CN115703817A - 一种靶向降解egfr突变体的双功能分子及其制备方法与应用 - Google Patents
一种靶向降解egfr突变体的双功能分子及其制备方法与应用 Download PDFInfo
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- CN115703817A CN115703817A CN202110922709.7A CN202110922709A CN115703817A CN 115703817 A CN115703817 A CN 115703817A CN 202110922709 A CN202110922709 A CN 202110922709A CN 115703817 A CN115703817 A CN 115703817A
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Abstract
本发明公开了一种靶向降解EGFR突变体的双功能分子及其制备方法与应用,属于药物化学技术领域。本发明公开的化合物能通过降解或抑制EGFR蛋白达到抑制肿瘤细胞增殖的目的,在治疗非小细胞肺癌方面具有巨大潜力。
Description
技术领域
发明属于药物化学领域,具体涉及一类新的双功能小分子(I)及其制备方法,以及含有这些化合物的药物组合物及其在治疗肿瘤等疾病中的用途。
技术背景
肺癌是全球恶性肿瘤新发和致死率最高的癌种,其中约85%为非小细胞肺癌(NSCLC),而大部分NSCLC患者的外显子19或21常发生突变(分别占45%和40%),并激活表皮生长因子中的酪氨酸激酶结构域受体(EGFR),导致恶性肿瘤细胞进一步增殖和分化。EGFR广泛分布于哺乳动物上皮细胞、成纤维细胞、胶质细胞等细胞表面。EGFR突变也是非小细胞肺癌患者中最常见的一种突变类型,尤其是在亚洲人群中可以占到40%~50%,因此,EGFR一直是药物研究最热门的靶点之一。由于耐药性的出现,已开发出了三代EGFR抑制剂用于临床肺癌患者的治疗。随着第三代EGFR抑制剂耐药性的出现,寻找新的技术解决不断出现的EGFR抑制剂耐药性问题成为研究的热点,已经成为产业界、医生和患者的新期待。
靶向蛋白质降解是近年来蓬勃兴起并备受制药工业界关注的研究领域,其中最具代表性的技术是蛋白降解靶向嵌合体(Proteolysis targeting chimeras,PROTAC)。PROTAC是一种可以募集靶蛋白和靶蛋白降解酶的杂合双功能化合物,利用泛素-蛋白酶体途径特异性地降解靶蛋白。作为一种新的药物开发策略,在克服药物耐药方面具有巨大的开发潜力。因此,PROTAC技术已经吸引了药物化学家和国际医药公司的广泛关注,成为抗肿瘤药物研究领域的热点之一。利用PROTAC技术,有望解决EGFR抑制剂耐药性和毒副作用等问题。
发明内容
发明目的:本发明要解决的技术问题是提供一类新的双功能小分子(I)。
本发明还要解决的技术问题是提供上述化合物的制备方法。
本发明最后要解决的技术问题是提供上述化合物在制备抗肿瘤药物中的应用。
技术方案:为解决上述技术问题,本发明提供如下技术方案:
一种如通式(I)所示的化合物或其药学上可接受的盐:
其中:
R1、R2分别代表H或C1~C4烷基;
R3代表H、F、Cl、Br、I、C1~C3烷基、C1~C3烷氧基、卤代烷基、卤代烷氧基、OH、CN或NO2;
R4代表H、F、Cl、Br、I、C1~C3烷基或卤代烷基;
R5代表NR6R7或取代的C2-C5的杂环烷基,其中R6、R7各自代表H或C1-C3的烷基,取代基为OH、F、Cl、Br、I、CH3、CF3、OCH3、OCF3或CN;所述杂环烷基为含有1~3个O、N或S原子的四元、五元或六元饱和杂环。
L是连接臂,代表脂肪链或芳香链中的任意一种,L为如下结构中的任意一种:
其中,X、Y独立为CH或N;m、n独立为1~10之间的任意一个整数。
R1优选H或C(CH3)3;
R2优选H或CH3;
R3优选H;
R4优选H或CH3;
R5优选NR6R7或取代的C2-C5的杂环烷基,其中,R6、R7各自代表H或C1-C3的烷基,取代基为OH、F、Cl、Br、I、CH3、CF3、OCH3、OCF3或CN;所述杂环烷基为含有1~3个O、N或S原子的四元、五元或六元饱和杂环;R5最优选N(CH3)2,N(CH2CH3)2、
L优选如下结构中的任意一种:
其中,m、n独立为1-10之间的任意一个整数。
上述化合物的药学上可接受的盐为通式(I)化合物与下列酸(A)形成的酸加成盐I.A,其中用于成盐的酸为:氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸。
本发明优选的化合物如下:
其中R1、R2、R3、R4和R5的定义同前;m、n独立为1~10之间的任意一个整数。
由化合物IIa与IIIa反应制备化合物IVa,所用的碱为三乙胺、N,N-二异丙基乙胺、碳酸钾、碳酸钠、氢氧化钠、氢氧化钾,钠氢、叔丁醇钾、甲醇钠或乙醇钠,优选钠氢;反应溶剂为乙酸乙酯、丙酮、四氢呋喃、二氯甲烷、甲苯、乙二醇二甲醚、二氧六环、N,N-二甲基甲酰胺或二甲亚砜中的一种或者任意两者的混合物,优选N,N-二甲基甲酰胺;反应温度为-20~40℃,优选-5~20℃。
由化合物IVa与铁粉、氯化铵反应制备化合物Va,反应溶剂为甲醇、乙醇和水的混合物,优选乙醇和水的混合物;反应温度为55~90℃,优选70~80℃。
由化合物Va与化合物VIa反应制备化合物VIIa,所用碱为三乙胺、N,N-二异丙基乙胺、钠氢、甲醇钠、乙醇钠、叔丁醇钾、氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、乙酸钠或乙酸钾,优选N,N-二异丙基乙胺;所用溶剂为二氯甲烷、四氢呋喃、乙腈、乙二醇单甲醚、N-甲基吡咯烷酮、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺中的一种或者任意两者的混合物,优选四氢呋喃;反应温度为-5~30℃,优选-5~20℃。
由化合物VIIIa与VHL-L反应制备化合物IXa,所用缩合剂为O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯(HATU)、1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(PyBOP)、二环己基碳二亚胺(DCC)、2-(1H-苯并三偶氮L-1-基)-1,1,3,3-四甲基脲四氟硼酸酯(TBTU)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCl)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(HOBT)的一种或者两者的混合物,优选HATU;所用碱为三乙胺、N,N-二异丙基乙胺、钠氢、甲醇钠、乙醇钠、叔丁醇钾、氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、乙酸钠或乙酸钾,优选N,N-二异丙基乙胺;所用溶剂为二氯甲烷、四氢呋喃、乙腈、乙二醇单甲醚、N-甲基吡咯烷酮、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺中的一种或者任意两者的混合物,优选二氯甲烷;反应温度-5~65℃,优选20~40℃。
由化合物IXa与叠氮化钠反应制备化合物Xa,所用溶剂为乙酸乙酯、二氯甲烷、甲苯、四氢呋喃、乙腈、乙二醇单甲醚、乙二醇二甲醚、甲基叔丁基醚、N-甲基吡咯烷酮、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺中的一种或者任意两者的混合物,优选N,N-二甲基甲酰胺;反应温度为0~80℃,优选25~65℃。
由化合物Xa与化合物VIIa反应制备化合物Ia,所用溶剂为四氢呋喃、乙腈、乙二醇单甲醚、N-甲基吡咯烷酮、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺中的一种与水的混合物,优选四氢呋喃和水的混合物;所用催化剂选自碘化亚铜,溴化亚铜,五水合硫酸铜中的一种与抗坏血酸钠的混合物,优选五水合硫酸铜和抗坏血酸钠的混合物;反应温度为-5~65℃,优选25~35℃。
其中R1、R2、R3、R4和R5的定义同前;m、n独立为1~10之间的任意一个整数。
由化合物IIb与对甲苯磺酰氯反应制备化合物IIIb,所用的碱为三乙胺、N,N-二异丙基乙胺、碳酸钾、碳酸钠、氢氧化钠、氢氧化钾,钠氢、叔丁醇钾、甲醇钠或乙醇钠,优选氢氧化钠;反应溶剂为乙酸乙酯、丙酮、四氢呋喃、二氯甲烷、甲苯、乙二醇二甲醚、二氧六环、N,N-二甲基甲酰胺或二甲亚砜中的一种或者任意两者的混合物,优选四氢呋喃;反应温度为-20~40℃,优选-5~10℃。
由化合物IIIb与氧化试剂反应制备化合物IVb,所用氧化剂为琼斯试剂、戴斯-马丁氧化剂、氯重铬酸吡啶、高锰酸钾、重铬酸钾或重铬酸钠,优选琼斯试剂;反应溶剂为乙酸乙酯、丙酮、四氢呋喃、二氯甲烷、甲苯、乙二醇二甲醚、二氧六环、N,N-二甲基甲酰胺或二甲亚砜中的一种或者任意两者的混合物,优选丙酮;反应温度为-20~50℃,优选-5~20℃。
由化合物IVb与VHL-L反应制备化合物Vb,所用缩合剂为O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯(HATU)、1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(PyBOP)、二环己基碳二亚胺(DCC)、2-(1H-苯并三偶氮L-1-基)-1,1,3,3-四甲基脲四氟硼酸酯(TBTU)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCl)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(HOBT)的一种或者两者的混合物,优选HATU;所用碱为三乙胺、N,N-二异丙基乙胺、钠氢、甲醇钠、乙醇钠、叔丁醇钾、氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、乙酸钠或乙酸钾,优选N,N-二异丙基乙胺;所用溶剂为二氯甲烷、四氢呋喃、乙腈、乙二醇单甲醚、N-甲基吡咯烷酮、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺中的一种或者任意两者的混合物,优选二氯甲烷;反应温度-5~65℃,优选20~40℃。
由化合物Vb与叠氮化钠反应制备化合物VIb,所用溶剂为乙酸乙酯、二氯甲烷、甲苯、四氢呋喃、乙腈、乙二醇单甲醚、乙二醇二甲醚、甲基叔丁基醚、N-甲基吡咯烷酮、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺中的一种或者任意两者的混合物,优选N,N-二甲基甲酰胺;反应温度为0~80℃,优选25~65℃。
由化合物VIb与化合物VIIa反应制备化合物Ib,所用溶剂为四氢呋喃、乙腈、乙二醇单甲醚、N-甲基吡咯烷酮、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺中的一种与水的混合物,优选四氢呋喃和水的混合物;所用催化剂选自碘化亚铜,溴化亚铜,五水合硫酸铜中的一种与抗坏血酸钠的混合物,优选五水合硫酸铜和抗坏血酸钠的混合物;反应温度为-5~65℃,优选25~35℃。
其中R1、R2、R3、R4和R5的定义同前;m、n独立为1~10之间的任意一个整数。
由化合物IIc与溴丙炔反应制备化合物IIIc,所用的碱为三乙胺、N,N-二异丙基乙胺、碳酸钾、碳酸钠、氢氧化钠、氢氧化钾,钠氢、叔丁醇钾、甲醇钠或乙醇钠,优选钠氢;反应溶剂为乙酸乙酯、丙酮、四氢呋喃、二氯甲烷、甲苯、乙二醇二甲醚、二氧六环、N,N-二甲基甲酰胺或二甲亚砜中的一种或者任意两者的混合物,优选四氢呋喃;反应温度为-20~40℃,优选-5~10℃。
由化合物IIIc与IIa制备化合物IVc,所用的碱为三乙胺、N,N-二异丙基乙胺、碳酸钾、碳酸钠、氢氧化钠、氢氧化钾,钠氢、叔丁醇钾、甲醇钠或乙醇钠,优选钠氢;反应溶剂为乙酸乙酯、丙酮、四氢呋喃、二氯甲烷、甲苯、乙二醇二甲醚、二氧六环、N,N-二甲基甲酰胺或二甲亚砜中的一种或者任意两者的混合物,优选四氢呋喃;反应温度为-20~40℃,优选-5~10℃。
由化合物IVc与铁粉、氯化铵反应制备化合物Vc,反应溶剂为甲醇、乙醇和水的混合物,优选乙醇和水的混合物;反应温度为55~90℃,优选70~80℃。
由化合物Vc与化合物VIa反应制备化合物VIc,所用碱为三乙胺、N,N-二异丙基乙胺、钠氢、甲醇钠、乙醇钠、叔丁醇钾、氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、乙酸钠或乙酸钾,优选N,N-二异丙基乙胺;所用溶剂为二氯甲烷、四氢呋喃、乙腈、乙二醇单甲醚、N-甲基吡咯烷酮、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺中的一种或者任意两者的混合物,优选四氢呋喃;反应温度为-5~30℃,优选-5~20℃。
由化合物VIc与化合物Xa反应制备化合物Ic,所用溶剂为四氢呋喃、乙腈、乙二醇单甲醚、N-甲基吡咯烷酮、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺中的一种与水的混合物,优选四氢呋喃和水的混合物;所用催化剂选自碘化亚铜,溴化亚铜,五水合硫酸铜中的一种与抗坏血酸钠的混合物,优选五水合硫酸铜和抗坏血酸钠的混合物;反应温度为-5~65℃,优选25~35℃。
其中R1、R2、R3、R4和R5的定义同前;m、n独立为1~10之间的任意一个整数。
由化合物VIc与化合物VIb反应制备化合物Id,所用溶剂为四氢呋喃、乙腈、乙二醇单甲醚、N-甲基吡咯烷酮、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺中的一种与水的混合物,优选四氢呋喃和水的混合物;所用催化剂选自碘化亚铜,溴化亚铜,五水合硫酸铜中的一种与抗坏血酸钠的混合物,优选五水合硫酸铜和抗坏血酸钠的混合物;反应温度为-5~65℃,优选25~35℃。
本发明还公开了一种药物组合物,其含有上述通式(I)化合物或其药学上可接受的盐及药学上可接受的载体。所述的上述通式(I)化合物可以添加药学上可接受的载体制成常见的药用制剂,如片剂、胶囊、糖浆、悬浮剂、注射剂,可以加入香料、甜味剂、液体或固体填料或稀释剂等常用药用辅料。
本发明所述的通式(I)的化合物或其药学上可接受的盐在制备EGFR蛋白降解剂药物中的应用在本发明的保护范围内,其中所述的EGFR蛋白降解剂是治疗肿瘤的药物。
有益效果:本发明公开了一类EGFR蛋白降解剂,该类化合物能通过降解EGFR蛋白达到抑制肿瘤细胞增殖的目的,在治疗非小细胞肺癌方面具有巨大潜力。
附图说明
图1.实施例化合物的EGFR蛋白降解活性。
图2.化合物Ia-4和Ia-5的浓度依赖性降解EGFR蛋白实验。
图3.化合物Ia-4和Ia-5的时间依赖性降解EGFR蛋白实验。
图4.化合物Ia-5的体内抗肿瘤活性。
具体实施方式
实施例1:
(2S,4R)-1-((S)-2-(5-(4-(((4-((3-氯-4-氟苯基)氨基)-6-((E)-4-(哌啶-1-基)丁-2-烯基)喹唑啉-7基)氧基)甲基)-1H-1,2,3-三唑-1-基)戊酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Ia-1:m=1,n=4,R1=C(CH3)3,R2=R3=H,R4=CH3,)的合成
N-(3-氯-4-氟苯基)-6-硝基-7-(丙-2-炔-1-基氧基)喹唑啉-4-胺(IVa-1:m=1)的合成
250mL三颈瓶中加入DMF(100mL)和炔丙醇(IIIa-1,2.50g,44.55mmol),搅拌条件下降温至0℃。分批加入60%NaH(1.60g,40.00mmol)后,继续在冰浴下搅拌20分钟,再将N-(3-氯-4-氟苯基)-7-氟-6-硝基喹唑啉-4-胺(IIa-1,5.00g,14.85mmol)加入到上述反应液中,在0℃下继续搅拌30分钟后,将混合物倒入800mL水中,抽滤,滤饼用水洗涤后真空干燥,得黄色固体(IVa-1)4.84g,收率87%。1H NMR(300MHz,DMSO-d6)δ(ppm):10.18(s,1H),9.25(s,1H),8.69(s,1H),8.14-8.18(m,1H),7.79-7.82(m,1H),7.57(s,1H),7.47(t,J=8.97Hz,1H),5.20(s,2H),3.77(s,1H).ESI-MS(m/z):373.2[M+H]+
N-(3-氯-4-氟苯基)-6-氨基-7-(丙-2-炔-1-基氧基)喹唑啉-4-胺(Va-1:m=1)的合成
向反应瓶中加入EtOH(100mL),H2O(20mL),铁粉(3.58g,64.10mmol)和NH4Cl(2.06g,38.46mmol),搅拌条件下升温至80℃,加入化合物IVa-1(4.77g,12.82mmol)后继续在80℃加热4小时。反应完成后,抽滤,滤液减压蒸除溶剂后,向残余物中加入水,抽滤,滤饼用水洗涤后真空干燥,得棕色固体(Va-1)3.81g,收率87%。1H NMR(300MHz,DMSO-d6)δ(ppm):9.43(s,1H),8.38(s,1H),8.17-8.20(m,1H),7.78-7.83(m,1H),7.37-7.45(m,2H),7.22(s,1H),5.38(s,2H),5.04(s,2H),3.69(s,1H).ESI-MS(m/z):343.1[M+H]+
将化合物VIa-1(3.80g,16.95mmol)溶解在DCM(100mL)后,再加入化合物Va-1(4.07g,11.87mmol)和DIEA(8.76g,67.80mmol)。将悬浊液在0℃下搅拌2小时。反应完成后,向反应液中加入DCM(80mL),分别用水洗(25mL×2)和饱和食盐水洗涤(30mL×1),有机相用无水硫酸钠干燥,抽滤,减压蒸馏,粗品经柱层析(DCM:MeOH=60:1)分离得棕色固体(VIIa-1)2.11g,收率36%。1HNMR(300MHz,DMSO-d6)δ(ppm):9.84(s,1H),9.73(s,1H),8.91(s,1H),8.56(s,1H),8.14(dd,J=6.84,2.64Hz,1H),7.78-7.83(m,1H),7.43(t,J=9.18Hz,1H),7.40(s,1H),6.76-6.85(m,1H),6.56(d,J=15.39Hz,1H),5.11(d,J=2.4Hz,2H),3.73(s,1H),3.07-3.19(m,2H),2.31-2.42(m,4H),1.51-1.55(m,4H),1.37-1.43(m,2H).ESI-MS(m/z):494.3[M+H]+
(2S,4R)-1-((S)-2-(5-溴戊酰胺)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(IXa-1:n=4,R1=C(CH3)3,R2=R3=H,R4=CH3)的合成
向VHL配体(VHL-L-1,1.00g,2.32mmol)和化合物VIIIa-1(0.50g,2.79mmol)的DCM(15mL)溶液中加入HATU(1.06g,2.79mmol)和DIEA(0.90g,6.96mmol)。将悬浮液放置室温搅拌5小时。反应完成后,有机相分别用水(10mL×3)和饱和盐水洗涤(10mL×1),无水硫酸钠干燥,抽滤,减压蒸馏,粗品经柱层析(DCM:MeOH=40:1)分离得白色固体(IXa-1)0.91g,收率66%。1HNMR(300MHz,DMSO-d6)δ(ppm):8.99(s,1H),8.58(t,J=6.30Hz,1H),7.92(d,J=9.27Hz,1H),7.37-7.44(m,4H),4.35-4.57(m,4H),4.21(dd,J=15.93,5.46Hz,1H),3.62-3.70(m,2H),3.53(t,J=6.57Hz,2H),2.45(s,3H),2.26-2.35(m,1H),2.12-2.21(m,1H),2.00-2.07(m,1H),1.86-1.94(m,1H),1.73-1.82(m,2H),1.57-1.68(m,2H),0.94(s,9H).ESI-MS(m/z):593.2[M+H]+
(2S,4R)-1-((S)-2-(5-叠氮基戊酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Xa-1:n=4,R1=C(CH3)3,R2=R3=H,R4=CH3)的合成
向中间体IXa-1(0.90g,1.52mmol)的DMF(10mL)溶液中加入NaN3(0.20g,3.03mmol)。将混合物在60℃下搅拌5小时。反应完成后,将其倒入水中(80mL)并搅拌5分钟。抽滤,滤饼用水洗涤后真空干燥,得黄色固体(Xa-1)0.75g,收率89%。1H NMR(300MHz,DMSO-d6)δ(ppm):8.99(s,1H),8.58(t,J=6.30Hz,1H),7.92(d,J=9.27Hz,1H),7.37-7.44(m,4H),4.35-4.57(m,4H),4.21(dd,J=15.93,5.46Hz,1H),3.62-3.70(m,2H),3.53(t,J=6.57Hz,2H),2.45(s,3H),2.26-2.35(m,1H),2.12-2.21(m,1H),2.00-2.07(m,1H),1.86-1.94(m,1H),1.73-1.82(m,2H),1.57-1.68(m,2H),0.94(s,9H).ESI-MS(m/z):593.2[M+H]+
(2S,4R)-1-((S)-2-(5-(4-(((4-((3-氯-4-氟苯基)氨基)-6-((E)-4-(哌啶-1-基)丁-2-烯基)喹唑啉-7基)氧基)甲基)-1H-1,2,3-三唑-1-基)戊酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Ia-1:m=1,n=4,R1=C(CH3)3,R2=R3=H,R4=CH3,)的合成
将化合物VIIa-1(0.15g,0.30mmol)和化合物Xa-1(0.22g,0.36mmol)溶解在THF(10mL)中。加入抗坏血酸钠(0.05g,0.23mmol)、CuSO4·5H2O(0.03g,0.11mmol)与水(3mL)的混合物。悬浊液放置室温搅拌10小时。反应完成后,减压蒸除溶剂后得粗品。粗品经柱层析纯化(DCM:MeOH=20:1)得黄色固体(Ia-1)0.08g,收率24%。1H NMR(300MHz,DMSO-d6)δ(ppm):9.81(s,1H),9.61(s,1H),8.98(s,1H),8.90(s,1H),8.58(t,J=6.00Hz,1H),8.54(s,1H),8.29(s,1H),8.13(dd,J=6.87,2.61Hz,1H),7.94(d,J=9.21Hz,1H),7.78-7.83(m,1H),7.54(s,1H),7.36-7.45(m,5H),6.75-6.84(m,1H),6.50-6.55(m,1H),5.44(s,2H),5.14(d,J=3.48Hz,1H),4.35-4.56(m,6H),4.14-4.20(m,1H),3.63-3.70(m,2H),3.09-3.13(m,2H),2.44(s,3H),2.32-2.36(m,4H),2.25-2.30(m,1H),2.15-2.23(m,1H),1.99-2.08(m,1H),1.90-1.94(m,1H),1.77-1.86(m,2H),1.47-1.56(m,6H),1.35-1.39(m,2H),0.92(s,9H).HRMS(ESI):m/z calcd for C53H62ClFN12O6S:1049.4387[M+H]+;found:1049.4373.
实施例2:
((2S,4R)-1-((S)-2-(8-(4-(((4-((3-氯-4-氟苯基)氨基)-6-((E)-4-(哌啶-1-基)丁-2-烯丙基)喹唑啉-7基)氧基)甲基)-1H-1,2,3-三唑-1-基)辛酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Ia-2:m=1,n=7,R1=C(CH3)3,R2=R3=H,R4=CH3,)的合成
(2S,4R)-1-((S)-2-(8-溴辛基氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(IXa-2:n=7,R1=C(CH3)3,R2=R3=H,R4=CH3)的合成
以VHL配体(VHL-L-1,1.00g,2.32mmol)和化合物VIIIa-2(0.62g,2.78mmol)为原料,操作过程同化合物IXa-1,得白色固体(IXa-2)0.85g,收率58%。1H NMR(300MHz,DMSO-d6)δ(ppm):8.99(s,1H),8.59(t,J=6.12Hz,1H),7.87(d,J=9.33Hz,1H),7.37-7.44(m,4H),4.35-4.57(m,4H),4.21(dd,J=15.87,5.40Hz,1H),3.60-3.71(m,4H),2.45(s,3H),2.22-2.32(m,1H),2.09-2.16(m,1H),2.00-2.07(m,1H),1.87-1.95(m,1H),1.65-1.80(m,2H),1.45-1.54(m,2H),1.29-1.35(m,6H),0.94(s,9H).ESI-MS(m/z):635.2[M+H]+
(2S,4R)-1-((S)-2-(8-叠氮基十八胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Xa-2:n=7,R1=C(CH3)3,R2=R3=H,R4=CH3)的合成
以化合物IXa-2(0.80g,1.26mmol)和NaN3(0.16g,2.42mmol)为原料,操作过程同化合物Xa-1,得黄色固体(Xa-2)0.66g,收率88%。1H NMR(300MHz,DMSO-d6)δ(ppm):8.99(s,1H),8.58(t,J=5.94Hz,1H),7.87(d,J=9.30Hz,1H),7.37-7.44(m,4H),4.36-4.57(m,4H),4.22(dd,J=15.81,5.45Hz,1H),3.63-3.71(m,2H),3.31(t,J=6.84Hz,2H),2.45(s,3H),2.22-2.32(m,1H),2.11-2.16(m,1H),2.00-2.09(m,1H),1.86-1.95(m,1H),1.44-1.57(m,4H),1.21-1.31(m,6H),0.94(s,9H).ESI-MS(m/z):598.3[M+H]+
((2S,4R)-1-((S)-2-(8-(4-(((4-((3-氯-4-氟苯基)氨基)-6-((E)-4-(哌啶-1-基)丁-2-烯丙基)喹唑啉-7-基)氧基)甲基)-1H-1,2,3-三唑-1-基)辛酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Ia-2:m=1,n=7,R1=C(CH3)3,R2=R3=H,R4=CH3,)的合成
以化合物VIIa-1(0.15g,0.30mmol)和化合物Xa-2(0.22g,0.36mmol)为原料,操作过程同化合物Ia-1,得黄色固体(Ia-2)0.09g,收率27%。1H NMR(300MHz,DMSO-d6)δ(ppm):9.82(s,1H),9.62(s,1H),8.99(s,1H),8.91(s,1H),8.59(t,J=6.03Hz,1H),8.55(s,1H),8.31(s,1H),8.13(dd,J=6.69,2.58Hz,1H),7.80-7.88(m,2H),7.54(s,1H),7.37-7.45(m,5H),6.76-6.84(m,1H),6.50-6.56(m,1H),5.45(s,2H),5.15(d,J=3.48Hz,1H),4.32-4.48(m,6H),4.19-4.25(m,1H),3.57-3.73(m,2H),3.04-3.18(m,2H),2.45(s,3H),2.31-2.41(m,4H),2.20-2.26(m,1H),2.10-2.16(m,1H),2.01-2.08(m,1H),1.90-1.96(m,1H),1.75-1.85(m,2H),1.42-1.62(m,6H),1.36-1.39(m,2H),1.18-1.32(m,6H),0.94(s,9H).HRMS(ESI):m/z calcd for C56H68ClFN12O6S:1091.4856[M+H]+;found:1091.4856.
实施例3:
(2S,4R)-1-((S)-2-(9-(4-(((4-((3-氯-4-氟苯基)氨基)-6-((E)-4-(哌啶-1-基)丁-2-烯氨基)喹唑啉-7基)氧基)甲基)-1H-1,2,3-三唑-1-基)壬酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Ia-3:m=1,n=8,R1=C(CH3)3,R2=R3=H,R4=CH3,)的合成(2S,4R)-1-((S)-2-(9-溴代萘并氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(IXa-3:n=8,R1=C(CH3)3,R2=R3=H,R4=CH3)的合成
以VHL配体(VHL-L-1,1.00g,2.32mmol)和化合物VIIIa-3(0.66g,2.78mmol)为原料,操作过程同化合物IXa-1,得白色固体(IXa-3)0.93g,收率62%。1H NMR(300MHz,DMSO-d6)δ(ppm):9.00(s,1H),8.60(t,J=6.24Hz,1H),7.87(d,J=9.31Hz,1H),7.36-7.43(m,4H),4.37-4.59(m,4H),4.22(dd,J=15.91,5.43Hz,1H),3.61-3.73(m,4H),2.45(s,3H),2.21-2.32(m,1H),2.09-2.15(m,1H),2.01-2.08(m,1H),1.86-1.93(m,1H),1.63-1.78(m,2H),1.46-1.55(m,2H),1.27-1.36(m,8H),0.95(s,9H).ESI-MS(m/z):649.2[M+H]+
(2S,4R)-1-((S)-2-(9-叠氮基萘并氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Xa-3:n=8,R1=C(CH3)3,R2=R3=H,R4=CH3)的合成
以化合物IXa-3(0.90g,1.39mmol)和NaN3(0.18g,2.78mmol)为原料,操作过程同化合物Xa-1,得黄色固体(Xa-3)0.71g,收率83%。1H NMR(300MHz,DMSO-d6)δ(ppm):8.99(s,1H),8.58(t,J=6.00Hz,1H),7.88(d,J=9.33Hz,1H),7.37-7.44(m,4H),4.36-4.57(m,4H),4.21(dd,J=15.93,5.42Hz,1H),3.61-3.73(m,2H),3.32(t,J=6.56Hz,2H),2.45(s,3H),2.21-2.33(m,1H),2.10-2.15(m,1H),2.01-2.10(m,1H),1.86-1.96(m,1H),1.44-1.59(m,4H),1.22-1.34(m,8H),0.95(s,9H).ESI-MS(m/z):612.3[M+H]+
(2S,4R)-1-((S)-2-(9-(4-(((4-((3-氯-4-氟苯基)氨基)-6-((E)-4-(哌啶-1-基)丁-2-烯氨基)喹唑啉-7基)氧基)甲基)-1H-1,2,3-三唑-1-基)壬酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Ia-3:m=1,n=8,R1=
以化合物VIIa-1(0.15g,0.30mmol)和化合物Xa-3(0.22g,0.36mmol)为原料,操作过程同化合物Ia-1,得黄色固体(Ia-3)0.12g,收率39%。1H NMR(300MHz,DMSO-d6)δ(ppm):9.81(s,1H),9.61(s,1H),8.98(s,1H),8.90(s,1H),8.57(t,J=6.09Hz,1H),8.54(s,1H),8.30(s,1H),8.14(dd,J=6.90,2.67Hz,1H),7.78-7.85(m,2H),7.53(s,1H),7.37-7.45(m,5H),6.76-6.85(m,1H),6.50-6.56(m,1H),5.44(s,2H),4.35-4.57(m,6H),4.19-4.25(m,1H),3.63-3.73(m,2H),3.10-3.18(m,2H),2.45(s,3H),2.35-2.44(m,4H),2.21-2.28(m,1H),2.10-2.18(m,1H),2.00-2.08(m,1H),1.87-1.95(m,1H),1.77-1.83(m,2H),1.45-1.57(m,6H),1.36-1.42(m,2H),1.17-1.32(m,8H),0.94(s,9H).HRMS(ESI):m/z calcd forC57H70ClFN12O6S:1105.5013[M+H]+;found:1105.4980.
实施例4:
(2S,4R)-1-((S)-2-(10-(4-(((4-((3-氯-4-氟苯基)氨基)-6-((E)-4-(哌啶-1-基)丁-2-烯基)喹唑啉-7-基)氧基)甲基)-1H-1,2,3-三唑-1-基)癸酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Ia-4:m=1,n=9,R1=C(CH3)3,R2=R3=H,R4=CH3,)的合成
(2S,4R)-1-((S)-2-(10-溴代卡那酰胺)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(IXa-4:n=9,R1=C(CH3)3,R2=R3=H,R4=CH3, )
以VHL配体(VHL-L-1,1.00g,2.32mmol)和化合物VIIIa-4(0.70g,2.78mmol)为原料,操作过程同化合物IXa-1,得白色固体(IXa-4)0.88g,收率57%。1H NMR(300MHz,DMSO-d6)δ(ppm):8.99(s,1H),8.59(t,J=6.14Hz,1H),7.88(d,J=9.28Hz,1H),7.36-7.43(m,4H),4.36-4.60(m,4H),4.21(dd,J=15.88,5.38Hz,1H),3.62-3.73(m,4H),2.45(s,3H),2.20-2.31(m,1H),2.10-2.16(m,1H),2.00-2.07(m,1H),1.85-1.96(m,1H),1.61-1.76(m,2H),1.44-1.57(m,2H),1.28-1.38(m,10H),0.94(s,9H).ESI-MS(m/z):663.3[M+H]+
(2S,4R)-1-((S)-2-(10-叠氮基十二烷基氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Xa-4:n=9,R1=C(CH3)3,R2=R3=H,R4=CH3,)
以化合物IXa-4(0.85g,1.28mmol)和NaN3(0.17g,2.57mmol)为原料,操作过程同化合物Xa-1,得黄色固体(Xa-4)0.75g,收率94%。1H NMR(300MHz,DMSO-d6)δ(ppm):8.99(s,1H),8.58(t,J=6.03Hz,1H),7.88(d,J=9.36Hz,1H),7.37-7.44(m,4H),4.36-4.57(m,4H),4.22(dd,J=15.84,5.39Hz,1H),3.61-3.73(m,2H),3.33(t,J=6.52Hz,2H),2.45(s,3H),2.21-2.33(m,1H),2.10-2.15(m,1H),2.01-2.10(m,1H),1.86-1.96(m,1H),1.44-1.59(m,4H),1.22-1.34(m,10H),0.95(s,9H).ESI-MS(m/z):626.3[M+H]+
(2S,4R)-1-((S)-2-(10-(4-(((4-((3-氯-4-氟苯基)氨基)-6-((E)-4-(哌啶-1-基)丁-2-烯基)喹唑啉-7-基)氧基)甲基)-1H-1,2,3-三唑-1-基)癸酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Ia-4:m=1,n=9,R1=C(CH3)3,R2=R3=H,R4=CH3,)的合成
以化合物VIIa-1(0.15g,0.30mmol)和化合物Xa-4(0.23g,0.36mmol)为原料,操作过程同化合物Ia-1,得黄色固体(Ia-4)0.11g,收率33%。1H NMR(400MHz,DMSO-d6)δ(ppm):9.83(s,1H),9.65(s,1H),8.99(s,1H),8.90(s,1H),8.59(t,J=6.24Hz,1H),8.55(s,1H),8.31(s,1H),8.14(dd,J=6.92,2.64Hz,1H),7.79-7.87(m,2H),7.54(s,1H),7.37-7.45(m,5H),6.77-6.84(m,1H),6.52-6.56(m,1H),5.45(s,2H),4.35-4.56(m,6H),4.18-4.25(m,1H),3.64-3.70(m,2H),3.15-3.18(m,2H),2.45(s,3H),2.32-2.44(m,4H),2.21-2.28(m,1H),2.07-2.14(m,1H),2.01-2.05(m,1H),1.88-1.94(m,1H),1.77-1.84(m,2H),1.45-1.57(m,6H),1.36-1.42(m,2H),1.17-1.26(m,10H),0.94(s,9H).MS(ESI):m/z calcd forC58H72ClFN12O6S:1119.5169[M+H]+;found:1119.5164.
实施例5:
(2S,4R)-1-((S)-2-(11-(4-(((4-((3-氯-4-氟苯基)氨基)-6-((E)-4-(哌啶-1-基)丁-2-烯丙基)喹唑啉-7-基)氧基)甲基)-1H-1,2,3-三唑-1-基)十一烷酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Ia-5:m=1,n=10,R1=C(CH3)3,R2=R3=H,R4=CH3,)的合成
(2S,4R)-1-((S)-2-(11-溴戊酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(IXa-5:n=10,R1=C(CH3)3,R2=R3=H,R4=CH3, )的合成
以VHL配体(VHL-L-1,1.00g,2.32mmol)和化合物VIIIa-5(0.74g,2.78mmol)为原料,操作过程同化合物IXa-1,得白色固体(IXa-5)0.94g,收率60%。1H NMR(300MHz,DMSO-d6)δ(ppm):8.99(s,1H),8.58(t,J=6.00Hz,1H),7.86(d,J=9.21Hz,1H),7.37-7.44(m,4H),4.35-4.36(m,4H),4.21(dd,J=15.87,5.40Hz,1H),3.61-3.67(m,2H),3.52(t,J=6.24Hz,2H),2.45(s,3H),2.21-2.31(m,1H),2.07-2.14(m,1H),1.99-2.05(m,1H),1.85-1.94(m,1H),1.73-1.82(m,2H),1.45-1.54(m,2H),1.33-1.38(m,2H),1.20-1.28(m,10H),0.93(s,9H).ESI-MS(m/z):677.3[M+H]+
(2S,4R)-1-((S)-2-(11-叠氮烷酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Xa-5:n=10,R1=C(CH3)3,R2=R3=H,R4=CH3,)的合成
以化合物IXa-5(0.85g,1.26mmol)和NaN3(0.16g,2.52mmol)为原料,操作过程同化合物Xa-1,得黄色固体(Xa-5)0.75g,收率94%。1H NMR(300MHz,DMSO-d6)δ(ppm):8.99(s,1H),8.58(t,J=6.00Hz,1H),7.86(d,J=9.30Hz,1H),7.37-7.44(m,4H),4.34-4.57(m,4H),4.22(dd,J=15.90,5.46Hz,1H),3.62-3.71(m,2H),3.30(t,J=6.84Hz,2H),2.45(s,3H),2.22-2.32(m,1H),2.08-2.15(m,1H),2.00-2.05(m,1H),1.86-1.95(m,1H),1.44-1.56(m,4H),1.22-1.34(m,12H),0.95(s,9H).ESI-MS(m/z):640.4[M+H]+
(2S,4R)-1-((S)-2-(11-(4-(((4-((3-氯-4-氟苯基)氨基)-6-((E)-4-(哌啶-1-基)丁-2-烯丙基)喹唑啉-7-基)氧基)甲基)-1H-1,2,3-三唑-1-基)十一烷酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Ia-5:m=1,n=10,R1=C(CH3)3,R2=R3=H,R4=CH3,)的合成
以化合物VIIa-1(0.15g,0.30mmol)和化合物Xa-5(0.23g,0.36mmol)为原料,操作过程同化合物Ia-1,得黄色固体(Ia-5)0.07g,收率26%。1H NMR(400MHz,DMSO-d6)δ(ppm):9.84(s,1H),9.64(s,1H),9.01(s,1H),8.92(s,1H),8.61(t,J=6.24Hz,1H),8.56(s,1H),8.33(s,1H),8.15(dd,J=6.95,2.67Hz,1H),7.80-7.90(m,2H),7.56(s,1H),7.39-7.48(m,5H),6.76-6.87(m,1H),6.52-6.57(m,1H),5.47(s,2H),5.17(s,1H),4.35-4.59(m,6H),4.18-4.26(m,1H),3.64-3.72(m,2H),3.05-3.18(m,2H),2.47(s,3H),2.32-2.44(m,4H),2.21-2.28(m,1H),2.11-2.18(m,1H),2.01-2.07(m,1H),1.91-1.97(m,1H),1.78-1.85(m,2H),1.49-1.58(m,6H),1.38-1.43(m,2H),1.16-1.29(m,12H),0.96(s,9H).MS(ESI):m/zcalcd for C59H74ClFN12O6S:1133.5326[M+H]+;found:1133.5316.
实施例6:
(2S,4R)-1-((S)-2-(10-(4-(5-((4-((3-氯-4-氟苯基)氨基)-6-((E)-4-(哌啶-1-基)-2-烯酰胺基)喹唑啉-7-基)氧基)戊基)-1H-1,2,3-三唑-1-基)癸酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Ia-6:m=5,n=9,R1=C(CH3)3,R2=R3=H,R4=CH3,)的合成
N-(3-氯-4-氟苯基)-7-(庚-6-炔-1-氧基)-6-硝基喹唑啉-4-胺(IVa-2:m=5)的合成
以IIa-1(5.00g,14.85mmol)和IIIa-2(5.00g,44.55mmol)为原料,操作过程同化合物IVa-1,得黄色固体(IVa-2)4.81g,收率76%。
1H NMR(300MHz,DMSO-d6)δ(ppm):10.15(s,1H),9.20(s,1H),8.63(s,1H),8.15(dd,J=5.19,2.01Hz,1H),7.78-7.82(m,1H),7.44(t,J=6.81Hz,1H),7.40(s,1H),4.26(t,J=4.71Hz,2H),2.91(s,1H),2.17-2.22(m,2H),1.75-1.81(m,2H),1.51-1.58(m,4H).
N-(3-氯-4-氟苯基)-7-(庚-6-炔-1-氧基)-6-氨基喹唑啉-4-胺(Va-2:m=5)的合成
以IVa-2(4.50g,10.52mmol)为原料,操作过程同化合物Va-1,得黄色固体(Va-2)4.00g,收率95%。ESI-MS(m/z):399.1[M+H]+
以化合物Va-2(3.90g,9.78mmol)和化合物VIa-1(2.75g,14.67mmol)为原料,操作过程同化合物VIIa-1,得浅黄色固体(VIIa-2)2.81g,收率52%。1H NMR(300MHz,DMSO-d6)δ(ppm):9.79(s,1H),9.49(s,1H),8.86(s,1H),8.53(s,1H),8.14(dd,J=6.87,2.61Hz,1H),7.78-7.83(m,1H),7.42(t,J=9.15Hz,1H),7.27(s,1H),6.75-6.85(m,1H),6.53(d,J=15.30Hz,1H),4.21(t,J=6.54Hz,2H),3.08-3.12(m,2H),2.76(t,J=2.61Hz,1H),2.32-2.40(m,4H),2.17-2.21(m,2H),1.83-1.88(m,2H),1.49-1.57(m,8H),1.39-1.43(m,2H).
(2S,4R)-1-((S)-2-(10-(4-(5-((4-((3-氯-4-氟苯基)氨基)-6-((E)-4-(哌啶-1-基)-2-烯酰胺基)喹唑啉-7-基)氧基)戊基)-1H-1,2,3-三唑-1-基)癸酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Ia-6:m=5,n=9,R1=C(CH3)3,R2=R3=H,R4=CH3,)的合成
以化合物VIIa-2(0.15g,0.27mmol)和化合物Xa-4(0.20,0.33mmol)为原料,操作过程同化合物Ia-1,得浅黄色固体(Ia-6)0.08g,收率22%。1H NMR(300MHz,DMSO-d6)δ(ppm):9.80(s,1H),9.51(s,1H),8.98(s,1H),8.88(s,1H),8.58(t,J=6.21Hz,1H),8.54(s,1H),8.14(dd,J=6.89,2.64Hz,1H),7.79-7.87(m,3H),7.36-7.45(m,5H),7.27(s,1H),6.76-6.85(m,1H),6.52-6.56(m,1H),4.18-4.56(m,9H),3.61-3.70(m,2H),3.11-3.14(m,2H),2.64(t,J=7.32Hz,2H),2.45(s,3H),2.20-2.36(m,5H),2.00-2.14(m,2H),1.85-1.95(m,3H),1.73-1.78(m,2H),1.63-1.70(m,2H),1.45-1.57(m,8H),1.36-1.40(m,2H),1.17-1.26(m,10H),0.94(s,9H).
实施例7:
(2S,4R)-1-((S)-2-(11-(4-((4-((3-氯-4-氟苯基)氨基)-6-((E)-4-(二乙氨基)-2-烯酰胺基)喹唑啉-7-基)氧基)甲基)-1H-1,2,3-三唑-1-基)十一烷酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Ia-7:m=1,n=10,R1=C(CH3)3,R2=R3=H,R4=CH3,)的合成(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(丙-2-炔-1-氧基)喹唑啉-6-基)-4-(二乙氨基)丁-2-烯酰胺(VIIa-2:m=1,)的合成
以化合物Va-1(4.07g,11.87mmol)和化合物VIa-2(3.13g,17.81mmol)为原料,操作过程同化合物VIIa-1,得黄色固体(VIIa-2)2.11g,收率37%。1H NMR(300MHz,DMSO-d6)δ(ppm):9.87(s,1H),9.76(s,1H),8.94(s,1H),8.56(s,1H),8.14(dd,J=6.84,2.64Hz,1H),7.79-7.87(m,1H),7.43(t,J=9.18Hz,1H),7.40(s,1H),6.83-6.91(m,1H),6.58-6.64(m,1H),5.2(d,J=2.37Hz,2H),3.73(s,1H),3.25-3.28(m,2H),2.45-2.49(m,4H),1.01(t,J=7.05Hz,6H).
(2S,4R)-1-((S)-2-(11-(4-((4-((3-氯-4-氟苯基)氨基)-6-((E)-4-(二乙氨基)-2-烯酰胺基)喹唑啉-7-基)氧基)甲基)-1H-1,2,3-三唑-1-基)十一烷酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Ia-7:m=1,n=10,R1=C(CH3)3,R2=R3=H,R4=CH3,)的合成
以化合物Xa-5(0.23g,0.36mmol)和化合物VIIa-2(0.14g,0.30mmol)为原料,操作过程同化合物Ia-1,得黄色固体(Ia-7)0.10g,收率30%。1H NMR(400MHz,DMSO-d6)δ(ppm):9.83(s,1H),9.65(s,1H),8.98(s,1H),8.90(s,1H),8.60(t,J=6.24Hz,1H),8.54(s,1H),8.31(s,1H),8.14(dd,J=6.92,2.64Hz,1H),7.79-7.87(m,2H),7.53(s,1H),7.37-7.44(m,5H),6.80-6.87(m,1H),6.56-6.60(m,1H),5.44(s,2H),4.54-4.56(m,1H),4.32-4.48(m,5H),4.19-4.25(m,1H),3.62-3.69(m,2H),3.30-3.32(m,2H),2.51-2.62(m,4H),2.45(s,3H),2.21-2.28(m,1H),2.02-2.13(m,2H),1.87-1.94(m,1H),1.76-1.83(m,2H),1.43-1.53(m,2H),1.17-1.26(m,12H),1.01(t,J=5.34Hz,6H),0.94(s,9H).
实施例8:
(2S,4R)-1-((S)-2-(11-(4-((3-氯-4-氟苯基)氨基)-6-((E)-4-(哌啶-1-基)-2-烯酰胺基)喹唑啉-7-基)氧基)甲基)-1H-1,2,3-三唑-1-基)十一胺基)-3,3-二甲基丁酰)-4-羟基-N-((R)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(Ia-8:m=1,n=10,R1=C(CH3)3,R2=CH3,R3=H,R4=CH3,)的合成
(2S,4R)-1-((S)-2-(11-溴代十二胺)-3,3-二甲基丁酰)-4-羟基-N-((R)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(IXa-6:n=10,R1=C(CH3)3,R2=CH3,R3=H,R4=CH3,)的合成
以VHL配体(VHL-L-2,0.50g,1.12mmol)和化合物VIIIa-5(0.37g,1.39mmol)为原料,操作过程同化合物IXa-1,得白色固体(IXa-6)0.47g,收率59%。1H NMR(300MHz,DMSO-d6)δ(ppm):8.99(s,1H),8.40(t,J=5.97Hz,1H),7.81(d,J=9.21Hz,1H),7.33-7.45(m,4H),4.87-4.92(m,1H),4.40-4.54(m,2H),4.26-4.29(m,1H),3.61-3.67(m,2H),3.52(t,J=6.24Hz,2H),2.46(s,3H),2.21-2.31(m,1H),2.07-2.14(m,1H),1.98-2.05(m,1H),1.70-1.84(m,3H),1.45-1.54(m,2H),1.33-1.38(m,5H),1.20-1.28(m,10H),0.93(s,9H).ESI-MS(m/z):691.3[M+H]+
11-叠氮-N-((S)-1-((2S,4R)-4-羟基-2-(((R)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)-l4-氮酰基)羰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁烷-2-基)十一烷酰胺(Xa-6:n=10,R1=C(CH3)3,R2=CH3,R3=H,R4=CH3,)的合成
以化合物IXa-6(0.40g,0.61mmol)和NaN3(0.08g,1.22mmol)为原料,操作过程同化合物Xa-1,得黄色固体(Xa-6)0.35g,收率88%。ESI-MS(m/z):654.4[M+H]+
(2S,4R)-1-((S)-2-(11-(4-((3-氯-4-氟苯基)氨基)-6-((E)-4-(哌啶-1-基)-2-烯酰胺基)喹唑啉-7-基)氧基)甲基)-1H-1,2,3-三唑-1-基)十一胺基)-3,3-二甲基丁酰)-4-羟基-N-((R)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(Ia-8:m=1,n=10,R1=C(CH3)3,R2=CH3,R3=H,R4=CH3,)的合成
以化合物VIIa-1(0.15g,0.30mmol)和化合物Xa-6(0.23g,0.35mmol)为原料,操作过程同化合物Ia-1,得黄色固体(Ia-8)0.07g,收率20%。1H NMR(300MHz,DMSO-d6)δ(ppm):9.85(s,1H),9.67(s,1H),9.01(s,1H),8.93(s,1H),8.57(s,1H),8.42(d,J=7.86Hz,1H),8.34(s,1H),8.17(dd,J=6.95,2.67Hz,1H),7.80-7.87(m,2H),7.56(s,1H),7.39-7.48(m,5H),6.69-6.87(m,1H),6.52-6.57(m,1H),5.47(s,2H),4.90-5.00(m,1H),4.54-4.57(m,1H),4.31-4.49(m,5H),3.64-3.72(m,2H),3.05-3.18(m,2H),2.47(s,3H),2.32-2.44(m,4H),2.21-2.28(m,1H),2.01-2.22(m,2H),1.85-1.91(m,3H),1.55-1.60(m,6H),1.38-1.43(m,5H),1.16-1.29(m,12H),0.96(s,9H).
实施例9:
(2S,4R)-1-((S)-2-(2-(2-(2-(4-(5-((4-((3-氯-4-氟苯基)氨基)-6-((E)-4-(哌啶-1-基)丁-2-烯酰胺基)喹唑啉-7-基)氧基)戊基)-1H-1,2,3-三唑-1-基)乙氧基)乙氧基)乙酰胺)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Ib-1:m=5,n=2,R1=C(CH3)3,R2=R3=H,R4=CH3,)的合成
2-(2-(2-羟基乙氧基)乙氧基)-4-甲苯磺酸乙酯(IIIb-1:n=2)的合成
向三甘醇(IIb-1,12.50g,83.24mmol)在THF(50mL)和H2O(10mL)的溶液中加入NaOH(0.50g,12.50mmol)。悬浮液在0℃搅拌10分钟,分批加入对甲苯磺酰氯(1.59g,8.34mmol),然后在25℃搅拌混合物5小时。反应完成后,减压旋去THF,残余物用DCM萃取(20mL×3),合并有机相并用饱和盐水洗涤,无水Na2SO4干燥过夜,抽滤旋干得黄色液体(IIIb-1)2.07g,收率81%。1H NMR(300MHz,CDCl3)δ(ppm):7.80(d,J=8.43Hz,2H),7.35(d,J=8.07Hz,2H),4.17(t,J=5.04Hz,2H),3.69-3.73(m,4H),3.56-3.61(m,6H),2.47(s,1H),2.45(s,3H).ESI-MS(m/z):305.1[M+H]+
2-(2-(2-(甲苯磺酰氧基)乙氧基)乙氧基)乙酸(IVb-1:n=2)的合成
将化合物IIIb-1(1.80g,5.91mmol)溶解在丙酮(10mL)中并将混合物冷却至0℃,将CrO3(1.77g,17.73mmol)、浓硫酸(1.6mL)和H2O(6.4mL)混合并加入反应中。混合物在0℃搅拌10小时。反应完成后,加入异丙醇(5mL)以淬灭Cr(VI),减压蒸发除去丙酮和异丙醇,残余物用DCM萃取(20mL×3),合并有机相并用饱和盐水洗涤,无水Na2SO4干燥过夜,抽滤旋干得黄色液体(IVb-1)1.41g,收率75%。1H NMR(300MHz,CDCl3)δ(ppm):7.81(d,J=8.34Hz,2H),7.35(d,J=8.19Hz,2H),4.12-4.22(m,4H),3.62-3.75(m,6H),2.45(s,3H).ESI-MS(m/z):319.0[M+H]+
2-(2-(2-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-)苄基)氨基甲酰)吡咯烷-1-)-3,3-二甲基-1-氧代丁烷-2-基)氨基)-2-氧代乙氧基)乙氧基)乙基-4-甲基苯磺酸(Vb-1:n=2,R1=C(CH3)3,R2=R3=H,R4=CH3)的合成
以VHL配体(VHL-L-1,1.00g,2.32mmol)和化合物IVb-1(0.88g,2.78mmol)为原料,操作过程同化合物IXa-1,得白色固体(Vb-1)0.98g,收率58%。1H NMR(300MHz,DMSO-d6)δ(ppm):8.99(s,1H),8.61(t,J=5.97Hz,1H),7.76(d,J=8.31Hz,2H),7.39-7.48(m,7H),5.18(d,J=3.48Hz,1H),4.35-4.57(m,4H),4.25(dd,J=15.72,5.67Hz,1H),4.12(t,J=4.41Hz,2H),3.94(s,2H),3.58-3.66(m,4H),3.53-3.56(m,2H),3.46-3.51(m,2H),2.45(s,3H),2.44(s,3H),2.02-2.09(m,1H),1.85-1.94(m,1H),0.93(s,9H).ESI-MS(m/z):731.3[M+H]+
(2S,4R)-1-((S)-2-(2-(2-(2-叠氮乙氧基)乙氧基)乙酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(VIb-1:n=2,R1=C(CH3)3,R2=R3=H,R4=CH3)的合成
以化合物Vb-1(0.91g,1.24mmol)和NaN3(0.16g,2.52mmol)为原料,操作过程同化合物Xa-1,得黄色固体(VIb-1)0.66g,收率67%。ESI-MS(m/z):602.3[M+H]+
(2S,4R)-1-((S)-2-(2-(2-(2-(4-(5-((4-((3-氯-4-氟苯基)氨基)-6-((E)-4-(哌啶-1-基)丁-2-烯酰胺基)喹唑啉-7-基)氧基)戊基)-1H-1,2,3-三唑-1-基)乙氧基)乙氧基)乙酰胺)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Ib-1:m=5,n=2,R1=C(CH3)3,R2=R3=H,R4=CH3,)的合成
以化合物VIIa-2(0.17g,0.30mmol)和化合物VIb-1(0.23g,0.66mmol)为原料,操作过程同化合物Ia-1,得黄色固体(Ib-1)0.08g,收率23%。1H NMR(300MHz,DMSO-d6)δ(ppm):9.81(s,1H),9.54(s,1H),8.97(s,1H),8.88(s,1H),8.62(t,J=5.94Hz,1H),8.54(s,1H),8.15(dd,J=6.87,2.61Hz,1H),7.79-7.84(m,2H),7.36-7.47(m,6H),7.27(s,1H),6.77-6.86(m,1H),6.54-6.59(m,1H),4.27-4.59(m,7H),4.18-4.29(m,2H),3.92-4.00(m,2H),3.82(t,J=4.89Hz,2H),3.53-3.69(m,6H),3.05-3.18(m,2H),2.64(t,J=7.59Hz,2H),2.38-2.45(m,7H),2.04-2.22(m,1H),1.82-1.95(m,3H),1.62-1.73(m,2H),1.48-1.58(m,6H),1.38-1.43(m,2H),0.93(s,9H).MS(ESI):m/z calcd for C58H72ClFN12O8S:1151.5068[M+H]+;found:1151.5055.
实施例10:
(2S,4R)-1-((S)-2-(叔丁基)-14-(4-(5-((4-((3-氯-4-氟苯基)氨基)-6-((E)-4-(哌啶-1-基)-2-烯酰胺基)喹唑啉-7-基)氧基)戊基)-1H-1,2,3-三唑-1-基)-4-氧代-6,9,12-三唑-3-氮杂十四烷基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Ib-2:m=5,n=3,R1=C(CH3)3,R2=R3=H,R4=CH3,)的合成
4-甲基苯磺酸2-(2-(2-(2-羟基乙氧基)乙氧基)乙氧基)乙酯(IIIb-2:n=3)的合成
以化合物IIb-2(20.37g,104.90mmol)和对甲苯磺酰氯(2.00g,10.49mmol)为原料,操作过程同化合物IIIb-1,得黄色液体(IIIb-2)2.38g,收率65%。1H NMR(300MHz,CDCl3)δ(ppm):7.81(d,J=8.31Hz,2H),7.36(d,J=8.22Hz,2H),4.18(t,J=4.83Hz,2H),3.56-3.74(m,14H),2.80(s,1H),2.46(s,3H).ESI-MS(m/z):349.2[M+H]+
2-(2-(2-(2-(甲苯磺酰氧基)乙氧基)乙氧基)乙氧基)乙酸(IVb-2:n=3)的合成
以化合物IIIb-2(2.00g,5.74mmol)为原料,操作过程同化合物IVb-1,得黄色液体(IVb-2)1.68g,收率81%。1H NMR(300MHz,CDCl3)δ(ppm):7.80(d,J=8.16Hz,2H),7.35(d,J=8.04Hz,2H),4.10-4.18(m,4H),3.57-3.76(m,10H),2.45(s,3H).ESI-MS(m/z):363.1[M+H]+
(S)-13-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-羰基)-14,14-二甲基-11-氧代-3,6,9-三氧基-12-氮杂十五烷基-4-甲基苯磺酸酯(Vb-2:n=3,R1=C(CH3)3,R2=R3=H,R4=CH3)的合成
以VHL配体(VHL-L-1,1.07g,2.30mmol)和化合物IVb-2(1.00g,2.76mmol)为原料,操作过程同化合物IXa-1,得白色固体(Vb-2)0.96g,收率54%。1H NMR(300MHz,DMSO-d6)δ(ppm):8.99(s,1H),8.61(t,J=6.03Hz,1H),7.77(d,J=8.21Hz,2H),7.40-7.48(m,7H),5.18(d,J=3.42Hz,1H),4.33-4.58(m,4H),4.25(dd,J=15.81,5.46Hz,1H),4.11(t,J=4.50Hz,2H),3.95(s,2H),3.53-3.69(m,8H),3.48-3.55(m,2H),3.48-3.52(m,2H),2.45(s,3H),2.43(s,3H),2.02-2.10(m,1H),1.82-1.92(m,1H),0.94(s,9H).ESI-MS(m/z):775.3[M+H]+
(S)-13-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨甲酰基)吡咯烷-1-羰基)-14,14-二甲基-11-氧代-3,6,9-三氧基-12-氮杂十五烷基-4-甲基苯磺酸(2S,4R)-1-((S)-14-叠氮基-2-(叔丁基)-4-氧代-6,9,12-三氧基-3-氮杂十四烷基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(VIb-2:n=3,R1=C(CH3)3,R2=R3=H,R4=CH3)的合成
以化合物Vb-2(0.91g,1.17mmol)和NaN3(0.15g,2.34mmol)为原料,操作过程同化合物Xa-1,得黄色固体(VIb-2)0.53g,收率70%。ESI-MS(m/z):646.3[M+H]+
(2S,4R)-1-((S)-2-(叔丁基)-14-(4-(5-((4-((3-氯-4-氟苯基)氨基)-6-((E)-4-(哌啶-1-基)-2-烯酰胺基)喹唑啉-7-基)氧基)戊基)-1H-1,2,3-三唑-1-基)-4-氧代-6,9,12-三唑-3-氮杂十四烷基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Ib-2:m=5,n=3,R1=C(CH3)3,R2=R3=H,R4=CH3,)的合成
以化合物VIIa-2(0.17g,0.30mmol)和化合物VIb-2(0.23g,0.66mmol)为原料,操作过程同化合物Ia-1,得黄色固体(Ib-2)0.07g,收率20%。1H NMR(300MHz,DMSO-d6)δ(ppm):9.81(s,1H),9.53(s,1H),8.98(s,1H),8.88(s,1H),8.62(t,J=5.91Hz,1H),8.53(s,1H),8.14(dd,J=6.93,2.61Hz,1H),7.79-7.84(m,2H),7.36-7.47(m,6H),7.27(s,1H),6.79-6.84(m,1H),6.52-6.57(m,1H),4.27-4.59(m,7H),4.18-4.29(m,2H),3.92-4.00(m,2H),3.83(t,J=4.86Hz,2H),3.52-3.69(m,10H),3.05-3.18(m,2H),2.64(t,J=7.62Hz,2H),2.38-2.45(m,7H),2.04-2.22(m,1H),1.82-1.95(m,3H),1.62-1.73(m,2H),1.48-1.58(m,6H),1.38-1.43(m,2H),0.94(s,9H).
实施例11:
(2S,4R)-1-((S)-2-(8-(4-((2-(2-(2-((4-((3-氯-4-氟苯基)氨基)-6-((E)-4-(哌啶-1-基)-2-烯酰胺基)喹唑啉-7-基)氧基)乙氧基)乙氧基)乙氧基)甲基)-1H-1,2,3-三唑-1-基)辛酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Ic-1:m=3,n=7,R1=C(CH3)3,R2=R3=H,R4=CH3,)的合成
2-(2-(2-(丙-2-1-丙氧基)乙氧基)乙烷-1-醇(IIIc-1:m=3)的合成
250ml反应瓶中加入IIc-1(5.00g,33.30mmol)和四氢呋喃50(mL),搅拌条件下降温至0℃。分批加入60%NaH(1.60g,39.95mmol),待没有气泡产生后加入溴丙炔(3.06g,25.74mmol)。室温搅拌12h后,用饱和氯化铵溶液淬灭NaH,水相用乙酸乙酯萃取(50mL×3),合并有机相并用饱和食盐水洗涤后无水Na2SO4干燥。抽滤旋干,粗品经柱层析(DCM:MeOH=80:1)分离得黄色液体(IIIc-1)3.51g,收率72%。ESI-MS(m/z):189.1[M+H]+
N-(3-氯-4-氟苯基)-6-硝基-7-(2-(2-(丙-2-1-丙氧基)乙氧基)乙氧基)喹唑啉-4-胺(IVc-1:m=3)的合成
以化合物IIc-1(3.50g,18.59mmol)和化合物IIa-1(2.09g,6.20mmol)为原料,操作过程同化合物IVa-1,得黄色固体(IVc-1)2.55g,收率81%。1H NMR(300MHz,DMSO-d6)δ(ppm):10.16(s,1H),9.21(s,1H),8.67(s,1H),8.16(dd,J=6.87,2.64Hz,1H),7.77-7.82(m,1H),7.44-7.51(m,2H),4.42-4.55(m,2H),4.13(d,J=2.40Hz,2H),3.81-3.84(m,2H),3.61-3.84(m,2H),3.52-3.56(m,6H),3.40-3.42(m,1H).
N-(3-氯-4-氟苯基)-6-氨基-7-(2-(2-(丙-2-1-丙氧基)乙氧基)乙氧基)喹唑啉-4-胺(Vc-1:m=3)的合成
以化合物IVc-1(2.50g,4.95mmol)为原料,操作过程同化合物Va-1,得黄色固体(Vc-1)2.01g,收率86%。ESI-MS(m/z):475.1[M+H]+
以化合物Vc-1(2.00g,4.21mmol)和化合物VIa-1(1.19g,6.32mmol)为原料,操作过程同化合物VIIa-1,得浅黄色固体(VIc-1)1.37g,收率52%。1H NMR(300MHz,DMSO-d6)δ(ppm):9.83(s,1H),9.65(s,1H),8.90(s,1H),8.54(s,1H),8.14(dd,J=6.84,2.64Hz,1H),7.78-7.83(m,1H),7.44(t,J=9.15Hz,1H),7.34(s,1H),6.76-6.85(m,1H),6.56(d,J=15.39Hz,1H),4.31-4.38(m,2H),4.10-4.15(m,2H),3.85-3.91(m,2H),3.61-3.65(m,2H),3.50-3.58(m,7H),3.38-3.44(m,2H),2.49-2.51(m,2H),1.61-1.78(m,4H),1.35-1.58(m,2H).
(2S,4R)-1-((S)-2-(8-(4-((2-(2-(2-((4-((3-氯-4-氟苯基)氨基)-6-((E)-4-(哌啶-1-基)-2-烯酰胺基)喹唑啉-7-基)氧基)乙氧基)乙氧基)乙氧基)甲基)-1H-1,2,3-三唑-1-基)辛酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Ic-1:m=3,n=7,R1=C(CH3)3,R2=R3=H,R4=CH3,)的合成
以化合物VIc-1(0.19g,0.30mmol)和化合物Xa-2(0.22g,0.36mmol)为原料,操作过程同化合物Ia-1,得黄色固体(Ic-1)0.07g,收率19%。1H NMR(300MHz,DMSO-d6)δ(ppm):9.84(s,1H),9.60(s,1H),8.99(s,1H),8.91(s,1H),8.61(t,J=5.94Hz,1H),8.54(s,1H),8.14(dd,J=6.93,2.61Hz,1H),8.06(s,1H),7.79-7.84(m,2H),7.36-7.47(m,5H),7.27(s,1H),6.79-6.84(m,1H),6.52-6.57(m,1H),4.18-4.56(m,11H),3.87-3.90(m,2H),3.62-3.66(m,4H),3.53-3.55(m,6H),3.20-3.22(m,2H),2.49-2.50(m,4H),2.44(s,3H),2.21-2.26(m,1H),2.00-2.10(m,2H),1.85-1.93(m,1H),1.71-1.81(m,2H),1.39-1.48(m,8H),1.15-1.22(m,6H),0.92(s,9H).
实施例12:
(2S,4R)-1-((S)-2-(叔丁基)-14-(4-((2-(2-(2-((4-((3-氯-4-氟苯基)氨基)-6-((E)-4-(哌啶-1-基)丁-2-烯酰胺基)喹唑啉-7-基)氧基)乙氧基)乙氧基)乙氧基)甲基)-1H-1,2,3-三唑-1-基)-4-氧代-6,9,12-三氧杂-3-氮杂十四烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(Id-1:m=3,n=3,R1=C(CH3)3,R2=R3=H,R4=CH3,)的合成
以化合物VIc-1(0.19g,0.30mmol)和化合物VIb-2(0.23g,0.66mmol)为原料,操作过程同化合物Ia-1,得黄色固体(Id-1)0.09g,收率24%。1H NMR(300MHz,DMSO-d6)δ(ppm):9.83(s,1H),9.60(s,1H),8.98(s,1H),8.91(s,1H),8.63(t,J=5.94Hz,1H),8.54(s,1H),8.14(dd,J=6.93,2.61Hz,1H),8.03(s,1H),7.81(s,1H),7.36-7.47(m,7H),6.79-6.84(m,1H),6.52-6.57(m,1H),4.23-4.59(m,11H),3.95-3.99(m,2H),3.86-3.89(m,2H),3.76-3.79(m,2H),3.60-3.78(m,4H),3.50-3.54(m,14H),3.20-3.22(m,2H),2.49-2.50(m,4H),2.44(s,3H),2.05-2.08(m,1H),1.91-1.95(m,1H),1.39-1.61(m,6H),0.94(s,9H).
实施例13:
本发明部分化合物的药理实验及结果如下:
1.激酶抑制活性测定
(1)实验方法:通过“Mobility shift assay”法测定化合物对野生型EGFR的激酶抑制活性。将化合物、阳性药、EGFR酶(Carna)、Kinase substrat22(GL)和ATP(Sigma)在激酶缓冲液稀释至预期浓度。将384板1000rpm离心后室温孵育20分钟。孵育完毕,加入终止检测液,再次离心后,用Caliper EZ Reader记录转化率。
(2)实验结果:如表1所示,实施例化合物对EGFR的抑制活性均在纳摩尔级别,其中部分化合物的IC50与母体小分子达克替尼相当。表明本专利实施例化合物保留了较强的EGFR激酶抑制活性。
表1.实施例化合物对EGFR的激酶抑制活性
备注:A:0.2~2.0nM;B:2.0~20.0nM.
2.肿瘤细胞增殖抑制活性测定
(1)肿瘤细胞来源及培养:HCC-827细胞购于中科院干细胞库。将HCC-827细胞系在含有10%胎牛血清(FBS),1%丙酮酸钠,1%谷氨酰胺和1%青霉素链霉素的RPMI-1640中培养。将A549细胞系在含有10%胎牛血清(FBS)和1%青霉素-链霉素的DMEM中培养。所有细胞均在37℃含5%CO2的潮湿气氛中培养。
(2)抗增殖活性测定:通过MTT测定法测定化合物对肿瘤细胞的抗增殖活性。将细胞(3000-8000/孔)接种在96孔板(100μL培养基/孔)中,孵育24小时后用一系列浓度的化合物处理细胞,再孵育72小时,向每个孔中加入10μL的MTT溶液(5mg/mL),并孵育4h。小心除去每个孔中的上清液,并加入150μLDMSO。通过酶标仪在490nm或570nm波长下确定每个孔的光密度。
(3)实验结果:如表2所示,本发明实施例化合物对EGFR突变型的非小细胞肺癌细胞系HCC-827具有显著的增殖抑制活性。
表2.实施例化合物对HCC-827细胞的抗增殖活性
备注:A:0.01~0.1μM;B:0.1~1μM;
3.蛋白降解活性测定(Western-Blot,WB实验)
(1)实验方法:将细胞(0.5~1×106/孔)接种在6孔板中,并孵育24小时。在指定的时间内用不同浓度的化合物处理细胞后,再用含有蛋白酶和磷酸酶抑制剂的裂解缓冲液(Beyotime)裂解细胞。将悬浮液以12000rpm离心20分钟后除去不溶物。通过8%SDS-PAGE分离蛋白质,并转移至PVDF膜(Millpore)。与一抗和二抗(碧云天)孵育后,将膜用成像系统(BIO-RAD)进行成像。Anti-EGFR购自Cell Signaling Technology。
(2)实验结果:
i:如图1所示,从WB实验中可以观察到,在HCC-827细胞系中,实施例化合物Ia-4,Ia-5,Ia-6,Ia-7,Ia-8,Ib-1和Ic-1在100nM浓度下具有显著的EGFR降解作用,而母体小分子达克替尼和空白对照组(DMSO组)均没有显示出EGFR蛋白降解活性。
ii:如图2所示,实施例化合物Ia-4和Ia-5均能以浓度依赖的方式诱导HCC-827细胞中的EGFR蛋白降解,DC50分别为3.57nM和7.95nM,Dmax(最大降解率)分别为98%和91%。
iii:如图3所示,实施例化合物Ia-4和Ia-5均以时间依赖的方式诱导HCC-827细胞中的EGFR蛋白降解,给药后36小时达到最大降解,且降解活性能持续72小时。
4.体内药效测定(异种移植瘤模型)
(1)实验方法:雄性BALB/c裸鼠(6-8周龄,杭州医学院)饲养在SPF级别设施中。每只裸鼠皮下接种悬浮于0.2mL PBS中的HCC-827细胞(5×106)。当肿瘤体积生长至150mm3时,随机分组。化合物Ia-5(30mg/kg),化合物Ia-5(15mg/kg)和溶媒通过腹腔注射给药,每两天给药一次,共计给药21天。每隔3天测量肿瘤体积及小鼠体重。用游标卡尺测定并计算肿瘤体积(肿瘤体积=a×b2/2),其中a和b分别代表游标卡尺测量的最长和最短直径。
(2)实验结果:
如表3和图4所示,实施例化合物Ia-5能够剂量依赖性地抑制肿瘤生长,并且高剂量组(30mg/kg)的抗肿瘤效果最优,抑瘤率达到90%。
综上所述,本发明实施例化合物具有显著的EGFR降解作用、细胞增殖抑制作用以及体内抗肿瘤作用,表明本发明的实施例化合物具有作为抗肿瘤药物治疗肿瘤的潜力。
表3.化合物Ia-5对人非小细胞肺癌HCC-827细胞裸小鼠移植瘤体积的影响
Claims (10)
4.根据权利要求1~3任一所述的化合物或其药学上可接受的盐,其特征在于,所述药学上可接受的盐为权利要求1的化合物与下列酸形成的酸加成盐:氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸。
8.一种药物组合物,其特征在于,包含权利要求1~3中任一项的化合物或其药学上可接受的盐及药学上可接受的载体。
9.权利要求1~3中任一项的化合物或其药学上可接受的盐在制备EGFR蛋白降解剂药物中的应用。
10.根据权利要求9所述的应用,所述的EGFR蛋白降解剂是治疗肿瘤的药物。
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