CN115403583B - 一种靶向降解fak蛋白的化合物及其用途 - Google Patents
一种靶向降解fak蛋白的化合物及其用途 Download PDFInfo
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Abstract
本发明提供了一种靶向降解FAK蛋白的化合物及其用途，属于化学医药领域。该化合物的结构如式I所示。本发明的化合物能有效降解FAK蛋白，能够通过同时阻断FAK激酶依赖和非激酶依赖的功能，发挥更强的抗肿瘤作用。本发明化合物在制备FAK降解剂，以及治疗与FAK蛋白相关的肿瘤的药物中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，具体涉及一种靶向降解FAK蛋白的化合物及其用途。
背景技术
局部黏着斑激酶(focal adhesion kinase，FAK)是一种非受体细胞内酪氨酸激酶，其同时具有激酶依赖和非激酶依赖的支架功能，在肿瘤的发生发展及转移侵袭中均起到重要作用，被认为是抗肿瘤药物研发的重要靶点。FAK是一个包含FERM结构域、激酶域、FAT结构域和脯氨酸富集区(PRR)的多结构域蛋白。其激酶域高度保守，对FAK及下游蛋白的磷酸化起重要作用。而FERM、FAT和PRR结构域主要通过蛋白-蛋白相互作用参与信号转导、激酶的定位以及为复合物形成提供骨架，例如，FERM结构域与EGFR、PDGFR、c-Met等膜蛋白相互作用，PRRs与含有SH3结构域的蛋白相互作用，而FAT结构域与黏着斑复合物的相关蛋白如桩蛋白、踝蛋白等相互作用。因此，FAK不仅能通过激酶结构域发挥催化功能，也能通过其他结构域发挥骨架作用，即FAK的非激酶依赖功能(kinase-independent function)。
目前已经有大量靶向作用FAK的小分子抑制剂被报道，其中，报道最多的是ATP竞争性抑制的FAK激酶抑制剂。例如以下化合物a、b、c，这三个化合物抑制FAK激酶活性的IC50值分别为3.4μM、50nM、86.7nM。但是，这些ATP竞争性抑制的FAK激酶抑制剂通常只能阻断FAK激酶依赖的功能，无法阻断FAK非激酶依赖的功能，对FAK的抑制作用有限。
研究发现，FAK的非激酶依赖功能对肿瘤生长、转移和维持干细胞特性也具有促进作用。例如，细胞核内的FAK通过FERM结构域与p53和E3连接酶MDM2结合，诱导p53泛素化降解，从而激活p53下游基因的转录并使细胞凋亡受到抑制。在乳腺癌中，FAK通过PRR结构域发挥骨架蛋白的功能，介导endophilin A2磷酸化，使上皮-间质转化(epithelial-mesenchymal transition,EMT)标志物表达上调，并使乳腺癌干细胞活力增加。因此，利用小分子靶向降解FAK蛋白可以同时阻断FAK的激酶依赖功能和非激酶依赖功能，可潜在地提升靶向FAK的抗肿瘤效果(J.Am.Chem.Soc.,2018,140,49,17019–17026；Exp.Cell Res.,2021,408,2,112868)。
开发出能够靶向降解FAK蛋白的新化合物对治疗与FAK蛋白相关的肿瘤具有重要意义。
发明内容
本发明的目的在于提供一种靶向降解FAK蛋白的化合物及其用途。
本发明提供了式I所示化合物、其药学上可接受的盐、其立体异构体、其水合物、其溶剂合物、其前药或其氘代化合物：
其中，p选自0～4的整数；
R1各自独立的选自氢、羟基、C1～8烷基、C1～8烷氧基；
X选自CONH、NHCO、NH、CO、O、S、COO、OCO、CH2、无；
A环选自5～6元饱和环烷基、5～6元不饱和环烷基、5～6元饱和杂环基、5～6元不饱和杂环基；
q选自0～5的整数；
R2各自独立的选自
氢、C1～8烷基、C1～8烷氧基、C2～8烯基、C2～8炔基、3～8元饱和环烷基、3～8元不饱和环烷基、3～8元饱和杂环基、3～8元不饱和杂环基；
Y选自无、C1～20亚烷基、
n选自1～20的整数，W选自O或S；
Z选自NH、O或S。
进一步地，所述化合物的结构如式II所示：
其中，p选自0～4的整数；
R1各自独立的选自氢、羟基、C1～8烷基、C1～8烷氧基；
R2选自
氢、C1～8烷基、C1～8烷氧基、C2～8烯基、C2～8炔基、3～8元饱和环烷基、3～8元不饱和环烷基、3～8元饱和杂环基、3～8元不饱和杂环基；
Y选自无、C1～20亚烷基、
n选自1～20的整数，W选自O或S；
Z选自NH、O或S。
进一步地，所述化合物的结构如式III所示：
其中，Y选自无、C1～20亚烷基、
n选自1～20的整数，W选自O或S；
Z选自NH、O或S；
R0选自氢、C1～8烷基。
进一步地，所述化合物的结构如式IV-1所示：
其中，m选自4～12的整数；
R0选自氢、C1～4烷基。
进一步地，所述化合物的结构如式IV-2所示：
其中，n选自1～3的整数；
R0选自氢、C1～4烷基。
进一步地，所述化合物选自以下化合物之一：
化合物D1：
化合物D2：
化合物D3：
化合物D4：
化合物D5：
化合物D6：
化合物D7：
化合物D8：
化合物D9：
化合物D10：
化合物D11：
化合物D12：
本发明还提供了一种靶向降解FAK蛋白的药物，它是以上述的化合物、其药学上可接受的盐、其立体异构体、其水合物、其溶剂合物、其前药或其氘代化合物为活性成分，加上药学上可接受的辅助性成分制得的制剂。
本发明还提供了上述的化合物、其药学上可接受的盐、其立体异构体、其水合物、其溶剂合物、其前药或其氘代化合物在制备FAK降解剂中的用途。
进一步地，所述FAK降解剂能够靶向降解FAK蛋白。
进一步地，所述FAK降解剂为预防和/或治疗与FAK蛋白相关的肿瘤的药物。
进一步地，所述FAK降解剂为抑制与FAK蛋白相关的肿瘤转移的药物。
进一步地，所述肿瘤为卵巢癌、肺癌、乳腺癌、前列腺癌、甲状腺癌、宫颈癌、结直肠癌、胃癌、胰腺癌、肝癌、葡萄膜黑色素瘤、黑色素瘤、间皮瘤、子宫癌、骨肿瘤。
进一步地，所述肿瘤为卵巢癌。
本发明还提供了一种抗肿瘤的联合用药物，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上述的化合物、其药学上可接受的盐、其立体异构体、其水合物、其溶剂合物、其前药或其氘代化合物和其它药物，以及药学上可接受的载体。
所述其它药物选自化疗药、用于免疫检查点疗法的药物、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；
用于免疫检查点疗法的药物包括但不限于
(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。
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。
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，C1～8烷基是指包含1～8个碳原子的直链或支链的烷基。
“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。
“盐”是将化合物与无机和/或有机酸和/或碱形成的酸式和/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。也可以是通过将化合物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。
本发明中所述“药学上可接受的盐”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。
“氘代化合物”指化合物中的一个或两个以上的氢原子被氘替换后得到的化合物。
“环烷基”指饱和或不饱和的环状烃取代基；环状烃可以是单环也可以是多环。
“饱和环烷基”指饱和的环烷基。例如，“3-8元饱和环烷基”指环碳原子数为3～8的饱和环烷基。
“不饱和环烷基”指不饱和的环烷基。例如，“3-8元不饱和环烷基”指环碳原子数为3～8的不饱和环烷基。
“杂环基”指饱和或不饱和的环状烃取代基；环状烃可以是单环也可以是多环，且携带至少一个环杂原子(包括但不限于O、S或N)。
“饱和杂环基”指饱和的杂环基。例如，“3-8元饱和杂环基”指环碳原子数为3～8的饱和杂环基。
“不饱和杂环基”指不饱和的杂环基。例如，“3-8元不饱和杂环基”指环碳原子数为3～8的不饱和杂环基。
实验结果表明，本发明的化合物能有效降解FAK蛋白，能够通过同时阻断FAK激酶依赖和非激酶依赖的功能，发挥更强的抗肿瘤作用，在制备治疗与FAK蛋白相关的肿瘤的药物中具有潜在的应用前景。
进一步的实验结果还证实，本发明化合物在体内外均能够有效抑制卵巢癌，发挥优异的抗癌效果。
本领域技术人员公知的，与FAK蛋白相关的肿瘤包括肿瘤为卵巢癌、肺癌、乳腺癌、前列腺癌、甲状腺癌、宫颈癌、结直肠癌、胃癌、胰腺癌、肝癌、葡萄膜黑色素瘤、黑色素瘤、间皮瘤、子宫癌、骨肿瘤等。本发明提供的化合物制备方法简单，在制备FAK降解剂，以及治疗与FAK蛋白相关的肿瘤的药物中具有广阔的应用前景。
实验结果还表明，本发明化合物与顺铂联用时能够明显提升药效。本发明提供的化合物在制备抗肿瘤的联合用药物中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：化合物B16、D1-D12对FAK蛋白的降解能力。
图2：化合物D4在不同处理浓度下对FAK蛋白的降解能力。
图3：化合物D4在不同处理时间下对FAK蛋白的降解能力。
图4：化合物D4在多种卵巢癌细胞中对FAK的降解。
图5：化合物D4抑制卵巢癌细胞克隆形成的结果。
图6：化合物D4、顺铂的体内抗卵巢癌活性。
具体实施方式
本发明所用原料与设备均为已知产品，可通过购买市售产品所得。
根据以下合成路线一，分别制得本发明目标化合物D1-D12：
实施例1制备化合物D1
化合物D1：N-(1-(4-((2-(2,6-二羰基哌啶-3-基)-1,3-二羰基异二氢吲哚-4-基)氧代)丁基)哌啶-4-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
按照申请号为202110548283.3的中国专利申请记载的方法，制得化合物B16。
将B16(51mg,0.1mmol)和4-(4-溴丁氧基)-2-(2,6-二羰基哌啶-3-基)异二氢吲哚-1,3-二酮(45mg,0.11mmol)溶于2mL超干DMF中，加入碳酸氢钠(12.6mg,15％mmol)和碘化钾(2.5mg,15％mmol)，氮气保护下升温至80℃反应2h。TLC监测反应完毕，将反应液倒入水中，有白色固体析出。抽滤，滤饼用二氯甲烷溶解后经制备TLC(DCM/methanol＝10:1)纯化得浅黄色固体，化合物D1(29mg,34％yield)。1H NMR(400MHz,Chloroform-d)δ9.86(s,1H),7.99(d,J＝8.5Hz,1H),7.71–7.55(m,3H),7.40(dd,J＝7.5,5.1Hz,2H),7.28(s,1H),7.14(dd,J＝15.1,8.2Hz,2H),7.04(d,J＝9.0Hz,1H),6.93(d,J＝3.7Hz,1H),6.82(s,1H),6.44(d,J＝3.5Hz,1H),5.03–4.92(m,1H),4.13(t,J＝7.2Hz,1H),4.04(s,2H),3.77(s,3H),3.20–3.10(m,2H),3.07(d,J＝11.2Hz,2H),2.88–2.73(m,5H),2.55(t,J＝6.0Hz,2H),2.44–2.27(m,3H),1.97(d,J＝12.7Hz,2H),1.87–1.72(m,6H).HRMS(ESI+):m/zcalcd forC45H44N8O9[M+H]+,841.3304；found,841.3310.
实施例2制备化合物D2
化合物D2：N-(1-(5-((2-(2,6-二羰基哌啶-3-基)-1,3-二羰基异二氢吲哚-4-基)氧代)戊基)哌啶-4-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
参照实施例1的方法，区别仅在于将合成路线一中的原料2进行对应替换，得到化合物D2。浅黄色固体(33％yield)。1H NMR(400MHz,Chloroform-d)δ9.83(s,1H),7.95(d,J＝8.4Hz,1H),7.69–7.56(m,3H),7.39(t,J＝7.1Hz,2H),7.26(d,J＝4.3Hz,2H),7.16(dd,J＝8.2,6.5Hz,2H),7.02–6.94(m,1H),6.91(d,J＝3.6Hz,1H),6.45(d,J＝3.5Hz,2H),5.01–4.91(m,1H),4.13(d,J＝6.5Hz,2H),3.95(s,1H),3.77(s,3H),3.14(t,J＝6.0Hz,2H),2.88(d,J＝14.5Hz,2H),2.78(dt,J＝21.0,8.5Hz,4H),2.55(t,J＝6.1Hz,2H),2.37(d,J＝8.0Hz,2H),2.11(d,J＝9.4Hz,2H),1.95(d,J＝12.3Hz,2H),1.84(t,J＝7.0Hz,2H),1.60(d,J＝14.8Hz,4H),1.50(d,J＝7.6Hz,2H).HRMS(ESI+):m/zcalcd for C46H46N8O9[M+H]+,855.3461；found,855.3470.
实施例3制备化合物D3
化合物D3：N-(1-(6-((2-(2,6-二羰基哌啶-3-基)-1,3-二羰基异二氢吲哚-4-基)氧代)己基)哌啶-4-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
参照实施例1的方法，区别仅在于将合成路线一中的原料2进行对应替换，得到化合物D3。浅黄色固体(30％yield)。1H NMR(400MHz,Chloroform-d)δ9.71(s,1H),7.93(d,J＝8.5Hz,1H),7.73–7.57(m,3H),7.41(d,J＝7.4Hz,2H),7.25(d,J＝2.1Hz,1H),7.21–7.11(m,2H),6.99–6.85(m,2H),6.47(d,J＝3.6Hz,1H),6.36(d,J＝7.6Hz,1H),4.95(dd,J＝12.1,5.1Hz,1H),4.14(t,J＝6.4Hz,2H),3.96(s,1H),3.79(s,3H),3.15(t,J＝6.0Hz,2H),2.90(t,J＝11.4Hz,3H),2.81(dd,J＝14.4,3.2Hz,2H),2.77–2.69(m,2H),2.59–2.53(m,2H),2.37(t,J＝7.8Hz,2H),2.17–2.08(m,3H),1.97(d,J＝12.9Hz,2H),1.84(t,J＝7.4Hz,2H),1.62(d,J＝11.3Hz,2H),1.52(s,4H).HRMS(ESI+):m/zcalcd for C47H48N8O9[M+H]+,869.3617；found,869.3627.
实施例4制备化合物D4
化合物D4：N-(1-(7-((2-(2,6-二羰基哌啶-3-基)-1,3-二羰基异二氢吲哚-4-基)氧代)庚基)哌啶-4-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
参照实施例1的方法，区别仅在于将合成路线一中的原料2进行对应替换，得到化合物D4。浅黄色固体(37％yield)。1H NMR(400MHz,Chloroform-d)δ9.76(s,1H),7.93(d,J＝8.4Hz,1H),7.71–7.58(m,3H),7.41(dd,J＝7.5,5.7Hz,2H),7.18(d,J＝8.2Hz,2H),6.99–6.87(m,2H),6.47(d,J＝3.6Hz,1H),6.36(d,J＝8.1Hz,1H),4.95(dd,J＝12.0,5.1Hz,1H),4.14(q,J＝6.6Hz,2H),3.97(d,J＝7.4Hz,1H),3.78(s,3H),3.15(t,J＝5.7Hz,2H),2.93(d,J＝10.9Hz,2H),2.88–2.80(m,2H),2.80–2.70(m,3H),2.57–2.53(m,2H),2.34(t,J＝7.8Hz,2H),2.15–2.06(m,3H),1.98(d,J＝12.6Hz,2H),1.83(t,J＝7.2Hz,2H),1.68–1.58(m,2H),1.40(d,J＝10.2Hz,3H),1.34–1.28(m,3H).HRMS(ESI+):m/zcalcd forC48H50N8O9[M+H]+,883.3774；found,883.3776.
实施例5制备化合物D5
化合物D5：N-(1-(8-((2-(2,6-二羰基哌啶-3-基)-1,3-二羰基异二氢吲哚-4-基)氧代)辛基)哌啶-4-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
参照实施例1的方法，区别仅在于将合成路线一中的原料2进行对应替换，得到化合物D5。浅黄色固体(35％yield)。1H NMR(400MHz,Chloroform-d)δ10.04(s,1H),7.88(d,J＝8.4Hz,1H),7.73(s,1H),7.62(dt,J＝12.5,7.8Hz,2H),7.39(t,J＝6.5Hz,2H),7.23(s,1H),7.16(d,J＝8.2Hz,2H),6.92(dd,J＝18.5,6.1Hz,2H),6.44(t,J＝5.7Hz,2H),4.94(dd,J＝11.7,5.5Hz,1H),4.12(q,J＝7.2Hz,2H),3.99–3.90(m,1H),3.76(s,3H),3.13(t,J＝5.8Hz,2H),2.94(d,J＝9.2Hz,2H),2.78(dtd,J＝26.8,17.1,15.7,8.8Hz,3H),2.54(t,J＝6.0Hz,2H),2.34(dt,J＝9.9,4.5Hz,2H),2.08(d,J＝10.5Hz,3H),2.02–1.92(m,2H),1.83(p,J＝6.9Hz,2H),1.63(t,J＝11.4Hz,3H),1.47(p,J＝7.6Hz,4H),1.33(s,5H).HRMS(ESI+):m/zcalcd for C49H52N8O9[M+H]+,897.3930；found,897.3939.
实施例6制备化合物D6
化合物D6：N-(1-(9-((2-(2,6-二羰基哌啶-3-基)-1,3-二羰基异二氢吲哚-4-基)氧代)壬基)哌啶-4-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
参照实施例1的方法，区别仅在于将合成路线一中的原料2进行对应替换，得到化合物D6。浅黄色固体(39％yield)。1H NMR(400MHz,Chloroform-d)δ9.55(s,1H),7.93(d,J＝8.4Hz,1H),7.73–7.60(m,3H),7.42(dd,J＝7.5,3.3Hz,2H),7.24(d,J＝1.8Hz,1H),7.19(d,J＝8.2Hz,2H),6.98–6.89(m,2H),6.49(d,J＝3.7Hz,1H),6.17(d,J＝8.0Hz,1H),4.93(dd,J＝12.0,5.3Hz,1H),4.23–4.07(m,2H),3.97(d,J＝10.8Hz,1H),3.81(s,3H),3.16(t,J＝6.0Hz,2H),2.97(s,2H),2.83(td,J＝15.0,14.1,3.9Hz,2H),2.78–2.66(m,2H),2.56(t,J＝6.1Hz,2H),2.43–2.26(m,3H),2.12(dq,J＝11.6,7.5,5.7Hz,3H),2.06–1.94(m,3H),1.84(h,J＝6.9Hz,2H),1.72–1.56(m,3H),1.52(p,J＝7.0Hz,4H),1.38(s,4H).HRMS(ESI+):m/zcalcd for C50H54N8O9[M+H]+,911.4087；found,911.4091.
实施例7制备化合物D7
化合物D7：N-(1-(10-((2-(2,6-二羰基哌啶-3-基)-1,3-二羰基异二氢吲哚-4-基)氧代)癸基)哌啶-4-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
参照实施例1的方法，区别仅在于将合成路线一中的原料2进行对应替换，得到化合物D7。浅黄色固体(37％yield)。1H NMR(400MHz,Chloroform-d)δ9.48(s,1H),7.93(d,J＝8.4Hz,1H),7.72–7.60(m,3H),7.42(dd,J＝7.5,3.1Hz,2H),7.24(d,J＝1.9Hz,1H),7.19(d,J＝8.1Hz,2H),6.94(dd,J＝7.7,2.6Hz,2H),6.50(d,J＝3.6Hz,1H),6.16(d,J＝7.9Hz,1H),4.94(dd,J＝12.2,5.4Hz,1H),4.23–4.07(m,2H),4.02–3.93(m,1H),3.82(s,3H),3.16(t,J＝5.9Hz,2H),3.03–2.93(m,2H),2.89–2.80(m,2H),2.79–2.63(m,2H),2.60–2.53(m,2H),2.35(td,J＝7.1,3.1Hz,2H),2.17–2.06(m,3H),2.03–1.94(m,2H),1.85(d,J＝8.0Hz,2H),1.63(d,J＝11.1Hz,3H),1.50(q,J＝7.2Hz,4H),1.38(d,J＝9.2Hz,4H),1.28–1.21(m,5H).HRMS(ESI+):m/zcalcd for C51H56N8O9[M+H]+,925.4243；found,925.4247.
实施例8制备化合物D8
化合物D8：N-(1-(11-((2-(2,6-二羰基哌啶-3-基)-1,3-二羰基异二氢吲哚-4-基)氧代)十一烷基)哌啶-4-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
参照实施例1的方法，区别仅在于将合成路线一中的原料2进行对应替换，得到化合物D8。浅黄色固体(32％yield)。1H NMR(400MHz,Chloroform-d)δ9.96(s,1H),7.89(d,J＝8.4Hz,1H),7.72(s,1H),7.63(dt,J＝12.1,7.8Hz,2H),7.40(t,J＝6.7Hz,2H),7.23(s,1H),7.18(d,J＝8.3Hz,2H),6.93(dd,J＝13.1,6.2Hz,2H),6.46(d,J＝3.5Hz,1H),6.37(d,J＝7.9Hz,1H),4.95(dd,J＝12.2,5.5Hz,1H),4.13(t,J＝6.6Hz,2H),4.02–3.92(m,1H),3.77(s,3H),3.14(t,J＝5.9Hz,2H),3.02–2.91(m,2H),2.90–2.67(m,3H),2.54(t,J＝5.9Hz,2H),2.36(t,J＝7.7Hz,2H),2.18–2.06(m,3H),1.99(d,J＝12.4Hz,2H),1.83(q,J＝7.1Hz,2H),1.64(t,J＝9.2Hz,3H),1.48(q,J＝7.2Hz,4H),1.31(d,J＝19.3Hz,8H),1.23(s,3H).HRMS(ESI+):m/zcalcd for C52H58N8O9[M+H]+,939.4400；found,939.4402.
实施例9制备化合物D9
化合物D9：N-(1-(12-((2-(2,6-二羰基哌啶-3-基)-1,3-二羰基异二氢吲哚-4-基)氧代)十二基)哌啶-4-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
参照实施例1的方法，区别仅在于将合成路线一中的原料2进行对应替换，得到化合物D9。浅黄色固体(36％yield)。1H NMR(400MHz,Chloroform-d)δ9.55(s,1H),7.93(d,J＝8.5Hz,1H),7.73–7.57(m,3H),7.42(dd,J＝7.4,4.8Hz,2H),7.24(d,J＝1.9Hz,1H),7.19(d,J＝8.2Hz,2H),7.00–6.89(m,2H),6.50(d,J＝3.4Hz,1H),6.19(d,J＝7.9Hz,1H),4.95(dd,J＝12.4,5.4Hz,1H),4.15(t,J＝6.5Hz,2H),3.98(d,J＝10.2Hz,1H),3.81(d,J＝2.2Hz,3H),3.16(t,J＝5.9Hz,2H),2.97(d,J＝11.1Hz,2H),2.86(td,J＝13.1,11.6,3.7Hz,2H),2.81–2.69(m,2H),2.56(t,J＝6.1Hz,2H),2.36(td,J＝7.1,2.8Hz,2H),2.20–2.07(m,4H),2.06–1.97(m,3H),1.86(p,J＝6.7Hz,3H),1.63(q,J＝12.9,12.4Hz,4H),1.50(q,J＝7.5Hz,5H),1.35(d,J＝22.8Hz,7H).HRMS(ESI+):m/zcalcd for C53H60N8O9[M+H]+,953.4556；found,953.4568.
实施例10制备化合物D10
化合物D10：N-(1-(2-(2-((2-(2,6-二羰基哌啶-3-基)-1,3-二羰基异二氢吲哚-4-基)氧代)乙氧基)乙基)哌啶-4-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
参照实施例1的方法，区别仅在于将合成路线一中的原料2进行对应替换，得到化合物D10。浅黄色固体(35％yield)。1H NMR(400MHz,Chloroform-d)δ10.19(s,1H),7.91(d,J＝8.4Hz,1H),7.63(dd,J＝14.4,6.7Hz,2H),7.55(t,J＝7.9Hz,1H),7.38(d,J＝7.7Hz,1H),7.32(d,J＝7.3Hz,1H),7.23(s,1H),7.14(dd,J＝13.0,8.2Hz,2H),6.93(dd,J＝13.7,6.1Hz,2H),6.51(d,J＝7.9Hz,1H),6.41(d,J＝3.5Hz,1H),5.02–4.90(m,1H),4.20(d,J＝4.6Hz,2H),3.95(s,1H),3.81(q,J＝7.8,6.1Hz,2H),3.73(d,J＝4.3Hz,5H),3.13(t,J＝5.9Hz,2H),2.94(s,2H),2.75(q,J＝14.2,13.2Hz,3H),2.62(t,J＝5.4Hz,2H),2.54(t,J＝6.1Hz,2H),2.21(t,J＝11.4Hz,2H),2.06(t,J＝6.6Hz,1H),1.92(d,J＝12.1Hz,2H),1.62(d,J＝11.9Hz,2H).HRMS(ESI+):m/zcalcd for C45H44N8O10[M+H]+,857.3253；found,857.3255.
实施例11制备化合物D11
化合物D11：N-(1-(2-(2-(2-((2-(2,6-二羰基哌啶-3-基)-1,3-二羰基异二氢吲哚-4-基)氧代)乙氧基)乙氧基)乙基)哌啶-4-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
参照实施例1的方法，区别仅在于将合成路线一中的原料2进行对应替换，得到化合物D11。浅黄色固体(29％yield)。1H NMR(400MHz,DMSO-d6)δ11.70(t,J＝2.1Hz,1H),11.11(s,1H),8.01(d,J＝7.8Hz,1H),7.94(d,J＝8.5Hz,1H),7.80(q,J＝7.7Hz,2H),7.55(dd,J＝10.8,8.0Hz,2H),7.51–7.43(m,2H),7.40(d,J＝1.8Hz,1H),7.27(d,J＝7.8Hz,1H),7.23–7.15(m,2H),6.40(dd,J＝3.6,1.9Hz,1H),5.09(dd,J＝12.9,5.4Hz,1H),4.35(t,J＝4.6Hz,2H),3.88(s,3H),3.82(t,J＝4.5Hz,2H),3.71(dd,J＝7.6,4.0Hz,1H),3.65(dd,J＝5.8,3.8Hz,2H),3.56–3.46(m,4H),3.16(t,J＝5.8Hz,2H),2.91–2.82(m,3H),2.63–2.52(m,4H),2.46(t,J＝6.0Hz,3H),2.07–2.01(m,2H),1.78–1.70(m,2H),1.55(qd,J＝12.4,3.9Hz,2H).HRMS(ESI+):m/zcalcd for C47H48N8O11[M+H]+,901.3516；found,901.3500.
实施例12制备化合物D12
化合物D12：N-(1-(2-(2-(2-(2-((2-(2,6-二羰基哌啶-3-基)-1,3-二羰基异二氢吲哚-4-基)氧代)乙氧基)乙氧基)乙氧基)乙基)哌啶-4-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
参照实施例1的方法，区别仅在于将合成路线一中的原料2进行对应替换，得到化合物D12。浅黄色固体(30％yield)。1H NMR(400MHz,DMSO-d6)δ11.70(t,J＝2.2Hz,1H),11.12(s,1H),8.01(d,J＝7.7Hz,1H),7.94(d,J＝8.4Hz,1H),7.86–7.74(m,2H),7.55(dd,J＝13.7,8.1Hz,2H),7.50–7.42(m,2H),7.40(d,J＝1.8Hz,1H),7.27(d,J＝7.8Hz,1H),7.22–7.15(m,2H),6.39(dd,J＝3.5,1.9Hz,1H),5.09(dd,J＝12.9,5.4Hz,1H),4.35(t,J＝4.5Hz,2H),3.88(s,3H),3.81(t,J＝4.5Hz,2H),3.72(dq,J＝7.3,3.7,3.2Hz,1H),3.65(dd,J＝6.0,3.6Hz,2H),3.58–3.41(m,8H),3.16(t,J＝5.9Hz,2H),2.88(dt,J＝11.6,3.8Hz,2H),2.58–2.52(m,4H),2.48–2.39(m,3H),2.08–1.94(m,3H),1.81–1.69(m,2H),1.55(qd,J＝12.3,3.9Hz,2H).HRMS(ESI+):m/zcalcd for C49H52N8O12[M+H]+,945.3778；found,945.3772.
以下通过实验例证明本发明的有益效果。
实验例1化合物D1～D12诱导FAK蛋白降解的能力
1、实验方法
培养并收集细胞并在RIPA缓冲液(Beyotime，北京，中国)中裂解。然后，将细胞裂解物在4℃下以13,000rpm离心10分钟，收集上清液。通过BCA法平衡蛋白质的浓度。用SDS-PAGE分离等量的总蛋白，并在250mA，2h条件下转移到硝酸纤维素膜上。在室温下用溶于TBS/T的5％脱脂牛奶封闭1.5小时后，将膜与一抗在室温下孵育2～4小时。在与辣根过氧化物酶偶联的二抗(中山公司，北京)孵育后，使用增强的化学发光底物在辣根过氧化物酶(Amersham，Piscataway，NJ)使蛋白质条带可视化。
2、实验结果
如图1所示，本发明化合物D1～D12对FAK蛋白均有不同程度的降解作用，而化合物B16的处理不会导致FAK蛋白水平降低。
接下来以化合物D4为例，进一步研究了其降解FAK蛋白的作用。如图2所示，化合物D4在较低浓度(10nM)下能明显降解FAK蛋白。并且随着D4浓度升高，FAK蛋白水平显著下降。然而，当D4浓度达到5μM或10μM时，FAK的蛋白水平相较于1μM处理组有略微回升(hookeffect)。随着FAK蛋白的降解程度增加，FAKY397磷酸化水平也逐渐降低。表明D4降解FAK和抑制p-FAK的作用均呈浓度依赖性。
如图3所示，500nM化合物D4处理细胞2小时后可观察到FAK蛋白水平下降，作用4小时后FAK明显被降解，并且在D4处理24小时后实现了细胞内FAK的完全降解，表明D4对FAK的降解作用具有时间依赖性。
如图4所示，化合物D4能在多种卵巢癌细胞中能够有效降解FAK。
来那度胺或蛋白酶体抑制剂MG132或MLN4924与D4共孵育时，FAK蛋白水平回复，表明D4诱导FAK降解依赖于泛素-蛋白酶体途径，是一种蛋白水解靶向嵌合体(PROTAC)。
上述结果表明，化合物B16无法降解FAK蛋白，但是，本发明的化合物能有效降解FAK蛋白，能够通过同时阻断FAK激酶依赖和非激酶依赖的功能，发挥更强的抗肿瘤作用，具有潜在的治疗优势。
实验例2化合物对FAK激酶的抑制活性
1、实验方法
FAK的激酶活性测试采用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。
2、实验结果
下表1为本发明合成的化合物对FAK激酶的抑制情况，以Defactinib作为阳性对照。“++++”代表IC50<50nM，“+++”代表50nM≤IC50＜100nM，“++”代表100nM≤IC50＜500nM，“+”代表IC50>500nM。
表1化合物对FAK的IC50
| 化合物编号 | IC50(nM) | 化合物编号 | IC50(nM) |
| D1 | ++++ | D2 | ++++ |
| D3 | ++++ | D4 | ++++ |
| D5 | ++++ | D6 | ++++ |
| D7 | ++++ | D8 | ++++ |
| D9 | ++++ | D10 | ++++ |
| D11 | ++++ | D12 | ++++ |
| Defactinib | ++++ |
可以看出，本发明化合物能有效抑制FAK激酶活性，IC50<50nM。
结合实验例1的结果可以看出，本发明的化合物不仅在激酶水平维持了对FAK良好的抑制活性，而且能有效降解FAK蛋白以同时阻断其激酶功能和非激酶功能。
实验例3化合物D4体外抑制卵巢癌细胞克隆形成
1、实验方法
将ES-2细胞(人卵巢癌细胞系)培养于6孔板中，用不同浓度化合物D4处理，每3天更换一次含有对应化合物浓度的新鲜培养基。9天后细胞用PBS洗涤，克隆用甲醇固定，0.5％结晶紫溶液染色15分钟，在显微镜下对克隆进行计数。
2、实验结果
如图5所示，化合物D4在1.25μM下显著降低ES-2细胞集落数量和集落大小，在2.5μM下几乎观察不到克隆形成，表明化合物D4以浓度依赖性的方式抑制卵巢癌细胞克隆形成。
上述结果证实了本发明化合物在体外能够有效抑制卵巢癌细胞。
实验例4化合物D4的体内抗卵巢癌活性
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5只小鼠)。溶媒为5％DMSO、40％PEG400和55％生理盐水，15mg/kg D4腹腔注射，每周5次，连续20天。顺铂(简称cis)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。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。肿瘤生长抑制率(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
如图6所示，给药20天后D4单药组具有有效的体内抗肿瘤增殖活性，肿瘤生长抑制率为55％，且没有表现出明显的毒副作用。
此外，D4与顺铂联用使小鼠肿瘤体积明显减小，肿瘤生长抑制率达到80.4％，表明D4与顺铂联用时对化合物的体内抗卵巢癌药效有明显提升作用。
上述结果证实了本发明化合物在体内能够有效抑制卵巢癌，并且与顺铂联用时能够明显提升药效。
综上，本发明提供了一种靶向降解FAK蛋白的化合物及其用途。本发明的化合物能有效降解FAK蛋白，能够通过同时阻断FAK激酶依赖和非激酶依赖的功能，发挥更强的抗肿瘤作用。本发明化合物在制备FAK降解剂，以及治疗与FAK蛋白相关的肿瘤的药物中具有广阔的应用前景。
Claims (10)
1.式IV-1所示化合物或其药学上可接受的盐，其特征在于：所述化合物的结构如式IV-1所示：
其中，m选自4～12的整数；
R0选自氢、C1～4烷基。
2.式IV-2所示的化合物或其药学上可接受的盐，其特征在于：所述化合物的结构如式IV-2所示：
其中，n选自1～3的整数；
R0选自氢、C1～4烷基。
3.根据权利要求1或2所述的化合物或其药学上可接受的盐，其特征在于：所述化合物选自以下化合物之一：
化合物D1：
化合物D2：
化合物D3：
化合物D4：
化合物D5：
化合物D6：
化合物D7：
化合物D8：
化合物D9：
化合物D10：
化合物D11：
化合物D12：
4.一种靶向降解FAK蛋白的药物，其特征在于：它是以权利要求1～3任一项所述的化合物或其药学上可接受的盐，加上药学上可接受的辅助性成分制得的制剂。
5.权利要求1～3任一项所述的化合物、其药学上可接受的盐在制备FAK降解剂中的用途。
6.根据权利要求5所述的用途，其特征在于：所述FAK降解剂为治疗与FAK蛋白相关的肿瘤的药物。
7.根据权利要求5所述的用途，其特征在于：所述FAK降解剂为抑制与FAK蛋白相关的肿瘤转移的药物。
8.根据权利要求6或7所述的用途，其特征在于：所述肿瘤为卵巢癌、肺癌、乳腺癌、前列腺癌、甲状腺癌、宫颈癌、结直肠癌、胃癌、胰腺癌、肝癌、葡萄膜黑色素瘤、黑色素瘤、间皮瘤、子宫癌、骨肿瘤。
9.根据权利要求8所述的用途，其特征在于：所述肿瘤为卵巢癌。
10.一种抗肿瘤的联合用药物，其特征在于：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权利要求1～3任一项所述的化合物、其药学上可接受的盐和其它药物，以及药学上可接受的载体；
所述其它药物选自化疗药、用于免疫检查点疗法的药物、激酶抑制剂、表观遗传学靶点抑制剂、聚二磷酸腺苷-核糖聚合酶抑制剂。
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