CN110963991A - 一种pi3k抑制剂及其制备方法和应用 - Google Patents
一种pi3k抑制剂及其制备方法和应用 Download PDFInfo
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- CN110963991A CN110963991A CN201811143116.5A CN201811143116A CN110963991A CN 110963991 A CN110963991 A CN 110963991A CN 201811143116 A CN201811143116 A CN 201811143116A CN 110963991 A CN110963991 A CN 110963991A
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- heteroaryl
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
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- 125000004429 atom Chemical group 0.000 claims description 11
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供一种PI3K抑制剂及其制备方法和应用，所述PI3K抑制剂为β位甲基取代的α，β不饱和酰胺基喹啉类化合物或其药学上可接受的盐。本发明中PI3Kα抑制剂化合物经药理活性筛选试验证明，其对PI3Kα显示了极强的抑制活性，所有化合物均明显优于阳性对照BEZ235，且β位甲基的引入使得该类化合物的体内药动学性质明显改善，为癌症治疗药物的研究提供了新的思路。另外，本发明中化合物制备方法设计合理，所需原料易得，操作简便，适于工业化生产。
Description
技术领域
本发明属药物领域，涉及一种PI3K抑制剂及其制备方法和应用。
技术背景
PI3K/Akt/mTOR信号通路作为细胞内重要的信号传导途径，在细胞的生长、存活、增殖、 凋亡等过程中发挥着重要的生物学功能，然而该通路的紊乱会引起一系列的疾病，包括癌症、 免疫系统和造血系统等疾病。相关研究表明该通路上的关键调控位点PI3K与肿瘤的发生、发 展密切相关，因此抑制PI3K的活性已成为当前抗肿瘤药物开发的重要策略之一 (Vanhaesebroeck B,Stephens L,Hawkins P,Nature Reviews Molecular CellBiology 2012, 13:195-203)。
磷脂酰肌醇3激酶(Phosphoinositide 3-kinase,PI3K)是一类包括多个成员的脂质激酶。 根据结构特征、活化机制和对脂类底物选择型的不同，PI3K激酶可主要分为I、II、III三类， 其中I类PI3K激酶包含PI3Kα、PI3Kβ、PI3Kδ和PI3Kγ四个亚型。I类PI3K激酶可磷酸化 磷脂酰-4,5-二磷酸脂(phosphatidylinositol-4,5-bisphosphate,PtdIns(4,5)P2)3位上的羟基生成 磷脂酰-3,4,5-三磷酸脂(phosphatidylinositol-3,4,5-triphosphate,PtdIns(3,4,5)P3)，后者作为细 胞内重要的第二信使作用与下游的丝/苏氨酸蛋白激酶Akt(也称蛋白激酶B，PKB)。被激活 的Akt进一步作用于包括哺乳动物雷帕霉素靶蛋白mTOR(mammalian target of rapamycin) 在内的下游效应蛋白来调节细胞内的多种生命活动(Liu PX,Cheng HL,Roberts TM,et al., Nature Reviews Drug Discovery2009,8:627-644)。
大量研究结果表明，人体内肿瘤的发生发展和PI3K/Akt/mTOR信号通路的异常活化密切 相关(Samuels Y,Wang ZH,Bardelli A,et al.,Science 2004,304:554-554；Bader AG,Kang SY, Vogt PK,Proceedings of the National Academy of Sciences ofthe United States of America 2006, 103:1475-1479；Huang CH,Mandelker D,Schmidt-Kittler O,et al.,Science 2007, 318:1744-1748)。I类PI3K的四种亚型和肿瘤的形成均有一定关系，其中PI3Kα和肿瘤的联 系最为密切。PI3Kα是由一个催化亚基p110α和一个调节亚基组成的二聚体。多种恶性肿瘤 中广泛存在着编码p110α的基因PIK3CA的突变、扩增和过表达，其突变主要发生在三个突 变频率最高的位点：配体螺旋域PI3Ka上谷氨酸E542和E545以及激酶催化域PI3Kc上组氨 酸H1047，这三个突变位点所引起的肿瘤约占了所有实体瘤的30％。而肿瘤抑制因子PTEN 的功能性缺失是引起肿瘤的另一个重要原因。正常情况下肿瘤抑制因子PTEN可使PtdIns(3,4,5)P3去磷酸化而拮抗PI3K的活性，而在病理条件下，功能缺失的PTEN则不能进 行上述过程，导致PI3K信号通路被过度激活，从而引起肿瘤的发生。
正因为PI3K在肿瘤的发生发展过程中起着关键性的作用，因此研发PI3K抑制剂是非常 具有前景的。
发明内容
本发明的目的是提供一种PI3K抑制剂及其制备方法和应用。
本发明的技术方案如下：
一种PI3K抑制剂，所述PI3K抑制剂为β位甲基取代的α，β不饱和酰胺基喹啉类化合物或其药学上可接受的盐，该化合物分子结构式如下：
其中：
R1选自C1-6烷基、C1-6卤代烷基、C1-6杂烷基、C3-6环烷基、C3-6杂环烷基、C5-6芳基、C5-6杂芳基、氟或氯；
R2选自羟基、烷氧基、胺基、C1-10胺烷基、C5-6芳胺基或C5-6芳杂胺基，其中所述烷氧基、胺基、C1-10胺烷基、C5-6芳胺基、C5-6芳杂胺基任一被1、2、3或4个独立选自D、F、 Cl、Br、CN、C1-6烷基、ORa、SRa或NRaRb取代基所取代；
R3选自C5-6芳基或C5-6杂芳基，其中所述C5-6芳基或C5-6杂芳基任一被1、2、3或4个独立选自D、F、Cl、Br、CN、C1-6烷基、ORa、SRa或NRaRb取代基所取代；
R4选自甲氧基或乙氧基；
Ra和Rb独立选自H、C1-6烷基、C1-6卤代烷基、C1-6杂烷基、C3-6环烷基、C3-6杂环烷基、C5-6芳基或C5-6杂芳基，其中所述C5-6杂芳基任选地被羟基、烷基、烷氧基、氨基、磺酰胺 基、氟、氯、三氟甲基或三氟甲氧基取代；当Ra、Rb与同一个氮原子连接时，Ra、Rb和与它 们连接的氮原子一起形成3-7个原子组成的杂环基。
进一步方案，所述化合物具体选自以下：
本发明的第二个发明目的是提供一种PI3K抑制剂组合物，其包括上述的PI3K抑制剂、 药学上可接受的载体或赋形剂、以及任选的其它治疗剂。
本发明的第三个发明目的是提供一种PI3K抑制剂的制备方法，其制备步骤如下：
(1)将4-醛基-6-溴喹啉I与烷基化试剂反应得到羟甲基喹啉衍生物II；
(2)将羟甲基喹啉衍生物II经氧化剂氧化得到4-羰基喹啉衍生物III；
(3)将4-羰基喹啉衍生物III与三乙基膦酰乙酸酯反应得到丙烯酸乙酯衍生物IV；
(4)在LiOH存在下水解生成丙烯酸衍生物V；
(5)在缩合试剂存在的条件下，丙烯酸衍生物V与胺类化合物反应或丙烯酸衍生物V 与氯甲酸乙酯、N-甲基吗啉、氨水反应均得到酰胺类化合物VI；
(6)酰胺类化合物VI与硼酸酯衍生物VII在Pd催化剂催化下发生Suzki偶联，生成α， β不饱和酰胺基喹啉类化合物VIII；然后经过层析柱得纯品；
(7)最后将其制备成生理条件下可接受的盐酸盐、醋酸盐或草酸盐；
进一步方案，其制备反应式如下：
其中：
R1选自C1-6烷基、C1-6卤代烷基、C1-6杂烷基、C3-6环烷基、C3-6杂环烷基、C5-6芳基、C5-6杂芳基、氟或氯；
R2选自羟基、烷氧基、胺基、C1-10胺烷基、C5-6芳胺基或C5-6芳杂胺基，其中所述烷氧基、胺基、C1-10胺烷基、C5-6芳胺基、C5-6芳杂胺基任一被1、2、3或4个独立选自D、F、 Cl、Br、CN、C1-6烷基、ORa、SRa或NRaRb取代基所取代；
R3选自C5-6芳基或C5-6杂芳基，其中所述C5-6芳基或C5-6杂芳基任一被1、2、3或4个独立选自D、F、Cl、Br、CN、C1-6烷基、ORa、SRa或NRaRb取代基所取代；
R4选自甲氧基或乙氧基；
Ra和Rb独立选自H、C1-6烷基、C1-6卤代烷基、C1-6杂烷基、C3-6环烷基、C3-6杂环烷基、C5-6芳基或C5-6杂芳基，其中所述C5-6杂芳基任选地被羟基、烷基、烷氧基、氨基、磺酰胺 基、氟、氯、三氟甲基或三氟甲氧基取代；当Ra、Rb与同一个氮原子连接时，Ra、Rb和与它 们连接的氮原子一起形成3-7个原子组成的杂环基。
进一步方案，步骤(1)中所述烷基化试剂为格氏试剂R1MgBr；步骤(2)中氧化剂为Dess-Martine试剂。
进一步方案，步骤(5)中缩合试剂为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐或 1-羟基苯并三唑。
进一步方案，步骤(6)中Pd催化剂为[1,1'-双(二苯基膦)二茂铁]二氯化钯；所述硼酸酯 衍生物VII为2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶-3-基) 苯磺酰胺。
本发明的第四个发明目的是提供上述PI3K抑制剂或PI3K抑制剂组合物在制备抗肿瘤药 物的应用，所述肿瘤为乳腺癌、结肠癌、前列腺癌、头颈部癌症、肺癌、甲状腺癌、子宫癌、 食管癌、卵巢癌、肝细胞癌、胶质母细胞癌或胃癌。
除非另外定义，所有本文使用的科技术语都具有与要求保护的主题所属领域的技术人员 一般理解相同的含义。
本发明中“C1-6烷基”指含有1～6个碳原子的烃部分去除一个氢原子衍生的直链或 支链的烷基，如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、4-甲基戊基、3-甲基戊基、 2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基 丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基和1-甲基-2-甲基丙基等。
“C1-6卤代烷基”是指采用氟、氯、溴、碘等取代烷基中至少一个氢基，在某些实施方式中，如果两个或更多氢原子被卤原子置换，所述卤原子彼此相同或不同。
“C1-6烷氧基”是指前文所定义的C1-6烷基通过氧原子与母体分子部分连接的基团，即 “C1-6烷基-O-”基团，如甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、叔丁氧基、正戊 氧基、新戊氧基和正己氧基等。
“芳香基”是指平面环具有离域的π电子系统并且含有4n+2个π电子，其中n是整数。芳香基环可以由五、六、七、八、九或多于九个原子构成。芳香基可以是任选取代的，还包 括碳环芳基(例如苯基)和杂环芳基(或杂芳基或杂芳香基)基团(例如吡啶)；包括单环或 稠环多环(即共用相邻的碳原子对的环)基团。
“芳基”是指芳香基环中每一个构成环的原子都是碳原子。芳基环可以由五、六、七、 八、九或多于九个原子构成。芳基可以是任选取代的。芳基的实例包括但不限于苯基、萘基、 菲基、蒽基、芴基和茚基。根据结构，芳基可以是单价基团或双价基团(即亚芳基)。
“环烷基”是指单环或多环基，其仅含有碳和氢。环烷基包括具有3-10个环原子的基团。 根据结构，环烷基可以是单价基团或双价基团(例如亚环烷基)。在本发明中，环烷基优选是 具有3-8个碳原子的环烷基，更优选具有3-6个碳原子的“低级环烷基”。
“杂芳基”是指芳基中包括一个或多个选自氮、氧和硫的环杂原子。含“杂芳基”部分 是指芳香基中环上至少有一个骨架原子是氮原子。杂芳基的实例包括但不限于吡啶基、咪唑 基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、吲唑基、 吲嗪基、酞嗪基、哒嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、噻二唑基、呋咱基、苯 并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、萘啶基和呋喃并吡啶基等。
“杂环烷基”是指非芳香基环中一个或多个构成环的原子是选自氮、氧和硫的杂原子。 杂环烷基环可以由三、四、五、六、七、八、九或多于九个原子构成。杂环烷基环可以是任选取代的。杂环烷基的实例包括但不限于内酰胺、内酯、环亚胶、环硫代亚胺、环氨基甲酸酯、四氢噻喃、4H-吡喃、四氢吡喃、哌啶、1，3-二噁英、1，3-二噁烷、1，4-二噁英、1， 4-二噁烷、哌嗪、1，3-氧硫杂环己烷、1，4-氧硫杂环己二烯、1，4-氧硫杂环己烷、四氢 -1，4-噻嗪、2H-1，2-噁嗪、马来酰亚胺、琥珀酰亚胺、巴比妥酸、硫代巴比妥酸、二氧代哌 嗪、乙内酰脲、二氢尿嘧啶、吗啉、三噁烷、六氢-1，3，5-三嗪、四氢噻吩、四氢呋喃、吡 咯啉、吡咯烷、咪唑烷，吡咯烷酮、吡唑啉、吡唑烷、咪唑啉、咪唑烷、1，3-二氧杂环戊 烯、1，3-二氧杂环戊烷、1，3-二硫杂环戊烯、1，3-二硫杂环戊烷、异噁唑啉、异噁唑烷、 噁唑啉、噁唑烷、噁唑烷酮、噻唑啉、噻唑烷和1，3-氧硫杂环戊烷。根据结构，杂环烷基 可以是单价基团或双价基团(即亚杂环烷基)。
“任一取代的”或“取代的”是指所提及的基团可以被一个或多个额外的基团取代，所 述额外的基团各自并且独立地选自烷基、环烷基、芳基、杂芳基、羟基、烷氧基、氰基、卤素、酰胺基、硝基、卤代烷基、氨基等。
本发明化合物经药理活性筛选试验证明，这类结构全新的化合物对PI3Kα显示了极强的 抑制活性，所有化合物均明显优于阳性对照BEZ235，且β位甲基的引入使得该类化合物的体 内药动学性质明显改善，为癌症治疗药物的研究提供了新的思路。
另外，本发明中化合物制备方法设计合理，所需原料易得，操作简便，适于工业化生产。
具体实施方式
本发明结合实施例作进一步的说明。以下的实施例是说明本发明，而不是以任何方式限 制本发明。
实施例1：
一种PI3K抑制剂的制备方法，其制备步骤如下：
(1)将4-醛基-6-溴喹啉I与格氏试剂R1MgBr反应得到羟甲基喹啉衍生物II；
(2)将羟甲基喹啉衍生物II经氧化剂Dess-Martine氧化得到4-羰基喹啉衍生物III；
(3)将4-羰基喹啉衍生物III与三乙基膦酰乙酸酯反应得到丙烯酸乙酯衍生物IV；
(4)在LiOH存在下水解生成丙烯酸衍生物V；
(5)在缩合试剂存在的条件下，丙烯酸衍生物V与胺类化合物反应或与氯甲酸乙酯、 N-甲基吗啉、氨水反应均得到酰胺类化合物VI；缩合试剂为1-乙基-(3-二甲基氨基丙基)碳酰 二亚胺盐酸盐或1-羟基苯并三唑。
(6)酰胺类化合物VI与硼酸酯衍生物VII在[1,1'-双(二苯基膦)二茂铁]二氯化钯催化下 发生Suzki偶联，生成α，β不饱和酰胺基喹啉类化合物VIII；然后经过层析柱得纯品；
(7)最后将其制备成生理条件下可接受的盐酸盐、醋酸盐或草酸盐；
其中：
R1选自C1-6烷基、C1-6卤代烷基、C1-6杂烷基、C3-6环烷基、C3-6杂环烷基、C5-6芳基、C5-6杂芳基、氟或氯；
R2选自羟基、烷氧基、胺基、C1-10胺烷基、C5-6芳胺基或C5-6芳杂胺基，其中所述烷氧基、胺基、C1-10胺烷基、C5-6芳胺基、C5-6芳杂胺基任一被1、2、3或4个独立选自D、F、 Cl、Br、CN、C1-6烷基、ORa、SRa或NRaRb取代基所取代；
R3选自C5-6芳基或C5-6杂芳基，其中所述C5-6芳基或C5-6杂芳基任一被1、2、3或4个独立选自D、F、Cl、Br、CN、C1-6烷基、ORa、SRa或NRaRb取代基所取代；
R4选自甲氧基或乙氧基；
Ra和Rb独立选自H、C1-6烷基、C1-6卤代烷基、C1-6杂烷基、C3-6环烷基、C3-6杂环烷基、C5-6芳基或C5-6杂芳基，其中所述C5-6杂芳基任选地被羟基、烷基、烷氧基、氨基、磺酰胺 基、氟、氯、三氟甲基或三氟甲氧基取代；当Ra、Rb与同一个氮原子连接时，Ra、Rb和与它 们连接的氮原子一起形成3-7个原子组成的杂环基。
实施例2：
一种PI3K抑制剂的制备方法，其制备步骤如下：
(1)制备1-(6-溴喹啉-4-基)乙基-1-醇(II)
在0℃条件下，将6-溴-4-醛基喹啉(I)(30.0g，127mmol)，MeMgBr(30.3g,84.8mL,3M) 溶于无水THF(800mL)，反应体系经氮气置换后，室温反应12小时。反应经饱和氯化铵溶液淬灭，随后以乙酸乙酯萃取，有机相无水硫酸钠干燥后减压除去溶剂，经硅胶层析柱纯化得黄色固体(28.0g,111mmol)。
产率：87％；1H NMR(400MHz,DMSO-d6)δ8.84(d,J＝4.5Hz,1H,Ar-H),8.37(d,J＝2.0 Hz,1H,Ar-H),7.91(d,J＝9.0Hz,1H,Ar-H),7.80(dd,J＝9.0,2.0Hz,1H,Ar-H),7.57(d,J＝4.5 Hz,1H,Ar-H),5.58(d,J＝4.3Hz,1H,OH),5.47-5.31(m,1H,CH),1.39(d,J＝6.5Hz,3H, CH3)；ESI-MS:m/z＝252[M+H]+。
(2)制备1-(6-溴喹啉-4-基)乙基-1-酮(III)
将1-(6-溴喹啉-4-基)乙基-1-醇(28.0g,111mmol),NaHCO3(9.33g,111mmol),Dess-Martine(71.0g,166mmol)溶于DCM(500mL)中，反应体系经氮气置换后，25℃条件 下反应4小时。随后加入亚硫酸钠搅拌10分钟，再加入碳酸氢钠，以乙酸乙酯萃取，有机相 无水硫酸钠干燥后减压除去溶剂，经硅胶层析柱纯化得黄色固体(20.6g,82.7mmol)as ayellow solid.
产率：75％；1H NMR(400MHz,DMSO-d6)δ9.11(d,J＝4.5Hz,1H,Ar-H),8.65(d,J＝2.0 Hz,1H,Ar-H),8.07-8.00(m,2H,Ar-H),7.78(m,1H,Ar-H),2.26(s,3H,CH3)；ESI-MS:m/z＝ 250[M+H]+。
(3)制备(E)-3-(6-溴喹啉-4-基)丁烯酸乙酯(IV)
将NaH(3.64g,152mmol)溶于无水THF中，0℃下缓慢滴加三乙基膦酰乙酸酯(42.5g, 190mmol,37.6mL)的THF溶液，反应30分钟，再缓慢滴加4-醛基-6-溴喹啉(31.6g,126 mmol)的THF溶液，继续反应1小时。反应结束后加入适量冰水至反应混合物中，搅拌10分钟，乙酸乙酯萃取，有机层以NaHCO3洗涤3次，水洗3次，有机层无水硫酸酶干燥后减 压浓缩，所得残余物经硅胶层析柱纯化得白色固体(9.55g，29.8mmol)。
产率：24％；1H NMR(400MHz,CDCl3)δ8.82(d,J＝4.3Hz,1H,Ar-H),7.97-7.91(m,2H, Ar-H),7.73(dd,J＝8.9,2.1Hz,1H,Ar-H),7.14(d,J＝4.3Hz,1H,Ar-H),5.89(d,J＝1.5Hz,1H, alkene hydrogen),4.21(q,J＝7.1Hz,2H,CH2),2.51(d,J＝1.5Hz,3H,CH3),1.28(t,J＝7.1Hz, 3H,CH3)；ESI-MS:m/z＝320[M+H]+。
(4)制备(E)-3-(6-溴喹啉-4-基)丁烯酸(V)
将(E)-3-(6-溴喹啉-4-基)丁烯酸乙酯(7.00g,21.8mmol)溶于THF(20.0mL)后，加到 LiOH·H2O(2.75g,65.5mmol)的水溶液中，25℃反应48小时，调稀盐酸调pH＝5时产生大量沉淀，过滤，滤饼水洗干燥得白色固体化合物(6.00g,20.54mmol)。
产率：94％；1H NMR(400MHz,DMSO-d6)δ9.04-8.84(brs,1H,Ar-H),8.81-7.91(m,2H, Ar-H),7.92(brd,J＝8.8Hz,1H,Ar-H),7.46(brs,1H,Ar-H),5.90(brs,1H,alkenehydrogen), 2.51(brs,3H,CH3)；ESI-MS:m/z＝292[M+H]+。
(5)制备酰胺类化合物VI，主要有以下5种：
A：制备(E)-3-(6-溴喹啉-4-基)-N-(2-羟乙基)-N-甲基丁烯酰胺(VIa)
将(E)-3-(6-溴喹啉-4-基)丁烯酸(100mg，0.34mmol)，EDCI(97mg，0.54mmol)和HOBt (69mg，0.54mmol)置于圆底烧瓶中，加入无水CH2Cl2(10mL),反应两小时后，加入三乙胺 (150μL，1.08mmol)，反应5分钟，加入N-甲基-2-羟基乙胺(51mg，0.68mmol)，继续反应 1小时。反应结束后再加入适量CH2Cl2，1N NaOH洗涤两次，水洗两次，所得有机层用无水 硫酸钠干燥后减压浓缩，残余物经硅胶层析柱纯化得白色固体(85mg，0.24mmol)。
产率：71％；1H NMR(400MHz,DMSO-d6)δ8.94(d,J＝1.6Hz,0.51H,Ar-H),8.93(d,J＝ 1.6Hz,0.45H,Ar-H),8.16(d,J＝2.0Hz,0.63H,Ar-H),8.12(d,J＝2.0Hz,0.39H,Ar-H),8.04(d, J＝3.2Hz,0.42H,Ar-H),8.02(d,J＝3.2Hz,0.58H,Ar-H),7.96–7.93(m,0.58H,Ar-H),7.93– 7.89(m,0.39H,Ar-H),6.38(d,J＝1.2Hz,0.64H,Ar-H),6.30(d,J＝1.2Hz,0.34H,alkene hydrogen),4.85(t,J＝5.2Hz,0.65H,OH),4.76(t,J＝5.2Hz,0.37H,OH),3.56(m,2H,CH2), 3.45(m,2H,CH2),3.10(s,1.12H,CH3),2.95(s,1.86H,CH3),2.30–2.22(m,3H,CH3)；ESI-MS: m/z＝349[M+H]+。
B：(E)-3-(6-溴喹啉-4-基)-1-(四氢吡咯-1-基)丁-2-烯-1-酮的制备(VIb)
制备方法同VIa，由(E)-3-(6-溴喹啉-4-基)丁烯酸(100mg，0.34mmol)和四氢吡咯烷(48 mg，0.68mmol)反应制得，经硅胶层析柱纯化得白色固体(89mg，0.26mmol)。
产率：76％；1H NMR(400MHz,DMSO-d6)δ8.94(d,J＝4.4Hz,1H,Ar-H),8.12(d,J＝2.0 Hz,1H,Ar-H),8.03(d,J＝8.8Hz,1H,Ar-H),7.93(dd,J＝8.8,2.0Hz,1H,Ar-H),7.49(d,J＝4.4 Hz,1H,Ar-H),6.23(d,J＝1.2Hz,1H,alkene hydrogen),3.47(t,J＝6.8Hz,2H,CH2),3.41(t,J＝6.8Hz,2H,CH2),2.40(d,J＝1.2Hz,3H,CH3),1.95–1.77(m,4H,CH2×2)；ESI-MS:m/z＝345 [M+H]+。
C：(E)-3-(6-溴喹啉-4-基)-1-吗啉丁-2-烯-1-酮的制备(VIc)
制备方法同VIa，由(E)-3-(6-溴喹啉-4-基)丁烯酸(100mg，0.34mmol)和吗啉(59mg， 0.68mmol)反应制得，经硅胶层析柱纯化得白色固体(93mg，0.26mmol)。
产率：76％；1H NMR(400MHz,DMSO-d6)δ8.94(d,J＝4.4Hz,1H,Ar-H),8.08(d,J＝2.0 Hz,1H,Ar-H),8.03(d,J＝8.8Hz,1H,Ar-H),7.93(dd,J＝8.8,2.0Hz,1H,Ar-H),7.51(d,J＝4.4 Hz,1H,Ar-H),6.34(d,J＝1.2Hz,1H,alkene hydrogen),3.64–3.52(m,8H,CH2×4),2.28(d,J ＝1.2Hz,3H,CH3)；ESI-MS:m/z＝361[M+H]+。
D：(E)-3-(6-溴喹啉-4-基)-1-(4-甲基哌嗪-1-基)丁-2-烯-1-酮的制备(VId)
制备方法同VIa，由(E)-3-(6-溴喹啉-4-基)丁烯酸(100mg，0.34mmol)和N-甲基哌嗪(68 mg，0.68mmol)反应制得，经硅胶层析柱纯化得白色固体(76mg，0.20mmol)。
产率：59％；1H NMR(400MHz,DMSO-d6)δ8.94(d,J＝4.4Hz,1H,Ar-H),8.08(d,J＝2.0 Hz,1H,Ar-H),8.03(d,J＝8.8Hz,1H,Ar-H),7.93(dd,J＝8.8,2.2Hz,1H,Ar-H),7.51(d,J＝4.4 Hz,1H,Ar-H),6.33(d,J＝1.2Hz,1H,alkene hydrogen),3.57(t,J＝4.4Hz,2H),3.52(t,J＝4.4 Hz,2H),2.37–2.30(m,4H),2.25(d,J＝1.2Hz,3H,CH3),2.21(s,3H,CH3)；ESI-MS:m/z＝374 [M+H]+。
E：(E)-3-(6-溴喹啉-4-基)-1-(4-羟基哌啶-1-基)丁-2-烯-1-酮的制备(VIe)
制备方法同VIa，由(E)-3-(6-溴喹啉-4-基)丁烯酸(100mg,0.34mmol)和4-羟基哌啶(69 mg,0.68mmol)反应制得，经硅胶层析柱纯化得白色固体(88mg,0.24mmol)。
产率：71％；1H NMR(400MHz,DMSO-d6)δ8.94(d,J＝4.4Hz,1H,Ar-H),8.08(d,J＝2.0 Hz,1H,Ar-H),8.03(d,J＝8.8Hz,1H,Ar-H),7.93(dd,J＝8.8,2.0Hz,1H,Ar-H),7.51(d,J＝4.4 Hz,1H,Ar-H),6.33(d,J＝1.2Hz,1H,alkene hydrogen),4.81(d,J＝3.2Hz,1H,OH),4.08–3.95 (m,1H,CH),3.75(m,2H,CH2),3.30–3.22(m,1H,CH2),3.19–3.11(m,1H,CH2),2.23(d,J＝ 1.2Hz,3H,CH3),1.77(m,2H,CH2),1.34(m,2H,CH2)；ESI-MS:m/z＝375[M+H]+。
F：制备(E)-3-(6-溴喹啉-4-基)丁烯酰胺(VIf)
将(E)-3-(6-溴喹啉-4-基)丁烯酸乙酯(100mg，0.35mmo)，氯甲酸乙酯(42mg，0.39mmo)， N-甲基吗啉(40mg，0.39mmo)溶于无水THF中，反应30分钟后，加入0.3mL氨水，室温反应4小时。反应混合物溶于适量乙酸乙酯中，以NaHSO3洗两次，水洗1次，有机层无 水硫酸钠干燥并减压浓缩，残留物经硅胶层析柱纯化得白色固体(72mg，0.25mmol)。
产率：71％；1H NMR(500MHz,DMSO-d6)δ8.93(d,J＝4.4Hz,1H,Ar-H),8.08(d,J＝2.2 Hz,1H,Ar-H),8.02(d,J＝9.0Hz,1H,Ar-H),7.93(dd,J＝9.0,2.2Hz,1H,Ar-H),7.55(s,1H, NH2),7.45(d,J＝4.4Hz,1H,Ar-H),7.16(s,1H,NH2),5.95(d,J＝1.4Hz,1H,alkenehydrogen), 2.49(d,J＝1.4Hz,3H,CH3)；ESI-MS:m/z＝291[M+H]+。
(6)制备α，β不饱和酰胺基喹啉类化合物(VIII)
A、(E)-3-(6-(5-(2,4-二氟苯磺酰胺基)-6-甲氧基吡啶-3-基)喹啉-4-基)-N-(2-羟乙基)-N-甲基 丁烯酰胺的制备(VIIIa)
将VIa(56mg，0.16mmol)，2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼 烷-2-基)吡啶-3-基)苯磺酰胺VII(68mg，0.16mmol)，Pd(dppf)2Cl2(12mg，0.016mmol)和 K2CO3(66mg，0.48mmol)置于两颈瓶中，加入dioxane/H2O(3/1)，反应体系经氮气置换后， 加热到100℃反应10小时。待反应冷却到室温后，减压浓缩，所得残留物溶解于CH2Cl2中， 水洗两次，有机相无水硫酸钠干燥后减压除去溶剂，经硅胶层析柱纯化得白色固体(20mg， 0.035mmol)。
产率：22％；1H NMR(400MHz,DMSO-d6)δ10.38(s,1H,NH),8.91(d,J＝4.4Hz,1H,Ar-H),8.43(d,J＝2.1Hz,1H,Ar-H),8.17(d,J＝8.7Hz,1H,Ar-H),8.12–8.03(m,2H,Ar-H),7.96(m,1H,Ar-H),7.80(m,1H,Ar-H),7.63–7.55(m,1H,Ar-H),7.47(d,J＝4.4Hz,0.36H,Ar-H),7.44(d,J＝4.4Hz,0.63H,Ar-H),7.23(m,1H,Ar-H),6.43(s,0.60H,alkenehydrogen), 6.34(s,0.37H,alkene hydrogen),4.82(t,J＝5.3Hz,0.63H,OH),4.76(t,J＝5.4Hz,0.39H,OH), 3.69(s,1.20H,OCH3),3.68(s,1.79H,OCH3),3.61–3.44(m,4H,CH2×2),3.13(s,1.12H,NCH3), 2.96(s,1.88H,NCH3),2.32(s,3H,CH3)；HRMS(ESI)m/z calcd forC28H27F2N4O5S[M+H]+ 569.1670,found 569.1665。
B、(E)-2,4-二氟-N-(2-甲氧基-5-(4-(4-羰基-4-(四氢吡咯-1-基)丁-2-烯-2-基)喹啉-6-基)吡啶 -3-基)苯磺酰胺的制备(VIII b)
制备方法同VIIIa，由VIb(55mg，0.16mmol)，2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基 -1,3,2-二氧杂环戊硼烷-2-基)吡啶-3-基)苯磺酰胺VII(68mg，0.16mmol)反应制得，经硅胶层 析柱纯化得白色固体(28mg，0.050mmol)。
产率：31％；1H NMR(400MHz,DMSO-d6)δ10.40(s,1H,NH),8.91(d,J＝3.8Hz,1H,Ar-H),8.45(s,1H,Ar-H),8.17(d,J＝8.7Hz,1H,Ar-H),8.09(m,2H,Ar-H),7.97(s,1H,Ar-H), 7.79(m,1H,Ar-H),7.59(m,1H,Ar-H),7.46(d,J＝3.8Hz,1H,Ar-H),7.24(m,1H,Ar-H),6.29(s, 1H,alkene hydrogen),3.69(s,3H,OCH3),3.54–3.42(m,4H,CH2×2),2.46(s,3H,CH3),1.86(m, 4H,CH2×2)；HRMS(ESI)m/z calcd for C29H27F2N4O4S[M+H]+565.1721,found565.1709。
C、(E)-2,4-二氟-N-(2-甲氧基-5-(4-(4-吗啉-4-羰基丁基-2-烯-2-基)喹啉-6-基)吡啶-3-基)苯 磺酰胺的制备(VIII c)
制备方法同VIIIa，由VIc(58mg，0.16mmol)，2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基 -1,3,2-二氧杂环戊硼烷-2-基)吡啶-3-基)苯磺酰胺VII(68mg,0.16mmol)反应制得，经硅胶层 析柱纯化得白色固体(22mg，0.038mmol)。
产率：24％；1H NMR(400MHz,DMSO-d6)δ10.41(s,1H,NH),8.91(d,J＝4.4Hz,1H,Ar-H),8.43(d,J＝1.6Hz,1H,Ar-H),8.17(d,J＝8.8Hz,1H,Ar-H),8.07(d,J＝8.8Hz,1H,Ar-H),8.06(s,1H,Ar-H),7.96(d,J＝1.6Hz,1H,Ar-H),7.79(m,1H,Ar-H),7.59(m,1H,Ar-H), 7.48(d,J＝4.4Hz,1H,Ar-H),7.23(m,1H,Ar-H),6.39(s,1H,alkene hydrogen),3.68(s,3H, OCH3),3.52-3.66(m,8H,CH2×4),2.34(s,3H,CH3)；HRMS(ESI)m/z calcd forC29H27F2N4O5S [M+H]+581.1670,found 581.1681。
D、(E)-2,4-二氟-N-(2-甲氧基-5-(4-(4-(4-甲基哌嗪-1-基)-4-羰基丁基-2-烯-2-基)喹啉-6-基) 吡啶-3-基)苯磺酰胺的制备(VIIId)
制备方法同VIIIa，由VId(60mg，0.16mmol)，2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基 -1,3,2-二氧杂环戊硼烷-2-基)吡啶-3-基)苯磺酰胺VII(68mg，0.16mmol)反应制得，经硅胶层 析柱纯化得白色固体(25mg，0.042mmol)。
产率：26％；1H NMR(400MHz,DMSO-d6)δ8.89(d,J＝4.4Hz,1H,Ar-H),8.26(d,J＝2.0 Hz,1H,Ar-H),8.15(d,J＝9.4Hz,1H,Ar-H),8.02(m,2H,Ar-H),7.87(d,J＝2.0Hz,1H,Ar-H), 7.80(m,1H,Ar-H),7.54–7.47(m,1H,Ar-H),7.46(d,J＝4.4Hz,1H,Ar-H),7.19(m,1H,Ar-H), 6.37(s,1H,alkene hydrogen),3.71(s,3H,OCH3),3.58(s,4H,CH2×2),2.34(s,4H,CH2×2), 2.31(s,3H,CH3),2.21(s,3H,CH3)；HRMS(ESI)m/z calcd for C30H30F2N5O4S[M+H]+ 594.1986,found 594.2008。
E、(E)-2,4-二氟-N-(5-(4-(4-(4-羟基哌啶-1-基)-4-羰基丁基-2-烯-2-基)喹啉-6-基)-2-甲氧基 吡啶-3-基)苯磺酰胺的制备(VIIIe)
制备方法同VIIIa，由VIe(60mg，0.16mmol)，2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基 -1,3,2-二氧杂环戊硼烷-2-基)吡啶-3-基)苯磺酰胺VII(68mg，0.16mmol)反应制得，经硅胶层 析柱纯化得白色固体(18mg，0.030mmol)。
产率：19％；1H NMR(400MHz,DMSO-d6)δ10.38(s,1H,NH),8.91(d,J＝4.4Hz,1H,Ar-H),8.41(d,J＝2.1Hz,1H,Ar-H),8.17(d,J＝9.4Hz,1H,Ar-H),8.05(m,2H,Ar-H),7.95(d, J＝2.1Hz,1H,Ar-H),7.80(m,1H,Ar-H),7.59(m,1H,Ar-H),7.48(d,J＝4.4Hz,1H,Ar-H), 7.23(m,1H,Ar-H),6.37(s,1H,alkene hydrogen),4.77(d,J＝4.0Hz,1H,OH),4.01(m,1H,CH), 3.77(m,2H,CH2),3.69(s,3H,OCH3),3.41(s,1H,CH2),3.17(m,1H,CH2),2.29(s,3H,CH3), 1.76(m,2H,CH2),1.42–1.31(m,2H,CH2)；HRMS(ESI)m/z calcd for C30H29F2N4O5S[M+H]+ 595.1826,found 595.1823。
F、(E)-3-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧吡啶基-3-基)喹啉-4-基)丁基-2-烯胺的制备 (VIIIf)
制备方法同VIIIa，由VIf(46mg，0.16mmol)，2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基 -1,3,2-二氧杂环戊硼烷-2-基)吡啶-3-基)苯磺酰胺VII(68mg，0.16mmol)反应制得，经硅胶层 析柱纯化得白色固体(12mg，0.024mmol)。
产率：15％；1H NMR(400MHz,DMSO-d6)δ10.39(s,1H,NH),8.91(d,J＝4.4Hz,1H,Ar-H),8.45(d,J＝2.2Hz,1H,Ar-H),8.17(d,J＝8.7Hz,1H,Ar-H),8.06(m,2H,Ar-H),7.97(d, J＝2.2Hz,1H,Ar-H),7.80(m,1H,Ar-H),7.60(m,2H,Ar-H and NH2),7.44(d,J＝4.4Hz,1H, Ar-H),7.24(m,2H,Ar-H and NH2),6.03(d,J＝1.2Hz,1H,alkene hydrogen),3.70(s,3H,OCH3), 2.57(d,J＝1.2Hz,3H,CH3)；HRMS(ESI)m/z calcd for C25H21F2N4O4S[M+H]+511.1251, found 511.1269。
生物实验实施例3：化合物对PI3Kα的抑制活性实验
将上述实施例2制备的五个目标化合物VIIIa、VIIIb、VIIIc、VIIId、VIIIe、VIIIf分别 对PI3Kα的抑制活性通过Kinase-Glo Plus Luminescent Kinase Assay来测定。首先将被测化合 物稀释成测试所需的一系列浓度，各取2.5μL加到384孔板上。随后用激酶缓冲溶液(50mM HEPES pH 7.5,3mM MgCl2,1mM EGTA,100mM NaCl,0.03％CHAPS,2mM DTT)将PI3Kα 稀释到1.65nM，然后以每孔2.5μL加到384孔板上；同样用激酶缓冲溶液将底物PIP2和ATP 分别稀释到50μM和25μM，并以每孔5μL加入上述384孔板中。反应1小时后，Kinase-Glo reagent以每孔10μL加到该384孔上，终止反应。样品经离心等处理后，利用酶标仪读取其RLU值。按下列公式计算抑制率：抑制率(％)＝(sample RLU-min)/(max-min)×100，其中“min” 表示无酶对照孔的RLU，“max”表示含有DMSO对照孔的RLU。结果表示为IC50值，如下表1所示。
表1.化合物对PI3Kα的抑制活性
| 化合物编号 | VIIIa | VIIIb | VIIIc | VIIId | VIIIe | VIIIf | BEZ235 |
| IC<sub>50</sub>(nM) | 1.5 | 1.2 | 1.1 | 0.8 | 1.4 | 0.6 | 35.2 |
上述各化合物对PI3Kα的活性测试结果如上表1显示，说明本发明制备的化合物都是 PI3Kα的高效抑制剂，所有化合物的PI3Kα抑制活性强于阳性对照BEZ235(其中BEZ235是本领域已知的PI3K抑制剂，目前已进入临床II期研究的PI3K抑制剂)。
生物实验实施例4：化合物药动学评价实验
选取本发明实施例2制备的化合物VIIId和已公开化合物IX(授权公告号CN104961725 B，结构如下所示)，测试其在大鼠体内初步的药物代谢情况。
(1)实验材料：
SD大鼠12只，雄性，体重200g左右，随机分成4组，每组3只。
(2)实验方法:
口服给药后，按设定的时间点取鼠尾静脉血0.5ml，置肝素化试管中，6000rpm离心10min， 分离血浆，于-20℃冰箱中冷藏。
采用LC-MS/MS法测定血浆中药物浓度。利用药动学软件的非房室模型计算给药后的药 代动力学参数。药时曲线图由Graphpad软件处理得到。
(3)实验结果：
口服给药5mg/kg VIIId和IX后的药动学参数见表2，结果表明：化合物VIIId的最大血 药浓度(Cmax)、暴露量(AUC0-t，AUC0-∞)较化合物IX有明显的改善。
表2大鼠口服给药5mg/kg后的药动学参数
上述实验结果显示，本发明制备的化合物都是PI3Kα的高效抑制剂，所有化合物的PI3Kα 抑制活性强于阳性对照BEZ235(表1)，且PK性质比类似化合物有明显的改善(表2)，以 上各实验说明该类化合物具有优异的抗肿瘤应用前景，因而具有良好的商业价值。
Claims (9)
1.一种PI3K抑制剂，其特征在于：所述PI3K抑制剂为β位甲基取代的α，β不饱和酰胺基喹啉类化合物或其药学上可接受的盐，该化合物分子结构式如下：
其中：
R1选自C1-6烷基、C1-6卤代烷基、C1-6杂烷基、C3-6环烷基、C3-6杂环烷基、C5-6芳基、C5-6杂芳基、氟或氯；
R2选自羟基、烷氧基、胺基、C1-10胺烷基、C5-6芳胺基或C5-6芳杂胺基，其中所述烷氧基、胺基、C1-10胺烷基、C5-6芳胺基、C5-6芳杂胺基任一被1、2、3或4个独立选自D、F、Cl、Br、CN、C1-6烷基、ORa、SRa或NRaRb取代基所取代；
R3选自C5-6芳基或C5-6杂芳基，其中所述C5-6芳基或C5-6杂芳基任一被1、2、3或4个独立选自D、F、Cl、Br、CN、C1-6烷基、ORa、SRa或NRaRb取代基所取代；
R4选自甲氧基或乙氧基；
Ra和Rb独立选自H、C1-6烷基、C1-6卤代烷基、C1-6杂烷基、C3-6环烷基、C3-6杂环烷基、C5-6芳基或C5-6杂芳基，其中所述C5-6杂芳基任选地被羟基、烷基、烷氧基、氨基、磺酰胺基、氟、氯、三氟甲基或三氟甲氧基取代；当Ra、Rb与同一个氮原子连接时，Ra、Rb和与它们连接的氮原子一起形成3-7个原子组成的杂环基。
2.根据权利要求1所述的一种PI3K抑制剂，其特征在于：所述化合物具体选自以下：
3.一种PI3K抑制剂组合物，其包括如权利要求1或2所述的PI3K抑制剂、药学上可接受的载体或赋形剂、以及任选的其它治疗剂。
4.一种PI3K抑制剂的制备方法，其特征在于：制备步骤如下：
(1)将4-醛基-6-溴喹啉I与烷基化试剂反应得到羟甲基喹啉衍生物II；
(2)将羟甲基喹啉衍生物II经氧化剂氧化得到4-羰基喹啉衍生物III；
(3)将4-羰基喹啉衍生物III与三乙基膦酰乙酸酯反应得到丙烯酸乙酯衍生物IV；
(4)在LiOH存在下水解生成丙烯酸衍生物V；
(5)丙烯酸衍生物V与胺类化合物在缩合试剂存在的条件下反应得到酰胺类化合物VI，或者丙烯酸衍生物V与氯甲酸乙酯、N-甲基吗啉、氨水反应亦得到酰胺类化合物VI；
(6)酰胺类化合物VI与硼酸酯衍生物VII在Pd催化剂催化下发生Suzuki偶联，生成α，β不饱和酰胺基喹啉类化合物VIII；然后经过层析柱得纯品；
(7)最后将其制备成生理条件下可接受的盐酸盐、醋酸盐或草酸盐。
5.根据权利要求4所述的制备方法，其特征在于：其制备反应式如下：
其中：
R1选自C1-6烷基、C1-6卤代烷基、C1-6杂烷基、C3-6环烷基、C3-6杂环烷基、C5-6芳基、C5-6杂芳基、氟或氯；
R2选自羟基、烷氧基、胺基、C1-10胺烷基、C5-6芳胺基或C5-6芳杂胺基，其中所述烷氧基、胺基、C1-10胺烷基、C5-6芳胺基、C5-6芳杂胺基任一被1、2、3或4个独立选自D、F、Cl、Br、CN、C1-6烷基、ORa、SRa或NRaRb取代基所取代；
R3选自C5-6芳基或C5-6杂芳基，其中所述C5-6芳基或C5-6杂芳基任一被1、2、3或4个独立选自D、F、Cl、Br、CN、C1-6烷基、ORa、SRa或NRaRb取代基所取代；
R4选自甲氧基或乙氧基；
Ra和Rb独立选自H、C1-6烷基、C1-6卤代烷基、C1-6杂烷基、C3-6环烷基、C3-6杂环烷基、C5-6芳基或C5-6杂芳基，其中所述C5-6杂芳基任选地被羟基、烷基、烷氧基、氨基、磺酰胺基、氟、氯、三氟甲基或三氟甲氧基取代；当Ra、Rb与同一个氮原子连接时，Ra、Rb和与它们连接的氮原子一起形成3-7个原子组成的杂环基。
6.根据权利要求4所述的制备方法，其特征在于：步骤(1)中所述烷基化试剂为格氏试剂R1MgBr；步骤(2)中氧化剂为Dess-Martine试剂。
7.根据权利要求4所述的制备方法，其特征在于：步骤(5)中缩合试剂为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐或1-羟基苯并三唑。
8.根据权利要求4所述的制备方法，其特征在于：步骤(6)中Pd催化剂为[1,1'-双(二苯基膦)二茂铁]二氯化钯；所述硼酸酯衍生物VII为2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶-3-基)苯磺酰胺。
9.如根据权利要求1或2所述的PI3K抑制剂在制备抗肿瘤药物的应用，其特征在于：所述肿瘤为乳腺癌、结肠癌、前列腺癌、头颈部癌症、肺癌、甲状腺癌、子宫癌、食管癌、卵巢癌、肝细胞癌、胶质母细胞癌或胃癌。
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