CN118164979A - 氮杂吲哚类PI3Kδ抑制剂、其制备方法和应用 - Google Patents
氮杂吲哚类PI3Kδ抑制剂、其制备方法和应用 Download PDFInfo
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- CN118164979A CN118164979A CN202410328079.4A CN202410328079A CN118164979A CN 118164979 A CN118164979 A CN 118164979A CN 202410328079 A CN202410328079 A CN 202410328079A CN 118164979 A CN118164979 A CN 118164979A
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- 229940124780 PI3K delta inhibitor Drugs 0.000 title description 4
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- 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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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Abstract
本发明公开了一类可作为PI3Kδ激酶抑制剂的含或不含杂原子(如氮杂原子等)的吲哚衍生物及其药物组合物，可用于治疗与PI3Kδ抑制相关的疾病、病症或病状，包括免疫病症、癌症和心血管疾病等。
Description
技术领域
本发明涉及药物化学领域，具体涉及一类氮杂吲哚类化合物及其制备方法和应用。
背景技术
一直以来，恶性肿瘤严重威胁着人类健康，特别是B细胞恶性肿瘤，包括慢性淋巴细胞白血病、急性淋巴细胞白血病、非霍奇金淋巴瘤、滤泡性淋巴瘤等。早期的治疗手段主要是通过传统的细胞毒药物来缓解患者的症状。随着生物学家们对肿瘤形成机制的深入研究，肿瘤细胞内各种生理过程如信号通路的转导、细胞周期的调控、细胞调亡、血管生成等逐渐被人们所认识。其中PI3K/Akt信号传导通路是哺乳动物中重要的信号通路，其信号传导的异常激活被认为与肿瘤的发生和发展密切相关。
磷脂酰肌醇-3-激酶(PI3K)是一种脂激酶家族成员，是PI3K/AKT/mTOR信号通路的重要组成部分，能够介导体内的磷酸化过程从而影响细胞的生长、增殖、分化、迁移、凋亡等一系列过程。研究发现，PI3K通路的异常激活与多种疾病的发生发展密切相关，不同类型的PI3K发挥着不同的功能。I型PI3K主要包括PI3Kα、PI3Kβ、PI3Kγ和PI3Kδ。其中PI3Kα的突变与肿瘤的发生发展有关；PI3Kβ能够激活血小板，与血栓性疾病的发展有关，并且在PTEN缺失的肿瘤中，PI3Kγ会促进肿瘤的恶变；PI3Kγ和PI3Kδ主要与免疫系统和造血系统有关，与免疫、血液肿瘤以及炎症的发生密切有关。Ⅱ型PI3K主要影响膜运输。Ⅲ型PI3K成员Vps34可影响细胞的胞吞作用和囊泡运输，调节细胞自噬，也可以通过mTOR来介导细胞的信号转导。
虽然PI3Kα和PI3Kβ在许多组织类型中表达，但PI3Kγ和PI3Kδ主要在白细胞中表达，并且因此被认为是用于治疗炎症性病症和其他与免疫系统相关的疾病的有吸引力的靶标，同时，研究也表明靶向所述四种I型PI3K亚型中的一种或多种可产生对癌症的适用治疗。编码P110α的基因在常见癌症中常被突变，所述常见癌症包括乳癌、脑癌、前列腺癌、结肠癌、胃癌、肺癌和子宫内膜癌。在其它PI3K亚型中尚未鉴定所述突变，但有证据表明它们可促进恶性肿瘤的发展和进展。PI3Kδ一贯地在急性成髓细胞性白血病中过度表达，并且PI3Kδ的抑制剂可防止白血病细胞的生长。
公开号为CN104619708A的专利说明书公开了一种氮杂吲哚类化合物，以氮杂吲哚作为结构母核，设计并合成了一系列小分子PI3Kδ抑制剂，并对该类化合物进行了PI3Kδ激酶抑制活性测试，表现出良好的激酶亚型选择性，并且对肿瘤细胞株表现出了更好的体外增殖抑制活性。
公开号为CN112794851A的专利说明书公开了一种3-(吡啶-3基)-7-氮杂吲哚衍生物PI3Kδ抑制剂，可抑制PI3Kδ激酶的活性，对于PI3Kδ激酶过表达相关的疾病、病症、病症具有潜在的治疗应用。
发明内容
本发明提供了一类可作为PI3Kδ激酶抑制剂的含或不含杂原子(如氮杂原子等)的吲哚衍生物及其药物组合物，可用于治疗与PI3Kδ抑制相关的疾病、病症或病状，包括免疫病症、癌症和心血管疾病等。
第一方面，本发明提供了具有式(I)所示结构的化合物，或其药学上可接受的盐，或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、可互变异构体：
式(1)中：
*表示手性碳；
W，X，Y和Z均为碳原子，或W，X，Y和Z至少一个是氮原子且其他是碳原子；
R1为H、卤素、硝基、氰基、氨基、羟基、羟甲基、羟乙基、巯基、羧基、酯基、取代或未取代的C1-6烷基、取代或未取代的C1-6环烷基、取代或未取代的C1-6杂环烷基、取代或未取代的C4-10芳基、取代或未取代的C1-8杂芳基、C2-10烯基、C2-10炔基、烷基单取代胺基、烷基双取代胺基、烷氧基、烷基羰氧基、环烷基羰氧基、杂芳基羰氧基、烷氧基羰基、环烷氧基羰基、杂芳氧基羰基、烷基羰胺基、环烷基羰胺基、杂芳基羰胺基、胺基羰基、烷氧甲酰胺基、烷巯基、羟基烷氧基、糖残基、磺酸基、磷酸基、多羟基烷氧基羰基、羧基烷氧基、羧基烷基甲酰氧基中的一个或多个；
R2选自芳基，杂芳基和C3-6杂环烷基；它们各自任选且独立地被一个或多个基团取代，所述基团选自卤素，羟基，氨基，硝基、氰基、氨基、羟基、羟甲基、羟乙基、巯基、羧基、酯基，取代或未取代的C1-6烷基，C2-10烯基、C2-10炔基，取代或未取代的C4-10芳基、取代或未取代的C1-8杂芳基、烷氧基羰基、环烷基羰胺基、烷巯基、羟基烷氧基、糖残基、磺酸基、磷酸基、多羟基烷氧基羰基、羧基烷氧基；
R3选自氢、取代或未取代的C1-6烷基、取代或未取代的C1-6环烷基、取代或未取代的C1-6杂环烷基；
R4为任选取代的包含至少两个单原子的单环或双环系统，并且所述环系当中至少有一个环为芳环，且芳环可以是未取代的或者例如被以下一个或多个，特别是1-3个下列取代基取代：卤素，羟基，氨基，硝基、氰基、氨基、羟基、羟甲基、羟乙基、巯基、羧基、酯基，取代或未取代的C1-6烷基，C2-10烯基、C2-10炔基，取代或未取代的C4-10芳基、取代或未取代的C1-8杂芳基、烷氧基羰基、环烷基羰胺基、烷巯基、羟基烷氧基、糖残基、磺酸基、磷酸基、多羟基烷氧基羰基、羧基烷氧基；其单环或双环包括但不限于苯基、萘基、茚基、薁基、芴基和蒽基，呋喃基、噻吩基、吡啶基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、吡唑烷基、异噁唑基、异三唑基、1,2,3-噁二唑基、1,2,3-三唑基、1,3,4-噻二唑基、哒嗪基、嘧啶基、吡嗪基、1,3,5-三嗪基、1,3,5-三噻烷基、中氮茚基、吲哚基、异氮茚基、二氢吲哚基、苯并[b]呋喃基、苯并[b]噻吩基、1H-吲唑基、苯并咪唑基、苯并噻唑基、嘌呤基、4H-喹嗪基、喹啉基、1,2,3,4-四氢异喹啉基、异喹啉基、1,2,3,4-四氢异喹啉基、肉啉基、2,3-二氮杂萘基、喹唑啉基、喹喔啉基、1,8-二氮杂萘基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基和吩噁嗪基。
进一步的，式(1)中手性碳的绝对构型可为S构型，如式(2)所示：
在一些优选方案中，W、X、Y、Z中有一个为氮原子，其余三个为碳原子，例如W或Z为氮原子，其余均为碳原子。
在一些优选方案中，R1为H或卤素(例如Cl等)。
在一些优选方案中，R2为取代或未取代的C1～C6烷基、吡啶基、苯基、吡唑基、噻吩基，其中取代基为吡啶基、C1～C6烷基、(C1～C6烷基)磺酰基、羟基、卤素(例如F等)中的一个或多个。
在一些优选方案中，R3为C1～C6的链烷基或C3～C6的环烷基。
在一些优选方案中，R4为具体的，所述化合物可为具有以下任一结构的化合物：
第二方面，本发明提供了化合物12～41的制备方法，采用反应路线I合成化合物12～41；
反应路线I包括以下过程：
化合物1与三氯化铝、乙酰氯在无水二氯甲烷中反应生成3-乙酰基-氮杂吲哚即化合物2，然后经碘化亚铜催化下的Ullmann偶联反应形成化合物3，接着与S-叔丁基亚磺酰胺缩合形成亚胺中间体4，再在二异丁基氢化铝DIBAL-H的作用下还原生成S构型的化合物5，接着在盐酸条件下水解得到化合物6，化合物6与氯代化合物R4-Cl进行亲核取代获得目标化合物。
进一步的，当R4为时，氯代化合物R4-Cl可采用反应路线II合成；反应路线II包括以下过程：
化合物7在N,N-二甲基甲酰胺DMF中和三氯氧磷反应，生成化合物8，化合物8与盐酸羟胺作用，醛基反应生成肟，得化合物9，接着在无水二氯甲烷DCM中和氯化亚砜反应脱水形成氰基得到化合物10，化合物10在1,4-二氧六环中与氨水作用生成目标化合物11。
按照上述制备方法制备得到的化合物、其药学上可接受的盐、水合物、溶剂合物、多晶型物或前药可以通过柱层析、高效液相色谱、结晶或其他适当的方法进行纯化。
第一方面所述的化合物可以表现出互变异构、结构异构和立体异构的现象。本发明包括其任意互变或结构或立体异构形式及其混合物，它们具有调节激酶活性的能力，并且此能力并不限于任何一种异构或其混合物的形式。
第三方面，本发明提供了一种药物组合物，包含第一方面所述的化合物，或其药学上可接受的盐，或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体，以及可药用载体、稀释剂、赋形剂中的至少一种。
药学上可接受的载体(即可药用载体)是指能与组合物中的活性成分相容(在一些实施方案中，能稳定活性成分)并且对所治疗的个体无害的载体。药用载剂和/或赋形剂可选自填充剂、盐、崩解剂、黏合剂、润滑剂、助流剂、润湿剂、控制释放基质、着色剂、调味剂、缓冲剂、稳定剂、增溶剂及其组合。
包含本文第一方面所述的化合物和/或其药学上可接受的盐的药物组合物可以以各种已知的方式、例如口服、局部、直肠、肠胃外、吸入或植入等方式施用。
根据治疗目的，可将药物组合物制成各种类型的给药单位剂型，如片剂、丸剂、粉剂、液体制剂、悬浮液、乳液、颗粒剂、胶囊、栓剂和针剂(溶液及悬浮液)等。
为了使片剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋形剂，例如，载体，如乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、结晶纤维素和硅酸等；粘合剂，如水、乙醇、丙醇、普通糖浆、葡萄糖溶液、淀粉溶液、明胶溶液，羧甲基纤维素、紫胶、甲基纤维素和磷酸钾、聚乙烯吡咯烷酮等；崩解剂，如干淀粉、藻酸钠、琼脂粉和海带粉，碳酸氢钠、碳酸钙、聚乙烯脱水山梨醇的脂肪酸酯、十二烷基硫酸钠、硬脂酸单甘酯、淀粉和乳糖等；崩解抑制剂，如白糖、甘油三硬脂酸酯、椰子油和氢化油；吸附促进剂，如季胺碱和十二烷基硫酸钠等；润湿剂，如甘油、淀粉等；吸附剂，如淀粉、乳糖、高岭土、膨润土和胶体硅酸等；以及润滑剂，如纯净的滑石，硬脂酸盐、硼酸粉和聚乙二醇等。还可以根据需要选用通常的涂渍材料制成糖衣片剂、涂明胶膜片剂、肠衣片剂、涂膜片剂、双层膜片剂及多层片剂。
为了使丸剂形式的药物组合物成形，可使用本领域任何己知的并广泛使用的赋形剂，例如，载体，如乳糖，淀粉，椰子油，硬化植物油，高岭土和滑石粉等；粘合剂，如阿拉伯树胶粉，黄蓍胶粉，明胶和乙醇等；崩解剂，如琼脂和海带粉等。
为了使栓剂形式的药物组合物成形，可使用本领域任何己知并广泛使用的赋性剂，例如，聚乙二醇，椰子油，高级醇，高级醇的酯，明胶和半合成的甘油酯等。
为了制备针剂形式的药物组合物，可将溶液或悬浮液消毒后(最好加入适量的氯化钠，葡萄糖或甘油等)，制成与血液等渗压的针剂。在制备针剂时，也可使用本领域内任何常用的载体，例如，水，乙醇，丙二醇，乙氧基化的异硬脂醇，聚氧基化的异硬脂醇和聚乙烯脱水山梨醇的脂肪酸酯等。此外，还可加入通常的溶解剂、缓冲剂和止痛剂等。
本发明中，所述药物组合物的给药方法没有特殊限制。可根据病人年龄、性别和其它条件及症状，选择各种剂型的制剂给药。例如，片剂、丸剂、溶液、悬浮液、乳液、颗粒剂或胶囊口服给药；针剂可以单独给药，或者和注射用输送液(如葡萄糖溶液及氨基酸溶液)混合进行静脉注射；栓剂为给药到直肠。
第四方面，本发明提供了一种体内或体外抑制PI3K活性的方法，其包括使用有效量的一种第一方面所述的化合物和/或其药学上可接受的盐与PI3K接触。
第五方面，本发明提供了一种体内或体外抑制PI3K活性的方法，其包括使能有效抑制PI3K活性的量的一种药物组合物与PI3K接触，所述药物组合物包含一种第一方面所述的化合物和/或一种其药学上可接受的盐，以及至少一种药学上可接受的赋形剂。
第六方面，本发明提供了一种治疗个体中对抑制PI3K有响应的疾病的方法，其包括给需要其的个体施用能有效抑制所述个体中PI3K的量的一种第一方面所述的化合物和/或一种其药学上可接受的盐。
第七方面，本发明提供了一种治疗个体中对抑制Pl3K有响应的疾病的方法，其包括给需要其的个体施用能有效抑制所述个体中PI3K的量的一种药物组合物，所述药物组合物包含一种第一方面所述的化合物和/或一种其药学上可接受的盐，以及至少一种药学上可接受的赋形剂。
第八方面，本发明提供了第一方面所述的化合物，或其药学上可接受的盐，或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体，或者第三方面所述的药物组合物在制备PI3Kδ激酶抑制剂中的应用。
第九方面，本发明提供了第一方面所述的化合物，或其药学上可接受的盐，或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体，或者第三方面所述的药物组合物在制备用于治疗对抑制PI3Kδ有响应的疾病的药剂中的应用。所述疾病包括炎症性疾病、自身免疫性疾病、癌症、感染性疾病、心脑血管疾病。
所述的炎症性疾病、自身免疫性疾病为类风湿性关节炎、慢性阻塞性肺病(COPD)、变应性鼻炎、哮喘、红斑狼疮、银屑病和多发性硬化。
所述的癌症为实体瘤或血液系统恶性肿瘤，其选自白血病、多发性骨髓瘤(MM)、淋巴瘤；所述的白血病为急性淋巴细胞白血病(ALL)、急性髓性白血病(AML)、慢性淋巴细胞白血病(CLL)和慢性髓性白血病(CML)；所述的淋巴瘤为霍奇金淋巴瘤、非霍奇金淋巴瘤(NHL)、套细胞淋巴瘤(MCL)、滤泡型淋巴瘤、B细胞淋巴瘤、细胞淋巴瘤、弥散性大B细胞淋巴瘤(DLBCL)。
所述的感染性疾病包括细菌性感染、真菌性感染、病毒性感染、寄生虫感染。
所述的心脑血管疾病包括急性心力衰竭、低血压、高血压、心绞痛、心肌梗塞、心肌病、充血性心力衰竭、动脉粥样硬化、冠心病、再狭窄和血管狭窄，以及外伤性脑损伤、中风、缺血再灌注损伤和动脉。
此外，本文第一方面所述的化合物和/或其药学上可接受的盐可与其它的活性成分联合用药，用于治疗炎症性疾病、自身免疫性疾病、癌症、感染性疾病或心脑血管疾病。第一方面所述的化合物和/或其药学上可接受的盐可与其它的活性成分分开用药或制成复方制剂。其它的活性成分是指那些已知的对治疗PI3K介导的疾病的有效的成分。
定义
术语“烷基”是指含有1-18个碳原子、例如1-12个碳原子、再例如1-6个碳原子、再例如1-4个碳原子的直链或支链的饱和烷基。例如，“C1～C6烷基”在“烷基”的范围内，表示所述的具有1-6个碳原子的烷基。烷基的例子包括但不限于甲基(“Me”)、乙基(“Et”)、正丙基(“n-Pr”)、异丙基(“i-Pr”)、正丁基(“n-Bu”)、异丁基(“i-Bu”)、仲丁基(“s-Bu”)和叔丁基(“t-Bu”)。
术语“卤素”(或“卤代”)是指氟、氯、溴和碘(或者称为氟代(F)、氯代(Cl)、溴代(Br)和碘代(I))。
术语“烷氧基”是指基团-O-烷基，其中烷基如上文所定义。烷氧基的例子包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基和已氧基，包括它们的异构体。
术语“芳基”是指由一个环或多个环稠合组成的含有6-14个环碳原子，例如6-12个环碳原子的碳环烃基，其中至少一个环是芳族环并且其它环不是如下文所定义的杂芳基，其连接点可以在芳族环上或在其它环上。芳基的例子包括但不限于苯基、萘基、1,2,3,4-四氢萘基、茚基、茚满基、奧基，优选苯基。
术语“杂芳基”或“杂芳的”是指选自4至12元单环的、双环的和三环的、饱和的和部分不饱和的环，其除了包含至少一个、例如1-4个、再例如1-3个或再例如1或2个选自O、S和N的杂原子外，还包含至少一个碳原子。杂芳基的连接点可以在杂原子上或在碳上。”杂芳基”或“杂芳的”也指单环，其包含至少一个选自O、S和N的杂原子；或者是稠环，其中至少一个环包含至少一个选自O、S和N的杂原子并且其它环不是杂芳基或芳基，其连接点可以在杂芳上或在其它环上。
如果本文的某个结构式包含星号“*”，则该结构式所表示的化合物为消旋体。
术语“被一个或多个取代基取代”意指给定的原子或基团上的一个或多个氢原子独立地被一个或多个选自给定基团的取代基替换。在一些实施方案中，“被一个或多个取代基取代”意指给定的原子或基团被1、2、3或4个独立地选自给定基团的取代基取代。
术语“药学上可接受的盐”是指所公开化合物的衍生物，其中母体化合物通过使现有酸或碱部分转化成其盐形式而得到改性。药学上可接受的盐包括但不限于：第一方面所述的化合物与无机酸或有机酸形成的酸加成盐，药学上可接受的盐也包括带有酸性基团的第一方面所述的化合物与药学上可接受的阳离子形成的碱加成盐。本发明的药学上可接受的盐可通过常规化学方法自含有碱性或酸性部分的母体化合物合成。一般来说，这些盐可通过使这些化合物的游离酸或碱形式与化学计算量的适当碱或酸在水或有机溶剂或两者的混合物中反应来制备。
术语“溶剂合物”意指包含化学计量的或非化学计量的溶剂量的溶剂加成形式。如果溶剂是水，则形成的溶剂合物是水合物，当溶剂是乙醇时，则形成的溶剂合物是乙醇合物。
术语“前药”指为化合物的非活性前体，在体内通过正常代谢途径转化为其活性形式的化合物。为了说明，可通过水解(例如)酯或酰胺键将前药转化为药理学活性形式，从而引入或暴露所生成的产物上的官能团。
本文所用的未具体定义的技术和科学术语具有本发明所属领域的技术人员通常理解的含义。
本发明与现有技术相比，有益效果有：本发明提供了一类可作为PI3Kδ激酶抑制剂的含或不含杂原子(如氮杂原子等)的吲哚衍生物及其药物组合物，可用于治疗与PI3Kδ抑制相关的疾病、病症或病状，包括免疫病症、癌症和心血管疾病等。
具体实施方式
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操作方法，通常按照常规条件，或按照制造厂商所建议的条件。
制备实施例1
将4-氯-7-氮杂吲哚(2g,13.11mmol)和三氯化铝(8.74g,65.55mmol)置于二口瓶中，抽真空通氩气，置换三次，加入无水二氯甲烷，在室温下反应30min后于0℃缓慢滴加乙酰氯(4.67mL,65.55mmol)，滴加完毕后，恢复室温反应3h，于0℃滴缓慢滴加甲醇淬灭乙酰氯。将反应液浓缩，往剩余物中加入水，并用氢氧化钠水溶液将反应液的pH值调至4左右，用乙酸乙酯萃取三次，合并有机层，饱和氯化钠洗，无水硫酸钠干燥，浓缩得到粗品，粗品用PE/EA重结晶，抽滤得到黄绿色固体2(2g,78％)。
制备实施例2
称取化合物2(2g,10.28mmol)、碘化亚铜(392mg,2.06mmol)、(1R,2R)-(-)-N,N'-二甲基-1,2-环己二胺(587g,4.12mmol)、碳酸钾(2.84g,20.56mmol)加入到二口瓶中，氩气保护加入二甲基亚砜，室温下加入3-溴吡啶(2.44g,15.42mmol)升温至90℃反应2h。反应完成后，冷却至室温，加入乙酸乙酯搅拌30min，抽滤除去不溶物，滤液用水萃取三次，合并有机层，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品用PE/EA(v/v，5:1)的淋洗剂经柱层析分离得到纯品3(2.24g,80％)。
制备实施例3
两口瓶中加入原料3(2.24g,8.26mmol)和S-叔丁基亚磺酰胺(2.00g,16.52mmol)，抽真空通氩气，置换三次，加入无水四氢呋喃，室温下加入钛酸四乙酯(3.77g,16.52mmol)升温至80℃回流反应过夜。反应完成后，冷却至室温，加入水乙酸乙酯搅拌30min，抽滤除去不溶物，滤液用水萃取三次，合并有机层，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品用PE/EA(v/v，1:1)的淋洗剂经柱层析分离得到淡黄色固体4(2.17g,70％)。
制备实施例4
两个瓶中加入原料4(2.17g,5.79mmol)，抽真空通氩气，置换三次，加入无水甲苯，于-78℃缓慢滴加DIBAL-H(11.58mL,11.58mmol)，滴加完毕于-78℃反应4h。反应完毕后，于低温下加入饱和NH4Cl搅拌30min，抽滤除去不溶物，滤液用水萃取三次，合并有机层，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品用PE/EA(v/v，1:1)的淋洗剂经柱层析分离得到白色固体5(1.79g,82％)。
制备实施例5
将原料5(1.79g,4.76mmol)加入单口瓶中，加入甲醇溶解，加入4N HCl于室温1h，反应完毕后，将反应液浓缩，往剩余物中加入水，并用氢氧化钠水溶液将反应液的pH值调至碱性，用二氯甲烷萃取三次，合并有机层，饱和氯化钠洗，无水硫酸钠干燥，浓缩得到粗品，粗品用DCM/MeOH重结晶，抽滤得到白色固体6(1.29g,100％)。
制备实施例6
耐压管中加入原料6(1.29g,4.76mmol)、原料11(887mg,5.24mmol)和DIPEA(921mg,7.14mmol)，加入正丁醇溶解于140℃反应过夜。反应结束后，冷却至室温，加入水稀释，用乙酸乙酯萃取三次，合并有机层，饱和氯化钠洗，无水硫酸钠干燥，浓缩，用DCM/MeOH(v/v，50:1)的淋洗剂经柱层析分离得到白色固体12(960mg,50％)。
1H NMR(400MHz,DMSO-d6)δ9.10(d,J＝2.4Hz,1H),8.59(dd,J＝4.8,1.6Hz,1H),8.30(ddd,J＝8.4,2.8,1.6Hz,1H),8.27(d,J＝5.2Hz,1H),8.11(s,1H),7.62(ddd,J＝8.4,4.8,0.8Hz,1H),7.36(d,J＝5.2Hz,1H),6.58(d,J＝8.0Hz,1H),6.54(s,2H),6.41(s,2H),5.96(p,J＝6.8Hz,1H),1.64(d,J＝6.8Hz,3H).13C NMR(100MHz,DMSO-d6)δ170.54,168.32,167.89,153.25,152.53,149.87,149.20,140.47,139.47,136.37,132.35,129.28,123.80,123.29,123.11,122.71,65.14,47.31,26.79.
制备实施例7(S)-2,4-二氨基-6-((1-(1-(吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-3-基)乙基)氨基)嘧啶-5-腈13
制备方法同制备实施方案1-6类似，更换反应物即可，下同，柱层析得白色固体13，收率53％。
1H NMR(500MHz,DMSO-d6)δ9.17(d,J＝2.5Hz,1H),8.53(dd,J＝4.5,1.5Hz,1H),8.38(ddd,J＝8.5,2.5,1.5Hz,1H),8.32(dd,J＝4.5,1.5Hz,1H),8.14(dd,J＝8.0,1.5Hz,1H),7.98(s,1H),7.59(ddd,J＝8.5,4.5,1.0Hz,1H),7.23(dd,J＝8.0,4.5Hz,1H),6.82(d,J＝8.5Hz,1H),6.58–6.44(m,4H),5.82–5.75(m,1H),1.66(d,J＝7.0Hz,3H).13C NMR(100MHz,DMSO-d6)δ165.96,163.54,163.21,147.57,146.96,144.33,143.90,135.24,130.60,129.11,125.33,124.47,120.71,119.95,118.23,117.52,60.09,41.96,20.79.
制备实施例8(S)-2,4-二氨基-6-((1-(6-氯-1-(吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-3-基)乙基)氨基)嘧啶-5-腈14
制备方法同制备实施案例1-6类似，柱层析得白色固体14，收率57％。
1H NMR(400MHz,Methanol-d4)δ9.10(m,1H),8.51(m,1H),8.34(ddd,J＝8.4,2.8,1.2Hz,1H),8.11(d,J＝8.4Hz,1H),7.79(s,1H),7.61(dd,J＝8.4,4.8Hz,1H),7.20(d,J＝8.4Hz,1H),5.91–5.80(m,1H),1.71(d,J＝6.8Hz,3H).13C NMR(100MHz,Methanol-d4)δ164.87,162.59,162.25,145.60,145.35,144.26,142.74,140.79,134.39,130.38,130.28,123.58,119.42,118.43,116.02,115.88,44.45,41.23,18.47.
制备实施例9(S)-2,4-二氨基-6-((1-(6-氯-1-(3-(甲磺酰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)乙基)氨基)嘧啶-5-腈15
制备方法同制备实施案例1-6类似，柱层析得白色固体15，收率60％。
1H NMR(500MHz,DMSO-d6)δ8.37–8.33(m,1H),8.28(dd,J＝8.0,2.0Hz,1H),8.20(d,J＝8.0Hz,1H),8.05(s,1H),7.94–7.90(m,1H),7.89–7.83(m,1H),7.32(d,J＝8.5Hz,1H),6.91(d,J＝8.5Hz,1H),6.65–6.35(m,4H),5.78(p,J＝7.0Hz,1H),3.32(s,3H),1.66(d,J＝7.0Hz,3H).13C NMR(100MHz,DMSO-d6)δ165.97,163.52,163.19,146.09,144.32,142.46,138.53,132.29,131.10,128.39,126.34,124.92,121.60,120.43,119.81,118.19,117.52,60.13,44.01,41.72,20.80.
制备实施例10(S)-2,4-二氨基-6-((1-(1-(吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-3-基)乙基)氨基)嘧啶-5-腈16
制备方法同制备实施案例1-6类似，柱层析得白色固体16，收率55％。
1H NMR(600MHz,DMSO-d6)δ8.88(d,J＝2.4Hz,1H),8.62(dd,J＝4.8,1.2Hz,1H),8.47(dd,J＝4.8,1.2Hz,1H),8.09(ddd,J＝8.4,2.4,1.8Hz,1H),8.01–7.95(m,2H),7.66–7.59(m,1H),7.27(dd,J＝8.4,4.8Hz,1H),7.02(d,J＝8.4Hz,1H),6.55(s,2H),6.46(s,2H),5.80(p,J＝7.2Hz,1H),1.64(d,J＝7.2Hz,3H).13C NMR(150MHz,DMSO-d6)δ165.61,163.59,163.34,148.03,145.64,145.06,143.78,135.56,131.53,129.04,128.76,125.06,120.49,118.66,118.24,118.17,60.23,42.97,23.11.
制备实施例11(S)-2,4-二氨基-6-((1-(1-(吡啶-3-基)-1H-吡咯并[2,3-c]吡啶-3-基)乙基)氨基)嘧啶-5-腈17
制备方法同制备实施案例1-6类似，柱层析得白色固体17，收率77％。
1H NMR(600MHz,Chloroform-d)δ8.89(s,1H),8.86(d,J＝2.4Hz,1H),8.70(dd,J＝4.8,1.8Hz,1H),8.35(d,J＝5.4Hz,1H),7.90–7.84(m,1H),7.63–7.58(m,1H),7.54(dd,J＝8.4,4.8Hz,1H),7.40(s,1H),5.80(p,J＝7.2Hz,1H),5.23(d,J＝8.4Hz,1H),5.07(s,2H),4.98(s,2H),1.73(d,J＝7.2Hz,3H).13C NMR(150MHz,Chloroform-d)δ165.10,163.04,162.96,148.60,145.59,145.59,140.00,135.20,133.53,133.53,132.62,131.53,127.84,124.37,120.41,114.45,62.35,42.44,20.97.
制备实施例12(S)-2,4-二氨基-6-((1-(1-(吡啶-3-基)-1H-吡咯并[3,2-c]吡啶-3-基)乙基)氨基)嘧啶-5-腈18
制备方法同制备实施案例1-6类似，柱层析得白色固体18，收率61％。
1H NMR(600MHz,DMSO-d6)δ9.00(d,J＝1.2Hz,1H),8.87(dd,J＝2.4,1.2Hz,1H),8.64(dd,J＝4.8,1.2Hz,1H),8.29(d,J＝5.4Hz,1H),8.09(ddd,J＝8.4,2.4,1.8Hz,1H),7.79(s,1H),7.64(ddd,J＝8.4,4.8,1.2Hz,1H),7.54(dd,J＝5.4,1.2Hz,1H),6.86(d,J＝8.4Hz,1H),6.51(s,4H),5.86(p,J＝7.2Hz,1H),1.67(d,J＝7.2Hz,3H).13C NMR(150MHz,DMSO-d6)δ165.94,163.52,163.15,148.31,145.21,143.58,142.33,139.47,135.28,131.77,127.23,125.06,124.74,121.42,118.17,106.11,60.07,41.72,21.09.
制备实施例13(S)-2,4-二氨基-6-((1-(5-氯-1-(吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-3-基)乙基)氨基)嘧啶-5-腈19
制备方法同制备实施案例1-6类似，柱层析得白色固体19，收率63％。
1H NMR(500MHz,DMSO-d6)δ9.11(dd,J＝2.5,1.0Hz,1H),8.56(dd,J＝4.5,1.5Hz,1H),8.36–8.30(m,3H),8.08(s,1H),7.60(ddd,J＝8.5,4.5,1.0Hz,1H),6.96(d,J＝8.5Hz,1H),6.64–6.35(m,4H),5.71(p,J＝7.0Hz,1H),1.66(d,J＝7.0Hz,3H).13CNMR(100MHz,DMSO-d6)δ166.03,163.45,163.18,147.44,145.81,144.51,141.93,134.75,130.89,128.44,127.75,124.51,124.26,121.50,119.65,118.18,60.12,42.06,20.68.
制备实施例14(S)-N-(1-(4-氯-1-(吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-3-基)乙基)-9H-嘌呤-6-胺20
制备方法同制备实施案例1-6类似，柱层析得白色固体20，收率64％。
1H NMR(400MHz,DMSO-d6)δ12.94(s,1H),9.07(s,1H),8.57(d,J＝4.8Hz,1H),8.32–8.20(m,3H),8.13(d,J＝17.6Hz,2H),7.80(s,1H),7.60(dd,J＝8.4,4.8Hz,1H),7.34(dd,J＝5.2,2.0Hz,1H),6.22(s,1H),1.71(d,J＝6.8Hz,3H).13C NMR(100MHz,DMSO-d6)δ152.90,148.51,147.91,147.77,145.29,145.06,144.51,139.34,139.32,135.76,134.76,131.95,131.56,127.18,124.56,118.52,117.95,52.52,22.59.
制备实施例15(S)-N6-(1-(4-氯-1-(吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-3-基)乙基)-9H-嘌呤-2,6-二胺21
制备方法同制备实施案例1-6类似，柱层析得白色固体21，收率52％。
1H NMR(600MHz,DMSO-d6)δ12.41(m,3H),9.09(d,J＝2.4Hz,1H),8.59(dd,J＝4.8,1.2Hz,1H),8.32–8.26(m,2H),8.22(s,1H),7.79(s,1H),7.62(dd,J＝8.4,4.8Hz,1H),7.35(d,J＝5.4Hz,1H),6.17–6.02(m,2H),1.71(d,J＝7.2Hz,3H).13C NMR(150MHz,DMSO-d6)δ160.62,148.45,147.82,147.69,144.99,144.78,144.37,135.75,134.75,131.48,124.49,124.49,118.47,118.44,118.44,117.91,117.90,55.38,49.07.
制备实施例16(S)-4-氨基-6-((1-(4-氯-1-(吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-3-基)乙基)氨基)嘧啶-5-腈22
制备方法同制备实施案例1-6类似，柱层析得白色固体22，收率49％。
1H NMR(600MHz,DMSO-d6)δ9.08(d,J＝2.4Hz,1H),8.58(dd,J＝4.8,1.2Hz,1H),8.29(ddd,J＝8.4,2.4,1.8Hz,1H),8.26(d,J＝5.4Hz,1H),8.11(s,1H),8.07(s,1H),7.61(dd,J＝8.4,4.8Hz,1H),7.38(d,J＝7.8Hz,1H),7.35(d,J＝5.4Hz,1H),7.21(s,2H),6.03(p,J＝7.2Hz,1H),1.65(d,J＝7.2Hz,3H).13C NMR(150MHz,DMSO-d6)δ164.90,161.93,160.22,148.46,147.75,145.04,144.46,135.61,134.66,131.56,127.43,124.49,118.76,118.49,117.92,116.10,68.31,43.16,21.79.
制备实施例17(S)-2,4-二氨基-6-((1-(4-氯-1-(4-羟基苯基)-1H-吡咯并[2,3-b]吡啶-3-基)乙基)氨基)嘧啶-5-腈23
制备方法同制备实施案例1-6类似，柱层析得白色固体23，收率64％。
1H NMR(600MHz,DMSO-d6)δ9.69(s,1H),8.19(d,J＝5.4Hz,1H),7.84(s,1H),7.52(d,J＝9.0Hz,2H),7.27(d,J＝5.4Hz,1H),6.93(d,J＝9.0Hz,2H),6.57(d,J＝8.4Hz,1H),6.52(s,2H),6.38(s,2H),5.97(p,J＝7.2Hz,1H),1.62(d,J＝7.2Hz,3H).13CNMR(150MHz,DMSO-d6)δ165.75,163.54,163.10,156.64,148.43,143.95,135.22,129.63,128.35,126.15,118.33,117.60,117.47,117.15,116.06,60.30,42.52,22.29.
制备实施例18(S)-2,4-二氨基-6-((1-(4-氯-1-(3-羟基苯基)-1H-吡咯并[2,3-b]吡啶-3-基)乙基)氨基)嘧啶-5-腈24
制备方法同制备实施案例1-6类似，柱层析得白色固体24，收率66％。
1H NMR(600MHz,DMSO-d6)δ9.80(s,1H),8.24(d,J＝5.4Hz,1H),7.93(s,1H),7.40–7.27(m,3H),7.26–7.17(m,1H),6.79(dd,J＝8.4,2.4Hz,1H),6.66(d,J＝8.4Hz,1H),6.54(s,2H),6.39(s,2H),5.98(p,J＝7.2Hz,1H),1.63(d,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ170.56,168.32,167.89,163.19,153.06,148.86,143.83,140.17,135.23,132.62,123.11,123.09,122.81,122.50,119.42,118.79,116.13,65.09,47.26,27.07.
制备实施例19(S)-2,4-二氨基-6-((1-(4-氯-1-(1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶-3-基)乙基)氨基)嘧啶-5-腈25
制备方法同制备实施案例1-6类似，柱层析得白色固体25，收率68％。
1H NMR(400MHz,DMSO-d6)δ13.09(s,1H),8.38(s,1H),8.26(d,J＝5.2Hz,1H),8.09(s,1H),7.95(s,1H),7.27(d,J＝5.2Hz,1H),6.56(d,J＝8.0Hz,1H),6.51(s,2H),6.39(s,2H),5.92(p,J＝6.8Hz,1H),1.62(d,J＝6.8Hz,3H).13C NMR(100MHz,DMSO-d6)δ165.77,163.57,163.13,148.00,144.28,135.40,132.37,127.61,121.71,121.35,118.37,117.75,117.66,117.20,60.38,42.56,22.03.
制备实施例20(S)-2,4-二氨基-6-((1-(4-氯-1-(1H-吡唑-3-基)-1H-吡咯并[2,3-b]吡啶-3-基)乙基)氨基)嘧啶-5-腈26
制备方法同制备实施案例1-6类似，柱层析得白色固体26，收率62％。
1H NMR(400MHz,DMSO-d6)δ12.87(s,1H),8.28(d,J＝5.2Hz,1H),8.05(s,1H),7.87(t,J＝2.0Hz,1H),7.31(d,J＝5.2Hz,1H),7.00(t,J＝2.0Hz,1H),6.89(d,J＝8.4Hz,1H),6.52(s,2H),6.34(s,2H),5.98(p,J＝6.8Hz,1H),1.60(d,J＝6.8Hz,3H).13CNMR(100MHz,DMSO-d6)δ165.86,163.53,163.20,147.80,146.26,144.43,135.46,130.64,125.27,119.05,118.34,117.97,117.58,97.33,60.37,42.48,22.53.
制备实施例21(S)-2,4-二氨基-6-((1-(4-氯-1-(吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-3-基)乙基)氨基)嘧啶-5-腈27
制备方法同制备实施案例1-6类似，柱层析得白色固体27，收率59％。
1H NMR(400MHz,DMSO-d6)δ8.73–8.68(m,2H),8.33(d,J＝5.2Hz,1H),8.22(s,1H),8.16–8.12(m,2H),7.41(d,J＝5.2Hz,1H),6.66(d,J＝8.0Hz,1H),6.52(s,2H),6.39(s,2H),5.95(p,J＝6.8Hz,1H),1.64(d,J＝6.8Hz,3H).13C NMR(100MHz,DMSO-d6)δ166.30,164.18,164.04,163.64,151.85,149.24,145.20,145.07,142.12,136.41,126.90,120.74,119.61,119.52,118.82,117.14,60.93,43.00,22.44.
制备实施例22(S)-2,4-二氨基-6-((1-(4-氯-1-(1-甲基-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶-3-基)乙基)氨基)嘧啶-5-腈28
制备方法同制备实施案例1-6类似，柱层析得白色固体28，收率55％。
1H NMR(400MHz,Methanol-d4)δ8.27(d,J＝2.4Hz,1H),8.22(dd,J＝5.2,2.0Hz,1H),7.96(s,1H),7.81–7.71(m,1H),7.22(d,J＝5.2Hz,1H),6.10–5.73(m,1H),3.97(s,3H),1.73(d,J＝6.8Hz,3H).13C NMR(150MHz,Methanol-d4)δ164.87,162.69,161.99,147.78,144.35,135.36,131.70,131.68,127.67,123.90,121.42,117.77,117.22,115.84,77.68,60.81,43.60,21.18.
制备实施例23(S)-2,4-二氨基-6-((1-(4-氯-1-(吡啶-2-基)-1H-吡咯并[2,3-b]吡啶-3-基)乙基)氨基)嘧啶-5-腈29
制备方法同制备实施案例1-6类似，柱层析得白色固体29，收率57％。
1H NMR(600MHz,DMSO-d6)δ8.79(d,J＝8.4Hz,1H),8.55(ddd,J＝4.8,1.8,1.2Hz,1H),8.45(s,1H),8.33(d,J＝5.4Hz,1H),8.03(ddd,J＝8.4,7.2,2.4Hz,1H),7.38(d,J＝5.4Hz,1H),7.35(ddd,J＝7.2,4.8,1.2Hz,1H),6.97(d,J＝8.4Hz,1H),6.52(s,2H),6.32(s,2H),6.00(p,J＝7.2Hz,1H),1.61(d,J＝7.2Hz,3H).13C NMR(150MHz,DMSO-d6)δ165.85,163.46,163.16,149.85,148.89,148.20,144.21,139.38,135.68,125.01,121.78,120.03,119.19,118.76,118.28,116.09,60.40,42.53,22.47.
制备实施例24(S)-2,4-二氨基-6-((1-(4-氯-1-(3-氟苯基)-1H-吡咯并[2,3-b]吡啶-3-基)乙基)氨基)嘧啶-5-腈30
制备方法同制备实施案例1-6类似，柱层析得白色固体30，收率61％。
1H NMR(600MHz,DMSO-d6)δ8.27(d,J＝5.4Hz,1H),8.07(s,1H),7.86(dt,J＝10.8,2.4Hz,1H),7.76(ddd,J＝8.4,2.4,1.2Hz,1H),7.60(td,J＝8.4,6.6Hz,1H),7.35(d,J＝5.4Hz,1H),7.22(td,J＝8.4,2.4Hz,1H),6.56(d,J＝7.8Hz,1H),6.52(s,2H),6.38(s,2H),5.96(p,J＝7.2Hz,1H),1.63(d,J＝7.2Hz,3H).13C NMR(150MHz,DMSO-d6)δ165.76,163.53,163.12,162.63(d,J＝241.5Hz),148.37,144.32,139.50(d,J＝12.0Hz),135.62,131.38(d,J＝9.0Hz),127.65,119.65(d,J＝3.0Hz),118.88,118.47,118.30,118.08,113.44(d,J＝21.0Hz),111.09(d,J＝25.5Hz),60.38,42.50,22.08.
制备实施例25(S)-2,4-二氨基-6-((1-(4-氯-1-(3,5-二氟苯基)-1H-吡咯并[2,3-b]吡啶-3-基)乙基)氨基)嘧啶-5-腈31
制备方法同制备实施案例1-6类似，柱层析得白色固体31，收率63％。
1H NMR(600MHz,DMSO-d6)δ8.31(d,J＝5.4Hz,1H),8.16(s,1H),7.89–7.82(m,2H),7.37(d,J＝5.4Hz,1H),7.26(tt,J＝9.0,2.4Hz,1H),6.55–6.47(m,3H),6.39(s,2H),5.94(p,J＝6.6Hz,1H),1.63(d,J＝6.6Hz,3H).13C NMR(150MHz,DMSO-d6)δ165.75,163.53,163.11,162.95(dd,J＝243.0,15.0Hz),148.47,144.46,140.21(t,J＝15.0Hz),135.79,127.42,119.35,118.85,118.51,118.28,106.74(dd,J＝22.5,6.0Hz),101.80(t,J＝25.5Hz),60.42,42.49,21.92.
制备实施例26(S)-2,4-二氨基-6-((1-(4-氯-1-(噻吩-3-基)-1H-吡咯并[2,3-b]吡啶-3-基)乙基)氨基)嘧啶-5-腈32
制备方法同制备实施案例1-6类似，柱层析得白色固体32，收率66％。
1H NMR(600MHz,DMSO-d6)δ8.28(d,J＝5.4Hz,1H),8.06(s,1H),8.04(dd,J＝3.6,1.2Hz,1H),7.79(dd,J＝5.4,1.8Hz,1H),7.73(dd,J＝5.4,3.6Hz,1H),7.31(d,J＝5.4Hz,1H),6.57(d,J＝8.4Hz,1H),6.51(s,2H),6.37(s,2H),5.94(p,J＝7.2Hz,1H),1.63(d,J＝7.2Hz,3H).13C NMR(150MHz,DMSO-d6)δ165.76,163.53,163.12,148.04,144.29,136.35,135.48,127.60,126.80,123.01,118.29,118.19,118.09,117.60,114.11,60.39,42.52,22.07.
制备实施例27(S)-2,4-二氨基-6-((1-(4-氯-1-(吡啶-2-基甲基)-1H-吡咯并[2,3-b]吡啶-3-基)乙基)氨基)嘧啶-5-腈33
制备方法同制备实施案例1-6类似，柱层析得白色固体33，收率65％。
1H NMR(400MHz,Methanol-d4)δ8.48(d,J＝4.8Hz,1H),8.12(d,J＝5.2Hz,1H),7.72(td,J＝7.6,1.6Hz,1H),7.57(s,1H),7.33–7.26(m,1H),7.16(d,J＝5.2Hz,1H),7.04(d,J＝7.6Hz,1H),5.92(q,J＝6.8Hz,1H),5.60(d,J＝3.6Hz,2H),1.67(d,J＝6.8Hz,3H).13C NMR(150MHz,Methanol-d4)δ165.09,163.07,162.68,156.69,149.54,149.06,143.64,137.12,136.01,126.58,122.78,121.94,117.17,117.16,116.73,116.33,62.29,50.01,43.47,21.76.
制备实施例28(S)-2,4-二氨基-6-((1-(4-氯-1-(噻吩-2-基)-1H-吡咯并[2,3-b]吡啶-3-基)乙基)氨基)嘧啶-5-腈34
制备方法同制备实施案例1-6类似，柱层析得白色固体34，收率59％。
1H NMR(400MHz,DMSO-d6)δ8.31(d,J＝5.2Hz,1H),8.05(s,1H),7.45(dd,J＝3.6,1.6Hz,1H),7.41(dd,J＝5.6,1.2Hz,1H),7.35(d,J＝5.2Hz,1H),7.09(dd,J＝5.6,3.6Hz,1H),6.70(d,J＝8.0Hz,1H),6.51(s,2H),6.37(s,2H),5.94(p,J＝7.2Hz,1H),1.62(d,J＝7.2Hz,3H).13C NMR(150MHz,DMSO-d6)δ165.79,163.51,163.12,147.72,144.45,138.86,135.75,127.67,125.88,121.91,119.26,118.46,118.27,117.70,117.60,60.42,42.44,22.03.
制备实施例29(S)-2,4-二氨基-6-((1-(4-氯-1-苯基-1H-吡咯并[2,3-b]吡啶-3-基)乙基)氨基)嘧啶-5-腈35
制备方法同制备实施案例1-6类似，柱层析得白色固体35，收率55％。
1H NMR(400MHz,DMSO-d6)δ8.24(d,J＝5.2Hz,1H),7.99(s,1H),7.86–7.80(m,2H),7.64–7.53(m,2H),7.44–7.37(m,1H),7.32(d,J＝5.2Hz,1H),6.61(d,J＝8.0Hz,1H),6.52(s,2H),6.39(s,2H),5.98(p,J＝6.8Hz,1H),1.64(d,J＝6.8Hz,3H).13C NMR(150MHz,DMSO-d6)δ165.77,163.54,163.12,148.35,144.15,138.05,135.44,129.71,127.90,126.97,124.30,118.37,118.32,118.08,117.70,60.35,42.53,22.21.
制备实施例30(S)-2,4-二氨基-6-((1-(4-氯-1-(间甲苯基)-1H-吡咯并[2,3-b]吡啶-3-基)乙基)氨基)嘧啶-5-腈36
制备方法同制备实施案例1-6类似，柱层析得白色固体36，收率51％。
1H NMR(400MHz,DMSO-d6)δ8.23(d,J＝5.2Hz,1H),7.96(s,1H),7.66–7.59(m,2H),7.47–7.40(m,1H),7.30(d,J＝5.2Hz,1H),7.20(d,J＝7.6Hz,1H),6.59(d,J＝8.0Hz,1H),6.52(s,2H),6.38(s,2H),5.98(p,J＝6.8Hz,1H),2.41(s,3H),1.63(d,J＝6.8Hz,3H).13CNMR(100MHz,DMSO-d6)δ165.80,163.57,163.15,148.39,144.16,139.25,138.04,135.43,129.52,128.02,127.68,124.79,121.56,118.37,118.27,118.04,117.69,60.38,42.56,22.26,21.55.
制备实施例31(S)-2,4-二氨基-6-((1-(4-氯-1-(4-氟苯基)-1H-吡咯并[2,3-b]吡啶-3-基)乙基)氨基)嘧啶-5-腈37
制备方法同制备实施案例1-6类似，柱层析得白色固体37，收率62％。
1H NMR(400MHz,DMSO-d6)δ8.29(dd,J＝4.8,1.6Hz,1H),8.11(dd,J＝8.0,1.6Hz,1H),7.93–7.91(m,1H),7.84(s,1H),7.43–7.35(m,2H),7.20(dd,J＝8.0,4.8Hz,1H),6.78(d,J＝8.4Hz,1H),6.50(d,J＝14.4Hz,4H),5.79(p,J＝7.2Hz,1H),1.65(d,J＝7.2Hz,3H).13C NMR(150MHz,DMSO-d6)δ165.92,164.88,163.52,163.17,162.70,160.28(d,J＝241.5Hz),147.41,143.67,134.97(d,J＝3.0Hz),128.84,125.83,125.48(d,J＝7.5Hz),120.38,119.04,118.19,117.09,116.36(d,J＝22.5Hz),60.05,41.89,20.84.
制备实施例32(S)-2,4-二氨基-6-((1-(4-氯-1-(3-(甲磺酰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)乙基)氨基)嘧啶-5-腈38
制备方法同制备实施案例1-6类似，柱层析得白色固体38，收率63％。
1H NMR(400MHz,DMSO-d6)δ8.41(s,1H),8.29(d,J＝5.6Hz,2H),8.16(s,1H),7.94(d,J＝7.6Hz,1H),7.86(t,J＝8.0Hz,1H),7.37(d,J＝5.2Hz,1H),6.67(d,J＝8.0Hz,1H),6.53(s,2H),6.39(s,2H),6.00(p,J＝6.8Hz,1H),3.32(s,3H),1.65(d,J＝6.8Hz,3H).13CNMR(100MHz,DMSO-d6)δ165.81,163.56,163.14,148.38,144.47,142.34,138.64,135.77,130.99,128.90,127.66,125.08,122.04,119.31,118.69,118.36,118.12,60.40,44.03,42.50,22.16.
制备实施例33(S)-2,4-二氨基-6-((1-(4-氯-1-(吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-3-基)丙基)氨基)嘧啶-5-腈39
制备方法同制备实施案例1-6类似，柱层析得白色固体39，收率61％。
1H NMR(600MHz,DMSO-d6)δ9.07(d,J＝2.4Hz,1H),8.58(dd,J＝4.8,1.2Hz,1H),8.33–8.22(m,2H),8.10(s,1H),7.61(dd,J＝8.4,4.8Hz,1H),7.36(d,J＝5.4Hz,1H),6.57–6.43(m,3H),6.31(s,2H),5.83(q,J＝7.2Hz,1H),2.10–1.92(m,2H),0.98(t,J＝7.2Hz,3H).13C NMR(150MHz,DMSO-d6)δ165.78,163.67,163.41,148.35,147.72,145.01,144.33,135.57,134.68,131.52,127.41,124.49,118.66,118.52,118.28,117.96,60.38,48.46,29.93,11.75.
制备实施例34(S)-2,4-二氨基-6-((4-氯-1-(吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-3-基)(环丙基)甲基)氨基)嘧啶-5-腈40
制备方法同制备实施案例1-6类似，柱层析得白色固体40，收率51％。
1H NMR(400MHz,DMSO-d6)δ9.10(d,J＝2.4Hz,1H),8.59(dd,J＝4.8,1.2Hz,1H),8.32(ddd,J＝8.4,2.4,1.6Hz,1H),8.29(s,1H),8.26(d,J＝5.2Hz,1H),7.66–7.57(m,1H),7.35(d,J＝5.2Hz,1H),6.57–6.51(m,3H),6.36(s,2H),5.49(t,J＝8.4Hz,1H),1.60(qt,J＝8.4,4.8Hz,1H),0.68(dq,J＝9.2,4.8Hz,1H),0.63–0.47(m,2H),0.30(dq,J＝9.6,4.8Hz,1H).13C NMR(100MHz,DMSO-d6)δ165.71,163.37,148.25,148.24,147.76,145.04,144.27,135.59,134.68,131.59,128.62,124.51,118.60,118.32,118.06,117.60,60.19,49.60,17.11,4.58,3.52.
制备实施例35(S)-2,4-二氨基-6-((1-(6-氯-1-(吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-3-基]乙基)氨基)嘧啶-5-腈41
制备方法同制备实施案例1-6类似，柱层析得白色固体41，收率58％。
1H NMR(400MHz,DMSO-d6)δ8.89(d,J＝2.8Hz,1H),8.65(dd,J＝4.8,1.2Hz,1H),8.48(d,J＝2.0Hz,1H),8.16–8.13(m,1H),8.11(d,J＝2.0Hz,1H),8.06(s,1H),7.63(dd,J＝8.4,4.8Hz,1H),6.84(d,J＝8.4Hz,1H),6.58(s,2H),6.48(s,2H),5.81(p,J＝6.8Hz,1H),1.63(d,J＝6.8Hz,3H).13C NMR(100MHz,DMSO-d6)δ165.61,163.52,163.33,148.45,145.31,144.12,142.36,135.15,131.88,130.48,129.17,125.55,125.13,120.80,118.47,118.20,60.30,42.49,22.65.
生物实验实施例1：PI3Kδ酶活性抑制IC50评价试验
采用ADP-GloTMKinase实验来测定受试化合物对ΡΙ3Kδ酶活性的抑制效果。首先，将受试化合物按照一定浓度梯度进行稀释，然后分别取50nL的不同浓度化合物溶液转移至384孔板中。在384孔板中设立阴性对照孔和阳性对照孔，其中阴性对照孔加入50nL的二甲基亚砜DMSO(溶剂对照)，阳性对照孔同样加入50nL的DMSO以及已知能有效抑制ΡΙ3Kδ酶活性的药物。接下来，将ΡΙ3Kδ酶用激酶缓冲溶液稀释至1.25nM的工作浓度，然后以每孔2μL的方式加入到包括对照孔在内的所有384孔中。随后，阴性和阳性对照孔中再分别加入2.5μL相应的对照试剂，通过离心30秒及振荡混匀后，在室温下孵育10分钟。此后，向每个孔中加入2.5μL预先配制好的ATP(三磷酸腺苷)和PIP2(磷脂酰肌醇二磷酸)混合溶液，重复离心和混匀操作后，在室温下继续孵育2小时，以模拟生理条件下的酶促反应过程。孵育完成后，向每个孔中加入5μLADP-Glo试剂，再次混匀并孵育3小时，目的是消耗剩余的ATP并将生成的ADP转化为发光信号。紧接着加入10μL酶检测试剂，混匀后再孵育1小时以便充分检测酶活性。经过一系列孵育和离心处理后，使用Enspire酶标仪读取各孔的RLU(相对光单位)值，据此计算出不同浓度受试化合物对应的酶活性抑制率。
最后，以化合物浓度的log值为X轴，对应百分比抑制率为Y轴，利用分析软件GraphPad Prism 5中的log(inhibitor)vs.response-Variable slope模块绘制量效曲线，从而精确求得各受试化合物对ΡΙ3Kδ酶活性的半数抑制浓度IC50值。
表1显示了本发明的化合物12-41和阳性对照药艾德拉尼对ΡΙ3Kδ活性的IC50值。
表1
| 化合物编号 | ΡΙ3KδIC50(nM) | 化合物编号 | ΡΙ3KδIC50(nM) |
| 12 | 11 | 27 | 32.3 |
| 13 | 64 | 28 | 103 |
| 14 | 11 | 29 | 116 |
| 15 | 17 | 30 | 895 |
| 16 | 5.82 | 31 | 641 |
| 17 | 537 | 32 | 393 |
| 18 | 146 | 33 | 93.2 |
| 19 | 120 | 34 | 448 |
| 20 | 1351 | 35 | 435 |
| 21 | 1014 | 36 | 1550 |
| 22 | 257 | 37 | 434 |
| 23 | 447 | 38 | 66.4 |
| 24 | 742 | 39 | 11.1 |
| 25 | 73.7 | 40 | 47.2 |
| 26 | 210 | 41 | 13.6 |
| 艾德拉尼 | 3 |
此外应理解，在阅读了本发明的上述描述内容之后，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.具有式(I)所示结构的化合物，或其药学上可接受的盐，或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、可互变异构体：
式(1)中：
＊表示手性碳；
W，X，Y和Z均为碳原子，或W，X，Y和Z至少一个是氮原子且其他是碳原子；
R1为H、卤素、硝基、氰基、氨基、羟基、羟甲基、羟乙基、巯基、羧基、酯基、取代或未取代的C1-6烷基、取代或未取代的C1-6环烷基、取代或未取代的C1-6杂环烷基、取代或未取代的C4-10芳基、取代或未取代的C1-8杂芳基、C2-10烯基、C2-10炔基、烷基单取代胺基、烷基双取代胺基、烷氧基、烷基羰氧基、环烷基羰氧基、杂芳基羰氧基、烷氧基羰基、环烷氧基羰基、杂芳氧基羰基、烷基羰胺基、环烷基羰胺基、杂芳基羰胺基、胺基羰基、烷氧甲酰胺基、烷巯基、羟基烷氧基、糖残基、磺酸基、磷酸基、多羟基烷氧基羰基、羧基烷氧基、羧基烷基甲酰氧基中的一个或多个；
R2选自芳基，杂芳基和C3-6杂环烷基；它们各自任选且独立地被一个或多个基团取代，所述基团选自卤素，羟基，氨基，硝基、氰基、氨基、羟基、羟甲基、羟乙基、巯基、羧基、酯基，取代或未取代的C1-6烷基，C2-10烯基、C2-10炔基，取代或未取代的C4-10芳基、取代或未取代的C1-8杂芳基、烷氧基羰基、环烷基羰胺基、烷巯基、羟基烷氧基、糖残基、磺酸基、磷酸基、多羟基烷氧基羰基、羧基烷氧基；
R3选自氢、取代或未取代的C1-6烷基、取代或未取代的C1-6环烷基、取代或未取代的C1-6杂环烷基；
R4为任选取代的包含至少两个单原子的单环或双环系统，并且所述环系当中至少有一个环为芳环，且芳环可以是未取代的或者例如被以下一个或多个，特别是1-3个下列取代基取代：卤素，羟基，氨基，硝基、氰基、氨基、羟基、羟甲基、羟乙基、巯基、羧基、酯基，取代或未取代的C1-6烷基，C2-10烯基、C2-10炔基，取代或未取代的C4-10芳基、取代或未取代的C1-8杂芳基、烷氧基羰基、环烷基羰胺基、烷巯基、羟基烷氧基、糖残基、磺酸基、磷酸基、多羟基烷氧基羰基、羧基烷氧基；其单环或双环包括但不限于苯基、萘基、茚基、薁基、芴基和蒽基，呋喃基、噻吩基、吡啶基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、吡唑烷基、异噁唑基、异三唑基、1,2,3-噁二唑基、1,2,3-三唑基、1,3,4-噻二唑基、哒嗪基、嘧啶基、吡嗪基、1,3,5-三嗪基、1,3,5-三噻烷基、中氮茚基、吲哚基、异氮茚基、二氢吲哚基、苯并[b]呋喃基、苯并[b]噻吩基、1H-吲唑基、苯并咪唑基、苯并噻唑基、嘌呤基、4H-喹嗪基、喹啉基、1,2,3,4-四氢异喹啉基、异喹啉基、1,2,3,4-四氢异喹啉基、肉啉基、2,3-二氮杂萘基、喹唑啉基、喹喔啉基、1,8-二氮杂萘基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基和吩噁嗪基。
2.根据权利要求1所述的化合物，或其药学上可接受的盐，或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、可互变异构体，其特征在于，式(1)中手性碳的绝对构型为S构型，如式(2)所示：
3.根据权利要求1或2所述的化合物，或其药学上可接受的盐，或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、可互变异构体，其特征在于，W、X、Y、Z中有一个为氮原子，其余三个为碳原子；
R1为H或卤素(例如Cl)；
R2为取代或未取代的C1～C6烷基、吡啶基、苯基、吡唑基、噻吩基，其中取代基为吡啶基、C1～C6烷基、(C1～C6烷基)磺酰基、羟基、卤素(例如F)中的一个或多个；
R3为C1～C6的链烷基或C3～C6的环烷基；
R4为
4.根据权利要求3所述的化合物，或其药学上可接受的盐，或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、可互变异构体，其特征在于，所述化合物为具有以下任一结构的化合物：
5.根据权利要求4所述的化合物的制备方法，其特征在于，采用反应路线I合成所述化合物；
反应路线I包括以下过程：
化合物1与三氯化铝、乙酰氯在无水二氯甲烷中反应生成3-乙酰基-氮杂吲哚即化合物2，然后经碘化亚铜催化下的Ullmann偶联反应形成化合物3，接着与S-叔丁基亚磺酰胺缩合形成亚胺中间体4，再在二异丁基氢化铝DIBAL-H的作用下还原生成S构型的化合物5，接着在盐酸条件下水解得到化合物6，化合物6与氯代化合物R4-Cl进行亲核取代获得目标化合物。
6.根据权利要求5所述的制备方法，其特征在于，R4为时，氯代化合物R4-Cl采用反应路线II合成；
反应路线II包括以下过程：
化合物7在N,N-二甲基甲酰胺DMF中和三氯氧磷反应，生成化合物8，化合物8与盐酸羟胺作用，醛基反应生成肟，得化合物9，接着在无水二氯甲烷DCM中和氯化亚砜反应脱水形成氰基得到化合物10，化合物10在1,4-二氧六环中与氨水作用生成目标化合物11。
7.一种药物组合物，其特征在于，包含权利要求1～4任一项所述的化合物，或其药学上可接受的盐，或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体，以及可药用载体、稀释剂、赋形剂中的至少一种。
8.根据权利要求1～4任一项所述的化合物，或其药学上可接受的盐，或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体，或者根据权利要求7所述的药物组合物在制备PI3Kδ激酶抑制剂中的应用。
9.根据权利要求1～4任一项所述的化合物，或其药学上可接受的盐，或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体，或者根据权利要求7所述的药物组合物在制备用于治疗对抑制PI3Kδ有响应的疾病的药剂中的应用，其特征在于，所述疾病包括炎症性疾病、自身免疫性疾病、癌症、感染性疾病、心脑血管疾病。
10.根据权利要求9所述的应用，其特征在于，所述的炎症性疾病、自身免疫性疾病为类风湿性关节炎、慢性阻塞性肺病、变应性鼻炎、哮喘、红斑狼疮、银屑病和多发性硬化；
所述的癌症为实体瘤或血液系统恶性肿瘤，其选自白血病、多发性骨髓瘤、淋巴瘤；所述的白血病为急性淋巴细胞白血病、急性髓性白血病、慢性淋巴细胞白血病和慢性髓性白血病；所述的淋巴瘤为霍奇金淋巴瘤、非霍奇金淋巴瘤、套细胞淋巴瘤、滤泡型淋巴瘤、B细胞淋巴瘤、细胞淋巴瘤、弥散性大B细胞淋巴瘤；
所述的感染性疾病包括细菌性感染、真菌性感染、病毒性感染、寄生虫感染；
所述的心脑血管疾病包括急性心力衰竭、低血压、高血压、心绞痛、心肌梗塞、心肌病、充血性心力衰竭、动脉粥样硬化、冠心病、再狭窄和血管狭窄，以及外伤性脑损伤、中风、缺血再灌注损伤和动脉。
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