CN118019735A - 作为ccr6抑制剂的芳基磺酰基化合物 - Google Patents
作为ccr6抑制剂的芳基磺酰基化合物 Download PDFInfo
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- CN118019735A CN118019735A CN202280065865.9A CN202280065865A CN118019735A CN 118019735 A CN118019735 A CN 118019735A CN 202280065865 A CN202280065865 A CN 202280065865A CN 118019735 A CN118019735 A CN 118019735A
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- Prior art keywords
- pyridin
- sulfonyl
- piperidin
- phenyl
- mixture
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Abstract
提供了具有式(I)的化合物,其可用于治疗至少部分地由CCR6调节的疾病或病症:式(I)。
Description
相关申请的交叉引用
本申请根据35U.S.C.§119(e)要求于2021年8月18日提交的美国临时申请序列号63/234,274的优先权权益,将其披露内容通过引用以其全文并入本文。
关于在联邦资助的研究和开发下完成的发明的权利的声明
不适用
对以光盘递交的“序列表”、表格或计算机程序列表附件的引用
不适用
背景技术
趋化因子是将巨噬细胞、T细胞、嗜酸性粒细胞、嗜碱性粒细胞和嗜中性粒细胞吸引到炎症位点的各种细胞释放的趋化性细胞因子(评论于Schall,Cytokine[细胞因子],3:165-183(1991);Schall等,Curr.Opin.Immunol.[免疫学目前视点]6:865-873(1994);以及Murphy,Rev.Immun.[免疫学评论],12:593-633(1994)中)。除了刺激趋化作用之外,反应细胞中的趋化因子还可以选择性地诱导其他变化,包括细胞形状的变化、细胞内游离钙离子([Ca2+])浓度的瞬间升高、颗粒胞吐、整合素上调、生物活性脂质(例如,白三烯)的形成以及呼吸爆发(与白细胞激活相关联)。因此,趋化因子是炎症反应的早期触发物,导致炎症介质释放、趋化作用和外渗到感染或炎症位点。
存在两类主要的趋化因子:CXC(α)和CC(β),这取决于前两个半胱氨酸被单个氨基酸分开(C-X-C)还是相邻(C-C)。α-趋化因子,如白细胞介素-8(IL-8)、嗜中性粒细胞激活蛋白-2(NAP-2)和黑色素瘤生长刺激活性蛋白(MGSA)主要对于嗜中性粒细胞是趋化性的,而β-趋化因子,如RANTES、MIP-la、MIP-lb、单核细胞趋化蛋白-l(MCP-l)、MCP-2、MCP-3和嗜酸性粒细胞趋化因子对于巨噬细胞、T-细胞、嗜酸性粒细胞和嗜碱性粒细胞是趋化性的(Deng等,Nature[自然],381:661-666(1996))。趋化因子结合了属于G-蛋白偶联的七跨膜结构域蛋白家族的特异性细胞表面受体(评论于Horuk,Trends Pharm.Sci.[药物科学趋势],15:159-165(1994)中),其被称作“趋化因子受体”。
在结合它们的同源配体时,趋化因子受体通过相关联的三聚G蛋白转导细胞内信号,导致细胞内钙浓度的迅速增加。存在至少十一种结合或应答于β-趋化因子的人趋化因子受体以及至少七种与α趋化因子结合的人趋化因子受体。另外,CX3CR1(分形趋化因子(fractalkine)受体)可以与分形趋化因子结合,该趋化因子通过前两个半胱氨酸之间的一连串三个氨基酸区分。趋化因子受体已经被认为是炎症和免疫调节的障碍和疾病的重要介质,这些障碍和疾病包括哮喘和过敏性疾病,以及自身免疫性病状如类风湿性关节炎和动脉粥样硬化。
已知CCR6首先在B细胞、IL17分泌T细胞、调控T细胞和树突细胞中表达,并且对其同源配体CCL20(MIP-3α)显示出强结合。CCR6在大约30%-60%的成人外周血效应子/记忆CD4+T细胞中表达。CCR6涉及白细胞归巢至炎症组织,特别是皮肤和肺,并且在几乎所有的具有皮肤归巢表型的T细胞,CLA+T细胞上共表达。因此,CCR6可能是白细胞参与其中的皮肤病状中的重要参与者。
CCR6表达以下列方式与银屑病相联系。在人中,外周血中的绝大多数皮肤归巢CD4T细胞以更大程度的CCL20-介导的趋化作用表达CCR6,该趋化作用发生于自银屑病患者分离的T细胞中(Homey等,JI[免疫学杂志],2000)。在几种炎症疾病中,IL17分泌细胞是中枢剂(central agent)。T细胞如γδT细胞和TH17 T细胞在激活之后产生IL17。IL17的致病效应与诸如以下的人疾病相关联:类风湿性关节炎(Patel DD等,Ann Rheum Dis[风湿病年鉴]2013)、多发性硬化(Zepp J、Wu L和X Li Trends Immunol[免疫学趋势]2011)、和银屑病(Martin DA等,J Invest Dermatol[皮肤病学研究杂志]2012)。IL17与银屑病之间的强有力联系的证据包括全基因组关联研究,这些研究表明银屑病与IL17信号传导通路的上游基因(IL-23)或下游基因(NFκb)以及在临床环境中靶向IL17的功效之间的强烈相关(Martin DA等,J.Invest Dermat.[皮肤病学研究杂志]2012;Papp等,NEJM[新英格兰医学杂志],2012;Papp等,NEJM[新英格兰医学杂志],2012)。除了增强的CCL20-介导的趋化作用之外,当与健康对照相比时,自银屑病患者分离的CCR6+T细胞优先分泌IL-17A、IL22、和TNFα(Kagami等,J.Invest.Dermatol.[皮肤病学研究杂志],2010)。最终,ccl20 mRNA在病灶性银屑病皮肤样本中上调(Homey等,JI[免疫学杂志],2000;Dieu-Nosjean等,JEM[实验医学杂志],2000)。在小鼠中,CCR6基因敲除小鼠免于IL-23驱动的银屑病侵害。因此,大量在小鼠和男性二者中的证据表明CCR6阻滞在银屑病和银屑病样模型中的保护性作用。
最近研究CCR6抑制剂化合物的工作描述于Tawaraishi等,Bioorg.Med.Chem.Lett.[生物有机与药物化学快报]28:3067-3072(2018)中。
鉴于CCR6的临床重要性,对调节CCR6功能的化合物的识别代表了开发新治疗剂的有吸引力的途径。本文提供了此类化合物及其使用方法。
发明内容
本文描述了具有式(I)的化合物:
其中Ar1、X、Y、Z、环A、下标m、R3和R4具有以下详述中提供的含义。这些化合物在至少部分地由CCR6调节的疾病或病症的治疗中有用。
还提供了具有式(I)的化合物的药物组合物。
本披露中进一步提供了用于合成具有式(I)的化合物的制备方法,以及在该制备中有用的选择的中间体。
附图说明
不适用。
具体实施方式
缩写和定义
除非另外说明,否则术语“烷基”本身或作为另一个取代基的一部分意指具有指定的碳原子数(即,C1-8意指一至八个碳)的直链或支链烃基团。烷基基团的实例包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基、正庚基、正辛基等。术语“烯基”是指具有一个或多个双键的不饱和烷基基团。类似地,术语“炔基”是指具有一个或多个三键的不饱和烷基基团。此类不饱和烷基基团的实例包括乙烯基、2-丙烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2,4-戊二烯基、3-(1,4-戊二烯基)、乙炔基、1-和3-丙炔基、3-丁炔基、以及高级的同系物和异构体。术语“环烷基”是指具有指定数目的环原子(例如,C3-6环烷基)并且完全饱和或在环顶点之间具有不超过一个双键的烃环。“环烷基”还意指双环和多环烃环,例如像双环[2.2.1]庚烷、双环[2.2.2]辛烷等。术语“杂环烷烃”或“杂环烷基”是指含有从一至五个选自N、O和S的杂原子的环烷基基团,其中氮和硫原子可选地被氧化,并且一个或多个氮原子可选地被季铵化。杂环烷烃可以是单环、双环或多环环系。杂环烷烃基团的非限制性实例包括吡咯烷、咪唑烷、吡唑烷、丁内酰胺、戊内酰胺、咪唑啉酮、乙内酰脲、二氧杂环戊烷、邻苯二甲酰亚胺、哌啶、1,4-二噁烷、吗啉、硫代吗啉、硫代吗啉-S-氧化物、硫代吗啉-S,S-氧化物、哌嗪、吡喃、吡啶酮、3-吡咯啉、噻喃、吡喃酮、四氢呋喃、四氢噻吩、奎宁环等。杂环烷烃基团可以通过环碳或杂原子附接至分子的其余部分。
术语“亚烷基”本身或作为另一个取代基的一部分意指衍生自烷烃的二价基团,如由-CH2CH2CH2CH2-举例说明。典型地,烷基(或亚烷基)基团将具有从1至24个碳原子,本发明中优选具有10个或更少碳原子的那些基团。“低级烷基”或“低级亚烷基”是较短链烷基或亚烷基,其通常具有四个或更少碳原子。类似地,“亚烯基”和“亚炔基”是指分别具有双键或三键的“亚烷基”的不饱和形式。
如本文所用,在本文所描绘的任何化学结构中与单键、双键或三键相交的波浪线表示单键、双键或三键与分子的其余部分的附接点。
术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)以其常规意义使用,并且是指分别经由氧原子、氨基基团、或硫原子附接至分子的其余部分的那些烷基基团。另外,对于二烷基氨基基团,烷基部分可以是相同或不同的并且也可以与各自所附接的氮原子组合形成3-7元环。因此,表示为二烷基氨基或-NRaRb的基团意指包括哌啶基、吡咯烷基、吗啉基、氮杂环丁烷基等。
术语“羟基烷基”是指其中氢原子中的一个、两个、或三个被羟基(-OH)基团取代的烷基基团。在一些实施例中,羟基烷基具有一至两个羟基基团。在一些实施例中,羟基烷基具有一个羟基基团。至于烷基部分,羟基烷基基团可以具有任何合适的碳原子数,如C1-6,并且可以是直链或支链的。羟基烷基基团包括例如羟基甲基、1-羟基乙基、2-羟基乙基、2-羟基丙-2-基等。
术语“二-(C1-4烷基)氨基-C1-4烷基”是指带有可以相同或不同的两个C1-4烷基基团(例如,甲基、乙基、丙基、异丙基、正丁基、仲丁基、异丁基和叔丁基)并且通过C1-4烷基基团(一至四个碳亚烷基连接基团)附接至分子的其余部分的氨基基团。二-(C1-4烷基)氨基-C1-4烷基基团的实例包括二甲氨基甲基、2-(乙基(甲基)氨基)乙基、3-(二甲氨基)丁基等。
除非另外说明,否则术语“卤代”或“卤素”本身或作为另一个取代基的一部分意指氟、氯、溴、或碘原子。另外,术语如“卤代烷基”意指包括单卤代烷基和多卤代烷基。例如,术语“C1-4卤代烷基”意指包括三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基等。
除非另外说明,否则术语“芳基”意指可以是单环或稠合在一起或共价连接的多个环(至多三个环)的多不饱和、典型地为芳香族的烃基团。术语“杂芳基”是指含有从一至五个选自N、O和S的杂原子的芳基基团(或环),其中氮和硫原子可选地被氧化,并且一个或多个氮原子可选地被季铵化。杂芳基基团可以通过杂原子附接至分子的其余部分。芳基基团的非限制性实例包括苯基、萘基和联苯基,而杂芳基基团的非限制性实例包括吡啶基、哒嗪基、吡嗪基、嘧啶基、三嗪基、喹啉基(quinolinyl)、喹喔啉基、喹唑啉基、噌啉基、酞嗪基、苯并三嗪基、嘌呤基、苯并咪唑基、苯并吡唑基、苯并三唑基、苯并异噁唑基、异苯并呋喃基、异吲哚基、吲嗪基、苯并三嗪基、噻吩并吡啶基、噻吩并嘧啶基、吡唑并嘧啶基、咪唑并吡啶、苯并噻唑基(benzothiaxolyl)、苯并呋喃基、苯并噻吩基、吲哚基、喹啉基(quinolyl)、异喹啉基、异噻唑基、吡唑基、吲唑基、蝶啶基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噻二唑基、吡咯基、噻唑基、呋喃基、噻吩基等。上述芳基和杂芳基环系中的每个的取代基选自下述可接受的取代基的组。
术语“芳烷基”意指包括其中芳基基团附接至烷基基团的那些基团(例如,苄基、苯乙基等)。类似地,术语“杂芳基-烷基”意指包括其中杂芳基基团附接至烷基基团的那些基团(例如,吡啶基甲基、噻唑基乙基等)。
如本文所用,术语“杂原子”意指包括氧(O)、氮(N)、硫(S)和硅(Si)。
更具体地,短语“具有1或2个选自N、O和S的杂原子作为环顶点的5元或6元杂环”是指具有5或6个环顶点的单环,其中环顶点中的1或2个是杂原子(N、O或S)。这类环的实例包括吗啉、吡咯烷、四氢呋喃、硫代吗啉、哌啶、哌嗪等。环在环顶点之间可以具有0或1个双键。
短语“具有0至4个选自N、O、S、和S(O)2的杂原子作为环顶点的双环9元或10元稠合芳香族或杂芳香族环”是指其中第一环的两个相邻环顶点也是第二环的相邻环顶点的环系(即,稠合环系),并且其中这两个环中的至少一个是芳香族的。在一些实施例中,两个环都具有芳香族特征(例如,萘、喹诺酮、喹唑啉、苯并咪唑、苯并噻吩、苯并吡唑)。在一些实施例中,仅一个环是芳香族的(例如,茚满、1,2,3,4-四氢萘、5,6,7,8-四氢喹啉、1,2,3,4-四氢异喹啉)。
短语“具有0至3个选自N、O和S的杂原子作为环顶点的单环5元或6元芳香族或杂芳香族环”是指芳香族单环(苯基)或杂芳香族单环(例如,吡啶、噻吩、呋喃、嘧啶、吡嗪)。
“3元至6元螺环”是指具有两个与碳原子附接的点的基团,该碳原子是环顶点或亚烷基基团一部分。例如,基团:
是具有1个杂原子作为环顶点的双环9元或10元稠合芳香族或杂芳香族环,并且其被3元螺环和氧代基取代。
术语“螺杂环”、“螺杂环基”或“螺杂环烷基”是指具有6至12个环原子的饱和或部分不饱和的双环,其中这两个环经由单个碳原子(也称为螺原子)连接。螺杂环基基团具有从一至五个选自N、O和S的杂原子作为环顶点,并且一个或多个氮原子可选地被季铵化。部分不饱和的螺杂环烷基基团在这些环中的一个中具有双键。代表性实例包括但不限于2,6-二氮杂螺[3.3]庚烷、2,6-二氮杂螺[3.4]辛烷、2-氮杂螺[3.4]辛烷、2-氮杂螺[3.5]-壬烷、2,7-二氮杂螺[4.4]壬烷等。
术语“药学上可接受的盐”意指包括活性化合物的盐,这些活性化合物根据在本文所述的化合物上见到的特定取代基用相对无毒的酸或碱制备。当本发明的化合物含有相对酸性的官能团时,碱加成盐可以通过使这类化合物的中性形式与足量的所希望的碱(纯碱或在合适的惰性溶剂中)接触来获得。衍生自药学上可接受的无机碱的盐的实例包括铝、铵、钙、铜、铁、亚铁、锂、镁、锰、二价锰、钾、钠、锌等。衍生自药学上可接受的有机碱的盐包括伯胺、仲胺和叔胺的盐,这些胺包括经取代的胺、环状胺、天然存在的胺等,如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、氨基葡萄糖、组氨酸、海巴明盐(hydrabamine)、异丙胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。当本发明的化合物含有相对碱性的官能团时,酸加成盐可以通过使这类化合物的中性形式与足量的所希望的酸(纯酸或在合适的惰性溶剂中)接触来获得。药学上可接受的酸加成盐的实例包括衍生自无机酸的那些,如盐酸、氢溴酸、硝酸、碳酸、一氢碳酸、磷酸、一氢磷酸、二氢磷酸、硫酸、一氢硫酸、氢碘酸、或亚磷酸等,以及衍生自相对无毒的有机酸的盐,如乙酸、丙酸、异丁酸、丙二酸、苯甲酸、琥珀酸、辛二酸、富马酸、杏仁酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲磺酸等。还包括氨基酸的盐如精氨酸盐等,和有机酸如葡糖醛酸或半乳糖醛酸等的盐(参见,例如,Berge,S.M.等,“Pharmaceutical Salts[药物盐]”,Journal of Pharmaceutical Science[药物科学杂志],1977,66,1-19)。本发明的某些特定化合物含有碱性官能团和酸性官能团二者,这允许化合物转化为碱加成盐或酸加成盐。
化合物的中性形式可以通过使该盐与碱或酸接触并且以常规方式分离母体化合物而再生。化合物的母体形式在某些物理特性(如在极性溶剂中的溶解度)方面不同于各种盐形式,但在其他方面,这些盐出于本发明的目的等效于化合物的母体形式。
除了盐形式之外,本发明还提供了以前药形式的化合物。本文描述的化合物的前药是在生理条件下容易经历化学变化以提供本发明的化合物的那些化合物。另外,前药可以在离体环境中通过化学或生化方法转化为本发明的化合物。例如,当将前药置于含有合适的酶或化学试剂的透皮贴剂储库中时,前药可以缓慢地转化为本发明的化合物。
本发明的某些化合物可以以非溶剂化形式以及溶剂化形式(包括水合形式)存在。一般而言,溶剂化形式等效于非溶剂化形式,并且旨在涵盖于本发明的范围内。本发明的某些化合物可以以多种结晶或无定形形式存在。一般而言,所有物理形式对于本发明考虑的用途都是等效的,并且旨在涵盖于本发明的范围内。
本发明的某些化合物具有不对称碳原子(光学中心)或双键;外消旋体、非对映异构体、几何异构体、位置异构体和单独异构体(例如,分离的对映异构体)全部旨在涵盖于本发明的范围内。本发明的化合物还可以在构成此类化合物的原子中的一个或多个处含有非天然比例的原子同位素。非天然比例的同位素可以定义为从自然中见到的量至组成为100%所考虑原子的量。例如,化合物可以掺入放射性同位素,例如像氚(3H)、碘-125(125I)或碳-14(14C),或非放射性同位素,如氘(2H)或碳-13(13C)。此类同位素变体可以为本申请别处描述的那些提供额外的效用。例如,本发明的化合物的同位素变体可以获得额外的效用,包括但不限于作为诊断和/或成像试剂、或作为细胞毒性/放射毒性的治疗剂。另外,本发明的化合物的同位素变体可以具有可以有助于增强治疗期间的安全性、耐受性或功效的改变的药代动力学和药效动力学特征。本发明的化合物的所有同位素变体,无论是否具有放射性,均旨在涵盖于本发明的范围内。
除非另有说明,否则术语“和酸电子等排体”意指可以替代羧酸的基团,其具有酸性官能团以及提供与羧酸类似的活性水平(或其他化合物特征如溶解度)的立体和电子特征。代表性的酸电子等排体包括异羟肟酸、磺酸、亚磺酸、磺酰胺、酰基-磺酰胺、膦酸、次膦酸、磷酸、四唑、和氧代-噁二唑。
具有式I的本发明化合物可以以不同的异构体形式存在。如本文所用,术语顺式或反式以其在化学领域中的常规意义使用,即,是指相对于参考平面(例如,双键)或环系(如萘烷型环系或氢化喹诺酮环系),取代基相对彼此的位置:在顺式异构体中,取代基是在参考平面的同一侧上,在反式异构体中,取代基是在相对侧上。另外,本发明还考虑不同的构象异构体以及不同的旋转异构体。构象异构体(Conformer)是可以通过旋转约一个或多个σ键而不同的构象异构体(conformational isomer)。旋转异构体是通过旋转约仅单一σ键而不同的构象异构体。
概述
本发明源于具有式I的化合物充当CCR6受体的有效拮抗剂的发现。这些化合物具有体内抗炎活性,并且具有优异的药代动力学特性。因此,本文提供的化合物可用于用于治疗CCR6-介导的疾病的药物组合物和方法中,并且可作为用于识别竞争性CCR6拮抗剂的测定中的对照。
III.化合物
在一方面,本文提供了具有式I的化合物:
或其药学上可接受的盐、水合物、溶剂化物、N-氧化物、光学富集形式、或旋转异构体,
其中
X是N或CH;
Z是O或N(Rf)-,其中Rf选自由氢、C1-4烷基、C1-4卤代烷基、C1-4羟基烷基、和C3-6环烷基组成的组;
环A是苯环或吡啶环;
Ar1是具有0至3个选自N、O和S的杂原子作为环顶点的单环5元或6元芳香族或杂芳香族环,其被从0至5个R1取代基取代,这些取代基独立地选自由卤素、CN、C1-8烷基、C3-8环烷基、C2-8烯基、C2-8炔基、C1-8卤代烷基、C1-8羟基烷基、-ORa、和-NRaRb组成的组;
Ra和Rb各自独立地选自由氢、羟基、C1-4烷基、C1-4卤代烷基、C1-4羟基烷基、和C3-6环烷基组成的组;
Y选自由以下项组成的组:
i)具有0至4个选自N、O、S和S(O)2的杂原子作为环顶点的双环9元或10元稠合芳香族或杂芳香族环,并且其被0至5个R2取代;
ii)具有1或2个选自N、O、S和S(O)2的杂原子作为环顶点的4元至7元单环杂环,并且其被0至5个R2取代;
iii)具有1至4个选自N、O、S和S(O)2的杂原子作为环顶点的6元至12元稠合或桥接杂环,并且其被0至6个R2取代;和
iv)具有0至4个选自N、O和S的杂原子作为环顶点的7元至12元螺杂环,并且其被0至6个R2取代;
每个R2独立地选自由以下项组成的组:卤素、CN、C1-8烷基、C3-8环烷基、C2-8烯基、C2-8炔基、C1-8卤代烷基、C1-8羟基烷基、-ORc、-SRc、-OSi(Rc)3、-CORc、-CO2Rc、-NRcRd、-NRcRe、-CONRcRd、-(CO)2NRcRd、-NRcCO2Rd、-NRcCORd、-NRcCONRcRd、-NRcSO2Rd、-SO2Rd、-CO-C1-4羟基烷基、-SO2NRcRd、-X2-NRcRd、-X2-CONRcRd、-X2-NRcCONRcRd、-X2-NRcCO2Rd、-X2-NRcCORd、-X2-NRcSO2Rd、-CO-X2-NRcCORd、氧代基、具有1或2个选自N、O、S和S(O)2的杂原子作为环顶点的4元至7元杂环、5元或6元杂芳基、和-X2-5元或6元杂芳基;并且其中R2的5元或6元杂芳基环和4元至7元杂环具有从1至3个选自N、O和S的杂原子,并且各自未被取代或被一个或两个独立地选自由卤素、羟基、氨基、C1-4烷基、C1-4烷氧基、C1-4卤代烷基、-CORc、-CO2Rc、和-CONRcRd组成的组中的成员取代;并且其中附接至同一碳原子上的两个R2基团可选地组合以形成3元至6元螺环或具有1至3个选自N、O和S的杂原子作为环顶点的3元至6元螺杂环,并且其未被取代或被1或2个独立地选自C1-4烷基、-CORc、-CO2Rc、和-CONRcRd的成员取代;
Rc和Rd各自独立地选自由氢、羟基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、和C3-6环烷基组成的组;或者Rc和Rd当附接至同一氮原子时连接以形成具有从0至2个选自O、S、S(O)、S(O)2、NH和N(C1-4烷基)的额外杂原子作为环顶点的4元至7元杂环;
每个Re选自由苯基组成的组;
X2是C1-4亚烷基或环丙基;
下标m是0、1或2;
每个R3是独立地选自由卤素、CN、C1-4烷基、C1-4烷氧基、C3-8环烷基、C1-4卤代烷基、C1-4卤代烷氧基、和C2-4羟基烷基组成的组的成员;并且
R4是选自由H、C1-4烷基、C3-8环烷基、和C1-4卤代烷基组成的组的成员。
在一组实施例中,提供了具有式(I)的化合物,其中Y是具有0至4个选自N、O和S的杂原子作为环顶点的双环9元或10元稠合芳香族或杂芳香族环,并且其被0至5个R2取代。在一些实施例中,Y被0、1、2、3或4个R2取代基取代。在相关实施例中,提供了具有式(I)的化合物,其中Y是选自由以下项组成的组的双环9元或10元稠合芳香族或杂芳香族环:
其各自被0至5个R2取代。在一些实施例中,Y被0、1、2、3或4个R2取代基取代。在其他相关实施例中,提供了具有式(I)的化合物,其中Y是选自由以下项组成的组的双环9元或10元稠合芳香族或杂芳香族环:
其各自被0至3个R2取代。在一些实施例中,Y被0、1、2或3个R2取代基取代。在仍其他相关实施例中,提供了具有式(I)的化合物,其中Y是选自由以下项组成的组的双环9元或10元稠合芳香族或杂芳香族环:
其各自被0至5个R2取代。在一些实施例中,Y被0、1、2、3或4个R2取代基取代。
在另一组实施例中,提供了具有式(I)的化合物,其中Y是具有1或2个选自N、O和S的杂原子作为环顶点的4元至7元单环杂环,并且其被0至5个R2取代。在一些实施例中,Y被0、1、2、3或4个R2取代基取代。在一些相关实施例中,Y是选自由氮杂环丁烷、吡咯烷、哌啶、哌嗪、吗啉、硫代吗啉、二氢吡喃、四氢吡啶和二氮杂环庚烷组成的组的4元至7元单环杂环,并且其被0至5个R2取代,并且在一些实施例中,每个Y环被0、1、2、3或4个R2取代基取代。在其他相关实施例中,Y是选自由以下项组成的组的4元至7元单环杂环:
其各自被0至5个R2取代。在一些实施例中,每个Y被0、1、2、3或4个R2取代基取代。
在又另一组实施例中,提供了具有式(I)的化合物,其中Y是具有1至4个选自N、O和S的杂原子作为环顶点的6元至12元稠合或桥接杂环,并且其被0至6个R2取代。在一些实施例中,Y被0、1、2、3、4或5个R2取代基取代。在一些相关实施例中,Y是选自由以下项组成的组的6元至12元稠合或桥接杂环:
其各自被0至4个R2取代。在一些实施例中,每个Y被0、1、2或3个R2取代基取代。
在仍另一组实施例中,提供了具有式(I)的化合物,其中Y是具有1或4个选自N、O和S的杂原子作为环顶点的7元至12元螺杂环,并且其被0至6个R2取代。在一些实施例中,Y被0、1、2、3、4或5个R2取代基取代。在一些相关实施例中,Y是选自由以下项组成的组的7元至12元螺杂环:
其各自被0至4个R2取代。在一些实施例中,每个Y被0、1、2或3个R2取代基取代。
在一些实施例中,提供了具有式(I)的化合物或上面提到的任何实施例,其中Ar1是苯基,其被从1至3个R1取代基取代。
在其他实施例中,提供了具有式(I)的化合物或上面对于“Y”基团提到的任何实施例,其中Ar1是吡啶基,其被从1至3个R1取代基取代。
在一些实施例中,提供了具有式(I)的化合物或上面提到的任何实施例,其中R3是H,Z是O,并且X是N。在其他实施例中,提供了具有式(I)的化合物(以及上面对于Y和Ar1或组合提到的任何实施例),其中R3是H,Z是O,并且X是CH。
在一些实施例中,提供了具有式(I)的化合物或上面提到的任何实施例,其具有式(Ia):
在一些选择的实施例中,提供了具有式(Ia)的化合物,其中每个R1独立地选自由CH3、CF3和CN组成的组。在一组实施例中,提供了具有式(Ia)的化合物,其中Y是具有0至4个选自N、O、S和S(O)2的杂原子作为环顶点的双环9元或10元稠合芳香族或杂芳香族环,并且其被0至5个R2取代。在另一组实施例中,提供了具有式(Ia)的化合物,其中Y是具有1至4个选自N、O、S和S(O)2的杂原子作为环顶点的6元至12元稠合或桥接杂环,并且其被0至6个R2取代。在又另一组实施例中,提供了具有式(Ia)的化合物,其中Y是具有0或4个选自N、O和S的杂原子作为环顶点的7元至12元螺杂环,并且其被0至5个R2取代。在仍另一组实施例中,提供了具有式(Ia)的化合物,其中Y是具有1或2个选自N、O、S和S(O)2的杂原子作为环顶点的4元至7元单环杂环,并且其被0至5个R2取代。
在其他实施例中,提供了具有式(I)的化合物或上面提到的任何实施例,其具有式(Ia1):
其中R1是-CN或-CF3。
在一些实施例中,提供了具有式(Ia1)的化合物,其中Y选自由以下项组成的组:
其各自被0至5个R2取代。
在一些实施例中,提供了具有式(Ia1)的化合物,其中Y选自由以下项组成的组:
其各自被0至3个R2取代。
在一些实施例中,提供了具有式(Ia1)的化合物,其中Y选自由以下项组成的组:
其各自被0至5个R2取代。
在一些实施例中,提供了具有式(Ia1)的化合物,其中Y选自由以下项组成的组:
其各自被0至4个R2取代。
在一些实施例中,包括上面提到的实施例,下标m是0(R3不存在)。在其他实施例中,包括上面提到的实施例,下标m是1。在仍其他实施例中,包括上面提到的实施例,下标m是2。
在仍其他选择的实施例中,具有式(I)的化合物选自表1中提供的化合物。
对于所有上面提到的实施例,除了游离碱或其他中性形式之外,还提供了以其药学上可接受的盐、水合物、溶剂化物、N-氧化物或旋转异构体形式的每种化合物作为额外的实施例。
化合物的制备
以下实例中的方案提供了某些合成途径,可以按照这些途径来获得本发明的某些化合物。其他途径或以下呈现的途径的修改对本领域技术人员将是显而易见的,并且在本发明的范围内。
一般合成方法
合适地,可以使1-N-保护的4-氨基-哌啶I与2-卤代-5-取代的吡啶II(X=F或Cl)和碱在SNAr取代反应中反应,以形成4-氨基吡啶基哌啶III。可以在适当的条件下去除保护基团,以得到以游离碱或具有抗衡离子的质子化物质形式的1-NH哌啶IV。可以将这种胺进一步用碱和带有取代基(如果需要的话)的4-溴磺酰氯V在磺酰胺化反应中处理,以得到4-氨基吡啶基-1-N-磺酰胺VI。
可以将4-氨基吡啶基-1-N-哌啶基-磺酰胺VI进一步在直接铃木交叉偶联反应(A=硼物质;芳基/杂芳基硼酸或酯)或在溴化物VI上进行的美由奈(Miyura)溴化物/硼酸酯交换,随后用芳基/杂芳基溴化物(A=Br)进行铃木偶联来精制,以得到最终化合物VII。
IV.药物组合物
除了上面提供的化合物之外,用于调节人和动物中的CCR6活性的组合物将典型地含有药物载体或稀释剂。
如本文所用,术语“组合物”旨在涵盖以所说明的量包含所说明的成分的产品,以及以所说明的量直接或间接获自所说明的成分的组合的任何产品。“药学上可接受的”意指载体、稀释剂或赋形剂必须与制剂的其他成分相容并且对其接受者无害。
用于施用本发明的化合物的药物组合物可以常规地以单位剂型存在,并且可以通过药学和药物递送领域中熟知的任何方法来制备。所有方法都包括使活性成分与构成一种或多种辅助成分的载体缔合的步骤。一般而言,药物组合物通过以下步骤制备:使活性成分与液体载体或细分散的固体载体或两者均匀并紧密地缔合,然后(如果需要)使产物成形为所希望的制剂。活性目标化合物以足够对疾病的过程或病症产生所希望的作用的量包括含药物组合物中。
含有活性成分的药物组合物可以呈适合口服使用的形式,例如,以片剂、糖剂、锭剂、水性或油性悬浮液、可分散性粉剂或颗粒剂、乳剂和自乳化剂(self-emulsifications)(如在美国专利号6,451,339中所述的)、硬胶囊剂或软胶囊剂、糖浆剂、酏剂、溶液剂、口腔贴剂、口服凝胶剂、口香糖、可咀嚼片剂、泡腾粉剂和泡腾片剂形式。旨在用于口服使用的组合物可以根据本领域已知的用于制造药物组合物的任何方法来制备,并且为了提供药学上精致的且适口的制剂,这类组合物可以含有选自由甜味剂、调味剂、着色剂、抗氧化剂和防腐剂组成的组的一种或多种药剂。片剂含有与适合制造片剂的无毒的药学上可接受的赋形剂混合的活性成分。这些赋形剂可以是例如惰性稀释剂,如纤维素、二氧化硅、氧化铝、碳酸钙、碳酸钠、葡萄糖、甘露糖醇、山梨糖醇、乳糖、磷酸钙或磷酸钠;制粒剂和崩解剂,例如玉米淀粉或海藻酸;粘合剂,例如PVP、纤维素、PEG、淀粉、明胶或阿拉伯胶;和润滑剂,例如硬脂酸镁、硬脂酸或滑石粉。片剂可以是未包衣的或者通过已知技术进行经肠溶或以其他方式包衣以延迟在胃肠道中的崩解和吸收,并且从而在较长的时间段内提供持久的作用。例如,可以采用延时材料,如单硬脂酸甘油酯或二硬脂酸甘油酯。它们也可以通过美国专利号4,256,108;4,166,452;和4,265,874中所述的技术进行包衣以形成用于控制释放的渗透治疗片剂。
用于口服使用的制剂还可以以硬明胶胶囊形式提供,其中活性成分与惰性固体稀释剂(例如碳酸钙、磷酸钙或高岭土)混合,或以软明胶胶囊形式提供,其中活性成分与水或油介质(例如花生油、液体石蜡或橄榄油)混合。另外,乳剂可以用非水混溶性成分(如油)制备并用表面活性剂(如单-二甘油酯、PEG酯等)稳定。
水性悬浮液含有与适合制造水性悬浮液的赋形剂混合的活性材料。这类赋形剂是助悬剂,例如羧甲纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯基-吡咯烷酮、黄蓍胶和阿拉伯胶;分散剂或润湿剂可以是天然存在的磷脂(例如卵磷脂)、或环氧烷与脂肪酸的缩合产物(例如聚氧乙烯硬脂酸酯)、或环氧乙烷与长链脂肪族醇的缩合产物(例如十七亚乙基氧基鲸蜡醇)、或环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物(如聚氧乙烯山梨糖醇单油酸酯)、或环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物(例如聚乙烯脱水山梨糖醇单油酸酯)。水性悬浮液还可以含有一种或多种防腐剂(例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯)、一种或多种着色剂、一种或多种调味剂、和一种或多种甜味剂如蔗糖或糖精。
可以通过将活性成分悬浮于植物油,例如花生油、橄榄油、芝麻油或椰子油,或矿物油如液体石蜡中来配制油性悬浮液。油性悬浮液可以含有增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。可以添加甜味剂如上面阐述的那些,和调味剂,以提供适口的口服制剂。这些组合物可以通过添加抗氧化剂如抗坏血酸来保存。
通过添加水而适合制备水性悬浮液的可分散性粉剂和颗粒剂提供了与分散剂或湿润剂、助悬剂和一种或多种防腐剂混合的活性成分。合适的分散剂或润湿剂和助悬剂通过上面已经提及的那些举例说明。还可以存在额外的赋形剂,例如甜味剂、调味剂和着色剂。
本发明的药物组合物还可以呈水包油乳剂的形式。油相可以是植物油(例如橄榄油或花生油),或矿物油(例如液态石蜡),或这些物质的混合物。合适的乳化剂可以是天然存在的树胶,例如阿拉伯树胶或黄芪胶,天然存在的磷脂,例如大豆、卵磷脂,和衍生自脂肪酸和己糖醇酐的酯或偏酯,例如脱水山梨糖醇单油酸酯,和所述偏酯与环氧乙烷的缩合产物,例如聚氧乙烯脱水山梨糖醇单油酸酯。乳剂还可以含有甜味剂和调味剂。
可以用甜味剂,例如甘油、丙二醇、山梨糖醇或蔗糖来配制糖浆和酏剂。这类制剂还可以含有润药剂、防腐剂和调味剂以及着色剂。口服溶液可以与例如环糊精、PEG和表面活性剂组合来制备。
药物组合物可以呈无菌的可注射水性或油性悬浮液的形式。这种悬浮液可以根据已知技术使用上面已经提及的那些合适的分散剂或润湿剂和助悬剂来配制。无菌的可注射制剂还可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌的可注射溶液或悬浮液,例如像在1,3-丁二醇中的溶液。在可以采用的可接受媒介和溶剂之中的是水、林格氏液(Ringer's solution)和等渗氯化钠溶液。另外,无菌的固定油被常规地用作溶剂或助悬介质。出于这一目的,可以采用任何温和的固定油,包括合成的单甘油酯或二甘油酯。另外,脂肪酸如油酸用于可注射剂的制备。
本发明的化合物还可以呈用于直肠施用药物的栓剂的形式施用。这些组合物可以通过将药物与合适的无刺激性赋形剂混合来制备,该无刺激性赋形剂在常温下是固体,但在直肠温度下是液体并且将因此在直肠中融化以释放药物。此类材料包含可可脂和聚乙二醇。另外,化合物可以借助于溶液或软膏经由眼部递送来施用。还进一步地,主题化合物的经皮递送可以借助于离子电渗(iontophoretic)贴剂等来完成。出于局部用途,采用含有本发明的化合物的乳膏、软膏、凝胶剂、溶液或悬浮液等。如本文所用,局部应用还意指包括使用漱口水和漱口剂。
本发明的化合物可以经配制以存放于医疗装置中,该医疗装置可以包括任何各种常规移植物、支架,包括支架移植物、导管、球囊、网篮(basket)或其他可以部署或永久植入体腔内的装置。作为特定的实例,将希望具有可以将本发明的化合物递送至已经通过介入技术治疗的身体区域的装置和方法。
在示例性实施例中,可以将本发明的抑制剂存放在医疗装置如支架内,并且递送至治疗部位以治疗身体的一部分。
支架已被用作治疗剂(即,药物)的递送媒介物。血管内支架通常永久地植入冠状或周围血管中。支架设计包括美国专利号4,733,655(Palmaz)、4,800,882(Gianturco)、或4,886,062(维克托Wiktor)的那些。此类设计包括金属支架和聚合物支架二者,以及自扩张和可球囊扩张支架。例如,支架还可以用于在与血管接触的部位递送药物,如在美国专利号5,102,417(Palmaz)以及国际专利申请号WO 91/12779(美敦力公司(Medtronic,Inc.))和WO 90/13332(雪松西奈医学中心(Cedars-Sanai Medical Center))、美国专利号5,419,760(Narciso,Jr.)和美国专利号5,429,634(Narciso,Jr.)中所披露的。支架还用于将病毒递送至内腔壁用于基因递送,如美国专利申请序列号5,833,651(Donovan等)中所披露的。
术语“存放”意指抑制剂通过本领域已知的方法涂覆、吸附、放置或以其他方式并入装置中。例如,抑制剂可以嵌入涂覆或跨越医疗装置的聚合物材料内并从这些聚合物材料内释放(“基质型”)或被这些聚合物材料包围并通过这些聚合物材料释放(“储库型”)。在后一实例中,抑制剂可以使用一种或多种本领域已知的产生此类材料的技术包埋在聚合物材料内或偶联至聚合物材料。在其他制剂中,抑制剂可以借助于可拆键连接至医疗装置的表面而无需涂层,并且随时间而释放,可以通过有效的机械或化学方法去除,或者以永久固定的形式在植入部位提供抑制剂。
在一个实施例中,抑制剂可以在形成医疗装置如支架的生物相容涂层期间与聚合物组合物一起并入。由这些组分产生的涂层典型地是均匀的并且可用于涂覆许多经设计用于植入的装置。
根据所希望的释放速率或所希望的聚合物稳定程度,聚合物可以是生物稳定的或生物可吸收的聚合物,但是生物可吸收的聚合物对于这个实施例是优选的,因为与生物稳定的聚合物不同,生物可吸收的聚合物在植入后不会存在很久,以免引起任何不良的慢性局部反应。可以使用的生物可吸收的聚合物包括但不限于聚(L-乳酸)、聚己内酯、聚乙交酯(PGA)、聚(丙交酯-共-乙交酯)(PLLA/PGA)、聚(羟基丁酸酯)、聚(羟基丁酸酯-共-戊酸酯)、聚二噁烷酮、聚原酸酯、聚酸酐、聚(乙醇酸)、聚(D-乳酸)、聚(L-乳酸)、聚(D,L-乳酸)、聚(D,L-丙交酯)(PLA)、聚(L-丙交酯)(PLLA)、聚(乙醇酸-共-碳酸三亚甲酯)(PGA/PTMC)、聚环氧乙烷(PEO)、聚二噁烷酮(PDS)、聚磷酸酯、聚磷酸酯氨基甲酸乙酯、聚(氨基酸)、氰基丙烯酸酯、聚(碳酸三亚甲酯)、聚(亚氨基碳酸酯)、共聚(醚-酯)(例如,PEO/PLA)、聚草酸亚烷基酯、聚磷腈和生物分子(如纤维蛋白、纤维蛋白原、纤维素、淀粉、胶原和透明质酸)、聚ε己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯、水凝胶的交联或两亲嵌段共聚物、和本领域中已知的其他合适的生物可吸收聚合物。此外,可以使用具有相对低的慢性组织反应的生物稳定聚合物,如聚氨酯、硅酮和聚酯,并且还可以使用其他聚合物,条件是这些聚合物可以在医疗装置上溶解和固化或聚合,如聚烯烃、聚异丁烯和乙烯-α烯烃共聚物;丙烯酸聚合物和共聚物、乙烯基卤化物聚合物和共聚物,如聚氯乙烯;聚乙烯吡咯烷酮;聚乙烯醚,如聚乙烯基甲基醚;聚偏二乙烯卤化物,如聚偏二氟乙烯和聚偏二氯乙烯;聚丙烯腈、聚乙烯酮;聚乙烯基芳香族物,如聚苯乙烯、聚乙烯酯,如聚乙酸乙烯酯;乙烯基单体与彼此和烯烃的共聚物,如乙烯-甲基丙烯酸甲酯共聚物、丙烯腈-苯乙烯共聚物、ABS树脂和乙烯-乙酸乙烯酯共聚物;吡喃共聚物;聚羟基丙基甲基丙烯酰胺-酚;聚羟基乙基-天冬酰胺-酚;经棕榈酰基残基取代的聚氧乙烯-聚赖氨酸;聚酰胺,如尼龙66和聚己内酰胺;醇酸树脂、聚碳酸酯;聚甲醛;聚酰亚胺;聚醚;环氧树脂、聚氨酯;人造纤维;人造纤维-三乙酸酯;纤维素、乙酸纤维素、丁酸纤维素;乙酸丁酸纤维素;塞璐芬(cellophane);硝酸纤维素;丙酸纤维素;纤维素醚;和羧甲基纤维素。
聚合物和半透性聚合物基质可以形成成型制品,如瓣膜、支架、导管、假体等。
在本发明的一个实施例中,本发明的抑制剂与形成为支架或支架-移植物装置的聚合物和半透性聚合物基质偶联。
典型地,聚合物通过旋涂、浸渍或喷涂施用于可植入装置的表面。出于这个目的,还可以利用本领域已知的额外方法。喷涂的方法包括传统的方法,以及用喷墨型施配器的微沉积技术。额外地,聚合物可以使用光图案化沉积在可植入装置上,以将聚合物仅放置在装置的特定部分上。装置的这个涂层在装置周围提供均匀的层,其允许改进多种分析物通过装置涂层的扩散。
在本发明的优选实施例中,抑制剂经配制以从聚合物涂层释放到放置医疗装置的环境中。优选地,使用几种熟知的涉及聚合物载体或层的技术中的至少一种来控制洗脱,经延长的时间范围(例如,数月)以受控的方式释放抑制剂。这些技术中的一些先前描述于美国专利申请20040243225A1中。
此外,如例如在美国专利号6,770,729中所述,可以操控聚合物组合物的试剂和反应条件,从而可以控制抑制剂从聚合物涂层的释放。例如,可以调节该一个或多个聚合物涂层的扩散系数以控制抑制剂从聚合物涂层的释放。在这个主题的变化形式中,可以控制该一个或多个聚合物涂层的扩散系数以调节放置医疗装置的环境中存在的分析物(例如,促进聚合物的一些部分分解或水解的分析物)接近聚合物组合物内的一种或多种组分的能力(并且例如,由此调节抑制剂从聚合物涂层的释放)。本发明的又另一个实施例包括具有多个聚合物涂层的装置,每个聚合物涂层具有多个扩散系数。在本发明的此类实施例中,抑制剂从聚合物涂层的释放可以通过多个聚合物涂层来调节。
在本发明的又另一个实施例中,抑制剂从聚合物涂层的释放通过调节聚合物组合物的特性中的一种或多种来控制,如一种或多种内源性或外源性化合物的存在,或者可替代地,聚合物组合物的pH。例如,某些聚合物组合物可以经设计以响应于聚合物组合物pH的下降而释放抑制剂。可替代地,某些聚合物组合物可以经设计以响应于氢过氧化物的存在而释放抑制剂。
V.治疗由CCR6调节的疾病的方法
在一方面,本发明提供了通过向患有CCR6-介导的病症或疾病的受试者施用治疗有效量的本发明的任何化合物来治疗或预防此种病症或疾病的方法。用于本发明方法的优选化合物是以上作为优选实施例提供的那些化合物,以及在以下实例中专门举例说明的并且具备本文中的特定结构的化合物。“受试者”在本文中定义为包括动物如哺乳动物,包括但不限于灵长类(例如,人)、牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠等。在优选的实施例中,受试者是人。
如本文所用,短语“CCR6-介导的病症或疾病”以及相关的短语和术语是指以不适当的(例如,小于或大于正常)CCR6功能活性为特征的病症或疾病。不适当的CCR6功能活性可能由于正常不表达CCR6的细胞中的CCR6表达、增加的CCR6表达(导致例如炎症和免疫调节的障碍和疾病)或降低的CCR6表达所致。不适当的CCR6功能活性还可能由于正常不分泌CCL20的细胞分泌CCL20、增加的CCL20表达(导致例如炎症和免疫调节的障碍和疾病)或降低的CCL20表达所致。CCR6-介导的病症或疾病可以通过不适当的CCR6功能活性完全地或部分地介导。然而,CCR6-介导的病症或疾病是调节CCR6对潜在的病症或疾病有所作用(例如,CCR6拮抗剂导致至少一些患者的患者健康有所改进)的病症或疾病。
术语“治疗有效量”意指主题化合物的量,该量将引起研究人员、兽医、医师或其他临床医生所寻求的组织、系统、动物或人的生物学或医学反应。
与炎症、感染和癌症相关联的疾病和病症可以用本发明化合物和组合物治疗或预防。在一组实施例中,人或其他物种的疾病或病症(包括慢性疾病)可以用具有CCR6功能的抑制剂治疗。这些疾病或病症包括:(1)过敏性疾病,如全身过敏反应或超敏性反应,药品过敏、昆虫叮咬过敏和食物过敏,(2)炎症性肠病,如克罗恩病、溃疡性结肠炎、回肠炎和肠炎,(3)阴道炎,(4)银屑病和炎症性皮肤病,如皮炎、湿疹、特应性皮炎、过敏性接触性皮炎、荨麻疹和瘙痒症、白癜风,(5)脉管炎,(6)脊柱关节病,(7)硬皮病,(8)哮喘和呼吸过敏性疾病,如过敏性哮喘、过敏性鼻炎、超敏性肺病等,(9)自身免疫性疾病,如关节炎(包括类风湿性关节炎和银屑病性关节炎)、以及例如桥本氏甲状腺炎和格雷夫斯病、多发性硬化症、全身性红斑狼疮、I型糖尿病、肾小球肾炎等,(10)移植物排斥(包括同种异体移植物排斥和移植物抗宿主病),和(11)有待抑制不希望的炎症反应的其他疾病,如动脉粥样硬化、肌炎、神经变性疾病(例如,阿尔茨海默病)、脑炎、脑膜炎、肝炎、肾炎、脓毒病、结节病、过敏性结膜炎、耳炎、慢性阻塞性肺病、鼻窦炎、贝赫切特综合征和痛风。
优选地,本发明方法涉及选自过敏性疾病,银屑病,皮肤病症如特应性皮炎和哮喘以及硬皮病的疾病或病症的治疗。
在另一组实施例中,可以调节依赖于CCR6调节的调控T细胞运输以治疗包括以下的疾病或病症:癌症、感染性疾病(病毒感染,例如HIV感染,和细菌感染)和免疫抑制性疾病,如器官移植病症和皮肤移植病症。术语“器官移植病症”意指包括骨髓移植病症和实体器官(例如,肾脏、肝脏、肺、心脏、胰腺或其组合)移植病症。
取决于所治疗的疾病和受试者的状况,本发明的化合物可以通过口腔、肠胃外(例如,肌内、腹腔内、静脉内、ICV、脑池内注射或输注,皮下注射,或植入)、吸入、鼻腔、阴道、直肠、舌下、或局部施用途径来施用,并且可以单独地或一起配制成适合于每种施用途径的含有常规的无毒的药学上可接受的载体、辅助剂和媒介物的合适的剂量单位制剂。本发明还考虑以贮库制剂施用本发明的化合物。
本领域技术人员将理解,调节CCR6活性的药剂在治疗方案中可以与其他治疗剂和/或与化疗剂或放射组合。在一些情况下,如果在不与本发明的组合物组合的情况下提供,则化疗剂或放射的量是将为未达治疗剂量的量。本领域技术人员将了解,“组合”可以包括治疗的组合(即,两种或更多种药物可以作为混合物施用,或者至少同时地或至少在不同的时间引入受试者中但使得同时都处于受试者的血流中)。另外,本发明的组合物可以在第二治疗方案之前或之后施用,例如在一定剂量的化疗或照射之前或之后施用。
本发明的化合物相应地可用于多种炎症和免疫调节的障碍和疾病的预防和治疗中。
在需要趋化因子受体调节的病症的治疗或预防中,适当的剂量水平将通常是每天每kg患者体重约0.001至100mg,其可以以单剂量或多剂量施用。优选地,剂量水平将是每天约0.01至约25mg/kg;更优选每天约0.05至约10mg/kg。合适的剂量水平可以是每天约0.01至25mg/kg、每天约0.05至10mg/kg、或每天约0.1至5mg/kg。在这个范围内,剂量可以是每天0.005至0.05、0.05至0.5或0.5至5.0mg/kg。对于口服施用,组合物优选以片剂的形式提供,这些片剂含有1.0至1000毫克的活性成分,特别地1.0、5.0、10.0、15.0、20.0、25.0、50.0、75.0、100.0、150.0、200.0、250.0、300.0、400.0、500.0、600.0、750.0、800.0、900.0、和1000.0毫克的活性成分,以有症状地调节给予待治疗的患者的剂量。化合物可以根据每天1至4次、优选每天一次或两次的方案施用。
然而,将理解对于任何特定患者而言具体的剂量水平和给药频率可以变化并且将取决于各种因素,包括所采用的具体化合物的活性,该化合物的代谢稳定性和作用长度,受试者的年龄、体重、遗传特征、整体健康、性别和饮食,以及施用的模式和时间,排泄率,药物组合,以及经历治疗的受试者的特定病症的严重程度。
与炎症、免疫障碍、感染和癌症相关联的疾病和病症可以用本发明的化合物、组合物和方法治疗或预防。
本发明的化合物和组合物可以与具有相关效用的其他化合物和组合物组合以预防和治疗所关注的病症或疾病,如炎症或自身免疫的障碍、病症和疾病,包括炎症性肠病、类风湿性关节炎、骨关节炎、银屑病性关节炎、多发性关节炎、多发性硬化症、过敏性疾病、银屑病、特应性皮炎和哮喘,以及以上提到的那些病状。
例如,在炎症或自身免疫或例如关节炎相关联的骨质疏松的治疗或预防中,本发明化合物和组合物可以与抗炎剂或止痛剂如阿片激动剂,脂氧合酶抑制剂,如5-脂氧合酶的抑制剂,环氧化酶抑制剂,如环氧化酶-2抑制剂,白细胞介素抑制剂,如白细胞介素-1抑制剂,NMDA拮抗剂,一氧化氮的抑制剂或一氧化氮的合成的抑制剂,非甾体抗炎剂,或细胞因子抑制性抗炎剂联合使用,例如与化合物如对乙酰氨基酚、阿司匹林、可待因、芬太尼、布洛芬、吲哚美辛、酮咯酸、吗啡、萘普生、非那西丁、吡罗昔康、甾体止痛剂、舒芬太尼(sufentanyl)、苏林酸(sunlindac)、替尼达普等联合使用。类似地,本发明化合物和组合物可以与以下项一起施用:以上列出的止痛剂;增效剂如咖啡因、H2拮抗剂(例如,雷尼替丁)、二甲基硅油、氢氧化铝或氢氧化镁;减充血剂如苯肾上腺素、苯丙醇胺、伪麻黄碱、羟甲唑啉、肾上腺素、萘甲唑林、赛洛唑啉、丙己君、或左旋脱氧麻黄碱;止咳药如可待因、氢可酮、卡拉美芬、喷托维林、或右美沙芬;利尿剂;以及镇静或非镇静抗组胺药。
同样,本发明的化合物和组合物可以与用于治疗、预防、抑制或缓解本发明的化合物和组合物对其有用的疾病或病症的其他药物组合使用。此类其他药物可以通过一定途径并且以其通常使用的量与本发明的化合物或组合物同时地或依次施用。当本发明的化合物或组合物与一种或多种其他药物同时使用时,优选除了本发明的化合物或组合物之外还含有此类其他药物的药物组合物。因此,本发明的药物组合物包括除了本发明的化合物或组合物之外还含有一种或多种其他活性成分或治疗剂的那些。可以与本发明的化合物或组合物组合的单独施用的或在同一药物组合物中施用的其他治疗剂的实例包括但不限于:(a)VLA-4拮抗剂,(b)皮质类固醇,如倍氯米松、甲泼尼龙、倍他米松、泼尼松、泼尼松龙、地塞米松、氟替卡松、氢化可的松、布地奈德、曲安西龙(triamcinolone)、沙美特罗、沙美特罗、沙丁胺醇、福莫特罗(formeterol);(c)免疫抑制剂如环孢菌素(环孢菌素A,)、他克莫司(FK-506,)、雷帕霉素(西罗莫司,)、托西替尼和其他FK-506型免疫抑制剂,和麦考酚酯(mycophenolate),例如吗替麦考酚酯(d)抗组胺药(H1-组胺拮抗剂)如溴苯那敏、氯苯那敏、右旋氯苯那敏、曲普利啶、氯马斯汀、苯海拉明、二苯拉林、曲吡那敏(tripelennamine)、羟嗪、甲地嗪、异丙嗪、异丁嗪、阿扎他定、赛庚啶、安他唑啉、非尼拉敏、吡拉明、阿司咪唑、特非那定、氯雷他定、西替利嗪、非索非那定、脱碳乙氧基氯雷他定等;(e)非甾体抗喘药(例如,特布他林、奥西那林、非诺特罗(fenoterol)、异他林(isoetharine)、舒喘宁(albuterol)、比托特罗和吡布特罗)、茶碱、色甘酸钠、阿托品、异丙托溴铵、白三烯拮抗剂(例如,扎鲁司特、孟鲁司特、普鲁司特、伊拉司特、泊比司特和SKB-106,203)、白三烯生物合成抑制剂(齐留通,BAY-1005);(f)非甾体抗炎剂(NSAID)如丙酸衍生物(例如,阿明洛芬、苯噁洛芬、布氯酸、卡洛芬、芬布芬、非诺洛芬、氟洛芬(fluprofen)、氟比洛芬、布洛芬、吲哚布洛芬、酮洛芬、咪洛芬、萘普生、奥沙普秦、吡洛芬、普拉洛芬、舒洛芬、噻洛芬酸和硫噁洛芬),乙酸衍生物(例如,吲哚美辛、阿西美辛、阿氯芬酸、环氯茚酸、双氯芬酸、芬氯酸、芬克洛酸、芬替酸、呋罗芬酸(furofenac)、异丁芬酸、伊索克酸、奥昔平酸、舒林酸、硫平酸、托麦汀、齐多美辛和佐美酸)、芬那酸衍生物(例如,氟芬那酸、甲氯芬那酸、甲芬那酸、尼氟酸和托芬那酸)、联苯甲酸衍生物(例如,二氟尼柳和氟苯柳)、昔康(例如,伊索昔康、吡罗昔康、舒多昔康和替诺昔康)、水杨酸盐(例如,乙酰基水杨酸和柳氮磺吡啶)以及吡唑啉酮(例如,阿扎丙宗(apazone)、bezpiperylon、非普拉宗、莫非布宗、羟基保泰松(oxyphenbutazone)和保泰松);(g)环氧化酶-2(COX-2)抑制剂如赛来昔布和罗非昔布(h)磷酸二酯酶IV型(PDE IV)的抑制剂;(i)金化合物如金诺芬和金硫葡糖,(j)依那西普(k)抗体治疗如orthoclone(OKT3)、达克利珠单抗巴司利昔单抗和英夫利昔单抗阿达木单抗戈利木单抗利妥昔单抗托珠单抗(l)趋化因子受体的其他拮抗剂,尤其是CCR5、CXCR2、CXCR3、CCR2、CCR3、CCR4、CCR7、CX3CR1和CXCR6;(m)润滑剂或润肤剂如凡士林和羊毛脂,(n)角质层分离剂(例如,他扎罗汀),(o)维生素D3衍生物,例如,卡泊三烯或卡泊三醇(p)PUVA,(q)地蒽酚(r)依曲替酯和异维甲酸,和(s)多发性硬化治疗剂如干扰素β-1β干扰素β-1α硫唑嘌呤(azathioprine)乙酸格拉替雷(glatiramer acetate)糖皮质激素(例如,泼尼松龙)和环磷酰胺,(t)DMARDS如甲氨蝶呤和来氟米特,(u)其他化合物如5-氨基水杨酸及其前药;羟氯喹;D-青霉胺;抗代谢物如硫唑嘌呤、6-巯基嘌呤和甲氨蝶呤;DNA合成抑制剂如羟基脲,和微管破裂剂如秋水仙碱,和蛋白酶体抑制剂如硼替佐米本发明的化合物与第二活性成分的重量比可以变化并且将取决于每种成分的有效剂量。通常,将使用每种的有效剂量。因此,例如,当本发明的化合物与NSAID组合时,本发明的化合物与NSAID的重量比将通常在从约1000:1至约1:1000、优选约200:1至约1:200的范围内。本发明的化合物和其他活性成分的组合将通常也在前述范围内,但在每种情况下,应使用每种活性成分的有效剂量。
VI.实例
提供以下实例以说明,但不限制要求保护的本发明。
以下使用的试剂和溶剂可以从商业来源如奥德里奇化工公司(Aldrich ChemicalCo.)(密尔沃基市,威斯康星州,美国)获得。在Varian Mercury 400MHz NMR光谱仪上记录1H-NMR。提供了相对于TMS的显著峰并按以下顺序制表:多重性(s,单重峰;d,双重峰;t,三重峰;q,四重峰;m,多重峰)和质子数。质谱法结果报告为质量相对电荷的比率、随后是每种离子的相对丰度(在括号内)。在表中,报告了含有最常见的原子同位素的M+H(或者,如所提及的,M-H)离子的单个m/e值。在所有情况下,同位素模式对应于期望的式。电喷雾电离(ESI)质谱分析在Hewlett-Packard MSD电喷雾质谱仪上,使用配备有供样品递送的Agilent Zorbax SB-C18,2.1X 50mm,5μ柱的HP1100 HPLC进行。通常,将分析物以0.1mg/mL溶解于甲醇中,并且将1微升的混合物与递送溶剂一起输注到质谱仪中,该质谱仪从100至1500道尔顿扫描。所有化合物均可以在正ESI模式下,使用含1%甲酸的乙腈/水作为递送溶剂进行分析。以下提供的化合物也可以在负ESI模式下,使用在乙腈/水中的2mM NH4OAc作为递送体系进行分析。
以下缩写在实例和整个发明说明中使用:
HPLC,高压液相色谱法;DMF,二甲基甲酰胺;TFA,三氟乙酸;THF,四氢呋喃;EtOAc,乙酸乙酯;BOC2O,二碳酸二叔丁酯或BOC酸酐;HPLC,高压液相色谱法;DIPEA,二异丙基乙基胺;HBTU,O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸盐;dppf,1,1'-双(二苯基膦基)二茂铁;Pd2(dba)3,三(二亚苄基丙酮)二钯(0);DIPEA,二异丙基乙基胺;DMP,邻苯二甲酸二甲酯;Me,甲基;Et,乙基;DCM,二氯甲烷。
可以如以下所述使用本领域技术人员已知的多种反应合成本发明范围内的化合物。本领域技术人员还将认识到,可以采用可替代方法来合成本发明的目标化合物,并且在本文档的主体内描述的方法并不详尽,但确实为感兴趣的化合物提供了广泛适用和实用的途径。
本专利中要求保护的某些分子可以以不同的对映异构体和非对映异构体形式存在并且要求保护这些化合物的所有这类变体。
在本文中用于合成关键化合物的实验程序的详细描述导致通过识别分子的物理数据以及与分子相关联的结构描绘来描述分子。
本领域技术人员还将认识到,在有机化学中在标准后处理程序期间,常使用酸和碱。在本专利内描述的实验程序期间,如果母体化合物具有必要的固有酸度或碱度,有时产生这些母体化合物的盐。
用于N-(1-((4-溴苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺(中间体1)的程序
步骤a:向圆底烧瓶中添加1-Boc-4-氨基哌啶(10.01g,50.0mmol,1.0当量)、K2CO3(20.73g,150.0mmol,3.0当量)、DMF(100mL)和2-氟-5-(三氟甲基)-吡啶(12.1mL,100.0mmol,2.0当量)。将反应混合物在100℃下搅拌过夜。将反应混合物冷却至室温,用H2O(200mL)和盐水(100mL)稀释,并且用EtOAc(3x 200mL)萃取。将合并的有机层用盐水(2x100mL)洗涤,经MgSO4干燥,过滤,并浓缩。通过硅胶柱色谱法(0%-100% MTBE/己烷)纯化,产生呈浅黄色固体的4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-甲酸叔丁酯。
步骤b:向圆底烧瓶中添加4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-甲酸叔丁酯(11.37g,32.9mmol,1.0当量)、二噁烷(100mL)和4M HCl/二噁烷(100mL)。将反应混合物在室温下搅拌过夜。将反应混合物浓缩并在真空下干燥,以产生呈灰白色固体的N-(哌啶-4-基)-5-(三氟甲基)吡啶-2-胺盐酸盐。
步骤c:向圆底烧瓶中添加N-(哌啶-4-基)-5-(三氟甲基)吡啶-2-胺盐酸盐(4.23g,15.0mmol,1.0当量)、THF(75mL)、iPr2NEt(10.5mL,60.0mmol,4.0当量)和4-溴苯磺酰氯(5.75g,22.5mmol,1.5当量)。将反应混合物在室温下搅拌1小时。将所得固体过滤,并且将滤液浓缩。通过硅胶柱色谱法(0%-100% EtOAc/己烷)纯化,产生呈浅黄色固体的N-(1-((4-溴苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺。
用于N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺(中间体2)的通用程序
向配备有搅拌棒的50-mL圆底烧瓶中添加溴化物(1.0当量)、双(频哪醇合)二硼(2.0当量)、KOAc(2.0当量)和Pd(dppf)Cl2·DCM(0.1当量)。将反应容器置于真空下2分钟。接着,经由注射器将无水二噁烷(约15-20mL,来自新瓶)添加到反应容器中,并且将N2气体鼓泡通过反应混合物2分钟。将反应加热至100℃持续16小时,并且通过LC-MS监测。一旦产物转化完成,就将粗反应物附着至并且使用EtOAc:己烷运行正相柱(产物在50%EtOAc下洗脱)。合并含有产物的级分并且将其在减压下浓缩,以产生灰白色固体。N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺
实例1:1-(2-(二甲基氨基)乙基)-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-甲腈
向1-(2-氨基乙基)-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-甲腈(40mg;0.06mmol)在1mL CH3CN中的溶液中添加AcOH(100uL;1.6mmol)和福尔马林(50uL)。将混合物搅拌1小时。向其中添加NaBH(CN)3(10mg,0.15mmol)。将混合物在室温下搅拌60小时。LC-MS指示所希望的产物。将反应物冷却,用50mL EtOAc稀释,通过注射过滤器过滤并浓缩。将材料通过反相制备型HPLC纯化,以得到1-(2-(二甲基氨基)乙基)-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-甲腈。MS:(ES)m/z,对于C29H30F3N7O2S[M+H]+,计算值为598.2,实测值为598.0。1H NMR(400MHz,DMSO-d6)δ8.87(d,J=2.1Hz,1H),8.63(s,1H),8.59(d,J=2.1Hz,1H),8.23-8.16(m,1H),8.11(d,J=8.2Hz,2H),7.86(d,J=8.2Hz,2H),7.59(dd,J=8.9,2.5Hz,1H),7.34(d,J=7.3Hz,1H),6.53(d,J=9.0Hz,1H),4.75(t,J=6.1Hz,2H),(m,5H),2.87(d,J=4.4Hz,6H),2.60-2.36(m,2H),2.01-1.92(m,2H),1.50(q,J=11.3,10.7Hz,2H)。
实例2:1'-(2-氨基乙基)-5'-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)螺[环丙烷-1,3'-吡咯并[2,3-b]吡啶]-2'(1'H)-酮
步骤a:向(2-(2'-氧代-5'-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)螺[环丙烷-1,3'-吡咯并[2,3-b]吡啶]-1'(2'H)-基)乙基)氨基甲酸叔丁酯(88.0mg;0.13mmol)在1mL CH2Cl2中的溶液中添加1mL TFA。将混合物搅拌16小时。LC-MS指示所希望的产物。浓缩混合物,以得到1'-(2-氨基乙基)-5'-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)螺[环丙烷-1,3'-吡咯并[2,3-b]吡啶]-2'(1'H)-酮。MS:(ES)m/z,对于C28H29F3N6O3S[M+H]+,计算值为587.2,实测值为587.0。1H NMR(400MHz,DMSO-d6)δ8.53(d,J=2.1Hz,1H),8.20(d,J=2.5Hz,1H),7.95(d,J=8.2Hz,2H),7.86(d,J=2.1Hz,1H),7.81(d,J=8.5Hz,2H),7.58(dd,J=9.0,2.6Hz,1H),7.29(d,J=7.3Hz,1H),6.52(d,J=8.9Hz,1H),3.81(td,J=24.3,21.7,11.9Hz,2H),3.55(d,J=12.1Hz,2H),2.82(t,J=6.9Hz,1H),2.60-2.43(m,2H),1.98-1.90(m,2H),1.82(q,J=4.0Hz,2H),1.71-1.56(m,2H),1.56-1.41(m,2H)。
步骤b:向在1mL THF中的2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)异二氢吲哚-1-酮(38.9mg;0.06mmol)中添加0.1mL在THF中的1M TBAF。将混合物搅拌1小时。LC-MS指示所希望的产物。将反应用10mL EtOAc稀释,用3x 5mL H2O和10mL盐水洗涤。将有机相用MgSO4干燥,过滤并浓缩。将粗残余物通过SiO2制备型平板色谱法纯化,以得到2-(2-羟基乙基)-5-[4-[[4-[[5-(三氟甲基)-2-吡啶基]氨基]-1-哌啶基]磺酰基]苯基]异二氢吲哚-1-酮。(ES)m/z对于C27H27F3N4O4S[M+H]+,计算值为561.2,实测值为560.9。1H NMR(400MHz,DMSO-d6)δ8.20(d,J=2.4Hz,1H),7.99(dd,J=9.2,2.4Hz,3H),7.85(dd,J=8.4,2.0Hz,3H),7.78(d,J=7.9Hz,1H),7.58(dd,J=9.1,2.6Hz,1H),7.29(d,J=7.4Hz,1H),6.52(d,J=8.8Hz,1H),4.93-4.79(m,1H),4.62(s,2H),3.76(bs,1H),3.67-3.52(m,6H),2.63-2.40(m,2H),1.95(d,J=12.7Hz,2H),1.58-1.43(m,2H)。
实例3:1-(2-(3-氰基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡咯并[2,3-b]吡啶-1-基)乙基)脲
向1-(2-氨基乙基)-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-甲腈(50mg;0.08mmol)在2mL CH3CN中的溶液中添加DIPEA(68uL,0.38mmol)和TMS异氰酸酯(23.5uL,0.17mmol)。将混合物在室温下搅拌2小时。LC-MS指示所希望的产物。将反应物浓缩,用15mL EtOAc稀释,用10mL饱和NH4Cl和饱和盐水洗涤。将有机相用MgSO4干燥,过滤并浓缩。将残余物通过SiO2色谱法纯化,以得到1-(2-(3-氰基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡咯并[2,3-b]吡啶-1-基)乙基)脲(27.3mg;0.04mmol,57.3%产率)。MS:(ES)m/z对于C28H27F3N8O3S[M+H]+,计算值为613.2,实测值为612.9。1H NMR(400MHz,DMSO-d6)δ8.83(d,J=2.1Hz,1H),8.53-8.43(m,2H),8.20(d,J=2.5Hz,1H),8.10(d,J=8.4Hz,2H),7.84(d,J=8.3Hz,2H),7.58(dd,J=8.9,2.6Hz,1H),7.30(d,J=7.4Hz,1H),6.53(d,J=8.9Hz,1H),6.06(t,J=6.0Hz,1H),4.37(t,J=5.8Hz,2H),3.74(d,J=12.9Hz,1H),3.58(d,J=12.0Hz,2H),3.46(q,J=5.9Hz,2H),2.63-2.40(m,2H),2.00-1.90(m,2H),1.49(q,J=13.1,11.9Hz,2H)。
实例4:(2-(2'-氧代-5'-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)螺[环丙烷-1,3'-吡咯并[2,3-b]吡啶]-1'(2'H)-基)乙基)氨基甲酸叔丁酯
向在4.8mL二噁烷中的N-[1-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基]磺酰基-4-哌啶基]-5-(三氟甲基)吡啶-2-胺(150.0mg,0.30mmol)中添加K2CO3(75.0mg,0.54mmol)、N-[2-(5'-溴-2'-氧代-螺[环丙烷-1,3'-吡咯并[2,3-b]吡啶]-1'-基)乙基]氨基甲酸叔丁酯(150.0mg,0.39mmol)、Pd(dppf)Cl2·DCM(27.0mg,0.03mmol)和1.2mL水。将混合物用氮气鼓泡10分钟。密封小瓶,将混合物在100℃下搅拌2小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法纯化,以得到(2-(2'-氧代-5'-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)螺[环丙烷-1,3'-吡咯并[2,3-b]吡啶]-1'(2'H)-基)乙基)氨基甲酸叔丁酯。MS:(ES)m/z对于C33H37F3N6O5SSi[M+H]+,计算值为687.3,实测值为687.0。1H NMR(400MHz,DMSO-d6)δ8.52(d,J=2.1Hz,1H),8.20(d,J=2.7Hz,1H),7.94(d,J=8.2Hz,2H),7.90-7.77(m,3H),7.58(dd,J=9.0,2.5Hz,1H),7.29(d,J=7.3Hz,1H),6.94(t,J=6.0Hz,1H),6.52(d,J=9.0Hz,1H),3.84(q,J=8.5,7.2Hz,2H),3.75(s,1H),3.61-3.50(m,2H),2.60-2.40(m,3H),1.95(d,J=13.3Hz,2H),1.80(q,J=3.8Hz,2H),1.61(q,J=4.5,3.9Hz,2H),1.48(q,J=12.3,11.3Hz,2H),1.29(s,9H)。
实例5:2-氧代-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)二氢吲哚-7-甲酰胺
向在隔膜帽小瓶中的2-氧代-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)二氢吲哚-7-甲酸甲酯中添加(NH4)2CO3(21mg,0.22mmol)、HATU(25mg,0.067mmol)和1mL DMF,随后添加DIPEA(39μL,0.22mmol)。将反应在室温下搅拌1小时。一旦完成,就将反应用dI H2O淬灭,并且经由反相HPLC纯化,以得到2-氧代-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)二氢吲哚-7-甲酰胺。MS:(ES)m/z对于C26H24F3N5O4S[M+H]+,计算值为560.2,实测值为560。1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),8.31(s,1H),8.23(s,1H),8.12(s,1H),8.02-7.97(m,2H),7.85-7.79(m,3H),7.65-7.59(m,2H),7.42(bs,1H),6.58(d,J=9.0Hz,1H),3.81-3.69(m,1H),3.65-3.54(m,4H),2.62-2.51(m,2H),2.02-1.92(m,2H),1.57-1.42(m,2H)。
实例6:1'-甲基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)螺[二氢吲哚-3,4'-哌啶]-2-酮
向在隔膜帽小瓶中的2-氧代-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)螺[二氢吲哚-3,4'-哌啶]-1'-鎓氯化物和13μL在MeOH(1mL)中的37%甲醛中添加NaBH(CN)3(7mg,0.11mmol)和20μL乙酸。将反应在室温下搅拌一小时。一旦完成,就将反应混合物经由反相HPLC纯化,以得到1'-甲基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)螺[二氢吲哚-3,4'-哌啶]-2-酮。MS:(ES)m/z对于C30H32F3N5O3S[M+H]+,计算值为600.2,实测值为600。1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),8.24-8.20(m,1H),7.93-7.88(m,2H),7.84-7.75(m,3H),7.65-7.56(m,2H),7.31(d,J=7.3Hz,1H),6.99(d,J=8.1Hz,1H),6.54(d,J=8.9Hz,1H),3.81-3.71(m,1H),3.62-3.53(m,2H),2.88(bs,1H),2.69(bs,1H),2.60-2.52(m,2H),2.46-2.30(m,3H),2.01-1.77(m,6H),1.56-1.44(m,2H)。
实例7:5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡唑并[3,4-b]吡嗪-3-胺
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、7-溴-1,4-二氢异喹啉-3(2H)-酮(22mg,0.10mmol)和Pd(dppf)Cl2·DCM(8.0mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡唑并[3,4-b]吡嗪-3-胺。MS:(ES)m/z对于C26H25F3N4O3S[M+H]+,计算值为531.2,实测值为531。1H NMR(400MHz,DMSO-d6)δ8.22(s,1H),8.08(s,1H),7.97-7.92(m,2H),7.84-7.80(m,2H),7.71(s,1H),7.67-7.63(m,1H),7.60(dd,J=9.0,2.6Hz,1H),7.36(d,J=8.0Hz,1H),7.31(d,J=7.3Hz,1H),6.54(d,J=8.9Hz,1H),4.43(s,2H),3.82-3.72(m,1H),3.61-3.53(m,2H),3.51(s,2H),2.64-2.53(m,2H),2.01-1.91(m,2H),1.57-1.43(m,2H)。
实例8:2-氧代-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)二氢吲哚-7-甲酸
将2-氧代-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)二氢吲哚-7-甲酸甲酯(76mg,0.13mmol)、K2CO3(20mg,0.15mmol)和1mL 4:1二噁烷:H2O添加到隔膜盖小瓶中。将反应加热至50℃并搅拌75分钟。一旦完成,就将反应冷却至室温,并且使固体沉淀并经由过滤分离。将固体再悬浮于dI H2O中,使用几滴冰醋酸酸化,并且用EtOAc萃取,以得到2-氧代-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)二氢吲哚-7-甲酸。MS:(ES)m/z,对于C26H23F3N4O5S[M-H]-,计算值为531.6,实测值为531。1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),8.23-8.21(m,1H),8.04-8.01(m,1H),7.94-7.90(m,2H),7.87-7.84(m,1H),7.83-7.79(m,2H),7.59(dd,J=9.0,2.5Hz,1H),7.35(d,J=7.3Hz,1H),6.55(d,J=8.9Hz,1H),3.83-3.72(m,1H),3.65(s,2H),3.60-3.51(m,2H),2.62-2.53(m,2H),2.00-1.91(m,2H),1.56-1.43(m,2H),没有观察到-COOH。
实例9:3,3-二甲基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)异二氢吲哚-1-酮
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、5-溴-3,3-二甲基异二氢吲哚-1-酮(23mg,0.10mmol)和Pd(dppf)Cl2·DCM(8.0mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1小时,并且当反应进行至完全时冷却。将混合物经由反相HPLC纯化,以得到3,3-二甲基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)异二氢吲哚-1-酮。MS:(ES)m/z对于C27H27F3N4O3S[M+H]+,计算值为545.2,实测值为545。1H NMR(400MHz,DMSO-d6)δ8.73(s,1H),8.20(s,1H),8.06-7.98(m,3H),7.87-7.79(m,3H),7.70(d,J=7.9Hz,1H),7.58(dd,J=8.9,2.4Hz,1H),7.29(d,J=7.2Hz,1H),6.52(d,J=8.9Hz,1H),3.81-3.68(m,1H),3.60-3.51(m,2H),2.59-2.53(m,2H),1.99-1.90(m,2H),1.55-1.42(m,8H)。
实例10:3-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-6,7-二氢-5H-吡咯并[3,4-b]吡啶-5-酮
向在隔膜盖小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、3-溴-6,7-二氢-5H-吡咯并[3,4-b]吡啶-5-酮(21mg,0.10mmol)和Pd(dppf)Cl2·DCM(8.0mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1小时,并且当反应进行至完全时冷却。将混合物经由反相HPLC纯化,以得到3-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-6,7-二氢-5H-吡咯并[3,4-b]吡啶-5-酮。MS:(ES)m/z对于C24H22F3N5O3S[M+H]+,计算值为518.2,实测值为518。1H NMR(400MHz,DMSO-d6)δ9.18(d,J=2.2Hz,1H),8.94(s,1H),8.42(d,J=2.2Hz,1H),8.22(s,1H),8.13(d,J=8.1Hz,2H),7.87(d,J=8.1Hz,2H),7.60(dd,J=8.7,2.0Hz,1H),7.32(d,J=7.3Hz,1H),6.54(d,J=8.9Hz,1H),4.52(s,2H),3.84-3.72(m,1H),3.63-3.53(m,2H),2.64-2.55(m,2H),2.02-1.92(m,2H),1.57-1.43(m,2H)。
实例11:6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-3,4-二氢喹唑啉-2(1H)-酮
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、6-溴-1,4-二氢异喹啉-3(2H)-酮(22mg,0.10mmol)和Pd(dppf)Cl2·DCM(8.0mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1小时,并且当反应进行至完全时冷却。将混合物经由反相HPLC纯化,以得到6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-3,4-二氢喹唑啉-2(1H)-酮。MS:(ES)m/z对于C25H24F3N5O3S[M+H]+,计算值为532.2,实测值为532。1H NMR(400MHz,DMSO-d6)δ9.23(d,J=2.0Hz,1H),8.22(s,1H),7.87(d,J=8.5Hz,2H),7.74(d,J=8.4Hz,2H),7.63-7.51(m,4H),7.31(d,J=7.3Hz,1H),6.94-6.86(m,2H),6.54(d,J=8.9Hz,1H),4.40(s,2H),3.82-3.70(m,1H),3.60-3.49(m,3H),2.61-2.50(m,2H),2.01-1.90(m,2H),1.57-1.42(m,2H)。
实例12:N-(2-(3-氰基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡咯并[2,3-b]吡啶-1-基)乙基)乙酰胺
向1-(2-氨基乙基)-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-甲腈(50mg;0.08mmol)在1mL DMF中的溶液中添加AcOH(10mg;0.1mmol)、DIPEA(101uL,0.58mmol)和HATU(50mg;0.13mmol)。将混合物搅拌2小时。LC-MS指示所希望的产物。将反应用15mL EtOAc稀释,用10mL饱和NH4Cl和饱和盐水洗涤。将有机相用MgSO4干燥,过滤并浓缩。将残余物通过制备型平板SiO2色谱法纯化,以得到N-(2-(3-氰基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡咯并[2,3-b]吡啶-1-基)乙基)乙酰胺。MS:(ES)m/z对于C28H28F3N7O3S[M+H]+,计算值为612.2,实测值为611.9。1H NMR(400MHz,DMSO-d6)δ8.84(d,J=2.1Hz,1H),8.55(s,1H),8.51(d,J=2.1Hz,1H),8.23-8.17(m,1H),8.10(d,J=8.3Hz,2H),7.95(q,J=7.2,6.6Hz,1H),7.84(d,J=8.1Hz,2H),7.58(dd,J=9.0,2.5Hz,1H),7.31(t,J=6.2Hz,1H),6.53(d,J=8.9Hz,1H),4.37(dt,J=18.0,5.5Hz,2H),3.80-3.72(m,1H),3.63-3.41(m,4H),2.62-2.43(m,2H),2.00-1.91(m,2H),1.72(s,3H),1.57-1.42(m,2H)。
实例13:6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1,4-二氢异喹啉-3(2H)-酮
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、6-溴-1,4-二氢异喹啉-3(2H)-酮(22mg,0.10mmol)和Pd(dppf)Cl2·DCM(8.0mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法纯化,以得到6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1,4-二氢异喹啉-3(2H)-酮。MS:(ES)m/z对于C26H25F3N4O3S[M+H]+,计算值为531.2,实测值为531。1H NMR(400MHz,DMSO-d6)δ8.22(s,1H),8.07(bs,1H),7.94(d,J=8.4Hz,2H),7.82(d,J=8.4Hz,2H),7.65-7.57(m,3H),7.42(d,J=8.4Hz,1H),7.32(d,J=7.3Hz,1H),6.54(d,J=8.9Hz,1H),4.40(s,2H),3.83-3.72(m,1H),3.62-3.51(m,4H),2.62-2.52(m,2H),2.00-1.92(m,2H),1.56-1.44(m,2H)。
实例14:1-(2-氨基乙基)-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-甲腈
向N-[2-[3-氰基-5-[4-[[4-[[5-(三氟甲基)-2-吡啶基]氨基]-1-哌啶基]磺酰基]苯基]吡咯并[2,3-b]吡啶-1-基]乙基]氨基甲酸叔丁酯(155mg;0.23mmol)在2mL CH2Cl2中的溶液中添加2mL 4.0M HCl。将混合物搅拌16小时。LC-MS指示所希望的产物。浓缩混合物,以得到1-(2-氨基乙基)-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-甲腈。MS:(ES)m/z对于C27H26F3N7O2S[M+H]+,计算值为570.2,实测值为569.9。
实例15:(2-(3-氰基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡咯并[2,3-b]吡啶-1-基)乙基)氨基甲酸叔丁酯
向在7.2mL二噁烷中的N-[1-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基]磺酰基-4-哌啶基]-5-(三氟甲基)吡啶-2-胺(150.0mg,0.29mmol)中添加K2CO3(75.0mg,0.53mmol)、N-[2-(5-溴-3-氰基-吡咯并[2,3-b]吡啶-1-基)乙基]氨基甲酸叔丁酯(150.0mg,0.41mmol)、Pd(dppf)Cl2·DCM(27.0mg,0.03mmol)和1.8mL水。将混合物用氮气鼓泡10分钟。密封小瓶,将混合物在100℃下搅拌2小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法纯化,以得到(2-(3-氰基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡咯并[2,3-b]吡啶-1-基)乙基)氨基甲酸叔丁酯。MS:(ES)m/z对于C32H34F3N7O4S[M+H]+,计算值为670.2,实测值为670.0。
实例16:2-氨基-6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)喹唑啉-4(1H)-酮
向在隔膜盖小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、2-氨基-6-溴喹唑啉-4(1H)-酮(23mg,0.10mmol)和Pd(dppf)Cl2·DCM(8.0mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌2小时,并且当反应进行至完全时冷却。将混合物经由反相HPLC纯化,以得到2-氨基-6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)喹唑啉-4(1H)-酮。MS:(ES)m/z对于C25H23F3N6O3S[M+H]+,计算值为545.2,实测值为545。1H NMR(400MHz,DMSO-d6)δ8.24-8.20(m,2H),8.02-7.95(m,3H),7.82(d,J=8.5Hz,2H),7.59(dd,J=9.0,2.7Hz,1H),7.35-7.28(m,2H),6.61(bs,2H),6.54(d,J=8.9Hz,1H),3.84-3.70(m,1H),3.61-3.51(m,2H),2.65-2.52(m,2H),2.01-1.92(m,2H),1.57-1.43(m,2H)。
实例17:6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-[1,2,4]三唑并[4,3-a]吡啶-3-胺
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、6-溴-[1,2,4]三唑并[4,3-a]吡啶-3-胺(21mg,0.10mmol)和Pd(dppf)Cl2·DCM(8.0mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌2小时,并且当反应进行至完全时冷却。将混合物经由反相HPLC纯化,以得到6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-[1,2,4]三唑并[4,3-a]吡啶-3-胺。MS:(ES)m/z对于C23H22F3N7O2S[M+H]+,计算值为518.2,实测值为518。1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),8.22(s,1H),7.98(d,J=8.4Hz,2H),7.89(d,J=8.5Hz,2H),7.63-7.57(m,3H),7.31(d,J=7.2Hz,1H),6.74(bs,2H),6.54(d,J=8.9Hz,1H),3.82-3.71(m,1H),3.62-3.52(m,2H),2.64-2.53(m,2H),2.01-1.92(m,2H),1.57-1.44(m,2H)。
实例18:5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡唑并[3,4-b]吡嗪-3-胺
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、5-溴-1H-吡唑并[3,4-b]吡嗪-3-胺(21mg,0.10mmol)和Pd(dppf)Cl2·DCM(8.0mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌2小时,并且当反应进行至完全时冷却。将混合物经由反相HPLC纯化,以得到5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡唑并[3,4-b]吡嗪-3-胺。MS:(ES)m/z对于C22H21F3N8O2S[M+H]+,计算值为519.2,实测值为519。1H NMR(400MHz,DMSO-d6)δ12.57(s,1H),9.15(s,1H),8.41(d,J=8.5Hz,2H),8.22(d,J=2.4Hz,1H),7.89(d,J=8.6Hz,2H),7.59(dd,J=9.1,2.7Hz,1H),7.30(d,J=7.3Hz,1H),6.54(d,J=8.9Hz,1H),5.88(s,2H),3.83-3.72(m,1H),3.62-3.53(m,2H),2.69-2.57(m,2H),1.96(d,J=12.1Hz,2H),1.56-1.43(m,2H)。
实例19:5-(2-甲基-4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)二氢吲哚-2-酮
步骤a:将N-(哌啶-4-基)-5-(三氟甲基)吡啶-2-胺盐酸盐(282mg,1.0mmol)、4-溴-3-甲基苯磺酰氯(404mg,1.5mmol)和K2CO3(553mg,4.0mmol)在2-甲基四氢呋喃(10mL)和水(2mL)中的混合物在室温下搅拌1.5小时。去除水层,并且将有机层浓缩并通过SiO2凝胶色谱法(0%-100% EtOAc/己烷)纯化,以得到N-(1-((4-溴-3-甲基苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺。
步骤b:向在隔膜帽小瓶中的N-(1-((4-溴-3-甲基苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺(48mg,0.10mmol)中添加K2CO3(30mg,0.22mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)二氢吲哚-2-酮(31mg,0.12mmol)、二噁烷(1.5mL)和水(0.5mmol)。将混合物用氮气鼓泡20分钟。添加Pd(dppf)Cl2·DCM(8mg,0.010mmol),并且将混合物用氮气鼓泡额外5分钟。密封小瓶,将混合物在100℃下搅拌17小时,并且当反应进行至完全时冷却。将反应混合物用EtOAc(10mL)稀释,通过过滤并浓缩。将混合物经由SiO2凝胶、随后制备型反相HPLC纯化,以得到5-(2-甲基-4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)二氢吲哚-2-酮。MS:(ES)m/z对于C26H26F3N4O3S[M+H]+,计算值为531.17,实测值为531.3。1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),8.26-8.20(m,1H),7.70-7.54(m,3H),7.46-7.39(m,1H),7.36-7.29(m,1H),7.28-7.24(m,1H),7.24-7.18(m,1H),6.95-6.87(m,1H),6.60-6.51(m,1H),3.84-3.70(m,1H),3.63-3.48(m,4H),2.62-2.50(m,2H),2.36(s,3H),2.03-1.90(m,2H),1.59-1.44(m,2H)。
实例20:2,2-二甲基-7-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺(51mg,0.10mmol)中添加K2CO3(41mg,0.30mmol)、7-溴-2,2-二甲基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(31mg,0.12mmol)、二噁烷(1.5mL)和水(0.5mmol)。将混合物用氮气鼓泡20分钟。添加Pd(dppf)Cl2·DCM(8mg,0.010mmol),并且将混合物用氮气鼓泡额外5分钟。密封小瓶,将混合物在100℃下搅拌17小时,并且当反应进行至完全时冷却。将反应混合物用EtOAc(10mL)稀释,通过过滤并浓缩。将混合物经由SiO2凝胶色谱法、随后制备型反相HPLC纯化,以得到2,2-二甲基-7-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮。MS:(ES)m/z对于C27H28F3N4O4S[M+H]+,计算值为561.18,实测值为561.3。1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.22(s,1H),7.92(d,J=8.6Hz,2H),7.77(d,J=8.5Hz,2H),7.59(dd,J=9.0,2.5Hz,1H),7.43-7.37(m,2H),7.31(d,J=7.3Hz,1H),7.01(d,J=8.0Hz,1H),6.54(d,J=8.9Hz,1H),3.82-3.70(m,1H),3.60-3.51(m,2H),2.62-2.53(m,2H),2.00-1.91(m,2H),1.55-1.46(m,2H),1.44(s,6H)。
实例21:1'-(2-羟基乙基)-5'-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-2,3,5,6-四氢螺[吡喃-4,3'-吡咯并[2,3-b]吡啶]-2'(1'H)-酮
步骤a:向在2.25mL二噁烷中的N-[1-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基]磺酰基-4-哌啶基]-5-(三氟甲基)吡啶-2-胺(40.0mg,0.08mmol)中添加K2CO3(25.0mg,0.18mmol)、5-溴-1-[2-[叔丁基(二甲基)甲硅烷基]氧基乙基]螺[吡咯并[2,3-b]吡啶-3,4'-四氢吡喃]-2-酮(40.0mg,0.10mmol)、Pd(dppf)Cl2·DCM(9.0mg,0.01mmol)和0.75mL水。将混合物用氮气鼓泡10分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法纯化,以得到1'-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-5'-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-2,3,5,6-四氢螺[吡喃-4,3'-吡咯并[2,3-b]吡啶]-2'(1'H)-酮。MS:(ES)m/z对于C33H41F3N4O4SSi[M+H]+,计算值为746.3,实测值为746.0。
步骤b:向在1mL THF中的2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)异二氢吲哚-1-酮(57.0mg;0.08mmol)中添加0.1mL在THF中的1M TBAF。将混合物搅拌1小时。LC-MS指示所希望的产物。将反应用10mL EtOAc稀释,用3x 5mL H2O和10mL盐水洗涤。将有机相用MgSO4干燥,过滤并浓缩。将粗残余物通过SiO2制备型平板色谱法纯化,以得到1'-(2-羟基乙基)-5'-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-2,3,5,6-四氢螺[吡喃-4,3'-吡咯并[2,3-b]吡啶]-2'(1'H)-酮。(ES)m/z对于C30H32F3N5O5S[M+H]+,计算值为632.2,实测值为632.2。1H NMR(400MHz,DMSO-d6)8.58(d,J=2.0Hz,1H),8.32(d,J=2.1Hz,1H),8.20(s,1H),8.00(d,J=8.5Hz,2H),7.81(d,J=8.5Hz,2H),7.58(dd,J=8.9,2.5Hz,1H),7.30(d,J=7.3Hz,1H),6.53(d,J=8.9Hz,1H),4.89-4.77(m,1H),4.03(ddd,J=11.8,7.4,4.1Hz,3H),3.88(dt,J=11.4,5.0Hz,2H),3.78(m,3H),3.65(t,J=6.2Hz,2H),3.57(d,J=11.9Hz,2H),2.60-2.40(m,2H),2.00-1.91(m,2H),1.89-1.73(m,3H),1.49(q,J=12.6,11.1Hz,2H)。
实例22:2-(2-羟基乙基)-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)异二氢吲哚-1-酮
步骤a:向在2.25mL二噁烷中的N-[1-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基]磺酰基-4-哌啶基]-5-(三氟甲基)吡啶-2-胺(40.0mg,0.07mmol)中添加K2CO3(25.0mg,0.18mmol)、1-[2-[叔丁基(二甲基)甲硅烷基]氧基乙基]-5-[4-[[4-[[5-(三氟甲基)-2-吡啶基]氨基]-1-哌啶基]磺酰基]苯基]吡咯并[2,3-b]吡啶-3-甲腈(40.0mg,0.11mmol)、Pd(dppf)Cl2·DCM(9.0mg,0.01mmol)和0.75mL水。将混合物用氮气鼓泡10分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法纯化,以得到2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)异二氢吲哚-1-酮。MS:(ES)m/z对于C33H41F3N4O4SSi[M+H]+,计算值为675.3,实测值为675.0。
实例23:6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1,3-二氢-2H-吡咯并[3,2-b]吡啶-2-酮
向在隔膜盖小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、6-溴-1,3-二氢-2H-吡咯并[3,2-b]吡啶-2-酮(21mg,0.10mmol)和Pd(dppf)Cl2·DCM(8.0mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌2小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1,3-二氢-2H-吡咯并[3,2-b]吡啶-2-酮。MS:(ES)m/z对于C24H22F3N5O3S[M+H]+,计算值为518.2,实测值为518。1H NMR(400MHz,DMSO-d6)δ10.76(s,1H),8.46(d,J=2.0Hz,1H),8.22(s,1H),7.97(d,J=8.4Hz,2H),7.84(d,J=8.4Hz,2H),7.60(dd,J=8.9,2.5Hz,1H),7.40(d,J=2.0Hz,1H),7.32(d,J=7.3Hz,1H),6.54(d,J=9.0Hz,1H),3.84-3.72(m,1H),3.62-3.51(m,2H),2.64-2.54(m,2H),2.01-1.93(m,2H),1.57-1.43(m,2H),一个亚甲基在残余溶剂峰下。
实例24:N-(1-((4-(4-甲基-1H-吡咯并[2,3-b]吡啶-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺(51mg,0.10mmol)中添加K2CO3(41mg,0.30mmol)、5-溴-4-甲基-1H-吡咯并[2,3-b]吡啶(25mg,0.12mmol)、二噁烷(1.5mL)和水(0.5mmol)。将混合物用氮气鼓泡20分钟。添加Pd(dppf)Cl2·DCM(8mg,0.010mmol),并且将混合物用氮气鼓泡额外5分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将反应混合物用EtOAc(10mL)稀释,通过过滤并浓缩。将混合物经由SiO2凝胶色谱法、随后制备型反相HPLC纯化,以得到N-(1-((4-(4-甲基-1H-吡咯并[2,3-b]吡啶-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺。MS:(ES)m/z对于C25H25F3N5O2S[M+H]+,计算值为516.17,实测值为516.3。1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),8.24(s,1H),8.12(s,1H),7.83(d,J=7.6Hz,2H),7.71(d,J=7.8Hz,2H),7.64-7.57(m,1H),7.54-7.48(m,1H),7.37-7.30(m,1H),6.64-6.53(m,2H),3.87-3.71(m,1H),3.67-3.56(m,2H),2.65-2.52(m,2H),2.50(s,3H),2.04-1.94(m,2H),1.60-1.45(m,2H)。
实例25:N-(1-((4-(6-甲基-1H-吡咯并[2,3-b]吡啶-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺(51mg,0.10mmol)中添加K2CO3(41mg,0.30mmol)、5-溴-6-甲基-1H-吡咯并[2,3-b]吡啶(25mg,0.12mmol)、二噁烷(1.5mL)和水(0.5mmol)。将混合物用氮气鼓泡20分钟。添加Pd(dppf)Cl2·DCM(8mg,0.010mmol),并且将混合物用氮气鼓泡额外5分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将反应混合物用EtOAc(10mL)稀释,通过过滤并浓缩。将混合物经由SiO2凝胶色谱法、随后制备型反相HPLC纯化,以得到N-(1-((4-(6-甲基-1H-吡咯并[2,3-b]吡啶-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺。MS:(ES)m/z对于C25H25F3N5O2S[M+H]+,计算值为516.17,实测值为516.3。1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),8.24(s,1H),7.87-7.78(m,3H),7.70(d,J=7.4Hz,2H),7.62(d,J=8.9Hz,1H),7.45(s,1H),7.34(s,1H),6.61-6.51(m,1H),6.45(s,1H),3.86-3.72(m,1H),3.67-3.55(m,2H),2.64-2.50(m,2H),2.50(s,3H),2.06-1.92(m,2H),1.60-1.44(m,2H)。
实例26:2-氧代-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)螺[二氢吲哚-3,4'-哌啶]-1'-甲酰胺
向在隔膜帽小瓶中的2-氧代-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)螺[二氢吲哚-3,4'-哌啶]-1'-鎓氯化物中添加THF(3mL)和DIPEA(56μL,0.32mmol),随后添加(三甲基甲硅烷基)异氰酸酯(12μL,0.090mmol)。将混合物在室温下搅拌,直到反应进行至完全。将混合物经由反相HPLC纯化,以得到2-氧代-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)螺[二氢吲哚-3,4'-哌啶]-1'-甲酰胺。MS:(ES)m/z对于C30H31F3N6O4S[M+H]+,计算值为629.2,实测值为629。
实例27:1'-乙酰基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)螺[二氢吲哚-3,4'-哌啶]-2-酮
向在隔膜帽小瓶中的2-氧代-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)螺[二氢吲哚-3,4'-哌啶]-1'-鎓氯化物中添加DMF(1mL)和DIPEA(56μL,0.32mmol),随后添加乙酸(9μL,0.090mmol),并且然后添加HATU(37mg,0.096mmol)。将混合物在室温下搅拌,直到反应进行至完全。将混合物经由反相HPLC纯化,以得到1'-乙酰基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)螺[二氢吲哚-3,4'-哌啶]-2-酮。MS:(ES)m/z对于C31H32F3N5O4S[M+H]+,计算值为628.2,实测值为628。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.20(s,1H),7.98-7.82(m,3H),7.80-7.69(m,2H),7.65-7.54(m,2H),7.32-7.24(m,1H),6.97(d,J=8.2Hz,1H),6.52(d,J=9.1Hz,1H),4.05-3.92(m,1H),3.89-3.49(m,6H),2.59-2.49(m,2H),2.06(s,3H),1.98-1.85(m,3H),1.84-1.61(m,3H),1.56-1.39(m,2H)。
实例28:2-氧代-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)二氢吲哚-7-甲酸甲酯
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、5-溴-2-氧代二氢吲哚-7-甲酸甲酯(26mg,0.1mmol)和Pd(dppf)Cl2·DCM(8.0mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌2小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到2-氧代-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)二氢吲哚-7-甲酸甲酯。MS:(ES)m/z对于C27H25F3N4O5S[M+H]+,计算值为575.2,实测值为575。1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),8.20(s,1H),8.02(s,1H),7.97-7.75(m,5H),7.63-7.54(m,1H),7.34(d,J=8.7Hz,1H),6.53(d,J=9.4Hz,1H),3.88(s,3H),3.79-3.69(m,1H),3.70-3.60(m,2H),3.60-3.48(m,2H),2.62-2.52(m,2H),2.00-1.87(m,2H),1.57-1.39(m,2H)。
实例29:2-氧代-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)螺[二氢吲哚-3,4'-哌啶]-1'-鎓氯化物
向在隔膜帽小瓶中的2-氧代-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)螺[二氢吲哚-3,4'-哌啶]-1'-甲酸叔丁酯中添加2mL二噁烷并搅拌内容物使其溶解。一旦溶解,就添加0.5mL在二噁烷中的4M HCl,并且将反应物在室温下搅拌24小时。一旦完成,就在减压下去除溶剂,并且将残余物再悬浮于CH3CN中并冻干,以得到2-氧代-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)螺[二氢吲哚-3,4'-哌啶]-1'-鎓氯化物。MS:(ES)m/z对于C29H30F3N5O3S[M+H]+,计算值为586.2,实测值为586。1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.22(d,J=3.8Hz,1H),8.05-7.55(m,7H),7.32(s,1H),7.06-6.97(m,1H),6.54(d,J=9.0Hz,1H),3.82-3.69(m,1H),3.64-3.52(m,2H),3.43-3.38(m,2H,在残余H2O峰下),3.26-3.14(m,2H),2.62-2.52(m,2H),2.05-1.81(m,6H),1.59-1.42(m,2H)。
实例30:1-(2-羟基乙基)-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-甲腈
步骤a:向在2.25mL二噁烷中的N-[1-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基]磺酰基-4-哌啶基]-5-(三氟甲基)吡啶-2-胺(40.0mg,0.07mmol)中添加K2CO3(25.0mg,0.18mmol)、1-[2-[叔丁基(二甲基)甲硅烷基]氧基乙基]-5-[4-[[4-[[5-(三氟甲基)-2-吡啶基]氨基]-1-哌啶基]磺酰基]苯基]吡咯并[2,3-b]吡啶-3-甲腈(40.0mg,0.11mmol)、Pd(dppf)Cl2·DCM(9.0mg,0.01mmol)和0.75mL水。将混合物用氮气鼓泡10分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法纯化,以得到1-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-甲腈。MS:(ES)m/z对于C33H39F3N6O3SSi[M+H]+,计算值为685.3,实测值为685.0。
步骤b:向1-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-甲腈(42.5mg;0.06mmol)在1mL THF中的溶液中添加0.1mL在THF中的1M TBAF。将混合物搅拌1小时。LC-MS指示所希望的产物。将反应用10mL EtOAc稀释,用3x 5mL H2O和10mL盐水洗涤。将有机相用MgSO4干燥,过滤并浓缩。将材料通过反相制备型HPLC纯化,以得到1-(2-羟基乙基)-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-甲腈。(ES)m/z对于C27H25F3N6O3S[M+H]+,计算值为571.2,实测值为570.9。1H NMR(400MHz,DMSO-d6)δ8.86(d,J=1.7Hz,1H),8.81(d,J=1.8Hz,1H),8.36(s,1H),8.21(d,J=2.3Hz,1H),8.13(d,J=8.5Hz,2H),7.88(d,J=8.5Hz,2H),7.58(dd,J=9.0,2.6Hz,1H),7.30(d,J=7.3Hz,1H),6.53(d,J=8.9Hz,1H),5.11(t,J=5.5Hz,1H),4.88(t,J=5.2Hz,2H),3.96(q,J=5.3Hz,2H),3.76(bs,1H),3.58(d,J=11.8Hz,2H),2.64-2.51(m,2H),1.96(d,J=12.6Hz,2H),1.50(d,J=11.4Hz,2H)。
实例31:N-(1-((4-(4-氟-1H-吡咯并[2,3-b]吡啶-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺(51mg,0.10mmol)中添加K2CO3(41mg,0.30mmol)、5-溴-4-氟-1H-吡咯并[2,3-b]吡啶(26mg,0.12mmol)、二噁烷(1.5mL)和水(0.5mmol)。将混合物用氮气鼓泡20分钟。添加Pd(dppf)Cl2·DCM(8mg,0.010mmol),并且将混合物用氮气鼓泡额外5分钟。密封小瓶,将混合物在100℃下搅拌2小时,并且当反应进行至完全时冷却。将反应混合物浓缩,并且经由SiO2凝胶色谱法、随后制备型反相HPLC纯化,以得到N-(1-((4-(4-氟-1H-吡咯并[2,3-b]吡啶-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺。MS:(ES)m/z对于C24H22F4N5O2S[M+H]+,计算值为520.14,实测值为520.3。1H NMR(400MHz,DMSO-d6)δ12.20(s,1H),8.42(d,J=10.3Hz,1H),8.23(s,1H),7.91(d,J=8.7Hz,2H),7.87(d,J=8.7Hz,2H),7.62-7.58(m,2H),7.33(d,J=7.3Hz,1H),6.64(d,J=3.4Hz,1H),6.55(d,J=8.9Hz,1H),3.86-3.74(m,1H),3.63-3.55(m,2H),2.65-2.57(m,2H),2.02-1.94(m,2H),1.58-1.46(m,2H)。
实例32:2,2-二甲基-6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺(51mg,0.10mmol)中添加K2CO3(41mg,0.30mmol)、6-溴-2,2-二甲基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(31mg,0.12mmol)、二噁烷(1.5mL)和水(0.5mmol)。将混合物用氮气鼓泡20分钟。添加Pd(dppf)Cl2·DCM(8mg,0.010mmol),并且将混合物用氮气鼓泡额外5分钟。密封小瓶,将混合物在100℃下搅拌2小时,并且当反应进行至完全时冷却。将反应混合物浓缩并且经由SiO2凝胶色谱法、随后制备型反相HPLC纯化,以得到2,2-二甲基-6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮。MS:(ES)m/z对于C27H28F3N4O4S[M+H]+,计算值为561.18,实测值为561.3。1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),8.22(s,1H),7.82(s,4H),7.60(dd,J=9.0,2.6Hz,1H),7.34(dd,J=8.3,2.2Hz,1H),7.31(d,J=7.4Hz,1H),7.21(d,J=2.2Hz,1H),7.08(d,J=8.3Hz,1H),6.54(d,J=8.7Hz,1H),3.84-3.70(m,1H),3.60-3.50(m,2H),2.62-2.54(m,2H),2.01-1.90(m,2H),1.57-1.47(m,2H),1.44(s,6H)。
实例33:N-(1-((4-(2,3-二氢苯并[b][1,4]二噁英-6-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺
向在隔膜帽小瓶中的N-(1-((4-溴苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺(46mg,0.10当量)中添加K2CO3(41mg,0.30mmol)、苯并二噁烷-6-硼酸(22mg,0.12mmol)、二噁烷(1.5mL)和水(0.5mL)以及Pd(dppf)Cl2·DCM(33mg,0.040mmol)。将混合物用氮气鼓泡20分钟。添加Pd(dppf)Cl2·DCM(8mg,0.010mmol),并且将混合物用氮气鼓泡额外5分钟。密封小瓶,将混合物在100℃下搅拌2小时,并且当反应进行至完全时冷却。将反应混合物用EtOAc(10mL)稀释,通过过滤并浓缩。将混合物经由SiO2凝胶色谱法、随后制备型反相HPLC纯化,以得到N-(1-((4-(2,3-二氢苯并[b][1,4]二噁英-6-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺。MS:(ES)m/z对于C25H25F3N3O4S[M+H]+,计算值为520.15,实测值为520.3。1H NMR(400MHz,DMSO-d6)δ8.22(s,1H),7.88(d,J=8.7Hz,2H),7.76(d,J=8.6Hz,2H),7.59(dd,J=8.8,2.4Hz,1H),7.31(d,J=7.4Hz,1H),7.29(d,J=2.3Hz,1H),7.25(dd,J=8.4,2.3Hz,1H),6.99(d,J=8.4Hz,1H),6.54(d,J=9.0Hz,1H),4.30(s,4H),3.82-3.70(m,1H),3.59-3.50(m,2H),2.61-2.52(m,2H),2.02-1.91(m,2H),1.56-1.43(m,2H)。
实例34:2-(2-羟基乙基)-6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)异二氢吲哚-1-酮
向在1mL THF中的2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)异二氢吲哚-1-酮(35.0mg;0.05mmol)中添加0.1mL在THF中的1M TBAF。将混合物搅拌1小时。LC-MS指示所希望的产物。将反应用10mL EtOAc稀释,用3x 5mL H2O和10mL盐水洗涤。将有机相用MgSO4干燥,过滤并浓缩。将材料通过反相制备型HPLC纯化,以得到2-(2-羟基乙基)-6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)异二氢吲哚-1-酮。MS:(ES)m/z对于C27H27F3N4O4S[M+H]+,计算值为5610.2,实测值为560.9。
实例35:N-(1-((4-(2',3',5',6'-四氢螺[二氢吲哚-3,4'-吡喃]-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺
向在2.25mL二噁烷中的N-[1-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基]磺酰基-4-哌啶基]-5-(三氟甲基)吡啶-2-胺(50.0mg,0.10mmol)中添加K2CO3(25.0mg,0.18mmol)、5-溴螺[二氢吲哚-3,4'-四氢吡喃](40.0mg,0.15mmol)、Pd(dppf)Cl2·DCM(9.0mg,0.01mmol)和0.75mL水。将混合物用氮气鼓泡10分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法纯化,以得到N-(1-((4-(2',3',5',6'-四氢螺[二氢吲哚-3,4'-吡喃]-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺。MS:(ES)m/z对于C29H31F3N4O3S[M+H]+,计算值为573.2,实测值为573.0。
实例36:N-(1-((4-(3,4-二氢-2H-苯并[b][1,4]噁嗪-6-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺(51mg,0.10mmol)中添加K2CO3(41mg,0.30mmol)、6-溴-3,4-二氢-2H-苯并[b][1,4]噁嗪(26mg,0.12mmol)、二噁烷(1.5mL)和水(0.5mmol)。将混合物用氮气鼓泡20分钟。添加Pd(dppf)Cl2·DCM(8mg,0.010mmol),并且将混合物用氮气鼓泡额外5分钟。密封小瓶,将混合物在100℃下搅拌2小时,并且当反应进行至完全时冷却。将反应混合物用EtOAc(10mL)稀释,通过过滤并浓缩。将混合物经由SiO2凝胶色谱法(0%-100% EtOAc/己烷)、随后制备型反相HPLC(H2O/MeCN+0.1% TFA)纯化,以得到N-(1-((4-(3,4-二氢-2H-苯并[b][1,4]噁嗪-6-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺。MS:(ES)m/z对于C25H26F3N4O3S[M+H]+,计算值为519.17,实测值为519.3。1H NMR(400MHz,DMSO-d6)δ8.22(s,1H),7.77(s,4H),7.60(d,J=9.0Hz,1H),7.30(d,J=6.2Hz,1H),6.93(s,1H),6.87(d,J=8.3Hz,1H),6.76(d,J=8.4Hz,1H),6.54(d,J=9.0Hz,1H),5.96(s,1H),4.17(s,2H),3.83-3.69(m,1H),3.60-3.48(m,2H),3.34-3.29(m,2H),2.63-2.50(m,2H),2.01-1.90(m,2H),1.57-1.43(m,2H)。
实例37:5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-2',3',5',6'-四氢螺[二氢吲哚-3,4'-吡喃]-2-酮
向在2.25mL二噁烷中的N-[1-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基]磺酰基-4-哌啶基]-5-(三氟甲基)吡啶-2-胺(50.0mg,0.10mmol)中添加K2CO3(25.0mg,0.18mmol)、5-溴螺[二氢吲哚-3,4'-四氢吡喃]-2-酮(40.0mg,0.15mmol)、Pd(dppf)Cl2·DCM(9.0mg,0.01mmol)和0.75mL水。将混合物用氮气鼓泡10分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法纯化,以得到5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-2',3',5',6'-四氢螺[二氢吲哚-3,4'-吡喃]-2-酮。MS:(ES)m/z对于C29H29F3N4O4S[M+H]+,计算值为587.2,实测值为586.9。1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),8.20(d,J=2.5Hz,1H),7.93(d,J=8.5Hz,2H),7.87(d,J=1.9Hz,1H),7.76(d,J=8.5Hz,2H),7.60(ddd,J=14.5,8.5,2.2Hz,2H),7.30(d,J=7.3Hz,1H),6.97(d,J=8.1Hz,1H),6.52(d,J=8.9Hz,1H),4.06(ddd,J=11.8,8.4,3.5Hz,2H),3.90-3.72(m,3H),3.59-3.51(m,2H),2.59-2.37(m,2H),2.00-1.80(m,4H),1.73(dt,J=13.6,4.4Hz,2H),1.56-1.41(m,2H)。
实例38:5'-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)螺[环丙烷-1,3'-二氢吲哚]-2'-酮
向在2.25mL二噁烷中的N-[1-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基]磺酰基-4-哌啶基]-5-(三氟甲基)吡啶-2-胺(50.0mg,0.10mmol)中添加K2CO3(25.0mg,0.18mmol)、5'-溴螺[环丙烷-1,3'-二氢吲哚]-2'-酮(35.0mg,0.15mmol)、Pd(dppf)Cl2·DCM(9.0mg,0.01mmol)和0.75mL水。将混合物用氮气鼓泡10分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法纯化,以得到5'-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)螺[环丙烷-1,3'-二氢吲哚]-2'-酮。MS:(ES)m/z对于C27H25F3N4O3S[M+H]+,计算值为543.2,实测值为443.0。1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.20(d,J=2.5Hz,1H),7.88(d,J=8.5Hz,2H),7.76(d,J=8.5Hz,2H),7.57(ddd,J=7.8,5.2,2.2Hz,2H),7.42(d,J=1.9Hz,1H),7.29(d,J=7.3Hz,1H),7.01(d,J=8.1Hz,1H),6.52(d,J=8.9Hz,1H),3.73(d,J=11.6Hz,1H),3.54(dd,J=10.4,6.0Hz,2H),2.56-2.43(m,2H),1.94(d,J=13.1Hz,2H),1.69(q,J=3.8Hz,2H),1.57-1.41(m,4H)。
实例39:2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)异二氢吲哚-1-酮
向在2.25mL二噁烷中的N-[1-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基]磺酰基-4-哌啶基]-5-(三氟甲基)吡啶-2-胺(50.0mg,0.10mmol)中添加K2CO3(25.0mg,0.18mmol)、6-溴-2-[2-[叔丁基(二甲基)甲硅烷基]氧基乙基]异二氢吲哚-1-酮(46.0mg,0.12mmol)、Pd(dppf)Cl2·DCM(9.0mg,0.01mmol)和0.75mL水。将混合物用氮气鼓泡10分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法纯化,以得到2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)异二氢吲哚-1-酮。MS:(ES)m/z对于C33H41F3N4O4SSi[M+H]+,计算值为675.3,实测值为675.0。1H NMR(400MHz,DMSO-d6)8.20(s,1H),8.07-7.95(m,4H),7.82(d,J=7.8Hz,2H),7.75(d,J=7.9Hz,1H),7.58(dd,J=8.8,2.5Hz,1H),7.30(d,J=7.3Hz,1H),6.52(d,J=9.0Hz,1H),4.61(s,2H),,3.67-3.52(m,4H),3.38(s,1H),3.28(s,2H),2.63-2.43(m,2H),1.99-1.91(m,2H),1.49(q,J=10.5,9.2Hz,2H),0.82(s,9H),0.0(s,6H)。
实例40:2-(3-氰基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡咯并[2,3-b]吡啶-1-基)乙酰胺
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺(51mg,0.10mmol)中添加K2CO3(41mg,0.30mmol)、2-(5-溴-3-氰基-1H-吡咯并[2,3-b]吡啶-1-基)乙酰胺(42mg,0.15mmol)、二噁烷(1.5mL)和水(0.5mmol)。将混合物用氮气鼓泡20分钟。添加Pd(dppf)Cl2·DCM(8mg,0.010mmol),并且将混合物用氮气鼓泡额外5分钟。密封小瓶,将混合物在100℃下搅拌2小时,并且当反应进行至完全时冷却。将反应混合物浓缩并经由制备型反相HPLC(H2O/MeCN+0.1% TFA)纯化,以得到2-(3-氰基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡咯并[2,3-b]吡啶-1-基)乙酰胺。MS:(ES)m/z对于C27H25F3N7O3S[M+H]+,计算值为584.17,实测值为584.4。1H NMR(400MHz,DMSO-d6)δ8.82(d,J=2.1Hz,1H),8.54-8.52(m,2H),8.24-8.20(m,1H),8.12(d,J=8.5Hz,2H),7.86(d,J=8.5Hz,2H),7.82(s,1H),7.60(dd,J=9.0,2.5Hz,1H),7.39(s,1H),7.32(d,J=7.3Hz,1H),6.54(d,J=8.9Hz,1H),5.04(s,2H),3.84-3.72(m,1H),3.63-3.52(m,2H),2.65-2.54(m,2H),2.02-1.93(m,2H),1.58-1.45(m,2H)。
实例41:2-(1-氧代-6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)异二氢吲哚-2-基)乙酰胺
向在2.25mL二噁烷中的N-[1-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基]磺酰基-4-哌啶基]-5-(三氟甲基)吡啶-2-胺(50.0mg,0.10mmol)中添加K2CO3(25.0mg,0.18mmol)、2-(6-溴-1-氧代-异二氢吲哚-2-基)乙酰胺(35.0mg,0.13mmol)、Pd(dppf)Cl2·DCM(9.0mg,0.01mmol)和0.75mL水。将混合物用氮气鼓泡10分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法纯化,以得到2-(1-氧代-6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)异二氢吲哚-2-基)乙酰胺。MS:(ES)m/z对于C27H26F3N5O4S[M+H]+,计算值为574.2,实测值为573.9。1H NMR(400MHz,DMSO-d6)δ8.20(d,J=2.4Hz,1H),8.10-7.97(m,4H),7.86-7.79(d,J=8.0Hz,2H),7.75(d,J=7.9Hz,1H),7.62-7.54(m,2H),7.30(d,J=7.2Hz,1H),7.22-7.16(m,1H),6.52(d,J=8.9Hz,1H),4.57(s,2H),4.15(s,2H),3.76(dd,J=15.0,8.1Hz,1H),3.56(d,J=12.3Hz,2H),2.64-2.50(m,2H),1.99-1.90(m,2H),1.49(q,J=9.7,9.3Hz,2H)。
实例42:1-环丙基-6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1,3-二氢-2H-苯并[d]咪唑-2-酮
向在2.25mL二噁烷中的N-[1-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基]磺酰基-4-哌啶基]-5-(三氟甲基)吡啶-2-胺(50.0mg,0.10mmol)中添加K2CO3(25.0mg,0.18mmol)、5-溴-3-(氧杂环丁烷-3-基)-1H-苯并咪唑-2-酮(35.0mg,0.13mmol)、Pd(dppf)Cl2·DCM(9.0mg,0.01mmol)和0.75mL水。将混合物用氮气鼓泡10分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法纯化,以得到1-环丙基-6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1,3-二氢-2H-苯并[d]咪唑-2-酮。MS:(ES)m/z对于C27H26F3N5O2S[M+H]+,计算值为574.2,实测值为573.9。1H NMR(400MHz,DMSO-d6)δ11.18(s,1H),8.20(d,J=2.5Hz,1H),7.91(d,J=8.4Hz,2H),7.80(d,J=8.5Hz,2H),7.76(d,J=1.8Hz,1H),7.58(dd,J=8.9,2.6Hz,1H),7.43(dd,J=8.2,1.7Hz,1H),7.30(d,J=7.4Hz,1H),7.14(d,J=8.1Hz,1H),6.52(d,J=8.9Hz,1H),5.53(p,J=6.9Hz,1H),5.14(t,J=6.5Hz,2H),4.95(q,J=7.6Hz,2H),3.75(s,1H),3.54(d,J=11.0Hz,2H),3.38-3.27(m,1H),,2.62-2.50(m,1H),1.95(d,J=13.7Hz,2H),1.49(q,J=11.0,10.1Hz,2H)。
实例43:(N-(1-((4-(6-氟-1H-吡咯并[2,3-b]吡啶-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺(51mg,0.10mmol)中添加K2CO3(41mg,0.30mmol)、5-溴-6-氟-1H-吡咯并[2,3-b]吡啶(26mg,0.12mmol)、二噁烷(1.5mL)和水(0.5mmol)。将混合物用氮气鼓泡20分钟。添加Pd(dppf)Cl2·DCM(8mg,0.010mmol),并且将混合物用氮气鼓泡额外5分钟。密封小瓶,将混合物在100℃下搅拌1小时,并且当反应进行至完全时冷却。将反应混合物用EtOAc(10mL)稀释,通过过滤并浓缩。将混合物经由SiO2凝胶色谱法(0%-100% EtOAc/己烷)纯化,随后通过制备型反相HPLC(H2O/MeCN+0.1% TFA)纯化,以得到(N-(1-((4-(6-氟-1H-吡咯并[2,3-b]吡啶-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺。MS:(ES)m/z对于C24H22F4N5O2S[M+H]+,计算值为520.14,实测值为520.3。1H NMR(400MHz,DMSO-d6)δ11.96(s,1H),8.33(d,J=10.0Hz,1H),8.23(s,1H),7.89(d,J=8.7Hz,2H),7.85(d,J=8.2Hz,2H),7.60(d,J=8.8Hz,1H),7.53(s,1H),7.33(d,J=7.4Hz,1H),6.62-6.50(m,2H),3.86-3.72(m,1H),3.67-3.49(m,2H),2.65-2.55(m,2H),2.04-1.92(m,2H),1.59-1.46(m,2H)。
实例44:5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1,3-二氢-2H-吡咯并[2,3-c]吡啶-2-酮
向在隔膜盖小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、5-溴-1,3-二氢-2H-吡咯并[2,3-c]吡啶-2-酮(21mg,0.10mmol)、和Pd(dppf)Cl2·DCM(8.0mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1,3-二氢-2H-吡咯并[2,3-c]吡啶-2-酮。MS:(ES)m/z对于C24H22F3N5O3S[M+H]+,计算值为518.2,实测值为518。1H NMR(400MHz,DMSO-d6)δ10.75(s,1H),8.26(dd,J=18.6,8.3Hz,3H),8.13-7.94(m,3H),7.82(d,J=7.8Hz,1H),7.61(d,J=9.7Hz,1H),7.38(bs,1H),6.56(d,J=9.1Hz,1H),3.82-3.51(m,5H),2.64-2.54(m,2H),2.03-1.89(m,2H),1.50(d,J=13.0Hz,2H)。
实例45:2-氧代-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)螺[二氢吲哚-3,4'-哌啶]-1'-氨基甲酸叔丁酯
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(160mg,1.2mmol)、5-溴-2-氧代螺[二氢吲哚-3,4'-哌啶]-1'-甲酸叔丁酯(150mg,0.40mmol)和Pd(dppf)Cl2·DCM(32mg,0.040mmol)。向其中添加3.2mL二噁烷和0.8mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶纯化,以得到2-氧代-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)螺[二氢吲哚-3,4'-哌啶]-1'-甲酸叔丁酯。MS:(ES)m/z对于C34H38F3N5O5S[M+H]+计算值为686.3,实测值为686。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.20(s,1H),7.93(d,J=8.1Hz,2H),7.85(s,1H),7.75(d,J=8.1Hz,2H),7.65-7.53(m,2H),7.29(d,J=7.3Hz,1H),6.97(d,J=8.0Hz,1H),6.52(d,J=9.0Hz,1H),3.79-3.62(m,5H),3.60-3.50(m,2H),2.61-2.49(m,2H),2.00-1.90(m,2H),1.84-1.65(m,4H),1.43(s,11H)。
实例46:7-甲氧基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)二氢吲哚-2-酮
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、5-溴-7-甲氧基二氢吲哚-2-酮(24mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1小时,并且当反应进行至完全时冷却。混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到7-甲氧基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)二氢吲哚-2-酮。MS:(ES)m/z对于C26H25F3N4O4S[M+H]+,计算值为547.2,实测值为547。1HNMR(400MHz,DMSO-d6)δ10.60(s,1H),8.23(s,1H),7.92(d,J=8.2Hz,2H),7.78(d,J=8.1Hz,2H),7.62(d,J=7.8Hz,1H),7.39(s,1H),7.27(s,2H),6.57(d,J=9.0Hz,1H),3.92(s,3H),3.82-3.69(m,1H),3.62-3.51(m,4H),2.61-2.51(m,2H),2.01-1.91(m,2H),1.57-1.44(m,2H)。
实例47:1-甲基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲唑-3-胺
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、5-溴-N-甲基-1H-吡唑并[3,4-b]吡啶-3-胺(22mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1小时,并且当反应进行至完全时冷却。将混合物经由反相HPLC纯化,以得到1-甲基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲唑-3-胺。MS:(ES)m/z对于C25H25F3N6O2S[M+H]+,计算值为531.2,实测值为531。1H NMR(400MHz,DMSO-d6)δ8.22(s,1H),8.17(d,J=1.3Hz,1H),7.93(d,J=8.4Hz,2H),7.82(d,J=8.5Hz,2H),7.71(dd,J=8.9,1.8Hz,1H),7.59(dd,J=8.9,2.6Hz,1H),7.46(d,J=8.8Hz,1H),7.31(d,J=7.2Hz,1H),6.54(d,J=8.9Hz,1H),5.60(s,2H),3.77(s,3H),3.61-3.52(m,2H),2.63-2.54(m,2H),2.01-1.91(m,2H),1.58-1.45(m,2H)。
实例48:7-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-3,4-二氢喹啉-2(1H)-酮
向在隔膜盖小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、7-溴-3,4-二氢喹啉-2(1H)-酮(22mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到7-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-3,4-二氢喹啉-2(1H)-酮。MS:(ES)m/z对于C26H25F3N4O3S[M+H]+,计算值为531.2,实测值为531。1HNMR(400MHz,DMSO-d6)δ10.24(s,1H),8.22(app s,1H),7.91-7.75(m,4H),7.65-7.54(m,1H),7.39-7.25(m,3H),7.21-7.13(m,1H),6.60-6.48(m,1H),3.85-3.71(m,1H),3.62-3.47(m,2H),3.33-3.23(m,2H,在残余H2O峰下),2.99-2.85(m,2H),2.65-2.55(m,2H),2.02-1.88(m,2H),1.58-1.40(m,2H)。
实例49:2-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-6,7-二氢噻唑并[5,4-c]吡啶-4(5H)-酮
向在隔膜盖小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、2-溴-6,7-二氢噻唑并[5,4-c]吡啶-4(5H)-酮(23mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到2-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-6,7-二氢噻唑并[5,4-c]吡啶-4(5H)-酮。MS:(ES)m/z对于C23H22F3N5O3S2[M+H]+,计算值为538.1,实测值为538。1H NMR(400MHz,DMSO-d6)δ8.25(d,J=8.5Hz,1H),8.22(s,1H),8.04(bs,1H),7.89(d,J=8.5Hz,2H),7.59(dd,J=9.0,2.6Hz,1H),7.29(d,J=7.4Hz,1H),6.53(d,J=8.9Hz,1H),3.84-3.73(m,1H),3.61-3.50(m,4H),3.12-3.03(m,2H),2.69-2.58(m,2H),1.99-1.91(m,2H),1.55-1.41(m,2H)。
实例50:N-甲基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-胺
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、5-溴-N-甲基-1H-吡唑并[3,4-b]吡啶-3-胺(22mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1小时,并且当反应进行至完全时冷却。将混合物经由反相HPLC纯化,以得到N-甲基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-胺。MS:(ES)m/z对于C24H24F3N7O2S[M+H]+,计算值为532.2,实测值为532。1H NMR(400MHz,DMSO-d6)δ12.21(s,1H),8.78(d,J=2.2Hz,1H),8.51(d,J=2.2Hz,1H),8.22(s,1H),7.96(d,J=8.2Hz,2H),7.85(d,J=8.2Hz,2H),7.60(dd,J=9.0,2.5Hz,1H),7.31(d,J=7.3Hz,1H),6.54(d,J=8.8Hz,1H),6.34(d,J=5.3Hz,1H),3.84-3.72(s,1H),3.63-3.52(m,2H),2.89(d,J=5.0Hz,3H),2.64-2.56(m,2H),2.03-1.92(m,2H),1.59-1.44(m,2H)。
实例51:5-(4-((4-((4-(三氟甲基)苯基)氨基)哌啶-1-基)磺酰基)苯基)二氢吲哚-2-酮
向在隔膜帽小瓶中的1-((4-溴苯基)磺酰基)-N-(4-(三氟甲基)苯基)哌啶-4-胺中添加K2CO3(41mg,0.29mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)二氢吲哚-2-酮(28mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法纯化,以得到5-(4-((4-((4-(三氟甲基)苯基)氨基)哌啶-1-基)磺酰基)苯基)二氢吲哚-2-酮。MS:(ES)m/z对于C26H24F3N3O3S[M+H]+,计算值为516.2,实测值为516。1H NMR(400MHz,DMSO-d6)δ10.57(s,1H),7.89(d,J=8.3Hz,2H),7.78(d,J=8.4Hz,2H),7.66-7.57(m,2H),7.33-7.27(m,2H),6.95(d,J=8.0Hz,1H),6.64(d,J=8.5Hz,2H),6.28(d,J=7.9Hz,1H),3.65-3.53(m,4H),3.32 -3.29(m,1H,在残余溶剂峰下),2.59-2.50(m,2H),2.02-1.92(m,2H),1.51-1.37(m,2H)。
实例52:5'-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)螺[环丙烷-1,3'-吡咯并[2,3-b]吡啶]-2'(1'H)-酮
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、5'-溴螺[环丙烷-1,3'-二氢吲哚]-2'-酮(25mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌2小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到5'-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)螺[环丙烷-1,3'-吡咯并[2,3-b]吡啶]-2'(1'H)-酮。MS:(ES)m/z对于C26H24F3N5O3S[M+H]+,计算值为544.2,实测值为544。1H NMR(400MHz,DMSO-d6)δ11.38(s,1H),8.49(d,J=2.1Hz,1H),8.22(d,J=2.4Hz,1H),7.96(d,J=8.5Hz,2H),7.86-7.79(m,3H),7.61(dd,J=8.7,2.2Hz,1H),7.37(s,1H),6.55(d,J=8.9Hz,1H),3.79-3.65(m,1H,在残余H2O峰下),3.61-3.53(m,2H),2.58-2.43(m,2H,在DMSO溶剂峰下),2.02-1.91(m,2H),1.79(q,J=3.9Hz,2H),1.59(q,J=3.7Hz,2H),1.57-1.43(m,2H)。
实例53:1-环丙基-6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1,3-二氢-2H-苯并[d]咪唑-2-酮
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、6-溴-1-环丙基-1,3-二氢-2H-苯并[d]咪唑-2-酮(25mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌2小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到1-环丙基-6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1,3-二氢-2H-苯并[d]咪唑-2-酮。MS:(ES)m/z对于C27H26F3N5O3S[M+H]+,计算值为558.2,实测值为558。1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.23(apps,1H),7.92(d,J=8.5Hz,2H),7.81(d,J=8.5Hz,2H),7.61(dd,J=9.1,2.5Hz,1H),7.46(s,1H),7.42-7.26(m,2H),7.08(d,J=8.1Hz,1H),6.56(d,J=9.0Hz,1H),3.83-3.70(m,1H),3.61-3.51(m,2H),2.95-2.85(m,1H),2.62-2.52(m,2H),2.02-1.92(m,2H),1.59-1.43(m,2H),1.10-1.00(m,2H),0.95-0.88(m,2H)。
实例54:1-(5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)异二氢吲哚-2-基)乙-1-酮
向在隔膜帽小瓶中的N-(1-((4-(异二氢吲哚-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺中添加DMF(2mL)和DIPEA(26μL,0.15mmol),随后添加乙酸(3μL,0.050mmol),并且然后添加HATU(28mg,0.075mmol)。将混合物在室温下搅拌,直到反应进行至完全。将混合物经由反相HPLC纯化,以得到1-(5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)异二氢吲哚-2-基)乙-1-酮。MS:(ES)m/z对于C27H27F3N4O3S[M+H]+,计算值为545.2,实测值为545。1H NMR(400MHz,DMSO-d6)δ8.23(app s,1H),7.97-7.92(m,2H),7.86-7.81(m,2H),7.77-7.68(m,2H),7.63(dd,J=9.1,2.6Hz,1H),7.50(t,J=7.2Hz,1H),7.46-7.39(m,1H),6.58(d,J=8.8Hz,1H),4.90(d,J=5.6Hz,2H),4.68(d,J=8.0Hz,2H),3.81-3.71(m,1H),3.62-3.51(m,2H),2.61-2.53(m,2H),2.09(d,J=2.1Hz,3H),2.01-1.91(m,2H),1.58-1.44(m,2H)。
实例55:5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)异二氢吲哚-2-甲酰胺
向在隔膜帽小瓶中的N-(1-((4-(异二氢吲哚-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺中添加DCM(3mL)和DIPEA(26μL,0.15mmol),随后添加(三甲基甲硅烷基)异氰酸酯(13μL,0.10mmol)。将混合物在室温下搅拌,直到反应进行至完全。将混合物经由反相HPLC纯化,以得到5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)异二氢吲哚-2-甲酰胺。MS:(ES)m/z对于C26H26F3N5O3S[M+H]+,计算值为546.2,实测值为546。1H NMR(400MHz,DMSO-d6)δ8.22(s,1H),7.98-7.92(m,2H),7.82(dd,J=8.6,2.2Hz,2H),7.73-7.65(m,2H),7.61(dd,J=8.9,2.5Hz,1H),7.47(d,J=7.7Hz,1H),7.35(bs,1H),6.55(d,J=8.9Hz,1H),6.01(bs,2H),4.70-4.56(m,4H),3.57-3.44(m,3H,在残余H2O峰下),2.63-2.53(m,2H),2.02-1.91(m,2H),1.58-1.45(m,2H)。
实例56:5-(4-((4-((4-(三氟甲基)苯基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲唑-3-甲腈
向在隔膜帽小瓶中的1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)-N-(4-(三氟甲基)苯基)哌啶-4-胺中添加K2CO3(41mg,0.29mmol)、5-溴-1H-吲唑-3-甲腈(22mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌3小时,并且当反应进行至完全时冷却。将混合物经由反相HPLC纯化,以得到5-(4-((4-((4-(三氟甲基)苯基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲唑-3-甲腈。MS:(ES)m/z对于C26H22F3N5O2S[M+H]+,计算值为526.2,实测值为526。1H NMR(400MHz,DMSO-d6)δ8.29-8.21(m,1H),8.14-8.03(m,2H),7.98-7.78(m,4H),7.34-7.23(m,2H),6.68-6.58(m,2H),3.67-3.54(m,2H),3.40-3.27(m,1H),2.60-2.51(m,2H),2.02-1.88(m,2H),1.51-1.35(m,2H)。
实例57:5-(4-((4-((4-(三氟甲基)苯基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-甲腈
向在隔膜盖小瓶中的1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)-N-(4-(三氟甲基)苯基)哌啶-4-胺中添加K2CO3(41mg,0.29mmol)、5-溴-1H-吡咯并[2,3-b]吡啶-3-甲腈(22mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1小时,并且当反应进行至完全时冷却。将混合物经由反相HPLC纯化,以得到5-(4-((4-((4-(三氟甲基)苯基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-甲腈。MS:(ES)m/z对于C26H22F3N5O2S[M+H]+,计算值为526.2,实测值为526。1H NMR(400MHz,DMSO-d6)δ13.03(bs,1H),8.83(s,1H),8.60-8.45(m,2H),8.20-8.07(m,2H),7.92-7.80(m,2H),7.38-7.25(m,2H),6.71-6.59(m,2H),3.69-3.55(m,2H),3.42-3.28(m,1H),2.63-2.53(m,2H),2.03-1.90(m,2H),1.53-1.36(m,2H)。
实例58:7-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)喹唑啉-2,4(1H,3H)-二酮
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、7-溴喹唑啉-2,4(1H,3H)-二酮(24mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌24小时,并且当反应进行至完全时冷却。将混合物经由反相HPLC纯化,以得到7-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)喹唑啉-2,4(1H,3H)-二酮。MS:(ES)m/z对于C25H22F3N5O4S[M+H]+,计算值为546.1,实测值为546。1H NMR(400MHz,DMSO-d6)δ11.39(s,1H),11.30(s,1H),8.23(s,1H),8.05-7.85(m,5H),7.66-7.50(m,2H),7.48-7.40(m,1H),7.34(app bs,1H),6.60-6.50(m,1H),3.57-3.44(m,3H,在残余H2O下),2.68-2.55(m,2H),2.02-1.90(m,2H),1.58-1.43(m,2H)。
实例59:N-(1-((4-(异二氢吲哚-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(82mg,0.58mmol)、5-溴异二氢吲哚(39mg,0.20mmol)和Pd(dppf)Cl2·DCM(16mg,0.020mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1.3小时,并且当反应进行至完全时冷却。将混合物经由反相HPLC纯化,以得到N-(1-((4-(异二氢吲哚-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺。MS:(ES)m/z对于C25H25F3N4O2S[M+H]+,计算值为503.2,实测值为503。1H NMR(400MHz,DMSO-d6)δ9.57-9.37(m,2H),8.27-8.18(m,1H),8.03-7.73(m,6H),7.67-7.51(m,2H),7.38-7.30(m,1H),6.60-6.51(m,1H),4.66-4.49(m,4H),3.84-3.69(m,1H),3.65-3.51(m,2H),2.66-2.51(m,2H),2.06-1.88(m,2H),1.61-1.42(m,2H)。
实例60:6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)酞嗪-1(2H)-酮
向在隔膜盖小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、6-溴酞嗪-1(2H)-酮(22mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1.5小时,并且当反应进行至完全时冷却。将混合物经由反相HPLC纯化,以得到6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)酞嗪-1(2H)-酮。MS:(ES)m/z对于C25H22F3N5O3S[M+H]+,计算值为530.2,实测值为530。1H NMR(400MHz,DMSO-d6)δ12.75(s,1H),8.50-8.42(m,1H),8.40-8.30(m,2H),8.29-8.19(m,2H),8.16-8.06(m,2H),7.98-7.86(m,2H),7.66-7.56(m,1H),7.39-7.29(m,1H),6.60-6.50(m,1H),3.86-3.72(m,1H),3.66-3.55(m,2H),2.70-2.56(m,2H),2.03-1.90(m,2H),1.58-1.42(m,2H)。
实例61:2-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)苯并[d]噻唑-6-甲腈
向在隔膜盖小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、2-溴苯并[d]噻唑-6-甲腈(23mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1.5小时,并且当反应进行至完全时冷却。将混合物经由反相HPLC纯化,以得到2-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)苯并[d]噻唑-6-甲腈。MS:(ES)m/z对于C25H20F3N5O2S2[M+H]+,计算值为544.1,实测值为544。1H NMR(400MHz,DMSO-d6)δ8.87(s,1H),8.46-8.37(m,2H),8.35-8.27(m,1H),8.22(s,1H),8.06-7.93(m,3H),7.65-7.57(m,1H),7.43-7.33(m,1H),6.60-6.51(m,1H),3.84-3.72(m,1H),3.64-3.54(m,2H),2.72-2.60(m,2H),2.03-1.91(m,2H),1.57-1.42(m,2H)。
实例62:4-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲哚-7-甲酰胺
向在隔膜盖小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、4-溴-1H-吲哚-7-甲酰胺(23mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1.5小时,并且当反应进行至完全时冷却。将混合物经由反相HPLC纯化,以得到4-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲哚-7-甲酰胺。MS:(ES)m/z对于C26H24F3N5O3S[M+H]+,计算值为544.2,实测值为544。1H NMR(400MHz,DMSO-d6)δ11.39(s,1H),8.30-8.12(m,2H),8.03-7.79(m,5H),7.68-7.59(m,1H),7.54-7.39(m,3H),7.30-7.21(m,1H),6.69-6.54(m,2H),3.88-3.72(m,1H),3.67-3.53(m,2H),2.68-2.55(m,2H),2.04-1.91(m,2H),1.63-1.44(m,2H)。
实例63:6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)苯并[d]异噻唑-3(2H)-酮1,1-二氧化物
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、6-溴苯并[d]异噻唑-3(2H)-酮1,1-二氧化物(26mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1.5小时,并且当反应进行至完全时冷却。将混合物经由反相HPLC纯化,以得到6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)苯并[d]异噻唑-3(2H)-酮1,1-二氧化物。MS:(ES)m/z对于C24H21F3N4O5S2[M+H]+,计算值为567.1,实测值为567。1H NMR(400MHz,DMSO-d6)δ8.51(s,1H),8.29-8.20(m,2H),8.16-8.09(m,2H),8.08-7.99(m,1H),7.92-7.83(m,2H),7.61(d,J=8.9Hz,1H),7.42-7.32(m,1H),6.56(d,J=8.5Hz,1H),3.85-3.71(m,1H,在残余H2O峰下),3.64-3.51(m,2H),2.71-2.54(m,2H),2.03-1.90(m,2H),1.58-1.42(m,2H)。
实例64:5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)苯并[d]异噻唑-3(2H)-酮1,1-二氧化物
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、5-溴苯并[d]异噻唑-3(2H)-酮1,1-二氧化物(26mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1.3小时,并且当反应进行至完全时冷却。将混合物经由反相HPLC纯化,以得到5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)苯并[d]异噻唑-3(2H)-酮1,1-二氧化物。MS:(ES)m/z对于C24H21F3N4O5S2[M+H]+,计算值为567.1,实测值为567。1H NMR(400MHz,DMSO-d6)δ8.36-8.18(m,4H),8.16-8.04(m,2H),7.94-7.82(m,2H),7.68-7.58(m,1H),7.44(bs,1H),6.58(d,J=8.8Hz,1H),3.85-3.71(m,1H),3.65-3.51(m,2H),2.67-2.54(m,2H),2.03-1.89(m,2H),1.59-1.43(m,2H)。
实例65:5'-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-2,3,5,6-四氢-螺[吡喃-4,3'-吡咯并[2,3-b]吡啶]-2'(1'H)-酮
向在隔膜盖小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、5'-溴-2,3,5,6-四氢螺[吡喃-4,3'-吡咯并[2,3-b]吡啶]-2'(1'H)-酮(28mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1.3小时,并且当反应进行至完全时冷却。将混合物经由反相HPLC纯化,以得到5'-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-2,3,5,6-四氢-螺[吡喃-4,3'-吡咯并[2,3-b]吡啶]-2'(1'H)-酮。MS:(ES)m/z对于C28H28F3N5O4S[M+H]+,计算值为588.2,实测值为588。1H NMR(400MHz,DMSO-d6)δ11.26(s,1H),8.53(s,1H),8.30(s,1H),8.26(s,1H),8.07-7.96(m,2H),7.87-7.75(m,2H),7.67-7.58(m,1H),7.40(bs,1H),6.57(d,J=8.9Hz,1H),4.08-3.97(m,2H),3.95-3.83(m,2H),3.82-3.69(m,1H),3.65-3.52(m,2H),2.62-2.52(m,2H),2.03-1.91(m,2H),1.84(s,4H),1.59-1.42(m,2H)。
实例66:6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)噁唑并[4,5-b]吡啶-2(3H)-酮
向在隔膜盖小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、6-溴噁唑并[4,5-b]吡啶-2(3H)-酮(21mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1.3小时,并且当反应进行至完全时冷却。将混合物经由反相HPLC纯化,以得到6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)噁唑并[4,5-b]吡啶-2(3H)-酮。MS:(ES)m/z对于C23H20F3N5O4S[M+H]+,计算值为520.1,实测值为520。1H NMR(400MHz,DMSO-d6)δ12.64(s,1H),8.49(s,1H),8.23(s,1H),8.13(s,1H),8.05-7.95(m,2H),7.88-7.77(m,2H),7.67-7.57(m,1H),7.46-7.31(m,1H),6.56(d,J=9.1Hz,1H),3.84-3.70(m,1H),3.65-3.49(m,2H),2.64-2.54(m,2H),2.03-1.88(m,2H),1.59-1.42(m,2H)。
实例67:7-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-3,4-二氢异喹啉-1(2H)-酮
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(49mg,0.35mmol)、7-溴-3,4-二氢异喹啉-1(2H)-酮(25mg,0.12mmol)和Pd(dppf)Cl2·DCM(10mg,0.012mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1.5小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到7-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-3,4-二氢异喹啉-1(2H)-酮。MS:(ES)m/z对于C26H25F3N4O3S[M+H]+,计算值为531.2,实测值为531。1H NMR(400MHz,DMSO-d6)δ8.29-8.15(m,2H),8.08(s,1H),8.01-7.93(m,2H),7.93-7.80(m,3H),7.63(d,J=8.8Hz,1H),7.52-7.38(m,2H),6.58(d,J=8.9Hz,1H),3.85-3.70(m,1H),3.63-3.51(m,2H),3.47-3.36(m,2H),3.03-2.91(m,2H),2.64-2.53(m,2H),2.02-1.88(m,2H),1.58-1.42(m,2H)。
实例68:6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(49mg,0.35mmol)、6-溴-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(25mg,0.12mmol)和Pd(dppf)Cl2·DCM(10mg,0.012mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1.5小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮。MS:(ES)m/z对于C23H21F3N6O3S[M+H]+,计算值为519.1,实测值为519。1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),11.08(s,1H),8.26(d,J=22.5Hz,2H),7.99-7.92(m,2H),7.85-7.77(m,2H),7.65-7.58(m,1H),7.55(s,1H),7.42-7.31(m,1H),6.56(d,J=8.4Hz,1H),3.86-3.71(m,1H,在残余H2O峰下),3.62-3.52(m,2H),2.63-2.53(m,2H),2.02-1.91(m,2H),1.58-1.43(m,2H)。
实例69:5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)环己-1,3-二烯-1-基)-1H-吡唑并[3,4-b]吡啶-3-胺
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(82mg,0.58mmol)、5-溴-1H-吡唑并[3,4-b]吡啶-3-胺(42mg,0.20mmol)和Pd(dppf)Cl2·DCM(16mg,0.020mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1.5小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)环己-1,3-二烯-1-基)-1H-吡唑并[3,4-b]吡啶-3-胺。MS:(ES)m/z对于C23H24F3N7O2S[M+H]+,计算值为520.2,实测值为520。1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),8.78(s,1H),8.55(s,1H),8.22(s,1H),7.97(d,J=7.8Hz,2H),7.86(d,J=8.2Hz,2H),7.60(d,J=8.9Hz,1H),7.31(d,J=6.0Hz,1H),6.54(d,J=7.8Hz,1H),5.73(bs,2H),3.86-3.71(m,1H),3.62-3.51(m,2H),2.65-2.54(m,2H),2.03-1.92(m,2H),1.59-1.44(m,2H)。
实例70:N,N-二甲基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)环己-1,3-二烯-1-基)-1H-吲唑-3-胺
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(82mg,0.58mmol)、5-溴-N,N-二甲基-1H-吲唑-3-胺(47mg,0.20mmol)和Pd(dppf)Cl2·DCM(16mg,0.020mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1.5小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到N,N-二甲基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)环己-1,3-二烯-1-基)-1H-吲唑-3-胺。MS:(ES)m/z对于C26H29F3N6O2S[M+H]+,计算值为547.2,实测值为547。1H NMR(400MHz,DMSO-d6)δ12.04(s,1H),8.22(s,1H),8.13(s,1H),8.03-7.94(m,2H),7.84-7.74(m,2H),7.72-7.65(m,1H),7.63-7.55(m,1H),7.50-7.42(m,1H),7.31(d,J=7.0Hz,1H),6.59-6.51(m,1H),3.84-3.71(m,1H),3.63-3.50(m,2H),3.04(s,6H),2.64-2.51(m,2H),2.03-1.90(m,2H),1.58-1.43(m,2H)。
实例71:5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1,3-二氢-2H-吡咯并[2,3-b]吡啶-2-酮
向在隔膜盖小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(82mg,0.58mmol)、5-溴-1,3-二氢-2H-吡咯并[2,3-b]吡啶-2-酮(34mg,0.20mmol)和Pd(dppf)Cl2·DCM(16mg,0.020mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1.5小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法及反相HPLC纯化,以得到5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1,3-二氢-2H-吡咯并[2,3-b]吡啶-2-酮。MS:(ES)m/z对于C24H22F3N5O3S[M+H]+,计算值为518.2,实测值为518。1H NMR(400MHz,DMSO-d6)δ11.20(s,1H),8.49(d,J=2.1Hz,1H),8.23(s,1H),7.98(s,1H),7.94(d,J=8.4Hz,2H),7.81(d,J=8.5Hz,2H),7.63(dd,J=9.3,2.6Hz,1H),7.48-7.35(m,1H),6.58(d,J=9.0Hz,1H),3.82-3.68(m,1H),3.65(s,2H),3.62-3.52(m,2H),2.62-2.52(m,2H),2.02-1.91(m,2H),1.58-1.42(m,2H)。
实例72:7-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮
向在隔膜帽小瓶中的N-(1-((4-溴苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺中添加K2CO3(45mg,0.32mmol)、7-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(30mg,0.11mmol)和Pd(dppf)Cl2·DCM(9mg,0.011mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1.5小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法纯化,以得到7-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮。MS:(ES)m/z对于C25H23F3N4O4S[M+H]+,计算值为533.2,实测值为533。1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.22(s,1H),7.91(d,J=8.1Hz,2H),7.78(d,J=7.9Hz,2H),7.60(d,J=8.7Hz,1H),7.39(app s,1H),7.30(d,J=7.4Hz,1H),7.02(d,J=8.9Hz,1H),6.54(d,J=9.1Hz,1H),4.65(s,2H),3.83-3.69(m,1H),3.62-3.47(m,2H),2.64-2.54(m,2H),2.03-1.89(m,2H),1.58-1.41(m,2H)。
实例73:6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-3,4-二氢异喹啉-1(2H)-酮
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、6-溴-3,4-二氢异喹啉-1(2H)-酮(22mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1.5小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法纯化,以得到6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-3,4-二氢异喹啉-1(2H)-酮。MS:(ES)m/z对于C26H25F3N4O3S[M+H]+,计算值为531.2,实测值为531。1H NMR(400MHz,DMSO-d6)δ8.22(s,1H),8.05-7.94(m,4H),7.85(d,J=8.2Hz,2H),7.78-7.69(m,2H),7.60(d,J=9.3Hz,1H),7.30(d,J=7.3Hz,1H),6.58-6.51(m,1H),3.85-3.72(m,1H),3.62-3.53(m,2H),3.47-3.39(m,2H),3.05-2.95(m,2H),2.64-2.55(m,2H),2.02-1.91(m,2H),1.57-1.44(m,2H)。
实例74:N-(1-((4-(3-甲氧基-1H-吲唑-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、5-溴-3-甲氧基-1H-吲唑(22mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法纯化,以得到N-(1-((4-(3-甲氧基-1H-吲唑-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺。MS:(ES)m/z对于C25H24F3N5O3S[M+H]+,计算值为532.2,实测值为532。1H NMR(400MHz,DMSO-d6)δ12.11(s,1H),8.22(s,1H),8.03-7.93(m,3H),7.83-7.73(m,3H),7.60(d,J=9.2Hz,1H),7.50(d,J=8.6Hz,1H),7.31(d,J=7.2Hz,1H),6.54(d,J=9.1Hz,1H),4.04(s,3H),3.84-3.72(m,1H),3.62-3.50(m,2H),2.64-2.53(m,2H),2.06-1.89(m,2H),1.59-1.43(m,2H)。
实例75:6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-3,4-二氢喹啉-2(1H)-酮
向在隔膜盖小瓶中的N-(1-((4-溴苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺中添加K2CO3(45mg,0.32mmol)、6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,4-二氢喹啉-2(1H)-酮(29mg,0.11mmol)和Pd(dppf)Cl2·DCM(9mg,0.011mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法纯化,以得到6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-3,4-二氢喹啉-2(1H)-酮。MS:(ES)m/z对于C26H25F3N4O3S[M+H]+,计算值为531.2,实测值为531。1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),8.22(s,1H),7.89(d,J=7.8Hz,2H),7.78(d,J=8.2Hz,2H),7.66-7.53(m,3H),7.35-7.25(m,1H),6.98(d,J=8.5Hz,1H),6.54(d,J=9.1Hz,1H),3.82-3.70(m,1H),3.60-3.50(m,2H),2.97(t,J=7.6Hz,2H),2.63-2.54(m,2H),2.00-1.90(m,2H),1.58-1.42(m,2H),一个亚甲基可能在溶剂峰下。
实例76:6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲哚-2-甲腈
向在隔膜盖小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、6-溴-1H-吲哚-2-甲腈(22mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法纯化,以得到6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲哚-2-甲腈。MS:(ES)m/z对于C26H22F3N5O2S[M+H]+,计算值为526.2,实测值为526。1H NMR(400MHz,DMSO-d6)δ12.60(s,1H),8.22(s,1H),8.00(d,J=8.2Hz,2H),7.88-7.77(m,4H),7.63-7.53(m,2H),7.44(s,1H),7.31(d,J=7.3Hz,1H),6.54(d,J=9.2Hz,1H),3.84-3.71(m,1H),3.63-3.51(m,2H),2.65-2.54(m,2H),2.02-1.91(m,2H),1.58-1.44(m,2H)。
实例77:5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲哚-3-甲酰胺
向在隔膜盖小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、5-溴-1H-吲哚-3-甲酰胺(23mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌12小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲哚-3-甲酰胺。MS:(ES)m/z对于C26H24F3N5O3S[M+H]+,计算值为544.2,实测值为544。1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),8.51(s,1H),8.23(s,1H),8.10(s,1H),7.93(d,J=7.9Hz,2H),7.83(d,J=8.3Hz,2H),7.65-7.50(m,4H),7.46-7.36(m,1H),6.63-6.52(m,1H),3.84-3.71(m,1H),3.62-3.49(m,2H),2.66-2.56(m,2H),2.03-1.90(m,2H),1.59-1.46(m,2H)。
实例78:6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)噁唑并[5,4-b]吡啶-2-胺
向在隔膜盖小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(82mg,0.58mmol)、6-溴噁唑并[4,5-b]吡啶-2-胺(42mg,0.20mmol)和Pd(dppf)Cl2·DCM(16mg,0.020mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法纯化,以得到6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)噁唑并[5,4-b]吡啶-2-胺。MS:(ES)m/z对于C23H21F3N6O3S[M+H]+,计算值为519.1,实测值为519。1H NMR(400MHz,DMSO-d6)δ8.23(app s,2H),8.00(d,J=8.1Hz,2H),7.94-7.88(m,3H),7.82(d,J=8.0Hz,2H),7.60(d,J=9.2Hz,1H),7.31(d,J=7.1Hz,1H),6.54(d,J=9.1Hz,1H),3.84-3.71(m,1H),3.63-3.52(m,2H),2.65-2.54(m,2H),2.07-1.88(m,2H),1.59-1.43(m,2H)。
实例79:5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)苯并-[d]噁唑-2(3H)-酮
向在隔膜盖小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(82mg,0.58mmol)、5-溴苯并[d]噁唑-2(3H)-酮(42mg,0.20mmol)和Pd(dppf)Cl2·DCM(16mg,0.020mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法纯化,以得到5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)苯并-[d]噁唑-2(3H)-酮。MS:(ES)m/z对于C24H21F3N4O4S[M+H]+,计算值为519.1,实测值为519。1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.22(s,1H),7.93(d,J=7.9Hz,2H),7.81(d,J=7.3Hz,2H),7.60(d,J=9.0Hz,1H),7.52-7.38(m,3H),7.31(d,J=7.6Hz,1H),6.54(d,J=8.9Hz,1H),3.85-3.69(m,1H),3.63-3.49(m,2H),2.64-2.54(m,2H),2.03-1.90(m,2H),1.58-1.43(m,2H)。
实例80:N-(1-((4-(1H-吡咯并[2,3-b]吡啶-4-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、4-溴-1H-吡咯并[2,3-b]吡啶(19mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法纯化,以得到N-(1-((4-(1H-吡咯并[2,3-b]吡啶-4-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺。MS:(ES)m/z对于C24H22F3N5O2S[M+H]+,计算值为502.2,实测值为502。1H NMR(400MHz,DMSO-d6)δ11.93(s,1H),8.35(d,J=4.9Hz,1H),8.23(s,1H),8.05(d,J=8.1Hz,2H),7.92(d,J=7.9Hz,2H),7.66-7.56(m,2H),7.36-7.25(m,2H),6.68(s,1H),6.55(d,J=9.1Hz,1H),3.86-3.74(m,1H),3.65-3.56(m,2H),2.68-2.58(m,2H),2.03-1.93(m,2H),1.61-1.42(m,2H)。
实例81:6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)二氢吲哚-2-酮
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(82mg,0.58mmol)、6-溴二氢吲哚-2-酮(42mg,0.20mmol)和Pd(dppf)Cl2·DCM(16mg,0.020mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌1小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)二氢吲哚-2-酮。MS:(ES)m/z对于C25H23F3N4O3S[M+H]+,计算值为517.2,实测值为517。1H NMR(400MHz,DMSO-d6)δ10.56(s,1H),8.22(s,1H),7.92-7.78(m,4H),7.60(d,J=9.1Hz,1H),7.38-7.25(m,3H),7.10(s,1H),6.54(d,J=9.0Hz,1H),3.84-3.73(m,1H),3.61-3.50(m,4H),2.63-2.54(m,2H),2.01-1.92(m,2H),1.57-1.44(m,2H)。
实例82:6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)咪唑并[1,2-a]吡啶-3-甲酰胺
向在隔膜盖小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、6-溴咪唑并[1,2-a]吡啶-3-甲腈(22mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌12小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)咪唑并[1,2-a]吡啶-3-甲酰胺。MS:(ES)m/z对于C25H23F3N6O3S[M+H]+,计算值为545.2,实测值为545。1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),8.51(s,1H),8.27-8.13(m,2H),8.07-7.87(m,6H),7.72-7.56(m,2H),7.46-7.33(m,1H),6.57(d,J=9.0Hz,1H),3.85-3.73(m,1H),3.63-3.52(m,2H),2.68-2.56(m,2H),2.03-1.92(m,2H),1.59-1.44(m,2H)。
实例83:6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)苯并-[d]噁唑-2-胺
向在隔膜盖小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、6-溴苯并[d]噁唑-2-胺(21mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌12小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)苯并-[d]噁唑-2-胺。MS:(ES)m/z对于C24H22F3N5O3S[M+H]+,计算值为518.2,实测值为518。1H NMR(400MHz,DMSO-d6)δ8.26-8.19(m,1H),7.99-7.90(m,2H),7.83-7.74(m,3H),7.67-7.49(m,4H),7.36-7.25(m,2H),6.58-6.50(m,1H),3.84-3.70(m,1H),3.62-3.52(m,2H),2.63-2.54(m,2H),2.02-1.91(m,2H),1.61-1.43(m,2H)。
实例84:5-(三氟甲基)-N-(1-((4-(3-(三氟甲基)-1H-吲唑-5-基)苯基)磺酰基)哌啶-4-基)吡啶-2-胺
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、5-溴-3-(三氟甲基)-1H-吲唑(26mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌12小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到5-(三氟甲基)-N-(1-((4-(3-(三氟甲基)-1H-吲唑-5-基)苯基)磺酰基)哌啶-4-基)吡啶-2-胺。MS:(ES)m/z对于C25H21F6N5O2S[M+H]+,计算值为570.1,实测值为570。1HNMR(400MHz,DMSO-d6)δ8.25-8.19(m,1H),8.14-8.07(m,1H),8.07-7.98(m,2H),7.97-7.80(m,4H),7.64-7.56(m,1H),7.34-7.28(m,1H),6.59-6.50(m,1H),3.84-3.70(m,1H),3.65-3.52(m,2H),2.64-2.55(m,2H),2.02-1.90(m,2H),1.59-1.44(m,2H)。
实例85:5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-甲腈
制备4:1二噁烷:dI H2O的溶液并且在真空下在剧烈搅拌下脱气20分钟。在将溶剂体系脱气的同时,将N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺(100mg,0.20mmol,1.0当量)、5-溴-1H-吡咯并[2,3-b]吡啶-3-甲腈(43mg,0.20mmol,1.0当量)、K2CO3(43mg,0.60mmol,3.0当量)和Pd(dppf)Cl2·DCM(16mg,0.02mmol,0.1当量)与搅拌棒一起添加到分开的容器中。一旦溶剂体系彻底脱气,就在剧烈搅拌下将氮气鼓泡通过4:1溶剂体系20分钟。在溶剂体系气氛被氮气彻底替代后,将2mL的4:1二噁烷:DI H2O溶液添加到含有试剂的反应容器中。然后将氮气鼓泡通过反应容器约2分钟,然后去除。将反应在100℃下加热并搅拌3小时,并且通过LC-MS监测。一旦反应完成,就将反应内含物附着至上,并且运行正相柱(12g柱,梯度:在DCM中的0%-100% EtOAc)。产物在约60% EtOAc下洗脱。合并纯级分,并且在减压下去除溶剂,以产生呈灰白色固体的标题化合物(48mg,46%)。MS:(ES)m/z对于C25H21F3N6O2S[M+H]+,计算值为526.5,实测值为527。1H NMR(400MHz,DMSO-d6)δ13.02(s,1H),8.82(s,1H),8.61-8.46(m,2H),8.22(s,1H),8.12(d,J=8.1Hz,2H),7.85(d,J=8.2Hz,2H),7.60(dd,J=9.0,2.6Hz,1H),7.31(d,J=7.2Hz,1H),6.55(d,J=8.8Hz,1H),3.84-3.71(m,1H),3.64-3.52(m,2H),2.65-2.54(m,2H),2.03-1.91(m,2H),1.59-1.43(m,2H)。
实例86:N-(1-((4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、5-溴-1H-吡咯并[2,3-b]吡啶(19mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌12小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到N-(1-((4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺。MS:(ES)m/z对于C24H22F3N5O2S[M+H]+,计算值为502.2,实测值为502。1HNMR(400MHz,DMSO-d6)δ11.84(s,1H),8.62(s,1H),8.39-8.32(m,1H),8.23(app s,1H),8.06-7.97(m,2H),7.87-7.78(m,2H),7.65-7.51(m,2H),7.35-7.27(m,1H),6.60-6.50(m,2H),3.84-3.72(m,1H),3.63-3.52(m,2H),2.65-2.54(m,2H),2.02-1.92(m,2H),1.60-1.44(m,2H)。
实例87:1-甲基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲唑-3-甲酰胺
1-甲基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲唑-3-甲酰胺作为水解产物从1-甲基-5-[4-[[4-[[5-(三氟甲基)-2-吡啶基]氨基]-1-哌啶基]磺酰基]苯基]吲唑-3-甲腈分离。MS:(ES)m/z对于C26H25F3N6O3S[M+H]+,计算值为559.2,实测值为558.9。
实例88:1-甲基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲唑-3-甲腈
向在2.25mL二噁烷中的N-[1-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基]磺酰基-4-哌啶基]-5-(三氟甲基)吡啶-2-胺(50.0mg,0.10mmol)中添加K2CO3(45.0mg,0.32mmol)、5-溴-1-甲基-吲唑-3-甲腈(50.0mg,0.21mmol)、Pd(dppf)Cl2·DCM(10.0mg,0.01mmol)和0.75mL水。将混合物用氮气鼓泡10分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法纯化,以得到1-甲基-5-[4-[[4-[[5-(三氟甲基)-2-吡啶基]氨基]-1-哌啶基]磺酰基]苯基]吲唑-3-甲腈。MS:(ES)m/z对于C26H23F3N6O2S[M+H]+,计算值为541.2,实测值为540.9。
实例89:N-(1-((4-(2-甲基-1H-苯并[d]咪唑-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺
向在隔膜帽小瓶中的N-(1-((4-溴苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺中添加K2CO3(45mg,0.32mmol)、(3-甲基-1H-吲唑-5-基)硼酸(19mg,0.11mmol)和Pd(dppf)Cl2·DCM(9.0mg,0.011mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌16-24小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和制备型反相HPLC纯化,以得到N-(1-((4-(2-甲基-1H-苯并[d]咪唑-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺。MS:(ES)m/z对于C25H24F3N5O2S[M+H]+,计算值为516.2,实测值为516。1H NMR(400MHz,DMSO-d6)δ8.20(s,1H),8.08(s,1H),8.05-7.96(m,2H),7.92-7.80(m,4H),7.62-7.53(m,1H),7.36-7.29(m,1H),6.56-6.49(m,1H),3.81-3.69(m,1H),3.64-3.53(m,2H),2.79(s,3H),2.60-2.51(m,2H),2.02-1.90(m,2H),1.58-1.43(m,2H)。
实例90:6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)异二氢吲哚-1-酮
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、6-溴异二氢吲哚-1-酮(21mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌24小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)异二氢吲哚-1-酮。MS:(ES)m/z对于C25H23F3N4O3S[M+H]+,计算值为517.2,实测值为517。1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.23(s,1H),8.11-7.95(m,4H),7.91-7.81(m,2H),7.74(dd,J=6.9,3.3Hz,1H),7.66-7.57(m,1H),7.46-7.33(m,1H),6.62-6.52(m,1H),4.46(s,2H),3.85-3.71(m,1H),3.65-3.51(m,2H),2.65-2.55(m,2H),2.05-1.90(m,2H),1.60-1.43(m,2H)。
实例91:N-(1-((4-(3-甲基-1H-吲唑-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺
向在隔膜帽小瓶中的N-(1-((4-溴苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺中添加K2CO3(45mg,0.32mmol)、(3-甲基-1H-吲唑-5-基)硼酸(19mg,0.11mmol)和Pd(dppf)Cl2·DCM(9.0mg,0.011mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌16-24小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和制备型反相HPLC纯化,以得到N-(1-((4-(3-甲基-1H-吲唑-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺。MS:(ES)m/z对于C25H24F3N5O2S[M+H]+,计算值为516.2,实测值为516。1H NMR(400MHz,DMSO-d6)δ8.23(s,1H),8.13(s,1H),8.01(d,J=8.1Hz,2H),7.82(d,J=8.1Hz,2H),7.74(d,J=8.8Hz,1H),7.66-7.55(m,2H),7.46-7.37(m,1H),6.57(d,J=9.1Hz,1H),3.85-3.70(m,1H),3.63-3.53(m,2H),2.64-2.53(m,5H),2.04-1.92(m,2H),1.61-1.44(m,2H)。
实例92:5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲唑-3-甲酰胺
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、5-溴-1H-吲唑-3-甲酰胺(23mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲唑-3-甲酰胺。MS:(ES)m/z对于C25H23F3N6O3S[M+H]+,计算值为545.2,实测值为545。1H NMR(400MHz,DMSO-d6)δ13.68(s,1H),8.48(s,1H),8.21(s,1H),7.96(d,J=8.1Hz,2H),7.88-7.70(m,5H),7.62-7.56(m,1H),7.48-7.32(m,2H),6.55(d,J=8.8Hz,1H),3.83-3.70(m,1H),3.61-3.49(m,2H),2.64-2.54(m,2H),2.01-1.89(m,2H),1.58-1.43(m,2H)。
实例93:N-(1-((4-(1H-吲唑-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、5-溴-1H-吲唑(19mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌24小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到N-(1-((4-(1H-吲唑-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺。MS:(ES)m/z对于C24H22F3N5O2S[M+H]+,计算值为502.2,实测值为502。1H NMR(400MHz,DMSO-d6)δ8.27-8.14(m,3H),7.99(d,J=8.3Hz,2H),7.83(d,J=8.1Hz,2H),7.76(dd,J=8.9,1.7Hz,1H),7.72-7.59(m,2H),7.52-7.42(m,1H),6.59(d,J=9.1Hz,1H),3.83-3.71(m,1H),3.64-3.54(m,2H),2.64-2.54(m,2H),2.03-1.93(m,2H),1.59-1.46(m,2H)。
实例94:6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)苯并-[d]噁唑-2(3H)-酮
向在隔膜盖小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、6-溴苯并[d]噁唑-2(3H)-酮(21mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌24小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)苯并-[d]噁唑-2(3H)-酮。MS:(ES)m/z对于C24H21F3N4O4S[M+H]+,计算值为519.1,实测值为519。1H NMR(400MHz,DMSO-d6)δ11.84(s,1H),8.23(app s,1H),7.95(d,J=8.1Hz,2H),7.86-7.73(m,3H),7.65-7.54(m,2H),7.44-7.36(m,1H),7.23(d,J=8.1Hz,1H),6.57(d,J=9.0Hz,1H),3.83-3.71(m,1H),3.62-3.52(m,2H),2.62-2.53(m,2H),2.02-1.91(m,2H),1.58-1.44(m,2H)。
实例95:5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲哚-2-甲酰胺
向在隔膜盖小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、5-溴-1H-吲哚-2-甲酰胺(23mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌24小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲哚-2-甲酰胺。MS:(ES)m/z对于C26H24F3N5O3S[M+H]+,计算值为544.2,实测值为544。1H NMR(300MHz,DMSO-d6)δ11.71(s,1H),8.23(app s,1H),8.06-7.94(m,3H),7.83-7.76(m,2H),7.66-7.49(m,3H),7.45-7.36(m,1H),7.23(s,1H),6.58(dd,J=8.2,4.2Hz,1H),3.86-3.66(m,3H),3.63-3.51(m,2H),2.63-2.53(m,2H),2.01-1.90(m,2H),1.61-1.43(m,2H)。
实例96:2-氨基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲哚-3-甲腈
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、2-氨基-5-溴-1H-吲哚-3-甲腈(23mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌24小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到2-氨基-5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲哚-3-甲腈。MS:(ES)m/z对于C26H23F3N6O2S[M+H]+,计算值为541.2,实测值为541。1H NMR(300MHz,DMSO-d6)δ10.88(s,1H),8.24(app s,1H),7.93(d,J=8.3Hz,2H),7.78(d,J=8.3Hz,2H),7.62(dd,J=9.0,2.5Hz,1H),7.52-7.38(m,2H),7.35-7.23(m,2H),6.58(d,J=8.9Hz,1H),3.75-3.58(m,3H,在残余H2O峰下),2.64-2.54(m,2H),2.04-1.89(m,2H),1.59-1.44(m,2H)。
实例97:5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲唑-3-甲腈
向在隔膜盖小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、5-溴-1H-吲唑-3-甲腈(22mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌24小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲唑-3-甲腈。MS:(ES)m/z对于C25H21F3N6O2S[M+H]+,计算值为527.2,实测值为527。1H NMR(300MHz,DMSO-d6)δ8.30-8.21(m,2H),8.09(d,J=8.3Hz,2H),7.99-7.81(m,4H),7.62(dd,J=9.1,2.6Hz,1H),7.45-7.36(m,1H),6.57(d,J=8.9Hz,1H),3.75-3.58(m,3H,在残余H2O峰下),2.65-2.53(m,2H),2.03-1.92(m,2H),1.60-1.44(m,2H)。
实例98:6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲哚-3-甲腈
向在隔膜盖小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、6-溴-1H-吲哚-3-甲腈(22mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌24小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和反相HPLC纯化,以得到6-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲哚-3-甲腈。MS:(ES)m/z对于C26H22F3N5O2S[M+H]+,计算值为526.2,实测值为526。1H NMR(300MHz,DMSO-d6)δ12.40(d,J=3.1Hz,1H),8.35(d,J=2.9Hz,1H),8.23(app s,1H),7.99(d,J=8.5Hz,2H),7.91-7.81(m,3H),7.78(d,J=8.3Hz,1H),7.69-7.57(m,2H),7.40(d,J=4.8Hz,1H),6.58(d,J=9.0Hz,1H),3.75-3.58(m,3H,在残余H2O峰下),2.66-2.55(m,2H),2.03-1.91(m,2H),1.60-1.42(m,2H)。
实例99:2-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-6,7-二氢噻唑并-[5,4-c]吡啶-5(4H)-甲酰胺
向在隔膜帽小瓶中的2-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-4,5,6,7-四氢-噻唑并[5,4-c]吡啶-5-鎓氯化物中添加DCM(3mL)和DIPEA(35μL,0.20mmol),随后添加(三甲基甲硅烷基)异氰酸酯(27uL,0.20mmol)。将混合物在室温下搅拌,直到反应进行至完全。将混合物经由SiO2凝胶色谱法纯化,以得到2-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-6,7-二氢噻唑并-[5,4-c]吡啶-5(4H)-甲酰胺。MS:(ES)m/z对于C24H25F3N6O3S2[M+H]+,计算值为567.2,实测值为567。1H NMR(300MHz,DMSO-d6)δ8.22(s,1H),8.13(d,J=8.5Hz,2H),7.85(d,J=8.5Hz,2H),7.59(dd,J=8.9,2.6Hz,1H),7.28(d,J=7.4Hz,1H),6.54(d,J=8.9Hz,1H),6.23(bs,2H),4.67(s,2H),3.84-3.75(m,1H),3.69(t,J=5.7Hz,2H),3.62-3.50(m,2H),2.85(t,J=5.8Hz,2H),2.69-2.58(m,2H),2.01-1.89(m,2H),1.58-1.42(m,2H)。
实例100:2-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-4,5,6,7-四氢噻唑并[5,4-c]吡啶-5-鎓氯化物
向在隔膜帽小瓶中的4-氧代-2-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-6,7-二氢噻唑并[5,4-c]吡啶-5(4H)-甲酸叔丁酯中添加3mL二噁烷和15滴浓HCl。将混合物在室温下搅拌90分钟,并且当反应进行至完全时去除溶剂。将混合物溶解于最少量的MeOH和丙酮中,并且固体沉淀,并且过滤,以得到2-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-4,5,6,7-四氢噻唑并[5,4-c]吡啶-5-鎓氯化物。MS:(ES)m/z对于C23H24F3N5O2S2(游离碱)[M+H]+,计算值为524.1,实测值为524。1H NMR(400MHz,DMSO-d6)1H NMR(400MHz,DMSO-d6)δ9.69-9.60(m,2H),8.22(s,1H),8.17(d,J=8.3Hz,2H),7.88(d,J=8.5Hz,2H),7.67(d,J=8.4Hz,1H),6.64(d,J=9.1Hz,1H),4.53-4.46(m,2H),3.84-3.74(m,1H),3.64-3.55(m,2H),3.56-3.46(m,2H),3.11(t,J=6.2Hz,2H),2.64-2.54(m,2H),2.02-1.91(m,2H),1.57-1.44(m,2H)。
实例101:5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-苯并[d]咪唑-2-胺
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(41mg,0.29mmol)、5-溴-1H-苯并[d]咪唑-2-胺(21mg,0.10mmol)和Pd(dppf)Cl2·DCM(8mg,0.010mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将混合物经由反相HPLC纯化,以得到5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-苯并[d]咪唑-2-胺。MS:(ES)m/z对于C24H23F3N6O2S[M+H]+,计算值为517.2,实测值为517。1H NMR(400MHz,DMSO-d6)δ10.85(bs,1H),8.22(s,1H),7.94-7.85(m,2H),7.76(d,J=8.1Hz,2H),7.62-7.56(m,1H),7.48(s,1H),7.35-7.17(m,3H),6.54(d,J=9.0Hz,1H),6.37-6.24(m,2H),3.83-3.69(m,1H),3.60-3.50(m,2H),2.63-2.53(m,2H),2.01-1.91(m,2H),1.59-1.44(m,2H)。
实例102:5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)二氢吲哚-2-酮
向在隔膜帽小瓶中的N-(1-((4-溴苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺中添加K2CO3(45mg,0.32mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)二氢吲哚-2-酮(28mg,0.11mmol)和Pd(dppf)Cl2·DCM(9.0mg,0.011mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和制备型反相HPLC纯化,以得到5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)二氢吲哚-2-酮。MS:(ES)m/z对于C25H23F3N4O3S[M+H]+,计算值为517.2,实测值为517。1H NMR(400MHz,DMSO-d6)δ10.56(s,1H),8.22(s,1H),7.88(d,J=8.2Hz,2H),7.78(d,J=8.2Hz,2H),7.65-7.56(m,3H),7.31(d,J=7.1Hz,1H),6.95(d,J=8.1Hz,1H),6.54(d,J=8.9Hz,1H),3.82-3.70(m,1H),3.61-3.51(m,2H),2.62-2.52(m,2H),2.01-1.92(m,2H),1.57-1.44(m,2H)。
实例103:N-(1-((4-(1H-苯并[d][1,2,3]三唑-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺
向在隔膜帽小瓶中的N-(1-((4-溴苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺中添加K2CO3(45mg,0.32mmol)、(1H-苯并[d][1,2,3]三唑-5-基)硼酸(18mg,0.11mmol)和Pd(dppf)Cl2·DCM(9.0mg,0.011mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将混合物经反相HPLC纯化,以得到N-(1-((4-(1H-苯并[d][1,2,3]三唑-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺。MS:(ES)m/z对于C23H21F3N6O2S[M+H]+,计算值为503.2,实测值为503。1H NMR(400MHz,DMSO-d6)δ8.30(bs,1H),8.23(s,1H),8.11-8.01(m,3H),7.90-7.81(m,3H),7.61(d,J=8.8Hz,1H),7.37(bs,1H),6.56(d,J=9.2Hz,1H),3.84-3.74(m,1H),3.64-3.55(m,2H),2.64-2.55(m,2H),2.02-1.92(m,2H),1.58-1.46(m,2H)。
实例104:N-(1-((4-(1H-苯并[d]咪唑-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺
向在隔膜盖小瓶中的N-(1-((4-溴苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺中添加K2CO3(45mg,0.32mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-苯并[d]咪唑(26mg,0.11mmol)和Pd(dppf)Cl2·DCM(9.0mg,0.011mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将混合物经由反相HPLC纯化,以得到N-(1-((4-(1H-苯并[d]咪唑-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺。MS:(ES)m/z对于C24H22F3N5O2S[M+H]+,计算值为502.2,实测值为502。1H NMR(400MHz,DMSO-d6)δ12.63(bs,1H),8.31(s,1H),8.22(s,1H),7.99(d,J=7.9Hz,2H),7.82(d,J=8.1Hz,2H),7.64-7.55(m,2H),7.31(d,J=7.1Hz,1H),6.55(d,J=8.9Hz,1H),3.84-3.73(m,1H),3.62-3.52(m,2H),2.65-2.54(m,2H),2.01-1.93(m,2H),1.58-1.44(m,2H)。
实例105:4-氧代-2-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-6,7-二氢噻唑并[5,4-c]吡啶-5(4H)-氨基甲酸叔丁酯
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(82mg,0.59mmol)、7-溴-3,4-二氢异喹啉-2(1H)-甲酸叔丁酯(62mg,0.20mmol)和Pd(dppf)Cl2·DCM(16mg,0.020mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法纯化,以得到4-氧代-2-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-6,7-二氢噻唑并[5,4-c]吡啶-5(4H)-甲酸叔丁酯。MS:(ES)m/z对于C28H32F3N5O4S2[M+H]+,计算值为624.2,实测值为624。1H NMR(400MHz,DMSO-d6)δ8.22(s,1H),8.13(d,J=8.2Hz,2H),7.85(d,J=8.3Hz,2H),7.59(dd,J=8.8,2.1Hz,1H),7.29(d,J=7.2Hz,1H),6.54(d,J=8.9Hz,1H),4.69(s,2H),3.81-3.75(m,1H),3.71(t,J=5.8Hz,2H),3.60-3.52(m,2H),2.91-2.82(m,2H),2.68-2.56(m,2H),2.02-1.88(m,2H),1.56-1.38(m,11H)。
实例106:5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲唑-3-胺
向在隔膜帽小瓶中的N-(1-((4-溴苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺中添加K2CO3(45mg,0.32mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吲唑-3-胺(28mg,0.11mmol)和Pd(dppf)Cl2·DCM(9.0mg,0.011mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将混合物经由反相HPLC纯化,以得到5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲唑-3-胺。MS:(ES)m/z对于C24H23F3N6O2S[M+H]+,计算值为517.2,实测值为518。1H NMR(400MHz,DMSO-d6)δ11.58(bs,1H),8.22(s,1H),8.18(s,1H),7.92(d,J=8.4Hz,2H),7.82(d,J=8.3Hz,2H),7.66(dd,J=8.7,1.8Hz,1H),7.59(dd,J=8.9,2.6Hz,1H),7.36(d,J=8.7Hz,1H),7.31(d,J=7.3Hz,1H),6.54(d,J=8.9Hz,1H),5.64(bs,2H),3.83-3.72(m,1H),3.61-3.51(m,2H),2.64-2.51(m,2H),2.02-1.91(m,2H),1.58-1.44(m,2H)。
实例107:5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲哚-2-甲腈
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(81mg,0.59mmol)、5-溴-1H-吲哚-2-甲腈(43mg,0.20mmol)和Pd(dppf)Cl2·DCM(16mg,0.020mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和制备型反相HPLC纯化,以得到5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲哚-2-甲腈。MS:(ES)m/z对于C26H22F3N5O2S[M+H]+,计算值为526.2,实测值为526。1H NMR(400MHz,DMSO-d6)δ12.58(s,1H),8.23(s,1H),8.10(s,1H),7.98(d,J=8.5Hz,2H),7.82(d,J=8.5Hz,2H),7.76(dd,J=8.7,1.8Hz,1H),7.65-7.59(m,2H),7.50-7.40(m,2H),6.58(d,J=9.1Hz,1H),3.83-3.71(m,1H),3.62-3.53(m,2H),2.63-2.52(m,2H),2.02-1.92(m,2H),1.57-1.44(m,2H)。
实例108:5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲哚-3-甲腈
向在隔膜帽小瓶中的N-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)磺酰基)哌啶-4-基)-5-(三氟-甲基)吡啶-2-胺中添加K2CO3(81mg,0.59mmol)、5-溴-1H-吲哚-3-甲腈(43mg,0.20mmol)和Pd(dppf)Cl2·DCM(16mg,0.020mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和制备型反相HPLC纯化,以得到5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1H-吲哚-3-甲腈。MS:(ES)m/z对于C26H22F3N5O2S[M+H]+,计算值为526.2,实测值为526。1H NMR(400MHz,DMSO-d6)δ12.37(s,1H),8.35(s,1H),8.23(s,1H),8.03(d,J=8.4Hz,2H),7.99(s,1H),7.82(d,J=8.3Hz,2H),7.70(s,2H),7.62(d,J=9.0Hz,1H),7.43(bs,1H),6.58(d,J=9.1Hz,1H),3.83-3.73(m,1H),3.63-3.53(m,2H),2.64-2.53(m,2H),2.02-1.92(m,2H),1.59-1.45(m,2H)。
实例109:5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1,3-二氢-2H-苯并[d]-咪唑-2-酮
向在隔膜帽小瓶中的N-(1-((4-溴苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺中添加K2CO3(45mg,0.32mmol)、(2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-基)硼酸(28mg,0.11mmol)和Pd(dppf)Cl2·DCM(9.0mg,0.011mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和制备型反相HPLC纯化,以得到5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)-1,3-二氢-2H-苯并[d]-咪唑-2-酮。MS:(ES)m/z对于C24H22F3N5O3S[M+H]+,计算值为518.2,实测值为518。1H NMR(400MHz,DMSO-d6)δ10.81(d,J=7.1Hz,2H),8.23(s,1H),7.88(d,J=8.3Hz,2H),7.78(d,J=8.3Hz,2H),7.63-7.59(m,1H),7.40-7.33(m,2H),7.26(s,1H),7.05(d,J=8.1Hz,1H),6.56(d,J=9.1Hz,1H),3.81-3.72(m,1H),3.60-3.52(m,2H),2.62-2.51(m,2H),2.01-1.91(m,2H),1.58-1.43(m,2H)。
实例110:5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)异二氢吲哚-1-酮
向在隔膜帽小瓶中的N-(1-((4-溴苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺中添加K2CO3(45mg,0.32mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)异二氢吲哚-1-酮(28mg,0.11mmol)和Pd(dppf)Cl2·DCM(9.0mg,0.011mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和制备型反相HPLC纯化,以得到5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)异二氢吲哚-1-酮。MS:(ES)m/z对于C25H23F3N4O3S[M+H]+,计算值为517.2,实测值为517。1H NMR(400MHz,DMSO-d6)δ8.67(s,1H),8.24-8.22(m,1H),8.01(d,J=8.4Hz,2H),7.96(s,1H),7.89-7.84(m,3H),7.80(d,J=7.9Hz,1H),7.61(dd,J=9.1,2.5Hz,1H),7.41-7.34(m,1H),6.56(d,J=8.9Hz,1H),4.46(s,2H),3.82-3.73(m,1H),3.63-3.53(m,2H),2.65-2.54(m,2H),2.02-1.92(m,2H),1.57-1.44(m,2H)。
实例111:5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)苯并[d]-噁唑-2-胺
向在隔膜盖小瓶中的N-(1-((4-溴苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺中添加K2CO3(45mg,0.32mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯并[d]噁唑-2-胺(28mg,0.11mmol)和Pd(dppf)Cl2·DCM(9.0mg,0.011mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和制备型反相HPLC纯化,以得到5-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)苯并[d]-噁唑-2-胺。MS:(ES)m/z对于C24H22F3N5O3S[M+H]+,计算值为518.2,实测值为518。1H NMR(400MHz,DMSO-d6)δ8.24(app s,1H),7.94(d,J=8.5Hz,2H),7.89(bs,2H),7.80(d,J=8.4Hz,2H),7.64(dd,J=8.9,2.5Hz,1H),7.59(d,J=1.8Hz,1H),7.52-7.46(m,2H),7.40(dd,J=8.3,1.9Hz,1H),6.59(d,J=8.9Hz,1H),3.83-3.72(m,1H),3.62-3.54(m,2H),2.62-2.51(m,2H),2.01-1.92(m,2H),1.59-1.45(m,2H)。
实例112:N-(1-((4-(1H-吲哚-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺
向在隔膜帽小瓶中的N-(1-((4-溴苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺中添加K2CO3(45mg,0.32mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吲哚(26mg,0.11mmol)和Pd(dppf)Cl2·DCM(9.0mg,0.011mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和制备型反相HPLC纯化,以得到N-(1-((4-(1H-吲哚-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺。MS:(ES)m/z对于C25H23F3N4O2S[M+H]+,计算值为501.2,实测值为501。1H NMR(400MHz,DMSO-d6)δ11.27(s,1H),8.23(app s,1H),7.95(d,J=8.2Hz,2H),7.79(d,J=8.4Hz,2H),7.63(d,J=8.8Hz,1H),7.55-7.40(m,4H),6.58(d,J=9.0Hz,1H),6.53(t,J=2.5Hz,1H),3.82-3.70(m,1H),3.61-3.52(m,2H),2.63-2.52(m,2H),2.03-1.91(m,2H),1.59-1.45(m,2H)。
实例113:N-(1-((4-(2,3-二氢-1H-茚-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺
向在隔膜帽小瓶中的N-(1-((4-溴苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺中添加K2CO3(45mg,0.32mmol)、2-(2,3-二氢-1H-茚-5-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(26mg,0.11mmol)和Pd(dppf)Cl2·DCM(9mg,0.01mmol)。向其中添加1.6mL二噁烷和0.4mL水。将混合物用氮气鼓泡20分钟。密封小瓶,将混合物在100℃下搅拌16小时,并且当反应进行至完全时冷却。将混合物经由SiO2凝胶色谱法和制备型反相HPLC纯化,以得到N-(1-((4-(2,3-二氢-1H-茚-5-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺。MS:(ES)m/z对于C26H26F3N3O2S[M+H]+,计算值为502.2,实测值为502。1H NMR(400MHz,DMSO-d6)δ8.23(app s,1H),7.91(d,J=8.4Hz,2H),7.80(d,J=8.4Hz,2H),7.64-7.59(m,2H),7.53-7.49(m,1H),7.43-7.34(d,J=8.2Hz,2H),6.57(d,J=8.9Hz,1H),3.82-3.72(m,1H),3.61-3.51(m,2H),2.93(dt,J=11.5,7.4Hz,4H),2.62-2.52(m,2H),2.06(p,J=7.4Hz,2H),2.01-1.91(m,2H),1.58-1.44(m,2H)。
实例114:N-(1-((4-(哌啶-1-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺
向隔膜帽小瓶中添加哌啶(13mg,0.15mmol)、N-(1-((4-溴苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺(46mg,0.10mmol)、(+/-)-BINAP(12mg,0.020mmol)、NaOtBu(19mg,0.20mmol)和二噁烷(2mL)。将混合物用N2鼓泡20分钟。添加Pd2(dba)3(9mg,0.010mmol),并且将反应混合物用N2鼓泡5分钟并且在90℃下搅拌3小时。将反应混合物冷却至室温,用乙酸乙酯(10mL)稀释,通过Celite过滤,并浓缩。通过SiO2凝胶色谱法(己烷/乙酸乙酯)、随后制备型反相HPLC纯化,得到N-(1-((4-(哌啶-1-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺。MS:(ES)m/z对于C22H28F3N4O2S[M+H]+,计算值为469.2,实测值为469.2。1H NMR(400MHz,DMSO-d6)δ8.22(d,J=2.5Hz,1H),7.60(dd,J=9.0,2.6Hz,1H),7.49(d,J=9.0Hz,2H),7.29(d,J=7.3Hz,1H),7.05(d,J=9.1Hz,2H),6.55(d,J=8.9Hz,1H),3.71(s,1H),3.52-3.41(m,2H),3.38-3.30(m,4H),2.42(dd,J=12.0,9.4Hz,2H),1.98-1.87(m,2H),1.59(d,J=3.9Hz,6H),1.53-1.41(m,2H)。
实例115:N-(1-((4-(4-(苯基氨基)哌啶-1-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺
将N-(1-((4-氟苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺(48mg,0.12mmol)、N-苯基哌啶-4-胺(42mg,0.24mmol)和碳酸钾(66mg,0.48mmol)在NMP(1mL)中的混合物在120℃下搅拌12小时。将反应混合物冷却至室温,并且用水(10mL)稀释。将所得固体过滤,用水洗涤,并且通过SiO2凝胶色谱法(己烷/乙酸乙酯)、随后制备型反相HPLC纯化,以得到N-(1-((4-(4-(苯基氨基)哌啶-1-基)苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺。MS:(ES)m/z对于C28H33F3N5O2S[M+H]+,计算值为560.2,实测值为560.4。1H NMR(400MHz,DMSO-d6)δ8.23(d,J=1.7Hz,1H),7.60(dd,J=9.0,2.6Hz,1H),7.51(d,J=8.9Hz,2H),7.30(d,J=7.3Hz,1H),7.12-7.02(m,4H),6.61(d,J=8.0Hz,2H),6.55(d,J=8.9Hz,1H),6.51(t,J=7.3Hz,1H),5.50(d,J=8.2Hz,1H),3.94-3.84(m,2H),3.71(s,1H),3.48(d,J=12.0Hz,3H),3.12-3.00(m,2H),2.43(t,J=11.1Hz,2H),1.97(t,J=15.3Hz,4H),1.56-1.34(m,4H)。
实例116:4-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)哌嗪-2-酮
向隔膜帽小瓶中添加2-氧代哌嗪(15mg,0.15mmol)、N-(1-((4-溴苯基)磺酰基)哌啶-4-基)-5-(三氟甲基)吡啶-2-胺(46mg,0.10mmol)、RuPhos(19mg,0.040mmol)、NaOtBu(19mg,0.20mmol)和二噁烷(2mL)。将混合物用N2鼓泡20分钟。添加Pd2(dba)3(9mg,0.010mmol),并且将反应混合物用N2鼓泡5分钟,并且在90℃下搅拌16小时。将反应混合物冷却至室温,用乙酸乙酯(10mL)稀释,通过Celite过滤,并浓缩。通过SiO2凝胶色谱法(己烷/乙酸乙酯,然后乙酸乙酯/甲醇)纯化,得到4-(4-((4-((5-(三氟甲基)吡啶-2-基)氨基)哌啶-1-基)磺酰基)苯基)哌嗪-2-酮。MS:(ES)m/z对于C21H25F3N5O3S[M+H]+,计算值为484.2,实测值为484.2。1H NMR(300MHz,DMSO-d6)δ8.24-8.17(m,2H),7.62-7.56(m,1H),7.55(d,J=9.0Hz,2H),7.30-7.25(m,1H),7.04(d,J=9.0Hz,2H),6.55(d,J=9.0Hz,1H),3.88(s,2H),3.71(s,1H),3.78-3.62(m,1H),3.59-3.53(m,2H),3.51-3.42(m,3H),2.45-2.38(m,2H),2.00-1.89(m,2H),1.56-1.40(m,2H)。
生物学实例1:迁移测定
趋化测定可以用来确定潜在的受体拮抗剂在阻断通过趋化因子受体如CCR6介导的迁移时的功效。这种测定使用具有5-μm孔径的聚碳酸酯膜的微室系统常规地进行。这种测定需要表达趋化因子受体的细胞。在这种情况下,使用转染了处于CMV启动子控制下的人CCR6基因的Ba/F3细胞(Palacios等,Nature[自然],309:126,1984)。为了开始这种测定,首先使hCCR6转染的Ba/F3细胞在补充有丁酸钠的培养基中生长24小时,丁酸钠经由CMV启动子增加CCR6转录。通过在室温下以400x g离心收集制备的Ba/F3细胞,然后将其以400万/毫升悬浮于人血清中。将正在测试的化合物从10μM的最大最终浓度(或其溶剂(DMSO)的当量体积)连续地稀释,并且然后添加到细胞/血清混合物中。单独地,将处于其EC50浓度(10nM)的重组人CCL20(MIP-3α/LARC)置于板的下孔中。将5-μm(孔径)聚碳酸酯膜放置在该板上,并且将20μL的细胞/化合物混合物转移到膜的每个孔上。将这些板在37℃下温育45分钟,然后去除聚碳酸酯膜并且将5μl的嵌入DNA的染料CyQUANT(英杰公司(Invitrogen),卡尔斯巴德市,加利福尼亚州)添加到这些下孔中。荧光的量,对应于迁移细胞的数目,使用Spectrafluor Plus板式读取器(帝肯公司(TECAN),圣何塞市,加利福尼亚州)来测量。
在表1中,迁移测定中IC50值小于5nM的化合物被标记为(+++);IC50值从5-100nM的化合物被标记为(++);并且IC50值小于或等于10μM但大于100nM的化合物被标记为(+)。
表1
应理解,本文描述的实例和实施例仅用于说明性目的,并且根据它们进行的各种修改或改变将被本领域技术人员知晓,并且将包括在本申请的构思和范围内以及所附权利要求的范围内。
本文引用的所有出版物、专利和专利申请均特此通过引用以其全文并入用于所有目的。
Claims (23)
1.一种具有式(I)的化合物:
或其药学上可接受的盐、水合物、溶剂化物、N-氧化物、光学富集形式、或旋转异构体,
其中
X是N或CH;
Z是O或-N(Rf)-,其中Rf选自由氢、C1-4烷基、C1-4卤代烷基、C1-4羟基烷基、和C3-6环烷基组成的组;
环A是苯环或吡啶环;
Ar1是具有0至3个选自N、O和S的杂原子作为环顶点的单环5元或6元芳香族或杂芳香族环,其被从0至5个R1取代基取代,这些取代基独立地选自由卤素、CN、C1-8烷基、C3-8环烷基、C2-8烯基、C2-8炔基、C1-8卤代烷基、C1-8羟基烷基、-ORa、和-NRaRb组成的组;
Ra和Rb各自独立地选自由氢、羟基、C1-4烷基、C1-4卤代烷基、C1-4羟基烷基、和C3-6环烷基组成的组;
Y选自由以下项组成的组:
i)具有0至4个选自N、O、S和S(O)2的杂原子作为环顶点的双环9元或10元稠合芳香族或杂芳香族环,并且其被0至5个R2取代;
ii)具有1或2个选自N、O、S和S(O)2的杂原子作为环顶点的4元至7元单环杂环,并且其被0至5个R2取代;
iii)具有1至4个选自N、O、S和S(O)2的杂原子作为环顶点的6元至12元稠合或桥接杂环,并且其被0至6个R2取代;和
iv)具有0至4个选自N、O和S的杂原子作为环顶点的7元至12元螺杂环,并且其被0至6个R2取代;
每个R2独立地选自由以下项组成的组:卤素、CN、C1-8烷基、C3-8环烷基、C2-8烯基、C2-8炔基、C1-8卤代烷基、C1-8羟基烷基、-ORc、-SRc、-OSi(Rc)3、-CORc、-CO2Rc、-NRcRd、-NRcRe、-CONRcRd、-(CO)2NRcRd、-NRcCO2Rd、-NRcCORd、-NRcCONRcRd、-NRcSO2Rd、-SO2Rd、-CO-C1-4羟基烷基、-SO2NRcRd、-X2-NRcRd、-X2-CONRcRd、-X2-NRcCONRcRd、-X2-NRcCO2Rd、-X2-NRcCORd、-X2-NRcSO2Rd、-CO-X2-NRcCORd、氧代基、具有1或2个选自N、O、S和S(O)2的杂原子作为环顶点的4元至7元杂环、5元或6元杂芳基、和-X2-5元或6元杂芳基;并且其中R2的5元或6元杂芳基环和4元至7元杂环具有从1至3个选自N、O和S的杂原子,并且各自未被取代或被一个或两个独立地选自由卤素、羟基、氨基、C1-4烷基、C1-4烷氧基、C1-4卤代烷基、-CORc、-CO2Rc、和-CONRcRd组成的组中的成员取代;并且其中附接至同一碳原子上的两个R2基团可选地组合以形成3元至6元螺环或具有1至3个选自N、O和S的杂原子作为环顶点的3元至6元螺杂环,并且其未被取代或被1或2个独立地选自C1-4烷基、-CORc、-CO2Rc、和-CONRcRd的成员取代;
Rc和Rd各自独立地选自由氢、羟基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、和C3-6环烷基组成的组;或者Rc和Rd当附接至同一氮原子时连接以形成具有从0至2个选自O、S、S(O)、S(O)2、NH和N(C1-4烷基)的额外杂原子作为环顶点的4元至7元杂环;
每个Re选自由苯基组成的组;
X2是C1-4亚烷基或环丙基;
下标m是0、1或2;
每个R3是独立地选自由卤素、CN、C1-4烷基、C1-4烷氧基、C3-8环烷基、C1-4卤代烷基、C1-4卤代烷氧基、和C2-4羟基烷基组成的组的成员;并且
R4是选自由H、C1-4烷基、C3-8环烷基、和C1-4卤代烷基组成的组的成员。
2.一种具有式(I)的化合物:
或其药学上可接受的盐、水合物、溶剂化物、N-氧化物、光学富集形式、或旋转异构体,
其中
X是N或CH;
Z是O或-NH;
环A是苯环或吡啶环;
Ar1是具有5元或6元芳香族或杂芳香族环,其被从0至5个R1取代基取代,这些取代基独立地选自由卤素、CN、C1-8烷基、C3-8环烷基、C2-8烯基、C2-8炔基、C1-8卤代烷基、C1-8羟基烷基、-ORa、和-NRaRb组成的组;
Ra和Rb各自独立地选自由氢、羟基、卤素、氰基、C1-4烷基、C1-4卤代烷基、C1-4羟基烷基、和C3-6环烷基组成的组;
Y选自由以下项组成的组:
i)具有0至4个选自N、O、S和S(O)2的杂原子作为环顶点的双环9元或10元稠合芳香族或杂芳香族环,并且其被0至5个R2取代;
ii)具有1或2个选自N、O、S和S(O)2的杂原子作为环顶点的4元至7元单环杂环,并且其被0至5个R2取代;
iii)具有1至4个选自N、O、S和S(O)2的杂原子作为环顶点的6元至12元稠合或桥接杂环,并且其被0至6个R2取代;和
iv)具有0至4个选自N、O和S的杂原子作为环顶点的7元至12元螺杂环,并且其被0至6个R2取代;
每个R2独立地选自由以下项组成的组:卤素、CN、C1-8烷基、C3-8环烷基、C2-8烯基、C2-8炔基、C1-8卤代烷基、C1-8羟基烷基、-ORc、-SRc、-OSi(Rc)3、-CORc、-CO2Rc、-NRcRd、-NRcRe、-CONRcRd、-(CO)2NRcRd、-NRcCO2Rd、-NRcCORd、-NRcCONRcRd、-NRcSO2Rd、-SO2Rd、-CO-C1-4羟基烷基、-SO2NRcRd、-X2-NRcRd、-X2-CONRcRd、-X2-NRcCONRcRd、-X2-NRcCO2Rd、-X2-NRcCORd、-X2-NRcSO2Rd、-CO-X2-NRcCORd、氧代基、具有1或2个选自N、O、S和S(O)2的杂原子作为环顶点的4元至7元杂环、5元或6元杂芳基、和-X2-5元或6元杂芳基;并且其中R2的5元或6元杂芳基环和4元至7元杂环各自未被取代或被一个或两个独立地选自由卤素、羟基、氨基、C1-4烷基、C1-4烷氧基、C1-4卤代烷基、-CORc、-CO2Rc、和-CONRcRd组成的组中的成员取代;并且其中附接至同一碳原子上的两个R2基团可选地组合以形成3元至6元螺环或具有0至3个选自N、O和S的杂原子作为环顶点的3元至6元螺杂环,并且其未被取代或被1或2个独立地选自C1-4烷基、-CORc、-CO2Rc、和-CONRcRd的成员取代;
Rc和Rd各自独立地选自由氢、羟基、卤素、氰基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、和C3-6环烷基组成的组;或者Rc和Rd当附接至同一氮原子时连接以形成具有从0至2个选自O、S、S(O)、S(O)2、NH和N(C1-4烷基)的额外杂原子作为环顶点的4元至7元杂环;
每个Re选自由苯基组成的组;
X2是C1-4亚烷基或环丙基;
下标m是0、1或2;
每个R3是独立地选自由卤素、CN、C1-4烷基、C1-4烷氧基、C3-8环烷基、C1-4卤代烷基、C1-4卤代烷氧基、和C2-4羟基烷基组成的组的成员;并且
R4是选自由H、C1-4烷基、C3-8环烷基、和C1-4卤代烷基组成的组的成员。
3.如权利要求1或2所述的化合物,或其药学上可接受的盐、水合物、溶剂化物、N-氧化物或旋转异构体,其中,Y是具有0至4个选自N、O和S的杂原子作为环顶点的双环9元或10元稠合芳香族或杂芳香族环,并且其被0至5个R2取代。
4.如权利要求3所述的化合物,或其药学上可接受的盐、水合物、溶剂化物、N-氧化物或旋转异构体,其中Y是选自由以下项组成的组的双环9元或10元稠合芳香族或杂芳香族环:
其各自被0至5个R2取代。
5.如权利要求3所述的化合物,或其药学上可接受的盐、水合物、溶剂化物、N-氧化物或旋转异构体,其中Y是选自由以下项组成的组的双环9元或10元稠合芳香族或杂芳香族环:
,
其各自被0至3个R2取代。
6.如权利要求1或2所述的化合物,或其药学上可接受的盐、水合物、溶剂化物、N-氧化物或旋转异构体,其中,Y是具有1或2个选自N、O和S的杂原子作为环顶点的4元至7元单环杂环,并且其被0至5个R2取代。
7.如权利要求6所述的化合物,或其药学上可接受的盐、水合物、溶剂化物、N-氧化物或旋转异构体,其中Y是选自由以下项组成的组的4元至7元单环杂环:
其各自被0至5个R2取代。
8.如权利要求1或2所述的化合物,或其药学上可接受的盐、水合物、溶剂化物、N-氧化物或旋转异构体,其中,Y是具有1至4个选自N、O和S的杂原子作为环顶点的6元至12元稠合或桥接杂环,并且其被0至6个R2取代。
9.如权利要求8所述的化合物,或其药学上可接受的盐、水合物、溶剂化物、N-氧化物或旋转异构体,其中Y是选自由以下项组成的组的6元至12元稠合或桥接杂环:
其各自被0至4个R2取代。
10.如权利要求1或2所述的化合物,或其药学上可接受的盐、水合物、溶剂化物、N-氧化物或旋转异构体,其中,Y是具有0至4个选自N、O和S的杂原子作为环顶点的7元至12元螺杂环,并且其被0至6个R2取代。
11.如权利要求10所述的化合物,或其药学上可接受的盐、水合物、溶剂化物、N-氧化物或旋转异构体,其中Y是选自由以下项组成的组的7元至12元螺杂环:
其各自被0至4个R2取代。
12.如权利要求1至11中任一项所述的化合物,其中Ar1是吡啶基,其被从1至3个R1取代基取代。
13.如权利要求1至11中任一项所述的化合物,或其药学上可接受的盐、水合物、溶剂化物、N-氧化物或旋转异构体,其中R3是H,Z是O,并且X是N。
14.如权利要求1至13中任一项所述的化合物,其具有式(Ia1):
其中R1是-CN或-CF3。
15.如权利要求14所述的化合物,其中Y选自由以下项组成的组:
其各自被0至5个R2取代。
16.如权利要求14所述的化合物,其中Y选自由以下项组成的组:
其各自被从0至3个R2取代。
17.如权利要求14所述的化合物,其中Y选自由以下项组成的组:
其各自被0至5个R2取代。
18.如权利要求14所述的化合物,其中Y选自由以下项组成的组:
其各自被0至4个R2取代。
19.如权利要求1或2所述的化合物,其选自由表1、2或3的化合物组成的组。
20.一种药物组合物,该药物组合物包含如权利要求1至19中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、N-氧化物或旋转异构体以及药学上可接受的赋形剂。
21.一种治疗至少部分地由CCR6调节的疾病或病症的方法,该方法包括向有需要的受试者施用如权利要求1至19中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、N-氧化物或旋转异构体;或如权利要求20所述的药物组合物。
22.如权利要求21所述的方法,其中所述疾病或病症是炎症疾病或病症。
23.如权利要求21所述的方法,其中所述疾病或病症是特应性皮炎或银屑病。
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