CN117337288A - Axl抑制剂化合物 - Google Patents
Axl抑制剂化合物 Download PDFInfo
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- CN117337288A CN117337288A CN202280034431.2A CN202280034431A CN117337288A CN 117337288 A CN117337288 A CN 117337288A CN 202280034431 A CN202280034431 A CN 202280034431A CN 117337288 A CN117337288 A CN 117337288A
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- cancer
- alkyl
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
本文描述了抑制AXL的式I化合物,和含有所述化合物的组合物以及用于合成所述化合物的方法。还描述了此类化合物和组合物用于治疗一系列不同疾病、病症和疾患的用途,所述疾病、病症和疾患包括至少部分地由AXL介导的癌症和免疫相关病症。
Description
相关申请的交叉引用
本申请根据35 U.S.C.§119(e)要求2021年5月21日提交的美国临时申请第63/191,636号的优先权,所述申请的公开内容出于所有目的通过引用整体并入本文。
发明背景
AXL是属于TAM家族的受体酪氨酸激酶(receptor tyrosine kina se;RTK)。AXL调节重要过程如细胞生长、迁移、聚集和细胞凋亡。AXL可通过多种机制,包括配体依赖性和配体非依赖性机制来激活。一旦激活,AXL参与多种信号通路,包括导致癌细胞增殖的RAS-RAF-MEK-ERK通路以及负责若干促存活蛋白质的PI3K/AKT通路。
已显示AXL在多种恶性病中过度表达。在癌症情况下,AXL过度表达与不良患者存活和抗性机制(靶向和非靶向)相关。
鉴于将AXL抑制与例如癌症的疾病相联系的研究,本领域中需要新型AXL抑制剂。本公开解决此需求并提供优于先前AXL抑制剂的额外优点。
发明内容
本公开涉及抑制AXL的活性的化合物。所述化合物由式(I)表示:
或其药学上可接受的盐、水合物或溶剂化物,其中R1、R2、下标n、稠环A和B,以及顶点G1、G2、G3、G4和G5具有下文中所定义的含义。
在一个相关方面,本文提供了用于治疗受试者(例如,人类)中的由AXL介导的疾病或病症的方法,所述方法包括向所述受试者施用有效量的至少一种本文所描述的AXL抑制剂。如下文所描述,由AXL介导的疾病和病症包括癌症、炎症、自身免疫性病症和代谢病症。可完全或部分地通过调节AXL活性而治疗或预防的其他疾病、病症和疾患是本文所提供的AXL抑制剂化合物的候选适应症。
本文也提供了所描述的AXL抑制剂以及一种或多种如下文所描述的额外药剂的用途。
具体实施方式
在进一步描述本公开之前,应理解,本公开不限于本文所阐述的特定实施方案,并且还应理解,本文所用的术语仅出于描述特定实施方案的目的而不旨在具限制性。
在提供值范围时,应理解本公开涵盖所述范围的上限与下限之间的每个中间值(除非上下文另外明确指出,否则达到下限单位的十分之一)和该所陈述范围内的任何其他所陈述或中间值。这些较小范围的上限和下限可独立地包括于较小范围内并且也涵盖于本公开内,在所陈述范围内受到任何特定排他性限制。当所陈述的范围包括界限中的一者或两者时,排除那些所包括的界限中的任一者或两者的范围也包括于本公开中。除非另外定义,否则本文所用的所有技术和科学术语都具有与本公开所属领域的普通技术人员所理解相同的含义。
除非本文另外明确规定,否则如本文所用,单数形式“一(a/an)”和“所述”包括复数个指示物。应进一步注意,权利要求书可撰写为排除任何任选的要素。因而,此陈述旨在与对权利要求要素的引述结合充当使用例如“仅仅(solely)”、“仅(only)”等的此类排他性术语或使用“负性”限制的前提基础。
本文所论述的公开仅仅提供其在本申请的申请日之前的公开内容。此外,所提供的公开日期可能与可能需要独立确认的实际公开日期不同。
定义
除非另外指示,否则以下术语旨在具有以下阐述的含义。其他术语在整个说明书中他处定义。
除非另外陈述,否则术语“烷基”本身或作为另一取代基的一部分意指具有所指定的碳原子数目的饱和直链或支链烃基(即,C1-8意指一至八个碳)。烷基可包括任何数目的碳,例如C1-2、C1-3、C1-4、C1-5、C1-6、C1-7、C1-8、C1-9、C1-10、C2-3、C2-4、C2-5、C2-6、C3-4、C3-5、C3-6、C4-5、C4-6和C5-6。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基、正庚基、正辛基等。
术语“羟烷基”是指具有所指示数目的碳原子(例如C1-6或C1-8)并且被一个或两个羟基(OH)取代的烷基。
术语“卤羟烷基”是指具有所指示数目的碳原子(例如C1-6或C1-8)并且被一个或两个羟基(OH)和一个至六个卤素原子(例如F、Cl)取代的烷基。
术语“亚烷基”是指具有指示碳原子数目并且连接至少两个其他基团(即二价烃基)的直链或支链饱和脂族基。与亚烷基连接的两个部分可与亚烷基的同一原子或不同原子连接。例如,直链亚烷基可为-(CH2)n-的二价基团,其中n为1、2、3、4、5或6。代表性亚烷基包括但不限于亚甲基、亚乙基、亚丙基、亚异丙基、亚丁基、亚异丁基、亚仲丁基、亚戊基和亚己基。在一些实施方案中,亚烷基可被取代或未被取代。当包含亚烷基的基团任选地被取代时,应理解,任选的取代可在所述部分的亚烷基部分上。
术语“环烷基”是指具有指示数目的环原子的单环、双环或多环非芳香族烃环系统(例如具有3至6个环碳原子的C3-6环烷基)。环烷基可为饱和或部分不饱和的,即环烷基的特征可在于一个或多个不饱和点,条件是不饱和点不会产生芳香族系统。单环环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基、环己烯基、环庚基、环辛基、环辛烯基、环辛二烯基等。“环烷基”还指双环和多环烃环,例如双环[2.2.1]庚烷、双环[2.2.2]辛烷等。在一些实施方案中,本公开的环烷基化合物为单环C3-6环烷基部分。
术语“杂环烷基”是指具有指示数目的环顶点(或成员)(例如3至14元、或4至10元、或4至8元、或4至6元)并且具有一至五个选自N、O和S的杂原子的单环、双环或多环环烷基环,所述杂原子呈化学稳定排列,其置换一至五个碳顶点,并且其中氮和硫原子任选地被氧化,并且氮原子任选地被季铵化。杂环烷基可为饱和或部分不饱和的,即杂环烷基的特征可在于一个或多个不饱和点,条件是不饱和点不会产生芳香族系统。双环和多环杂环烷基的环可为稠合、桥联或螺环的。杂环烷基的非限制性实例包括吡咯烷、咪唑烷、吡唑烷、丁内酰胺、戊内酰胺、咪唑烷酮、乙内酰脲、二氧戊环、邻苯二甲酰亚胺、哌啶、1,4-二噁烷、吗啉、硫代吗啉、硫代吗啉-S-氧化物、硫代吗啉-S,S-氧化物、3-氧杂-6-氮杂双环[3.1.1]庚烷、8-氮杂双环[3.2.1]辛烷、哌嗪、吡喃、吡啶酮、氧杂环丁烷、3-吡咯啉、噻喃、吡喃酮、四氢呋喃、四氢噻吩、氮杂环丁烷、奎宁环等。杂环烷基经由环碳原子与分子的其余部分连接。当杂环烷基被取代时,当化学上可容许时,所述取代基经由环碳原子或环杂原子与杂环烷基连接。
如本文所用,在本文描绘的任何化学结构中与单键、双键或三键相交的波浪线表示单键、双键或三键与分子的其余部分的连接点。此外,自取代基延伸至环(例如苯环)中心的键意在指示所述取代基与环在任一可用的环顶点处的连接,即以使得所述取代基与所述环的连接产生化学稳定排列。
如本文中所提及,二价组分包括所述组分的任一定向(正向或反向)。例如,基团“-C(O)NH-”意在包括在任一定向上的键联:-C(O)NH-或-NHC(O)-,并且类似地“-O-CH2CH2-”意在包括-O-CH2CH2-和-CH2CH2-O-两者。
除非另外陈述,否则术语“卤基”或“卤素”本身或作为另一取代基的部分意指氟、氯、溴或碘原子。此外,例如“卤烷基”的术语意在包括单卤烷基和多卤烷基。例如,术语“C1-4卤基烷基”意在包括三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基等。
除非另外陈述,否则术语“芳基”意指单环、双环或三环芳香族烃基。双环和三环环系统可稠合在一起或共价键联。芳基的非限制性实例包括苯基、萘基和联苯基。所述术语还意在包括稠合的环烷基苯基和杂环烷基苯基环系统,例如茚烷、四氢萘、色原烷和异色原烷环。作为取代基,稠环系统与分子的其余部分的连接点可经由芳香族部分上的任何碳原子、环烷基部分上的碳原子或杂环烷基部分上的原子。
术语“杂芳基”是指含有一个至五个呈化学稳定排列的选自N、O和S的杂原子的单环或稠合双环芳香族基团(或环),其中氮和硫原子任选地被氧化,并且氮原子任选地被季铵化。杂芳基可经由杂原子或碳原子与分子的其余部分连接。杂芳基的非限制性实例包括吡啶基、哒嗪基、吡嗪基、嘧啶基、三嗪基、喹啉基、喹噁啉基、喹唑啉基、噌啉基、酞嗪基、苯并三嗪基、嘌呤基、苯并咪唑基、苯并吡唑基、苯并三唑基、苯并异噁唑基、异苯并呋喃基、异吲哚基、吲嗪基、苯并三嗪基、噻吩并吡啶基、噻吩并嘧啶基、吡唑并嘧啶基、咪唑并吡啶、苯并噻唑基(benzothiaxolyl)、苯并呋喃基、苯并噻吩基、吲哚基、喹啉基、异喹啉基、异噻唑基、吡唑基、吲唑基、蝶啶基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噻二唑基、吡咯基、噻唑基、呋喃基、噻吩基等。当杂芳基被取代时,当化学上可容许时,所述取代基经由环碳原子或环杂原子与杂芳基连接。杂芳基环的取代基可选自下文所描述的可接受取代基的组。
如本文所用,术语“杂原子”意在包括氧(O)、氮(N)、硫(S)和硅(Si)。在一些实施方案中,杂原子为N、O或S。
术语“药学上可接受的盐”意在包括取决于本文所描述的化合物上发现的特定取代基,利用相对无毒的酸或碱制备的活性化合物的盐。当本公开化合物含有相对酸性官能团时,碱加成盐可通过使此类化合物的中性形式与足量的所需碱在无溶剂下或在适合惰性溶剂中接触来获得。衍生自药学上可接受的无机碱的盐的实例包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。衍生自药学上可接受的有机碱的盐包括伯、仲和叔胺的盐,包括被取代的胺、环胺、天然存在的胺等,例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苯甲基乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、氨基葡萄糖、组氨酸、海卓胺(hydrabamine)、异丙胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因(procaine)、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、缓血酸胺等。当本公开化合物含有相对碱性官能团时,酸加成盐可通过使此类化合物的中性形式与足量的所需酸在无溶剂下或在适合惰性溶剂中接触来获得。药学上可接受的酸加成盐的实例包括:衍生自无机酸的那些酸加成盐,所述无机酸如盐酸、氢溴酸、硝酸、碳酸、一氢碳酸、磷酸、一氢磷酸、二氢磷酸、硫酸、一氢硫酸、氢碘酸或亚磷酸等;以及衍生自相对无毒性有机酸的盐,所述有机酸如乙酸、丙酸、异丁酸、丙二酸、苯甲酸、丁二酸、辛二酸、反丁烯二酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯基磺酸、柠檬酸、酒石酸、甲磺酸等。还包括例如精氨酸等的氨基酸的盐,以及如葡糖醛酸或半乳糖醛酸等的有机酸的盐(参见例如Berge,S.M.等人,“Pharmaceutical Salts”,Journal ofPharmaceutical Science,1977,66,1-19)。本公开的某些特定化合物含有允许所述化合物转化成碱加成盐或酸加成盐的碱性和酸性官能团两者。
所述化合物的中性形式可通过使盐与碱或酸接触并且以常规方式分离母体化合物而再生。化合物的母体形式与各种盐形式的不同之处在于某些物理特性,例如在极性溶剂中的溶解性,但出于本公开的目的,在其他方面,所述盐等效于化合物的母体形式。
除盐形式以外,本公开提供了呈前药形式的化合物。本文所描述的化合物的前药是容易在生理条件下经历化学变化以提供本公开化合物的那些化合物。另外,前药可通过化学或生物化学方法在离体环境中转化成本公开化合物。例如,当与适合酶或化学试剂一起置于透皮贴剂储集器中时,前药可缓慢转化成本公开化合物。
某些本公开化合物可以非溶剂化形式以及溶剂化形式(包括水合形式)存在。某些本公开化合物可以多种结晶形式或非晶形式存在。
某些本公开化合物具有不对称碳原子(光学中心)或双键;外消旋物、非对映异构体、几何异构体、区位异构体和个别异构体(例如独立对映异构体)都旨在涵盖于本公开的范围内。当显示立体化学描述时,意在指其中存在所描绘异构体并且基本上不含其他异构体的化合物。‘基本上不含’其他异构体指示至少80/20比率的所描绘异构体与其他异构体,更优选地90/10、或95/5或更高。在一些实施方案中,异构体中的一者将以至少99%的量存在。
本公开化合物也可在构成此类化合物的原子中的一者或多者处含有非天然比例的原子同位素。非天然比例的同位素可定义为在于自然界中所发现的量至由100%所讨论的原子组成的量的范围内。例如,化合物可并入放射性同位素,例如氚(3H)、碘-125(125I)或碳-14(14C);或非放射性同位素,例如氘(2H)或碳-13(13C)。此类同位素变体可为在本申请内他处描述的那些提供额外效用。例如,本公开化合物的同位素变体可具有额外效用,包括但不限于作为诊断和/或成像试剂或作为细胞毒性/放射毒性治疗剂。此外,本公开化合物的同位素变体可具有改变的药物动力学和药效学特征。本公开化合物的所有同位素变体无论是否具放射性都旨在涵盖于本公开的范围内。
术语“患者”或“受试者”可互换地使用以指人类或非人类动物(例如,哺乳动物)。
术语“治疗(treat/treating/treatment)”等是指在疾病、病症或疾患或其症状已经诊断、观测等之后起始以便暂时或永久地消除、减轻、抑制、缓和或改善折磨受试者的疾病、病症或疾患的根本病因中的至少一者或与折磨受试者的疾病、病症、疾患相关的症状中的至少一者的作用过程(例如施用AXL抑制剂或包含其的药物组合物)。因此,治疗包括抑制(例如遏制疾病、病症或疾患或与其相关的临床症状的发展或进一步发展)活动性疾病。
如本文所用,术语“需要治疗”是指由医师或其他照顾者作出的受试者需要或将受益于治疗的判断。基于在医师或照顾者的专门知识范围内的多种因素作出此判断。
术语“预防(prevent/preventing/prevention)”等是指一般在受试者倾向于患特定疾病、病症或疾患的情况下,以暂时或永久地预防、抑止、抑制或减轻受试者罹患疾病、病症、疾患等的风险(如通过例如临床症状的不存在判定)或延迟其发作的方式起始(例如在疾病、病症、疾患或其症状发作之前)的作用过程(例如施用AXL抑制剂或包含其的药物组合物)。在某些情况下,所述术语也是指减缓疾病、病症或疾患的进展或抑制其进展成有害或其他不希望的状态。
如本文所用,术语“需要预防”是指由医师或其他照顾者作出的受试者需要或将受益于预防性照护的判断。基于在医师或照顾者的专门知识范围内的多种因素作出此判断。
短语“治疗有效量”是指以当向受试者施用时能够对于疾病、病症或疾患的任何症状、方面或特征具有任何可检测的正面效果的量,单独或作为药物组合物的一部分并且以单次剂量或作为一系列剂量的一部分,向受试者施用药剂(例如根据本公开的化合物)。治疗有效量可通过测量相关生理作用确定,并且其可结合给药方案和对受试者疾患的诊断分析等进行调节。举例来说,施用后测量在特定时间的AXL抑制剂(或例如其代谢物)的血清水平可指示是否已使用治疗有效量。此外,本公开的AXL抑制剂的治疗有效剂量可为当以一次或多次剂量施用受试者时产生相对于健康受试者的所需结果的量。例如,针对经历特定病症的受试者,有效剂量可为将所述病症的诊断参数、测量值、标志物等改善至少约5%、至少约10%、至少约20%、至少约25%、至少约30%、至少约40%、至少约50%、至少约60%、至少约70%、至少约80%、至少约90%或超过90%的剂量,其中100%定义为由正常受试者呈现的诊断参数、测量值、标志物等。
短语“实现变化的足够量”意指在施用特定疗法之前(例如基线水平)和之后在测量的指示物水平之间存在可检测差异。指示物包括任何客观参数(例如,血清浓度)或主观参数(例如,受试者的健康感觉)。
术语“抑制剂”和“拮抗剂”、或“活化剂”和“激动剂”分别是指例如用于活化例如配体、受体、辅因子、基因、细胞、组织或器官的抑制或活化分子。抑制剂是减少、阻断、预防、延迟活化、失活、脱敏或下调例如基因、蛋白质、配体、受体或细胞的分子。抑制剂也可定义为降低、阻断或钝化组成活性的分子。活化剂是增加、活化、促进、增强活化、敏化或上调例如基因、蛋白质、配体、受体或细胞的分子。“激动剂”是与目标相互作用以引起或促进目标活化增加的分子。“拮抗剂”是对抗激动剂的作用的分子。拮抗剂防止、降低、抑制或中和激动剂的活性,并且拮抗剂还可防止、抑制或减轻目标(例如目标受体)的组成活性,甚至当不存在所鉴定激动剂时也如此。
术语“调节(modulate/modulation)”等是指分子(例如,活化剂或抑制剂)直接或间接增加或降低特定目标(例如AXL)的功能或活性的能力。调节剂可单独起作用,或者其可使用辅因子,例如蛋白质、金属离子或小分子。调节剂的实例包括小分子化合物(例如根据本公开的化合物)和其他生物有机分子。
分子的“活性”可描述或是指分子与配体或受体的结合;催化活性;刺激基因表达或细胞信号传导、分化或成熟的能力;抗原活性;其他分子活性的调节;等。术语“增殖活性”涵盖促进例如以下各者、为以下各者所必需或与以下各者特定相关的活性:正常细胞分裂,以及癌症、肿瘤、发育不良、细胞转化、癌转移和血管生成。
如本文所用,“相当的”、“相当的活性”、“与……相当的活性”、“相当的效果”、“与……相当的效果”等是可定量和/或定性地观察的相对术语。所述术语的含义通常取决于其使用的上下文。举例来说,都激活受体的两种剂可根据定性观点视为具有相当的效果,但如果以在本领域公认的测定法(例如,剂量反应测定法)或在本领域公认的动物模型中所测定,一种剂仅能够达到另一剂活性的20%,则两种剂可根据定量观点视为缺乏相当的效果。在比较一个结果与另一结果(例如一个结果与参考标准)时,“相当的”通常(但未必总是)意指一个结果偏离参考标准小于35%、小于30%、小于25%、小于20%、小于15%、小于10%、小于7%、小于5%、小于4%、小于3%、小于2%或小于1%。在特定实施方案中,如果一个结果与参考标准偏离小于15%、小于10%或小于5%,则其与参考标准相当。举例来说(但不限制),活性或效果可指功效、稳定性、溶解性或免疫原性。
“基本上纯”指示组分(例如根据本公开的化合物)占组合物总含量的大于约50%,并且通常占总含量的大于约60%。更通常,“基本上纯”是指其中总组合物的至少75%、至少85%、至少90%或更多为所关注组分的组合物。在一些情况下,所关注组分将占组合物总含量的大于约90%或大于约95%。
例如细胞、组织、器官或生物体的术语“反应”涵盖生物化学或生理行为(例如浓度、密度、粘着力或生物代谢区内的迁移、基因表达率或分化状态)的变化,其中所述变化与活化、刺激或治疗或与内部机制(例如遗传程序化)相关。在某些情况下,术语“活化”、“刺激”等是指如通过内部机制以及通过外部或环境因素调节的细胞活化;而术语“抑制”、“下调”等是指相反效果。
选择性的化合物可尤其适用于治疗某些病症或可提供减小非所要副作用的可能性。在一个实施方案中,本公开化合物相对于其他受体酪氨酸激酶(例如MER和/或TYRO3)具有选择性。选择性可例如通过比较如本文所描述的化合物针对AXL的抑制与所述化合物针对另一受体酪氨酸激酶(例如MER和/或TYRO3)的抑制来测定。在一个实施方案中,AXL的选择性抑制比其他受体酪氨酸激酶的抑制大至少1000倍、大500倍、大100倍、大50倍、大40倍、大30倍或大20倍。
本公开化合物
在一个特定方面,本文提供了具有式(I)的化合物:
或其药学上可接受的盐、水合物或溶剂化物,其中:
G1为N或CRG1;
G2为CRG2或N;
G3为CRG3或N;
G4为CRG4或N;
G5为CRG5或N;
RG1选自由以下组成的组:H、C1-3烷基、卤素、C1-3卤烷基和CN;
每个RG2、RG3、RG4和RG5独立地选自由以下组成的组:H、卤基、CN、C1-7烷基、C3-7环烷基、C1-3卤烷基、-O-C1-3烷基、-O-C1-3卤烷基、-NRaRb和具有1-3个选自由O、N和S组成的组的杂原子环顶点的4至8元杂环烷基,并且其中所述环烷基和所述杂环烷基被0-3个独立地选自以下的基团取代:卤基、CN、C1-4烷基、C1-4卤烷基、C1-4羟烷基、-O-C1-4烷基和OH;
R1选自由以下组成的组:H、C1-4烷基和NH2;
A为选自由以下组成的组的稠环:氮杂环庚烷、哌啶、环庚烷、环己烷、环戊烷、1,4-氧氮杂环庚烷、氧杂环庚烷、四氢吡喃、1,4-二氮杂环庚烷、双环[4.2.1]壬烷、双环[4.1.1]辛烷、螺[4.6]十一烷、1-氮杂螺[4.6]十一烷和环辛烷,其中的每一者未被取代或被1至4个R2取代,并且进一步被0或1个邻接于氮原子的氧代基(=O)取代;
B为选自由以下组成的组的稠环:1,4-氧氮杂环庚烷、环庚烷、四氢吡喃、异噻唑烷1,1-二氧化物、氧杂环庚烷、1,4,5-氧硫氮杂环庚烷4,4-二氧化物、环己烷、环戊烷、氮杂环庚烷、吡咯烷、哌啶、哌嗪、吗啉、二氮杂环庚烷和1,3-二氧戊环,其中的每一者未被取代或被1至4个R4取代;并且进一步被0或1个邻接于氮原子的氧代基(=O)取代;
每个R2独立地选自由以下组成的组:卤基、OH、C1-7烷基、C3-7烯基、C3-7炔基、C3-7环烷基、-C(O)-C1-7烷基、-C(O)-C3-7环烷基、-C(O)-C1-7亚烷基-OH、-Y1-O-C1-7烷基、-Y1-O-C3-7环烷基、-NRaRb、-S(O)2-C1-7烷基、-S(O)2-C3-7环烷基、-C(O)NRaRb、4至8元杂环烷基和-NRa-(4至8元杂环烷基),其中所述4至8元杂环烷基具有1-3个选自由O、N和S组成的组的杂原子环顶点,并且其中所述环烷基和所述杂环烷基被0-3个独立地选自以下的基团取代:卤基、CN、C1-4烷基、C1-4卤烷基、C1-4羟烷基、-O-C1-4烷基和OH;
下标n为0、1、2或3;
每个R3独立地选自由以下组成的组:卤素、CN、C1-7烷基、C2-7烯基、C3-7炔基、C3-7环烷基、C1-6卤烷基、C1-6羟烷基、C1-6卤羟烷基、-O-C1-7烷基、-O-C3-7环烷基、-O-C1-6卤烷基、-X1-CN、-X1-O-C1-7烷基、-O-Y1-O-C1-7烷基、-NRaRb、-X1-NRaRb、-O-Y1-NRaRb、-C(O)-NRaRb、-S(O)2-NRaRb、-S(O)(NH)-C1-7烷基、-S(O)2-C1-7烷基、-S(O)2-C1-7卤烷基、-S(O)2-C3-7环烷基、-S(O)2-Y1-O-C1-3烷基、-S(O)2-(4至8元杂环烷基)、-C(O)NH-(4至8元杂环烷基)、4至8元杂环烷基和-O-X1-(4至8元杂环烷基),其中所述4至8元杂环烷基具有1-2个选自由O、N和S组成的组的杂原子环顶点;并且其中所述环烷基和所述杂环烷基被0-3个独立地选自以下的基团取代:卤基、CN、C1-4烷基、C1-4卤烷基、C1-4羟烷基、-O-C1-4烷基和OH;
每个R4独立地选自由以下组成的组:H、卤素、羟基、CN、C1-7烷基、C2-7烯基、C3-7炔基、C3-7环烷基、C1-6卤烷基、C1-6羟烷基、C1-6卤羟烷基、-O-C1-7烷基、-O-C3-7环烷基、-O-C1-6卤烷基、-X1-CN、-X1-O-C1-7烷基、-S(O)2-C1-4烷基、-S(O)2-C3-7环烷基、-C(O)NRaRb、-NRaRb、-NRa-C(O)-C1-7烷基、-NRa-C(O)-C3-7环烷基、-NRa-S(O)2-C1-7烷基和-NRa-S(O)2-C3-7环烷基,其中-NRaRb、-NRa-C(O)-C1-7烷基、-NRa-C(O)-C3-7环烷基、-NRa-S(O)2-C1-7烷基和-NRa-S(O)2-C3-7环烷基不与氮环顶点直接连接以形成N-N键;
或与共同碳连接的两个R4组合以形成未被取代或被1-3个独立地选自F、Cl、OH和CH3的成员取代的C3-6螺环烷基;
每个X1为C1-7亚烷基或C3-7亚环烷基;
每个Y1为C2-7亚烷基或C3-7亚环烷基,其中两个连接的杂原子不与共同碳原子连接;
每个Ra和Rb独立地选自由以下组成的组:H、C1-7烷基、C1-7卤烷基、C1-4烷氧基C1-4烷基和C3-7环烷基;或
Ra和Rb与其所连接的氮一起形成具有0-2个选自由O、N和S组成的组的额外杂原子环顶点并且被0-3个独立地选自以下的基团取代的4-8元杂环烷基环:卤素、CN、C1-4烷基、C1-4卤烷基、C1-4羟烷基、-O-C1-4烷基、氧代基和OH。
在一些所选实施方案中,所述式(I)化合物或其药学上可接受的盐、水合物或溶剂化物为其中G1为N的化合物。在其他所选实施方案中,所述式(I)化合物或其药学上可接受的盐、水合物或溶剂化物为其中G1为CH的化合物。
在一些所选实施方案中,所述式(I)化合物或其药学上可接受的盐、水合物或溶剂化物(包括以上的任何所选实施方案)为其中G2为CH或CF的化合物。
在一些所选实施方案中,所述式(I)化合物或其药学上可接受的盐、水合物或溶剂化物(包括以上的所选实施方案)为其中G3选自由CH、CF、C(CH3)和N组成的组的化合物。
在一些所选实施方案中,所述式(I)化合物或其药学上可接受的盐、水合物或溶剂化物(包括以上的任何所选实施方案)为其中G4为CH、CCl或N的化合物。
在一些所选实施方案中,所述式(I)化合物或其药学上可接受的盐、水合物或溶剂化物(包括以上的任何所选实施方案)为其中G5为CH或N的化合物。
在一些所选实施方案中,所述式(I)化合物或其药学上可接受的盐、水合物或溶剂化物为其中G1为N并且G2为CH的化合物。在其他所选实施方案中,G1为N,G2为CH并且G3为CH。在又其他所选实施方案中,G1为N,G2为CH,G3为CH并且G4为CH。在另其他所选实施方案中,G1为N,G2为CH,G3为CH,G4为CH并且G5为CH。
关于环A,应理解,环A与包含G3、G4和G5的芳香族环稠合,并且环A的存在不会破坏芳香族环的芳香性。具体来说,将两个环稠合在一起的环顶点为sp2杂交碳原子。因此,这些环顶点中的每一者具有参与芳香族环的共轭π体系的p轨道。因此,应理解,所有环A部分在与分子的其余部分的稠合点处均具有不饱和点。例如,在环A处的环戊烷是指环戊烯,其中双键在与化合物的其余部分稠合的两个碳原子之间。
类似于环A,环B与芳香族苯环稠合,并且环B的存在不会破坏苯环的芳香性。因此,应理解,所有环B部分在与分子的其余部分的稠合点处都具有不饱和点。例如,在环B处的环庚烷是指环庚烯,其中双键在与化合物的其余部分稠合的两个碳原子之间。
在一些所选实施方案中,所述式(I)化合物或其药学上可接受的盐、水合物或溶剂化物(包括以上的任何所选实施方案)为其中稠环A具有选自由以下组成的组的式的化合物:
其中的每一者未被取代或被1至4个R2取代。在又其他所选实施方案中,稠环A具有下式:
在另其他所选实施方案中,所述式(I)化合物或其药学上可接受的盐、水合物或溶剂化物(包括以上的任何所选实施方案)为其中一个R2为-NRaRb的化合物。在又其他所选实施方案中,Ra和Rb与其各自连接的氮组合以形成4至6元杂环烷基环,其具有0-2个选自由O、N和S组成的组的额外杂原子环顶点,并且经0-3个独立地选自以下的基团取代:卤素、CN、C1-4烷基、C1-4卤烷基、C1-4羟烷基、-O-C1-4烷基、氧代基和OH。在其他实施方案中,Ra和Rb与其各自连接的氮组合以形成未被取代或被1-3个独立地选自以下的基团取代的吡咯烷基环:卤素、CN、C1-4烷基、C1-4卤烷基、C1-4羟烷基、-O-C1-4烷基、氧代基和OH。
在一些所选实施方案中,所述式(I)化合物或其药学上可接受的盐、水合物或溶剂化物(包括以上的任何所选实施方案)为其中稠环A具有选自由以下组成的组的式的化合物:
其中的每一者任选地被额外1至2个R2取代。在又其他所选实施方案中,稠环A具有下式:
在另其他所选实施方案中,所述式(I)化合物或其药学上可接受的盐、水合物或溶剂化物(包括以上的任何所选实施方案)为其中R2选自由以下组成的组的化合物:C1-7烷基、C3-7环烷基、-C(O)-C1-7烷基、-C(O)-C3-7环烷基、-C(O)-C1-7亚烷基-OH、-Y1-O-C1-7烷基、-Y1-O-C3-7环烷基、-S(O)2-C1-7烷基、-S(O)2-C3-7环烷基、-C(O)NRaRb和4至8元杂环烷基,其中所述4至8元杂环烷基具有1-3个选自由O、N和S组成的组的杂原子环顶点,并且其中所述环烷基和所述杂环烷基被0-3个独立地选自以下的基团取代:卤基、CN、C1-4烷基、C1-4卤烷基、C1-4羟烷基、-O-C1-4烷基和OH。
在一些所选实施方案中,所述式(I)化合物或其药学上可接受的盐、水合物或溶剂化物(包括以上的任何所选实施方案)为其中稠环B选自由以下组成的组的化合物:1,4-氧氮杂环庚烷、四氢吡喃、异噻唑烷1,1-二氧化物、1,4,5-氧硫氮杂环庚烷4,4-二氧化物、氮杂环庚烷和吡咯烷,其中的每一者未被取代或被1至3个R4取代;并且进一步被0或1个邻接于氮原子的氧代基(=O)取代。在其他所选实施方案中,每个R4独立地选自由以下组成的组:卤素、C1-4烷基、C1-4卤烷基和OH,或与共同碳连接的两个R4组合以形成未被取代或被1-3个独立地选自F、Cl、OH和CH3的成员取代的C3-6螺环烷基。
在一些所选实施方案中,所述式(I)化合物或其药学上可接受的盐、水合物或溶剂化物(包括以上的任何所选实施方案)为化合物,其中稠环B具有选自由以下组成的组的式:
其中的每一者未被取代或被1至2个R4取代。在一些其他所选实施方案中,稠环B未被取代。在其他所选实施方案中,稠环B为
在一些所选实施方案中,所述式(I)化合物或其药学上可接受的盐、水合物或溶剂化物(包括以上的任何所选实施方案)为其中稠环B具有选自由以下组成的组的式的化合物:
其中的每一者未被取代或被1至4个R4取代。在一些其他所选实施方案中,稠环B被1至4个R4取代,R4中的每一者独立地选自由以下组成的组:卤素、C1-4烷基、C1-4卤烷基和OH。
在其他所选实施方案中,所述式(I)化合物或其药学上可接受的盐、水合物或溶剂化物(包括以上的任何所选实施方案)为其中稠环B具有选自由以下组成的组的式的化合物:
其中的每一者未被取代或被1至3个R4取代。在一些其他所选实施方案中,每个R4独立地选自由以下组成的组:C1-4烷基和C1-4卤烷基。
在一些所选实施方案中,提供了表1中的任一种化合物或其药学上可接受的盐、溶剂化物或水合物。
合成方法
用于制备权利要求书的化合物的通用方法
不加限制地,适用于构建根据本公开的化合物的方法可由可以任何次序进行的四个部分组成:连接a和b片段、连接b和c片段、连接c和d片段或修饰所有片段中存在的官能团。本公开化合物的通用逆合成解连接成适用于构建所述化合物的片段a-d显示如下:
用于制备所要求保护的化合物的若干方法是示例性的(反应式1-6)。反应式(1)展示一种经由还原胺化在片段a与b之间形成键的方法。片段a与b之间形成键可发生在片段b与c之间形成键之前或之后。在反应式(1)的情况下,所需胺经由使用氢化物源和乙酸或已知用于还原胺化的任何其他条件而与所需酮连接。
胺和酮的相对位置也可颠倒,如反应式(2)中所示例。本领域技术人员将认识到,存在将产生所需连接性和产物的其他可能条件。
反应式(3)展示另一种经由两种搭配物的初始缩合和缩醛胺形成,接着添加格林纳试剂(Grignard reagent)而形成a-b片段的方法。此顺序在邻接于胺氮原子的碳原子上产生额外烷基取代基。
片段b与c之间形成键可产生在片段a与b之间或片段c与d之间形成键之前或之后。反应式(4)展示一种经由交叉偶联连接b和c片段的方法。Y可选自适当组,如B(OH)2、B(OR)2、ZnCl、MgBr、SnR3等。Z可选自适当组,如Cl、Br、I、OTf等。偶联是由过渡金属催化剂(优选地钯)与适当配体介导的。所述偶联可通过有机或无机碱辅助。在双环部分上使用保护基如SEM、Boc、THP、PMB、MOM、MEM、TIPS等,通常提高所需产物的产量和纯度。
偶联搭配物的相对官能化也可颠倒,如反应式(5)中所示。本领域技术人员将认识到,存在也将产生所需产物的其他可能组合和条件。
片段c与d之间形成键可发生在片段b与c之间形成键之前或之后。反应式(6)展示一种经由交叉偶联连接c和d片段的方法。Y可选自适当组,如B(OH)2、B(OR)2、ZnCl、MgBr、SnR3等。Z可选自适当组,如Cl、Br、I、OTf等。偶联是由过渡金属催化剂(优选地钯)与适当配体介导的。所述偶联可通过有机或无机碱辅助。在双环部分上使用保护基如SEM、Boc、THP、PMB、MOM、MEM、TIPS等,通常提高所需产物的产量和纯度。
对于本公开的任何特定化合物的最有效制备而言,片段的连接时序和顺序和任一片段中存在的官能团的修饰可变化,并且将取决于所存在的官能团。上文描述的多种方法已用于制备本公开化合物,并且示例于下文。下文实施例的氘化形式可使用适当氘化中间体来合成。
治疗性和预防性用途
本公开涵盖本文所描述的AXL抑制剂在治疗或预防一系列疾病、病症和/或疾患和/或其症状中的用途。虽然下文详细地描述特定用途,但应理解本公开不限于此。此外,尽管下文阐述通用类别的特定疾病、病症和疾患,但一些疾病、病症和疾患可为超过一个类别的成员,并且其他可不为所公开类别中的任一者的成员。
在一些实施方案中,本文所描述的AXL抑制剂以有效逆转、阻止或减缓AXL介导的失调的进展的量施用。
肿瘤学相关病症。本文所描述的AXL抑制剂可用于治疗或预防增殖性疾患或病症,包括癌症,例如子宫癌、宫颈癌、乳腺癌、前列腺癌、睾丸癌、胃肠道癌(例如,食道癌、口咽癌、胃癌、小肠或大肠癌、结肠癌或直肠癌)、肾癌、肾细胞癌、膀胱癌、骨癌、骨髓癌、皮肤癌、头或颈癌、肝癌、胆囊癌、心脏癌、肺癌、胰腺癌、唾液腺癌、肾上腺癌、甲状腺癌、脑癌(例如,神经胶质瘤)、神经节癌、中枢神经系统癌症(CNS)和外周神经系统癌症(PNS)、造血系统癌症和免疫系统(例如,脾脏或胸腺)癌症以及骨髓发育不良综合征。本公开还提供了治疗或预防其他癌症相关疾病、病症或疾患的方法,所述疾病、病症或疾患包括例如免疫原性肿瘤、非免疫原性肿瘤、休眠肿瘤、病毒诱导的癌症(例如,上皮细胞癌、内皮细胞癌、鳞状细胞癌和乳头状瘤病毒)、腺癌、淋巴瘤、癌瘤、黑色素瘤、白血病、骨髓瘤、肉瘤、畸胎癌、化学诱导的癌症、癌转移和血管生成。在特定实施方案中,肿瘤或癌症为结肠癌、卵巢癌、乳腺癌、膀胱癌(例如尿路上皮癌)、食道癌、肾癌(例如透明细胞肾细胞癌)、胰腺癌(例如胰管腺癌)、黑色素瘤、肝癌(例如肝细胞癌)、肺癌(例如非小细胞肺癌)、头颈癌(例如头颈部鳞状细胞癌)、神经胶母细胞瘤、白血病(例如急性骨髓性白血病和慢性淋巴细胞性白血病)或骨髓发育不良综合征。在一些实施方案中,癌症为白血病(例如急性骨髓性白血病)、肺癌(例如非小细胞肺癌)或肾癌(例如透明细胞肾细胞癌)。术语癌症相关疾病、病症和疾患的使用意在广泛指与癌症直接或间接相关的疾患,并且包括例如血管生成和癌变前疾患如发育不良。
在一些实施方案中,根据本公开的化合物适用于治疗肾癌。在其他实施方案中,肾癌为肾细胞癌。在另外其他实施方案中,肾细胞癌为透明细胞肾癌(ccRCC)。
在一些实施方案中,根据本公开的化合物适用于治疗肺癌。在其他实施方案中,肺癌为非小细胞肺癌(NSCLC)。在另外其他实施方案中,NSCLC为鳞状细胞肺癌或肺腺癌。在一些实施方案中,NSCLC为EGFR突变型NSCLC。
在一些实施方案中,根据本公开的化合物适用于治疗白血病。在其他实施方案中,白血病为急性骨髓性白血病(AML)。在另外其他实施方案中,AML为复发性AML。
在一些实施方案中,根据本公开的化合物适用于治疗乳腺癌。在其他实施方案中,乳腺癌为激素受体阳性(例如ERα阳性乳腺癌、PR阳性乳腺癌、ERα阳性和PR阳性乳腺癌)、HER2阳性乳腺癌、HER2过度表达乳腺癌或其任何组合。在另外其他实施方案中,乳腺癌为三阴性乳腺癌。
在一些实施方案中,根据本公开的化合物适用于治疗胰腺癌。在其他实施方案中,胰腺癌为胰腺神经内分泌肿瘤或胰腺腺癌(即,胰管腺癌(PDAC))。
在某些实施方案中,癌症可为转移性的或具有变成转移性的风险,或者可出现在弥漫性组织中,包括血液或骨髓的癌症(例如白血病或骨髓发育不良综合征)。
肿瘤微环境的低氧条件已显示上调AXL的表达。因此,在一些实施方案中,根据本公开的AXL抑制剂适用于治疗低氧肿瘤。
在一个或多个实施方案中,癌症为致癌基因成瘾癌症。致癌基因成瘾癌症是生长和存活依赖于显性致癌基因的癌症,例如ALK、ABL、AURORA、AKT、PDGFR、KIT、EGFR、VEGF、FGFR3、FLT-3、MYC、RET、BRAF、PI3K、NF-κB、JAK、STAT、BCL-2、MCL-1、KRAS、HRAS、MEK、ERK、HER-2、HER-3或MET。
在一些实施方案中,本公开提供了用AXL抑制剂和至少一种额外治疗或诊断剂治疗增生性疾患、癌症、肿瘤或癌变前疾患的方法,其实例在本文中他处阐述。
免疫和炎症相关病症。可用本公开的化合物和组合物治疗或预防的免疫和炎症相关疾病、病症和疾患的非限制性列表包括关节炎(例如,类风湿性关节炎)、肾衰竭、狼疮、哮喘、牛皮癣、结肠炎、胰腺炎、过敏、纤维化、手术并发症(例如,其中炎性细胞因子阻止愈合)、贫血和纤维肌痛。可与慢性炎症相关的其他疾病和病症包括阿尔茨海默病(Alzheimer's disease)、充血性心力衰竭、中风、主动脉瓣狭窄、动脉硬化、骨质疏松、帕金森病(Parkinson's disease)、感染、炎症性肠病(例如,克罗恩病(Crohn's disease)和溃疡性结肠炎)、慢性阻塞性肺病(COPD)、动脉粥样硬化、过敏性接触性皮炎和其他湿疹、全身性硬化、移植和多发性硬化。
在本公开的特定实施方案中,AXL抑制剂用于通过提供佐剂活性来增加或增强对抗原的免疫反应。在一个特定实施方案中,向受试者施用至少一种抗原或疫苗与至少一种本公开的AXL抑制剂的组合以延长对所述抗原或疫苗的免疫反应。还提供了治疗组合物,其包括:至少一种抗原性剂或疫苗组分,包括但不限于病毒、细菌和真菌或其部分、蛋白质、肽、肿瘤特异性抗原和核酸疫苗,以及至少一种本公开的AXL抑制剂。
在一些实施方案中,本文所描述的AXL抑制剂可与免疫抑制剂组合以减少免疫效应细胞的数目。
其他病症。本公开的实施方案涵盖向受试者施用本文所描述的AXL抑制剂以用于治疗或预防可得益于至少一定水平的AXL抑制的任何其他病症。此类疾病、病症和疾患包括例如心血管病症(例如,心脏缺血)和代谢病症(例如,糖尿病、胰岛素抗性、肥胖)。
患者的选择
在一些实施方案中,通过评估相关组织或样品中的AXL表达(例如可溶性AXL(即sAXL)、细胞表面AXL或总AXL)来选择患者。在一些实施方案中,通过进一步评估相关组织或样品中的GAS6表达来选择患者。在一些实施方案中,本公开提供了一种用如本文所描述的化合物来治疗AXL表达升高的患者的癌症的方法。在一个实施方案中,本公开提供了一种用如本文所描述的化合物来治疗细胞表面AXL表达升高的患者的癌症的方法。在另一个实施方案中,本公开提供了一种用如本文所描述的化合物来治疗sAXL表达升高的患者的癌症的方法。在再一个实施方案中,本公开提供了一种用如本文所描述的化合物来治疗sAXL表达与GAS6表达的比率升高的患者的癌症的方法。在一些实施方案中,本公开提供了一种基于AXL表达的相对量的测定,向个体施用治疗有效量的AXL抑制剂以治疗癌症的方法。在另一个实施方案中,本公开提供了一种基于细胞表面AXL表达的相对量的测定,向个体施用治疗有效量的AXL抑制剂以治疗癌症的方法。在另一个实施方案中,本公开提供了一种基于sAXL表达的相对量的测定,向个体施用治疗有效量的AXL抑制剂以治疗癌症的方法。在再一个实施方案中,本公开提供了一种基于sAXL表达与GAS6表达的相对比率的测定,向个体施用治疗有效量的AXL抑制剂以治疗癌症的方法。
药物组合物
本公开的AXL抑制剂可呈适合于向受试者施用的组合物形式。一般来说,此类组合物为“药物组合物”,其包含如本文所描述的AXL抑制剂或其药学上可接受的盐以及药学上可接受的赋形剂。在某些实施方案中,AXL抑制剂以有效量存在。药物组合物可用于本公开的方法中。
本公开的药物组合物可经配制以与预期方法或施用途径相容;示例性施用途径在本文中阐述。此外,药物组合物可与其他治疗活性剂或如本文中所描述的化合物组合使用以便治疗或预防如由本公开涵盖的疾病、病症和疾患。
含有活性成分(例如AXL抑制剂)的药物组合物可呈适用于口服使用的形式,例如呈片剂、胶囊、锭剂、糖锭、水性或油状悬浮液、可分散散剂或颗粒剂、乳液、硬或软胶囊、或糖浆、溶液、微珠或酏剂形式。预期用于口服使用的药物组合物可使用一种或多种赋形剂(例如甜味剂、调味剂、着色剂和防腐剂)来制备,以便提供药学上精致且可口的制剂。片剂、胶囊等含有与适合于制造的无毒的药学上可接受的赋形剂掺合的活性成分。这些赋形剂可为例如稀释剂,如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;造粒剂和崩解剂,例如玉米淀粉或褐藻酸;粘合剂,例如淀粉、明胶或阿拉伯胶;以及润滑剂,例如硬脂酸镁、硬脂酸或滑石。
用于口服使用的制剂也可以硬明胶胶囊形式呈现,其中将活性成分与惰性固体稀释剂(例如碳酸钙、磷酸钙、高岭土或微晶纤维素)混合;或以软明胶胶囊形式呈现,其中将活性成分与水或油状介质(例如花生油、液体石蜡或橄榄油)混合。
水性悬浮液含有与适合于其制造的赋形剂掺合的活性材料。此类赋形剂可为悬浮剂,例如羧甲基纤维素钠、甲基纤维素、羟基-丙基甲基纤维素、海藻酸钠、聚乙烯-吡咯烷酮、黄蓍胶(gum tragacanth)和阿拉伯胶;分散剂或润湿剂,例如天然存在的磷脂(例如,卵磷脂)、或环氧烷与脂肪酸的缩合产物(例如,聚氧乙烯硬脂酸酯)、或环氧乙烷与长链脂族醇的缩合产物(例如,十七亚乙基氧基十六醇)、或环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物(例如,聚氧化乙烯山梨糖醇单油酸酯),或环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物(例如,聚乙烯脱水山梨糖醇单油酸酯)。水性悬浮液还可含有一种或多种防腐剂。
油性悬浮液可通过将活性成分悬浮于植物油(例如,花生油、橄榄油、芝麻油或椰子油)中或矿物油(例如液体石蜡)中来配制。油性悬浮液可含有增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。可添加甜味剂(例如上文所阐述的那些甜味剂)和调味剂,以提供可口的口服制剂。
适合于通过添加水来制备水性悬浮液的可分散散剂和颗粒剂提供与分散剂或润湿剂、悬浮剂和一种或多种防腐剂掺合的活性成分。适合的分散剂或润湿剂和悬浮剂示例于本文中。
本公开的药物组合物也可呈水包油乳液形式。油相可为植物油,例如橄榄油或花生油;或矿物油,例如液体石蜡,或这些的混合物。适合的乳化剂可为天然存在的胶,例如阿拉伯胶或黄蓍胶;天然存在的磷脂,例如大豆、卵磷脂,和衍生自脂肪酸的酯或偏酯;己糖醇酐,例如脱水山梨糖醇单油酸酯;和偏酯与氧化乙烯的缩合产物,例如聚氧化乙烯脱水山梨糖醇单油酸酯。
药物组合物通常包含治疗有效量的本公开所涵盖的AXL抑制剂和一种或多种药学上和生理学上可接受的配制剂。合适的药学上可接受或生理学上可接受的稀释剂、载剂或赋形剂包括但不限于抗氧化剂(例如抗坏血酸和硫酸氢钠)、防腐剂(例如苯甲醇、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯)、乳化剂、悬浮剂、分散剂、溶剂、填充剂、增积剂、洗涤剂、缓冲剂、媒介物、稀释剂和/或佐剂。例如,合适的媒介物可为生理盐水溶液或柠檬酸盐缓冲盐水,其可能补充有用于肠胃外施用的药物组合物中常见的其他材料。中性缓冲盐水或与血清白蛋白混合的盐水为其他示例性媒介物。本领域技术人员将易于认识到可用于本文所涵盖的药物组合物和剂型中的各种缓冲剂。药物组合物中可包括的典型缓冲剂包括但不限于药学上可接受的弱酸、弱碱或其混合物。作为实例,缓冲剂组分可为水溶性材料如磷酸、酒石酸、乳酸、丁二酸、柠檬酸、乙酸、抗坏血酸、天冬氨酸、谷氨酸和其盐。可接受的缓冲剂包括例如Tris缓冲液、N-(2-羟乙基)哌嗪-N′-(2-乙磺酸)(HEPES)、2-(N-吗啉基)乙磺酸(MES)、2-(N-吗啉基)乙磺酸钠盐(MES)、3-(N-吗啉基)丙磺酸(MOPS)和N-三[羟甲基]甲基-3-氨基丙磺酸(TAPS)。
在已配制药物组合物之后,可将其以溶液、悬浮液、凝胶、乳液、固体或脱水或冻干粉末形式储存于无菌小瓶中。此类制剂可以即用形式、需要在使用之前重构的冻干形式、需要在使用之前稀释的液体形式或其他可接受的形式储存。在一些实施方案中,药物组合物以单次用容器(例如单次用小瓶、安瓿、注射器或自动注射器)形式提供,而在其他实施方案中以多次用容器(例如多次用小瓶)的形式提供。
药物组合物可呈无菌可注射水性或油性悬浮液形式。此悬浮液可使用赋形剂(如合适的分散剂、润湿剂和/或悬浮剂)配制。无菌可注射制剂也可为于作为赋形剂的无毒肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如呈于1,3-丁二醇中的溶液形式。可采用的可接受的稀释剂、溶剂和分散介质包括水、林格氏溶液(Ringer'ssolution)、等张氯化钠溶液、Cremophor ELTM(BASF,Parsippany,NJ)或磷酸盐缓冲盐水(PBS)、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇)和其适合的混合物。另外,可采用无菌不挥发性油作为溶剂或悬浮介质。出于此目的,可采用任何温和的不挥发性油,包括合成单甘油酯或二甘油酯。此外,脂肪酸如油酸可用于制备可注射剂。特定可注射制剂的延长吸收可通过包括延迟吸收的药剂(例如单硬脂酸铝或明胶)来实现。
本公开涵盖的AXL抑制剂可呈目前已知或将来开发的任何其他适合的药物组合物(例如用于经鼻或吸入用途的喷雾剂)形式。
施用途径
本公开涵盖以任何适当方式施用AXL抑制剂和其组合物。合适的施用途径包括口服、肠胃外(例如,肌肉内、静脉内、皮下(例如,注射或植入)、腹膜内、脑池内、关节内、脑内(脑实质内)和脑室内)、经鼻、经阴道、舌下、眼内、经直肠、局部(例如,透皮)、经颊和吸入。也可利用通常皮下或肌肉内施用的储槽式注射剂来经限定时段释放本文所公开的AXL抑制剂。
本公开的特定实施方案涵盖口服施用。
组合疗法
本公开涵盖AXL抑制剂单独或与一种或多种活性治疗剂组合的用途。其他活性治疗剂可为小化学分子;大分子,例如蛋白质、抗体、肽体、肽、DNA、RNA或此类大分子的片段;或细胞或基因疗法。组合疗法可靶向不同但互补的作用机制并且由此对潜在疾病、病症或疾患具有协同的治疗或预防作用。另外或替代地,组合疗法可允许药剂中的一者或多者的剂量减少,由此改善、减少或消除与药剂中的一者或多者相关的不良反应。
此类组合疗法中的活性治疗剂可配制为单一组合物或单独组合物。如果分别施用,则可在相同或大约相同的时间或在不同时间给与组合中的每个治疗剂。此外,“组合”施用治疗剂,即使其具有不同的施用形式(例如,口服胶囊和静脉内),其以不同的剂量间隔给药,一种治疗剂以恒定给药方案给药,而滴定增加、滴定减小或中断另一治疗剂,或组合中的每个治疗剂的剂量在患者的治疗疗程期间独立地滴定增加、滴定减小、增加或减小,或中断和/或恢复治疗。如果组合配制为单独组合物,则在一些实施方案中,单独组合物一起提供于药盒中。
在一些实施方案中,根据本公开的AXL抑制剂与至少一种额外治疗剂组合。在一些实施方案中,所述至少一种额外治疗剂包含一种或多种独立地选自由以下组成的组的剂:CD47-SIRPα通路抑制剂(例如抗CD47抗体)、HIF抑制剂(例如HIF-2α抑制剂)、免疫检查点抑制剂、靶向腺苷的胞外产生的剂(例如CD73抑制剂、CD39抑制剂和/或腺苷受体抑制剂(例如A2AR和/或A2BR抑制剂)、放射疗法和化学治疗剂。额外治疗剂中的每一者进一步详细描述于下文中。
在一些实施方案中,额外治疗剂中的一者或多者为免疫调节剂。本公开涵盖的合适的免疫调节剂包括CD40L、B7和B7RP1;刺激性受体的活化单克隆抗体(mAb),如抗CD40、抗CD38、抗ICOS和4-IBB配体;树突状细胞抗原负载(体外或体内);抗癌疫苗,例如树突状细胞癌症疫苗;细胞因子/趋化因子,例如IL1、IL2、IL12、IL18、ELC/CCL19、SLC/CCL21、MCP-1、IL-4、IL-18、TNF、IL-15、MDC、IFNa/b、M-CSF、IL-3、GM-CSF、IL-13和抗IL-10;细菌性脂多糖(LPS);吲哚胺2,3-双加氧酶1(IDO1)抑制剂;和免疫刺激寡核苷酸。
在某些实施方案中,本公开提供了用于肿瘤生长的肿瘤抑制的方法,所述方法包括施用与信号转导抑制剂(signal transduction inhibito r;STI)组合的本文所描述的AXL抑制剂以实现肿瘤生长的相加或协同抑制。如本文所用,术语“信号转导抑制剂”是指选择性地抑制信号通路中的一个或多个步骤的剂。本公开涵盖的信号转导抑制剂(STI)包括:(i)BCR-ABL激酶抑制剂(例如);(ii)表皮生长因子受体酪氨酸激酶抑制剂(EGFR TKI),包括小分子抑制剂(例如吉非替尼(gefitinib)、埃罗替尼(erlotinib)、阿法替尼(afatinib)和奥希替尼(osimertinib))和抗EGFR抗体;(iii)跨膜酪氨酸激酶的人类表皮生长因子(HER)家族的抑制剂,例如HER-2/neu受体抑制剂(例如/> )和HER-3受体抑制剂;(iv)血管内皮生长因子受体(VEGFR)抑制剂,包括小分子抑制剂(例如阿西替尼(axitinib)、舒尼替尼(sunitinib)和索拉非尼(sorafenib))和抗VEGF抗体(例如贝伐单抗(bevacizuma b));(v)AKT家族激酶或AKT通路的抑制剂(例如雷帕霉素(rapamycin));(vi)丝氨酸/苏氨酸蛋白激酶B-Raf(BRAF)的抑制剂,例如维罗非尼(vemurafenib)、达拉非尼(dabrafenib)和恩拉非尼(encorafenib);(vii)转染重排(RET)抑制剂,包括例如塞尔帕替尼(selpercatinib)和普拉替尼(pralsetinib);(viii)酪氨酸蛋白激酶Met(MET)抑制剂(例如特泼替尼(tepotinib)、提瓦替尼(tivantinib)、卡博替尼(cabozantinib)、帕唑帕尼(pazopanib)、替沃扎尼(tivozanib)、XL-092和克卓替尼(crizotini b));(ix)间变性淋巴瘤激酶(ALK)抑制剂(例如恩莎替尼(ensartinib)、塞利替尼(ceritinib)、劳拉替尼(lorlatinib)、克卓替尼(crizotinib)和布加替尼(brigatinib));(x)如本文他处中所描述的RAS信号通路抑制剂(例如KRAS、HRAS、RAF、MEK、ERK的抑制剂);(xi)FLT-3抑制剂(例如吉列替尼(gilteritinib));(xii)Trop-2抑制剂;(xiii)JAK/STAT通路抑制剂,例如JAK抑制剂(包括托法替尼(tofacitinib)和卢利替尼(ruxolitinib))或STAT抑制剂(例如那帕布新(napabucasin));(xiv)NF-κB抑制剂;(xv)细胞周期激酶抑制剂(例如夫拉平度(flavopiridol));(xvi)磷脂酰肌醇激酶(PI3K)抑制剂;和(xvii)蛋白激酶B(AKT)抑制剂(例如卡匹色替(capivasertib)、米拉替布(miransertib))。参与免疫调节的剂也可与本文所描述的AXL抑制剂组合使用以抑制癌症患者中的肿瘤生长。在一个或多个实施方案中,额外治疗剂包含EGFR、VEGFR、HER-2、HER-3、BRAF、RET、MET、ALK、RAS(例如,KRAS、MEK、ERK)、FLT-3、JAK、STAT、NF-κB、PI3K、AKT、BCL-2、MCL-1、CD47或其任何组合的抑制剂。
在一些实施方案中,额外治疗剂中的一者或多者包含化学治疗剂。化学治疗剂的实例包括但不限于:烷基化剂,如噻替派(thiotepa)和环磷酰胺;磺酸烷基酯,如白消安(busulfan)、英丙舒凡(improsulfa n)和哌泊舒凡(piposulfan);氮丙啶(aziridine),如苯唑多巴(benzodopa)、卡波醌(carboquone)、米特多巴(meturedopa)和尤利多巴(uredopa);亚乙亚胺和甲基三聚氰胺,包括六甲蜜胺(altretamine)、曲他胺(triethylenemelamine)、三亚乙基磷酰胺、三亚乙基硫代磷酰胺和三羟甲基三聚氰胺;氮芥(nitrogen mustard),如苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、氯磷酰胺、雌氮芥(estramustine)、异环磷酰胺、甲氮芥(mechlorethamine)、甲氮芥氧化物盐酸盐、美法仑(melphalan)、新氮芥(novembichin)、苯芥胆甾醇(phenesterine)、泼尼氮芥(prednimu stine)、曲磷胺、尿嘧啶氮芥(uracil mustard);亚硝基脲,如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)、雷莫司汀(ranimustine);抗生素,如阿克拉霉素(aclacinomysin)、放线菌素(actinomycin)、安曲霉素(authramycin)、偶氮丝氨酸、博来霉素(bleomycin)、放线菌素C(cac tinomycin)、卡奇霉素(calicheamicin)、卡拉比辛(carabicin)、洋红霉素(caminomycin)、嗜癌菌素(carzinophilin)、色霉素(chromomycin)、放线菌素D(dactinomycin)、道诺霉素(daunorubicin)、地托比星(detorubicin)、6-重氮-5-氧代-L-正亮氨酸、多柔比星(doxorubicin)、表柔比星(epirubicin)、依索比星(esorubicin)、埃达霉素(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素(mitomycin)、霉酚酸(mycophenolic acid)、诺拉霉素(nogalamycin)、橄榄霉素(olivomycin)、泊利度胺(pomalidomid e)、培洛霉素(peplomycin)、泼非霉素(potfiromycin)、嘌呤霉素(puro mycin)、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑菌素(streptonigrin)、链脲菌素(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他丁(zinostatin)、左柔比星(zorubicin);抗代谢物,如甲氨蝶呤(methotrexate)和5-氟尿嘧啶(5-FU);叶酸类似物,如迪诺特宁(denopterin)、甲氨蝶呤、蝶罗呤(pteropterin)、曲美沙特(tri metrexate);嘌呤类似物,如氟达拉宾(fludarabine)、6-巯基嘌呤、硫咪嘌呤(thiamiprine)、硫鸟嘌呤;嘧啶类似物,如安西他滨(ancitabine)、氮胞苷(azacitidine)、6-氮尿苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、二脱氧尿苷、脱氧氟尿苷、依诺他滨(enocitabine)、氟尿苷、5-FU;雄激素,如卡鲁睾酮(calusterone)、丙酸屈他雄酮、环硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾内酯(testolactone);抗肾上腺素,如氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂,如醛叶酸(folinic acid);乙酰葡醛酯;醛磷酰胺糖苷;氨基乙酰丙酸;安吖啶(amsacrine);贝斯布西(bestra bucil);比生群(bisantrene);埃达曲克(edatraxate);得弗伐胺(defofamine);地美可辛(demecolcine);地吖醌(diaziquone);艾福米辛(elformit hine);依利醋铵(elliptinium acetate);依托格鲁(etoglucid);硝酸镓;羟基脲;蘑菇多糖(lentinan);氯尼达明(lonidamine);丙脒腙(mitogua zone);米托蒽醌(mitoxantrone);莫哌达醇(mopidamol);二胺硝吖啶(nitracrine);喷司他丁(pentostatin);苯来美特(phenamet);吡柔比星(pir arubicin);鬼臼酸(podophyllinic acid);2-乙基酰肼;丙卡巴肼(procarbazine);雷佐生(razoxane);西索菲兰(sizofiran);螺旋锗(spirogerman ium);细交链孢菌酮酸(tenuazonic acid);三亚胺醌(triaziquone);2,2',2”-三氯三乙胺;尿烷(urethan);长春地辛(vindesine);达卡巴嗪(dacar bazine);甘露醇氮芥(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);加西托星(gacytosine);阿拉伯糖苷(arabinoside)(Ara-C);环磷酰胺;噻替派(thiotepa);类紫杉醇(taxoid),例如太平洋紫杉醇(paclitaxel)、nab-太平洋紫杉醇和多西他赛(docetaxel);苯丁酸氮芥(chlorambucil);吉西他滨(gemcitabine);6-硫代鸟嘌呤;巯基嘌呤;甲氨蝶呤;铂和铂配位络合物,如顺铂、卡铂和奥沙利铂(oxaliplatin);长春碱(vinblastine);依托泊苷(etoposid e)(VP-16);异环磷酰胺;丝裂霉素C;米托蒽醌(mitoxantrone);长春新碱(vincristine);长春瑞宾(vinorelbine);温诺平(navelbine);诺安托(novantrone);替尼泊苷(teniposide);道诺霉素(daunomycin);氨基蝶呤(aminopterin);希罗达(xeloda);伊班膦酸盐(ibandronate);CPT11;拓扑异构酶抑制剂;二氟甲基鸟氨酸(DMFO);视黄酸;埃斯波霉素(esperamicin);卡培他滨(capecitabine);蒽环霉素(anthracycline);以及以上中的任一者的药学上可接受的盐、酸或衍生物。在一些实施方案中,化学治疗剂为基于铂、基于蒽环霉素或基于类紫杉醇的化学治疗剂。在一些实施方案中,化学治疗剂为顺铂、卡铂、奥沙利铂、多柔比星、多西他赛或太平洋紫杉醇。
化学治疗剂还包括用来调节或抑制激素对肿瘤的作用的抗激素剂,如抗雌激素,包括例如他莫昔芬(tamoxifen)、雷诺昔芬(raloxifene)、芳香酶抑制性4(5)-咪唑、4-羟基他莫昔芬、曲沃昔芬(trioxifene)、那洛昔芬(keoxifene)、奥那司酮(onapristone)和托瑞米芬(toremifene);和抗雄激素,如阿比特龙(abiraterone)、恩杂鲁胺(enzalutamide)、阿珀鲁胺(apalutamide)、达鲁胺(darolutamide)、氟他胺、尼鲁胺(nilutamide)、比卡鲁胺(bicalutamide)、亮丙立德(leuprolide)和戈舍瑞林(goserelin);和以上中的任一者的药学上可接受的盐、酸或衍生物。在某些实施方案中,组合疗法包含包括一种或多种化学治疗剂的化学疗法方案。在某些实施方案中,组合疗法包含施用激素或相关激素剂。
还考虑根据本公开的AXL抑制剂与聚(ADP-核糖)聚合酶(PARP)抑制剂的组合。本公开涵盖的示例性PARP抑制剂包括奥拉帕尼(olaparib)、尼拉帕尼(niraparib)和卢卡帕尼(rucaparib)。
可与AXL抑制剂组合使用的额外治疗模态包括放射疗法、针对肿瘤抗原的单克隆抗体、单克隆抗体和毒素的复合物、T细胞佐剂、骨髓移植或抗原呈递细胞(例如,树突状细胞疗法),包括用于刺激此类抗原呈递细胞的TLR激动剂。
在某些实施方案中,本公开涵盖本文所描述的化合物与过继性细胞疗法(一种其中向癌症患者施用具有抗肿瘤活性的免疫细胞的个性化免疫疗法的新颖和有前景的形式)的组合的用途。正使用经工程化以表达例如嵌合抗原受体(chimeric antigen receptor;CAR)或T细胞受体(T cell receptor;TCR)的肿瘤浸润性淋巴细胞(tumor-infiltratinglymphocyte;TIL)和T细胞来探索过继性细胞疗法。过继性细胞疗法通常涉及从个体采集T细胞,对其进行基因修饰以靶向特异性抗原或增强其抗肿瘤效果,使其扩增至充足数目,以及将经基因修饰的T细胞输注至癌症患者中。T细胞可采集自稍后将向其重新输注经扩增细胞的患者(例如自体)或可采集自供体患者(例如,同种异体)。
在某些实施方案中,本公开涵盖本文所描述的化合物与基于RNA干扰的疗法组合以使基因表达静默的用途。RNAi开始于将较长双链RNA裂解成小干涉RNA(siRNA)。将siRNA中的一条链并入至称为RNA诱导型静默复合物(RNA-induced silencing complex;RISC)的核糖核蛋白复合物中,其接着用于识别与所并入siRNA链至少部分互补的mRNA分子。RISC可与mRNA结合或裂解mRNA,其两者都抑制翻译。
在某些实施方案中,本公开涵盖本文所描述的化合物与靶向腺苷的胞外产生的组合的用途。此类治疗剂可对催化ATP转化为腺苷的胞外核苷酸起作用,包括将ATP水解为ADP并且将ADP水解为AMP的胞外核苷三磷酸二磷酸水解酶1(ENTPD1,也称为CD39或分化簇(Cluster of Differentiation)39)和将AMP转化为腺苷的胞外5'-核苷酸酶(NT5E或5NT,也称为CD73或分化簇73)。CD39和CD73的酶促活性在校准递送至各种细胞(例如,免疫细胞)的嘌呤型信号的持续时间、量值和化学性质方面发挥关键作用。这些酶促活性的更改可改变若干病理生理学事件(包括癌症、自身免疫疾病、感染、动脉粥样硬化和局部缺血-再灌注损伤)的过程或指示其结果,表明这些胞外酶表示用于管理各种病症的新颖的治疗目标。示例性抗CD39和抗CD73抗体包括ES002023、TTX-030、IPH-5201、SRF-617、CPI-006、奥勒鲁单抗(oleclumab)(MEDI9447)、NZV930、IPH5301、优利来单抗(uliledlimab)(TJD5、TJ004309)和BMS-986179。在一个或多个实施方案中,本公开涵盖与CD73抑制剂组合,所述CD73抑制剂例如WO 2017/120508、WO 2018/094148、WO 2018/067424和WO 2020/046813中所描述的那些。在一个实施方案中,CD73抑制剂为昆利司他(quemliclustat)(AB680)。
靶向腺苷的胞外产生的另一方法为靶向腺苷A2A和/或A2B受体。因此,在一些实施方案中,本公开涵盖根据本公开的化合物与靶向A2A和/或A2B受体的剂的组合。此类治疗剂可为腺苷2受体(A2R)(例如A2A和/或A2B)拮抗剂。腺苷可与四种不同的G-蛋白偶联受体结合并且活化所述G-蛋白偶联受体:A1R、A2AR、A2BR和A3R。将腺苷与在T细胞、自然杀手细胞和例如树突状细胞的骨髓细胞上表达的A2AR受体结合导致胞内环状AMP水平增加以及此类细胞的成熟和/或活化减弱。此过程显著削弱免疫系统针对癌细胞的活化。另外,A2AR已涉及选择性地增强抗炎性细胞因子,从而促进PD-1和CTLA-4的上调,促进LAG-3和Foxp3+调节性T细胞的产生并且介导对调节性T细胞的抑制。本文中进一步论述PD-1、CTLA-4和其他免疫检查点。本文中所描述的组合中组合A2R拮抗剂可鉴于其不同的作用机制提供至少相加效应。在一个实施方案中,治疗剂可为如以下中所描述的腺苷受体拮抗剂:WO/2018/136700、WO2018/204661或WO 2020/023846。在一个实施方案中,腺苷受体拮抗剂为AB928(即,艾鲁美冷(etrumadenant))。
在某些实施方案中,本公开涵盖本文所描述的化合物与磷脂酰肌醇3-激酶(PI3K)抑制剂,尤其PI3Kγ同功异型物组合的用途。PI3Kγ抑制剂可经由调节骨髓细胞,例如通过抑制抑止性骨髓细胞,抑制免疫抑止性肿瘤浸润性巨噬细胞或通过刺激巨噬细胞和树突状细胞来刺激抗癌免疫反应,以产生有助于有效T细胞反应的细胞因子,导致癌症发展和扩散减少。PI3Kγ抑制剂包括WO 2020/0247496A1中描述的那些。
在某些实施方案中,本公开涵盖本文所描述的化合物与精氨酸酶的抑制剂组合的用途,已显示所述抑制剂负责或参与炎症触发的免疫功能异常、肿瘤免疫逃逸、免疫抑制和感染性疾病的免疫病理学。示例性精氨酸酶化合物可见于例如PCT/US2019/020507和WO2020/102646中。
在某些实施方案中,本公开涵盖根据本公开的AXL抑制剂与HIF-2α的抑制剂的用途,其在对于低氧可用性的细胞反应中起整体作用。在低氧条件下,低氧诱导因子(hypoxia-inducible factor;HIF)转录因子可激活调节代谢、血管生成、细胞增殖和存活、免疫逃避和发炎反应的基因的表达。HIF-2α过度表达已与患有多种癌症的患者的不良临床结果相关;在许多急性和慢性炎症性病症如炎症性肠道疾病和类风湿性关节炎中,低氧也普遍存在。示例性HIF-2α抑制剂包括贝珠替凡(belzutifan)、ARO-HIF2、PT-2385、AB521和WO 2021113436和WO 2021188769中描述的那些。在一些实施方案中,根据本公开的AXL抑制剂与AB521组合。
本公开还涵盖本文所描述的AXL抑制剂与一种或多种RAS信号传导抑制剂的组合。RAS基因家族,例如HRAS、KRAS和NRAS中的致癌突变与多种癌症相关。例如,已在多个肿瘤类型中观测到KRAS家族基因中的G12C、G12D、G12V、G12A、G13D、Q61H、G13C和G12S等突变。已经研究直接和间接抑制策略以用于抑制突变型RAS信号传导。间接抑制剂靶向RAS信号通路中除RAS以外的效应物,并且包括但不限于RAF、MEK、ERK、PI3K、PTEN、SOS(例如SOS1)、mTOR(例如mTORC1)、SHP2(PTPN11)和AKT的抑制剂。处于开发中的间接抑制剂的非限制性实例包括RMC-4630、RMC-5845、RMC-6291、RMC-6236、JAB-3068、JAB-3312、TNO155、RLY-1971、BI1701963。还已研究RAS突变体的直接抑制剂,并且通常靶向KRAS-GTP复合物或KRAS-GDP复合物。处于开发中的示例性直接RAS抑制剂包括但不限于索妥昔布(sotorasib)(AMG510)、MRTX849、mRNA-5671和ARS1620。在一些实施方案中,一种或多种RAS信号传导抑制剂选自由以下组成的组:RAF抑制剂、MEK抑制剂、ERK抑制剂、PI3K抑制剂、PTEN抑制剂、SOS1抑制剂、mTOR抑制剂、SHP2抑制剂和AKT抑制剂。在其他实施方案中,一种或多种RAS信号传导抑制剂直接抑制RAS突变体。
在一些实施方案中,额外治疗剂中的一者或多者为:(i)抑制酶聚(ADP-核糖)聚合酶的剂(例如奥拉帕尼(olaparib)、尼拉帕尼(niraparib)和卢卡帕尼(rucaparib)等);(ii)Bcl-2蛋白家族的抑制剂(例如维纳妥拉(venetoclax)、纳维克拉斯(venetoclax)等);(iii)MCL-1抑制剂;(iv)CD47-SIRPα通路抑制剂(例如抗CD47抗体);(v)异柠檬酸脱氢酶(IDH)抑制剂,例如IDH-1或IDH-2抑制剂(例如艾伏尼布(ivosidenib)、艾那尼布(enasidenib)等)。
免疫检查点抑制剂。本公开涵盖本文所描述的AXL抑制剂与免疫检查点抑制剂组合的用途。
作为所有癌症的特征的极大数目的遗传和表观遗传改变提供免疫系统可用于区分肿瘤细胞与其正常对应物的不同组的抗原。在T细胞的情况下,经由T细胞受体(TCR)的抗原识别起始的反应的极限强度(例如细胞因子产生或增殖的水平)和质量(例如所产生免疫反应的类型,例如细胞因子产生模式)是通过共刺激信号与抑制信号(免疫检查点)之间的平衡调节。在正常生理条件下,免疫检查点对于自身免疫的预防(即,维持自身耐受性)并且还对于在免疫系统对病原性感染作出反应时保护组织免受损伤而言是至关重要的。免疫检查点蛋白的表达可由肿瘤失调作为重要免疫耐受机制。
T细胞由于以下而为治疗学上操纵内源性抗肿瘤免疫的主要工作焦点:i)其选择性识别所有细胞区室中衍生自蛋白质的肽的能力;ii)其直接识别和杀死抗原表达细胞(通过CD8+效应T细胞;也称为细胞毒性T淋巴细胞(CTL))的能力;以及iii)其通过整合后天和先天效应机制的CD4+辅助T细胞来协调不同免疫反应的能力。
在临床环境中,免疫检查点的阻断(其引起抗原特异性T细胞反应放大)显示为人类癌症疗法中的有前景的方法。
T细胞介导的免疫性包括多个依序步骤,其中的每一者通过均衡刺激和抑制信号来调节以便使反应优化。虽然免疫反应中几乎所有抑制信号最终调节细胞内信号通路,但许多经由膜受体起始,其配体为膜结合或可溶的(细胞因子)。虽然调节T细胞活化的共刺激和抑制受体和配体相对于正常组织常常在癌症中不过度表达,但在组织中调节T细胞效应功能的抑制配体和受体通常在肿瘤细胞上或在与肿瘤微环境相关的未经转化细胞上过度表达。可溶和膜结合受体-配体免疫检查点的功能可使用激动剂抗体(对于共刺激通路)或拮抗剂抗体(对于抑制通路)来调节。因此,与目前批准用于癌症疗法的大多数抗体相反,阻断免疫检查点的抗体不直接靶向肿瘤细胞,而靶向淋巴细胞受体或其配体以便增强内源抗肿瘤活性。[参见Pardoll,(2012年4月)Nature Rev.Cancer 12:252-64]。
作为阻断的候选物的免疫检查点(配体和受体)的实例(其中一些在各种类型的肿瘤细胞中选择性上调)包括PD-1(程序性细胞死亡蛋白1);PD-L1(PD-1配体);BTLA(B和T淋巴细胞衰减因子);CTLA-4(细胞毒性T淋巴细胞相关抗原4);TIM-3(T细胞膜蛋白3);LAG-3(淋巴细胞活化基因3);TIGIT(具有Ig和ITIM域的T细胞免疫受体);和杀手抑制受体,其可基于其结构特征分成两种类别:i)杀手细胞免疫球蛋白样受体(KIR)和ii)C型凝集素受体(II型跨膜受体家族的成员)。其他较不定义明确的免疫检查点已描述于文献中,包括受体(例如2B4(也称为CD244)受体)和配体(例如某些B7家族抑制配体,如B7-H3(也称为CD276)和B7-H4(也称为B7-S1、B7x和VCTN1))。[参见Pardoll,(2012年4月)Nature Rev.Cancer12:252-64]。
本公开涵盖本文中所描述的AXL抑制剂与前述免疫检查点受体和配体以及将描述的免疫检查点受体和配体的抑制剂组合的用途。免疫检查点的某些调节剂目前经批准,并且许多其他调节剂处于发展中。完全人源化CTLA-4单克隆抗体伊匹单抗(ipilimumab)( Bristol-Myers Squibb)在2011年被批准用于治疗黑色素瘤时成为接受美国监管批准的第一种免疫检查点抑制剂。包含CTLA4和抗体(CTLA4-Ig;阿巴西普(abatcept)(/>Bristol-Myers Squi bb))的融合蛋白已用于治疗类风湿性关节炎,并且其他融合蛋白已显示为在对爱泼斯坦-巴尔病毒(Epstein Barr Virus)敏感的肾移植患者中有效。接受监管批准的另一类免疫检查点抑制剂是针对PD-1和其配体PD-L1和PD-L2。经批准的抗PD-1抗体包括用于各种癌症的纳武单抗(nivolumab)(/>Bristol-Myers Squibb)和帕博利珠单抗(pembrolizumab)(/>Merck),所述癌症包括鳞状细胞癌、典型霍奇金淋巴瘤(classical Hodgkin lymphoma)和尿路上皮癌。经批准的抗PD-L1抗体包括用于某些癌症(包括尿路上皮癌)的阿维单抗(avelumab)(EMD Serono&Pfizer)、阿特珠单抗(atezolizumab)(/>Roche/Genentech)和德瓦鲁单抗(durval umab)(/>AstraZeneca)。靶向PD-1受体的另一方法为由PD-L2(B7-DC)的胞外域与IgGl的Fc部分融合而构成的重组蛋白质,其称为AMP-224。尽管不存在靶向TIGIT或其配体CD155和CD112的经批准的治疗剂,但发展中的治疗剂包括BMS-986207(Bristol-My ers Squibb)、替拉格鲁单抗(tiragolumab)(Roche/Genentech)、OMP-31M32(OncoMed)、艾吉利单抗(etigilimab)、欧司珀利单抗(ociperlimab)、韦博妥单抗(vibostolimab)、AB308和AB154(多凡单抗(domvana limab))。
在一些实施方案中,额外治疗剂中的一者或多者为免疫肿瘤学剂(例如免疫检查点抑制剂)。在一些实施方案中,免疫肿瘤学剂为PD-1拮抗剂,例如拮抗性PD-1抗体。合适的PD-1抗体包括例如(纳武单抗)、/>(帕博利珠单抗)、MEDI-0680(AMP-514;WO2012/145493)、巴提利单抗(balstilimab)、布地格单抗(budigalimab)、卡瑞利珠单抗(camrelizumab)、西米普利单抗(cemiplimab)、多斯利单抗(dostarlimab)、依普利单抗(emiplimab)、埃本利单抗(ezabenlimab)、皮米单抗(pimivalimab)、瑞弗利单抗(retifanlimab)、萨桑利单抗(sasanlimab)、斯巴达珠单抗(spartalizumab)、辛迪单抗(sintilmab)、替雷利珠单抗(tislelizumab)、特瑞普利单抗(toripalimab)或赛帕利单抗(zimberelimab)。免疫肿瘤学剂还可包括皮立珠单抗(pidilizumab)(CT-011),尽管已经质疑其对于PD-1结合的特异性。
在一些实施方案中,免疫肿瘤学剂靶向PD-L1并且为PD-L1拮抗剂,例如拮抗性PD-L1抗体。合适的PD-L1抗体包括例如 (阿特珠单抗;MPDL3280A;WO2010/077634)、/>(德瓦鲁单抗、MEDI4736)、BMS-936559(WO2007/005874)、科西贝利单抗(cosibelimab)、恩沃利单抗(envafolimab)和阿维单抗(avelumab)(MSB0010718C;WO2013/79174)。
在一些本文提供的组合中,根据本公开的化合物与一种或多种选自以下的免疫检查点抑制剂组合:MEDI-0608、纳武单抗、皮立珠单抗、帕博利珠单抗、阿维单抗、阿特珠单抗、德瓦鲁单抗、西米普利单抗、辛替单抗(sentilimab)、替雷利珠单抗、AB308、多凡单抗和赛帕利单抗。
在本公开的一个方面,所要求保护的AXL抑制剂与作为以下的免疫肿瘤学剂组合:(i)刺激(包括共刺激)受体的激动剂,或(ii)T细胞上的抑制(包括共抑制)信号的拮抗剂,其两者均引起放大抗原特异性T细胞反应。某些刺激和抑制分子为免疫球蛋白超家族(IgSF)的成员。与共刺激或共抑制受体结合的膜结合配体的一个重要家族为B7家族,其包括B7-1、B7-2、B7-H1(PD-L1)、B7-DC(PD-L2)、B7-H2(ICOS-L)、B7-H3、B7-H4、B7-H5(VISTA)、B7-H6和B7-H7(HHLA2)。与共刺激或共抑制受体结合的另一膜结合配体家族是与同源TNF受体家族成员结合的分子的TNF家族,其包括CD40和CD40L、OX-40、OX-40L、CD70、CD27L、CD30、CD30L、4-1BBL、CD137(4-1BB)、TRAIL/Apo2-L、TRAILR1/DR4、TRAILR2/DR5、TRAILR3、TRAILR4、OPG、RANK、RANKL、TWEAKR/Fn14、TWEAK、BAFFR、EDAR、XEDAR、TACI、APRIL、BCMA、LT13R、LIGHT、DcR3、HVEM、VEGI/TL1A、TRAMP/DR3、EDAR、EDA1、XEDAR、EDA2、TNFR1、淋巴毒素a/TNF13、TNFR2、TNFa、LT13R、淋巴毒素a 1132、FAS、FASL、RELT、DR6、TROY、NGFR。
在另一方面,免疫肿瘤学剂为抑制T细胞活化的细胞因子(例如IL-6、IL-10、TGF-B、VEGF和其他免疫抑制细胞因子)或刺激T细胞活化以便刺激免疫反应的细胞因子。
在一个方面,T细胞反应可通过所公开的AXL抑制剂与以下中的一者或多者的组合来刺激:(i)抑制T细胞活化的蛋白质的拮抗剂(例如免疫检查点抑制剂),如CTLA-4、PD-1、PD-L1、PD-L2、LAG-3、TIM-3、半乳糖凝集素9、CEACAM-1、BTLA、CD69、半乳糖凝集素-1、TIGIT、CD113、GPR56、VISTA、2B4、CD48、GARP、PD1H、LAIR1、TIM-1和TIM-4;和/或(ii)刺激T细胞活化的蛋白质的激动剂,如B7-1、B7-2、CD28、4-1BB(CD137)、4-1BBL、ICOS、ICOS-L、OX40、OX40L、GITR、GITRL、CD70、CD27、CD40、DR3和CD2。可与本公开的AXL抑制剂组合用于治疗癌症的其他药剂包括NK细胞上的抑制受体的拮抗剂或NK细胞上的活化受体的激动剂。例如,本文中的化合物可与KIR的拮抗剂如利瑞路单抗(lirilumab)组合。
用于组合疗法的其他药剂包括抑制或消耗巨噬细胞或单核细胞的药剂,包括但不限于:CSF-1R拮抗剂,如CSF-1R拮抗剂抗体,包括RG7155(WO11/70024、WO11/107553、WO11/131407、WO13/87699、WO13/119716、WO13/132044)或FPA-008(WO11/140249、WO13169264、WO14/036357)。
在另一方面,所公开的AXL抑制剂可与以下中的一者或多者一起使用:接合阳性共刺激受体的激动剂;减弱经由抑制受体的信号传导的阻断剂;拮抗剂;和全身性增加抗肿瘤T细胞的出现率的一种或多种剂;克服肿瘤微环境内不同免疫抑制通路(例如阻断抑制受体接合(例如PD-L1/PD-1相互作用)、耗乏或抑制Treg(例如使用抗CD25单克隆抗体(例如达利珠单抗(daclizumab))或通过离体抗CD25珠粒消耗)或逆转/防止T细胞失能或耗竭)的剂;和触发肿瘤位点处的先天性免疫活化和/或炎症的剂。
在一个方面,免疫肿瘤学剂为CTLA-4拮抗剂,如拮抗性CTLA-4抗体。合适的CTLA-4抗体包括例如(伊匹单抗)或曲美单抗(tremelimumab)。
在另一方面,免疫肿瘤学剂为PD-1拮抗剂,如本文他处描述的那些。
在另一方面,免疫肿瘤学剂为PD-L1拮抗剂,如本文他处描述的那些。
在另一方面,免疫肿瘤学剂为TIGIT拮抗剂,如本文他处描述的那些。
在另一方面,免疫肿瘤学剂为LAG-3拮抗剂,如拮抗性LAG-3抗体。合适的LAG-3抗体包括例如BMS-986016(WO10/19570、WO14/08218)或IMP-731或IMP-321(WO08/132601、WO09/44273)。
在另一方面,免疫肿瘤学剂为CD137(4-1BB)激动剂,如激动性CD137抗体。合适的CD137抗体包括例如乌瑞鲁单抗(urelumab)和PF-05082566(WO12/32433)。
在另一方面,免疫肿瘤学剂为GITR激动剂,如激动性GITR抗体。合适的GITR抗体包括例如BMS-986153、BMS-986156、TRX-518(WO06/105021、WO09/009116)和MK-4166(WO11/028683)。
在另一方面,免疫肿瘤学剂为OX40激动剂,如激动性OX40抗体。合适的OX40抗体包括例如MEDI-6383或MEDI-6469。
在另一方面,免疫肿瘤学剂为OX40L拮抗剂,如拮抗性OX40抗体。合适的OX40L拮抗剂包括例如RG-7888(WO06/029879)。
在另一方面,免疫肿瘤学剂为CD40激动剂,如激动性CD40抗体。在又另一个实施方案中,免疫肿瘤学剂为CD40拮抗剂,如拮抗性CD40抗体。合适的CD40抗体包括例如鲁卡木单抗(lucatumumab)或达西珠单抗(dacetuzumab)。
在另一方面,免疫肿瘤学剂为CD27激动剂,如激动性CD27抗体。合适的CD27抗体包括例如瓦里木单抗(varlilumab)。
在另一方面,免疫肿瘤学剂为MGA271(针对B7H3)(W011/109400)。
适用于治疗心血管和/或代谢相关疾病、病症和疾患的组合疗法的治疗剂的实例包括:他汀类(statin)(例如 和/>),其抑制胆固醇的酶促合成;胆汁酸树脂(例如COLESTID、LO-CHOLEST、/>和),其隔绝胆固醇并防止其吸收;依泽麦布(ezetimibe)/>其阻断胆固醇吸收;纤维酸(例如/>),其减少三酸甘油酯并且可适度地增加HDL;烟酸(例如/>),其适度地降低LDL胆固醇和三酸甘油酯;和/或前述的组合(例如VYTORIN(依泽麦布与辛伐他汀(simvastatin)))。可为用于与本文所描述的AXL抑制剂组合使用的候选物的替代胆固醇治疗剂包括各种补充剂和草本植物(例如大蒜、甘蔗原素(policosanol)和印度香胶树(guggul))。
适用于免疫和炎症相关疾病、病症或疾患的组合疗法的治疗剂的实例包括但不限于以下:非类固醇抗炎药(NSAID),如阿司匹林(aspi rin)、布洛芬(ibuprofen)和其他丙酸衍生物(阿明洛芬(alminoprofen)、苯恶洛芬(benoxaprofen)、布氯酸(bucloxic acid)、卡洛芬(carprofen)、芬布芬(fenbufen)、非诺洛芬(fenoprofen)、氟洛芬(fluprofen)、氟比洛芬(flurbiprofen)、吲哚洛芬(indoprofen)、酮洛芬(ketoprofen)、咪洛芬(miroprofen)、萘普生(naproxen)、奥沙普嗪(oxaprozin)、吡洛芬(pirprofe n)、普拉洛芬(pranoprofen)、舒洛芬(suprofen)、噻洛芬酸(tiaprofenic acid)和硫恶洛芬(tioxaprofen))、乙酸衍生物(吲哚美辛(indomethacin)、阿西美辛(acemetacin)、阿氯芬酸(alclofenac)、环氯茚酸(clidanac)、双氯芬酸(diclofenac)、芬氯酸(fenclofenac)、芬克洛酸(fenclozic acid)、芬替酸(fentiazac)、弗洛芬克(fuirofenac)、异丁芬酸(ibufenac)、伊索克酸(isoxepac)、奥昔平酸(oxpinac)、舒林酸(sulindac)、硫平酸(tiopinac)、托美丁(tolmetin)、齐多美辛(zidometacin)和佐美酸(zomepirac))、芬那酸衍生物(氟芬那酸(flufenamic acid)、甲氯芬那酸(meclofenamic aci d)、甲芬那酸(mefenamic acid)、氟尼酸(niflumic acid)和托芬那酸(tol fenamic acid))、联苯羧酸衍生物(二氟尼柳(diflunisal)和氟苯柳(flufeni sal))、昔康(oxicam)(伊索昔康(isoxicam)、吡罗昔康(piroxicam)、舒多昔康(sudoxicam)和替诺昔康(tenoxican))、水杨酸盐(乙酰基水杨酸、柳氮磺胺吡啶)和吡唑啉酮(阿帕宗(apazone)、苯哌隆(bezpiperylon)、非普拉宗(feprazone)、莫非布宗(mofebutazone)、羟布宗(oxyphenbutazone)、苯基丁氮酮(phenylbutazone))。其他组合包括环加氧酶-2(COX-2)抑制剂。
用于组合的其他活性剂包括类固醇,如泼尼松龙(prednisolone)、泼尼松(prednisone)、甲基泼尼松龙(methylprednisolone)、倍他米松(betamethasone)、地塞米松(dexamethasone)或氢皮质酮(hydrocortisone)。此种组合可尤其有利,这是因为可通过使所需类固醇剂量逐渐减少来减少或甚至消除类固醇的一种或多种不良反应。
可以组合形式用于治疗例如类风湿性关节炎的活性剂的额外实例包括细胞因子抑制抗炎药(CSAID);针对其他人类细胞因子或生长因子的抗体或其他人类细胞因子或生长因子的拮抗剂,所述人类细胞因子或生长因子例如TNF、LT、IL-10、IL-2、IL-6、IL-7、IL-8、IL-15、IL-16、IL-18、EMAP-II、GM-CSF、FGF或PDGF。
活性剂的特定组合可在不同位置在自身免疫和后续炎性级联反应中干扰,并且包括TNF拮抗剂,如嵌合、人源化或人类TNF抗体、抗TNF抗体片段(例如,CDP870)和可溶p55或p75 TNF受体、其衍生物、p75TNFRIgG/>或p55TNFR1gG(LENERCEPT)、可溶IL-13受体(sIL-13)以及TNFa转化酶(TACE)抑制剂;类似地,IL-1抑制剂(例如,白细胞介素-1转化酶抑制剂)可为有效的。其他组合包括白细胞介素11、抗P7s和p-选择素糖蛋白配体(PSGL)。适用于与本文所描述的AXL抑制剂组合的药剂的其他实例包括干扰素-131a/>干扰素-13lb/> 克帕松(copaxone);高压氧;静脉内免疫球蛋白;克拉屈滨(clabribine);和针对其他人类细胞因子或生长因子的抗体或其他人类细胞因子或生长因子的拮抗剂(例如针对CD40配体和CD80的抗体)。
在一个或多个实施方案中,还考虑根据本公开的AXL抑制剂与DNA甲基转移酶(DNMT)抑制剂或低甲基化剂的组合。示例性DNMT抑制剂包括地西他滨(decitabine)、泽布拉恩(zebularine)和阿扎他定(azacitadine)。
在一个或多个实施方案中,还考虑根据本公开的AXL抑制剂与组蛋白脱乙酰基酶(HDAC)抑制剂的组合。示例性HDAC抑制剂包括伏立诺他(vorinostat)、吉韦诺他(givinostat)、阿贝司他(abexinostat)、帕比诺他(panobinostat)、贝利司他(belinostat)和曲古霉素A(trichostat in A)。
在一些实施方案中,根据本公开的AXL抑制剂与menin-MLL抑制剂组合。
在一些实施方案中,还考虑根据本公开的AXL抑制剂与异柠檬酸脱氢酶(IDH)抑制剂(例如IDH-1或IDH-2)的组合。示例性IDH-1抑制剂为艾伏尼布(ivosidenib)。示例性IDH-2抑制剂为艾那尼布(enasidenib)。
本公开涵盖以上中的任一者的药学上可接受的盐、酸或衍生物。
额外治疗剂的选择可通过特定癌症和/或受试者癌症的突变状态和/或疾病阶段的目前照护标准告知。例如通过National Comprehensi ve Cancer Network(NCCN)公开详细的照护标准指南。参见例如NC CN Acute Myeloid Leukemia v1.2022、NCCN AcuteLymphoblastic Leukemia v1.2022、NCCN Multiple Myeloma v5.2022、NCCN Non-SmallCell Lung Cancer v3.2022、NCCN Kidney Cancer v4.2022、NCCN Colon Cancerv1.2022、NCCN Rectal Cancer v1.2022、NCC N Hepatobiliary Cancer v1.2022、NCCNPancreatic Adenocarcinoma v1.2022、NCCN Esophageal and EsophagogastricJunction Cancers v2.2022、NCCN Prostate Cancer v3.2022、NCCN Gastric Cancerv2.2022、Cervical Cancer v1.2022、Ovarian Cancer/Fallopian Tube Ca ncer/PrimaryPeritoneal Cancer v1.2022、NCCN Breast Cancer v2.2022。
给药
本公开的AXL抑制剂可以取决于例如以下的量向受试者施用:施用目标(例如所需分辨率);施用制剂的受试者的年龄、体重、性别以及健康和身体状况;施用途径;和疾病、病症、疾患或其症状的性质。给药方案还可考虑与正施用的药剂和先前或伴随疗法相关的任何不良反应的存在、性质和程度。有效剂量和给药方案可根据例如安全性和剂量递增试验、体内研究(例如动物模型)确定。
一般来说,给药参数规定剂量小于可对受试者不可逆地有毒的量(最大耐受剂量(maximum tolerated dose;MTD))并且不小于产生对受试者的可测量效果需要的量。此类量由例如与ADME相关的药物动力学和药物效应动力学参数,考虑施用途径和其他因素来确定。
一般来说,所公开的方法包括向有需要的受试者施用有效量的本文所描述的化合物或其药学上可接受的盐或溶剂化物或其组合物。关于本公开的AXL抑制剂,“有效量”意指化合物的量足够以指示化合物的效力的水平接合目标(通过抑制、激动或拮抗目标)。对于AXL而言,目标接合可通过一种或多种产生EC50、ED50、EC90、IC50或类似值的生物化学或细胞测定法来确定,所述测定法可用作化合物的效力的一种评估。用于测定目标接合的测定法包括但不限于实施例中描述的那些。有效量可以单一量或以多次较小量(例如呈具有“x”量的一个片剂、呈各自具有“x/2”量的两个片剂等)形式施用。
在某些实施方案中,本公开涵盖的AXL抑制剂可以约0.01mg/kg至约50mg/kg或约1mg/kg至约25mg/kg受试者体重/天的剂量水平,一天一或多次施用(例如经口、肠胃外等),以获得所需治疗效果。
对于经口药剂的施用而言,组合物可以含有1至1000毫克活性成分(即,式(I)化合物,特别是1、3、5、10、15、20、25、50、75、100、150、200、250、300、400、500、600、750、800、900和1000毫克活性成分)的片剂、胶囊等形式提供。
在某些实施方案中,所需AXL抑制剂的剂量含于“单位剂型”中。短语“单位剂型”是指物理离散单位,每个单位含有足以产生所需效果的单独或与一种或多种额外药剂组合的预定量的AXL抑制剂。应了解,单位剂型的参数将取决于特定药剂和待实现的效果。对于静脉内施用而言,单位剂型可含有1至1000毫克活性成分(即,式(I)化合物,特别是1、10、25、50、100、200、300或500毫克)。
药盒
本公开还涵盖包含本文所描述的化合物和其药物组合物的药盒。药盒通常呈如下文所描述的容纳各种组分的实体结构形式,并且可用于例如实践上文所描述的方法。
药盒可包括本文中所公开的化合物中的一者或多者(例如提供于无菌容器中),所述化合物可呈适合于向受试者施用的药物组合物形式。本文所描述的化合物可以随时可用的形式(例如片剂或胶囊)或以例如需要在施用之前重构或稀释的形式(例如散剂)提供。当本文所描述的化合物呈需要使用者重构或稀释的形式时,药盒还可包括与本文所描述的化合物一起或分开包装的稀释剂(例如无菌水)、缓冲液、药学上可接受的赋形剂等。在考虑组合疗法时,药盒可单独地含有若干药剂或其可已经在药盒中组合。药盒的每个组分可密封于个别容器内,并且所有各种容器可在单一包装内。本公开的药盒可经设计用于必需适当地维持其中容纳的组分的情况(例如制冷或冷冻)。
药盒可含有标签或包装插页,所述包装插页包括其中组分的识别信息和其使用说明(例如给药参数;活性成分的临床药理学,包括作用机制、药物动力学和药效学、不良反应、禁忌等)。标签或插页可包括制造商信息,例如批次编号和有效期。标签或包装插页可例如整合至容纳组分的实体结构中,单独地含于实体结构内,或粘附至药盒的组件(例如,安瓿、管或小瓶)上。
此外,标签或插页可包括计算机可读介质或并入其中。在一些实施方案中,实际说明不存在于药盒中,但提供用于从远程源,例如经由互联网获得说明的手段。
实验
提出以下实施例以向本领域普通技术人员提供关于如何制造和使用本公开的完整公开和描述;并且并不旨在限制本发明人视为其发明的范围。已努力确保关于所使用的数字(例如量、温度等)的准确性,但应考虑存在一些实验性误差和偏差。
除非另外指示,否则温度以摄氏度(℃)为单位,并且压力为在大气压下或附近。使用标准缩写,包括以下:rt或r.t.=室温;min=分钟;h或hr=小时;ng=纳克;μg=微克;mg=毫克;g=克;kg=千克;μl或μL=微升;ml或mL=毫升;l或L=升;μM=微摩尔浓度;mM=毫摩尔浓度;M=摩尔浓度;mol=摩尔;mmol=毫摩尔;aq.=水性;calcd=计算值;DCM=二氯甲烷;DCE=1,2-二氯乙烷;MTBE=甲基叔丁基醚;THF=四氢呋喃;EtOAc=乙酸乙酯;ACN=乙腈;NMP=N-甲基-2-吡咯烷酮;DMF=N,N-二甲基甲酰胺;DMSO=二甲亚砜;IPA=异丙醇;EtOH=乙醇;MeOH=甲醇;H2=氢气;N2=氮气;DIPEA=N,N-二异丙基乙胺;DMEDA=N,N-二甲基乙烷-1,2-二胺;HATU=N-[(二甲氨基)-1H-1,2,3-三唑并-[4,5-b]吡啶-1-基亚甲基]-N-甲基甲铵六氟磷酸盐N-氧化物;EDC=1-乙基-3-(3-二甲氨基丙基)碳化二亚胺;HOBt=羟基苯并三唑;NBS=N-溴丁二酰亚胺;KOAc=乙酸钾;TFA=三氟乙酸;(dppf)PdCl2=[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II);B2pin2=双(频哪醇合)二硼;DMAP=4-二甲基氨基吡啶;MHz=兆赫兹;Hz=赫兹;ppm=百万分率;ESIMS-电喷雾电离质谱;NMR=核磁共振。
材料和方法
以下一般材料和方法在指示时使用或者可用于以下实施例中:
在配备有Oxford AS400磁体的Varian 400MHz NMR光谱仪上记录1H NMR光谱。化学位移(δ)以相对于作为内部参考物的残留非氘化溶剂的百万分率(ppm)形式报告。
实施例
实施例1:8-{5-[7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基]-1H-吡唑并[3,4-b]吡啶-3-基}-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
步骤a:在室温下向4-溴-2-羟基苯甲酸甲酯(4.62g,20.0mmol)、K2CO3(5.53g,40.0mmol)和DMF(40mL)的混合物中添加(2-溴乙基)氨基甲酸叔丁酯(4.71g,21.0mmol)。在65℃下搅拌反应混合物3小时,冷却至室温,用EtOAc(200mL)稀释,用9:1水:盐水(4×200mL)洗涤,经Na2SO4干燥并浓缩。粗物质通过柱色谱法(120g硅胶,己烷:EtOAc,0%至50%梯度(25分钟))纯化,得到呈浅黄色油状的所需产物(7.02g;94%)。
步骤b:在室温下搅拌来自步骤a的产物(7.02g,18.8mmol)和含4M HCl的二噁烷(38mL)的混合物30分钟,并用MTBE(300mL)稀释。通过过滤收集沉淀的固体,用MTBE洗涤并干燥,得到呈白色固体状的所需产物(5.07g;87%)。
步骤c:在室温下向来自步骤b的产物(5.07g,16.3mmol)和MeOH(41mL)的混合物中添加NaOMe(7.47mL,32.6mmol,25wt%于MeOH中)。在65℃下搅拌反应混合物1小时,冷却至室温,用饱和NH4Cl(aq.)(7.5mL)淬灭,并用EtOAc(150mL)稀释。有机相用水(1x 100mL)洗涤,经Na2SO4干燥并浓缩。粗物质通过柱色谱法(80g硅胶,CH2Cl2:MeOH,0%至10%梯度(30分钟))纯化,得到呈白色固体状的所需产物(3.82g;97%)。
步骤d:将来自步骤c的产物(1.21g,5.00mmol)、B2pin2(1.27g,5.00mmol)、(dppf)PdCl2(183mg,0.250mmol)和KOAc(981mg,10.0mmol)的混合物置于氮气下。添加脱气二噁烷(25mL),并且在100℃下搅拌反应混合物1小时。将混合物冷却至室温,浓缩,用EtOAc(250mL)稀释,经由硅藻土过滤以去除固体,并且再次浓缩,得到所需产物,其以粗物质形式用于下一步骤中。
步骤e:经约20min,在0℃下分3份向5-溴-3-碘-1H-吡唑并[3,4-b]吡啶(40.3g,124mmol)于DMF(124mL)中的悬浮液中添加固体NaOt-Bu(14.6g,130mmol),然后再搅拌混合物10min。经30分钟添加(2-(氯甲氧基)乙基)三甲基硅烷(23.0mL,130mmol),然后搅拌反应物15h,在冷却浴到期时升温至室温。将混合物冷却至0℃并用H2O(500mL)稀释。通过过滤收集沉淀的固体,用H2O洗涤并真空干燥,得到呈浅黄色固体状的所需产物(51.2g;91%)。
步骤f:在N2下向步骤e的产物(4.76g,10.5mmol)、K2CO3(2.90g,21.0mmol)和(dppf)PdCl2(766mg,1.05mmol)的混合物中添加步骤d的粗产物(10.5mmol)于脱气二噁烷(48mL)中的溶液,接着添加脱气H2O(12mL)。在85℃下搅拌反应混合物20h,冷却至室温并倒入H2O(100mL)中。所得溶液用EtOAc(3x)萃取,然后经合并的有机相用水和盐水洗涤,经无水Na2CO3干燥并浓缩。粗残余物通过硅胶色谱法(100%己烷至100%EtOAc)纯化,得到呈浅棕色固体状的所需产物(3.39g;66%)。
步骤g:向2-溴-5,6,8,9-四氢-7H-苯并环庚烯-7-酮(1.03g,4.31mmol)和吡咯烷(0.43mL,5.17mmol)于DCE(21.5mL)中的混合物中添加AcOH(0.25mL,4.31mmol),接着添加NaBH(OAc)3(1.19g,5.60mmol)。在室温下搅拌反应物16h,并且小心地用H2O和接着NaHCO3饱和水溶液淬灭。分离各层,并且水层用CH2Cl2(2x 20mL)萃取。经合并的有机层用盐水洗涤,经无水Na2SO4干燥并浓缩。残余物通过硅胶色谱法(100%CH2Cl2至10%MeOH/CH2Cl2+0.5%NEt3)纯化,得到呈粘稠橙色油状的所需产物(978mg;77%)。
步骤h:向步骤g的产物(191mg,0.649mmol)、B2pin2(214mg,0.844mmol)和KOAc(83mg,0.844mmol)的混合物中添加二噁烷(6.5mL),然后悬浮液用N2脱气10min。添加(dppf)PdCl2(24mg,0.0325mmol),并且在90℃下搅拌反应混合物3h。在冷却后,添加EtOAc(20mL),并且经由硅藻土过滤混合物。浓缩滤液,得到呈粘稠棕色油状的粗物质。
步骤i:向步骤f的产物(144mg,0.295mmol)、步骤h的粗产物(0.325mmol)和Na2CO3(63mg,0.590mmol)的混合物中添加二噁烷(5.3mL)和H2O(0.60mL),然后悬浮液用N2脱气10min。添加(dppf)PdCl2(11mg,0.0148mmol),并且在80℃下搅拌反应混合物14h。在冷却后,添加CH2Cl2(15mL),并且使混合物经无水MgSO4干燥,过滤并浓缩。残余物通过硅胶色谱法(100%CH2Cl2至10%MeOH/CH2Cl2+1%NH3)纯化,得到呈棕色固体状的所需产物(127mg;69%)。
步骤j:向步骤i的产物(129mg,0.207mmol)于CH2Cl2(1.1mL)中的溶液中添加TFA(1.1mL)。在室温下搅拌反应物2h,然后浓缩。向残余物中添加含NH3的MeOH(7N溶液,2.1mL),并且在室温下搅拌反应混合物14h。冷却后,浓缩反应混合物。通过C18反相色谱法(100%H2O至100%ACN+0.1%TFA)和反相HPLC(10至70%ACN/H2O+0.1%TFA)纯化,然后冻干,得到呈浅黄色固体状的标题化合物(5mg,4%)。1H NMR(400MHz,甲醇-d4)δ8.79(d,J=2.0Hz,1H),8.58(d,J=2.0Hz,1H),8.00(d,J=8.2Hz,1H),7.83(dd,J=8.2,1.8Hz,1H),7.69(d,J=1.7Hz,1H),7.54(d,J=2.0Hz,1H),7.51(dd,J=7.7,2.0Hz,1H),7.31(d,J=7.7Hz,1H),4.46(dd,J=5.3,4.3Hz,2H),3.65-3.53(m,3H),3.51(dd,J=5.2,4.4Hz,2H),3.29-3.17(m,2H),3.11-2.86(m,4H),2.53-2.42(m,2H),2.22-2.05(m,2H),2.03-1.95(m,2H),1.57(p,J=11.6,11.2Hz,2H)。C30H32N5O2的ESIMS[M+H]+计算值494.3,实验值494.2。
实施例2:8-{5-[6-(吡咯烷-1-基)-5,6,7,8-四氢萘-2-基]-1H-吡唑并[3,4-b]吡啶-3-基}-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
以类似于实施例1的方式制备标题化合物。1H NMR(400MHz,甲醇-d4)δ8.75(d,J=2.0Hz,1H),8.54(d,J=2.1Hz,1H),7.99(dd,J=8.2,0.4Hz,1H),7.81(dd,J=8.2,1.7Hz,1H),7.67(d,J=1.3Hz,1H),7.53-7.46(m,2H),7.27(d,J=7.9Hz,1H),4.46(dd,J=5.5,4.0Hz,2H),3.86-3.73(m,2H),3.66-3.55(m,1H),3.51(dd,J=5.6,4.1Hz,2H),3.41-3.34(m,1H),3.30-3.23(m,2H),3.17-2.94(m,3H),2.51-2.39(m,1H),2.30-2.16(m,2H),2.14-2.01(m,2H),1.94(ddt,J=17.2,11.8,5.7Hz,1H)。C29H30N5O2的ESIMS[M+H]+计算值480.2,实验值480.2。
实施例3:8-{5-[7-(吡咯烷-1-基)-5,6,7,8-四氢萘-2-基]-1H-吡唑并[3,4-b]吡啶-3-基}-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
以类似于实施例1的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),8.87(d,J=2.1Hz,1H),8.67(d,J=2.1Hz,1H),8.41(t,J=5.4Hz,1H),7.96(d,J=8.2Hz,1H),7.89(dd,J=8.2,1.7Hz,1H),7.69-7.65(m,2H),7.63(s,1H),7.30(d,J=8.0Hz,1H),4.38(dd,J=5.3,4.1Hz,2H),3.72-3.58(m,3H),3.47-3.30(m,3H),3.30-3.12(m,2H),3.08-2.96(m,2H),2.95-2.83(m,1H),2.40-2.29(m,1H),2.14-2.00(m,2H),1.98-1.76(m,3H)。C29H30N5O2的ESIMS[M+H]+计算值480.2,实验值480.2。
实施例4:8-[5-(6-{[(3S)-氧杂环戊烷-3-基]氨基}-5,6,7,8-四氢萘-2-基)-1H-吡唑并[3,4-b]吡啶-3-基]-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
以类似于实施例1的方式制备标题化合物。1H NMR(400MHz,甲醇-d4)δ9.17(d,J=1.9Hz,1H),9.11(d,J=1.9Hz,1H),8.06(dd,J=8.2,0.4Hz,1H),7.85(dd,J=8.2,1.7Hz,1H),7.72(dd,J=1.7,0.4Hz,1H),7.67-7.58(m,2H),7.37(d,J=7.6Hz,1H),4.51-4.46(m,2H),4.28-4.20(m,1H),4.14-4.01(m,2H),3.93(dt,J=10.9,5.7Hz,1H),3.79(ddd,J=8.9,8.2,7.3Hz,1H),3.75-3.65(m,1H),3.53(dd,J=5.5,4.1Hz,2H),3.43(dd,J=16.2,5.4Hz,1H),3.22-2.95(m,3H),2.54-2.38(m,2H),2.21-2.05(m,1H),1.94(qd,J=11.6,5.9Hz,1H)。C29H30N5O3的ESIMS[M+H]+计算值496.2,实验值496.2。
实施例5:8-[5-(6-{[(3R)-氧杂环戊烷-3-基]氨基}-5,6,7,8-四氢萘-2-基)-1H-吡唑并[3,4-b]吡啶-3-基]-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
以类似于实施例1的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ9.31-8.95(m,2H),8.87(d,J=2.1Hz,1H),8.67(d,J=2.1Hz,1H),8.41(t,J=5.3Hz,1H),7.96(d,J=8.2Hz,1H),7.89(dd,J=8.2,1.7Hz,1H),7.68(dd,J=1.7,0.3Hz,1H),7.67-7.62(m,2H),7.29(d,J=7.8Hz,1H),4.38(dd,J=5.4,4.1Hz,2H),4.17-4.07(m,1H),4.00-3.83(m,3H),3.70(q,J=7.7Hz,1H),3.65-3.47(m,2H),3.37-3.26(m,2H),3.09-2.86(m,3H),2.38-2.24(m,2H),2.14-2.01(m,1H),1.90-1.76(m,1H)。C29H30N5O3的ESIMS[M+H]+计算值496.2,实验值496.2。
实施例6:6-氟-8-(5-{7-[(2R)-2-甲基吡咯烷-1-基]-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基}-1H-吡唑并[3,4-b]吡啶-3-基)-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
以类似于实施例1的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.87(d,J=2.0Hz,1H),8.72(d,J=2.1Hz,1H),8.55(t,J=6.1Hz,1H),7.80(dd,J=10.8,1.5Hz,1H),7.65-7.61(m,2H),7.57(dd,J=7.6,2.0Hz,1H),7.27(dd,J=7.8,1.3Hz,1H),4.27(t,J=5.5Hz,2H),3.33-3.29(m,2H),3.01-2.77(m,5H),2.77-2.65(m,2H),2.44(q,J=8.3Hz,1H),2.07-1.94(m,2H),1.88-1.75(m,1H),1.68-1.49(m,2H),1.49-1.37(m,1H),1.34-1.21(m,2H),1.02(d,J=6.0Hz,3H)。C31H33FN5O2的ESIMS[M+H]+计算值526.3,实验值526.3。
实施例7:8-[5-(3-环戊基-2,3,4,5-四氢-1H-3-苯并氮杂卓-7-基)-1H-吡唑并[3,4-b]吡啶-3-基]-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
步骤a:向7-溴-2,3,4,5-四氢-1H-3-苯并氮杂卓盐酸盐(272mg,1.04mmol)和环戊酮(0.11mL,1.29mmol)于DCE(5.2mL)中的混合物中添加AcOH(60μL,1.04mmol),接着添加NaBH(OAc)3(331mg,1.56mmol)。在室温下搅拌反应物17h,然后小心地用NaHCO3饱和水溶液淬灭。分离各层,并且水层用CH2Cl2(2x 10mL)萃取。经合并的有机层用盐水洗涤,经无水MgSO4干燥,并浓缩,得到呈无色油状的所需产物(293mg,96%)。
步骤b:向步骤a的产物(111mg,0.377mmol)、B2pin2(129mg,0.490mmol)和KOAc(48mg,0.490mmol)的混合物中添加二噁烷(3.8mL),然后悬浮液用N2脱气10min。添加(dppf)PdCl2(14mg,0.0189mmol),并且在90℃下搅拌反应混合物3h。在冷却后,添加EtOAc(15mL),并且经由硅藻土过滤混合物。浓缩滤液,得到呈粘稠棕色油状的粗物质。
步骤c:向实施例1步骤f的产物(168mg,0.343mmol)、步骤b的粗产物(0.377mmol)和Na2CO3(73mg,0.685mmol)的混合物中添加二噁烷(6.2mL)和H2O(0.70mL),然后悬浮液用N2脱气10min。添加(dppf)PdCl2(13mg,0.0148mmol),并且在80℃下搅拌反应混合物14h。在冷却后,添加CH2Cl2(15mL),并且使混合物经无水MgSO4干燥,过滤并浓缩。残余物通过硅胶色谱法(100%CH2Cl2至10%MeOH/CH2Cl2+1%NH3)纯化,得到呈棕色固体状的所需产物(144mg;67%)。
步骤d:向步骤c的产物(144mg,0.231mmol)于CH2Cl2(1.1mL)中的溶液中添加TFA(1.1mL)。在室温下搅拌反应物1.5h,然后浓缩。向残余物中添加含NH3的MeOH(7N溶液,2.3mL),并且在室温下搅拌反应混合物14h。在冷却后,浓缩反应物。通过C18反相色谱法(100%H2O至100%ACN+0.1%TFA)和反相HPLC(10至90%ACN/H2O+0.1%TFA)纯化,然后冻干,得到呈浅黄色固体状的标题化合物(44mg,31%)。1H NMR(400MHz,甲醇-d4)δ8.81(d,J=2.1Hz,1H),8.61(d,J=2.1Hz,1H),8.01(dd,J=8.2,0.4Hz,1H),7.85(dd,J=8.2,1.7Hz,1H),7.71(dd,J=1.7,0.4Hz,1H),7.60-7.43(m,2H),7.28(d,J=7.6Hz,1H),4.46(dd,J=5.5,4.0Hz,2H),3.51(dd,J=5.4,4.2Hz,2H),3.12-3.02(m,5H),3.00-2.71(m,4H),2.06-1.93(m,2H),1.84-1.69(m,2H),1.69-1.46(m,4H)。C30H32N5O2的ESIMS[M+H]+计算值494.3,实验值494.2。
实施例8:8-[5-(8-氯-2-环戊基-1,2,3,4-四氢异喹啉-6-基)-1H-吡唑并[3,4-b]吡啶-3-基]-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
以类似于实施例7的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ10.02(brs,1H),8.96(d,J=2.1Hz,1H),8.82(d,J=2.1Hz,1H),8.42(t,J=5.3Hz,1H),8.05(d,J=1.7Hz,1H),7.98(d,J=8.2Hz,1H),7.92(dd,J=8.2,1.7Hz,1H),7.86(d,J=1.4Hz,1H),7.71(d,J=1.6Hz,1H),4.57(d,J=16.9Hz,1H),4.45-4.35(m,3H),3.87-3.76(m,2H),3.43-3.34(m,3H),3.30-3.21(m,2H),2.23-2.09(m,2H),1.96-1.69(m,4H),1.69-1.52(m,2H)。C29H29ClN5O2的ESIMS[M+H]+计算值514.2,实验值514.2。
实施例9:8-(5-(2-环戊基-1,2,3,4-四氢异喹啉-6-基)-1H-吡唑并[3,4-b]吡啶-3-基)-3,4-二氢苯并[f][1,4]氧氮杂卓-5(2H)-酮
以类似于实施例7的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.82(d,J=2.1Hz,1H),8.63(d,J=2.1Hz,1H),8.36(t,J=5.4Hz,1H),7.95-7.82(m,2H),7.65(d,J=1.6Hz,1H),7.55(d,J=8.0Hz,2H),7.17(d,J=7.8Hz,1H),4.34(dd,J=5.3,4.1Hz,2H),3.63(s,2H),3.40-3.33(m,2H),2.87(t,J=5.9Hz,2H),2.73-2.58(m,3H),1.87(d,J=6.3Hz,2H),1.62(d,J=7.3Hz,2H),1.57-1.34(m,4H)。C29H30N5O2的ESIMS[M+H]+计算值480.2,实验值480.2。
实施例10:8-(5-(2-环戊基-1,2,3,4-四氢异喹啉-7-基)-1H-吡唑并[3,4-b]吡啶-3-基)-3,4-二氢苯并[f][1,4]氧氮杂卓-5(2H)-酮
以类似于实施例7的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.81(d,J=2.1Hz,1H),8.62(d,J=2.1Hz,1H),8.35(t,J=5.4Hz,1H),7.95-7.82(m,2H),7.64(dd,J=1.7,0.5Hz,1H),7.59-7.48(m,2H),7.20(d,J=7.9Hz,1H),4.34(dd,J=5.4,4.1Hz,2H),3.68(s,2H),3.35(q,J=5.0Hz,2H),2.85-2.78(m,2H),2.73-2.58(m,3H),1.88(d,J=5.7Hz,2H),1.62(d,J=7.3Hz,2H),1.58-1.35(m,4H)。C29H30N5O2的ESIMS[M+H]+计算值480.2,实验值480.2。
实施例11:8-(5-(3-(氧杂环丁-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)-1H-吡唑并[3,4-b]吡啶-3-基)-3,4-二氢苯并[f][1,4]氧氮杂卓-5(2H)-酮
以类似于实施例7的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.86(d,J=2.1Hz,1H),8.66(d,J=2.1Hz,1H),8.38(t,J=5.4Hz,1H),7.96-7.89(m,1H),7.85(dd,J=8.2,1.7Hz,1H),7.75(d,J=2.0Hz,1H),7.72-7.61(m,2H),7.37(d,J=7.9Hz,1H),4.83(t,J=7.1Hz,2H),4.72(t,J=7.5Hz,2H),4.44(s,1H),4.38-4.31(m,2H),3.36(q,J=5.0Hz,2H),3.29-2.94(m,6H),2.91(s,2H)。C28H28N5O3的ESIMS[M+H]+计算值482.2,实验值482.2。
实施例12:8-(5-(2-(氧杂环丁-3-基)-1,2,3,4-四氢异喹啉-6-基)-1H-吡唑并[3,4-b]吡啶-3-基)-3,4-二氢苯并[f][1,4]氧氮杂卓-5(2H)-酮
以类似于实施例7的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),8.88(d,J=2.1Hz,1H),8.70(d,J=2.1Hz,1H),8.38(t,J=5.4Hz,1H),7.93(dd,J=8.2,0.4Hz,1H),7.87(dd,J=8.2,1.7Hz,1H),7.76(d,J=7.7Hz,2H),7.65(dd,J=1.7,0.5Hz,1H),7.30(d,J=8.1Hz,1H),4.81(d,J=6.5Hz,4H),4.56(d,J=23.2Hz,2H),4.38-4.31(m,2H),4.24(s,1H),3.36(q,J=5.1Hz,2H),3.17(s,4H)。C27H26N5O3的ESIMS[M+H]+计算值468.2,实验值468.2。
实施例13:8-(5-(2-(2-甲氧基乙基)-1,2,3,4-四氢异喹啉-6-基)-1H-吡唑并[3,4-b]吡啶-3-基)-3,4-二氢苯并[f][1,4]氧氮杂卓-5(2H)-酮
以类似于实施例7的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.88(d,J=2.1Hz,1H),8.70(d,J=2.1Hz,1H),8.38(t,J=5.4Hz,1H),7.93(dd,J=8.2,0.4Hz,1H),7.87(dd,J=8.2,1.7Hz,1H),7.79-7.72(m,2H),7.65(dd,J=1.7,0.5Hz,1H),7.34(d,J=8.7Hz,1H),4.58(d,J=15.5Hz,1H),4.44-4.31(m,3H),3.84-3.69(m,3H),3.53-3.33(m,7H),3.26-3.07(m,3H)。C27H28N5O3的ESI MS[M+H]+计算值470.2,实验值470.2。
实施例14:3-环戊基-7-(3-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)-1H-吡唑并[3,4-b]吡啶-5-基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓
以类似于实施例7的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ13.98(s,1H),9.67(s,1H),8.86(d,J=2.0Hz,1H),8.69(d,J=2.1Hz,1H),8.07(dd,J=1.7,0.4Hz,1H),7.93(dd,J=8.4,1.7Hz,1H),7.77-7.66(m,2H),7.55(dd,J=8.4,0.4Hz,1H),7.35(d,J=7.8Hz,1H),3.67(s,2H),3.15(qd,J=28.3,27.2,14.3Hz,7H),2.02(d,J=9.7Hz,2H),1.72(d,J=14.7Hz,4H),1.54(s,2H)。C27H27F2N4O2的ESI MS[M+H]+计算值489.2,实验值489.2。
实施例15:8-(5-(3-(2-甲氧基乙基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)-1H-吡唑并[3,4-b]吡啶-3-基)-3,4-二氢苯并[f][1,4]氧氮杂卓-5(2H)-酮
以类似于实施例7的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ9.87(s,1H),8.85(d,J=2.1Hz,1H),8.65(d,J=2.1Hz,1H),8.38(t,J=5.4Hz,1H),7.93(dd,J=8.1,0.4Hz,1H),7.85(dd,J=8.2,1.7Hz,1H),7.74-7.61(m,3H),7.34(d,J=7.8Hz,1H),4.38-4.31(m,2H),3.73-3.65(m,3H),3.31(s,9H),3.11(td,J=17.0,16.1,8.0Hz,4H)。C28H30N5O3的ESIMS[M+H]+计算值484.2,实验值484.2。
实施例16:8-{5-[3-(2-甲基丙酰基)-2,3,4,5-四氢-1H-3-苯并氮杂卓-7-基]-1H-吡唑并[3,4-b]吡啶-3-基}-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
步骤a:向7-溴-2,3,4,5-四氢-1H-3-苯并氮杂卓盐酸盐(84mg,0.320mmol)于CH2Cl2(3.2mL)中的悬浮液中添加NEt3(0.13mL,0.960mmol),接着添加2-甲基丙酰氯(40μL,0.384mmol)。在室温下搅拌反应物17h,然后小心地用NH4Cl饱和水溶液淬灭。分离各层,并且水层用CH2Cl2(2x 5mL)萃取。经合并的有机层用盐水洗涤,经无水MgSO4干燥并浓缩。将粗残余物溶解于CH2Cl2(5mL)中,并用NaHCO3饱和水溶液洗涤,然后水层用CH2Cl2(2x 5mL)萃取。经合并的有机层用盐水洗涤,经无水MgSO4干燥并浓缩,得到呈微粉色粘稠油状的所需产物(94mg,99%)。
步骤b:向实施例1步骤f的产物(481mg,0.983mmol)、B2pin2(300mg,1.18mmol)和KOAc(125mg,1.28mmol)的混合物中添加二噁烷(9.8mL),然后悬浮液用N2脱气10min。添加(dppf)PdCl2(36mg,0.0492mmol),并且在80℃下搅拌反应混合物4h。在冷却后,添加EtOAc(30mL),并且经由硅藻土过滤混合物。浓缩滤液,得到呈粘稠棕色油状的粗物质。
步骤c:向步骤a的产物(94mg,0.320mmol)、步骤b的粗产物(0.246mmol)和Na2CO3(74mg,0.492mmol)的混合物中添加二噁烷(4.4mL)和H2O(0.50mL),然后悬浮液用N2脱气10min。添加(dppf)PdCl2(9mg,0.0123mmol),并且在100℃下搅拌反应混合物4h。在冷却后,添加CH2Cl2(15mL),并且使混合物经无水MgSO4干燥,过滤并浓缩。残余物通过硅胶色谱法(100%己烷至100%EtOAc至10%MeOH/EtOAc)纯化,得到呈浅棕色固体状的所需产物(105mg;68%)。
步骤d:向步骤c的产物(105mg,0.168mmol)于CH2Cl2(1.7mL)中的溶液中添加TFA(1.7mL)。在室温下搅拌反应物2h,然后浓缩。向残余物中添加含NH3的MeOH(7N溶液,3.4mL),并且在40℃下搅拌反应混合物2h。在冷却后,浓缩反应物并通过硅胶色谱法(100%CH2Cl2至10%MeOH/CH2Cl2)纯化并真空干燥,得到呈灰白色固体状的标题化合物(29mg,35%)。1H NMR(400MHz,DMSO-d6)δ8.88(d,J=2.0Hz,1H),8.69(d,J=2.1Hz,1H),8.40(t,J=5.4Hz,1H),7.95(d,J=8.2Hz,1H),7.90(dd,J=8.2,1.7Hz,1H),7.69-7.65(m,2H),7.62(dd,J=7.8,1.9Hz,1H),7.31(dd,J=7.7,3.6Hz,1H),4.38(dd,J=5.3,4.1Hz,2H),3.65(dt,J=17.6,8.3Hz,4H),3.43-3.34(m,2H),3.10-2.83(m,5H),1.03(dd,J=6.7,2.9Hz,6H)。C29H30N5O3的ESIMS[M+H]+计算值496.2,实验值496.2。
实施例17:8-[5-(3-环丙羰基-2,3,4,5-四氢-1H-3-苯并氮杂卓-7-基)-1H-吡唑并[3,4-b]吡啶-3-基]-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
以类似于实施例16的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.88(s,1H),8.69(s,1H),8.40(t,J=5.3Hz,1H),7.95(d,J=8.1Hz,1H),7.90(dd,J=8.2,1.7Hz,1H),7.74-7.65(m,2H),7.62(dd,J=7.7,2.0Hz,1H),7.32(t,J=8.5Hz,1H),4.38(dd,J=5.4,4.0Hz,2H),3.85(t,J=8.0Hz,2H),3.64(t,J=8.5Hz,2H),3.43-3.38(m,2H),3.12-2.98(m,2H),2.98-2.85(m,2H),2.21-1.92(m,1H),0.89-0.55(m,4H)。C29H28N5O3的ESIMS[M+H]+计算值494.2,实验值494.2。
实施例18:8-[5-(3-甲磺酰基-2,3,4,5-四氢-1H-3-苯并氮杂卓-7-基)-1H-吡唑并[3,4-b]吡啶-3-基]-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
以类似于实施例16的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.88(d,J=2.1Hz,1H),8.69(d,J=2.1Hz,1H),8.40(t,J=5.3Hz,1H),7.96(d,J=8.2Hz,1H),7.90(dd,J=8.2,1.7Hz,1H),7.70(d,J=2.0Hz,1H),7.68(d,J=1.7Hz,1H),7.65(dd,J=7.7,2.0Hz,1H),7.33(d,J=7.8Hz,1H),4.38(dd,J=5.4,4.1Hz,2H),3.43-3.35(m,6H),3.17-2.98(m,4H),2.89(s,3H)。C26H26N5O4S的ESIMS[M+H]+计算值504.2,实验值504.2。
实施例19:8-(5-(3-(2-羟基-2-甲基丙酰基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)-1H-吡唑并[3,4-b]吡啶-3-基)-3,4-二氢苯并[f][1,4]氧氮杂卓-5(2H)-酮
以类似于实施例16的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.89-8.82(m,1H),8.70-8.62(m,1H),8.37(t,J=5.3Hz,1H),7.96-7.82(m,2H),7.70-7.60(m,2H),7.57(dd,J=7.7,2.0Hz,1H),7.28(d,J=7.9Hz,1H),4.34(dd,J=5.4,4.1Hz,2H),3.57(s,2H),3.36(q,J=5.1Hz,2H),2.95(s,2H),1.67-1.55(m,1H),1.33(s,6H)。C29H30N5O4的ESIMS[M+H]+计算值512.2,实验值512.2。
实施例20:8-(5-(3-环丙基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)-1H-吡唑并[3,4-b]吡啶-3-基)-3,4-二氢苯并[f][1,4]氧氮杂卓-5(2H)-酮
步骤a:向7-溴-2,3,4,5-四氢-1H-3-苯并氮杂卓盐酸盐(100mg,0.38mmol)、(1-乙氧基环丙氧基)三甲基硅烷(264.9mg,1.5mmol)和THF/MeOH(1:1,1.5mmol)的混合物中添加AcOH(217.5mL,3.8mmol)和NaBH3CN(107.4mg,1.7mmol),并且在50℃下加热24h。在冷却至室温后,过滤反应混合物以去除任何不可溶物质,浓缩并通过柱色谱法(SiO2,0至100%含CH2Cl2/MeOH/7N甲醇NH3(90:10:1)的CH2Cl2)纯化,得到呈浅棕色油状的所需产物(62mg,61%)。
步骤b:将来自步骤a的产物(62mg,0.23mmol)、B2pin2(60mg,0.23mmol)、KOAc(46mg,0.47mmol)和(dppf)PdCl2(9mg,0.01mmol)的混合物置于氮气气氛下。向此混合物中添加脱气二噁烷(1.5mL),并在100℃下加热6h。在冷却至室温后,过滤反应混合物以去除任何不可溶物质,浓缩并直接用于下一步骤中。
步骤c:将获自步骤b的粗物质(假定0.23mmol)、实施例1步骤f的产物(114mg,0.23mmol)、K2CO3(65mg,0.47mmol)和(dppf)PdCl2(9mg,0.01mmol)的混合物置于氮气气氛下。向此混合物中添加脱气二噁烷(1.5mL)和H2O(0.5mL),并在100℃下加热14h。在冷却至室温后,添加EtOAc(20mL)。分离各相,并且水相用EtOAc(2×20mL)萃取。经合并的有机相经Na2SO4干燥,浓缩并通过柱色谱法(SiO2,0至100%含CH2Cl2/MeOH/7N甲醇NH3(90:10:1)的CH2Cl2)纯化,得到呈茶色固体状的所需产物(63mg,45%)。
步骤d:向来自步骤c的产物(63mg,0.11mmol)于CH2Cl2(1.0mL)中的溶液中添加TFA(1.0mL)。在室温下搅拌反应混合物4h。去除溶剂,并且将粗物质重悬于MeOH(1.0mL)中。向此混合物中添加DMEDA(0.5mL),并在60℃下搅拌1h。在冷却至室温后,去除溶剂,并且粗物质通过使用H2O+0.1%TFA和CH3CN+0.1%TFA作为流动相的反相HPLC来纯化,得到呈黄色固体状的所需产物(15mg;26%)。1H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.86(d,J=2.1Hz,1H),8.66(d,J=2.1Hz,1H),8.38(t,J=5.4Hz,1H),7.93(dd,J=8.2,0.4Hz,1H),7.90-7.82(m,1H),7.81-7.62(m,3H),7.37(d,J=7.9Hz,1H),4.38-4.30(m,2H),3.77(s,2H),3.36(q,J=5.0Hz,2H),3.16(dtd,J=29.8,16.7,15.5,8.0Hz,6H),2.94(s,1H),1.04(s,2H),0.87(d,J=7.1Hz,2H)。C28H28N5O2的ESIMS[M+H]+计算值466.2,实验值466.2。
实施例21:8-(5-(2-环丙基-1,2,3,4-四氢异喹啉-6-基)-1H-吡唑并[3,4-b]吡啶-3-基)-3,4-二氢苯并[f][1,4]氧氮杂卓-5(2H)-酮
以类似于实施例20的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),8.89(d,J=2.1Hz,1H),8.70(d,J=2.1Hz,1H),8.38(t,J=5.4Hz,1H),7.93(dd,J=8.2,0.4Hz,1H),7.86(dd,J=8.2,1.7Hz,1H),7.77(d,J=5.0Hz,2H),7.65(dd,J=1.7,0.5Hz,1H),7.37(d,J=8.6Hz,1H),4.66(d,J=16.3Hz,1H),4.55(s,1H),4.35(dd,J=5.4,4.1Hz,2H),3.79(s,2H),3.56(s,2H),3.36(q,J=5.0Hz,2H),3.02(s,1H),1.02(d,J=11.8Hz,2H),0.90(d,J=7.3Hz,2H)。C27H26N5O的ESIMS[M+H]+计算值452.2,实验值452.2。
实施例22:8-{5-[7-甲基-7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基]-1H-吡唑并[3,4-b]吡啶-3-基}-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
步骤a:向2-溴-5,6,8,9-四氢-7H-苯并环庚烯-7-酮(205mg,0.857mmol)、B2pin2(218mg,0.857mmol)和KOAc(93mg,0.943mmol)的混合物中添加二噁烷(4.3mL),然后悬浮液用N2脱气10min。添加(dppf)PdCl2(31mg,0.0429mmol),并且在80℃下搅拌反应混合物3h。在冷却后,添加EtOAc(15mL),并且经由硅藻土过滤混合物。浓缩滤液,得到呈粘稠棕色油状的粗物质。
步骤b:向实施例1步骤f的产物(445mg,0.909mmol)、步骤a的粗产物(0.857mmol)和Na2CO3(182mg,1.71mmol)的混合物中添加二噁烷(7.7mL)和H2O(0.90mL),然后悬浮液用N2脱气10min。添加(dppf)PdCl2(31mg,0.0429mmol),并且在90℃下搅拌反应混合物15h。在冷却后,添加CH2Cl2(20mL),并且使混合物经无水MgSO4干燥,过滤并浓缩。残余物通过硅胶色谱法(100%己烷至100%EtOAc)纯化,得到呈棕色固体状的所需产物(438mg;90%)。
步骤c:向步骤b的产物(115mg,0.202mmol)和吡咯烷(19μL,0.222mmol)于甲苯(50mL)中的混合物中添加1H-1,2,3-三唑(14μL,0.242mmol),并且在100℃下搅拌反应混合物24h。添加额外吡咯烷(2.0mL,23.9mmol),然后在回流下搅拌反应混合物17h,同时经由迪安-斯塔克分离器(Dean-Stark trap)收集水。在冷却后,经30min将甲苯溶液添加至MeMgBr溶液(3M于Et2O中,2.33mL,6.99mmol)和THF(10mL)的冷却(0℃)混合物中。在0℃下搅拌反应混合物1h,然后升温至室温并搅拌1h。再次将反应混合物冷却至0℃,并且小心地添加NH4Cl饱和水溶液,接着添加H2O。水层用EtOAc(3x 20mL)萃取,然后经合并的有机层用NaOH溶液(2N于H2O中,2x 30mL)和盐水洗涤,经无水MgSO4干燥并浓缩,得到起始材料和所需中间体的混合物(约1:1)。向粗物质于CH2Cl2(1.0mL)中的溶液中添加TFA(1.0mL)。在室温下搅拌反应物2h,然后浓缩。向残余物于EtOH(1.0mL)和二噁烷(0.5mL)中的溶液中添加NaOH溶液(2N于H2O中,1.0mL),并且在室温下搅拌反应混合物1h。添加NaHCO3饱和水溶液,并且混合物用含10%MeOH的CH2Cl2(3x 10mL)萃取,然后浓缩经合并的有机层。通过反相HPLC(10至70%ACN/H2O+0.1%TFA)纯化并冻干,得到呈浅黄色固体状的标题化合物(19mg,15%,约1:1d.r.)。1H NMR(400MHz,DMSO-d6)δ9.35(p,J=5.8Hz,1H),8.89(d,J=2.1Hz,1H),8.68(d,J=2.1Hz,1H),8.41(t,J=5.4Hz,1H),7.96(d,J=8.2Hz,1H),7.89(dd,J=8.2,1.7Hz,1H),7.71(d,J=2.0Hz,1H),7.68(d,J=1.6Hz,1H),7.63(dd,J=7.7,2.0Hz,1H),7.33(d,J=7.8Hz,1H),4.38(dd,J=5.4,4.1Hz,2H),3.39(q,J=5.0Hz,2H),3.35-3.25(m,4H),3.02-2.76(m,4H),2.15-2.04(m,2H),1.99-1.77(m,4H),1.74(d,J=12.5Hz,1H),1.67(d,J=12.8Hz,1H),1.52(s,3H)。C31H34N5O2的ESIMS[M+H]+计算值508.3,实验值508.2。
实施例23:8-(5-{7-甲基-7-[(2R)-2-甲基吡咯烷-1-基]-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基}-1H-吡唑并[3,4-b]吡啶-3-基)-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
以类似于实施例22的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.85(dd,J=2.1,0.8Hz,1H),8.70-8.53(m,2H),8.38(t,J=5.4Hz,1H),7.93(d,J=8.3Hz,1H),7.86(ddd,J=8.2,1.7,0.5Hz,1H),7.67(s,1H),7.64(d,J=1.7Hz,1H),7.60(dd,J=7.7,2.0Hz,1H),7.30(dd,J=8.0,1.4Hz,1H),4.34(dd,J=5.4,4.1Hz,2H),4.18-4.01(m,1H),3.36(q,J=5.1Hz,2H),3.33-3.21(m,2H),3.01-2.72(m,4H),2.27-2.11(m,1H),2.10-1.98(m,1H),1.97-1.55(m,6H),1.51(s,3H),1.25(d,J=6.6Hz,3H)。C32H36N5O2的ESIMS[M+H]+计算值522.3,实验值522.2。
实施例24:8-(5-{7-甲基-7-[(2S)-2-甲基吡咯烷-1-基]-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基}-1H-吡唑并[3,4-b]吡啶-3-基)-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
以类似于实施例22的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.85(dd,J=2.1,0.8Hz,1H),8.69-8.61(m,2H),8.38(t,J=5.3Hz,1H),7.93(d,J=8.2Hz,1H),7.86(dd,J=8.1,1.4Hz,1H),7.67(s,1H),7.64(d,J=1.7Hz,1H),7.60(dd,J=7.8,2.0Hz,1H),7.30(dd,J=7.7,1.4Hz,1H),4.34(dd,J=5.4,4.1Hz,2H),4.13-4.06(m,1H),3.39-3.22(m,4H),2.97-2.75(m,4H),2.26-2.10(m,1H),2.10-1.97(m,1H),1.97-1.78(m,3H),1.77-1.56(m,3H),1.51(s,3H),1.25(d,J=6.7Hz,3H)。C32H36N5O2的ESIMS[M+H]+计算值522.3,实验值522.2。
实施例25:8-(5-{7-[(2R)-2-乙基吡咯烷-1-基]-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基}-1H-吡唑并[3,4-b]吡啶-3-基)-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
以类似于实施例22的方式制备标题化合物。1H NMR(400MHz,氯仿-d)δ11.90(br.s,1H),8.88(dd,J=2.0,0.9Hz,1H),8.51(d,J=2.0Hz,1H),8.19(d,J=8.4Hz,1H),7.85-7.77(m,1H),7.70(td,J=1.1,0.5Hz,1H),7.44-7.38(m,2H),7.30-7.24(m,1H),6.69(t,J=5.4Hz,1H),4.58-4.40(m,2H),3.60(q,J=5.1Hz,2H),3.03-2.82(m,5H),2.82-2.73(m,1H),2.73-2.64(m,1H),2.51(q,J=8.4Hz,1H),2.25-2.07(m,2H),1.83(dt,J=11.8,7.6Hz,1H),1.80-1.51(m,4H),1.47(td,J=10.5,9.0,6.0Hz,1H),1.43-1.35(m,1H),1.24(dq,J=15.4,7.6Hz,1H),0.91(t,J=7.4Hz,3H)。C32H36N5O2的ESIMS[M+H]+计算值522.3,实验值522.2。
实施例26:7-[5-(3-环戊基-2,3,4,5-四氢-1H-3-苯并氮杂卓-7-基)-1H-吡唑并[3,4-b]吡啶-3-基]-4-甲基-3,4-二氢-2H-1-苯并吡喃-4-醇
步骤a:在室温下,经由注射泵,经40min将7-溴色满酮(1.00g,4.40mmol)于THF(9.8mL)中的溶液添加至甲基溴化镁(3.0M于Et2O中)(3.1mL,9.3mmol)于THF(4.9mL)中的溶液中。在添加完成后,在室温下再搅拌混合物1h。然后,将混合物倒入冰/饱和NH4Cl(aq)(50mL)中。将产物萃取至EtOAc(3x 25mL)中,并且经合并的有机相用盐水(50mL)洗涤并干燥(MgSO4)。所述物质以粗物质形式用于下一步骤中。
步骤b:步骤a的产物(4.30mmol)、B2pin2(1.09g,4.30mmol)、KOAc(0.844g,8.60mmol)和二噁烷(21.5mL)的混合物用氮气鼓泡10min,然后添加(dppf)PdCl2(0.157g,0.215mmol)并继续鼓泡5min。在100℃下加热混合物2h,然后冷却至室温并用EtOAc(100mL)稀释。经由硅藻土垫过滤混合物,浓缩滤液,并且粗物质用于下一步骤中。
步骤c:实施例1步骤e的产物(1.33g,2.90mmol)、步骤b的产物(3.23mmol)和碳酸钠(0.615g,5.80mmol)于9:1二噁烷:H2O(29mL)中的溶液用氮气鼓泡10min。添加(dppf)PdCl2(0.424g,0.580mmol),并且继续再鼓泡5min。在100℃下搅拌混合物过夜,然后冷却至室温。添加CH2Cl2(60mL),并且所述溶液经MgSO4干燥,浓缩并通过快速色谱法(SiO2,0至50%EtOAc/己烷)纯化,得到呈米色固体状的产物(0.741g;52%)。
步骤d:以类似于步骤c的方式制备所需产物(136mg;54%)。
步骤e:在70℃下加热步骤d的产物(63.8mg,0.102mmol)和含1M TBAF的THF(1.0mL)的混合物过夜。浓缩混合物,然后用饱和NaHCO3(aq)(5mL)稀释。将产物萃取至CHCl3:IPA 9:1(3x 5mL)中。将经合并的有机相干燥(Na2SO4)并浓缩。将残余物溶解于MeOH(1.0mL)中并用DMEDA(0.08mL,0.77mmol)处理。在45℃下搅拌混合物30min并且然后浓缩。残余物通过快速色谱法(1至10%含MeOH/NH3(aq)10:1的CH2Cl2)纯化,得到呈灰白色固体状的标题化合物(24.7mg,49%)。1H NMR(400MHz,DMSO-d6)δ13.85(br.s,1H),8.85(d,J=2.1Hz,1H),8.58(d,J=2.1Hz,1H),7.64(d,J=1.1Hz,2H),7.59(d,J=2.0Hz,1H),7.55(dd,J=7.7,2.0Hz,1H),7.39(t,J=1.0Hz,1H),7.26(d,J=7.8Hz,1H),5.26(s,1H),4.32(ddd,J=11.3,7.7,3.7Hz,1H),4.24(ddd,J=10.9,6.9,3.7Hz,1H),2.99-2.97(m,2H),2.94-2.90(m,2H),2.87(p,J=7.8Hz,1H),2.72-2.60(m,4H),2.09-1.94(m,2H),1.87-1.75(m,2H),1.69-1.56(m,2H),1.55-1.50(m,2H),1.55(s,3H),1.46-1.33(m,2H)。C31H35N4O2的ESIMS[M+H]+计算值495.3,实验值495.2。
实施例27:2-[5-(3-环戊基-2,3,4,5-四氢-1H-3-苯并氮杂卓-7-基)-1H-吡唑并[3,4-b]吡啶-3-基]-5-甲基-6,7,8,9-四氢-5H-苯并[7]轮烯-5-醇
以类似于实施例26的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ13.81(br.s,1H),8.84(d,J=2.1Hz,1H),8.63(d,J=2.1Hz,1H),7.89(dd,J=8.2,1.9Hz,1H),7.82(d,J=8.2Hz,1H),7.75(d,J=1.9Hz,1H),7.59(d,J=2.0Hz,1H),7.55(dd,J=7.6,2.0Hz,1H),7.26(d,J=7.8Hz,1H),5.04(s,1H),3.10(dd,J=14.2,7.0Hz,1H),3.02-2.90(m,5H),2.87(p,J=8.0Hz,1H),2.73-2.58(m,4H),2.00-1.73(m,7H),1.70-1.56(m,2H),1.55-1.36(m,5H),1.52(s,3H)。C33H39N4O的ESIMS[M+H]+计算值507.3,实验值507.2。
实施例28:(8-[5-(3-环戊基-2,3,4,5-四氢-1H-3-苯并氮杂卓-7-基)-1H-吡唑并[3,4-b]吡啶-3-基]-5-甲基-2,3,4,5-四氢-1-苯并噁呯-5-醇)
以类似于实施例26的方式制备标题化合物。1H NMR(400MHz,氯仿-d)δ11.49(br.s,1H),8.85(d,J=2.0Hz,1H),8.49(d,J=2.1Hz,1H),7.76(dd,J=8.1,1.7Hz,1H),7.73(d,J=7.8Hz,1H),7.65(d,J=1.4Hz,1H),7.40(d,J=7.5Hz,1H),7.39-7.37(m,1H),7.26-7.23(m,1H),4.24(ddd,J=12.0,6.0,3.6Hz,1H),3.96(ddd,J=11.7,8.5,2.9Hz,1H),3.04(ddd,J=13.7,5.7,4.0Hz,4H),2.90(p,J=8.0Hz,1H),2.81-2.72(m,4H),2.48(s,1H),2.24-1.96(m,4H),1.95-1.83(m,2H),1.69(s,3H),1.66-1.41(m,6H)。C32H37N4O2的ESIMS[M+H]+计算值509.3,实验值509.2。
实施例29:4-甲基-7-(5-{7-[(2R)-2-甲基吡咯烷-1-基]-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基}-1H-吡唑并[3,4-b]吡啶-3-基)-3,4-二氢-2H-1-苯并吡喃-4-醇
以类似于实施例26的方式制备标题化合物。1H NMR(400MHz,氯仿-d)δ11.03(br.s,1H),8.83(d,J=2.0Hz,1H),8.47(d,J=2.0Hz,1H),7.66(d,J=8.1Hz,1H),7.60(dd,J=8.1,1.7Hz,1H),7.46(d,J=1.7Hz,1H),7.43-7.35(m,2H),7.30-7.22(m,1H),4.42-4.27(m,2H),3.03-2.82(m,6H),2.82-2.69(m,1H),2.50(q,J=8.4Hz,2H),2.23-2.07(m,4H),1.97(s,1H),1.88(ddt,J=12.4,9.0,6.6Hz,1H),1.71(s,3H),1.66-1.54(m,2H),1.48-1.32(m,2H),1.11(d,J=6.0Hz,3H)。C32H37N4O2的ESIMS[M+H]+计算值509.3,实验值509.2。
实施例30:1-甲基-5-{5-[(7S)-7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基]-1H-吡唑并[3,4-b]吡啶-3-基}-2,3-二氢-1H-茚-1-醇
步骤a:以类似于实施例26步骤a的方式制备所需产物(2.01g;93%)。
步骤b:以类似于实施例26步骤b的方式制备所需产物。
步骤c:以类似于实施例26步骤c的方式制备所需产物(107mg;23%)。
步骤d:在室温下向来自步骤c的产物(107mg,0.310mmol)、三乙胺(0.09mL,0.62mmol)、DMAP(3.9mg,0.031mmol)和CH2Cl2(1.6mL)的溶液中添加Boc酸酐(71.1mg,0.326mmol)。在室温下搅拌混合物30min,然后真空浓缩。残余物通过快速色谱法(EtOAc/己烷,0至50%)纯化,得到所需产物(97mg;70%)。
步骤e:在室温下向(7S)-6,7,8,9-四氢-7-(1-吡咯烷基)-5H-苯并环庚烯-2-胺(2.3g,10mmol)、AcOH(33.3mL)和浓HBr(2.3mL,20mmol)的混合物中添加tBuNO2(1.3mL,11mmol)。在室温下搅拌混合物30min。将溶解于AcOH(20mL)中的CuBr(2.9g,20mmol)滴加至反应混合物中,并在室温下搅拌3h。添加H2O(100mL)以稀释反应混合物,接着缓慢添加28wt%NH3(aq)以调节至pH约10-11。然后,粗产物用CH2Cl2(2×100mL)萃取。经合并的有机相经Na2SO4干燥,浓缩并通过柱色谱法(SiO2,0至100%含CH2Cl2/MeOH/7N甲醇NH3(90:10:1)的CH2Cl2)纯化,得到呈浅棕色油状的所需产物(2.2g,75%)。
步骤f:以类似于实施例26步骤b的方式制备所需产物。
步骤g:以类似于实施例26步骤c的方式制备所需产物(26mg,24%)。1H NMR(400MHz,甲醇-d4)δ8.76(d,J=2.1Hz,1H),8.53(d,J=2.1Hz,1H),7.87-7.83(m,1H),7.83-7.81(m,1H),7.50(d,J=7.8Hz,1H),7.45(d,J=2.0Hz,1H),7.42(dd,J=7.6,2.0Hz,1H),7.23(d,J=7.7Hz,1H),3.11(dt,J=16.1,6.7Hz,1H),3.01-2.76(m,6H),2.73(d,J=6.5Hz,4H),2.59(t,J=10.7Hz,1H),2.34-2.26(m,2H),2.22(t,J=7.0Hz,2H),1.81(p,J=3.1Hz,4H),1.56(s,3H),1.40(p,J=11.4Hz,2H)。C31H35N4O的ESIMS[M+H]+计算值479.3,实验值479.2。
实施例31:4-甲基-7-{5-[(7S)-7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基]-1H-吡唑并[3,4-b]吡啶-3-基}-3,4-二氢-2H-1-苯并吡喃-4-醇
以类似于实施例30的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ13.85(br.s,1H),8.85(d,J=2.1Hz,1H),8.58(d,J=2.1Hz,1H),7.64(d,J=1.1Hz,2H),7.60(d,J=2.0Hz,1H),7.53(dd,J=7.7,2.0Hz,1H),7.40(t,J=1.1Hz,1H),7.26(d,J=7.8Hz,1H),5.26(s,1H),4.32(ddd,J=11.3,7.7,3.6Hz,1H),4.24(ddd,J=10.9,6.8,3.7Hz,1H),3.20-2.99(m,2H),2.76-2.59(m,2H),2.60-2.53(m,4H),2.01(qdt,J=11.4,7.6,3.4Hz,2H),1.95-1.82(m,3H),1.75-1.69(m,4H),1.66-1.58(m,2H),1.55(s,3H)。C31H35N4O2的ESIMS[M+H]+计算值495.3,实验值495.2。
实施例32:3,3-二甲基-6-{5-[7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基]-1H-吡唑并[3,4-b]吡啶-3-基}-2,3-二氢-1λ6,2-苯并噻唑-1,1-二酮
步骤a:在室温下向NaH(800g,20.0mmol,60wt%于油中)于THF(40mL)中的混合物中滴加苯甲基硫醇(2.35mL,20.0mmol)。在室温下搅拌反应混合物30分钟,以整份装入4-溴-2-氟苯甲酸甲酯(4.66g,20.0mmol),在室温下搅拌16小时,浓缩至硅胶上,并通过柱色谱法(120g硅胶,己烷:EtOAc,0%至25%梯度(25分钟))纯化,得到呈白色固体状的所需产物(5.86g;87%)。
步骤b:在室温下向来自步骤a的产物(5.86g,17.4mmol)和19:1AcOH:水(87mL)的混合物中以整份添加NCS(6.96g,52.1mmol)。在室温下搅拌反应混合物1小时,浓缩,用EtOAc(125mL)稀释,用1:1饱和NHCO3(aq):水(2x 100mL)洗涤,经Na2SO4干燥并浓缩,得到所需产物,其以粗物质形式用于下一步骤中。
步骤c:在室温下向来自步骤b的产物(假定17.4mmol)、Et3N(12.1mL,87.0mmol)和CH2Cl2(87mL)的混合物中添加t-BuNH2(5.49mL,52.2mmol)。在室温下搅拌反应混合物3小时,浓缩至硅胶上,并通过柱色谱法(120g硅胶,己烷:EtOAc,0%至50%梯度(20分钟))纯化,得到呈白色固体状的所需产物(5.39g;89%;两个步骤)。
步骤d:向在0℃的来自步骤c的产物(4.96g,14.2mmol)于THF(71mL)中的混合物中滴加MeMgBr(18.9mL,56.6mmol,3M于Et2O中)。在0℃下搅拌反应混合物45分钟,在室温下搅拌14小时,用饱和NH4Cl(aq)淬灭,用EtOAc(142mL)稀释,经Na2SO4干燥并浓缩,得到所需产物,其以粗物质形式用于下一步骤中。
步骤e:在室温下向来自步骤d的产物(假定14.2mmol)、NaI(4.09g,27.3mmol)和ACN(68mL)的混合物中添加氯三甲基硅烷(3.47mL,27.3mmol)。在67℃下搅拌反应混合物2小时,冷却至室温,用10wt%NaHSO3(aq)(142mL)淬灭,并用EtOAc(284mL)稀释。有机相经Na2SO4干燥并浓缩。粗物质通过柱色谱法(40g硅胶,己烷:EtOAc,0%至100%梯度(25分钟))纯化,得到呈白色固体状的所需产物(2.11g;54%;两个步骤)。
步骤f:以类似于实施例1步骤d的方式制备所需产物。
步骤g:在室温下向5-溴-1H-吡唑并[3,4-b]吡啶(19.8g,100mmol)、樟脑磺酸(2.32g,10mmol)和THF(250mL)的混合物中添加3,4-二氢-2H-吡喃(18.3mL,200mmol)。在65℃下搅拌反应混合物4小时,冷却至室温,并用28wt%NH3(aq)(10mL)淬灭。将混合物浓缩至硅胶上并通过柱色谱法(330g硅胶,己烷:EtOAc,0%至50%梯度(20分钟))纯化,得到呈红色油状的所需产物(26.7g;95%)。
步骤h:将2-溴-5,6,8,9-四氢-7H-苯并环庚烯-7-酮(17.9g,75.0mmol)、B2pin2(19.1g,75.0mmol)、(dppf)PdCl2(2.74g,3.75mmol)和KOAc(14.7g,150mmol)的混合物置于氮气下。添加脱气二噁烷(224mL),并且在100℃下搅拌反应混合物1小时。将混合物冷却至室温并浓缩。添加MTBE(375mL),经由硅藻土过滤混合物,用MTBE洗涤并浓缩,得到所需产物,其以粗物质形式用于下一步骤中。
步骤i:将来自步骤g的产物(21.2g,75mmol)、来自步骤h的产物(假定75.0mmol)和(dppf)PdCl2(5.49g,7.50mmol)的混合物置于氮气下。添加脱气二噁烷(375mL)和脱气2MNa2CO3(aq)(75mL),并且在95℃下搅拌反应混合物14小时(或直至完成)。将混合物冷却至室温,浓缩至接近干燥,溶解于乙基EtOAc(375mL)中,经Na2SO4干燥并再次浓缩。添加含3M HCl的MeOH(400mL),并且在室温下搅拌反应混合物2小时并用MTBE(4.00L)稀释。通过过滤收集沉淀的固体,用MTBE洗涤并真空干燥,得到呈棕色固体状的所需产物(19.4g;82%;两个步骤)。
步骤j:在70℃下搅拌来自步骤i的产物(19.4g,61.8mmol)、乙二醇(17.2mL,309mmol)的混合物24小时,用28wt%NH3(aq)(20mL)淬灭并浓缩。添加EtOAc(500mL)和水(250mL),并且通过过滤收集固体,用EtOAc/水洗涤。有机相用水(2x 250mL)洗涤,经Na2SO4干燥,浓缩,并与先前收集的固体合并。粗物质通过柱色谱法(330g硅胶,CH2Cl2:MeOH,0%至3%梯度(20分钟);3%至5%梯度(10分钟))纯化,得到呈橙色固体状的所需产物(14.8g;75%)。
步骤k:在室温下向来自步骤j的产物(14.8g,46.1mmol)和2:1CH2Cl2:AcOH(138mL)的混合物中添加NBS(8.62g,48.5mmol)。在室温下搅拌反应混合物14小时,浓缩至硅胶上,并通过柱色谱法(330g硅胶,CH2Cl2:MeOH,0%至5%梯度(15分钟);5%至7.5%梯度(5分钟))纯化,得到呈棕色固体状的所需产物(21.4g;74.5wt%;其余为丁二酰亚胺)。如果纯,则15.9g(86%产率)。
步骤l:在室温下向来自步骤k的产物(21.4g,39.7mmol,74.5%wt%)、DMAP(486mg,3.97mmol)、Et3N(26.4mL,189mmol)和CH2Cl2(199mL)的混合物中以整份添加二碳酸二叔丁酯(21.7g,99.4mmol)。在室温下搅拌反应混合物1小时,浓缩至硅胶上,并通过柱色谱法(330g硅胶,己烷:EtOAc,0%至50%梯度(25分钟))纯化,得到呈白色固体状的所需产物(18.2g;77.4wt%;其余为N-Boc-丁二酰亚胺)。如果纯,则14.1g(71%产率)。
步骤m:以类似于实施例7步骤c的方式制备所需产物(110mg;53%)。
步骤n:在70℃下搅拌来自步骤m的产物(110mg,0.213mmol)、HCl(426μL,0.426mmol,1M于水中)和THF(1.1mL)的混合物1小时。将混合物冷却至室温,用饱和NaHCO3(aq)中和,用盐水(1.1mL)洗涤,浓缩,用CH2Cl2(10mL)稀释,经Na2SO4干燥并再次浓缩。添加吡咯烷(21μL,0.26mmol)、AcOH(12μL,0.21mmol)和DCE(1.1mL),接着添加NaBH(OAc)3(67mg,0.32mmol)。在室温下搅拌反应混合物4小时,用1:1饱和NaHCO3(aq):水(8.0mL)淬灭,并用4:1CH2Cl2:IPA(1x 25mL)萃取。有机相经Na2SO4干燥并浓缩。粗物质通过HPLC((H2O/ACN)+0.1%TFA,5%至95%梯度(30分钟))纯化,得到呈浅黄色固体状的所需产物(106mg;79%)。1H NMR(400MHz,DMSO-d6)δ8.87(d,J=2.1Hz,1H),8.70(d,J=2.1Hz,1H),8.44(dd,J=8.2,1.6Hz,1H),8.32(dd,J=1.6,0.6Hz,1H),8.04(s,1H),7.85(dd,J=8.2,0.6Hz,1H),7.60(d,J=2.0Hz,1H),7.54(dd,J=7.7,2.0Hz,1H),7.25(d,J=7.8Hz,1H),3.19-2.96(m,2H),2.76-2.61(m,2H),2.61-2.43(m,5H),2.03-1.80(m,2H),1.80-1.66(m,4H),1.60(s,8H)。C30H34N5O2S的ESIMS[M+H]+计算值528.2,实验值528.3。
实施例33:3,3-二甲基-6-(5-{7-[(2R)-2-甲基吡咯烷-1-基]-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基}-1H-吡唑并[3,4-b]吡啶-3-基)-2,3-二氢-1λ6,2-苯并噻唑-1,1-二酮
以类似于实施例32的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.88(dd,J=2.0,0.8Hz,1H),8.71(d,J=0.6Hz,1H),8.44(ddd,J=8.2,1.6,0.6Hz,1H),8.32(dt,J=1.5,0.7Hz,1H),8.04(s,1H),7.85(d,J=8.1Hz,1H),7.62(t,J=2.6Hz,1H),7.56(dd,J=7.7,2.0Hz,1H),7.27(dd,J=7.7,1.3Hz,1H),3.01-2.77(m,5H),2.77-2.65(m,2H),2.44(q,J=8.2Hz,1H),2.06-1.95(m,2H),1.87-1.77(m,1H),1.67-1.50(m,8H),1.44(t,J=12.3Hz,1H),1.34-1.21(m,2H),1.02(d,J=6.0Hz,3H)。C31H36N5O2S的ESIMS[M+H]+计算值542.3,实验值542.2。
实施例34:6-(5-{7-[(2R)-2-(羟基甲基)吡咯烷-1-基]-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基}-1H-吡唑并[3,4-b]吡啶-3-基)-3,3-二甲基-2,3-二氢-1λ6,2-苯并噻唑-1,1-二酮
以类似于实施例32的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.88(d,J=1.9Hz,1H),8.71(d,J=2.0Hz,1H),8.44(dd,J=8.1,1.6Hz,1H),8.32(dt,J=1.5,0.7Hz,1H),8.04(s,1H),7.85(dd,J=8.1,0.7Hz,1H),7.64-7.60(m,1H),7.56(dd,J=7.7,2.0Hz,1H),7.27(d,J=7.8Hz,1H),3.38-3.34(m,1H),3.16-3.09(m,1H),2.99-2.81(m,4H),2.80-2.65(m,3H),2.54-2.51(m,1H),2.12-2.02(m,2H),1.72-1.53(m,10H),1.46-1.25(m,2H)。C31H36N5O3S的ESIMS[M+H]+计算值558.3,实验值558.2。
实施例35:3,3-二甲基-8-{5-[7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基]-1H-吡唑并[3,4-b]吡啶-3-基}-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
步骤a:向在0℃的4-溴-2-氟苯甲腈(2.00g,10.0mmol)、2-氨基-2-甲基-1-丙醇(954μL,10.0mmol)和THF(20mL)的混合物中以整份添加NaH(400g,10.0mmol,60wt%于油中)。在0℃下搅拌反应混合物1小时,在室温下搅拌14小时,浓缩至硅胶上,并通过柱色谱法(80g硅胶,CH2Cl2:MeOH,0%至20%梯度(30分钟))纯化,得到呈黄色固体状的所需产物(1.82g;68%)。
步骤b:在90℃下搅拌来自步骤a的产物(1.82g,6.76mmol)、NaOH(848mg,21.2mmol)和4:1EtOH:水(14mL)的混合物14小时,冷却至室温,并浓缩以去除EtOH。所得混合物通过添加2M HCl(aq)(约2.5eq)调整至pH约4。通过过滤收集所形成固体,用水洗涤并干燥,得到呈浅棕色固体状的所需产物(1.93g;99%)。
步骤c:在室温下向来自步骤b的产物(1.93g,6.70mmol)、HOBt水合物(1.13g,7.37mmol)、Et3N(3.73mL,26.8mmol)和DMF(33mL)的混合物中以整份添加1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(1.93g,10.1mmol)。在40℃下搅拌反应混合物3天,用EtOAc(125mL)稀释,用9:1水:盐水(4x 100mL)洗涤,经Na2SO4干燥并浓缩。粗物质通过柱色谱法(40g硅胶,己烷:EtOAc,0%至100%梯度(25分钟))纯化,得到呈黄色固体状的所需产物(1.24g;69%)。
步骤d:以类似于实施例1步骤d的方式制备所需产物。
步骤e:以类似于实施例7步骤c的方式制备所需产物(103mg;50%)。
步骤f:以类似于实施例32步骤n的方式制备所需产物(37mg;37%)。1H NMR(400MHz,DMSO-d6)δ8.86(d,J=2.1Hz,1H),8.67(d,J=2.1Hz,1H),8.35(d,J=8.4Hz,1H),8.24(s,1H),7.86(dd,J=8.5,1.8Hz,1H),7.69(d,J=1.8Hz,1H),7.61(d,J=2.0Hz,1H),7.54(dd,J=7.6,2.0Hz,1H),7.25(d,J=7.8Hz,1H),4.18(s,2H),3.18-2.98(m,2H),2.77-2.61(m,2H),2.61-2.45(m,5H),2.01-1.79(m,2H),1.79-1.65(m,4H),1.65-1.49(m,2H),1.27(s,6H)。C32H36N5O2的ESIMS[M+H]+计算值522.3,实验值522.3。
实施例36:8-(5-{7-[(2R)-2-甲基吡咯烷-1-基]-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基}-1H-吡唑并[3,4-b]吡啶-3-基)-4,5-二氢-2H-螺[1,4-苯并氧氮杂卓-3,1'-环丙烷]-5-酮
以类似于实施例35的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ14.04(s,1H),8.87(d,J=2.0Hz,1H),8.70(s,1H),8.68(d,J=2.0Hz,1H),7.91(dd,J=8.2,1.5,0.6Hz,1H),7.88(d,J=8.2Hz,1H),7.69(d,J=1.5Hz,1H),7.62(t,J=2.3Hz,1H),7.55(dd,J=7.7,2.0Hz,1H),7.27(d,J=7.2Hz,1H),4.27(s,2H),3.01-2.76(m,5H),2.76-2.67(m,2H),2.44(q,J=8.3Hz,1H),2.06-1.94(m,2H),1.88-1.76(m,1H),1.68-1.49(m,2H),1.49-1.37(m,1H),1.35-1.20(m,2H),1.02(d,J=5.9Hz,3H),0.79(d,J=7.1Hz,4H)。C33H36N5O2的ESI MS[M+H]+计算值534.3,实验值534.3。
实施例37:8-(5-{7-[(2R)-2-甲基吡咯烷-1-基]-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基}-1H-吡唑并[3,4-b]吡啶-3-基)-4,5-二氢-2H-螺[1,4-苯并氧氮杂卓-3,1'-环丁烷]-5-酮
以类似于实施例35的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.86(d,J=2.0Hz,1H),8.70(s,1H),8.67(d,J=2.1Hz,1H),8.19(d,J=8.4Hz,1H),7.85(ddd,J=8.4,1.8,0.5Hz,1H),7.70(d,J=1.7Hz,1H),7.62(t,J=2.3Hz,1H),7.55(dd,J=7.7,2.0Hz,1H),7.27(d,J=7.0Hz,1H),4.40(s,2H),3.02-2.77(m,5H),2.77-2.65(m,2H),2.44(q,J=8.2Hz,1H),2.25-2.14(m,2H),2.13-2.05(m,2H),2.05-1.95(m,2H),1.87-1.73(m,3H),1.68-1.49(m,2H),1.49-1.39(m,1H),1.34-1.21(m,2H),1.03(d,J=6.0Hz,3H)。C34H38N5O2的ESI MS[M+H]+计算值548.3,实验值548.3。
实施例38:3,3-二甲基-6-(5-{7-[(2R)-2-甲基吡咯烷-1-基]-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基}-1H-吡唑并[3,4-b]吡啶-3-基)-2,3-二氢-1H-异吲哚-1-酮
以类似于实施例35的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ13.96(s,1H),8.86(d,J=1.5Hz,1H),8.78(s,1H),8.63(dd,J=2.1,1.0Hz,1H),8.33(dd,J=7.9,1.6Hz,1H),8.18(dd,J=1.6,0.7Hz,1H),7.79(d,J=7.9Hz,1H),7.60(t,J=2.4Hz,1H),7.54(dd,J=7.7,2.0Hz,1H),7.26(d,J=7.4Hz,1H),3.02-2.76(m,5H),2.76-2.63(m,2H),2.44(q,J=8.2Hz,1H),2.07-1.93(m,2H),1.88-1.76(m,1H),1.69-1.37(m,9H),1.35-1.19(m,2H),1.02(d,J=6.0Hz,3H)。C32H36N5O的ESIMS[M+H]+计算值506.3,实验值506.3。
实施例39:3,3-二甲基-8-(5-{2-[(2S)-2-甲基吡咯烷-1-基]-2,3-二氢-1H-茚-5-基}-1H-吡唑并[3,4-b]吡啶-3-基)-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
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以类似于实施例35的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),8.84(d,J=2.1Hz,1H),8.65(dd,J=2.2,0.6Hz,1H),8.32(dt,J=8.5,0.5Hz,1H),8.21(s,1H),7.82(ddd,J=8.5,1.8,0.6Hz,1H),7.77-7.72(m,1H),7.71-7.64(m,2H),7.40(dd,J=7.9,5.9Hz,1H),4.30(dt,J=11.6,7.9Hz,1H),3.93-3.25(m,6H),3.18(td,J=14.9,6.2Hz,3H),2.23(dq,J=14.1,7.3Hz,1H),1.94(ddq,J=28.1,13.9,7.2,6.7Hz,2H),1.64(dq,J=14.1,7.3Hz,1H),1.39(d,J=6.6Hz,3H),1.23(s,6H)。C31H34N5O2的ESIMS[M+H]+计算值508.3,实验值508.2。
实施例40:7-甲基-8-(5-{7-[(2R)-2-甲基吡咯烷-1-基]-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基}-1H-吡唑并[3,4-b]吡啶-3-基)-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
以类似于实施例35的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.86(d,J=2.1Hz,1H),8.39(t,J=5.4Hz,1H),8.27(d,J=2.1Hz,1H),7.78(d,J=0.8Hz,1H),7.54(s,1H),7.48(d,J=7.5Hz,1H),7.25-7.19(m,2H),4.32(dd,J=5.3,4.2Hz,2H),3.41-3.35(m,2H),2.97-2.75(m,4H),2.75-2.63(m,2H),2.42(d,J=8.5Hz,1H),2.39(d,J=0.7Hz,3H),2.34-2.31(m,1H),2.03-1.91(m,2H),1.88-1.74(m,1H),1.68-1.49(m,2H),1.46-1.35(m,1H),1.33-1.18(m,2H),1.01(d,J=6.0Hz,3H)。C32H36N5O2的ESIMS[M+H]+计算值522.3,实验值522.3。
实施例41:9-甲基-8-(5-{7-[(2R)-2-甲基吡咯烷-1-基]-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基}-1H-吡唑并[3,4-b]吡啶-3-基)-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
以类似于实施例35的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.83(d,J=2.1Hz,1H),8.37(t,J=5.5Hz,1H),8.23(d,J=2.1Hz,1H),7.59(d,J=8.0Hz,1H),7.53(d,J=2.2Hz,1H),7.47(dd,J=7.7,2.0Hz,1H),7.42(d,J=8.0Hz,1H),7.21(d,J=7.7Hz,1H),4.33(d,J=5.3Hz,2H),3.55-3.23(m,2H),2.96-2.62(m,7H),2.42(q,J=8.3Hz,1H),2.33(s,3H),2.03-1.93(d,J=13.1Hz,2H),1.86-1.74(m,1H),1.68-1.50(m,2H),1.46-1.36(m,1H),1.32-1.20(m,2H),1.01(d,J=6.0Hz,3H)。C32H36N5O2的ESIMS[M+H]+计算值522.3,实验值522.3。
实施例42:8-{5-[7-(环戊基氨基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基]-1H-吡唑并[3,4-b]吡啶-3-基}-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
步骤a:向实施例22步骤b的产物(635mg,1.12mmol)于CH2Cl2(2.8mL)中的溶液中添加TFA(2.8mL)。在室温下搅拌反应物2h,然后浓缩。向残余物于EtOH(5.6mL)中的悬浮液中添加NaOH溶液(2N于H2O中,5.6mL)。添加二噁烷(10mL),并且在室温下搅拌反应混合物2h。添加NaHCO3饱和水溶液,并且混合物用含10%MeOH的CH2Cl2(3x 15mL)萃取,然后浓缩经合并的有机层,得到呈黄色固体状的产物(230mg;47%)。
步骤b:向步骤a的产物(58mg,0.132mmol)和环戊胺(14μL,0.139mmol)于1,2-二氯乙烷(1.4mL)中的混合物中添加AcOH(7μL,0.132mmol),并且在室温下搅拌混合物30min,然后添加NaBH(OAc)3(63mg,0.296mmol)。在室温下搅拌反应混合物15h,并且小心地用H2O、然后NaHCO3饱和水溶液淬灭。混合物用含10%MeOH的CH2Cl2(3x 10mL)萃取,然后浓缩经合并的有机层。通过反相HPLC(10至70%ACN/H2O+0.1%TFA)纯化并冻干,得到呈白色固体状的标题化合物(16mg,19%)。1H NMR(400MHz,CD3OD)δ8.82(d,J=2.0Hz,1H),8.62(d,J=2.1Hz,1H),8.02(d,J=8.2Hz,1H),7.86(dd,J=8.2,1.7Hz,1H),7.72(d,J=1.6Hz,1H),7.57(d,J=2.0Hz,1H),7.54(dd,J=7.7,2.0Hz,1H),7.33(d,J=7.7Hz,1H),4.46(dd,J=5.1,4.4Hz,2H),3.80(p,J=7.4Hz,1H),3.56-3.46(m,3H),3.11-3.04(m,1H),3.04-2.93(m,3H),2.53-2.40(m,2H),2.25-2.08(m,2H),1.92-1.78(m,2H),1.78-1.56(m,4H),1.56-1.38(m,2H)。C31H34N5O2的ESI MS[M+H]+计算值508.3,实验值508.2。
实施例43:8-(5-{7-[(2S)-2-甲基吡咯烷-1-基]-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基}-1H-吡唑并[3,4-b]吡啶-3-基)-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
以类似于实施例42的方式制备标题化合物。1H NMR(400MHz,甲醇-d4)δ8.73(dd,J=2.1,1.0Hz,1H),8.49(dd,J=2.1,1.1Hz,1H),7.97(dd,J=8.2,0.4Hz,1H),7.77(dd,J=8.2,1.7Hz,1H),7.63(dd,J=1.6,0.4Hz,1H),7.48(t,J=2.2Hz,1H),7.44(ddd,J=7.7,2.1,0.9Hz,1H),7.26(d,J=7.8Hz,1H),4.49-4.37(m,2H),3.85-3.63(m,2H),3.54-3.48(m,2H),3.48-3.38(m,1H),3.30-3.18(m,1H),3.11-2.82(m,4H),2.43-2.33(m,2H),2.29(dq,J=13.6,6.9Hz,1H),2.02(p,J=7.4Hz,2H),1.74(dq,J=13.0,7.9Hz,1H),1.68-1.50(m,2H),1.47(d,J=6.4Hz,3H)。C31H34N5O2的ESIMS[M+H]+计算值508.3,实验值508.2。
实施例44:8-(5-{7-[(2R)-2-甲基吡咯烷-1-基]-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基}-1H-吡唑并[3,4-b]吡啶-3-基)-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
以类似于实施例42的方式制备标题化合物。1H NMR(400MHz,甲醇-d4)δ8.73(dd,J=2.1,1.0Hz,1H),8.49(dd,J=2.1,1.1Hz,1H),7.97(dd,J=8.2,0.3Hz,1H),7.77(dd,J=8.2,1.7Hz,1H),7.63(d,J=1.6Hz,1H),7.48(t,J=2.2Hz,1H),7.44(dd,J=7.7,1.8Hz,1H),7.26(d,J=7.8Hz,1H),4.44(dd,J=5.5,4.1Hz,2H),3.85-3.63(m,2H),3.52-3.48(m,2H),3.48-3.40(m,1H),3.28-3.19(m,1H),3.09-2.85(m,4H),2.43-2.33(m,2H),2.29(dq,J=13.6,6.9Hz,1H),2.02(p,J=7.4Hz,2H),1.74(dq,J=13.0,7.9Hz,1H),1.68-1.50(m,2H),1.47(d,J=6.4Hz,3H)。C31H34N5O2的ESIMS[M+H]+计算值508.3,实验值508.2。
实施例45:8-[5-(7-{[(3S)-氧杂环戊烷-3-基]氨基}-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)-1H-吡唑并[3,4-b]吡啶-3-基]-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
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以类似于实施例42的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.89(d,J=2.0Hz,1H),8.69(d,J=2.1Hz,1H),8.64-8.46(m,2H),8.41(t,J=5.4Hz,1H),7.96(dd,J=8.2,0.4Hz,1H),7.90(dd,J=8.2,1.7Hz,1H),7.71-7.66(m,2H),7.63(dd,J=7.7,1.9Hz,1H),7.32(d,J=7.8Hz,1H),4.38(dd,J=5.4,4.1Hz,2H),4.16-4.00(m,1H),3.95(td,J=8.3,5.4Hz,1H),3.85(d,J=4.9Hz,2H),3.71-3.64(m,1H),3.58-3.43(m,1H),3.39(q,J=5.0Hz,2H),3.10-2.76(m,4H),2.43-2.25(m,3H),2.02-1.92(m,1H),1.36(p,J=12.6,12.0Hz,2H)。C30H32N5O3的ESIMS[M+H]+计算值510.2,实验值510.2。
实施例46:8-[5-(7-{[(3R)-氧杂环戊烷-3-基]氨基}-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)-1H-吡唑并[3,4-b]吡啶-3-基]-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
以类似于实施例42的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.89(d,J=2.1Hz,1H),8.69(d,J=2.1Hz,1H),8.65-8.49(m,2H),8.41(t,J=5.4Hz,1H),7.96(d,J=8.2Hz,1H),7.90(dd,J=8.2,1.7Hz,1H),7.68(d,J=1.5Hz,2H),7.63(dd,J=7.8,2.0Hz,1H),7.32(d,J=7.8Hz,1H),4.38(dd,J=5.3,4.1Hz,2H),4.15-4.03(m,1H),3.95(td,J=8.4,5.3Hz,1H),3.85(d,J=5.0Hz,2H),3.68(ddd,J=8.7,7.8,7.1Hz,1H),3.55-3.43(m,1H),3.39(q,J=5.0Hz,2H),3.04-2.82(m,4H),2.42-2.24(m,3H),2.03-1.91(m,1H),1.36(p,J=12.1Hz,2H)。C30H32N5O3的ESIMS[M+H]+计算值510.2,实验值510.2。
实施例47:8-{5-[7-(吗啉-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基]-1H-吡唑并[3,4-b]吡啶-3-基}-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
以类似于实施例42的方式制备标题化合物。1H NMR(400MHz,甲醇-d4)δ8.78(d,J=2.0Hz,1H),8.56(dd,J=2.1,0.9Hz,1H),8.00(d,J=8.2Hz,1H),7.82(ddd,J=8.2,1.7,0.6Hz,1H),7.68(d,J=1.6Hz,1H),7.53(s,1H),7.49(dd,J=7.7,1.8Hz,1H),7.30(d,J=7.7Hz,1H),4.45(dd,J=5.6,4.4Hz,2H),4.13-4.03(m,2H),3.81(ddd,J=13.4,10.0,3.9Hz,2H),3.61(tt,J=15.2,4.0Hz,1H),3.51(dd,J=5.4,4.2Hz,2H),3.36-3.34(m,4H),3.15-2.83(m,4H),2.45(t,J=10.1Hz,2H),1.64(p,J=12.0Hz,2H)。C30H32N5O3的ESIMS[M+H]+计算值510.2,实验值510.2。
实施例48:8-{5-[7-(哌嗪-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基]-1H-吡唑并[3,4-b]吡啶-3-基}-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
以类似于实施例42的方式制备标题化合物。1H NMR(400MHz,甲醇-d4)δ8.78(d,J=2.0Hz,1H),8.57(d,J=2.0Hz,1H),8.00(d,J=8.2Hz,1H),7.82(dd,J=8.2,1.7Hz,1H),7.68(d,J=1.7Hz,1H),7.55(d,J=2.0Hz,1H),7.50(dd,J=7.7,2.0Hz,1H),7.31(d,J=7.8Hz,1H),4.46(dd,J=5.3,4.2Hz,2H),3.73(tt,J=11.9,2.5Hz,1H),3.60(s,8H),3.51(t,J=5.3,4.4Hz,2H),3.16-2.86(m,4H),2.44(t,J=10.0Hz,2H),1.66(p,J=12.3Hz,2H)。C30H33N6O2的ESIMS[M+H]+计算值509.3,实验值509.2。
实施例49:8-(5-{7-[(2R)-2-(羟基甲基)吡咯烷-1-基]-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基}-1H-吡唑并[3,4-b]吡啶-3-基)-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
以类似于实施例42的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.83(d,J=2.0Hz,1H),8.63(d,J=2.1Hz,1H),8.36(t,J=5.4Hz,1H),7.92(d,J=8.2Hz,1H),7.86(dd,J=8.2,1.6Hz,1H),7.65(dd,J=1.7,0.5Hz,1H),7.58(d,J=2.0Hz,1H),7.52(dd,J=7.6,2.0Hz,1H),7.23(d,J=7.7Hz,1H),4.34(dd,J=5.4,4.1Hz,2H),3.40-3.32(m,3H),3.08(t,J=9.0Hz,1H),2.98-2.59(m,7H),2.03(m,2H),1.69-1.18(m,8H)。C31H34N5O3的ESIMS[M+H]+计算值524.3,实验值524.2。
实施例50:8-(5-{7-[(2S)-2-(羟基甲基)吡咯烷-1-基]-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基}-1H-吡唑并[3,4-b]吡啶-3-基)-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
以类似于实施例42的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.83(d,J=2.1Hz,1H),8.63(d,J=2.1Hz,1H),8.37(t,J=5.4Hz,1H),7.92(d,J=8.2Hz,1H),7.86(dd,J=8.2,1.7Hz,1H),7.65(d,J=1.6Hz,1H),7.58(d,J=2.0Hz,1H),7.51(dd,J=7.7,2.0Hz,1H),7.23(d,J=7.8Hz,1H),4.34(dd,J=5.4,4.1Hz,2H),3.40-3.34(m,4H),3.10(dd,J=10.5,7.7Hz,1H),2.97-2.58(m,8H),2.03(s,2H),1.68-1.14(m,7H)。C31H34N5O3的ESIMS[M+H]+计算值524.3,实验值524.2。
实施例51:8-(5-(7-((R)-3-羟基吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)-1H-吡唑并[3,4-b]吡啶-3-基)-3,4-二氢苯并[f][1,4]氧氮杂卓-5(2H)-酮
以类似于实施例42的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.83(d,J=2.1Hz,1H),8.63(d,J=2.1Hz,1H),8.37(t,J=5.4Hz,1H),7.95-7.82(m,2H),7.65(dd,J=1.7,0.5Hz,1H),7.58(s,1H),7.51(d,J=7.8Hz,1H),7.23(d,J=7.8Hz,1H),4.34(dd,J=5.4,4.1Hz,2H),4.19(s,1H),3.35(d,J=4.6Hz,2H),3.02(s,4H),2.86(s,1H),2.69(s,4H),1.96(d,J=13.4Hz,2H),1.53(s,4H)。C30H32N5O3的ESIMS[M+H]+计算值510.2,实验值510.2。
实施例52:8-(5-(7-(氮杂环丁烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)-1H-吡唑并[3,4-b]吡啶-3-基)-3,4-二氢苯并[f][1,4]氧氮杂卓-5(2H)-酮
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以类似于实施例42的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),8.85(d,J=2.1Hz,1H),8.65(d,J=2.1Hz,1H),8.37(t,J=5.4Hz,1H),7.96-7.82(m,2H),7.67-7.55(m,3H),7.28(d,J=7.8Hz,1H),4.34(dd,J=5.4,4.1Hz,2H),4.17(p,J=9.5Hz,2H),4.01(d,J=9.6Hz,2H),3.46-3.31(m,4H),2.97(dd,J=14.5,7.4Hz,1H),2.88(dd,J=14.6,7.3Hz,1H),2.74(q,J=11.5Hz,2H),2.16(s,2H),1.11(p,J=12.4Hz,2H)。C29H30N5O2的ESIMS[M+H]+计算值480.2,实验值480.2。
实施例53:8-(5-(2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)-1H-吡唑并[3,4-b]吡啶-3-基)-3,4-二氢苯并[f][1,4]氧氮杂卓-5(2H)-酮
步骤a:向7-溴-2,3,4,5-四氢-1H-3-苯并氮杂卓盐酸盐(200mg,0.76mmol)、Et3N(0.3mL,0.22mmol)、DMAP(10mg,0.8mmol)和CH2Cl2(5mL)的混合物中添加Boc2O(176mg,0.76mmol),并且在室温下搅拌14h。过滤反应混合物以去除任何不可溶物质,浓缩并通过柱色谱法(SiO2,0至90%EtOAc/己烷)纯化,得到呈白色固体状的所需产物(219mg;88%)。
步骤b:以类似于实施例20步骤b的方式制备所需产物。
步骤c:以类似于实施例20步骤c的方式制备所需产物(351mg;定量)。
步骤d:以类似于实施例20步骤d的方式制备所需产物(45mg;59%)。1H NMR(400MHz,DMSO-d6)δ8.86(d,J=2.1Hz,2H),8.65(d,J=2.1Hz,1H),8.38(t,J=5.4Hz,1H),7.93(dd,J=8.2,0.4Hz,1H),7.85(dd,J=8.2,1.7Hz,1H),7.74-7.61(m,3H),7.34(d,J=7.8Hz,1H),4.34(dd,J=5.4,4.1Hz,2H),3.36(q,J=5.0Hz,2H),3.29-3.05(m,8H)。C25H24N5O2的ESIMS[M+H]+计算值426.2,实验值426.2。
实施例54:8-(5-(1,2,3,4-四氢异喹啉-6-基)-1H-吡唑并[3,4-b]吡啶-3-基)-3,4-二氢苯并[f][1,4]氧氮杂卓-5(2H)-酮
以类似于实施例53的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),8.87(d,J=2.1Hz,1H),8.69(d,J=2.1Hz,1H),8.38(t,J=5.4Hz,1H),7.93(dd,J=8.2,0.4Hz,1H),7.86(dd,J=8.2,1.7Hz,1H),7.73(d,J=7.1Hz,2H),7.65(dd,J=1.6,0.4Hz,1H),7.34(d,J=8.4Hz,1H),4.43-4.27(m,4H),3.40-3.29(m,4H),3.08(t,J=6.3Hz,2H)。C24H22N5O2的ESIMS[M+H]+计算值412.2,实验值412.2。
实施例55:8-(5-(1,2,3,4-四氢异喹啉-7-基)-1H-吡唑并[3,4-b]吡啶-3-基)-3,4-二氢苯并[f][1,4]氧氮杂卓-5(2H)-酮
以类似于实施例53的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ9.06(s,1H),8.87(d,J=2.1Hz,1H),8.67(d,J=2.1Hz,1H),8.38(t,J=5.4Hz,1H),7.93(dd,J=8.2,0.4Hz,1H),7.85(dd,J=8.2,1.7Hz,1H),7.80-7.70(m,2H),7.65(dd,J=1.7,0.4Hz,1H),7.36(d,J=8.0Hz,1H),4.38-4.31(m,4H),3.37(tt,J=13.6,7.5Hz,4H),3.03(t,J=6.2Hz,2H)。C24H22N5O2的ESIMS[M+H]+计算值412.2,实验值412.2。
实施例56:8-{5-[(7R)-7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基]-1H-吡唑并[3,4-b]吡啶-3-基}-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
实施例57:8-{5-[(7S)-7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基]-1H-吡唑并[3,4-b]吡啶-3-基}-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
步骤a:使用半制备型对掌性AD-H柱(20x 250mm;30%EtOH/己烷+0.1%Et2NH)分离来自实施例1的外消旋物质。对映异构体1(分析保留时间=18.7min):白色粉末,8mg,>98:2e.r.,并且任意地指定为实施例56。对映异构体2(分析保留时间=24.5min):白色粉末,12mg,88:12e.r.,并且随后指定为实施例57。
实施例58:8-(5-{3-氟-7-[(2R)-2-甲基吡咯烷-1-基]-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基}-1H-吡唑并[3,4-b]吡啶-3-基)-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
步骤a:在100℃下搅拌1-溴-2-氟-4,5-二甲基苯(1.03g,5.07mmol)、KMnO4(3.21g,20.3mmol)和水(41mL)的混合物14小时,用10wt%NaHSO3(aq)(20mL)淬灭,并用2MNaOH(aq)调整至pH约12。通过过滤去除固体并用水洗涤。滤液用4M HCl(aq)酸化至pH约2,用4:1CH2Cl2/IPA(1x 250mL)萃取,经Na2SO4干燥并浓缩,得到呈白色固体状的所需产物(418mg;31%)。
步骤b:在0℃下向来自步骤a的产物(418g,1.59mmol)和THF(7.9mL)的混合物中滴加硼烷二甲基硫醚(452μL,4.77mmol)。在0℃下搅拌反应混合物10分钟,然后升温至55℃并在55℃下搅拌14小时。将混合物冷却至室温,滴加2M NaOH(aq)(7.2mL),并且在室温下搅拌混合物1小时。滴加12M HCl(aq)(0.10mL),并且浓缩所得有机相并用EtOAc(10mL)稀释。所得水相用EtOAc(1x 10mL)萃取,经合并的有机相用1:5水:盐水(10mL)洗涤,经Na2SO4干燥并浓缩,得到所需产物,其以粗物质形式用于下一步骤中。
步骤c:在90℃下搅拌来自步骤b的产物和HBr(1.6mL,48wt%于H2O中)的混合物2小时。将混合物冷却至室温,用CH2Cl2(3x 10mL)萃取,经Na2SO4干燥并浓缩,得到呈棕色油状的所需产物(534mg;93%;两个步骤)。
步骤d:在40℃下剧烈搅拌来自步骤c的产物(534mg,1.48mmol)、1,3-丙酮二甲酸二甲酯(309mg,1.78mmol)、四丁基溴化铵(239mg,0.740mmol)、NaHCO3(622mg,7.40mmol)、CH2Cl2(3.0mL)和水(7.4mL)的混合物3天。分离有机相,浓缩,用EtOAc(10mL)稀释,用9:1水:盐水(4x 10mL)洗涤,经Na2SO4干燥并浓缩。将残余物溶解于EtOH(11mL)中,并且添加2MNaOH(aq)(7.4mL)。在90℃下搅拌反应混合物2小时。将混合物冷却至室温,并且通过添加12MHCl(aq)调整至pH约7。减压去除EtOH,并且所得水相用CH2Cl2(3x10mL)萃取。有机相经Na2SO4干燥并浓缩。粗物质通过柱色谱法(24g硅胶,己烷:EtOAc,0%至20%梯度(20分钟);20%至35%梯度(10分钟))纯化,得到呈橙色油状的所需产物(141mg;37%)。
步骤e:以类似于实施例1步骤d的方式制备所需产物。
步骤f:以类似于实施例1步骤g的方式制备所需产物(26.8g;85%)。
步骤g:以类似于实施例7步骤c的方式制备所需产物(341mg;77%)。
步骤h:以类似于实施例7步骤c的方式制备所需产物(199mg;67%)。
步骤i:在室温下向来自步骤h的产物(199mg,0.368mmol)、(R)-2-甲基吡咯烷(38mg,0.44mmol)、AcOH(21μL,0.37mmol)和DCE(1.8mL)的混合物中添加NaBH(OAc)3(117mg,0.552mmol)。在40℃下搅拌反应混合物14小时,用饱和NaHCO3(aq)(10mL)淬灭并用CH2Cl2(10mL)萃取。有机相经Na2SO4干燥并浓缩,得到所需产物,其以粗物质形式用于下一步骤中。
步骤j:在室温下搅拌来自步骤i的产物(假定0.368mmol)和含3M HCl的MeOH(3.7mL)的混合物5小时,并用MTBE(30mL)稀释。通过过滤收集沉淀的固体并用MTBE洗涤。粗物质通过柱色谱法(43gC18,(H2O/ACN)+0.1%TFA,5%至50%梯度(25分钟))纯化,得到呈白色固体状的所需产物(50mg;26%)。1H NMR(400MHz,DMSO-d6)δ8.72(t,J=2.0Hz,1H),8.64(d,J=1.2Hz,1H),8.40(t,J=5.4Hz,1H),7.94(d,J=8.2Hz,1H),7.85(dd,J=8.2,1.7Hz,1H),7.65(d,J=1.4Hz,1H),7.48(dd,J=8.2,2.4Hz,1H),7.17(dd,J=11.4,2.5Hz,1H),4.37(dd,J=5.4,4.1Hz,2H),3.38(q,J=5.1Hz,2H),2.99-2.78(m,4H),2.78-2.62(m,3H),2.44(q,J=8.3Hz,1H),2.05-1.91(m,2H),1.87-1.75(m,1H),1.68-1.51(m,2H),1.45(q,J=12.1Hz,1H),1.34-1.21(m,2H),1.02(d,J=6.0Hz,3H)。C31H33FN5O2的ESIMS[M+H]+计算值526.3,实验值526.2。
实施例59:(2R)-2-甲基-8-(5-{7-[(2R)-2-甲基吡咯烷-1-基]-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基}-1H-吡唑并[3,4-b]吡啶-3-基)-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
步骤a:向在0℃的4-溴-2-羟基苯甲酸甲酯(2.31g,10.0mmol)、((S)-2-羟基丙基)氨基甲酸叔丁酯(1.75g,10.0mmol)、PPh3(2.75g,10.5mmol)和THF(25mL)的混合物中滴加偶氮二甲酸二异丙酯(2.07mL,10.5mmol)。在0℃下搅拌反应混合物30分钟,在室温下搅拌14小时,浓缩至硅胶上,并通过柱色谱法(80g硅胶,己烷:EtOAc,0%至35%梯度(25分钟))纯化,得到呈无色油状的所需产物(3.44g;89%)。
步骤b:以类似于实施例1步骤b的方式制备所需产物(2.79g;97%)。
步骤c:以类似于实施例1步骤c的方式制备所需产物(2.08g;94%)。
步骤d:以类似于实施例1步骤d的方式制备所需产物。
步骤e:以类似于实施例7步骤c的方式制备所需产物(113mg;57%)。
步骤f:在70℃下搅拌来自步骤e的产物(113mg,0.228mmol)、HCl(455μL,0.455mmol,1M于水中)和THF(1.1mL)的混合物1小时,冷却至室温,用饱和NaHCO3(aq)(1.0mL)中和,用水(20mL)稀释并过滤以收集沉淀的固体。固体用水洗涤并干燥。在室温下,向此固体(R)-2-甲基吡咯烷(31mg,0.37mmol)、AcOH(21μL,0.37mmol)和DMF(0.90mL)的混合物中添加NaBH(OAc)3(97mg,0.46mmol)。在40℃下搅拌反应混合物3小时,用EtOAc(18mL)、水(18mL)和盐水(3.0mL)稀释。水相用2M NaOH(aq)调整至pH约12。有机相用水:2MNaOH(aq):盐水(8:1:1)(1x 10mL)洗涤,经Na2SO4干燥并浓缩。粗物质通过柱色谱法(43g C18,(H2O/ACN)+0.1%TFA,5%至50%梯度(25分钟))纯化,得到呈灰白色固体状的所需产物(87mg;77%)。1HNMR(400MHz,DMSO-d6)δ8.87(d,J=2.1Hz,1H),8.66(d,J=1.8Hz,1H),8.40(t,J=5.7Hz,1H),7.95(dd,J=8.1,1.7Hz,1H),7.79(d,J=8.4Hz,1H),7.65(d,J=1.6Hz,1H),7.61(t,J=2.3Hz,1H),7.55(dd,J=7.7,1.9Hz,1H),7.27(dd,J=7.9,1.3Hz,1H),4.59(td,J=6.4,3.6Hz,1H),3.33-3.29(m,1H),3.10-3.00(m,1H),3.00-2.76(m,5H),2.76-2.65(m,2H),2.44(q,J=8.2Hz,1H),2.06-1.94(m,2H),1.87-1.76(m,1H),1.69-1.49(m,2H),1.49-1.39(m,1H),1.35-1.22(m,5H),1.02(d,J=6.0Hz,3H)。C32H36N5O2的ESIMS[M+H]+计算值522.3,实验值522.3。
实施例60:9-氟-8-(5-{7-[(2R)-2-甲基吡咯烷-1-基]-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基}-1H-吡唑并[3,4-b]吡啶-3-基)-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
以类似于实施例59的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.89(d,J=2.0Hz,1H),8.54(t,J=5.4Hz,1H),8.41(s,1H),7.71(dd,J=8.4,1.3Hz,1H),7.63(dd,J=8.4,6.2Hz,1H),7.55(s,1H),7.49(dd,J=7.8,2.0Hz,1H),7.26(d,J=7.8Hz,1H),4.53-4.41(m,2H),3.44(q,J=5.1Hz,2H),2.99-2.75(m,5H),2.74-2.63(m,2H),2.47-2.40(m,1H),2.34-2.30(m,1H),2.05-1.94(m,2H),1.87-1.74(m,1H),1.68-1.50(m,2H),1.48-1.38(m,1H),1.34-1.21(m,3H),1.02(d,J=5.9Hz,3H)。C31H33FN5O2的ESIMS[M+H]+计算值526.3,实验值526.2。
实施例61:7-氟-8-(5-{7-[(2R)-2-甲基吡咯烷-1-基]-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基}-1H-吡唑并[3,4-b]吡啶-3-基)-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
以类似于实施例59的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.88(d,J=2.1Hz,1H),8.56(d,J=5.4Hz,1H),8.41(t,J=2.6Hz,1H),7.71(d,J=11.2Hz,1H),7.56-7.50(m,2H),7.50-7.46(m,1H),7.25(d,J=7.7Hz,1H),4.39-4.30(m,2H),3.42-3.37(m,2H),2.97-2.75(m,4H),2.75-2.65(m,2H),2.47-2.38(m,1H),2.34-2.30(m,1H),2.04-1.93(m,2H),1.86-1.76(m,2H),1.65-1.52(m,1H),1.49-1.37(m,1H),1.35-1.20(m,1H),1.02(d,J=6.0Hz,3H)。C31H33FN5O2的ESIMS[M+H]+计算值526.3,实验值526.2。
实施例62:(2S)-2-甲基-8-(5-{7-[(2R)-2-甲基吡咯烷-1-基]-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基}-1H-吡唑并[3,4-b]吡啶-3-基)-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
以类似于实施例59的方式制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.87(d,J=2.1Hz,1H),8.66(d,J=2.1Hz,1H),8.40(t,J=5.7Hz,1H),7.95(ddd,J=8.1,1.7,0.8Hz,1H),7.79(dd,J=8.2,0.6Hz,1H),7.65(d,J=1.3Hz,1H),7.64-7.58(m,1H),7.55(dd,J=7.9,1.8Hz,1H),7.27(d,J=6.7Hz,1H),4.59(td,J=6.4,3.6Hz,1H),3.33-3.28(m,1H),3.05(dt,J=15.3,6.0Hz,1H),3.00-2.76(m,5H),2.76-2.67(m,2H),2.44(q,J=8.2Hz,1H),2.07-1.95(m,2H),1.87-1.76(m,1H),1.69-1.50(m,2H),1.49-1.39(m,1H),1.34-1.22(m,5H),1.02(d,J=6.0Hz,3H)。C32H36N5O2的ESIMS[M+H]+计算值522.3,实验值522.3。
实施例63:8-{5-[7-(吡咯烷-1-基)-5H,6H,7H,8H,9H-环庚烯[b]吡啶-2-基]-1H-吡唑并[3,4-b]吡啶-3-基}-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
步骤a:在0℃下,将硼氢化锂(于THF中的2.0M溶液)(13.6mL,27.2mmol)滴加至6-氯吡啶-2,3-二甲酸二甲酯(2.50g,10.9mmol)于38:1THF:MeOH(34.5mL)中的溶液中。去除冷浴,并且在室温下搅拌混合物2.5h。将混合物倒入饱和NaHCO3(aq)(100mL)中,并且将产物萃取至EtOAc(5x 100mL)中。将经合并的有机相干燥(Na2SO4),浓缩,并且以粗物质形式用于下一步骤中。
步骤b:在0℃下,将三溴化磷(1.33mL,9.28mmol)滴加至步骤a的粗产物(10.9mmol)于THF(54mL)中的悬浮液中。去除冷浴,并且在室温下搅拌混合物5h。然后,将混合物冷却至0℃,并且小心地用NaHCO3(aq)(150mL)中和。分离各层,并且将额外产物萃取至CH2Cl2(2x 150mL)中。将经合并的有机相干燥(Na2SO4),浓缩,并且以粗物质形式用于下一步骤中。
步骤c:在40℃下加热来自步骤b的粗产物(10.9mmol)、3-氧代戊二酸1,5-二甲酯(1.42mL,9.82mmol)、TBAB(1.32g,4.09mmol)、碳酸氢钠(3.44g,40.9mmol)、CH2Cl2(16.4mL)和H2O(40.9mL)的混合物过夜。真空去除CH2Cl2,并且将残余物溶解于EtOAc(40mL)中。溶液用9:1H2O:盐水(4x 40mL)洗涤,干燥(Na2SO4),浓缩,并且以粗物质形式用于下一步骤中。
步骤d:将来自步骤c的粗产物溶解于EtOH(63mL)中,并且添加2N NaOH(aq)(42mL)。在90℃下加热混合物2h。真空去除EtOH,并且溶液用12N HCl(aq)酸化至pH 6。将产物萃取至CH2Cl2(2x 30mL)中,并且将经合并的物质干燥(Na2SO4)并浓缩。粗物质通过快速色谱法(0至100%EtOAc/己烷)纯化,得到呈白色固体状的所需产物(355mg;22%)。
步骤e:将三乙酰氧基硼氢化钠(288mg,1.36mmol)和乙酸(0.05mL,0.906mmol)添加至来自步骤d的产物(177mg,0.906mmol)和吡咯烷(0.09mL,1.09mmol)于DCE(4.5mL)中的溶液中,并且在室温下搅拌混合物过夜。反应物用饱和NaHCO3(aq)(10mL)淬灭,并且将产物萃取至CH2Cl2(3x 10mL)中。经合并的有机相用盐水(10mL)洗涤,干燥(Na2SO4),浓缩,并且以粗物质形式用于下一步骤中。
步骤f:以类似于实施例1步骤d的方式制备所需产物。
步骤g:以类似于实施例26步骤c的方式制备所需产物(60.3mg;33%)。
步骤h:将含3N HCl的MeOH(2.1mL)添加至来自步骤g的产物(60.3mg,0.104mmol)中,并且在室温下搅拌混合物过夜。浓缩反应物,并且粗产物依次用MTBE和ACN湿磨,得到所需产物(26.6mg;42%)。1H NMR(400MHz,DMSO-d6)δ11.22(br.s,1H),9.21(d,J=24.7Hz,2H),8.49-8.41(m,1H),8.21(d,J=7.5Hz,1H),8.15(br.s,1H),7.99(d,J=8.1Hz,1H),7.94(d,J=7.4Hz,1H),7.74(d,J=1.4Hz,1H),4.44-4.37(m,2H),3.67-3.55(m,2H),3.54-3.38(m,4H),3.25-3.08(m,2H),2.92(t,J=13.3Hz,1H),2.52-2.41(m,4H),2.04-1.84(m,4H),1.85-1.75(m,1H),1.73-1.61(m,1H)。C29H31N6O2的ESI MS[M+H]+计算值495.3,实验值495.2。
实施例64:8-(5-{3-甲基-7-[(2R)-2-甲基吡咯烷-1-基]-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基}-1H-吡唑并[3,4-b]吡啶-3-基)-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
步骤a:向在0℃的4-甲基邻苯二甲酸(18.0g,100mmol)、NaOH(12.0g,300mmol)和水(100mL)的混合物滴加Br2(5.12mL,100mmol)。完成后,使反应混合物升温至80℃并在80℃下搅拌1.5小时。将混合物冷却至室温,并且添加水(100mL),接着添加2M HCl(aq)(150mL)。通过过滤收集固体,用水洗涤并干燥,得到呈白色固体状的所需产物(5.58g;22%)。
步骤b:向在0℃的来自步骤a的产物(5.70g,22.0mmol)和THF(110mL)的混合物中滴加硼烷二甲基硫醚(6.26mL,66.0mmol)。在0℃下搅拌反应混合物10分钟,然后升温至55℃并在55℃下搅拌14小时。将混合物冷却至室温,滴加2M NaOH(aq)(100mL),并且在室温下搅拌混合物1小时。滴加12M HCl(aq)(17mL),并浓缩所得有机相并且用EtOAc(50mL)稀释。所得水相用EtOAc(1x 50mL)萃取,经合并的有机相用1:5水:盐水(60mL)洗涤,经Na2SO4干燥并浓缩,得到呈白色固体状的所需产物(4.57g;90%)。
步骤c:在90℃下搅拌来自步骤b的产物和HBr(20mL,48wt%于H2O中)的混合物2小时。将混合物冷却至室温,通过过滤收集固体并用水洗涤,得到所需产物,其以粗物质形式用于下一步骤中。
步骤d:在40℃下剧烈搅拌来自步骤c的产物(假定19.8mmol)、1,3-丙酮二甲酸二甲酯(4.14g,23.6mmol)、四丁基溴化铵(3.19g,9.90mmol)、NaHCO3(8.32g,99.0mmol)、CH2Cl2(40mL)和水(99mL)的混合物4天。分离有机相,浓缩,用EtOAc(100mL)稀释,用9:1水:盐水(4x 100mL)洗涤,经Na2SO4干燥并浓缩。将残余物溶解于EtOH(152mL)中,并且添加2MNaOH(aq)(99mL)。在90℃下搅拌反应混合物2小时。将混合物冷却至室温,并通过添加12MHCl(aq)(15mL)调整至pH约7。减压去除EtOH,并且所得水相用CH2Cl2(150L)萃取。有机相经Na2SO4干燥并浓缩。粗物质通过柱色谱法(80g硅胶,己烷:EtOAc,0%至20%梯度(20分钟);20%至35%梯度(10分钟))纯化,得到呈浅黄色固体状的所需产物(2.35g;47%;两个步骤)。
步骤e:以类似于实施例7步骤c的方式制备所需产物(138mg;85%)。
步骤f:在室温下向来自步骤e的产物(138mg,0.257mmol)、(R)-2-甲基吡咯烷(44mg,0.51mmol)、AcOH(30μL,0.51mmol)和THF(1.3mL)的混合物中添加NaBH(OAc)3(136mg,0.643mmol)。在40℃下搅拌反应混合物3小时,用EtOAc(15mL)、水(15mL)和盐水(2.0mL)稀释。水相用2M NaOH(aq)调整至pH约12。有机相用水:2M NaOH(aq):盐水(8:1:1)(1x20mL)洗涤,经Na2SO4干燥并浓缩。添加含3M HCl的MeOH(1.3mL)。在室温下搅拌反应混合物2小时并用MTBE(20mL)稀释。通过过滤收集沉淀的固体并用MTBE洗涤。粗物质通过柱色谱法(43g C18,(H2O/ACN)+0.1%TFA,5%至50%梯度(25分钟))纯化,得到呈白色固体状的所需产物(43mg;32%)。1H NMR(400MHz,DMSO-d6)δ8.54(dd,J=2.0,0.4Hz,1H),8.47(dd,J=2.0,0.9Hz,1H),8.39(t,J=5.4Hz,1H),7.91(d,J=8.2Hz,1H),7.85(dd,J=8.2,1.7Hz,1H),7.65(d,J=1.7Hz,1H),7.12(s,1H),7.11(s,1H),4.35(dd,J=5.4,4.1Hz,2H),3.37(q,J=5.1Hz,2H),2.95-2.59(m,7H),2.43(q,J=8.2Hz,1H),2.20(s,3H),2.06-1.90(m,2H),1.86-1.76(m,1H),1.68-1.49(m,2H),1.43(q,J=11.8Hz,1H),1.34-1.20(m,2H),1.02(d,J=5.1Hz,3H)。C32H36N5O2的ESIMS[M+H]+计算值522.3,实验值522.3。
实施例65:8-(5-{4-氯-7-[(2R)-2-甲基吡咯烷-1-基]-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基}-1H-吡唑并[3,4-b]吡啶-3-基)-2,3,4,5-四氢-1,4-苯并氧氮杂卓-5-酮
步骤a:在75℃下搅拌5-溴-1,2-二甲基-3-硝基苯(4.60g,20.0mmol)、铁粉(5.59g,100mmol)、NH4Cl(5.35g,100mmol)和2:1EtOH:水(80mL)的混合物90分钟,冷却至室温,经由硅藻土过滤以去除固体(用EtOAc(200mL)洗涤)。有机相经Na2SO4干燥,浓缩,用EtOAc(20mL)稀释,再次经Na2SO4干燥,并且再次浓缩,得到呈橙色油状的所需产物(4.02g;>100%)。
步骤b:在室温下向来自步骤a的产物(4.02g,20.0mmol)于EtOH(20mL)中的混合物中滴加12M HCl(aq)(8.0mL)。将混合物冷却至0℃,并且滴加NaNO2(1.79g,26.0mmol)于水(8.0mL)中的溶液。在0℃下搅拌反应混合物1小时,小心地装入固体CuCl(3.96g,40.0mmol)和12M HCl(aq)(8.0mL),在80℃下搅拌1小时,冷却至室温,并用己烷(2x 20mL)萃取。使经合并的有机相经Na2SO4干燥并浓缩,得到呈橙色油状的所需产物(4.06g;92%;两个步骤)。
步骤c:以类似于实施例58步骤a的方式制备所需产物(1.46g;28%)。
步骤d:以类似于实施例58步骤b的方式制备所需产物(1.04g;80%)。
步骤e:以类似于实施例64步骤c的方式制备所需产物(4.15mmol;假定100%产率)。
步骤f:以类似于实施例64步骤d的方式制备所需产物(165mg;15%)。
步骤g:以类似于实施例7步骤c的方式制备所需产物(235mg;70%)。
步骤h:以类似于实施例64步骤f的方式制备所需产物(18mg;8%)。1H NMR(400MHz,DMSO-d6)δ8.89(d,J=2.1Hz,1H),8.74(d,J=2.1Hz,1H),8.40(t,J=5.4Hz,1H),7.96(d,J=8.2Hz,1H),7.91(dd,J=8.3,1.7Hz,1H),7.78(d,J=1.9Hz,1H),7.70(d,J=1.5Hz,1H),7.66-7.62(m,1H),4.38(dd,J=5.4,4.1Hz,2H),3.43-3.35(m,2H),3.08-2.90(m,2H),2.90-2.78(m,2H),2.77-2.67(m,2H),2.67-2.56(m,1H),2.48-2.39(m,1H),2.08-1.95(m,2H),1.88-1.76(m,1H),1.67-1.50(m,2H),1.50-1.35(m,1H),1.36-1.15(m,2H),1.02(d,J=5.9Hz,3H)。C31H33ClN5O2的ESIMS[M+H]+计算值542.2,实验值542.2。
实施例66:7-(5-{7-[(2R)-2-甲基吡咯烷-1-基]-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基}-1H-吡唑并[3,4-b]吡啶-3-基)-3,4-二氢-2H-5,1λ6,2-苯并氧硫氮杂卓-1,1-二酮
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步骤a:向4-溴-2-氟苯磺酰氯(1.02g,3.73mmol)于THF(8.2mL)和H2O(4.1mL)中的混合物中添加K2CO3(515mg,3.73mmol),并且在室温下搅拌混合物10min。缓慢添加2-氨基乙醇(0.22mL,3.73mmol),并且在室温下搅拌反应混合物16h。添加EtOAc(15mL)和H2O(15mL),并且分离各层。水层用EtOAc(2x 15mL)萃取,然后经合并的有机层用盐水洗涤,经MgSO4干燥,并浓缩,得到呈浅棕色固体状的产物(986mg;89%)。
步骤b:在室温下,向步骤a的产物(986mg,3.31mmol)于DMSO(6.6mL)中的溶液中添加KOt-Bu(928mg,8.27mmol),并且在80℃下搅拌反应混合物24h。在冷却后,添加H2O(10mL),接着添加NH4Cl饱和水溶液(10mL),并且混合物用EtOAc(3x 15mL)萃取。经合并的有机层用盐水洗涤,经无水MgSO4干燥,浓缩,并且通过硅胶色谱法(100%CH2Cl2至10%EtOAc/CH2Cl2至10%MeOH/CH2Cl2)纯化,得到呈白色固体状的所需产物(544mg;59%)。
步骤c:向步骤b的产物(245mg,0.881mmol)、B2pin2(268mg,1.06mmol)和KOAc(112mg,1.15mmol)的混合物中添加二噁烷(8.8mL),然后悬浮液用N2脱气10min。添加(dppf)PdCl2(32mg,0.0441mmol),并且在90℃下搅拌反应混合物2.5h。在冷却后,添加EtOAc(20mL),并且经由硅藻土过滤混合物。浓缩滤液,得到呈粘稠棕色油状的粗物质。
步骤d:向实施例1步骤e的产物(364mg,0.800mmol)、步骤c的粗产物(0.881mmol)和Na2CO3(170mg,1.60mmol)的混合物中添加二噁烷(7.2mL)和H2O(0.80mL),然后悬浮液用N2脱气10min。添加(dppf)PdCl2(29mg,0.0400mmol),并且在90℃下搅拌反应混合物13h。在冷却后,添加CH2Cl2(20mL),并且使混合物经无水MgSO4干燥,过滤并浓缩。残余物通过硅胶色谱法(100%CH2Cl2至10%CH2Cl2/MeOH)纯化,得到呈橙色固体状的所需产物(378mg;90%)。
步骤e:向步骤d的产物(378mg,0.719mmol)、实施例32步骤h的产物(1.34mmol)和Na2CO3(152mg,1.44mmol)的混合物中添加二噁烷(6.5mL)和H2O(0.70mL),然后悬浮液用N2脱气10min。添加(dppf)PdCl2(26mg,0.0360mmol),并且在90℃下搅拌反应混合物15h。在冷却后,添加CH2Cl2(20mL),并且使混合物经无水MgSO4干燥,过滤并浓缩。残余物通过硅胶色谱法(100%CH2Cl2至10%CH2Cl2/MeOH)纯化,得到呈橙色固体状的所需产物(244mg;56%)。
步骤f:向步骤e的产物(78mg,0.129mmol)和(2R)-2-甲基吡咯烷(30μL,0.296mmol)于DMF(2.7mL)中的混合物中添加AcOH(15μL,0.270mmol),并且在室温下搅拌混合物30min,然后添加NaBH(OAc)3(63mg,0.296mmol)。在室温下搅拌反应混合物14h,并且小心地用H2O、然后NaHCO3饱和水溶液淬灭。混合物用EtOAc(3x 10mL)萃取,然后经合并的有机层用盐水洗涤,经无水MgSO4干燥并浓缩。通过硅胶色谱法(100%CH2Cl2至10%MeOH/CH2Cl2+1%NH3)纯化,得到呈橙色固体状的所需产物(67mg;37%,约1:1d.r.)。
步骤g:向步骤f的产物(67mg,0.0994mmol)于CH2Cl2(1.4mL)中的溶液中添加TFA(0.70mL)。在室温下搅拌反应物1h,然后浓缩。向残余物于MeOH(2.0mL)中的溶液中添加DMEDA(80μL,0.746mmol),并且在45℃下搅拌混合物1h。在冷却后,反应物用H2O(5mL)和CH2Cl2(5mL)稀释,并且分离各层。水层用含10%MeOH的CH2Cl2(2x 10mL)萃取,然后浓缩经合并的有机层。通过反相HPLC(10至70%ACN/H2O+0.1%TFA)纯化并冻干,得到呈灰白色固体状的标题化合物(4mg,6%)。1H NMR(400MHz,甲醇-d4)δ8.82(d,J=2.1Hz,1H),8.63(d,J=2.1Hz,1H),7.99-7.96(m,2H),7.88(dd,J=1.1,0.7Hz,1H),7.59(d,J=2.0Hz,1H),7.55(dd,J=7.7,1.9Hz,1H),7.34(d,J=7.8Hz,1H),4.28-4.21(m,2H),3.86-3.69(m,2H),3.60(dd,J=4.9,3.8Hz,2H),3.47-3.39(m,1H),3.29-3.23(m,1H),3.11-2.90(m,4H),2.45-2.34(m,2H),2.30(dq,J=13.8,7.1Hz,1H),2.11-1.95(m,2H),1.81-1.68(m,1H),1.68-1.53(m,2H),1.47(d,J=6.6Hz,3H)。C30H34N5O3S的ESIMS[M+H]+计算值544.2,实验值544.2。
生物学实施例
测量Axl抑制剂的胞内结合
根据制造商的建议进行Axl NanoBRETTM胞内激酶测定(Promeg a,N2540)。简言之,根据制造商的建议,在实验前一天,利用Fuge ne HD转染试剂(Promega,E2311),用Axl-NanoLuc融合载体(Prome ga,NV1071)短暂转染HEK-293细胞。
在测定当天,收集细胞并以2e5个细胞/毫升浓度重悬于Opti-ME M培养基(ThermoFisher,31985070)中。连续稀释测试化合物,并以200nL(于100%DMSO中)分配至白色384孔聚苯乙烯板中。然后对于具有0.5%DMSO的8K个细胞/孔的最终条件,每孔添加40μL重悬细胞。在37℃和5%CO2下一小时化合物预温育后,细胞与0.35μM K-5NanoBRET示踪剂一起在37℃和5%CO2下进一步温育两小时。根据试剂盒手册制备20ml的3X底物加抑制剂溶液,并且将其添加至细胞中,接着30秒脉冲离心旋转。然后,立即利用Envi sion(PerkinElmer)板读取器读取板。通过采用在610nm与450nm下读取的发光的比率来测量BRET信号。化合物结合是基于由替换K-5示踪剂引起的BRET信号减少。DMSO处理的活性用作中性对照并针对100%活性进行归一化,并且达到100%抑制的在20μM下的CEP-40783对照化合物用作阳性对照并针对0%活性进行归一化。通过在GraphPad Prism软件中活性百分比的4参数非线性回归拟合来确定化合物的IC50值。值报告于表1(细胞结合)中。
Axl抑制剂的生物化学化合物效力的测量
纯化的重组人类AXL、TYRO3和MER蛋白购自InvitrogenTM。将10nM AXL、2nM TYRO3或MER与不同浓度的化合物一起在384孔微量板(CorningTM#3640)中的20μl总体积的50mMHEPES、pH7.4、10mM MgCl2、0.01%BSA、1mM DTT和2%DMSO中在室温温育1h。AXL、TYRO3和MER酶反应通过以下来起始:将10μl酶和化合物混合物转移至在384孔微量板(CorningTM#3640)中的50mM HEPES、pH 7.4、10mM MgCl2、0.01%BSA、1mM DTT中在室温预温育的10μl1.6μM TK底物-生物素(KinEASE-TK试剂盒,Cisbio)和1400μM ATP中,得到最终反应条件:含5nm AXL、1nM TYRO3或MER、800nM TK底物-生物素和700μM ATP的50mM HEPES、pH7.4、10mM MgCl2、0.01%BSA、1mM DTT和1%DMSO中,与不同浓度的化合物。在室温温育2h后,AXL、TYRO3和MER酶反应通过以下来终止:将10μl反应物转移至白色384孔微量板(Perkin Elmer,OptiPlate 384)中的10μl检测混合物(400nM抗生蛋白链菌素-XL665,TK抗体-穴状合物200倍稀释液和检测缓冲液,/>KinEASE-TK试剂盒,Cisbio)中。对于HTRF,在室温下温育1h后,将板放入板读取器(Evision)中以在665/620nm(受体/供体)下读取。DMSO空白组(最小抑制=100%活性)的值用作阴性对照。阳性对照通过如下来确立:添加5μl酶和DMSO混合物至10μl检测混合物中,接着添加5μl TK底物-生物素和ATP混合物(最大抑制=0%活性)。为了计算活性百分比,使用等式1。比率665/620是在所给出化合物浓度下的值:
导致50%的酶活性损失的化合物浓度(IC50)是通过GraphPad Prism,使用等式2(其中N为希尔(Hill)系数)来计算:
值报告于表1(生物化学效力)中。
表1:具体实施例的生物化学效力和细胞效力(IC50:+意指>1μM,++意指100nM至1μM,+++意指<100nM)
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本文中描述本公开的特定实施方案,包括本发明人已知的用于实施本发明的最佳模式。在阅读前述描述后,所公开实施方案的变化对于在本领域中工作的个体可变得显而易见,并且预期本领域技术人员可在适当时采用此类变化。因此,预期本公开以不同于如本文所特定描述来实践,并且本公开包括如由适用法律准许的在所附权利要求书中叙述的主题的所有修改和等同物。此外,除非本文另外指示或另外与上下文明显矛盾,否则本公开涵盖上文所描述的要素在其所有可能变化中的任何组合。
在本说明书中所引用的所有出版物、专利申请、登录号和其他参考文献都通过引用并入本文,如同每个个别出版物或专利申请特定地且个别地指示为通过引用并入一般。
Claims (66)
1.一种由式(I)表示的化合物,
或其药学上可接受的盐,其中:
G1为N或CRG1;
G2为CRG2或N;
G3为CRG3或N;
G4为CRG4或N;
G5为CRG5或N;
RG1选自由以下组成的组:H、C1-3烷基、卤素、C1-3卤烷基和CN;
每个RG2、RG3、RG4和RG5独立地选自由以下组成的组:H、卤基、CN、C1-7烷基、C3-7环烷基、C1-3卤烷基、-O-C1-3烷基、-O-C1-3卤烷基、-NRaRb和具有1-3个选自由O、N和S组成的组的杂原子环顶点的4至8元杂环烷基,并且其中所述环烷基和所述杂环烷基被0-3个独立地选自以下的基团取代:卤基、CN、C1-4烷基、C1-4卤烷基、C1-4羟烷基、-O-C1-4烷基和OH;
R1选自由以下组成的组:H、C1-4烷基和NH2;
A为选自由以下组成的组的稠环:氮杂环庚烷、哌啶、环庚烷、环己烷、环戊烷、1,4-氧氮杂环庚烷、氧杂环庚烷、四氢吡喃、1,4-二氮杂环庚烷、双环[4.2.1]壬烷、双环[4.1.1]辛烷、螺[4.6]十一烷、1-氮杂螺[4.6]十一烷和环辛烷,其中的每一者未被取代或被1至4个R2取代,并且进一步被0或1个邻接于氮原子的氧代基(=O)取代;
B为选自由以下组成的组的稠环:1,4-氧氮杂环庚烷、环庚烷、四氢吡喃、异噻唑烷1,1-二氧化物、氧杂环庚烷、1,4,5-氧硫氮杂环庚烷4,4-二氧化物、环己烷、环戊烷、氮杂环庚烷、吡咯烷、哌啶、哌嗪、吗啉、二氮杂环庚烷和1,3-二氧戊环,其中的每一者未被取代或被1至4个R4取代;并且进一步被0或1个邻接于氮原子的氧代基(=O)取代;
每个R2独立地选自由以下组成的组:卤基、OH、C1-7烷基、C3-7烯基、C3-7炔基、C3-7环烷基、-C(O)-C1-7烷基、-C(O)-C3-7环烷基、-C(O)-C1-7亚烷基-OH、-Y1-O-C1-7烷基、-Y1-O-C3-7环烷基、-NRaRb、-S(O)2-C1-7烷基、-S(O)2-C3-7环烷基、-C(O)NRaRb、4至8元杂环烷基和-NRa-(4至8元杂环烷基),其中所述4至8元杂环烷基具有1-3个选自由O、N和S组成的组的杂原子环顶点,并且其中所述环烷基和所述杂环烷基被0-3个独立地选自以下的基团取代:卤基、CN、C1-4烷基、C1-4卤烷基、C1-4羟烷基、-O-C1-4烷基和OH;
下标n为0、1、2或3;
每个R3独立地选自由以下组成的组:卤素、CN、C1-7烷基、C2-7烯基、C3-7炔基、C3-7环烷基、C1-6卤烷基、C1-6羟烷基、C1-6卤羟烷基、-O-C1-7烷基、-O-C3-7环烷基、-O-C1-6卤烷基、-X1-CN、-X1-O-C1-7烷基、-O-Y1-O-C1-7烷基、-NRaRb、-X1-NRaRb、-O-Y1-NRaRb、-C(O)-NRaRb、-S(O)2-NRaRb、-S(O)(NH)-C1-7烷基、-S(O)2-C1-7烷基、-S(O)2-C1-7卤烷基、-S(O)2-C3-7环烷基、-S(O)2-Y1-O-C1-3烷基、-S(O)2-(4至8元杂环烷基)、-C(O)NH-(4至8元杂环烷基)、4至8元杂环烷基和-O-X1-(4至8元杂环烷基),其中所述4至8元杂环烷基具有1-2个选自由O、N和S组成的组的杂原子环顶点;并且其中所述环烷基和所述杂环烷基被0-3个独立地选自以下的基团取代:卤基、CN、C1-4烷基、C1-4卤烷基、C1-4羟烷基、-O-C1-4烷基和OH;
每个R4独立地选自由以下组成的组:H、卤素、羟基、CN、C1-7烷基、C2-7烯基、C3-7炔基、C3-7环烷基、C1-6卤烷基、C1-6羟烷基、C1-6卤羟烷基、-O-C1-7烷基、-O-C3-7环烷基、-O-C1-6卤烷基、-X1-CN、-X1-O-C1-7烷基、-S(O)2-C1-4烷基、-S(O)2-C3-7环烷基、-C(O)NRaRb、-NRaRb、-NRa-C(O)-C1-7烷基、-NRa-C(O)-C3-7环烷基、-NRa-S(O)2-C1-7烷基和-NRa-S(O)2-C3-7环烷基,其中-NRaRb、-NRa-C(O)-C1-7烷基、-NRa-C(O)-C3-7环烷基、-NRa-S(O)2-C1-7烷基和-NRa-S(O)2-C3-7环烷基不与氮环顶点直接连接以形成N-N键;
或与共同碳连接的两个R4组合以形成未被取代或被1-3个独立地选自F、Cl、OH和CH3的成员取代的C3-6螺环烷基;
每个X1为C1-7亚烷基或C3-7亚环烷基;
每个Y1为C2-7亚烷基或C3-7亚环烷基,其中两个连接的杂原子不与共同碳原子连接;
每个Ra和Rb独立地选自由以下组成的组:H、C1-7烷基、C1-7卤烷基、C1-4烷氧基C1-4烷基和C3-7环烷基;或
Ra和Rb与其所连接的氮一起形成4-8元杂环烷基环,其具有0-2个选自由O、N和S组成的组的额外杂原子环顶点,并且被0-3个独立地选自以下的基团取代:卤素、CN、C1-4烷基、C1-4卤烷基、C1-4羟烷基、-O-C1-4烷基、氧代基和OH。
2.如权利要求1所述的化合物或其药学上可接受的盐,其中G1为N。
3.如权利要求1所述的化合物或其药学上可接受的盐,其中G1为CH。
4.如权利要求1-3中任一项所述的化合物或其药学上可接受的盐,其中G2为CH或CF。
5.如权利要求1-4中任一项所述的化合物或其药学上可接受的盐,其中G3选自由以下组成的组:CH、CF、C(CH3)和N。
6.如权利要求1-5中任一项所述的化合物或其药学上可接受的盐,其中G4为CH、CCl或N。
7.如权利要求1-6中任一项所述的化合物或其药学上可接受的盐,其中G5为CH或N。
8.如权利要求1所述的化合物或其药学上可接受的盐,其中G1为N并且G2为CH。
9.如权利要求8所述的化合物或其药学上可接受的盐,其中G3为CH。
10.如权利要求9所述的化合物或其药学上可接受的盐,其中G4为CH。
11.如权利要求10所述的化合物或其药学上可接受的盐,其中G5为CH。
12.如权利要求1-11中任一项所述的化合物或其药学上可接受的盐,其中稠环A具有选自由以下组成的组的式:
其中的每一者被1至4个R2取代。
13.如权利要求12所述的化合物或其药学上可接受的盐,其中稠环A具有下式:
14.如权利要求13所述的化合物或其药学上可接受的盐,其中一个R2为-NRaRb。
15.如权利要求14所述的化合物或其药学上可接受的盐,其中一个R2为吡咯烷基,其未被取代或被1-3个独立地选自由以下组成的组的取代基取代:卤素、CN、C1-4烷基、C1-4卤烷基、C1-4羟烷基、-O-C1-4烷基、氧代基和OH。
16.如权利要求1-12中任一项所述的化合物或其药学上可接受的盐,其中环B选自由以下组成的组:1,4-氧氮杂环庚烷、四氢吡喃、异噻唑烷1,1-二氧化物、1,4,5-氧硫氮杂环庚烷4,4-二氧化物、氮杂环庚烷和吡咯烷,其中的每一者未被取代或被1至3个R4取代;并且进一步被0或1个邻接于氮原子的氧代基(=O)取代。
17.如权利要求1-16中任一项所述的化合物或其药学上可接受的盐,其中每个R4独立地选自由以下组成的组:卤素、C1-4烷基、C1-4卤烷基和OH,或与共同碳连接的两个R4组合以形成未被取代或被1-3个独立地选自F、Cl、OH和CH3的成员取代的C3-6螺环烷基。
18.如权利要求1-11中任一项所述的化合物或其药学上可接受的盐,其中稠环A具有选自由以下组成的组的式:
其中的每一者任选地被额外1至2个R2取代。
19.如权利要求18所述的化合物或其药学上可接受的盐,其中稠环A具有下式:
20.如权利要求18或19所述的化合物或其药学上可接受的盐,其中连接至氮的R2选自由以下组成的组:C1-7烷基、C3-7环烷基、-C(O)-C1-7烷基、-C(O)-C3-7环烷基、-C(O)-C1-7亚烷基-OH、-Y1-O-C1-7烷基、-Y1-O-C3-7环烷基、-S(O)2-C1-7烷基、-S(O)2-C3-7环烷基、-C(O)NRaRb和4至8元杂环烷基,其中4至8元杂环烷基具有1-3个选自由O、N和S组成的组的杂原子环顶点,并且其中所述环烷基和所述杂环烷基被0-3个独立地选自以下的基团取代:卤基、CN、C1-4烷基、C1-4卤烷基、C1-4羟烷基、-O-C1-4烷基和OH。
21.如权利要求1-11或18-20中任一项所述的化合物或其药学上可接受的盐,其中稠环B具有选自由以下组成的组的式:
其中的每一者未被取代或被1至2个R4取代。
22.如权利要求21所述的化合物或其药学上可接受的盐,其中稠环B未被取代。
23.如权利要求21所述的化合物或其药学上可接受的盐,其中稠环B为
24.如权利要求1-11或18-20中任一项所述的化合物或其药学上可接受的盐,其中稠环B具有选自由以下组成的组的式:
其中的每一者未被取代或被1至4个R4取代。
25.如权利要求24所述的化合物或其药学上可接受的盐,其中稠环B被1至4个R4取代,R4中的每一者独立地选自由以下组成的组:卤素、C1-4烷基、C1-4卤烷基和OH。
26.如权利要求1-11或18-20中任一项所述的化合物或其药学上可接受的盐,其中稠环B具有选自由以下组成的组的式:
其中的每一者未被取代或被1至3个R4取代。
27.如权利要求26所述的化合物或其药学上可接受的盐,其中每个R4独立地选自由以下组成的组:C1-4烷基和C1-4卤烷基。
28.如权利要求1所述的化合物或其药学上可接受的盐,其选自由以下组成的组:
29.如权利要求1所述的化合物或其药学上可接受的盐,其选自由以下组成的组:
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30.一种药物组合物,所述药物组合物包含权利要求1-29中任一项所述的化合物或其药学上可接受的盐,和药学上可接受的赋形剂。
31.一种治疗至少部分地由AXL介导的疾病、病症或疾患的方法,所述方法包括向有需要的受试者施用有效量的权利要求1-29中任一项所述的化合物或其药学上可接受的盐或权利要求30所述的药物组合物。
32.如权利要求31所述的方法,其中所述化合物以有效逆转、减缓或阻止AXL介导的失调的进展的量施用。
33.如权利要求31-32中任一项所述的方法,其中所述疾病、病症或疾患为癌症。
34.如权利要求33所述的方法,其中所述癌症为前列腺癌、结肠癌、直肠癌、胰腺癌、宫颈癌、胃癌、子宫内膜癌、子宫癌、脑癌、肝癌、膀胱癌、卵巢癌、睾丸癌、头癌、颈癌、皮肤癌(包括黑色素瘤和基底癌)、间皮内膜癌、白细胞癌(包括淋巴瘤和白血病)、食道癌、乳腺癌、肌肉癌、结缔组织癌、肠癌、肺癌(包括小细胞肺癌和非小细胞肺癌)、肾上腺癌、甲状腺癌、肾癌或骨癌;或者为神经胶母细胞瘤、间皮瘤、肾细胞癌、胃癌、肉瘤(包括卡波西肉瘤)、绒毛膜癌、皮肤基底细胞癌或睾丸精原细胞瘤。
35.如权利要求33所述的方法,其中所述癌症选自由以下组成的组:黑色素瘤、结肠直肠癌、胰腺癌、乳腺癌、前列腺癌、肺癌、白血病、脑瘤、淋巴瘤、卵巢癌、卡波西肉瘤、肾细胞癌、头颈癌、食道癌和尿道上皮癌。
36.如权利要求31或32所述的方法,其中所述疾病、病症或疾患为免疫相关疾病、病症或疾患。
37.如权利要求36所述的方法,其中所述免疫相关疾病、病症或疾患选自由以下组成的组:类风湿性关节炎、肾衰竭、狼疮、哮喘、牛皮癣、结肠炎、胰腺炎、过敏、纤维化、贫血、纤维肌痛、阿尔茨海默病、充血性心力衰竭、中风、主动脉瓣狭窄、动脉硬化、骨质疏松、帕金森病、感染、克罗恩病、溃疡性结肠炎、过敏性接触性皮炎和其他湿疹、全身性硬化和多发性硬化。
38.如权利要求31至35中任一项所述的方法,所述方法还包括至少一种额外治疗剂。
39.如权利要求38所述的方法,其中所述至少一种额外治疗剂包含一种或多种独立地选自由以下组成的组的药剂:CD47-SIRPα通路抑制剂(例如抗CD47抗体)、HIF抑制剂(例如HIF-2α抑制剂)、免疫检查点抑制剂、靶向腺苷的胞外产生的剂、放射疗法和化学治疗剂。
40.如权利要求38所述的方法,其中所述至少一种额外治疗剂包含CD47-SIRPα通路的。
41.如权利要求38或权利要求40所述的方法,其中所述至少一种额外治疗剂包含一种或多种阻断以下中的至少一者的活性的免疫检查点抑制剂:PD-1、PD-L1、BTLA、LAG-3、B7家族成员、TIM-3、TIGIT或CTLA-4。
42.如权利要求41所述的方法,其中所述一种或多种免疫检查点抑制剂包含阻断PD-1或PD-L1的活性的免疫检查点抑制剂。
43.如权利要求42所述的方法,其中阻断PD-1或PD-L1的活性的所述免疫检查点抑制剂选自由以下组成的组:阿维单抗、阿特珠单抗、巴提利单抗、布地格单抗、卡瑞利珠单抗、科西贝利单抗、多斯利单抗、德瓦鲁单抗、依普利单抗、恩沃利单抗、埃本利单抗、纳武单抗、帕博利珠单抗、皮立珠单抗、皮米单抗、瑞弗利单抗、萨桑利单抗、斯巴达珠单抗、辛迪单抗、替雷利珠单抗、特瑞普利单抗和赛帕利单抗。
44.如权利要求42所述的方法,其中阻断PD-1或PD-L1的活性的所述免疫检查点抑制剂为赛帕利单抗。
45.如权利要求41所述的方法,其中所述一种或多种免疫检查点抑制剂包含阻断TIGIT的活性的免疫检查点抑制剂。
46.如权利要求45所述的方法,其中阻断TIGIT的活性的所述免疫检查点抑制剂选自AB308、多凡单抗、艾吉利单抗、欧司珀利单抗、替拉格鲁单抗或韦博妥单抗。
47.如权利要求45所述的方法,其中阻断TIGIT的活性的所述免疫检查点抑制剂为AB308或多凡单抗。
48.如权利要求38-47中任一项所述的方法,其中所述至少一种额外治疗剂包含一种或多种选自由以下组成的组的靶向腺苷的胞外产生的剂:A2aR/A2bR拮抗剂、CD73抑制剂和CD39抑制剂。
49.如权利要求48所述的方法,其中所述一种或多种靶向腺苷的胞外产生的剂选自由以下组成的组:艾鲁美冷(etrumadenant)、艾露帕冷(inupadenant)、他米那冷(taminadenant)、柠檬酸咖啡因、埃玛瑞冷(imaradenant)、赛佛瑞冷(ciforadenant)和昆利司他(quemliclustat)。
50.如权利要求48所述的方法,其中所述一种或多种靶向腺苷的胞外产生的剂为艾鲁美冷和/或昆利司他。
51.如权利要求38-50中任一项所述的方法,其中所述至少一种额外治疗剂包含选自由以下组成的组的HIF-2α抑制剂:贝珠替凡、ARO-HIF2、PT-2385和AB521。
52.如权利要求51所述的方法,其中所述HIF-2α抑制剂为AB521。
53.如权利要求38-52中任一项所述的方法,其中所述至少一种额外治疗剂包含化学治疗剂。
54.如权利要求38-53中任一项所述的方法,其中所述至少一种额外治疗剂包含放射。
55.如权利要求38-54中任一项所述的方法,其中所述化合物和所述至少一种额外治疗剂是以组合形式施用的。
56.如权利要求38-54中任一项所述的方法,其中所述化合物和所述至少一种额外治疗剂是依序施用的。
57.如权利要求38-54中任一项所述的方法,其中施用所述化合物和所述至少一种额外治疗剂的治疗期重叠。
58.一种组合,所述组合包含权利要求1-29中任一项所述的化合物或其药学上可接受的盐,和至少一种额外治疗剂。
59.如权利要求58所述的组合,其中所述至少一种额外治疗剂包含一种或多种独立地选自由以下组成的组的药剂:CD47-SIRPα通路抑制剂(例如抗CD47抗体)、HIF抑制剂(例如HIF-2α抑制剂)、免疫检查点抑制剂、靶向腺苷的胞外产生的剂、放射治疗和化学治疗剂。
60.如权利要求59所述的组合,其中所述至少一种额外治疗剂包含CD47-SIRPα通路抑制剂。
61.如权利要求59或60所述的组合,其中所述至少一种额外治疗剂包含一种或多种阻断以下中的至少一者的活性的免疫检查点抑制剂:PD-1、PD-L1、BTLA、LAG-3、B7家族成员、TIM-3、TIGIT或CTLA-4。
62.如权利要求61所述的组合,其中所述一种或多种免疫检查点抑制剂包含阻断PD-1或PD-L1的活性的免疫检查点抑制剂。
63.如权利要求61所述的组合,其中所述一种或多种免疫检查点抑制剂包含阻断TIGIT的活性的免疫检查点抑制剂。
64.如权利要求59-63中任一项所述的组合,其中所述至少一种额外治疗剂包含基于铂、基于蒽环霉素或基于类紫杉醇的化学治疗剂。
65.如权利要求64所述的组合,其中所述化学治疗剂选自由以下组成的组:顺铂、卡铂、奥沙利铂、多柔比星、多西他赛和太平洋紫杉醇。
66.一种抑制受试者中的AXL的活性的方法,所述方法包括向所述受试者施用权利要求1至29中任一项所述的化合物或其药学上可接受的盐或权利要求30所述的药物组合物。
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WO2024020034A1 (en) | 2022-07-20 | 2024-01-25 | Arcus Biosciences, Inc. | Cbl-b inhibitors and methods of use thereof |
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Family Cites Families (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI380996B (zh) | 2004-09-17 | 2013-01-01 | Hoffmann La Roche | 抗ox40l抗體 |
PT2343320T (pt) | 2005-03-25 | 2018-01-23 | Gitr Inc | Anticorpos anti-gitr e as suas utilizações |
KR101607288B1 (ko) | 2005-07-01 | 2016-04-05 | 이. 알. 스퀴부 앤드 선즈, 엘.엘.씨. | 예정 사멸 리간드 1 (피디-엘1)에 대한 인간 모노클로날 항체 |
EP1987839A1 (en) | 2007-04-30 | 2008-11-05 | I.N.S.E.R.M. Institut National de la Sante et de la Recherche Medicale | Cytotoxic anti-LAG-3 monoclonal antibody and its use in the treatment or prevention of organ transplant rejection and autoimmune disease |
WO2009009116A2 (en) | 2007-07-12 | 2009-01-15 | Tolerx, Inc. | Combination therapies employing gitr binding molecules |
EP2044949A1 (en) | 2007-10-05 | 2009-04-08 | Immutep | Use of recombinant lag-3 or the derivatives thereof for eliciting monocyte immune response |
AR072999A1 (es) | 2008-08-11 | 2010-10-06 | Medarex Inc | Anticuerpos humanos que se unen al gen 3 de activacion linfocitaria (lag-3) y los usos de estos |
SG196798A1 (en) | 2008-12-09 | 2014-02-13 | Genentech Inc | Anti-pd-l1 antibodies and their use to enhance t-cell function |
RU2646139C1 (ru) | 2009-09-03 | 2018-03-01 | Мерк Шарп И Доум Корп. | Анти-gitr-антитела |
CN102791738B (zh) | 2009-12-10 | 2015-10-07 | 霍夫曼-拉罗奇有限公司 | 优先结合人csf1r胞外域4的抗体及其用途 |
PL2542256T3 (pl) | 2010-03-04 | 2020-01-31 | Macrogenics, Inc. | Przeciwciała reaktywne wobec b7-h3, ich immunologicznie czynne fragmenty i ich zastosowania |
EP2542587A1 (en) | 2010-03-05 | 2013-01-09 | F. Hoffmann-La Roche AG | Antibodies against human csf-1r and uses thereof |
EP2542588A1 (en) | 2010-03-05 | 2013-01-09 | F. Hoffmann-La Roche AG | Antibodies against human csf-1r and uses thereof |
EP3943154A1 (en) | 2010-05-04 | 2022-01-26 | Five Prime Therapeutics, Inc. | Antibodies that bind csf1r |
SG10201506906VA (en) | 2010-09-09 | 2015-10-29 | Pfizer | 4-1bb binding molecules |
ES2669310T3 (es) | 2011-04-20 | 2018-05-24 | Medimmune, Llc | Anticuerpos y otras moléculas que se unen con B7-H1 y PD-1 |
PT2785375T (pt) | 2011-11-28 | 2020-10-29 | Merck Patent Gmbh | Anticorpos anti-pd-l1 e usos destes |
JP6242804B2 (ja) | 2011-12-15 | 2017-12-06 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | ヒトcsf−1rに対する抗体及びその使用 |
MX2014008961A (es) | 2012-02-06 | 2014-10-14 | Genentech Inc | Composiciones y metodos para utilizar inhibidores de csf1r. |
AR090263A1 (es) | 2012-03-08 | 2014-10-29 | Hoffmann La Roche | Terapia combinada de anticuerpos contra el csf-1r humano y las utilizaciones de la misma |
KR20220162819A (ko) | 2012-05-11 | 2022-12-08 | 파이브 프라임 테라퓨틱스, 인크. | 콜로니 자극 인자 1 수용체(csf1r)에 결속하는 항체들에 의한 질병 상태의 치료 방법 |
AR091649A1 (es) | 2012-07-02 | 2015-02-18 | Bristol Myers Squibb Co | Optimizacion de anticuerpos que se fijan al gen de activacion de linfocitos 3 (lag-3) y sus usos |
CN104684582A (zh) | 2012-08-31 | 2015-06-03 | 戊瑞治疗有限公司 | 用结合群落刺激因子1受体(csf1r)的抗体治疗病状的方法 |
BR112018013827B1 (pt) | 2016-01-08 | 2024-02-20 | Arcus Biosciences, Inc | Moduladores de 5-nucleotidase, ecto, composição farmacêutica, combinação, kit e uso dos mesmos |
US11058704B2 (en) | 2016-10-03 | 2021-07-13 | Arcus Biosciences, Inc. | Inhibitors of adenosine 5′-nucleotidase |
CN110022881B (zh) | 2016-11-18 | 2023-05-02 | 艾库斯生物科学有限公司 | Cd73介导的免疫抑制的抑制剂 |
TWI812494B (zh) | 2017-01-20 | 2023-08-11 | 美商阿克思生物科學有限公司 | 用於治療癌症相關病症之唑嘧啶 |
EP3618829B1 (en) | 2017-05-05 | 2023-06-07 | Arcus Biosciences, Inc. | Quinazoline-pyridine derivatives for the treatment of cancer-related disorders |
EP3829581B1 (en) | 2018-07-27 | 2024-04-03 | Arcus Biosciences, Inc. | Pyridone a2r antagonists |
US11931343B2 (en) | 2018-08-27 | 2024-03-19 | Arcus Biosciences, Inc. | CD73 inhibitors |
CN113382998A (zh) | 2018-11-16 | 2021-09-10 | 艾库斯生物科学有限公司 | Arg1和/或arg2的抑制剂 |
WO2020103896A1 (en) * | 2018-11-22 | 2020-05-28 | Beigene, Ltd. | Pyrrolo[2,3-b]pyridines as hpk1 inhibitor and uses thereof |
JP2022535120A (ja) | 2019-06-04 | 2022-08-04 | アーカス バイオサイエンシーズ インコーポレイテッド | 2,3,5-三置換ピラゾロ[1,5-a]ピリミジン化合物 |
TW202116773A (zh) * | 2019-07-04 | 2021-05-01 | 英屬開曼群島商百濟神州有限公司 | 作為HPK1抑制劑之吡咯并[2,3-b]吡及其用途 |
AU2020395783A1 (en) | 2019-12-04 | 2022-06-09 | Arcus Biosciences, Inc. | Inhibitors of HIF-2alpha |
IL295569A (en) | 2020-03-19 | 2022-10-01 | Arcus Biosciences Inc | Tetralin and tetrahydroquinoline compounds as inhibitors of hif-2alpha |
-
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- 2022-05-20 EP EP22731890.4A patent/EP4341262A1/en active Pending
- 2022-05-20 WO PCT/US2022/030230 patent/WO2022246179A1/en active Application Filing
- 2022-05-20 CN CN202280034431.2A patent/CN117337288A/zh active Pending
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