CN102459267A - 用作jak抑制剂的二氢吡咯并萘啶酮化合物 - Google Patents
用作jak抑制剂的二氢吡咯并萘啶酮化合物 Download PDFInfo
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- CN102459267A CN102459267A CN2010800328533A CN201080032853A CN102459267A CN 102459267 A CN102459267 A CN 102459267A CN 2010800328533 A CN2010800328533 A CN 2010800328533A CN 201080032853 A CN201080032853 A CN 201080032853A CN 102459267 A CN102459267 A CN 102459267A
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- Prior art keywords
- naphthyridines
- oxo
- pyrrolo
- methyl
- ketone
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- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 229950005839 vinzolidine Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 210000000707 wrist Anatomy 0.000 description 1
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Abstract
本发明公开式(I)的JAK抑制剂,其中G1、R1、R2、R3、R4、R5、R6和R7如说明书中定义。本发明还公开了含有所述化合物的药物组合物、试剂盒和制品、制备所述化合物的方法和材料,以及使用所述化合物治疗涉及免疫系统和炎症(包括类风湿性关节炎、血液恶性肿瘤、上皮癌(即恶性上皮肿瘤))的疾病、病症或症状以及其它与JAK相关的疾病、病症或症状的方法。
Description
发明领域
本发明涉及药物化学以及制药科学。本文提供可抑制詹纳斯氏激酶(Janus kinase,JAK)的化合物。
发明背景
纳斯氏激酶(JAK)为细胞质蛋白酪氨酸激酶的一族,包括JAK1、JAK2、JAK3和TYK2。每一种JAK激酶对于某些细胞因子受体是具有选择性的,尽管多种JAK激酶可能受特定细胞因子或信号途径的影响,包括对于IL-2、IL-4、IL-7、IL-9、IL-15以及IL-21的途径。
磷酸化的JAK激酶和许多信号传导子和转录激活子(SignalTransducer and Activator of Transcription,STAT)蛋白质结合。STAT蛋白质为受酪氨酸残基磷酸化作用而活化的DNA结合蛋白,并且起着信号分子和转录因子两者的功能,以及和细胞因子反应基因启动子的特定DNA序列结合。
细胞因子影响细胞分化、增殖以及活化。细胞因子调节炎症反应和免疫反应两者。
在如过敏症、哮喘、自身免疫疾病(如移植排斥、类风湿性关节炎、肌萎缩性侧索硬化症和多发性硬化)以及在实体和血液恶性肿瘤(如白血病和淋巴瘤)的症状中可观察到异常的JAK/STAT信号传送。JAK途径的抑制剂(特别是JAK3)被认为对于治疗此类症状是有治疗作用的。
在WO 2007/077949以及WO 2008/084861中公开了某些JAK抑制剂。
发明概述
本发明提供式I化合物,
或其药学上可接受的盐类,其中:
G1选自由N和CR8所组成的组;
R1选自由任选取代的C3-8环烷基、任选取代的C3-6杂环烷基、任选取代的C4-14芳基、任选取代的C1-10杂芳基以及任选取代的C1-6烷基组成的组;
R2和R3各自独立地选自由氢和任选取代的C1-4烷基组成的组,或者R2、R3和它们所连接的碳原子形成羰基;
R4选自由氢、任选取代的C1-4烷基、任选取代的C1-4烷氧基、卤基、羟基和氨基所组成的组;
R5选自由氢、任选取代的C1-4烷基、C3-8环烷基和卤基组成的组;
R6和R7各自独立地选自由氢和任选取代的C1-4烷基组成的组,或者R6、R7以及它们所连接的碳原子形成羰基;
R8选自由氢、任选取代的C1-6烷基、任选取代的C1-4烷氧基、C1-9酰胺、C1-5氧代羰基、氰基、任选取代的C3-8环烷基、任选取代的C4-14芳基、任选取代的C1-10杂芳基以及卤基所组成的组;以及
附带条件为不多于一个羰基是由R2、R3、R6和R7形成。
本发明的一方面提供药物组合物,其包括如上定义的式I化合物或药学上可接受的盐,以及药学上可接受的赋形剂。
本发明的另一个方面提供如上定义的式I化合物或药学上可接受的盐类作为药剂的用途。
本发明的另一个方面提供如上定义的式I化合物或药学上可接受的盐用于制备用于治疗与JAK相关的疾病、病症或症状的药剂的用途。
本发明另一个方面提供治疗受试者中与JAK相关的疾病、病症或症状的方法,该方法包括对受试者施用有效量的如上定义的式I化合物或药学上可接受的盐。
本发明的另一个方面提供治疗受试者中的疾病或症状的方法,该方法包括对受试者施用有效量的如上定义的式I化合物或药学上可接受的盐,其中所述疾病或症状选自过敏性鼻炎、过敏性哮喘、特应性皮炎、类风湿性关节炎、多发性硬化、系统性红斑性狼疮、牛皮癣、免疫性血小板减少性紫癜、慢性阻塞性肺疾病以及血栓形成。
本发明的另一个方面提供治疗受试者中的疾病或症状的方法,该方法包含对受试者施用有效量的如上定义的式I化合物或药学上可接受的盐,其中所述疾病或症状选自血液恶性肿瘤以及上皮癌。
本发明的另一个方面提供有效量的如上定义的式I化合物或药学上可接受的盐以及至少一种另外的药理学活性剂的结合物。
本发明还提供制品,其包括至少一种式I化合物和标签。本发明还提供试剂盒,其包括至少一种式I化合物、标签以及用于施用抑制剂的装置。
本发明还提供制备JAK抑制剂及其中间体的方法。
本发明的化合物包括该化合物的所有药学上可接受的复合物、盐类、溶剂化物以及水合物。本发明的化合物还包括该化合物的所有立体异构体、互变异构体以及多晶型物,包括所有晶形和非晶形,无论它们是否为纯的、大体上纯的或混合物。
发明详述
除非另有说明,本公开内容使用如下文提供的定义。
当用在与化学取代基或基元(例如烷基)有关时,术语“取代的(substituted)”是指取代基或基元上的一个或多个氢原子被一个或多个非氢原子或基团所取代,条件是要符合配价要求并且取代成化学上稳定的化合物。
当用在与可测量的数值变量有关时,术语“大约(about)”或“大约(approximately)”是指变量所指的数值以及落于所指数值的实验性误差内(例如在平均值的95%置信区间)或在所指数值的±百分之10之内的变量的所有数值,无论何者较高。
术语“C2-4烯基”是指具有自二至四个碳原子以及一个或多个碳-碳双键的直链或分枝的烯基链,且包括乙烯、丙烯、异丙烯、丁烯、异丁烯、仲丁烯等。
术语“C1-4烷基”是指具有自一至四个碳原子的直链或分枝的烷基链。
术语“任选取代的C1-4烷基”是指任选具有自1至5个取代基的C1-4烷基,该取代基独立地选自由氨基、C1-7酰氨基、C1-8烷基氨基、C2-4烯基、C1-4烷氧基、C1-4硫代烷氧基、C1-9酰胺、C1-5氧代羰基、氰基、C3-8环烷基、C3-8环烷氧基、卤基、羟基、氧代、C1-8磺酰基、任选取代的C1-10杂芳基、任选取代的C3-6杂环烷基、任选取代的C1-10杂芳基以及任选取代的苯基组成的组。
术语“C1-6烷基”是指具有自一至六个碳原子的直链或分枝的烷基链。
术语“任选取代的C1-6烷基”是指任选具有自1至7个取代基的C1-6烷基,该取代基独立地选自由氨基、C1-7酰氨基、C1-8烷基氨基、C2-4烯基、C1-4烷氧基、C1-4硫代烷氧基、C1-14酰胺、C1-5氧代羰基、氰基、C3-8环烷基、C3-8环烷氧基、卤基、羟基、氧代、C1-8磺酰基、任选取代的C1-10杂芳基、任选取代的C3-6杂环烷基、任选取代的C1-10杂芳基以及任选取代的苯基组成的组。
术语“C1-8磺酰基”是指连接至C1-6烷基、C3-8环烷基或任选取代的苯基的磺酰基。
术语“C1-4烷氧基”是指通过氧原子连接的C1-4烷基。
术语“任选取代的C1-4烷氧基”是指任选具有自1至6个取代基的C1-4烷氧基,该取代基独立地选自由C2-4烯基、C1-4烷氧基、C1-9酰胺、C1-5氧代羰基、氰基、C3-8环烷基、卤基、羟基、任选取代的C1-10杂芳基以及任选取代的苯基组成的组。
术语“C1-9酰胺”是指具有两个基团的酰胺,该基团独立地选自由氢和C1-4烷基组成的组,例如,-CONH2、-CONHCH3和-CON(CH3)2。
术语“C1-14酰胺”是指(a)具有两个连接至氮原子的基团的酰胺,该基团独立地选自氢和任选取代的C1-4烷基,例如-CONH2、-CONHCH3和-CON(CH3)2;或(b)在氮原子上具有一个氢和一个非氢取代基的酰胺,其中非氢取代基选自任选取代的C1-4烷基、任选取代的C1-4烷氧基、任选取代的C3-8环烷基、任选取代的C3-6杂环烷基、任选取代的C4-14芳基以及任选取代的C1-10杂芳基,例如,-CONH-(环戊基)、-CONH-(芳基)、-CONH-CH2-(苯基)等。
术语“C1-7酰氨基”是指-NHC(O)R基团,其中R为C1-6烷基。
术语“C1-5氨甲酰基”是指具有末端C1-4烷基的O-或N-连接的氨基甲酸酯。
术语“C1-5脲基”是指具有C1-4烷基的尿素。
术语“C1-8烷基氨基”是指具有一或二个C1-4烷基的氨基。
术语“C4-14芳基”是指具有芳族性以及具有四至十四个碳原子的单环或多环的未饱和、共轭烃,并且包括苯基、联苯、茚基、环戊二烯基、芴基以及萘基。
术语“任选取代的C4-14芳基”是指任选具有1至5个取代基的C4-14芳基,该取代基独立地选自由氨基、C1-8烷基氨基、C1-7酰氨基、C1-5氨甲酰基、C1-6磺酰胺基、C0-6磺酰氨基、C1-5脲基、任选取代的C1-4烷基、任选取代的C1-4烷氧基、氰基、卤素、羟基、硝基、C1-5氧代羰基以及C1-8磺酰基组成的组。
术语“C1-5氧代羰基”是指氧代羰基(-CO2H)以及其C1-4烷基酯。
术语“C3-8环烷基”是指具有自3至8个碳原子的烷基环,且包括环丙基、2-甲基环丙基、环丁基、环戊基、环己基等。
术语“任选取代的C3-8环烷基”是指任选具有1至6个取代基的C3-8环烷基,该取代基独立地选自由任选取代的C1-4烷基、C2-4烯基、C1-4烷氧基、C1-9酰胺、C1-7酰氨基、C1-8烷基氨基、C1-5氧代羰基、氰基、C3-8环烷基、C3-8环烷氧基、卤代、羟基、硝基、氧代、任选取代的C1-10杂芳基以及任选取代的苯基组成的组。
术语“C3-8环烷氧基”是指通过氧原子连接的C3-8环烷基。
术语“卤素(halogen)”和“卤代(halo)”是指氯代、氟代、溴代或碘代。
术语“C3-6杂环烷基”是指具有一至四个杂原子的4至10元饱和的单环或部分(但非完全)未饱和的环,该杂原子选自由氮、氧和硫组成的组。该氮和硫杂原子可任选被氧化。举例来说,该术语包括氮杂环丁烷、吡咯烷、哌啶、哌嗪、吗啉、四氢吡喃、四氢呋喃、六氢嘧啶、四氢嘧啶、二氢咪唑等。
术语“任选取代的C3-6杂环烷基”是指在环碳原子上任选被1至4个取代基取代的C3-6杂环烷基,该取代基独立地选自由任选取代的C1-4烷基、C2-4烯基、C1-4烷氧基、C1-9酰胺、C1-7酰氨基、C1-8烷基氨基、C1-5氧代羰基、氰基、C3-8环烷基、C3-8环烷氧基、卤代、羟基、硝基、氧代和任选取代的苯基组成的组;以及在任一环上的氮原子任选被取代基取代,该取代基独立地选自由任选取代的C1-4烷基、C2-4烯基、C3-8环烷基、任选取代的C3-6杂环烷基、任选取代的C1-10杂芳基、任选取代的苯基以及C1-8磺酰基组成的组。
术语“C1-10杂芳基”是指五至十二元单环或多环,其具有未饱和的、共轭的环,该环具有芳族性以及具有一至十个碳原子和一个或多个(典型地为1至4个)杂原子,该杂原子选自由氮、氧和硫组成的组。该氮以及硫杂原子可任选被氧化。举例来说,该术语包括氮杂、二氮杂、呋喃、噻吩、咪唑、异噻唑、异噁唑、噁二唑、噁唑、吡嗪、吡唑、哒嗪、吡啶、嘧啶、噻唑、噻二唑、三唑、四唑、苯并氮杂、苯并二氮杂、苯并呋喃、苯并噻吩、苯并咪唑、咪唑并吡啶、吡唑并吡啶、吡咯并吡啶、喹唑啉、噻吩并吡啶、吲哚嗪、咪唑并吡啶、喹啉、异喹啉、吲哚、异吲哚、苯并噁唑、苯并噁二唑、苯并吡唑、苯并噻唑等。
术语“任选取代的C1-10杂芳基”是指在碳上任选具有1至5个取代基的C1-10杂芳基,该取代基独立地选自由氨基、C1-7酰氨基、C1-8烷基氨基、C1-5氨甲酰基、C1-6磺酰胺基、C0-6磺酰氨基、C1-5脲基、任选取代的C1-4烷基、任选取代的C1-4烷氧基、氰基、卤素、羟基、氧代、硝基、C1-5氧代羰基和C1-8磺酰基组成的组,并且在每一氮上任选具有取代基,该取代基独立地选自由任选取代的C1-4烷基、C1-8磺酰基、任选取代的C3-6杂环烷基和任选取代的苯基组成的组。
术语“氧代”是指对所连接的碳具有双键以生成酮、醛或酰胺的羰基的氧原子。已了解氧代可连接至具有氧代取代基的基团上任何可行的位置。举例来说,乙酰基自由基(-C(O)CH3)被设想为被氧代取代的烷基,且吡啶酮自由基设想为被氧代取代的C1-10杂芳基。
术语“任选取代的苯基”是指任选具有1至5个取代基的苯基,该取代基独立地选自由氨基、C2-4烯基、C1-4烷基、C1-4烷氧基、C1-9酰胺、C1-8烷基氨基、C1-5氧代羰基、氰基、卤素、氢、羟基、硝基、C1-8磺酰基和三氟甲基组成的组。
术语“C1-6磺酰胺基”是指-NHS(O)2-R基团,其中R为C1-6烷基。
术语“C0-6磺酰氨基”是指-S(O)2NH-R基团,其中R为选自由氢和C1-6烷基组成的组。
术语“C1-4硫代烷氧基”是指通过硫原子连接的C1-4烷基。
术语“反向对映体(opposite enantiomer)”是指为参考分子的不重叠镜像的分子,其可通过反转参考分子的所有手性中心而获得。举例来说,如果参考分子具有S绝对立体化学构型,那么其反向对映体具有R绝对立体化学构型。同样地,如果参考分子具有S,S绝对立体化学构型,那么其反向对映体具有R,R绝对立体化学构型等。
术语“立体异构体(stereoisomers)”当用在与具有所给的立体化学构型的化合物相关时,是指该化合物的反向对映体,以及是指任何非对映异构体,包括该化合物的几何异构体(Z/E)。举例来说,若化合物具有S,R,Z立体化学构型,其立体异构体将包括其具有R,S,Z构型的反向对映体,以及其具有S,S,Z构型、R,R,Z构型、S,R,E构型、R,S,E构型、S,S,E构型以及R,R,E构型的非对映异构体。若化合物的立体化学构型为未确定的,那么“立体异构体”是指化合物的可能的立体化学构型。
短语“大体上纯的立体异构体”及其变体是指包含至少约95%立体异构体的样本。
短语“纯的立体异构体”及其变体是指包含至少约99.5%立体异构体的样本。
短语“药学上可接受的”是指那些在合理的医学的判断范围内适于用在与患者的组织接触而没有过度的毒性、辐射和过敏反应等,具有合理的效益/风险比率,且可有效地用于预期的目的物质。
术语“赋形剂”是指可能影响药物的生物药效率、但在其他方面不具有药理学活性的任何物质。
术语“药学上可接受的盐类”是指药学上可接受的有机酸和有机碱或无机酸和无机碱的盐类。具使用潜力的酸加成和碱盐描述于S.M.Berge等人,J.Pharm.Sci.(1977)66:1-19以及于Stahl和Wermuth,Handbook of Pharmaceutical Salts:Properties,Selection,and Use(2002)。药学上可接受的盐类的例子包括盐酸盐以及甲磺酸盐。
已了解的是,当本文中所定义的术语提及碳原子的数目时,其所提及的数目是指提及的基团,且不包括可能存在于任何任选的取代基的任何碳。
本领域技术人员将了解本发明的某些化合物以异构体的形式存在。本发明的化合物的立体异构体(以任何比率)和特定的几何异构体、对映体以及非对映体的所有混合物皆在本发明的范围中。
本领域技术人员将了解本发明的某些化合物以互变异构体形式存在。本发明的化合物的所有互变异构体形式皆在本发明的范围中。
短语“本发明的化合物”是指以式I定义的化合物以及在式I范围内的特定化合物,包括在本说明书、实施例和权利要求书中特别指明的化合物。
表1列出本说明书全文使用的缩写。
表1.缩写表
此公开内容和式I化合物有关,包括在说明书和权利要求书中特别指明的化合物,以及其药学可接受的复合物、盐类、溶剂化物和水合物。此公开内容还涉及用于制备式I化合物、包含它们的药物组合物的材料和方法,以及它们用于治疗包括免疫系统和炎症(包括类风湿性关节炎和血液恶性肿瘤、上皮癌(例如恶性上皮肿瘤))的病症、疾病和症状以及其它与JAK相关的疾病、病症或症状的用途。式I化合物包括下列实施方案。
a.一个实施方案与式I化合物有关,其中R4选自由氢、C1-4烷基以及卤代组成的组。
b.另一个实施方案与式I化合物有关,其中R5选自由氢和C1-4烷基组成的组。
c.另一个实施方案与式I化合物有关,其中R4为氢。
d.另一个实施方案与式I化合物有关,其中R5为氢。
e.另一个实施方案与式I化合物有关,其中R4和R5每一个为氢。
f.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d和e的任选地任何一个中,式I中的G为CR8。
g.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d和e的任选地任何一个中,式I中的G为CR8,且R8选自由氢、卤代以及任选取代的C1-6烷基组成的组。
h.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d和e的任选地任何一个中,式I中的G为CR8,且R8选自由氢、卤代以及C1-4烷基组成的组。
i.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d和e的任选地任何一个中,式I中的G为CR8,且R8为卤代。
j.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d和e的任选地任何一个中,式I中的G为CR8,且R8为C1-4烷基。
k.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d和e的任选地任何一个中,式I中的G为CR8,并且R8为甲基。
l.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d和e的任选地任何一个中,式I中的G为N。
m.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k和l的任选地任何一个中,式I中的R1为任选取代的C3-8环烷基。
n.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k和l的任选地任何一个中,式I中的R1为任选取代的C3-6杂环烷基。
o.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k和l的任选地任何一个中,式I中的R1为含氮的C3-6杂环烷基,其在环碳原子上被C1-4烷基取代且在环氮原子上被任选取代的C1-4烷基取代。
p.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k和l的任选地任何一个中,式I中的R1为任选取代的C4-14芳基。
q.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k和l的任选地任何一个中,式I中的R1为任选取代的C1-10杂芳基。
r.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k和l的任选地任何一个中,式I中的R1为任选取代的C1-6烷基。
s.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k和l的任选地任何一个中,式I中的R1为具有氧代取代基的C1-6烷基,以及任选取代的C3-6杂环烷基。
t.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k和l的任选地任何一个中,式I中的R1为具有氧代取代基的C1-6烷基,以及连接于C1-6烷基相同碳原子上的任选取代的C3-6杂环烷基。
u.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k和l的任选地任何一个中,式I中的R1为被C1-14酰胺取代的C1-6烷基。
v.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k、l、m、n、o、p、q、r、s、t和u的任选地任何一个中,式I中的R2和R3连同它们一起连接的碳原子形成羰基。
w.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k、l、m、n、o、p、q、r、s、t和u的任选地任何一个中,式I中的R2和R3连同它们一起连接的碳原子形成羰基,并且式I中的R6和R7每一个为氢。
x.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k、l、m、n、o、p、q、r、s、t和u的任选地任何一个中,式I中的R6和R7连同它们一起连接的碳原子形成羰基。
y.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k、l、m、n、o、p、q、r、s、t和u的任选地任何一个中,式I中的R6和R7连同它们一起连接的碳原子形成羰基,并且式I中的R2和R3每一个为氢。
本发明中的化合物可通过许多步骤制备,其中的一些描述如下。除非另有说明,所有取代基为如前定义。每一步骤的产物可通过常规方法回收,包括萃取、蒸发、沉淀、色谱法、过滤、研磨、结晶等。这些步骤可能需要保护某些基团,举例来说,羟基、氨基或羧基,以避免不希望的反应。这些保护基的选择、使用及移除是熟知的且可为常规作法,例如,见T.W.Greene and P.G.M.Wuts,Protective Groupsin Organic Chemistry,John Wiley and Sons(1991)。
方案A
方案A描述了式I化合物的形成,其中将R2和R3一起连同它们所连接的碳原子形成羰基(式IA)。
方案A中的步骤1描述了适当的式(a)化合物与适当的式(b)化合物的反应,以提供式(c)化合物。适当的式(a)化合物为其中G1、R4以及R6/R7如同在式IA的最终化合物中所需的化合物,或造成G1、R4以及R6/R7如同在式IA的最终化合物中所需的化合物,且G2为氢或为保护基,并且G3为C1-4烷基(特别地为甲基或乙基)。式(a)的化合物很容易通过多种方法制备,该方法包括烷基-吡咯并吡啶-4-羧酸酯或烷基-吡咯并嘧啶-4-羧酸酯的甲酰化,且如有需要,可通过随后的精制,包括加入有机金属试剂、氧化、转变为卤素以及本领域所熟知的其他反应。适当的式(b)化合物为其中R1如同在式IA的最终化合物中所需的化合物,或造成R1如同在式IA的最终化合物中所需的化合物。
特别地,方案A中的步骤1描述了式(a)化合物和适当的式(b)化合物的还原胺化反应,以提供式(c)的化合物。举例来说,还原胺化反应使用还原剂(例如硼氢化钠、三乙酰氧基硼氢化钠、锌/盐酸、硼氢化锌、氰基硼氢化钠等)于多种条件下进行。该反应在溶剂(例如甲醇、THF等)中进行。典型地,该反应可于约0℃至约60℃的温度范围下进行并典型地需要约1至约24小时以完成。当使用氰基硼氢化钠时,该反应于溶剂(例如甲醇、乙醇、异丙醇以及水或其混合物)中进行。如同本领域所熟知的,在此反应期间监测和调节pH是有利的。
替代地,此还原胺化反应可通过透过在催化剂上的氢化作用进行。多种催化剂适合这一目的,包括钯、铂以及镍催化剂。此氢化作用在适当的溶剂(例如乙酸乙酯、乙醇、甲醇、异丙醇等)中进行,且于大气压至约300psi(2068kPa)的压力范围内以及室温至约100℃的温度下进行。
方案A中的步骤2描述了式(c)化合物的转化,以提供式(d)的化合物。可认识到从酯转化为酸是常见的转化,并有数种方法可影响此反应,包括使用多种在含有溶剂的水中的酸类和碱类的水解作用。
方案A中的步骤3描述了将式(d)化合物转化为式IA的化合物形成酰胺键。此酰胺形成反应为本领域所熟知且领会的。举例来说,可使用常规的酰胺形成条件,例如使用偶联剂的那些条件,该偶联剂包括在肽偶联中使用的那些(例如2-(3H-[1,2,3]三唑并[4,5-b]吡啶-3-基)-1,1,3,3-四甲基脲六氟磷酸酯(V)(HATU)、1,3-二环己基碳二亚胺(DCC)以及N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺(EDC)盐酸盐)。如有必要或需要,可使用添加剂(例如4-(二甲基氨基)吡啶、1H-苯并[d][1,2,3]三唑-1-醇(HOBt)等)以促进反应。此反应一般使用碱(例如N-甲基吗啉或三乙胺)于各式各样合适的溶剂(例如二氯甲烷、二甲基甲酰胺、THF等)中进行。
方案B描述了式I化合物的形成,其中将R6和R7一起连同它们所连接的碳原子形成羰基(式IB)。该方案B中的方法步骤与方案A中描述的那些相同。然而,起始材料式(a’)化合物在3-位具有-C(O)OG3基团且在4-位具有羰基(-C(O)-R2/R3),其造成式IA在R6和R7的氧取代。
方案B
在方案A和B中描述的方法可依照需要而改变。举例来说,可在沿着描述于方案A和B的途径的不同步骤中加入或移除保护基。此外,在步骤3中形成的化合物可通过烷基化、酰化、水解、氧化、还原、酰胺化、磺化、炔基化、烯基化等被进一步精制,以给出如最终产物所需的R1。
此外,在任选的步骤(未示出)中,式I化合物可被转化为药学上可接受的盐。举例来说,可将式I化合物和适当的酸或碱反应,以提供所需要的盐。替代地,可将式I化合物的前体和碱或碱反应以移除对酸或碱不稳定的保护基或打开前体的内酯或内酰胺基团。另外,式I化合物的盐可通过以适当的酸或碱处理或通过和离子交换树脂接触而转化为另一种盐。反应后,如果该盐能从溶液中沉淀,则可通过过滤而分离所述盐,或者通过蒸发而回收所述盐。盐的离子化程度可由完全离子化变化至几乎无离子化。
式I化合物的有用的盐可包括酸加成盐(包括二酸)以及碱加成盐。药学上可接受的酸加成盐可包括衍生自无机酸(例如盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸、氢氟酸和亚磷酸)的无毒盐类,以及衍生自有机酸(例如脂肪族单羧酸以及脂肪族二羧酸、被苯基取代的链烷酸、羟基烷羧酸、链烷二羧酸、芳香酸、脂族磺酸和芳族磺酸等)的无毒盐类。此盐类包括乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐、碳酸盐、硫酸氢盐、硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己氨基磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、反丁烯二酸盐、葡庚糖酸盐、葡糖酸盐、葡萄糖醛酸盐、六氟磷酸盐、羟苯酰苯酸盐、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲硫酸盐、萘二甲酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐、磷酸氢盐、磷酸二氢盐、焦谷氨酸盐、蔗糖盐、硬脂酸盐、琥珀酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐和羟萘甲酸盐。
有用的碱加成盐类可包括衍生自碱类的无毒盐类,包括金属阳离子(例如碱金属阳离子或碱土族金属阳离子,以及胺类)。合适的金属阳离子的例子可包括钠(Na+)、钾(K+)、镁(Mg2+)、钙(Ca2+)、锌(Zn2+)以及铝(Al3+)。合适的胺类的例子可包括精氨酸、N,N’-二苄基乙二胺、氯普鲁卡因、胆碱、二乙胺、二乙醇胺、二环己胺、乙二胺、甘氨酸、赖氨酸,N-甲基葡萄糖胺、醇胺(olamine)、2-氨基-2-羟甲基-丙烷-1,3-二醇以及普鲁卡因。
本发明所述的化合物可单独施用或以药物组合物的形式施用。实际上,本发明所述的化合物通常以药物组合物的形式投药,即,以与至少一种药学上可接受的赋形剂形成的混合物的形式,其比例和性质可通过本发明所选化合物性质、所选给药途径以及常规药学实践来决定。
在另一个实施方案中,本发明提供药物组合物,其包含:本发明的化合物以及药学上可接受的赋形剂。本领域的技术人员可根据所选化合物的特定特征、所治疗的病症或症状、该病症或症状的阶段以及其他相关的情况,容易地选择施用的量、形式和途径。
本发明的药物组合物以药学领域所熟知的方式制备,且包括为活性成分的至少一种本发明的化合物。本发明的化合物的量可根据其特定性质而改变,以及可能合宜地介于剂型重量的约1%至约70%。本药物组合物优选以单位剂型配制,每种剂量典型地包含约0.5mg至约200mg的本发明的化合物。术语“单位剂型”是指物理学上的离散单位,每种单位包含预定量的活性成分(其与合适的药物赋形剂结合),通过在整个给药方案中使用一种或多种单位剂型以产生所需的治疗效果。
在对患者的有效治疗上,本发明的化合物可以任何形式和途径施用,其使得该化合物为生物可利用的。本发明的化合物可通过多种途径施用,包括口服和肠胃外途径,更特别地,通过吸入、皮下注射、肌肉注射、静脉注射、经皮给药、鼻内给药、直肠给药、阴道给药、眼部给药、局部给药、舌下给药及口腔给药、腹腔内给药、静脉注射、动脉内给药、经皮给药、舌下给药、肌肉注射、直肠给药、经口含化、鼻内给药、脂肪内给药以及鞘内给药。举例来说,本发明的药物组合物可以片剂、胶囊剂、扁囊剂、纸剂、锭剂、糯米纸、酏剂、软膏剂、透皮贴剂、气雾剂、吸入剂、栓剂、溶液剂以及混悬剂的形式施用给患者。
术语“药学上可接受的赋形剂”是指典型地用于制备药物组合物以及应为药学上纯的且以其所使用的量为无毒性的那些赋形剂。它们一般来说为固体、半固体或液体材料,其可用作活性成分的媒介物或介质或有助于储存、施用或制造所述组合物。药学上可接受的赋形剂的一些例子可参见Remington’s Pharmaceutical Sciences and theHandbook of Pharmaceutical Excipients,且包括稀释剂、媒介物、载体、软膏基质、粘结剂、崩解剂、润滑剂、助流剂、甜味剂、调味剂、凝胶基质、持续释放基质、稳定剂、防腐剂、溶剂、悬浮剂、缓冲剂、乳化剂、染剂、推进剂、涂层剂以及其他。
在一个特定的变体中,药物组合物适于口服施用,例如片剂或胶囊剂或液体制剂(例如,溶液剂或混悬剂)。在另一个特定的变体中,药物组合物为适用于肠胃外施用的液体制剂。
在另一个实施方案中,本发明提供了治疗与JAK相关的疾病、病症或症状的方法。该方法包括对需要其治疗的患者施用有效量的本发明的化合物。在另一个实施方案中,本发明提供了抑制JAK的方法,其包括将本发明的化合物施用给患者,以抑制体内的JAK途径。在另一个实施方案中,本发明提供抑制JAK的方法,其包括将在体内转化为本发明化合物的第一化合物施用给受试者。
在另一个实施方案中,提供本发明的化合物作为药剂使用。本发明还提供本发明的化合物用于制备药剂的用途,以治疗如本文所述的与JAK相关的疾病、病症或症状。
如本文所用,术语“症状”、“病症”和“疾病”和任一种不健康或不正常的状况有关。短语“与JAK相关的疾病、病症或症状”包括其中JAK抑制作用提供良好的治疗效果的任何疾病、病症或症状,例如那些以异常JAK/STAT信号为特征的,包括增生性病症、心脏病症、神经退化性病症、自身免疫病症、器官移植、炎性病症、免疫病症以及过敏性症状、食物过敏、特应性皮炎和鼻炎。其中本文使用一般术语,以描述与JAK相关的症状,可理解的是,在各种诊断手册和其他材料中提及的更具体描述的症状包括在本发明的范围中。举例来说,可理解增生性病症包括癌症。此外,举例来说,可理解关节炎目前分为数种更具体的病症(例如骨关节炎和类风湿性关节炎和其他),且其全部被本发明所考虑。另一个实施例为系统性炎症反应综合征,其描述和败血症、胰腺炎、多发性创伤、撕裂伤、脑损伤或外科手术、出血性休克、免疫器官损伤以及其它相关的炎症事件,其全部被本发明所考虑。
术语“治疗(treat)”、“治疗(treatment)”和“治疗(treating)”包括改善本文所述的疾病、病症或症状。同时,也可领略本领域的技术人员可通过治疗目前受该疾病、病症或症状所苦的患者、或通过预防性治疗被认为对此症状敏感的患者,而以本发明化合物的有效量影响该状况。因此,术语“治疗(treat)”、“治疗(treatment)”和“治疗(treating)”包括提供减缓、阻断、延迟、控制或停止本文所述的疾病、病症或症状的进程的所有方法,但并不一定表明完全消除所有的症状或治愈该病情。此外,此术语的用途旨在包括对任何一种特定的疾病、病症或症状的预防性和治疗性的处理。
术语“受试者”和“患者”可交替使用,且包括人类和非人类的动物(例如,哺乳动物(如小鼠、大鼠、天竺鼠、狗、猫、兔、牛、马、绵羊、山羊以及猪))。该术语还包括鸟、鱼、爬行动物、两栖动物等。应理解更特别的受试者或患者为人类。同时,更特别的受试者或患者可为非人类的哺乳动物(例如小鼠、大鼠以及狗)。
如本文所用,术语“有效量”是指本发明的化合物在治疗(以单剂量或多剂量施用)患有与JAK相关的疾病、病症或症状的患者的量。有效量可以被为本领域技术人员的主治的诊断医生,通过使用已知技术且通过在类似情况下获得的观察结果而容易地测定。在测定有效量(剂量)时,主治的诊断医生考虑的许多因素包括但不限于:患者的种族、其大小、年龄和综合健康;相关的特定症状、病症或疾病;特定症状、病症或疾病的程度、相关性或严重性;个别患者的反应;所施用的特定化合物;给药途径;施用制剂的生物可利用性的特征;所选的给药方案;合并用药的使用;以及其他有关的情况。本文用途发明的有效量,包括本发明的化合物预期由约每天每公斤体重0.1毫克(mg/kg/天)至约20mg/kg/天变化。具体的量可由熟知的技术人员确定。
如上述所提及的,式I化合物可用来治疗与JAK相关的疾病、病症或症状,且该疾病、病症或症状通常与受试者中的不健康或异常状况有关,JAK的抑制对此提供了良好的治疗效果。更特别地,此病症、疾病和症状可包括免疫系统和炎症反应,包括I型过敏性(变态性)反应(过敏性鼻炎、过敏性哮喘以及特应性皮炎);自身免疫疾病(类风湿性关节炎、多发性硬化、系统性红斑性狼疮、牛皮癣、免疫性血小板减少性紫癜、肌萎缩性侧索硬化症以及器官移植排斥);肺的炎症(慢性阻塞性肺疾病)以及血栓形成。式I化合物还可用于治疗与异常细胞生长相关的病症、疾病和症状,抱括血液恶性肿瘤,例如急性骨髓性白血病、B细胞慢性淋巴性白血病、B细胞淋巴瘤(例如,套细胞淋巴瘤)和T细胞淋巴瘤(例如,外周T细胞淋巴瘤),以及上皮癌(即恶性上皮肿瘤),例如肺癌(小细胞肺癌及非小细胞肺癌)、胰脏癌和结肠癌。
除了上述提及的血液恶性肿瘤和上皮癌,式I化合物还可用于治疗其他种类的癌症,包括白血病(慢性骨髓性白血病及慢性淋巴性白血病);乳腺癌、泌尿生殖癌、皮肤癌、骨癌、前列腺癌以及肝癌;脑癌;喉、胆囊、直肠、副甲状腺、甲状腺、肾上腺、神经组织、膀胱、头、颈、胃、支气管以及肾脏的癌症;基底细胞癌、鳞状细胞癌、转移性皮肤癌、骨肉瘤、尤文肉瘤、网状细胞肉瘤以及卡波西肉瘤;骨髓瘤、巨细胞瘤、胰岛细胞瘤、急性及慢性淋巴性和粒细胞瘤、毛细胞瘤、腺瘤、髓样癌、嗜铬细胞瘤、粘膜神经瘤、肠神经节细胞瘤、增生性角膜神经瘤、类马伐氏综合征瘤、威尔姆氏肿瘤、精原细胞瘤、卵巢瘤、平滑肌瘤、子宫颈发育不良、神经母细胞瘤、视网膜母细胞瘤、骨髓增生异常综合征、横纹肌肉瘤、星状细胞瘤、非霍奇金淋巴瘤、恶性高钙血症、真性红血胞增多症、腺癌、多形性胶质母细胞瘤、神经胶质瘤、淋巴瘤及恶性黑色素瘤等等。
除了癌症以外,式I化合物还可用于治疗其他与异常细胞生长相关的疾病,包括非恶性增生性疾病,例如良性前列腺肥大、再狭窄、增生、滑膜增生病症、视网膜病变或其他的眼部新生血管性病症等等。
式I化合物还可用于治疗除了上述列举的那些以外的自身免疫疾病。此病症、疾病和症状包括克隆氏病、皮肌炎、I型糖尿病、古德巴斯德综合征(Goodpasture′s syndrome)、格雷夫斯氏病(Graves′disease)、格巴二氏综合征(Guillain-Barre syndrome)、桥本氏病(Guillain-Barre syndrome)、混合性结缔组织损伤、重症肌无力、嗜睡、寻常性天疱疮、恶性贫血、多发性肌炎,原发性胆汁性肝硬化、舍格伦综合征(syndrome)、颞动脉炎、溃疡性结肠炎、血管炎及韦格纳肉芽肿(Wegener′s granulomatosis)等等。
此外,式I化合物可用于治疗炎性疾病,其包括哮喘、慢性炎症、慢性前列腺炎、肾小球性肾炎、过敏、炎性肠病(除了克隆氏病外的溃疡性结肠炎)、骨盆发炎症、再灌流损伤、移植排斥、血管炎及全身性炎症反应综合征。
式I化合物还可用于治疗特定疾病,其可能属于一种或多种上述一般疾病,包括关节炎。除了类风湿关节炎、舍格伦综合征、系统性红斑性狼疮、儿童和青少年的SLE以外,式I化合物还可用于治疗其他关节炎疾病,包括关节强硬性脊椎炎、缺血性坏死、贝塞特氏病(Bechet′s disease)、滑囊炎、双氢氧化焦磷酸钙沈积疾病(假性痛风)、腕隧道综合征、艾登二氏综合征(Ehlers-Danlos syndrome)、纤维肌痛、第五疾病、巨大细胞动脉炎、痛风、幼年型皮肌炎、幼年型类风湿性关节炎、幼年型脊椎关节病变、莱姆病(Lyme disease)、马凡氏综合征(Marfan syndrome)、肌炎、骨关节炎、成骨不全症、骨质疏松症、柏哲德氏症(Paget′s disease)、牛皮癣关节炎、雷诺氏现象(Raynaud′s phenomenon)、反应性关节炎、反射性交感神经营养不良综合征、硬皮症、脊髓狭窄、史提耳氏病(Still′s disease)及腱炎等等。
可将所要求以及所公开的化合物和一种或多种其他具药理活性的化合物或疗法结合,用于治疗一种或多种与JAK相关的疾病、病症或症状,其包括涉及免疫系统、炎症以及异常细胞生长的疾病、病症或症状。举例来说,可将式I化合物(包括本说明书和权利要求书特别指明的化合物)以及它们药学上可接受的复合物、盐类、溶剂化物以及水合物,和一种或多种化合物或疗法结合且同时、连续或分开施用,其用于治疗关节炎(包括类风湿性关节炎和骨性关节炎),或用于治疗癌症(包括血液恶性肿瘤(例如急性骨髓白血病、B细胞慢性淋巴白血病、B细胞淋巴瘤和T细胞淋巴瘤)以及恶性肿瘤(例如肺癌、胰脏癌以及结肠癌))。此结合可提供显著的治疗效益,包括较少的副作用、对于服务不足的患者人群改善治疗的能力或协同活性。
举例来说,当用来治疗关节炎时,可将式I化合物和一种或多种非类固醇抗炎药(NSAIDs)、镇痛剂、皮质类固醇、生物反应调节剂以及蛋白质-A免疫吸附疗法结合。替代地或另外地,当治疗类风湿性关节炎时,可将式I化合物和一种或多种缓解病情抗风湿药物(DMARDs)结合,以及当治疗骨性关节炎时,可将式I化合物和一种或多种骨质疏松剂结合。
代表性的NSAIDs包括阿扎丙宗(apazone)、阿斯匹灵、希乐葆(celecoxib)、待克菲那(diclofenac)(带有以及不带有米索前列醇)、待福索(diflunisal)、免痛炎(etodolac)、非诺洛芬(fenoprofen)、氟比洛芬(flurbiprofen)、布洛芬(ibuprofen)、引朵美洒辛(indomethacin)、可多普洛菲(ketoprofen)、甲氯胺苯酸钠(meclofenamate sodium)、甲芬那酸、美洛西卡(meloxicam)、萘丁美酮(nabumetone)、那普洛仙(naproxen)、奥沙普秦(oxaprozin)、苯基丁氮酮(phenylbutazone)、匹洛西卡(piroxicam)、胆碱和水杨酸镁、双水杨酸盐(salsalate)和苏林达克(sulindac)。代表性的镇痛剂包括对乙酰氨基酚和硫酸吗啡以及可待因、二氢可待因酮(hydrocodone)、氧可酮(oxycodone)、普帕西芬(propoxyphene)以及妥美度(tramadol),其全部带有或不带对乙酰氨基酚。代表性的皮质类固醇包括倍他米松(betamethasone)、醋酸可的松(cortisoneacetate)、地塞米松(dexamethasone)、氢化可的松(hydrocortisone)、甲基强的松龙(methylprednisolone)、强的松龙(prednisolone)以及强的松(prednisone)。代表性的生物反应调节剂包括TNF-α抑制剂,例如阿达木(adalimumab)、依那西普(etanercept)以及因福利美(infliximab);选择性的B-细胞抑制剂,例如利妥昔单抗(rituximab);IL-1抑制剂,例如阿那白滞素(anakinra)以及选择性的共同刺激调节剂,例如阿巴西普(abatacept)。
代表性的DMARDs包括金诺芬(口服金)、咪唑硫嘌呤(azathioprine)、苯丁酸氮芥(chlorambucil)、环磷酰胺、环孢霉素、硫代苹果酸金钠(注射用金)、羟化氯喹、艾炎宁(leflunomide)、甲氨蝶呤、米诺环素(minocycline)、山喜多(myophenolate mofetil)、青霉胺以及柳氮磺胺吡啶。代表性的骨质疏松剂包括双膦酸盐类,例如阿仑膦酸钠(alendronate)、伊班膦酸钠(ibandronate)、利塞膦酸盐(risedronate)和唑来膦酸(zoledronic acid);选择的雌激素受体调节子,例如屈洛昔芬(droloxifene)、拉索昔芬(lasofoxifene)以及雷洛昔芬(raloxifene);荷尔蒙,例如降钙素、雌激素和副甲状腺素;以及免疫抑制剂例如咪唑硫嘌呤(azathioprine)、环孢霉素以及雷帕霉素。
对于治疗类风湿性关节炎特别有用的组合包括式I化合物和甲氨蝶呤,其可单独或和一种或多种生物反应调节剂例如艾炎宁(lefluonomide)、依那西普(etanercept)、阿达木(adalimumab)以及因福利美(infliximab)结合。
对于治疗血栓和再狭窄,可将式I化合物和一种或多种心血管药剂例如钙通道阻滞剂、他汀类(statins)、纤维酸类(fibrates)、β受体阻滞剂、ACE抑制剂以及血小板聚集抑制剂结合。
还可将式I化合物和一种或多种治疗癌症的化合物或疗法结合。这些包括化疗药(即细胞毒性或抗癌药)例如烷基化剂、抗生素、抗代谢剂、植物源性药物以及拓朴异构酶抑制剂,以及通过使用涉及肿瘤生长和进展的特定分子干扰而阻止癌症生长和扩散的分子靶向药物。分子靶向药物包括小分子和生物制剂两者。
代表性的烷基化剂包括双氯乙基胺(氮芥类(例如,苯丁酸氯芥、环磷酰胺、异环磷酰胺、氮芥、美法仑(melphalan)、尿嘧啶氮芥);氮丙啶(例如噻替派(thiotepa));烷基酮磺酸盐(例如马利兰);亚硝基脲(例如卡莫司汀、洛莫司汀和链脲佐菌素);非典型烷基化剂(例如六甲蜜胺、达卡巴嗪和丙卡巴肼);以及铂化合物(例如卡铂、顺铂、奈达铂、奥沙利铂、沙铂以及三铂四硝酸盐(triplatin tetranitrate))。
代表性的抗生素包括蒽环类(例如阿克拉霉素(aclarubicin)、氨柔比星(amrubicin)、柔红霉素(daunorubicin)、阿霉素(doxorubicin)、表柔比星(epirubicin)、伊达比星(idarubicin)、吡柔比星(pirarubicin)、戊柔比星(valrubicin)以及佐柔比星(zorubicin));蒽醌类(例如米托蒽醌(mitoxantrone)和匹杉琼(pixantrone));以及链霉菌属(例如放线菌素、博来霉素(bleomycin)、更生霉素(dactinomycin)、丝裂霉素C(mitomycin C)以及普卡霉素(plicamycin))。
代表性的抗代谢剂包括二氢叶酸还原酶抑制剂(例如氨蝶呤、甲氨蝶呤和爱宁达(pemetrexed));胸苷合成酶抑制剂(例如雷替曲塞(raltitrexed)和爱宁达(pemetrexed));亚叶酸(例如甲酰四氢叶酸);腺苷脱氨酶抑制剂(例如喷司他丁(pentostatin));卤代/核糖核苷酸还原酶抑制剂(例如克拉屈滨、克罗拉滨和氟达拉滨);硫嘌呤类(例如硫鸟嘌呤和巯嘌呤);胸苷酸合成酶抑制剂(例如氟尿嘧啶、卡培他滨、替加氟(tegafur)、卡莫氟(carmofur)和氟尿苷);DNA聚合酶抑制剂(例如阿糖胞苷(cytarabine));核糖核苷酸还原酶抑制剂(例如吉西他滨(gemcitabine));去甲基化剂(例如阿扎胞苷(azacitidine)和地西他滨(decitabine);以及核糖核苷酸还原酶抑制剂(例如羟基脲);以及降天冬酰胺药(例如天冬酰胺酶)。
代表性的植物源性药物包括长春花生物碱类(例如:长春新碱、长春碱、长春地辛、长春利定和长春瑞滨)、鬼臼毒素类(例如:依托泊苷和替尼泊苷)以及紫杉烷类(例如:多西他赛(docetaxel)、莱龙太素(larotaxel)、奥他赛(ortataxel)、紫杉醇(paclitaxel)和替司他赛(tesetaxel))。
代表性的I型拓朴异构酶抑制剂包括喜树碱(例如贝洛替康(belotecan)、伊立替康(irinotecan)、鲁比替康(rubitecan)以及拓扑替康(topotecan))。代表性的II型拓朴异构酶抑制剂包括安吖啶(amsacrine)、依托泊甘(etoposide)、磷酸依托泊甘以及替尼泊苷,其为鬼臼素(epipodophyllotoxins)的衍生物。
分子靶向疗法包括生物制剂例如细胞激素以及其他免疫调节剂。有效用的细胞激素包括白细胞介素-2(IL-2,阿地白介素)、白细胞介素4(IL-4)、白细胞介素12(IL-12)以及干扰素,其包括多于23种相关的亚型。其他细胞激素包括粒细胞集落刺激因子(非格司亭(filgrastim))以及粒细胞-巨噬细胞集落刺激因子CSF(沙格莫丁(sargramostim))。其他免疫调节剂包括卡介苗、左美索(levamisole)以及奥曲肽(octreotide);抗肿瘤抗原的单株抗体,例如曲妥珠单抗(trastuzumab)和利妥昔单抗(rituximab);以及癌症疫苗,其诱发对肿瘤的免疫反应。
此外,用涉及肿瘤生长和进展的特定分子干扰的分子靶向药物包括表皮生长因子(EGF)、转化生长因子-α(TGFα)、TGFβ、调蛋白、类胰岛素生长因子(IGF)、纤维母细胞生长因子(FGF)、角质细胞生长因子(KGF)、细胞集落刺激因子(CSF)、红血球生成素(EPO)、白细胞介素-2(IL-2)、神经生长因子(NGF)、血小板源生长因子(PDGF)、肝细胞生长因子(HGF)、血管表皮细胞生长因子(VEGF)、血管生成素、表皮生长因子受体(EGFR)、人类表皮细胞生长因子受体2(HER2)、HER4、类胰岛素生长因子1受体(IGF1R)、IGF2R、纤维母细胞生长因子1受体(FGF1R)、FGF2R、FGF3R、FGF4R、血管表皮细胞生长因子受体(VEGFR)、带有类免疫球蛋白和类上皮细胞生长因子区域2(Tie-2)的酪氨酸激酶、血小板源生长因子受体(PDGFR)、Abl、Bcr-Abl、Raf、类FMS酪氨酸激酶3(FLT3)、c-Kit、Src、蛋白激酶c(PKC)、原肌凝蛋白受体激酶(Trk)、Ret、雷帕霉素的哺乳动物靶(mTOR)、极光激酶、保罗样激酶(PLK)、丝裂原活化蛋白激酶(MEK)、间质-上皮转变因子(c-MET)、细胞周期蛋白依赖性激酶(CDK)、Akt、细胞外信号调节激酶(ERK)、聚(腺苷二磷酸核糖)聚合酶(PARP)等的抑制剂。
特定的分子靶向药物包括选择性雌激素受体调节子,例如它莫西芬(tamoxifen)、托瑞米芬(toremifene)、氟维司群(fulvestrant)和雷洛昔芬(raloxifene);抗雄激素,例如比卡鲁胺(bicalutamide)、尼鲁米特(nilutamide)、甲地孕酮(megestrol)和氟他胺(flutamide);以及芳香酶抑制剂,例如依西美坦(exemestane)、阿那曲唑(anastrozole)和来曲唑(letrozole)。其他具体的分子靶向药物包括抑制信号转导的药剂,例如伊马替尼(imatinib)、达沙替尼(dasatinib)、尼洛替尼(nilotinib)、曲妥珠单抗(trastuzumab)、吉非替尼(gefitinib)、埃罗替尼(erlotinib),西妥昔单抗(cetuximab)、拉帕替尼(lapatinib)、帕尼单抗(panitumumab)和特癌适(temsirolimus);诱发细胞凋亡的药剂,例如波替单抗(bortezomib);阻止血管生成的药剂,例如贝伐单抗(bevacizumab)、索拉非尼(sorafenib)和舒尼替尼(sunitinib);帮助免疫系统摧毁癌细胞的药剂,例如利妥昔单抗(rituximab)和阿来组单抗(alemtuzumab);以及输送毒性分子至癌细胞的单株抗体,例如吉妥单抗(gemtuzumab ozogamicin)、托西莫单抗(tositumomab)、131碘-托西莫单抗和替伊莫单抗(ibritumomab tiuxetan)。
本发明还提供制成品,其包括至少一种本发明的化合物以及标签。该标签可包括关于制造商、剂量、欲治疗症状以及该化合物或药物组合物的用途的信息。
在另一个实施方案中,本发明提供试剂盒:其包括至少一种本发明的化合物、标签以及投药装置。该装置可能包括混合瓶、用于形成溶液或悬浮液的液体、管子、注射器等。
生物活性:JAK抑制作用
可使用各种方法评估化合物抑制JAK活性的能力,包括体外和体内的试验。下列体外的试验测量测试化合物抑制JAK2和JAK3介导的FAM标记的JAK专一性底物磷酸化作用的能力。
纯化的JAK2和JAK3蛋白质购买自Invitrogen。、使用在包含50mM HEPES、10mM NaCl、10mM MgCl2、0.2mM EDTA、0.01%EDA(35)、1mM DTT、0.1mg/mL BSA的缓冲液中的黑色384细胞微孔培养板在pH 7.3下测定JAK2和JAK3抑制作用。每一种测试化合物在DMSO中使用2倍系列稀释为11个数据点,并且被加入缓冲液中,使得每一种稀释包含3%DMSO。
JAK2抑制作用试验
往每一个孔中加入2μL的3μM5FAM-KKKKEEIYFFFG-NH2和45μM ATP(在缓冲液中)、2μL被稀释的测试化合物(在培养基中有3%DMSO)以及2μL的在缓冲液中的0.6nM JAK2。将反应混合物于室温下培养60分钟并通过加入50mM HEPeX、30mM EDTA以及0.1%Tx-100(pH 7.3)进行淬灭。在反应后为定量荧光标记的底物和产物,将测试板装于通过基于微流体的分离而测量转换百分率的Caliper LC-3000上。
JAK3抑制作用试验
于每一个孔中加入2μL的3μM5FAM-KKKKEEIYFFFG-NH2和15μM ATP(在缓冲液中)、2μL被稀释的测试化合物(在培养基中有3%DMSO)以及2μL的在缓冲液中的1.2nM JAK3。将反应混合物于室温下培养60分钟并通过加入50mM HEPES、30mM EDTA以及0.1%Tx-100(pH 7.3)进行淬灭。在反应后为定量荧光标记的底物和产物,将测试板装于通过基于微流体的分离而测量转换百分率的Caliper LC-3000上。
通过该化合物浓度和抑制百分率对标准IC50方程的的非线性曲线拟合计算相应的IC50数值。
实施例
本发明进一步以下列实施例和制备说明。这些实施例和制备不以任何方式限制本发明的范围。在下述实施例中的许多化合物获得了1H核磁共振(NMR)光谱。从四甲基硅烷的百万分之几的低场给出化学位移特征(δ),对于主要波峰的指定使用常见的缩写,包括s(单峰)、d(双重峰)、t(三重峰)、q(四重峰)、m(多重峰)以及br(宽峰)。对于常见的溶剂使用下列缩写:CDCl3(氘代氯仿)、DMSO-d6(氘代二甲基亚砜)、CD3OD(氘代甲醇)以及THF-d8(氘代四氢呋喃)。使用电喷雾电离(ESI)或大气压化学电离(APCI)记录质谱([M+H])。
其中指出,某些制备和实施例的产物通过批量操作触发器HPLC(泵:WatersTM 2525;MS:zQTM;软体:MassLynxTM)、快速色谱法或制备薄层色谱法(TLC)纯化。使用酸性或碱性条件进行制备HPLC。酸性条件典型地为在带有0.05%TFA的溶剂A:水中的梯度液以及在带有0.035%TFA的溶剂B:乙腈中的梯度液;碱性条件为在溶剂A:10nM NH4HCO3(在水中)中的梯度液以及在溶剂B:10nMNH4HCO3(在20/80(v/v)水/乙腈)中的梯度液。除非指出为碱性条件,否则所提的制备HPLC条件使用酸性条件。制备基TLC典型地在硅胶60F254板上进行。在通过色谱法分离后,溶剂被移除且通过在离心蒸发器(例如GeneVacTM)、旋转型蒸发器、真空瓶等干燥而获得产物。在惰性气氛(例如氮气)或反应气氛(例如H2)下的反应典型地在约1个大气压(14.7psi)下而进行。
许多用于实施例中的缩写列于上述的表1中。除非在说明书中另有说明,未列于表1的缩写具有其通常含义。
制备A:3-甲酰-1H-吡咯并[2,3-b]吡啶-4-甲酸甲酯
将1H-吡咯并[2,3-b]吡啶-4-甲酸甲酯(500mg,2.84mmol)以及六亚甲基四胺(796mg,5.68mmol)于水(8mL)和冰乙酸(16mL)中合并,并且于100℃加热过夜,然后冷却至室温。将反应混合物用乙酸乙酯萃取并将有机物经由MgSO4干燥,并在真空中浓缩,以提供残余物。通过硅胶色谱法(50%EtOAc/己烷)纯化残余物,以提供为白色固体的标题化合物。1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.57(s,1H),8.48(d,1H,J=4.8Hz),7.48(d,1H,J=4.8Hz),5.74(d,1H,J=6.8Hz),3.91(s,3H),2.78(s,3H)。[M+H]测量值为205。
制备B:4-甲基-3-甲酰-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁酯
将3-甲酰-1H-吡咯并[2,3-b]吡啶-4-甲酸甲酯(150mg,0.735mmol)溶解于DMF(5mL)中,并且将三乙胺(0.31mL,2.20mmol)加至溶液中。然后加入二碳酸二叔丁酯(240mg,1.10mmol),并使混合物于室温下搅拌3小时。将溶液在真空中浓缩。通过硅胶色谱法(30%EtOAc/己烷)纯化,以提供165mg为白色固体的标题化合物。1H NMR(400MHz,CD3OD)δ10.16(s,1H),8.64(s,1H),8.57(d,1H,J=5.0Hz),7.63(d,1H,J=5.1Hz),4.00(s,3H),1.72(s,9H)。[M+H]测量值为305。
实施例1:4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-羧酸叔丁酯
将3-甲酰-1H-吡咯并[2,3-b]吡啶-4-甲酸甲酯(160mg,0.784mmol)以及4-氨基哌啶-1-羧酸叔丁酯(188mg,0.940mmol)于MeOH(3mL)和THF(3mL)中在50℃下合并3小时。然后于室温下加入硼氢化钠(59mg,1.567mmol)并使其搅拌10分钟。将混合物用水淬灭并用乙酸乙酯萃取。将有机物经由MgSO4干燥,并在真空中浓缩,以提供3-((1-(叔丁氧基羰基)哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸甲酯(60mg),将其用于下一步骤。1H NMR(400MHz,CD3OD)δ8.32(d,1H,J=5.1Hz),7.61-7.62(m,2H),4.07-4.13(m,4H),4.01(s,3H),2.81-2.84(m,3H),1.96-1.98(m,2H),1.45-1.47(m,2H),1.45(s,9H)。[M+H]测量值为389。
将3-((1-(叔丁氧基羰基)哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸甲酯(60mg,0.154mmol)于MeOH(2mL)、1N NaOH(3mL)和THF(2mL)中搅拌16小时。然后将1N HCl逐滴加入直到pH=5并将该混合物用水稀释且用乙酸乙酯萃取。分离有机物,经由MgSO4干燥,并在其空中浓缩。经由基础制备HPLC纯化,用在A中的10%至35%B洗脱,以提供50mg的3-((1-(叔丁氧基羰基)哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸。1H NMR(400MHz,CD3OD)δ11.84(s,1H),8.21(d,1H,J=4.8Hz),7.67(s,1H),7.34(d,1H,J=4.8Hz),4.14(m,2H),3.96(m,2H),3.04-3.09(m,1H),2.77(m,2H),2.02-2.03(m,2H),1.42-1.43(m,2H),1.40(s,9H)。[M+H]测量值为375。
将3-((1-(叔丁氧基羰基)哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸(35mg,0.093mmol)、HATU(71mg,0.187mmol)和吡啶(0.023mL,0.280mmol)在DMF(3mL)中于室温下搅拌2小时。将溶液在真空中浓缩,并经由基础制备HPLC纯化,用在A中的10%至35%B洗脱,以提供18mg为黄色固体的标题化合物。1H NMR(400MHz,CD3OD)δ7.59(m,1H),7.39-7.49(m,1H),4.98(d,2H,J=1.5Hz),4.77-4.79(m,1H),4.25-4.28(m,2H),2.87-2.92(m,2H),1.91-1.94(m,2H),1.78-1.90(m,2H),1.48(s,9H)。[M+H]测量值为357。
实施例2:4-(哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de]]2,6]萘啶-5(1H)-酮
将4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-羧酸叔丁酯(18mg,0.051mmol)溶解于TFA(1mL)和DCM(2mL)中,并使其在室温下搅拌15分钟。将混合物在真空中浓缩,并经由制备HPLC用在A中的10%至40%B纯化,并提供12mg为其TFA盐的标题化合物。1H NMR(400MHz,CD3OD)δ8.71-8.72(s,1H),8.42(d,1H,J=8.4Hz),7.62(s,1H),7.48-7.49(m,2H),5.02(s,1H),4.69-4.75(m,2H),3.58-3.61(m,2H),3.19-3.26(m,2H),2.33-2.39(m,2H),2.10-2.15(m,2H)。[M+H]测量值为257。
实施例3:3-氧代-3-(4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-基)丙腈
将4-(哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮(34mg,0.133mmol)和三乙胺(0.055mL,0.398mmol)溶解于EtOH(4mL)中,并冷却至0℃且使其搅拌10分钟。接着将溶解于EtOH(1mL)的2-氰乙酸2,5-二氧代吡咯烷-1-基酯(29mg,0.159mmol)逐滴加入并使混合物于0℃下搅拌30分钟。将溶液在真空中浓缩,并经由制备HPLC纯化,用在A中的10%至40%B洗脱,并提供10mg为其TFA盐的标题化合物。1H NMR(400MHz,CD3OD)δ7.60(m,1H),7.43(m,1H),4.98(s,2H),4.84-4.88(m,1H),4.68-4.72(m,1H),3.89-3.95(m,3H),3.33(m,1H),2.80-2.88(m,1H),1.86-2.05(m,4H)。[M+H]测量值为324。
实施例4:4-甲基-4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-羧酸叔丁酯
将3-甲酰-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯(71mg,0.233mmol)溶解于DCM(5mL)并将4-氨基-4-甲基哌啶-1-羧酸叔丁酯(50mg,0.233mmol)加至溶液中,并使其于室温下搅拌2小时。然后加入三乙酰氧基硼氢化钠(148mg,0.700mmol)并将混合物于室温下搅拌2小时。将溶液用水淬灭并用DCM萃取。将有机物经由MgSO4干燥,并在真空中浓缩。经由硅胶色谱法(70%EtOAc/己烷)纯化,以提供90mg的3-((1-(叔丁氧基羰基)-4-甲基哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基-4-甲酯。[M+H]测量值为403。
将3-((1-(叔丁氧基羰基)-4-甲基哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基-4-甲酯(90mg,0.179mmol)于MeOH(2mL)、1N NaOH(3mL)以及THF(2mL)中搅拌16小时。将混合物在真空中浓缩。经由基础制备HPLC用在A中的15%至35%B进行纯化,以提供34mg的3-((1-(叔丁氧基羰基)-4-甲基哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸。[M+H]测量值为389。
将3-((1-(叔丁氧基羰基)-4-甲基哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸(34mg,0.088mmol)、HATU(67mg,0.175mmol)以及吡啶(0.021mL,0.263mmol)在DMF(3mL)中于室温下搅拌2小时。将溶液在真空中浓缩,以提供标题化合物,无需进一步纯化即可使用。
实施例5:4-(4-甲基哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮
将于实施例4中获得的粗3-((1-(叔丁氧基羰基)-4-甲基哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸溶解于DCM(3mL)和TFA(1mL)中,并使其于室温下搅拌1小时。将溶液在真空中浓缩,并经由制备HPLC用在A中的5%至20%B进行纯化,以提供21mg为其TFA盐的标题化合物。1H NMR(400MHz,CD3OD)δ8.74(s,1H),8.42(m,1H),7.59(m,1H),7.43(m,1H),5.05(s,2H),3.29-3.33(m,2H),3.22-3.23(m,2H),2.93-2.97(m,2H),2.20-2.26(m,2H),3.17(s,3H)。[M+H]测量值为271。
实施例6:3-(4-甲基-4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-基)-3-氧代丙腈
将4-(4-甲基哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮(21mg,0.078mmol)以及三乙胺(0.032mL,0.233mmol)溶解于EtOH(4mL)并冷却至0℃,并使其搅拌10分钟。然后将溶解于EtOH(1mL)中的2-氰乙酸2,5-二氧代吡咯烷-1-基酯(17mg,0.093mmol)逐滴加入,并使混合物于0℃下搅拌30分钟。将溶液在真空中浓缩,并经由制备HPLC用在A中的10%至40%B进行纯化,以提供13mg为其TFA盐的标题化合物。1H NMR(400MHz,CD3OD)δ7.61(m,1H),7.43(m,1H),5.08(s,2H),3.90(m,2H),3.72(m,1H),3.61-3.62(m,1H),3.51-3.52(m,2H),2.65-2.69(m,1H),2.51-2.57(m,1H),2.22-2.26(m,1H),2.10-2.12(m,1H),1.66(s,3H)。[M+H]测量值为338。
实施例7:4-乙基-4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-羧酸叔丁酯
将3-甲酰-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯(211mg,0.692mmol)溶解于MeOH(10mL)并加入4-氨基-4-乙基哌啶-1-羧酸叔丁酯(158mg,0.692mmol),接着加入2滴乙酸。让溶液于室温下搅拌2小时。然后在6小时期间内于室温下加入氰基硼氢化钠(44mg,0.692mmol)。将溶液用水淬灭并用乙酸乙酯萃取。将有机物经由MgSO4干燥,并在真空中浓缩。经由硅胶色谱法(70%EtOAc/己烷)纯化,以提供127mg的3-((1-(叔丁氧基羰基)-4-乙基哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯。[M+H]测量值为417。
将3-((1-(叔丁氧基羰基)-4-乙基哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯(123mg,0.238mmol)于MeOH(3mL)、1N NaOH(3mL)以及THF(2mL)中搅拌16小时。将混合物在真空中浓缩。经由基础制备HPLC用在A中的20%至50%B进行纯化,以提供60mg的3-((1-(叔丁氧基羰基)-4-乙基哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸。1H NMR(400MHz,CD3OD)δ8.29(d,1H,J=4.8Hz),7.68(s,1H),7.52(d,1H,J=5.1Hz),4.31(s,2H),3.95-4.01(m,1H),2.03(q,2H,J=7.6Hz),1.92-1.94(m,4H),1.47(s,9H),1.46(m,2H),1.07(t,1H,J=7.3Hz)。[M+H]测量值为403。
将3-((1-(叔丁氧基羰基)-4-乙基哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸(50mg,0.124mmol)、HATU(94mg,0.248mmol)以及4-二甲基氨基吡啶(46mg,0.373mmol)在DMF(3mL)中于室温下搅拌1小时。将溶液在真空中浓缩,以提供标题化合物,无需进一步纯化即可使用。
实施例8:4-(4-乙基哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮
将4-乙基-4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-羧酸叔丁酯(50mg,0.124mmol)、HATU(94mg,0.248mmol)以及4-二甲基氨基吡啶(46mg,0.373mmol)在DMF(3mL)中于室温下搅拌1小时。将溶液在真空中浓缩并溶解于DCM(3mL)和TFA(1mL)中,并使其于室温下搅拌1小时。将溶液在真空中浓缩,并经由制备HPLC用在A中的10%至30%B进行纯化,以提供28mg为其TFA盐的标题化合物。1H NMR(400MHz,CD3OD)δ7.36(m,1H),7.27(m,1H),5.04(s,2H),3.22-3.34(m,2H),3.19-3.21(m,2H),2.95-2.98(m,2H),2.13-2.23(m,4H),0.97(t,3H,J=7.6Hz)。[M+H]测量值为285。
实施例9:3-(4-乙基-4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-基)-3-氧代丙腈
将4-(4-乙基哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮(25mg,0.088mmol)和三乙胺(0.037mL,0.264mmol)溶解于EtOH(3mL)并冷却至0℃,并使其搅拌10分钟。然后将溶解于EtOH(1mL)的2-氰乙酸2,5-二氧代吡咯烷-1-基酯(19mg,0.106mmol)逐滴加入,并使混合物于0℃下搅拌30分钟。将溶液在真空中浓缩,并经由制备HPLC用在A中的10%至50%B进行纯化,以提供16mg为其TFA盐的标题化合物。1H NMR(400MHz,CD3OD)δ7.03(m,1H),6.86(m,1H),4.53(d,2H,J=2.0Hz),3.08-3.11(m,2H),2.93-2.94(m,2H),2.72-2.73(m,2H),2.04-2.09(m,1H),1.91-1.94(m,1H),1.36-1.72(m,4H),0.35(t,3H,J=7.6Hz)。[M+H]测量值为352。
实施例10:4-(戊烷-3-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮
将戊-3-胺(18mg,0.21mmol)加至在带有AcOH(2滴)的MeOH(3mL)中的3-甲酰-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯(40mg,0.13mmol)的溶液。在室温下搅拌90分钟后,加入氰基硼氢化钠(33mg,0.53mmol),并将反应物搅拌另外的3小时。将混合物用NaHCO3饱和溶液淬灭,并用乙酸乙酯萃取。将有机物经由MgSO4干燥,并在真空中浓缩,以提供为澄清油状物的42mg粗3-((戊烷-3-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯,无需进一步纯化即可使用。[M+H]测量值为376。
将于带有1N NaOH(1mL)的MeOH(3mL)中的3-((戊烷-3-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯(42mg,0.11mmol)在50℃下搅拌3小时。将反应物冷却至室温,用1N HCl中和,并在真空中浓缩。将残余物溶解于DMF(3mL)中。加入HATU(71mg,0.187mmol),并将反应物于室温下搅拌2小时。将溶液在真空中浓缩,并经由制备HPLC用在溶剂A中的15%至70%溶剂B梯度液洗脱纯化,以提供为灰白色固体的16mg标题化合物。1H NMR(400MHz,CD3OD)δ8.33(d,1H,J=4.8Hz),7.38(d,1H,J=4.8Hz),7.18(s,1H),4.76(s,2H),4.68-4.80(m,1H),1.60-1.71(m,4H),0.87(s,6H)。[M+H]测量值为244。
实施例11:4-(1-环丙基-3-羟丙基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮
将3-氨基-3-环丙基丙-1-醇(30mg,0.26mmol)加至在带有AcOH(2滴)的MeOH(3mL)中的3-甲酰-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯(39.6mg,0.13mmol)的溶液中。于室温下搅拌90分钟后,加入氰基硼氢化钠(33mg,0.53mmol)并将反应物搅拌另外的3小时。将混合物用NaHCO3饱和溶液淬灭,并用乙酸乙酯萃取。将有机物经由MgSO4干燥,并在真空中浓缩,以提供为黄色油状物的50mg粗3-((1-环丙基-3-羟丙基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯,无需进一步纯化即可使用。[M+H]测量值为404。
将3-((1-环丙基-3-羟丙基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯(50mg,0.12mmol)在带有1N NaOH(1mL)的MeOH(3mL)中于室温下搅拌16小时。将反应物用1N HCl中和,并在真空中浓缩。将残余物溶解于DMF(3mL)。加入HATU(47mg,0.12mmol),并将反应物于室温下搅拌2小时。将溶液在真空中浓缩,并经由制备HPLC用在溶剂A中的15%至70%溶剂B梯度液洗脱纯化,以提供为灰白色固体的16mg标题化合物。1H NMR(400MHz,CD3OD)δ8.34(d,1H,J=4.8Hz),7.35(d,1H,J=4.8Hz),7.28(s,1H),5.10(AB q,2H,J=76.4,16.8Hz),4.08-4.20(m,1H),3.59(t,2H,J=6.4Hz),2.02-2.14(m,2H),1.17-1.30(m,1H),0.73-0.79(m,1H),0.42-0.54(m,2H),0.24-0.33(m,1H)。[M+H]测量值为272。
实施例12:3-((5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)甲基)吡咯烷-1-羧酸叔丁酯
将AcOH(5滴)和3-(氨基甲基)吡咯烷-1-羧酸叔丁酯(90mg,0.45mmol)加入3-甲酰-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯(91mg,0.3mmol)于MeOH(2mL)的溶液中。在室温下搅拌60分钟后,将反应混合物冷却至0℃。加入氰基硼氢化钠(57mg,0.9mmol),并将反应混合物于室温下搅拌另外的3小时。将混合物用水淬灭并用乙酸乙酯萃取。将合并的有机层用NaHCO3饱和溶液和盐水洗涤,经由Na2SO4干燥,并在真空中浓缩,以提供为无色油状物的125mg粗3-(((1-(叔丁氧基羰基)吡咯烷-3-基)甲基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯,无需进一步纯化即可使用。[M+H]测量值为489.40。
将1N LiOH(0.358mL,0.358mmol)于0℃加至3-(((1-(叔丁氧基羰基)吡咯烷-3-基)甲基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯(70mg,0.143mmol)于二噁烷(2mL)的溶液中,并于室温下搅拌4小时。将反应混合物用醚萃取并用1N HCl中和水层,并在真空中浓缩,以提供为灰白色固体的3-(((1-(叔丁氧基羰基)吡咯烷-3-基)甲基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸。[M+H]测量值为375。
将3-(((1-(叔丁氧基羰基)吡咯烷-3-基)甲基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸溶解于DMF(3mL)中。加入HATU(158mg,0.417mmol)和DMAP(40mg,0.278mmol)。并将反应物于室温下搅拌2小时。在真空中浓缩,并经由制备HPLC用在溶剂A中的30%至50%溶剂B梯度液洗脱纯化,以提供为浅棕色油状物的14.5mg标题化合物。1H NMR(400MHz,CD3OD)δ1.46(br.s.,9H)1.70-1.81(m,1H)1.99-2.11(m,1H)2.78(dt,J=14.34,7.11Hz,1H)3.11-3.22(m,1H)3.32-3.36(m,1H)3.47-3.57(m,2H)3.72(d,J=7.33Hz,1H)3.76-3.89(m,1H)5.09(s,2H)7.38(s,1H)7.51(d,J=5.31Hz,1H)8.42(d,J=5.56Hz,1H)。[M+H]测量值为357。
实施例13:4-(吡咯烷-3-基甲基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮
将在二噁烷(0.019mL,0.075mmol)中的4N HCl于0℃加至3-((5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)甲基)吡咯烷-1-羧酸叔丁酯(10mg,0.03mmol)于二噁烷的溶液中,并将反应混合物搅拌1小时,以提供固体物。将固体物过滤并干燥,以提供为其HCl盐的标题化合物(8.0mg)。1H NMR(400MHz,CD3OD)δ1.90(br.s.,1H)2.24(br.s.,1H)2.96(br.s.,1H)3.17(br.s.,2H)3.59(d,J=5.05Hz,1H)3.71-3.83(m,2H)3.87(br.s.,1H)5.18(br.s.,2H)7.64(br.s.,1H)7.80(br.s.,1H)8.55(br.s.,1H)。[M+H]测量值为257。
实施例14:3-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-羧酸叔丁酯
将3-氨基哌啶-1-羧酸叔丁酯(300mg,1.50mmol)于0℃加至3-甲酰-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯(304mg,1.00mmol)于9∶1MeOH-乙酸(2mL)的溶液中,并将反应混合物于室温下搅拌1小时。将氰基三氢硼化钠(314mg,5.00mmol)分批缓慢加入,并将反应混合物于室温下搅拌过夜,用水淬灭,并用乙酸乙酯萃取。将合并的有机层用饱和NaHCO3和盐水洗涤,经由Na2SO4干燥,并在真空中浓缩。将残余物经由硅胶色谱法(30%至70%己烷-EtOAc)纯化,以提供为无色油状物的307mg 3-((1-(叔丁氧基羰基)哌啶-3-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸甲酯。[M+H]测量值为389。
将1N LiOH(2.03mL,2.03mmol)于0℃加至3-((1-(叔丁氧基羰基)哌啶-3-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸甲酯(315mg,0.811mmol)于二噁烷(5mL)的溶液中并于室温下搅拌4小时。将反应混合物在醚和水之间分配,将分离的水层用1N HCl中和,并在真空中浓缩,以提供为灰白色固体的3-((1-(叔丁氧基羰基)哌啶-3-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸。[M+H]测量值为375。
将3-((1-(叔丁氧基羰基)哌啶-3-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸溶解于DMF(5mL)。加入HATU(914mg,2.4mmol)和DMAP(196mg,1.6mmol),并将反应物于室温下搅拌2小时。将溶液在真空中浓缩,并经由制备HPLC用在溶剂A中的30%至50%溶剂B梯度液洗脱纯化,以提供为浅黄色固体的123mg标题化合物。1H NMR(400MHz,CD3OD)δ1.48(s,9H)1.59-1.70(m,1H)1.88(d,J=13.39Hz,1H)1.95-2.02(m,1H)2.06(dd,J=12.25,3.92Hz,1H)2.75(br.s.,1H)3.15(t,J=11.62Hz,1H)4.04-4.20(m,2H)4.51(br.s.,1H)4.93-5.14(m,2H)7.44(s,1H)7.58(d,J=5.31Hz,1H)8.43(d,J=5.56Hz,1H)。[M+H]测量值为357。
实施例15:4-(哌啶-3-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮
将在二噁烷(0.018mL,0.07mmol)中的4N HCl于0℃加至3-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-羧酸叔丁酯(10mg,0.028mmol)于二噁烷的溶液中,并将反应混合物搅拌1小时。以提供固体物。将固体物过滤并干燥,以提供为其HCl盐的标题化合物(5.6mg)。1H NMR(400MHz,CD3OD)δ1.82-2.13(m,2H)2.13-2.31(m,2H)3.02(td,J=13.07,2.91Hz,1H)3.41(d,J=1.77Hz,1H)3.44-3.51(m,2H)4.68-4.84(m,1H)5.00-5.19(m,2H)7.59(s,1H)7.73(d,J=6.06Hz,1H)8.52(d,J=6.06Hz,1H))。[M+H]测量值为257。
实施例16:4-(4-乙基-1-丙酰基哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮
将4-(4-乙基哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮(12mg,0.042mmol)、丙酸(4mg,0.055mmol)、4-二甲基氨基吡啶(10mg,0.084mmol)和HATU(32mg,0.084mmol)于室温溶解于DMF(3mL)中,并使其搅拌3小时。将溶液在真空中浓缩,并经由制备HPLC用在A中的10%至40%B进行纯化,以提供4.6mg为其TFA盐的标题化合物。1H NMR(400MHz,CD3OD)δ7.58(m,1H),7.41(m,1H),5.12(s,2H),3.70-3.74(m,1H),3.59-3.63(m,3H),2.58-2.61(m,1H),2.41-2.43(m,3H),2.21-2.30(m,4H),1.11(t,3H,J=7.6Hz),0.94(t,3H,J=7.6Hz)。[M+H]测量值为341。
实施例17:4-(4-乙基-1-(嘧啶-4-基)哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮
将4-(4-乙基哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮(10mg,0.035mmol)、三乙胺(0.049mL,0.352mmol)以及4-氯嘧啶(8mg,0.070mmol)溶解于DMF(1.5mL),并于140℃微波辐射加热30分钟。将溶液在真空中浓缩,并经由制备HPLC用在A中的10%至40%B进行纯化,以提供6.5mg为其TFA盐的标题化合物。1HNMR(400MHz,CD3OD)δ8.66(s,1H),8.14(dd,1H,J=7.6,1.3Hz),7.51(s,1H),7.37(s,1H),7.11(d,1H,J=7.5Hz),5.14(s,2H),4.27(m,1H),4.11(m,1H),3.86-3.87(m,1H),3.80-3.82(m,1H),2.86(m,1H),2.73(m,1H),2.38(m,1H),2.24-2.31(m,4H),0.99(t,3H,J=7.6Hz)。MS(ES)[M+H]测量值为363。
制备C:(S)-2-氨基-1-(吡咯烷-1-基)丁-1-酮
步骤A:(S)-1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基羧酸叔丁酯
将Et3N(1.920mL,13.78mmol)加至(S)-2-(叔丁氧基羰基氨基)丁酸(1.4g,6.89mmol)、HATU(3.14g,8.27mmol)以及吡咯烷(1.216mL,13.78mmol)于DCM(50mL)的混合物中。将反应混合物于室温下搅拌5小时,然后用NaHCO3饱和水溶液和盐水洗涤。将有机物经由MgSO4干燥并浓缩。经由二氧化硅柱色谱法(MeOH/DCM,0-10%)纯化,以提供为浅黄色油状物的标题化合物(1.75g,99%)。1H NMR(500MHz,CDCl3)δ0.94(t,J=7.57Hz,3H)1.34-1.48(m,9H),1.49-1.68(m,1H)1.68-1.81(m,1H)1.81-1.92(m,2H)1.92-2.03(m,2H)3.34-3.47(m,2H)3.52(dt,J=12.08,7.14Hz,1H)3.65(dt,J=10.13,6.65Hz,1H)4.30-4.42(m,1H)5.35(d,J=8.30Hz,1H)。
步骤B:(S)-2-氨基-1-(吡咯烷-1-基)丁-1-酮
将(S)-1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基羧酸叔丁酯(1.75g,6.83mmol)于50%TFA/DCM(10mL)中搅拌1小时。将反应混合物浓缩并分离为澄清油状物的TFA盐。经由快速柱色谱法(MeOH/DCM,0-10%)纯化,以提供为白色固体的标题化合物(游离碱,0.85g,5.44mmol,79%)。1H NMR(500MHz,CDCl3)δ1.02(t,J=7.45Hz,3H)1.78-2.01(m,6H)3.30-3.46(m,2H)3.51(dt,J=12.20,7.32Hz,1H)3.59(dt,J=10.25,6.59Hz,1H)4.14(t,J=6.10Hz,1H)8.38(br.s.,3H)。
实施例18:(S)-4-(1-氧代-1-(吡咯烷-1-基)丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
步骤A:(S)-4-((1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯
将三乙酰氧基硼氢化钠(279mg,1.315mmol)和(S)-2-氨基-1-(吡咯烷-1-基)丁-1-酮(123mg,0.789mmol)于DCE(2mL)中的混合物于室温下搅拌30分钟。将反应混合物冷却至0℃。加入4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(200mg,0.657mmol)于DCE(2mL)中的溶液,接着加入乙酸(1滴)。将反应物于0℃搅拌30分钟,然后于室温下搅拌3小时。经由二氧化硅柱色谱法(EtOAc/DCM,0-10%)纯化,以提供为黄色油状物的标题化合物(83mg,28.4%)。对于C23H32N4O5,[M+H]计算值为445;测量值为445.5。
步骤B:(S)-4-((1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
将(S)-4-((1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(88mg,0.198mmol)、MeOH(1mL)和THF(1mL)加至带有搅拌子的20mL圆底烧瓶中。加入NaOH(12N,1mL)水溶液,并将反应混合物于53℃下搅拌16小时。将溶剂移除并将生成的残余物进一步经由制备批量操作触发器LC-MS(AcCN/H2O,1-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(6mg,9.17%)。对于C17H22N4O3,[M+H]计算值为331;测量值为331.6。
步骤C:(S)-4-(1-氧代-1-(吡咯烷-1-基)丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
将(S)-4-((1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸(6mg,0.018mmol)加至为搅拌配备的8mL闪烁管中。加入N,N-二甲基甲酰胺(2mL)、HATU(8.29mg,0.022mmol)以及4-甲基吗啉(2.2mg,0.022mmol)并使溶液于室温下搅拌1小时。将溶剂移除并将生成的残余物进一步经由制备批量操作触发器LC-MS(AcCN/H2O,5-90%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色固体的标题化合物(2.8mg,49.4%)。1H NMR(500MHz,CD3OD)δ0.97(t,J=7.32Hz,3H)1.74-1.98(m,5H)1.98-2.14(m,1H)3.08-3.22(m,1H)3.37-3.47(m,1H)3.65-3.77(m,1H)4.07(s,1H)5.05(s,2H)5.62(dd,J=8.54,7.08Hz,1H)7.11(d,J=4.88Hz,1H)7.80(s,1H)8.29(br.s.,1H)。对于C17H20N4O2,[M+H]计算值为313;测量值为313.6。
制备D:(R)-2-氨基-1-(吡咯烷-1-基)丁-1-酮
步骤A:(R)-1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基羧酸叔丁酯
往(R)-2-(叔丁氧基羰基氨基)丁酸(1.5g,7.38mmol)、HATU(3.37g,8.86mmol)和吡咯烷(1.303mL,14.76mmol)于DCM(50mL)中的混合物中加入Et3N(2.057mL,14.76mmol)。将反应混合物于室温下搅拌5小时,然后用NaHCO3饱和水溶液和盐水洗涤。将有机物经由MgSO4干燥并浓缩。经由二氧化硅柱色谱法(MeOH/DCM,0-10%)纯化,以提供为浅黄色油状物的标题化合物(1.6g,85%)。1H NMR(500MHz,CDCl3)δ0.88-1.04(m,3H)1.38-1.48(m,9H)1.52-1.64(m,1H)1.69-1.79(m,1H)1.82-1.92(m,2H)1.92-2.02(m,2H)3.36-3.47(m,2H)3.53(dt,J=12.08,7.14Hz,1H)3.65(dt,J=10.01,6.47Hz,1H)4.30-4.43(m,1H)5.37(d,J=8.30Hz,1H)。
步骤B:(R)-2-氨基-1-(吡咯烷-1-基)丁-1-酮
将在50%TFA/DCM(10mL)中的(R)-1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基羧酸叔丁酯(1.6g,6.24mmol)搅拌1小时。将反应混合物浓缩并分离为澄清油状物的TFA盐。经由二氧化硅柱色谱法(MeOH/DCM,0-10%)纯化,以提供为白色固体的标题化合物(游离碱,0.91g,5.82mmol,79%)。1H NMR(400MHz,CDCl3)δ1.03(t,J=7.45Hz,3H)1.78-2.03(m,6H)3.29-3.46(m,2H)3.46-3.54(m,1H)3.54-3.66(m,1H)4.14(t,J=6.19Hz,1H)。
实施例19:(R)-4-(1-氧代-1-(吡咯烷-1-基)丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
步骤A:(R)-4-((1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯
将三乙酰氧基硼氢化钠(237mg,1.116mmol)和(R)-2-氨基-1-(吡咯烷-1-基)丁-1-酮(131mg,0.837mmol)于DCE(2mL)的混合物中在室温下搅拌30分钟。将反应混合物冷却至0℃。加入4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(200mg,0.657mmol)于DCE(2mL)中的溶液,接着加入乙酸(1滴)。将反应物于0℃下搅拌30分钟,然后在室温下搅拌3小时。经由二氧化硅柱色谱法(EtOAc/DCM,0-10%)纯化,以提供为黄色油状物的标题化合物(260mg,93%)。对于C23H32N4O5,[M+H]计算值为445;测量值为445.5。
步骤B:(R)-4-((1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
将(R)-4-((1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(150mg,0.337mmol)、MeOH(1mL)和THF(1mL)加至带有搅拌子的20mL圆底烧瓶。加入NaOH(12N,1mL)水溶液,并将反应混合物于53℃下搅拌16小时。将溶剂移除,并将生成的残余物进一步经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(8.7mg,0.026mmol,7.80%)。对于C17H22N4O3,[M+H]计算值为331;测量值为331.6。
步骤C:(R)-4-(1-氧代-1-(吡咯烷-1-基)丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
将(S)-4-((1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸(8.7mg,0.026mmol)加至为搅拌配备的8mL闪烁管中。加入N,N-二甲基甲酰胺(2mL)、HATU(12.02mg,0.032mmol)和4-甲基吗啉(3.20mg,0.022mmol),并使溶液于室温下搅拌1小时。将溶剂移除,并将生成的残余物进一步经由制备批量操作触发器LC-MS(AcCN/H2O,5-90%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色固体的标题化合物(1.6mg,19.5%)。1H NMR(500MHz,CD3OD)δ0.88-1.04(m,3H)1.75-1.98(m,4H)1.98-2.05(m,2H)3.43-3.50(m,3H)3.50-3.57(m,1H)5.07(s,2H)5.62(dd,J=8.79,6.83Hz,1H)7.13(d,J=4.88Hz,1H)7.81(s,1H)8.28(d,J=5.37Hz,1H)。对于C17H20N4O2,[M+H]计算值为313;测量值为313.6。
制备E:(R)-2-氨基-3-甲基-1-(吡咯烷-1-基)丁-1-酮
步骤A:(R)-3-甲基-1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基羧酸叔丁酯
往(R)-2-(叔丁氧基羰基氨基)-3-甲基丁酸(1.0g,4.60mmol)、HATU(2.1g,5.52mmol)和吡咯烷(0.812mL,9.21mmol)于DCM(30mL)的混合物中加入Et3N(1.28mL,9.21mmol)。将反应混合物于室温下搅拌5小时,然后用饱和NaHCO3水溶液和盐水洗涤。将有机物经由MgSO4干燥并浓缩。经由二氧化硅柱色谱法(MeOH/DCM,0-10%)纯化,以提供为浅黄色油状物的标题化合物(1.18g,95%)。1H NMR(400MHz,CDCl3)δ0.95(d,J=18.95Hz,3H)0.95(d,J=5.31Hz,3H)1.30-1.53(m,9H)1.77-2.07(m,5H)3.33-3.59(m,3H)3.59-3.80(m,1H)4.25(dd,J=9.35,6.57Hz,1H)5.30(d,J=9.09Hz,1H)。
步骤B:(R)-2-氨基-3-甲基-1-(吡咯烷-1-基)丁-1-酮
将在50%TFA/DCM(10mL)中的(R)-1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基羧酸叔丁酯(1.18g,4.37mmol)搅拌1小时。将反应混合物浓缩并分离为澄清油状物的TFA盐。经由快速柱色谱法(MeOH/DCM,0-10%)纯化,以提供为白色固体的标题化合物(游离碱,0.69g,92%)。1H NMR(400MHz,CDCl3)δ1.08(d,J=7.07Hz,3H)1.06(d,J=7.07Hz,3H)1.77-2.04(m,4H)2.12-2.26(m,1H)3.26-3.45(m,2H)3.45-3.58(m,1H)3.63(dt,J=9.98,6.51Hz,1H)4.01(d,J=5.56Hz,1H)。
实施例20:(R)-4-(3-甲基-1-氧代-1-(吡咯烷-1-基)丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
步骤A:(R)-3-甲基4-((3-甲基-1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁酯
将在DCE(2mL)中的三乙酰氧基硼氢化钠(139mg,0.657mmol)和(R)-2-氨基-3-甲基-1-(吡咯烷-1-基)丁-1-酮(84mg,0.493mmol)的混合物于室温下搅拌30分钟。将反应混合物冷却至0℃。加入4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(100mg,0.329mmol)于DCE(2mL)中的溶液,接着加入乙酸(1滴)。将反应物于0℃下搅拌30分钟,并接着于室温下搅拌3小时。经由二氧化硅柱色谱法(EtOAc/DCM,0-10%)纯化,以提供为黄色油状物的标题化合物(128mg,85%)。对于C24H34N4O5,[M+H]计算值为459;测量值为459.6。
步骤B:(R)-4-((3-甲基-1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
将(R)-4-((3-甲基-1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(134mg,0.292mmol)加至为搅拌配备的8mL闪烁管中。加入NaOH水溶液(12N,2mL)和MeOH(1mL),并将溶液于53℃下搅拌48小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,5-90%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物。
步骤C:(R)-4-(3-甲基-1-氧代-1-(吡咯烷-1-基)丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
以类似于实施例19的步骤C的方式,在THF(2mL)、HATU(133mg,0.351mmol)和4-甲基吗啉(35.5mg,0.351mmol)的混合物中将(R)-4-((3-甲基-1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸环化,并将生成的产物经由制备批量操作触发器LC-MS(AcCN/H2O,1-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(28mg,29.4%来自步骤B的起始材料)。1H NMR(400MHz,CD3OD)δ0.92(d,J=6.57Hz,3H)1.04(d,J=6.32Hz,3H)1.78-1.94(m,3H)1.94-2.02(m,1H)2.02(s,1H)2.45-2.65(m,1H)3.38-3.56(m,2H)3.61-3.79(m,2H)5.04-5.15(m,1H)5.45(d,J=11.12Hz,1H)7.30(d,J=5.56Hz,1H)7.91(s,1H)8.35(d,J=5.56Hz,1H)。对于C18H22N4O2,[M+H]计算值为327;测量值为327.6。
制备F:(R)-2-氨基-4-甲基-1-(吡咯烷-1-基)戊-1-酮
步骤A:(R)-4-甲基-1-氧代-1-(吡咯烷-1-基)戊烷-2-基氨基羧酸叔丁酯
往(R)-2-(叔丁氧基羰基氨基)-4-甲基戊酸(1.0g,4.32mmol)、HATU(1.97g,5.19mmol)和吡咯烷(0.76mL,8.65mmol)于DCM(30mL)的混合物中加入Et3N(1.2mL,8.65mmol)。将反应混合物于室温下搅拌5小时,并接着以饱和NaHCO3水溶液和盐水洗涤。将有机物经由MgSO4干燥并浓缩。经由二氧化硅柱色谱法(MeOH/DCM,0-10%)纯化,以提供为浅黄色油状物的标题化合物(1.17g,95%)。
步骤B:(R)-2-氨基-4-甲基-1-(吡咯烷-1-基)戊-1-酮
将在50%TFA/DCM(10mL)中的(R)-4-甲基-1-氧代-1-(吡咯烷-1-基)戊烷-2-基氨基羧酸叔丁酯搅拌1小时。将反应混合物浓缩并分离为澄清油状物的TFA盐。经由快速柱色谱法(MeOH/DCM,0-10%)纯化,以提供为白色固体的标题化合物(游离碱,0.71g,93%)。1H NMR(400MHz,CDCl3)δ0.96(t,J=6.57Hz,6H)1.42-1.60(m,1H)1.75-2.04(m,6H)3.26-3.44(m,2H)3.45-3.56(m,1H)3.61(dt,J=9.85,6.57Hz,1H)4.15(dd,J=8.84,4.29Hz,1H)。
实施例21:(R)-4-(4-甲基-1-氧代-1-(吡咯烷-1-基)戊烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
步骤A:(R)-4-((4-甲基-1-氧代-1-(吡咯烷-1-基)戊烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯
将三乙酰氧基硼氢化钠(139mg,0.657mmol)和(R)-2-氨基-4-甲基-1-(吡咯烷-1-基)戊-1-酮(91mg,0.493mmol)于DCE(2mL)中的混合物于室温下搅拌30分钟。将反应混合物冷却至0℃。加入3-甲基4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁酯(100mg,0.329mmol)于DCE(2mL)中的溶液,接着加入乙酸(1滴)。将反应物于0℃下搅拌30分钟,并接着于室温下搅拌3小时。经由二氧化硅柱色谱法(EtOAc/DCM,0-10%)纯化,以提供为黄色油状物的标题化合物(160mg,93%)。对于C25H36N4O5,[M+H]计算值为473;测量值为473.7。
步骤B:(R)-4-((4-甲基-1-氧代-1-(吡咯烷-1-基)戊烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
将(R)-3-甲基4-((4-甲基-1-氧代-1-(吡咯烷-1-基)戊烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁酯(160mg,0.339mmol)于氮气下加至为搅拌配备的8mL闪烁管中。加入NaOH水溶液(12N,2mL)和MeOH(1mL),并将溶液于53℃下搅拌48小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,5-90%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物。
步骤C:(R)-4-(4-甲基-1-氧代-1-(吡咯烷-1-基)戊烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
以类似于实施例19的步骤C的方式,在THF(2mL)、HATU(133mg,0.351mmol)和4-甲基吗啉(35.5mg,0.351mmol)的混合物中将(R)-4-((4-甲基-1-氧代-1-(吡咯烷-1-基)戊烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸环化,并将生成的产物经由制备批量操作触发器LC-MS(AcCN/H2O,1-50%)纯化。将馏分收集、浓缩并在真空中干燥,以提供为黄色油状物的标题化合物(53mg,46%来自步骤B的起始材料)。1H NMR(400MHz,CDCl3)δ0.96(t,J=6.57Hz,6H)1.42-1.60(m,1H)1.75-2.04(m,6H)3.26-3.44(m,2H)3.45-3.56(m,1H)3.61(dt,J=9.85,6.57Hz,1H)4.15(dd,J=8.84,4.29Hz,1H)。对于C19H24N4O2,[M+H]计算值为341;测量值为341.6。
制备G:(R)-2-氨基-N-环戊基-3-甲基丁酰胺
步骤A:(R)-1-(环戊基氨基)-3-甲基-1-氧代丁烷-2-基氨基羧酸叔丁酯
往(R)-2-(叔丁氧基羰基氨基)-3-甲基丁酸(0.5g,2.301mmol)、HATU(1.05g,2.76mmol)和环戊胺(0.455mL,4.60mmol)于DCM(20mL)的混合物中加入Et3N(0.642mL,4.60mmol)。将反应混合物于室温下搅拌5小时,用NaHCO3饱和水溶液和盐水洗涤,经由MgSO4干燥并浓缩。经由二氧化硅柱色谱法(MeOH/DCM,0-10%)纯化,以提供标题化合物(0.61g,94%)。
步骤B:(R)-2-氨基-N-环戊基-3-甲基丁酰胺
将在50%TFA/DCM(10mL)中的(R)-1-(环戊基氨基)-3-甲基-1-氧代丁烷-2-基氨基羧酸叔丁酯搅拌1小时。将反应混合物浓缩,并分离为澄清油状物的TFA盐。经由快速柱色谱法(MeOH/DCM,0-10%)纯化,以提供为白色固体的标题化合物(游离碱,0.37g,92%)。1H NMR(400MHz,CDCl3)δ0.96-1.08(m,6H)1.35-1.51(m,1H)1.51-1.74(m,4H)1.90(td,J=12.82,6.19Hz,3H)2.08-2.23(m,1H)3.82(d,J=6.82Hz,1H)4.02-4.21(m,1H)7.32-7.53(m,0H)7.40(d,J=7.07Hz,1H)。
实施例22:(R)-N-环戊基-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
步骤A:(R)-3-甲基4-((1-(环戊基氨基)-3-甲基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁酯
将三乙酰氧基硼氢化钠(104mg,0.493mmol)和(R)-2-氨基-N-环戊基-3-甲基丁酰胺(68.1mg,0.370mmol)于DCE(2mL)的混合物于室温下搅拌30分钟。将反应混合物冷却至0℃。加入4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(75mg,0.246mmol)于DCE(2mL)中的溶液,再加入乙酸(1滴)。将反应混合物于0℃下搅拌30分钟,并接着于室温下搅拌3小时。经由二氧化硅柱色谱法(EtOAc/DCM,0-10%)纯化,以提供为黄色油状物的标题化合物(105mg,90%)。对于C25H36N4O5,[M+H]计算值为473;测量值为473.7。
步骤B:(R)-4-((1-(环戊基氨基)-3-甲基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
将(R)-4-((1-(环戊基氨基)-3-甲基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(105mg,0.222mmol)于氮气下加至为搅拌配备的8mL闪烁管中。加入NaOH水溶液(12N,2mL)和MeOH(1mL),并将溶液于53℃下搅拌48小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,5-90%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物。
步骤C:(R)-N-环戊基-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
以类似于实施例19的步骤C的方式,在THF(2mL)、HATU(101mg,0.267mmol)和4-甲基吗啉(27.0mg,0.267mmol)的混合物中将(R)-4-((1-(环戊基氨基)-3-甲基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸环化,并将生成的产物经由制备批量操作触发器LC-MS(AcCN/H2O,1-50%)纯化。将馏分收集、浓缩并在真空中干燥,以提供为黄色油状物的标题化合物(23mg,30%来自步骤B的起始材料)。1H NMR(400MHz,CD3OD)δ0.99-1.04(m,3H)1.04-1.08(m,3H)1.28-1.38(m,1H)1.42-1.67(m,4H)1.72(br.s.,2H)1.77-2.00(m,2H)2.79-2.90(m,1H)4.02-4.21(m,2H)5.12(d,J=9.35Hz,1H)7.78(d,J=5.31Hz,1H)7.93-8.08(m,1H)8.63(d,J=5.30Hz,1H)。对于C19H24N4O2,[M+H]计算值为341;测量值为341.4。
制备H:(2R,3R)-2-氨基-N-环戊基-3-甲基戊酰胺
步骤A:(2R,3R)-1-(环戊基氨基)-3-甲基-1-氧代戊烷-2-基氨基羧酸叔丁酯
往(2R,3R)-2-(叔丁氧基羰基氨基)-3-甲基戊酸(0.5g,2.162mmol)、HATU(0.986g,2.59mmol)和环戊胺(0.427mL,4.32mmol)于DCM(10mL)的混合物中加入Et3N(0.603mL,4.32mmol)。将反应混合物于室温下搅拌5小时,然后用NaHCO3饱和水溶液和盐水洗涤,将有机物经由MgSO4干燥并浓缩。经由二氧化硅柱色谱法(MeOH/DCM,0-10%)纯化,以提供标题化合物(0.56g,87%)。1H NMR(400MHz,CDCl3)δ0.82-0.89(m,3H)0.92(t,J=7.45Hz,3H)1.32-1.41(m,6H)1.44(s,9H)1.55-1.77(m,3H)1.84-2.04(m,2H)2.99(d,J=4.29Hz,1H)3.96(dd,J=8.72,5.43Hz,1H)4.21(dt,J=13.89,6.95Hz,1H)5.02(br.s.,1H)5.93(br.s.,1H)。
步骤B:(2R,3R)-2-氨基-N-环戊基-3-甲基戊酰胺
将(2R,3R)-1-(环戊基氨基)-3-甲基-1-氧代戊烷-2-基氨基羧酸叔丁酯和50%TFA/DCM(10mL)的混合物搅拌1小时。将反应混合物浓缩,并分离为澄清油状物的TFA盐类。经由快速柱色谱法(MeOH/DCM,0-10%)纯化,以提供为白色固体的标题化合物(游离碱,0.34g,90%)。经由TLC(经由茚三酮染色而显现)得到纯化产物。
实施例23:(2R,3R)-N-环戊基-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)戊酰胺
步骤A:3-甲基4-(((2R,3R)-1-(环戊基氨基)-3-甲基-1-氧代戊烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁酯
将三乙酰氧基硼氢化钠(104mg,0.493mmol)和(2R,3R)-2-氨基-N-环戊基-3-甲基戊酰胺(48.9mg,0.246mmol)于DCE(2mL)中的混合物于室温下搅拌30分钟。将4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(75mg,0.246mmol)加至混合物中。将反应混合物于室温下搅拌1小时并随后浓缩,以提供为粗中间体的标题化合物。对于C26H38N4O5,[M+H]计算值为487;测量值为487.7。
步骤B:4-(((2R,3R)-1-(环戊基氨基)-3-甲基-1-氧代戊烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
将粗4-(((2R,3R)-1-(环戊基氨基)-3-甲基-1-氧代戊烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯加入MeOH(1mL)和NaOH水溶液(12N,2mL)。将反应混合物于53℃下搅拌16小时,然后经由制备批量操作触发器LC-MS(AcCN/H2O,5-90%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供标题化合物。对于C20H28N4O3,[M+H]计算值为373;测量值为373.7。
步骤C:(2R,3R)-N-环戊基-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)戊酰胺
以类似于实施例19的步骤C的方式,在THF(2mL)、HATU(112mg,0.296mmol)和4-甲基吗啉(37.4mg,0.370mmol)的混合物中将4-(((2R,3R)-1-(环戊基氨基)-3-甲基-1-氧代戊烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸环化,并将生成的产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(32mg,37%来自步骤A的起始材料)。1H NMR(400MHz,CD3OD)δ0.61-0.72(m,2H)0.90-1.06(m,5H)1.37-1.66(m,7H)1.66-1.77(m,2H)1.77-1.99(m,4H)3.98-4.22(m,1H)4.85-4.97(m,2H)5.21(d,J=9.35Hz,1H)。对于C20H26N4O2,[M+H]计算值为355;测量值为355.5。
实施例24:(2R,3S)-N-环戊基-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)戊酰胺
步骤A:(2R,3S)-2-((1-(叔丁氧基羰基)-3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)-3-甲基戊酸
将三乙酰氧基硼氢化钠(104mg,0.493mmol)、(2R,3S)-2-氨基-3-甲基戊酸(43.1mg,0.329mmol)和DCM(2mL)加至10mL圆底烧瓶中。将混合物于室温下搅拌30分钟,之后加入在DCM(2mL)中的4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(50mg,0.164mmol)。将反应物于室温下搅拌2小时,再用MeOH淬灭(3滴)。将混合物浓缩,以提供标题化合物,使其无需进一步纯化即可用于下一步骤。对于C21H29N3O6,[M+H]计算值为420;测量值为420.6。
步骤B:4-(((2R,3S)-1-(环戊基氨基)-3-甲基-1-氧代戊烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯
往(2R,3S)-2-((1-(叔丁氧基羰基)-3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)-3-甲基戊酸中加入THF(2mL),接着加入HATU(94mg,0.246mmol)、环戊胺(70.0mg,0.822mmol)和4-甲基吗啉(83mg,0.822mmol)。将悬浮液于43℃搅拌36小时,以提供标题化合物,使其无需进一步纯化即可用于下一步骤。对于C26H38N4O5,[M+H]计算值为487;测量值为487.7。
步骤C:4-(((2R,3S)-1-(环戊基氨基)-3-甲基-1-氧代戊烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
将粗4-(((2R,3S)-1-(环戊基氨基)-3-甲基-1-氧代戊烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯进行浓缩并重新溶解于MeOH(1mL)。加入NaOH(12N,2mL)水溶液,并将反应混合物于53℃搅拌16小时。将产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供标题化合物。对于C20H28N4O3,[M+H]计算值为373;测量值为373.7。
步骤D:(2R,3S)-N-环戊基-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)戊酰胺
以类似于实施例19的步骤C的方式,在THF(2mL)、HATU(94mg,0.246mmol)和4-甲基吗啉(83mg,0.822mmol)的混合物中将4-(((2R,3S)-1-(环戊基氨基)-3-甲基-1-氧代戊烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸环化,并将生成的产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(6mg,10%来自步骤A的起始材料)。1H NMR(500MHz,CD3OD)δ0.89(d,J=6.35Hz,3H)0.95-1.06(m,3H)1.15-1.26(m,1H)1.35-1.45(m,1H)1.45-1.63(m,4H)1.70(br.s.,1H)1.81-2.02(m,2H)2.10-2.19(m,1H)2.28(br.s.,1H)3.34(s,1H)4.02-4.16(m,1H)5.04-5.18(m,1H)5.40-5.56(m,1H)7.29(d,J=5.37Hz,1H)7.90(s,1H)8.34(d,J=5.37Hz,1H)。对于C20H26N4O2,[M+H]计算值为355;测量值为355.5。
实施例25:(R)-N-环戊基-2-环丙基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)乙酰胺
步骤A:(R)-2-((1-(叔丁氧基羰基)-3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)-2-环丙基乙酸
将三乙酰氧基硼氢化钠(104mg,0.493mmol)、(R)-2-氨基-2-环丙基乙酸(37.8mg,0.329mmol)和DCM(2mL)加至10mL圆底烧瓶中。将反应混合物于室温下搅拌30分钟,之后加入在DCM(2mL)中的4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(50mg,0.164mmol)。将反应物于室温下搅拌2小时,然后用MeOH淬灭(3滴)。将混合物浓缩,以提供标题化合物,使其无需进一步纯化即可用于下一步骤。对于C20H25N3O6,[M+H]计算值为404;测量值为404.3。
步骤B:(R)-4-((2-(环戊基氨基)-1-环丙基-2-氧代乙基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯
往(R)-2-((1-(叔丁氧基羰基)-3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)-2-环丙基乙酸中加入THF(2mL),接着加入HATU(94mg,0.246mmol)、环戊胺(70.0mg,0.822mmol)和4-甲基吗啉(83mg,0.822mmol)。将悬浮液于43℃搅拌36小时,以提供标题化合物,使其无需进一步纯化即可用于下一步骤。对于C25H34N4O5,[M+H]计算值为471;测量值为471.5。
步骤C:(R)-4-((2-(环戊基氨基)-1-环丙基-2-氧代乙基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
将粗(R)-4-((2-(环戊基氨基)-1-环丙基-2-氧代乙基氨基)甲基)-1-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯进行浓缩并重新溶解于MeOH(1mL)中。加入NaOH(12N,2mL)水溶液,并将反应混合物于53℃搅拌16小时。将产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供标题化合物。对于C19H24N4O3,[M+H]计算值为357;测量值为357.5。
步骤D:(R)-N-环戊基-2-环丙基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)乙酰胺
以类似于实施例19的步骤C的方式,在THF(2mL)、HATU(94mg,0.246mmol)和4-甲基吗啉(83mg,0.822mmol)的混合物中将(R)-4-((2-(环戊基氨基)-1-环丙基-2-氧代乙基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸环化,并将生成的产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(4.4mg,8%来自步骤A的起始材料)。1H NMR(500MHz,CD3OD)δ0.38(d,J=5.37Hz,1H)0.73(t,J=4.90Hz,1H)0.82(br.s.,1H)1.45-1.57(m,2H)1.60(s,2H)1.73(br.s.,2H)1.83-1.98(m,2H)3.09-3.22(m,1H)3.68-3.77(m,1H)4.13(d,J=5.86Hz,1H)5.48-5.58(m,2H)7.29(d,J=5.37Hz,1H)7.84(s,1H)8.35(br.s.,1H)。对于C19H22N4O2,[M+H]计算值为339;测量值为339.5。
实施例26:(R)-N-环戊基-3,3-二甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
步骤A:(R)-2-((1-(叔丁氧基羰基)-3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)-3,3-二甲基丁酸
将三乙酰氧基硼氢化钠(104mg,0.493mmol)、(R)-2-氨基-3,3-二甲基丁酸(43.1mg,0.329mmol)和DCM(2mL)加至10mL圆底烧瓶中。将混合物于室温下搅拌30分钟,之后加入在DCM(2mL)中的4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(50mg,0.164mmol)。将反应物于室温下搅拌2小时,然后用MeOH淬灭(3滴)。将混合物浓缩,以提供标题化合物,使其无需进一步纯化即可用于下一步骤。对于C21H29N3O6,[M+H]计算值为420;测量值为420.3。
步骤B:(R)-3-甲基4-((1-(环戊基氨基)-3,3-二甲基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁酯
将THF(2mL)、HATU(94mg,0.246mmol)、环戊胺(70.0mg,0.822mmol)和4-甲基吗啉(83mg,0.822mmol)加至(R)-2-((1-(叔丁氧基羰基)-3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)-3,3-二甲基丁酸中,将悬浮液于43℃搅拌36小时,以提供标题化合物,使其无需进一步纯化即可用于下一步骤。对于C26H38N4O5,[M+H]计算值为487;测量值为487.6。
步骤C:(R)-4-((1-(环戊基氨基)-3,3-二甲基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
将粗(R)-4-((1-(环戊基氨基)-3,3-二甲基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯浓缩并重新溶解于MeOH(1mL)中。加入NaOH(12N,2mL)水溶液,并将反应混合物于53℃搅拌16小时。将产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供标题化合物。对于C20H28N4O3,[M+H]计算值为373;测量值为373.6。
步骤D:(R)-N-环戊基-3,3-二甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
以类似于实施例19的步骤C的方式,在THF(2mL)、HATU(94mg,0.246mmol)和4-甲基吗啉(83mg,0.822mmol)的混合物中将(R)-4-((1-(环戊基氨基)-3,3-二甲基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸环化,并将生成的产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(9.2mg,15.8%来自步骤A的起始材料)。1H NMR(400MHz,CD3OD)δ1.16(s,9H)1.36-1.65(m,4H)1.65-1.77(m,2H)1.78-2.05(m,2H)4.11(t,J=6.82Hz,1H)5.30-5.51(m,2H)5.51-5.69(m,1H)7.13-7.31(m,1H)7.25(d,J=5.56Hz,1H)7.87(s,1H)8.32(d,J=5.31Hz,1H)。对于C20H26N4O2,[M+H]计算值为355;测量值为355.6。
实施例27:(R)-N,2-二环戊基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)乙酰胺
步骤A:(R)-2-((1-(叔丁氧基羰基)-3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)-2-环戊基乙酸
将三乙酰氧基硼氢化钠(104mg,0.493mmol)、(R)-2-氨基-2-环戊基乙酸(47.1mg,0.329mmol)和DCM(2mL)加至10mL圆底烧瓶中。将混合物于室温下搅拌30分钟,之后加入在DCM(2mL)中的4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(50mg,0.164mmol)。将反应物于室温下搅拌2小时,然后用MeOH淬灭(3滴)。浓缩混合物,以提供标题化合物,使其无需进一步纯化即可用于下一步骤。对于C22H29N3O6,[M+H]计算值为432;测量值为432.4。
步骤B:(R)-4-((1-环戊基-2-(环戊基氨基)-2-氧基乙基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯
将THF(2mL)、HATU(94mg,0.246mmol)、环戊胺(70.0mg,0.822mmol)和4-甲基吗啉(83mg,0.822mmol)加至(R)-2-((1-(叔丁氧基羰基)-3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)-2-环戊基乙酸中。将悬浮液于43℃搅拌36小时,以提供标题化合物,使其无需进一步纯化即可用于下一步骤。对于C27H38N4O5,[M+H]计算值为499;测量值为499.6。
步骤C:(R)-4-((1-环戊基-2-(环戊基氨基)-2-氧代乙基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
将粗(R)-4-((1-环戊基-2-(环戊基氨基)-2-氧代乙基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯浓缩并重新溶解于MeOH(1mL)中。加入NaOH(12N,2mL)水溶液,并将反应混合物于53℃搅拌16小时。将产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供标题化合物。对于C21H28N4O3,[M+H]计算值为384;测量值为384.6。
步骤D:(R)-N,2-二环戊基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)乙酰胺
以类似于实施例19的步骤C的方式,在THF(2mL)、HATU(94mg,0.246mmol)和4-甲基吗啉(83mg,0.822mmol)的混合物中将(R)-4-((1-环戊基-2-(环戊基氨基)-2-氧代乙基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸环化,并将生成的产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(11mg,18.7%来自步骤A的起始材料)。1H NMR(400MHz,CD3OD)δ1.22-1.34(m,1H)1.34-1.45(m,2H)1.54-1.78(m,10H)1.78-2.00(m,3H)2.65-2.84(m,1H)4.00-4.15(m,1H)5.08(d,J=11.37Hz,1H)5.21(s,1H)5.47(s,1H)7.12-7.36(m,1H)7.24(d,J=5.31Hz,1H)7.86(s,1H)8.32(d,J=5.31Hz,1H)。对于C21H26N4O2,[M+H]计算值为367;测量值为367.6。
实施例28:(R)-N-环戊基-4,4,4-三氟-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
步骤A:(R)-2-((1-(叔丁氧基羰基)-3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)-4,4,4-三氟丁酸
将三乙酰氧基硼氢化钠(104mg,0.493mmol)、2-氨基-4,4,4-三氟丁酸(51.6mg,0.329mmol)和DCM(2mL)加至10mL圆底烧瓶中。将混合物于室温下搅拌30分钟,之后加入在DCM(2mL)中的4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(50mg,0.164mmol)。将反应物于室温下搅拌2小时,然后用MeOH淬灭(3滴)。将混合物浓缩,以提供标题化合物,使其无需进一步纯化即可用于下一步骤。对于C19H22F3N3O6,[M+H]计算值为446;测量值为446.5。
步骤B:(R)-4-((1-(环戊基氨基)-4,4,4-三氟-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯
将THF(2mL)、HATU(94mg,0.246mmol)、环戊胺(70.0mg,0.822mmol)和4-甲基吗啉(83mg,0.822mmol)加至(R)-2-((1-(叔丁氧基羰基)-3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)-4,4,4-三氟丁酸中。将生成的悬浮液于43℃下搅拌36小时,以提供标题化合物,使其无需进一步纯化即可用于下一步骤。对于C24H31F3N4O5,[M+H]计算值为513;测量值为513.6。
步骤C:(R)-4-((1-(环戊基氨基)-4,4,4-三氟-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
将粗(R)-4-((1-(环戊基氨基)-4,4,4-三氟-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯进行浓缩并重新溶解于MeOH(1mL)中。加入NaOH(12N,2mL)水溶液,并将反应混合物于53℃搅拌16小时。将产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供标题化合物。对于C18H21F3N4O3,[M+H]计算值为399;测量值为399.6。
步骤D:(R)-N-环戊基-4,4,4-三氟-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
以类似于实施例19的步骤C的方式,在THF(2mL)、HATU(94mg,0.246mmol)和4-甲基吗啉(83mg,0.822mmol)的混合物中将(R)-4-((1-(环戊基氨基)-4,4,4-三氟-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸环化,并将生成的产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(4.5mg,7.2%来自步骤A的起始材料)。1H NMR(400MHz,CD3OD)δ1.32-1.62(m,4H)1.62-1.78(m,2H)1.82-2.05(m,2H)2.87-3.07(m,1H)3.07-3.21(m,1H)4.10-4.24(m,1H)5.13(d,J=19.20Hz,1H)5.26(d,J=18.95Hz,1H)5.41(dd,J=8.08,5.31Hz,1H)7.24(d,J=5.31Hz,1H)7.90(s,1H)8.36(d,J=5.05Hz,1H)。对于C18H19F3N4O2,[M+H]计算值为381;测量值为381.5。
制备I:(R)-2-氨基-N-环戊基-3-羟基-3-甲基丁酰胺
步骤A:(R)-1-(环戊基氨基)-3-羟基-3-甲基-1-氧代丁烷-2-基氨基羧酸叔丁酯
往(R)-2-(叔丁氧基羰基氨基)-3-羟基-3-甲基丁酸(0.5g,2.144mmol)、HATU(0.978g,2.57mmol)和环戊胺(0.423mL,4.29mmol)于DCM(10mL)的混合物中加入Et3N(0.598mL,4.29mmol)。将反应混合物于室温下搅拌5小时,然后用NaHCO3饱和水溶液和盐水洗涤,将有机物经由MgSO4干燥、浓缩,并经由二氧化硅柱色谱法(MeOH/DCM,0-10%)纯化,以提供标题化合物(0.6g,93%)。
步骤B:(R)-2-氨基-N-环戊基-3-羟基-3-甲基丁酰胺
将(R)-1-(环戊基氨基)-3-羟基-3-甲基-1-氧代丁烷-2-基氨基羧酸叔丁酯和50%TFA/DCM(10mL)的混合物搅拌1小时。将生成的产物浓缩并分离为澄清油状物的TFA盐。经由快速柱色谱法(MeOH/DCM,0-10%)纯化,以提供为白色固体的标题化合物(游离碱,0.37g,93%)。1H NMR(400MHz,DMSO-d6)δ1.13(s,3H)1.23(s,3H)1.40(s,2H)1.44-1.69(m,4H)1.73-2.01(m,2H)3.48(s,1H)3.89-4.16(m,1H)5.33(s,1H)7.87-7.89(m,2H)8.33(d,J=7.33Hz,1H)。
实施例29:(R)-N-环戊基-3-羟基-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
步骤A:(R)-4-((1-(环戊基氨基)-3-羟基-3-甲基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯
将三乙酰氧基硼氢化钠(104mg,0.493mmol)和(R)-2-氨基-N-环戊基-3-羟基-3-甲基丁酰胺(49.4mg,0.246mmol)于DCE(2mL)的混合物于室温下搅拌30分钟。加入4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(75mg,0.246mmol),并将反应混合物于室温下搅拌1小时。反应后,将混合物浓缩,以提供标题化合物。对于C25H36N4O6,[M+H]计算值为489;测量值为489.3。
步骤B:(R)-4-((1-(环戊基氨基)-3-羟基-3-甲基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
往(R)-4-((1-(环戊基氨基)-3-羟基-3-甲基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯中加入MeOH(1mL)和NaOH水溶液(12N,2mL)。将反应混合物于53℃下搅拌16小时,并将生成的产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-90%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供标题化合物。对于C19H26N4O4计算[M+H],375;测量值为374.5。
步骤C:(R)-N-环戊基-3-羟基-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
以类似于实施例19的步骤C的方式,在THF(2mL)、HATU(112mg,0.296mmol)和4-甲基吗啉(37.4mg,0.370mmol)的混合物中将(R)-4-((1-(环戊基氨基)-3-羟基-3-甲基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸环化,并将生成的产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(6.5mg,7.4%来自步骤A的起始材料)。1H NMR(500MHz,CD3OD)δ1.20(s,3H)1.37-1.41(m,3H)1.41-1.79(m,5H)1.85-2.00(m,3H)4.19(s,1H)5.14-5.26(m,1H)5.35(s,1H)5.64-5.77(m,1H)7.22(d,J=5.37Hz,1H)7.89(s,1H)8.31(d,J=5.37Hz,1H)。对于C19H24N4O3计算[M+H],357;测量值为357.5。
制备J:(R)-2-氨基-3-氰基-N-环戊基丙酰胺
步骤A:(R)-3-氰基-1-(环戊基氨基)-1-氧代丙烷-2-基氨基羧酸叔丁酯
往(R)-2-(叔丁氧基羰基氨基)-3-氰丙酸(0.5g,2.334mmol)、HATU(0.986g,2.59mmol)和环戊胺(0.461mL,4.67mmol)于DCM(10mL)的混合物中加入Et3N(0.651mL,4.67mmol)。将反应混合物于室温下搅拌5小时,然后用NaHCO3饱和水溶液和盐水洗涤,将有机物经由MgSO4干燥并浓缩。经由二氧化硅柱色谱法(MeOH/DCM,0-10%)纯化,以提供标题化合物(0.61g,93%)。1H NMR(400MHz,CD3OD)δ1.50(s,9H)1.57-1.73(m,4H)1.79-1.87(m,3H)1.89-2.02(m,1H)2.05-2.19(m,3H)2.76-2.95(m,1H)3.87(t,J=7.07Hz,1H)。
步骤B:(R)-2-氨基-3-氰基-N-环戊基丙酰胺
将(R)-3-氰基-1-(环戊基氨基)-1-氧代丙烷-2-基氨基羧酸叔丁酯和50%TFA/DCM(10mL)的混合物搅拌1小时。反应后,将混合物浓缩,以提供为澄清油状物的标题化合物(TFA盐,0.265g,41%)。经由TLC(经由茚三酮染色而显现)使产物纯化。
制备K:5-氯-4-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸
步骤A:5-氯-3-碘代-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-甲醛
往5-氯-1H-吡咯并[2,3-b]吡啶-4-甲醛(5.0g,27.7mmol)于EtOH(100mL)的溶液中加入碘(8.43g,33.2mmol)、碘化钠(4.98g,33.2mmol)和NaOH水溶液(1N,35mL,35mmol)。在室温下搅拌4小时后,将反应混合物用水(200mL)稀释。经由过滤收集橙色沉淀物,并在真空下干燥。将固体溶解于DMF(60mL)中并缓慢加入氢化钠(60%,1.33g,33.2mmol)。将深红色溶液于室温下搅拌30分钟。加入甲苯磺酰氯(5.81g,30.5mmol),并将混合物于室温下搅拌2小时。将混合物用EtOAc稀释,并将反应物用水淬灭。将有机物分离,用NaHSO3(0.1N)水溶液和盐水洗涤,经由MgSO4干燥并浓缩。经由硅胶色谱法(3∶1∶1己烷/DCM/EtOAc)纯化,以提供为黄色固体的标题化合物(8.96g,70%)。1H NMR(500MHz,DMSO-d6)δ3.15(s,3H),8.24(d,J=8.5Hz,2H),8.81(d,J=8.5Hz,2H),9.17(s,1H),9.38(s,1H),11.81(s,1H)。对于C15H10ClIN2O3S,[M+H]计算值为461,463;测量值为461,463。
步骤B:5-氯-4-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸
将氯化锂(1.05g,24.7mmol)和一水合甲酸锂(1.73g,24.7mmol)于氮气下在干燥可密封的管中合并。加入DMF(20mL)、5-氯-3-碘代-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-甲醛(3.8g,8.25mmol)、乙酸酐(1.56mL,16.5mmol)和乙酸钯(185mg,0.83mmol)。将DIPEA(2.87mL)加入,并将反应管密封并于52℃加热3小时。用MeOH/DCM(20%)吸收反应混合物并过滤,以移除不溶的黑色的碳材料。将黄色溶液在真空中浓缩,溶解于MeOH/DCM(10%)中并用HCl水溶液(0.1N)清洗。将水层用MeOH/DCM(10%,2x)萃取。将有机物合并,经由MgSO4干燥,并在真空中浓缩。经由硅胶色谱法(10-15%MeOH/DCM)纯化,以提供为浅棕黄色固体的标题化合物(2.34g,75%)。1H NMR(500MHz,CD3OD)δ3.15(s,3H),8.24(d,J=8.5Hz,2H),8.81(d,J=8.5Hz,2H),9.17(s,1H),9.38(s,1H),11.81(s,1H)。对于C16H11ClN2O5S,[M+H]计算值为379、381;测量值为379、381。
实施例30:(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-氰基-N-环戊基丙酰胺
步骤A:(R)-5-氯-4-((3-氰基-1-(环戊基氨基)-1-氧代丙烷-2-基氨基)甲基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸
将三乙酰氧基硼氢化钠(26.5mg,0.125mmol)和(R)-2-氨基-3-氰基-N-环戊基丙酰胺(22.70mg,0.125mmol)于DCM(1mL)的混合物在室温下搅拌10分钟。将反应混合物冷却至0℃。加入在DCM(1mL)中的5-氯-4-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸(30mg,0.063mmol)的溶液。将反应混合物于0℃下搅拌20分钟,然后浓缩,以提供标题化合物。对于C26H28ClN5O5S,[M+H]计算值为544;测量值为544.2。
步骤B:(R)-2-(6-氯-3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-氰基-N-环戊基丙酰胺
将(R)-5-氯-4-((3-氰基-1-(环戊基氨基)-1-氧代丙烷-2-基氨基)甲基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸、THF(5mL)、HATU(28.6mg,0.075mmol)和4-甲基吗啉(19.01mg,0.188mmol)的混合物于室温下搅拌2小时。将产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-90%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供标题化合物。对于C25H24ClN5O4S,[M+H]计算值为526;测量值为526.2。
步骤C:(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-氰基-N-环戊基丙酰胺
将(R)-2-(6-氯-3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-氰基-N-环戊基丙酰胺于MeOH(2mL)的溶液中加入NaOH水溶液(1N,0.5mL)。将反应混合物搅拌20分钟,并将产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(0.5mg,2.1%来自步骤A的起始材料)。1H NMR(400MHz,CD3OD)δ1.37-1.72(m,4H)1.83-1.95(m,4H)3.22-3.26(m,2H)3.69-3.76(m,1H)5.11(s,1H)5.14-5.17(m,1H)5.18(s,1H)7.88(s,1H)8.27(s,1H)。对于C18H18ClN5O2,[M+H]计算值为372;测量值为372.4。
实施例31:N-环戊基-1-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)环戊烷甲酰胺
步骤A:1-((1-(叔丁氧基羰基)-3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)环戊烷甲酸
将在DCM(2mL)中的三乙酰氧基硼氢化钠(104mg,0.493mmol)和1-氨基环戊烷甲酸(42.4mg,0.329mmol)加至10mL圆底烧瓶中。将反应混合物于室温下搅拌30分钟,之后加入在DCM(2mL)中的4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(50mg,0.164mmol)。将反应物于室温下搅拌2小时,然后用MeOH淬灭(3滴)。将混合物浓缩,以提供标题化合物,使其无需进一步纯化即可用于下一步骤。对于C21H27N3O6,[M+H]计算值为418;测量值为418.3。
步骤B:4-((1-(环戊基氨甲酰基)环戊基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯
将THF(2mL)、HATU(94mg,0.246mmol)、环戊胺(70.0mg,0.822mmol)和4-甲基吗啉(83mg,0.822mmol)加至1-((1-(叔丁氧基羰基)-3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)环戊烷甲酸中。将悬浮液于43℃下搅拌36小时,以提供标题化合物,使其无需进一步纯化即可用于下一步骤。对于C26H36N4O5,[M+H]计算值为485;测量值为485.4。
步骤C:4-((1-(环戊基氨甲酰基)环戊基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
将粗3-甲基4-((1-(环戊基氨甲酰基)环戊基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁酯浓缩并重新溶解于MeOH(1mL)中。加入NaOH(12N,2mL)水溶液,并将反应混合物于53℃搅拌16小时。将产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供标题化合物。对于C20H26N4O3,[M+H]计算值为371;测量值为371.6。
步骤D:N-环戊基-1-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)环戊烷甲酰胺
以类似于实施例19的步骤C的方式,在THF(2mL)、HATU(94mg,0.246mmol)和4-甲基吗啉(83mg,0.822mmol)的混合物中将4-((1-(环戊基氨甲酰基)环戊基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸环化,并将产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(2.7mg,4.8%来自步骤A的起始材料)。1H NMR(500MHz,CD3OD)δ1.45(d,J=7.32Hz,1H)1.52(d,J=4.88Hz,1H)1.61(br.s.,1H)1.79(br.s.,2H)1.82-1.91(m,1H)1.96-2.02(m,1H)2.06-2.23(m,4H)2.50(d,J=13.18Hz,1H)2.98(br.s.,1H)3.21-3.29(m,2H)3.38-3.42(m,1H)4.03-4.17(m,1H)5.29(s,1H)7.20(br.s.,1H)7.75(s,1H)8.31(br.s.,1H)。对于C20H24N4O2,[M+H]计算值为353;测量值为353.5。
制备L:(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸
步骤A:(R)-2-((5-氯-3-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)甲氨基)-3-甲基丁酸叔丁酯
将三乙酰氧基硼氢化钠(517mg,2.44mmol)和D-缬氨酸叔丁酯、HCl盐(512mg,2.44mmol)于DCM(15mL)中合并。将反应混合物于室温下搅拌20分钟并冷却至0℃。加入5-氯-4-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸(660mg,1.74mmol),并将反应物于0℃下搅拌1小时。将溶液在真空中浓缩,以提供为黄色泡沫物的标题化合物,使其无需进一步纯化即可用于下一步骤。
步骤B:(R)-2-(6-氯-3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸叔丁酯
将(R)-2-((5-氯-3-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)-3-甲基丁酸叔丁酯重新溶解于THF(40mL)。加入HATU(994mg,2.61mmol)和N-甲基吗啉(291μL,2.61mmol)并将反应混合物于50℃下搅拌2小时。加入另外的HATU(497mg,1.30mmol)和N-甲基吗啉(85μL,1.30mmol),并将反应混合物于50℃下搅拌另外的2小时。然后将反应混合物冷却,用EtOAc稀释,并用盐水洗涤。将有机物经由MgSO4干燥,并在真空中浓缩。经由硅胶色谱法(1∶2∶2EtOAc/己烷/DCM)纯化,以提供为黄色固体的标题化合物(660mg,73%来自步骤A的起始材料)。1H NMR(500MHz,CDCl3)δ0.80(d,J=7.0Hz,3H),1.01(d,J=7.0Hz,3H),1.36(s,9H),2.29-2.36(m,1H),2.34(s,3H),4.77-5.04(m,3H),7.44(d,J=8.5Hz,2H),8.06(d,J=8.5Hz,2H),8.28(s,1H),8.47(s,1H)。对于C25H28ClN3O5S,[M+H]计算值为518,520;测量值为518,520。
步骤C:(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸
将(R)-2-(6-氯-3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸叔丁酯(650mg,1.25mmol)、EtOH(4mL)和NaOH水溶液(1N,2mL)的混合物于室温下搅拌40分钟。然后将混合物用DCM稀释,并用盐水洗涤。将有机物经由MgSO4干燥,并在真空中浓缩。经由硅胶色谱法(5%MeOH/DCM)纯化,以提供黄色油状物(425mg),将其溶解于50%TFA/DCM中。将溶液于室温下搅拌1小时,浓缩并在真空下干燥,以提供为黄色固体的标题化合物(360mg,93%)。1H NMR(500MHz,CD3OD)δ0.91(d,J=7.0Hz,3H),1.11(d,J=7.0Hz,3H),2.36-2.47(m,1H),4.80-5.08(m,3H),7.76(s,1H),8.19(s,1H)。对于C14H14ClN3O3,[M+H]计算值为308,310;测量值为308,310。
实施例32:(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-(氰甲基)-3-甲基丁酰胺
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(10mg,0.032mmol)加至为搅拌配备的8mL闪烁管中。将THF(0.5mL)、2-氨基乙腈(3.64mg,0.065mmol)和HATU(14.83mg,0.039mmol)加入并将溶液于25℃下搅拌1小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(3.8mg,33.8%)。1H NMR(400MHz,CD3OD)δ0.85-0.97(m,3H)1.02(d,J=6.57Hz,1H)1.07(d,J=6.32Hz,2H)2.53(dt,J=11.18,6.54Hz,1H)3.52-3.86(m,2H)4.89-5.04(m,1H)5.07(d,J=11.37Hz,1H)5.51(d,J=10.86Hz,1H)7.80-7.89(m,1H)8.13-8.34(m,1H)。对于C16H16ClN5O2,[M+H]计算值为346;测量值为346.4。
实施例33:1-((R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)吡咯烷-3-甲腈
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(10mg,0.032mmol)加至为搅拌配备的8mL闪烁管中。将THF(0.5mL)、吡咯烷-3-甲腈(3.12mg,0.032mmol)和HATU(14.83mg,0.039mmol)加入并将溶液于25℃下搅拌1小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(1.3mg,10.4%)。1H NMR(400MHz,CD3OD)δ0.92(s,3H)1.00-1.12(m,3H)2.27-2.35(m,1H)2.56(d,J=6.57Hz,1H)3.40(d,J=6.82Hz,1H)3.51-3.68(m,1H)3.74(d,J=6.57Hz,1H)3.79-3.94(m,1H)3.96-4.03(m,1H)4.88-5.00(m,2H)5.03-5.23(m,1H)5.39-5.48(m,1H)7.87(d,J=12.63Hz,1H)8.21-8.30(m,1H)。对于C19H20ClN5O2,[M+H]计算值为386;测量值为386.4。
实施例34:(R)-1-(2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)哌啶-4-甲腈
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(10mg,0.032mmol)加至为搅拌配备的8mL闪烁管中。将THF(0.5mL)、哌啶-4-甲腈(3.58mg,0.032mmol)和HATU(14.83mg,0.039mmol)加入并将溶液于25℃下搅拌1小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在其空中干燥,以提供为黄色油状物的标题化合物(3.3mg,25.4%)。1H NMR(400MHz,CD3OD)δ0.84-0.93(m,3H)0.96-1.08(m,3H)1.42-1.60(m,1H)1.72-1.82(m,2H)1.82-2.00(m,1H)2.49-2.66(m,1H)2.92-3.07(m,1H)3.49-3.73(m,2H)3.78-4.00(m,1H)4.00-4.11(m,1H)4.90(d,J=7.58Hz,1H)4.92-5.01(m,1H)5.53(dd,J=10.86,3.54Hz,1H)7.82-7.92(m,1H)8.15-8.30(m,1H)。对于C20H22ClN5O2,[M+H]计算值为400;测量值为400.4。
实施例35:(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-(4-氰苯基)-3-甲基丁酰胺
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(10mg,0.032mmol)加至为搅拌配备的8mL闪烁管中。将THF(0.5mL)、4-氨基苄腈(7.68mg,0.065mmol)和HATU(14.83mg,0.039mmol)加入并将溶液于25℃下搅拌1小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(2mg,15.1%)。1H NMR(400MHz,CD3OD)δ0.90-1.03(m,3H)1.07-1.15(m,3H)2.59(dt,J=11.24,6.63Hz,1H)5.01(d,J=19.45Hz,1H)5.21(d,J=11.12Hz,1H)5.42(d,J=19.45Hz,1H)7.64-7.66(m,1H)7.66-7.68(m,1H)7.80-7.82(m,1H)7.82-7.84(m,1H)7.86(s,1H)8.25(s,1H)。对于C21H18ClN5O2,[M+H]计算值为408;测量值为408.4。
实施例36:(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-(3-氰苯基)-3-甲基丁酰胺
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(10mg,0.032mmol)加至为搅拌配备的8mL闪烁管中。将THF(0.5mL)、3-氨基苄腈(7.68mg,0.065mmol)和HATU(14.83mg,0.039mmol)加入并将溶液于25℃下搅拌1小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(1.8mg,13.58%)。1H NMR(400MHz,CD3OD)δ1.00(d,J=6.60Hz,3H)1.12(d,J=6.57Hz,3H)2.60(s,1H)5.02(d,J=19.71Hz,1H)5.20(d,J=11.12Hz,1H)5.43(d,J=19.71Hz,1H)7.43(dt,J=7.77,1.42Hz,1H)7.48(t,J=7.96Hz,1H)7.81-7.85(m,1H)7.86(s,1H)8.08(t,J=1.64Hz,1H)8.25(s,1H)。对于C21H18ClN5O2,[M+H]计算值为408;测量值为408.4。
实施例37:(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-((S)-1-氰基丁烷-2-基)-3-甲基丁酰胺
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(10mg,0.032mmol)加至为搅拌配备的8mL闪烁管中。将THF(0.5mL)、(S)-3-氨基戊腈(3.19mg,0.032mmol)和HATU(14.83mg,0.039mmol)加入并将溶液于25℃下搅拌1小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(3.1mg,24.6%)。1H NMR(400MHz,CD3OD)δ0.93(d,J=6.57Hz,3H)0.97(t,J=7.33Hz,3H)1.07(d,J=6.57Hz,3H)1.51-1.69(m,2H)2.44-2.58(m,2H)2.58-2.72(m,1H)4.07(br.s.,1H)4.86-4.97(m,1H)5.08(d,J=11.12Hz,1H)5.31(d,J=19.71Hz,1H)7.84(s,1H)8.23(s,1H)。对于C19H22ClN5O2,[M+H]计算值为388;测量值为388.4。
实施例38:(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-((R)-1-氰基丁烷-2-基)-3-甲基丁酰胺
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(10mg,0.032mmol)加至为搅拌配备的8mL闪烁管中。将THF(0.5mL)、(R)-3-氨基戊腈(3.19mg,0.032mmol)和HATU(14.83mg,0.039mmol)加入并将溶液于25℃下搅拌1小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(2.9mg,23.01%)。1H NMR(400MHz,CD3OD)δ0.82(t,J=7.45Hz,3H)0.89-0.99(m,3H)1.11(d,J=6.57Hz,3H)1.44-1.68(m,2H)2.41-2.56(m,1H)2.63(dd,J=16.93,7.33Hz,1H)2.76(dd,J=16.93,5.05Hz,1H)3.99(d,J=10.61Hz,1H)4.95(d,J=19.96Hz,1H)5.05(d,J=11.37Hz,1H)5.35(d,J=19.71Hz,1H)7.85(s,1H)8.20-8.27(m,1H)。对于C19H22ClN5O2,[M+H]计算值为388;测量值为388.4。
实施例39:(R)-1-(2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)氮杂环丁烷-3-甲腈
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(10mg,0.032mmol)加至为搅拌配备的8mL闪烁管中。将THF(0.5mL)、氮杂环丁烷-3-甲腈(2.7mg,0.032mmol)、4-甲基吗啉(4.93mg,0.049mmol)和HATU(14.83mg,0.039mmol)加入并将溶液于25℃下搅拌1小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为半固体的标题化合物(3.7mg,30.6%)。1H NMR(400MHz,CD3OD)δ0.94(t,J=6.32Hz,3H)1.07(dd,J=18.19,6.32Hz,3H)2.44-2.59(m,1H)3.47-3.79(m,1H)4.15-4.40(m,2H)4.57(dt,J=9.73,4.99Hz,1H)4.63-4.78(m,1H)4.84(d,J=19.71Hz,1H)5.06-5.30(m,2H)7.82(d,J=11.37Hz,1H)8.25(d,J=5.56Hz,1H)。对于C18H18ClN5O2,[M+H]计算值为372;测量值为372.4。
制备M:(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3,3-二甲基丁酸
步骤A:(R)-4-((1-(苄氧基)-3,3-二甲基-1-氧代丁烷-2-基氨基)甲基)-5-氯-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸
将三乙酰氧基硼氢化钠(86mg,0.407mmol)、(R)-2-氨基-3,3-二甲基丁酸苄酯(130mg,0.407mmol)和DCM(2mL)加至10mL圆底烧瓶中。将混合物于室温下搅拌10分钟,再冷却至0℃。将5-氯-4-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸(130mg,0.271mmol)加入,并将反应混合物于0℃下搅拌20分钟,以提供标题化合物。对于C29H30ClN3O6S,[M+H]计算值为584;测量值为584.0。
步骤B:(R)-2-(6-氯-3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3,3-二甲基丁酸苄酯
将粗(R)-4-((1-(苄氧基)-3,3-二甲基-1-氧代丁烷-2-基氨基)甲基)-5-氯-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸于HATU(124mg,0.326mmol)和4-甲基吗啉(82mg,0.814mmol)中回流加热3小时。随后将反应混合物浓缩并且在真空中干燥,以提供标题化合物。对于C29H28ClN3O5S,[M+H]计算值为566;测量值为566.0。
步骤C:(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3,3-二甲基丁酸
将粗(R)-2-(6-氯-3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3,3-二甲基丁酸苄酯溶解于MeOH/THF(50%,5mL)中。加入NaOH水溶液(1N,2mL)。将反应混合物于50℃下搅拌16小时并经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(34mg,38.9%来自步骤A的起始材料)。1H NMR(400MHz,CD3OD)δ1.22-1.32(m,9H)4.92(br.s.,1H)5.18(d,J=18.95Hz,1H)5.33(d,J=18.95Hz,1H)7.88(s,1H)8.29(s,1H)。对于C15H16ClN3O3,[M+H]计算值为322;测量值为322.5。
实施例40:(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-(2-氰乙基)-3,3-二甲基丁酰胺
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3,3-二甲基丁酸(5mg,0.016mmol)加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、3-氨基丙腈(1.089mg,0.016mmol)、HOBt(3.57mg,0.023mmol)、EDC(4.47mg,0.023mmol)和N,N-二甲基吡啶-4-胺(1.898mg,0.016mmol)加入并将溶液于25℃下搅拌4小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化。将馏分收集、浓缩,并且在其空中干燥,以提供为黄色油状物的标题化合物(3.2mg,55.1%)。1H NMR(500MHz,CD3OD)δ1.19(s,9H)2.63-2.72(m,2H)3.38-3.53(m,2H)4.89(br.s.,1H)5.29(d,J=19.04Hz,1H)5.41(d,J=19.00Hz,2H)7.85(s,1H)8.24(s,1H)8.55(d,J=4.88Hz,1H)。对于C18H20ClN5O2,[M+H]计算值为374;测量值为374.5。
实施例41:(R)-1-(2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3,3-di甲基丁酰基)氮杂环丁烷-3-甲腈
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3,3-二甲基丁酸(25mg,0.078mmol)于氮气下加至为搅拌配备的8mL闪烁管中。将THF(0.5mL)、氮杂环丁烷-3-甲腈盐酸盐(18.45mg,0.155mmol)、HATU和4-甲基吗啉(11.79mg,0.117mmol)加入并将溶液于25℃下搅拌1小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,15-40%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色半固体的标题化合物(4.1mg,13.7%)。1H NMR(400MHz,CD3OD)δ1.17(s,9H)3.50-3.78(m,1H)4.17(br.s.,1H)4.25-4.37(m,1H)4.41-4.69(m,2H)5.17-5.30(m,2H)5.44(s,1H)7.87(br.s.,1H)8.25(s,1H)。对于C19H20ClN5O2,[M+H]计算值为386;测量值为386.4。
制备N:5-氟-4-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸
步骤A:(5-氟-1H-吡咯并[2,3-b]吡啶-4-基)甲醇
将5-氟-1H-吡咯并[2,3-b]吡啶-4-甲酸甲酯(2.4g,12.36mmol)于氮气下加至烘干的为搅拌配备的200mL圆底烧瓶。加入THF(100mL)并将无色溶液冷却至0℃。加入氢化铝锂(27.2mL,27.2mmol)并将溶液于0℃下搅拌3小时。将反应物用EtOAc(100mL)淬灭;加入盐水(100mL),并用EtOAc萃取水相三次。将有机物经由Na2SO4干燥并浓缩,以提供为黄色细粉的标题化合物(2.01g,98%)。1H NMR(400MHz,CD3OD)δ4.96(d,J=1.26Hz,2H)6.72(d,J=3.54Hz,1H)7.44(d,J=3.54Hz,1H)8.06(d,J=2.78Hz,1H)。对于C8H7FN2O,[M+H]计算值为167;测量值为167.5。
步骤B:5-氟-1H-吡咯并[2,3-b]吡啶-4-甲醛
将在THF(100mL)中的(5-氟-1H-吡咯并[2,3-b]吡啶-4-基)甲醇(2.01g,12.10mmol)于氮气下加至装有搅拌棒的250mL圆底烧瓶中。加入二氧化锰(10.52g,121mmol)并将反应混合物于60℃下搅拌2小时。将有机物经由硅藻土垫过滤,用EtOAc(100mL)冲洗并浓缩。将生成的固体用EtOAc(50mL)湿磨并过滤,以提供为浅黄色固体的标题化合物(1.3g,65.5%)。1H NMR(400MHz,CD3OD)δ4.59(s,1H)5.34(d,J=3.54Hz,1H)5.86-6.08(m,1H)6.58(d,J=3.28Hz,1H)。对于C8H5FN2O,[M+H]计算值为165;测量值为165.5。
步骤C:5-氟-3-碘代-1H-吡咯并[2,3-b]吡啶-4-甲醛
往5-氯-1H-吡咯并[2,3-b]吡啶-4-甲醛(2.45g,14.93mmol)于EtOH(20mL)的溶液中加入碘(4.55g,17.91mmol)、碘化钠(2.68g,17.91mmol)和NaOH水溶液(1N,15mL)。将反应混合物在25℃下搅拌4小时,并用NaHSO3(0.1N)水溶液稀释。经由过滤收集橙色沉淀物,并在真空下干燥,以提供为黄色固体的标题化合物(6.54g,82%)。对于C8H4FIN2O,[M+H]计算值为291;测量值为291.5。
步骤D:5-氟-3-碘代-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-甲醛
往5-氟-3-碘代-1H-吡咯并[2,3-b]吡啶-4-甲醛于DMF(12mL)的溶液中加入NaOH(0.716g,17.91mmol)。将深红色溶液搅拌30分钟,之后加入4-甲苯-1-磺酰氯(3.13g,16.42mmol)。将反应混合物搅拌2小时,随后用EtOAc稀释,并且用水和盐水洗涤。将萃取物经由MgSO4干燥并浓缩。经由二氧化硅柱色谱法(DCM,100%)纯化,以提供为浅黄色固体的标题化合物(3.65g,55%)。1H NMR(400MHz,DMSO-d6)δ2.36(s,3H)7.45(m,J=8.08Hz,2H)8.02(m,J=8.34Hz,2H)8.42(s,1H)8.59(d,J=2.53Hz,1H)11.13(s,1H)。对于C15H10FIN2O3S,[M+H]计算值为445;测量值为445.1。
步骤E:5-氟-4-甲酰基-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸
将氯化锂(0.472g,11.14mmol)和甲酸锂(0.579g,11.14mmol)在可密封的干燥管中合并。加入DMF(10mL)、5-氟-3-碘代-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-甲醛(1.650g,3.71mmol)、乙酸酐(0.702mL,7.43mmol)和二乙酰氧基钯(0.083g,0.371mmol)。将N-乙基-N-异丙基丙-2-胺(1.294mL,7.43mmol)加入,并将混合物密封并于56℃加热3小时。用MeOH/DCM(20%)吸收反应混合物并过滤。将黄色溶液浓缩,并将残余物溶解于MeOH/DCM(10%)并用HCl水溶液(0.1N)洗涤。将水层再萃取两次。将有机物合并,经由MgSO4干燥,并浓缩为橙色油状物,将其于醚(300mL)中湿磨。过滤沉淀物,并且在真空中干燥,以提供为浅黄色固体的标题化合物(1.15g,77%)。1H NMR(400MHz,DMSO-d6)δ2.37(s,3H)7.47(d,J=8.08Hz,2H)8.10(d,J=8.10Hz,2H)8.54-8.65(m,2H)10.60(s,1H)13.45(br.s.,1H)。对于C15H10FIN2O3S,[M+H]计算值为363;测量值为363.4。
制备O:(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸
步骤A:(R)-4-((1-叔丁氧基-3-甲基-1-氧代丁烷-2-基氨基)甲基)-5-氟-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸
将三乙酰氧基硼氢化钠(1.143g,5.39mmol)、(R)-2-氨基-3-甲基丁酸叔丁酯盐酸盐(1.131g,5.39mmol)和DCM(20mL)的混合物于室温下搅拌10分钟。将反应混合物冷却至0℃。加入5-氟-4-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸酯(1.299g,3.60mmol)并将反应物于0℃下搅拌20分钟,以提供标题化合物。对于C25H30FN3O6S,[M+H]计算值为520;测量值为520.2。
步骤B:(R)-2-(6-氟-3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸叔丁酯
将粗(R)-4-((1-叔丁氧基-3-甲基-1-氧代丁烷-2-基氨基)甲基)-5-氟-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸于HATU(2.60g,7.19mmol)和4-甲基吗啉(1.091g,10.79mmol)中回流加热3小时。经由LC-MS使反应并不完全。加入HATU(1.37g,mmol,3.79mmol)和4-甲基吗啉(1.091g,10.79mmol)并将反应混合物回流搅拌16小时。反应后,将混合物用NaHCO3(饱和)水溶液洗涤并用DCM萃取。将有机物用盐水洗涤,经由Na2SO4干燥,并浓缩成棕色油状物。经由二氧化硅柱色谱法(EtOAc/DCM,0-20%)纯化,以提供为白色泡沫物的标题化合物(0.933g,51.7%)。1H NMR(400MHz,DMSO-d6)δ0.80(d,J=6.57Hz,3H)1.02(d,J=6.57Hz,3H)1.39(s,9H)2.31-2.39(m,4H)4.77(d,J=10.61Hz,1H)5.02(d,J=7.58Hz,2H)7.46(d,J=7.83Hz,2H)8.08(d,J=8.34Hz,2H)8.29(s,1H)8.44(d,J=2.78Hz,1H)。对于C25H28FN3O5S,[M+H]计算值为502;测量值为502.3。
步骤C:(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸叔丁酯
往(R)-2-(6-氟-3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸叔丁酯(933mg,1.860mmol)于MeOH(4mL)的搅拌溶液中加入NaOH水溶液(1N,2mL)。将反应混合物于25℃下搅拌40分钟。将反应物在DCM和盐水之间分配。将有机物经由MgSO4干燥并浓缩。经由二氧化硅柱色谱法(MeOH/DCM,0-5%)纯化,以提供为黄色油状物的标题化合物(0.39g,60.4%)。对于C18H22FN3O3,[M+H]计算值为348;测量值为348.5。
步骤D:(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸
将在DCM/TFA(50%,10mL)中的(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸叔丁酯搅拌1小时,浓缩并且在真空中干燥,以提供为淡棕色固体的标题化合物(0.32g,59.1%)。1H NMR(400MHz,DMSO-d6)δ0.84(d,J=6.30Hz,3H)1.04(d,J=6.32Hz,3H)2.39(dt,J=10.61,6.57Hz,1H)4.83(d,J=10.61Hz,1H)5.04(d,J=9.60Hz,2H)7.98(s,1H)8.26(s,1H)12.39(br.s.,1H)。对于C14H14FN3O3,[M+H]计算值为292;测量值为292.5。
实施例42:(R)-1-(2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)氮杂环丁烷-3-甲腈
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(60mg,0.206mmol)加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、氮杂环丁烷-3-甲腈盐酸盐(0.309,36.6mg)、HOBt(47.3mg,0.309mmol)、EDC(59.2mg,0.309mmol)和N,N-二甲基吡啶-4-胺(37.7mg,0.309mmol)加入并将溶液于25℃下搅拌4小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为TFA盐的标题化合物。使用二氧化硅柱色谱法(MeOH/DCM,0-10%)将残余物进一步纯化,提供为白色固体的标题化合物(游离碱,25.2mg,34.4%)。1H NMR(400MHz,DMSO-d6)δ0.78(dd,J=6.57,3.79Hz,3H)0.95(dd,J=13.01,6.44Hz,3H)1.09(t,J=6.95Hz,1H)3.53-3.86(m,1H)3.94-4.10(m,1H)4.10-4.29(m,2H)4.29-4.48(m,1H)4.87(dd,J=18.82,8.21Hz,1H)4.96-5.14(m,2H)7.99(dd,J=5.43,2.40Hz,1H)8.25(t,J=2.78Hz,1H)12.39(br.s.,1H)。对于C18H18FN5O2,[M+H]计算值为356;测量值为356.5。
实施例43:(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、3-(甲基氨基)丙腈(0.077,6.5mg)、HOBt(11.83mg,0.077mmol)、EDC(14.81mg,0.077mmol)和N,N-二甲基吡啶-4-胺(9.44mg,0.077mmol)加入并将溶液于25℃下搅拌4小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化。将馏分收集并冻干,以提供为黄色油状物的标题化合物(6.1mg,33.1%)。1H NMR(400MHz,CD3OD)δ0.79-0.93(m,3H)0.97-1.06(m,3H)2.49-2.67(m,1H)2.71-2.80(m,2H)3.00(s,1H)3.24(s,2H)3.57-4.02(m,2H)4.99(s,1H)5.08-5.22(m,1H)5.52-5.63(m,1H)7.80-7.96(m,1H)8.16(d,J=3.03Hz,1H)。对于C18H20FN5O2,[M+H]计算值为358;测量值为358.4。
实施例44:(2R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基-N-(四氢呋喃-3-基)丁酰胺
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、四氢呋喃-3-胺(0.077,6.7mg)、HOBt(11.83mg,0.077mmol)、EDC(14.81mg,0.077mmol)和N,N-二甲基吡啶-4-胺(9.44mg,0.077mmol)加入并将溶液于25℃下搅拌4小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化。将馏分收集并冻干,以提供为白色固体的标题化合物(7.3mg,39.3%)。1H NMR(400MHz,CD3OD)δ0.93(d,J=6.57Hz,3H)1.04(dd,J=6.57,2.78Hz,3H)1.74-1.95(m,1H)2.21(d,J=7.83Hz,1H)2.42-2.54(m,1H)3.50-3.67(m,1H)3.69-3.97(m,3H)4.37(td,J=3.85,1.89Hz,1H)4.96-5.12(m,2H)5.36-5.52(m,1H)7.86(s,1H)8.17(d,J=3.28Hz,1H)。对于C18H21FN4O3,[M+H]计算值为361;测量值为361.4。
实施例45:(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基-N-(1,1-二氧代四氢噻吩-3-基)丁酰胺
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、1,1-二氧代四氢噻吩-3-基胺(10.4mg,0.077)、HOBt(11.83mg,0.077mmol)、EDC(14.81mg,0.077mmol)和N,N-二甲基吡啶-4-胺(9.44mg,0.077mmol)加入并将溶液于25℃下搅拌4小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化。将馏分收集并冻干,以提供为白色固体的标题化合物(5.1mg,24.3%)。1H NMR(400MHz,CD3OD)δ0.93(dd,J=6.57,1.26Hz,3H)1.05(dd,J=6.32,3.79Hz,3H)2.06-2.28(m,1H)2.40-2.59(m,2H)2.98(td,J=12.57,7.45Hz,1H)3.04-3.18(m,1H)3.21-3.29(m,1H)3.35-3.53(m,1H)4.51-4.66(m,1H)4.95-5.12(m,2H)5.40(dd,J=19.20,13.39Hz,1H)7.83-7.89(m,1H)8.17(dd,J=3.28,1.52Hz,1H)。对于C18H21FN4O4S,[M+H]计算值为409;测量值为409.3。
实施例46:(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基-N-(2-(甲磺酰基)乙基)丁酰胺
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)于氮气下加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、2-(甲磺酰基)乙胺盐酸盐(8.2mg,0.051mmol)、HOBt(11.83mg,0.077mmol)、EDC(14.81mg,0.077mmol)和N,H-二甲基吡啶-4-胺(9.44mg,0.077mmol)加入并将溶液于25℃下搅拌4小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化。将馏分收集并冻干,以提供为白色固体的标题化合物(8mg,39.2%)。1H NMR(400MHz,CD3OD)δ0.91(d,J=6.82Hz,3H)1.05(d,J=6.32Hz,3H)2.50(dq,J=17.94,6.57Hz,1H)2.92(s,3H)3.22-3.28(m,1H)3.33-3.38(m,1H)3.61(dt,J=14.40,6.57Hz,1H)3.73(dt,J=14.40,6.57Hz,1H)4.94-5.13(m,2H)5.19-5.40(m,1H)7.85(s,1H)8.17(d,J=3.28Hz,1H)。对于C17H21FN4O4S,[M+H]计算值为398;测量值为398.3。
制备P:(1,1-二氧代-六氢-6-噻喃-4-基)-胺盐酸盐
将苄基-(1,1-二氧代-六氢-6-噻喃-4-基)胺(500mg,2.089mmol)和钯/碳(111mg,1.045mmol)于氮气下加至为搅拌配备的100mL圆底烧瓶中。将甲醇(15mL)和HCl水溶液(4N,0.172mL,2.089mmol)加入,并将溶液于60℃下搅拌48小时。将反应混合物经由硅藻土过滤并浓缩,以提供为橙色固体的标题化合物(241mg,62.1%)。1H NMR(400MHz,DMSO-d6)δ1.88-2.12(m,2H)2.26(d,J=11.87Hz,2H)3.08-3.22(m,2H)3.23-3.29(m,2H)3.39(br.s.,1H)8.34(br.s.,2H)。
实施例47:(R)-N-(1,1-二氧代-六氢-6-噻喃)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基-N-4-基)丁酰胺
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)于氮气下加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、(1,1-二氧代-六氢-6-噻喃-4-基)胺盐酸盐(10mg,0.051mmol)、HOBt(11.83mg,0.077mmol)、EDC(14.81mg,0.077mmol)和N,N-二甲基吡啶-4-胺(9.44mg,0.077mmol)加入并将溶液于25℃下搅拌4小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化。将馏分收集并冻干,以提供为黄色油状物的标题化合物(6.4mg,29.4%)。1H NMR(500MHz,CD3OD)δ0.93(d,J=6.83Hz,3H)1.04(dd,J=6.35,2.93Hz,3H)1.61-1.80(m,1H)1.89-2.01(m,1H)2.06-2.30(m,4H)2.36-2.54(m,2H)3.32-3.38(m,1H)4.19-4.38(m,1H)4.93-5.11(m,2H)5.45(dd,J=18.79,5.13Hz,1H)7.86(s,1H)8.17(d,J=2.93Hz,1H)。对于C19H23FN4O4S,[M+H]计算值为423;测量值为423.3。
实施例48:4-{(1R)-1-[(1,1-二氧代硫代吗啉-4-基)羰基]-2-甲基丙基}-6-氟-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、1,1-二氧化硫代吗啉盐酸盐(8.84mg,0.51mmol)、HOBt(11.83mg,0.077mmol)、EDC(14.81mg,0.077mmol)和N,N-二甲基吡啶-4-胺(9.44mg,0.077mmol)加入并将溶液于25℃下搅拌4小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化。将馏分收集并冻干,以提供为白色固体的标题化合物(9.8mg,46.6%)。1H NMR(400MHz,CD3OD)δ0.92(d,J=6.82Hz,3H)1.02(d,J=6.32Hz,3H)2.60(dt,J=10.61,6.57Hz,1H)2.90-3.03(m,1H)3.03-3.25(m,3H)3.86-4.01(m,1H)4.13(ddd,J=14.78,8.59,2.40Hz,1H)4.21-4.41(m,2H)4.92-5.06(m,1H)5.06-5.18(m,1H)5.57(d,J=10.61Hz,1H)7.89(s,1H)8.18(d,J=3.28Hz,1H)。对于C18H21FN4O4S,[M+H]计算值为409;测量值为409.3。
实施例49:(R)-N-(环丙基甲氧基)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰胺
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、O-(环丙基甲基)羟基胺盐酸盐(6.4mg,0.051mmol)、HOBt(11.83mg,0.077mmol)、EDC(14.81mg,0.077mmol)和N,N-二甲基吡啶-4-胺(9.44mg,0.077mmol)加入并将溶液于25℃下搅拌4小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化。将馏分收集并冻干,以提供为白色固体的标题化合物(5mg,23%)。1H NMR(400MHz,CD3OD)δ0.16-0.24(m,2H)0.39-0.55(m,2H)0.93(d,J=6.57Hz,3H)1.05(d,J=6.32Hz,3H)1.06-1.15(m,1H)2.53(dt,J=11.24,6.51Hz,1H)3.55-3.73(m,2H)4.94(d,J=11.37Hz,1H)5.07(d,J=19.20Hz,1H)5.46(d,J=18.44Hz,1H)7.86(s,1H)8.17(d,J=3.28Hz,1H)。对于C18H21FN4O3,[M+H]计算值为361;测量值为361.4。
制备Q:3,3-二氟环戊胺
步骤A:3,3-二氟环戊基氨基羧酸叔丁酯
往3-氧代环戊基氨基羧酸叔丁酯(0.5g,2.509mmol)于DCM(12mL)的溶液中于0℃逐滴加入DeoxofluorTM(0.658mL,5.02mmol)。在加入完成后,使反应混合物温热至室温,并搅拌18小时。将反应混合物缓慢倒入冰冷的NaHCO3(饱和)水溶液中。将水层用DCM萃取3次。将合并的有机层经由MgSO4干燥、浓缩并且在其空中干燥。经由二氧化硅柱色谱法(MeOH/DCM,0-5%)纯化,以提供为黄色油状物的标题化合物(0.52g,94%)。
步骤B:3,3-二氟环戊胺
将3,3-二氟环戊基氨基羧酸叔丁酯和DCM/TFA(50%,7mL)的混合物于25℃下搅拌30分钟。将反应混合物浓缩下来并在其空中干燥,以提供为橙色半固体、TFA盐的标题化合物(0.51g,99%)。1H NMR(400MHz,DMSO-d6)δ1.69-1.88(m,1H)2.00-2.22(m,3H)2.22-2.38(m,1H)2.56(d,J=6.32Hz,1H)3.71(d,J=5.31Hz,1H)8.20(br.s.,3H)。
实施例50:(2R)-N-(3,3-二氟环戊基)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰胺
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)于氮气下加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、3,3-二氟环戊胺(11.2mg,0.051mmol)、HOBt(11.83mg,0.077mmol)、EDC(14.81mg,0.077mmol)和N,N-二甲基吡啶-4-胺(9.44mg,0.077mmol)加入并将溶液于25℃下搅拌4小时。经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化反应混合物。将馏分收集并冻干,以提供为棕色油状物的标题化合物(8mg,39.4%)。1H NMR(500MHz,CD3OD)δ0.93(d,J=6.83Hz,3H)1.04(dd,J=6.35,2.93Hz,3H)1.62-1.80(m,1H)1.87-2.02(m,1H)2.14-2.28(m,2H)2.35-2.58(m,2H)3.35(s,1H)4.22-4.35(m,1H)4.94-5.10(m,2H)5.45(dd,J=18.79,5.13Hz,1H)7.86(s,1H)8.17(d,J=2.93Hz,1H)。对于C19H21F3N4O2,[M+H]计算值为395;测量值为395.4。
制备R:3-(氟甲基)氮杂环丁烷-3-甲腈、TFA盐
步骤A:3-氰基-3-(氟甲基)氮杂环丁烷-1-羧酸叔丁酯
将二异丙基胺(0.659mL,4.66mmol)于氮气下加至为搅拌配备的烘干的25mL圆底烧瓶中。将THF(5mL)加入,并将无色溶液冷却至0℃。将n-BuLi(2.92mL,4.66mmol)加至此溶液,并将溶液于0℃下搅拌30分钟。将溶液冷却至-78℃,并加入3-氰基氮杂环丁烷-1-羧酸叔丁酯(0.5g,2.74mmol)于THF(3mL)的溶液,并将溶液于-78℃下搅拌30分钟。将氟溴甲烷(0.403g,3.57mmol)于-78℃逐滴加入。将反应混合物搅拌30分钟,然后使其温热至25℃并搅拌16小时。用NH4Cl水溶液(5mL)于0℃淬灭反应混合物并用DCM(3x)萃取。将萃取物经由Na2SO4干燥。经由二氧化硅柱色谱法(MeOH/DCM,0-5%)纯化,以提供为黄色油状物的标题化合物(0.52g,94%)。
步骤B:3-(氟甲基)氮杂环丁烷-3-甲腈,TFA盐
将3-氰基-3-(氟甲基)氮杂环丁烷-1-羧酸叔丁酯和DCM/TFA(50%,5mL)于25℃下搅拌30分钟。将反应混合物浓缩并于高度真空下干燥,以提供为橙色半固体的标题化合物(145mg,0.687mmol,25%)。1H NMR(400MHz,CDCl3)δ1.47(dd,J=5.05,2.02Hz,9H)4.03(br.s.,2H)4.29(br.s.,2H)4.62(br.s.,1H)4.73(br.s.,1H)。
实施例51:(R)-3-(氟甲基)-1-(3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰基)氮杂环丁烷-3-甲腈
将(R)-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸(80mg,0.293mmol)于氮气下加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、3-(氟甲基)氮杂环丁烷-3-甲腈(93mg,0.439mmol)、HOBt(67.2mg,0.439mmol)、EDC(84mg,0.439mmol)和N,N-二甲基吡啶-4-胺(53.6mg,0.439mmol)加入,将溶液于25℃下搅拌4小时。经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化反应混合物。将馏分收集并冻干,以提供为白色固体的标题化合物(34.5mg,25.3%)。1H NMR(400MHz,DMSO-d6)δ0.78(dd,J=6.57,3.79Hz,3H)0.97(dd,J=12.88,6.32Hz,3H)2.30-2.41(m,1H)3.99(dd,J=9.98,4.42Hz,1H)4.22(d,J=9.35Hz,2H)4.36(s,1H)4.62-4.71(m,1H)4.76-4.88(m,2H)4.87-5.03(m,1H)5.02-5.09(m,1H)7.09(t,J=4.80Hz,1H)7.88(dd,J=5.56,2.27Hz,1H)8.27(t,J=5.31Hz,1H)12.25(d,J=8.84Hz,1H)。对于C19H20FN5O2,[M+H]计算值为370;测量值为370.5。
制备S:3-氰基-3-甲基氮杂环丁烷,TFA盐
步骤A:3-氰基-3-甲基氮杂环丁烷-1-羧酸叔丁酯
将二异丙基胺(1.318mL,9.33mmol)于氮气下加至为搅拌配备的、烘干的25mL圆底烧瓶中。将THF(10mL)加入,并将无色溶液冷却至0℃。将在己烷中的n-BuLi(1.6N,5.83mL,9.33mmol)逐滴加入,并将溶液于0℃下搅拌30分钟。将溶液冷却至-78℃,并加入3-氰基氮杂环丁烷-1-羧酸叔丁酯(1g,5.49mmol)于THF(3mL)的溶液,并将溶液于-78℃下搅拌30分钟。将碘甲烷(0.445mL,7.13mmol)于-78℃逐滴加入。将反应混合物搅拌30分钟;然后使其缓慢温热至25℃并搅拌16小时。用NH4Cl水溶液(5mL)于0℃淬灭反应混合物并用DCM(3次)萃取。将萃取物经由Na2SO4干燥。经由二氧化硅柱色谱法(MeOH/DCM,0-5%)纯化,以提供为黄色油状物的标题化合物(0.35g,32%)。1H NMR(500MHz,CDCl3)δ1.45(s,9H)1.67(s,3H)3.80(d,J=8.30Hz,2H)4.29(d,J=8.79Hz,2H)。
步骤B:3-氰基-3-甲基氮杂环丁烷、TFA盐
将3-氰基-3-甲基氮杂环丁烷-1-羧酸叔丁酯(0.345g,1.758mmol)和DCM/TFA(50%,7mL)的混合物于25℃下搅拌30分钟。将反应混合物浓缩,并且在真空中干燥,以提供为橙色半固体的标题化合物(0.22g,1.139mmol,64.8%)。1H NMR(400MHz,DMSO-d6)δ1.65(s,3H)3.92(d,J=11.12Hz,2H)4.34(d,J=11.12Hz,2H)9.23(br.s.,2H)。
实施例52:(R)-1-(2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)-3-甲基氮杂环丁烷-3-甲腈
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、3-氰基-3-甲基氮杂环丁烷(15mg,0.077mmol)、HOBt(11.83mg,0.077mmol)、EDC(14.81mg,0.077mmol)和N,N-二甲基吡啶-4-胺(9.44mg,0.077mmol)加入并将溶液于25℃下搅拌4小时。经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化反应混合物。将馏分收集并冻干,以提供为白色固体的标题化合物(9mg,47.3%)。1H NMR(400MHz,DMSO-d6)δ0.79(dd,J=6.69,2.91Hz,3H)0.96(dd,J=9.09,6.57Hz,3H)1.41-1.73(m,3H)2.26-2.44(m,1H)3.85(dd,J=15.66,9.85Hz,1H)4.06(d,J=9.35Hz,2H)4.61(s,1H)4.88(dd,J=19.20,6.82Hz,1H)5.03(d,J=11.12Hz,1H)5.07-5.18(m,1H)7.99(t,J=3.16Hz,1H)8.25(t,J=2.65Hz,1H)12.40(br.s.,1H)。对于C19H20FN5O2,[M+H]计算值为370;测量值为370.5。
实施例53:(R)-3-甲基-1-(3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰基)氮杂环丁烷-3-甲腈
将(R)-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸(80mg,0.293mmol)加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、3-氰基-3-甲基氮杂环丁烷(85mg,0.439mmol)、HOBt(67.2mg,0.439mmol)、EDC(84mg,0.439mmol)和N,N-二甲基吡啶-4-胺(53.6mg,0.439mmol)加入并将溶液于25℃下搅拌4小时。将馏分收集并冻干,以提供为白色固体的标题化合物(31.5mg,30.6%)。1HNMR(400MHz,DMSO-d6)δ0.78(dd,J=6.82,3.28Hz,3H)0.96(dd,J=8.59,6.32Hz,3H)1.44-1.68(m,3H)2.26-2.44(m,1H)3.84(dd,J=9.47,5.18Hz,1H)3.99-4.14(m,1H)4.21(dd,J=9.47,5.68Hz,1H)4.34-4.65(m,1H)4.85(dd,J=19.45,5.56Hz,1H)4.96-5.11(m,2H)7.08(d,J=5.05Hz,1H)7.86(d,J=4.04Hz,1H)8.26(dd,J=4.80,3.28Hz,1H)12.22(br.s.,1H)。对于C19H21N5O2,[M+H]计算值为352;测量值为352.5。
制备T:带有2,2,2-三氟乙酸(1∶1)的(R)-2-((3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)丁酸化合物
步骤A:(R)-4-((1-叔丁氧基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯
将三乙酰氧基硼氢化钠(9.86mmol)和(R)-2-氨基丁酸叔丁酯盐酸盐(5.59mmol)加至100mL的圆底烧瓶中,然后加入DCE(20mL)。将反应混合物于室温下搅拌30分钟并冷却至0℃。加入4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(3.29mmol)于DCE(20mL)的溶液。将反应混合物于0℃下搅拌30分钟,并于室温搅拌3小时。经由二氧化硅柱色谱法(EtOAc/DCM,0-10%)纯化,以提供为黄色油状物的标题化合物(1.4g,95%)。对于C23H33N3O6,[M+H]计算值为448;测量值为448.6。
步骤B:带有2,2,2-三氟乙酸(1∶1)的(R)-2-((3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)丁酸化合物
将(R)-4-((1-叔丁氧基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(1.45g,3.24mmol)和DCM(10mL)加至为搅拌配备的100mL圆底烧瓶中。加入TFA(10mL)并将反应混合物于室温下搅拌30分钟。将反应混合物浓缩并且在真空中干燥,以提供为黄色油状物的标题化合物(1.3g,99%)(TFA盐)。对于C14H17N3O4,[M+H]计算值为292;测量值为292.6。
实施例54至74
根据下列的一般程序A制造实施例54至74的化合物。
将(R)-2-((3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)丁酸(43.4mg,0.149mmol)和HATU(68.0mg,0.179mmol)加至为搅拌配备的8mL闪烁管中。加入THF(2mL)、4-甲基吗啉(0.049mL,0.447mmol)和合适的胺NHR1R2(0.447mmol)。将悬浮液于室温下搅拌4小时且然后浓缩,以提供粗中间体A,随后将其再溶解于MeOH(1mL)中。加入NaOH水溶液(12N,2mL)并且将反应混合物于53℃下搅拌16小时。经由制备批量操作触发器LC-ms(AcCN/H2O,1-50%)纯化残余物。将馏分收集、浓缩、并且在真空中干燥,以提供中间体B,在THF(2mL)、HATU(68.0mg,0.179mmol)和4-甲基吗啉(0.049mL,0.447mmol)的混合物中于室温下将中间体B环化4至16小时。经由制备批量操作触发器LC-MS(AcCN/H2O,1-50%)纯化产物。将馏分收集、浓缩,并且在真空中干燥,以提供标题化合物。
实施例54:(R)-4-(1-吗啉代-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
使用吗啉作为胺NHR1R2(2.1mg,4.2%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.96(t,J=7.45Hz,3H)1.99-2.13(m,2H)3.43-3.51(m,1H)3.53-3.62(m,2H)3.62-3.73(m,4H)5.06(d,J=10.86Hz,2H)5.66-5.78(m,1H)7.21(d,J=5.31Hz,1H)7.86(s,1H)8.32(d,J=5.31Hz,1H)。对于C17H20N4O3,[M+H]计算值为329;测量值为329.6。
实施例55:(R)-4-(1-(4-甲基哌嗪-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
使用1-甲基哌嗪作为胺NHR1R2(3.2mg,6.3%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ-0.52(t,J=7.33Hz,3H)0.42-0.60(m,2H)1.33(s,3H)1.43(d,J=12.88Hz,3H)1.58-1.74(m,1H)1.84-1.93(m,3H)1.93-2.05(m,2H)4.28(s,1H)5.64(d,J=5.31Hz,1H)6.34(s,1H)6.81(d,J=5.05Hz,1H)。对于C18H23N5O2,[M+H]计算值为342;测量值为342.6。
实施例56:4-((2R)-1-(3-羟基吡咯烷-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
使用1-吡咯烷-3-醇作为胺NHR1R2(16mg,32.7%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.90-1.08(m,3H)1.82-2.12(m,4H)2.91(s,1H)3.41-3.67(m,2H)3.74(t,J=11.60Hz,2H)4.28-4.50(m,1H)4.85-4.98(m,2H)7.13(d,J=5.31Hz,1H)7.81(t,J=3.41Hz,1H)8.28(d,J=5.81Hz,1H)。对于C17H20N4O3,[M+H]计算值为329;测量值为329.6。
实施例57:(R)-N-环戊基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
使用环戊胺作为NHR1R2(6.3mg,13%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.98(q,J=7.50Hz,3H)1.38-1.52(m,2H)1.52-1.63(m,2H)1.63-1.79(m,2H)1.80-2.01(m,2H)2.12-2.17(m,2H)3.99-4.19(m,1H)5.23(dd,J=9.35,6.82Hz,1H)5.27-5.37(m,1H)5.48(s,2H)7.23(d,J=5.56Hz,1H)7.85(s,1H)8.32(d,J=5.56Hz,1H)。对于C18H22N4O2,[M+H]计算值为327;测量值为327.6。
实施例58:4-((2R)-1-(3-(4-氟苯基)吡咯烷-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
使用3-(4-氟苯基)吡咯烷作为胺NHR1R2(14mg,23.1%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.89-1.06(m,3H)1.80(s,2H)2.19-2.39(m,2H)3.33-3.55(m,2H)3.56-3.65(m,1H)3.68-3.83(m,1H)3.84-3.96(m,1H)3.98-4.24(m,1H)5.03-5.35(m,2H)6.68-6.83(m,1H)6.86-6.99(m,1H)6.99-7.09(m,2H)7.10-7.37(m,1H)7.78-7.95(m,1H)8.34(d,J=5.31Hz,1H)。对于C23H23FN4O2,[M+H]计算值为407;测量值为407.6。
实施例59:4-((2R)-1-(3-(二甲基氨基)吡咯烷-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
使用N,N-二甲基吡咯烷-3-胺作为NHR1R2(20mg,37.8%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.87-1.05(m,3H)1.88-2.12(m,2H)2.12-2.26(m,1H)2.43(d,J=8.84Hz,1H)2.64-2.85(m,3H)2.85-3.02(m,4H)3.43-3.68(m,1H)3.68-3.90(m,1H)3.90-4.03(m,1H)4.03-4.26(m,0H)4.99-5.19(m,2H)5.51-5.71(m,1H)7.08-7.25(m,1H)7.79-7.92(m,1H)8.32(d,J=5.31Hz,1H)。对于C19H25N5O2,[M+H]计算值为356;测量值为356.6。
实施例60:4-((2R)-1-(3-(甲氧基甲基)吡咯烷-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
使用3-(甲氧基甲基)吡咯烷作为胺NHR1R2(12mg,22.6%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.98(td,J=7.39,1.89Hz,3H)1.62-1.80(m,1H)1.85-2.12(m,5H)2.35-2.60(m,1H)3.32-3.35(m,3H)3.37-3.51(m,2H)3.52-3.70(m,1H)3.70-3.85(m,1H)5.06-5.29(m,2H)5.53-5.69(m,1H)7.19-7.35(m,1H)7.89(s,1H)8.34(d,J=5.31Hz,1H)。对于C19H24N4O3,[M+H]计算值为357;测量值为357.6。
实施例61:4-((2R)-1-(3-甲基哌啶-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
使用3-甲基哌啶作为胺NHR1R2(10.8mg,21.3%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.71(d,J=6.32Hz,1H)0.83-1.04(m,7H)1.14(br.s.,1H)1.68(d,J=10.36Hz,2H)1.81-2.07(m,2H)2.54-2.77(m,1H)2.95-3.10(m,1H)4.01(d,J=14.65Hz,1H)4.20-4.51(m,1H)4.89-5.04(m,1H)5.04-5.18(m,1H)5.71-5.87(m,1H)7.19-7.26(m,1H)7.89(d,J=4.80Hz,1H)8.33(d,J=5.31Hz,1H)。对于C19H24N4O2,[M+H]计算值为341;测量值为341.6。
实施例62:(R)-4-(1-(4-(2-羟基丙烷-2-基)哌啶-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
使用2-(哌啶-4-基)丙-2-醇作为胺NHR1R2(10mg,17.5%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.80(s,3H)0.85(s,3H)0.92-1.00(m,3H)1.43-1.56(m,1H)1.60(d,J=13.89Hz,1H)1.77(d,J=12.88Hz,1H)1.83-1.95(m,2H)1.95-2.06(m,2H)2.48-2.66(m,1H)2.86-3.07(m,1H)4.16(d,J=15.66Hz,1H)4.64(d,J=14.15Hz,1H)4.87-5.03(m,1H)5.03-5.19(m,1H)5.75(t,J=7.58Hz,1H)7.23(d,J=5.31Hz,1H)7.81-7.94(m,1H)8.23-8.37(m,1H)。对于C21H28N4O3,[M+H]计算值为385;测量值为385.6。
实施例63:(R)-4-(1-(4-(甲基磺酰基)哌嗪-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
使用1-(甲基磺酰基)哌嗪作为胺NHR1R2(7.3mg,12.1%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.97(t,J=7.45Hz,3H)1.85-2.06(m,2H)2.75(s,3H)3.06(br.s.,1H)3.09-3.19(m,1H)3.26(dd,J=3.16,1.64Hz,2H)3.68(br.s.,1H)3.74(br.s.,1H)3.79(br.s.,2H)4.96-5.14(m,2H)5.76(dd,J=8.34,6.82Hz,1H)7.23(d,J=5.31Hz,1H)7.89(s,1H)8.32(d,J=5.56Hz,1H)。对于C18H23N5O4S,[M+H]计算值为406;测量值为406.6。
实施例64:(R)-4-(1-氧代-1-(4-(吡啶-2-基)哌嗪-1-基)丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
使用1-(吡啶-2-基)哌嗪作为胺NHR1R2(3步骤,5.2%),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.88-1.04(m,3H)1.93-2.09(m,2H)3.54-3.63(m,1H)3.69(d,J=11.12Hz,1H)3.72-3.87(m,3H)3.87-3.95(m,2H)3.98(br.s.,1H)5.05(q,J=19.28Hz,2H)5.80(dd,J=8.34,6.82Hz,1H)6.99(t,J=6.69Hz,1H)7.14(d,J=5.05Hz,1H)7.33(d,J=9.35Hz,1H)7.84(s,1H)7.92(dd,J=6.32,1.26Hz,1H)8.01(ddd,J=9.22,7.20,1.77Hz,1H)8.29(d,J=5.30Hz,1H)。对于C22H24N6O2,[M+H]计算值为405;测量值为405.6。
实施例65:(R)-N-环丙基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
使用环丙胺作为胺NHR1R2(1.7mg,2.2%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.44-0.53(m,2H)0.96(t,J=7.33Hz,3H)2.66-2.73(m,4H)3.71-3.81(m,1H)5.05-5.29(m,1H)5.44-5.52(m,2H)7.52(dd,J=8.46,4.42Hz,1H)8.43(dd,J=8.34,1.26Hz,1H)8.73(d,J=3.54Hz,1H)。对于C16H18N4O2,[M+H]计算值为299;测量值为299.6。
实施例66:(R)-N-(环丙基甲基)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
使用环丙基甲胺作为NHR1R2(9mg,11.2%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.13-0.22(m,2H)0.40-0.48(m,2H)0.90-1.06(m,4H)1.86-2.01(m,1H)2.05-2.16(m,1H)3.06(d,J=6.82Hz,2H)5.04-5.13(m,1H)5.13-5.22(m,1H)5.28(dd,J=9.47,6.69Hz,1H)7.14(d,J=5.05Hz,1H)7.81(s,1H)8.29(d,J=4.80Hz,1H)。对于C17H20N4O2,[M+H]计算值为313;测量值为313.6。
实施例67:(R)-N-异丁基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
使用2-甲基丙-1-胺作为NHR1R2(5.2mg,6.4%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.87(d,J=6.32Hz,6H)0.99(t,J=7.45Hz,3H)1.78(dt,J=13.58,6.73Hz,1H)1.95(ddd,J=14.15,9.35,7.33Hz,1H)2.11(dt,J=14.65,7.33Hz,1H)3.01(dd,J=6.95,1.64Hz,2H)5.04-5.19(m,1H)5.19-5.32(m,2H)7.24(d,J=5.31Hz,1H)7.87(s,1H)8.33(d,J=5.56Hz,1H)。对于C17H22N4O2,[M+H]计算值为315;测量值为315.6。
实施例68:(R)-N-异丁基-N-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
使用N,2-二甲基丙-1-胺作为NHR1R2(10.5mg,12.4%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.85(td,J=6.95,6.06Hz,5H)0.90-1.09(m,4H)1.84-2.09(m,4H)2.94(s,1H)3.05-3.16(m,2H)3.24(dd,J=7.45,3.92Hz,1H)3.46(dd,J=14.27,8.21Hz,1H)5.11(s,1H)5.68-5.90(m,1H)7.15-7.33(m,1H)7.88(d,J=3.28Hz,1H)8.32(dd,J=5.31,3.03Hz,1H)。对于C18H24N4O2,[M+H]计算值为329;测量值为329.6。
实施例69:(2R)-N-(1-羟基丙烷-2-基)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
使用2-氨基丙-1-醇作为胺NHR1R2(27mg,33.1%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.88-1.03(m,2H)1.04-1.19(m,2H)1.85-2.00(m,1H)2.04-2.17(m,1H)2.75-2.87(m,1H)2.87-3.05(m,1H)3.05-3.21(m,1H)3.38-3.56(m,2H)3.93-4.05(m,1H)4.97-5.13(m,1H)5.13-5.32(m,1H)7.05-7.19(m,1H)7.80(s,1H)8.27(d,J=5.05Hz,1H)。对于C16H20N4O3,[M+H]计算值为317;测量值为317.6。
实施例70:(R)-N-(2-羟基-2-甲基丙基)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
使用1-氨基-2-甲基丙-2-醇作为胺NHR1R2(12mg,14.1%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ1.00(t,J=7.33Hz,3H)1.13(d,J=2.27Hz,6H)1.90-2.02(m,1H)2.08-2.22(m,1H)3.15-3.26(m,2H)5.07-5.21(m,1H)5.21-5.37(m,2H)7.28(d,J=5.56Hz,1H)7.89(s,1H)8.34(d,J=5.56Hz,1H)。对于C17H22N4O3,[M+H]计算值为331;测量值为331.6。
实施例71:(R)-N-((S)-2,3-二羟丙基)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
使用(S)-3-氨基丙烷-1,2-二醇作为胺NHR1R2(1.9mg,2.2%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.98(t,J=7.33Hz,2H)1.29(s,1H)1.86-2.02(m,1H)2.06-2.19(m,1H)2.70(s,1H)3.08-3.29(m,1H)3.40-3.51(m,2H)3.61-3.77(m,1H)5.02-5.32(m,3H)7.16(d,J=4.80Hz,1H)7.82(s,1H)8.31(br.s.,1H)。对于C16H20N4O4,[M+H]计算值为333;测量值为333.6。
实施例72:(R)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-苯基丁酰胺
使用苯胺作为胺NHR1R2(5mg,5.8%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ1.05(t,J=7.33Hz,3H)2.04-2.13(m,1H)2.13-2.28(m,1H)5.11-5.27(m,1H)5.31-5.47(m,2H)7.00-7.14(m,1H)7.21(d,J=5.31Hz,1H)7.23-7.36(m,2H)7.54(dd,J=8.59,1.01Hz,2H)7.85(s,1H)8.32(br.s.,1H)。对于C19H18N4O2,[M+H]计算值为335;测量值为335.6。
实施例73:(R)-N-(1-(甲基磺酰基)哌啶-4-基)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
使用1-(甲基磺酰基)哌啶-4-胺作为NHR1R2(20mg,18.5%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.99(t,J=7.33Hz,2H)1.26-1.42(m,2H)1.46-1.67(m,2H)1.84-2.00(m,2H)2.06-2.25(m,1H)2.76-2.94(m,4H)3.22(quin,J=6.95Hz,1H)3.33-3.39(m,2H)3.59-3.88(m,3H)5.11-5.27(m,1H)7.29(d,J=5.31Hz,1H)7.89(s,1H)8.35(d,J=5.31Hz,1H)。对于C19H25N5O4S,[M+H]计算值为420;测量值为420.6。
实施例74:(2R)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-((四氢呋喃-2-基)甲基)丁酰胺
使用(四氢呋喃-2-基)甲胺作为NHR1R2(3.1mg,3.5%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.98(td,J=7.39,1.64Hz,3H)1.55(s,1H)1.75-2.02(m,4H)2.12(dt,J=14.46,7.29Hz,1H)3.18-3.30(m,2H)3.57-3.73(m,1H)3.73-3.87(m,1H)3.96(dd,J=11.12,6.32Hz,1H)5.01-5.22(m,2H)5.29(dt,J=9.35,6.82Hz,1H)7.16(d,J=5.05Hz,1H)7.83(s,1H)8.30(d,J=5.05Hz,1H)。对于C18H22N4O3,[M+H]计算值为343;测量值为343.6。
实施例75:(2R)-N-(1-氰乙基)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰胺
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)、HOBt水合物(9.46mg,0.062mmol)和EDC盐酸盐(14.81mg,0.077mmol)于DMF(2mL)中合并。将2-氨基丙腈盐酸盐(8.23mg,0.077mmol)和4-甲基吗啉(0.023mL,0.206mmol)加入,并将反应混合物于室温下搅拌2小时。反应后,经由制备HPLC(带有0.035%TFA的10-55%AcCN/H2O)纯化产物,在真空中浓缩并且冻干,以提供为白色固体的标题化合物(11mg,62%)。1H NMR(500MHz,DMSO-d6)δ1.20-1.26(m,3H),1.32-1.39(m,3H),1.77-1.82(m,3H),2.76-2.84(m,1H),5.06-5.22(m,1H),5.36-5.44(m,2H),5.77(dd,J=19.0,2.0Hz,1H),8.38(dd,J=10.5,2.0Hz,1H),8.65(t,J=3.0Hz,1H),9.47(d,J=2.0Hz,1H),12.78(br d,J=7.5Hz,1H)。对于C17H18FN5O2,[M+H]计算值为344;测量值为344。
实施例76:(R)-4-(1-(3,3-二氟氮杂环丁烷-1-基)-3-甲基-1-氧代丁烷-2-基)-6-氟-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)、HOBt水合物(9.46mg,0.062mmol)和EDC盐酸盐(14.81mg,0.077mmol)于DMF(2mL)中合并。将3,3-二氟氮杂环丁烷盐酸盐(10.0mg,0.077mmol)和4-甲基吗啉(0.023mL,0.206mmol)加入,并将反应混合物于室温下搅拌2小时。反应后,经由制备HPLC(带有0.035%TFA的10-60%AcCN/H2O)纯化产物,在真空中浓缩并且冻干,以提供为白色固体的标题化合物(10mg,53%)。1H NMR(500MHz,DMSO-d6)δ0.80(d,J=6.0Hz,3H),0.96(d,J=6.0Hz,3H),2.30-2.41(m,1H),4.26-4.36(m,2H),4.41-4.51(m,1H),4.70-4.79(m,1H),5.00(AB q,J=104.5,22.0Hz,2H),5.07(d,J=23.0Hz,1H),7.99(d,J=2.5Hz,1H),8.24(d,J=2.5Hz,1H),12.40(s,1H)。对于C17H17F3N4O2,[M+H]计算值为367;测量值为367。
实施例77:(R)-6-氟-4-(3-甲基-1-氧代-1-(1,1-二氧化噻唑烷-3-基)丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)、HOBt水合物(9.46mg,0.062mmol)和EDC盐酸盐(14.81mg,0.077mmol)于DMF(2mL)中合并。将1,1-二氧化噻唑烷盐酸盐(12.17mg,0.077mmol)和4-甲基吗啉(0.023mL,0.206mmol)加入,并将反应混合物于室温下搅拌2小时。经由制备HPLC(带有0.035%TFA的10-45%AcCN/H2O)纯化产物,在其空中浓缩并且冻干,以提供为白色固体的标题化合物(8.8mg,43%)。1H NMR(500MHz,DMSO-d6)δ0.76-0.81(m,3H),0.95(d,J=6.5Hz,3H),2.41-2.50(m,1H),3.35-3.45(m,2H),3.80-3.89(m,2H),4.49-4.91(m,4H),5.18-5.42(m,1H),8.01(d,J=2.5Hz,1H),8.24(d,J=2.5Hz,1H),12.43(s,1H)。对于C17H19FN4O4S,[M+H]计算值为395;测量值为395。
实施例78:(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N,3-二甲基-N-(2-(甲基磺酰基)乙基)丁酰胺
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)、HOBt水合物(9.46mg,0.062mmol)和EDC盐酸盐(14.81mg,0.077mmol)于DMF(2mL)中合并。将N-甲基-2-(甲基磺酰基)乙胺(10.60mg,0.077mmol)和4-甲基吗啉(0.023mL,0.206mmol)加入,并将反应混合物于室温下搅拌2小时。经由制备HPLC(带有0.035%TFA的10-45%AcCN/H2O)纯化产物,在真空中浓缩并且冻干,以提供为白色固体的标题化合物(12mg,57%产率)。1H NMR(500MHz,CD3OD)δ0.77(d,J=6.5Hz,3H),0.95(d,J=6.5Hz,3H),2.41-2.49(m,1H),2.97(s,3H),3.05(s,3H),3.36(t,J=6.5Hz,2H),3.78(t,J=6.5Hz,2H),4.81-4.96(m,2H),5.36(d,J=11.0Hz,1H),7.97(d,J=2.5Hz,1H),8.23(d,J=2.5Hz,1H),12.39(s,1H)。对于C18H23FN4O4S,[M+H]计算值为411;测量值为411。
实施例79:(R)-N-(氰甲基)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N,3-二甲基丁酰胺
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)、HOBt水合物(9.46mg,0.062mmol)和EDC盐酸盐(14.81mg,0.077mmol)于DMF(2mL)中合并。将2-(甲基氨基)乙腈(5.41mg,0.077mmol)和4-甲基吗啉(0.023mL,0.206mmol)加入,并将反应混合物于室温下搅拌2小时。经由制备HPLC(带有0.035%TFA的10-55%AcCN/H2O)纯化产物,在真空中浓缩并且冻干,以提供为浅黄色固体的标题化合物(7.8mg,44%)。1HNMR(500MHz,DMSO-d6)δ0.78(d,J=6.5Hz,3H),0.92(d,J=6.5Hz,3H),2.44-2.51(m,1H),3.12(s,3H),4.39(AB q,J=84.5,17.5Hz,2H),4.89(d,J=5.5Hz,2H),5.42(d,J=11.0Hz,1H),8.00(d,J=2.5Hz,1H),8.24(d,J=2.5Hz,1H),12.43(s,1H)。对于C17H18FN5O2,[M+H]计算值为344;测量值为344。
实施例80:(R)-4-(1-(3-(二氟甲基)氮杂环丁烷-1-基)-3-甲基-1-氧代丁烷-2-基)-6-氟-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)、HOBt水合物(9.46mg,0.062mmol)和EDC盐酸盐(14.81mg,0.077mmol)于DMF(2mL)中合并。将3-(二氟甲基)氮杂环丁烷(8.27mg,0.077mmol)和4-甲基吗啉(0.023mL,0.206mmol)加入,并将反应混合物于室温下搅拌2小时。经由制备HPLC(带有0.035%TFA的10-60%AcCN/H2O)纯化产物,在真空中浓缩并且冻干,以提供为白色固体的标题化合物(9.8mg,50%)。1H NMR(500MHz,DMSO-d6)δ0.78(d,J=6.0Hz,3H),0.94(d,J=6.0Hz,3H),2.31-2.39(m,1H),2.99-3.15(m,1H),3.77-4.35(m,4H),4.82-5.11(m,3H),6.10-6.41(m,1H),7.98(d,J=2.5Hz,1H),8.24(d,J=2.5Hz,1H),12.39(s,1H)。对于C18H19F3N4O2,[M+H]计算值为381;测量值为381。
制备U:4-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸
步骤A:3-碘代-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-甲醛
往1H-吡咯并[2,3-b]吡啶-4-甲醛(2.0g,13.7mmol)于EtOH(40mL)的溶液中加入碘(4.17g,16.4mmol)、碘化钠(2.46g,16.4mmol)和NaOH水溶液(1N,16mL)。在室温下搅拌4小时后,将反应混合物用水(200mL)稀释,并经由过滤收集橙色沉淀物,并在真空下干燥。将固体溶解于DMF(20mL)中;缓慢加入氢化钠(60%,660mg,16.4mmol),并且将深红色溶液于室温下搅拌30分钟后,加入甲苯磺酰氯(2.87g,15.1mmol)。将反应混合物于室温下搅拌另外的2小时,然后用EtOAc稀释,并用水淬灭。将有机物分离,用NaHSO3水溶液(0.1N)和盐水洗涤,经由MgSO4干燥并在真空中浓缩。经由硅胶色谱法(3∶1∶1己烷/DCM/EtOAc)纯化,以提供为黄色固体的标题化合物(3.48g,60%)。1H NMR(500MHz,DMSO-d6)δ2.33(s,3H),7.43(d,J=8.5Hz,2H),7.63(d,J=5.0Hz,1H),8.03(d,J=8.5Hz,2H),8.39(s,1H),8.60(d,J=5.0Hz,1H),11.31(s,1H)。对于C15H11IN2O3S,[M+H]计算值为427;测量值为427。
步骤B:4-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸
将氯化锂(358mg,8.45mmol)和一水合甲酸锂(591mg,8.45mmol)于氮气下在干燥可密封管中合并。加入DMF(12mL)、3-碘代-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-甲醛(1.2g,2.82mmol)、乙酸酐(532mL,5.63mmol)和乙酸钯(63mg,0.28mmol)。加入DIPEA(981μL),且将反应管密封并于56℃加热4小时。用MeOH/DCM(20%)吸收反应混合物并过滤以移除不溶的黑色的碳材料。将黄色溶液在真空中浓缩,溶解于MeOH/DCM(10%)中并用HCl水溶液(0.1N)洗涤。将水层用MeOH/DCM(10%)萃取两次。将有机物合并,经由MgSO4干燥,并在真空中浓缩。经由硅胶色谱法(10-15%MeOH/DCM)纯化,以提供为棕黄色固体的标题化合物(866mg,89%)。1H NMR(500MHz,DMSO-d6)δ2.35(s,3H),7.45(d,J=8.5Hz,2H),7.62(d,J=5.0Hz,1H),8.11(d,J=8.5Hz,2H),8.58-8.62(m,2H),11.02(s,1H),13.20(br s,1H)。对于C16H12N2O5S,[M+H]计算值为345;测量值为345。
制备V:(R)-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸
步骤A:(R)-3-甲基-2-(3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸叔丁酯
将三乙酰氧基硼氢化钠(603mg,2.85mmol)和D-缬胺酸叔丁酯HCl盐(597mg,2.85mmol)于DCM(15mL)中合并。将反应混合物于室温下搅拌20分钟,然后冷却至0℃。加入4-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸(700mg,2.03mmol),并将溶液搅拌1小时。将溶液在其空中浓缩,以提供白色泡沫物,将其再溶解于THF(40mL)中。加入HATU(1.16g,3.05mmol)和N-甲基吗啉(339μL,3.05mmol),并将反应混合物于52℃下搅拌2小时。加入另外的HATU(580mg,1.53mmol)和N-甲基吗啉(170μL,1.53mmol),并将反应混合物于52℃下另外搅拌2小时。随后将溶液冷却,用EtOAc稀释,并用盐水洗涤。将有机物经由MgSO4干燥,并在其空中浓缩。经由硅胶色谱法(1∶2∶2EtOAc/己烷/DCM)纯化,以提供为黄色油状物的标题化合物,将其静置凝固(840mg,85%)。1H NMR(500MHz,CDCl3)δ0.86(d,J=7.0Hz,3H),1.08(d,J=7.0Hz,3H),1.42(s,9H),2.25-2.34(m,1H),2.35(s,3H),4.77-5.14(m,3H),7.05(d,J=5.0Hz,1H),7.28(d,J=7.5Hz,2H),8.05-8.10(m,3H),8.45(d,J=5.0Hz,1H)。对于C25H29N3O5S,[M+H]计算值为484;测量值为484。
步骤B:(R)-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸
将(R)-3-甲基-2-(3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸叔丁酯(840mg,1.74mmol)、MeOH(4mL)和NaOH水溶液(1N,2mL)的混合物于室温下搅拌40分钟。将材料用DCM稀释并用盐水洗涤。将有机物经由MgSO4干燥,并在真空中浓缩。经由硅胶色谱法(5%MeOH/DCM)纯化,以提供黄色油状物(390mg),将其溶解于TFA/DCM(50%)并于室温下搅拌1小时。将此溶液浓缩并在真空下干燥,以提供为棕黄色固体的标题化合物(320mg,67%)。1H NMR(500MHz,CD3OD)δ0.88(d,J=7.0Hz,3H),1.10(d,J=7.0Hz,3H),2.35-2.44(m,1H),4.95-5.33(m,3H),7.34(d,J=6.0Hz,1H),7.90(s,1H),8.33(d,J=6.0Hz,1H)。对于C14H15N3O3,[M+H]计算值为274;测量值为274。
实施例81:(R)-1-(3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰基)氮杂环丁烷-3-甲腈
将(R)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸-3-甲酸(80mg,0.29mmol)、HOBt(54mg,0.35mmol)和EDC(84mg,0.44mmol)于DMF(2mL)中合并。将氮杂环丁烷-3-甲腈HCl盐(52mg,0.44mmol)和N-甲基吗啉(130μL,1.17mmol)加入,并将溶液于室温下搅拌2小时。经由制备HPLC(带有0.035%TFA的10-45%AcCN/水)纯化,接着经由硅胶色谱法(8%MeOH/DCM)纯化,以提供为白色固体的标题化合物(28mg,28%)。1H NMR(500MHz,DMSO-d6)δ0.90(dd,J=6.5,2.0Hz,3H),1.06(dd,J=6.5,2.0Hz,3H),2.42-2.51(m,1H),3.61-3.75(m,1H),4.15-4.68(m,4H),4.95-5.21(m,3H),7.09(t,J=5.0Hz,1H),7.81(d,J=12.5Hz,1H),8.27(t,J=5.0Hz,1H)。对于C18H19N5O2,[M+H]计算值为338;测量值为338。
制备W:(R)-3,3-二甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸
步骤A:(R)-2-氨基-3,3-二甲基丁酸苄酯,TFA盐
将苄基溴(2.26mL,19.0mmol)于0℃加至(R)-2-(叔丁氧基羰基氨基)-3-3-二甲基丁酸(4.0g,17.3mmol)于AcCN(80mL)的搅拌溶液中。将DBU(3.13mL,20.8mmol)缓慢加入,且将溶液搅拌3小时,同时温热至室温。将溶液在真空中浓缩,用EtOAc吸收,并用HCl水溶液(1N)、NaHCO3(饱和)水溶液和盐水洗涤。将有机物经由MgSO4干燥并浓缩。将得到的澄清油状物溶解于TFA/DCM(50%,16mL)中并于室温下搅拌1小时。将此溶液浓缩并经由短二氧化硅柱(10%MeOH/DCM)纯化,以提供为白色粉末的标题化合物(5.02g,87%)。1H NMR(500MHz,DMSO-d6)δ1.05(s,9H),3.72(s,1H),5.17(AB q,J=40.0,12.0Hz,2H),7.25-7.35(m,5H),8.20(br s,2H)。
步骤B:(R)-3,3-二甲基-2-(3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸苄酯
将三乙酰氧基硼氢化钠(665mg,3.14mmol)和(R)-2-氨基-3,3-二甲基丁酸苄酯,TFA盐(1.05g,2.85mmol)于DCM(15mL)中合并。将反应混合物于室温下搅拌20分钟,然后冷却至0℃。将4-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸(900mg,2.61mmol)加入,并将反应混合物搅拌1小时。将溶液在真空中浓缩,以提供棕黄色泡沫物,将其再溶解于THF(40mL)中。加入HATU(1.49g,3.92mmol)和N-甲基吗啉(436μL,3.92mmol),并将反应混合物于52℃下搅拌2小时。加入另外的HATU(750mg,1.96mmol)和N-甲基吗啉(218μL,1.96mmol)。将反应混合物另外搅拌2小时、冷却、用EtOAc稀释、并以盐水洗涤。将有机物经由MgSO4干燥,并在其空中浓缩。经由硅胶色谱法(1∶2∶2 EtOAc/己烷/DCM)纯化,以提供为淡黄色油状物/泡沫物的标题化合物(970mg,70%)。1H NMR(500MHz,CDCl3)δ1.12(s,9H),2.33(s,3H),5.06(AB q,J=66.5,24.0Hz,2H),5.11(s,2H),5.48(br s,1H),6.98(d,J=5.0Hz,1H),7.14-7.28(m,7H),8.03-8.11(m,3H),8.42(d,J=5.0Hz,1H)。对于C29H29N3O5S,[M+H]计算值为532;测量值为532。
步骤C:(R)-3,3-二甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸
将(R)-3,3-二甲基-2-(3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸苄酯(950mg,1.79mmol)、MeOH(4mL)和NaOH水溶液(1N,2mL)的混合物于室温下搅拌40分钟。将混合物用DCM稀释并用盐水洗涤。将有机物经由MgSO4干燥,并在真空中浓缩。经由硅胶色谱法(5%MeOH/DCM)纯化,以提供黄色油状物(500mg),将其用MeOH吸收并用10%Pd/C于H2气球在室温下搅拌1小时。将反应混合物经由硅藻土过滤,并在真空中浓缩,以提供为灰白色固体的标题化合物(380mg,74%)。1H NMR(500MHz,DMSO-d6)δ1.13(s,9H),4.12(br s,1H),5.05-5.15(m,2H),7.08(d,J=5.0Hz,1H),7.84(d,J=2.5Hz,1H),8.25(d,J=5.0Hz,1H)。对于C15H17N3O3,[M+H]计算值为288;测量值为288。
实施例82:(R)-1-(3,3-二甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰基)氮杂环丁烷-3-甲腈
将(R)-3,3-二甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸(80mg,0.278mmol)、HOBt水合物(51.2mg,0.334mmol)和EDC盐酸盐(80mg,0.418mmol)于DMF(2mL)中合并。将氮杂环丁烷-3-甲腈盐酸盐(49.5mg,0.418mmol)和4-甲基吗啉(0.124mL,1.114mmol)加入,并将反应混合物于室温下搅拌2小时。经由制备HPLC(带有0.035%TFA的10-50%AcCN/H2O)纯化产物,在真空中浓缩,并经由快速柱色谱法(8%MeOH/DCM)纯化,以提供标题化合物(38mg,39%)。1H NMR(500MHz,CD3OD)δ1.17(s,9H),3.58-3.72(m,1H),4.13-4.65(m,4H),5.35-5.45(m,3H),7.28-7.38(m,1H),7.95(d,J=15.5Hz,1H),8.33-8.40(m,1H)。对于C19H21N5O2,[M+H]计算值为352;测量值为352。
实施例83:(R)-N-(氰甲基)-3,3-二甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
将(R)-3,3-二甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸(40.0mg,0.139mmol)、HOBt水合物(25.6mg,0.167mmol)和EDC盐酸盐(40.0mg,0.209mmol)于DMF(2mL)中合并。将2-氨基乙腈(11.71mg,0.209mmol)和4-甲基吗啉(0.062mL,0.557mmol)加入,并将反应混合物于室温下搅拌2小时。经由制备HPLC(带有0.035%TFA的10-45%AcCN/H2O)纯化产物,在真空中浓缩并且冻干,以提供为浅黄色固体的标题化合物(36mg,59%)。1H NMR(500MHz,DMSO-d6)δ1.09(s,9H),4.01-4.12(m,2H),5.13-5.22(m,2H),5.33(br s,1H),7.10(d,J=4.5Hz,1H),7.87(s,1H),8.26(d,J=4.5Hz,1H),8.86(br s,1H),12.25(br s,1H)。对于C17H19N5O2,[M+H]计算值为326;测量值为326。
实施例84:(S)-1-((R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)吡咯烷-2-甲腈
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(10mg,0.032mmol)、HATU(15mg,0.039mmol)、(S)-吡咯烷-2-甲腈盐酸盐(4mg,0.032mmol)和N-甲基吗啉(90μL,0.097mmol)在THF(0.5mL)中合并。,将反应混合物于氮气在40℃下搅拌10分钟,然后于室温下搅拌30分钟。将此溶液浓缩并经由制备HPLC(带有0.035%TFA的10-50%AcCN/H2O)纯化,以提供为黄色薄膜的标题化合物(4mg,29%)。1H NMR(500MHz,CD3OD)δ0.94(d,J=6.9Hz,3H),1.06(d,J=6.3Hz,3H),1.04-1.13(m,1H),2.12-2.17(m,2H),2.25-2.29(m,2H),2.60-2.63(m,1H),3.72-3.75(m,1H),3.83-3.87(m,1H),4.90(d,J=13.7Hz,1H),5.05(d,J=12.7Hz,1H),5.50(d,J=7.3Hz,1H),7.86(s,1H),8.25(s,1H)。对于C19H20ClN5O2,[M+H]计算值为386;测量值为386。
实施例85:(R)-1-((R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)吡咯烷-2-甲腈
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(10mg,0.032mmol)、HATU(15mg,0.039mmol)、(R)-吡咯烷-2-甲腈盐酸盐(4mg,0.032mmol)和N-甲基吗啉(90μL,0.097mmol)在THF(0.5mL)中合并。将反应混合物于氮气在40℃下搅拌10分钟,然后于室温下搅拌30分钟。将此溶液浓缩并经由制备HPLC(带有0.035%TFA的10-50%AcCN/H2O)纯化,以提供为白色固体的标题化合物(2mg,18%)。1H NMR(500MHz,CD3OD)δ0.94(d,J=6.9Hz,3H),1.06(d,J=6.3Hz,3H),1.03-1.12(m,1H),2.12-2.17(m,2H),2.25-2.27(m,2H),2.59-2.63(m,1H),3.72-3.74(m,1H),3.83-3.86(m,1H),4.92(d,J=5.9Hz,1H),5.06(d,J=13.2Hz,1H),5.46(d,J=11.8Hz,1H),7.86(s,1H),8.25(s,1H)。对于C19H20ClN5O2,[M+H]计算值为386;测量值为386。
实施例86:(2S,4S)-1-((R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)-4-氟吡咯烷-2-甲腈
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(10mg,0.032mmol)、HATU(15mg,0.039mmol)、(2S,4S)-4-氟吡咯烷-2-甲腈(4mg,0.032mmol)和N-甲基吗啉(90μL,0.097mmol)于THF(0.5mL)中合并。将反应混合物于氮气下在40℃下搅拌10分钟,且然后于室温下搅拌30分钟。将此溶液浓缩并经由制备HPLC(带有0.035%TFA的10-50%AcCN/H2O)纯化,以提供为白色固体的标题化合物(2mg,12%)。1H NMR(500MHz,CD3OD)δ0.94(d,J=6.3Hz,3H),1.05(d,J=6.3Hz,3H),1.03-1.15(m,1H),2.56-2.65(m,3H),23.89-3.91(m,1H),4.25-4.30(m,1H),4.83-4.87(m,1H),5.09-5.13(m,1H),5.39-5.41(m,1H),5.47-5.66(m,1H),7.87(s,1H),8.27(s,1H)。对于C19H19ClFN5O2,[M+H]计算值为404;测量值为404。
制备X:(R)-3,3-二甲基-2-(6-甲基-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸
步骤A:(R)-3,3-二甲基-2-(6-甲基-3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸
将(R)-2-(6-氯-3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3,3-二甲基丁酸苄酯(10mg,0.018mmol)、Pd(Ph3P)4(10mg,0.009mmol)和二噁烷(1mL)在2mL微波瓶中合并。将混合物用氮吹扫,并加入三甲基铝(2.0M/甲苯,0.053mL,0.11mmol)。将瓶密封,并将反应混合物在Biotage InitiatorTM微波炉中于120℃加热1小时。将反应重复三次,每次反应中增加(R)-2-(6-氯-3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3,3-二甲基丁酸苄酯(30mg)的量。将反应混合物合并,将得到的混合物浓缩,并经由制备HPLC(带有0.035%TFA的30-70%AcCN/H2O)纯化,以提供为黄色油状物的标题化合物(36mg,44%)。1H NMR(500MHz,CD3OD)δ1.21(s,9H),2.30(s,3H),2.36(s,3H),4.94(s,1H),5.07(d,J=18.6Hz,1H),5.21(d,J=19.0Hz,1H),7.36(d,J=8.3Hz,2H),8.04(d,J=4.9Hz,2H),8.10(s,1H),8.22(s,1H)。对于C23H25N3O5S,[M+H]计算值为456;测量值为456。
步骤B:(R)-3,3-二甲基-2-(6-甲基-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸
在50mL圆底烧瓶中将(R)-3,3-二甲基-2-(6-甲基-3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸(36mg,0.079mmol)溶解于THF(3mL)、MeOH(3mL)和NaOH水溶液(1N,3mL)中。将反应混合物在油浴中于50℃加热30分钟,然后冷却至室温。将此溶液浓缩并经由制备HPLC(带有0.035%TFA的10-35%AcCN/H2O)纯化,以提供标题化合物(10mg,42%)。1H NMR(500MHz,CD3OD)δ1.25(s,9H),2.29(s,3H),4.87(s,1H),5.21(d,J=19.5Hz,1H),5.37(d,J=19.5Hz,1H),7.87(s,1H),8.23(s,1H)。对于C16H19N3O3,[M+H]计算值为302;测量值为302。
实施例87:(R)-1-(3,3-二甲基-2-(6-甲基-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰基)氮杂环丁烷-3-甲腈
将(R)-3,3-二甲基-2-(6-甲基-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸(10mg,0.033mmol)、DMAP(6mg,0.05mmol)、4-甲基吗啉(0.015mL,0.13mmol)、EDC盐酸盐(10mg,0.050mmol)、HOBt水合物(8mg,0.050mmol)和氮杂环丁烷-3-甲腈盐酸盐(6mg,0.050mmol)溶解于DMF(2mL)中。将反应混合物在氮气下于室温搅拌3小时。将此溶液浓缩并经由制备HPLC(带有0.035%TFA的10-30%AcCN/H2O)纯化,以提供标题化合物(1.4mg,12%)。1H NMR(500MHz,CD3OD)δ1.18(s,9H),2.35(d,J=8.8Hz,3H)4.17-4.18(m,1H),4.29-4.31(m,2H),4.52-4.62(m,1H),4.64-4.69(m,1H),5.19-5.23(m,2H),5.45(s,1H),7.83(d,J=16.1Hz,3H),8.19(s,1H)。对于C20H23N5O2,[M+H]计算值为366;测量值为366。
实施例88:(R)-1-(3-甲基-2-(6-甲基-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰基)氮杂环丁烷-3-甲腈
将(R)-1-(2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)氮杂环丁烷-3-甲腈(30mg,0.081mmol)、Pd(Ph3P)4(47mg,0.04mmol)和二噁烷(2mL)在5mL微波瓶中合并。将混合物用氮吹扫,并加入三甲基铝(2.0M/甲苯,0.24mL,0.48mmol)。将瓶密封,并将反应混合物在Biotage InitiatorTM微波炉中于120℃加热1小时。将反应以相同规模重复四次。将反应混合物合并,并将生成的混合物用水(0.5mL)淬灭、浓缩,并经由制备HPLC(带有0.035%TFA的10-30%AcCN/H2O)纯化,接着经由快速色谱法(5%MeOH/95%DCM)纯化,以提供淡黄色固体的标题化合物(41mg,29%)。1HNMR(500MHz,CD3OD)δ0.92(d,J=6.8Hz,3H),1.07(dd,J=15.9,6.1Hz,3H),2.42(d,J=6.35Hz,3H),3.69-3.77(m,1H),4.19-4.22(m,1H),4.32-4.34(m,1H),4.53-4.59(m,1H),4.68-4.72(m,1H),5.20-5.33(m,3H),7.98(d,J=19.5Hz,1H),8.27(s,1H)。对于C19H21N5O2,[M+H]计算值为352;测量值为352。
下面的表2列举对于实施例中所述的许多化合物的JAK3和JAK2抑制数据。根据说明书第38页描述的测定测试化合物。抑制数据报告为pIC50,即-log10(IC50),其中IC50为在50%抑制时的摩尔浓度。较大的pIC50数值代表较高的效力。
表2.JAK2和JAK3抑制
Claims (24)
1.一种式I化合物
或其药学上可接受的盐,其中:
G1选自由N和CR8组成的组;
R1选自由任选取代的C3-8环烷基、任选取代的C3-6杂环烷基、任选取代的C4-14芳基、任选取代的C1-10杂芳基以及任选取代的C1-6烷基组成的组;
R2和R3各自独立地选自由氢和任选取代的C1-4烷基组成的组,或者R2、R3和它们所连接的碳原子形成羰基;
R4选自由氢、任选取代的C1-4烷基、任选取代的C1-4烷氧基、卤基、羟基和氨基组成的组;
R5选自由氢、任选取代的C1-4烷基、C3-8环烷基和卤基组成的组;
R6和R7各自独立地选自由氢和任选取代的C1-4烷基组成的组,或者R6、R7和它们所连接的碳原子形成羰基;
R8选自由氢、任选取代的C1-6烷基、任选取代的C1-4烷氧基、C1-9酰胺、C1-5氧代羰基、氰基、任选取代的C3-8环烷基、任选取代的C4-14芳基、任选取代的C1-10杂芳基以及卤基组成的组;以及
附带条件是不多于一个羰基是由R2和R3及R6和R7形成。
2.根据权利要求1所述的化合物或药学上可接受的盐,其中R4和R5每一个为氢。
3.根据前述任一项权利要求所述的化合物或药学上可接受的盐,其中G为CR8。
4.根据前述任一项权利要求所述的化合物或药学上可接受的盐,其中G为CR8,且R8选自氢、卤基和任选取代的C1-6烷基。
5.根据权利要求4所述的化合物或药学上可接受的盐,其中G为CR8,且R8选自氢、卤基和C1-4烷基。
6.根据权利要求1-2任一项所述的化合物或药学上可接受的盐,其中G为N。
7.根据权利要求1-6任一项所述的化合物或药学上可接受的盐,其中R1为任选取代的C3-8环烷基。
8.根据权利要求1-6任一项所述的化合物或药学上可接受的盐,其中R1为任选取代的C3-6杂环烷基。
9.根据权利要求1-6任一项所述的化合物或药学上可接受的盐,其中R1为任选取代的C4-14芳基。
10.根据权利要求1-6任一项所述的化合物或药学上可接受的盐,其中R1为任选取代的C1-10杂芳基。
11.根据权利要求1-6任一项所述的化合物或药学上可接受的盐,其中R1为任选取代的C1-6烷基。
12.根据权利要求1-11任一项所述的化合物或药学上可接受的盐,其中R2、R3和它们所连接的碳原子形成羰基。
13.根据权利要求12所述的化合物或药学上可接受的盐,其中R6和R7每一个为氢。
14.根据权利要求1-11任一项所述的化合物或药学上可接受的盐,其中R6、R7和它们所连接的碳原子形成羰基。
15.根据权利要求14所述的化合物或药学上可接受的盐,其中R2和R3每一个为氢。
16.根据权利要求1所述的化合物,其选自:
4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-羧酸叔丁酯;
4-(哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮;
3-氧代-3-(4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-基)丙腈;
4-甲基-4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-羧酸叔丁酯;
4-(4-甲基哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮;
3-(4-甲基-4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-基)-3-氧代丙腈;
4-乙基-4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-羧酸叔丁酯;
4-(4-乙基哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮;
3-(4-乙基-4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-基)-3-氧代丙腈;
4-(戊烷-3-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮;
4-(1-环丙基-3-羟丙基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮;
3-((5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)甲基)吡咯烷-1-羧酸叔丁酯;
4-(吡咯烷-3-基甲基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮;
3-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-羧酸叔丁酯;
4-(哌啶-3-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮;
4-(4-乙基-1-丙酰基哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮;
4-(4-乙基-1-(嘧啶-4-基)哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮;
(S)-4-(1-氧代-1-(吡咯烷-1-基)丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-4-(1-氧代-1-(吡咯烷-1-基)丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-4-(3-甲基-1-氧代-1-(吡咯烷-1-基)丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-4-(4-甲基-1-氧代-1-(吡咯烷-1-基)戊烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-N-环戊基-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(2R,3R)-N-环戊基-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)戊酰胺;
(2R,3S)-N-环戊基-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)戊酰胺;
(R)-N-环戊基-2-环丙基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)乙酰胺;
(R)-N-环戊基-3,3-二甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(R)-N,2-二环戊基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)乙酰胺;
(R)-N-环戊基-4,4,4-三氟-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(R)-N-环戊基-3-羟基-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-氰基-N-环戊基丙酰胺;
N-环戊基-1-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)环戊烷甲酰胺;
(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-(氰甲基)-3-甲基丁酰胺;
1-((R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)吡咯烷-3-甲腈;
(R)-1-(2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)哌啶-4-甲腈;
(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-(4-氰苯基)-3-甲基丁酰胺;
(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-(3-氰苯基)-3-甲基丁酰胺;
(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-((S)-1-氰基丁烷-2-基)-3-甲基丁酰胺;
(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-((R)-1-氰基丁烷-2-基)-3-甲基丁酰胺;
(R)-1-(2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)氮杂环丁烷-3-甲腈;
(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-(2-氰乙基)-3,3-二甲基丁酰胺;
(R)-1-(2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3,3-二甲基丁酰基)氮杂环丁烷-3-甲腈;
(R)-1-(2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)氮杂环丁烷-3-甲腈;
(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸;
(2R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基-N-(四氢呋喃-3-基)丁酰胺;
(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基-N-(1,1-二氧代四氢噻吩-3-基)丁酰胺;
(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基-N-(2-(甲基磺酰基)乙基)丁酰胺;
(R)-N-(1,1-二氧代-六氢-6-噻喃)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基-N-4-基)丁酰胺;
4-{(1R)-1-[(1,1-二氧代硫代吗啉-4-基)羰基]-2-甲基丙基}-6-氟-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-N-(环丙基甲氧基)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰胺;
(2R)-N-(3,3-二氟环戊基)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰胺;
(R)-3-(氟甲基)-1-(3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰基)氮杂环丁烷-3-甲腈;
(R)-1-(2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)-3-甲基氮杂环丁烷-3-甲腈;
(R)-3-甲基-1-(3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰基)氮杂环丁烷-3-甲腈;
(R)-4-(1-吗啉基-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-4-(1-(4-甲基哌嗪-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
4-((2R)-1-(3-羟基吡咯烷-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-N-环戊基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
4-((2R)-1-(3-(4-氟苯基)吡咯烷-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
4-((2R)-1-(3-(二甲基氨基)吡咯烷-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
4-((2R)-1-(3-(甲氧基甲基)吡咯烷-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
4-((2R)-1-(3-甲基哌啶-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-4-(1-(4-(2-羟基丙烷-2-基)哌啶-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-4-(1-(4-(甲基磺酰基)哌嗪-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-4-(1-氧代-1-(4-(吡啶-2-基)哌嗪-1-基)丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-N-环丙基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(R)-N-(环丙基甲基)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(R)-N-异丁基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(R)-N-异丁基-N-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(2R)-N-(1-羟基丙烷-2-基)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(R)-N-(2-羟基-2-甲基丙基)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(R)-N-((S)-2,3-二羟丙基)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(R)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-苯基丁酰胺;
(R)-N-(1-(甲基磺酰基)哌啶-4-基)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(2R)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-((四氢呋喃-2-基)甲基)丁酰胺;
(2R)-N-(1-氰乙基)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰胺;
(R)-4-(1-(3,3-二氟氮杂环丁烷-1-基)-3-甲基-1-氧代丁烷-2-基)-6-氟-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-6-氟-4-(3-甲基-1-氧代-1-(噻唑烷-3-基-1,1-二氧化物)丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N,3-二甲基-N-(2-(甲基磺酰基)乙基)丁酰胺;
(R)-N-(氰甲基)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N,3-二甲基丁酰胺;
(R)-4-(1-(3-(二氟甲基)氮杂环丁烷-1-基)-3-甲基-1-氧代丁烷-2-基)-6-氟-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-1-(3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰基)氮杂环丁烷-3-甲腈;
(R)-1-(3,3-二甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰基)氮杂环丁烷-3-甲腈;
(R)-N-(氰甲基)-3,3-二甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(S)-1-((R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)吡咯烷-2-甲腈;
(R)-1-((R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)吡咯烷-2-甲腈;
(2S,4S)-1-((R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)-4-氟吡咯烷-2-甲腈;
(R)-1-(3,3-二甲基-2-(6-甲基-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰基)氮杂环丁烷-3-甲腈;
(R)-1-(3-甲基-2-(6-甲基-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰基)氮杂环丁烷-3-甲腈;
任何上述化合物的立体异构体;以及
任何一种上述立体异构体或化合物的药学上可接受的盐类。
17.一种药物组合物,包含如权利要求1-16任一项定义的化合物或药学上可接受的盐类、以及药学上可接受的赋形剂。
18.如权利要求1-16任一项定义的化合物或药学上可接受的盐作为药剂的用途。
19.如权利要求1-16任一项定义的化合物或药学上可接受的用于制备治疗与JAK相关的疾病、病症或症状的药剂的用途。
20.一种治疗受试者中与JAK相关的疾病、病症或症状的方法,所述方法包括对受试者施用有效量的如权利要求1-16任一项定义的化合物或药学上可接受的盐。
21.根据权利要求20所述的方法,其中所述疾病、病症或症状选自过敏性鼻炎、过敏性哮喘、特应性皮炎、类风湿性关节炎、多发性硬化、系统性红斑性狼疮、牛皮癣、免疫性血小板减少性紫癜、慢性阻塞性肺疾病以及血栓形成。
22.一种有效量的如权利要求1-16任一项定义的化合物或药学上可接受的盐以及至少一种另外的药理学活性剂的结合物。
23.根据权利要求22所述的结合物,其中所述另外的药理学活性剂为DMARD。
24.根据权利要求23所述的结合物,其中所述DMARD为甲氨蝶呤。
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WO2012078802A1 (en) | 2010-12-08 | 2012-06-14 | Takeda Pharmaceutical Company Limited | PREPARATION OF SUBSTITUTED-4,5-DIHYDROPYRROLO[4,3,2-de][2,6]NAPHTHYRIDIN-3(1H)-ONES |
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KR101836822B1 (ko) * | 2016-10-17 | 2018-03-09 | 주식회사 엔지켐생명과학 | 모노아세틸디아실글리세롤 화합물을 함유하는 건선의 예방 또는 치료용 조성물 |
EP3305786A3 (de) | 2018-01-22 | 2018-07-25 | Bayer CropScience Aktiengesellschaft | Kondensierte bicyclische heterocyclen-derivate als schädlingsbekämpfungsmittel |
WO2020092015A1 (en) | 2018-11-02 | 2020-05-07 | University Of Rochester | Therapeutic mitigation of epithelial infection |
CN110016030B (zh) * | 2019-05-22 | 2021-02-09 | 南京合巨药业有限公司 | 一种5-氟-1H-吡咯-[2,3-b]吡啶-4-甲醛的制备方法 |
CN112390799B (zh) * | 2019-08-16 | 2022-04-29 | 科岭源生物科技(深圳)有限公司 | 一种含氮杂环类5-ht3受体调节剂及其制备方法和用途 |
US11561787B2 (en) | 2021-05-13 | 2023-01-24 | International Business Machines Corporation | Application invocation on specified operating system version |
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HK1167654A1 (zh) | 2012-12-07 |
HUE026518T2 (en) | 2016-06-28 |
PT2440558E (pt) | 2015-08-27 |
CA2764885A1 (en) | 2010-12-16 |
US8785429B2 (en) | 2014-07-22 |
CN102459267B (zh) | 2014-11-26 |
EP2440558A1 (en) | 2012-04-18 |
DK2440558T3 (en) | 2015-07-06 |
JP5719840B2 (ja) | 2015-05-20 |
US20110136780A1 (en) | 2011-06-09 |
US8420816B2 (en) | 2013-04-16 |
WO2010144486A1 (en) | 2010-12-16 |
EP2440558B1 (en) | 2015-04-01 |
US20130184252A1 (en) | 2013-07-18 |
SI2440558T1 (sl) | 2015-10-30 |
CA2764885C (en) | 2018-05-15 |
HRP20150701T1 (hr) | 2015-08-28 |
ES2540964T3 (es) | 2015-07-15 |
JP2012529437A (ja) | 2012-11-22 |
PL2440558T3 (pl) | 2015-10-30 |
SMT201500156B (it) | 2015-09-07 |
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