CN101426778A - N-substituted-azacyclylamines as histamine-3 antagonists - Google Patents

Abstract

The present invention provides a compound of formula and its use for the treatment of central nervous system disorders related to or affected by the histamine-3 receptor.

Description

Translated fromChinese

作为组胺-3拮抗剂的N-经取代-氮杂环基胺N-substituted-azaheterocyclylamines as histamine-3 antagonists

技术领域technical field

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背景技术Background technique

组胺-3(H3)受体为四种组胺受体亚型(H1-H4)中的一种，所有这些受体亚型都是受体较大的G蛋白偶合受体(GPCR)超家族的成员。H3受体主要在中枢神经系统中表达。在大脑中其位于与学习和记忆相关的区域，诸如大脑皮层、海马区和纹状体。H3受体作为自身受体和异源受体起作用以调节组胺和其它神经递质的释放。在皮层内，H3受体似乎直接改变GABA自皮层中间神经元的释放。H3受体的拮抗作用造成GABA释放减少和皮层胆碱系统抑制解除，导致乙酰胆碱含量升高(巴西奥替尼(Bacciottini，L)等人，行为大脑研究(Behavioral Brain Research)，124，2001，183-194)。除直接调节胆碱神经传递之外，H3受体还展示调节多巴胺、血清素和去甲肾上腺素的释放(莱斯(Leurs，R.)等人，药理科学趋势(Trends in Pharmacological Sciences)，19，1998，177-183)。人类的死后研究表明脑组胺含量的减少可能直接或经由胆碱系统造成阿兹海默氏症(Alzheimer′s disease)中出现的认知衰退(帕努拉(Panula，P.)等人，神经科学(Neuroscience)，82，1998，993-997)。已报导H3激动剂损害各种任务中的记忆，诸如目标识别、被动回避(布兰迪那(Blandina，P.)等人，英国药理学杂志(British Journal ofPharmacology)，119(8)，1996，1656-1664)和社会嗅觉记忆(social olfactory memory)(普拉斯特(Prast，H.)等人，734，1996，316-318)，而已报导H3拮抗剂援救药理学或遗传上造成的损害，即宫崎(Miyazaki，S.)等人，生命科学(Life Sciences)，61，1997，355-361；目黑(Meguro，K.)等人，药理学、生物化学和行为(Pharmacology，Biochemistry andBehavior)，50，1995，321-325；福克斯(Fox，G.B.)等人，行为大脑研究(Beharioral BrainResearch)，131，2002，151-161；和科马特(Komater，V.A.)等人，精神药理学(Psychopharmacology)，167，2003，363-372。The histamine-3 (H3) receptor is one of four histamine receptor subtypes (H1-H4), all of which are receptors for the larger G protein-coupled receptor (GPCR) super members of the family. H3 receptors are mainly expressed in the central nervous system. In the brain it is located in areas associated with learning and memory, such as the cerebral cortex, hippocampus and striatum. H3 receptors function as autoreceptors and heteroreceptors to regulate the release of histamine and other neurotransmitters. Within the cortex, H3 receptors appear to directly alter GABA release from cortical interneurons. Antagonism of H3 receptors results in decreased GABA release and release of cortical cholinergic system inhibition, resulting in elevated acetylcholine levels (Bacciottini, L et al., Behavioral Brain Research, 124,2001 , 183 -194). In addition to directly modulating choline neurotransmission, H3 receptors have been shown to modulate the release of dopamine, serotonin, and norepinephrine (Leurs, R. et al., Trends in Pharmacological Sciences, 19 ,1998 , 177-183). Postmortem studies in humans suggest that reduced brain histamine content may contribute directly or via the choline system to the cognitive decline seen in Alzheimer's disease (Panula, P. et al. , Neuroscience (Neuroscience), 82,1998 , 993-997). H3 agonists have been reported to impair memory in various tasks such as object recognition, passive avoidance (Blandina, P. et al., British Journal of Pharmacology, 119(8),1996 , 1656-1664) and social olfactory memory (social olfactory memory) (Prast (Prast, H.) et al., 734,1996 , 316-318), H3 antagonists have been reported to rescue pharmacologically or genetically induced damage , namely Miyazaki (Miyazaki, S.) et al., Life Sciences (Life Sciences), 61,1997 , 355-361; Meguro (Meguro, K.) et al., Pharmacology, Biochemistry and Behavior (Pharmacology, Biochemistry and Behavior), 50,1995 , 321-325; Fox, GB et al., Beharioral Brain Research, 131,2002 , 151-161; and Komater, VA et al., Psychopharmacology Psychopharmacology, 167, 2003, 363-372.

神经解剖学、神经化学、药理学和行为数据一起支持H3受体拮抗剂可改善疾病病况(诸如轻度认知障碍和阿兹海默氏症)中的认知表现且可在注意力不足过动症(ADHD)、精神分裂症、肥胖和睡眠障碍的治疗中具有治疗价值的概念。Together, neuroanatomical, neurochemical, pharmacological, and behavioral data support that H3 receptor antagonists improve cognitive performance in disease states such as mild cognitive impairment and Alzheimer's concepts with therapeutic value in the treatment of ADHD, schizophrenia, obesity and sleep disorders.

因此，本发明的目的在于提供为H3受体抑制剂且可在各种与H3受体相关或由H3受体影响的中枢神经系统病症的治疗中用作治疗剂的化合物。Accordingly, it is an object of the present invention to provide compounds which are H3 receptor inhibitors and which can be used as therapeutic agents in the treatment of various central nervous system disorders associated with or influenced by H3 receptors.

本发明的另一目的在于提供可用于治疗与H3受体相关或由H3受体影响的中枢神经系统病症的治疗方法和医药组合物。Another object of the present invention is to provide therapeutic methods and pharmaceutical compositions useful for the treatment of central nervous system disorders associated with or affected by H3 receptors.

本发明的特征在于所提供的化合物还可用于进一步研究和阐明H3受体。A feature of the present invention is that the provided compounds are also useful for further research and elucidation of H3 receptors.

发明内容Contents of the invention

本发明提供式I的N-经取代-氮杂环基胺化合物：The present invention provides N-substituted-azacyclylamine compounds of formula I:

其中in

X为CO、CH₂或SO_m；X is CO,_CH2 or_SOm ;

p和n各自独立地为1、2或3的整数；p and n are each independently an integer of 1, 2 or 3;

m为0或为1或2的整数；m is 0 or an integer of 1 or 2;

R₁和R₂各自独立地为H或视情况经取代的烷基，或R₁和R₂可连同其所连接的原子一起形成视情况含有一或两个选自N、O或S的额外杂原子的视情况经取代的4至7元环；R₁ and R₂ are each independently H or optionally substituted alkyl, or R₁ and R₂ may be taken together with the atoms to which they are attached to form optionally one or two additional compounds selected from N, O or S optionally substituted 4 to 7 membered rings of heteroatoms;

R₃为NR₄R₅或芳基或杂芳基，各基团视情况经取代；R₃ is NR₄ R₅ or aryl or heteroaryl, each group is optionally substituted;

R₄和R₅连同其所连接的原子一起形成视情况含有一至三个选自N、O或S的额外杂原子的视情况经取代的稠合双环、三环或四环9至15元环系统；R_andR together with the atoms to which they are attached form an optionally substituted fused bicyclic, tricyclic or tetracyclic 9 to 15 membered ring optionally containing one to three additional heteroatoms selected from N, O or S system;

R₆和R₇各自独立地为H、卤素、OR₁₀或各自视情况经取代的烷基、烯基、炔基、环烷基、环杂烷基、芳基或杂芳基；R_andR are each independently H, halogen, OR_, or each optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl;

R₈和R₉各自独立地为H或各自视情况经取代的烷基、环烷基或芳基；且R_andR are each independently H or each optionally substituted alkyl, cycloalkyl, or aryl; and

R₁₀为H或视情况经取代的烷基；或R₁₀ is H or optionally substituted alkyl; or

其立体异构体或其医药学上可接受的盐。Stereoisomers thereof or pharmaceutically acceptable salts thereof.

本发明还提供可用于治疗性治疗与组胺-3受体相关或由组胺-3受体影响的中枢神经系统病症的方法和组合物。The present invention also provides methods and compositions useful for the therapeutic treatment of central nervous system disorders associated with or affected by histamine-3 receptors.

附图说明Description of drawings

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具体实施方式Detailed ways

阿兹海默氏症(AD)的特征在于记忆和认知功能的进行性丧失且为老年人痴呆症最常见的病因。相信世界范围内AD影响约1千5百万至2千万人。AD治疗的目的除了扭转疾病进程之外还在于在患有轻度至中度疾病的患者中改善或至少减慢记忆和认知的丧失和维持独立功能。AD的特征在于神经递质功能的许多不足(穆勒(

，H-J.)，欧洲神经精神药理学(European Neuropsychopharmacology)，9，1999，S53-S59)，另外人类的死后研究表明脑组胺含量的减少可能直接或经由胆碱系统造成与AD相关的认知衰退(帕努拉(Panula，P.)等人，神经科学(Neuroscience)，82，1998，993-997)。已报导组胺-3(H3)受体拮抗剂援救药理学或遗传上造成的损害(宫崎(Miyazaki，S.)等人，生命科学(Life Sciences)，61，1997，355-361；目黑(Meguro，K.)等人，药理学、生物化学和行为(Pharmacology，Biochemistry and Behavior)，50，1995，321-325；福克斯(Fox，G.B.)等人，行为大脑研究(Beharioral Brain Research)，131，2002，151-161；和科马特(Komater，V.A.)等人，精神药理学(Psychopharmacology)，167，2003，363-372)。神经解剖学、神经化学、药理学和行为数据支持H3受体拮抗剂可改善疾病病况(诸如轻度认知障碍和阿兹海默氏症)中的认知表现且可在注意力不足过动症(ADHD)、精神分裂症、肥胖和睡眠障碍的治疗中具有治疗价值的观点。因此，认真地寻找抑制H3受体且作为H3拮抗剂起作用的化合物。Alzheimer's disease (AD) is characterized by progressive loss of memory and cognitive function and is the most common cause of dementia in older adults. AD is believed to affect approximately 15 to 20 million people worldwide. The aim of AD treatment is to improve or at least slow down the loss of memory and cognition and maintain independent function in patients with mild to moderate disease, in addition to reversing the disease course. AD is characterized by numerous deficits in neurotransmitter function (Muller (

, HJ.), European Neuropsychopharmacology (European Neuropsychopharmacology), 9, 1999, S53-S59), and other human postmortem studies have shown that the reduction of brain histamine content may cause AD-related cognition directly or through the choline system. cognitive decline (Panula, P. et al., Neuroscience, 82,1998 , 993-997). Histamine-3 (H3) receptor antagonists have been reported to rescue pharmacologically or genetically induced damage (Miyazaki, S. et al., Life Sciences, 61,1997 , 355-361; Black (Meguro, K.) et al., Pharmacology, Biochemistry and Behavior (Pharmacology, Biochemistry and Behavior), 50,1995 , 321-325; Fox (Fox, GB) et al., Beharioral Brain Research , 131,2002 , 151-161; and Komater, VA et al., Psychopharmacology, 167, 2003, 363-372). Neuroanatomical, neurochemical, pharmacological and behavioral data support that H3 receptor antagonists improve cognitive performance in disease conditions such as mild cognitive impairment and Alzheimer's A therapeutic perspective in the treatment of ADHD, schizophrenia, obesity and sleep disorders. Therefore, compounds that inhibit the H3 receptor and act as H3 antagonists are actively sought.

令人吃惊的是，现已发现式I的N-经取代-氮杂环基胺化合物显示H-3亲和力连同显著的亚型选择性且充当H-3拮抗剂。有利的是，所述式I化合物为用于治疗与H-3受体相关或由H-3受体影响的中枢神经系统(CNS)病症的有效治疗剂。因此，本发明提供式I的N-经取代-氮杂环基胺化合物：Surprisingly, it has now been found that N-substituted-azacyclylamine compounds of formula I show H-3 affinity together with remarkable subtype selectivity and act as H-3 antagonists. Advantageously, said compounds of formula I are effective therapeutic agents for the treatment of central nervous system (CNS) disorders associated with or affected by H-3 receptors. Accordingly, the present invention provides N-substituted-azacyclylamine compounds of formula I:

其中in

X为CO、CH₂或SO_m；X is CO,_CH2 or_SOm ;

p和n各自独立地为1、2或3的整数；p and n are each independently an integer of 1, 2 or 3;

m为0或为1或2的整数；m is 0 or an integer of 1 or 2;

R₁和R₂各自独立地为H或视情况经取代的烷基，或R₁和R₂可连同其所连接的原子一起形成视情况含有一或两个选自N、O或S的额外杂原子的视情况经取代的4至7元环；R₁ and R₂ are each independently H or optionally substituted alkyl, or R₁ and R₂ may be taken together with the atoms to which they are attached to form optionally one or two additional compounds selected from N, O or S optionally substituted 4 to 7 membered rings of heteroatoms;

R₃为NR₄R₅或芳基或杂芳基，各基团视情况经取代；R₃ is NR₄ R₅ or aryl or heteroaryl, each group is optionally substituted;

R₄和R₅连同其所连接的原子一起形成视情况含有一至三个选白N、O或S的额外杂原子的视情况经取代的稠合双环、三环或四环9至15元环系统；R_andR together with the atoms to which they are attached form an optionally substituted fused bicyclic, tricyclic or tetracyclic 9 to 15 membered ring optionally containing one to three additional heteroatoms selected from N, O or S system;

R₆和R₇各自独立地为H、卤素、OR₁₀或各自视情况经取代的烷基、烯基、炔基、环烷基、环杂烷基、芳基或杂芳基；R_andR are each independently H, halogen, OR_, or each optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl;

R₈和R₉各自独立地为H或各自视情况经取代的烷基、环烷基或芳基；且R_andR are each independently H or each optionally substituted alkyl, cycloalkyl, or aryl; and

R₁₀为H或视情况经取代的烷基；或R₁₀ is H or optionally substituted alkyl; or

其立体异构体或其医药学上可接受的盐。Stereoisomers thereof or pharmaceutically acceptable salts thereof.

应了解权利要求涵盖所有可能的立体异构体和前药。另外，除非另有说明，否则预期各烷基、烯基、炔基、环烷基、环杂烷基、芳基或杂芳基视情况经取代。It should be understood that the claims encompass all possible stereoisomers and prodrugs. Additionally, unless otherwise specified, each alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl group is intended to be optionally substituted.

视情况经取代的部分可经一个或一个以上取代基取代。视情况存在的取代基可为通常用于研发医药化合物或修饰所述化合物以影响其结构/活性、持续性、吸收、稳定性或其它有益性质的取代基中的一或多种。所述取代基的特定实例包括卤素原子、硝基、氰基、硫氰氧基、氰氧基、氧代基、羟基、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基、烷基氨基、二烷基氨基、甲酰基、烷氧基羰基、羧基、烷酰基(诸如C₁-C₆烷基羰基)、烷基硫基、烷基亚磺酰基、烷基磺酰基、氨甲酰基、烷基酰胺基、芳基(诸如苯基)、芳氧基(诸如苯氧基)、芳基烷基(诸如苯甲基)、芳基烷氧基(诸如苯甲氧基)、杂环基(例如杂芳基、环杂烷基)或环烷基，优选为卤素原子或低碳烷基或低碳烷氧基。除非另有特定说明，否则通常可存在0-4个取代基。当任何前述取代基表示或含有烷基取代基时，其可为直链或支链且可含有至多12个碳原子，优选至多6个碳原子，更优选至多4个碳原子。An optionally substituted moiety may be substituted with one or more substituents. Optional substituents may be one or more of those commonly used in the development of pharmaceutical compounds or in modifying such compounds to affect their structure/activity, persistence, absorption, stability or other beneficial properties. Specific examples of the substituents include halogen atoms, nitro, cyano, thiocyano, cyanoxy, oxo, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkyl Amino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl (such as C₁ -C₆ alkylcarbonyl), alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl , alkylamido, aryl (such as phenyl), aryloxy (such as phenoxy), arylalkyl (such as benzyl), arylalkoxy (such as benzyloxy), heterocyclic group (such as heteroaryl, cycloheteroalkyl) or cycloalkyl, preferably a halogen atom or lower alkyl or lower alkoxy. Typically 0-4 substituents may be present unless specifically stated otherwise. When any of the foregoing substituents represents or contains an alkyl substituent, it may be straight or branched and may contain up to 12 carbon atoms, preferably up to 6 carbon atoms, more preferably up to 4 carbon atoms.

如本文所用的术语烷基在作为基团或含有烷基部分的基团(诸如烷氧基、烷基亚磺酰基、卤代烷氧基、烷基氨基等)的部分时包括(C₁-C₁₀)直链和(C₃-C₁₂)支链(除非另有定义)单价饱和烃部分。饱和烃烷基部分的实例包括(但不限于)具有1-6个碳原子的化学基团，诸如甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基；高碳同系物，诸如正戊基、正己基和其类似基团。烷基的定义内尤其包括视情况经取代的所述烷基。合适的烷基取代包括(但不限于)CN、OH、NR₁₀R₁₁、卤素、苯基、氨甲酰基、羰基、烷氧基或芳氧基。The term alkyl as used herein includes (C₁ -C₁₀ ) linear and (C₃ -C₁₂ ) branched (unless otherwise defined) monovalent saturated hydrocarbon moieties. Examples of saturated hydrocarbon alkyl moieties include, but are not limited to, chemical groups having 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl radical, sec-butyl; higher homologues such as n-pentyl, n-hexyl and the like. Included within the definition of alkyl are especially included said alkyl groups optionally substituted. Suitable alkyl substitutions include, but are not limited to, CN, OH, NR₁₀ R₁₁ , halo, phenyl, carbamoyl, carbonyl, alkoxy, or aryloxy.

如本文所用的术语卤代烷基表示具有1至2n+1个可相同或不同的卤素原子的C_nH_2n+1基团。卤代烷基的实例包括CF₃、CH₂Cl、C₂H₃BrCl、C₃H₅F₂或其类似基团。The term haloalkyl as used herein denotes a C_n H_2n+1 group having 1 to 2n+1 halogen atoms which may be the same or different. Examples of haloalkyl groups include CF₃ , CH₂ Cl, C₂ H₃ BrCl, C₃ H₅ F₂ or similar groups.

如本文所用的术语卤素表示氟、氯、溴和碘。The term halogen as used herein denotes fluorine, chlorine, bromine and iodine.

如本文所用的术语烯基是指含有至少一个双键的(C₂-C₁₀)直链或(C₃-C₁₀)支链单价烃部分。所述烃烯基部分可为单不饱和或多不饱和烃烯基部分且可以E或Z构型存在。本发明的化合物打算包括所有可能的E和Z构型。单不饱和或多不饱和烃烯基部分的实例包括(但不限于)诸如乙烯基、2-丙烯基、异丙烯基、巴豆基、2-异戊烯基、丁二烯基、2-(丁二烯基)、2，4-戊二烯基、3-(1，4-戊二烯基)和高碳同系物、异构体或其类似基团的化学基团。The term alkenyl as used herein refers to a (C₂ -C₁₀ ) straight chain or (C₃ -C₁₀ ) branched chain monovalent hydrocarbon moiety containing at least one double bond. The hydrocarbon alkenyl moieties may be monounsaturated or polyunsaturated hydrocarbon alkenyl moieties and may exist in the E or Z configuration. The compounds of the present invention are intended to include all possible E and Z configurations. Examples of monounsaturated or polyunsaturated hydrocarbon alkenyl moieties include, but are not limited to, such as vinyl, 2-propenyl, isopropenyl, crotyl, 2-isopentenyl, butadienyl, 2-( butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl) and higher homologues, isomers or the like.

如说明书和权利要求中所用的术语炔基表示具有至少一个三键的(C₂-C₁₀)直链或(C₃-C₁₀)支链单价烃部分。所述烃炔基部分可为单不饱和或多不饱和烃炔基部分。单不饱和或多不饱和烃炔基部分的实例包括(但不限于)丙炔基、丁炔基、1，3-丁二炔基、戊炔基、己炔基或其类似基团。The term alkynyl as used in the description and claims denotes a (C₂ -C₁₀ ) straight-chain or (C₃ -C₁₀ ) branched monovalent hydrocarbon moiety having at least one triple bond. The alkynyl moieties may be monounsaturated or polyunsaturated alkynyl moieties. Examples of monounsaturated or polyunsaturated hydrocarbynyl moieties include, but are not limited to, propynyl, butynyl, 1,3-butadiynyl, pentynyl, hexynyl, or the like.

如本文所用的术语环烷基是指具有3-10个碳原子的单环、双环、三环、稠合、桥接或螺单价饱和烃部分。环烷基部分的实例包括(但不限于)诸如环丙基、环丁基、环戊基、环己基、环庚基、降冰片基、金刚烷基、螺[4.5]癸基或其类似基团的化学基团。The term cycloalkyl as used herein refers to a monocyclic, bicyclic, tricyclic, fused, bridged or spiro monovalent saturated hydrocarbon moiety having 3-10 carbon atoms. Examples of cycloalkyl moieties include, but are not limited to, groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl, spiro[4.5]decyl, or the like. group of chemical groups.

如本文所用的术语环杂烷基表示含有1、2或3个选自N、O或S且可相同或不同的杂原子且视情况含有一个双键的5至7元环烷基环系统。包括在如本文所示的术语中的环杂烷基环系统的实例为下列环，其中X₁为NR′、O或S且R′为H或如上文所定义的任选取代基。The term cycloheteroalkyl as used herein denotes a 5 to 7 membered cycloalkyl ring system containing 1, 2 or 3 heteroatoms selected from N, O or S, which may be the same or different, and optionally one double bond. Examples of cycloheteroalkyl ring systems encompassed by the term as indicated herein are rings wherein X₁ is NR', O or S and R' is H or an optional substituent as defined above.

如本文所用的术语芳基是指具有至多20个碳原子(例如6-20个碳原子)的芳香族碳环部分，所述芳香族碳环部分可为单一环(单环)或稠合在一起或共价键联的多个环(双环，至多3环)。芳基部分的实例包括(但不限于)诸如苯基、1-萘基、2-萘基、联苯基、蒽基、菲基、芴基、茚满基、苊基或其类似基团的化学基团。The term aryl as used herein refers to an aromatic carbocyclic moiety having up to 20 carbon atoms (eg, 6-20 carbon atoms), which may be a single ring (monocyclic) or fused in Multiple rings (bicyclic, up to 3 rings) together or linked covalently. Examples of aryl moieties include, but are not limited to, moieties such as phenyl, 1-naphthyl, 2-naphthyl, biphenyl, anthracenyl, phenanthrenyl, fluorenyl, indanyl, acenaphthyl, or the like chemical group.

如本文所用的术语杂芳基表示芳香族杂环系统，所述芳香族杂环系统可为(例如)具有5至11个环成员的单一环(单环)或稠合在一起或共价键联的多个环(双环，至多3环)。杂芳基优选为5至6元环或稠合双环9至11元环系统。所述环可含有1至4个选自氮、氧或硫的杂原子，其中氮原子或硫原子视情况经氧化，或氮原子视情况经季铵化。杂芳基部分的实例包括(但不限于)：杂环，诸如呋喃、噻吩、吡咯、吡唑、咪唑、噁唑、异噁唑、噻唑、异噻唑、噁二唑、三唑、吡啶、嘧啶、吡嗪、哒嗪、苯并咪唑、苯并噁唑、苯并异噁唑、苯并噻唑、苯并呋喃、苯并噻吩、噻嗯、二苯并呋喃、二苯并噻吩、吲哚、吲唑、氮杂吲哚、氮杂吲唑、咪唑并吡啶、吲哚啉、吡啶并吲哚、喹啉、异喹啉、喹唑啉、喹喔啉、嘌呤、四氢咔唑、六氢吲嗪并吲哚酮、四氢吡喃并吲哚、四氢喹啉、二氢二苯并氮杂卓或其类似物，优选为苯并咪唑、吲哚、吲唑、氮杂吲哚或氮杂吲唑。The term heteroaryl as used herein denotes an aromatic heterocyclic ring system which may be, for example, a single ring (monocyclic) having 5 to 11 ring members or fused together or covalently bonded Linked multiple rings (double rings, up to 3 rings). Heteroaryl is preferably a 5 to 6 membered ring or a fused bicyclic 9 to 11 membered ring system. The ring may contain 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur, wherein the nitrogen or sulfur atom is optionally oxidized, or the nitrogen atom is optionally quaternized. Examples of heteroaryl moieties include, but are not limited to: heterocycles such as furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, triazole, pyridine, pyrimidine , pyrazine, pyridazine, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzofuran, benzothiophene, thiane, dibenzofuran, dibenzothiophene, indole, Indazole, azaindole, azaindazole, imidazopyridine, indoline, pyridoindole, quinoline, isoquinoline, quinazoline, quinoxaline, purine, tetrahydrocarbazole, hexahydro Indolazinoindolone, tetrahydropyranoindole, tetrahydroquinoline, dihydrodibenzazepine or analogues thereof, preferably benzimidazole, indole, indazole, azaindole or Azaindazole.

R₄和R₅连同其所连接的氮原子一起形成的稠合双环、三环或四环9至15元环系统的实例包括吲哚、吲唑、苯并咪唑、1H-咔唑、2，3，4，9-四氢-1H-咔唑、5，6，11，11b-四氢-1H-吲嗪并[8，7-b]吲哚、1，2，5，6，11，11b-六氢-3H-吲嗪并[8，7-b]吲哚、咪唑并[4，5-b]吡啶、吲哚啉、1，2，3，4-四氢喹啉、咪唑或二苯并[b，f]氮杂卓或其类似物。Examples of fused bicyclic, tricyclic or tetracyclic 9 to 15 membered ring systems formed by R_andR together with the nitrogen atom to which they are attached include indole, indazole, benzimidazole, 1H-carbazole, 2, 3,4,9-tetrahydro-1H-carbazole, 5,6,11,11b-tetrahydro-1H-indazino[8,7-b]indole, 1,2,5,6,11, 11b-hexahydro-3H-indazino[8,7-b]indole, imidazo[4,5-b]pyridine, indoline, 1,2,3,4-tetrahydroquinoline, imidazole or Dibenzo[b,f]azepine or its analogues.

除非另有说明，否则本文描绘的结构还打算包括结构的所有立体化学形式；即各不对称中心的R和S构型。因此，本发明化合物的单一立体化学异构体以及对映异构体和非对映异构体混合物在本发明的范围内。除非另有说明，否则本文所描绘的结构还打算包括仅由于存在一个或一个以上同位素富集原子而不同的化合物。举例来说，具有本发明结构但氢经氘或氚置换或碳经¹³C或¹⁴C富集碳置换的化合物在本发明的范围内。Unless otherwise indicated, structures depicted herein are also intended to include all stereochemical forms of the structure; ie, the R and S configurations of each asymmetric center. Accordingly, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the compounds of the present invention are within the scope of the present invention. Unless otherwise indicated, structures depicted herein are also intended to include compounds that differ only by the presence of one or more isotopically enriched atoms. For example, compounds having structures of the present invention but with hydrogen replaced by deuterium or tritium or carbon replaced^by13Cor14C enriched carbon are within the scope of the present invention.

可使用沿用已久的程序将本发明的化合物转化成盐，尤其医药学上可接受的盐。与碱形成的合适盐为(例如)金属盐(诸如碱金属或碱土金属盐，例如钠、钾或镁盐)或与氨或有机胺(诸如吗啉、硫代吗啉、哌啶、吡咯烷、单、二或三低碳烷基胺(例如乙基-叔丁胺、二乙胺、二异丙胺、三乙胺、三丁胺或二甲基丙胺)或单羟基、二羟基或三羟基低碳烷基胺(例如单、二或三乙醇胺))形成的盐。另外可形成内盐。如本文所用的术语“低碳”表示1-6个碳原子。还包括不适用于医药用途但可用于(例如)分离或纯化游离化合物或其医药学上可接受的盐的盐。当本发明的化合物含有碱性部分时，如本文所用的术语“医药学上可接受的盐”是指衍生自有机酸和无机酸的盐，所述有机酸和无机酸诸如乙酸、丙酸、乳酸、柠檬酸、酒石酸、丁二酸、富马酸、马来酸、丙二酸、扁桃酸、苹果酸、邻苯二甲酸、盐酸、氢溴酸、磷酸、硝酸、硫酸、甲烷磺酸、萘磺酸、苯磺酸、甲苯磺酸、樟脑磺酸和类似已知的可接受的酸。当本发明的化合物含有羧酸酯或酚部分或能形成碱加成盐的类似部分时，还可自有机碱和无机碱形成盐，优选为碱金属盐(例如钠、锂或钾盐)。The compounds of the invention may be converted into salts, especially pharmaceutically acceptable salts, using well established procedures. Suitable salts with bases are, for example, metal salts such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or organic amines such as morpholine, thiomorpholine, piperidine, pyrrolidine , mono-, di-, or tri-lower alkylamines (such as ethyl-tert-butylamine, diethylamine, diisopropylamine, triethylamine, tributylamine, or dimethylpropylamine) or mono-, di-, or tri-hydroxyl lower Salts of alkylamines such as mono-, di- or triethanolamine. In addition, inner salts may form. The term "lower carbon" as used herein means 1-6 carbon atoms. Also included are salts which are unsuitable for medical use but which are useful, for example, for the isolation or purification of the free compound or a pharmaceutically acceptable salt thereof. When the compound of the present invention contains a basic moiety, the term "pharmaceutically acceptable salt" as used herein refers to salts derived from organic and inorganic acids such as acetic acid, propionic acid, Lactic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, phthalic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, Naphthalenesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, camphorsulfonic acid and similar known acceptable acids. Salts may also be formed from organic and inorganic bases, preferably alkali metal salts such as sodium, lithium or potassium, when compounds of the present invention contain a carboxylate or phenolic moiety or similar moieties capable of forming base addition salts.

本发明的化合物包括酯、氨基甲酸酯或其它常规前药形式，其一般为本发明化合物的官能衍生物且易于在活体内转化成本发明的活性部分。因此，本发明的方法涵盖以式I化合物或以未特定揭示但当投药时在活体内转化为式I化合物的化合物治疗上述各种病状。还包括本发明化合物的代谢物，其被定义为当将这些化合物引入生物系统中时所产生的活性物质。The compounds of the invention include esters, carbamates or other conventional prodrug forms, which are generally functional derivatives of the compounds of the invention and are readily converted in vivo to the active moieties of the invention. Accordingly, the methods of the present invention encompass the treatment of the various conditions described above with compounds of formula I or with compounds not specifically disclosed but which are converted to compounds of formula I in vivo when administered. Also included are metabolites of the compounds of the invention, which are defined as active species produced when these compounds are introduced into a biological system.

基团R₃-(CR₈R₉)_n-可在-X-基团的邻位、间位或对位。The group R₃ -(CR₈ R₉ )_n - may be in the ortho, meta or para position to the -X- group.

p的实例为1和2。Examples of p are 1 and 2.

n的实例为1。An instance of n is 1.

R₁和/或R₂的实例为H、甲基、乙基、丙基、羟乙基。Examples of_R1 and/or_R2 are H, methyl, ethyl, propyl, hydroxyethyl.

R₁和R₂连同其所连接的氮一起形成的环的实例为：视情况经取代的吡咯烷、吗啉、哌啶、哌嗪、氮杂环庚烷、1，4-二氮杂环庚烷、氮杂环丁烷，诸如2-甲基吡咯烷、2-苯甲基吡咯烷、2-甲基哌啶、3-甲基哌啶或4-甲基哌啶、3，5-二甲基哌啶、顺2，6-二甲基吗啉、3-甲基哌嗪或4-甲基哌嗪。Examples of rings formed by R_andR together with the nitrogen to which they are attached are: optionally substituted pyrrolidine, morpholine, piperidine, piperazine, azepane, 1,4-diazepine Heptane, azetidine, such as 2-methylpyrrolidine, 2-benzylpyrrolidine, 2-methylpiperidine, 3-methylpiperidine or 4-methylpiperidine, 3,5- Dimethylpiperidine, cis 2,6-dimethylmorpholine, 3-methylpiperazine or 4-methylpiperazine.

R₃的实例为视情况经取代的苯基、苯并咪唑(例如苯并咪唑-2-基)、吲哚(例如吲哚-2-基)，且当R₃为NR₄R₅(其中R₄和R₅一起为稠合双环、三环或四环)时，实例包括视情况经取代的吲哚、吲唑、苯并咪唑、1H-咔唑、2，3，4，9-四氢-1H-咔唑、5，6，11，11b-四氢-1H-吲嗪并[8，7-b]吲哚、1，2，5，6，11，11b-六氢-3H-吲嗪并[8，7-b]吲哚、咪唑并[4，5-b]吡啶、吲哚啉、1，2，3，4-四氢喹啉、咪唑或二苯并[b，f]氮杂卓环。Examples of R₃ are optionally substituted phenyl, benzimidazole (eg benzimidazol-2-yl), indole (eg indol-2-yl), and when R₃ is NR₄ R₅ (where When R and_R together are fused bicyclic, tricyclic or tetracyclic), examples include optionally substituted_indole , indazole, benzimidazole, 1H-carbazole, 2,3,4,9-tetracyclic Hydrogen-1H-carbazole, 5,6,11,11b-tetrahydro-1H-indazino[8,7-b]indole, 1,2,5,6,11,11b-hexahydro-3H- Indazo[8,7-b]indole, imidazo[4,5-b]pyridine, indoline, 1,2,3,4-tetrahydroquinoline, imidazole or dibenzo[b,f ] Azapine ring.

例如-NR₁R₂上或R₃上的任选取代基的实例为芳基(例如苯基)、卤素(例如氟、氯、溴)、烷基(例如甲基、乙基、丙基、异丙基、异丁基)、烷氧基(例如甲氧基)、烷氧基烷基(例如甲氧基乙基)、氧代基(例如为C＝O的环原子)、氰基、甲酰胺、COO烷基(例如乙氧基羰基)、三氟甲基、羟基烷基、苯基烷基(例如苯甲基、苯乙基)、芳基磺酰基(例如苯基磺酰基)、苯甲氧基和环烷基甲基(例如环丙基甲基)。Examples of optional substituents such as -NR₁ R₂ or on R₃ are aryl (eg phenyl), halogen (eg fluorine, chlorine, bromine), alkyl (eg methyl, ethyl, propyl, isopropyl, isobutyl), alkoxy (e.g. methoxy), alkoxyalkyl (e.g. methoxyethyl), oxo (e.g. a ring atom being C=O), cyano, Formamide, COOalkyl (e.g. ethoxycarbonyl), trifluoromethyl, hydroxyalkyl, phenylalkyl (e.g. benzyl, phenethyl), arylsulfonyl (e.g. phenylsulfonyl), Benzyloxy and cycloalkylmethyl (eg cyclopropylmethyl).

R₆和/或R₇的实例为H、卤基(例如氟、氯)、烷基(例如甲基)、烷氧基(例如甲氧基)。Examples of_R6 and/or_R7 are H, halo (eg fluorine, chlorine), alkyl (eg methyl), alkoxy (eg methoxy).

R₈的实例为H和烷基(例如甲基)。Examples of_R8 are H and alkyl (eg methyl).

本发明的优选化合物为那些X为CO或CH₂的式I化合物。另一类优选化合物为那些n为1且p为1或2的式I化合物。那些R₈和R₉各自独立地为H或甲基的式I化合物也是优选的。Preferred compounds of the invention are those compounds of formula I wherein X is CO or_CH2 . Another class of preferred compounds are those compounds of formula I in which n is 1 and p is 1 or 2. Also preferred are those compounds of formula I in which_R8 and_R9 are each independently H or methyl.

本发明的更优选化合物为那些X为CO或CH₂且R₁和R₂连同其所连接的原子一起形成5元环的式I化合物。另一类更优选化合物为那些X为CO或CH₂且R₃为NR₄R₅或视情况经取代的吲哚、吲唑、苯基或苯并咪唑环的式I化合物。另一类更优选化合物为那些X为CO；n为1；p为1或2；R₁和R₂连同其所连接的原子一起形成5元环；且R₃为NR₄R₅或视情况经取代的苯并咪唑或吲哚环的式I化合物。更优选的式I化合物也是那些R₃为视情况经取代的苯并咪唑环(在所述苯并咪唑环的2位连接)或R₃为NR₄R₅；且R₄和R₅连同其所连接的原子一起形成视情况经取代的吲哚、吲唑或苯并咪唑环的式I化合物。More preferred compounds of the invention are those compounds of formula I wherein X is CO or_CH2 and_R1 and_R2 together with the atoms to which they are attached form a 5 membered ring. Another more preferred class of compounds are those compounds of formula I_wherein X is CO or_CH2 and_R3 is_NR4R5 or an optionally substituted indole, indazole, phenyl or benzimidazole ring. Another class of more preferred compounds are those where X is CO; n is 1; p is 1 or 2; R₁ and R₂ together with the atoms to which they are attached form a 5-membered ring; and R₃ is NR₄ R₅ or optionally Compounds of formula I with substituted benzimidazole or indole rings. More preferred compounds of formula I are also those where R is an optionally substituted benzimidazole ring_{(attached at the 2-position of said benzimidazole ring) or R is NR 4 R 5 ; and R 4andR5togetherwith} their The atoms attached together form a compound of formula I of an optionally substituted indole, indazole or benzimidazole ring.

本发明的优选化合物为：Preferred compounds of the present invention are:

N，N-二甲基-1-{4-[(2-苯基-1H-苯并咪唑-1-基)甲基]-苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl-1-{4-[(2-phenyl-1H-benzimidazol-1-yl)methyl]-benzoyl}pyrrolidin-3-ylamine;

(3-S)-N，N-二甲基-1-{4-[(2-苯基-1H-苯并咪唑-1-基)甲基]-苯甲酰基}吡咯烷-3-基胺；(3-S)-N,N-Dimethyl-1-{4-[(2-phenyl-1H-benzimidazol-1-yl)methyl]-benzoyl}pyrrolidin-3-yl amine;

(3-R)-N，N-二甲基-1-{4-[(2-苯基-1H-苯并咪唑-1-基)甲基]-苯甲酰基}吡咯烷-3-基胺；(3-R)-N,N-Dimethyl-1-{4-[(2-phenyl-1H-benzimidazol-1-yl)methyl]-benzoyl}pyrrolidin-3-yl amine;

N，N-二甲基-1-{4-[(6-氟-1H-苯并咪唑-1-基)甲基]-苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl-1-{4-[(6-fluoro-1H-benzimidazol-1-yl)methyl]-benzoyl}pyrrolidin-3-ylamine;

N，N-二甲基-1-{4-[(6-甲基-1H-苯并咪唑-1-基)甲基]-苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl-1-{4-[(6-methyl-1H-benzimidazol-1-yl)methyl]-benzoyl}pyrrolidin-3-ylamine;

N，N-二甲基-1-{4-[(5-氟-1H-苯并咪唑-1-基)甲基]-苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl-1-{4-[(5-fluoro-1H-benzimidazol-1-yl)methyl]-benzoyl}pyrrolidin-3-ylamine;

N，N-二甲基-1-{4-[(4-氟-1H-苯并咪唑-1-基)甲基]-苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl-1-{4-[(4-fluoro-1H-benzimidazol-1-yl)methyl]-benzoyl}pyrrolidin-3-ylamine;

N，N-二甲基-1-[3-(1H-苯并咪唑-1-基)甲基]-苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl-1-[3-(1H-benzimidazol-1-yl)methyl]-benzoyl}pyrrolidin-3-ylamine;

N，N-二甲基1-[4-(1H-吲哚-1-基甲基)苯甲酰基]吡咯烷-3-基胺；N,N-Dimethyl 1-[4-(1H-indol-1-ylmethyl)benzoyl]pyrrolidin-3-ylamine;

N，N-二甲基1-{[4-(2，3，4，9-四氢-1H-咔唑)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(2,3,4,9-tetrahydro-1H-carbazole)methyl]benzoyl}pyrrolidin-3-ylamine;

N，N-二甲基1-{[4-(2-甲基-1H-吲哚-1-基)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(2-methyl-1H-indol-1-yl)methyl]benzoyl}pyrrolidin-3-ylamine;

N，N-二甲基1-{[4-(2-苯基-1H-吲哚-1-基)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(2-phenyl-1H-indol-1-yl)methyl]benzoyl}pyrrolidin-3-ylamine;

N，N-二甲基1-{[4-(5-甲氧基-1H-吲哚-1-基)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(5-methoxy-1H-indol-1-yl)methyl]benzoyl}pyrrolidin-3-ylamine;

N，N-二甲基1-{[4-(5-甲氧基-2-苯基-1H-吲哚-1-基)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(5-methoxy-2-phenyl-1H-indol-1-yl)methyl]benzoyl}pyrrolidin-3-ylamine;

N，N-二甲基1-{[4-(7-氮杂-1H-吲哚-1-基)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(7-aza-1H-indol-1-yl)methyl]benzoyl}pyrrolidin-3-ylamine;

N，N-二甲基1-{[4-(1H-苯并[d]咪唑-1-基)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(1H-benzo[d]imidazol-1-yl)methyl]benzoyl}pyrrolidin-3-ylamine;

N，N-二甲基1-{[4-(2-甲基-1H-苯并[d]咪唑-1-基)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(2-methyl-1H-benzo[d]imidazol-1-yl)methyl]benzoyl}pyrrolidin-3-ylamine;

N，N-二甲基1-{[4-(5-羟基-1H-吲哚-1-基)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(5-hydroxy-1H-indol-1-yl)methyl]benzoyl}pyrrolidin-3-ylamine;

N，N-二甲基1-{[4-(1，2，3，4-四氢喹啉-1-基)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(1,2,3,4-tetrahydroquinolin-1-yl)methyl]benzoyl}pyrrolidin-3-ylamine;

N，N-二甲基1-{[4-(5-氟-1H-吲哚-1-基)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(5-fluoro-1H-indol-1-yl)methyl]benzoyl}pyrrolidin-3-ylamine;

N，N-二甲基1-{[4-(3-氰基-1H-吲哚-1-基)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(3-cyano-1H-indol-1-yl)methyl]benzoyl}pyrrolidin-3-ylamine;

N，N-二甲基1-{[4-(2-苯基-1H-咪唑-1-基)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(2-phenyl-1H-imidazol-1-yl)methyl]benzoyl}pyrrolidin-3-ylamine;

1′-{4-[(2-苯基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；1'-{4-[(2-phenyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

1′-{4-[(5-氯-2-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；1'-{4-[(5-chloro-2-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

1′-{4-[(6-氯-2-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；1'-{4-[(6-chloro-2-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

1′-{4-[(6-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；1'-{4-[(6-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

1′-{4-[(5-氟-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；1'-{4-[(5-fluoro-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

(2-R)-1′-[4-(1H-苯并咪唑-1-基甲基)苯甲酰基]-2-甲基-1，3′-联吡咯烷；(2-R)-1'-[4-(1H-benzimidazol-1-ylmethyl)benzoyl]-2-methyl-1,3'-bipyrrolidine;

(3′-R)-1′-{4-[(2-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'-R)-1'-{4-[(2-Methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

(3′-S)-1′-{4-[(2-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'-S)-1'-{4-[(2-Methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

(3′S)-[4-(1H-吲哚-1-基甲基)苯甲酰基]-1，3′-联吡咯烷；(3'S)-[4-(1H-indol-1-ylmethyl)benzoyl]-1,3'-bipyrrolidine;

(3′S)-[4-(1H-吲唑-1-基甲基)苯甲酰基]-1，3′-联吡咯烷；(3'S)-[4-(1H-indazol-1-ylmethyl)benzoyl]-1,3'-bipyrrolidine;

(3′S)-1′-{4-[(5-氯-2-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(5-chloro-2-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

(3′S)-1′-{4-[(6-氯-2-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(6-Chloro-2-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

(3′S)-1′-{4-[(6-氟-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(6-fluoro-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

(3′S)-1′-{4-[(6-氟-1H-苯并咪唑-1-基)甲基]苯甲基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(6-fluoro-1H-benzimidazol-1-yl)methyl]benzyl}-1,3'-bipyrrolidine;

(3′S)-1′-{4-[(5-氟-1H-苯并咪唑-1-基)甲基]苯甲基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(5-fluoro-1H-benzimidazol-1-yl)methyl]benzyl}-1,3'-bipyrrolidine;

(3′S)-1′-{4-[(5-氟-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(5-fluoro-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

(3′S)-1′-{4-[(7-氯-1H-吲哚-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(7-Chloro-1H-indol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

9-{4-[(3′S)-1，3′-联吡咯烷-1-基羰基]苯甲基}-9H-咔唑；9-{4-[(3′S)-1,3′-bipyrrolidin-1-ylcarbonyl]benzyl}-9H-carbazole;

(3′-S)-1′-{4-[(1S)-1-(2-甲基-1H-苯并咪唑-1-基)乙基]苯甲酰基}-1，3′-联吡咯烷；(3'-S)-1'-{4-[(1S)-1-(2-Methyl-1H-benzimidazol-1-yl)ethyl]benzoyl}-1,3'-linked pyrrolidine;

(3′-S)-1′-{4-[(1R)-1-(2-甲基-1H-苯并咪唑-1-基)乙基]苯甲酰基}-1，3′-联吡咯烷；(3'-S)-1'-{4-[(1R)-1-(2-Methyl-1H-benzimidazol-1-yl)ethyl]benzoyl}-1,3'-linked pyrrolidine;

(3′-S)-1′-[4-(1H-苯并咪唑-1-基甲基)苯甲基]-1，3′-联吡咯烷；(3'-S)-1'-[4-(1H-benzimidazol-1-ylmethyl)benzyl]-1,3'-bipyrrolidine;

(3′-S)-1′-[4-(1H-苯并咪唑-1-基甲基)苯甲酰基]-1，3′-联吡咯烷；(3'-S)-1'-[4-(1H-benzimidazol-1-ylmethyl)benzoyl]-1,3'-bipyrrolidine;

N，N-二甲基-1-{4-[(2-苯基-1H-苯并咪唑-1-基)甲基]-苯甲基}吡咯烷-3-基胺；N,N-Dimethyl-1-{4-[(2-phenyl-1H-benzimidazol-1-yl)methyl]-benzyl}pyrrolidin-3-ylamine;

(3-S)-N，N-二甲基-1-{4-[(2-苯基-1H-苯并咪唑-1-基)甲基]-苯甲基}吡咯烷-3-基胺；(3-S)-N,N-Dimethyl-1-{4-[(2-phenyl-1H-benzimidazol-1-yl)methyl]-benzyl}pyrrolidin-3-yl amine;

(3-R)-N，N-二甲基-1-{4-[(2-苯基-1H-苯并咪唑-1-基)甲基]-苯甲基}吡咯烷-3-基胺；(3-R)-N,N-Dimethyl-1-{4-[(2-phenyl-1H-benzimidazol-1-yl)methyl]-benzyl}pyrrolidin-3-yl amine;

N，N-二甲基-1-{4-[(6-氟-1H-苯并咪唑-1-基)甲基]-苯甲基}吡咯烷-3-基胺；N,N-Dimethyl-1-{4-[(6-fluoro-1H-benzimidazol-1-yl)methyl]-benzyl}pyrrolidin-3-ylamine;

N，N-二甲基-1-{4-[(6-甲基-1H-苯并咪唑-1-基)甲基]-苯甲基}吡咯烷-3-基胺；N,N-Dimethyl-1-{4-[(6-methyl-1H-benzimidazol-1-yl)methyl]-benzyl}pyrrolidin-3-ylamine;

N，N-二甲基-1-{4-[(5-氟-1H-苯并咪唑-1-基)甲基]-苯甲基}吡咯烷-3-基胺；N,N-Dimethyl-1-{4-[(5-fluoro-1H-benzimidazol-1-yl)methyl]-benzyl}pyrrolidin-3-ylamine;

N，N-二甲基-1-{4-[(4-氟-1H-苯并咪唑-1-基)甲基]-苯甲基}吡咯烷-3-基胺；N,N-Dimethyl-1-{4-[(4-fluoro-1H-benzimidazol-1-yl)methyl]-benzyl}pyrrolidin-3-ylamine;

N，N-二甲基-1-[3-(1H-苯并咪唑-1-基)甲基]-苯甲基}吡咯烷-3-基胺；N,N-Dimethyl-1-[3-(1H-benzimidazol-1-yl)methyl]-benzyl}pyrrolidin-3-ylamine;

N，N-二甲基1-[4-(1H-吲哚-1-基甲基)苯甲基]吡咯烷-3-基胺；N,N-Dimethyl 1-[4-(1H-indol-1-ylmethyl)benzyl]pyrrolidin-3-ylamine;

N，N-二甲基1-{[4-(2，3，4，9-四氢-1H-咔唑)甲基]苯甲基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(2,3,4,9-tetrahydro-1H-carbazole)methyl]benzyl}pyrrolidin-3-ylamine;

(3′S)-1′-[4-(1H-吲哚-3-基甲基)苯甲酰基]-1，3′-联吡咯烷；(3'S)-1'-[4-(1H-indol-3-ylmethyl)benzoyl]-1,3'-bipyrrolidine;

(3′S)-1′-{4-[(1-甲基-1H-吲哚-3-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1-Methyl-1H-indol-3-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

(3S)-N，N-二甲基-1-{4-[(1-甲基-1H-吲哚-3-基)甲基]苯甲酰基}吡咯烷-3-胺；(3S)-N,N-Dimethyl-1-{4-[(1-methyl-1H-indol-3-yl)methyl]benzoyl}pyrrolidin-3-amine;

2-{4-[(3-哌啶-1-基吡咯烷-1-基)羰基]苯甲基}-1H-苯并咪唑；2-{4-[(3-piperidin-1-ylpyrrolidin-1-yl)carbonyl]benzyl}-1H-benzimidazole;

1′-{4-[(1-乙基-1H-苯并咪唑-2-基)甲基]苯甲酰基}-1，3′-联吡咯烷；1'-{4-[(1-Ethyl-1H-benzimidazol-2-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

1′-{4-[(1-甲基-1H-苯并咪唑-2-基)甲基]苯甲酰基}-1，3′-联吡咯烷；1'-{4-[(1-Methyl-1H-benzimidazol-2-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

1-甲基-2-{4-[(3-哌啶-1-基吡咯烷-1-基)羰基]苯甲基}-1H-苯并咪唑；1-methyl-2-{4-[(3-piperidin-1-ylpyrrolidin-1-yl)carbonyl]benzyl}-1H-benzimidazole;

1′-[4-(1H-苯并咪唑-2-基甲基)苯甲酰基]-1，3′-联吡咯烷；1'-[4-(1H-benzimidazol-2-ylmethyl)benzoyl]-1,3'-bipyrrolidine;

(3′S)-1′-(4-苯甲基苯甲酰基)-1，3′-联吡咯烷；(3'S)-1'-(4-benzylbenzoyl)-1,3'-bipyrrolidine;

(3′S)-1′-{4-[(1-丙基-1H-苯并咪唑-2-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1-Propyl-1H-benzimidazol-2-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

(3′S)-1′-{4-[(1-异丙基-1H-苯并咪唑-2-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1-isopropyl-1H-benzimidazol-2-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

(3′S)-1′-{4-[(1-异丁基-1H-苯并咪唑-2-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1-isobutyl-1H-benzimidazol-2-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

(3′S)-1′-(4-{[1-(环丙基甲基)-1H-苯并咪唑-2-基]甲基}苯甲酰基)-1，3′-联吡咯烷；(3'S)-1'-(4-{[1-(cyclopropylmethyl)-1H-benzimidazol-2-yl]methyl}benzoyl)-1,3'-bipyrrolidine ;

(3′S)-1′-(4-{[1-(苯基磺酰基)-1H-苯并咪唑-2-基]甲基}苯甲酰基)-1，3′-联吡咯烷；(3'S)-1'-(4-{[1-(phenylsulfonyl)-1H-benzimidazol-2-yl]methyl}benzoyl)-1,3'-bipyrrolidine;

(3′S)-1′-(4-{[1-(2-甲氧基乙基)-1H-苯并咪唑-2-基]甲基}苯甲酰基)-1，3′-联吡咯烷；(3′S)-1′-(4-{[1-(2-methoxyethyl)-1H-benzimidazol-2-yl]methyl}benzoyl)-1,3′-linked pyrrolidine;

2-(2-{4-[(3′S)-1，3′-联吡咯烷-1′-基羰基]苯甲基}-1H-苯并咪唑-1-基)乙醇；2-(2-{4-[(3'S)-1,3'-bipyrrolidin-1'-ylcarbonyl]benzyl}-1H-benzimidazol-1-yl)ethanol;

(3′S)-1′-{4-[(1-乙基-1H-苯并咪唑-2-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1-Ethyl-1H-benzimidazol-2-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

(3′S)-1′-(4-{[1-(2-苯基乙基)-1H-苯并咪唑-2-基]甲基}苯甲酰基)-1，3′-联吡咯烷；(3'S)-1'-(4-{[1-(2-phenylethyl)-1H-benzimidazol-2-yl]methyl}benzoyl)-1,3'-bipyrrole alkyl;

(3′S)-1′-{4-[(1-乙基-1H-苯并咪唑-2-基)甲基]苯甲基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1-Ethyl-1H-benzimidazol-2-yl)methyl]benzyl}-1,3'-bipyrrolidine;

(3′S)-1′-{4-[(1-苯基-1H-苯并咪唑-2-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1-phenyl-1H-benzimidazol-2-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

1′-{4-[(5-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；1'-{4-[(5-Methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

5-甲基-1-{4-[(3-哌啶-1-基吡咯烷-1-基)羰基]苯甲基}-1H-苯并咪唑；5-methyl-1-{4-[(3-piperidin-1-ylpyrrolidin-1-yl)carbonyl]benzyl}-1H-benzimidazole;

4-氟-1-{4-[(3-哌啶-1-基吡咯烷-1-基)甲基]苯甲基}-1H-苯并咪唑；4-fluoro-1-{4-[(3-piperidin-1-ylpyrrolidin-1-yl)methyl]benzyl}-1H-benzimidazole;

1′-[4-(1H-苯并咪唑-1-基甲基)-3-氯苯甲基]-1，3′-联吡咯烷；1'-[4-(1H-benzimidazol-1-ylmethyl)-3-chlorobenzyl]-1,3'-bipyrrolidine;

1-{4-[(4-氟-1H-苯并咪唑-1-基)甲基]苯甲基}-N，N-二甲基吡咯烷-3-胺；1-{4-[(4-fluoro-1H-benzimidazol-1-yl)methyl]benzyl}-N,N-dimethylpyrrolidin-3-amine;

5-甲基-1-(4-{[3-(2-甲基哌啶-1-基)吡咯烷-1-基]羰基}苯甲基)-1H-苯并咪唑；5-methyl-1-(4-{[3-(2-methylpiperidin-1-yl)pyrrolidin-1-yl]carbonyl}benzyl)-1H-benzimidazole;

5-甲基-1-{4-[(3-吗啉-4-基吡咯烷-1-基)羰基]苯甲基}-1H-苯并咪唑；5-methyl-1-{4-[(3-morpholin-4-ylpyrrolidin-1-yl)carbonyl]benzyl}-1H-benzimidazole;

5-甲基-1-(4-{[3-(4-甲基哌啶-1-基)吡咯烷-1-基]羰基}苯甲基)-1H-苯并咪唑；5-methyl-1-(4-{[3-(4-methylpiperidin-1-yl)pyrrolidin-1-yl]carbonyl}benzyl)-1H-benzimidazole;

5-甲基-1-(4-{[3-(4-甲基哌嗪-1-基)吡咯烷-1-基]羰基}苯甲基)-1H-苯并咪唑；5-methyl-1-(4-{[3-(4-methylpiperazin-1-yl)pyrrolidin-1-yl]carbonyl}benzyl)-1H-benzimidazole;

5-甲基-1-(4-{[3-(3-甲基哌啶-1-基)吡咯烷-1-基]羰基}苯甲基)-1H-苯并咪唑；5-methyl-1-(4-{[3-(3-methylpiperidin-1-yl)pyrrolidin-1-yl]carbonyl}benzyl)-1H-benzimidazole;

((2s)-1′-{4-[5-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷-2-基)甲醇；((2s)-1'-{4-[5-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidin-2-yl)methanol;

N，N-二甲基-1-{4-[(5-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}吡咯烷-3-胺；N,N-Dimethyl-1-{4-[(5-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}pyrrolidin-3-amine;

N-乙基-N-甲基-1-{4-[(5-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}吡咯烷-3-胺；N-ethyl-N-methyl-1-{4-[(5-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}pyrrolidin-3-amine;

1-{2-氯-4-[(3-哌啶-1-基吡咯烷-1-基)甲基]苯甲基}-1H-苯并咪唑；1-{2-Chloro-4-[(3-piperidin-1-ylpyrrolidin-1-yl)methyl]benzyl}-1H-benzimidazole;

1-[4-(1H-苯并咪唑-1-基甲基)-2-甲氧基苯甲酰基]-N，N-二甲基吡咯烷-3-胺；1-[4-(1H-benzimidazol-1-ylmethyl)-2-methoxybenzoyl]-N,N-dimethylpyrrolidin-3-amine;

1-[4-(1H-苯并咪唑-1-基甲基)-3-氯苯甲基]-N-乙基-N甲基吡咯烷-3-胺；1-[4-(1H-benzimidazol-1-ylmethyl)-3-chlorobenzyl]-N-ethyl-N-methylpyrrolidin-3-amine;

(2R)-1′-[4-(1H-苯并咪唑-1-基甲基)-2-甲氧基苯甲酰基]-2-甲基-1，3′-联吡咯烷；(2R)-1'-[4-(1H-benzimidazol-1-ylmethyl)-2-methoxybenzoyl]-2-methyl-1,3'-bipyrrolidine;

2-苯甲基-1′-{4-[(5-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；2-Benzyl-1'-{4-[(5-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

1′-{4-[(7-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；1'-{4-[(7-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

(2R)-1′-{4-[(5-氟-1H-苯并咪唑-1-基)甲基]苯甲酰基}-2-甲基-1，3′-联吡咯烷；(2R)-1'-{4-[(5-fluoro-1H-benzimidazol-1-yl)methyl]benzoyl}-2-methyl-1,3'-bipyrrolidine;

(2R)-2-甲基-1′-{4-[(5-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(2R)-2-methyl-1'-{4-[(5-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

1-[4-(1H-苯并咪唑-1-基甲基)-3-氯苯甲基]-N，N-二甲基吡咯烷-3-胺；1-[4-(1H-benzimidazol-1-ylmethyl)-3-chlorobenzyl]-N,N-dimethylpyrrolidin-3-amine;

(2S)-1′-{4-[(5-氟-1H-苯并咪唑-1-基)甲基]苯甲酰基}-2-甲基-1，3′-联吡咯烷；(2S)-1'-{4-[(5-fluoro-1H-benzimidazol-1-yl)methyl]benzoyl}-2-methyl-1,3'-bipyrrolidine;

1-{4-[(3-氮杂环庚烷-1-基吡咯烷-1-基)羰基]苯甲基}-5-甲基-1H-苯并咪唑；1-{4-[(3-Azepan-1-ylpyrrolidin-1-yl)carbonyl]benzyl}-5-methyl-1H-benzimidazole;

5-甲基-1-(4-{[3-(4-甲基-1，4-二氮杂环庚烷-1-基)吡咯烷-1-基]羰基}苯甲基)-1H-苯并咪唑；5-methyl-1-(4-{[3-(4-methyl-1,4-diazepan-1-yl)pyrrolidin-1-yl]carbonyl}benzyl)-1H - benzimidazole;

(3′S)-1′-{4-[(5-氟-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(5-fluoro-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

(3′S)-1′-{4-[(5-氟-1H-苯并咪唑-1-基)甲基]苯甲基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(5-fluoro-1H-benzimidazol-1-yl)methyl]benzyl}-1,3'-bipyrrolidine;

7-甲基-1-{4-[(3-哌啶-1-基吡咯烷-1-基)羰基]苯甲基}-1H-苯并咪唑；7-methyl-1-{4-[(3-piperidin-1-ylpyrrolidin-1-yl)carbonyl]benzyl}-1H-benzimidazole;

(2R)-1′-{4-[(5-氟-1H-苯并咪唑-1-基)甲基]苯甲基}-2-甲基-1，3′-联吡咯烷；(2R)-1'-{4-[(5-fluoro-1H-benzimidazol-1-yl)methyl]benzyl}-2-methyl-1,3'-bipyrrolidine;

1-{4-[(3-氮杂环丁烷-1-基吡咯烷-1-基)羰基]苯甲基}-5-甲基-1H-苯并咪唑；1-{4-[(3-azetidin-1-ylpyrrolidin-1-yl)carbonyl]benzyl}-5-methyl-1H-benzimidazole;

1′-[4-(1H-苯并咪唑-1-基甲基)-2-氟苯甲酰基]-1，3′-联吡咯烷；1'-[4-(1H-benzimidazol-1-ylmethyl)-2-fluorobenzoyl]-1,3'-bipyrrolidine;

(3′S)-1′-{4-[(7-氟-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(7-fluoro-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

1-(4-{[(3S)-3-氮杂环庚烷-1-基吡咯烷-1-基]羰基}苯甲基)-7-氟-1H-苯并咪唑；1-(4-{[(3S)-3-azepan-1-ylpyrrolidin-1-yl]carbonyl}benzyl)-7-fluoro-1H-benzimidazole;

7-氟-1-(4-{[(3S)-3-哌啶-1-基吡咯烷-1-基]羰基}苯甲基)-1H-苯并咪唑；7-fluoro-1-(4-{[(3S)-3-piperidin-1-ylpyrrolidin-1-yl]carbonyl}benzyl)-1H-benzimidazole;

(3S)-N-乙基-1-{4-[(7-氟-1H-苯并咪唑-1-基)甲基]苯甲酰基}-N-甲基吡咯烷-3-胺；(3S)-N-ethyl-1-{4-[(7-fluoro-1H-benzimidazol-1-yl)methyl]benzoyl}-N-methylpyrrolidin-3-amine;

7-氟-1-(4-{[(3S)-3-(3-甲基哌啶-1-基)吡咯烷-1-基]羰基}苯甲基)-1H-苯并咪唑；7-fluoro-1-(4-{[(3S)-3-(3-methylpiperidin-1-yl)pyrrolidin-1-yl]carbonyl}benzyl)-1H-benzimidazole;

1-(4-{[(3S)-3-氮杂环丁烷-1-基吡咯烷-1-基]羰基}苯甲基)-7-氟-1H-苯并咪唑；1-(4-{[(3S)-3-azetidin-1-ylpyrrolidin-1-yl]carbonyl}benzyl)-7-fluoro-1H-benzimidazole;

(3′S)-1′-(4-{[2-(三氟甲基)-1H-苯并咪唑-1-基]甲基}苯甲酰基)-1，3′-联吡咯烷；(3'S)-1'-(4-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)-1,3'-bipyrrolidine;

(3′S)-1′-{4-[1-(7-氯-1H-吲哚-1-基)乙基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[1-(7-Chloro-1H-indol-1-yl)ethyl]benzoyl}-1,3'-bipyrrolidine;

(3′S)-1′-{4-[1-(5-氯-2-甲基-1H-苯并咪唑-1-基)乙基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[1-(5-Chloro-2-methyl-1H-benzimidazol-1-yl)ethyl]benzoyl}-1,3'-bipyrrole alkyl;

(3′S)-1′-{4-[(1S)-1-(1H-苯并咪唑-1-基)乙基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1S)-1-(1H-benzimidazol-1-yl)ethyl]benzoyl}-1,3'-bipyrrolidine;

(3′S)-1′-{4-[(1R)-1-(1H-苯并咪唑-1-基)乙基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1R)-1-(1H-benzimidazol-1-yl)ethyl]benzoyl}-1,3'-bipyrrolidine;

(3′S)-1′-{4-[(5-氯-2-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(5-chloro-2-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

(3′S)-1′-{4-[(6-氯-2-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(6-Chloro-2-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

(3′S)-1′-{4-[(1S)-1-(5-氯-2-甲基-1H-苯并咪唑-1-基)乙基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1S)-1-(5-chloro-2-methyl-1H-benzimidazol-1-yl)ethyl]benzoyl}-1,3 '-Bipyrrolidine;

(3′S)-1′-{4-[(1S)-1-(6-氯-2-甲基-1H-苯并咪唑-1-基)乙基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1S)-1-(6-chloro-2-methyl-1H-benzimidazol-1-yl)ethyl]benzoyl}-1,3 '-Bipyrrolidine;

(3′S)-1′-{4-[(1R)-1-(5-氯-2-甲基-1H-苯并咪唑-1-基)乙基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1R)-1-(5-chloro-2-methyl-1H-benzimidazol-1-yl)ethyl]benzoyl}-1,3 '-Bipyrrolidine;

(3′S)-1′-{4-[(1R)-1-(6-氯-2-甲基-1H-苯并咪唑-1-基)乙基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1R)-1-(6-chloro-2-methyl-1H-benzimidazol-1-yl)ethyl]benzoyl}-1,3 '-Bipyrrolidine;

(3S)-1-{4-[(1R)-1-(6-氯-2-甲基-1H-苯并咪唑-1-基)乙基]苯甲酰基}吡咯烷-3-胺；(3S)-1-{4-[(1R)-1-(6-Chloro-2-methyl-1H-benzimidazol-1-yl)ethyl]benzoyl}pyrrolidin-3-amine;

(3S)-1-{4-[(1R)-1-(5-氯-2-甲基-1H-苯并咪唑-1-基)乙基]苯甲酰基}吡咯烷-3-胺；(3S)-1-{4-[(1R)-1-(5-Chloro-2-methyl-1H-benzimidazol-1-yl)ethyl]benzoyl}pyrrolidin-3-amine;

(3′S)-1′-{4-[(5-氯-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(5-Chloro-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

(3′S)-1′-{4-[(6-氯-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(6-Chloro-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;

(3S)-1-{4-[(5-氯-1H-苯并咪唑-1-基)甲基]苯甲酰基}吡咯烷-3-胺；(3S)-1-{4-[(5-Chloro-1H-benzimidazol-1-yl)methyl]benzoyl}pyrrolidin-3-amine;

(3S)-1-{4-[(1S)-1-(6-氯-2-甲基-1H-苯并咪唑-1-基)乙基]苯甲酰基}吡咯烷-3-胺；(3S)-1-{4-[(1S)-1-(6-Chloro-2-methyl-1H-benzimidazol-1-yl)ethyl]benzoyl}pyrrolidin-3-amine;

(3S)-1-{4-[(1S)-1-(5-氯-2-甲基-1H-苯并咪唑-1-基)乙基]苯甲酰基}吡咯烷-3-胺；(3S)-1-{4-[(1S)-1-(5-Chloro-2-methyl-1H-benzimidazol-1-yl)ethyl]benzoyl}pyrrolidin-3-amine;

(3′S)-1′-{4-[1-(5-氯-1H-吲哚-1-基)乙基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[1-(5-Chloro-1H-indol-1-yl)ethyl]benzoyl}-1,3'-bipyrrolidine;

1-(1-{4-[(3′S)-1，3′-联吡咯烷-1′-基羰基]苯基}乙基)-1H-吲哚-5-甲腈；1-(1-{4-[(3′S)-1,3′-bipyrrolidin-1′-ylcarbonyl]phenyl}ethyl)-1H-indole-5-carbonitrile;

2-甲基-1-[1-(4-{[(1R，4R)-5-甲基-2，5-二氮杂双环[2.2.1]庚-2-基]羰基}苯基]-1H-苯并咪唑；2-Methyl-1-[1-(4-{[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}phenyl] -1H-benzimidazole;

1-{4-[(3-吡咯烷-1-基哌啶-1-基)羰基]苯甲基}-1H-苯并咪唑；1-{4-[(3-Pyrrolidin-1-ylpiperidin-1-yl)carbonyl]benzyl}-1H-benzimidazole;

1′-[4-(1H-苯并咪唑-1-基甲基)苯甲酰基]-1，3′-联哌啶；1'-[4-(1H-benzimidazol-1-ylmethyl)benzoyl]-1,3'-bipiperidine;

1-(4-{[3-(2-甲基吡咯烷-1-基)哌啶-1-基]羰基}苯甲基)-1H-苯并咪唑；1-(4-{[3-(2-methylpyrrolidin-1-yl)piperidin-1-yl]carbonyl}benzyl)-1H-benzimidazole;

4-(1H-苯并咪唑-1-基甲基)-N-(2-吡咯烷-1-基乙基)苯甲酰胺；4-(1H-benzimidazol-1-ylmethyl)-N-(2-pyrrolidin-1-ylethyl)benzamide;

4-[(2-甲基-1H-苯并咪唑-1-基)甲基]-N-(2-吡咯烷-1-基乙基)苯甲酰胺；4-[(2-Methyl-1H-benzimidazol-1-yl)methyl]-N-(2-pyrrolidin-1-ylethyl)benzamide;

1-(4-{[3-(4-甲基哌啶-1-基)吡咯烷-1-基]羰基}苯甲基)-1H-苯并咪唑；1-(4-{[3-(4-methylpiperidin-1-yl)pyrrolidin-1-yl]carbonyl}benzyl)-1H-benzimidazole;

(2R，3′R)-1′-[4-(1H-苯并咪唑-1-基甲基)苯甲酰基]-2-甲基-1，3′-联吡咯烷；(2R,3'R)-1'-[4-(1H-benzimidazol-1-ylmethyl)benzoyl]-2-methyl-1,3'-bipyrrolidine;

(2S，3′R)-1′-[4-(1H-苯并咪唑-1-基甲基)苯甲酰基]-2-甲基-1，3′-联吡咯烷；(2S,3'R)-1'-[4-(1H-benzimidazol-1-ylmethyl)benzoyl]-2-methyl-1,3'-bipyrrolidine;

其立体异构体；或其医药学上可接受的盐。its stereoisomer; or its pharmaceutically acceptable salt.

可使用常规合成方法且在必要时使用标准分离或拆分技术来制备本发明的化合物。举例来说，可如下制备式I化合物(其中X为CO且p为1)(Ia)：使用标准肽形成条件使式II的苯甲酸与3-羟基吡咯烷反应，诸如在存在1-羟基苯并三唑(HOBT)的情况下在溶剂(诸如二氯甲烷)中以合适碳化二亚胺(诸如1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺)活化羧酸，以得到式III的酰胺；使式III的酰胺与甲烷磺酰氯在存在碱(诸如二异丙基乙胺)的情况下在溶剂(诸如二氯甲烷)中反应以得到相应甲磺酸酯；且以胺HNR₁R₂在溶剂(诸如N，N-二甲基甲酰胺(DMF))中在微波条件下置换所述酯以得到所要式Ia化合物。有利的是，在初始偶合步骤中使用手性3-羟基吡咯烷允许立体特异性合成式III化合物。由于置换反应是以构型反转的立体特异性方式进行，因此使用手性式III化合物会立体特异性地得到所要式Ia化合物。当然，应了解使用外消旋3-羟基吡咯烷将最终得到所需外消旋式Ia产物。反应展示于流程I中。The compounds of the invention can be prepared using conventional synthetic methods and, if necessary, standard separation or resolution techniques. For example, compounds of formula I (where X is CO and p is 1) (Ia) can be prepared by reacting a benzoic acid of formula II with 3-hydroxypyrrolidine using standard peptide-forming conditions, such as in the presence of 1-hydroxybenzene In the case of triazole (HOBT), activation of the carboxylate with a suitable carbodiimide, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, in a solvent such as dichloromethane acid to give the amide of formula III; reacting the amide of formula III with methanesulfonyl chloride in the presence of a base such as diisopropylethylamine in a solvent such as dichloromethane to give the corresponding mesylate and displacement of the ester with the amine HNR₁ R₂ in a solvent such as N,N-dimethylformamide (DMF) under microwave conditions to give the desired compound of formula Ia. Advantageously, the use of a chiral 3-hydroxypyrrolidine in the initial coupling step allows for the stereospecific synthesis of compounds of formula III. Since the displacement reaction proceeds in a stereospecific manner with inversion of configuration, use of a chiral compound of formula III will stereospecifically give the desired compound of formula Ia. Of course, it is understood that use of racemic 3-hydroxypyrrolidine will ultimately give the desired racemic product of formula Ia. The reactions are shown in Scheme I.

流程IProcess I

可如下制备式II化合物(其中R₃为视情况经取代的苯并咪唑-2-基)(IIa)：使式IV的苯甲酸溴甲酯在溶剂(诸如二甲亚砜(DMSO))中与氰化钠反应以得到相应腈化合物；以HCI甲醇溶液水解所述腈以得到相应二酯；选择性地皂化所述二酯以得到式V的羧酸；使用标准肽形成条件使式V的酸与式VI的苯二胺偶合，例如在存在1-羟基苯并三唑(HOBT)的情况下在溶剂(诸如二氯甲烷)中以合适碳化二亚胺(诸如1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺)活化羧酸，以得到相应的酰胺；经由在140℃下以乙酸处理来环化所述酰胺，继而碱水解以得到所要式IIa的苯并咪唑-2-基化合物。反应展示于流程II中，其中R′为C₁-C₄烷基；R为如上所述的任选取代基；且p为0、1或2。Compounds of formula II (where R is optionally substituted benzimidazol-₂ -yl) (IIa) can be prepared by allowing bromomethyl benzoate of formula IV in a solvent such as dimethyl sulfoxide (DMSO) Reaction with sodium cyanide to give the corresponding nitrile compound; hydrolysis of the nitrile with methanolic HCI to give the corresponding diester; selective saponification of the diester to give the carboxylic acid of formula V; use of standard peptide formation conditions to make the carboxylic acid of formula V Acids are coupled with phenylenediamines of formula VI, for example in the presence of 1-hydroxybenzotriazole (HOBT) in a solvent such as methylene chloride with a suitable carbodiimide such as 1-(3-dimethyl (aminopropyl)-3-ethylcarbodiimide) to give the corresponding amide; cyclization of the amide via treatment with acetic acid at 140 °C, followed by base hydrolysis to give the desired benzene of formula IIa And imidazol-2-yl compounds. The reaction is shown in Scheme II, where R' is_Ci -_C4 alkyl; R is an optional substituent as described above; and p is 0, 1 or 2.

流程IIProcess II

可如下制备式I化合物(其中X为CO；p为1；且R₃为NR₄R₅)(Ib)：使式IV的苯甲酸溴甲酯在存在碱(诸如氢化钠或叔丁醇钾)的情况下与式VII的环胺反应以得到式VIII化合物；通过在合适溶剂(诸如甲醇/水)中酸水解或碱水解(例如硫酸或氢氧化锂)来水解式VIII的酯以得到式IX的相应酸：且使式IX的酸与式X的3-氨基吡咯烷化合物在存在合适偶合剂(诸如二异丙基碳化二亚胺)的情况下偶合以得到所要式Ib化合物。反应展示于流程III中，其中R′为C₁-C₄烷基。Compounds of formula I (wherein X is CO; p is 1; and R₃ is NR₄ R₅ ) (Ib) can be prepared by reacting bromomethyl benzoate of formula IV in the presence of a base such as sodium hydride or potassium tert-butoxide ) with a cyclic amine of formula VII to give a compound of formula VIII; hydrolysis of an ester of formula VIII by acid hydrolysis or basic hydrolysis (for example sulfuric acid or lithium hydroxide) in a suitable solvent such as methanol/water to give a compound of formula The corresponding acid of IX: and the acid of formula IX is coupled with a 3-aminopyrrolidine compound of formula X in the presence of a suitable coupling agent such as diisopropylcarbodiimide to give the desired compound of formula Ib. The reaction is shown in Scheme III, where R' is C₁ -C₄ alkyl.

流程IIIProcess III

视情况可将式IX的酸转化成活化部分，诸如通过以乙二酰氯处理而转化成相应酰基氯或通过以三甲基乙酰氯和三乙胺处理而转化成混合酸酐；且可使活化酸与式X的3-氨基吡咯烷偶合以得到所要式Ib化合物。The acid of formula IX can optionally be converted to the activated moiety, such as by treatment with oxalyl chloride to the corresponding acid chloride or to the mixed anhydride by treatment with trimethylacetyl chloride and triethylamine; and the activated acid can be made Coupling with a 3-aminopyrrolidine of formula X affords the desired compound of formula Ib.

或者，可如下制备式Ib化合物：使式IX的苯甲酸与乙二酰氯反应以形成相应酰基氯；使所述酰基氯与3-吡咯烷醇偶合以得到式XI化合物；使式XI化合物与甲烷磺酰氯反应以得到式XII的相应甲磺酸酯；且使所述甲磺酸酯与胺HNR₁R₂反应以得到所要式Ib化合物。反应展示于流程IV中，其中Ms表示CH₃SO₂。Alternatively, compounds of formula Ib can be prepared by reacting a benzoic acid of formula IX with oxalyl chloride to form the corresponding acid chloride; coupling the acid chloride with 3-pyrrolidinol to give a compound of formula XI; reacting a compound of formula XI with methane The sulfonyl chloride is reacted to give the corresponding mesylate of formula XII; and the mesylate is reacted with the amine HNR₁ R₂ to give the desired compound of formula Ib._The reaction is shown in Scheme IV, where Ms represents_CH3SO2 .

流程IVProcess IV

还可通过反转反应序列来制备式Ib化合物，例如可使式XIII的氯甲基苯甲酰氯与式X的3-氨基吡咯烷在存在合适碱(诸如二异丙基乙胺)的情况下偶合以得到式XIV的氯甲基苯甲酰胺且可使所述氯甲基式XIV化合物与式VII的环胺如上文在反应流程III中所述偶合以得到所需式Ib化合物。反应展示于流程V中。Compounds of formula Ib can also be prepared by reversing the reaction sequence, for example chloromethylbenzoyl chloride of formula XIII can be combined with 3-aminopyrrolidine of formula X in the presence of a suitable base such as diisopropylethylamine Coupling gives chloromethyl benzamides of formula XIV and can be coupled with cyclic amines of formula VII as described above in Reaction Scheme III to give the desired compounds of formula Ib. The reactions are shown in Scheme V.

流程VProcess V

可通过使式XV的苯磺酰氯与式X的3-氨基吡咯烷或3-氨基哌啶反应以得到所要式Ic化合物来制备式I化合物(其中X为SO₂)(Ic)。反应展示于流程VI中。Compounds of formula I (where X is_SO2 ) (Ic) can be prepared by reacting benzenesulfonyl chloride of formula XV with 3-aminopyrrolidine or 3-aminopiperidine of formula X to give the desired compound of formula Ic. The reactions are shown in Scheme VI.

流程VIProcess VI

可通过以合适还原剂(诸如LiAlH₄或硼烷)还原式Ia化合物以得到所要式Ib化合物来容易地制备式I化合物(其中X为CH₂且p为1)(Id)。反应展示于流程VII中。Compounds of formula I (where X is CH2 and_p is 1) (Id) can be readily prepared by reducing compounds of formula Ia with a suitable reducing agent such as_LiAlH4 or borane to give the desired compound of formula Ib. The reaction is shown in Scheme VII.

流程VIIProcess VII

可如流程I、III、IV、V和VII中所示且以相应3-羟基哌啶或3-羟基高哌啶或哌啶-3-基胺或高哌啶-3-基胺化合物替代3-羟基吡咯烷或吡咯烷-3-基胺来制备式Ia、Ib和Id的化合物(其中p为2或3)。3 can be as shown in Schemes I, III, IV, V and VII and replaced by the corresponding 3-hydroxypiperidine or 3-hydroxyhomopiperidine or piperidin-3-ylamine or homopiperidin-3-ylamine compound -Hydroxypyrrolidine or pyrrolidin-3-ylamine to prepare compounds of formulas Ia, Ib and Id (where p is 2 or 3).

有利的是，本发明提供一种制备式I化合物的方法，所述方法包含使式XVI化合物在存在微波照射的情况下视情况在存在溶剂的情况下与胺HNR₁R₂反应。方法展示于流程VIII中。Advantageously, the present invention provides a process for the preparation of a compound of formula I comprising reacting a compound of formula XVI with an amine HNR₁ R₂ in the presence of microwave irradiation, optionally in the presence of a solvent. The method is shown in Scheme VIII.

流程VIIIProcess VIII

适用于本发明的方法中的溶剂包括二甲基甲酰胺、乙腈、四氢呋喃或其类似物。Solvents suitable for use in the process of the present invention include dimethylformamide, acetonitrile, tetrahydrofuran or the like.

有利的是，本发明的式I化合物可用于治疗与组胺-3受体相关或由组胺-3受体影响的CNS病症，所述病症包括认知障碍(例如阿兹海默氏症)、轻度认知障碍、注意力不足过动症、精神分裂症、记忆丧失、睡眠障碍、肥胖或其类似病症。因此，本发明提供一种治疗有需要的患者的与组胺-3受体相关或由组胺-3受体影响的中枢神经系统病症的方法，所述方法包含向所述患者提供治疗有效量的如上所述的式I化合物。可通过经口或不经肠投药或已知可将治疗剂有效投与有需要的患者的任何常用方式提供化合物。Advantageously, the compounds of formula I according to the invention are useful in the treatment of CNS disorders associated with or affected by histamine-3 receptors, including cognitive disorders (such as Alzheimer's disease) , mild cognitive impairment, ADHD, schizophrenia, memory loss, sleep disturbance, obesity, or similar conditions. Accordingly, the present invention provides a method of treating a central nervous system disorder associated with or affected by histamine-3 receptors in a patient in need thereof, said method comprising providing said patient with a therapeutically effective amount of A compound of formula I as described above. The compounds may be provided by oral or parenteral administration or any conventional means known to effectively administer a therapeutic agent to a patient in need thereof.

如本文所用的关于提供由本发明涵盖的化合物或物质的术语“提供”表示直接投与所述化合物或物质，或投与在体内形成等量的化合物或物质的前药、衍生物或类似物。The term "providing" as used herein in relation to providing a compound or substance encompassed by the present invention means administering said compound or substance directly, or administering a prodrug, derivative or analog that forms an equivalent amount of the compound or substance in vivo.

本发明的方法包括：一种治疗精神分裂症的方法；一种治疗与记忆、认知或学习不足相关的疾病或认知障碍(诸如阿兹海默氏症或注意力不足过动症)的方法；一种治疗轻度认知障碍的方法；一种治疗发育障碍(诸如精神分裂症)的方法；一种治疗睡眠障碍或任何与H3受体相联系或相关的其它CNS疾病或病症的方法。The methods of the invention include: a method of treating schizophrenia; a method of treating a disease or cognitive impairment associated with memory, cognition or learning deficits such as Alzheimer's disease or attention deficit hyperactivity disorder A method; a method of treating mild cognitive impairment; a method of treating developmental disorders such as schizophrenia; a method of treating sleep disorders or any other CNS disease or condition linked or associated with H3 receptors .

在一实施例中，本发明提供一种治疗儿童与成年人的注意力不足过动症(ADHD，也称为注意力不足症或ADD)的方法。因此，在此实施例中，本发明提供一种治疗儿科患者的注意力不足症的方法。In one embodiment, the present invention provides a method of treating Attention Deficit Hyperactivity Disorder (ADHD, also known as Attention Deficit Disorder or ADD) in children and adults. Thus, in this embodiment, the invention provides a method of treating attention deficit disorder in a pediatric patient.

因此，本发明提供一种治疗患者(优选人类)的上文列出的各病状的方法，所述方法包含向所述患者提供治疗有效量的如上所述的式I化合物。可通过经口或不经肠投药或已知可将治疗剂有效投与有需要的患者的任何常用方式提供化合物。Accordingly, the present invention provides a method of treating each of the above-listed conditions in a patient, preferably a human, comprising providing said patient with a therapeutically effective amount of a compound of formula I as described above. The compounds may be provided by oral or parenteral administration or any conventional means known to effectively administer a therapeutic agent to a patient in need thereof.

在特定CNS病症的治疗中所提供的治疗有效量可根据所治疗的特定病状、患者的体型、年龄和反应模式、病症严重性、主治医师的判断和其类似因素而变化。大体来说，每日经口投药的有效量可为约0.01至1,000mg/kg、优选约0.5至500mg/kg且不经肠投药的有效量可为约0.1至100mg/kg、优选约0.5至50mg/kg。A therapeutically effective amount provided in the treatment of a particular CNS disorder may vary depending on the particular condition being treated, the size, age and response pattern of the patient, the severity of the disorder, the judgment of the attending physician, and the like. In general, the effective amount for oral administration can be about 0.01 to 1,000 mg/kg, preferably about 0.5 to 500 mg/kg per day, and the effective amount for parenteral administration can be about 0.1 to 100 mg/kg, preferably about 0.5 to 500 mg/kg. 50mg/kg.

在实际操作中，通过单独或与一种或一种以上常规医药载剂或赋形剂组合投与固体或液体形式的化合物或其前体来提供本发明的化合物。因此，本发明提供医药组合物，所述医药组合物包含医药学上可接受的载剂和有效量的如上所述的式I化合物。In practice, the compounds of the invention are provided by administering the compounds, or precursors thereof, in solid or liquid form, alone or in combination with one or more conventional pharmaceutical carriers or excipients. Accordingly, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective amount of a compound of formula I as described above.

在一实施例中，本发明涉及包含至少一种式I化合物或其医药学上可接受的盐和一种或一种以上医药学上可接受的载剂、赋形剂或稀释剂的组合物。所述组合物包括治疗或控制中枢神经系统的疾病病况或病状的医药组合物。在某些实施例中，所述组合物包含一种或一种以上式I化合物的混合物。In one embodiment, the present invention relates to a composition comprising at least one compound of formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, excipients or diluents . Such compositions include pharmaceutical compositions that treat or manage disease states or conditions of the central nervous system. In certain embodiments, the composition comprises a mixture of one or more compounds of Formula I.

在某些实施例中，本发明涉及包含至少一种式I化合物或其医药学上可接受的盐和一种或一种以上医药学上可接受的载剂、赋形剂或稀释剂的组合物。根据可接受的医药程序制备所述组合物。医药学上可接受的载剂为与调配物中的其它成分相容且在生物学上可接受的载剂。In certain embodiments, the present invention relates to a combination comprising at least one compound of formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, excipients or diluents thing. The compositions are prepared according to accepted pharmaceutical procedures. A pharmaceutically acceptable carrier is one that is compatible with the other ingredients in the formulation and is biologically acceptable.

可经口或不经肠地单独或与常规医药载剂组合投与式I化合物。可应用的固体载剂可包括一种或一种以上还可充当调味剂、润滑剂、增溶剂、悬浮剂、填充剂、助流剂、压缩助剂、粘合剂、片剂崩解剂或包装材料的物质。在散剂中，载剂为与细粉状活性成分混合的细粉状固体。在片剂中，活性成分以合适比例与具有必需压缩性质的载剂混合且压制成所要形状和尺寸。散剂和片剂优选含有至多99％的活性成分。合适的固体载剂包括(例如)磷酸钙、硬脂酸镁、滑石、糖、乳糖、糊精、淀粉、明胶、纤维素、甲基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷、低熔点蜡和离子交换树脂。Compounds of formula I can be administered orally or parenterally, alone or in combination with conventional pharmaceutical carriers. Applicable solid carriers may include one or more substances that may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, tablet disintegrating agents or The substance of the packaging material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with the carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Powders and tablets preferably contain up to 99% active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, Low melting point waxes and ion exchange resins.

在某些实施例中，以适用于儿科投药的崩解片剂调配物提供式I化合物。In certain embodiments, the compound of Formula I is provided in a disintegrating tablet formulation suitable for pediatric administration.

液体载剂可用于制备溶液、悬浮液、乳液、糖浆和酏剂。可将活性成分溶于或悬浮于医药学上可接受的液体载剂(诸如水、有机溶剂、两者的混合物或医药学上可接受的油或脂肪)中。液体载剂可含有其它合适医药添加剂，诸如增溶剂、乳化剂、缓冲剂、防腐剂、甜味剂、调味剂、悬浮剂、增稠剂、着色剂、粘度调节剂、稳定剂或渗透调节剂。用于经口和不经肠投药的液体载剂的合适实例包括水(尤其含有上述添加剂，例如纤维素衍生物，优选羧甲基纤维素钠溶液)、醇类(包括一元醇和多元醇，例如二醇)和其衍生物和油类(例如经分馏的椰子油和花生油)。对于不经肠投药来说，载剂还可为油性酯，诸如油酸乙酯和肉豆蔻酸异丙酯。在用于不经肠投药的无菌液体形式组合物中使用无菌液体载剂。用于加压组合物的液体载剂可为卤化烃或其它医药学上可接受的推进剂。Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators . Suitable examples of liquid carriers for oral and parenteral administration include water (especially containing the above-mentioned additives, such as cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric and polyhydric alcohols, such as glycols) and their derivatives and oils (such as fractionated coconut oil and peanut oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.

在某些实施例中，提供液体医药组合物，其中所述组合物适用于儿科投药。在其它实施例中，液体组合物为糖浆或悬浮液。In certain embodiments, liquid pharmaceutical compositions are provided, wherein the compositions are suitable for pediatric administration. In other embodiments, the liquid composition is a syrup or suspension.

可通过(例如)肌肉内、腹膜内或皮下注射来投与作为无菌溶液或悬浮液的液体医药组合物。还可静脉内投与无菌溶液。用于经口投药的组合物可采取液体或固体形式。Liquid pharmaceutical compositions can be administered as sterile solutions or suspensions, for example, by intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration may take liquid or solid form.

可以常规栓剂的形式经直肠或经阴道投与式I化合物。对于通过鼻内或支气管内吸入或吹入的投药来说，可将式I化合物调配成水溶液或部分水溶液，接着可以气雾剂的形式使用。还可经由使用皮肤贴来经皮投与式I化合物，所述皮肤贴含有活性化合物和对所述活性化合物呈惰性、对皮肤无毒且允许用于全身吸收的药剂经由皮肤递送至血流中的载剂。所述载剂可采取多种形式，诸如乳膏和软膏、糊剂、凝胶和闭塞装置。乳膏和软膏可为水包油型或油包水型粘性液体或半固体乳液。由分散于含有活性成分的石油或亲水性石油中的吸收性粉末构成的糊剂也合适。各种闭塞装置可用于将活性成分释放至血流中，诸如覆盖含有活性成分且有或无载剂的容器或含有活性成分的基质的半透膜。文献中已知其它闭塞装置。Compounds of formula I may be administered rectally or vaginally in the form of conventional suppositories. For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of formula I may be formulated as aqueous or partially aqueous solutions which may then be administered in aerosol form. Compounds of Formula I may also be administered transdermally via the use of a skin patch containing the active compound and an agent that is inert to the active compound, nontoxic to the skin, and allows transdermal delivery of the agent for systemic absorption into the bloodstream. carrier. The carrier may take various forms, such as creams and ointments, pastes, gels and occlusive devices. Creams and ointments may be viscous liquid or semisolid emulsions of the oil-in-water or water-in-oil type. Pastes consisting of absorbent powder dispersed in petroleum or hydrophilic petroleum containing the active ingredient are also suitable. Various occlusive devices can be used to release the active ingredient into the bloodstream, such as a semipermeable membrane covering a container containing the active ingredient with or without a carrier or a matrix containing the active ingredient. Other occlusive devices are known in the literature.

医药组合物优选采取单位剂型，例如片剂、胶囊、散剂、溶液、悬浮液、乳液、颗粒或栓剂。在所述形式中，组合物细分为含有适量活性成分的单位剂量；单位剂型可为包装组合物，例如包装粉末、小瓶、安瓶、预填充注射器或含有液体的药囊。举例来说，单位剂型自身可为胶囊或片剂，或其可为包装形式的适当数目的任何所述组合物。Pharmaceutical compositions are preferably in unit dosage form, such as tablets, capsules, powders, solutions, suspensions, emulsions, granules or suppositories. In such form, the composition is subdivided into unit doses containing appropriate quantities of the active ingredient; the unit dosage form can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. For example, the unit dosage form can be a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

向患者提供的式I化合物的治疗有效量将视所投与的物质、投药目的(诸如预防或治疗)、患者状态、投药方式或类似因素而变化。在治疗应用中，式I化合物是以足以治疗或至少部分治疗病状和其并发症的症状的量提供给受病状困扰的患者。足够实现此目的的量为如上文所述的“治疗有效量”。欲用于治疗特定病例的剂量必须由主治医师凭主观决定。所涉及的变数包括特定病状和患者体型、年龄和反应模式。大体来说，开始剂量为每日约5mg，每日剂量逐渐增加至每日约150mg以在患者体内提供所需的剂量水平。The therapeutically effective amount of a compound of formula I provided to a patient will vary depending on the substance being administered, the purpose of the administration (such as prophylaxis or therapy), the state of the patient, the mode of administration, or the like. In therapeutic applications, compounds of formula I are administered to a patient afflicted by the condition in an amount sufficient to treat, or at least partially treat, the symptoms of the condition and its complications. An amount sufficient to accomplish this is a "therapeutically effective amount" as described above. The dosage to be used in the treatment of a particular case must be determined subjectively by the attending physician. The variables involved include the specific condition and patient size, age and response pattern. In general, the starting dose is about 5 mg per day and the daily dose is gradually increased to about 150 mg per day to provide the desired dosage level in the patient.

在某些实施例中，本发明涉及式I化合物的前药。如本文所用的术语“前药”意谓可在活体内通过代谢方式(例如通过水解)转化成式I化合物的化合物。所属领域中已知各种形式的前药，诸如论述于(例如)下列文献中的形式：邦加德(Bundgaard)(编)，前药设计(Design of Prodrugs)，爱思唯尔公司(Elsevier)(1985)；韦德(Widder)等人(编)，酶学方法(Methods in Enzymology)，第4卷，学术出版社(Academic Press)(1985)；克洛斯加德-拉尔森(Krogsgaard-Larsen)等人(编)“前药设计和应用以及药物设计和研发的教科书”(＂Design and Application of Prodrugs，Textbook of Drug Design andDevelopment＂)，第5章，113-191(1991)，邦加德(Bundgaard)等人，药物递送综述杂志(Journal of Drug Delivery Reviews)，8：1-38(1992)，邦加德(Bundgaard)，药学杂志(J.ofPharmaceutical Sciences)，77：285和以下(1988)；和桶口(Higuchi)和斯特拉(Stella)(编)作为新颖药物递送系统的前药(Prodrugs as Novel Drug Delivery Systems)，美国化学协会(American Chemical Society)(1975)。In certain embodiments, the present invention relates to prodrugs of compounds of Formula I. The term "prodrug" as used herein means a compound that can be converted into a compound of formula I in vivo by metabolic means, for example by hydrolysis. Various forms of prodrugs are known in the art, such as those discussed in, for example, Bundgaard (ed.), Design of Prodrugs, Elsevier ) (1985); Widder et al (eds), Methods in Enzymology, Volume 4, Academic Press (1985); Krogsgaard-Larson -Larsen) et al. (eds.) "Design and Application of Prodrugs, Textbook of Drug Design and Development", Chapter 5, 113-191 (1991), Bang Bundgaard et al., Journal of Drug Delivery Reviews, 8:1-38 (1992), Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975).

为更清楚地理解且为更清楚地说明本发明，下文列出其特定实例。下列实例仅具说明性且不应理解为以任何方式限制本发明的范围和基本原则。术语HPLC和¹H NMR分别表示高效液相色谱和质子核磁共振。术语MS表示质谱分析，其中(+)是指一般得到M+1(或M+H)吸收(其中M＝分子质量)的正离子模式。至少通过MS和¹H NMR分析所有化合物。术语DMF和THF分别表示二甲基甲酰胺和四氢呋喃。在化学图式中，术语Ph表示苯基。除非另有说明，否则所有份数都是重量份数。For a clearer understanding and to more clearly illustrate the present invention, specific examples thereof are listed below. The following examples are illustrative only and should not be construed as limiting the scope and underlying principles of the invention in any way. The terms HPLC and¹ H NMR denote high performance liquid chromatography and proton nuclear magnetic resonance, respectively. The term MS means mass spectrometry, where (+) refers to the positive ion mode which generally gives M+1 (or M+H) absorption (where M=molecular mass). All compounds were analyzed by at least MS and¹ H NMR. The terms DMF and THF denote dimethylformamide and tetrahydrofuran, respectively. In chemical schemes, the term Ph means phenyl. All parts are by weight unless otherwise indicated.

实例1Example 1

N，N-二甲基-1-{4-[(2-苯基-1H-苯并咪唑-1-基)甲基]-苯甲酰基}吡咯烷-3-基胺的制备Preparation of N,N-dimethyl-1-{4-[(2-phenyl-1H-benzimidazol-1-yl)methyl]-benzoyl}pyrrolidin-3-ylamine

步骤1.将2-苯基苯并咪唑(5mmol，0.97g)溶于THF/DMF(5:1，20mL)中且添加氢化钠(0.5g)。在室温下搅拌10分钟之后，添加4-(溴甲基)苯甲酸甲酯(1.4g，6mmo1)。将反应在室温下搅拌整夜，接着以EtOAc(100mL)稀释且以饱和NaHCO₃洗涤，经MgSO₄干燥且浓缩。通过HPLC^*和MS[343.2m/e(M+H)]鉴定所得残余物且将其用于下一步骤。Step 1. 2-Phenylbenzimidazole (5 mmol, 0.97 g) was dissolved in THF/DMF (5:1, 20 mL) and sodium hydride (0.5 g) was added. After stirring at room temperature for 10 minutes, methyl 4-(bromomethyl)benzoate (1.4 g, 6 mmol) was added. The reaction was stirred at room temperature overnight, then diluted with EtOAc (100 mL) and washed with sat. NaHCO₃ , dried over MgSO₄ and concentrated. The resulting residue was identified by HPLC^* and MS [343.2 m/e (M+H)] and used in the next step.

步骤2.将步骤1中所获得的4-(2-苯基-苯并咪唑-1-基甲基)-苯甲酸甲酯溶于MeOH/水(2:1，30mL)中，以氢氧化锂(0.42g，10mmol)处理，在室温下搅拌整夜，蒸发以去除MeOH，以1N氢氧化钠(50mL)稀释，以EtOAc洗涤，以浓HCl酸化且以EtOAc萃取。合并萃取物，经MgSO₄干燥且浓缩。通过HPLC^*和MS[329.2m/e(M+H)]鉴定所得残余物且将其用于下一步骤。Step 2. Dissolve the 4-(2-phenyl-benzimidazol-1-ylmethyl)-benzoic acid methyl ester obtained in step 1 in MeOH/water (2:1, 30 mL) and Lithium (0.42 g, 10 mmol), stirred overnight at room temperature, evaporated to remove MeOH, diluted with 1 N sodium hydroxide (50 mL), washed with EtOAc, acidified with conc. HCl and extracted with EtOAc. The extracts were combined, dried over MgSO₄ and concentrated. The resulting residue was identified by HPLC^* and MS [329.2 m/e (M+H)] and used in the next step.

步骤3.将步骤2中所获得的4-(2-苯基-苯并咪唑-1-基甲基)-苯甲酸(0.2mmol)溶于DCM(5mL)中且添加乙二酰氯(0.2mL，0.4mmol，DCM中的2M溶液)和DMF(2滴)。将溶液在室温下搅拌2小时，接着在真空中浓缩。将残余物溶于THF中，以二异丙基乙胺(DIEA)(0.09mL，0.5mmol)和3-(二甲基氨基)吡咯烷(0.22mmol，22μL)处理，在室温下搅拌整夜，接着浓缩。将此残余物溶于DMSO、MeOH和水的混合物(1.5mL)中且通过逆相半制备型HPLC¹纯化为呈白色粉末的标题产物(13mg)，由HPLC²和MS[425.2m/e(M+H)]加以鉴定。Step 3. 4-(2-Phenyl-benzimidazol-1-ylmethyl)-benzoic acid (0.2 mmol) obtained in step 2 was dissolved in DCM (5 mL) and oxalyl chloride (0.2 mL , 0.4 mmol, 2M solution in DCM) and DMF (2 drops). The solution was stirred at room temperature for 2 hours, then concentrated in vacuo. The residue was dissolved in THF, treated with diisopropylethylamine (DIEA) (0.09 mL, 0.5 mmol) and 3-(dimethylamino)pyrrolidine (0.22 mmol, 22 μL) and stirred at room temperature overnight , followed by concentration. This residue was dissolved in a mixture of DMSO, MeOH and water (1.5 mL) and purified by reverse phase semi-preparative HPLC¹ to give the title product (13 mg) as a white powder by HPLC² and MS [425.2 m/e ( M+H)] to be identified.

实例2Example 2

(3-S)-N，N-二甲基-1-{4-[(2-苯基-1H-苯并咪唑-1-基)甲基]-苯甲酰基}吡咯烷-3-基胺的(3-S)-N,N-Dimethyl-1-{4-[(2-phenyl-1H-benzimidazol-1-yl)methyl]-benzoyl}pyrrolidin-3-yl Amine制备preparation

基本上使用实例1中所述的相同程序且在步骤3中使用(3-S)-二甲基氨基吡咯烷，获得标题化合物且由HPLC和质谱分析加以鉴定。MS[425.2]m/e(M+H)，滞留时间2.94min。Using essentially the same procedure as described in Example 1 and using (3-S)-dimethylaminopyrrolidine in step 3, the title compound was obtained and identified by HPLC and mass spectral analyses. MS[425.2]m/e(M+H), retention time 2.94min.

实例3Example 3

(3-R)-N，N-二甲基-1-{4-[(2-苯基-1H-苯并咪唑-1-基)甲基]-苯甲酰基}吡咯烷-3-基胺的制(3-R)-N,N-Dimethyl-1-{4-[(2-phenyl-1H-benzimidazol-1-yl)methyl]-benzoyl}pyrrolidin-3-yl Amine production备prepare

基本上使用实例1中所述的相同程序且在步骤3中使用(3-R)-二甲基氨基吡咯烷，获得标题化合物且由HPLC和质谱分析加以鉴定。MS[425.2]m/e(M+H)，滞留时间2.92min。Using essentially the same procedure as described in Example 1 and using (3-R)-dimethylaminopyrrolidine in step 3, the title compound was obtained and identified by HPLC and mass spectral analyses. MS[425.2]m/e(M+H), retention time 2.92min.

实例4-7Example 4-7

N，N-二甲基-1-{4-[(经取代-1H-苯并咪唑-1-基)甲基]-苯甲酰基}吡咯烷-3-基胺的制备Preparation of N, N-dimethyl-1-{4-[(substituted-1H-benzimidazol-1-yl)methyl]-benzoyl}pyrrolidin-3-ylamine

基本上使用实例1中所述的相同程序且在步骤1中使用适当苯并咪唑，获得表I中所示的化合物且由HPLC和质谱分析加以鉴定。HPLC条件：A＝水中0.02％的TFA，B＝乙腈中0.02％的TFA，5min.内为10-95％B，1.0mL/min，50℃，215nm检测，Waters Xterra^TM2×50mm管柱。Using essentially the same procedure as described in Example 1 and using the appropriate benzimidazole in Step 1, the compounds shown in Table I were obtained and identified by HPLC and mass spectral analyses. HPLC conditions: A=0.02% TFA in water, B=0.02% TFA in acetonitrile, 10-95% B within 5min., 1.0mL/min, 50°C, 215nm detection, Waters Xterra^TM 2×50mm column.

表ITable I

实例8-11Example 8-11

N-经取代-1-[3-(1H-苯并咪唑-1-基)甲基]-苯甲酰基}氮杂环-3-基胺的制备Preparation of N-substituted-1-[3-(1H-benzimidazol-1-yl)methyl]-benzoyl}azacyclo-3-ylamine

基本上使用实例1中所述的相同程序且在步骤1中使用3-溴甲基苯甲酸甲酯并在步骤3中使用适当吡咯烷-3-基-胺或哌啶-3-基-胺，获得表II中所示的化合物且由HPLC和质谱分析或由¹H NMR和质谱分析加以鉴定。Using essentially the same procedure as described in Example 1 and using methyl 3-bromomethylbenzoate in step 1 and the appropriate pyrrolidin-3-yl-amine or piperidin-3-yl-amine in step 3 , the compounds shown in Table II were obtained and identified by HPLC and mass spectrometry or by¹ H NMR and mass spectrometry.

表IITable II

实例12Example 12

1-[4-(1H-吲哚-1-基甲基)苯甲酰基]-N，N-二甲基吡咯烷-3-基胺的制备Preparation of 1-[4-(1H-indol-1-ylmethyl)benzoyl]-N,N-dimethylpyrrolidin-3-ylamine

步骤1.将3-(二甲基氨基)吡咯烷(2.5g，22mmol)于乙腈中的溶液添加至4-(氯甲基)苯甲酰氯(5.0g，26mmol)于乙腈中的冰冷溶液中，在温至室温的同时搅拌2小时，接着在真空中浓缩。将所得残余物悬浮于乙醚中且过滤以得到呈白色固体的1-(4-氯甲基苯甲酰基)-3-(N，N-二甲基氨基)吡咯烷盐酸盐，由NMR和MS[267m/e(M+H)]加以鉴定。Step 1. A solution of 3-(dimethylamino)pyrrolidine (2.5 g, 22 mmol) in acetonitrile was added to an ice-cold solution of 4-(chloromethyl)benzoyl chloride (5.0 g, 26 mmol) in acetonitrile , stirred for 2 hours while warming to room temperature, then concentrated in vacuo. The resulting residue was suspended in diethyl ether and filtered to give 1-(4-chloromethylbenzoyl)-3-(N,N-dimethylamino)pyrrolidine hydrochloride as a white solid, which was determined by NMR and It was identified by MS [267m/e (M+H)].

步骤2.在室温下以氢化钠(30mg)处理吲哚(29mg，0.25mmol)于DMF(5mL)中的溶液，搅拌10分钟，以1-(4-氯甲基苯甲酰基)-3-(N，N-二甲基氨基)吡咯烷盐酸盐(113mg，0.37mmol)处理，在室温下搅拌整夜且在真空中浓缩。将所得残余物溶于DMSO、MeOH和水的混合物(1.5mL)中且通过逆相半制备型HPLC纯化以得到呈白色粉末的标题产物(63mg)，由HPLC和质谱分析加以鉴定。MS[348.2m/e(M+H)]，滞留时间2.58min。Step 2. A solution of indole (29mg, 0.25mmol) in DMF (5mL) was treated with sodium hydride (30mg) at room temperature, stirred for 10 minutes, and 1-(4-chloromethylbenzoyl)-3- (N,N-Dimethylamino)pyrrolidine hydrochloride (113 mg, 0.37 mmol) was treated, stirred at room temperature overnight and concentrated in vacuo. The resulting residue was dissolved in a mixture of DMSO, MeOH and water (1.5 mL) and purified by reverse phase semi-preparative HPLC to give the title product (63 mg) as a white powder, identified by HPLC and mass spectral analyses. MS [348.2m/e (M+H)], retention time 2.58min.

实例13-39Examples 13-39

N，N-二甲基1-[4-(1H-吲哚-1-基甲基)苯甲酰基]吡咯烷-3-基胺的制备Preparation of N,N-dimethyl 1-[4-(1H-indol-1-ylmethyl)benzoyl]pyrrolidin-3-ylamine

基本上使用实例12中所述的相同程序且在步骤2中使用适当双环胺HNR₄R₅，获得表III中所示的化合物且由HPLC和质谱分析加以鉴定。Using essentially the same procedure as described in Example 12 and using the appropriate bicyclic amine_HNR4R5 in step 2, the compounds shown in Table III were_obtained and identified by HPLC and mass spectral analyses.

表IIITable III

表III(续)Table III (continued)

实例40Example 40

N-乙基-N-甲基-1-{4-[(2-苯基-1H-苯并咪唑-1-基)甲基]苯甲酰基}吡咯烷-3-胺的制备Preparation of N-ethyl-N-methyl-1-{4-[(2-phenyl-1H-benzimidazol-1-yl)methyl]benzoyl}pyrrolidin-3-amine

步骤1.以两滴DMF接着以乙二酰氯(3mL，6mmol，DCM中的2M溶液)处理4-(2-苯基-苯并咪唑-1-基甲基)-苯甲酸(1g，3mmol)于DCM中的溶液，在室温下搅拌2小时且在真空中浓缩。将所得残余物溶于DCM中，以3-吡咯烷醇(0.3mL，3.6mmol)处理，在室温下搅拌8小时，接着浓缩以得到1-{4-[(2-苯基-1H-苯并咪唑-1-基)甲基]苯甲酰基}吡咯烷-3-醇，由HPLC和MS[398.4m/e(M+H)]加以鉴定。Step 1. 4-(2-Phenyl-benzimidazol-1-ylmethyl)-benzoic acid (1 g, 3 mmol) was treated with two drops of DMF followed by oxalyl chloride (3 mL, 6 mmol, 2M solution in DCM) The solution in DCM was stirred at room temperature for 2 hours and concentrated in vacuo. The resulting residue was dissolved in DCM, treated with 3-pyrrolidinol (0.3 mL, 3.6 mmol), stirred at room temperature for 8 hours, then concentrated to give 1-{4-[(2-phenyl-1H-benzene (imidazol-1-yl)methyl]benzoyl}pyrrolidin-3-ol, identified by HPLC and MS [398.4 m/e (M+H)].

步骤2.在0℃下以三乙胺(0.91mL，6.6mmol)接着以甲基磺酰氯(0.25mL，3.3mmol)处理1-{4-[(2-苯基-1H-苯并咪唑-1-基)甲基]苯甲酰基}吡咯烷-3-醇(0.85g，3mmol)于DCM中的溶液，在室温下搅拌整夜且浓缩以得到呈白色粉末的甲烷磺酸1-[4-(2-苯基-苯并咪唑-1-基甲基)-苯甲酰基]-吡咯烷-3-基酯(1.4g)，由HPLC和MS[476.3m/e(M+H)]加以鉴定。Step 2. Treatment of 1-{4-[(2-phenyl-1H-benzimidazole- A solution of 1-yl)methyl]benzoyl}pyrrolidin-3-ol (0.85 g, 3 mmol) in DCM was stirred at room temperature overnight and concentrated to give methanesulfonic acid 1-[4 as a white powder -(2-Phenyl-benzimidazol-1-ylmethyl)-benzoyl]-pyrrolidin-3-yl ester (1.4 g) by HPLC and MS [476.3 m/e (M+H)] be identified.

步骤3.以N-乙基甲胺(0.038mL，0.45mmol)处理甲烷磺酸1-[4-(2-苯基-苯并咪唑-1-基甲基)-苯甲酰基]-吡咯烷-3-基酯(71mg，0.15mmol)于DMF中的溶液，在室温下搅拌整夜且在真空中浓缩。将所得残余物溶于DMSO、MeOH和水的混合物(1.5mL)中且通过逆相半制备型HPLC¹纯化以得到呈白色粉末的标题产物(6.4mg)，由HPLC²和MS[439.6m/e(M+H)]加以鉴定，滞留时间1.48min。Step 3. Treatment of 1-[4-(2-phenyl-benzimidazol-1-ylmethyl)-benzoyl]-pyrrolidine methanesulfonate with N-ethylmethylamine (0.038 mL, 0.45 mmol) A solution of the -3-yl ester (71 mg, 0.15 mmol) in DMF was stirred at room temperature overnight and concentrated in vacuo. The resulting residue was dissolved in a mixture of DMSO, MeOH and water (1.5 mL) and purified by reverse phase semi-preparative HPLC¹ to give the title product (6.4 mg) as a white powder, which was determined by HPLC² and MS [439.6 m/ e(M+H)] to be identified, the retention time is 1.48min.

实例41-85Examples 41-85

N-经取代-1-[(杂芳基甲基)苯甲酰基]吡咯烷-3-基胺化合物的制备Preparation of N-substituted-1-[(heteroarylmethyl)benzoyl]pyrrolidin-3-ylamine compounds

基本上使用实例40中所述的相同程序且在步骤1中使用所要苯甲酸并在步骤3中使用适当胺HNR₁R₂，获得表IV中所示的化合物且由质谱和HPLC或¹H NMR分析加以鉴定。Using essentially the same procedure as described in Example 40 and using the desired benzoic acid in step 1 and the appropriate amine HNR₁ R₂ in step 3, the compounds shown in Table IV were obtained and analyzed by mass spectrometry and HPLC or¹ H NMR analyzed to be identified.

表IVTable IV

表IV(续)Table IV (continued)

表IV(续)Table IV (continued)

实例86-88Examples 86-88

N-经取代-1-[3-(1H-苯并咪唑-1-基)甲基]苯甲酰基]-吡咯烷-3-基胺化合物的制备Preparation of N-substituted-1-[3-(1H-benzimidazol-1-yl)methyl]benzoyl]-pyrrolidin-3-ylamine compound

基本上使用实例40中所述的相同程序且在步骤1中使用3-(苯并咪唑-1-基甲基)苯甲酸并在步骤3中使用适当胺HNR₁R₂，获得表V中所示的化合物且由HPLC和质谱分析加以鉴定。Using essentially the same procedure as described in Example 40 and using 3-(benzimidazol-1-ylmethyl)benzoic acid in Step 1 and the appropriate amine HNR₁ R₂ in Step 3, the compounds listed in Table V were obtained. The indicated compounds were identified by HPLC and mass spectrometry.

表VTable V

实例89和90Examples 89 and 90

N-经取代-1-[2-(1H-苯并咪唑-1-基)甲基)苯甲酰基]-吡咯烷-3-基胺化合物的制备Preparation of N-substituted-1-[2-(1H-benzimidazol-1-yl)methyl)benzoyl]-pyrrolidin-3-ylamine compound

基本上使用实例40中所述的相同程序且在步骤1中使用2-(苯并咪唑-1-基甲基)苯甲酸并在步骤3中使用适当胺HNR₁R₂，获得表VI中所示的化合物且由HPLC和质谱分析加以鉴定。Using essentially the same procedure as described in Example 40 and using 2-(benzimidazol-1-ylmethyl)benzoic acid in step 1 and the appropriate amine HNR₁ R₂ in step 3, the compounds listed in Table VI were obtained. The indicated compounds were identified by HPLC and mass spectrometry.

表VITable VI

实例91Example 91

1′-{4-[(5-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷盐酸盐的制备Preparation of 1'-{4-[(5-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine hydrochloride

步骤1)4-{[(4-甲基-2-硝基苯基)-(2，2，2-三氟乙酰基)氨基]甲基}-苯甲酸甲酯Step 1) 4-{[(4-Methyl-2-nitrophenyl)-(2,2,2-trifluoroacetyl)amino]methyl}-benzoic acid methyl ester

以己烷预洗涤一份于矿物油中的60％NaH(2.9g，71.8mmol，1.1eq)且在氮下悬浮于无水DMF中。在冰浴中冷却浆料且经15分钟逐滴添加2，2，2-三氟-N-(4-甲基-2-硝基苯基)-乙酰胺(16.2g，65.3mmol，1.0eq)于无水DMF中的溶液。移除冷却浴且将混合物搅拌30分钟。再次冷却反应混合物且经10分钟逐滴添加4-溴甲基苯甲酸甲酯(20g，65.3mmol，1.0eq)于无水DMF中的溶液。将反应混合物在室温下搅拌18小时且在减压下蒸发以得到残余物。将残余物在乙酸乙酯与水之间分溶。相继以水和盐水洗涤有机层，干燥(Na₂SO₄)且浓缩以得到黄色固体。由柱色谱纯化黄色固体(硅胶230-400目：溶离剂CHCl₃MeOH：0→5％)以得到4-{[(4-甲基-2-硝基苯基)-(2，2，2-三氟乙酰基)氨基]甲基}苯甲酸甲酯，产率：59％。¹H NMR(400MHz，CDCl₃)：7.97(m，3H)；7.27(m，3H)；6.76(d，J＝8Hz，1H)；5.66 & 4.26(2H)；3.92(s，3H)；2.46(s，3H)。A portion of 60% NaH in mineral oil (2.9 g, 71.8 mmol, 1.1 eq) was prewashed with hexanes and suspended in anhydrous DMF under nitrogen. Cool the slurry in an ice bath and add 2,2,2-trifluoro-N-(4-methyl-2-nitrophenyl)-acetamide (16.2 g, 65.3 mmol, 1.0 eq) dropwise over 15 minutes ) in anhydrous DMF solution. The cooling bath was removed and the mixture was stirred for 30 minutes. The reaction mixture was cooled again and a solution of methyl 4-bromomethylbenzoate (20 g, 65.3 mmol, 1.0 eq) in anhydrous DMF was added dropwise over 10 minutes. The reaction mixture was stirred at room temperature for 18 hours and evaporated under reduced pressure to give a residue. The residue was partitioned between ethyl acetate and water. The organic layer was washed successively with water and brine, dried (_Na2SO4 ) and concentrated to give a yellow solid_. The yellow solid was purified by column chromatography (silica gel 230-400 mesh: eluent_CHCl3MeOH : 0→5%) to give 4-{[(4-methyl-2-nitrophenyl)-(2,2, Methyl 2-trifluoroacetyl)amino]methyl}benzoate, yield: 59%.¹ H NMR (400MHz, CDCl₃ ): 7.97(m, 3H); 7.27(m, 3H); 6.76(d, J=8Hz, 1H); 5.66 &4.26(2H); 3.92(s, 3H); 2.46 (s, 3H).

步骤2)4-[(4-甲基-2-硝基苯基氨基)甲基]苯甲酸甲酯Step 2) Methyl 4-[(4-methyl-2-nitrophenylamino)methyl]benzoate

以溴化四丁基铵(1.13g，3.5mmol)和20％ KOH水溶液(100mL)处理4-{[(4-甲基-2-硝基苯基)(2，2，2-三氟乙酰基)-氨基]甲基}苯甲酸甲酯(14.0g，35mmol)于CH₂Cl₂中的搅拌溶液。将反应混合物加热至38℃达3小时且冷却至室温。分离各相且以CH₂Cl₂萃取水相。以盐水洗涤经合并的萃取物和有机相，经无水Na₂SO₄干燥且在真空中浓缩以得到呈橙色固体的4-[(4-甲基-2-硝基苯基氨基)甲基]-苯甲酸甲酯。产率：90％。¹H NMR(400MHz，CDCl₃)：8.37(bs，1H)；8.02(m，3H)；7.40(d，J＝8Hz，2H)；7.19(d，J＝8Hz，1H)；6.63(d，J＝8Hz，1H)；4.60(d，J＝8Hz，2H)；3.91(s，3H)；2.35(s，1H)。4-{[(4-Methyl-2-nitrophenyl)(2,2,2-trifluoroacetyl A stirred solution_of methyl)-amino]methyl}benzoate (14.0 g, 35 mmol) in_CH2Cl2 . The reaction mixture was heated to 38 °C for 3 hours and cooled to room temperature. The phases were separated and the_aqueous phase was extracted with_CH2Cl2 ._The combined extracts and organic phase were washed with brine, dried over anhydrous_Na2SO4 and concentrated in vacuo to give 4-[(4-methyl-2-nitrophenylamino)methyl as an orange solid ]-methyl benzoate. Yield: 90%.¹ H NMR (400MHz, CDCl₃ ): 8.37(bs, 1H); 8.02(m, 3H); 7.40(d, J=8Hz, 2H); 7.19(d, J=8Hz, 1H); J=8Hz, 1H); 4.60(d, J=8Hz, 2H); 3.91(s, 3H); 2.35(s, 1H).

步骤3)4-[(5-甲基苯并咪唑-1-基)甲基]苯甲酸甲酯Step 3) Methyl 4-[(5-methylbenzimidazol-1-yl)methyl]benzoate

以5％Pd/C(50％湿润，30％重量/重量)和水合肼(5.8g，116mmol)处理4-[(4-甲基-2-硝基苯基氨基)甲基]苯甲酸甲酯(7.0g，23mmol)于CH₃OH中的搅拌溶液。将反应混合物加热至回流温度达2小时，冷却至室温且滤过硅藻土。蒸发滤液以得到残余物。将残余物溶于CH₂Cl₂中，以水洗涤，经无水Na₂SO₄干燥且蒸发以得到4-[(2-氨基-4-甲基苯基氨基)甲基]苯甲酸甲酯，其不经进一步纯化而用于下一步骤。产率：93％。¹H NMR(400MHz，CDCl₃)8.0(d，J＝8Hz，2H)；7.70(d，J＝8Hz，2H)；6.60(m，2H)；6.49(d，1H)；4.3(s，2H)；3.90(d，3H)；2.21(s，3H)。LCMS(ESI⁺)271(MH+)。以甲酸(1.0g)处理粗4-[(2-氨基-4-甲基苯基氨基)甲基]苯甲酸甲酯(6g，22mmol)于原甲酸三甲酯中的搅拌溶液，回流2小时，冷却至室温且在减压下蒸发。通过使用1％MeOH/CHCl₃的柱色谱纯化所得残余物以得到4-[(5-甲基苯并咪唑-1-基)甲基]苯甲酸甲酯。产率：16％。¹H NMR(400MHz，CDCl₃)：8.0(d，J＝8Hz，1H)；7.93(s，1H)；7.62(s，1H)；7.26(s，1H)；7.21(d，J＝8Hz，2H)；7.08(m，2H)；5.39(s，2H)；3.90(s，3H)；2.47(s，3H)。LCMS(ESI⁺)281(MH+)。4-[(4-Methyl-2-nitrophenylamino)methyl]benzoic acid formazan was treated with 5% Pd/C (50% wet, 30% w/w) and hydrazine hydrate (5.8 g, 116 mmol) Stirred solution of ester (7.0 g, 23 mmol) in_CH3OH . The reaction mixture was heated to reflux temperature for 2 hours, cooled to room temperature and filtered through celite. The filtrate was evaporated to give a residue. The residue was dissolved_inCH2Cl2 , washed with water, dried over anhydrous_Na2SO4 and evaporated to give methyl 4-[(_2- amino-4-methylphenylamino)methyl]benzoate , which was used in the next step without further purification. Yield: 93%.¹ H NMR (400MHz, CDCl₃ ) 8.0(d, J=8Hz, 2H); 7.70(d, J=8Hz, 2H); 6.60(m, 2H); 6.49(d, 1H); 4.3(s, 2H ); 3.90 (d, 3H); 2.21 (s, 3H). LCMS (ESI⁺ ) 271 (MH+). A stirred solution of crude methyl 4-[(2-amino-4-methylphenylamino)methyl]benzoate (6 g, 22 mmol) in trimethyl orthoformate was treated with formic acid (1.0 g) and refluxed for 2 hours , cooled to room temperature and evaporated under reduced pressure. The resulting residue was purified by column chromatography using 1% MeOH/CHCl₃ to give methyl 4-[(5-methylbenzimidazol-1-yl)methyl]benzoate. Yield: 16%.¹ H NMR (400MHz, CDCl₃ ): 8.0(d, J=8Hz, 1H); 7.93(s, 1H); 7.62(s, 1H); 7.26(s, 1H); 7.21(d, J=8Hz, 2H); 7.08 (m, 2H); 5.39 (s, 2H); 3.90 (s, 3H); 2.47 (s, 3H). LCMS (ESI⁺ ) 281 (MH+).

步骤4)甲烷磺酸1-{[4-(5-甲基苯并咪唑-1-基)甲基]苯甲酰基}-吡咯烷-3-基酯Step 4) 1-{[4-(5-methylbenzimidazol-1-yl)methyl]benzoyl}-pyrrolidin-3-yl methanesulfonate

将4-[(5-甲基苯并咪唑-1-基)甲基]苯甲酸甲酯水解成相应的苯甲酸且基本上使用实例37步骤1和步骤2中所述的相同程序，获得甲烷磺酸1-{[4-(5-甲基苯并咪唑-1-基)甲基]苯甲酰基}吡咯烷-3-基酯。¹H NMR(400MHz，CDCl₃)：7.93(s，1H)；7.62(s，1H)；7.46-7.53(m，2H)；7.07-7.22(m，4H)；5.37(s，2H)；5.37&5.24(bs，1H)；3.55-3.93(m，4H)；3.08 & 3.01(s，3H)；2.47(s，3H)；2.17-2.34(m，2H)。LCMS(ESI⁺)414(MH+)。Hydrolysis of methyl 4-[(5-methylbenzimidazol-1-yl)methyl]benzoate to the corresponding benzoic acid and using essentially the same procedure described in Example 37 Step 1 and Step 2 afforded methane 1-{[4-(5-methylbenzimidazol-1-yl)methyl]benzoyl}pyrrolidin-3-ylsulfonate.¹ H NMR (400MHz, CDCl₃ ): 7.93(s, 1H); 7.62(s, 1H); 7.46-7.53(m, 2H); 7.07-7.22(m, 4H); 5.37(s, 2H); 5.37 & 5.24 (bs, 1H); 3.55-3.93 (m, 4H); 3.08 & 3.01 (s, 3H); 2.47 (s, 3H); 2.17-2.34 (m, 2H). LCMS (ESI⁺ ) 414 (MH+).

步骤5)1′-{4-[(5-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷盐酸盐Step 5) 1'-{4-[(5-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine hydrochloride

基本上使用实例37步骤3中所述的相同程序且使用甲烷磺酸1-{[4-(5-甲基苯并咪唑-1-基)甲基]苯甲酰基}-吡咯烷-3-基酯和吡咯烷作为起始物质，获得标题产物且由NMR和质谱分析加以鉴定。¹H NMR(300MHz，353K，DMSO-d₆)：11.81(s br，1H)；9.64(s，1H)；7.72(d，1H)；7.68(m，1H)；7.57(d，2H)；7.50(d，2H)；7.39(dd，1H)；5.78(s，2H)；3.97-3.67(m，4H)；3.52-2.95(m br，5H)；2.50(s，3H)；2.29(m，2H)；2.05-1.91(m，4H)。LCMS(ESI⁺)389.3(MH+)。Using essentially the same procedure as described in Example 37, Step 3 and using 1-{[4-(5-methylbenzimidazol-1-yl)methyl]benzoyl}-pyrrolidine-3-methanesulfonate Starting from the base ester and pyrrolidine, the title product was obtained and identified by NMR and mass spectral analyses.¹ H NMR (300MHz, 353K, DMSO-d₆ ): 11.81(s br, 1H); 9.64(s, 1H); 7.72(d, 1H); 7.68(m, 1H); 7.57(d, 2H); 7.50(d, 2H); 7.39(dd, 1H); 5.78(s, 2H); 3.97-3.67(m, 4H); 3.52-2.95(m br, 5H); 2.50(s, 3H); 2.29(m , 2H); 2.05-1.91 (m, 4H). LCMS (ESI⁺ ) 389.3 (MH+).

实例92-117Examples 92-117

1′-{4-[(经取代-1H-苯并咪唑-1-基)甲基]苯甲酰基}-吡咯烷-3-基胺的制备Preparation of 1'-{4-[(substituted-1H-benzimidazol-1-yl)methyl]benzoyl}-pyrrolidin-3-ylamine

基本上使用实例91中所述的相同程序且在步骤1中使用经适当取代的邻硝基苯甲酰胺并在步骤5中使用所要胺HNR₁R₂，获得表VII中所示的化合物且由¹H NMR和质谱分析加以鉴定。Using essentially the same procedure as described in Example 91 and using an appropriately substituted o-nitrobenzamide in Step 1 and the desired amine HNR₁ R₂ in Step 5, the compounds shown in Table VII were obtained and obtained from It was identified by¹ H NMR and mass spectrometry.

表VIITable VII

表VII(续)Table VII (continued)

实例118Example 118

11-(4-{[3-(二甲基氨基)吡咯烷-1-基]羰基}苯甲基)-9-甲氧基-11b-甲基-1，2，5，6，11，11b-11-(4-{[3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}benzyl)-9-methoxy-11b-methyl-1,2,5,6,11, 11b-六氢-3H-吲嗪并[8，7-b]吲哚-3-酮的制备Preparation of Hexahydro-3H-indolazino[8,7-b]indol-3-one

步骤1.将6-甲氧基色胺(0.95g，5mmol)与乙酰丙酸(0.7g，6mmol)于乙氧基乙醇中的混合物在回流温度下加热16小时，冷却至室温且在真空中浓缩以得到9-甲氧基-11b-甲基-1，2，5，6，11，11b-六氢-吲嗪并[8，7-b]吲哚-3-酮(0.97g)，由NMR、HPLC和MS[271.2m/e(M+H)]加以鉴定。Step 1. A mixture of 6-methoxytryptamine (0.95 g, 5 mmol) and levulinic acid (0.7 g, 6 mmol) in ethoxyethanol was heated at reflux temperature for 16 hours, cooled to room temperature and concentrated in vacuo To obtain 9-methoxy-11b-methyl-1,2,5,6,11,11b-hexahydro-indazino[8,7-b]indol-3-one (0.97 g), obtained by It was identified by NMR, HPLC and MS [271.2m/e(M+H)].

步骤2.以氢化钠(50mg)处理9-甲氧基-11b-甲基-1，2，5，6，11，11b-六氢-吲嗪并[8，7-b]吲哚-3-酮(54mg，0.2mmol)于DMF中的溶液，在室温下搅拌10分钟，以(4-氯甲基-苯甲酰基)-N，N-二甲基氨基吡咯烷-3-胺盐酸盐(72mg，0.24mmol)处理，在室温下搅拌整夜且在真空中浓缩。将所得残余物溶于DMSO、MeOH和水的混合物(1.5mL)中且通过逆相半制备型HPLC¹纯化以得到呈白色粉末的标题产物(49mg)，由HPLC和MS[501.7m/e(M+H)]加以鉴定。Step 2. Treatment of 9-methoxy-11b-methyl-1,2,5,6,11,11b-hexahydro-indazino[8,7-b]indole-3 with sodium hydride (50 mg) - A solution of ketone (54mg, 0.2mmol) in DMF, stirred at room temperature for 10 minutes, dissolved in (4-chloromethyl-benzoyl)-N,N-dimethylaminopyrrolidin-3-amine hydrochloride Salt (72mg, 0.24mmol) was worked up, stirred at room temperature overnight and concentrated in vacuo. The resulting residue was dissolved in a mixture of DMSO, MeOH and water (1.5 mL) and purified by reverse phase semi-preparative HPLC¹ to give the title product (49 mg) as a white powder, determined by HPLC and MS [501.7 m/e ( M+H)] to be identified.

实例119-126Examples 119-126

11-(4-{[3-(二甲基氨基)吡咯烷-1-基]羰基}苯甲基)-9，11b-经二取代-1，2，5，6，11，11b-六11-(4-{[3-(dimethylamino)pyrrolidin-1-yl]carbonyl}benzyl)-9,11b-disubstituted-1,2,5,6,11,11b-hexa氢-3H-吲嗪并[8，7-b]吲哚-3-酮化合物的制备Preparation of Hydrogen-3H-Indolazino[8,7-b]indol-3-one Compounds

基本上使用实例118中所述的相同程序且在步骤1中使用经适当取代的色胺和乙酰丙酸，获得表VIII中所示的化合物且由质谱和HPLC分析加以鉴定。Using essentially the same procedure described in Example 118 and using appropriately substituted tryptamine and levulinic acid in Step 1, the compounds shown in Table VIII were obtained and identified by mass spectrometry and HPLC analyses.

表VIIITable VIII

实例127Example 127

(3′S)-1′-[4-(1H-吲哚-1-基甲基)苯甲酰基]-1，3′-联吡咯烷的制备Preparation of (3'S)-1'-[4-(1H-indol-1-ylmethyl)benzoyl]-1,3'-bipyrrolidine

步骤1.在0℃下以二碳酸二叔丁酯[(Boc)₂O](2.5g，1eq)处理(S)-3-氨基吡咯烷(1mL，11.6mmol)于MeOH中的溶液，在室温下搅拌整夜且在真空中浓缩以得到残余物。Step 1. A solution of (S)-3-aminopyrrolidine (1 mL, 11.6 mmol) in MeOH was treated with di-tert-butyl dicarbonate [(Boc)_2O ] (2.5 g, 1 eq) at 0 °C, in Stir overnight at room temperature and concentrate in vacuo to give a residue.

步骤2.以1，4-二溴丁烷(13.9mmol，1.7mL)和K₂CO₃(3.2g，23.2mmol)处理步骤1的残余物于甲苯中的溶液，在110℃下搅拌整夜，冷却至室温，以EtOAc稀释，以水洗涤，经MgSO₄干燥且在真空中浓缩以得到Boc-吡咯烷并-吡咯烷。Step 2. A solution of the residue from_Step 1 in toluene was treated with 1,4-dibromobutane (13.9 mmol, 1.7 mL) and_K2CO3 (3.2 g, 23.2 mmol) and stirred overnight at 110 °C , cooled to room temperature, diluted with EtOAc, washed with water, dried over MgSO₄ and concentrated in vacuo to give Boc-pyrrolidino-pyrrolidine.

步骤3.将步骤2的Boc-吡咯烷并-吡咯烷(1g，粗，4.2mmol)与2N HCl于二噁烷中的混合物在室温下搅拌3小时且浓缩成浓稠油状物。将油状物溶于DCM中，冷却至0℃，以二异丙基乙胺(5eq)和4-(氯甲基)苯甲酰氯(0.8g，4.2mmol)处理，在温至室温下搅拌2小时，以EtOAc稀释，以饱和NaHCO₃洗涤，经MgSO₄干燥且在真空中浓缩以得到呈棕色油状的[1，3′]联吡咯烷-1′-基-(4-氯甲基-苯基)-甲酮(1.3g)，由HPLC和MS[293m/e(M+H)]加以鉴定。Step 3. A mixture of Boc-pyrrolidino-pyrrolidine from Step 2 (1 g, crude, 4.2 mmol) and 2N HCl in dioxane was stirred at room temperature for 3 h and concentrated to a thick oil. The oil was dissolved in DCM, cooled to 0 °C, treated with diisopropylethylamine (5 eq) and 4-(chloromethyl)benzoyl chloride (0.8 g, 4.2 mmol), stirred at warming to room temperature for 2 hours, diluted with EtOAc, washed with saturated NaHCO₃ , dried over MgSO₄ and concentrated in vacuo to give [1,3′]bipyrrolidin-1′-yl-(4-chloromethyl-benzene base)-methanone (1.3 g), identified by HPLC and MS [293 m/e (M+H)].

步骤4.以氢化钠(50mg)接着以[1，3′]联吡咯烷-1′-基-(4-氯甲基-苯基)-甲酮(0.15mmol，43mg)处理吲哚(0.15mmol，19mg)于DMF/THF混合物(1:4，2mL)中的溶液，在室温下搅拌整夜且在真空中浓缩。将所得残余物溶于DMSO、MeOH和水的混合物(1.5mL)中且通过逆相半制备型HPLC¹纯化以得到呈白色粉末的标题产物(8mg)，由HPLC和质谱分析加以鉴定。滞留时间1.86min.，MS[374.2m/e(M+H)]。Step 4. Treatment of indole (0.15 mmol, 19 mg) in a DMF/THF mixture (1:4, 2 mL), stirred overnight at room temperature and concentrated in vacuo. The resulting residue was dissolved in a mixture of DMSO, MeOH and water (1.5 mL) and purified by reverse phase semi-preparative HPLC¹ to give the title product (8 mg) as a white powder, identified by HPLC and mass spectral analyses. Retention time 1.86min., MS [374.2m/e(M+H)].

实例128-144Examples 128-144

(3′S)-1′-[4-(杂芳基烷基)苯甲酰基]-1，3′-联吡咯烷的制备Preparation of (3'S)-1'-[4-(heteroarylalkyl)benzoyl]-1,3'-bipyrrolidine

基本上使用实例127中所述的相同程序且在步骤3中使用经适当取代的4-氯甲基苯甲酰氯并在步骤4中使用所要环胺HNR₄R₅，获得表IX中所示的化合物且由质谱和¹HNMR或HPLC分析加以鉴定。通过使用标准手性HPLC技术手性分离相应外消旋化合物来获得表IX中的化合物(其中R₈为(R)或(S)对映异构体)。Using essentially the same procedure as described in Example 127 with appropriately substituted 4-chloromethylbenzoyl chloride in Step 3 and the desired cyclic amine HNR₄ R₅ in Step 4, the compounds shown in Table IX were obtained. Compounds were identified by mass spectrometry and¹ HNMR or HPLC analyses. Compounds in Table IX (where R is_the (R) or (S) enantiomer) were obtained by chiral separation of the corresponding racemic compounds using standard chiral HPLC techniques.

表IXTable IX

表IX(续)Table IX (continued)

实例159-163Examples 159-163

(3S)-1-[4-(杂芳基烷基)苯甲酰基]-吡咯烷-3-胺的制备Preparation of (3S)-1-[4-(heteroarylalkyl)benzoyl]-pyrrolidin-3-amine

基本上使用实例127中所述的相同程序且使用(S)-3-氨基吡咯烷作为起始物质并在步骤3中使用经适当取代的4-氯甲基苯甲酰氯并在步骤4中使用所要双环胺HNR₄R₅，获得表X中所示的化合物且由质谱和¹H NMR分析加以鉴定。通过使用标准手性HPLC技术手性分离相应外消旋化合物来获得表X中的化合物(其中R₈为(R)或(S)对映异构体)。Using essentially the same procedure as described in Example 127 and using (S)-3-aminopyrrolidine as starting material and using appropriately substituted 4-chloromethylbenzoyl chloride in step 3 and using Desired bicyclic amine HNR₄ R₅ , compounds shown in Table X were obtained and identified by mass spectral and¹ H NMR analyses. Compounds in Table X (where R₈ is the (R) or (S) enantiomer) were obtained by chiral separation of the corresponding racemic compounds using standard chiral HPLC techniques.

表XTable X

实例164Instance 164

1′-[4-(1H-苯并咪唑-1-基甲基)苯甲基]-1，3′-联吡咯烷盐酸盐的制备Preparation of 1'-[4-(1H-benzimidazol-1-ylmethyl)benzyl]-1,3'-bipyrrolidine hydrochloride

以硼烷(四氢呋喃中的1.0M，0.8mL)在氮下处理1′-[4-(1H-苯并咪唑-1-基甲基)苯甲酰基]-1，3′-联吡咯烷(0.16mmol)于无水四氢呋喃中的溶液，在回流温度下加热1.5小时，以额外硼烷(四氢呋喃中的1.0M，0.8mL，0.8mmol)处理，在回流温度下加热6小时，冷却至室温，以甲醇(5mL)处理且在真空中浓缩。以氯化氢甲醇溶液(5mL)处理所得残余物，在回流温度下加热1小时且在真空中浓缩。将此残余物分散于氢氧化钠水溶液(2.5M，5mL)中且以二氯甲烷萃取。将萃取物合并，干燥(硫酸钠)且蒸发。由快速柱色谱(硅石，二氯甲烷:甲醇9:1)纯化所得残余物，接着形成盐酸盐，得到呈疏松固体的标题产物，由NMR和质谱分析加以鉴定，[M+H]361.2。1'-[4-(1H-benzimidazol-1-ylmethyl)benzoyl]-1,3'-bipyrrolidine was treated with borane (1.0M in tetrahydrofuran, 0.8 mL) under nitrogen ( 0.16 mmol) in anhydrous THF, heated at reflux temperature for 1.5 h, treated with additional borane (1.0 M in THF, 0.8 mL, 0.8 mmol), heated at reflux temperature for 6 h, cooled to room temperature, Treated with methanol (5 mL) and concentrated in vacuo. The resulting residue was treated with methanolic hydrogen chloride (5 mL), heated at reflux temperature for 1 h and concentrated in vacuo. This residue was dispersed in aqueous sodium hydroxide (2.5M, 5 mL) and extracted with dichloromethane. The extracts were combined, dried (sodium sulfate) and evaporated. The resulting residue was purified by flash column chromatography (silica, dichloromethane:methanol 9:1), followed by formation of the hydrochloride salt, to give the title product as a loose solid, identified by NMR and mass spectral analyses, [M+H] 361.2.

实例165-172Examples 165-172

1-[4-(杂芳基甲基)苯甲基]吡咯烷-3-基胺盐酸盐化合物的制备Preparation of 1-[4-(heteroarylmethyl)benzyl]pyrrolidin-3-ylamine hydrochloride compound

基本上使用实例164中所述的相同程序且使用适当的1-[4-(杂芳基甲基)苯甲酰基]吡咯烷-3-基胺作为起始物质，获得表XI中所示的化合物且由质谱和¹H NMR或HPLC分析加以鉴定。Using essentially the same procedure as described in Example 164 and using the appropriate 1-[4-(heteroarylmethyl)benzoyl]pyrrolidin-3-ylamine as starting material, the compounds shown in Table XI were obtained. Compounds were identified by mass spectrometry and¹ H NMR or HPLC analyses.

表XITable XI

实例173-179Examples 173-179

1-[3-(杂芳基甲基)苯甲基]吡咯烷-3-基胺盐酸盐化合物的制备Preparation of 1-[3-(heteroarylmethyl)benzyl]pyrrolidin-3-ylamine hydrochloride compound

基本上使用实例164中所述的相同程序且使用适当的1-[3-(杂芳基甲基)苯甲酰基]吡咯烷-3-基胺作为起始物质，获得表XII中所示的化合物且由¹H NMR、HPLC和质谱分析加以鉴定。Using essentially the same procedure as described in Example 164 and using the appropriate 1-[3-(heteroarylmethyl)benzoyl]pyrrolidin-3-ylamine as starting material, the compounds shown in Table XII were obtained. Compounds were identified by¹ H NMR, HPLC and mass spectrometry.

表XIITable XII

实例180Instance 180

1-[2-(1H-苯并咪唑-1-基甲基)苯甲基]吡咯烷-3-基哌啶盐酸盐的制备Preparation of 1-[2-(1H-benzimidazol-1-ylmethyl)benzyl]pyrrolidin-3-ylpiperidine hydrochloride

基本上使用实例113中所述的相同程序且使用1-[2-(1H-苯并咪唑-1-基甲基)苯甲酰基]吡咯烷-3-基哌啶作为起始物质，获得标题化合物且由¹H NMR、HPLC和质谱分析加以鉴定，[M+H]375.3。Using essentially the same procedure as described in Example 113 and using 1-[2-(1H-benzimidazol-1-ylmethyl)benzoyl]pyrrolidin-3-ylpiperidine as starting material, the title The compound was identified by¹ H NMR, HPLC and mass spectrometry, [M+H] 375.3.

实例181-201Examples 181-201

经取代-1-[2-(1H-苯并咪唑-1-基)甲基)苯甲酰基]-吡咯烷-3-基胺化合物的制备Preparation of substituted-1-[2-(1H-benzimidazol-1-yl)methyl)benzoyl]-pyrrolidin-3-ylamine compounds

基本上使用实例127中所述的相同程序且在步骤3中使用适当的Boc保护吡咯烷和所要4-氯甲基-苯甲酰氯，获得表XIII中所示的化合物且由¹H NMR、HPLC和质谱分析加以鉴定。Using essentially the same procedure as described in Example 127 and using the appropriate Boc-protected pyrrolidine and the desired 4-chloromethyl-benzoyl chloride in step 3, the compounds shown in Table XIII were obtained and analyzed by¹ H NMR, HPLC identified by mass spectrometry.

表XIIITable XIII

实例202-205Instances 202-205

1-[4-(1H-苯并咪唑-1-基甲基)苯甲基]吡咯烷-3-基胺盐酸盐化合物的制备Preparation of 1-[4-(1H-benzimidazol-1-ylmethyl)benzyl]pyrrolidin-3-ylamine hydrochloride compound

基本上使用实例164中所述的相同程序且使用经适当取代的1-[4-(1H-苯并咪唑-1-基甲基)苯甲酰基]-吡咯烷-3-基胺作为起始物质，获得表XIV中所示的化合物且由¹H NMR和质谱分析加以鉴定。Using essentially the same procedure as described in Example 164 and starting with appropriately substituted 1-[4-(1H-benzimidazol-1-ylmethyl)benzoyl]-pyrrolidin-3-ylamine material, the compounds shown in Table XIV were obtained and identified^by1H NMR and mass spectral analyses.

表XIVTable XIV

实例206和207Instances 206 and 207

N-经取代-1-[(杂芳基甲基)苯甲酰基]吡咯烷-3-基胺化合物的制备Preparation of N-substituted-1-[(heteroarylmethyl)benzoyl]pyrrolidin-3-ylamine compounds

基本上使用实例40中所述的相同程序且在步骤1中使用所要苯甲酸并在步骤3中使用适当胺HNR₁R₂，获得表XV中所示的化合物且由¹H NMR和质谱分析加以鉴定。Using essentially the same procedure as described in Example 40 and using the desired benzoic acid in Step 1 and the appropriate amine HNR₁ R₂ in Step 3, the compounds shown in Table XV were obtained and confirmed by¹ H NMR and mass spectral analyses. Identification.

表XVTable XV

实例208Instance 208

4-((1H-苯并[d]咪唑-2-基)甲基)苯甲酸甲酯的制备Preparation of methyl 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoate

步骤1：4-(氰基甲基)苯甲酸甲酯Step 1: Methyl 4-(cyanomethyl)benzoate

在40℃下以4-(溴甲基)苯甲酸甲酯(52g，0.227mol)于二甲亚砜中的溶液逐滴处理氰化钠(20g，0.41mol)于二甲亚砜中的溶液，搅拌90分钟，冷却至室温，以饱和氯化钠水溶液中止反应且以乙酸乙酯萃取。以饱和氯化钠水溶液洗涤经合并萃取物，经硫酸钠干燥且在减压下浓缩。经由柱色谱(硅石，己烷:乙酸乙酯0→5％)纯化浓缩物得到4-(氰基甲基)苯甲酸甲酯(55％)。¹H NMR(400MHz，CDCl₃)：8.05(d，J＝8Hz，2H)；7.42(d，J＝8Hz，2H)；3.93(s，3H)；3.81(s，2H)。[M+H]176。A solution of sodium cyanide (20 g, 0.41 mol) in dimethyl sulfoxide was treated dropwise with a solution of methyl 4-(bromomethyl)benzoate (52 g, 0.227 mol) in dimethyl sulfoxide at 40 °C , stirred for 90 minutes, cooled to room temperature, quenched with saturated aqueous sodium chloride and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The concentrate was purified via column chromatography (silica, hexane:ethyl acetate 0→5%) to give methyl 4-(cyanomethyl)benzoate (55%).¹ H NMR (400 MHz, CDCl₃ ): 8.05 (d, J=8 Hz, 2H); 7.42 (d, J=8 Hz, 2H); 3.93 (s, 3H); 3.81 (s, 2H). [M+H] 176.

步骤2：2-(4-(甲氧基羰基)苯基)乙酸Step 2: 2-(4-(Methoxycarbonyl)phenyl)acetic acid

在回流条件下将氯化氢气体鼓入4-(氰基甲基)苯甲酸甲酯(22.0g，0.125mol)于甲醇(550mL)中的搅拌溶液中达8小时。将反应混合物冷却至20℃，再搅拌24小时且过滤。在减压下蒸发滤液。将所得残余物溶于乙醚中，相继以水和饱和碳酸氢钠水溶液洗涤，经硫酸钠干燥且蒸发以得到呈固体残余物的甲酯。¹H NMR(400MHz，CDCl₃)：8.00(d，J＝8Hz，2H)；7.35(d，J＝8.4Hz，2H)；3.91(s3H)；3.70(s，3H)；3.68(s，2H)。GCMS：209(M+H)。将甲酯(8.21g，0.039mmol)溶于甲醇中，以氢氧化钠(1.58g，0.039mol)处理，加热至50℃，搅拌4小时，冷却至室温，再搅拌24小时且在真空中浓缩。将所得残余物在乙醚与水之间分溶。以浓HCl酸化水层。通过过滤去除所得沉淀且在真空下干燥整夜以得到呈灰白色固体的2-(4-(甲氧基羰基)苯基)-乙酸(80％)。¹H NMR(400MHz，DSMO-d₆)：7.90(d，J＝8Hz，2H)；7.422(d，J＝8Hz，2H)；3.85(s，3H)；3.68(s，2H)。[M+H]195。Hydrogen chloride gas was bubbled through a stirred solution of methyl 4-(cyanomethyl)benzoate (22.0 g, 0.125 mol) in methanol (550 mL) at reflux for 8 hours. The reaction mixture was cooled to 20 °C, stirred for an additional 24 hours and filtered. The filtrate was evaporated under reduced pressure. The resulting residue was dissolved in diethyl ether, washed successively with water and saturated aqueous sodium bicarbonate, dried over sodium sulfate and evaporated to give the methyl ester as a solid residue.¹ H NMR (400MHz, CDCl₃ ): 8.00(d, J=8Hz, 2H); 7.35(d, J=8.4Hz, 2H); 3.91(s3H); 3.70(s, 3H); 3.68(s, 2H ). GCMS: 209 (M+H). The methyl ester (8.21 g, 0.039 mmol) was dissolved in methanol, treated with sodium hydroxide (1.58 g, 0.039 mol), heated to 50 °C, stirred for 4 hours, cooled to room temperature, stirred for another 24 hours and concentrated in vacuo . The resulting residue was partitioned between ether and water. The aqueous layer was acidified with concentrated HCl. The resulting precipitate was removed by filtration and dried under vacuum overnight to give 2-(4-(methoxycarbonyl)phenyl)-acetic acid (80%) as an off-white solid.¹ H NMR (400 MHz, DSMO-d₆ ): 7.90 (d, J=8 Hz, 2H); 7.422 (d, J=8 Hz, 2H); 3.85 (s, 3H); 3.68 (s, 2H). [M+H] 195.

步骤3和步骤4：4-((1H-苯并[d]咪唑-2-基)甲基)苯甲酸甲酯Step 3 and Step 4: Methyl 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoate

在0℃下以1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(0.236g，1.237mmol)和1-羟基苯并三唑(HOBT)(0.153g，1.13mmol)处理2-(4-(甲氧基羰基)苯基)乙酸(0.2g，1.03mmol)于二氯甲烷中的悬浮液，搅拌30分钟，以苯二胺(0.12g，1.12mmol)处理，在室温下搅拌24小时且以水中止反应。分离有机相，相继以饱和碳酸氢钠水溶液和饱和氯化钠水溶液洗涤，经硫酸钠干燥且在减压下浓缩至干燥以获得呈灰白色固体的所要酰胺(68％)。[M+H]285。将所述酰胺(12.0g，0.04mol)于乙酸中的溶液加热至140℃达1小时，冷却至室温且在减压下浓缩。以氢氧化钠水溶液(1.0N，100mL)中和所得残余物且以乙酸乙酯萃取。将萃取物合并，经硫酸钠干燥且在减压下浓缩。由柱色谱(硅石，氯仿:甲醇0→5％)纯化浓缩物得到呈白色固体的标题产物(47％)。¹H NMR(400MHz，DMSO-d₆)：7.95(d，J＝8Hz，2H)；7.52(s，2H)；7.325(d，J＝8Hz，2H)；7.23(m，2H)；4.30(s，2H)；3.89(s，3H)。[M+H]267。At 0°C, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.236g, 1.237mmol) and 1-hydroxybenzotriazole (HOBT) (0.153g , 1.13mmol) treated a suspension of 2-(4-(methoxycarbonyl)phenyl)acetic acid (0.2g, 1.03mmol) in dichloromethane, stirred for 30 minutes, and phenylenediamine (0.12g, 1.12mmol ), stirred at room temperature for 24 hours and quenched with water. The organic phase was separated, washed sequentially with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated to dryness under reduced pressure to afford the desired amide (68%) as an off-white solid. [M+H] 285. A solution of the amide (12.0 g, 0.04 mol) in acetic acid was heated to 140 °C for 1 hour, cooled to room temperature and concentrated under reduced pressure. The resulting residue was neutralized with aqueous sodium hydroxide solution (1.0 N, 100 mL) and extracted with ethyl acetate. The extracts were combined, dried over sodium sulfate and concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, chloroform:methanol 0→5%) to give the title product (47%) as a white solid.¹ H NMR (400MHz, DMSO-d₆ ): 7.95(d, J=8Hz, 2H); 7.52(s, 2H); 7.325(d, J=8Hz, 2H); 7.23(m, 2H); 4.30( s, 2H); 3.89 (s, 3H). [M+H] 267.

实例209Example 209

甲烷磺酸1-(4-((1H-苯并[d]咪唑-2-基)甲基)苯甲酰基)吡咯烷-3-基酯的制备Preparation of 1-(4-((1H-benzo[d]imidazol-2-yl)methyl)benzoyl)pyrrolidin-3-yl methanesulfonate

步骤1：[4-(1H-苯并咪唑-2-基甲基)-苯基]-(3-羟基-吡咯烷-1-基)-甲酮Step 1: [4-(1H-Benzimidazol-2-ylmethyl)-phenyl]-(3-hydroxy-pyrrolidin-1-yl)-methanone

以氢氧化钠(1.50g，0.037mol)和水处理4-((1H-苯并[d]咪唑-2-基)甲基)苯甲酸甲酯(5g，0.019mol)于甲醇中的溶液，加热至65℃，搅拌3小时且在减压下浓缩。将所得残余物溶于水中且以浓HCl酸化。通过过滤去除所得沉淀且在真空下干燥整夜以得到4-((1H-苯并[d]咪唑-2-基)甲基)苯甲酸(82.0％)。¹H NMR(400MHz，DSMO-d₆)：7.96(d，J＝8Hz，2H)，7.91(m，J＝9Hz，2H)，7.60(d，J＝8Hz，2H)，7.52(m，J＝6Hz，2H)，4.65(s，2H)。LCMS(ESI⁺)253(M+H)。将一份4-((1H-苯并[d]咪唑-2-基)甲基)苯甲酸(5.0g，0.020mol)溶于二氯甲烷中，冷却至0℃，以1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(4.50g，0.023mol)、1-羟基苯并三唑(HOBT)(3.21g，0.024mol)和二异丙基乙胺(6.41g，0.049mol)处理，在室温下搅拌30分钟，冷却至0℃，以3-吡咯烷醇(1.89g，0.021mol)于二氯甲烷中的溶液处理，在室温下搅拌24小时且以水稀释。分离各相且相继以饱和NaHCO₃水溶液、饱和NaCl水溶液洗涤有机相，经硫酸钠干燥且在减压下浓缩至干燥以得到呈黄色固体的[4-(1H-苯并咪唑-2-基甲基)-苯基]-(3-羟基-吡咯烷-1-基)-甲酮(34％)。¹H NMR(400MHz，DMSO-d₆)：7.47(s，4H)，7.38(d，J＝7.6Hz，2H)，4.87(s，J＝4.2Hz，1H)，4.21(d，2H)，3.48(m，4H)，1.85(m，2H)。LCMS(ESI⁺)322(M+H)。A solution of methyl 4-((lH-benzo[d]imidazol-2-yl)methyl)benzoate (5 g, 0.019 mol) in methanol was treated with sodium hydroxide (1.50 g, 0.037 mol) and water, Heat to 65°C, stir for 3 hours and concentrate under reduced pressure. The resulting residue was dissolved in water and acidified with concentrated HCl. The resulting precipitate was removed by filtration and dried under vacuum overnight to give 4-((lH-benzo[d]imidazol-2-yl)methyl)benzoic acid (82.0%).¹ H NMR (400MHz, DSMO-d₆ ): 7.96(d, J=8Hz, 2H), 7.91(m, J=9Hz, 2H), 7.60(d, J=8Hz, 2H), 7.52(m, J =6Hz, 2H), 4.65(s, 2H). LCMS (ESI⁺ ) 253 (M+H). A portion of 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoic acid (5.0g, 0.020mol) was dissolved in dichloromethane, cooled to 0°C, and 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.50g, 0.023mol), 1-hydroxybenzotriazole (HOBT) (3.21g, 0.024mol) and diisopropylethyl Treat with amine (6.41 g, 0.049 mol), stir at room temperature for 30 min, cool to 0 °C, treat with 3-pyrrolidinol (1.89 g, 0.021 mol) in dichloromethane, stir at room temperature for 24 h And dilute with water. The phases were separated and the organic phase was washed sequentially with saturated aqueous NaHCO₃ , saturated aqueous NaCl, dried over sodium sulfate and concentrated to dryness under reduced pressure to give [4-(1H-benzimidazol-2-ylmethanol) as a yellow solid yl)-phenyl]-(3-hydroxy-pyrrolidin-1-yl)-methanone (34%).¹ H NMR (400MHz, DMSO-d₆ ): 7.47(s, 4H), 7.38(d, J=7.6Hz, 2H), 4.87(s, J=4.2Hz, 1H), 4.21(d, 2H), 3.48 (m, 4H), 1.85 (m, 2H). LCMS (ESI⁺ ) 322 (M+H).

步骤2：甲烷磺酸1-(4-((1H-苯并[d]咪唑-2-基)甲基)苯甲酰基)吡咯烷-3-基酯Step 2:1-(4-((1H-Benzo[d]imidazol-2-yl)methyl)benzoyl)pyrrolidin-3-yl methanesulfonate

将一份[4-(1H-苯并咪唑-2-基甲基)-苯基]-(3-羟基-吡咯烷-1-基)-甲酮(1.00g，3.1mmol)溶于二氯甲烷中，以二异丙基乙胺(0.60g，4.6mmol)处理，冷却至0℃，以甲烷磺酰氯(0.49g，4.3mmol)于二氯甲烷中的溶液逐滴处理，在0℃下搅拌10分钟且在真空下浓缩以得到固体残余物。由柱色谱(硅石，氯仿:甲醇0→5％)纯化此残余物，得到呈黄色固体的标题产物(62％)。¹H NMR(400MHz，CDCl₃)：7.58(m，2H)，7.56(m，4H)，7.22(m，2H)，5.27(d，J＝5.4Hz1H)，4.35(s，2H)，3.93(s，1H)，3.80(s，1H)，3.63(m，4H)，3.09(m，3H)，2.31(m，2H)。[M+H]400。A portion of [4-(1H-benzimidazol-2-ylmethyl)-phenyl]-(3-hydroxy-pyrrolidin-1-yl)-methanone (1.00 g, 3.1 mmol) was dissolved in dichloro In methane, treat with diisopropylethylamine (0.60 g, 4.6 mmol), cool to 0 °C, and treat with a solution of methanesulfonyl chloride (0.49 g, 4.3 mmol) in dichloromethane dropwise at 0 °C Stir for 10 minutes and concentrate in vacuo to give a solid residue. The residue was purified by column chromatography (silica, chloroform:methanol 0→5%) to give the title product (62%) as a yellow solid.¹ H NMR (400MHz, CDCl₃ ): 7.58(m, 2H), 7.56(m, 4H), 7.22(m, 2H), 5.27(d, J=5.4Hz1H), 4.35(s, 2H), 3.93( s, 1H), 3.80 (s, 1H), 3.63 (m, 4H), 3.09 (m, 3H), 2.31 (m, 2H). [M+H] 400.

实例210Example 210

4-((1-甲基-1H-苯并[d]咪唑-2-基)甲基)苯甲酸甲酯的制备Preparation of methyl 4-((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)benzoate

以碳酸钾(0.31g，2.2mmol)处理4-((1H-苯并[d]咪唑-2-基)甲基)苯甲酸甲酯(0.2g，0.75mmol)于丙酮中的溶液，冷却至0℃，以碘代甲烷(0.070mL，1.1mmol)逐滴处理，在40℃下加热12小时，冷却至室温且过滤。在减压下蒸发滤液。由柱色谱(硅石，氯仿)纯化所得残余物，得到标题产物(28％)。¹H NMR(400MHz，CDCl₃)：7.98(d，J＝8.4Hz，2H)，7.7(m，1H)，7.37(m，5H)，4.38(s，2H)，3.9(s，3H)，3.5(s，3H)。[M+H]281。A solution of methyl 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoate (0.2g, 0.75mmol) in acetone was treated with potassium carbonate (0.31g, 2.2mmol) and cooled to 0 °C, treated dropwise with iodomethane (0.070 mL, 1.1 mmol), heated at 40 °C for 12 hours, cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure. The resulting residue was purified by column chromatography (silica, chloroform) to give the title product (28%).¹ H NMR (400MHz, CDCl₃ ): 7.98(d, J=8.4Hz, 2H), 7.7(m, 1H), 7.37(m, 5H), 4.38(s, 2H), 3.9(s, 3H), 3.5(s, 3H). [M+H] 281.

实例211Example 211

甲烷磺酸1-(4-((1-甲基-1H-苯并[d]咪唑-2-基)甲基)苯甲酰基)吡咯烷-3-基酯的制备Preparation of 1-(4-((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)benzoyl)pyrrolidin-3-yl methanesulfonate

基本上使用实例209中所述的相同程序且在步骤1中使用4-((1-甲基-1H-苯并[d]咪唑-2-基)甲基)苯甲酸甲酯，获得呈黄色固体的标题产物，¹H NMR(400MHz，CDCl₃)7.77(m，1H)，7.44-7.50(m，2H)，7.21-7.30(m，5H)，5.23 & 5.37(bs，1H)，4.37(s，2H)，3.93(s，1H)，3.75-3.82(bs，1H)3.70-3.80(m，2H)，3.58-3.65(m，1H)，3.61(s，3H)，3.08 & 2.98(s，3H)，2.33-2.35(m，1H)。[M+H]414。Using essentially the same procedure as described in Example 209 and using methyl 4-((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)benzoate in step 1, a yellow The title product as a solid,¹ H NMR (400 MHz, CDCl₃ ) 7.77 (m, 1H), 7.44-7.50 (m, 2H), 7.21-7.30 (m, 5H), 5.23 & 5.37 (bs, 1H), 4.37 ( s, 2H), 3.93(s, 1H), 3.75-3.82(bs, 1H), 3.70-3.80(m, 2H), 3.58-3.65(m, 1H), 3.61(s, 3H), 3.08 & 2.98(s , 3H), 2.33-2.35 (m, 1H). [M+H] 414.

实例212Example 212

富马酸1，3′-联吡咯烷-1′-基{4-[(1H-苯并[d]咪唑-2-基)甲基]-苯基}甲酮的制备Preparation of Fumaric Acid 1,3'-bipyrrolidin-1'-yl{4-[(1H-benzo[d]imidazol-2-yl)methyl]-phenyl}methanone

将甲烷磺酸1-(4-((1H-苯并[d]咪唑-2-基)甲基)苯甲酰基)吡咯烷-3-基酯(0.8g，2.0mmol)与吡咯烷(1.14g，16mmol)的混合物置于密封管中且加热至110℃达3小时。冷却试管，小心地打开且在减压下蒸发过量吡咯烷。由柱色谱(中性氧化铝，氯仿:甲醇0→5％)纯化所得残余物。以甲醇/二氯甲烷中的富马酸处理经纯化的材料以得到呈白色固体的标题产物。¹H NMR(300MHz，DMSO-d₆)：7.48(m，2H)；7.45(d，2H)；7.39(d，2H)；7.12(m，2H)；6.64(s，2H)；4.23(s，2H)；3.75-3.22(m，6H)；2.89(m，1H)；2.59-2.49(m，2H)；2.08-1.79(m，2H)；1.70(m，4H)。[M+H]375.2。1-(4-((1H-benzo[d]imidazol-2-yl)methyl)benzoyl)pyrrolidin-3-yl methanesulfonate (0.8g, 2.0mmol) and pyrrolidine (1.14 g, 16 mmol) of the mixture was placed in a sealed tube and heated to 110 °C for 3 hours. The tube was cooled, opened carefully and excess pyrrolidine evaporated under reduced pressure. The resulting residue was purified by column chromatography (neutral alumina, chloroform:methanol 0→5%). The purified material was treated with fumaric acid in methanol/dichloromethane to give the title product as a white solid.¹ H NMR (300MHz, DMSO-d₆ ): 7.48(m, 2H); 7.45(d, 2H); 7.39(d, 2H); 7.12(m, 2H); 6.64(s, 2H); 4.23(s , 2H); 3.75-3.22 (m, 6H); 2.89 (m, 1H); 2.59-2.49 (m, 2H); 2.08-1.79 (m, 2H); 1.70 (m, 4H). [M+H] 375.2.

实例213-215Instances 213-215

{4-[(1H-苯并[d]咪唑-2-基)甲基]苯基}[(3-氮杂环基)吡咯烷-1-基]甲酮的制备Preparation of {4-[(1H-benzo[d]imidazol-2-yl)methyl]phenyl}[(3-azacyclyl)pyrrolidin-1-yl]methanone

基本上使用实例212中所述的相同程序且使用适当的甲烷磺酸1-(4-((1H-苯并[d]咪唑-2-基)甲基)苯甲酰基)吡咯烷-3-基酯和所要胺，获得表XVI中所示的化合物且由¹HNMR和质谱分析加以鉴定。Using essentially the same procedure as described in Example 212 and using the appropriate 1-(4-((1H-benzo[d]imidazol-2-yl)methyl)benzoyl)pyrrolidine-3-methanesulfonate Based esters and desired amines, the compounds shown in Table XVI were obtained and identified^by1HNMR and mass spectral analyses.

表XVITable XVI

实例216Instance 216

{1，3′-联吡咯烷-1′-基{4-[(1-乙基-1H-苯并[d]咪唑-2-基)甲基]苯基}}甲酮盐酸盐的制{1,3'-bipyrrolidin-1'-yl{4-[(1-ethyl-1H-benzo[d]imidazol-2-yl)methyl]phenyl}}methanone hydrochloride system备prepare

步骤1：甲烷磺酸1-{4-[(1-乙基-1H-苯并[d]咪唑-2-基)甲基]苯甲酰基}吡咯烷-3-基酯Step 1: 1-{4-[(1-Ethyl-1H-benzo[d]imidazol-2-yl)methyl]benzoyl}pyrrolidin-3-yl methanesulfonate

以碳酸钾(0.260g，1.9mmol)处理甲烷磺酸1-{4-[(1H-苯并[d]咪唑-2-基)甲基]苯甲酰基}-吡咯烷-3-基酯(0.250g，0.6mmol)于DMF中的搅拌溶液，冷却至-5℃，在0℃下经20分钟以碘乙烷(0.24g，1.5mmol)逐滴处理，温至室温，在50℃下加热3小时，冷却至室温且过滤。在真空中浓缩滤液。将所得残余物溶于乙酸乙酯中，以水洗涤，经硫酸钠干燥且在真空中浓缩。由柱色谱(中性氧化铝，氯仿:甲醇100:0→98:2)纯化此残余物，得到甲烷磺酸1-{4-[(1-乙基-1H-苯并[d]咪唑-2-基)甲基]苯甲酰基}吡咯烷-3-基酯(19％)。¹H NMR(400MHz，CDCl₃)：7.79-7.77(m，1H)，7.44-7.51(m，3H)，7.32-7.25(m，4H)，5.37 & 5.23(bs，1H)，4.36(s，2H)，4.05-4.10(q，J＝8Hz，2H)，3.93(bs，1H)，3.82(m，1H)，3.57-3.71(bs，2H)，3.08 & 3.00(s，3H)，2.33-2.36(m，1H)，2.17-2.21(m，1H)，1.18-1.22(t，J＝8Hz，3H)。[M+H]428。1-{4-[(1H-Benzo[d]imidazol-2-yl)methyl]benzoyl}-pyrrolidin-3-yl methanesulfonate was treated with potassium carbonate (0.260 g, 1.9 mmol) ( 0.250 g, 0.6 mmol) in DMF, cooled to -5 °C, treated dropwise with iodoethane (0.24 g, 1.5 mmol) at 0 °C for 20 minutes, warmed to room temperature, heated at 50 °C 3 hours, cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate, washed with water, dried over sodium sulfate and concentrated in vacuo. Purification of this residue by column chromatography (neutral alumina, chloroform:methanol 100:0→98:2) gave methanesulfonic acid 1-{4-[(1-ethyl-1H-benzo[d]imidazole- 2-yl)methyl]benzoyl}pyrrolidin-3-yl ester (19%).¹ H NMR (400MHz, CDCl₃ ): 7.79-7.77(m, 1H), 7.44-7.51(m, 3H), 7.32-7.25(m, 4H), 5.37 & 5.23(bs, 1H), 4.36(s, 2H), 4.05-4.10(q, J=8Hz, 2H), 3.93(bs, 1H), 3.82(m, 1H), 3.57-3.71(bs, 2H), 3.08 & 3.00(s, 3H), 2.33- 2.36 (m, 1H), 2.17-2.21 (m, 1H), 1.18-1.22 (t, J=8Hz, 3H). [M+H] 428.

步骤2：{1，3′-联吡咯烷-1′-基{4-[(1-乙基-1H-苯并[d]咪唑-2-基)甲基]苯基}}甲酮盐酸盐Step 2: {1,3'-bipyrrolidin-1'-yl{4-[(1-ethyl-1H-benzo[d]imidazol-2-yl)methyl]phenyl}}methanone salt salt

将甲烷磺酸1-{4-[(1-乙基-1H-苯并[d]咪唑-2-基)甲基]苯甲酰基}吡咯烷-3-基酯(0.06g，0.14mmol)与吡咯烷(0.08g，1.12mmol)的混合物置于微波试管中且以微波照射在110℃下加热15分钟。在减压下蒸发过量吡咯烷且由柱色谱(中性氧化铝，氯仿:甲醇100:0→95:5)纯化所得残余物。以HCl乙醚溶液处理经纯化材料以得到标题产物。¹H NMR(300MHz，DMSO-d₆)：7.83-7.73(m，2H)；7.56(d，2H)；7.48(d，2H)；7.48-7.43(m，2H)；4.63(s，2H)；4.44(q，2H)；4.03-3.25(m，7H)；3.07(m，2H)；2.30(m，2H)；2.14-1.84(m，4H)；1.27(t，3H)。[M+H]403.2。1-{4-[(1-Ethyl-1H-benzo[d]imidazol-2-yl)methyl]benzoyl}pyrrolidin-3-yl methanesulfonate (0.06g, 0.14mmol) The mixture with pyrrolidine (0.08 g, 1.12 mmol) was placed in a microwave test tube and heated at 110° C. for 15 minutes under microwave irradiation. Excess pyrrolidine was evaporated under reduced pressure and the resulting residue was purified by column chromatography (neutral alumina, chloroform:methanol 100:0→95:5). The purified material was treated with ethereal HCl to give the title product.¹ H NMR (300 MHz, DMSO-d₆ ): 7.83-7.73 (m, 2H); 7.56 (d, 2H); 7.48 (d, 2H); 7.48-7.43 (m, 2H); 4.63 (s, 2H) ; 4.44(q, 2H); 4.03-3.25(m, 7H); 3.07(m, 2H); 2.30(m, 2H); 2.14-1.84(m, 4H); 1.27(t, 3H). [M+H] 403.2.

实例217-222Examples 217-222

(3′S)-1′-{4-[(1-烷基-1H-苯并咪唑-2-基)甲基]苯甲酰基}-1，3′-联吡咯烷富马酸酯的制(3′S)-1′-{4-[(1-Alkyl-1H-benzimidazol-2-yl)methyl]benzoyl}-1,3′-bipyrrolidine fumarate system备prepare

步骤1：4-[(1-烷基-1H-苯并[d]咪唑-2-基)甲基]苯甲酸甲酯Step 1: Methyl 4-[(1-Alkyl-1H-Benzo[d]imidazol-2-yl)methyl]benzoate

以石油醚洗涤氢化钠(矿物油中的60％分散液，48mg，1.24mmol)，将其悬浮于N，N-二甲基甲酰胺中，冷却至0℃，以4-[(1H-苯并[d]咪唑-2-基)甲基]苯甲酸甲酯(300mg，1.13mmol)于DMF中的溶液处理，在0℃下搅拌10分钟，在室温下搅拌15分钟，冷却至0℃，以所选溴代烷或碘代烷(1.24mmol)于DMF中的溶液经10分钟逐滴处理，在室温下搅拌5小时且在减压下浓缩。将所得残余物在水与二氯甲烷之间分溶。分离有机相，经硫酸钠干燥且在减压下蒸发至干燥。由快速柱色谱(硅石，石油醚:乙酸乙酯8:2至1:1)纯化此残余物以得到4-[(1-烷基-1H-苯并[d]咪唑-2-基)甲基]苯甲酸甲酯。Sodium hydride (60% dispersion in mineral oil, 48 mg, 1.24 mmol) was washed with petroleum ether, suspended in N, N-dimethylformamide, cooled to 0 °C, and 4-[(1H-benzene And [d] imidazol-2-yl) methyl] benzoic acid methyl ester (300 mg, 1.13 mmol) in DMF solution treatment, stirred at 0 ° C for 10 minutes, stirred at room temperature for 15 minutes, cooled to 0 ° C, A solution of the selected alkyl bromide or iodide (1.24 mmol) in DMF was treated dropwise over 10 min, stirred at room temperature for 5 h and concentrated under reduced pressure. The resulting residue was partitioned between water and dichloromethane. The organic phase was separated, dried over sodium sulfate and evaporated to dryness under reduced pressure. This residue was purified by flash column chromatography (silica, petroleum ether:ethyl acetate 8:2 to 1:1) to give 4-[(1-alkyl-1H-benzo[d]imidazol-2-yl)methanol base] methyl benzoate.

步骤2：(3′S)-1′-{4-[(1-烷基-1H-苯并咪唑-2-基)甲基]苯甲酰基}-1，3′-联吡咯烷富马酸酯Step 2: (3'S)-1'-{4-[(1-Alkyl-1H-benzimidazol-2-yl)methyl]benzoyl}-1,3'-bipyrrolidine fumar Ester

将苯甲酸酯(0.8mmol)溶于甲醇中，以氢氧化钠水溶液(2.5M，2.0mmol)处理，在回流下加热4小时且在真空中浓缩。将残余物分散于水中且以过量甲酸酸化。通过过滤去除所得沉淀，以水洗涤且在真空下干燥整夜以得到相应苯甲酸。将苯甲酸(0.381mmol)溶于DMF中，以1-(3-二甲基-氨基丙基)-3-乙基碳化二亚胺盐酸盐(87.7mg，0.457mmol)和1-羟基苯并三唑(56.6mg，0.419mmol)处理，在室温下搅拌30分钟，以(3′S)-1，3′-联吡咯烷(79.8mg，0.57mmol)于DMF中的溶液处理，在室温下搅拌6小时且在真空中浓缩。将此残余物在碳酸钾水溶液(1.0M)与二氯甲烷之间分溶。分离有机相，以水洗涤，经硫酸钠干燥且在减压下浓缩。由快速柱色谱(硅石，二氯甲烷:甲醇20:1至10:1)纯化此浓缩物，接着以二氯甲烷/甲醇中的富马酸处理以得到表XVII中所示的化合物。由¹H NMR和质谱分析鉴定表XVII中的化合物。The benzoate (0.8 mmol) was dissolved in methanol, treated with aqueous sodium hydroxide (2.5M, 2.0 mmol), heated at reflux for 4 hours and concentrated in vacuo. The residue was dispersed in water and acidified with excess formic acid. The resulting precipitate was removed by filtration, washed with water and dried under vacuum overnight to give the corresponding benzoic acid. Benzoic acid (0.381mmol) was dissolved in DMF, and 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (87.7mg, 0.457mmol) and 1-hydroxybenzene Triazole (56.6 mg, 0.419 mmol) was treated, stirred at room temperature for 30 minutes, treated with a solution of (3'S)-1,3'-bipyrrolidine (79.8 mg, 0.57 mmol) in DMF, and stirred at room temperature Stirred at low temperature for 6 hours and concentrated in vacuo. The residue was partitioned between aqueous potassium carbonate (1.0 M) and dichloromethane. The organic phase was separated, washed with water, dried over sodium sulfate and concentrated under reduced pressure. This concentrate was purified by flash column chromatography (silica, dichloromethane:methanol 20:1 to 10:1), followed by treatment with fumaric acid in dichloromethane/methanol to give the compounds shown in Table XVII. The compounds in Table XVII were identified^by1H NMR and mass spectral analysis.

表XVIITable XVII

实例223Example 223

2-(2-{4-[(3′S)-1，3′-联吡咯烷-1′-基羰基]苯甲基}-1H-苯并咪唑-1-基)乙醇富马酸酯的2-(2-{4-[(3′S)-1,3′-Bipyrrolidin-1′-ylcarbonyl]benzyl}-1H-benzimidazol-1-yl)ethanol fumarate of制备preparation

基本上使用实例217-222中所述的相同程序且使用4-((1H-苯并[d]咪唑-2-基)甲基)苯甲酸甲酯和2-(2-溴乙氧基)四氢-2H-吡喃作为起始物质，获得(3′S)-1′-{4-[(1-(2-(四氢-吡喃-2-基氧基)-乙基)-1H-苯并咪唑-2-基)甲基]苯甲酰基}-1，3′-联吡咯烷，[M+H]503.2。以于乙醚/乙醇中的氯化氢处理一份(3′S)-1′-{4-[(1-(2-(四氢-吡喃-2-基氧基)-乙基)-1H-苯并咪唑-2-基)甲基]苯甲酰基}-1，3′-联吡咯烷，在室温下搅拌且在真空中浓缩。将所得残余物在碳酸钾水溶液(1.0M)与二氯甲烷之间分溶。分离有机相，以水洗涤，经硫酸钠干燥且在减压下浓缩。以于二氯甲烷/甲醇中的富马酸处理此残余物以得到标题产物。¹H NMR(300MHz，DMSO-d₆+TFA)：7.94(m，1H)，7.79(m，1H)，7.57(d，2H)，7.57(m，2H)，7.49(d，2H)，6.65(s，2H)，4.74(s，2H)，4.58(t，2H)，3.92(m，2H)，3.80(t，2H)，3.74(m，2H)，3.51(m，2H)，3.44-3.06(br.s，3H)，2.33(m，1H)，2.21(m，1H)，1.99(m，4H)。[M+H]419.17。Essentially using the same procedure described in Examples 217-222 and using methyl 4-((lH-benzo[d]imidazol-2-yl)methyl)benzoate and 2-(2-bromoethoxy) Tetrahydro-2H-pyran as starting material affords (3′S)-1′-{4-[(1-(2-(tetrahydro-pyran-2-yloxy)-ethyl)- 1H-benzimidazol-2-yl)methyl]benzoyl}-1,3'-bipyrrolidine, [M+H] 503.2. A portion of (3'S)-1'-{4-[(1-(2-(tetrahydro-pyran-2-yloxy)-ethyl)-1H- Benzimidazol-2-yl)methyl]benzoyl}-1,3'-bipyrrolidine, stirred at room temperature and concentrated in vacuo. The resulting residue was partitioned between aqueous potassium carbonate (1.0M) and dichloromethane. The organic phase was separated, washed with water, dried over sodium sulfate and concentrated under reduced pressure. Treatment of this residue with fumaric acid in dichloromethane/methanol gave the title product.¹ H NMR (300MHz, DMSO-d₆ +TFA): 7.94(m, 1H), 7.79(m, 1H), 7.57(d, 2H), 7.57(m, 2H), 7.49(d, 2H), 6.65 (s, 2H), 4.74(s, 2H), 4.58(t, 2H), 3.92(m, 2H), 3.80(t, 2H), 3.74(m, 2H), 3.51(m, 2H), 3.44- 3.06 (br.s, 3H), 2.33 (m, 1H), 2.21 (m, 1H), 1.99 (m, 4H). [M+H] 419.17.

实例224Example 224

(3′S)-1′-{4-[(1-苯乙基-1H-苯并咪唑-2-基)甲基]苯甲酰基}-1，3′-联吡咯烷富马酸酯的(3′S)-1′-{4-[(1-Phenylethyl-1H-benzimidazol-2-yl)methyl]benzoyl}-1,3′-bipyrrolidine fumarate of制备preparation

步骤1：4-(1-苯乙基-1H-苯并咪唑-2-基甲基)苯甲酸甲酯Step 1: Methyl 4-(1-phenethyl-1H-benzimidazol-2-ylmethyl)benzoate

以(2-溴乙基)苯(209mg，1.13mmol)和碳酸钾(143mg，0.90mmol)处理4-((1H-苯并[d]咪唑-2-基)甲基)苯甲酸甲酯(200mg，0.75mmol)于乙腈中的溶液。以微波照射将反应混合物在100℃下加热2小时。在减压下去除溶剂且将残余物在水与二氯甲烷之间分溶。分离有机相，经硫酸钠干燥且在真空中浓缩。由快速柱色谱(硅石，石油醚:乙酸乙酯8:2至1:1)纯化所得残余物，得到4-(1-苯乙基-1H-苯并咪唑-2-基甲基)-苯甲酸甲酯(30％)。[M+H]371.2。Methyl 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoate ( 200mg, 0.75mmol) in acetonitrile solution. The reaction mixture was heated at 100° C. for 2 hours under microwave irradiation. The solvent was removed under reduced pressure and the residue was partitioned between water and dichloromethane. The organic phase was separated, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica, petroleum ether:ethyl acetate 8:2 to 1:1) to give 4-(1-phenethyl-1H-benzimidazol-2-ylmethyl)-benzene Methyl formate (30%). [M+H] 371.2.

步骤2：(3′S)-1′-{4-[(1-苯乙基-1H-苯并咪唑-2-基)甲基]苯甲酰基}-1，3′-联吡咯烷富马酸酯Step 2: (3'S)-1'-{4-[(1-Phenylethyl-1H-benzimidazol-2-yl)methyl]benzoyl}-1,3'-bipyrrolidine Maleate

基本上使用实例217-222步骤2中所述的相同程序且使用4-(1-苯乙基-1H-苯并咪唑-2-基甲基)-苯甲酸甲酯作为起始物质，获得标题产物。¹H NMR(300MHz，DMSO-d₆)：7.54-7.61(m，1H)，7.41-7.49(m，3H)，7.16-7.32(m，7H)，7.08(dd，2H)，6.64(s，2H)，4.34-4.43(m，2H)，4.06-4.20(m，2H)，3.38-3.62(m，5H)，3.32(dd，1H)，2.80-2.94(m，3H)，2.42-2.58(m，2H)，1.93-2.08(m，1H)，1.76-1.90(m，1H)，1.63-1.74(m，4H)，[M+H]379.22。Using essentially the same procedure as described in Step 2 of Examples 217-222 and using 4-(1-phenethyl-1H-benzimidazol-2-ylmethyl)-benzoic acid methyl ester as starting material, the title product.¹ H NMR (300MHz, DMSO-d₆ ): 7.54-7.61(m, 1H), 7.41-7.49(m, 3H), 7.16-7.32(m, 7H), 7.08(dd, 2H), 6.64(s, 2H), 4.34-4.43(m, 2H), 4.06-4.20(m, 2H), 3.38-3.62(m, 5H), 3.32(dd, 1H), 2.80-2.94(m, 3H), 2.42-2.58( m, 2H), 1.93-2.08 (m, 1H), 1.76-1.90 (m, 1H), 1.63-1.74 (m, 4H), [M+H] 379.22.

实例225Example 225

(3′S)-1′-[4-(1H-苯并咪唑-2-基甲基)苯甲酰基]-1，3′-联吡咯烷的制备Preparation of (3'S)-1'-[4-(1H-benzimidazol-2-ylmethyl)benzoyl]-1,3'-bipyrrolidine

以氢氧化钠水溶液(2.5M，3.75mmol)处理4-((1H-苯并[d]咪唑-2-基)甲基)苯甲酸甲酯(400mg，1.5mmol)于甲醇中的溶液，在回流温度下加热3小时且在真空中浓缩。将所得残余物分散于水中且以过量甲酸酸化。通过过滤去除所得沉淀，以水洗涤且在真空下干燥整夜以得到呈白色固体的4-((1H-苯并[d]咪唑-2-基)甲基)苯甲酸(92％)，[M+H]253.2。以1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(183mg，0.952mmol)和1-羟基苯并三唑(134mg，0.873mmol)处理4-((1H-苯并[d]咪唑-2-基)甲基)苯甲酸(200mg，0.79mmol)于DMF中的溶液，在室温下搅拌3小时，以(3′S)-1，3′-联吡咯烷(166.6mg，1.19mmol)于DMF中的溶液处理，在室温下搅拌6小时且在真空中浓缩。将此残余物在碳酸钾水溶液(1.0M)与二氯甲烷之间分溶。以水洗涤有机相，经硫酸钠干燥且在减压下浓缩。由快速柱色谱(硅石，二氯甲烷:甲醇20:1至10:1)纯化浓缩物，得到标题化合物(73％)，由质谱分析加以鉴定。[M+H]253.2。A solution of methyl 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoate (400mg, 1.5mmol) in methanol was treated with aqueous sodium hydroxide (2.5M, 3.75mmol) in Heat at reflux for 3 hours and concentrate in vacuo. The resulting residue was dispersed in water and acidified with excess formic acid. The resulting precipitate was removed by filtration, washed with water and dried under vacuum overnight to give 4-((lH-benzo[d]imidazol-2-yl)methyl)benzoic acid (92%) as a white solid, [ M+H] 253.2. 4-((( A solution of 1H-benzo[d]imidazol-2-yl)methyl)benzoic acid (200mg, 0.79mmol) in DMF was stirred at room temperature for 3 hours, and (3′S)-1,3′-linked A solution of pyrrolidine (166.6 mg, 1.19 mmol) in DMF was worked up, stirred at room temperature for 6 hours and concentrated in vacuo. The residue was partitioned between aqueous potassium carbonate (1.0 M) and dichloromethane. The organic phase was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The concentrate was purified by flash column chromatography (silica, dichloromethane:methanol 20:1 to 10:1) to afford the title compound (73%), which was identified by mass spectral analysis. [M+H] 253.2.

实例226Example 226

(3′S)-1′-{4-[(1-苯基-IH-苯并咪唑-2-基)甲基]苯甲酰基}-1，3′-联吡咯烷富马酸酯的制(3′S)-1′-{4-[(1-phenyl-IH-benzimidazol-2-yl)methyl]benzoyl}-1,3′-bipyrrolidine fumarate system备prepare

以吡啶(34μL，0.42mmol)、接着以苯基硼酸(50.7mg，0.42mmol)、乙酸铜(II)(56mg，0.31mmol)和4

分子筛处理(3′S)-1′-[4-(1H-苯并咪唑-2-基甲基)苯甲酰基]-1，3′-联吡咯烷(78mg，0.21mmol)于二氯甲烷中的溶液，在室温下搅拌24小时且过滤。在减压下蒸发滤液且将所得残余物在碳酸钾水溶液(1.0M)与二氯甲烷之间分溶。分离有机相，以水洗涤，经硫酸钠干燥且在减压下浓缩。由快速柱色谱(硅石，二氯甲烷:甲醇98:2至90:10)纯化所得残余物。以于二氯甲烷/甲醇中的富马酸处理经纯化材料以得到标题产物，¹H NMR(300MHz，DMSO-d₆)：7.65-7.73(m，1H)，7.49-7.62(m，3H)，7.39-7.48(m，2H)，7.35(d，2H)，7.16-7.29(m，2H)，7.05-7.15(m，3H)，6.61(s，2H)，4.22(s，2H)，3.00-3.78(m，7H)，2.54-2.66(m，2H)，1.97-2.11(m，1H)，1.63-1.89(m，5H)。[M+H]451.33。With pyridine (34 μL, 0.42 mmol), followed by phenylboronic acid (50.7 mg, 0.42 mmol), copper (II) acetate (56 mg, 0.31 mmol) and 4

Molecular sieve treatment of (3'S)-1'-[4-(1H-benzimidazol-2-ylmethyl)benzoyl]-1,3'-bipyrrolidine (78mg, 0.21mmol) in dichloromethane The solution in was stirred at room temperature for 24 hours and filtered. The filtrate was evaporated under reduced pressure and the resulting residue was partitioned between aqueous potassium carbonate (1.0 M) and dichloromethane. The organic phase was separated, washed with water, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica, dichloromethane:methanol 98:2 to 90:10). Purified material was treated with fumaric acid in dichloromethane/methanol to give the title product,¹ H NMR (300 MHz, DMSO-d₆ ): 7.65-7.73 (m, 1H), 7.49-7.62 (m, 3H) , 7.39-7.48(m, 2H), 7.35(d, 2H), 7.16-7.29(m, 2H), 7.05-7.15(m, 3H), 6.61(s, 2H), 4.22(s, 2H), 3.00 -3.78 (m, 7H), 2.54-2.66 (m, 2H), 1.97-2.11 (m, 1H), 1.63-1.89 (m, 5H). [M+H] 451.33.

实例227Example 227

(3′S)-1′-(4-{[1-(苯基磺酰基)-1H-苯并咪唑-2-基]甲基}-苯甲酰基)-1，3′-联吡咯烷富马(3'S)-1'-(4-{[1-(phenylsulfonyl)-1H-benzimidazol-2-yl]methyl}-benzoyl)-1,3'-bipyrrolidine Fuma酸酯的制备Preparation of esters

在惰性气氛下将(3′S)-1′-[4-(1H-苯并咪唑-2-基甲基)苯甲酰基]-1，3′-联吡咯烷(100mg，0.267mmol)于无水二氯甲烷中的溶液冷却至0℃，以三乙胺(TEA)(32mg，0.32mmol)处理，接着逐滴添加苯磺酰氯(51.7mg，0.293mmol)于无水二氯甲烷中的溶液，在0℃下搅拌1小时，温至室温达1小时且在减压下浓缩。将所得残余物在二氯甲烷与5％NaHCO₃水溶液之间分溶。分离有机相，以水洗涤，经硫酸钠干燥且在减压下浓缩以得到残余物。以于二氯甲烷/甲醇中的富马酸处理此残余物以得到标题化合物，¹H NMR(300MHz，DMSO-d₆+TFA)：7.96(d，1H)，7.90(d，2H)，7.78-7.66(m，2H)，7.59(m，2H)，7.49(d，2H)，7.45-7.29(m，4H)，6.63(s，2H)，4.67(s，2H)，3.58-3.41(m，4H)，3.10-2.76(m，5H)，2.19(m，1H)，2.00(m，1H)，1.91-1.73(m，4H)。[M+H]515.1。(3'S)-1'-[4-(1H-benzimidazol-2-ylmethyl)benzoyl]-1,3'-bipyrrolidine (100mg, 0.267mmol) was dissolved in an inert atmosphere The solution in anhydrous dichloromethane was cooled to 0 °C, treated with triethylamine (TEA) (32 mg, 0.32 mmol), followed by the dropwise addition of benzenesulfonyl chloride (51.7 mg, 0.293 mmol) in anhydrous dichloromethane. The solution was stirred at 0 °C for 1 h, warmed to room temperature for 1 h and concentrated under reduced pressure. The resulting residue was partitioned between dichloromethane and 5% aqueous NaHCO₃ . The organic phase was separated, washed with water, dried over sodium sulfate and concentrated under reduced pressure to give a residue. Treatment of this residue with fumaric acid in dichloromethane/methanol gave the title compound,¹ H NMR (300 MHz, DMSO-d₆ +TFA): 7.96 (d, 1H), 7.90 (d, 2H), 7.78 -7.66(m, 2H), 7.59(m, 2H), 7.49(d, 2H), 7.45-7.29(m, 4H), 6.63(s, 2H), 4.67(s, 2H), 3.58-3.41(m , 4H), 3.10-2.76 (m, 5H), 2.19 (m, 1H), 2.00 (m, 1H), 1.91-1.73 (m, 4H). [M+H] 515.1.

实例228Example 228

(3′S)-1′-[4-(1H-吲哚-1-基甲基)苯甲酰基]-1，3′-联吡咯烷的制备Preparation of (3'S)-1'-[4-(1H-indol-1-ylmethyl)benzoyl]-1,3'-bipyrrolidine

以NaOH水溶液(4.15mL，1N，4.15mmol)处理4-((1H-吲哚-3-基)甲基)苯甲酸甲酯(四面体快报(Tet.Lett.)44(2003)4589-4591)(0.50g，1.88mmol)于甲醇中的溶液，加热至回流温度达3小时且在真空中浓缩。将所得固体残余物溶于H₂O中且以HCl酸化。通过过滤去除所得沉淀且干燥以得到0.468g(99％)呈白色固体的4-((1H-吲哚-3-基)甲基)苯甲酸。将PS-碳化二亚胺(0.275g，1.2mmol/g，0.33mmol)装入微波瓶中。向瓶中添加4-((1H-吲哚-3-基)甲基)-苯甲酸(0.070g，0.28mmol)于CH₃CN中的溶液、HOBT(0.045g，0.33mmol)于CH₃CN中的溶液、(S)-1，3′-联吡咯烷(0.065g，0.31mmol)于CH₃CN中的溶液和0.11mL三乙胺。将反应混合物在爱姆瑞优化器(Emry′s Optimizer)中在110℃下照射6分钟且接着在减压下浓缩。由快速色谱纯化所得残余物以得到0.064g(68％)呈白色固体的标题产物，熔点141-153℃，由H¹NMR和质谱分析加以鉴定。MS(ES)m/z 372.2。Methyl 4-((1H-indol-3-yl)methyl)benzoate was treated with aqueous NaOH (4.15 mL, 1 N, 4.15 mmol) (Tet. Lett. 44 (2003) 4589-4591 ) (0.50 g, 1.88 mmol) in methanol, heated to reflux temperature for 3 hours and concentrated in vacuo. The resulting solid residue was dissolved in_H2O and acidified with HCl. The resulting precipitate was removed by filtration and dried to afford 0.468 g (99%) of 4-((lH-indol-3-yl)methyl)benzoic acid as a white solid. PS-carbodiimide (0.275 g, 1.2 mmol/g, 0.33 mmol) was charged into a microwave vial. To the bottle was added a solution of 4-((1H-indol-3-yl)methyl)-benzoic acid (0.070 g, 0.28 mmol) in_CH3CN , HOBT (0.045 g, 0.33 mmol) in_CH3CN A solution in CH 3 CN, a solution of (S)-1,3′-bipyrrolidine (0.065 g, 0.31 mmol) in CH₃ CN and 0.11 mL of triethylamine. The reaction mixture was irradiated in Emry's Optimizer at 110°C for 6 minutes and then concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 0.064 g (68%) of the title product as a white solid, mp 141-153 °C, identified by^H1 NMR and mass spectral analyses. MS (ES) m/z 372.2.

实例229Example 229

(3′S)-1′-{4-[(1-甲基-1H-吲哚-3-基)甲基]苯甲酰基}-1，3′-联吡咯烷的制备Preparation of (3'S)-1'-{4-[(1-methyl-1H-indol-3-yl)methyl]benzoyl}-1,3'-bipyrrolidine

步骤1：4-((1-甲基-1H-吲哚-3-基)甲基)苯甲酸甲酯Step 1: Methyl 4-((1-methyl-1H-indol-3-yl)methyl)benzoate

将4-((1H-吲哚-3-基)甲基)苯甲酸甲酯(0.250g，0.94mmol)于THF中的溶液逐滴添加至NaH(0.048g，1.19mmol)于THF中的悬浮液中。将混合物搅拌15分钟，以碘代甲烷(0.154g，1.08mmol)处理，搅拌30分钟且在真空中浓缩。将所得固体残余物在CH₂Cl₂与H₂O之间分溶。分离有机相，经Na₂SO₄干燥且浓缩至干燥以得到4-((1-甲基-1H-吲哚-3-基)甲基)苯甲酸甲酯。A solution of methyl 4-((1H-indol-3-yl)methyl)benzoate (0.250 g, 0.94 mmol) in THF was added dropwise to a suspension of NaH (0.048 g, 1.19 mmol) in THF in the liquid. The mixture was stirred for 15 minutes, treated with iodomethane (0.154 g, 1.08 mmol), stirred for 30 minutes and concentrated in vacuo._The resulting solid residue was partitioned between_CH2Cl2 and_H2O . The organic phase was separated, dried over_Na2SO4 and concentrated to dryness to give methyl 4-((1-methyl-1H-indol-3_- yl)methyl)benzoate.

步骤2：(3′S)-1′-{4-[(1-甲基-1H-吲哚-3-基)甲基]苯甲酰基}-1，3′-联吡咯烷Step 2: (3'S)-1'-{4-[(1-Methyl-1H-indol-3-yl)methyl]benzoyl}-1,3'-bipyrrolidine

基本上使用实例167中所述的相同程序且使用4-((1-甲基-1H-吲哚-3-基)甲基)苯甲酸甲酯作为起始物质，获得呈白色固体的标题产物，熔点73-78℃，由H¹NMR和质谱分析加以鉴定。MS(ES)m/z 388.2；MS(ES)m/z 410.2。Using essentially the same procedure as described in Example 167 and using methyl 4-((1-methyl-1H-indol-3-yl)methyl)benzoate as starting material, the title product was obtained as a white solid , melting point 73-78 ° C, identified by H¹ NMR and mass spectrometry. MS (ES) m/z 388.2; MS (ES) m/z 410.2.

实例230instance 230

(3S)-N，N-二甲基-1-{4-[(1-甲基-1H-吲哚-3-基)甲基]苯甲酰基}吡咯烷-3-胺的制备Preparation of (3S)-N, N-dimethyl-1-{4-[(1-methyl-1H-indol-3-yl)methyl]benzoyl}pyrrolidin-3-amine

基本上使用实例228中所述的相同程序且使用4-((1-甲基-1H-吲哚-3-基)甲基)苯甲酸甲酯和(S)-N，N-二甲基吡咯烷-3-胺作为起始物质，获得呈白色固体的标题化合物，熔点101-105℃，由H¹NMR和质谱分析加以鉴定。MS(ES)m/z 362.2；MS(ES)m/z 723.4。Using essentially the same procedure as described in Example 228 and using methyl 4-((1-methyl-1H-indol-3-yl)methyl)benzoate and (S)-N,N-dimethyl Starting from pyrrolidin-3-amine, the title compound was obtained as a white solid, mp 101-105°C, identified by^H1 NMR and mass spectral analyses. MS (ES) m/z 362.2; MS (ES) m/z 723.4.

实例231Example 231

(3′S)-1′-(4-苯甲基苯甲酰基)-1，3′-联吡咯烷盐酸盐的制备Preparation of (3'S)-1'-(4-benzylbenzoyl)-1,3'-bipyrrolidine hydrochloride

在室温下相继以0.85mL三乙胺和固体六氟磷酸苯并三唑-1-基-氧基三吡咯烷鏻(1.2g，2.4mmol)处理3-(吡咯烷并)吡咯烷盐酸盐(0.44g，2.1mmmol)和4-苯甲基苯甲酸(0.34g，1.6mmmol)于CH₂Cl₂中的混合物，在氮下搅拌16小时，以CH₂Cl₂稀释，相继以水和盐水洗涤，经MgSO₄干燥且在真空中浓缩。经色谱纯化浓缩物。以HCl乙醚溶液处理经纯化材料以得到标题化合物，由H¹NMR和质谱分析加以鉴定。3-(Pyrrolidino)pyrrolidine hydrochloride was treated sequentially with 0.85 mL of triethylamine and solid benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate (1.2 g, 2.4 mmol) at room temperature (0.44g, 2.1mmmol) and 4-benzylbenzoic acid (0.34g,_1.6mmmol ) in_CH2Cl2 , stirred under nitrogen for₁₆ hours, diluted with_CH2Cl2 , washed successively with water and brine Washed, dried over MgSO₄ and concentrated in vacuo. The concentrate was purified by chromatography. Treatment of the purified material with ethereal HCl gave the title compound, which was identified by^H1 NMR and mass spectrometry.

实例232Example 232

(3′S)-1′-{4-[(1-乙基-1H-苯并咪唑-2-基)甲基]苯甲基}-1，3′-联吡咯烷的制备Preparation of (3'S)-1'-{4-[(1-ethyl-1H-benzimidazol-2-yl)methyl]benzyl}-1,3'-bipyrrolidine

向1，3′-联吡咯烷-1′-基(4-((1-乙基-1H-苯并[d]咪唑-2-基)甲基)苯基)甲酮(69mg，0.172mmol，1eq)于无水四氢呋喃(3mL)中的溶液中添加硼烷-四氢呋喃络合物(860μL，0.860mmol，四氢呋喃中的1M)且将反应混合物加热至回流且搅拌3小时。将反应混合物冷却至室温，通过逐滴添加甲醇中止反应且在减压下蒸发溶剂。以于甲醇(5mL)中的氯化氢处理残余物且在回流下加热1小时。在减压下蒸发溶剂且将残余物在二氯甲烷与1.0N氢氧化钠水溶液之间分溶。分离有机层且干燥(硫酸钠)且在真空中去除溶剂。由快速柱色谱纯化残余物以得到标题产物(65％)。¹H NMR(300MHz，DMSO-d₆)：7.74-7.86(m，2H)，7.43-7.56(m，6H)，6.64(s，2H)，4.62(s，2H)，4.46(q，2H)，4.22(s，2H)，4.00-4.10(m，1H)，3.44-3.55(m，1H)，3.24-3.40(m，6H)，3.09-3.18(m，1H)，2.35-2.45(m，1H)，2.12-2.24(m，1H)，1.91-2.02(m，4H)，1.27(t，3H)。389.22(M+H)。To 1,3'-bipyrrolidin-1'-yl (4-((1-ethyl-1H-benzo[d]imidazol-2-yl)methyl)phenyl)methanone (69mg, 0.172mmol , 1 eq) To a solution in anhydrous THF (3 mL) was added borane-THF complex (860 μL, 0.860 mmol, 1 M in THF) and the reaction mixture was heated to reflux and stirred for 3 hours. The reaction mixture was cooled to room temperature, quenched by dropwise addition of methanol and the solvent was evaporated under reduced pressure. The residue was treated with hydrogen chloride in methanol (5 mL) and heated at reflux for 1 h. The solvent was evaporated under reduced pressure and the residue was partitioned between dichloromethane and 1.0N aqueous sodium hydroxide solution. The organic layer was separated and dried (sodium sulfate) and the solvent was removed in vacuo. The residue was purified by flash column chromatography to give the title product (65%).¹ H NMR (300MHz, DMSO-d₆ ): 7.74-7.86(m, 2H), 7.43-7.56(m, 6H), 6.64(s, 2H), 4.62(s, 2H), 4.46(q, 2H) , 4.22(s, 2H), 4.00-4.10(m, 1H), 3.44-3.55(m, 1H), 3.24-3.40(m, 6H), 3.09-3.18(m, 1H), 2.35-2.45(m, 1H), 2.12-2.24(m, 1H), 1.91-2.02(m, 4H), 1.27(t, 3H). 389.22 (M+H).

实例233Example 233

(2R，3′R)-1′-[4-(1H-苯并咪唑-1-基甲基)苯甲酰基]-2-甲基-1，3′-联吡咯烷盐酸盐的制Preparation of (2R, 3'R)-1'-[4-(1H-benzimidazol-1-ylmethyl)benzoyl]-2-methyl-1,3'-bipyrrolidine hydrochloride备prepare

基本上使用实例40中所述的相同程序且在步骤1中使用4-(1H-苯并咪唑-1-基甲基)苯甲酸并在步骤3中使用(2R)-2-甲基吡咯烷，获得呈黄色固体的标题产物且由质谱和¹HNMR分析加以鉴定。MS[389.2m/e(M+H]。Essentially using the same procedure described in Example 40 and using 4-(1H-benzimidazol-1-ylmethyl)benzoic acid in step 1 and (2R)-2-methylpyrrolidine in step 3 , the title product was obtained as a yellow solid and identified by mass spectral^and1HNMR analyses. MS [389.2 m/e (M+H].

实例234Instance 234

(2S，3′R)-1′-[4-(1H-苯并咪唑-1-基甲基)苯甲酰基]-2-甲基-1，3′-联吡咯烷盐酸盐的制Preparation of (2S, 3'R)-1'-[4-(1H-benzimidazol-1-ylmethyl)benzoyl]-2-methyl-1,3'-bipyrrolidine hydrochloride备prepare

基本上使用实例40中所述的相同程序且在步骤1中使用4-(1H-苯并咪唑-1-基甲基)苯甲酸并在步骤3中使用(2S)-2-甲基吡咯烷，获得呈黄色固体的标题产物且由质谱和¹HNMR分析加以鉴定。MS[389.2m/e(M+H]。Using essentially the same procedure as described in Example 40 and using 4-(1H-benzimidazol-1-ylmethyl)benzoic acid in step 1 and (2S)-2-methylpyrrolidine in step 3 , the title product was obtained as a yellow solid and identified by mass spectral^and1HNMR analyses. MS [389.2 m/e (M+H].

实例235Example 235

人类组胺H3受体细胞系中甲基组胺结合的评估Evaluation of methylhistamine binding inhuman histamineH3 receptor cell lines

以下列方式评估测试化合物对组胺3(H3)受体的亲和力。在含有10％热失活FBS和G-418(500μg/ml)的DMEM中生长经稳定转染的HEK293T细胞。自培养盘刮下细胞，转移至离心管中，通过在索沃(Sorvall)RT7Plus离心机中离心(2000rpm，10分钟，4℃)而在PBS中洗涤一次。将所得离心块储存在-80℃下直至使用。将细胞再悬浮于缓冲液(50mM Tris，pH＝7.5)中且置于杜恩斯(Dounce)均质机中，吸打(douncing)10次以均质化细胞。通过离心(索沃(Sorvall)RT7 Plus，1800rpm，10分钟，4℃)使匀浆旋转下降。将上清液置于可莱(Corex)管中且通过离心(索沃(Sorvall)RC 5c Plus，17,000rpm，20分钟，4℃)旋转下降。将离心块再悬浮于缓冲液(50mM Tris，pH7.5)中。使用Micro-BCA蛋白质测定法来测定蛋白质浓度(μg/μl)。在96孔微量滴定盘中建立结合检定，总体积为250μL。在存在10μM氯苯普吡(clobenpropit)的情况下测定非特异性结合。最终放射性配体浓度为1nM。使用贝克曼(Beckman)Biomek2000将测试化合物连续稀释至100μM至100pM的最终大致范围。将膜悬浮于缓冲液中，使用设在功率档5的维曲斯(Vitris)机械均质机以2次10秒脉冲均质化。将10μg膜添加至各孔中。在30℃下培育1小时之后，通过添加冰冷缓冲液且用派卡德费特美特收集器(PackardFiltermate Harvester)经由以1％PEI预浸1小时的GF/B过滤器快速过滤来终止反应。将培养盘在37℃下干燥1小时且将60μL微闪烁闪烁剂(Microscint Scintillant)添加至各孔中。在派卡德顶级计数NXT(Packard Top Count NXT)上测量每孔的CPM。以nM为单位测定Ki值。自IC₅₀(即，置换50％放射性配体的特异性结合的竞争配体浓度)计算Ki。CPM值表述为特异性结合％且对化合物浓度绘制曲线。使用4参数对数拟合法拟合曲线且确定IC₅₀值。使用陈-普(Cheng-Prusoff)等式自IC₅₀计算Ki：pKi＝IC₅₀/1+(L/Kd)，其中L＝用于检定中的游离放射性配体的浓度，且Kd为受体的放射性配体的解离常数。通过对经稀释放射性配体的等分试样(对应于添加至各孔的试样)计数来测定各实验的L，且先前已在与所述细胞系/放射性配体相同的条件下测定Kd。The affinity of test compounds for the histamine 3 (H3) receptor was evaluated in the following manner. Stably transfected HEK293T cells were grown in DMEM containing 10% heat-inactivated FBS and G-418 (500 μg/ml). Cells were scraped from the plates, transferred to centrifuge tubes and washed once in PBS by centrifugation in a Sorvall RT7 Plus centrifuge (2000 rpm, 10 min, 4°C). The resulting pellets were stored at -80°C until use. Cells were resuspended in buffer (50 mM Tris, pH=7.5) and placed in a Dounce homogenizer, douncing 10 times to homogenize the cells. The homogenate was spun down by centrifugation (Sorvall RT7 Plus, 1800 rpm, 10 min, 4°C). The supernatant was placed in a Corex tube and spun down by centrifugation (Sorvall RC 5c Plus, 17,000 rpm, 20 min, 4°C). The pellet was resuspended in buffer (50 mM Tris, pH 7.5). Protein concentrations (μg/μl) were determined using the Micro-BCA protein assay. Binding assays were set up in 96-well microtiter plates with a total volume of 250 μL. Nonspecific binding was determined in the presence of 10 [mu]M clobenpropit. The final radioligand concentration was 1 nM. Test compounds were serially diluted to a final approximate range of 100 μΜ to 100 pM using a Beckman Biomek 2000. Membranes were suspended in buffer and homogenized using a Vitris mechanical homogenizer set at power 5 with 2 10 second pulses. 10 μg of membrane was added to each well. After incubation for 1 hour at 30°C, the reaction was terminated by addition of ice-cold buffer and rapid filtration with a Packard Filtermate Harvester through GF/B filters pre-soaked with 1% PEI for 1 hour. Plates were dried at 37°C for 1 hour and 60 μL of Microscint Scintillant was added to each well. CPM per well was measured on a Packard Top Count NXT. Ki values were determined in nM. Ki was calculated from the_IC50 (ie, the concentration of competing ligand that displaces 50% of the specific binding of the radioligand). CPM values are expressed as % specific binding and plotted against compound concentration. Curves were fitted using a 4 parameter logarithmic fit and_IC50 values determined. Ki was calculated from_IC50 using the Cheng-Prusoff equation: pKi=_IC50 /1+(L/Kd), where L=concentration of free radioligand used in the assay and Kd is the receptor The dissociation constant of the radioligand. The L for each experiment was determined by counting an aliquot of the diluted radioligand (corresponding to that added to each well) and the Kd had previously been determined under the same conditions as the cell line/radioligand .

组胺受体H3拮抗活性的环状AMP检定Cyclic AMP Assay for Histamine Receptor H3 Antagonistic Activity

在组织培养烧瓶中将稳定H3细胞维持在含有高葡萄糖、10％FBS、1×青霉素/链霉素、500μg/ml GY18的DMEM中直至实验。去除培养基且以PBS w/Ca++和Mg++加上500μM IBMX洗涤细胞两次。接着通过轻敲烧瓶侧壁来分离细胞且再悬浮于相同缓冲液中。在96孔培养盘中将每孔两千个细胞与1μM组胺加上10μM弗斯可林(forskolin)加上各种浓度化合物以总体积30μL在30℃下培育30分钟。在全对数稀释度(full logdilution)下最终测试化合物浓度在10-4M至10-9.5M范围内。根据制造商的说明书使用希特亨特(HitHunter)cAMP试剂盒(迪斯科沃公司(Discoverx)，目录号900041)测量环状AMP含量。使用顶级计数(Top Count)(派卡德(Packard))检测化学发光信号。认为接受10μM弗斯可林加上100nM组胺的对照细胞中的环状AMP含量为0％，且认为接受10μM弗斯可林加上100nM组胺加上1μM氯苯普吡的细胞中的环状AMP含量为100％。数据表达为对照％且使用普瑞森(Prizm)软件进行分析。使用以下等式计算Kb值：KB＝EC₅₀或IC₅₀/[1+(配体/Kd)]。资料展示于下表XVIII中。Stable H3 cells were maintained in tissue culture flasks in DMEM containing high glucose, 10% FBS, 1X penicillin/streptomycin, 500 μg/ml GY18 until experiments. Media was removed and cells were washed twice with PBS w/Ca++ and Mg++ plus 500 μM IBMX. Cells were then detached by tapping the side of the flask and resuspended in the same buffer. Two thousand cells per well were incubated with 1 μM histamine plus 10 μM forskolin plus various concentrations of compounds in a total volume of 30 μL for 30 minutes at 30° C. in a 96-well culture plate. Final test compound concentrations ranged from 10-4M to 10-9.5M at full log dilutions. Cyclic AMP content was measured using the HitHunter cAMP kit (Discoverx, Cat# 900041 ) according to the manufacturer's instructions. Chemiluminescence signals were detected using Top Count (Packard). The cyclic AMP content in control cells that received 10 μM forskolin plus 100 nM histamine was considered to be 0%, and the cyclic AMP content in cells that received 10 μM forskolin plus 100 nM histamine plus 1 μM clofenproril was considered The AMP content is 100%. Data are expressed as % of control and analyzed using Prizm software. Kb values were calculated using the following equation: KB=_EC50 or_IC50 /[1+(ligand/Kd)]. The data are presented in Table XVIII below.

对于表XVIIIFor Table XVIII

A＝≤10nMA=≤10nM

B＝10.1nM-25.0nMB=10.1nM-25.0nM

C＝25.1nM-50.0nMC=25.1nM-50.0nM

D＝50.1nM-100nMD=50.1nM-100nM

E＝>100nME=>100nM

表XVIIITable XVIII

实例编号      H3结合Ki(nM)      cAMP Kb(nM)Instance No. H3 Binding Ki(nM) cAMP Kb(nM)

   1              D                  B1 D B

   2              D                  B2 D B

   3              E                  E3 E E

   4              E                  --4 E E --

   5              E                  --5 E E --

   6              D                  --6 D D --

   7              C                  --7 C C --

   8              E                  --8 E E --

   9              B                  B9 B B B

   10             C                  --10 C C --

   11             D                  --11 D D --

   12             D                  A12 D D A A

   13             E                  B13 E E B

   14             E                  --14 E E --

   15             E                  --15 E E --

   16             E                  --16 E E --

   17             E                  B17 E E B

   18             E                  --18 E E --

   19             E                  --19 E E --

   20             E                  --20 E E --

   21             E                  --21 E E --

   22             E                  A22 E E A

   23             E                  B23 E E B

   24             E                  --24 E E --

   25             E                  A25 E E A

   26             E                  --26 E E --

   27             E                  --27 E E --

   28             B                  --28 B B --

实例编号     H3结合Ki(nM)      cAMP Kb(nM)Instance No. H3 Binding Ki(nM) cAMP Kb(nM)

   29            E                 --29 E E --

   30            --                --30 -- --

   31            E                 --31 E E --

   32            E                 --32 E E --

   33            E                 --33 E E --

   34            E                 --34 E E --

   35            --                --35 -- -- --

   36            E                 --36 E E --

   37            D                 --37 D D --

   38            E                 --38 E E --

   39            E                 --39 E E --

   40            D                 --40 D D --

   41            A                 A41 A A A

   42            E                 --42 E E --

   43            E                 --43 E E --

   44            E                 C44 E E E C

   45            E                 --45 E E --

   46            B                 A46 B B A A

   47            A                 A47 A A A

   48            B                 A48 B B A A

   49            D                 A49 D D A

   50            C                 B50 C B

   51            E                 E51 E E

   52            D                 A52 D D A

   53            B                 A53 B B A A

   54            B                 A54 B B A A

   55            B                 --55 B B --

   56            B                 A56 B B A A

   57            C                 B57 C B

   58            B                 A58 B B A A

   59            A                 A59 A A A

   60C           C                 B60C C B

   61            C                 A61 C A

   62            C                 B62 C B

   63            B                 A63 B B A A

   64            C                 B64 C B

   65            A                 A65 A A A

   66            B                 A66 B B A A

   67            A                 --67 A A --

   68            A                 --68 A A --

   69            C                 --69 C --

   70            A                 B70 A A B

   71            D                 --71 D D --

   72            C                 --72 C --

   73            C                 --73 C --

   74            --                --74 -- -- --

   75            A                 A75 A A A

   76            B                 --76 B B --

   77            A                 A77 A A A

   78            B                 B78 B B B

实例编号     H3结合Ki(nM)       cAMP Kb(nM)Instance No. H3 Binding Ki(nM) cAMP Kb(nM)

   79             A                 A79 A A A

   80             C                 --80 C --

   81             A                 A81 A A A

   82             A                 --82 A A --

   83             A                 --83 A A --

   84             A                 --84 A A --

   85             A                 A85 A A A

   86             E                 --86 E E --

   87             E                 --87 E E --

   88             E                 --88 E E --

   89             E                 --89 E E --

   90             E                 --90 E E --

   91             A                 --91 A A --

   92             B                 --92 B B --

   93             A                 --93 A A --

   94             E                 --94 E E --

   95             D                 --95 D D --

   96             E                 --96 E E --

   97             E                 --97 E E --

   98             B                 --98 B B --

   99             C                 --99 C --

   100            D                 --100 D D --

   101            E                 --101 E E --

   102            E                 --102 E E --

   103            A                 A103 A A A

   104            A                 --104 A A --

   105            A                 --105 A A --

   106            A                 --106 A A --

   107            A                 --107 A A --

   108            E                 --108 E E --

   109            A                 --109 A A --

   110            A                 --110 A A --

   111            B                 --111 B B --

   112            A                 --112 A A --

   113            A                 --113 A A --

   114            A                 --114 A A --

   115            A                 --115 A A --

   116            A116 A

   117            A117 A

   118            E                 --118 E E --

   119            E                 --119 E E --

   120            C                 --120 C --

   121            D                 --121 D D --

   122            E                 --122 E E --

   123            C                 --123 C --

   124            E                 --124 E E --

   125            C                 B125 C B

   126            E                 C126 E E E C

   127            B                 A127 B B A A

   128            C                 A128 C A

实例编号      H3结合Ki(nM)     cAMP Kb(nM)Instance No. H3 Binding Ki(nM) cAMP Kb(nM)

  129              C               A129 C A

  130              D               A130 D D A

  131              B               A131 B B A A

  132              E               A132 E E A

  133              B               A133 B B A A

  134              E               A134 E E A

  135              E               A135 E E A

  136              A               A136 A A A

  137              A               A137 A A A

  138              E               B138 E E B

  139              --              --139 -- --

  140              A               A140 A A A

  141              A               A141 A A A

  142              A               A142 A A A

  143              A               --143 A A --

  144              A               --144 A A --

  145              A               --145 A A --

  146              A               --146 A A --

  147              A               --147 A A --

  148              A               --148 A A --

  149              A               --149 A A --

  150              A               --150 A A --

  151              A               --151 A A --

  152              A               --152 A A --

  153              A               A153 A A A

  154              A               --154 A A --

  155              A               A155 A A A

  156              A               --156 A A --

  157              A               --157 A A --

  158              A               --158 A A --

  159              B               --159 B B --

  160              E               --160 E E --

  161              D               --161 D D --

  162              E               --162 E --

  163              E               --163 E --

  164              A               A164 A A A

  165              A               --165 A A --

  166              A               A166 A A A

  167              B167 B

  168              A               A168 A A A

  169              B               --169 B B --

  170              A               --170 A A --

  171              --              --171 -- --

  172              A               --172 A A --

  173              E               --173 E E --

  174              E               --174 E E --

  175              E               --175 E E --

  176              E               --176 E E --

  177              B               --177 B B --

  178              A               A178 A A A

实例编号H3      结合Ki(nM)       cAMP Kb(nM)Instance No. H3 Binding Ki(nM) cAMP Kb(nM)

   179             A                 --179 A A --

   180             E                 --180 E E --

   181             B                 --181 B B --

   182             C                 --182 C --

   183             B                 --183 B B --

   184             A                 A184 A A A

   185             C                 --185 C --

   186             C                 --186 C --

   187             A                 --187 A A --

   188             B                 --188 B B --

   189             A                 --189 A A --

   190             A                 --190 A A --

   191             A                 --191 A A --

   192             B                 --192 B B --

   193             B                 --193 B B --

   194             C                 --194 C --

   195             B                 --195 B B --

   196             B                 --196 B B --

   197             B                 --197 B B --

   198             C                 --198 C --

   199             A                 --199 A A --

   200             A                 --200 A A --

   201             B                 --201 B B --

   202             A                 A202 A A A

   203             B                 --203 B B --

   204             A                 --204 A A --

   205             B                 --205 B B --

   206             A                 --206 A A --

   207             A                 --207 A A --

   212             B                 --212 B B --

   213             C                 --213 C --

   214             A                 --214 A A --

   215             C                 --215 C --

   216             A                 --216 A A --

   217             A                 --217 A A --

   218             A                 --218 A A --

   219             B                 --219 B B --

   220             B                 --220 B B --

   221             C                 --221 C --

   222             B                 --222 B B --

   223             D                 --223 D D --

   224             A                 --224 A A --

   225             --                --225 -- --

   226             B                 --226 B B --

   227             E                 --227 E E --

   228             A                 --228 A A --

   229             B                 --229 B B --

   230             E                 --230 E E --

   231             A                 --231 A A --

   232             C                 --232 C --

实例编号      H3结合Ki(nM)       cAMP Kb(nM)Instance No. H3 Binding Ki(nM) cAMP Kb(nM)

  233            C233 C

  234            B234 B

Claims (15)

Translated fromChinese

1.一种式I化合物：1. A compound of formula I:

其中inX为CO、CH₂或SO_m；X is CO,_CH2 or_SOm ;p和n各自独立地为1、2或3的整数；p and n are each independently an integer of 1, 2 or 3;m为0或为1或2的整数；m is 0 or an integer of 1 or 2;R₁和R₂各自独立地为H或视情况经取代的烷基，或R₁和R₂可连同其所连接的原子一起形成视情况含有一或两个选自N、O或S的额外杂原子的视情况经取代的4至7元环；R₁ and R₂ are each independently H or optionally substituted alkyl, or R₁ and R₂ may be taken together with the atoms to which they are attached to form optionally one or two additional compounds selected from N, O or S optionally substituted 4 to 7 membered rings of heteroatoms;R₃为NR₄R₅或芳基或杂芳基，各基团视情况经取代；R₃ is NR₄ R₅ or aryl or heteroaryl, each group is optionally substituted;R₄和R₅连同其所连接的原子一起形成视情况含有一至三个选自N、O或S的额外杂原子的视情况经取代的稠合双环、三环或四环9至15元环系统；R_andR together with the atoms to which they are attached form an optionally substituted fused bicyclic, tricyclic or tetracyclic 9 to 15 membered ring optionally containing one to three additional heteroatoms selected from N, O or S system;R₆和R₇各自独立地为H、卤素、OR₁₀或各自视情况经取代的烷基、烯基、炔基、环烷基、环杂烷基、芳基或杂芳基；R_andR are each independently H, halogen, OR_, or each optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl;R₈和R₉各自独立地为H或各自视情况经取代的烷基、环烷基或芳基；且R_andR are each independently H or each optionally substituted alkyl, cycloalkyl, or aryl; andR₁₀为H或视情况经取代的烷基；或R₁₀ is H or optionally substituted alkyl; or其立体异构体或其医药学上可接受的盐。Stereoisomers thereof or pharmaceutically acceptable salts thereof.2.根据权利要求1所述的化合物，其中X为CO或CH₂。2. The compound according to claim 1, wherein X is CO or_CH2 .3.根据权利要求1或2所述的化合物，其中n为1且p为1或2。3. The compound according to claim 1 or 2, wherein n is 1 and p is 1 or 2.4.根据权利要求1至3中任一权利要求所述的化合物，其中R₈和R₉各自独立地为H或甲基。4. The compound according to any one of claims 1 to 3, wherein_R8 and_R9 are each independently H or methyl.5.根据权利要求1至4中任一权利要求所述的化合物，其中R₁和R₂连同其所连接的原子一起形成5元环。5. The compound according to any one of claims 1 to 4, wherein_R1 and_R2 together with the atoms to which they are attached form a 5 membered ring.6.根据权利要求1至5中任一权利要求所述的化合物，其中R₃为NR₄R₅或视情况经取代的吲哚、吲唑、苯基或苯并咪唑环。6. A compound according to any one of claims₁ to 5, wherein_R3 is_NR4R5 or an optionally substituted indole, indazole, phenyl or benzimidazole ring.7.根据权利要求1至5中任一权利要求所述的化合物，其中R₃为NR₄R₅或在所述苯并咪唑环的2位连接的视情况经取代的苯并咪唑环；且R₄和R₅连同其所连接的原子一起形成视情况经取代的吲哚、吲唑或苯并咪唑环。7. The compound of any one of claims_{1 to 5, wherein R is NR R 5oran} optionally substituted benzimidazole ring attached at the 2-position of the benzimidazole ring; and R₄ and R₅ together with the atoms to which they are attached form an optionally substituted indole, indazole or benzimidazole ring.8.根据权利要求1所述的化合物，其为下列各物中的一种：8. The compound of claim 1, which is one of the following:N，N-二甲基-1-{4-[(2-苯基-1H-苯并咪唑-1-基)甲基]-苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl-1-{4-[(2-phenyl-1H-benzimidazol-1-yl)methyl]-benzoyl}pyrrolidin-3-ylamine;(3-S)-N，N-二甲基-1-{4-[(2-苯基-1H-苯并咪唑-1-基)甲基]-苯甲酰基}吡咯烷-3-基胺；(3-S)-N,N-Dimethyl-1-{4-[(2-phenyl-1H-benzimidazol-1-yl)methyl]-benzoyl}pyrrolidin-3-yl amine;(3-R)-N，N-二甲基-1-{4-[(2-苯基-1H-苯并咪唑-1-基)甲基]-苯甲酰基}吡咯烷-3-基胺；(3-R)-N,N-Dimethyl-1-{4-[(2-phenyl-1H-benzimidazol-1-yl)methyl]-benzoyl}pyrrolidin-3-yl amine;N，N-二甲基-1-{4-[(6-氟-1H-苯并咪唑-1-基)甲基]-苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl-1-{4-[(6-fluoro-1H-benzimidazol-1-yl)methyl]-benzoyl}pyrrolidin-3-ylamine;N，N-二甲基-1-{4-[(6-甲基-1H-苯并咪唑-1-基)甲基]-苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl-1-{4-[(6-methyl-1H-benzimidazol-1-yl)methyl]-benzoyl}pyrrolidin-3-ylamine;N，N-二甲基-1-{4-[(5-氟-1H-苯并咪唑-1-基)甲基]-苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl-1-{4-[(5-fluoro-1H-benzimidazol-1-yl)methyl]-benzoyl}pyrrolidin-3-ylamine;N，N-二甲基-1-{4-[(4-氟-1H-苯并咪唑-1-基)甲基]-苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl-1-{4-[(4-fluoro-1H-benzimidazol-1-yl)methyl]-benzoyl}pyrrolidin-3-ylamine;N，N-二甲基-1-[3-(1H-苯并咪唑-1-基)甲基]-苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl-1-[3-(1H-benzimidazol-1-yl)methyl]-benzoyl}pyrrolidin-3-ylamine;N，N-二甲基1-[4-(1H-吲哚-1-基甲基)苯甲酰基]吡咯烷-3-基胺；N,N-Dimethyl 1-[4-(1H-indol-1-ylmethyl)benzoyl]pyrrolidin-3-ylamine;N，N-二甲基1-{[4-(2，3，4，9-四氢-1H-咔唑)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(2,3,4,9-tetrahydro-1H-carbazole)methyl]benzoyl}pyrrolidin-3-ylamine;N，N-二甲基1-{[4-(2-甲基-1H-吲哚-1-基)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(2-methyl-1H-indol-1-yl)methyl]benzoyl}pyrrolidin-3-ylamine;N，N-二甲基1-{[4-(2-苯基-1H-吲哚-1-基)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(2-phenyl-1H-indol-1-yl)methyl]benzoyl}pyrrolidin-3-ylamine;N，N-二甲基1-{[4-(5-甲氧基-1H-吲哚-1-基)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(5-methoxy-1H-indol-1-yl)methyl]benzoyl}pyrrolidin-3-ylamine;N，N-二甲基1-{[4-(5-甲氧基-2-苯基-1H-吲哚-1-基)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(5-methoxy-2-phenyl-1H-indol-1-yl)methyl]benzoyl}pyrrolidin-3-ylamine;N，N-二甲基1-{[4-(7-氮杂-1H-吲哚-1-基)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(7-aza-1H-indol-1-yl)methyl]benzoyl}pyrrolidin-3-ylamine;N，N-二甲基1-{[4-(1H-苯并[d]咪唑-1-基)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(1H-benzo[d]imidazol-1-yl)methyl]benzoyl}pyrrolidin-3-ylamine;N，N-二甲基1-{[4-(2-甲基-1H-苯并[d]咪唑-1-基)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(2-methyl-1H-benzo[d]imidazol-1-yl)methyl]benzoyl}pyrrolidin-3-ylamine;N，N-二甲基1-{[4-(5-羟基-1H-吲哚-1-基)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(5-hydroxy-1H-indol-1-yl)methyl]benzoyl}pyrrolidin-3-ylamine;N，N-二甲基1-{[4-(1，2，3，4-四氢喹啉-1-基)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(1,2,3,4-tetrahydroquinolin-1-yl)methyl]benzoyl}pyrrolidin-3-ylamine;N，N-二甲基1-{[4-(5-氟-1H-吲哚-1-基)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(5-fluoro-1H-indol-1-yl)methyl]benzoyl}pyrrolidin-3-ylamine;N，N-二甲基1-{[4-(3-氰基-1H-吲哚-1-基)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(3-cyano-1H-indol-1-yl)methyl]benzoyl}pyrrolidin-3-ylamine;N，N-二甲基1-{[4-(2-苯基-1H-咪唑-1-基)甲基]苯甲酰基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(2-phenyl-1H-imidazol-1-yl)methyl]benzoyl}pyrrolidin-3-ylamine;1′-{4-[(2-苯基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；1'-{4-[(2-phenyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;1′-{4-[(5-氯-2-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；1'-{4-[(5-chloro-2-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;1′-{4-[(6-氯-2-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；1'-{4-[(6-chloro-2-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;1′-{4-[(6-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；1'-{4-[(6-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;1′-{4-[(5-氟-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；1'-{4-[(5-fluoro-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;(2-R)-1′-[4-(1H-苯并咪唑-1-基甲基)苯甲酰基]-2-甲基-1，3′-联吡咯烷；(2-R)-1'-[4-(1H-benzimidazol-1-ylmethyl)benzoyl]-2-methyl-1,3'-bipyrrolidine;(3′-R)-1′-{4-[(2-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'-R)-1'-{4-[(2-Methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;(3′-S)-1′-{4-[(2-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'-S)-1'-{4-[(2-Methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;(3′S)-[4-(1H-吲哚-1-基甲基)苯甲酰基]-1，3′-联吡咯烷；(3'S)-[4-(1H-indol-1-ylmethyl)benzoyl]-1,3'-bipyrrolidine;(3′S)-[4-(1H-吲唑-1-基甲基)苯甲酰基]-1，3′-联吡咯烷；(3'S)-[4-(1H-indazol-1-ylmethyl)benzoyl]-1,3'-bipyrrolidine;(3′S)-1′-{4-[(5-氯-2-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(5-chloro-2-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;(3′S)-1′-{4-[(6-氯-2-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(6-Chloro-2-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;(3′S)-1′-{4-[(6-氟-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(6-fluoro-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;(3′S)-1′-{4-[(6-氟-1H-苯并咪唑-1-基)甲基]苯甲基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(6-fluoro-1H-benzimidazol-1-yl)methyl]benzyl}-1,3'-bipyrrolidine;(3′S)-1′-{4-[(5-氟-1H-苯并咪唑-1-基)甲基]苯甲基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(5-fluoro-1H-benzimidazol-1-yl)methyl]benzyl}-1,3'-bipyrrolidine;(3′S)-1′-{4-[(5-氟-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(5-fluoro-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;(3′S)-1′-{4-[(7-氯-1H-吲哚-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(7-Chloro-1H-indol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;9-{4-[(3′S)-1，3′-联吡咯烷-1-基羰基]苯甲基}-9H-咔唑；9-{4-[(3′S)-1,3′-bipyrrolidin-1-ylcarbonyl]benzyl}-9H-carbazole;(3′-S)-1′-{4-[(1S)-1-(2-甲基-1H-苯并咪唑-1-基)乙基]苯甲酰基}-1，3′-联吡咯烷；(3'-S)-1'-{4-[(1S)-1-(2-Methyl-1H-benzimidazol-1-yl)ethyl]benzoyl}-1,3'-linked pyrrolidine;(3′-S)-1′-{4-[(1R)-1-(2-甲基-1H-苯并咪唑-1-基)乙基]苯甲酰基}-1，3′-联吡咯烷；(3'-S)-1'-{4-[(1R)-1-(2-Methyl-1H-benzimidazol-1-yl)ethyl]benzoyl}-1,3'-linked pyrrolidine;(3′-S)-1′-[4-(1H-苯并咪唑-1-基甲基)苯甲基]-1，3′-联吡咯烷；(3'-S)-1'-[4-(1H-benzimidazol-1-ylmethyl)benzyl]-1,3'-bipyrrolidine;(3′-S)-1′-[4-(1H-苯并咪唑-1-基甲基)苯甲酰基]-1，3′-联吡咯烷；(3'-S)-1'-[4-(1H-benzimidazol-1-ylmethyl)benzoyl]-1,3'-bipyrrolidine;N，N-二甲基-1-{4-[(2-苯基-1H-苯并咪唑-1-基)甲基]-苯甲基}吡咯烷-3-基胺；N,N-Dimethyl-1-{4-[(2-phenyl-1H-benzimidazol-1-yl)methyl]-benzyl}pyrrolidin-3-ylamine;(3-S)-N，N-二甲基-1-{4-[(2-苯基-1H-苯并咪唑-1-基)甲基]-苯甲基}吡咯烷-3-基胺；(3-S)-N,N-Dimethyl-1-{4-[(2-phenyl-1H-benzimidazol-1-yl)methyl]-benzyl}pyrrolidin-3-yl amine;(3-R)-N，N-二甲基-1-{4-[(2-苯基-1H-苯并咪唑-1-基)甲基]-苯甲基}吡咯烷-3-基胺；(3-R)-N,N-Dimethyl-1-{4-[(2-phenyl-1H-benzimidazol-1-yl)methyl]-benzyl}pyrrolidin-3-yl amine;N，N-二甲基-1-{4-[(6-氟-1H-苯并咪唑-1-基)甲基]-苯甲基}吡咯烷-3-基胺；N,N-Dimethyl-1-{4-[(6-fluoro-1H-benzimidazol-1-yl)methyl]-benzyl}pyrrolidin-3-ylamine;N，N-二甲基-1-{4-[(6-甲基-1H-苯并咪唑-1-基)甲基]-苯甲基}吡咯烷-3-基胺；N,N-Dimethyl-1-{4-[(6-methyl-1H-benzimidazol-1-yl)methyl]-benzyl}pyrrolidin-3-ylamine;N，N-二甲基-1-{4-[(5-氟-1H-苯并咪唑-1-基)甲基]-苯甲基}吡咯烷-3-基胺；N,N-Dimethyl-1-{4-[(5-fluoro-1H-benzimidazol-1-yl)methyl]-benzyl}pyrrolidin-3-ylamine;N，N-二甲基-1-{4-[(4-氟-1H-苯并咪唑-1-基)甲基]-苯甲基}吡咯烷-3-基胺；N,N-Dimethyl-1-{4-[(4-fluoro-1H-benzimidazol-1-yl)methyl]-benzyl}pyrrolidin-3-ylamine;N，N-二甲基-1-[3-(1H-苯并咪唑-1-基)甲基]-苯甲基}吡咯烷-3-基胺；N,N-Dimethyl-1-[3-(1H-benzimidazol-1-yl)methyl]-benzyl}pyrrolidin-3-ylamine;N，N-二甲基1-[4-(1H-吲哚-1-基甲基)苯甲基]吡咯烷-3-基胺；N,N-Dimethyl 1-[4-(1H-indol-1-ylmethyl)benzyl]pyrrolidin-3-ylamine;N，N-二甲基1-{[4-(2，3，4，9-四氢-1H-咔唑)甲基]苯甲基}吡咯烷-3-基胺；N,N-Dimethyl 1-{[4-(2,3,4,9-tetrahydro-1H-carbazole)methyl]benzyl}pyrrolidin-3-ylamine;(3′S)-1′-[4-(1H-吲哚-3-基甲基)苯甲酰基]-1，3′-联吡咯烷；(3'S)-1'-[4-(1H-indol-3-ylmethyl)benzoyl]-1,3'-bipyrrolidine;(3′S)-1′-{4-[(1-甲基-1H-吲哚-3-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1-Methyl-1H-indol-3-yl)methyl]benzoyl}-1,3'-bipyrrolidine;(3S)-N，N-二甲基-1-{4-[(1-甲基-1H-吲哚-3-基)甲基]苯甲酰基}吡咯烷-3-胺；(3S)-N,N-Dimethyl-1-{4-[(1-methyl-1H-indol-3-yl)methyl]benzoyl}pyrrolidin-3-amine;2-{4-[(3-哌啶-1-基吡咯烷-1-基)羰基]苯甲基}-1H-苯并咪唑；2-{4-[(3-piperidin-1-ylpyrrolidin-1-yl)carbonyl]benzyl}-1H-benzimidazole;1′-{4-[(1-乙基-1H-苯并咪唑-2-基)甲基]苯甲酰基}-1，3′-联吡咯烷；1'-{4-[(1-Ethyl-1H-benzimidazol-2-yl)methyl]benzoyl}-1,3'-bipyrrolidine;1′-{4-[(1-甲基-1H-苯并咪唑-2-基)甲基]苯甲酰基}-1，3′-联吡咯烷；1'-{4-[(1-Methyl-1H-benzimidazol-2-yl)methyl]benzoyl}-1,3'-bipyrrolidine;1-甲基-2-{4-[(3-哌啶-1-基吡咯烷-1-基)羰基]苯甲基}-1H-苯并咪唑；1-methyl-2-{4-[(3-piperidin-1-ylpyrrolidin-1-yl)carbonyl]benzyl}-1H-benzimidazole;1′-[4-(1H-苯并咪唑-2-基甲基)苯甲酰基]-1，3′-联吡咯烷；1'-[4-(1H-benzimidazol-2-ylmethyl)benzoyl]-1,3'-bipyrrolidine;(3′S)-1′-(4-苯甲基苯甲酰基)-1，3′-联吡咯烷；(3'S)-1'-(4-benzylbenzoyl)-1,3'-bipyrrolidine;(3′S)-1′-{4-[(1-丙基-1H-苯并咪唑-2-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1-Propyl-1H-benzimidazol-2-yl)methyl]benzoyl}-1,3'-bipyrrolidine;(3′S)-1′-{4-[(1-异丙基-1H-苯并咪唑-2-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1-isopropyl-1H-benzimidazol-2-yl)methyl]benzoyl}-1,3'-bipyrrolidine;(3′S)-1′-{4-[(1-异丁基-1H-苯并咪唑-2-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1-isobutyl-1H-benzimidazol-2-yl)methyl]benzoyl}-1,3'-bipyrrolidine;(3′S)-1′-(4-{[1-(环丙基甲基)-1H-苯并咪唑-2-基]甲基}苯甲酰基)-1，3′-联吡咯烷；(3'S)-1'-(4-{[1-(cyclopropylmethyl)-1H-benzimidazol-2-yl]methyl}benzoyl)-1,3'-bipyrrolidine ;(3′S)-1′-(4-{[1-(苯基磺酰基)-1H-苯并咪唑-2-基]甲基}苯甲酰基)-1，3′-联吡咯烷；(3'S)-1'-(4-{[1-(phenylsulfonyl)-1H-benzimidazol-2-yl]methyl}benzoyl)-1,3'-bipyrrolidine;(3′S)-1′-(4-{[1-(2-甲氧基乙基)-1H-苯并咪唑-2-基]甲基}苯甲酰基)-1，3′-联吡咯烷；(3′S)-1′-(4-{[1-(2-methoxyethyl)-1H-benzimidazol-2-yl]methyl}benzoyl)-1,3′-linked pyrrolidine;2-(2-{4-[(3′S)-1，3′-联吡咯烷-1′-基羰基]苯甲基}-1H-苯并咪唑-1-基)乙醇；2-(2-{4-[(3'S)-1,3'-bipyrrolidin-1'-ylcarbonyl]benzyl}-1H-benzimidazol-1-yl)ethanol;(3′S)-1′-{4-[(1-乙基-1H-苯并咪唑-2-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1-Ethyl-1H-benzimidazol-2-yl)methyl]benzoyl}-1,3'-bipyrrolidine;(3′S)-1′-(4-{[1-(2-苯基乙基)-1H-苯并咪唑-2-基]甲基}苯甲酰基)-1，3′-联吡咯烷；(3'S)-1'-(4-{[1-(2-phenylethyl)-1H-benzimidazol-2-yl]methyl}benzoyl)-1,3'-bipyrrole alkyl;(3′S)-1′-{4-[(1-乙基-1H-苯并咪唑-2-基)甲基]苯甲基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1-Ethyl-1H-benzimidazol-2-yl)methyl]benzyl}-1,3'-bipyrrolidine;(3′S)-1′-{4-[(1-苯基-1H-苯并咪唑-2-基)甲基]苯甲酰基}-1，3′-联吡咯烷；-[(5-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1-phenyl-1H-benzimidazol-2-yl)methyl]benzoyl}-1,3'-bipyrrolidine;-[(5 -Methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;5-甲基-1-{4-[(3-哌啶-1-基吡咯烷-1-基)羰基]苯甲基}-1H-苯并咪唑；5-methyl-1-{4-[(3-piperidin-1-ylpyrrolidin-1-yl)carbonyl]benzyl}-1H-benzimidazole;4-氟-1-{4-[(3-哌啶-1-基吡咯烷-1-基)甲基]苯甲基}-1H-苯并咪唑；4-fluoro-1-{4-[(3-piperidin-1-ylpyrrolidin-1-yl)methyl]benzyl}-1H-benzimidazole;1′-[4-(1H-苯并咪唑-1-基甲基)-3-氯苯甲基]-1，3′-联吡咯烷；1'-[4-(1H-benzimidazol-1-ylmethyl)-3-chlorobenzyl]-1,3'-bipyrrolidine;1-{4-[(4-氟-1H-苯并咪唑-1-基)甲基]苯甲基}-N，N-二甲基吡咯烷-3-胺；1-{4-[(4-fluoro-1H-benzimidazol-1-yl)methyl]benzyl}-N,N-dimethylpyrrolidin-3-amine;5-甲基-1-(4-{[3-(2-甲基哌啶-1-基)吡咯烷-1-基]羰基}苯甲基)-1H-苯并咪唑；5-methyl-1-(4-{[3-(2-methylpiperidin-1-yl)pyrrolidin-1-yl]carbonyl}benzyl)-1H-benzimidazole;5-甲基-1-{4-[(3-吗啉-4-基吡咯烷-1-基)羰基]苯甲基}-1H-苯并咪唑；5-methyl-1-{4-[(3-morpholin-4-ylpyrrolidin-1-yl)carbonyl]benzyl}-1H-benzimidazole;5-甲基-1-(4-{[3-(4-甲基哌啶-1-基)吡咯烷-1-基]羰基}苯甲基)-1H-苯并咪唑；5-methyl-1-(4-{[3-(4-methylpiperidin-1-yl)pyrrolidin-1-yl]carbonyl}benzyl)-1H-benzimidazole;5-甲基-1-(4-{[3-(4-甲基哌嗪-1-基)吡咯烷-1-基]羰基}苯甲基)-1H-苯并咪唑；5-methyl-1-(4-{[3-(4-methylpiperazin-1-yl)pyrrolidin-1-yl]carbonyl}benzyl)-1H-benzimidazole;5-甲基-1-(4-{[3-(3-甲基哌啶-1-基)吡咯烷-1-基]羰基}苯甲基)-1H-苯并咪唑；5-methyl-1-(4-{[3-(3-methylpiperidin-1-yl)pyrrolidin-1-yl]carbonyl}benzyl)-1H-benzimidazole;((2s)-1′-{4-[(5-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷-2-基)甲醇；((2s)-1′-{4-[(5-Methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3′-bipyrrolidin-2-yl)methanol ;N，N-二甲基-1-{4-[(5-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}吡咯烷-3-胺；N,N-Dimethyl-1-{4-[(5-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}pyrrolidin-3-amine;N-乙基-N-甲基-1-{4-[(5-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}吡咯烷-3-胺；N-ethyl-N-methyl-1-{4-[(5-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}pyrrolidin-3-amine;1-{2-氯-4-[(3-哌啶-1-基吡咯烷-1-基)甲基]苯甲基}-1H-苯并咪唑；1-{2-Chloro-4-[(3-piperidin-1-ylpyrrolidin-1-yl)methyl]benzyl}-1H-benzimidazole;1-[4-(1H-苯并咪唑-1-基甲基)-2-甲氧基苯甲酰基]-N，N-二甲基吡咯烷-3-胺；1-[4-(1H-benzimidazol-1-ylmethyl)-2-methoxybenzoyl]-N,N-dimethylpyrrolidin-3-amine;1-[4-(1H-苯并咪唑-1-基甲基)-3-氯苯甲基]-N-乙基-N甲基吡咯烷-3-胺；1-[4-(1H-benzimidazol-1-ylmethyl)-3-chlorobenzyl]-N-ethyl-N-methylpyrrolidin-3-amine;(2R)-1′-[4-(1H-苯并咪唑-1-基甲基)-2-甲氧基苯甲酰基]-2-甲基-1，3′-联吡咯烷；(2R)-1'-[4-(1H-benzimidazol-1-ylmethyl)-2-methoxybenzoyl]-2-methyl-1,3'-bipyrrolidine;2-苯甲基-1′-{4-[(5-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；2-Benzyl-1'-{4-[(5-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;1′-{4-[(7-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；1'-{4-[(7-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;(2R)-1′-{4-[(5-氟-1H-苯并咪唑-1-基)甲基]苯甲酰基}-2-甲基-1，3′-联吡咯烷；(2R)-1'-{4-[(5-fluoro-1H-benzimidazol-1-yl)methyl]benzoyl}-2-methyl-1,3'-bipyrrolidine;(2R)-2-甲基-1′-{4-[(5-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(2R)-2-methyl-1'-{4-[(5-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;1-[4-(1H-苯并咪唑-1-基甲基)-3-氯苯甲基]-N，N-二甲基吡咯烷-3-胺；1-[4-(1H-benzimidazol-1-ylmethyl)-3-chlorobenzyl]-N,N-dimethylpyrrolidin-3-amine;(2S)-1′-{4-[(5-氟-1H-苯并咪唑-1-基)甲基]苯甲酰基}-2-甲基-1，3′-联吡咯烷；(2S)-1'-{4-[(5-fluoro-1H-benzimidazol-1-yl)methyl]benzoyl}-2-methyl-1,3'-bipyrrolidine;1-{4-[(3-氮杂环庚烷-1-基吡咯烷-1-基)羰基]苯甲基}-5-甲基-1H-苯并咪唑；1-{4-[(3-Azepan-1-ylpyrrolidin-1-yl)carbonyl]benzyl}-5-methyl-1H-benzimidazole;5-甲基-1-(4-{[3-(4-甲基-1，4-二氮杂环庚烷-1-基)吡咯烷-1-基]羰基}苯甲基)-1H-苯并咪唑；5-methyl-1-(4-{[3-(4-methyl-1,4-diazepan-1-yl)pyrrolidin-1-yl]carbonyl}benzyl)-1H - benzimidazole;(3′S)-1′-{4-[(5-氟-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(5-fluoro-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;(3′S)-1′-{4-[(5-氟-1H-苯并咪唑-1-基)甲基]苯甲基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(5-fluoro-1H-benzimidazol-1-yl)methyl]benzyl}-1,3'-bipyrrolidine;7-甲基-1-{4-[(3-哌啶-1-基吡咯烷-1-基)羰基]苯甲基}-1H-苯并咪唑；7-methyl-1-{4-[(3-piperidin-1-ylpyrrolidin-1-yl)carbonyl]benzyl}-1H-benzimidazole;(2R)-1′-{4-[(5-氟-1H-苯并咪唑-1-基)甲基]苯甲基}-2-甲基-1，3′-联吡咯烷；(2R)-1'-{4-[(5-fluoro-1H-benzimidazol-1-yl)methyl]benzyl}-2-methyl-1,3'-bipyrrolidine;1-{4-[(3-氮杂环丁烷-1-基吡咯烷-1-基)羰基]苯甲基}-5-甲基-1H-苯并咪唑；1-{4-[(3-azetidin-1-ylpyrrolidin-1-yl)carbonyl]benzyl}-5-methyl-1H-benzimidazole;1′-[4-(1H-苯并咪唑-1-基甲基)-2-氟苯甲酰基]-1，3′-联吡咯烷；1'-[4-(1H-benzimidazol-1-ylmethyl)-2-fluorobenzoyl]-1,3'-bipyrrolidine;(3′S)-1′-{4-[(7-氟-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(7-fluoro-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;1-(4-{[(3S)-3-氮杂环庚烷-1-基吡咯烷-1-基]羰基}苯甲基)-7-氟-1H-苯并咪唑；1-(4-{[(3S)-3-azepan-1-ylpyrrolidin-1-yl]carbonyl}benzyl)-7-fluoro-1H-benzimidazole;7-氟-1-(4-{[(3S)-3-哌啶-1-基吡咯烷-1-基]羰基}苯甲基)-1H-苯并咪唑；7-fluoro-1-(4-{[(3S)-3-piperidin-1-ylpyrrolidin-1-yl]carbonyl}benzyl)-1H-benzimidazole;(3S)-N-乙基-1-{4-[(7-氟-1H-苯并咪唑-1-基)甲基]苯甲酰基}-N-甲基吡咯烷-3-胺；(3S)-N-ethyl-1-{4-[(7-fluoro-1H-benzimidazol-1-yl)methyl]benzoyl}-N-methylpyrrolidin-3-amine;7-氟-1-(4-{[(3S)-3-(3-甲基哌啶-1-基)吡咯烷-1-基]羰基}苯甲基)-1H-苯并咪唑；7-fluoro-1-(4-{[(3S)-3-(3-methylpiperidin-1-yl)pyrrolidin-1-yl]carbonyl}benzyl)-1H-benzimidazole;1-(4-{[(3S)-3-氮杂环丁烷-1-基吡咯烷-1-基]羰基}苯甲基)-7-氟-1H-苯并咪唑；1-(4-{[(3S)-3-azetidin-1-ylpyrrolidin-1-yl]carbonyl}benzyl)-7-fluoro-1H-benzimidazole;(3′S)-1′-(4-{[2-(三氟甲基)-1H-苯并咪唑-1-基]甲基}苯甲酰基)-1，3′-联吡咯烷；(3'S)-1'-(4-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)-1,3'-bipyrrolidine;(3′S)-1′-{4-[1-(7-氯-1H-吲哚-1-基)乙基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[1-(7-Chloro-1H-indol-1-yl)ethyl]benzoyl}-1,3'-bipyrrolidine;(3′S)-1′-{4-[1-(5-氯-2-甲基-1H-苯并咪唑-1-基)乙基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[1-(5-Chloro-2-methyl-1H-benzimidazol-1-yl)ethyl]benzoyl}-1,3'-bipyrrole alkyl;(3′S)-1′-{4-[(1S)-1-(1H-苯并咪唑-1-基)乙基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1S)-1-(1H-benzimidazol-1-yl)ethyl]benzoyl}-1,3'-bipyrrolidine;(3′S)-1′-{4-[(1R)-1-(1H-苯并咪唑-1-基)乙基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1R)-1-(1H-benzimidazol-1-yl)ethyl]benzoyl}-1,3'-bipyrrolidine;(3′S)-1′-{4-[(5-氯-2-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(5-chloro-2-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;(3′S)-1′-{4-[(6-氯-2-甲基-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(6-Chloro-2-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;(3′S)-1′-{4-[(1S)-1-(5-氯-2-甲基-1H-苯并咪唑-1-基)乙基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1S)-1-(5-chloro-2-methyl-1H-benzimidazol-1-yl)ethyl]benzoyl}-1,3 '-Bipyrrolidine;(3′S)-1′-{4-[(1S)-1-(6-氯-2-甲基-1H-苯并咪唑-1-基)乙基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1S)-1-(6-chloro-2-methyl-1H-benzimidazol-1-yl)ethyl]benzoyl}-1,3 '-Bipyrrolidine;(3′S)-1′-{4-[(1R)-1-(5-氯-2-甲基-1H-苯并咪唑-1-基)乙基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1R)-1-(5-chloro-2-methyl-1H-benzimidazol-1-yl)ethyl]benzoyl}-1,3 '-Bipyrrolidine;(3′S)-1′-{4-[(1R)-1-(6-氯-2-甲基-1H-苯并咪唑-1-基)乙基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(1R)-1-(6-chloro-2-methyl-1H-benzimidazol-1-yl)ethyl]benzoyl}-1,3 '-Bipyrrolidine;(3S)-1-{4-[(1R)-1-(6-氯-2-甲基-1H-苯并咪唑-1-基)乙基]苯甲酰基}吡咯烷-3-胺；(3S)-1-{4-[(1R)-1-(6-Chloro-2-methyl-1H-benzimidazol-1-yl)ethyl]benzoyl}pyrrolidin-3-amine;(3S)-1-{4-[(1R)-1-(5-氯-2-甲基-1H-苯并咪唑-1-基)乙基]苯甲酰基}吡咯烷-3-胺；(3S)-1-{4-[(1R)-1-(5-Chloro-2-methyl-1H-benzimidazol-1-yl)ethyl]benzoyl}pyrrolidin-3-amine;(3′S)-1′-{4-[(5-氯-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(5-Chloro-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;(3′S)-1′-{4-[(6-氯-1H-苯并咪唑-1-基)甲基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[(6-Chloro-1H-benzimidazol-1-yl)methyl]benzoyl}-1,3'-bipyrrolidine;(3S)-1-{4-[(5-氯-1H-苯并咪唑-1-基)甲基]苯甲酰基}吡咯烷-3-胺；(3S)-1-{4-[(5-Chloro-1H-benzimidazol-1-yl)methyl]benzoyl}pyrrolidin-3-amine;(3S)-1-{4-[(1S)-1-(6-氯-2-甲基-1H-苯并咪唑-1-基)乙基]苯甲酰基}吡咯烷-3-胺；(3S)-1-{4-[(1S)-1-(6-Chloro-2-methyl-1H-benzimidazol-1-yl)ethyl]benzoyl}pyrrolidin-3-amine;(3S)-1-{4-[(1S)-1-(5-氯-2-甲基-1H-苯并咪唑-1-基)乙基]苯甲酰基}吡咯烷-3-胺；(3S)-1-{4-[(1S)-1-(5-Chloro-2-methyl-1H-benzimidazol-1-yl)ethyl]benzoyl}pyrrolidin-3-amine;(3′S)-1′-{4-[1-(5-氯-1H-吲哚-1-基)乙基]苯甲酰基}-1，3′-联吡咯烷；(3'S)-1'-{4-[1-(5-Chloro-1H-indol-1-yl)ethyl]benzoyl}-1,3'-bipyrrolidine;1-(1-{4-[(3′S)-1，3′-联吡咯烷-1′-基羰基]苯基}乙基)-1H-吲哚-5-甲腈；1-(1-{4-[(3′S)-1,3′-bipyrrolidin-1′-ylcarbonyl]phenyl}ethyl)-1H-indole-5-carbonitrile;2-甲基-1-[1-(4-{[(1R，4R)-5-甲基-2，5-二氮杂双环[2.2.1]庚-2-基]羰基}苯基]-1H-苯并咪唑；2-Methyl-1-[1-(4-{[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}phenyl] -1H-benzimidazole;1-{4-[(3-吡咯烷-1-基哌啶-1-基)羰基]苯甲基}-1H-苯并咪唑；1-{4-[(3-Pyrrolidin-1-ylpiperidin-1-yl)carbonyl]benzyl}-1H-benzimidazole;1′-[4-(1H-苯并咪唑-1-基甲基)苯甲酰基]-1，3′-联哌啶；1'-[4-(1H-benzimidazol-1-ylmethyl)benzoyl]-1,3'-bipiperidine;1-(4-{[3-(2-甲基吡咯烷-1-基)哌啶-1-基]羰基}苯甲基)-1H-苯并咪唑；1-(4-{[3-(2-methylpyrrolidin-1-yl)piperidin-1-yl]carbonyl}benzyl)-1H-benzimidazole;4-(1H-苯并咪唑-1-基甲基)-N-(2-吡咯烷-1-基乙基)苯甲酰胺；4-(1H-benzimidazol-1-ylmethyl)-N-(2-pyrrolidin-1-ylethyl)benzamide;4-[(2-甲基-1H-苯并咪唑-1-基)甲基]-N-(2-吡咯烷-1-基乙基)苯甲酰胺；4-[(2-Methyl-1H-benzimidazol-1-yl)methyl]-N-(2-pyrrolidin-1-ylethyl)benzamide;1-(4-{[3-(4-甲基哌啶-1-基)吡咯烷-1-基]羰基}苯甲基)-1H-苯并咪唑；1-(4-{[3-(4-methylpiperidin-1-yl)pyrrolidin-1-yl]carbonyl}benzyl)-1H-benzimidazole;(2R，3′R)-1′-[4-(1H-苯并咪唑-1-基甲基)苯甲酰基]-2-甲基-1，3′-联吡咯烷；(2R,3'R)-1'-[4-(1H-benzimidazol-1-ylmethyl)benzoyl]-2-methyl-1,3'-bipyrrolidine;(2S，3′R)-1′-[4-(1H-苯并咪唑-1-基甲基)苯甲酰基]-2-甲基-1，3′-联吡咯烷；(2S,3'R)-1'-[4-(1H-benzimidazol-1-ylmethyl)benzoyl]-2-methyl-1,3'-bipyrrolidine;其立体异构体；或its stereoisomers; or其医药学上可接受的盐。its pharmaceutically acceptable salt.9.一种治疗有需要的患者的与组胺-3受体相关或由组胺-3受体影响的中枢神经系统病症的方法，其包含对所述患者提供治疗有效量的根据权利要求1至8中任一权利要求所述的式I化合物。9. A method of treating a central nervous system disorder associated with or affected by histamine-3 receptors in a patient in need thereof, comprising providing said patient with a therapeutically effective amount of to the compound of formula I according to any one of claims 8 to 8.10.根据权利要求9所述的方法，其中所述病症为认知障碍、发育障碍或睡眠障碍。10. The method of claim 9, wherein the condition is a cognitive impairment, a developmental disorder, or a sleep disorder.11.根据权利要求9所述的方法，其中所述病症为认知障碍。11. The method of claim 9, wherein the disorder is cognitive impairment.12.根据权利要求9所述的方法，其中所述病症选自由阿兹海默氏症(Alzheimer′sdisease)、学习障碍、注意力不足症和精神分裂症组成的群组。12. The method of claim 9, wherein the disorder is selected from the group consisting of Alzheimer's disease, learning disabilities, attention deficit disorder, and schizophrenia.13.一种抑制H3受体的方法，其包含使所述受体与有效量的根据权利要求1至8中任一权利要求所述的式I化合物或其立体异构体或医药学上可接受的盐接触。13. A method for inhibiting H3 receptors, comprising making said receptors and an effective amount of a compound of formula I according to any one of claims 1 to 8 or a stereoisomer thereof or a pharmaceutically acceptable Accepted salt exposure.14.一种医药组合物，其包含医药学上可接受的载剂和根据权利要求1至8中任一权利要求所述的式I化合物或其立体异构体或医药学上可接受的盐。14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of formula I or its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1 to 8 .15.一种制备根据权利要求1所述的式I化合物的方法，15. A method for preparing a compound of formula I according to claim 1,所述方法包含使式XVI化合物The method comprises making the compound of formula XVI

其中X、n、p、R₃、R₆、R₇、R₈和R₉如上文所定义，wherein X, n, p, R₃ , R₆ , R₇ , R₈ and R₉ are as defined above,与其中R₁和R₂如上文所定义的胺HNR₁R₂在存在微波照射的情况下视情况在存在溶剂的情况下反应；Reaction with an amine HNR₁ R 2 wherein R₁ and_{R 2are} as defined above in the presence of microwave irradiation, optionally in the presence of a solvent;和必要时转化成其医药学上可接受的盐；And converted into its pharmaceutically acceptable salt when necessary;和/或and / or分离其特定立体异构体。Its specific stereoisomers were isolated.