WO2023024545A1 - Fgfr4抑制剂、组合物及其在药物制备中的用途 - Google Patents
Fgfr4抑制剂、组合物及其在药物制备中的用途 Download PDFInfo
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Abstract
一种以3,4-二氢嘧啶[4,5-d]嘧啶-2(1H)-酮为母核且具有共价结构的FGFR4抑制剂，其中LX01、LX05、LX06、LX07、LX08等化合物只能和FGFR4中的Cys552共价结合，不能和FGFR4中的Cys477共价结合，而化合物LX09可以与FGFR4中两个半胱氨酸Cys552和Cys477进行共价结合。
Description
本发明描述的是一种化合物、制备该化合物的方法、以及使用所述化合物和组合物用以抑制酪胺酸激酶活性的方法。
成纤维细胞生长因子受体(FGFR)是一个受体酪氨酸激酶家族，包含FGFR1，FGFR2，FGFR3、FGFR4和其他18种不同FGF配体的高亲和力受体。这些配体-受体组合可调节人类组织发育过程中多种信号传导和内分泌活动。FGFR的遗传改变，包括突变、融合和基因扩增都会导致异常的信号通路激活并驱动癌细胞的生长。研究者已在多种癌症类型中检测到FGFR的遗传改变，包括乳腺癌，肝癌，鳞状非小细胞肺癌，鳞状头颈癌和胆管癌等。而以FGFR作为治疗靶标的临床验证已在膀胱癌，肝癌，肺癌，乳腺癌和胃癌中得到证实。
近年来，异常的成纤维细胞生长因子受体4(FGFR4)信号已被确定为HCC肿瘤发生和发展的主要驱动力。FGFR4是肝细胞中表达最高的同种型，其配体FGF19与共受体β-Klotho独家结合于FGFR4以调节肝细胞的增殖，FGF19蛋白过多会增加HCC细胞系的增殖和侵袭的几率。FGFR4高表达的肝癌异型移植的小鼠在抑制FGF19-FGFR4生成或使用FGFR4抗体，能有效消除了小鼠模型中的肝癌发生。临床研究表明，在所有HCC的患者中有一半患者FGFR4过表达，大部分HCC患者FGF19和FGFR4均上调，而FGF19水平与肿瘤大小和肝切除术后复发呈正相关，FGF19过表达的HCC患者比FGF19低表达的HCC患者生存时间短五年。因此，可开发FGFR4选择性抑制剂来治疗由异常FGFR4信号驱动的癌症患者。
FGFR4在癌细胞转移和耐药性方面起着非常重要的作用，具有良好抑制FGFR4效力的FGFR不可逆抑制剂将显示出广阔的应用前景。在对FGFR4的抑制具有高效力和选择性的共价抑制剂中，BLU9931、BLU-554和H3B-6527都是与FGFR4蛋白铰链区的Cys552巯基共价结合，而PRN1371、FIIN-2和TAS-120是与FGFR4蛋白p环中的Cys477共价结合，都只能和其中的一个半胱氨酸残基进行共价结合，还没有发现可以和FGFR4蛋白中的两个半胱氨酸残基同时共价结合的抑制剂。且这些不可逆抑制剂在临床试验过程中有些产生了耐药突变，如BLU-554的临床Ⅰ期试验中发现肝癌细胞的Cys552突变。本发明则是通过药物拼合、基团替换、碳链增长、结构简化等策略开发出一种可以和FGFR4蛋白中的两个半胱氨酸同时进行共价结合的FGFR4双共价抑制剂。
发明内容
本发明的目的提出一种结构优化的FGFR4抑制剂，其具有优异的抑制成纤维细胞生长因子受体4的效果。
本发明还提出一种FGFR4的抑制剂，其中含有一种可以和FGFR4蛋白中的两个半胱氨酸(Cys477和Cys552)同时进行共价结合的FGFR4双共价抑制剂。
本发明的化合物具有式I的结构：
其中，R
1指的是能够与亲核剂形成共价键的部分；R
2是芳基或杂环基团；L是-[C(R5)(R6)]q-，其中R5和R6各自独立地是H或C1-C6烷基，其中q是1-3；其中A为苯基，R
3为A苯基上的氢或甲基。
在一种具体实施方式中，R
1为丙烯酰基。
在一种具体实施方式中，L独立地为C1-C3的烷基。
在一种具体实施方式中，R
2为苯基。
在本发明的合成实施例中，合成了下述化合物：
N-(4-((7-((2-丙烯酰胺基-6-甲基苯基)氨基)-3-(3,5-二甲氧基苯基)-2-氧-3,4-二氢嘧啶[4,5-d]嘧啶-1(2H)-基)甲基)苯基)丙烯酰胺；
2-氰基-N-(4-((7-((2-(2-氰基-3-甲基-2-丁烯酰胺基)-6-甲基苯基)氨基)-3-(3,5-二甲氧基苯基)-2-氧代-3,4-二氢嘧啶[4,5-d]嘧啶-1(2H)-基)甲基)苯基)-3-甲基-2-丁烯酰胺；
N-(4-((3-(3,5-二甲氧基苯基)-7-((2-甲基-6-(乙烯磺酰胺基)苯基)氨基)-2-氧代-3,4-二氢嘧啶[4,5-d]嘧啶-1(2H)-基)甲基)苯基)乙烯磺酰胺；
2-氯-N-(4-((7-((2-(2-氯代乙酰胺基)-6-甲基苯基)氨基)-3-(3,5-二甲氧基苯基)-2-氧代-3,4-二氢嘧啶[4,5-d]嘧啶-1(2H)-基)甲基)苯基)乙酰胺；
N-(3-((7-((2-丙烯酰胺基-6-甲基苯基)氨基)-3-(3,5-二甲氧基苯基)-2-氧-3,4-二氢嘧啶[4,5-d]嘧啶-1(2H)-基)甲基)苯基)丙烯酰胺；
N-(2-((8(3-(4-丙烯酰基哌嗪-1-基)丙基)-6-(3,5-二甲氧基苯基)-7-氧代-5,6,7,8-四氢嘧啶基[4,5-d]嘧啶-2-基)氨基)-3-甲基苯基)丙烯酰胺；
N-(2-((8-(4-丙烯酰胺基苄基)-6-(3,5-二甲氧基苯基)-7-氧代-5,6,7,8-四氢嘧啶基[4,5-d]嘧啶-2-基)氨基)苯基)丙烯酰胺；
N-(2-((8-(4-丙烯酰胺基苯乙基)-6-(3,5-二甲氧基苯基)-7-氧代-5,6,7,8-四氢嘧啶基[4,5-d]嘧啶-2-基)氨基)苯基)丙烯酰胺；
N-(2-((8-(3-(4-丙烯酰基哌嗪-1-基)丙基)-6-(3,5-二甲氧基苯基)-7-氧代-5,6,7,8-四氢嘧啶基[4,5-d]嘧啶-2-基)氨基)苯基)丙烯酰胺；
根据本发明的化合物是一种高效的FGFR4特异性的共价抑制剂。
图1为化合物LX01与FGFR4的两个半胱氨酸(Cys477和Cys552)结合前后的质谱图比较；
图2为化合物LX05与FGFR4的两个半胱氨酸(Cys477和Cys552)结合前后的质谱图比较；
图3为化合物LX06与FGFR4的两个半胱氨酸(Cys477和Cys552)结合前后的质谱图比较；
图4为化合物LX07与FGFR4的两个半胱氨酸(Cys477和Cys552)结合前后的质谱图比较；
图5为化合物LX08与FGFR4的两个半胱氨酸(Cys477和Cys552)结合前后的质谱图比较；
图6为化合物LX09与FGFR4的两个半胱氨酸(Cys477和Cys552)结合前后的质谱图比较。
除非特别说明，本文单独或作为另一基团的部分所使用的术语“环烷基”包括包含1至2个环的饱和或部分不饱和(包含1或多个双键)环状烃基团，优选包括3至10个碳，例如环丙基、环丁基、环戊基、环己基、环庚基、环辛基和环癸基。“取代的环烷基”包括环烷基，其被一个或多个取代基如卤素、烷基、烷氧基、羟基、芳基、芳氧基、芳基烷基、环烷基、烷基酰氨基、烷酰基氨基、氧代、酰基、芳基羰基氨基、氨基、硝基、氰基、硫醇和/或烷基硫代和/或包括在“取代的烷基”定义中的任何取代基任选取代。
除非特别说明，本文中单独或作为另一基团的部分使用的术语“芳基”或“Ar”是指在环部分中包含6至10个碳的单环和多环芳香基团(如苯基或萘基，包括1-萘基和2-萘基)和可任选地包括稠合至碳环或杂环(如芳基、环烷基、杂芳基或环杂烷基环)上的一个至三个额外的环。
除非另有所指，本文所用的术语“杂环”或“杂环”表示未取代的或取代的稳定5-至10-元单环体系，其可为饱和或不饱和的，由碳原子和选自N、O或S的1至4个杂原子组成，且其中氮和硫杂原子可任选地被氧化，且氮杂原子 可任选地被季铵化。这种杂环基团的例子包括，哌啶基、哌嗪基、氧哌嗪基、吡咯基、吡咯烷基、呋喃基、噻吩基、吡唑基、吡唑烷基、咪唑基。
式I的化合物可作为可药用盐存在，这也在本发明的范围内。如果式I化合物具有例如至少一个碱性中心，它们可形成酸加成盐。这些例如使用强无机酸、强有机羧酸或有机磺酸形成，该强无机酸如矿物酸例如硫酸、磷酸或氢卤酸，该强有机羧酸如未取代的或取代(例如被卤素取代)的1至4个碳原子的烷烃羧酸例如乙酸、如饱和或不饱和二羧酸例如草酸、丙二酸、琥珀酸、马来酸、富马酸、邻苯二甲酸或对苯二甲酸、如羟基羧酸例如抗坏血酸、乙醇酸、乳酸、苹果酸、酒石酸或柠檬酸、如氨基酸(例如天冬氨酸或谷氨酸或赖氨酸或精氨酸)、或苯甲酸，该有机磺酸如未取代的或取代(例如被卤素取代)的(C1-C4)烷基或芳基磺酸例如甲基或对甲苯-磺酸而形成。如果需要，也可额外衍生一个碱性中心以形成相应的酸加成盐。
本发明化合物可以药物组合物的形式使用，其中包含治疗有效量的本文所限定的本发明化合物和可药用载体或稀释剂。
本发明的药物可用于治疗FGR4介导的病症，尤其是癌症。这些癌症包括肝细胞癌、膀胱癌、乳腺癌、子宫颈癌、结肠直肠癌、子宫内膜癌、胃癌、头颈部癌、肾癌、肝癌、卵巢癌、前列腺癌、食管癌、胆囊癌、胰脏癌、肺癌、间皮瘤、睾丸癌、鳞状细胞癌瘤、甲状腺癌、皮肤癌、白血病、多发性骨髓瘤、慢性淋巴细胞性淋巴瘤、成人T细胞白血病、B细胞淋巴瘤、急性骨髓性白血病、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、瓦尔登斯特伦士巨球蛋白血症、毛状细胞淋巴瘤、伯克特淋巴瘤、神经胶母细胞瘤、黑素瘤以及横纹肌肉瘤。
可以调节根据本发明的药物组合物的形式，以适于用多种给药途径向需要治疗的患者例如哺乳动物如人患者给药，例如口服给药、鼻内给药、腹膜内给药、或非消化道给药、通过静脉内、肌内、局部或皮下路径给药、或通过注射入组织给药。这种组合物和制剂应该包含至少0.01％的一种或多种本发明化合物。组合物和制剂的百分数当然可以变化和可以例如是给定单元剂型的约0.05％至约2％重量。化合物在这种治疗有用的组合物中的量使得获得有效的剂量水平。
本发明化合物可全身给药，如口服、与可药用载体如惰性稀释剂或可同化的食用载体组合、或通过吸入或吹入。它们可被包封在硬或软壳胶囊中、可被压成片剂、或可与病人食用的食品直接混合。对于口服治疗给药，本发明化合物可与一种或多种赋形剂组合和以可摄取的片剂、口含片剂、锭剂、胶囊、酏剂、悬浮液、糖浆、干胶片(wafer))等的形式使用。该化合物可与细的惰性粉状载体组合和由患者吸入或吹入。这种组合物和制剂应该包含至少0.1％的一种或多种本发明化合物。
片剂、锭剂、丸剂、胶囊等也可包含：粘合剂如西黄蓍胶、阿拉伯胶、玉米淀粉或明胶；赋形剂如磷酸二钙；崩解剂如玉米淀粉、马铃薯淀粉、藻酸等；润滑剂如硬脂酸镁；和甜味剂如蔗糖、果糖、乳糖或阿司帕坦，或可加入芳香剂如薄荷、冬青油或樱桃调味剂。当单元剂型是胶囊时，除了以上类型的材料，它还可包含液体载体如植物油或聚乙二醇。各种其它材料可存在作为涂层或以 其它方式改变固体单元剂型的外形(physical form)。例如，片剂、丸剂或胶囊可涂有明胶、蜡、虫胶、糖等。糖浆或酏剂可包含活性化合物、作为甜味剂的蔗糖或果糖、作为防腐剂的对羟基苯甲酸甲酯和对羟基苯甲酸丙酯、染料、和调味剂如樱桃或橙子调味剂。当然，用于制备任何单元剂型的任何材料在用量上应该是可药用的和实质上无毒的。另外，本发明化合物可引入持续释放制剂和设备。例如，化合物可引入延时释放(time release)胶囊、延时释放片剂和延时释放丸剂。
本发明化合物也可通过输注或注射而静脉内或腹膜内给药。化合物的溶液可在水中制备，任选地与非毒性表面活性剂混合。适用于注射或输注的药物剂型可包括无菌水溶液或分散体或无菌粉末。液体载体可以是溶剂或液体介质，包括例如水、乙醇、多元醇(例如甘油、丙二醇、液体聚乙二醇等)、植物油、非毒性甘油酯、和其合适的混合物。
对于局部给药，本发明化合物可以纯的形式使用。但是，通常期望将它们作为组合物或制剂与可以是固体或液体的皮肤学上可接受载体一起向皮肤给药。
有用的固体载体包括细分散的固体如滑石、粘土、微晶纤维素、硅石、矾土等。其它固体载体包括非毒性聚合物纳米颗粒或微颗粒。有用的液体载体包括水、醇或二醇或水/醇/二醇共混物，其中本发明化合物可在有效的水平下任选地借助于非毒性表面活性剂而溶解或分散。可加入助剂如香料和另外的抗微生物剂以针对给定用途而优化性能。所得液体组合物可由吸收剂垫施用、用于浸渍绷带和其它敷料、或使用泵-型或气溶胶喷雾器喷雾到受影响的区域上。
增稠剂如合成聚合物、脂肪酸、脂肪酸盐和酯、脂肪醇、改性的纤维素或改性的矿物材料也可与液体载体一起使用以形成可铺展的糊、凝胶、软膏、皂等，用于直接施用到使用者的皮肤上。
化合物在液体组合物如洗剂中的浓度可以是约0.1至约25％重量，或约0.5至约10％重量。在半固体或固体组合物如凝胶或粉末中的浓度可以是约0.1至约5％重量，或约0.5至约2.5％重量。
本发明化合物用于治疗所需的量不仅随着所选的特定盐变化，而且随着给药路径、正在治疗的病况的性质以及病人的年龄和病况而变化，且最终由主治医师或临床医师决定。
本发明试剂给药的有效剂量和路径是常规的。试剂的精确量(有效剂量)因患者不同而变化，取决于例如患者的种类、年龄、重量和一般或临床状态、正在治疗的任何病症的严重性或机理、所用的特定试剂或载体、给药的方法和进度等。治疗有效剂量可通过本领域技术人员已知的常规程序经验地确定。
合成实施例1共价化合物LX01的合成
步骤1：5-(羟甲基)嘧啶-2,4-二醇的合成
于100mL单口烧瓶中依次加入尿嘧啶(20.0g，178mmol)、多聚甲醛(6.50 g，72.1mmol)、氢氧化钾(6.50g，116mmol)和160mL水，在60℃下反应72h，65℃下减压抽除溶剂，残余物加入50ml丙酮，搅拌2h后过滤，干燥得26.3g目标化合物，白色固体，收率100％。mp:290℃
步骤2：2,4-二氯-5-(氯甲基)嘧啶的合成
于100mL单口烧瓶中加入5-羟甲基嘧啶-2,4-二醇(5.00g，35.2mmol)、
三氯氧磷(27.2g，177mmol)和10mL甲苯，冰浴下通过恒压滴管往单口烧瓶中缓慢滴加DIEA(14.5g，112mmol)，搅拌5min后升温至115℃反应1h，再升温至125℃反应5h，TLC监控至反应完全(乙酸乙酯:石油醚＝1:1)，冷却反应至室温，缓慢加入50mL冰水淬灭反应，甲苯(50mL×3)萃取，合并有机相，无水硫酸钠干燥，减压抽除溶剂，残余物经硅胶柱层析纯化得到5.2g目标化合物，无色油状物，收率74.9％。
1H NMR(500MHz,DMSO-d
6):δ8.97(s,1H),4.86(s,2H).
步骤3：N-((2,4二氯嘧啶)-5-甲基)-3,5-二甲氧基苯胺(1)的合成
在50mL单口烧瓶中依次加入2,4-二氯-5-(氯甲基)嘧啶(4.00g，20.3
mmol)、碘化钾(3.50g，21.0mmol)、25mL丙酮，25℃反应15min，再将反应升温至60℃反应30min，趁热过滤得母液，待母液冷却至室温加入3,5-二甲氧基苯胺(3.70g，24.2mmol)和碳酸钾(4.80g，34.5mmol)，25℃搅拌10h。TLC监控反应，反应完全后减压抽除溶剂，加入25mL乙醇，冰浴下搅拌30min，析出白色固体，过滤干燥得5.3g化合物1，白色固体，收率84.4％。
1H NMR(500MHz,CDCl
3):δ8.51(s,1H),5.92(s,1H),5.72(s,2H),4.39(s,2H),4.27(s,1H),3.72(s,6H).
步骤4：2-氯-5-(((3,5-二甲氧基苯基)氨基)甲基)-N-(4-硝基苄基)嘧啶-4-胺(2)的合成
往50mL单口烧瓶中加入化合物1(2.51g，8.00mmol)、4-硝基苄胺盐
酸盐(2.00g，10.6mmol)、DIEA(3.28g，25.4mmol)和20mL二氧六环。 60℃温度下反应10h，TLC监控反应(石油醚:乙酸乙酯:甲醇:三乙胺＝20:8:1:1)，待反应完全后直接抽除溶剂，残余物经硅胶柱层析纯化得粗品2.86g，再用少量乙酸乙酯打浆，过滤干燥后得2.4g化合物2，黄色固体，收率70.0％。
1H NMR(500MHz,CDCl
3):δ8.12(d,J＝9.0Hz,1H),7.95(s,1H),7.50(m,1H),7.46(d,J＝8.4Hz,1H),6.05(s,1H),5.98(s,2H),4.78(d,J＝6.0Hz,2H),4.26(s,2H),3.71(s,6H).
步骤5：7-氯-3-(3,5-二甲氧基苯基)-1-(4-硝基苄基)-3,4-二氢嘧啶[4,5-d]嘧啶-2(1H)-酮(3)的合成
往25mL单口烧瓶中加入化合物2(2.00g，4.65mmol)、三光气(695mg，2.31mmol)和15mL干燥的THF，冰浴下缓慢滴加三乙胺(940mg，9.32mmol)搅拌1h，再将反应升温至70℃反应10h，TLC监控至原料反应完全(石油醚:乙酸乙酯＝2:1)，加入5mL冰水淬灭反应，减压抽除溶剂THF，乙酸乙酯(20mL×3)萃取，依次用饱和碳酸氢钠、饱和NaCl洗涤，合并有机相，无水硫酸钠干燥，残余物经硅胶柱层析纯化得到1.76g化合物3，淡黄色固体，收率82.9％。
1H NMR(500MHz,DMSO-d
6):δ8.41(s,1H),8.19(d,J＝8.5Hz,2H),7.61(d,J＝8.5Hz,2H),6.61(d,J＝2.0Hz,2H),6.47(s,1H),5.25(s,2H),4.92(s,2H),3.75(s,6H).
13C NMR(125MHz,DMSO-d
6):δ160.51,158.06,157.60,154.72,151.33,146.56,145.32,143.54,128.24,123.52,111.86,104.41,98.68,55.42,46.37,43.87.
步骤6：3-(3,5-二甲氧基苯基)-7-((2-甲基-6-硝基苯基)氨基)-1-(4-硝基苄基)-3,4-二氢嘧啶[4,5-d]嘧啶-2(1H)-酮(4)的合成
依次称取化合物3(1.14g，2.5mmol)、2-甲基-6-硝基苯胺(570mg，3.75mmol)、碳酸铯(2.44g，7.50mmol)、XPhos(238mg，0.50mmol) 和Pd
2(dba)
3(
229mg，0.25mmol)于25mL Schlenk管中，再加入4mL干燥的DMA，氮气保护下110℃反应3h。TLC监控至原料反应完全(石油醚:乙酸乙酯:甲醇＝10:10:1)，乙酸乙酯(30mL×3)萃取，饱和碳酸氢钠洗涤，合并有机相，无水硫酸钠干燥，残余物经硅胶柱层析纯化得到756mg化合物4，淡黄色固体，收率52.9％。
1H NMR(500MHz,DMSO-d
6):δ9.17(s,1H),8.07(s,1H),8.01(s,2H),7.80(d,J＝7.5Hz,1H),7.62(d,J＝7.5Hz,1H),7.40(t,J＝15.5Hz,1H),7.26(s,1H),6.60(s,2H),6.45(s,1H),5.04(s,2H),4.74(s,2H),3.75(s,6H),2.18(s,3H).
步骤7：N-(4-((7-((2-丙烯酰胺基-6-甲基苯基)氨基)-3-(3,5-二甲氧基苯基)-2-氧-3,4-二氯嘧啶[4,5-d]嘧啶-1(2H)-基)甲基)苯基)丙烯酰胺(LX01)的合成
往50mL单口烧瓶中加入化合物4(500mg，0.88mmol)、2mL Raney nickel/H
2O和20mL甲醇，氢气置换三次后于25℃反应10h，TLC监控反应至原料反应完全，反应液经过硅藻土过滤得母液，减压抽除溶剂，真空干燥12h得430mg化合物5，淡黄色固体，收率96.1％。取化合物5(200mg，0.39mmol)于25mL双口瓶中，加入10mL干燥的DCM，三乙胺(87mg，0.86mmol)，氮气保护，在冰盐浴下搅拌10min，缓慢滴加丙烯酰氯(68mg，0.76mmol)的二氯甲烷(1mL)溶液，TLC监控原料至反应完全(石油醚:乙酸乙酯:甲醇＝10:10:1)，加入2mL冰水淬灭反应，乙酸乙酯(20mL×3)萃取，依次用饱和碳酸氢钠、饱和NaCl洗涤，合并有机相，无水硫酸钠干燥，减压抽除溶剂，残余物经硅胶柱层析纯化得到45mg化合物LX01，白色固体，收率18.6％。
1H NMR(500MHz,DMSO-d
6):δ10.05(s,1H),9.49(s,1H),8.28(s,1H),8.01(s,1H),7.72(s,1H),7.45(s,2H),7.22(t,J＝7.6Hz,1H),7.12(d,J＝4.3Hz,1H),6.54(d,J＝1.9Hz,2H),6.51(t,J＝6.3Hz,1H), 6.42(q,J＝4.3Hz,2H),6.23(m,J＝7.1Hz,2H),5.72(t,J＝11.8Hz,2H),4.81(s,2H),4.66(s,2H),3.74(s,6H),2.09(s,3H).
13C NMR(500MHz,MeOD-d
4):δ166.51,166.06,162.73,161.93,157.98,155.03,145.36,139.08,138.47,136.22,135.37,132.49,132.24,131.77,130.37,128.74,128.05,128.00,127.70,122.71,121.17,105.62,100.34,55.99,44.67,18.68.HRMS[M+H]+m/z calculated for C
34H
33N
7O
5,620.2577；found,620.2612.
合成实施例2共价化合物LX02的合成
步骤1：2-氰基-3-甲基-2-丁烯酸(6)的合成
往50mL单口烧瓶中加入氰乙酸(2.55g，30.0mmol)、丙酮(3.48g，60.0mmol)和25mL甲苯，50℃反应10h，TLC监控反应至原料反应完全(乙酸乙酯:石油醚＝2:1)，甲苯(20mL×3)萃取，合并有机相，无水硫酸钠干燥，减压抽除溶剂得2.25g化合物6，白色晶体，收率60.0％。
1H NMR(500MHz,CDCl
3):δ10.03(s,1H),2.43(s,3H),2.37(s,3H).
步骤2：2-氰基-N-(4-((7-((2-(2-氰基-3-甲基-2-丁烯酰胺基)-6-甲基苯基)氨基)-3-(3,5-二甲氧基苯基)-2-氧代-3,4-二氢嘧啶[4,5-d]嘧啶-1(2H)-基)甲基)苯基)-3-甲基-2-丁烯酰胺(LX02)的合成
往25mL单口烧瓶中加入6(500mg，4.0mmol)和12mL二氯亚砜，85℃反应4h，
TLC监控反应至原料反应完全(石油醚:乙酸乙酯:甲醇＝10:10:1)，减压抽除溶剂，得550mg化合物7。往25mL双口烧瓶中加入5(200mg，0.39mmol)，12mL干燥的二氯甲烷，三乙胺(87mg，0.86mmol)，氮气保护，在冰盐浴下搅拌10min，缓慢加入化合物7(108mg，0.76mmol)的二氯甲烷(1mL)溶液，TLC监控原料反应完全(石油醚:乙酸乙酯:甲醇＝10:10:1)， 加入2mL冰水淬灭反应，二氯甲烷(20mL×3)萃取，依次用饱和碳酸氢钠、饱和NaCl洗涤，
合并有机相，用无水硫酸钠干燥，减压抽除溶剂，残余物经硅胶柱层析纯化得到25mg化合物LX02，白色固体，收率8.8％。
1H NMR(500MHz,CDCl
3):δ8.75(s,1H),7.93(s,1H),7.89(d,J＝7.0Hz,2H),7.75(s,1H),7.30(t,J＝7.9Hz,1H),7.19(d,J＝7.5Hz,2H),7.12(s,1H),6.88(s,1H),6.47(d,J＝2.2Hz,2H),6.39(t,J＝2.1Hz,1H),5.05(s,2H),4.64(s,2H),3.78(s,6H),2.40(d,J＝18.4Hz,6H),2.30(d,J＝6.8Hz,6H),2.23(s,3H).
13C NMR(500MHz,CDCl
3):δ171.23,170.98,161.30,160.43,159.77,159.44,157.45,153.52,153.09,144.04,135.94,134.94,130.11,127.65,120.51,117.03,116.80,106.80,106.53,104.37,102.96,99.46,55.68,47.60,44.01,27.49,18.67.
合成实施例3共价化合物LX03的合成
步骤1：乙烯磺酰氯(8)的合成
往25mL单口烧瓶中加入2-氯乙烷磺酰氯(2.57g，15.8mmol)和10mL乙醚，在-60℃温度下缓慢滴加2,4,6-三甲基吡啶(2.30g，19.0mmol)的乙醚(5mL)溶液，反应10min后移至25℃再反应50min，冰浴下加入2mL浓度为1％的硫酸溶液淬灭反应，再用乙酸乙酯(2×20mL)萃取，饱和NaCl洗涤，合并有机相，无水硫酸钠干燥，减压抽除溶剂后得1.5g化合物8，无色油状物，收率75.2％。
步骤2：N-(4-((3-(3,5-二甲氧基苯基)-7-((2-甲基-6-(乙烯磺酰胺基)苯基)氨基)-2-氧代-3,4-二氢嘧啶[4,5-d]嘧啶-1(2H)-基)甲基)苯基)乙烯磺酰胺(LX03)的合成
往25mL双口烧瓶中加入5(200mg，0.39mmol)、三乙胺(87mg，0.86mmol)和12mL干燥的二氯甲烷，氮气保护，在冰盐浴下搅拌10min，缓慢加入化合物8(108mg，0.76mmol)的二氯甲烷(1mL)溶液，反应4h，TLC监控原料至反应完全(石油醚:乙酸乙酯:甲醇＝10:10:1)，加入5mL冰水淬灭反应，乙酸乙酯(20mL×3)萃取，依次用饱和碳酸氢钠、饱和NaCl洗涤，合并有机相，无水硫酸钠干燥，减压抽除溶剂，残余物经硅胶柱层析纯化得到56mg化合物LX03，白色固体，收率21.3％。
1H NMR(500MHz,DMSO-d
6):δ9.90(s,1H),9.02(s,1H),8.42(s,1H),8.05(s,1H),7.22(t,J＝8.9Hz, 2H),7.13(d,J＝6.8Hz,1H),6.95(s,3H),6.73(q,J＝10Hz,2H),6.57(d,J＝1.9Hz,2H),6.44(s,2H),6.09(d,J＝16.4Hz,1H),6.00(d,J＝9.9Hz,2H),5.66(s,1H),4.82(s,2H),4.69(s,2H),3.74(s,6H),2.04(s,3H).HRMS[M+H]+m/z calculated for C
32H
33N
7O
7S
2,692.1916；found,692.1954。
合成实施例4共价化合物LX04的合成
步骤1：2-氯-N-(4-((7-((2-(2-氯代乙酰胺基)-6-甲基苯基)氨基)-3-(3,5-二甲氧基苯基)-2-氧代-3,4-二氢嘧啶[4,5-d]嘧啶-1(2H)-基)甲基)苯基)乙酰胺(LX04)的合成
往25mL双口烧瓶中加入5(160mg，0.31mmol)、三乙胺(84mg，0.78mmol)和10mL干燥的二氯甲烷，氮气保护，在冰盐浴下搅拌10min，缓慢加入氯乙酰氯(70mg，0.62mmol)的二氯甲烷(1mL)溶液，TLC监控原料至反应完全(石油醚:乙酸乙酯:甲醇＝10:10:1)，加入5mL冰水淬灭反应，乙酸乙酯(20mL×3)萃取，依次用饱和碳酸氢钠、饱和NaCl洗涤，合并有机相，无水硫酸钠干燥，减压抽除溶剂，残余物经硅胶柱层析纯化得到36mg化合物LX04，白色固体，收率17.3％。
1H NMR(500MHz,DMSO-d
6):δ10.23(s,1H),9.43(s,1H),8.49(s,1H),8.04(s,1H),7.78(s,1H),7.35(q,J＝4.8Hz,2H),7.23(t,J＝7.6Hz,2H),7.12(d,J＝6.9Hz,1H),6.81(s,1H),6.54(d,J＝2.0Hz,2H),6.43(s,1H),4.67(s,2H),4.29(s,2H),4.23(s,2H),3.74(s,6H),2.54(s,2H),2.10(s,3H).HRMS[M+H]+m/z calculated for C
32H
31Cl
2N
7O
5,664.1797；found,664.1838。
合成实施例5共价化合物LX05的合成
步骤1：2-氯-5-(((3,5-二甲氧基苯基)氨基)甲基)-N-(3-硝基苄基)嘧啶-4-胺(9)的合成
往50mL单口烧瓶中加入化合物1(2.51g，8.0mmol)、3-硝基苄胺盐酸盐(2.00g，10.6mmol)、DIEA(3.28g，25.4mmol)和20mL二氧六环，60℃反应10h，TLC监控原料至反应完全(石油醚:乙酸乙酯:甲醇:三乙胺＝20:8:1:1)，抽除溶剂，残余物经硅胶柱层析纯化得2.8g化合物9，淡黄色油状物，收率51.0％。
1H NMR(500MHz,CDCl
3):δ8.11(s,1H),8.05(d,J＝8.5Hz,1H),7.88(s,1H),7.63(d,J＝7.6Hz,1H),7.46(t,J＝7.9Hz,1H),6.91(t,J＝5.9Hz,2H),5.93(s,1H),5.87(d,J＝1.8Hz,2H),4.76(d,J＝5.9Hz,2H),4.11(d,J＝5.2Hz,2H),3.89(t,J＝5.2Hz,1H),3.70(s,6H).
步骤2：7-氯-3-(3,5-二甲氧基苯基)-1-(3-硝基苄基)-3,4-二氢嘧啶[4,5-d]嘧啶-2(1H)-酮(10)的合成
往25mL单口烧瓶中加入化合物9(1.50g，3.5mmol)、三光气(517mg，2.3mmol)和15mL干燥的THF，冰浴下缓慢滴加三乙胺(940mg，7.0mmol)，搅拌1h后将反应升温至70℃反应10h，TLC监控原料至反应完全(石油醚:乙酸乙酯＝2:1)，加入5mL冰水淬灭反应，乙酸乙酯(20mL×3)萃取，依次用饱和碳酸氢钠、饱和NaCl洗涤，合并有机相，无水硫酸钠干燥，减压抽除溶剂，残余物经硅胶柱层析纯化得到1.12g化合物10，淡黄色固体，收率70.2％。
1H NMR(500MHz,CDCl
3):δ8.40(s,1H),8.17(s,1H),8.13(d,J＝7.3Hz,1H),7.88(d,J＝7.6Hz,1H),7.50(t,J＝7.9Hz,1H),6.46(d,J＝1.9Hz,2H),6.42(d,J＝1.9Hz,1H),5.36(s,2H),4.79(s,2H),3.79(s,6H).
步骤3：3-(3,5-二甲氧基苯基)-7-((2-甲基-6-硝基苯基)氨基)-1-(3-硝基苄基)-3,4-二氢嘧啶[4,5-d]嘧啶-2(1H)-酮(11)的合成
依次称取化合物10(1.00g，2.5mmol)、2-甲基-6硝基苯胺(570mg，3.8mmol)、碳酸铯(2.44g，7.5mmol)、XPhos(238mg，0.50mmol)和Pd
2(dba)
3(229mg，0.25mmol)于25mL Schlenk管中，再加入4mL无水DMA，氮气保护下110℃反应3h。TLC监控至原料反应完全(石油醚:乙酸乙酯:甲醇＝10:10:1)，乙酸乙酯(30mL×3)萃取，饱和碳酸氢钠洗涤，合并有机相，无水硫酸钠干燥，减压抽除溶剂，残余物经硅胶柱层析纯化得到756mg化合物11，淡黄色固体，收率52.9％。
1H NMR(500MHz,CDCl
3):δ8.07(d,J＝7.2Hz,2H),8.00(s,1H),7.88(d,J＝7.3Hz,1H),7.88(d,J＝7.9Hz,1H),7.61(s,1H),7.54(d,J＝7.5Hz,1H),7.50(s,1H),7.37(t,J＝8.0Hz,1H),7.32(t,J＝7.9Hz,1H),6.50(d,J＝2.1Hz,2H),6.43(t,J＝2.1Hz,1H),5.18(s,2H),4.71(s,2H),3.82(s,6H),2.31(s,3H).
步骤4：N-(3-((7-((2-丙烯酰胺基-6-甲基苯基)氨基)-3-(3,5-二甲氧基苯基)-2-氧-3,4-二氯嘧啶[4,5-d]嘧啶-1(2H)-基)甲基)苯基)丙烯酰胺(LX05)的合成
往50mL单口烧瓶中加入化合物11(500mg，0.87mmol)、2mL Raney nickel/H
2O和20mL甲醇，氢气置换三次后于25℃反应10h，TLC监控反应至原料反应完全(石油醚:乙酸乙酯:甲醇＝10:20:1)。将反应液经过硅藻土过滤得母液，减压抽除溶剂，真空干燥12h，得430mg化合物12，灰白色固体，收率96.0％。取化合物12(400mg，0.76mmol)于25mL双口瓶中，再加入三乙胺(87mg，0.86mmol)和10mL干燥的二氯甲烷，氮气保护，在冰盐浴下搅拌10min，缓慢滴加丙烯酰氯(68mg，0.76mmol)的二氯甲烷(1mL)溶液，TLC监控原料反应完全(石油醚:乙酸乙酯:甲醇＝10:10:1)，加入2mL冰水淬灭反应，再用乙酸乙酯(20mL×3)萃取，饱和碳酸氢钠洗涤，合并有 机相，无水硫酸钠干燥，减压抽除溶剂经柱层析纯化得到45mg化合物LX05，白色固体，收率18.6％。
1H NMR(500MHz,DMSO-d
6):δ8.27(s,1H),8.03(s,1H),7.70(d,J＝6.4Hz,1H),7.55(d,J＝7.7Hz,2H),7.18(t,J＝7.8Hz,1H),7.06(d,J＝7.5Hz,2H),6.58(d,J＝2.2Hz,2H),6.48(q,J＝10.2Hz,1H),6.42(q,J＝3.1Hz,2H),6.23(t,J＝1.7Hz,1H),6.20(t,J＝1.8Hz,1H),5.71(m,J＝1.7Hz,2H),4.86(s,2H),4.70(s,2H),3.74(s,6H),2.02(s,3H).HRMS[M+H]+m/z calculated for C
34H
33N
7O
5,620.2577；found,620.2618.
合成实施例6共价化合物LX06的合成
步骤1：4-(3-氨基丙基)哌嗪-1-羧酸叔丁酯(14)的合成
往50mL单口烧瓶中加入N-(3-溴丙基)苯二胺(10.00g，37.3mmol)、1-Boc-哌嗪(7.00g，37.6mmol)、碘化钾(12.40g，74.6mmol)、碳酸钾(8.88g，63.4mmol)和50mL N,N-二甲基乙酰胺，30℃反应18h，TLC监控原料反应完全(乙酸乙酯:石油醚＝1:8)，乙酸乙酯(50mL×3)萃取，依次用饱和碳酸氢钠洗涤、饱和NaCl洗涤，合并有机相，无水硫酸钠干燥，减压抽除溶剂后加入20mL乙酸乙酯打浆，过滤得12.2g中间体13，白色固体，收率87.6％。取中间体13(7.40g，19.8mmol)于50mL单口烧瓶中，加入30mL乙醇和8mL水合肼，70℃反应3h，TLC监控原料至反应完全(乙酸乙酯:石油醚＝1:5)，冷却反应液至常温，减压抽滤得母液，减压抽除溶剂，冷却后加入20mL乙醚和少量无水硫酸钠，于0℃下搅拌10min，再减压抽滤得母液，抽除溶剂得3.9g化合物14，无色油状物，收率81.2％。
1H NMR(500MHz,CDCl
3):δ3.41(t,J＝4.8Hz,4H),2.74(t,J＝6.8Hz,4H),2.38(q,J＝7.2Hz,6H),1.62(m,J＝7.0Hz,2H),1.44(s,9H).
步骤2：4-(3-((2-氯-5-(((3,5二甲氧基苯基)氨基)甲基)嘧啶-4-基)氨基)丙基)哌嗪-1-甲酸叔丁酯(15)的合成
往50mL单口烧瓶中加入化合物1(2.51g，8.00mmol)、化合物14(2.58g，10.6mmol)、DIEA(3.28g，25.4mmol)和20mL二氧六环于60℃反应10h，TLC监控反应至原料反应完全(石油醚:乙酸乙酯:甲醇:三乙胺＝16:8:1:1)，减压抽除溶剂，残余物通过柱层析纯化得3.16g化合物15，淡黄色油状物，收率76.0％。
1H NMR(500MHz,CDCl
3):δ7.89(d,J＝1.4Hz,1H),6.55(s,1H),5.97(t,J＝2.0Hz,1H),5.86(d,J＝2.1Hz,2H),4.07(d,J＝3.3Hz,2H),3.74(s,6H),3.73(s,2H),3.55(q,J＝6.1Hz,2H),3.37(s,4H),2.35(s,4H),1.45(s,2H),1.44(s,9H).
步骤3：4-(3-(7-氯-3-(3,5-二甲氧基苯基)-2-氧代-3,4-二氢嘧啶基[4,5-d]嘧啶-1(2H)-基)丙基)-1-甲酸叔丁酯(16)的合成
往25mL单口烧瓶中加入化合物15(1.50g，2.88mmol)、三光气(427
m g，1.44mmol)和15mL干燥的THF，冰浴下缓慢滴加三乙胺(58.2mg，5.76mmol)，搅拌1h后将反应升温至70℃反应10h，TLC监控反应(石油醚:乙酸乙酯＝2:1)，反应完全后冷却至0℃，加入5mL冰水淬灭反应，减压抽除溶剂，乙酸乙酯(20mL×3)萃取，饱和碳酸氢钠洗涤，合并有机相，无水硫酸钠干燥，减压抽除溶剂，残余物经硅胶柱层析纯化得到1.36g粗品，再用异丙醇/石油醚重结晶得920mg化合物16，白色固体，收率58.4％。
1H NMR(500MHz,CDCl
3):δ8.12(s,1H),6.45(d,J＝2.15Hz,2H),6.41(t,J＝2.15Hz,1H),4.74(s 2H),4.15(t,J＝7.25Hz,2H),3.79(s,6H),3.51(s,4H),2.58(s,4H),2.52(s,2H),1.99(s,2H),1.45(s,9H).
步骤4：4-(3-(3-(3,5-二甲氧基苯基)-7-((2-甲基-6-硝基苯基)氨基)-2-氧代-3,4-二氢嘧啶[4,5-d]嘧啶-1(2H)-基)丙基)哌嗪-1-甲酸叔丁酯(17)的合成
依次称取化合物16(850mg，1.55mmol)、2-甲基-6硝基苯胺(354mg，2.33mmol)、碳酸铯(1.51g，4.65mmol)、XPhos(151mg，0.31mmol)和Pd
2(dba)
3(146mg，0.16mmol)于25mL Schlenk管中，再加入3mL干燥的DMA，氮气保护下110℃反应3h。TLC监控至原料反应完全(石油醚:乙酸乙酯:甲醇＝10:10:1)，乙酸乙酯(30mL×3)萃取，依次用饱和碳酸氢钠洗涤、饱和NaCl洗涤，合并有机相，无水硫酸钠干燥，减压抽除溶剂，残余物经硅胶柱层析纯化得到620mg化合物17，淡黄色固体，收率60.4％。
步骤5：N-(2-((8(3-(4-丙烯酰基哌嗪-1-基)丙基)-6-(3,5-二甲氧基苯基)-7-氧代-5,6,7,8-四氢嘧啶基[4,5-d]嘧啶-2-基)氨基)-3-甲基苯基)丙烯酰胺(LX06)的合成
往50mL单口烧瓶中加入化合物17(600mg，0.91mmol)、1mL Raney nickel/H
2O、20mL甲醇，氢气置换三次后于25℃反应10h，TLC监控反应至原料反应完全，将反应液经过硅藻土过滤得母液，减压抽除溶剂，真空干燥12 h，得561mg化合物18，白色固体，收率97.1％。取化合物18(561mg，0.89mmol)于25mL单口瓶中，加入15mL干燥的二氯甲烷，1mL三氟乙酸，27℃搅拌过夜，TLC监控原料反应完全(石油醚:乙酸乙酯:甲醇＝10:10:1)，冰浴下将反应液加入到30mL的饱和碳酸氢钠溶液中，搅拌10min，再用二氯甲烷(20mL×3)萃取，饱和碳酸氢钠洗涤，合并有机相，无水硫酸钠干燥，减压抽除溶剂得450mg化合物19。取化合物19(200mg，0.38mmol)于25mL双口瓶中，加入10mL干燥的二氯甲烷、三乙胺(94mg，0.86mmol)，氮气保护，冰盐浴下搅拌10min，缓慢滴加丙烯酰氯(68mg，0.76mmol)的二氯甲烷(1mL)溶液，TLC监控原料反应完全，加入2mL冰水淬灭反应，乙酸乙酯(20mL×3)萃取，依次用饱和碳酸氢钠、饱和NaCl洗涤，合并有机相，无水硫酸钠干燥，减压抽除溶剂，残余物经硅胶柱层析纯化得到32mg化合物LX06，白色固体，收率13.1％。
1H NMR(500MHz,CDCl
3):δ8.32(s,1H),7.93(s,1H),7.91(s,1H),7.21(t,J＝7.8Hz,1H),7.07(d,J＝7.1Hz,1H),6.88(s,1H),6.54(q,J＝10.6Hz,1H),6.44(d,J＝2.1Hz,2H),6.37(m,J＝2.8Hz,2H),6.28(t,J＝1.7Hz,1H),6.20(q,J＝10.4Hz,1H),5.69(m,J＝8.2Hz,2H),4.61(s,2H),3.86(s,2H),3.77(s,6H),3.63(s,2H),3.51(s,2H),2.34(s,4H),2.25(s,3H),1.72(s,3H).
13C NMR(500MHz,CDCl
3):δ165.46,161.36,161.23,161.02,157.55,153.14,152.85,143.88,136.23,131.48,128.00,127.73,127.55,127.38,126.91,104.22,102.83,99.13,55.60,53.05,52.60,47.48,45.76,41.94,40.12,24.77,18.74.HRMS[M+H]+m/z calculated for C
34H
40N
8O
5,641.3155；found,641.3198.
合成实施例7共价化合物LX07的合成
步骤1：7-((2-氨基苯基)氨基)-3-(3,5-二甲氧基苯基)-1-(4-硝基苄基)-3,4-二氢嘧啶基[4,5-d]嘧啶-2(1H)-酮(20)的合成
依次称取化合物3(500mg，1.25mmol)、邻苯二胺(570mg，1.88mmol)、三氟乙酸(214mg，1.88mmol)和4mL仲丁醇于25mL Schlenk管中，氮气保护下100℃反应10h。TLC监控反应至反应完全(乙酸乙酯:石油醚:TEA＝10:10:1)，乙酸乙酯(30mL×3)萃取，饱和碳酸氢钠洗涤，合并有机相，无水硫酸钠干燥，减压抽除溶剂，残余物经硅胶柱层析纯化得到346mg 化合物20，黄色固体，收率52.5％。
1H NMR(500MHz,DMSO-d
6):δ8.49(s,1H),8.09(s,3H),7.46(d,J＝7.6Hz,2H),7.10(d,J＝7.4Hz,1H),6.89(t,J＝6.9Hz,1H),6.75(d,J＝7.0Hz,1H),6.58(s,2H),6.47(q,J＝7.0Hz,2H),5.14(s,2H),4.83(s,2H),4.73(s,2H),3.74(s,6H),3.63(s,2H),3.51(s,2H),2.34(s,4H),2.25(s,3H),1.72(s,3H).
13C NMR(500MHz,DMSO-d
6):δ160.44,160.26,155.73,153.99,152.46,146.35,146.15,144.16,142.54,128.89,125.69,125.23,124.66,123.25,116.06,115.56,104.33,101.52,98.34,55.38,46.62,43.28。
步骤2：N-(2-((8-(4-丙烯酰胺基苄基)-6-(3,5-二甲氧基苯基)-7-氧代-5,6,7,8-四氢嘧啶基[4,5-d]嘧啶-2-基)氨基)苯基)丙烯酰胺(LX07)的合成
往50mL单口烧瓶中加入化合物20(346mg，0.66mmol)、2mL Raney
nickel/H
2O和20mL甲醇，氢气置换三次后于25℃反应10h TLC监控反应至原料反应完全(乙酸乙酯:石油醚:TEA＝10:5:1)。将反应液经过硅藻土过滤得母液，减压抽除溶剂，真空干燥12h得312mg化合物21，白色固体，收率97.6％。取化合物21(312mg，0.63mmol)于25mL双口瓶中，加入三乙胺(171mg，1.57mmol)和10mL干燥的二氯甲烷，氮气保护，在冰盐浴下搅拌10min，再缓慢滴加丙烯酰氯(115mg，0.76mmol)的二氯甲烷(1mL)溶液，TLC监控原料至反应完全(石油醚:乙酸乙酯:甲醇＝10:10:1)，加入2mL冰水淬灭反应，二氯甲烷(30mL×2)萃取，依次用饱和碳酸氢钠、饱和NaCl洗涤，合并有机相，无水硫酸钠干燥，减压抽除溶剂，残余物经硅胶柱层析纯化得到56mg化合物LX07，白色固体，收率14.6％。
1H NMR(500MHz,DMSO-d
6):δ10.11(s,1H),9.88(s,1H),8.60(s,2H),8.11(s,1H),7.55(d,J＝7.6Hz,4H),7.19(d,J＝7.7Hz,2H),7.11(s,2H),6.59(s,2H),6.52(q,J＝10.3Hz,1H),6.42(q,J＝8.9Hz,2H),6.30(d,J＝17.0Hz,1H),6.24(d,J＝16.9Hz,1H),5.78(d,J＝9.9Hz,1H),6.24(d,J＝9.9Hz,1H),5.04(s,2H),4.74(s,2H),3.75(s,6H).
13C NMR(500MHz,DMSO-d
6):δ163.78,163.03,160.45,159.28,155.95,153.78,152.50,144.25, 137.71,133.13,132.37,131.90,131.50,129.96,128.16,127.25,126.81,125.17,124.57,124.44,123.67,119.19,104.32,102.81,98.38,55.40,46.53,43.03.HRMS[M+H]+m/z calculated for C
33H
31N
7O
5,606.2420；found,606.2615.
合成实施例8共价化合物LX08的合成
步骤1：2-氯-5-(((3,5-二甲氧基苯基)氨基)甲基)-N-(4-硝基苯乙基)嘧啶-4-胺(22)的合成
往50mL单口烧瓶中加入化合物1(2.00g，6.41mmol)、4-硝基苯乙胺盐酸盐(1.67g，8.32mmol)、DIEA(3.28g，25.4mmol)和20mL二氧六环，60℃温度下反应10h，TLC监控反应至原料反应完全(石油醚:乙酸乙酯:甲醇:三乙胺＝20:8:1:1)，减压抽除溶剂，残余物通过柱层析纯化得2.05g化合物22，黄色油状物，收率72.3％。
1H NMR(500MHz,CDCl
3):δ8.01(s,1H),7.99(s,1H),7.83(s,1H),7.28(s,1H),6.35(t,J＝5.3Hz,1H),5.99(t,J＝2.0Hz,1H),5.77(d,J＝2.1Hz,2H),4.00(s,2H),3.78(q,J＝6.1Hz,2H),3.74(s,6H),3.00(t,J＝6.7Hz,2H).
13C NMR(500MHz,CDCl
3):δ162.45,161.81,160.29,154.82,149.00,146.71,146.44,129.65,123.79,112.72,93.288,91.42,55.256,43.78,41.41,35.00.步骤2：7-氯-3-(3,5-二甲氧基苯基)-1-(4-硝苯乙基)-3,4-二氢嘧啶[4,5-d]嘧啶-2(1H)-酮(23)的合成
往25mL单口烧瓶中加入化合物2(1.00g，2.25mmol)、三光气(335m g，1.13mmol)和15mL干燥的THF，冰浴下缓慢滴加三乙胺(4.24g，5.76mmol)，搅拌1h后将反应升温至70℃反应10h，TLC监控反应至原料反应完全(石油醚:乙酸乙酯＝2:1)，加入5mL冰水淬灭反应，减压抽除溶剂THF，乙酸乙酯(20mL×3)萃取，依次用饱和碳酸氢钠、饱和NaCl洗涤，合并有机相，无水硫酸钠干燥，减压抽除溶剂，残余物经硅胶柱层析纯化得到812mg化合物23，淡黄色固体，收率76.9％。
1H NMR(500MHz,DMSO-d
6):δ8.35(s,1H),8.16(d,J＝7.9Hz,2H),7.53(d,J＝7.9Hz,2H),6.50(s,2H),6.44(s,1H),4.81(s,2H),4.20(t,J＝6.7Hz,2H),3.73(s,6H),3.06(t,J＝3.5Hz,2H).
13C NMR(500MHz,DMSO-d
6):δ160.44,158.17,157.60,154.48,151.17,147.27,146.16,143.58,130.24,123.45,111.71,104.16,98.61,55.37,46.09,45.35,33.17.
步骤3：7-((2-氨基苯基)氨基)-3-(3,5-二甲氧基苯基)-1-(4-硝基苯乙基)-3,4-二氢嘧啶基[4,5-d]嘧啶-2(1H)-酮(24)的合成
依次称取化合物23(469mg，1.00mmol)、邻苯二胺(162mg，1.50mmol)、三氟乙酸(171mg，1.50mmol)和3mL仲丁醇于25mL Schlenk管中，氮气保护下100℃反应10h。TLC监控反应至原料反应完全(乙酸乙酯:石油醚:TEA＝10:10:1)，乙酸乙酯(30mL×3)萃取，饱和碳酸氢钠洗涤，合并有机相，无水硫酸钠干燥，减压抽除溶剂，残余物经硅胶柱层析纯化得到302mg化合物24，黄色固体，收率55.8％。
1H NMR(500MHz,CDCl
3):δ8.07(s,1H),8.05(s,1H),7.98(s,1H),7.37(d,J＝7.8Hz,1H),7.19(t,J＝7.45Hz,1H),7.14(d,J＝7.7Hz,2H),6.94(s,2H),6.88(d,J＝5.25Hz,1H),6.84(t,J＝7.6Hz,1H),6.46(d,J＝1.95Hz,1H),6.41(s,1H),4.64(s,2H),4.10(t,J＝8.25Hz,2H),3.79(s,6H),2.99(t,J＝8.0Hz,2H).
步骤4：N-(2-((8-(4-丙烯酰胺基苯乙基)-6-(3,5-二甲氧基苯基)-7-氧代-5,6,7,8-四氢嘧啶基[4,5-d]嘧啶-2-基)氨基)苯基)丙烯酰胺(LX08)的合成
往50mL单口烧瓶中加入化合物24(200mg，0.37mmol)、1mL Raney nickel/H
2O和20mL甲醇，氢气置换三次后于25℃反应10h，TLC监控反应至原料反应完全(乙酸乙酯:石油醚:TEA＝10:10:1)。将反应液经过硅藻土过滤得母液，减压抽除溶剂，真空干燥12h得183mg化合物25，白色固体。取化合物25(180mg，0.36mmol)于25mL双口瓶中，加入10mL干燥的二氯甲烷，三乙胺(98mg，0.89mmol)，氮气保护，在冰盐浴下搅拌10min，缓慢滴加丙烯酰氯(65mg，0.72mmol)的二氯甲烷(1mL)溶液，反应2h，TLC监控原料至反应完全(石油醚:乙酸乙酯:甲醇＝10:10:1)，加入2mL冰水淬灭反应，二氯甲烷(30mL×2)萃取，依次用饱和碳酸氢钠、饱和NaCl洗涤，合并有机相，无水硫酸钠干燥，减压抽除溶剂，残余物经硅胶柱层析纯化得到36mg化合物LX08，白色固体，收率16.1％。
1H NMR(500MHz,DMSO-d
6):δ10.10(s,1H),9.94(s,1H),8.60(s,1H),8.11(s,1H),7.81(q,J＝6.5Hz,1H),7.58(d,J＝8.4Hz,3H),7.18(m,J＝7.6Hz,2H),7.05(d,J＝8.3Hz,2H),6.54(m,J＝3.9Hz,3H),6.43(m,J＝2.2Hz,2H),6.31(q,J＝17.0Hz,1H),6.25(q,J＝17.0Hz,1H),5.79(t,J＝10.9Hz,1H),5.75(q,J＝10.0Hz,1H),4.68(s,2H),3.99(t,J＝7.7Hz,2H),3.74(s,6H),2.78(t,J＝7.9Hz,2H).
13C NMR(500MHz,DMSO-d
6):δ164.29,163.45,160.86,159.99,156.57,154.14,152.63,144.68,137.74,134.41,133.01,132.41,131.95,130.56,129.52,127.74,127.17,125.77,125.11,124.17,119.80,104.62,103.37,98.83,55.84,46.90,42.87,33.51.HRMS[M+H]+m/z calculated for C
34H
33N
7O
5,620.2577；found,620.2616.
合成实施例9共价化合物LX09的合成
步骤1：4-(3-(7-((2-氨基苯基)氨基)-3-(3,5-二甲氧基苯基)-2-氧代-3,4-二氢嘧啶[4,5-d]嘧啶-1(2H)-基)丙基)哌嗪-1-甲酸叔丁酯(26)的合成
依次称取化合物16(547mg，1.00mmol)、邻苯二胺(162mg，1.50mmol)、碳酸铯(975mg，3.00mmol)、XPhos(98mg，0.20mmol)和Pd
2(dba)
3(92mg，0.10mmol)于25mL Schlenk管中，再加入3mL无水DMA，氮气保护下110℃反应3h。TLC监控原料至反应完全(乙酸乙酯:石油醚:TEA＝10:10:1)，乙酸乙酯(30mL×3)萃取，饱和碳酸氢钠洗涤，合并有机相，无水硫酸钠干燥，减压抽除溶剂，残余物经硅胶柱层析纯化得到328mg化合物26，黄色油状，收率53.1％。
1H NMR(500MHz,CDCl
3):δ7.93(d,J＝7.1Hz,1H),7.03(d,J＝6.0Hz,2H),6.80(s,2H),6.45(s,2H),6.37(s,1H),4.59(s,2H),3.97(s,2H),3.85(s,2H),3.77(s,6H),3.38(s,1H),2.32(s,6H),1.84(s,2H),1.44(s,9H).
13C NMR(500MHz,CDCl
3):δ161.07,160.677,157.15,154.77,153.16,152.96,143.94,141.37,126.48,125.83,125.68,119.14,116.98,104.05,102.27,99.01,79.60,55.99,55.50,52.84,47.41,40.07,28.45,25.06.
步骤2：N-(2-((8-(3-(4-丙烯酰基哌嗪-1-基)丙基)-6-(3,5-二甲氧基苯基)-7-氧代-5,6,7,8-四氢嘧啶基[4,5-d]嘧啶-2-基)氨基)苯基)丙烯酰胺(LX09)的合成
取化合物26(320mg，0.52mmol)于25mL单口瓶中，加入15mL干燥的二氯甲烷和1mL三氟乙酸，27℃搅拌过夜，TLC监控至原料反应完全(乙酸乙酯:石油醚:TEA＝10:5:1)，冰浴下将反应液加入到30mL饱和碳酸氢钠溶液中，搅拌10min，二氯甲烷(20mL×3)萃取，饱和碳酸氢钠洗涤，合并有机相，无水硫酸钠干燥，减压抽除溶剂得254mg化合物19。取化合物19(200mg，0.39mmol)于25mL双口瓶中，加入三乙胺(94mg，0.86mmol)和10mL干燥的二氯甲烷，氮气保护，在冰盐浴下搅拌10min，缓慢滴加丙烯酰氯(70mg，0.78mmol)的二氯甲烷(1mL)溶液，TLC监控原料反应完全(石油醚:乙酸乙酯:甲醇＝10:10:1)，加入2mL冰水淬灭反应，二氯甲烷(20mL×3)萃取，依次用饱和碳酸氢钠、饱和NaCl洗涤，合并有机相，无水硫酸钠干燥，减压抽除溶剂，残余物经硅胶柱层析纯化得到36mg化合物LX09，白色固体，收率14.7％。
1H NMR(500MHz,CDCl
3):δ8.62(s,1H),7.92(s,1H),7.63(q,J＝8.4Hz,3H),7.16(t,J＝8.2Hz,3H),6.53(q,J＝5.9Hz,1H),6.45(s,2H),6.39(t,J＝12.2Hz,2H),6.25(t,J＝9.7Hz,2H),5.69(q,J＝7.3Hz,2H),4.60(s,2H),3.97(s,2H),3.76(s,6H),3.58(s,2H),3.47(s,2H),2.34(s,4H),2.30(s,2H),1.81(s,2H).HRMS[M+H]+m/z calculated for C
34H
40N
8O
5,627.2999；found,627.3036.
化合物对FGFR激酶的抑制活性检测
采用ADP-Glo
TMKinase Assay(promega,Part No#V9101)测定化合物对FGFR1-4及FGFR4突变体的抑制活性。具体实验过程如下：
1、在白色不透光384孔板中进行激酶反应，用本实验室表达纯化的激酶(0.1μM)、ATP(10μM)、底物(50μg/ml，Part No#ab204877，abcam)以及等倍稀释的化合物，在激酶反应缓冲液(40mM Tris-HCl pH 7.5,20mM MgCl2,20mM NaCl,0.1mg/mL BSA,1mM TCEP,and 4％DMSO)中室温下孵育反应30分钟；
2、添加反应终止液ADP-Glo室温孵育40分钟，终止反应；
3、加入检测液避光室温孵育30-60分钟，使激酶反应产生的ADP转化为ATP，产生冷发光；
4、在酶标仪中测量发光值，用GraphPad Prism软件中计算化合物的IC50，其结果如下表1所示。
表1激酶活性检测结果(IC50,nM)
从激酶活性来看，这些具有双共价结构的化合物主要对FGFR4具有较强的抑制活性，而对FGFR1-3的活性较弱。对比LX01、LX02、LX03、LX04对FGFR4的激酶活性，丙烯酰胺基团在我们所选亲电基团中表现最优。尾巴R
2结构是六元环的活性比苯环减弱约3-6倍，比如LX01、LX05与LX06的IC50对比，LX08和LX09的IC50对比。对于FGFR4中的两个半胱氨酸(Cys477和Cys552)，C552A对活性的影响比C477A大，化合物LX07、LX08对C552A活性比野生型至少降低约25倍，LX09对C552A的活性降低约12倍，而LX07、LX08、LX09对C477A活性仅比野生型降低4-5倍。在这9个化合物当中，化合物LX01、LX05、LX07、LX08和LX09对FGFR4具有较高的抑制活性，具有潜在的药用前景。
化合物对FGFR高表达的细胞的增殖实验
本发明通过存活率的实验来评价化合物对依赖于FGFR信号通路的细胞增殖的抑制效果，使用CCK-8(Vazyme,Part No#A311)来测量。选用本实验构建的FGFR高表达的Ba\F3细胞，具体实验过程如下：
1、将50μL的Ba\F3细胞接种到96孔板中(约2000个/孔)，在37℃5％二氧化碳培养箱中培养过夜；
2、次日加入50μL预热的用培养基稀释的化合物，混匀后培养72小时；
3、每孔加入10μL CCK-8检测试剂，混匀后于培养箱中反应1-2小时；
4、在酶标仪中检测450nm的吸光值，用GraphPad Prism软件中计算化合物的IC50，其结果如下表2所示。
表2细胞活性检测结果(IC50,nM)
从细胞活性来看，这些化合物对Ba\F3细胞抑制效果与激酶的抑制效果一致，对FGFR4信号通路激活的Ba\F3细胞有较强的抑制增殖效果。综合激酶和细胞活性结果，本发明系列化合物对FGFR4具有非常好的选择性。
化合物与FGFR4共价结合检测
为测试根据本发明的对FGFR4具有显著抑制效果的化合物与FGFR4中的两个半胱氨酸(Cys477和Cys552)共价结合情况，采用基质辅助激光解吸/电离飞行时间质谱法(MALDI-TOF-MS)检测结合化合物前后激酶突变体FGFR4(C477A)和FGFR4(C552A)的分子量变化。具体实验过程如下：
1、将蛋白与化合物按摩尔比1：5在室温反应1h；
2、用ddH
2O稀释至1ml，用3kD的超滤管浓缩至约0.5-1mg/mL；
3、选择检测大分子量的线性正离子模式的一级质谱的方法，以芥子酸为基质(20mg/mL)，将样品与饱和基质溶液按1:1的体积比混合，放入质谱仪(AB SCIEX，5800MADI-TOF)中检测；
4、在data explorer和origin程序中处理数据，结果如图1-6所示。
从质谱结果来看，化合物LX01、LX05、LX06、LX07、LX08都只与FGFR4中的Cys552共价结合，不与FGFR4中的Cys477共价结合，而化合物LX09可以与FGFR4中两个半胱氨酸Cys552和Cys477进行共价结合。
综合激酶活性、细胞活性及质谱结果，本发明系列化合物对于FGFR4具有较好的选择性，与FGFR4单一半胱氨酸(Cys552)共价结合或者同时与FGFR4两个半胱氨酸(Cys477和Cys552)共价结合，有望开发成新一代选择性的FGFR4抑制剂，满足临床应用要求。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (18)
- 一种FGFR4抑制剂，其选自下列化合物构成的组：
- 一种药物组合物，包含治疗有效量的权利要求1所述的FGFR4抑制剂或其可药用盐，以及可药用载体。
- 一种药物组合物，包含治疗有效量的权利要求1所述的FGFR4抑制剂或其可药用盐，以及可药用稀释剂。
- 一种药物组合物，包含治疗有效量的权利要求1所述的FGFR4抑制剂或其可药用盐，以及可药用助剂。
- 如权利要求1所述的FGFR4抑制剂或其可药用盐在制造用于治疗FGFR4介导的病症的药物中的用途。
- 如权利要求5所述的用途，其中所述病症为癌症。
- 如权利要求6所述的用途，其中所述癌症选自膀胱癌、乳腺癌、子宫颈癌、结肠直肠癌、子宫内膜癌、胃癌、头颈部癌、肾癌、肝癌、卵巢癌、前列腺癌、食管癌、胆囊癌、胰脏癌、肺癌、间皮瘤、睾丸癌、鳞状细胞癌瘤、甲状腺癌、皮肤癌、白血病、B细胞淋巴瘤、神经胶母细胞瘤、黑素瘤以及横纹肌肉瘤。
- 如权利要求6所述的用途，其中所述癌症为肝细胞癌。
- 如权利要求6所述的用途，其中所述癌症为成人T细胞白血病或急性骨髓性白血病。
- 如权利要求6所述的用途，其中所述癌症为霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤。
- 如权利要求6所述的用途，其中所述癌症为多发性骨髓瘤。
- 如权利要求6所述的用途，其中所述癌症是慢性淋巴细胞性淋巴瘤。
- 如权利要求6所述的用途，其中所述癌症是瓦尔登斯特伦氏巨球蛋白血症。
- 如权利要求6所述的用途，其中所述癌症是毛状细胞淋巴瘤。
- 如权利要求6所述的用途，其中所述癌症是伯克特淋巴瘤。
- 下列任一化合物在制备用于抑制FGFR4或其突变体在患者或者生物样品中的活性的药物中的用途：
- 如权利要求16所述的用途，其中所述FGFR4或其突变体的活性被不可逆地抑制。
- 如权利要求17所述的用途，其中所述FGFR4或其突变体的活性通过共价修饰FGFR4的Cys477和Cys552被不可逆地抑制。
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