CN110903286B - 4,6-双取代吡啶[3,2-d]嘧啶类化合物及其制备和应用 - Google Patents
4,6-双取代吡啶[3,2-d]嘧啶类化合物及其制备和应用 Download PDFInfo
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- CN110903286B CN110903286B CN201911290773.7A CN201911290773A CN110903286B CN 110903286 B CN110903286 B CN 110903286B CN 201911290773 A CN201911290773 A CN 201911290773A CN 110903286 B CN110903286 B CN 110903286B
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Abstract
本发明属于医药技术领域，具体涉及4,6‑双取代吡啶[3,2‑d]嘧啶类化合物及其药学上可接受的盐，化合物的制备方法，以该化合物为活性成分的药物组合物，以及在制备MNK抑制剂及其用于治疗和/或预防各种癌症和/或代谢性疾病的药物中的用途。本发明涉及式Ⅰ、Ⅱ、Ⅲ或、Ⅳ所示的化合物、及其药学上可接受的盐、水合物、溶剂化物、代谢化物：其中，各变量如权利要求和说明书所述。
Description
技术领域：
本发明属于医药技术领域，具体涉及4,6-双取代吡啶[3,2-d]嘧啶类化合物及其药学上可接受的盐，化合物的制备方法，以该化合物为活性成分的药物组合物，以及在制备MNK抑制剂及其用于治疗和/或预防各种癌症和/或代谢性疾病的药物中的用途。
背景技术：
有丝分裂原激活的蛋白激酶作用激酶(MAP kinase-interacting kinase or MAPkinase signal-integrating kinase，Mnk)是一类丝氨酸/苏氨酸激酶，属于Ca2+/钙调蛋白依赖激酶家族，处于负责调控细胞存活增殖的MAPK信号通路下游。在肿瘤细胞中，MAPK信号通路的调节异常通常加剧细胞分裂、侵袭、存活等，其中细胞代谢和蛋白质合成的失调成为主要原因。真核细胞通过调节mRNA翻译而严格调控蛋白质合成，主要依赖于结合mRNA的5’7-甲基鸟苷酸的真核细胞起始因子4F(eIF4F)复合物，该复合物包括真核细胞起始因子4E(eIF4E)，解旋酶4A(eIF4A)和骨架蛋白eIF4G，其中eIF4E作为该复合物中的关键因子，成为PI3K/Akt/mTOR和Ras/Raf/MEK/ERK信号通路介导的肿瘤存活及增殖的关键。ERK和p38激酶活化后，可激活MNK1/2，后者磷酸化底物蛋白eIF4E 209位的丝氨酸，继而提升在mRNA水平具有5’帽子结构的肿瘤相关蛋白(如c-Myc、细胞周期蛋白Cyclin D1、抗凋亡蛋白Mcl-1、Bcl-2，血管表皮生长因子VEGF、HDM2、缺氧诱导因子HIF-1α、基质金属蛋白酶MMP-3/9、SNAIL等)的核质转运及翻译过程。Mnk对eIF4E的磷酸化作用是后者发挥致癌作用的关键。Mnk通过介导eIF4E的磷酸化调控相关蛋白的翻译过程，这些蛋白在肿瘤细胞促存活、抗凋亡、促转移和耐药性机制中发挥着重要作用；除此之外，研究表明Mnk在代谢性疾病的发生发展过程中也发挥重要作用。开发Mnk抑制剂已经成为一种新兴的肿瘤和代谢性疾病治疗策略。
本发明人设计并合成了一系列4,6-双取代吡啶[3,2-d]嘧啶类衍生物，经酶活性筛选，所合成的化合物普遍具有很好的Mnk抑制活性，并且在实体瘤及血液癌细胞中均表现出明显的抗增殖活性。
发明内容：
本发明所解决的技术问题是提供4,6-双取代吡啶[3,2-d]嘧啶类衍生物的制备方法，及其作为Mnk抑制剂在预防和/或治疗肿瘤、代谢性疾病中的应用。
本发明涉及式Ⅰ、Ⅱ、Ⅲ或、Ⅳ所示的化合物、及其药学上可接受的盐、水合物、溶剂化物、代谢化物：
其中，
A、B、C、D独立选自C或N；
X为-NH-、-NHC(O)-；X左边连接吡啶并嘧啶母核；
Y为
Y左边连接吡啶并嘧啶母核；
R1、R2、R3、R4、R5各自独立的选自：H、羟基、卤素、硝基、氨基、氰基、取代或未取代的(C1-C4)烷基或亚烷基(取代基为卤素、羟基、氨基)、取代或未取代的(C1-C4)烷氧基或亚烷氧基(取代基为卤素、羟基、氨基)、(C2-C5)炔基、CF3SO2-、CF2SO2-、CH3SO2-、CH3SO2NH-、-NC(O)R8、-C(O)R9；取代氨基(取代基为(C1-C4)烷基、卤代(C1-C4)烷基或亚烷基、羟基取代(C1-C4)烷基或亚烷基、氨基取代(C1-C4)烷基或亚烷基)；
R2、R3可通过氮原子、碳原子或者氧原子相连，形成5-10元芳杂环，所述芳杂环可任选含有1-3个O、N或S的杂原子；
R7为氢、卤素；
R8为(C1-C4)烷基；
R9为
R10、R11独立选自氢原子、取代或未取代的的(C1-C4)烷基或亚烷基、取代或未取代的3-7元饱和或不饱和杂环基或环烷基；其中所述的杂环基包含1-3个选自下组的杂原子：N、O或S；(取代基可以为羟基、卤素、氨基、乙酰基、(C1-C4)烷基、(C1-C4)烷氧基、羟基或氨基取代的(C1-C4)烷基等；)或者R10和R11通过氮原子、碳原子或者氧原子相连，形成至少包含一个杂原子的5元到7元的杂环；
R12为氢、卤素、氰基、羟基、甲基、甲氧基、三氟甲基等；
R13为
卤素；R13左侧与Y相连；
本发明优选具有如下结构的化合物、及其药学上可接受的盐、水合物、溶剂化物、代谢化物：
其中，
A、B、C、D独立选自C或N；
X为-NH-、-NHC(O)-；X左边连接吡啶并嘧啶母核；
Y为
Y左边连接吡啶并嘧啶母核；
R1、R2、R3、R4、R5各自独立的选自：H、羟基、卤素、硝基、氨基、氰基、取代或未取代的(C1-C4)烷基或亚烷基(取代基为卤素、羟基、氨基)、取代或未取代的(C1-C4)烷氧基或亚烷氧基(取代基为卤素、羟基、氨基)、(C2-C5)炔基、-NC(O)R8、-C(O)R9；
R2、R3可通过氮原子、碳原子或者氧原子相连，形成5-6元芳杂环，所述芳杂环可任选含有1-3个O、N或S的杂原子；
R7为氢、卤素；
R8为(C1-C4)烷基；
R9为
R10、R11独立选自氢原子、取代或未取代的的(C1-C4)烷基或亚烷基、取代或未取代的3-7元饱和或不饱和杂环基或环烷基；其中所述的杂环基包含1-3个选自下组的杂原子：N、O或S；(取代基可以为羟基、卤素、氨基、乙酰基)；或者R10和R11通过氮原子、碳原子或者氧原子相连，形成至少包含一个杂原子的5元到7元的杂环；
R12为氢、卤素、氰基、羟基、甲基、甲氧基、三氟甲基；
R13为
卤素；R13左侧与Y相连；
本发明优选如下结构的化合物、及其药学上可接受的盐、水合物、溶剂化物、代谢化物：
其中，
A、B、C、D独立选自C或N；
X为-NH-、-NHC(O)-；X左边连接吡啶并嘧啶母核；
Y为
Y左边连接吡啶并嘧啶母核；
R1、R2、R3、R4、R5各自独立的选自：H、羟基、卤素、氰基、取代或未取代的(C1-C4)烷基或亚烷基(取代基为卤素)、取代或未取代的(C1-C4)烷氧基或亚烷氧基(取代基为卤素)、乙炔基、-C(O)R9；
R2、R3可通过氮原子、碳原子或者氧原子相连，形成5-6元芳杂环，所述芳杂环可任选含有1-3个O、N或S的杂原子；
R7为氢、卤素；
R9为
R10、R11独立选自氢原子、取代或未取代的的(C1-C4)烷基或亚烷基、取代或未取代的3-7元饱和或不饱和杂环基或环烷基；其中所述的杂环基包含1-3个选自下组的杂原子：N、O或S；(取代基可以为羟基、卤素、氨基、乙酰基)；或者R10和R11通过氮原子、碳原子或者氧原子相连，形成至少包含一个杂原子的5元到7元的杂环；
R12为氢、卤素、氰基、甲基、甲氧基、三氟甲基等；
R13为
卤素；R13左侧与Y相连；
本发明选如下结构的化合物、及其药学上可接受的盐、水合物、溶剂化物、代谢化物：
其中，
A、B、C、D独立选自C或N；
X为-NH-、-NHC(O)-；X左边连接吡啶并嘧啶母核；
Y为
Y左边连接吡啶并嘧啶母核；
R1、R2、R3、R4、R5各自独立的选自：H、羟基、卤素、氰基、(C1-C4)烷基、卤素取代的(C1-C4)烷基或亚烷基、(C1-C4)烷氧基、卤素取代的(C1-C4)烷氧基；
R2、R3可通过氮原子、碳原子或者氧原子相连，形成5-6元芳杂环，所述芳杂环可任选含有1-3个O、N或S的杂原子；
R7为氢、卤素；
R9为
R10、R11独立选自氢原子、取代或未取代的的(C1-C4)烷基或亚烷基、取代或未取代的3-7元饱和或不饱和杂环基或环烷基；其中所述的杂环基包含1-3个选自下组的杂原子：N、O或S；(取代基可以为羟基、卤素、氨基、乙酰基)；或者R10和R11通过氮原子、碳原子或者氧原子相连，形成至少包含一个杂原子的5元到7元的杂环；
R12为氢、卤素、氰基、甲基、甲氧基、三氟甲基等；
R13为
氟、氯；R13左侧与Y相连；
本发明优如下结构的化合物、及其药学上可接受的盐、水合物、溶剂化物、代谢化物：
本发明包括药物组合物，该组合物含有通式I、II、III或IV的4，6-双取代吡啶[3，2-d]嘧啶类化合物，及其药物上可接受的赋形剂。所述药物上可接受的赋形剂是指任何可用于药物领域的稀释剂、辅助剂和/或载体。本发明的物可以与其他活性成分组合使用，只要它们不产生其他不利的作用，例如过敏反应。
本发明的药物组合物可配制成若干种剂型，其中含有药物领域中常用的一些赋形剂，例如，口服制剂(如片剂，胶囊剂，溶液或混悬液)；可注射的制剂(如可注射的溶液或混悬液，或者是可注射的干燥粉末，在注射前加入注射用水可立即使用)；局部制剂(例如软膏或溶液)。
用于本发明药物组合物的载体是药物领域中可得到的常见类型，包括：口服制剂用的粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、色素、矫味剂等；可注射制剂用的防腐剂、加溶剂、稳定剂等；局部制剂用的基质、稀释剂、润滑剂、防腐剂等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药，如果某些药物在胃部条件下是不稳定的，可将其配制成肠衣片剂。
通过体外抑酶试验筛选，我们发现本发明化合物可抑制Mhk活力，因此，本发明化合物可用于与Mhk异常表达相关的疾病中的应用，如各种癌症、代谢性疾病等。
通过体外活性筛选，我们发现本发明化合物具有抗肿瘤活性，因此本发明化合物可以用于制备治疗和/或预防各种癌症的药物，如乳腺、肺、结肠、直肠、胃、前列腺、膀胱、子宫、胰腺和卵巢的癌。
本发明活性化合物可作为唯一的抗癌药物使用，或者与一种或多种其它抗肿瘤药物联合使用。联合治疗通过将各个治疗组分同时、顺序或隔开给药来实现。
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解，下述实施例和制备例的范围并不以任何方式限制本发明的范围。
A01-A13合成路线：
试剂与反应条件：a)浓硝酸，浓硫酸，120℃；b)氰化亚铜，N-甲基吡咯烷酮，180℃；c)氯化亚锡，乙醇，室温；d)原甲酸三乙酯，143℃；e)N，N-二甲基苯胺，三氯氧磷，106℃；f)三甲基硅乙炔，双三苯基膦二氯化钯，碘化亚铜，三乙胺，氮气保护，室温；g)碳酸钾(水溶液)，甲醇，室温；h)三乙胺，异丙醇，82℃；i)11，双三苯基膦二氯化钯，碘化亚铜，三乙胺/四氢呋喃(1：1)，氮气保护，室温；j)不同种类的胺或醇，2-(7-氧化苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯，4-二甲氨基吡啶，N，N-二异丙基乙胺，四氢呋喃。
B01-B14合成路线：
试剂与反应条件：a)溴乙酸甲酯或溴乙酸乙酯，碳酸铯，干燥的N，N-二甲基甲酰胺，25℃，然后升温至40℃，最后升温至100℃；b)氢气，钯/碳，甲醇，25℃；c)化合物5，三乙胺，异丙醇，50℃；d)氢氧化钠，二甲基甲酰胺，80℃；e)不同种类的胺，2-(7-氧化苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯，4-二甲氨基吡啶，N，N-二异丙基乙胺，N，N-二甲基甲酰胺，25℃。
C01-C20合成路线：
试剂与反应条件：a)浓硝酸，浓硫酸，120℃；b)氰化亚铜，N-甲基吡咯烷酮，180℃；c)硫代硫酸钠，二氯甲烷，水，室温；d)原甲酸三乙酯，醋酸铵，126℃；e)碳酸钾，四(三苯基膦)钯，取代苯硼酸/吡啶-3-硼酸，1，4-二氧六环/水，90℃；f)苯甲酸，2-(7-氧化苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯，4-二甲氨基吡啶，N，N-二异丙基乙胺，二氯甲烷，室温。
D01-D39合成路线：
试剂与反应条件：a)取代的苯胺，三乙胺，异丙醇，50℃；b)4-羧基苯硼酸或3-羧基苯硼酸，四(三苯基膦)钯，碳酸钾，1，4-二氧六环/水，90℃；c)不同种类的胺，2-(7-氧化苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯，4-二甲氨基吡啶，N，N-二异丙基乙胺，N，N-二甲基甲酰胺，25℃；d)HCl/乙酸乙酯，室温；e)苯硼酸，四(三苯基膦)钯，碳酸钾，1，4-二氧六环/水，90℃。
E01-E25合成路线：
试剂与反应条件：a)发烟硝酸，室温；b)氰化亚铜，N-甲基吡咯烷酮，180℃；c)氯化亚锡，乙醇，78℃；d)原甲酸三乙酯，146℃；e)三氯氧磷，N，N-二甲基苯胺，107℃；f)取代的吲哚啉/取代的7-氮杂吲哚，三乙胺，异丙醇，50℃；g)4-羧基苯硼酸或3-羧基苯硼酸，四(三苯基膦)钯，碳酸钾，1，4-二氧六环/水，90℃；h)不同种类的胺，2-(7-氧化苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯，4-二甲氨基吡啶，N，N-二异丙基乙胺，N，N-二甲基甲酰胺，25℃；i)HCl/乙酸乙酯，室温。
LB01-LB22系列合成路线：
试剂与反应条件：a)氯化亚锡，乙醇，室温；b)原甲酸三乙酯，143℃；c)N，N-甲基苯胺，三氯氧磷，107℃；d)取代的苯胺，二氯甲烷，三乙胺，室温；e)二氯亚锡，乙醇，78℃；f)三乙胺，异丙醇，50℃；g)胺，2-(7-氧化苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯，4-二甲氨基吡啶，N，N-二异丙基乙胺，四氢呋喃，室温；h)碳酸钾，四(三苯基膦)钯，1，4-二氧六环，水，氮气保护；i)HCl/乙酸乙酯，室温。
具体实施方式：
实施例旨在阐述而不是限制本发明的范围。凡基于本发明上述内容所实现的技术均属于本发明的范围。
化合物的核磁共振谱用BrukerARX-600核磁共振波谱仪在CDCl3或DMSO-d6中以TMS为内标测定，低分辨质谱用Agilent 1100 SL型离子阱质谱仪测定，高分辨质谱用Brukermicro-TOF-Q测定。
实施例1：3-((2-((6-氯吡啶并[3，2-d]嘧啶-4-基)氨基)苯基)乙炔基)-N-甲基苯甲酰胺(A01)的制备
步骤A：2，6-二氯-3-硝基吡啶(1)的制备
冰浴下将10mL浓硫酸滴加到10mL浓硝酸中配制混酸溶液，搅拌10min，将2，6-二氯吡啶(44g，30mmol)置于100mL茄型瓶中，加入20mL浓硫酸，冰浴并搅拌下滴加配置好的混酸溶液。搅拌1h后升温至120℃继续搅拌，用碱性溶液吸收尾气。4h后停止反应，冷却至室温。冰浴下将反应液滴入氢氧化钠水溶液，析出大量淡黄色固体，反应液滴完后，用碱液调节pH至8，搅拌10min，抽滤得淡黄色固体48g，收率81％。
步骤B：2-氰基-3-硝基-6-氯吡啶(2)的制备
于250mL茄型瓶中加入1(10.0g，52mmol)、氰化亚铜(93g，104mmol)和150mLN-甲基吡咯烷酮，油浴锅快速升温至180℃，搅拌2h后，TLC监测反应完全，冷却至室温，将反应液倒入600mL冰水混合物中，搅拌30min，抽滤得褐色固体，水洗滤饼。滤饼溶于150mL甲苯，加热回流10min，趁热过滤，残余物重复该操作两次，合并滤液，用水洗三次，饱和食盐水洗一次，无水硫酸钠干燥后蒸除甲苯，柱层析得黄色固体4.0g，收率41％。M.p：106-108℃.LC-MS：184.5[M+H]+.1H-NMR(600MHz，DMSO-d6)δ882(d，J＝88Hz，1H)，818(d，J＝88Hz，1H)。
步骤C：3-氨基-6-氯吡啶酰胺(3)的制备
于50mL茄形瓶中加入2(2.0g，10.9mmol)、氯化亚锡(10.0g，43.6mmol)和20mL乙醇，室温搅拌2h，TLC监测反应完全，冷却至室温，蒸干溶剂，用乙酸乙酯重新溶解所得固体，用2mol/L氢氧化钠水溶液调pH至6，用饱和碳酸氢钠水溶液继续调pH至7，过滤，收集滤液，分离有机层，水层用乙酸乙酯萃取两遍，合并有机层，饱和氯化钠洗一遍，无水硫酸钠干燥，滤液蒸干得黄色固体2.5g，收率67％。1H-NMR(600MHz,DMSO-d6)δ7.70(s,1H),7.40(s,1H),7.29(d,J＝8.7Hz,1H),7.23(d,J＝8.7Hz,1H),6.99(s,2H)。
步骤D：6-氯吡啶并[3,2-d]嘧啶-4(1H)-酮(4)的制备
于250mL茄形瓶中加入3(2.5g,14.6mmol)与原甲酸三乙酯(100mL,60mmol)，140℃反应2h，TLC监测反应完全，冷却至室温，过滤得滤饼，干燥得淡黄色固体2.1g，收率80％。1H-NMR(600MHz,DMSO-d6)δ12.73(s,1H),8.20(s,1H),8.14(d,J＝8.6Hz,1H),7.88(d,J＝8.6Hz,1H)。
步骤E：4,6-二氯吡啶并[3,2-d]嘧啶(5)的制备
将4(1.5g,8.3mmol)加入50mL茄形瓶中，加入30mL三氯氧磷与2滴N,N-二甲基苯胺，107℃反应1h，TLC监测反应完全，冷却，蒸干溶剂，用二氯甲烷重新溶解所得固体，饱和碳酸氢钠水溶液调pH至7，过滤除去不溶固体，分离二氯甲烷层和水层，水层用二氯甲烷萃取两遍，合并二氯甲烷层，无水硫酸钠干燥。柱层析得白色固体1.1g，收率65％。1H-NMR(600MHz,DMSO-d6)δ8.29(s,1H),8.16(d,J＝8.6Hz,1H),7.89(d,J＝8.6Hz,1H)。
步骤F：2-((三甲基甲硅烷基)乙炔基)苯胺(7)的制备
将2-碘苯胺(2.2g，10mmol)，双三苯基磷二氯化钯(70mg，0.1mmol)和碘化亚酮(16mg，0.083mmol)置于干燥的两颈瓶中，加入25ml三乙胺，N2保护，室温下搅拌10min后加入三甲基硅基乙炔(1.1g，11mmol)，继续在室温下搅拌30min。TLC监测反应完全后，加入25ml水，二氯甲烷萃取3次，合并有机层，饱和氯化钠溶液洗3次，无水硫酸钠干燥，过滤，浓缩，得棕褐色油状液体。柱层析分离纯化，得棕黄色液体，收率89％。
步骤G：2-氨基苯乙炔(8)的制备
将7(1.2g，10mmol)置于100mL茄形瓶中，加入20ml甲醇，室温下缓慢滴加10ml10％的碳酸钾水溶液，滴加完毕后继续搅拌1h。TLC监测反应完全，蒸除甲醇，二氯甲烷萃取3次，合并有机层，饱和氯化钠溶液洗1次，无水硫酸钠干燥，过滤，浓缩，得黑色油状液体。柱层析分离纯化，得棕黄色液体，收率64％。
步骤H：6-氯-N-(2-乙炔基苯基)吡啶并[3,2-d]嘧啶-4-胺(9)的制备
将5(1.0g，5mmol)和8(0.6g，5mmol)置于100mL茄形瓶中，加入25ml异丙醇和3滴三乙胺，加热回流3h。TLC监测反应完全，冷却至室温，抽滤，得棕褐色滤饼，滤饼用异丙醇洗3次，干燥得1.1g棕褐色固体，收率79％。
步骤J：3-碘-N-甲基苯甲酰胺(11a)的制备
将3-碘苯甲酸(750mg,3mmol)、HATU(1.4g，3.6mmol)、DMAP(440mg，3.6mmol)和DIEA(460mg，3.6mmol)置于100mL茄形瓶中，加入30ml四氢呋喃，室温搅拌20min后加入甲胺盐酸盐(240mg，3.6mmol)，室温下继续搅拌30min。TLC监测反应完全,蒸干溶剂，加入二氯甲烷溶解，分别用10％的盐酸溶液、水、饱和碳酸氢钠溶液、水和饱和氯化钠溶液洗1次。无水硫酸钠干燥，过滤，蒸干，得无色油状液体。收率93％。
用类似的方法合成化合物11b-11m。
步骤I：3-((2-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)苯基)乙炔基)-N-甲基苯甲酰胺(A01)的制备
将9(560mg，2mmol)、双三苯基磷二氯化钯(14mg，0.02mmol)和碘化亚酮(4mg，0.017mmol)置于干燥的两颈瓶中，加入10ml四氢呋喃和10ml三乙胺，N2保护，室温下搅拌10min。取1a(520mg，2mmol)溶于20ml三乙胺和四氢呋喃1:1的混合液中，将该混合液加入反应瓶，升温至50℃搅拌4h。TLC监测反应完全，冷却，蒸干溶剂，加入二氯甲烷重新溶解，氯化钠溶液洗1次。无水硫酸钠干燥，过滤，蒸干，得棕褐色固体。柱层析分离纯化，得淡黄色固体，收率53％。M.p.:240.7-241.9℃.1H-NMR(600MHz,DMSO-d6)δ9.93(s,1H),8.85(d,J＝8.3Hz,1H),8.82(s,1H),8.53(d,J＝4.2Hz,1H),8.33(d,J＝8.7Hz,1H),8.08(s,1H),8.01(d,J＝8.7Hz,1H),7.89(t,J＝8.2Hz,2H),7.68(dd,J＝7.6,1.1Hz,1H),7.58-7.54(m,2H),7.23(t,J＝7.8Hz,1H),2.79(d,J＝4.5Hz,3H).13C-NMR(100MHz,DMSO-d6)δ166.2,156.1,155.9,149.5,144.3,140.5,139.3,135.7,134.4,132.4,131.6,130.8,130.5,130.3,129.3,128.3,124.2,122.1,120.7,113.2,96.7,85.3,26.7.HRMS(ESI,m/z)calcd forC23H16ClN5O[M+H]+,414.1116；found,414.1068。
实施例2：3-((2-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)苯基)乙炔基)-N-异丙基苯甲酰胺(A02)的制备
按照实施例1的制备方法，将11a替换为3-碘-N-异丙基苯甲酰胺(11b)，制备标题化合物。淡黄色固体，收率50％。M.p.:231.1-232.3℃.1H-NMR(600MHz,DMSO-d6)δ9.92(s,1H),8.85(d,J＝8.3Hz,1H),8.81(s,1H),8.38-8.28(m,2H),8.10(s,1H),8.00(d,J＝8.7Hz,1H),7.88(d,J＝7.5Hz,2H),7.67(d,J＝7.5Hz,1H),7.55(dd,J＝10.4,4.6Hz,2H),7.22(t,J＝7.4Hz,1H),4.10(dq,J＝13.1,6.5Hz,1H),1.17(d,J＝6.5Hz,6H).13C-NMR(100MHz,DMSO-d6)δ165.0,156.1,155.9,149.5,144.2,140.4,139.3,136.0,134.4,132.3,131.5,130.8,130.5,130.3,129.2,128.6,124.2,121.9,120.5,113.2,96.9,85.3,41.6,22.7.HRMS(ESI,m/z)calcd for C25H20ClN5O[M+H]+,442.1429；found,442.1408。
实施例3：3-((2-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)苯基)乙炔基)-N,N-二甲基苯甲酰胺(A03)的制备
按照实施例1的制备方法，将11a替换为3-碘-N,N-二甲基苯甲酰胺(11c)，制备标题化合物。淡黄色固体，收率45％。M.p.:178.2-178.8℃.1H-NMR(600MHz,DMSO-d6)δ9.89(s,1H),8.84(d,J＝8.3Hz,1H),8.80(s,1H),8.32(d,J＝8.7Hz,1H),8.01(d,J＝8.7Hz,1H),7.77(d,J＝7.6Hz,1H),7.67(d,J＝10.2Hz,2H),7.54(td,J＝7.7,2.7Hz,2H),7.46(d,J＝7.6Hz,1H),7.22(t,J＝7.5Hz,1H),3.01(s,3H),2.89(s,3H).13C-NMR(100MHz,DMSO-d6)δ169.5,156.2,156.0,149.4,144.4,140.5,139.3,137.7,132.6,132.5,131.4,130.7,130.5,129.8,129.3,127.9,124.3,122.2,120.7,113.2,96.5,85.6,38.6,35.1.HRMS(ESI,m/z)calcd for C24H18ClN5O[M+H]+,428.1273；found,428.1290。
实施例4：3-((2-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)苯基)乙炔基)-N-丙基苯甲酰胺(A04)的制备
按照实施例1的制备方法，将11a替换为3-碘-N-丙基苯甲酰胺(11d)，制备标题化合物。淡黄色固体，收率48％。M.p.:215.6-216.6℃.1H-NMR(600MHz,DMSO-d6)δ9.94(s,1H),8.85(d,J＝8.3Hz,1H),8.82(s,1H),8.55(t,J＝5.4Hz,1H),8.33(d,J＝8.7Hz,1H),8.10(s,1H),8.01(d,J＝8.7Hz,1H),7.89(d,J＝7.8Hz,2H),7.68(dd,J＝7.6,1.2Hz,1H),7.56(dt,J＝5.2,4.5Hz,2H),7.23(t,J＝7.8Hz,1H),3.22(dd,J＝13.1,6.7Hz,2H),1.54(dd,J＝14.4,7.3Hz,2H),0.90(t,J＝7.4Hz,3H).13C-NMR(100MHz,DMSO-d6)δ165.8,156.2,156.0,149.5,144.2,140.5,139.3,136.0,134.3,132.4,131.4,130.8,130.5,130.3,129.3,128.5,124.2,121.9,120.6,113.2,96.8,85.2,41.6,22.7,11.8.HRMS(ESI,m/z)calcd for C25H20ClN5O[M+H]+,442.1429；found,442.1458。
实施例5：3-((2-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)苯基)乙炔基)-N-(2-甲氧乙基)苯甲酰胺(A05)的制备
按照实施例1的制备方法，将11a替换为3-碘-N-(2-甲氧乙基)苯甲酰胺(11e)，制备标题化合物。淡黄色固体，收率56％。M.p.:202.6-203.4℃.1H-NMR(600MHz,DMSO-d6)δ9.96(s,1H),8.85(d,J＝8.3Hz,1H),8.83(s,1H),8.63(t,J＝5.2Hz,1H),8.35(d,J＝8.7Hz,1H),8.11(s,1H),8.02(d,J＝8.8Hz,1H),7.90(d,J＝7.6Hz,2H),7.69(d,J＝7.6Hz,1H),7.60-7.55(m,2H),7.24(t,J＝7.6Hz,1H),3.47(d,J＝5.8Hz,2H),3.43(t,J＝5.2Hz,2H),3.27(s,3H).13C-NMR(100MHz,DMSO-d6)δ166.0,156.2,156.0,149.6,144.3,140.5,139.4,135.6,134.5,132.4,131.6,130.8,130.6,130.4,129.3,128.5,124.3,122.1,120.7,113.2,99.9,96.7,85.3,70.7,58.3.HRMS(ESI,m/z)calcd for C25H20ClN5O[M+H]+,458.1378；found,458.1400。
实施例6：3-((2-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)苯基)乙炔基)-N-(3-甲氧丙基)苯甲酰胺(A06)的制备
按照实施例1的制备方法，将11a替换为3-碘-N-(3-甲氧丙基)苯甲酰胺(11f)，制备标题化合物。淡黄色固体，收率53％。M.p.:174.1-175.7℃.1H-NMR(600MHz,DMSO-d6)δ9.91(s,1H),8.84(d,J＝8.3Hz,1H),8.80(s,1H),8.56(t,J＝5.1Hz,1H),8.31(d,J＝8.7Hz,1H),8.09(s,1H),7.99(d,J＝8.7Hz,1H),7.89(d,J＝5.2Hz,2H),7.66(d,J＝7.5Hz,1H),7.56(d,J＝7.9Hz,2H),7.22(t,J＝7.5Hz,1H),3.37(t,J＝6.2Hz,2H),3.32-3.28(m,2H),3.23(s,3H),1.80-1.71(m,2H).13C-NMR(100MHz,DMSO-d6)δ165.9,156.2,155.9,149.5,144.2,140.5,139.3,135.8,134.4,132.4,131.4,130.7,130.5,130.4,129.3,128.5,124.2,122.0,120.6,113.1,96.6,85.3,70.2,58.4,37.0,29.6.HRMS(ESI,m/z)calcd for C26H22ClN5O[M+H]+,472.1535found,472.1534。
实施例7：1-(4-(3-((2-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)苯基)乙炔基)苯甲酰)(哌嗪-1-基)乙-1-酮(A07)的制备
按照实施例1的制备方法，将11a替换为1-(4-(3-碘苯甲酰基)哌嗪-1-基)乙酮(11g)，制备标题化合物。淡黄色固体，收率49％。M.p.:234.6-235.6℃.1H-NMR(600MHz,DMSO-d6)δ9.90(s,1H),8.84(d,J＝8.3Hz,1H),8.81(s,1H),8.33(d,J＝8.7Hz,1H),8.01(d,J＝8.7Hz,1H),7.81(d,J＝7.7Hz,1H),7.71(s,1H),7.67(dd,J＝7.6,1.1Hz,1H),7.60-7.52(m,2H),7.50(d,J＝7.6Hz,1H),7.23(t,J＝7.5Hz,1H),3.66-3.60(m,2H),3.54(brs,2H),3.42(brs,2H),3.28(brs,2H),2.04-1.99(m,3H).13C-NMR(100MHz,DMSO-d6)δ168.9,168.5,156.2,156.0,149.5,144.3,140.5,139.3,136.9,133.0,132.5,131.5,130.8,130.6,129.9,129.6,128.0,124.3,122.4,120.7,113.2,96.5,85.6,96.5,85.6,49.1,21.6.HRMS(ESI,m/z)calcd for C28H23ClN6O2[M+H]+,511.1644；found,511.1609。
实施例8：(3-((2-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)苯基)乙炔基)苯基)(哌嗪-1-基)甲酮(A08)的制备
按照实施例1的制备方法，将11a替换为(3-碘苯基)(哌嗪-1-基)甲酮(11h)，制备标题化合物。淡黄色固体，收率40％。M.p.:191.1-192.0℃.1H-NMR(600MHz,DMSO-d6)δ9.92(s,1H),8.86(d,J＝8.3Hz,1H),8.82(s,1H),8.34(d,J＝8.7Hz,1H),8.03(d,J＝8.7Hz,1H),7.78(d,J＝7.7Hz,1H),7.68(d,J＝7.0Hz,2H),7.55(q,J＝8.0Hz,2H),7.44(d,J＝7.6Hz,1H),7.23(t,J＝7.5Hz,1H),4.09(s,1H),3.57(brs,2H),3.17(brs,2H),2.76(brs,2H),2.62(brs,2H).13C-NMR(100MHz,DMSO-d6)δ168.6,156.2,156.0,149.5,144.4,140.6,139.4,136.2,133.3,132.5,131.5,130.8,130.6,130.0,129.6,128.2,124.3,122.4,120.8,113.3,96.4,85.8,49.1,49.1,43.0,43.0.HRMS(ESI,m/z)calcd for C26H21ClN6O[M+H]+,469.1538；found,469.1482。
实施例9：(3-((2-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)苯基)乙炔基)苯基)(吗啉基)甲酮(A09)的制备
按照实施例1的制备方法，将11a替换为(3-碘苯基)(吗啉基)甲酮(11i)，制备标题化合物。淡黄色固体，收率51％。M.p.:243.2-244.6℃.1H-NMR(600MHz,CDCl3-d6)δ10.14(s,1H),8.97(d,J＝8.3Hz,1H),8.87(s,1H),8.39(d,J＝7.3Hz,1H),7.88(d,J＝7.6Hz,1H),7.80(s,1H),7.76(d,J＝8.7Hz,1H),7.62(dd,J＝7.7,1.2Hz,1H),7.52-7.48(m,1H),7.46(d,J＝7.6Hz,1H),7.44-7.41(m,1H),7.20(t,J＝7.4Hz,1H),3.80(brs,4H),3.63(brs,2H),3.46(brs,2H).13C-NMR(100MHz,CDCl3-d6)δ169.3,157.1,153.6,150.9,136.3,136.1,134.8,133.4,133.1,132.8,132.7,130.4,130.3,129.4,129.1,128.0,127.2,122.5,121.7,115.6,98.1,84.1,77.4,67.0.HRMS(ESI,m/z)calcd for C26H20ClN5O2[M+H]+,470.1378；found,470.1362。
实施例10：3-((2-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)苯基)乙炔基)-N-环丙基苯甲酰胺(A10)的制备
按照实施例1的制备方法，将11a替换为N-环丙基-3-碘-苯甲酰胺(11j)，制备标题化合物。淡黄色固体，收率56％。M.p.:243.5-244.8℃.1H-NMR(600MHz,DMSO-d6)δ9.95(s,1H),8.84(d,J＝13.4Hz,2H),8.53(s,1H),8.35(d,J＝8.7Hz,1H),8.12-7.99(m,2H),7.94-7.83(m,2H),7.69(d,J＝7.3Hz,1H),7.57(d,J＝5.6Hz,2H),7.24(t,J＝6.5Hz,1H),2.86(s,1H),0.70(d,J＝4.8Hz,2H),0.56(s,2H).13C-NMR(100MHz,CDCl3-d6)δ168.1,156.0,156.0,149.6,143.9,139.3,138.9,135.0,134.9,132.0,131.7,129.8,129.6,129.4,128.8,127.5,123.4,122.9,119.8,113.0,96.3,85.1,53.5,30.0,23.2.HRMS(ESI,m/z)calcd for C25H18ClN5O[M+H]+,440.1273；found,440.1347。
实施例11：(3-((2-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)苯基)乙炔基)苯基)(吡咯-1-基)甲酮(A11)的制备
按照实施例1的制备方法，将11a替换为(3-碘苯基)(吡咯-1-基)甲酮(11k)，制备标题化合物。淡黄色固体，收率42％。M.p.:204.9-205.2℃.1H-NMR(600MHz,CDCl3-d6)δ9.99(s,1H),8.99(d,J＝8.3Hz,1H),8.84(s,1H),8.20(d,J＝8.6Hz,1H),7.89(s,1H),7.87(d,J＝7.7Hz,1H),7.71(d,J＝8.7Hz,1H),7.59(d,J＝7.6Hz,1H),7.52(d,J＝7.7Hz,1H),7.50-7.42(m,2H),7.15(t,J＝7.5Hz,1H),3.67(t,J＝6.9Hz,2H),3.44(t,J＝6.6Hz,2H),2.06-1.93(m,2H),1.92-1.81(m,2H).13C-NMR(100MHz,CDCl3-d6)δ168.7,156.1,155.6,149.9,138.9,138.8,137.8,133.2,132.0,129.9,129.8,129.7,128.5,127.3,123.6,122.6,119.9,113.3,96.8,84.9,77.2,49.5,46.2,26.4,24.8.HRMS(ESI,m/z)calcd forC26H20ClN5O[M+H]+,454.1429；found,454.1445。
实施例12：3-((2-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)苯基)乙炔基)苯甲酸甲酯(A12)的制备
按照实施例1的制备方法，将11a替换为3-碘-苯甲酸甲酯(11l)，制备标题化合物。淡黄色固体，收率45％。M.p.:189.5-190.2℃.1H-NMR(600MHz,CDCl3-d6)δ10.13(s,1H),8.96(d,J＝8.4Hz,1H),8.86(s,1H),8.34(d,J＝11.9Hz,2H),8.08-8.01(m,2H),7.74(d,J＝8.7Hz,1H),7.62(d,J＝7.7Hz,1H),7.49(t,J＝7.8Hz,2H),7.19(t,J＝7.5Hz,1H),3.95(s,3H).13C-NMR(100MHz,CDCl3-d6)δ166.3,156.3,154.8,150.5,138.3,137.8,136.3,132.6,132.2,131.2,130.6,130.3,129.9,128.6,124.2,122.8,120.2,113.6,100.0,96.7,84.8,52.4.HRMS(ESI,m/z)calcd for C23H15ClN4O2[M+H]+,415.0956；found,415.0974。
实施例13：3-((2-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)苯基)乙炔基)苯甲酸乙酯(A13)的制备
按照实施例1的制备方法，将11a替换为3-碘-苯甲酸乙酯(11m)，制备标题化合物。淡黄色固体，收率50％。M.p.:161.3-162.7℃.1H-NMR(600MHz,CDCl3-d6)δ10.17(s,1H),8.96(d,J＝8.3Hz,1H),8.87(s,1H),8.37(s,1H),8.33(s,1H),8.07(d,J＝7.8Hz,1H),8.04(d,J＝7.6Hz,1H),7.75(d,J＝8.7Hz,1H),7.64(s,1H),7.49(t,J＝7.7Hz,2H),7.20(t,J＝7.5Hz,1H),4.41(q,J＝7.1Hz,2H),1.41(t,J＝7.1Hz,3H).13C-NMR(100MHz,CDCl3-d6)δ165.8,156.3,154.8,150.6,138.2,137.8,136.3,132.5,132.1,131.2,131.0,130.9,130.3,129.8,128.8,128.5,124.2,122.6,120.2,113.6,96.7,84.4,61.2,14.3.HRMS(ESI,m/z)calcd for C24H17ClN4O2[M+H]+,429.1113；found,429.1103。
实施例14：5-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)-2-甲基苯并呋喃-2-甲酸甲酯(15a/B02)的制备
步骤A：3-甲基-5-硝基苯并呋喃-2-甲酸甲酯(13a)的制备
将2-硝基-5-硝基苯乙酮(3.3g,18.2mmol)置于250mL茄形瓶中，加入80mL经无水硫酸钠干燥的N,N-二甲基甲酰胺，室温搅拌下加入碳酸铯(7.1g,2.2mmol)，搅拌10min后滴加溴乙酸甲酯(2.0mL,18mmol)，滴毕，升温至40℃搅拌1h，再升温至100℃搅拌1h，TLC监测反应进程。反应完毕后，将反应液倒入500mL冰水中，搅拌10min，析出大量黄色固体，抽滤，滤饼用水洗三次，干燥得黄色固体3.8g，收率91％。1H-NMR(600MHz,DMSO-d6)δ8.83-8.75(m,1H),8.38(dd,J＝9.1,2.3Hz,1H),7.93(dd,J＝9.9,3.8Hz,1H),3.92(s,3H),2.61(s,3H)。
3-甲基-5-硝基苯并呋喃-2-甲酸乙酯(13b)的制备
以2-硝基-5-硝基苯乙酮和溴乙酸乙酯为原料，按照13a的合成方法，得到13b，收率为94％。
步骤B：5-氨基-3-甲基苯并呋喃-2-甲酸甲酯(14a)的制备
将13a(1.0g,4mmol)、质量分数5％的钯/碳(135mg,1.3mmol)和50mL无水甲醇置于100mL茄形瓶中，通入氢气，室温搅拌30min。TLC监测反应进程，反应完毕后，过滤，蒸除无水甲醇，得黄色固体820mg，收率为98％。1H-NMR(600MHz,DMSO-d6)δ7.31(d,J＝8.8Hz,1H),6.82(dd,J＝8.8,2.3Hz,1H),6.75(d,J＝2.2Hz,1H),5.05(s,2H),3.85(s,3H),2.43(s,3H)。
5-氨基-3-甲基苯并呋喃-2-甲酸乙酯(14b)
以14a为原料，按照13b的合成方法，得到14b，收率98％。1H-NMR(600MHz,DMSO-d6)δ7.32(d,J＝8.8Hz,1H),6.82(dd,J＝8.8,2.3Hz,1H),6.75(d,J＝2.1Hz,1H),5.05(s,2H),4.31(q,J＝7.1Hz,2H),2.43(s,3H),1.32(t,J＝7.1Hz,3H)。
步骤C：5-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)-2-甲基苯并呋喃-2-甲酸甲酯(15a/B02)的制备
将中间体5(100mg,0.5mmol)、14a(210mg,0.55mmol)、三乙胺(2滴)和20mL异丙醇置于50mL茄形瓶中，升温至50℃进行反应。随反应进行，析出大量黄色固体，TLC监测反应进程。反应完毕后，抽滤，滤饼干燥得黄色固体1.4g，收率88％。M.p.:221.1-223.0℃.1H-NMR(600MHz,DMSO-d6)δ11.06(s,1H),8.83(s,1H),8.36(d,J＝8.8Hz,1H),8.26(d,J＝2.0Hz,1H),8.09(d,J＝8.8Hz,1H),7.96(dd,J＝8.9,2.2Hz,1H),7.74(d,J＝8.9Hz,1H),3.91(s,3H),2.56(s,3H).13C-NMR(100MHz,DMSO-d6)δ160.0,158.1,153.4,151.6,149.6,141.2,132.9,131.4,130.4,128.6,125.4,125.3,116.7,112.2,52.1,9.2.HRMS(ESI,m/z)calcdfor C18H13ClN4O3[M+H]+,369.0749；found,369.0769。
实施例15：5-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)-3-甲基苯并呋喃-2-甲酸乙酯(15b/B03)的制备
按照实施例14的制备方法，将14a替换为14b，制备标题化合物。收率90％。M.p.:229.3-230.1℃.1H-NMR(600MHz,DMSO-d6)δ10.75(s,1H),8.77(s,1H),8.32(d,J＝8.8Hz,1H),8.30(d,J＝2.0Hz,1H),8.04(d,J＝8.8Hz,1H),7.98(dd,J＝8.9,2.1Hz,1H),7.73(d,J＝8.9Hz,1H),4.37(q,J＝7.1Hz,2H),2.56(s,3H),1.36(t,J＝7.1Hz,3H).13C-NMR(150MHz,DMSO-d6)δ159.6,157.4,154.7,151.1,148.9,141.2,137.6,133.6,130.8,130.6,128.6,125.4,124.7,115.7,112.0,61.0,14.2,9.3.HRMS(ESI,m/z)calcd for C19H15ClN4O3[M+H]+,383.0905；found,383.0928。
实施例16：5-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)-3-甲基苯并呋喃-2-甲酸(16/B01)的制备
将中间体15(0.2g,0.52mmol)和20mL无水乙醇置于100mL茄形瓶中，升温至80℃，搅拌下加入0.24mLNaOH水溶液(0.042g/0.238mL水)，TLC监测反应进程。反应完毕后，将反应液倒入100mL冰水中，用质量分数为10％的盐酸溶液调节pH至3，抽滤，滤饼干燥得黄色固体160mg，收率87％。M.p.:267.6-268.5℃.1H-NMR(600MHz,DMSO-d6)δ10.49(s,1H),8.72(s,1H),8.31(d,J＝2.0Hz,1H),8.29(d,J＝8.8Hz,1H),8.01(d,J＝8.8Hz,1H),8.00-7.98(m,1H),7.69(d,J＝8.9Hz,1H),2.54(s,3H).13C-NMR(150MHz,DMSO-d6)δ161.1,156.9,155.8,150.7,148.3,144.0,142.0,139.6,134.1,131.2,130.0,128.7,124.6,124.0,114.9,111.8,9.3.HRMS(ESI,m/z)calcd for C17H11ClN4O3[M-H]-,353.0447；found,353.0404。
实施例17：5-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)-N,3-二甲基苯并呋喃-2-甲酰胺(B04)的制备
将中间体16(200mg,0.56mmol)、HATU(260mg,0.68mmol)、DMAP(38mg,0.37mmol)、DIEA(150g,1.1mmol)和30mL N,N-二甲基甲酰胺置于100mL茄形瓶中，搅拌30min，将甲胺盐酸盐(46mg,0.68mmol)加入该混合液，25℃搅拌1h。TLC监测反应完毕，向反应液中加入150mL二氯甲烷，依次用质量分数为10％的盐酸溶液、水、饱和碳酸氢钠溶液、水、饱和氯化钠各洗一次，无水硫酸钠干燥，过滤，蒸除二氯甲烷，柱层析得黄色固体，收率86％。M.p.:267.6-268.5℃.1H-NMR(600MHz,DMSO-d6)δ10.28(s,1H),8.67(s,1H),8.50(d,J＝4.2Hz,1H),8.26(s,1H),8.25(s,1H),7.98(d,J＝8.6Hz,2H),7.60(d,J＝8.8Hz,1H),2.79(d,J＝4.3Hz,3H),2.53(s,3H).13C-NMR(100MHz,DMSO-d6)δ159.9,156.9,155.8,149.7,148.3,144.1,143.9,139.5,134.0,131.2,130.0,129.3,123.0,120.3,114.7,111.3,25.6,8.8.HRMS(ESI,m/z)calcd for C18H14ClN5O2[M+H]+,368.0909；found,368.0899。
实施例18：5-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)-N,N,3-三甲基苯并呋喃-2-甲酰胺(B05)的制备
按照实施例17的制备方法，将甲胺盐酸盐替换为二甲胺盐酸盐，制备标题化合物。黄色固体，收率53％。M.p.:229.3-230.1℃.1H-NMR(600MHz,DMSO-d6)δ10.21(s,1H),8.66(s,1H),8.26(d,J＝8.8Hz,1H),8.24(d,J＝2.0Hz,1H),7.97(d,J＝8.8Hz,1H),7.96-7.94(m,1H),7.62(d,J＝8.9Hz,1H),3.08(d,J＝65.8Hz,6H),2.35(s,3H).13C-NMR(100MHz,DMSO-d6)δ159.3,156.9,155.9,149.7,148.2,144.2,144.1,139.7,134.0,131.2,129.9,129.3,122.9,120.5,114.6,111.3,22.5,11.5,8.8.HRMS(ESI,m/z)calcd for C19H16ClN5O2[M+H]+,382.1065；found,382.1047。
实施例19：5-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)-N-异丙基-3-甲基苯并呋喃-2-甲酰胺(B06)的制备
按照实施例17的制备方法，将甲胺盐酸盐替换为异丙胺，制备标题化合物。黄色固体，收率48％。M.p.:218.1-219.3℃.1H-NMR(600MHz,DMSO-d6)δ10.21(s,1H),8.66(s,1H),8.31(d,J＝8.1Hz,1H),8.27(d,J＝1.7Hz,1H),8.26(d,J＝8.8Hz,1H),7.99(dd,J＝8.9,2.1Hz,1H),7.97(d,J＝8.7Hz,1H),7.61(d,J＝8.9Hz,1H),4.19-4.08(m,1H),2.53(s,3H),1.19(d,J＝6.6Hz,6H).13C-NMR(100MHz,DMSO-d6)δ158.5,156.9,155.9,149.7,148.2,144.2,144.1,139.7,134.0,131.2,129.9,129.3,122.9,120.5,114.5,111.3,22.3,8.9.HRMS(ESI,m/z)calcd for C20H18ClN5O2[M+H]+,396.1222；found,396.1186。
实施例20：5-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)-3-甲基-N-丙基苯并呋喃-2-甲酰胺(B07)的制备
按照实施例17的制备方法，将甲胺盐酸盐替换为丙胺，制备标题化合物。黄色固体，收率56％。M.p.:190.5-191.6℃.1H-NMR(600MHz,DMSO-d6)δ10.21(s,1H),8.66(s,1H),8.54(t,J＝5.8Hz,1H),8.28(d,J＝2.0Hz,1H),8.25(d,J＝8.7Hz,1H),7.99(dd,J＝8.9,2.1Hz,1H),7.97(d,J＝8.7Hz,1H),7.60(d,J＝8.9Hz,1H),3.22(q,J＝13.9,6.3Hz,2H),2.53(s,3H),1.59-1.51(m,2H),0.89(t,J＝7.4Hz,3H).13C-NMR(100MHz,DMSO-d6)δ161.0,156.9,155.9,150.0,148.2,145.1,144.2,139.7,134.0,131.3,129.9,128.6,122.3,118.9,114.4,111.3,37.8,35.2,8.7.HRMS(ESI,m/z)calcd for C20H18ClN5O2[M+H]+,396.1222；found,396.1230。
实施例21：5-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)-N-(2-甲氧基乙基)-3-甲基苯并呋喃-2-甲酰胺(B08)的制备
按照实施例17的制备方法，将甲胺盐酸盐替换为2-甲氧基乙胺，制备标题化合物。黄色固体，收率60％。M.p.:223.0-224.1℃.1H-NMR(600MHz,DMSO-d6)δ10.36(s,1H),8.69(s,1H),8.48(t,J＝5.4Hz,1H),8.27(d,J＝2.4Hz,1H),8.27(d,J＝4.6Hz,1H),8.00(s,1H),7.98(s,1H),7.62(d,J＝8.9Hz,1H),3.48(t,J＝5.5Hz,2H),3.44(q,J＝11.1,5.4Hz,2H),3.28(s,3H),2.54(s,3H).13C-NMR(100MHz,DMSO-d6)δ159.4,157.1,155.4,149.9,148.5,143.9,138.9,133.8,131.1,130.2,129.3,123.2,120.8,114.9,111.4,70.3,57.9,38.1,8.8.HRMS(ESI,m/z)calcd for C20H18ClN5O3[M+H]+,412.1171；found,412.1997。
实施例22：5-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)-N-(3-甲氧基丙基)-3-甲基苯并呋喃-2-甲酰胺(B09)的制备
按照实施例17的制备方法，将甲胺盐酸盐替换为3-甲氧基丙胺，制备标题化合物。黄色固体，收率58％。M.p.:189.6-190.2℃.1H-NMR(600MHz,DMSO-d6)δ10.22(s,1H),8.67(s,1H),8.55(t,J＝5.8Hz,1H),8.28(d,J＝2.1Hz,1H),8.26(d,J＝8.8Hz,1H),8.00(dd,J＝8.9,2.2Hz,1H),7.97(d,J＝8.8Hz,1H),7.61(d,J＝8.9Hz,1H),3.39(t,J＝6.3Hz,2H),3.31(m,2H),3.25(s,3H),2.54(s,3H),1.81-1.75(m,2H).13C-NMR(100MHz,DMSO-d6)δ159.4,156.9,155.9,149.7,148.2,144.2,144.0,139.7,134.1,131.3,129.9,129.3,123.0,120.5,114.6,111.3,70.0,58.0,36.1,29.3,8.8.HRMS(ESI,m/z)calcd forC21H20ClN5O3[M+H]+,426.1327；found,426.1358。
实施例23：(5-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)-3-甲基苯并呋喃-2-基)(哌嗪-1-基)甲酮(B10)的制备
按照实施例17的制备方法，将甲胺盐酸盐替换为1-Boc-哌嗪，制备标题化合物。黄色固体，收率40％。M.p.:101.3-102.4℃.1H-NMR(600MHz,DMSO-d6)δ10.21(s,1H),8.65(s,1H),8.26(d,J＝8.7Hz,1H),8.24(d,J＝2.0Hz,1H),7.97(d,J＝8.8Hz,1H),7.95(dd,J＝8.9,2.2Hz,1H),7.62(d,J＝8.9Hz,1H),3.54(s,4H),2.75(s,4H),2.33(s,3H).13C-NMR(150MHz,DMSO-d6)δ159.9,157.0,155.9,150.1,148.3,144.4,144.2,139.7,134.1,131.3,130.0,128.6,122.6,119.6,114.5,111.5,55.0,8.8.HRMS(ESI,m/z)calcd forC21H19ClN6O2[M+H]+,423.1331；found,423.1293。
实施例24：(5-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)-3-甲基苯并呋喃-2-基)(吗啉基)甲酮(B11)的制备
按照实施例17的制备方法，将甲胺盐酸盐替换为吗啉，制备标题化合物。黄色固体，收率50％。M.p.:232.2-233.4℃.1H-NMR(600MHz,DMSO-d6)δ10.27(s,1H),8.67(s,1H),8.26(d,J＝8.8Hz,1H),8.25(d,J＝2.0Hz,1H),7.98(d,J＝8.7Hz,1H),7.96(d,J＝2.1Hz,1H),7.63(d,J＝8.9Hz,1H),3.65(s,8H),2.36(s,3H).13C-NMR(150MHz,DMSO-d6)δ159.9,157.0,155.7,150.1,148.4,144.4,143.8,139.3,134.0,131.2,130.1,128.6,122.6,119.6,114.6,111.5,66.4,8.7.HRMS(ESI,m/z)calcd for C21H18ClN5O3[M+H]+,424.1171；found,424.1175。
实施例25：5-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)-3-甲基-N-(1-甲基哌啶-4-基)苯并呋喃-2-甲酰胺(B12)的制备
按照实施例17的制备方法，将甲胺盐酸盐替换为1-甲基哌啶-4-氨基，制备标题化合物。黄色固体，收率32％。M.p.:200.1-201.8℃.1H-NMR(600MHz,DMSO-d6)δ10.22(s,1H),8.66(s,2H),8.30(d,J＝1.2Hz,1H),8.26(d,J＝8.7Hz,1H),8.02(dd,J＝9.0,1.3Hz,1H),7.98(d,J＝8.7Hz,1H),7.62(d,J＝8.9Hz,1H),4.05(s,1H),3.38(d,J＝10.1Hz,2H),3.05(s,2H),2.71(s,3H),2.54(s,3H),1.97(s,4H).13C-NMR(100MHz,DMSO-d6)δ159.1,156.9,155.9,149.7,148.3,144.2,143.7,139.7,134.1,131.2,129.9,129.2,123.2,121.1,114.6,111.4,8.9.HRMS(ESI,m/z)calcd for C23H23ClN6O2[M+H]+,451.1644；found,451.1617。
实施例26：1-(4-(5-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)-3-甲基苯并呋喃-2-羰基)哌嗪-1-基)乙-1-酮(B13)的制备
按照实施例17的制备方法，将甲胺盐酸盐替换为N-乙酰基哌嗪，制备标题化合物。黄色固体，收率47％。M.p.:192.2-193.2℃.1H-NMR(600MHz,DMSO-d6)δ10.23(s,1H),8.66(s,1H),8.27(d,J＝3.3Hz,1H),8.26(d,J＝3.4Hz,1H),7.98(dd,J＝8.8,1.8Hz,2H),7.63(d,J＝8.9Hz,1H),3.70-3.66(m,2H),3.61(m,J＝6.2,3.6Hz,2H),3.55(s,4H),2.37(s,3H),2.04(s,3H).13C-NMR(150MHz,DMSO-d6)δ168.6,167.1,160.0,157.0,155.9,150.1,148.3,144.4,144.2,139.7,134.1,131.3,130.0,128.6,122.6,114.5,111.5,21.4,8.8.HRMS(ESI,m/z)calcd for C23H21ClN6O3[M+H]+,465.1436；found,465.1441。
实施例27：5-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)-3-甲基苯并呋喃-2-基)(吡咯-1-基)甲酮(B14)的制备
按照实施例17的制备方法，将甲胺盐酸盐替换为吡咯，制备标题化合物。黄色固体，收率42％。M.p.:237.1-238.5℃.1H-NMR(600MHz,DMSO-d6)δ10.21(s,1H),8.66(s,1H),8.26(s,1H),8.25(s,1H),7.98(d,J＝3.1Hz,1H),7.96(d,J＝3.0Hz,1H),7.62(d,J＝8.9Hz,1H),3.79(t,J＝6.6Hz,2H),3.51(t,J＝6.7Hz,2H),2.46(s,3H),1.96-1.89(m,2H),1.89-1.83(m,2H).13C-NMR(100MHz,DMSO-d6)δ159.0,156.9,155.9,149.9,148.2,145.2,144.2,139.7,134.0,131.3,129.1,128.7,122.7,120.7,114.4,111.4,47.6,46.6,26.0,23.4,9.1.HRMS(ESI,m/z)calcd for C21H18ClN5O2[M+H]+,408.1222；found,408.1204。
实施例28：N-(6-苯基吡啶并[3,2-d]嘧啶-4-基)苯甲酰胺(C01)的制备
步骤C：2-氰基-3-氨基-6-氯吡啶(17)的制备
将2(5.0g，27.3mmol)、四丁基溴化铵(4.0g，13mmol)和100mL二氯甲烷加入250mL茄型瓶，加入新配制的保险粉水溶液(35g in 100mL water,202mmol)，室温搅拌过夜，TLC监测反应完全后，分液保留有机相，水相用二氯甲烷萃取三遍，合并有机相，饱和食盐水洗一遍，无水硫酸钠干燥，蒸除溶剂得淡黄色固体3.3g，收率80％。1H-NMR(600MHz,DMSO-d6)δ7.41(d,J＝8.9Hz,1H),7.30(d,J＝8.9Hz,1H),6.93(s,2H)。
步骤D：6-氯-吡啶并[3,2-d]嘧啶-4-胺(18)的制备
将17(3.0g，17.8mmoL)和乙酸铵(7.6g，98mmol)加入250mL茄型瓶，加入96mL原甲酸三乙酯，126℃搅拌2h，TLC监测反应完全，冷却，减压整除溶剂，柱层析得黄色固体。1H-NMR(600MHz,DMSO-d6)δ8.44(s,1H),8.13(d,J＝8.8Hz,1H),8.03(s,1H),7.92(s,1H),7.86(d,J＝8.8Hz,1H)。
步骤E：6-苯基吡啶并[3,2-d]嘧啶-4-胺(19a)的制备
于100mL茄型瓶中加入18(1.0g，5.6mmoL)、苯硼酸(0.8g，6.7mmol)、碳酸钾(1.6g，11.2mmoL)和四(三苯基膦)钯(0.35g，0.17mmol)，加入混合溶剂1，4-二氧六环/水(30/7.5mL)，90℃回流1.5h，TLC监测反应完全，冷却，抽滤得淡黄色固体1.0g，收率85％。LC-MS:223.1[M+H]+。
6-(4-氯苯基)吡啶并[3,2-d]嘧啶-4-胺(19b))的制备
以18与对氯苯硼酸为原料，按照19a合成方法，得到化合物19b，收率79％。LC-MS:257.2[M+H]+.1H-NMR(600MHz,DMSO-d6)δ8.48(d,J＝8.6Hz,2H),8.44(d,J＝8.8Hz,1H),8.41(s,1H),8.17(s,1H),8.13(d,J＝8.8Hz,1H),7.99(s,1H),7.58(d,J＝8.6Hz,2H)。
6-(吡啶-3-基)吡啶并[3,2-d]嘧啶-4-胺(19c))的制备
以28与吡啶-3-硼酸为原料，按照19a合成方法，得到化合物19c，收率75％。LC-MS:224.0[M+H]+。
6-(4-氟吡啶-3-基)吡啶并[3,2-d]嘧啶-4-胺(19d))的制备
以28与4-氟吡啶-3-硼酸为原料，按照19a合成方法，得到化合物19d，收率82％。LC-MS:242.1[M+H]+。
步骤F：N-(6-苯基吡啶并[3,2-d]嘧啶-4-基)苯甲酰胺(C01)的制备
于25mL茄型瓶中加入19a(888mg，4.0mmoL)、苯甲酸(586mg，4.8mmol)、HATU(1872mg，4.8mmoL)、DMAP(586mg，4.8mmol)和DIEA(620mg，4.8mmol)，加入50mL四氢呋喃后室温搅拌过夜。TLC监测反应完全，蒸除溶剂，用乙酸乙酯重新溶解所得固体，水洗三遍，饱和氯化钠洗一遍，无水硫酸钠干燥。柱层析得淡黄色固体678mg，收率62％。M.p.:158.4-162.1℃.1H-NMR(600MHz,DMSO-d6)δ11.12(s,1H),9.01(s,1H),8.60(d,J＝8.7Hz,1H),8.44(d,J＝8.1Hz,1H),8.33(d,J＝2.0Hz,2H),8.1-8.06(m,2H),7.70(t,J＝7.3Hz,1H),7.62(t,J＝7.6Hz,2H),7.59-7.52(m,3H).13C-NMR(150MHz,CDCl3-d6)δ164.1,157.6,156.5,155.9,144.9,137.9,137.7,134.3,133.2,131.3,130.8,129.5,129.4,127.8,127.7,126.9.HRMS(ESI,m/z)calcd for C20H14N4O[M+H]+,327.1240；found,327.1247。
实施例29：4-氯-N-(6-苯基吡啶并[3,2-d]嘧啶-4-基)苯甲酰胺(C02)的制备
按照实施例28的制备方法，将苯甲酸替换为4-氯苯甲酸，制备标题化合物。收率60％。M.p.:216.0-217.3℃.1H-NMR(600MHz,CDCl3-d6)δ10.88(s,1H),9.19(s,1H),8.43(d,J＝8.8Hz,1H),8.33(d,J＝8.8Hz,1H),8.13(dd,J＝8.0,1.4Hz,2H),8.05(d,J＝8.6Hz,2H),7.67-7.50(m,5H).13C-NMR(150MHz,CDCl3-d6)δ163.1,157.7,156.4,155.7,144.7,139.6,137.7,137.6,132.5,131.1,130.8,129.6,129.4,129.2,127.6,127.0.HRMS(ESI,m/z)calcd for C20H13ClN4O[M+H]+,361.0851；found,361.0858。
实施例30：4-甲氧基-N-(6-苯基吡啶并[3,2-d]嘧啶-4-基)苯甲酰胺(C03)的制备
按照实施例28的制备方法，将苯甲酸替换为4-甲氧基苯甲酸，制备标题化合物。收率57％。M.p.:195.8-196.8℃.1H-NMR(600MHz,DMSO-d6)δ10.97(s,1H),9.02(s,1H),8.61(d,J＝7.5Hz,1H),8.45(d,J＝7.1Hz,1H),8.35(d,J＝0.8Hz,2H),8.06(d,J＝8.5Hz,2H),7.58-7.50(m,3H),7.16(d,J＝7.7Hz,2H),3.88(s,3H).13C-NMR(150MHz,CDCl3-d6)δ163.6,163.4,157.5,156.7,155.8,144.5,137.7,137.6,131.2,130.7,129.9,129.4,127.6,126.9,126.4,114.5,55.8.HRMS(ESI,m/z)calcd for C20H16N4O2[M+H]+,357.1346；found,357.1356。
实施例31：4-甲基-N-(6-苯基吡啶并[3,2-d]嘧啶-4-基)苯甲酰胺(C04)的制备
按照实施例28的制备方法，将苯甲酸替换为4-甲基苯甲酸，制备标题化合物。收率60％。M.p.:180.0-181.2℃.1H-NMR(600MHz,DMSO-d6)δ11.02(s,1H),9.03(s,1H),8.62(d,J＝8.6Hz,1H),8.46(d,J＝8.6Hz,1H),8.35(d,J＝6.6Hz,2H),7.98(d,J＝8.1Hz,2H),7.58-7.55(m,3H),7.43(d,J＝7.3Hz,2H),2.43(s,3H).13C-NMR(150MHz,CDCl3-d6)δ164.2,157.6,156.6,155.9,144.9,144.1,137.9,137.8,131.4,131.3,130.8,130.1,129.5,127.9,127.7,126.9,21.9.HRMS(ESI,m/z)calcd for C21H16N4O[M+H]+,341.1397；found,341.1464。
实施例32：N-(6-(4-氯苯基)吡啶并[3,2-d]嘧啶-4-基)苯甲酰胺(C07)的制备
按照实施例28的制备方法，将19a替换为19b，制备标题化合物。收率60％。M.p.:223.5-224.2℃.1H-NMR(600MHz,DMSO-d6)δ11.13(s,1H),9.04(s,1H),8.63(d,J＝6.2Hz,1H),8.47(s,1H),8.41(s,1H),8.06(d,J＝7.7Hz,2H),7.70(d,J＝5.7Hz,1H),7.67-7.54(m,4H).13C-NMR(150MHz,CDCl3-d6)δ164.0,156.4,156.4,156.1,144.9,138.1,137.1,136.1,134.2,133.2,131.2,129.7,129.3,128.8,127.8,126.5.HRMS(ESI,m/z)calcd forC20H13ClN4O[M+H]+,361.0851；found,361.0912。
实施例33：4-氯-N-(6-(4-氯苯基)吡啶并[3,2-d]嘧啶-4-基)苯甲酰胺(C08)的制备
按照实施例28的制备方法，将19a替换为19b，将苯甲酸替换为4-氯苯甲酸，制备标题化合物。收率57％。M.p.:215.1-217.1℃.1H-NMR(600MHz,DMSO-d6)δ11.23(s,1H),8.97(s,1H),8.60(d,J＝8.3Hz,1H),8.43(d,J＝7.6Hz,1H),8.37(d,J＝1.6Hz,2H),8.06(d,J＝8.5Hz,2H),7.68(d,J＝8.3Hz,2H),7.63(d,J＝8.4Hz,2H).13C-NMR(150MHz,CDCl3-d6)δ163.1,156.6,156.4,155.9,144.8,139.7,138.1,137.3,136.1,132.5,131.1,129.7,129.7,129.2,128.8,126.7.HRMS(ESI,m/z)calcd for C20H12Cl2N4O[M+H]+,395.0461；found,395.0473。
实施例34：N-(6-(4-氯苯基)吡啶并[3,2-d]嘧啶-4-基)-4-甲氧基苯甲酰胺(C09)的制备
按照实施例28的制备方法，将19a替换为19b，将苯甲酸替换为4-甲氧基苯甲酸，制备标题化合物。收率54％。M.p.:220.5-221.2℃.1H-NMR(600MHz,DMSO-d6)δ10.41(s,1H),8.98(s,1H),8.60(d,J＝8.8Hz,1H),8.41(d,J＝8.8Hz,1H),8.28(d,J＝8.3Hz,2H),7.64(d,J＝8.3Hz,2H),7.38(d,J＝8.2Hz,2H),6.97(d,J＝8.3Hz,2H),3.74(s,3H)。
实施例35：N-(6-(4-氯苯基)吡啶并[3,2-d]嘧啶-4-基)-4-甲基苯甲酰胺(C10)的制备
按照实施例28的制备方法，将19a替换为19b，将苯甲酸替换为4-甲基苯甲酸，制备标题化合物。收率56％。M.p.:222.1-223.2℃.1H-NMR(600MHz,CDCl3-d6)δ10.85(s,1H),9.19(s,1H),8.42(d,J＝8.8Hz,1H),8.29(d,J＝8.8Hz,1H),8.09(d,J＝8.5Hz,2H),8.01(d,J＝8.1Hz,2H),7.58(d,J＝8.5Hz,2H),7.41(d,J＝7.9Hz,2H),2.50(s,3H).13C-NMR(150MHz,CDCl3-d6)δ163.9,156.6,156.3,156.1,144.8,144.1,138.0,137.1,136.1,131.4,131.3,130.0,129.7,128.8,127.8,126.5,21.8.HRMS(ESI,m/z)calcd for C21H15ClN4O[M+H]+,375.1007；found,375.1032。
实施例36：4-甲基-N-(6-(吡啶-3-基)吡啶并[3,2-d]嘧啶-4-基)苯甲酰胺(C11)的制备
按照实施例28的制备方法，将19a替换为19c，将苯甲酸替换为4-甲基苯甲酸，制备标题化合物。收率52％。M.p.:214.1-216.0℃.1H-NMR(600MHz,DMSO-d6)δ11.11(s,1H),9.56(s,1H),9.03(s,1H),8.73(d,J＝4.3Hz,2H),8.69(d,J＝8.6Hz,2H),8.50(d,J＝6.8Hz,1H),7.97(d,J＝8.1Hz,2H),7.63-7.56(m,1H),7.42(d,J＝7.6Hz,2H),2.43(s,3H).13C-NMR(150MHz,DMSO-d6)δ157.4,155.2,154.3,151.0,148.9,145.1,143.1,137.6,135.1,132.8,131.4,129.4,129.3,129.1,128.3,126.8,124.0,21.2.HRMS(ESI,m/z)calcd for C20H15N5O[M+H]+,342.1349；found,342.1415。
实施例37：N-(6-(6-氟吡啶-3-基)吡啶并[3,2-d]嘧啶-4-基)苯甲酰胺(C12)的制备
按照实施例28的制备方法，将19a替换为19d，制备标题化合物。收率50％。M.p.:240.2-241.7℃.HRMS(ESI,m/z)calcd for C19H12FN5O[M+H]+,346.1099；found,346.1126。
实施例38：4-氯-N-(6-(6-氟吡啶-3-基)吡啶并[3,2-d]嘧啶-4-基)苯甲酰胺(C13)的制备
按照实施例28的制备方法，将19a替换为19d，将苯甲酸替换为4-氯苯甲酸，制备标题化合物。收率51％。M.p.:258.8-259.7℃.1H-NMR(600MHz,DMSO-d6)δ11.39(s,1H),9.25(s,1H),9.01-8.89(m,2H),8.67(d,J＝8.8Hz,1H),8.48(d,J＝8.8Hz,1H),8.05(d,J＝8.5Hz,2H),7.66(d,J＝8.5Hz,2H),7.40(dd,J＝8.6,2.4Hz,1H).HRMS(ESI,m/z)calcd forC19H11ClFN5O[M+H]+,380.0709；found,380.0719。
实施例39：N-(6-(6-氟吡啶-3-基)吡啶并[3,2-d]嘧啶-4-基)-4-甲氧基苯甲酰胺(C14)的制备
按照实施例28的制备方法，将19a替换为19d，将苯甲酸替换为4-甲氧基苯甲酸，制备标题化合物。收率55％。M.p.:174.3-175.4℃.1H-NMR(600MHz,DMSO-d6)δ11.05(s,1H),9.28(s,1H),9.02(s,1H),8.98(d,J＝6.2Hz,1H),8.68(d,J＝8.6Hz,1H),8.50(d,J＝8.7Hz,1H),8.04(d,J＝8.5Hz,1H),7.42(d,J＝7.5Hz,1H),7.14(d,J＝8.0Hz,2H),3.88(s,3H).HRMS(ESI,m/z)calcd for C20H14FN5O2[M+H]+,376.1204；found,376.1238。
实施例40：N-(6-(6-氟吡啶-3-基)吡啶并[3,2-d]嘧啶-4-基)-4-甲基苯甲酰胺(C15)的制备
按照实施例28的制备方法，将19a替换为19d，将苯甲酸替换为4-甲基苯甲酸，制备标题化合物。收率56％。M.p.:190.4-192.3℃.1H-NMR(600MHz,DMSO-d6)δ11.11(s,1H),9.28(d,J＝1.6Hz,1H),9.03(s,1H),8.98(td,J＝8.3,2.1Hz,1H),8.69(d,J＝8.9Hz,1H),8.51(d,J＝8.8Hz,1H),7.96(d,J＝8.0Hz,2H),7.42(d,J＝7.9Hz,2H),2.43(s,3H).HRMS(ESI,m/z)calcd for C20H14FN5O[M+H]+,360.1255；found,360.1272。
实施例41：5-氯-N-(6-苯基吡啶并[3,2-d]嘧啶-4-基)烟酰胺(C16)的制备
按照实施例28的制备方法，将苯甲酸替换为5-氯烟酸，制备标题化合物。收率48％。M.p.:191.4-192.2℃.1H-NMR(600MHz,CDCl3-d6)δ10.89(s,1H),9.19(d,J＝1.8Hz,1H),9.18(s,1H),8.85(d,J＝2.3Hz,1H),8.45(d,J＝8.8Hz,1H),8.41(t,J＝2.1Hz,1H),8.36(d,J＝8.8Hz,1H),8.17-8.11(m,2H),7.67-7.50(m,3H).13C-NMR(150MHz,CDCl3-d6)δ161.4,158.1,156.0,155.6,152.7,145.8,145.0,138.0,137.4,136.1,133.3,131.1,131.1,129.6,127.7,127.3.HRMS(ESI,m/z)calcd for C19H12ClN5O[M+H]+,362.0803；found,362.0804。
实施例42：2-氯-N-(6-苯基吡啶并[3,2-d]嘧啶-4-基)烟酰胺(C17)的制备
按照实施例28的制备方法，将苯甲酸替换为2-氯烟酸，制备标题化合物。收率42％。M.p.:127.4-128.5℃.1H-NMR(600MHz,CDCl3-d6)δ11.17(s,1H),9.07(s,1H),8.61(dd,J＝4.7,1.9Hz,1H),8.43(d,J＝8.8Hz,1H),8.35(d,J＝8.9Hz,1H),8.32(dd,J＝7.6,1.4Hz,1H),8.17(dd,J＝8.0,1.3Hz,2H),7.61-7.53(m,3H),7.49(dd,J＝7.6,4.8Hz,1H).13C-NMR(150MHz,CDCl3-d6)δ162.7,158.3,156.1,154.9,152.0,147.0,144.5,145.0,137.3,137.2,131.1,131.0,130.7,129.4,127.8,127.2,123.3.HRMS(ESI,m/z)calcd forC19H12ClN5O[M+H]+,362.0803；found,362.0819。
实施例43：5-氯-N-(6-(吡啶-3-基)吡啶并[3,2-d]嘧啶-4-基)烟酰胺(C18)的制备
按照实施例28的制备方法，将19a替换为19b，将苯甲酸替换为5-氯烟酸，制备标题化合物。收率40％。M.p.:236.4-237.8℃.1H-NMR(600MHz,DMSO-d6)δ9.62(d,J＝2.0Hz,1H),8.80(dt,J＝8.0,1.6Hz,1H),8.68(dd,J＝4.7,1.3Hz,1H),8.52(d,J＝8.8Hz,1H),8.42(s,1H),8.24(s,1H),8.17(d,J＝8.8Hz,1H),8.02(dd,J＝4.0,1.8Hz,1H),7.56(dd,J＝8.0,4.8Hz,2H).13C-NMR(150MHz,DMSO-d6)δ166.3,162.0,156.2,151.9,150.4,148.8,148.6,145.9,144.1,136.5,134.6,134.4,132.9,131.5,131.0,128.8,125.1,123.8。
实施例44：6-氯-N-(6-(吡啶-3-基)吡啶并[3,2-d]嘧啶-4-基)烟酰胺(C19)的制备
按照实施例28的制备方法，将19a替换为19c，将苯甲酸替换为6-氯烟酸，制备标题化合物。收率40％。M.p.:269.1-271.5℃.1H-NMR(600MHz,DMSO-d6)δ11.73(s,1H),9.74(s,1H),8.90(d,J＝7.6Hz,1H),8.85(s,1H),8.74-8.72(m,2H),8.57(dd,J＝4.8,1.7Hz,1H),8.50(d,J＝8.9Hz,1H),8.14(dd,J＝7.5,1.7Hz,1H),7.63-7.58(m,2H).13C-NMR(150MHz,DMSO-d6)δ164.9,156.4,154.8,154.6,151.1,150.7,149.4,146.1,145.5,138.4,137.5,135.4,133.0,132.6,131.1,126.8,123.8,123.3.HRMS(ESI,m/z)calcd for C18H11ClN6O[M+H]+,363.0756；found,363.0771。
实施例45：2-氯-N-(6-(6-氟吡啶-3-基)吡啶并[3,2-d]嘧啶-4-基)烟酰胺(C20)的制备
按照实施例28的制备方法，将19a替换为19d，将苯甲酸替换为2-氯烟酸，制备标题化合物。收率45％。M.p.:287.0-288.0℃.1H-NMR(600MHz,DMSO-d6)δ11.77(s,1H),9.43(d,J＝1.4Hz,1H),9.16(t,J＝7.4Hz,1H),8.82(s,1H),8.72(d,J＝8.9Hz,1H),8.57(dd,J＝4.8,1.9Hz,1H),8.48(d,J＝8.9Hz,1H),8.14(dd,J＝7.5,1.8Hz,1H),7.59(dd,J＝7.5,4.9Hz,1H),7.42(dd,J＝8.6,2.4Hz,1H).HRMS(ESI,m/z)calcd for C18H10ClFN6O[M+H]+,381.0661；found,381.0666。
实施例46：N,6-二苯基吡啶并[3,2-d]嘧啶-4-胺(D01)的制备
步骤A：6-氯-N-苯基吡啶并[3,2-d]嘧啶-4-胺(20a)的制备
于50mL茄形瓶中加入5(1.0g，5.05mmol)、苯胺(0.52g，5.56mmol)、三乙胺(1.0g，10.1mmol)和异丙醇20mL，50℃搅拌10min，TLC监测反应完全，蒸干溶剂，用乙酸乙酯重新溶解所得固体，水洗三遍，饱和氯化钠水溶液洗一遍，无水硫酸钠干燥，过滤，蒸干得淡黄色固体1.1g，收率85％。
以5与4-甲基苯胺、4-三氟甲基苯胺、4-甲氧基苯胺、4-羟基苯胺、4-氰基苯胺、3-氟苯胺、2-氟苯胺、3-甲氧基苯胺、2-甲氧基苯胺、4-氟-3-甲氧基苯胺、4-氟-2-甲氧基苯胺、4-氟-2-异丙氧基苯胺、3,4-二氟苯胺、2,4-二氟苯胺和3-氯-4-氟苯胺为原料，按照20a的合成方法，分别得到20b-20p。收率60％-90％。
步骤E：N,6-二苯基吡啶并[3,2-d]嘧啶-4-胺(D01)的制备
于50mL茄形瓶中加入20a(300mg，1.17mmol)、苯硼酸(170mg，1.4mmol)、四(三苯基膦)钯(41mg，0.035mmol)及新研磨的碳酸钾(323mg，2.34mmol)，加入混合溶剂二氧六环/水(18/4.5mL)，90℃搅拌1.5h。冷却，蒸除溶剂，柱层析得白色固体296mg，收率85％。M.p.:190.4-191.0℃.1H-NMR(600MHz,DMSO-d6)δ10.06(s,1H),8.65(s,1H),8.53(t,J＝7.8Hz,3H),8.27(d,J＝8.8Hz,1H),8.02(d,J＝7.9Hz,2H),7.59(t,J＝7.3Hz,2H),7.54(t,J＝7.1Hz,1H),7.44(t,J＝7.8Hz,2H),7.19(t,J＝7.3Hz,1H).13C-NMR(150MHz,DMSO-d6)δ157.4,155.1,155.1,143.8,138.4,137.2,136.8,131.0,130.1,128.9,128.5,127.7,125.5,124.1,122.4.HRMS(ESI,m/z)calcd for C19H14N4[M+H]+,299.1291；found,299.1332。
实施例47：N-甲基-4-(4-(苯氨基)吡啶并[3,2-d]嘧啶-6-基)苯甲酰胺(D02)的制备
步骤B：4-(4-(苯胺)吡啶并[3,2-d]嘧啶-6-基)苯甲酸(21a)的制备
于50mL茄形瓶中加入20a(300mg，1.17mmol)、对羧基苯硼酸(230mg，1.4mmol)、四(三苯基膦)钯(41mg，0.035mmol)及新研磨的碳酸钾(323mg，2.3mmol)，加入混合溶剂二氧六环/水(18/4.5mL)，90℃搅拌1.5h。冷却，蒸除溶剂，柱层析得白色固体320mg，收率80％。
以20b-20p与对羧基苯硼酸为原料，按照21a的合成方法，分别得到21b-21p；以20a-20c和间羧基苯硼酸为原料，按照21a的合成方法，分别得到21q-21s。收率50-85％。
步骤C或C/D：N-甲基-4-(4-(苯氨基)吡啶并[3,2-d]嘧啶-6-基)苯甲酰胺(D02)的制备
于25mL茄形瓶中加入21a(150mg，0.44mmol)、HATU(201mg，0.53mmol)、DMAP(65mg，0.53mmol)、DIEA(68mg，0.53mmol)和四氢呋喃15mL，于室温下搅拌，加入甲胺盐酸盐(36mg，0.53mmol)继续搅拌1h。TLC监测反应完全，蒸除溶剂，用二氯甲烷重新溶解所得固体，水洗三遍，饱和氯和钠溶液洗一遍，无水硫酸钠干燥，柱层析得淡黄色固体110mg，收率71％。M.p.:267.4-270.2℃.1H-NMR(600MHz,DMSO-d6)δ10.14(s,1H),8.65(s,1H),8.63(d,J＝8.5Hz,2H),8.60(d,J＝8.8Hz,2H),8.29(d,J＝8.8Hz,1H),8.02(d,J＝8.5Hz,2H),8.00(d,J＝7.7Hz,2H),7.45(t,J＝7.9Hz,2H),7.20(t,J＝7.4Hz,1H),2.84(d,J＝4.5Hz,3H).13C-NMR(150MHz,DMSO-d6)δ166.2,157.6,155.5,154.2,144.1,139.5,138.5,137.0,135.6,131.2,128.6,127.7,127.6,125.9,124.3,122.8,26.4.HRMS(ESI,m/z)calcd for C21H17N5O[M+H]+,356.1506；found,356.1524。
实施例48：N-异丙基-4-(4-(苯氨基)吡啶并[3,2-d]嘧啶-6-基)苯甲酰胺(D03)的制备
按照实施例47的制备方法，将甲胺替换为异丙胺，制备标题化合物。淡黄色固体，收率72％.M.p.:232.9-234.1℃.1H-NMR(600MHz,DMSO-d6)δ10.12(s,1H),8.65(s,1H),8.64-8.59(m,3H),8.38(d,J＝7.7Hz,1H),8.29(d,J＝8.8Hz,1H),8.04(d,J＝8.5Hz,2H),8.01(d,J＝7.6Hz,2H),7.45(t,J＝7.9Hz,2H),7.20(t,J＝7.4Hz,1H),4.15(dq,J＝13.4,6.7Hz,1H),1.21(d,J＝6.6Hz,6H).13C-NMR(150MHz,DMSO-d6)δ164.9,157.5,155.4,154.2,144.0,139.4,138.4,136.9,135.8,131.1,128.6,127.8,127.5,125.8,124.2,122.6,41.1,22.4.HRMS(ESI,m/z)calcd for C23H21N5O[M+H]+,384.1819；found,384.1853。
实施例49：N-环戊基-4-(4-(苯氨基)吡啶并[3,2-d]嘧啶-6-基)苯甲酰胺(D04)的制备
按照实施例47的制备方法，将甲胺替换为环戊胺，制备标题化合物。淡黄色固体，收率80％。M.p.:276.8-277.7℃.1H-NMR(600MHz,DMSO-d6)δ10.12(s,1H),8.65(s,1H),8.62(d,J＝5.3Hz,2H),8.60(d,J＝5.6Hz,1H),8.44(d,J＝7.2Hz,1H),8.30(d,J＝8.8Hz,1H),8.03(d,J＝8.4Hz,2H),8.01(d,J＝7.7Hz,2H),7.45(t,J＝7.9Hz,2H),7.20(t,J＝7.4Hz,1H),4.33-4.19(m,1H),1.95-1.91(m,2H),1.80-1.65(m,2H),1.64-1.50(m,4H).13C-NMR(150MHz,DMSO-d6)δ165.4,157.5,155.4,154.2,144.0,139.4,138.4,136.9,135.8,131.1,128.6,127.8,127.4,125.8,124.2,122.6,51.0,32.2,23.7.HRMS(ESI,m/z)calcd forC25H23N5O[M+H]+,410.1975；found,410.1990。
实施例50：(4-(4-(苯氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)(哌嗪-1-基)甲酮(D05)的制备
于25mL茄形瓶中加入21a(150mg，0.44mmol)、HATU(201mg，0.53mmol)、DMAP(65mg，0.53mmol)、DIEA(68mg，0.53mmol)和四氢呋喃15mL，于室温下搅拌，加入N-Boc-哌嗪(98mg，0.53mmol)继续搅拌1h。TLC监测反应完全，蒸干溶剂，用二氯甲烷重新溶解所得固体，水洗三遍，饱和氯和钠溶液洗一遍，无水硫酸钠干燥，柱层析得淡黄色固体；将该固体溶解于盐酸/乙酸乙酯溶液(10mL)，室温下搅拌过夜，过滤，滤饼用少量二氯甲烷洗；然后将滤饼重新溶解于水中，用饱和碳酸氢钠溶液调节pH至8，二氯甲烷萃取三次，合并有机层，饱和氯化钠溶液洗一次，无水硫酸钠干燥，蒸除溶剂得淡黄色固体，HPLC纯化得D05。淡黄色固体，收率72％。M.p.:129.5-131.2℃.1H-NMR(600MHz,DMSO-d6)δ10.11(s,1H),8.65(s,1H),8.59(d,J＝7.8Hz,2H),8.56(d,J＝8.8Hz,1H),8.29(d,J＝8.8Hz,1H),8.01(d,J＝7.9Hz,2H),7.56(d,J＝8.0Hz,2H),7.45(t,J＝7.7Hz,2H),7.19(t,J＝7.3Hz,1H),3.58(brs,2H),3.30(brs,2H),2.76(brs,2H),2.67(brs,2H).13C-NMR(150MHz,DMSO-d6)δ168.5,157.4,155.3,154.2,143.9,138.4,138.0,137.5,136.9,131.0,128.5,127.7,127.4,125.6,124.1,122.4,54.9,48.4,45.7,42.6.HRMS(ESI,m/z)calcd for C24H22N6O[M+H]+,411.1928；found,411.1952。
实施例51：(4-(4-(4-氟苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)(哌嗪-1-基)甲酮(D06)的制备
按照实施例50的制备方法，将21a替换为21b，制备标题化合物。淡黄色固体，收率70％。M.p.:178.8-179.8℃.1H-NMR(600MHz,DMSO-d6)δ10.17(s,1H),8.63(s,1H),8.59(d,J＝8.3Hz,2H),8.56(d,J＝8.8Hz,1H),8.28(d,J＝8.8Hz,1H),8.00(dd,J＝9.0,5.0Hz,2H),7.56(d,J＝8.3Hz,2H),7.29(t,J＝8.8Hz,2H),3.59(brs,2H),3.32(brs,2H),2.77(brs,2H),2.67(brs,2H).HRMS(ESI,m/z)calcd for C24H21FN6O[M+H]+,429.1834；found,429.1866。
实施例52：(4-(4-(4-甲基苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)(哌嗪-1-基)甲酮(D07)的制备
按照实施例50的制备方法，将21a替换为21c，制备标题化合物。淡黄色固体，收率69％。M.p.:137.5-138.6℃.1H-NMR(600MHz,DMSO-d6)δ10.06(s,1H),8.62(s,1H),8.59(d,J＝8.0Hz,2H),8.55(d,J＝8.7Hz,1H),8.27(d,J＝8.8Hz,1H),7.88(d,J＝8.1Hz,2H),7.55(d,J＝7.7Hz,2H),7.25(d,J＝8.1Hz,2H),3.58-3.51(m,2H),3.30-3.23(m,2H),2.76(s,2H),2.67(s,2H),2.34(s,3H).13C-NMR(150MHz,DMSO-d6)δ168.6,157.4,155.4,154.2,143.9,138.0,137.5,136.9,135.9,133.3,131.1,129.0,127.8,127.4,125.6,122.5,55.0,40.1,20.6.HRMS(ESI,m/z)calcd for C25H24N6O[M+H]+,425.2084；found,425.2109。
实施例53：哌嗪-1-基(4-(4-((4-(三氟甲氧基)苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)甲酮(D08)的制备
按照实施例50的制备方法，将21a替换为21d，制备标题化合物。淡黄色固体，收率85％.M.p.:122.5-132.2℃.1H-NMR(600MHz,DMSO-d6)δ10.36(s,1H),8.75(s,1H),8.61(d,J＝8.3Hz,3H),8.34(d,J＝8.5Hz,3H),7.81(d,J＝8.4Hz,2H),7.58(d,J＝7.9Hz,2H),3.59(brs,2H),3.34(brs,2H),2.78(brs,2H),2.68(brs,2H).13C-NMR(150MHz,DMSO-d6)δ168.5,157.3,155.0,154.7,144.1,142.3,137.9,137.7,137.1,131.0,127.9,127.4,126.0,125.8,125.7,121.9,48.5,45.9,45.4,42.7.13C-NMR(150MHz,DMSO)δ168.6,168.5,157.3,155.0,154.7,144.1,142.2,137.9,137.6,137.1,131.0,127.9,127.4,126.0,125.8,125.7,121.9,54.9,40.1.HRMS(ESI,m/z)calcd for C25H21F3N6O[M+H]+,479.1802；found,479.1790。
实施例54：(4-(4-(4-甲氧基苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)(哌嗪-1-基)甲酮(D09)的制备
按照实施例50的制备方法，将21a替换为21e，制备标题化合物。淡黄色固体，收率65％。M.p.:160.2-162.0℃.1H-NMR(600MHz,DMSO-d6)δ10.07(s,1H),8.59(d,J＝7.9Hz,2H),8.57(s,1H),8.55(d,J＝8.8Hz,1H),8.25(d,J＝8.8Hz,1H),7.84(d,J＝8.7Hz,2H),7.55(d,J＝8.1Hz,2H),7.01(d,J＝8.8Hz,2H),3.79(s,3H),3.59(brs,2H),3.30(brs,2H),2.77(brs,2H),2.67(brs,2H).13C-NMR(150MHz,DMSO-d6)δ168.6,157.5,156.1,155.5,154.0,143.9,138.0,137.5,136.8,131.3,131.1,127.7,127.4,125.5,124.4,113.7,55.3,48.6,45.9,45.4,42.7.HRMS(ESI,m/z)calcd for C25H24N6O2[M+H]+,441.2034；found,441.2039。
实施例55：(4-(4-((4-羟基苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)(哌嗪-1-基)甲酮(D10)的制备
按照实施例50的制备方法，将21a替换为21f，制备标题化合物。淡黄色固体，收率26％。M.p.:164.2-165.8℃.1H-NMR(600MHz,DMSO-d6)δ9.98(s,1H),9.40(s,1H),8.58(d,J＝8.2Hz,2H),8.54(s,1H),8.53(d,J＝8.8Hz,1H),8.23(d,J＝8.8Hz,1H),7.68(d,J＝8.7Hz,2H),7.54(d,J＝8.2Hz,2H),6.83(d,J＝8.7Hz,2H),5.75(s,1H),3.59(brs,2H),2.78(brs,2H),2.68(brs,2H).HRMS(ESI,m/z)calcd for C24H22N6O2[M+H]+,427.1877；found,427.1852。
实施例56：(4-((6-(4-(哌嗪-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)苯甲腈(D11)的制备
按照实施例50的制备方法，将21a替换为21g，制备标题化合物。淡黄色固体，收率60％。M.p.:117.8-120.0℃.1H-NMR(600MHz,DMSO-d6)δ10.20(s,1H),8.73(s,1H),8.59(dd,J＝8.4,4.3Hz,3H),8.32(d,J＝8.8Hz,1H),8.09(d,J＝11.7Hz,1H),7.89(d,J＝8.1Hz,1H),7.57(d,J＝8.1Hz,2H),7.47(dd,J＝15.2,8.0Hz,1H),7.13-6.90(m,1H),3.59(brs,2H),3.28(brs,2H),2.77(brs,2H),2.67(brs,2H).13C-NMR(150MHz,DMSO-d6)δ168.6,157.2,154.8,154.8,144.2,142.9,137.9,137.6,137.2,132.9,131.0,127.9,127.4,126.1,121.8,119.2,105.2,54.9,40.1.HRMS(ESI,m/z)calcd for C25H21N7O[M+H]+,436.1880；found,436.1889。
实施例57：(4-(4-(3-氟苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)(哌嗪-1-基)甲酮(D12)的制备
按照实施例50的制备方法，将21a替换为21h，制备标题化合物。淡黄色固体，收率62％。M.p.:117.8-120.0℃.1H-NMR(600MHz,DMSO-d6)δ10.20(s,1H),8.73(s,1H),8.59(dd,J＝8.4,4.3Hz,3H),8.32(d,J＝8.8Hz,1H),8.09(d,J＝11.7Hz,1H),7.89(d,J＝8.1Hz,1H),7.57(d,J＝8.1Hz,2H),7.47(dd,J＝15.2,8.0Hz,1H),7.13-6.90(m,1H),3.59(brs,2H),3.28(brs,2H),2.77(brs,2H),2.67(brs,2H).13C-NMR(150MHz,DMSO-d6)δ168.5,162.8,161.2,157.3,155.1,154.5,144.0,137.9,137.6,137.0,131.0,130.1,127.9,127.4,125.9,117.9,110.4,108.9,48.6,46.0,45.5,42.8.HRMS(ESI,m/z)calcd forC24H21FN6O[M+H]+,429.1834；found,429.1890。
实施例58：(4-(4-(2-氟苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)(哌嗪-1-基)甲酮(D13)的制备
按照实施例50的制备方法，将21a替换为21i，制备标题化合物。淡黄色固体，收率69％。M.p.:167.8-169.3℃.1H-NMR(600MHz,DMSO-d6)δ10.11(s,1H),8.59(s,1H),8.58(d,J＝8.1Hz,1H),8.54(d,J＝8.2Hz,2H),8.31(d,J＝8.8Hz,1H),7.95(td,J＝7.8,2.0Hz,1H),7.56(d,J＝8.3Hz,2H),7.44-7.36(m,1H),7.36-7.29(m,2H),3.58(s,2H),3.29(brs,2H),2.76(brs,2H),2.67(brs,2H).13C-NMR(150MHz,DMSO-d6)δ168.6,158.2,156.9,155.5,155.3,154.3,143.9,138.0,137.6,137.0,130.9,127.6,127.5,127.2,125.8,124.6,115.9,48.4,45.8,45.3,42.6.HRMS(ESI,m/z)calcd for C24H21FN6O[M+H]+,429.1834；found,429.1813。
实施例59：(4-(4-(3-甲氧基苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)(哌嗪-1-基)甲酮(D14)的制备
按照实施例50的制备方法，将21a替换为21j，制备标题化合物。淡黄色固体，收率64％。M.p.:122.4-123.8℃.1H-NMR(600MHz,DMSO-d6)δ10.05(s,1H),8.68(s,1H),8.61-8.55(m,3H),8.30(d,J＝8.4Hz,1H),7.72(s,1H),7.64(d,J＝7.2Hz,1H),7.58(d,J＝7.2Hz,2H),7.35(t,J＝7.7Hz,1H),6.77(d,J＝7.2Hz,1H),3.81(s,3H),3.62(brs,2H),3.38(brs,2H),2.83(brs,2H),2.74(brs,2H).13C-NMR(150MHz,DMSO-d6)δ168.7,168.6,159.5,157.4,155.3,154.3,144.0,139.6,138.1,137.3,137.0,131.1,129.4,127.8,127.5,125.8,114.6,109.4,108.2,55.3,47.6,45.2,44.8,41.9.HRMS(ESI,m/z)calcd forC25H24N6O2[M+H]+,441.2034；found,441.2020。
实施例60：(4-(4-(2-甲氧基苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)(哌嗪-1-基)甲酮(D15)的制备
按照实施例50的制备方法，将21a替换为21k，制备标题化合物。淡黄色固体，收率60％。M.p.:161.6-163.4℃.1H-NMR(600MHz,DMSO-d6)δ10.10(s,1H),8.71(s,1H),8.63(d,J＝7.7Hz,1H),8.57(d,J＝8.6Hz,1H),8.41(d,J＝7.7Hz,2H),8.32(d,J＝8.8Hz,1H),7.63(d,J＝7.6Hz,2H),7.22-7.12(m,2H),7.08(t,J＝6.8Hz,1H),4.01(s,3H),3.61(brs,2H),3.38(brs,2H),2.79(brs,2H),2.71(brs,2H).13C-NMR(150MHz,DMSO-d6)δ168.5,156.7,155.5,154.1,149.5,143.5,137.9,137.6,137.2,131.1,127.8,127.4,127.2,125.8,124.2,120.7,120.5,111.1,56.3,48.2,45.7,45.2,42.5.HRMS(ESI,m/z)calcd forC25H24N6O2,441.2034；found,441.1999。
实施例61：(4-(4-(4-氟-3-甲氧基苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)(哌嗪-1-基)甲酮(D16)的制备
按照实施例50的制备方法，将21a替换为21l，制备标题化合物。淡黄色固体，收率63％。M.p.:140.6-143.3℃.1H-NMR(600MHz,DMSO-d6)δ10.11(s,1H),8.65(s,1H),8.59(d,J＝8.3Hz,2H),8.57(d,J＝8.9Hz,1H),8.29(d,J＝8.8Hz,1H),7.84(dd,J＝7.9,2.3Hz,1H),7.68-7.63(m,1H),7.57(d,J＝8.3Hz,2H),7.28(dd,J＝11.3,8.8Hz,1H),3.90(s,3H),3.61(brs,2H),3.40(brs,2H),2.81(brs,2H),2.72(brs,2H).13C-NMR(150MHz,DMSO-d6)δ168.7,157.5,155.3,154.3,149.0,147.4,146.8,144.0,138.2,137.0,135.2,131.0,127.8,127.5,125.7,115.5,115.4,114.8,108.9,56.1,54.9,40.1.HRMS(ESI,m/z)calcd forC25H23FN6O2[M+H]+,459.1939；found,459.1906。
实施例62：(4-(4-(4-氟-2-甲氧基苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)(哌嗪-1-基)甲酮(D17)的制备
按照实施例50的制备方法，将21a替换为21m，制备标题化合物。淡黄色固体，收率66％。M.p.:250.9-251.6℃.1H-NMR(600MHz,DMSO-d6)δ9.94(s,1H),8.64(s,1H),8.56(d,J＝8.8Hz,1H),8.45(dd,J＝8.8,6.4Hz,1H),8.41(d,J＝8.3Hz,2H),8.29(d,J＝8.8Hz,1H),7.61(d,J＝8.3Hz,2H),7.12(dd,J＝10.7,2.7Hz,1H),6.90(td,J＝8.7,2.7Hz,1H),3.98(s,3H),3.59(brs,2H),3.31(brs,2H),2.77(brs,2H),2.67(brs,2H).13C-NMR(150MHz,DMSO-d6)δ168.5,160.0,158.4,157.0,155.5,154.1,151.5,143.5,137.8,137.1,131.0,127.7,127.2,125.7,123.7,122.4,106.4,100.1,56.8,48.6,46.0,45.5,42.9.HRMS(ESI,m/z)calcd for C25H23FN6O2[M+H]+,459.1939；found,459.1943。
实施例63：(4-(4-((4-氟-2-异丙氧基苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)(哌嗪-1-基)甲酮(D18)的制备
按照实施例50的制备方法，将21a替换为21n，制备标题化合物。淡黄色固体，收率70％。M.p.:210.9-211.5℃.1H-NMR(600MHz,DMSO-d6)δ10.03(s,1H),8.81(dd,J＝8.9,6.5Hz,1H),8.71(s,1H),8.56(d,J＝8.8Hz,1H),8.39(d,J＝8.2Hz,2H),8.30(d,J＝8.8Hz,1H),7.55(d,J＝8.2Hz,2H),7.16(dd,J＝10.7,2.6Hz,1H),6.88(td,J＝8.7,2.6Hz,1H),4.86(dt,J＝12.0,6.0Hz,1H),3.58(brs,2H),3.29(brs,2H),2.77(brs,2H),2.67(brs,2H),1.43(d,J＝6.0Hz,6H).13C-NMR(150MHz,DMSO-d6)δ168.3,157.1,156.1,155.3,154.1,147.86,143.4,137.8,137.2,131.0,127.5,127.1,125.7,124.9,120.1,106.3,101.8,101.5,71.7,54.9,40.3,21.8.HRMS(ESI,m/z)calcd for C27H27FN6O2[M+H]+,487.2252；found,487.2232。
实施例64：(4-(4-(3,4-二氟苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)(哌嗪-1-基)甲酮(D19)的制备
按照实施例50的制备方法，将21a替换为21o，制备标题化合物。淡黄色固体，收率41％。M.p.:101.8-102.5℃.1H-NMR(600MHz,DMSO-d6)δ10.23(s,1H),8.70(s,1H),8.61-8.56(m,3H),8.31(d,J＝8.8Hz,1H),8.29-8.22(m,1H),7.87(d,J＝8.6Hz,1H),7.56(d,J＝8.0Hz,2H),7.51(q,J＝9.6Hz,1H),3.59(brs,2H),3.28(brs,2H),2.77(brs,2H),2.67(brs,2H).13C-NMR(150MHz,DMSO-d6)δ168.5,157.3,155.1,154.5,144.0,137.9,137.7,137.0,135.6,130.9,127.8,127.4,125.8,118.9,117.1,111.4,69.8,48.6,46.0,45.4,42.8.HRMS(ESI,m/z)calcd for C25H22F2N6O[M+H]+,447.1739；found,447.1761。
实施例65：(4-(4-(2,4-二氟苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)(哌嗪-1-基)甲酮(D20)的制备
按照实施例50的制备方法，将21a替换为21p，制备标题化合物。淡黄色固体，收率68％。M.p.:200.5-201.2℃.1H-NMR(600MHz,DMSO-d6)δ10.13(s,1H),8.59(d,J＝9.0Hz,1H),8.56(d,J＝8.7Hz,3H),8.30(d,J＝8.8Hz,1H),7.84(dd,J＝15.1,8.6Hz,1H),7.55(d,J＝8.0Hz,2H),7.44(t,J＝8.6Hz,1H),7.21(t,J＝8.5Hz,1H),3.58(brs,2H),3.29(brs,2H),2.76(brs,2H),2.66(brs,2H).13C-NMR(150MHz,DMSO-d6)δ168.5,158.5,155.4,154.3,143.9,137.9,137.6,136.9,130.8,129.2,129.1,127.6,127.4,125.7,111.5,111.3,104.7,104.5,48.6,46.0,45.5,42.9.HRMS(ESI,m/z)calcd for C24H20F2N6O[M+H]+,447.1439；found,447.1777。
实施例66：(4-(4-((3-氯-4-氟苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)(哌嗪-1-基)甲酮(D21)的制备
按照实施例50的制备方法，将21a替换为21q，制备标题化合物。淡黄色固体，收率71％。M.p.:246.7-248.5℃.1H-NMR(600MHz,DMSO-d6)δ11.49(s,1H),9.65(s,2H),8.92(s,1H),8.82(d,J＝9.0Hz,1H),8.64(d,J＝7.8Hz,2H),8.53(d,J＝8.9Hz,1H),7.86(dd,J＝8.8,5.7Hz,1H),7.75(dd,J＝8.5,2.8Hz,1H),7.69(d,J＝8.3Hz,2H),7.45(td,J＝8.5,2.8Hz,1H),3.88(brs,2H),3.63(brs,2H),3.16(brs,4H).13C-NMR(150MHz,DMSO-d6)δ168.8,160.3,159.9,155.9,152.4,137.6,137.1,131.4,131.3,130.8,130.4,130.3,129.4,128.1,128.0,127.8,127.7,126.9,117.3,115.3,59.8,56.1,55.0,42.4.HRMS(ESI,m/z)calcd for C24H20ClFN6O[M+H]+,463.1444；found,463.1447。
实施例67：(3-(4-(苯氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)(哌嗪-1-基)甲酮(D22)的制备
按照实施例50的制备方法，将21a替换为21r，制备标题化合物。淡黄色固体，收率74％。M.p.:168.6-170.5℃.1H-NMR(600MHz,DMSO-d6)δ10.14(s,1H),8.64(s,1H),8.59(dd,J＝11.8,10.2Hz,2H),8.48(s,1H),8.28(d,J＝8.7Hz,1H),7.98(d,J＝7.7Hz,2H),7.64(t,J＝7.7Hz,1H),7.52(d,J＝7.4Hz,1H),7.45(t,J＝7.4Hz,2H),7.19(t,J＝7.2Hz,1H),3.61(brs,2H),3.27(brs,2H),2.79(brs,2H),2.68(brs,2H).13C-NMR(150MHz,DMSO-d6)δ168.6,157.5,155.3,154.4,144.0,138.4,137.5,137.1,136.9,131.0,129.0,128.6,128.5,128.3,125.8,125.7,124.2,122.7,59.8,48.7,45.9,45.5,42.9.HRMS(ESI,m/z)calcd forC24H22N6O[M+H]+,411.1928；found,411.1958。
实施例68：(3-(4-((4-氟苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)(哌嗪-1-基)甲酮(D23)的制备
按照实施例50的制备方法，将21a替换为21s，制备标题化合物。淡黄色固体，收率70％。M.p.:230.6-231.0℃.1H-NMR(600MHz,DMSO-d6)δ10.19(s,1H),8.62(s,1H),8.60(d,J＝8.0Hz,1H),8.58(d,J＝8.8Hz,1H),8.48(s,1H),8.27(d,J＝8.8Hz,1H),7.98(dd,J＝8.9,5.0Hz,2H),7.64(t,J＝7.7Hz,1H),7.51(d,J＝7.5Hz,1H),7.29(t,J＝8.8Hz,2H),3.62(brs,2H),3.31(brs,2H),2.79(brs,2H),2.68(brs,2H).13C-NMR(150MHz,DMSO-d6)δ168.7,159.6,158.0,157.6,155.3,154.4,144.0,137.5,137.0,136.9,134.8,131.0,129.2,128.6,128.4,125.9,124.9,115.3,48.3,45.6,45.2,42.4.HRMS(ESI,m/z)calcdfor C24H21FN6O[M+H]+,429.1834；found,429.1864。
实施例69：哌嗪-1-基(3-(4-((4-三氟甲基)苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)甲酮(D24)的制备
按照实施例50的制备方法，将21a替换为21t，制备标题化合物。淡黄色固体，收率62％。M.p.:130.0-131.8℃.1H-NMR(600MHz,DMSO-d6)δ10.38(s,1H),8.75(s,1H),8.62(d,J＝8.7Hz,2H),8.50(s,1H),8.33(dd,J＝8.4,5.5Hz,3H),7.81(d,J＝8.5Hz,2H),7.66(t,J＝7.6Hz,1H),7.54(d,J＝7.5Hz,1H),3.63(brs,2H),3.32(brs,2H),2.81(brs,2H),2.71(brs,2H).13C-NMR(150MHz,DMSO-d6)δ168.7,157.4,155.0,154.9,144.2,142.3,137.4,137.1,137.1,131.0,129.1,128.7,128.5,126.1,126.0,125.8,125.8,122.0,48.5,45.8,45.3,42.7.HRMS(ESI,m/z)calcd for C25H21F3N6O[M+H]+,479.1802；found,479.1812。
实施例70：(R)-(3-氨基哌啶-1-基)(4-(4-((4-(三氟甲基)苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)甲酮(D25)的制备
按照实施例50的制备方法，将21a替换为21d，将N-Boc-哌嗪替换为(R)-3-Boc-氨基哌啶，制备标题化合物。淡黄色固体，收率43％。M.p.:178.8-180.0℃.1H-NMR(600MHz,DMSO-d6)δ10.40(s,1H),8.77(s,1H),8.63(d,J＝8.5Hz,3H),8.36(d,J＝8.8Hz,1H),8.33(d,J＝8.3Hz,2H),7.82(d,J＝8.3Hz,2H),7.64(d,J＝7.3Hz,2H),4.35-4.21(m,1H),3.84-3.60(m,1H),3.31-3.02(m,4H),2.03(brs,1H),1.81-1.74(m,1H),1.60-1.56(m,2H).13C-NMR(150MHz,DMSO-d6)δ158.2,157.9,157.5,154.9,154.7,143.9,142.2,137.3,136.9,131.0,127.9,127.5,126.2,125.8,125.8,122.1,47.1,46.2,44.0,28.0,22.6.HRMS(ESI,m/z)calcd for C26H23F3N6O[M+H]+,493.1958；found,493.1940。
实施例71：(R)-(3-氨基哌啶-1-基)(4-(4-((4-(三氟甲基)苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)甲酮(D25)的制备
按照实施例50的制备方法，将21a替换为21d，将N-Boc-哌嗪替换为(R)-3-Boc-氨基哌啶，制备标题化合物。淡黄色固体，收率43％。M.p.:178.8-180.0℃.1H-NMR(600MHz,DMSO-d6)δ10.40(s,1H),8.77(s,1H),8.63(d,J＝8.5Hz,3H),8.36(d,J＝8.8Hz,1H),8.33(d,J＝8.3Hz,2H),7.82(d,J＝8.3Hz,2H),7.64(d,J＝7.3Hz,2H),4.35-4.21(m,1H),3.84-3.60(m,1H),3.31-3.02(m,4H),2.03(brs,1H),1.81-1.74(m,1H),1.60-1.56(m,2H).13C-NMR(150MHz,DMSO-d6)δ158.2,157.9,157.5,154.9,154.7,143.9,142.2,137.3,136.9,131.0,127.9,127.5,126.2,125.8,125.8,122.1,47.1,46.2,44.0,28.0,22.6.HRMS(ESI,m/z)calcd for C26H23F3N6O[M+H]+,493.1958；found,493.1940。
实施例71：(S)-(3-氨基哌啶-1-基)(4-(4-((4-(三氟甲基)苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)甲酮(D26)的制备
按照实施例50的制备方法，将21a替换为21d，将N-Boc-哌嗪替换为(S)-3-Boc-氨基哌啶，制备标题化合物。淡黄色固体，收率40％。M.p.:127.6-129.6℃.1H-NMR(600MHz,DMSO-d6)δ10.36(s,1H),8.76(s,1H),8.61(d,J＝8.3Hz,3H),8.35(d,J＝8.7Hz,3H),7.81(d,J＝8.2Hz,2H),7.58(d,J＝7.7Hz,2H),4.36-4.18(m,1H),3.60-3.42(m,2H),3.04-2.94(m,1H),2.84-2.73(m,2H),1.90(d,J＝12.3Hz,1H),1.78-1.64(m,1H),1.47-1.32(m,2H).13C-NMR(150MHz,DMSO-d6)δ168.7,157.4,155.0,154.7,144.1,142.3,137.9,137.1,131.0,127.9,127.3,126.0,125.8,125.7,121.9,54.5,47.4,41.6,33.1,23.9.HRMS(ESI,m/z)calcd for C26H23F3N6O[M+H]+,493.1958；found,493.1914。
实施例72：(R)-(3-氨基哌啶-1-基)(4-(4-((4-氟苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)甲酮(D27)的制备
按照实施例50的制备方法，将21a替换为21b，将N-Boc-哌嗪替换为(R)-3-Boc-氨基哌啶，制备标题化合物。淡黄色固体，收率48％。M.p.:109.2-110.0℃.1H-NMR(600MHz,DMSO-d6)δ10.18(s,1H),8.63(s,1H),8.59(d,J＝7.8Hz,2H),8.57(d,J＝8.9Hz,1H),8.29(d,J＝8.8Hz,1H),8.09-7.93(m,2H),7.56(d,J＝8.0Hz,2H),7.29(t,J＝8.8Hz,2H),4.26(dd,J＝94.0,14.9Hz,1H),3.63-3.41(m,1H),3.00-2.92(m,1H),2.80-2.70(m,1H),2.67-2.54(m,1H),1.87(d,J＝9.8Hz,1H),1.75-162(m,1H),1.54-1.46(m,2H),1.24(d,J＝17.7Hz,2H).13C-NMR(150MHz,DMSO-d6)δ168.6,159.9,157.5,155.2,154.3,143.9,137.9,136.9,134.7,131.0,127.7,127.3,125.6,124.7,115.2,115.0,54.9,47.3,40.2,33.8.HRMS(ESI,m/z)calcd for C25H23FN6O[M+H]+,443.1990；found,443.1997。
实施例73：(S)-(3-氨基哌啶-1-基)(4-(4-((4-氟苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)甲酮(D28)的制备
按照实施例50的制备方法，将21a替换为21b，将N-Boc-哌嗪替换为(S)-3-Boc-氨基哌啶，制备标题化合物。淡黄色固体，收率66％。M.p.:111.5-113.0℃.1H-NMR(600MHz,DMSO-d6)δ10.18(s,1H),8.63(s,1H),8.61-8.54(m,3H),8.29(d,J＝8.1Hz,1H),8.00(s,2H),7.56(d,J＝6.2Hz,2H),7.29(t,J＝7.6Hz,2H),4.34-4.18(m,1H),3.58-3.46(m,1H),3.17(s,1H),3.00-2.92(m,1H),2.79-2.73(m,1H),2.65-2.61(m,1H),1.87(s,1H),1.73-1.63(m,1H),1.45(s,1H),1.24(d,J＝13.4Hz,2H).HRMS(ESI,m/z)calcd for C25H23FN6O[M+H]+,443.1990；found,443.1966。
实施例74：(R)-(3-氨基哌啶-1-基)(4-(4-((4-羟基苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)甲酮(D29)的制备
按照实施例50的制备方法，将21a替换为21f，将N-Boc-哌嗪替换为(R)-3-Boc-氨基哌啶，制备标题化合物。淡黄色固体，收率18％。M.p.:175.2-176.8℃.1H-NMR(600MHz,DMSO-d6)δ9.99(s,1H),9.41(s,1H),8.58(d,J＝7.9Hz,2H),8.53(d,J＝9.9Hz,2H),8.24(d,J＝8.8Hz,1H),7.68(d,J＝8.8Hz,2H),7.54(d,J＝8.1Hz,2H),6.83(d,J＝8.8Hz,2H),4.19-4.09(m,1H),3.57-3.46(m,1H),3.17(s,1H),2.30-2.91(m,1H),2.78-2.71(m,1H),2.66-2.55(m,1H),1.87(d,J＝11.4Hz,1H),1.75-1.63(m,1H),1.44(s,1H),1.32-1.21(m,2H).HRMS(ESI,m/z)calcd for C25H24N6O2[M+H]+,441.2034；found,441.2002。
实施例75：(R)-4-((6-(4-(3-氨基哌啶-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)苯甲腈(D30)的制备
按照实施例50的制备方法，将21a替换为21g，将N-Boc-哌嗪替换为(R)-3-Boc-氨基哌啶，制备标题化合物。淡黄色固体，收率27％。M.p.:188.1-188.8℃.1H-NMR(600MHz,DMSO-d6)δ10.39(s,1H),8.78(s,1H),8.60(t,J＝8.7Hz,3H),8.46-8.27(m,3H),7.90(d,J＝8.2Hz,2H),7.57(d,J＝7.3Hz,2H),4.36-4.19(m,1H),3.56-3.47(m,2H),3.01-2.92(m,2H),2.79(s,1H),2.72-2.52(m,1H),2.01-1.86(m,2H),1.78-1.41(m,2H).HRMS(ESI,m/z)calcd for C26H23N7O[M+H]+,450.2037；found,450.2053。
实施例76：(R)-(3-氨基哌啶-1-基)(4-(4-((4-氟-2-甲氧基苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)甲酮(D31)的制备按照实施例50的制备方法，将21a替换为21m，将N-Boc-哌嗪替换为(R)-3-Boc-氨基哌啶，制备标题化合物。淡黄色固体，收率41％。M.p.:178.1-178.8℃.1H-NMR(600MHz,DMSO-d6)δ9.95(s,1H),8.65(s,1H),8.56(d,J＝8.8Hz,1H),8.47-8.43(m,1H),8.42(d,J＝7.8Hz,2H),8.30(d,J＝8.8Hz,1H),7.61(d,J＝7.8Hz,2H),7.13(d,J＝10.7Hz,1H),6.90(t,J＝8.6Hz,1H),4.35-4.19(m,1H),3.58-3.48(m,1H),3.03-2.90(m,1H),2.84-2.55(m,2H),1.87(d,J＝10.1Hz,1H),1.75-1.63(m,3H),1.44(brs,1H),1.28-1.22(m,1H).13C-NMR(150MHz,DMSO-d6)δ168.6,160.3,157.9,156.9,155.4,154.1,151.36,143.4,138.0,137.7,137.0,130.9,127.4,127.2,125.6,123.7,122.3,106.3,100.0,56.7,54.9,47.7,33.6,23.2.HRMS(ESI,m/z)calcd for C26H25FN6O2[M+H]+,473.2096；found,473.2063。
实施例77：(R)-(4-(4-((4-氟苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)(3-甲基哌嗪-1-基)甲酮(D32)的制备
按照实施例50的制备方法，将21a替换为21b，将N-Boc-哌嗪替换为(R)-1-N-Boc-2-甲基哌嗪，制备标题化合物。淡黄色固体，收率67％。M.p.:182.0-182.8℃.1H-NMR(600MHz,DMSO-d6)δ10.18(s,1H),8.63(s,1H),8.60(d,J＝7.8Hz,1H),8.57(d,J＝8.8Hz,1H),8.29(d,J＝8.8Hz,1H),8.00(dd,J＝8.3,5.1Hz,2H),7.55(d,J＝7.9Hz,2H),7.29(t,J＝8.6Hz,2H),4.34(brs,1H),3.45(brs,1H),3.05-2.96(m,1H),2.79(brs,1H),2.64(brs,2H),2.42(brs,1H),1.03-0.85(m,3H).13C-NMR(150MHz,DMSO-d6)δ168.4,159.6,158.0,157.5,155.3,154.2,144.0,138.0,136.9,134.8,131.0,127.8,127.4,126.8,125.6,124.7,115.2,50.7,48.7,47.9,45.7,19.2.HRMS(ESI,m/z)calcd for C25H23FN6O[M+H]+,443.1990；found,443.1964。
实施例78：(S)-(4-(4-((4-氟苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)(3-甲基哌嗪-1-基)甲酮(D33)的制备
按照实施例50的制备方法，将21a替换为21b，将N-Boc-哌嗪替换为(S)-1-N-Boc-2-甲基哌嗪，制备标题化合物。淡黄色固体，收率65％。M.p.:217.8-218.4℃.1H-NMR(600MHz,DMSO-d6)δ11.51(s,1H),9.90(d,J＝8.9Hz,1H),9.42(d,J＝10.3Hz,1H),8.94(s,1H),8.79(d,J＝9.0Hz,1H),8.67(d,J＝8.2Hz,2H),8.52(d,J＝8.9Hz,1H),7.83(dd,J＝8.9,5.0Hz,2H),7.66(d,J＝8.3Hz,2H),7.39(t,J＝8.8Hz,2H),3.96(brs,2H),3.38(brs,2H),3.26-3.12(m,2H),3.08-2.95(m,1H),1.39(d,J＝7.1Hz,3H).13C-NMR(150MHz,DMSO-d6)δ168.9,161.2,159.5,159.4,155.9,151.9,137.5,132.8,130.7,129.7,128.1,127.5,127.3,127.1,115.8,115.6,45.7,42.3,15.6.HRMS(ESI,m/z)calcd for C25H23FN6O[M+H]+,443.1990；found,443.1978。
实施例79：(R)-(4-(4-((4-氟苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)(2-甲基哌嗪-1-基)甲酮(D34)的制备
按照实施例50的制备方法，将21a替换为21b，将N-Boc-哌嗪替换为(R)-1-N-Boc-3-甲基哌嗪，制备标题化合物。淡黄色固体，收率62％。M.p.:217.6-218.6℃.1H-NMR(600MHz,DMSO-d6)δ10.17(s,1H),8.63(s,1H),8.59(d,J＝8.1Hz,2H),8.56(d,J＝8.8Hz,1H),8.28(d,J＝8.8Hz,1H),8.00(dd,J＝8.9,5.0Hz,2H),7.53(d,J＝8.1Hz,2H),7.29(t,J＝8.8Hz,2H),3.07(brs,1H),2.86(brs,1H),2.77-2.70(m,2H),2.55(dd,J＝12.7,10.4Hz,2H),1.27(d,J＝6.4Hz,3H).13C-NMR(150MHz,DMSO-d6)δ168.8,159.6,158.0,157.5,155.3,154.3,143.9,138.0,137.9,136.9,134.8,134.8,131.0,127.8,127.0,125.6,124.7,124.7,115.2,115.1,49.8,45.7,15.4.HRMS(ESI,m/z)calcd for C25H23FN6O[M+H]+,443.1990；found,443.2010。
实施例80：(S)-(4-(4-((4-氟苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)(2-甲基哌嗪-1-基)甲酮(D35)的制备
按照实施例50的制备方法，将21a替换为21b，将N-Boc-哌嗪替换为(S)-1-N-Boc-3-甲基哌嗪，制备标题化合物。淡黄色固体，收率65％。M.p.:181.0-181.9℃.1H-NMR(600MHz,DMSO-d6)δ10.18(s,1H),8.63(s,1H),8.60(d,J＝7.7Hz,2H),8.57(d,J＝8.8Hz,1H),8.29(d,J＝8.8Hz,1H),8.00(dd,J＝7.7,5.4Hz,2H),7.55(d,J＝7.8Hz,2H),7.29(t,J＝8.5Hz,2H),4.34(d,J＝10.6Hz,1H),3.45(brs,1H),3.01-2.94(m,1H),2.76(d,J＝14.8Hz,1H),2.65(brs,1H),2.38(brs,1H),1.03-0.85(m,3H).13C-NMR(150MHz,DMSO-d6)δ168.5,158.0,157.6,155.3,154.2,144.0,138.0,136.9,134.8,131.0,127.8,127.4,125.6,124.7,115.2,115.1,50.7,48.8,45.8,42.1,19.3.HRMS(ESI,m/z)calcd forC25H23FN6O[M+H]+,443.1990；found,443.2024。
实施例81：(S)-(4-(4-((4-氟-2-甲氧基苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)(3-甲基哌嗪-1-基)甲酮(D36)的制备
按照实施例50的制备方法，将21a替换为21m，将N-Boc-哌嗪替换为(S)-1-N-Boc-2-甲基哌嗪，制备标题化合物。淡黄色固体，收率62％。M.p.:172.3-174.0℃.1H NMR(600MHz,DMSO-d6)δ9.93(s,1H),8.64(s,1H),8.55(d,J＝8.8Hz,1H),8.44(dd,J＝8.7,6.6Hz,1H),8.41(d,J＝8.1Hz,2H),8.29(d,J＝8.8Hz,1H),7.60(d,J＝8.3Hz,2H),7.12(dd,J＝10.7,2.7Hz,1H),6.89(td,J＝8.6,2.7Hz,1H),4.35(d,J＝9.8Hz,1H),3.98(s,3H),3.47(d,J＝2.0Hz,1H),3.06-2.95(m,1H),2.79(brs,1H),2.65(d,J＝0.9Hz,2H),2.41(d,J＝4.4Hz,1H),1.03-0.86(m,3H).13C NMR(150MHz,DMSO-d6)δ168.4,160.0,158.4,157.0,155.5,154.1,151.6,151.5,143.5,137.8,137.1,131.0,127.7,127.3,125.7,123.7,123.7,122.6,106.4,106.3,100.1,99.9,56.8,50.7,48.8,45.7,40.1,19.3.HRMS(ESI,m/z)calcd for C26H25FN6O2[M+H]+,473.2096；found,473.2121。
实施例82：(R)-(4-(4-((4-氟-2-甲氧基苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)(3-甲基哌嗪-1-基)甲酮(D37)的制备
按照实施例50的制备方法，将21a替换为21m，将N-Boc-哌嗪替换为(R)-1-N-Boc-2-甲基哌嗪，制备标题化合物。淡黄色固体，收率61％。M.p.:171.1-172.0℃.1H NMR(600MHz,DMSO-d6)δ9.93(s,1H),8.64(s,1H),8.56(d,J＝8.8Hz,1H),8.44(dd,J＝8.8,6.8Hz,1H),8.41(d,J＝8.2Hz,2H),8.29(d,J＝8.8Hz,1H),7.60(d,J＝8.3Hz,2H),7.12(dd,J＝10.7,2.7Hz,1H),6.90(td,J＝8.7,2.7Hz,1H),4.35(d,J＝10.6Hz,1H),3.98(s,3H),3.47(d,J＝3.8Hz,1H),3.06-2.95(m,1H),2.79(brs,1H),2.65(d,J＝1.4Hz,1H),2.39(brs,1H),1.04-0.86(m,3H).HRMS(ESI,m/z)calcd for C26H25FN6O2[M+H]+,473.2096；found,473.2094。
实施例83：(4-(4-((4-氟苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)(吗啉基)甲酮(D38)的制备
按照实施例47的制备方法，将21a替换为21b，将甲胺替换为吗啉，制备标题化合物。淡黄色固体，收率80％。M.p.:206.3-207.2℃.1H-NMR(600MHz,DMSO-d6)δ10.18(s,1H),8.63(s,1H),8.61(d,J＝8.2Hz,2H),8.57(d,J＝8.8Hz,1H),8.29(d,J＝8.8Hz,1H),8.00(dd,J＝8.9,5.0Hz,2H),7.60(d,J＝8.2Hz,2H),7.29(t,J＝8.8Hz,2H),3.67-3.59(m,6H),3.48-3.35(m,2H).13C-NMR(150MHz,DMSO-d6)δ168.7,159.6,158.0,157.6,155.3,154.2,144.0,138.2,136.9,136.9,134.8,134.7,131.3,127.8,127.5,125.7,124.7,124.7,115.2,115.1,66.1,54.9.HRMS(ESI,m/z)calcd for C24H20FN5O2[M+H]+,430.1674；found,430.1696。
实施例84：(4-(4-((4-氟-2-甲氧基苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯基)(吗啉基)甲酮(D39)的制备
按照实施例47的制备方法，将21a替换为21m，将甲胺替换为吗啉，制备标题化合物。淡黄色固体，收率75％。M.p.:202.1-203.8℃.1H-NMR(600MHz,DMSO-d6)δ9.94(s,1H),8.65(s,1H),8.56(d,J＝8.8Hz,1H),8.48-8.44(m,1H),8.43(d,J＝8.0Hz,2H),8.29(d,J＝8.8Hz,1H),7.65(d,J＝8.2Hz,2H),7.12(dd,J＝10.6,2.5Hz,1H),6.90(td,J＝8.6,2.5Hz,1H),3.67(d,J＝4.9Hz,4H),3.60(s,2H),3.42(d,J＝6.0Hz,2H).13C NMR(150MHz,DMSO-d6)δ168.6,157.0,155.5,154.1,151.6,143.5,138.1,137.1,131.0,127.9,127.3,125.8,123.7,122.6,106.4,106.3,100.1,99.9,66.1,56.8,40.1.HRMS(ESI,m/z)calcd forC25H22FN5O3[M+H]+,460.1779；found,460.1790。
实施例85：4-(-(吲哚啉-1基)吡啶[3,2-d]嘧啶-6-基)-N-甲基苯甲酰胺(E01)的制备
步骤F：6-氯-4-(吲哚啉-1-基)吡啶[3,2-d]嘧啶(22)的制备
将4,6-二氯吡啶[3,2-d]嘧啶(1.76g，8.84mmol)和吲哚啉(0.238g,10.60mmol)加入100mL茄形瓶中，加入1.0ml三乙胺，50ml异丙醇做溶剂，50℃反应30min，TLC监测反应完全，冷却，蒸干溶剂，用二氯甲烷重新溶解所得固体，水洗二氯甲烷层2遍，饱和氯化钠洗1一遍，无水硫酸钠干燥。得2.4g白色固体，收率95％。
步骤G：4-(4-(吲哚啉-1-基)吡啶[3,2-d]嘧啶-6-基)苯甲酸(23)的制备
于250ml反应瓶中加入6-氯-4-(吲哚啉-1-基)吡啶[3,2-d]嘧啶(1400mg,5.0mmol)、对羧基苯硼酸(1660mg,10.0mmol)、Pd(dppf)Cl2(183mg,0.25mmol)和碳酸钾(2070mg,15.0mmol)，加入二氧六环(80ml)和水(20ml)做溶剂，氮气保护，90℃反应1h，TLC监测反应完全，冷却，将反应液倒入200ml冷水中，HCl调pH至5，过滤，滤饼干燥得1500mg，收率81％
步骤H：4-(-(吲哚啉-1基)吡啶[3,2-d]嘧啶-6-基)-N-甲基苯甲酰胺(E01)的制备
于100ml反应瓶中依次加入23(300mg，0.82mmol)、甲胺盐酸盐(66mg，0.98mmol)、HATU(372mg，0.98mmol)、DMAP(120mg，0.98mmol)和DIEA(315mg，2.45mmol)，加入50ml THF做溶剂，25℃反应5h，TLC监测反应完全，蒸干溶剂，用二氯甲烷重新溶解所得固体，水洗2遍，饱和氯化钠洗1遍，无水硫酸钠干燥。柱层析得白色固体200mg，收率65％。M.p.:211.2-212.6℃.1H-NMR(600MHz,DMSO-d6)δ8.71(s,1H),8.53(d,J＝8.8Hz,1H),8.50(d,J＝8.1Hz,1H),8.36(d,J＝8.4Hz,2H),8.28(d,J＝8.8Hz,1H),8.12(d,J＝8.4Hz,2H),7.37(d,J＝7.2Hz,1H),7.26(t,J＝7.6Hz,1H),7.09(t,J＝7.3Hz,1H),5.06(t,J＝8.2Hz,2H),3.90(s,3H),3.32-3.25(m,2H),3.17(d,J＝4.0Hz,1H).LC-MS m/z:384.2[M+H]+.
实施例86：4-(-(吲哚啉-1基)吡啶[3,2-d]嘧啶-6-基)-N-异丙基基苯甲酰胺(E02)的制备
按照实施例85的制备方法，制备标题化合物。M.p.:249.0-250.4℃.1H-NMR(600MHz,DMSO-d6)δ8.71(s,1H),8.53(d,J＝8.8Hz,1H),8.51(d,J＝8.1Hz,1H),8.35(d,J＝7.7Hz,1H),8.30(d,J＝8.4Hz,2H),8.28(d,J＝8.9Hz,1H),8.03(d,J＝8.4Hz,2H),7.37(d,J＝7.3Hz,1H),7.26(t,J＝7.7Hz,1H),7.09(t,J＝7.3Hz,1H),5.08(t,J＝8.2Hz,2H),4.14(dq,J＝13.5,6.6Hz,1H),3.44-3.18(m,2H),1.20(d,J＝6.6Hz,6H).LC-MS m/z:411.2[M+H]+.
实施例87：4-(-(吲哚啉-1基)吡啶[3,2-d]嘧啶-6-基)-N-丙基基苯甲酰胺(E03)的制备
按照实施例85的制备方法，制备标题化合物。1H-NMR(600MHz,DMSO)δ8.71(s,1H),8.58(t,J＝5.5Hz,1H),8.53(d,J＝8.9Hz,1H),8.51(d,J＝8.1Hz,1H),8.30(d,J＝8.4Hz,2H),8.27(d,J＝8.8Hz,1H),8.03(d,J＝8.4Hz,2H),7.37(d,J＝7.3Hz,1H),7.26(t,J＝7.6Hz,1H),7.09(t,J＝7.3Hz,1H),5.08(t,J＝8.2Hz,2H),3.31-3.28(m,2H),3.26(dd,J＝13.1,6.7Hz,2H),1.60–1.52(m,2H),0.92(t,J＝7.4Hz,3H).
实施例88：N-(3-羟丙基)-4-(4-(吲哚啉-1基)吡啶[3,2-d]嘧啶-6-基)-苯甲酰胺(E04)的制备
按照实施例85的制备方法，制备标题化合物。1H-NMR(600MHz,DMSO)δ8.72(s,1H),8.57(t,J＝5.5Hz,1H),8.54(d,J＝8.9Hz,1H),8.51(d,J＝8.2Hz,1H),8.31(d,J＝8.4Hz,2H),8.29(d,J＝8.8Hz,1H),8.02(d,J＝8.4Hz,2H),7.38(d,J＝7.3Hz,1H),7.27(t,J＝7.7Hz,1H),7.09(t,J＝7.4Hz,1H),5.09(t,J＝8.2Hz,2H),4.50(t,J＝5.2Hz,1H),3.49(dd,J＝11.6,6.1Hz,2H),3.38-3.34(m,2H),3.30(d,J＝8.3Hz,2H).
实施例89：4-(4-(吲哚啉-1基)吡啶[3,2-d]嘧啶-6-基)-N-(2-甲氧基乙基)苯甲酰按(E05)的制备
按照实施例85的制备方法，制备标题化合物。
1H-NMR(600MHz,DMSO)δ8.72(s,1H),8.65(t,J＝5.2Hz,1H),8.54(d,J＝8.8Hz,1H),8.50(d,J＝8.1Hz,1H),8.31(d,J＝8.4Hz,2H),8.28(d,J＝8.8Hz,1H),8.04(d,J＝8.4Hz,2H),7.37(d,J＝7.2Hz,1H),7.26(t,J＝7.7Hz,1H),7.09(t,J＝7.3Hz,1H),5.08(t,J＝8.2Hz,2H),3.50(d,J＝5.5Hz,2H),3.47(t,J＝5.1Hz,2H),3.29(s,3H).
实施例90：4-(4-(吲哚啉-1基)吡啶[3,2-d]嘧啶-6-基)-N-(3-甲氧基丙基)苯甲酰按(E06)的制备
按照实施例85的制备方法，制备标题化合物。M.p.:208.7-210.2℃.1H-NMR(600MHz,DMSO-d6)δ8.71(s,1H),8.59(t,J＝5.4Hz,1H),8.54(d,J＝8.8Hz,1H),8.51(d,J＝8.1Hz,1H),8.31(d,J＝8.4Hz,2H),8.28(d,J＝8.8Hz,1H),8.02(d,J＝8.3Hz,2H),7.37(d,J＝7.3Hz,1H),7.26(t,J＝7.7Hz,1H),7.09(t,J＝7.3Hz,1H),5.08(t,J＝8.1Hz,2H),3.40(t,J＝6.3Hz,2H),3.37-3.33(m,2H),3.32-3.28(m,3H),3.25(s,2H),1.89-1.65(m,2H).
实施例91：4-(-(吲哚啉-1基)吡啶[3,2-d]嘧啶-6-基)-N，N-二甲基苯甲酰胺(E07)的制备
按照实施例85的制备方法，制备标题化合物。1H-NMR(600MHz,DMSO)δ8.71(s,1H),8.53(d,J＝8.8Hz,1H),8.51(d,J＝8.1Hz,1H),8.35(d,J＝7.7Hz,1H),8.30(d,J＝8.4Hz,2H),8.28(d,J＝8.9Hz,1H),8.03(d,J＝8.4Hz,2H),7.37(d,J＝7.3Hz,1H),7.26(t,J＝7.7Hz,1H),7.09(t,J＝7.3Hz,1H),5.08(t,J＝8.2Hz,2H),4.14(dq,J＝13.5,6.6Hz,1H),3.44-3.18(m,2H),1.20(d,J＝6.6Hz,6H).
实施例92：N-(2-(二甲氨基)乙基)-4-(4-(吲哚啉-1基)吡啶[3,2-d]嘧啶-6-基)-苯甲酰胺(E08)的制备
按照实施例85的制备方法，制备标题化合物。1H-NMR(600MHz,DMSO)δ8.72(s,1H),8.60(t,J＝6.1Hz,1H),8.55(d,J＝8.8Hz,1H),8.51(d,J＝8.0Hz,1H),8.32(d,J＝8.3Hz,2H),8.29(d,J＝8.8Hz,1H),8.04(d,J＝8.2Hz,2H),7.38(d,J＝7.3Hz,1H),7.27(t,J＝7.7Hz,1H),7.09(t,J＝7.3Hz,1H),5.09(t,J＝8.1Hz,2H),3.45(dd,J＝11.7,5.9Hz,2H),3.30(d,J＝8.3Hz,2H),2.69-2.58(m,2H),2.36(s,6H).
实施例93：N-(环丙基-4-(4-(吲哚啉-1基)吡啶[3,2-d]嘧啶-6-基)-苯甲酰胺(E09)的制备
按照实施例85的制备方法，制备标题化合物。1H-NMR(600MHz,DMSO)δ8.70(s,1H),8.55(d,J＝4.1Hz,1H),8.51(t,J＝9.0Hz,2H),8.28(d,J＝8.4Hz,2H),8.26(d,J＝8.8Hz,1H),8.00(d,J＝8.3Hz,2H),7.36(d,J＝7.2Hz,1H),7.25(t,J＝7.7Hz,1H),7.08(t,J＝7.3Hz,1H),5.06(t,J＝8.2Hz,2H),3.28(t,J＝8.1Hz,2H),2.90(tq,J＝7.8,4.0Hz,1H),0.94-0.67(m,2H),0.66-0.50(m,2H).
实施例94：4-(4-(吲哚啉-1基)吡啶[3,2-d]嘧啶-6-基)-苯基)(吡咯烷-1-基)甲酮(E10)的制备
按照实施例85的制备方法，制备标题化合物。1H-NMR(600MHz,DMSO)δ8.70(s,1H),8.58-8.45(m,2H),8.26(d,J＝8.4Hz,3H),7.70(d,J＝8.2Hz,2H),7.36(d,J＝7.2Hz,1H),7.26(t,J＝7.7Hz,1H),7.08(t,J＝7.3Hz,1H),5.07(t,J＝8.2Hz,2H),3.50(t,J＝6.8Hz,2H),3.45(t,J＝6.4Hz,2H),3.29(t,J＝8.1Hz,2H),1.89(dt,J＝13.0,6.4Hz,2H),1.86-1.81(m,2H).
实施例95：4-(4-(吲哚啉-1基)吡啶[3,2-d]嘧啶-6-基)-苯基)(哌啶-1-基)甲酮(E11)的制备
按照实施例85的制备方法，制备标题化合物。M.p.:287.2-288.5℃.1H-NMR(600MHz,DMSO-d6)δ8.71(s,1H),8.52(t,J＝9.4Hz,2H),8.41(d,J＝6.3Hz,1H),8.29-8.26(m,3H),8.03(d,J＝7.4Hz,2H),7.37(d,J＝6.5Hz,1H),7.26(t,J＝7.2Hz,1H),7.09(t,J＝6.7Hz,1H),5.07(t,J＝7.4Hz,2H),4.27-4.26(m,1H),3.32-3.26(m,2H),1.90(brs,2H),1.72(brs,2H),1.56(brs,4H).13C-NMR(150MHz,DMSO-d6)δ165.4,157.5,154.3,153.0,146.8,143.9,140.1,136.7,135.6,133.1,133.0,128.1,126.8,126.5,125.1,124.8,123.7,118.7,107.0,54.1,51.0,32.2,28.8,23.7.HRMS(ESI,m/z)calcd for C27H25N5O[M+H]+,436.2132；found,436.2131.
LC-MS m/z:436.21[M+H]+
实施例96：4-(4-(吲哚啉-1基)吡啶[3,2-d]嘧啶-6-基)-苯基)(哌嗪-1-基)甲酮(E12)的制备
按照实施例85的制备方法，制备标题化合物。1H-NMR(600MHz,DMSO)δ8.70(s,1H),8.50(t,J＝9.6Hz,2H),8.28(d,J＝7.9Hz,1H),8.26(d,J＝8.8Hz,1H),8.17(s,1H),7.65(t,J＝7.7Hz,1H),7.52(d,J＝7.5Hz,1H),7.36(d,J＝7.3Hz,1H),7.25(t,J＝7.7Hz,1H),7.08(t,J＝7.3Hz,1H),5.06(t,J＝8.2Hz,2H),3.60(s,2H),3.32(s,2H),3.31-3.27(m,2H),2.78(s,2H),2.66(s,2H),1.22(s,1H).13C-NMR(151MHz,DMSO)δ168.6,157.5,154.3,153.1,146.8,143.9,138.1,137.0,136.8,133.1,132.9,129.5,128.3,128.0,126.6,125.2,125.1,124.9,123.7,118.7,54.1,48.6,31.3,28.8.
实施例97：1-(4-(4-(4-(吲哚啉-1基)吡啶[3,2-d]嘧啶-6-基)-苯甲酰)哌嗪-1-基)甲酮(E13)的制备
按照实施例85的制备方法，制备标题化合物。1H-NMR(600MHz,DMSO)δ8.71(s,1H),8.55–8.48(m,2H),8.30(d,J＝8.2Hz,2H),8.28(d,J＝8.9Hz,1H),7.62(d,J＝8.2Hz,2H),7.37(d,J＝7.2Hz,1H),7.26(t,J＝7.7Hz,1H),7.09(t,J＝7.3Hz,1H),5.08(t,J＝8.1Hz,2H),3.82-3.37(m,8H),3.29(d,J＝8.1Hz,2H),2.03(d,J＝1.0Hz,3H).
实施例98：4-(4-(吲哚啉-1基)吡啶[3,2-d]嘧啶-6-基)-苯基)-吗啉)甲酮(E14)的制备
按照实施例85的制备方法，制备标题化合物。1H-NMR(600MHz,DMSO)δ8.70(s,1H),8.57–8.45(m,2H),8.29-8.26(m,3H),7.60(d,J＝8.0Hz,2H),7.36(d,J＝7.2Hz,1H),7.26(t,J＝7.6Hz,1H),7.08(t,J＝7.3Hz,1H),5.07(t,J＝8.1Hz,2H),3.63(brs,6H),3.41(brs,2H),3.29(t,J＝8.1Hz,2H).
实施例99：(R)-(3-氨基哌啶-1-基)4-(4-(吲哚啉-1基)吡啶[3,2-d]嘧啶-6-基)-苯基)甲酮(E15)的制备
按照实施例85的制备方法，制备标题化合物。1H-NMR(600MHz,DMSO)δ8.70(s,1H),8.51(d,J＝8.5Hz,2H),8.28(dd,J＝8.3,3.3Hz,3H),7.57(d,J＝8.1Hz,2H),7.37(d,J＝7.3Hz,1H),7.26(t,J＝7.7Hz,1H),7.09(t,J＝7.3Hz,1H),5.08(t,J＝8.0Hz,2H),4.26(dd,J＝84.6,15.7Hz,1H),3.53(dd,J＝52.6,13.0Hz,1H),3.30(d,J＝8.0Hz,2H),2.96(dd,J＝58.3,13.9Hz,1H),2.86–2.62(m,2H),2.25(d,J＝27.2Hz,1H),1.88(dd,J＝9.9,2.0Hz,1H),1.69(dd,J＝67.2,13.1Hz,1H),1.44(d,J＝11.8Hz,1H),1.34-1.18(m,2H).
实施例100：(S)-(3-氨基哌啶-1-基)4-(4-(吲哚啉-1基)吡啶[3,2-d]嘧啶-6-基)-苯基)甲酮(E16)的制备
按照实施例85的制备方法，制备标题化合物。1H-NMR(600MHz,DMSO)δ8.70(s,1H),8.50(dd,J＝8.4,2.5Hz,2H),8.27(dd,J＝8.4,3.5Hz,3H),7.56(d,J＝8.2Hz,2H),7.37(d,J＝7.2Hz,1H),7.26(t,J＝7.7Hz,1H),7.08(t,J＝7.2Hz,1H),5.08(t,J＝8.1Hz,2H),4.56-3.95(m,1H),3.71-3.41(m,1H),3.37-3.18(m,2H),2.96(dd,J＝46.5,10.9Hz,1H),2.82-2.54(m,2H),1.87(dd,J＝10.9,1.2Hz,1H),1.75(d,J＝7.5Hz,2H),1.48-1.34(m,1H),1.26(dd,J＝24.5,13.0Hz,2H).
实施例101：(R)-(3-氨基吡咯-1-基)4-(4-(吲哚啉-1基)吡啶[3,2-d]嘧啶-6-基)-苯基)甲酮(E17)的制备
按照实施例85的制备方法，制备标题化合物。1H-NMR(600MHz,DMSO)δ8.70(s,1H),8.51(d,J＝8.8Hz,2H),8.27(d,J＝8.4Hz,3H),7.69(t,J＝8.0Hz,2H),7.37(d,J＝7.3Hz,1H),7.26(t,J＝7.7Hz,1H),7.09(t,J＝7.3Hz,1H),5.08(t,J＝8.1Hz,2H),3.66–3.60(m,1H),3.60–3.54(m,1H),3.54-3.48(m,1H),3.45-3.43(m,1H),3.29(d,J＝8.1Hz,2H),3.16(ddd,J＝14.8,11.1,4.4Hz,1H),2.03-1.94(m,1H),1.84(d,J＝6.7Hz,2H),1.69-1.58(m,1H).
实施例102：(S)-(3-氨基吡咯-1-基)4-(4-(吲哚啉-1基)吡啶[3,2-d]嘧啶-6-基)-苯基)甲酮(E18)的制备
按照实施例85的制备方法，制备标题化合物。1H-NMR(600MHz,DMSO)δ8.70(s,1H),8.51(d,J＝8.8Hz,2H),8.27(d,J＝8.4Hz,3H),7.69(t,J＝8.0Hz,2H),7.37(d,J＝7.3Hz,1H),7.26(t,J＝7.7Hz,1H),7.09(t,J＝7.3Hz,1H),5.08(t,J＝8.1Hz,2H),3.66-3.60(m,1H),3.60-3.54(m,1H),3.54-3.48(m,1H),3.45-3.43(m,1H),3.29(d,J＝8.1Hz,2H),3.16(ddd,J＝14.8,11.1,4.4Hz,1H),2.03-1.94(m,1H),1.84(d,J＝6.7Hz,2H),1.69-1.58(m,1H).
实施例103：4-(4-(5-氟吲哚啉-1基)吡啶[3,2-d]嘧啶-6-基)-苯基)-吗啉)甲酮(E19)的制备
按照实施例85的制备方法，制备标题化合物。1H-NMR(600MHz,DMSO)δ8.69(s,1H),8.54(dd,J＝8.9,5.0Hz,1H),8.50(d,J＝8.8Hz,1H),8.28(d,J＝8.3Hz,2H),8.26(d,J＝8.9Hz,1H),7.60(d,J＝8.2Hz,2H),7.23(dd,J＝8.3,2.4Hz,1H),7.09(td,J＝9.0,2.7Hz,1H),5.11(t,J＝8.2Hz,2H),3.66-3.59(m,7H),3.41(s,2H),3.34-3.25(m,2H).
实施例104：(4-(4-(2,3-二氢-1H-吡咯[2,3-b]吡啶-1-基)吡啶[3,2-d]嘧啶-6-基)苯基)(哌嗪-1-基)甲酮(E20)的制备
按照实施例85的制备方法，制备标题化合物。LC-MS m/z:438.20[M+H]+M.p.:262.8-263.8℃.1H-NMR(600MHz,DMSO-d6)δ8.69(s,1H),8.54(dd,J＝8.9,5.0Hz,1H),8.50(d,J＝8.8Hz,1H),8.27(dd,J＝8.5,4.8Hz,3H),7.57(d,J＝8.2Hz,2H),7.23(dd,J＝8.3,2.4Hz,1H),7.09(td,J＝8.9,2.6Hz,1H),5.11(t,J＝8.2Hz,2H),3.58(brs,2H),3.30(d,J＝8.7Hz,4H),2.77(brs,2H),2.67(brs,2H).13C-NMR(150MHz,DMSO-d6)δ168.5,157.8,157.2,154.3,153.1,146.7,140.3,138.8,137.3,136.8,135.7,132.9,127.8,127.2,125.0,119.8,112.8,112.0,54.4,48.5,45.8,45.4,42.7,28.9.HRMS(ESI,m/z)calcd forC26H23FN6O[M+H]+,455.1990；found,455.1996.
实施例105：N-环戊基-4-(4-(吲哚啉-1基)吡啶[3,2-d]嘧啶-6-基)-苯甲酰胺(E21)的制备
按照实施例85的制备方法，制备标题化合物。LC-MS m/z:437.21[M+H]+M.p.:187.0-188.2℃.1H-NMR(600MHz,DMSO-d6)δ8.69(s,1H),8.54(dd,J＝8.9,5.0Hz,1H),8.50(d,J＝8.8Hz,1H),8.28(d,J＝8.3Hz,2H),8.26(d,J＝8.9Hz,1H),7.60(d,J＝8.2Hz,2H),7.23(dd,J＝8.3,2.4Hz,1H),7.09(td,J＝9.0,2.7Hz,1H),5.11(t,J＝8.2Hz,2H),3.66-3.59(m,7H),3.41(s,2H),3.34-3.25(m,2H).13C-NMR(150MHz,DMSO-d6)δ168.6,157.2,154.2,153.0,146.7,140.2,138.9,136.7,135.7,132.9,127.8,127.1,125.0,119.7,112.8,111.9,66.1,54.9,54.3,28.8.HRMS(ESI,m/z)calcd for C26H22FN5O2[M+H]+,456.1830；found,456.1825.
实施例106：(5-(4-(吲哚啉-1基)吡啶[3,2-d]嘧啶-6-基)吡啶-2-基)(哌嗪-1-基)甲酮(E22)的制备
按照实施例85的制备方法，制备标题化合物。LC-MS m/z:438.19[M+H]+M.p.:198.3-199.5℃.1H-NMR(600MHz,DMSO-d6)δ8.70(s,1H),8.62(s,1H),8.55(d,J＝8.8Hz,1H),8.52(d,J＝8.2Hz,1H),8.48(d,J＝7.2Hz,1H),8.36(d,J＝7.8Hz,1H),8.30(d,J＝8.8Hz,1H),7.96(d,J＝7.7Hz,1H),7.65(t,J＝7.7Hz,1H),7.37(d,J＝7.3Hz,1H),7.26(t,J＝7.7Hz,1H),7.08(t,J＝7.3Hz,1H),5.11(t,J＝8.2Hz,2H),4.36-4.22(m,1H),3.28(t,J＝8.2Hz,2H),1.99-1.86(m,2H),1.81-1.68(m,2H),1.61-1.56(m,4H).13C-NMR(150MHz,DMSO-d6)δ165.7,157.5,154.3,153.3,146.8,143.9,137.9,136.8,135.7,133.0,132.9,129.4,129.1,128.8,126.6,125.8,125.0,124.9,123.7,118.7,54.1,51.0,32.2,28.8,23.7.HRMS(ESI,m/z)calcd for C27H25N5O[M+H]+,436.2132；found,436.2120.
实施例107：(3-(4-(吲哚啉-1基)吡啶[3,2-d]嘧啶-6-基)苯基(哌嗪-1-基)甲酮(E23)的制备
按照实施例85的制备方法，制备标题化合物。M.p.:253.8-254.6℃.1H-NMR(600MHz,DMSO-d6)δ8.70(s,1H),8.50(t,J＝9.6Hz,2H),8.28(d,J＝7.9Hz,1H),8.26(d,J＝8.8Hz,1H),8.17(s,1H),7.65(t,J＝7.7Hz,1H),7.52(d,J＝7.5Hz,1H),7.36(d,J＝7.3Hz,1H),7.25(t,J＝7.7Hz,1H),7.08(t,J＝7.3Hz,1H),5.06(t,J＝8.2Hz,2H),3.60(s,2H),3.32(s,2H),3.31-3.27(m,2H),2.78(s,2H),2.66(s,2H).
实施例108：N-环戊基-3-(4-(吲哚啉-1基)吡啶[3,2-d]嘧啶-6-基)-苯甲酰胺(E24)的制备
按照实施例85的制备方法，制备标题化合物。1H-NMR(600MHz,DMSO)δ8.70(s,1H),8.62(s,1H),8.55(d,J＝8.8Hz,1H),8.52(d,J＝8.2Hz,1H),8.48(d,J＝7.2Hz,1H),8.36(d,J＝7.8Hz,1H),8.30(d,J＝8.8Hz,1H),7.96(d,J＝7.7Hz,1H),7.65(t,J＝7.7Hz,1H),7.37(d,J＝7.3Hz,1H),7.26(t,J＝7.7Hz,1H),7.08(t,J＝7.3Hz,1H),5.11(t,J＝8.2Hz,2H),4.36-4.22(m,1H),3.28(t,J＝8.2Hz,2H),1.99-1.86(m,2H),1.81-1.68(m,2H),1.61-1.56(m,4H).13C-NMR(150MHz,DMSO)δ165.7,157.5,154.3,153.3,146.8,143.9,137.9,136.8,135.7,133.0,132.9,129.4,129.1,128.8,126.6,125.8,125.0,124.9,123.7,118.7,54.1,51.0,48.6,32.2,28.8,23.7.
实施例109：N-环戊基-3-(4-(吲哚啉-1基)吡啶[3,2-d]嘧啶-6-基)-苯甲酰胺(E25)的制备
按照实施例85的制备方法，制备标题化合物。LC-MS m/z:455.20[M+H]+M.p.:202.5-204.3℃.1H-NMR(600MHz,DMSO-d6)δ8.69(s,1H),8.52(t,J＝8.1Hz,2H),8.28(d,J＝8.0Hz,1H),8.26(d,J＝8.8Hz,1H),8.17(s,1H),7.65(t,J＝7.7Hz,1H),7.52(d,J＝7.6Hz,1H),7.23(dd,J＝8.4,2.5Hz,1H),7.08(td,J＝9.0,2.7Hz,1H),5.11(t,J＝8.2Hz,2H),3.60(brs,2H),3.30(d,J＝8.4Hz,4H),2.78(brs,2H),2.67(brs,2H).13C-NMR(150MHz,DMSO-d6)δ168.6,157.7,157.2,154.3,153.2,146.7,140.3,138.0,137.0,136.8,135.66,132.8,129.5,128.3,128.0,125.2,125.1,119.7,112.82,112.0,54.9,54.4,40.1,28.8.HRMS(ESI,m/z)calcd for C26H23FN6O[M+H]+,455.1990；found,455.1951.
实施例110：N-甲基-4-((6-(4-(哌嗪-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)苯甲酰胺(LB-01)的制备
步骤D：N-甲基-4-硝基苯甲酰胺(24a)的制备
将0.870g(13.00mmol)甲胺盐酸盐置于100ml茄形瓶中，加入30ml干燥的四氢呋喃和1.5ml三乙胺，室温搅拌20分钟后，将2.000g(11.30mmol)对硝基苯甲酰氯溶于20ml干燥的四氢呋喃，在冰浴下滴加入茄形瓶中，滴加完毕后，继续在冰浴下反应。反应结束后，过滤，蒸干滤液，加入200ml二氯甲烷，1mol/L盐酸洗二氯甲烷层一次，饱和氯化钠洗二氯甲烷层一次，无水硫酸钠干燥，过滤，蒸干得白色固体，无需纯化可直接投下一步，收率：65.2％。
步骤E：4-氨基-N-甲基苯甲酰胺(25a)的制备
将1.000g(5.54mmol)24a和5.000g(22.15mmol)氯化亚锡置于50ml茄形瓶中，向茄形瓶中加入20ml无水乙醇，室温反应。反应结束后，蒸干溶剂，加入约200ml乙酸乙酯，用饱和碳酸氢钠溶液调pH至8左右，过滤，水层用20ml乙酸乙酯萃取三次，合并有机层，饱和氯化钠溶液洗乙酸乙酯层1次，无水硫酸钠干燥，过滤，蒸干得白色固体，用快速制备液相纯化二氯甲烷：甲醇＝100:1)，得白色蓬松状固体，收率：67.4％。
步骤F：4-((6-氯吡啶并[3,2-d]嘧啶-4-基)氨基)-N-甲基苯甲酰胺(26a)的制备
将0.300g(1.50mmol)5和0.270g(1.80mmol)25a置于50ml茄形瓶中，向茄形瓶中加入0.4ml(1.80mmol)三乙胺和20ml异丙醇，于50℃反应。反应结束后，冷却反应液至室温，过滤，滤饼用乙酸乙酯洗涤，干燥，得白色固体，无需纯化可直接投下一步，收率：87.3％。
步骤G：(4-(4-(叔丁氧基羰基)哌嗪-1-羰基)苯基)硼酸(27a)的制备
将2.000g(12.00mmol)对羧基苯硼酸、1.760g(14.40mmol)DMAP、5.470g(14.40mmol)HATU以及1.860g(14.40mmol)DIEA置于250ml茄形瓶中，向茄形瓶中加入120ml干燥的四氢呋喃，室温下搅拌20分钟，加入2.68g(14.40mol)Boc-哌嗪，继续在室温下反应。反应结束后，蒸干反应液，用200ml二氯甲烷重新溶解，之后用1mol/L盐酸洗一次，水洗一次，饱和碳酸氢钠溶液洗一次，饱和氯化钠洗一次，无水硫酸钠干燥过夜，过滤，蒸干，得白色固体，用快速制备液相纯化(二氯甲烷：甲醇＝10:1)，得白色固体，收率53.0％。
步骤H：4-(4-(4-((4-(甲基氨基甲酰基)苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯甲酰基)哌嗪-1-羧酸叔丁酯(28a)的制备
将0.320g(1.00mmol)26a和0.400g(1.20mmol)27a置于50ml两颈瓶中，将0.410g(3.00mmol)碳酸钾溶于5ml水加入到两颈瓶中，之后向两颈瓶中加入0.060g(0.05mmol)四(三苯基膦)钯和20ml二氧六环，将反应体系置于氮气保护下，90℃反应。反应结束后，蒸干溶剂，加入100ml二氯甲烷溶解，用1mol/L盐酸洗一次，水洗一次，饱和碳酸氢钠溶液洗一次，饱和氯化钠洗一次，无水硫酸钠干燥过夜，过滤，蒸干，得白色固体，用快速制备液相纯化(二氯甲烷：甲醇＝100:1)，得淡黄色固体，收率45.2％。
步骤I：N-甲基-4-((6-(4-(哌嗪-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)苯甲酰胺(LB-01)的制备
将0.200g(0.43mmol)28a置于100ml茄形瓶中，向茄形瓶中加入40ml饱和的氯化氢-乙酸乙酯溶液，室温下反应。反应结束后，过滤，滤饼用乙酸乙酯洗一次，干燥，溶解于30ml水中，用饱和碳酸氢钠溶液调节pH至9，过滤，滤饼用3ml乙酸乙酯洗两遍，得淡黄色固体，收率80.1％。1H-NMR(δppm DMSO-d6)δ10.23(s,1H),8.72(s,1H),8.59(d,J＝7.4Hz,2H),8.58(d,J＝8.7Hz,1H),8.44(q,J＝4.2Hz,1H),8.32(d,J＝8.7Hz,1H),8.17(d,J＝8.4Hz,2H),7.92(d,J＝8.4Hz,2H),7.57(d,J＝7.4Hz,2H),3.58(s,2H),3.30(s,2H),2.81(d,J＝4.2Hz,3H),2.77(s,2H),2.67(s,2H),1.22(s,1H).
实施例111：N-异丙基-4-((6-(4-(哌嗪-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)苯甲酰胺(LB-02)的制备
按照实施例110的制备方法，原料甲胺盐酸盐替换为异丙胺，制备标题化合物。淡黄色固体，收率81.1％。1H-NMR(δppm DMSO-d6)δ10.23(s,1H),8.73(s,1H),8.60(d,J＝7.5Hz,2H),8.59(d,J＝8.0Hz,1H),8.33(d,J＝8.8Hz,1H),,8.19(d,J＝8.6Hz,2H)8.17(d,J＝8.0Hz,1H),7.94(d,J＝8.6Hz,2H),7.57(d,J＝7.5Hz,2H),4.13(dq,J＝13.3,6.5Hz,1H),3.59(s,2H),3.32(s,2H),2.77(s,2H),2.67(s,2H),1.23(s,2H),1.19(d,J＝6.6Hz,6H).
实施例112：N-环丙基-4-((6-(4-(哌嗪-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)苯甲酰胺(LB-03)的制备
按照实施例110的制备方法，将原料甲胺盐酸盐替换为环丙胺，制备标题化合物。白色固体，收率64.4％。1H-NMR(δppm DMSO-d6)δ10.22(s,1H),8.73(s,1H),8.60(d,J＝7.7Hz,2H),8.58(d,J＝8.7Hz,1H),8.41(s,1H),8.32(d,J＝8.7Hz,1H),8.16(d,J＝8.2Hz,2H),7.91(d,J＝8.2Hz,2H),7.57(d,J＝7.7Hz,2H),3.59(s,2H),3.25(s,2H),2.86(s,1H),2.78(s,2H),2.68(s,2H),1.22(s,1H),0.71(d,J＝5.6Hz,2H),0.59(s,2H).
实施例113：N-环戊基-4-((6-(4-(哌嗪-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)苯甲酰胺(LB-04)的制备
按照实施例110的制备方法，将原料甲胺盐酸盐替换为环戊胺，制备标题化合物。白色固体，收率60.8％。1H-NMR(δppm DMSO-d6)δ10.23(s,1H),8.73(s,1H),8.60(d,J＝7.7Hz,2H),8.59(d,J＝8.6Hz,1H),8.32(d,J＝8.1Hz,1H),8.24(d,J＝8.6Hz,1H),8.16(d,J＝8.2Hz,2H),7.93(d,J＝8.2Hz,2H),7.57(d,J＝7.7Hz,2H),4.25(dd,J＝11.1,9.3Hz,1H),3.59(s,2H),3.40(s,2H),2.78(s,2H),2.68(s,2H),1.91(s,2H),1.72(s,2H),1.55(s,4H),1.23(s,1H).
实施例114：N-环己基-4-((6-(4-(哌嗪-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)苯甲酰胺(LB-05)的制备
按照实施例110的制备方法，将原料甲胺盐酸盐替换为环己胺，制备标题化合物。白色固体，收率62.2％。1H-NMR(δppm DMSO-d6)δ10.22(s,1H),10.22(s,1H),8.72(s,1H),8.59(d,J＝7.4Hz,2H),8.57(d,J＝8.6Hz,1H),8.32(d,J＝8.1Hz,1H),8.17(d,J＝6.4Hz,2H),8.15(d,J＝8.6Hz,1H),7.93(d,J＝7.4Hz,2H),7.57(d,J＝7.4Hz,2H),3.84–3.73(m,1H),3.59(s,2H),3.39(s,2H),2.76(s,2H),2.67(s,2H),1.84(s,2H),1.75(s,2H),1.32(s,4H),1.22(s,1H),1.15(s,2H).
实施例115：N-苯基-4-((6-(4-(哌嗪-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)苯甲酰胺(LB-06)的制备
按照实施例110的制备方法，将原料甲胺盐酸盐替换为苯胺，制备标题化合物。白色固体，收率61.4％。1H-NMR(δppm DMSO-d6)δ10.30(s,1H),10.25(s,1H),8.76(s,1H),8.61(d,J＝8.1Hz,2H),8.60(d,J＝8.8Hz,1H),8.34(d,J＝8.8Hz,1H),8.26(d,J＝8.7Hz,2H),8.08(d,J＝8.7Hz,2H),7.82(d,J＝7.7Hz,2H),7.59(d,J＝8.1Hz,2H),7.37(t,J＝8.1Hz,2H),7.10(t,J＝8.1Hz,1H),3.62(s,2H),3.39(s,2H),2.81(s,2H),2.73(s,2H),1.22(s,1H).
实施例116：4-((6-(4-(哌嗪-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)-N-(对甲苯基)苯甲酰胺(LB-07)的制备
按照实施例110的制备方法，将原料甲胺盐酸盐替换为对甲苯胺，制备标题化合物。白色固体，收率62.3％。1H-NMR(δppm DMSO-d6)δ10.30(s,1H),10.18(s,1H),8.76(s,1H),8.62(d,J＝8.2Hz,2H),8.60(d,J＝8.8Hz,1H),8.34(d,J＝8.8Hz,1H),8.25(d,J＝8.7Hz,2H),8.08(d,J＝8.7Hz,2H),7.70(d,J＝8.3Hz,2H),7.58(d,J＝8.3Hz,2H),7.17(d,J＝8.2Hz,2H),3.60(s,2H),3.33(s,2H),2.78(s,2H),2.68(s,2H),2.29(s,3H),1.23(s,1H).
实施例117：N-(4-甲氧基苯基)-4-((6-(4-(哌嗪-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)苯甲酰胺(LB-08)的制备
按照实施例110的制备方法，将原料甲胺盐酸盐替换为对甲氧基苯胺，制备标题化合物。白色固体，收率62.3％。1H-NMR(δppm DMSO-d6)δ10.29(s,1H),10.10(s,1H),8.75(s,1H),8.61(d,J＝8.3Hz,2H),8.60(d,J＝8.8Hz,1H),8.34(d,J＝8.8Hz,1H),8.25(d,J＝8.7Hz,2H),8.05(d,J＝8.7Hz,2H),7.70(d,J＝9.0Hz,2H),7.58(d,J＝8.3Hz,2H),6.94(d,J＝9.0Hz,2H),3.76(s,3H),3.60(s,2H),3.33(s,2H),2.78(s,2H),2.68(s,2H),1.23(s,1H).
实施例118：4-((6-(4-(哌嗪-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)-N-(4-(三氟甲基)苯基)苯甲酰胺(LB-09)的制备
按照实施例110的制备方法，将原料甲胺盐酸盐替换为对三氟甲基苯胺，制备标题化合物。白色固体，收率62.8％。1H-NMR(δppm DMSO-d6)δ10.60(s,1H),10.30(s,1H),8.75(s,1H),8.59(d,J＝8.3Hz,2H),8.55(d,J＝7.4Hz,1H)8.32(d,J＝7.4Hz,1H),8.28(d,J＝8.7Hz,2H),8.10(d,J＝8.7Hz,2H),8.06(d,J＝8.3Hz,2H),7.73(d,J＝8.3Hz,2H),7.58(d,J＝8.3Hz,2H)),3.59(s,2H),3.44(s,2H),2.77(s,2H),2.68(s,2H),1.21(s,1H).
实施例119：N-(4-氟苯基)-4-((6-(4-(哌嗪-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)苯甲酰胺(LB-10)的制备
按照实施例110的制备方法，将原料甲胺盐酸盐替换为对氟苯胺，制备标题化合物。白色固体，收率66.6％。1H-NMR(δppm DMSO-d6)δ10.30(s,1H),10.27(s,1H),8.75(s,1H),8.61(d,J＝8.0Hz,2H),8.60(d,J＝8.8Hz,1H),8.34(d,J＝8.8Hz,1H),8.26(d,J＝8.5Hz,2H),8.06(d,J＝8.5Hz,2H),7.82(dd,J＝8.4,5.1Hz,2H),7.58(d,J＝8.0Hz,2H),7.21(t,J＝8.4Hz,2H),3.59(s,2H),3.32(s,2H),2.77(s,2H),2.67(s,2H),1.22(s,1H).
实施例120：N-(3-氯-4-氟苯基)-4-((6-(4-(哌嗪-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)苯甲酰胺(LB-11)的制备
按照实施例110的制备方法，将原料甲胺盐酸盐替换为3-氯-4-氟苯胺，制备标题化合物。白色固体，收率65.4％。1H-NMR(δppm DMSO-d6)δ10.47(s,1H),10.32(s,1H),8.76(s,1H),8.62(d,J＝8.3Hz,2H),8.60(d,J＝8.8Hz,1H),8.35(d,J＝8.8Hz,1H),8.28(d,J＝8.7Hz,2H),8.14(dd,J＝6.9,2.5Hz,1H),8.09(d,J＝8.7Hz,2H),7.82–7.77(m,1H),7.58(d,J＝8.3Hz,2H),7.43(t,J＝9.1Hz,1H),3.59(s,2H),3.31(s,2H),2.78(s,2H),2.68(s,2H),1.23(s,1H).
实施例121：(S)-N-甲基-4-((6-(4-(3-甲基哌嗪-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)苯甲酰胺(LB-12)的制备
步骤G：(4-(4-(叔丁氧基羰基)哌嗪-1-羰基)苯基)硼酸(27b)的制备
室温下，将2.000g(12.0mmol)对羧基苯硼酸、1.760g(14.4mmol)DMAP、5.470g(14.40mmol)HATU以及1.860g(14.40mmol)DIEA置于250ml茄形瓶中，向茄形瓶中加入120ml干燥的四氢呋喃，室温下搅拌20分钟，加入3.140g(14.40mol)(S)-3-甲基-Boc哌嗪，继续在室温下反应。反应结束后，蒸干反应液，加入200ml二氯甲烷，之后用1mol/L盐酸洗一次，水洗一次，饱和碳酸氢钠溶液洗一次，饱和氯化钠洗一次，无水硫酸钠干燥过夜，过滤，蒸干，得白色固体，用快速制备液相纯化(二氯甲烷：甲醇＝10:1)，得白色固体，收率53.1％。
步骤H：(S)-3-甲基-4-(4-(4-((4-(甲基氨基甲酰基)苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)苯甲酰基)哌嗪-1-羧酸叔丁酯(28l)的制备
将0.28g(0.50mmol)26a、0.23g(0.60mmol)HATU、0.073g(0.60mmol)DMAP以及0.074g(0.60mmol)DIEA置于50ml茄形瓶中，向茄形瓶中加入30ml干燥的四氢呋喃，室温下搅拌20分钟，加入0.12g(0.60mol)(S)-3-甲基-Boc-哌嗪，继续在室温下反应。反应结束后，蒸干反应液，用50ml二氯甲烷溶解，之后用1mol/L盐酸洗一次，水洗一次，饱和碳酸氢钠溶液洗一次，饱和氯化钠洗一次，无水硫酸钠干燥过夜，过滤，蒸干，得黄色固体，用快速制备液相纯化(二氯甲烷：甲醇
＝10:1)，得淡黄色固体，收率49.5％。
步骤I：(S)-N-甲基-4-((6-(4-(3-甲基哌嗪-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)苯甲酰胺(LB-12)的制备
将0.120g(0.20mmol)28l置于100ml茄形瓶中，向茄形瓶中加入40ml饱和的氯化氢-乙酸乙酯溶液，室温下反应。反应结束后，过滤，滤饼用乙酸乙酯洗一次，干燥，溶解于30ml水中，用饱和碳酸氢钠溶液调节pH至9，过滤，滤饼用3ml乙酸乙酯洗两遍，得淡黄色固体，收率76.3％。1H-NMR(δppm DMSO-d6)δ10.23(s,1H),8.73(s,1H),8.61(d,J＝8.3Hz,2H),8.60(d,J＝8.8Hz,1H),8.41(q,J＝4.2Hz,1H),8.33(d,J＝8.8Hz,1H),8.17(d,J＝8.7Hz,2H),7.93(d,J＝8.7Hz,2H),7.58(d,J＝8.3Hz,2H),4.37(s,1H),3.48(s,1H),3.04(d,J＝67.2Hz,1H),2.85(s,1H),2.81(d,J＝4.5Hz,3H),2.72(s,1H),2.47(s,1H),1.23(s,1H),0.97(d,J＝4.2Hz,3H).
实施例122：(S)-N-异丙基-4-((6-(4-(3-甲基哌嗪-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)苯甲酰胺(LB-13)的制备
按照实施例121的制备方法，将原料甲胺盐酸盐替换为异丙胺，制备标题化合物。淡黄色固体，收率82.7％。1H-NMR(δppm DMSO-d6)δ10.23(s,1H),8.73(s,1H),8.61(d,J＝8.1Hz,2H),8.59(d,J＝8.7Hz,1H),8.33(d,J＝8.8Hz,1H),8.17(d,J＝8.5Hz,3H),7.94(d,J＝8.5Hz,2H),7.57(d,J＝8.1Hz,2H),4.36(s,1H),4.20–4.06(m,1H),3.46(s,1H),3.01(d,J＝62.4Hz,1H),2.80(s,1H),2.66(s,2H),2.42(s,1H),1.23(s,1H),1.19(d,J＝6.6Hz,6H),0.95(d,J＝4.2Hz,3H).
实施例123：(S)-N-环丙基-4-((6-(4-(3-甲基哌嗪-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)苯甲酰胺(LB-14)的制备
按照实施例121的制备方法，将原料甲胺盐酸盐替换为环丙胺，制备标题化合物。淡黄色固体，收率88.4％。1H-NMR(δppm DMSO-d6)δ10.23(s,1H),8.73(s,1H),8.61(d,J＝8.3Hz,2H),8.60(d,J＝8.8Hz,1H),8.44(d,J＝8.8Hz,1H),8.33(d,J＝8.8Hz,1H),8.16(d,J＝8.7Hz,2H),7.92(d,J＝8.7Hz,2H),7.57(d,J＝8.3Hz,2H),δ4.35(s,1H),3.47(s,1H),3.02(d,J＝61.4Hz,1H),2.86(qd,J＝7.7,4.0Hz,1H),2.81(s,1H),2.66(s,2H),2.44(s,1H),1.23(s,1H),0.95(d,J＝4.3Hz,3H),δ0.64–0.47(m,1H).
实施例124：(S)-N-环戊基-4-((6-(4-(3-甲基哌嗪-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)苯甲酰胺(LB-15)的制备
按照实施例121的制备方法，将原料甲胺盐酸盐替换为环戊胺，制备标题化合物。淡黄色固体，收率84.3％。1H-NMR(δppm DMSO-d6)δ10.22(s,1H),8.72(s,1H),8.60(d,J＝8.1Hz,2H),8.58(d,J＝8.8Hz,1H),8.31(d,J＝8.8Hz,1H),8.16(d,J＝8.4Hz,2H),7.93(d,J＝8.4Hz,2H),7.57(d,J＝8.1Hz,2H),4.34(s,1H),4.30(s,1H),3.46(s,1H),3.00(d,J＝64.8Hz,1H),2.80(s,1H),2.66(s,2H),δ2.42(s,1H),1.91–1.78(m,2H),1.76–1.67(m,2H),1.55(s,2H),1.35–1.27(m,2H),1.22(s,1H),1.04(s,1H),0.95(d,J＝4.3Hz,3H).
实施例125：((S)-N-环己基-4-((6-(4-(3-甲基哌嗪-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)苯甲酰胺(LB-16)的制备
按照实施例121的制备方法，将原料甲胺盐酸盐替换为环己胺，制备标题化合物。淡黄色固体，收率70.2％。1H-NMR(δppm DMSO-d6)δ10.23(s,1H),8.73(s,1H),8.60(d,J＝8.6Hz,2H),8.59(d,J＝8.8Hz,1H),8.32(d,J＝8.8Hz,1H),8.16(d,J＝8.4Hz,2H),8.15(d,J＝6.5Hz,1H),7.93(d,J＝8.4Hz,2H),7.57(d,J＝8.1Hz,2H),4.35(s,1H),3.78(s,1H),3.46(s,1H),3.00(d,J＝4.2Hz,1H),2.79(s,1H),2.66(s,2H),2.43(s,1H),1.85(d,J＝7.6Hz,2H),1.75(d,J＝7.7Hz,2H),1.62(d,J＝12.7Hz,1H),1.38–1.27(m,4H),1.22(s,1H),1.14(dd,J＝22.1,13.8Hz,1H),0.95(d,J＝4.3Hz,3H).
实施例126：(S)-N-苯基-4-((6-(4-(3-甲基哌嗪-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)苯甲酰胺(LB-17)的制备
按照实施例121的制备方法，将原料甲胺盐酸盐替换为苯胺，制备标题化合物。淡黄色固体，收率81.2％。1H-NMR(δppm DMSO-d6)δ10.31(s,1H),10.22(s,1H),8.76(s,1H),8.63(d,J＝8.3Hz,2H),8.61(d,J＝9.8Hz,1H),8.35(d,J＝8.7Hz,1H),8.26(d,J＝8.4Hz,2H),8.07(d,J＝8.4Hz,2H),7.80(d,J＝7.8Hz,2H),7.60(d,J＝7.9Hz,2H),7.37(t,J＝7.6Hz,2H),7.11(t,J＝7.1Hz,1H),4.39(s,1H),3.52(s,1H),3.12(d,J＝57.9Hz,1H),2.92(s,1H),2.77(s,2H),2.40(s,1H),1.23(s,1H),1.03(d,J＝4.2Hz,3H).
实施例127：(S)-4-((6-(4-(3-甲基哌嗪-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)-N-(对甲苯基)苯甲酰胺(LB-18)的制备
按照实施例121的制备方法，将原料甲胺盐酸盐替换为对甲苯胺，制备标题化合物。淡黄色固体，收率80.2％。1H-NMR(δppm DMSO-d6)δ10.30(s,1H),10.13(s,1H),8.75(s,1H),8.62(d,J＝8.0Hz,2H),8.60(d,J＝8.8Hz,1H),8.34(d,J＝8.8Hz,1H),8.25(d,J＝8.5Hz,2H),8.05(d,J＝8.5Hz,2H),7.68(d,J＝8.1Hz,2H),7.58(d,J＝8.1Hz,2H),7.17(d,J＝8.0Hz,2H),4.36(s,1H),3.47(s,1H),3.02(d,J＝72.3Hz,1H),2.80(s,1H),2.67(s,2H),2.44(s,1H),2.29(s,3H),1.23(s,1H),0.95(d,J＝4.2Hz,3H).
实施例128：(S)-N-(4-甲氧基苯基)-4-((6-(4-(3-甲基哌嗪-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)苯甲酰胺(LB-19)的制备
按照实施例121的制备方法，将原料甲胺盐酸盐替换为对甲氧基苯胺，制备标题化合物。淡黄色固体，收率85.8％。1H-NMR(δppm DMSO-d6)δ10.29(s,1H),10.09(s,1H),8.75(s,1H),8.61(d,J＝8.1Hz,2H),8.60(d,J＝8.8Hz,1H),8.34(d,J＝8.8Hz,1H),8.24(d,J＝8.5Hz,2H),8.05(d,J＝8.5Hz,2H),7.70(d,J＝8.8Hz,2H),7.58(d,J＝8.1Hz,2H),6.94(d,J＝8.8Hz,2H),4.36(s,1H),3.76(s,3H),3.48(s,1H),3.02(d,J＝59.0Hz,1H),2.81(s,1H),2.66(s,2H),2.43(s,1H),1.22(s,1H),0.95(d,J＝4.2Hz,3H).
实施例129：(S)-4-((6-(4-(3-甲基哌嗪-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)-N-(4-(三氟甲基)苯基)苯甲酰胺(LB-20)的制备
按照实施例121的制备方法，将原料甲胺盐酸盐替换为对三氟甲基苯胺，制备标题化合物。淡黄色固体，收率85.3％。1H-NMR(δppm DMSO-d6)δ10.66(s,1H),10.33(s,1H),8.76(s,1H),8.62(d,J＝8.6Hz,2H),8.61(d,J＝8.8Hz,1H),8.34(d,J＝8.8Hz,1H),8.28(d,J＝8.7Hz,2H),8.13(d,J＝8.7Hz,2H),8.08(d,J＝8.4Hz,2H),7.73(d,J＝8.6Hz,2H),7.58(d,J＝8.4Hz,2H),4.35(d,J＝4.5Hz,1H),3.46(s,1H),3.02(d,J＝72.1Hz,1H),2.79(s,1H),2.71–2.61(m,2H),2.43(s,1H),1.22(s,1H),0.95(d,J＝4.3Hz,3H).
实施例130：(S)-N-(4-氟苯基)-4-((6-(4-(3-甲基哌嗪-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)苯甲酰胺(LB-21)的制备
按照实施例121的制备方法，将原料甲胺盐酸盐替换为对氟苯胺，制备标题化合物。淡黄色固体，收率88.4％。1H-NMR(δppm DMSO-d6)δ10.30(s,1H),10.27(s,1H),8.75(s,2H),8.61(d,J＝6.8Hz,2H),8.60(d,J＝8.8Hz,1H),8.33(d,J＝8.8Hz,1H),8.25(d,J＝8.7Hz,2H),8.06(d,J＝8.7Hz,2H),7.81(dd,J＝9.0,5.1Hz,2H),7.57(d,J＝8.3Hz,2H),7.20(t,J＝7.8Hz,2H),4.34(s,1H),3.46(s,1H),3.01(d,J＝58.2Hz,1H),2.80(s,1H),2.65(s,2H),2.43(s,1H),1.22(s,1H),0.95(d,J＝4.3Hz,3H).
实施例131：(S)-N-(3-氯-4-氟苯基)-4-((6-(4-(3-甲基哌嗪-1-羰基)苯基)吡啶并[3,2-d]嘧啶-4-基)氨基)苯甲酰胺(LB-22)的制备
按照实施例121的制备方法，将原料甲胺盐酸盐替换为3-氯-4-氟苯胺，制备标题化合物。淡黄色固体，收率80.8％。1H-NMR(δppm DMSO-d6)δ10.40(s,1H),10.31(s,1H),8.76(s,1H),8.61(d,J＝8.3Hz,2H),8.60(d,J＝8.8Hz,1H),8.35(d,J＝8.8Hz,1H),8.27(d,J＝8.7Hz,2H),8.10(dd,J＝6.9,2.5Hz,1H),8.06(d,J＝8.7Hz,2H),7.79–7.72(m,1H),7.57(d,J＝8.2Hz,2H),7.43(t,J＝9.1Hz,1H),δ4.35(s,1H),3.46(s,1H),3.01(d,J＝62.8Hz,1H),2.80(s,1H),2.65(s,2H),2.44(s,1H),1.18(s,1H),0.95(d,J＝4.2Hz,3H).
本发明产物药理作用研究
Mnk激酶活性测试
采用上海CisBio公司的丝氨酸/苏氨酸激酶试剂盒进行Mnk激酶的活性筛选，以Staurosporine和CGP57380作为阳性对照药，Mnk蛋白购买自日本的Carna Biosciences。3μL配置好的0.33ng/μL Mnk1/2和4μL配置好的不同浓度的待测样品加入到混悬均匀的3μL反应混合液(1μM底物S1,39.2μMATP,10mM MgCl2,1mM二硫苏糖醇DTT和1×KinEASE酶缓冲液)，室温下共孵育60min。根据试剂盒说明加入由5μL SA-XL665和5μL STKAb配置的反应混合物作为检测试剂终止酶反应，随后在室温下孵育60min。采用
F500酶标仪(Tecan,Switzerland)读取在615和665nm处的HTRF信号的比值。测试样品的信号值减去空白的信号值，再比上未加药组的信号值，即得一定浓度下样品抑制酶活性的抑制率。通过抑制率并采用非线性回归计算IC50。
采用HTRF法考察目标化合物对Mnk1/2的半数抑制浓度(IC50值)，结果见表：
表1化合物A01-A13对Mnk1/2的半数抑制浓度(IC50值)
表2化合物B01-B14对Mnk1/2的半数抑制浓度(IC50值)
表3化合物C01-C20对Mnk1/2在1μM和10μM的抑制率
表4化合物D01-D39对Mnk1/2的半数抑制浓度(IC50值)
表5化合物E01-E25对Mnk1/2的半数抑制浓度(IC50值)
表6化合物LB-16-LB-21对Mnk1/2的半数抑制浓度(IC50值)
细胞抗增殖活性测试
人结肠癌HCT-116细胞以每孔2,000个细胞的密度埋入96孔测试板中，在保持5％CO2的培养箱中37℃孵育24小时使其贴壁生长，随后加入不同浓度的待测试化合物。在培养箱中孵育96小时后，每孔中加入50μL的MTT溶液(2mg/mL)，继续孵育4小时后弃去上层培养液，用200μL DMSO溶解四唑盐。96孔板在室温下轻轻震荡10分钟，然后用酶标仪测定在570nm波长下的吸光度，根据以下公式计算细胞的生长抑制率：
抑制率(％)＝[(A加药-A空白)/A对照]×100％
GI50值为抑制一半细胞生长时所加的药物浓度，根据药物浓度和抑制率结果，采用GraphPad Prism 5软件通过量效曲线计算出GI50。
人白血病MOLM-13细胞按50,000细胞每孔的密度接种到24孔板中，加入设定浓度的待测样品，在保持5％CO2的培养箱中37℃共孵育3天。结束后将细胞重悬，吸取50μL细胞液与等体积的0.4％的台盼蓝溶液轻轻混合，吸取9μL的混合液置于血球计数板上，在显微镜下对总细胞数进行计数，生长抑制率由加药组的细胞数除以未加药组的细胞数计算得来。并根据抑制率及相应的浓度用GraphPad Prism 5软件进行非线性回归计算GI50值。
表7化合物A01-A13，B01-B14对HCT-116的GI50值
表8化合物D01-D39对HCT-116，MOLM-13的GI50值
表9化合物E01-E25，LB-01-LB-22对HCT-116的GI50值
注：“-”表示未检测到酶活性和细胞活性。
上述试验结果表明，本发明要保护的通式的化合物具有良好Mnk1/2激酶抑制作用，并且在实体瘤及血液癌细胞中均表现出明显的抗增殖活性。本发明的化合物具有很好的工业应用前景。
Claims (9)
1.通式Ⅰ、Ⅱ、Ⅲ或Ⅳ所示的化合物、及其药学上可接受的盐：
其中，
式I中，
A、B、C独立选自C；
X为-NH-；X左边连接吡啶并嘧啶母核；
Y为
Y左边连接吡啶并嘧啶母核；
R1、R2、R3、R4、R5各自独立的选自：H、羟基、卤素、硝基、氨基、氰基、取代或未取代的(C1-C4)烷基、取代或未取代的(C1-C4)烷氧基，所述取代基为卤素、羟基或氨基；
或R1、R2、R4、R5各自独立的选自：H，R3选自-C(O)R9；
R9为
R10、R11独立选自氢原子、未取代的(C1-C4)烷基、未取代的3-7元饱和碳环；
R13为
R13左侧与Y相连；
R10、R11独立选自氢原子、未取代的(C1-C4)烷基、未取代的3-7元饱和碳环；
或者
R12为氢、卤素、氰基、羟基、甲基、甲氧基、三氟甲基；
式II中，
D选自C；
Y为
Y左边连接吡啶并嘧啶母核；
R10、R11独立选自氢原子、取代或未取代的(C1-C4)烷基、未取代的3-7元饱和碳环；所述取代基为羟基、氨基、(C1-C4)烷氧基；或者
R7为氢、卤素；
式III中，
R10、R11独立选自氢原子、取代或未取代的(C1-C4)烷基；所述取代基为(C1-C4)烷氧基；
或者
式IV中，
R10、R11独立选自氢原子、取代或未取代的(C1-C4)烷基、未取代的3-7元饱和碳环；所述取代基为(C1-C4)烷氧基；
或者
2.如权利要求1所述的化合物、及其药学上可接受的盐：
其中，
式I中，
式II中，
式III中，
式IV中，
3.如下的化合物、及其药学上可接受的盐：
4.权利要求1所述的通式I、Ⅱ、Ⅲ或Ⅳ所示的化合物、及其药学上可接受的盐的制备方法，其特征在于，合成路线为：
R1如权利要求1式IV中R6所述；
或
R2如权利要求1式III中R6所述；
或
R1如权利要求1式I中R1、R2、R3、R4或R5所述；
如权利要求1式I中R13所述；
或
R1如权利要求1式II化合物中R7所述；X如权利要求1式II化合物中D所述；
如式II中
所述；
或
R1如权利要求1式I化合物中R9所述；
如式I化合物中R13所述。
5.如权利要求3所述的化合物、及其药学上可接受的盐的制备方法，其特征在于，化合物C01-C20的合成方法如下：
6.一种药物组合物，其特征在于：包含权利要求1-3中任何一项的化合物、及其药学上可接受的盐以及药学上可接受的赋形剂。
7.权利要求1-3中任何一项的化合物、及其药学上可接受的盐或权利要求6所述的药物组合物在制备用于治疗和/或预防Mnk异常表达的各种癌症疾病或代谢性疾病药物中的应用。
8.如权利要求7所述的应用，其特征在于，所述的癌症为乳腺癌、肺癌、结肠癌、直肠癌、胃癌、前列腺癌、膀胱癌、子宫癌、胰腺癌、卵巢癌或白血病。
9.如权利要求7所述的应用，其特征在于，所述的代谢性疾病为糖尿病。
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| WO2024086296A1 (en) * | 2022-10-20 | 2024-04-25 | Mekanistic Therapeutics Llc | Compounds useful in modulating egfr and pi3k |
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