CN117658915A - 三并环类化合物及其制备方法和应用 - Google Patents
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- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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- C07D221/06—Ring systems of three rings
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Abstract
本发明提供了一种三并环类化合物及其制备方法和应用。具体地，本发明提供了具有式(I)所示结构的化合物，用作HIF‑2α(Hypoxia‑Inducible Factors‑2α)抑制剂，用于制备治疗和/或者预防哺乳动物与HIF‑2α相关的疾病的药物。
Description
技术领域
本发明属于药物化学领域，具体地，本发明涉及一种三并环类化合物及其制备方法和应用。
背景技术
肾癌是泌尿系统最常见的10种癌症之一。据估计，我国每年肾癌新增患者约5.2-7.8万人，肾癌病人总数预计46万以上。透明细胞肾细胞癌(ccRCC)是最常见的肾癌形式，虽然靶向治疗和免疫治疗显著改善了ccRCC患者的预后，但只有12％的晚期或转移性疾病患者能存活5年。对于有转移性疾病的ccRCC患者来说，有必要寻求更好的治疗方案。
HIF-2α活性已被证明是ccRCC的关键致癌驱动因子，其表达水平受到VHL(VonHippel-Lindau，一种肿瘤抑制基因)的调控。VHL基因突变，染色体缺失以及基因水平甲基化修饰均可导致VHL基因的失活或活性降低，HIF2α不能及时降解，发生累积并进入细胞核内跟HIF1β形成复合体，导致一系列下游基因的转录，例如血管生成因子(VEGF)，血小板源性生长因子(PDGF)，细胞周期蛋白D(Cyclin D)，葡萄糖转运(GLUT1)，氧气转运和代谢，细胞增殖和迁移等，最终导致肿瘤的发生和转移。HIF-2α抑制剂可以治疗/预防HIF-2α过表达引起的疾病，例如肾细胞癌。
HIF2α抑制剂也可用于其他肿瘤的治疗。由于抑制HIF-2a蛋白能降低与血管新生相关的因子，包括血管内皮生长因子(VEGF)、血小板源性生长因子(PDGF)、表皮生长因子(EGF)等的转录以及表达，从而可以抑制肿瘤新生血管的形成，具有抗血管生成药物的作用机制，因此其单用或者与免疫检查点抑制剂药物的联合用药也可以拓展到现有抗血管生成药物的多个适应症肿瘤中，除肾癌外，还包括肺癌、结直肠癌、卵巢癌、乳腺癌、宫颈癌、胃癌、肝癌、甲状腺癌以及多发性骨髓瘤、神经内分泌肿瘤、胰腺癌、胆道肿瘤、胰岛细胞腺瘤、肉瘤、胶质母细胞瘤等。此外，研究表明HIF2α抑制剂作用于肿瘤微环境中的免疫细胞群，可以通过提高T细胞对肿瘤的杀伤作用或者降低具有免疫抑制功能细胞的效应，起到抑制肿瘤生长的作用。表明HIF2α抑制剂单用或者与其他药物联用可能对肝癌、胰腺导管癌、肺鳞状细胞癌、结肠癌等有治疗效应。另外，HIF2α抑制剂在血管瘤治疗中的应用等也值得关注。
最后，HIF2α在非肿瘤领域如VHL综合征、肺动脉高压、高原反应、红细胞增多症、反流性食管炎、炎症性肠病等疾病的发生发展中也具有重要作用，HIF2a抑制剂的成功开发也将能为这些疾病的患者提供新的治疗选择。
鉴于此，本领域亟需开发一种合成路线简洁、工艺简单可靠的HIF2a抑制剂。
发明内容
本发明的目的在于提供一类三并环类化合物及其制备方法和应用，用于制备治疗和/或预防哺乳动物与HIF-2α相关的疾病的药物。
本发明的第一方面，提供了通式(I)所示的化合物或其立体异构体、光学异构体、药学上可接受的盐、前药或溶剂合物，
式中，
环A为5-6元杂环基，所述的杂环中具有1-2个选自N、O和S的杂原子，其中至少一个杂原子为N原子；且所述的杂环基为饱和的或不饱和的；
R1、R2、R3和R4各自独立地为H、卤素、氰基；
RAr选自取代或未取代的C6-C14芳基、取代或未取代的5-12元杂芳基，所述的取代是指一个或多个氢被选自下组的取代基取代：卤素、氰基、硝基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基；
Q为N或CH；
Z为氢、R5或-C(＝O)R5，其中，R5为取代或未取代的C1-C4烷基；
X为CR4或N；
W为其中，G选自S和P；M选自取代或未取代的直链或支链C1-C4烷基，取代或未取代的C3-C6环烷基；当G为P时，/>为单键，则T为C1-C4烷基；当G为S时，/>为双键，则T选自O、NH；所述的取代是指一个或多个氢原子被卤素取代。
在另一优选例中，所述的化合物具有式I’所示结构：
式中，
环A、R1、R2、R3、R4、RAr、Z、X、Q和W如本发明第一方面所述。
在另一优选例中，所述的化合物具有式I’所示的结构：
式中，
RAr选自取代或未取代的C6-C10芳基、取代或未取代的5-10元杂芳基，所述的取代是指一个或多个氢被选自下组的取代基取代：卤素、氰基、C1-C6烷基；
W选自
环A、R1、R2、R3、R4、X、Q和Z如本发明第一方面所述。
在另一优选例中，所述的化合物具有如式Ia、Ib或Ic所示的结构：
其中，R1、R2、R3、R4、RAr、Z、W和X的定义如本发明第一方面所述。
在另一优选例中，所述的化合物具有式8所示的结构：
式中，n为1或2；RAr选自取代或未取代的C6-C14芳基、取代或未取代的5-12元杂芳基，所述的取代是指一个或多个氢被选自下组的取代基取代：卤素、氰基、硝基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基。
在另一优选例中，RAr选自
在另一优选例中，所述的化合物选自下组：
在本发明的第二方面，提供了一种药物组合物，包含：
(a)作为活性成分的本发明第一方面所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物；以及
(b)药学上可接受的载体。
在另一优选例中，组分(a)占所述药物组合物总重量的0.001-99.99wt％；较佳地为0.01-99.9wt％；更佳地为0.05-90wt％。
在另一优选例中，所述药物组合物的剂型为注射剂、片剂、胶囊剂、丸剂、悬浮剂或乳剂。
在另一优选例中，所述的药物组合物中还包括第二活性成分，所述的第二活性成分选自下组：免疫检测点抑制剂、VEGF抑制剂、VEGFR抑制剂、PDGFR抑制剂、FGFR抑制剂、CDK4/6抑制剂、mTOR抑制剂、CAIX抑制剂、EPO抑制剂、EPOR抑制剂、EGFR抑制剂，或其组合。
在另一优选例中，所述的免疫检测点抑制剂选自下组：抗PD-1单抗、抗PD-L1单抗、抗CTLA-4单抗、抗LAG-3单抗、抗TIGIT单抗、抗CD47单抗，或其组合。
在另一优选例中，所述的VEGF抑制剂选自下组：阿西替尼、帕唑帕尼、索拉菲尼、舒尼替尼、安罗替尼、乐伐替尼、卡博替尼，贝伐单抗，或其组合。
在另一优选例中，所述的VEGFR抑制剂选自下组：替沃扎尼、西地尼布、沃罗拉尼、多韦替尼、替拉替尼、brivanib，或其组合。
在另一优选例中，所述的PDGFR抑制剂选自下组：奥拉木单抗、瑞戈非尼、盐酸培唑帕尼，或其组合。
在另一优选例中，所述的FGFR抑制剂自下组：厄达替尼、培米替尼、英菲格拉替尼，或其组合。
在另一优选例中，所述的CDK4/6抑制剂选自下组：哌柏西利、达尔西利、阿贝西利，或其组合。
另一优选例中，所述的mTOR抑制剂选自下组：雷帕霉素、依维莫司。
另一优选例中，所述的EGFR抑制剂选自下组：吉非替尼、厄洛替尼、埃克替尼、阿法替尼、奥希替尼、阿美替尼、伏美替尼，或其组合。
在本发明的第三方面，提供了本发明第一方面所述化合物或本发明第二方面所述药物组合物的用途，用于制备治疗和/或预防哺乳动物与HIF-2α相关的疾病或病症的药物。
另一优选例中，所述的与HIF-2α相关的疾病或病症选自下组：肾癌、脑胶质瘤、脑膜瘤、VonHippel-Lindau(VHL)综合征、肺癌、结直肠癌、卵巢癌、乳腺癌、宫颈癌、胃癌、肝癌、甲状腺癌、多发性骨髓瘤、肝癌、胰腺导管癌、肺鳞状细胞癌、结肠癌、血管瘤、肺动脉高压、炎症性肠病(IBD)、红细胞增多症、高原反应、反流性食管炎，或其组合。
在本发明的第四方面，提供了一种治疗和/或预防哺乳动物与HIF-2α相关的疾病或病症的方法，包括：向有需要的对象施用治疗有效量的本发明第一方面所述化合物或本发明第二方面所述药物组合物。
在本发明的第五方面，一种用于制备本发明第一方面所述化合物的中间体，具有如式IIa，式IIb或式IIc所示的结构：
其中n＝1或2；RAr选自取代或未取代的C6-C14芳基、取代或未取代的5-12元杂芳基，所述的取代是指一个或多个氢被选自下组的取代基取代：卤素、氰基、硝基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本申请人经过广泛而深入的研究，经过大量的实验，首次开发出了一种三并环化合物，用于制备治疗和/或预防哺乳动物与HIF-2α相关的疾病的药物。在此基础上，完成了本发明。
术语
除非另有说明，在本发明说明书和权利要求书中出现的以下术语具有下述含义：
术语“5-6元杂环基”本身或者与其他术语联合分别表示由5至6个环原子组成的饱和环状基团，其中1或2个环原子为各自独立地选自O、S和N的杂原子，其余为碳原子。包括但不限于吡咯烷基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)等。
术语“C1-C4烷基”是指具有1、2、3、4个碳原子的直链或支链的饱和单价烃基团。上述C1-C4烷基的例子包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基等。
术语“卤素”是指氟、氯、溴、碘。
术语“5-12元杂芳基”表示具有5至12个环原子的单环或稠合环基团，含有一个、两个、三个或四个选自N、O或S的环杂原子，其余环原子是C，另外具有完全共轭的π电子系统；典型地，所述杂芳基的例子包括但不限于：吡啶基、噻吩基、吡喃基、噻唑基、吡咯基、呋喃基等。
术语“芳基”表示6至14个碳原子的全碳单环或稠合多环基团，具有完全共轭的π电子系统。芳基的非限制性实施例有苯基。芳基可以是取代的或未取代的。
术语“取代”是指在所述基团上一个或多个氢被选自指出的基团替换，条件是：不超过所指定原子的现有情况下的正常价，并且该取代产生稳定化合物。取代基和/或变量可以组合，只要这种组合可以产生稳定化合物。
本发明还涉及本文公开的化合物的可用形式，例如，代谢物、水合物、溶剂化物、前药、盐，尤其是药学上可接受的盐，以及共沉淀。
进一步的，本发明的化合物可以游离形式存在，例如，作为游离碱或游离酸或两性离子，或可以以盐形式存在。所述盐可以是药学通常使用的任何盐，有机或无机加成盐，尤其是任何药学上可接受的有机或无机加成盐。
本发明化合物的药学上可接受的盐可以是，例如，链或环中携带氮原子的本发明化合物的酸加成盐，例如，充分碱性的本发明化合物的酸加成盐，例如，与无机酸形成的酸加成盐，例如，盐酸、氢溴酸、氢碘酸、硫酸、重硫酸、磷酸或硝酸，或与有机酸形成的酸加成盐，例如，甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)-苯甲酸、樟脑酸、肉桂酸、环戊酸、二葡糖酸、3-羟基-2-萘酸、烟酸、双羟萘酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、新戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚糖酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸。
本发明的化合物可以在一个或者多个构成该化合物的原子上包含非天然比例同位素，例如用重氢取代氢形成氘代药物。
如本文所用，术语“立体异构体”指具有相同化学构成、但在原子或基团的空间排列方面不同的化合物。立体异构体包括对映异构体、非对映异构体和构象异构体等。
如本文所用，术语“对映异构体”指化合物的彼此是不可重叠的镜像的两种立体异构体。
如本文所用，术语“非对映异构体”指具有两个或更多个手性中心并且其分子彼此不是镜像的立体异构体。非对映异构体具有不同的物理性质，例如熔点、沸点、光谱性质或生物活性。非对映异构体的混合物可以用手性HPLC分离。
采用萤光素酶报告基因实验(Luciferase assay)检测化合物对HIF-2α转录活性的抑制，结果显示化合物对HIF-2α转录活性具有很好抑制效果。
本领域技术人员应当理解的是，一些式(I)化合物可以包含一个或多个手性中心，因此存在两个或更多个立体异构体。因此，本发明的化合物可以以单个立体异构体(例如对映异构体、非对映异构体)及其任意比例的混合物例如外消旋物的形式存在，以及在适当的情况下，可以以其互变异构体和几何异构体的形式存在。
三并环类化合物
本发明提供了一种通式(I)所示的化合物或其立体异构体、光学异构体、药学上可接受的盐、前药或溶剂合物，
环A为5-6元杂环基，所述的杂环中具有1-2个选自N、O和S的杂原子，其中至少一个杂原子为N原子；且所述的杂环基为饱和的或不饱和的；
R1、R2、R3和R4各自独立地为H、卤素、氰基；
RAr选自取代或未取代的C6-C14芳基、取代或未取代的5-12元杂芳基，所述的取代是指一个或多个氢被选自下组的取代基取代：卤素、氰基、硝基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基；
Q为N或CH；
Z为氢、R5或-C(＝O)R5，其中，R5为取代或未取代的C1-C4烷基；
X为CR4或N；
W为其中，G选自S和P；M选自取代或未取代的直链或支链C1-C4烷基，取代或未取代的C3-C6环烷基；当G为P时，/>为单键，则T为C1-C4烷基；当G为S时，/>为双键，则T选自O、NH、C1-C4烷基；所述的取代是指一个或多个氢原子被卤素取代。
进一步地，所述的化合物具有式I’所示结构：
式中，
环A、R1、R2、R3、R4、RAr、Z、X、Q和W如权利要求1中所述。
具体地，所述的化合物具有如式Ia、Ib和Ic所示的结构：
其中，R1、R2、R3、R4、RAr、Z、W、X的定义如上所述。
在一个实施方式中，所述的式I化合物具有式8所示的结构：
式中，n为1或2,；RAr选自取代或未取代的C6-C14芳基、取代或未取代的5-12元杂芳基，所述的取代是指一个或多个氢被选自下组的取代基取代：卤素、氰基、硝基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基。
RAr选自
具体地，所述的化合物为
式I所示化合物的制备方法
在一个实施方式中，本发明还提供了一种式I所示化合物的制备方法，典型地，所述的方法包括：
(a)在惰性溶剂中，化合物1与甲磺酸反应，得到化合物2；
(b)在惰性溶剂中，在铜盐试剂的存在下，化合物2与硼酸类化合物发生偶联反应，得到化合物3；
(c)在惰性溶剂中，化合物3与烯丙基溴化镁反应，得到化合物4；
(d)在惰性溶剂中，在Pd2(dba)3和三乙胺的存在下，化合物4发生关环反应，得到化合物5；
(e)在惰性溶剂中，化合物5与氟化试剂反应，得到化合物6；
(f)在惰性溶剂中，在高碘酸钠和三氯化钌的存在下，化合物6发生氧化反应，得到化合物7；
(g)在惰性溶剂中，在CBS催化剂和硼烷试剂的存在下，化合物7发生还原反应，得到化合物8；
其中，各基团的定义如本发明第一方面中所述。
在另一优选例中，在步骤(b)中，所述的铜盐试剂为醋酸铜。
在另一优选例中，在步骤(b)中，所述的硼酸类化合物选自下组：(3-氰基-5-氟苯基)硼酸、(5-氰基吡啶-3-基)硼酸，或其组合。
在另一优选例中，在步骤(e)中，所述的氟化试剂选自下组：二乙胺基三氟化硫(DAST)。
在另一优选例中，在步骤(g)中，所述的硼烷试剂为硼烷二甲硫醚。
在另一优选例中，在步骤(g)中，所述的CBS催化剂为(R)-2-甲基-CBS-恶唑硼烷。
在另一优选例中，所述的惰性溶剂选自下组：C1-6烃类溶剂、C2-6醚类溶剂、芳香烃类溶剂、C2-6腈类溶剂、水，或其组合。
在另一优选例中，所述的惰性溶剂选自下组：二氯甲烷、四氢呋喃、甲苯、乙腈、水，或其组合。
在另一优选例中，步骤(a)中，反应时间为3-6h，反应温度为80-120℃。
在另一优选例中，步骤(b)中，反应时间为10-15h，反应温度为10-40℃。
在另一优选例中，步骤(c)中，反应时间为2-3h，反应温度为-10-5℃。
在另一优选例中，步骤(d)中，反应时间为3-6h，反应温度为80-100℃。
在另一优选例中，步骤(e)中，反应时间为2-4h，反应温度为-10-5℃。
在另一优选例中，步骤(f)中，反应时间为1-3h，反应温度为-10-5℃。
在另一优选例中，步骤(g)中，反应时间为1-3h，反应温度为-25--5℃。
药物组合物和施用方法
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药学上可接受的盐及一种或多种药学上可以接受的赋形剂或载体。其中“治疗有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有5-100mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选5～100mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
HIF-2α相关的疾病或病症
本发明所述的式(I)所示的化合物用于治疗和/或预防与HIF-2α相关的疾病或病症，所述的疾病或病症为肿瘤或肿瘤相关综合征，包括但不限于，肾癌、脑胶质瘤、脑膜瘤、VonHippel-Lindau(VHL)综合征、肺癌、结直肠癌、卵巢癌、乳腺癌、宫颈癌、胃癌、肝癌、甲状腺癌、多发性骨髓瘤、肝癌、胰腺导管癌、肺鳞状细胞癌、结肠癌、血管瘤等；非肿瘤疾病，包括但不限于，肺动脉高压、炎症性肠病(IBD)、红细胞增多症、高原反应、反流性食管炎等。
与现有技术相比，本发明的主要优点在于：
(1)本发明提供了一系列结构全新的HIF-2a抑制剂，其能够有效抑制HIF应答原件(HRE)依赖表达的荧光素酶水平，可用于治疗和/或预防哺乳动物与HIF-2α相关的疾病或病症。
(2)本发明提供的HIF-2a抑制剂的制备方法具有路线简洁、工艺简单可靠和纯度高的优点。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
在本发明实施例中，若无特殊说明，所有原料组分均为本领域技术人员熟知的市售产品；在本发明实施例中，若未具体指明，所用的技术手段均为本领域技术人员所熟知的常规手段。本发明反应的进程可采用本领域中的常规监测方法(例如TLC、LCMS或NMR)进行监测，一般以反应底物消失时为反应终点。
实施例1
化合物1：3-氟-5-((2aS,4R)-2a-氟-4-羟基-5-(甲磺酰基)-2,2a,3,4-四氢-1H-环戊基[cd]吲哚-1-基)苄氰
本实施例提供的化合物1的制备方法包括如下步骤：
步骤一：向反应瓶中加入4-溴吲哚-3-酮(化合物1，5g，23.58mmol)、甲磺酸50mL，加毕，在氮气保护下，100℃反应4小时，TLC点板监控原料完全反应后，减压浓缩黄色油状中间体2(4.7g，收率68.7％)。LCMS：(MS-ESI,m/z):[M+H]+＝290.3。
步骤二：向反应瓶中加入中间体2(1g，3.45mmol)、醋酸铜(751.25mg，4.14mmol)、(3-氰基-5-氟苯基)硼酸(625.32mg，3.79mmol)以及溶剂二氯甲烷(20mL)，加毕，在氧气保护下，20℃反应12小时，TLC点板监控，原料反应完全后停止反应，加入50mL水淬灭反应，分液，二氯甲烷萃取水相3次(20mL*3)，合并二氯甲烷相，减压浓缩，用柱层析硅胶过柱，用乙酸乙酯：石油醚体系洗脱(PE:EA＝1:1)，得黄色粉末状固体中间体3(0.71g，收率50.3％)。LCMS：(MS-ESI,m/z):[M+H]+＝409.1。
步骤三：向反应瓶中加入中间体3(0.7g，1.71mmol)、无水四氢呋喃15mL，加毕，搅拌降温至0℃，在氮气保护下，缓慢滴加烯丙基溴化镁(1M in THF,2.57mL,2.57mmol),加毕，保持0℃反应2小时，TLC点板监控，原料反应完全后停止反应，加入20mL饱和氯化铵水溶液淬灭反应，减压浓缩，乙酸乙酯萃取浓缩液3次(30mL*3)，合并乙酸乙酯相，用柱层析硅胶过柱，用乙酸乙酯：石油醚体系洗脱(EA:PE＝1:2)，得黄色油状中间体4(0.45g，收率58.2％)。LCMS：(MS-ESI,m/z):[M+H]+＝451.1。
步骤四：氮气氛围下，将溶有中间体4(0.45g，997.10μmol)，Pd2(dba)3(91.4mg，99.81μmmol)和三乙胺(302.70mg，2.99mmol)的甲苯(20mL)溶液90℃反应3h。TLC显示反应完毕后，恢复至室温，减压浓缩，浓缩液加50mL水，乙酸乙酯萃取(30mL*3)，合并有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩后得粗品经柱层析过柱，用二氯甲烷：甲醇体系洗脱(DCM:MeOH＝60:1)，得到黄色油状中间体5(0.31g,收率83.94％，通过Mosher法确定化合物光学纯度(ee值)＞95％)。LCMS：(MS-ESI,m/z):[M+H]+＝371.2。
步骤五：在氮气保护下，将中间体5(0.31g,836.94μmol)溶解于20mL二氯甲烷中，体系降温到0℃后，缓慢加入(269.81mg,1.67mmol)二乙胺基三氟化硫(DAST)后，反应在室温下搅拌3小时，加入10mL碳酸氢钠水溶液淬灭反应，。用二氯甲烷(30mL*3)萃取水相。合并有机相，并用饱和氯化钠洗涤后，无水硫酸钠干燥。粗品用(乙酸乙酯：石油醚＝1:1)纯化，得到了浅黄色固体中间体6(0.26g,收率83.42％)。LCMS：(MS-ESI,m/z):[M+H]+＝373.2。
步骤六：0℃下，向溶有中间体(0.26g，698.19μmol)的乙腈(18mL)和水(3mL)的混合溶剂中加入高碘酸钠(0.75g，350mmol)和三氯化钌(19mg,91.6μmol)并搅拌1h。TLC显示反应完毕后，饱和亚硫酸钠水溶液洗，乙酸乙酯(30mL*3)萃取，合并有机相，饱和食盐水洗涤1次,无水硫酸钠干燥，过滤，减压浓缩后得粗品经柱层析(乙酸乙酯：石油醚＝2:1)得到无色油状中间体7(150mg,收率57.39％)。LCMS：(MS-ESI,m/z):[M+H]+＝375.1。
步骤七：向反应瓶中加入中间体7(150mg,400.68μmol)以及二氯甲烷(10mL)，搅拌降温至-20℃，用氮气置换空气后，往反应瓶中加入(R)-2-甲基-CBS-恶唑硼烷(11.1mg,40.04μmol)催化剂，搅拌0.5小时，随后缓慢滴加硼烷二甲硫醚(1M in THF,1.2mL,1.20mmol)，滴加完后反应2小时，TLC显示反应完毕后，升温至室温，加入1mL甲醇淬灭反应，反应液过滤，滤饼以少量二氯甲烷清洗，滤液减压浓缩得淡黄色粘稠液体，粗品经柱层析(二氯甲烷：甲醇＝30:1)得到白色固体化合物1(60mg,收率39.8％)，通过手性Y分析色谱柱(4.6×250mm)进行手性HPLC测定纯度(purity)为97.2％。LCMS：(MS-ESI,m/z):[M+H]+＝377.2。1H NMR(400MHz，DMSO-d6)：δ7.83(m，2H)，7.71(dt，J＝9.6,2.4Hz,1H)，7.42(m，1H)，7.11(d，J＝8Hz，1H)，6.56(d，J＝8Hz，1H)，5.22(t,J＝14.4Hz,1H),4.60-4.44(m，2H)，3.40(s，3H),2.89-2.70(m,2H).
实施例2
化合物2：5-((2aS,4R)-2a-氟-4-羟基-5-(甲磺酰基)-2,2a,3,4-四氢-1H-环戊烷[cd]吲哚-1-基)烟碱甲腈
参照实施例1的制备方法，将步骤二的替换为/>制得化合物2
化合物2(23mg，收率25.1％，纯度为96.9％)。LCMS：(MS-ESI,m/z):[M+H]+＝360.21H NMR：(400MHz,DMSO-d6,ppm):δ8.49-8.42(m,2H)，7.71-7.66(m，1H),7.51(dd,J＝8.4,4.8Hz,1H),7.15(d,J＝8.4Hz,1H),6.02–5.78(m,1H)，5.12(t,J＝13.4Hz,1H),4.61-4.51(m，2H)，3.41(s，3H),2.89-2.72(m,2H)。
实施例3
化合物3：3-氟-5-((3aS,5R)-3a-氟-5-羟基-6-(甲磺酰基)-3,3a,4,5-四氢环戊烷[de]喹啉-1(2H)-基)苄氰
参照实施例1的制备方法，将步骤一的替换为/>制得化合物3
化合物2(33mg，收率45.2％,纯度97.2％))。LCMS：(MS-ESI,m/z):[M+H]+＝391.21H NMR：(400MHz,DMSO-d6,ppm):δ7.14(d,J＝8.4Hz,1H),7.12–7.06(m,1H),7.02(s,1H)，6.96(d，J＝8.4Hz,1H)，6.91(dt，J＝2.3,9.5Hz，1H)，6.63(dd，J＝2.8，9.6Hz，1H)，6.10–6.06(m,1H),5.15(dt,J＝7.6,5.2Hz,1H),3.41(s，3H)3.18–3.01(m,2H),2.93(dd,J＝6.0,18.4Hz,1H),2.54(d，J＝18.4Hz,1H)。
实施例4
化合物2：5-((3aS,5R)-3a-氟-5-羟基-6-(甲磺酰基)-3,3a,4,5-四氢环戊烷[de]q喹啉-1(2H)-基)烟碱甲腈
参照实施例1的制备方法，将步骤一的替换为/>同时将将步骤二的/>替换为/>制得化合物4
化合物4(26mg，收率29.8％,纯度为97.8％)。LCMS：(MS-ESI,m/z):[M+H]+＝374.11H NMR：(400MHz,DMSO-d6,ppm):δ8.38(dd，J＝1.6，2.8Hz,2H)，7.81-7.72(m，1H),7.53(dt，J＝2.5,9.1Hz，1H),7.25(d，J＝8.4Hz,1H),6.12–6.01(m,1H)，5.25(dt,J＝7.3,4.2Hz,1H),3.33(s，3H)3.18–3.11(m，2H),2.,1(dd,J＝6.0,18.2Hz,1H),2.51(d，J＝18.2Hz,1H)
实施例5
化合物2：5-((2aS,4R)-2a-氟-4-羟基-5-(甲磺酰基)-2,2a,3,4-四氢-1H-环戊烷[cd]吲哚-1-基)烟碱甲腈
本实施例以实施例1制备所得化合物1为原料，进行乙酰化反应，从而制备得化合物5
操作步骤如下：
将实施例1制备所得化合物1(20mg,53.14μmol)以及吡啶(4.2mg，53.14μmol)溶解于5ml二氯甲烷中，随后将反应体系降温至0℃，醋酸酐(5.97mg，58.45μmol)缓慢加入反应体系中，维持反应体系温度0-5℃，搅拌1小时，通过TLC监控反应进度。反应结束后，将反应液旋干，通过柱层析(PE:EA＝1:1)纯化可得白色固体化合5(18mg，收率80.9％,纯度为98.1％)。LCMS：(MS-ESI,m/z):[M+H]+＝419.2 1HNMR：(400MHz,DMSO-d6,ppm):δ7.81(m，2H)，7.70(dt,J＝9.5,2.4Hz,1H)，7.51(m，1H)，7.08(d，J＝8Hz，1H)，6.57(d，J＝8Hz，1H)，5.21(t,J＝14.3Hz,1H),4.60-4.46(m，2H)，3.41(s，3H),2.90-2.70(m,2H)，2.23(s,3H)。
测试例1(萤光素酶报告基因实验(Luciferase assay)检测化合物对HIF-2α转录活性的抑制)
利用商业化慢病毒感染的786-O细胞(VHL缺陷细胞)来获得786-O-HRE-Luc细胞，其中，HRE为原癌基因MYC的一个突变位点，HIF2α与HRE特异性结合后影响发光的强度。筛选出合适的786-O-HRE-Luc单细胞克隆，扩大培养并用于后续荧光素酶实验。
对于荧光素酶实验，将溶解有药物的100x DMSO储备液用实验培养基(含2％FBS的RPMI-1640；FBS：10099141C，Gibco；RPMI-1640：12440053，Gibco)配制成10x化合物的系列稀释液，取20μL 10x化合物稀释液加到透明平底的96孔板(3599，Corning)中。然后将180μL培养基中的约100,000个786-O-HRE-Luc细胞接种到上述96孔板中。每个孔中DMSO(D2650，Sigma)的最终浓度为0.1％。在培养箱中培养约24小时后，遵照制造商推荐的方法，采用Dual-LuciferaseReporter Assay System(E1960，Promega)试剂确定荧光素酶活性。使用剂量-响应-抑制(四参数)等式通过GraphPadPrism软件计算EC50值。实验结果如表1所示。
表1荧光素酶实验中的选定化合物的EC50值
| 化合物编号 | 荧光素酶EC50(nM) |
| 化合物1 | A |
| 化合物2 | A |
| 化合物3 | B |
| 化合物4 | A |
| 化合物5 | C |
备注：A<50；50<B<200；C>200；
如表1实验结果可知，本发明化合物具有优异的体外活性，能够抑制HIF应答原件(HRE)依赖表达的荧光素酶水平。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.通式(I)所示的化合物或其立体异构体、光学异构体、药学上可接受的盐、前药或溶剂合物，
式中，
环A为5-6元杂环基，所述的杂环中具有1-2个选自N、O和S的杂原子，其中至少一个杂原子为N原子；且所述的杂环基为饱和的或不饱和的；
R1、R2、R3和R4各自独立地为H、卤素、氰基；
RAr选自取代或未取代的C6-C14芳基、取代或未取代的5-12元杂芳基，所述的取代是指一个或多个氢被选自下组的取代基取代：卤素、氰基、硝基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基；
Q为N或CH；
Z为氢、R5或-C(＝O)R5，其中，R5为取代或未取代的C1-C4烷基；
X为CR4或N；
W为其中，G选自S和P；M选自取代或未取代的直链或支链C1-C4烷基，取代或未取代的C3-C6环烷基；当G为P时，/>为单键，则T为C1-C4烷基；当G为S时，/>为双键，则T选自O、NH；所述的取代是指一个或多个氢原子被卤素取代。
2.如权利要求1所述的化合物，其特征在于，所述的化合物具有式I’所示的结构：
式中，
RAr选自取代或未取代的C6-C10芳基、取代或未取代的5-10元杂芳基，所述的取代是指一个或多个氢被选自下组的取代基取代：卤素、氰基、C1-C6烷基；
W选自
环A、R1、R2、R3、R4、X、Q和Z如权利要求1中所述。
3.如权利要求1所述的化合物，其特征在于，所述的化合物具有如式Ia、Ib或Ic所示的结构：
其中，R1、R2、R3、R4、RAr、Z、W和X的定义如权利要求1中所述。
4.如权利要求1所述的化合物，其特征在于，具有式8所示的结构：
式中，n为1或2；RAr选自取代或未取代的C6-C14芳基、取代或未取代的5-12元杂芳基，所述的取代是指一个或多个氢被选自下组的取代基取代：卤素、氰基、硝基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基。
5.如权利要求1所述的化合物，其特征在于，RAr选自
6.如权利要求1所述的化合物，其特征在于，所述的化合物选自下组：
7.一种药物组合物，其特征在于，包含：
(a)作为活性成分的权利要求1-6中任一项所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物；以及
(b)药学上可接受的载体。
8.权利要求1所述的化合物或权利要求7所述的药物组合物的用途，其特征在于，用于制备治疗和/或预防哺乳动物与HIF-2α相关的疾病或病症的药物。
9.如权利要求8所述的用途，其特征在于，所述的与HIF-2α相关的疾病或病症选自下组：肾癌、脑胶质瘤、脑膜瘤、VonHippel-Lindau(VHL)综合征、肺癌、结直肠癌、卵巢癌、乳腺癌、宫颈癌、胃癌、肝癌、甲状腺癌、多发性骨髓瘤、肝癌、胰腺导管癌、肺鳞状细胞癌、结肠癌、血管瘤、肺动脉高压、炎症性肠病(IBD)、红细胞增多症、高原反应、反流性食管炎，或其组合。
10.一种用于制备权利要求1所述化合物的中间体，其特征在于，具有如式IIa，式IIb或式IIc所示的结构：
其中n＝1或2；RAr选自取代或未取代的C6-C14芳基、取代或未取代的5-12元杂芳基，所述的取代是指一个或多个氢被选自下组的取代基取代：卤素、氰基、硝基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基。
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