d6-DMSO):9.94-9.75(m,1H),7.89-7.68(m,1H),7.67-7.54(m,4H),7.53-7.49(m,1H),7.43-7.38(m,1H),7.37-7.33(m,1H),7.32-7.28(m,1H),7.21-7.17(m,1H),7.08-7.05(m,1H),7.00-6.96(m,1H),3.59-3.46(m,6H),2.46-2.39(m,4H)。
实例130:N-1,2-苯并异噁唑-3-基-4-(3-{4-[(三氟甲基)硫基]苯氧基}- 苄基)哌嗪-1-甲酰胺
MS:529.2.1H NMR(d4-MeOH):7.89-7.81(m,1H),7.70-7.64(m,2H),7.62-7.56(m,1H),7.55-7.52(m,1H),7.44-7.38(m,1H),7.35-7.28(m,1H),7.26-7.22(m,1H),7.17-7.13(m,1H),7.09-7.05(m,2H),7.04-7.01(m,1H),3.69-3.58(m,6H),2.64-2.49(m,4H)。
实例131:N-1,2-苯并异噁唑-3-基-4-{3-[(2,2-二氟-1,3-苯并二氧杂环 戊烯-5-基)氧基]苄基}哌嗪-1-甲酰胺
MS:509.2.1H NMR(d4-MeOH):7.87-7.83(m,1H),7.62-7.56(m,1H),7.55-7.52(m,1H),7.39-7.29(m,2H),7.21-7.14(m,2H),7.08-7.05(m,1H),6.97-6.92(m,2H),6.84-6.77(m,1H),3.69-3.61(m,4H),3.61-3.59(m,2H),2.63-2.47(m,4H)。
实例132:N-1,2-苯并异噁唑-3-基-4-(3-{4-[(三氟甲基)磺酰基]苯氧 基}-苄基)哌嗪-1-甲酰胺
MS:561.2.1H NMR(d4-MeOH):8.10-8.02(m,2H),7.87-7.81(m,1H),7.62-7.56(m,1H),7.56-7.47(m,2H),7.38-7.28(m,2H),7.29-7.23(m,3H),7.15-7.09(m,1H),3.80-3.45(m,6H),2.67-2.47(m,4H)。
实例133:N-1,2-苯并异噁唑-3-基-4-{[3-(苯基乙炔基)苯基]甲基}哌 嗪-1-甲酰胺
MS:437.2.1H NMR(CDCl3):8.14-7.98(m,1H),7.62-7.33(m,12H),3.75-3.48(m,6H),2.68-2.48(m,4H)。
实例134:N-异噁唑-3-基-4-{3-[4-(三氟甲氧基)苯氧基]苄基}哌嗪-1- 甲酰胺
MS:463.2.1H NMR(d6-DMSO):9.99-9.91(m,1H),8.66-8.63(m,1H),7.50-7.44(m,1H),7.39-7.34(m,2H),7.27-7.15(m,2H),7.14-7.09(m,3H),6.72-6.70(m,1H),4.36-4.26(m,2H),4.22-4.13(m,2H),3.35-3.24(m,2H),3.16-2.94(m,4H)。
实例135:4-[4-(苄氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺
MS:393.5.1H NMR(CDCl3):8.22(d,J=1.6,1H),7.85(s,1H),7.48-7.32(m,5H),7.25(d,J=8.6,2H),6.99(d,J=1.8,1H),6.96(d,J=8.7,2H),5.08(s,2H),3.58-3.52(m,4H),3.50(s,2H),2.54-2.44(m,4H)。
实例136:4-[3-(3-氯苯氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺
MS:413.4.1H NMR(CDCl3):8.23(d,J=1.7,1H),7.81(s,1H),7.34(t,J=7.8,1H),7.29-7.25(m,1H),7.15-7.04(m,3H),7.01-6.98(m,2H),6.96-6.90(m,2H),3.58-3.53(m,6H),2.55-2.47(m,4H)。
实例137:N-异噁唑-3-基-4-{3-[4-(2,2,2-三氟乙氧基)苯氧基]苄基} 哌嗪-1-甲酰胺
MS:477.5.1H NMR(CDCl3):8.22(d,J=1.7,1H),8.07(s,1H),7.31-7.25(m,1H),7.06(d,J=7.8,1H),7.03-6.98(m,4H),6.95(d,J=9.2,2H),6.88-6.85(dd,J=8.1,1.8,1H),4.39-4.33(q,J=8.1,2H),3.60-3.55(m,4H),3.53(s,2H),2.55-2.43(m,4H)。
实例138:4-(1苯并呋喃-2-基甲基)-N-异噁唑-3-基哌嗪-1-甲酰胺
MS:327.4.1H NMR(CDCl3):8.23(s,1H),8.21(d,J=1.8,1H),7.56(d,J=7.5,1H),7.51(d,J=8.1,1H),7.31-7.27(m,1H),7.26-7.22(dt,J=7.5,1.0,1H),6.99(d,J=1.7,1H),6.64(s,1H),3.76(s,2H),3.66-3.60(m,4H),2.66-2.59(m,4H)。
实例139:4-[3-(3-氰基苯氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺
MS:404.5.1H NMR(d6-DMSO):9.72(s,1H),8.66(d,J=1.7,1H),7.62-7.57(m,2H),7.51-7.49(m,1H),7.42-7.38(m,1H),7.36-7.33(m,1H),7.17(d,J=7.6,1H),7.04(s,1H),6.99-6.96(m,1H),6.76(d,J=1.7,1H),3.52(s,2H),3.46-3.43(m,4H),2.39-2.34(m,4H)。
实例140:4-[3-(2-氯苯氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺
MS:413.4.1H NMR(d6-DMSO):9.72(s,1H),8.66(d,J=1.7,1H),7.63-7.58(m,1H),7.40-7.32(m,2H),7.25-7.21(m,1H),7.13-7.07(m,2H),6.92(s,1H),6.85-6.82(m,1H),6.76(d,J=1.7,1H),3.49(s,2H),3.46-3.41(m,4H),2.37-2.33(m,4H)。
实例141:4-{3-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)氧基]苄 基}-N-异噁唑-3-基哌嗪-1-甲酰胺
MS:459.5.1H NMR(d6-DMSO):9.72(s,1H),8.66(d,J=1.6,1H),7.42(d,J=8.8,1H),7.37-7.32(m,1H),7.27(d,J=2.4,1H),7.10(d,J=7.6,1H),6.98(s,1H),6.91-6.88(m,1H),6.87-6.83(m,1H),6.76(d,J=1.7,1H),3.49(s,2H),3.47-3.42(m,4H),2.39-2.32(m,4H)。
实例142:4-(1-苯并噻吩-2-基甲基)-N-异噁唑-3-基哌嗪-1-甲酰胺
MS:343.4.1H NMR(d6-DMSO):9.75(s,1H),8.66(d,J=1.8,1H),7.90(d,J=7.7,1H),7.76(d,J=7.2,1H),7.36-7.28(m,3H),6.77(d,J=1.8,1H),3.82(s,2H),3.53-3.44(m,4H),2.48-2.44(m,4H)。
实例143:4-(1.3-苯并二氧杂环戊烯-5-基甲基)-N-异噁唑-3-基哌嗪-1- 甲酰胺
MS:331.4.1H NMR(d6-DMSO):9.73(s,1H),8.66(d,J=1.7,1H),6.88-6.83(m,2H),6.77-6.74(m,2H),5.99(s,2H),3.49-3.41(m,4H),3.40(s,2H),2.35-2.31(m,4H)。
实例144:N-异噁唑-3-基-4-(萘-2-基甲基)哌嗪-1-甲酰胺
MS:337.4.1H NMR(d6-DMSO):9.73(s,1H),8.66(d,J=1.7,1H),7.91-7.87(m,3H),7.81(s,1H),7.54-7.46(m,3H),6.77(d,J=1.6,1H),3.66(s,2H),3.51-3.44(m,4H),2.43-2.39(m,4H)。
实例145:4-[3-(4-溴苯氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺
MS:457.4.1H NMR(CDCl3):8.22-8.17(m,2H),7.43(d,J=9.0,2H),7.32-7.28(m,1H),7.09(d,J=7.6,1H),7.01(s,1H),6.99(d,J=1.7,1H),6.91-6.87(m,3H),3.58-3.51(m,6H),2.52-2.46(m,4H)。
实例146:4-喹啉-2-基甲基-哌嗪-1-羧酸异噁唑-3-基酰胺
MS:338.4.1H NMR(CDCl3):8.19(d,J=1.2,1H),8.15(d,J=8.4,1H),8.08(d,J=8.4,1H),7.92(br hump,1H),7.82-7.81(m,1H),7.73-7.70(m,1H),7.63(d,J=8.4,1H),7.55-7.52(m,1H),6.97(d,J=1.2,1H),3.89(s,2H),3.59(t,J=4.8,4H),2.62(t,J=4.8,4H)。
实例147:4-喹啉-3-基甲基-哌嗪-1-羧酸异噁唑-3-基酰胺
MS:338.4.1H NMR(CDCl3):8.92(d,J=2.4,1H),8.21(d,J=1.8,1H),8.11(d,J=9.0,1H),8.07(d,J=1.2,1H),7.83-7.81(m,1H),7.73-7.70(m,1H),7.58-7.55(m,1H),7.48(br hump,1H),6.96(d,J=1.8,1H),3.74(s,2H),3.55(t,J=4.8,4H),2.56(t,J=4.8,4H)。
实例148:4-(4-溴-苄基)-哌嗪-1-羧酸异噁唑-3-基酰胺
MS:363.3.1H NMR(CDCl3):8.19(d,J 1.2,1H),7.46-7.45(m,2H),7.21(d,J=8.4,2H),6.99(d,J=1.8,1H),3.57(t,J=4.8,4H),3.48(s,2H),2.48(t,J=4.8,4H)。
实例149:4-(1H-吲哚-6-基甲基)-哌嗪-1-羧酸异噁唑-3-基酰胺
MS:326.4.1H NMR(CDCl3):8.19(d,J=1.8,1H),8.16(br s,1H),7.73(br s,1H),7.56(s,1H),7.36(d,J=8.4,1H),7.225-7.216(m,1H),7.19-7.17(dd,J=1.2,8.4,1H),6.96(d,J=1.8,1H),6.54-6.53(m,1H),3.64(s,2H),3.53(t,J=4.8,4H),2.52(t,J=4.8,4H)。
实例150:4-[3-(萘-2-基氧基)-苄基]-哌嗪-1-羧酸异噁唑-3-基酰胺
MS:429.5.1H NMR(CDCl3):8.19(d,J=1.2,1H),7.88(br hump,1H),7.83(m,2H),7.70(d,J=9.0,1H),7.47-7.46(m,1H),7.45-7.40(m,1H),7.33-7.31(m,2H),7.28-7.24(m,1H),7.11-7.08(m,2H),6.99-6.97(m,2H),3.54-3.49(m,6H),2.50(br hump,4H)。
实例151:4-(4-溴-3-氟-苄基)-哌嗪-1-羧酸异噁唑-3-基酰胺
MS:381.3.1H NMR(CDCl3):8.20(d,J=1.8,1H),8.13(br s,1H),7.50-7.48(dd,J=7.2,7.8,1H),7.17-7.15(dd,J=1.8,9.0,1H),7.01-6.99(dd,J=1.2,8.4,1H),6.98(d,J=1.2,1H),3.56(t,J=4.8,4H),3.49(s,2H),2.49(t,J=4.8,4H)。
实例152:4-[3-(4-氰基-苯氧基)-苄基]-哌嗪-1-羧酸异噁唑-3-基酰胺
MS:404.5.1H NMR(CDCl3):8.20(d,J=1.2,1H),8.07(br s,1H),7.62-.760(m,2H),7.61(t,J=7.8,1H),7.19(d,J=7.8,1H),7.08(s,1H),7.01(d,J=9.0,2H),6.98-6.96(m,2H),3.56-3.55(m,6H),2.50(t,J=4.8,4H)。
实例153:4-[3-(3,4-二氟苯氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺
MS:415.5.1H NMR(d4-MeOH):8.42(d,J=1.7,1H),7.35(t,J=7.9,1H),7.29-7.21(m,1H),7.17-7.13(m,1H),7.06-7.03(m,1H),6.96-6.89(m,2H),6.81-6.76(m,1H),6.73(d,J=1.7,1H),3.58-3.51(m,6H),2.52-2.45(m,4H)。
实例154:4-(3,4-二溴苄基)-N-异噁唑-3-基哌嗪-1-甲酰胺
MS:445.3.1H NMR(d4-MeOH):8.43(d,J=1.8,1H),7.71(d,J=1.9,1H),7.64(d,J=8.2,1H),7.27-7.23(dd,J=8.2,2.0,1H),6.73(d,J=1.8,1H),3.58-3.49(m,6H),2.52-2.43(m,4H)。
实例155:N-异噁唑-3-基-4-(3-{4-[(三氟甲基)硫基]苯氧基}苄基)-哌 嗪-1-甲酰胺
MS:479.5.1H NMR(d4-MeOH):8.42(d,J=1.8,1H),7.68-7.63(m,2H),7.39(t,J=7.9,1H),7.23-7.19(m,1H),7.12-7.10(m,1H),7.07-7.02(m,2H),7.02-6.98(m,1H),6.73(d,J=1.8,1H),3.59-3.52(m,6H),2.53-2.45(m,4H)。
实例156:4-{3-[4-氟-3-(三氟甲基)苯氧基]苄基}-N-异噁唑-3-基哌嗪 -1-甲酰胺
MS:465.5.1H NMR(d4-MeOH):8.43(d,J=1.8,1H),7.41-7.24(m,4H),7.20-7.16(m,1H),7.09-7.06(m,1H),6.98-6.94(m,1H),6.73(d,J=1.8,1H),3.62-3.52(m,6H),2.59-2.47(m,4H)。
实例157:4-[3-(3-溴苯氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺
MS:457.4.1H NMR(d4-MeOH):8.42(d,J=1.7,1H),7.36(t,J=7.9,1H),7.28-7.24(m,2H),7.17-7.15(m,1H),7.11-7.10(m,1H),7.06-7.05(m,1H),6.97-6.93(m,2H),6.73(d,J=1.7,1H),3.58-3.52(m,6H),2.50-2.47(m,4H)。
实例158:N-异噁唑-3-基-4-(3-{4-[(三氟甲基)磺酰基]苯氧基}苄基)- 哌嗪-1-甲酰胺
MS:511.1.1H NMR(d4-MeOH):8.42(d,J=1.8,1H),8.05-8.01(m,2H),7.49-7.44(m,1H),7.33-7.29(m,1H),7.26-7.22(m,2H),7.21-7.19(m,1H),7.10-7.07(m,1H),6.73(d,J=1.8,1H),3.61(s,2H),3.57-3.53(m,4H),2.53-2.46(m,4H)。
实例159:N-异噁唑-3-基-4-{3-[3-(三氟甲氧基)苯氧基]苄基}哌嗪-1- 甲酰胺
MS:463.2.1H NMR(d4-MeOH):8.42(d,J=1.8,1H),7.45-7.35(m,2H),7.20-7.16(m,1H),7.10-7.06(m,1H),7.03-6.93(m,3H),6.86-6.82(m,1H),6.73(d,J=1.8,1H),3.60-3.50(m,6H),2.53-2.45(m,4H)。
实例160:4-(3,4-二氯苄基)-N-异噁唑-3-基哌嗪-1-甲酰胺
MS:442.2.1H NMR(d4-MeOH):8.45(d,J=1.6,1H),7.58-7.54(m,1H),7.50(d,J=8.2,1H),6.76-6.73(m,1H),4.70-4.53(m,6H),3.59-3.56(m,4H)。
实例161:N-异噁唑-3-基-4-{3-[4-(三氟甲基)苯氧基]苄基}哌嗪-1-甲 酰胺
MS:447.2.1H NMR(d4-MeOH):8.33-8.31(dd,J=7.1,2.1,1H),7.65-7.58(m,1H),7.57-7.51(m,1H),7.50-7.45(m,1H),7.44-7.39(m,1H),7.35-7.28(m,2H),7.26-7.21(m,1H),7.15-7.10(m,1H),7.03-6.97(m,1H),6.55-6.44(m,1H),3.76-3.66(m,4H),3.65-3.60(m,2H),2.68-2.45(m,4H)。
实例162:N-异噁唑-3-基-4-[3-(喹啉-6-基氧基)苄基]哌嗪-1-甲酰胺
MS:430.2.1H NMR(d4-MeOH):8.82-8.73(m,1H),8.46-8.41(m,1H),8.27-8.22(m,1H),8.09-8.03(m,1H),7.59-7.55(dd,J=9.2,2.7,1H),7.53-7.50(dd,J=8.3,4.3,1H),7.45-7.39(m,1H),7.37-7.34(m,1H),7.22(d,J=7.6,1H),7.18-7.15(m,1H),7.08-7.04(m,1H),6.74(d,J=1.8,1H),3.63-3.58(m,2H),3.58-3.53(m,4H),2.59-2.44(m,4H)。
实例163:4-{3-[4-氰基-3-(三氟甲基)苯氧基]苄基}-N-异噁唑-3-基哌 嗪-1-甲酰胺
MS:472.2.1H NMR(d4-MeOH):8.47-8.41(m,1H),8.00-7.93(m,1H),7.52-7.45(m,1H),7.45-7.41(m,1H),7.36-7.27(m,2H),7.23-7.19(m,1H),7.13-7.08(m,1H),6.77-6.72(m,1H),3.66-3.59(m,2H),3.59-3.55(m,4H),2.59-2.44(m,4H)。
实例164:4-[3-(4-氯苯氧基)苄基]-N-(5-甲基异噁唑-3-基)哌嗪-1-甲 酰胺
MS:427.2.1H NMR(d6-acetone):9.01(s,1H),7.51-7.44(m,1H),7.42-7.36(m,3H),7.32-7.28(m,1H),7.14-7.10(m,1H),7.08-7.03(m,2H),6.52(s,1H),4.48(s,2H),4.22-3.69(m,4H),3.49-3.29(m,4H),2.34(s,3H)。
实例165:4-(喹啉-3-基甲基)-N-1H-四唑-5-基哌嗪-1-甲酰胺
MS:339.4.1H NMR(d6-DMSO):10.66(s,1H),8.88(d,J=2.1,1H),8.25(d,J=1.3,1H),8.04-7.96(m,2H),7.77-7.72(m,1H),7.63-7.59(m,1H),3.74(s,2H),3.58-3.50(m,4H),2.48-2.44(m,4H)。
实例166:4-[3-(萘-2-基氧基)苄基]-N-1H-四唑-5-基哌嗪-1-甲酰胺
MS:430.5.1H NMR(d6-DMSO):10.65(s,1H),7.98(d,J=8.9,1H),7.92(d,J=7.9,1H),7.82(d,J=8.0,1H),7.52-7.39(m,3H),7.38(d,J=7.9,1H),7.32-7.28(dd,J=8.9,2.5,1H),7.13(d,J=7.7,1H),7.05(s,1H),7.01-6.97(dd,J=8.1,1.8,1H),3.52(s,2H),3.51-3.47(m,4H),2.41-2.37(m,4H)。
实例167:4-(3,4-二溴苄基)-N-1H-四唑-5-基哌嗪-1-甲酰胺
MS:444.3.1H NMR(d6-DMSO):10.63(s,1H),7.72(d,J=8.2,1H),7.70(d,J=1.9,1H),7.29-7.26(dd,J=8.2,1.9,1H),3.53-3.50(m,4H),3.49(s,2H),2.41-2.36(m,4H)。
实例168:4-(4-溴-3-氟苄基)-N-1H-四唑-5-基哌嗪-1-甲酰胺
MS:384.4.1H NMR(d6-DMSO):10.69(s,1H),7.66(t,J=7.8,1H),7.34-7.31(dd,J=9.9,1.6,1H),7.16-7.12(dd,J=8.2,1.5,1H),3.56-3.48(m,6H),2.42-2.37(m,4H)。
实例169:4-[3-(3,4-二氟苯氧基)苄基]-N-1H-四唑-5-基哌嗪-1-甲酰
胺
MS:416.5.1H NMR(d6-DMSO):10.37(s,1H),7.50-7.42(dd,J=19.5,9.3,1H),7.37(t,J=7.9,1H),7.24-7.16(m,1H),7.13(d,J=7.6,1H),7.00(s,1H),6.95-6.91(m,1H),6.88-6.83(m,1H),3.54-3.46(m,6H),2.41-2.34(m,4H)。
实例170:4-{3-[4-氰基-3-(三氟甲基)苯氧基]苄基}-N-1H-四唑-5-基
哌嗪-1-甲酰胺
MS:473.5.1H NMR(d6-DMSO):8.14(d,J=8.7,1H),7.53(s,1H),7.48(t,J=7.8,1H),7.33(d,J=7.6,1H),7.28(d,J=7.4,1H),7.17(s,1H),7.13(d,J=8.2,1H),3.60-3.46(m,6H),2.43-2.36(m,4H)。
实例171:N-1H-四唑-5-基-4-{3-[4-(三氟甲基)苯氧基]苄基}哌嗪-1-
甲酰胺
MS:448.5.1H NMR(d6-DMSO):15.39(s,1H),10.64(s,1H),7.74(d,J=8.6,2H),7.45-7.40(m,1H),7.21(d,J=7.6,1H),7.15(d,J=8.6,2H),7.10-7.08(m,1H),7.05-7.02(m,1H),3.56-3.48(m,6H),2.43-2.35(m,4H)。
实例172:N-1H-四唑-5-基-4-(3-{4-[(三氟甲基)硫基]苯氧基}苄基)-
哌嗪-1-甲酰胺
MS:480.5.1H NMR(d6-DMSO):15.35(s,1H),10.48(s,1H),7.72(d,J=8.7,2H),7.45-7.40(m,1H),7.20(d,J=7.6,1H),7.12-7.08(m,3H),7.04-7.01(m,1H),3.56-3.46(m,6H),2.42-2.35(m,4H)。
实例173:N-1H-四唑-5-基-4-{3-[3-(三氟甲氧基)苯氧基]苄基}哌嗪
-1-甲酰胺
MS:464.5.1H NMR(d6-DMSO):15.37(s,1H),10.60(s,1H),7.54-7.48(m,1H),7.42-7.38(m,1H),7.17(d,J=7.6,1H),7.13(d,J=8.3,1H),7.06-6.97(m,4H),3.55-3.46(m,6H),2.40-2.36(m,4H)。
实例174:4-[3-(3,4-二氯苯氧基)苄基]-N-1H-四唑-5-基哌嗪-1-甲酰
胺
MS:448.4.1H NMR(d6-DMSO):15.44(s,1H),10.77(s,1H),7.64(d,J=8.9,1H),7.46-7.39(m,1H),7.31(s,1H),7.22-7.17(m,1H),7.12-6.99(m,3H),3.73-3.36(m,6H),2.47-2.25(m,4H)。
实例175:4-(喹啉-2-基甲基)-N-1H-四唑-5-基哌嗪-1-甲酰胺
MS:339.4.1H NMR(d6-DMSO):15.40(s,1H),10.72(s,1H),8.35(d,J=8.5,1H),8.00-7.95(m,2H),7.77-7.72(m,1H),7.67(d,J=8.5,1H),7.61-7.57(m,1H),3.82(s,2H),3.60-3.52(m,4H),2.50-2.46(m,4H)。
实例176:4-(萘-2-基甲基)-N-1H-四唑-5-基哌嗪-1-甲酰胺
MS:338.4.1H NMR(d6-DMSO):10.57(s,1H),7.93-7.87(m,3H),7.81(s,1H),7.53-7.46(m,3H),3.67(s,2H),3.57-3.50(m,4H),2.46-2.39(m,4H)。
实例177:4-(4-溴-苄基)-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺
MS:366.3.1H NMR(d6-DMSO):7.52(d,J=8.4,2H),7.28(d,J=8.4,2H),3.51(t,J=4.8,4H),3.48(s,2H),2.37(t,J=4.8,4)。
实例178:4-(1H-吲哚-6-基甲基)-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺
MS:327.4.1H NMR(d6-DMSO):11.02(s,1H),10.59(br s,1H),7.44(s,1H),7.34-7.30(m,2H),7.05(d,J=8.4,1H),6.38(s,1H),3.56(s,2H),3.50(br s,4H),2.39(br t,J=5.4,4H)。
实例179:4-(3-苄氧基-苄基)-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺
MS:394.5.1H NMR(d6-DMSO):15.35(br s,1H),10.65(s,1H),7.45(d,J=7.8,2H),7.39(t,J=7.8,2H),7.32(t,J=7.2,1H),7.24(t,J=7.8,1H),6.96(m,1H),6.92-6.88(m,2H),5.10(s,2H),3.50-3.48(m,6H),3.33(s,2H),2.36(t,J=4.8,4H)。
实例180:4-苯并[1,3]二氧杂环戊烯-5-基甲基-哌嗪-1-羧酸(2H-四唑
-5-基)-酰胺
MS:332.4.1H NMR(d6-DMSO):15.34(br s,1H),10.66(s,1H),6.87(s,1H),6.85(d,J=7.8,1H),6.75(d,J=7.2,1H),5.99(s,2H),3.50(br s,4H),3.41(s,2H),2.36(t,J=4.8,4H)。
实例181:4-(3-苯氧基-苄基)-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺
MS:380.5.1H NMR(d6-DMSO):10.23(br s,1H),7.39(t,J=7.8,2H),7.34(t,J=7.8,1H),7.14(t,J=7.2,1H),7.08(d,J=7.2,1H),7.01(d,J=7.8,2H),6.98(s,1H),6.90-6.88(m,1H),3.50-3.48(m,6H),2.37(br s,4H)。
实例182:4-(3,4-二氯-苄基)-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺
1H NMR(d6-DMSO):10.56(br s,1H),7.60-7.57(m,2H),7.33-7.32(dd,J=1.8,8.4,1H),3.52-3.51(m,6H),2.39(t,J=4.8,4H)。
实例183:4-苯并[b]噻吩-2-基甲基-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺
MS:344.4.1H NMR(d6-DMSO):15.22(br s,1H),10.67(br s,1H),7.89(d,J=7.8,1H),7.76(d,J=7.2,1H),7.35-7.29(m,3H),3.83(s,2H),3.54(t,J=4.8,4H),2.52-2.48(m,4H)。
实例184:4-[3-(3-氰基-苯氧基)-苄基]-哌嗪-1-羧酸(2H-四唑-5-基)-
酰胺
MS:405.5.1H NMR(d6-DMSO):15.38(br s,1H),10.67(s,1H),7.61-7.57(m,2H),7.49(t,J=1.2,1H),7.40(t,J=7.8,1H),7.35-7.33(m,1H),7.17(d,J=7.8,1H),7.04(br s,1H),6.98-6.97(dd,J=1.8,8.4,1H),3.53(s,2H),3.51(br t,J=4.2,4H),2.39(t,J=4.8,4H)。
实例185:4-{3-[4-氟-3-(三氟甲基)苯氧基]苄基}-N-2H-四唑-5-基哌
嗪-1-甲酰胺
MS:466.2.1H NMR(d6-DMSO):10.45-9.75(m,1H),7.50-7.24(m,1H),7.22-7.14(m,3H),6.98-6.92(m,1H),6.85-6.82(m,1H),6.79-6.73(m,1H),3.37-3.21(m,6H),2.23-2.09(m,4H)。
实例186:N-2H-四唑-5-基-4-{3-[3-(三氟甲基)苯氧基]苄基}哌嗪-1-
甲酰胺
MS:448.2.1H NMR(d6-DMSO):10.84-10.43(m,1H),7.66-7.59(m,1H),7.52-7.47(m,1H),7.43-7.38(m,1H),7.34-7.27(m,2H),7.20-7.15(m,1H),7.08-7.04(m,1H),7.02-6.98(m,1H),3.58-3.45(m,6H),2.45-2.30(m,4H)。
实例187:4-[3-(4-氰基苯氧基)苄基]-N-2H-四唑-5-基哌嗪-1-甲酰胺
MS:405.2.1H NMR(d6-DMSO):10.84-10.41(m,1H),7.95-7.67(m,2H),7.48-7.38(m,2H),7.26-7.19(m,1H),7.13-7.08(m,2H),7.07-7.03(m,1H),3.62-3.41(m,6H),2.43-2.31(m,4H)。
实例188:N-2H-四唑-5-基-4-{3-[4-(2,2,2-三氟乙氧基)苯氧基]苄基}-
哌嗪-1-甲酰胺
MS:478.2.1H NMR(d6-DMSO):10.76-10.52(m,1H),7.35-7.28(m,1H),7.13-7.07(m,2H),7.07-7.01(m,3H),6.94-6.90(m,1H),6.85-6.80(m,1H),4.76-4.74(q,J=8.9,2H),3.58-3.41(m,6H),2.44-2.25(m,4H)。
实例189:4-{3-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)氧基]苄
基}-N-2H-四唑-5-基哌嗪-1-甲酰胺
MS:460.2.1H NMR(d6-DMSO):10.84-10.18(m,1H),7.42(d,J=8.8,1H),7.37-7.32(m,1H),7.26(d,J=2.4,1H),7.13-7.08(m,1H),7.01-6.96(m,1H),6.92-6.87(m,1H),6.87-6.83(dd,J=8.8,2.4,1H),3.60-3.43(m,6H),2.44-2.30(m,4H)。
实例190:4-[3-(2-氯苯氧基)苄基]-N-2H-四唑-5-基哌嗪-1-甲酰胺
MS:414.2.1H NMR(d6-DMSO):10.87-10.51(m,1H),7.62-7.59(dd,J=8.0,1.6,1H),7.41-7.30(m,2H),7.25-7.21(dt,J=7.7,1.5,1H),7.13-7.07(m,2H),6.95-6.91(m,1H),6.86-6.82(m,1H),3.54-3.48(m,6H),2.44-2.30(m,4H)。
实例191:4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(1,5-二甲基-1H-吡
唑-3-基)-酰胺三氟乙酸盐
MS:440.2.1H NMR(d6-acetone):10.03(s,1H),7.49,(t,J=7.8,1H),7.41-7.38(m,3H),7.31(t,J=1.8,1H),7.14-7.12(m,1H),7.08-7.05(m,2H),6.46(d,J=2.4,1H),4.50(s,2H),3.80(d,J=1.8,3H),4.55-3.05(brhump,8H),2.36(s,3H)。
实例192:4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(4-溴-1-甲基-1H-吡
唑-3-基)-酰胺三氟乙酸盐
MS:504.1.1H NMR(d6-acetone):7.66(s,1H),7.50(t,J=7.8,1H),7.41-7.39(m,3H),7.31(t,J=2.4,1H),7.15-7.13(dd,J=2.4,7.8,1H),7.08-7.06(m,2H),4.52(s,2H),4.33(br hump,2H),3.79(s,3H),3.52(brhump,6H)。
实例193:4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(2-乙基-2H-吡唑-3-
基)-酰胺三氟乙酸盐
MS:440.2.1H NMR(d6-acetone):7.51-7.48(m,2H),7.41-7.39(m,3H),7.30(t,J=2.4,1H),7.15-7.13(m,1H),7.08-7.06(m,2H),4.53(s,2H),4.30(br hump,2H),4.09-4.05(m,2H),3.51(br hump,6H),1.34(t,J=7.2,3H)。
实例194:4-[3-(4-氯苯氧基)苄基]-N-(5-甲基-1H-吡唑-3-基)哌嗪-1-
甲酰胺
MS:426.2.1H NMR(d6-acetone):7.51-7.38(m,5H),7.35-7.31(m,1H),7.15-7.11(m,1H),7.09-7.06(m,2H),4.48(s,2H),4.24-3.66(m,4H),3.50-3.35(m,4H),2.32(s,3H)。
实例195:4-(3,4-二溴苄基)-N-哒嗪-3-基哌嗪-1-甲酰胺
MS:454.2.1H NMR(d4-MeOH):8.81-8.76(m,1H),8.11(d,J=9.0,1H),7.71(d,J=1.9,1H),7.64(d,J=8.2,1H),7.60-7.57(m,1H),7.27-7.24(dd,J=8.2,1.9,1H),3.63-3.59(m,4H),3.53(s,2H),2.54-2.47(m,4H)。
实例196:4-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)甲基]-N-哒嗪-3-
基哌嗪-1-甲酰胺
MS:378.2.1H NMR(d4-MeOH):8.81-8.76(m,1H),8.11(d,J=8.8,1H),7.60-7.57(dd,J=9.1,4.7,1H),7.27-7.24(m,1H),7.15-7.13(m,2H),3.63-3.59(m,4H),3.58(s,2H),2.53-2.49(m,4H)。
实例197:N-哒嗪-3-基-4-(喹啉-3-基甲基)哌嗪-1-甲酰胺
MS:349.2.1H NMR(d4-MeOH):8.90-8.87(m,1H),8.80-8.77(m,1H),8.31-8.29(m,1H),8.13-8.09(m,1H),8.04(d,J=8.5,1H),7.95(d,J=8.1,1H),7.79-7.75(m,1H),7.65-7.61(m,1H),7.60-7.57(m,1H),3.81(s,2H),3.66-3.62(m,4H),2.62-2.57(m,4H)。
实例198:N-哒嗪-3-基-4-(喹啉-2-基甲基)哌嗪-1-甲酰胺
MS:349.2.1H NMR(d4-MeOH):8.81-8.77(m,1H),8.34(d,J=8.5,1H),8.12(d,J=9.1,1H),8.03(d,J=8.5,1H),7.94-7.91(m,1H),7.78-7.73(m,2H),7.61-7.56(m,2H),3.89(s,2H),3.67-3.62(m,4H),2.66-2.59(m,4H)。
实例199:4-(3,4-二氯苄基)-N-哒嗪-3-基哌嗪-1-甲酰胺
MS:366.1.1H NMR(d4-MeOH):8.82-8.76(m,1H),8.15-8.07(m,1H),7.61-7.58(dd,J=9.1,4.7,1H),7.56(d,J=1.9,1H),7.48(d,J=8.2,1H),7.32-7.28(dd,J=8.2,2.0,1H),3.64-3.59(m,4H),3.55(s,2H),2.56-2.47(m,4H)。
实例200:4-(萘-2-基甲基)-N-哒嗪-3-基哌嗪-1-甲酰胺
MS:348.4.1H NMR(d4-MeOH):8.80-8.76(m,1H),8.10(d,J=9.0,1H),7.87-7.81(m,3H),7.80-7.78(m,1H),7.61-7.57(dd,J=9.1,4.7,1H),7.55-7.52(dd,J=8.5,1.6,1H),7.50-7.43(m,2H),3.74(s,2H),3.65-3.59(m,4H),2.61-2.53(m,4H)。
实例201:4-(1H-吲哚-5-基甲基)-N-哒嗪-3-基哌嗪-1-甲酰胺
MS:337.2.1H NMR(d4-MeOH):8.80-8.75(m,1H),8.10(d,J=9.1,1H),7.60-7.55(m,1H),7.52-7.50(m,1H),7.37-7.34(m,1H),7.23-7.20(m,1H),7.13-7.10(m,1H),6.43-6.40(m,1H),3.65(s,2H),3.62-3.58(m,4H),2.58-2.52(m,4H)。
实例202:N-2,1,3-苯并噻二唑-4-基-4-{[3-(苯基乙炔基)苯基]甲基}-
哌嗪-1-甲酰胺
MS:454.2.1H NMR(CDCl3):8.28-8.22(m,1H),7.88(s,1H),7.59-7.56(m,2H),7.55-7.51(m,3H),7.47-7.44(m,1H),7.38-7.30(m,5H),3.67-3.62(m,4H),3.57(s,2H),2.61-2.52(m,4H)。
实例203:N-2,1,3-苯并噁二唑-4-基-4-{[3-(苯基乙炔基)苯基]甲基}-
哌嗪-1-甲酰胺
MS:438.2.1H NMR(CDCl3):8.07-8.01(m,1H),7.60-7.51(m,3H),7.50-7.45(m,1H),7.44-731(m,7H),3.72-3.51(m,6H),2.66-2.46(m,4H)。
使用与实例28中所述的那些类似的方法制备实例204-209中的化合物。
实例204:4-[3-(3-氯-4-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d] 异噁唑-3-基酰胺三氟乙酸盐
1H NMR(CDCl3):9.68(s,1H),7.92(d,J=8.0,1H),7.51(t,J=7.0,1H),7.42(t,J=8.0,1H),7.36(d,J=8.5,1H),7.27-7.22(m,2H),7.12-7.10(m,2H),7.05(d,J=2.5,1H),6.90-6.88(dd,J=2.5,8.5,1H),4.18(s,2H),3.93(br hump,4H),3.22(br hump,4H)。
实例205:4-[3-(4-氯-3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d] 异噁唑-3-基酰胺三氟乙酸盐
1H NMR(CDCl3):9.62(s,1H),7.94(d,J=8.5,1H),7.54-7.51(m,1H),7.44(d,J=8.5,1H),7.41-7.37(m,2H),7.30-7.26(m,2H),7.17(d,J=7.5,1H),7.08-7.04(m,3H),4.18(s,2H),3.93(br hump,4H),3.21(brhump,4H)。
实例206:4-[3-(4-氯-3-氟-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑 -3-基酰胺
1H NMR(CDCl3):8.24(s,1H),8.08(d,J=8.5,1H),7.55-7.52(m,1H),7.45(d,J=8.5,1H),7.36-7.29(m,3H),7.16(d,J=7.5,1H),7.07(s,1H),6.96-6.94(dd,J=2.0,7.5,1H),6.82-6.79(dd,J=2.5,10.0,1H),6.77-6.75(m,1H),3.66(t,J=5.0,4H),3.57(s,2H),2.56(t,J=5.0,4H)。
实例207:4-[3-(3-氯-4-氟-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑 -3-基酰胺
1H NMR(CDCl3):8.67(s,1H),8.08(d,J=8.0,1H),7.55-7.52(m,1H),7.44(d,J=8.0,1H),7.32-7.28(m,2H),7.08-7.04(m,4H),6.92-6.88(m,2H),3.67(t,J=4.5,4H),3.56(s,2H),2.56(t,J=5.0,4H)。
实例208:4-[3-(4-氟-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基 酰胺
1H NMR(CDCl3):8.69(s,1H),8.08(d,J=8.0,1H),7.55-7.51(m,1H),7.44(d,J=8.5,1H),7.31-7.27(m,2H),7.04-6.98(m,6H),6.89-6.87(dd,J=2.0,8.0,1H),3.68(br s,4H),3.55(s,2H),2.55(br s,4H)。
实例209:4-[3-(4-丁基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3- 基酰胺
1H NMR(CDCl3):8.53(br s,1H),8.08(d,J=8.0,1H),7.54-7.51(m,1H),7.45(d,J=8.5,1H),7.29(d,J=8.0,1H),7.15(d,J=8.5,2H),7.07(br d,J=7.0,1H),7.04(br s,1H),6.96-6.93(m,2H),6.91-6.89(dd,J=2.0,8.0,1H),3.68(br s,4H),3.56(s,2H),2.61(t,J=7.5,2H),2.56(br s,4H),1.64-1.58(m,2H),1.42-1.34(m,2H),0.95(t,J=7.5,3H)。
使用与实例58中所述的那些类似的方法制备实例210-244中的化合物。
实例210:4-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)甲基]-N-吡嗪-2-
基哌嗪-1-甲酰胺
MS:378.4.1H NMR(CDCl3):9.38(d,J=1.5,1H),8.26(d,J=2.6,1H),8.17-8.16(dd,J=2.6,1.6,1H),7.14(s,1H),7.11(s,1H),7.03-7.01(m,2H),3.60-3.55(m,4H),3.54(s,2H),2.55-2.47(m,4H)。
实例211:4-(1,3-苯并二氧杂环戊烯-5-基甲基)-N-吡嗪-2-基哌嗪-1-
甲酰胺
MS:342.4.1H NMR(CDCl3):9.38(d,J=1.5,1H),8.26(d,J=2.6,1H),8.17-8.15(dd,J=2.6,1.6,1H),7.10(s,1H),6.88(d,J=0.9,1H),6.80-6.74(m,2H),5.97(s,2H),3.59-3.53(m,4H),3.47(s,2H),2.53-2.48(m,4H)。
实例212:4-(4-溴苄基)-N-吡嗪-2-基哌嗪-1-甲酰胺
MS:376.4.1H NMR(CDCl3):9.38(d,J=1.5,1H),8.26(d,J=2.6,1H),8.17-8.16(dd,J=2.6,1.6,1H),7.48(d,J=8.4,2H),7.23(d,J=8.4,2H),7.10(s,1H),3.61-3.53(m,4H),3.51(s,2H),2.54-2.47(m,4H)。
实例213:4-(萘-2-基甲基)-N-吡嗪-2-基哌嗪-1-甲酰胺
MS:348.5.1H NMR(CDCl3):9.38(d,J=1.4,1H),8.26(d,J=2.6,1H),8.17-8.15(dd,J=2.6,1.6,1H),7.88-7.82(m,3H),7.76(s,1H),7.55-7.46(m,3H),7.07(s,1H),3.73(s,2H),3.62-3.55(m,4H),2.61-2.53(m,4H)。
实例214:N-吡嗪-2-基-4-{3-[4-(2,2,2-三氟乙氧基)苯氧基]苄基}-哌
嗪-1-甲酰胺
MS:488.5.1H NMR(CDCl3):9.38(d,J=1.4,1H),8.26(d,J=2.6,1H),8.18-8.16(dd,J=2.6,1.6,1H),7.31-7.26(m,1H),7.09-6.93(m,7H),6.88-6.85(dd,J=8.0,2.1,1H),4.40-4.33(q,J=8.1,2H),3.60-3.51(m,6H),2.57-2.47(m,4H)。
实例215:N-吡嗪-2-基-4-{3-[4-(三氟甲基)苯氧基]苄基}哌嗪-1-甲酰
胺
MS:458.5.1H NMR(CDCl3):9.38(d,J=1.5,1H),8.26(d,J=2.6,1H),8.18-8.15(dd,J=2.6,1.6,1H),7.60(d,J=8.9,2H),7.37(t,J=7.8,1H),7.17(d,J=7.6,1H),7.11-7.04(m,4H),7.00-6.96(dd,J=8.0,1.7,1H),3.61-3.52(m,6H),2.56-2.50(m,4H)。
实例216:4-(1H-吲哚-5-基甲基)-N-吡嗪-2-基哌嗪-1-甲酰胺
MS:337.5.1H NMR(CDCl3):9.38(d,J=1.5,1H),8.25(d,J=2.6,1H),8.19(s,1H),8.17-8.15(dd,J=2.6,1.6,1H),7.59(s,1H),7.39(d,J=8.3,1H),7.26-7.23(m,1H),7.22-7.19(dd,J=8.3,1.5,1H),7.06(s,1H),6.57-6.54(m,1H),3.67(s,2H),3.61-3.51(m,4H),2.61-2.47(m,4H)。
实例217:4-(3,4-二溴苄基)-N-吡嗪-2-基哌嗪-1-甲酰胺
MS:453.3.1H NMR(CDCl3):9.35(d,J=1.5,1H),8.24(d,J=2.6,1H),8.15-8.13(m,1H),7.62(d,J=2.0,1H),7.57(d,J=8.2,1H),7.16-7.10(m,2H),3.59-3.53(m,4H),3.47(s,2H),2.53-2.46(m,4H)。
实例218:4-(1-苯并噻吩-2-基甲基)-N-吡嗪-2-基哌嗪-1-甲酰胺
MS:354.4.1H NMR(CDCl3):9.36(d,J=1.5,1H),8.23(d,J=2.6,1H),8.14-8.12(m,1H),7.82-7.77(m,1H),7.71-7.68(m,1H),7.36-7.26(m,2H),7.17-7.12(m,2H),3.84(br s,2H),3.62-3.54(m,4H),2.64-2.56(m,4H)。
实例219:4-[4-(苄氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺
MS:404.5.1H NMR(CDCl3):9.36(d,J=1.5,1H),8.23(d,J=2.6,1H),8.14-8.12(m,1H),7.46-7.14(m,8H),6.94(d,J=8.7,1H),5.06(s,2H),3.58-3.51(m,4H),3.48(s,2H),2.52-2.43(m,4H)。
实例220:4-(3,4-二氯苄基)-N-吡嗪-2-基哌嗪-1-甲酰胺
MS:366.4.1H NMR(CDCl3):9.35(d,J=1.5,1H),8.24(d,J=2.6,1H),8.15-8.13(m,1H),7.45(d,J=2.0,1H),7.40(d,J=8.2,1H),7.19-7.15(m,1H),7.12(s,1H),3.60-3.52(m,4H),3.49(s,2H),2.52-2.47(m,4H)。
实例221:4-[3-(4-溴苯氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺
MS:469.5.1H NMR(d6-DMSO):9.49(s,1H),9.01(d,J=1.5,1H),8.30-8.27(m,1H),8.20(d,J=2.6,1H),7.58-7.53(m,2H),7.39-7.35(m,1H),7.13(d,J=7.6,1H),7.01-7.00(m,1H),6.99-6.97(m,2H),6.95-6.92(m,1H),3.53-3.46(m,6H),2.41-2.35(m,4H)。
实例222:4-(4-溴-3-氟苄基)-N-吡嗪-2-基哌嗪-1-甲酰胺
MS:395.4.1H NMR(d6-DMSO):9.51(s,1H),9.03(d,J=1.5,1H),8.30-8.28(m,1H),8.21(d,J=2.6,1H),7.69-7.64(m,1H),7.35-7.31(m,1H),7.16-7.13(m,1H),3.55-3.48(m,6H),2.43-2.35(m,4H)。
实例223:4-[3-(苄氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺
MS:404.5.1H NMR(d6-DMSO):9.50(s,1H),9.03(d,J=1.5,1H),8.31-8.26(m,1H),8.20(d,J=2.6,1H),7.45(d,J=7.0,2H),7.39(t,J=7.4,2H),7.35-7.31(m,1H),7.27-7.23(m,1H),6.97(s,1H),6.93-6.88(m,2H),5.10(s,2H),3.53-3.43(m,6H),2.39-2.32(m,4H)。
实例224:N-吡嗪-2-基-4-(喹啉-3-基甲基)哌嗪-1-甲酰胺
MS:349.5.1H NMR(d6-DMSO):9.52(s,1H),9.03(d,J=1.5,1H),8.89(d,J=2.1,1H),8.30-8.28(m,1H),8.26-8.25(m,1H),8.20(d,J=2.6,1H),8.04-7.98(m,2H),7.77-7.72(m,1H),7.63-7.60(m,1H),3.74(s,2H),3.55-3.50(m,4H),2.49-2.43(m,4H)。
实例225:4-[3-(3-氯苯氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺
MS:424.5.1H NMR(CDCl3):9.36(d,J=1.5,1H),8.24(d,J=2.6,1H),8.16-8.14(m,1H),7.35-7.29(m,1H),7.28-7.23(m,1H),7.13-7.03(m,4H),6.99-6.97(m,1H),6.95-6.88(m,2H),3.58-3.53(m,6H),2.54-2.48(m,4H)。
实例226:N-吡嗪-2-基-4-(3-{4-[(三氟甲基)磺酰基]苯氧基}苄基)-
哌嗪-1-甲酰胺
MS:522.5.1H NMR(CDCl3):9.36(d,J=1.5,1H),8.24(d,J=2.6,1H),8.16-8.14(m,1H),7.97(d,J=8.9,2H),7.45-7.39(m,1H),7.28-7.25(m,1H),7.16-7.12(m,3H),7.08(s,1H),7.04-7.01(m,1H),3.61-3.54(m,6H),2.57-2.49(m,4H)。
实例227:4-(3-苯氧基-苄基)-哌嗪-1-羧酸吡嗪-2-基酰胺
MS:390.5.1H NMR(CDCl3):9.36(d,J=1.8,1H),8.24(d,J=2.4,1H),8.144-8.137(m,1H),7.36-7.33(m,2H),7.29(t,J=7.8,1H),7.12-7.10(m,2H),7.06(d,J=7.8,1H),7.03-7.00(m,3H),6.92-6.90(m,1H),3.55(t,J=4.8,4H),3.53(s,2H),2.51(t,J=4.8,4H)。
实例228:4-[3-(萘-2-基氧基)-苄基]-哌嗪-1-羧酸吡嗪-2-基酰胺
MS:440.5.1H NMR(CDCl3):9.36(d,J=1.8,1H),8.24(d,J=5.0,1H),8.145-8.138(dd,J=1.2,3.0,1H),7.84(t,J=8.4,2H),7.71(d,J=7.2,1H),7.48-7.45(m,1H),7.43-7.40(m,1H),7.33-7.31(m,2H),7.27-7.25(m,1H),7.11-7.07(m,3H),6.99-6.97(m,1H),3.55-3.53(m,6H),2.51(t,J=4.8,4H)。
实例229:4-[3-(4-氰基-苯氧基)-苄基]-哌嗪-1-羧酸吡嗪-2-基酰胺
MS:415.5.1H NMR(CDCl3):9.36(d,J=1.8,1H),8.25(d,J=2.4,1H),8.15-8.14(m,1H),7.62-7.60(m,2H),7.37(t,J=7.8,1H),7.19(d,J=7.8,1H),7.09-7.06(m,2H),7.02-7.00(m,2H),6.98-6.97(dd,J=1.8,7.2,1H),3.56-3.55(m,6H),2.52(t,J=4.8,4H)。
实例230:4-苯并呋喃-2-基甲基-哌嗪-1-羧酸吡嗪-2-基酰胺
MS:338.4.1H NMR(CDCl3):9.35(s,1H),8.24(d,J=3.0,1H),8.15-8.14(dd,J=1.8,2.4,1H),7.56-7.54(m,1H),7.50-7.49(m,1H),7.29-7.27(m,1H),7.24-7.22(m,1H),7.10(s,1H),6.64(s,1H),3.76(s,2H),3.61(t,J=4.8,4H),2.63(t,J=4.8,4H)。
实例231:4-[3-(3,4-二氟苯氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺
MS:426.5.1H NMR(d4-MeOH):9.04-9.01(m,1H),8.30-8.25(m,1H),8.17-8.15(m,1H),7.35(t,J=7.9,1H),7.29-7.21(m,1H),7.17-7.14(m,1H),7.07-7.04(m,1H),6.96-6.89(m,2H),6.81-6.76(m,1H),3.62-3.54(m,6H),2.55-2.46(m,4H)。
实例232:N-吡嗪-2-基-4-[3-(喹啉-6-基氧基)苄基]哌嗪-1-甲酰胺
MS:441.5.1H NMR(d4-MeOH):9.04-9.01(m,1H),8.78-8.74(m,1H),8.29-8.26(m,1H),8.25-8.22(m,1H),8.17-8.15(m,1H),8.07-8.02(m,1H),7.58-7.54(m,1H),7.52-7.48(m,1H),7.43-7.38(m,1H),7.36-7.33(m,1H),7.23-7.19(m,1H),7.17-7.14(m,1H),7.07-7.02(m,1H),3.61-3.55(m,6H),2.58-2.47(m,4H)。
实例233:N-吡嗪-2-基-4-{3-[4-(三氟甲氧基)苯氧基]苄基}哌嗪-1-
甲酰胺
MS:474.5.1H NMR(d4-MeOH):9.04-9.01(m,1H),8.29-8.26(m,1H),8.17-8.15(m,1H),7.39-7.32(m,1H),7.29-7.25(m,2H),7.18-7.14(m,1H),7.08-7.03(m,3H),6.96-6.92(m,1H),3.61-3.55(m,6H),2.53-2.48(m,4H)。
实例234:N-吡嗪-2-基-4-(3-{4-[(三氟甲基)硫基]苯氧基}苄基)-哌嗪
-1-甲酰胺
MS:490.5.1H NMR(d4-MeOH):9.04-9.02(m,1H),8.30-8.26(m,1H),8.18-8.15(m,1H),7.69-7.63(m,2H),7.43-7.37(m,1H),7.25-7.19(m,1H),7.14-7.11(m,1H),7.08-6.98(m,3H),3.64-3.55(m,6H),2.55-2.48(m,4H)。
实例235:4-[3-(3-氰基苯氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺
MS:415.2.1H NMR(d4-MeOH):9.04-9.01(m,1H),8.29-8.25(m,1H),8.16-8.14(m,1H),7.55-7.49(m,1H),7.47-7.43(m,1H),7.42-7.36(m,1H),7.31-7.26(m,2H),7.23-7.19(m,1H),7.11-7.08(m,1H),7.00-6.95(m,1H),3.62-3.55(m,6H),2.56-2.47(m,4H)。
实例236:4-{3-[4-氰基-3-(三氟甲基)苯氧基]苄基}-N-吡嗪-2-基哌嗪
-1-甲酰胺
MS:483.2.1H NMR(d4-MeOH):9.04-9.01(m,1H),8.29-8.26(m,1H),8.17-8.15(m,1H),7.95-7.92(m,1H),7.49-7.45(m,1H),7.42-7.40(m,1H),7.33-7.31(m,1H),7.29-7.26(m,1H),7.21-7.19(m,1H),7.10-7.07(m,1H),3.63-3.56(m,6H),2.54-2.50(m,4H)。
实例237:4-{3-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)氧基]苄
基}-N-吡嗪-2-基哌嗪-1-甲酰胺
MS:470.2.1H NMR(d4-MeOH):9.04-9.00(m,1H),8.29-8.25(m,1H),8.17-8.14(m,1H),7.36-7.30(m,1H),7.19-7.11(m,2H),7.05-7.01(m,1H),6.95-6.89(m,2H),6.80-6.76(m,1H),3.61-3.53(m,6H),2.55-2.46(m,4H)。
实例238:4-[3-(2-氯苯氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺
MS:424.2.1H NMR(d4-MeOH):9.03-9.00(m,1H),8.29-8.23(m,1H),8.17-8.13(m,1H),7.52-7.47(m,1H),7.34-7.27(m,2H),7.19-7.13(m,1H),7.11-7.07(m,1H),7.06-7.01(m,1H),6.97-6.93(m,1H),6.86-6.80(m,1H),3.60-3.51(m,6H),2.54-2.43(m,4H)。
实例239:N-吡嗪-2-基-4-(喹啉-2-基甲基)哌嗪-1-甲酰胺
MS:349.5.1H NMR(CDCl3):9.39(d,J=1.5,1H),8.26(d,J=2.6,1H),8.20-8.15(m,2H),8.11(d,J=8.4,1H),7.84(d,J=8.0,1H),7.76-7.71(m,1H),7.65(d,J=8.4,1H),7.58-7.54(m,1H),7.10(s,1H),3.92(s,2H),3.65-3.60(m,4H),2.69-2.61(m,4H)。
实例240:4-[3-(3-溴苯氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺
MS:468.1.1H NMR(d4-MeOH):9.05(d,J=1.5,1H),8.30-8.28(dd,J=2.6,1.6,1H),8.17(d,J=2.6,1H),7.38(t,J=7.9,1H),7.29-7.26(m,2H),7.20-7.16(m,1H),7.13-7.11(m,1H),7.09-7.07(m,1H),7.00-6.94(m,2H),3.66-3.52(m,6H),2.55-2.49(m,4H)。
实例241:4-{3-[4-氟-3-(三氟甲基)苯氧基]苄基}-N-吡嗪-2-基哌嗪-1-
甲酰胺
MS:476.2.1H NMR(d4-MeOH):9.07-9.02(m,1H),8.34-8.25(m,1H),8.20-8.16(m,1H),7.45-7.32(m,2H),7.32-7.25(m,2H),7.23-7.18(m,1H),7.11-7.08(m,1H),6.99-6.94(m,1H),3.64-3.56(m,6H),2.59-2.44(m,4H)。
实例242:N-吡嗪-2-基-4-{3-[3-(三氟甲氧基)苯氧基]苄基}哌嗪-1-
甲酰胺
MS:474.2.1H NMR(d4-MeOH):9.08-8.99(m,1H),8.35-8.24(m,1H),8.19-8.16(m,1H),7.48-7.33(m,2H),7.23-7.18(m,1H),7.12-7.09(m,1H),7.05-6.96(m,3H),6.89-6.84(m,1H),3.66-3.53(m,6H),2.58-2.43(m,4H)。
实例243:4-[3-(4-氯苯氧基)苄基]-N-(3-氯吡嗪-2-基)哌嗪-1-甲酰胺
MS:458.1.1H NMR(CDCl3):8.26(s,1H),8.00(s,1H),7.32-7.27(m,3H),7.11-7.06(m,1H),7.03-6.87(m,5H),3.64-3.48(m,6H),2.56-2.46(m,4H)。
实例244:4-[3-(4-氯苯氧基)苄基]-N-(5-苯基-1H-吡唑-3-基)哌嗪-1-
甲酰胺三氟乙酸盐
MS:488.2.1H NMR(d6-acetone):7.96-7.78(dd,J=1.8,8.4,2H),7.50(t,J=7.8,1H),7.45(d,J=7.2,1H),7.41-7.34(m,7H),7.15-7.13(m,1H),7.08-7.06(m,2H),4.58(s,2H),3.62(br hump,8H)。
使用与实例1所述的那些类似的方法制备实例245-246中的化合物。
实例245:4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(6-氟-苯并[d]异噁唑 -3-基)-酰胺
MS:481.1.1H NMR(d6-acetone):8.02-7.56(m,2H),7.49(t,J=8.4,1H),7.43-7.34(m,4H),7.31(t,J=1.8,1H),7.14-7.11(m,2H),7.06-7.04(m,2H),4.51(s,2H),3.49(br hump,8H)。
实例246:4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸哒嗪-3-基酰胺
MS:424.2.1H NMR(CDCl3):8.81(s,1H),8.26(s,2H),7.44-7.36(m,1H),7.32-7.26(m,3H),7.08(d,J=7.6,1H),7.02-6.99(m,1H),6.96-6.92(m,2H),6.91-6.88(dd,J=8.1,2.4,1H),3.64-3.55(m,4H),3.52(s,2H),2.51-2.47(m,4H)。
生物学测试:
●测定方法1
A.用人FAAH进行细胞转染
将带有汇合单层的SK-N-MC细胞的10-cm组织培养皿在转染前2天(d)分割。使用无菌技术,移除培养基并通过加入胰蛋白酶使细胞与培养皿分离。然后将五分之一的细胞放置在新的10-cm培养皿上。让细胞在37℃的具有5%CO2的孵育器中、在含10%胎牛血清的Eagle最小必需培养基中生长。两天后,细胞大约80%汇合。用胰蛋白酶将这些细胞从培养皿中移出,并在医用离心机中离心沉淀成小丸。将沉淀小丸重新悬浮在400mL的完全培养基中,并转移至电极间隙为0.4cm的电穿孔管中。将超螺旋的人FAAH cDNA(1μg)加至细胞中并混合。将电穿孔电压设定为0.25kV,并且将电容设定为960mF。电穿孔后,将细胞稀释至完全培养基(10mL)中,并铺至4个10-cm培养皿上。由于电穿孔功效的可变性,将4种不同浓度的细胞进行铺板。所使用的比率是1∶20、1∶10和1∶5,将剩余的细胞加至第四个培养皿。使细胞恢复24小时,然后加入选择培养基(含有600μg/mL G418的完全培养基)。10天后,分析培养皿中存活的细胞集落。使用细胞集落分开良好的培养皿。将来自各个集落的细胞分离并测试。将显示具有最大FAAH活性的克隆用于进一步的研究,FAAH活性通过花生四烯酸乙醇胺水解测量。
B.FAAH测定
将T84冷冻细胞沉淀丸或转染的SK-N-MC细胞(1×15cm培养皿中的内容物)在50μl FAAH测定缓冲液(125mM Tris、1mM EDTA、0.2%甘油、0.02%Triton X-100、0.4mM Hepes,pH 9)中均化。测定混合物由50μL细胞匀浆物、10μL试验化合物和40μL花生四烯酸乙醇胺[1-3H-乙醇胺](3H-AEA,Perkin-Elmer,10.3Ci/mmol)组成,花生四烯酸乙醇胺最后加入,最终示踪浓度为80nM。将反应混合物在室温下孵育1小时。在孵育过程中,用25μL活性炭(Multiscreen柱填充物,目录号MACL09625,Millipore)装填96-孔Multiscreen滤板(目录号MAFCNOB50;Millipore,Bedford,Massachussetts,USA),并且用100μL MeOH洗涤一次。同样在孵育过程中,用100μL MicroScint40(目录号6013641,Packard Bioscience,Meriden,CT,USA)装填96-孔DYNEXMicroLite板(目录号NL510410)。孵育1小时后,将60μL反应混合物转移至炭板上,然后使用离心配准框(Centrifuge Alignment Frame)(目录号MACF09604,Millipore)将其装配到DYNEX板的顶部。未结合的标记乙醇胺被离心透至底板(2000rpm,5分钟),该板预装填了闪烁体,如上所述。将板密封并在室温下放置1小时,然后在Hewlett PackardTopCount上计数。
●测定方法2
A.用大鼠FAAH进行细胞转染
将带有汇合单层的SK-N-MC细胞的10-cm组织培养皿在转染前两天分割。使用无菌技术,移除培养基,并通过加入胰蛋白酶来将细胞与培养皿分离。然后将五分之一的细胞放置在新的10-cm培养皿上。让细胞在37℃的含有5%CO2的孵育器中、在含10%胎牛血清的Eagle最小必需培养基中生长。两天后,细胞汇合了大约80%。用胰蛋白酶将这些细胞从培养皿中移出,并在医学离心机中沉淀成小丸。将沉淀小丸重新悬浮在400μL的完全培养基中,并转移至电极间隙为0.4cm的电穿孔管中。将超螺旋的大鼠FAAH cDNA(1μg)加入细胞中并混合。将电穿孔电压设定为0.25kV,并且将电容设定为960mF。电穿孔后,将细胞稀释进完全培养基(10mL)中,并铺至4个10-cm培养皿上。由于电穿孔功效的可变性,将4种不同浓度的细胞进行铺板。所使用的比率是1∶20、1∶10和1∶5,将剩余的细胞加至第四个培养皿。使细胞恢复24小时,然后加入选择培养基(含有600μg/mL G418的完全培养基)。10天后,分析培养皿中存活的细胞集落。使用细胞集落分开良好的培养皿。将来自各个集落的细胞分离并测试。将显示具有最大FAAH活性的克隆用于进一步的研究,FAAH活性通过花生四烯酸乙醇胺水解测量。
B.FAAH测定
将T84冷冻细胞沉淀小丸或转染的SK-N-MC细胞(1×15cm培养皿中的内容物)在50ml FAAH测定缓冲液(125mM Tris、1mM EDTA、0.2%甘油、0.02%Triton X-100、0.4mM Hepes,pH 9)中均化。测定混合物由50mL细胞匀浆物、10mL试验化合物和40mL花生四烯酸乙醇胺[1-3H-乙醇胺](3H-AEA,Perkin-Elmer,10.3Ci/mmol)组成,花生四烯酸乙醇胺最后加入,最终示踪浓度为80nM。将反应混合物在室温下孵育1小时。在孵育过程中,用25μL活性炭(Multiscreen柱填充物,目录号MACL09625,Millipore)装填96-孔Multiscreen滤板(目录号MAFCNOB50;Millipore,Bedford,Massachussetts,USA),并且用100μL MeOH洗涤一次。同样在孵育过程中,用100μL MicroScint40(目录号6013641,Packard Bioscience,Meriden,CT,USA)装填96-孔DYNEXMicroLite板(目录号NL510410)。孵育1小时后,将60μL反应混合物转移至炭板上,然后使用离心配准框(Centrifuge Alignment Frame)(目录号MACF09604,Millipore)将其装配到DYNEX板的顶部。未结合的标记乙醇胺被离心透至底板(2000rpm,5分钟),该板预装填了闪烁体,如上所述。将板密封并在室温下放置1小时,然后在Hewlett PackardTopCount上计数。
在这些测定中所试验的化合物的结果汇总于表1中,结果为获得的结果的平均值。所试验的化合物为游离碱、盐酸盐和/或三氟乙酸盐形式。其中活性显示为大于(>)一特定值,该值是化合物在测定介质中的溶解限度或者为测定中所试验的最高浓度。
表1
实例 | 测定法1IC50(μM) | 测定法2IC50(μM) | 实例 | 测定法1IC50(μM) | 测定法2IC50(μM) | |
1 | 0.103 | 0.337 | 124 | 0.055 | 0.200 | |
2 | 0.212 | 10.000 | 125 | 0.015 | 0.012 | |
3 | 1.200 | 9.000 | 126 | 0.060 | 0.200 | |
4 | 0.059 | 0.260 | 127 | 0.040 | 0.040 | |
5 | 0.170 | 1.200 | 128 | 0.230 | 0.400 | |
6 | 0.308 | 0.352 | 129 | 0.080 | 0.120 | |
7 | 2.000 | 2.400 | 130 | 0.020 | 0.004 | |
8 | 0.770 | 0.290 | 131 | 0.007 | 0.004 | |
9 | 0.552 | 0.057 | 132 | 0.023 | 0.005 | |
10 | 0.244 | 0.036 | 133 | 0.024 | 0.115 | |
11 | 1.000 | 0.170 | 134 | 0.010 | 0.100 | |
12 | 5.000 | 3.000 | 135 | 0.825 | 10.000 | |
13 | 0.005 | 0.087 | 136 | 0.055 | 1.000 | |
14 | 0.218 | 0.063 | 137 | 0.060 | 0.360 | |
15 | 0.059 | 0.023 | 138 | 5.000 | >10 | |
16 | 0.039 | 0.005 | 139 | 0.860 | >10 | |
17 | 10.000 | 0.517 | 140 | 0.700 | 6.001 | |
18 | >10 | 8.999 | 141 | 0.050 | 0.870 |
19 | 1.500 | 0.055 | 142 | 2.000 | 10.000 | |
20 | 0.935 | 0.250 | 143 | >10 | >10 | |
21 | 0.043 | 0.007 | 144 | 0.350 | 3.000 | |
22 | 0.108 | 0.077 | 145 | 0.016 | 0.430 | |
23 | 10.000 | 5.000 | 146 | 3.000 | 10.000 | |
24 | 10.000 | 4.000 | 147 | 10.000 | >10 | |
25 | 1.300 | 1.300 | 148 | 5.000 | >10 | |
26 | 5.000 | 1.000 | 149 | 10.000 | 10.000 | |
27 | 0.077 | 0.047 | 150 | 0.400 | 1.200 | |
28 | 0.095 | 0.017 | 151 | 3.000 | 6.001 | |
29 | 0.016 | 0.023 | 152 | 0.330 | 5.000 | |
30 | 0.0001 | 0.014 | 153 | 0.460 | 8.000 | |
31 | 0.022 | 0.017 | 154 | 1.300 | 10.000 | |
32 | 0.003 | 0.004 | 155 | 0.020 | 0.270 | |
33 | 0.052 | 0.030 | 156 | 0.043 | 5.000 | |
34 | 0.152 | 0.190 | 157 | 0.080 | 0.360 | |
35 | 0.005 | 0.020 | 158 | 0.010 | 0.150 | |
36 | 0.008 | 0.010 | 159 | 0.050 | 0.300 | |
37 | 0.032 | 0.006 | 160 | 3.000 | 8.000 | |
38 | 0.070 | 0.009 | 161 | 0.004 | 0.160 | |
39 | 0.310 | 0.573 | 162 | 0.240 | 6.400 | |
40 | 0.156 | 0.015 | 163 | 1.000 | >10 | |
41 | 0.048 | 0.141 | 164 | 0.141 | 7.000 | |
42 | 0.311 | 0.018 | 165 | 8.000 | 6.001 | |
43 | 0.983 | 0.006 | 166 | 0.013 | 0.007 | |
44 | 0.643 | 0.046 | 167 | 0.340 | 0.080 | |
45 | 1.500 | 0.410 | 168 | 1.200 | 0.480 | |
46 | 0.615 | 0.025 | 169 | 0.610 | 0.600 | |
47 | 1.145 | 0.066 | 170 | 1.200 | 1.800 | |
48 | 0.627 | 0.049 | 171 | 0.200 | 0.035 | |
49 | 2.000 | 0.360 | 172 | 0.050 | 0.010 |
50 | 0.042 | 0.018 | 173 | 0.225 | 0.200 | |
51 | 0.028 | 0.029 | 174 | 0.100 | 0.030 | |
52 | 0.074 | 0.322 | 175 | 10.000 | 1.000 | |
53 | 0.210 | 0.030 | 176 | 2.000 | 0.450 | |
54 | 0.370 | 0.050 | 177 | 5.000 | 1.700 | |
55 | 7.746 | 0.764 | 178 | >10 | >10 | |
56 | 1.500 | 0.550 | 179 | 1.600 | 1.200 | |
57 | 0.068 | 0.167 | 180 | >10 | 10.000 | |
58 | 0.084 | 0.009 | 181 | 5.000 | 1.600 | |
59 | 0.270 | 0.022 | 182 | 1.700 | 0.340 | |
60 | 0.166 | 0.016 | 183 | 1.400 | 0.430 | |
61 | 2.300 | 7.000 | 184 | 10.000 | 10.000 | |
62 | 0.041 | 0.035 | 185 | 0.450 | 0.440 | |
63 | 0.070 | 0.077 | 186 | 0.330 | 0.160 | |
64 | 0.105 | 0.080 | 187 | 1.600 | 1.000 | |
65 | 0.395 | 0.300 | 188 | 0.080 | 0.020 | |
66 | 0.024 | 0.046 | 189 | 0.070 | 0.017 | |
67 | 0.006 | 0.052 | 190 | 3.000 | 3.700 | |
68 | 0.016 | 0.315 | 191 | 3.000 | >10 | |
69 | 0.044 | 2.000 | 192 | 4.000 | >10 | |
70 | 0.046 | 0.046 | 193 | 0.327 | 6.001 | |
71 | 0.013 | 0.050 | 194 | 0.220 | 4.000 | |
72 | 0.024 | 0.030 | 195 | 0.110 | 0.310 | |
73 | 0.024 | 0.033 | 196 | 6.001 | 1.600 | |
74 | 0.410 | 0.325 | 197 | 1.300 | 8.999 | |
75 | 0.123 | 0.110 | 198 | 0.390 | 6.001 | |
76 | 0.010 | 0.400 | 199 | 0.280 | 0.590 | |
77 | 0.012 | 0.064 | 200 | 0.038 | 0.500 | |
78 | 0.059 | 0.410 | 201 | >10 | >10 | |
79 | 0.046 | 0.320 | 202 | 0.045 | 0.085 | |
80 | 5.000 | 4.000 | 203 | 0.210 | 0.350 |
81 | 0.453 | 0.238 | 204 | 0.014 | 0.032 | |
82 | 0.272 | 0.256 | 205 | 0.106 | 0.225 | |
83 | 0.035 | 0.020 | 206 | 0.011 | 0.021 | |
84 | 0.016 | 0.295 | 207 | 0.034 | 0.046 | |
85 | 0.018 | 0.023 | 208 | 0.021 | 0.017 | |
86 | 3.000 | 0.580 | 209 | 0.009 | 0.002 | |
87 | 2.000 | 0.480 | 210 | 1.750 | 1.160 | |
88 | 0.015 | 0.065 | 211 | 3.000 | >10 | |
89 | 0.645 | 0.544 | 212 | 0.500 | 8.000 | |
90 | 0.195 | 0.815 | 213 | 0.100 | 0.320 | |
91 | 0.030 | 0.021 | 214 | 0.015 | 0.090 | |
92 | 0.027 | 0.262 | 215 | 0.001 | 0.030 | |
93 | 0.102 | 0.225 | 216 | >10 | >10 | |
94 | 0.380 | 0.630 | 217 | 0.150 | 0.250 | |
95 | 2.800 | 10.000 | 218 | 0.170 | 0.700 | |
96 | 0.200 | 1.100 | 219 | 0.230 | 10.000 | |
97 | 0.270 | 5.000 | 220 | 0.320 | 0.430 | |
98 | 0.022 | 0.300 | 221 | 0.003 | 0.050 | |
99 | 0.016 | 0.260 | 222 | 0.700 | 0.600 | |
100 | >10 | >10 | 223 | 0.180 | 10.000 | |
101 | 6.299 | 10.000 | 224 | 4.000 | >10 | |
102 | >10 | >10 | 225 | 0.043 | 0.535 | |
103 | 0.120 | 0.110 | 226 | 0.006 | 0.040 | |
104 | 0.037 | 0.690 | 227 | 0.400 | 5.300 | |
105 | 0.100 | 0.013 | 228 | 0.030 | 0.080 | |
106 | 0.080 | 0.027 | 229 | 0.200 | 3.000 | |
107 | 0.080 | 0.037 | 230 | 4.000 | 6.001 | |
108 | 0.140 | 0.050 | 231 | 0.130 | 3.600 | |
109 | 0.006 | 0.004 | 232 | 0.040 | 0.240 | |
110 | 0.045 | 0.042 | 233 | 0.010 | 0.140 | |
111 | 0.035 | 0.040 | 234 | 0.006 | 0.012 |
112 | 0.040 | 0.270 | 235 | 0.600 | 6.001 | |
113 | 0.020 | 0.030 | 236 | 0.300 | 8.000 | |
114 | 0.020 | 0.020 | 237 | 0.005 | 0.030 | |
115 | 0.040 | 0.025 | 238 | 0.200 | 1.600 | |
116 | 0.400 | 0.760 | 239 | 0.700 | 6.001 | |
117 | 0.130 | 0.440 | 240 | 0.020 | 0.080 | |
118 | 1.800 | 8.000 | 241 | 0.008 | 0.370 | |
119 | 0.045 | 0.009 | 242 | 0.009 | 0.050 | |
120 | 0.080 | 0.120 | 243 | 0.002 | 0.009 | |
121 | 0.017 | 0.025 | 244 | 1.400 | 7.000 | |
122 | 0.148 | 0.115 | 245 | 0.019 | 0.015 | |
123 | 0.020 | 0.040 | 246 | 0.010 | 0.199 |
●测定方法3-大鼠的轻度热损伤模型(MTI)
从Harlan Industries(San Diego,CA)购买无病原体的雄性白色Sprague-Dawley大鼠,并将它们保持在12小时光照/黑夜循环(上午9:00开始光照,下午9:00停止光照)的气候受控室中。直到测试时都可随意地获得食物和水。
在进行异氟烷/氧气麻醉后,如下进行一度烧伤(有红斑而不起泡):将大鼠左后掌的底面置于用水湿润的56℃热板上20秒并通过将84g砝码施加至背面来维持稳定接触(根据Nozaki-Taguchi&Yaksh,Neurosci.Lett.1998,254,25-28)。
轻度热损伤导致左后掌机械痛敏。机械(触觉)痛敏可通过测定受影响脚掌撤离施加的梯度刺激(范围为0.41至15.8g的von Frey丝)的中间阈值来评估,该刺激是穿过丝网观察笼垂直施加,力量足以使vonFrey丝稍微弯曲并抵在第三和第四趾表面近端一半处保持2-3秒。在除去刺激的过程中或在除去刺激物后立即缩回脚掌被认为是阳性反应。撤足阈值(PWT)可通过连续增加和减小刺激强度并用所描述的Dixonup-down方法(Chaplan等人,J.Neurosci.1994,53,55-63)的改进方法分析缩回数据而测得。大鼠只有在其PWT基线是3.1623g或更低(取对数为4.5)时才能包含在研究中。
测试大鼠在轻度热损伤前的伤前阈值并再次测试在产生了机械痛敏后的基线阈值。在测量基线后立即经口施用试验化合物或赋形剂,并且在施用0.5小时后重新进行测量。将触觉阈值(对数值)转换成最大可能效果的百分比(%MPE):%MPE=[阈值(t)-阈值(基线)]100/[阈值(伤前)-阈值(基线)],其中t=处理后的时间。数据表示为平均值±平均值的标准误差(S.E.M.)。统计分析采用双向ANOVA完成,重复测量的显著水平为p<0.05。
在该测定中所试验的化合物的结果在表2中示出,该结果为获得的结果的平均值。所试验的化合物为游离碱、盐酸盐和/或三氟乙酸盐形式。
表2
实例 | 口服剂量 | %MPE |
36 | 20mg/Kg | 38+/-13 |
46 | 6mg/Kg | 0 |
58 | 20mg/Kg | 52+/-7 |
109 | 10mg/Kg | 0 |
245 | 10mg/Kg | 36+/-10 |
246 | 20mg/Kg | 32+/-3 |
虽然已经结合了示例性实施例和优选实施例来对本发明进行说明,但应当理解,本发明无意于受限于上述具体描述,而是受按照专利法原则正确解释的所附权利要求书限定。
Claims (51)
1.一种式(I)化合物或所述化合物的可药用盐、可药用前药或药学活性代谢物:
其中:
Ar1是苯并[d]异噁唑-3-基、6-氟苯并[d]异噁唑-3-基、3-苯基-[1,2,4]噻二唑-5-基、1H-四唑-5-基、苯并[1,2,5]噻二唑-4-基、苯并[1,2,5]噁二唑-4-基、噻吩-2-基、噻吩-3-基、6-氯-哒嗪-3-基、吡嗪-2-基、异噁唑-3-基、1H-苯并三唑-5-基、[1,5]萘啶-2-基、喹啉-2-基、苯并噻唑-6-基、喹啉-5-基、1H-吡唑-3-基、5-甲基吡嗪-2-基、3-氯吡嗪-2-基、哒嗪-3-基、6-甲氧基哒嗪-3-基、5-甲基异噁唑-3-基、1,5-二甲基-1H-吡唑-3-基、4-溴-1-甲基-1H-吡唑-3-基、2-乙基-2H-吡唑-3-基、5-甲基-1H-吡唑-3-基或5-苯基-1H-吡唑-3-基;
Z是-N-或>CH;并且
Ar2是:
(i)未被Ra部分取代或被一个或两个Ra部分取代的苯基;
其中每个Ra部分独立地是-C1-4烷基、-C≡C-Rd、-OC1-4烷基、卤素、-CF3、-OCF3、-OCH2CF3、-SCF3、-S(O)0-2C1-4烷基、-SO2CF3、-OSO2C1-4烷基、-(CH2)0-1CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(O)NRbRc、-NO2或-(CH2)0-1CN;
或者两个相邻的Ra部分合在一起形成-O(CH2)1-2O-或-OCF2O-;
其中Rb和Rc各自独立地是-H或-C1-4烷基;并且
Rd是H、C3-6环烷基或-CH2NReRf;
其中Re和Rf各自独立地是H或C1-4烷基;
(ii)在3-位置或4-位置处被-L-Ar3取代、未被Ra取代或被Ra取代的苯基,其中:
L是选自由以下连接基组成的组的连接基:-(CH2)1-3-、-CH=CH-、-O-、-OCH2-、-CH2O-、-NH-、>NC1-4烷基、-S-、-C≡C-、-C(=O)-和共价键;并且
Ar3是:
(a)苯基;
(b)萘基;或
(c)单环杂芳基或双环杂芳基;或
(iii)9元或10元稠合双环杂芳基;
其中当Ar1为6-氯-哒嗪-3-基、异噁唑-3-基或1H-吡唑-3-基时,则Ar2不是苯并[1,3]二氧杂环戊烯-5-基或2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基。
2.根据权利要求1所述的化合物或可药用盐,其中Ar1是苯并[d]异噁唑-3-基、6-氟苯并[d]异噁唑-3-基、苯并[1,2,5]噻二唑-4-基、苯并[1,2,5]噁二唑-4-基、6-氯-哒嗪-3-基、吡嗪-2-基、异噁唑-3-基、1H-苯并三唑-5-基、苯并噻唑-6-基或1H-吡唑-3-基。
3.根据权利要求1所述的化合物或可药用盐,其中Ar1是苯并[d]异噁唑-3-基。
4.根据权利要求1所述的化合物或可药用盐,其中Ar1是吡嗪-2-基。
5.根据权利要求1所述的化合物或可药用盐,其中Ar1是异噁唑-3-基。
6.根据权利要求1所述的化合物或可药用盐,其中Ar1是哒嗪-3-基。
7.根据权利要求1所述的化合物或可药用盐,其中Z是-N-。
8.根据权利要求1所述的化合物或可药用盐,其中Z是>CH。
9.根据权利要求1所述的化合物或可药用盐,其中Ar2是苯基,所述苯基被一个或两个Ra部分取代。
10.根据权利要求9所述的化合物或可药用盐,其中每个Ra部分独立地选自由以下基团组成的组:氯、氰基、异丁基、甲硫基、甲磺酰基、三氟甲基、三氟甲氧基、2,2,2-三氟乙氧基、氟、甲基、甲氧基、叔丁基、溴、甲氧羰基、氰甲基、甲氧羰基甲基、三氟甲烷磺酰基、三氟甲硫基和丁基;或者两个相邻的Ra部分合在一起形成-OCH2O-或-OCF2O-。
11.根据权利要求1所述的化合物或可药用盐,其中Ar2是在3-位置或4-位置处被-L-Ar3取代、未被Ra部分取代或被一个或两个Ra部分取代的苯基。
12.根据权利要求11所述的化合物或可药用盐,其中L是-CH2CH2-、-O-、-OCH2-或-C≡C-。
13.根据权利要求11所述的化合物或可药用盐,其中Ar3是苯基。
14.根据权利要求13所述的化合物或可药用盐,其中每个Ra部分独立地选自由以下基团组成的组:氯、氰基、异丁基、甲硫基、甲磺酰基、三氟甲基、三氟甲氧基、2,2,2-三氟乙氧基、氟、甲基、甲氧基、叔丁基、溴、甲氧羰基、氰甲基、甲氧羰基甲基、三氟甲烷磺酰基、三氟甲硫基和丁基;或者两个相邻的Ra部分合在一起形成-OCH2O-或-OCF2O-。
15.根据权利要求11所述的化合物或可药用盐,其中Ar3是萘基。
16.根据权利要求11所述的化合物或可药用盐,其中Ar3是单环杂芳基或双环杂芳基。
17.根据权利要求16所述的化合物或可药用盐,其中Ar3是噻吩基、嘧啶基、吡啶基、吡嗪基或喹啉基。
18.根据权利要求1所述的化合物或可药用盐,其中Ar2是9元或10元稠合双环杂芳基。
19.根据权利要求18所述的化合物或可药用盐,其中Ar2是苯并咪唑基、吲唑基、苯并噻吩基、喹啉基、吲哚基或苯并呋喃基。
20.一种式(Ia)化合物或所述化合物的可药用盐、可药用前药或药学活性代谢物:
其中:
Ar1是苯并[d]异噁唑-3-基、6-氟苯并[d]异噁唑-3-基、3-苯基-[1,2,4]噻二唑-5-基、1H-四唑-5-基、苯并[1,2,5]噻二唑-4-基、苯并[1,2,5]噁二唑-4-基、噻吩-2-基、噻吩-3-基、6-氯-哒嗪-3-基、吡嗪-2-基、异噁唑-3-基、1H-苯并三唑-5-基、[1,5]萘啶-2-基、喹啉-2-基、苯并噻唑-6-基、喹啉-5-基或1H-吡唑-3-基;
Z是-N-或>CH;并且
Ar2是:
(i)被一个或两个Ra部分取代的苯基或3-苯氧基苯基;
其中每个Ra部分独立地是-C1-4烷基、-OC1-4烷基、卤素、-CF3、-OCF3、-OCH2CF3、-SCF3、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(O)NRbRc、-NO2或-CN;
其中Rb和Rc各自独立地是-H或-C1-4烷基;或者
(ii)苯并[1,3]二氧杂环戊烯-5-基、2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基或萘基;
其中当Ar1是6-氯-哒嗪-3-基、异噁唑-3-基或1H-吡唑-3-基时,则Ar2不是苯并[1,3]二氧杂环戊烯-5-基或2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基。
21.根据权利要求20所述的化合物或可药用盐,其中Ar1是苯并[d]异噁唑-3-基、6-氟苯并[d]异噁唑-3-基、苯并[1,2,5]噻二唑-4-基、苯并[1,2,5]噁二唑-4-基、6-氯-哒嗪-3-基、吡嗪-2-基、异噁唑-3-基、1H-苯并三唑-5-基、苯并噻唑-6-基或1H-吡唑-3-基。
22.根据权利要求20所述的化合物或可药用盐,其中Ar1是苯并[d]异噁唑-3-基。
23.根据权利要求20所述的化合物或可药用盐,其中Ar1是吡嗪-2-基。
24.根据权利要求20所述的化合物或可药用盐,其中Ar1是异噁唑-3-基。
25.根据权利要求20所述的化合物或可药用盐,其中Ar1是哒嗪-3-基。
26.根据权利要求20所述的化合物或可药用盐,其中Ar2是被一个或两个Ra部分取代的3-苯氧基苯基,所述Ra部分独立地选自由以下部分组成的组:氟、氯、溴、-CF3、-OCF3和-OCH2CF3。
27.根据权利要求20所述的化合物或可药用盐,其中Ar2是萘基。
28.一种化合物或可药用盐,所述化合物或可药用盐选自由以下化合物及其可药用盐组成的组:
4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸(3-苯基-[1,2,4]噻二唑-5-基)-酰胺;
4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸(1H-四唑-5-基)-酰胺;
4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸苯并[1,2,5]噻二唑-4-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸苯并[1,2,5]噁二唑-4-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸(3H-苯并三唑-5-基)-酰胺;
4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸噻吩-2-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸噻吩-3-基酰胺;
4-萘-2-基甲基-哌啶-1-羧酸(6-氯-哒嗪-3-基)-酰胺;
4-萘-2-基甲基-哌啶-1-羧酸吡嗪-2-基酰胺;
4-萘-2-基甲基-哌啶-1-羧酸异噁唑-3-基酰胺;
4-萘-2-基甲基-哌啶-1-羧酸(3-苯基-[1,2,4]噻二唑-5-基)-酰胺;
4-萘-2-基甲基-哌啶-1-羧酸(1H-四唑-5-基)-酰胺;
4-萘-2-基甲基-哌啶-1-羧酸(2H-吡唑-3-基)-酰胺;
4-萘-2-基甲基-哌啶-1-羧酸苯并[1,2,5]噁二唑-4-基酰胺;
4-萘-2-基甲基-哌啶-1-羧酸(1H-苯并三唑-5-基)-酰胺;
4-萘-2-基甲基-哌啶-1-羧酸[1,5]萘啶-2-基酰胺;
4-萘-2-基甲基-哌啶-1-羧酸喹啉-2-基酰胺;
4-萘-2-基甲基-哌啶-1-羧酸苯并噻唑-6-基酰胺;
4-萘-2-基甲基-哌啶-1-羧酸喹啉-5-基酰胺;
4-萘-2-基甲基-哌啶-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-(4-氟-苄基)-哌啶-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-(4-氟-苄基)-哌啶-1-羧酸(6-氯-哒嗪-3-基)-酰胺;
4-(4-氟-苄基)-哌啶-1-羧酸异噁唑-3-基酰胺;
4-(3-三氟甲基-苄基)-哌啶-1-羧酸(6-氯-哒嗪-3-基)-酰胺;
4-(3-三氟甲基-苄基)-哌啶-1-羧酸异噁唑-3-基酰胺;
4-(3-三氟甲基-苄基)-哌啶-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-氟-3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(3-三氟甲氧基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-三氟甲氧基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(3-溴-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-溴-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(3,4-二氟-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(3,5-二氟-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-{3-[4-(2,2,2-三氟-乙氧基)-苯氧基]-苄基}-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸苯并[1,2,5]噻二唑-4-基酰胺;
4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯并[1,2,5]噻二唑-4-基酰胺;
4-[3-(3,5-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯并[1,2,5]噻二唑-4-基酰胺;
4-[3-(3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[1,2,5]噻二唑-4-基酰胺;
4-(3-三氟甲氧基-苄基)-哌嗪-1-羧酸苯并[1,2,5]噻二唑-4-基酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(6-氯-哒嗪-3-基)-酰胺;
4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸(6-氯-哒嗪-3-基)-酰胺;
4-[3-(3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸(6-氯-哒嗪-3-基)-酰胺;
4-(4-氟-3-苯氧基-苄基)-哌嗪-1-羧酸(6-氯-哒嗪-3-基)-酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-[3-(3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-(4-氟-3-苯氧基-苄基)-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-(3-三氟甲氧基-苄基)-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(1H-吡唑-3-基)-酰胺;
4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸(1H-吡唑-3-基)-酰胺;
4-[3-(3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸(1H-吡唑-3-基)-酰胺;
4-(4-氟-3-苯氧基-苄基)-哌嗪-1-羧酸(1H-吡唑-3-基)-酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(1H-四唑-5-基)-酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸吡嗪-2-基酰胺;
4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸吡嗪-2-基酰胺;
4-[3-(3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸吡嗪-2-基酰胺;以及
4-(3-三氟甲氧基-苄基)-哌嗪-1-羧酸吡嗪-2-基酰胺。
29.一种化合物或可药用盐,所述化合物或可药用盐选自由以下化合物及其可药用盐组成的组:
N-1,2-苯并异噁唑-3-基-4-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)甲基]哌啶-1-甲酰胺;
4-(3-邻甲苯基乙炔基-苄基)-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
N-1,2-苯并异噁唑-3-基-4-(3-{[2-(三氟甲基)-苯基]-乙炔基}苄基)-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2-甲氧苯基)-乙炔基]-苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2-氟代苯基)乙炔基]-苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2-溴代苯基)-乙炔基]苄基}-哌嗪-1-甲酰胺;
4-(3-乙炔基-苄基)-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[3-(二甲基氨基)丙-1-炔-1-基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(环己基乙炔基)苄基]-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(环戊基乙炔基)苄基]-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2-氯苯基)-乙炔基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(3-氯苯基)乙炔基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(4-氯苯基)乙炔基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(3,4-二氯苯基)乙炔基]-苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(环丙基乙炔基)苄基]-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(噻吩-3-基乙炔基)苄基]-哌嗪-1-甲酰胺;
4-{3-[(2-氯苯基)乙炔基]苄基}-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-{3-[(2-氯苯基)乙炔基]苄基}-N-哒嗪-3-基哌嗪-1-甲酰胺;
4-{3-[(2-氯苯基)乙炔基]苄基}-N-(5-甲基吡嗪-2-基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2,4-二氯苯基)-乙炔基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(3-{[2-(三氟甲氧基)苯基]-乙炔基}苄基)-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(3,5-二氯苯基)乙炔基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2,5-二氯苯基)乙炔基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2-氰基苯基)乙炔基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(萘-1-基乙炔基)苄基]哌嗪-1-甲酰胺;
2-[(3-{[4-(1,2-苯并异噁唑-3-基氨基甲酰基)哌嗪-1-基]甲基}苯基)乙炔基]苯甲酸甲酯;
N-1,2-苯并异噁唑-3-基-4-{3-[(3-氰基苯基)乙炔基]苄基}哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(1,3-苯并二氧杂环戊烯-5-基乙炔基)苄基]-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2,3-二氯苯基)乙炔基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2-氰基-3-氟代苯基)乙炔基]-苄基}哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(3-{[2-(氰甲基)苯基]乙炔基}-苄基)哌嗪-1-甲酰胺;
{2-[(3-{[4-(1,2-苯并异噁唑-3-基氨基甲酰基)哌嗪-1-基]甲基}苯基)乙炔基]苯基}乙酸甲酯;
4-[3-(2-邻甲苯基-乙基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(嘧啶-2-基氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(吡啶-2-基氧基)苄基]哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(吡嗪-2-基氧基)苄基]哌嗪-1-甲酰胺;
4-[3-(2-氰基-苄氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(苄氧基)苄基]哌嗪-1-甲酰胺;
4-(1H-苯并咪唑-6-基甲基)-N-1,2-苯并异噁唑-3-基哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(1H-吲唑-6-基甲基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[4-(甲磺酰基)苄基]哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[4-(三氟甲氧基)苄基]哌嗪-1-甲酰胺;
4-[3-(4-氯苯氧基)苄基]-N-(6-甲氧基哒嗪-3-基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[4-氯-3-(三氟甲氧基)苄基]-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[4-氟-3-(三氟甲氧基)苄基]-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-氯-4-(三氟甲氧基)苄基]-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-氟-4-(三氟甲氧基)苄基]-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[4-(三氟甲基)苯氧基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(3-苯氧基苄基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(3,4-二氯苄基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[4-(苄氧基)苄基]哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(1-苯并噻吩-2-基甲基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(喹啉-6-基氧基)苄基]哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(4-溴-3-氟苄基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(1,3-苯并二氧杂环戊烯-5-基甲基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(喹啉-3-基甲基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(1H-吲哚-5-基甲基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(萘-2-基氧基)苄基]哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(4-溴苄基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(3,4-二溴苄基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(2-氯苯氧基)苄基]哌嗪-1-甲酰胺;
4-萘-2-基甲基-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-喹啉-2-基甲基-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-氰基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-苯并呋喃-2-基甲基-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(3-氯苯氧基)苄基]哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[4-氰基-3-(三氟甲基)苯氧基]苄基}哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(3-氰基苯氧基)苄基]哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(3-{4-[(三氟甲基)硫基]苯氧基}-苄基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)氧基]苄基}哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(3-{4-[(三氟甲基)磺酰基]苯氧基}-苄基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{[3-(苯基乙炔基)苯基]甲基}哌嗪-1-甲酰胺;
N-异噁唑-3-基-4-{3-[4-(三氟甲氧基)苯氧基]苄基}哌嗪-1-甲酰胺;
4-[4-(苄氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-[3-(3-氯苯氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺;
N-异噁唑-3-基-4-{3-[4-(2,2,2-三氟乙氧基)苯氧基]苄基}哌嗪-1-甲酰胺;
4-(1-苯并呋喃-2-基甲基)-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-[3-(3-氰基苯氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-[3-(2-氯苯氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-{3-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)氧基]苄基}-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-(1-苯并噻吩-2-基甲基)-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-(1,3-苯并二氧杂环戊烯-5-基甲基)-N-异噁唑-3-基哌嗪-1-甲酰胺;
N-异噁唑-3-基-4-(萘-2-基甲基)哌嗪-1-甲酰胺;
4-[3-(4-溴苯氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-喹啉-2-基甲基-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-(4-溴-苄基)-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-(1H-吲哚-6-基甲基)-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-[3-(萘-2-基氧基)-苄基]-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-(4-溴-3-氟-苄基)-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-[3-(4-氰基-苯氧基)-苄基]-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-[3-(3,4-二氟苯氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-(3,4-二溴苄基)-N-异噁唑-3-基哌嗪-1-甲酰胺;
N-异噁唑-3-基-4-(3-{4-[(三氟甲基)硫基]苯氧基}苄基)-哌嗪-1-甲酰胺;
4-{3-[4-氟-3-(三氟甲基)苯氧基]苄基}-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-[3-(3-溴苯氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺;
N-异噁唑-3-基-4-(3-{4-[(三氟甲基)磺酰基]苯氧基}苄基)-哌嗪-1-甲酰胺;
N-异噁唑-3-基-4-{3-[3-(三氟甲氧基)苯氧基]苄基}哌嗪-1-甲酰胺;
4-(3,4-二氯苄基)-N-异噁唑-3-基哌嗪-1-甲酰胺;
N-异噁唑-3-基-4-{3-[4-(三氟甲基)苯氧基]苄基}哌嗪-1-甲酰胺;
N-异噁唑-3-基-4-[3-(喹啉-6-基氧基)苄基]哌嗪-1-甲酰胺;
4-{3-[4-氰基-3-(三氟甲基)苯氧基]苄基}-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-[3-(4-氯苯氧基)苄基]-N-(5-甲基异噁唑-3-基)哌嗪-1-甲酰胺;
4-(喹啉-3-基甲基)-N-1H-四唑-5-基哌嗪-1-甲酰胺;
4-[3-(萘-2-基氧基)苄基]-N-1H-四唑-5-基哌嗪-1-甲酰胺;
4-(3,4-二溴苄基)-N-1H-四唑-5-基哌嗪-1-甲酰胺;
4-(4-溴-3-氟苄基)-N-1H-四唑-5-基哌嗪-1-甲酰胺;
4-[3-(3,4-二氟苯氧基)苄基]-N-1H-四唑-5-基哌嗪-1-甲酰胺;
4-{3-[4-氰基-3-(三氟甲基)苯氧基]苄基}-N-1H-四唑-5-基哌嗪-1-甲酰胺;
N-1H-四唑-5-基-4-{3-[4-(三氟甲基)苯氧基]苄基}哌嗪-1-甲酰胺;
N-1H-四唑-5-基-4-(3-{4-[(三氟甲基)硫基]苯氧基}苄基)-哌嗪-1-甲酰胺;
N-1H-四唑-5-基-4-{3-[3-(三氟甲氧基)苯氧基]苄基}哌嗪-1-甲酰胺;
4-[3-(3,4-二氯苯氧基)苄基]-N-1H-四唑-5-基哌嗪-1-甲酰胺;
4-(喹啉-2-基甲基)-N-1H-四唑-5-基哌嗪-1-甲酰胺;
4-(萘-2-基甲基)-N-1H-四唑-5-基哌嗪-1-甲酰胺;
4-(4-溴-苄基)-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺;
4-(1H-吲哚-6-基甲基)-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺;
4-(3-苄氧基-苄基)-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺;
4-苯并[1,3]二氧杂环戊烯-5-基甲基-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺;
4-(3-苯氧基-苄基)-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺;
4-(3,4-二氯-苄基)-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺;
4-苯并[b]噻吩-2-基甲基-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺;
4-[3-(3-氰基-苯氧基)-苄基]-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺;
4-{3-[4-氟-3-(三氟甲基)苯氧基]苄基}-N-2H-四唑-5-基哌嗪-1-甲酰胺;
N-2H-四唑-5-基-4-{3-[3-(三氟甲基)苯氧基]苄基}哌嗪-1-甲酰胺;
4-[3-(4-氰基苯氧基)苄基]-N-2H-四唑-5-基哌嗪-1-甲酰胺;
N-2H-四唑-5-基-4-{3-[4-(2,2,2-三氟乙氧基)苯氧基]苄基}-哌嗪-1-甲酰胺;
4-{3-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)氧基]苄基}-N-2H-四唑-5-基哌嗪-1-甲酰胺;
4-[3-(2-氯苯氧基)苄基]-N-2H-四唑-5-基哌嗪-1-甲酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(1,5-二甲基-1H-吡唑-3-基)-酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(4-溴-1-甲基-1H-吡唑-3-基)-酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(2-乙基-2H-吡唑-3-基)-酰胺;
4-[3-(4-氯苯氧基)苄基]-N-(5-甲基-1H-吡唑-3-基)哌嗪-1-甲酰胺;
4-(3,4-二溴苄基)-N-哒嗪-3-基哌嗪-1-甲酰胺;
4-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)甲基]-N-哒嗪-3-基哌嗪-1-甲酰胺;
N-哒嗪-3-基-4-(喹啉-3-基甲基)哌嗪-1-甲酰胺;
N-哒嗪-3-基-4-(喹啉-2-基甲基)哌嗪-1-甲酰胺;
4-(3,4-二氯苄基)-N-哒嗪-3-基哌嗪-1-甲酰胺;
4-(萘-2-基甲基)-N-哒嗪-3-基哌嗪-1-甲酰胺;
4-(1H-吲哚-5-基甲基)-N-哒嗪-3-基哌嗪-1-甲酰胺;
N-2,1,3-苯并噻二唑-4-基-4-{[3-(苯基乙炔基)苯基]甲基}-哌嗪-1-甲酰胺;
N-2,1,3-苯并噁二唑-4-基-4-{[3-(苯基乙炔基)苯基]甲基}-哌嗪-1-甲酰胺;
4-[3-(3-氯-4-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-氯-3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-氯-3-氟-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(3-氯-4-氟-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-氟-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-丁基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)甲基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-(1,3-苯并二氧杂环戊烯-5-基甲基)-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-(4-溴苄基)-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-(萘-2-基甲基)-N-吡嗪-2-基哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-{3-[4-(2,2,2-三氟乙氧基)苯氧基]苄基}-哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-{3-[4-(三氟甲基)苯氧基]苄基}哌嗪-1-甲酰胺;
4-(1H-吲哚-5-基甲基)-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-(3,4-二溴苄基)-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-(1-苯并噻吩-2-基甲基)-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-[4-(苄氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-(3,4-二氯苄基)-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-[3-(4-溴苯氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-(4-溴-3-氟苄基)-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-[3-(苄氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-(喹啉-3-基甲基)哌嗪-1-甲酰胺;
4-[3-(3-氯苯氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-(3-{4-[(三氟甲基)磺酰基]苯氧基}苄基)-哌嗪-1-甲酰胺;
4-(3-苯氧基-苄基)-哌嗪-1-羧酸吡嗪-2-基酰胺;
4-[3-(萘-2-基氧基)-苄基]-哌嗪-1-羧酸吡嗪-2-基酰胺;
4-[3-(4-氰基-苯氧基)-苄基]-哌嗪-1-羧酸吡嗪-2-基酰胺;
4-苯并呋喃-2-基甲基-哌嗪-1-羧酸吡嗪-2-基酰胺;
4-[3-(3,4-二氟苯氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-[3-(喹啉-6-基氧基)苄基]哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-{3-[4-(三氟甲氧基)苯氧基]苄基}哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-(3-{4-[(三氟甲基)硫基]苯氧基}苄基)-哌嗪-1-甲酰胺;
4-[3-(3-氰基苯氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-{3-[4-氰基-3-(三氟甲基)苯氧基]苄基}-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-{3-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)氧基]苄基}-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-[3-(2-氯苯氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-(喹啉-2-基甲基)哌嗪-1-甲酰胺;
4-[3-(3-溴苯氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-{3-[4-氟-3-(三氟甲基)苯氧基]苄基}-N-吡嗪-2-基哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-{3-[3-(三氟甲氧基)苯氧基]苄基}哌嗪-1-甲酰胺;
4-[3-(4-氯苯氧基)苄基]-N-(3-氯吡嗪-2-基)哌嗪-1-甲酰胺;
4-[3-(4-氯苯氧基)苄基]-N-(5-苯基-1H-吡唑-3-基)哌嗪-1-甲酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(6-氟-苯并[d]异噁唑-3-基)-酰胺;和
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸哒嗪-3-基酰胺;
30.一种用于治疗由FAAH活性介导的疾病、障碍或医学病症的药物组合物,所述药物组合物包含:
(a)有效量的至少一种活性剂,所述活性剂选自由以下化合物组成的组:
式(I)化合物以及所述式(I)化合物的可药用盐、可药用前药和药学活性代谢物:
其中:
Ar1是苯并[d]异噁唑-3-基、6-氟苯并[d]异噁唑-3-基、3-苯基-[1,2,4]噻二唑-5-基、1H-四唑-5-基、苯并[1,2,5]噻二唑-4-基、苯并[1,2,5]噁二唑-4-基、噻吩-2-基、噻吩-3-基、6-氯-哒嗪-3-基、吡嗪-2-基、异噁唑-3-基、1H-苯并三唑-5-基、[1,5]萘啶-2-基、喹啉-2-基、苯并噻唑-6-基、喹啉-5-基、1H-吡唑-3-基、5-甲基吡嗪-2-基、3-氯吡嗪-2-基、哒嗪-3-基、6-甲氧基哒嗪-3-基、5-甲基异噁唑-3-基、1,5-二甲基-1H-吡唑-3-基、4-溴-1-甲基-1H-吡唑-3-基、2-乙基-2H-吡唑-3-基、5-甲基-1H-吡唑-3-基或5-苯基-1H-吡唑-3-基;
Z是-N-或>CH;并且
Ar2是:
(i)未被Ra部分取代或被一个或两个Ra部分取代的苯基;
其中每个Ra部分独立地是-C1-4烷基、-C≡C-Rd、-OC1-4烷基、卤素、-CF3、-OCF3、-OCH2CF3、-SCF3、-S(O)0-2C1-4烷基、-SO2CF3、-OSO2C1-4烷基、-(CH2)0-1CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(O)NRbRc、-NO2或-(CH2)0-1CN;
或者两个相邻的Ra部分合在一起形成-O(CH2)1-2O-或-OCF2O-;
其中Rb和Rc各自独立地是-H或-C1-4烷基;并且
Rd是H、C3-6环烷基或-CH2NReRf;
其中Re和Rf各自独立地是H或C1-4烷基;
(ii)在3-位置或4-位置处被-L-Ar3取代、未被Ra部分取代或被一个或两个Ra部分取代的苯基,其中:
L是选自由以下连接基组成的组的连接基:-(CH2)1-3-、-CH=CH-、-O-、-OCH2-、-CH2O-、-NH-、>NC1-4烷基、-S-、-C≡C-、-C(=O)-和共价键;并且
Ar3是:
(a)苯基;
(b)萘基;或
(c)单环杂芳基或双环杂芳基;或
(iii)9元或10元稠合双环杂芳基;
其中当Ar1为6-氯-哒嗪-3-基、异噁唑-3-基或1H-吡唑-3-基时,则Ar2不是苯并[1,3]二氧杂环戊烯-5-基或2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基;
和
(b)可药用赋形剂。
31.根据权利要求30所述的药物组合物,其中所述活性剂选自由以下化合物及其可药用盐组成的组:
N-1,2-苯并异噁唑-3-基-4-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)甲基]哌啶-1-甲酰胺;
4-(3-邻甲苯基乙炔基-苄基)-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
N-1,2-苯并异噁唑-3-基-4-(3-{[2-(三氟甲基)-苯基]-乙炔基}苄基)-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2-甲氧苯基)-乙炔基]-苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2-氟代苯基)乙炔基]-苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2-溴代苯基)-乙炔基]苄基}-哌嗪-1-甲酰胺;
4-(3-乙炔基-苄基)-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[3-(二甲基氨基)丙-1-炔-1-基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(环己基乙炔基)苄基]-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(环戊基乙炔基)苄基]-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2-氯苯基)-乙炔基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(3-氯苯基)乙炔基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(4-氯苯基)乙炔基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(3,4-二氯苯基)乙炔基]-苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(环丙基乙炔基)苄基]-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(噻吩-3-基乙炔基)苄基]-哌嗪-1-甲酰胺;
4-{3-[(2-氯苯基)乙炔基]苄基}-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-{3-[(2-氯苯基)乙炔基]苄基}-N-哒嗪-3-基哌嗪-1-甲酰胺;
4-{3-[(2-氯苯基)乙炔基]苄基}-N-(5-甲基吡嗪-2-基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2,4-二氯苯基)-乙炔基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(3-{[2-(三氟甲氧基)苯基]-乙炔基}苄基)-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(3,5-二氯苯基)乙炔基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2,5-二氯苯基)乙炔基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2-氰基苯基)乙炔基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(萘-1-基乙炔基)苄基]哌嗪-1-甲酰胺;
2-[(3-{[4-(1,2-苯并异噁唑-3-基氨基甲酰基)哌嗪-1-基]甲基}苯基)乙炔基]苯甲酸甲酯;
N-1,2-苯并异噁唑-3-基-4-{3-[(3-氰基苯基)乙炔基]苄基}哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(1,3-苯并二氧杂环戊烯-5-基乙炔基)苄基]-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2,3-二氯苯基)乙炔基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2-氰基-3-氟代苯基)乙炔基]-苄基}哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(3-{[2-(氰甲基)苯基]乙炔基}-苄基)哌嗪-1-甲酰胺;
{2-[(3-{[4-(1,2-苯并异噁唑-3-基氨基甲酰基)哌嗪-1-基]甲基}苯基)乙炔基]苯基}乙酸甲酯;
4-[3-(2-邻甲苯基-乙基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(嘧啶-2-基氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(吡啶-2-基氧基)苄基]哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(吡嗪-2-基氧基)苄基]哌嗪-1-甲酰胺;
4-[3-(2-氰基-苄氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(苄氧基)苄基]哌嗪-1-甲酰胺;
4-(1H-苯并咪唑-6-基甲基)-N-1,2-苯并异噁唑-3-基哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(1H-吲唑-6-基甲基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[4-(甲磺酰基)苄基]哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[4-(三氟甲氧基)苄基]哌嗪-1-甲酰胺;
4-[3-(4-氯苯氧基)苄基]-N-(6-甲氧基哒嗪-3-基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[4-氯-3-(三氟甲氧基)苄基]-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[4-氟-3-(三氟甲氧基)苄基]-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-氯-4-(三氟甲氧基)苄基]-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-氟-4-(三氟甲氧基)苄基]-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[4-(三氟甲基)苯氧基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(3-苯氧基苄基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(3,4-二氯苄基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[4-(苄氧基)苄基]哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(1-苯并噻吩-2-基甲基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(喹啉-6-基氧基)苄基]哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(4-溴-3-氟苄基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(1,3-苯并二氧杂环戊烯-5-基甲基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(喹啉-3-基甲基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(1H-吲哚-5-基甲基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(萘-2-基氧基)苄基]哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(4-溴苄基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(3,4-二溴苄基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(2-氯苯氧基)苄基]哌嗪-1-甲酰胺;
4-萘-2-基甲基-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-喹啉-2-基甲基-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-氰基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-苯并呋喃-2-基甲基-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(3-氯苯氧基)苄基]哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[4-氰基-3-(三氟甲基)苯氧基]苄基}哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(3-氰基苯氧基)苄基]哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(3-{4-[(三氟甲基)硫基]苯氧基}-苄基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)氧基]苄基}哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(3-{4-[(三氟甲基)磺酰基]苯氧基}-苄基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{[3-(苯基乙炔基)苯基]甲基}哌嗪-1-甲酰胺;
N-异噁唑-3-基-4-{3-[4-(三氟甲氧基)苯氧基]苄基}哌嗪-1-甲酰胺;
4-[4-(苄氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-[3-(3-氯苯氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺;
N-异噁唑-3-基-4-{3-[4-(2,2,2-三氟乙氧基)苯氧基]苄基}哌嗪-1-甲酰胺;
4-(1-苯并呋喃-2-基甲基)-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-[3-(3-氰基苯氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-[3-(2-氯苯氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-{3-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)氧基]苄基}-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-(1-苯并噻吩-2-基甲基)-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-(1,3-苯并二氧杂环戊烯-5-基甲基)-N-异噁唑-3-基哌嗪-1-甲酰胺;
N-异噁唑-3-基-4-(萘-2-基甲基)哌嗪-1-甲酰胺;
4-[3-(4-溴苯氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-喹啉-2-基甲基-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-(4-溴-苄基)-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-(1H-吲哚-6-基甲基)-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-[3-(萘-2-基氧基)-苄基]-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-(4-溴-3-氟-苄基)-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-[3-(4-氰基-苯氧基)-苄基]-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-[3-(3,4-二氟苯氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-(3,4-二溴苄基)-N-异噁唑-3-基哌嗪-1-甲酰胺;
N-异噁唑-3-基-4-(3-{4-[(三氟甲基)硫基]苯氧基}苄基)-哌嗪-1-甲酰胺;
4-{3-[4-氟-3-(三氟甲基)苯氧基]苄基}-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-[3-(3-溴苯氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺;
N-异噁唑-3-基-4-(3-{4-[(三氟甲基)磺酰基]苯氧基}苄基)-哌嗪-1-甲酰胺;
N-异噁唑-3-基-4-{3-[3-(三氟甲氧基)苯氧基]苄基}哌嗪-1-甲酰胺;
4-(3,4-二氯苄基)-N-异噁唑-3-基哌嗪-1-甲酰胺;
N-异噁唑-3-基-4-{3-[4-(三氟甲基)苯氧基]苄基}哌嗪-1-甲酰胺;
N-异噁唑-3-基-4-[3-(喹啉-6-基氧基)苄基]哌嗪-1-甲酰胺;
4-{3-[4-氰基-3-(三氟甲基)苯氧基]苄基}-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-[3-(4-氯苯氧基)苄基]-N-(5-甲基异噁唑-3-基)哌嗪-1-甲酰胺;
4-(喹啉-3-基甲基)-N-1H-四唑-5-基哌嗪-1-甲酰胺;
4-[3-(萘-2-基氧基)苄基]-N-1H-四唑-5-基哌嗪-1-甲酰胺;
4-(3,4-二溴苄基)-N-1H-四唑-5-基哌嗪-1-甲酰胺;
4-(4-溴-3-氟苄基)-N-1H-四唑-5-基哌嗪-1-甲酰胺;
4-[3-(3,4-二氟苯氧基)苄基]-N-1H-四唑-5-基哌嗪-1-甲酰胺;
4-{3-[4-氰基-3-(三氟甲基)苯氧基]苄基}-N-1H-四唑-5-基哌嗪-1-甲酰胺;
N-1H-四唑-5-基-4-{3-[4-(三氟甲基)苯氧基]苄基}哌嗪-1-甲酰胺;
N-1H-四唑-5-基-4-(3-{4-[(三氟甲基)硫基]苯氧基}苄基)-哌嗪-1-甲酰胺;
N-1H-四唑-5-基-4-{3-[3-(三氟甲氧基)苯氧基]苄基}哌嗪-1-甲酰胺;
4-[3-(3,4-二氯苯氧基)苄基]-N-1H-四唑-5-基哌嗪-1-甲酰胺;
4-(喹啉-2-基甲基)-N-1H-四唑-5-基哌嗪-1-甲酰胺;
4-(萘-2-基甲基)-N-1H-四唑-5-基哌嗪-1-甲酰胺;
4-(4-溴-苄基)-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺;
4-(1H-吲哚-6-基甲基)-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺;
4-(3-苄氧基-苄基)-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺;
4-苯并[1,3]二氧杂环戊烯-5-基甲基-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺;
4-(3-苯氧基-苄基)-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺;
4-(3,4-二氯-苄基)-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺;
4-苯并[b]噻吩-2-基甲基-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺;
4-[3-(3-氰基-苯氧基)-苄基]-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺;
4-{3-[4-氟-3-(三氟甲基)苯氧基]苄基}-N-2H-四唑-5-基哌嗪-1-甲酰胺;
N-2H-四唑-5-基-4-{3-[3-(三氟甲基)苯氧基]苄基}哌嗪-1-甲酰胺;
4-[3-(4-氰基苯氧基)苄基]-N-2H-四唑-5-基哌嗪-1-甲酰胺;
N-2H-四唑-5-基-4-{3-[4-(2,2,2-三氟乙氧基)苯氧基]苄基}-哌嗪-1-甲酰胺;
4-{3-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)氧基]苄基}-N-2H-四唑-5-基哌嗪-1-甲酰胺;
4-[3-(2-氯苯氧基)苄基]-N-2H-四唑-5-基哌嗪-1-甲酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(1,5-二甲基-1H-吡唑-3-基)-酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(4-溴-1-甲基-1H-吡唑-3-基)-酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(2-乙基-2H-吡唑-3-基)-酰胺;
4-[3-(4-氯苯氧基)苄基]-N-(5-甲基-1H-吡唑-3-基)哌嗪-1-甲酰胺;
4-(3,4-二溴苄基)-N-哒嗪-3-基哌嗪-1-甲酰胺;
4-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)甲基]-N-哒嗪-3-基哌嗪-1-甲酰胺;
N-哒嗪-3-基-4-(喹啉-3-基甲基)哌嗪-1-甲酰胺;
N-哒嗪-3-基-4-(喹啉-2-基甲基)哌嗪-1-甲酰胺;
4-(3,4-二氯苄基)-N-哒嗪-3-基哌嗪-1-甲酰胺;
4-(萘-2-基甲基)-N-哒嗪-3-基哌嗪-1-甲酰胺;
4-(1H-吲哚-5-基甲基)-N-哒嗪-3-基哌嗪-1-甲酰胺;
N-2,1,3-苯并噻二唑-4-基-4-{[3-(苯基乙炔基)苯基]甲基}-哌嗪-1-甲酰胺;
N-2,1,3-苯并噁二唑-4-基-4-{[3-(苯基乙炔基)苯基]甲基}-哌嗪-1-甲酰胺;
4-[3-(3-氯-4-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-氯-3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-氯-3-氟-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(3-氯-4-氟-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-氟-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-丁基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)甲基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-(1,3-苯并二氧杂环戊烯-5-基甲基)-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-(4-溴苄基)-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-(萘-2-基甲基)-N-吡嗪-2-基哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-{3-[4-(2,2,2-三氟乙氧基)苯氧基]苄基}-哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-{3-[4-(三氟甲基)苯氧基]苄基}哌嗪-1-甲酰胺;
4-(1H-吲哚-5-基甲基)-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-(3,4-二溴苄基)-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-(1-苯并噻吩-2-基甲基)-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-[4-(苄氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-(3,4-二氯苄基)-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-[3-(4-溴苯氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-(4-溴-3-氟苄基)-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-[3-(苄氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-(喹啉-3-基甲基)哌嗪-1-甲酰胺;
4-[3-(3-氯苯氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-(3-{4-[(三氟甲基)磺酰基]苯氧基}苄基)-哌嗪-1-甲酰胺;
4-(3-苯氧基-苄基)-哌嗪-1-羧酸吡嗪-2-基酰胺;
4-[3-(萘-2-基氧基)-苄基]-哌嗪-1-羧酸吡嗪-2-基酰胺;
4-[3-(4-氰基-苯氧基)-苄基]-哌嗪-1-羧酸吡嗪-2-基酰胺;
4-苯并呋喃-2-基甲基-哌嗪-1-羧酸吡嗪-2-基酰胺;
4-[3-(3,4-二氟苯氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-[3-(喹啉-6-基氧基)苄基]哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-{3-[4-(三氟甲氧基)苯氧基]苄基}哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-(3-{4-[(三氟甲基)硫基]苯氧基}苄基)-哌嗪-1-甲酰胺;
4-[3-(3-氰基苯氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-{3-[4-氰基-3-(三氟甲基)苯氧基]苄基}-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-{3-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)oxy]苄基}-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-[3-(2-氯苯氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-(喹啉-2-基甲基)哌嗪-1-甲酰胺;
4-[3-(3-溴苯氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-{3-[4-氟-3-(三氟甲基)苯氧基]苄基}-N-吡嗪-2-基哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-{3-[3-(三氟甲氧基)苯氧基]苄基}哌嗪-1-甲酰胺;
4-[3-(4-氯苯氧基)苄基]-N-(3-氯吡嗪-2-基)哌嗪-1-甲酰胺;
4-[3-(4-氯苯氧基)苄基]-N-(5-苯基-1H-吡唑-3-基)哌嗪-1-甲酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(6-氟-苯并[d]异噁唑-3-基)-酰胺;以及
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸哒嗪-3-基酰胺。
32.根据权利要求30所述的药物组合物,所述药物组合物还包含:选自由阿片和非甾体抗炎药组成的组的止痛药。
33.根据权利要求30所述的药物组合物,所述药物组合物还包含:选自由阿司匹林、对乙酰氨基酚、阿片、布洛芬、萘普生、COX-2抑制剂、加巴喷丁、普瑞巴林和曲马多组成的组的另外的活性成分。
34.一种用于治疗由FAAH活性介导的疾病、障碍或医学病症的药物组合物,所述药物组合物包含:
(a)有效量的至少一种活性剂,所述活性剂选自由以下化合物组成的组:
式(Ia)化合物以及所述式(Ia)化合物的可药用盐、可药用前药和药学活性代谢物:
其中:
Ar1是苯并[d]异噁唑-3-基、6-氟苯并[d]异噁唑-3-基、3-苯基-[1,2,4]噻二唑-5-基、1H-四唑-5-基、苯并[1,2,5]噻二唑-4-基、苯并[1,2,5]噁二唑-4-基、噻吩-2-基、噻吩-3-基、6-氯-哒嗪-3-基、吡嗪-2-基、异噁唑-3-基、1H-苯并三唑-5-基、[1,5]萘啶-2-基、喹啉-2-基、苯并噻唑-6-基、喹啉-5-基或1H-吡唑-3-基;
Z是-N-或>CH;并且
Ar2是:
(i)被一个或两个Ra部分取代的苯基或3-苯氧基苯基;
其中每个Ra部分独立地是-C1-4烷基、-OC1-4烷基、卤素、-CF3、-OCF3、-OCH2CF3、-SCF3、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(O)NRbRc、-NO2或-CN;
其中Rb和Rc各自独立地是-H或-C1-4烷基;或者
(ii)苯并[1,3]二氧杂环戊烯-5-基、2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基或萘基;
其中当Ar1为6-氯-哒嗪-3-基、异噁唑-3-基或1H-吡唑-3-基时,则Ar2不是苯并[1,3]二氧杂环戊烯-5-基或2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基;
和
(b)可药用赋形剂。
35.根据权利要求34所述的药物组合物,其中所述活性剂选自由以下化合物及其可药用盐组成的组:
4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸(3-苯基-[1,2,4]噻二唑-5-基)-酰胺;
4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸(1H-四唑-5-基)-酰胺;
4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸苯并[1,2,5]噻二唑-4-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸苯并[1,2,5]噁二唑-4-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸(3H-苯并三唑-5-基)-酰胺;
4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸噻吩-2-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸噻吩-3-基酰胺;
4-萘-2-基甲基-哌啶-1-羧酸(6-氯-哒嗪-3-基)-酰胺;
4-萘-2-基甲基-哌啶-1-羧酸吡嗪-2-基酰胺;
4-萘-2-基甲基-哌啶-1-羧酸异噁唑-3-基酰胺;
4-萘-2-基甲基-哌啶-1-羧酸(3-苯基-[1,2,4]噻二唑-5-基)-酰胺;
4-萘-2-基甲基-哌啶-1-羧酸(1H-四唑-5-基)-酰胺;
4-萘-2-基甲基-哌啶-1-羧酸(2H-吡唑-3-基)-酰胺;
4-萘-2-基甲基-哌啶-1-羧酸苯并[1,2,5]噁二唑-4-基酰胺;
4-萘-2-基甲基-哌啶-1-羧酸(1H-苯并三唑-5-基)-酰胺;
4-萘-2-基甲基-哌啶-1-羧酸[1,5]萘啶-2-基酰胺;
4-萘-2-基甲基-哌啶-1-羧酸喹啉-2-基酰胺;
4-萘-2-基甲基-哌啶-1-羧酸苯并噻唑-6-基酰胺;
4-萘-2-基甲基-哌啶-1-羧酸喹啉-5-基酰胺;
4-萘-2-基甲基-哌啶-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-(4-氟-苄基)-哌啶-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-(4-氟-苄基)-哌啶-1-羧酸(6-氯-哒嗪-3-基)-酰胺;
4-(4-氟-苄基)-哌啶-1-羧酸异噁唑-3-基酰胺;
4-(3-三氟甲基-苄基)-哌啶-1-羧酸(6-氯-哒嗪-3-基)-酰胺;
4-(3-三氟甲基-苄基)-哌啶-1-羧酸异噁唑-3-基酰胺;
4-(3-三氟甲基-苄基)-哌啶-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-氟-3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(3-三氟甲氧基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-三氟甲氧基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(3-溴-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-溴-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(3,4-二氟-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(3,5-二氟-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-{3-[4-(2,2,2-三氟-乙氧基)-苯氧基]-苄基}-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸苯并[1,2,5]噻二唑-4-基酰胺;
4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯并[1,2,5]噻二唑-4-基酰胺;
4-[3-(3,5-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯并[1,2,5]噻二唑-4-基酰胺;
4-[3-(3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[1,2,5]噻二唑-4-基酰胺;
4-(3-三氟甲氧基-苄基)-哌嗪-1-羧酸苯并[1,2,5]噻二唑-4-基酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(6-氯-哒嗪-3-基)-酰胺;
4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸(6-氯-哒嗪-3-基)-酰胺;
4-[3-(3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸(6-氯-哒嗪-3-基)-酰胺;
4-(4-氟-3-苯氧基-苄基)-哌嗪-1-羧酸(6-氯-哒嗪-3-基)-酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-[3-(3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-(4-氟-3-苯氧基-苄基)-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-(3-三氟甲氧基-苄基)-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(1H-吡唑-3-基)-酰胺;
4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸(1H-吡唑-3-基)-酰胺;
4-[3-(3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸(1H-吡唑-3-基)-酰胺;
4-(4-氟-3-苯氧基-苄基)-哌嗪-1-羧酸(1H-吡唑-3-基)-酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(1H-四唑-5-基)-酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸吡嗪-2-基酰胺;
4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸吡嗪-2-基酰胺;
4-[3-(3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸吡嗪-2-基酰胺;以及
4-(3-三氟甲氧基-苄基)-哌嗪-1-羧酸吡嗪-2-基酰胺。
36.根据权利要求34所述的药物组合物,所述药物组合物还包含:选自由阿片和非甾体抗炎药组成的组的止痛药。
37.根据权利要求34所述的药物组合物,所述药物组合物还包含:选自由阿司匹林、对乙酰氨基酚、阿片、布洛芬、萘普生、COX-2抑制剂、加巴喷丁、普瑞巴林和曲马多组成的组的另外的活性成分。
38.一种治疗患有或诊断患有由FAAH活性介导的疾病、障碍或医学病症的受试者的方法,所述方法包括:向需要这种治疗的所述受试者施用有效量的至少一种选自式(I)化合物以及所述式(I)化合物的可药用盐、可药用前药和药学活性代谢物的活性剂:
其中:
Ar1是苯并[d]异噁唑-3-基、6-氟苯并[d]异噁唑-3-基、3-苯基-[1,2,4]噻二唑-5-基、1H-四唑-5-基、苯并[1,2,5]噻二唑-4-基、苯并[1,2,5]噁二唑-4-基、噻吩-2-基、噻吩-3-基、6-氯-哒嗪-3-基、吡嗪-2-基、异噁唑-3-基、1H-苯并三唑-5-基、[1,5]萘啶-2-基、喹啉-2-基、苯并噻唑-6-基、喹啉-5-基、1H-吡唑-3-基、5-甲基吡嗪-2-基、3-氯吡嗪-2-基、哒嗪-3-基、6-甲氧基哒嗪-3-基、5-甲基异噁唑-3-基、1,5-二甲基-1H-吡唑-3-基、4-溴-1-甲基-1H-吡唑-3-基、2-乙基-2H-吡唑-3-基、5-甲基-1H-吡唑-3-基或5-苯基-1H-吡唑-3-基;
Z是-N-或>CH;并且
Ar2是:
(i)未被Ra部分取代或被一个或两个Ra部分取代的苯基;
其中每个Ra部分独立地是-C1-4烷基、-C≡C-Rd、-OC1-4烷基、卤素、-CF3、-OCF3、-OCH2CF3、-SCF3、-S(O)0-2C1-4烷基、-SO2CF3、-OSO2C1-4烷基、-(CH2)0-1CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(O)NRbRc、-NO2或-(CH2)0-1CN;
或者两个相邻的Ra部分合在一起形成-O(CH2)1-2O-或-OCF2O-;
其中Rb和Rc各自独立地是-H或-C1-4烷基;并且
Rd是H、C3-6环烷基或-CH2NReRf;
其中Re和Rf各自独立地是H或C1-4烷基;
(ii)在3-位置或4-位置处被-L-Ar3取代、未被Ra部分取代或被一个或两个Ra部分取代的苯基,其中:
L是选自由以下连接基组成的组的连接基:-(CH2)1-3-、-CH=CH-、-O-、-OCH2-、-CH2O-、-NH-、>NC1-4烷基、-S-、-C≡C-、-C(=O)-和共价键;并且
Ar3是:
(a)苯基;
(b)萘基;或
(c)单环杂芳基或双环杂芳基;或
(iii)9元或10元稠合双环杂芳基;
其中当Ar1为6-氯-哒嗪-3-基、异噁唑-3-基或1H-吡唑-3-基时,则Ar2不是苯并[1,3]二氧杂环戊烯-5-基或2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基。
39.根据权利要求38所述的方法,其中所述活性剂选自由以下化合物及其可药用盐组成的组:
N-1,2-苯并异噁唑-3-基-4-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)甲基]哌啶-1-甲酰胺;
4-(3-邻甲苯基乙炔基-苄基)-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
N-1,2-苯并异噁唑-3-基-4-(3-{[2-(三氟甲基)-苯基]-乙炔基}苄基)-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2-甲氧苯基)-乙炔基]-苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2-氟代苯基)乙炔基]-苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2-溴代苯基)-乙炔基]苄基}-哌嗪-1-甲酰胺;
4-(3-乙炔基-苄基)-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[3-(二甲基氨基)丙-1-炔-1-基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(环己基乙炔基)苄基]-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(环戊基乙炔基)苄基]-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2-氯苯基)-乙炔基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(3-氯苯基)乙炔基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(4-氯苯基)乙炔基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(3,4-二氯苯基)乙炔基]-苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(环丙基乙炔基)苄基]-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(噻吩-3-基乙炔基)苄基]-哌嗪-1-甲酰胺;
4-{3-[(2-氯苯基)乙炔基]苄基}-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-{3-[(2-氯苯基)乙炔基]苄基}-N-哒嗪-3-基哌嗪-1-甲酰胺;
4-{3-[(2-氯苯基)乙炔基]苄基}-N-(5-甲基吡嗪-2-基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2,4-二氯苯基)-乙炔基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(3-{[2-(三氟甲氧基)苯基]-乙炔基}苄基)-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(3,5-二氯苯基)乙炔基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2,5-二氯苯基)乙炔基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2-氰基苯基)乙炔基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(萘-1-基乙炔基)苄基]哌嗪-1-甲酰胺;
2-[(3-{[4-(1,2-苯并异噁唑-3-基氨基甲酰基)哌嗪-1-基]甲基}苯基)乙炔基]苯甲酸甲酯;
N-1,2-苯并异噁唑-3-基-4-{3-[(3-氰基苯基)乙炔基]苄基}哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(1,3-苯并二氧杂环戊烯-5-基乙炔基)苄基]-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2,3-二氯苯基)乙炔基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2-氰基-3-氟代苯基)乙炔基]-苄基}哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(3-{[2-(氰甲基)苯基]乙炔基}-苄基)哌嗪-1-甲酰胺;
{2-[(3-{[4-(1,2-苯并异噁唑-3-基氨基甲酰基)哌嗪-1-基]甲基}苯基)乙炔基]苯基}乙酸甲酯;
4-[3-(2-邻甲苯基-乙基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(嘧啶-2-基氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(吡啶-2-基氧基)苄基]哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(吡嗪-2-基氧基)苄基]哌嗪-1-甲酰胺;
4-[3-(2-氰基-苄氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(苄氧基)苄基]哌嗪-1-甲酰胺;
4-(1H-苯并咪唑-6-基甲基)-N-1,2-苯并异噁唑-3-基哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(1H-吲唑-6-基甲基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[4-(甲磺酰基)苄基]哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[4-(三氟甲氧基)苄基]哌嗪-1-甲酰胺;
4-[3-(4-氯苯氧基)苄基]-N-(6-甲氧基哒嗪-3-基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[4-氯-3-(三氟甲氧基)苄基]-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[4-氟-3-(三氟甲氧基)苄基]-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-氯-4-(三氟甲氧基)苄基]-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-氟-4-(三氟甲氧基)苄基]-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[4-(三氟甲基)苯氧基]苄基}-哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(3-苯氧基苄基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(3,4-二氯苄基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[4-(苄氧基)苄基]哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(1-苯并噻吩-2-基甲基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(喹啉-6-基氧基)苄基]哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(4-溴-3-氟苄基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(1,3-苯并二氧杂环戊烯-5-基甲基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(喹啉-3-基甲基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(1H-吲哚-5-基甲基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(萘-2-基氧基)苄基]哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(4-溴苄基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(3,4-二溴苄基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(2-氯苯氧基)苄基]哌嗪-1-甲酰胺;
4-萘-2-基甲基-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-喹啉-2-基甲基-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-氰基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-苯并呋喃-2-基甲基-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(3-氯苯氧基)苄基]哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[4-氰基-3-(三氟甲基)苯氧基]苄基}哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-[3-(3-氰基苯氧基)苄基]哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(3-{4-[(三氟甲基)硫基]苯氧基}-苄基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{3-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)氧基]苄基}哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-(3-{4-[(三氟甲基)磺酰基]苯氧基}-苄基)哌嗪-1-甲酰胺;
N-1,2-苯并异噁唑-3-基-4-{[3-(苯基乙炔基)苯基]甲基}哌嗪-1-甲酰胺;
N-异噁唑-3-基-4-{3-[4-(三氟甲氧基)苯氧基]苄基}哌嗪-1-甲酰胺;
4-[4-(苄氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-[3-(3-氯苯氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺;
N-异噁唑-3-基-4-{3-[4-(2,2,2-三氟乙氧基)苯氧基]苄基}哌嗪-1-甲酰胺;
4-(1-苯并呋喃-2-基甲基)-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-[3-(3-氰基苯氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-[3-(2-氯苯氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-{3-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)氧基]苄基}-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-(1-苯并噻吩-2-基甲基)-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-(1,3-苯并二氧杂环戊烯-5-基甲基)-N-异噁唑-3-基哌嗪-1-甲酰胺;
N-异噁唑-3-基-4-(萘-2-基甲基)哌嗪-1-甲酰胺;
4-[3-(4-溴苯氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-喹啉-2-基甲基-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-(4-溴-苄基)-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-(1H-吲哚-6-基甲基)-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-[3-(萘-2-基氧基)-苄基]-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-(4-溴-3-氟-苄基)-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-[3-(4-氰基-苯氧基)-苄基]-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-[3-(3,4-二氟苯氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-(3,4-二溴苄基)-N-异噁唑-3-基哌嗪-1-甲酰胺;
N-异噁唑-3-基-4-(3-{4-[(三氟甲基)硫基]苯氧基}苄基)-哌嗪-1-甲酰胺;
4-{3-[4-氟-3-(三氟甲基)苯氧基]苄基}-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-[3-(3-溴苯氧基)苄基]-N-异噁唑-3-基哌嗪-1-甲酰胺;
N-异噁唑-3-基-4-(3-{4-[(三氟甲基)磺酰基]苯氧基}苄基)-哌嗪-1-甲酰胺;
N-异噁唑-3-基-4-{3-[3-(三氟甲氧基)苯氧基]苄基}哌嗪-1-甲酰胺;
4-(3,4-二氯苄基)-N-异噁唑-3-基哌嗪-1-甲酰胺;
N-异噁唑-3-基-4-{3-[4-(三氟甲基)苯氧基]苄基}哌嗪-1-甲酰胺;
N-异噁唑-3-基-4-[3-(喹啉-6-基氧基)苄基]哌嗪-1-甲酰胺;
4-{3-[4-氰基-3-(三氟甲基)苯氧基]苄基}-N-异噁唑-3-基哌嗪-1-甲酰胺;
4-[3-(4-氯苯氧基)苄基]-N-(5-甲基异噁唑-3-基)哌嗪-1-甲酰胺;
4-(喹啉-3-基甲基)-N-1H-四唑-5-基哌嗪-1-甲酰胺;
4-[3-(萘-2-基氧基)苄基]-N-1H-四唑-5-基哌嗪-1-甲酰胺;
4-(3,4-二溴苄基)-N-1H-四唑-5-基哌嗪-1-甲酰胺;
4-(4-溴-3-氟苄基)-N-1H-四唑-5-基哌嗪-1-甲酰胺;
4-[3-(3,4-二氟苯氧基)苄基]-N-1H-四唑-5-基哌嗪-1-甲酰胺;
4-{3-[4-氰基-3-(三氟甲基)苯氧基]苄基}-N-1H-四唑-5-基哌嗪-1-甲酰胺;
N-1H-四唑-5-基-4-{3-[4-(三氟甲基)苯氧基]苄基}哌嗪-1-甲酰胺;
N-1H-四唑-5-基-4-(3-{4-[(三氟甲基)硫基]苯氧基}苄基)-哌嗪-1-甲酰胺;
N-1H-四唑-5-基-4-{3-[3-(三氟甲氧基)苯氧基]苄基}哌嗪-1-甲酰胺;
4-[3-(3,4-二氯苯氧基)苄基]-N-1H-四唑-5-基哌嗪-1-甲酰胺;
4-(喹啉-2-基甲基)-N-1H-四唑-5-基哌嗪-1-甲酰胺;
4-(萘-2-基甲基)-N-1H-四唑-5-基哌嗪-1-甲酰胺;
4-(4-溴-苄基)-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺;
4-(1H-吲哚-6-基甲基)-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺;
4-(3-苄氧基-苄基)-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺;
4-苯并[1,3]二氧杂环戊烯-5-基甲基-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺;
4-(3-苯氧基-苄基)-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺;
4-(3,4-二氯-苄基)-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺;
4-苯并[b]噻吩-2-基甲基-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺;
4-[3-(3-氰基-苯氧基)-苄基]-哌嗪-1-羧酸(2H-四唑-5-基)-酰胺;
4-{3-[4-氟-3-(三氟甲基)苯氧基]苄基}-N-2H-四唑-5-基哌嗪-1-甲酰胺;
N-2H-四唑-5-基-4-{3-[3-(三氟甲基)苯氧基]苄基}哌嗪-1-甲酰胺;
4-[3-(4-氰基苯氧基)苄基]-N-2H-四唑-5-基哌嗪-1-甲酰胺;
N-2H-四唑-5-基-4-{3-[4-(2,2,2-三氟乙氧基)苯氧基]苄基}-哌嗪-1-甲酰胺;
4-{3-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)氧基]苄基}-N-2H-四唑-5-基哌嗪-1-甲酰胺;
4-[3-(2-氯苯氧基)苄基]-N-2H-四唑-5-基哌嗪-1-甲酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(1,5-二甲基-1H-吡唑-3-基)-酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(4-溴-1-甲基-1H-吡唑-3-基)-酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(2-乙基-2H-吡唑-3-基)-酰胺;
4-[3-(4-氯苯氧基)苄基]-N-(5-甲基-1H-吡唑-3-基)哌嗪-1-甲酰胺;
4-(3,4-二溴苄基)-N-哒嗪-3-基哌嗪-1-甲酰胺;
4-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)甲基]-N-哒嗪-3-基哌嗪-1-甲酰胺;
N-哒嗪-3-基-4-(喹啉-3-基甲基)哌嗪-1-甲酰胺;
N-哒嗪-3-基-4-(喹啉-2-基甲基)哌嗪-1-甲酰胺;
4-(3,4-二氯苄基)-N-哒嗪-3-基哌嗪-1-甲酰胺;
4-(萘-2-基甲基)-N-哒嗪-3-基哌嗪-1-甲酰胺;
4-(1H-吲哚-5-基甲基)-N-哒嗪-3-基哌嗪-1-甲酰胺;
N-2,1,3-苯并噻二唑-4-基-4-{[3-(苯基乙炔基)苯基]甲基}-哌嗪-1-甲酰胺;
N-2,1,3-苯并噁二唑-4-基-4-{[3-(苯基乙炔基)苯基]甲基}-哌嗪-1-甲酰胺;
4-[3-(3-氯-4-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-氯-3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-氯-3-氟-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(3-氯-4-氟-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-氟-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-丁基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)甲基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-(1,3-苯并二氧杂环戊烯-5-基甲基)-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-(4-溴苄基)-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-(萘-2-基甲基)-N-吡嗪-2-基哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-{3-[4-(2,2,2-三氟乙氧基)苯氧基]苄基}-哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-{3-[4-(三氟甲基)苯氧基]苄基}哌嗪-1-甲酰胺;
4-(1H-吲哚-5-基甲基)-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-(3,4-二溴苄基)-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-(1-苯并噻吩-2-基甲基)-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-[4-(苄氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-(3,4-二氯苄基)-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-[3-(4-溴苯氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-(4-溴-3-氟苄基)-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-[3-(苄氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-(喹啉-3-基甲基)哌嗪-1-甲酰胺;
4-[3-(3-氯苯氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-(3-{4-[(三氟甲基)磺酰基]苯氧基}苄基)-哌嗪-1-甲酰胺;
4-(3-苯氧基-苄基)-哌嗪-1-羧酸吡嗪-2-基酰胺;
4-[3-(萘-2-基氧基)-苄基]-哌嗪-1-羧酸吡嗪-2-基酰胺;
4-[3-(4-氰基-苯氧基)-苄基]-哌嗪-1-羧酸吡嗪-2-基酰胺;
4-苯并呋喃-2-基甲基-哌嗪-1-羧酸吡嗪-2-基酰胺;
4-[3-(3,4-二氟苯氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-[3-(喹啉-6-基氧基)苄基]哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-{3-[4-(三氟甲氧基)苯氧基]苄基}哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-(3-{4-[(三氟甲基)硫基]苯氧基}苄基)-哌嗪-1-甲酰胺;
4-[3-(3-氰基苯氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-{3-[4-氰基-3-(三氟甲基)苯氧基]苄基}-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-{3-[(2,2-二氟-1,3-苯并二氧杂环戊烯-5-基)氧基]苄基}-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-[3-(2-氯苯氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-(喹啉-2-基甲基)哌嗪-1-甲酰胺;
4-[3-(3-溴苯氧基)苄基]-N-吡嗪-2-基哌嗪-1-甲酰胺;
4-{3-[4-氟-3-(三氟甲基)苯氧基]苄基}-N-吡嗪-2-基哌嗪-1-甲酰胺;
N-吡嗪-2-基-4-{3-[3-(三氟甲氧基)苯氧基]苄基}哌嗪-1-甲酰胺;
4-[3-(4-氯苯氧基)苄基]-N-(3-氯吡嗪-2-基)哌嗪-1-甲酰胺;
4-[3-(4-氯苯氧基)苄基]-N-(5-苯基-1H-吡唑-3-基)哌嗪-1-甲酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(6-氟-苯并[d]异噁唑-3-基)-酰胺;以及
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸哒嗪-3-基酰胺;
40.根据权利要求38所述的方法,其中所述疾病、障碍或医学病症选自由如下疾病、障碍或医学病症组成的组:焦虑、抑郁、疼痛、睡眠障碍、进食障碍、炎症、移动障碍、HIV衰竭综合征、封闭型颅脑损伤、中风、学习记忆障碍、阿尔茨海默病、癫痫、图雷特综合征、尼曼-匹克病、帕金森病、亨廷顿舞蹈病、视神经炎、自身免疫性葡萄膜炎、药物戒断、恶心、呕吐、性功能障碍、创伤后应激障碍、脑血管痉挛、青光眼、过敏性肠综合征、炎性肠疾病、免疫抑制、胃食管反流性疾病、麻痹性肠梗阻、分泌性腹泻、胃溃疡、类风湿性关节炎、意外妊娠、高血压、癌、肝炎、过敏性气管病、自身免疫性糖尿病、顽固性瘙痒以及神经炎。
41.根据权利要求38所述的方法,其中所述疾病、障碍或医学病症是疼痛或炎症。
42.根据权利要求38所述的方法,其中所述疾病、障碍或医学病症是焦虑、睡眠障碍、进食障碍或移动障碍。
43.根据权利要求38所述的方法,其中所述疾病、障碍或医学病症是多发性硬化症。
44.根据权利要求38所述的方法,其中所述疾病、障碍或医学病症是能量代谢疾病或骨内环境稳定疾病。
45.一种治疗患有或被诊断患有由FAAH活性介导的疾病、障碍或医学病症的方法,所述方法包括向需要这种治疗的所述受试者施用有效量的至少一种选自式(Ia)化合物以及所述式(Ia)化合物的可药用盐、可药用前药和药学活性代谢物的活性剂:
其中:
Ar1是苯并[d]异噁唑-3-基、6-氟苯并[d]异噁唑-3-基、3-苯基-[1,2,4]噻二唑-5-基、1H-四唑-5-基、苯并[1,2,5]噻二唑-4-基、苯并[1,2,5]噁二唑-4-基、噻吩-2-基、噻吩-3-基、6-氯-哒嗪-3-基、吡嗪-2-基、异噁唑-3-基、1H-苯并三唑-5-基、[1,5]萘啶-2-基、喹啉-2-基、苯并噻唑-6-基、喹啉-5-基或1H-吡唑-3-基;
Z是-N-或>CH;并且
Ar2是:
(i)被一个或两个Ra部分取代的苯基或3-苯氧基苯基;
其中每个Ra部分独立地是-C1-4烷基、-OC1-4烷基、卤素、-CF3、-OCF3、-OCH2CF3、-SCF3、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(O)NRbRc、-NO2或-CN;
其中Rb和Rc各自独立地是-H或-C1-4烷基;或者
(ii)苯并[1,3]二氧杂环戊烯-5-基、2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基或萘基;
其中当Ar1为6-氯-哒嗪-3-基、异噁唑-3-基或1H-吡唑-3-基时,则Ar2不是苯并[1,3]二氧杂环戊烯-5-基或2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基。
46.根据权利要求45所述的方法,其中所述活性剂选自由以下化合物及其可药用盐组成的组:
4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸(3-苯基-[1,2,4]噻二唑-5-基)-酰胺;
4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸(1H-四唑-5-基)-酰胺;
4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸苯并[1,2,5]噻二唑-4-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸苯并[1,2,5]噁二唑-4-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸(3H-苯并三唑-5-基)-酰胺;
4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸噻吩-2-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基甲基)-哌嗪-1-羧酸噻吩-3-基酰胺;
4-萘-2-基甲基-哌啶-1-羧酸(6-氯-哒嗪-3-基)-酰胺;
4-萘-2-基甲基-哌啶-1-羧酸吡嗪-2-基酰胺;
4-萘-2-基甲基-哌啶-1-羧酸异噁唑-3-基酰胺;
4-萘-2-基甲基-哌啶-1-羧酸(3-苯基-[1,2,4]噻二唑-5-基)-酰胺;
4-萘-2-基甲基-哌啶-1-羧酸(1H-四唑-5-基)-酰胺;
4-萘-2-基甲基-哌啶-1-羧酸(2H-吡唑-3-基)-酰胺;
4-萘-2-基甲基-哌啶-1-羧酸苯并[1,2,5]噁二唑-4-基酰胺;
4-萘-2-基甲基-哌啶-1-羧酸(1H-苯并三唑-5-基)-酰胺;
4-萘-2-基甲基-哌啶-1-羧酸[1,5]萘啶-2-基酰胺;
4-萘-2-基甲基-哌啶-1-羧酸喹啉-2-基酰胺;
4-萘-2-基甲基-哌啶-1-羧酸苯并噻唑-6-基酰胺;
4-萘-2-基甲基-哌啶-1-羧酸喹啉-5-基酰胺;
4-萘-2-基甲基-哌啶-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-(4-氟-苄基)-哌啶-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-(4-氟-苄基)-哌啶-1-羧酸(6-氯-哒嗪-3-基)-酰胺;
4-(4-氟-苄基)-哌啶-1-羧酸异噁唑-3-基酰胺;
4-(3-三氟甲基-苄基)-哌啶-1-羧酸(6-氯-哒嗪-3-基)-酰胺;
4-(3-三氟甲基-苄基)-哌啶-1-羧酸异噁唑-3-基酰胺;
4-(3-三氟甲基-苄基)-哌啶-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-氟-3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(3-三氟甲氧基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-三氟甲氧基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(3-溴-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-溴-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(3,4-二氟-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(3,5-二氟-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-{3-[4-(2,2,2-三氟-乙氧基)-苯氧基]-苄基}-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸苯并[1,2,5]噻二唑-4-基酰胺;
4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯并[1,2,5]噻二唑-4-基酰胺;
4-[3-(3,5-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯并[1,2,5]噻二唑-4-基酰胺;
4-[3-(3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[1,2,5]噻二唑-4-基酰胺;
4-(3-三氟甲氧基-苄基)-哌嗪-1-羧酸苯并[1,2,5]噻二唑-4-基酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(6-氯-哒嗪-3-基)-酰胺;
4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸(6-氯-哒嗪-3-基)-酰胺;
4-[3-(3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸(6-氯-哒嗪-3-基)-酰胺;
4-(4-氟-3-苯氧基-苄基)-哌嗪-1-羧酸(6-氯-哒嗪-3-基)-酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-[3-(3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-(4-氟-3-苯氧基-苄基)-哌嗪-1-羧酸异噁唑-3-基酰胺;
4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-(3-三氟甲氧基-苄基)-哌嗪-1-羧酸苯并[d]异噁唑-3-基酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(1H-吡唑-3-基)-酰胺;
4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸(1H-吡唑-3-基)-酰胺;
4-[3-(3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸(1H-吡唑-3-基)-酰胺;
4-(4-氟-3-苯氧基-苄基)-哌嗪-1-羧酸(1H-吡唑-3-基)-酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸(1H-四唑-5-基)-酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸吡嗪-2-基酰胺;
4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸吡嗪-2-基酰胺;
4-[3-(3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸吡嗪-2-基酰胺;和
4-(3-三氟甲氧基-苄基)-哌嗪-1-羧酸吡嗪-2-基酰胺。
47.根据权利要求45所述的方法,其中所述疾病、障碍或医学病症选自由以下疾病、障碍或医学病症组成的组:焦虑、抑郁、疼痛、睡眠障碍、进食障碍、炎症、移动障碍、HIV衰竭综合征、封闭型颅脑损伤、中风、学习记忆障碍、阿尔茨海默病、癫痫、图雷特综合征、尼曼-匹克病、帕金森病、亨廷顿舞蹈病、视神经炎、自身免疫性葡萄膜炎、药物戒断、恶心、呕吐、性功能障碍、创伤后应激障碍、脑血管痉挛、青光眼、过敏性肠综合征、炎性肠疾病、免疫抑制、胃食管反流性疾病、麻痹性肠梗阻、分泌性腹泻、胃溃疡、类风湿性关节炎、意外妊娠、高血压、癌、肝炎、过敏性气管病、自身免疫性糖尿病、顽固性瘙痒以及神经炎。
48.根据权利要求45所述的方法,其中所述疾病、障碍或医学病症是疼痛或炎症。
49.根据权利要求45所述的方法,其中所述疾病、障碍或医学病症是焦虑、睡眠障碍、进食障碍或移动障碍。
50.根据权利要求45所述的方法,其中所述疾病、障碍或医学病症是多发性硬化症。
51.根据权利要求45所述的方法,其中所述疾病、障碍或医学病症是能量代谢疾病或骨内环境稳定疾病。
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US93192007P | 2007-05-25 | 2007-05-25 | |
US60/931,920 | 2007-05-25 | ||
PCT/US2008/006607 WO2008153752A2 (en) | 2007-05-25 | 2008-05-23 | Heteroaryl-substituted urea modulators of fatty acid amide hydrolase |
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US (1) | US20090062294A1 (zh) |
EP (1) | EP2164493A2 (zh) |
JP (1) | JP2010528114A (zh) |
KR (1) | KR20100017885A (zh) |
CN (1) | CN101686979A (zh) |
AU (1) | AU2008263166A1 (zh) |
CA (1) | CA2688343A1 (zh) |
MX (1) | MX2009012765A (zh) |
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Cited By (2)
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CN102465157A (zh) * | 2010-11-04 | 2012-05-23 | 浙江九洲药业股份有限公司 | 生物酶法制备普瑞巴林手性中间体 |
CN114605385A (zh) * | 2022-03-25 | 2022-06-10 | 河南大学 | 吲哚哌啶脲类trpv1拮抗/faah抑制双靶点药物及制备方法和应用 |
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EP2937341B1 (en) | 2004-12-30 | 2017-07-05 | Janssen Pharmaceutica N.V. | 4-(benzyl)-piperazine-1-carboxylic acid phenylamide derivatives and related compounds as modulators of fatty acid amide hydrolase (faah) for the treatment of anxiety, pain and other conditions |
CA2663984C (en) | 2006-10-18 | 2012-02-21 | Pfizer Products Inc. | Biaryl ether urea compounds |
US8461159B2 (en) | 2008-11-25 | 2013-06-11 | Jannsen Pharmaceutica BV | Heteroaryl-substituted urea modulators of fatty acid amide hydrolase |
WO2010068452A1 (en) | 2008-11-25 | 2010-06-17 | Janssen Pharmaceutica Nv | Heteroaryl-substituted urea modulators of fatty acid amide hydrolase |
WO2010064597A1 (ja) * | 2008-12-01 | 2010-06-10 | 武田薬品工業株式会社 | ピペリジン誘導体 |
US8901111B2 (en) | 2009-06-05 | 2014-12-02 | Janssen Pharmaceutica Nv | Aryl-substituted heterocyclic urea modulators of fatty acid amide hydrolase |
EP2332939A1 (en) | 2009-11-26 | 2011-06-15 | Æterna Zentaris GmbH | Novel Naphthyridine derivatives and the use thereof as kinase inhibitors |
WO2011085216A2 (en) | 2010-01-08 | 2011-07-14 | Ironwood Pharmaceuticals, Inc. | Use of faah inhibitors for treating parkinson's disease and restless legs syndrome |
US20130224151A1 (en) | 2010-03-31 | 2013-08-29 | United States Of America | Use of FAAH Inhibitors for Treating Abdominal, Visceral and Pelvic Pain |
UA108233C2 (uk) | 2010-05-03 | 2015-04-10 | Модулятори активності гідролази амідів жирних кислот | |
EP2606033A1 (de) * | 2010-08-20 | 2013-06-26 | Grünenthal GmbH | Substituierte cyclische carboxamid- und harnstoff-derivate als liganden des vanilloid-rezeptors |
WO2014179144A1 (en) * | 2013-04-29 | 2014-11-06 | E. I. Du Pont De Nemours And Company | Fungicidal heterocyclic compounds |
US10570146B2 (en) | 2014-07-25 | 2020-02-25 | Northeastern University | Urea/carbamates FAAH MAGL or dual FAAH/MAGL inhibitors and uses thereof |
BR112017006117A2 (pt) | 2014-09-26 | 2017-12-19 | Changzhou Yinsheng Pharmaceutical Co Ltd | análogo de benzofurano como inibidor de ns4b |
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- 2008-05-23 JP JP2010510299A patent/JP2010528114A/ja not_active Withdrawn
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102465157A (zh) * | 2010-11-04 | 2012-05-23 | 浙江九洲药业股份有限公司 | 生物酶法制备普瑞巴林手性中间体 |
CN102465157B (zh) * | 2010-11-04 | 2014-11-26 | 浙江九洲药业股份有限公司 | 生物酶法制备普瑞巴林手性中间体 |
CN114605385A (zh) * | 2022-03-25 | 2022-06-10 | 河南大学 | 吲哚哌啶脲类trpv1拮抗/faah抑制双靶点药物及制备方法和应用 |
CN114605385B (zh) * | 2022-03-25 | 2023-09-08 | 河南大学 | 吲哚哌啶脲类trpv1拮抗/faah抑制双靶点药物及制备方法和应用 |
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JP2010528114A (ja) | 2010-08-19 |
MX2009012765A (es) | 2009-12-16 |
RU2009148304A (ru) | 2011-06-27 |
AU2008263166A1 (en) | 2008-12-18 |
CA2688343A1 (en) | 2008-12-18 |
KR20100017885A (ko) | 2010-02-16 |
EP2164493A2 (en) | 2010-03-24 |
US20090062294A1 (en) | 2009-03-05 |
WO2008153752A2 (en) | 2008-12-18 |
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