WO2019196937A1 - 选择性jak2抑制剂及其应用 - Google Patents

选择性jak2抑制剂及其应用 Download PDF

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WO2019196937A1
WO2019196937A1 PCT/CN2019/082496 CN2019082496W WO2019196937A1 WO 2019196937 A1 WO2019196937 A1 WO 2019196937A1 CN 2019082496 W CN2019082496 W CN 2019082496W WO 2019196937 A1 WO2019196937 A1 WO 2019196937A1
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cancer
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李洪林
徐玉芳
赵振江
朱丽丽
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East China University of Science and Technology
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East China University of Science and Technology
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Priority to US17/046,996 priority Critical patent/US20210179598A1/en
Priority to KR1020207032819A priority patent/KR20210023814A/ko
Priority to JP2020556321A priority patent/JP2021521214A/ja
Priority to EP19784682.7A priority patent/EP3782993A4/en
Priority to CN201980025717.2A priority patent/CN112119070B/zh
Publication of WO2019196937A1 publication Critical patent/WO2019196937A1/zh
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Definitions

  • R 4 is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, C 1 -C 10 acyl;
  • R 1 and R 3 have the same definitions as before;
  • the MDS/MPN comprises chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, atypical chronic myeloid leukemia, and unclassified MDS/MPN-U (eg, refractory anemia with toroidal iron) Granulocyte and thrombocytosis (RARS-T)).
  • chronic myelomonocytic leukemia juvenile myelomonocytic leukemia
  • atypical chronic myeloid leukemia eg, and unclassified MDS/MPN-U (eg, refractory anemia with toroidal iron) Granulocyte and thrombocytosis (RARS-T)
  • RARS-T Granulocyte and thrombocytosis
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • the compounds of the present invention can be prepared according to conventional routes or methods, or can be obtained according to the methods or routes described herein. For example, route 1 or route 2.

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Abstract

一种选择性JAK2抑制剂及其应用。具体而言，涉及下式I所示化合物及所述化合物在治疗JAK2介导的相关疾病以及制备治疗JAK2介导的相关疾病的药物中的用途。

Description

选择性JAK2抑制剂及其应用 技术领域
本发明涉及药物化学领域；具体来说本发明涉及JAK2抑制剂及其应用。
背景技术
JAKs(Janus kinase)是一种胞质内非受体型可溶性蛋白酪氨酸激酶。JAKs家族共有四个家族成员，分别是JAKl、JAK2、JAK3和TYK2(Tyrosine kinase)，在生物体内JAK1，JAK2，TYK2三者广泛存在于各种组织和细胞中，而JAK3主要表达在造血组织。其中，JAK2由1132个氨基酸组成，相对分子质量为13493，其编码基因位于9号染色体短臂2区4带。JAK2从N末端到C端依次由7个不同长度的JAK同源区(JAK homology，JH)构成，C端有两个同源激酶域JH1和JH2；N端有五个同源区域JH3-JH7。JH1位于羧基末端，是JAK2的催化活性区，具有酪氨酸激酶活性；JH2无激酶活性，其功能为抑制JH1的作用；JH3-JH7能介导JAK2与细胞因子受体的结合。
信号转导和转录激活蛋白(Signal transducers and activators of transcriptions，STAT)起源于对INF-γ信号转导研究，是JAK激酶的下游底物，其通过将信号直接传递到核内，发挥对特定基因表达的调节功能。JAK-STAT是Janus激酶-细胞信号转导及转录活化因子通路，是当前细胞因子研究领域的热点。在多种生理过程如细胞生长、分化、免疫功能和造血等起着重要作用。JAK-STAT信号传导通常包括四个过程：①细胞因子与其相应配体进行结合，诱导受体二聚化；②受体与JAKs发生聚集，使得邻近的JAKs相互发生磷酸化进而被活化；③JAKs的JH1结构域催化STATs上相应部位的酪氨酸残基磷酸化，与此同时STATs的SH2功能区与受体中磷酸化的酪氨酸残基发生相互作用进而使STATs活化；④STATs以同源或异源二聚化、多聚化形式进入核内同其他转录因子相互作用从而调控基因转录，完成细胞因子介导的信号转到全过程。
JAK-STAT信号通路其功能缺失会使细胞因子无法通过受体传递信号，造成免疫缺陷。在许多恶性实体瘤，如结肠癌、头颈部癌、肺癌、乳腺癌和一些血液性疾病如白血病、淋巴瘤、多发性骨髓瘤中，都发现有JAK2的持续性活化。JAK激酶是一类非常重要的药物靶点，针对这一靶点而研发的JAK抑制剂主要用于筛选血液系统疾病、肿瘤、类风湿性关节炎及银屑病等治疗药物。迄今为止，已有31种激酶抑制剂获得FDA批准用于临床，JAK激酶抑制剂tofacitinib和Jakafi(ruxolitinib)分别用于临床治疗类风湿关节炎和骨髓纤维化。
JAK2抑制剂通过影响JAK2-STAT通路来降低一些炎症反应细胞因子从而影响其产物的调控，达到临床效果。利用JAK2抑制剂的研制不仅对骨髓纤维化的治疗意义重大，而且一些JAK2抑制剂将取代传统药物，为骨髓增殖性肿瘤的治疗开辟新途径。上述针免疫炎症和骨髓增殖癌治疗的JAK2抑制剂的研究都取得了较好的结果，但在临床研究中其安全性还有待进一步评价，而且有些抑制剂的选择性不高，对多种靶点都会产生影响，造成副作用，因此对于具有高选择性、高效的靶向JAK2抑制剂的研究是十分重要的。
综上所述，研究开发靶向于JAK2激酶的小分子抑制剂具有重要的临床意义和应用前景。
发明内容
本发明的目的在于设计合成一种高效、高选择性、毒性低，安全性好的JAK2抑制剂。
本发明第一方面提供了式I所示的化合物或其立体异构体或光学异构体，或其药学上可接受的盐、前药或溶剂化物，
Figure PCTCN2019082496-appb-000001
式中
R 1选自下组：氢、卤素、C 1-C 10烷基、卤代C 1-C 10烷基、C 1-C 10烷氧基、卤代C 1-C 10烷氧基、取代或未取代的苯基、取代或未取代的苄基、取代或未取代的5元或6元杂环、取代或未取代的9元或10元杂环、-NR 5(R 6)；所述取代是指上述基团被氧代(＝O)或者上述基团上的一个或多个氢原子被选自下组的基团所取代：C1-C4烷基(较佳地甲基)、氰基、-R 7-O-R 8、取代或未取代的含有一个或两个选自氮、氧或硫的杂原子的四至六元环基；
R 5选自下组：氢、C1-C4烷基、卤代C1-C4烷基；R 6选自下组：C 1-C 10烷基、卤代C 1-C 10烷基、取代或未取代的苯基、取代或未取代的苄基、取代或未取代的5元或6元杂环、取代或未取代的9元或10元杂环；其中，所述取代是指上述基团上的一个或多个氢原子被选自下组的基团所取代：C1-C4烷基、氰基、卤素；
R 7为无或取代或未取代的C1-C6亚烷基；R 8选自下组：C1-C6烷基、卤代C1-C6烷基、取代或未取代的含有一个或两个选自氮、氧或硫的杂原子的四至六元环基、取代或未取代的含有一个或两个选自氮、氧或硫的杂原子的四至六元环基-C1-C4烷基；
R 2选自下组：取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的嘧啶或取代或未取代的C 5-C 7环烷基；所述取代是指上述基团上的一个或多个氢原子被选自下组的基团所取代：氢、卤素、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基、卤代C 1-C 3烷氧基；
R 3选自下组：氢、卤素、C 1-C 10烷基、卤代C 1-C 10烷基、羟基、C 1-C 10烷氧基；
R 4选自下组：氢、C 1-C 10烷基、C 1-C 10酰基；
X选自下组：CH 2、O、NH、S、SO、SO 2；
除非特别说明，上述取代是指基团(如，C1-C6亚烷基、含有一个或两个选自氮、氧或硫的杂原子的四至六元环基、含有一个或两个选自氮、氧或硫的杂原子的四至六元环基-C1-C4烷基)中一个或多个氢被选自下组的基团所取代：C1-C4烷基、C1-C4卤代烷基、氰基、卤素。
在另一优选例中，所述化合物如式II所示：
Figure PCTCN2019082496-appb-000002
式中
R 1和R 3的定义同前；
R 2’选自下组：氢、卤素、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基、卤代C 1-C 3烷氧基；
X选自下组：O、NH、S；
n为1、2、3或4。
在另一优选例中，X选自下组：O、S。
在另一优选例中，R 3为甲基。
在另一优选例中，所述5元或6元杂环或所述9元或10元杂环含至少一个氮杂原子。
在另一优选例中，所述5元或6元杂环或所述9元或10元杂环含1、2或3个选自氮、氧或硫的杂原子。
在另一优选例中，所述5元或6元杂环或所述9元或10元杂环仅含1、2或3个杂原子，且所述杂原子为氮。
在另一优选例中，所述9元或10元杂环含1、2或3个氮杂原子。
在另一优选例中，所述5元或6元杂环仅含1、2或3个杂原子，且所述杂原子为氮。
在另一优选例中，所述9元或10元杂环为稠环。
在另一优选例中，所述5元或6元杂环选自下组：吡咯、吡唑、吡啶。
在另一优选例中，所述9元或10元杂环选自下组：
Figure PCTCN2019082496-appb-000003
Figure PCTCN2019082496-appb-000004
在另一优选例中，R 1选自下组：取代或未取代的5元或6元杂环；其中，所述取代是指上述基团上的一个或多个氢原子被选自下组的基团所取代：C1-C4烷基(较佳地甲基)、氰基、-R 7-O-R 8、含有一个或两个选自氮、氧或硫的杂原子的饱和四至六元环；其中，R 7为C1-C6亚烷基(较佳地，为C1-C6直链亚烷基)；R 8选自下组：C1-C6烷基、卤代C1-C6烷基。
在另一优选例中，R 1选自下组：
Figure PCTCN2019082496-appb-000005
在另一优选例中，所述含有一个或两个选自氮、氧或硫的杂原子的四至六元环为
Figure PCTCN2019082496-appb-000006
其中，R 10选自：NH 2、氧、硫；R 9选自：N、CH。
在另一优选例中，所述含有一个或两个选自氮、氧或硫的杂原子的四至六元环选自下组： 哌啶、哌嗪、吗啉、氧杂环丁烷、四氢呋喃。
在另一优选例中，
Figure PCTCN2019082496-appb-000007
为选自下组的基团：
Figure PCTCN2019082496-appb-000008
其中，R 2’的定义同前。
在另一优选例中，所述化合物选自下组：
Figure PCTCN2019082496-appb-000009
Figure PCTCN2019082496-appb-000010
Figure PCTCN2019082496-appb-000011
本发明第二方面提供了一种药物组合物，所述药物组合物含有第一方面所述的化合物或其立体异构体或光学异构体，或其药学上可接受的盐、前药或溶剂化物，以及药学上可接受的载体或赋形剂。
本发明第三方面提供了第一方面所述的化合物或其立体异构体或光学异构体，或其药学上可接受的盐、前药或溶剂化物的用途，用于制备用于预防或治疗JAK2介导的疾病的药物；和/或用于制备JAK2抑制剂。
在另一优选例中，所述JAK2介导的疾病为骨髓增生异常综合征(MDS)、嗜酸粒细胞增多症、肿瘤、炎性疾病或细菌、病毒或真菌引起的感染。
在另一优选例中，所述肿瘤选自下组：骨髓增殖癌(MPN)、黑色素瘤、肺癌(优选非小细胞肺癌)、肾癌、卵巢癌、前列腺癌、乳腺癌、结肠癌、骨癌、胰腺癌、皮肤癌、头颈癌、子宫癌、直肠癌、肛门癌、胃癌、睾丸癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、何杰金氏病、非何杰金淋巴瘤、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、急性髓性白血病、慢性髓性白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、小儿实体瘤、淋巴细胞性淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊轴瘤、脑干神经胶质瘤、垂体腺瘤、卡波西肉瘤、表皮样癌、鳞状细胞癌、T细胞淋巴瘤。
在另一优选例中，所述炎性疾病选自下组：类风湿性关节炎、强直性脊柱炎、自身免疫性溶血性贫血、关节炎、重症肌无力、系统性红斑狼疮、恶性贫血、多肌炎。
在另一优选例中，所述病毒选自下组：肝炎病毒(甲型、乙型和丙型)、孢疹病毒、流感病毒、腺病毒、冠状病毒、麻疹病毒、登革热病毒、脊髓灰质炎病毒、狂犬病病毒。
在另一优选例中，所述细菌选自下组：衣原体、立克次氏体、分枝杆菌、葡萄球菌、肺炎球菌、霍乱、破伤风。
在另一优选例中，所述真菌选自下组：假丝酵母、曲霉、皮炎芽酵母。
在另一优选例中，MPN分类包括慢性粒细胞白血病、真性红细胞增多症、原发性血小板增多症、原发性骨髓纤维化、慢性嗜中性白血病、慢性嗜酸性粒细胞白血病、肥大细胞增多症和未分类的MPN-U。
在另一优选例中，MDS/MPN包括慢性骨髓单核细胞白血病、幼年型骨髓单核细胞白血病、非典型慢性粒细胞白血病和未分类的MDS/MPN-U(例如难治性贫血伴环形铁粒幼细胞和血小板增多症(RARS-T))。
本发明第四方面提供了一种JAK2抑制剂，其含有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，或其药学上可接受的盐、前药或溶剂化物或第二方面所述的药物组合物。
本发明提供了一种治疗方法，所述方法包括步骤：给需要的对象施用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，或其药学上可接受的盐、前药或溶剂化物。
在另一优选例中，所述需要的对象患有JAK2介导的疾病。
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。
附图说明
图1为MXY-193手性拆分色谱图(220nm)。
图2为MXY-193手性拆分色谱图(254nm)。
具体实施方式
本发明人通过广泛而深入的研究，意外发现了一系列氨基吡啶类化合物，该类化合物能够选择性抑制JAK2激酶，从而成为研究JAK2抑制剂的小分子先导药物，进而为免疫炎症和抗肿瘤药物的发展提供基础。在此基础上完成了本发明。
除非另有定义，本文中使用的所有技术和科学术语具有与所公开的发明所属领域的技术人员的普遍理解相同的含义。为便于理解本发明，对本发明涉及的相关术语作如下定义，但本发明的范围并不限于这些具体的定义。
术语
本文中，“JAK2”是指Janus激酶2，是一种胞质内非受体型可溶性蛋白酪氨酸激酶。JAK-STAT是Janus激酶-细胞信号转导及转录活化因子通路，是当前细胞因子研究领域的热点。
本文中，“C 1-C 10烷基”指碳链长度为1-10个碳原子的饱和的支链或直链烷基，优选的烷基为1-3个碳原子的烷基。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、庚基等。
本文中，“C 5-C 7环烷基”指碳链长度为5-7个碳原子的饱和环烷基，例如环戊基、环己基等类似基团。
本文中，“C1-C6亚烷基”包括直链或支链形式的亚烷基，优选的亚烷基为含1-3个碳原子的亚烷基。亚烷基的例子包括但不限于CH 2、(CH 2) 2、(CH 2) 2、CH(CH 3)、CH(CH 3)CH 2等。
本文中，“烷氧基”指被烷基取代的氧基。优选的烷氧基是1-10个碳原子长的烷氧基，更优选为1-4个碳原子长的烷氧基。烷氧基的例子包括但不限于甲氧基、乙氧基、丙氧基等。在具体的实施方式中，烷氧基可以是取代的烷氧基，例如，卤素取代的烷氧基。在具体的实施方式中，优选卤素取代的C1-C3烷氧基。
本文所用“杂环基”或“杂环”包括但不限于含有1-3个选自O、S或N的杂原子的5元或6元杂环基团，包括但不限于呋喃基、噻吩基、吡咯基、吡咯烷基、吡唑基、咪唑基、三唑基、噁唑基、吡喃基、吡啶基、嘧啶基、吡嗪基、哌啶基、吗啉基、异吲哚基等。
本文中，“卤素”指氟、氯、溴和碘。在优选的实施方式中，卤素是氯或氟。
本文中，“卤代”指氟代、氯代、溴代和碘代。
活性成分
如本文所用，“本发明化合物”指式(I)所示的化合物，并且还包括及式(I)化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
如本文所用，“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸，苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。
除非特别说明，本发明所描述的结构式意在包括所有的同分异构形式(如对映异构，非对映异构和几何异构体(或构象异构体))：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体等。因此，本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒，从而互相转化。比如，质子互变异构体(即质子移变)包括通过质子迁移进行互变，如1H-吲唑与2H-吲唑。化合价互变异构体包括通过一些成键电子重组而进行互变。
“溶剂合物”是指本发明化合物与溶剂分子配位形成特定比例的配合物。
“水合物”是指本发明化合物与水进行配位形成的配合物。
药物组合物和施用方法
由于本发明化合物具有优异的JAK激酶的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗(稳定、减轻或治愈)JAK激酶相关疾病。
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及药学上可以接受的赋形剂或载体。其中“安全有效量”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10-200mg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。“相容性”在此指的是组合物中各组份能和本发明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
Figure PCTCN2019082496-appb-000012
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，如水或其它溶剂，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。
联合给药时，所述药物组合物还包括与一种或多种(2种，3种，4种，或更多种)其他药学上可接受的化合物。该其他药学上可接受的化合物中的一种或多种可与本发明的化合物同时、分开或顺序地施用。
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20～500mg。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。
制备方法
本发明的化合物可以按照常规路线或方法制备得到，也可以按照本文中描述的方法或路线获得。例如路线1或路线2。
合成路线1：
Figure PCTCN2019082496-appb-000013
合成路线2：
Figure PCTCN2019082496-appb-000014
本发明的主要优点在于：
1.本发明的化合物结构新颖且具有优异的JAK激酶抑制剂作用；
2.本发明的化合物对于JAK1的选择抑制性更好。
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，否则百分比和份数是重量百分比和重量份数。以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
本文中，“reflux”表示回流。
实施例1 制备化合物WWQ-131
1)1-(2-氯-5-氟苯基)乙醇的合成
Figure PCTCN2019082496-appb-000015
将原料(1g,5.8mmol)放于50mL反应瓶中，无水甲醇溶解，氩气保护，冰浴搅拌30分钟后，缓慢加入NaBH 4(331mg,8.7mmol)，逐渐升至室温，在室温下搅拌，TLC跟踪点板，6小时反应完成，在冰浴下加水淬灭，旋掉甲醇，加DCM和水萃取三遍，有机相用饱和食盐水萃取三遍，收集有机相，加无水硫酸钠干燥，抽滤，旋干有机相，得到无色油状液体，960mg，产率为95％。 1H NMR(400MHz,CDCl 3):δ7.25(dd,J 1＝2.4Hz,J 2＝6.8Hz,1H),7.20(dd,J 1＝4.0Hz,J 2＝5.2Hz,1H),6.83(td,J 1＝2.8Hz,J 2＝8.4Hz,1H),5.15(q,J＝6.4Hz,1H),2.06(s,1H),1.39(d,J＝6.4Hz,3H).GC-MS:m/z:174.1.
2)3-羟基-5-溴-2-硝基吡啶
Figure PCTCN2019082496-appb-000016
将3-羟基-5-溴-吡啶(25g,0.145mol)放于250mL反应瓶中，浓硫酸50mL溶解，冰浴搅拌30分钟后，缓慢滴加浓硝酸(19.5g,0.201mol)，逐渐升至室温，在室温下搅拌，TLC跟踪点板，6小时反应完成，将反应液缓慢滴加到在冰水中，析出白色固体，抽滤，滤饼用水洗涤3次，红外烘箱烘干，得到白色固体，21.5g，产率为68.25％。 1H NMR(400MHz,CDCl 3):δ10.28(s,1H),8.24(d,J＝2.0Hz,1H).GC-MS:m/z:218.1.
3)3-[1-(2-氯-5-氟苯基)乙氧基]-5-溴-2-硝基吡啶
Figure PCTCN2019082496-appb-000017
称取1-(2-氯-5-氟苯基)乙醇(2.20g,12.6mmol)，3-羟基-5-溴2-硝基吡啶(2.75g,12.6mmol)，三苯基膦(3.97g,15.1mmol)于50mL两口瓶中，加入THF使其溶解。氩气保护，在冰浴搅拌下缓慢滴加DIAD(3.06g,15.1mmol)，滴毕，升温至室温，TLC跟踪点板，反应4小时后，反应完成，硅胶柱层析(PE to PE:EA＝100:1)，得到白色固体4.232g，产率为89.5％。 1H NMR(400MHz,CDCl 3):δ8.11(d,J＝2.0Hz,1H),7.40(dd,J 1＝4.8Hz,J 2＝8.4Hz,1H),7.38(d,J＝1.6Hz,1H),7.24(dd,J 1＝2.8Hz,J 2＝8.8Hz,1H),7.03-6.99(m,1H),5.78(q,J＝6.4Hz,1H),1.69(d,J＝ 6.0Hz,3H)。GC-MS:m/z＝375.9。
4)3-[1-(2-氯-5-氟苯基)乙氧基]-5-溴-2-氨基吡啶
Figure PCTCN2019082496-appb-000018
称取3-[1-(2-氯-5-氟苯基)乙氧基]-5-溴-2-硝基吡啶(4.232g,11.3mmol)，铁粉(1.58g,28.2mmol)放入100mL反应瓶中，加乙醇和醋酸(1:1)使其溶解，78℃回流，TLC跟踪点板，3小时反应完成，旋干，加NaOH调节pH至碱性，将固体抽滤，滤液用DCM/H 2O萃取三遍，有机相用饱和食盐水萃取三遍，无水硫酸钠干燥，抽滤，滤液旋干，硅胶柱层析(DCM)。得到乳白固体3.735g，产率为96.25％。 1H NMR(400MHz,CDCl 3):δ7.68(d,J＝1.6Hz,1H),7.38(dd,J 1＝4.8Hz,J 2＝8.8Hz,1H),7.09(dd,J 1＝3.2Hz,J 2＝9.2Hz,1H),7.00-6.95(m,1H),6.70(d,J＝1.6Hz,1H),5.59(q,J＝6.4Hz,1H),4.86(s,1H),1.66(d,J＝6.4Hz,3H)。GC-MS:m/z＝345.9。
5)4-{3-[1-(2-氯-5-氟苯基)乙氧基]-2-氨基吡啶}吡唑-1-羧酸叔丁基酯哌啶
Figure PCTCN2019082496-appb-000019
称取3-[1-(2-氯-5-氟苯基)乙氧基]-5-溴-2-氨基吡啶(3.735g,10.8mmol),4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基]哌啶-1-甲酸叔丁酯(4.915g,13.0mmol)，碳酸铯(12.382g,38.0mmol)加入到100mL三口瓶中，加甲苯和水(10:1)使其溶解，进行氩气除氧20分钟，加入Pd催化剂再除氧10分钟，在氩气保护下，80℃回流搅拌，TLC跟踪点板，12小时反应完成，旋干，硅胶柱层析(DCM：MeOH＝100:1)，得到黄色油状液体4.76g，收率为85％。 1H NMR(400MHz,CDCl 3):δ7.75(d,J＝1.6Hz,1H),7.53(s,1H),7.46(s,1H),7.37(dd,J 1＝5.6Hz,J 1＝8.8Hz,1H),7.15(dd,J 1＝3.2Hz,J 2＝9.2Hz,1H),6.97-6.92(m,1H),6.75(d,J＝1.6Hz,1H),5.70(q,J＝6.0Hz,1H),4.84(s,2H),4.27-4.21(m,1H),2.89(t,J＝12.0Hz,2H),2.12(dd,J 1＝2.0Hz,J 2＝12.4Hz,2H),1.96-1.89(m,4H),1.68(d,J＝6.4Hz,3H),1.48(s,9H)。
6)4-{3-[1-(2-氯-5-氟苯基)乙氧基]-2-氨基吡啶}吡唑-1-哌啶WWQ-131
Figure PCTCN2019082496-appb-000020
称取4-{3-[1-(2-氯-5-氟苯基)乙氧基]-2-氨基吡啶}吡唑-1-羧酸叔丁基酯哌啶(4.76g,9mmol)，加入DCM使其溶解，在冰浴下滴加三氟乙酸(12mL)，滴毕，升温至室温，TLC跟踪点板，12小时显示反应完成，用饱和NaHCO 3中和至碱性，用DCM/H 2O萃取三遍，有机相用饱和食盐水萃取三遍，无水硫酸钠干燥，抽滤，滤液旋干，二氯甲烷和石油醚重结晶，抽滤， 得到白色固体2.20g，产率为57.44％。 1H NMR(400MHz,CDCl 3):δ7.78(s,1H),7.54(s,1H),7.48(s,1H),7.37(dd,J 1＝4.8Hz,J 2＝8.8Hz,1H),7.15(dd,J 1＝3.2Hz,J 2＝9.2Hz,1H),6.96-6.91(m,1H),6.74(d,J＝1.6Hz,1H),5.70(q,J＝6.0Hz,1H),4.79(s,2H),4.26-4.21(m,1H),3.31(d,J＝12.4Hz,2H),3.05(m,2H),2.87-2.80(m,2H),2.19(d,J＝10.8Hz,2H),2.03-1.94(m,2H),1.67(d,J＝6.4Hz,3H)。 13C NMR(100MHz,CDCl 3):δ148.6,141.8,139.9,135.9,131.1,126.2,122.7,119.9,119.3,116.6,116.4,115.8,113.8,113.5,72.5,58.8,44.9,32.8,22.6.HRMS(ESI)(m/z):[M+H] +计算值C 21H 23ClFN 5O,416.1609；实测值,416.1649。HPLC纯度:98.63％,保留时间＝9.925min.
实施例2 制备WWQ-133
1)3-[1-(2,6-二氯苯基)乙氧基]-2-硝基吡啶
Figure PCTCN2019082496-appb-000021
称取原料1-(2,6-二氯苯基)乙醇(1g,5.23mmol)，3-羟基-2-硝基吡啶(807mg,5.75mmol)，三苯基膦(1.647g,6.27mmol)于50mL两口瓶中，加入THF使其溶解。氩气保护，在冰浴搅拌下缓慢滴加DIAD(1.236mL,6.27mmol)，滴毕，升温至室温，TLC跟踪点板，反应4小时后，反应完成，硅胶柱层析(PE:EA＝50:1)，得到白色固体804mg，产率为48.5％。 1H NMR(400MHz,CDCl 3):δ8.01(dd,J 1＝1.2Hz,J 2＝3.2Hz,1H),7.36-7.33(m,1H),7.32(s,1H),7.30(s,1H),7.23(dd,J＝0.8,7.6Hz,1H),7.18(t,J＝8.0Hz,1H),6.13(q,J＝6.4Hz,1H),1.85(d,J＝6.8Hz,3H)。GC-MS:m/z＝312.1。
2)3-[1-(2,6-二氯苯基)乙氧基]-2-氨基吡啶
Figure PCTCN2019082496-appb-000022
称取3-[1-(2,6-二氯苯基)乙氧基]-2-硝基吡啶(804mg,2.56mmol)，铁粉(360mg,6.41mmol)放入50mL两口瓶中，加EtOH使其溶解，90℃下回流30分钟后加入HCl。TLC跟踪点板，反应完成，旋干，加NaOH调pH至碱性，用DCM/H 2O萃取三遍，有机相用饱和食盐水萃取三遍，无水硫酸钠干燥，抽滤，滤液旋干得到产物，硅胶柱层析，得到乳白色固体650mg，产率为89.9％。 1H NMR(400MHz,CDCl 3):δ7.58(d,J＝4.4Hz,1H),7.29(d,J＝8Hz,2H),7.14(t,J＝8Hz,1H),6.73(d,J＝7.6Hz,1H),6.47(t,J＝5.2Hz,1H),6.40(q,J＝6.4Hz,1H),4.86(s,2H),1.81(d,J＝6.8Hz,3H)。GC-MS:m/z＝282.0。
3)3-[1-(2,6-二氯苯基)乙氧基]-5-溴-2-氨基吡啶
Figure PCTCN2019082496-appb-000023
将上步产物(650mg,2.30mmol)放入50mL两口瓶中，加入AcOH(10mL)使其溶解，氩气 保护，在冰浴下滴加BR 2(436mg,2.76mmol)，滴毕，升温至室温，TLC跟踪点板，2小时反应完成，得到黄色固体480mg，产率为57.9％。 1H NMR(400MHz,CDCl 3):δ7.55(d,J＝2.0Hz,1H),7.34(s,1H),7.32(s,1H),7.18(t,J＝8.0Hz,1H),6.86(d,J＝2.0Hz,1H),6.02(q,J＝6.8Hz,1H),5.53(s,2H),1.83(d,J＝6.8Hz,3H)。GC-MS:m/z＝360.1。
4)4-{3-[1-(2,6-二氯苯基)乙氧基]-2-氨基吡啶}吡唑-1-羧酸叔丁基酯哌啶
Figure PCTCN2019082496-appb-000024
称取溴代产物(450mg,1.25mmol)，4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基]哌啶-1-甲酸叔丁酯(565mg,1.5mmol)，碳酸铯(1.425g,4.38mmol)加入到50mL三口瓶中，加甲苯10mL和水1mL溶解，除氧20分钟，再加入Pd催化剂，继续除氧10分钟，在氩气保护下，80℃回流搅拌，TLC跟踪点板，12小时反应完成，旋干，硅胶柱层析(DCM:MeOH＝100:1)，得到乳白色固体260mg，产率为39.1％。 1H NMR(400MHz,CDCl 3):δ7.72(d,J＝2.0Hz,1H),7.56(s,1H),7.49(s,1H),7.32(s,1H),7.30(s,1H),7.15(t,J＝8.0Hz,1H),6.90(d,J＝1.6Hz,1H),6.10(q,J＝6.8Hz,1H),4.88(s,2H),4.28-4.21(m,1H),2.90(t,J＝11.2Hz,2H),2.13(d,J＝10.0Hz,2H),2.04(m,2H),1.93(td,J 1＝4.0Hz,J 2＝12.0Hz,2H),1.85(d,J＝6.8Hz,3H),1.48(s,9H)。LC-MS:m/z:532.1(M+H) +。
5)4-{3-[1-(2,6-二氯苯基)乙氧基]-2-氨基吡啶}吡唑-1-哌啶WWQ-133
Figure PCTCN2019082496-appb-000025
称取上步产物(246mg,0.463mmol)，加入DCM使其溶解，在冰浴下滴加三氟乙酸(2mL)，滴毕，升温至室温，TLC跟踪点板，3小时显示反应完成，用饱和NaHCO 3中和至碱性，用DCM/H 2O萃取三遍，有机相用饱和食盐水萃取三遍，无水硫酸钠干燥，抽滤，滤液旋干，硅胶柱层析(DCM:MeOH＝50:1)，得到白色固体91mg，产率为45.5％。 1H NMR(400MHz,CDCl 3):δ7.48(d,J＝2.0Hz,1H),7.57(s,1H),7.51(s,1H),7.32(s,1H),7.30(s,1H),7.14(t,J＝8.0Hz,1H),6.90(d,J＝1.6Hz,1H),6.10(q,J＝6.8Hz,1H),4.79(s,2H),4.25-4.17(m,1H),3.27(d,J＝12.8Hz,2H),2.79(td,J 1＝2.4Hz,J 2＝12.4Hz,2H),2.19-2.12(m,2H),1.96-1.89(m,2H),1.86(d,J＝6.4Hz,3H)。 13C NMR(100MHz,CDCl 3):δ148.96,140.0,135.7,135.3,135.0,134.5,129.6,122.5,120.1,119.2,115.1,72.3,59.4,45.4,33.5,19.0.HRMS(ESI)(m/z):[M+H] +计算值C 21H 23Cl 2N 5O,432.1373；实测值,432.1361.HPLC纯度:97.82％,保留时间＝9.935min.
实施例3 制备WWQ-153(按类似实施例的方法合成WWQ系列化合物)
4-{3-[1-(2,6-二氯-3-氟苯基)甲氧基]-2-氨基吡啶}吡唑-1-哌啶
Figure PCTCN2019082496-appb-000026
得到白色固体43mg，产率为45.1％，熔点：195.0-196.5℃。 1H NMR(400MHz,CDCl 3):δ7.87(d,J＝2.0Hz,1H),7.67(s,1H),7.60(s,1H),7.52(dd,J 1＝2.8Hz,J 2＝6.4Hz,1H),7.39(dd,J 1＝2.4Hz,J 2＝5.6Hz,1H),7.07(d,J＝1.6Hz,1H),5.15(s,2H),4.69(s,2H),4.28-4.21(m,1H),3.26(d,J＝12.8Hz,2H),2.78(td,J 1＝2.0Hz,J 2＝12.4Hz,2H),2.19(dd,J 1＝2.0Hz,J 2＝12.4Hz,2H),1.98-1.88(m,2H),1.83(s,1H). 13C NMR(100MHz,CDCl 3):δ153.4,148.6,140.8,136.7,135.8,130.2,129.8,127.7,126.4,126.2,122.9,122.4,119.7,115.2,63.5,59.9,45.7,34.0.HRMS(ESI)(m/z):[M+H] +计算值C 20H 20Cl 2FN 5O,436.1062；实测值,436.1100.HPLC纯度:97.76％,保留时间＝10.879min.
实施例4 制备WWQ-175
4-{3-[1-(2-氯-3氟-6-甲氧基苯基)乙氧基]-2-氨基吡啶}吡唑-1-哌啶
Figure PCTCN2019082496-appb-000027
得到白色固体97mg，收率为56.2％，熔点：189.8-191.3℃。 1H NMR(400MHz,CDCl 3):δ7.73(d,J＝1.6Hz,1H),7.53(s,1H),7.50(s,1H),7.03(t,J＝8.8Hz,1H),6.96(d,J＝2.0Hz,1H),6.76(dd,J 1＝2.8Hz,J 2＝9.2Hz,1H),6.06(q,J＝6.4Hz,2H),4.76(s,2H),4.25-4.17(m,1H),3.89(s,3H),3.26(d,J＝12.8Hz,2H),2.78(td,J 1＝2.0Hz,J 2＝12.4Hz,2H),2.17(d,J＝12.4Hz,2H),2.02(s,1H),1.96-1.85(m,2H),1.81(d,J＝6.8Hz,3H). 13C NMR(100MHz,CDCl 3):δ153.9,149.2,140.3,135.6,135.2,127.9,122.5,121.2,120.1,119.7,115.7,115.4,110.1,77.3,59.8,56.4,45.7,34.0,19.3.HRMS(ESI)(m/z):[M+H] +计算值C 22H 25ClFN 5O 2,446.1714；实测值,446.1735.HPLC纯度:96.00％,保留时间＝10.530min.
实施例5 WWQ-189(以(S)-1-(2,6-二氯-3-氟苯基)乙醇为原料进行制备)
(R)-5-[1-(2,6-二氯-3-氟苯基)乙氧基]-[3,3'-二吡啶]-6-胺
Figure PCTCN2019082496-appb-000028
得到棕色固体83mg，收率为55.6％，熔点：158.8-159.8℃。 1H NMR(400MHz,CDCl 3):δ8.55(s,1H),8.55(d,J＝4.0Hz,1H),7.88(s,1H),7.69-7.66(m,1H),7.34-7.30(m,2H),7.07(t,J＝8.0Hz,1H),6.98(d,J＝2.0Hz,1H),6.13(q,J＝6.8Hz,1H),5.05(s,2H),1.88(d,J＝6.8Hz,3H). 13C NMR(100MHz,CDCl 3):δ150.1,148.1,147.3,140.0,136.6,136.2,134.4,133.8,133.3,130.0, 129.0,123.7,123.6,122.2,122.0,117.0,116.8,115.7,72.8,18.9.HRMS(ESI)(m/z):[M+H] +计算值C 18H 14Cl 2FN 3O,378.0532；实测值,378.0570.HPLC纯度:95.50％,保留时间＝10.510min.
实施例6 WWQ-191(以(S)-1-(2,6-二氯-3-氟苯基)乙醇为原料制备)
(R)-5-[1-(2,6-二氯-3-氟苯基)乙氧基]-6'-哌嗪-[3,3'-二吡啶]-6-胺
Figure PCTCN2019082496-appb-000029
得到浅褐色固体78mg，收率为46.0％，熔点：197.8-198.5℃。 1H NMR(400MHz,CDCl 3):δ8.23(s,1H),7.78(s,1H),7.50(d,J＝8.4Hz,1H),7.32-7.28(m,2H),7.05(t,J＝8.4Hz,1H),6.92(s,1H),6.67(d,J＝8.4Hz,1H),6.11(q,J＝6.4Hz,1H),4.84(s,2H),3.56(s,4H),3.03(s,4H),1.86(d,J＝6.4Hz,3H). 13C NMR(100MHz,CDCl 3):δ158.6,149.3,145.3,139.9,137.0,136.4,135.3,129.0,124.6,123.7,122.1,121.9,116.8,116.6,115.2,107.0,72.4,46.3,45.8,18.9.HRMS(ESI)(m/z):[M+H] +计算值C 22H 22Cl 2FN 5O,462.1219；实测值,462.1265.HPLC纯度:97.82％,保留时间＝9.935min.
实施例7 WWQ-197
4-{3-[1-环己烷乙氧基]-2-氨基吡啶}吡唑-1-哌啶
Figure PCTCN2019082496-appb-000030
得到黄色固体78mg，收率为52.3％，熔点：192.2-193.4℃。 1H NMR(400MHz,CDCl 3):δ7.77(d,J＝2.0Hz,1H),7.66(s,1H),7.59(s,1H),6.96(d,J＝1.6Hz,1H),4.64(s,2H),4.27-4.17(m,2H),3.26(d,J＝12.8Hz,2H),2.78(td,J 1＝2.4Hz,J 2＝12.8Hz,2H),2.19(dd,J 1＝2.4Hz,J 2＝12.4Hz,2H),1.81-1.62(m,4H),1.28(d,J＝6.8Hz,3H),1.24-1.05(m,4H). 13C NMR(100MHz,CDCl 3):δ149.6,140.9,135.9,135.2,122.8,120.2,119.5,115.6,78.5,59.8,45.7,43.2,34.0,28.9,28.5,26.5,26.1,16.5.HRMS(ESI)(m/z):[M+H] +计算值C 21H 31N 5O,370.2562；实测值,370.2601.HPLC纯度:95.58％,保留时间＝10.841min.
实施例8 制备WWQ-1093-13
4-{3-[1-(2,6-二氯-3氟苯基)丙氧基]-2-氨基吡啶}吡唑-1-哌啶
Figure PCTCN2019082496-appb-000031
得到浅黄色固体110mg，收率为60.2％，熔点：196.6-197.1℃。 1H NMR(400MHz,CDCl 3): δ7.78(s,1H),7.56(s,1H),7.49(s,1H),7.34(dd,J 1＝2.4Hz,J 2＝6.0Hz,1H),7.25(dd,J 1＝2.8Hz,J 2＝5.6Hz,1H),6.79(s,1H),5.41(t,J＝6.4Hz,1H),4.74(s,2H),4.26-4.20(m,1H),3.30(d,J＝12.8Hz,2H),2.80(t,J＝12.0Hz,2H),2.44(s,1H),2.23(d,J＝10.8Hz,2H),2.09-1.92(m,4H),1.05(t,J＝7.2Hz,3H)。 13C NMR(100MHz,CDCl 3):δ148.8,139.9,136.3,130.2,129.9,125.5,122.8,119.7,119.5,115.6,74.4,59.5,45.4,33.5,29.9,9.8.HRMS(ESI)(m/z):[M+H] +计算值C 22H 24Cl 2FN 5O,464.1375；实测值,464.1418.HPLC纯度:96.85％,保留时间＝11.222min.
实施例9 制备WWQ-1093-23
(R)-5-[1-(2,6-二氯-3-氟苯基)乙氧基]-5'-哌嗪-[3,3'-二吡啶]-6-胺
Figure PCTCN2019082496-appb-000032
得到白色固体36mg，收率为49.2％，熔点：189.7-190.6℃。 1H NMR(400MHz,CDCl 3):δ8.22(d,J＝2.4Hz,1H),8.13(d,J＝2.0Hz,1H),7.86(d,J＝1.6Hz,1H),7.30(dd,J 1＝4.8Hz,J 2＝8.8Hz,1H),7.09-7.04(m,2H),6.93(d,J＝2.4Hz,1H),6.10(q,J＝6.4Hz,1H),4.96(s,2H),3.25-3.22(m,4H),3.11-3.08(m,4H),2.30(s,1H),1.87(d,J＝6.8Hz,3H). 13C NMR(100MHz,CDCl 3):δ149.1,142.2,140.6,135.9,135.6,128.9,128.0,125.4,122.8,120.1,119.3,116.7,77.2,59.2,45.2,33.2,24.3.HRMS(ESI)(m/z):[M+H] +计算值C 22H 22Cl 2FN 5O,462.1219；实测值,462.1268.HPLC纯度:91.95％,保留时间＝9.311min.
实施例10 制备WWQ-1093-25
4-[3-(1-苯基丙氧基)-2-氨基吡啶]吡唑-1-哌啶
Figure PCTCN2019082496-appb-000033
得到浅黄色固体56mg，收率为53.4％，熔点：194.2-195.0℃。 1H NMR(400MHz,CDCl 3):δ7.74(d,J＝1.6Hz,1H),7.48(s,1H),7.44(s,1H),7.37-7.34(m,4H),7.31-7.29(m,1H),6.83(d,J＝1.6Hz,1H),5.34(q,J＝6.4Hz,1H),4.74(s,2H),4.25-4.18(m,1H),3.28(d,J＝12.0Hz,2H),2.80(t,J＝11.6Hz,2H),2.62(s,1H),2.16(d,J＝11.2Hz,2H),1.94(q,J＝3.2Hz,2H),1.69(d,J＝2.4Hz,3H). 13C NMR(100MHz,CDCl 3):δ149.1,142.2,140.6,135.9,135.6,128.9,128.0,122.8,120.1,119.3,116.7,77.2,59.2,45.2,33.2,24.3.HRMS(ESI)(m/z):[M+H] +计算值C 21H 25N 5O,364.2093；实测值,364.2133.HPLC纯度:95.93％,保留时间＝9.597min.
实施例11 制备WWQ-1093-27
4-{3-[1-(2,6-二氯-3氟苯基)乙氧基]-2-氨基吡啶}吡唑-1-吗啉
Figure PCTCN2019082496-appb-000034
得到浅棕色固体37mg，收率为53.0％，熔点：188.1-190.4℃。 1H NMR(400MHz,CDCl 3):δ7.74(d,J＝2.0Hz,1H),7.58(s,1H),7.51(s,1H),7.31(dd,J＝4.8Hz,1H),7.06(t,J＝8Hz,1H),6.89(d,J＝1.6Hz,1H),6.08(q,J＝6.8Hz,1H),4.98(s,2H),4.38-4.31(m,1H),4.12(d,J＝11.6Hz,2H),3.56(td,J 1＝3.2Hz,J 2＝11.6Hz,2H),2.12-2.08(m,4H),1.87(d,J＝6.8Hz,3H). 13C NMR(100MHz,CDCl 3):δ140.2,136.6,136.5,135.8,132.5,122.7,119.4,119.1,117.1,116.8,115.6,77.2,66.8,58.3,33.4,29.7,24.9,18.9.HRMS(ESI)(m/z):[M+H] +计算值C 21H 21Cl 2FN 4O 2,451.1059；实测值,451.1100.HPLC纯度:99.22％,保留时间＝12.897min.
实施例12 制备WWQ-1093-65
4-{3-[1-(2,6-二氯-3氟苯基)乙氧基]-2-氨基吡啶}吡唑-1-哌啶
Figure PCTCN2019082496-appb-000035
得到白色固体41mg，收率为50.3％，熔点：189.6-190.9℃。 1H NMR(400MHz,CDCl 3):δ7.94(s,1H),7.78(s,1H),7.58(s,2H),7.45(s,1H),6.91(s,1H),6.09(d,J＝2.4Hz,1H),5.77(s,1H),5.70(s,2H),4.39(s,1H),2.95(t,J＝3.6Hz,2H),2.11-2.04(m,4H),1.80(d,J＝6.4Hz,3H),0.84(t,J＝2.4Hz,2H). 13C NMR(100MHz,CDCl 3):δ148.9,139.8,136.9,135.6,135.5,129.0,128.9,122.5,119.9,119.3,116.8,116.6,114.9,72.4,59.8,45.7,33.9,18.9.HRMS(ESI)(m/z):[M+H] +计算值C 21H 22Cl 2FN 5O,450.1219；实测值,450.1260.HPLC纯度:97.77％,保留时间＝10.460min.
实施例13 制备化合物WWQ-1093-71
Figure PCTCN2019082496-appb-000036
得到黄色固体27mg，收率为35.1％，熔点：191.6-192.3℃。 1H NMR(400MHz,DMSO-d 6):δ7.98(s,1H),7.76(d,J＝2.0Hz,1H),7.67(s,1H),7.32(dd,J 1＝2.8,J  2＝9.6Hz,1H),7.08-7.04(m,3H),6.01(s,2H),5.82(q,J＝6.0Hz,1H),4.49-4.44(m,1H),3.89(s,3H),3.78-3.37(m,2H),3.06(td,J 1＝4.8Hz,J 2＝7.6Hz,2H),2.20-2.14(m,4H),1.56(d,J＝6.4Hz,3H),1.23(s,1H). 13C NMR(100MHz,DMSO-d 6):δ157.8,155.5,152.1,149.6,139.4,135.3,131.9,124.1,119.2,117.2,115.4,114.9,114.6,112.9,112.6,112.4,68.8,56.3,55.1,28.5,21.9.
HRMS(ESI)(m/z):[M+H] +计算值C 22H 26FN 5O 2,412.2104；实测值,412.2148.HPLC纯度:97.44％,保留时间＝10.154min
实施例14 制备WWQ-1093-73
4-{3-[1-(2,6-二氯-3氟苯基)乙氨基]-2-氨基吡啶}吡唑-1-哌啶
Figure PCTCN2019082496-appb-000037
得到浅棕色固体38mg，收率为40.2％，熔点：191.5-191.7℃。 1H NMR(400MHz,CDCl 3):δ7.78(s,1H),7.48(s,1H),7.44(s,1H),7.36(t,J＝8.8Hz,1H),6.29(d,J＝1.6Hz,1H),5.77(s,2H),5.65(d,J＝7.6Hz,1H),5.28-5.23(m,1H),4.36-4.29(m,1H),3.24(d,J＝12.8Hz,2H),2.89(t,J＝10.8Hz,2H),2.11-1.94(m,4H),1.68(d,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ146.9,139.4,134.6,131.0,128.3,123.1,120.0,117.3,110.8,58.4,43.0,30.3,18.4.HRMS(ESI)(m/z):[M+H] +计算值C 21H 23Cl 2FN 6,449.1379；实测值,449.1424.HPLC纯度:97.37％,保留时间＝10.300min。
实施例15 制备WWQ-1093-75
3-(1-(2-氯-5-氟苯基)乙氧基)-2-氨基-5-苯基吡啶
Figure PCTCN2019082496-appb-000038
得到黄色固体67mg，收率为51.7％，熔点：199.0-199.8℃。 1H NMR(400MHz,CDCl 3):δ7.89(s,1H),7.39-7.34(m,5H),7.28(d,J＝6.8Hz,1H),7.17(dd,J 1＝2.4Hz,J 2＝8.8Hz,1H),6.96-6.91(m,1H),6.88(s,1H),5.73(q,J＝6.0Hz,1H),4.91(s,2H),1.68(d,J＝6.4Hz,3H). 13C NMR(100MHz,CDCl 3):δ163.3,160.8,149.3,141.7,140.0,138.2,137.0,131.1,129.0,127.4,127.0,126.2,116.8,116.5,116.3,113.7,113.5,72.7,22.5.HRMS(ESI)(m/z):[M+H] +计算值C 19H 16ClFN 2O,343.0969；实测值,343.1011.HPLC纯度:96.54％,保留时间＝14.294min
实施例16 制备WWQ-1093-81
3-(1-(2-氯-5-氟苯基)乙氧基)-2-氨基-5-吡唑吡啶
Figure PCTCN2019082496-appb-000039
得到浅黄色固体67mg，收率为58.8％，，熔点：183.8-184.6℃。 1H NMR(400MHz,CDCl 3): δ7.80(s,1H),7.66(s,2H),7.37(d,J＝4.8Hz,1H),7.15(dd,J 1＝2.8Hz,J 2＝8.8Hz,1H),6.99-6.92(m,1H),6.77(s,1H),5.71(q,J＝6.0Hz,1H),5.06(s,2H),1.68(d,J＝6.4Hz,3H). 13C NMR(100MHz,CDCl 3):δ163.3,160.9,148.7,141.7,140.1,135.5,131.1,131.0,126.2,126.1,116.6,116.4,116.1,113.8,113.5.HRMS(ESI)(m/z):[M+H] +计算值C 16H 14ClFN 4O,333.0874；实测值,333.0919.HPLC纯度:96.37％,保留时间＝11.513min
实施例17 制备化合物WWQ-1093-83
Figure PCTCN2019082496-appb-000040
得到浅棕色固体136mg，收率为60.4％，熔点：160.4-161.4℃。 1H NMR(400MHz,CDCl 3):δ7.87(d,J＝1.6Hz,1H),7.21-7.36(m,4H),7.32-7.27(m,2H),7.06(t,J＝8.4Hz,1H),7.23(d,J＝1.6Hz,1H),6.13(q,J＝6.8Hz,1H),4.99(s,2H),1.86(d,J＝6.8Hz,3H). 13C NMR(100MHz,CDCl 3):δ149.6,139.8,138.2,136.9,136.6,130.0,129.0,128.9,127.2,126.9,126.1,122.2,122.0,116.8,116.6,116.1,72.6,18.9.HRMS(ESI)(m/z):[M+H] +计算值C 19H 15Cl 2FNO,377.0579；实测值,377.0623.HPLC纯度:99.02％,保留时间＝14.543min
实施例18 制备化合物WWQ-1093-85
Figure PCTCN2019082496-appb-000041
得到浅棕色固体45mg，收率为50.2％，熔点：191.1-193.7℃。 1H NMR(400MHz,CDCl 3):δ7.84(s,1H),7.36-7.33(m,1H),7.27(s,1H),7.25(s,1H),7.16(dd,J 1＝2.0,J  2＝8.8Hz,1H),6.92(d,J＝8.0Hz,3H),6.84(s,1H),5.71(q,J＝6.4Hz,1H),4.79(s,2H),3.17(d,J＝4.8Hz,4H),3.06(d,J＝4.8Hz,4H),2.29(s,1H),1.67(d,J＝6.4Hz,3H). 13C NMR(100MHz,CDCl 3):δ163.3,160.8,150.5,148.8,141.8,139.9,136.7,131.0,130.9,129.8,127.3,126.9,126.2,116.5,116.2,113.7,113.5,72.6,49.8,45.7,22.5.HRMS(ESI)(m/z):[M+H] +计算值C 23H 24ClFN 4O,427.1656；实测值,427.1700.HPLC纯度:96.10％,保留时间＝10.662min.
实施例19 制备化合物WWQ-1093-87
Figure PCTCN2019082496-appb-000042
得到浅棕色固体43mg，收率为54.1％，熔点：189.8-191.0℃。 1H NMR(400MHz,CDCl 3): δ7.88(s,1H),7.36(dd,J 1＝4.4Hz,J 2＝8.8Hz,1H),7.31-7.22(m,4H),7.16(d,J＝6.8Hz,1H),6.94(t,J＝7.6Hz,1H),6.88(s,1H),5.72(q,J＝6.4Hz,1H),4.87(s,2H),3.29(d,J＝12.0Hz,2H),3.06(s,1H),2.81(t,J＝8.0Hz,2H),2.66(t,J＝11.6Hz,1H),1.90-1.75(m,4H),1.67(d,J＝6.4Hz,3H). 13C NMR(100MHz,CDCl 3):δ163.2,160.8,149.3,144.4,141.8,140.0,137.2,136.4,131.0,127.3,126.6,116.6,116.5,116.3,113.7,113.4,72.6,46.3,41.9,33.0,29.7,22.5.HRMS(ESI)(m/z):[M+H] +计算值C 24H 25ClFN 3O,426.1704；实测值,426.1746.HPLC纯度:97.45％,保留时间＝10.951min.
实施例20 制备化合物WWQ-1093-89
Figure PCTCN2019082496-appb-000043
得到浅黄色固体45mg，收率为55.1％，熔点：190.8-191.6℃。 1H NMR(400MHz,CDCl 3):δ7.86(s,1H),7.36(dd,J 1＝5.2Hz,J 2＝8.8Hz,1H),7.29-7.24(m,1H),7.16(dd,J 1＝2.4Hz,J 2＝8.8Hz,1H),6.96-6.93(m,5H),5.71(q,J＝6.4Hz,1H),5.62(s,1H),4.90(s,2H),3.38(d,J＝4.4Hz,4H),3.28(d,J＝4.0Hz,4H),1.67(d,J＝6.0Hz,3H). 13C NMR(100MHz,CDCl 3):δ163.3,160.8,151.0,149.4,141.9,139.8,139.4,137.2,131.0,129.8,127.3,126.2,118.9,116.8,115.4,114.8,113.8,72.6,48.1,44.3,29.7,22.6.HRMS(ESI)(m/z):[M+H] +计算值C 23H 24ClFN 4O,427.1656；实测值,427.1700.HPLC纯度:97.55％,保留时间＝10.854min.
实施例21 制备化合物WWQ-1093-91
Figure PCTCN2019082496-appb-000044
得到浅黄色固体43mg，收率为50.3％，熔点：192.1-193.4℃。 1H NMR(400MHz,CDCl 3):δ7.87(s,1H),7.38(dd,J 1＝5.2Hz,J 2＝8.8Hz,1H),7.32(t,J＝8.4Hz,1H),7.22-7.15(m,4H),7.30(td,J 1＝2.8Hz,J 2＝8.4Hz,1H),6.86(s,1H),5.74(q,J＝6.4Hz,1H),4.90(s,2H),3.57(d,J＝8.4Hz,2H),3.00(t,J＝12.4Hz,2H),2.76(t,J＝11.6Hz,2H),2.14-2.01(m,4H),1.87(d,J＝6.4Hz,3H). 13C NMR(100MHz,CDCl 3):δ163.3,160.8,149.4,144.4,141.8,139.8,138.8,137.3,131.1,129.4,127.1,126.2,125.1,116.7,116.4,113.8,113.5,72.6,44.7,40.9,30.4,22.6.HRMS(ESI)(m/z):[M+H] +计算值C 24H 25ClFN 3O,426.1704；实测值,426.1746.HPLC纯度:95.06％,保留时间＝11.077min.
MXY系列化合物参考以下合成路线：
Figure PCTCN2019082496-appb-000045
以化合物193为例：
Figure PCTCN2019082496-appb-000046
试剂和条件:(a)NaBH 4,MeOH,0℃；(b)H 2SO 4,HNO 3,0℃；(c)PPh 3,DIAD,THF,0℃；(d)1:1CH 3COOH:CH 3CH 2OH,Fe,78℃；(e)Cs 2CO3,Pd(dppf)Cl2,甲苯,H 2O,80℃.
Figure PCTCN2019082496-appb-000047
试剂和条件:(h)Pd(OAc)2,4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(Xantphos),二氧六环,100℃,12h；(i)1:1CH 3COOH:CH 3CH 2OH,Fe,78℃.
实施例22 制备化合物MXY-89
Figure PCTCN2019082496-appb-000048
得到白色固体68mg,收率为60.8％。 1H NMR(400MHz,CDCl 3)δppm 7.89(d,J＝1.56Hz,1H),7.36(dd,J＝8.67,4.66Hz,2H),7.30(d,J＝8.24Hz,1H),7.24-7.18(m,2H),7.09-7.03(m, 2H),6.98-6.93(m,2H),5.70(q,J＝6.28Hz,1H),4.82(s,2H),3.77(s,3H),1.69(d,J＝6.35Hz,3H). 13C NMR(100MHz,DMSO-d6)δppm 162.0,149.8,142.8,139.2,137.4,137.4,137.0,131.8,126.7,126.5,125.8,121.9,120,4,119.7,119.1,117.09,114.3,112.7,110.5,72.0,32.9,22.5.HRMS(EI)m/z:计算值C 22H 19ClFN 3O 395.1201；实测值395.1198.
实施例23 制备化合物MXY-97
Figure PCTCN2019082496-appb-000049
得到浅棕色固体67mg，收率为60.8％。 1H NMR(400MHz,CDCl 3δppm 8.43(d,J＝7.03Hz,1H),7.92(s,1H),7.87(d,J＝1.57Hz,1H),7.39-7.33(m,2H),7.18(dd,J＝9.05,3.02Hz,1H),7.09-7.03(m,1H),6.99-6.93(m,1H),6.81(d,J＝1.54Hz,1H),6.74(t,J＝6.50Hz,1H),5.71(q,J＝6.29Hz,1H),4.91(s,2H),1.69(d,J＝6.35Hz,3H). 13C NMR(100MHz,DMSO-d6)δppm 161.9,150.3,142.7,139.8,139.2,137.2,136.1,131.7,129.7,126.7,124.4,117.5,117.2,177.1,116.7,114.5,112.7,109.8,71.9,22,5.HRMS(EI)m/z:计算值C 20H 16ClFN 4O 382.0097；实测值382.0998.
实施例24 制备化合物MXY-111
Figure PCTCN2019082496-appb-000050
得到白色固体，产率76.2％。 1H NMR(400MHz,DMSO-d6ppm 8.09(d,J＝2.99Hz,1H),8.03(s,1H),7.95(dd,J＝8.79,2.94Hz,1H),7.79(d,J＝1.72Hz,1H),7.66(s,1H),7.17(d,J＝1.54Hz,1H),5.84(s,2H),5.72(q,J＝6.06Hz,1H),4.20-4.10(m,1H),3.96(s,3H),3.03(d,J＝12.37Hz,2H),2.58(dd,J＝11.97,10.75Hz,2H),1.95(dd,J＝11.60,1.88Hz,2H),1.77(qd,J＝12.04,3.95Hz,2H),1.56(d,J＝6.26Hz,3H). 13C NMR(100MHz,DMSO-d6)δppm 156.7,155.9,154.7,150.4,139.3,136.0,135.1,132.5,126.6,124.1,119.6,118.1,116.0,69.4,59.7,54.4,45.6,34.1,21.6.HRMS(EI)m/z:计算值C 21H 25FN 6O 2 412.2023；实测值412.2021.
实施例25 制备化合物MXY-137
Figure PCTCN2019082496-appb-000051
得到浅棕色固体，产率48.3％。 1H NMR(400MHz,DMSO-d6ppm 11.18(s,1H),7.78(d,J＝1.79Hz,1H),7.58(dd,J＝8.86,5.08Hz,1H),7.47(dd,J＝9.56,3.12Hz,1H),7.42(d,J＝ 2.49Hz,1H),7.39(d,J＝8.12Hz,1H),7.28(d,J＝7.99Hz,1H),7.26-7.20(m,1H),7.13-7.08(m,1H),7.00-6.97(m,1H),6.97-6.95(m,1H),5.84(s,2H),5.81-5.76(m,1H),1.64(d,J＝6.32Hz,3H). 13C NMR(100MHz,DMSO-d6)δppm 162.0,149.7,142.8,139.1,137.1,137.0,131.8,126.7,125.4,122.2,121.8,120.8,119.6,118.9,117.2,117.0,114.3,113.5,112.3,72.0,22.5.HRMS(EI)m/z:计算值C 21H 17ClFN 3O 381.1044；实测值381.1045.
实施例26 制备化合物MXY-141
Figure PCTCN2019082496-appb-000052
得到浅棕色固体，产率51.2％。 1H NMR(400MHz,DMSO-d6ppm 11.31(s,1H),8.05(d,J＝1.73Hz,1H),7.62(dd,J＝9.69,3.10Hz,1H),7.53(dd,J＝8.85,5.11Hz,1H),7.46(d,J＝7.74Hz,1H),7.33(d,J＝7.99Hz,1H),7.30(d,J＝1.63Hz,1H),7.19(td,J＝8.52,3.12Hz,1H),7.06-7.01(m,1H),6.98-6.93(m,1H),6.53(d,J＝1.51Hz,1H),6.19(s,2H),5.89(q,J＝6.11Hz,1H),5.76(s,1H),1.63(d,J＝6.26Hz,3H). 13C NMR(100MHz,DMSO-d6):δ161.9,151.5,142.6,139.2,137.2,136.8.136.6,131.6,129.1,126.7,121.3,119.8,119.7,117.5,117.1,115.3,114.7,111.3,96.9,72.0,22.2.HRMS(EI)m/z:计算值C 21H 17ClFN 3O 381.1044；实测值381.1042.
实施例27 制备化合物MXY-171
Figure PCTCN2019082496-appb-000053
得到白色固体，产率37.2％。 1H NMR(400MHz,DMSO-d6ppm 8.56(s,1H),8.04-7.90(m,3H),7.59(d,J＝2.09Hz,1H),7.55(dd,J＝8.85,5.08Hz,1H),7.45-7.37(m,3H),7.19(td,J＝8.52,3.14Hz,1H),6.67-6.56(m,1H),6.52(d,J＝8.42Hz,1H),5.64(q,J＝6.20Hz,1H),5.51(s,2H),1.60(d,J＝6.31Hz,3H). 13C NMR(100MHz,DMSO-d6)δppm 161.9,147.4,146.3,142.5,139.0,132.1,131.8,129.4,129.3,126.7,118.1,117.0,114.2,113.9,113.8,72.0,66.8,22.4.HRMS(EI)m/z:计算值C 19H 17ClFN 3O 357.1044；实测值357.1049.
实施例28 制备化合物MXY-175
Figure PCTCN2019082496-appb-000054
得到白色固体，产率41.7％。 1H NMR(400MHz,DMSO-d6ppm 8.57(s,1H),7.97(dd,J＝5.00,1.29Hz,1H),7.59(d,J＝2.07Hz,1H),7.55(dd,J＝8.85,5.08Hz,1H),7.44(d,J＝1.97 Hz,1H),7.43-7.37(m,2H),7.19(td,J＝8.53,3.14Hz,1H),6.72-6.55(m,1H),6.53(d,J＝8.42Hz,1H),5.64(q,J＝6.19Hz,1H),5.50(s,2H),1.60(d,J＝6.31Hz,3H). 13C NMR(100MHz,DMSO-d6)δppm 161.8,156.8,147.6,146.5,142.7,138.7,137.4,131.7,130.1,129.2,126.7,117.0,116.8,114.1,113.7,112.6,109.7,72.0,22.5.HRMS(EI)m/z:计算值C 18H 16ClFN 4O 358.0977；实测值358.1000.
实施例29 制备化合物MXY-181
Figure PCTCN2019082496-appb-000055
得到黄色固体，产率10.2％。 1H NMR(400MHz,DMSO-d6ppm 9.06(d,J＝6.86Hz,1H),8.53(s,2H),8.19(s,1H),7.70(s,1H),7.53(dd,J＝8.70,5.06Hz,1H),7.46(dd,J＝9.50,2.73Hz,1H),7.15(dt,J＝8.48,2.72Hz,1H),7.02(dd,J＝6.83,3.98Hz,1H),5.95(s,2H),5.80(q,J＝5.67,5.42Hz,1H),1.63(d,J＝6.16Hz,3H). 13C NMR(100MHz,DMSO-d6)δppm 161.8,150.1,149.9,143.9,142.7,142.6,141.6,139.1,136.6,131.6,126.9,117.1,116.8,116.1,113.2,108.9,107.4,72.1,22.4.HRMS(EI)m/z:计算值C 19H 15ClFN 5O 383.0949；实测值383.0948.
实施例30 制备化合物MXY-193
Figure PCTCN2019082496-appb-000056
得到白色固体，产率68.9％。 1H NMR(400MHz,CDCl 3ppm 7.78(d,J＝1.69Hz,1H),7.55(s,1H),7.48(s,1H),7.36(dd,J＝8.81,4.96Hz,1H),7.15(dd,J＝9.09,3.04Hz,1H),6.94(ddd,J＝8.75,7.73,3.05Hz,1H),6.74(d,J＝1.68Hz,1H),5.70(q,J＝6.22Hz,1H),4.81(s,2H),4.39-4.27(m,1H),4.14-4.09(m,2H),3.58-3.50(m,2H),2.14-2.03(m,4H),1.67(d,J＝6.35Hz,2H). 13C NMR(100MHz,CDCl 3)δppm 162.1,148.7,141.8,139.9,135.9,135.8,131.0,126.21,122.6,112.0,119.3,116.5,115.8,113.7,72.5,66.8,58.3,33.3,22.6.HRMS(EI)m/z:计算值C 21H 22ClFN 4O 2 416.1415；实测值416.1413.
实施例31 制备化合物MXY-191
Figure PCTCN2019082496-appb-000057
得到棕色固体，产率43.5％。 1H NMR(400MHz,DMSO-d6ppm 7.76(s,1H),7.54(dd,J＝8.84,5.08Hz,1H),7.47(d,J＝2.17Hz,1H),7.35(dd,J＝9.58,3.12Hz,1H),7.22-7.16(m, 1H),7.15(d,J＝2.16Hz,1H),5.59(q,J＝6.24Hz,1H),5.29(s,1H),5.17(s,2H),3.53(s,3H),2.52-2.49(m,1H),2.13(s,3H),1.59(d,J＝6.31Hz,3H). 13C NMR(100MHz,DMSO-d6)δppm161.8,151.0,144.2,142.9,142.8,139.2,138.8,132.6,131.8,126.5,126.4,116.8,114.0,109.1,92.7,72.0,35.6,22.4,11.1.HRMS(EI)m/z:计算值C 18H 19ClFN 5O 375.1262；实测值375.1261.
实施例32 制备化合物MXY-032-45
Figure PCTCN2019082496-appb-000058
得到白色固体，产率67.4％。 1H NMR(400MHz,DMSO-d6ppm 9.06(s,1H),8.95(s,2H),7.98(d,J＝1.78Hz,1H),7.61(m,1H),7.50(dd,J＝8.83,5.11Hz,1H),7.30(d,J＝1.57Hz,1H),7.18(dt,J＝8.55,3.10Hz,1H),6.35(s,2H),5.94(q,J＝5.96Hz,1H),1.61(d,J＝6.23Hz,3H). 13C NMR(100MHz,DMSO-d6)δppm 161.8,156.7,153.8,152.5,142.5,139.3,138.2,131.8,131.6,126.7,117.9,117.1,116.1,114.8,72.2,22.1.HRMS(EI)m/z:计算值C 17H 14ClFN 4O 344.0840；实测值344.0842.
实施例33 制备化合物MXY-032-37
Figure PCTCN2019082496-appb-000059
得到白色固体，产率23.5％。 1H NMR(400MHz,DMSO-d6ppm 11.41(s,1H),8.35(dd,J＝4.53,1.37Hz,1H),8.31(d,J＝1.66Hz,1H),7.90(d,J＝1.52Hz,1H),7.88(s,1H),7.76(dd,J＝8.19,1.35Hz,1H),7.55-7.45(m,2H),7.18-7.09(m,2H),5.85-5.77(m,3H),1.64(d,J＝6.30Hz,3H). 13C NMR(100MHz,DMSO-d6)δppm 161.8,149.5,143.7,142.9,142.7,139.0,136.6,131.6,130.0,126.9,124.8,120.2,119.1,116.9,116.9,116.8,114.3,112.5,72.0,22.4.HRMS(EI)m/z:计算值C 20H 16ClFN 4O 382.0997；实测值382.0995.
实施例34 制备化合物MXY-032-51
Figure PCTCN2019082496-appb-000060
得到淡黄色固体，产率67.8％。 1H NMR(400MHz,CDCl 3ppm 7.77(s,1H),7.62(d,J＝3.40Hz,2H),7.37(dd,J＝8.70,4.93Hz,1H),7.15(dd,J＝8.96,2.68Hz,1H),6.95(dt,J＝8.66,2.80Hz,1H),6.75(s,1H),5.71(dd,J＝11.99,5.81Hz,1H),5.53-5.33(m,1H),5.06(d,J＝7.05 Hz,1H),4.93(s,2H),1.68(d,J＝6.27Hz,3H). 13C NMR(100MHz,CDCl 3)δppm 162.1,148.6,141.5,140.2,137.2,134.3,131.1,126.2,124.1,120.6,118.8,116.6,116.1,113.7,77.7,72.8,55.7,22.6.HRMS(EI)m/z:计算值C 19H 18ClFN 4O 2 388.1102；实测值388.1099.
实施例35 制备化合物MXY-032-53
Figure PCTCN2019082496-appb-000061
得到淡黄色固体，产率63.9％。 1H NMR(400MHz,CDCl 3ppm 7.77(d,J＝1.65Hz,1H),7.53(d,J＝7.28Hz,1H),7.36(dd,J＝8.74,4.94Hz,1H),7.15(dd,J＝9.07,2.98Hz,1H),6.98-6.90(m,1H),6.74(s,1H),5.70(q,J＝6.19Hz,1H),5.04-4.91(m,1H),4.82(s,2H),4.17-4.02(m,3H),3.98-3.91(m,1H),2.51-2.40(m,1H),2.38-2.27(m,1H),1.67(d,J＝6.35Hz,3H). 13C NMR(100MHz,CDCl 3)δppm 162.1,148.6,141.8,140.0,136.3,135.6,131.0,126.2,123.6,120.5,119.2,116.5,115.8,113.7,72.9,72.6,67.5,61.9,33.2,22.6.HRMS(EI)m/z:计算值C 20H 20ClFN 4O 2 402.1259；实测值402.1256.
实施例36 制备化合物MXY-032-55
Figure PCTCN2019082496-appb-000062
得到淡黄色固体，产率71.8％。 1H NMR(400MHz,CDCl 3ppm 7.87(d,J＝1.47Hz,1H),7.36-7.24(m,2H),7.16(dd,J＝9.04,2.94Hz,1H),6.97-6.91(m,1H),6.90-6.79(m,4H),5.72(q,J＝6.20Hz,1H),4.91(s,2H),3.91-3.85(m,4H),3.19-3.15(m,4H),1.68(d,J＝6.34Hz,3H). 13C NMR(100MHz,CDCl 3)δppm 162.1,151.7,149.3,141.9,139.8,139.2,136.9,130.9,129.7,127.7,126.2,118.0,117.0,116.4,114.4,113.7,113.5,72.7,67.0,49.3,22.6.HRMS(EI)m/z:计算值C 23H 23ClFN 3O 2 427.1463；实测值427.1466.
实施例37 制备化合物MXY-02-69
Figure PCTCN2019082496-appb-000063
得到淡绿色固体，产率34.8％。 1H NMR(400MHz,DMSO-d6ppm 8.87(s,1H),8.45(s,1H),7.86(d,J＝8.02Hz,1H),7.56(d,J＝2.02Hz,1H),7.54-7.49(m,3H),7.46(dd,J＝9.59,3.09Hz,1H),7.25-7.19(m,2H),7.12(d,J＝1.97Hz,1H),6.66(s,1H),5.68(dd,J＝12.53,6.23Hz,1H),5.63(s,2H),1.61(d,J＝6.28Hz,1H). 13C NMR(100MHz,DMSO-d6)δppm 161.9,154.1, 151.7,147.3,142.7,138.9,138.6,131.9,131.7,130.8,128.6,128.1,126.6,125.2,123.7,123.1,117.0,114.3,113.7,98.0,72.1,22.5.HRMS(EI)m/z:计算值C 22H 18ClFN 4O 408.1153；实测值408.1151.
实施例38 制备化合物MXY-032-85
Figure PCTCN2019082496-appb-000064
得到淡绿色固体，产率41.7％。 1H NMR(400MHz,DMSO-d6ppm 9.06(s,1H),7.94(d,J＝8.90Hz,1H),7.83(s,2H),7.66(d,J＝7.82Hz,1H),7.56-7.46(m,4H),7.26-7.18(m,2H),6.87(d,J＝8.90Hz,1H),5.74(dd,J＝11.63,5.41Hz,1H),5.60(s,2H),1.64(d,J＝6.22Hz,3H). 13C NMR(100MHz,DMSO-d6)δppm 161.9,154.8,147.5,146.8,142.8,138.6,137.1,131.8,130.2,129.7,129.0,127.9,126.5,123.8,122.6,116.9,114.3,114.0,112.3,72.2,22.3.HRMS(EI)m/z:计算值C 22H 18ClFN 4O 408.1153；实测值408.1150.
实施例39 制备化合物MXY-032-87
Figure PCTCN2019082496-appb-000065
得到淡绿色固体，产率43.6％。 1H NMR(400MHz,DMSO-d6ppm 8.88(s,1H),8.41(d,J＝8.38Hz,1H),7.81-7.74(m,3H),7.66(t,J＝7.18Hz,1H),7.60-7.52(m,3H),7.47(dd,J＝9.60,3.09Hz,1H),7.20(dt,J＝8.52,3.12Hz,1H),7.04(d,J＝5.73Hz,1H),5.70-5.59(m,3H),1.61(d,J＝6.29Hz,3H). 13C NMR(100MHz,DMSO-d6)δppm 161.9,153.5,147.3,142.8,141.1,138.4,137.3,132.4,131.6,130.4,128.4,127.2,126.6,126.5,123.5,118.6,116.9,114.7,114.3,111.9,72.1,22.4.HRMS(EI)m/z:计算值C 22H 18ClFN 4O 408.1153；实测值408.1148.
实施例40 制备化合物MXY-032-91
Figure PCTCN2019082496-appb-000066
得到白色固体，产率78.6％。 1H NMR(400MHz,CDCl 3ppm 7.81(d,J＝1.74Hz,1H),7.63(d,J＝1.51Hz,1H),7.55(d,J＝0.67Hz,1H),7.37(dd,J＝8.71,4.96Hz,1H),7.19-7.14(m,1H),6.98-6.91(m,1H),6.76(s,1H),5.71(q,J＝6.28Hz,1H),5.49(q,J＝6.00Hz,1H),4.77(s,2H),3.52-3.42(m,1H),3.39-3.30(m,1H),1.70-1.64(m,6H),1.16(dt,J＝7.01,0.76Hz,3H). 13C NMR(100MHz,CDCl 3)δppm 161.9,150.5,142.7,139.2,136.3,135.7,131.6,126.7,123.8,120.6, 117.5,117.1,115.9,114.8,86.8,72.0,63.5,22.2,21.7,15.2.HRMS(EI)m/z:计算值C 20H 22ClFN 4O 2 404.1415；实测值404.1413.
实施例41 制备化合物MXY-032-93
Figure PCTCN2019082496-appb-000067
得到白色固体，产率75.9％。 1H NMR(400MHz,CDCl 3ppm 7.76(d,J＝1.66Hz,1H),7.54(s,1H),7.42(s,1H),7.36(dd,J＝8.81,4.96Hz,1H),7.15(dd,J＝9.07,3.02Hz,1H),7.04-6.87(m,1H),6.74(d,J＝1.68Hz,1H),5.70(q,J＝6.29Hz,1H),4.86(s,2H),4.21(t,J＝6.86Hz,3H),3.34-3.30(m,5H),2.15-2.06(m,2H),1.67(d,J＝6.35Hz,3H). 13C NMR(100MHz,CDCl 3)δppm 162.1,148.6,141.8,140.0,136.3,135.7,131.0,126.2,125.6,119.8,119.4,116.4,115.8,113.6,72.6,69.0,58.7,49.0,30.3,22.6.HRMS(EI)m/z:计算值C 20H 22ClFN 4O 2 404.1415；实测值404.1413.
实施例42 制备化合物MXY-032-95
Figure PCTCN2019082496-appb-000068
得到白色固体，产率67.9％。 1H NMR(400MHz,CDCl 3ppm 7.78(d,J＝1.63Hz,1H),7.55(s,1H),7.52(s,1H),7.36(dd,J＝8.81,4.96Hz,1H),7.15(dd,J＝9.10,3.02Hz,1H),6.97-6.88(m,1H),6.74(d,J＝1.65Hz,1H),5.69(q,J＝6.25Hz,1H),4.77(s,2H),4.27(t,J＝5.20Hz,2H),3.74(t,J＝5.18Hz,2H),3.34(s,3H),1.67(d,J＝6.35Hz,3H). 13C NMR(100MHz,CDCl 3)δppm 162.1,148.6,141.8,139.9,136.3,135.8,131.0,126.2,126.1,120.1,119.4,116.5,115.8,113.6,72.5,71.1,59.0,52.3,22.6.HRMS(EI)m/z:计算值C 19H 20ClFN 4O 2 390.1259；实测值390.1261.
实施例43 制备化合物MXY-032-73
Figure PCTCN2019082496-appb-000069
得到白色固体，产率67.9％。 1H NMR(400MHz,DMSO-d6ppm 9.20(s,1H),8.31(d,J＝4.41Hz,2H),7.69(s,1H),7.55(dd,J＝8.40,4.85Hz,1H),7.49-7.37(m,2H),7.22-7.15(m,1H),6.71(t,J＝4.29Hz,1H),5.66-5.54(m,3H),1.60(d,J＝5.95Hz,3H). 13C NMR(100MHz, DMSO-d6)δppm 163.1,160.6,158.3,146.9,142.7,138.5,131.6,130.6,127.9,126.7,116.9,114.2,112.7,112.1,72.1,22.5.HRMS(EI)m/z:计算值C 17H 15ClFN 5O 359.0949；实测值359.0950.
XFL系列化合物参考以下路线：
Figure PCTCN2019082496-appb-000070
(a)NaBH 4,MeOH,0℃至r.t.；(b)5-溴-2-硝基吡啶-3-醇,DIAD,PPh3,THF,0℃至r.t.；(c)Fe,AcOH,EtOH,回流；
(d)3,5-二甲基-4-(4,4,5,5-四甲基-1,3-二氧戊环-2-基)-1H-吡唑,Cs 2CO 3,PdCl 2(dppf),二甲氧基乙烷,80℃。
实施例44 制备化合物XFL-107
Figure PCTCN2019082496-appb-000071
得到黄色固体22mg，收率为21.01％。 1H-NMR(400MHz,CDCl 3):δ7.40(s,1H),7.37(s,1H),7.27(dd,J＝8.8Hz,J＝4.8Hz,1H),7.05(dd,J＝8.8Hz,J＝2.8Hz,1H),6.87(td,J＝8.0Hz,J＝3.2Hz,1H),5.56(m,1H),1.99(s,6H),1.61(d,J＝6.4Hz,3H).LC-MS:m/z:361.1(M+H) +.
实施例45 制备化合物XFL-111
Figure PCTCN2019082496-appb-000072
得到浅棕色固体28mg，收率为27.83％。 1H-NMR(400MHz,CDCl 3):δ7.65(s,1H),7.43(s,1H),7.32(s,1H),7.30(dd,J＝8.8Hz,J＝4.8Hz,1H),7.08(dd,J＝9.2Hz,J＝3.2Hz,1H),6.88(td,J＝8.2Hz,J＝3.2Hz,1H),6.67(s,1H),5.64(m,1H),5.02(s,2H),3.83(s,3H),1.61(d,J＝6.4Hz,3H).LC-MS:m/z:347.1(M+H) +.
实施例46 制备化合物XFL-137
Figure PCTCN2019082496-appb-000073
得到深棕色固体58mg，收率为24.04％。 1H-NMR(400MHz,DMSO):δ8.86(s,1H),7.51(dd,J＝8.4Hz,J＝5.2Hz,1H),7.49(dd,J＝9.2Hz,J＝3.2Hz,1H),7.37(d,J＝1.6Hz,1H),7.19(td,J＝8.4Hz,J＝3.2Hz,1H),7.11(t,J＝10.8Hz,1H),6.74(d,J＝1.6Hz,1H),5.72(m,1H),1.59(d,J＝6.4Hz,3H).LC-MS:m/z:334.1(M+H) +.
实施例47 制备化合物XFL-141
Figure PCTCN2019082496-appb-000074
得到白色固体47mg，收率为16.16％。 1H-NMR(400MHz,DMSO):δ12.69(s,1H),7.95(s,1H),7.68(d,J＝1.2Hz,1H),7.53(dd,J＝8.8Hz,J＝5.2Hz,1H),7.20(s,1H),7.18(td,J＝8.4Hz,J＝3.2Hz,1H),6.46(s,1H),6.10(s,3H),6.00(s,1H),5.78(m,1H),1.62(d,J＝6.0Hz,3H).LC-MS:m/z:333.1(M+H) +.
实施例48 制备化合物XFL-147
Figure PCTCN2019082496-appb-000075
得到黄色固体101mg，收率为33.56％。 1H-NMR(400MHz,DMSO):δ12.52(s,1H),7.58(s,1H),7.53(dd,J＝8.8Hz,J＝5.2Hz,1H),7.47(dd,J＝9.6Hz,J＝3.2Hz,1H),7.19(td,J＝8.0Hz,J＝3.2Hz,1H),6.74(d,J＝1.6Hz,1H),5.85(s,1H),5.76(m,1H),2.11(s,3H),1.62(d,J＝6.4Hz,3H).LC-MS:m/z:347.1(M+H) +.
实施例49 制备化合物XFL-169
Figure PCTCN2019082496-appb-000076
得到黄色固体54mg，收率为31.85％。 1H NMR(400MHz,CDCl 3)δ8.12(d,J＝1.8Hz,1H),7.69(d,J＝3.3Hz,1H),7.31(dd,J 1＝8.8,J 2＝5.0Hz,1H),7.23(d,J＝1.7Hz,1H),7.15(d,J＝3.3Hz,1H),7.08(dd,J＝9.0,3.0Hz,1H),6.92–6.85(m,1H),5.73(q,J＝5.9Hz,1H),5.39(s,2H),1.63(d,J＝6.3Hz,3H).LC-MS:m/z:350.1(M+H) +.
实施例50 制备化合物XFL-171
Figure PCTCN2019082496-appb-000077
得到浅棕色固体40mg，收率为35.40％。 1H NMR(400MHz,CDCl 3)δ7.94(s,1H),7.33(s,1H),7.26(dd,J 1＝8.8,J 2＝5.0Hz,1H),7.11(d,J＝3.0Hz,1H),7.05(d,J＝1.4Hz,1H),6.85(ddd,J 1＝8.7,J 2＝7.7,J 3＝3.1Hz,2H),5.68(q,J＝6.3Hz,1H),4.85(s,2H),3.60(s,3H),1.59(d,J＝6.3Hz,3H).LC-MS:m/z:347.1(M+H) +.
实施例51 制备化合物XFL-179
Figure PCTCN2019082496-appb-000078
得到黄色固体20mg，收率为10.36％。 1H NMR(400MHz,CDCl 3)δ7.90(s,1H),7.59(s,2H),7.29(dd,J 1＝8.8,J 2＝5.0Hz,1H),7.10(d,J＝3.0Hz,1H),7.04(s,1H),6.88(ddd,J 1＝8.7,J 2＝7.7,J 3＝3.0Hz,1H),6.33(t,J＝2.1Hz,1H),5.68(q,J＝6.3Hz,1H),4.87(s,2H),1.62(d,J＝6.3Hz,3H).LC-MS:m/z:333.1(M+H) +.
实施例52 制备化合物XFL-201
Figure PCTCN2019082496-appb-000079
得到深棕色固体40mg，收率为35.40％。 1H NMR(600MHz,DMSO)δ11.67(s,1H),7.92(s,1H),7.49(ddd,J 1＝13.7,J 2＝9.0,J 3＝2.1Hz,3H),7.34(s,1H),7.27(d,J＝5.0Hz,1H),7.19–7.14(m,1H),6.21(t,J＝6.6Hz,1H),6.03(s,2H),5.72(q,J＝6.0Hz,1H),1.58(d,J＝6.3Hz,3H).LC-MS:m/z:360.1(M+H) +.
实施例53 制备化合物XFL-1146-13
Figure PCTCN2019082496-appb-000080
得到黑色固体40mg，收率为35.40％。 1H NMR(400MHz,DMSO)δ7.94(s,1H),7.63(dd,J 1＝6.7,J 2＝1.9Hz,1H),7.55(dd,J 1＝9.6,J 2＝3.1Hz,1H),7.49(dd,J 1＝8.9,J 2＝5.1Hz,1H),7.45(dd,J 1＝7.0,J 2＝2.0Hz,1H),7.32(d,J＝1.6Hz,1H),7.17(td,J 1＝8.5,J 2＝3.1Hz,1H),6.24(t,J ＝6.8Hz,1H),6.12(s,2H),5.75(q,J＝6.1Hz,1H),3.45(s,3H),1.58(d,J＝6.3Hz,3H).LC-MS:m/z:374.1(M+H) +.
实施例54 制备化合物XFL-1146-23
Figure PCTCN2019082496-appb-000081
得到棕色油状化合物66mg，收率为34.38％。 1H NMR(400MHz,DMSO)δ8.28(d,J＝2.9Hz,1H),8.16(d,J＝1.5Hz,1H),7.68(d,J＝8.8Hz,1H),7.56–7.53(m,1H),7.53–7.49(m,1H),7.47(d,J＝1.5Hz,1H),7.42(dd,J 1＝8.8,J 2＝2.9Hz,1H),7.17(td,J 1＝8.5,J 2＝3.1Hz,1H),6.19(s,2H),5.83(q,J＝6.1Hz,1H),4.28(t,J＝5.2Hz,2H),3.16(s,2H),2.89(s,4H),1.80(s,4H),1.60(d,J＝6.3Hz,3H).HRMS(EI)(m/z):[M]+计算值456.1728；实测值,456.1729.
实施例55 制备化合物XFL-1146-29
Figure PCTCN2019082496-appb-000082
得到浅棕色固体46mg，收率为31.57％。 1H NMR(400MHz,CDCl 3)δ7.97(d,J＝1.4Hz,1H),7.53(s,1H),7.30(dd,J 1＝8.8,J 2＝5.0Hz,1H),7.09(dd,J 1＝9.1,J 2＝3.0Hz,1H),7.00(d,J＝1.5Hz,1H),6.90–6.84(m,1H),5.69(q,J＝6.3Hz,1H),4.98(s,2H),4.11(s,3H),1.62(d,J＝6.3Hz,3H).LC-MS:m/z:348.1(M+H) +.
实施例56 制备化合物XFL-1146-31
Figure PCTCN2019082496-appb-000083
得到黄色固体120mg，收率为44.98％。 1H NMR(400MHz,CDCl 3)δ7.75(s,1H),7.65–7.61(m,1H),7.51(td,J＝7.7,1.3Hz,1H),7.31(dd,J＝7.8,6.8Hz,2H),7.26(d,J＝5.2Hz,1H),7.11(dd,J＝9.1,3.0Hz,1H),6.90–6.86(m,1H),6.85(d,J＝1.7Hz,1H),5.66(q,J＝6.2Hz,1H),4.96(s,1H),1.63(d,J＝6.3Hz,3H).LC-MS:m/z:368.1(M+H) +.
实验例 JAK2抑制剂分子水平活性测试
实验原理：
JAK2能催化三磷酸腺苷(ATP)的一个磷酸基团转移到多肽底物上，而多肽底物标记有两个荧光基团香豆素(coumarin)和荧光素(fluorescein)。基于荧光能量共振转移(FRET)的方法，JAK2 催化ATP发生反应导致两个荧光基团接近，供体(coumarin)在400nM处被激发，部分能量释放，发射波长为445nM，另一部分能量转移到fluorescein，发射波长为520nM。不同化合物对JAK2的抑制程度不同，导致底物磷酸化的程度不同，从而通过测定酶催化底物磷酸化百分比的比值，计算不同化合物的抑制率。
实验方法：
在384孔板中加入2.5μL测试化合物，5μL激酶/肽底物混合物，2.5μL ATP溶液，10μL反应体系振荡30s混匀，室温孵育1h；加入5μL蛋白水解酶，15μL反应体系振荡30s混匀，室温孵育1h；加入5μL停止试剂，总体积20μL反应体系振荡30s混匀，使用酶标仪进行荧光信号的检测，激发波长为400nm，发射波长分别为445nm和520nm。测定化合物在7个浓度梯度下的抑制率，通过Origin 8.0拟合曲线计算各个化合物的IC 50值。实验过程进行阳性对照确证反应体系可行性，每次实验三个平行。实验过程采用Ruxolitinib为阳性对照，每次实验至少设三个平行。
表1 JAK2激酶活性测试结果
Figure PCTCN2019082496-appb-000084
Figure PCTCN2019082496-appb-000085
CCK-8细胞增殖检测原理：
WST-8(化学名：2-(2-甲氧基-4-硝基苯基)-3-(4-硝基苯基)-5-(2,4-二磺酸苯)-2H-四唑单钠盐)，它在电子载体1-甲氧基-5-甲基吩嗪鎓硫酸二甲酯(1-Methoxy PMS)的作用下被细胞中的脱氢酶还原为具有高度水溶性的黄色甲瓒产物(Formazan dye)。生成的甲瓒物的数量与活细胞的数量成正比。因此可以通过测定450nm处的光吸收值间接计算出细胞的存活率。通过CCK-8法测定化合物对H3122、SET2、HEL细胞增殖的半数抑制率。
实验方法：
使用含有10％FBS的RPIM培养基培养细胞，每孔加入100μL,3500个细胞接种至96孔板，置于37℃，5％CO 2培养箱中培养24h，待细胞汇合度达到50％-70％，分别加入不同浓度梯度的药物，继续孵育72h之后，每孔加入10μL CCK-8震荡混匀，37℃孵育2h，最后在450nm波长下，测定各孔光吸收值。最后通过origin软件进行计算IC 50值，结果如表2所示。
ALK激酶IC 50测试原理：
HTRF方法在多肽底物上标记了一个生物素，它能够和XL665标记的链合亲和素特异性的结合。当激酶在第一步给多肽底物加上磷酸基团后，其Eu标记的特异性磷酸化抗体就能与之识别并结合。这样，在第二步检测时，就能够形成一个XL665标记的链合亲和素，磷酸化的多肽底物以及Eu标记的磷酸化抗体三者结合的复合物。由于XL665和Eu的距离较短，能够形成FRET。另一方面，Eu的荧光半衰期比较长，可以应用于时间分辨荧光的检测。
实验方法：
在384孔板中加入4μL测试化合物，2μL激酶，2μL生物素标记的底物，2μL ATP，10μL反应体系振荡30s混匀，室温孵育1h；加入5μL Eu标记的磷酸化位点特异性抗体，5μL XL665标记的链霉亲和素，反应体系振荡30s混匀，室温孵育1h，使用酶标仪进行荧光信号的检测。测定化合物在8个浓度梯度下的抑制率，通过Origin 8.0拟合曲线计算各个化合物的IC50值。实验过程进行阳性对照确证反应体系可行性，每次实验三个平行，结果如表2所示。
注：HEL，SET-2，H3122细胞均购自ATCC(American type culture collection)，Z'-LYTETM kinase assay platform购自Invitrogen，HTRF KinEASETM-TK购自Cisbio,
Cell Counting Kit-8购自碧云天。
表2
Figure PCTCN2019082496-appb-000086
Figure PCTCN2019082496-appb-000087
由于化合物MXY-193在活性保持单纳摩尔的同时，又有着非常高的选择性，因此将其进行手性柱拆分，拆分方法如下：
色谱柱 超手性 S‐OD
色谱柱尺寸 0.46cm I.D.×15cm长,5um
注射 3ul
流动相 MeOH/DEA＝100/0.05(v/v/v)
流速 0.8ml/min
波长 UV 220,254nm
温度 40.0℃
旋转探测器 高级激光偏光仪
样品结构 MXY‐193,原料
拆分结果如表3A、3B、图1和图2所示；
表3A 色谱峰表：220nm
No. t R(min) 面积 面积％ T.板 拖尾 分离度
1 3.757 676097 6.2813 2910.445 -- --
2 3.927 5026115 46.6951 6046.936 -- 0.709
3 4.453 5061483 47.0237 6180.037 1.100 2.454
表3B 色谱峰表：254nm
No. t R(min) 面积 面积％ T.板 拖尾 分离度
1 3.760 416648 6.2690 2999.444 -- --
2 3.929 3116954 46.8988 6085.704 -- 0.709
3 4.454 3112526 46.8322 6222.500 1.104 2.461
两种构型：构型1(peak 1，R构型)和构型2(peak 2，S构型)的活性分别如表4所示：
表4
Figure PCTCN2019082496-appb-000088
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 (14)

  1. 式I所示的化合物或其立体异构体或光学异构体，或其药学上可接受的盐、前药或溶剂化物，
    Figure PCTCN2019082496-appb-100001
    式中
    R 1选自下组：氢、卤素、C 1-C 10烷基、卤代C 1-C 10烷基、C 1-C 10烷氧基、卤代C 1-C 10烷氧基、取代或未取代的苯基、取代或未取代的苄基、取代或未取代的5元或6元杂环、取代或未取代的9元或10元杂环、-NR 5(R 6)；所述取代是指上述基团被氧代(＝O)或者上述基团上的一个或多个氢原子被选自下组的基团所取代：C1-C4烷基、C1-C4卤代烷基、氰基、-R 7-O-R 8、取代或未取代的含有一个或两个选自氮、氧或硫的杂原子的四至六元环基；
    R 5选自下组：氢、C1-C4烷基；R 6选自下组：C 1-C 10烷基、卤代C 1-C 10烷基、取代或未取代的苯基、取代或未取代的苄基、取代或未取代的5元或6元杂环、取代或未取代的9元或10元杂环；其中，所述取代是指上述基团上的一个或多个氢原子被选自下组的基团所取代：C1-C4烷基、C1-C4卤代烷基、氰基、卤素；
    R 7为无或取代或未取代的C1-C6亚烷基；R 8选自下组：C1-C6烷基、卤代C1-C6烷基、取代或未取代的含有一个或两个选自氮、氧或硫的杂原子的四至六元环基、取代或未取代的含有一个或两个选自氮、氧或硫的杂原子的四至六元环基-C1-C4烷基；
    R 2选自下组：取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的嘧啶基、取代或未取代的C 5-C 7环烷基；所述取代是指上述基团上的一个或多个氢原子被选自下组的基团所取代：氢、卤素、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基、卤代C 1-C 3烷氧基；
    R 3选自下组：氢、卤素、C 1-C 10烷基、卤代C 1-C 10烷基、羟基、C 1-C 10烷氧基；
    R 4选自下组：氢、C 1-C 10烷基、C 1-C 10酰基；
    X选自下组：CH 2、O、NH、S、SO、SO 2；
    除非特别说明，上述取代是指基团中一个或多个氢被选自下组的基团所取代：C1-C4烷基、C1-C4卤代烷基、卤素。
  2. 如权利要求1所述的化合物或其立体异构体或光学异构体，或其药学上可接受的盐、前药或溶剂化物，其特征在于，所述化合物如式II所示：
    Figure PCTCN2019082496-appb-100002
    式中
    R 1和R 3的定义同前；
    R 2’选自下组：氢、卤素、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基、卤代C 1-C 3烷氧基；
    X选自下组：O、NH、S；
    n为1、2、3或4。
  3. 如权利要求1或2所述的的化合物或其立体异构体或光学异构体，或其药学上可接受的盐、前药或溶剂化物，其特征在于，所述5元或6元杂环或所述9元或10元杂环含至少一个氮杂原子。
  4. 如权利要求1或2所述的化合物或其立体异构体或光学异构体，或其药学上可接受的盐、前药或溶剂化物，其特征在于，所述5元或6元含氮杂环选自下组：吡咯、吡唑、吡啶。
  5. 如权利要求1或2所述的化合物或其立体异构体或光学异构体，或其药学上可接受的盐、前药或溶剂化物，其特征在于，所述9元或10元杂环选自下组：
    Figure PCTCN2019082496-appb-100003
    Figure PCTCN2019082496-appb-100004
  6. 如权利要求1或2所述的的化合物或其立体异构体或光学异构体，或其药学上可接受的盐、前药或溶剂化物，其特征在于，
    R 1选自下组：取代或未取代的5元或6元杂环；其中，所述取代是指上述基团上的一个或多个氢原子被选自下组的基团所取代：C1-C4烷基、氰基、-R 7-O-R 8、含有一个或两个选自氮、氧或硫的杂原子的饱和四至六元环；其中，R 7为C1-C6亚烷基；R 8选自下组：C1-C6烷基、卤代C1-C6烷基；或者，
    R 1选自下组：
    Figure PCTCN2019082496-appb-100005
  7. 如权利要求1或2所述的化合物或其立体异构体或光学异构体，或其药学上可接受的盐、前药或溶剂化物，其特征在于，所述含有一个或两个选自氮、氧或硫的杂原子的四至六元环选自下组：哌啶、哌嗪、吗啉、氧杂环丁烷、四氢呋喃。
  8. 如权利要求2所述的的化合物或其立体异构体或光学异构体，或其药学上可接受的盐、前药或溶剂化物，其特征在于，
    Figure PCTCN2019082496-appb-100006
    为选自下组的基团：
    Figure PCTCN2019082496-appb-100007
    其中，R 2’的定义同前。
  9. 如权利要求1所述的化合物或其立体异构体或光学异构体，或其药学上可接受的盐、前药或溶剂化物，其特征在于，所述化合物选自下组：
    Figure PCTCN2019082496-appb-100008
    Figure PCTCN2019082496-appb-100009
  10. 一种药物组合物，其特征在于，所述药物组合物含有权利要求1-5中任一项所述的化合物或其立体异构体或光学异构体，或其药学上可接受的盐、前药或溶剂化物，以及药学上可接受的载体或赋形剂。
  11. 权利要求1-9中任一项所述的化合物或其立体异构体或光学异构体，或其药学上可接受的盐、前药或溶剂化物的用途，其特征在于，用于制备用于预防或治疗JAK2介导的疾病的药物；和/或用于制备JAK2抑制剂。
  12. 如权利要求11所述的用途，其特征在于，所述JAK2介导的疾病为骨髓增生异常综合征(MDS)、嗜酸粒细胞增多症、肿瘤、炎性疾病或细菌、病毒或真菌引起的感染。
  13. 如权利要求12所述的用途，其特征在于，
    所述肿瘤选自下组：骨髓增殖癌(MPN)、黑色素瘤、肺癌、肾癌、卵巢癌、前列腺癌、乳腺癌、结肠癌、骨癌、胰腺癌、皮肤癌、头颈癌、子宫癌、直肠癌、肛门癌、胃癌、睾丸癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、何杰金氏病、非何杰金淋巴瘤、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、急性髓性白血病、慢性髓性白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、小儿实体瘤、淋巴细胞性淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊轴瘤、脑干神经胶质瘤、垂体腺瘤、卡波西肉瘤、表皮样癌、鳞状细胞癌、T细胞淋巴瘤；和/或
    所述炎性疾病选自下组：类风湿性关节炎、强直性脊柱炎、自身免疫性溶血性贫血、关节炎、重症肌无力、系统性红斑狼疮、恶性贫血、多肌炎；和/或
    所述病毒选自下组：肝炎病毒(甲型、乙型和丙型)、孢疹病毒、流感病毒、腺病毒、冠状病毒、麻疹病毒、登革热病毒、脊髓灰质炎病毒、狂犬病病毒；和/或
    所述细菌选自下组：衣原体、立克次氏体、分枝杆菌、葡萄球菌、肺炎球菌、霍乱、破伤风；和/或
    所述真菌选自下组：假丝酵母、曲霉、皮炎芽酵母。
  14. 一种JAK2抑制剂，其特征在于，含有权利要求1-9中任一项所述的化合物或其立体异构体或光学异构体，或其药学上可接受的盐、前药或溶剂化物或权利要求10所述的药物组合物。
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