CN107050030A - 用于治疗前庭障碍的选择性组胺h4受体拮抗剂 - Google Patents
用于治疗前庭障碍的选择性组胺h4受体拮抗剂 Download PDFInfo
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- CN107050030A CN107050030A CN201710057965.8A CN201710057965A CN107050030A CN 107050030 A CN107050030 A CN 107050030A CN 201710057965 A CN201710057965 A CN 201710057965A CN 107050030 A CN107050030 A CN 107050030A
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- bases
- pyrimidine
- amine
- methyl
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- 239000003396 histamine H4 receptor antagonist Substances 0.000 title claims abstract description 32
- 208000027601 Inner ear disease Diseases 0.000 title claims abstract description 27
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- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 claims description 433
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- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 256
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- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 125
- YAAWASYJIRZXSZ-UHFFFAOYSA-N pyrimidine-2,4-diamine Chemical class NC1=CC=NC(N)=N1 YAAWASYJIRZXSZ-UHFFFAOYSA-N 0.000 claims description 117
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- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 claims description 43
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Abstract
本发明涉及用于治疗和/或预防前庭障碍的选择性组胺H4受体拮抗剂或组胺H4受体基因表达抑制剂。选择性H4受体拮抗剂指对H4受体的亲和性比对H1、H2或H3受体任一个的亲和性高至少10倍、优选25倍、优选50倍、更优选100倍、并且甚至更优选500倍的分子。选择性H4受体拮抗剂是(i)Ki H3:Ki H4和(ii)IC50 H3:IC50 H4比率之一高于10:1、优选25:1、优选50:1、更优选100:1并且甚至更优选在500:1至1000:1之间的分子。
Description
本申请是申请日为2009年12月23日的PCT国际专利申请PCT/EP2009/067897进入中国国家阶段的中国专利申请号200980157367.1、发明名称为“用于治疗前庭障碍的选择性组胺H4受体拮抗剂”的分案申请。
技术领域
本发明涉及用于治疗和/或预防前庭障碍的选择性组胺H4受体拮抗剂或者组胺H4受体基因表达的抑制剂。
背景技术
前庭(内耳)障碍可引起头晕、眩晕、失衡、听觉改变、恶心、疲劳、焦虑、集中困难和其他症状,对人的每日功能、工作能力、与家人和朋友的关系以及生活质量具有潜在的破坏性影响。
抗组胺化合物广泛用作治疗前庭障碍,如眩晕。组胺激活剂和拮抗剂外周性和中枢性作用于前庭系统,并且可干扰周边前庭病变后的恢复过程(Lacour和Sterkers,2001)。组胺受体家族包括四个亚型:于1966年发现的H1和H2受体,于1983年发现的H3受体和于2000年鉴定的H4受体。H4受体基于其与H3受体的同源性而鉴定(在蛋白质水平具有31%同源性并且在跨膜内具有54%同源性)。在四个组胺受体(HR1至HR4)当中,HR3显示调节前庭输入(Chavez 2005)。在眩晕的组胺治疗领域中,倍他司汀(BH)是一系列抗眩晕化合物之一。BH的促进剂作用已经描述于中枢前庭代偿中(Lacour和Sterkers,2001;Tighilet等,2005),但是其对外周前庭受体的作用仅在低等脊椎动物中有所报导(Housley等,1988;Tomoda等,1997;Botta等,1998;Soto等,2001;Chavez等,2005)。已经报导BH呈现出作为H1组胺受体的激动剂和作为H3受体的拮抗剂的复合功能(Arrang等,1985)。在从蝾螈分离的外周前庭受体中,BH抑制传入放电,IC50为800μM,最大作用在10mM左右(Chavez 2005)。这些研究得出组胺H3受体是BH主要靶标的结论(Van Cauwenberge和De Moor 1997;Soto2001;Chavez 2005)。在体外维持7天的培养的大鼠前庭神经元中开展的最近研究表明,施用BH诱导神经元膜的可逆去极化并且抑制引起的放电,而不影响动作电位的固有特性。
然而,还没有针对前庭障碍研究组胺H4受体。
发明内容
本发明涉及用于治疗和/或预防前庭障碍的选择性组胺H4受体拮抗剂。本发明还涉及用于治疗和/或预防前庭障碍的选择性组胺H4受体拮抗剂。
本发明还涉及用于治疗和/或预防前庭障碍的组胺H4受体基因表达抑制剂。
附图说明
图1.VUF 6002对去极化诱导的放电冲动排的影响。在应用100μM VUF 6002(A)、10μm(B)和1μM(C)后从各个神经元得到的典型的轨迹。在用对照培养基漂洗过程中抑制性反应被逆转。附图显示在应用VUF 6002之前(a)、过程中(b)和之后(c)各个冲动排;
图2.VUF 6002对通过标准去极化诱导的放电冲动排的剂量依赖性效应。与单项Hill方程拟合的曲线(黑色线)得出IC50为5.8μM。数据是对照反应的平均抑制百分数。实验数在误差线上面指出;
图3.倍他司汀对去极化诱导的放电冲动排的影响。在应用5mM倍他司汀后从各个神经元得到的典型的轨迹。附图显示在应用倍他司汀之前(a)、过程中(b)和之后(c)各个冲动排。注意由倍他司汀诱导的大约15mV的强去极化。这些反应在用对照培养基漂洗过程中被快速逆转;
图4.VUF 6002、倍他司汀和噻普酰胺对膜电位变动的影响。虽然VUF 6002没有诱导膜改变,但是其它两个化合物在高浓度时产生强的去极化。星号表示诱导90%的放电抑制的浓度。
具体实施方式
定义:
术语“组胺H4受体”具有其在本领域的一般含义。该术语可包括天然存在的组胺H4受体及其变体和修改形式。组胺H4受体可以来自任何来源,但是有代表性地是哺乳动物(例如人和非人灵长类)组胺H4受体,特别是人组胺H4受体。对于组胺H4受体的序列已经以参考号NM_021624(智人)、NM_153087(小家鼠)和NM_131909(褐家鼠)公布。
“基因表达抑制剂”指具有抑制或者显著降低基因表达的生物学作用的天然或合成的化合物。因此,“组胺H4受体基因表达抑制剂”指具有抑制或者显著降低编码组胺H4受体基因表达的生物学作用的天然或合成的化合物。
“受体拮抗剂”意思是指具有与受体激动剂相反的生物学作用的天然或合成化合物。该术语一般用于指受体的“真”拮抗剂和反激动剂。“真”受体拮抗剂是例如通过与所述受体的激动剂竞争而结合受体并阻断受体生物学活化并由此阻断受体激动剂作用的化合物。反激动剂是与激动剂结合同一受体但是具有相反作用的化合物。反激动剂具有在激动剂缺乏下降低受体活化组成型水平的能力。
术语“组胺H4受体拮抗剂”包括当施用于患者时导致患者中与组胺H4受体活化有关的生物学活性的抑制或下调(包括以另外的方式源于组胺H4受体与其天然配体结合的任何下游生物学作用)的任何化学实体。此类组胺H4受体拮抗剂包括可阻断组胺H4受体活化或者组胺H4受体活化的任何下游生物学效应的试剂。例如,此类组胺H4受体拮抗剂可以通过占据组胺H4受体的配体结合部位或其部分,由此使得受体得不到其天然配体以致于其正常生物学活性被阻止或降低而起作用。
在本发明背景下,组胺H4受体拮抗剂相对于其它组胺受体例如组胺H1受体、组胺H2受体和组胺H3受体而言对组胺H4受体具有选择性。“选择性”意思是指拮抗剂对人组胺H4受体的亲和性比对其它的人组胺受体(H1、H2和H3)的亲和性高至少10倍、优选25倍、更优选100倍、仍然优选500倍。
拮抗剂对组胺H4受体的亲和性可通过测量在一系列浓度所述拮抗剂存在下组胺H4受体的活性以便建立剂量-反应曲线而定量。从该剂量反应曲线中可以推导出IC50值,其表示对确定浓度激动剂反应50%抑制所需的拮抗剂浓度。IC50值可以通过如De Lean等(1979)所述将剂量-反应图与剂量-反应方程拟合,由本领域技术人员容易地确定。使用Cheng和Prusoff(1973)的假设可将IC50数值转换成亲和常数(Ki)。
因此,选择性组胺H4受体拮抗剂是比率(i)Ki H3:Ki H4,和(ii)IC50H3:IC50H4的至少一个高于10:1、优选25:1、更优选100:1、仍然优选1000:1的化合物。
化合物对于组胺H4受体的拮抗活性可以使用多种方法,例如Thurmond RL等(2004)或Venable JD.等(2005)中所述的那些方法测定。
术语“小的有机分子”指大小与通常用于药物的那些有机分子可比的分子。该术语排除生物学大分子(例如蛋白质、核酸等)。优选的小的有机分子大小范围可达大约5000Da、更优选可达2000Da、并且最优选可达大约1000Da。
如本文所使用,术语“受试者”指哺乳动物,例如啮齿动物、猫科动物、犬科动物和灵长类动物。优选地,根据本发明的受试者是人。
术语“前庭障碍”指特征在于头晕、视觉或注视失调和平衡障碍的病症。前庭障碍可源自内耳的种种损伤或功能障碍,当中尤其是急性和慢性综合症。本发明考虑的前庭障碍实例包括但不限于眩晕、良性阵发性眩晕、前庭神经炎、阵发梅尼埃病、内淋巴积水、外淋巴瘘、带有前庭障碍的头损伤、迷路出血、慢性或急性迷路感染、浆液性迷路、气压伤、自身免疫性内耳病、偏头痛与前庭综合征、中耳外科手术治疗后的前庭综合征、中耳、内淋巴囊或小脑桥脑角、内耳通道病变、慢性梅尼埃病、前庭、神经鞘瘤、presbyvestibulia(老年性前庭病)、家族性发作性眩晕和共济失调.
以其最广的含义,术语“治疗”(treating或treatment)指逆转、缓解、抑制其进程或者预防此术语应用的疾病或病症,或者此疾病或病症的一个或更多个症状。
具体而言,“预防”前庭障碍指施用本发明的化合物预防前庭障碍的症状。
“药物用”或“可药用”指当根据情况施用于哺乳动物,特别是人时不产生不利的、变态的或其它不良的反应的分子实体和成分。可药用载体或赋形剂指非毒性固体、半固体或液体填充剂、稀释剂、包封材料或任何类型的制剂助剂。
治疗方法和用途
本发明提供用于治疗前庭障碍或者用于在治疗前庭障碍中使用的方法和组合物(例如药物组合物)。
根据第一个方面,本发明涉及用于治疗前庭障碍或者用于在治疗前庭障碍中使用的选择性组胺H4受体拮抗剂。
在一个实施方案中,选择性组胺H4受体拮抗剂可以是低分子量拮抗剂,例如小的有机分子。
根据本发明的一个实施方案,选择性H4受体拮抗剂指对H4受体的亲和性比对H1、H2或H3受体任一个的亲和性高至少10倍、优选25倍、优选50倍、更优选100倍、并且甚至更优选500倍的分子。
根据本发明的另一实施方案中,选择性H4受体拮抗剂是(i)Ki H3:Ki H4和(ii)IC50H3:IC50H4比率之一高于10:1、优选25:1、优选50:1、更优选100:1并且甚至更优选在500:1至1000:1之间的分子。
对H4受体和其它(H1、H2和H3)受体的亲和性可通过本领域已知的任何常规技术表征。例如,可以通过结合测定法确定。所述的测定法使用来自细胞,例如以人、大鼠或小鼠H4、H3、H2或H1受体转染的SK-N-MC或HEK293T细胞的细胞沉淀物(Lovenberg等,1999,Liu等,2001a,b,Thurmond等,2004)。细胞可以在包含5mM EDTA的50mM Tris pH 7.5中匀浆,并且收集来自800g旋转的上清液并在30 000g下离心30分钟。然后将沉淀物在包含5mM EDTA的50mM Tris pH 7.5中匀浆。对于H4竞争性结合研究,使用不同浓度的[3H]组胺(对每一物种特异性的,例如分别为10、40和50nM),在待测试分子存在或缺乏下将人、小鼠或大鼠细胞于25℃孵育大约45分钟。使用100μM未标记的组胺或者使用10-6M特异性或选择性H4受体拮抗剂例如JNJ-7777120或JNJ-10191584确定非特异性结合。使用该方法确定的对于人、小鼠和大鼠H4受体的Kd值分别是5、42和178nM,并且所确定的Bmax值分别是1.12、1.7和0.68pmol/mg蛋白。类似地,用于H3受体结合测定的配体是例如[3H]N-a-甲基组胺,并且使用100μM未标记组胺确定非特异性结合。使用该方法确定的对于人H3受体的Kd值为1nM并且Bmax值为2.13pmol/mg蛋白。用于H1受体结合的配体是[3H]吡拉明并且非特异性活性使用10μM未标记苯海拉明确定。使用该方法确定的对于人H1受体的Kd值是1nM并且Bmax值是2.68pmol/mg蛋白。在这些测定中,细胞有代表性地与不同浓度例如10-11至10-4M的待测试分子孵育。
愿意证明或确定待测试分子的拮抗剂活性的本领域技术人员可使用本领域中已知的任何方法,并且例如基于细胞的cAMP测定。所述测定使用以在环AMP-应答元件控制下的H4、H3、H2或H1受体和报告基因构建体例如b-半乳糖苷酶转染的SK-n-MC细胞系。在测定前将细胞铺板过夜。组胺用作激动剂分子。为了测定拮抗剂活性,在加入激动剂之前10分钟加入待测试的分子。在加入组胺后10分钟加入福司柯林(5μM终浓度)。然后将细胞保持于37℃下6小时,并且在洗涤之后,以大约25μl的0.1×测定缓冲液(10mM磷酸钠,pH 8,0.2mMMgSO4和0.01mM MnCl2)裂解并于室温孵育10分钟。然后将细胞与大约100μl的包含0.5%(v/v)Trition X-100和40mMβ-巯基乙醇的1×测定缓冲液孵育10分钟。使用25μl的1mg/ml底物溶液,例如氯酚红b-D-吡喃半乳糖苷显色,并且通过测量570nm处的吸光度定量。对于每一浓度-反应曲线得到的数据拟合成S形曲线以得到最大反应、Hill系数和EC50。
本发明考虑的示例性选择性组胺H4拮抗剂包括但不限于在美国专利号6,803,362;美国专利申请公布号2004/0105856、2004/0127395、2004/0132715、2004/0048878、2004/0058934、2005/0070527、2005/0070550、2005/0261309、2007/0238771、2008/0269239、2008/0261946、2008/0188452、2009/275748、和国际专利申请号WO2005/054239、WO2005/014556、WO2007/031529、WO2007/072163、WO2007/090852、WO2007/117399、WO2007/120690、WO2008/074445、WO2008/008359、WO2008/031556、WO2008/100565、WO2008/003702、WO2009/134726、WO2009/115496、WO2009/114575、WO2009/080721、WO2009/077608、WO2009/071625、WO2009/068512、WO2009/056551、WO2009/038673、WO2009/077608、WO2009/079001和WO2009/047255中描述的那些,每一文献通过引用并入本文。
本文明考虑的另外的示例性选择性组胺H4拮抗剂包括但不限于在JablonowskiJA等(2003)、Venable JD.等(2005)、Thurmond RL.等(2004)、Herman D.等(2005)、RobinL.等(2004)、Cowart MD.等(2008)和Liu H.等(2008)中描述的那些。
有代表性地,本发明可以考虑的化合物是例如描述于WO2005/054239或WO2005/014556中的2-氨基嘧啶衍生物,或者例如描述于WO2008/003702中的喹唑啉衍生物。
在本发明的一个实施方案中,选择性H4拮抗剂选自双环杂芳基取代的咪唑化合物,例如在WO2009/079001和WO2007/120690中描述的那些;噻吩并-和氟-嘧啶化合物,例如在WO2009/038673中描述的那些;2-氨基嘧啶化合物,例如在WO2008/100565、WO2009077608、WO2009/068512、WO2005/054239、WO2008/031556、WO2008122378和WO2005/014556中描述的那些;苯并呋喃-和苯并噻吩并嘧啶化合物,例如WO2008/008359中描述的那些;呋喃[3,2-d]嘧啶衍生物,例如WO2009/056551和WO2009/115496中描述的那些;4-氨基-嘧啶衍生物,例如WO2009/080721中描述的那些;氨基嘧啶化合物,例如WO2007/090852中描述的那些;氨基嘧啶化合物对映异构体,例如WO2007/090853中描述的那些;氮杂环丁烷氨基嘧啶化合物,例如WO2007/090854中描述的那些;嘧啶化合物,例如WO2007/039467、WO2006/050965和WO2007/072163中描述的那些;美喹他嗪,例如WO2009/071625中描述的那些;取代的嘧啶衍生物,特别是大环稠合的取代的嘧啶衍生物,例如WO2009/134726中描述的那些;大环螺环嘧啶化合物,特别是三环螺环嘧啶化合物,例如WO2009/114575中描述的那些;大环苯并稠合的嘧啶化合物,例如WO2008/060767中描述的那些;杂芳基-稠合大环嘧啶衍生物,特别是杂芳基-稠合大环2,4-二氨基嘧啶化合物,例如WO2009137492中描述的那些;5,6,7,8-四氢喹唑啉-2-胺衍生物,例如WO2009123967中描述的那些;八氢吡咯并[3,4-c]吡咯衍生物,例如WO2006056848中描述的那些;三环和杂三环衍生物,例如WO2008/074445中描述的那些;杂二环化合物,例如WO2009047255中描述的那些;喹唑啉和相关的杂环化合物,例如WO2008/003702中描述的那些;哌啶的咪唑衍生物,例如WO2005/014579中描述的那些;双环嘧啶化合物,例如WO2009107767中描述的那些(所有参考文献通过引用并入本文)。
在具体实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2007/120690中描述的那些:(1H-苯并咪唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(1H-苯并咪唑-2-基)-(4-乙基-哌嗪-1-基)-甲酮;(1H-苯并咪唑-2-基)-(3-甲基-哌嗪-1-基)-甲酮;(1H-苯并咪唑-2-基)-(4-甲基-[1,4]二氮杂环庚烷-1-基)-甲酮;1H-苯并咪唑-2-羧酸(8-甲基-8-氮杂-二环[3.2.1]辛-3-基)-酰胺;(5-氯-1H-苯并咪唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(5-氯-1H-苯并咪唑-2-基)-哌嗪-1-基-甲酮;(5-氯-1H-苯并咪唑-2-基)-(3-甲基-哌嗪-1-基)-甲酮;(5,6-二氟-1H-苯并咪唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(5,6-二氟-1H-苯并咪唑-2-基)-(4-乙基-哌嗪-1-基)-甲酮;(5,6-二氟-1H-苯并咪唑-2-基)-(3-甲基-哌嗪-1-基)-甲酮;(5,6-二氟-1H-苯并咪唑-2-基)-(4-甲基-[1,4]二氮杂环庚烷-1-基)-甲酮;5,6-二氟-1H-苯并咪唑-2-羧酸(8-甲基-8-氮杂-二环[3.2.1]辛-3-基)-酰胺;(6-氯-5-氟-1H-苯并咪唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(6-氯-5-氟-1H-苯并咪唑-2-基)-(4-甲基-[1,4]二氮杂环庚烷-1-基)-甲酮;6-氯-5-氟-1H-苯并咪唑-2-羧酸(8-甲基-8-氮杂-二环[3.2.1]辛-3-基)-酰胺;(5-氯-6-甲基-1H-苯并咪唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(5-氯-6-甲基-1H-苯并咪唑-2-基)-哌嗪-1-基-甲酮;(4-甲基-1H-苯并咪唑-2-基)-(3-甲基-哌嗪-1-基)-甲酮;(4-乙基-哌嗪-1-基)-(4-甲基-1H-苯并咪唑-2-基)-甲酮;(4-甲基-1H-苯并咪唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(4-甲基-1H-苯并咪唑-2-基)-哌嗪-1-基-甲酮;4-甲基-1H-苯并咪唑-2-羧酸(8-甲基-8-氮杂-二环[3.2.1]辛-3-基)-酰胺;5-甲基-1H-苯并咪唑-2-羧酸(8-甲基-8-氮杂-二环[3.2.1]辛-3-基)-酰胺;(5-甲基-1H-苯并咪唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(4-甲基-哌嗪-1-基)-(5-三氟甲基-1H-苯并咪唑-2-基)-甲酮;哌嗪-1-基-(5-三氟甲基-1H-苯并咪唑-2-基)-甲酮;(5-氟-1H-苯并咪唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(4-乙基-哌嗪-1-基)-(5-氟-1H-苯并咪唑-2-基)-甲酮;(5-氟-1H-苯并咪唑-2-基)-哌嗪-1-基-甲酮;(5-氟-1H-苯并咪唑-2-基)-(3-甲基-哌嗪-1-基)-甲酮;5-氟-1H-苯并咪唑-羧酸(8-甲基-8-氮杂-二环[3.2.1]辛-3-基)-酰胺;苯并唑-2-基-(4-甲基-哌嗪-1-基)-甲酮;(7-甲基-苯并唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(5-甲基-苯并唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(4-甲基-苯并唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;苯并噻唑-2-基-(4-甲基-哌嗪-1-基)-甲酮;(5-苯甲酰基-1H-苯并咪唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(4-氯-1H-苯并咪唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(4-甲基-哌嗪-1-基)-(4-硝基-1H-苯并咪唑-2-基)-甲酮;(4-氨基-1H-苯并咪唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(4-异丙基氨基-1H-苯并咪唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;C-(5-氯-1H-苯并咪唑-2-基)-C-(4-甲基-哌嗪-1-基)-亚甲基胺;(4,6-二氟-1H-苯并咪唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(4-甲基-哌嗪-1-基)-(5-硝基-1H-苯并咪唑-2-基)-甲酮;(5-氟-4-甲基-1H-苯并咪唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(5-溴-1H-苯并咪唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(5,6-二氯-1H-苯并咪唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(4,5-二甲基-1H-苯并咪唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(5,6-二甲基-1H-苯并咪唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(5-甲氧基-1H-苯并咪唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(5-氯-苯并唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(5-氟-苯并唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(6-氟-苯并唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(5,7-二氟-苯并唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(4-甲基-哌嗪-1-基)-(5-三氟甲氧基-苯并唑-2-基)-甲酮;(5-氯-苯并噻唑-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(4-甲基-哌嗪-1-基)-(5-三氟甲基-苯并噻唑-2-基)-甲酮;(4-甲基-哌嗪-1-基)-(6H-噻吩并[2,3-b]吡咯-5-基)-甲酮;(六氢-吡咯并[1,2-a]吡嗪-2-基)-(6H-噻吩并[2,3-b]吡咯-5-基)-甲酮;(2-氯-6H-噻吩并[2,3-b]吡咯-5-基)-(4-甲基-哌嗪-1-基)-甲酮;(2-氯-6H-噻吩并[2,3-b]吡咯-5-基)-(六氢-吡咯并[1,2-a]吡嗪-2-基)-甲酮;(2-氯-6H-噻吩并[2,3-b]吡咯-5-基)-哌嗪-1-基-甲酮;(4H-呋喃[3,2-b]吡咯-5-基)-(4-甲基-哌嗪-1-基)-甲酮;(4-甲基-哌嗪-1-基)-(4H-噻吩并[3,2-b]吡咯-5-基)-甲酮;哌嗪-1-基-(4H-噻吩并[3,2-b]吡咯-5-基)-甲酮;(3-甲基-哌嗪-1-基)-(4H-噻吩并[3,2-b]吡咯-5-基)-甲酮;(2-氯-4H-噻吩并[3,2-b]吡咯-5-基)-(4-甲基-哌嗪-1-基)-甲酮;(2-氯-4H-噻吩并[3,2-b]吡咯-5-基)-(六氢-吡咯并[1,2-a]吡嗪-2-基)-甲酮;(3-溴-4H-噻吩并[3,2-b]吡咯-5-基)-(4-甲基-哌嗪-1-基)-甲酮;4-甲基-哌嗪-1-基)-(3-甲基-4H-噻吩并[3,2-b]吡咯-5-基)-甲酮;(2-甲基-4H-呋喃[3,2-b]吡咯-5-基)-(4-甲基-哌嗪-1-基)-甲酮;(2,3-二甲基-4H-呋喃[3,2-b]吡咯-5-基)-(4-甲基-哌嗪-1-基)-甲酮;(2.3-二甲基-4H-噻吩并[3,2-b]吡咯-5-基)-(4-甲基-哌嗪-1-基)-甲酮;(2,3-二氯-6H-噻吩并[2,3-b]吡咯-5-基)-(4-甲基-哌嗪-1-基)-甲酮;(2-甲基-4H-呋喃[3,2-b]吡咯-5-基)-哌嗪-1-基-甲酮;(3-溴-4H-噻吩并[3,2-b]吡咯-5-基)-哌嗪-1-基-甲酮;(3-溴-4H-噻吩并[3,2-b]吡喃醇-5-基)-(3-甲基-哌嗪-1-基)-甲酮;(3-甲基-4H-噻吩并[3,2-b]吡咯-5-基)-哌嗪-1-基-甲酮;(3-甲基-哌嗪-1-基)-(3-甲基-4H-噻吩并[3,2-b]吡咯-5-基)-甲酮;(2-氯-3-甲基-4H-噻吩并[3,2-b]吡咯-5-基)-(4-甲基-哌嗪-1-基)-甲酮;(2-氯-3-甲基-4H-噻吩并[3,2-b]吡咯-5-基)-哌嗪-1-基-甲酮;(2,3-二氯-4H-噻吩并[3,2-b]吡咯-5-基)-(4-甲基-哌嗪-1-基)-甲酮;(2,3-二甲基-6H-噻吩并[2,3-b]吡咯-5-基)-(4-甲基-哌嗪-1-基)-甲酮;(2-氯-3-甲基-6H-噻吩并[2,3-b]吡咯-5-基)-(4-甲基-哌嗪-1-基)-甲酮;(3-氯-2-甲基-6H-噻吩并[2,3-b]吡咯-5-基)-(4-甲基-哌嗪-1-基)-甲酮;(2-溴-6H-噻吩并[2,3-b]吡喃醇-5-基)-(4-甲基-哌嗪-1-基)-甲酮;(3-溴-6H-噻吩并[2,3-b]吡咯-5-基)-(4-甲基-哌嗪-1-基)-甲酮;(4-甲基-哌嗪-1-基)-(2-苯基-6H-噻吩并[2,3-b]吡咯-5-基)-甲酮;[2-(4-氯-苯基)-6H-噻吩并[2,3-b]吡咯-5-基]-(4-甲基-哌嗪-1-基)-甲酮;(3-溴-4H-噻吩并[3,2-b]吡喃醇-5-基)-(3,4-二甲基-哌嗪-1-基)-甲酮;(3,4-二甲基-哌嗪-1-基)-(3-甲基-4H-噻吩并[3,2-b]吡咯-5-基)-甲酮;(2-溴-3-甲基-4H-噻吩并[3,2-b]吡咯-5-基)-(4-甲基-哌嗪-1-基)-甲酮;(3-溴-2-氯-4H-噻吩并[3,2-b]吡咯-5-基)-(4-甲基-哌嗪-1-基)-甲酮;(2,3-二氯-4H-噻吩并[3,2-b]吡咯-5-基)-(3-甲基-哌嗪-1-基)-甲酮;(4-甲基-哌嗪-1-基)-(2-苯基-4H-噻吩并[3,2-b]吡咯-5-基)-甲酮;(4-甲基-哌嗪-1-基)-[2-(4-三氟甲基-苯基)-4H-噻吩并[3,2-b]-吡咯-5-基]-甲酮;8-甲基-3-(4-甲基-哌嗪-1-基)-1H-喹喔啉-2-酮;8-甲基-3-哌嗪-1-基-1H-喹喔啉-2-酮;8-硝基-3-哌嗪-1-基-1H-喹喔啉-2-酮;7,8-二氟-3-哌嗪-1-基-1H-喹喔啉-2-酮;8-甲基-3-(3-甲基-哌嗪-1-基)-1H-喹喔啉-2-酮;3-(3-甲基-哌嗪-1-基)-1H-喹喔啉-2-酮;3-[4-(2-羟基-乙基)-哌嗪-1-基]-8-甲基-1H-喹喔啉-2-酮;6-氯-3-(4-甲基-哌嗪-1-基)-1H-喹喔啉-2-酮;7-氯-3-(4-甲基-哌嗪-1-基)-1H-喹喔啉-2-酮;3-(4-甲基-哌嗪-1-基)-6-三氟甲基-1H-喹喔啉-2-酮;3-(4-甲基-哌嗪-1-基)-7-三氟甲基-1H-喹喔啉-2-酮;6,7-二氯-3-(4-甲基-哌嗪-1-基)-1H-喹喔啉-2-酮;6,7-二氯-3-哌嗪-1-基-1H-喹喔啉-2-酮;6,7-二氯-3-(4-甲基-[1,4]二氮杂环庚烷-1-基)-1H-喹喔啉-2-酮;6,7-二氟-3-(4-甲基-哌嗪-1-基)-1H-喹喔啉-2-酮;7-氯-6-甲基-3-(4-甲基-哌嗪-1-基)-1H-喹喔啉-2-酮;6-氯-7-甲基-3-(4-甲基-哌嗪-1-基)-1H-喹喔啉-2-酮;6-氟-3-(4-甲基-哌嗪-1-基)-1H-喹喔啉-2-酮;7,8-二氟-3-(4-甲基-哌嗪-1-基)-1H-喹喔啉-2-酮;8-氯-3-(4-甲基-哌嗪-1-基)-6-三氟甲基-1H-喹喔啉-2-酮;3-哌嗪-1-基-6-三氟甲基-1H-喹喔啉-2-酮;3-哌嗪-1-基-7-三氟甲基-1H-喹喔啉-2-酮;6-氯-7-氟-3-(4-甲基-哌嗪-1-基)-1H-喹喔啉-2-酮;7-氯-6-氟-3-(4-甲基-哌嗪-1-基)-1H-喹喔啉-2-酮;7-氯-3-哌嗪-1-基-1H-喹喔啉-2-酮;6-氯-3-哌嗪-1-基-1H-喹喔啉-2-酮;6-氯-3-(3-甲基-哌嗪-1-基)-1H-喹喔啉-2-酮;7-氯-3-(3-甲基-哌嗪-1-基)-1H-喹喔啉-2-酮;3-(3-甲基-哌嗪-1-基)-6-三氟甲基-1H-喹喔啉-2-酮;3-(3-甲基-哌嗪-1-基)-7-三氟甲基-1H-喹喔啉-2-酮;2-{2-氯-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-4,5-二甲基-1H-苯并咪唑;2-{2-氯-4-[3-(1-甲基-哌啶-4-基)-丙氧基]-苯基}-4-甲基-1H-苯并咪唑;2-{2-氯-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-5-三氟甲氧基-1H-苯并咪唑;5-叔丁基-2-{3-氯-4-[3-(4-甲基-[1,4]二氮杂环庚烷-1-基)-丙氧基]-苯基}-1H-苯并咪唑;5-叔丁基-2-{3-氯-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;4,5-二甲基-2-{3-甲基-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;5-叔丁基-2-{3-[4-(4-甲基-哌嗪-1-基)-丁氧基]-苯基}-1H-苯并咪唑;5-叔丁基-2-{3-[4-(4-甲基-[1,4]二氮杂环庚烷-1-基)-丁氧基]-苯基}-1H-苯并咪唑;(1-{3-[4-(5-叔丁基-1H-苯并咪唑-2-基)-2-氯-苯氧基]-丙基}-吡咯烷-3-基)-二甲基胺;2-{3-氟-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-4-甲基-1H-苯并咪唑;5-甲基-2-{4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-萘-1-基}-1H-苯并咪唑;4-[3-(5-叔丁基-1H-苯并咪唑-2-基)-苯氧基]-1-(4-甲基-哌嗪-1-基)-丁-1-酮;5-氯-2-[3-氯-4-(3-哌嗪-1-基-丙氧基)-苯基]-6-氟-1H-苯并咪唑;5-叔丁基-2-{3-甲基-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;2-{2-氯-4-[3-(1-甲基-哌啶-4-基)-丙氧基]-苯基}-4,6-二甲基-1H-苯并咪唑;2-{2-氯-4-[2-甲基-3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-4-甲基-1H-苯并咪唑;5-氯-2-{3-氯-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-6-甲基-1H-苯并咪唑;6-氯-2-{2-氯-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-4-乙基-1H-苯并咪唑;5-叔丁基-2-{3-氯-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;5-氯-2-{3-氟-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;2-{2-氯-4-[3-(4-甲基-[1,4]二氮杂环庚烷-1-基)-丙氧基]-苯基}-4,6-二甲基-1H-苯并咪唑;5-氯-6-甲基-2-{3-[4-(4-甲基-哌嗪-1-基)-丁氧基]-苯基}-1H-苯并咪唑;2-{3-氟-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-5-甲基-1H-苯并咪唑;5,6-二氟-2-{3-氟-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;2-{3-氟-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;2-{2-氯-4-[3-(4-甲基-[1,4]二氮杂环庚烷-1-基)-丙氧基]-苯基}-4,5-二甲基-1H-苯并咪唑;5,6-二甲基-2-{3-[4-(4-甲基-哌嗪-1-基)-丁氧基]-苯基}-1H-苯并咪唑;2-{2-氯-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-4,6-二甲基-1H-苯并咪唑;2-{2-氯-4-[3-(4-甲基-[1,4]二氮杂环庚烷-1-基)-丙氧基]-苯基}-4-甲基-1H-苯并咪唑;5-叔丁基-2-{2-氯-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;2-{3-甲氧基-4-[3-(4-甲基-哌嗪-1-基)-丙氧基3-苯基}-5-三氟甲基-1H-苯并咪唑;5-氯-2-{3-氯-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-6-氟-1H-苯并咪唑;5,6-二氯-2-{2-氯-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;5-氯-2-{2-氯-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;5-氯-2-{2-氯-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-6-氟-1H-苯并咪唑;5-氯-2-{3-甲基-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;2-{3-氯-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-5-甲基-1H-苯并咪唑;5,6-二氯-2-{3-氯-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;5-氯-6-甲基-2-{3-甲基-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;2-{2-氯-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-5-甲基-1H-苯并咪唑;5-氯-2-{3-氯-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;2-{3-氯-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-5-三氟甲基-1H-苯并咪唑;5-氯-6-氟-2-{3-甲基-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;5-甲基-2-{3-甲基-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;2-{3-氯-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;2-{3-甲基-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;2-{2-氯-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;5-氯-6-氟-2-{3-甲氧基-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;2-{3-氯-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-5-甲氧基-1H-苯并咪唑;5-叔丁基-2-{3,5-二溴-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;2-{2-甲氧基-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-5-三氟甲基-1H-苯并咪唑;2-{2-氯-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-5-三氟甲基-1H-苯并咪唑;2-{3-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;(2-{3-[4-(4-甲基-哌嗪-1-基)-丁氧基]-苯基}-1H-苯并咪唑-5-基)-苯基-甲酮;6-氯-2-{2-氯-4-[3-(1-甲基-哌啶-4-基)-丙氧基]-苯基}-4-甲基-1H-苯并咪唑;5-叔丁基-2-{3-氯-4-[3-(1-甲基-哌啶-4-基)-丙氧基]-苯基}-1H-苯并咪唑;2-{2-氯-4-[3-(1-甲基-哌啶-4-基)-丙氧基]-苯基}-4,5-二甲基-1H-苯并咪唑;5-氯-6-甲基-2-{4-[3-(1-甲基-哌啶-4-基)-丙氧基]-苯基}-1H-苯并咪唑;5-氯-2-{4-[3-(1-甲基-哌啶-4-基)-丙氧基]-苯基}-1H-苯并咪唑;5-氯-6-氟-2-{4-[3-(1-甲基-哌啶-4-基)-丙氧基]-苯基}-1H-苯并咪唑;5-叔丁基-2-{4-[3-(1-甲基-哌啶-4-基)-丙氧基]-苯基}-1H-苯并咪唑;5-甲基-2-{4-[3-(1-甲基-哌啶-4-基)-丙氧基]-苯基}-1H-苯并咪唑;2-{4-[3-(1-甲基-哌啶-4-基)-丙氧基]-苯基}-1H-苯并咪唑;6-氯-2-{2-氟-4-[3-(1-甲基-哌啶-4-基)-丙氧基]-苯基}-4-甲基-1H-苯并咪唑;5-氟-2-{2-甲基-4-[3-(1-甲基-哌啶-4-基)-丙氧基]-苯基}-1H-苯并咪唑;4-氯-2-{2-甲基-4-[3-(1-甲基-哌啶-4-基)-丙氧基]-苯基}-1H-苯并咪唑;6-氯-4-甲基-2-{2-甲基-4-[3-(1-甲基-哌啶-4-基)-丙氧基]-苯基}-1H-苯并咪唑;2-{2-氯-4-[3-(1-甲基-哌啶-4-基)-丙氧基]-苯基}-3H-萘并[1,2-d]咪唑;4,6-二甲基-2-{2-甲基-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;2-{2-氯-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-4-甲基-1H-苯并咪唑;2-{2-氯-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-5-氟-4-甲基-1H-苯并咪唑;2-{2-氯-4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-3H-萘并[1,2-d]咪唑;6-氯-2-{2-氯-4-[3-(4-甲基-[1,4]二氮杂环庚烷-1-基)-丙氧基]-苯基}-4-甲基-1H-苯并咪唑;2-{3-氯-4-[3-(4-甲基-[1,4]二氮杂环庚烷-1-基)-丙氧基]-苯基}-4-甲基-1H-苯并咪唑;4,6-二甲基-2-{3-[4-(4-甲基-[1,4]二氮杂环庚烷-1-基)-丁氧基]-苯基}-1H-苯并咪唑;5-氯-2-{4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;2-{4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;{2-(6-氯-4-甲基-1H-苯并咪唑-2-基)-5-[3-(1-甲基-哌啶-4-基)-丙氧基]-苄基}-二甲基-胺;{2-(5-氟-4-甲基-1H-苯并咪唑-2-基)-5-[3-(1-甲基-哌啶-4-基)-丙氧基]-苄基}-二甲基-胺;4-{3-[4-(6-氯-4-甲基-1H-苯并咪唑-2-基)-3-甲基-苯氧基]-丙基}-[1,4]二氮杂环庚烷-5-酮;4-{3-[4-(5-叔丁基-1H-苯并咪唑-2-基)-3-甲基-苯氧基]-丙基}-1-甲基-[1,4]二氮杂环庚烷-5-酮;5-叔丁基-2-{2-甲基-4-[3-(2-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;5-叔丁基-2-{2-甲基-4-[3-(2-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-苯并咪唑;6-氯-4-甲基-2-[2-甲基-4-(3-哌啶-4-基-丙氧基)-苯基]-1H-苯并咪唑;5-氟-4-甲基-2-[2-甲基-4-(3-哌啶-4-基-丙氧基)-苯基]-1H-苯并咪唑;6-氯-2-{4-[3-(1-乙基-哌啶-4-基)-丙氧基]-2-甲基-苯基}-4-甲基-1H-苯并咪唑;{2-[3-氯-4-(4-甲基-1H-苯并咪唑-2-基)-苯氧基]-乙基}-甲基-(1-甲基-哌啶-4-基)-胺;6-氯-4-甲基-2-{2-甲基-4-[2-(1-甲基-哌啶-4-基氧基)-乙氧基]-苯基}-1H-苯并咪唑;6-氯-4-甲基-2-{2-甲基-4-[3-(1-甲基-1,2-6-四氢-吡啶-4-基)-丙氧基]-苯基}-1H-苯并咪唑;5-氟-4-甲基-2-{2-甲基-4-[3-(1-甲基-1,2,3,6-四氢-吡啶-4-基)-丙氧基]-苯基}-1H-苯并咪唑;6-氟-7-甲基-2-{3-[4-(1-甲基-哌啶-4-基)-丁氧基]-苯基}-1H-苯并咪唑;7-甲基-2-{3-[4-(1-甲基-哌啶-4-基)-丁氧基]-苯基}-1H-苯并咪唑;6,7-二甲基-2-{3-[4-(1-甲基-哌啶-4-基)-丁氧基]-苯基}-1H-苯并咪唑;(5-氯-1H-吲哚-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(5-氟-1H-吲哚-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(5-溴-1H-吲哚-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(1H-吲哚-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(5-苄基氧基-1H-吲哚-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(5-甲基-1H-吲哚-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(5,6-二甲氧基-1H-吲哚-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(4-甲基-哌嗪-1-基)-(7-硝基-1H-吲哚-2-基)-甲酮;(4-甲基-哌嗪-1-基)-(5-硝基-3-苯基-1H-吲哚-2-基)-甲酮;(4-甲基-哌嗪-1-基)-(5-三氟甲氧基-1H-吲哚-2-基)-甲酮;(6-氯-1H-吲哚-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(5,7-二氟-1H-吲哚-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(6-氟-1H-吲哚-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(4,6-二氯-1H-吲哚-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(1H-吲哚-2-基)-(4-辛基-哌嗪-1-基)-甲酮;(4-乙基-哌嗪-1-基)-(1H-吲哚-2-基)-甲酮;(1H-吲哚-2-基)-(4-异丙基-哌嗪-1-基)-甲酮;[4-(3-二甲基氨基-丙基)-哌嗪-1-基]-(1H-吲哚-2-基)-甲酮;(4-丁基-哌嗪-1-基)-(1H-吲哚-2-基)-甲酮;(4-环戊基-哌嗪-1-基)-(1H-吲哚-2-基)-甲酮;(1H-吲哚-2-基)-(4-苯乙基-哌嗪-1-基)-甲酮;(1H-吲哚-2-基)-[4-(2-哌啶-1-基-乙基)-哌嗪-1-基]-甲酮;[4-(2-乙氧基-乙基)-哌嗪-1-基]-(1H-吲哚-2-基)-甲酮;(4-仲丁基-哌嗪-1-基)-(1H-吲哚-2-基)-甲酮;[4-(1-乙基-丙基)-哌嗪-1-基]-(1H-吲哚-2-基)-甲酮;(1H-吲哚-2-基)-[4-(3-苯基-丙基)-哌嗪-1-基]-甲酮;(1H-吲哚-2-基)-[4-(1-甲基-哌啶-4-基)-哌嗪-1-基]-甲酮;[4-(2-二丙基氨基-乙基)-哌嗪-1-基]-1H-吲哚-2-基)-甲酮;(1H-吲哚-2-基)-[4-(3-苯基-烯丙基)-哌嗪-1-基]-甲酮;(1H-吲哚-2-基)-(4-戊基-哌嗪-1-基)-甲酮;(4-庚基-哌嗪-1-基)-(1H-吲哚-2-基)-甲酮;[4-(2-二乙基氨基-乙基)-哌嗪-1-基]-(1H-吲哚-2-基)-甲酮;(1H-吲哚-2-基)-[4-(4-甲氧基-丁基)-哌嗪-1-基]-甲酮;5-氯-7-甲基-2-{3-[4-(1-甲基-哌啶-4-基)-丁氧基]-苯基}-1H-苯并咪唑;5,7-二甲基-2-{2-甲基-3-[4-(1-甲基-哌啶-4-基)-丁氧基]-苯基}-1H-苯并咪唑;5-氯-7-甲基-2-{2-甲基-3-[4-(1-甲基-哌啶-4-基)-丁氧基]-苯基}-1H-苯并咪唑;6-氟-7-甲基-2-{2-甲基-3-[4-(1-甲基-哌啶-4-基)-丁氧基]-苯基}-1H-苯并咪唑;6-氟-7-甲基-2-{3-[3-(1-甲基-哌啶-4-基氧基)-丙氧基]-苯基}-1H-苯并咪唑;{2-(5-氟-4-甲基-1H-苯并咪唑-2-基)-5-[3-(1-甲基-哌啶-4-基)-丙氧基]-苯基}-甲醇;6-氯-4-甲基-2-{6-[3-(4-甲基-哌嗪-1-基)-丙氧基]-吡啶-3-基}-1H-苯并咪唑;4-甲基-2-{6-[3-(4-甲基-哌嗪-1-基)-丙氧基]-吡啶-3-基}-1H-苯并咪唑;5-氟-4-甲基-2-{6-[3-(4-甲基-哌嗪-1-基)-丙氧基]-吡啶-3-基}-1H-苯并咪唑;4-甲基-2-{6-[3-(1-甲基-哌啶-4-基)-丙氧基]-吡啶-3-基}-1H-苯并咪唑;4,5-二甲基-2-{6-[3-(1-甲基-哌啶-4-基)-丙氧基]-吡啶-3-基}-1H-苯并咪唑;4-氯-2-{6-[3-(1-甲基-哌啶-4-基)-丙氧基]-吡啶-3-基}-1H-苯并咪唑;5-氟-4-甲基-2-{4-甲基-6-[3-(1-甲基-哌啶-4-基)-丙氧基]-吡啶-3-基}-1H-苯并咪唑;4,5-二甲基-2-{4-甲基-6-[3-(1-甲基-哌啶-4-基)-丙氧基]-吡啶-3-基}-1H-苯并咪唑;4,6-二甲基-2-{4-甲基-6-[3-(1-甲基-哌啶-4-基)-丙氧基]-吡啶-3-基}-1H-苯并咪唑;4-氯-2-{4-甲基-6-[3-(1-甲基-哌啶-4-基)-丙氧基]-吡啶-3-基}-1H-苯并咪唑;2-{4-氯-6-[3-(1-甲基-哌啶-4-基)-丙氧基]-吡啶-3-基}-5-氟-4-甲基-1H-苯并咪唑;2-{4-氯-6-[3-(1-甲基-哌啶-4-基)-丙氧基]-吡啶-3-基}-4-甲基-1H-苯并咪唑;6-氯-2-{4-氯-6-[3-(1-甲基-哌啶-4-基)-丙氧基]-吡啶-3-基}-4-甲基-1H-苯并咪唑;2-{4-氯-6-[3-(1-甲基-哌啶-4-基)-丙氧基]-吡啶-3-基}-4,6-二甲基-1H-苯并咪唑;2-{4-甲氧基-6-[3-(1-甲基-哌啶-4-基)-丙氧基]-吡啶-3-基}-4-甲基-1H-苯并咪唑;5-氟-2-{4-甲氧基-6-[3-(1-甲基-哌啶-4-基)-丙氧基]-吡啶-3-基}-4-甲基-1H-苯并咪唑;5-氟-4-甲基-2-{6-[3-(1-甲基-1,2,3,6-四氢-吡啶-4-基)-丙氧基]-吡啶-3-基}-1H-苯并咪唑;4-甲基-2-{6-[3-(1-甲基-1,2,3,6-四氢-吡啶-4-基)-丙氧基]-吡啶-3-基}-1H-苯并咪唑;6-氯-4-甲基-2-{6-[3-(1-甲基-1,2,3,6-四氢-吡啶-4-基)-丙氧基]-吡啶-3-基}-1H-苯并咪唑;4,5-二甲基-2-{6-[3-(1-甲基-1,2,3,6-四氢-吡啶-4-基)-丙氧基]-吡啶-3-基}-1H-苯并咪唑;4,6-二甲基-2-{6-[3-(1-甲基-1,2,3,6-四氢-吡啶-4-基)-丙氧基]-吡啶-3-基}-1H-苯并咪唑;5-氯-4-甲基-2-{6-[3-(1-甲基-1,2,3,6-四氢-吡啶-4-基)-丙氧基]-吡啶-3-基}-1H-苯并咪唑;5-氟-4-甲基-2-{6-[3-(1-甲基-哌啶-4-基)-丙氧基]-4-吡咯烷-1-基甲基-吡啶-3-基}-1H-苯并咪唑;2-{5-溴-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-4-甲基-1H-苯并咪唑;2-{5-溴-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-5-氟-4-甲基-1H-苯并咪唑;2-{5-溴-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-6-氯-4-甲基-1H-苯并咪唑;2-{5-溴-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-4,6-二甲基-1H-苯并咪唑;2-{5-溴-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-4,5-二甲基-1H-苯并咪唑;2-{5-溴-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-5-氯-4-甲基-1H-苯并咪唑;2-{5-溴-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-5-叔丁基-1H-苯并咪唑;5-叔丁基-2-{2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-1H-苯并咪唑;2-{5-氯-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-5-氟-4-甲基-1H-苯并咪唑;2-{5-氯-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-4,5-二甲基-1H-苯并咪唑;4,6-二甲基-2-{2-[4-(4-甲基-哌嗪-1-基)-丁氧基]-吡啶-4-基}-1H-苯并咪唑;4-甲基-2-{2-[4-(4-甲基-哌嗪-1-基)-丁氧基]-吡啶-4-基}-1H-苯并咪唑;4,5-二甲基-2-{2-[4-(4-甲基-哌嗪-1-基)-丁氧基]-吡啶-4-基}-1H-苯并咪唑;5-氟-4-甲基-2-{2-[4-(4-甲基-哌嗪-1-基)-丁氧基]-吡啶-4-基}-1H-苯并咪唑;6-氯-4-甲基-2-{2-[4-(4-甲基-哌嗪-1-基)-丁氧基]-吡啶-4-基}-1H-苯并咪唑;5-氟-4-甲基-2-{2-[4-(4-甲基-[1,4]二氮杂环庚烷-1-基)-丁氧基]-吡啶-4-基}-1H-苯并咪唑;4,5-二甲基-2-{2-[4-(4-甲基-[1,4]二氮杂环庚烷-1-基)-丁氧基]-吡啶-4-基}-1H-苯并咪唑;4,6-二甲基-2-{2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-1H-苯并咪唑;4-甲基-2-{2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-1H-苯并咪唑;5-氟-4-甲基-2-{2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-1H-苯并咪唑;4-氯-2-{2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-1H-苯并咪唑;4,5-二甲基-2-{2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-1H-苯并咪唑;6-氯-4-甲基-2-{2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-1H-苯并咪唑;5-叔丁基-2-[2-(4-哌啶-4-基-丁氧基)-吡啶-4-基]-1H-苯并咪唑;4,6-二甲基-2-[2-(4-哌啶-4-基-丁氧基)-吡啶-4-基]-1H-苯并咪唑;2-{2-[4-(1-乙基-哌啶-4-基)-丁氧基]-吡啶-4-基}-4,5-二甲基-1H-苯并咪唑;4,6-二甲基-2-{3-甲基-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-1H-苯并咪唑;4-甲基-2-{3-甲基-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-1H-苯并咪唑;6-氯-4-甲基-2-{3-甲基-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-1H-苯并咪唑;2-{3-氯-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-4-甲基-1H-苯并咪唑;2-{3-氯-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-4,5-二甲基-1H-苯并咪唑;4-氯-2-{3-氯-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-1H-苯并咪唑;2-{3-氯-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-5-氟-4-甲基-1H-苯并咪唑;2-{3-氯-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-4,6-二甲基-1H-苯并咪唑;6-氯-2-{3-氯-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-4-甲基-1H-苯并咪唑;5-氟-4-甲基-2-{5-甲基-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-1H-苯并咪唑;5-氯-6-氟-2-{5-甲基-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-1H-苯并咪唑;5-叔丁基-2-{5-甲基-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-1H-苯并咪唑;4,5-二甲基-2-{5-甲基-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-1H-苯并咪唑;2-{5-氯-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-4,6-二甲基-1H-苯并咪唑;5-叔丁基-2-{5-氯-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-1H-苯并咪唑;2-{5-溴-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-4-氯-1H-苯并咪唑;2-{5-溴-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-5-氯-6-氟-1H-苯并咪唑;2-{5-溴-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶-4-基}-5-氯-1H-苯并咪唑;1-(3-{4-[4,5-双-(4-溴-苯基)-1H-咪唑-2-基]-3-氯-苯氧基}-丙基)-4-甲基-哌嗪;1-{3-[3-氯-4-(4,5-联苯基-1H-咪唑-2-基)-苯氧基]-丙基}-4-甲基-哌嗪;1-(3-{4-[4,5-双-(4-甲氧基-苯基)-1H-咪唑-2-基]-3-氯-苯氧基}-丙基)-4-甲基-哌嗪;1-{3-[3-氯-4-(4,5-二-对甲苯基-1H-咪唑-2-基)-苯氧基]-丙基}-4-甲基-哌嗪;1-(3-{4-[4,5-双-(3-甲氧基-苯基)-1H-咪唑-2-基]-3-氯-苯氧基}-丙基)-4-甲基-哌嗪;1-(3-{4-[4,5-双-(3-甲氧基-苯基)-1H-咪唑-2-基]-2-氟-苯氧基}-丙基)-4-甲基-哌嗪;1-(3-{4-[4,5-双-(4-溴-苯基)-1H-咪唑-2-基]-3-氯-苯氧基}-丙基)-4-甲基-[1,4]二氮杂环庚烷;1-(3-{4-[4,5-双-(3-甲氧基-苯基)-1H-咪唑-2-基]-3-氯-苯氧基}-丙基)-4-甲基-[1,4]二氮杂环庚烷;2-{3-氯-4-[3-(4-甲基-[1,4]二氮杂环庚烷-1-基)-丙氧基]-苯基}-4,5,6,7-四氢-1H-苯并咪唑;2-{2-氯-4-[3-(4-甲基-[1,4]二氮杂环庚烷-1-基)-丙氧基]-苯基}-4,5,6,7-四氢-1H-苯并咪唑;1-甲基-4-{3-[3-甲基-4-(4-苯基-5-三氟甲基-1H-咪唑-2-基)-苯氧基]-丙基}-哌啶;4-{3-[3-氯-4-(4-苯基-5-三氟甲基-1H-咪唑-2-基)-苯氧基]-丙基}-1-甲基-哌啶;4-(3-{3-氯-4-[5-甲基-4-(3-三氟甲基-苯基)-1H-咪唑-2-基]-苯氧基}-丙基)-1-甲基-哌啶;4-(3-{3-氯-4-[4-(3,5-二氯-苯基)-5-甲基-1H-咪唑-2-基]-苯氧基}-丙基)-1-甲基-哌啶;4-(3-{4-[4-(3,5-二氯-苯基)-5-甲基-1H-咪唑-2-基]-3-甲基-苯氧基}-丙基)-1-甲基-哌啶;4-(3-{3-氯-4-[4-(4-氯-苯基)-5-甲基-1H-咪唑-2-基]-苯氧基}-丙基)-1-甲基-哌啶;4-(3-{4-[4,5-双-(4-氟-苯基)-1H-咪唑-2-基]-3-氯-苯氧基}-丙基)-1-甲基-哌啶;4-(3-{4-[4,5-双-(3-甲氧基-苯基)-1H-咪唑-2-基]-3-氯-苯氧基}-丙基)-1-甲基-哌啶;4-(3-{3-氯-4-[4-(4-氯-苯基)-5-对甲苯基-1H-咪唑-2-基]-苯氧基}-丙基)-1-甲基-哌啶;2-{2-氯-4-[3-(1-甲基-哌啶-4-基)-丙氧基]-苯基}-4,5,6,7-四氢-1H-苯并咪唑;4-{3-[3-氯-4-(4-甲基-5-丙基-1H-咪唑-2-基)-苯氧基]-丙基}-1-甲基-哌啶;4-{3-[3-氯-4-(5-乙基-4-甲基-1H-咪唑-2-基)-苯氧基]-丙基}-1-甲基哌啶;1-甲基-4-(2-{3-甲基-4-[5-甲基-4-(3-三氟甲基-苯基)-1H-咪唑-2-基]-苯氧基}-乙氧基)-哌啶;5-[4-(4-氯-苯基)-5-甲基-1H-咪唑-2-基]-2-[3-(1-甲基-哌啶-4-基)-丙氧基]-吡啶;2-[3-(1-甲基-哌啶-4-基)-丙氧基]-5-[5-甲基-4-(3-三氟甲基-苯基)-1H-咪唑-2-基]-吡啶;2-[3-(1-甲基-哌啶-4-基)-丙氧基]-5-[5-甲基-4-(4-三氟甲基-苯基)-1H-咪唑-2-基]-吡啶;2-[3-(1-甲基-哌啶-4-基)-丙氧基]-5-(4-苯基-5-三氟甲基-1H-咪唑-2-基)-吡啶;1-甲基-4-(3-{5-[5-甲基-4-(4-三氟甲基-苯基)-1H-咪唑-2-基]-吡啶-2-基氧基}-丙基)-哌嗪;1-甲基-4-(3-{5-[5-甲基-4-(3-三氟甲基-苯基)-1H-咪唑-2-基]-吡啶-2-基氧基}-丙基)-哌嗪;4-(4-{3-[4-(4-氯-苯基)-5-甲基-1H-咪唑-2-基]-苯氧基}-丁基)-1-甲基-哌啶;1-甲基-4-{4-[3-(4-苯基-5-三氟甲基-1H-咪唑-2-基)-苯氧基]-丁基}-哌啶;2-[4-(1-甲基-哌啶-4-基)-丁氧基]-4-(4-苯基-5-三氟甲基-1H-咪唑-2-基)-吡啶;2-[4-(1-甲基-哌啶-4-基)-丁氧基]-4-[5-甲基-4-(3-三氟甲基-苯基)-1H-咪唑-2-基]-吡啶;4-{3-[4-(5-异丁基-4-甲基-1H-咪唑-2-基)-3-甲基-苯氧基]-丙基}-1-甲基-哌啶;4-[4-(4-氯-苯基)-5-甲基-1H-咪唑-2-基]-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶;4-{3-[3-氯-4-(5-异丁基-4-甲基-1H-咪唑-2-基)-苯氧基]-丙基}-1-甲基-哌啶;1-甲基-4-(4-{3-[5-甲基-4-(4-三氟甲基-苯基)-1H-咪唑-2-基]-苯氧基}-丁基)-哌啶;1-{3-[2-氯-4-(1H-咪唑-2-基)-苯氧基]-丙基}-4-甲基-哌嗪;1-{3-[3-氯-4-(4,5-二甲基-1H-咪唑-2-基)-苯氧基]-丙基}-4-甲基-哌嗪;1-{3-[3-氯-4-(4-苯基-5-三氟甲基-1H-咪唑-2-基)-苯氧基]-丙基}-4-甲基-哌嗪;1-{3-[2-氯-4-(4-苯基-5-三氟甲基-1H-咪唑-2-基)-苯氧基]-丙基}-4-甲基-[1,4]二氮杂环庚烷;1-甲基-4-(3-{3-甲基-4-[5-甲基-4-(3-三氟甲基-苯基)-1H-咪唑-2-基]-苯氧基}-丙基)-哌啶;4-(3-{4-[4-(4-氯-苯基)-5-甲基-1H-咪唑-2-基]-3-甲基-苯氧基}-丙基)-1-甲基-哌啶;4-(2-{4-[4-(4-氯-苯基)-5-甲基-1H-咪唑-2-基]-3-甲基-苯氧基}-乙氧基)-1-甲基-哌啶;1-(3-{4-[4-(4-氯-苯基)-5-甲基-1H-咪唑-2-基]-3-甲基-苯氧基}-2-甲基-丙基)-4-甲基-哌嗪;2-[4-(4-氯-苯基)-5-甲基-1H-咪唑-2-基]-6-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶;4-甲基-2-[3-(1-甲基-哌啶-4-基)-丙氧基]-5-[5-甲基-4-(3-三氟甲基-苯基)-1H-咪唑-2-基]-吡啶;5-溴-4-[4-(4-氯-苯基)-5-甲基-1H-咪唑-2-基]-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶;2,4-二甲基-1-{3-[4-(4-苯基-5-三氟甲基-1H-咪唑-2-基)-苯氧基]-丙基}-哌嗪;1,2-二甲基-4-{3-[4-(4-苯基-5-三氟甲基-1H-咪唑-2-基)-苯氧基]-丙基}-哌嗪;3-氯-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-4-(4-苯基-5-三氟甲基-1H-咪唑-2-基)-吡啶;1-甲基-4-(4-{4-[5-甲基-4-(3-三氟甲基-苯基)-1H-咪唑-2-基]-吡啶-2-基氧基}-丁基)-[1,4]二氮杂环庚烷;5-溴-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-4-[5-甲基-4-(3-三氟甲基-苯基)-1H-咪唑-2-基]-吡啶;4-[4-(4-氯-苯基)-5-三氟甲基-1H-咪唑-2-基]-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-嘧啶;4-(3-{4-[5-环丙基甲基-4-(3-三氟甲基-苯基)-1H-咪唑-2-基]-3-甲基-苯氧基)-丙基)-1-甲基-哌啶;1-{4-[4-(4-氯-苯基)-5-甲基-1H-咪唑-2-基]-3-甲基-苯氧基}-3-(4-甲基-哌嗪-1-基)-丙-2-醇;4-(3-{3-氯-4-[4-(4-氯-苯基)-5-甲基-1H-咪唑-2-基]-苯氧基}-丙基)-哌啶;4-(3-{3-氯-4-[4-(4-氯-苯基)-5-甲基-1H-咪唑-2-基]-苯氧基}-丙基)-1-乙基-哌啶;4-(3-{3-氯-4-[4-(4-氯-苯基)-5-甲基-1H-咪唑-2-基]-苯氧基}-丙基)-1-异丙基-哌啶;1-甲基-4-{3-[4-(4-苯基-5-三氟甲基-1H-咪唑-2-基)-萘-1-基氧基]-丙基}-哌啶;1-(4-甲基-哌嗪-1-基)-3-{5-[5-甲基-4-(4-三氟甲基-苯基)-1H-咪唑-2-基]-吡啶-2-基氧基}-丙-1-酮;6-[4-(4-氯-苯基)-5-甲基-1H-咪唑-2-基]-3-氟-2-[4-(1-甲基-哌啶-4-基)-丁氧基]-吡啶;1-甲基-4-(4-{3-甲基-6-[5-甲基-4-(3-三氟甲基-苯基)-1H-咪唑-2-基]-吡啶-2-基氧基}-丁基)-哌嗪;1-甲基-4-{3-[4-(5-甲基-4-噻吩-2-基-1H-咪唑-2-基)-苯氧基]-丙基}-哌啶;2-{3-[4-(1-甲基-哌啶-4-基)-丁氧基]-苯基}-3H-咪唑并[4,5-b]吡啶;(5-氯-1H-吲哚-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(5-氟-1H-吲哚-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(5-溴-1H-吲哚-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(5-甲基-1H-吲哚-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(5,7-二氟-1H-吲哚-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(7-氯-1H-吲哚-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(5,7-二氯-1H-吲哚-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(3,5-二氯-1H-吲哚-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(6-氯-1H-吲哚-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(1H-吲哚-2-基)-(3-甲基-哌嗪-1-基)-甲酮;(7-溴-1H-吲哚-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(5-溴-苯并呋喃-2-基)-(4-甲基-哌嗪-1-基)-甲酮;(1H-吲哚-2-基)-(4-甲基-哌嗪-1-基)-甲硫酮;[5-(5-氟-4-甲基-1H-苯并咪唑-2-基)-4-甲基-嘧啶-2-基]-[3-(1-甲基-哌啶-4-基)-丙基]-胺;和[5-(4,6-二甲基-1H-苯并咪唑-2-基)-4-甲基-嘧啶-2-基]-[3-(1-甲基-哌啶-4-基)-丙基]-胺及其可药用盐。
在另一实施方案中,选择性组胺H4拮抗剂选自在国际专利申请WO2009/079001中描述的那些:5-氟-4-甲基-2-{4-甲基-1-[3-(1-甲基-哌啶-4-基)-丙基]-2,3-二氢-1H-吲哚-5-基}-1H-苯并咪唑;4,5-二甲基-2-{4-甲基-1-[3-(1-甲基-哌啶-4-基)-丙基]-2,3-二氢-1H-吲哚-5-基}-1H-苯并咪唑;2-{4-氯-1-[3-(1-甲基-哌啶-4-基)-丙基]-2,3-二氢-1H-吲哚-5-基}-4,6-二甲基-1H-苯并咪唑;2-{4-氯-1-[3-(1-甲基-哌啶-4-基)-丙基]-2,3-二氢-1H-吲哚-5-基}-5-氟-4-甲基-1H-苯并咪唑;2-{4-氯-1-[3-(1-甲基-哌啶-4-基)-丙基]-2,3-二氢-1H-吲哚-5-基}-1H-苯并咪唑-5-羧酸甲酯;5-氟-2-{4-氟-1-[3-(1-甲基-哌啶-4-基)-丙基]-2,3-二氢-1H-吲哚-5-基}-4-甲基-1H-苯并咪唑;5-氟-4-甲基-2-{4-甲基-1-[3-(1-甲基-哌啶-4-基)-丙基]-1H-吲哚-5-基}-1H-苯并咪唑;2-{4-氯-1-[3-(1-甲基-哌啶-4-基)-丙基]-1H-吲哚-5-基}-5-氟-4-甲基-1H-苯并咪唑;2-{4-氯-1-[3-(1-甲基-哌啶-4-基)-丙基]-1H-吲哚-5-基}-4,6-二甲基-1H-苯并咪唑;5-氯-2-{4-甲基-1-[3-(1-甲基-哌啶-4-基)-丙基]-1H-吲哚-5-基}-1H-苯并咪唑;5-氟-4-甲基-2-{1-[3-(1-甲基-哌啶-4-基)-丙基]-1H-吲哚-5-基}-1H-苯并咪唑;4-甲基-2-{1-[3-(1-甲基-哌啶-4-基)-丙基]-1H-吲哚-5-基}-1H-苯并咪唑;5-氟-4-甲基-2-{1-[3-(4-甲基-哌嗪-1-基)-丙基]-1H-吲哚-5-基}-1H-苯并咪唑;2-{2,3-二甲基-1-[3-(1-甲基-哌啶-4-基)-丙基]-1H-吲哚-5-基}-4,6-二甲基-1H-苯并咪唑;2-{2,3-二甲基-1-[3-(1-甲基-哌啶-4-基)-丙基]-1H-吲哚-5-基}-5-氟-4-甲基-1H-苯并咪唑;5-氟-4-甲基-2-{1-[4-(1-甲基-哌啶-4-基)-丁基]-1H-吲哚-4-基}-1H-苯并咪唑;4-氯-2-{1-[4-(1-甲基-哌啶-4-基)-丁基]-1H-吲哚-4-基}-1H-苯并咪唑;2-{1-[4-(1-甲基-哌啶-4-基)-丁基]-1H-吲哚-4-基}-5-三氟甲基-1H-苯并咪唑;6-{1-[4-(1-甲基-哌啶-4-基)-丁基]-1H-吲哚-4-基}-5H-[1,3]二氧并[4’,5’:4,5]苯并[1,2-d]-咪唑;(2-{1-[4-(1-甲基-哌啶-4-基)-丁基]-1H-吲哚-4-基}-1H-苯并咪唑-5-基)-苯基-甲酮;2-{1-[4-(1-甲基-哌啶-4-基)-丁基]-1H-吲哚-4-基}-1H-萘并[2,3-d]咪唑;6-氯-4-甲基-2-{1-[4-(1-甲基-哌啶-4-基)-丁基]-1H-吲哚-4-基}-1H-苯并咪唑;4-甲基-2-{1-[4-(1-甲基-哌啶-4-基)-丁基]-1H-吲哚-4-基}-1H-苯并咪唑;5-叔丁基-2-{1-[4-(1-甲基-哌啶-4-基)-丁基]-1H-吲哚-4-基}-1H-苯并咪唑;4,6-二甲基-2-{1-[4-(1-甲基-哌啶-4-基)-丁基]-1H-吲哚-6-基}-1H-苯并咪唑;5-氟-4-甲基-2-{1-[4-(1-甲基-哌啶-4-基)-丁基]-1H-吲哚-6-基}-1H-苯并咪唑;4-甲基-2-{1-[4-(1-甲基-哌啶-4-基)-丁基]-1H-吲哚-6-基}-1H-苯并咪唑;5-叔丁基-2-{3-氯-1-[3-(1-甲基-哌啶-4-基)-丙基]-1H-吲哚-5-基}-1H-苯并咪唑;6-氯-2-{3-氯-1-[3-(1-甲基-哌啶-4-基)-丙基]-1H-吲哚-5-基}-4-甲基-1H-苯并咪唑;2-{3-氯-1-[4-(1-甲基-哌啶-4-基)-丁基]-1H-吲哚-4-基}-5-三氟甲基-1H-苯并咪唑;2-{3-氯-1-[4-(1-甲基-哌啶-4-基)-丁基]-1H-吲哚-4-基}-5-氟-4-甲基-1H-苯并咪唑;2-{3-氯-1-[4-(1-甲基-哌啶-4-基)-丁基]-1H-吲哚-4-基}-5,6-二氟-1H-苯并咪唑;5-氟-4-甲基-2-[1-(3-哌嗪-1-基-丙基)-1H-吲哚-5-基]-1H-苯并咪唑;5-叔丁基-2-[3-氯-1-(3-哌啶-4-基-丙基)-1H-吲哚-5-基]-1H-苯并咪唑;5-氟-4-甲基-2-[1-(4-哌啶-4-基-丁基)-1H-吲哚-4-基]-1H-苯并咪唑;4-氯-2-[1-(4-哌啶-4-基-丁基)-1H-吲哚-4-基]-1H-苯并咪唑;4,6-二甲基-2-[1-(4-哌啶-4-基-丁基)-1H-吲哚-6-基]-1H-苯并咪唑;5-氟-4-甲基-2-[1-(4-哌啶-4-基-丁基)-1H-吲哚-6-基]-1H-苯并咪唑;[5-(5-叔丁基-1H-苯并咪唑-2-基)-1-(4-哌啶-4-基-丁基)-1H-吲哚-3-基甲基]-二甲基-胺;5-氟-4-甲基-1'-[3-(1-甲基-哌啶-4-基)-丙基]-1H,1'H-[2,5']二苯并咪唑基;5-氟-4-甲基-3'-[3-(1-甲基-哌啶-4-基)-丙基]-1H,3Η-[2,5']二苯并咪唑基;4-甲基-1'-[4-(1-甲基-哌啶-4-基)-丁基]-1H,1’H-[2,5’]二苯并咪唑基;4-甲基-3l-[4-(1-甲基-哌啶-4-基)-丁基]-1H,3’H-[2,5’]二苯并咪唑基;5-氟-4-甲基-1'-[4-(1-甲基-哌啶-4-基)-丁基]-1H,1’Η-[2,5']二苯并咪唑基;5-氟-4-甲基-3'-[4-(1-甲基-哌啶-4-基)-丁基]-1H,3’Η-[2,5']二苯并咪唑基;5-氟-4-甲基-2-{1-[3-(1-甲基-哌啶-4-基)-丙基]-1H-吡咯并[2,3-b]吡啶-5-基}-1H-苯并咪唑;4,5-二甲基-2-{1-[3-(1-甲基-哌啶-4-基)-丙基]-1H-吡咯并[2,3-b]吡啶-5-基}-1H-苯并咪唑;2-{6-氯-1-[3-(1-甲基-哌啶-4-基)-丙基]-1H-吲哚-5-基}-4,6-二氟-1H-苯并咪唑;2-[6-氯-1-(3-哌啶-4-基-丙基)-1H-吲哚-5-基]-5-氟-4-甲基-1H-苯并咪唑;2-{6-氯-1-[3-(1-甲基-哌啶-4-基)-丙基]-1H-吲哚-5-基}-5-氟-4-甲基-1H-苯并咪唑;5-氟-4,4’-二甲基-1'-[3-(1-甲基-哌啶-4-基)-丙基]-1H,1’H-[2,5']二苯并咪唑基;5,4'-三甲基-1’[3-(1-甲基-哌啶-4-基)-丙基]-1H,1’Η-[2,5']二苯并咪唑基;4,4’-二甲基-1’-[3-(1-甲基-哌啶-4-基)-丙基]-1H,1’Η-[2,5']二苯并咪唑基;5-氯-4,4'-二甲基-1’-[3-(1-甲基-哌啶-4-基)-丙基]-1H,1’H-[2,5']二苯并咪唑基;6-氟-4,4'-二甲基-1’-[3-(1-甲基-哌啶-4-基)-丙基]-1H,1’H-[2,5']二苯并咪唑基;4,5-二甲基-2-[1-(3-哌啶-4-基-丙基)-2,3-二氢-1H-吲哚-5-基]-1H-苯并咪唑;4,6-二甲基-2-{4-甲基-1-[3-(1-甲基-哌啶-4-基)-丙基]-2,3-二氢-1H-吲哚-5-基}-1H-苯并咪唑;5-氯-2-{4-甲基-1-[3-(1-甲基-哌啶-4-基)-丙基]-2,3-二氢-1H-吲哚-5-基}-1H-苯并咪唑;6-氟-4-甲基-2-{4-甲基-1-[3-(1-甲基-哌啶-4-基)-丙基]-2,3-二氢-1H-吲哚-5-基}-1H-苯并咪唑;2-甲基-7-{4-甲基-1-[3-(1-甲基-哌啶-4-基)-丙基]-2,3-二氢-1H-吲哚-5-基}-6H-咪唑并{4’,5’:3,4]苯并[2,1-d]噻唑;4,6-二甲基-2-{4-甲基-1-[3-(1-甲基-哌啶-4-基)-丙基]-1H-吲哚-5-基}-1H-苯并咪唑;4,5-二甲基-2-[1-(3-哌嗪-1-基-丙基)-1H-吲哚-5-基]-1H-苯并咪唑;5-叔丁基-2-[1-(3-哌嗪-1-基-丙基)-1H-吲哚-5-基]-1H-苯并咪唑;5-氯-2-[1-(3-哌嗪-1-基-丙基)-1H-吲哚-5-基]-1H-苯并咪唑;5-氯-2-{1-[3-(4-甲基-哌嗪-1-基)-丙基]-1H-吲哚-5-基}-1H-苯并咪唑;4-甲基-2-[1-(4-哌啶-4-基-丁基)-1H-吲哚-4-基]-1H-苯并咪唑;5,6-二氟-2-{1-[4-(1-甲基-哌啶-4-基)-丁基]-1H-吲哚-4-基}-1H-苯并咪唑;5-氯-2-{1-[4-(1-甲基-哌啶-4-基)-丁基]-1H-吲哚-4-基}-1H-苯并咪唑;5-氟-2-{1-[4-(1-甲基-哌啶-4-基)-丁基]-1H-吲哚-4-基}-1H-苯并咪唑;4,6-二氟-2-{1-[4-(1-甲基-哌啶-4-基)-丁基]-1H-吲哚-4-基}-1H-苯并咪唑;2-{1-[4-(1-甲基-哌啶-4-基)-丁基]-1H-吲哚-4-基}-1H-萘并[1,2-d]咪唑;(2-{3-氯-1-[4-(1-甲基-哌啶-4-基)-丁基]-1H-吲哚-4-基}-3H-苯并咪唑-4-基)-苯基-甲酮;2-[3-氯-1-(4-哌啶-4-基-丁基)-1H-吲哚-4-基]-4,5-二甲基-1H-苯并咪唑;2-{3-氯-1-[4-(1-甲基-哌啶-4-基)-丁基]-1H-吲哚-4-基}-4,5-二甲基-1H-苯并咪唑;2-{3-氯-1-[4-(1-甲基-哌啶-4-基)-丁基]-1H-吲哚-4-基}-4,5-二氟-1H-苯并咪唑;6-[1-(4-哌啶-4-基-丁基)-1H-吲哚-4-基]-5H-[1.3二氧并[4’,5’:4,5]-苯并[1,2-d]咪唑;苯基-{2-[1-(4-哌啶-4-基-丁基)-1H-吲哚-4-基]-1H-苯并咪唑-5-基}-甲酮;4,5-二甲基-2-{1-[4-(1-甲基-哌啶-4-基)-丁基]-1H-吲哚-4-基}-1H-苯并咪唑;1-[3-(4-甲基-哌嗪-1-基)-丙基]-5-[5-甲基-4-(3-三氟甲基-苯基)-1H-咪唑-2-基]-1H-吲哚;5-[4-(4-氯-苯基)-5-甲基-1H-咪唑-2-基]-1-[3-(4-甲基-哌嗪-1-基)-丙基]-1H-吲哚;4-甲基-1-[3-(1-甲基-哌啶-4-基)-丙基]-5-(4-甲基-5-丙基-1H-咪唑-2-基)-1H-苯并咪唑;4-甲基-1-[3-(1-甲基-哌啶-4-基)-丙基]-5-[4-甲基-5-(4-三氟甲基-苯基)-1H-咪唑-2-基]-1H-苯并咪唑;5-[5-(3,5-二氯-苯基)-4-甲基-1H-咪唑-2-基]-4-甲基-1-[3-(1-甲基-哌啶-4-基)-丙基]-1H-苯并咪唑;4-甲基-1-[3-(1-甲基-哌啶-4-基)-丙基]-5-(5-苯基-4-三氟甲基-1H-咪唑-2-基)-1H-苯并咪唑;5-[5-(4-氯-苯基)-4-对甲苯基-1H-咪唑-2-基]-4-甲基-1-[3-(1-甲基-哌啶-4-基)-丙基]-1H-苯并咪唑;{5-(5-氟-4-甲基-1H-苯并咪唑-2-基)-1-[3-(1-甲基-哌啶-4-基)-丙基]-1H-吲哚-3-基甲基}-二甲基-胺;2-[3-氯-1-(3-哌啶-4-基-丙基)-1H-吲哚-5-基]-5-氟-4-甲基-1H-苯并咪唑;2-{3-氯-1-[3-(1-甲基-哌啶-4-基)-丙基]-1H-吲哚-5-基}-5-氟-4-甲基-1H-苯并咪唑;2-[2,3-二甲基-1-(3-哌啶-4-基-丙基)-1H-吲哚-5-基]-4,6-二甲基-1H-苯并咪唑;2-[2,3-二甲基-1-(3-哌啶-4-基-丙基)-1H-吲哚-5-基]-5-氟-4-甲基-1H-苯并咪唑;5-氟-4-甲基-2-[1-(3-哌啶-4-基-丙基)-1H-吡咯并[2,3-b]吡啶-5-基]-1H-苯并咪唑;5-叔丁基-2-{1-[3-(1-甲基-哌啶-4-基)-丙基]-1H-吡咯并[2,3-b]吡啶-5-基}-1H-苯并咪唑;5-氟-4-甲基-2-[1-(3-哌啶-4-基-丙基)-2,3-二氢-1H-吲哚-5-基]-1H-苯并咪唑;5-氯-2-[1-(3-哌啶-4-基-丙基)-2,3-二氢-1H-吲哚-5-基]-1H-苯并咪唑;4-甲基-2-[1-(3-哌啶-4-基-丙基)-2,3-二氢-1H-吲哚-5-基]-1H-苯并咪唑;5-氟-4-甲基-2-{1-[3-(1-甲基-哌啶-4-基)-丙基]-2,3-二氢-1H-吲哚-5-基}-1H-苯并咪唑;5-氯-2-{1-[3-(1-甲基-哌啶-4-基)-丙基]-2,3-二氢-1H-吲哚-5-基}-1H-苯并咪唑;4-甲基-2-{1-[3-(1-甲基-哌啶-4-基)-丙基]-2,3-二氢-1H-吲哚-5-基}-1H-苯并咪唑;2-[6-氯-1-(3-哌啶-4-基-丙基)-1H-吲哚-5-基]-4,6-二氟-1H-苯并咪唑;2-[6-氯-1-(3-哌啶-4-基-丙基)-1H-吲哚-5-基]-4,5-二甲基-1H-苯并咪唑;5-氯-2-[6-氯-1-(3-哌啶-4-基-丙基)-1H-吲哚-5-基]-1H-苯并咪唑;5-氯-2-{6-氯-1-[3-(1-甲基-哌啶-4-基)-丙基]-1H-吲哚-5-基}-1H-苯并咪唑;2-{6-氯-1-[3-(1-甲基-哌啶-4-基)-丙基]-1H-吲哚-5-基}-4,5-二甲基-1H-苯并咪唑;6-氯-4-甲基-2-[1-(4-哌啶-4-基-丁基)-1H-吲哚-4-基]-1H-苯并咪唑;5-叔丁基-2-[1-(4-哌啶-4-基-丁基)-1H-吲哚-4-基]-1H-苯并咪唑;6,7-二甲基-2-[1-(4-哌啶-4-基-丁基)-1H-吲哚-4-基]-1H-苯并咪唑;4-甲基-2-[1-(4-哌啶-4-基-丁基)-1H-吲哚-6-基]-1H-苯并咪唑;6-氯-4-甲基-2-[1-(4-哌啶-4-基-丁基)-1H-吲哚-6-基]-1H-苯并咪唑;5-叔丁基-2-[1-(4-哌啶-4-基-丁基)-1H-吲哚-6-基]-1H-苯并咪唑;4,5-二氟-2-[1-(4-哌啶-4-基-丁基)-1H-吲哚-4-基]-1H-苯并咪唑;4,4’-二甲基-1’-(3-哌啶-4-基-丙基)-1H,1'H-[2,5l]二苯并咪唑基;6-氟-4,4’-二甲基-1'-(3-哌啶-4-基-丙基)-1H,1’H-[2,5’]二苯并咪唑基;5-氯-4,4’-二甲基-1'-(3-哌啶-4-基-丙基)-1H,1’H-[2,5’]二苯并咪唑基;5-氟-4,4’-二甲基-1'-(3-哌啶-4-基-丙基)-1H,1’H-[2,5’]二苯并咪唑基;5-氟-2-[1-(4-哌啶-4-基-丁基)-1H-吲哚-4-基]-1H-苯并咪唑;4,6-二氟-2-[1-(4-哌啶-4-基-丁基)-1H-吲哚-4-基]-1H-苯并咪唑;4-甲基-1’-(4-哌啶-4-基-丁基)-1H,1’H-[2,5’]二苯并咪唑基;4,5-二甲基-1'-(4-哌啶-4-基-丁基)-1H,1'H-[2,5’]二苯并咪唑基;5-氟-1'-(4-哌啶-4-基-丁基)-1H,1'H-[2,4']二苯并咪唑基;5-氟-1'-[4-(1-甲基-哌啶-4-基)-丁基]-1H,1’Η-[2,4']二苯并咪唑基;4,5-二甲基-1’-[4-(1-甲基-哌啶-4-基)-丁基]-1H,1'H-[2,5']二苯并咪唑基;4-甲基-3’-(4-哌啶-4-基-丁基)-1H,3Η-[2,5’]二苯并咪唑基;4,5-二甲基-3’-(4-哌啶-4-基-丁基)-1H,3Η-[2,5’]二苯并咪唑基;5-氟-3’-(4-哌啶-4-基-丁基)-1H,3Η-[2,5’]二苯并咪唑基;4,5-二甲基-3'-[4-(1-甲基-哌啶-4-基)-丁基]-1H,3Η-[2,5’]二苯并咪唑基;5-氟-3'-[4-(1-甲基-哌啶-4-基)-丁基]-1H,3'H[2,5’]二苯并咪唑基;2-[1-(4-哌啶-4-基-丁基)-1H-吲哚-4-基]-1H-萘并[2,3-d]咪唑;2-[1-(4-哌啶-4-基-丁基)-1H-吲哚-4-基]-1H-萘并[1,2-d]咪唑;{2-[3-氯-1-(4-哌啶-4-基-丁基)-1H-吲哚-4-基]-1H-苯并咪唑-5-基}-苯基-甲酮;2-[3-氯-1-(4-哌啶-4-基-丁基)-1H-吲哚-4-基]-5-三氟甲基-1H-苯并咪唑;2-[3-氯-1-(4-哌啶-4-基-丁基)-1H-吲哚-4-基]-5,6-二氟-1H-苯并咪唑;2-[3-氯-1-(4-哌啶-4-基-丁基)-1H-吲哚-4-基]-4,5-二氟-1H-苯并咪唑;2-[3-氯-1-(4-哌啶-4-基-丁基)-1H-吲哚-4-基]-5-氟-4-甲基-1H-苯并咪唑;7-[3-氯-1-(4-哌啶-4-基-丁基)-1H-吲哚-4-基]-2-甲基-8H-2-[3-氯-1-(4-哌啶-4-基-丁基)-1H-吲哚-4-基]-3H-苯并咪唑-5-羧酸甲酯;2-{3-氯-1-[4-(1-甲基-哌啶-4-基)-丁基]-1H-吲哚-4-基}-3H-苯并咪唑-5-羧酸甲酯;4,5,4'-三甲基-1'-(3-哌啶-4-基-丙基)-1’H,1Η-[2,5']二苯并咪唑基;4,6-二甲基-2-[1-(4-哌啶-4-基-丁基)-1H-吲哚-4-基]-1H-苯并咪唑;6-氯-2-[1-(4-哌啶-4-基-丁基)-1H-吲哚-4-基]-1H-苯并咪唑;2-[1-(4-哌啶-4-基-丁基)-1H-吲哚-4-基]-6-三氟甲基-1H-苯并咪唑;4-甲基-1-[3-(1-甲基-哌啶-4-基)-丙基]-5-[4-甲基-5-(4-三氟甲基-苯基)-1H-咪唑-2-基]-1H-苯并咪唑;5-[5-(4-甲氧基-苯基)-4-甲基-1H-咪唑-2-基]-4-甲基-1-[3-(1-甲基-哌啶-4-基)-丙基]-1H-苯并咪唑;及其可药用盐、前体药物和活性代谢物。
在另一具体实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2009/038673中描述的那些:4-(4-甲基-哌嗪-1-基)-噻吩并[3,2-d]嘧啶-2-基胺;4-(4-甲基-哌嗪-1-基)-6,7,8,9-四氢-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;4-哌嗪-1-基-6,7,8,9-四氢-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;4-[(3aR,6aR)-六氢吡咯并[3,4-b]吡咯-5(1H)-基]-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-(4-甲基-哌嗪-1-基)-6,7,8,9-四氢-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-哌嗪-1-基-6,7,8,9-四氢-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-[(3aR,6aR)-六氢吡咯并[3,4-b]吡咯-5(1H)-基]-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;4-(4-甲基-哌嗪-1-基)-6,7,8,9-四氢-苯并[4,5]呋喃[3,2-d]嘧啶;4-哌嗪-1-基-6,7,8,9-四氢-苯并[4,5]呋喃[3,2-d]嘧啶;4-(4-甲基-哌嗪-1-基)-6,7,8,9-四氢-苯并[4,5]噻吩并[3,2-d]嘧啶;4-哌嗪-1-基-6,7,8,9-四氢-苯并[4,5]噻吩并[3,2-d]嘧啶;7-甲基-4-[(3R)-3-(甲基氨基)吡咯烷-1-基]噻吩并[3,2-d]嘧啶-2-胺;7-甲基-4-(4-甲基哌嗪-1-基)噻吩并[3,2-d]嘧啶-2-胺;7-溴-4-[(3R)-3-(甲基氨基)吡咯烷-1-基]噻吩并[3,2-d]嘧啶-2-胺;6-叔丁基-4-(4-甲基哌嗪-1-基)噻吩并[3,2-d]嘧啶-2-胺;6-叔丁基-4-[(3R)-3-(甲基氨基)吡咯烷-1-基]噻吩并[3,2-d]嘧啶-2-胺;6-叔丁基-4-哌嗪-1-基噻吩并[3,2-d]嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-6-叔丁基噻吩并[3,2-d]嘧啶-2-胺;6-叔丁基-4-(八氢-6H-吡咯并[3,4-b]吡啶-6-基)噻吩并[3,2-d]嘧啶-2-胺;4-[(4aR,7aR)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;4-(1,4-二氮杂环庚烷-1-基)-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;4-(3-氨基氮杂环丁烷-1-基)-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;N4-(2-氨基乙基)-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2,4-二胺;4-(3,8-二氮杂二环[3.2.1]辛-3-基)6,7,8,9-四氢[1]苯并呋喃[3,2d]嘧啶-2-胺;N-(6,7,8,9-四氢[1]苯并呋喃[3,2d]嘧啶-4-基)乙烷-1,2-二胺;(3R)-N-甲基-1-(6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-4-基)吡咯烷-3-胺;N-(6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-4-基)乙烷-1,2-二胺;(3R)-N-甲基-1-(6,7,8,9-四氢三苯并噻吩并[3,2d]嘧啶-4-基)吡咯烷-3-胺;4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-[(4aR,7aR)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-六氢吡咯并[3,4-c]吡咯-2(1H)-基]-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-[(3S)-3-氨基哌啶-1-基]-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-[(1S,4S)-2,5-二氮杂二环[2.2.1]庚-2-基]-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-[(1R,4R)-2,5-二氮杂二环[2.2.1]庚-2-基]-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-(1,4-二氮杂环庚烷-1-基)-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;(3S,4S)-1-(2-氨基-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-4-基)-4-(甲基氨基)吡咯烷-3-醇;4-[(3R)-3-(二甲基氨基)吡咯烷-1-基]-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-[(3R)-3-(乙基氨基)吡咯烷-1-基]-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-[(3R)-3-(氨基甲基)吡咯烷-1-基]-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-(3-氨基氮杂环丁烷-1-基)-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;8-甲基-4-(4-甲基哌嗪-1-基)-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;8-甲基-4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;8-甲基-4-[(4aR,7aR)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-(4-甲基哌嗪-1-基)-7,8,9,10-四氢-6H-芳庚并[4,5]噻吩并[3,2-d]嘧啶-2-胺;4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-7,8,9,10-四氢-6H-芳庚并[4,5]噻吩并[3,2-d]嘧啶-2-胺;4-[(4aR,7aR)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]-7,8,9,10-四氢-6H-芳庚并[4,5]噻吩并[3,2-d]嘧啶-2-胺;4-[4-(2-氨基乙基)哌嗪-1-基]-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-[4-(1-甲基乙基)哌嗪-1-基]-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-(4-乙基哌嗪-1-基)-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-(八氢-2H-吡啶并[1,2-a]吡嗪-2-基)-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-(5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基)-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-[(3S)-3-(甲基氨基)吡咯烷-1-基]-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;8,8-二氟-4-(4-甲基哌嗪-1-基)-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;8,8-二氟-4-哌嗪-1-基-6,7,8,9-四氢三苯并噻吩并[3,2d]嘧啶-2-胺;8,8-二氟-4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-(3,8-二氮杂-二环[3.2.1]辛-3-基)-8-甲氧基-6,7,8,9-四氢-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;8-叔丁基-4-(4-甲基-哌嗪-1-基)-6,7,8,9-四氢-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;4-[1,4]二氮杂环庚烷-1-基-8-三氟甲基-6,7,8,9-四氢-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;4-(3(S)-氨基-吡咯烷-1-基)-8-叔丁基-6,7,8,9-四氢-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;4-(3,8-二氮杂二环[3.2.1]辛-3-基)-8-甲基-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;8-叔丁基-4-(3,8-二氮杂二环[3.2.1]辛-3-基)-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;8-甲氧基-4-(4-甲基哌嗪-1-基)-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-[3-(氨基甲基)氮杂环丁烷-1-基]-8-叔丁基-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-(3,4-二氮杂二环[3.2.1]辛-3-基)-8-甲基-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-8-甲氧基-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-哌嗪-1-基-8-(三氟甲基)-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;4-(4-甲基哌嗪-1-基)-8-(三氟甲基)-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;8-叔丁基-4-(4-甲基哌嗪-1-基)-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;8-甲基-4-哌嗪-1-基-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;8-甲基-4-(4-甲基哌嗪-1-基)-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;6,6-二甲基-4-(4-甲基哌嗪-1-基)-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-(1,4-二氮杂环庚烷-1-基)-8-甲氧基-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;8-叔丁基-4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-8-(三氟甲基)-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;4-[(3S)-3-氨基吡咯烷-1-基]-8-甲氧基-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;8-甲氧基-4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-8-(三氟甲基)-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-8-(三氟甲基)-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;4-[(3S)-3-氨基吡咯烷-1-基]-8-(三氟甲基)-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-8-甲基-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-[(3S)-3-氨基吡咯烷-1-基]-8-甲基-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-[3-(氨基甲基)氮杂环丁烷-1-基]-8-甲氧基-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-[(3S)-3-氨基吡咯烷-1-基]-6,6-二甲基-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-6,6-二甲基-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;6,6-二甲基-4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;4-[3-(氨基甲基)氮杂环丁烷-1-基]-6,6-二甲基-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;6,6-二甲基-4-[(3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基]-6,7,8,9-四氢三苯并噻吩并[3,2-d]嘧啶-2-胺;8-叔丁基-4-[(3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基]-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-[(3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基]-8-(三氟甲基)-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;8-甲氧基-4-[(3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基]-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-[(3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基]-8-(三氟甲基)-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;8-甲基-4-[(3ar,6aS)-5-甲基六氢吡咯[3,4-c]吡咯-2(1H)-基]-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;4-(1,4-二氮杂环庚烷-1-基)-6,6-二甲基-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;6,6-二甲基-4-哌嗪-1-基-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;6,6-二甲基-4-(4-甲基哌嗪-1-基)-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;N4-(2-氨基乙基)-N4,6,6-三甲基-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2,4-二胺;N4-(2-氨基乙基)-N4,6,6-三甲基-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2,4-二胺;N4-(2-氨基乙基)-8-甲氧基-N4-甲基-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2,4-二胺;N4-(2-氨基乙基)-8-甲氧基-N4-甲基-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2,4-二胺;N4-(2-氨基乙基)-8-叔丁基-N4-甲基-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2,4-二胺;N4-(2-氨基乙基)-8-叔丁基-N4-甲基-6,7,8,9-四氢[1]苯并呋喃[3,2-]嘧啶-2,4-二胺;N4-(2-氨基乙基)-N4-甲基-8-(三氟甲基)-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2,4-二胺;N4-(2-氨基乙基)-N4-甲基-8-(三氟甲基)-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2,4-二胺;N4-(2-氨基乙基)-N4,8-二甲基-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2,4-二胺;N4-(2-氨基乙基)-N4,8-二甲基-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2,4-二胺;8,8-二氟-4-[(3S)-3-(甲基氨基)吡咯烷-1-基]-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-8,8-二氟-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-(1,4-二氮杂环庚烷-1-基)-8,8-二氟-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;N4-(2-氨基乙基)-8,8-二氟-N4-甲基-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2,4-二胺;8,8-二氟-4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-8,8-二氟-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;8,8-二氟-4-哌嗪-1-基-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;4-[(3S)-3-氨基吡咯烷-1-基]-8,8-二氟-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-(3-氨基氮杂环丁烷-1-基)-8,8-二氟-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;8,8-二氟-4-[(3S)-3-(甲基氨基)吡咯烷-1-基]-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;8,8-二氟-4-(4-甲基哌嗪-1-基)-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;4-((R,R)-八氢吡咯并[3,4-b]吡啶-6-基)-8,8-二氟-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;N4-(2-氨基乙基)-8,8-二氟-N4-甲基-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2,4-二胺;4-[(3S)-3-氨基吡咯烷-1-基]-8,8-二氟-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;4-(3-氨基氮杂环丁烷-1-基)-8,8-二氟-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;N4-(2-氨基乙基)-8,8-二氟-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2,4-二胺;8,8-二氟-4-[(3aR,6aS)-六氢吡咯并[3,4-c]吡咯-2(1H)-基]-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-(1,4-二氮杂环庚烷-1-基)-8,8-二氟-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;8,8-二甲基-4-(4-甲基哌嗪-1-基)-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-(1,4-二氮杂环庚烷-1-基)-8,8-二甲基-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;N4-(2-氨基乙基)-N4,8,8-三甲基-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2,4-二胺;8,8-二甲基-4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;8,8-二甲基-4-[(3S)-3-(甲基氨基)吡咯烷-1-基]-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-8,8-二甲基-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;8,8-二甲基-4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;4-(4-甲基哌嗪-1-基)-8-(三氟甲基)-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-8-叔丁基-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;8-甲基-4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-8-(三氟甲基)-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;8-叔丁基-4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-[3-(氨基甲基)氮杂环丁烷-1-基]-8-甲基-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-8-甲基-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;4-(1,4-二氮杂环庚烷-1-基)-8-甲基-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;8-甲基-4-哌嗪-1-基-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-(3,8-二氮杂二环[3.2.1]辛-3-基)-8-(三氟甲基)-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-哌嗪-1-基-8-(三氟甲基)-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-(1,4-二氮杂环庚烷-1-基)-8-甲基-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;8-甲氧基-4-哌嗪-1-基-6,7,8,9-四氢[1]苯并噻吩并[3,2-d]嘧啶-2-胺;4-(3,8-二氮杂二环[3.2.1]辛-3-基)-6,6-二甲基-6,7,8,9-四氢[1]苯并呋喃[3,2-d]嘧啶-2-胺;及其可药用盐、前体药物和活性代谢物。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2008/100565中描述的那些:4-环戊基-6-(4-甲基-哌嗪-1-基)-嘧啶-2-基胺;4-环戊基-6-(4-甲基-哌嗪-1-基)-嘧啶-2-基胺;(R)-4-(3-氨基-哌啶-1–基)-6-环戊基-嘧啶-2-基胺;(R)-4-环戊基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;反式-1-(2-氨基-6-环戊基-嘧啶-4-基)-4-甲基氨基-吡咯烷-3-醇;4-环戊基-6-(顺式-六氢-吡咯并[3,4-b]吡咯-5-基)-嘧啶-2-基胺;4-环戊基-6-(顺式-八氢-吡咯并[3,4-b]吡啶-6-基)-嘧啶-2-基胺;4-异丙基-6-哌嗪-1-基-嘧啶-2-基胺;(R)-4-(3-氨基-哌啶-1-基)-6-异丙基-嘧啶-2-基胺;(S)-4-(3-氨基-哌啶-1-基)-6-异丙基-嘧啶-2-基胺;(R)-4-异丙基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-6-异丙基-嘧啶-2-基胺;反式-1-(2-氨基-6-异丙基-嘧啶-4-基)-4-甲基氨基-吡咯烷-3-醇;(S,S)-4-(2,5-二氮杂-二环[2.2.1]庚-2-基)-6-异丙基-嘧啶-2-基胺;(R;R)-4-(2,5-二氮杂-二环[2.2.1]庚-2-基)-6-异丙基-嘧啶-2-基胺;4-(顺式-六氢-吡咯并[3,4-b]吡咯-5-基)-6-异丙基-嘧啶-2-基胺;(R,R)-4-(六氢-吡咯并[3,4-b]吡咯-5-基)-6-异丙基-嘧啶-2-基胺;4-异丙基-6-(顺式-5-甲基-六氢-吡咯并[3,4-c]吡咯-2-基)-嘧啶-2-基胺;4-异丙基-6-(顺式-八氢-吡咯并[3,4-b]吡啶-6-基)-嘧啶-2-基胺;(R,R)-4-异丙基-6-(顺式-八氢-吡咯并[3,4-b]吡啶-6-基)-嘧啶-2-基胺;(R)-4-甲基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;4-甲基-6-(顺式-八氢-吡咯并[3,4-b]吡啶-6-基)-嘧啶-2-基胺;4,5-二甲基-6-哌嗪-1-基-嘧啶-2-基胺;4,5-二甲基-6-(4-甲基-哌嗪-1-基)-嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-5,6-二甲基-嘧啶-2-基胺;(R)-4,5-二甲基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;4-(顺式-六氢-吡咯并[3,4-b]吡咯-5-基)-5,6-二甲基-嘧啶-2-基胺;4,5-二甲基-6-(顺式-5-甲基-六氢-吡咯并[3,4-c]吡咯-2-基)-嘧啶-2-基胺;4,5-二甲基-6-(顺式-八氢-吡咯并[3,4-b]吡啶-6-基)-嘧啶-2-基胺;(S,S)-4-(2,5-二氮杂-二环[2.2.1]庚-2-基)-5,6-二甲基-嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-6-乙基-嘧啶-2-基胺;(R)-4-乙基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;(R,R)-(4-乙基-6-六氢-吡咯并[3,4-b]吡咯-5-基)-嘧啶-2-基胺;4-乙基-6-(c/s-六氢-吡咯并[3,4-c]吡咯-2-基)-嘧啶-2-基胺;(R,R)-(4-乙基-6-八氢-吡咯并[3,4-b]吡啶-6-基)-嘧啶-2-基胺;4-环丙基-6-(4-甲基-哌嗪-1-基)-嘧啶-2-基胺;(R)-4-环丙基-6-3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;4-环丙基-6-(顺式-八氢-吡咯并[3,4-b]吡啶-6-基)-嘧啶-2-基胺;4-环丁基-6-哌嗪-1-基-嘧啶-2-基胺;4-环丁基-6-(4-甲基-哌嗪-1-基)-嘧啶-2-基胺;(R)-4-(3-氨基-哌啶-1-基)-6-环丁基-嘧啶-2-基胺;(R)-4-环丁基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;4-环丁基-6-(顺式-六氢-吡咯并[3,4-b]吡咯-5-基)-嘧啶-2-基胺;4-环丁基-6-(顺式-六氢-吡咯并[3,4-c]吡咯-2-基)-嘧啶-2-基胺;4-环丁基-6-(顺式-5-甲基-六氢-吡咯并[3,4-c]吡咯-2-基)-嘧啶-2-基胺;4-环丁基-6-(顺式-八氢-吡咯并[3,4-b]吡啶-6-基)-嘧啶-2-基胺;(R,R)-(4-环丁基-6-顺式-八氢-吡咯并[3,4-b]吡啶-6-基)-嘧啶-2-基胺;4-环己基-6-(4-甲基-哌嗪-1-基)-嘧啶-2-基胺;(R)-(4-环己基-6-3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;4-环己基-6-(顺式-六氢-吡咯并[3,4-b]吡咯-5-基)-嘧啶-2-基胺;(R,R)-4-环己基-6-(八氢-吡咯并[3,4-b]吡啶-6-基)-嘧啶-2-基胺;4-哌嗪-1-基-6-(四氢-呋喃-3-基)-嘧啶-2-基胺;4-(4-甲基-哌嗪-1-基)-6-(四氢-呋喃-3-基)-嘧啶-2-基胺;4-哌嗪-1-基-6-(四氢-吡喃-4-基)-嘧啶-2-基胺;4-(4-甲基-哌嗪-1-基)-6-(四氢-吡喃-4-基)-嘧啶-2-基胺;(R)-4-(3-甲基氨基-吡咯烷-1-基)-6-(四氢-吡喃-4-基)-嘧啶-2-基胺;(R,R)-4-(八氢-吡咯并[3,4-b]吡啶-6-基)-6-(四氢-吡喃-4-基)-嘧啶-2-基胺;4-苄基-6-哌嗪-1-基-嘧啶-2-基胺;4-苄基-6-(4-甲基-哌嗪-1-基)-嘧啶-2-基胺;(R)-苄基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;(R,R)-4-苄基-6-(八氢-吡咯并[3,4-b]吡啶-6-基)-嘧啶-2-基胺;4-(4-甲基-哌嗪-1-基)-5,6,7,8-四氢-喹唑啉-2-基胺;4-(4-哌嗪-1-基)-5,6,7,8-四氢-喹唑啉-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-5,6,7,8-四氢-喹唑啉-2-基胺;(R)-4-(3-甲基氨基-吡咯烷-1-基)-5,6,7,8-四氢-喹唑啉-2-基胺;(R,R)-4-(六氢-吡咯并[3,4-b]吡咯-5-基)-5A7,8-四氢-喹唑啉-2-基胺;4-(顺式-八氢-吡咯并[3,4-b]吡啶-6-基)-5,6,7,8-四氢-喹唑啉-2-基胺;(R,R)-4-(八氢-吡咯并[3,4-b]吡啶-6-基)-5,6,7,8-四氢-喹唑啉-2-基胺;(S,S)-4-(2,5-二氮杂-二环[2.2.1]庚-2-基)-5,6,7,8-四氢-喹唑啉-2-基胺;4-(4-甲基-哌嗪-1-基)-6,7-二氢-5H-环戊二烯并嘧啶-2-基胺;(R,R)-4-(4-甲基氨基-吡咯烷-1-基-6,7-二氢-5H-环戊二烯并嘧啶-2-基胺;4-叔丁基-6-哌嗪-1-基-嘧啶-2-基胺;4-叔丁基-6-(4-甲基-哌嗪-1-基)-嘧啶-2-基胺;(R)-4-叔丁基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;(R,R)-4-叔丁基-6-(八氢-吡咯并[3,4-b]吡啶-6-基)-嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-6-环戊基-嘧啶-2-基胺;(R,R)-4-环戊基-6-(八氢-吡咯并[3,4-b]吡啶-6-基)-嘧啶-2-基胺;4-环戊基-6-(顺式-5-甲基-六氢-吡咯并[3,4-c]吡咯-2-基)-嘧啶-2-基胺;(R,R)-4-环戊基-6-(六氢-吡咯并[3,4-b]吡咯-5-基)-嘧啶-2-基胺;4-环戊基-6-(顺式-1,7-二氮杂-螺[4.4]壬-7-基)-嘧啶-2-基胺;4-(3-氨基-氮杂环丁烷-1-基)-6-环戊基-嘧啶-2-基胺;4-环戊基-6-(反式-六氢-吡咯并[3,4-b][1,4]嗪-6-基)-嘧啶-2-基胺;4-环戊基-6-(六氢-吡咯并[3,4-c]吡咯-2-基)-嘧啶-2-基胺;4-环戊基-6-(顺式-六氢-吡咯并[3,4-b][1,4]嗪-6-基)-嘧啶-2-基胺;(2-氨基-乙基)-6-异丙基-嘧啶-2,4-二胺;4-(3-氨基-氮杂环丁烷-1-基)-6-异丙基-嘧啶-2-基胺;4-(1,7-二氮杂-螺[4.4]壬-7-基)-6-异丙基-嘧啶-2-基胺;N4-(2-氨基-乙基)-6-异丙基-N4-甲基-嘧啶-2,4-二胺;4-(顺式-六氢-吡咯并[3,4-b][1,4]嗪-6-基)-6-异丙基-嘧啶-2-基胺;4-(反式-六氢-吡咯并[3,4-b][1,4]嗪-6-基)-6-异丙基-嘧啶-2-基胺;4-异丙基-6-(4-甲基-哌嗪-1-基)-嘧啶-2-基胺;4-(4-甲基-哌嗪-1-基)-7,8-二氢-5H-吡喃并[4,3-d]嘧啶-2-基胺;(R,R)-4-(八氢-吡咯并[3,4-b]吡啶-6-基)-7,8-二氢-5H-吡喃并[4,3-d]嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-7,8-二氢-5H-吡喃并[4,3-d]嘧啶-2-基胺;(R)-4-(3-甲基氨基-吡咯烷-1-基)-7,8-二氢-5H-吡喃并[4,3-d]嘧啶-2-基胺;4-哌嗪-1-基-7,8-二氢-5H-吡喃并[4,3-d]嘧啶-2-基胺;4-丁基-5-甲氧基-6-哌嗪-1-基-嘧啶-2-基胺;4-丁基-6-[1,4]二氮杂环庚烷-1-基-5-甲氧基-嘧啶-2-基胺;4-(3-氨基-氮杂环丁烷-1-基)-6-丁基-5-甲氧基-嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-6-丁基-5-甲氧基-嘧啶-2-基胺;(S)-4-(3-氨基-吡咯烷-1-基)-6-丁基-5-甲氧基-嘧啶-2-基胺;(R)-4-丁基-5-甲氧基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;(S)-4-丁基-5-甲氧基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;4-丁基-5-甲氧基-6-(4-甲基-哌嗪-1-基)-嘧啶-2-基胺;N4-(2-氨基-乙基)-6-丁基-5-甲氧基-N4-甲基-嘧啶-2,4-二胺;N4-(2-氨基-乙基)-6-丁基-5-甲氧基-嘧啶-2,4-二胺;4-(3-氨基-氮杂环丁烷-1-基)-6-环戊基-5-甲氧基-嘧啶-2-基胺;4-环戊基-6-[1,4]二氮杂环庚烷-1-基-5-甲氧基-嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-6-环戊基-5-甲氧基-嘧啶-2-基胺;(S)-4-环戊基-5-甲氧基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;N4-(2-氨基-乙基)-6-环戊基-5-甲氧基-N4-甲基-嘧啶-2,4-二胺;N4-(2-氨基-乙基)-6-环戊基-5-甲氧基-嘧啶-2I4-二胺;4-[1,4]二氮杂环庚烷-1–基)-6-甲氧甲基-嘧啶-2-基胺;(S)-4-(3-氨基-吡咯烷-1-基)-6-甲氧甲基-嘧啶-2-基胺;(S)-4-甲氧甲基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;4-环丙基-6-(顺式-5-甲基-六氢-吡咯并[3,4-c]吡咯-2-基)-嘧啶-2-基胺;4-环丙基-6-哌嗪-1-基-嘧啶-2-基胺;4-(3-氨基-氮杂环丁烷-1-基)-6-环丙基-嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-6-环丙基-嘧啶-2-基胺;4-环丙基-6-(顺式-六氢-吡咯并[3,4-c]吡咯-2-基)-嘧啶-2-基胺;(S)-4-异丙基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;(S)-4-(3-氨基-吡咯烷-1-基)-6-异丙基-嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-6-叔丁基-嘧啶-2-基胺;4-叔丁基-6-(顺式-5-甲基-六氢-吡咯并[3,4-c]吡咯-2-基)-嘧啶-2-基胺;(S)-4-(3-氨基-吡咯烷-1-基)-6-叔丁基-嘧啶-2-基胺;(S)-4-叔丁基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;N4-(2-氨基-乙基)-6-叔丁基-N4-甲基-嘧啶-2,4-二胺;4-叔丁基-6-(顺式-六氢-吡咯并[3,4-c]吡咯-2-基)-嘧啶-2-基胺;4-(3-氨基-氮杂环丁烷-1-基)-6-叔丁基-嘧啶-2-基胺;4-叔丁基-6-(3,8-二氮杂-二环[3.2.1]辛-3-基)-嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-6-丁基-嘧啶-2-基胺;4-丁基-6-(4-甲基-哌嗪-1-基)-嘧啶-2-基胺;(R)-4-丁基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;N4-(2-氨基-乙基)-6-丁基-N4-甲基-嘧啶-2,4-二胺;4-丁基-6-(顺式-5-甲基-六氢-吡咯并[3,4-c]吡咯-2-基)-嘧啶-2-基胺;丁基-6-(顺式-六氢-吡咯并[3,4-c]吡咯-2-基)-嘧啶-2-基胺;4-丁基-6-(顺式-八氢-吡咯并[3,4-b]吡啶-6-基)-嘧啶-2-基胺;4-丁基-6-哌嗪-1-基-嘧啶-2-基胺;4-丁基-6-(3,8-二氮杂-二环[3.2.1]辛-3-基)-嘧啶-2-基胺;4-(4-甲基-哌嗪-1-基)-6-丙基-嘧啶-2-基胺;4-(顺式-5-甲基-六氢-吡咯并[3,4-c]吡咯-2-基)-6-丙基-嘧啶-2-基胺;4-异丁基-6-(4-甲基-哌嗪-1-基)-嘧啶-2-基胺;4-异丁基-6-哌嗪-1-基-嘧啶-2-基胺;(R)-4-异丁基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-6-异丁基-嘧啶-2-基胺;(S)-4-乙基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;(R)-4-金刚烷-1-基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;4-金刚烷-1-基-6-(4-甲基-哌嗪-1-基)-嘧啶-2-基胺;4-(4-甲基-四氢-吡喃-4-基)-6-哌嗪-1-基-嘧啶-2-基胺;4-(4-甲基-哌嗪-1-基)-6-(4-甲基-四氢-吡喃-4-基)-嘧啶-2-基胺;(R)-4-(3-甲基氨基-吡咯烷-1-基)-6-(4-甲基-四氢-吡喃-4-基)-嘧啶-2-基胺;4-(反式-2-苯基-环丙基)-6-哌嗪-1-基-嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-6-(反式-2-苯基-环丙基)-嘧啶-2-基胺;4-(4-甲基-哌嗪-1-基)-6-(反式-2-苯基-环丙基)-嘧啶-2-基胺;N4-(2-氨基-乙基)-6-(反式-2-苯基-环丙基)-嘧啶-2,4-二胺;(R)-4-(3-甲基氨基-吡咯烷-1-基)-6-(反式-2-苯基-环丙基)-嘧啶-2-基胺;4-(3-氨基-氮杂环丁烷-1-基)-6-茚满-2-基-嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-6-茚满-2-基-嘧啶-2-基胺;4-茚满-2-基-6-(4-甲基-哌嗪-1-基)-嘧啶-2-基胺;(R)-4-茚满-2-基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;4-茚满-2-基-6-哌嗪-1-基-嘧啶-2-基胺;4-(3-氨基-氮杂环丁烷-1-基)-6-苄基-嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-6-苄基-嘧啶-2-基胺;N4-(2-氨基-乙基)-6-茚满-2-基-嘧啶-2,4-二胺;(R)-4-(2,3-二氢-苯并呋喃-2-基)-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;4-(顺式-六氢-吡咯并[3,4-c]吡咯-2-基)-6-(4-甲基-四氢-吡喃-4-基)-嘧啶-2-基胺;4-(2,3-二氢-苯并呋喃-2-基)-6-哌嗪-1-基-嘧啶-2-基胺;4-(3-氨基-氮杂环丁烷-1-基)-6-(2,3-二氢-苯并呋喃-2-基)-嘧啶-2-基胺;4-(顺式-六氢-吡咯并[3,4-c]吡咯-2-基)-6-茚满-2-基-嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-6-(4-甲基-四氢-吡喃-4-基)-嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-6-(四氢-吡喃-4-基)-嘧啶-2-基胺;N4-(2-氨基-乙基)-6-(四氢-吡喃-4-基)-嘧啶-2,4-二胺;N4-(2-氨基-乙基)-N4-甲基-6-(四氢-吡喃-4-基)-嘧啶-2,4-二胺;(R)-4-(3-氨基-吡咯烷-1-基)-6-苯乙基-嘧啶-2-基胺;4-(4-甲基-哌嗪-1-基)-6-苯乙基-嘧啶-2-基胺;(R)-4-(3-甲基氨基-吡咯烷-1-基)-6-苯乙基-嘧啶-2-基胺;4-(4-甲基-哌嗪-1-基)-6-(3,3,3-三氟-丙基)-嘧啶-2-基胺;4-哌嗪-1-基-6-(3,3,3-三氟-丙基)-嘧啶-2-基胺;(R)-4-(3-甲基氨基-吡咯烷-1-基)-6-(3,3,3-三氟-丙基)-嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-6-(3,3,3-三氟-丙基)-嘧啶-2-基胺;4-环戊基-5-甲氧基-6-(4-甲基-哌嗪-1-基)-嘧啶-2-基胺;4-环戊基-5-甲氧基-6-哌嗪-1-基-嘧啶-2-基胺;(R)-4-环戊基-5-甲氧基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;(R,R)-4-环戊基-5-甲氧基-6-(八氢-吡咯并[3,4-b]吡啶-6-基)-嘧啶-2-基胺;N4-(2-氨基-乙基)-N4-甲基-6-(四氢-呋喃-3-基)-嘧啶-2,4-二胺;4-(顺式-八氢-吡咯并[3,4-b]吡啶-6-基)-6-(四氢-呋喃-3-基)-嘧啶-2-基胺;(R)-4-(3-甲基氨基-吡咯烷-1-基)-6-(四氢-呋喃-3-基)-嘧啶-2-基胺;4-[1,4]二氮杂环庚烷-1-基-6-(四氢-呋喃-3-基)-嘧啶-2-基胺;(-)-4-哌嗪-1-基-6-(四氢-呋喃-3-基)-嘧啶-2-基胺;(+)-4-哌嗪-1-基-6-(四氢-呋喃-3-基)-嘧啶-2-基胺;N4-(2-氨基-乙基)-6-(四氢-呋喃-3-基)-嘧啶-2,4-二胺;N4-(3-氨基-丙基)-6-(四氢-呋喃-3-基)-嘧啶-2,4-二胺;N4-甲基-N4-(2-甲基氨基-乙基)-6-(四氢-呋喃-3-基)-嘧啶-2,4-二胺;N4-(2-甲基氨基-乙基)-6-(四氢-呋喃-3-基)-嘧啶-2,4-二胺;5-氟-4-甲基-6-(4-甲基-哌嗪-1-基)-嘧啶-2-基胺;5-氟-4-甲基-6-(八氢-吡咯并[3,4-b]吡啶-6-基)-嘧啶-2-基胺;5-氟-4-甲基-6-哌嗪-1-基-嘧啶-2-基胺;(R)-5-氟-4-甲基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;N4-(2-氨基-乙基)-5-氟-6,N4-二甲基-嘧啶-2,4-二胺;4-哌嗪-1-基-6-吡啶-4-基甲基-嘧啶-2-基胺;(R)-4-(3-甲基氨基-吡咯烷-1-基)-6-吡啶-4-基甲基-嘧啶-2-基胺;4-(4-甲基-哌嗪-1-基)-6-吡啶-4-基甲基-嘧啶-2-基胺;4-(4-甲基-哌嗪-1-基)-6-噻吩-3-基甲基-嘧啶-2-基胺;(R)-4-(3-甲基氨基-吡咯烷-1-基)-6-噻吩-3-基甲基-嘧啶-2-基胺;4-哌嗪-1-基-6-噻吩-3-基甲基-嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-6-噻吩-3-基甲基-嘧啶-2-基胺;4-(顺式-八氢-吡咯并[3,4-b]吡啶-6-基)-6-噻吩-3-基甲基-嘧啶-2-基胺;N4-(2-氨基-乙基)-6-噻吩-3-基甲基-嘧啶-2,4-二胺;4-(4-甲基-哌嗪-1-基)-6-噻吩-2-基甲基-嘧啶-2-基胺;(R)-4-(3-甲基氨基-吡咯烷-1-基)-6-噻吩-2-基甲基-嘧啶-2-基胺;4-哌嗪-1-基-6-噻吩-2-基甲基-嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-6-噻吩-2-基甲基-嘧啶-2-基胺;4-(顺式-八氢-吡咯并[3,4-b]吡啶-6-基)-6-噻吩-2-基甲基-嘧啶-2-基胺;N4-(2-氨基-乙基)-6-噻吩-2-基甲基-嘧啶-2,4-二胺;N4-(2-氨基-乙基)-6-甲氧甲基-嘧啶-2,4-二胺;4-(3-氨基-氮杂环丁烷-1-基)-6-甲氧甲基-嘧啶-2-基胺;(R)-4-甲氧甲基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1–基)-6-甲氧甲基-嘧啶-2-基胺;4-甲氧甲基-6-(4-甲基-哌嗪-1-基)-嘧啶-2-基胺;4-甲氧甲基-6-哌嗪-1-基-嘧啶-2-基胺;(R)-4-(3-氨基-哌啶-1-基)-6-甲氧甲基-嘧啶-2-基胺;(R,R)-4-甲氧甲基-6-(八氢-吡咯并[3,4-b]吡啶-6-基)-嘧啶-2-基胺;4-(4-甲基-哌嗪-1-基)-6-(四氢-呋喃-2-基甲基)-嘧啶-2-基胺;(R)-4-(3-甲基氨基-吡咯烷-1-基)-6-(四氢-呋喃-2-基甲基)-嘧啶-2-基胺;4-(顺式-5-甲基-六氢-吡咯并[3,4-c]吡咯-2-基)-6-(四氢-呋喃-2-基甲基)-嘧啶-2-基胺;4-哌嗪-1-基-6-(四氢-呋喃-2-基甲基)-嘧啶-2-基胺;4-(顺式-八氢-吡咯并[3,4-b]吡啶-6-基)-6-(四氢-呋喃-2-基甲基)-嘧啶-2-基胺;4-(4-氯-苄基)-6-(4-甲基-哌嗪-1-基)-嘧啶-2-基胺;4-(4-氯-苄基)-6-哌嗪-1-基-嘧啶-2-基胺;(R)-4-(4-氯-苄基)-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-6-(4-氯-苄基)-嘧啶-2-基胺;4-(4-氯-苄基)-6-(顺式-5-甲基-六氢-吡咯并[3,4-c]吡咯-2-基)-嘧啶-2-基胺;4-(4-氯-苄基)-6-(顺式-六氢-吡咯并[3,4-c]吡咯-2-基)-嘧啶-2-基胺;N4-(2-氨基-乙基)-6-(4-氯-苄基)-N4-甲基-嘧啶-2,4-二胺;4-乙氧甲基-6-(4-甲基-哌嗪-1-基)-嘧啶-2-基胺;4-乙氧基甲基-6-哌嗪-1-基-嘧啶-2-基胺;(R)-乙氧基甲基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;(R)-乙氧基甲基-6-(3-氨基-吡咯烷-1-基)-嘧啶-2-基胺;异丙氧基甲基-6-((R)-3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;4-异丙氧基甲基-6-哌嗪-1-基-嘧啶-2-基胺;(R)-异丙氧基甲基-6-(3-氨基-吡咯烷-1-基)-嘧啶-2-基胺;4-异丙氧基甲基-6-(4-甲基-哌嗪-1-基)-嘧啶-2-基胺;4-苯乙基-6-哌嗪-1-基-嘧啶-2-基胺;4-(3-氨基-氮杂环丁烷-1-基)-6-苯乙基-嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-6-(四氢-吡喃-4-基)-嘧啶-2-基胺;N4-(2-氨基-乙基)-6-苄基-N4-甲基-嘧啶-2,4-二胺;4-茚满-2-基-6-(八氢-吡咯并[3,4-b]吡啶-6-基)-嘧啶-2-基胺;4-(3-氨基-氮杂环丁烷-1-基)-7,8-二氢-5H-吡喃并[4,3-d]嘧啶-2-基胺;4-(3-氨基-氮杂环丁烷-1-基)-5,6,7,8-四氢-喹唑啉-2-基胺;4-(顺式-5-甲基-六氢-吡咯并[3,4-c]吡咯-2-基)-7,8-二氢-5H-吡喃并[4,3-d]嘧啶-2-基胺;(R)-4-(3-甲基氨基-吡咯烷-1-基)-6-苯基-环丙基)-嘧啶-2-基胺(非对映异构体1);(R)-4-(3-甲基氨基-吡咯烷-1-基)-6-(2-苯基-环丙基)-嘧啶-2-基胺(非对映异构体2);4-环戊基-6-(顺式-1,7-二氮杂-螺[4.4]壬-7-基)-嘧啶-2-基胺(对映异构体1);4-环戊基-6-(顺式-1,7-二氮杂-螺[4.4]壬-7-基)-嘧啶-2-基胺(对映异构体2);(R)-4-异丙氧基甲基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-6-异丙氧基甲基-嘧啶-2-基胺;4-异丙氧基甲基-6-哌嗪-1-基-嘧啶-2-基胺;4-异丙氧基甲基-6-(4-甲基-哌嗪-1-基)-嘧啶-2-基胺;4-(3-氨基-氮杂环丁烷-1-基)-6-异丙氧基甲基-嘧啶-2-基胺;4-异丙氧基甲基-6-(8-甲基-3,8-二氮杂-二环[3.2.1]辛-3-基)-嘧啶-2-基胺;(R)-4-环丙氧基甲基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;(R)-(4-氨基-吡咯烷-1-基)-6-环丙氧基甲基-嘧啶-2-基胺;4-环丙氧基甲基-6-哌嗪-1-基-嘧啶-2-基胺;4-环丙氧基甲基-6-(4-甲基-哌嗪-1-基)-嘧啶-2-基胺;4-(3-氨基-氮杂环丁烷-1-基)-6-环丙氧基甲基-嘧啶-2-基胺;4-环丙氧基甲基-6-(8-甲基-3,8-二氮杂-二环[3.2.1]辛-3-基)-嘧啶-2-基胺;(R)-4-叔丁氧基甲基-6-(3-甲基氨基-吡咯烷-1-基)-嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-6-叔丁氧基甲基-嘧啶-2-基胺;4-叔丁氧基甲基-6-哌嗪-1-基-嘧啶-2-基胺;4-叔丁氧基甲基-6-(4-甲基-哌嗪-1-基)-嘧啶-2-基胺;4-(3-氨基-氮杂环丁烷-1-基)-6-叔丁氧基甲基-嘧啶-2-基胺;4-叔丁氧基甲基-6-(8-甲基-3,8-二氮杂-二环[3.2.1]辛-3-基)-嘧啶-2-基胺;4-乙基-6-(8-甲基-3,8-二氮杂-二环[3.2.1]辛-3-基)-嘧啶-2-基胺;4-(8-甲基-3,8-二氮杂-二环[3.2.1]辛-3-基)-6-丙基-嘧啶-2-基胺;4-异丙基-6-(8-甲基-3,8-二氮杂-二环[3.2.1]辛-3-基)-嘧啶-2-基胺;4-环戊基-6-(8-甲基-3,8-二氮杂-二环[3.2.1]辛-3-基)-嘧啶-2-基胺;及其可药用盐。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2008/008359中描述的那些:8-氯-4-(4-甲基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;6,8-二氯-4-(八氢-吡咯并[3,4-b]吡啶-6-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-氯-4-(4-异丙基-[1,4]二氮杂环庚烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-(3-氨基-吡咯烷-1-基)-6,8-二氯-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R)-6,8-二氯-4-(3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R)-4-(3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-氯-4-[1,4]二氮杂环庚烷-1-基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-氯-4-(八氢-吡啶并[1,2-a]吡嗪-2-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-氯-8-(八氢-吡咯并[3,4-b]吡啶-6-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-氯-4-(4-甲基-[1,4]二氮杂环庚烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S,S)-8-氯-4-(2,5-二氮杂-二环[2.2.1]庚-2-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-氯-4-(3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S)-4-(3-氨基-哌啶-1-基)-8-氯-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-氯-4-哌嗪-1-基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-氯-4-(3-二甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-(3-氨基-吡咯烷-1-基)-8-氯-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S)-8-氯-4-(3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R)-8-氯-4-(3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R)-8-溴-4-(3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-溴-4-(六氢-吡咯并[1,2-a]吡嗪-2-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-(3-氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R)-4-(3-二甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-哌嗪-1-基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R)-8-氯-4-(3-二甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-8-氯-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S)-4-(3-氨基甲基-吡咯烷-1-基)-8-氯-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-氯-4-(六氢-吡咯并[3,4-c]吡咯-2-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R)-4-(3-氨基-哌啶-1-基)-8-氯-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-(3-氨基甲基-吡咯烷-1-基)-8-氯-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R)-4-(3-氨基甲基-吡咯烷-1-基)-8-氯-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;6,8-二氯-4-哌嗪-1-基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;6,8-二氯-4-[1,4]二氮杂环庚烷-1-基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S,S)-4-(2,5-二氮杂-二环[2.2.1]庚-2-基)-苯并[415]呋喃[3,2-d]嘧啶-2-基胺;8-氯-4-(4-异丙基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;6,8-二氯-4-(3-二甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-(八氢-吡啶并[1,2-a]吡嗪-2-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;6,8-二氯-4-(八氢-吡啶并[1,2-a]吡嗪-2-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S,S)-6,8-二氯-4-(2,5-二氮杂-二环[2.2.1]庚-2-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R)-8-氟-4-(3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-氟-4-(六氢-吡咯并[1,2-a]吡嗪-2-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-氟-N4-甲基-N4-(1-甲基-吡咯烷-3-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2,4-二胺;(R)-8-(3-甲基氨基-吡咯烷-1-基)-9-氧杂-1,5,7-三氮杂-芴-6-基胺;8-(八氢-吡咯并[3,4-b]吡啶-6-基)-9-氧杂-1,5,7-三氮杂-芴-6-基胺;4-(4-甲基-哌嗪-1-基)-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;8-溴-4-(八氢-吡咯并[3,4-b]吡啶-6-基)-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;7-溴-4-(八氢-吡咯并[3,4-b]吡啶-6-基)-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;(S)-8-溴-4-(3-甲基氨基-吡咯烷-1-基)-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;(R)-8-溴-4-(3-甲基氨基-吡咯烷-1-基)-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;(S,S)-8-溴-4-(2,5-二氮杂-二环[2.2.1]庚-2-基)-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;8-溴-4-(4-甲基-哌嗪-1-基)-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;(S)-4-(3-甲基氨基-吡咯烷-1-基)-7-三氟甲基-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;(R)-4-(3-甲基氨基-吡咯烷-1-基)-7-三氟甲基-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;(S,S)-4-(2,5-二氮杂-二环[2.2.1]庚-2-基)-7-三氟甲基-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;4-(4-甲基-哌嗪-1-基)-7-三氟甲基-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;7-溴-4-(4-甲基-哌嗪-1-y])-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;(R)-7-溴4-(3-甲基氨基-吡咯烷-1-基)-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;(S)-7-溴-4-(3-甲基氨基-吡咯烷-1-基)-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;4-(八氢-吡咯并[3,4-b]吡啶-6-基)-7-三氟甲基-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;7-氯-4-(八氢-吡咯并[3,4-b]吡啶-6-基)-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;(R)-7-氯-4-(3-甲基氨基-吡咯烷-1-基)-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;(S)-7-氯-4-(3-甲基氨基-吡咯烷-1-基)-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;(S,S)-7-氯-4-(2,5-二氮杂-二环[2.2.1]庚-2-基)-苯并[4I5]噻吩并[3,2-d]嘧啶-2-基胺;7-氯-4-(4-甲基-哌嗪-1-基)-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;8-氯-4-(八氢-吡咯并[3,4-b]吡啶-6-基)-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;(S)-8-氯-4-(3-甲基氨基-吡咯烷-1-基)-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;(R)-8-氯-4-(3-甲基氨基-吡咯烷-1-基)-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;8-氯-4-(4-甲基-哌嗪-1-基)-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;(S,S)-8-氯-4-(2,5-二氮杂-二环[2.2.1]庚-2-基)-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;8-氯-4-(六氢-吡咯并[1,2-a]吡嗪-2-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-氟-4-(4-甲基-哌嗪-1-基)-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;8-氟-4-(六氢-吡咯并[3,4-b]吡咯-5-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S)-8-氯-4-(3-乙基氨基-哌啶-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R)-8-氯-4-(3-乙基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S)-8-氯-4-(3-甲基氨基-哌啶-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S)-8-氯-4-(3-二甲基氨基-哌啶-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R)-8-氟-4-(3-甲基氨基-吡咯烷-1-基)-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;(S,S)-7-溴-4-(2,5-二氮杂-二环p[2.2.1]庚-2-基)-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;4-(6-氨基-3-氮杂-二环[3.1.0]hex-3-基)-8-氯-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R)-4-(2-氨基甲基-吡咯烷-1-基)-8-氯-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-氯-4-(六氢-吡咯并[3,4-b]吡咯-5-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R,R)-8-氯-4-(2,δ-二氮杂-二环[2.2.1]庚-2-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R,R)-8-氯-4-(八氢-吡咯并[3,4-b]吡啶-6-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-氯-4-(八氢-吡咯并[3,4-b]吡啶-6-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R)-4-(3-甲基氨基-吡咯烷-1-基)-9-三氟甲基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S,S)-4-(2,5-二氮杂-二环[2.2.1]庚-2-基)-9-甲氧基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;9-甲氧基-4-哌嗪-1-基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S)-4-(3-氨基-哌啶-1-基)-9-甲氧基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;9-甲氧基-4-(4-甲基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-甲氧基-4-(4-甲基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-哌嗪-1-基-9-三氟甲基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-(4-甲基-哌嗪-1-基)-9-三氟甲基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S)-4-(3-氨基-哌啶-1-基)-9-三氟甲基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S)-4-(3-氨基-哌啶-1-基)-8,9-二氯-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S,S)-4-(2,5-二氮杂-二环[2.2.1]庚-2-基)-9-三氟甲基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(顺式)-8-氯-4-(六氢-吡咯并[3,4-b]吡咯-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;N4-(2-氨基-乙基)-8-氯-N4-甲基-苯并[4,5]呋喃[3,2-d]嘧啶-2,4-二胺;8-氯-4-(3,8-二氮杂-二环[3.2.1]辛-3-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S,S)-8,9-二氯-4-(2,5-二氮杂-二环[2.2.1]庚-2-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R)-8,9–二氯-4(3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R)-9-甲氧基-4-(3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8,9-二氯-4-(4-甲基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R)-8-甲氧基-4-(3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-(3-氨基甲基-氮杂环丁烷-1-基)-8-氯-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8,9-二氯-4-哌嗪-1-基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(顺式)-8-甲氧基-4-(八氢-吡咯并[3,4-b]吡啶-6-基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S,S)-8-氯-4-(5-甲基-2,5-二氮杂-二环[2.2.1]庚-2-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S)-4-(3-氨基-哌啶-1-基)-8-甲氧基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R)-4-(3-氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R)-3-氯-8-(3-甲基氨基-吡咯烷-1-基)-9-氧杂-1,5,7-三氮杂-芴-6-基胺;N4-氮杂环丁烷-3-基甲基-8-氯-苯并[4,5]呋喃[3,2-d]嘧啶-2,4-二胺;N4-氮杂环丁烷-3-基-8-氯-苯并[4,5]呋喃[3,2-d]嘧啶-2,4-二胺;N4-(2-氨基-乙基)-8-氯-苯并[4,5]呋喃[3,2-d]嘧啶-2,4-二胺;(S,S)-4-(2,5-二氮杂-二环[2.2.1]庚-2-基)-8-甲氧基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(顺式)-4-(六氢-吡咯并[3,4-b]吡咯-5-基)-8-甲氧基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;2-[8-氯-4-(4-甲基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基氨基]-乙醇;2-[4-(4-甲基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基氨基]-乙醇;(顺式)-2-[8-氯-4-八氢-吡咯[3,4-b]吡啶-6-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基氨基]-乙醇;2-[8-甲氧基-4-(4-甲基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基氨基]-乙醇;[8-氯-4-(4-甲基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-环丙基-胺;[8-氯-4-(4-甲基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-异丁基-胺;烯丙基-[8-氯-4-(4-甲基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-胺;N1-[8-氯-4-(4-甲基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-丙烷-1,3-二胺;[8-氯-4-(4-甲基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-(2-甲基硫烷基-乙基)-胺;[8-氯-4-(4-甲基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-甲基-胺;(S,S)-2-[8-氯-4-(2,5-二氮杂-二环[2.2.1]庚-2-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基氨基]-乙醇;2-[8-氯-4-(3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基氨基]-乙醇;2-[8-氯-4-(4-甲基-[1,4]二氮杂环庚烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基氨基]-乙醇;8-氯-4-(3,5-二甲基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-(3-氨基-氮杂环丁烷-1-基)-8-氯-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(2S,5R)-8-氯-4-(2,5-二甲基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S)-8-氯-4-(2-甲基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d3嘧啶-2-基胺;(R)-8-氯-4-(2-甲基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S)-8-氯-4-(5-甲基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R)-8-氯-4-(5-甲基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;9-氟-4-(4-甲基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R)-9-氟-4-(3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;9-氟-4-哌嗪-1-基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-(3-氨基-氮杂环丁烷-1-基)-9-氟-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-(4-甲基-哌嗪-1-基)-8-三氟甲基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R)-4-(3-甲基氨基-吡咯烷-1-基)-8-三氟甲基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S)-4-(3-氨基-哌啶-1-基)-8-三氟甲基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-哌嗪-1-基-8-三氟甲基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S,S)-4,2,5-二氮杂-二环[2.2.1]庚-2-基)-8-三氟甲基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-(3-氨基-氮杂环丁烷-1-基)-8-三氟甲基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8,9-二氟-4-(4-甲基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8,9-二氟-4-哌嗪-1-基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S)-4-(3-氨基-哌啶-1-基)-8,9-二氟-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R)-8,9-二氟-4-(3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S,S)-4-(2,5-二氮杂-二环[2.2.1]庚-2-基)-8,9-二氟-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-(3-氨基-氮杂环丁烷-1-基)-8,9-二氟-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;9-氯-4-(4-甲基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R)-9-氯-4-(3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;9-氯-4-哌嗪-1-基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S)-4-(3-氨基-哌啶-1-基)-9-氯-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S,S)-9-氯-4-(2I5-二氮杂-二环[2.2.1]庚-2-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-(3-氨基-氮杂环丁烷-1-基)-9-氯-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(R)-7-甲氧基-4-(3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;(S)-7-甲氧基-4-(3-甲基氨基-吡咯烷-1-基)-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;7-甲氧基--(4-甲基-哌嗪-1-基)-苯并[4,5]噻吩并[3,2-d]嘧啶-2-基胺;(S)-2-[4-(3-氨基-哌啶-1-基)-8-氯-苯并[4,5]呋喃[3,2-d]嘧啶-2-基氨基]-乙醇;2-(8-氯-4-哌嗪-1-基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基氨基)-乙醇;2-[4-(3-氨基-氮杂环丁烷-1-基)-8-氯-苯并[4,5]呋喃[3,2-d]嘧啶-2-基氨基]-乙醇;[8-氯-4-(4-甲基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-二甲基-胺;及其可药用盐。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2009077608中描述的那些:4-环己基氧甲基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-环己基氧甲基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-(环丙基甲氧基甲基)-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-(环丙基甲氧基甲基)-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-环丁氧基甲基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-环丁氧基甲基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-环戊氧甲基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-环戊氧甲基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-异丙氧基甲基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-异丙氧基甲基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-异丁氧基甲基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-异丁氧基甲基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-(2,2-二甲基丙氧基甲基)-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-(2,2-二甲基丙氧基甲基)-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-叔丁氧基甲基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-(环戊基甲氧基甲基)-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-(环戊基甲氧基甲基)-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-(((1S,2R,4R)-二环[2.2.1]庚-2-基氧基)甲基)-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-(((1S,2R,4R)-二环[2.2.1]庚-2-基氧基)甲基)-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-苄基氧基甲基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-苄基氧基甲基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;6-甲氧甲基-4-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;6-甲氧甲基-4-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-(3-(甲基氨基)氮杂环丁烷-1-基)-6-苯氧基甲基嘧啶-2-胺;6-(2-甲氧乙基)4-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-(4-氟苯氧基甲基)-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-(2,4-二氟苯氧基甲基)-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-(3,4-二氟苯氧基甲基)-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-(2,4-二氟苯氧基甲基)-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-(3,4-二氟苯氧基甲基)-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-(3-氨基氮杂环丁烷-1-基)-6-异丙氧基甲基嘧啶-2-胺;4-((3R)-3-氨基吡咯烷-1-基)-6-异丙氧基甲基嘧啶-2-胺;4-(3-(甲基氨基)氮杂环丁烷-1-基)-6-(四氢吡喃-4-基)嘧啶-2-胺;4-(3-(甲基氨基)氮杂环丁烷-1-基)-6-((S)-四氢呋喃-2-基)嘧啶-2-胺;4-((3R)-3-(甲基氨基)吡咯烷-1-基)-6-((S)-四氢呋喃-2-基)嘧啶-2-胺;4-(3-(甲基氨基)氮杂环丁烷-1-基)-6-((R)-四氢呋喃-2-基)嘧啶-2-胺;4-((3R)-3-(甲基氨基)吡咯烷-1-基)-6-((R)-四氢呋喃-2-基)嘧啶-2-胺;4-(2-(4-氯苯氧基)丙-2-基)-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-(2-(4-氯苯氧基)丙-2-基)-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;6-((R)-1-甲氧乙基)-4-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-(3-(甲基氨基)氮杂环丁烷-1-基)-6-((R)-苯基(甲氧基)甲基)嘧啶-2-胺;4-((3R)-3-(甲基氨基)吡咯烷-1-基)-6-((R)-苯基(甲氧基)甲基)嘧啶-2-胺;4-(3-(甲基氨基)氮杂环丁烷-1-基)-6-((S)-苯基(甲氧基)甲基)嘧啶-2-胺;4-环己基氧甲基-6-[3-甲基-3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2-胺;4-异丁氧基甲基-6-[3-甲基-3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2-胺;4-异丙氧基甲基-6-[3-甲基-3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2-胺;4-(1,1-二甲基-2-甲氧乙基)-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-(2-异丙氧基乙基)-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-(1-(甲氧基甲基)环戊基)-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-[3-甲基-3-(甲基氨基)氮杂环丁烷-1-基]-6-[(2S)-四氢呋喃-2-基]嘧啶-2-胺;4-[(二环丙基甲氧基)甲基]-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-(1-(甲氧基甲基)环戊基)-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;甲基3-(((2-氨基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-基)甲氧基)甲基)苯甲酸酯;甲基-4-(((2-氨基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-基)甲氧基)甲基)苯甲酸酯;甲基-2-(((2-氨基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-基)甲氧基)甲基)苯甲酸酯;4-(3-(甲基氨基)氮杂环丁烷-1-基)-6-((4-(甲基磺酰)苄基氧基)甲基)嘧啶-2-胺;4-(3-(甲基氨基)氮杂环丁烷-1-基)-6-((3-(甲基磺酰)苄基氧基)甲基)嘧啶-2-胺;2-[3-(((2-氨基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-基)甲氧基)甲基)苯基]丙-2-醇;[3-(((2-氨基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-基)甲氧基)甲基)苯基]甲醇;[4-(((2-氨基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-基)甲氧基)甲基)苯基]甲醇;[2-(((2-氨基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-基)甲氧基)甲基)苯基]甲醇;3-[((2-氨基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-基)甲氧基)甲基]苯甲酸;3-[((2-氨基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-基)甲氧基)甲基]苯甲酰胺;和3-[((2-氨基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-基)甲氧基)甲基]-N-丁基苯甲酰胺,或其盐。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2009/056551中描述的那些:4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-6,7,8,9-四氢苯并呋喃[3,2-d]嘧啶-2-胺;4-[3-(甲基氨基)氮杂环丁烷-1-基]-6,7,8,9-四氢苯并呋喃[3,2-d]嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-6,7,8,9-四氢苯并呋喃[3,2-d]嘧啶-2-胺;4-(3-氨基氮杂环丁烷-1-基)-6,7,8,9-四氢苯并呋喃[3,2-d]嘧啶-2-胺;4-[(4aR,7aR)-八氢-6H-吡咯并[3,4-b]嘧啶-6-基]-6,7,8,9-四氢苯并呋喃[3,2-d]嘧啶-2-胺;4-[3-甲基-3-(甲基氨基)氮杂环丁烷-1-基]-6,7,8,9-四氢苯并呋喃[3,2-d]嘧啶-2-胺;4-哌嗪-1-基-6,7,8,9-四氢苯并呋喃[3,2-d]嘧啶-2-胺;4-(1,4-二氮杂环庚烷-1-基)-6,7,8,9-四氢苯并呋喃[3,2-d]嘧啶-2-胺;4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-6,7,8,9-四氢苯并呋喃[3,2-d]嘧啶;4-[3-(甲基氨基)氮杂环丁烷-1-基]-6,7,8,9-四氢苯并呋喃[3,2-d]嘧啶;4-(1,4-二氮杂环庚烷-1-基)-6,7,8,9-四氢苯并呋喃[3,2-d]嘧啶;4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-7,8,9,10-四氢-6H-芳庚并[4,5]呋喃[3,2-d]嘧啶-2-胺;4-[3-(甲基氨基)氮杂环丁烷-1-基]-7,8,9,10-四氢-6H-芳庚并[4,5]呋喃[3,2-d]嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-7,8,9,10-四氢-6H-芳庚并[4,5]呋喃[3,2-d]嘧啶-2-胺;4-[3-甲基-3-(甲基氨基)氮杂环丁烷-1-基]-7,8,9,10-四氢-6H-芳庚并[4,5]呋喃[3,2-d]嘧啶-2-胺;4-[3-(甲基氨基)氮杂环丁烷-1-基]-7,8-二氢-6H-环戊二烯并[4,5]呋喃[3,2-d]嘧啶-2-胺;4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-7,8-二氢-6H-环戊二烯并[4,5]呋喃[3,2-d]嘧啶-2-胺;N4-[(3R)-1-(甲基吡咯烷-3-基]氨基-6,7,8,9-四氢苯并呋喃[3,2-d]嘧啶-2,4-二胺;4-(4-甲基哌嗪-1-基)-6,7,8,9-四氢苯并呋喃[3,2-d]嘧啶-2-胺;(S)-4-(3-甲基哌嗪-1-基)-6,7,8,9-四氢苯并呋喃[3,2-d]嘧啶-2-胺;和4-(4-甲基哌嗪-1-基)-6,7,8,9-四氢苯并呋喃[3,2-d]嘧啶及其盐。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2009/068512中描述的那些:4-(环丙基甲基)-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-环丙基甲基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-环丙基甲基-6-((3R)-3-氨基吡咯烷-1-基)嘧啶-2-胺;4-环丙基甲基-6-(哌嗪-1-基)嘧啶-2-胺;4-环丙基甲基-6-(3-甲基-3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-(3-氨基氮杂环丁烷-1-基)-6-环丙基甲基-嘧啶-2-胺;4-环丙基甲基-6-(1,4-二氮杂环庚烷-1-基)嘧啶-2-胺;4-(4-氨基哌啶-1-基)-6-环丙基甲基-嘧啶-2-胺;4-环丙基甲基-6-((4aR,7aR)-八氢吡咯并[3,4-b]吡啶-6-基)嘧啶-2-胺;4-环丙基甲基-6-((3S)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;(R)-4-环丙基甲基-6-[(N-甲基吡咯烷-3-基)胺]嘧啶-2-胺;(S)-4-环丙基甲基-6-(3-甲基哌嗪-1-基)嘧啶-2-胺;(R)-4-环丙基甲基-6-(3-甲基哌嗪-1-基)嘧啶-2-胺;4-环丙基甲基-6-[3-(吡咯烷-1-基)氮杂环丁烷-1-基]嘧啶-2-胺;4-(环丙基甲基)-6-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)嘧啶-2-胺;(S)-4-(环丙基甲基)-6-(六氢吡咯并[1,2-a)]-2(1H)-基)嘧啶-2-胺;4-异丙基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-异丙基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-叔丁基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-叔丁基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-(3-(甲基氨基)氮杂环丁烷-1-基)-6-丙基嘧啶-2-胺;4-((3R)-3-(甲基氨基)吡咯烷-1-基)-6-丙基嘧啶-2-胺;4-环丙基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-环丙基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-乙基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-乙基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-丁基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-丁基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-环戊基甲基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-环戊基甲基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-异丁基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-异丁基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-(2,2-二甲基丙基)-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-(2,2-二甲基丙基)-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;反式-4-(2-苯基环丙基)-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;(R)-4-叔丁基-6-[(N-甲基吡咯烷-3-基)胺]嘧啶-2-胺;4-(2-环戊基乙基)-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-(2-环戊基乙基)-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-(2-环丙基乙基)-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-((3R)-3-(甲基氨基)吡咯烷-1-基)-6-(4-甲基戊基)嘧啶-2-胺;4-(3-(甲基氨基)氮杂环丁烷-1-基)-6-(4-甲基戊基)嘧啶-2-胺;4-(3-环戊基丙基)-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-(4-环己基丁基)-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-2-胺;4-(4-环己基丁基)-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;(S)-4-(2-环丙基乙基)-6-(3-甲基哌嗪-1-基)嘧啶-2-胺;4-(3-氨基氮杂环丁烷-1-基)-6-(环戊基甲基)嘧啶-2-胺;4-(3-(甲基氨基)氮杂环丁烷-1-基)-6-(2,2,3,3-四甲基环丙基)嘧啶-2-胺;4-环丁基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-环戊基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-((3R)-3-(甲基氨基)吡咯烷-1-基)-6-(2,2,3,3-四甲基环丙基)嘧啶-2-胺;4-异丁基-6-(3-甲基-3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-(3-甲基-3-(甲基氨基)氮杂环丁烷-1-基)-6-新戊基嘧啶-2-胺;(S)-4-(3-甲基哌嗪-1-基)-6-新戊基嘧啶-2-胺;4-(3-(甲基氨基)氮杂环丁烷-1-基)-6-(1-甲基环丙基)嘧啶-2-胺;(R)-4-(环丙基甲基)-6-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)嘧啶-2-胺;4-环戊基-6-(3-甲基-3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-环丁基-6-(3-甲基-3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;4-(3-甲基-3-(甲基氨基)氮杂环丁烷-1-基)-6-(2,2,3,3-四甲基环丙基)嘧啶-2-胺;(S)-4-(3-甲基哌嗪-1-基)-6-(2,2,3,3-四甲基环丙基)嘧啶-2-胺;4-(3-(甲基氨基)氮杂环丁烷-1-基)-6-(戊-3-基)嘧啶-2-胺;4-((3R)-3-(甲基氨基)吡咯烷-1-基)-6-(戊-3-基)嘧啶-2-胺;4-((1S,2S,4S)-二环[2.2.1]庚-2-基)-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺;和4-((1S,2R,4S)-二环[2.2.1]庚-2-基)-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-2-胺及其盐。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2009/080721中描述的那些:2-异丁基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-4-胺;2-环己基甲基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-4-胺;2-(4-氟苄基)-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-胺;2-异丁基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-胺;2-环丙基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-胺;2-叔丁基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-胺;2-异丙基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-胺;2-(环丙基甲基)-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-胺;6-(3-(甲基氨基)氮杂环丁烷-1-基)-2-(苯氧基甲基)嘧啶-4-胺;2-环丙基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-4-胺;2-叔丁基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-4-胺;2-异丙基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-4-胺;6-((3R)-3-(甲基氨基)吡咯烷-1-基)-2-(苯氧基甲基)嘧啶-4-胺;6-(3-氨基氮杂环丁烷-1-基)-2-异丁基嘧啶-4-胺;2-异丁基-6-(3-甲基-3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-胺;6-((3R)-3-氨基吡咯烷-1-基)-2-异丁基嘧啶-4-胺;2-环丁基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-胺;2-环丁基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-4-胺;2-环戊基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-胺;2-环戊基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-4-胺;2-(2,2-二甲基丙基)-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-胺;2-(2,2-二甲基丙基)-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-4-胺;2-(2-环戊基乙基)-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-4-胺;2-环己基甲基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-胺;2-环丙基甲基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-4-胺;2-环己基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-胺;2-环己基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-4-胺;和2-(4-氟苄基)-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-4-胺,或其盐。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2009/115496中描述的那些:7-环丙基-4-(4-甲基哌嗪-1-基)呋喃[3,2-d]嘧啶-2-胺;7-环丙基-4-[(3S)-(3-甲基哌嗪-1-基)呋喃[3,2-d]嘧啶-2-胺;7-乙基-4-[4-甲基哌嗪-1-基)呋喃[3,2-d]嘧啶-2-胺;4-[4-甲基哌嗪-1-基)-7-丙基呋喃[3,2-d]嘧啶-2-胺;7-环丙基-4-(3-(甲基氨基)氮杂环丁烷-1-基)呋喃[3,2-d]嘧啶-2-胺;7-环丙基-4-[(3R)-3-(甲基氨基)吡咯烷-1-基)呋喃[3,2-d]嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基)-7-环丙基呋喃[3,2-d]嘧啶-2-胺;4-(3-氨基氮杂环丁烷-1-基)-7-环丙基呋喃[3,2-d]嘧啶-2-胺;7-环丙基-4-(3-甲基-3-(甲基氨基)氮杂环丁烷-1-基)呋喃[3,2-d]嘧啶-2-胺;7-环丙基-4-(哌嗪-1-基)呋喃[3,2-d]嘧啶-2-胺;7-环丙基-4-(1,4-二氮杂环庚烷-1-基)呋喃[3,2-d]嘧啶-2-胺;7-乙基-4-(3-(甲基氨基)氮杂环丁烷-1-基)呋喃[3,2-d]嘧啶-2-胺;7-乙基-4-[(3R)-3-(甲基氨基)吡咯烷-1-基)呋喃[3,2-d]嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-7-乙基呋喃[3,2-d]嘧啶-2-胺;7-乙基-4-(3-甲基-3-(甲基氨基)氮杂环丁烷-1-基)呋喃[3,2-d]嘧啶-2-胺;7-乙基-4-(哌嗪-1-基)呋喃[3,2-d]嘧啶-2-胺;4-(3-(甲基氨基)氮杂环丁烷-1-基)-7-丙基呋喃[3,2-d]嘧啶-2-胺;4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-7-丙基呋喃[3,2-d]嘧啶-2-胺;4-[(3R)-3-(氨基吡咯烷-1-基)-7-丙基呋喃[3,2-d]嘧啶-2-胺;4-(3-甲基-3-(甲基氨基)氮杂环丁烷-1-基]-7-丙基呋喃[3,2-d]嘧啶-2-胺;4-(哌嗪-1-基]-7-丙基呋喃[3,2-d]嘧啶-2-胺;7-异丙基-4-(3-(甲基氨基)氮杂环丁烷-1-基]呋喃[3,2-d]嘧啶-2-胺;7-异丙基-4-[(3R)-3-(甲基氨基)吡咯烷-1-基]呋喃[3,2-d]嘧啶-2-胺;7-苄基-4-(3-(甲基氨基)氮杂环丁烷-1-基]呋喃[3,2-d]嘧啶-2-胺;7-苄基-4-[(3R)-3-(甲基氨基)吡咯烷-1-基]呋喃[3,2-d]嘧啶-2-胺;7-环丁基-4-(3-(甲基氨基)氮杂环丁烷-1-基)呋喃[3,2d]嘧啶-2-胺;7-环丁基-4-[(3R)-3-甲基氨基)吡咯烷-1-基)呋喃[3,2d]嘧啶-2-胺;7-环戊基-4-(3-(甲基氨基)氮杂环丁烷-1-基)呋喃[3,2d]嘧啶-2-胺;7-环戊基-4-[(3R)-3-甲基氨基)吡咯烷-1-基)呋喃[3,2d]嘧啶-2-胺;7-异丁基-4-(3-(甲基氨基)氮杂环丁烷-1-基)呋喃[3,2d]嘧啶-2-胺;7-异丁基-4-[(3R)-3-甲基氨基)吡咯烷-1-基)呋喃[3,2d]嘧啶-2-胺;4-(3-(甲基氨基)氮杂环丁烷-1-基)-7-苯基呋喃[3,2d]嘧啶-2-胺;4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-7-苯基呋喃[3,2d]嘧啶-2-胺;7-叔丁基-4-(3-(甲基氨基)氮杂环丁烷-1-基)呋喃[3,2d]嘧啶-2-胺;7-叔丁基-4-[(3R)-3-甲基氨基)吡咯烷-1-基)呋喃[3,2d]嘧啶-2-胺;7-环丙基-4-(3-(甲基氨基)氮杂环丁烷-1-基)呋喃[3,2d]嘧啶-2-胺;6-氯-7-环丁基-4-(3-(甲基氨基)氮杂环丁烷-1-基)呋喃[3,2-d]嘧啶-2-胺;6-氯-7-环丙基-4-(3-(甲基氨基)氮杂环丁烷-1-基)呋喃[3,2-d]嘧啶-2-胺;6-氯-7-环丙基-4-[(3R)-3-(甲基氨基)吡咯烷-1-基]呋喃[3,2-d]嘧啶-2-胺;6-氯-7-异丙基-4-(3-(甲基氨基)氮杂环丁烷-1-基)呋喃[3,2-d]嘧啶-2-胺;6-氯-7-异丙基-4-[(3R)-3-(甲基氨基)吡咯烷-1-基]呋喃[3,2-d]嘧啶-2-胺;6-氯-7-环戊基-4-[(3R)-3-(甲基氨基)吡咯烷-1-基]呋喃[3,2-d]嘧啶-2-胺;4-(3-(甲基氨基)氮杂环丁烷-1-基)-7-(四氢-2H-吡喃-4-基)呋喃[3,2-d]嘧啶-2-胺;2-氨基-7-异丙基-4-((3R)-3-(甲基氨基)吡咯烷-1-基)呋喃[3,2-d]嘧啶-6-甲腈;2-氨基-7-环丙基-4-(3-(甲基氨基)氮杂环丁烷-1-基)呋喃[3,2-d]嘧啶-6-甲腈;7-(1-(甲氧基甲基)环丙基)-4-(3-(甲基氨基)氮杂环丁烷-1-基)呋喃[3,2-d]嘧啶-2-胺及其盐。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2007/090852中描述的那些:[(R)-1-(2-氨基-8-氯苯并[4,5]呋喃[3,2-d]-嘧啶-4-基)吡咯烷-3-基]N-甲基胺;[(S)-1-(2-氨基-8-氯苯并[4,5]呋喃[3,2-d]-嘧啶-4-基)吡咯烷-3-基]N-甲基胺;[1-(2-乙基氨基-8-氯苯并[4,5]呋喃[3,2-d]-嘧啶-4-基)氮杂环丁烷-3-基]N-乙基胺;4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-甲基-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-氟-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-溴-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;7-氯-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;N-[1-(2-氨基-8-氯苯并[4,5]呋喃[3,2-d]嘧啶-4-基)氮杂环丁烷-3-基]N-甲基胺;4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-溴-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-甲基-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-氟-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-甲氧基-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-((R)-3-甲基氨基-吡咯烷-1-基)-8-三氟甲氧基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;9-氟-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;9-甲基-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;9-甲氧基-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;7-甲基-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;7-甲氧基-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-((R)-3-甲基氨基-吡咯烷-1-基)-7-三氟甲基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;6-氯-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;6-甲基-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;6-甲氧基-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-甲氧基-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-(3-甲基氨基-氮杂环丁烷-1-基)-8-三氟甲氧基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;9-氟-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;9-甲基-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;9-甲氧基-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;7-甲基-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;7-甲氧基-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-(3-甲基氨基-氮杂环丁烷-1-基)-7-三氟甲基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;6-氯-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;6-甲基-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;6-甲氧基-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-氯-4-[3-(环丙基甲基-氨基)-吡咯烷-1-基]-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-氯-4-((R)-3-二甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-((R)-3-氨基-吡咯烷-1-基)-8-氯-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-氯-4-(4-甲基氨基-哌啶-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-(4-氨基-哌啶-1-基)-8-氯-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-(3-氨基-氮杂环丁烷-1-基)-8-氯-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;[8-氯-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-甲基-胺;[8-氯-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-二甲基-胺;N-[8-氯-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-乙酰胺;N-[8-氯-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-甲基磺酰胺;[8-氯-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-环丙基-胺;[8-氯-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-甲基-胺;[8-氯-4-(3-甲基氨基-氮杂环丁烷-1-基)苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-二甲基-胺;N-[8-氯-4-(3-甲基氨基-氮杂环丁烷-1-基)苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-乙酰胺;N-[8-氯-4-(3-甲基氨基-氮杂环丁烷-1-基)苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-甲基磺酰胺;[8-氯-4-(3-甲基氨基-氮杂环丁烷-1-基)苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-环丙基-胺及其盐。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2007/090853中描述的那些:[(R)-1-(2-氨基-8-氯苯并[4,5]呋喃[3,2-d]-嘧啶-4-基)吡咯烷-3-基]N-甲基胺;4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-甲基-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-氟-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-溴-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;7-氯-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-甲氧基-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-((R)-3-甲基氨基-吡咯烷-1-基)-8-三氟甲氧基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;9-氟-4-((R)-3-甲基氨基-吡咯烷-1l-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;9-甲基-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;9-甲氧基-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;7-甲基-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;7-甲氧基-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-((R)-3-甲基氨基-吡咯烷-1-基)-7-三氟甲基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;6-氯-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;6-甲基-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;6-甲氧基-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-氯-4-[3-(环丙基甲基-氨基)-吡咯烷-1-基]-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-氯-4-((R)-3-二甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-((R)-3-氨基-吡咯烷-1-基)-8-氯-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;[8-氯-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-甲基-胺;[8-氯-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-二甲基-胺;N-[8-氯-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-乙酰胺;N-[8-氯-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-甲基磺酰胺;[8-氯-4-((R)-3-甲基氨基-吡咯烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-环丙基-胺。一些所述的化合物和/或其盐或酯将以不同的立体异构体形式存在。所有这些形式是本发明的主题,只要是与嘧啶环4-位中的吡咯烷环连接的氨基显示为R-构型即可。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2007/090854中描述的那些:[1-(2-乙基氨基-8-氯苯并[4,5]呋喃[3,2-d]-嘧啶-4-基)氮杂环丁烷-3-基]N-乙基胺;N-[1-(2-氨基-8-氯苯并[4,5]呋喃[3,2-d]嘧啶-4-基)氮杂环丁烷-3-基]N-甲基胺;4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-溴-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-甲基-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-氟-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-甲氧基-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-(3-甲基氨基-氮杂环丁烷-1-基)-8-三氟甲氧基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;9-氟-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;9-甲基-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;9-甲氧基-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;7-甲基-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;7-甲氧基-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-(3-甲基氨基-氮杂环丁烷-1-基)-7-三氟甲基-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;6-氯-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;6-甲基-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;6-甲氧基-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-(3-氨基-氮杂环丁烷-1-基)-8-氯-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;[8-氯-4-(3-甲基氨基-氮杂环丁烷-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-甲基-胺;[8-氯-4-(3-甲基氨基-氮杂环丁烷-1-基)苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-二甲基-胺;N-[8-氯-4-(3-甲基氨基-氮杂环丁烷-1-基)苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-乙酰胺;N-[8-氯-4-(3-甲基氨基-氮杂环丁烷-1-基)苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-甲基磺酰胺;[8-氯-4-(3-甲基氨基-氮杂环丁烷-1-基)苯并[4,5]呋喃[3,2-d]嘧啶-2-基]-环丙基-胺。一些所述的化合物和/或其盐或酯将以不同的立体异构体形式存在。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2007/039467中描述的那些:N-[(R,S)-1-(8-氯-2-甲基苯并[4,5]呋喃[3,2-d]-嘧啶-4-基)-吡咯烷-3-基]-N-甲基胺;N-[(R,S)-1-(8-氯苯并[4,5]呋喃[3,2-d]-嘧啶-4-基)-吡咯烷-3-基]-N-甲基胺;[(R,S)-1-(8-氯-2-甲基苯并[4,5]呋喃[3,2-d]嘧啶-4-基)吡咯烷-3-基]二甲基胺;N-[(R)-1-(8-氯苯并[4,5]呋喃[3,2-d]嘧啶-4-基)吡咯烷-3-基]N-甲基胺;N-[(S)-1-(8-氯苯并[4,5]呋喃[3,2-d]嘧啶-4-基)吡咯烷-3-基]N-甲基胺;N-[1-(8-氯苯并[4,5]呋喃[3,2-d]嘧啶-4-基)氮杂环丁烷-3-基]胺;N-[1-(8-氯苯并[4,5]呋喃[3,2-d]嘧啶-4-基)氮杂环丁烷-3-基]N-甲基胺;N-1-(8-氯苯并[4,5]呋喃[3,2-d]嘧啶-4-基)氮杂环丁烷-3-基]N,N-二甲基胺;N-[1-(8-氯苯并[4,5]呋喃[3,2-d]嘧啶-4-基)氮杂环丁烷-3-基]N,N-二甲基胺;[(R,S)-1-(8-氯苯并[4,5]呋喃[3,2-d]嘧啶-4-基)吡咯烷-3-基]胺;[(R,S)-1-(8-氯苯并[4,5]呋喃[3,2-d]嘧啶-4-基)吡咯烷-3-基]二甲基胺;[(R,S)-1-(8-甲基苯并[4,5]呋喃[3,2-d]嘧啶-4-基)吡咯烷-3-基]-N-甲基胺;[(R)-1-(8-氯苯并[4,5]呋喃[3,2-d]嘧啶-4-基)吡咯烷-3-基]胺;[(S)-1-(8-氯苯并[4,5]呋喃[3,2-d]嘧啶-4-基)吡咯烷-3-基];N-[(R)-1-(8-三氟甲基苯并[4,5]呋喃[3,2-d]嘧啶-4-基)吡咯烷-3-基]N-甲基胺;N-[(S)-1-(8-三氟甲基苯并[4,5]呋喃[3,2-d]嘧啶-4-基)吡咯烷-3-基]N-甲基胺;N-[(R)-1-(8-甲基苯并[4,5]呋喃[3,2-d]嘧啶-4-基)吡咯烷-3-基]N-甲基胺;N-[(S)-1-(8-甲基苯并[4,5]呋喃[3,2-d]嘧啶-4-基)吡咯烷-3-基]N-甲基胺;N-[(R)-1-(8-氯-2-三氟甲基苯并[4,5]呋喃[3,2-d]嘧啶-4-基)吡咯烷-3-基]N-甲基胺;N-[(S)-1-(8-氯-2-三氟甲基苯并[4,5]呋喃[3,2-d]嘧啶-4-基)吡咯烷-3-基]N-甲基胺;N-[1-(8-氯苯并[4,5]呋喃[3,2-d]嘧啶-4-基)氮杂环丁烷-3-基]N-乙基胺;[(R,S)-1-(8-氯苯并[4,5]呋喃[3,2-d]嘧啶-4-基)-3-甲基吡咯烷-3-基]-N-甲基胺;N-[1-(8-氯苯并[4,5]呋喃[3,2-d]嘧啶-4-基)氮杂环丁烷-3-基]N-环丙基胺;和[(3RS,4RS)-1-(8-氯苯并[4,5]呋喃[3,2-d]嘧啶-4-基)-4-氟吡咯烷-3-基]N-甲基胺。一些所述的化合物和/或其盐或酯将以不同的立体异构体形式存在。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2009/071625中描述的那些:10-[(3R)-1-氮杂二环[2.2.2]辛-3-基甲基]-10H-吩噻嗪(右旋对映异构体);10-[(3S)-1-氮杂二环[2.2.2]辛-3-基甲基]-10H-吩噻嗪(左旋对映异构体);两种对映异构体10-[(3R,3S)-1-氮杂二环[2.2.2]辛-3-基甲基]-10H-吩噻嗪的外消旋混合物。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2009/134726中描述的那些:4-哌嗪-1-基-5,6,7a,8,9,10,11,11a-八氢[1]苯并呋喃[2,3-h]喹唑啉-2-胺;4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-5,6,7a,8,9,10,11,11a-八氢[1]苯并呋喃[2,3-h]喹唑啉-2-胺;(7aS,11aS)-4-哌嗪-1-基-5,6,7a,8,9,10,11,11a-八氢[1]苯并呋喃[2,3-h]喹唑啉-2-胺;(7aR,11aR)-4-哌嗪-1-基-5,6,7a,8,9,10,11,11a-八氢[1]苯并呋喃[2,3-h]喹唑啉-2-胺;4-(4-甲基-1,4-二氮杂环庚烷-1-基)-5,6,7a,8,9,10,11,11a-八氢[1]苯并呋喃[2,3-h]喹唑啉-2-胺;4-(4-甲基哌嗪-1-基)-5,6,7a,8,9,10,11,11a-八氢[1]苯并呋喃[2,3-h]喹唑啉-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-7a,8,9,10,11,11a-六氢[1]苯并呋喃[2,3-h]喹唑啉-2-胺;4-[(1R,5S)-3,6-二氮杂二环[3.2.0]庚-6-基]-7a,8,9,10,11,11a-六氢[1]苯并呋喃[2,3-h]喹唑啉-2-胺;4-(1,4-二氮杂环庚烷-1-基)-5,6,7a,8,9,10,11,11a-八氢[1]苯并呋喃[2,3-h]喹唑啉-2-胺;4-(4-异丙基-1,4-二氮杂环庚烷-1-基)-5,6,7a,8,9,10,11,11a-八氢[1]苯并呋喃[2,3-h]喹唑啉-2-胺;4-(4-环丁基-1,4-二氮杂环庚烷-1-基)-5,6,7a,8,9,10,11,11a-八氢[1]苯并呋喃[2,3-h]喹唑啉-2-胺;反式-4-哌嗪-1-基-5,6,6a,7,8,9,10,10a-八氢苯并[h]喹唑啉-2-胺;顺式-4-哌嗪-1-基-5,6,6a,7,8,9,10,10a-八氢苯并[h]喹唑啉-2-胺;反式-4-[3-(甲基氨基)氮杂环丁烷-1-基]-5,6,6a,7,8,9,10,10a-八氢苯并[h]喹唑啉-2-胺;反式-4-[3-(乙基氨基)氮杂环丁烷-1-基]-5,6,6a,7,8,9,10,10a-八氢苯并[h]喹唑啉-2-胺;反式-4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-5,6,6a,7,8,9,10,10a-八氢苯并[h]喹唑啉-2-胺;反式-4-[(3R)-3-氨基吡咯烷-1-基]-5,6,6a,7,8,9,10,10a-八氢苯并[h]喹唑啉-2-胺;反式-4-八氢-6H-吡咯并[3,4-b]吡啶-6-基-5,6,6a,7,8,9,10,10a-八氢苯并[h]喹唑啉-2-胺;顺式-4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-5,6,6a,7,8,9,10,10a-八氢苯并[h]喹唑啉-2-胺;顺式-4-[(3R)-3-氨基吡咯烷-1-基]-5,6,6a,7,8,9,10,10a-八氢苯并[h]喹唑啉-2-胺;顺式-4-[顺式-八氢-6H-吡咯并[3,4-b]吡啶-6-基]-5,6,6a,7,8,9,10,10a-八氢苯并[h]喹唑啉-2-胺;顺式-4-[3-(甲基氨基)氮杂环丁烷-1-基]-5,6,6a,7,8,9,10,10a-八氢苯并[h]喹唑啉-2-胺;顺式-4-[3-(乙基氨基)氮杂环丁烷-1-基]-5,6,6a,7,8,9,10,10a-八氢苯并[h]喹唑啉-2-胺;4-顺式-八氢-6H-吡咯并[3,4-6]吡啶-6-基-6,7,7a,8,11,11a-六氢-5H-8,11-桥亚乙基苯并[6,7]芳庚并[1,2-d]嘧啶-2-胺;4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-6,7,7a,8,11,11a-六氢-5H-8,11-桥亚乙基苯并[6,7]芳庚并[1,2-d]嘧啶-2-胺;4-哌嗪-1-基-6,7,7a,8,11,11a-六氢-5H-8,11-桥亚乙基苯并[6,7]芳庚并[1,2-d]嘧啶-2-胺;4-顺式-八氢-6H-吡咯并[3,4-b]吡啶-6-基-6,7,7a,8,9,10,11,11a-八氢-5H-8,11-桥亚乙基苯并[6,7]芳庚并[1,2-d]嘧啶-2-胺;或4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-6,7,7a,8,9,10,11,11a-八氢-5H-8,11-桥亚乙基苯并[6,7]芳庚并[1,2-d]嘧啶-2-胺。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2009/114575中描述的那些:(R)-4’-(3-(甲基氨基)吡咯烷-1-基)-6',7'-二氢-5Η-螺[环戊烷-1,8'-喹唑啉]-2'-胺;4'-(哌嗪-1-基)-6',7'-二氢-5Η-螺[环戊烷-1,8'-喹唑啉]-2’-胺;4'-(3-(甲基氨基)氮杂环丁烷-1-基)-6’,7'-二氢-5Η-螺[环戊烷-1,8’-喹唑啉]-2'-胺;(R)-4'-(3-氨基吡咯烷-1-基)-6'7'-二氢-5’Η-螺[环戊烷-1,8’-喹唑啉]-2'-胺;(S)-4’-(3-氨基吡咯烷-1-基)-6'7'-二氢-5’Η-螺[环戊烷-1,8’-喹唑啉]-2'-胺;4’-((3aR,6aR)-六氢吡咯并[3,4-b]吡咯-1(2H)-基)-6l,7l-二氢-5Η-螺[环戊烷-1,8'-喹唑啉]-2'-胺;4’-((3aS,6aS)-六氢吡咯并[3,4-b]吡咯-1(2H)-基)-6’7’-二氢-5Η-螺[环戊烷-1,8'-喹唑啉]-2'-胺;4'-(1,4-二氮杂环庚烷-1-基)-6',7'-二氢-5’H-螺[环戊烷-1,8'-喹唑啉]-2’-胺;4’-((4aR,7aR)-四氢-1H-吡咯并[3,4-b]吡啶-6(2H,7H,7aH)-基)-6',7’-二氢-5'H-螺[环戊烷-1,8'-喹唑啉]-2'-胺;N4’-(1-甲基哌啶-4-基)-6',7'-二氢-5Η-螺[环戊烷-1,8'-喹唑啉]-2',4'-二胺;甲基4-氨基-1-(2’-氨基-6',7’-二氢-5'H-螺[环戊烷-1,8'-喹唑啉]-4'-基)哌啶-4-羧酸酯;4-氨基-1-(2'-氨基-6’,7'-二氢-5Η-螺[环戊烷-1,8'-喹唑啉]-4’-基)哌啶-4-羧酸;4'-(3-氨基氮杂环丁烷-1-基)-6’,7’-二氢-5'H-螺[环戊烷-1,8'-喹唑啉]-2'-胺;4'-(2-(二甲基氨基)乙氧基)-6’,7'-二氢-5'H-螺[环戊烷-1,8’-喹唑啉]-2'-胺;(R)-4'-(1-甲基吡咯烷-3-基氧基)-6'7'-二氢-5’Η-螺[环戊烷-1,8’-喹唑啉]-2'-胺;4-(哌嗪-1-基)-5,6,7,8-四氢螺[芳庚并[d]嘧啶-9,1'-环己]-2-胺;(R)-4-(3-氨基吡咯烷-1-基-5,6,7,8-四氢螺[芳庚并[d]嘧啶-9,1'-环己]-2-胺;4-((4aR,7aR)-四氢-1H-吡咯并[3,4-b]吡啶-6(2H,7H,7aH)-基)-5,6,7,8-四氢螺[芳庚并[d]嘧啶-9,1’-环己]-2-胺;4-(哌嗪-1-基)-1’,3',5,6,7,8-六氢螺[芳庚并[d]嘧啶-9,2'-茚]-2-胺;和(R)-4-(3-氨基吡咯烷-1-基)-1’,3’,5,6,7,8-六氢螺[芳庚并[d]嘧啶-9,2'-茚]-2-胺。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2008/060767中描述的那些:6-甲基-4-[(3R)-3-甲基氨基-吡咯烷-1-基]-5,6-二氢-苯并[h]喹唑啉-2-基胺;6-甲基-4-(3-甲基氨基-氮杂环丁烷-1-基)-5,6-二氢-苯并[h]喹唑啉-2-基胺;4-(3-甲基氨基-氮杂环丁烷-1-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;6-甲基-4-哌嗪-1-基-5,6-二氢-苯并[h]喹唑啉-2-基胺;4-(3-(R)-甲基氨基-吡咯烷-1-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;4-哌嗪-1-基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;1-(3-甲基氨基-氮杂环丁烷-1-基)-10H-9-氧杂-2,4-二氮杂-菲-3-基胺;1-{3-(R)-甲基氨基-吡咯烷-1-基)-10H-9-氧杂-2,4-二氮杂-菲-3-基胺;1-哌嗪-1-基-10H-9-氧杂-2,4-二氮杂-菲-3-基胺;10-氟-4-(3-(R)-甲基氨基-吡咯烷-1-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;10-氟-4-(3-甲基氨基-氮杂环丁烷-1-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;10-氟-4-哌嗪-1-基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;4-[(3S)-3-甲基氨基-吡咯烷-1-基]-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;4-((3aR,6aR)-1-甲基-六氢-吡咯并[3,4-b]吡咯-5-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;4-((3R)-3-氨基-吡咯烷-1-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;4-((1S,4S)-2,5-二氮杂-二环[2.2.1]庚-2-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;4-(3-哌啶-1-基-吡咯烷-1-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;4-{(3aR,6aR)-六氢-吡咯并[3,4-b]吡咯-1-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;4-哌嗪-1-基-5,6,7,8-四氢-1,3-二氮杂-二苯并[a,c]环辛-2-基胺;4-哌嗪-1-基-6,7,8,9-四氢-5H-1,3-二氮杂-二苯并[a,c]环壬烯-2-基胺;4-(六氢-吡咯并[3,4-c]吡咯-2-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;4-{3-(R)-甲基氨基-吡咯烷-1-基)-6,7,8,9-四氢-5H-1,3-二氮杂-二苯并[a,c]环壬烯-2-基胺;4-({R)-3-氨基-吡咯烷-1-基)-6,7,8,9-四氢-5H-1,3-二氮杂-二苯并[a,c]环壬烯-2-基胺;4-{(S)-3'氨基-吡咯烷-1-基)-6,7,8,9-四氢-5H-1,3-二氮杂-二苯并[a,c]环壬烯-2-基胺;4-(3-甲基氨基-氮杂环丁烷-1-基)-6,7,8,9-四氢-5H-1,3-二氮杂-二苯并[a,c]环壬烯-2-基胺;4-{(3aS,6aS)-六氢-吡咯并[3,4-b]吡咯-1-基)-6,7,8,9-四氢-5H-1,3-二氮杂-二苯并[a,c]环壬烯-2-基胺;4-((1S,4S)-2,5-二氮杂-二环[2.2.1]庚-2-基)-6,7,8,9-四氢-5H-1,3-二氮杂-二苯并[a,c]环壬烯-2-基胺;4-{4-甲基-哌嗪-1-基)-5,6-二氢-7-氧杂-1,3-二氮杂-二苯并[a,c]环庚烯-2-基胺;4-哌嗪-1-基-5,6-二氢-7-氧杂-1,3-二氮杂-二苯并[a,c]环庚烯-2-基胺;4-((R)-3-甲基氨基-吡咯烷-1-基)-5,6-二氢-7-氧杂-1,3-二氮杂-二苯并[a,c]环庚烯-2-基胺,4-(3-甲基氨基-氮杂环丁烷-1-基)-5,6-二氢-7-氧杂-1,3-二氮杂-二苯并[a,c]环庚烯-2-基胺;4-(3-甲基氨基-氮杂环丁烷-1-基)-5,6-二氢-7-硫杂-1,3-二氮杂-二苯并[a,c]环庚烯-2-基胺;4-(3-(R)-甲基氨基-吡咯烷-1-基)-5,6-二氢-7-硫杂-1,3-二氮杂-二苯并[a,c]环庚烯-2-基胺;4-{3-(R)-氨基-吡咯烷-1-基)-5,6-二氢-7-硫杂-1,3-二氮杂-二苯并[a,c]环庚烯-2-基胺;4-哌嗪-1-基-5,6-二氢-7-硫杂-1,3-二氮杂-二苯并[a,c]环庚烯-2-基胺;4-(3-甲基氨基-氮杂环丁烷-1-基)-7-氧杂-6,7-二氢-5H-7λ4-硫杂-1,3-二氮杂-二苯并[a,c]环庚烯-2-基胺;4-(3-甲基氨基-氮杂环丁烷-1-基)-7,7-二氧杂-6,7-二氢-5H-7λ6-硫杂-1,3-二氮杂-二苯并[a,c]环庚烯-2-基胺;4-(3-(R)-甲基氨基-吡咯烷-1-基)-5,6-二氢-苯并[h]喹唑啉-2-基胺;4-(3-甲基氨基-氮杂环丁烷-1-基)-5t6-二氢-苯并[h]喹唑啉-2-基胺;4-哌嗪-1-基-5,6-二氢-苯并[h]喹唑啉-2-基胺;10-氯-4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-5,6-二氢[1]苯并氧杂并[5,4-d]嘧啶-2-胺;10-甲基-4-[(3R)-3-{甲基氨基)吡咯烷-1-基]-5,6-二氢[1]苯并氧杂并[5,4-of]嘧啶-2-胺;10-甲氧基-4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-5,6-二氢[1]苯并氧杂并[5,4-d]嘧啶-2-胺;9-氯-4-[(3R)--3-(甲基氨基)吡咯烷-1-基]-5,6-二氢[1]苯并氧杂并[5,4-d]嘧啶-2-胺;9-甲基-4-[{3R)-3-(甲基氨基)吡咯烷-1-基]-5,6'-二氢[1]苯并氧杂并[5,4-d]嘧啶-2-胺;9-甲氧基-4-[(3R)-3-{甲基氨基)吡咯烷-1-基]-5,6-二氢[1]苯并氧杂并[5,4-d]嘧啶-2-胺;8-氯-4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-5,6-二氢[1]苯并氧杂并[5,4-d]嘧啶-2-胺;8-甲基-4-((R)-3-甲基氨基-吡咯烷-1-基)-5,6-二氢-7-氧杂-1,3-二氮杂-二苯并[a,c]环庚烯-2-基胺;8-甲氧基-4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-5,6-二氢[1]苯并氧杂并[5,4-d]嘧啶-2-胺;4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-5,6,7,8-四氢苯并[7,8]芳辛并[1,2-d]嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-5,6,7,8-四氢苯并[7,8]芳辛并[1,2-d]嘧啶-2-胺;4-[(3S)-3-氨基吡咯烷-1-基]-5,6,7,8-四氢苯并[7,8]芳辛并[1,2-d]嘧啶-2-胺;4-(3-氨基氮杂环丁烷-1–基)-5,6,7,8-四氢苯并[7,8]芳辛并[1,2-d]嘧啶-2-胺;4-[(3aR,6aR)-六氢吡咯并[3,4-b]吡咯-1(2H)-基]-5,6,7,8-四氢苯并[7,8]芳辛并[1,2-d]嘧啶-2-胺;4-八氢-6H-吡咯并[3,4-b]吡啶-6-基-6,7-二氢-5H-苯并[6,7l芳庚并[1,2-d]嘧啶-2-胺;4-(2,8-二氮杂螺[4.5]十二-8-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-胺;4-(1,5-二氮杂环辛烷-1-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-胺;4-{4-氨基哌啶-1-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-胺;N4-(2-氮杂环丁烷-2-基乙基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2,4-二胺;N4-[(2R)-氮杂环丁烷-2-基甲基]-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2,4-二胺;N4-(1-甲基哌啶-4-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2,4-二胺;N4-[(1R,5S)-8-甲基-8-氮杂二环[3.2.1]辛-3-基]-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2,4-二胺;4-(5-甲基-1,4-二氮杂环庚烷-1-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-胺;4-(1-甲基-哌啶-4-基氧基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;4-(1-甲基-哌啶-3-基氧基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;4-((R)-1-甲基-吡咯烷-3-基氧基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;4-((S)-1-甲基-吡咯烷-3-基氧基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺,4-(哌啶-4-基氧基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;4-((S)-吡咯烷-3-基氧基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺,4-(2-二甲基氨基-乙氧基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;4-(1,9-二氮杂-螺[5.5]十一碳-9-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;4-((R)-3-二甲基氨基-吡咯烷-1-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;4-(2,6-二氮杂-螺[3.5]壬-2-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;4-(2,5-二氮杂-螺[3.5]壬-2-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;4-(八氢-吡咯并[3,4-c]吡啶-2-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;4-(八氢-吡咯并[1,2-a]吡嗪-2-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;4-(3,6-二氮杂-二环[3.2.1]辛-6-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;4-(2,6-二氮杂-二环[3.2.1]辛-2-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;N-(4-哌嗪-1-基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基)-乙酰胺,N-(4-哌嗪-1-基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基)-苯甲酰胺,4-(5-甲基-八氢-吡咯并[3,4-c]吡啶-2-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺,4-(3-甲基-3,6-二氮杂-二环[3.2.1]辛-6-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺,2-二甲基氨基-N-(4-哌嗪-1-基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基)-乙酰胺;2-甲基氨基-N-(4-哌嗪-1-基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基)-乙酰胺;2-氨基-N-(4-哌嗪-1-基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基)-乙酰胺;1-甲基-3-(4-哌嗪-1-基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基)-尿;4-氨基-N-(4-哌嗪-1-基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基)-丁酰胺;6-{2-吡啶-3-基甲基氨基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-4-基)八氢-1H-吡咯并[3,4-b]吡啶;3-氨基-N-(4-哌嗪-1-基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基)-丙酰胺;4-[1,4,7]三氮杂环壬烷-1-基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;N,N-二甲基-N'-(4-哌嗪-1-基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基)-乙烷-1,2-二胺;4-(八氢-吡咯并[3,4-b]吡啶-6-基)-5,6-二氢-7-硫杂-1,3-二氮杂-二苯并[a,c]环庚烯-2-基胺;4-((R)-3-甲基氨基-吡咯烷-1-基)-6,7,9,10,11,12-六氢-5H-1,3-二氮杂-苯并[3,4]芳庚并[1,2-b]萘-2-基胺;4'(八氢-吡咯并[3,4-b]吡啶-6-基)-6,7,9,10,11,12-六氢-5H-1,3-二氮杂-苯并[3,4]芳庚并[1,2-b]萘-2-基胺;4-哌嗪-1-基-6,7,9,10,11,12-六氢-5H-1,3-二氮杂-苯并[3,4]芳庚并[1,2-b]萘-2-基胺;9-碘代-4-({R)-3-甲基氨基-吡咯烷-1-基)-5,6-二氢-7-氧杂-1,3-二氮杂-二苯并[a,c]环庚烯-2-基胺;9-碘代-4-哌嗪-1-基-5,6-二氢-7-氧杂-1,3-二氮杂-二苯并[a,c]环庚烯-2-基胺;9-碘代-4-八氢-吡咯并[3,4-b]吡啶-6-基-5,6-二氢-7-氧杂-1,3-二氮杂-二苯并[a,c]环庚烯-2-基胺;2,4-二-哌嗪-1-基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶;2-氨基-4-八氢-吡咯并[3,4-b]吡啶-6-基-5,6-二氢-7-氧杂-1,3-二氮杂-二苯并[a,c]环庚烯-9-甲腈;4-八氢-吡咯并[3,4-b]吡啶-6-基-9-苯基-5,6-二氢-7-氧杂-1,3-二氮杂-二苯并[a,c]环庚烯-2-基胺;4-八氢-吡咯并[3,4-b]吡啶-6-基-9-吡啶-3-基-5,6-二氢-7-氧杂-1,3-二氮杂-二苯并[a,c]环庚烯-2-基胺;4-((R)-3-甲基氨基-吡咯烷-1-基)-6,7-二氢-5-硫杂-1,3-二氮杂-二苯并[a,c]环庚烯-2-基胺;2-氨基-4-八氢-吡咯并[3,4-b]吡啶-6-基-5,6-二氢-7-氧杂-1,3-二氮杂-二苯并[a,c]环庚烯-9-羧酸甲酯;4-哌嗪-1-基-6,7-二氢-5-硫杂-1,3-二氮杂-二苯并[a,c]环庚烯-2-基胺;4-(八氢-吡咯并[3,4-b]吡啶-6-基)-6,7-二氢-5-硫杂-1,3-二氮杂-二苯并[a.c]环庚烯-2-基胺;4-((R)-3-甲基氨基-吡咯烷-1-基)-5,5-二氧杂-6,7-二氢-5H-5λ6-硫杂-1,3-二氮杂-二苯并[a,c]环庚烯-2-基胺;4-((R)-3-甲基氨基-吡咯烷-1-基)-5-氧杂-6,7-二氢-5-硫杂-1,3-二氮杂-二苯并[a,c]环庚烯-2-基胺;N4-(3-哌啶-1-基-丙基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-]嘧啶-2,4-二胺;4-(4-二甲基氨基-哌啶-1-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;10-氟-4-八氢-6H-吡咯并[3,4-b]吡啶-6-基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-胺;4-[1,4]二氮杂环庚烷-1-基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;(1R,5S)-4-(3,6-二氮杂-二环[3.2.0]庚-6-基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;4-哌嗪-1-基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶;(3aS,6aS)-4-(六氢-吡咯并[3,4-b]吡咯-1-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;{1S,5S)-4-(3,6-二氮杂-二环[3.2.0]庚-3-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;N4-哌啶-3-基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2,4-二胺;N4-(八氢-异吲哚-4-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2,4-二胺;甲基-{4-哌嗪-1-基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基)-胺;4-{3-(R)-甲基氨基-吡咯烷-1-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶;[1-(6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-4-基)-氮杂环丁烷-3-基]-胺;8,10-二甲基-哌嗪-1-基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺;6-{2-(1H-咪唑-4-基)乙基氨基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-4-基)八氢-1H-吡咯并[3,4-b]吡啶;(2-氨基-4-哌嗪-1-基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-10-基)-甲基-氨基甲酸甲酯;10-N-甲基-4-哌嗪-1-基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2,10-二胺;(2-氨基-4-八氢-吡咯并[3,4-b]吡啶-6-基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-10-基)-甲基-氨基甲酸甲酯;10-N-甲基-4-[(4aR,7aR)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2,10-二胺;N-{2-氨基-4-哌嗪-1-基-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-11-基)-乙酰胺;4-(八氢-吡咯并[3,4-b]吡啶-6-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-羧酸甲酯;4-(八氢-吡咯并[3,4-b]吡啶-6-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-羧酸。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2009137492中描述的那些:4-八氢-6H-吡咯并[3,4-b]吡啶-6-基-6,7-二氢-5H-噻吩并[2',3':6,7]芳庚并[1,2-d]嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-6,7-二氢-5H-噻吩并[2',3':6,7]芳庚并[1,2-d]嘧啶-2-胺;4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-6,7-二氢-5H-噻吩并[2',3':6,7]芳庚并[1,2-d]嘧啶-2-胺;4-八氢-6H-吡咯并[3,4-b]吡啶-6-基-6,7-二氢-5H-呋喃[2',3':6,7]芳庚并[1,2-d]嘧啶-2-胺;9-甲基-4-八氢-6H-吡咯并[3,4-b]吡啶-6-基-6,7-二氢-5H-呋喃[2',3':6,7]芳庚并[1,2-d]嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-9-甲基-6,7-二氢-5H-呋喃[2',3':6,7]芳庚并[1,2-d]嘧啶-2-胺;4-八氢-6H-吡咯并[3,4-b]吡啶-6-基-6,7-二氢-5H-呋喃[3',2':6,7]芳庚并[1,2-d]嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-8-甲基-5,6,7,8-四氢吡唑并[3',4':6,7]芳庚并[1,2-d]嘧啶-2-胺;8-叔丁基-4-八氢-6H-吡咯并[3,4-b]吡啶-6-基-5,6,7,8-四氢吡唑并[3',4':6,7]芳庚并[1,2-d]嘧啶-2-胺;4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-8-苯基-5,6,7,8-四氢吡唑并[3',4':6,7]芳庚并[1,2-d]嘧啶-2-胺;9-溴-4-八氢-6H-吡咯并[3,4-b]吡啶-6-基-6,7-二氢-5H-噻吩并[2',3':6,7]芳庚并[1,2-d]嘧啶-2-胺;4-八氢-6H-吡咯并[3,4-b]吡啶-6-基-9-苯基-6,7-二氢-5H-噻吩并[2',3':6,7]芳庚并[1,2-d]嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-6,7-二氢-5H-吡啶并[3',2':6,7]芳庚并[1,2-d]嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-10-甲基-6,7-二氢-5H-异唑并[5',4':6,7]芳庚并[1,2-d]嘧啶-2-胺;4-[(4aR,7aR)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]-6,7-二氢-5H-噻吩并[2',3':6,7]芳庚并[1,2-d]嘧啶-2-胺;或其可药用盐。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2009123967中描述的那些:(R)-4-(3-氨基吡咯烷-1-基)-9,9-二甲基-6,7.8.9-四氢-5H-芳庚并[d]嘧啶-2-胺;9,9-二甲基-4-(哌嗪-1-基)-6,7,8,9-四氢-5H-芳庚并[d]嘧啶-52-胺;(R)-4-(3-氨基吡咯烷-1-基)-9,9-二乙基-6,7,8,9-四氢-5H-芳庚并[d]嘧啶-2-胺;(R)-4-(3-氨基吡咯烷-1-基)-9,9-二苄基-6,7,8,9-四氢-5H-芳庚并[d]嘧啶-2-胺;8-苯基-4-(哌嗪-1-基)-6,7,8,9-四氢-5H-芳庚并[d]嘧啶-2-胺;8-苯基-4-(四氢-1H-吡咯并[3,4-b]吡啶-692H,7H,7aH0-基)-6,7,8,9-四氢-5H-芳庚并[d]嘧啶-2-胺;4-((R)-3-(甲基氨基)吡咯烷-1-基)-8-苯基-6,7,8,9-四氢-5H-5-芳庚并[d]嘧啶-2-胺;4-(3-氨基氮杂环丁烷-1-基)-8-苯基-6,7,8,9-四氢-5H-芳庚并[d]嘧啶-2-胺;8-苯基-4-(哌嗪-1-基)-5,6,7,8-四氢喹唑啉-2-胺;8-苯基-4-((4aR,7aR)-四氢-1H-吡咯并[3,4-b]吡啶-6(2H,7H,7aH)-基)-5,6,7,8-四氢喹唑啉-2-胺;4-((R)-3-(甲基氨基)吡咯烷-1-基)-8-苯基-5,6,7,8-四氢喹唑啉-2-胺;8,8-二甲氧基-4-(哌嗪-1-基)-5,6,7,8-四氢喹唑啉-2-胺;4-(哌嗪-1-基)-6,7,8,9-四氢-5H-芳庚并[d]嘧啶-2-胺;9-(2-甲基吡啶-4-基)-4-(哌嗪-1-基)-6,7,8,9-四氢-5H-芳庚并[d]嘧啶-2-胺;甲基5-(2-氨基-4-(哌嗪-1-基)-6,7,8,9-四氢-5H-芳庚并[d]嘧啶-9-基)烟酸酯;5-(2-氨基-4-(哌嗪-1-基)-6,7,8,9-四氢-5H-芳庚并[d]嘧啶-9-基)烟酸;4-((R)-3-(甲基氨基)吡咯烷-1-基)-9-苯基-6,7,8,9-四氢-5H-芳庚并[d]嘧啶-2-胺;4-(3-(甲基氨基)氮杂环丁烷-1-基)-9-苯基-6,7,8,9-四氢-5H-芳庚并[d]嘧啶-2-胺;9-苯基-4-(哌嗪-1-基)-6,7,8,9-四氢-5H-芳庚并[d]嘧啶-2-胺;9-苯基-4-四氢-1H-吡咯并[3,4-b]吡啶-6(2H,7H,7aH)-6,7,8,9-四氢-5H-芳庚并[d]嘧啶-2-胺;或5,9-苯基-4-((4aR,7aR)-四氢-1H-吡咯并[3,4-b]吡啶-6(2H,7H,7aH)-基)-6,7,8,9-四氢-5H-芳庚并[d]嘧啶-2-胺。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2005/054239中描述的那些:4-[八氢-6H-吡咯并[3,4-b]吡啶-6-基]-6-苯基嘧啶-2-胺;4-(3-甲氧苯基)-6-[八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2-胺;3-{2-氨基-6-[八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-4-基}苄腈;4-(1-萘基)-6-[八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2-胺;4-(3-甲基苯基)-6-[八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2-胺;4-(3-氯苯基)-6-[八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2-胺;4-[八氢-6H-吡咯并[3,4-b]吡啶-6-基]-6-[3-(三氟甲基)苯基]嘧啶-2-胺;1-(3-{2-氨基-6-[八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-4-基}苯基)乙酮;4-(3-硝基苯基)-6-[八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2-胺;(3-{2-氨基-6-[八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-4-基}苯基)甲醇;4-(3,4-二氯苯基)-6-[八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2-胺;4-(4-硝基苯基)-6-[八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2-胺;4-(3-氟苯基)-6-[八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2-胺;5-甲基-4-[八氢-6H-吡咯并[3,4-b]吡啶-6-基]-6-苯基嘧啶-2-胺;4-[八氢-6H-吡咯并[3,4-b]吡啶-6-基]-6-(3-噻吩基)嘧啶-2-胺;4-(3-氯苯基)-5-甲基-6-[八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2-胺;5-甲基-4-(3-甲基苯基)-6-[八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2-胺;4-(3-氟苯基)-5-甲基-6-[八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2-胺;4-(3-氨基吡咯烷-1-基)-6-苯基嘧啶-2-胺;4-[3-(甲基氨基)氮杂环丁烷-1-基]-6-苯基嘧啶-2-胺;4-[3-(二甲基氨基)氮杂环丁烷-1-基]-6-苯基嘧啶-2-胺;4-(3-氯苯基)-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2-胺;4-[3-(甲基氨基)氮杂环丁烷-1-基]-6-(3-甲基苯基)嘧啶-2-胺;4-(3-氟苯基)-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2-胺;4-(3-甲氧苯基)-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2-胺;3-{2-氨基-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-4-基}苄腈;1-(3-{2-氨基-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-4-基}苯基)乙酮;4-[3-(甲基氨基)氮杂环丁烷-1-基]-6-(3-硝基苯基)嘧啶-2-胺;3-{2-氨基-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-4-基}苯酚;4-(3-氨基苯基)-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2-胺;5-氟-4-[3-(甲基氨基)氮杂环丁烷-1-基]-6-苯基嘧啶-2-胺;5-甲基-4-[3-(甲基氨基)氮杂环丁烷-1-基]-6-苯基嘧啶-2-胺;4-[3-(甲基氨基)氮杂环丁烷-1-基]-6-[3-(三氟甲基)苯基]嘧啶-2-胺;4-[3-(二甲基氨基)苯基]-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2-胺;4-[3-(甲基氨基)氮杂环丁烷-1-基]-6-(1-萘基)嘧啶-2-胺;4-[3-(甲基氨基)氮杂环丁烷-1-基]-6-(4-甲基苯基)嘧啶-2-胺;4-(4-氯苯基)-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2-胺;4-(4-氟苯基)-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2-胺;4-(4-甲氧苯基)-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2-胺;4-{2-氨基-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-4-基}苄腈;4-[3-(甲基氨基)氮杂环丁烷-1-基]-6-(4-硝基苯基)嘧啶-2-胺;和4-{2-氨基-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-4-基}苯酚;4-[(4aR,7aR)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]-6-苯基嘧啶-2-胺三盐酸化物;4-(3-甲氧苯基)-6-[(4aR,7aR)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2-胺三盐酸化物;3-{2-氨基-6-[(4aR,7aR)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-4-基}苄腈三盐酸化物;4-(1-萘基)-6-[(4aR,7aR)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2-胺三盐酸化物;4-(3-甲基苯基)-6-[(4aR,7aR)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2-胺三盐酸化物;4-(3-氯苯基)-6-[(4aR,7aR)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2-胺三盐酸化物;4-[(4aR,7aR)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]-6-[3-(三氟甲基)苯基]嘧啶-2-胺三盐酸化物;1-(3-{2-氨基-6-[(4aR,7aR)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-4-基}苯基)乙酮三盐酸化物;4-(3-硝基苯基)-6-[(4aR,7aR)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2-胺三盐酸化物;(3-{2-氨基-6-[(4aR,7aR)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-4-基}苯基)甲醇三盐酸化物;4-(3,4-二氯苯基)-6-[(4aR,7aR)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2-胺二盐酸化物;4-(4-硝基苯基)-6-[(4aR,7aR)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2-胺二盐酸化物;4-(3-氟苯基)-6-[(4aR,7aR)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2-胺二盐酸化物;5-甲基-4-[(4aR,7aR)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]-6-苯基嘧啶-2-胺二盐酸化物;4-[(4aR,7aR)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]-6-(3-噻吩基)嘧啶-2-胺二盐酸化物;4-(3-氯苯基)-5-甲基-6-[(4aR,7aR)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2-胺二盐酸化物;5-甲基-4-(3-甲基苯基)-6-[(4aR,7aR)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2-胺二盐酸化物;和4-(3-氟苯基)-5-甲基-6-[(4aR,7aR)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2-胺二盐酸化物。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2005/014556中描述的那些:4-(3-氨基吡咯烷-1-基)-6-苯基嘧啶-2-胺三盐酸化物;4-[3-(二甲基氨基)吡咯烷-1-基]-6-苯基嘧啶-2-胺三盐酸化物;4-[3-(甲基氨基)吡咯烷-1-基]-6-苯基嘧啶-2-胺三盐酸化物;4-[3-(甲基氨基)吡咯烷-1-基]-6-(3-硝基苯基)嘧啶-2-胺三盐酸化物;4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-6-(3-硝基苯基)嘧啶-2-胺三盐酸化物;4-[(3S)-3-(甲基氨基)吡咯烷-1-基]-6-(3-硝基苯基)嘧啶-2-胺三盐酸化物;4-[(3S)-3-(甲基氨基)吡咯烷-1-基]-6-苯基嘧啶-2-胺三盐酸化物;4-[(3R)-3-(甲基氨基)吡咯烷-1-基]-6-苯基嘧啶-2-胺三盐酸化物;4-[3-(甲基氨基)吡咯烷-1-基]-6-(3-甲基苯基)嘧啶-2-胺三盐酸化物;1-(3-{2-氨基-6-[3-(甲基氨基)吡咯烷-1-基]嘧啶-4-基}苯基)乙酮三盐酸化物;3-{2-氨基-6-[3-(甲基氨基)吡咯烷-1-基]嘧啶-4-基}苯酚三盐酸化物;(3-{2-氨基-6-[3-(甲基氨基)吡咯烷-1-基]嘧啶-4-基}苯基)甲醇三盐酸化物;和3-{2-氨基-6-[3-(甲基氨基)吡咯烷-1-基]嘧啶-4-基}苄腈三盐酸化物;3-[2-氨基-6-(4-甲基哌嗪-1-基)嘧啶-4-基]苯酚;1-{3-[2-氨基-6-(4-甲基哌嗪-1-基)嘧啶-4-基]苯基}乙酮;{3-[2-氨基-6-(4-甲基哌嗪-1-基)嘧啶-4-基]苯基}甲醇;4-(4-甲基哌嗪-1-基)-6-[3-(三氟甲基)苯基]嘧啶-2-胺;4-联苯基-3-基-6-(4-甲基哌嗪-1-基)嘧啶-2-胺三盐酸化物;4-[3-(二甲基氨基)苯基]-6-(4-甲基哌嗪-1-基)嘧啶-2-胺;4-(4-甲基哌嗪-1-基)-6-(1-萘基)嘧啶-2-胺;和3-[2-氨基-6-(4-甲基哌嗪-1-基)嘧啶-4-基]苄腈。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2006/056848中描述的那些:(5-氯-1H-吲哚-2-基)-(4-甲基-哌嗪-1-基)-甲酮;W002/072548中描述的那些:6-溴-4-甲基-2-{[(3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基]羰基}-1H-苯并咪唑和6-氟-4-甲基-2-{[(3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基]羰基}-1H-苯并咪唑。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2007/072163中描述的那些:N4-(环丙基甲基)-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺,N4-(环丙基甲基)-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺酒石酸盐,N4-异丁基-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺,N4-(2,2-二甲基丙基)-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺-N-异丁基-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-4-胺,N-(环丙基甲基)-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-4-胺,N4-(2,2-二甲基丙基)-6-[(4aR*,7aR*)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2,4-二胺,N4-环丙基-6-[(4aR*,7aR*)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2,4-二胺,N4-环丁基-6-[(4aR*,7aR*)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2,4-二胺,N4-(2,2-二甲基丙基)-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2,4-二胺,6-(3-甲基氨基-氮杂环丁烷-1-基)-N4-(3,3,3-三氟-丙基)-嘧啶-2,4-二胺,N4-环丙基甲基-6-(3-甲基氨基-氮杂环丁烷-1-基)-嘧啶-2,4-二胺,N4-(3,3-二甲基-丁基)-6-(3-甲基氨基-氮杂环丁烷-1-基)-嘧啶-2,4-二胺,N4-(3-氟-benzyI)-6-(3-甲基氨基-氮杂环丁烷-1-基)-嘧啶-2,4-二胺,N4-环戊基甲基-6-(3-甲基氨基-氮杂环丁烷-1-基)-嘧啶-2,4-二胺,N4-异丁基-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2,4-二胺,6-[3-(甲基氨基)氮杂环丁烷-1-基]-N4-丙基嘧啶-2,4-二胺,N4-(2-甲氧苄基)-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2,4-二胺,N4-(2,2-二甲基丙基)-6-[(3R)-3-甲基哌嗪-1-基]嘧啶-2,4-二胺,N4-乙基-6-(4-甲基哌嗪-1-基)嘧啶-2,4-二胺,N4-(环丙基甲基)-6-(4-甲基哌嗪-1-基)嘧啶-2,4-二胺,6-[3-(甲基氨基)氮杂环丁烷-1-基]-N4-(2-甲基丁基)嘧啶-2,4-二胺,N4-(2,5-二氟苄基)-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2,4-二胺,N4-(2,3-二氟苄基)-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2,4-二胺,N4-丁基-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2,4-二胺,6-[(3R)-3-(甲基氨基)吡咯烷-1-基]-N4-(2-甲基环丙基)嘧啶-2,4-二胺,N4-异丁基-6-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-2,4-二胺,N4-(环丙基甲基)-6-(3-吡咯烷-1-基氮杂环丁烷-1-基)嘧啶-2,4-二胺,N4-二环[1.1.1]戊-1-基-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺,6-[3-甲基-3-(甲基氨基)氮杂环丁烷-1-基]-N4-丙基嘧啶-2,4-二胺,N4-(2,2-二甲基丙基)-6-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)嘧啶-2,4-二胺,N4-(2,2-二甲基丙基)-6-(3-吡咯烷-1-基氮杂环丁烷-1-基)嘧啶-2,4-二胺,N4-(2,2-二甲基丙基)-6-[3-(异丙基氨基)氮杂环丁烷-1-基]嘧啶-2,4-二胺,N4-(叔丁基)-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺,6-[(3R)-3-(甲基氨基)吡咯烷-1-基]-N4-(1-甲基环丙基)嘧啶-2,4-二胺,N4-(叔丁基)-6-[(4aS*,7aS*)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2,4-二胺,N4-(2,2-二甲基丙基)-6-哌嗪-1-基嘧啶-2,4-二胺,N4-(2,2-二甲基丙基)-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2,4-二胺盐酸化物,N4-(2,2-二甲基丙基)-6-[(3aR*,7aS*)-八氢-5H-吡咯并[3,2-c]吡啶-5-基]嘧啶-2,4-二胺,6-哌嗪-1-基-N4-丙基嘧啶-2,4-二胺,N4-(环丙基甲基)-6-[4aR,7aR]-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2,4-二胺,N4-(2,2-二甲基丙基)-6-[(4aS,7aS)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2,4-二胺N4-(环丙基甲基)-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺,N4-异丙基-6-[(4aS,7aS)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2,4-二胺,4-[3-(甲基氨基)氮杂环丁烷-1-基]-6-(4-甲基哌啶-1-基)嘧啶-2-胺,N4-(环戊基甲基)-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺,N4-环丁基-6-[(4aS,7aS)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2,4-二胺,6-[(3R)-3-(甲基氨基)吡咯烷-1-基]-N4-丙基嘧啶-2,4-二胺和N4-乙基-6-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-2,4-二胺。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2008/074445中描述的那些:4-(4-甲基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;8-氯-4-(4-甲基-哌嗪-1-基)-苯并[4,5]呋喃[3,2-d]嘧啶-2-基胺;4-(4-甲基哌嗪-1-基)吡啶并[3',2':4,5]呋喃[3,2-d]嘧啶-2-胺;8-氯-4-(4-甲基哌嗪-1-基)[1]苯并呋喃[3,2-d]嘧啶-2-胺;8-氯-4-[(3S)-3-甲基哌嗪-1-基][1]苯并呋喃[3,2-d]嘧啶-2-胺;8-甲氧基-4-哌嗪-1-基[1]苯并呋喃[3,2-d]嘧啶-2-胺,二乙酸盐;N4-1-氮杂二环[2.2.2]辛-3-基-8-氯[1]苯并呋喃[3,2-d]嘧啶-2,4-二胺;4-(3-氨基吡咯烷-1-基)-8-甲氧[1]苯并呋喃[3,2-d]嘧啶-2-胺;4-(3-氨基吡咯烷-1-基)-7-氯[1]苯并呋喃[3,2-d]嘧啶-2-胺;7-氯-4-哌嗪-1-基[1]苯并呋喃[3,2-αf]嘧啶-2-胺;8-氯-4-哌嗪-1-基[1]苯并呋喃[3,2-d]嘧啶-2-胺,二盐酸化物;8-(2-甲氧乙氧基)-4-哌嗪-1-基[1]苯并呋喃[3,2-d]嘧啶-2-胺;8-乙氧基-4-哌嗪-1-基[1]苯并呋喃[3,2-d]嘧啶-2-胺;8-氯-4-(3-乙基哌嗪-1-基)[1]苯并呋喃[3,2-d]嘧啶-2-胺;8-氯-4-[(3S)-3-异丙基哌嗪-1-基][1]苯并呋喃[3,2-d]嘧啶-2-胺;8-氯-4-哌嗪-1-基[1]苯并呋喃[3,2-d]嘧啶-2-胺;8-氯-4-(1,4-二氮杂环庚烷-1-基)[1]苯并呋喃[3,2-d]嘧啶-2-胺;8-氯-4-[(3aR,6aS)-六氢吡咯并[3,4-c]吡咯-2(1H)-基][1]苯并呋喃[3,2-d]嘧啶-2-胺;8-氯-[(3S)-3-甲基-1,4-二氮杂环庚烷-1-基][1]苯并呋喃[3,2-d]嘧啶-2-胺;(8-氯-N4-[2-(甲基氨基)乙基][1]苯并呋喃[3I2-c0嘧啶-2,4-二胺;8-氯-N4-吡咯烷-3-基[1]苯并呋喃[3,2-d]嘧啶-2,4-二胺;(7-氯-4-(4-甲基哌嗪-1-基)[1]苯并呋喃[3,2-d]嘧啶-2-胺,甲酸盐;2-氨基-4-(3-氨基吡咯烷-1-基)[1]苯并呋喃[3,2-d]嘧啶-8-醇;4-(4-甲基-哌嗪-1-基)-5H-茚并[1,2-d]嘧啶-2-基胺;8-氯-4-(4-甲基-哌嗪-1-基)-5H-茚并[1,2-d]嘧啶-2-基胺;8-溴-4-[(3S)-3-甲基哌嗪-1-基][1]苯并呋喃[3,2-d]嘧啶-2-胺);8-溴-4-哌嗪-1-基[1]苯并呋喃[3,2-d]嘧啶-2-胺;8-溴-4-(1,4-二氮杂环庚烷-1-基)[1]苯并呋喃[3,2-d]嘧啶-2-胺;甲基-2-氨基-4-[(3S)-3-甲基哌嗪-1-基][1]苯并呋喃[3,2-d]嘧啶-8-羧酸酯;甲基-2-氨基-4-(1,4-二氮杂环庚烷-1-基)[1]苯并呋喃[3,2-d]嘧啶-8-羧酸酯;2-氨基-4-[(3S)-3-甲基哌嗪-1-基][1]苯并呋喃[3,2-d]嘧啶-8-羧酸;4-(4-甲基哌嗪-1-基)[1]苯并呋喃[3,2-d]嘧啶-2-胺;8-氯-4-(4-甲基哌嗪-1-基)[1]苯并呋喃[3,2-d]嘧啶-2-胺;4-(4-甲基哌嗪-1-基)-5H-茚并[1,2-d]嘧啶-2-胺;8-氯-4-[(3R)-3-甲基哌嗪-1-基][1]苯并呋喃[3,2-d]嘧啶-2-胺;4-(3-氨基吡咯烷-1-基)-7-氯[1]苯并呋喃[3,2-d]嘧啶-2-胺;7-氯-4-哌嗪-1-基[1]苯并呋喃[3,2-d]嘧啶-2-胺;7-氯-4-(4-甲基哌嗪-1-基)[1]苯并呋喃[3,2-d]嘧啶-2-胺,甲酸盐;4-(4-甲基哌嗪-1-基)吡啶并[3',2':4,5]呋喃[3,2-d]嘧啶-2-胺;8-氯-4-[(3aR,6aS)-六氢吡咯并[3,4-c]吡咯-2(1H)-基][1]苯并呋喃[3,2-d]嘧啶-2-胺;8-氯-4-(4-甲基哌嗪-1-基)-5H-茚并[1,2-d]嘧啶-2-胺;8-氯-4-[(3S)-3-甲基-1,4-二氮杂环庚烷-1-基][1]苯并呋喃[3,2-d]嘧啶-2-胺;4-(3-氨基吡咯烷-1-基)-8-甲氧[1]苯并呋喃[3,2-d]嘧啶-2-胺;8-氯-4-哌嗪-1-基[1]苯并呋喃[3,2-d]嘧啶-2-胺;2-氨基-4-(3-氨基吡咯烷-1-基)[1]苯并呋喃[3,2-d]嘧啶-8-醇;8-氯-N4-[2-(甲基氨基)乙基][1]苯并呋喃[3,2-d]嘧啶-2,4-二胺;8-氯-4-(1,4-二氮杂环庚烷-1-基)[1]苯并呋喃[3,2-d]嘧啶-2-胺;8-甲氧基-4-哌嗪-1-基[1]苯并呋喃[3,2-d]嘧啶-2-胺,二乙酸盐;8-氯-4-[(3S)-3-甲基哌嗪-1-基][1]苯并呋喃[3,2-d]嘧啶-2-胺;8-氯-4-哌嗪-1-基[1]苯并呋喃[3,2-d]嘧啶-2-胺,二盐酸化物;8-溴-4-[(3S)-3-甲基哌嗪-1-基][1]苯并呋喃[3,2-d]嘧啶-2-胺;8-溴-4-哌嗪-1-基[1]苯并呋喃[3,2-d]嘧啶-2-胺;8-溴-4-(1,4-二氮杂环庚烷-1-基)[1]苯并呋喃[3,2-d]嘧啶-2-胺;甲基-2-氨基-4-[(3S)-3-甲基哌嗪-1-基][1]苯并呋喃[3,2-d]嘧啶-8-羧酸酯;甲基-2-氨基-4-(1,4-二氮杂环庚烷-1-基)[1]苯并呋喃[3,2-d]嘧啶-8-羧酸酯;2-氨基-4-[(3S)-3-甲基哌嗪-1-基][1]苯并呋喃[3,2-d]嘧啶-8-羧酸;8-乙氧基-4-哌嗪-1-基[1]苯并呋喃[3,2-d]嘧啶-2-胺;8-氯-4-[(3S)-3-甲基-1,4-二氮杂环庚烷-1-基][1]苯并呋喃[3,2-d]嘧啶-2-胺;4-(3-氨基吡咯烷-1-基)-8-甲氧[1]苯并呋喃[3,2-d]嘧啶-2-胺;8-氯-4-哌嗪-1-基[1]苯并呋喃[3,2-d]嘧啶-2-胺;2-氨基-4-(3-氨基吡咯烷-1-基)[1]苯并呋喃[3,2-d]嘧啶-8-醇;8-氯-N4-[2-(甲基氨基)乙基][1]苯并呋喃l[3,2-d]嘧啶-2,4-二胺;8-氯-4-(1,4-二氮杂环庚烷-1-基)[1]苯并呋喃[3,2-d]嘧啶-2-胺;8-甲氧基-4-哌嗪-1-基[1]苯并呋喃[3,2-d]嘧啶-2-胺,二乙酸盐;8-氯-4-[(3S)-3-甲基哌嗪-1-基][1]苯并呋喃[3,2-d]嘧啶-2-胺;8-氯-4-哌嗪-1-基[1]苯并呋喃[3,2-cy]嘧啶-2-胺,二盐酸化物;8-溴-4-[(3S)-3-甲基哌嗪-1-基][1]苯并呋喃[3,2-d]嘧啶-2-胺;8-溴-4-哌嗪-1-基[1]苯并呋喃[3,2-d]嘧啶-2-胺;8-溴-4-(1,4-二氮杂环庚烷-1-基)[1]苯并呋喃[3,2-d]嘧啶-2-胺。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2008/031556中描述的那些:4-(4-甲基哌嗪-1-基)-6-哌啶-1-基嘧啶-2-胺;4-(1,3-二氢-2H-异吲哚-2-基)-6-(4-甲基哌嗪-1-基)嘧啶-2-胺;4-(4-甲基哌嗪-1-基)-6-(4-甲基哌啶-1-基)嘧啶-2-胺;4-[4-(2-甲氧苯基)哌啶-1-基]-6-(4-甲基哌嗪-1-基)嘧啶-2-胺;4-(3,4-二氢异喹啉-2(1H)-基)-6-(4-甲基哌嗪-1-基)嘧啶-2-胺;4-(5-氟-1,3-二氢-2H-异吲哚-2-基)-6-(4-甲基哌嗪-1-基)嘧啶-2-胺;4-(3-氨基吡咯烷-1-基)-6-(1,3-二氢-2H-异吲哚-2-基)嘧啶-2-胺;4-(4-甲基哌嗪-1-基)-6-(2-甲基吡咯烷-1-基)嘧啶-2-胺;4-(2-乙基哌啶-1-基)-6-(4-甲基哌嗪-1-基)嘧啶-2-胺;4-[3-(2-甲氧苯基)吡咯烷-1-基]-6-(4-甲基哌嗪-1-基)嘧啶-2-胺;4-[3-(4-氯苯基)吡咯烷-1-基]-6-(4-甲基哌嗪-1-基)嘧啶-2-胺;4-(2-甲基吡咯烷-1-基)-6-哌嗪-1-基嘧啶-2-胺;4-(4-甲基哌嗪-1-基)-6-[(2R)-2-甲基吡咯烷-1-基]嘧啶-2-胺;4-(4-甲基哌嗪-1-基)-6-[(2S)-2-甲基吡咯烷-1-基]嘧啶-2-胺;4-(2,6-二甲基哌啶-1-基)-6-(4-甲基哌嗪-1-基)嘧啶-2-胺;4-(6-氮杂二环[3.2.1]辛-6-基)-6-(4-甲基哌嗪-1-基)嘧啶-2-胺;4-氮杂环庚烷-1-基-6-(4-甲基哌嗪-1-基)嘧啶-2-胺;1-[2-氨基-6-(4-甲基哌嗪-1-基)嘧啶-4-基]-4-(4-氯苯基)哌啶-4-醇;4-(4-甲基哌嗪-1-基)-6-(3-苯基哌啶-1-基)嘧啶-2-胺;N4-环己基-6-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)嘧啶-2,4-二胺;N4-金刚烷-1-基-6-(4-甲基哌嗪-1-基)嘧啶-2,4-二胺;6-(4-甲基哌嗪-1-基)-N4-(1,3,3-三甲基二环[2.2.1]庚-2-基)嘧啶-2,4-二胺;N4-金刚烷-2-基-6-(4-甲基哌嗪-1-基)嘧啶-2,4-二胺;6-(4-甲基哌嗪-1-基)-N4(1R;4R)(1,7,7-三甲基二环[2.2.1]庚-2-基)嘧啶-2,4-二胺;N4-环己基-N4-甲基-6-(4-甲基哌嗪-1-基)嘧啶-2,4-二胺;4-(7-氮杂二环[2.2.1]庚-7-基)-6-(4-甲基哌嗪-1-基)嘧啶-2-胺;4-(3-氨基吡咯烷-1-基)-6-(5-氟-1,3-二氢-2H-异吲哚-2-基)嘧啶-2-胺;4-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)-6-(2-甲基吡咯烷-1-基)嘧啶-2-胺;N4-1-氮杂二环[2.2.2]辛-3-基-6-(1,3-二氢-2H-异吲哚-2-基)嘧啶-2,4-二胺;4-(3-甲基-3,4-二氢异喹啉-2(1H)-基)-6-(4-甲基哌嗪-1-基)嘧啶-2-胺;N4-1-氮杂二环[2.2.2]辛-3-基-6-(2-甲基吡咯烷-1-基)嘧啶-2,4-二胺;6-(2-甲基吡咯烷-1-基)-N4-吡咯烷-3-基嘧啶-2,4-二胺;4-[4-(甲基氨基)哌啶-1-基]-6-(2-甲基吡咯烷-1-基)嘧啶-2-胺;4-(1,3-二氢-2H-异吲哚-2-基)-6-[4-(甲基氨基)哌啶-1-基]嘧啶-2-胺;4-(1,3-二氢-2H-异吲哚-2-基)-6-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-2-胺;6-[(3R)-3-氨基吡咯烷-1-基]-N4-环己基嘧啶-2,4-二胺三乙酸盐;4(R)-(3-甲基-3,4-二氢异喹啉-2(1H)-基)-6-(4-甲基哌嗪-1-基)嘧啶-2-胺;4(S)-(3-甲基-3,4-二氢异喹啉-2(1H)-基)-6-(4-甲基哌嗪-1-基)嘧啶-2-胺;N4-环己基-N6-[2-(二甲基氨基)乙基]嘧啶-2,4,6-三胺;N4-环己基-6-[4-(甲基氨基)哌啶-1-基]嘧啶-2,4-二胺;6-[(3S)-3-氨基吡咯烷-1-基]-N4-环己基嘧啶-2,4-二胺;N4-环戊基-6-(4-甲基哌嗪-1-基)嘧啶-2,4-二胺;N4-环戊基-N4-甲基-6-(4-甲基哌嗪-1-基)嘧啶-2,4-二胺;N4-环庚基-6-(4-甲基哌嗪-1-基)嘧啶-2,4-二胺;4-[(1R*,5S*)-8-氮杂二环[3.2.1]辛-8-基]-6-(4-甲基哌嗪-1-基)嘧啶-2-胺;N4-[(1R*,2S*,4S*)-二环[2.2.1]庚-2-基]-6-(4-甲基哌嗪-1-基)嘧啶-2,4-二胺;N4-二环[2.2.1]庚-2-基-6-(4-甲基哌嗪-1-基)嘧啶-2,4-二胺;N4-[(1R*,2S*,4S*)-二环[2.2.1]庚-2-基]-N6-二甲基氨基乙基嘧啶-2,4-三胺;N4-[(1R*,2S*,4S*)-二环[2.2.1]庚-2-基]-6-[(3aR*,6aS*)-六氢吡咯并[3,4-c]吡咯-2(1H)-基]嘧啶-2,4-二胺;4-环己基-6-(4-甲基哌嗪-1-基)嘧啶-2-胺;4-金刚烷-2-基-6-(4-甲基哌嗪-1-基)嘧啶-2-胺;4-异丙基-6-(4-甲基哌嗪-1-基)嘧啶-2-胺;4-(1-甲基戊基)-6-(4-甲基哌嗪-1-基)嘧啶-2-胺;4-环戊基-6-(4-甲基哌嗪-1-基)嘧啶-2-胺;4-(1-乙基丙基)-6-(4-甲基哌嗪-1-基)嘧啶-2-胺;4-环己基-6-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)嘧啶-2-胺;4-环己基-6-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-2-胺;4-环己基-6-(4-乙基哌嗪-1-基)嘧啶-2-胺;4-环己基-6-[3-(二甲基氨基)吡咯烷-1-基]嘧啶-2-胺;6-环己基-N4-甲基-N4-(1-甲基吡咯烷-3-基)嘧啶-2,4-二胺;6-环己基-N4-(1-甲基哌啶-4-基)嘧啶-2,4-二胺;4(R)-(4-甲基哌嗪-1-基)-6-(1-苯基乙基)嘧啶-2-胺;4(S)-(4-甲基哌嗪-1-基)-6-(1-苯基乙基)嘧啶-2-胺;4-(3-氨基吡咯烷-1-基)-6-环丙基嘧啶-2-胺;4-环丙基-6-[3-(甲基氨基)吡咯烷-1-基]嘧啶-2-胺;4-(3-氨基吡咯烷-1-基)-6-(4-甲基环己-1-烯-1-基)嘧啶-2-胺二-三氟乙酸盐;6-环己-1-烯-1-基-N4-[2-(二甲基氨基)乙基]嘧啶-2,4-二胺;4-叔丁基-6-(4-甲基哌嗪-1-基)嘧啶-2-胺乙酸盐;4-叔丁基-6-[3-(甲基氨基)吡咯烷-1-基]嘧啶-2-胺乙酸盐;4-[金刚烷-2-基]-6-[(3S)-3-氨基吡咯烷-1-基]嘧啶-2-胺;4-[金刚烷-2-基]-6-[(3S)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2-胺;4-环庚-1-烯-1-基-6-(4-甲基哌嗪-1-基)嘧啶-2-胺;4-环戊基-6-(3-甲基哌嗪-1-基)嘧啶-2-胺;4-(3-氨基氮杂环丁烷-1-基)-6-环己-1-烯-1-基嘧啶-2-胺;4-环己基-6-(3-甲基哌嗪-1-基)嘧啶-2-胺;4-(3-氨基氮杂环丁烷-1-基)-6-环己基嘧啶-2-胺;4-(4-甲基哌嗪-1-基)-6-(1,2,3,4-四氢萘-2-基)嘧啶-2-胺;4-[3-(甲基氨基)吡咯烷-1-基]-6-(1,2,3,4-四氢萘-2-基)嘧啶-2-胺;4-(3-氨基吡咯烷-1-基)-6-(1,2,3,4-四氢萘-2-基)嘧啶-2-胺;4-环戊基-6-[(3S)-3-甲基哌嗪-1-基]嘧啶-2-胺;4-环戊基-6-[(3R)-3-甲基哌嗪-1-基]嘧啶-2-胺;4-环己基-6-[(2S)-2-甲基哌嗪-1-基]嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-6-[(1E)-3,3-二甲基-1-丁烯-1-基]嘧啶-2-胺;4-[3-(氨基甲基)氮杂环丁烷-1-基]-6-环己基嘧啶-2-胺;4-(3-氨基氮杂环丁烷-1-基)-6-环戊基嘧啶-2-胺;4-环戊基-6-(3-乙基哌嗪-1-基)嘧啶-2-胺;4-环戊基-6-[(3S)-3-异丙基哌嗪-1-基]嘧啶-2-胺;4-环戊基-6-(3,8-二氮杂二环[3.2.1]辛-3-基)嘧啶-2-胺;N4-(2,3-二氢-1H-茚-2-基)-6-[3-甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺;4-环戊基-6-[(3S)-3-异丁基哌嗪-1-基]嘧啶-2-胺;4-环戊基-6-[3-(乙基氨基)氮杂环丁烷-1-基]嘧啶-2-胺;6-(4-甲基哌嗪-1-基)-N4-(四氢-2H-吡喃-4-基)嘧啶-2,4-二胺;6-(4-甲基哌嗪-1-基)-N4-(四氢-2H-吡喃-4-基)嘧啶-2,4-二胺乙酸盐;N4-环己基-6-(4-甲基哌嗪-1-基)嘧啶-2,4-二胺;4-(1,3-二氢-2H-异吲哚-2-基)-6-哌嗪-1-基嘧啶-2-胺;4-(3-氨基吡咯烷-1-基)-6-(2-甲基吡咯烷-1-基)嘧啶-2-胺;4-[3-(甲基氨基)吡咯烷-1-基]-6-(2-甲基吡咯烷-1-基)嘧啶-2-胺;6-(3-氨基吡咯烷-1-基)-N4-[(1R*,2S*,4S*)-二环[2.2.1]庚-2-基]嘧啶-2,4-二胺;N4-[(1R*,2S*,4S*)-二环[2.2.1]庚-2-基]-6-[3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺;6-[(3S)-3-氨基吡咯烷-1-基]-N4-[(1R*,2S*,4S*)-二环[2.2.1]庚-2-基]嘧啶-2,4-二胺;6-[(3R)-3-氨基吡咯烷-1-基]-N4-[(1R*,2S*,4S*)-二环[2.2.1]庚-2-基]嘧啶-2,4-二胺;6-[(3S)-3-氨基吡咯烷-1-基]-N4-[(1R*,2R*,4S*)-二环[2.2.1]庚-2-基]嘧啶-2,4-二胺;6-[(3R)-3-氨基吡咯烷-1-基]-N4-[(1R*,2R*,4S*)-二环[2.2.1]庚-2-基]嘧啶-2,4-二胺;N4-[外式-二环[2.2.1]庚-2-基]-6-[(3S)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺;N4-[(1R*,2S*,4S*)-二环[2.2.1]庚-2-基]-6-[3R]-3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺;N4-[(1R*,2S*,4S*)-二环[2.2.1]庚-2-基]-6-[(3S)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺;N4-[(1R*,2S*,4S*)-二环[2.2.1]庚-2-基]-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺;N4-[(1R*,2S*,4S*)-二环[2.2.1]庚-2-基]-6-(3-甲基哌嗪-1-y)嘧啶-2,4-二胺;N4-[(1R*,2R*,4S*)-二环[2.2.1]庚-2-基]-6-(1,4-二氮杂环庚烷-1-基)嘧啶-2,4-二胺;N4-[(1R*,2R*,4S*)-二环[2.2.1]庚-2-基]-6-((4aR*,7aR*)-八氢-6H-吡咯并[3,4-b]吡啶-6-基)嘧啶-2,4-二胺;N4-[(1R*,2R*,4S*)-二环[2.2.1]庚-2-基]-6-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)嘧啶-2,4-二胺;N4-[(1R*,2R*,4S*)-二环[2.2.1]庚-2-基]-6-哌嗪-1-基-嘧啶-2,4-二胺;4-(3-氨基吡咯烷-1-基)-6-环戊基嘧啶-2-胺;4-金刚烷-2-基-6-(3-氨基吡咯烷-1-基)嘧啶-2-胺;4-环戊基-6-[3-(甲基氨基)吡咯烷-1-基]嘧啶-2-胺;4-[(3S)-3-氨基吡咯烷-1-基]-6-环己基嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-6-环己基嘧啶-2-胺;4-(3-氨基吡咯烷-1-基)-6-(环己基甲基)嘧啶-2-胺;4-环戊基-6-哌嗪-1-基嘧啶-2-胺;4-[金刚烷-2-基]-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2-胺;4-[金刚烷-2-基]-6-[(3R)-3-氨基吡咯烷-1-基]嘧啶-2-胺;4-(环戊基甲基)-6-(3-甲基哌嗪-1-基)嘧啶-2-胺;4-(3-氨基吡咯烷-1-基)-6-(环戊基甲基)嘧啶-2-胺;4-环己基-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2-胺;4-环戊基-6-[(4aR*,7aR*)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2-胺;4-环己基-6-(1,4-二氮杂环庚烷-1-基)嘧啶-2-胺;4-环戊基-6-(1,4-二氮杂环庚烷-1-基)嘧啶-2-胺;6-环戊基-N4-[2-(甲基氨基)乙基]嘧啶-2,4-二胺;4-[(3R)-3-氨基吡咯烷-1-基]-6-环己-1-烯-1-基嘧啶-2-胺;N4-环己基-6-(4-甲基哌嗪-1-基)嘧啶-2,4-二胺;4-(1,3-二氢-2H-异吲哚-2-基)-6-哌嗪-1-基嘧啶-2-胺;4-(3-氨基吡咯烷-1-基)-6-(2-甲基吡咯烷-1-基)嘧啶-2-胺;4-[3-(甲基氨基)吡咯烷-1-基]-6-(2-甲基吡咯烷-1-基)嘧啶-2-胺;6-(3-氨基吡咯烷-1-基)-N4-[(1R*,2S*,4S*)-二环[2.2.1]庚-2-基]嘧啶-2,4-二胺;N4-[(1R*,2S*,4S*)-二环[2.2.1]庚-2-基]-6-[3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺;6-[(3S)-3-氨基吡咯烷-1-基]-N4-[(1R*,2S*,4S*)-二环[2.2.1]庚-2-基]嘧啶-2,4-二胺;6-[(3R)-3-氨基吡咯烷-1-基]-N4-[(1R*,2S*,4S*)-二环[2.2.1]庚-2-基]嘧啶-2,4-二胺;6-[(3S)-3-氨基吡咯烷-1-基]-N4-[(1R*,2R*,4S*)-二环[2.2.1]庚-2-基]嘧啶-2,4-二胺;6-[(3R)-3-氨基吡咯烷-1-基]-N4-[(1R*,2R*,4S*)-二环[2.2.1]庚-2-基]嘧啶-2,4-二胺;N4-[外式-二环[2.2.1]庚-2-基]-6-[(3S)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺;N4-[(1R*,2R*,4S*)-二环[2.2.1]庚-2-基]-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺;N4-[(1R*,2S*,4S*)-二环[2.2.1]庚-2-基]-6-[(3S)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺;N4-[(1R,2S*,4S*)-二环[2.2.1]庚-2-基]-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺;N4-[(1R*,2R*,4S*)-二环[2.2.1]庚-2-基]-6-(3-甲基哌嗪-1-基)嘧啶-2,4-二胺;N4-[(1R*,2R*,4S*)-二环[2.2.1]庚-2-基]-6-(1,4-二氮杂环庚烷-1-基)嘧啶-2,4-二胺;N4-[(1R*,2R*,4S*)-二环[2.2.1]庚-2-基]-6-((4aR*,7aR*)-八氢-6H-吡咯并[3,4-b]吡啶-6-基)嘧啶-2,4-二胺;N4-[(1R*,2R*,4S*)-二环[2.2.1]庚-2-基]-6-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)嘧啶-2,4-二胺;N4-[(1R*,2R*,4S*)-二环[2.2.1]庚-2-基]-6-哌嗪-1-基嘧啶-2,4-二胺;4-(3-氨基吡咯烷-1-基)-6-环戊基嘧啶-2-胺;4-金刚烷-2-基-6-(3-氨基吡咯烷-1-基)嘧啶-2-胺;4-环戊基-6-[3-(甲基氨基)吡咯烷-1-基]嘧啶-2-胺;4-[(3S)-3-氨基吡咯烷-1-基]-6-环己基嘧啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-6-环己基嘧啶-2-胺;4-(3-氨基吡咯烷-1-基)-6-(环己基甲基)嘧啶-2-胺;4-环戊基-6-哌嗪-1-基嘧啶-2-胺;4-[金刚烷-2-基]-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2-胺;4-[金刚烷-2-基]-6-[(3R)-3-氨基吡咯烷-1-基]嘧啶-2-胺;4-(环戊基甲基)-6-(3-甲基哌嗪-1-基)嘧啶-2-胺;4-(3-氨基吡咯烷-1-基)-6-(环戊基甲基)嘧啶-2-胺;4-环己基-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2-胺;4-环戊基-6-[(4aR*,7aR*)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2-胺;4-环己基-6-(1,4-二氮杂环庚烷-1-基)嘧啶-2-胺;4-环戊基-6-(1,4-二氮杂环庚烷-1-基)嘧啶-2-胺;6-环戊基-N4-(甲基氨基)乙基]嘧啶-2,4-二胺;4-[(3R)-3-氨基吡咯烷-1-基]-6-环己-1-烯-1-基嘧啶-2-胺。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2008122378中描述的那些:6-环己-1-烯-1-基-4-[3-(甲基氨基)吡咯烷-1-基]吡啶-2-胺;6-(4-氯苯基)-4-(4-甲基哌嗪-1-基)吡啶-2-胺;6-(4-甲基环己-1-烯-1-基)-4-(4-甲基哌嗪-1-基)吡啶-2-胺;6-金刚烷-2-基-4-(4-甲基哌嗪-1-基)吡啶-2-胺;4-(3-氨基吡咯烷-1-基)-6-环己-1-烯-1-基吡啶-2-胺;6-(3-甲基苯基)-4-(4-甲基哌嗪-1-基)吡啶-2-胺;4-[(3R)-3-氨基吡咯烷-1-基]-6-(4-氯苯基)吡啶-2-胺;4-(4-甲基哌嗪-1-基)-6-(4-甲基哌啶-1-基)吡啶-2-胺;N-环庚基-4-(4-甲基哌嗪-1-基)吡啶-2,6-二胺;4-[3-(甲基氨基)吡咯烷-1-基]-6-(2-甲基吡咯烷-1-基)吡啶-2-胺;4-(4-甲基哌嗪-1-基)-6-(2-甲基吡咯烷-1-基)吡啶-2-胺;4-[3-(甲基氨基)吡咯烷-1-基]-6-(4-甲基哌啶-1-基)吡啶-2-胺;4-[(3-甲基氨基)吡咯烷-1-基]-6-(4-三氟甲基苯基)吡啶-2-胺;4-[(3-甲基氨基)吡咯烷-1-基]-6-(4-三氟甲氧基苯基)吡啶-2-胺;6-(4-氯苯基)-4-[(3-甲基氨基)吡咯烷-1-基)吡啶-2-胺;4-[(3-甲基氨基)吡咯烷-1-基]-6-(3-甲基苯基)吡啶-2-胺;N-环庚基-4-(4-甲基哌嗪-1-基)吡啶-2,6-二胺;4-[3-(甲基氨基)吡咯烷-1-基]-6-(2-甲基吡咯烷-1-基)吡啶-2-胺;4-[(3-甲基氨基)吡咯烷-1-基]-6-(3-甲基苯基)吡啶-2-胺;6-环己-1-烯-1-基-4-[3-(甲基氨基)吡咯烷-1-基]吡啶-2-胺;6-(4-氯苯基)-4-[(3-甲基氨基)吡咯烷-1-基)吡啶-2-胺。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2009047255中描述的那些:4-(4-甲基哌嗪-1-基)-7-苯基-5,6,7,8-四氢喹唑啉-2-胺;4-(3-氨基氮杂环丁烷-1-基)-7-苯基-5,6,7,8-四氢喹唑啉-2-胺;4-(3-氨基吡咯烷-1-基)-7-苯基-5,6,7,8-四氢喹唑啉-2-胺;4-[(4aR*,7aR*)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]-7-苯基-5,6,7,8-四氢喹唑啉-2-胺;4-(3-甲基哌嗪-1-基)-7-苯基-5,6,7,8-四氢喹唑啉-2-胺;7-(3-氯苯基)-4-(4-甲基哌嗪-1-基)-5,6,7,8-四氢喹唑啉-2-胺;7-(3-氯苯基)-4-(1,4-二氮杂环庚烷-1-基)-5,6,7,8-四氢喹唑啉-2-胺;7-(3-氯苯基)-4-[(4aR*,7aR*)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]-5,6,7,8-四氢喹唑啉-2-胺;7,7-二甲基-4-(4-甲基哌嗪-1-基)-5,6,7,8-四氢喹唑啉-2-胺;4-(1,4-二氮杂环庚烷-1-基)-7,7-二甲基-5,6,7,8-四氢喹唑啉-2-胺;4-(3-氨基吡咯烷-1-基)-7,7-二甲基-5,6,7,8-四氢喹唑啉-2-胺;7,7-二甲基-4-[(4aR*,7aR*)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]-5,6,7,8-四氢喹唑啉-2-胺;4-(3-氨基吡咯烷-1-基)-7-(3-氯苯基)-5,6,7,8-四氢喹唑啉-2-胺;7,7-二甲基-4-(3-甲基哌嗪-1-基)-5,6,7,8-四氢喹唑啉-2-胺;7,7-二甲基-4-哌嗪-1-基-5,6,7,8-四氢喹唑啉-2-胺;7-(2-氯苯基)-4-(4-甲基哌嗪-1-基)-5,6,7,8-四氢喹唑啉-2-胺;7-(2-氯苯基)-4-(1,4-二氮杂环庚烷-1-基)-5,6,7,8-四氢喹唑啉-2-胺;4-(3-氨基吡咯烷-1-基)-7-(2-氯苯基)-5,6,7,8-四氢喹唑啉-2-胺;4-(1,4-二氮杂环庚烷-1-基)-7-(4-氟苯基)-5,6,7,8-四氢喹唑啉-2-胺;7-(4-氟苯基)-4-(4-甲基哌嗪-1-基)-5,6,7,8-四氢喹唑啉-2-胺;4-哌嗪-1-基-7-吡啶-2-基-5,6,7,8-四氢喹唑啉-2-胺;4-(4-甲基哌嗪-1-基)-7-吡啶-2-基-5,6,7,8-四氢喹唑啉-2-胺;4-(1,4-二氮杂环庚烷-1-基)-7-吡啶-2-基-5,6,7,8-四氢喹唑啉-2-胺;7-(5-氯-2-噻吩基)-4-哌嗪-1-基-5,6,7,8-四氢喹唑啉-2-胺;5-(5-氯-2-噻吩基)-4-哌嗪-1-基-5,6,7,8-四氢喹唑啉-2-胺;5-(5-氯-2-噻吩基)-4-(4-甲基哌嗪-1-基)-5,6,7,8-四氢喹唑啉-2-胺;7-(5-氯-2-噻吩基)-4-(4-甲基哌嗪-1-基)-5,6,7,8-四氢喹唑啉-2-胺;5-(5-氯-2-噻吩基)-4-(1,4-二氮杂环庚烷-1-基)-5,6,7,8-四氢喹唑啉-2-胺;7-(5-氯-2-噻吩基)-4-(1,4-二氮杂环庚烷-1-基)-5,6,7,8-四氢喹唑啉-2-胺;7-(4-氟苯基)-4-[(4aR*,7aR*)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]-5,6,7,8-四氢喹唑啉-2-胺三氟乙酸盐;7-(4-氟苯基)-N-4-[2-(甲基氨基)乙基]-5,6,7,8-四氢喹唑啉-2,4-二胺;7,7-二甲基-N-4-[2-(甲基氨基)乙基]-5,6,7,8-四氢喹唑啉-2,4-二胺;4-(六氢吡咯并[3,4-c]吡咯-2(1H)-基)-7,7-二甲基-5,6,7,8-四氢喹唑啉-2-胺;7,7-二甲基-4-[(3S)-3-甲基-1,4-二氮杂环庚烷-1-基]-5,6,7,8-四氢喹唑啉-2-胺;8,8-二甲基-4-(3-甲基哌嗪-1-基)-5,6,7,8-四氢喹唑啉-2-胺;4-(3-氨基氮杂环丁烷-1-基)-8,8-二甲基-5,6,7,8-四氢喹唑啉-2-胺;8,8-二甲基-N-4-哌啶-4-基-5,6,7,8-四氢喹唑啉-2,4-二胺;8,8-二甲基-N-4-吡咯烷-3-基-5,6,7,8-四氢喹唑啉-2,4-二胺;8,8-二甲基-4-[(3S)-3-甲基哌嗪-1-基]-5,6,7,8-四氢喹唑啉-2-胺;6,6-二甲基-4-(4-甲基哌嗪-1-基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-2-胺;4-(4-甲基哌嗪-1-基)-7-[4-(三氟甲基)嘧啶-2-基]-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-2-胺;7,7-二甲基-4-(4-甲基哌嗪-1-基)-5,6,7,8-四氢喹唑啉-2-胺;4-(1,4-二氮杂环庚烷-1-基)-7,7-二甲基-5,6,7,8-四氢喹唑啉-2-胺;4-(3-氨基吡咯烷-1-基)-7,7-二甲基-5,6,7,8-四氢喹唑啉-2-胺;7,7-二甲基-4-[(4aR*,7aR*)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]-5,6,7,8-四氢喹唑啉-2-胺;7,7-二甲基-4-(3-甲基哌嗪-1-基)-5,6,7,8-四氢喹唑啉-2-胺;7,7-二甲基-4-哌嗪-1-基-5,6,7,8-四氢喹唑啉-2-胺;7-(5-氯-2-噻吩基)-4-哌嗪-1-基-5,6,7,8-四氢喹唑啉-2-胺;7-(5-氯-2-噻吩基)-4-(1,4-二氮杂环庚烷-1-基)-5,6,7,8-四氢喹唑啉-2-胺;4-(3-氨基氮杂环丁烷-1-基)-7,7-二甲基-5,6,7,8-四氢喹唑啉-2-胺;7-异丁基-4-哌嗪-1-基-5,6,7,8-四氢喹唑啉-2-胺;8,8-二甲基-4-(4-甲基哌嗪-1-基)-5,6,7,8-四氢喹唑啉-2-胺;4-(1,4-二氮杂环庚烷-1-基)-8,8-二甲基-5,6,7,8-四氢喹唑啉-2-胺二乙酸盐;7,7-二甲基-4-[3-(甲基氨基)吡咯烷-1-基]-5,6,7,8-四氢喹唑啉-2-胺;7,7-二甲基-4-[(3S)-3-甲基哌嗪-1-基]-5,6,7,8-四氢喹唑啉-2-胺;4-(1,4-二氮杂环庚烷-1-基)-7-异丁基-5,6,7,8-四氢喹唑啉-2-胺乙酸盐;7-异丁基-4-(4-甲基哌嗪-1-基)-5,6,7,8-四氢喹唑啉-2-胺乙酸盐;7,7-二甲基-4-[3-(甲基氨基)氮杂环丁烷-1-基]-5,6,7,8-四氢喹唑啉-2-胺;8,8-二甲基-4-[(4aR*,7aR*)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]-5,6,7,8-四氢喹唑啉-2-胺;4'-(4-甲基哌嗪-1-基)-5',8'-二氢-6'H-螺[环己烷-1,7'-喹唑啉]-2'-胺;4'-[(4aR*,7aR*)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]-5',8'-二氢-6'H-螺[环己烷-1,7'-喹唑啉]-2'-胺;4'-[(3S)-3-甲基哌嗪-1-基]-5',8'-二氢-6'H-螺[环己烷-1,7'-喹唑啉]-2'-胺二乙酸盐;4'-(1,4-二氮杂环庚烷-1-基)-5',8'-二氢-6'H-螺[环己烷-1,7'-喹唑啉]-2'-胺二乙酸盐;4'-哌嗪-1-基-5',8'-二氢-6'H-螺[环己烷-1,7'-喹唑啉]-2'-胺二乙酸盐;4'-[3-(甲基氨基)氮杂环丁烷-1-基]-5',8'-二氢-6'H-螺[环己烷-1,7'-喹唑啉]-2'-胺二乙酸盐;4-(3-氨基吡咯烷-1-基)-7-异丁基-5,6,7,8-四氢喹唑啉-2-胺二乙酸盐;7-异丙基-4-(4-甲基哌嗪-1-基)-5,6,7,8-四氢喹唑啉-2-胺;7-异丙基-4-[(3S)-3-甲基哌嗪-1-基]-5,6,7,8-四氢喹唑啉-2-胺二乙酸盐;7-异丙基-4-[(4aR*,7aR*)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]-5,6,7,8-四氢喹唑啉-2-胺;7-异丙基-4-[3-(甲基氨基)氮杂环丁烷-1-基]-5,6,7,8-四氢喹唑啉-2-胺;叔丁基-4-(2-氨基-7,7-二甲基-5,6,7,8-四氢喹唑啉-4-基)-1,4-二氮杂环庚烷-1-羧酸酯。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2008/003702中描述的那些:4-氨基-6-氯-2-(4-甲基哌嗪基)-喹唑啉,2-(4-甲基哌嗪基)-4-苯氧基喹唑啉,4-(苄基氧基)-2-(4-甲基哌嗪基)-喹唑啉,2-(4-甲基哌嗪基)-喹啉,2-(4-甲基哌嗪基)-喹喔啉,6-氯-2-(4-甲基-哌嗪基)-喹啉,6-氯-2-(4-甲基哌嗪基)-喹喔啉,2-(4-甲基哌嗪基)-喹唑啉,3-(4-甲基哌嗪基)-异喹啉,1-(4-甲基哌嗪基)-异喹啉,3-苄基-2-(4-甲基哌嗪基)-喹喔啉,6,7-二氯-2-甲氧基-3-(4-甲基哌嗪基)-喹喔啉和7-氯-2-甲氧基-3-(4-甲基哌嗪基)-喹喔啉。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2006/050965中描述的那些:8-氯-2-甲基-4-(4-甲基哌嗪-1-基)苯并[4,5]呋喃[3,2-d]嘧啶;8-氯-4-(4-甲基哌嗪-1-基)苯并[4,5]呋喃[3,2-d]嘧啶;4-(4-甲基哌嗪-1-基)苯并[4,5]呋喃[3,2-d]嘧啶;6-氯-l-(4-甲基哌嗪-1-基)-9H-2,4,9-三氮杂芴;4-(哌嗪-1-基)苯并[4,5]呋喃[3,2-d]嘧啶;4-(哌嗪-1-基)苯并[4,5]噻吩并[3,2-d]嘧啶;8-氯-4-(1,4-二氮杂环庚烷-1-基)苯并[4,5]噻吩并[3,2-d]嘧啶;8-氯-2-环丙基-4-(4-甲基哌嗪-1-基)苯并[4,5]呋喃[3,2-d]嘧啶;8-氯-4-(4-甲基哌嗪-1-基)-2-三氟甲基苯并[4,5]呋喃[3,2-d]嘧啶;8-氯-4-(1-甲基哌啶-4-基)苯并[4,5]呋喃[3,2-d]嘧啶;8-氯-4-[(1S,4S)-2,5-二氮杂二环[2.2.1]庚-2-基]苯并[4,5]呋喃[3,2-d]嘧啶;8-氯-4-(3-甲基哌嗪-1-基)苯并[4,5]呋喃[3,2-d]嘧啶;8-氯-4-[(1S,4S)-5-甲基-2,5-二氮杂二环[2.2.1]庚-2-基]苯并[4,5]呋喃[3,2-d]嘧啶;8-氯-4-(3,4-二甲基哌嗪-1-基)苯并[4,5]呋喃[3,2-d]嘧啶;8-氯-4-(1-甲基吡咯烷-3-基)苯并[4,5]呋喃[3,2-d]嘧啶;8-氯-4-(8-甲基-3,8-二氮杂二环[3.2.1]辛-3-基)苯并[4,5]呋喃[3,2-d]嘧啶;8-氯-4-[(1R,4R)-5-甲基-2,5-二氮杂二环[2.2.1]庚-2-基]苯并[4,5]呋喃[3,2-d]嘧啶;8-氯-4-[5-甲基-2,5-二氮杂二环[2.2.2]辛-2-基]苯并[4,5]呋喃[3,2-d]嘧啶;和8-氯-4-[5-甲基-2,5-二氮杂二环[3.2.1]辛-2-基]苯并[4,5]呋喃[3,2-d]嘧啶。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2005/014579中描述的那些:4-(1H-咪唑-4-基甲氧基)-1-(1-氧杂-3-苯基丁基)-哌啶;4-(1H-咪唑-4-基甲氧基)-1-[[4-(三氟甲基)苯基]乙酰基]-哌啶;1-[2-(4-羟基苯基)-1-氧杂丙基]-4-[(5-甲基-1H-咪唑-4-基)甲氧基]-哌啶;1-[(4-氟苯基)乙酰基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[(2-氯苯基)乙酰基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[(4-氯苯基)乙酰基]-4-(1H-咪唑-4-基甲氧基)-哌啶;4-(H-咪唑-4-基甲氧基)-1-(苯基乙酰基)-哌啶;1-(4-环己基苯甲酰基)-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[(3,4-二氯苯基)乙酰基]-4-(H-咪唑-4-基甲氧基)-哌啶;4-(1H-咪唑-4-基甲氧基)-1-[(4-甲基苯基)乙酰基]-哌啶;1-[(3,4-二氟苯基)乙酰基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[(2,4-二氟苯基)乙酰基]-4-(1H-咪唑-4-基甲氧基)-哌啶;4-(1H-咪唑-4-基甲氧基)-1-[(4'-丙基[1,1'-联苯基]-4-基)羰基]-哌啶;1-[2-(4-羟基苯基)-1-氧杂丙基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[(2E)-3-(3,4-二氯苯基)-1-氧杂-2-丙烯基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[3-(2,4-二氯苯基)-1-氧杂丙基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[(2,4-二氯苯基)乙酰基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[(2-溴苯基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[(3-溴-2-噻吩基)甲基]-4-[(5-甲基-1H-咪唑-4-基)甲氧基]-哌啶;1-[(3-溴-2-噻吩基)甲基]-4-(lH-咪唑-4-基甲氧基)-哌啶;1-[(4-乙炔基苯基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;4-(1H-咪唑-4-基甲氧基)-1-[[3-(4-甲基苯氧基)苯基]甲基]-哌啶;4-(1H-咪唑-4-基甲氧基)-1-[[4-(2-丙烯基氧基)苯基]甲基]-哌啶;4-[[4-(1H-咪唑-4-基甲氧基)-1-哌啶基]甲基]-苯酚;4-(1H-咪唑-4-基甲氧基)-1-[(2-甲氧苯基)甲基]-哌啶;4-(1H-咪唑-4-基甲氧基)-1-[[3-(4-甲氧苯氧基)苯基]甲基]-哌啶;1-[(2,3-二氯苯基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[(2-氯-4-氟苯基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-(2-二苯并呋喃基甲基)-4-(1H-咪唑-4-基甲氧基)-哌啶;4-(1H-咪唑-4-基甲氧基)-1-[[2-(甲基硫代)苯基]甲基]-哌啶;4-(1H-咪唑-4-基甲氧基)-1-(噻吩并[2,3-b][l]苯并噻吩-2-基甲基)-哌啶;1-[(2-氯-5-硝基苯基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1H-吡咯,2-[[4-(1H-咪唑-4-基甲氧基)-1-哌啶基]甲基]-1-[(4-甲基苯基)磺酰]-;2-乙氧基-6-[[4-(1H-咪唑-4-基甲氧基)-1-哌啶基]甲基]-苯酚;1-(1,3-苯并二氧醇-5-基甲基)-4-(1H-咪唑-4-基甲氧基)-哌啶;4-(1H-咪唑-4-基甲氧基)-1-[[4-(苯基甲氧基)苯基]甲基]-哌啶;1-[[2-氟-4-(三氟甲基)苯基]甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[(4-溴苯基)甲基]-4-(IH-咪唑-4-基甲氧基)-哌啶;4-(1H-咪唑-4-基甲氧基)-1-[(4-甲基苯基)甲基]-哌啶;4-(H-咪唑-4-基甲氧基)-1-(2-噻吩基甲基)-哌啶;1-[(4-氯苯基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[(2-氯-6-氟苯基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;4-(1H-咪唑-4-基甲氧基)-1-[(3-甲基-2-噻吩基)甲基]-哌啶;4-(1H-咪唑-4-基甲氧基)-1-(2-萘基甲基)-哌啶;4-(1H-咪唑-4-基甲氧基)-1-(1-萘基甲基)-哌啶;4-(1H-咪唑-4-基甲氧基)-1-[(2-硝基苯基)甲基]-哌啶;4-(1H-咪唑-4-基甲氧基)-1-(3-噻吩基甲基)-哌啶;1-([1,1'-联苯基]-4-基甲基)-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[(2,5-二氟苯基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;4-(1H-咪唑-4-基甲氧基)-1-[(3-苯氧基苯基)甲基]-哌啶;4-(1H-咪唑-4-基甲氧基)-1-[(3-甲基苯基)甲基]-哌啶;1-(2-呋喃基甲基)-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[(2,6-二氯苯基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[(4-氟苯基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[(3-氟苯基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-(3-呋喃基甲基)-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[(4-乙基苯基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;4-(1H-咪唑-4-基甲氧基)-1-[(2-甲基苯基)甲基]-哌啶;1-[(3-氯苯基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;4-(1H-咪唑-4-基甲氧基)-1-[(5-甲基-2-噻吩基)甲基]-哌啶;1-[(4-溴-2-噻吩基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-([2,2'-二噻吩]-5-基甲基)-4-(1H-咪唑-4-基甲氧基)-哌啶;3,5-二氯-2-[[4-(1H-咪唑-4-基甲氧基)-1-哌啶基]甲基]-苯酚;1-[(3,4-二氟苯基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[(3,5-二氟苯基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[(6-氯-1,3-苯并二氧醇-5-基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[[4-[4-(1,1-二甲基乙基)-2-噻唑基]苯基]甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;4-(1H-咪唑-4-基甲氧基)-1-[(1-甲基-1H-吡咯-2-基)甲基]-哌啶;1H-吲哚,3-[[4-(1H-咪唑-4-基甲氧基)-1-哌啶基]甲基]-1-(苯基甲基)-;1-[(5-氯-2-噻吩基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-(1,3-苯并二氧醇-4-基甲基)-4-(1H-咪唑-4-基甲氧基)-哌啶;2-噻吩甲腈,3-[[4-[[4-(1H-咪唑-4-基甲氧基)-1-哌啶基]甲基]苯氧基]甲基]-哌啶;4-(1H-咪唑-4-基甲氧基)-1-[[5-(苯基乙炔基)-2-噻吩基]甲基]-哌啶;4-(1H-咪唑-4-基甲氧基)-1-[[5-(4-硝基苯基)-2-呋喃基]甲基]-哌啶;4-(1H-咪唑-4-基甲氧基)-1-[[5-(5-(3-硝基苯基)-2-呋喃基]甲基]-哌啶;1-[(4-氯-1H-吡唑-3-基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[(4-溴-1-甲基-1H-吡唑-3-基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[(4-溴-1H-吡唑-3-基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;2-[[4-(1H-咪唑-4-基甲氧基)-1-哌啶基]甲基]-苄腈;4-(1H-咪唑-4-基甲氧基)-1-[(4-碘代苯基)甲基]-哌啶;1-[(5-乙基-2-噻吩基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;4-(1H-咪唑-4-基甲氧基)-1-[[5-(甲基硫代)-2-噻吩基]甲基]-哌啶;1-[[1-(3,5-二氯苯基)-1H-吡咯-2-基]甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[[1-(4-氯苯基)-lH-吡咯-2-基]甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;4-(1H-咪唑-4-基甲氧基)-1-[[4-(苯基乙炔基)-2-噻吩基]甲基]-哌啶;4-(1H-咪唑-4-基甲氧基)-1-[(3-苯氧基-2-噻吩基)甲基]-哌啶;1-[[2-氯-5-(三氟甲基)苯基]甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;4-(1H-咪唑-4-基甲氧基)-1-[(4-丙氧基苯基)甲基]-哌啶;2-[[4-(1H-咪唑-4-基甲氧基)-1-哌啶基]甲基]-苯酚;1-[(2,4-二氟苯基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;3-[[4-(1H-咪唑-4-基甲氧基)-1-哌啶基]甲基]-2-噻吩甲腈;1-(苯并lb]噻吩-3-基甲基)-4-(1H-咪唑-4-基甲氧基)-哌啶;2-氯-3-[[4-(1H-咪唑-4-基甲氧基)-1-哌啶基]甲基]-吡啶;3-[[4-(1H-咪唑-4-基甲氧基)-1-哌啶基]甲基]-2-(2-丙烯基)-苯酚;1-[(4-氯-3-氟苯基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;4-(1H-咪唑-4-基甲氧基)-1-[[4-(三氟甲氧基)苯基]甲基]-哌啶;1-[(2,6-二氟苯基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[(4-溴-2-氟苯基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[(2,2-二氟-1,3-苯并二氧醇-5-基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;1-[(4-丁氧基苯基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;4-(1H-咪唑-4-基甲氧基)-1-[(2,3,5-三氯苯基)甲基]-哌啶;1-[(2,5-二氯苯基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶;4-(H-咪唑-4-基甲氧基)-1-[[2-(三氟甲基)苯基)甲基]-哌啶,或1-[(4-氯-2-硝基苯基)甲基]-4-(1H-咪唑-4-基甲氧基)-哌啶或其可药用盐或溶剂合物。
在另一实施方案中,选择性组胺H4拮抗剂选自国际专利申请WO2009107767中描述的那些。
在具体实施方案中,组胺H4受体拮抗剂是Herman D.等(2005)描述的1-[(5-氯-1H-苯并咪唑-2-基)羰基]-4-甲基哌嗪(也称作JNJ 10191584或VUF6002)。该选择性拮抗剂以高亲和性结合人组胺H4受体(Ki=26nM)。该亲和性比H3受体的亲和性(Ki=14.1μM)(Zhang M.等,2007)高540倍。
在具体实施方案中,选择性组胺H4受体拮抗剂是Robin L.等(2004)描述的1-[(5-氯-1H-吲哚-2-基)羰基]-4-甲基哌嗪(也称作JNJ 7777120)。
在具体实施方案中,选择性组胺H4受体拮抗剂是Cowart MD.等(2008)描述的4-((3R)-3-氨基吡咯烷-1-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺(也称作A-943931)。
在具体实施方案中,选择性组胺H4受体拮抗剂是Liu H等(2008)描述的顺式-4-(哌嗪-1-基)-5,6,7a,8,9,10,11,11a-八氢苯并呋喃[2,3-h]喹唑啉-2-胺(也称作A-987306)。
在另一实施方案中,选择性组胺H4受体拮抗剂可由能阻断组胺H4受体活化的抗体(该术语包括抗体片段)组成。
具体而言,选择性组胺H4受体拮抗剂可由抗组胺H4受体或组胺H4受体配体的抗体组成,以此方式所述抗体损害H4配体与所述受体的结合。
抗组胺H4受体的抗体可以根据已知方法通过向所选择的宿主动物,例如猪、牛、马、兔、山羊、绵羊、以及特别是小鼠施用适当的抗原或表位产生。本领域已知的多种佐剂可以用于增强抗体产生。虽然用于实施本发明的抗体可以是多克隆的,但是单克隆抗体是优选的。抗组胺H4受体或者组胺H4受体配体的单克隆抗体可以使用提供由培养的连续细胞系生产抗体分子的任何技术来制备和分离。用于生产和分离的技术包括但不限于由Kohler和Milstein(1975)最初描述的杂交瘤技术;人B细胞杂交瘤技术(Cote等,1983);和EBV-杂交瘤技术(Cole等,1985)。备选地,对于生产单链抗体描述的技术(见例如美国专利号4,946,778)可以被调整以生产抗H4或抗H4配体的单链抗体。用于实施本发明的组胺H4受体拮抗剂还包括抗H4或抗H4配体抗体片段,包括但不限于可通过将完整抗体分子进行胃蛋白酶消化产生的F(ab')2片段和可通过还原F(ab')2片段二硫键产生的Fab片段。备选地,可构建Fab和/或scFv表达文库以允许快速鉴定对组胺H4受体具有期望特异性的片段。
人源化抗组胺H4受体或抗H4配体抗体及其抗体片段还可以根据已知技术制备。“人源化抗体”是包含最低限度的来源于非人免疫球蛋白序列的非人(例如啮齿动物)嵌合抗体形式。人源化抗体的大部分是人免疫球蛋白(接受者抗体),其中来自接受者的高变区(CDR)的残基被来自非人物种(供体抗体)例如小鼠、大鼠、兔或非人灵长类的具有预期特异性、亲和性和能力的高变区的残基替代。在一些情况中,人免疫球蛋白的框架区(FR)残基被相应的非人残基替代。此外,人源化抗体可包含在接受这抗体或供体抗体中不存在的残基。可进行这些修改以进一步精修抗体的性能。通常,人源化抗体将包含至少一个并且通常两个可变区的基本上全部,其中全部或者基本上全部的超变环对应于非人免疫球蛋白的那些,并且全部或者基本上全部FR是人免疫球蛋白序列的那些。人源化抗体任选地还包括至少一部分免疫球蛋白恒定区(Fc),有代表性地是人免疫球蛋白的那些。制造人源化抗体的方法描述于,例如Winter(美国专利号5,225,539)和Boss(Celltech,美国专利号4,816,397)。
如上所述产生抗组胺H4受体的抗体之后,本领域技术人员可容易地选择阻断组胺H4受体活化的那些。
在另一实施方案中,选择性组胺H4受体拮抗剂是适体。适体是在分子识别方面表现出替代抗体的一类分子。适体是具有以高亲和性和特异性识别实际上任何类型靶分子能力的寡核苷酸或寡肽序列。此类配体可通过如Tuerk C.和Gold L.,1990中所述的随机序列文库的指数富集性配体系统进化(SELEX)分离。随机序列文库通过DNA的组合化学合成得到。在该文库中,每一成员是独特序列的最终被化学修饰的线性寡聚体。该类分子的可能的修饰、用途和优势已经综述于Jayasena S.D.,1999中。肽适体包括通过双杂交方法从组合文库选择的由平台蛋白例如大肠杆菌硫氧还蛋白A展示的构象受限抗体可变区(Colas等,1996)。
在如上述产生抗组胺H4受体的适体之后,本领域技术人员可容易地选择阻断组胺H4受体活化的那些。
本发明的另一方面涉及组胺H4受体基因表达抑制剂的用途。
组胺受体(H1、H2、H3或H4)序列显示具有低的序列同一性,通过与其它组胺受体(H1、H2或H3)表达相比,根据本发明可使用的组胺H4受体基因表达抑制剂有利地提供对组胺H4受体基因表达的选择性抑制。
用于在本发明中使用的组胺H4受体基因表达抑制剂可以基于反义寡核苷酸构建体。反义寡核苷酸,包括反义RNA分子和反义DNA分子,将通过与组胺H4受体mRNA结合并且因此阻止蛋白质翻译或增加mRNA降解,而发挥作用来直接阻断组胺H4受体mRNA的翻译,因此降低细胞中的组胺H4受体水平并且因此降低组胺H4受体活性。例如,可以通过例如常规磷酸二酯技术合成至少大约15个碱基并且与编码组胺H4受体的mRNA转录物序列独特区互补的反义寡核苷酸,并且通过例如静脉内注射或灌注施用。使用反义技术特异性抑制序列已知的基因的表达的方法在本领域是众所周知的(例如见美国专利号6,566,135;6,566,131;6,365,354;6,410,323;6,107,091;6,046,321;和5,981,732)。
小的抑制性RNA(siRNA)也可作为组胺H4受体基因表达的抑制剂起作用而用于本发明中。组胺H4受体基因表达可通过将受试者或细胞与小的双链RNA(dsRNA)或者引起产生小的双链RNA的载体或构建体接触,从而组胺H4受体基因表达被特异性抑制(即RNA干扰或RNAi)而降低。选择对于序列已知的基因的适宜dsRNA或dsRNA-编码载体的方法是本领域众所周知的(例如见Tuschl,T.等(1999);Elbashir,S.M.等(2001);Hannon,GJ.(2002);McManus,MT.等(2002);Brummelkamp,TR.等(2002);美国专利号6,573,099和6,506,559;和国际专利公布号WO 01/36646、WO 99/32619和WO 01/68836)。
核酶还可作为用于本发明的组胺H4受体基因表达抑制剂起作用。核酶是能够催化RNA特异性切割的酶性RNA分子。核酶的作用机制涉及核酶分子与互补靶RNA的序列特异性杂交,接着是内切核苷酸切割。特异性和有效催化组胺H4受体mRNA序列的内切核苷酸切割的工程改造的发夹或锤头模体核酶分子从而可以在本发明范围内使用。通过扫描靶分子中的核酶切割位点(有代表性的包括下列序列:GUA、GUU和GUC)最初鉴定任何潜在RNA靶内的特异核酶切位点。一旦鉴定出之后,评价对应于包含切割位点的靶基因区的在大约15和20个核糖核苷酸之间的短RNA序列的预测结构特征,例如致使寡核苷酸序列不适宜的二级结构。候选靶的适宜性还可通过使用例如核酶保护测定法测试它们与互补寡核苷酸杂交的可进入性来评价。
可以通过已知方法制备用作组胺H4受体基因表达抑制剂的反义寡核苷酸和核酶。这包括用于化学合成的技术,例如通过固相亚磷酰胺化学合成。备选地,反义RNA分子可以通过编码RNA分子的DNA序列的体外或体内转录产生。此类DNA序列可以整合入多种整合有适宜RNA聚合酶启动子例如T7或SP6聚合酶启动子的载体中。可以向本发明的寡核苷酸引入多种修改作为提高细胞内稳定性和半寿期的手段。可能的修改包括但不限于向分子的5'和/或3'末端添加核糖核苷酸或脱氧核糖核苷酸侧翼序列,或者在寡核苷酸主链内使用磷硫酰键或2'-O-甲基而不是使用磷酸二酯键。
本发明的反义寡核苷酸siRNA和核酶可以单独地或者与载体一起体内递送。“载体”以其最广的含义是能够促进反义寡核苷酸siRNA或核酶核酸转移至细胞并且优选表达组胺H4受体的细胞的任何媒介物。优选地,载体以相对于在缺乏载体下所导致的降解程度更低的降解将核酸转移至细胞。通常,用于本发明的载体包括,但不限于,质粒、噬菌粒、病毒、衍生自病毒或细菌来源的已经被操作插入或整合入反义寡核苷酸siRNA或核酶核酸序列的其它媒介物。病毒载体是优选的载体类型,并且包括,但不限于来自下列病毒的核酸序列:反转录病毒,例如莫洛尼鼠白血病病毒,harvey鼠肉瘤病毒,鼠乳腺肿瘤病毒和劳斯肉瘤病毒;腺病毒,腺伴随病毒;SV40型病毒;多瘤病毒;埃-巴病毒;乳头瘤病毒;疱疹病毒;痘苗病毒;脊髓灰质炎病毒;和RNA病毒例如反转录病毒。可以容易地采用未命名但本领域已知的其它病毒。
优选的病毒载体基于其中非必需基因已经被目的基因替换的非细胞病真核病毒。非细胞病病毒包括反转录病毒(例如慢病毒),其生活周期涉及到病毒基因组RNA反转录成DNA,随后前病毒整合入宿主细胞DNA中。反转录病毒已经被批准用于人基因治疗试验。最有用的是复制缺陷的那些反转录病毒(即能够指导所希望蛋白质的合成,但是不能够产生感染颗粒)。此类基因工程改变的逆病毒表达载体通常可用于体内高效率转导基因。用于产生复制缺陷型反转录病毒的标准方案(包括外源遗传物质向质粒中的整合、以质粒转染包装细胞、由包装细胞系产生重组反转录病毒、从组织培养基收集病毒颗粒、和以病毒颗粒感染靶细胞的步骤)在Kriegler,1990和Murry,1991中提供。
对于特定应用的优选病毒是腺病毒和腺伴随病毒,其是已经批准用于人基因治疗用途的双链DNA病毒。腺伴随病毒可以被工程改造成复制缺陷型的并且能够感染广范围的细胞类型和种类。其还具有优点例如,热和脂溶剂稳定性;在不同谱系细胞,包括造血细胞中的高转导率;和缺乏重叠感染抑制因此允许多重级数转导。据报导,腺伴随病毒可以以位点特异性的方式整合入人细胞DNA中,由此使反病毒感染特有的插入诱变和所插入基因表达变异性的可能性最小化。此外,在缺乏选择压力的情况下,野生型腺伴随病毒感染可在组织培养中持续大约100次传代,这意味着腺伴随病毒基因组整合是相对稳定的事件。腺伴随病毒还可以以染色体外方式起作用。
其它载体包括质粒载体。质粒载体已经在本领域中广泛描述并且是本领域技术人员众所周知的。见例如Sambrook等,1989。在最近几年中,质粒载体已经用作DNA疫苗用于向细胞体内递送编码抗原的基因。对于此它们是特别有益的,因为它们不具有像许多病毒载体所具有的安全性问题。然而,具有与宿主细胞相容的启动子的这些质粒可从质粒内有效编码的基因表达肽。一些通常使用的质粒包括pBR322、pUC18、pUCl9、pRC/CMV、SV40和pBlueScript。其它质粒是本领域普通技术人员众所周知的。此外,质粒可以使用限制酶和连接反应以去除和添加特定的DNA片断而定制设计。质粒可以通过多种肠胃外、黏膜和局部途径递送。例如,DNA质粒可以通过肌内、真皮内、皮下或其它途径注射。其还可通过鼻内喷雾剂或滴剂、直肠栓剂和经口施用。它还可使用基因枪施用入表皮或粘膜表面。质粒可在水溶液中、在金颗粒上干燥或与另外的DNA递送系统包括但不限于脂质体、树状聚体、脂质卷和微囊化结合提供。
本发明的另一目的涉及治疗和/或预防前庭障碍的方法,包括向需要其的受试者施用选择性组胺H4受体拮抗剂或组胺H4受体基因表达抑制剂。
选择性组胺H4受体拮抗剂或组胺H4受体基因表达抑制剂可以以如下定义的药物组合物形式施用。
优选地,所述拮抗剂或抑制剂以治疗有效量施用。
“治疗有效量”意思是指足够以适用于任何医学治疗的合理的利益/风险比治疗和/或预防前庭障碍的选择性组胺H4受体拮抗剂或组胺H4受体基因表达抑制剂的量。
应当理解,本发明化合物和组合物的总的日使用量可由主治医师在合理的医学判断范围内决定。对于任何特定患者的特定的治疗有效剂量水平将取决于多种因素,包括正在治疗的病症和病症的严重性;所采用特定化合物的活性;所采用的特定组合物、患者的年龄、体重、总体健康状况、性别和饮食;施用时间、施用途径和所采用特定化合物的排泄率;治疗持续时间;用于与所采用特定多肽联合或同时使用的药物;以及医药领域众所周知的因素。例如,本领域技术人员已知,以比达到预期治疗效果所需水平低的水平开始化合物的剂量并且逐渐增加剂量直到达到预期效果。然而,产品的每日剂量可在从0.01至1,000mg/成年人/天的大范围内变化。优选地,对于待治疗患者剂量的对症调整,组合物包含0.01、0.05、0.1、0.5、1.0、2.5、5.0、10.0、15.0、25.0、50.0、100、250和500mg活性成分。药剂有代表性地包含从大约0.01mg至大约500mg活性成分,优选地从1mg至大约100mg活性成分。有效量的药物通常以从0.0002mg/kg体重/天至大约20mg/kg体重/天,特别是从大约0.001mg/kg体重/天至7mg/kg体重/天的剂量水平提供。
筛选方法:
可通过本领域技术水平所描述的筛选方法进一步鉴定本发明的抑制剂。本发明的筛选方法可以根据已知方法开展。
筛选方法可以通过与候选化合物直接或间接结合的的标记的方式测量候选化合物与受体、或者与携带受体的细胞或膜、或者其融合蛋白结合。备选地,筛选方法可包括测量或者(定性或定量)检测候选化合物与标记竞争物(例如拮抗剂或激动剂)与受体的竞争性结合。此外,筛选方法使用对于携带受体的细胞所适宜的检测系统可测试候选化合物是否引起由受体拮抗剂所产生的信号。可在已知激动剂(例如组胺)存在下测定拮抗剂并且观察在候选化合物存在下对由激动剂活化的影响。使用已知激动剂例如组胺的竞争性结合也是适宜的。
候选化合物对组胺H4受体的拮抗活性可以例如使用多种模型确定。例如,可以使用在Thurmond RL等(2004)或Venable JD.等(2005)中描述的方法。
药物组合物:
选择性组胺H4受体拮抗剂或组胺H4受体基因表达抑制剂可以与可药用赋形剂和任选的持续释放基质例如生物可降解聚合物组合,以形成治疗组合物。
在本发明的药物组合物中,活性物质单独或与另一活性物质的组合可以以单位施用形式作为与常规制药支持物的混合物向动物和人施用。适宜的单位施用形式包括经口途径形式例如片剂、凝胶胶囊剂、散剂、颗粒剂和口服混悬剂或溶液剂、舌下和颊施用形式、气溶胶、埋植剂、皮下、经皮、局部、腹膜内、肌内、静脉内、真皮下、经皮、鞘内和鼻内施用形式以及直肠施用形式。
优选地,药物组合物包含对于能够注射的制剂而言可药用的媒介物。具体而言,它们可以是等渗、无菌盐溶液(磷酸一钠或二钠、氯化钠、氯化钾、氯化钙或氯化镁等等或者此类盐的混合物),或者干燥的,尤其是冷冻干燥的组合物,当根据情况向干燥的组合物中加入无菌水或生理盐水时可构成可注射溶液。
适宜可注射使用的药物形式包括无菌水溶液或分散剂;包括芝麻油、花生油或水性丙二醇的制剂;和用于临时制备无菌可注射溶液或分散剂的无菌散剂。在所有情况下,剂型必须是无菌的并且必须是存在容易注射程度的流动性。它必须是在制造和储存条件下稳定的并且必须抗微生物如细菌和真菌的污染作用。
包含作为游离碱或可药用盐的本发明化合物的溶液可以在适当与表面活性剂如羟基丙基纤维素混合的水中制备。分散剂还可以在甘油、液体聚乙二醇及其混合物中和在油类中制备。在常规储存和使用条件下,这些制剂包含防腐剂以阻止微生物的生长。
本发明的选择性组胺H4受体拮抗剂或组胺H4受体基因表达抑制剂可以配制成中性或盐形式的组合物。可药用盐包括酸加成盐(与蛋白质的游离氨基形成)以及与无机酸例如盐酸或磷酸,或此类有机酸如乙酸、草酸、酒石酸、扁桃酸等等形成的那些酸加成盐。与游离羧基形成的盐还可以来自于无机碱例如,氢氧化钠、氢氧化钾、氢氧化铵、氢氧化钙或氢氧化铁,以及此类有机碱如异丙基胺、三甲基胺、组氨酸、普鲁卡因等等。
载体还可以是包含例如水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇等等)、它们的适宜混合物以及植物油的溶剂或分散介质。可以通过例如使用包衣如卵磷脂、在分散剂的情况下通过维持所需要的颗粒大小和通过使用表面活性剂维持适当的流动性。防止微生物的作用可以通过多种抗菌剂和抗真菌剂例如,对羟基苯甲酸酯、三氯叔丁醇、苯酚、山梨酸、硫柳汞等等实现。在许多情况中,优选包括等渗剂,例如糖或氯化钠。可注射组合物的延长吸收可以通过在组合物中使用延缓吸收的试剂例如单硬脂酸铝和明胶实现。
无菌可注射溶液通过向根据需要含多种上述其它成分的适宜溶剂中加入所需量的活性多肽,接着过滤除菌实现。通常,分散剂通过向包含基础分散介质和所需的上述那些其它成分的无菌媒介物中加入多种无菌活性成分制备。在用于制备无菌可注射溶液的无菌散剂的情况下,优选的制备方法是真空干燥和冷冻干燥技术,其从其先前无菌过滤溶液得到活性成分加上任何另外所希望成分的粉末。
经配制,溶液将以与剂量形式相容的方式和具有治疗效果的量施用。制剂以多种剂量形式容易地施用,例如上述的可注射溶液类型,但是还可采用药物释放胶囊等等。
对于在水溶液中的肠胃外施用,例如,必要时将溶液适当缓冲并且首先用足够的盐或葡萄糖使液体稀释剂等渗。这些特定水溶液特别适宜于静脉内、肌内、皮下和腹膜内施用。在这一点上,根据本公开,可以采用的无菌水介质将是本领域技术人员已知的。例如,一次剂量可溶解于1ml等渗NaCl溶液中并且或者加入至1000ml皮下灌注流体中或者在所计划灌注部位注射。取决于所治疗的受试者的情况,剂量必然出现一些变化。无论如何,负责施用的人会确定对于个体受试者的适宜剂量。
本发明的选择性组胺H4受体拮抗剂或者组胺H4受体基因表达抑制剂将配制成治疗混合物中以包含大约0.0001至1.0mg、或大约0.001至0.1mg、或大约0.1至1.0或者甚至大约10mg/剂量左右。还可以施用多次剂量。
除了将本发明的化合物配制成肠胃外施用,例如静脉内或肌内注射之外,其它可药用形式包括例如片剂或用于口服施用的其它固体;脂质体制剂;定时释放胶囊;和当前使用的任何其它形式。
在具体实施方案中,选择性组胺H4受体拮抗剂或组胺H4受体基因表达抑制剂在内耳中通过鼓膜直接施用。对于向前庭引入直接且长效的效应优选该施用模式。因此,在优选的实施方案中,选择性组胺H4受体拮抗剂或组胺H4受体基因表达抑制剂在凝胶制剂中施用以使得所述拮抗剂或抑制剂在内耳内长期释放。
通过实施例进一步阐述本发明。
实施例:
方法:
药物/化学品:1-[(5-氯-1H-苯并咪唑-2-基)羰基]-4-甲基哌嗪马来酸盐(JNJ10191584马来酸盐或VUF 6002)购自Tocris Bioscience(Bristol,英国),并且1-[(5-氯-1H-吲哚-2-基)羰基]-4-甲基哌嗪马来酸盐(JNJ 7777120)从Sigma(Sigma-Aldrich,St-Quentin Fallavier,法国)得到。如提供者所推荐,在100%二甲基亚砜中制备50mM的储存溶液。倍他司汀二盐酸盐(购自Sigma-Aldrich,St-Quentin Fallavier,法国)和N-环己基-4-(1H-咪唑-4-基)-1-哌啶硫代甲酰胺马来酸盐(噻普酰胺,Sigma-Aldrich)的储存溶液在记录介质中分别制备成1M和0.01M。然后在使用前在工作溶液中将药物稀释。
细胞培养:前庭神经节神经元从2至6天龄Wistar大鼠(Centre d'ElevageJanvier,Le Genest-Saint-Isle,法国)无菌性移植。所有操作按照French/EuropeanCommunities Council Directive 86/609/EEC开展。将脑干半切并且跟进第八神经至平衡器水平并且紧靠嘴侧切断它。
切断前庭神经节,置于Leibovitz介质(L15,Invitrogen,Cergy Pontoise,法国)中,并且酶性分离(胶原酶0.75mg/ml,分散酶1mg/ml和DNA酶0.75mg/ml,于25℃下15分钟)。用无Ca2+和Mg2+的Tyrode溶液洗涤酶,并且在培养基中用吸管温和地分离神经节神经元。将神经元置于培养皿中,培养皿先前以5μg/ml聚-L-鸟氨酸、10μg/ml层粘连蛋白包被然后加入添加有2%N2营养素葡萄糖(5g/l)、谷氨酰胺(1.5mM)、碳酸氢钠(1.1g/l)、HEPES缓冲液(15mM,pH 7.4)、AraC 2μM、脑衍生神经营养因子10μg/ml和1%青霉素/链霉素的0.5ml的Dulbecco改良eagle培养基和Ham F-12培养基的1:1混合物(Invitrogen)。然后,在膜片钳试验前,将低密度的培养物于37℃,5%CO2下维持7至8天。
膜片钳记录:使用Axopatch 200B放大器(Axon Instruments;Molecular DevicesCorp.,Sunnyvale,CA,美国)得到全细胞(电流钳配置)的反应记录。细胞外溶液包含(mM):NaCl 135,HEPES 10,葡萄糖10,MgCl2 1,KCl 5和CaCl2 4,pH 7.35(采用NaOH)。记录吸管(2-3MΩ)从微量血细胞比容管(Modulohm I/S,Herlev,丹麦)抽取并填充下列溶液(mM):KCl 135,HEPES 10,葡萄糖10,NaCl 5,EGTA 5,Mg-ATP 3,GTP-Na 1,pH 7.35(采用KOH)。所有溶液的渗透性设置成300mOsm/l-1。用PC计算机和Tecmar Labmaster模拟界面(Axoninstruments,CA)控制实验参数和数据采集。从表现出静息电位位于-45和-65mV之间的神经元记录电压瞬变。使用每6.5s应用一次的1s,200pA去极化脉冲引起动作电位(AP)序列。使用pCLAMP软件(v 10.2,Axon instruments)对电流信号以10KHz过滤、数据化和储存。
药物应用:使用多毛细管灌流系统(流速500μl/分钟)应用对照和测试溶液。在每一次应用所测试的药物之后,用对照缓冲液洗涤细胞。
数据分析和统计学方法:结果表示为平均值±S.E.M。所给出的样品大小的数量(n)是所测试神经元的数量。膜电位改变和AP数量使用pCLAMP软件(v10.2,Axoninstruments)分析。药物的浓度-效应关系以I(x)=A*xn/(IC5On+xn)形式的Hill方程拟合。
结果:
通过使用结合组胺H4受体的抗体的Western印迹和免疫组织化学的免疫化学研究分别显示了组胺H4受体蛋白质存在于主要前庭神经节中和鉴定了其在细胞中定位于神经元的细胞膜(数据未显示)。
在相差显微镜下,培养的前庭神经节神经元具有直径范围10和25μm之间的折射胞体。所有记录的神经元具有长的神经炎过程。
所记录的神经元表现出-50.3±3.6mV(n=116,范围-45至-65mV)的静息电位。当应用去极化脉冲(1s,200pA)时,记录了两种类型的AP放电脉冲排。位相性放电由1至4AP组成,而紧张性放电表现出10至80AP(平均29.3±14.3,n=92),(图1A-C a)。除非应用抑制剂,否则这些放电模式将稳定直至30分钟。
当放电模式为分相时,应用1mM VUF 6002完全消除了放电(n=6)。在表现出紧张性反应的神经元中,应用VUF 6002以剂量依赖方式减少所激发AP的数量。图1表明放电的抑制。在100μM时,抑制是91%(图1A),而化合物仅诱导轻微的细胞膜超极化(大约-3mV)(图4)。
应用10μm、1μM和100nM的VUF 6002分别抑制放电55%(n=6)、37%(n=11)和20%(n=10)。通过随后灌注对照培养基完全逆转这些抑制性效应,表明了反应的可逆性(图1B-C)。动作电位内在的特性,例如波峰振幅、达波峰时间、上升和衰减时间常数,表现出不受VUF 6002影响。
还研究了另一H4受体拮抗剂JNJ 7777120的作用。JNJ 7777120在低浓度时(在100nM时为3%的抑制,n=7)比VUF 6002效率低,而在更高浓度时差异不明显(p>0.05)(在1μM时为29%,n=7;在10μM时为41%,n=9)。此外,7777120没有诱导膜去极化,甚至在高浓度应用时也是如此(1mM)。
以1nM和1mM之间的浓度建立VUF 6002的剂量-反应抑制相关关系(图2)。在我们的记录条件下,最大抑制发生于100μM左右(90%抑制)并且剂量-反应相互关系具有5.8μM的IC50。
对于0.1μM和1000μM之间的JNJ 7777120计算的剂量-反应抑制相互关系得出的IC50为10μM。
两种选择性H4受体拮抗剂VUF 6002和JNJ 7777120对放电和膜电位变化两者表现出非常相似的效应。
通过比较,对于应用BH(一种组胺H3受体拮抗剂)确立了反应(Arrang等,1985)。BH以相同的方式抑制放电脉冲排。BH对在标准去极化刺激过程中引起的放电脉冲排的最大抑制为10mM左右。在2mM应用过程中,膜电位没有受影响,但是通过5mM的BH处理诱导神经元的强的去极化(14.3±4.7mV,n=16)(图3,图4)。通过随后灌注对照培养基快速消除了放电抑制和去极化,表明了反应的可逆性(图3)。剂量-反应相互关系表现出IC50为2.2mM。
测试了H3和H4受体两者的组胺拮抗剂噻普酰胺(Gbahou等,2006)对培养的前庭神经元的影响。在低浓度(0.01至10μM)时,噻普酰胺抑制神经元的放电脉冲排,而不去极化(在0.1μM时为10%和在10μM时为24%,分别为n=9和13)。相反地,更高的浓度封闭神经元的活性(在500μM时为87%,n=10),接着是强的膜去极化(图4)。应用噻普酰胺对放电的抑制在漂洗过程中仅轻微可逆,特别是应用高浓度噻普酰胺时。剂量-反应相互关系表现出IC50为100μM。
噻普酰胺表现出位于VUF 6002和BH的效应之间的效应。
本研究结果第一次证明,选择性组胺H4受体拮抗剂是哺乳动物前庭主要神经元放电的有效抑制剂。
-选择性组胺H4受体拮抗剂可逆性并且剂量依赖性方式抑制前庭神经元的放电,而不诱导膜去极化。
-倍他司汀(H3拮抗剂)和噻普酰胺(H3和H4拮抗剂,即非选择性组胺H4受体拮抗剂)抑制前庭神经元的放电,但是它们的使用需要高浓度以得到与选择性组胺H4受体拮抗剂相当的反应。在这些高浓度时,倍他司汀和噻普酰胺诱导神经元的显著去极化。此外,应用噻普酰胺仅稍微可逆。
-选择性组胺H4受体拮抗剂比典型的抗眩晕处方药更有效。
-选择性组胺H4受体拮抗剂的药理学特性使其可作为能在前庭障碍治疗中带来治疗效果的强的前庭药。
因此,组胺H4受体基因表达和/或活性的选择性抑制剂可用于治疗前庭障碍。
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Claims (12)
1.选择性组胺H4受体拮抗剂在制备用于治疗和/或预防前庭障碍的药物中的用途。
2.根据权利要求1的用途,其中所述选择性组胺H4受体拮抗剂选自由小的有机分子、抗体和适体组成的组。
3.根据权利要求1或2的用途,其中所述选择性组胺H4受体拮抗剂选自由以下组成的组:1-[(5-氯-1H-苯并咪唑-2-基)羰基]-4-甲基哌嗪、1-[(5-氯-1H-吲哚-2-基)羰基]-4-甲基哌嗪、4-((3R)-3-氨基吡咯烷-1-基)-6,7-二氢-5H-苯并[6,7]芳庚并[1,2-d]嘧啶-2-基胺、顺式-4-(哌嗪-1-基)-5,6,7a,8,9,10,11,11a-八氢苯并呋喃[2,3-h]喹唑啉-2-胺、2-异丁基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-胺、N4-(环丙基甲基)-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺或(R)-4-(3-氨基-吡咯烷-1-基)-6-异丙基-嘧啶-2-基胺和它们的衍生物。
4.根据权利要求1-3任一项的用途,其中所述选择性组胺H4受体拮抗剂选自由以下组成的组:2-异丁基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-胺、2-异丁基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-4-胺、2-环己基甲基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-4-胺、2-(4-氟苄基)-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-胺、2-环丙基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-胺、2-叔丁基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-胺、2-异丙基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-胺、2-(环丙基甲基)-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-胺、6-(3-(甲基氨基)氮杂环丁烷-1-基)-2-(苯氧基甲基)嘧啶-4-胺、2-环丙基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-4-胺、2-叔丁基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-4-胺、2-异丙基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-4-胺、6-((3R)-3-(甲基氨基)吡咯烷-1-基)-2-(苯氧基甲基)嘧啶-4-胺、6-(3-氨基氮杂环丁烷-1-基)-2-异丁基嘧啶-4-胺、2-异丁基-6-(3-甲基-3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-胺、6-((3R)-3-氨基吡咯烷-1-基)-2-异丁基嘧啶-4-胺、2-环丁基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-胺、2-环丁基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-4-胺、2-环戊基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-胺、2-环戊基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-4-胺、2-(2,2-二甲基丙基)-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-胺、2-(2,2-二甲基丙基)-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-4-胺、2-(2-环戊基乙基)-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-4-胺、2-环己基甲基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-胺、2-环丙基甲基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-4-胺、2-环己基-6-(3-(甲基氨基)氮杂环丁烷-1-基)嘧啶-4-胺、2-环己基-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-4-胺和2-(4-氟苄基)-6-((3R)-3-(甲基氨基)吡咯烷-1-基)嘧啶-4-胺。
5.根据权利要求1-3任一项的用途,其中所述选择性组胺H4受体拮抗剂选自由以下组成的组:N4-(环丙基甲基)-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺、N4-(环丙基甲基)-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺酒石酸盐、N4-异丁基-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺、N4-(2,2-二甲基丙基)-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺、N-异丁基-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-4-胺、N-(环丙基甲基)-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-4-胺、N4-(2,2-二甲基丙基)-6-[(4aR*,7aR*)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2,4-二胺、N4-环丙基-6-[(4aR*,7aR*)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2,4-二胺、N4-环丁基-6-[(4aR*,7aR*)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2,4-二胺、N4-(2,2-二甲基丙基)-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2,4-二胺、6-(3-甲基氨基-氮杂环丁烷-1-基)-N4-(3,3,3-三氟-丙基)-嘧啶-2,4-二胺、N4-环丙基甲基-6-(3-甲基氨基-氮杂环丁烷-1-基)-嘧啶-2,4-二胺、N4-(3,3-二甲基-丁基)-6-(3-甲基氨基-氮杂环丁烷-1-基)-嘧啶-2,4-二胺、N4-(3-氟-苄基)-6-(3-甲基氨基-氮杂环丁烷-1-基)-嘧啶-2,4-二胺、N4-环戊基甲基-6-(3-甲基氨基-氮杂环丁烷-1-基)-嘧啶-2,4-二胺、N4-异丁基-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2,4-二胺、6-[3-(甲基氨基)氮杂环丁烷-1-基]-N4-丙基嘧啶-2,4-二胺、N4-(2-甲氧苄基)-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2,4-二胺、N4-(2,2-二甲基丙基)-6-[(3R)-3-甲基哌嗪-1-基]嘧啶-2,4-二胺、N4-乙基-6-(4-甲基哌嗪-1-基)嘧啶-2,4-二胺、N4-(环丙基甲基)-6-(4-甲基哌嗪-1-基)嘧啶-2,4-二胺、6-[3-(甲基氨基)氮杂环丁烷-1-基]-N4-(2-甲基丁基)嘧啶-2,4-二胺、N4-(2,5-二氟苄基)-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2,4-二胺、N4-(2,3-二氟苄基)-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2,4-二胺、N4-丁基-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2,4-二胺、6-[(3R)-3-(甲基氨基)吡咯烷-1-基]-N4-(2-甲基环丙基)嘧啶-2,4-二胺、N4-异丁基-6-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-2,4-二胺、N4-(环丙基甲基)-6-(3-吡咯烷-1-基氮杂环丁烷-1-基)嘧啶-2,4-二胺、N4-二环[1.1.1]戊-1-基-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺,6-[3-甲基-3-(甲基氨基)氮杂环丁烷-1-基]-N4-丙基嘧啶-2,4-二胺、N4-(2,2-二甲基丙基)-6-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)嘧啶-2,4-二胺、N4-(2,2-二甲基丙基)-6-(3-吡咯烷-1-基氮杂环丁烷-1-基)嘧啶-2,4-二胺、N4-(2,2-二甲基丙基)-6-[3-(异丙基氨基)氮杂环丁烷-1-基]嘧啶-2,4-二胺、N4-(叔丁基)-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺,6-[(3R)-3-(甲基氨基)吡咯烷-1-基]-N4-(1-甲基环丙基)嘧啶-2,4-二胺、N4-(叔丁基)-6-[(4aS*,7aS*)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2,4-二胺、N4-(2,2-二甲基丙基)-6-哌嗪-1-基嘧啶-2,4-二胺、N4-(2,2-二甲基丙基)-6-[3-(甲基氨基)氮杂环丁烷-1-基]嘧啶-2,4-二胺盐酸化物、N4-(2,2-二甲基丙基)-6-[(3aR*,7aS*)-八氢-5H-吡咯并[3,2-c]吡啶-5-基]嘧啶-2,4-二胺、6-哌嗪-1-基-N4-丙基嘧啶-2,4-二胺、N4-(环丙基甲基)-6-[4aR,7aR]-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2,4-二胺、N4-(2,2-二甲基丙基)-6-[(4aS,7aS)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2,4-二胺、N4-(环丙基甲基)-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺、N4-异丙基-6-[(4aS,7aS)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2,4-二胺、4-[3-(甲基氨基)氮杂环丁烷-1-基]-6-(4-甲基哌啶-1-基)嘧啶-2-胺、N4-(环戊基甲基)-6-[(3R)-3-(甲基氨基)吡咯烷-1-基]嘧啶-2,4-二胺、N4-环丁基-6-[(4aS,7aS)-八氢-6H-吡咯并[3,4-b]吡啶-6-基]嘧啶-2,4-二胺、6-[(3R)-3-(甲基氨基)吡咯烷-1-基]-N4-丙基嘧啶-2,4-二胺和N4-乙基-6-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-2,4-二胺。
6.组胺H4受体基因表达抑制剂在制备用于治疗和/或预防前庭障碍的药物中的用途。
7.根据权利要求6的用途,其中所述组胺H4受体基因表达抑制剂选自由以下组成的组:反义RNA或DNA分子、小的抑制性RNA和核酶。
8.根据权利要求1-7中任一项权利要求的用途,其中所述前庭障碍选自前庭神经炎、阵发梅尼埃病、内淋巴积水、外淋巴瘘、带有前庭障碍的头损伤、迷路出血、慢性或急性迷路感染、浆液性迷路、带有前庭障碍的气压伤、前庭性偏头痛、内耳通道病变、慢性梅尼埃病和presbyvestibulia。
9.根据权利要求1-8中任一项的用途,其中所述药物用于缓解或降低前庭障碍的至少一个症状的频率或发生率。
10.根据权利要求9的用途,其中所述前庭障碍的至少一个症状选自由以下组成的组:眩晕、头晕、失衡和恶心。
11.根据权利要求10的用途,其中所述眩晕是良性阵发性眩晕或家族性发作性眩晕。
12.根据权利要求1-11中任一项的用途,其中所述药物用于通过鼓膜施用或用于全身施用。
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DK2382013T3 (en) | 2016-11-14 |
CY1118106T1 (el) | 2017-06-28 |
JP2016041694A (ja) | 2016-03-31 |
JP5814126B2 (ja) | 2015-11-17 |
JP2012513968A (ja) | 2012-06-21 |
ES2597834T3 (es) | 2017-01-23 |
EP2382013B1 (en) | 2016-07-13 |
KR101749285B1 (ko) | 2017-06-20 |
HRP20161290T1 (hr) | 2016-11-18 |
HK1163571A1 (zh) | 2012-09-14 |
RU2589846C2 (ru) | 2016-07-10 |
IL213540A (en) | 2015-10-29 |
LT2382013T (lt) | 2016-10-25 |
IL213540A0 (en) | 2011-07-31 |
CA2748159A1 (en) | 2010-07-01 |
SI2382013T1 (sl) | 2017-02-28 |
HUE031645T2 (en) | 2017-07-28 |
SMT201600368B (it) | 2016-11-10 |
US10195195B2 (en) | 2019-02-05 |
RU2012101595A (ru) | 2013-07-27 |
EP2201982A1 (en) | 2010-06-30 |
KR20110117661A (ko) | 2011-10-27 |
WO2010072829A1 (en) | 2010-07-01 |
CA2748159C (en) | 2017-06-27 |
PL2382013T3 (pl) | 2017-01-31 |
CN102325566A (zh) | 2012-01-18 |
US9526725B2 (en) | 2016-12-27 |
US20120039913A1 (en) | 2012-02-16 |
EP2382013A1 (en) | 2011-11-02 |
EP3130376A1 (en) | 2017-02-15 |
PT2382013T (pt) | 2016-10-25 |
US20170056397A1 (en) | 2017-03-02 |
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