CN115160298B - 一种他克林-磺酰胺类衍生物及其制备方法与应用 - Google Patents
一种他克林-磺酰胺类衍生物及其制备方法与应用 Download PDFInfo
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Abstract
本发明涉及一种他克林‑磺酰胺类衍生物及其制备方法与作为CDK2/9抑制剂的应用,本发明所涉及的他克林‑磺酰胺类衍生物具有结构新颖,高的抗增殖活性和CDK2/9抑制活性,所有化合物对所测肿瘤细胞系的GI50值都达到了10微摩尔以内,并且部分化合物具有较高的CDK2选择性。因此,该类化合物在制备预防或治疗肿瘤中具有重要作用。所述的衍生物结构通式如式I所示:
Description
技术领域
本发明属于有机化合物合成与医药应用技术领域,具体涉及一种他克林-磺酰胺类衍生物及其制备方法与作为CDK2和CDK9抑制剂的应用。
背景技术
在癌症的复杂性和特异性之下,有少量的“关键任务”事件驱动着肿瘤细胞不受控制的增殖和侵袭。其中的关键是细胞增殖失调和凋亡抑制,它们提供了一个最小的“平台”来支持进一步的肿瘤进展。
细胞周期蛋白依赖激酶(CDKs)是丝氨酸/苏氨酸激酶的21个成员家族,通过与细胞周期蛋白伙伴形成复合物来调节细胞周期进程(CDKs 1、2、4、6)或调节转录(CDKs 7、8、9等)。CDK2是研究最多的成员之一,CDK2的失调导致细胞不断增殖。CDK2与CyclinE形成异二聚体复合物,通过磷酸化视网膜母细胞瘤(Rb)蛋白启动S期。CDK2/cyclin A维持Rb蛋白的磷酸化,以促进S/G2转换。
在过去的三十年里,人们开发了大量的小分子CDK抑制剂。然而,由于CDK的高度保守结构,大多数CDK抑制剂,特别是那些在临床开发中的,是广谱的,可能会导致不可预测的副作用。Palbociclib是第一个上市的CDK抑制剂,它的成功为CDK抑制剂的选择性提供了更重要的视角。在接下来的几年中,连续的CDK4/6双靶点抑制剂被批准。由于CDK的高度保守ATP结合位点,开发选择性CDK抑制剂的机会面临挑战。
CDK2是最早研究的CDKs组的一员,已发表了大量与蛋白质空腔共结晶的抑制剂。不幸的是,目前还没有针对CDK2的批准药物,甚至还有一些药物正在进行CDK2的临床试验。这是由于CDK2的口袋自由度较低,并且抑制剂对其具有活性,而对其他成员(如CDK9)通常具有较高的活性。因此,开发CDK2抑制剂既困难又重要。
他克林于1945年被发现。成功地具有良好的胆碱酯酶活性,但因肝毒性而失败。近年来,他克林以其独特的结构被用于设计抗癌分子抑制剂。然而,开发用于癌症治疗的新他克林衍生物的主要挑战是减少他克林支架诱导的肝毒性,并加强对ChE的抗癌靶点的选择性。
发明内容
发明目的:本发明提出一种他克林-磺酰胺类衍生物及其制备方法与作为CDK2/9抑制剂的应用,其目的在于提供一种具有抑制CDK2/9的他克林-磺酰胺类衍生物或其药学上可接受的盐以及所述他克林-磺酰胺类衍生物的制备方法,同时还指出他克林-磺酰胺类衍生物在制备治疗癌症药物中的应用。
技术方案:
一种他克林-磺酰胺类衍生物或其药学上可接受的盐,所述的衍生物结构通式如式I所示:
其中:
A环为哌啶或苯环;
R选自二甲基氨基、乙基、环丙基、甲基、N-甲基哌嗪基、四氢吡咯基、哌嗪基或者吗啉基;
n各自独立地为1或者2。
下列化合物或其在药学上可接受的盐,选自:
一种所述化合物的制备方法,化合物的制备方法包括以下步骤:
(1)以化合物1为原料,加入环酮,在POCl3中110℃回流,反应得到化合物2;
(2)在化合物2中加入苯酚和催化量的碘化钠,并加入(S)-3-(Boc-氨基)吡咯烷或者(R)-3-(Boc-氨基)吡咯烷,反应得到化合物3a-3c;
(3)将化合物3a-3c溶于无水二氧六环中,加入4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)、乙酸钾和二(三苯基磷)氯化钯,反应得到化合物4a-4c;
(4)将4-溴-2-氟吡啶(5)在四氢呋喃中溶解并与4-N-1-Boc-哌啶进行亲核取代得到化合物6;
(5)二甲氨基磺酰氯、乙磺酰氯或者环丙烷磺酰氯分别用化合物6进行亲核取代得到化合物7a-7c;
(6)将化合物7a-7c溶于二氧六环:水=4:1的溶剂中,加入4a-4c、碳酸铯和二(三苯基磷)氯化钯,然后将产物溶于乙酸乙酯中,加入HCl-EtOAc,反应得到目标化合物反应得到化合物ZLHT-3、ZLHT-5或ZLHT-6;
(7)将化合物8a或者8b溶于无水二氯甲烷中,加入不同取代基的氨和三乙胺,反应得到9b-9h;
(8)将4-溴吡啶-2-胺溶于DMF中,在冰浴条件下加入NaH反应30min,将9a或者9b-9h溶解在DMF中,然后缓慢添加到反应溶液中,反应得到10a-10h;(9)将化合物10a-10h代替化合物7a-d溶于无水二氧六环中,重复步骤(6),反应得到目标化合物43、44、45、46、47、48、49、50、ZLHT-7、ZLHT-8、ZLHT-9、ZLHT-10、ZLHT-11、ZLHT-12、ZLHT-13、ZLHT-14、ZLHT-15、ZLHT-16、ZLHT-17、ZLHT-18、ZLHT-19、ZLHT-20或ZLHT-21。
优选的,不同取代基的氨为二甲胺、四氢吡咯、哌嗪、N-甲基哌嗪、吗啉中的一种。
一种药物组合物,所述的式I或其药学上可接受的盐以及药学上可接受的辅料。所述式I添加一种或多种药学上可接受的辅料制成制剂,所述制剂的剂型为胶囊剂、丸剂、片剂、颗粒剂或注射剂。
所述化合物或其药学上可用的盐在制备治疗肿瘤中的应用。
所述化合物或其药学上可用的盐在制备CDK2抑制剂和CDK9抑制剂中的应用。
有益效果:
与现有的技术相比,本发明所涉及的他克林-磺酰胺类衍生物具有结构新颖,高的抗增殖活性和CDK2/9抑制活性,所有化合物对所测肿瘤细胞系的GI50值都达到了10微摩尔以内,并且部分化合物具有较高的CDK2选择性。因此,该类化合物在制备预防或治疗肿瘤中具有重要作用。
附图说明
图1为化合物44-50、ZLHQ-3-5和ZLHT-7-21的制备方法示意图。
具体实施方式
下面通过具体实施例对本发明进行说明,但本发明并不局限于这些实施例。通过核磁共振(NMR)和高分辨质谱(HR-MS)确定化合物的结构。NMR的测定是使用BrukerAVANCE-300/600核磁共振仪,测定的溶剂是DMSO-d6,内标为TMS。柱层析采用200-300目硅胶(青岛海洋化工厂生产)。
如图1所示,将环己酮(1.2当量)添加到2-氨基-5-溴苯甲酸(化合物1)(1当量)的POCl3(30mL)溶液中,将其加热至110℃并回流3小时,然后冷却至室温并浓缩。残渣用乙酸乙酯稀释,然后用K2CO3水溶液中和后用水和盐水冲洗。浓缩后,得到中间体化合物2a,该中间体无需进一步纯化,直接使用。产率88%,淡黄色固体。
实施例2 2-溴-11-氯-7,8,9,10-四氢-6H-环庚烷[b]喹啉(化合物2b)
如图1所示,环庚酮替换环己酮,其他条件不变,合成方法如实施例1,得到化合物2b。产率84%,淡黄色固体。1H NMR(400MHz,DMSO-d6):δ8.25(s,1H),7.89(s,2H),3.34(s,2H),3.20(s,2H),1.85(s,2H),1.69(s,6H).ESI-MS:m/z310.1[M+H]+。
如图1所示,将化合物2a(1当量)、碘化钠(0.2当量)和苯酚(2当量)在90℃下在圆底烧瓶(100mL)中搅拌0.5h,然后加入(S)-3-(Boc-氨基)吡咯烷(5当量)。将反应温度升高至170℃并保持0.5小时,冷却至室温,用乙酸乙酯稀释,并用2M NaOH溶液中和至弱碱性。用水和盐水冲洗有机层,并在无水Na2SO4上干燥。通过蒸发滤液获得中间体化合物3a,该中间体无需进一步纯化,直接使用。产率82%,纯白色固体。
如图1所示,(R)-3-(Boc-氨基)吡咯烷替换(S)-3-(Boc-氨基)吡咯烷,其他条件不变,合成方法如实施例3,得到化合物3b。产率86%,纯白色固体。
如图1所示,2b替换2a,其他条件不变,合成方法如实施例3,得到化合物3c。产率79%,纯白色固体。1H NMR(400MHz,DMSO-d6):δ8.16(d,J=2.3Hz,1H),7.82(d,J=8.8Hz,1H),7.72(dd,J=8.9,2.3Hz,1H),7.34(d,J=6.7Hz,1H),4.28(q,J=6.4Hz,1H),3.49–3.38(m,2H),3.32–3.25(m,1H),3.17(dd,J=8.7,5.3Hz,1H),3.15–3.10(m,2H),2.95–2.87(m,2H),2.30(dtd,J=12.6,7.3,5.4Hz,1H),2.04(ddt,J=12.5,7.8,6.3Hz,1H),1.82(q,J=5.9Hz,2H),1.67(q,J=6.2Hz,4H),1.42(s,9H).ESI-MS:m/z 460.2[M+H]+。
如图1所示,向化合物3a(1当量)和4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)(1.2当量)在无水二氧六环的溶液中添加KOAc(3当量)和Pd(dppf)Cl2(0.05%mol)。在氮气保护下,在90℃下反应12h后,浓缩溶剂并向反应瓶中加水,然后收集滤饼以获得中间体化合物4a,该中间体直接使用,无需进一步纯化,产率89%,棕褐色固体。
如图1所示,化合物3b替换化合物3a,其他条件不变,合成方法如实施例6,得到化合物4b。产率84%,棕褐色固体。
实施例8叔丁基(S)-(1-(2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-7,8,9,10-四氢-6H-环庚[b]喹啉-11-基)吡咯烷-3-基)氨基甲酸酯(化合物4c)
如图1所示,化合物3c替换化合物3a,其他条件不变,合成方法如实施例6,得到化合物4c。产率91%,棕褐色固体。
实施例9 4-((4-溴吡啶-2-基)氨基)-N,N-二甲基哌啶-1-磺酰胺(7a)
将4-溴-2-氟吡啶(1当量)、4-氨基-1-Boc-哌啶(2当量)、三乙胺(3当量)加入装有10mL四氢呋喃的耐压管中,并在120℃下反应2小时。减压蒸馏后,用水洗涤,得到产物,干燥后,除去Boc,得到中间体化合物6。将二甲氨基磺酰氯(1当量,100mg)溶于四氢呋喃中,加入三乙胺(1.5当量)和中间体化合物6(1.1当量)得到化合物7a。该中间体直接使用,无需进一步纯化,产率74%,白色固体。
实施例10 4-溴-N-(1-(乙基磺酰基)哌啶-4-基)吡啶-2-胺(7b)
如图1所示,乙磺酰氯替换二甲氨基磺酰氯,其他条件不变,合成方法如实施例9,得到化合物7b。产率71%,棕褐色固体。
实施例11 4-溴-N-(1-(环丙基磺酰基)哌啶-4-基)吡啶-2-胺(7c)
如图1所示,环丙烷磺酰氯替换二甲氨基磺酰氯,其他条件不变,合成方法如实施例9,得到化合物7c。产率89%,白色固体。
实施例12 4-溴-N-(4-(甲基磺酰基)苯基)吡啶-2-胺(化合物10a)
如图1所示,将NaH(5当量)添加到4-溴吡啶-2-胺(1.2当量)的DMF(20mL)溶液中,然后在冰浴中反应30分钟。之后,将9a(1-氟-4-(甲基磺酰基)苯)(1当量)溶解在DMF(10mL)中,然后缓慢添加到反应溶液中,并在80℃下反应2小时。然后蒸发溶剂,加入冰水,抽滤得到中间体化合物10a。该中间体直接使用,无需进一步纯化,产率85%,棕褐色固体。
实施例13 4-((4-溴吡啶-2-基)氨基)-N,N-二甲基苯磺酰胺(化合物10b)
如图1所示,将二甲胺(1当量)和4-氟苯磺酰氯(化合物8a)(1.2当量)溶于50mL二氯甲烷中,加入三乙胺(3当量),在室温下反应30min。然后蒸发溶剂,加入冰水,抽滤得到中间体化合物9b。该中间体直接使用,无需进一步纯化。将NaH(5当量)添加到4-溴吡啶-2-胺(1.2当量)的DMF(20mL)溶液中,然后在冰浴中反应30分钟。之后,将9b(1-氟-4-(甲基磺酰基)苯)(1当量)溶解在DMF(10mL)中,然后缓慢添加到反应溶液中,并在80℃下反应2小时。然后蒸发溶剂,加入冰水,抽滤得到中间体化合物10b。该中间体直接使用,无需进一步纯化,产率73%,棕褐色固体。
如图1所示,N-甲基哌嗪替换二甲胺,其他条件不变,合成方法如实施例13,得到化合物10c。产率67%,棕褐色固体。
实施例15 4-溴-N-(4-(吡咯烷-1-基磺酰基)苯基)吡啶-2-胺(化合物10d)
如图1所示,四氢吡咯替换二甲胺,其他条件不变,合成方法如实施例13,得到化合物10d。产率74%,棕褐色固体。
实施例16 4-溴-N-(4-(哌嗪-1-基磺酰基)苯基)吡啶-2-胺(化合物10e)
如图1所示,哌嗪替换二甲胺,其他条件不变,合成方法如实施例13,得到化合物10e。产率69%,棕褐色固体。
实施例17 4-溴-N-(3-(哌嗪-1-基磺酰基)苯基)吡啶-2-胺(化合物10f)
如图1所示,哌嗪替换二甲胺,8b替换8a,其他条件不变,合成方法如实施例13,得到化合物10f。产率69%,棕褐色固体。
实施例18 4-溴-N-(4-(吗啉磺酰基)苯基)吡啶-2-胺(化合物10g)
如图1所示,吗啉替换二甲胺,其他条件不变,合成方法如实施例13,得到化合物10g。产率72%,棕褐色固体。
实施例19 4-溴-N-(3-(吗啉磺酰基)苯基)吡啶-2-胺(化合物10h)
吗啉替换二甲胺,8b替换8a其他条件不变,合成方法如实施例13,得到化合物10h。产率67%,棕褐色固体。
实施例20(S)-N-(4-(11-(3-氨基吡咯烷-1-基)-7,8,9,10-四氢-6H-环庚[b]喹啉-2-基)吡啶-2-基)环丙烷甲酰胺盐酸盐(化合物24)
如图1所示,向中间体化合物4b(1当量)和化合物8a(1.2equiv)在二氧六环/水(4:1)中的溶液中加入Cs2CO3(3当量)和Pd(dppf)Cl2(0.05%mol)。将反应混合物在95℃搅拌12小时,然后将反应混合物用水(100mL)稀释并用乙酸乙酯(3×50mL)萃取。合并的有机层用盐水(200mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。反应粗产物经快速柱层析纯化,得到化合物9a。化合物9a的Boc基团用4M HCl-EtOAc在25℃下脱保护1h得到化合物24。产率72%,黄色固体。1H NMR(400MHz,DMSO-d6):δ11.92(s,1H),8.54(s,1H),8.48(d,J=5.4Hz,3H),8.44(d,J=5.7Hz,2H),8.20–8.15(m,2H),7.76(dd,J=5.7,1.9Hz,1H),4.37(dd,J=12.3,6.3Hz,1H),4.19(t,J=7.3Hz,2H),4.04(dt,J=14.2,5.4Hz,1H),3.95(q,J=5.2Hz,1H),3.21(t,J=5.6Hz,2H),2.93(t,J=5.4Hz,2H),2.36(dq,J=14.3,7.6Hz,1H),2.19(ddd,J=12.7,10.4,5.7Hz,1H),2.12(ddd,J=12.3,7.7,4.8Hz,1H),1.83(hept,J=5.2,4.2Hz,2H),1.81–1.69(m3H),1.63(h,J=5.8Hz,1H),0.93(tt,J=8.8,4.1Hz,4H).13C NMR(151MHz,DMSO-d6):δ174.5,172.5,159.4,157.8,151.4,150.9,138.3,132.4,130.2,125.4,120.0,118.0,117.9,116.2,112.2,58.63,53.3,49.3,33.8,31.1,30.2,29.3,28.4,25.5,15.0,9.0(2).HR-ESI-MS:442.2620[M+H]+,(calcd for C27H31N5O,442.2601)。
实施例20(S)-4-(11-(3-氨基吡咯烷-1-基)-7,8,9,10-四氢-6H-环庚[b]喹啉-2-基)-N-(4-(甲基磺酰基)苯基)吡啶-2-胺盐酸盐(化合物44)
如图1所示,向中间体化合物10a(1当量)和化合物4c(1.2equiv)在二氧六环/水(4:1)中的溶液中加入Cs2CO3(3当量)和Pd(dppf)Cl2(0.05%mol)。将反应混合物在95℃搅拌12小时,然后将反应混合物用水(100mL)稀释并用乙酸乙酯(3×50mL)萃取。合并的有机层用盐水(200mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。反应粗产物经快速柱层析纯化,然后Boc基团用4M HCl-EtOAc在25℃下脱保护1h得到化合物44。产率72%,黄色固体。1HNMR(400MHz,DMSO-d6):δ10.59(s,1H),8.70(d,J=5.4Hz,3H),8.54(s,1H),8.36(d,J=5.5Hz,1H),8.22(d,J=2.2Hz,2H),8.05(d,J=8.8Hz,2H),7.83(d,J=8.9Hz,2H),7.77(d,J=1.6Hz,1H),7.39(dd,J=5.6,1.6Hz,1H),4.45(dd,J=12.0,6.5Hz,1H),4.17(p,J=5.3,4.8Hz,3H),4.08–3.98(m,1H),3.25(t,J=5.3Hz,2H),3.17(s,3H),2.93(t,J=5.3Hz,2H),2.42–2.30(m,1H),2.19(dq,J=12.7,6.4Hz,1H),1.83(q,J=5.4Hz,2H),1.77(s,2H),1.68(s,2H).13C NMR(151MHz,DMSO-d6):δ159.0,158.1,155.8,148.3,147.5,146.3,138.0,133.3,132.2,130.1,128.7(2),124.6,120.0,118.4,117.9(2),117.2,114.1,110.4,58.3,53.7,49.5,44.6,33.7,31.2,30.2,29.4,28.3,25.5.HR-ESI-MS:528.2429[M+H]+,(calcdfor C30H33N5O2S,528.2428)。
实施例21(S)-4-((4-(11-(3-氨基吡咯烷-1-基)-7,8,9,10-四氢-6H-环庚[b]喹啉-2-基)吡啶-2-基)氨基)-N,N-二甲基苯磺酰胺盐酸盐(化合物45)
如图1所示,10b替换10a,其他条件不变,合成方法如实施例20,得到化合物45。产率75%,黄色固体。1H NMR(400MHz,DMSO-d6):δ10.63(s,1H),8.72(d,J=5.3Hz,3H),8.54(d,J=1.7Hz,1H),8.34(d,J=5.5Hz,1H),8.28–8.17(m,2H),8.10–8.00(m,2H),7.78(d,J=1.6Hz,1H),7.71–7.64(m,2H),7.39(dd,J=5.6,1.6Hz,1H),4.45(dd,J=12.0,6.5Hz,2H),4.19–4.13(m,2H),4.03(s,1H),3.25(t,J=5.3Hz,2H),2.93(t,J=5.4Hz,2H),2.60(s,6H),2.42–2.32(m,1H),2.19(dd,J=12.4,6.3Hz,1H),1.83(d,J=5.6Hz,2H),1.77(d,J=7.8Hz,2H),1.68(s,2H).13C NMR(151MHz,DMSO-d6):δ159.0,158.1,155.7,148.4,147.1,145.8,138.0,133.2,130.1,129.4(2),125.9,124.6,120.0,118.4,118.1(2),117.2,114.1,110.4,58.3,53.7,49.5,38.2(2),33.7,31.2,30.2,29.4,28.3,25.5.HR-ESI-MS:557.2701[M+H]+,(calcd for C31H36N6O2S,557.2693)。
实施例22(S)-4-(11-(3-氨基吡咯烷-1-基)-7,8,9,10-四氢-6H-环庚[b]喹啉-2-基)-N-(4-(吡咯烷-1-基磺酰基)苯基)吡啶-2-胺盐酸盐(化合物46)
如图1所示,10d替换10a,其他条件不变,合成方法如实施例20,得到化合物46。产率57%,黄色固体。1H NMR(400MHz,DMSO-d6):δ10.51(s,1H),8.68(d,J=5.6Hz,3H),8.54(s,1H),8.35(d,J=5.5Hz,1H),8.21(d,J=2.1Hz,2H),8.04(d,J=8.5Hz,2H),7.75(d,J=1.6Hz,1H),7.74–7.69(m,2H),7.37(dd,J=5.5,1.6Hz,1H),4.44(dd,J=12.0,6.6Hz,1H),4.17(dd,J=7.8,3.9Hz,2H),4.14(t,J=5.4Hz,2H),3.30–3.21(m,2H),3.16–3.09(m,4H),2.93(t,J=5.5Hz,2H),2.36(dq,J=13.9,7.1Hz,1H),2.18(dq,J=12.6,6.4Hz,1H),1.84(p,J=6.1Hz,2H),1.77(q,J=7.0,6.0Hz,2H),1.72–1.60(m,6H).13C NMR(151MHz,DMSO-d6):δ159.0,158.1,156.0,148.1,147.7,145.9,137.9,133.4,130.1,129.1(2),127.3,124.5,120.0,118.4,117.8(2),117.20,114.0,110.3,58.3,53.7,49.5,48.3(2),33.8,31.2,30.2,29.4,28.3,25.5,25.1(2).HR-ESI-MS:583.2861[M+H]+,(calcd forC33H38N6O2S,583.2850)。
实施例23(S)-4-(11-(3-氨基吡咯烷-1-基)-7,8,9,10-四氢-6H-环庚[b]喹啉-2-基)-N-(4-(哌嗪-1-基磺酰基)苯基)吡啶-2-胺盐酸盐(化合物47)
如图1所示,10f替换10a,其他条件不变,合成方法如实施例20,得到化合物47。产率64%,黄色固体。1H NMR(400MHz,DMSO-d6):δ10.57(s,1H),9.33(s,1H),8.72(d,J=5.5Hz,3H),8.54(d,J=1.7Hz,1H),8.37(d,J=5.4Hz,1H),8.26–8.19(m,2H),8.11(d,J=8.7Hz,2H),7.77(d,J=1.6Hz,1H),7.68(d,J=8.7Hz,2H),7.38(dd,J=5.4,1.6Hz,1H),4.45(dd,J=12.0,6.6Hz,1H),4.17(q,J=3.4Hz,3H),4.03(q,J=6.8Hz,1H),3.25(t,J=5.6Hz,2H),3.17(s,2H),3.15(s,6H),2.93(t,J=5.5Hz,2H),2.36(dq,J=13.9,7.1,6.6Hz,1H),2.18(h,J=6.4Hz,1H),1.83(q,J=6.0Hz,2H),1.77(d,J=7.0Hz,2H),1.67(d,J=9.9Hz,2H).13CNMR(151MHz,DMSO-d6):δ159.0,158.1,156.2,148.2,147.8,146.8,137.9,133.5,130.1,129.5(2),124.8,124.4,120.0,118.5,117.8(2),117.3,114.2,110.3,58.3,53.7,49.5,43.3(2),42.6(2),33.7,31.2,30.1,29.4,28.3,25.5.HR-ESI-MS:598.2966[M+H]+,(calcd for C33H39N7O2S,598.2959)。
实施例24(S)-4-(11-(3-氨基吡咯烷-1-基)-7,8,9,10-四氢-6H-环庚[b]喹啉-2-基)-N-(4-((4-甲基哌嗪-1-基)磺酰基)苯基)吡啶-2-胺盐酸盐(化合物48)
如图1所示,10c替换10a,其他条件不变,合成方法如实施例20,得到化合物48。产率48%,黄色固体。1H NMR(400MHz,DMSO-d6):δ10.59(s,1H),8.71(d,J=5.3Hz,3H),8.54(s,1H),8.37(d,J=5.5Hz,1H),8.22(d,J=2.5Hz,2H),8.10(d,J=8.8Hz,2H),7.77(d,J=1.6Hz,1H),7.72–7.66(m,2H),7.39(dd,J=5.5,1.6Hz,1H),4.45(dd,J=12.0,6.6Hz,1H),4.20–4.12(m,3H),4.06–3.99(m,1H),3.73(d,J=12.4Hz,2H),3.44(d,J=12.0Hz,2H),3.26(t,J=5.3Hz,2H),3.15(t,J=8.2Hz,2H),2.93(t,J=5.3Hz,2H),2.73(d,J=4.0Hz,5H),2.42–2.31(m,1H),2.19(dd,J=12.5,6.4Hz,1H),1.84(d,J=5.8Hz,2H),1.77(s,2H),1.68(s,2H).13C NMR(151MHz,DMSO-d6):δ159.0,158.1,156.0,148.0,147.9,146.7,137.9,133.5,130.1,129.5(2),124.9,124.5,120.0,118.5,117.8(2),117.3,114.3,110.4,58.3,53.7,52.0(2),49.5,43.6,42.3(2),33.7,31.2,30.1,29.4,28.3,25.5.HR-ESI-MS:612.3129[M+H]+,(calcd for C34H41N7O2S,612.3115)。
实施例25(S)-4-(11-(3-氨基吡咯烷-1-基)-7,8,9,10-四氢-6H-环庚[b]喹啉-2-基)-N-(4-(吗啉磺酰基)苯基)吡啶-2-胺盐酸盐(化合物49)
如图1所示,10g替换10a,其他条件不变,合成方法如实施例20,得到化合物49。产率62%,黄色固体。1H NMR(400MHz,DMSO-d6):δ10.56(s,1H),8.68(d,J=5.4Hz,3H),8.54(s,1H),8.36(d,J=5.5Hz,1H),8.22(s,2H),8.11–8.05(m,2H),7.76(d,J=1.6Hz,1H),7.69–7.63(m,2H),7.39(dd,J=5.5,1.6Hz,1H),4.45(dd,J=12.0,6.5Hz,1H),4.17(d,J=4.1Hz,3H),4.03(t,J=5.5Hz,1H),3.68–3.61(m,4H),3.30–3.20(m,2H),2.93(t,J=5.3Hz,2H),2.89–2.82(m,4H),2.42–2.32(m,1H),2.19(dt,J=12.2,6.0Hz,1H),1.83(d,J=5.8Hz,2H),1.78(d,J=8.8Hz,2H),1.68(s,2H).13C NMR(151MHz,DMSO-d6):δ159.0,158.1,155.9,148.1,147.7,146.3,137.9,133.4,130.1,129.5(2),125.2,124.5,120.0,118.4,117.8(2),117.2,114.2,110.3,65.8(2),58.3,53.7,49.5,46.4(2),33.8,31.2,30.2,29.4,28.3,25.5.HR-ESI-MS:599.2820[M+H]+,(calcd for C33H38N6O3S,599.2799)。
实施例26(S)-4-(11-(3-氨基吡咯烷-1-基)-7,8,9,10-四氢-6H-环庚[b]喹啉-2-基)-N-(3-(吗啉磺酰基)苯基)吡啶-2-胺盐酸盐(化合物50)
如图1所示,10h替换10a,其他条件不变,合成方法如实施例20,得到化合物50。产率67%,黄色固体。1H NMR(400MHz,DMSO-d6):δ10.54(s,1H),8.79–8.64(m,3H),8.54(s,1H),8.30(d,J=5.5Hz,1H),8.26–8.17(m,3H),8.08(dd,J=8.1,2.1Hz,1H),7.69(s,1H),7.60(t,J=7.9Hz,1H),7.37(d,J=5.6Hz,1H),7.31(d,J=7.6Hz,1H),4.43(dd,J=12.1,6.3Hz,1H),4.15(dd,J=12.2,4.6Hz,3H),4.01(d,J=7.3Hz,1H),3.65(dd,J=5.9,3.3Hz,4H),3.26(d,J=5.4Hz,2H),2.93(dd,J=6.2,3.3Hz,6H),2.36(dd,J=13.8,7.0Hz,1H),2.18(dt,J=12.4,6.4Hz,1H),1.87–1.79(m,2H),1.76(s,2H),1.67(s,2H).13C NMR(151MHz,DMSO-d6):δ172.5,159.0,158.4,155.7,149.0,142.1,138.0,135.5,133.5,130.4,130.0,124.7,123.6,120.6,120.0,118.3,117.7,117.0,113.6,110.0,65.8(2),58.3,53.7,49.4,46.4(2),33.7,31.2,30.2,29.4,28.3,25.5.HR-ESI-MS:599.2818[M+H]+,(calcd forC33H38N6O3S,599.2799)。
实施例27(S)-4-((4-(9-(3-氨基吡咯烷-1-基)-5,6,7,8-四氢吖啶-2-基)吡啶-2-基)氨基)-N,N-二甲基哌啶-1-磺酰胺(化合物ZLHT-3)
如图1所示,7a替换10a,4a替换4c,其他条件不变,合成方法如实施例20,得到化合物ZLHT-3。产率66%,黄色固体。1H NMR(400MHz,Deuterium Oxide)δ8.29(d,J=2.0Hz,1H),7.93(dd,J=8.9,1.8Hz,1H),7.77–7.69(m,2H),7.12–7.06(m,2H),4.36(ddd,J=18.1,12.2,6.6Hz,1H),4.21–3.90(m,4H),3.72(tt,J=10.3,3.5Hz,1H),3.58–3.52(m,2H),3.02–2.91(m,4H),2.81–2.73(m,2H),2.70(s,6H),2.42(dp,J=14.5,7.5,6.8Hz,1H),2.12(ddt,J=13.0,7.5,5.4Hz,1H),1.98(dd,J=14.3,3.5Hz,2H),1.79(p,J=6.6Hz,2H),1.61(d,J=5.9Hz,1H),1.61–1.51(m,3H);13C NMR(100MHz,Deuterium Oxide)δ160.03,153.15,151.79,138.67,137.25,131.75,130.54,125.58,124.21,119.29,119.24,118.31,115.99,11,56.85,52.98,49.56,48.30,44.71(2C),37.51(2C),30.19(2C),29.22,27.94,23.72,22.06,20.17;HR-ESI-MS:550.2955[M+H]+,(calcd for C29H39N7O2S,550.2959)。
实施例28(S)-4-(9-(3-氨基吡咯烷-1-基)-5,6,7,8-四氢吖啶-2-基)-N-(1-(乙基磺酰基)哌啶-4-基)吡啶-2-胺(化合物ZLHT-4)
如图1所示,7b替换10a,4a替换4c,其他条件不变,合成方法如实施例20,得到化合物ZLHT-4。产率79%,黄色固体。1H NMR(400MHz,Deuterium Oxide)δ8.37(d,J=1.9Hz,1H),8.02(dd,J=8.8,1.9Hz,1H),7.82(d,J=6.8Hz,1H),7.79(d,J=8.7Hz,1H),7.19(d,J=1.7Hz,1H),7.16(dd,J=6.8,1.8Hz,1H),4.44(dd,J=12.2,6.6Hz,1H),4.24(dt,J=11.6,7.4Hz,1H),4.18(ddd,J=11.6,8.1,5.5Hz,1H),4.14–4.08(m,2H),3.83(tt,J=10.3,4.0Hz,1H),3.70(dd,J=13.0,4.2Hz,2H),3.16(q,J=7.4Hz,2H),3.08(td,J=13.1,12.2,2.6Hz,2H),3.02(t,J=6.7Hz,2H),2.86(q,J=5.7Hz,2H),2.48(dq,J=14.5,7.4Hz,1H),2.19(ddt,J=13.1,7.5,5.3Hz,1H),2.14–2.02(m,2H),1.87(p,J=6.4Hz,2H),1.70–1.60(m,4H),1.26(t,J=7.4Hz,3H);13C NMR(100MHz,Deuterium Oxide)δ176.66,160.05,153.20,151.82,138.69,135.35,131.83,130.61,125.59,119.26,118.36,116.05,111.52,110.45,69.72,61.69,57.41,52.92,49.48,48.27,44.18(2C),30.55(2C),29.58,29.02,20.18,16.76,6.88;HR-ESI-MS:535.2842[M+H]+,(calcd for C29H38N6O2S,535.2850)。
实施例29(S)-4-(9-(3-氨基吡咯烷-1-基)-5,6,7,8-四氢吖啶-2-基)-N-(1-(环丙基磺酰基)哌啶-4-基)吡啶-2-胺(化合物ZLHT-5)
如图1所示,7c替换10a,4a替换4c,其他条件不变,合成方法如实施例20,得到化合物ZLHT-5。产率67%,黄色固体。1H NMR(400MHz,Deuterium Oxide)δ8.36(d,J=1.9Hz,1H),8.02(dd,J=8.9,1.8Hz,1H),7.83(d,J=6.7Hz,1H),7.79(d,J=8.9Hz,1H),7.18(d,J=1.7Hz,1H),7.16(dd,J=6.9,1.7Hz,1H),4.44(dd,J=12.2,6.6Hz,1H),4.23(dt,J=11.6,7.4Hz,1H),4.17(ddd,J=11.6,8.1,5.5Hz,1H),4.10(ddd,J=11.6,6.7,4.8Hz,1H),4.03(dd,J=12.1,4.5Hz,1H),3.83(ddt,J=10.5,8.2,4.0Hz,1H),3.69(dd,J=12.9,4.4Hz,2H),3.15–3.08(m,2H),3.02(q,J=6.6Hz,2H),2.85(q,J=5.8Hz,2H),2.57(tt,J=7.6,5.2Hz,1H),2.48(dq,J=14.6,7.4Hz,1H),2.18(ddt,J=13.1,7.3,5.3Hz,1H),2.15–2.07(m,2H),1.87(p,J=6.4Hz,2H),1.67(qd,J=12.9,11.1,7.5Hz,4H),1.07(tq,J=6.2,3.6,2.9Hz,4H);13C NMR(100MHz,Deuterium Oxide)δ160.03,153.51,153.22,151.96,138.69,135.58,131.88,130.61,125.55,119.65,119.27,118.39,116.11,111.51,57.14,52.90,52.61,49.47,44.66(2C),30.28(2C),29.21,27.85,25.67,25.65,22.06,20.18,4.28(2C);HR-ESI-MS:547.2841[M+H]+,(calcd for C30H38N6O2S,547.2850)。
实施例30(S)-4-(9-(3-氨基吡咯烷-1-基)-5,6,7,8-四氢吖啶-2-基)-N-(4-(甲基磺酰基)苯基)吡啶-2-胺(化合物ZLHT-7)
如图1所示,4a替换4c,其他条件不变,合成方法如实施例20,得到化合物ZLHT-7。产率66%,黄色固体。1H NMR(400MHz,Deuterium Oxide)δ8.10(d,J=2.0Hz,1H),7.90(d,J=6.2Hz,1H),7.83(dd,J=8.9,1.9Hz,1H),7.64(d,J=8.3Hz,2H),7.60(d,J=8.7Hz,1H),7.28(d,J=8.3Hz,2H),7.21(dd,J=6.3,1.8Hz,1H),7.12(s,1H),4.29(dd,J=12.0,6.7Hz,1H),4.09(dt,J=11.4,7.4Hz,1H),4.08–4.01(m,1H),3.98(ddd,J=11.4,7.9,5.7Hz,1H),3.92(dd,J=12.1,5.0Hz,1H),3.06(s,3H),2.85(t,J=6.8Hz,2H),2.69(q,J=5.2,4.6Hz,2H),2.42(dq,J=14.5,7.4Hz,1H),2.11(ddt,J=13.2,7.4,5.4Hz,1H),1.74(ddt,J=9.7,6.7,3.0Hz,2H),1.59–1.52(m,2H);13C NMR(100MHz,Deuterium Oxide)δ159.47,153.36,152.93,151.21,142.61,139.97,138.45,133.80,131.44,130.45,129.86,128.88,125.20,120.80,119.44,118.53,116.79,115.19,114.38,110.41,56.95,53.10,49.39,43.47,29.14,27.88,27.77,21.95,20.05;HR-ESI-MS:514.2262[M+H]+,(calcd forC29H31N5O2S,514.2271)。
实施例31(R)-4-(9-(3-氨基吡咯烷-1-基)-5,6,7,8-四氢吖啶-2-基)-N-(4-(甲基磺酰基)苯基)吡啶-2-胺(化合物ZLHT-8)
如图1所示,4b替换4c,其他条件不变,合成方法如实施例20,得到化合物ZLHT-8。产率42%,黄色固体。1H NMR(400MHz,Deuterium Oxide)δ8.16(d,J=1.9Hz,1H),7.91(d,J=6.5Hz,1H),7.85(dd,J=8.8,1.8Hz,1H),7.72–7.64(m,2H),7.62(d,J=8.8Hz,1H),7.29(dd,J=8.7,7.0Hz,3H),7.22(d,J=1.7Hz,1H),4.32(dd,J=12.1,6.7Hz,1H),4.18–3.91(m,4H),3.07(s,3H),2.86(t,J=6.7Hz,2H),2.76–2.68(m,2H),2.42(dq,J=14.5,7.4Hz,1H),2.12(ddt,J=13.2,7.5,5.5Hz,1H),1.75(s,2H),1.57(qd,J=6.1,4.4,3.2Hz,2H);13CNMR(100MHz,Deuterium Oxide)δ159.62,153.83,153.33,150.70,142.09,138.83,138.60,134.58,131.11,130.44,129.04(2C),125.54,121.39(2C),119.44,118.38,116.49,114.45,110.67,57.07,53.15,49.42,43.44,29.12,27.89,22.00,20.37,20.08;HR-ESI-MS:514.2259[M+H]+,(calcd for C29H31N5O2S,514.2271)。
实施例32(S)-4-((4-(9-(3-氨基吡咯烷-1-基)-5,6,7,8-四氢吖啶-2-基)吡啶-2-基)氨基)-N,N-二甲基苯磺酰胺(化合物ZLHT-9)
如图1所示,10b替换10a,4a替换4c,其他条件不变,合成方法如实施例20,得到化合物ZLHT-9。产率51%,黄色固体。1H NMR(400MHz,Deuterium Oxide)δ7.93(d,J=1.9Hz,1H),7.83(d,J=5.9Hz,1H),7.74(dd,J=8.9,1.8Hz,1H),7.53(dd,J=14.8,7.8Hz,1H),7.33(d,J=8.3Hz,2H),7.18–7.12(m,2H),7.05(dd,J=6.1,1.7Hz,1H),6.86(s,1H),4.24(dd,J=11.9,6.8Hz,1H),4.09–4.00(m,2H),3.90(tt,J=11.9,5.4Hz,2H),2.80(t,J=6.7Hz,2H),2.63(q,J=5.1Hz,2H),2.44(s,6H),2.42(dd,J=13.8,6.7Hz,1H),2.16–2.08(m,1H),1.72–1.65(m,2H),1.53(dq,J=11.6,6.3,5.9Hz,2H);13C NMR(100MHz,DeuteriumOxide)δ159.04,153.51,151.87,142.55,138.10,135.44,131.76,130.39,129.09(2C),126.82,124.56,119.54,119.43,118.86,117.67,116.81,116.27,113.96,109.68,56.74,53.12,49.38,37.44(2C),29.26,27.94,27.71,21.84,19.99;HR-ESI-MS:542.2237[M+H]+,(calcd for C29H39N7O2S,542.2240)。
实施例33(S)-4-(9-(3-氨基吡咯烷-1-基)-5,6,7,8-四氢吖啶-2-基)-N-(4-((4-甲基哌嗪-1-基)磺酰基)苯基)吡啶-2-胺(化合物ZLHT-10)
如图1所示,10c替换10a,4a替换4c,其他条件不变,合成方法如实施例20,得到化合物ZLHT-10。产率45%,黄色固体。1H NMR(400MHz,Deuterium Oxide)δ8.29(d,J=1.9Hz,1H),7.93(dd,J=8.9,1.9Hz,1H),7.77(dd,J=6.8,0.8Hz,1H),7.70(d,J=8.9Hz,1H),7.16–7.08(m,2H),4.37(dd,J=12.1,6.5Hz,1H),4.22–3.99(m,4H),2.94(t,J=6.7Hz,2H),2.78(td,J=5.8,2.0Hz,2H),2.41(dq,J=14.5,7.4,6.9Hz,1H),2.18–2.07(m,1H),1.80(p,J=6.6Hz,2H),1.60(m,2H);13C NMR(100MHz,Deuterium Oxide)δ160.06,154.36,153.90,153.26,138.72,135.51,131.72,130.63,125.63,119.31,118.39,116.14,111.78,110.49,61.73,57.21,52.98,49.52,29.63,27.89,22.10,20.20;HR-ESI-MS:598.2968[M+H]+,(calcd for C33H39N7O2S,598.2959)。
实施例34(R)-4-(9-(3-氨基吡咯烷-1-基)-5,6,7,8-四氢吖啶-2-基)-N-(4-((4-甲基哌嗪-1-基)磺酰基)苯基)吡啶-2-胺(化合物ZLHT-11)
如图1所示,10c替换10a,4b替换4c,其他条件不变,合成方法如实施例20,得到化合物ZLHT-11。产率57%,黄色固体。1H NMR(400MHz,Deuterium Oxide)δ8.89(d,J=5.4Hz,3H),8.54(s,1H),8.33(d,J=5.6Hz,1H),8.23–8.15(m,2H),8.06(d,J=8.8Hz,2H),7.93–7.78(m,1H),7.73–7.66(m,2H),7.41(dd,J=5.6,1.6Hz,1H),4.51(dd,J=11.9,6.5Hz,1H),4.31(ddt,J=29.7,11.9,5.9Hz,2H),4.18(dt,J=11.9,7.1Hz,1H),4.11–3.99(m,1H),3.74(d,J=12.3Hz,2H),3.48–3.36(m,2H),3.12(p,J=12.6,10.7Hz,4H),2.88(ddt,J=15.4,11.5,6.2Hz,2H),2.83–2.75(m,2H),2.73(d,J=3.1Hz,3H),2.39(p,J=6.8Hz,1H),2.27(dt,J=11.9,6.0Hz,1H),1.85(q,J=7.4Hz,2H),1.68(q,J=6.9,6.5Hz,2H);13CNMR(100MHz,Deuterium Oxide)δ171.76,159.05,154.81,152.49,148.40,146.23,138.73,132.89,130.53,129.46(2C),125.56,125.06,119.84,118.54(2C),118.21,115.12,114.17,110.46,55.41,51.93,49.48,45.74(2C),43.51,42.27(2C),29.61,26.97,22.63,21.57,20.71;HR-ESI-MS:598.2953[M+H]+,(calcd for C33H39N7O2S,598.2959)。
实施例35(S)-4-(9-(3-氨基吡咯烷-1-基)-5,6,7,8-四氢吖啶-2-基)-N-(4-(吡咯烷-1-基磺酰基)苯基)吡啶-2-胺(化合物ZLHT-12)
如图1所示,10d替换10a,4a替换4c,其他条件不变,合成方法如实施例20,得到化合物ZLHT-12。产率38%,黄色固体。1H NMR(400MHz,Deuterium Oxide)8.89(d,J=5.3Hz,3H),8.54(s,1H),8.30(d,J=5.6Hz,1H),8.17(d,J=2.1Hz,2H),7.98(d,J=8.5Hz,2H),7.81(s,1H),7.72(d,J=8.5Hz,2H),7.45–7.36(m,1H),4.52(dd,J=11.9,6.5Hz,1H),4.40–3.98(m,4H),3.20–3.03(m,6H),2.90(tq,J=16.1,10.1,7.9Hz,2H),2.40(hept,J=10.6,8.8Hz,1H),2.33–2.15(m,1H),1.86(t,J=6.9Hz,2H),1.75–1.65(m,6H);13C NMR(100MHz,Deuterium Oxide)δ172.40,159.03,155.23,152.54,148.52,145.28,138.75,132.78,130.49,129.11(2C),128.04,125.05,119.86,118.57(2C),118.41,115.21,113.89,110.36,58.39,53.75,49.52,48.26(2C),29.63,28.23,27.22,25.14(2C),22.63,20.70;HR-ESI-MS:569.2691[M+H]+,(calcd for C32H36N6O2S,569.2693)。
实施例36(R)-4-(9-(3-氨基吡咯烷-1-基)-5,6,7,8-四氢吖啶-2-基)-N-(4-(吡咯烷-1-基磺酰基)苯基)吡啶-2-胺(化合物ZLHT-13)
如图1所示,10d替换10a,4b替换4c,其他条件不变,合成方法如实施例20,得到化合物ZLHT-13。产率57%,黄色固体。1H NMR(400MHz,Deuterium Oxide)8.89(d,J=5.3Hz,3H),8.54(s,1H),8.30(d,J=5.6Hz,1H),8.17(d,J=2.1Hz,2H),7.98(d,J=8.5Hz,2H),7.81(s,1H),7.72(d,J=8.5Hz,2H),7.45–7.36(m,1H),4.52(dd,J=11.9,6.5Hz,1H),4.40–3.98(m,4H),3.20–3.03(m,6H),2.90(tq,J=16.1,10.1,7.9Hz,2H),2.40(hept,J=10.6,8.8Hz,1H),2.33–2.15(m,1H),1.86(t,J=6.9Hz,2H),1.75–1.65(m,6H);13C NMR(100MHz,Deuterium Oxide)δ172.40,159.03,155.23,152.54,148.52,145.28,138.75,132.78,130.49,129.11(2C),128.04,125.05,119.86,118.57(2C),118.41,115.21,113.89,110.36,58.39,53.75,49.52,48.26(2C),29.63,28.23,27.22,25.14(2C),22.63,20.70;HR-ESI-MS:569.2691[M+H]+,(calcd for C32H36N6O2S,569.2693)。
实施例37(S)-4-(9-(3-氨基吡咯烷-1-基)-5,6,7,8-四氢吖啶-2-基)-N-(4-(哌嗪-1-基磺酰基)苯基)吡啶-2-胺(化合物ZLHT-14)
如图1所示,10e替换10a,4a替换4c,其他条件不变,合成方法如实施例20,得到化合物ZLHT-14。产率59%,黄色固体。1H NMR(400MHz,Deuterium Oxide)δ8.20(s,1H),7.96(dd,J=7.2,3.1Hz,1H),7.91(s,1H),7.62(d,J=15.1Hz,3H),7.37(s,2H),7.29(s,2H),4.34(dd,J=12.1,6.7Hz,1H),4.18–3.91(m,4H),3.21(d,J=7.5Hz,8H),2.91(s,2H),2.74(s,2H),2.44(dq,J=14.6,7.5Hz,1H),2.13(dd,J=13.4,6.6Hz,1H),1.78(s,2H),1.59(s,2H);13C NMR(100MHz,Deuterium Oxide)δ159.57,153.50,153.30,151.24,142.56,139.96,138.50,131.63,130.57,129.44(2C),128.77,125.38,121.02(2C),119.51,118.71,117.04,114.58,110.72,56.98,53.01,49.45,42.79(4C),29.58,29.16,27.95,21.97,20.09;HR-ESI-MS:584.2791[M+H]+,(calcd for C32H37N7O2S,584.2802)。
实施例38(R)-4-(9-(3-氨基吡咯烷-1-基)-5,6,7,8-四氢吖啶-2-基)-N-(4-(哌嗪-1-基磺酰基)苯基)吡啶-2-胺(化合物ZLHT-15)
如图1所示,10e替换10a,4b替换4c,其他条件不变,合成方法如实施例20,得到化合物ZLHT-15。产率49%,黄色固体。1H NMR(400MHz,Deuterium Oxide)9.55(s,1H),8.92–8.87(m,3H),8.54(s,1H),8.33(d,J=5.5Hz,1H),8.19(d,J=1.9Hz,2H),8.12–8.03(m,2H),7.80(d,J=1.6Hz,1H),7.72–7.64(m,2H),7.39(dd,J=5.6,1.5Hz,1H),4.51(dd,J=11.8,6.5Hz,1H),4.39–4.24(m,2H),4.18(dd,J=11.6,5.8Hz,2H),3.16(s,8H),3.12(t,J=6.7Hz,2H),2.99–2.81(m,2H),2.40(dq,J=14.0,7.1Hz,1H),2.26(dq,J=12.6,6.5Hz,1H),1.86(d,J=7.4Hz,2H),1.69(s,2H);13C NMR(100MHz,Deuterium Oxide)δ172.40,170.80,159.03,155.74,152.55,147.44,146.50,138.69,133.10,130.53,129.45(2C),124.92,119.87,118.65,117.98(2C),115.28,114.11,110.33,60.21,58.38,49.50(2C),43.23,42.51(2C),34.61,31.77,29.63,28.25,28.10;HR-ESI-MS:584.2791[M+H]+,(calcdfor C32H37N7O2S,584.2802)。
实施例39(S)-4-(9-(3-氨基吡咯烷-1-基)-5,6,7,8-四氢吖啶-2-基)-N-(3-(哌嗪-1-基磺酰基)苯基)吡啶-2-胺(化合物ZLHT-16)
如图1所示,10f替换10a,4a替换4c,其他条件不变,合成方法如实施例20,得到化合物ZLHT-16。产率44%,黄色固体。1H NMR(400MHz,Deuterium Oxide)δ9.51(s,1H),8.87(dd,J=11.4,5.4Hz,3H),8.53(d,J=4.9Hz,1H),8.37–8.22(m,2H),8.20–8.04(m,3H),7.71–7.56(m,2H),7.34(dd,J=13.9,6.6Hz,2H),4.58–3.88(m,5H),3.28–3.20(m,4H),3.18(d,J=6.7Hz,4H),3.10(q,J=6.3Hz,2H),2.91(tq,J=15.4,8.6Hz,2H),2.38(td,J=18.3,15.8,10.5Hz,1H),2.27(dt,J=12.4,6.6Hz,1H),1.88(dq,J=15.2,8.1Hz,2H),1.69(dp,J=13.3,6.7,6.2Hz,2H);13C NMR(100MHz,Deuterium Oxide)δ159.08,155.81,152.50,151.91,148.30,146.83,142.45,138.71,137.62,135.51,131.68,130.52,125.02,123.60,119.83,118.56,117.27,115.13,113.55,109.81,58.39,53.72,49.52,43.24(2C),42.59(2C),29.63,28.24,28.13,22.64,20.72;HR-ESI-MS:584.2795[M+H]+,(calcd forC32H37N7O2S,584.2802)。
实施例40(R)-4-(9-(3-氨基吡咯烷-1-基)-5,6,7,8-四氢吖啶-2-基)-N-(3-(哌嗪-1-基磺酰基)苯基)吡啶-2-胺(化合物ZLHT-17)
如图1所示,10f替换10a,4b替换4c,其他条件不变,合成方法如实施例20,得到化合物ZLHT-17。产率38%,黄色固体。1H NMR(400MHz,Deuterium Oxide)δ9.63(s,1H),8.92(d,J=5.8Hz,3H),8.53(d,J=14.5Hz,1H),8.32–8.22(m,2H),8.18(s,2H),8.10–8.01(m,1H),7.76–7.71(m,1H),7.63(q,J=8.2Hz,1H),7.43–7.34(m,2H),4.52(dd,J=11.8,6.4Hz,1H),4.37(dt,J=13.2,7.3Hz,1H),4.27(dd,J=12.0,4.2Hz,1H),4.19(s,2H),3.29–3.23(m,4H),3.17(s,4H),3.10(d,J=6.8Hz,2H),2.91(q,J=7.2,6.6Hz,2H),2.40(dq,J=14.2,7.3Hz,1H),2.29(td,J=11.8,9.3,5.8Hz,1H),1.86(s,2H),1.72–1.64(m,2H);13C NMR(100MHz,Deuterium Oxide)δ159.05,155.22,152.49,148.99,145.23,141.88,138.82,135.68,133.48,132.64,130.67,130.49,125.23,120.92,119.82,118.49,117.93,115.06,113.56,109.97,60.21,58.40,55.41(2C),49.72,43.19,42.55,34.61,31.76,22.64,21.56,20.69;HR-ESI-MS:584.2797[M+H]+,(calcd for C32H37N7O2S,584.2802)。
实施例41(S)-4-(9-(3-氨基吡咯烷-1-基)-5,6,7,8-四氢吖啶-2-基)-N-(4-(吗啉磺酰基)苯基)吡啶-2-胺(化合物ZLHT-18)
如图1所示,10g替换10a,4a替换4c,其他条件不变,合成方法如实施例20,得到化合物ZLHT-18。产率59%,黄色固体。1H NMR(400MHz,Deuterium Oxide)δ8.24–8.20(m,1H),8.01(d,J=6.3Hz,1H),7.95(dd,J=8.9,1.8Hz,1H),7.72(d,J=8.8Hz,1H),7.62–7.56(m,2H),7.44–7.37(m,2H),7.31(dd,J=6.4,1.7Hz,1H),7.24(d,J=1.7Hz,1H),4.39(dd,J=12.1,6.7Hz,1H),4.24–3.93(m,4H),3.72–3.65(m,4H),2.97(t,J=6.4Hz,2H),2.92(t,J=4.8Hz,4H),2.79(d,J=6.9Hz,2H),2.50(dq,J=14.5,7.3Hz,1H),2.24–2.14(m,1H),1.88–1.80(m,2H),1.66(d,J=7.3Hz,2H);13C NMR(100MHz,Deuterium Oxide)δ159.56,153.48,153.12,151.40,142.32,140.08,138.48,135.92,131.67,130.52,129.50,128.37(2C),125.26,124.16,120.89(2C),118.66,114.36,110.48,65.72,56.95,53.02,49.41,45.83(2C),29.15(2C),27.92,27.85,21.96,20.13;HR-ESI-MS:585.2640[M+H]+,(calcd forC32H36N6O3S,585.2642)。
实施例42(R)-4-(9-(3-氨基吡咯烷-1-基)-5,6,7,8-四氢吖啶-2-基)-N-(4-(吗啉磺酰基)苯基)吡啶-2-胺(化合物ZLHT-19)
如图1所示,10g替换10a,4b替换4c,其他条件不变,合成方法如实施例20,得到化合物ZLHT-19。产率66%,黄色固体。1H NMR(400MHz,Deuterium Oxide)δ8.10(d,J=1.8Hz,1H),7.91(d,J=6.3Hz,1H),7.82(dd,J=8.9,1.8Hz,1H),7.61(d,J=8.7Hz,1H),7.45(d,J=8.5Hz,2H),7.27(d,J=8.5Hz,2H),7.22(dd,J=6.4,1.7Hz,1H),7.11(d,J=1.8Hz,1H),4.31(dt,J=10.6,5.2Hz,1H),4.11(dt,J=11.0,7.3Hz,1H),4.06(td,J=7.0,3.5Hz,1H),3.99(ddd,J=11.4,7.8,5.5Hz,1H),3.94(dd,J=12.1,5.0Hz,1H),3.63–3.55(m,4H),2.87(t,J=6.7Hz,2H),2.81(t,J=4.7Hz,4H),2.69(dd,J=12.2,6.1Hz,2H),2.43(dq,J=14.5,7.4Hz,1H),2.15–2.10(m,1H),1.77–1.70(m,2H),1.60–1.53(m,2H);13C NMR(100MHz,Deuterium Oxide)δ159.45,153.46,152.88,151.09,142.05,139.85,138.44,131.34,130.44,129.47(2C),128.39,125.23,120.75(2C),119.51,118.60,117.01,114.27,110.36,65.70(2C),56.97,53.14,49.41,45.83(2C),29.17,27.95,27.79,21.96,20.12;HR-ESI-MS:585.2637[M+H]+,(calcd for C32H36N6O3S,585.2642)。
实施例43(S)-4-(9-(3-氨基吡咯烷-1-基)-5,6,7,8-四氢吖啶-2-基)-N-(3-(吗啉磺酰基)苯基)吡啶-2-胺(化合物ZLHT-20)
如图1所示,10h替换10a,4a替换4c,其他条件不变,合成方法如实施例20,得到化合物ZLHT-20。产率51%,黄色固体。1H NMR(400MHz,Deuterium Oxide)δ8.16(dd,J=7.1,1.9Hz,1H),7.89(d,J=6.4Hz,1H),7.84(dd,J=8.9,1.8Hz,1H),7.62(d,J=8.8Hz,1H),7.56–7.51(m,2H),7.45(dd,J=20.6,8.2Hz,2H),7.21(dd,J=6.4,1.7Hz,1H),7.13(s,1H),4.33(td,J=12.0,6.7Hz,1H),4.12(dt,J=11.9,7.2Hz,1H),4.09–3.99(m,2H),3.93(ddd,J=25.1,12.1,4.8Hz,1H),3.57(t,J=4.7Hz,4H),2.88(dt,J=19.7,5.8Hz,6H),2.75(dq,J=20.8,5.7Hz,2H),2.41(ddt,J=21.2,14.5,7.3Hz,1H),2.10(dtd,J=13.2,7.9,3.8Hz,1H),1.77(h,J=6.7Hz,2H),1.59(dp,J=10.5,6.5,4.5Hz,2H);13C NMR(100MHz,Deuterium Oxide)δ160.00,153.15,151.53,138.76,137.71,137.35,135.91,135.37,131.57,131.34,130.47,128.90,125.79,124.24,122.22,119.29,118.15,115.81,113.93,110.08,65.74(2C),57.19,53.03,49.42,45.79(2C),29.00,27.87(2C),22.07,20.15;HR-ESI-MS:585.2632[M+H]+,(calcd for C32H36N6O3S,585.2640)。
实施例44(R)-4-(9-(3-氨基吡咯烷-1-基)-5,6,7,8-四氢吖啶-2-基)-N-(3-(吗啉磺酰基)苯基)吡啶-2-胺(化合物ZLHT-21)
如图1所示,10h替换10a,4b替换4c,其他条件不变,合成方法如实施例20,得到化合物ZLHT-21。产率44%,黄色固体。1H NMR(400MHz,Deuterium Oxide)δ8.54(dd,J=32.9,1.9Hz,1H),8.30–8.22(m,2H),8.15(d,J=5.5Hz,3H),8.00–7.93(m,2H),7.74–7.62(m,1H),7.54–7.46(m,1H),4.56–4.45(m,1H),4.37–4.20(m,2H),4.18–4.09(m,1H),4.03(s,1H),3.68–3.62(m,4H),3.08(d,J=7.4Hz,2H),3.05(s,2H),2.98–2.90(m,4H),2.41(dt,J=12.4,7.4Hz,1H),2.25–2.12(m,1H),1.88(p,J=6.9,5.9Hz,2H),1.69(d,J=13.1Hz,2H);13C NMR(100MHz,Deuterium Oxide)δ159.64,159.46,152.04,151.50,147.24,142.40,139.07,137.95,136.10,131.57,130.99,130.80,127.90,125.94,124.90,122.88,119.74,117.74,113.74,110.44,65.81(2C),53.47,49.63,49.08,46.39(2C),29.44,28.09,22.72,22.18,20.75;HR-ESI-MS:585.2635[M+H]+,(calcd for C32H36N6O3S,585.2640)。
实施例45:抗增殖活性的评价
通过MTT测定法评估化合物的抗增殖活性。将细胞接种在96孔板中并使其粘附过夜。然后将细胞暴露于不同浓度的化合物72h后。将MTT溶液(20μL,0.5mg/mL)添加到每个孔中,将细胞与MTT在37℃下孵育4h。吸去上清液后,加入DMSO(150μL),在490nm处读取吸光度。所有测定平行重复上次。使用GraphPad prism 8.0软件用于确定线性回归参数并计算IC50值。结论:实验结果如表1-3所示,本发明所制备的大部分化合物的抗增殖活性较强,大部分化合物达到10微摩尔以内。
实施例46:CDK2/9抑制活性的评价
根据生产商说明,使用ADP-Glo激酶检测试剂盒(Promega)测定化合物对CDK的抑制作用。简言之,向各孔中加入1μL供试化合物(溶于二甲基亚砜,得到浓度为10mM的化合物,并在试验缓冲液中预稀释至所需浓度)和2μL(5ng)酶,然后加入1×激酶缓冲液,其中含有2μL Rb底物-生物素和ATP。25℃孵育60min/120min后,5μL Sa-XL 665Rb抗体-Cryptate将ADP转化为ATP,并持续1h,最后用多功能酶标仪(665/615nm)记录发光值。通过GraphPadPrism 8.0软件计算目标化合物的IC50值。结论:实验结果如表1-3所示,本发明所制备的大部分化合物具有较强的CDK2/9抑制活性,部分化合物达到纳摩尔水平,并且部分化合物具有较高的CDK2选择性。
表1 化合物44-50的CDK2/9抑制活性和抗增殖活性
aIC50 values were calculated from the average of two independentexperiments.bInhibition(%)at 500nM.cGI50 values are average±SD of at leastthree independent experiments in triplicate.
表2.化合物ZLHT-3-6的抗增殖活性和CDK抑制活性
表3.化合物ZLHQ-7-21的抗增殖活性和CDK抑制活性
Inhibition%at 0.5μM;IC50 data are testing one time;GI50 values areaverage±SD of at least two independent experiments in triplicate;ND:notdetermined。
Claims (7)
3.一种如权利要求2所述化合物的制备方法,其特征在于,化合物的制备方法包括以下步骤:
(1)以化合物1为原料,加入相应的环酮,在POCl3中110℃回流,反应得到化合物2;
(2)在化合物2中加入苯酚和催化量的碘化钠,并加入(S)-3-(Boc-氨基)吡咯烷或者(R)-3-(Boc-氨基)吡咯烷,反应得到化合物3a-3c;
(3)将化合物3a-3c溶于无水二氧六环中,加入4,4,4',4',5,5,5',5'-八甲基-2,2-联(1,3,2-二氧杂环戊硼烷)、乙酸钾和二(三苯基磷)氯化钯,反应得到化合物4a-4c;
(4)将4-溴-2-氟吡啶(5)在四氢呋喃中溶解并与4-氨基-1-Boc哌啶进行亲核取代并脱保护基得到化合物6;
(5)二甲氨基磺酰氯、乙磺酰氯或者环丙烷磺酰氯分别用化合物6进行亲核取代得到化合物7a-7c;
(6)将化合物7a-7c溶于二氧六环:水=4:1的溶剂中,加入4a-4c、碳酸铯和二(三苯基磷)氯化钯,然后将产物溶于乙酸乙酯中,加入HCl-EtOAc,反应得到目标化合物反应得到化合物ZLHT-3-5;
(7)将化合物8a或者8b溶于无水二氯甲烷中,加入不同取代基的氨和三乙胺,反应得到9b-9h;所述不同取代基的氨为二甲胺、四氢吡咯、哌嗪、N-甲基哌嗪、吗啉中的一种;
(8)将4-溴吡啶-2-胺溶于DMF中,在冰浴条件下加入NaH反应30min,将9a或者9b-9h溶解在DMF中,然后缓慢添加到反应溶液中,反应得到10a-10h;
(9)将化合物10a-10h代替化合物7a-d溶于无水二氧六环中,重复步骤(6),反应得到目标化合物44、45、46、47、48、49、50、ZLHT-7、ZLHT-8、ZLHT-9、ZLHT-10、ZLHT-11、ZLHT-12、ZLHT-13、ZLHT-14、ZLHT-15、ZLHT-16、ZLHT-17、ZLHT-18、ZLHT-19、ZLHT-20或ZLHT-21。
4.一种药物组合物,其特征在于,含有权利要求1-2任意一项所述的化合物或其药学上可接受的盐以及药学上可接受的辅料。
5.根据权利要求4所述的药物组合物,其特征在于,由如权利要求1-2任意一项所述化合物添加一种或多种药学上可接受的辅料制成制剂,所述制剂的剂型为胶囊剂、丸剂、片剂、颗粒剂或注射剂。
6.如权利要求1-2任意一项所述化合物或其药学上可用的盐在制备治疗肿瘤药物中的应用。
7.如权利要求1-2任意一项所述化合物或其药学上可用的盐在制备CDK2抑制剂和CDK9抑制剂中的应用。
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