CN115368364B - 7H-吡咯并[2,3-d]嘧啶衍生物及其制备方法和用途 - Google Patents
7H-吡咯并[2,3-d]嘧啶衍生物及其制备方法和用途 Download PDFInfo
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- CN115368364B CN115368364B CN202210542535.6A CN202210542535A CN115368364B CN 115368364 B CN115368364 B CN 115368364B CN 202210542535 A CN202210542535 A CN 202210542535A CN 115368364 B CN115368364 B CN 115368364B
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Abstract
本发明提供了7H‑吡咯并[2,3‑d]嘧啶衍生物及其制备方法和用途，属于化学医药领域。该衍生物是式I所示的化合物、或其盐、或其立体异构体、或其光学异构体、或其同位素化合物、或其水合物、或其溶剂合物、或其前药。本发明化合物对FAK激酶有显著的抑制作用，可以用于制备FAK抑制剂；还可以用于制备预防和/或治疗与FAK活性有关的疾病的药物，如制备预防和/或治疗癌症、纤维化疾病、自身免疫性疾病、感染性疾病或细胞增殖紊乱等疾病的药物。同时，本发明化合物药代动力学良好，具有广阔的应用前景。
Description
技术领域
本发明属于化学医药领域，具体涉及7H-吡咯并[2,3-d]嘧啶衍生物及其制备方法和用途。
背景技术
黏着斑激酶FAK是一个非受体酪氨酸激酶。当FAK被整合素、受体酪氨酸激酶、G蛋白偶联受体和细胞因子受体等膜受体激活后，能引发下游PI3K-AKT、ERK和JNK等信号通路的激活，以发挥多种生理功能。FAK在多种癌症中过表达，通过促进细胞运动、增殖和存活以及血管生成发挥促进肿瘤进展的作用，也能调节细胞因子和趋化因子的表达，促进纤维化和免疫抑制肿瘤微环境的形成。
转移的发生是癌症致死的重要原因。尽管对癌症转移机制的研究不断加深，但目前的临床治疗方案在控制癌症转移、提高转移型患者的生存期方面仍然面临巨大挑战，患者需要更加有效的治疗策略。作为与癌症侵袭和转移密切相关的靶点，靶向FAK是阻断癌症进程、抑制癌症转移的潜在治疗方式。目前已有FAK抑制剂进入临床试验，然而，癌症患者对FAK抑制剂单药治疗的应答有限。
因此有必要开发更具疗效和安全性的FAK抑制剂用于FAK相关疾病的治疗。
发明内容
本发明的目的是提供7H-吡咯并[2,3-d]嘧啶衍生物及其制备方法和用途。
本发明提供了式I所示的化合物、或其盐、或其立体异构体、或其光学异构体、或其同位素化合物、或其水合物、或其溶剂合物、或其前药：
其中，
R1选自氢、C1～C10烷基；
R20选自氢、卤素、C1～C10烷基；
R2选自-OR3、被0～5个R4取代的3～10元环烷基、被0～5个R4取代的3～10元杂环基、被0～5个R4取代的5～10元芳基、被0～5个R4取代的5～10元杂芳基；
R3选自被0～5个R4取代的5～10元芳基、被0～5个R4取代的5～10元杂芳基；
R4分别独立选自C1～C10烷基、C1～C10烷氧基、卤素、羟基、氨基、羧基、硝基、氰基；或者同一个碳原子上的两个R4组成＝O；
X选自-NR5-、-CR5R6-、-O-、-S-；
R5、R6分别独立选自氢、C1～C10烷基；
A环选自被1～5个R7取代的5～10元芳基、被1～5个R7取代的5～10元杂芳基；
R7分别独立选自卤素、羟基、氨基、羧基、硝基、氰基、被0～5个R8取代的C1～C10烷基、被0～5个R8取代的C1～C10烷氧基、被0～5个R8取代的3～10元杂环基、-C(O)R9、-C(O)NR9R10；或者同一个碳原子上的两个R7组成＝O；
R8分别独立选自卤素、羟基、氨基、羧基、硝基、氰基、-C(O)R9、-NR9R10、被0～5个R11取代的C1～C10烷基、被0～5个R11取代的3～10元杂环基；
R9、R10分别独立选自氢、C1～C10烷基、C1～C10烷氧基、3～10元环烷基、3～10元杂环基；或者，R9、R10连接形成3～8元杂环基；所述杂环基环状结构中的亚烷基可以被1～3个N、O、S、NR12任意替代；
R11选自C1～C10烷基、3～10元环烷基；
R12选自氢、C1～C10烷基、3～10元环烷基、C2～C6烯基、C2～C6炔基。
进一步地，
R1选自氢、C1～C6烷基；
R20选自氢、卤素；
R2选自-OR3、被0～1个R4取代的5～9元杂芳基；所述杂芳基中杂原子为N，所述杂原子的个数为1或2；
R3选自被0～3个R4取代的5～9元芳基；
R4分别独立选自C1～C6烷基、C1～C6烷氧基、卤素、羟基、氨基、羧基、硝基、氰基；或者同一个碳原子上的两个R4组成＝O；
X选自-NR5-；
R5独立选自氢、C1～C6烷基；
A环选自被1～3个R7取代的5～6元芳基、被1～3个R7取代的5～9元杂芳基；所述杂芳基中杂原子为N，所述杂原子的个数为1或2；
R7分别独立选自卤素、羟基、氨基、羧基、硝基、氰基、被0～3个R8取代的C1～C6烷基、被0～3个R8取代的C1～C6烷氧基、被0～3个R8取代的4～7元杂环基、-C(O)R9、-C(O)NR9R10；或者同一个碳原子上的两个R7组成＝O；所述杂环基的杂原子为N、O；所述杂原子的个数为1或2；
R8分别独立选自卤素、-C(O)R9、-NR9R10、被0～3个R11取代的C1～C6烷基、被0～1个R11取代的4～6元杂环基；所述杂环基的杂原子为N、O；所述杂原子的个数为1或2；
R9、R10分别独立选自氢、C1～C6烷基、C1～C6烷氧基、3～6元环烷基、3～6元杂环基；所述杂环基的杂原子为N、O；所述杂原子的个数为1或2；或者，R9、R10连接形成3～8元杂环基；所述杂环基环状结构中的亚烷基可以被1～3个N、O、S、NR12任意替代；
R11选自C1～C6烷基、3～6元环烷基；
R12分别选自氢、C1～C6烷基、3～6元环烷基、C2～C6烯基、C2～C6炔基。
进一步地，
R1选自氢、C1～C3烷基；
R20选自氢、卤素；
R2选自-OR3、
R3选自
R4’选自氢、C1～C3烷基、卤素、羟基、氨基、羧基、硝基、氰基；
X选自-NR5-；
R5独立选自氢、C1～C3烷基；
A环选自被1～3个R7取代的苯基、被1～3个R7取代的吡啶基、被1～3个R7取代的嘧啶基、被1～3个R7取代的吡唑基、
R7分别独立选自卤素、氰基、被0～3个R8取代的C1～C3烷基、被0～3个R8取代的C1～C3烷氧基、被0～2个R8取代的吗啉基、被0～1个R8取代的哌啶基、被0～2个R8取代的哌嗪基、-C(O)R9、-C(O)NR9R10；
R8分别独立选自卤素、-C(O)R9、-NR9R10、被0～1个R11取代的C1～C3烷基、被0～1个R11取代的哌嗪基、氧杂环丁烷；
R9、R10分别独立选自氢、C1～C3烷基、C1～C3烷氧基、3～6元环烷基、哌啶基；或者，R9、R10连接形成3～8元杂环基；所述杂环基环状结构中的亚烷基可以被1～3个N、O、S、NR12任意替代；
R11选自C1～C3烷基、3～6元环烷基；
R12分别选自氢、C1～C6烷基、3～6元环烷基、C2～C6烯基、C2～C6炔基。
进一步地，所述化合物如式II所示：
其中，
Y、Y’分别独立选自-CR7b或-N-；
R7a、R7b、R7c分别独立选自氢、卤素、氰基、被0～3个R8取代的C1～C3烷基、被0～3个R8取代的C1～C3烷氧基、被0～2个R8取代的吗啉基、被0～1个R8取代的哌啶基、被0～1个R8取代的哌嗪基、-C(O)R9、-C(O)NR9R10；
R8分别独立选自卤素、-C(O)R9、-NR9R10、被0～1个R11取代的C1～C3烷基、被0～1个R11取代的哌嗪基、氧杂环丁烷；
R9、R10分别独立选自氢、C1～C3烷基、C1～C3烷氧基、3～6元环烷基、哌啶基；或者，R9、R10连接形成3～8元杂环基；所述杂环基环状结构中的亚烷基可以被1～3个N、O、S、NR12任意替代；
R11选自C1～C3烷基、3～6元环烷基；
R12分别选自氢、C1～C6烷基、3～6元环烷基、C2～C6烯基、C2～C6炔基。
进一步地，所述化合物如式III所示：
其中，
Y、Y’分别独立选自-CR7b或-N-；
R7a、R7b、R7c分别独立选自氢、卤素、氰基、被0～3个R8取代的C1～C3烷基、被0～3个R8取代的C1～C3烷氧基、被0～2个R8取代的吗啉基、被0～1个R8取代的哌啶基、被0～1个R8取代的哌嗪基、-C(O)R9、-C(O)NR9R10；
R8分别独立选自卤素、-C(O)R9、-NR9R10、被0～1个R11取代的C1～C3烷基、被0～1个R11取代的哌嗪基、氧杂环丁烷；
R9、R10分别独立选自氢、C1～C3烷基、C1～C3烷氧基、3～6元环烷基、哌啶基；或者，R9、R10连接形成3～8元杂环基；所述杂环基环状结构中的亚烷基可以被1～3个N、O、S、NR12任意替代；
R11选自C1～C3烷基、3～6元环烷基；
R12分别选自氢、C1～C6烷基、3～6元环烷基、C2～C6烯基、C2～C6炔基。
进一步地，所述化合物如式IV所示：
其中，
Y、Y’分别独立选自-CR7b或-N-；
R7a、R7b、R7c分别独立选自氢、卤素、氰基、被0～3个R8取代的C1～C3烷基、被0～3个R8取代的C1～C3烷氧基、被0～2个R8取代的吗啉基、被0～1个R8取代的哌啶基、被0～1个R8取代的哌嗪基、-C(O)R9、-C(O)NR9R10；
R8分别独立选自卤素、-C(O)R9、-NR9R10、被0～1个R11取代的C1～C3烷基、被0～1个R11取代的哌嗪基、氧杂环丁烷；
R9、R10分别独立选自氢、C1～C3烷基、C1～C3烷氧基、3～6元环烷基、哌啶基；或者，R9、R10连接形成3～8元杂环基；所述杂环基环状结构中的亚烷基可以被1～3个N、O、S、NR12任意替代；
R11选自C1～C3烷基、3～6元环烷基；
R12分别选自氢、C1～C6烷基、3～6元环烷基、C2～C6烯基、C2～C6炔基。
进一步地，所述化合物如式V所示：
其中，
R4’选自氢、C1～C3烷基、卤素；
Y、Y’分别独立选自-CR7b或-N-；
R7a、R7b、R7c分别独立选自氢、卤素、氰基、被0～3个R8取代的C1～C3烷基、被0～3个R8取代的C1～C3烷氧基、被0～2个R8取代的吗啉基、被0～1个R8取代的哌啶基、被0～1个R8取代的哌嗪基、-C(O)R9、-C(O)NR9R10；
R8分别独立选自卤素、-C(O)R9、-NR9R10、被0～1个R11取代的C1～C3烷基、被0～1个R11取代的哌嗪基、氧杂环丁烷；
R9、R10分别独立选自氢、C1～C3烷基、C1～C3烷氧基、3～6元环烷基、哌啶基；或者，R9、R10连接形成3～8元杂环基；所述杂环基环状结构中的亚烷基可以被1～3个N、O、S、NR12任意替代；
R11选自C1～C3烷基、3～6元环烷基；
R12分别选自氢、C1～C6烷基、3～6元环烷基、C2～C6烯基、C2～C6炔基。
进一步地，所述化合物为如下化合物之一：
本发明还提供了前述的化合物、或其盐、或其立体异构体、或其光学异构体、或其同位素化合物、或其水合物、或其溶剂合物、或其前药在制备FAK抑制剂中的用途。
本发明前述的化合物、或其盐、或其立体异构体、或其光学异构体、或其同位素化合物、或其水合物、或其溶剂合物、或其前药能够用来制备预防和/或治疗与FAK活性有关的疾病的药物。与FAK活性有关的疾病包括癌症、纤维化疾病、自身免疫性疾病、感染性疾病或细胞增殖紊乱等。具体包括但不限于：卵巢癌、胃癌、胰腺癌、前列腺癌、结直肠癌、肝癌、乳腺癌、葡萄膜黑色素瘤、甲状腺癌、肺癌、黑色素瘤、间皮瘤、子宫癌、骨肿瘤、纤维化、肝纤维化。
本发明还提供了一种药物，它是由前述的化合物、或其盐、或其立体异构体、或其光学异构体、或其同位素化合物、或其水合物、或其溶剂合物、或其前药为活性成分，加上药物上可接受的辅料或辅助性成分制备而成的制剂。
本发明还提供了一种联合用药物，它含有相同或不同规格单位制剂的用于同时或者分别给药的前述的化合物、或其盐、或其立体异构体、或其光学异构体、或其同位素化合物、或其水合物、或其溶剂合物、或其前药和其它药物，以及药学上可接受的载体；
所述其它药物选自化疗药、免疫检查点疗法、激酶抑制剂、表观遗传学靶点抑制剂、聚ADP(二磷酸腺苷)-核糖聚合酶(PARP)抑制剂。
本发明所述化合物可以以药学组合物形式给药。在本专利化合物与其他治疗药物合用情况下，本专利化合物的药物组合物给药途径可与其他药物相同，或由于物理和化学性质不同，给药途径可以不相同。例如，本专利化合物口服给药可产生并维持良好血药水平，而另一种治疗药物可能需要静脉给药。因此本专利化合物与另一合用药物可同时、先后或分别给药。
本发明化合物与如下一种或多种药物合用预期有效：化疗药、免疫检查点疗法、激酶抑制剂及抗体、表观遗传学靶点抑制剂、聚ADP(二磷酸腺苷)-核糖聚合酶(PARP)抑制剂。
化疗药包括但不限于紫杉醇、多西他赛、(注射用紫杉醇(白蛋白结合型))、顺铂、(奥沙利铂)、(卡铂)、吉西他滨等；
免疫检查点疗法包括但不限于(nivolumab)、(pembrolizumab)、(atezolizumab)、(durvalumab)、(avelumab)、(ipilimumab)；
激酶抑制剂及抗体包括但不限于：trametinib、RO5126766、cobimetinib、binimetinib、selumetinib、binimetinib、ramucirumab、sorafenib、sunitinib、cabozantinib、axitinib、foretinib、nintedanib、regorafenib、lenvatinib、anlotinib、bevacizumab、dabrafenib；
表观遗传学靶点抑制剂包括但不限于vorinostat(SAHA)、mocetinostat、romidepsin、panobinostat、tazemetostat。
聚ADP(二磷酸腺苷)-核糖聚合酶(PARP)抑制剂包括但不限于talazoparib、rucaparib、niraparib、olaparib。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社，Columbus，OH)命名系统命名。
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀Ca～b烷基表明任何含“a”至“b”个碳原子的烷基。因此，例如，“C1～4烷基”是指包含1～4个碳原子的烷基；“C1～4烷氧基”是指包含1～4个碳原子的烷氧基。
“烷基”是指具有指定数目的碳原子的饱和烃链。例如，C1～6烷基是指具有1至6个碳原子，例如1、2、3、4、5或6个碳原子的烷基基团。烷基基团可以是直链或支链的。代表性的支链烷基基团具有一个、两个或三个支链。烷基基团也可以是其他基团的一部分，所述其他基团为例如C1～6烷氧基。
“环烷基”是指具有3至10个碳原子且没有环杂原子且具有单个环或多个环(包括稠合、桥连和螺环体系)的饱和或部分饱和的非芳香性环状基团。环烷基基团的实例包括例如，金刚烷基、环丙基、环丁基、环己基、环戊基、环辛基。包括多双环烷基环体系的环烷基基团的实例是双环己基、双环戊基、双环辛基等。下面例举并命名两种此类双环烷基多环结构：双环己基双环己基。
“杂环基”指包含至少一个杂原子的饱和或部分饱和的非芳香性环状基团；包括单个环或多个环(包括稠合、桥连和螺环体系)；其中杂原子指氮原子、氧原子、硫原子。杂环烷基基团的实例包括例如，哌啶基、哌嗪基、吗啉基。
“芳基”指具有5至10个碳原子且没有环杂原子且具有单个环或多个环(包括稠合、桥连和螺环体系)的含有芳香性不饱和的基团，如苯基、蒽基、萘基、
“杂芳基”指包含至少一个杂原子的芳香性不饱和环；包括单个环或多个环(包括稠合、桥连和螺环体系)；其中杂原子指氮原子、氧原子、硫原子。如吡啶基、吡嗪基、吡唑基，还包括等。
“卤素”为氟、氯、溴或碘。
“立体异构体”包括对映异构体和非对映异构体。
本发明中“R9、R10连接形成3～8元杂环基；所述杂环基环状结构中的亚烷基可以被1～3个N、O、S、NR12任意替代”是指“NR9R10”中，R9和R10与N连接形成3～8元杂环基，如连接形成 或者连接形成部分饱和的非芳香族环，如等；杂环基中的碳原子可以被N、O、S、NR12任意替代。
本发明中盐为“药学上可接受的盐”。
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。
术语“盐”和“可药用的盐”是指上述化合物或其立体异构体，与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物，或其立体异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐等。
在某些实施方式中，本发明的一种或多种化合物可以彼此联合使用。也可选择将本发明的化合物与任何其它的活性试剂结合使用，用于制备调控细胞功能或治疗疾病的药物或药物组合物。如果使用的是一组化合物，则可将这些化合物同时、分别或有序地对受试对象进行给药。
本发明化合物对FAK激酶有显著的抑制作用，可以用于制备FAK抑制剂；还可以用于制备预防和/或治疗与FAK活性有关的疾病的药物，如制备预防和/或治疗癌症、纤维化疾病、自身免疫性疾病、感染性疾病或细胞增殖紊乱等疾病的药物。同时，本发明化合物药代动力学良好，具有广阔的应用前景。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。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。
附图说明
图1为化合物B16在体外抗卵巢癌细胞PA-1迁移和侵袭的活性结果：A为迁移结果；B为侵袭结果。
图2为化合物B16对小鼠体重和体内肿瘤体积的影响结果：A为体内肿瘤体积；B为小鼠体重。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
实施例1、化合物A1～A17以及化合物A22～A26的制备
合成路线1：
反应条件：(a)2-(三甲基硅烷基)乙氧甲基氯，KOH，DMF，0℃，3～5h；(b)1H-苯并[d]咪唑或1H-吲哚，t-BuONa，DMF，0℃，1～2h；(b’)1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑，Pd(dppf)Cl2，K2CO3，1,4-二氧六环/水(5:1，v/v)，70℃，8h；(c)R1-NH2，Pd2(dba)3，BINAP，K2CO3，1,4-二氧六环，95℃，24h；(d)第一步：CF3COOH，CHCl3，45℃，8h；第二步：氨水，1,4-二氧六环，45℃，8h。
SEM是(三甲基硅)乙氧基甲基(分子式：C6H15OSi-；分子量：131.27)，是一种氨基保护基。
1、中间体1a：2,4-二氯-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶
将2,4-二氯-7H-吡咯并[2,3-d]嘧啶(9.4g,50mmol)溶于干燥DMF中(50mL)，降温至0℃，搅拌下加入氢氧化钾(5g,90mmol)。0℃搅拌0.5h后滴加2-(三甲基硅烷基)乙氧甲基氯(10.6mL,60mmol)，滴加完毕后继续反应5h。TLC监测反应完毕，将反应液倒入冰水中(500mL)，EA(500mL)萃取。有机相水洗两次，经无水硫酸钠干燥后过滤浓缩。柱层析(EA15％，PE 85％，体积比)得到无色油状液体(14.3g，收率为90％)。1H NMR(400MHz,DMSO-d6)δ7.87(d,J＝3.7Hz,1H),6.73(d,J＝3.7Hz,1H),5.57(s,2H),3.54–3.45(m,2H),0.81(dd,J＝8.6,7.5Hz,2H),-0.12(s,9H).MS(ESI)m/z 318.1[M+H]+.
2、中间体1b：4-(1H-苯并[d]咪唑-1-基)-2-氯-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶
将2,4-二氯-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(中间体1a,1.27g,4mmol)溶于干燥DMF中(10mL)，0℃下加入叔丁醇钠(0.58g,6mmol)并搅拌30min。苯并咪唑(0.57g,4.8mmol)溶于DMF(3mL)后滴加至反应瓶中。TLC监测反应完毕，将反应液倒入水中(50mL)，EA萃取(150mL)。有机相水洗两次后经无水硫酸钠干燥后过滤浓缩。柱层析(EA20％，PE 80％，体积比)得到白色固体(1.2g，收率为75％)。1H NMR(400MHz,DMSO-d6)δ9.20(s,1H),8.47(dd,J＝7.8,1.3Hz,1H),7.98(d,J＝3.8Hz,1H),7.92–7.86(m,1H),7.50(dtd,J＝22.6,7.4,1.3Hz,2H),7.29(d,J＝3.8Hz,1H),5.71(s,2H),3.65(dd,J＝8.7,7.5Hz,2H),0.98–0.88(m,2H),0.00(s,9H).MS(ESI)m/z 400.1[M+H]+.
3、中间体1c：2-氯-4-(1H-吲哚-1-基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶
中间体1c的制备方法与中间体1b类似，将苯并咪唑替换为吲哚。得到白色固体(收率为70％)。1H NMR(400MHz,DMSO-d6)δ8.63(dd,J＝8.4,1.0Hz,1H),8.28(d,J＝3.6Hz,1H),7.91(d,J＝3.8Hz,1H),7.77(dt,J＝7.5,1.0Hz,1H),7.44(ddd,J＝8.4,7.2,1.4Hz,1H),7.35(td,J＝7.5,1.1Hz,1H),7.15(d,J＝3.7Hz,1H),7.01(dd,J＝3.7,0.7Hz,1H),5.70(s,2H),3.70–3.53(m,3H),0.94(dd,J＝8.6,7.6Hz,2H),0.00(s,9H).MS(ESI)m/z 399.1[M+H]+.
4、中间体1f：2-氯-4-(1-甲基-1H-吡唑-4-基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶
将2,4-二氯-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(1.14g,3.6mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑(624mg,3mmol)、Pd(dppf)Cl2(110mg,0.18mmol)和K2CO3(636mg,6mmol)加入30mL 1,4-二氧六环/H2O(5:1,v/v)混合溶液中，氮气保护下升温至70℃反应8h。TLC监测反应完毕后浓缩反应液，剩余物加EA溶解后经硅藻土过滤，滤液浓缩。柱层析(EA 30％，PE 70％，体积比)得白色固体(0.54g，收率为50％)。1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.37(s,1H),7.86(d,J＝3.7Hz,1H),7.20(d,J＝3.7Hz,1H),5.66(s,2H),4.05(s,3H),3.69–3.57(m,2H),0.93(t,J＝8.0Hz,2H),0.00(s,9H).MS(ESI)m/z 386.1[M+Na]+.
5、中间体SEM-A1：4-(1H-苯并[d]咪唑-1-基)-N-(4-(4-甲基哌嗪-1-基)苯基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-胺
将4-(1H-苯并[d]咪唑-1-基)-2-氯-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(中间体1b,150mg,0.38mmol)、4-(4-甲基哌嗪)苯胺(86mg,0.45mmol)、Pd2(dba)3(34mg,10％mmol)、BINAP(23mg,10％mmol)和K2CO3(103mg,0.75mmol)加入干燥1,4-二氧六环中(15mL)。氮气保护下升温至95℃反应24h。TLC检测反应完毕后浓缩反应液。剩余物加DCM溶解经硅藻土过滤，滤液浓缩后用制备TLC(DCM/methanol＝20:1，v/v)纯化得黄色固体(170mg，收率为82％)。1H NMR(400MHz,Chloroform-d)δ8.69(s,1H),8.26–8.19(m,1H),7.90–7.84(m,1H),7.64–7.58(m,2H),7.39–7.35(m,2H),7.14(d,J＝3.7Hz,1H),7.07(s,1H),7.00–6.93(m,2H),6.58(d,J＝3.7Hz,1H),5.58(s,2H),3.65–3.58(m,2H),3.21(t,J＝5.0Hz,4H),2.62(t,J＝5.0Hz,4H),1.00–0.91(m,2H),-0.05(s,9H).MS(ESI)m/z 577.3[M+Na]+.
采用制备中间体SEM-A1的类似方法制备得到中间体SEM-A2～SEM-A17以及SEM-A22～SEM-A26：
6、化合物A1～A17以及化合物A22～A26的制备
化合物A1：4-(1H-苯并[d]咪唑-1-基)-N-(4-(4-甲基哌嗪-1-基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-胺
第一步：将SEM-A1溶于氯仿中(5mL)，加入0.5mL三氟乙酸(0.5mL)，45℃反应8小时。浓缩反应液。第二步：将剩余物分散于1,4-二氧六环中(3mL)，加入氨水(1mL)并升温至45℃反应8小时。反应液浓缩后用制备TLC(DCM/methanol＝15:1，v/v)纯化得白色固体(27mg，收率为21％)。1H NMR(400MHz,DMSO-d6)δ11.83(s,1H),9.23(s,1H),9.04(s,1H),8.65–8.45(m,1H),7.90–7.74(m,1H),7.74–7.61(m,2H),7.44–7.33(m,2H),7.28(dd,J＝3.6,2.3Hz,1H),6.98–6.83(m,2H),6.77(dd,J＝3.7,1.7Hz,1H),3.09(t,J＝4.9Hz,4H),2.47(t,J＝5.0Hz,4H),2.23(s,3H).13C NMR(101MHz,DMSO-d6)δ156.33,156.12,149.09,146.59,144.18,143.18,133.58,132.58,124.46,124.23,123.99,121.00,120.19,116.43,116.34,101.04,100.12,55.21,49.45,46.25.HRMS(ESI+):m/z calcd for C24H24N8[M+H]+,425.2197；found,425.2199.
化合物A2：4-(1H-苯并[d]咪唑-1-基)-N-(4-吗啉代苯基)-7H-吡咯并[2,3-d]嘧啶-2-胺
以SEM-A2为原料，采用制备化合物A1的类似方法制备得到化合物A2，白色固体(收率为38％)。1H NMR(400MHz,DMSO-d6)δ11.84(t,J＝2.1Hz,1H),9.27(s,1H),9.05(s,1H),8.64–8.52(m,1H),7.86–7.78(m,1H),7.74–7.64(m,2H),7.45–7.34(m,2H),7.29(dd,J＝3.7,2.3Hz,1H),6.99–6.87(m,2H),6.78(dd,J＝3.7,1.8Hz,1H),3.85–3.70(m,4H),3.14–3.00(m,4H).13C NMR(101MHz,DMSO-d6)δ156.29,156.11,149.09,146.56,144.18,143.19,133.91,132.58,124.47,124.26,124.00,120.96,120.20,116.33,116.19,101.08,100.13,66.68,49.87.HRMS(ESI+):m/z calcd for C23H21N7O[M+H]+,412.1881；found,412.1883.
化合物A3：4-(1H-苯并[d]咪唑-1-基)-N-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-胺
以SEM-A3为原料，采用制备化合物A1的类似方法制备得到化合物A3，浅黄色固体(收率为35％)。1H NMR(400MHz,DMSO-d6)δ11.77(s,1H),9.02(s,1H),8.34(d,J＝7.9Hz,1H),8.04(s,1H),7.87–7.74(m,1H),7.68(d,J＝8.7Hz,1H),7.41–7.21(m,3H),6.76(dd,J＝3.7,1.8Hz,1H),6.68(d,J＝2.6Hz,1H),6.52(dd,J＝8.7,2.5Hz,1H),3.80(s,3H),3.16(dd,J＝6.3,3.8Hz,4H),2.50(d,J＝1.9Hz,4H),2.25(s,3H).13C NMR(101MHz,DMSO-d6)δ157.42,156.45,152.94,149.18,149.10,144.12,143.13,132.56,125.21,124.39,124.16,123.92,121.37,120.14,116.29,107.38,100.86,100.76,100.00,56.02,55.18,49.24,46.21.HRMS(ESI+):m/z calcd for C25H26N8O[M+H]+,455.2303；found,455.2310.
化合物A4：4-(1H-苯并[d]咪唑-1-基)-N-(2-甲氧基-4-吗啉代苯基)-7H-吡咯并[2,3-d]嘧啶-2-胺
以SEM-A4为原料，采用制备化合物A1的类似方法制备得到化合物A4，浅黄色固体(收率为30％)。1H NMR(400MHz,Chloroform-d)δ9.15(s,1H),8.71(s,1H),8.32(d,J＝8.7Hz,1H),8.30–8.21(m,1H),7.93–7.83(m,1H),7.45(s,1H),7.40(dd,J＝6.1,3.2Hz,2H),7.01(t,J＝3.1Hz,1H),6.63–6.48(m,3H),4.00–3.80(m,7H),3.15(s,4H).HRMS(ESI+):m/z calcd for C24H23N7O2[M+H]+,442.1986；found,442.1993.
化合物A5：4-(1H-苯并[d]咪唑-1-基)-N-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-胺
以SEM-A5为原料，采用制备化合物A1的类似方法制备得到化合物A5，白色固体(收率为27％)。1H NMR(400MHz,DMSO-d6)δ11.76(s,1H),9.02(s,1H),8.34(d,J＝7.8Hz,1H),8.02(s,1H),7.81–7.70(m,1H),7.65(d,J＝8.6Hz,1H),7.39–7.21(m,3H),6.75(d,J＝3.7Hz,1H),6.67(d,J＝2.5Hz,1H),6.52(dd,J＝8.7,2.5Hz,1H),3.80(s,3H),3.72(d,J＝12.2Hz,2H),2.73–2.62(m,2H),2.34(d,J＝12.9Hz,5H),2.18(s,3H),2.04–1.91(m,1H),1.86(d,J＝12.4Hz,2H),1.54(td,J＝13.6,12.9,9.3Hz,2H),1.37–1.26(m,2H),0.85(t,J＝6.7Hz,1H).13C NMR(101MHz,DMSO-d6)δ157.45,156.46,152.94,149.10,149.10,144.12,143.12,132.56,125.24,124.39,124.15,123.91,121.12,120.15,116.29,107.82,101.17,100.85,99.98,56.00,55.55,49.37,48.96,46.11,28.30.HRMS(ESI+):m/z calcd forC30H35N9O[M+H]+,538.3038；found,538.3043.
化合物A6：1-(4-(4-((4-(1H-苯并[d]咪唑-1-基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-3-甲氧苯基)哌嗪-1-基)乙烷-1-酮
以SEM-A6为原料，采用制备化合物A1的类似方法制备得到化合物A6，白色固体(收率为22％)。1H NMR(400MHz,DMSO-d6)δ11.79(s,1H),9.02(s,1H),8.36(d,J＝7.7Hz,1H),8.06(s,1H),7.84–7.66(m,2H),7.42–7.19(m,3H),6.81–6.67(m,2H),6.55(dd,J＝8.7,2.6Hz,1H),3.82(s,3H),3.61(q,J＝6.1Hz,4H),3.14(dt,J＝23.1,5.1Hz,4H),2.06(s,3H).13C NMR(101MHz,DMSO-d6)δ168.70,157.28,156.41,152.78,149.11,148.87,144.14,143.14,132.55,124.92,124.42,124.23,123.93,122.01,120.16,116.24,107.98,101.50,100.97,100.02,56.09,50.03,46.08,21.68.HRMS(ESI+):m/z calcd for C26H26N8O2[M+H]+,483.2252；found,483.2252.
化合物A7：4-((4-(1H-苯并[d]咪唑-1-基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-环丙基-3-甲氧基苯酰胺
以SEM-A7为原料，采用制备化合物A1的类似方法制备得到化合物A7，白色固体(收率为25％)。1H NMR(400MHz,DMSO-d6)δ12.05(s,1H),9.04(s,1H),8.47(d,J＝8.3Hz,1H),8.45–8.37(m,1H),8.34(d,J＝4.0Hz,1H),8.22(s,1H),7.87–7.77(m,1H),7.56–7.47(m,2H),7.46–7.34(m,3H),6.82(dd,J＝3.7,1.7Hz,1H),3.97(s,3H),2.85(dq,J＝7.3,3.7Hz,1H),0.72(td,J＝7.1,4.7Hz,2H),0.63–0.53(m,2H).13C NMR(101MHz,DMSO-d6)δ172.22,160.45,159.84,153.78,153.07,148.99,148.12,137.23,137.16,132.79,130.17,129.40,128.82,125.14,125.10,123.05,120.44,114.67,107.18,105.00,61.27,28.26,11.05.HRMS(ESI+):m/z calcd for C24H21N7O2[M+Na]+,462.1650；found,462.1645.
化合物A8：N-(4-(2-氧杂-5-氮杂二环[2.2.1]庚烷-5-基)-2-甲氧苯基)-4-(1H-苯并[d]咪唑-1-基)-7H-吡咯并[2,3-d]嘧啶-2-胺
以SEM-A8为原料，采用制备化合物A1的类似方法制备得到化合物A8，浅黄色固体(收率为19％)。1H NMR(400MHz,Chloroform-d)δ9.79(s,1H),8.72(s,1H),8.33–8.21(m,1H),8.08(d,J＝8.7Hz,1H),7.92–7.82(m,1H),7.39(dt,J＝6.0,3.6Hz,2H),7.23(s,1H),6.85(s,1H),6.51(dd,J＝3.7,1.8Hz,1H),6.22(s,2H),4.65(s,1H),4.38(s,1H),3.97(d,J＝7.3Hz,1H),3.90(s,3H),3.86(d,J＝7.5Hz,1H),3.59(s,1H),3.19(s,1H),2.04(dd,J＝9.7,2.2Hz,1H),2.00–1.92(m,1H).HRMS(ESI+):m/z calcd for C25H23N7O2[M+Na]+,476.1806；found,476.1808.
化合物A9：4-(1H-苯并[d]咪唑-1-基)-N-(4-((2S,6R)-2,6-二甲基吗啉代)-2-甲氧苯基)-7H-吡咯并[2,3-d]嘧啶-2-胺
以SEM-A9为原料，采用制备化合物A1的类似方法制备得到化合物A9，浅黄色固体(收率为25％)。1H NMR(400MHz,DMSO-d6)δ11.78(s,1H),9.02(s,1H),8.35(d,J＝7.8Hz,1H),8.04(s,1H),7.79(dd,J＝7.4,1.5Hz,1H),7.70(d,J＝8.7Hz,1H),7.38–7.32(m,2H),7.25(dd,J＝3.7,2.2Hz,1H),6.76(dd,J＝3.7,1.8Hz,1H),6.70(d,J＝2.5Hz,1H),6.53(dd,J＝8.8,2.6Hz,1H),3.82(s,3H),3.73(ddd,J＝10.3,6.2,2.3Hz,2H),3.65–3.53(m,2H),2.28(dd,J＝11.8,10.2Hz,2H),1.18(d,J＝6.3Hz,6H).13C NMR(101MHz,DMSO-d6)δ157.38,156.44,152.94,149.10,148.81,144.13,143.13,132.56,125.10,124.41,124.18,123.92,121.50,120.16,116.25,107.17,100.92,100.60,100.00,71.57,56.09,55.04,19.38.HRMS(ESI+):m/z calcd for C26H27N7O2[M+H]+,470.2299；found,470.2302.
化合物A10：4-(1H-苯并[d]咪唑-1-基)-N-(3-((2S,6R)-2,6-二甲基吗啉代)-2-甲氧苯基)-7H-吡咯并[2,3-d]嘧啶-2-胺
以SEM-A10为原料，采用制备化合物A1的类似方法制备得到化合物A10，白色固体(收率为21％)。1H NMR(400MHz,Chloroform-d)δ9.12(s,1H),8.73(s,1H),8.37–8.26(m,2H),7.98–7.78(m,2H),7.45–7.36(m,2H),7.12–7.01(m,2H),6.69–6.56(m,2H),3.97(s,3H),3.89(ddd,J＝10.1,6.2,2.2Hz,2H),3.41(dt,J＝10.6,1.8Hz,2H),2.44(dd,J＝11.7,10.1Hz,2H),1.26(d,J＝6.3Hz,6H).13C NMR(101MHz,Chloroform-d)δ155.89,155.75,149.31,144.17,141.94,140.79,134.03,132.34,124.44,124.24,123.86,122.84,120.49,114.61,113.18,111.76,102.43,100.56,77.22,72.20,58.91,56.26,19.08.HRMS(ESI+):m/z calcd for C26H27N7O2[M+H]+,470.2299；found,470.2302.
化合物A11：4-(1H-苯并[d]咪唑-1-基)-N-(2-甲氧基-6-(4-甲基哌嗪-1-基)吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-2-胺
以SEM-A11为原料，采用制备化合物A1的类似方法制备得到化合物A11，浅黄色固体(收率为20％)。1H NMR(400MHz,DMSO-d6)δ11.76(s,1H),9.03(s,1H),8.35(d,J＝7.8Hz,1H),8.20(s,1H),7.78(d,J＝8.1Hz,2H),7.40–7.25(m,2H),7.24(dd,J＝3.7,2.2Hz,1H),6.77(dd,J＝3.8,1.8Hz,1H),6.37(d,J＝8.4Hz,1H),3.82(s,3H),3.47(t,J＝4.9Hz,4H),2.44(t,J＝5.0Hz,4H),2.24(s,3H).13C NMR(101MHz,DMSO-d6)δ157.84,156.54,156.48,155.06,149.18,144.11,143.10,137.13,132.57,124.34,124.08,123.93,120.14,116.41,113.26,100.70,99.99,98.50,54.85,53.13,46.30,45.52.HRMS(ESI+):m/z calcd forC24H25N9O[M+H]+,456.2255；found,456.2262.
化合物A12：4-(1H-苯并[d]咪唑-1-基)-N-(3-甲基-4-(4-甲基哌嗪-1-基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-胺
以SEM-A12为原料，采用制备化合物A1的类似方法制备得到化合物A12，浅黄色固体(收率为32％)。1H NMR(400MHz,DMSO-d6)δ11.84(s,1H),9.27(s,1H),9.05(s,1H),8.63–8.52(m,1H),7.88–7.75(m,1H),7.70–7.55(m,2H),7.47–7.33(m,2H),7.30(dd,J＝3.7,2.2Hz,1H),7.00(d,J＝8.6Hz,1H),6.79(dd,J＝3.7,1.7Hz,1H),2.83(t,J＝4.7Hz,4H),2.49(s,4H),2.25(d,J＝4.5Hz,6H).13C NMR(101MHz,DMSO-d6)δ156.11,156.05,149.04,145.93,144.20,143.21,136.63,132.56,132.44,124.47,124.02,122.32,120.21,119.35,118.03,116.31,101.22,100.13,55.78,52.13,46.35,18.15.HRMS(ESI+):m/z calcd forC25H26N8[M+H]+,439.2353；found,439.2358.
化合物A13：4-(1H-吲哚-1-基)-N-(4-(4-甲基哌嗪-1-基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-胺
以SEM-A13为原料，采用制备化合物A1的类似方法制备得到化合物A13，浅黄色固体(收率为27％)。1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),9.11(s,1H),8.64(d,J＝8.1Hz,1H),8.12(d,J＝3.6Hz,1H),7.68(t,J＝8.9Hz,3H),7.24(ddd,J＝18.1,10.2,5.1Hz,3H),6.90(d,J＝8.7Hz,2H),6.84(d,J＝3.5Hz,1H),6.64(dd,J＝3.7,1.7Hz,1H),3.08(t,J＝5.0Hz,4H),2.47(t,J＝5.0Hz,4H),2.23(s,3H).13C NMR(101MHz,DMSO-d6)δ156.24,155.84,151.45,146.38,135.59,133.89,130.18,127.61,123.50,123.35,122.26,121.05,120.81,116.44,106.88,100.96,100.39,99.99,55.23,49.50,46.27.HRMS(ESI+):m/zcalcd for Chemical Formula:C25H25N7[M+Na]+,446.2064；found,446.2067.
化合物A14：4-(1H-吲哚-1-基)-N-(4-吗啉代苯基)-7H-吡咯并[2,3-d]嘧啶-2-胺
以SEM-A14为原料，采用制备化合物A1的类似方法制备得到化合物A14，浅黄色固体(收率为30％)。1H NMR(400MHz,DMSO-d6)δ11.71(s,1H),9.14(s,1H),8.65(d,J＝8.2Hz,1H),8.12(d,J＝3.6Hz,1H),7.72(d,J＝8.6Hz,2H),7.67(d,J＝7.6Hz,1H),7.31–7.18(m,3H),6.92(d,J＝8.7Hz,2H),6.85(d,J＝3.5Hz,1H),6.64(dd,J＝3.6,1.8Hz,1H),3.75(t,J＝4.7Hz,4H),3.05(t,J＝4.7Hz,4H).13C NMR(101MHz,DMSO-d6)δ156.20,155.82,151.46,146.35,135.59,134.21,130.19,127.62,123.51,123.39,122.27,121.06,120.77,116.38,116.20,106.89,101.00,100.39,66.69,49.91.HRMS(ESI+):m/z calcd for ChemicalFormula:C24H22N6O[M+Na]+,433.1748；found,433.1746.
化合物A15：4-(1H-吲哚-1-基)-N-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-胺
以SEM-A15为原料，采用制备化合物A1的类似方法制备得到化合物A15，浅黄色固体(收率为36％)。1H NMR(400MHz,Chloroform-d)δ9.60(s,1H),8.43(d,J＝8.2Hz,1H),8.32(d,J＝8.7Hz,1H),7.88(d,J＝3.5Hz,1H),7.68–7.60(m,1H),7.37(s,1H),7.33–7.27(m,1H),7.25–7.21(m,1H),6.83(dd,J＝3.7,2.1Hz,1H),6.77(d,J＝3.5Hz,1H),6.60(d,J＝2.6Hz,1H),6.59–6.50(m,2H),3.91(s,3H),3.20(t,J＝5.0Hz,4H),2.63(t,J＝5.0Hz,4H),2.38(s,3H).13C NMR(101MHz,Chloroform-d)δ156.19,155.60,152.05,149.51,147.12,135.56,130.23,126.76,123.27,122.91,121.88,121.54,120.82,120.49,115.16,108.49,106.52,102.06,100.99,100.85,55.72,55.17,50.24,46.03.HRMS(ESI+):m/zcalcd for Chemical Formula:C26H27N7O[M+H]+,454.2350；found,454.2350.
化合物A16：4-(1H-吲哚-1-基)-N-(2-甲氧基-4-吗啉代苯基)-7H-吡咯并[2,3-d]嘧啶-2-胺
以SEM-A16为原料，采用制备化合物A1的类似方法制备得到化合物A16，浅黄色固体(收率为35％)。1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.49–8.40(m,1H),8.10(d,J＝3.5Hz,1H),7.86(s,1H),7.80(d,J＝8.6Hz,1H),7.69–7.61(m,1H),7.26–7.16(m,3H),6.83(d,J＝3.5Hz,1H),6.70(d,J＝2.4Hz,1H),6.63(dd,J＝3.7,1.7Hz,1H),6.52(dd,J＝8.7,2.5Hz,1H),3.83(s,3H),3.77(t,J＝4.7Hz,4H),3.12(t,J＝4.7Hz,4H).13C NMR(101MHz,DMSO-d6)δ157.09,156.11,152.37,151.49,148.78,135.57,130.14,127.55,124.38,123.46,123.37,122.21,122.06,121.04,116.25,107.13,106.90,100.91,100.52,100.29,66.67,56.06,49.76.HRMS(ESI+):m/z calcd for Chemical Formula:C25H24N6O2[M+Na]+,463.1854；found,463.1861.
化合物A17：4-(1H-吲哚-1-基)-N-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-胺
以SEM-A17为原料，采用制备化合物A1的类似方法制备得到化合物A17，浅黄色固体(收率为31％)。1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),8.49–8.38(m,1H),8.09(d,J＝3.6Hz,1H),7.82(s,1H),7.76(d,J＝8.7Hz,1H),7.69–7.60(m,1H),7.19(dd,J＝6.2,3.3Hz,3H),6.82(d,J＝3.5Hz,1H),6.71–6.59(m,2H),6.51(dd,J＝8.7,2.5Hz,1H),3.81(s,3H),3.70(d,J＝12.4Hz,2H),2.66(td,J＝12.2,2.4Hz,3H),2.30(ddd,J＝15.0,7.7,4.0Hz,5H),2.15(s,3H),1.85(d,J＝11.4Hz,2H),1.53(qd,J＝12.1,3.9Hz,2H).13C NMR(101MHz,DMSO-d6)δ157.15,156.14,152.33,151.49,148.83,135.58,130.14,127.53,124.42,123.44,123.33,122.18,121.52,121.03,116.24,107.84,106.88,101.16,100.89,100.27,61.36,56.02,55.63,49.47,49.04,46.22,28.33.HRMS(ESI+):m/z calcd forChemical Formula:C31H36N8O[M+H]+,537.3085；found,537.3082.
化合物A22：4-(1-甲基-1H-吡唑-4-基)-N-(4-(4-甲基哌嗪-1-基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-胺
以SEM-A22为原料，采用制备化合物A1的类似方法制备得到化合物A22，浅黄色固体(收率为37％)。1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),8.83(s,1H),8.52(s,1H),8.17(s,1H),7.76–7.63(m,2H),7.15(dd,J＝3.6,2.2Hz,1H),6.92–6.81(m,2H),6.73(dd,J＝3.7,1.8Hz,1H),3.96(s,3H),3.05(t,J＝4.9Hz,4H),2.46(t,J＝4.9Hz,4H),2.22(s,3H).13C NMR(101MHz,DMSO-d6)δ156.65,154.34,151.22,145.77,138.99,134.67,131.88,123.32,121.63,119.80,116.56,107.41,100.46,55.26,49.66,46.27.HRMS(ESI+):m/zcalcd for Chemical Formula:C21H24N8[M+H]+,389.2197；found,389.2198.
化合物A23：4-(1-甲基-1H-吡唑-4-基)-N-(4-吗啉代苯基)-7H-吡咯并[2,3-d]嘧啶-2-胺
以SEM-A23为原料，采用制备化合物A1的类似方法制备得到化合物A23，浅黄色固体(收率为34％)。1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),8.86(s,1H),8.53(s,1H),8.18(s,1H),7.74(d,J＝8.8Hz,2H),7.16(dd,J＝3.6,2.0Hz,1H),6.90(d,J＝8.7Hz,2H),6.74(dd,J＝3.7,1.6Hz,1H),3.97(s,3H),3.74(t,J＝4.7Hz,4H),3.03(t,J＝4.7Hz,4H).13CNMR(101MHz,DMSO-d6)δ156.63,154.33,151.23,145.74,139.00,134.98,131.90,123.36,121.62,119.80,116.32,107.44,100.46,66.70,50.09.HRMS(ESI+):m/z calcd forChemical Formula:C20H21N7O[M+H]+,376.1881；found,376.1885.
化合物A24：N-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-4-(1-甲基-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-2-胺
以SEM-A24为原料，采用制备化合物A1的类似方法制备得到化合物A24，白色固体(收率为35％)。1H NMR(400MHz,DMSO-d6)δ11.46(t,J＝2.1Hz,1H),8.55(s,1H),8.24(d,J＝8.8Hz,1H),8.19(s,1H),7.37(s,1H),7.16(dd,J＝3.6,2.2Hz,1H),6.74(dd,J＝3.6,1.8Hz,1H),6.66(d,J＝2.6Hz,1H),6.52(dd,J＝8.9,2.5Hz,1H),3.95(s,3H),3.87(s,3H),3.11(dd,J＝6.2,3.7Hz,4H),2.47(t,J＝4.9Hz,4H),2.23(s,3H).13C NMR(101MHz,DMSO-d6)δ156.48,154.30,151.41,149.48,146.95,139.07,132.04,123.49,122.91,121.43,120.08,107.59,100.77,100.53,56.19,55.26,49.59,46.27.HRMS(ESI+):m/z calcd forChemical Formula:C22H26N8O[M+H]+,419.2303；found,419.2303.
化合物A25：N-(2-甲氧基-4-吗啉代苯基)-4-(1-甲基-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-2-胺
以SEM-A25为原料，采用制备化合物A1的类似方法制备得到化合物A25，浅黄色固体(收率为29％)。1H NMR(400MHz,DMSO-d6)δ11.48(s,1H),8.56(s,1H),8.27(d,J＝8.8Hz,1H),8.19(s,1H),7.40(s,1H),7.17(dd,J＝3.6,2.2Hz,1H),6.75(dd,J＝3.6,1.8Hz,1H),6.68(d,J＝2.5Hz,1H),6.54(dd,J＝8.8,2.5Hz,1H),3.96(s,3H),3.88(s,3H),3.76(t,J＝4.7Hz,4H),3.09(dd,J＝5.8,3.7Hz,4H).13C NMR(101MHz,DMSO-d6)δ156.44,154.28,151.41,149.50,146.93,139.08,132.06,123.52,123.20,121.41,120.05,107.58,107.34,100.54,66.69,56.22,50.03.HRMS(ESI+):m/z calcd for Chemical Formula:C21H23N7O2[M+H]+,406.1986；found,406.1982.
化合物A26：N-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1-甲基-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-2-胺
以SEM-A26为原料，采用制备化合物A1的类似方法制备得到化合物A26，黄色固体(收率为36％)。1H NMR(400MHz,DMSO-d6)δ11.46(d,J＝2.2Hz,1H),8.55(s,1H),8.27–8.14(m,2H),7.37(s,1H),7.16(dd,J＝3.6,2.2Hz,1H),6.74(dd,J＝3.6,1.8Hz,1H),6.65(d,J＝2.6Hz,1H),6.53(dd,J＝8.8,2.6Hz,1H),3.96(s,3H),3.86(s,3H),3.65(dt,J＝12.5,3.5Hz,2H),2.62(td,J＝12.1,2.4Hz,3H),2.41–2.22(m,5H),2.15(s,3H),1.84(d,J＝11.5Hz,2H),1.52(qd,J＝12.0,3.8Hz,3H),1.25(d,J＝8.5Hz,2H).13C NMR(101MHz,DMSO-d6)δ156.49,154.30,151.40,149.45,147.08,139.06,132.03,123.48,122.78,121.44,120.09,108.13,107.56,101.27,100.53,61.39,56.17,55.62,49.80,49.02,46.20,39.26,28.40.HRMS(ESI+):m/z calcd for Chemical Formula:C27H35N9O[M+H]+,502.3038；found,502.3034.
实施例2、化合物B1～B29、B30～B33以及化合物B34～B37的制备
合成路线2：
反应条件：(a)2-(三甲基硅烷基)乙氧甲基氯，KOH，DMF，0℃，3～5h；(b)7-羟基-1-茚酮或4-氯-7-羟基-2,3-二氢-1H-茚-1-酮或7-羟基-4-甲基-2,3-二氢-1H-茚-1-酮，碳酸钾，DMF，80℃，7h；(c)R1-NH2，Pd2(dba)3，BINAP，K2CO3，1,4-二氧六环，95℃，24h；(d)第一步：CF3COOH，CHCl3，45℃，8h；第二步：氨水，1,4-二氧六环，45℃，8h。
1、中间体1a：2,4-二氯-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶
采用实施例1所述方法制备中间体1a。
2、中间体2b：7-((2-氯-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
将2,4-二氯-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(1a,1.05g,3.3mmol)、7-羟基-1-茚酮(444mg,3mmol)和碳酸钾(828mg,6mmol)加入干燥DMF中(10mL)，氮气保护下升温至80℃反应7h。TLC监测反应完毕，将反应液倒入水中(150mL)，EA萃取两次(2×100mL)。有机相合并，用无水硫酸钠干燥后过滤浓缩。柱层析(EA20％，PE80％，体积比)得浅黄色固体(1.1g，收率为85％)。1H NMR(400MHz,DMSO-d6)δ7.78(td,J＝7.9,1.5Hz,1H),7.67(dd,J＝3.7,1.3Hz,1H),7.54(d,J＝7.7Hz,1H),7.28(d,J＝7.8Hz,1H),6.63(dd,J＝3.7,1.2Hz,1H),5.58(s,2H),3.61–3.51(m,2H),3.16(t,J＝5.7Hz,2H),2.62–2.53(m,2H),0.93–0.80(m,2H),-0.06(d,J＝1.4Hz,9H).MS(ESI)m/z 452.1[M+Na]+.
3、中间体2c：4-氯-7-((2-氯-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
中间体2c的制备方法与中间体2b类似，将7-羟基-1-茚酮替换为4-氯-7-羟基-2,3-二氢-1H-茚-1-酮。得到浅灰色固体(收率为77％)。1H NMR(400MHz,DMSO-d6)δ7.88(d,J＝8.5Hz,1H),7.69(d,J＝3.7Hz,1H),7.38(d,J＝8.4Hz,1H),6.68(d,J＝3.6Hz,1H),5.58(s,2H),3.61–3.51(m,2H),3.15–3.04(m,2H),2.69–2.59(m,2H),0.86(dd,J＝8.6,7.6Hz,2H),-0.06(s,9H).MS(ESI)m/z 464.1[M+H]+.
4、中间体2d：7-((2-氯-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-4-甲基-2,3-二氢-1H-茚-1-酮
中间体2d的制备方法与中间体2b类似，将7-羟基-1-茚酮替换为7-羟基-4-甲基-2,3-二氢-1H-茚-1-酮。得到白色固体(收率为82％)。1H NMR(400MHz,DMSO-d6)δ7.72(d,J＝3.6Hz,1H),7.65(dd,J＝8.0,0.9Hz,1H),7.25(d,J＝8.0Hz,1H),6.68(d,J＝3.6Hz,1H),5.63(s,2H),3.68–3.54(m,2H),3.16–3.05(m,2H),2.68–2.60(m,2H),2.43(s,3H),0.98–0.85(m,2H),0.00(s,9H).MS(ESI)m/z 444.1[M+H]+.
5、中间体SEM-B1～SEMB38的制备
采用制备中间体SEM-A1的类似方法制备得到中间体SEM-B1～SEM-B38：
6、化合物B1～B29、B30～B33以及化合物B34～B38的制备
化合物B1：7-((2-((2-甲氧苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B1为原料，采用制备化合物A1的类似方法制备得到化合物B1，浅黄色固体(收率为40％)。1H NMR(400MHz,Chloroform-d)δ9.15(s,1H),7.90–7.78(m,1H),7.68(t,J＝7.8Hz,1H),7.42(d,J＝8.0Hz,2H),7.21(d,J＝7.9Hz,1H),6.86(dd,J＝3.7,2.2Hz,1H),6.81(dd,J＝6.5,1.8Hz,2H),6.61(ddd,J＝8.5,6.3,2.4Hz,1H),6.52(dd,J＝3.6,2.1Hz,1H),3.83(s,3H),3.21–3.12(m,2H),2.61–2.52(m,2H).13C NMR(101MHz,Chloroform-d)δ203.24,162.65,156.84,155.39,154.97,150.26,147.40,135.77,129.95,129.71,123.65,121.42,120.50,120.46,120.37,117.56,109.67,99.77,99.26,55.65,36.66,25.73.HRMS(ESI+):m/z calcd for C22H18N4O3[M+Na]+,409.1272；found,409.1270.
化合物B2：7-((2-((2-(二氟甲氧基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B2为原料，采用制备化合物A1的类似方法制备得到化合物B2，浅黄色固体(收率为32％)。1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),7.78–7.68(m,3H),7.53(d,J＝7.6Hz,1H),7.24(d,J＝8.0Hz,1H),7.13(t,J＝6.2Hz,2H),7.05–6.99(m,1H),6.96–6.92(m,2H),6.35(dt,J＝3.8,1.9Hz,1H),3.17–3.11(m,2H),2.52(d,J＝7.4Hz,2H).13C NMR(101MHz,DMSO-d6)δ203.39,162.37,157.60,155.51,154.83,149.61,141.21,136.61,132.47,129.53,125.55,124.66,122.61,122.46,121.62,121.55,119.47,117.26,99.20,98.87,36.84,25.75.HRMS(ESI+):m/z calcd for C22H16F2N4O[M+Na]+,445.1083；found,445.1081.
化合物B3：7-((2-((2-(三氟甲氧基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B3为原料，采用制备化合物A1的类似方法制备得到化合物B3，浅黄色固体(收率为37％)。1H NMR(400MHz,Chloroform-d)δ9.34(s,1H),7.99(dd,J＝8.2,1.8Hz,1H),7.68(t,J＝7.8Hz,1H),7.44(d,J＝7.6Hz,1H),7.20(d,J＝7.9Hz,1H),7.16(dt,J＝8.0,1.8Hz,1H),7.07(s,1H),6.90(dd,J＝7.6,1.7Hz,1H),6.88–6.82(m,2H),6.50(dd,J＝3.6,2.0Hz,1H),3.21–3.12(m,2H),2.63–2.55(m,2H).13C NMR(101MHz,Chloroform-d)δ203.29,162.63,156.90,155.08,154.23,150.08,137.30,135.88,132.92,129.64,126.63,123.85,121.38,120.97,120.80,120.18,119.68,99.87,99.80,36.64,25.72.HRMS(ESI+):m/zcalcd for C22H15F3N4O3[M+Na]+,463.0989；found,463.0986.
化合物B4：7-((2-((2-异丙氧基苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B4为原料，采用制备化合物A1的类似方法制备得到化合物B4，浅棕色固体(收率为33％)。1H NMR(400MHz,DMSO-d6)δ11.59(s,1H),7.78(t,J＝7.7Hz,1H),7.70(dd,J＝8.1,1.6Hz,1H),7.57(d,J＝7.6Hz,1H),7.33(d,J＝3.7Hz,1H),7.25(d,J＝7.8Hz,1H),7.14(dd,J＝3.6,2.2Hz,1H),6.94(d,J＝8.2Hz,1H),6.78(td,J＝7.7,1.7Hz,1H),6.55(t,J＝7.7Hz,1H),6.35(dd,J＝3.6,1.9Hz,1H),4.58(dq,J＝12.4,6.1Hz,1H),3.16(t,J＝5.9Hz,2H),2.51(d,J＝2.8Hz,2H),1.27(d,J＝6.0Hz,6H).1H NMR(400MHz,DMSO-d6)δ11.59(s,1H),7.78(t,J＝7.7Hz,1H),7.70(dd,J＝8.1,1.6Hz,1H),7.57(d,J＝7.6Hz,1H),7.33(d,J＝3.7Hz,1H),7.25(d,J＝7.8Hz,1H),7.14(dd,J＝3.6,2.2Hz,1H),6.94(d,J＝8.2Hz,1H),6.78(td,J＝7.7,1.7Hz,1H),6.55(t,J＝7.7Hz,1H),6.35(dd,J＝3.6,1.9Hz,1H),4.58(dq,J＝12.4,6.1Hz,1H),3.16(t,J＝5.9Hz,2H),2.51(d,J＝2.8Hz,2H),1.27(d,J＝6.0Hz,6H).HRMS(ESI+):m/z calcd for C24H22N4O3[M+Na]+,437.1585；found,437.1590.
化合物B5：7-((2-((2-甲氧基-4-吗啉代苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B5为原料，采用制备化合物A1的类似方法制备得到化合物B5，浅棕色固体(收率为35％)。1H NMR(400MHz,DMSO-d6)δ11.48(t,J＝2.2Hz,1H),7.74(t,J＝7.8Hz,1H),7.59(d,J＝8.7Hz,1H),7.52(d,J＝7.6Hz,1H),7.21(d,J＝7.9Hz,1H),7.16(s,1H),7.05(dd,J＝3.5,2.2Hz,1H),6.57(d,J＝2.5Hz,1H),6.30(dd,J＝3.5,1.9Hz,1H),6.22(dd,J＝8.8,2.5Hz,1H),3.82–3.68(m,7H),3.14(t,J＝5.9Hz,2H),3.03(dd,J＝5.8,3.8Hz,4H),2.56–2.51(m,2H).13C NMR(101MHz,DMSO-d6)δ203.37,162.33,157.54,155.73,155.54,149.76,149.70,147.21,136.52,124.54,122.50,121.88,121.55,120.50,106.78,100.34,98.84,98.59,66.66,56.06,49.87,36.89,25.79.HRMS(ESI+):m/z calcd for C26H25N5O4[M+Na]+,494.1800；found,494.1804.
化合物B6：7-((2-((4-((2S,6R)-2,6-二甲基吗啉代)-2-甲氧苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B6为原料，采用制备化合物A1的类似方法制备得到化合物B6，白色固体(收率为22％)。1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),7.75(t,J＝7.8Hz,1H),7.58(d,J＝8.8Hz,1H),7.52(d,J＝7.6Hz,1H),7.21(d,J＝7.9Hz,1H),7.15(s,1H),7.10–6.99(m,1H),6.57(d,J＝2.6Hz,1H),6.28(dd,J＝3.6,1.8Hz,1H),6.23(dd,J＝8.9,2.5Hz,1H),3.77(s,3H),3.70(ddt,J＝10.1,6.7,3.8Hz,2H),3.47(d,J＝11.5Hz,2H),3.19–3.07(m,2H),2.53(d,J＝5.4Hz,2H),2.19(t,J＝11.0Hz,2H),1.16(d,J＝6.1Hz,6H).13C NMR(101MHz,DMSO-d6)δ203.40,162.31,157.55,155.72,155.60,149.91,149.68,146.95,136.54,129.52,124.54,122.28,121.85,121.54,120.70,106.88,100.43,98.84,98.57,71.54,56.07,55.26,36.89,25.78,19.38.HRMS(ESI+):m/z calcd for C28H29N5O4[M+Na]+,522.2113；found,522.2127.
化合物B7：7-((2-((4-(2-氧杂-5-氮杂二环[2.2.1]庚烷-5-基)-2-甲氧苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B7为原料，采用制备化合物A1的类似方法制备得到化合物B7，浅黄色固体(收率为19％)。1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),7.73(t,J＝7.8Hz,1H),7.50(d,J＝7.6Hz,1H),7.43(d,J＝8.6Hz,1H),7.20(d,J＝7.9Hz,1H),7.10(s,1H),7.01(dd,J＝3.5,2.2Hz,1H),6.26(dd,J＝3.6,1.8Hz,1H),6.21(d,J＝2.4Hz,1H),6.00–5.87(m,1H),4.58(d,J＝2.3Hz,1H),4.54–4.47(m,1H),3.74(s,4H),3.66(d,J＝7.3Hz,1H),3.47(d,J＝8.7Hz,1H),3.13(t,J＝5.9Hz,2H),2.93(d,J＝9.3Hz,1H),2.53(d,J＝5.8Hz,2H),1.91(d,J＝9.5Hz,1H),1.82(d,J＝9.5Hz,1H).13C NMR(101MHz,DMSO-d6)δ203.40,162.28,157.50,156.10,155.89,149.73,144.00,136.48,129.55,124.45,122.43,121.56,121.53,119.55,104.43,98.32,97.58,84.01,76.08,71.41,58.81,57.42,55.94,36.88,25.76.HRMS(ESI+):m/z calcd for C27H25N5O4[M+Na]+,506.1800；found,506.1806.
化合物B8：7-((2-((2-甲氧基-4-(哌嗪-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B8为原料，采用制备化合物A1的类似方法制备得到化合物B8，浅黄色固体(收率为20％)。1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),7.75(t,J＝7.8Hz,1H),7.54(dd,J＝13.9,8.2Hz,2H),7.21(d,J＝7.8Hz,1H),7.15(s,1H),7.05(dd,J＝3.6,1.6Hz,1H),6.54(d,J＝2.5Hz,1H),6.29(d,J＝3.5Hz,1H),6.21(dd,J＝8.8,2.6Hz,1H),3.76(s,3H),3.14(t,J＝5.9Hz,2H),2.99(dd,J＝6.4,3.5Hz,4H),2.87(dd,J＝6.4,3.5Hz,4H),2.56–2.52(m,2H),1.23(s,1H).13C NMR(101MHz,DMSO-d6)δ203.40,162.32,157.54,155.73,155.56,149.76,149.69,147.78,136.54,129.55,124.54,122.21,121.86,121.56,120.54,107.04,100.63,98.83,98.54,56.00,50.44,45.89,36.88,25.79.HRMS(ESI+):m/z calcd forC26H26N6O3[M+H]+,471.2140；found,471.2142.
化合物B9：7-((2-((2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B9为原料，采用制备化合物A1的类似方法制备得到化合物B9，浅黄色固体(收率为29％)。1H NMR(400MHz,DMSO-d6)δ11.48(t,J＝2.2Hz,1H),7.74(t,J＝7.8Hz,1H),7.54(dd,J＝17.0,8.2Hz,2H),7.21(d,J＝7.9Hz,1H),7.15(s,1H),7.05(dd,J＝3.5,2.2Hz,1H),6.55(d,J＝2.6Hz,1H),6.29(dd,J＝3.6,1.9Hz,1H),6.22(dd,J＝8.9,2.5Hz,1H),3.76(s,3H),3.14(t,J＝5.8Hz,2H),3.06(t,J＝4.9Hz,4H),2.52(d,J＝4.2Hz,2H),2.47(t,J＝4.9Hz,4H),2.23(s,3H).13C NMR(101MHz,DMSO-d6)δ203.39,162.32,157.54,155.74,155.58,149.77,149.70,147.20,136.52,129.54,124.53,122.20,121.84,121.53,120.57,107.01,100.56,98.83,98.56,56.03,55.16,49.38,46.17,36.88,25.78.HRMS(ESI+):m/z calcd for C27H28N6O3[M+H]+,485.2296；found,485.2299.
化合物B10：7-((2-((4-(4-(环丙基甲基)哌嗪-1-基)-2-甲氧苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B10为原料，采用制备化合物A1的类似方法制备得到化合物B10，浅黄色固体(收率为21％)。1H NMR(400MHz,DMSO-d6)δ11.39(d,J＝2.3Hz,1H),7.64(t,J＝7.8Hz,1H),7.43(t,J＝8.6Hz,2H),7.11(d,J＝7.9Hz,1H),7.04(s,1H),6.94(dd,J＝3.6,2.2Hz,1H),6.45(d,J＝2.5Hz,1H),6.19(dd,J＝3.6,1.9Hz,1H),6.11(dd,J＝8.9,2.5Hz,1H),3.65(s,3H),3.04(t,J＝5.9Hz,2H),2.96(t,J＝4.8Hz,4H),2.47(t,J＝4.9Hz,4H),2.44–2.40(m,2H),2.12(d,J＝6.6Hz,2H),0.76(tt,J＝6.2,4.1Hz,1H),0.42–0.33(m,2H),0.03–-0.07(m,2H).13C NMR(101MHz,DMSO-d6)δ203.40,162.32,157.55,155.74,155.60,149.82,149.69,147.37,136.54,129.56,124.55,122.15,121.83,121.56,120.69,107.00,100.59,98.82,98.53,63.30,55.99,53.25,49.59,36.88,25.79,8.76,4.19.HRMS(ESI+):m/z calcd for C30H32N6O3[M+Na]+,547.2429；found,547.2430.
化合物B11：7-((2-((4-(4-乙酰基哌嗪-1-基)-2-甲氧苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B11为原料，采用制备化合物A1的类似方法制备得到化合物B11，白色固体(收率为23％)。1H NMR(400MHz,DMSO-d6)δ11.49(t,J＝2.1Hz,1H),7.75(t,J＝7.8Hz,1H),7.59(d,J＝8.7Hz,1H),7.53(d,J＝7.6Hz,1H),7.22(d,J＝7.9Hz,1H),7.16(s,1H),7.06(dd,J＝3.5,2.2Hz,1H),6.60(d,J＝2.5Hz,1H),6.36–6.18(m,2H),3.77(s,3H),3.57(q,J＝5.9Hz,4H),3.14(t,J＝6.0Hz,2H),3.03(dt,J＝23.7,5.1Hz,4H),2.52(dd,J＝4.9,2.9Hz,2H),2.04(s,3H).13C NMR(101MHz,DMSO-d6)δ203.38,168.64,162.33,157.56,155.71,155.47,149.70,149.67,146.95,136.53,129.54,124.55,122.83,121.92,121.56,120.33,107.68,101.36,98.84,98.62,56.09,50.27,46.09,36.90,25.79,21.66.HRMS(ESI+):m/z calcd for C28H28N6O4[M+H]+,513.2245；found,513.2242.
化合物B12：7-((2-((2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B12为原料，采用制备化合物A1的类似方法制备得到化合物B12，浅黄色固体(收率为34％)。1H NMR(400MHz,DMSO-d6)δ11.47(d,J＝2.6Hz,1H),7.74(t,J＝7.8Hz,1H),7.53(t,J＝8.8Hz,2H),7.21(d,J＝7.9Hz,1H),7.14(s,1H),7.09–6.98(m,1H),6.54(d,J＝2.5Hz,1H),6.29(dd,J＝3.6,1.8Hz,1H),6.21(dd,J＝8.8,2.5Hz,1H),3.75(s,3H),3.62–3.55(m,2H),3.39(s,3H),3.14(t,J＝5.8Hz,2H),2.63–2.51(m,5H),2.39–2.20(m,5H),2.14(s,3H),1.89–1.76(m,2H),1.50(qd,J＝12.1,3.9Hz,2H).13C NMR(101MHz,DMSO-d6)δ203.37,162.32,157.53,155.74,155.58,149.73,149.70,147.35,136.52,129.54,124.51,122.03,121.83,121.55,120.56,107.52,101.05,98.82,98.55,61.34,56.00,55.63,49.65,49.02,46.22,36.89,28.34,25.78.HRMS(ESI+):m/z calcd for C32H37N7O3[M+H]+,568.3031；found,568.3038.
化合物B13：7-((2-((2-甲氧基-6-(4-甲基哌嗪-1-基)吡啶-3-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B13为原料，采用制备化合物A1的类似方法制备得到化合物B13，白色固体(收率为33％)。1H NMR(400MHz,DMSO-d6)δ11.45(t,J＝2.2Hz,1H),7.73(t,J＝7.8Hz,1H),7.63(d,J＝8.4Hz,1H),7.49(d,J＝7.6Hz,1H),7.28–7.12(m,2H),7.02(dd,J＝3.5,2.2Hz,1H),6.27(dd,J＝3.5,1.9Hz,1H),6.08(d,J＝8.5Hz,1H),3.76(s,3H),3.36(t,J＝5.1Hz,4H),3.13(t,J＝5.9Hz,2H),2.53(dd,J＝4.9,2.8Hz,2H),2.41(t,J＝5.0Hz,4H),2.22(s,3H).13C NMR(101MHz,DMSO-d6)δ203.36,162.33,157.49,156.20,155.86,153.85,153.48,149.67,136.46,132.85,129.53,124.49,121.67,121.51,114.24,98.79,98.47,97.99,54.83,46.30,45.61,36.87,25.73.HRMS(ESI+):m/z calcd for C26H27N7O3[M+H]+,486.2248；found,486.2253.
化合物B14：甲基3-甲氧基-4-((4-((3-羰基-2,3-二氢-1H-茚-4-基)氧代)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)苯酸酯
以SEM-B14为原料，采用制备化合物A1的类似方法制备得到化合物B14，白色固体(收率为30％)。1H NMR(400MHz,DMSO-d6)δ11.76(s,1H),7.97(d,J＝8.5Hz,1H),7.81(t,J＝7.8Hz,1H),7.67–7.55(m,2H),7.42(d,J＝1.8Hz,1H),7.32–7.23(m,2H),7.23–7.19(m,1H),6.43(dd,J＝3.6,1.8Hz,1H),3.89(s,3H),3.82(s,3H),3.16(t,J＝5.8Hz,2H),2.53(d,J＝5.5Hz,2H).13C NMR(101MHz,DMSO-d6)δ203.44,166.42,162.42,157.71,155.12,153.65,149.53,146.87,136.76,134.56,129.48,124.82,123.31,122.66,121.69,121.53,115.92,110.60,99.72,99.01,56.44,52.33,36.88,25.81.HRMS(ESI+):m/z calcd forC24H20N4O5[M+Na]+,467.1327；found,467.1329.
化合物B15：N-环丙基-3-甲氧基-4-((4-((3-羰基-2,3-二氢-1H-茚-4-基)氧代)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)苯酰胺
以SEM-B15为原料，采用制备化合物A1的类似方法制备得到化合物B15，浅黄色固体(收率为32％)。1H NMR(400MHz,DMSO-d6)δ11.69(d,J＝2.3Hz,1H),8.24(d,J＝3.9Hz,1H),7.93(d,J＝8.5Hz,1H),7.79(t,J＝7.8Hz,1H),7.57(d,J＝7.6Hz,1H),7.48(s,1H),7.39(d,J＝1.9Hz,1H),7.26(d,J＝7.8Hz,1H),7.21–7.13(m,2H),6.39(dd,J＝3.5,1.8Hz,1H),3.87(s,3H),3.17(t,J＝5.9Hz,2H),2.86–2.73(m,1H),2.53(dd,J＝4.7,2.8Hz,2H),0.69(dt,J＝6.9,3.3Hz,2H),0.61–0.50(m,2H).13C NMR(101MHz,DMSO-d6)δ203.44,167.48,162.39,157.69,155.22,154.04,149.52,146.82,136.68,132.47,129.46,126.78,124.80,122.96,121.58,120.27,116.10,109.35,99.47,98.98,56.42,36.89,25.79,23.44,6.30.HRMS(ESI+):m/z calcd for C26H23N5O4[M+Na]+,492.1643；found,492.1643.
化合物B16：3-甲氧基-4-((4-((3-羰基-2,3-二氢-1H-茚-4-基)氧代)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-(哌啶-4-基)苯酰胺
以SEM-B16为原料，采用制备化合物A1的类似方法制备得到化合物B16，白色固体(收率为37％)。1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),8.04(d,J＝7.8Hz,1H),7.95(d,J＝8.6Hz,1H),7.79(t,J＝7.8Hz,1H),7.57(d,J＝7.6Hz,1H),7.49(s,1H),7.42(d,J＝1.9Hz,1H),7.27(d,J＝7.9Hz,1H),7.24–7.16(m,2H),6.40(d,J＝3.5Hz,1H),3.88(s,3H),3.82(dt,J＝7.8,3.9Hz,1H),3.16(t,J＝5.8Hz,2H),3.01–2.92(m,2H),2.54(s,4H),2.47(s,1H),1.74(dd,J＝12.7,3.8Hz,2H),1.43(tt,J＝12.1,6.2Hz,2H).13C NMR(101MHz,DMSO-d6)δ203.42,165.43,162.39,157.68,155.23,154.09,149.54,146.86,136.68,132.43,129.46,127.14,124.78,122.95,121.58,120.50,116.20,109.47,99.49,56.48,47.46,45.48,36.89,32.93,25.78.HRMS(ESI+):m/z calcd for C28H28N6O4[M+H]+,513.2245；found,513.2242.
化合物B17：7-((2-((4-吗啉代苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B17为原料，采用制备化合物A1的类似方法制备得到化合物B17，白色固体(收率为37％)。1H NMR(400MHz,DMSO-d6)δ11.43(t,J＝2.2Hz,1H),8.71(s,1H),7.75(t,J＝7.8Hz,1H),7.52(d,J＝7.6Hz,1H),7.33(d,J＝8.5Hz,2H),7.21(d,J＝7.8Hz,1H),7.04(dd,J＝3.5,2.2Hz,1H),6.75–6.56(m,2H),6.29(dd,J＝3.5,1.9Hz,1H),3.78–3.65(m,4H),3.14(t,J＝5.9Hz,2H),3.04–2.90(m,4H),2.53(dd,J＝5.0,2.9Hz,2H).13C NMR(101MHz,DMSO-d6)δ203.37,162.27,157.55,155.74,155.59,149.87,145.76,136.56,134.40,129.62,124.46,121.66,121.56,119.72,115.88,98.81,98.41,66.67,49.96,36.90,25.81.HRMS(ESI+):m/z calcd for C25H23N5O3[M+H]+,442.1874；found,442.1874.
化合物B18：7-((2-((4-(哌嗪-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B18为原料，采用制备化合物A1的类似方法制备得到化合物B18，浅黄色固体(收率为28％)。1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),8.71(s,1H),7.75(t,J＝7.8Hz,1H),7.52(d,J＝7.6Hz,1H),7.31(d,J＝8.6Hz,2H),7.22(d,J＝7.8Hz,1H),7.04(dd,J＝3.5,1.8Hz,1H),6.65(d,J＝8.8Hz,2H),6.29(dd,J＝3.5,1.4Hz,1H),3.14(t,J＝5.9Hz,2H),2.97–2.90(m,4H),2.89–2.80(m,4H),2.53(dd,J＝4.9,2.8Hz,2H),1.28–1.24(m,1H).13C NMR(101MHz,DMSO-d6)δ203.40,162.26,157.55,155.74,155.60,149.86,146.33,136.58,134.13,129.62,124.46,121.65,121.57,119.70,116.21,98.80,98.36,50.54,45.88,36.89,25.81.HRMS(ESI+):m/z calcd for C25H24N6O2[M+H]+,441.2034；found,441.2034.
化合物B19：7-((2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B19为原料，采用制备化合物A1的类似方法制备得到化合物B19，浅黄色固体(收率为33％)。1H NMR(400MHz,DMSO-d6)δ11.43(t,J＝2.2Hz,1H),8.68(s,1H),7.74(t,J＝7.8Hz,1H),7.52(d,J＝7.6Hz,1H),7.31(d,J＝8.6Hz,2H),7.21(d,J＝7.8Hz,1H),7.03(dd,J＝3.5,2.2Hz,1H),6.74–6.57(m,2H),6.29(dd,J＝3.5,1.9Hz,1H),3.14(t,J＝5.9Hz,2H),2.99(t,J＝5.0Hz,4H),2.52(dd,J＝4.9,2.9Hz,2H),2.44(t,J＝5.0Hz,4H),2.22(s,3H).13C NMR(101MHz,DMSO-d6)δ203.37,157.54,155.75,155.63,149.87,145.80,136.56,134.08,129.61,124.44,121.63,121.55,119.76,116.14,98.81,98.38,55.20,49.54,46.24,36.89,25.81.HRMS(ESI+):m/z calcd for C26H26N6O2[M+H]+,455.2190；found,455.2195.
化合物B20：7-((2-((4-(4-甲基哌嗪-1-基)-2-(三氟甲基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B20为原料，采用制备化合物A1的类似方法制备得到化合物B20，白色固体(收率为35％)。1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),7.80(s,1H),7.67(t,J＝7.8Hz,1H),7.42(d,J＝7.6Hz,1H),7.18(dd,J＝18.7,8.2Hz,2H),7.08–6.93(m,3H),6.18(dd,J＝3.5,1.9Hz,1H),3.16(t,J＝4.9Hz,4H),3.09(t,J＝5.9Hz,2H),2.57–2.51(m,2H),2.47(d,J＝5.2Hz,4H),2.25(s,3H).13C NMR(101MHz,DMSO-d6)δ203.24,162.26,157.81,157.30,156.00,149.69,148.54,136.35,131.26,129.42,124.27,121.52,121.26,119.48,98.68,98.44,54.90,48.39,46.12,36.79,25.67.HRMS(ESI+):m/z calcd for C27H25F3N6O2[M+H]+,523.2064；found,523.2067.
化合物B21：7-((2-((2-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B21为原料，采用制备化合物A1的类似方法制备得到化合物B21，白色固体(收率为33％)。1H NMR(400MHz,DMSO-d6)δ11.32(t,J＝2.2Hz,1H),7.82(s,1H),7.68(t,J＝7.8Hz,1H),7.42(d,J＝7.6Hz,1H),7.16(d,J＝7.8Hz,1H),7.00(d,J＝8.7Hz,1H),6.94(dd,J＝3.5,2.2Hz,1H),6.67(d,J＝2.8Hz,1H),6.57(dd,J＝8.7,2.8Hz,1H),6.17(dd,J＝3.5,1.9Hz,1H),3.07(dt,J＝15.2,5.4Hz,6H),2.58–2.50(m,2H),2.45(t,J＝4.9Hz,4H),2.22(s,3H),2.02(s,3H).13C NMR(101MHz,DMSO-d6)δ203.30,162.27,157.65,157.32,156.25,149.80,148.32,136.34,133.85,131.08,129.54,126.72,124.22,121.28,121.13,117.57,113.39,98.67,98.06,55.19,49.16,46.24,36.82,25.71,18.89.HRMS(ESI+):m/zcalcd for C27H28N6O2[M+H]+,469.2347；found,469.2352.
化合物B22：7-((2-((3-氟-4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B22为原料，采用制备化合物A1的类似方法制备得到化合物B22，白色固体(收率为38％)。1H NMR(400MHz,DMSO-d6)δ11.54(d,J＝2.2Hz,1H),9.01(s,1H),7.75(t,J＝7.8Hz,1H),7.52(d,J＝7.6Hz,1H),7.42(d,J＝15.8Hz,1H),7.23(d,J＝7.8Hz,1H),7.12–7.03(m,2H),6.76(t,J＝9.4Hz,1H),6.34(dd,J＝3.5,1.8Hz,1H),3.14(t,J＝5.9Hz,2H),2.88(t,J＝4.7Hz,4H),2.57–2.51(m,2H),2.44(t,J＝4.8Hz,4H),2.21(s,3H).13C NMR(101MHz,DMSO-d6)δ203.41,162.29,157.70,155.46,155.00,153.96,149.68,137.22,136.63,133.16,129.48,124.67,122.14,121.51,119.28,114.23,106.19,98.87,98.80,55.27,50.94,46.27,36.91,25.77.HRMS(ESI+):m/z calcd for C26H25FN6O2[M+H]+,473.2096；found,473.2099.
化合物B23：7-((2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B23为原料，采用制备化合物A1的类似方法制备得到化合物B23，白色固体(收率为30％)。1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),9.02(s,1H),7.75(t,J＝7.8Hz,1H),7.66(d,J＝2.5Hz,1H),7.52(d,J＝7.6Hz,1H),7.31(dd,J＝8.8,2.6Hz,1H),7.23(d,J＝7.9Hz,1H),7.10(dd,J＝3.5,2.2Hz,1H),6.87(d,J＝8.8Hz,1H),6.33(dd,J＝3.6,1.8Hz,1H),3.13(d,J＝6.0Hz,2H),2.85(t,J＝4.8Hz,4H),2.56–2.51(m,2H),2.45(s,4H),2.22(s,3H).13C NMR(101MHz,DMSO-d6)δ203.40,162.30,157.70,155.40,154.99,149.65,142.32,137.94,136.64,129.42,127.99,124.75,122.21,121.48,120.71,119.63,117.87,98.94,98.89,55.38,51.55,46.27,36.92,25.86.HRMS(ESI+):m/z calcd for C26H25ClN6O2[M+H]+,489.1801；found,489.1803.
化合物B24：2-(4-甲基哌嗪-1-基)-5-((4-((3-羰基-2,3-二氢-1H-茚-4-基)氧代)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)苯甲腈
以SEM-B24为原料，采用制备化合物A1的类似方法制备得到化合物B24，白色固体(收率为34％)。1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),9.16(s,1H),7.89(d,J＝2.7Hz,1H),7.75(t,J＝7.8Hz,1H),7.59(dd,J＝9.1,2.7Hz,1H),7.51(d,J＝7.6Hz,1H),7.23(d,J＝7.8Hz,1H),7.11(dd,J＝3.5,2.2Hz,1H),6.94(d,J＝9.0Hz,1H),6.35(dd,J＝3.5,1.8Hz,1H),3.16(t,J＝5.8Hz,2H),2.99(t,J＝4.6Hz,4H),2.57–2.52(m,2H),2.48(t,J＝5.5Hz,4H),2.23(s,3H).13C NMR(101MHz,DMSO-d6)δ203.47,162.36,157.69,155.30,154.84,149.54,149.26,136.67,136.60,129.34,124.94,124.41,122.35,122.22,121.49,119.82,118.61,105.80,99.08,98.94,55.19,52.00,46.15,36.91,25.80.HRMS(ESI+):m/zcalcd for C27H25N7O2[M+H]+,480.2143；found,480.2149.
化合物B25：7-((2-((4-(4-(环丙基甲基)哌嗪-1-基)-3-甲基苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B25为原料，采用制备化合物A1的类似方法制备得到化合物B25，浅黄色固体(收率为28％)。1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),8.76(s,1H),7.77(t,J＝7.7Hz,1H),7.54(d,J＝7.6Hz,1H),7.24(d,J＝7.4Hz,3H),7.08(t,J＝2.9Hz,1H),6.76(d,J＝8.4Hz,1H),6.33(dd,J＝3.5,1.8Hz,1H),3.17(dt,J＝11.7,4.5Hz,2H),2.77(t,J＝4.7Hz,4H),2.67–2.53(m,6H),2.25(d,J＝6.6Hz,2H),2.08(s,3H),0.87(p,J＝6.7Hz,1H),0.54–0.44(m,2H),0.17–0.07(m,2H).13C NMR(101MHz,DMSO-d6)δ203.38,162.26,157.55,155.66,155.50,149.83,145.12,136.95,136.58,132.07,129.56,124.55,121.84,121.59,121.08,118.82,116.90,98.81,98.53,63.40,53.77,52.20,36.89,25.81,18.01,8.79,4.21.HRMS(ESI+):m/z calcd for C30H32N6O2[M+H]+,509.2660；found,509.2665.
化合物B26：7-((2-((3-甲基-4-(4-(噁丁环-3-基)哌嗪-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B26为原料，采用制备化合物A1的类似方法制备得到化合物B26，浅黄色固体(收率为31％)。1H NMR(400MHz,DMSO-d6)δ11.44(t,J＝2.1Hz,1H),8.75(s,1H),7.75(t,J＝7.8Hz,1H),7.52(d,J＝7.6Hz,1H),7.30–7.15(m,3H),7.06(dd,J＝3.5,2.2Hz,1H),6.74(d,J＝8.4Hz,1H),6.31(dd,J＝3.5,1.8Hz,1H),4.55(t,J＝6.5Hz,2H),4.46(t,J＝6.1Hz,2H),3.46(p,J＝6.4Hz,1H),3.14(t,J＝5.9Hz,2H),2.76(t,J＝4.7Hz,4H),2.52(dd,J＝5.0,2.9Hz,2H),2.38(s,4H),2.05(s,3H).13C NMR(101MHz,DMSO-d6)δ203.39,162.27,157.55,155.66,155.47,149.83,144.97,137.08,136.59,132.13,129.56,124.55,121.87,121.59,121.03,118.94,116.87,98.81,98.55,74.90,59.04,51.92,50.09,36.89,17.97.HRMS(ESI+):m/z calcd for C29H30N6O3[M+H]+,511.2452；found,511.2457.
化合物B27：7-((2-((4-(2-(二甲氨基)乙氧基)-3-甲基苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B27为原料，采用制备化合物A1的类似方法制备得到化合物B27，黄色固体(收率为25％)。1H NMR(400MHz,DMSO-d6)δ11.42(t,J＝2.1Hz,1H),8.67(s,1H),7.74(t,J＝7.8Hz,1H),7.50(d,J＝7.6Hz,1H),7.34–7.14(m,3H),7.04(dd,J＝3.5,2.2Hz,1H),6.63(d,J＝8.5Hz,1H),6.30(dd,J＝3.5,1.9Hz,1H),3.95(t,J＝5.8Hz,2H),3.13(t,J＝5.9Hz,2H),2.61(t,J＝5.8Hz,2H),2.56–2.51(m,2H),2.23(s,6H),1.98(s,3H).13C NMR(101MHz,DMSO-d6)δ203.38,162.26,157.52,155.72,155.64,151.26,149.82,136.54,134.64,129.52,125.79,124.51,121.71,121.55,121.51,117.20,111.80,98.82,98.45,67.03,58.37,46.14,36.89,25.78,16.66.HRMS(ESI+):m/z calcd for C26H27N5O3[M+H]+,458.2187；found,458.2185.
化合物B28：7-((2-((1-异丙基-3-甲基-1H-吡唑-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B28为原料，采用制备化合物A1的类似方法制备得到化合物B28，白色固体(收率为37％)。1H NMR(400MHz,DMSO-d6)δ11.50(s,1H),8.52(s,1H),7.72(t,J＝7.8Hz,1H),7.48(d,J＝7.6Hz,1H),7.20(d,J＝7.9Hz,1H),7.04(dd,J＝3.6,2.2Hz,1H),6.24(dd,J＝3.5,1.9Hz,1H),5.58(s,1H),4.34(p,J＝6.5Hz,1H),3.12(t,J＝6.0Hz,2H),2.57–2.52(m,2H),2.04(s,3H),1.21(d,J＝6.6Hz,6H).13C NMR(101MHz,DMSO-d6)δ203.34,162.50,157.48,156.29,155.83,149.63,145.28,138.01,136.50,129.51,124.48,122.01,121.48,98.81,98.74,47.54,36.87,25.71,22.78,14.51.HRMS(ESI+):m/z calcd for C22H22N6O2[M+Na]+,425.1697；found,425.1697.
化合物B29：5-((4-((3-羰基-2,3-二氢-1H-茚-4-基)氧代)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)异二氢吲哚-1-酮
以SEM-B29为原料，采用制备化合物A1的类似方法制备得到化合物B29，浅黄色固体(收率为23％)。1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),9.48(s,1H),8.15(s,1H),7.81(t,J＝7.8Hz,1H),7.66(s,1H),7.58(d,J＝7.6Hz,1H),7.44(dd,J＝8.5,1.8Hz,1H),7.33(d,J＝8.4Hz,1H),7.27(d,J＝7.9Hz,1H),7.17(dd,J＝3.5,2.2Hz,1H),6.41(dd,J＝3.6,1.8Hz,1H),4.10(s,2H),3.18–3.13(m,2H),2.58–2.52(m,2H).13C NMR(101MHz,DMSO-d6)δ202.92,170.12,161.87,157.15,154.84,154.12,149.31,145.05,144.35,136.17,128.98,124.85,124.11,122.58,122.22,121.28,117.29,110.95,98.69,98.38,44.74,36.40,25.29.HRMS(ESI+):m/z calcd for C23H17N5O3[M+Na]+,434.1224；found,434.1223.
化合物B30：4-氯-7-((2-((2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B30为原料，采用制备化合物A1的类似方法制备得到化合物B30，浅黄色固体(收率为26％)。1H NMR(400MHz,DMSO-d6)δ11.49(d,J＝2.3Hz,1H),7.84(d,J＝8.4Hz,1H),7.42(d,J＝8.7Hz,1H),7.29(d,J＝8.4Hz,1H),7.20(s,1H),7.06(dd,J＝3.6,2.2Hz,1H),6.54(d,J＝2.5Hz,1H),6.35(dd,J＝3.6,1.8Hz,1H),6.19(dd,J＝8.9,2.5Hz,1H),3.74(s,3H),3.07(t,J＝5.0Hz,6H),2.60–2.53(m,2H),2.46(t,J＝4.9Hz,4H),2.23(s,3H).HRMS(ESI+):m/z calcd for C27H27ClN6O3[M+H]+,519.1906；found,519.1907.
化合物B31：4-氯-7-((2-((2-甲氧基-4-吗啉代苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B31为原料，采用制备化合物A1的类似方法制备得到化合物B31，浅黄色固体(收率为22％)。1H NMR(400MHz,DMSO-d6)δ11.52(d,J＝2.3Hz,1H),7.84(d,J＝8.4Hz,1H),7.47(d,J＝8.8Hz,1H),7.30(d,J＝8.4Hz,1H),7.23(s,1H),7.07(dd,J＝3.5,2.2Hz,1H),6.56(d,J＝2.6Hz,1H),6.35(dd,J＝3.6,1.9Hz,1H),6.20(dd,J＝8.9,2.5Hz,1H),3.74(d,J＝7.8Hz,7H),3.10–3.00(m,6H),2.61–2.53(m,2H).13C NMR(101MHz,DMSO-d6)δ202.59,162.09,155.87,155.55,154.22,150.20,148.54,147.42,135.79,131.44,128.47,123.97,122.27,122.04,121.13,106.46,100.33,98.74,98.43,66.64,56.00,49.81,36.67,25.18.HRMS(ESI+):m/z calcd for C26H24ClN5O4[M+Na]+,528.1410；found,528.1416.
化合物B32：4-氯-7-((2-((2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-2,3-二氢-1H-茚-1-酮
以SEM-B32为原料，采用制备化合物A1的类似方法制备得到化合物B32，浅黄色固体(收率为25％)。1H NMR(400MHz,DMSO-d6)δ11.49(d,J＝2.3Hz,1H),7.84(d,J＝8.4Hz,1H),7.40(d,J＝8.8Hz,1H),7.30(d,J＝8.4Hz,1H),7.19(s,1H),7.06(dd,J＝3.5,2.2Hz,1H),6.53(d,J＝2.6Hz,1H),6.35(dd,J＝3.6,1.9Hz,1H),6.19(dd,J＝8.8,2.5Hz,1H),3.74(s,3H),3.66–3.56(m,2H),3.49(s,1H),3.42(t,J＝5.2Hz,1H),3.10–2.99(m,2H),2.57(ddd,J＝19.1,14.3,10.4Hz,6H),2.31(d,J＝25.4Hz,5H),2.17(s,3H),1.84(d,J＝12.3Hz,2H),1.50(dd,J＝11.8,3.8Hz,2H).HRMS(ESI+):m/z calcd for C32H36ClN7O3[M+H]+,602.2641；found,602.2640.
化合物B33：4-((4-((7-氯-3-羰基-2,3-二氢-1H-茚-4-基)氧代)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基-N-(哌啶-4-基)苯酰胺
以SEM-B33为原料，采用制备化合物A1的类似方法制备得到化合物B33，浅黄色固体(收率为23％)。1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),8.04(d,J＝7.8Hz,1H),7.94(d,J＝8.4Hz,1H),7.88(d,J＝8.4Hz,1H),7.53(s,1H),7.41(d,J＝1.9Hz,1H),7.36(d,J＝8.4Hz,1H),7.26–7.17(m,2H),6.43(d,J＝3.5Hz,1H),3.88(s,3H),3.85–3.77(m,1H),3.09(t,J＝5.9Hz,2H),3.04–2.93(m,2H),2.62–2.51(m,4H),1.79–1.70(m,2H),1.50–1.29(m,3H).13C NMR(101MHz,DMSO-d6)δ202.67,165.37,162.13,155.32,154.42,154.05,148.35,147.08,135.94,132.28,131.27,128.75,127.43,123.96,123.11,120.41,116.55,109.45,99.39,98.91,56.43,47.74,45.76,36.68,33.41,25.17.HRMS(ESI+):m/z calcd forC28H27ClN6O4[M+H]+,547.1855；found,547.1855.
化合物B34：7-((2-((2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-4-甲基-2,3-二氢-1H-茚-1-酮
以SEM-B34为原料，采用制备化合物A1的类似方法制备得到化合物B34，浅黄色固体(收率为26％)。1H NMR(400MHz,DMSO-d6)δ11.45(t,J＝2.2Hz,1H),7.56(d,J＝7.8Hz,2H),7.12(t,J＝4.0Hz,2H),7.03(dd,J＝3.5,2.2Hz,1H),6.55(d,J＝2.5Hz,1H),6.28(dd,J＝3.5,1.8Hz,1H),6.18(dd,J＝8.8,2.5Hz,1H),3.76(s,3H),3.03(dt,J＝17.2,5.3Hz,6H),2.56–2.51(m,2H),2.46(t,J＝4.9Hz,4H),2.39(s,3H),2.23(s,3H).13C NMR(101MHz,DMSO-d6)δ203.81,162.51,156.17,155.66,155.56,149.78,147.62,147.18,136.55,133.26,129.16,122.18,121.72,121.61,120.64,106.84,100.59,98.87,98.50,56.00,55.18,49.42,46.21,36.76,24.77,17.46.HRMS(ESI+):m/z calcd for C28H30N6O3[M+H]+,499.2452；found,499.2450.
化合物B35：7-((2-((2-甲氧基-4-吗啉代苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-4-甲基-2,3-二氢-1H-茚-1-酮
以SEM-B35为原料，采用制备化合物A1的类似方法制备得到化合物B35，浅黄色固体(收率为30％)。1H NMR(400MHz,DMSO-d6)δ11.53–11.40(m,1H),7.58(dd,J＝11.6,8.2Hz,2H),7.12(d,J＝6.4Hz,2H),7.04(dt,J＝3.8,2.0Hz,1H),6.57(t,J＝2.1Hz,1H),6.28(dt,J＝3.7,1.9Hz,1H),6.19(d,J＝8.8Hz,1H),3.74(dd,J＝8.7,5.0Hz,7H),3.07–2.97(m,6H),2.56–2.52(m,2H),2.39(s,3H).13C NMR(101MHz,DMSO-d6)δ203.79,162.52,156.17,155.65,155.52,149.77,147.63,147.16,136.55,133.28,129.15,122.50,121.75,121.62,120.54,106.61,100.37,98.87,98.54,66.66,56.04,49.86,36.76,24.77,17.48.HRMS(ESI+):m/z calcd for C27H27N5O4[M+Na]+,508.1956；found,508.1960.
化合物B36：7-((2-((2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧代)-4-甲基-2,3-二氢-1H-茚-1-酮
以SEM-B36为原料，采用制备化合物A1的类似方法制备得到化合物B36，浅黄色固体(收率为23％)。1H NMR(400MHz,DMSO-d6)δ11.45(d,J＝2.3Hz,1H),7.55(t,J＝8.3Hz,2H),7.12(d,J＝8.8Hz,2H),7.03(dd,J＝3.5,2.2Hz,1H),6.54(d,J＝2.5Hz,1H),6.27(dd,J＝3.6,1.9Hz,1H),6.18(dd,J＝8.9,2.5Hz,1H),3.75(s,3H),3.60(dd,J＝9.6,5.9Hz,2H),3.07–2.95(m,2H),2.65–2.51(m,7H),2.49(d,J＝1.9Hz,2H),2.38(s,3H),2.36–2.20(m,4H),2.15(s,3H),1.83(d,J＝12.3Hz,2H),1.50(qd,J＝12.1,4.0Hz,2H).13C NMR(101MHz,DMSO-d6)δ203.79,162.50,156.16,155.67,155.56,149.72,147.27,136.55,133.24,129.16,122.02,121.62,120.60,107.34,101.06,98.86,98.49,61.33,55.98,55.62,49.63,49.02,46.21,36.76,28.34,24.77,17.47.HRMS(ESI+):m/z calcd forC33H39N7O3[M+H]+,582.3187；found,582.3189.
化合物B37：3-甲氧基-4-((4-((7-甲基-3-羰基-2,3-二氢-1H-茚-4-基)氧代)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-(哌啶-4-基)苯酰胺
以SEM-B37为原料，采用制备化合物A1的类似方法制备得到化合物B37，浅黄色固体(收率为20％)。1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),8.05(d,J＝7.9Hz,1H),7.93(d,J＝8.5Hz,1H),7.60(d,J＝8.0Hz,1H),7.47(s,1H),7.40(d,J＝2.0Hz,1H),7.17(q,J＝4.5,3.3Hz,3H),6.38(d,J＝3.5Hz,1H),3.87(s,3H),3.80(td,J＝7.6,4.0Hz,1H),3.05–2.94(m,4H),2.57–2.51(m,4H),2.41(s,3H),1.78–1.68(m,2H),1.48–1.26(m,3H).13C NMR(101MHz,DMSO-d6)δ203.83,165.39,162.55,156.33,155.19,154.11,147.49,146.94,136.66,133.56,132.37,129.10,127.20,122.79,121.59,120.44,116.46,109.37,99.42,99.00,56.42,47.78,45.82,36.75,33.50,24.76,17.47.HRMS(ESI+):m/z calcd forC29H30N6O4[M+H]+,527.2402；found,527.2405.
化合物B38：7-((2-((4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)胺)-7H-吡咯[2,3-d]嘧啶-4-基)氧代)-4-甲基-2,3-二氢-1H-茚-1-酮
以SEM-B38为原料，采用制备化合物A1的类似方法制备得到化合物B38，浅黄色固体(收率为24％)。1H NMR(400MHz,DMSO-d6)δ11.62(d,J＝2.2Hz,1H),9.31(s,1H),7.84(d,J＝2.3Hz,1H),7.81–7.68(m,2H),7.52(d,J＝7.6Hz,1H),7.32(d,J＝8.7Hz,1H),7.25(d,J＝7.8Hz,1H),7.14(dd,J＝3.6,2.2Hz,1H),6.36(dd,J＝3.5,1.8Hz,1H),3.47(s,2H),3.14(t,J＝5.9Hz,2H),2.53(dd,J＝4.9,2.9Hz,2H),2.35(s,8H),2.18(s,3H).13C NMR(101MHz,DMSO-d6)δ203.37,162.29,157.60,155.28,154.78,149.66,140.71,136.66,131.00,129.49,128.34,127.47,124.60,122.53,121.55,121.20,99.21,98.92,57.85,55.26,53.05,46.16,36.86,25.77.HRMS(ESI+):m/z calcd for C28H27F3N6O2[M+H]+,537.2221；found,537.2219.
以下通过具体的试验例证明本发明的有益效果。
试验例1、化合物对FAK的抑制活性(IC50)
1、实验方法
FAK的激酶活性测试由采用Lantha screen方法，ATP浓度为Km。在1×激酶缓冲液中配制FAK溶液，浓度为各试剂最终浓度的2倍。除无酶的对照孔外，每孔加5μL的1×激酶缓冲液。在1×激酶反应缓冲液中制备荧光素-聚乳酸和ATP的底物溶液，其浓度为实验中每种试剂最终浓度的2倍。每孔加底物溶液5μL，开始反应。盖上实验板，室温孵育30分钟。在抗体稀释缓冲液中配制2倍最终浓度的检测液。每孔加检测液10μL，停止反应。用离心机简单混合并孵育60分钟，然后在酶标仪上读取荧光。在340nm激发，520nm和495nm发射下，在Envision上收集数据。设置阳性对照，阳性对照为市售FAK抑制剂Defactinib。
2、实验结果
下表1为本发明合成的系列化合物对FAK激酶的抑制情况。“++++”代表FAK IC50<50nM，“+++”代表50nM≤FAK IC50＜100nM，“++”代表100nM≤FAK IC50＜500nM，“+”代表FAKIC50>500nM。
表1化合物对FAK的IC50
上述实验结果说明：本发明化合物对FAK激酶均具有一定抑制作用，其中化合物B5～B13、B15～B19、B21～B23、B25～B27、B29～B37对FAK激酶抑制效果优异(FAK IC50<20nM)。
试验例2、化合物抗肿瘤细胞增殖的活性
1、实验方法
取对数生长期的细胞，每孔以2.5×103-1×104的细胞数量接种于96孔板，细胞培养箱中培养过夜24小时(37℃、5％CO2)，对应培养基稀释待测化合物的DMSO溶液并加入到96孔板中，每种药物8个梯度(含3个复孔)。加药组按梯度(30、10、3.3、1.1、0.37、0.12、0.04、0.01μM)每孔加入100μL化合物的培养基溶液；阴性对照组每孔中加入含1‰DMSO的空白培养基100μL，共6个复孔；空白组各孔中加入100μL培养基。将96孔板置于细胞培养孵箱内培养3天(37℃、5％CO2)。药物处理组、阴性对照组和空白组每孔加入20μL MTT溶液(5mg/mL)，继续培养2-4小时，待甲瓒形成终止培养，上清液除去后每孔加150μL DMSO，悬浮细胞则加入50μL SDS溶液(20％)，在摇床上摇15～20分钟。用酶标仪检测各孔细胞吸光度(OD570)，取其平均值记录结果。细胞增殖抑制率＝(对照组OD570-实验组OD570)/(对照组OD570-空白组OD570)×100％，Graphpad Prism软件拟合半数抑制浓度。
2、实验结果
下表2和表3分别为用MTT法测得本发明合成的化合物在体外抑制胃癌和卵巢癌细胞株增殖的活性。
表2化合物抗胃癌细胞增殖的IC50
表3化合物抗卵巢癌细胞增殖的IC50
上述实验结果说明：本发明化合物对多种胃癌和卵巢癌细胞均具有抑制作用，进一步说明本发明化合物可用于癌症治疗，特别是胃癌和卵巢癌。
试验例3、化合物的水溶性和体外肝微粒体代谢稳定性
1、实验方法
通过HPLC分析确定所选化合物的水溶性。将粉末称重并加入1mL水中。将悬浮液在37℃水浴中摇动24小时。过饱和溶液离心并过滤。将20μL滤液注入配备C18反相柱的HPLC系统中。水和甲醇用作流动相。通过注入20μL相应浓度的已知化合物的缓冲溶液进行单点校准。
体外代谢稳定性的评价方法：分别加入肝微粒体与测试物溶液或探针底物溶液，再加入辅酶NADPH和UDPGA启动反应，孵育0、15、30、60、90和120分钟。终止反应：取孵化液加入预冷的甲醇，沉淀蛋白，离心取上清，LC-MS/MS检测样品中的测试物母体剩余量。数据分析：母体剩余百分率(％of 0min)＝Tx的母体量/T0的母体量×100％(Tx：孵育时间点；T0：0分钟)。母体消除半衰期T1/2＝0.693/K(K为消除速率常数；将母体剩余百分率对数值对孵育时间作图，所得直线斜率Slope)。体外清除率(Clint)：Clint＝(0.693/T1/2)×(1/微粒体蛋白浓度)×比例因子。
2、实验结果
下表4为本发明合成的化合物在水中的溶解度和体外人肝微粒代谢稳定性参数。
表4化合物的水溶性及肝微粒体代谢稳定性
上述实验结果说明：本发明化合物具有良好的水溶性和体外肝微粒体代谢稳定性，其中化合物B9、B12、B16、B25和B36效果优异。
试验例4、化合物在体外抑制卵巢癌细胞迁移和侵袭
1、实验方法
将200μL无血清培养基中的PA-1细胞(5×104)添加到上腔室中，并将600μL含有10％FBS的培养基添加到底部。将化合物添加到小室中。使细胞迁移24小时。使用棉签去除上腔室中未迁移的细胞。将迁移的细胞用4％多聚甲醛固定，并分别用0.5％结晶紫溶液染色15分钟。随机选择迁移的细胞区域，使用光学显微镜计数并拍照。
对于侵袭实验，Transwell的上表面涂有稀释的基质胶(1:4，50μL/孔，BDBiosciences)。当稀释的基质胶固化后，将200μL无血清培养基中的PA-1细胞(1×106)添加到上腔室中，并将600μL包含10％FBS的培养基添加到底部。其他步骤与博伊登室迁移实验相同。
2、实验结果
图1为化合物B16在体外抗卵巢癌细胞PA-1迁移和侵袭的活性考察。B16在2μM下显著抑制卵巢癌细胞的迁移和侵袭。
试验例5、化合物的体内抗肿瘤药效学
1、实验方法
雌性BALB/c小鼠(6～8周)购自北京华阜康生物科技股份有限公司。将含有5×106个PA-1细胞的100μL培养基皮下注射到雌性BALB/c裸鼠右侧。在肿瘤体积达到约100mm3时，将小鼠随机分组(每组6只小鼠)。然后分别给予灌胃剂(v/v)(5％DMSO，40％PEG400，55％生理盐水)，60mg/kg B16口服21天。顺铂5mg/kg水溶，每9天腹腔注射1次。用数字卡尺测量肿瘤体积，记录小鼠体重，每天观察临床症状。最后，所有动物均进行安乐死。肿瘤体积按以下公式计算：肿瘤体积(mm3)＝0.5×L×W2，其中L为长，W为宽。数据以平均值±SEM表示。肿瘤生长抑制(TGI)的计算方程：TGI＝[1-(T-T0)/(C-C0)]×100％，T和T0表示治疗组给药的最后一天和第一天的平均肿瘤体积。C和C0表示溶媒组给药的最后一天和第一天的平均肿瘤体积。
2、实验结果
图2为构建PA-1小鼠皮下异种移植瘤模型，并通过连续口服给药21天观察B16的药效。化合物B16能显著抑制PA-1肿瘤生长，其肿瘤生长抑制率(tumor growth inhibition,TGI)为72.5％。化合物B16与顺铂联用的TGI为78.4％。无论是B16单药组还是与顺铂联用组的小鼠都没有出现明显的体重减轻，表明化合物B16具有较好的耐受性。
综上，本发明化合物对FAK激酶有显著的抑制作用，可以用于制备FAK抑制剂；还可以用于制备预防和/或治疗与FAK活性有关的疾病的药物，如制备预防和/或治疗癌症、纤维化疾病、自身免疫性疾病、感染性疾病或细胞增殖紊乱等疾病的药物。同时，本发明化合物药代动力学良好，具有广阔的应用前景。
Claims (12)
1.式I所示的化合物或其盐：
其中，
R1选自氢；
R20选自氢；
R2选自-OR3、
R3选自
R4’选自氢、C1～C3烷基、卤素；
X选自-NR5-；
R5选自氢；
A环选自被1～3个R7取代的苯基、被1～3个R7取代的吡啶基、被1～3个R7取代的吡唑基、
R7分别独立选自卤素、氰基、被0～3个R8取代的C1～C3烷基、被0～3个R8取代的C1～C3烷氧基、被0～2个R8取代的吗啉基、被0～1个R8取代的哌啶基、被0～2个R8取代的哌嗪基、-C(O)R9、-C(O)NR9R10；
R8分别独立选自卤素、-C(O)R9、-NR9R10、被0～1个R11取代的C1～C3烷基、被0～1个R11取代的哌嗪基、氧杂环丁烷；
R9、R10分别独立选自氢、C1～C3烷基、C1～C3烷氧基、3～6元环烷基、哌啶基；
R11选自C1～C3烷基、3～6元环烷基。
2.根据权利要求1所述的化合物或其盐，其特征在于：所述化合物如式II所示：
其中，
Y、Y’分别独立选自-CR7b或-N-，且Y、Y’不同时为N；
R7a、R7b、R7c分别独立选自氢、卤素、氰基、被0～3个R8取代的C1～C3烷基、被0～3个R8取代的C1～C3烷氧基、被0～2个R8取代的吗啉基、被0～1个R8取代的哌啶基、被0～1个R8取代的哌嗪基、-C(O)R9、-C(O)NR9R10；R7a、R7b、R7c不同时选自氢；
R8分别独立选自卤素、-C(O)R9、-NR9R10、被0～1个R11取代的C1～C3烷基、被0～1个R11取代的哌嗪基、氧杂环丁烷；
R9、R10分别独立选自氢、C1～C3烷基、C1～C3烷氧基、3～6元环烷基、哌啶基；
R11选自C1～C3烷基、3～6元环烷基。
3.根据权利要求1所述的化合物或其盐，其特征在于：所述化合物如式III所示：
其中，
Y、Y’分别独立选自-CR7b或-N-，且Y、Y’不同时为N；
R7a、R7b、R7c分别独立选自氢、卤素、氰基、被0～3个R8取代的C1～C3烷基、被0～3个R8取代的C1～C3烷氧基、被0～2个R8取代的吗啉基、被0～1个R8取代的哌啶基、被0～1个R8取代的哌嗪基、-C(O)R9、-C(O)NR9R10；R7a、R7b、R7c不同时选自氢；
R8分别独立选自卤素、-C(O)R9、-NR9R10、被0～1个R11取代的C1～C3烷基、被0～1个R11取代的哌嗪基、氧杂环丁烷；
R9、R10分别独立选自氢、C1～C3烷基、C1～C3烷氧基、3～6元环烷基、哌啶基；
R11选自C1～C3烷基、3～6元环烷基。
4.根据权利要求1所述的化合物或其盐，其特征在于：所述化合物如式IV所示：
其中，
Y、Y’分别独立选自-CR7b或-N-，且Y、Y’不同时为N；
R7a、R7b、R7c分别独立选自氢、卤素、氰基、被0～3个R8取代的C1～C3烷基、被0～3个R8取代的C1～C3烷氧基、被0～2个R8取代的吗啉基、被0～1个R8取代的哌啶基、被0～1个R8取代的哌嗪基、-C(O)R9、-C(O)NR9R10；R7a、R7b、R7c不同时选自氢；
R8分别独立选自卤素、-C(O)R9、-NR9R10、被0～1个R11取代的C1～C3烷基、被0～1个R11取代的哌嗪基、氧杂环丁烷；
R9、R10分别独立选自氢、C1～C3烷基、C1～C3烷氧基、3～6元环烷基、哌啶基；
R11选自C1～C3烷基、3～6元环烷基。
5.根据权利要求1所述的化合物或其盐，其特征在于：所述化合物如式V所示：
其中，
R4’选自氢、C1～C3烷基、卤素；
Y、Y’分别独立选自-CR7b或-N-，且Y、Y’不同时为N；
R7a、R7b、R7c分别独立选自氢、卤素、氰基、被0～3个R8取代的C1～C3烷基、被0～3个R8取代的C1～C3烷氧基、被0～2个R8取代的吗啉基、被0～1个R8取代的哌啶基、被0～1个R8取代的哌嗪基、-C(O)R9、-C(O)NR9R10；R7a、R7b、R7c不同时选自氢；
R8分别独立选自卤素、-C(O)R9、-NR9R10、被0～1个R11取代的C1～C3烷基、被0～1个R11取代的哌嗪基、氧杂环丁烷；
R9、R10分别独立选自氢、C1～C3烷基、C1～C3烷氧基、3～6元环烷基、哌啶基；
R11选自C1～C3烷基、3～6元环烷基。
6.根据权利要求1所述的化合物或其盐，其特征在于：所述化合物为如下化合物之一：
7.权利要求1～6任一项所述的化合物或其盐在制备FAK抑制剂中的用途。
8.根据权利要求7所述的用途，其特征在于：所述FAK抑制剂为治疗与FAK活性有关疾病的药物。
9.根据权利要求8所述的用途，其特征在于：所述FAK抑制剂为治疗癌症、纤维化疾病、自身免疫性疾病、感染性疾病或细胞增殖紊乱的药物。
10.根据权利要求9所述的用途，其特征在于：所述癌症选自卵巢癌、胃癌、胰腺癌、前列腺癌、结直肠癌、肝癌、乳腺癌、甲状腺癌、肺癌、黑色素瘤、间皮瘤、子宫癌、骨肿瘤；
所述纤维化疾病为肺纤维化、肝纤维化。
11.根据权利要求10所述的用途，其特征在于：所述黑色素瘤选自葡萄膜黑色素瘤。
12.一种药物，其特征在于：它是由权利要求1～6任一项所述的化合物或其盐为活性成分，加上药物上可接受的辅料或辅助性成分制备而成的制剂。
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