CN110404073A - 治疗乙型肝炎病毒感染的方法和药物组合物 - Google Patents
治疗乙型肝炎病毒感染的方法和药物组合物 Download PDFInfo
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- CN110404073A CN110404073A CN201910760011.2A CN201910760011A CN110404073A CN 110404073 A CN110404073 A CN 110404073A CN 201910760011 A CN201910760011 A CN 201910760011A CN 110404073 A CN110404073 A CN 110404073A
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- benzimidazole
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- carboxylic acid
- acetamide
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Abstract
本发明涉及治疗乙型肝炎病毒感染的方法和药物组合物。具体地,本发明涉及类法尼醇X受体(FXR)激动剂,其用于治疗有此需要的个体的乙型肝炎病毒感染的方法中。
Description
本申请是2014年09月10日提交的发明名称为“治疗乙型肝炎病毒感染的方法和药物组合物”的第201480059747.2号中国专利申请的分案申请。
发明领域
本发明涉及治疗乙型肝炎病毒感染的方法和药物组合物。
发明背景
HBV是包膜病毒,其含有3.2-kb的具有4个开放阅读框的部分双链DNA基因组。这些开放阅读框编码逆转录酶、前核心蛋白和核心蛋白;3个表面抗原蛋白(前-S1、前-S2和S);以及X蛋白。HBV转录的调控处在4个启动子(核心蛋白、前-S1、前-S2/S和X启动子)和两个增强子区(EN1和EN2)的控制下。HBV命名为A至H的8个具有一些位置分布的基因型已经确定。该病毒不引起细胞病变,并具有病毒特异性细胞免疫力作为暴露于HBV的结果的主要决定因素—6个月分辨出肝病的急性感染,或通常与进行性肝损伤有关的慢性HBV感染。通过常规的诊断性免疫分析检测血清中的HBsAg(其是HBV感染的关键性诊断标记物),且超过6个月持续检测到血清中的HBsAg是慢性HBV感染的标志。临床上明显的HBV复制的最佳标记物是血清中的HBV DNA水平,其由基于灵敏聚合酶链式反应(PCR)的分析来检测。全球超过3亿5千万人被HBV慢性感染,因而具有发展为严重肝病的风险—如慢性肝炎、肝硬化、肝衰竭和肝细胞癌(HCC)。
治疗慢性乙型肝炎(CHB)的主要目标是长期抑制HBV复制并防止或改善肝病。目前可用于治疗CHB感染的有7种药物—常规干扰素、聚乙二醇化的干扰素和直接抗病毒剂。直接抗病毒剂(核苷类似物/核苷酸类似物)属于三类:L-核苷(拉米夫定、替比夫定和恩曲他滨);脱氧鸟苷类似物(恩替卡韦)和核苷磷酸酯(阿德福韦和替诺福韦),其主要作为链终止子来直接干扰HBV DNA复制。干扰素治疗的关键性限制为:副作用大、HBV DNA抑制率低和ALT标准化率低;直接抗病毒剂治疗的关键性限制为:发展出抗性;停止要求延长的终生治疗后HBV复制反弹、HBsAg清除率极低、延长的终生治疗带来增加的不良事件风险。重要的是,当前的直接抗病毒剂抑制前基因组病毒RNA逆转录为基因组DNA。因而它们在病毒cccDNA形成(进入肝细胞后形成)的下游发挥作用。cccDNA位于细胞核中作为转录为病毒mRNA的另外的微型染色体,并在肝细胞分裂时传递至子细胞中。当前的直接抗病毒剂对HBVcccDNA库和病毒基因的表达没有作用或作用极小。因此,当前可用的治疗为次优方案并伴有严重的副作用。因而,存在对满足HBV感染尤其是CHB感染的治疗目标的更好治疗的需要。间接作用的抗病毒剂(IAD)除了干扰素外,作为极具前景的抗病毒剂替代性药物类型而出现。阻止细胞蛋白与病毒蛋白相互作用的小分子已成功研制出来,以阻止HIV进入和HCV复制。病毒进入和先天免疫力是用于确定新治疗靶标的待筛选的明显细胞功能。但是,不同于HIV和HCV,我们对HBV用来在肝细胞中复制的具体细胞功能了解还很有限,需要系统性筛选来确定这些主要的宿主因素,以增加有效治疗靶标和分子的多样性。因此,主要目标是确定这些功能以通过对于抗性具有高障碍的更加安全和广谱的分子来阻止其作用和/或病毒干扰。
最近的数据有力地表明,类法尼醇(farnesoid)X受体(FXR),作为核受体超家族成员,涉及HBV核心启动子活性的调节,且胆酸可在HBV感染的自然历程中发挥重要作用(Ramière C,Scholtès C,Diaz O,Icard V,Perrin-Cocon L,Trabaud MA,Lotteau V,AndréP.Transactivation of the hepatitis B virus core promoter by the nuclearreceptor FXRalpha.Journal of Virology,2008;82:10832–10840)。具体而言,是在具有各种HBV感染载体的Huh-7细胞系中感染的特定细胞模型中,数据显示FXRα激动剂增加病毒复制,而FXRα的拮抗剂可代表能够用于通过抑制HBV复制来治疗HBV感染的新化合物类型。
发明概述
本发明提供治疗患有乙型肝炎病毒感染的患者的新方法。具体而言,本发明由所附的权利要求书来限定。
发明详述
本发明涉及类法尼醇X受体(FXR)激动剂,其用于治疗有此需要的个体的乙型肝炎病毒感染的方法中。
如本文所用,“感染乙型肝炎病毒的患者”是指感染任何乙型肝炎病毒基因型,例如,基因型A、基因型B、基因型C、基因型D等的患者。
根据本发明,术语“个体”或“患者”和“有此需要的个体”或“有此需要的患者”是指感染或很可能感染乙型肝炎病毒的人或非人的哺乳动物。在一些实施方案中,所述个体患有慢性HBV感染。
如本文所用,术语“治疗(treatment/treat)”是指预防的治疗或预防性治疗以及治愈性治疗或疾病调理治疗,包括治疗有感染该疾病的风险或怀疑已感染该疾病的患者,以及已发病的患者或已被诊断为患有疾病或处于医疗病况下的患者,并且包括抑制临床的疾病复发。该治疗可施用于具有医疗病症或最终患有该病症的个体,以便防止病症、治愈病症、延迟病症发作、降低其严重性或缓解病症的一种或多种症状或病症复发,或者以便延长个体的存活以超过无该治疗下的预期存活。“治疗方案”是指治疗疾病的方式,例如,HBV治疗期间采用的给药方式。治疗方案可包括诱导方案和维持方案。词语“诱导方案”或“诱导期”是指用于疾病的最初治疗的治疗方案(或部分治疗方案)。诱导方案的总目标是在治疗方案初始期为患者提供高的药物水平。诱导方案可(部分或全部)采用“加载方案”,其可包括施用大于医生在维持方案期间所采用的剂量的药物,施用大于医生在维持方案期间所采用的频率的药物,或二者。词语“维持方案”或“维持期”是指治疗疾病期间用于维持患者的治疗方案(或部分治疗方案),例如,使得患者长期(数月或数年)保持缓解。维持方案可采用连续治疗(例如,按规则的间隔给药,如,每周、每月、每年等)或间歇治疗(例如,中断的治疗、间歇的治疗、复发期治疗或达到具体的预期标准(如疼痛、疾病表现等)的治疗。
治疗方案的功效可采用标准方法来检测。治疗后可测定血清的HBV水平和测量血清的ALT水平。例如,可评估患者血清中HBV DNA的存在。可在治疗期间按规则的间隔测量HBV DNA(IU/mL),例如,第1天(给药前以及给药后4、8和12小时),以及(如合适)第2天、第3天、第8天、第15天、第29天和第12周、第24周、第36周、第48周、第72周的给药前,以及随后的测量。因此,治疗的功效可采用国际上接受的参数来检测:a)基于PCR的灵敏定量分析来检测血清HBV DNA水平以评估对病毒复制的作用;b)对于HBeAg-阳性患者—HbeAg与相应的抗-HBe一起检测以测定是否发生了HBe-血清转化;c)检测ALT和/或AST的血清水平以评估对肝炎和肝细胞死亡的影响;以及d)与相应的抗-HBs一起定性和定量地检测血清HBsAg,以测定是否发生了HBs-血清转化,因为HBsAg清除和血清转化将表明最佳的治疗结果。最后,即便并非真实的临床常规实践,可通过特定的PCR来评估cccDNA持续性,以定量肝脏活体检查中的病毒微型染色体。
术语“FXR”是指类法尼醇X受体,其是由超生理水平的法尼醇激活的核受体(Forman等,Cell,1995,81,687-693)。FXR也称为NR1H4,维甲酸X受体-相互作用蛋白14(RIP14)和胆酸受体(BAR)。含有保守的DNA结合结构域(DBD)和C端配体结合结构域,FXR与众多天然发生的胆酸(BA)(包括初级胆酸鹅脱氧胆酸(CDCA)及其牛磺酸和甘氨酸缀合物)结合并被激活(Makishima等,1999;Parks等,1999;Wang等,1999)。一旦激活,FXR-RXR异二聚体结合靶基因的启动子区,并调节涉及胆酸体内平衡的几个基因的表达。肝脏FXR靶基因分为两大组(Edwards PA.等,2002,Kapadia SB.等,2005)。第一组的作用是通过增加输出和降低其合成来降低肝脏的胆酸浓度。第二组FXR靶基因,如磷脂运输蛋白PLTP和载脂蛋白,调节血清中的脂蛋白水平,并降低血浆中甘油三酯的浓度。FXR调节的基因详细情况参见例如,WO 03/016288第22-23页。美国专利第6,005,086号公开了编码哺乳动物FXR蛋白的核酸序列。人的FXR多肽序列以登录号NM_005123、Q96RI1、NP_005114、AAM53551、AAM53550、AAK60271保存于核苷酸和蛋白数据库。
在本说明书中,术语“FXR激动剂”具有本领域的通用含义,并具体指通过靶向和选择性结合类法尼醇X受体(FXR)起作用的化合物,在Maloney等人描述的分析中其通过超过背景至少40%来激活FXR(J.Med.Chem.2000,43:2971-2974)。
在一些实施方案中,本发明的所述FXR激动剂是选择性FXR激动剂。如本文所用,术语“选择性FXR激动剂”是指针对选自以下一组核受体中的一个或多个,理想地基本上全部,没有表现出明显的交叉反应的FXR激动剂:LXRα、LXRβ、PPARα、PPARγ、PPARδ、RXRα、RARγ、VDR、SXR、ERα、ERβ、GR、AR、MR和PR。确定明显的交叉反应的方法描述于J.Med.Chem.2009,52,904-907。
FXR激动剂为本领域技术人员所熟知。例如本领域技术人员很容易从以下出版物中确定FXR激动剂:
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通常FXR激动剂包括类固醇FXR激动剂和非类固醇FXR激动剂两类。
在本发明的某些实施方案中,所述FXR激动剂选自作为FXR调节剂且已经在以下出版物中公开的小分子化合物:
EP1392714;
EP1568706;
EP2128158;
EP2289883;
JP2005281155;
US20030203939;
US2005080064;
US2006128764;
US20070010562;
US20070015796;
US20080038435;
US20080300235;
US20090062526;
US20090163552;
US20100093818;
US20100184809;
US20110077273;
US20110105475;
US6984560;
US7671085;
WO2000037077;
WO200040965;
WO200076523;
WO2001017994;
WO2003015771;
WO2003016280;
WO2003016288;
WO2003030612;
WO2003060078;
WO2003080803;
WO2003090745;
WO2004007521;
WO2004046162;
WO2004048349;
WO2005082925;
WO2005092328;
WO2005097097;
WO2006020680;
WO2007076260;
WO2007076260;
WO2007092751;
WO2007140174;
WO2007140183;
WO2008000643;
WO2008002573;
WO2008025539;
WO2008025540;
WO2008051942;
WO2008073825;
WO2008157270;
WO2009005998;
WO2009012125;
WO2009027264;
WO2009062874;
WO2009080555;
WO2009127321;
WO2009149795;
WO2010028981;
WO2010034649,
WO2010034657;
WO2010069604;
WO2011020615;
WO2013007387;
和WO2013037482。
FXR激动剂的具体实例包括但不限于:GW4064(其公开于PCT公开WO 00/37077或US2007/0015796)、6-乙基-鹅脱氧胆酸(6ECDCA),尤其是3α,7α-二羟基7α-二羟基-6α-乙基-5β-胆烷-24-酸,也称为INT-747;6-乙基-熊脱氧胆酸、INT-1103、UPF-987、WAY-362450、MFA-1、GW9662、T0901317、Fexaramine、胆酸、脱氧胆酸、甘氨胆酸、甘氨脱氧胆酸、牛磺胆酸、牛磺双氢褐霉素(taurodihydrofusidate)、牛磺脱氧胆酸、胆酸盐、甘氨胆酸盐、脱氧胆酸盐、牛磺胆酸盐、牛磺脱氧胆酸盐、鹅脱氧胆酸、7-B-甲基胆酸、甲基石胆酸。
在一些实施方案中,所述FXR激动剂不是选自天然胆酸,优选鹅脱氧胆酸[CDCA]或者牛磺酸-或甘氨酸-缀合的CDCA[牛磺-CDCA或甘氨-CDCA],以及天然胆酸的合成衍生物,优选6-乙基-CDCA或者牛磺酸-或甘氨酸-缀合的6-乙基-CDCA,天然非甾类激动剂,优选二萜类,如咖啡醇和咖啡白脂或合成的非甾类FXR激动剂。
在一些实施方案中,所述FXR激动剂选自:GW4064、6ECDCA以及由CAS登录号1192171-69-9确定的化合物(描述于WO 2009127321,也称为PXL007):
在一些实施方案中,所述FXR激动剂是具有下式的化合物:
在一些实施方案中,所述FXR激动剂是具有下式的化合物:
在一些实施方案中,所述FXR激动剂是具有下式的化合物:
在一些实施方案中,所述FXR激动剂选自:
在一些实施方案中,所述FXR激动剂选自WO2013007387中公开的化合物,即:
在一些实施方案中,所述FXR激动剂选自WO2011020615中公开的化合物,即:
3-(2-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)环丙基)苯甲酸
(-)-3-(2-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)环丙基)苯甲酸
(+)-3-(2-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)环丙基)苯甲酸
3-(2-(2-氯-4-((3-(2,6-二氯苯基)-5-异丙基异噁唑-4-基)甲氧基)苯基)环丙基)苯甲酸
3-(2-(2-氯-4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)苯基)环丙基)苯甲酸
4-(4-((4-(2-(3-羧基苯基)环丙基)-3-氯苯氧基)甲基)-5-环丙基异噁唑-3-基)-3,5-二氯吡啶1-氧化物
3-(2-(2-氯-4-((1-(2,6-二氯苯基)-4-异丙基-1H-1,2,3-三唑-5-基)甲氧基)苯基)环丙基)苯甲酸
4-((4-(2-(6-(1/-/-四唑-5-基)吡啶-3-基)环丙基)-3-氯苯氧基)甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑
5-(2-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)环丙基)吡啶甲酸
4-(2-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)环丙基)苯甲酸
1,3-二羟基-2-(羟基甲基)丙-2-胺4-(2-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)环丙基)苯甲酸酯
(+)-4-(2-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)环丙基)苯甲酸
(-)-4-(2-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)环丙基)苯甲酸
6-(2-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)环丙基)-1-甲基-1H-吲唑-3-羧酸
(+)-6-(2-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)环丙基)-1-甲基-1H-吲唑-3-羧酸
(-)-6-(2-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)环丙基)-1-甲基-1H-吲唑-3-羧酸
4-(2-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)环丙基)-N-(甲磺酰)苯甲酰胺
2-(4-(2-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)环丙基)苯甲酰胺基)乙磺酸
4-((4-(2-(4-(1H-四唑-5-基)苯基)环丙基)-3-氯苯氧基)甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑
4-(2-(2-氯-4-((3-(2,6-二氯苯基)-5-(2-羟基丙-2-基)异噁唑-4-基)甲氧基)苯基)环丙基)苯甲酸
5-(2-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)环丙基)-1-异丙基-1H-吡唑-3-羧酸
6-(2-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)环丙基)-1-异丙基-1H-吲唑-3-羧酸
4-(2-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)环丙基)-2,6-二甲基苯甲酸
4-(2-(2-氯-4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)苯基)环丙基)苯甲酸
(+)-2-(4-(2-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)环丙基)苯甲酰胺基)乙磺酸
2-(4-(2-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)环丙基)苯甲酰胺基)乙酸
以及4-(2-(2-氯-4-((4-(2,6-二氯苯基)-1-异丙基-1H-1,2,3-三唑-5-基)甲氧基)苯基)环丙基)苯甲酸。
在一些实施方案中,所述FXR激动剂选自WO2009149795中公开的化合物,即:
在一些实施方案中,所述FXR激动剂选自WO2008025539中公开的化合物,即:
在一些实施方案中,所述FXR激动剂选自WO2008025540中公开的化合物,即:
在一些实施方案中,所述FXR激动剂选自WO2009127321中公开的化合物,即:
4-(4-溴-2-乙氧羰基-苯并呋喃-5-基)-哌嗪-1-羧酸叔丁酯
4-(4-溴-2-羧基-苯并呋喃-5-基)-哌嗪-1-羧酸叔丁酯
-4-(2-羧基-苯并呋喃-5-基)-哌嗪-1-羧酸叔丁酯
5-[4-(3-甲氧基-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸酰胺
5-[4-(4-甲氧基-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸酰胺
-4-(2-乙氧羰基-苯并呋喃-5-基)-哌嗪-1-羧酸叔丁酯
5-[4-(3-三氟甲基-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸酰胺
-5-[4-(3-氯-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸酰胺
-5-[4-(3-氟-苯甲酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸酰胺
-4-溴-5-[4-(4-甲氧基-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸酰胺-5-(4-苯磺酰基-哌嗪-1-基)-苯并呋喃-2-羧酸
-4-溴-5-[4-(3-氟-苯甲酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(3-氯-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(3-氟-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(吡咯烷-1-羰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(3-氯-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-(2-羧基-苯并呋喃-5-基氨基)-哌啶-1-羧酸叔丁酯
-2-[4-(4-溴-2-羧基-苯并呋喃-5-基)-哌嗪-1-羰基]-吡咯烷-1-羧酸叔丁酯
-4-(4-氯-2-乙氧羰基-苯并呋喃-5-基)-哌嗪-1-羧酸叔丁酯
-4-(2-羧基-4-氯-苯并呋喃-5-基)-哌嗪-1-羧酸叔丁酯
-5-(4-苄基-哌嗪-1-基)-苯并呋喃-2-羧酸
-4-溴-5-[4-(3-三氟甲基-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-5-[4-(3-甲氧基-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(3-甲氧基-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(4-甲氧基-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(吡咯烷-2-羰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-5-[4-(金刚烷-1-羰基)-哌嗪-1-基]-4-溴-苯并呋喃-2-羧酸
-4-溴-5-[4-(3-氯-苯甲酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(2-氟-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(3-氟-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-5-(4-苯甲酰基-哌嗪-1-基)-4-溴-苯并呋喃-2-羧酸
-4-溴-5-[4-(3-三氟甲基-苄氧基)-哌啶-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(3-氯-苄氧基)-哌啶-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(2-氯-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(4-氯-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(4-氟-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(2-氯-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(4-氯-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(吡啶-2-基氧基)-哌啶-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(3-三氟甲基-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸酰胺
-5-[4-(3-三氟甲氧基-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸酰胺
-4-溴-5-[4-(3-三氟甲氧基-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸酰胺
-4-溴-5-[4-(3-氰基-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-(4-叔丁基氨甲酰基-哌嗪-1-基)-苯并呋喃-2-羧酸
-4-溴-5-[4-(3-氟-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸酰胺
-4-溴-5-[4-(3,5-二氯-苯甲酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸酰胺
-4-溴-5-[4-(3,5-二氟-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸酰胺
-4-溴-5-(4-吡啶-3-基甲基-哌嗪-1-基)-苯并呋喃-2-羧酸
-4-溴-5-(4-吡啶-4-基甲基-哌嗪-1-基)-苯并呋喃-2-羧酸
-4-溴-5-[4-(3-三氟甲氧基-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(3-苯氧基-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(3,5-二甲氧基-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-5-[4-(3-烯丙基-2-羟基-苄基)-哌嗪-1-基]-4-溴-苯并呋喃-2-羧酸-5-(4-苯磺酰基-哌嗪-1-基)-4-溴-苯并呋喃-2-羧酸
-4-溴-5-(4-叔丁基氨甲酰基-哌啶-1-基)-苯并呋喃-2-羧酸
-4-氯-5-[4-(2-氯-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(3-氯-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(4-氯-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(2-氟-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(3-氟-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(4-氟-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(3-三氟甲基-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(3-三氟甲氧基-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-5-[4-(3-羰基-苄基)-哌嗪-1-基]-4-氯-苯并呋喃-2-羧酸
-4-氯-5-(4-吡啶-3-基甲基-哌嗪-1-基)-苯并呋喃-2-羧酸
-4-氯-5-[4-(2-氯-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(3-氯-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(4-氯-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(4-甲氧基-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(3-甲氧基-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(3-氟-苯甲酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(3,5-二氯-苯甲酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(3-氟-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(3-氰基-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(2-氯-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸酰胺
-4-溴-5-[4-(3-氟-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸乙氧基酰胺
-4-溴-5-[4-(3-三氟甲基-苯甲酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(3-三氟甲氧基-苯甲酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(3-甲氧基-苯甲酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(2,5-二氯-苯甲酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(3,5-二氯-苯甲酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(2-甲基-1H-苯并咪唑-4-羰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(5-三氟甲基-吡啶-2-基氧基)-哌啶-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(3-氯-苯甲酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(2,5-二氯-苯甲酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸-4-氯-5-[4-(3-甲氧基-苯甲酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(3-三氟甲基-苯甲酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(3-三氟甲氧基-苯甲酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(2-甲基-1H-苯并咪唑-4-羰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-5-[4-(1H-苯并咪唑-5-羰基)-哌嗪-1-基]-4-氯-苯并呋喃-2-羧酸
-4-氯-5-[4-(2,5-二氯-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(3,5-二甲氧基-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸-4-氯-5-[4-(3-氯-苯基甲磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-5-[4-(2-氯-苯磺酰基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-羧酸
-5-[4-(3-氟-苯磺酰基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-羧酸
-4-(2-羰基-4-甲基-苯并呋喃-5-基)-哌嗪-1-羧酸叔丁酯
-4-(2-羰基-4-氯-苯并呋喃-5-基)-[1,4]二氮杂环庚烷-1-羧酸叔丁酯
-4-(4-溴-2-羰基-苯并呋喃-5-基)-[1,4]二氮杂环庚烷-1-羧酸叔丁酯
-4-溴-5-[4-(2-氯-苯磺酰基)-[1,4]二氮杂环庚烷-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(2-氯-苯磺酰基)-[1,4]二氮杂环庚烷-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(5-三氟甲基-吡啶-2-基氧基)-哌啶-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[1-(3-氯-苯磺酰基)-哌啶-4-基氨基]-苯并呋喃-2-羧酸
-{4-溴-5-[4-(2-氯-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-基}-吗啉-4-基-甲酮
-4-溴-5-[4-(2-氯-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸(2-甲氧基-乙基)-酰胺
-4-溴-5-[4-(2,5-二氯-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(2,5-二氯-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-5-[4-(1H-苯并咪唑-5-羰基)-哌嗪-1-基]-4-溴-苯并呋喃-2-羧酸
-4-溴-5-[4-(2,6-二氯-苯甲酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-5-[4-(2,6-二氯-苯甲酰基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-羧酸
-5-[4-(2,5-二氯-苯甲酰基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-羧酸
-4-甲基-5-[4-(3-三氟甲氧基-苯甲酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-5-[4-(2-氯-苄基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-羧酸
-5-[4-(3-氯-苄基)-哌嗪-1-基H-甲基-苯并呋喃-羧酸
-5-[4-(2,5-二氯-苄基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-羧酸
-5-[4-(3-氟-苄基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-羧酸
-4-甲基-5-[4-(3-三氟甲基-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-甲基-5-[4-(3-三氟甲氧基-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-5-[4-(3-氯-苯磺酰基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-羧酸
-5-[4-(2,5-二氯-苯磺酰基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-羧酸
-5-[4-(3-氯-苯基甲磺酰基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-羧酸
-4-溴-5-[4-(2-氯-6-氟-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(2-氯-6-氟-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(3-氯-苯基甲磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[1-(3-氯-苯磺酰基)-哌啶-4-基氨基]-苯并呋喃-2-羧酸
-4-溴-5-(3,4-二氢-1H-异喹啉-2-基)-苯并呋喃-2-羧酸
-4-溴-5-[4-(3-氯-苯氧基)-哌啶-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(4-三氟甲基-嘧啶-2-基氧基)-哌啶-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(2-氟-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-5-[4-(2-氟-苯磺酰基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-羧酸
-4-溴-5-[4-(2,6-二氯-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-5-[4-(2,6-二氯-苯磺酰基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-羧酸
-4-氯-5-[4-(2,6-二氯-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(2,3-二氯-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-5-[4-(2,3-二氯-苯磺酰基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-羧酸
-4-氯-5-[4-(2,3-二氯-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(2,5-二氯-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(2,3-二氯-苯甲酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-甲基-5-[4-(3-三氟甲基-苯甲酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-甲基-5-[4-(2-甲基-1H-苯并咪唑-4-羰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-5-[4-(2-氟-苄基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-羧酸
-5-[4-(2-氯-6-氟-苄基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-羧酸
-5-[4-(2,6-二氯-苄基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-羧酸
-4-溴-5-[4-(3,5-二氯-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-5-[4-(3,5-二氯-苄基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-羧酸
-4-氯-5-[4-(3,5-二氯-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-5-[4-(3-烯丙基-2-羟基-苄基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-羧酸
-5-[4-(2,3-二甲氧基-苄基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-羧酸
-4-溴-5-[4-(5-氯-噻吩-2基甲基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-甲基-5-[4-(5-三氟甲基-吡啶-2-基氧基)-哌啶-1-基]-苯并呋喃-2-羧酸
-4-(2-羰基-4-氰基-苯并呋喃-5-基)-哌嗪-1-羧酸叔丁酯
-4-溴-5-[4-(4-氯-苯氧基)-哌啶-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(3-乙氧基-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(2-氯-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸苯甲酰胺
-5-(4-苯并[1,3]二氧杂环戊烯-4-基甲基-哌嗪-1-基)-4-溴-苯并呋喃-2-羧酸
-4-溴-5-[4-(2,6-二氯-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(2,4-二氯-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-5-[4-(2-烯丙氧基-苄基)-哌嗪-1-基]-4-溴-苯并呋喃-2-羧酸
-4-溴-5-[4-(3-三氟甲基-苯氧基)-哌啶-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(4-三氟甲基-苯氧基)-哌啶-1-基]-苯并呋喃-2-羧酸
-4-溴-5-{4-[环丙烷羰基-(2,4-二氯-苯基)-氨基]-哌啶-1-基}-苯并呋喃-2-羧酸
-4-溴-5-{4-[(4-氯-苄基)-环丙烷羰基-氨基]-哌啶-1-基}-苯并呋喃-2-羧酸
-5-{4-[3-(2,6-二氯-苯基)-5-异丙基-异噁唑-4-羰基]-哌嗪-1-基}-4-甲基-苯并呋喃-2-羧酸
-4-溴-5-[4-(2-三氟甲基-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-5-[4-(3-烯丙氧基-苄基)-哌嗪-1-基]-4-溴-苯并呋喃-2-羧酸
-5-[4-(3-烯丙基-2-甲氧基-苄基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-羧酸
-4-溴-5-[4-(3-叔丁基-2-羟基-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-甲基-5-(4-萘-1-基甲基-哌嗪-1-基)-苯并呋喃-2-羧酸
-4-溴-5-[4-(2-羟基-萘-1-基甲基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(2-三氟甲基-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(3-三氟甲基-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-溴-5-[4-(2,6-二氯-苯磺酰基)-[1,4]二氮杂环庚烷-1-基]-苯并呋喃-2-羧酸
-{4-溴-5-[4-(2,6-二氯-苯磺酰基)-[1,4]二氮杂环庚烷-1-基]-苯并呋喃-2-基}-吗啉-4-基-甲酮
-{4-溴-5-[4-(2,6-二氯-苯磺酰基)-[1,4]二氮杂环庚烷-1-基]-苯并呋喃-2-基}-哌啶-1-基-甲酮
-{5-[4-(3,5-二氯-2-羟基-苯磺酰基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-基}-吗啉-4-基-甲酮
-{4-溴-5-[4-(2-氟-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-基}-吗啉-4-基-甲酮
-{4-溴-5-[4-(2-氯-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-基}-哌啶-1-基-甲酮
-{4-溴-5-[4-(2,6-二氯-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-基}-哌啶-1-基-甲酮
-{4-溴-5-[4-(2,6-二氯-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-基}-吗啉-4-基-甲酮
-4-溴-5-[4-(2,6-二氯-苯甲酰基)-[1,4]二氮杂环庚烷-1-基]-苯并呋喃-2-羧酸
-5-[4-(3-烯丙基-2-羟基-苄基)-[1,4]二氮杂环庚烷-1-基]-4-溴-苯并呋喃-2-羧酸
-5-[4-(3,5-二氯-2-羟基-苄基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-羧酸
-4-甲基-5-[4-(2,3,6-三氯-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-5-[4-(2,3-二氯-苄基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-羧酸
-4-溴-5-{4-[4-溴-5-(4-氟-2-甲氧基-苯基)-3-甲基-吡唑-1-基]-哌啶-1-基}-苯并呋喃-2-羧酸
-4-溴-5-(4-{[(4-氯-苄基)-环丙基甲基-氨基]-甲基}-哌啶-1-基)-苯并呋喃-2-羧酸
-{4-溴-5-[4-(2,6-二氯-苯甲酰基)-[1,4]二氮杂环庚烷-1-基]-苯并呋喃-2-基}-吗啉-4-基-甲酮
-4-氯-5-[4-(2,6-二氯-苯甲酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[1-(2,6-二氯-苯磺酰基)-哌啶-4-基氨基]-苯并呋喃-2-羧酸
-{4-氯-5-[4-(2,3-二氯-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-基}-吗啉-4-基-甲酮
-{4-溴-5-[4-(2,6-二氯-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-基}-(4-甲基-哌嗪-1-基)-甲酮
-4-溴-5-[4-(2,6-二氯-苯磺酰基)-哌嗪-1-基]-苯并呋喃-2-羧酸(2-二甲基氨基-乙基)-酰胺
-4-氯-5-[4-(2-羟基-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-{5-[4-(2,6-二氯-苄基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-基}-吗啉-4-基-甲酮
-4-氯-5-[4-(2,6-二氯-苯磺酰基)-[1,4]二氮杂环庚烷-1-基]-苯并呋喃-2-羧酸
-5-[4-(2,3-二氯-苯磺酰基)-[1,4]二氮杂环庚烷-1-基]-4-甲基-苯并呋喃-2-羧酸
-{5-[4-(2,3-二氯-苯磺酰基)-[1,4]二氮杂环庚烷-1-基]-4-甲基-苯并呋喃-2-基}-吗啉-4-基-甲酮
-4-氯-5-[4-(2,3-二氯-苯磺酰基)-[1,4]二氮杂环庚烷-1-基]-苯并呋喃-2-羧酸
-{4-氯-5-[4-(2,3-二氯-苯磺酰基)-[1,4]二氮杂环庚烷-1-基]-苯并呋喃-2-基}-吗啉-4-基-甲酮
-4-氯-5-[4-(2,5-二氯-苯磺酰基)-[1,4]二氮杂环庚烷-1-基]-苯并呋喃-2-羧酸
-{4-氯-5-[4-(2,5-二氯-苯磺酰基)-[1,4]二氮杂环庚烷-1-基]-苯并呋喃-2-基}-吗啉-4-基-甲酮
-5-[4-(2,5-二氯-苯磺酰基)-[1,4]二氮杂环庚烷-1-基]-4-甲基-苯并呋喃-2-羧酸
-{5-[4-(2,5-二氯-苯磺酰基)-[1,4]二氮杂环庚烷-1-基]-4-甲基-苯并呋喃-2-基}-吗啉-4-基-甲酮
-{4-氯-5-[4-(2,6-二氯-苯磺酰基)-[1,4]二氮杂环庚烷-1-基]-苯并呋喃-2-基}-吗啉-4-基-甲酮
-4-氯-5-[4-(2-氯-6-羟基-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(2-氯-6-甲氧基-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(3-乙氧基-2-羟基-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(2-氯-3-三氟甲基-苄基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-5-{4-[3-(2,6-二氯-苯基)-5-异丙基-异噁唑-4-基甲基]-哌嗪-1-基}-4-甲基-苯并呋喃-2-羧酸
-5-[4-(2,6-二氯-苄基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-羧酸酰胺
-5-[4-(2,6-二氯-苄基)-[1,4]二氮杂环庚烷-1-基]-4-甲基-苯并呋喃-2-羧酸
-{5-[4-(2,6-二氯-苄基)-[1,4]二氮杂环庚烷-1-基]-4-甲基-苯并呋喃-2-基}-(4-甲基-哌嗪-1-基)-甲酮
-{4-溴-5-[4-(2,6-二氯-苯甲酰基)-[1,4]二氮杂环庚烷-1-基]-苯并呋喃-2-基}-哌啶-1-基-甲酮
-4-溴-5-[1-(2,6-二氯-苯甲酰基)-哌啶-4-基氨基]-苯并呋喃-2-羧酸
-4-溴-5-[1-(2,3-二氯-苯甲酰基)-哌啶-4-基氨基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(2,3-二氢-吲哚-1-基)-哌啶-1-基]-苯并呋喃-2-羧酸
-4-[2-(1H-四唑-5-基)-苯并呋喃-5-基]-哌嗪-1-羧酸叔丁酯
-5-(4-二苯甲基-哌嗪-1-基)-4-甲基-苯并呋喃-2-羧酸
-4-溴-5-[4-(2,6-二氯-苯磺酰基氨基)-哌啶-1-基]-苯并呋喃-2-羧酸
-4-氯-5-[4-(2-甲基-5-噻吩-2-基-2H-吡唑-3-基甲基)-哌嗪-1-基]-苯并呋喃-2-羧酸
-5-[(1S,4S)-5-(2,6-二氯-苯磺酰基)-2,5-二氮杂-二环[2.2.1]庚-2-基]-4-甲基-苯并呋喃-2-羧酸
-5-[4-(2,4-二氯-苯基氨甲酰基)-哌啶-1-基]-4-甲基-苯并呋喃-2-羧酸及其立体异构形式、立体异构形式的混合物或药物可接受的其盐形式。
在一些实施方案中,所述FXR激动剂选自WO2008000643中公开的化合物,即:
2,N-二环己基-2-(2-苯基-苯并咪唑-l-基)-乙酰胺氯化氢,
2-[2-(4-氯-苯基)-苯并咪唑-1-基]-4-甲基-戊酸环己酰胺,
4-{1-[环己基-(4-吗啉-4-基-苯基氨甲酰基)-甲基]-1H-苯并咪唑-2-基}-苯甲酸甲酯盐酸盐,
2,N-二环己基-2-[5,6-二氯-2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
2-环己基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-N-异丙基-乙酰胺氯化氢,
2,N-二环己基-2-[2-(4-甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺氯化氢,
2,N-二环己基-2-[2-(3-甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺氯化氢,
2,N-二环己基-2-[2-(2-甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺氯化氢,
2,N-二环己基-2-(2-萘-1-基-苯并咪唑-1-基)-乙酰胺氯化氢,
2,N-二环己基-2-[2-(3-乙氧基-苯基)-苯并咪唑-1-基]-乙酰胺氯化氢,
N-环己基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-4-苯基-丁酰胺,
N-环己基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-3-甲基-丁酰胺氯化氢,
N-环己基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-3-苯基-丙酰胺氯化氢,
N-环己基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-2-吡啶-2-基-乙酰胺氯化氢,
N-环己基-2-环戊基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺氯化氢,
4-{l-[环己基-(环己基氨甲酰基-甲基)]-1H-苯并咪唑-2-基}-苯甲酸甲酯,
2,N-二环己基-2-(2-萘-2-基-苯并咪唑-l-基)-乙酰胺,
2,N-二环己基-2-[2-(3-噻吩-2基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(5-苯基-噻吩-2-基)-苯并咪唑-1-基]-乙酰胺,
3-{1-[环己基-(环己基氨甲酰基-甲基)]-1H-苯并咪唑-2-基}-苯甲酸甲酯,
2-[2-(3-羟基-苯基)-苯并咪唑-1-基]-4-甲基-戊酸环己酰胺,
2-[2-(4-羟基甲基-苯基)-苯并咪唑-1-基]-4-甲基-戊酸环己酰胺,
2-[2-(lH-吲哚-5-基)-苯并咪唑-1-基]-4-甲基-戊酸环己酰胺,
2-[2-(lH-吲哚-6-基)-苯并咪唑-1-基]-4-甲基-戊酸环己酰胺,
2-[2-(4-氨基-苯基)-苯并咪唑-1-基]-4-甲基-戊酸环己酰胺,
2-环己基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-N-((R)1-苯基-乙基)-乙酰胺,
2,N-二环己基-2-[2-(4-羟基甲基-苯基)-苯并咪唑-1-基]-乙酰胺,
N-环己基-2-[2-(2,3-二甲氧基-苯基)-苯并咪唑-1-基]-4-苯基-丁酰胺,
2-[2-(3-氰基-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2,N-二环己基-2-{2-[4-(lH-四唑-5-基)-苯基]-苯并咪唑-l-基}-乙酰胺氯化氢,
3-[1-(苄基氨甲酰基-环戊基-甲基)-1H-苯并咪唑-2-基]-苯甲酸甲酯,
2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-己酸环己酰胺,
2,N-二环己基-2-[2-(3-甲磺酰基-苯基)-苯并咪唑-1-基]-乙酰胺氯化氢,
N-苄基-2-环己基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
2-环己基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-N-(1-甲基-丁基)-乙酰胺,
4-[1-(苄基氨甲酰基-环戊基-甲基)-1H-苯并咪唑-2-基]-苯甲酸甲酯,
N-环戊基-2-[2-(3-甲氧基-苯基)-苯并咪唑-1-基]-4-苯基-丁酰胺氯化氢,
2,N-二环己基-2-[2-(2,4-二甲氧基-苯基)-5-甲基-苯并咪唑-1-基]-乙酰胺氯化氢,
2-[2-(4-氯-苯基)-苯并咪唑-1-基]-2,N-二环戊基-乙酰胺氯化氢,
N-二苯甲基-2-环己基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
N-苄基-2-(2-萘-l-基-苯并咪唑-l-基)-4-苯基-丁酰胺,
2-环己基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-N-(4-甲氧基-苯基)-乙酰胺,
2,N-二环己基-2-[2-(2,4-二甲氧基-苯基)-4-甲基-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-{2-[3-(2-氧代-吡咯烷-l-基)-苯基]-苯并咪唑-1-基}-乙酰胺氯化氢,
2,N-二环己基-2-[2-(2-氧代-l,2-二氢-吡啶-4-基)-苯并咪唑-1-基]-乙酰胺,
N-环戊基-2-[2-(2-甲氧基-苯基)-苯并咪唑-1-基]-4-苯基-丁酰胺,
2-环己基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-N-戊基-乙酰胺,
N-苄基-2-[2-(4-氯-苯基)-苯并咪唑-1-基]-2-环戊基-乙酰胺氯化氢,
2,N-二环戊基-2-(2-萘-1-基-苯并咪唑-1-基)-乙酰胺,
2-[2-(3-氰基-苯基)-苯并咪唑-1-基]-N-环己基-4-苯基-丁酰胺,
2-[2-(4-羟基-苯基)-苯并咪唑-1-基]-4-甲基-戊酸环己酰胺氯化氢,
N-叔丁基-2-环己基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
4-[l-(l-苄基氨甲酰基-3-苯基-丙基)-1H-苯并咪唑-2-基]-苯甲酸甲酯,
4-[l-(l-环己基氨甲酰基-3-苯基-丙基)-1H-苯并咪唑-2-基]-苯甲酸甲酯,
2,N-二环戊基-2-[2-(2-甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(2,4-二甲氧基-苯基)-萘并[2,3-d]咪唑-1-基]-乙酰胺,
2-[2-(2,3-二甲氧基-苯基)-苯并咪唑-1-基]-4-甲基-戊酸环己酰胺,
N-苄基-2-[2-(2-甲氧基-苯基)-苯并咪唑-1-基]-4-苯基-丁酰胺,
2-环己基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-N-(3-异丙氧基-丙基)-乙酰胺,
2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-N-异丙基-4-苯基-丁酰胺,
N-苄基-2-环戊基-2-(2-萘-1-基-苯并咪唑-1-基)-乙酰胺,
2,N-二环己基-2-[2-(2,3-二甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-4-甲基-戊酸环己酰胺,
2-环己基-2-[2-(2,3-二甲氧基-苯基)-苯并咪唑-1-基]-N-异丙基-乙酰胺,
2-[2-(2,3-二甲氧基-苯基)-苯并咪唑-1-基]-N-异丙基-4-苯基-丁酰胺,
2-[2-(4-乙酰基-苯基)-苯并咪唑-1-基]-N-环己基-4-苯基-丁酰胺,
N-苄基-2-[2-(4-氯-苯基)-苯并咪唑-1-基]-4-苯基-丁酰胺氯化氢,
4-[1-(l-异丙基氨甲酰基-戊基)-1H-苯并咪唑-2-基]-苯甲酸甲酯,
N-丁基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-2-苯基-乙酰胺,
2-[2-(2,3-二甲氧基-苯基)-苯并咪唑-1-基]-4-甲基-戊酸异丙基酰胺,
2-苯并[l,3]二氧杂环戊烯-5-基-N-丁基-2-[2-(2,3-二甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
2-苯并[l,3]二氧杂环戊烯-5-基-N-丁基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
N-丁基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-2-(2-氟-苯基)-乙酰胺,
N-环戊基-2-[2-(3-羟基-苯基)-苯并咪唑-1-基]-4-苯基-丁酰胺,
2-[2-(4-乙酰基-苯基)-苯并咪唑-1-基]-己酸异丙基酰胺,
N-丁基-2-[2-(2,3-二甲氧基-苯基)-苯并咪唑-1-基]-2-苯基-乙酰胺,
2-[2-(4-乙酰基-苯基)-苯并咪唑-1-基]-4-甲基-戊酸环己酰胺,
N-丁基-2-[2-(2,3-二甲氧基-苯基)-苯并咪唑-1-基]-2-邻-甲苯基-乙酰胺,
N-丁基-2-[2-(2,3-二甲氧基-苯基)-苯并咪唑-1-基]-2-(4-甲氧基-苯基)-乙酰胺,
N-丁基-2-[2-(2,3-二甲氧基-苯基)-苯并咪唑-1-基]-2-(2-氟-苯基)-乙酰胺,
N-丁基-2-[2-(2,3-二甲氧基-苯基)-苯并咪唑-1-基]-2-(4-二甲基氨基-苯基)-乙酰胺,
2-[2-(2,3-二甲氧基-苯基)-苯并咪唑-1-基]-己酸异丙基酰胺,
4-{1-[(2-氟-苯基)-异丙基氨甲酰基-甲基]-1H-苯并咪唑-2-基}-苯甲酸甲酯,
2-[2-(3-氰基-苯基)-苯并咪唑-1-基]-4-甲基-戊酸环己酰胺,
2-[2-(3-氯-苯基)-苯并咪唑-1-基]-4-甲基-戊酸环己酰胺,
N-丁基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-2-(4-甲氧基-苯基)-乙酰胺,
N-苄基-2-[2-(3-甲氧基-苯基)-苯并咪唑-1-基]-4-苯基-丁酰胺氯化氢,
2-(4-氯-苯基)-2-[2-(2,3-二甲氧基-苯基)-苯并咪唑-1-基]-N-异丙基-乙酰胺,
N-丁基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-2-(4-二甲基氨基-苯基)-乙酰胺,
2-[2-(4-羟基-苯基)-苯并咪唑-1-基]-N-异丙基-4-苯基-丁酰胺,
2-[2-(4-羟基-苯基)-苯并咪唑-1-基]-4-甲基-戊酸环己酰胺,
2-[2-(3-氯-苯基)-苯并咪唑-1-基]-N-异丙基-4-苯基-丁酰胺,
N-丁基-2-(4-氯-苯基)-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
2-[2-(3-氰基-苯基)-苯并咪唑-1-基]-N-异丙基-4-苯基-丁酰胺,
2-[2-(4-乙酰基-苯基)-苯并咪唑-1-基]-N-异丙基-2-(4-甲氧基-苯基)乙酰胺,
4-{1-[异丙基氨甲酰基-(4-甲氧基-苯基)-甲基]-1H-苯并咪唑-2-基}-苯甲酸甲酯,
4-[1-(异丙基氨甲酰基-苯基-甲基)-1H-苯并咪唑-2-基]-苯甲酸甲酯,
N-异丙基-2-[2-(l-甲基-lH-吡咯-2-基)-苯并咪唑-1-基]-4-苯基-丁酰胺,
2-[2-(3-氰基-苯基)-苯并咪唑-1-基]-己酸异丙基酰胺,
2-[2-(4-羟基-苯基)-苯并咪唑-1-基]-戊酸异丙基酰胺,
2-苯并[1,3]二氧杂环戊烯-5-基-N-丁基-2-[2-(1-甲基-1H-吡咯-2-基)-苯并咪唑-1-基]-乙酰胺,
2-环己基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-N-(2,6-二甲基-苯基)-乙酰胺,
2,N-二环己基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
2-环己-3-烯基-N-环己基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
2-[2-(4-氰基-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺氯化氢,
2-环己基-N-环戊基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(2,4-二甲氧基-苯基)-5,6-二氟-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(2,4-二甲氧基-苯基)-6-甲基-苯并咪唑-1-基]-乙酰胺,
2-[2-(4-氯-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2,N-二环己基-2-[2-(4-氨磺酰基-苯基)-苯并咪唑-1-基]-乙酰胺氯化氢,
2-环己基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-N-(1,1,3,3-四甲基-丁基)-乙酰胺,
4-{[1-环戊基-(环戊基氨甲酰基-甲基)]-1H-苯并咪唑-2-基}-苯甲酸甲酯氯化氢,
2,N-二环己基-2-(2-喹啉-6-基-苯并咪唑-1-基)-乙酰胺氯化氢,
2-[2-(4-氨基-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-5-苯基-戊酸环己酰胺氯化氢,
4-[1-(1-环戊基氨甲酰基-3-苯基-丙基)-1H-苯并咪唑-2-基]-苯甲酸甲酯,
2,N-二环己基-2-[2-(4-二甲基氨磺酰基-苯基)-苯并咪唑-1-基]-乙酰胺氯化氢,
2,N-二环己基-2-[2-(3-氨磺酰基-苯基)-苯并咪唑-1-基]-乙酰胺氯化氢,
2,N-二环己基-2-{2-[3-(lH-四唑-5-基)-苯基]-苯并咪唑-l-基}-乙酰胺氯化氢,
2,N-二环己基-2-{2-[4-(lH-咪唑-2-基)-苯基]-苯并咪唑-l-基}-乙酰胺氯化氢,
2,N-二环己基-2-[2-(4-咪唑-1-基-苯基)-苯并咪唑-1-基]-乙酰胺氯化氢,
2,N-二环己基-2-[2-(4-[1,2,4]三唑-4-基-苯基)-苯并咪唑-1-基]-乙酰胺氯化氢,
2,N-二环己基-2-{2-[4-(lH-吡唑-4-基)-苯基]-苯并咪唑-1-基}-乙酰胺氯化氢,
2,N-二环己基-2-[2-(4-[1,2,3]噻二唑-4-基-苯基)-苯并咪唑-1-基]-乙酰胺氯化氢,
2,N-二环己基-2-[2-(l,3-二氧代-2,3-二氢-1H-异吲哚-5-基)-苯并咪唑-1-基]-乙酰胺氯化氢,
2,N-二环己基-2-[2-(3-四唑-l-基-苯基)-苯并咪唑-1-基]-乙酰胺氯化氢,
4-[1-(环己基-3-甲氧基羰基苯基氨甲酰基-甲基)-1H-苯并咪唑-2-基]-苯甲酸甲酯氯化氢,
反式4-(l-{环己基-[(4-甲氧基羰基-环己基甲基)-氨甲酰基]-甲基}-1H-苯并咪唑-2-基)-苯甲酸甲酯氯化氢,
4-{2-环己基-2-[2-(4-甲氧基羰基-苯基)-苯并咪唑-1-基]-乙酰基氨基}-哌啶-1-羧酸乙酯氯化氢,
N-环己基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-2-苯基-乙酰胺氯化氢,
4-(l-{环己基-[3-(2-氧代-吡咯烷-1-基)-丙基氨甲酰基]-甲基}-1H-苯并咪唑-2-基)-苯甲酸甲酯氯化氢,
4-{1-[环己基-(3-甲氧基羰基-丙基氨甲酰基)-甲基]-1H-苯并咪唑-2-基}-苯甲酸甲酯氯化氢,
4-{1-[环己基-(4-甲氧基羰基-丁基氨甲酰基)-甲基]-1H-苯并咪唑-2-基}-苯甲酸甲酯氯化氢,
4-{1-[环己基-(5-甲氧基羰基-戊基氨甲酰基)-甲基]-1H-苯并咪唑-2-基}-苯甲酸甲酯氯化氢,
2-环己基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-N-甲基-乙酰胺氯化氢,
2-[2-(4-乙酰基氨基-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[2-(3-乙酰基氨基-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
4-{1-[环己基-(3-甲酰基氨基-苯基氨甲酰基)-甲基]-1H-苯并咪唑-2-基}-苯甲酸甲酯氯化氢,
N-环戊基-2-(2-萘-1-基-苯并咪唑-1-基)-丙酰胺,
2,N-二环己基-2-(2-苯基-苯并咪唑-l-基)-乙酰胺,
2-[1-(环己基-环己基氨甲酰基-甲基)-1H-苯并咪唑-2-基]-苯甲酰胺,
2-[2-(5-氨基-吡啶-2-基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2,N-二环己基-2-[2-(2-乙基-5-甲基-2H-吡唑-3-基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(5-甲基-异噁唑-4-基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(lH-吡咯-2-基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-(2-呋喃-2-基-苯并咪唑-l-基)-乙酰胺,
2-[6-溴-2-(4-氯-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[6-氯-2-(4-氯-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[2-(4-氯-苯基)-6-甲氧基-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
[6-氯-2-(4-氯-苯基)-5-氟-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
(S)-2,N-二环己基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
(S)-2-[2-(4-氯-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[1-(环己基-环己基氨甲酰基-甲基)-1H-苯并咪唑-2-基]-N-甲基-苯甲酰胺,
2,N-二环己基-2-(2-呋喃-3-基-苯并咪唑-1-基)-乙酰胺,
2,N-二环己基-2-[2-(3-甲基-呋喃-2-基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(3-甲基-异噁唑-5-基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-(2-间-甲苯基-苯并咪唑-1-基)-乙酰胺,
2,N-二环己基-2-[2-(3-氟-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(2-氟-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(3,5-二甲基-异噁唑-4-基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(3-甲基-噻吩-2-基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(4-乙烯基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(2,3-二甲基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(3,4-二甲基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(4-乙基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(2,4-二甲基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(2-乙基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(4-氟-3-甲基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(3-氟-4-甲基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(2,6-二氟-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(3,5-二氟-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(2,5-二氟-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(3,4-二氟-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(2,3-二氟-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(lH-吲哚-4-基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(lH-吲哚-6-基)-苯并咪唑-1-基]-乙酰胺,
2-[2-(5-氯-噻吩-2-基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[2-(4-乙酰基-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[2-(2-乙酰基-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2,N-二环己基-2-[2-(4-异丙基-苯基)-苯并咪唑-1-基]-乙酰胺,
2-[2-(4-氰基-2-氟-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2,N-二环己基-2-[2-(2-二甲基氨基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(3-二甲基氨基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(4-甲氧基-3-甲基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(4-甲氧基-2-甲基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(3-甲氧基-4-甲基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(2-乙氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
2-[2-(6-氯-吡啶-3-基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[2-(2-氯-吡啶-4-基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[2-(4-氯-苯基)-6-氟-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2,N-二环己基-2-[2-(3-氟-4-甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺,2-[2-(4-氯-3-甲基-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[2-(3-氯-2-甲基-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[2-(4-氯-3-氟-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[2-(3-氯-4-氟-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2,N-二环己基-2-[2-(5-甲基-1H-吲哚-2-基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(2,3,4-三氟-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(2,4,5-三氟-苯基)-苯并咪唑-1-基]-乙酰胺,
2-(2-苯并[b]噻吩-2-基-苯并咪唑-l-基)-2,N-二环己基-乙酰胺,
2,N-二环己基-2-[2-(5-氟-1H-吲哚-2-基)-苯并咪唑-1-基]-乙酰胺,
2-(2-苯并噻唑-6-基-苯并咪唑-l-基)-2,N-二环己基-乙酰胺,
2,N-二环己基-2-[2-(4-异丙氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(3,4-二甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(2,5-二甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(2-二氟甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(4-二氟甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(3-二氟甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(4-三氟甲基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(3,4-二氯-苯基)-苯并咪唑-1-基]-乙酰胺,
2-[2-(4-溴-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2,N-二环己基-2-[2-(6-甲氧基-萘-2-基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(3-三氟甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(7-乙氧基-苯并呋喃-2-基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(3-氟-4-三氟甲基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(6-二乙基氨基-吡啶-3-基)-苯并咪唑-1-基]-乙酰胺,
2-[2-(2-氯-5-甲基-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[2-(5-氯-2-甲基-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[2-(2-氯-6-甲基-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2,N-二环己基-2-(2-喹喔啉-6-基-苯并咪唑-l-基)-乙酰胺,
2-[2-(5-氯-2-氟-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2,N-二环己基-2-[2-(4-甲氧基-3,5-二甲基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(2,3-二甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
2-[2-(3-氯-4-甲氧基-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2,N-二环己基-2-[2-(2,5-二氯-苯基)-苯并咪唑-1-基]-乙酰胺,
2-[2-(3-氯-2,4-二氟-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[2-(2-氯-4,5-二氟-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2,N-二环己基-2-[2-(4-二乙基氨基-苯基)-苯并咪唑-1-基]-乙酰胺,
2-[2-(4-苯甲酰基-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
(S)-2-[2-(4-氰基-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2,N-二环己基-2-[2-(4-苯氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(2-苯氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(3-苯氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-{2-[2-(1,1,2,2-四氟-乙氧基)-苯基]-苯并咪唑-1-基}-乙酰胺,
2,N-二环己基-2-{2-[3-(1,1,2,2-四氟-乙氧基)-苯基]-苯并咪唑-1-基}-乙酰胺,
2,N-二环己基-2-{2-[4-(1,1,2,2-四氟-乙氧基)-苯基]-苯并咪唑-1-基}-乙酰胺,
2,N-二环己基-2-[2-(4’-三氟甲基-联苯基-4-基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(3’,4’-二氯-联苯基-4-基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(2,4-二氯-5-氨磺酰基-苯基)-苯并咪唑-1-基]-乙酰胺,
(S)-2-[6-氯-2-(4-氯-苯基)-5-氟-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2,N-二环己基-2-(2-吡啶-2-基-苯并咪唑-1-基)-乙酰胺,
2,N-二环己基-2-[2-(6-甲基-吡啶-3-基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(3-甲基-吡啶-2-基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(6-甲基-吡啶-2-基)-苯并咪唑-1-基]-乙酰胺,
2-[2-(2-氨基-吡啶-3-基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[2-(6-氰基-吡啶-3-基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2,N-二环己基-2-[2-(2-甲氧基-吡啶-3-基)-苯并咪唑-1-基]-乙酰胺,
2-[2-(2-氯-6-甲基-吡啶-3-基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[2-(2-氯-6-甲基-吡啶-4-基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2,N-二环己基-2-(2-喹啉-3-基-苯并咪唑-l-基)-乙酰胺,
2,N-二环己基-2-(2-喹啉-4-基-苯并咪唑-l-基)-乙酰胺,
2-[2-(3-氯-4-三氟甲基-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
(S)-2-[2-(4-氯-苯基)-苯并咪唑-1-基]-4-甲基-戊酸环己酰胺,
2-(4-氯-苯基)-2-[2-(4-氯-苯基)-苯并咪唑-1-基]-N-环己基-乙酰胺,
2-[2-(4-氯-苯基)-苯并咪唑-1-基]-N-环己基-2-(4-三氟甲基-苯基)-乙酰胺,
2-[2-(4-氯-苯基)-苯并咪唑-1-基]-N-环己基-2-(3,4-二氯-苯基)-乙酰胺,
2-[2-(4-氯-苯基)-苯并咪唑-1-基]-N-环己基-2-(3-甲氧基-苯基)-乙酰胺,
2-[2-(4-氯-苯基)-苯并咪唑-1-基]-N-环己基-2-对甲苯基-乙酰胺,
2-[2-(4-氯-苯基)-苯并咪唑-1-基]-N-环己基-2-(3-氟-苯基)-乙酰胺,
2-[2-(4-氯-苯基)-苯并咪唑-1-基]-N-环己基-2-(4-二氟甲氧基-苯基)-乙酰胺,
2-[2-(4-氯-苯基)-苯并咪唑-1-基]-N-环己基-2-(2,5-二氟-苯基)-乙酰胺,
2-[2-(4-氯-苯基)-苯并咪唑-1-基]-N-环己基-2-(2-氟-5-甲氧基-苯基)-乙酰胺,
(S)-2-[2-(5-氯-2-氟-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
(S)-2,N-二环己基-2-[2-(2,3-二甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
(S)-2-[2-(3-氯-4-甲氧基-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
(S)-2-环己基-2-[2-(2,4-二甲氧基-苯基)-苯并咪唑-1-基]-N-(2,6-二甲基-苯基)-乙酰胺,
2-[2-(4-氯-苯基)-苯并咪唑-1-基]-2-环己基-N-(4,4-二氟-环己基)-乙酰胺,
(S)-2-[2-(4-氯-苯基)-苯并咪唑-1-基]-2-环己基-N-(4,4-二氟-环己基)-乙酰胺,
(S)-2-[2-(2-氨基-吡啶-3-基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2,N-二环己基-2-(6-氟-2-吡啶-2-基-苯并咪唑-l-基)-乙酰胺,
2,N-二环己基-2-[2-(2,4-二甲氧基-苯基)-6-氟-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[6-氟-2-(4-甲氧基-苯基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(2,3-二氟-苯基)-6-氟-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(2,3-二甲氧基-苯基)-6-氟-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(2-乙基-5-甲基-2H-吡唑-3-基)-6-氟-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(3,5-二甲基-异噁唑-4-基)-6-氟-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[6-氟-2-(lH-吡唑-4-基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(l,5-二甲基-1H-吡唑-3-基)-6-氟-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[6-氟-2-(3-甲基-异噁唑-5-基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[6-氟-2-(lH-吡咯-2-基)-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[6-氟-2-(3-甲基-噻吩-2-基)-苯并咪唑-1-基]-乙酰胺,
N-苄基-2-[2-(4-氯-苯基)-苯并咪唑-1-基]-2-环己基-乙酰胺,
N-丁基-2-[2-(4-氯-苯基)-苯并咪唑-1-基]-2-环己基-乙酰胺,
2-[2-(4-氯-苯基)-苯并咪唑-1-基]-N-环己基-2-(四氢-吡喃-4-基)-乙酰胺,
2-[5-氯-2-(4-氯-苯基)-6-氟-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[2-(4-氯-苯基)-5,6-二氟-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[2-(4-氯-苯基)-苯并咪唑-1-基]-2-环己基-N-(四氢-吡喃-4-基)-乙酰胺,
2-[2-(4-氯-苯基)-苯并咪唑-1-基]-2-环己基-N-环丙基-乙酰胺,
2,N-二环己基-2-[2-(6-吗啉-4-基-吡啶-3-基)-苯并咪唑-1-基]-乙酰胺,
(S)-2-[2-(4-氯-苯基)-苯并咪唑-1-基]-2-环己基-N-(四氢-吡喃-4-基)-乙酰胺,
(S)-2,N-二环己基-2-[2-(4-甲磺酰基-苯基)-苯并咪唑-1-基]-乙酰胺,
(S)-2-[2-(4-氯-苯基)-苯并咪唑-1-基]-2-环己基-N-环丙基-乙酰胺,
2-[6-氯-2-(4-氯-苯基)-5-氟-苯并咪唑-1-基]-N-环己基-2-(四氢-吡喃-4-基)-乙酰胺,
(S)-2-[2-(4-氯-苯基)-苯并咪唑-1-基]-N-环己基-2-(四氢-吡喃-4-基)-乙酰胺,
(S)-2-[6-氯-2-(4-氯-苯基)-5-氟-苯并咪唑-1-基]-N-环己基-2-(四氢-吡喃-4-基)-乙酰胺,
(S)-2-[2-(4-氯-苯基)-5,6-二氟-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
(S)-2-[2-(5-氯-噻吩-2-基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
(S)-2,N-二环己基-2-[2-(2,3-二氟-苯基)-6-氟-苯并咪唑-1-基]-乙酰胺,
2-[6-氯-2-(4-氯-苯基)-5-氟-苯并咪唑-1-基]-N-环己基-2-环戊基-乙酰胺,
(S)-2-[6-氯-2-(4-氯-苯基)-5-氟-苯并咪唑-1-基]-庚酸环己酰胺,
(S)-2-[6-氯-2-(4-氯-苯基)-5-氟-苯并咪唑-1-基]-N-环己基-2-环戊基-乙酰胺,
2-[2-(4-氯-苯基)-5-氟-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[1-(环己基-环己基氨甲酰基-甲基)-5,6-二氟-1H-苯并咪唑-2-基]-苯甲酸甲酯,
2,N-二环己基-2-(5,6-二氟-2-吡啶-2-基-苯并咪唑-l-基)-乙酰胺,
2-[2-(5-氯-噻吩-2-基)-5,6-二氟-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[6-氯-l-(环己基-环己基氨甲酰基-甲基)-5-氟-1H-苯并咪唑-2-基]-苯甲酸甲酯,
2-(6-氯-5-氟-2-吡啶-2-基-苯并咪唑-l-基)-2,N-二环己基-乙酰胺,
2-(6-氯-5-氟-2-吡啶-3-基-苯并咪唑-l-基)-2,N-二环己基-乙酰胺,
2-(6-氯-5-氟-2-吡啶-4-基-苯并咪唑-l-基)-2,N-二环己基-乙酰胺,
2-[6-氯-2-(3-氯-噻吩-2-基)-5-氟-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[6-氯-2-(5-氯-噻吩-2-基)-5-氟-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
(S)-2-[6-氯-2-(4-氯-苯基)-5-氟-苯并咪唑-1-基]-3-乙基-戊酸环己酰胺,
2-[6-氯-5-氟-2-(4-氟-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[2-(4-氯-苯基)-苯并咪唑-1-基]-2-环己基-N-(l-异丙基-2-甲基-丙基)-乙酰胺,
2-[6-氯-2-(4-氯-苯基)-5-氟-苯并咪唑-1-基]-2-环己基-N-环戊基-乙酰胺,
2-[2-(4-氯-苯基)-5,6-二氟-苯并咪唑-1-基]-N-环己基-2-(四氢-吡喃-4-基)-乙酰胺,
(S)-2-[2-(4-氯-苯基)-5-氟-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[2-(4-氯-苯基)-5,6-二氟-苯并咪唑-1-基]-2-环己基-N-(四氢-吡喃-4-基)-乙酰胺,
2-[6-氯-2-(4-氯-苯基)-5-氟-苯并咪唑-1-基]-2-环己基-N-(四氢-吡喃-4-基)-乙酰胺,
2,N-二环己基-2-[2-(3-二甲基氨基-苯基)-5,6-二氟-苯并咪唑-1-基]-乙酰胺,
2,N-二环己基-2-[2-(3-二甲基氨基-苯基)-6-氟-苯并咪唑-1-基]-乙酰胺,
2-[2-(4-氯-苯基)-5,6-二氟-苯并咪唑-1-基]-2-环己基-N-(l-异丙基-2-甲基-丙基)-乙酰胺,
2-[6-氯-2-(4-氯-苯基)-5-氟-苯并咪唑-1-基]-2-环己基-N-(l-异丙基-2-甲基-丙基)-乙酰胺,
2-[2-(3-氯-苯基)-5,6-二氟-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[2-(2-氯-苯基)-5,6-二氟-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
(S)-2-[6-氯-5-氟-2-(4-氟-苯基)-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
(S)-2-[2-(4-氯-苯基)-5,6-二氟-苯并咪唑-1-基]-N-环己基-2-(四氢-吡喃-4-基)-乙酰胺,
2-[2-(4-氯-苯基)-5-氟-苯并咪唑-1-基]-N-环己基-2-(四氢-吡喃-4-基)-乙酰胺,
2-[2-(4-氯-苯基)-6-氟-苯并咪唑-1-基]-N-环己基-2-(四氢-吡喃-4-基)-乙酰胺,
2-[2-(4-氯-苯基)-6-氟-苯并咪唑-1-基]-N-环己基-2-(四氢-吡喃-2-基)-乙酰胺,
2-[6-氯-2-(4-氯-苯基)-5-氟-苯并咪唑-1-基]-N-环己基-2-(四氢-吡喃-2-基)-乙酰胺,
(S)-2,N-二环己基-2-[6-氟-2-(3-甲基-噻吩-2-基)-苯并咪唑-1-基]-乙酰胺,
(S)-2-[2-(2-氯-苯基)-5,6-二氟-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
(S)-2-[2-(4-氯-苯基)-5-氟-苯并咪唑-1-基]-N-环己基-2-(四氢-吡喃-4-基)-乙酰胺,
(S)-2-[2-(4-氯-苯基)-6-氟-苯并咪唑-1-基]-N-环己基-2-(四氢-吡喃-4-基)-乙酰胺,
(S)-2-[2-(4-氯-苯基)-6-氟-苯并咪唑-1-基]-N-环己基-2-(R)-四氢-吡喃-2-基-乙酰胺,
(S)-2-[2-(4-氯-苯基)-6-氟-苯并咪唑-1-基]-N-环己基-2-(S)-四氢-吡喃-2-基-乙酰胺,
2-[2-(4-氯-苯基)-5-氟-苯并咪唑-1-基]-N-环己基-2-(四氢-吡喃-2-基)-乙酰胺,
2,N-二环己基-2-[2-(3,4-二氯-苯基)-6-甲氧基-苯并咪唑-1-基]-乙酰胺,
2-[2-(4-氯-苯基)-6-甲氧基-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[2-(5-氯-噻吩-2-基)-6-甲氧基-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[2-(3-氯-4-甲氧基-苯基)-6-甲氧基-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[2-(4-氯-3-氟-苯基)-6-甲氧基-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-环己基-N-环戊基-2-[2-(3,4-二氯-苯基)-6-甲氧基-苯并咪唑-1-基]-乙酰胺,
2-[2-(4-氯-苯基)-6-甲氧基-苯并咪唑-1-基]-2-环己基-N-环戊基-乙酰胺,
2-[2-(3-氯-苯基)-6-甲氧基-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2,N-二环戊基-2-[2-(3,4-二氯-苯基)-6-甲氧基-苯并咪唑-1-基]-乙酰胺,
2-[2-(4-氯-苯基)-6-甲氧基-苯并咪唑-1-基]-N-环己基-2-环戊基-乙酰胺,
2-[2-(4-氯-3-氟-苯基)-6-甲氧基-苯并咪唑-1-基]-2-环己基-N-环戊基-乙酰胺,
2-[2-(3-氯-4-甲氧基-苯基)-6-甲氧基-苯并咪唑-1-基]-2-环己基-N-环戊基-乙酰胺,
2,N-二环己基-2-[2-(4-氟-苯基)-6-甲氧基-苯并咪唑-1-基]-乙酰胺,
2-[2-(3-氯-苯基)-6-甲氧基-苯并咪唑-1-基]-2-环己基-N-环戊基-乙酰胺,
2-[2-(3-氯-4-甲氧基-苯基)-6-甲氧基-苯并咪唑-1-基]-N-环己基-2-环戊基-乙酰胺,
2-[2-(5-氯-噻吩-2-基)-6-甲氧基-苯并咪唑-1-基]-N-环己基-2-环戊基-乙酰胺,
2-环丁基-N-环己基-2-[2-(3,4-二氯-苯基)-6-甲氧基-苯并咪唑-1-基]-乙酰胺,
2-[2-(5-氯-噻吩-2-基)-6-甲氧基-苯并咪唑-1-基]-2-环己基-N-环戊基-乙酰胺,
2-[2-(6-氯-吡啶-3-基)-6-甲氧基-苯并咪唑-1-基]-2,N-二环己基-乙酰胺,
2-[2-(3-氯-苯基)-6-甲氧基-苯并咪唑-1-基]-N-环己基-2-环戊基-乙酰胺,
2-[2-(3-氯-4-甲氧基-苯基)-6-甲氧基-苯并咪唑-1-基]-2,N-二环戊基-乙酰胺,
2,N-二环己基-2-[6-甲氧基-2-(6-三氟甲基-吡啶-3-基)-苯并咪唑-1-基]-乙酰胺,
2-[2-(5-氯-噻吩-2-基)-6-甲氧基-苯并咪唑-1-基]-2-环丁基-N-环己基-乙酰胺,
2-[2-(3-氯-苯基)-6-甲氧基-苯并咪唑-1-基]-2-环丁基-N-环己基-乙酰胺,和
N-环己基-2-环戊基-2-[2-(4-氟-苯基)-6-甲氧基-苯并咪唑-1-基]-乙酰胺,
及其药物可接受的盐和酯。
在一些实施方案中,所述FXR激动剂选自US2009215748中公开的化合物,即:
(3,4-二氟-苯甲酰基)-4,4-二甲基-5,6-二氢-4H-噻吩并[2,3-d]氮杂环庚三烯-8-羧酸乙酯;
3-(3,4-二氟苯甲酰基)-1,1,6-三甲基-1,2,3,6-四氢氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
3-(3,4-二氟-苯甲酰基)-1,1-二亚甲基-1,2,3,6-四氢-氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
3-(3,4-二氟-苯甲酰基)-1,1-二亚甲基-1,2,3,6-四氢-氮杂环庚三烯并[4,5-b]吲哚-5-羧酸异丙酯;
3-(3,4-二氟苯甲酰基)-1,1-四亚甲基-1,2,3,6-四氢氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
3-(3,4-二氟-苯甲酰基)-1,1-三亚甲基-1,2,3,6-四氢-氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
3-(3,4-二氟苯甲酰基)-1-甲基-1,2,3,6-四氢氮杂环庚三烯并[4,5-b]吲哚-5-羧酸环丁酰胺;
3-(3,4-二氟苯甲酰基)-2-甲基-1,2,3,6-四氢氮杂环庚三烯并[4,5-b]吲哚-5-羧酸环丁酰胺;
3-(3-氟苯甲酰基)-1,2,3,6-四氢氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
3-(4-氟-苯甲酰基)-1,1-二甲基-1,2,3,4,5,6,7,8,9,10-十氢氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
3-(4-氟-苯甲酰基)-1,1-二甲基-1,2,3,6,7,8,9,10-八氢-氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
3-(4-氟-苯甲酰基)-1,1-二甲基-1,2,3,6-四氢-氮杂环庚三烯并[4,5-b]吲哚-5-羧酸异丙基酰胺;
3-(4-氟-苯甲酰基)-1,1-二甲基-9-(3-甲基-丁酰基氨基)-1,2,3,6-四氢-氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
3-(4-氟-苯甲酰基)-1,1-二甲基-9-苯基乙酰基氨基-1,2,3,6-四氢-氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
3-(4-氟-苯甲酰基)-1,1-二甲基-1,2,3,6,7,8,9,10-八氢-氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
3-(4-氟-苯甲酰基)-1,2,3,4,5,6,7,8,9,10-十氢-氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
3-(4-氟-苯甲酰基)-1,2,3,6,7,8,9,10-八氢-氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
3-(4-氟苯甲酰基)-1,2,3,6-四氢氮杂环庚三烯并[4,5-b]吲哚-5-羧酸环丁酰胺;
3-(4-氟苯甲酰基)-2-甲基-1,2,3,6-四氢氮杂环庚三烯并[4,5-b]吲哚-5-羧酸环丁酰胺;
6-(3,4-二氟-苯并基)-1,4,4-三甲基-1,4,5,6-四氢-吡咯并[2,3-d]氮杂环庚三烯-2,8-二羧酸2-乙酯8-异丙酯;
6-(3,4-二氟-苯并基)-4,4-二甲基-1-1,4,5,6-四氢-吡咯并[2,3-d]氮杂环庚三烯-2,8-二羧酸2-乙酯8-异丙酯;
6-(3,4-二氟-苯甲酰基)-4,4-二甲基-1,4,5,6-四氢-吡咯并[2,3-d]氮杂环庚三烯-2,8-二羧酸二甲酯;
6-(3,4-二氟-苯甲酰基)-4,4-二甲基-1,4,5,6-四氢-吡咯并[2,3-d]氮杂环庚三烯-2,8-二羧酸二乙酯;
6-(3,4-二氟-苯甲酰基)-4,4-二甲基-5,6-二氢-4H-噻吩并[2,3-d]氮杂环庚三烯-8-羧酸乙酯;
6-(3,4-二氟-苯甲酰基)-5,6-二氢-4H-噻吩并[2,3-D]氮杂环庚三烯-8-羧酸乙酯;
6-(4-氟-苯甲酰基)-3,6,7,8-四氢-咪唑并[4,5-D]氮杂环庚三烯-4-羧酸乙酯;
9-(1-苄基-3,3-二甲基-脲基)-3-(4-氟-苯甲酰基)-1,1-二甲基-1,2,3,6-四氢-氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
9-(2,2-二甲基-丙酰基氨基)-3-(4-氟-苯甲酰基)-1,1-二甲基-1,2,3,6-四氢-氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
9-(乙酰基-甲基-氨基)-3-(4-氟-苯甲酰基)-1,1-二甲基-1,2,3,6-四氢-氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
9-[苄基-(2-噻吩-2-基-乙酰基)-氨基]-3-(4-氟-苯甲酰基)-1,1-二甲基-1,2,3,6-四氢-氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
9-二甲基氨基-3-(4-氟苯甲酰基)-1,1-二甲基-1,2,3,6-四氢氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
9-氟-3-(3,4-二氟-苯甲酰基)-1,1-二甲基-1,2,3,6-四氢-氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
9-氟-3-(3,4-二氟-苯甲酰基)-1,1-二甲基-1,2,3,6-四氢-氮杂环庚三烯并[4,5-b]吲哚-5-羧酸异丙基酰胺;
9-氟-3-(4-氟-苯甲酰基)-1,1-二甲基-1,2,3,6-四氢-氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
9-氟-3-(4-氟-苯甲酰基)-1,1-二甲基-1,2,3,6-四氢-氮杂环庚三烯并[4,5-b]吲哚-5-羧酸异丙酯;
9-氟-3-环己烷羰基-1,1-二甲基-1,2,3,6-四氢-氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
环丁基3-(3,4-二氟苯甲酰基)-1,1-二甲基-1,2,3,6-四氢氮杂环庚三烯并[4,5-b]吲哚-5-甲酰胺;
3-(4-氟苯甲酰基-1,2,3,6-四氢氮杂环庚三烯并[4,5-b]吲哚-2,5-二羧酸二乙酯;
1,1-二甲基-1,2,3,6-四氢-氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
1,1-二甲基-3-(4-氟苯甲酰基)-1,2,3,6-四氢-氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
3-(3,4-二氟苯甲酰基)-1,1-二甲基-1,2,3,6-四氢氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
3-(3,4-二氟苯甲酰基)-1-甲基-1,2,3,6-四氢氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
3-(4-氯苯甲酰基)-1,1-二甲基-1,2,3,6-四氢氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
3-(4-氯苯甲酰基)-1-甲基-1,2,3,6-四氢氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
3-(4-氟苯甲酰基)-1,2,3,6-四氢氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
3-(4-氟苯甲酰基)-1-甲基-1,2,3,6-四氢-氮杂环庚三烯并[4,5-b]吲哚-5-羧酸乙酯;
3-(3,4-二氟苯甲酰基)-1,1-二甲基-1,2,3,6-四氢氮杂环庚三烯并[4,5-b]吲哚-5-羧酸异丙酯;
3-(3,4-二氟苯甲酰基)-1-甲基-1,2,3,6-四氢氮杂环庚三烯并[4,5-b]吲哚-5-羧酸异丙酯;
3-(4-氟苯甲酰基)-2-甲基-1,2,3,6-四氢氮杂环庚三烯并[4,5-b]吲哚-5-羧酸正丙酯;和
3-(4-氟苯甲酰基)-2-甲基-8-氟-1,2,3,6-四氢氮杂环庚三烯并[4,5-b]吲哚-5-羧酸正丙酯。
在一些实施方案中,所述FXR激动剂选自WO2013037482中公开的化合物,即:
4-(((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-(三氟甲基)吡啶-3-基)(甲基)氨基)甲基)苯甲酸;
3-(2-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)环丙基)苯甲酸;
4-(2-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)环丙基)苯甲酸;
5-(2-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)环丙基)-1-异丙基-1H-吡唑-3-羧酸;
6-(2-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)环丙基)-1-甲基-1H-吲唑-3-羧酸;
6-(2-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)环丙基)-1-异丙基-1H-吲唑-3-羧酸;
3-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基环丁基)苯甲酸;
5-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基环丁基)-1-异丙基-1H-吡唑-3-羧酸;
6-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基环丁基)-1-甲基-1H-吲唑-3-羧酸;
4-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基环丁基)苯甲酸;
3-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基氮杂环丁烷1-基)苯甲酸;和
5-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基氮杂环丁烷1-基)烟酸。
通常本领域技术人员利用基于如PCT/US99/30947中描述的分析(其教导通过引用整体并入本文),能够确定可用于本发明的其他FXR激动剂。通常,采用核受体-肽分析来确定FXR激动剂。该分析利用荧光共振能量转移(FRET),并可用于测试推定的配体是否结合FXR。该FRET分析基于以下原理:配体诱导核受体中的构象变化,该受体促进其与转录激活所需的共激活蛋白的相互作用。在FRET中,荧光供体分子通过非放射性偶极-偶极相互作用将能量转移至受体分子(其通常为荧光分子)。
通常将治疗有效量的本发明FXR激动剂施用于个体。如上所述,“治疗有效量”的FXR激动剂是指可应用于任何医学治疗而以合理的益处/风险率治疗乙型肝炎病毒感染的足够量FXR激动剂。然而应理解,本发明的化合物和组合物的总体每日使用,可由主治医师在合理的医疗判断范围内决定。针对任何特定患者的具体治疗有效量水平取决于以下各种因素:包括接受治疗的病症和该病症的严重性;所用的具体化合物的活性;所用的具体组合物、患者的年龄、体重、总体健康、性别和饮食;施用时间、施用途径和所用具体化合物的排泄率;治疗时长;与所用具体激动剂联合使用的药物;等等医药领域技术人员熟知的因素。例如,完全在本领域技术范围内的是,以低于达到期望的治疗效果所需剂量的水平开始,并逐渐增加剂量直至实现期望的效果。然而,所述产物的每日剂量可在0.01-1,000mg/成人/天的宽范围内变化。优选地,针对待接受治疗患者剂量的症状调节,所述组合物含有0.01mg、0.05mg、0.1mg、0.5mg、1.0mg、2.5mg、5.0mg、10.0mg、15.0mg、25.0mg、50.0mg、100mg、250mg和500mg活性成分。药物通常含有约0.01mg至约500mg的活性成分,优选1mg至约100mg的活性成分。有效量的该药物通常以每天0.0002mg/kg体重至约20mg/kg体重的剂量水平提供,尤其是每天约0.001mg/kg体重至7mg/kg体重。
任何上述治疗方案可施用于已诊断患有HBV感染的个体。任何上述治疗方案可施用于针对HBV感染的既往治疗已经失败的个体(治疗失败的患者)。如本文所用,“治疗失败的患者”通常是指未能应答针对HBV的既往治疗的HBV-感染患者(称为“非应答者”)或者起初应答既往治疗而其体内所述治疗应答没有得到维持的HBV-感染患者(称为“复发者”)。既往和当前可用的治疗通常可包括使用以下药物的治疗:抗病毒药物,如拉米夫定(Epivir)、阿德福韦(Hepsera)、替诺福韦(Viread)、替比夫定(Tyzeka)和恩替卡韦(Baraclude),以及两种免疫系统调节剂干扰素α-2a、聚乙二醇化的干扰素α-2a(Pegasys)和干扰素α-2b(ViraferonPeg ou Introna)。
具体地,本发明的FXR激动剂可联合当前可用的治疗施用于所述个体,所述治疗包括采用抗病毒药物,如逆转录酶抑制剂,拉米夫定(Epivir)、阿德福韦(Hepsera)、替诺福韦(Viread)、替比夫定(Tyzeka)和恩替卡韦(Baraclude),以及如免疫系统调节剂,干扰素α-2a、聚乙二醇化的干扰素α-2a(Pegasys)或干扰素α-2b(ViraferonPeg ou Introna)。
本发明的FXR激动剂可与药物可接受的赋形剂和任选的缓释基质(如生物可降解聚合物)组合以形成药物组合物。
“药物的”或“药物可接受的”是指适当地施用于哺乳动物尤其是人时,不产生副作用、过敏反应或其他不良反应的分子实体和组合物。药物可接受的载体或赋形剂是指非毒性的固体、半固体或液体填充剂、稀释剂、包封物质或任何种类的制剂助剂。
在用于口服、舌下、皮下、肌肉内、静脉内、经皮、局部或直肠施用的本发明药物组合物中,所述活性成分可单独地或与另一活性成分结合,作为与常规药物载体的混合物,以单位给药形式施用于动物和人。合适的单位给药形式包括口服施用形式如片剂、凝胶胶囊、粉剂、颗粒剂、口服悬浮剂或溶液,舌下和经口给药形式、气溶胶、植入物,皮下、经皮、局部、腹膜内、肌肉内、静脉内、皮下、经皮、鞘内注射和鼻内给药形式和直肠给药形式。
具体地,所述药物组合物含有药物可接受的用于能够被注射的制剂的媒介物。具体地,它们可以为等渗、无菌、含盐的溶液(磷酸二氢钠或磷酸二钠、氯化钠、氯化钾、氯化钙或氯化镁等或上述盐的混合物),或者干的特别是冻干的组合物,根据情况其添加无菌水或生理盐水以便能够形成可注射溶液。
适于注射应用的药物形式包括无菌水溶液或分散剂;包含芝麻油、花生油或丙二醇水溶液的制剂;以及用于即时配制无菌注射溶液或分散剂的无菌粉末。在所有情况下,所述形式必须为无菌的且必须为以达到可注射性的程度而存在的流体。其必须在生产和储存条件下稳定且其必须抗如细菌和真菌的微生物污染作用而保存。
包含作为游离碱或药物可接受的盐的本发明化合物的溶液,可通过与表面活性剂如羟丙基纤维素在水中适当地混合来制备。也可在甘油、液体聚乙二醇及其混合物和在油中制备分散剂。在正常储存和应用条件下,这些制剂含有防腐剂以防止微生物生长。
本发明的FXR激动剂可以中性形式或盐形式配制为组合物。药物可接受的盐包括酸加成盐(与蛋白的游离氨基形成),且其与无机酸(例如盐酸或磷酸)或者有机酸(例如醋酸、草酸、酒石酸、扁桃酸等)形成。与游离羰基形成的盐也可衍生自无机碱,例如氢氧化钠、氢氧化钾、氢氧化铵、氢氧化钙或氢氧化铁,以及有机碱,例如异丙胺、三甲胺、组氨酸、普鲁卡因等。
所述载体可为溶剂或包含例如水、乙醇、多元醇(例如甘油,丙二醇,和液体聚乙二醇等)的分散媒介、其合适的混合物以及植物油。可通过以下办法来维持适当的流动性,例如,通过使用涂层如卵磷脂,在分散剂情形下通过维持所需的粒径,以及通过使用表面活性剂。防止微生物的作用可通过各种抗菌剂和抗真菌剂来实现,例如对羟基苯甲酸酯类、氯丁醇、苯酚、山梨酸、硫柳汞等。在许多情况下,优选包括等渗剂,例如糖或氯化钠。可注射组合物的延长的吸收可通过在该组合物中使用延迟吸收剂来实现,例如单硬脂酸铝和明胶。
无菌可注射溶液通过如下方法制备:按照要求将所需量的所述活性肽掺入至含有不同比例的以上所列其他成分的合适溶剂中,然后过滤灭菌。通常,分散剂通过如下方法制备:将各种无菌活性成分掺入至含有碱性分散介质和所需的如上所列其他成分的无菌媒介中。在用于制备无菌可注射溶液的无菌粉末的情形下,优选的制备方法为:真空干燥和冷冻干燥技术,其产生活性成分加上来自此前经无菌过滤的其溶液的任何其他所需成分的粉末。
在配制制剂时,溶液必须以与该剂型相容的形式施用且其用量为治疗上有效的。所述制剂容易采用各种剂型施用,如以上描述的可注射溶液的类型,但也可采用药物释放胶囊等。
对于在水溶液中进行肠胃外施用,例如,如需要应对溶液进行适当地缓冲,首先用足够的盐或葡萄糖使液体稀释剂等渗。这些特定的水溶液尤其适用于静脉内、肌肉内、皮下和腹膜内施用。因此,鉴于本文的公开可用的无菌含水介质为本领域技术人员所熟知。例如,一个剂量可溶解于1ml等渗NaCl溶液,加入至1000ml皮下灌注流体中或者在建议的输注位置进行注射。根据受治疗个体的条件,必须在剂量上进行一些改变。在任何事件中,负责施用的人员将确定用于单个个体的合适剂量。
本发明的FXR激动剂可在治疗混合物中进行配制,以使得每个剂量包含约0.0001-1.0毫克,或约0.001-0.1毫克,或约0.1-1.0毫克,或甚至约10毫克左右。也可施用多个剂量。
除了配制用于如静脉内或肌肉内注射的肠胃外给药的本发明化合物,其他药物可接受的形式包括:例如,用于口服施用的片剂或其他固体形式;脂质体制剂;延时释放胶囊;以及当前使用的任何其他形式。
下列附图和实施例将进一步阐述本发明。然而,这些实施例和附图不应解释为以任何形式限制本发明的范围。
附图说明
图1–在FXR调节剂存在下,HBV感染的HepaRG细胞系上清液中分泌的表面HBs抗原(HBsAg)。
用HBV感染分化的HepaRG细胞(100geq/细胞,24hr),然后用FXR调节剂以指定的μM浓度连续处理3次(感染后第4天、第7天和第11天)。感染后第14天收集细胞上清液用于定量HBsAg(Architec Abbott)。
图2–在HBV感染的HepaRG上清液中分泌的HBV表面抗原(HBsAg)、核心(HBeAg)抗原和HBV DNA。
用HBV感染分化的HepaRG细胞(100geq/细胞,24hr),然后用FXR激动剂和拮抗剂或FXR惰性的胆酸UDCA以指定的μM浓度连续处理3次(感染后第4天、第7天和第11天)。感染后第14天收集细胞上清液用于采用rcDNA引物(n=3±SEM)通过定量PCR来定量HBsAg、HBeAg(Architec Abbott)或HBV DNA。A–两种FXR激动剂GW4064和6ECDCA均以剂量依赖性方式抑制HBsAg和HBeAg在上清液中的分泌,而UDCA和052EDL133对抗原分泌无影响。B–两种FXR激动剂GW4064和6ECDCA均以剂量依赖性方式抑制感染性HBV DNA阳性病毒颗粒在上清液中的分泌。UDCA和052EDL133对病毒粒子分泌影响有限或无影响。C–FXR激动剂PXL007以剂量依赖性方式抑制HBsAg、HBeAg和HBV DNA。
图3–在FXR激动剂存在或不存在下,HepaRG细胞中的HBV核心蛋白(HBc)表达。
生长在玻片上的分化的HepaRG细胞被感染且如图1图例中所述进行处理(n=3±SEM)。感染后第14天将细胞固定,且进行用抗-HBc抗体的免疫细胞化学。荧光显微镜检揭示,FXR激动剂GW4064和6ECDCA明显降低HBc在感染细胞中的表达。UDCA和052EDL133没有显示出改变HBc表达。
图4–在FXR激动剂存在或不存在下,在HBV感染的HepaRG细胞系中的HBV前基因组/前核心区mRNA和cccDNA表达。
分化的HepaRG细胞被感染,且如图1图例中所述进行处理。将细胞裂解并提取RNA,然后逆转录为cDNA以用于定量PCR(qRT-PCR)(A),或者用于Northern印迹实验(B)。重复相同的实验并提取DNA。在经质粒安全的脱氧核糖核酸酶处理后,通过qPCR实验采用特定的HBV cccDNA引物和TaqMan探针(n=3±SEM)定量cccDNA表达(C)。将cccDNA定量归一化为β珠蛋白基因的数目。定量HBV前基因组基因的表达水平,以及3个管家基因用于归一化(n=3±SEM)。两种FXR激动剂GW4064和6ECDCA均以剂量依赖性方式抑制HBV前基因组/前核心区mRNA的表达。在Northern印迹(3,4-3,5Kb条带)中确认了该降低。其他HBV mRNA(S:2,1-2,4Kb;X:0,7Kb)的表达也降低,如所述密度测量图中所示(n=3±SEM)。用FXR激动剂处理后,cccDNA水平也降低了超过50%。
图5–HBV进入抑制剂环孢菌素A(CyA)对FXR激动剂调节HBV感染的HepaRG细胞上清液中的HBsAg和HBeAg分泌的作用。
分化的HepaRG细胞被感染,且如图1图例中所述进行处理。除了此前描述的常规方案,在HBV感染期间(即持续24hr),或用FXRα激动剂进行第一处理期间(即持续72hr;感染后第4-7天),用环孢菌素A(CyA)处理细胞。感染后第14天收集细胞上清液用于定量HBsAg和HBeAg(n=3±SEM)。A)HBV感染期间的CyA处理以剂量依赖性方式抑制病毒进入,且不损害用FXR激动剂处理后HBsAg和HBeAg分泌的降低。B)无论存在或不存在FXR激动剂,感染后的CyA处理对HBV抗原分泌无影响。
图6–FXR和HBx蛋白的免疫共沉淀分析
将HEK293T细胞与融合蛋白3XF-HBx和编码质粒的Gluc-FXR的共转染。转染后48h,将细胞裂解,并与事先偶联有抗-3XF抗体的蛋白G免疫共沉淀。通过Western印迹分析细胞裂解物(lysate)和共免疫沉淀产物;用抗-Gluc抗体检测FXR表达。在对照、仅Gluc-FXR或在测试细胞中的FXR表达,Gluc-FXR和3XF-HBx的共表达为相似的,如左侧的Western印迹所示。用抗-3XF抗体进行免疫沉淀后,FXR融合蛋白在测试条件明显被检测到,而在对照中没有检测到(右侧的Western印迹)。这些观察有力表明了病毒HBx蛋白和核受体FXR之间的相互作用。
图7–FXR的mRNA表达及其调控的两个基因
分化的HepaRG细胞被感染,且如图1图例中所述进行处理。将细胞裂解并提取RNA,然后逆转录为cDNA用于qPCR。定量3个相关基因的表达水平:FXRα、SHP和APOA1,以及3个管家基因用于归一化(n=3±SEM)。FXR激动剂GW4064和6ECDCA均以剂量依赖性方式抑制FXRmRNA的表达。SHP和APOA1为在FXR调控下的两个基因:SHP由FXR诱导,而APOA1被抑制。此处,采用GW4064和6ECDCA处理,SHP mRNA表达增加,而APOA1mRNA表达降低。这表明FXR的激活作用,尽管其表达降低。
图8–用拉米夫定(有效的核苷类似物逆转录酶抑制剂)共处理FXR激动剂
分化的HepaRG细胞被感染,且如图1图例中所述进行处理。感染后第14天收集细胞上清液。(A)定量HBsAg和HBeAg分泌。(B)通过DNA提取和通过qPCR定量来定量分泌的感染性颗粒。用拉米夫定以10μM浓度处理对HBV抗原分泌的作用非常有限,而其HBV DNA分泌的作用近乎完全使细胞上清液中HBV DNA降低了97%。
实施例
方法:
源自人肝细胞癌的HepaRG细胞系,在确定的条件下培养4周后能够分化并重新获得许多肝细胞的表型性状(Hantz O.等,2009.J Gen Virol90:127-135)。分化后,这些细胞易于被HepG2.2.15细胞系产生的HBV病毒粒子以高MOI进行感染。感染后第二周,在这些条件下可观察到病毒的产生。该系统允许研究病毒复制循环的大多数步骤,包括渗透进入细胞、病毒基因易位进入细胞核、cccDNA的修复和合成、前基因组和病毒mRNA的转录,以及包括病毒蛋白合成、感染性病毒粒子的组装和分泌以及病毒蛋白HBs和HBe分泌的复制循环的后续阶段。
因此所述HepaRG系统允许在用从HepG2.2.15细胞系制备的HBV感染性病毒粒子母液感染后,监测HBsAg和HBeAg的分泌以及病毒粒子整合的DNA进入细胞培养物上清液。该系统还允许监测前基因组和病毒mRNA以及细胞质复制的中间物和cccDNA。探究了分子对细胞生理学和细胞分化作用的作用,包括定量肝标记物,如白蛋白和载脂蛋白B。通过分析和定量FXR mRNA以及编码mRNAs的SHP和apoA1(其表达处于FXR的控制下),监测所述化合物对细胞胆酸途径的影响。
结果:
FXR激动剂是有效的HBV复制抑制剂:
如Ramière C,等,2008,J Virol;82:10832-10840中所描述,针对Huh-7细胞系中在包含两个FXR应答元件的HBV Enh2/核心启动子区控制下的报告基因表达,首先测试了一组分子,此前未描述且为FXR活性的最初的或参考调节剂。然后分别基于在FXR的转录控制下所述报告基因表达的增加或减少,将分子归类为FXR激动剂或拮抗剂。一些分子具有中等的特性,单独测试时为中等的激动剂,与参考激动剂竞争时被测试为弱的拮抗剂(数据未显示)。针对用HepG2.2.15产生的HBV自然地感染的HepaRG细胞培养系统的培养物上清液中HBsAg的合成和分泌的作用,首先评估了最有效和代表性的化合物(图1)。出人意料的是,最有效的拮抗剂(即100ED0038、100ED0136、100ED0137和100ED0166)以及专利WO 2007052843描述的参考拮抗剂052EDL133(Takeda Pharmaceutical Co.Ltd.,Osaka,Japan)对HBsAg分泌无影响或影响很小。令人惊奇的是,如PCT公开号WO 00/37077或US2007/0015796公开的激动剂GW4064对HBsAg分泌具有强的剂量依赖性抑制作用(在10μM时约70%抑制)。部分激动剂如来自专利WO2009127321的PXL0914(4-溴-5-[4-(2-氯-苯磺酰基)-[1,4]二氮杂环庚烷-1-基]-苯并呋喃-2-羧酸、来自专利WO2009127321的PXL0924(5-[4-(2,6-二氯-苯甲酰基)-哌嗪-1-基]-4-甲基-苯并呋喃-2-羧酸和来自专利WO2009127321的PXL0743(4-溴-5-[4-(2,6-二氯-苯磺酰基氨基)-哌啶-1-基]-苯并呋喃-2-羧酸具有抑制的中等特性。因此一些分子以剂量依赖性方式减少HBsAg的产生。通过在含有报告基因构建体的Huh-7细胞中筛选测试,如果所述活性分子被归类为拮抗剂、激动剂或“部分的”激动剂,出人意料地显示,对HBsAg产生的抑制作用随该分子成为有效的FXR激动剂的趋势而增长。
为确认该发现,我们接着测试几个分子,参考FXR拮抗剂052EDL133(参见上文)、两个充分定征的FXR激动剂(其属于不同化学类别)GW4064(参见上文)和6ECDCA(胆酸盐衍生物和有效的FXR激动剂,当前处在临床试验,用于原发型胆汁性肝硬化和胰岛素耐受,参见上文)以及胆酸盐类似物熊脱氧胆酸(其不是FXR配体)(Parks DJ1,等Science.1999May21;284(5418):1365-8.Makishima M1,等Science.1999May 21;284(5418):1362-5)。图2A显示,在处理后10天的感染细胞的HepaRG上清液中,仅GW4064和6ECDCA是剂量依赖性的且对HBsAg和HBeAg的分泌具有强抑制作用。胆汁盐熊脱氧胆酸盐在任何剂量均未抑制病毒蛋白的分泌,且FXR拮抗剂052EDL133没有抑制作用或作用很小。当在上清液中测试这些分子对病毒DNA分泌的影响时,观察到类似的发现(图2B)。使用两种激动剂观察到高达80%的强抑制作用,而UDCA没有调节病毒DNA的分泌。然而,应注意到拮抗剂052EDL133在10μM时中等地降低了病毒DNA分泌量(接近20%抑制)。最后,在相同的分析中测试了由CAS登录号1192171-69-9确定的化学上不同的FXR激动剂PXL007(描述于WO 2009127321)对病毒复制的活性。该FXR激动剂也强烈抑制病毒蛋白和DNA分泌(图2C)。
通过免疫荧光我们进一步探究了GW4064和6ECDCA对病毒核心蛋白HBc的细胞表达的影响(图3)。这两种FXR激动剂再次强烈抑制感染的细胞中的HBc表达,而UDCA和052EDL133没有明显地调节HBc合成。
最后,通过定量RT-PCR和Northern印迹,我们定量了在由GW4064和6ECDCA处理或未处理的感染细胞中病毒RNA的量以及cccDNA库的变种(图4)。如定量RT-PCR所测,两种3.4和3.5前核心区和前基因组RNA的存在由FXR激动剂以剂量依赖性方式降低了高达75%(图A)。三类病毒mRNA的存在,即3.4和3.5前核心区和前基因组RNA、2.1-2.4S mRNA和0.7XmRNA,通过Northern印迹测量在10μM时被降低至类似的程度(图B)。令人感兴趣的是,用这两种激动剂以10μM处理后,cccDNA库也降低了超过50%(图C)。
作用机制
最近在肝细胞的底外侧质膜上确认牛磺胆酸钠协同转运肽(NTCP)为HBsAg的受体。NTCP表达是病毒进入肝细胞所必需的。牛磺胆酸钠协同转运多肽是人乙型和丁型肝炎病毒的功能受体(Yan H.等Elife(Cambridge).2012Nov 13;1:e00049.doi:10.7554/eLife.00049)。HBV和胆酸在NTCP上有共同的结合位点而争夺受体(Yan H.等JVirol.2014Mar;88(6):3273-84.doi:10.1128/JVI.03478-13.Epub 2014Jan 3)。由于FXR激动剂是直接源自胆酸或与胆酸共享一些分子决定因子的分子,所以FXR激动剂可能通过争夺受体而仅抑制病毒进入。因此我们测试了添加环孢菌素A(CsA)的FXR激动剂(抑制NTCP介导的胆酸吸收的分子,在与前-S1肽结合位点相同或重叠的位点结合NTCP)的作用(Nkongolo S,等J Hepatol.2014Apr;60(4):723-31.doi:10.1016/j.jhep.2013.11.022.Epub2013Dec 1)。感染期间,当增加浓度的CsA被引入至培养基中时,我们观察到与HBV进入的剂量依赖性竞争,且如所预期地抑制HBsAg和HBeAg分泌。用GW4064或6ECDCA处理还降低了病毒蛋白的分泌(图5A)。相反,在感染期后添加CsA,对具有保守的HBsAg和HBeAg分泌的HBV复制无影响,也不调节FXR激动剂的作用(图5B)。如此前所述,考虑到在该系统中培养期间很少有病毒扩散或无病毒扩散,我们的结论是,FXR激动剂的抗病毒活性与直接抑制NTCP无关,而是调节感染循环的后续步骤。
我们接着采用标记的病毒蛋白和FXR,通过免疫共沉淀研究了病毒蛋白是否能够干扰FXR。我们发现,针对一种或其他蛋白,HBx病毒蛋白和FXR能够通过抗体导向被免疫沉淀(图6)。该数据表明了HBx和FXR之间的相互作用,强化了病毒紧密地调控FXR活性的假说。
接着,我们研究了FXR激动剂对编码FXR自身以及SHP和ApoA1的mRNA表达水平的影响,这两个基因的表达分别处在FXR的阳性和阴性控制下。我们发现,用FXR激动剂GW4064和6ECDCA处理10天增加了SHP mRNA的表达,而降低了ApoA1mRNA的表达,这表明FXR激动剂确实提高了FXR活性(图7)。令人感兴趣的是,FXR mRNA表达也被两种激动剂强烈抑制,很可能是由于针对FXR表达的SHP依赖性阴性对照环路。因此,用FXR激动剂处理明显且持久地调节了胆酸代谢,随着FXR表达降低而增加了FXR的活性。
FXR激动剂和针对HBV复制的逆转录酶抑制剂联合处理的作用。
因此,FXR激动剂表现为在病毒进入后发生的步骤抑制HBV复制,且主要针对cccDNA库的稳定性和表达,从而在逆转录步骤之前。因而我们测试了联合处理HBV感染的HepaRG细胞对病毒复制的作用(图8)。我们观察到,用核苷类似物逆转录酶抑制剂拉米夫定处理,即使在高浓度(10μM,IC50为6nM,Lada O,等Antivir Ther.2004Jun;9(3):353-63)仅微弱地抑制HBsAg和HBeAg分泌,但如所预期地非常有效地降低了HBV DNA阳性病毒粒子分泌。在该条件下添加FXR激动剂表现为没有进一步降低病毒DNA分泌,但有效抑制了病毒蛋白的合成和分泌。
讨论:
我们揭示了,FXR是HBV在肝细胞中发展的主要宿主因子,且出人意料地,在HepaRG细胞系中针对HBV复制,FXR激动剂是比拮抗剂更有效的抑制剂。用结构极为多样且具有选择性的FXR激动剂GW4064、PXL007(具有CAS登录号:1192171-69-9的分子)、胆酸衍生物6ECDCA等证明了该抗病毒活性。这降低了“脱靶”作用的可能性。FXR激动剂表现为主要作用于病毒mRNA转录和来自病毒微型染色体的表达以及作用于cccDNA稳定性。全部的FXR激动剂,除了降低病毒DNA复制和感染性病毒粒子的产生(可用逆转录酶聚合酶抑制剂有效而安全地获得的作用),具有独特的能力来降低病毒蛋白的合成和分泌,并减小cccDNA库的大小。这两个后作用无法通过聚合酶抑制剂获得,而仅有低百分比的用干扰素治疗的患者能实现。降低病毒蛋白分泌和cccDNA库是治愈HBV感染的主要目标,因为在另一方面,已经表明病毒蛋白主要通过与TLR相互作用抑制固有的免疫反应,并维持针对病毒的免疫-耐受状态,另一方面,病毒的持久性和潜伏期取决于cccDNA的持续存在。
持久的HBV复制也要求存在支持性的细胞环境,具体地,条件是用于病毒基因表达的活性转录细胞机构。通过所述病毒来调控FXR活性可能是用于控制其自身复制的病毒策略的一部分。的确,HBV病毒粒子和胆酸之间针对NTCP的争夺降低细胞内胆酸的总量,进而导致降低FXR活性和增加FXR表达水平(Oehler N,等Hepatology.2014Apr 8.doi:10.1002/hep.27159.[出版前的电子公开])。用FXR激动剂处理被证明逆转了由所述病毒诱导的胆酸代谢改变,从而其表现为支持病毒复制的有利条件。
长期治疗期间具有良好耐受性的在两种分别的适应证(即原发型胆汁性肝硬化和胰岛素耐受)中进行临床研究的分子—6ECDCA的抗病毒作用的发现,提供了“重新定位”治疗HBV感染的分子的机会。总之,我们确认了调控(降低)HBV感染的新分子(即FXR激动剂)。这将允许用已经在临床试验的FXR激动剂,筛选能够在小鼠模型中或直接在人中进行测试的候选药物。
参考文献:
在整个本申请中,各种参考文献描述了与本发明相关的现有技术。这些参考文献公开的内容通过引用并入本公开。
Claims (7)
1.类法尼醇X受体(FXR)激动剂在制备用于治疗有此需要的个体的乙型肝炎病毒(HBV)感染的药物中的用途。
2.如权利要求1所述的用途,其中所述个体感染任何乙型肝炎病毒基因型,包括基因型A、B、C或D。
3.如权利要求1所述的用途,其中所述个体患有慢性HBV感染。
4.如权利要求1所述的用途,其中所述FXR激动剂选自通过CAS登录号1192171-69-9确定的化合物、GW4064、6ECDCA、PXL0914(4-溴-5-[4-(2-氯-苯磺酰基)-[1,4]二氮杂环庚烷-1-基]-苯并呋喃-2-羧酸)、PXL0743(4-溴-5-[4-(2,6-二氯-苯磺酰基氨基)-哌啶-1-基]-苯并呋喃-2-羧酸)、4-(2-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)环丙基)苯甲酸、fexaramine、
5.如权利要求1所述的用途,其中所述个体未能应答对HBV感染的既往治疗。
6.如权利要求5所述的用途,其中所述既往治疗选自:抗病毒药物,所述抗病毒药物包括拉米夫定(Epivir)、阿德福韦(Hepsera)、替诺福韦(Viread)、替比夫定(Tyzeka)和恩替卡韦(Baraclude),以及两种免疫系统调节剂,干扰素α-2a和聚乙二醇化的干扰素α-2a(Pegasys)或干扰素α-2b(ViraferonPeg ou Introna)。
7.如权利要求1-6中任一项所述的用途,其中与选自以下的治疗联合施用所述FXR激动剂:抗病毒药物,所述抗病毒药物包括拉米夫定(Epivir)、阿德福韦(Hepsera)、替诺福韦(Viread)、替比夫定(Tyzeka)和恩替卡韦(Baraclude),以及两种免疫系统调节剂,干扰素α-2a和聚乙二醇化的干扰素α-2a(Pegasys)以及干扰素α-2b(ViraferonPeg ou Introna)。
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CN115666528A (zh) * | 2020-03-18 | 2023-01-31 | 梅塔科林公司 | 法尼醇x受体激动剂的制剂 |
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