CN116496219A - 六元并五元杂环类化合物及其药物组合物和应用 - Google Patents
六元并五元杂环类化合物及其药物组合物和应用 Download PDFInfo
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Abstract
本发明公开了一种六元并五元杂环类化合物及其药物组合物和应用。该类化合物结构如下，还包含其药学上可接受的盐，可有效抑制FGFR激酶活性，尤其是对FGFR1和FGFR4激酶的抑制活性，还表现出来对单一激酶的高选择性；同时对多种肿瘤细胞增殖、FGFR‑ERK信号通路均具有显著的抑制作用。该类化合物应用广泛，可制备为抗肿瘤药物，在分子水平、细胞水平和信号通路水平均表现出显著的抑制活性，并且对正常细胞无明显毒性。
Description
技术领域
本发明涉及一种六元并五元杂环类化合物及其药物组合物和应用，尤其涉及一种可制备为抗肿瘤药物的六元并五元杂环类化合物及其药物组合物和应用。
背景技术
成纤维细胞生长因子受体(Fibroblast Growth Factor Receptor，FGFR)是蛋白酪氨酸激酶(Protein Tyrosine Kinase，PTK)家族成员之一，包含四个保守的跨膜酪氨酸激酶受体(FGFR1-4)，能够通过转移ATP的γ-磷酸基团使酪氨酸磷酸化，并参与调控细胞的增殖、分化、迁移和代谢等进程。研究表明，当FGFR与配体结合时会诱导FGFR形成二聚体，催化自身发生磷酸化并激活下游信号通路，如RAS/RAF/MAPK信号通路、PI3K/AKT信号通路、信号转导子和转录激活子(STAT)以及磷脂酶Cγ(PLCγ)。此外，由FGFR介导的信号传导通路还参与新血管生成、细胞增殖和迁移、调节器官发育、伤口愈合等生理过程。当FGFR发生突变或者过表达时，会引起FGFR信号通路的过度激活，并诱发正常细胞癌变。其中，RAS/RAF/MAPK的过度激活可刺激细胞增殖与分化；PI3K/AKT过度激活会使得细胞凋亡受抑制；STAT与促进肿瘤侵袭和转移，增强肿瘤免疫逃逸能力密切相关；PLCγ信号通路则是肿瘤细胞转移调控的重要途径。因此，FGFRs被认为是一个非常有希望的抗癌治疗靶点。
目前已获批上市的可作用于FGFR靶点的小分子抑制剂主要分为两类：一类是多靶点酪氨酸激酶抑制剂，如多韦替尼(Dovitinib)、尼达尼布(Nintedanib)和乐伐替尼(Lenvatinib)等，不过FGFR不是其主要靶点；虽然它们在临床应用中呈现出较好的疗效，但因选择性低不可避免地造成脱靶毒性和多种不良反应。另一类是FGFR抑制剂，如厄达替尼(Erdafitinib)和培米替尼(Pemigatinib)，不过它们属于泛FGFR抑制剂，对FGFR的四种亚型无明显选择性；其主要作用机制是靶向膜内酪氨酸激酶域，与FGFR蛋白非共价可逆结合，抑制FGFR的催化活性或酪氨酸自磷酸化。
发明内容
发明目的：针对现有FGFR抑制剂药物存在的选择性低、与靶点结合力弱等不足，本发明旨在提供一种具有优异的选择性抑制活性的六元并五元杂环类化合物及其药物组合物和应用。
技术方案：共价不可逆抑制剂，是指一类能够与特定靶蛋白相互作用并形成共价键，导致靶蛋白构象发生不可逆改变，从而抑制蛋白活性的一类小分子抑制剂。与非共价可逆抑制剂相比，共价不可逆抑制剂在生物活性方面具有很大优势。由于特殊的药代动力学性质，共价不可逆抑制剂的有效浓度较低、有效作用时间较长，还可以有效克服非共价可逆抑制剂耐药。目前已经证实许多重大疾病如恶性肿瘤等，均受激酶的调节，而这些酶也成为引人注目的药物作用靶点。因此，通过合理的设计、筛选和结构优化获得共价不可逆抑制剂已成为靶向药物研发的热点。鉴于临床应用的第一代非共价可逆FGFR抑制剂已经出现不同程度耐药，结合共价不可逆抑制剂的优势开发新一代FGFR抑制剂来克服第一代抑制剂的耐药和毒性是十分必要的。
本发明通过在含有不同N原子数的六元并五元杂环母体上，分别以对氨基苯甲酸、5-溴甲基-2-氟苯胺和对氨基溴苄为连接体偶联迈克尔受体，设计了一系列具有共价不可逆FGFR抑制活性的化合物。
作为本发明涉及的第一方面，本发明的六元并五元杂环类化合物具有如下结构，还包含其药学上可接受的盐，
其中：
并环环系选自/>
U、V、W、X、Y、Z选自N或CH，中最多含有2个N，/>中最多含有3个N；
L选自羰基、CH2；
M选自O、NH；
P、Q选自卤素、优选为3'、4'、5'位取代基；
R1、R2选自H、卤素；
R3选自C1-C4烷基、C1-C4卤代烷基、C3-C7环烷基、C3-C7卤代环烷基；
R4选自乙烯基、2-丙烯基、1-(2-甲基)丙烯基、C1-C4烷基、C1-C4卤代烷基、C3-C7环烷基、C3-C7卤代环烷基；
R5选自卤素、苯基、取代苯基、噻吩基、苯并噻吩基、苯并呋喃基，其中取代基选自至少一个卤素、C1-C4烷氧基、C1-C4烷基、C1-C4卤代烷基。
优选，上述六元并五元杂环类化合物具有式I至式V中的任一结构：
其中：
R1、R2选自Cl、Br；
R3选自C1-C2烷基、C1-C2卤代烷基、C3-C5环烷基、C3-C5卤代环烷基；
R4选自乙烯基、2-丙烯基、1-(2-甲基)丙烯基、C1-C3烷基、C1-C3卤代烷基、C3-C5环烷基、C3-C5卤代环烷基；
R5选自苯基、取代苯基、噻吩基、苯并噻吩基、苯并呋喃基，其中取代基选自至少一个卤素、C1-C2烷氧基、C1-C2烷基、C1-C2卤代烷基。
进一步优选，上述结构中：
R1、R2选自4位、5位、6位取代的Cl、Br；
R3选自甲基、卤代乙基、卤代环丁基；
R4选自乙烯基、2-丙烯基、1-(2-甲基)丙烯基、乙基、卤代乙基、异丙基、环丙基；
R5选自苯基、取代苯基、噻吩基、苯并噻吩基、苯并呋喃基，其中取代基选自2个卤素、C1-C2烷氧基、C1-C2烷基、C1-C2卤代烷基。
更近一步优选，上述结构中：
R3选自甲基、2,2-二氟乙基、3,3-二氟环丁基；
R4选自乙烯基、2-丙烯基、1-(2-甲基)丙烯基、乙基、2-氯乙基、1-氯乙基、异丙基、环丙基；
R5为选自苯基、取代苯基、噻吩基、苯并噻吩基、苯并呋喃基，其中取代基选自间位或/和对位取代的2个氟、甲氧基。
最优选地，上述六元并五元杂环类化合物选自以下任一化合物：
上述六元并五元杂环类化合物所述药学上可接受的盐为其与以下任一酸形成的盐：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸。
具体上述化合物的制备方法如下：
I所示化合物由4-丙烯酰胺苯甲酸与含有不同N原子数的六元并五元杂环化合物I-M1为原料，通过缩合反应得到，反应式如下：
反应条件：(i)HATU,DIPEA,DMF,0℃～R.T.,0.5h；其中，I-M1和I所示化合物结构中X、Y、Z和R1代表的原子及R1在六元并五元杂环里的位置如前定义；
制备4-丙烯酰胺苯甲酸酯及其酸的反应式如下：
反应条件：(ii)Acryloylchloride,TEA,DCM,0℃～R.T.,0.5h；(iii)TFA,DCM。
II所示化合物是以4-氟-3-硝基溴苄与含有不同N原子数的六元并五元杂环化合物II-M1为原料，通过取代反应得到中间体II-M2，然后将硝基还原得到中间体II-M3，再与丙烯酰氯发生缩合反应得到，反应式如下：
反应条件：(i)K2CO3,MeCN,80℃,12h；(ii)Fe粉,NH4Cl,EtOH/H2O,76℃,6h；(iii)Acryloylchloride,TEA,DCM,0℃～R.T.,0.5h；其中，II-M1、II-M2、II-M3和II所示化合物结构中U、V、W、X、Y、Z和R2代表的原子及R2在六元并五元杂环里的位置如前定义。
III所示化合物是以1H-苯并三氮唑-7-羧酸和脂肪醇或脂肪胺类化合物为原料，通过缩合反应得到中间体III-M1，然后与4-氟-3-硝基溴苄发生取代反应得到中间体III-M2，再将III-M2中硝基还原得到中间体III-M3，最后与丙烯酰氯发生缩合反应得到，反应式如下：
反应条件：(i)HATU,DIPEA,DMF,45℃,6h；(ii)K2CO3,MeCN,80℃,12h；(iii)Fe粉,NH4Cl,EtOH/H2O,76℃,6h；(iv)Acryloylchloride,TEA,DCM,0℃～R.T.；其中，III-M1、III-M2、III-M3和III所示化合物结构中M、R3代表的原子或基团如前定义。
IV所示化合物是以6-氯嘌呤和对硝基苄溴为原料，通过取代反应得到中间体IV-M1，将IV-M1中硝基还原得到中间体IV-M2，然后与IV-M3发生缩合反应得到，反应式如下：
反应条件：(i)K2CO3,MeCN,80℃,12h；(ii)Fe粉,NH4Cl,EtOH/H2O,76℃,6h；(iii)TEA,DCM,0℃；其中，IV-M1和IV所示化合物结构中R4代表的原子或基团如前定义。
V所示化合物是以IV-M2和含有硼酸基团的芳香类化合物V-M1为原料，通过偶联反应得到中间体V-M2，然后再与丙烯酰氯发生缩合反应得到，反应式如下：
反应条件：(i)Pd(PPh3)4,K2CO3,1,4-Dioxane,80℃,8h；(b)Acryloylchloride,TEA,DCM，0℃～R.T.,0.5h；其中，V-M1、V-M2和V所示化合物结构中R5代表的原子或基团如前定义。
制备I-V所示化合物的反应条件中，HATU代表缩合剂2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐，DIPEA代表N,N-二异丙基乙胺，TEA代表三乙胺，TFA代表三氟乙酸，DCM代表二氯甲烷，DMF代表N,N-二甲基甲酰胺，R.T.代表室温。
将相应的酸与以上方法制备的六元并五元杂环类化合物成盐，即得其药学上可接受的盐。
作为本发明涉及的第二方面，上述六元并五元杂环类化合物以及药学上可接受的载体构成本发明的药物组合物。具体通过添加药学上可接受的载体制成常见的药用制剂，如片剂、胶囊、糖浆、悬浮剂或注射剂，制剂可以加入香料、甜味剂、液体/固体填料、稀释剂等常用药用辅料。
作为本发明涉及的第三方面，上述六元并五元杂环类化合物及其药物组合物应用于制备FGFR抑制药物，优选为FGFR1、FGFR4抑制剂药物，具体为抗肿瘤药物，更具体为治疗乳腺癌、肝癌和食管癌的药物。
有益效果：与现有技术相比，本发明具有如下显著优点：
1、该类化合物及其药物组合物可有效抑制FGFR激酶活性，尤其是对FGFR1和FGFR4激酶的抑制活性，IC50值最优低于0.5μM；还表现出来对单一激酶的高选择性，最优达到40倍以上；同时对多种肿瘤细胞增殖、FGFR-ERK信号通路均具有显著的抑制作用；
2、应用广泛，可制备为抗肿瘤药物药物，在分子水平、细胞水平和信号通路水平均表现出显著的抑制活性，并且对正常细胞无明显毒性。
附图说明
图1为Westernblot分析化合物30对EGFR-ERK信号通路的影响结果。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
实施例中所用试剂均为分析纯。化合物结构表征所用的核磁数据由Bruker ARX-600核磁共振仪测定，TMS作为内标；高分辨质谱采用Agilent6224 TOF LC/MS仪测定。
实施例1：化合物1的制备
(a)4-丙烯酰胺苯甲酸叔丁基酯的制备
将5.79g(30mmol)4-氨基苯甲酸叔丁酯置于500mL的茄形瓶中，加入200mL的无水二氯甲烷，于0℃下搅拌均匀，缓慢滴加4.55g(45mmol)三乙胺和2.26g(36mmol)丙烯酰氯，然后在室温下搅拌。TLC监测至反应原料完全反应，加入适量蒸馏水淬灭反应，用二氯甲烷萃取(50mL×3)，收集有机相，用50mL饱和食盐水洗涤，无水硫酸钠干燥。有机相减压浓缩后用柱层析分离，洗脱液为石油醚-乙酸乙酯体系(PE/EA＝6/1-5/1,v/v)，最终得到白色固体(6.1g)，产率67％。1H NMR(600MHz,DMSO-d6)δ10.45(s,1H),7.87(d,J＝8.8Hz,2H),7.78(d,J＝8.8Hz,2H),6.46(dd,J＝17.0,10.1Hz,1H),6.30(dd,J＝17.0,1.8Hz,1H),5.81(dd,J＝10.1,1.8Hz,1H),1.54(s,9H)ppm.13C NMR(150MHz,DMSO-d6)δ167.15,164.15,143.53,141.02,132.95,132.03,130.80,128.30,127.76,127.08,125.40,123.93,123.48,119.38,119.10,118.65,118.17ppm.
(b)4-丙烯酰胺苯甲酸的制备
将0.65g(2.6mmol)的4-丙烯酰胺苯甲酸叔丁基酯加入到150mL的茄形瓶中，随后倒入50mL无水二氯甲烷，于室温下搅拌均匀，缓慢滴加7～8mL三氟乙酸后，室温下持续搅拌。TLC监测至原料反应完全，减压浓缩除去溶剂，用饱和碳酸氢钠溶液调节pH至碱性，随后缓慢滴加3M盐酸溶液调节至不再产生气泡，过滤，真空干燥得到白色固体(0.40g)，产率62％。1H NMR(600MHz,DMSO-d6)δ12.73(s,1H),10.43(s,1H),7.91(d,J＝8.7Hz,2H),7.78(d,J＝8.7Hz,2H),6.46(dd,J＝17.0,10.2Hz,1H),6.30(dd,J＝17.0,1.9Hz,1H),5.95-5.57(m,1H)ppm.
(c)化合物1的制备
将0.19g(1mmol)4-丙烯酰胺苯甲酸置于25mL的茄形瓶中，缓缓加入10mL DMF，45℃下搅拌均匀，将0.46g(1.2mmol)HATU加入到反应液中，45℃下搅拌10min，随后滴加0.26g(2mmol)DIPEA，在此温度下搅15min后，加入0.2g(1mmol)6-溴-1H-吲唑，氮气保护，45℃下反应6h。TLC监测至反应原料完全反应，乙酸乙酯萃取三次(20mL×3)，收集有机相，用饱和食盐水洗涤(50mL×1)，无水硫酸钠干燥，有机相减压浓缩后柱层析分离，洗脱液为石油醚-乙酸乙酯体系(PE/EA＝5/1～1/1，v/v)，最终得到白色固体(0.24g)，产率60％。1H NMR(600MHz,DMSO-d6)δ10.58(s,1H),8.59(d,J＝19.1Hz,2H),8.08(d,J＝8.7Hz,2H),7.94(d,J＝8.4Hz,1H),7.87(d,J＝8.7Hz,H),7.72-7.62(m,1H),6.50(dd,J＝17.0,10.1Hz,1H),6.38-6.30(m,1H),5.85-5.83(m,1H)ppm.13C NMR(150MHz,DMSO-d6)δ167.15,164.15,143.53,141.02,132.95,132.03,130.80,128.30,127.76,127.08,125.40,123.93,123.48,119.38,119.10,118.65,118.17ppm.HR-MS(m/z)(ESI):calcd for C17H12BrN3O2[M+H]+:370.0185；found 370.0185.
实施例2：化合物2的制备
以4-丙烯酰胺苯甲酸和5-氯-1H-吡咯并[2,3-b]吡啶为原料，参考化合物1的合成方法得到白色固体(0.24g)，产率为70％。1H NMR(600MHz,DMSO-d6)δ10.44(s,1H),8.77(dd,J＝4.4,1.4Hz,2H),8.54(dd,J＝8.4,1.4Hz,2H),7.96-7.85(m,1H),7.84-7.74(m,1H),7.52(dd,J＝8.4,4.4Hz,2H),6.46(dd,J＝16.9,10.1Hz,1H),6.30(dd,J＝17.0,1.8Hz,1H),5.81(dd,J＝10.1,1.9Hz,1H)ppm.13C NMR(150MHz,DMSO-d6)δ167.37,164.02,151.55,143.48,140.07,135.08,132.01,130.86,129.27,128.15,125.86,121.16,119.15ppm.HR-MS(m/z)(ESI):calcd for C17H12ClN3O2[M+H]+:326.0690；found:326.0688.
实施例3：化合物3的制备
以4-丙烯酰胺苯甲酸和4-氯-7H-吡咯并[2,3-d]嘧啶为原料，参考化合物1的合成方法得到白色固体(0.15g)，产率为55％。1H NMR(600MHz,DMSO-d6)δ10.59(s,1H),8.66(s,1H),8.09(d,J＝4.0Hz,1H),7.91(d,J＝8.7Hz,1H),7.84(s,2H),7.78(d,J＝8.7Hz,1H),6.96(d,J＝4.0Hz,1H),6.57-6.43(m,1H),6.40-6.19(m,1H),5.83(m,1H)ppm.13C NMR(150MHz,DMSO-d6)δ160.99,154.73,153.04,149.80,140.68,134.98,130.34,128.31,122.17,102.25,97.66ppm.HR-MS(m/z)(ESI):calcd for C16H11ClN4O2[M+H]+:327.0643；found:327.0642.
实施例4：化合物4的制备
以4-丙烯酰胺苯甲酸和1H-吡唑并[3,4-b]吡啶为原料，参考化合物1的合成方法得到白色固体(0.56g)，产率为60％。1H NMR(600MHz,DMSO-d6)δ10.55(s,1H),8.74(dd,J＝4.6,1.6Hz,1H),8.55(s,1H),8.43(dd,J＝8.0,1.6Hz,1H),7.96(d,J＝8.8Hz,2H),7.86(d,J＝8.8Hz,2H),7.50(dd,J＝8.0,4.6Hz,1H),6.49(dd,J＝17.0,10.2Hz,1H),6.34(dd,J＝17.0,1.8Hz,1H),6.02-5.66(m,1H)ppm.13C NMR(150MHz,DMSO-d6)δ165.84,164.18,152.39,150.87,143.62,138.83,132.79,132.00,131.74,128.34,127.74,120.64,118.72,118.21ppm.HR-MS(m/z)(ESI):calcd for C16H12N4O2[M+H]+:293.1033；found:293.1032.
实施例5：化合物5的制备
以4-丙烯酰胺苯甲酸和5-溴-7-氮杂吲哚吡啶为原料，参考化合物1的合成方法得到白色固体(0.70g)，产率为60％。1H NMR(600MHz,DMSO-d6)δ10.54(s,1H),8.37(d,J＝2.3Hz,1H),8.31(d,J＝2.2Hz,1H),7.94(d,J＝4.0Hz,1H),7.85-7.80(m,2H),7.79-7.72(m,2H),6.80(d,J＝4.0Hz,1H),6.49(dd,J＝17.0,10.2Hz,1H),6.33(dd,J＝17.0,1.8Hz,1H),5.84(dd,J＝10.1,1.8Hz,1H)ppm.13C NMR(150MHz,DMSO-d6)δ166.72,164.13,146.58,144.35,143.99,132.23,132.14,131.98,130.21,128.37,127.98,124.99,118.83,114.70,105.36ppm.HR-MS(m/z)(ESI):calcd for C17H12BrN3O2[M+H]+:370.0186；found 370.0183.
实施例6：化合物6的制备
(a)中间体II-M2的合成
将0.98g(5mmol)6-溴吲哚和1.38g(10mmol)无水碳酸钾置于250mL的茄形瓶中，加入150mL无水乙腈，80℃下回流搅拌30min，加入1.17g(5mmol)4-氟-3-硝基溴苄，回流反应12h。TLC监测至反应原料完全反应，然后用乙酸乙酯萃取三次(50mL×3)，收集有机相，用饱和食盐水洗涤(50mL×1)，无水硫酸钠干燥，有机相减压浓缩后柱层析分离，洗脱液为石油醚-乙酸乙酯体系(PE/EA＝15/1，v/v)，最终得到黄色固体(0.96g)，产率为55％。1H NMR(600MHz,DMSO-d6)δ8.86(s,1H),8.80(s,1H),8.28(dd,J＝7.1,2.3Hz,1H),7.83(ddd,J＝8.6,4.2,2.4Hz,1H),7.59(dd,J＝11.2,8.7Hz,1H),5.64(s,2H)ppm.
(b)中间体II-M3的合成
将0.56g(10mmol)铁粉和1.07g(20mmol)氯化铵置于100mL的茄形瓶中，加入20mL乙醇和蒸馏水的混合溶液，体积比EtOH/H2O＝5/1，在76℃下反应30min，加入0.70g(2mmol)II-M2到茄形瓶中，在76℃下搅拌6h。TLC监测至反应原料完全反应。趁热用硅藻土过滤，滤液减压浓缩后柱层析分离，洗脱液为石油醚-乙酸乙酯体系(PE/EA＝5/1，v/v)，得到灰色固体(0.45g)，产率为70％。1H NMR(600MHz,DMSO-d6)δ8.79(s,2H),6.94(s,1H),6.65(s,1H),6.51(s,1H),5.38(s,2H),5.17(s,2H)ppm.
(c)化合物6的合成
以中间体II-M3和丙烯酰氯为原料，参考实施例1中4-丙烯酰胺苯甲酸叔丁基酯的合成方法，得到最终产物，白色固体(0.48g)，产率为61％。1H NMR(600MHz,DMSO-d6)δ9.91(s,1H),7.87(d,J＝5.9Hz,1H),7.71(s,1H),7.54-7.49(m,2H),7.25-7.20(m,1H),7.14(d,J＝8.2Hz,1H),6.97(s,1H),6.57(dd,J＝16.9,10.4Hz,1H),6.52(d,J＝2.7Hz,1H),6.24(d,J＝17.0Hz,1H),5.75(d,J＝10.1Hz,1H),5.42(s,2H)ppm.13C NMR(150MHz,DMSO-d6)δ163.90,137.04,δ134.61(d,J＝3.2Hz),131.69,130.53,127.93,127.77,126.56,126.52(d,J＝12.1Hz),124.43(d,J＝7.8Hz),122.69,122.54,116.12,115.99,114.62,113.30,101.99,48.93ppm.HR-MS(m/z)(ESI):calcd for C18H14BrFN2O[M+H]+:332.0708；found:332.0706.
实施例7：化合物7的制备
以6-溴吲唑和4-氟-3-硝基溴苄为原料，先后参考实施例6中II-M2和II-M3及实施例1中4-丙烯酰胺苯甲酸叔丁基酯的合成方法，得到第一步中间体产物，黄色固体(1.00g)，产率为27％。1H NMR(600MHz,DMSO-d6)δ8.68(s,1H),8.25(dd,J＝7.2,2.3Hz,1H),8.19(d,J＝8.3Hz,1H),7.84-7.75(m,1H),7.60(dd,J＝11.3,8.7Hz,1H),7.38(d,J＝8.3Hz,1H),5.60(s,2H)ppm；第二步中间体产物，灰色固体(0.93g)，产率为40％。1H NMR(600MHz,DMSO-d6)δ8.58(s,1H),8.17(d,J＝8.2Hz,1H),7.36(d,J＝8.3Hz,1H),7.09-6.85(m,1H),6.61(d,J＝8.4Hz,1H),6.46(s,1H),5.32(s,2H),5.18(s,2H)ppm；最终产物，白色固体(0.46g)，产率30％。1H NMR(600MHz,DMSO-d6)δ9.90(s,1H),8.15(d,J＝0.8Hz,1H),8.09(s,1H),7.91(d,J＝6.4Hz,1H),7.74(d,J＝8.5Hz,1H),7.27(dd,J＝8.5,1.5Hz,1H),7.22(dd,J＝10.8,8.5Hz,1H),7.06-7.02(m,1H),6.56(dd,J＝17.0,10.2Hz,1H),6.24(dd,J＝17.0,1.9Hz,1H),5.75(dd,J＝10.2,1.8Hz,1H),5.64(s,2H)ppm.13C NMR(150MHz,DMSO-d6)δ163.88,140.55,134.25,δ133.93(d,J＝3.3Hz),131.69,127.93,126.48(d,J＝11.9Hz),124.93(d,J＝7.7Hz),124.26,123.62,123.25,123.13,120.41,116.08,115.94,112.98,51.60ppm.HR-MS(m/z)(ESI):calcd for C17H13BrFN3O[M+H]+:374.0304；found:374.0302.
实施例8：化合物8的制备
以4-氯-7-氮杂吲哚和4-氟-3-硝基溴苄为原料，先后参考实施例6中II-M2和II-M3及实施例1中4-丙烯酰胺苯甲酸叔丁基酯的合成方法，得到第一步中间体产物，黄色固体(2.10g)，产率为56％。1H NMR(600MHz,DMSO-d6)δ8.21-8.04(m,1H),7.89(d,J＝7.0Hz,1H),7.77-7.71(m,1H),7.58(dd,J＝11.2,8.7Hz,1H),7.39-7.07(m,2H),6.64(t,J＝5.8Hz,1H),5.23(s,2H)ppm；第二步中间体产物，黄色固体(1.30g)，产率为90％。1H NMR(600MHz,DMSO-d6)δ7.87(d,J＝7.0Hz,1H),7.21(d,J＝5.0Hz,2H),6.92(dd,J＝11.4,8.3Hz,1H),6.67(d,J＝7.3Hz,1H),6.62(t,J＝6.1Hz,1H),6.50-6.40(m,1H),5.15(s,2H),4.93(s,2H)ppm；最终产物，白色固体(0.73g)，产率为50％。1H NMR(600MHz,DMSO-d6)δ9.94(s,1H),7.96(d,J＝6.5Hz,1H),7.88(d,J＝7.1Hz,1H),7.28-7.24(m,1H),7.24-7.19(m,2H),7.14-7.09(m,1H),6.63(ddd,J＝8.4,5.0,2.5Hz,1H),6.61-6.55(m,1H),6.26(dd,J＝17.0,1.9Hz,1H),5.77(dd,J＝10.2,1.9Hz,1H),5.08(s,2H)ppm.13C NMR(150MHz,DMSO-d6)δ163.87,148.08,143.85,134.88,δ134.64(d,J＝3.4Hz),131.67,130.77,127.97,126.45(d,J＝12.0Hz),124.81(d,J＝7.5Hz),123.47,119.32,116.24,116.12,115.99,98.23,47.54ppm.HR-MS(m/z)(ESI):calcd for C17H13ClFN3O[M+H]+:330.0804；found:330.0802.
实施例9：化合物9的制备
以5-溴-7-氮杂吲哚和4-氟-3-硝基溴苄为原料，先后参考实施例6中II-M2和II-M3及实施例1中4-丙烯酰胺苯甲酸叔丁基酯的合成方法，得到第一步中间体产物，黄色固体(3.70g)，产率为90％。1H NMR(600MHz,DMSO-d6)δ8.25(d,J＝5.1Hz,1H),8.13(dd,J＝7.2,2.2Hz,1H),7.85(d,J＝3.6Hz,1H),7.67(ddd,J＝8.6,4.3,2.3Hz,1H),7.54(dd,J＝11.3,8.7Hz,1H),7.28(d,J＝5.1Hz,1H),6.62(d,J＝3.6Hz,1H),5.60(s,2H)ppm；第二步中间体产物，灰色固体(1.33g)，产率为75％。1H NMR(600MHz,DMSO-d6)δ8.24(s,1H),7.70(s,1H),7.25(s,1H),6.90(s,1H),6.57(s,2H),6.41(s,1H),5.35(s,2H),5.12(s,2H)ppm；最终产物，白色固体(0.68g)，产率为45％。1H NMR(600MHz,DMSO-d6)δ9.91(s,1H),8.24(d,J＝5.1Hz,1H),7.92(d,J＝6.3Hz,1H),7.77(d,J＝3.5Hz,1H),7.26(d,J＝5.1Hz,1H),7.21(dd,J＝10.8,8.5Hz,1H),7.12-6.96(m,1H),6.59(d,J＝3.5Hz,1H),6.58-6.52(m,1H),6.24(dd,J＝17.0,1.9Hz,1H),5.75(dd,J＝10.2,1.9Hz,1H),5.48(s,2H)ppm.13C NMR(150MHz,DMSO-d6)δ163.88,145.88,143.08,134.68(d,J＝3.4Hz),131.69,131.44,131.12,127.93,126.46(d,J＝12.1Hz),124.76(d,J＝7.7Hz),123.45,122.34,116.10,115.96,111.57,99.95,47.29ppm.HR-MS(m/z)(ESI):calcd for C17H13BrFN3O[M+H]+:374.0299；found:374.0299.
实施例10：化合物10的制备
以1H-吡唑并[3,4-c]吡啶和4-氟-3-硝基溴苄为原料，先后参考实施例6中II-M2和II-M3及实施例1中4-丙烯酰胺苯甲酸叔丁基酯的合成方法，得到第一步中间体产物，黄色固体(2.47g)，产率为57％。1H NMR(600MHz,DMSO-d6)δ8.34(s,1H),8.30-8.18(m,1H),8.09(dd,J＝7.2,2.2Hz,1H),7.78(d,J＝3.5Hz,1H),7.65(ddd,J＝8.6,4.2,2.3Hz,1H),7.59-7.44(m,1H),6.55(d,J＝3.5Hz,1H),5.57(s,2H)ppm；第二步中间体产物，白色固体(1.23g)，产率为88％。1H NMR(600MHz,DMSO-d6)δ8.32(s,1H),8.23(s,1H),7.67-7.57(m,1H),6.98-6.78(m,1H),6.57(d,J＝7.8Hz,1H),6.50(s,1H),6.39(s,1H),5.30(s,2H),5.09(s,2H)ppm；最终产物，白色固体(0.62g)，产率为50％。1H NMR(600MHz,DMSO-d6)δ9.90(s,1H),8.32(d,J＝2.2Hz,1H),8.24(d,J＝2.2Hz,1H),7.90(d,J＝6.6Hz,1H),7.70(d,J＝3.5Hz,1H),7.20(dd,J＝10.8,8.5Hz,1H),7.05-7.00(m,1H),6.56(dd,J＝17.1,10.3Hz,1H),6.52(d,J＝3.5Hz,1H),6.24(dd,J＝17.0,1.9Hz,1H),5.75(dd,J＝10.2,1.9Hz,1H),5.45(s,2H)ppm.13C NMR(150MHz,DMSO-d6)δ163.87,150.14,149.45,δ134.10(d,J＝3.3Hz),133.20,131.69,131.12,127.94,126.46(d,J＝12.0Hz),125.03(d,J＝7.7Hz),123.61,117.63,116.06,115.92,115.59,49.82ppm.HR-MS(m/z)(ESI):calcd forC16H13FN4O[M+H]+:297.1146；found:297.1160.
实施例11：化合物11的制备
以5-氯-3H-咪唑[4,5-b]吡啶和4-氟-3-硝基溴苄为原料，先后参考实施例6中II-M2和II-M3及实施例1中4-丙烯酰胺苯甲酸叔丁基酯的合成方法，得到第一步中间体产物，黄色固体(2.4g)，产率为50％。1H NMR(600MHz,DMSO-d6)δ8.06(dd,J＝7.1,1.9Hz,1H),7.83(s,1H),7.61-7.58(m,H),7.57-7.54(m,1H),7.53(d,J＝8.3Hz,1H),7.16(dd,J＝8.4,1.5Hz,1H),6.56(d,J＝3.1Hz,1H),5.54(s,2H)ppm；第二步中间体产物，白色固体(0.50g)，产率为71％。1H NMR(600MHz,DMSO-d6)δ7.65(s,1H),7.51(d,J＝8.4Hz,1H),7.45(d,J＝3.1Hz,1H),7.13(dd,J＝8.4,1.7Hz,1H),6.91(dd,J＝11.5,8.3Hz,1H),6.53(dd,J＝8.7,2.0Hz,1H),6.50(d,J＝3.1Hz,1H),6.35(ddd,J＝8.0,4.2,2.2Hz,1H),5.26(s,2H),5.12(s,2H)ppm；最终产物，白色固体(0.45g)，产率为70％。1H NMR(600MHz,DMSO-d6)δ9.96(s,1H),8.64(s,1H),8.18(d,J＝8.3Hz,1H),7.98(d,J＝6.1Hz,1H),7.37(d,J＝8.3Hz,1H),7.27(dd,J＝10.8,8.5Hz,1H),7.14-7.10(m,1H),6.58(dd,J＝17.0,10.2Hz,1H),6.25(dd,J＝17.0,1.9Hz,1H),5.77(dd,J＝10.2,1.9Hz,1H),5.47(s,2H)ppm.13C NMR(150MHz,DMSO-d6)δ163.93,146.52,146.47,144.83,134.48,δ133.30(d,J＝3.2Hz),131.65,131.10,128.04,126.66(d,J＝12.1Hz),124.95(d,J＝7.3Hz),123.48,118.75,116.33,116.20,46.28ppm.HR-MS(m/z)(ESI):calcd for C16H12ClFN4O[M+H]+:331.0756；found:331.0757.
实施例12：化合物12的制备
以4-氯吡咯并[2,3-D]嘧啶和4-氟-3-硝基溴苄为原料，先后参考实施例6中II-M2和II-M3及实施例1中4-丙烯酰胺苯甲酸叔丁基酯的合成方法，得到第一步中间体产物，黄色固体(2.12g)，产率为60％。1H NMR(600MHz,DMSO-d6)δ8.61(s,1H),8.31(d,J＝7.0Hz,1H),8.27(s,1H),8.15-8.04(m,1H),7.67(s,1H),7.55(t,J＝9.6Hz,1H),7.29(s,1H),5.82(s,2H)ppm；第二步中间体产物，灰色固体(0.56g)，产率为70％。1H NMR(600MHz,DMSO-d6)δ8.58(d,J＝3.5Hz,1H),8.27(d,J＝7.8Hz,1H),8.19(s,1H),7.24(dd,J＝7.6,4.4Hz,1H),6.94-6.79(m,1H),6.64(d,J＝8.2Hz,1H),6.43(s,1H),5.51(s,2H),5.13(s,2H)ppm；最终产物，白色固体(0.57g)，产率为70％。1H NMR(600MHz,DMSO-d6)δ9.94(s,1H),8.65(s,1H),8.20(d,J＝3.2Hz,1H),7.82(d,J＝6.5Hz,1H),7.24(dd,J＝10.8,8.6Hz,1H),6.86(d,J＝3.2Hz,2H),6.58(dd,J＝17.0,10.2Hz,1H),6.24(dd,J＝17.0,1.9Hz,1H),5.77(dd,J＝10.1,1.9Hz,1H),5.76(s,2H)ppm.13C NMR(150MHz,DMSO-d6)δ163.91,152.69,149.93,141.73,139.82,δ134.82(d,J＝3.2Hz),131.66,128.03,126.73(d,J＝12.0Hz),123.45(d,J＝7.7Hz),123.35,122.08,116.29,116.16,102.74,51.12ppm.HR-MS(m/z)(ESI):calcdfor C16H12ClFN4O[M+H]+:331.0756；found:331.0761.
实施例13：化合物13的制备
以4-氯-7H-吡咯并[2,3-d]嘧啶和4-氟-3-硝基溴苄为原料，先后参考实施例6中II-M2和II-M3及实施例1中4-丙烯酰胺苯甲酸叔丁基酯的合成方法，得到第一步中间体产物，黄色固体(2.35g)，产率为53％。1H NMR(600MHz,DMSO-d6)δ8.21(d,J＝3.9Hz,2H),8.11(dd,J＝7.2,2.2Hz,1H),7.81-7.72(m,1H),7.67(ddd,J＝8.6,4.2,2.3Hz,1H),7.55(dd,J＝11.2,8.7Hz,1H),7.30(d,J＝8.5Hz,1H),5.78(s,2H)ppm；第二步中间体产物，白色固体(0.91g)，产率为87％。1H NMR(600MHz,DMSO-d6)δ8.12(s,1H),8.00(s,1H),7.73(d,J＝8.5Hz,1H),7.26(d,J＝8.4Hz,1H),6.90(dd,J＝11.2,8.4Hz,1H),6.58(d,J＝8.0Hz,1H),6.50-6.35(m,1H),5.49(s,2H),5.12(s,2H)ppm；最终产物，白色固体(0.65g)，产率为62％。1H NMR(600MHz,DMSO-d6)δ9.92(s,1H),8.67(s,1H),7.96(d,J＝6.1Hz,1H),7.86(d,J＝3.6Hz,1H),7.23(dd,J＝10.8,8.5Hz,1H),7.08(ddd,J＝8.3,4.6,2.3Hz,1H),6.70(d,J＝3.6Hz,1H),6.57(dd,J＝17.0,10.2Hz,1H),6.25(dd,J＝17.0,1.9Hz,1H),5.76(dd,J＝10.2,1.9Hz,1H),5.50(s,2H)ppm.13C NMR(150MHz,DMSO-d6)δ163.91,151.23,150.99,δ133.82(d,J＝3.3Hz),131.87,131.33,130.42,128.00,126.60(d,J＝12.0Hz),124.95(d,J＝7.9Hz),123.55,117.24,116.24,116.11,99.42,47.75ppm.HR-MS(m/z)(ESI):calcd forC16H12ClFN4O[M+H]+:331.0756；found:331.0744.
实施例14：化合物14的制备
以6-氯-9H-嘌呤和4-氟-3-硝基溴苄为原料，先后参考实施例6中II-M2和II-M3及实施例1中4-丙烯酰胺苯甲酸叔丁基酯的合成方法，得到第一步中间体产物，黄色固体(2.10g)，产率为56％。1H NMR(600MHz,DMSO-d6)δ8.83-8.59(m,1H),8.18(dd,J＝7.2,2.2Hz,1H),7.93(d,J＝3.6Hz,1H),7.72(ddd,J＝8.6,4.2,2.3Hz,1H),7.56(t,J＝9.9Hz,1H),6.73(dd,J＝3.5,1.7Hz,1H),5.63(s,2H)ppm；第二步中间体产物，黄色固体(1.30g)，产率为90％。1H NMR(600MHz,DMSO-d6)δ8.66(s,1H),7.78(s,1H),7.05-6.82(m,1H),6.69(s,1H),6.57(d,J＝7.3Hz,1H),6.43(s,1H),5.35(s,2H),5.14(s,2H)ppm；最终产物，白色固体(0.61g)，产率为40％。1H NMR(600MHz,DMSO-d6)δ9.95(s,1H),8.84(s,1H),8.80(s,1H),8.03(d,J＝6.0Hz,1H),7.26(dd,J＝10.8,8.5Hz,1H),7.20-7.15(m,1H),6.58(dd,J＝17.0,10.2Hz,1H),6.25(dd,J＝17.0,1.9Hz,1H),5.76(dd,J＝10.2,1.9Hz,1H),5.52(s,2H)ppm.13C NMR(150MHz,DMSO-d6)δ163.95,152.23,149.65,147.88,132.67(d,J＝3.4Hz),131.65,131.31,130.43,128.05,126.68(d,J＝12.1Hz),125.29(d,J＝7.7Hz),123.83,116.37,116.24,46.98ppm.HR-MS(m/z)(ESI):calcd for C15H11ClFN5O[M+H]+:332.0709；found 332.0706.
实施例15：化合物15的制备
以2-氯-9H-嘌呤和4-氟-3-硝基溴苄为原料，先后参考实施例6中II-M2和II-M3及实施例1中4-丙烯酰胺苯甲酸叔丁基酯的合成方法，得到第一步中间体产物，黄色固体(1.35g)，产率为62％。1H NMR(600MHz,DMSO-d6)δ9.13(s,1H),8.79(s,1H),8.27(dd,J＝7.1,2.3Hz,1H),7.90-7.69(m,1H),7.61(dd,J＝11.3,8.7Hz,1H),5.60(s,2H)ppm；第二步中间体产物，灰色固体(0.22g)，产率为70％。1H NMR(600MHz,DMSO-d6)δ9.12(s,1H),8.73(s,1H),6.95(dd,J＝11.5,8.3Hz,1H),6.62(dd,J＝8.6,2.1Hz,1H),6.48(ddd,J＝8.0,4.1,2.2Hz,1H),5.33(s,2H),5.20(s,2H)ppm；最终产物，白色固体(0.14g)，产率为62％。1HNMR(600MHz,DMSO-d6)δ9.98(s,1H),9.13(s,1H),8.78(s,1H),8.01(d,J＝5.9Hz,1H),7.28(dd,J＝10.8,8.5Hz,1H),7.19-7.10(m,1H),6.59(dd,J＝17.0,10.2Hz,1H),6.25(dd,J＝17.0,1.9Hz,1H),5.77(dd,J＝10.1,1.8Hz,1H),5.48(s,2H)ppm.13C NMR(150MHz,DMSO-d6)δ163.95,153.44,150.53,148.56,133.51,δ132.59(d,J＝3.3Hz),131.65,131.33,128.07,126.73(d,J＝12.1Hz),125.14(d,J＝7.8Hz),123.64,116.43,116.29,46.43ppm.HR-MS(m/z)(ESI):calcd for C15H11ClFN5O[M+H]+:332.0709；found:332.0714.
实施例16：化合物16的制备
以1H-苯[d]并[1,2,3]三唑-4-羧酸甲酯和4-氟-3-硝基溴苄为原料，先后参考实施例6中II-M2和II-M3及实施例1中4-丙烯酰胺苯甲酸叔丁基酯的合成方法，得到第一步中间体产物，黄色固体(0.96g)，产率为44％。1H NMR(600MHz,DMSO-d6)δ8.69(dd,J＝1.3,0.8Hz,1H),8.27(dd,J＝7.2,2.2Hz,1H),8.20(dd,J＝8.7,0.8Hz,1H),7.97(dd,J＝8.7,1.4Hz,1H),7.79(ddd,J＝8.6,4.2,2.4Hz,1H),7.59(dd,J＝11.3,8.7Hz,1H),6.22(s,2H),3.93(s,3H)ppm；第二步中间体产物，黄色固体(0.65g)，产率为78％。1H NMR(600MHz,DMSO-d6)δ8.56(d,J＝103.5Hz,1H),8.13(dd,J＝52.0,7.6Hz,1H),7.99-7.75(m,1H),6.95(s,1H),6.74-6.48(m,2H),5.91(d,J＝45.4Hz,2H),5.20(s,2H),3.91(s,3H)ppm；最终产物，黄色固体(0.36g)，产率为45％。1H NMR(600MHz,DMSO-d6)δ9.95(s,1H),8.62(d,J＝50.3Hz,1H),8.20-8.09(m,1H),8.08-8.03(m,1H),8.02-7.94(m,1H),7.30-7.25(m,1H),7.18(ddd,J＝10.6,7.5,2.1Hz,1H),6.58(dd,J＝17.0,10.2Hz,1H),6.25(dd,J＝17.0,1.0Hz,1H),6.10(s,1H),6.03(s,1H),5.76(dd,J＝10.2,1.6Hz,1H),3.91(d,J＝4.5Hz,3H)ppm.13C NMR(150MHz,DMSO-d6)δ166.31,163.94,147.73,145.46,135.42,132.95,δ132.37(d,J＝3.4Hz),131.63,129.11,128.08(d,J＝4.1Hz),126.81(d,J＝10.8Hz),124.75,122.03,120.08,113.61,111.65,53.04,50.98ppm.HR-MS(m/z)(ESI):calcd for C18H15FN4O3[M+H]+:355.1201；found:355.1208.
实施例17：化合物17的制备
(a)中间体III-M1的合成
以1H-苯并三氮唑-7-羧酸和2,2-二氟乙胺为原料，参考化合物1的合成方法，得到第一步中间体产物(III-M1)，黄色固体(3.17g)，产率为65％。1H NMR(600MHz,DMSO-d6)δ15.99(s,1H),9.04(s,1H),8.57(s,1H),7.97(s,2H),6.16(tt,J＝56.0,4.1Hz,1H),3.73(tdd,J＝15.6,5.7,4.2Hz,2H)ppm；
(b)化合物17的合成
以III-M1为原料，先后参考实施例6中II-M2和II-M3及实施例1中4-丙烯酰胺苯甲酸叔丁基酯的合成方法，得到第二步中间体产物(III-M2)，黄色固体(1.28g)，产率为60％。1H NMR(600MHz,DMSO-d6)δ9.04(t,J＝5.8Hz,1H),8.58-8.39(m,1H),8.31(dd,J＝7.2,2.2Hz,1H),8.03(dd,J＝9.0,0.8Hz,1H),7.92(dd,J＝9.0,1.5Hz,1H),7.88(ddd,J＝8.6,4.2,2.3Hz,1H),7.63(dd,J＝11.3,8.7Hz,1H),6.32-6.03(m,3H),3.81-3.64(m,2H)ppm；第三步中间体产物(III-M3)，黄色固体(0.19g)，产率95％。1H NMR(600MHz,DMSO-d6)δ9.03(s,1H),8.49(s,1H),8.01(d,J＝8.8Hz,1H),7.90(d,J＝8.8Hz,1H),7.06-6.89(m,1H),6.76(d,J＝8.1Hz,1H),6.57(s,1H),6.15(t,J＝56.0Hz,1H),5.84(s,2H),5.22(s,2H),3.72(t,J＝14.9Hz,2H)ppm；最终产物，白色固体(0.14g)，产率为58％。1H NMR(600MHz,DMSO-d6)δ9.97(s,1H),9.03(s,1H),8.50(s,1H),8.12(d,J＝6.5Hz,1H),8.02(d,J＝8.9Hz,1H),7.91(d,J＝8.7Hz,1H),7.32-7.27(m,1H),7.24(s,1H),6.59(dd,J＝16.8,10.2Hz,1H),6.25(d,J＝16.6Hz,1H),6.11(d,J＝56.0Hz,1H),6.02(s,2H),5.77(d,J＝10.1Hz,1H),3.76-3.68(m,2H)ppm.13C NMR(150MHz,DMSO-d6)δ166.99,163.98,145.57,143.79,132.41,131.64,128.08,δ126.74(d,J＝11.9Hz),125.98(d,J＝11.5Hz),124.37(d,J＝1.6Hz),118.44(d,J＝11.7Hz),116.59,116.33,116.20,115.00,113.40,59.73,42.24(t,J＝26.5Hz)ppm.HR-MS(m/z)(ESI):calcd for C19H16F3N5O2[M+H]+:404.1328；found:404.1327.
实施例18：化合物18的制备
以1H-苯[d]并[1,2,3]三唑-7-羧酸和3,3-二氟环丁胺为原料，参考实施例17中III-M1的合成方法得到第一步中间体产物，灰色固体(2.82g)，产率为69％。1H NMR(600MHz,DMSO-d6)δ15.97(s,1H),9.00(d,J＝6.4Hz,1H),8.49(s,1H),7.95(s,2H),4.83-4.02(m,1H),3.06-2.91(m,2H),2.85-2.67(m,2H)ppm。再先后参考实施例6中II-M2和II-M3及实施例1中4-丙烯酰胺苯甲酸叔丁基酯的合成方法，得到第二步中间体产物，黄色固体(1.58g)，产率为54％。1H NMR(600MHz,DMSO-d6)δ8.99(d,J＝6.5Hz,1H),8.49(s,1H),8.30(dd,J＝7.2,2.2Hz,1H),8.02(dd,J＝9.0,0.8Hz,1H),7.92-7.88(m,1H),7.87(dq,J＝6.5,2.1Hz,1H),7.63(dd,J＝11.3,8.7Hz,1H),6.18(s,2H),4.30(dt,J＝14.9,6.8Hz,1H),3.04-2.90(m,2H),2.84-2.65(m,2H)ppm；第三步中间体产物，黄色固体(0.18g)，产率为90％。1H NMR(600MHz,DMSO-d6)δ8.96(s,1H),8.44(s,1H),7.92(d,J＝61.9Hz,2H),7.19-6.33(m,3H),5.84(s,2H),5.22(s,2H),4.31(s,1H),2.99(s,2H),2.79(s,2H)ppm；最终产物，白色固体(0.11g)，产率为51％。1H NMR(600MHz,DMSO-d6)δ9.97(s,1H),8.98(d,J＝6.5Hz,1H),8.64-8.37(m,1H),8.12(d,J＝5.9Hz,1H),8.06-7.97(m,1H),7.88(dd,J＝9.0,1.5Hz,1H),7.29(dd,J＝10.7,8.5Hz,1H),7.26-7.20(m,1H),6.59(dd,J＝17.0,10.2Hz,1H),6.25(dd,J＝17.0,1.9Hz,1H),6.01(s,2H),5.77(dd,J＝10.2,1.9Hz,1H),4.30(s,1H),3.04-2.92(m,2H),2.82-2.75(m,2H)ppm.13C NMR(150MHz,DMSO-d6)δ166.37,163.99,145.53,143.81,132.80,δ131.67(d,J＝3.7Hz),128.05,126.74(d,J＝12.0Hz),125.96(d,J＝9.4Hz),124.36,121.83,120.06,118.38,118.22,116.31,116.17,59.72,42.50(dd,J＝23.0,21.6Hz),42.35,35.05(d,J＝5.6Hz),34.92(d,J＝5.6Hz)ppm.HR-MS(m/z)(ESI):calcd for C21H18F3N5O2[M+H]+:430.1485；found:430.1499.
实施例19：化合物19的制备
(a)中间体IV-M1的合成
以6-氯-9H-嘌呤和对硝基溴化苄为原料，参考实施例6中II-M2的合成方法得到黄色固体(3.90g)，产率为52％。1H NMR(600MHz,DMSO-d6)δ8.88(s,1H),8.79(s,1H),8.20(d,J＝8.7Hz,2H),7.58(d,J＝8.8Hz,2H),5.71(s,2H)ppm.
(b)中间体IV-M2的合成
以中间体IV-M1为原料，参考实施例6中II-M3的合成方法得到黄色固体(1.42g)，产率为57％。1H NMR(600MHz,DMSO-d6)δ8.80(s,1H),8.76(s,1H),7.09(d,J＝8.4Hz,2H),6.50(d,J＝8.5Hz,2H),5.30(s,2H),5.14(s,2H)ppm.
(c)化合物19的合成
以中间体IV-M2和丙烯酰氯为原料，参考实施例6中化合物6的合成方法，得到最终产物，黄色固体(0.70g)，产率为41％。1H NMR(600MHz,DMSO-d6)δ10.25(s,1H),8.82(d,J＝22.5Hz,2H),7.64(d,J＝8.5Hz,2H),7.34(d,J＝8.5Hz,2H),6.43(dd,J＝17.0,10.2Hz,1H),6.24(dd,J＝17.0,1.8Hz,1H),5.74(dd,J＝10.2,1.8Hz,1H),5.49(s,2H)ppm.13C NMR(150MHz,DMSO-d6)δ163.63,152.29,152.26,149.58,147.89,139.32,132.24,131.37,131.31,128.84,127.44,120.00,47.17ppm.HR-MS(m/z)(ESI):calcd for C15H12ClN5O[M+H]+:314.0803；found:314.0808.
实施例20：化合物20的制备
以实施例19中IV-M2和甲基丙烯酰氯为原料，参考实施例6中化合物6的合成方法，得到白色固体(0.31g)，产率为56％。1H NMR(600MHz,DMSO-d6)δ9.85(s,1H),8.84(s,1H),8.80(s,1H),7.65(d,J＝8.6Hz,2H),7.33(d,J＝8.6Hz,2H),5.79(s,1H),5.53-5.50(m,1H),5.48(s,2H),1.92(dd,J＝1.6,1.2Hz,3H)ppm.13C NMR(150MHz,DMSO-d6)δ167.24,152.24,152.15,149.56,147.91,140.67,139.36,131.30,131.29,128.60,120.82,120.62,47.19,19.19ppm.HR-MS(m/z)(ESI):calcd for C16H14ClN5O[M+H]+:328.0959；found:328.0966.
实施例21：化合物21的制备
以实施例19中IV-M2和3-甲基巴豆酰氯为原料，参考实施例6中化合物6的合成方法，得到白色固体(0.18g)，产率为51％。1H NMR(600MHz,DMSO-d6)δ9.86(s,1H),8.83(s,1H),8.80(s,1H),7.58(d,J＝8.3Hz,2H),7.31(d,J＝8.3Hz,2H),5.83(s,1H),5.46(s,2H),2.13(s,3H),1.85(s,3H)ppm.13C NMR(150MHz,DMSO-d6)δ165.04,152.23,152.16,152.01,149.57,147.86,139.84,131.30,130.69,128.78,119.63,119.49,47.21,27.50,19.95ppm.HR-MS(m/z)(ESI):calcd for C17H16ClN5O[M+H]+:342.1116；found:342.1119.
实施例22：化合物22的制备
以实施例19中IV-M2和丙酰氯为原料，参考实施例6中化合物6的合成方法，得到白色固体(0.35g)，产率为61％。1H NMR(600MHz,DMSO-d6)δ9.89(s,1H),8.82(s,1H),8.80(s,1H),7.55(d,J＝8.5Hz,2H),7.30(d,J＝8.6Hz,2H),5.46(s,2H),2.29(q,J＝7.5Hz,2H),1.05(t,J＝7.5Hz,3H)ppm.13C NMR(150MHz,DMSO-d6)δ172.47,152.23,152.16,149.57,147.87,139.66,131.30,130.72,128.77,119.62,47.18,29.91,10.07ppm.HR-MS(m/z)(ESI):calcd for C15H14ClN5O[M+H]+:316.0959；found:316.0968.
实施例23：化合物23的制备
以实施例19中IV-M2和氯乙酰氯为原料，参考实施例6中化合物6的合成方法，得到白色固体(0.22g)，产率为61％。1H NMR(600MHz,DMSO-d6)δ10.69(s,1H),8.85(s,1H),8.79(s,1H),7.60(d,J＝8.6Hz,2H),7.35(d,J＝8.6Hz,2H),5.49(s,2H),4.28(s,2H)ppm.13CNMR(150MHz,DMSO-d6)δ165.19,152.24,152.16,149.56,147.91,138.87,131.67,131.30,128.88,120.00,47.15,43.94ppm.HR-MS(m/z)(ESI):calcd for C14H11Cl2N5O[M+H]+:336.0413；found:336.0409.
实施例24：化合物24的制备
以实施例19中IV-M2和2-氯丙酰氯为原料，参考实施例6中化合物6的合成方法，得到白色固体(0.34g)，产率为72％。1H NMR(600MHz,DMSO-d6)δ10.36(s,1H),8.81(d,J＝19.7Hz,2H),7.57(d,J＝8.3Hz,2H),7.35(d,J＝8.3Hz,2H),5.49(s,2H),4.93-4.30(m,1H),1.59(d,J＝6.5Hz,3H)ppm.13C NMR(150MHz,DMSO-d6)δ167.77,152.25,152.17,149.58,147.88,138.74,131.80,131.31,128.91,120.11,55.1847.14,21.43ppm.HR-MS(m/z)(ESI):calcd for:C15H13Cl2N5O[M+H]+:3,50.0569；found:350.0584.
实施例25：化合物25的制备
以实施例19中IV-M2和异丁酰氯为原料，参考实施例6中化合物6的合成方法，得到白色固体(0.32g)，产率为58％。1H NMR(600MHz,DMSO-d6)δ9.87(s,1H),8.82(s,1H),8.80(s,1H),7.60-7.54(m,2H),7.31(d,J＝8.5Hz,2H),5.46(s,2H),2.60-2.52(m,1H),1.07(d,J＝6.8Hz,6H)ppm.13C NMR(150MHz,DMSO-d6)δ175.71,152.22,152.15,149.56,147.85,139.75,131.30,130.74,128.77,119.74,47.20,35.33,19.92ppm.HR-MS(m/z)(ESI):calcdfor C16H16ClN5O[M+H]+:330.11161；found:330.11251.
实施例26：化合物26的制备
以实施例19中IV-M2和环丙基甲酰氯为原料，参考实施例6中化合物6的合成方法，得到白色固体(0.25g)，产率为63％。1H NMR(600MHz,DMSO-d6)δ10.23(s,1H),8.82(s,1H),8.80(s,1H),7.55(d,J＝8.5Hz,2H),7.31(d,J＝8.6Hz,2H),5.47(s,2H),1.85-1.65(m,1H),0.90-0.57(m,4H)ppm.13C NMR(150MHz,DMSO-d6)δ172.12,152.23,152.16,149.57,147.87,139.63,131.30,130.74,128.80,119.60,47.17,14.96,7.67ppm.HR-MS(m/z)(ESI):calcd for:C16H14ClN5O[M+H]+:328.0959；found 328.0971.
实施例27：化合物27的制备
将0.10g(0.39mmol)IV-M2(参见实施例19)和0.11g(0.77mmol)碳酸钾于150mL的双颈圆底烧瓶中，加入30mL(v1/v2＝3/1)1,4-二氧六环和水的混合溶剂，然后加入0.044g(0.039mmol)四三苯基磷钯，抽真空并且氮气保护，再将溶于少量1,4-二氧六环的0.064g(0.5mmol)噻吩-2-苯硼酸注入反应瓶，在80℃下反应8h。TLC监测至原料完全反应，用硅藻土过滤，滤液减压浓缩除去溶剂，柱层析分离得到灰色中间体V-M2。以V-M2和丙烯酰氯为原料，参考实施例6中化合物6的合成方法，得到白色固体(0.058g)，产率为61％。1H NMR(600MHz,DMSO-d6)δ10.39(s,1H),8.96(s,1H),8.90(s,1H),8.74(d,J＝3.6Hz,1H),8.02(d,J＝5.0Hz,1H),7.76(d,J＝8.4Hz,2H),7.49-7.39(m,3H),6.54(dd,J＝16.9,10.2Hz,1H),6.34(dd,J＝17.0,1.6Hz,1H),5.84(dd,J＝10.2,1.6Hz,1H),5.59(s,2H)ppm.13C NMR(150MHz,DMSO-d6)δ163.61,152.52,152.22,148.92,147.05,140.20,139.23,132.84,132.25,132.12,131.82,129.53,128.79,128.55,127.42,119.99,46.65ppm.HR-MS(m/z)(ESI):calcd for:C19H15N5OS[M+H]+:362.1070；found:362.1070.
实施例28：化合物28的制备
以中间体IV-M2(参见实施例19)和苯硼酸为原料，先后参考实施例27中V-M2和实施例6中化合物6的合成方法得到白色固体(0.061g)，产率为55％。1H NMR(600MHz,DMSO-d6)δ10.24(s,1H),9.01(s,1H),8.88-8.78(m,2H),7.68-7.54(m,6H),7.37(d,J＝8.5Hz,2H),6.42(dd,J＝17.0,10.2Hz,1H),6.24(dd,J＝17.0,1.9Hz,1H),5.74(dd,J＝10.2,1.9Hz,1H),5.51(s,2H)ppm.13C NMR(150MHz,DMSO-d6)δ163.60,153.12,152.78,152.43,146.95,139.22,135.85,132.24,131.98,131.91,131.85,131.53,130.80,129.82,129.26,129.19,129.14,128.83,127.43,120.01,46.64ppm.HR-MS(m/z)(ESI):calcd for:C21H17N5O[M+H]+:356.1505；found:356.1500.
实施例29：化合物29的制备
以中间体IV-M2(参见实施例19)和3,4-二氟苯硼酸为原料，先后参考实施例27中V-M2和实施例6中化合物6的合成方法得到黄色固体(0.062g)，产率为53％。1H NMR(600MHz,DMSO-d6)δ10.23(s,1H),9.02(s,1H),8.87(s,1H),8.86-8.80(m,1H),8.79-8.74(m,1H),7.70(dt,J＝10.4,8.6Hz,1H),7.64(d,J＝8.6Hz,2H),7.37(d,J＝8.7Hz,2H),6.42(dd,J＝17.0,10.2Hz,1H),6.24(dd,J＝17.1,1.8Hz,1H),5.79-5.69(m,1H),5.51(s,2H)ppm.13C NMR(150MHz,DMSO-d6)δ163.60,152.93,152.54,152.39,150.50,147.50,139.23,δ133.38(dd,J＝5.8,3.4Hz),132.21,131.72,130.67,128.84,127.47,127.09(dd,J＝6.5,3.4Hz),120.00,118.60,118.49,118.35,46.72ppm.HR-MS(m/z)(ESI):calcd for:C21H15F2N5O[M+H]+:392.1317；found:392.1323.
实施例30：化合物30的制备
以中间体IV-M2(参见实施例19)和3,4-二甲氧基苯硼酸为原料，先后参考实施例27中V-M2和实施例6中化合物6的合成方法得到灰色固体(0.31g)，产率为60％。1HNMR(600MHz,DMSO-d6)δ10.18(s,1H),9.00(s,1H),8.82(s,1H),8.09(d,J＝2.3Hz,2H),7.64(d,J＝8.6Hz,2H),7.36(d,J＝8.6Hz,2H),6.72(t,J＝2.3Hz,1H),6.40(dd,J＝17.0,10.2Hz,1H),6.24(dd,J＝16.8,1.8Hz,1H),5.74(dd,J＝10.1,2.0Hz,1H),5.50(s,2H),3.85(s,6H)ppm.13C NMR(150MHz,DMSO-d6)δ163.59,161.01,152.84,152.59,152.27,147.06,139.18,137.68,132.19,131.84,130.86,128.82,127.49,120.00,107.68,103.57,55.85,46.65ppm.HR-MS(m/z)(ESI):calcd for:C23H21N5O3[M+H]+:416.1717；found:416.1735.
实施例31：化合物31的制备
以中间体IV-M2(参见实施例19)和苯并呋喃-2-硼酸为原料，先后参考实施例27中V-M2和实施例6中化合物6的合成方法得到白色固体(0.060g)，产率为58％。1H NMR(600MHz,DMSO-d6)δ10.22(s,1H),9.01(s,1H),8.88(s,1H),8.35(s,1H),7.88(d,J＝7.7Hz,1H),7.78(d,J＝8.3Hz,1H),7.65(d,J＝8.6Hz,2H),7.56-7.47(m,1H),7.42-7.35(m,3H),6.42(dd,J＝17.0,10.2Hz,1H),6.24(dd,J＝17.0,1.9Hz,1H),5.74(dd,J＝10.2,1.9Hz,1H),5.52(s,2H)ppm.13C NMR(150MHz,DMSO-d6)δ163.60,155.39,152.56,152.32,151.08,147.62,145.01,139.23,132.21,131.76,129.51,128.86,128.43,127.49,127.41,124.19,123.16,120.01,113.72,112.28,46.71ppm.HR-MS(m/z)(ESI):calcd for:C23H17N5O2[M+H]+:396.1455；found:396.1450.
实施例32：化合物32的制备
以中间体IV-M2(参见实施例19)和苯并噻吩-2-硼酸为原料，先后参考实施例27中V-M2和实施例6中化合物6的合成方法得到黄色固体(0.050g)，产率为69％。1H NMR(600MHz,DMSO-d6)δ10.21(s,1H),9.03(s,1H),8.96(s,1H),8.88(s,1H),8.14-8.02(m,2H),7.65(d,J＝8.6Hz,2H),7.47(p,J＝8.1,7.5Hz,2H),7.38(d,J＝8.6Hz,2H),6.41(dd,J＝17.0,10.2Hz,1H),6.24(dd,J＝17.0,1.9Hz,1H),5.82-5.68(m,1H),5.52(s,2H)ppm.13CNMR(150MHz,DMSO-d6)δ163.60,152.57,152.31,148.83,147.59,140.93,140.55,140.41,139.23,132.22,131.91,131.77,129.99,129.49,129.19,128.83,127.47,126.93,125.80,125.46,123.25,120.01,46.74ppm.HR-MS(m/z)(ESI):calcd for:C23H17N5OS[M+H]+:412.1226；found:412.1225.
实施例33：化合物的酶活性
1、实验方法：选用上海抚生实业有限公司提供的商业化FGFR1和FGFR4激酶(人源)ELISA检测/抑制剂筛选分析试剂盒测试本发明所得代表性化合物对FGFR1和FGFR4的抑制能力，以已知的FGFR抑制剂AZD4547和SSR128129E为阳性对照。
2、实验步骤：从试剂盒中取出96孔板，放入37℃细胞培养箱中解冻，之后将96孔板划分为三块区域，分别为待测组、阳性对照组和空白组。在96孔板各孔板中加入50μL 60U/L的FGFR1和FGFR4酶反应液，在待测组和阳性对照组各孔板中分别加入5个浓度梯度(500、250、50、10和5nM)的新鲜待测化合物溶液和AZD4547和SSR128129E溶液，空白组各孔中只需加入等体积的DMSO溶剂。密封后放入37℃孵箱中孵育2h。结束后除空白组外，其余组各孔中分别加入50.0μL FGFR1或者FGFR4酶连物，继续孵育30min，之后在各孔中分别加入50μL显色剂A和50μL显色剂B，轻轻震荡摇匀后，在37℃下避光孵10min，结束后在各孔中再加入50.0μL终止液，室温下孵育10min，终止反应，此时蓝色立即转为黄色。最后以空白孔调零，并在酶标仪450nm波长下测定吸光度值(OD值)，每个化合物平行三次独立实验，结果取三次实验平均值±SD值，利用SPSS 16.0软件计算各个化合物对FGFR1和FGFR4的半抑制浓度(IC50)。
3、实验结果
表1.化合物对FGFR酶的抑制能力和对细胞的抗增殖活性
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如表1所示，阳性药物AZD4547和SSR128129E对外源性FGFR1酶的IC50值分别为0.95μM和0.66μM。本发明所得的代表性化合物对外源性FGFR1酶的IC50值小于0.66μM的有11个，分别为1、6、7、9、11、14、19、29、30、31和32，其中化合物7的抑制活性最强，分别是AZD4547和SSR128129E活性的5.3倍和3.7倍。AZD4547和SSR128129E对FGFR4酶的抑制活性相对较弱，IC50值分别为11.48μM和1.64μM。所得化合物对FGFR4酶的IC50值小于1μM的有11个，分别是4、6、8、11、14、17、19、20、24、29和30，其中化合物4的抑制活性最高，分别是AZD4547、SSR128129E活性的35.9倍和5.1倍。由构效关系分析可知，当对氨基苯甲酸为连接体时，所得化合物(1-5)中仅有1和4对FGFR1和FGFR4具有较好的抑制活性，特别是化合物4表现出对FGFR不同亚型的高选择性，其对FGFR1的抑制活性仅为14.74μM，而对FGFR4的抑制活性为0.32μM，两者相差46倍。当以4-氟-3-硝基溴苄为连接体时，所得化合物(6-18)对FGFR1的抑制活性普遍较高，其中IC50值小于0.5μM的有5个，分别是化合物6、7、9、11和16，其中以6-溴吲哚为母体的化合物对FGFR1的抑制活性最好，IC50值为0.18μM；以6-氯嘌呤为母体的化合物对FGFR1和FGFR4亚型没有表现出明显的选择性，不过抑制活性较高，其IC50值分别为0.58μM和0.73μM；当用2-氯嘌呤为母体时所得化合物对FGFR1的抑制活性一般，IC50值为6.42μM。基于此，选用6-氯嘌呤为母体，以对氨基溴苄为连接体，使用不同的迈克尔受体与短链脂肪酸作用得到化合物19-28。相比于化合物14，选用对氨基溴苄为连接体得到的化合物19，对FGFR1和FGFR4的抑制活性均有提升。当将迈克尔受体丙烯酰胺改为甲基丙烯酰胺或3-甲基巴豆酰胺时，化合物对FGFR的抑制活性没有提升；当选用脂肪链酰胺如丙酰胺、氯乙酰胺、2-氯乙酰胺等取代丙酰胺时，除了化合物24外，其它化合物对FGFR的抑制活性都未能有效提高。以丙烯酰胺作为迈克尔受体，采用6-氯嘌呤为母体和对氨基溴苄为连接体，选用2-噻吩硼酸、苯硼酸、3,4-二氟苯硼酸和3,5-二甲氧基苯硼酸等含有硼酸基团的芳香族化合物对母体结构进行修饰得到化合物27-32。发现3,4-二氟苯硼酸和3,5-二甲氧基苯硼酸修饰6-氯嘌呤母核得到的化合物29和30可以有效提高其对FGFR1和FGFR4的抑制活性，其中化合物30的抑制活最佳，其对FGFR1和FGFR4的IC50值分别为0.20μM和0.40μM。
实施例34：化合物的体外抗增殖活性
1、实验方法
选用食管鳞癌细胞(KYSE-150)、乳腺癌细胞(MDA-MB-435)、肝癌细胞(HepG2)、三阴性乳腺癌细胞(MDA-MB-231)和人脐静脉内皮细胞(HUVEC)评价化合物的抗增殖活性，观察化合物在不同浓度下对不同细胞生长的抑制情况，计算抑制率和IC50值，以AZD4547和SSR128129E作为阳性对照。
2、实验步骤
(1)化合物的配置：用DMSO作为溶剂将所有化合物配置成2mol/L的溶液，之后再用培养基将其梯度稀释，稀释液中的DMSO的体积含量须小于0.4％。
(2)细胞培养：将细胞培养在培养基(含有10％胎牛血清、100μg/mL链霉素和100μg/mL氨苄青霉素钠的DMEM)中。在细胞传代时，首先把旧的培养基弃去，用PBS缓慢冲洗两遍(5.0mL×2)，加入3.0mL不含有EDTA的0.25％的蛋白胰酶消化液消化细胞，待消化结束后，加入一定量的血清使其停止消化。将细胞溶液转移到15mL离心管中，1500r/min离心5min，弃去上清，加入适量的培养基将其吹散成单个细胞悬浮液，并将单细胞悬浮液分装到新的细胞培养瓶中，并补足培养基。将细胞培养瓶放在37℃，含95％空气和5％ CO2的细胞培养箱中孵育，待细胞形态稳定后再进行各种细胞实验。
(3)细胞毒性测定：将上述单一细胞悬浮液，接种在96孔板中，每个孔中的细胞密度大约为1×104，放置于细胞培养箱中培养过夜，弃去旧培养基，加入150.0μL含有不同浓度目标化合物的新鲜培养基。放入细胞培养箱继续孵育72h。孵育结束后弃去旧培养基，加入10.0μL浓度为5mg/mL的MTT溶液，继续放入培养箱中孵育4h，弃去每个孔中MTT溶液，加入100.0μL DMSO轻轻摇晃使其溶解，使用酶标仪测定其在490nm处的吸光度值，使用SPSS18软件作出浓度-抑制率曲线，计算IC50值。
3、实验结果
IC50值是以三次独立实验的平均值±SD表示，结果见表1。
所得化合物对癌细胞的抗增殖活性数据如表1所示，阳性药物AZD4547和SSR128129E对四种癌细胞仅显示中等的细胞毒活性，只有AZD4547对HepG2细胞表现出较强抑制能力，其IC50值为3.128μM。化合物中有部分化合物对癌细胞的抗增殖活性与酶抑制活性成正相关，如化合物1对FGFR1的抑制活性较高，对KYSE-150和MDA-MB-435细胞也呈现较好的抑制活性；化合物19对两种FGFR酶具有强抑制能力，对四种癌细胞也表现出强的抗增殖活性，特别是对KYSE-150、HepG2和MDA-MB-231细胞的IC50值均小于3μM，优于阳性药物。化合物30对FGFR1和FGFR4的抑制能力最强，其对KYSE-150和MDA-MB-231细胞也表现出强抑制活性，IC50值分别为1.965μM和1.893μM，分别是AZD4547活性的4.5倍和3.8倍。值得注意的是，所得化合物对正常细胞HUVEC的毒性较小。
实施例35：Western blot分析化合物的对FGFR-ERK信号通路的影响
1、实验方法
(1)蛋白提取：在6孔板的每个孔中加入2.0mL浓度为1×105cell/mL的MDA-MB-231的细胞悬浮液，随后将其放在37℃的细胞培养箱中培养12h。然后向每个孔中加入20.0μL浓度为5.0μM的AZD4547和不同浓度的化合物30(2.5、5.0和10.0μM)以及相同体积的DMSO，继续放在细胞培养箱中培养24h。培养结束后，用15mL的离心管将细胞收集，以1500r/min离心5min，倒掉上清液后，用2.0mL PBS缓慢淋洗两次。随后将离心管放置于碎冰上，加入80μL的细胞裂解液进行裂解30min，裂解完成后，将其转到2mL的离心管中，并在冷冻离心机上15000r/min离心15min，将其上清液置于-20℃冰箱中保存。
(2)蛋白的定量与制样：首先在多模微板分光光度计上测定蛋白质的含量，随后在蛋白中加入Loading Buffer，在100℃下存放15min。
(3)凝胶的制备和上样：在事先配置好的分离胶中加入TEME并使之均匀，随后将其转入到电泳仪的凹凸玻璃板中，立即用水密封。随后将其中的水去除，加入6％的浓缩胶，插入槽齿。待胶完全凝固后，缓慢地将槽齿拔掉，并在凝胶的槽齿中加入10μL用SDS稀释的上述样品，使用Marker作为参考。调节电泳池的电压，观察到Marker完全分开且LoadingBuffer跑到最下方时停止跑胶。
(4)转膜：用甲醇浸湿PVDF膜后，将其和滤纸一齐在转膜液中浸泡。将上述凝胶中的目标蛋白部分在转膜液里完全浸泡片刻，之后和PVDF一起放在半干转膜仪上，在350mA电流下处理1h。结束后将PVDF膜放在5％的脱脂奶粉中，放置在摇床上摇1h。
(5)免疫与曝光：用TBST清洗上面处理后的PVDF膜。在4℃下孵育一抗过夜，在摇床上每隔30min用TBST清洗一次，共清洗五次。37℃下孵育二抗1h，随后用TBST重复清洗五次，最后使用Odyssey扫描系统进行成像。
2、实验结果
采用Westernblot技术分析了化合物30在不同浓度下对p-EGFR1、ERK和p-ERK蛋白表达的影响，结果如图1所示。实验结果表明化合物30对p-EGFR1和p-ERK蛋白表达呈现剂量依赖性抑制，在相同浓度下对p-EGFR1和p-ERK蛋白表达的抑制能力明显优于AZD4547。这说明化合物30对内源性FGFR1蛋白活性具有较强抑制作用，能够有效抑制EGFR-ERK信号通路。
综上所述，通过考察本发明所得的代表性化合物对FGFR1和FGFR4酶的抑制能力，发现一些化合物对两种FGFR亚型都显示较强的抑制活性，IC50值小于1μM。其中，化合物19和30不仅具有强的酶抑制活性，而且对癌细胞的抗增殖活性也较强，特别是化合物30对KYSE-150和MDA-MB-231细胞的IC50值均小于2μM，优于阳性对照药物AZD4547和SSR128129E，可作为潜在的FGFR抑制剂用于制备抗肿瘤药物。
Claims (10)
1.一种六元并五元杂环类化合物，其特征在于，具有如下结构，还包含其药学上可接受的盐，
其中：
并环环系选自/>U、V、W、X、Y、Z选自N或CH，/>中最多含有2个N，/>中最多含有3个N；
L选自羰基、CH2；
M选自O、NH；
P、Q选自卤素、
R1、R2选自H、卤素；
R3选自C1-C4烷基、C1-C4卤代烷基、C3-C7环烷基、C3-C7卤代环烷基；
R4选自乙烯基、2-丙烯基、1-(2-甲基)丙烯基、C1-C4烷基、C1-C4卤代烷基、C3-C7环烷基、C3-C7卤代环烷基；
R5选自卤素、苯基、取代苯基、噻吩基、苯并噻吩基、苯并呋喃基，其中取代基选自至少一个卤素、C1-C4烷氧基、C1-C4烷基、C1-C4卤代烷基。
2.根据权利要求1所述的六元并五元杂环类化合物，其特征在于，具有式I至式V中的任一结构：
其中：
R1、R2选自Cl、Br；
R3选自C1-C2烷基、C1-C2卤代烷基、C3-C5环烷基、C3-C5卤代环烷基；
R4选自乙烯基、2-丙烯基、1-(2-甲基)丙烯基、C1-C3烷基、C1-C3卤代烷基、C3-C5环烷基、C3-C5卤代环烷基；
R5选自苯基、取代苯基、噻吩基、苯并噻吩基、苯并呋喃基，其中取代基选自至少一个卤素、C1-C2烷氧基、C1-C2烷基、C1-C2卤代烷基。
3.根据权利要求2所述的六元并五元杂环类化合物，其特征在于，所述结构中：
R1、R2选自4位、5位、6位取代的Cl、Br；
R3选自甲基、卤代乙基、卤代环丁基；
R4选自乙烯基、2-丙烯基、1-(2-甲基)丙烯基、乙基、卤代乙基、异丙基、环丙基；
R5选自苯基、取代苯基、噻吩基、苯并噻吩基、苯并呋喃基，其中取代基选自2个卤素、C1-C2烷氧基、C1-C2烷基、C1-C2卤代烷基。
4.根据权利要求3所述的六元并五元杂环类化合物，其特征在于，所述结构中：
R3选自甲基、2,2-二氟乙基、3,3-二氟环丁基；
R4选自乙烯基、2-丙烯基、1-(2-甲基)丙烯基、乙基、2-氯乙基、1-氯乙基、异丙基、环丙基；
R5为选自苯基、取代苯基、噻吩基、苯并噻吩基、苯并呋喃基，其中取代基选自间位或/和对位取代的2个氟、甲氧基。
5.根据权利要求1所述的六元并五元杂环类化合物，其特征在于，选自以下任一化合物：
6.根据权利要求1所述的六元并五元杂环类化合物，其特征在于，所述药学上可接受的盐为所述化合物与以下任一酸形成的盐：
盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸。
7.一种药物组合物，其特征在于，所述药物组合物包含权利要求1所述六元并五元杂环类化合物以及药学上可接受的载体。
8.一种权利要求1任一所述的六元并五元杂环类化合物或权利要求7所述的药物组合物在制备FGFR抑制剂药物中的应用。
9.根据权利要求8所述的应用，其特征在于，所述FGFR抑制剂药物选自FGFR1、FGFR4抑制剂药物。
10.根据权利要求8所述的应用，其特征在于，所述FGFR抑制剂药物为抗肿瘤药物。
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