CN116406357A - Mas相关g蛋白受体x2的调节剂及相关产物和方法 - Google Patents
Mas相关g蛋白受体x2的调节剂及相关产物和方法 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/40—Nitrogen atoms attached in position 8
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A—HUMAN NECESSITIES
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- A61P37/00—Drugs for immunological or allergic disorders
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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Abstract
Description
背景技术
技术领域
本发明涉及Mas相关G蛋白偶联受体X2的调节剂、含有所述调节剂的产物以及其使用和制备方法。
相关技术描述
Mas相关G蛋白受体(MRGPR)是一组在非常专门的组织中表达有限的孤儿受体。对大多数这些受体的功能知之甚少。此类中存在八种在人类中表达的相关受体,其中只有四种在其它物种中具有易于鉴定的直系同源物(即,MRGPR D、E、F和G)。其它四种受体(MRGPRX1、X2、X3和X4)中的一些在高等物种(包括狗和马)中具有对应物,但它们在啮齿动物中没有单一的相应直系同源物。
发明内容
本发明部分地基于MRGPR X2或MRGPR X2直系同源物调节剂化合物的鉴定。MRGPRX2在功能上对应于肥大细胞中的小鼠mrgprb2和狗MRGPRX2。MRGPR X2及其直系同源物受体介导病症,包括假过敏反应(包括假过敏性药物反应)、慢性瘙痒(例如,瘙痒症)、炎症病症、疼痛病症、皮肤病症、伤口愈合、心血管疾病和肺部炎症/COPD。在一个实施方案中,mrgprb2和MRGPR X2表达都主要限于肥大细胞。肥大细胞是先天免疫细胞,主要存在于暴露于外部环境的部位,诸如皮肤、口腔/胃肠粘膜和呼吸道。肥大细胞表达许多响应机械和化学刺激的受体。在典型地被IgE活化后,肥大细胞释放从颗粒预先形成的介质(例如,组胺、蛋白酶和肝素)和引起过敏应答和炎症应答的新合成的介质(例如,血栓烷、前列腺素D2、白三烯C4、肿瘤坏死因子α、嗜酸性趋化因子和血小板活化因子)。组胺扩张毛细血管后微静脉,活化内皮,并增加血管渗透性。这导致局部水肿、发热、发红和其它炎症细胞对释放部位的趋化性。组胺也促成导致疼痛或瘙痒的神经元致敏。MRGPR X2和mrgprb2介导肥大细胞不依赖于免疫球蛋白E(IgE)的活化。MRGPR X2和mrgprb2是各种配体的受体(或对各种配体的活化作用敏感),这些配体包括碱性促分泌素(小阳离子分子)、某些药物(例如,阳离子肽能药物)、神经肽和抗微生物肽,因此对于非IgE介导的假过敏反应、炎症、疼痛和瘙痒病状而言很重要。肥大细胞还可通过促进局部组织微环境中的慢性炎症并最终向Th17免疫应答极化而促成自身免疫病症的进展。因此,调节MRGPR X2或MRGPR X2直系同源物可以治疗自身免疫性疾病、假过敏性药物反应、疼痛、瘙痒和炎性病症,诸如炎症性肠病、荨麻疹、窦炎、哮喘、酒渣鼻、子宫内膜异位和如下文更详细解释的其他MRGPR X2或MRGPR X2直系同源物依赖性病状。
在一个实施方案中,提供了一种通过向有需要的受试者施用有效量的本发明的调节剂化合物的药物组合物来治疗MRGPR X2或MRGPR X2直系同源物依赖性病状的方法。
因此,在一个实施方案中,提供了具有结构(I)的化合物:
或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素,其中W、Z、R1、R2、R3、R4、R5、R6和Rx如本文所定义。
在其他实施方案中,提供了具有如本文所定义的式(Ia)、(Ib)、(Ic)、(Id)、(Ie)或(If)的化合物,或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素。
在其他实施方案中,提供了药物组合物,这些药物组合物包含载体或赋形剂和具有结构(I)的化合物或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素。
在具体实施方案中,提供了药物组合物,这些药物组合物包含具有如本文所定义的式(Ia)、(Ib)、(Ic)、(Id)、(Ie)或(If)的结构(I)的亚结构或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素。
在另一个实施方案中,提供了用于通过向有需要的受试者施用有效量的具有结构(I)的化合物或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素来治疗MRGPR X2或MRGPR X2直系同源物依赖性病状的方法。
在一些实施方案中,该MRGPR X2或MRGPR X2直系同源物依赖性病状是假过敏反应、瘙痒相关病状、疼痛相关病状、炎症相关病状或自身免疫性病症中的一种或多种病状。
在一个实施方案中,提供了治疗该MRGPR X2或该MRGPR X2直系同源物依赖性病状的方法,其包括施用有效量的具有如本文所定义的式(Ia)、(Ib)、(Ic)、(Id)、(Ie)或(If)的结构(I)的化合物或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素。
在另一个实施方案中,提供了化合物或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素,这些化合物具有本文所公开的结构中的一种或多种结构。
具体实施方式
如上所述,本发明涉及MRGPR X2的调节剂、含有所述调节剂的产物以及其使用和制备方法。本发明部分地基于MRGPR X2调节剂化合物的鉴定。mrgprb2和MRGPR X2两者都在肥大细胞和背根神经节中表达。MRGPR X2和mrgprb2两者都是多种配体的受体(或对多种配体的活化作用敏感),这些配体包括碱性促分泌素、某些药物、神经肽、抗微生物肽,因此在暴露时对于假过敏反应、瘙痒、疼痛或炎性病症而言很重要。
MRGPR似乎是感觉受体,其识别针对外源性或内源性信号/化学物质的其外部环境。这些受体可能对多种化学配体/激动剂作出应答。例如,MRGPR X2将化合物48/80、物质P、黄峰毒素、艾替班特(icatibant)、环丙沙星和苯磺阿曲库铵(tracurium)识别为激动剂信号。在某些实施方案中,本发明的分子通过充当能够阻断多种化学实体的反向激动剂和/或作为能够特异性阻断单个配体的竞争性拮抗剂来调节MRGPR X2。在一个实施方案中,此类调节对其它MRGPR有选择性,如MRGPR X1、X3和/或X4。
定义
如本文所用,除非上下文另有说明,否则下列术语具有下文所定义的含义。
″调节″MRGPR X2是指化合物与MRGPR X2相互作用的方式使得其充当受体的反向激动剂和/或作为受体的竞争性拮抗剂。在一个实施方案中,此类调节部分地或完全地对其它MRGPR有选择性,如MRGPR X1、X3和/或X4。
″MRGPR″是指Mas相关G蛋白偶联受体中的一者或多者,其是一组在非常专门的组织(例如,肥大细胞和背根神经节中)和屏障组织中表达有限的孤儿受体。此类中存在八种在人类中表达的相关受体,其中只有4种在其它物种中具有易于鉴定的直系同源物(即,MRGPR D、E、F和G)。基于同源性,其它四种受体(MRGPR X1、X2、X3和X4)在非人物种中没有对应物。
″MRGPRX2″,也称为″MRGX2″或″MGRG3″,是指在肥大细胞上表达的并且能够响应于配体结合介导IgE非依赖性活化(例如,肥大细胞脱粒)的MRGPR家族成员。示例性的人MRGPRX2氨基酸序列示于Uniprot Q96LB 1中。
″有效量″是指足以在用所述药剂治疗的受试者中实现期望效果的指定药剂的量。理想地,药剂的有效量是足以抑制或治疗疾病而不在受试者中引起显著毒性的量。药剂的有效量将取决于被治疗的受试者、病痛的严重程度和药物组合物的施用方式。根据本公开,本领域技术人员将理解确定足以在受试者中实现期望效果的所公开的化合物的有效量的方法。
″烷基″意指具有1个到8个碳原子,在一些实施方案中为1个到6个碳原子,在一些实施方案中为1个到4个碳原子,并且在一些实施方案中为1个到3个碳原子的饱和或不饱和直链或支链烷基。饱和直链烷基的示例包括但不限于甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基和正辛基。支链烷基的示例包括但不限于异丙基、异丁基、仲丁基、叔丁基、新戊基、异戊基和2,2-二甲基丙基。不饱和烷基包含如下文定义的烯基和炔基。
″烯基″意指具有2个到8个碳原子,在一些实施方案中为2个到6个碳原子,在一些实施方案中为2个到4个碳原子,并且在一些实施方案中为2个到3个碳原子的直链或支链烯基。烯基是含有至少一个碳碳双键的不饱和烃。低级烯基的实例包括但不限于乙烯基、丙烯基、丁烯基、戊烯基和己烯基。
″炔基″意指具有2个到8个碳原子,在一些实施方案中为2个到6个碳原子,在一些实施方案中为2个到4个碳原子,并且在一些实施方案中为2个到3个碳原子的直链或支链炔基。炔基是包含至少一个碳碳三键的不饱和烃。炔基的实例包括但不限于乙炔基、丙炔基、丁炔基、戊炔基和己炔基。
″卤代″或″卤素″是指氟、氯、溴和碘。
″羟基″是指-OH。
″氰基″是指-CN。
氨基是指-NH2、-NH烷基或N(烷基)2,其中烷基如上文所定义。氨基的示例包括但不限于-NH2、-NHCH3、-N(CH3)2等。
″卤代烷基″是指一个或多个氢原子被卤素置换的如上文所定义的烷基。低级卤代烷基的实例包括但不限于-CF3、-CHF2等。
″烷氧基″是指通过氧原子连接的如上定义的烷基(即,-O-烷基)。烷氧基的示例包括但不限于甲氧基、乙氧基、正丙氧基、正丁氧基、异丙氧基、仲丁氧基、叔丁氧基等。
″卤代烷氧基″是指通过氧原子连接的如上文所定义的卤代烷基(即,-O-卤代烷基)。低级卤代烷氧基的实例包括但不限于-OCF3等。
″环烷基″是指形成环结构的烷基,所述环烷基可以是经取代的或未经取代的,其中环是完全饱和的、部分不饱和的或完全不饱和的,其中如果存在不饱和,环中π电子的共轭不会产生芳香性。环烷基的示例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基和环辛基。在一些实施方案中,环烷基具有3个到8个环成员,然而在其他实施方案中,环碳原子的数量在3个到5个、3个到6个或3个到7个的范围内。环烷基进一步包含如但不限于降冰片基、金刚烷基、冰片基、莰稀基、异莰稀基和蒈稀基的多环环烷基和如但不限于十氢萘酯等的稠环。
″芳基″是不含有杂原子的环状芳香族烃。代表性芳基包括但不限于苯基、薁基、庚基、联苯基、茚基、芴基、菲基、三亚苯基、芘基、萘基、芘基、亚联苯基、蒽基和萘基。在一些实施方案中,芳基在基团的环部分中含有6个到14个碳。术语″芳基″和″芳基基团″包括稠环,其中至少一个环但不一定所有环是芳香族的,诸如稠合的芳香族-脂肪族环系(例如,茚满基、四氢萘基等)。在一个实施方案中,芳基是苯基或萘基,并且在另一个实施方案中,芳基是苯基。
″碳环″是指形成环结构的烷基,所述碳环可以是经取代的或未经取代的,其中环是完全饱和的、部分不饱和的或完全不饱和的,其中如果存在不饱和,环中π电子的共轭可以产生芳香性。在一个实施方案中,碳环包含如上文所定义的环烷基。在另一个实施方案中,碳环包含如上文所定义的芳基。
″杂环″是指含有3个或更多个环成员的芳香族和非芳香族环部分,其中一个或多个是杂原子,诸如但不限于N、O、S或P。在一些实施方案中,杂环基包含3个到20个环成员,而其它此类基团具有3个到15个环成员。至少一个环含有杂原子,但多环体系中的每个环不需要含有杂原子。例如,二氧戊环基和苯并二氧戊环体系(亚甲基二氧苯基环体系)均为本文含义内的杂环基。
杂环基还包含稠环物质,包含具有稠合芳香族和非芳香族基团的那些。杂环基还包含含有杂原子如但不限于奎宁环基的多环体系,并且还包含具有取代基的杂环基,包括但不限于烷基、卤基、氨基、羟基、氰基、羧基、硝基、硫代基或烷氧基,与环成员之一键合。如本文所定义的杂环基可以是杂芳基或包含至少一个环杂原子的部分或完全饱和的环状基团。杂环基包括但不限于吡咯烷基、呋喃基、四氢呋喃基、二氧戊环基、哌啶基、哌嗪基、吗啉基、吡咯基、吡唑基、三唑基、四唑基、噁唑基、异噁唑基、噻唑基、吡啶基、噻吩基、苯并噻吩基、苯并呋喃基、二氢苯并呋喃基、吲哚基、二氢吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、氮杂苯并咪唑基、苯并噁唑基、苯并噻唑基、苯并噻二唑基、咪唑并吡啶基、异噁唑并吡啶基、噻萘基、嘌呤基、黄嘌呤基、腺嘌呤基、鸟噪呤基、喹啉基、异喹啉基、四氢喹啉基、喹喔啉基和喹唑啉基。
在一个实施方案中,杂环基包括杂芳基。
″杂芳基″是指含有5个或更多个环成员的芳香族环部分,其中一个或多个是杂原子,诸如但不限于N、O和S。杂芳基包括但不限于基团,诸如吡咯基、吡唑基、吡啶基、哒嗪基、嘧啶基(pyrimidyl)、吡嗪基(pyrazyl)、吡嗪基(pyrazinyl)、嘧啶基(pyrimidinyl)、噻吩基、三唑基、四唑基、三嗪基、噻唑基、苯硫基、噁唑基、异噁唑基、苯并噻吩基、苯并呋喃基、吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、氮杂苯并咪唑基、苯并噁唑基、苯并噻唑基、苯并噻二唑基、咪唑并吡啶基、异噁唑并吡啶基、噻萘基、嘌呤基、黄嘌呤基、腺嘌呤基、鸟嘌呤基、喹啉基、异喹啉基、四氢喹啉基、四氢异喹啉基、喹喔啉基和喹唑啉基。术语″杂芳基″和″杂芳基基团″包括稠环化合物,诸如其中至少一个环但不一定所有环是芳族的,包括四氢喹啉基、四氢异喹啉基、吲哚基和2,3-二氢吲哚基。
″异构体″在本文中用于涵盖结构的所有手性形式、非对映体形式或外消旋形式(也称为立体异构体,与结构异构体或位置异构体完全不同),除非具体指出特定的立体化学或异构体形式。此类化合物可以在任何或所有不对称原子处以任何富集程度富集或解析光学异构体,如由图式可显而易见。外消旋和非对映体混合物两者以及单独的光学异构体可以经合成以基本上不含其对映体或非对映体配偶体,并且这些都在本发明的某些实施方案的范围内。由手性中心的存在产生的异构体包括一对称为″对映异构体″的不可重叠的异构体。纯化合物的单一对映体是光学活性的(即,它们能够旋转平面偏振光的平面并且被指定为R或S)。
″经分离的光学异构体″意指已经从相同式的对应光学异构体中基本上纯化的化合物。例如,按重量计,经分离的异构体的纯度可以是至少约80%、至少80%或至少85%。在其他实施方案中,分离的异构体为按重量计至少90%纯的或至少98%纯的、或至少99%纯的。
″基本上对映或非对映″纯度是指一种对映体相对于另一种对映体或非对映体的对映体富集水平或非对映体富集水平为至少约80%,并且更具体地超过80%、85%、90%、95%、98%、99%、99.5%或99.9%。
术语″外消旋体″和″外消旋混合物″是指两种对映异构体的等量混合物。外消旋体被标记为″(±)″,因为它不是旋光性的(即,不会沿任一方向旋转平面偏振光,因为它的组成对映异构体彼此抵消)。所有与叔碳或季碳相邻的带有星号(*)的化合物都是光学活性异构体,其可以从相应的外消旋体中纯化和/或通过适当的手性合成来合成。
″水合物″是与水分子结合存在的化合物。结合可以包含化学计量量的水,如一水合物或二水合物,或者可以包含随机量的水。如本文所用的术语″水合物″是指固体形式;换句话说,水溶液中的化合物尽管可以是水合的,但不是如本文所用的术语的水合物。
″溶剂化物″类似于水合物,不同之处在于存在除水之外的溶剂。例如,甲醇或乙醇可以形成″醇化物″,其同样可以是化学计量的或非化学计量的。如本文所用的术语″溶剂化物″是指固体形式;换句话说,溶剂溶液中的化合物尽管可以是溶剂化的,但不是如本文所用的术语的溶剂化物。
″同位素″是指质子数相同但中子数不同的原子,并且结构(I)的化合物的同位素包括其中一个或多个原子被该原子的同位素替代的任何这样的化合物。例如,碳12是最常见的碳形式,具有六个质子和六个中子,而碳13具有六个质子和七个中子,并且碳14具有六个质子和八个中子。氢具有两种稳定同位素,氘(一个质子和一个中子)和氚(一个质子和两个中子)。虽然氟具有多个同位素,但氟19的寿命最长。因此,具有结构(I)的结构的化合物的同位素包括但不限于结构(I)的化合物,其中一个或多个碳12原子被碳13和/或碳14原子替代,其中一个或多个氢原子被氘和/或氚替代,和/或其中一个或多个氟原子被氟19替代。
″盐″通常是指与抗衡离子结合的呈离子形式的有机化合物,诸如羧酸或胺。例如,阴离子形式的酸与阳离子之间形成的盐称为″酸加成盐″。相反,阳离子形式的碱与阴离子之间形成的盐称为″碱加成盐″。
术语″药学上可接受的″是指已经批准用于人类食用并且通常是无毒的药剂。例如,术语″药学上可接受的盐″是指无毒的无机酸或有机酸和/或碱加成盐(参见例如Lit等人,Salt Selection for Basic Drugs,Int.J.Pharm.,33,201-217,1986)(以引用方式并入本文)。
本发明的化合物的药学上可接受的碱加成盐包含例如金属盐,其包含碱金属盐、碱土金属盐以及过渡金属盐,例如钙盐、镁盐、钾盐、钠盐、以及锌盐。药学上可接受的碱加成盐还包括由碱性胺例如N,N′-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、葡甲胺(N-甲基葡糖胺)和普鲁卡因制备的有机盐。
药学上可接受的酸加成盐可以由无机酸或有机酸制备。无机酸的示例包含盐酸、氢溴酸、氢碘酸、硝酸、碳酸、硫酸和磷酸。合适的有机酸可选自脂族、脂环族、芳族、芳族脂族、杂环、羧酸和磺酸类有机酸,其示例包括甲酸、乙酸、丙酸、琥珀酸、乙醇酸、葡糖酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、葡糖醛酸、马来酸、富马酸、丙酮酸、天冬氨酸、谷氨酸、苯甲酸、邻氨基苯甲酸、4-羟基苯甲酸、苯乙酸、扁桃酸、马尿酸、丙二酸、草酸、扑酸(双羟萘酸)、甲磺酸、乙磺酸、苯磺酸、泛酸、三氟甲磺酸、2-羟基乙磺酸、对甲苯磺酸、磺胺酸、环己基氨基磺酸、硬脂酸、海藻酸、β羟基丁酸、水杨酸、半乳糖二酸和半乳糖醛酸。
本公开的化合物(即,结构(I)的化合物及其实施方案)或其药学上可接受的盐可以含有一个或多个几何不对称中心,并且因此可以产生对映异构体、非对映异构体和其他立体异构形式,其根据绝对立体化学被定义为(R)-或(S)-,或针对氨基酸定义为(D)-或(L)-。因此,实施方案包括所有这些可能的异构体,以及它们的外消旋和光学纯形式。光学活性的(+)和(-)、(R)-和(S)-、或(D)-和(L)-异构体可使用手性合成子或手性试剂制备,或使用常规技术例如色谱法和分级结晶拆分。用于制备/分离单个对映异构体的常规技术包括从合适的光学纯前体手性合成或使用例如手性高压液相色谱法(HPLC)拆分外消旋体(或盐或衍生物的外消旋体)。当本文所述的化合物含有烯烃双键或其他几何不对称中心时,除非另有说明,否则所述化合物意欲包括E和Z几何异构体。同样,也包括所有互变异构形式。
尽管药学上不可接受的盐通常不能用作药物,但此类盐可以用作例如具有结构(I)的化合物的合成中的中间体,例如,通过重结晶对其进行纯化。
如本文所使用的,短语″MRGPR X2依赖性病状″意指其中通过天然或合成配体对MRGPR X2进行活化、过度致敏或脱敏引发、介导、维持或增强病理病状的病状。例如,已知一些阳离子肽能药物在患者中引起假过敏反应。MRGPR X2对促分泌素、阳离子肽能药物(包括艾替班特、亮丙瑞林或加尼瑞克)、中性和阴离子肽能药物(例如,艾塞那肽、胰高血糖素、利拉鲁肽、恩夫韦地、多粘菌素E甲磺酸)、非类固醇激动剂(阿曲库铵、米库氯铵)、非类固醇拮抗药、神经肽和抗微生物肽敏感(或被这些活化)。而且,MRGPR X2的过表达和/或MRGPR X2的过度活性还可致使肥大细胞对内源配体和/或外源配体的活化更敏感。不受理论的限制,应当理解,通过调节MRGPR X2,可以减轻假过敏反应、瘙痒、疼痛、炎症或自身免疫性病症。
在一些实施方案中,MRGPR X2依赖性病状是由MRGPR X2的IgE非依赖性活化引起的病状。MRGPR X2的IgE非依赖性活化能够诱导肥大细胞脱粒。例如,肥大细胞IgE非依赖性活化与慢性荨麻疹和其它肥大细胞介导的病状的一些病例相关,这些病例对当前的抗IgE或抗组胺疗法没有反应性。因此,本公开的化合物可以用于治疗通过MRGPR X2的IgE依赖性活化引起的并且将受益于调节MRGPR X2的MRGPR X2依赖性病状。
在一些实施方案中,MRGPR X2依赖性病状是瘙痒相关病状、疼痛相关病状、假过敏反应或自身免疫性或炎性病症。
如本文所用,短语″假过敏反应″是指IgE非依赖性过敏反应,其特征在于组胺释放、炎症、气道收缩或它们的任何组合。假过敏反应可以是全身性过敏反应。假过敏反应可由一系列阳离子物质引起,这些阳离子物质统称为碱性促分泌素,包括炎性肽和与过敏型反应相关的药物。因此,在一个实施方案中,提供本发明的方法来治疗假过敏反应,诸如由促分泌素、阳离子肽能药物、阴离子肽能药物、中性肽能药物、非类固醇拮抗剂药物、神经肽和抗微生物肽引起的假过敏反应。在一个实施方案中,假过敏反应是由以下物质引起的:MCD肽、物质P、VIP、PACAP、强啡肽、生长抑制素、化合物48/80、皮质抑素-14、黄蜂毒素、蜂毒肽、抗菌肽、环丙沙星、万古霉素、亮丙瑞林、戈舍瑞林、组氨瑞林、曲普瑞林、西曲瑞克、加尼瑞克、地加瑞克、奥曲肽、兰瑞肽、帕瑞肽、舍莫瑞林、替莫瑞林、艾替班特、醋酸格拉替雷、特立帕肽、普兰林肽、博来霉素、艾塞那肽、胰高血糖素、利拉鲁肽、恩夫韦地、多粘菌素E甲磺酸、琥珀酰胆碱、筒箭毒碱、阿曲库铵、米库氯铵和罗库溴铵。
如本文所使用的,短语″瘙痒相关病状″意指与任何病状相关联的瘙痒症(包含急性瘙痒症和慢性瘙痒症)。瘙痒感可以源自例如外周神经系统(例如,皮肤或神经性瘙痒)或源自中枢神经系统(例如,神经性、神经源性或精神性瘙痒)。因此,在一个实施方案中,提供本发明的方法来治疗瘙痒相关病状,诸如慢性瘙痒;接触性皮炎;过敏性睑缘炎;过敏性反应;类过敏药物反应;过敏性休克;贫血;特应性皮炎;大疱性类天疱疮;念珠菌病;水痘;终末期肾衰竭;血液透析;胆汁淤积性瘙痒症;慢性荨麻疹;接触性皮炎、疱疹样皮炎;糖尿病;药物过敏、皮肤干燥;出汗障碍性皮炎;异位性湿疹;嗜酸性筋膜炎;大疱性表皮松解;红癣;食物过敏;毛囊炎;皮肤真菌感染;痔疮;疱疹;HIV感染;霍奇金病;甲状腺机能亢进;碘化造影染料过敏;缺铁性贫血;肾病;白血病、卟啉症;淋巴瘤;肥大细胞活化综合征;恶性肿瘤;肥大细胞增多症;多发性骨髓瘤;神经性皮炎;盘尾丝虫病;佩吉特病;虱病;真性红细胞增多症;结节性痒疹;扁平苔藓;硬化性苔藓;肛门瘙痒;假过敏反应;假狂犬病;银屑病;直肠脱垂;结节病肉芽肿;疥疮;血吸虫病;硬皮病、严重应激、淤积性皮炎;泳痒;甲状腺疾病;股癣;尿毒症瘙痒;酒渣鼻;皮肤淀粉样变性;硬皮病;痤疮;伤口愈合;烧伤愈合;眼痒;和荨麻疹。
如本文所使用的,短语″疼痛相关病状″意指由于医学病状引起的任何疼痛。因此,在一个实施方案中,提供本发明的方法来治疗疼痛相关病状,诸如急性疼痛、晚期前列腺癌、AIDS相关疼痛、强直性脊柱炎、蛛网膜炎、关节炎、关节纤维化、共济失调性脑瘫、自身免疫性萎缩性胃炎、缺血性坏死、背痛、白塞氏病(综合征)(Behcet′s disease)、灼口综合征、滑囊炎、癌痛、腕管、马尾神经综合征、中枢性疼痛综合征、脑瘫、颈椎管狭窄、腓骨肌萎缩(CMT)病、慢性疲劳综合征(CFS)、慢性功能性腹痛(CFAP)、慢性疼痛、慢性胰腺炎、慢性盆腔疼痛综合征、肺塌陷(气胸)、复杂的局部疼痛综合征(RSD)、角膜神经性疼痛、克罗恩氏病(Crohn′s disease)、退行性椎间盘疾病、牙痛、德尔肯氏病(Dercum′s disease)、皮肌炎、糖尿病外周神经病变(DPN)、肌张力障碍、埃勒斯-当洛斯综合征(Ehlers-DanlosSyndrome,EDS)、子宫内膜异位症、嗜酸性粒细胞增多症-肌痛综合征(EMS)、红斑性肢痛症、纤维肌痛、痛风、头痛、椎间盘突出、脑积水、肋间神经痛、间质性膀胱炎、肠易激综合征(IBS)、青少年皮炎(皮肌炎)、膝关节损伤、腿痛、腰痛血尿综合征、狼疮、莱姆病(lymedisease)、髓质海绵肾(MSK)、感觉异常性股痛、间皮瘤、偏头痛、肌肉骨骼疼痛、肌筋膜疼痛、肌炎、颈部疼痛、神经性疼痛、枕神经痛、骨关节炎、佩吉特病(Paget′s disease)、帕森那-特纳综合征(Parsonage-Turner syndrome)、盆腔痛、牙周炎疼痛、外周神经病变、幻肢疼痛、神经受压、多囊肾病、风湿性多肌痛、多肌炎、卟啉症、疝修补术后疼痛综合征、乳房切除术后、术后疼痛、疼痛综合征、中风后疼痛、胸廓切开术后疼痛综合征、带状疱疹后遗神经痛(带状疱疹)、脊髓灰质炎后综合征、原发性侧索硬化症、银屑病关节炎、阴部神经痛、神经根病、雷诺氏病(Raynaud′s disease)、类风湿性关节炎(RA)、骶髂关节功能障碍、结节病、舒尔曼氏后凸病(Scheuemann′s kyphosis disease)、坐骨神经痛、脊柱侧弯、带状疱疹(shingles,Herpes Zoster)、干燥综合征(Sjogren′s syndrome)、痉挛性斜颈、扩约肌功能不全(sphincter of oddi dysfunction)、脊髓小脑共济失调(SCA共济失调)、脊髓损伤、椎管狭窄、脊髓空洞症、塔洛夫囊肿(tarlov cysts)、横贯性脊髓炎、三叉神经痛、神经性疼痛、溃疡性结肠炎、血管疼痛和外阴痛。
如本文所使用的,术语″自身免疫性病症″或″炎性病症″意指由个体自身组织或器官引起和/或针对个体自身组织或器官的疾病或病症,或其共分离或表现,或由此产生的病状。通常,可以存在各种自身免疫性疾病的临床和实验室标志物,包括但不限于高丙种球蛋白血症、高水平的自身抗体、组织中的抗原抗体复合物沉积物、皮质类固醇或免疫抑制治疗的临床益处以及受影响的组织中的淋巴细胞聚集体。因此,在一个实施方案中,提供本发明的方法来治疗自身免疫病症,诸如慢性炎症、肥大细胞活化综合征、多发性硬化症、史蒂文约翰逊综合征、中毒性表皮坏死松解症、阑尾炎、滑囊炎、皮肤狼疮、结肠炎、膀胱炎、皮炎、静脉炎、反射性交感神经营养不良/复杂的局部疼痛综合征(rsd/crps)、鼻炎、肌腱炎、扁桃腺炎、寻常痤疮、窦炎、酒渣鼻、银屑病、移植物抗宿主病、反应性气道病症、哮喘、气道感染、过敏性鼻炎、自身炎性疾病、乳糜泻、慢性前列腺炎、憩室炎、肾小球性肾炎、化脓性汗腺炎、超敏反应、肠道病症、上皮性肠道病症、炎症性肠病、肠易激综合征、克罗恩氏病、溃疡性结肠炎、红斑狼疮、间质性膀胱炎、耳炎、盆腔炎、子宫内膜疼痛、再灌注损伤、风湿热、类风湿性关节炎、结节病、移植排斥、银屑病、肺部炎症、慢性阻塞性肺病、永久性痰嗜酸性粒细胞增多症、嗜酸性粒细胞白血病、嗜酸性粒细胞性食管炎、嗜酸性粒细胞性胃炎、肥大细胞胃肠道疾病、高嗜酸性粒细胞综合征、阿司匹林加重的呼吸道疾病、鼻息肉病、慢性鼻窦炎、抗体依赖性细胞介导的细胞毒性、神经纤维瘤病、swannamatoisis、肾小管间质性肾炎、肾小球肾炎、糖尿病肾病、同种异体移植物排斥、淀粉样变性、肾血管缺血、反流性肾病、多囊性肾病、肝纤维化/肝硬化、自身免疫性肝病、胆道闭锁、急慢性乙型和丙型肝炎病毒、肝肿瘤和肝癌、酒精性肝病、多囊性肝病、肝胆管癌、视神经脊髓炎谱系障碍、心血管疾病和血管炎。
如本文所用,短语″癌症相关病状″意指由恶性癌细胞的增殖引起的任何疾病。因此,在一个实施方案中,提供本发明的方法来治疗癌症/肿瘤相关病状,诸如腺样囊性癌、肾上腺肿瘤、淀粉样变性、肛门癌、阑尾癌、星形细胞瘤、共济失调毛细血管扩张症、贝克威斯-维德曼综合征(beckwith-wiedemann syndrome)、胆管癌、birt-hogg-dube综合征、骨癌、脑干胶质瘤、脑肿瘤、乳腺癌(炎性乳腺癌、转移性乳腺癌、男性乳腺癌)、前列腺癌、基底细胞癌、黑色素瘤、结肠癌、结直肠癌、膀胱癌、肾癌、泪腺癌、喉癌和下咽癌、肺癌(非小细胞肺癌、小细胞肺癌)、白血病(急性淋巴母细胞性白血病、急性淋巴细胞性白血病、急性骨髓性白血病、B细胞幼淋巴细胞性白血病、慢性淋巴细胞性白血病、慢性骨髓性白血病、慢性T细胞淋巴细胞性白血病、嗜酸性粒细胞白血病)、肝癌、Li-Fraumei综合征、淋巴瘤(霍奇金淋巴瘤和非霍奇金淋巴瘤)、林奇综合征(lynch syndrome)、肥大细胞增多症、成神经管细胞瘤、脑膜瘤、间皮瘤、多发性内分泌瘤病、多发性骨髓瘤、MUTYH相关息肉病、骨髓增生异常综合征、鼻腔和鼻窦癌、成神经细胞瘤、神经内分泌肿瘤、神经纤维瘤病、阴茎癌、甲状旁腺癌、卵巢输卵管和腹膜癌、骨肉瘤、垂体瘤、胸膜肺母细胞瘤、口腔和口咽癌、甲状腺癌、子宫癌、胰腺癌、carney综合征、脑和脊髓癌、宫颈癌、cowden综合征、颅咽管瘤、硬纤维瘤、促纤维增生性婴儿神经节胶质瘤、室管膜瘤、食道癌、尤因肉瘤、眼癌、眼睑癌、家族性腺瘤性息肉病、家族性GIST、家族性恶性黑色素瘤、家族性胰腺癌、胆囊癌、胃肠道间质瘤、生殖细胞瘤、妊娠滋养细胞疾病、头颈癌、遗传性乳腺癌和卵巢癌、遗传性弥漫性胃癌、遗传性平滑肌瘤病和肾细胞癌、遗传性胰腺炎、遗传性乳头状肾癌、遗传性混合息肉病综合征、HIV/AIDS相关癌症、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、卡波西肉瘤(Kaposi sarcoma)、小肠癌、胃癌、睾丸癌、胸腺瘤和胸腺癌、甲状腺癌、阴道癌、culver癌、沃纳综合征(wemer syndrome)和着色性干皮病。
如本文所使用的,术语″施用″是指提供如本文所描述的化合物或包括所述化合物的药物组合物。化合物或组合物可以由另一个人向受试者施用,或者器可以由受试者自行施用。施用途径的非限制性示例是口服、肠胃外(例如,静脉内)或局部。
如本文所使用的,术语″治疗″是指改善疾病或病理病状的体征或症状的干预。如本文所用,关于疾病、病理状况或症状的术语″治疗″也是指治疗的任何可观察到的有益效果。有益效果可以通过例如以下来证明:易感受试者中疾病的临床症状的延迟发作、疾病的一些或所有临床症状的严重程度降低、疾病的进展减慢、疾病复发的次数降低、受试者的整体健康或福祉的改善或者通过本领域众所周知的对特定疾病具有特异性的其他参数来证明。预防性治疗是对未表现出疾病体征或仅表现出早期体征的受试者施用的治疗,目的是降低发生病理的风险。治疗性治疗是在疾病的体征和症状出现后给予受试者的治疗。
如本文所用,术语″受试者″是指动物(例如,哺乳动物,诸如人、狗或马)。要根据本文所描述的方法治疗的受试者可以是已被诊断患有MRGPR X2依赖性病状或mrgpr X2直系同源物b2依赖性病状,诸如假过敏反应、瘙痒相关病状、疼痛相关病状、炎性或自身免疫性病症的受试者。诊断可以通过本领域已知的任何方法或技术进行。本领域技术人员将理解,根据本公开内容要治疗的受试者可以已经接受标准测试,或者可以在未经检查的情况下被鉴定为由于存在一种或多种与疾病或病状相关联的风险因素而有风险。术语″患者″可与术语″受试者″互换使用。受试者可以指成年受试者或儿科受试者。
《联邦食品、药品和化妆品法案》将″儿科″定义为在诊断或治疗时年龄为21岁或更小的受试者。儿科亚群进一步表征为:(i)新生儿-从出生到生命的前28天;(ii)婴儿-29天到小于2岁;(iii)儿童-2岁到小于12岁;以及(iv)青少年-12至21岁。尽管有定义,但根据易感患者群体和临床试验评价,批准的监管标签可包括明确修饰儿科群体的范围的短语,例如高达22岁的儿科患者。
在另一个实施方案中,本文所描述的治疗患有MRGPR X2依赖性病状(例如,瘙痒相关病状、疼痛相关病状、假过敏反应或炎性或自身免疫性病症)的受试者的方法进一步包括向受试者施用药学有效量的第二治疗剂。在一个实施方案中,瘙痒相关病状是假过敏病状。
在一个实施方案中,第二治疗剂是抗组胺,诸如H1受体拮抗剂或H2受体拮抗剂。在一个实施方案中,第二治疗剂是H1受体拮抗剂抗组胺,诸如左西替利嗪(1evocetirizine)、氯雷他定(loratadine)、非索非那定(fexofenadine)、西替利嗪(cetirizine)、地氯雷他定(desloratadine)、奥洛他定(olopatadine)、苯海拉明(diphenhydramine)、赛庚啶(cyproheptadine)或双羟萘酸羟嗪(hydroxyzine pamoate)。在一个实施方案中,第二治疗剂是H2受体拮抗剂,诸如西咪替丁(cimetidine)、尼扎替丁(nizatidine)、雷尼替丁(ranitidine)或法莫替丁(famotidine)。在一个实施方案中,第二治疗剂是白三烯受体拮抗剂或白三烯合成抑制剂,诸如孟鲁司特(montelukast)、扎鲁司特(zafirlukast)、普鲁司特(pranlukast)或5-脂氧合酶抑制剂(例如,齐留通(zileuton)、贯叶连翘(hypericumperforatum))。在一个实施方案中,第二治疗剂是免疫调节剂诸如奥马珠单抗(Omalizumab)或免疫球蛋白疗法。在一个实施方案中,第二治疗剂是皮质类固醇,诸如氢化可的松、可的松、ethamethasoneb、去炎松、泼尼松、泼尼松龙或氟氢可的松。在一个实施方案中,第二治疗剂是可以缓解瘙痒的三环抗抑郁剂,诸如多塞平(doxepin)、阿米替林(amitriptyline)或去甲替林(nortriptyline)。在一个实施方案中,第二治疗剂是抗炎药,诸如氨苯砜(dapsone)、柳氮磺胺吡啶、羟化氯喹或秋水仙碱。在一个实施方案中,第二治疗剂是免疫抑制剂,诸如环孢霉素、氨甲蝶呤、霉酚酸或他克莫司(tacromilus)。
第二治疗剂可以与本公开的化合物同时、分别或依次施用。如果同时施用,则本公开的第二治疗剂和化合物可以以分开的剂型或以相同的剂型施用。
在另一个实施方案中,提供了一种治疗患有瘙痒相关病状的受试者的方法,所述方法包括向受试者施用药学有效量的具有结构(I)的化合物,或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素,或其药物组合物。在一个实施方案中,瘙痒相关病状是荨麻疹、瘙痒症、特应性皮炎、皮肤干燥、银屑病、接触性皮炎或湿疹。在另一个实施方案中,提供了一种治疗患有炎症或自身免疫相关病状的受试者的方法,所述方法包括向受试者施用药学有效量的具有结构(I)的化合物,或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素,或其药物组合物。在一个实施方案中,炎症或自身免疫相关病状是窦炎、哮喘、酒渣鼻或子宫内膜异位。
在另一个实施方案中,提供了一种治疗患有疼痛相关病状的受试者的方法,所述方法包括向受试者施用药学有效量的具有结构(I)的化合物,或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素,或其药物组合物。在一个实施方案中,疼痛相关病状是慢性盆腔疼痛综合征、子宫内膜异位疼痛、纤维肌痛、偏头痛或术后疼痛。
化合物
如上详述,本公开提供了化合物,该化合物显示出作为MRGPR X2拮抗剂的显著活性。因此,一个实施方案提供了具有以下结构(I)的化合物:
或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素,其中:
R1为环烷基、芳基、杂环基、-(CH2)nQ、-CHQR或-CQ(R)2,其中Q是C1-6烷基、芳基、环烷基、杂环基、-OR、-CH2C(O)OR、-C(O)OR、-C(O)NHR、-OC(O)R、-CX3、-CX2H、-C(X)H2、-CN、-N(R)2、-N(R)C(O)R、-N(R)C(O)OR或-N(R)S(O)2R,并且其中R1和/或Q任选地被一个或多个Rq取代;
每个R独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、烷基氨基、-(CH2)nR’、X、芳基、环烷基、杂芳基或杂环基,或者两个R基团与其所附接的原子一起形成碳环或杂环,其中C1-6烷基任选地被X、卤代烷基或卤代烷氧基中的一者或多者取代;
每个Rq独立地为C1-6烷基、C2-6烯基、C2-6炔基、芳基、环烷基、杂芳基、杂环基、-OR、-O(CH2)nR、-OX3、-OX2H、-O(X)H2、-C(O)OR、-C(O)R、-OC(O)R、X、-CX3、-CX2H、-C(X)H2、-CN、-N(R)2、-N(R)C(O)R、-N(R)S(O)2R、S(O)2R、-B(OR)2、-C(H)Q’R或-(CH2)nQ’,其中Q’为C1-6烷基、芳基、环烷基、杂环基、OR’、-C(O)OR’、-OC(O)R’、X、-CX3、-CX2H、-C(X)H2、-CN、-N(R’)2、-N(R’)C(O)R’或-N(R’)S(O)2R’;
R2、R3、R4、R5和R6独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、芳基、环烷基、杂芳基、杂环基、-OR、-C(O)OR、-OC(O)R、X、-CX3、-CX2H、-C(X)H2、C(X)2R、-C(X)(R)2、-CN、-N(R)2、-N(R)C(O)R、-N(R)S(O)2R或S(O)2R;
每个Rx独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、芳基、环烷基、杂芳基、杂环基、-OR、-C(O)OR、-OC(O)R、X、-CX3、-CX2H、-C(X)H2、-CN、-N(R)2、-N(R)C(O)R、-N(R)S(O)2R或S(O)2R;
W为N或CRw;
Z为N或CRz;
Rw为H、C1-6烷基、C2-6烯基、C2-6炔基、芳基、环烷基、杂芳基或杂环基;
Rz为H、C1-6烷基、C2-6烯基、C2-6炔基、芳基、环烷基、杂芳基或杂环基;
每个R′独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、芳基、环烷基、杂芳基或杂环基;
每个X独立地为F、Cl、Br或I;并且
每个n独立地为0、1、2、3、4或5。
在另一个实施方案中,提供了式(Ia)的化合物:
或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素,其中:
R1a为环烷基、-(CH2)nQ、-CHQR或-CQ(R)2,
Q为环烷基、-OR、-C(O)OR、-OC(O)R、-CX3、-CX2H、-C(X)H2、-CN、-N(R)2、-N(R)C(O)R或-N(R)S(O)2R,并且
其中R1a和/或Q任选地被一个或多个Rq取代。
在一个实施方案中,R1a为环烷基。
在一些实施方案中,R1a和/或Q被一个或多个Rq取代。在其他实施方案中,取代基选自C1-6烷基、C2-6烯基、芳基、环烷基、杂环基、-OR、-O(CH2)nR、-OX3、-OX2H、-O(X)H2、-C(O)OR、-C(O)R、-OC(O)R、X、-CX3、-CX2H、-C(X)H2、-CN、-N(R)2、-N(R)C(O)R、-N(R)S(O)2R、S(O)2R、-C(H)Q’R或-(CH2)nQ’,其中Q’为C1-6烷基、芳基、环烷基、杂环基、OR’、-C(O)OR’、-OC(O)R’、X、-CX3、-CX2H、-C(X)H2、-CN、-N(R’)2、-N(R’)C(O)R’或-N(R’)S(O)2R’。在其他实施方案中,取代基为C1-6烷基、芳基、杂环基、-OR、-CN、-C(O)OR或-(CH2)nQ’。
在其他实施方案中,R4和R6独立地为C1-6烷基、C2-6烯基、C2-6炔基、OR、-C(O)OR、-OC(O)R、X、-CX3、-CX2H、-C(X)H2、-CN、-N(R)2、-N(R)C(O)R、-N(R)S(O)2R或S(O)2R。在一些实施方案中,R6为X、-CX3、-CX2H或-C(X)H2。在其他实施方案中,R6为-CF3、-CF2H或CFH2。
在一个实施方案中,Rx为H。
在另一个实施方案中,提供了式(Ia)的化合物,其中W为N并且Z为CH。在又一个实施方案中,提供了式(Ia)的化合物,其中W为CH并且Z为N。
在一个实施方案中,提供了式(Ib)的化合物:
或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素,其中:
R1b为芳基、-(CH2)nQ、-CHQR和-CQ(R)2,
其中Q为芳基、-OR、-C(O)OR、-OC(O)R、-CX3、-CX2H、-C(X)H2、-CN、-N(R)2、-N(R)C(O)R或-N(R)S(O)2R,并且
其中R1b和/或Q任选地被一个或多个Rq取代。
在一个实施方案中,R1b为芳基。在另一个实施方案中,R1b为苯基。
在一些实施方案中,R1b和/或Q被一个或多个Rq取代。在其他实施方案中,取代基选自C1-6烷基、C2-6烯基、芳基、环烷基、杂环基、-OR、-O(CH2)nR、-OX3、-OX2H、-O(X)H2、-C(O)OR、-C(O)R、-OC(O)R、X、-CX3、-CX2H、-C(X)H2、-CN、-N(R)2、-N(R)C(O)R、-N(R)S(O)2R、S(O)2R、-B(OR)2、-C(H)Q’R或-(CH2)nQ’,其中Q’为C1-6烷基、芳基、环烷基、杂环基、OR’、-C(O)OR’、-OC(O)R’、X、-CX3、-CX2H、-C(X)H2、-CN、-N(R’)2、-N(R’)C(O)R’或-N(R’)S(0)2R’。
在其他实施方案中,任选地被一个或多个Rq取代的R1b具有以下结构中的一者:
在其他实施方案中,R4和R6独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、芳基、环烷基、杂芳基、杂环基、-OR、-C(O)OR、-OC(O)R、X、-CX3、-CX2H、-C(X)H2、-CN、-N(R)2、-N(R)C(O)R、-N(R)S(O)2R或S(O)2R。在具体的实施方案中,R6为X、-CX3、-CX2H或-C(X)H2。
在一些实施方案中,R6为-CF3、-CF2H或CFH2。
在一个实施方案中,Rx为H。
在另一个实施方案中,提供了式(Ib)的化合物,其中W为N并且Z为CH。在又一个实施方案中,提供了式(Ib)的化合物,其中W为CH并且Z为N。
在一个实施方案中,提供了式(Ic)的化合物:
或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素,其中:
R1c为杂芳基、-(CH2)nQ、-CHQR或-CQ(R)2,
其中Q为杂环基、-OR、-C(O)OR、-OC(O)R、-CX3、-CX2H、-C(X)H2、-CN-N(R)2、-N(R)C(O)R或-N(R)S(O)2R,并且
其中R1c和/或Q任选地被一个或多个Rq取代。
在一个实施方案中,R1c为杂环基。
在另一个实施方案中,杂环基是含有3个或更多个环成员的芳族和非芳族环部分,其中一个或多个环成员是杂原子并且其中该杂原子选自N、O、S或P。
在一些实施方案中,R1c和/或Q被一个或多个Rq取代。
在其他实施方案中,取代基选自C1-6烷基、C2-6烯基、芳基、环烷基、杂环基、-OR、-O(CH2)nR、-OX3、-OX2H、-O(X)H2、-C(O)OR、-C(O)R、-OC(O)R、X、-CX3、-CX2H、-C(X)H2、-CN、-N(R)2、-N(R)C(O)R、-N(R)S(O)2R、S(O)2R、-C(H)Q’R或-(CH2)nQ’,其中Q’为C1-6烷基、芳基、环烷基、杂环基、OR’、-C(O)OR’、-OC(O)R’、X、-CX3、-CX2H、-C(X)H2、-CN、-N(R’)2、-N(R’)C(O)R’或-N(R’)S(O)2R’。
在一些实施方案中,任选地被一个或多个Rq取代的R1c具有以下结构中的一者:
在其他实施方案中,R4和R6在每次出现时独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、芳基、环烷基、杂芳基、杂环基、-OR、-C(O)OR、-OC(O)R、X、-CX3、-CX2H、-C(X)H2、-CN、-N(R)2、-N(R)C(O)R、-N(R)S(O)2R或S(O)2R。
在具体的实施方案中,R6为X、-CX3、-CX2H或-C(X)H2。在其他实施方案中,R6为-CF3、-CF2H或CFH2。
在一个实施方案中,Rx为H。
在另一个实施方案中,提供了式(Ic)的化合物,其中W为N并且Z为CH。在又一个实施方案中,提供了式(Ic)的化合物,其中W为CH并且Z为N。
在一个实施方案中,提供了式(Id)的化合物:
或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素,其中:
R1d为CQ(R)2,
其中Q为C1-6烷基、芳基、环烷基、杂环基、-OR、-CH2C(O)OR、-C(O)OR、-C(O)NHR、-OC(O)R、-CX3、-CX2H、-C(X)H2、-CN、-N(R)2、-N(R)C(O)R、-N(R)C(O)OR或-N(R)S(O)2R,并且
其中Rid和/或Q任选地被一个或多个Rq取代。
在具体的实施方案中,Q选自C1-6烷基、芳基、环烷基、杂环基和N(R)C(O)R。
在其他实施方案中,R独立地为C1-6烷基、C2-6烯基、C2-6炔基、烷基氨基、-(CH2)nR’、X、H、芳基、环烷基或杂环基。
在一个实施方案中,R6为X、-CX3、-CX2H或-C(X)H2。在其他实施方案中,R6为-CF3、-CF2H或CFH2。
在一个实施方案中,Rx为H。
在另一个实施方案中,提供了式(Id)的化合物,其中W为N并且Z为CH。在又一个实施方案中,提供了式(Id)的化合物,其中W为CH并且Z为N。
在一个实施方案中,提供了式(Ie)的化合物:
或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素,其中:
R1e为-CHQR,
其中Q为C1-6烷基、芳基、环烷基、杂环基、-OR、-CH2C(O)OR、-C(O)OR、-C(O)NHR、-OC(O)R、-CX3、-CX2H、-C(X)H2、-CN、-N(R)2、-N(R)C(O)R、-N(R)C(O)OR或-N(R)S(O)2R,并且
其中每个R1e和/或Q任选地被一个或多个Rq取代。
在具体的实施方案中,Q选自C1-6烷基、芳基、环烷基、杂环基、-N(R)C(O)R和-N(R)C(O)OR。
在其他实施方案中,R独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、烷基氨基、-(CH2)nR’、X、芳基、环烷基或杂环基。
在具体的实施方案中,R6为X、-CX3、-CX2H或-C(X)H2。在其他实施方案中,R6为-CF3、-CF2H或CFH2。
在一个实施方案中,Rx为H。
在另一个实施方案中,提供了式(Ie)的化合物,其中W为N并且Z为CH。在又一个实施方案中,提供了式(Ie)的化合物,其中W为CH并且Z为N。
在一个实施方案中,提供了式(If)的化合物:
或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素,其中:
RW或Rz独立地为C1-6烷基、C2-6烯基、C2-6炔基、H、芳基、环烷基、杂芳基或杂环基。
在具体的实施方案中,R6为X、-CX3、-CX2H或-C(X)H2。在其他实施方案中,R6为-CF3、-CF2H或CFH2。
在一个具体的实施方案中,Rw和Rz都为H。
在另一个实施方案中,Rx为H。
在一个实施方案中,化合物选自表I所列化合物中的任一者或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素。
表I.具有结构(I)的代表性化合物
在另一个实施方案中,在适用的情况下,结构(I)以及式(Ia)到(If)的代表性化合物包括但不限于下文以其IUPAC名称列出的化合物中的任一者,以及其药学上可接受的盐、异构体、水合物、溶剂化物或同位素。
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-甲磺酰胺基苯甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-(甲基氨基)苯甲酰胺;
3-乙磺酰胺基-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-(丙-2-磺酰胺基)苯甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吲哚-3-甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]咪唑并[1,2-a]吡啶-6-甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡咯并[2,3-b]吡啶-4-甲酰胺;
3-氟-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-甲磺酰基苯甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-(丙-2-磺酰基)苯甲酰胺;
3-氯-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-甲磺酰基苯甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-甲磺酰基-3-甲基苯甲酰胺;
2-氟-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-甲磺酰基苯甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-(1H-咪唑-1-基)苯甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-(吡咯烷-1-基)苯甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-(1H-1,2,3,4-四唑-1-基)苯甲酰胺;
4-氯-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
4-氰基-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
2-乙酰胺基-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]吡啶-4-甲酰胺;
3-(1-氰基乙基)-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-(甲基氨基)苯甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-羟基苯甲酰胺;
3-(二甲基氨基)-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-甲氧基苯甲酰胺;
2-氯-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-5-甲磺酰胺基苯甲酰胺;
2,6-二氟-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-(丙-1-磺酰胺基)苯甲酰胺;
1-乙基-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-(甲基氨基)苯甲酰胺;
2-氰基-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
2-氯-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-甲基苯甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-甲氧基苯甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2,6-二氟-3-(丙-2-磺酰胺基)苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2,6-二氟-3-甲磺酰胺基苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-乙磺酰胺基-2,6-二氟苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-氟-5-(丙-1-磺酰胺基)苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]吡唑并[1,5-a]吡啶-2-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-(1H-咪唑-1-基)苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-(1H-1,2,3,4-四唑-1-基)苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-氟苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-甲磺酰胺基苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-乙磺酰胺基苯甲酰胺;
3-羟基-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-(2-甲基丙酰胺基)苯甲酰胺;
3-甲磺酰胺基-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-(甲基氨基)苯甲酰胺;
3-(二甲基氨基)-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-氟-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-甲氧基-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-(甲基氨基)苯甲酰胺;
2-氯-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-甲磺酰基苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-乙基-1H-吡唑-5-甲酰胺;
2-氯-4-甲磺酰基-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
1-乙基-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-(甲基氨基)苯甲酰胺;
2-(1-甲基-1H-吲哚-3-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]乙酰胺;
2,6-二甲氧基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]嘧啶-4-甲酰胺;
N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1,2,3-噻二唑-4-甲酰胺;
N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
2-氰基-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
2-甲基-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
2-甲氧基-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
2-氯-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
2-氯-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-甲基苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-甲氧基苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-氰基苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-(丙-2-磺酰胺基)苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1,3-苯并噻唑-7-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]咪唑并[1,2-a]嘧啶-3-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-氟-1H-吲唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]咪唑并[1,2-a]吡啶-6-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吲哚-4-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2,3-二氧代-2,3-二氢-1H-吲哚-7-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4,5,6,7-四氢-1H-1,3-苯并二唑-5-甲酰胺;
4-氯-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-乙酰胺基吡啶-4-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-(1-氰基乙基)苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-(甲基氨基)苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-羟基苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-(二甲基氨基)苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-(吡咯烷-1-基)苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吲哚-3-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-氰基苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-甲氧基苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡咯并[2,3-b]吡啶-4-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-(甲基氨基)苯甲酰胺;
N-[(1R,3S)-3-[(6-氯-2-甲基喹啉-4-基)氨基]环己基]-4-甲氧基苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-甲磺酰胺基苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-(2-甲基丙酰胺基)苯甲酰胺;
3,3-二甲氧基-1-甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]环丁烷-1-甲酰胺;
3,4-二氯-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1,2-噻唑-5-甲酰胺;
6-甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-苯并噻吩-2-甲酰胺;
7-甲氧基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-3,4-二氢-2H-1-苯并吡喃-3-甲酰胺;
3-氯-2-碘-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
2-(2,3-二甲基苯基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]乙酰胺;
(1r,4r)-4-[(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)甲基]-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]环己烷-1-甲酰胺;
2-甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-4H-噻吩并[3,2-b]吡咯-5-甲酰胺;
2-氯-4-(4-甲基哌嗪-1-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-甲基-4-氧代-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-3H,4H-咪唑并[4,3-d][1,2,3,5]四嗪-8-甲酰胺;
3-(环丙基甲氧基)-4-(二氟甲氧基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
6-氟-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-3,4-二氢-2H-1-苯并吡喃-2-甲酰胺;
N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]吡唑并[1,5-a]吡啶-2-甲酰胺;
2,3-二氧代-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-2,3-二氢-1H-吲哚-7-甲酰胺;
1-苯基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡咯-2-甲酰胺;
3-甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-苯并呋喃-2-甲酰胺;
5-氯-2-甲氧基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]吡啶-4-甲酰胺;
N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1,3-苯并噻唑-7-甲酰胺;
3-(1-氰基乙基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
4-氟-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吲唑-5-甲酰胺;
4-(3-甲基-5-氧代-4,5-二氢-1H-吡唑-1-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
2-苯氧基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
2-(4-二氯苯基)-2-甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]丙酰胺;
1,3-二甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-噻吩并[2,3-c]吡唑-5-甲酰胺;
4-氟-3-(三氟甲氧基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-氯-1-(3-氯吡啶-2-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑-5-甲酰胺;
1-(吡啶-3-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑-4-甲酰胺;
4-氧代-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-4H-色烯-3-甲酰胺;
N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-3,4-二氢-2H-吡喃-6-甲酰胺;
2-甲基-4-(2-甲基苯甲酰胺)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
4-氟-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吲哚-3-甲酰胺;
3-(1H-1,2,4-三唑-1-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
(1R,4S)-4,7,7-三甲基-3-氧代-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-氧杂双环[2.2.1]庚烷-1-甲酰胺;
2-[(2,5-二氯苯基)甲酰胺基]-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]乙酰胺;
1-甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-4,5,6,7-四氢-1H-吲唑-3-甲酰胺;
2-甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-2H-吲唑-3-甲酰胺;
5-(呋喃-2-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1,2-噁唑-3-甲酰胺;
2-氯-4-甲磺酰基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
1-(2-氯苯甲酰基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]哌啶-4-甲酰胺;
N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1,6-萘啶-2-甲酰胺;
1-氰基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]环丙烷-1-甲酰胺;
5-氟-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-苯并呋喃-2-甲酰胺;
7-甲氧基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-苯并呋喃-2-甲酰胺;
2-(1,2-苯并噁唑-3-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]乙酰胺;
N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]咪唑并[1,2-a]嘧啶-3-甲酰胺;
N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-2H-1,3-苯并间二氧杂环戊烯-4-甲酰胺;
2-乙酰胺基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]吡啶-4-甲酰胺;
2-(3-氧代-3,4-二氢-2H-1,4-苯并噁嗪-4-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]乙酰胺;
6-氧代-2-苯基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-3,6-二氢嘧啶-4-甲酰胺;
6-氯-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]咪唑并[1,2-b]哒嗪-2-甲酰胺;
2-[5-甲基-3-(三氟甲基)-1H-吡唑-1-基]-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]乙酰胺;
N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡咯并[2,3-b]吡啶-4-甲酰胺;
N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-4,5,6,7-四氢-1-苯并噻吩-2-甲酰胺;
1-(4-甲基苯磺酰基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡咯-3-甲酰胺;
2-氧代-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-2,3-二氢吡啶-4-甲酰胺;
2-(噻吩-3-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]乙酰胺;
2-(吗啉-4-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]吡啶-4-甲酰胺;
2-(1H-吲哚-1-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]乙酰胺;
1-[5-(三氟甲基)吡啶-2-基]-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]哌啶-4-甲酰胺;
1-甲基-3-(2-甲基丙基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑-5-甲酰胺;
5-(2-氯苯基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑-3-甲酰胺;
5-(丙-2-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑-3-甲酰胺;
3-氯-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-苯并噻吩-2-甲酰胺;
3-叔丁基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-2H-吡唑并[3,4-b]吡啶-3-甲酰胺;
N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-4,5,6,7-四氢-1H-1,3-苯并二唑-6-甲酰胺;
3-(2-氟苯基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑-5-甲酰胺;
5-氟-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡咯并[2,3-b]吡啶-2-甲酰胺;
(2R)-2-(3-乙酰胺基丙酰胺基)-3-(1H-咪唑-5-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]丙酰胺;
2-(吡啶-4-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4基]氨基}环己基]-1H-1,3-苯并二唑-5-甲酰胺;
7-甲基-2-丙基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-1,3-苯并二唑-5-甲酰胺;
2-氯-6-氟-3-甲氧基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
(2S)-3-苯基-2-[(吡嗪-2-基)甲酰胺基]-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]丙酰胺;
3-(4-氯-3-氟苯基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]丙酰胺;
4-(4-乙基苯基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]丁酰胺;
1-(4-氯苯基)-5-甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑-4-甲酰胺;
5-(噻吩-2-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]吡啶-3-甲酰胺;
(1R,2R)-2-(2-氟苯基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]环丙烷-1-甲酰胺;
(2R,3R)-2-(2-甲氧基苯基)-5-氧代-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]氧戊环-3-甲酰胺;
5-氯-1-苯基-3-(三氟甲基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑-4-甲酰胺;
1-叔丁基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-1,2,3-三唑-4-甲酰胺;
1-[(4-氟苯基)甲基]-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吲哚-3-甲酰胺;
1-(3-氟苯基)-5-(三氟甲基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑-4-甲酰胺;
4-丁酰胺基-3-甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-(5-溴-2-氟苯基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]丙酰胺;
1-(2,4-二氯苯基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]环丁烷-1-甲酰胺;
N-[3-({[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]氨甲酰基}甲基)苯基]苯甲酰胺;
(3S)-3-甲基-3-{[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]氨甲酰基}丙酸叔丁酯;
3-{[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]氨甲酰基}丙酸苯酯;
N-(2,6-二氟苯基)-N′-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]乙二酰胺;
4-甲氧基-N-[(1R,3S)-3-{[3-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
N-[(1R,3S)-3-[(2-氰基喹啉-4-基)氨基]环己基]-4-甲氧基苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
N-[(1R,3S)-3-{[2-(二氟甲基)喹啉-4-基]氨基}环己基]-4-甲氧基苯甲酰胺;
4-甲氧基-N-[(1R,3S)-3-{[5-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
4-甲氧基-N-[(1R,3S)-3-{[7-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-(2-氧代吡咯烷-1-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
1-甲磺酰基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]哌啶-4-甲酰胺;
1-(3-甲氧基苯基)-5-氧代-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]吡咯烷-3-甲酰胺;
N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]咪唑并[1,2-a]吡嗪-2-甲酰胺;
2-(环丁基甲酰胺基)-2-甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]丙酰胺;
N-甲基-N-[(S)-苯基({[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]氨甲酰基})甲基]甲酸叔丁酯;
1-(2,2-二氟乙基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑-3-甲酰胺;
1-乙烯基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-氧杂双环[2.2.2]辛烷-4-甲酰胺;
2,6,6-三甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]双环[3.1.1]庚烷-3-甲酰胺;
1,4-二甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吲哚-2-甲酰胺;
3-甲基-4-氧代-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-3,4-二氢喹唑啉-7-甲酰胺;
5-(吡啶-3-基氧基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]呋喃-2-甲酰胺;
5-氧代-1-苯基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]吡咯烷-2-甲酰胺;
2-甲基-3-氧代-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-3,4-二氢-2H-1,4-苯并噁嗪-6-甲酰胺;
2-氧代-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H,2H,3H-吡啶并[2,3-b][1,4]噻嗪-7-甲酰胺;
6-(氧杂-4-基氧基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]吡啶-2-甲酰胺;
2-甲氧基-4-(三氟甲基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1,3-噻唑-5-甲酰胺;
6-(2-甲氧基苯基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]吡啶-3-甲酰胺;
5-(三氟甲基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡咯并[2,3-b]吡啶-3-甲酰胺;
4-甲基-2-(吡啶-2-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1,3-噻唑-5-甲酰胺;
2-氧代-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-2H-色烯-6-甲酰胺;
3,6-二氟-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]吡啶-2-甲酰胺;
1-乙基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑-5-甲酰胺;
1-{[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]氨甲酰基}环丁烷-1-甲酸乙酯;
2-苄基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-2,3-二氢-1H-异吲哚-4-甲酰胺;
3-(2-氯-6-氟苯基)-5-甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1,2-噁唑-4-甲酰胺;
1-[(4-甲氧基苯基)甲基]-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑-4-甲酰胺;
2,4-二氯-3-氰基-5-氟-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
5-苯甲酰基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-2,3-二氢-1H-吡咯嗪-1-甲酰胺;
2,6-二氟-3-(丙烷-1-磺胺)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
4-[(喹啉-2-基)甲氧基]-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
(3S,4R)-3-(噻吩-3-基)-4-{[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]氨甲酰基}吡咯烷-1-甲酸叔丁酯;
4-丙基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1,2,3-噻二唑-5-甲酰胺;
2-甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]吡唑并[1,5-a]嘧啶-6-甲酰胺;
3-{[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]氨甲酰基}-1-氧杂-2,7-二氮杂螺[4.5]癸-2-烯-7-甲酸叔丁酯;
7-(苄氧基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吲哚-3-甲酰胺;
4-(5-环丙基-1,2,4-噁二唑-3-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-[(4-甲氧基苯基)甲氧基]-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1,2-噁唑-5-甲酰胺;
5-氰基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吲唑-3-甲酰胺;
2-(5-甲氧基-2-甲基-1H-吲哚-3-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]乙酰胺;
2-[2-(二氟甲氧基)-6-氟苯基]-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]乙酰胺;
4-苄基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]吗啉-3-甲酰胺;
N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]咪唑并[1,5-a]吡啶-1-甲酰胺;
1-(吡嗪-2-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]环丙烷-1-甲酰胺;
2-(5-氰基-1-甲基-1H-吡咯-2-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]乙酰胺;
N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-4H,5H,6H,7H-吡唑并[1,5-a]吡啶-2-甲酰胺;
4-{[(1S,3R)-3-(4-甲氧基苯甲酰胺基)环己基]氨基}-2-(三氟甲基)喹啉-8-甲酸甲酯;
2,2-二甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]丙酰胺;
N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]丙酰胺;
3-苯基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]丙酰胺;
N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]环己烷甲酰胺;
2-甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]丙酰胺;
N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]环丙烷甲酰胺;
N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]吡啶-2-甲酰胺;
N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]吡啶-3-甲酰胺;
N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]吡啶-4-甲酰胺;
4-(吗啉-4-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
4-(甲基氨基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-(甲基氨基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
2-(甲基氨基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
6-(二甲基氨基)-2-甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]吡啶-3-甲酰胺;
N-[(1R,3S)-3-{[7-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-甲氧基苯甲酰胺;
N-[(1R,3S)-3-{[5-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-甲氧基苯甲酰胺;
N-[(1R,3S)-3-{[8-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-甲氧基苯甲酰胺;
N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
4-(二甲基氨基)-2-甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-氰基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-{[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]氨甲酰基}苯甲酸甲酯;
2-氰基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
4-氰基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
4-氯-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-氟-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
2-氟-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-甲氧基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
2-甲氧基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
2-甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
4-甲氧基-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-甲氧基苯甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-甲氧基苯甲酰胺;
4-甲氧基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
4-(4-甲基哌嗪-1-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
4-乙酰胺基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
4-{[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]氨甲酰基}苯甲酸甲酯;
4-乙基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
4-甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-乙酰胺基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-乙基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-氯-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
2-乙基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
2-(二甲基氨基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
2-氯-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
4-(二甲基氨基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-(二甲基氨基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
4-氟-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-氰基-N-((1R,3S)-3-((7-甲基-3-(三氟甲基)萘-1-基)氨基)环己基)苯甲酰胺;
N-((1R,3S)-3-((7-氯-3-(三氟甲基)萘-1-基)氨基)环己基)-3-氰基苯甲酰胺;
3-氰基-N-((1R,3S)-3-((7-氟-3-(三氟甲基)萘-1-基)氨基)环己基)苯甲酰胺;
(2E)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-(2,3,4-三甲氧基苯基)丙-2-烯酰胺;
1,3,5-三甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑-4-甲酰胺;
1,3-二乙基-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑-5-甲酰胺;
1-乙烯基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-氧杂双环[2.2.2]辛烷-4-甲酰胺;
1-乙基-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-甲基-1H-吡唑-5-甲酰胺;
1-乙基-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-甲基-1H-吡唑-5-甲酰胺;
1-乙基-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑-5-甲酰胺;
1-叔丁基-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑-5-甲酰胺;
2-(2H-1,2,3-三唑-2-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
2-(5-氯-1H-吲唑-3-基)-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]乙酰胺;
2-(环己基氧基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]乙酰胺;
2,6-二氟-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-(丙-2-磺酰胺基)苯甲酰胺;
2,6-二氟-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-甲磺酰胺基苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-羟基-3-甲基氮杂环丁烷-1-甲酰胺;
2-[4-(2,2-二氯环丙基)苯氧基]-2-甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]丙酰胺;
2-[5-氟-2-(三氟甲基)苯基]-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]乙酰胺;
2-{5-溴-1H-吡咯并[2,3-b]吡啶-3-基}-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]乙酰胺;
2-乙酰胺基-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]吡啶-4-甲酰胺;
2-乙酰胺基-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]吡啶-4-甲酰胺;
2-氨基-3-(1H-咪唑-4-基)-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]丙酰胺;
2-苄基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]丙-2-烯酰胺;
2-氯-4-碘-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]吡啶-3-甲酰胺;
2-氯-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
2-氯-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
2-氟-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-甲磺酰基苯甲酰胺;
2-氟-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-5-(丙-1-磺酰胺基)苯甲酰胺;
2-氟-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
2-亚氨基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1,3-噻唑烷-4-甲酰胺;
2-甲基-5-{[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]氨甲酰基}吡嗪-1-鎓-1-氧代高氯酸盐;
3-(1-氰基乙基)-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-乙酰胺基-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-乙酰胺基-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-溴-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-5-乙酰胺基苯甲酰胺;
3-氯-4-(丙-2-基氧基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-氯-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-氯-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-氰基-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-氰基-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-环丙基-1-乙基-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑-5-甲酰胺;
3-乙磺酰胺基-2,6-二氟-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-氟-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-甲磺酰胺基-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
3-甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1,2-噁唑-4-甲酰胺;
4-(1,1-二氧代-1λ6-硫代吗啉基-4-基)-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
4-(1H-咪唑-1-基)-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
4-(3-甲基-5-氧代-4,5-二氢-1H-吡唑-1-基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
4-(二甲基氨基)-N-[(1S,3R)-3-(4-甲氧基苯甲酰胺基)环己基]苯甲酰胺;
4-溴-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-氰基苯甲酰胺;
4-氯-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
4-氰基-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
4-氟-N-[(1R,3S)-3-{[2-(三氟甲基)喹唑啉-4-基]氨基}环己基]苯甲酰胺;
4-氟-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吲唑-5-甲酰胺;
4-氟-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
4-碘-1-甲基-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑-3-甲酰胺;
4-甲氧基-N-[(1R,3S)-3-[(萘-1-基)氨基]环己基]苯甲酰胺;
4-甲氧基-N-[(1R,3S)-3-{[2-(三氟甲基)喹唑啉-4-基]氨基}环己基]苯甲酰胺;
4-甲氧基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-5-基]氨基}环己基]苯甲酰胺;
4-甲氧基-N-[(1R,3S)-3-{[3-(三氟甲基)异喹啉-1-基]氨基}环己基]苯甲酰胺;
(2R,3R)-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-(羟甲基)-2-甲基吡咯烷-1-甲酰胺
4-甲氧基-N-[(1R,3S)-3-{[3-(三氟甲基)萘-1-基]氨基}环己基]苯甲酰胺;
4-甲氧基-N-[(1R,3S)-3-{[6-甲氧基-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
4-甲氧基-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
5-溴-2-(甲基磺酰基)-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]嘧啶-4-甲酰胺;
5-溴-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]咪唑并[1,2-a]吡啶-2-甲酰胺;
5-溴-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-氰基苯甲酰胺;
5-溴-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吲哚-7-甲酰胺;
5-氯-3-(二氟甲基)-1-甲基-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑-4-甲酰胺;
6-氯-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-2H-色烯-3-甲酰胺;
6-氯-N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]咪唑并[1,2-b]哒嗪-2-甲酰胺;
7-溴-2-甲基-N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]咪唑并[1,2-a]吡啶-3-甲酰胺;
5-{[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]氨甲酰基}-1-乙基-1H-吡唑-3-甲酸甲酯;
N-[(R)-{[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]氨甲酰基}(苯基)甲基]氨基甲酸甲酯;
N-[(1R,3R)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-甲氧基苯甲酰胺;
N-[(1R,3R)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-甲氧基苯甲酰胺;
N-[(1R,3S)-3-{[2-(二氟甲基)喹啉-4-基]氨基}环己基]-4-甲氧基苯甲酰胺;
N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H,4H,6H,7H-吡南并[4,3-c]吡唑-3-甲酰胺;
N-[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]呋喃-3-甲酰胺;
N-[(1R,3S)-3-{[3-氰基-6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-甲氧基苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-[1,2,4]三唑并[1,5-a]吡啶-6-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-[1,2,4]三唑并[4,3-a]吡啶-6-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-(2,2,2-三氟乙基)-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-(2,2-二氟乙基)-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-(2-氟乙基)-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-(2-甲基丙基)-1H-吡唑-5-甲酰胺;
5-氯-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-(2-氰基乙基)-1H-吡唑-4-甲酰胺;
4-(二甲基氨基)-N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-(二甲基氨基)-1,3-噻唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-[(2-氟乙基)氨基]嘧啶-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2,5-二甲基-1H-吡咯-3-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-乙基-1H-吡咯-3-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-氰基-1-(二氟甲基)-1H-吡唑-4-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-(二氟甲基)-1-(氟甲基)-1H-吡唑-4-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-(丙-2-基)-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1,3-苯并噻唑-4-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1,3-二乙基-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-环丁基-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-环己基-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-环戊基-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-环丙基-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-乙基-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-乙基-3-(丙-2-基)-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-乙基-3-(三氟甲基)-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-乙基-3-甲基-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-乙基-3-苯基-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-乙基-4-甲基-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吲哚-3-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吲哚-4-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑-3-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑-4-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑并[4,3-b]吡啶-7-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡咯并[2,3-b]吡啶-4-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-甲基-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-苯基-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-丙基-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-氰基-4-氟苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-乙基-4,5,6,7-四氢-2H-吲唑-3-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-氟-3-甲磺酰胺基苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-氟-5-(丙-1-磺酰胺基)苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-羟基吡啶-4-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-甲基咪唑并[1,2-a]吡啶-6-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-氧代-2H-色烯-6-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-(二氟甲磺酰胺基)苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-(N-甲基甲磺酰胺基)苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-(三氟甲磺酰胺基)苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3,5-二羟基苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-乙酰胺基-5-甲氧基苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-乙酰胺基苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-氰基苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-环丙基-1-乙基-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-甲磺酰胺基苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-甲磺酰胺基苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-甲基咪唑并[1,2-a]吡啶-6-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-(1,1-二氧代-1λ6-硫代吗啉基-4-基)苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-(甲基氨基)苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-(N-甲基甲磺酰胺基)苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-氟-3-甲磺酰胺基苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-6-甲基-1H-1,3-苯并二唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]咪唑并[1,2-a]吡啶-6-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]咪唑并[1,2-a]吡啶-7-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]咪唑并[1,2-a]嘧啶-6-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]咪唑并[1,5-a]吡啶-6-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]咪唑并[1,5-a]吡啶-7-甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-[1,2,4]三唑并[1,5-a]吡啶-6-甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-[1,2,4]三唑并[4,3-a]吡啶-6-甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-(2-甲基丙基)-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-(丙-2-基)-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1,3-苯并噻唑-7-甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-甲基-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-丙基-1H-吡唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2,3-二氧代-2,3-二氢-1H-吲哚-7-甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-甲基咪唑并[1,2-a]吡啶-6-甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-氧代-2,3-二氢吡啶-4-甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-氧代-2H-色烯-6-甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-(2-甲基丙酰胺基)苯甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3H,3aH-吡唑并[1,5-a]吡啶-2-甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-甲基咪唑并[1,2-a]吡啶-6-甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-(N-甲基甲磺酰胺基)苯甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4,5,6,7-四氢-1H-1,3-苯并二唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-甲磺酰基-3-甲基苯甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]咪唑并[1,2-a]吡啶-7-甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]咪唑并[1,2-a]嘧啶-3-甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]咪唑并[1,2-a]嘧啶-6-甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]咪唑并[1,5-a]吡啶-6-甲酰胺;
N-[(1R,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]咪唑并[1,5-a]吡啶-7-甲酰胺;
N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1,3-苯并噻唑-7-甲酰胺;
N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吲哚-3-甲酰胺;
N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吲哚-4-甲酰胺;
N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡咯并[2,3-b]吡啶-4-甲酰胺;
N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2,3-二氧代-2,3-二氢-1H-吲哚-7-甲酰胺;
N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-氧代-2,3-二氢吡啶-4-甲酰胺;
N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-[(三氟甲基)磺酰基]苯甲酰胺;
N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-(1H-1,2,3,4-四唑-1-基)苯甲酰胺;
N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-(甲基氨基)苯甲酰胺;
N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-(N-甲基甲磺酰胺基)苯甲酰胺;
N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-(吡咯烷-1-基)苯甲酰胺;
N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]咪唑并[1,2-a]吡啶-6-甲酰胺;
N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]咪唑并[1,2-a]嘧啶-3-甲酰胺;
N-[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]吡唑并[1,5-a]吡啶-2-甲酰胺;
N-[(1S,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-甲氧基苯甲酰胺;
N-[(1S,3S)-3-{[6-氟-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-甲氧基苯甲酰胺;
7-{[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]氨甲酰基}-1,2,3,4-四氢异喹啉-2-甲酸叔丁酯;
7-{[(1R,3S)-3-{[6-甲基-2-(三氟甲基)喹啉-4-基]氨基}环己基]氨甲酰基}-1,2,3,4-四氢异喹啉-2-甲酸叔丁酯;
N-[(1S)-2-(戊-4-烯-1-基氧基)-1-{[(1R,3S)-3-{[2-(三氟甲基)喹啉-4-基]氨基}环己基]氨甲酰基}乙基]氨基甲酸叔丁酯;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-(吗啉-4-羰基)苯甲酰胺;
6-氨基-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]吡啶-3-甲酰胺;
2-氨基-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]嘧啶-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]哌嗪-1-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-甲基哌嗪-1-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-(丙-2-基)哌嗪-1-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-(2-甲基丙酰基)哌嗪-1-甲酰胺;
4-氨基-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]哌啶-1-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]吡咯烷-1-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-(三氟甲基)-1H-吡咯-3-甲酰胺;
5-氯-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡咯-3-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-(2-氯乙基)-1H-吡唑-4-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-[1,2,4]三唑并[4,3-a]吡啶-7-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡唑并[4,3-c]吡啶-7-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-(二氟甲基)-1H-吡唑-4-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-(二氟甲基)-1H-吡唑-4-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-甲基-1H-吡唑-4-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1,3-二甲基-1H-吡唑-4-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1,3-二甲基-1H-吡唑-4-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-甲基-1-(丙-2-基)-1H-吡唑-4-甲酰胺;
(3S)-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-氟哌啶-1-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-6-甲基吡啶-3-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-6-甲基吡啶-3-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-(二氟甲基)-1-甲基-1H-吡唑-4-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-(二氟甲基)-1-甲基-1H-吡唑-4-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-5-环丙基-1H-吡唑-4-甲酰胺;
3-氯-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-(二氟甲基)-1H-吡唑-4-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-(氧杂环丁烷-3-基)-1H-吡唑-4-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-5-氰基-1H-吡咯-3-甲酰胺;
2-氨基-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]吡啶-3-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-氟-3-甲基氮杂环丁烷-1-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-[(二甲基氨基)]苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-6-氟吡啶-3-甲酰胺;
2-氯-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-甲基-1H-咪唑-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-甲氧基-3-(甲基氨基)苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3,3-二氟哌啶-1-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-6-甲氧基吡啶-3-甲酰胺;
4-(氮杂丙环烷-1-基)-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]苯甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-甲基-1H-吡咯-3-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1,4-二甲基-1H-吡咯-3-甲酰胺;
5-氨基-2-氯-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]吡啶-3-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-5-甲基呋喃-3-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-5-氮杂螺[2.3]己烷-5-甲酰胺;
6-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-5H,6H,7H-吡咯并[3,4-b]吡啶-7-酮;以及
N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-3-羟基-3-甲基氮杂环丁烷-1-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-氟-3-甲基氮杂环丁烷-1-甲酰胺;
3-氯-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-(2-氰基乙基)-1H-吡唑-4-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-(2-氟乙基)-1H-吡咯-3-甲酰胺;
5-氯-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-甲基-1H-吡咯-3-甲酰胺;
5-氯-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-(2,2-二氟乙基)-1H-吡咯-3-甲酰胺;
3-氯-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-甲磺酰基-1H-吡唑-4-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-(2-氟乙基)-2-甲基-1H-吡咯-3-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-(2-氟乙基)-5-甲基-1H-吡咯-3-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-(2,2-二氟乙基)-2-甲基-1H-吡咯-3-甲酰胺;
5-氯-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-乙基-1H-吡咯-3-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-(2,2-二氟乙基)-5-甲基-1H-吡咯-3-甲酰胺;
3-氯-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1-(氧杂环丁烷-3-基)-1H-吡唑-4-甲酰胺;
6-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-5H,6H,7H-吡咯并[3,4-b]吡啶-7-酮;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-甲基-4H,5H,6H,7H-[1,3]噻唑并[5,4-c]吡啶-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-2-甲基-4H,5H,6H,7H-[1,3]噻唑并[5,4-c]吡啶-5-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-(丙-2-基)哌嗪-1-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-4-甲基哌嗪-1-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-3-氟-3-甲基吡咯烷-1-甲酰胺;
N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-5-甲基噻吩-2-甲酰胺;
2-氯-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-1H-吡咯-3-甲酰胺;以及
(4-{[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]氨甲酰基}苯基)硼酸。
在某些实施方案中,本发明提供了一种药物组合物,该药物组合物包含结构(I)或式(Ia)到(If)中的任一者的化合物,或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素,以及至少一种药学上可接受的载体、稀释剂或赋形剂。例如,活性化合物通常与载体混合或由载体稀释或封装在载体中,所述载体可以呈安瓿、胶囊、小药囊、纸或其他容器的形式。当活性化合物与载体混合时,或当载体用作稀释剂时,所述载体可以是充当活性化合物的媒剂、赋形剂或介质的固体、半固体或液体材料。活性化合物可以吸附在粒状固体载体上,例如含在小药囊中。合适载体的一些示例是水、盐溶液、醇、聚乙二醇、聚羟基乙氧基化蓖麻油、花生油、橄榄油、明胶、乳糖、白土、蔗糖、糊精、碳酸镁、糖、环糊精、直链淀粉、硬脂酸镁、滑石粉、明胶、琼脂、果胶、阿拉伯胶、硬脂酸或纤维素的低级烷基醚、硅酸、脂肪酸、脂肪酸胺、脂肪酸单甘油酯和甘油二酯、季戊四醇脂肪酸酯、聚氧乙烯、羟甲基纤维素和聚乙烯吡咯烷酮。类似地,载体或稀释剂可以包含如单硬脂酸甘油酯或二硬脂酸甘油酯等本领域已知的任何缓释材料,其单独或与蜡混合。
如本文所使用的,术语″药物组合物″是指含有本文所描述的化合物中的一种或多种化合物或其药学上可接受的异构体、外消旋体、水合物、溶剂化物、同位素或盐,与药学上可接受的载体一起调配的组合物,其还可以包含其它添加剂,并经政府监管机构的批准制造或销售以作为治疗哺乳动物疾病的治疗方案的一部分。药物组合物可以配制成例如以单位剂型(例如,片剂、胶囊、囊片、软胶囊或糖浆)口服施用;局部施用(例如,作为霜膏、凝胶、洗剂或软膏);静脉内施用(例如,作为不合颗粒栓子的无菌溶液和在适于静脉内使用的溶剂体系中);向儿科受试者施用(例如,溶液、糖浆、混悬剂、酏剂、用于重构为混悬剂或溶液的粉末、可分散/泡腾片剂、咀嚼片剂、棒棒糖、冰棒、锭剂、口服薄条、口服崩解片、口服崩解条和喷洒口服粉末或粒剂);或以本文所述的任何其他制剂形式。用于选择和制备合适制剂的常规程序和成分描述于例如Remington:The S cience and Practice of Pharmacy,第21版,Gennaro编辑,Lippencott Williams&Wilkins(2005)和出版于2013年的The UnitedStates Pharmacopeia:The National Formulary(USP 36NF31)中。
在一些实施方案中,包含结构(I)或式(Ia)到(If)中的任一者的化合物,或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素,以及至少一种药学上可接受的载体、稀释剂或赋形剂的药物组合物还包含第二治疗剂。
在一个实施方案中,第二治疗剂是抗组胺,诸如H1受体拮抗剂或H2受体拮抗剂。在一个实施方案中,第二治疗剂是H1受体拮抗剂抗组胺,诸如左西替利嗪(levocetirizine)、氯雷他定(loratadine)、非索非那定(fexofenadine)、西替利嗪(cetirizine)、地氯雷他定(desloratadine)、奥洛他定(olopatadine)、苯海拉明(diphenhydramine)、赛庚啶(cyproheptadine)或双羟萘酸羟嗪(hydroxyzine pamoate)。在一个实施方案中,第二治疗剂是H2受体拮抗剂,诸如西咪替丁(cimetidine)、尼扎替丁(nizatidine)、雷尼替丁(ranitidine)或法莫替丁(famotidine)。在一个实施方案中,第二治疗剂是白三烯受体拮抗剂白三烯合成抑制剂,诸如孟鲁司特(montelukast)、扎鲁司特(zafirlukast)、普鲁司特(pranlukast)或5-脂氧合酶抑制剂(例如,齐留通(zileuton)、贯叶连翘(hypericumperforatum))。在一个实施方案中,第二治疗剂是免疫调节剂诸如奥马珠单抗(Omalizumab)或免疫球蛋白疗法。在一个实施方案中,第二治疗剂是皮质类固醇,诸如氢化可的松、可的松、ethamethasoneb、去炎松、泼尼松、泼尼松龙或氟氢可的松。在一个实施方案中,第二治疗剂是可以缓解瘙痒的三环抗抑郁剂,诸如多塞平(doxepin)、阿米替林(amitriptyline)或去甲替林(nortriptyline)。在一个实施方案中,第二治疗剂是抗炎药,诸如氨苯砜(dapsone)、柳氮磺胺吡啶、羟化氯喹或秋水仙碱。在一个实施方案中,第二治疗剂是免疫抑制剂,诸如环孢霉素、氨甲蝶呤、霉酚酸或他克莫司(tacromilus)。
在一个实施方案中,第二治疗剂是H1受体拮抗剂抗组胺,诸如左西替利嗪(levocetirizine)、氯雷他定(loratadine)、非索非那定(fexofenadine)、西替利嗪(cetirizine)、地氯雷他定(desloratadine)、奥洛他定(olopatadine)、苯海拉明(diphenhydramine)、赛庚啶(cyproheptadine)或双羟萘酸羟嗪(hydroxyzine pamoate)。在一个实施方案中,第二治疗剂是H2受体拮抗剂,诸如西咪替丁(cimetidine)、尼扎替丁(nizatidine)、雷尼替丁(ranitidine)或法莫替丁(famotidine)。在一个实施方案中,第二治疗剂是白三烯受体拮抗剂或白三烯合成抑制剂,诸如孟鲁司特(montelukast)、扎鲁司特(zafirlukast)、普鲁司特(pranlukast)或5-脂氧合酶抑制剂(例如,齐留通(zileuton)、贯叶连翘(hypericum perforatum))。在一个实施方案中,第二治疗剂是免疫调节剂诸如奥马珠单抗(Omalizumab)或免疫球蛋白疗法。在一个实施方案中,第二治疗剂是皮质类固醇,诸如氢化可的松、可的松、ethamethasoneb、去炎松、泼尼松、泼尼松龙或氟氢可的松。在一个实施方案中,第二治疗剂是可以缓解瘙痒的三环抗抑郁剂,诸如多塞平(doxepin)、阿米替林(amitriptyline)或去甲替林(nortriptyline)。在一个实施方案中,第二治疗剂是抗炎药,诸如氨苯砜(dapsone)、柳氮磺胺吡啶、羟化氯喹或秋水仙碱。在一个实施方案中,第二治疗剂是免疫抑制剂,诸如环孢霉素、氨甲蝶呤、霉酚酸或他克莫司(tacromilus)。
如本文所用,术语″药学上可接受的载体″是指除所公开的化合物或其药学上可接受的异构体、外消旋体、水合物、溶剂化物、同位素或盐(例如,能够悬浮或溶解活性化合物的载体)之外的并且具有对患者无毒和非炎性的性质的任何成分。赋形剂可以包含例如:抗粘剂、抗氧化剂、粘合剂、包衣、压缩助剂、崩解剂、染料(着色剂)、润肤剂、乳化剂、填充剂(稀释剂)、成膜剂或包衣、调味剂、香料、助流剂(流动增强剂)、润滑剂、防腐剂、印刷油墨、吸附剂、悬浮剂或分散剂、甜味剂或水合水。示例性赋形剂包括但不限于:丁基化羟基甲苯(BHT)、碳酸钙、磷酸钙(二元)、硬脂酸钙、交联羧甲基纤维素、交联聚乙烯吡咯烷酮、柠檬酸、交聚维酮、半胱氨酸、乙基纤维素、明胶、羟丙基纤维素、羟丙基甲基纤维素、乳糖、硬脂酸镁、麦芽糖醇、甘露醇、甲硫氨酸、甲基纤维素、对羟基苯甲酸甲酯、微晶纤维素、聚乙二醇、聚乙烯吡咯烷酮、聚维酮、预胶化淀粉、对羟基苯甲酸丙酯、棕榈酸视黄酯、虫胶、二氧化硅、羧甲基纤维素钠、柠檬酸钠、羧基乙酸淀粉钠、山梨糖醇、淀粉(玉米)、硬脂酸、硬脂酸、蔗糖、滑石粉、二氧化钛、维生素A、维生素E、维生素C和木糖醇。
调配物可以与不会与活性化合物发生有害反应的辅助试剂混合。此类添加剂可以包含润湿剂、乳化剂和悬浮剂、影响渗透压的盐、缓冲剂和/或着色物质、防腐剂、甜味剂或调味剂。如果期望的话,也可以对组合物进行灭菌。
施用途径可以是将本发明的活性化合物有效转运到适当或期望的作用部位的任何途径,如口腔、鼻腔、肺、颊、皮下、皮内、经皮或肠胃外,包含静脉内、皮下和/或肌肉。在一个实施方案中,施用途径是口服。在另一个实施方案中,施用途径是局部的。
剂型可以每天施用一次,或每天施用多于一次,如每天两次或三次。可替代地,如果处方医师或药物的处方信息认为是可取的,则剂型可以比每天更短的频率施用,如每隔一天或每周施用一次。给药方案包含例如将剂量滴定到要治疗的适应症所需或有用的程度,从而使患者的身体适应治疗,以最小化或避免与治疗相关联的不想要的副作用,和/或最大化本发明化合物的治疗效果。其他剂型包含延迟或控释形式。合适的剂量方案和/或形式包括例如在Physicians’Desk Reference的最新版中阐述的那些,其以引用方式并入本文。
用于儿科患者的恰当剂量可以使用已知方法确定,包括体重、年龄、体表面积和模型诸如儿科模拟建模(CERTARA,Princeton,N.J.),这些模型可用于建立考虑患者年龄、消除式(Ia)至(If)中的任一者的化合物的清除途径的个体发生和体表面积(BSA)进行给药的药代动力学方法。在一个实施方案中,配制剂型以提供为成人剂量的约30%至约100%,或成人剂量的约35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%或100%的儿科剂量。
在一个实施方案中,本发明提供了一种口服药物组合物,该口服药物组合物包含结构(I)或式(Ia)到(If)中的任一者的化合物,或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素,以及至少一种药学上可接受的口服载体、稀释剂或赋形剂。在另一个实施方案中,本发明提供了一种局部药物组合物,该局部药物组合物包含结构(I)或式(Ia)到(If)中的任一者的化合物,或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素,以及至少一种药学上可接受的局部载体、稀释剂或赋形剂。例如,提供口服药物组合物以治疗胆汁淤积性瘙痒症,其中给药方案是例如每天一次。在一个实施方案中,提供局部药物组合物以治疗特应性皮炎。
在另一个实施方案中,提供了制备本文所描述的化合物的组合物的方法,所述方法包含将本发明的化合物与药学上可接受的载体或稀释剂一起调配。在一些实施方案中,药学上可接受的载体或稀释剂适于口服施用。在一些此类实施方案中,方法可以进一步包含将组合物调配成片剂或胶囊的步骤。在其他实施方案中,药学上可接受的载体或稀释剂适于肠胃外施用。在一些此类实施方案中,方法进一步包含冻干组合物以形成冻干制剂的步骤。在一些实施方案中,将组合物配制成适于治疗儿科受试者的儿科剂型。
在某些实施方案中,本发明提供了一种具有结构(I)或式(Ia)到(If)中的任一者的化合物,或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素。此类化合物可以使用本领域技术人员已知的标准合成技术合成。例如,本发明的化合物可以使用以下实例和反应方案中阐述的适当修改的合成程序来合成。
为此,本文所描述的反应、过程和合成方法不限于以下实验部分中描述的特定条件,而是旨在作为对本领域的合适技术人员的指导。例如,反应可以在任何合适的溶剂或其他试剂中进行以进行必要的转化。通常,合适的溶剂是质子或非质子溶剂,其在反应进行的温度(即,可以在冷冻至沸腾温度范围内的温度)处基本上不与反应物、中间体或产物反应。给定的反应可以在一种溶剂或多于一种溶剂的混合物中进行。取决于具体的反应,可以采用用于反应后具体后处理的合适的溶剂。
实验部分未描述合成的所有试剂均可商购获得的,或者是已知化合物,或者可以由本领域技术人员通过已知方法由已知化合物形成。根据本发明的方法产生的化合物和中间体可能需要纯化。有机化合物的纯化是本领域技术人员众所周知的,并且可以有若干种方法来纯化相同的化合物。在一些情况下,可能不需要纯化。在一些情况下,化合物可以通过结晶来纯化。在一些情况下,可以使用合适的溶剂搅拌出杂质。在一些情况下,化合物可以通过色谱法,具体地快速柱色谱法,使用特制的或预装的硅胶柱和如溶剂梯度等洗脱液来纯化,所述溶剂如庚烷、乙醚、乙酸乙酯、乙腈、乙醇等。在一些情况下,可以使用如本文所描述的方法通过制备型HPLC来纯化化合物。
如本文所描述的纯化方法可以以盐的形式提供本发明的具有足够碱性或酸性官能性的化合物,如在本发明的化合物具有足够碱性的情况下,提供三氟乙酸盐或甲酸盐,或者在本发明的化合物具有足够酸性的情况下,提供铵盐。此类型的盐可以通过本领域技术人员已知的各种方法分别转化为其游离碱或游离酸形式,或者在随后的生物测定中用作盐。应当理解,如分离的和如本文所描述的本发明化合物的特定形式不一定是所述化合物可以用于生物测定以定量特定生物活性的唯一形式。
化学名称是使用珀金埃尔默信息有限公司(PerkinElmer Informatics,Inc)的ChemDraw命名软件(版本17.0.0.206)生成的。在一些情况下,使用普遍接受的可商购获得的试剂名称代替由命名软件生成的名称。
实施例
一般方法
1H NMR(400MHz)光谱是在氘代氯仿(CDCl3)、氘代甲醇(CD3OD)或二甲亚砜-D6(DMSO)溶液中获得的。使用以下方法之一获得HPLC保留时间、纯度和质谱(LCMS):
方法1:配备有Agilent Poroshell 120 EC-18,2.7μm,4.6×100mm柱的Agilent1260Infinity II系统在30℃处,使用含0.1%甲酸的H2O作为流动相A,并且使用含0.1%甲酸的MeCN作为流动相B。使用正模式下的ESI检测器。梯度在12分钟内为5%-95%流动相B,然后在95%下保持1.8分钟,然后在0.2分钟内返回到10%流动相B。流速为1mL/分钟。
方法2:配备有Kinetex EVO C18 2.1×30mm柱(5μm颗粒)的SHIMADZU LCMS-2020系统,使用含0.0375%三氟乙酸的H2O作为流动相A,并且使用含0.01875%三氟乙酸的MeCN作为流动相B。使用正模式下的ESI检测器。梯度为在0.00分钟5%B和在0.00分钟-0.80分钟5%-90%B,在0.80分钟-0.12分钟90%-95%B,然后在0.01分钟95%-5%B,5%B保持0.34分钟,流速为1.5ml/分钟。
方法3:配备有Kinetex C18 50*2.1mm柱(5μm颗粒)的Agilent 1200系统,使用含0.037%三氟乙酸的H2O作为流动相A,并且使用含0.018%三氟乙酸的MeCN作为流动相B。使用正模式下的ESI检测器。梯度为在0.00分钟5%B和在0.00分钟-0.80分钟5%-90%B,在0.80分钟-0.12分钟90%-95%B,然后在0.01分钟95%-5%B,5%B保持0.34分钟,流速为1.5ml/分钟。
方法4:配备有Kinetex EVO C18 2.1×30mm柱(5μm颗粒)的SHIMADZU LCMS-2020系统,使用含0.0375%三氟乙酸的H2O作为流动相A,并且使用含0.01875%三氟乙酸的MeCN作为流动相B。使用正模式下的ESI检测器。梯度为在0.00分钟5%B和在0.00分钟-0.80分钟5%-90%B,在0.80分钟-0.12分钟90%-95%B,然后在0.01分钟95%-5%B,5%B保持0.34分钟,流速为1.5ml/分钟。
方法5:配备有Xbridge Shield RP18 2.1*50mm柱(5μm颗粒)的Agilent 1200系统,使用含10mM NH4HCO3的H2O作为流动相A,并且使用MeCN作为流动相B。使用正模式下的ESI检测器。梯度为在0.30分钟内5%-95%B和在0.30分钟-0.80分钟内30%-95%B,95%B保持0.4分钟,然后在0.01分钟内95%-5%B,流速为1.5ml/分钟。
方法6:配备有Kinetex EVO C182.1×30mm柱(5μm颗粒)的SHIMADZU LCMS-2020系统,使用含0.0375%三氟乙酸的H2O作为流动相A,并且使用含0.01875%三氟乙酸的MeCN作为流动相B。使用正模式下的ESI检测器。梯度为在0.00分钟5%B和在0.00分钟-0.80分钟5%-90%B,在0.80分钟-0.12分钟90%-95%B,然后在0.01分钟95%-5%B,5%B保持0.34分钟,流速为1.5ml/分钟。
方法7:配备有Chromolith@Flash RP-18E 25-2mm柱的SHIMADZU LCMS-2020系统含0.0375%三氟乙酸的H2O作为流动相A,并且使用含0.01875%三氟乙酸的MeCN作为流动相B。使用正模式下的ESI检测器。梯度为在0.00分钟5%B和在0.00分钟-0.80分钟5%-90%B,在0.80分钟-0.12分钟90%-95%B,然后在0.01分钟95%-5%B,5%B保持0.34分钟,流速为1.5ml/分钟。
方法8:配备有Kinetex EVO C18 2.1×30mm柱(5μm颗粒)的SHIMADZU LCMS-2020系统,使用含0.0375%三氟乙酸的H2O作为流动相A,并且使用含0.01875%三氟乙酸的MeCN作为流动相B。使用正模式下的ESI检测器。梯度为在0.00分钟5%B和在0.00分钟-0.80分钟5%-90%B,在0.80分钟-0.12分钟90%-95%B,然后在0.01分钟95%-5%B,5%B保持0.34分钟,流速为1.5ml/分钟。
方法9:配备有Agilent Poroshell 120EC-18,2.7μm,4.61×100mm柱的Agilent1290Infinity II系统在35℃处,使用含0.1%甲酸的H2O作为流动相A,并且使用含0.1%甲酸的MeCN作为流动相B。使用正模式下的ESI检测器。梯度在8.0分钟内为5%-95%流动相B,然后在95%下保持1.8分钟,然后在0.2分钟内返回到20%流动相B。流速为0.7mL/分钟。
方法10:配备有Agilent Poroshell 120 EC-18,2.7μm,4.6×100mm柱的Agilent1260Infinity II系统在30℃处,使用含0.1%甲酸的H2O作为流动相A,并且使用含0.1%甲酸的MeCN作为流动相B。使用正模式下的ESI检测器。梯度在5分钟内为5%-95%流动相B,然后在95%下保持1.8分钟,然后在0.2分钟内返回到20%流动相B。流速为1mL/分钟。
方法11:配备有Agilent Poroshell 120 EC-18,1.9μm,2.1×50mm柱的Agilent1290 Infinity II系统在35℃处,使用含0.1%甲酸的H2O作为流动相A,并且使用含0.1%甲酸的MeCN作为流动相B。使用正模式下的ESI检测器。梯度在0.8分钟内为20%-95%流动相B,然后在95%下保持0.7分钟,然后在0.7分钟内返回到20%流动相B。流速为0.7mL/分钟。
在程序中使用的吡啶、二氯甲烷(DCM)、四氢呋喃(THF)和甲苯来自在氮气(N2)下保存的A1drich Sure-Seal瓶。其他溶剂按原样使用。所有反应均用磁力搅拌,并且温度为外部反应温度。色谱法通常使用配备有Redisep(Teledyne Isco)Rf金正相硅胶(SiO2)柱的Combiflash Rf快速纯化系统(Teledyne Isco)或通过使用类似系统来进行。
制备型HPLC纯化通常使用下列系统之一进行:1)配备有Waters 2489uv/vis检测器、Aquity QDA检测器、Waters xBridge Prep C 185μm OBD、30×150mm柱并且用各种梯度的H2O/MeCN(0.1%甲酸)以30mL/分钟流速洗脱的Waters系统,2)配备有Waters xBridgePrep C18 5μm OBD、30×150mm柱并且用各种梯度的H2O/MeCN(0.1%甲酸)以42.5mL/分钟流速洗脱的Teledyne IscoHP150UV系统,或3)柱:Phenomenex SynergiC18150×30mm-4μm;流动相:[H2O(0.225%甲酸)-MeCN];B%:55%-85%,12分钟)并且通常使用Genevac EZ-2浓缩。
使用了以下另外的缩写:乙酸乙酯(EA)、三乙胺(TEA)、水(H2O)、氯化钠(NaCl)、盐酸(HCl)、甲醇(MeOH)、二甲亚砜(DMSO)、硅胶(SiO2)、二异丁基氢化铝(DIBAL)、三氟乙酸(TFA)、4-二甲基氨基吡啶(DMAP)、叠氮磷酸二苯酯(DPPA)、过氧化苯甲酰(BPO)、1,1′-双(二苯基膦基)二茂铁(dppf)、双(频哪醇合)二硼(B2pin2)、四氢呋喃(THF)、1,4-二氮杂二环[2.2.2]辛烷双(二氧化硫)加合物(DABSO)、六氟磷酸氮杂苯并三唑四甲基脲(HATU)、羟基苯并三唑(HOBt)、N-甲基吗啉(NMM)、N-溴代琥珀酰亚胺(NBS)、二异丙基乙胺(DIPEA或DIEA)、偶氮二甲酸二乙酯(DEAD)、偶氮二甲酸二异丙酯(DIAD)、2-[2-(二环己基膦基)苯基]-N-甲基吲哚(CM-Phos)、三氟甲磺酸(TfOH)、1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC)、异丙醇(IPA)、二甲基甲酰胺(DMF)、二甲基乙酰胺(DMA)、二氯甲烷(DCM)、1,2-二氯乙烷(DCE)、乙腈(MeCN或ACN)、1,1′-硫代羰基二咪唑(TCDI)、石油醚(PE)、未测定(ND)、保留时间(RT)、分子量(mw)、室温(rt)、小时(h)和不适用(N/A)。
方案1
试剂:步骤1-1.R1COCl、碱(DIPEA)、溶剂(DCM);步骤1-2.HCl、溶剂(1,4-二噁烷);步骤1-3.R2X、碱(DIPEA)、溶剂(DMSO、NMP),加热
实施例1
实施例1的合成
步骤1-1.((1S,3R)-3-(4-甲氧基苯甲酰胺基)环己基)氨基甲酸叔丁酯的合成
向(1S,3R)-3-氨基-1-(Boc-氨基)环己烷(1.142g,1.0当量,5.329mmol)在DCM(30mL)中的搅拌冰冷溶液中添加DIPEA(1.377g,1.9mL,2.0当量,10.66mmol),随后缓慢添加4-甲氧基苯甲酰氯(954.5mg,758μL,1.05当量,5.595mmol)。将所得混合物在室温处搅拌。搅拌18小时后,过滤反应混合物,并将滤饼用DCM洗涤并在高真空下干燥,得到((1S,3R)-3-(4-甲氧基苯甲酰胺基)环己基)氨基甲酸叔丁酯(1.659g,4.761mmol,89.35%收率)。
LCMS-ESI(m/z)计算值为:348.44,实测值为:349.2[M+H]+,RT=4.239分钟(方法10)。
1H NMR(400MHz,DMSO-d6)δ8.09(d,J=7.9Hz,1H),7.82(d,J=8.4Hz,2H),6.97(d,J=8.4Hz,2H),6.83(d,J=8.1Hz,1H),3.80(s,3H),3.79-3.71(m,1H),3.31-3.22(m,1H),1.93(d,J=12.0Hz,1H),1.77-1.68(m,3H),1.38(s,9H),1.31-1.17(m,3H),1.11-1.01(m,1H)。
步骤1-2.N-((1R,3S)-3-氨基环己基)-4-甲氧基苯甲酰胺的合成
向((1S,3R)-3-(4-甲氧基苯甲酰胺基)环己基)氨基甲酸叔丁酯(1.654g,1当量,4.747mmol)在EtOH(40mL)中的搅拌悬浮液中添加1.25M氯化氢的1,4-二噁烷(1.731g,37.97mL,1.25摩尔,10当量,47.47mmol)。将所得混合物在50℃处搅拌17小时。将反应混合物直接浓缩,得到白色固体,将其在高真空下进一步干燥,得到N-((1R,3S)-3-氨基环己基)-4-甲氧基苯甲酰胺盐酸盐(1.331g,4.674mmol,98.46%)。其用于下一步骤,无需进一步纯化。
LCMS-ESI(m/z)计算值为:248.44,实测值为:249.2[M+H]+,RT=1.665分钟(方法10)。
1H NMR(400MHz,DMSO-d6)δ8.26(d,J=7.9Hz,1H),8.09(s,3H),7.84(d,J=8.4Hz,2H),6.98(d,J=8.4Hz,2H),3.91-3.81(m,1H),3.80(s,3H),3.13-3.05(m,1H),2.12(d,J=11.6Hz,1H),1.91(d,J=12.0Hz,1H),1.78(d,J=12.0Hz,2H),1.44-1.21(m,4H)。
步骤1-3.N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-4-甲氧
基苯甲酰胺(实施例1)的合成
将DIPEA(0.11g,0.15mL,4.0当量,0.84mmol)装入含有4,6-二氯-2-(三氟甲基)喹啉(56mg,1.0当量,0.21mmol)和N-((1R,3S)-3-氨基环己基)-4-甲氧基苯甲酰胺盐酸盐(60mg,1.0当量,0.21mmol)在DMSO(2mL)中的溶液的压力小瓶中。将小瓶封闭,并将所得溶液在130℃处搅拌。搅拌20小时后,将反应混合物冷却至室温。过滤反应混合物,并将滤液通过制备型HPLC(ISCO ACCQPrep 150)纯化,得到N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-4-甲氧基苯甲酰胺(20mg,42μmol,20%收率)。
LCMS-ESI(m/z)计算值为:477.91,实测值为:478.2[M+H]+,RT=7.477分钟(方法9)。
1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),8.18(d,J=7.9Hz,1H),7.89(d,J=9.0Hz,1H),7.83(d,J=8.5Hz,2H),7.74(dd,J=9.0,2.1Hz,1H),7.50(d,J=8.0Hz,1H),7.01-6.89(m,3H),4.07-3.98(m,1H),3.92-3.84(m,1H),3.80(s,3H),2.16(d,J=11.9Hz,1H),1.97(d,J=12.3Hz,1H),1.91-1.78(m,2H),1.60-1.47(m,2H),1.44-1.29(m,2H)。
实施例2
实施例2的合成
步骤1-1.((1S,3R)-3-苯甲酰胺基环己基)氨基甲酸叔丁酯的合成
向(1S,3R)-3-氨基-1-(Boc-氨基)环己烷(1.238g,1当量,5.777mmol)在DCM(30mL)中的冰冷溶液中添加DIPEA(1.493g,2.0mL,2当量,11.55mmol),随后添加苯甲酰氯(852.6mg,704.1μL,1.05当量,6.066mmol)。将所得混合物在室温处搅拌1小时。过滤反应混合物,并将滤饼用DCM洗涤并在高真空下干燥,得到((1S,3R)-3-苯甲酰胺基环己基)氨基甲酸叔丁基酯(1.575g,4.946mmol,85.63%收率)。
LCMS-ESI(m/z)计算值为:318.30,实测值为:319.2[M+H]+,RT=4.237分钟(方法10)。
1H NMR(400MHz,DMSO-d6)δ8.26(d,J=7.9Hz,1H),7.83(d,J=7.5Hz,2H),7.53-7.42(m,3H),6.84(d,J=8.0Hz,1H),3.84-3.74(m,1H),3.31-3.23(m,1H),1.95(d,J=12.0Hz,1H),1.79-1.68(m,3H),1.38(s,9H),1.31-1.17(m,3H),1.11-1.02(m,1H)。
步骤1-2.N-((1R,3S)-3-氨基环己基)苯甲酰胺盐酸盐的合成
向((1S,3R)-3-苯甲酰胺基环己基)-氨基甲酸叔丁酯(1.570g,1当量,4.931mmol)在1,4-二噁烷(35mL)中的搅拌白色悬浮液中添加4M氯化氢的1,4-二噁烷(10当量,49.31mmol)。将所得混合物在50℃处搅拌19小时。将反应混合物直接浓缩,在高真空下干燥,得到N-((1R,3S)-3-氨基环己基)苯甲酰胺盐酸盐(1.201g,4.714mmol,95.61%收率)。
LCMS-ESI(m/z)计算值为:218.30,实测值为:219.2[M+H]+,RT=0.261分钟(方法11)。
1H NMR(400MHz,DMSO-d6)δ8.42(d,J=7.9Hz,1H),8.11(s,3H),7.85(d,J=7.5Hz,2H),7.55-7.41(m,3H),3.93-3.80(m,1H),3.18-3.04(m,1H),2.14(d,J=11.8Hz,1H),1.92(d,J=12.0Hz,1H),1.79(d,J=11.4Hz,2H),1.48-1.20(m,4H)。
步骤1-3.N-((1R,3S)-3-((2-(三氟甲基)喹啉-4-基)氨基)环己基)苯甲酰胺(实
施例2)的合成
向4-氯-2-(三氟甲基)喹啉(55mg,1当量,0.24mmol)和N-((1R,3S)-3-氨基环己基)苯甲酰胺盐酸盐(60mg,1当量,0.24mmol)在DMSO(2mL)中的溶液中添加DIPEA(0.12g,0.16mL,4当量,0.94mmol)。将小瓶加盖,并将所得溶液在130℃处搅拌18小时。将反应混合物冷却至室温,通过注射器式过滤器,并将滤液通过制备型HPLC(ISCO ACCQPrep 150)纯化,得到N-((1R,3S)-3-((2-(三氟甲基)喹啉-4-基)氨基)环己基)苯甲酰胺(13.4mg,32.4μmol,14%收率)。
LCMS-ESI(m/z)计算值为:413.44,实测值为:414.3[M+H]+,RT=5.687分钟(方法9)。
1H NMR(400MHz,DMSO-d6)δ8.42(d,J=8.5Hz,1H),8.34(d,J=7.9Hz,1H),7.92-7.80(m,3H),7.73(t,J=7.6Hz,1H),7.58-7.37(m,5H),6.90(s,1H),4.10-3.99(m,1H),3.93-3.82(m,1H),2.19(d,J=12.0Hz,1H),2.01-1.80(m,3H),1.56(q,J=12.1Hz,2H),1.46-1.29(m,2H)。
实施例3
实施例3的合成
步骤1-1.N-[(1S,3R)-3-[(4-氟苯甲酰基)氨基]环己基]氨基甲酸叔丁酯的合成
在0℃处,向N-[(1S,3R)-3-氨基环己基]氨基甲酸叔丁酯(0.8g,3.73mmol,1当量)和TEA(566.62mg,5.60mmol,779.39μL,1.5当量)在DCM(5mL)中的溶液中添加4-氟苯甲酰氯(591.90mg,3.73mmol,448.41μL,1当量)。将所得混合物在0℃处搅拌1小时。将反应混合物用H2O(50mL)和EA(50mL)稀释。过滤混合物,将滤饼减压浓缩,得到粗产物。将滤液用EA(50mL×2)萃取。将合并的有机层用饱和NaCl水溶液(50mL×3)洗涤,经无水Na2SO4干燥,过滤并减压浓缩,得到粗产物。粗产物即用于下一步骤,无需进一步纯化。得到化合物N-[(1S,3R)-3-[(4-氟苯甲酰基)氨基]环己基]氨基甲酸叔丁酯(1.26g,粗产物)。
LCMS-ESI(m/z)计算值为:336.40,实测值为:237.2[M+H-Boc]+,RT=0.9分钟(方法2)。
1H NMR(400MHz,DMSO-d6)δ=8.30(d,J=8.0Hz,1H),7.92-7.88(m,2H),7.30-7.24(m,2H),6.85(d,J=8.0Hz,1H),3.81-3.73(m,1H),3.27-3.28(m,1H),1.95(d,J=11.2Hz,1H),1.78-1.71(m,3H),1.37(s,9H),1.31-1.02(m,4H)。
步骤1-2.N-[(1R,3S)-3-氨基环己基]-4-氟-苯甲酰胺的合成
在25℃处,将N-[(1S,3R)-3-[(4-氟苯甲酰基)氨基]环己基]氨基甲酸叔丁酯(1.16g,3.45mmol,1当量)添加到HCl/MeOH(4M,15mL,17.40当量)中。将混合物在25℃处搅拌1小时。将反应混合物减压浓缩,得到残余物。将残余物溶解在MeOH(50mL)中,然后添加树脂(碱),过滤,以去除不溶性颗粒。将滤液减压浓缩,得到粗产物。粗产物即用于下一步骤,无需进一步纯化。得到化合物N-[(1R,3S)-3-氨基环己基]-4-氟-苯甲酰胺(0.81g,3.43mmol,99.41%收率)。
1H NMR(400MHz,DMSO-d6)δ=8.52-8.46(m,1H),7.96-7.92(m,2H),7.30-7.25(m,2H),3.85-3.83(m,1H),3.06-3.01(m,1H),2.14(d,J=10.8Hz,1H),1.93(d,J=11.2Hz,1H),1.78-1.76(m,2H),1.49-1.26(m,4H)。
步骤1-3. 4-氟-N-[(1R,3S)-3-[[2-(三氟甲基)喹唑啉-4-基]氨基]环己基]苯甲
酰胺(实施例3)的合成
将4-氯-2-(二氟甲基)喹啉(80mg,343.95μmol,1当量)、N-[(1R,3S)-3-氨基环己基]-4-氟苯甲酰胺(162.54mg,687.91μmol,2当量)和DIEA(222.27mg,1.72mmol,299.55μL,5当量)在DMSO(2mL)中的混合物在120℃处搅拌1小时。过滤反应混合物。将滤液通过制备型HPLC(柱:Unisil 3-100C18 Ultra 150*50mm*3μm;流动相:[水(0.225%FA)-ACN];B%:50%-70%,10分钟)纯化,并冻干。得到化合物4-氟-N-[(1R,3S)-3-[[2-(三氟甲基)-喹唑啉-4-基]氨基]环己基]苯甲酰胺(59.5mg,137.60μmol,40.01%收率)。
LCMS-ESI(m/z)计算值为:432.4,实测值为:433.2[M+H-Boc]+,RT=0.941分钟(方法2)。
1H NMR(400MHz,DMSO-d6)δ=8.54(d,J=8.0Hz,1H),8.45-8.38(m,2H),7.93-7.81(m,4H),7.69-7.65(m,1H),7.31-7.25(m,2H),4.34-4.29(m,1H),4.00-3.89(m,1H),2.19(d,J=11.6Hz,1H),1.99-1.85(m,3H),1.62-1.30(m,4H)。
实施例4
实施例4的合成
步骤1-3. 4-甲氧基-N-[(1R,3S)-3-[[5-甲基-2-(三氟甲基)-4-喹啉基]氨基]环
己基]苯甲酰胺的合成
将4-氯-5-甲基-2-(三氟甲基)喹啉(120mg,488.54μmol,1当量)、N-[(1R,3S)-3-氨基环己基]-4-甲氧基-苯甲酰胺(170mg,684.60μmol,1.4当量)和DIEA(189.42mg,1.47mmol,255.28μL,3当量)在NMP(1mL)中的混合物在120℃处搅拌16小时。将混合物冷却至室温,过滤并浓缩。将滤液通过制备型HPLC(柱:Phenomenex luna C18 150*25mm*10μm;流动相:[水(0.225%FA)-ACN];B%:32%-62%,10分钟)并冻干,得到化合物4-甲氧基-N-[(1R,3S)-3-[[5-甲基-2-(三氟甲基)-4-喹啉基]氨基]环己基]苯甲酰胺(8.7mg,19μmol,4%收率)。
LCMS-ESI(m/z)计算值为:457.5,实测值为:458.1[M+H]+,RT=0.846分钟(方法8)。
1H NMR(400MHz,DMSO-d6)δ=8.44-8.38(m,1H),8.18(br d,J=7.6Hz,1H),7.84(d,J=8.9Hz,2H),7.70(d,J=8.1Hz,1H),7.58-7.51(m,1H),7.28(d,J=7.0Hz,1H),6.97(d,J=8.9Hz,2H),6.90-6.85(m,1H),6.31(br d,J=7.5Hz,1H),4.06-3.95(m,1H),3.85-3.75(m,4H),2.96-2.90(m,3H),2.32-2.24(m,1H),2.11-2.03(m,1H),1.89(br d,J=10.8Hz,1H),1.81(br d,J=13.1Hz,1H),1.61-1.45(m,2H),1.39-1.26(m,2H)。
实施例5
实施例5的合成
4-氯-7-甲基-2-(三氟甲基)喹啉的合成
将7-甲基-2-(三氟甲基)喹啉-4-醇(150mg,660.26μmol,1当量)和POCl3(2.02g,13.21mmol,1.23mL,20当量)在ACN(1mL)中的混合物在90℃处搅拌2小时。将混合物冷却至20℃并缓慢倒入水(20mL)中,用EtOAc(20mL)萃取,收集有机层并减压浓缩。粗产物(150mg)直接用于下一步骤,无需纯化。
LCMS-ESI(m/z)计算值为:245.6,实测值为:246.0[M+H]+,RT=1.018分钟(方法2)。
步骤1-2. 4-甲氧基-N-[(1R,3S)-3-[[7-甲基-2-(三氟甲基)-4-喹啉基]氨基]环
己基]苯甲酰胺的合成
将4-氯-7-甲基-2-(三氟甲基)喹啉(150mg,610.68μmol,1当量)、N-[(1R,3S)-3-氨基环己基]-4-甲氧基-苯甲酰胺(227mg,914.14μmol,1.5当量)和DIEA(236.77mg,1.83mmol,319.10μL,3当量)在NMP(0.5mL)中的混合物在120℃处搅拌16小时。将混合物冷却至室温,过滤并浓缩。将滤液通过制备型HPLC(柱:Phenomenex luna C18 150*25mm*10μm;流动相:[水(0.225%FA)-ACN];B%:32%-62%,10分钟)纯化,并冻干,得到4-甲氧基-N-[(1R,3S)-3-[[7-甲基-2-(三氟甲基)-4-喹啉基]氨基]环己基]苯甲酰胺(23.51mg,50.71μmol)。
LCMS-ESI(m/z)计算值为:457.49,实测值为:458.1[M+H]+,RT=0.818分钟(方法2)。
1H NMR(400MHz,DMSO-d6)δ=8.31(d,J=8.8Hz,1H),8.21-8.13(m,1H),7.83(d,J=8.8Hz,2H),7.67(s,1H),7.39(dd,J=1.3,8.7Hz,1H),7.31(d,J=8.1Hz,1H),6.97(d,J=8.8Hz,2H),6.82(s,1H),4.07-3.96(m,1H),3.80(s,4H),2.47(s,3H),2.20-2.12(m,1H),2.00-1.93(m,1H),1.91-1.78(m,2H),1.61-1.47(m,2H),1.45-1.27(m,2H)。
实施例6
实施例6的合成
步骤1-1:N-[(1R,3S)-3-[[8-溴-2-(三氟甲基-4-喹啉基]氨基]环己基]-4-甲氧
基-苯甲酰胺的合成
向8-溴-4-氯-2-(三氟甲基)喹啉(60mg,193.24μmol,1当量)的DMSO(1mL)溶液中添加N[(1R,3S)-3-氨基环己基]-4-甲氧基-苯甲酰胺(52.78mg,212.56μmol,1.1当量)和DIEA(49.95mg,386.48μmol,67.32μL,2当量)。将混合物在125℃处搅拌12小时。向反应混合物中添加水(20mL),并用EA(20mL×2)萃取。将有机层用盐水洗涤,用Na2SO4干燥。将溶液浓缩,得到残余物。将残余物通过制备型TLC(SiO2,PE∶EA=2∶1)纯化,得到N-[(1R,3S)-3-[[8-溴-2-(三氟甲基)-4-喹啉基]氨基]环己基]-4-甲氧基-苯甲酰胺(60mg,114.86μmol,59%收率)。
LCMS-ESI(m/z)计算值为:522.6,实测值为:522.1/524.1[M+H]+,RT=0.977分钟(方法2)。
步骤1-2:4-[[(1S,3R)-3-[(4-甲氢基苯甲酰基)氨基]环己基]氨基]-2-(三氟甲
基)喹啉-8-羧酸酯的合成
在25℃处,向N-[(1R,3S)-3-[[8-溴-2-(三氟甲基)-4-喹啉基]氨基]环己基]-4-甲氧基-苯甲酰胺(60mg,114.86μmol,1当量)、Et3N(34.87mg,344.59μmol,47.96μL,3当量)在MeOH(10mL)中的溶液中添加Pd(dppf)Cl2.CH2Cl2(9.38mg,11.49μmol,0.1当量)。将悬浮液真空脱气并用CO吹扫数次。然后升温至70℃,并在CO(50psi)气氛下搅拌16小时。在25℃处,向反应混合物中添加Et3N(34.87mg,344.59μmol,47.96μL,3当量)和Pd(dppf)Cl2.CH2Cl2(28.14mg,34.46μmol,0.3当量)。将悬浮液真空脱气并用CO吹扫数次。然后升温至70℃,并在CO(50psi)气氛下搅拌16小时。向反应混合物中添加硫脲(树脂)(1g)并在20℃处搅拌2小时。然后将混合物过滤。将滤饼用MeOH(10mL×3)洗涤。将滤液浓缩,得到残余物,将其通过制备型HPLC(柱:Phenomenex luna C18 150*25mm*10μm;流动相:[水(0.225%FA)-ACN];B%:35%-65%,10分钟)纯化。将纯化的溶液冻干,得到4-[[(1S,3R)-3-[(4-甲氧基苯甲酰基)氨基]环己基]氨基]-2-(三氟甲基)喹啉-8-甲酸甲酯(7.4mg,14.8μmol,13%收率)。
LCMS-ESI(m/z)计算值为:501.5,实测值为:502.3[M+H]+,RT=0.980分钟(方法2)。
1H NMR(400MHz,DMSO)δ=8.56(d,J=7.6Hz,1H),8.18(d,J=7.8Hz,1H),7.89-7.80(m,3H),7.59(dd,J=7.2,8.4Hz,1H),7.53(d,J=8.2Hz,1H),7.00-6.94(m,3H),4.09-3.96(m,1H),3.87(s,4H),3.80(s,3H),2.17(br d,J=11.9Hz,1H),1.97(br d,J=11.5Hz,1H),1.92-1.77(m,2H),1.55(q,J=12.0Hz,2H),1.46-1.26(m,2H)。
表1中列出的化合物是使用方案1的程序制备的。
表1
方案2
试剂:碱(t-Bu-ONa、TEA、Cs2CO3...),偶联剂(Pd(OAc)2、1-BuXPhosPd、Pd(dppf)Cl2),溶剂(1,4-二噁烷)
实施例7
实施例7的合成
步骤2:4-甲氧基-N-((1R,3S)-3-((2-(三氟甲基)喹啉-5-基)氨基)环己基)苯甲
酰胺的合成
将5-溴-2-(三氟甲基)喹啉(96.9mg,1当量,351μmol)、N-((1R,3S)-3-氨基环己基)-4-甲氧基苯甲酰胺盐酸盐(100mg,1当量,351μmol)、碳酸铯(343mg,3当量,1.05mmol)、乙酸钯(II)(3.94mg,0.05当量,17.6μmol)和BINAP(21.9mg,0.10当量,35.1μmol)在1,4-二噁烷(3mL)中的混合物用氮气脱气5分钟。将小瓶加盖,并将所得混合物在100℃处搅拌。搅拌20小时后,将反应混合物冷却至室温,通过注射器式过滤器,并将滤液直接上样/通过制备型HPLC(ISCO ACCQPrep 150)纯化。将相关级分冻干,得到4-甲氧基-N-((1R,3S)-3-((2-(三氟甲基)喹啉-5-基)氨基)环己基)苯甲酰胺(49.1mg,111μmol,31.5%收率)。
LCMS-ESI(m/z)计算值为:443.47,实测值为:444.2[M+H]+,RT=0.987分钟(方法11)。
1H NMR(400MHz,DMSO-d6)δ9.02(d,J=8.8Hz,1H),8.16(d,J=7.8Hz,1H),7.81(dd,J=8.7,6.8Hz,3H),7.66(t,J=8.1Hz,1H),7.29(d,J=8.3Hz,1H),6.97(d,J=8.4Hz,2H),6.81(d,J=7.9Hz,1H),6.43(d,J=7.6Hz,1H),4.02-3.92(m,1H),3.79(s,3H),3.65-3.56(m,1H),2.27(d,J=12.1Hz,1H),2.09-2.03(m,1H),1.92-1.80(m,2H),1.56-1.27(m,4H)。
实施例8
实施例8的合成
步骤2:4-甲氧基-N-((1R,3S)-3-((3-(三氟甲基)喹啉-4-基)氨基)环己基)苯甲
酰胺的合成
将4-溴-3-(三氟甲基)喹啉(96.9mg,1当量,351μm0l)、N-((1R,3S)-3-氨基环己基)-4-甲氧基苯甲酰胺盐酸盐(100mg,1当量,351μmol)、碳酸铯(343mg,3当量,1.05mmol)、乙酸钯(II)(3.94mg,0.05当量,17.6μmol)和BINAP(21.9mg,0.10当量,35.1μmol)在1,4-二噁烷(3mL)中的混合物用氮气脱气。将小瓶加盖,并将所得混合物在100℃处搅拌。搅拌20小时后,将反应混合物冷却至室温,通过注射器式过滤器,并将滤液直接上样/通过制备型HPLC(ISCO ACCQPrep 150)纯化。将相关级分直接冻干,得到4-甲氧基-N-((1R,3S)-3-((3-(三氟甲基)喹啉-4-基)氨基)环己基)苯甲酰胺(6.5mg,15μmol,4.2%收率)。
LCMS-ESI(m/z)计算值为:443.47,实测值为:444.2[M+H]+,RT=0.488分钟(方法11)。
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.37(d,J=8.6Hz,1H),8.18(d,J=7.7Hz,1H),7.93(d,J=8.4Hz,1H),7.80(d,J=8.2Hz,3H),7.61(t,J=7.6Hz,1H),6.96(d,J=8.4Hz,2H),6.03(d,J=9.9Hz,1H),3.79(s,5H),2.07(d,J=12.0Hz,1H),1.95(d,J=12.5Hz,1H),1.80(d,J=9.0Hz,2H),1.65-1.47(m,2H),1.37-1.24(m,2H)。
表2中列出的化合物是使用方案2的程序制备的。
表2
实施例9
实施例9的合成
2-(二氟甲基)喹啉-4-醇的合成
在140℃处,向PPA(26.85mmol,10mL,5.00当量)中添加苯胺(0.5g,5.37mmol,490.20μL,1当量)和4,4-二氟-3-氧代丁酸乙酯(891.92mg,5.37mmol,1当量),然后将反应混合物在140℃处搅拌12小时。将反应混合物倒入水(50mL)中并用乙酸乙酯(4×50mL)萃取。将合并的有机相干燥并真空浓缩,得到残余物。将残余物通过柱色谱法(硅胶,石油醚/乙酸乙酯=1:2)纯化,得到2-(二氟甲基)喹啉-4-醇(0.2g,1.02mmol,19.09%收率)。
LCMS-ESI(m/z)计算值为:195.17,实测值为:196.4[M+H]+,RT=0.777分钟(方法2)。
4-氯-2-(二氟甲基)喹啉的合成
在0℃处,向2-(二氟甲基)喹啉-4-醇(200mg,1.02mmol,1当量)的DCE(3mL)溶液中滴加POCl3(430mg,2.80mmol,260.61μL,2.74当量)。并将混合物在80℃处搅拌12小时。将反应混合物减压浓缩,得到棕色油。将残余物通过柱色谱法(硅胶,石油醚/乙酸乙酯=10∶1)纯化,得到4-氯-2-(二氟甲基)喹啉(200mg,936.28μmol,91.36%收率)。
LCMS-ESI(m/z)计算值为:213.61,实测值为:214.0[M+H]+,RT=0.930分钟(方法2)。
步骤2:N-[(1R,3S)-3-[[2-(二氟甲基)-4-喹啉基]氨基]环己基]-4-甲氧基-苯甲
酰胺的合成
将4-氯-2-(二氟甲基)喹啉(30mg,140.44μmol,1当量)、N-[(1R,3S)-3-氨基环己基]-4-甲氧基苯甲酰胺(34.87mg,140.44μmol,1当量)、[2-(2-氨基苯基)苯基]-甲基磺酰基氧基-钯;与二叔丁基-[2-(2,4,6-三异丙基苯基)苯基]膦(22.31mg,28.09μmol,0.2当量)和t-BuONa(26.99mg,280.88μmol,2当量)的叔戊醇(1mL)的混合物在100℃处搅拌3小时。将反应混合物倒入水(10mL)中并用乙酸乙酯(2*10mL)萃取,将有机相干燥并真空浓缩,得到残余物。将残余物通过制备型HPLC(柱:Waters Xbridge 150*25mm*5μm;流动相:[水(10mM NH4HCO3)-ACN];B%:32%-62%,8分钟)纯化,得到N-[(1R,3S)-3-[[2-(二氟甲基)-4-喹啉基]氨基]环己基]-4-甲氧基-苯甲酰胺(3mg,6.69μmol,4.76%收率)。
LCMS-ESI(m/z)计算值为:425.47,实测值为:426.2[M+H]+,RT=0.797分钟(方法2)。
方案3
试剂:步骤3-1.R1X、碱(DIPEA)、溶剂(DMSO、NMP),130℃;步骤3-2.HCl、溶剂(1,4-二噁烷);步骤3-3.R2COCl、碱(DIPEA)、溶剂(DMF)
实施例10
实施例10的合成
步骤3-1.((1R,3S)-3-((2-(三氟甲基)喹啉-4-基)氨基)环己基)氨基甲酸叔丁酯
的合成
向4-氯-2-(三氟甲基)喹啉(1.08g,1当量,4.65mmol)和((1R,3S)-3-氨基环己基)氨基甲酸叔丁酯(0.996g,1当量,4.65mmol)在DMSO(12mL)中的溶液中添加DIPEA(2.40g,3.2mL,4当量,18.6mmol)。将小瓶加盖,并将所得溶液在130℃处搅拌。搅拌3小时后,将反应混合物冷却至室温。将反应混合物用水稀释并用EtOAc萃取3次。将有机层合并,用盐水洗涤并减压浓缩。将残余物通过快速柱色谱法(ISCO Gold 120g,0%-80%EtOAc/己烷)纯化,得到((1R,3S)-3-((2-(三氟甲基)喹啉-4-基)氨基)环己基)氨基甲酸叔丁酯(0.584g,1.43mmol,30.7%收率)。
LCMS-ESI(m/z)计算值为:409.45,实测值为:410.3[M+H]+,RT=4.976分钟(方法10)。
1H NMR(400MHz,DMSO-d6)δ8.40(d,J=8.5Hz,1H),7.87(d,J=8.4Hz,1H),7.72(t,J=7.6Hz,1H),7.54(t,J=7.6Hz,1H),7.35(d,J=8.1Hz,1H),6.94-6.75(m,2H),3.81-3.70(m,1H),3.52-3.39(m,1H),2.07(d,J=12.0Hz,1H),1.91(d,J=12.2Hz,1H),1.84-1.71(m,2H),1.50-1.28(m,12H),1.17-1.07(m,1H)。
步骤3-2.(1S,3R)-N1-(2-(三氟甲基)喹啉-4-基)环己烷-1,3-二胺盐酸盐的合成
向((1R,3S)-3-((2-(三氟甲基)喹啉-4-基)氨基)环己基)氨基甲酸叔丁酯(580mg,1当量,1.42mmol)在1,4-二噁烷(10mL)中的搅拌悬浮液中添加4M氯化氢的1,4-二噁烷(3.54mL,4.00摩尔,10当量,14.2mmol)。将所得混合物在50℃处搅拌16小时。过滤反应混合物,并将滤饼用乙醚洗涤并在高真空下干燥,得到(1S,3R)-N1-(2-(三氟甲基)喹啉-4-基)环己烷-1,3-二胺盐酸盐(491mg,1.42mmol,100%)。
LCMS-ESI(m/z)计算值为:309.2,实测值为:310.2[M+H]+,RT=1.294分钟(方法10)。
1H NMR(400MHz,DMSO-d6)δ8.59(d,J=8.5Hz,1H),8.22(s,4H),7.99(d,J=8.4Hz,1H),7.83(t,J=7.7Hz,1H),7.63(t,J=7.6Hz,1H),7.03(s,1H),4.06-3.94(m,1H),3.32-3.20(m,1H),2.25(d,J=11.7Hz,1H),2.03-1.81(m,3H),1.68-1.56(m,1H),1.54-1.41(m,2H),1.39-1.27(m,1H)。
步骤3-3. 3-甲氧基-N-((1R,3S)-3-((2-(三氟甲基)喹啉-4-基)氨基)环己基)苯
甲酰胺的合成
向(1S,3R)-N1-(2-(三氟甲基)喹啉-4-基)环己烷-1,3-二胺(20mg,1当量,65μmol)和DIEA(25mg,3当量,0.19mmol)在DMF(1.5mL)中的溶液中添加3-(甲氧基羰基)苯甲酸氯(12mg,1.2当量,78μmol)。将混合物溶液在25℃处搅拌18小时。将粗混合物用水制剂(20%-90%0.1%甲酸的MeCN和0.1%甲酸的水)纯化,得到3-甲氧基-N-((1R,3S)-3-((2-(三氟甲基)喹啉-4-基)氨基)环己基)苯甲酰胺(8.4mg,19μmol,29%收率)。
LCMS-ESI(m/z)计算值为:443.47,实测值为:444.20[M+H]+,RT=7.592分钟(方法1)。
1H NMR(400MHz,DMSO-d6)δ8.43(d,J=8.5Hz,1H),8.32(d,J=7.9Hz,1H),7.89(d,J=8.4Hz,1H),7.74(t,J=7.7Hz,1H),7.56(t,J=7.6Hz,1H),7.52-7.30(m,4H),7.08(d,J=8.2Hz,1H),6.90(s,1H),4.05(d,J=11.8Hz,1H),3.88(d,J=7.9Hz,1H),3.80(d,J=1.8Hz,3H),2.19(d,J=12.1Hz,1H),1.99(d,J=12.2Hz,1H),1.87(dd,J=25.2,12.8Hz,2H),1.72-1.53(m,2H),1.51-1.20(m,2H)。
实施例11
实施例11的合成
步骤3-1.((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)氨基甲酸
叔丁酯的合成
向4,6-二氯-2-(三氟甲基)喹啉(1.241g,1当量,4.666mmol)和((1R,3S)-3-氨基环己基)氨基甲酸叔丁酯(1.0g,1当量,4.666mmol)在DMSO(6mL)中的搅拌溶液中添加DIPEA(2.41g,3.30mL,4当量,18.7mmol)。将小瓶加盖并在130℃处搅拌3小时。将反应混合物冷却至室温,用水(10mL)稀释,并用EtOAc(3×15mL)萃取。将有机层合并,用盐水洗涤并真空浓缩。将粗残余物通过快速硅胶柱色谱法(0%-100%10%MeOH的EtOAc和己烷)纯化,得到((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)氨基甲酸叔丁酯(1.229g,2.768mmol,59%收率)。
步骤3-2.N-[(1R,3S)-3-[[7-氯-2-(三氟甲基)-4-喹啉基]氨基]环己基]丙酰胺
的合成
向((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)氨基甲酸叔丁酯(1.229g,1当量,2.768mmol)的1,4-二噁烷(10mL)中添加的4M氯化氢的1,4-二噁烷(1.51g,10.4mL,4.00摩尔,15当量,41.5mmol)。将小瓶加盖并在50℃处加热14小时。将反应混合物冷却至室温,过滤,并将滤饼用乙醚(2×10mL)洗涤并在高真空下干燥,得到(1S,3R)-N1-(6-氯-2-(三氟甲基)喹啉-4-基)环己烷-1,3-二胺盐酸盐(1.15g,3.02mmol,100%收率)。
LCMS-ESI(m/z)计算值为:343.1,实测值为:344.1[M+H]+,RT=0.66分钟(方法11)
1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),7.95(d,J=9.0Hz,1H),7.91-7.84(m,1H),7.79(d,J=8.9Hz,1H),6.97(s,1H),3.97-3.85(m,1H),3.57(s,3H),3.31-3.19(m,1H),2.30-2.22(m,1H),2.04-1.89(m,2H),1.88-1.79(m,1H),1.64-1.27(m,4H)。
步骤3-3.N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-2-甲基
苯甲酰胺的合成
向(1S,3R)-N1-(6-氯-2-(三氟甲基)喹啉-4-基)环己烷-1,3-二胺盐酸盐(60mg,1当量,0.16mmol)的DMF(2mL)溶液中添加DIPEA(0.11mL,4当量,0.63mmol),随后添加2-甲基苯甲酰氯(26mg,22μL,1.05当量,0.17mmol)。将所得混合物在室温处搅拌1小时。将反应混合物通过注射器式过滤器,并将滤液直接上样/通过制备型HPLC(ISCO ACCQPrep 150)纯化。将相关级分直接冻干,得到N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-2-甲基苯甲酰胺(20mg,43μmol,27%收率)。
LCMS-ESI(m/z)计算值为:461.91,实测值为:462.2[M+H]+,RT=1.025分钟(方法11)
1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),8.24(d,J=8.1Hz,1H),7.89(d,J=9.0Hz,1H),7.74(d,J=8.9Hz,1H),7.50(d,J=8.1Hz,1H),7.32-7.19(m,4H),6.96(s,1H),4.05-3.86(m,2H),2.32(s,3H),2.17(d,J=12.1Hz,1H),1.98-1.87(m,2H),1.81(d,J=13.3Hz,1H),1.60-1.45(m,2H),1.39-1.22(m,2H)。
实施例12
实施例12的合成
步骤3-1.((1R,3S)-3-((6-甲基-2-(三氟甲基)喹啉-4-基)氨基)环己基)氨基甲
酸叔丁酯的合成
向((1R,3S)-3-氨基环己基)氨基甲酸叔丁酯(1.0g,1当量,4.7mmol)和4-氯-6-甲基-2-(三氟甲基)喹啉(1.1g,1当量,4.7mmol)在DMSO(12mL)中的溶液中添加DIPEA(1.2g,1.6mL,2当量,9.3mmol)。将小瓶加盖,并将所得溶液在130℃处搅拌。搅拌3小时后,将反应混合物冷却至室温。将反应混合物用水稀释并用EtOAc(3×10mL)萃取。将有机层合并,用盐水洗涤并减压浓缩。将残余物溶解在DCM中并通过快速柱色谱法(ISCO Gold 120g,0%-80%EtOAc/己烷,11CV梯度)纯化。将相关级分合并并减压浓缩,得到((1R,3S)-3-((6-甲基-2-(三氟甲基)喹啉-4-基)氨基)环己基)氨基甲酸叔丁酯(1.3g,3.1mmol,66%收率)。
LCMS-ESI(m/z)计算值为:423.48,实测值为:424.2[M+H]+,RT=5.092分钟(方法10)。
步骤3-2.(1S,3R)-N1-(6-甲基-2-(三氟甲基)喹啉-4-基)环己烷-1,3-二胺盐酸
盐的合成
向((1R,3S)-3-((6-甲基-2-(三氟甲基)喹啉-4-基)氨基)环己基)氨基甲酸叔丁酯(1.3g,1当量,3.1mmol)的1,4-二噁烷(10mL)中添加的4M氯化氢的1,4-二噁烷(7.7mL,4.00摩尔,10当量,31mmol)。在50℃处搅拌18小时后,过滤反应混合物,并将滤饼用乙醚洗涤并在高真空下干燥,得到(1S,3R)-N1-(6-甲基-2-(三氟甲基)喹啉-4-基)环己烷-1,3-二胺盐酸盐(1.1g,3.1mmol,100%收率)。
LCMS-ESI(m/z)计算值为:323.82,实测值为:324.2[M+H]+,RT=2.28分钟(方法10)。
步骤3-3.N-((1R,3S)-3-((6-甲基-2-(三氟甲基)喹啉-4-基)氨基)环己基)苯甲
酰胺的合成
向(1S,3R)-N1-(6-甲基-2-(三氟甲基)喹啉-4-基)环己烷-1,3-二胺盐酸盐(75mg,1当量,0.21mmol)的DMF(1.5mL)溶液中添加DIPEA(0.15mL,4当量,0.83mmol),随后添加苯甲酰氯(31mg,1.05当量,0.22mmol)。将所得混合物在室温处搅拌18小时。将反应混合物通过注射器式过滤器,并将滤液直接上样/通过制备型HPLC(ISCO ACCQPrep 150)纯化。将相关级分合并并冻干,得到N-((1R,3S)-3-((6-甲基-2-(三氟甲基)喹啉-4-基)氨基)环己基)苯甲酰胺(9.1mg,21μmol,10%收率)。
LCMS-ESI(m/z)计算值为:427.47,实测值为:428.3[M+H]+,RT=0.848分钟(方法11)
1H NMR(400MHz,DMSO-d6)δ8.33(d,J=7.9Hz,1H),8.21(s,1H),7.89-7.71(m,3H),7.60-7.40(m,4H),7.24(d,J=8.0Hz,1H),6.84(s,1H),4.09-3.98(m,1H),3.89-3.79(m,1H),2.49(s,3H),2.19(d,J=12.0Hz,1H),2.01-1.79(m,3H),1.62-1.48(m,2H),1.45-1.30(m,2H)。
实施例13
实施例13的合成
步骤3-3.N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)苯甲酰
胺的合成
向(1S,3R)-N1-(6-氯-2-(三氟甲基)喹啉-4-基)环己烷-1,3-二胺盐酸盐(45mg,1当量,0.12mmol)的DMF(1.5mL)溶液中添加DIPEA(83μL,4当量,0.47mmol),随后添加苯甲酰氯(17mg,1.05当量,0.12mmol)。将所得混合物在室温处搅拌1小时。将反应混合物通过注射器式过滤器,并将滤液直接上样/通过制备型HPLC(ISCO ACCQPrep 150)纯化。将相关级分直接冻干,得到N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)苯甲酰胺(5mg,0.01mmol,9%收率)。
LCMS-ESI(m/z)计算值为:447.89,实测值为:448.2[M+H]+,RT=1.000分钟(方法11)
1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),8.34(d,J=7.9Hz,1H),7.89(d,J=9.0Hz,1H),7.83(d,J=7.6Hz,2H),7.74(d,J=9.0Hz,1H),7.53-7.42(m,4H),6.95(s,1H),4.09-4.01(m,1H),3.93-3.84(m,1H),2.17(d,J=12.0Hz,1H),1.97(d,J=12.2Hz,1H),1.92-1.80(m,2H),1.60-1.50(m,2H),1.43-1.30(m,2H)。
表3中列出的化合物是使用方案3的程序制备的。
表3
方案4
试剂:步骤2-4.R2COOH、肽偶联反应(HATU)、碱(DIPEA)、溶剂(DMF)
实施例14
实施例14的合成
步骤4.N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-3-(甲基
磺酰胺基)苯甲酰胺的合成
向(1S,3R)-N1-(6-氯-2-(三氟甲基)喹啉-4-基)环己烷-1,3-二胺盐酸盐(90mg,1当量,0.24mmol)在DMF(2mL)中的搅拌溶液中添加3-(甲基磺酰胺基)苯甲酸(51mg,1当量,0.24mmol)、HATU(0.10g,1.1当量,0.26mmol)和N-乙基-N-异丙基丙-2-胺(DIPEA)(92mg,0.12mL,3当量,0.71mmol)。将反应混合物在室温下搅拌过夜。将该反应混合物过滤并通过反相制备型HPLC纯化(35-->55%0.1%甲酸的MeCN溶液和0.1%甲酸的H2O溶液),得到N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-3-(甲基磺酰胺基)苯甲酰胺(66.4mg,123μmol,52%收率)。
LCMS-ESI(m/z)计算值为:540.99,实测值为:541.2[M+H]+,RT=0.906分钟(方法11)
实施例15
实施例15的合成
步骤4:2-氨基-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]嘧
啶-5-甲酰胺的合成
向2-氨基嘧啶-5-甲酸(12mg,1当量,87μmol)的DMF(2mL)溶液中添加HATU(50mg,1.5当量,0.13mmol)。将所得溶液在室温处搅拌10分钟。随后向混合物中添加(1S,3R)-N1-(6-氯-2-(三氟甲基)喹啉-4-基)环己烷-1,3-二胺(30mg,1当量,87μmol)。将所得混合物在室温处搅拌19小时。将粗产物直接通过制备型HPLC纯化,得到2-氨基-N-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]嘧啶-5-甲酰胺(33mg,71μmol,82%收率)。
LCMS-ESI(m/z)计算值为:464.88,实测值为:465.2[M+H]+,RT=7.332分钟(方法1)
1H NMR(400MHz,DMSO)δ8.67(d,J=1.6Hz,2H),8.61(d,J=2.4Hz,1H),8.14(d,J=7.8Hz,1H),7.90(d,J=9.0Hz,1H),7.74(dd,J=9.1,2.2Hz,1H),7.50(d,J=7.9Hz,1H),7.18(s,2H),6.94(s,1H),4.12-3.76(m,2H),2.18(d,J=12.0Hz,1H),1.98(d,J=12.1Hz,1H),1.86(dd,J=26.2,13.0Hz,2H),1.53(dq,J=23.5,12.6,11.9Hz,2H),1.45-1.18(m,2H)。
实施例16
实施例16的合成
步骤4.N-[(1R,3S)-3-[[2-(三氟甲基)-4-喹啉基]氨基]环己基]丙酰胺的合成
向丙酸(5mg,64μmol,5μL,1当量)在DMF(2mL)中的混合物中添加DIPEA(8mg,64μmol,11.10μL,1当量)、(1S,3R)-N1-[2-(三氟甲基)-4-喹啉基]环己烷-1,3-二胺(25mg,70μmol,1.1当量,HCl)和HATU(24mg,64μmol,1当量)。将反应混合物在30℃处搅拌12小时。将反应混合物真空浓缩,得到残余物。将残余物通过制备型HPLC(柱:Unisil 3-100C18 Ultra150*50mm*3μm;流动相:[水(0.225%FA)-ACN];B%:30%-50%,10分钟)纯化,得到N-[(1R,3S)-3-[[2-(三氟甲基)-4-喹啉基]氨基]环己基]丙酰胺(3mg,7μmol,12%收率)。
LCMS-ESI(m/z)计算值为:365.4,实测值为:366.1[M+H]+,RT=0.731分钟(方法6)。
实施例17
实施例17的合成
N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-2-甲氧基-1-甲
基-1H-咪唑-5-甲酰胺
将2-氯-N-[(1R,3S)-3-[[6-氯-2-(三氟甲基)-4-喹啉基]氨基]环己基]-3-甲基-咪唑-4-甲酰胺(20mg,1当量,41.13μmol)和CH3ONa(5.4M,3当量,22.85μL)的溶液添加到2-甲基丁-2-醇(2mL)中。将所得溶液在70℃处搅拌23小时。将粗产物直接通过制备型HPLC纯化,得到N-[(1R,3S)-3-[[6-氯-2-(三氟甲基)-4-喹啉基]氨基]-环己基]-2-甲氧基-3-甲基-咪唑-4-甲酰胺(3.0mg,5.67μmol,14%收率)。
LCMS-ESI(m/z)计算值为:481.9,实测值为:482.3[M+H]+,RT=0.472分钟(方法2)。
1H NMR(400MHz,DMSO-d6)δ8.62-8.58(m,1H),8.37-8.29(m,1H),7.94(d,J=8.0Hz,1H),7.89(d,J=9.0Hz,1H),7.76-7.71(m,1H),7.48(d,J=8.0Hz,1H),7.28(s,1H),6.92(s,1H),3.95(s,4H),3.88-3.80。
实施例18
实施例18的合成
N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-6-((2-氟乙基)
氨基)烟酰胺的合成
向N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-6-氟烟酰胺(50mg,1当量,0.11mmol)的NMP(4mL)溶液中加入2-氟乙-1-胺(6.8mg,1当量,0.11mmol)和DIPEA(42mg,56μL,3当量,0.32mmol)。将所得黄色溶液在75℃处搅拌18小时。将粗产物直接通过制备型HPLC纯化,得到N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-6-((2-氟乙基)氨基)烟酰胺(9.0mg,18μmol,16%收率)。
LCMS-ESI(m/z)计算值为:509.93,实测值为:510.2[M+H]+,RT=7.013分钟(方法1)。
表4中列出的化合物是使用方案4的程序制备的。
表4
方案5
试剂:步骤5-1.R2-卤化物、碱(NaH);步骤5-2.NaOH水溶液/THF;步骤5-3.肽偶联条件(HATU)、碱(DIPEA)、溶剂(DMF)
实施例19
实施例19的合成
N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-1-(2-氟乙基)-
1H-吡咯-3-甲酰胺的合成
在0℃处,向1H-吡咯-3-甲酸甲酯(250mg,1当量,2.00mmol)在DMF(4mL)中的搅拌溶液中添加氢化钠(95.9mg,60重量%,1.2当量,2.40mmol)。将反应混合物搅拌10分钟。添加1-溴-2-氟乙烷(380mg,1.5当量,3.00mmol)并将反应混合物升温至室温。在室温处搅拌过夜后,添加H2O(5mL)。将水层用EtOAc(3×5mL)萃取,用H2O(3×5mL)洗涤,经硫酸钠干燥,经硅藻土过滤,并真空浓缩,得到粗料。将粗料通过硅胶色谱法(0-->50%EtOAc和己烷)纯化,得到1-(2-氟乙基)-1H-吡咯-3-甲酸甲酯(205.3mg,1.199mmol,60.0%收率)。
LCMS-ESI(m/z)计算值为:171.07,实测值为:172.0[M+H]+,RT=0.660分钟(方法11)
向1-(2-氟乙基)-1H-吡咯-3-甲酸甲酯(205.3mg,1当量,1.199mmol)在THF(6mL)中的搅拌溶液中添加氢氧化钠(239.9mg,5.997mL,1摩尔,5当量,5.997mmol)。将反应混合物在50℃处搅拌12小时。仍然保留SM。添加额外的氢氧化钠(239.9mg,5.997mL,1摩尔,5当量,5.997mmol)并在70℃处加热过夜。添加3M HCl(10mL),用EtOAc(3×10mL)萃取,经硫酸钠干燥,经硅藻土过滤,并真空浓缩,得到1-(2-氟乙基)-1H-吡咯-3-甲酸(169.2mg,1.077mmol,90%收率)。
LCMS-ESI(m/z)计算值为:157.05,实测值为:158.0[M+H]+,RT=0.487分钟(方法11)
使用方案4合成N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-1-(2-氟乙基)-1H-吡咯-3-甲酰胺,并从1-(2-氟乙基)-1H-吡咯-3-甲酸和(1S,3R)-N1-(6-氯-2-(三氟甲基)喹啉-4-基)环己烷-1,3-二胺盐酸盐开始。
LCMS-ESI(m/z)计算值为:482.15,实测值为:483.2[M+H]+,RT=9.764分钟(方法1)
1H NMR(400MHz,DMSO)δ8.61(s,1H),7.93-7.88(m,1H),7.77-7.14(m,1H),7.64-7.59(m,1H),7.52-7.47(m,1H),7.35(s,1H),6.93(s,1H),6.79-6.75(m,1H),6.51-6.47(m,1H),4.75-4.69(m,1H),4.62-4.58(m,1H),4.28-4.21(m,1H),4.20-4.14(m,1H),4.04-3.93(m,1H),3.91-3.79(m,1H),2.17-2.09(m,1H),2.01-1.91(m,1H),1.90-1.78(m,2H),1.58-1.23(m,5H)。
实施例20
实施例20的合成
N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-3-氰基-1-(二氟
甲基)-1H-吡唑-4-甲酰胺的合成
N-[(1R,3S)-3-[[6-氯-2-(三氟甲基)-4-喹啉基]氨基]环己基]-3-氰基-1H-吡唑-4-甲酰胺(60mg,1当量,129.63μmol)、(2-氯-2,2-二氟-乙酰基)氧钠(39.53mg,2当量,259.26μmol)和Cs2CO3(84.47mg,2当量,259.26μmol)在DMF(1mL)中的溶液。将所得溶液在100℃处搅拌1小时。将粗产物直接通过制备型HPLC纯化,得到N-[(1R,3S)-3-[[6-氯-2-(三氟甲基)-4-喹啉基]氨基]环己基]-3-氰基-1-(二氟甲基)吡唑-4-甲酰胺(2.3mg,4.45μmol,3.44%收率)。
LCMS-ESI(m/z)计算值为:512.87,实测值为:513.2[M+H]+,RT=0.575分钟(方法2)
1H NMR(400MHz,氯仿-d)δ8.46(s,1H)8.03(br d,J=8.88Hz,1H)7.71(s,1H)7.65(br d,J=8.76Hz,1H)7.04-7.26(m,1H)6.78(s,1H)6.24(br d,J=6.88Hz,1H)5.01(br d,J=6.88Hz,1H)4.16-4.25(m,1H)3.73(br d,J=7.00Hz,1H)2.63(br d,J=11.13Hz,1H)2.18-2.31(m,2H)2.01-2.06(m,1H)1.29-1.45(m,4H)。
实施例21
实施例21的合成
N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-3-(二氟甲基)-
1-(氟甲基)-1H-吡唑-4-甲酰胺的合成
向N-[(1R,3S)-3-[[6-氯-2-(三氟甲基)-4-喹啉基]氨基]环己基]-3-(二氟甲基)-1H-吡唑-4-甲酰胺(100mg,1当量,188.58μmol)的MeCN(2mL)溶液中添加氟(碘)甲烷(33.18mg,1.1当量,207.44μmol)和K2CO3(52.13mg,2当量,377.16μmol)并在50℃处搅拌2小时。将粗产物直接通过制备型HPLC纯化,得到N-[(1R,3S)-3-[[6-氯-2-(三氟甲基)-4-喹啉基]氨基]环己基]-5-(二氟甲基)-1-(氟甲基)吡唑-4-甲酰胺(11.7mg,22.24μmol,11.79%收率)。
LCMS-ESI(m/z)计算值为:519.2,实测值为:520.2[M+H]+,RT=0.517分钟(方法2)
1H NMR(400MHz,DMSO-d6)δ=8.60(d,J=2.1Hz,1H),8.49(d,J=7.9Hz,1H),8.27(s,1H),7.90(d,J=9.0Hz,1H),7.88-7.60(m,2H),7.50(br d,J=8.0Hz,1H),6.95(s,1H),6.33(s,1H),6.20(s,1H),4.11-3.83。
实施例22
实施例22的合成
5-氯-N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-1-甲基-
1H-吡咯-3-甲酰胺的合成
在0℃处,向5-氯-N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-1H-吡咯-3-甲酰胺(50mg,1当量,0.11mmol)的DMF(2mL)溶液中添加氢化钠(5.1mg,60重量%,1.2当量,0.13mmol)。搅拌30分钟后,添加碘甲烷(23mg、9.9μL、1.5当量、0.16mmol),并将所得混合物在室温处搅拌18小时。将粗产物直接通过制备型HPLC纯化,得到5-氯-N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-1-甲基-1H-吡咯-3-甲酰胺(23.8mg,49.0μmol,46%)。
LCMS-ESI(m/z)计算值为:485.33,实测值为:485.2[M+H]+,RT=9.522分钟(方法1)。
1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),7.89(d,J=8.9Hz,1H),7.73(d,J=9.2Hz,1H),7.66(d,J=8.1Hz,1H),7.48(d,J=7.9Hz,1H),7.36(s,1H),6.92(s,1H),6.54(s,1H),3.99-3.80(m,2H),3.56(s,3H),2.12(d,J=12.1Hz,1H),1.95(d,J=12.4Hz,1H),1.87-1.76(m,2H),1.59-1.42(m,2H),1.39-1.23(m,2H)。
实施例23
实施例23的合成
5-氯-N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-1-(2,2-二
氟乙基)-1H-吡咯-3-甲酰胺的合成
在0℃处,向5-氯-N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-1H-吡咯-3-甲酰胺(88mg,1当量,0.19mmol)的DMF(2mL)溶液中添加氢化钠(9.0mg,60重量%,1.2当量,0.22mmol)。搅拌30分钟后,添加三氟甲磺酸2,2-二氟乙酯(60mg,37μL,1.5当量,0.28mmol),并将所得混合物在室温处搅拌18小时。将粗产物直接通过制备型HPLC纯化,得到5-氯-N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-1-(2,2-二氟乙基)-1H-吡咯-3-甲酰胺(53.7mg,100μmol,54%)。
LCMS-ESI(m/z)计算值为:535.34,实测值为:535.2[M+H]+,RT=9.755分钟(方法1)。
1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),7.89(d,J=9.1Hz,1H),7.75(dd,J=14.6,8.8Hz,2H),7.52-7.41(m,2H),6.92(s,1H),6.62(s,1H),6.31(t,J=54.6Hz,1H),4.45(t,J=15.6Hz,2H),4.02-3.81(m,2H),2.12(d,J=11.9Hz,1H),1.96(d,J=12.4Hz,1H),1.88-1.77(m,2H),1.60-1.43(m,2H),1.40-1.23(m,2H)。
实施例24
实施例24的合成
3-氯-N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-1-(甲基磺
酰基)-1H-吡唑-4-甲酰胺的合成
向3-氯-N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-1H-吡唑-4-甲酰胺(100mg,1当量,212μmol)在DCM(3mL)中的悬浮液中添加三乙胺(85.7mg,118μL,4当量,847μmol),随后添加DMAP(5.17mg,0.2当量,42.3μmol)和甲磺酸酐(73.8mg,2当量,423μmol)。将所得混合物在室温处搅拌1小时,然后在50℃处搅拌1小时。将粗产物直接通过制备型HPLC纯化,得到3-氯-N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-1-(甲基磺酰基)-1H-吡唑-4-甲酰胺(19.4mg,35.2μmol,16.6%收率)。
LCMS-ESI(m/z)计算值为:550.38,实测值为:550.1[M+H]+,RT=9.645分钟(方法1)
1H NMR(400MHz,DMSO-d6)δ8.88(s,1H),8.59(s,1H),8.29(d,J=7.7Hz,1H),7.90(d,J=9.0Hz,1H),7.74(d,J=9.1Hz,1H),7.48(d,J=8.0Hz,1H),6.95(s,1H),4.01-3.83(m,2H),3.68(s,3H),2.17(d,J=11.8Hz,1H),2.01-1.78(m,3H),1.60-1.34(m,3H),1.29-1.19(m,1H)。
表5中列出的化合物是使用方案5的程序制备的。
表5
方案6
试剂:X独立地为C或N。步骤6-1.碱(DIPEA)、溶剂(DMF);步骤6-2.NaOH水溶液/THF;步骤5-3.肽偶联条件(HATU)、碱(DIPEA)、溶剂(DMF)
实施例25
实施例25的合成
6-[(1R,3S)-3-{[6-氯-2-(三氟甲基)喹啉-4-基]氨基}环己基]-5H,6H,7H-吡咯
并[3,4-b]吡啶-7-酮的合成
向(1S,3R)-N1-(6-氯-2-(三氟甲基)喹啉-4-基)环己烷-1,3-二胺盐酸盐(50mg,1当量,0.13mmol)在DMF(1.5mL)中的搅拌溶液中添加N-乙基-N-异丙基丙-2-胺(DIPEA)(85mg,0.12mL,5当量,0.66mmol)和3-(溴甲基)吡啶甲酸甲酯(46mg,1.5当量,0.20mmol)。将小瓶加盖并在40℃处加热过周末。将粗产物通过反相制备型HPLC(35-->55%0.1%甲酸的H2O和0.1%甲酸的MeCN)纯化,得到6-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-5,6-二氢-7H-吡咯并[3,4-b]吡啶-7-酮(37.1mg,80.5μmol,61%收率)。
LCMS-ESI(m/z)计算值为:460.13,实测值为:461.2[M+H]+,RT=8.116分钟(方法1)
1H NMR(400MHz,DMSO)δ8.72(s,1H),8.61(s,1H),8.07(d,J=7.9Hz,1H),7.91(d,J=8.7Hz,1H),7.75(d,J=9.6Hz,1H),7.60-7.51(m,2H),7.00(s,1H),4.52(app q,J=13.0Hz,2H),4.43-4.29(m,1H),4.09-3.98(m,1H),2.20-2.12(m,1H),2.04-1.98(m,1H),1.94-1.76(m,3H),1.69-1.56(m,2H),1.52-1.40(m,1H)。
方案7
试剂:R2R3NH、二(1H-咪唑-1-基)甲酮或三光气、碱(TEA)、溶剂(DCM)
实施例26
实施例26的合成
步骤7.N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-4-异丁酰
基哌嗪-1-甲酰胺
在0℃处,向二(1H-咪唑-1-基)甲酮(2.14g,5当量,13.2mmol)和三乙胺(348mg,479μL,1.3当量,3.44mmol)在DCM(20mL)中的搅拌溶液中分两份添加(1S,3R)-N1-(6-氯-2-(三氟甲基)喹啉-4-基)环己烷-1,3-二胺盐酸盐(1.00g,1当量,2.64mmol),间隔10分钟。将反应混合物在0℃处搅拌1小时,然后在室温处搅拌30分钟。将反应混合物真空浓缩,得到N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-1H-咪唑-1-甲酰胺,将其在高真空下干燥并原样使用。
向N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-1H-咪唑-1-甲酰胺(100mg,50重量%,1当量,114μmol)在DCM(1.5mL)中的搅拌溶液中添加2-甲基-1-(哌嗪-1-基)-丙-1-酮(89.2mg,5当量,571μmol)和N-乙基-N-异丙基丙-2-胺(DIPEA)(73.8mg,99.5μL,5当量,571μmol)。将反应混合物在室温下搅拌过夜。将粗产物通过反相制备型HPLC纯化,得到N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-4-异丁酰基哌嗪-1-甲酰胺(29.1mg,55.3μmol)。
LCMS-ESI(m/z)计算值为:526,实测值为:526.3[M+H]+,RT=8.141分钟(方法1)。
实施例27
实施例27的合成
步骤5.N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-3-氟-3-
甲基氮杂环丁烷-1-甲酰胺的合成
在室温处,向N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-3-羟基-3-甲基氮杂环丁烷-1-甲酰胺(40mg,1.0当量,0.088mmol)在DCM(0.5mL)中的搅拌溶液中添加脱氧氟(29mg,1.5当量,0.13mm0l)溶液。将反应混合物在室温处搅拌5分钟。滴加饱和氯化铵溶液(2mL)。将水层用EtOAc/MeOH(5:1)(2×5mL)萃取,经硫酸钠干燥,经硅藻土过滤,并真空浓缩。将粗混合物通过制备型HPLC纯化,得到N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-3-氟-3-甲基氮杂环丁烷-1-甲酰胺(23.5mg,51.2μmol,58%)。
LCMS-ESI(m/z)计算值为:458.15,实测值为:459.2[M+H]+,RT=8.638分钟(方法1)
实施例28
实施例28的合成
N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-2-甲基-6,7-二
氢噻唑并[5,4-c]吡啶-5(4H)-甲酰胺的合成
向(1S,3R)-N1-(6-氯-2-(三氟甲基)喹啉-4-基)环己烷-1,3-二胺(60mg,1当量,0.16mmol)和DIPEA(0.10g,0.14mL,5当量,0.79mmol)在MeCN(2mL)中的冰冷溶液中一次性添加三光气(47mg,1当量,0.16mmol)。将所得混合物在0℃处搅拌10分钟。随后向混合物中添加4,5,6,7-四氢-2-甲基噻唑并[5,4-c]吡啶(61mg,2.5当量,0.39mmol),随后添加DIPEA(50mg,70μL,2.5当量)。将所得混合物在50℃处搅拌18小时。将粗产物直接通过制备型HPLC纯化,得到N-((1R,3S)-3-((6-氯-2-(三氟甲基)喹啉-4-基)氨基)环己基)-2-甲基-6,7-二氢噻唑并[5,4-c]吡啶-5(4H)-甲酰胺(52.6mg,100μmol,64%收率)。
LCMS-ESI(m/z)计算值为:524.00,实测值为:524.2[M+H]+,RT=8.534分钟(方法1)
1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),7.89(d,J=9.1Hz,1H),7.73(d,J=9.1Hz,1H),7.45(d,J=7.8Hz,1H),6.88(s,1H),6.51(d,J=7.6Hz,1H),4.51(s,2H),3.82-3.60(m,4H),2.67(s,2H),2.58(s,3H),2.11(d,J=11.7Hz,1H),1.94(d,J=12.2Hz,1H),1.79(t,J=15.3Hz,2H),1.53-1.37(m,2H),1.35-1.19(m,2H)。
表6中列出的化合物是使用方案7的程序制备的。
表6
实施例29
MRGPR X2活性
将稳定转染以表达人MRGPR X2的CHO细胞维持在37℃的具有5%CO2的温育箱中,并使其在含10%胎牛血清(FBS)、1%Glutamax、1%青霉素/链霉素、800μg/mL遗传霉素(G418)和300μg/mL潮霉素B的F12(HAM)培养基中生长。
将细胞以每孔20,000个细胞接种在12μL Opti-MEM中的384孔测定板中,并在温育箱中过夜。在测定当天,使用Tecan D300E数字分配器按照10点曲线添加以10mM溶解于DMSO中的化合物(最终最高浓度为30μM,以1∶3连续稀释)。将激动剂在测定缓冲液中稀释(最终浓度为5.7mM Tris-HCl、43mM NaCl、50mM LiCl,pH=8),并在每个孔中添加2μL激动剂皮质抑素-14(CPC Scientific,目录号CORT-002)。激动剂的最终浓度为0.3μM皮质抑素。整个板中DMSO的最终浓度保持一致。将板在37℃处在黑暗中温育1小时,并且然后在室温下温育1小时。根据从Cisbio(部件编号62IPAPEJ)购买的IP-One-Gq试剂盒添加IP-1标准品和HTRF检测试剂,并在室温下在黑暗中温育1小时。在分子装置公司SpectraMax iD5读板仪上读取板。HTRF比率是根据原始数据计算的,并使用GraphPad Prism绘图以计算每种化合物的IC50值。
所选MRGPR X2拮抗剂(相对于0.3μM皮质抑素-14激动剂)的活性数据显示在表6中。活性范围表示如下:″+++++″表示拮抗剂活性<100nM;″++++″表示拮抗剂活性介于100nM至500nM之间;″+++″表示活性介于501nM至1000nM之间;″++″表示活性介于1001nM至2500nM之间;″+″表示活性>2500nM
表6
实施例30
肥大细胞β-氨基己糖苷酶释放测定
将人LAD2细胞(NIH)维持在37℃、5%CO2的温育箱中,并在补充有2mM L-谷氨酰胺、100U/ml青霉素、50mg/ml链霉素和100ng/ml SCF(Invitrogen PEP0860)的StemPro-34无血清培养基(Gibco 10639011)中培养,浓度为2-5×105个细胞/mL,每1-2周损耗一半。
将细胞以2.5×105个细胞/mL转移至无SCF的培养基中并保持在温育箱中过夜。在测定当天,将细胞在测定缓冲液(最终浓度10mM HEPES、137mM NaCl、5.6mM D-葡糖、2.7mMKCl、1mM MgCl、1.8mM CalCl2、0.4mM Na2HPO4.7H2O、0.04%BSA,pH=7.4)中洗涤两次,并以20,000个细胞/孔接种在96孔v形底板中的80μL测定缓冲液中。按照10点曲线将以10mM溶解于DMSO中的拮抗剂化合物在测定缓冲液中稀释到10X最终期望浓度(最终最高浓度为10μM,1:3连续稀释)并且每孔添加10μL。然后将板在37℃处孵育1小时。将激动剂在测定缓冲液中稀释到10X期望浓度,并向每个孔中添加10μL适当的激动剂。拮抗剂测定中使用的皮质抑素-14(Tocris 3374)的最终浓度为500nM。整个板中DMSO的最终浓度保持一致。然后将板在热空气烘箱中在37℃处温育30分钟,接着在4℃处以450×g离心5分钟。然后将每个孔的50μL上清液转移到96孔平底板中,每孔含有100μL底物溶液(3.5mg/mL对硝基苯-N-乙酰基-β-D-氨基葡糖苷(Sigma 487052)在含有最终浓度40mM的柠檬酸、20mM Na2HPO4.7H2O的柠檬酸缓冲液中,pH=4.5)。然后向每个孔中留在剩余测定缓冲液中的细胞沉淀中添加150μL0.1%Triton-X-100,通过上下移液重悬浮,并将50μL细胞溶解产物转移到每孔含有100μL底物溶液的第二张96孔平底板中。然后将含有转移的上清液和细胞溶解产物的板在热空气烘箱中在37℃处温育90分钟。温育后,向每个孔中添加50μL的400mM甘氨酸缓冲液(pH10.7),并且在Molecular Devices SpectraMax iD5读板仪上读取板(吸收在405nm处,参考滤波器在620nm处)。减除背景后,按照100×(上清液值)/(上清液+溶解产物值)计算脱粒百分比(β-氨基己糖苷酶释放百分比),接着使用GraphPad Prism软件进行分析以计算每种化合物的IC50值。
在肥大细胞β-氨基己糖苷酶释放测定中所选MRGPR X2拮抗剂的活性数据显示在表7中。活性范围表示如下:″+++++″表示拮抗剂活性<100nM;″++++″表示拮抗剂活性介于100nM至500nM之间;″+++″表示活性介于501nM至1000 nM之间;″++″表示活性介于1001nM至2500nM之间;并且″+″表示活性>2500nM。
表7
实施例31
小鼠药代动力学研究
在不合Ca和Mg的5%DMSO、5%Solutol和90%PBS(pH 7.4)中以5mg/mL的浓度配制化合物。在非禁食条件下通过口服管饲向雄性C57BL/6小鼠(n=3/化合物)施用50mg/kg剂量每种化合物。在给药后0.25小时、0.5小时、1小时、2小时、4小时、8小时和24小时,通过隐静脉将血样收集到K2-EDTA上,并且制备血浆并储存在-80℃下直到分析为止。用于分析的血浆样品制备是通过使用乙腈(包含维拉帕米(Verapamil)作为内标物)进行蛋白质沉淀然后离心来完成的。使用LC-MS/MS相对于覆盖1nM到4000nM范围的12点标准曲线测定经提取的血浆中的化合物浓度。使用Phoenix WinNonlin进行非房室分析来估计药代动力学参数,包含曲线下面积、清除率和半衰期。通过UPLC-UV相对于单点校准样品分析残留剂量材料来确认施用剂量。这些研究的结果呈现于表8中。
表8
实施例32
伊文思蓝血管渗透性测定
8-10周龄的C57BL/6J小鼠(品系000664;Jackson Laboratories)或MrgprX2敲入小鼠(Mrgb2KI;Escient Pharmaceuticals Inc.)在开始研究前5天至6天,用异氟烷麻醉并且背部剃毛。在研究当天,在注射伊文思蓝前3小时给予小鼠100mg/kg、30mg/kg、20mg/kg、10mg/kg或3mg/kg的媒介物或EP8615。限制动物并静脉(IV)注射200μl在0.9%盐水中的1%伊文思蓝(产品目录号314-13-6;Fisher Chemical),之后置于异氟烷下。IV注射后十分钟,将动物维持在麻醉下并皮内注射25μl媒介物PBS、皮质抑素-14(C-14;300nM;产品目录号3374;Tocris Bioscience);艾替班特(HOE-140;38μM;产品目录号3014;TocrisBioscience)或山羊抗小鼠IgE(50μg/ml;ab9162;Abcam)。皮内注射后十分钟,对动物拍照并处死。用8mm圆形皮肤穿孔器刺穿注射部位周围的皮肤,称重并置于1.5ml Eppendorf管中。通过在管中添加1ml甲酰胺(BP227-500;Fisher Scientific)从组织中提取伊文思蓝染料,然后将管用箔包裹涡旋并置于55℃处过夜。然后将200μl在甲酰胺中的提取染料连同标准曲线的已知伊文思蓝浓度标准品一起置于96孔板中,一式两份。在读板仪上在620nM处读取板并将结果表示为μg染料/mg组织。用软件Graphpad Prism 8(Graphpad Software)进行统计学检验。数据表示为平均值和平均值标准误差。使用非配对t-检验比较组间的统计学差异。
可以组合上述各种实施方案来提供另外的实施方案。本说明书中提到的和/或专利申请数据表中所列的所有美国专利、美国专利申请公布、美国专利申请、外国专利、外国专利申请和非专利公布均全文以引用方式并入本文。如果需要,可以修改实施方案的各个方面以采用各专利、申请和出版物的概念来提供进一步的实施方案。
鉴于上文的详细说明,可以对这些实施方案作出这些和其他改变。一般来说,在随后的权利要求中,使用的术语不应解释成将权利要求书限制在本说明书和权利要求书中披露的具体实施方案中,而应解释成包括所有可能的实施方案以及这类权利要求书赋予的等效物的全部范围。因此,权利要求并不受本公开内容所限定。
本申请要求于2020年9月25日提交的美国临时申请号63/083,638、于2021年2月3日提交的美国临时申请号63/145,407和于2021年6月17日提交的63/211,987的优先权,这些申请的全部内容以引用方式并入本文。
Claims (61)
1.一种化合物,所述化合物具有结构(I):
或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素,其中:
R1为环烷基、芳基、杂环基、-(CH2)nQ、-CHQR或-CQ(R)2,其中Q是C1-6烷基、芳基、环烷基、杂环基、-OR、-CH2C(O)OR、-C(O)OR、-C(O)NHR、-OC(O)R、-CX3、-CX2H、-C(X)H2、-CN、-N(R)2、-N(R)C(O)R、-N(R)C(O)OR或-N(R)S(O)2R,并且其中R1和/或Q任选地被一个或多个Rq取代;
每个R独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、烷基氨基、-(CH2)nR’、X、芳基、环烷基、杂芳基或杂环基,或者两个R基团与其所附接的原子一起形成碳环或杂环,其中C1-6烷基任选地被X、卤代烷基或卤代烷氧基中的一者或多者取代;
每个Rq独立地为C1-6烷基、C2-6烯基、C2-6炔基、芳基、环烷基、杂芳基、杂环基、-OR、-O(CH2)nR、-OX3、-OX2H、-O(X)H2、-C(O)OR、-C(O)R、-OC(O)R、X、-CX3、-CX2H、-C(X)H2、-CN、-N(R)2、-N(R)C(O)R、-N(R)S(O)2R、S(O)2R、-B(OR)2、-C(H)Q’R或-(CH2)nQ’,其中Q’为C1-6烷基、芳基、环烷基、杂环基、OR’、-C(O)OR’、-OC(O)R’、X、-CX3、-CX2H、-C(X)H2、-CN、-N(R’)2、-N(R’)C(O)R’或-N(R’)S(O)2R’;
R2、R3、R4、R5和R6独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、芳基、环烷基、杂芳基、杂环基、-OR、-C(O)OR、-OC(O)R、X、-CX3、-CX2H、-C(X)H2、C(X)2R、-C(X)(R)2、-CN、-N(R)2、-N(R)C(O)R、-N(R)S(O)2R或S(O)2R;
每个Rx独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、芳基、环烷基、杂芳基、杂环基、-OR、-C(O)OR、-OC(O)R、X、-CX3、-CX2H、-C(X)H2、-CN、-N(R)2、-N(R)C(O)R、-N(R)S(O)2R或S(O)2R;
W为N或CRw;
Z为N或CRz;
Rw为H、C1-6烷基、C2-6烯基、C2-6炔基、芳基、环烷基、杂芳基或杂环基;
Rz为H、C1-6烷基、C2-6烯基、C2-6炔基、芳基、环烷基、杂芳基或杂环基;
每个R′独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、芳基、环烷基、杂芳基或杂环基;
每个X独立地为F、Cl、Br或I;并且
每个n独立地为0、1、2、3、4或5。
3.根据权利要求2所述的化合物,其中R1a为环烷基。
4.根据权利要求2至3中任一项所述的化合物,其中R1a和/或Q被一个或多个Rq取代。
5.根据权利要求4所述的化合物,其中R1a被C1-6烷基、C2-6烯基、芳基、环烷基、杂环基、-OR、-O(CH2)nR、-OX3、-OX2H、-O(X)H2、-C(O)OR、-C(O)R、-OC(O)R、X、-CX3、-CX2H、-C(X)H2、-CN、-N(R)2、-N(R)C(O)R、-N(R)S(O)2R、S(O)2R、-C(H)Q’R或-(CH2)nQ’取代,其中Q’为C1-6烷基、芳基、环烷基、杂环基、OR’、-C(O)OR’、-OC(O)R’、X、-CX3、-CX2H、-C(X)H2、-CN、-N(R’)2、-N(R’)C(O)R’或-N(R’)S(O)2R’。
6.根据权利要求4所述的化合物,其中所述一个或多个Rq为C1-6烷基、芳基、杂环基、-OR、-CN、-C(O)OR或-(CH2)nQ’。
7.根据权利要求2至6中任一项所述的化合物,其中R4和R6独立地为C1-6烷基、C2-6烯基、C2-6炔基、OR、-C(O)OR、-OC(O)R、X、-CX3、-CX2H、-C(X)H2、-CN、-N(R)2、-N(R)C(O)R、-N(R)S(O)2R或S(O)2R。
8.根据权利要求7所述的化合物,其中R6为X、-CX3、-CX2H或-C(X)H2。
9.根据权利要求8所述的化合物,其中R6为-CF3、-CF2H或CFH2。
10.根据权利要求2至9中任一项所述的化合物,其中Rx为H。
11.根据权利要求2至10中任一项所述的化合物,其中W为N并且Z为CH,或者其中W为CH并且Z为N。
13.根据权利要求12所述的化合物,其中R1b为芳基。
14.根据权利要求13所述的化合物,其中R1b为苯基。
15.根据权利要求12至14中任一项所述的化合物,其中R1b和/或Q被一个或多个Rq取代。
16.根据权利要求15所述的化合物,其中R1b被C1-6烷基、C2-6烯基、芳基、环烷基、杂环基、-OR、-O(CH2)nR、-OX3、-OX2H、-O(X)H2、-C(O)OR、-C(O)R、-OC(O)R、X、-CX3、-CX2H、-C(X)H2、-CN、-N(R)2、-N(R)C(O)R、-N(R)S(O)2R、S(O)2R、-B(OR)2、-C(H)Q’R或-(CH2)nQ’取代,其中Q’为C1-6烷基、芳基、环烷基、杂环基、OR’、-C(O)OR’、-OC(O)R’、X、-CX3、-CX2H、-C(X)H2、-CN、-N(R’)2、-N(R’)C(O)R’或-N(R’)S(O)2R’。
18.根据权利要求12至17中任一项所述的化合物,其中R4和R6独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、芳基、环烷基、杂芳基、杂环基、-OR、-C(O)OR、-OC(O)R、X、-CX3、-CX2H、-C(X)H2、-CN、-N(R)2、-N(R)C(O)R、-N(R)S(O)2R或S(O)2R。
19.根据权利要求18所述的化合物,其中R6为X、-CX3、-CX2H或-C(X)H2。
20.根据权利要求19所述的化合物,其中R6为-CF3、-CF2H或CFH2。
21.根据权利要求12至20中任一项所述的化合物,其中Rx为H。
22.根据权利要求12至21中任一项所述的化合物,其中W为N并且Z为CH,或者其中W为CH并且Z为N。
24.根据权利要求23所述的化合物,其中R1c为杂环基。
25.根据权利要求24所述的化合物,其中杂环是含有3个或更多个环成员的芳族和非芳族环部分,其中一个或多个环成员是杂原子并且选自N、O、S或P。
26.根据权利要求23至25中任一项所述的化合物,其中R1c和/或Q被一个或多个Rq取代。
27.根据权利要求26所述的化合物,其中R1c被C1-6烷基、C2-6烯基、芳基、环烷基、杂环基、-OR、-O(CH2)nR、-OX3、-OX2H、-O(X)H2、-C(O)OR、-C(O)R、-OC(O)R、X、-CX3、-CX2H、-C(X)H2、-CN、-N(R)2、-N(R)C(O)R、-N(R)S(O)2R、S(O)2R、-C(H)Q’R或-(CH2)nQ’取代,其中Q’为C1-6烷基、芳基、环烷基、杂环基、OR’、-C(O)OR’、-OC(O)R’、X、-CX3、-CX2H、-C(X)H2、-CN、-N(R’)2、-N(R’)C(O)R’或-N(R’)S(O)2R’。
29.根据权利要求23至28中任一项所述的化合物,其中R4和R6独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、芳基、环烷基、杂芳基、杂环基、-OR、-C(O)OR、-OC(O)R、X、-CX3、-CX2H、-C(X)H2、-CN、-N(R)2、-N(R)C(O)R、-N(R)S(O)2R或S(O)2R。
30.根据权利要求29所述的化合物,其中R6为X、-CX3、-CX2H或-C(X)H2。
31.根据权利要求30所述的化合物,其中R6为-CF3、-CF2H或CFH2。
32.根据权利要求23至31中任一项所述的化合物,其中Rx为H。
33.根据权利要求23至32中任一项所述的化合物,其中W为N并且Z为CH,或者其中W为CH并且Z为N。
35.根据权利要求34所述的化合物,其中Q选自C1-6烷基、芳基、环烷基、杂环基或N(R)C(O)R。
36.根据权利要求35所述的化合物,其中R独立地为C1-6烷基、C2-6烯基、C2-6炔基、烷基氨基、-(CH2)nR’、X、H、芳基、环烷基或杂环基。
37.根据权利要求34至36中任一项所述的化合物,其中R6为X、-CX3、-CX2H或-C(X)H2。
38.根据权利要求37所述的化合物,其中R6为-CF3、-CF2H或CFH2。
39.根据权利要求34至38中任一项所述的化合物,其中Rx为H。
40.根据权利要求34至39中任一项所述的化合物,其中W为N并且Z为CH,或者其中W为CH并且Z为N。
42.根据权利要求41所述的化合物,其中Q选自C1-6烷基、芳基、环烷基、杂环基、-N(R)C(O)R或-N(R)C(O)OR。
43.根据权利要求42所述的化合物,其中R独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、烷基氨基、-(CH2)nR’、X、芳基、环烷基或杂环基。
44.根据权利要求41至43中任一项所述的化合物,其中R6为X、-CX3、-CX2H或-C(X)H2。
45.根据权利要求44所述的化合物,其中R6为-CF3、-CF2H或CFH2。
46.根据权利要求41至45中任一项所述的化合物,其中Rx为H。
47.根据权利要求41至46中任一项所述的化合物,其中W为N并且Z为CH,或者其中W为CH并且Z为N。
49.根据权利要求48所述的化合物,其中R6为X、-CX3、-CX2H或-C(X)H2。
50.根据权利要求49所述的化合物,其中R6为-CF3、-CF2H或CFH2。
51.根据权利要求48至50中任一项所述的化合物,其中Rw和Rz都为H。
52.根据权利要求48至51中任一项所述的化合物,其中Rx为H。
53.一种化合物或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素,所述化合物选自表I中所列的化合物中的任一种。
54.一种药物组合物,所述药物组合物包含根据权利要求1至53中任一项所述的化合物或其药学上可接受的盐、异构体、水合物、溶剂化物或同位素,以及至少一种药学上可接受的赋形剂。
55.一种调节Mas相关G-蛋白受体(MRGPR)X2或MRGPR X2直系同源物的方法,所述方法通过使MRGPR X2或MRGPR X2直系同源物与有效量的根据权利要求54所述的药物组合物接触来进行。
56.一种治疗MRGPR X2或MRGPR X2直系同源物依赖性病状的方法,所述方法通过向有需要的受试者施用有效量的根据权利要求54所述的药物组合物来进行。
57.一种治疗假过敏反应、瘙痒相关病状、疼痛相关病状、炎性或自身免疫性病症的方法,所述方法通过向有需要的受试者施用有效量的根据权利要求54所述的药物组合物来进行。
58.根据权利要求57所述的方法,其中所述瘙痒相关病状是慢性瘙痒;
接触性皮炎;过敏性睑缘炎;贫血;特应性皮炎;大疱性类天疱疮;念珠菌病;水痘;终末期肾衰竭;血液透析;慢性荨麻疹;接触性皮炎、特应性皮炎;疱疹样皮炎;糖尿病;药物过敏、皮肤干燥;出汗障碍性皮炎;异位性湿疹;嗜酸性筋膜炎;大疱性表皮松解;红癣;食物过敏;毛囊炎;皮肤真菌感染;痔疮;疱疹;HIV感染;霍奇金病;甲状腺机能亢进;碘化造影染料过敏;缺铁性贫血;肾病;白血病、卟啉症;淋巴瘤;恶性肿瘤;肥大细胞增多症;多发性骨髓瘤;神经性皮炎;盘尾丝虫病;佩吉特病;虱病;
真性红细胞增多症;结节性痒疹;扁平苔藓;硬化性苔藓;肛门瘙痒;假狂犬病;银屑病;直肠脱垂;结节病肉芽肿;疥疮;血吸虫病;硬皮病、严重应激、淤积性皮炎;泳痒;甲状腺疾病;股癣;酒渣鼻;皮肤淀粉样变性;硬皮病;痤疮;伤口愈合;烧伤愈合;眼痒;或荨麻疹。
59.根据权利要求58所述的方法,其中所述瘙痒相关病状是荨麻疹、瘙痒症、特应性皮炎、皮肤干燥、银屑病、接触性皮炎或湿疹。
60.根据权利要求57所述的方法,其中所述疼痛相关病状是急性疼痛、晚期前列腺癌、AIDS相关疼痛、强直性脊柱炎、蛛网膜炎、关节炎、关节纤维化、共济失调性脑瘫、自身免疫性萎缩性胃炎、缺血性坏死、背痛、白塞氏病(综合征)、灼口综合征、滑囊炎、癌痛、腕管、马尾神经综合征、中枢性疼痛综合征、脑瘫、颈椎管狭窄、腓骨肌萎缩(CMT)病、慢性疲劳综合征(CFS)、慢性功能性腹痛(CFAP)、慢性疼痛、慢性胰腺炎、慢性盆腔疼痛综合征、肺塌陷(气胸)、复杂的局部疼痛综合征(RSD)、角膜神经性疼痛、克罗恩氏病、退行性椎间盘疾病、牙痛、德尔肯氏病、皮肌炎、糖尿病外周神经病变(DPN)、肌张力障碍、埃勒斯-当洛斯综合征(EDS)、子宫内膜异位症、嗜酸性粒细胞增多症-肌痛综合征(EMS)、红斑性肢痛症、纤维肌痛、痛风、头痛、椎间盘突出、脑积水、肋间神经痛、间质性膀胱炎、肠易激综合征(IBS)、青少年皮炎(皮肌炎)、膝关节损伤、腿痛、腰痛血尿综合征、狼疮、莱姆病、髓质海绵肾(MSK)、感觉异常性股痛、间皮瘤、偏头痛、肌肉骨骼疼痛、肌筋膜疼痛、肌炎、颈部疼痛、神经性疼痛、枕神经痛、骨关节炎、佩吉特病、帕森那-特纳综合征、盆腔痛、牙周炎痛、外周神经病变、幻肢疼痛、神经受压、多囊肾病、风湿性多肌痛、多肌炎、卟啉症、疝修补术后疼痛综合征、乳房切除术后、术后疼痛、疼痛综合征、中风后疼痛、胸廓切开术后疼痛综合征、带状疱疹后遗神经痛(带状疱疹)、脊髓灰质炎后综合征、原发性侧索硬化症、银屑病关节炎、阴部神经痛、神经根病、雷诺氏病、类风湿性关节炎(RA)、骶髂关节功能障碍、结节病、舒尔曼氏后凸病、坐骨神经痛、脊柱侧弯、带状疱疹(shingles,HerpesZoster)、干燥综合征、痉挛性斜颈、扩约肌功能不全、脊髓小脑共济失调(SCA共济失调)、脊髓损伤、椎管狭窄、脊髓空洞症、塔洛夫囊肿、横贯性脊髓炎、三叉神经痛、神经性疼痛、溃疡性结肠炎、血管疼痛或外阴痛。
61.根据权利要求57所述的方法,其中所述炎性或自身免疫性病症是慢性炎症、肥大细胞活化综合征、多发性硬化症、史蒂文约翰逊综合征、中毒性表皮坏死松解症、阑尾炎、滑囊炎、皮肤狼疮、结肠炎、膀胱炎、皮炎、静脉炎、反射性交感神经营养不良/复杂的局部疼痛综合征(rsd/crps)、鼻炎、肌腱炎、扁桃体炎、寻常痤疮、窦炎、酒渣鼻、银屑病、移植物抗宿主病、反应性气道病症、哮喘、气道感染、自身炎性疾病、乳糜泻、慢性前列腺炎、憩室炎、肾小球肾炎、化脓性汗腺炎、过敏症、肠道病症、上皮性肠道病症、炎症性肠病、肠易激综合征、克罗恩氏病、溃疡性结肠炎、红斑狼疮、间质性膀胱炎、耳炎、盆腔炎、子宫内膜疼痛、再灌注损伤、风湿热、类风湿性关节炎、结节病、移植排斥、银屑病、肺部炎症、慢性阻塞性肺病、心血管疾病或血管炎。
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