CN117417338A - 一类新型brd4蛋白靶向降解剂、其制备方法及应用 - Google Patents
一类新型brd4蛋白靶向降解剂、其制备方法及应用 Download PDFInfo
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- CN117417338A CN117417338A CN202210809311.7A CN202210809311A CN117417338A CN 117417338 A CN117417338 A CN 117417338A CN 202210809311 A CN202210809311 A CN 202210809311A CN 117417338 A CN117417338 A CN 117417338A
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- 238000006731 degradation reaction Methods 0.000 title claims abstract description 16
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
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Abstract
本发明公开了一类新型BRD4蛋白靶向降解剂、其制备方法及应用。属于药物化学领域;活性测试结果表明,本发明的新型靶向降解BRD4的PROTAC分子利用泛素‑蛋白酶体途径直接降解BRD4蛋白,其降解效率显著,能直接杀伤BRD4蛋白高表达的肿瘤细胞,效果优于阳性对照药(+)‑JQ‑1。同时,这些PROTAC分子能避免应用BRD4的常规小分子抑制剂(+)‑JQ‑1引起的靶蛋白含量反馈性上升的调节。
Description
技术领域
本发明涉及医药技术领域,具体涉及一类新型BRD4蛋白靶向降解剂、其制备方法及应用。
背景技术
组蛋白赖氨酸的乙酰化是基因转录并翻译后一种重要的修饰方式,溴结构域和超末端(bromodomain and extra-terminal,BET)蛋白能识别组蛋白和非组蛋白中的乙酰化赖氨酸残基进而产生结合,并调节染色质动力学、细胞过程和疾病进程。BRD4蛋白作为BET家族蛋白包括四种亚型之一,研究最为深入,BRD4能激活转录初始应答基因,调节转录因子C-MYC和BCL2等,参与细胞周期、细胞增殖和细胞凋亡等进程。BRD4的表达上调会导致其下游基因表达异常,在白血病、乳腺癌、黑色素瘤、肝癌、肺癌等肿瘤的发生与发展中具有重要作用。目前BRD4抑制剂研究火热,(+)-JQ-1为最早报道的BRD4抑制剂,此外现已有多款药物进入临床研究,如OTX-015、GSK525762、I-BET151、ABBV-075等。
BRD4抑制剂的使用能够降低其下游蛋白的表达从而控制病情,但是BRD4蛋白的抑制会引起BRD4蛋白表达量反馈性的升高,导致大大影响抑制剂的作用效果。此外,在BRD4抑制剂的研究过程中,也发现一些肿瘤(如三阴性乳腺癌)能够对BRD4的靶向疗法产生耐药性,所以针对靶点BRD4开发新机制的药物有着现实的临床意义。
蛋白水解靶向嵌合体(Proteolytic Targeting Chimera,PROTAC)技术是通过连接链将E3泛素连接酶的配体和靶向目标蛋白的分子相连,从而实现目标蛋白、PROTAC分子和E3泛素连接酶三元复合物的形成。目标蛋白在E3泛素连接酶作用下被泛素化,并进一步被蛋白酶体降解,而丧失作用。对比传统的小分子抑制剂,PROTAC技术具有能应用于传统意义上难以开发成药靶点、蛋白降解效率高、不容易引起靶蛋白负反馈升高的优势。因此针对BRD4小分子抑制剂遇到的临床瓶颈,开发靶向BRD4蛋白的PROTAC分子能够直接克服BRD4小分子抑制剂引起靶蛋白代偿性升高的局限,并避免这一方面可能出现的耐药性问题。
发明内容
本发明的目的在于提供一类靶向降解BRD4蛋白的化合物及其制备与应用,具体为基于Cereblon的E3泛素连接酶配体的吡咯并吡嗪酮类PROTAC分子及其制备方法,以及该类化合物作为BRD4蛋白降解剂在治疗或预防肿瘤、炎症、代谢等疾病中的应用。
本发明的目的在于提供一些新的吡咯并吡嗪酮类小分子或其立体异构体、互变异构体及其药学上可接受的盐、水合物、前药和以该化合物为活性成分的药物组合。
本发明的目的在于提供一类新型抗肿瘤化合物,其目标肿瘤可为但不限于多发性骨髓瘤、胃癌、肺癌、乳腺癌、食管癌、结肠癌、髓母细胞瘤、急性粒细胞白血病、慢性白血病、黑色素瘤、前列腺癌、肝细胞瘤、肾细胞瘤、宫颈癌、皮肤癌、卵巢癌、结肠癌、神经胶质瘤、甲状腺癌或胰腺癌。
本发明的目的还在于提供一种合成新的吡咯并吡嗪酮类双功能小分子的制备方法。
本发明的另一目的在于提供一种含有新的吡咯并吡嗪酮类双功能小分子的药物制剂。
一类新型靶向降解BRD4的PROTAC分子,所述的靶向降解BRD4的PROTAC分子选自通式(Ⅰ)所示的化合物或其立体异构体、互变异构体及其药学上可接受的盐、水合物或前药:
其中:
R1或R2选自C1-12亚烷基、-CH2(CH2OCH2)nCH2-,n=1-10的整数,
R3选自-H、Cl-5烷基,
作为本发明的一种优选,
R1选自C1-5亚烷基;
R2选自C2-l2亚烷基、-CH2(CH2OCH2)nCH2-,n=1-5的整数;
R3选自Cl-5烷基。
作为本发明的进一步优选,
R1选自C2-4亚烷基;
R2选自C4-10亚烷基、-CH2(CH2OCH2)nCH2-,n=2-4的整数;
R3选自Cl-3烷基。
在本发明的一些优选实施方式中,所述的靶向降解BRD4的PROTAC分子选自下式所示的化合物或其立体异构体、互变异构体及其药学上可接受的盐、水合物或前药:
R1选自-(CH2)2-、-(CH2)3-;
R2选自C4-l0亚烷基、-CH2(CH2OCH2)nCH2-,n=1-4的整数;
R3选自甲基。
在本发明的另一些优选实施方式中,所述的靶向降解BRD4的PROTAC分子选自下式所示的化合物或其立体异构体、互变异构体及其药学上可接受的盐、水合物或前药:
R1选自-(CH2)2-;
R2选自C4-l0亚烷基、-CH2(CH2OCH2)nCH2-,n=1-4的整数;
R3选自甲基。
在本发明的优选实施例中,所述靶向降解BRD4的PROTAC分子选自以下化合物或其立体异构体、互变异构体及其药学上可接受的盐、水合物或前药:
进一步的,其立体异构体、互变异构体及其药学上可接受的盐,选自乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己氨磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、盐酸盐/氧化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双氢萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、糖二酸盐、硬脂酸盐、丁二酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐及昔萘酸盐、铝盐、精氨酸盐、苄星青霉素盐、钙盐、胆碱盐、二乙胺盐、二乙醇胺盐、甘氨酸盐、赖氨酸盐、镁盐、葡甲胺盐、乙醇胺盐、钠盐、钾盐、铵盐、氨丁三醇盐及锌盐;
进一步的,其立体异构体、互变异构体及其药学上可接受的盐、水合物、前药可以作为肿瘤治疗药物单独使用,也可与现已上市的肿瘤治疗药物联合应用,发挥协同作用,用于肿瘤治疗及预防;
进一步的,其立体异构体、互变异构体及其药学组合物的剂型可以是片剂、胶囊、丸剂、栓剂、软胶囊、口服液、混悬剂、注射液等药剂学上常用的剂型,并含有治疗有效量的化合物和药学上可接受的辅料;
进一步的,所述化合物的制备方法,所述方法按照反应路线如下:
其中R1、R2如技术方案中任一项所定义,
所述方法包括以下步骤:
以3-甲基-1H-吡咯-2-羧酸乙酯、2-溴-1-氟-4-硝基苯、3-氟邻苯二甲酰亚胺、4-氟邻苯二甲酰亚胺为原料,经13步合成反应得到最终产物化合物1-11;
(1)以3-甲基-1H-吡咯-2-羧酸乙酯a和溴乙醛缩二乙醇为原料,在NaH作用下进行取代反应,得到b;
(2)化合物b在碱性条件中发生酯水解,得到c;
(3)化合物c与氯化铵在有机碱性条件中通过缩合剂进行酰胺缩合反应,得到d;
(4)化合物d在酸性条件中发生自身环化,得到e;
(5)化合物e发生溴代反应,得到f;
(6)以2-溴-1-氟-4-硝基苯g为反应物,与苯酚反应得到h;
(7)化合物h通过铁粉还原得到i;
(8)化合物i与联硼酸频那醇酯经钯催化剂催化,得到j;
(9)化合物j与化合物f发生Suzuki偶联反应得到k;
(10)化合物k与丁二酸酐缩合成酰胺,分别得到l;
(11)以3-氟邻苯二甲酰亚胺m-1与3-氨基-2,6-哌啶二酮盐酸盐发生取代反应得到n-1;
(12)化合物n-1与N-Boc-二胺反应得到化合物o-1~o-8;
(13)化合物o-1~o-8与化合物l在缩合剂催化中缩合得到最终产物化合物1-8;
化合物9-11的制备与化合物1-8不同在于(11)中3-氟邻苯二甲酰亚胺m-1替换为4-氟邻苯二甲酰亚胺m-2。
本发明所述的靶向降解BRD4的PROTAC分子在制备治疗和/或预防肿瘤的药物中的应用;所述肿瘤优选多发性骨髓瘤、胃癌、肺癌、乳腺癌、食管癌、髓母细胞瘤、急性髓细胞性白血病、慢性白血病、黑色素瘤、前列腺癌、肝细胞瘤、肾细胞瘤、宫颈癌、皮肤癌、卵巢癌、结肠癌、神经胶质瘤、甲状腺癌和胰腺癌任意一种。
作为本发明的一种优选,所述的靶向降解BRD4的PROTAC分子作为唯一有效成分,或与其他抗肿瘤化合物一起作为有效成分在制备治疗和/或预防肿瘤的药物中的应用。
一种药物制剂组合物,该制剂包含作为活性剂的通式(I)化合物或其药用盐和药学上可接受的载体。药学上可接受的载体是指一种或几种惰性的、非毒性的固体或液体填充物、稀释剂、助剂等,它们不逆向与活性化合物或病人发生作用;
进一步的,所述剂型可以是片剂、胶囊、丸剂、栓剂、软胶囊、口服液、混悬剂、注射液等药剂学上常用的剂型。口服用药品和胶囊含有传统的赋形剂如填充物、稀释剂、润滑剂、分散剂以及粘合剂。可按照本领域内熟知的方法进行制备;
所给药的本发明的化合物的量会取决于所治疗的个体、给药的速率、化合物的处置及处方医师的判断。一般而言,已证明有利的量为达到所需结果,每千克体重24小时给药的式(I)化合物的总量为约0.01-80mg,优选总量约0.1-40mg/kg。如果必要,以几次单剂量的形式给药。
有益效果:
本发明的新型靶向降解BRD4的PROTAC分子利用泛素-蛋白酶体途径直接降解BRD4蛋白,其降解效率显著,能直接杀伤BRD4蛋白高表达的肿瘤细胞,效果优于阳性对照药(+)-JQ-1。同时,这些PROTAC分子能避免应用BRD4的常规小分子抑制剂(+)-JQ-1引起的靶蛋白含量反馈性上升的调节。
附图说明
图1化合物(+)-JQ-1和化合物7有效降低MV4-11细胞中BRD4蛋白及其下游蛋白c-Myc的表达量;*p<0.05,**p<0.01,***p<0.001,和对照组相比较。
具体实施方式
为了使本发明的目的和技术方案更加清楚,以下结合具体实施例进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。并且,下列实施例中未提及的具体实验方法,均按照常规实验方法进行。
化合物的结构通过核磁共振波谱(1H NMR、13C NMR)和质谱(LC-MS)来确证;反应的监测采用薄层色谱法(TLC)或LC-MS,使用的展开剂体系有:二氯甲烷和甲醇体系、正己烷和乙酸乙酯体系、石油醚和乙酸乙酯体系。
化合物使用柱色谱法进行纯化,柱色谱法一般使用200~300目硅胶为固定相;洗脱剂的体系包括:二氯甲烷和甲醇体系,正己烷和乙酸乙酯体系,溶剂的体积比根据化合物的不同极性而进行调节。
在以下实施例中,如无特殊说明,反应的温度为室温(20℃~30℃)。
下面结合实施例对本发明作进一步说明。需要说明的是,下述实施例仅用于说明,而并非用于限制本发明。本领域技术人员根据本发明的教导所做出的各种变化均应在本申请权利要求所要求的保护范围之内。
实施例1
化合物b的制备
将化合物a(1.0mmol,153.18mg),溴代乙醛缩二乙醇(1.5mmol,226μL)和Cs2CO3(1.3mmol,423.56mg)溶于5mL的DMF中,氮气保护条件下110℃反应24h。TLC监测反应完全后,冷却反应至室温。用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到黄色油状液体化合物b 234.2mg,收率为87.0%。1H NMR(300MHz,CDCl3)δ(ppm)6.77(d,J=2.5Hz,1H),5.94(d,J=2.5Hz,1H),4.64(t,J=5.3Hz,1H),4.29(m,4H),3.67(m,2H),3.38(m,2H),2.32(s,3H),1.36(t,J=7.1Hz,3H),1.14(t,J=7.0Hz,6H).LC-MS(ESI+)calcd.for C14H23NO4Na[M+Na]+:292.15,found292.19.
实施例2
化合物c的制备
将化合物b(0.5mmol,134.67mg),一水合氢氧化锂(2.5mmol,104.9mg)溶于3mL乙醇与3mL水的混合溶剂中,75℃反应18h。TLC监测反应完全后,冷却反应至室温,用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到白色固体化合物c 100.3mg,收率为83.2%。1H NMR(300MHz,DMSO-d6)δ(ppm)12.21(s,1H),6.89(d,J=2.5Hz,1H),5.93(d,J=2.3Hz,1H),4.59(t,J=5.3Hz,1H),4.26(d,J=5.3Hz,2H),3.57(m,2H),3.29(m,3H),2.23(s,3H),1.03(t,J=7.0Hz,6H).LC-MS(ESI-)calcd.for C12H18NO4[M-H]-:240.13,found 240.24.
实施例3
化合物d的制备
将化合物c(0.4mmol,96.5mg),氯化铵(64.19mg,1.2mmol),HATU(0.6mmol,228.14mg)溶于3mL的DMF溶剂中,再加入DIPEA(2.0mmol,348μL),室温反应12h。TLC监测反应完全后,用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到白色固体化合物d 82.1mg,收率为85.5%。1H NMR(300MHz,DMSO-d6)δ(ppm)7.05(s,2H),6.74(d,J=2.5Hz,1H),5.84(d,J=2.4Hz,1H),4.59(t,J=5.3Hz,1H),4.17(d,J=5.3Hz,2H),3.57(m,2H),3.32(m, 2H),2.19(s,3H),1.05(t,J=7.0Hz,6H).LC-MS(ESI+)calcd.for C12H20N2O3Na[M+Na]+:263.14,found263.09.
实施例4
化合物e的制备
将化合物d(0.5mmol,120mg)溶于4mL的冰醋酸溶剂中,100℃反应1h。反应结束后待其冷却至室温,用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到白色固体化合物e 62mg,收率为83.7%。1HNMR(300MHz,CDCl3)δ(ppm)10.42(s,1H),7.00(d,J=2.6Hz,1H),6.87(d,J=5.8Hz,1H),6.40(t,J=5.2Hz,1H),6.36(d,J=2.9Hz,1H),2.60(s,3H).LC-MS(ESI+)calcd.forC8H8N2O[M+H]+:149.07,found 149.45.
实施例5
化合物f的制备
将化合物e(0.34mmol,50mg)溶于2mL二氯甲烷和1mL三氟乙酸的混合溶剂中,先于0℃冰浴中搅拌,再加入N-溴代琥珀酰亚胺(0.31mmol,55mg)于0℃冰浴反应30min。反应结束后蒸除溶剂,加入饱和碳酸氢钠溶液,室温搅拌20min,析出白色固体,抽滤,水洗滤饼,烘干后得到白色固体化合物f 71mg,收率为92.4%。1H NMR(300MHz,CDCl3)δ(ppm)10.30(s,1H),7.00(d,J=6.0Hz,1H),6.53(t,J=6.0Hz,1H),6.43(s,1H),2.60(s,3H).LC-MS(ESI+)calcd.for C8H8BrN2O[M+H]+:228.07,found 228.93.
实施例6
化合物h的制备
将化合物g(1.5mmol,330mg),苯酚(1.8mmol,158μL)和碳酸钾(4.5mmol,621.94mg)溶于4mL的DMF中,90℃加热反应2h。反应结束后,冷却至室温,用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到黄色油状液体h 420.12mg,收率为95.6%。1H NMR(300MHz,CDCl3)δ(ppm)8.55(d,J=2.7Hz,1H),8.09(dd,J=9.1,2.7Hz,1H),7.52–7.39(m,2H),7.34–7.25(m,1H),7.10(d,J=7.4Hz,2H),6.83(d,J=9.1Hz,1H).LC-MS(ESI-)calcd.for C12H8BrNO3[M-H]-:291.98,found 291.96.
实施例7
化合物i的制备
将化合物h(1.5mmol,441mg),铁粉(10.5mmol,588mg),冰醋酸(10.5mmol,606μL)溶于12mL乙醇中,85℃加热回流反应3h。反应结束后冷却至室温,用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得黄色油状液体化合物i 175.8mg,收率为44.6%。1H NMR(300MHz,CDCl3)δ(ppm)7.42–7.22(m,2H),7.05(t,J=7.4Hz,1H),6.99(d,J=2.7Hz,1H),6.91(d,J=8.9Hz,3H),6.64(dd,J=8.6,2.7Hz,1H).LC-MS(ESI+)calcd.for C12H11BrNO[M+H]+:264.00,found 264.07.
实施例8
化合物j的制备
将化合物i(0.5mmol,131.5mg),联硼酸频那醇酯(1.0mmol,253.9mg),Pd(dppf)Cl2(0.025mmol,18.30mg),醋酸钾(1.0mmol,98.14mg)溶于5mL无水1,4-二氧六环溶剂中,氮气保护条件下,100℃加热回流反应12小时。TLC监测反应完全后,冷却反应至室温。用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得棕色油状液体j 74.9mg,收率为48.1%。LC-MS(ESI+)calcd.forC18H22BNO3[M+H]+:312.18,found 312.56.
实施例9
化合物k的制备
将化合物f(0.22mmol,48.9mg),化合物j(0.24mmol,74mg),Pd(PPh3)4(0.01mmol,12.50mg),K2CO3(0.43mmol,59.8mg)溶于3mL的1,4-二氧六环与1mL H2O的混合溶剂中,氮气保护条件下,100℃加热回流反应12h。TLC监测反应完全后,冷却反应至室温。用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得类白色固体化合物k 54.9mg,收率为75.4%。1H NMR(300MHz,DMSO-d6)δ(ppm)10.37–10.07(d,1H),7.19(t,J=7.5Hz,2H),6.88(dt,J=15.7,6.8Hz,3H),6.78–6.51(m,4H),6.44(t,J=5.1Hz,1H),6.25(s,1H),5.21(s,2H),2.38(s,3H).LC-MS(ESI+)calcd.forC20H18N3O2[M+H]+:332.14,found 332.87.
实施例10
化合物l的制备
将化合物k(0.08mmol,26.48mg)和丁二酸酐(0.096mmol,9.60mg)溶于3mL的甲苯溶剂中,氮气保护条件下,115℃加热回流反应6h。TLC监测反应完全后,冷却反应至室温,有固体析出,抽滤,用正己烷洗涤三次,干燥,得到白色固体l 30.5mg,收率为88.4%LC-MS(ESI+)calcd.for C24H22N3O5[M+H]+:432.16,found 432.12.
实施例11
化合物n-1的制备
将化合物m-1(0.5mmol,83.06mg)与3-氨基-2,6-哌啶二酮(0.5mmol,82.30mg)溶于6mL的醋酸溶剂中,再加入乙酸钠(0.6mmol,49.22mg),120℃加热回流反应12h。TLC监测反应完全后,冷却反应至室温。用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到白色固体n-1 102.69mg,收率为74.4%。LC-MS(ESI+)calcd.for C13H10FN2O4[M+H]+:277.06,found 277.14.
实施例12
化合物n-2的制备
将化合物m-2(0.5mmol,83.06mg)与3-氨基-2,6-哌啶二酮(0.5mmol,82.30mg)溶于6mL的醋酸溶剂中,再加入乙酸钠(0.6mmol,49.22mg),120℃加热回流反应12h。TLC监测反应完全后,冷却反应至室温。用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到白色固体n-2 90.68mg,收率为65.7%。LC-MS(ESI+)calcd.for C13H10FN2O4[M+H]+:277.06,found 277.14.
实施例13
化合物o-1的制备
将化合物n-1(0.45mmol,124.30mg),N-(叔丁氧羰基)-1,4-丁二胺(0.585mmol,110.13mg)与DIPEA(1.35mmol,235μL)溶于6mL的N-甲基吡咯烷酮中,100℃加热回流反应12h。TLC监测反应完全后,冷却反应液至室温。用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到黄色油状液体o-1105.46mg,收率为52.76%LC-MS(ESI-)calcd.for C22H27N4O6[M-H]-:443.20,found 443.29.
实施例14
化合物o-2的制备
将化合物n-1(0.45mmol,124.30mg),N-(叔丁氧羰基)-1,5-戊二胺(0.585mmol,118.27mg)与DIPEA(1.35mmol,235μL)溶于6mL的N-甲基吡咯烷酮中,100℃加热回流反应12h。TLC监测反应完全后,冷却反应液至室温。用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到黄色油状液体o-2108.38mg,收率为52.6%。LC-MS(ESI-)calcd.for C23H29N4O6[M-H]-:457.22,found 457.33.
实施例15
化合物o-3的制备
将化合物n-1(0.45mmol,124.30mg),N-(叔丁氧羰基)-1,6-己二胺(0.585mmol,126.47mg)与DIPEA(1.35mmol,235μL)溶于6mL的N-甲基吡咯烷酮中,100℃加热回流反应12h。TLC监测反应完全后,冷却反应至室温。用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到黄色油状液体o-3152.58mg,收率为71.8%。LC-MS(ESI-)calcd.for C24H31N4O6[M-H]-:471.23,found 471.33.
实施例16
化合物o-4的制备
将化合物n-1(0.45mmol,124.30mg),N-(叔丁氧羰基)-1,8-辛二胺(0.585mmol,142.87mg)与DIPEA(1.35mmol,235μL)溶于6mL的N-甲基吡咯烷酮中,100℃加热回流反应12h。TLC监测反应完全后,冷却反应至室温。用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到黄色油状液体o-4153.75mg,收率为68.4%。LC-MS(ESI-)calcd.for C26H35N4O6[M-H]-:499.26,found 499.31.
实施例17
化合物o-5的制备
将化合物n-1(0.45mmol,124.30mg),N-(叔丁氧羰基)-1,10-癸二胺(0.585mmol,159.26mg)与DIPEA(1.35mmol,235μL)溶于6mL的N-甲基吡咯烷酮中,100℃加热回流反应12h。TLC监测反应完全后,冷却反应至室温。用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到黄色油状液体o-5149.53mg,,收率为63.0%。LC-MS(ESI-)calcd.for C28H39N4O6[M-H]-:527.29,found527.43.
实施例18
化合物o-6的制备
将化合物n-1(0.45mmol,124.30mg),N-叔丁氧羰基-2-(2-氨基乙氧基)乙胺(0.585mmol,119.43mg)与DIPEA(1.35mmol,235μL)溶于6mL的N-甲基吡咯烷酮中,100℃加热回流反应12h。TLC监测反应完全后,冷却反应至室温。用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到黄色油状液体o-6 110.79mg,收率为53.5%。LC-MS(ESI-)calcd.for C22H27N4O7[M-H]-:459.20,found459.11.
实施例19
化合物o-7的制备
将化合物n-1(0.45mmol,124.30mg),N-叔丁氧羰基-2,2′-(亚乙二氧基)二乙胺(0.585mmol,145.18mg)与DIPEA(1.35mmol,235μL)溶于6mL的N-甲基吡咯烷酮中,100℃加热回流反应12h。TLC监测反应完全后,冷却反应至室温。用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到黄色油状液体o-7 112.54mg,收率为49.6%。LC-MS(ESI-)calcd.for C24H31N4O8[M-H]-:503.22,found503.26.
实施例20
化合物o-8的制备
将化合物n-1(0.45mmol,124.30mg),13-氨基-5,8,11-三氧杂-2-氮杂十三烷酸-1,1-叔丁酯(0.585mmol,170.94mg)与DIPEA(1.35mmol,235μL)溶于6mL的N-甲基吡咯烷酮中,100℃加热回流反应12h。TLC监测反应完全后,冷却反应至室温。用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到黄色油状液体o-8 137.42mg,收率为55.8%。LC-MS(ESI-)calcd.for C26H35N4O9[M-H]-:547.25,found 547.31.
实施例21
化合物o-9的制备
将化合物n-2(0.45mmol,124.30mg),N-(叔丁氧羰基)-1,5-戊二胺(0.585mmol,118.27mg)与DIPEA(1.35mmol,235μL)溶于6mL的N-甲基吡咯烷酮中,100℃加热回流反应12h。TLC监测反应完全后,冷却反应至室温。用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到黄色油状液体o-953.47mg,收率为25.9%。LC-MS(ESI-)calcd.for C23H29N4O6[M-H]-:457.22,found 457.29.
实施例22
化合物o-10的制备
将化合物n-2(0.45mmol,124.30mg),N-(叔丁氧羰基)-1,8-辛二胺(0.585mmol,142.87mg)与DIPEA(1.35mmol,235μL)溶于6mL的N-甲基吡咯烷酮中,100℃加热回流反应12h。TLC监测反应完全后,冷却反应至室温。用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到黄色油状液体o-10129.44mg,收率为57.5%。LC-MS(ESI-)calcd.for C26H35N4O6[M-H]-:499.26,found 499.38.
实施例23
化合物o-11的制备
将化合物n-2(0.45mmol,124.30mg),N-(叔丁氧羰基)-1,10-癸二胺(0.585mmol,159.26mg)与DIPEA(1.35mmol,235μL)溶于6mL的N-甲基吡咯烷酮中,100℃加热回流反应12h。TLC监测反应完全后,冷却反应至室温。用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到黄色油状液体o-11145.97mg,,收率为61.4%。LC-MS(ESI-)calcd.for C28H39N4O6[M-H]-:527.29,found527.39.
实施例24
N1-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-氨基)丁基)-N4-(3-(8-甲基-1-氧代-1,2-二氢吡咯并[1,2-a]吡嗪-6-基)-4-苯氧基苯基)丁二酰胺(化合物1)的制备
将化合物o-1(0.06mmol,26.65mg)溶于二氯甲烷溶剂(3mL),再加入三氟乙酸(1mL),室温条件下反应1h。反应结束后,减压浓缩反应液,备用。然后将中间体l(0.06mmol,25.87mg),DIPEA(0.24mmol,42μL)和HATU(0.15mmol,57.03mg)溶于DMF溶剂(3mL),室温反应12h。TLC监测反应完全后,用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到黄色固体目标化合物1 22.83mg,收率为50.2%。Mp:178–180℃.1H NMR(300MHz,DMSO-d6)δ(ppm)11.12(s,1H),10.24(d,J=5.3Hz,1H),10.13(s,1H),7.92(t,J=5.5Hz,1H),7.78(d,J=2.5Hz,1H),7.59(m,2H),7.27(t,J=8.0Hz,2H),7.04(m,4H),6.84(t,J=5.7Hz,3H),6.55(t,J=5.8Hz,1H),6.45(t,J=5.7Hz,1H),6.34(s,1H),5.06(dd,J=12.8,5.3Hz,1H),3.29(dd,J=12.6,6.3Hz,2H),3.09(dd,J=12.0,6.2Hz,2H),2.98–2.80(m,1H),2.65–2.52(m,4H),2.45(m,2H),2.41(s,3H),2.08–2.00(m,1H),1.52(m,4H).13C NMR(75MHz,DMSO-d6)δ(ppm)173.30,171.47,171.02,170.59,169.38,167.76,157.64,157.36,149.28,146.82,136.71,136.14,132.63,130.27,125.65,123.43,123.03,122.38,121.25,120.84,120.78,117.88,117.66,114.89,114.43,110.83,109.43,106.27,48.99,41.98,38.59,32.14,31.44,30.73,27.02,26.62,22.62,12.72.HPLC purity:>95.0%.LC-MS(ESI+)calcd.for C41H40N7O8[M+H]+:758.29,found758.60.
实施例25
N1-(5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-氨基)戊基)-N4-(3-(8-甲基-1-氧代-1,2-二氢吡咯并[1,2-a]吡嗪-6-基)-4-苯氧基苯基)丁二酰胺(化合物2)的制备
将化合物o-2(0.06mmol,27.49mg)溶于二氯甲烷溶剂(3mL),再加入三氟乙酸(1mL),室温条件下反应1h。反应结束后,减压浓缩反应液,备用。然后将中间体l(0.06mmol,25.87mg),DIPEA(0.24mmol,42μL)和HATU(0.15mmol,57.03mg)溶于DMF溶剂(3mL),室温反应12h。TLC监测反应完全后,用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到黄色固体目标化合物2 21.33mg,收率为46.1%。Mp:159–161℃.1H NMR(300MHz,DMSO-d6)δ(ppm)11.11(s,1H),10.24(d,J=5.3Hz,1H),10.13(s,1H),7.88(t,J=5.4Hz,1H),7.78(d,J=2.5Hz,1H),7.59(m,2H),7.27(t,J=8.0Hz,2H),7.12–6.97(m,4H),6.84(t,J=5.8Hz,3H),6.53(t,J=5.7Hz,1H),6.45(t,J=5.7Hz,1H),6.33(s,1H),5.06(dd,J=12.7,5.3Hz,1H),3.25(dd,J=13.0,6.6Hz,2H),3.05(dd,J=12.0,6.2Hz,2H),2.98–2.79(m,1H),2.69–2.51(m,4H),2.43(m,2H),2.41(s,3H),2.03(m,1H),1.56(m,2H),1.36(m,4H).13C NMR(75MHz,DMSO-d6)δ(ppm)173.21,171.43,171.05,170.51,169.43,167.76,157.64,157.41,149.36,146.89,136.71,136.15,132.66,130.24,125.67,123.41,123.08,122.45,122.41,121.30,120.90,120.78,117.88,117.61,114.89,114.42,110.85,109.55,106.25,49.05,42.30,38.81,32.23,31.45,30.82,29.32,28.84,24.13,22.64,12.68.HPLC purity:>95.0%.LC-MS(ESI+)calcd.forC42H42N7O8[M+H]+:772.31,found 772.49.
实施例26
N1-(6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-氨基)己基)-N4-(3-(8-甲基-1-氧代-1,2-二氢吡咯并[1,2-a]吡嗪-6-基)-4-苯氧基苯基)丁二酰胺(化合物3)的制备
将化合物o-3(0.06mmol,28.33mg)溶于二氯甲烷溶剂(3mL),再加入三氟乙酸(1mL),室温条件下反应1h。反应结束后,减压浓缩反应液,备用。然后将中间体l(0.06mmol,25.87mg),DIPEA(0.24mmol,42μL)和HATU(0.15mmol,57.03mg)溶于DMF溶剂(3mL),室温反应12h。TLC监测反应完全后,用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到黄色固体目标化合物3 18.99mg,收率为40.3%。Mp:158–160℃.1H NMR(300MHz,DMSO-d6)δ(ppm)11.12(s,1H),10.25(d,J=5.3Hz,1H),10.14(s,1H),7.86(t,J=5.4Hz,1H),7.78(d,J=2.5Hz,1H),7.69–7.50(m,2H),7.33–7.22(m,2H),7.12–6.97(m,4H),6.85(t,J=6.4Hz,3H),6.53(t,J=5.7Hz,1H),6.46(t,J=5.7Hz,1H),6.34(s,1H),5.06(dd,J=12.8,5.4Hz,1H),3.26(dd,J=12.9,6.5Hz,2H),3.03(dd,J=12.0,6.2Hz,2H),2.96–2.76(m,1H),2.57(m,4H),2.41(s,3H),2.38(m,2H),2.04(m,1H),1.65–1.49(m,2H),1.46–1.22(m,6H).13C NMR(75MHz,DMSO-d6)δ(ppm)173.30,171.37,171.03,170.59,169.40,167.76,157.64,157.36,149.28,146.84,136.72,136.15,132.64,130.26,125.65,123.42,123.02,122.38,121.25,120.84,120.78,117.87,117.60,114.89,114.43,110.82,109.44,106.28,48.98,42.21,38.90,32.16,31.44,30.75,29.56,29.07,26.57,26.51,22.62,12.72.HPLC purity:>95.0%.LC-MS(ESI+)calcd.for C43H44N7O8[M+H]+:786.33,found 786.57.
实施例27
N1-(8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-氨基)辛基)-N4-(3-(8-甲基-1-氧代-1,2-二氢吡咯并[1,2-a]吡嗪-6-基)-4-苯氧基苯基)丁二酰胺(化合物4)的制备
将化合物o-4(0.06mmol,30.02mg)溶于二氯甲烷溶剂(3mL),再加入三氟乙酸(1mL),室温条件下反应1h。反应结束后,减压浓缩反应液,备用。然后将中间体l(0.06mmol,25.87mg),DIPEA(0.24mmol,42μL)和HATU(0.15mmol,57.03mg)溶于DMF溶剂(3mL),室温反应12h。TLC监测反应完全后,用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到黄色固体目标化合物4 25.81mg,收率为52.9%。Mp:157–159℃.1H NMR(300MHz,DMSO-d6)δ(ppm)11.12(s,1H),10.25(d,J=5.3Hz,1H),10.13(s,1H),7.85(t,J=5.4Hz,1H),7.78(d,J=2.4Hz,1H),7.69–7.47(m,2H),7.27(t,J=7.9Hz,2H),7.14–6.94(m,4H),6.85(t,J=6.5Hz,3H),6.52(t,J=5.7Hz,1H),6.46(t,J=5.7Hz,1H),6.34(s,1H),5.06(dd,J=12.8,5.3Hz,1H),3.27(dd,J=12.8,6.4Hz,2H),3.02(dd,J=12.4,6.4Hz,2H),2.98–2.76(m,1H),2.57(m,4H),2.41(s,3H),2.39(m,2H),2.03(m,1H),1.54(m,2H),1.46–1.20(m,10H).13C NMR(75MHz,DMSO-d6)δ(ppm)173.30,171.35,171.03,170.59,169.41,167.77,157.65,157.36,149.28,146.86,136.73,136.14,132.64,130.27,125.66,123.43,123.02,122.38,121.25,120.85,120.77,117.88,117.62,114.89,114.43,110.83,109.43,106.28,48.99,42.28,38.92,32.19,31.44,30.76,29.59,29.18,29.13,26.79,26.75,22.62,12.72.HPLC purity:>95.0%.LC-MS(ESI+)calcd.for C45H48N7O8[M+H]+:814.36,found 814.59.
实施例28
N1-(10-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-氨基)癸基)-N4-(3-(8-甲基-1-氧代-1,2-二氢吡咯并[1,2-a]吡嗪-6-基)-4-苯氧基苯基)丁二酰胺(化合物5)的制备
将化合物o-5(0.06mmol,31.70mg)溶于二氯甲烷溶剂(3mL),再加入三氟乙酸(1mL),室温条件下反应1h。反应结束后,减压浓缩反应液,备用。然后将中间体l(0.06mmol,25.87mg),DIPEA(0.24mmol,42μL)和HATU(0.15mmol,57.03mg)溶于DMF溶剂(3mL),室温反应12h。TLC监测反应完全后,用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到黄色固体目标化合物5 19.03mg,收率为37.7%。Mp:139–141℃.1H NMR(300MHz,DMSO-d6)δ(ppm)11.12(s,1H),10.24(d,J=5.3Hz,1H),10.12(s,1H),7.84(t,J=5.4Hz,1H),7.78(d,J=2.4Hz,1H),7.68–7.51(m,2H),7.27(t,J=7.9Hz,2H),7.11–6.96(m,4H),6.85(t,J=6.5Hz,3H),6.52(t,J=5.7Hz,1H),6.46(t,J=5.7Hz,1H),6.34(s,1H),5.06(dd,J=12.8,5.3Hz,1H),3.27(dd,J=13.0,6.5Hz,2H),3.02(dd,J=12.2,6.2Hz,2H),2.95–2.77(m,1H),2.57(m,4H),2.41(s,3H),2.38(m,2H),2.10–2.01(m,1H),1.64–1.48(m,2H),1.43–1.20(m,14H).13C NMR(75MHz,DMSO-d6)δ(ppm)173.29,171.34,171.01,170.58,169.41,167.77,157.65,157.36,149.28,146.87,136.72,136.15,132.64,130.26,125.66,123.43,123.02,122.38,121.23,120.85,120.75,117.88,117.62,114.88,114.42,110.82,109.43,106.27,48.99,42.28,38.93,32.19,31.44,30.76,29.62,29.41,29.21,29.14,26.84,26.79,22.62,12.72.HPLCpurity:>95.0%.LC-MS(ESI+)calcd.for C47H52N7O8[M+H]+:842.39,found 842.67.
实施例29
N1-(2-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异喹啉-4-基)氨基)乙氧基)-N4-(3-(8-甲基-1-氧代-1,2-二氢吡咯[1,2-a]吡嗪-6-基)-4-苯氧基苯基)丁二酰胺(化合物6)的制备
将化合物o-6(0.06mmol,27.61mg)溶于二氯甲烷溶剂(3mL),再加入三氟乙酸(1mL),室温条件下反应1h。反应结束后,减压浓缩反应液,备用。然后将中间体l(0.06mmol,25.87mg),DIPEA(0.24mmol,42μL)和HATU(0.15mmol,57.03mg)溶于DMF溶剂(3mL),室温反应12h。TLC监测反应完全后,用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到黄色固体目标化合物6 25.84mg,收率为55.7%。Mp:155–157℃.1H NMR(300MHz,DMSO-d6)δ(ppm)11.12(s,1H),10.25(d,J=5.1Hz,1H),10.13(s,1H),7.94(t,J=4.7Hz,1H),7.77(s,1H),7.59(dd,J=16.2,8.3Hz,2H),7.27(t,J=7.6Hz,2H),7.13(d,J=8.6Hz,1H),7.03(t,J=7.2Hz,3H),6.84(d,J=7.3Hz,3H),6.62(t,J=5.5Hz,1H),6.46(t,J=5.5Hz,1H),6.34(s,1H),5.07(dd,J=12.4,4.9Hz,1H),3.60(t,J=4.9Hz,2H),3.54–3.41(m,4H),3.34–3.18(m,2H),2.87(m,1H),2.69–2.52(m,4H),2.45(m,2H),2.41(s,3H),2.03(m,1H).13C NMR(75MHz,DMSO-d6)δ(ppm)173.28,171.76,171.03,170.57,169.43,167.75,157.65,157.36,149.29,146.82,136.71,136.13,132.53,130.28,125.66,123.44,123.03,122.39,121.25,120.84,120.78,117.89,114.90,114.43,111.16,109.71,106.29,69.42,69.01,49.01,42.06,38.96,32.02,31.44,30.58,22.61,12.73.HPLC purity:>95.0%.LC-MS(ESI+)calcd.for C41H40N7O9[M+H]+:774.29,found 774.56.
实施例30
N1-(2-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异喹啉-4-基)氨基)乙氧基)乙基)-N4-(3-(8-甲基-1,2-二氢吡咯[1,2-a]吡嗪-6-基)-4-苯氧基苯基)丁二酰胺(化合物7)的制备
将化合物o-7(0.06mmol,30.25mg)溶于二氯甲烷溶剂(3mL),再加入三氟乙酸(1mL),室温条件下反应1h。反应结束后,减压浓缩反应液,备用。然后将中间体l(0.06mmol,25.87mg),DIPEA(0.24mmol,42μL)和HATU(0.15mmol,57.03mg)溶于DMF溶剂(3mL),室温反应12h。TLC监测反应完全后,用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到黄色固体目标化合物7 21.48mg,收率为43.8%。Mp:122–124℃.1H NMR(300MHz,DMSO-d6)δ(ppm)11.12(s,1H),10.25(d,J=5.3Hz,1H),10.13(s,1H),7.94(t,J=5.4Hz,1H),7.78(d,J=2.3Hz,1H),7.68–7.51(m,2H),7.27(t,J=7.9Hz,2H),7.14(d,J=8.6Hz,1H),7.03(dd,J=7.9,4.9Hz,3H),6.85(t,J=6.2Hz,3H),6.61(t,J=5.5Hz,1H),6.46(t,J=5.7Hz,1H),6.34(s,1H),5.07(dd,J=12.7,5.3Hz,1H),3.61(t,J=5.1Hz,2H),3.54(d,J=5.2Hz,4H),3.50–3.44(m,2H),3.40(t,J=5.9Hz,2H),3.20(dd,J=11.0,5.4Hz,2H),2.99–2.79(m,1H),2.57(dd,J=15.5,8.9Hz,4H),2.43(d,J=7.4Hz,2H),2.41(s,3H),2.04(d,J=5.2Hz,1H).13C NMR(75MHz,DMSO-d6)δ(ppm)173.30,171.70,171.00,170.58,169.40,167.75,157.65,157.36,149.29,146.83,136.68,136.14,132.54,130.28,125.66,123.44,123.03,122.39,121.25,120.85,120.78,117.89,114.90,114.44,111.14,109.68,106.29,70.14,70.06,69.63,69.33,49.01,42.14,39.04,32.03,31.45,30.59,22.60,12.72.HPLC purity:>95.0%.LC-MS(ESI+)calcd.for C43H44N7O10[M+H]+:818.32,found 818.72.
实施例31
N1-(2-(2-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异喹啉-4-基)氨基)乙氧基)乙氧基)乙氧基)-N4-(3-(8-甲基-1-氧基-1,2-二氢吡咯[1,2-a]吡嗪-6-基)-4-苯氧基苯基)丁二酰胺(化合物8)的制备
将化合物o-8(0.06mmol,32.89mg)溶于二氯甲烷溶剂(3mL),再加入三氟乙酸(1mL),室温条件下反应1h。反应结束后,减压浓缩反应液,备用。然后将中间体l(0.06mmol,25.87mg),DIPEA(0.24mmol,42μL)和HATU(0.15mmol,57.03mg)溶于DMF溶剂(3mL),室温反应12h。TLC监测反应完全后,用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到黄色固体目标化合物8 18.86mg,收率为36.5%。Mp:132–135℃.1H NMR(300MHz,DMSO-d6)δ(ppm)11.12(s,1H),10.25(d,J=5.3Hz,1H),10.13(s,1H),7.95(t,J=5.5Hz,1H),7.78(d,J=2.5Hz,1H),7.67–7.51(m,2H),7.34–7.19(m,2H),7.14(d,J=8.6Hz,1H),7.03(dd,J=8.0,5.5Hz,3H),6.85(t,J=6.2Hz,3H),6.61(t,J=5.6Hz,1H),6.46(t,J=5.7Hz,1H),6.34(s,1H),5.07(dd,J=12.8,5.4Hz,1H),3.62(t,J=5.3Hz,2H),3.58–3.43(m,10H),3.39(d,J=6.1Hz,2H),3.19(q,J=5.8Hz,2H),2.99–2.78(m,1H),2.57(m,4H),2.45(d,J=7.0Hz,2H),2.41(s,3H),2.04(d,J=4.7Hz,1H).13C NMR(75MHz,DMSO-d6)δ(ppm)173.30,171.70,171.00,170.56,169.39,167.75,157.65,157.36,149.29,146.84,136.67,136.14,132.53,130.27,125.66,123.43,123.03,122.39,122.36,121.25,120.85,120.78,117.89,114.90,114.44,111.13,109.67,106.29,70.24,70.04,69.57,69.33,49.01,42.13,39.04,32.04,31.44,30.59,22.61,12.72.HPLC purity:>95.0%.LC-MS(ESI+)calcd.for C45H48N7O11[M+H]+:862.34,found862.60.
实施例32
N1-(5-(2,6-二氧哌啶-3-基)-1,3-二氧异喹啉-5-基)氨基)戊基)-N4-(3-(8-甲基-1-氧代-1,2-二氢吡咯[1,2-a]吡嗪-6-基)-4-苯氧基苯基)丁二酰胺(化合物9)的制备
将化合物o-9(0.06mmol,27.49mg)溶于二氯甲烷溶剂(3mL),再加入三氟乙酸(1mL),室温条件下反应1h。反应结束后,减压浓缩反应液,备用。然后将中间体l(0.06mmol,25.87mg),DIPEA(0.24mmol,42μL)和HATU(0.15mmol,57.03mg)溶于DMF溶剂(3mL),室温反应12h。TLC监测反应完全后,用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到黄色固体目标化合物9 22.17mg,收率为47.9%。Mp:175–177℃.1H NMR(300MHz,DMSO-d6)δ(ppm)11.08(s,1H),10.24(d,J=5.3Hz,1H),10.13(s,1H),7.88(t,J=5.5Hz,1H),7.78(d,J=2.5Hz,1H),7.61(dd,J=8.9,2.6Hz,1H),7.55(d,J=8.4Hz,1H),7.33–7.20(m,2H),7.09(t,J=5.0Hz,1H),7.02(dd,J=8.1,6.2Hz,2H),6.93(d,J=1.6Hz,1H),6.84(t,J=5.6Hz,4H),6.45(t,J=5.7Hz,1H),6.33(s,1H),5.04(dd,J=12.7,5.4Hz,1H),3.19–3.03(m,4H),2.97–2.80(m,1H),2.56(dd,J=14.5,7.4Hz,4H),2.46–2.35(m,2H),2.41(s,3H),2.00(m,1H),1.56(dt,J=13.6,6.9Hz,2H),1.33(m,4H).13C NMR(75MHz,DMSO-d6)δ(ppm)173.30,171.42,171.03,170.66,168.16,167.61,157.64,157.35,154.86,149.29,136.12,134.64,130.27,125.65,125.57,123.43,123.02,122.38,121.25,121.24,120.84,120.77,117.88,116.22,114.88,114.42,106.27,49.05,42.89,38.81,32.14,31.45,30.74,29.38,28.35,24.33,22.70,12.72.HPLCpurity:>95.0%.LC-MS(ESI+)calcd.for C42H42N7O8[M+H]+:772.31,found 772.49.
实施例33
N1-(8-(2,6-二氧哌啶-3-基)-1,3-二氧异喹啉-5-基)氨基)辛基)-N4-(3-(8-甲基-1-氧代-1,2-二氢吡咯[1,2-a]吡嗪-6-基)-4-苯氧基苯基)丁二酰胺(化合物10)的制备
将化合物o-10(0.06mmol,30.02mg)溶于二氯甲烷溶剂(3mL),再加入三氟乙酸(1mL),室温条件下反应1h。反应结束后,减压浓缩反应液,备用。然后将中间体l(0.06mmol,25.87mg),DIPEA(0.24mmol,42μL)和HATU(0.15mmol,57.03mg)溶于DMF溶剂(3mL),室温反应12h。TLC监测反应完全后,用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到黄色固体目标化合物10 23.25mg,收率为47.6%。Mp:143–145℃.1H NMR(300MHz,DMSO-d6)δ(ppm)11.08(s,1H),10.25(d,J=5.2Hz,1H),10.13(s,1H),7.85(t,J=5.4Hz,1H),7.78(d,J=2.4Hz,1H),7.61(dd,J=8.9,2.4Hz,1H),7.56(d,J=8.4Hz,1H),7.27(t,J=7.9Hz,2H),7.11(t,J=4.8Hz,1H),7.03(dd,J=8.0,5.2Hz,2H),6.94(s,1H),6.85(t,J=6.9Hz,4H),6.46(t,J=5.7Hz,1H),6.34(s,1H),5.04(dd,J=12.7,5.3Hz,1H),3.13(dd,J=12.2,6.3Hz,2H),3.02(dd,J=12.2,6.3Hz,2H),2.87(m,1H),2.57(m,4H),2.41(s,3H),2.39(d,J=7.2Hz,2H),1.99(m,1H),1.63–1.48(m,2H),1.45–1.24(m,10H).13C NMR(75MHz,DMSO-d6)δ(ppm)173.31,171.36,171.03,170.67,168.17,167.62,157.66,157.35,154.90,149.29,136.13,134.65,130.27,125.67,125.57,123.44,123.02,122.39,121.26,120.84,120.78,117.88,116.19,114.89,114.43,106.29,49.06,42.93,38.93,32.17,31.45,30.74,29.60,29.22,29.21,28.68,26.96,26.81,22.70,12.72.HPLC purity:>95.0%.LC-MS(ESI+)calcd.for C45H48N7O8[M+H]+:814.36,found 814.66.
实施例34
N1-(10-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异喹啉-5-基)氨基)癸基)-N4-(3-(8-甲基-1-氧代-1,2-二氢吡咯[1,2-a]吡嗪-6-基)-4-苯氧基苯基)丁二酰胺(化合物11)的制备
将化合物o-11(0.06mmol,31.70mg)溶于二氯甲烷溶剂(3mL),再加入三氟乙酸(1mL),室温条件下反应1h。反应结束后,减压浓缩反应液,备用。然后将中间体l(0.06mmol,25.87mg),DIPEA(0.24mmol,42μL)和HATU(0.15mmol,57.03mg)溶于DMF溶剂(3mL),室温反应12h。TLC监测反应完全后,用水和乙酸乙酯萃取,收集有机层,无水硫酸钠干燥,抽滤,减压浓缩滤液,利用硅胶柱层析法对产物进行纯化,得到黄色固体目标化合物11 24.58mg,收率为48.7%。Mp:132–134℃.1H NMR(300MHz,DMSO-d6)δ(ppm)11.08(s,1H),10.25(d,J=5.0Hz,1H),10.13(s,1H),7.84(t,J=4.6Hz,1H),7.78(s,1H),7.59(dd,J=17.5,8.6Hz,2H),7.27(t,J=7.6Hz,2H),7.11(s,1H),7.07–6.98(m,2H),6.94(s,1H),6.84(d,J=7.8Hz,4H),6.46(t,J=5.5Hz,1H),6.34(s,1H),5.04(dd,J=12.5,5.0Hz,1H),3.07(dd,J=34.7,5.5Hz,4H),2.95–2.77(m,1H),2.55(m,4H),2.41(s,3H),2.40–2.20(m,2H),1.95(m,1H),1.54(t,J=5.3Hz,2H),1.44–1.25(m,14H).13C NMR(75MHz,DMSO-d6)δ(ppm)173.30,171.34,171.02,170.66,168.17,167.61,157.65,157.36,154.90,149.28,136.14,134.65,130.26,125.66,125.56,123.43,123.02,122.38,121.24,120.85,120.76,117.88,116.19,114.89,114.42,106.28,49.06,42.94,38.94,32.17,31.46,30.76,29.62,29.46,29.43,29.27,29.23,28.70,27.01,26.85,22.70,12.72.HPLC purity:>95.0%.LC-MS(ESI+)calcd.for C47H52N7O8[M+H]+:842.39,found 842.71.
实施例35
1.CCK-8细胞毒性实验
利用CCK-8法检测化合物对人髓性单核细胞白血病细胞系MV4-11、人急性单核细胞白血病细胞系THP-1和人原髓细胞白血病细胞系HL-60的抗增殖作用。
实验步骤:培养MV4-11、THP-1及HL-60细胞系至对数生长期,收集细胞并离心弃去培养基,加入无血清培养基吹打至其成为细胞悬液,使用细胞计数板于显微镜下进行观察计数,随后调整细胞液浓度至2×105/mL。将细胞接种于96孔板,每孔加入50μL细胞悬液,边缘孔加入灭菌的PBS溶液。然后每孔加入50μL含不同浓度药物的完全培养基。设置药物的初始浓度为10μM,并依次进行3倍的浓度梯度稀释,每个浓度均设置3个复孔。将96孔板放置于细胞培养箱中,在5%CO2,37℃的条件下孵育72小时。孵育结束后,每孔加入10μL CCK-8检测试剂,培养箱中继续孵育3小时。孵育结束后,使用酶标仪测定在450nm吸收波长下的OD值。最后应用GraphPad Prism 8.0软件拟合得到各个化合物的IC50值,如下表1所示。
表1化合物1-14的在MV4-11、THP-1和HL-60细胞系上的抗肿瘤增殖活性
a所有实验平行三次进行。
化合物7在多种实体瘤细胞株上的抗肿瘤活性见表2。
表2化合物7在多种实体瘤细胞株上的抗肿瘤增殖活性
a所有实验平行三次进行。
以下试验以化合物7和化合物(+)-JQ-1为例。
2.Western Blot蛋白免疫印迹实验
通过蛋白质免疫印迹法探究化合物7和参照化合物(+)-JQ-1的对肿瘤细胞中BRD4蛋白表达程度的影响。
实验步骤:将MV4-11细胞培养至对数生长期后收集细胞,调整细胞液浓度为2×106/mL。6孔板中每孔添加1mL细胞悬液,继续孵育12小时待细胞贴壁,加入1mL含不同浓度药液的完全培养基继续孵育24小时。孵育结束后,收集细胞液,离心并弃去上清液。加入预冷的PBS洗涤2~3次,离心弃去上清液。每个样品中加入100μL含1mM PMSF的RIPA裂解液,吹打混匀,放置于冰上摇动裂解30min。在4℃,15 000rpm离心15min,取上清液置于另一新的1.5mL EP管中,-20℃保存。随后利用BCA蛋白定量试剂盒对蛋白提取液的浓度进行测定,并计算出20μg蛋白相应的上样体积。利用SDS-PAGE对蛋白进行电泳分离,电泳结束后根据蛋白marker位置切下含有目标蛋白的胶。湿法转膜使蛋白质条带转移到PVDF膜上,TBST简单清洗后,用含5%脱脂奶粉的封闭液于摇床上摇动封闭1小时。封闭结束后,TBST洗涤PVDF膜4~5次,每次10分钟,随后利用相应的一抗稀释液,于4℃条件下过夜孵育条带。TBST洗涤PVDF膜4~5次,每次10分钟,用二抗稀释液室温孵育条带2小时。在ECL化学发光液下使蛋白条带显影,观察并拍照。最后利用Image J软件及GraphPad Prism 8.0软件对蛋白条带进行灰度分析。
化合物7和参照化合物(+)-JQ-1对MV4-11细胞中BRD4蛋白的降解作用见图1
以上药理学数据显示,本发明通式(I)的化合物能有效降低BRD4蛋白丰度,阻断BRD4下游信号传导,具有优异的抗肿瘤增殖活性。
实施例36
含化合物7的片剂:
按常规方法将原辅料混合,制粒,干燥,压片。
尽管已经通过特定实施方案描述了本发明,但修改和等价变化对于精通此领域的技术人员而言是显见的,且它们都包含在本发明范围之内。
Claims (10)
1.一类新型靶向降解BRD4的PROTAC分子,其特征在于,所述的靶向降解BRD4的PROTAC分子选自通式(Ⅰ)所示的化合物或其立体异构体、互变异构体及其药学上可接受的盐、水合物或前药:
其中:
R1或R2选自C1-12亚烷基、-CH2(CH2OCH2)nCH2-,n=1-10的整数,
R3选自-H、Cl-5烷基。
2.根据权利要求1所述的一类新型靶向降解BRD4的PROTAC分子,其特征在于:
R1选自C1-5亚烷基,优选C2-4亚烷基;
R2选自C2-l2亚烷基、-CH2(CH2OCH2)nCH2-,n=1-5的整数;优选C4-10亚烷基、-CH2(CH2OCH2)nCH2-,n=2-4的整数;
R3选自Cl-5烷基,优选Cl-3烷基。
3.根据权利要求2所述的一类新型靶向降解BRD4的PROTAC分子,其特征在于:所述的靶向降解BRD4的PROTAC分子选自下式所示的化合物或其立体异构体、互变异构体及其药学上可接受的盐、水合物或前药:
R1选自-(CH2)2-、-(CH2)3-;
R2选自C4-l0亚烷基、-CH2(CH2OCH2)nCH2-,n=1-4的整数;
R3选自甲基。
4.根据权利要求2所述的一类新型靶向降解BRD4的PROTAC分子,其特征在于:所述的靶向降解BRD4的PROTAC分子选自下式所示的化合物或其立体异构体、互变异构体及其药学上可接受的盐、水合物或前药:
R1选自-(CH2)2-、-(CH2)3-;
R2选自C4-l0亚烷基、-CH2(CH2OCH2)nCH2-,n=1-4的整数;
R3选自甲基。
5.根据权利要求1所述的一类新型靶向降解BRD4的PROTAC分子,其特征在于,所述靶向降解BRD4的PROTAC分子选自以下化合物或其立体异构体、互变异构体及其药学上可接受的盐、水合物或前药:
6.根据权利要求1-5中任一项的靶向降解BRD4的PROTAC分子,其特征在于,所述的药学上可接受的盐,选自乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己氨磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、盐酸盐/氧化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双氢萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、糖二酸盐、硬脂酸盐、丁二酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐及昔萘酸盐、铝盐、精氨酸盐、苄星青霉素盐、钙盐、胆碱盐、二乙胺盐、二乙醇胺盐、甘氨酸盐、赖氨酸盐、镁盐、葡甲胺盐、乙醇胺盐、钠盐、钾盐、铵盐、氨丁三醇盐或锌盐。
7.权利要求1-5中任意一项所述的靶向降解BRD4的PROTAC分子在制备治疗和/或预防肿瘤的药物中的应用;所述肿瘤优选多发性骨髓瘤、胃癌、肺癌、乳腺癌、食管癌、髓母细胞瘤、急性髓细胞性白血病、慢性白血病、黑色素瘤、前列腺癌、肝细胞瘤、肾细胞瘤、宫颈癌、皮肤癌、卵巢癌、结肠癌、神经胶质瘤、甲状腺癌和胰腺癌任意一种。
8.根据权利要求7所述的应用,其特征在于,权利要求1-5中任意一项所述的靶向降解BRD4的PROTAC分子作为唯一有效成分,或与其他抗肿瘤化合物一起作为有效成分在制备治疗和/或预防肿瘤的药物中的应用。
9.一种药物制剂组合物,其特征在于,含有治疗有效量的权利要求1-5中任意一项所述的靶向降解BRD4的PROTAC分子和药学上可接受的辅料;所述的药物组合物的剂型优选片剂、胶囊、丸剂、栓剂、软胶囊、口服液、混悬剂或注射液。
10.制备权利要求1-5中任一项所述的靶向降解BRD4的PROTAC分子的方法,其特征在于,所述方法按照反应路线如下:
其中R1、R2如权利要求1-4中任一项所定义,
所述方法包括以下步骤:
以3-甲基-1H-吡咯-2-羧酸乙酯、2-溴-1-氟-4-硝基苯、3-氟邻苯二甲酰亚胺、4-氟邻苯二甲酰亚胺为原料,经13步合成反应得到最终产物化合物1-11;
(1)以3-甲基-1H-吡咯-2-羧酸乙酯a和溴乙醛缩二乙醇为原料,在NaH作用下进行取代反应,得到b;
(2)化合物b在碱性条件中发生酯水解,得到c;
(3)化合物c与氯化铵在有机碱性条件中通过缩合剂催化,得到酰胺d;
(4)化合物d酸性条件中发生自身环化,得到e;
(5)化合物e发生溴代反应得到f;
(6)以2-溴-1-氟-4-硝基苯g为反应物,与苯酚反应得到h;
(7)化合物h经铁粉还原得i;
(8)化合物i与联硼酸频那醇酯经钯催化剂催化,得到j;
(9)化合物j与化合物f发生Suzuki偶联反应,得到k;
(10)化合物k与丁二酸酐缩合成酰胺,分别得到l;
(11)以3-氟邻苯二甲酰亚胺m-1与3-氨基-2,6-哌啶二酮盐酸盐发生取代反应得到n-1;
(12)化合物n-1与N-Boc-二胺反应得到化合物o-1~o-8;
(13)化合物o-1~o-8与化合物l经酰胺缩合得到最终产物1-8;
化合物9-11的制备与化合物1-8不同在于(11)中3-氟邻苯二甲酰亚胺m-1替换为4-氟邻苯二甲酰亚胺m-2。
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