CN116836179A - 具有肿瘤靶向的溴结构域蛋白brd4抑制剂 - Google Patents
具有肿瘤靶向的溴结构域蛋白brd4抑制剂 Download PDFInfo
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Abstract
本发明涉及溴结构域蛋白BRD4抑制剂与热休克蛋白HSP90抑制剂形成的化合物,其存在一定的抗肿瘤活性,可克服BRD4抑制剂对肿瘤组织选择性差,毒性高等缺点。
Description
技术领域
本发明涉及BRD4蛋白抑制剂与HSP90抑制剂形成的化合物,其具有一定的抗肿瘤活性,可克服一般BRD4抑制剂对的肿瘤组织选择性的问题。
背景技术
溴结构域和超末端蛋白家族(BET)蛋白家族参与了许多人类疾病的发生和发展,在DNA损伤修复、转录表达以及染色体重塑等生物过程起着重要作用。该家族主要包含了四种亚型:BRD2,BRD3,BRD4和BRDT。BET家族中溴结构域蛋白4(BRD4)作为家族中最重要的的成员,可通过组蛋白乙酰化调节DNA的修复,控制基因表达,进而可影响细胞周期。BRD4具有两个溴结构域BD1以及BD2,其作用机制是能与染色质上的超乙酰化组蛋白区域结合,在转录过程中积累并在起始和延伸步骤中促进基因转录。
BRD4能够促进肿瘤的发展和转移等过程,在黑色素瘤、骨髓瘤和乳腺癌等多种肿瘤中过表达。BRD4的具体作用机制主要有:促进c-MYC基因、B淋巴细胞瘤2基因的转录;上调肿瘤细胞中PD-L1的表达,促进肿瘤细胞增殖;加剧免疫抑制;修复损伤的DNA;促进端粒延伸。BRD4对肿瘤组织的重要作用使得此靶点成为药物研发的重点。
目前,采用的策略包括抑制BRD4或直接利用降解剂降解肿瘤细胞中过度表达的BRD4,研究表明,多种BRD4抑制剂和降解剂均具有良好的抗肿瘤效果,包括最早的抑制剂(+)-JQ-1在内,目前已有多种处于临床研究阶段,表现出良好的应用前景,本章将选取药物构效关系和生物活性等研究最为透彻的(+)-JQ-1作为BRD4的靶蛋白配体。
虽然,BRD4抑制剂针对多种疾病类型尤其是血液肿瘤疾病,显示出了较好的疗效,但仍然具有一些应用限制。由于这些药物都是根据占据驱动的药理学原理可逆的结合靶蛋白,导致常常需要高剂量给药来达到治疗效果,临床试验中表现剂量限制毒性如:血小板减少、疲劳、腹泻、呕吐、贫血和高胆红素血症等。部分抑制剂如OTX-015和IBET-151,由于其对实体肿瘤的治疗效果有限而被迫终止。泛BET抑制剂,由于其对多个溴结构域没有选择性,会导致脱靶效应并产生严重的安全性问题。近年来越来越多的选择性BRD4抑制剂被开发出来,这些抑制剂只干扰了BRD4上两个域中的其中一个,提高了药物的选择性,效价有待进一步提升。
PROTAC技术的不断发展,为BRD4抑制剂的应用提供了新的思路。BRD4配体、E3泛素连接酶配体和中间连接链,构成了基于PROTAC技术的BRD4降解剂的基本结构。近些年来,研究人员设计合成了一系列BRD4降解剂,这些降解剂可根据E3泛素连接酶的类型不同分为两类:基于CRBN的BRD4降解剂,如dBET-1、BETd-260、ARV-825;和基于VHL的BRD4降解剂,如MZ1、MZP-54、ARV-771。以BETd-260为例,降解剂可以在血液瘤中以DC50=30pM的浓度下有效诱导靶蛋白的降解,并且体外抗肿瘤效果也比对应的抑制剂高一个数量级。BRD4降解剂可有效诱导BRD4降解,其抑制肿瘤细胞生长和促进细胞凋亡的能力远胜于相应抑制剂,是一种极具前景的针对BRD4的肿瘤治疗策略。
虽然基于主流E3泛素连接酶配体VHL及CRBN的BRD4降解剂疗效较好,但也存在一些问题,比如:两者都属于无组织特异性的E3连接酶,可能导致全身性的脱靶和毒副作用;两者都属于肿瘤生长的非必需蛋白,基于两者的PROTAC小分子药物容易产生耐药。
为了克服BRD4抑制剂和PROTACs的缺点,提高药物的抗肿瘤活性降低毒副作用。一方面,可以开发具有高选择性、低毒性的WEE1抑制剂;另一方面,可以通过探索WEE1抑制剂与其他药物联用或制成化合物的方式来提高药物活性。
HSP90作为一种伴侣蛋白,是细胞内含量最高的蛋白之一,约占细胞蛋白总量的1-3%,本身也是一种已知的肿瘤靶点。由于HSP90分布较广,且通常在肿瘤组织中高表达,因此针对该靶点的抑制剂具有较强的肿瘤组织选择性,HSP90近年来逐步成为抗肿瘤药物研究的热点。临床实验结果表明,HSP90抑制剂往往需要高剂量才能起效。正因为如此,HSP90在临床表现出较多的副作用,例如视觉毒性、胃肠道毒性、肝毒性、神经毒性等,大大的限制了其应用,至今也还未有HSP90抑制剂被批准上市。另外,本领域已有将HSP90抑制剂与其它抗癌物质组合应用的报道,也有将HSP90抑制剂与BRD4抑制剂制成化合物的报道,但未披露具体的活性数据。因此,本发明将针对BRD4抑制剂(+)-JQ-1,设计一系列HSP90-BRD4化合物分子。
发明内容
本发明在实验中发现,由于HSP90在肿瘤细胞中的持续分泌,因此当BRD4抑制剂与HSP90抑制剂形成化合物时,可利用HSP90抑制剂对肿瘤细胞进行靶向,由此显著提高BRD4抑制剂在肿瘤细胞中抑制靶蛋白的作用,进而解决现有BRD4抑制剂选择性,毒副作用大的缺点。另外,本发明还发现HSP90作为伴侣蛋白可以介导四百多种客户蛋白的折叠和成熟。BRD4作为其客户蛋白之一,在本发明的化合物中或许能通过HSP90抑制剂的作用实现选择性降解。
因此,本发明涉及一种化合物,其包括BRD4抑制部分与HSP90抑制部分,两者通过连接链连接;或其药学上可接受的盐、溶剂合物、互变异构体、立体异构体、外消旋体或前药。
在一个实施方案中,前述连接链是指在HSP90抑制部分和BRD4抑制部分之间形成共价结合的键或者连接基团,这些连接链包括:化学键(包括碳碳键、碳氮键、碳硫键、碳磷键、氮氮键)、酯键(包括羧酸酯键、磺酸酯键、氨基甲酸酯键)、羰基(-C(=O)-)、C1-6亚烷基、酰胺键、醚键、二硫键等及其组合。
在所述化合物的一个优选实施方案中,HSP90抑制部分包括但不限于如下结构,以及由这些结构衍生而成的可以和连接链形成各类共价键的结构或基团:
或其药学上可接受的盐、溶剂合物、互变异构体、立体异构体、外消旋体或前药。
在所述化合物的一个优选实施方案中,BRD4抑制部分包括但不限于如下结构,以及由这些结构衍生而成的可以和连接链形成各类共价键的结构或基团:
或其药学上可接受的盐、溶剂合物、互变异构体、立体异构体、外消旋体或前药。
在所述化合物的一个优选的实施方案中,HSP90抑制部分包括上述NVP-AUY922、AT13387或STA9090类似物的结构,或由NVP-AUY922、AT13387或STA9090类似物衍生的结构;BRD4抑制部分包括上述(+)-JQ-1的结构,或由(+)-JQ-1衍生的结构;连接链选自化学键、酰胺键、羰基、C1-6亚烷基及其组合,
或其药学上可接受的盐、溶剂合物、互变异构体、立体异构体、外消旋体或前药。
在所述化合物的一个更优选的实施方案中,
HSP90抑制部分包含从以下结构中除去一个氢原子后得到的一价基团:
其中R1表示-COOH,R2表示-NHC(=O)CH2CH2COOH,R3表示-CH2COOH;
BRD4抑制部分包含从以下结构中除去一个氢原子后得到的一价基团:
连接链选自化学键:-NH-(CH2)n-NH-,-NH-(CH2CH2O)n-CH2CH2-NH-;或其药学上可接受的盐、溶剂合物、互变异构体、立体异构体、外消旋体或前药。
在一个进一步优选的实施方案中,本发明的化合物为如下所示的HTT-1~HTT-18,
或其药学上可接受的盐、溶剂合物、互变异构体、立体异构体、外消旋体或前药。
在一个实施方案中,本发明涉及一种药物组合物,其包含如前文所述的本发明的化合物或其药学上可接受的盐、溶剂合物、互变异构体、立体异构体、外消旋体或前药,以及一种或多种药用载体。
在一个实施方案中,本发明的药物组合物中还包含其它治疗药物。在另一个实施方案中,本发明的药物组合物与其它治疗药物组合使用。所述其它治疗药物例如为肿瘤化疗药物、肿瘤靶向药物、肿瘤免疫治疗药物、肿瘤药物偶联物(例如抗体药物偶联物、小分子药物化合物和微型药物化合物)。
另一个实施方案涉及本发明的化合物或药物组合物用于制备药物的用途,所述药物用于预防或***。
本发明的化合物具有良好的BRD4抑制活性和HSP90抑制活性,特别是由于HSP90抑制活性所带来的靶向作用而使得BRD4抑制活性得以增强,在一定程度上解决了BRD4抑制剂靶向性差、毒副作用大的缺点,为癌症的临床治疗提供了有希望的选择。本发明的化合物在癌细胞株(MM1S)中,取得了一定的癌症细胞抑制效果。
附图说明
图1:化合物HTT-4处理肿瘤细胞MM1S 24h后的Western实验结果。
具体实施方式
本说明书所用术语“改造”是指出于将具有某种活性的物质(如BRD4抑制剂和HSP90抑制剂)制成化合物的目的,而将该化合物进行结构修饰,但修饰后的部分仍包含原物质的主体结构或活性结构,并保留(甚至在形成化合物后可能提高)原抑制剂的药理活性。
本说明书所用术语“抑制部分”(如BRD4抑制部分和HSP90抑制部分)是指将相应的抑制剂(如BRD4抑制剂和HSP90抑制剂)经过上述改造后得到的部分,该部分可为一价或更高价基团,并且与连接链连接。
本说明书所用术语“连接链”是指连接两个或多个抑制部分的化学部分,可为如前文所定义的化学键或化学基团。连接链(或其部分)可存在于改造前的活性物质分子或改造后的抑制部分中,也可为新增加的连接键或基团。
本说明书所用术语“化合物”是指通过连接链将至少两个上述抑制部分连接后而获得的化合物。
本说明书所用术语“前药”是以非活性或非完全活性形式给药并随后通过代谢过程转化成活性物质(例如本发明的化合物)的物质。前药可用于改进活性物质的吸收、分布、代谢和/或***,也可用于改进活性物质针对特定细胞或过程相互作用的选择性,由此例如可降低活性物质的不良反应或非预期作用。
本说明书所用术语“约”表示在相应数值上下浮动10%的范围。例如,若某种成分的浓度为约5mM,表明其浓度为4.5-5.5mM;若某种成分的浓度范围为约5-10mM,表明其浓度范围为4.5-11mM。
此外,本说明书所用其它术语均具有本领域通用的含义。
为了获得本发明的化合物,需要首先对活性物质进行改造,再将改造后的物质通过连接链连接起来。下面以BRD4抑制剂(+)-JQ-1和HSP90抑制剂NVP-AUY922、AT13387和STA9090类似物为例,对一般反应路线进行说明。
首先,如反应式1所示,可按常规的有机化学反应合成方法,将BRD4抑制剂(+)-JQ-1(A1)改造成含有羧基的化合物2。
接下来,如反应式2所示,可将HSP90抑制剂NVP-AUY922、AT13387和STA9090改造成含有羧基基团的化合物3、5、6,再与前述化合物2通过linker连接。
对于化合物合成的具体方法,将在下文实施例部分进一步详述。
本发明的化合物可用于制备***的药物。具体而言,所述肿瘤包括但不限于胰腺癌、结肠癌、大肠癌、卵巢癌、***、贲门癌、睾丸癌、***癌、肝癌、非小细胞肺癌、小细胞肺癌、肺腺癌、头颈部细胞癌、膀胱癌、胃癌、肾癌、胆管癌、脑癌、乳腺癌、上皮细胞癌、皮肤癌、食管癌、淋巴瘤、神经胶质瘤、黑色素瘤、多发性骨髓瘤和白血病等,包括在其他远离肿瘤原发部位的组织或器官的转移病变。
本发明的化合物可以使用能够产生所需结果的任何方便的手段给药于治疗对象,例如人类患者,例如可以将所述化合物制成如前文所述的药物组合物,和/或制成已知的或新开发的剂型(如片剂、胶囊剂、注射剂等)中。
此外,本发明的化合物可以与其它治疗药物组合使用。所述其它治疗药物包括肿瘤化疗药物、肿瘤靶向药物、肿瘤免疫治疗药物、肿瘤药物偶联物(例如抗体药物偶联物、小分子药物化合物和微型药物化合物)。本发明的化合物可以与其它治疗药物制成同一剂型,或分别制成单独的剂型。
本发明的更具体的实施方式将通过以下实施例并结合附图进行例示性解释说明,但应认识到这些实施例并非意在限制本发明的范围。
实施例
本说明书实施例中所用的合成原料、试验物质等,均为本领域技术人员所公知并且可通过市售或文献方法获得的物质。所用的试验或表征方法也是本领域技术人员公知的方法。
在下文各中间体实施例中,作为起始物质的A1至A4的来源分别参见以下文献:J.Med.Chem.2020,63,5421-5441;Expert Opin.Ther.Patents 2014,24(2),185-199;J.Med.Chem.2014,57,2258-2274;Mol Cancer Ther 2020 19(8):1613–1622.
在下文各药理实施例中,将产物实施例1-6中获得的化合物HTT-1~HTT-18称为“本发明的化合物”。另外,各药理实施例中所用的细胞株来源于:中国科学院大学上海药物研究所(SIMM)。
中间体实施例1
将化合物A1(2.0g,1.7mmol)溶解于10mL体积比为50%的TFA/DCM溶液中,室温条件下,反应3h。待反应结束后,减压除去溶剂,得到目标产物2,黄色固体1.5g,产率86%。
中间体实施例2
将化合物A2(2.0g,3.2mmol)溶于20mL甲醇中,加入10%的钯碳(200mg),置换氮气和氢气,室温下反应8h。待反应完全后,硅藻土抽滤,减压除去溶剂,得到粗产物。粗产物用硅胶柱层析分离,得到目标产物3,灰白色固体1.35g,产率85%。1H NMR(400MHz,DMSO-d6)δ10.62(s,2H),9.78(s,1H),9.68(s,1H),7.69(s,2H),7.37–7.16(m,5H),6.80(s,2H),6.74(s,1H),3.47(s,4H),3.19(m,1H),2.40(s,4H),1.17(d,J=6.9Hz,6H).13C NMR(100MHz,DMSO-d6)δ173.2,161.9,158.3,151.9,132.46,132.1,130.9,129.1,122.2,114.5,100.8,97.8,66.0,62.3,53.0,26.2,22.4.
中间体实施例3
氮气条件下,将化合物A3(5.0g,9.58mmol)溶解于50mL的甲醇中,加入1.5g 10%Pd/C,置换氢气,室温条件下,反应4h。待反应完全后,垫硅藻土抽滤,除去钯碳。滤液减压除去,得到粗产物。粗产物用DCM和甲醇(10:1)打浆,得到化合物4,黄色固体2.54g,产率85%。1HNMR(400MHz,DMSO-d6)δ9.89(s,1H),9.77(s,1H),7.65(d,J=0.6Hz,1H),7.27(d,J=7.5Hz,1H),6.82–6.66(m,2H),6.52(s,1H),4.66(dd,J=35.0,5.3Hz,2H),4.21(t,J=7.1Hz,2H),3.31–2.97(m,3H),1.22(d,J=6.8Hz,6H).13C NMR(100MHz,DMSO-d6)δ168.12,161.88,157.58,145.00,135.15,131.62,128.07,127.30,119.12,115.05,113.96,112.23,101.86,48.07,27.13,26.65,22.38.
中间体实施例4
将化合物4(2.0g,6.41mmol)和丁二酸酐(774mg,7.69mmol)溶解于20mL的甲苯中,加热至回流,反应12h。待反应完全后,减压除去溶剂,得到粗产物。粗产物用硅胶柱层析,得到化合物5,淡黄色固体2.24g,产率85%。1H NMR(400MHz,DMSO-d6)δ9.89(s,1H),9.72(s,1H),9.19(s,1H),7.65(d,J=0.6Hz,1H),7.56(dd,J=7.5,1.5Hz,1H),7.34(q,J=1.1Hz,1H),7.30(d,J=7.5Hz,1H),6.53(s,1H),4.30–4.05(m,2H),3.16(dtd,J=18.9,7.0,0.9Hz,3H),2.68–2.59(m,2H),2.59–2.48(m,2H),1.22(d,J=6.8Hz,6H).13C NMR(100MHz,DMSO-d6)δ175.04,170.94,167.33,161.76,158.59,138.62,137.57,130.15,127.67,126.80,119.68,117.32,116.56,113.66,101.77,47.57,31.77,28.84,27.00,22.43.
中间体实施例5
将化合物A4(1.0g,1.73mmol)溶解于20mL体积比为20%的TFA/DCM溶液中,室温条件下,反应2h。待反应结束后,减压除去溶剂,得到目标产物6,黄色固体750mg,收率83%。
中间体实施例6:7a-7d的通用合成路线
将化合物2(1eq)、2a~2d(1eq)和HATU(1.2eq)依次加入两口瓶中,在氮气保护下注射加入无水DMF溶液,搅拌并溶解后,滴加DIPEA(3eq)。滴毕,反应体系在室温下搅拌过夜。检测反应完全后,加水淬灭,乙酸乙酯萃取得粗产品,干燥后硅胶柱层析分离纯化,得到相应的产物7a~7d。
化合物7a的合成
以化合物2和2a为原料,按照中间体实施例6的通用合成方法得到化合物7a,淡黄色固体150mg,产率90%。1H NMR(400MHz,DMSO)δ8.23(t,J=5.1Hz,1H),7.49(d,J=8.3Hz,2H),7.42(d,J=8.4Hz,2H),6.83–6.77(m,1H),4.50(t,J=7.0Hz,1H),3.17–3.09(m,4H),3.05–3.01(m,2H),2.60(s,3H),2.41(s,3H),1.63(s,3H),1.38(s,9H).13C NMR(101MHz,DMSO)δ170.20,169.74,163.49,161.71,156.08,155.58,150.30,137.23,135.67,132.75,131.17,130.63,130.31,130.04,128.95,78.15,54.24,54.07,28.69,23.09,18.55,17.20,14.54,13.15,12.96,11.77.
化合物7b的合成
以化合物2和2b为原料,按照中间体实施例6的通用合成方法得到化合物7b,淡黄色固体155mg,产率89%。1H NMR(400MHz,DMSO)δ8.20(t,J=5.5Hz,1H),7.49(d,J=8.4Hz,2H),7.42(d,J=8.4Hz,2H),6.78(s,1H),4.50(dd,J=8.3,5.8Hz,1H),3.21–2.94(m,6H),2.60(s,3H),2.41(s,3H),1.61(d,J=8.3Hz,3H),1.37(s,9H),1.25(d,J=5.6Hz,2H).13CNMR(101MHz,DMSO)δ169.99,163.51,156.03,155.58,150.29,137.24,135.65,132.75,131.16,130.63,130.30,130.04,128.93,77.93,54.35,38.13,36.74,28.72,14.53,13.15,11.78.
化合物7c的合成
以化合物2和2c为原料,按照中间体实施例6的通用合成方法得到化合物7c,淡黄色固体140mg,产率90%。1H NMR(400MHz,DMSO)δ8.18(t,J=5.4Hz,1H),7.50(d,J=8.3Hz,2H),7.41(d,J=8.4Hz,2H),6.79(d,J=5.8Hz,1H),4.50(dd,J=8.2,5.9Hz,1H),3.20–3.02(m,4H),2.89(s,2H),2.59(s,3H),2.41(s,3H),1.62(s,3H),1.42(s,4H),1.37(s,9H).13C NMR(101MHz,DMSO)δ169.81,169.35,163.47,161.35,156.08,155.60,150.27,137.24,135.68,132.74,131.17,130.58,130.29,130.04,128.96,77.80,55.39,54.35,38.74,28.74,27.43,27.06,23.08,14.53,13.15,11.78.
化合物7d的合成
以化合物2和2d为原料,按照中间体实施例6的通用合成方法得到化合物7d,淡黄色固体140mg,产率88%。1H NMR(400MHz,DMSO)δ8.16(t,J=5.4Hz,1H),7.49(d,J=8.2Hz,2H),7.42(d,J=8.4Hz,2H),6.77(s,1H),4.50(t,J=7.0Hz,1H),3.16(m,J=18.9,12.3,5.5Hz,4H),2.91–2.87(m,2H),2.59(s,3H),2.41(s,3H),1.62(s,3H),1.37(s,9H),1.28–1.24(m,8H).13C NMR(101MHz,DMSO)δ169.77,163.46,156.05,155.60,150.26,137.24,135.71,132.74,131.17,130.57,130.29,130.06,128.93,77.74,54.39,54.08,38.89,38.13,29.94,29.69,28.74,26.55,26.49,18.56,17.21,14.52,13.15,11.76.
中间体实施例7:化合物8a~8d的通用合成方法
将化合物7a~7d(1eq)加入到三氟醋酸和二氯甲烷(1:1比例)的混合溶液中,室温搅拌3小时。待检测反应完全后,减压浓缩,得到黄色固体化合物8a~8d。
中间体实施例8
将化合物2(1eq)、、2e;2f(1eq)和HATU(1.2eq)依次加入两口瓶中,在氮气保护下注射加入无水DMF溶液,搅拌并溶解后,滴加DIPEA(3eq)。滴毕,反应体系在室温下搅拌过夜。检测反应完全后,加水淬灭,乙酸乙酯萃取得粗产品,干燥后硅胶柱层析分离纯化,得到相应的产物9e;9f。
中间体实施例9
将化合物9e;9f(1eq)加入到三氟醋酸和二氯甲烷(1:1比例)的混合溶液中,室温搅拌3小时。待检测反应完全后,减压浓缩,得到黄色固体化合物10e;10f。
产物实施例1:化合物HTT-1~HTT-4的通用合成方法
将化合物8a~8d(1eq)、5(1eq)和HATU(1.2eq)依次加入两口瓶中,在氮气保护下注射加入无水DMF溶液,搅拌并溶解后,滴加DIPEA(3eq)。滴毕,反应体系在室温下搅拌过夜。检测反应完全后,加水淬灭,乙酸乙酯萃取得粗产品,干燥后硅胶柱层析分离纯化,得到相应的产物HTT-1~HTT-4。
化合物HTT-1的合成
以化合物8a和5为原料,按照化合物HTT-1~HTT-4的通用合成方法得到HTT-1,白色固体45mg,产率65%。1H NMR(400MHz,DMSO)δ9.90(s,1H),9.74(s,1H),9.61(s,1H),8.25(s,1H),7.91(s,1H),7.57(s,1H),7.49(d,J=8.2Hz,2H),7.42(d,J=8.2Hz,3H),7.26(s,1H),6.97(s,1H),6.40(s,1H),4.51(t,J=6.8Hz,1H),3.95(t,J=7.8Hz,2H),3.25(d,J=6.6Hz,2H),3.13(d,J=20.9Hz,6H),3.02(t,J=7.7Hz,3H),2.59(s,3H),2.41(s,5H),1.62(s,3H),1.12(d,J=6.7Hz,6H).13C NMR(101MHz,DMSO)δ171.94,170.55,170.22,167.72,163.53,157.13,155.59,153.47,150.35,138.66,137.21,135.74,135.51,133.40,132.73,131.17,130.63,130.32,130.05,128.96,126.00,117.75,116.36,115.67,102.86,54.26,49.28,38.95,38.82,38.12,32.07,30.92,27.93,26.30,23.14,14.54,13.15,11.78.HRMS(ESI):m/z calcd for(M+H)+:837.3952;found:837.3635.
化合物HTT-2的合成
以化合物8b和5为原料,按照化合物HTT-1~HTT-4的通用合成方法得到HTT-2,白色固体40mg,产率75%。1H NMR(400MHz,DMSO)δ9.87(s,1H),9.74(s,1H),9.61(s,1H),8.19(s,1H),7.87(s,1H),7.56(s,1H),7.49(d,J=8.5Hz,2H),7.42(d,J=8.4Hz,2H),7.25(d,J=7.2Hz,1H),6.97(s,1H),6.40(s,1H),4.51(t,J=7.0Hz,1H),3.94(t,J=8.1Hz,2H),3.27–2.97(m,11H),2.59(s,4H),2.40(s,5H),1.64–1.55(m,5H),1.12(d,J=6.8Hz,6H).13C NMR(101MHz,DMSO)δ171.65,170.55,169.94,163.53,157.14,155.59,153.51,150.30,137.24,135.68,133.43,132.73,131.16,130.61,130.32,130.05,128.96,126.01,117.76,116.39,102.90,100.00,54.34,40.63,40.42,40.21,40.00,39.80,39.59,39.38,38.13,36.95,32.15,30.90,29.79,26.31,23.13,14.52,13.15,11.78.HRMS(ESI):m/zcalcd for(M+H)+:851.4631;found:851.4611.
化合物HTT-3的合成
以化合物8c和5为原料,按照化合物HTT-1~HTT-4的通用合成方法得到HTT-3,白色固体36mg,产率75%。1H NMR(400MHz,DMSO)δ9.89(s,1H),9.77(s,1H),9.65(s,1H),8.21(s,1H),7.87(s,1H),7.56(s,1H),7.48(s,2H),7.43(s,2H),7.27(s,1H),6.97(s,1H),6.41(s,1H),4.48(s,1H),3.95(s,2H),3.02(s,10H),2.55(s,3H),2.41(s,4H),1.62(s,3H),1.44(s,4H),1.24(s,3H),1.12(d,J=4.8Hz,6H).13C NMR(101MHz,DMSO)δ171.54,170.57,169.84,163.49,157.15,155.59,153.48,150.30,143.32,137.22,135.70,135.59,133.44,132.73,131.17,130.59,130.30,130.04,128.95,125.99,124.18,119.20,117.73,117.70,116.36,115.64,110.63,102.88,54.35,49.25,38.71,38.09,32.21,30.92,27.15,27.08,26.30,23.13,14.53,13.15,11.78.HRMS(ESI):m/z calcd for(M+H)+:865.4862;found:865.4811.
化合物HTT-4的合成
以化合物8d和5为原料,按照化合物HTT-1~HTT-4的通用合成方法得到HTT-4,白色固体50mg,产率70%。1H NMR(400MHz,DMSO)δ9.88(s,1H),9.75(s,1H),9.62(s,1H),8.18(t,J=5.5Hz,1H),7.85(t,J=5.4Hz,1H),7.56(s,1H),7.48(d,J=8.7Hz,2H),7.42(d,J=8.5Hz,2H),7.26(s,1H),6.98(s,1H),6.40(s,1H),4.51(t,J=7.1Hz,1H),3.95(t,J=8.3Hz,2H),3.26–3.20(m,2H),3.13–3.00(m,8H),2.59(s,3H),2.40(d,J=8.6Hz,5H),1.62(s,3H),1.48–1.34(m,5H),1.31–1.25(m,5H),1.12(d,J=6.9Hz,6H).13C NMR(101MHz,DMSO)δ171.47,170.57,169.82,167.74,163.48,157.14,155.60,153.49,150.28,138.64,137.22,135.72,135.58,133.43,132.72,131.18,130.57,130.29,130.04,128.93,126.01,117.73,116.35,115.65,102.88,54.38,49.30,38.90,38.12,32.22,30.92,29.65,29.60,28.00,26.57,26.55,26.31,23.12,14.52,13.14,11.76.HRMS(ESI):m/z calcd for(M+H)+:893.5532;found:893.5012.
产物实施例2:化合物的HTT-5~HTT-8的通用合成方法
将化合物8a~8d(1eq)、3(1eq)和HATU(1.2eq)依次加入两口瓶中,在氮气保护下注射加入无水DMF溶液,搅拌并溶解后,滴加DIPEA(3eq)。滴毕,反应体系在室温下搅拌过夜。检测反应完全后,加水淬灭,乙酸乙酯萃取得粗产品,干燥后硅胶柱层析分离纯化,得到相应的产物HTT-5~HTT-8。
化合物HTT-5的合成
以化合物8a和3为原料,化合物的HTT-5~HTT-8的通用合成方法得到HTT-5,白色固体40mg,产率60%。1H NMR(400MHz,DMSO)δ9.90(s,1H),9.74(s,1H),9.61(s,1H),8.25(s,1H),7.91(s,1H),7.57(s,1H),7.49(d,J=8.2Hz,2H),7.42(d,J=8.2Hz,3H),7.26(s,1H),6.97(s,1H),6.40(s,1H),4.51(t,J=6.8Hz,1H),3.95(t,J=7.8Hz,2H),3.25(d,J=6.6Hz,2H),3.13(d,J=20.9Hz,6H),3.02(t,J=7.7Hz,3H),2.59(s,3H),2.41(s,5H),1.62(s,3H),1.12(d,J=6.7Hz,6H).13C NMR(101MHz,DMSO)δ171.94,170.55,170.22,167.72,163.53,157.13,155.59,153.47,150.35,138.66,137.21,135.74,135.51,133.40,132.71,131.17,130.63,130.32,130.05,128.96,126.00,117.75,116.36,115.67,102.86,54.26,49.28,38.95,38.82,38.12,32.07,30.92,27.93,26.30,23.14,14.54,13.15,11.78.HRMS(ESI):m/z calcd for(M+H)+:865.4862;found:865.4811.
化合物HTT-6的合成
以化合物8b和3为原料,按照化合物的HTT-5~HTT-8的通用合成方法得到HTT-6,白色固体35mg,产率55%。1H NMR(400MHz,DMSO)δ9.95(s,1H),9.69(s,1H),9.60(s,1H),8.25(s,1H),7.91(s,1H),7.57(s,1H),7.49(d,J=8.2Hz,2H),7.42(d,J=8.2Hz,3H),7.26(s,1H),6.97(s,1H),6.45(s,1H),4.51(t,J=6.8Hz,1H),3.95(t,J=7.8Hz,2H),3.25(d,J=6.6Hz,2H),3.13(d,J=20.9Hz,6H),3.02(t,J=7.7Hz,3H),2.59(s,3H),2.41(s,5H),1.62(s,3H),1.12(d,J=6.7Hz,6H).13C NMR(101MHz,DMSO)δ171.94,170.55,170.22,167.72,163.53,157.13,155.59,153.47,150.35,138.66,137.21,135.74,135.51,133.40,132.73,131.17,130.63,130.32,130.05,128.96,126.00,117.75,116.35,115.67,102.86,54.20,49.28,38.95,38.82,38.12,32.07,30.92,27.93,26.30,23.11,14.54,13.15,11.71.HRMS(ESI):m/z calcd for(M+H)+:877.4604;found:877.4591.
化合物HTT-7的合成
以化合物8c和3为原料,按照化合物HTT-5~HTT-8的通用合成方法得到HTT-7,白色固体45mg,产率60%。1H NMR(400MHz,MeOD)δ7.41(dd,J=17.4,8.0Hz,4H),7.30–7.20(m,4H),6.78(s,1H),6.35(s,1H),4.67–4.60(m,1H),3.64(s,4H),3.49–3.33(m,7H),3.28(s,1H),3.10–3.01(m,1H),2.68(s,3H),2.43(s,6H),1.66(d,J=17.9Hz,7H),1.29(s,1H),0.95(d,J=6.8Hz,6H).13C NMR(101MHz,DMSO)δ170.13,169.58,163.51,157.78,156.63,156.52,155.59,154.90,150.28,148.20,140.10,137.22,135.70,134.44,132.75,131.17,130.62,130.28,130.04,129.52,128.96,127.75,126.33,125.91,103.06,102.96,61.91,61.84,54.39,53.41,53.02,38.18,36.52,36.22,34.02,30.07,25.71,22.78,14.96,14.55,13.13,11.78.HRMS(ESI):m/z calcd for(M+H)+:891.5102;found:891.5032.
化合物HTT-8的合成
以化合物8d和3为原料,按照化合物HTT-5~HTT-8的通用合成方法得到HTT-8,白色固体45mg,产率70%。1H NMR(400MHz,MeOD)δ7.38(dd,J=17.4,8.0Hz,4H),7.30–7.25(m,4H),6.77(s,1H),6.35(s,1H),4.67–4.60(m,1H),3.64(s,4H),3.49–3.33(m,7H),3.28(s,1H),3.11–3.01(m,1H),2.68(s,3H),2.43(s,6H),1.66(m,J=17.9Hz,11H),1.29(s,1H),0.93(d,J=6.8Hz,6H).13C NMR(101MHz,DMSO)δ170.13,169.58,163.51,157.78,156.63,156.52,155.59,154.90,150.28,148.20,140.10,137.22,135.70,134.44,132.75,131.17,130.62,130.28,130.04,129.52,128.96,127.75,126.33,125.91,103.06,102.96,61.91,61.84,54.39,53.41,53.02,38.18,36.52,36.22,34.02,30.07,25.75,22.78,14.96,14.55,13.13,11.78.HRMS(ESI):m/z calcd for(M+H)+:919.5536;found:919.5499.
产物实施例3:化合物的HTT-9~HTT-12的通用合成方法
将化合物8a~8d(1eq)、6(1eq)和HATU(1.2eq)依次加入两口瓶中,在氮气保护下注射加入无水DMF溶液,搅拌并溶解后,滴加DIPEA(3eq)。滴毕,反应体系在室温下搅拌过夜。检测反应完全后,加水淬灭,乙酸乙酯萃取得粗产品,干燥后硅胶柱层析分离纯化,得到相应的产物HTT-9~HTT-12。
化合物HTT-9的合成
以化合物8a和6为原料,按照化合物HTT-9~HTT-12的通用合成方法得到HTT-9,白色固体35mg,产率55%。1H NMR(400MHz,DMSO)δ10.59(s,1H),9.76(s,1H),8.95(t,J=5.6Hz,1H),8.28(s,1H),7.79(s,1H),7.48(d,J=8.3Hz,2H),7.42(d,J=8.3Hz,2H),7.35(d,J=8.1Hz,2H),7.29(d,J=8.1Hz,2H),6.57(s,1H),6.35(s,1H),4.52(t,J=6.9Hz,1H),3.44(s,2H),3.28–3.15(m,9H),2.88(d,J=10.1Hz,3H),2.59(s,3H),2.40(d,J=17.1Hz,10H),1.62(s,3H),1.03(t,J=7.1Hz,3H),0.79(d,J=6.7Hz,6H).13C NMR(101MHz,DMSO)δ170.33,169.94,163.53,157.75,156.62,156.53,155.57,154.88,150.31,148.21,140.09,137.24,135.69,134.43,132.74,131.17,130.63,130.31,130.02,129.58,128.95,127.74,126.32,125.94,103.04,102.97,61.94,61.75,54.23,53.40,53.03,38.87,38.13,34.02,25.70,22.77,14.95,14.54,13.13,11.77.HRMS(ESI):m/z calcd for(M+H)+:947.5911;found:947.5801.
化合物HTT-10的合成
以化合物8b和6为原料,按照化合物HTT-9~HTT-12的通用合成方法得到HTT-10,白色固体39mg,产率60%。1H NMR(400MHz,DMSO)δ10.60(s,1H),9.78(s,1H),8.96(t,J=5.8Hz,1H),8.26(t,J=5.5Hz,1H),7.79(t,J=5.8Hz,1H),7.49(d,J=8.6Hz,2H),7.43(d,J=8.5Hz,2H),7.35(d,J=8.3Hz,2H),7.29(d,J=8.3Hz,2H),6.57(s,1H),6.36(s,1H),4.52(dd,J=8.2,5.9Hz,1H),3.46(s,1H),3.39–3.29(m,6H),3.17(dd,J=13.4,6.9Hz,6H),2.89(d,J=9.9Hz,3H),2.59(s,3H),2.41(d,J=17.4Hz,10H),1.61(s,3H),1.03(t,J=7.2Hz,3H),0.79(d,J=6.9Hz,6H).13C NMR(101MHz,DMSO)δ170.13,169.58,163.51,157.78,156.63,156.52,155.59,154.90,150.28,148.20,140.10,137.22,135.70,134.44,132.75,131.17,130.62,130.28,130.04,129.52,128.96,127.75,126.33,125.91,103.06,102.96,61.91,61.84,54.39,53.41,53.02,38.18,36.52,36.22,34.02,30.07,25.71,22.78,14.96,14.55,13.13,11.78.HRMS(ESI):m/z calcd for(M+H)+:961.6113;found:961.5819.
化合物HTT-11的合成
以化合物8c和6为原料,按照化合物HTT-9~HTT-12的通用合成方法得到HTT-11,白色固体45mg,产率78%。1H NMR(400MHz,DMSO)δ10.59(s,1H),9.70(s,1H),8.95(t,J=5.7Hz,1H),8.20(t,J=5.2Hz,1H),7.59(t,J=5.6Hz,1H),7.50(d,J=8.2Hz,2H),7.42(d,J=8.4Hz,2H),7.37(d,J=8.2Hz,2H),7.29(d,J=8.2Hz,2H),6.57(s,1H),6.34(s,1H),4.54–4.49(m,1H),3.48(s,1H),3.30–3.08(m,10H),2.90(s,3H),2.59(s,3H),2.42(d,J=14.0Hz,10H),1.62(s,3H),1.44(s,4H),1.03(t,J=7.1Hz,3H),0.80(d,J=6.8Hz,6H).13CNMR(101MHz,DMSO)δ169.83,169.47,163.48,157.74,156.62,156.52,155.59,154.89,150.28,148.20,140.08,137.24,135.69,134.44,132.74,131.17,130.58,130.29,130.04,129.56,128.96,127.75,126.36,125.92,103.04,102.99,61.90,61.83,54.35,53.40,53.02,38.71,38.37,38.12,34.02,27.23,27.14,25.71,22.79,14.95,14.54,13.14,11.77.HRMS(ESI):m/z calcd for(M+H)+:975.6813;found:975.6599.
化合物HTT-12的合成
以化合物8d和6为原料,按照化合物HTT-9~HTT-12的通用合成方法得到HTT-12,白色固体35mg,产率55%。1H NMR(400MHz,DMSO)δ10.60(s,1H),9.73(s,1H),8.95(t,J=5.8Hz,1H),8.17(t,J=5.4Hz,1H),7.65(t,J=5.8Hz,1H),7.48(d,J=8.5Hz,2H),7.43(d,J=8.4Hz,2H),7.39(d,J=8.2Hz,2H),7.26(d,J=8.2Hz,2H),6.55(s,1H),6.34(s,1H),4.55–4.48(m,1H),3.49(s,2H),3.27–3.03(m,9H),2.93–2.84(m,3H),2.59(s,3H),2.42(d,J=12.0Hz,10H),1.62(s,3H),1.41(dd,J=13.7,6.8Hz,4H),1.26(d,J=15.9Hz,4H),1.03(t,J=7.2Hz,3H),0.79(d,J=6.9Hz,6H).13C NMR(101MHz,DMSO)δ169.80,169.36,163.47,157.74,156.62,156.54,155.60,154.88,150.27,148.21,140.09,137.23,135.71,134.44,132.73,131.18,130.57,130.28,130.05,129.57,128.93,127.75,126.33,125.91,103.04,102.99,61.89,61.82,54.39,53.37,53.03,40.63,40.42,40.21,40.00,39.79,39.58,39.37,38.82,38.53,38.13,34.02,29.66,26.52,26.47,25.71,22.79,14.95,14.52,13.15,11.76.HRMS(ESI):m/z calcd for(M+H)+:1003.6880;found:1003.6723.
产物实施例4:化合物的HTT-13;HTT-14的通用合成方法
将化合物10e;10f(1eq)、5(1eq)和HATU(1.2eq)依次加入两口瓶中,在氮气保护下注射加入无水DMF溶液,搅拌并溶解后,滴加DIPEA(3eq)。滴毕,反应体系在室温下搅拌过夜。检测反应完全后,加水淬灭,乙酸乙酯萃取得粗产品,干燥后硅胶柱层析分离纯化,得到相应的产物HTT-13;HTT-14。
化合物HTT-13的合成
以化合物10e和5为原料,按照化合物HTT-13;HTT-14的通用合成方法得到HTT-13,白色固体35mg,产率75%。1H NMR(400MHz,DMSO)δ9.87(s,1H),9.73(s,1H),9.60(s,1H),8.28(t,J=5.3Hz,1H),7.95(t,J=5.2Hz,1H),7.55(s,1H),7.46(d,J=8.5Hz,2H),7.40(d,J=8.3Hz,2H),7.25(d,J=4.6Hz,1H),6.97(s,1H),6.39(s,1H),4.51(t,J=7.0Hz,1H),3.94(t,J=8.2Hz,2H),3.44(dd,J=12.2,5.9Hz,5H),3.25(dt,J=14.7,6.0Hz,7H),3.11–3.06(m,1H),3.02(t,J=8.2Hz,2H),2.59(s,3H),2.42(d,J=8.2Hz,6H),1.61(s,3H),1.11(d,J=6.9Hz,6H).13C NMR(101MHz,DMSO)δ171.84,170.53,170.19,157.12,155.57,153.47,150.30,137.19,135.72,132.71,131.10,130.62,130.36,130.03,128.94,125.97,69.44,69.38,54.32,39.02,30.74,26.26,23.13,14.53,13.13,11.74.HRMS(ESI):m/z calcd for(M+H)+:881.4580;found:881.4329.
化合物HTT-14的合成
以化合物10f和5为原料,按照化合物HTT-13;HTT-14的通用合成方法得到HTT-14,白色固体40mg,产率70%。1H NMR(400MHz,DMSO)δ9.87(s,1H),9.73(s,1H),9.61(s,1H),8.30(t,J=5.5Hz,1H),7.95(t,J=5.5Hz,1H),7.55(s,1H),7.47(s,2H),7.42(d,J=8.5Hz,2H),7.25(s,1H),6.97(s,1H),6.40(s,1H),4.50(d,J=7.7Hz,1H),3.95(t,J=8.3Hz,2H),3.53(s,5H),3.46(t,J=5.8Hz,3H),3.41(t,J=5.9Hz,4H),3.29–3.19(m,7H),3.05(dt,J=16.5,7.6Hz,4H),2.59(s,3H),2.41(s,5H),1.62(s,3H),1.12(d,J=6.9Hz,6H).13C NMR(101MHz,DMSO)δ171.82,170.54,170.18,163.49,157.13,155.57,153.48,150.30,137.23,135.69,133.43,132.74,131.17,130.62,130.30,130.02,128.93,126.01,117.73,116.35,115.67,102.87,70.05,69.68,69.62,54.30,39.11,39.05,37.97,32.07,30.75,26.30,23.13,14.53,13.15,11.77.HRMS(ESI):m/z calcd for(M+H)+:925.5233;found:925.4905.
产物实施例5:化合物的HTT-15;HTT-16的通用合成方法
将化合物10e;10f(1eq)、3(1eq)和HATU(1.2eq)依次加入两口瓶中,在氮气保护下注射加入无水DMF溶液,搅拌并溶解后,滴加DIPEA(3eq)。滴毕,反应体系在室温下搅拌过夜。检测反应完全后,加水淬灭,乙酸乙酯萃取得粗产品,干燥后硅胶柱层析分离纯化,得到相应的产物HTT-15;HTT-16。
化合物HTT-15的合成
以化合物10e和3为原料,按照化合物HTT-15;HTT-16的通用合成方法得到HTT-15,白色固体35mg,产率79%。1H NMR(400MHz,DMSO)δ10.09(s,1H),9.73(s,1H),8.96(t,J=5.8Hz,1H),8.28(t,J=5.4Hz,1H),7.72(t,J=5.6Hz,1H),7.48(d,J=8.6Hz,2H),7.46(d,J=8.5Hz,2H),7.37(d,J=8.3Hz,2H),7.21(d,J=8.3Hz,2H),6.55(s,1H),6.34(s,1H),4.55–4.50(m,1H),3.46(d,J=5.7Hz,6H),3.32–3.13(m,9H),2.91(d,J=10.1Hz,3H),2.59(s,3H),2.41(d,J=14.2Hz,10H),1.61(s,3H),1.03(t,J=7.2Hz,3H),0.79(d,J=6.9Hz,6H).13C NMR(101MHz,DMSO)δ170.17,169.76,163.48,157.74,156.61,156.52,155.57,154.88,150.27,148.20,140.10,137.24,135.70,134.43,132.75,131.16,130.61,130.30,130.02,129.55,128.93,127.73,126.33,125.92,103.03,101.98,69.34,61.86,61.69,54.33,53.34,53.06,39.10,38.51,38.02,34.01,25.70,22.78,14.96,14.53,13.14,11.76.HRMS(ESI):m/z calcd for(M+H)+:907.5312;found:907.4849.
化合物HTT-16的合成
以化合物10f和3为原料,按照化合物HTT-15;HTT-16的通用合成方法得到HTT-16,白色固体45mg,产率75%。1H NMR(400MHz,DMSO)δ9.87(s,1H),9.73(s,1H),9.60(s,1H),8.28(t,J=5.3Hz,1H),7.95(t,J=5.2Hz,1H),7.55(s,1H),7.42(d,J=8.5Hz,2H),7.35(d,J=8.4Hz,2H),7.25(d,J=4.6Hz,1H),6.97(s,1H),6.39(s,1H),4.51(t,J=7.0Hz,1H),3.94(t,J=8.2Hz,2H),3.44(dd,J=12.2,5.9Hz,6H),3.25(dt,J=14.7,6.0Hz,10H),3.11–3.06(m,1H),3.02(t,J=8.2Hz,2H),2.59(s,3H),2.42(d,J=8.2Hz,6H),1.61(s,3H),1.18(d,J=6.9Hz,6H).13C NMR(101MHz,DMSO)δ171.84,170.53,170.19,157.12,155.57,153.47,150.30,137.19,135.72,132.71,131.10,130.62,130.36,130.03,128.98,125.97,69.44,69.38,54.52,39.02,30.74,26.26,23.13,14.53,13.13,11.74.HRMS(ESI):m/z calcd for(M+H)+:951.5466;found:951.5378.
产物实施例6:化合物的HTT-17;HTT-18的通用合成方法
将化合物10e;10f(1eq)、6(1eq)和HATU(1.2eq)依次加入两口瓶中,在氮气保护下注射加入无水DMF溶液,搅拌并溶解后,滴加DIPEA(3eq)。滴毕,反应体系在室温下搅拌过夜。检测反应完全后,加水淬灭,乙酸乙酯萃取得粗产品,干燥后硅胶柱层析分离纯化,得到相应的产物HTT-17;HTT-18。
化合物HTT-17的合成
以化合物10e和6为原料,按照化合物HTT-17;HTT-18的通用合成方法得到HTT-17,白色固体25mg,产率70%。1H NMR(400MHz,DMSO)δ10.61(s,1H),9.76(s,1H),8.96(t,J=5.8Hz,1H),8.28(t,J=5.4Hz,1H),7.72(t,J=5.6Hz,1H),7.46(d,J=8.6Hz,2H),7.40(d,J=8.5Hz,2H),7.33(d,J=8.3Hz,2H),7.28(d,J=8.3Hz,2H),6.57(s,1H),6.34(s,1H),4.55–4.50(m,1H),3.46(d,J=5.7Hz,6H),3.32–3.13(m,9H),2.91(d,J=10.1Hz,3H),2.59(s,3H),2.41(d,J=14.2Hz,10H),1.61(s,3H),1.03(t,J=7.2Hz,3H),0.79(d,J=6.9Hz,6H).13C NMR(101MHz,DMSO)δ170.17,169.74,163.48,157.74,156.61,156.52,155.57,154.88,150.27,148.20,140.10,137.24,135.70,134.43,132.75,131.16,130.61,130.30,130.02,129.55,128.93,127.73,126.33,125.92,103.03,102.98,69.34,61.86,61.69,54.33,53.34,53.06,39.10,38.51,38.02,34.01,25.70,22.78,14.96,14.53,13.14,11.76.HRMS(ESI):m/z calcd for(M+H)+:991.6533;found:991.6250.
化合物HTT-18的合成
以化合物10f和6为原料,按照化合物HTT-17;HTT-18的通用合成方法得到白色固体HTT-18,白色固体55mg,产率75%。1H NMR(400MHz,DMSO)δ10.61(s,1H),9.76(s,1H),8.96(t,J=5.8Hz,1H),8.28(t,J=5.4Hz,1H),7.72(t,J=5.6Hz,1H),7.46(d,J=8.6Hz,2H),7.41(d,J=8.5Hz,2H),7.33(d,J=8.3Hz,2H),7.29(d,J=8.3Hz,2H),6.57(s,1H),6.34(s,1H),4.55–4.50(m,1H),3.46(d,J=5.7 Hz,8H),3.32–3.13(m,11H),2.91(d,J=10.1 Hz,3H),2.59(s,3H),2.41(d,J=14.2 Hz,10H),1.61(s,3H),1.03(t,J=7.2 Hz,3H),0.79(d,J=6.9 Hz,6H).13CNMR(101 MHz,DMSO)δ170.17,169.74,163.48,157.74,156.61,156.52,155.58,154.88,150.27,148.20,140.10,137.24,135.70,134.43,132.75,131.16,130.65,130.30,130.02,129.55,128.93,127.73,126.33,125.95,103.03,102.98,69.34,61.86,61.69,54.33,53.34,53.06,39.10,38.51,38.02,34.01,25.70,22.78,14.96,14.50,13.14,11.66.HRMS(ESI):m/z calcd for(M+H)+:1035.6833;found:1035.6523.药理实施例1:化合物HTT-1~HTT-18的HSP90酶抑制活性实验
为评价化合物对HSP90酶活性的影响,采用荧光偏振法对HSP90酶活性进行测试。用10%DMSO的缓冲溶液制备一系列测试化合物的稀释液,并将10μL稀释液加入到100μL反应中,反应在室温下进行。5nM FITC标记的格尔德霉素和测试化合物的100μL混合物进行反应3小时。使用Tecan Infinite M1000酶标仪在485nm和530nm激发下测量荧光强度,使用Tecan Magellan 6软件将荧光强度转换为荧光偏振。根据下式计算化合物的活性百分比:活性%=(FP-FPb)/(FPt-FPb)×100%,其中FP=化合物存在下的荧光偏振。
表1.化合物的HSP90酶活性
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a Data is the mean value of two independent determinations.
b Positive control.
如Table 1所示,以HSP90抑制剂STA9090作为阳性对照,测试了18个目标化合物对HSP90酶的抑制活性。其中,STA9090对HSP90(IC50=15nM)激酶表现出极强的抑制活性。总体上,这些基于HSP90的肿瘤靶向BRD4抑制剂在100nM时对酶的抑制率都较高,说明对HSP90抑制剂的改造和设计基本不影响其靶点活性。其中,基于AT13387的化合物HTT-1;HTT-3;HTT-4;HTT-13和基于STA9090的双功能分子HTT-10;HTT-11;HTT-12对HSP90的单浓度抑制率在90%以上,除了HTT-13(100nM,Inhibition rate=93%),其他六个化合物linker均为烷基链,以丁烷和己烷为linker时酶抑制活性最好。该实验结果表明,linker为烷基链且较长时,化合物的HSP90靶点结合活性较好。
药理实施例2:化合物HTT-1;HTT-2;HTT-3;HTT-4;HTT-13;HTT-14对肿瘤细胞株的增殖抑制活性实验
化合物对肿瘤细胞生长抑制检测采用CCK8方法。具体步骤如下:处于对数生长期的细胞按合适密度接种至96孔培养板,每孔100μL完全培养基培养过夜。加入一系列浓度的化合物,每个浓度设置三个复孔,并设置无化合物作用的阳性对照孔及无细胞阴性对照孔。将细胞培养在37℃条件下72h。药物作用结束后,每孔加入10μL CCK-8试剂,置于37℃培养箱中放置3小时后,使用全波长式微孔板酶标仪SpectraMax 190测定450nm波长下的光密度(OD值)。
表2.化合物在体外对MM1S肿瘤细胞的抑制活性
a Data is the mean±SD value of three independent determinations.
b Positive control.
(+)-JQ-1和HSP90抑制剂AUY922作为阳性化合物。如Table 2所示,在肿瘤细胞MM1S上,与HSP90抑制剂AUY922(IC50=27nM)和BRD4抑制剂(+)-JQ-1(IC50=26.5nM)相比,化合物IC50均在微摩尔水平,其中化合物HTT-4(linker长度为6个碳原子,IC50=0.6μM)与其他化合物而言对MM1S细胞的抗增殖作用相对较强。
药理实施例3:化合物HTT-4的蛋白免疫印迹实验
用Western实验进一步探究化合物HTT-4对肿瘤细胞抑制能力和对BRD4蛋白的影响。细胞接种于六孔板中,培养过夜后加不同浓度的化合物处理24小时后收集细胞。预冷PBS洗一次,加入1×SDS上样缓冲液裂解细胞。收集细胞裂解物,沸水浴加热10min后于4℃12000rpm离心5min。取上清液进行SDS-PAGE电泳。电泳结束后并转移,转移结束后,用丽春红染色确定转移情况和蛋白条带在硝酸纤维素膜上的位置,标记后将目的条带用封闭液于摇床室温封闭1h。然后,将膜置于一抗中4摄氏度孵育过夜。用TBST洗涤液室温洗涤三次,每次10min。加入辣根过氧化物酶标记的二抗,摇床室温孵育1h。再用TBST洗涤三次,每次10min后,显色,曝光。
如附图1,化合物作用MM1S细胞24h后,HTT-4在0.2μM浓度下即可下调BRD4和c-MYC的表达。
本发明利用烷基和PEG类linker连接HSP90抑制剂和BRD4抑制剂改造的配体,设计合成了一系列具有肿瘤靶向的BRD4抑制剂。在HSP90酶抑制实验中一系列化合物均表现出较好的酶活性,在细胞毒实验和Western实验中,化合物HTT-4都表现出一定的抗肿瘤活性,本发明化合物有望用于BRD4过表达的肿瘤治疗。
Claims (10)
1.一种化合物,其包括BRD4抑制部分与HSP90抑制部分,两者通过连接链连接;或其药学上可接受的盐、溶剂合物、互变异构体、立体异构体、外消旋体或前药;
2.根据权利要求1所述的化合物,其中所述连接链包含在HSP90抑制部分和BRD4抑制部分之间形成共价结合的键或者连接基团,所述连接链选自:化学键、酯键、羰基、C1-6亚烷基、酰胺键、醚键、二硫键及其组合;
或其药学上可接受的盐、溶剂合物、互变异构体、立体异构体、外消旋体或前药。
3.根据权利要求1或2所述的化合物,其中所述HSP90抑制部分选自如下结构,以及由这些结构衍生而成的能够和连接链形成各类共价键的结构或基团:
或其药学上可接受的盐、溶剂合物、互变异构体、立体异构体、外消旋体或前药。
4.根据权利要求1所述的化合物,其中所述BRD4抑制部分选自如下结构,以及由这些结构衍生而成的能够和连接链形成各类共价键的结构或基团:
或其药学上可接受的盐、溶剂合物、互变异构体、立体异构体、外消旋体或前药。
5.根据权利要求3或4所述的化合物,其中所述HSP90抑制部分包括所述NVP-AUY922、AT13387或STA9090类似物的结构,或由NVP-AUY922、AT13387或STA9090类似物衍生的结构;BRD4抑制部分包括所述(+)-JQ-1的结构,或由(+)-JQ-1衍生的结构;连接链选自化学键、酰胺键、羰基、C1-6亚烷基及其组合,或其药学上可接受的盐、溶剂合物、互变异构体、立体异构体、外消旋体或前药。
6.根据权利要求3、4或5所述的化合物,其中,
HSP90抑制部分包含从以下结构中除去一个氢原子后得到的一价基团:
其中R1表示-COOH,R2表示-NHC(=O)CH2CH2COOH,R3表示-CH2COOH;
BRD4抑制部分包含从以下结构中除去一个氢原子后得到的一价基团:
连接链选自化学键:-NH-(CH2)n-NH-,-NH-(CH2CH2O)n-CH2CH2-NH-;
或其药学上可接受的盐、溶剂合物、互变异构体、立体异构体、外消旋体或前药。
7.根据前述任一项权利要求所述的化合物,其为如下所示的HTT-1~HTT-18,
或其药学上可接受的盐、溶剂合物、互变异构体、立体异构体、外消旋体或前药。
8.一种药物组合物,其包含根据前述任一项权利要求所述的化合物或其药学上可接受的盐、溶剂合物、互变异构体、立体异构体、外消旋体或前药,以及一种或多种药用载体。
9.根据权利要求8所述的药物组合物,其还包含其它治疗药物,所述其它治疗药物为肿瘤化疗药物、肿瘤靶向药物、肿瘤免疫治疗药物及肿瘤药物偶联物。
10.一种权利要求1-7中任一项所述的化合物或权利要求8-9中任一项所述的药物组合物用于制备预防或***药物的用途。
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