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CN1545501A - 新型环己基砜化合物 - Google Patents

新型环己基砜化合物 Download PDF

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Publication number
CN1545501A
CN1545501A CNA028163257A CN02816325A CN1545501A CN 1545501 A CN1545501 A CN 1545501A CN A028163257 A CNA028163257 A CN A028163257A CN 02816325 A CN02816325 A CN 02816325A CN 1545501 A CN1545501 A CN 1545501A
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China
Prior art keywords
represent
alkyl
compound
acceptable salt
phenyl
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CNA028163257A
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CN1276914C (zh
Inventor
I
I·丘彻
���ڶ���
K·丁内尔
�������ɭ
T·哈里森
S·克尔拉德
���ɶ��ؼ�����
A·J·纳丁
¿
P·J·奥克利
�Ф
D·E·肖
���ٶ���԰�������޹�˾
M·R·蒂尔
B·J·威廉斯
S·威廉斯
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Msd Uk Ltd
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Merck and Co Inc
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Priority claimed from PCT/GB2001/003741 external-priority patent/WO2002081435A1/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of CN1545501A publication Critical patent/CN1545501A/zh
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Publication of CN1276914C publication Critical patent/CN1276914C/zh
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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Abstract

公开了式I的新型砜化合物。该化合物能通过γ－分泌酶调节淀粉样前体蛋白质的加工，并因此可用于治疗或预防阿尔茨海默病。

Description

新型环己基砜化合物
本发明涉及一类新型化合物、它们的盐、包含它们的药物组合物、它们的制备方法和它们在人体治疗方面的应用。特别地，本发明涉及新型砜化合物，其通过γ-分泌酶(secretase)调节APP的加工，并因此用于阿尔茨海默病的治疗和预防。
阿尔茨海默病(AD)是痴呆症最为普遍的形式。尽管其主要是一种老年疾病，感染了多达10％的65岁以上的人口，AD也感染了很多有遗传性诱因的年轻患者。这是一种神经退行性失调，临床特征为记忆力和认知功能的进行性丧失，病理学特征为患者大脑皮层和相关区域内细胞外蛋白质蚀斑沉积。这些蚀斑主要包括β-淀粉样肽(Aβ)的纤维状聚集体。分泌酶，包括所谓的γ-分泌酶在加工淀粉样前体蛋白(APP)以形成Aβ中的作用在文献中清楚地记载并，例如，在WO01/70677中进行了综述。
在文献中基于细胞的分析检测中，关于对γ-分泌酶有抑制活性的化合物的报导较少。这些在WO 01/70677中进行了综述。许多相关的化合物是肽或肽衍生物。
本发明提供了新的一类非肽类化合物，其通过所谓的γ-分泌酶来调节APP的加工，这样抑制Aβ的产生而用于治疗或预防AD。
本发明提供了式I的化合物：
Figure A0281632500051
其中：
m是0或1；
Z代表CN，OR2a，CO2R2a或CON(R2a)2；
R1b代表H，C1-4烷基或OH；
R1c代表H或C1-4烷基；
Ar1代表苯基或吡啶基，二者中的任何一个均带有0-3个取代基，所述取代基独立地选自卤素，CN，NO2，CF3，OH，OCF3，C1-4烷氧基或C1-4烷基，其任选地带有选自卤素，CN，NO2，CF3，OH和C1-4烷氧基的取代基。
Ar2代表2-和5-位上被卤素取代的苯基。
R2a代表H，C1-6烷基，C3-6环烷基，C3-6环烷基C1-6烷基，C2-6链烯基，其中的任何基团任选地带有选自卤素，CN，NO2，CF3，OR2b，CO2R2b，N((R2b)2，CON(R2b)2，Ar和COAr的取代基；或者R2a代表Ar；或者两个R2a基团和它们共同连接的氮原子一起形成一个N-杂环基团，其带有0-4个独立地选自＝0，＝S，卤素，C1-4烷基，CN，NO2，CF3，OH，C1-4烷氧基，C1-4烷氧基羰基，CO2H，氨基，C1-4烷基氨基，二(C1-4烷基)氨基，氨基甲酰基，Ar和COAr的取代基；
R2b代表H，C1-6烷基，C3-6环烷基，C3-6环烷基C1-6烷基，C2-6链烯基，其中任何的基团任选地带有选自卤素，CN，NO2，CF3，OH，C1-4烷氧基，C1-4烷氧基羰基，CO2H，氨基，C1-4烷基氨基，二(C1-4烷基)氨基，氨基甲酰基，Ar和COAr的取代基；或者R2b代表Ar；或者两个R2b基团与它们共同连接的氮原子一起形成一个N-杂环基团，其带有0-4个独立地选自＝0，＝S，卤素，C1-4烷基，CN，NO2，CF3，OH，C1-4烷氧基，C1-4烷氧基羰基，CO2H，氨基，C1-4烷基氨基，二(C1-4烷基)氨基，氨基甲酰基，Ar和COAr的取代基；
Ar代表苯基或杂芳基，其带有0-3个选自卤素，C1-4烷基，CN，NO2，CF3，OH，C1-4烷氧基，C1-4烷氧基羰基，氨基，C1-4烷基氨基，二(C1-4烷基)氨基，氨基甲酰基，C1-4烷基氨基甲酰基和二(C1-4烷基)氨基甲酰基的取代基；
或其药物可接受的盐。
其中除非另有说明，当在式I中或在其上的一个取代基中，变化不止一次时，所述变化的单独发生彼此间相互独立。
本文中使用的表达式“C1-X烷基”，其中X是大于1的整数，指的是直链或支化的烷基，其中组成碳原子数为1-X。具体的烷基包括甲基，乙基，正丙基，异丙基和叔丁基。衍生的表达式如“C2-6链烯基”，“羟基C1-6烷基”，“杂芳基”C1-6烷基，“C2-6炔基”和“C1-6烷氧基”应以相似的方式理解。
本文中使用的表达式“C3-6环烷基”指非芳族单环或稠合双环烃环体系，其包含3-6个环原子。实例包括环丙基，环丁基，环戊基，环己基和环己基甲基。
本文中使用的表达式“C3-6环烷基C1-6烷基”包括环丙基甲基，环丁基甲基，环戊基甲基和环己基甲基。
本文中使用的表达式“N-杂环基”指最多为10个选自C，N，O和S的环原子的环状或多环体系，其中的组成环都不是芳族的且其中至少一个环原子是氮且通过该环氮原子进行键接。优选的N-杂环基团是4-6元的单环体系，如氮杂环丁烷基，吡咯烷基，哌啶基，哌嗪基，吗啉基，硫代吗啉基，咪唑烷基，噁唑烷基和噻唑烷基。
本文中使用的表达式“杂芳基”指最多为10个选自C，N，O和S的环原子的环状或多环体系，其中至少一个组成环是芳族的且包含至少一个非碳环原子。优选的杂芳基团为5或6元单环体系，如吡啶基，哒嗪基，嘧啶基，吡嗪基，吡咯基，呋喃基，噻吩基，吡唑基，噁唑基，异噁唑基，噻唑基，异噻唑基，咪唑基，噁二唑基，三唑基，和噻二唑基。其它的杂芳基团的实例包括四唑，1，2，4-三嗪和1，3，5-三嗪。
本文中使用的术语“卤素”包括，氟，氯，溴和碘，其中优选氟和氯。
为了在药物中使用，式I化合物为药物可接受盐形式是有利的，但是其它的盐可用于制备所述化合物或其药物可接受盐。本发明化合物的适当的药物可接受盐包括酸加成盐，如那些与盐酸，硫酸，甲磺酸，富马酸，马来酸，琥珀酸，醋酸，苯甲酸，草酸，柠檬酸，酒石酸，碳酸，或磷酸形成的盐，并且，当本发明的化合物携带酸部分时，包括钠，钾，钙或镁盐，以及与适当的有机配体形成的盐，例如季铵盐或吡啶鎓盐。
当本发明的化合物具有至少一个非对称中心时，其可能因此以对映体形式存在。当本发明的化合物具有两个或更多个非对称中心时，它们可能另外地以非对映异构体形式存在。应当这样理解，即所有这些异构体以及它们以任意比例形成的混合物都包含在本发明的范围之内。
无论非对称中心存在与否，某些本发明的化合物因其分子整体上的非对称性而可能以对映体形式存在。应当认为，在这样的情况下，对映体及其任意比例的混合物都包括在本发明的范围内，并且除非另有说明，描绘此类分子的结构式应代表两种可能的对映体。
在式I化合物中，Ar1代表被任选取代的苯基或吡啶基，特别是被任选取代的苯基或3-吡啶基。Ar1优选选自在4-位上被卤素，甲基，或三氟甲基取代的苯基和在3-和4-位上被卤素取代的苯基。
Ar2优选为2，5-二氟苯基。
在具体实施方案中，Ar1是4-氯苯基或4-三氟甲基苯基以及Ar2是2，5-二氟苯基。
R1b一般代表H，甲基或OH，优选H。
R1c一般代表H或甲基，优选H。
当m是1时，优选R1b和R1c不都代表C1-4烷基。
R2a的具体含意包括，H，苯基，吡啶基，C3-6环烷基(如环丙基，环丁基和环戊基)，C3-6环烷基C1-6烷基(如环丙基甲基)，C2-6链烯基(如烯丙基)，以及任选被CF3，Ar，OR2b，N(R2b)2，CO2R2b或CON(R2b)2取代的线型或支化的C1-6烷基。
由N(R2a)2所代表的N-杂环基团的实例包括哌啶-1-基(任选被OH，CO2H，CO2C1-4烷基，甲基或苯基取代)，哌嗪-1-基(任选被甲基或苯基取代)，吗啉-4-基，硫代吗啉-4-基，1，1-二氧代-硫代吗啉-4-基，2-氧代-咪唑烷-1-基，5，5-二甲基-2，2-二氧代-噁唑烷-3-基，2，5-二氧代-咪唑烷-1-基，2-氧代-噁唑烷-3-基，2-氧代-吡啶烷-1-基，和2-氧代-吡咯烷-1-基。
R2b一般代表H或C1-4烷基。
当Z代表OR2a时，R2a倾向于代表H，Ar(特别是吡啶基)，烷基(如甲基，乙基，丙基或丁基)，或取代烷基(特别是CH2Ar如苄基或吡啶基甲基)。
当Z代表CO2R2a时，R2a倾向于代表H或烷基(如甲基，乙基，丙基或丁基)。
当Z代表CON(R2a)2时，R2a基团独立代表H或被任选取代的烷基，环烷基，环烷基烷基或链烯基，或一起构成N-杂环基团。非常有倾向出现的是，一个R2a代表H，另一个代表H，烷基(如甲基，乙基，正丙基，异丙基，正丁基，仲丁基，叔丁基或1-乙基丙基)，链烯基(如烯丙基)，环烷基(如环丙基，环丁基或环戊基)，环烷基烷基(如环丙基甲基)，或取代烷基(如被Ar取代的烷基，特别是2-吡啶基乙基，3-(咪唑-1-基)丙基或2-苯基乙基，或被CF3，CO2R2b或CON(R2b)2取代的烷基，特别是2，2，2-三氟乙基，甲氧基羰基甲基或氨基甲酰基甲基)。或者，这两个R2a基团形成一个N-杂环基团，如吗啉，硫代吗啉，硫代吗啉-1，1-二氧化物，4-甲基哌嗪，4-苯基哌嗪，哌啶，4-羟基哌啶，或在3-或4-位上被CO2R2b和/或C1-4烷取代的哌啶，特别是3-或4-羧基哌啶，3-或4-乙氧基羰基哌啶，3-羧基-3-甲基哌啶和3-乙氧基羰基-3-甲基哌啶。
本发明式I的个别化合物的实例提供在所附的实施例部分中。
式I化合物具有作为通过γ-分泌酶进行APP加工的调节剂的活性。
本发明还提供了包含一种或多种式I化合物或其药物可接受盐和药物可接受载体的药物组合物。这些组合物优选为单位剂型，如片剂，丸剂，胶囊，药粉，颗粒，非胃肠道给药的灭菌溶液或悬浮体，计量气溶胶或液体喷雾剂，滴剂，安瓿剂，皮肤贴，自动式注射器装置或栓剂；以通过口服，胃肠道外，鼻内，舌下或直肠给药，或通过吸入或吹入给药。为制备固体组合物如片剂，将主要活性成分与药物载体如本领域技术人员所熟知的常规片剂成分相混合，如例如WO 01/70677中所描述，并形成单位剂型。典型的单位剂型含有0.1-500毫克，例如1，2，5，10，25，50，100或200毫克的活性成分。可以对本发明的新型组合物的片剂或丸剂进行包衣或复合处理以提供具有长效优点的剂型，如在WO 01/70677中所述。
为了能口服或注射给药，可以将本发明的新型组合物加入液体形式当中，所述液体形式包括水溶液，经适当调味的糖浆，水或油的悬浮体，和用食用油调味的乳液如WO 01/70677中所描述。
本发明还提供了用于人体治疗方法中的式I化合物或其药物可接受盐。优选所述的治疗是针对与β-淀粉样蛋白的沉积相关的疾病。优选所述疾病是与β-淀粉样蛋白质的沉积相关的神经疾病如阿尔茨海默病。
本发明还提供了式I化合物或其药物可接受盐在生产用于治疗或预防阿尔茨海默病的药物的用途。
还公开了治疗患有或易患阿尔茨海默病的病人的方法，包括使患者服用有效量的式I化合物或其药物可接受盐。
为治疗或预防阿尔茨海默病，适当的剂量水平是约0.01-250毫克/千克/天，优选为约0.05-100毫克/千克/天，特别是约0.1-50毫克/千克体重/天。按医嘱，该化合物每天可服用1-4次。然而，在一些情况下，超出这些限制的剂量也可以使用。
当式I化合物中的m是O及Z是CO2R2a或CON(R2a)2时，该化合物可以通过(分别)用R2aOH或HN(R2a)2与羧酸(1)偶合来制备，
Figure A0281632500101
其中Ar1，Ar2，R1c和R2a具有与前面相同的含义。可以采用任何的标准偶合技术，包括使用偶合剂如二甲基胺基吡啶，羟基苯并三唑，二环己基碳二亚胺，羰酰二咪唑等。在一个优选方法中，将酸转化为相应的酰氯(例如通过用草酰氯在DMF中的溶液处理)并直接与所需的亲核体反应。在另一个优选方法中，将酸转化为具有活性的酯类衍生物如五氟代苯酚酯(例如通过在二环己基碳二亚胺存在下与苯酚偶合)，并使该中间体与所需亲核体反应。
酸(1)可通过酯(2)的水解获得，一般在碱性条件下如用LiOH的乙醇溶液处理：
Figure A0281632500102
其中R2代表烷基如甲基或乙基，且Ar1，Ar2和R1c具有与前面相同的含义。
酯(2)可以通过还原亚烷基衍生物(3)获得，任选然后使用(C1-4烷基)-L进气烷基化作用，其中当R1c不是H时，L是离去基团(特别是溴化物或碘化物)：
Figure A0281632500111
其中Ar1，Ar2和R2具有与前面相同的含义。还原反应可以采用硼氢化钠和氯化镍(II)在乙醇中进行，而任选的烷基化作用可以按以下步骤进行：用强碱(例如二(三甲基甲硅烷基)酰胺钠)在非质子溶剂中于低温下处理该酯(2，R1c＝H)，接下来用(C1-4烷基)-L处理并加温至室温。
如果需要，在还原该烯键之前，可以将不饱合酯(3)水解为相应的酸并通过与HN(R2a)2反应转化为酰胺。
不饱合酯(3)可以从酮(4)与Ph3P＝CHCO2R2的缩合反应获得：
Figure A0281632500112
其中Ar1，Ar2和R2具有与前面相同的含义，而酮(4)通过烯醇(5)的脱羧作用获得，而烯醇(5)由砜(6)与至少两个当量的丙烯酸酯(7)反应形成：
Figure A0281632500113
其中Ar1，Ar2和R2具有与前面相同的含义。脱羧作用可以通过在氯化钠和水存在下在DMSO中加热至150℃来完成，而(6)和(7)的反应可以在室温下，在惰性溶剂如THF中，在强碱如叔丁醇钾存在下进行。
砜化合物(6)通过硫醚Ar2-CH2-SAr1(8)的氧化来制备，而该硫醚(8)通过硫醇Ar1SH(9)与苄基衍生物Ar2CH2-L(10)的反应形成，其中L是离去基团如氯或溴且Ar1和Ar2具有与前面相同的含义。(9)和(10)之间的反应在惰性溶剂如二氯甲烷中，在碱如三乙胺的存在下发生，而由(8)向(6)的氧化反应可便利地通过间氯过氧苯甲酸来进行，这也要在惰性溶剂如二氯甲烷中进行。
当式I化合物中的m是0且Z是CN或OR2a时，式I化合物可通过磺酸酯(11)(分别)与氰化物离子或R2aOH反应获得：
其中L1代表磺酸酯离去基团(如甲磺酰酯，甲苯磺酰酯，或triflate)且Ar1，Ar2，R1c和R2a具有与前面相同的含义。置换反应可以在DMF中，在高温，例如在约80℃下进行。当亲核体是R2aOH时，在其与(11)反应前用氢化钠进行处理产生相应的阴离子是有利的。
磺酸酯(11)通过醇(12)与适当的磺酰氯的反应制备(例如在无水条件下、低温和叔胺的存在下)。
Figure A0281632500122
醇(12)从烯(13)的硼氢化作用获得：
Figure A0281632500131
其中Ar1，Ar2，和R1c具有与前面相同的含义。该方法一般涉及室温下在THF中与硼烷的反应，接下来用碱性过氧化氢处理并通过色谱法分离出所需的顺式异构体。烯(13)通过与Ph3P＝CHR1c的缩合反应从酮(4)得到，其中R1c具有与前面相同的含义。
当醇(12)中R1c是H时，制备醇(12)的备选途径涉及还原酮(4)(例如用氢硼化物)为相应的仲醇(14)，将该醇(14)转化为相应的甲磺酰酯(或等效的离去基团)，用氰化物离子进行亲核取代，水解得到的腈为相应的羧酸，接下来还原为伯醇。水解反应一般在酸性条件下(例如在醋酸和浓盐酸的混合物中，在110℃下)进行且还原反应通过用异丁基氯甲酸酯和硼氢化物在THF中的顺序处理而方便地进行。
当式I化合物中的m是1且R1b是H或C1-4烷基时，该化合物可以通过将醇(12)氧化成相应的醛或酮来获得，且羰基的加工按前述将酮(4)转化为m是0的式I化合物的方式进行。例如，当醇(12)中的R1c是氢时，将醇(12)氧化提供了相应的环己烷酰基醛化合物，其可与Ph3P＝CO2Et缩合生成2-环己基丙烯酸乙酯化合物。接下来，可以氢化为相应的2-环己基丙酸乙酯，可任选使其经过烷基化，和/或水解成为相应的酸，和/或转化为多种酰胺或其它的酯衍生物。
当原料和试剂本身不能商购获得时，在上述合成方案中使用的原料和试剂可通过对可商购的原料施用有机合成的标准方法来获得。
应该意识到许多上述的合成方案会生成立体异构体的混合物。特别地，所形成的某些产物可能为顺、反异构体的混合物，其中，一个特定的环状取代基在该环的同或异侧如芳基磺酰基。这样的混合物可以通过常规手段如分级结晶和制备色谱来分离。
本发明的某些化合物，可能由于存在一个或多个手性中心或因为分子整体的非对称性而以光学异构体形式存在。这样的化合物可以以外消旋体形式制备，或者通过对映体特效合成方法或通过拆分来制备单独的对映体。所述的新型化合物，例如，可以通过标准技术拆分为它们的组分对映体，如通过制备HPLC，或通过与旋光酸成盐而形成非对映体对子，旋光酸如(-)-二-对甲苯酰-d-酒石酸和/或(+)-二-对甲苯酰-1-酒石酸，然后进行分级结晶并重新生成游离碱。所述新型化合物也可以通过形成非对映的酯或酰胺，接下来用色谱分离并除去手性的助剂来拆分。
在上述任意的合成程序中，对任意有关分子上的敏感或反应性基团进行保护可能是必要和/或需要的。这可以通过使用常规保护基团来实现，如在《有机化学中的保护基团》，ed.J.F.W.McOmie，PlenumPress，1973；和T.W.REENE & P.G.M.Wuts的《有机合成中的保护基团》，John Wiley & Sons，1991中描述的那些。该保护基团可以在后序方便的步骤中采用本领域已知的方法除去。
评估本发明的化合物对γ-分泌酶的活性水平的适当方法公开在WO 01/70677和《生物化学》，2000，39(30)，8698-8704中。
在至少一个上述参考的评估方法中，本发明的实施例均具有低于10μM的ED50，优选低于1μM且最优选低于100nM。
以下实施例说明本发明。
                         实施例
中间体1
4-氯苯硫酚(3.6克，0.025摩尔)在二氯甲烷(100毫升)中用2，5-二氟溴苄(5.17克，0.025摩尔)和三乙胺(3.9毫升，0.028摩尔)进行处理，将反应搅拌2小时然后用二氯甲烷(250毫升)稀释并用水(100毫升)和盐水(100毫升)洗涤。对经分离的有机层进行干燥(MgSO4)并蒸干。将产品用己烷-乙酸乙酯混合物通过硅胶柱洗脱对其进行提纯。5.12克。1H NMR CDCl3 7.23(4H，s)，6.69-6.86(3H，m)和4.04(2H，s).
将该硫醚(5.12克，0.018摩尔)溶解于二氯甲烷(100毫升)中并用间氯过氧苯甲酸(14.3克，0.042摩尔，(50％W/W))进行处理并搅拌2小时。然后用Na2S2O5(5％溶液，100毫升)，盐水(50毫升)洗涤反应物，干燥(MgSO4)并蒸干。将砜产物在硅胶柱上用己烷-乙酸乙酯混合物洗提来提纯，3.6克。
1H NMR CDCl3 7.61(2H，d，J＝8.6Hz)，7.45(2H，d，J＝8.6Hz)，7.13-7.08(1H，m)，7.05-7.01(1H，m)，7.05-7.00(1H，m)，6.99-6.87(1H，m)和4.36(2h，s).
中间体2
按照中间体1的方法制备，采用4-三氟甲基苯硫酚，以固体形式得到产品。
1H NMR(360MHz，CDCl3)δ7.85-7.83(2H，m)，7.76-7.74(2H，m)，7.15-7.10(1H，m)，7.06-7.0(1H，m)，6.92-6.86(1H，m)和4.46(2H，s).
制备1
Figure A0281632500152
向中间体1(1克，3，31毫摩尔)和丙烯酸甲酯(0.84毫升，9.27毫摩尔)在四氢呋喃(30毫升)中的溶液中逐滴加入叔丁醇钾(3.64毫升在四氢呋喃中的1M溶液，3.64毫摩尔)处理。反应物搅拌2小时，用乙酸乙酯(100毫升)稀释并用水(50毫升)和盐水(50毫升)洗涤。分离出有机相，干燥(MgSO4)并蒸干，将产物在硅胶柱上用己烷-乙酸乙酯混合物洗提来提纯。(1.0克)。
1H
NMR CDCl3 12.0(1H，s)，7.41(4H，s)，7.06-7.0(2H，m)，6.87-6.81(1H，s)，3.81(3H，s)，3.38(1H，dd，J＝3.2，15.8Hz)，3.02-2.92(2H，m)，2.52(1H，dd，J＝5.7，18.5Hz)，2.3-2.2(1H，m)和2.2-2.1(1H，m).
制备2
用NaCl(0.3克，4.96毫摩尔)和水(0.9毫升，4.96毫摩尔)处理由制备1获得的酯(1.0克，2.25毫摩尔)的二甲亚砜(10毫升)溶液并在150℃加热2小时。用乙酸乙酯(100毫升)稀释冷却的反应混合物，用饱和NH4Cl(100毫升)洗涤，分离出有机相，干燥(MgSO4)并蒸干.在硅胶柱上用己烷-乙酸乙酯混合物洗提来提纯产物，0.5克。
1H NMR CDCl3 7.43-7.37(4H，m)，7.22-7.1(2H，m)，6.97-6.9(1H，m)，3.05-2.98(2H，m)和2.61-2.53(2H，m).
制备3
通过制备1和2的方法进行制备，采用中间体2得到固体产物。(0.3克)。
1H NMR(360MHz，CDCl3)δ7.71-7.69(2H，d，J＝7.5Hz)，6.62-6.60(2H，d，J＝7.4Hz)，7.22-7.11(2H，m)，6.95-6.88(1H，m)，3.02-2.99(2H，m)，2.63-2.54(4H，m)和2.25-2.16(2H，m).
制备4
向氢化钠浆液(在矿物油中的60％分散体，988毫克，24.7毫摩尔)在四氢呋喃(60毫升)中的溶液中滴加乙基(二乙氧基氧膦基)乙酸酯(5.16毫升，26毫摩尔)并在室温下搅拌混合物1小时。用20分钟滴加从制备2得到的酮(5克，13毫摩尔)的四氢呋喃(50毫升)溶液并在室温下搅拌混合物18小时。加入水并用乙酸乙酯萃取混合物。用水洗涤合并的有机部分，干燥(MgSO4)并在减压下蒸去溶剂。通过闪蒸塔色谱法，在硅胶上用异己烷∶EtOAc＝85∶15的混合物洗提来提纯残余物，得到白色固体产物(5.2克，88％)。
1H NMR(400MHz，CDCl3)δ7.41-7.36(4H，m)，7.18-7.13(1H，m)，7.11-7.05(1H，m)，6.93-6.86(1H，m)，5.64(1H，s)，4.14-4.10(2H，m)，3.99-3.96(1H，m)，2.91-2.80(2H，m)，2.42-2.38(1H，m)，2.31-2.04(3H，m)，1.89-1.78(1H，m)，1.28-1.24(3H，m).
制备5
用硼氢化钠(0.098克，0.26毫摩尔)处理制备2得到的酮(0.1克，0.26毫摩尔)在甲醇(2毫升)中的溶液并搅拌1小时。将反应用HCl(1N，10毫升)淬灭，用乙酸乙酯(20毫升)稀释，然后分离出有机相，干燥(MgSO4)并蒸干。在硅胶柱上用己烷-乙酸乙脂混合物洗提来提纯顺式和反式的产物。
(a)(反式)0.052g.1H NMR CDCl37.39-7.33(4H，m)，7.11-7.02(2H，m)，6.88-6.82(1H，m)，3.80-3.73(1H，m)，2.80-2.60(2H，m)，2.22-2.16(2H，m)，2.08-2.04(2H，m)，1.53(1H，br)和1.27-1.13(2H，m).
(b)(顺式)1H NMR(CDCl3)7.40(4H，s)，7.16-7.03(2H，m)，6.90-6.83(1H，m)，3.97-3.95(1H，m)，3.77-3.68(1H，m)，3.51-3.49(1H，m)，2.61-2.53(2H，m)，1.91-1.83(2H，m)和1.50-1.42(2H，m).
制备6
Figure A0281632500181
在-30℃，用甲磺酰氯(0.645毫升，8.9毫摩尔)处理制备5得到的反式环己醇(2.7克，6.9毫摩尔)和三乙胺(1.45毫升，10.3毫摩尔)在二氯甲烷(50毫升)中的溶液。30分钟后用水(20毫升)，10％柠檬酸水溶液(20毫升)和饱和的碳酸氢钠水溶液(50毫升)洗涤混合物，干燥(MgSO4)并蒸干。用乙醚与固体一起研磨得到甲磺酸酯(2.6克)。
1H NMR(CDCl3)7.40-7.37(4H，m)，7.12-7.07(2H，m)，6.92-6.83(1H，m)，4.78-4.65(1H，m)，2.96(3H，s)，2.88-2.52(2H，m)，2.29-2.21(4H，m)和1.59-1.47(2H，m).
制备7
Figure A0281632500191
将制备6得到的反式甲磺酸酯(103毫克，0.22毫摩尔)溶于甲苯(20毫升)中并加入氰化四丁基铵(354毫克，1.32毫摩尔)的预共沸样品中，并用18小时将混合物加温至70℃然后冷却至室温。用水(10毫升)稀释溶液并用乙酸乙酯(2×50毫升)洗涤。用盐水(10毫升)洗涤有机相，干燥(MgSO4)并蒸发。将得到的透明油状物通过硅胶柱色谱法用10-20％乙酸乙酯的己烷溶液洗提来提纯，得到氰化物。
1HNMR(CDCl3)7.42-7.36(4H，s)，7.10-7.05(2H，m)，6.89-6.84(1H，m)，2.88-2.86(1H，m)，2.76-2.72(2H，m)，2.52-2.45(1H，m)，2.12-2.07(1H，m)和1.56-1.49(1H，m).
制备8
Figure A0281632500192
将制备7中得到的氰化物(143毫克，0.36毫摩尔)溶解/悬浮于冰醋酸(10毫升)和浓盐酸(6毫升)的混合物中并在110℃加热15小时。冷却混合物，用乙酸乙酯稀释并用水(×3)洗涤，经干燥(MgSO4)并蒸干。该粗残余物(153毫克)通过制备薄层色谱法(含5％甲醇的二氯甲烷溶液/1％乙酸)提纯。
1HNMR(CDCl3)7.38-7.35(4H，s)，7.08-7.06(2H，m)，6.90-6.84(1H，m)，2.65-2.58(2H，m)，2.38-2.33(3H，m)，和1.75-1.49(4H，m).
制备9
将制备8得到的氰化物(50毫克，0.12毫摩尔)溶解于四氢呋喃(4.5毫升)和水(0.5毫升)的混合物中并在20℃下搅拌。用过氧化氢(20毫升，0.6毫摩尔)处理混合物，然后用氢氧化锂(6毫克，0.25毫摩尔)处理2小时。加入过氧化氢(20毫升，0.6毫摩尔)然后加入氢氧化锂(6毫克，0.25毫摩尔)并在室温下搅拌混合物72小时。冷却混合物，用乙酸乙酯稀释并用水(×2)和饱和亚硫酸氢钠溶液洗涤，干燥(MgSO4)并蒸干。该粗残余物(51毫克)通过制备薄层色谱法(20％乙酸乙酯在己烷中的溶液)提纯。
1H NMR(CDCl3)7.37(4H，s)，7.10-7.02(2H，m)，6.90-6.84(1H，m)，5.57(2H，brs)，2.54-2.48(3H，m)，2.43-2.39(1H，m)，2.19-2.15(2H，m)和1.62-1.50(3H，m).
实施例1
向制备4中得到的不饱和酯(3.74克，8.23毫摩尔)和氯化镍(II)(2.67克，20.6毫摩尔)在乙醇(100毫升)中的混合物中加入硼氢化钠(313毫克，8.23毫摩尔)。在室温下搅拌混合物20分钟，然后加入水(100毫升)。通过HyfloTM过滤混合物，用乙醇和乙酸乙酯洗涤。在减压下蒸去溶剂并将残余物在乙酸乙酯和水间进行分配。收集有机层，进行干燥(MgSO4)并在减压下蒸去溶剂。残余物通过硅胶闪蒸塔色谱法用异己烷∶EtOAc(85∶15)的混合物洗提进行提纯，得到较快流出的顺式异构体，呈油状(1.36克，36％)，
1H NMR(400MHz，CDCl3)δ7.37-7.30(4H，m)，7.09-7.00(2H，m)，6.86-6.79(1H，m)，4.14(2H，q，J＝7.1Hz)，2.47(2H，d，J＝7.6Hz)，2.46-2.38(2H，m)，2.19-2.14(1H，m)，1.76-1.71(2H，m)，1.57-1.48(4H，m)，1.27(3H，t，J 7.1Hz)；
和较慢流出的反式异构体，呈油状(200毫克，5.3％)。
实施例2
Figure A0281632500211
向实施例1得到的顺式酯(1.33克，2.91毫摩尔)在乙醇(40毫升)的溶液中加入氢氧化锂(350毫克，14.57毫摩尔)。对混合物脱气并在室温及氮气保护下搅拌5小时。将混合物倒入(1M)盐酸水溶液中并用乙酸乙酯萃取。干燥(MgSO4)有机萃取物并在减压下蒸去溶剂得到白色固体，然后将其从IPA中重结晶得到白色固体产物(950毫克，76％)。
1H NMR(400MHz，CD3OD)δ7.51-7.49(2H，m)，7.40-7.37(2H，m)，7.19-7.10(2H，m)，7.00-6.94(1H，m)，2.51-2.35(6H，m)，2.13-2.10(1H，m)，1.78-1.74(2H，m)，1.57-1.50(2H，m).
实施例3
Figure A0281632500221
在室温下氮气保护下，搅拌在四氢呋喃中的实施例2得到的酸(50毫克，0.117毫摩尔)，吗啉(30微升，0.351毫摩尔)，1-羟基苯并三唑(24毫克，0.176毫摩尔)和三乙胺(65微升，0.468毫摩尔)的混合物10分钟。向混合物中加入1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(45毫克，0.234毫摩尔)并搅拌24小时。将混合物倒入氢氧化钠水溶液(1M)中并用乙酸乙酯萃取。干燥(MgSO4)有机萃取物并在减压下蒸去溶剂。残余物通过硅胶闪蒸塔色谱法，用5-10％的甲醇的二氯甲烷溶液洗提来提纯，得到白色泡沫状产品(50毫克，86％)。
1H NMR(400MHz，CD3OD)δ7.50(2H，d，J 8.6Hz)，7.37(2H，d，J 8.6Hz)，7.19-7.09(2H，m)，7.00-6.93(1H，m)，3.69-3.63(4H，m)，3.59-3.56(4H，m)，2.55(2H，d，J 7.4Hz)，2.47-2.39(4H，m)，2.16-2.07(1H，m)，1.78-1.74(2H，m)，1.58-1.51(2H，m).m/z(ES+)(M+1)498+500.
实施例4-15
采用适当的胺替代吗啉，按照实施例3的方法制备下面的化合物。
实施例16-33
采用适当的不含胺的碱或经在前的中和作用的胺盐，按照下面的方法制备这些实施例。
向搅拌中的顺式4-(4-氯苯磺酰)-4-(2，5-二氟苯基)环己烷乙酸(实施例2，0.15克，0.35毫摩尔)在二氯甲烷(5毫升)中形成的悬浮体内加入草酰氯(0.05毫升，0.57毫摩尔)和二甲基甲酰胺(1滴)。30分钟后，将溶液蒸发至小体积并向残余物在二氯甲烷(5毫升)的溶液中加入需要的胺(1.75毫摩尔)。搅拌该溶液20分钟后，在真空下除去溶剂并通过硅胶色谱法用递增浓度的乙酸乙酯的异己烷溶液(25％，50％)洗提来提纯残余物。蒸发含有产物的馏分得到酰胺产物。根据需要在硅胶上采用适当浓度的乙酸乙酯在异己烷中的溶液，乙酸乙酯或甲醇在乙酸乙酯中的溶液进行色谱提纯。
Figure A0281632500251
实施例33
向制备9中得到的顺式酰胺(46毫克)和吡啶(0.053毫升)在四氢呋喃(1毫升)的溶液中加入三氟乙酸酐(0.056毫升)。将溶液在室温下搅拌2小时，然后加入0.5M-HCl(水溶液)和乙酸乙酯。干燥有机相(MgSO4)，蒸至小体积并用硅胶色谱法，用异己烷∶乙酸乙酯(5∶1)混合物洗提进行提纯得到无色固状所需产物。
1H NMR(360MHz，CDCl3)δ1.61-1.70(2H，m)，1.86-1.94(2H，m)，2.03-2.10(1H，m)，2.42-2.45(4H，m)，2.51(2H，dJ 8.0Hz)，6.8(1H，m)，7.02-7.09(2H，m)，7.30(2H，dJ 8.6Hz)，7.36(2H，dJ 8.7Hz).
实施例34
将制备8中得到的酸(153毫克)溶于无水四氢呋喃(10毫升)中并在氮气保护下冷却至0℃。加入三乙胺(61微升，0.43毫摩尔)和异丁基氯甲酸酯(57微升，0.43毫摩尔)并在0℃下搅拌混合物一小时。过滤除去形成的沉淀并用另外5毫升无水THF洗涤。将合并的THF层再冷却至0℃，在泡腾状态下加入硼氢化钠(70毫克，1.84毫摩尔)在水(2毫升)中的溶液。在0℃搅拌30分钟后，用乙酸乙酯稀释反应物，用氯化铵溶液，碳酸氢钠溶液和盐水洗涤，然后干燥(MgSO4)并蒸干。残余物用柱色谱法，以乙酸乙酯∶己烷(1∶3)混合物洗提来提纯，得到需要的醇(75毫克)。
1H NMR(CDCl3)7.39-7.31(4H，m)，7.10-7.01(2H，m)，6.88-6.81(1H，m)，3.71(2H，d，J＝7.5Hz)，2.46-2.32(4H，m)，1.90-1.85(2H，m)，1.78-1.74(1H，m)和1.54-1.44(2H，m).m/z＝423[MNa]+
实施例35
Figure A0281632500271
步骤1
向实施例2中得到的酸(1克)在DCM(50毫升)和乙酸乙酯(30毫升)中的溶液中加入五氟苯酚(1.5当量)和DCC(1.5当量)并在室温下搅拌1小时。将反应混合物在真空下蒸发，溶于乙酸乙酯中并过滤。将滤液在真空下蒸发得到足够纯度的五氟苯酚酯以用于下面的反应中。
步骤2
在氮气保护下，向溶于DMF(3毫升)的步骤1中制备的五氟苯酚酯(155毫克，0.25毫摩尔)中加入甘氨酸甲酯盐酸盐(125毫克，1.0毫摩尔)和三乙胺(0.15毫升)。2小时后，用水稀释反应物，用乙酸乙酯萃取(×3)，用水，盐水洗涤，干燥(MgSO4)，过滤并蒸发。用闪蒸塔色谱法(1∶1异己烷/乙酸乙酯-9∶1乙酸乙酯/甲醇)提纯得到白色固体(55毫克)。
1HNMR(CDCl3)1.08-1.16(1H，m)，1.30-1.37(1H，m)，1.67-1.71(1H，m)，1.75-1.79(2H，m)，1.91-1.95(1H，m)，2.20-2.26(1H，m)，2.41(4H，d，J＝7.8Hz)，3.77(3H，s)，4.05(2H，d，J＝5.1Hz)，6.19(1H，br)，6.79-6.85(1H，m)，7.00-7.07(2H，m)，7.30-7.37(4H，m).
实施例36
Figure A0281632500281
将实施例35制备的甘氨酸酯(50毫克，0.1毫摩尔)在密封管中溶解在2M的氨的甲醇溶液(3毫升)中，在50℃加热3小时。冷却至室温后将反应混合物浓缩并通过与乙醚一起研磨提纯而得到白色固体(28毫克)。MS(EI+)：485(MH+)
实施例37
Figure A0281632500282
将实施例34得到的醇(4克，10毫摩尔)溶解在二氯甲烷(280毫升)中并用Dess Martin Periodinane(4.66克，11毫摩尔)处理，搅拌混合物45分钟然后加入饱和亚硫酸氢钠溶液(100毫升)，5分钟后，分离混合物，有机相用饱和碳酸氢钠水溶液(100毫升)洗涤，干燥(MgSO4)并蒸干。将粗残余物(4克)溶解在无水二氯甲烷(100毫升)中并用三苯基膦基乙酸甲酯(4.7克，14毫摩尔)处理，在室温下搅拌16小时。蒸去溶剂并用柱色谱法在硅胶上，用10-20％乙酸乙酯的己烷溶液洗提来提纯残余物得到产物。
1H NMR(CDCl3)7.37-7.36(4H，m)，7.10-7.02(3H，m)，6.87-6.83(1H，m)，5.91(1H，d，J＝16Hz)，3.77(3H，s)，2.55-2.45(3H，m)，2.40-2.38(2H，m)，1.95-1.90(2H，m)和1.65-1.52(2H，m).
实施例38
Figure A0281632500291
将实施例37得到的烯(3.6克，9毫摩尔)溶解在乙酸乙酯(350毫升)中。将烧瓶脱气，然后加入10％的钯碳(400毫克)，在氢气氛围中搅拌混合物45分钟。用CeliteTM过滤溶液并蒸发。将得到的透明油状物通过制备薄层色谱法，以5％乙酸乙酯的己烷溶液洗提来提纯。然后，将得到的油状物通过硅胶上的柱色谱法，以5-10％乙酸乙酯的己烷溶液洗提进行进一步提纯以得到产物。
1H NMR(CDCl3)7.37-7.34(4H，m)，7.08-7.00(2H，m)，6.85-6.81(1H，m)，3.67(3H，s)，2.45-2.39(4H，m)，2.33(2H，t，J＝8.4Hz)，1.81(2H，q，J＝8.4Hz)，1.72-1.68(2H，m)和1.60-1.43(3H，m).
实施例39
Figure A0281632500292
将实施例8得到的酯(104毫克，0.23毫摩尔)溶于乙醇(10毫升)和水(3毫升)的混合物中并在20℃下搅拌。将烧瓶脱气，然后加入氢氧化锂(27毫克，1.15毫摩尔)。在室温下搅拌混合物3小时。然后加入1N的盐酸并用乙酸乙酯(2×50毫升)洗涤混合物。用盐水(50毫升)洗涤有机相，干燥(MgSO4)并蒸发。然后通过制备薄层色谱法，以乙酸乙酯洗提来进一步提纯得到的油状物，得到酸。
1H NMR(CDCl3)7.37-7.30(4H，m)，7.09-6.99(2H，m)，6.85-6.79(1H，m)，2.42-2.36(6H，m)，1.85-1.79(2H，m)，1.73-1.69(2H，m)，1.63-1.58(1H，m)和1.53-1.45(2H，m).
实施例40
Figure A0281632500301
将实施例39得到的酸(52毫克，0.118毫摩尔)在二氯甲烷(2毫升)中的溶液用草酰氯(88微升，2M的二氯甲烷溶液，0.176毫摩尔)处理。加入1滴N，N-二甲基甲酰胺并使溶液搅拌2小时。这段时间之后，在真空下除去溶剂并将残余物重新溶于二氯甲烷(1毫升)中。将溶液滴加入甲醇氨(2M，2毫升)中。使反应物在真空中蒸发，将残余物用80％乙酸乙酯的己烷溶液洗提通过硅胶色谱。将得到的物质用制备薄层色谱法，以100％乙酸乙酯洗提并随后从己烷中重结晶进一步提纯，得到产物(7.4毫克，14％)。
1H NMR(360MHz，CDCl3)，1.45-1.53(2H，m)，1.57-1.65(1H，br)，1.70-1.75(2H，m)，1.78-1.84(2H，m)，2.32(2H，t，J＝15.3Hz)，2.38-2.44(4H，br)，2.95(3H，s)，3.02(3H，s)，6.79-6.86(1H，m)，7.00-7.09(2H，m)，7.31-7.37(4H，m)；ms.(ES+)，470(M+1)，294(M+175).
实施例41
Figure A0281632500302
将实施例1中得到的顺式酯(669毫克，1.467毫摩尔)在四氢呋喃(14毫升)中的溶液冷却至-78℃，用二(三甲基甲硅烷基)氨基化钠(2.20毫升，1M的四氢呋喃溶液，2.20毫摩尔)处理并搅拌，同时经过2小时升温至室温。然后，在-20℃下向混合物中加入碘甲烷(457微升，7.36毫摩尔)，继续搅拌，再次用2小时升温至室温。用冰醋酸(132微升，2.20毫摩尔)淬灭反应，用氯化铵溶液(50％水溶液，80毫升)稀释并用乙酸乙酯(3×100毫升)萃取。然后，用盐水(饱和的，200毫升)洗涤合并的有机相，干燥(MgSO4)并在真空中蒸发得到粗品(670毫克)。将该物质用8％乙酸乙酯的己烷溶液洗提在硅胶上进行色谱层析得到产物(272毫克，40％)。
1H NMR(400MHz，CDCl3)，1.16(3H，d，J＝6.9Hz)，1.28(3H，t，J＝7.1Hz)，1.45-1.51(2H，m)，1.71-1.77(2H，m)，1.89-1.94(1H，m)，2.28-2.48(3H，br)，2.54-2.60(1H，br)，2.70-2.74(1H，m)，4.09-4.18(2H，m)，6.77-6.84(1H，m)，6.99-7.08(2H，m)，7.26-7.36(4H，m).
实施例42
按照制备4和实施例1和2的方法从制备3得到的酮进行制备。
1H NMR(360MHz，CDCl3)1.52-1.61(2H，m)，1.76-1.81(2H，m)，2.20-2.26(1H，m)，2.39(2H，d，J＝7.6Hz)，2.40-2.50(4H，m)，5.37(1H，br)，5.51(1H，br)，6.75-6.83(1H，m)，7.01-7.08(2H，m)，7.51(2H，d，J＝8.3Hz)和7.64(2H，d，J＝8.3Hz).
实施例43
Figure A0281632500321
按照实施例35的方法，在第二步中采用氨，从实施例42的酸进行制备。MS MH+462(463)。
实施例44
按照制备5-8和实施例34，37，38和39的方法从制备3的酮进行制备。
1H NMR(360MHz，CDCl3)δ10.1(1H，m)，7.64(2H，d，J＝8.3Hz)，7.53(2H，d，J＝8.3Hz)，7.09-7.00(2H，m)，6.83-6.76(1H，m)，2.50-2.37(6H，m)，1.85-1.81(2H，q，J＝7.4Hz)，1.75-1.70(2H，m)，1.63-1.59)(1H，m)，1.55-1.45(2H，m).
MS(EI+)477(MH+).

Claims (14)

1.式I的化合物或其药物可接受的盐
其中：
m是0或1；
Z代表CN，OR2a，CO2R2a或CON(R2a)2；
R1b代表H，C1-4烷基或OH；
R1C代表H或C1-4烷基；
Ar1代表苯基或吡啶基，二者中的任何一个均带有0-3个取代基，所述取代基独立地选自卤素，CN，NO2，CF3，OH，OCF3，C1-4烷氧基或C1-4烷基，其任选地带有选自卤素，CN，NO2，CF3，OH和C1-4烷氧基的取代基；
Ar2代表2-和5-位上被卤素取代的苯基；
R2a代表H，C1-6烷基，C3-6环烷基，C3-6环烷基C1-6烷基，C2-6链烯基，其中的任何一个任选带有选自卤素，CN，NO2，CF3，OR2b，CO2R2b，N((R2b)2，CON(R2b)2，Ar和COAr的取代基；或者R2a代表Ar；或者两个R2a基团和它们共同连接的氮原子一起形成一个N-杂环基团，其带有0-4个独立地选自＝0，＝S，卤素，C1-4烷基，CN，NO2，CF3，OH，C1-4烷氧基，C1-4烷氧基羰基，CO2H，氨基，C1-4烷基氨基，二(C1-4烷基)氨基，氨基甲酰基，Ar和COAr的取代基；
R2b代表H，C1-6烷基，C3-6环烷基，C3-6环烷基C1-6烷基，C2-6链烯基，其中任何一个任选带有选自卤素，CN，NO2，CF3，OH，C1-4烷氧基，C1-4烷氧基羰基，CO2H，氨基，C1-4烷基氨基，二(C1-4烷基)氨基，氨基甲酰基，Ar和COAr的取代基；或者R2b代表Ar；或者两个R2b基团与它们共同连接氮原子一起形成一个N-杂环基团，其带有0-4个独立地选自＝O，＝S，卤素，C1-4烷基，CN，NO2，CF3，OH，C1-4烷氧基，C1-4烷氧基羰基，CO2H，氨基，C1-4烷基氨基，二(C1-4烷基)氨基，氨基甲酰基，Ar和COAr的取代基；
Ar代表苯基或杂芳基，其带有0-3个选自卤素，C1-4烷基，CN，NO2，CF3，OH，C1-4烷氧基，C1-4烷氧基羰基，氨基，C1-4烷基氨基，二(C1-4烷基)氨基，氨基甲酰基，C1-4烷基氨基甲酰基和二(C1-4烷基)氨基甲酰基的取代基。
2.权利要求1的化合物，其中Ar1选自在4-位上被卤素、甲基或三氟甲基取代的苯基，和在3-和4-位上被卤素取代的苯基。
3.权利要求1或2的化合物，其中Ar1是4-氯苯基或4-三氟甲基苯基，Ar2是2，5-二氟苯基。
4.权利要求1-3中任意一项的化合物，其中Z代表CO2R2a且R2a代表H或C1-6烷基。
5.权利要求1的化合物或其药物可接受盐，其中m是1，Ar1代表4-氯苯基，Ar2代表2，5-二氟苯基，R1b和R1C都代表H，且Z代表CO2H。
6.权利要求1的化合物或其药物可接受盐，其中m是1，Ar1代表4-三氟甲基苯基，Ar2代表2，5-二氟苯基，R1b和R1C都代表H，且Z代表CO2H。
7.权利要求1的化合物或其药物可接受盐，其中m是0，Ar1代表4-氯苯基，Ar2代表2，5-二氟苯基，R1C代表H及Z代表CONH2。
8.权利要求1的化合物或其药物可接受盐，其中m是0，Ar1代表4-三氟甲基苯基，Ar2代表2，5-二氟苯基，R1C代表H及Z代表CONH2。
9.权利要求1的化合物或其药物可接受盐，其中m是0，Ar1代表4-氯苯基，Ar2代表2，5-二氟苯基，R1C代表H及Z代表CONHCH2CH3。
10.权利要求1的化合物或其药物可接受盐，其中m是0，Ar1代表4-氯苯基，Ar2代表2，5-二氟苯基，R1C代表H及Z代表CN。
11.包含权利要求1-10中任意一项的化合物或其药物可接受盐以及药物可接受载体的药物组合物。
12.权利要求1-10任意一项的化合物或其药物可接受盐在人体治疗方法中的应用。
13.权利要求1-10任意一项的化合物或其药物可接受盐在制造用于治疗或预防阿尔茨海默病的药物中的应用。
14.患有或易患阿尔茨海默病的患者的治疗方法，该方法包含使患者服用有效量的权利要求1定义的式I化合物或其药物可接受盐。
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