CN117430565A - 一种hdac8抑制剂及其制备方法和应用 - Google Patents
一种hdac8抑制剂及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种HDAC8抑制剂及其制备方法和应用。该HDAC8抑制剂为二酮哌嗪类衍生物,可用于治疗HDAC8活性相关的疾病或病症,可用于制备治疗、预防肿瘤和/或炎症的抗肿瘤/增强肿瘤免疫和/或抗炎药物。
Description
技术领域
本发明涉及医药技术领域,具体涉及一种可作为HDAC8抑制剂的二酮哌嗪类衍生物及其制备方法和应用。
背景技术
组蛋白去乙酰化酶(HDACs)催化从组蛋白和非组蛋白赖氨酸残基中去除乙酰基。HDACs在表观遗传学和肿瘤生物学中已经确立了角色,这些酶的新细胞角色正以惊人的速度被揭示。
尽管在临床前模型中取得了初步进展,但大多数已知的组蛋白去乙酰化酶抑制剂(HDACis)作为单一制剂,未能在几乎所有类型的实体肿瘤中显示出临床疗效。因此,HDACis在实体肿瘤中的疗效仍不确定。
HDACis不仅可以靶向肿瘤细胞本身,还可以靶向肿瘤微环境和免疫环境,使HDAC抑制剂成为根除免疫逃逸的癌症的一种有前景的策略。目前,大多数处于临床研究阶段的HDACis都是非选择性的,这些非选择性的HDACis会导致比较严重的副作用最常见的有血小板减少、嗜中性白血球减少症、贫血、疲乏和腹泻等。因此,开发具有选择性的HDAC抑制剂已经成为了重要的科学问题,但由于HDAC家族成员激酶结构域的序列和结构相似性,因此,对各个亚型进行选择性地精准调控是一个重要挑战。
HDAC8在多种癌症中高表达,如结肠癌、乳腺癌、肺癌和成神经细胞瘤。因此,HDAC8被确定为一个潜在的癌症治疗靶点,同时也被认为是一个适合的癌细胞生物标志物,在侵袭性结肠癌、肺癌和胰腺癌、急性淋巴细胞白血病、急性髓系白血病和儿童神经母细胞瘤中上调。
HDAC8影响基因组完整性,是多发性骨髓瘤的新型治疗靶点。组蛋白去乙酰化酶抑制剂(HDACi),如OJI-1,正在成为与当前抗骨髓瘤药物联合使用的一种有前途的治疗策略。
有研究表明,HDAC8是血液系统恶性肿瘤的治疗靶点,急性骨髓细胞白血病(AML)中,AML细胞系经过PCI-34051(一种具有选择性的HDAC8抑制剂)治疗后,HDAC8的抑制会引起细胞毒性作用,细胞周期停滞,随后在THP-1细胞中凋亡,而在缺乏p53的HL60细胞中则具有细胞抑制作用。
在肿瘤免疫中,有研究表明,非选择性HDAC抑制剂可以通过减少自然杀伤细胞和树突状细胞的激活和细胞因子的产生,在患者中显示出免疫抑制作用,且这种非选择性HDAC抑制剂还能够增强调节性T(Treg)细胞和骨髓来源的抑制性细胞(MDSCs)的产生和免疫抑制功能,从而促进肿瘤生长。
HDAC8是I类HDAC家族成员之一,由于其在多种人类癌症中异常表达,已引发癌症研究人员的关注。先前已有文献报道,在肝细胞癌中,HDAC8过表达介导的表观遗传修饰会激活Wnt/β-catenin信号通路,这可以促进免疫逃逸和对免疫检查点抑制剂的耐药性。
发明内容
第一方面,本发明提供了一种HDAC8抑制剂,为具有如下式I所示化学结构的化合物和/或其可药用的盐:
式I中,R1为H、C1~C6烷基或2-丙炔基;
和/或,具有如下式II所示化学结构的化合物和/或其可药用的盐:
式II中,R1为H、C1~C6烷基或2-丙炔基,R2为C1~C12亚烷基、苯基、苄基;
和/或,具有如下式III所示化学结构的化合物和/或其可药用的盐:
式III中,R1为H、C1~C6烷基或2-丙炔基,R3为O或亚氨基,R4为空或苯基;
和/或,具有如下式IV所示化学结构的化合物和/或其可药用的盐:
式IV中,R1为H、C1~C6烷基或2-丙炔基,M为2或3;
和/或,具有如下式V所示化学结构的化合物和/或其可药用的盐:
式V中,R1为H、C1~C6烷基或2-丙炔基,R5为取代或未取代的苯基、噻吩基、呋喃基、萘基或联苯基,其中所述苯基上的取代基为C1~C6烷基、C1~C6烷氧基、卤素、卤素取代的C1~C6烷基或二甲氨基。
所述的HDAC8抑制剂具体可选自以下化合物或其可药用的盐中的至少一种:
第二方面,本发明提供了第一方面所述的HDAC8抑制剂在制备用于抑制HDAC8的药物中的应用。
第三方面,本发明提供了第一方面所述的HDAC8抑制剂在制备用于治疗和/或预防与HDAC8异常活性相关的疾病的药物中的应用。
所述的疾病可为炎症和/或癌症。
所述癌症可为乳腺癌、子宫内膜癌、卵巢癌、阴道癌、输卵管癌、宫颈癌、肾癌、膀胱癌、尿路上皮癌、尿道癌、前列腺癌、睾丸癌、结直肠癌、肉瘤、骨癌、多发性骨髓瘤、白血病、粘液瘤、横纹肌瘤、平滑肌瘤、纤维瘤、脂肪瘤、畸胎瘤、咽喉癌、鼻咽癌、口腔癌、肺癌、肺泡癌、淋巴瘤、间皮瘤、小肠癌、胃癌、食道癌、胰腺癌、肝癌、胆管癌、神经纤维瘤、神经胶质瘤、神经母细胞瘤、成神经细胞瘤、黑色素瘤、皮肤癌、基底细胞癌、鳞状细胞癌、甲状腺癌、头颈癌、唾液腺癌、胃肠道间质瘤。
所述炎症可为肠炎、银屑病、皮炎、脑炎、角膜炎、结膜炎、鼻炎、中耳炎、牙龈炎、咽炎、扁桃体炎、肺炎、肝炎、痢疾、前列腺炎、子宫内膜炎、宫颈炎、盆腔炎、甲沟炎、心肌炎。
第四方面,本发明提供了一种药物组合物,包括药学上可接受的载体、稀释剂、赋形剂中的一种或多种,以及第一方面所述的HDAC8抑制剂。
第五方面,本发明提供了第一方面所述的HDAC8抑制剂的制备方法。
所述HDAC8抑制剂为具有如式I所示化学结构的化合物,其合成路线A包括:
合成路线A中,X为卤素原子,化合物a与化合物b、可选择性加入的化合物c(当不加入化合物c时后续产物中R1为H)在Cs2CO3的N,N-二甲基甲酰胺(DMF)溶液中反应得到化合物d,然后在乙酸肼(CH3COOH·NH2NH2)的作用下,化合物d在三乙胺(Et3N)的甲醇(CH3OH)溶液中脱去乙酰基(Ac)保护基,得到化合物e,接着在三氟乙酸(TFA)作用下,化合物e在二氯甲烷(DCM)中脱去叔丁基保护基,得到化合物f,化合物f与化合物g在N,N-二异丙基乙胺(DIPEA)中通过多肽缩合试剂HATU(2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯)发生酰胺化反应得到化合物h,化合物h与一水合对甲苯磺酸(pTsOH·H2O)在甲醇(MeOH)中反应,得到具有如式I所示化学结构的化合物;或者,
所述HDAC8抑制剂为具有如式II所示化学结构的化合物,其合成路线B包括:
合成路线B中,化合物f与化合物i在N,N-二异丙基乙胺中通过多肽缩合试剂HATU发生酰胺化反应得到化合物j,然后在三氟乙酸作用下,化合物j在二氯甲烷中脱去叔丁基保护基,得到化合物k,化合物k与化合物g在N,N-二异丙基乙胺中通过多肽缩合试剂HATU发生酰胺化反应得到化合物m,化合物m与一水合对甲苯磺酸在甲醇中反应,得到具有如式II所示化学结构的化合物;或者,
所述HDAC8抑制剂为具有如式III所示化学结构的化合物,其合成路线为C1或C2,其中合成路线C1包括:
合成路线C1中,X为卤素原子,对羟基苯甲醛与化合物n在25-80℃下于K2CO3的N,N-二甲基甲酰胺溶液中反应得到化合物o,化合物o与化合物a、可选择性加入的化合物c在Cs2CO3的N,N-二甲基甲酰胺溶液中反应得到化合物p,然后在乙酸肼的作用下,化合物p在三乙胺的甲醇溶液中脱去乙酰基保护基,得到化合物q,接着在三氟乙酸作用下,化合物q在二氯甲烷中脱去叔丁基保护基,得到化合物r,化合物r与化合物g在N,N-二异丙基乙胺中通过多肽缩合试剂HATU发生酰胺化反应得到化合物s,化合物s与一水合对甲苯磺酸在甲醇中反应,得到具有如式III1所示化学结构的化合物;
合成路线C2包括:
合成路线C2中,X为卤素原子,化合物a与化合物t、可选择性加入的化合物c在Cs2CO3的N,N-二甲基甲酰胺溶液中反应得到化合物u,然后在乙酸肼的作用下,化合物u在三乙胺的甲醇溶液中脱去乙酰基保护基,得到化合物v,接着在三氟乙酸作用下,化合物v在二氯甲烷中脱去叔丁氧羰基保护基,得到化合物w,化合物w与化合物b在氰基硼氢化钠作用下于乙酸/甲醇混合体系中发生亚胺还原反应,得到化合物x,接着在三氟乙酸作用下,化合物x在二氯甲烷中脱去叔丁基保护基,得到化合物y,化合物y与化合物g在N,N-二异丙基乙胺中通过多肽缩合试剂HATU发生酰胺化反应得到化合物z,化合物z与一水合对甲苯磺酸在甲醇中反应,得到具有如式III2所示化学结构的化合物;或者,
所述HDAC8抑制剂为具有如式IV所示化学结构的化合物,其合成路线D包括:
合成路线D中,化合物f与化合物a1在N,N-二异丙基乙胺中通过多肽缩合试剂HATU发生酰胺化反应得到化合物a2,接着在三氟乙酸作用下,化合物a2在二氯甲烷中脱去叔丁氧羰基(Boc)保护基,得到化合物a3,化合物a3与化合物a4在N,N-二异丙基乙胺中通过多肽缩合试剂HATU发生酰胺化反应得到化合物a5,然后在三氟乙酸作用下,化合物a5在二氯甲烷中脱去叔丁基保护基,得到化合物a6,化合物a6与化合物g在N,N-二异丙基乙胺中通过多肽缩合试剂HATU发生酰胺化反应得到化合物a7,化合物a7与一水合对甲苯磺酸在甲醇中反应,得到具有如式IV所示化学结构的化合物;或者,
所述HDAC8抑制剂为具有如式V所示化学结构的化合物,其合成路线E包括:
合成路线E中,X为卤素原子,化合物b1与化合物b2在PdCl2和K2CO3的2-甲基咪唑/N,N-二甲基甲酰胺混合体系中反应,得到化合物b3,化合物b3与化合物a、可选择性加入的化合物c在Cs2CO3的N,N-二甲基甲酰胺溶液中反应得到化合物b4,然后在乙酸肼的作用下,化合物b4在三乙胺的甲醇溶液中脱去乙酰基保护基,得到化合物b5,接着在三氟乙酸作用下,化合物b5在二氯甲烷中脱去叔丁基保护基,得到化合物b6,化合物b6与化合物g在N,N-二异丙基乙胺中通过多肽缩合试剂HATU发生酰胺化反应得到化合物b7,化合物b7与一水合对甲苯磺酸在甲醇中反应,得到具有如式V所示化学结构的化合物。
本发明与现有技术相比,有益效果有:本发明的HDAC8抑制剂具有较强的HDAC8抑制活性,并且该类化合物具有反应原料易得,容易制备等优点,在制备抗肿瘤或抗炎药物领域,可以用作抗肿瘤或抗炎的治疗剂。
具体实施方式
下面结合具体实施例,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。下述实施例中所述实验方法,如无特殊说明,均为常规方法;所述试剂和生物材料,如无特殊说明,均为市售。
实施例1
合成路线如下:
步骤1:(Z)-4-((4-乙酰基-3,6-二氧-1-(丙炔)哌嗪-2-亚烷基)甲基)苯甲酸叔丁酯的合成
准确称取198.18mg(1.0mmol)二乙酰二酮哌嗪、515.2mg(2.5mmol)4-醛基苯甲酸叔丁酯溶解于10mL DMF中,加入814.6mg(2.5mmol)碳酸铯,将反应瓶置换氮气3次以后,再向反应混合液中加入295mg(2.5mmol)溴丙炔,在N2保护下,于室温下搅拌5h。反应结束后加入100mL的水稀释,然后用二氯甲烷萃取3次,收集合并有机相并用饱和食盐水洗涤3次,经无水硫酸钠干燥,过滤旋干后得到粗产物。粗产物通过硅胶柱层析进行分离得到(Z)-4-((4-乙酰基-3,6-二氧-1-(丙炔)哌嗪-2-亚烷基)甲基)苯甲酸叔丁酯(收率48.0%)。
结构确证数据如下:
1H NMR(600MHz,CDCl3-d1)δ:8.03(d,J=8.4,2H),7.47(s,1H),7.41(d,J=7.8,2H),4.58(s,2H),4.27(d,J=2.6,2H),2.66(s,3H),2.15(t,J=2.6,1H),1.62(s,3H).ESI-MS m/z:383.1602[M+H]+。
步骤2:(Z)-4-((3,6-二氧-1-(丙炔)哌嗪-2-亚烷基)甲基)苯甲酸叔丁酯的合成
准确称取25.0mg(0.077mmol)(Z)-4-((4-乙酰基-3,6-二氧-1-(丙炔)哌嗪-2-亚烷基)甲基)苯甲酸叔丁酯溶解于2mL甲醇中,称取21.2mg(0.23mmol)乙酸肼和23.3mg(0.23mmol)三乙胺,常温下搅拌5h,反应结束后,减压浓缩得到的粗产物经硅胶柱层析进行分离得到(Z)4-((3,6-二氧-1-(丙炔)哌嗪-2-亚烷基)甲基)苯甲酸叔丁酯(收率84.5%)。
结构确证数据如下:
1H NMR(600MHz,CDCl3-d1)δ:8.01(d,J=8.4,2H),7.39(d,J=7.8,2H),7.38(s,1H),4.27(d,J=2.6,2H),4.18(s,2H),2.13(t,J=2.6,1H),1.61(s,3H).ESI-MS m/z:341.1496[M+H]+。
步骤3:(Z)-4-((3,6-二氧-1-(丙炔)哌嗪-2-亚烷基)甲基)苯甲酸的合成
准确称取137.9mg(0.41mmol)(Z)4-((3,6-二氧-1-(丙炔)哌嗪-2-亚烷基)甲基)苯甲酸叔丁酯溶解于3mL二氯甲烷(CH2Cl2)中,加入等体积三氟乙酸(TFA),常温下搅拌3h,减压浓缩得到(Z)4-((3,6-二氧-1-(丙炔)哌嗪-2-亚烷基)甲基)苯甲酸(收率为100%)。
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:8.02(d,J=8.4,2H),7.60(d,J=7.8,2H),6.84(s,1H),4.73(d,J=2.3,2H),3.84(s,2H),2.66(t,J=2.4,1H).ESI-MS m/z:285.0870[M+H]+。
步骤4:(Z)-4-((3-6-二氧-1-(丙炔)哌嗪-2-亚烷基)甲基)-N-苯甲酰胺((四氢-2H-吡喃)-2-氧)的合成
准确称取30.0mg(0.078mmol)(Z)4-((3,6-二氧-1-(丙炔)哌嗪-2-亚烷基)甲基)苯甲酸溶解于2mL DMF中,称取60.6mg(0.16mmol)2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、54.6mg(0.42mmol)N,N-二异丙基乙胺(DIPEA),常温下搅拌6h,减压浓缩后得到的粗产物采用硅胶柱层析进行分离得到(Z)-4-((3-6-二氧-1-(丙炔)哌嗪-2-亚烷基)甲基)-N-苯甲酰胺((四氢-2H-吡喃)-2-氧)(收率52.1%)。
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:7.96(d,J=8.4,2H),7.61(d,J=7.8,2H),6.76(s,1H),4.99(t,J=6.7,1H),4.69(d,J=2.3,2H),3.75(m,2H),2.66(t,J=2.4,1H),1.80(m,2H),1.61-1.65(m,4H).ESI-MS m/z:406.1374[M+Na]+。
步骤5:化合物1的合成
准确称取30.0mg(0.078mmol)(Z)-4-((3-6-二氧-1-(丙炔)哌嗪-2-亚烷基)甲基)-N-苯甲酰胺((四氢-2H-吡喃)-2-氧)溶解于2mL甲醇中,加入3.0mg(0.016mmol)一水合对甲苯磺酸(pTsOH·H2O),常温下反应过夜,反应结束后减压浓缩所得的粗产物经HPLC高压液相制备(20-100%甲醇+0.1%三氟乙酸/水+0.1%三氟乙酸40min)得到化合物1(收率为81.6%)。
化合物1结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:11.29(s,1H),9.10(s,1H),8.47(s,1H),7.77(d,J=8.4,2H),7.48(d,J=7.8,2H),7.11(s,1H),4.13(d,J=2.1,1H),4.02(d,J=2.1,2H),3.12(t,J=2.7,2H).13C NMR(151MHz,DMSO-d6)δ:165.56,163.57,163.03,136.16,132.45,130.79,129.33,126.97,119.57,77.99,74.71,44.47,33.11.ESI-MS m/z:300.0972[M+H]+。
实施例2
参考实施例1,步骤1中用碘甲烷替代溴丙炔,得到化合物2。
化合物2:1H NMR(600MHz,DMSO-d6):δ11.27(s,1H),10.09(s,1H),9.05(s,1H),8.36(s,1H),7.77(d,J=8.5Hz,2H),7.55(d,J=8.0Hz,2H),6.69(s,1H),4.01(d,J=2.1Hz,2H).13C NMR(151MHz,DMSO-d6)δ164.7,159.7,136.3,131.5,129.1,127.0,112.8,48.6,44.8.ESI-MS m/z:262.0813[M+H]+。
实施例3~实施例10
合成路线如下:
先参考实施例1合成化合物f,然后参考实施例1的对应反应条件通过更换相应底物完成各反应步骤,得到相应化合物。
化合物3:1H NMR(600MHz,DMSO-d6):δ10.33(s,1H),8.49(t,J=5.6Hz,1H),8.43(s,1H),7.85(d,J=8.0Hz,2H),7.42(d,J=8.0Hz,2H),7.00(s,1H),4.00(d,J=2.1Hz,2H),3.96(s,2H),3.24(q,J=7.1Hz,2H),2.71(s,3H),1.94(t,J=7.3Hz,2H),1.46-1.51(m,4H),1.24-1.30(m,4H).13C NMR(151MHz,CD3OD-d4)δ169.1,165.7,165.6,162.5,136.6,133.9,133.5,129.3,127.0,117.2,55.0,48.6,44.6,34.7,32.2,29.0,28.3,26.2,25.1.ESI-MS m/z:403.1976[M+H]+。
化合物4:1H NMR(600MHz,DMSO-d6):δ11.14(s,1H),10.51(s,1H),8.97(s,1H),8.50(s,1H),7.99(d,J=8.9Hz,2H),7.85(d,J=8.9Hz,2H),7.75(d,J=8.4Hz,2H),7.58(d,J=8.4Hz,2H),7.17(s,1H),4.18(d,J=2.1Hz,2H),4.05(d,J=1.8Hz,2H),3.17(d,J=5.1Hz,2H),3.16(d,J=2.4Hz,2H).13C NMR(151MHz,DMSO-d6)δ165.5,165.2,162.9,134.3,131.0,129.6,129.3,127.9,127.6,127.0,119.6,119.4,77.9,74.9,74.8,44.5,33.1.ESI-MS m/z:419.1350[M+H]+。
化合物5:1H NMR(600MHz,DMSO-d6):δ11.14(s,1H),10.49(s,1H),8.46(s,1H),7.98(d,J=8.9Hz,2H),7.86(d,J=8.9Hz,2H),7.75(d,J=8.4Hz,2H),7.52(d,J=8.4Hz,2H),7.50(d,J=8.4Hz,2H),7.04(s,1H),4.03(d,J=1.8Hz,2H),2.75(s,3H).13CNMR(151MHz,DMSO-d6)δ165.7,162.4,137.5,133.8,133.2,129.4,127.6,125.8,119.6,117.5,117.0,54.9,53.6,48.58,44.6,34.8,18.1,16.7.ESI-MS m/z:395.1350[M+H]+。
化合物6:1H NMR(600MHz,DMSO-d6):δ11.17(s,1H),9.17(t,J=6.0Hz,1H),8.99(s,1H),7.92(d,J=7.9Hz,2H),7.71(d,J=8.4Hz,2H),7.50(d,J=8.4Hz,2H),7.39(d,J=7.9Hz,2H),7.13(s,1H),4.51(d,J=6.8Hz,2H),4.14(d,J=1.8Hz,2H),4.03(d,J=2.9Hz,2H),3.12(t,J=2.4Hz,1H).13C NMR(151MHz,DMSO-d6)δ170.3,165.7,165.5,163.0,136.4,129.3,127.4,127.1,126.9,119.5,78.0,74.7,59.7,54.9,44.5,42.4,33.1.ESI-MS m/z:433.1507[M+H]+。
化合物7:1H NMR(600MHz,DMSO-d6):δ11.18(brs,1H),9.16(t,J=6.0Hz,1H),8.99(s,1H),7.92(d,J=8.3Hz,2H),7.71(d,J=8.3Hz,2H),7.45(d,J=8.3Hz,2H),7.38(d,J=8.3Hz,2H),7.01(s,1H),4.51(d,J=5.8Hz,2H),4.14(d,J=1.8Hz,2H),4.01(d,J=2.0Hz,2H),2.72(s,3H).13C NMR(151MHz,DMSO-d6)δ165.8,165.7,162.5,142.9,137.0,133.6,133.3,131.3,129.4,127.1,127.1,126.9,117.1,48.6,44.6,42.4,34.8.ESI-MS m/z:409.1507[M+H]+。
化合物8:1H NMR(600MHz,DMSO-d6):δ11.17(brs,1H),10.10(s,1H),9.14(s,1H),9.00(s,1H),8.37(s,1H),7.92(d,J=6.6Hz,2H),7.71(d,J=6.6Hz,2H),7.58(d,J=6.6Hz,2H),7.38(d,J=6.6Hz,2H),6.71(s,1H),4.53(d,J=3.3Hz,2H),4.01(s,2H).13CNMR(151MHz,DMSO-d6)δ165.23,161.87,160.27,157.58,130.09,129.62,128.55,128.01,127.54,127.47,125.05,117.83,113.38,110.59,45.32,42.93.ESI-MS m/z:395.1350[M+H]+。
化合物9:1H NMR(600MHz,DMSO-d6):δ11.21(s,1H),10.46(s,1H),9.06(s,1H),8.50(s,1H),8.19(td,J=6.2Hz;J=2.8Hz,1H),8.01(d,J=8.5Hz,2H),7.56(d,J=8.5Hz,2H),7.43(m,2H),7.17(s,1H),4.18(d,J=2.2Hz,2H),4.05(d,J=2.2Hz,2H),3.14(t,J=2.4Hz,1H).13C NMR(151MHz,DMSO-d6)δ165.6,165.0,164.2,163.0,139.2,136.8,134.3,133.4,131.0,129.3,128.6,127.8,122.9,121.7,120.0,78.0,74.8,44.5,33.1.ESI-MS m/z:419.1350[M+H]+。
化合物10:1H NMR(600MHz,CD3OD-d4):δ7.91(d,J=7.4Hz,2H),7.76(s,1H),7.64(d,J=7.4Hz,1H),7.55(d,J=7.4Hz,1H),7.44(d,J=7.7Hz,1H),7.28(s,1H),4.63(s,2H),4.25(d,J=2.2Hz,2H),4.10(s,2H),2.55(t,J=2.4Hz,1H).13C NMR(151MHz,CD3OD-d4)δ169.4,168.1,167.3,166.0,140.9,138.3,135.6,133.9,131.9,131.7,130.7,129.9,128.7,127.3,126.9,122.7,45.8,44.3,34.7.ESI-MS m/z:433.1507[M+H]+。
实施例11~实施例23
合成路线如下:
按照上述合成路线,与实施例1相同的反应过程采用相同的反应条件,其它反应过程介绍如下:
1)对羟基苯甲醛与化合物n在25-80℃下于K2CO3的N,N-二甲基甲酰胺溶液中反应得到化合物o。根据不同产物,选择化合物n中的相应R4基团。
2)化合物w与化合物b在氰基硼氢化钠作用下于乙酸/甲醇混合体系中发生亚胺还原反应,得到化合物x。
化合物11:1H NMR(600MHz,DMSO-d6):δ11.17(s,1H),8.17(s,1H),7.70(d,J=8.6Hz,2H),7.41(d,J=8.6Hz,2H),7.07(d,J=8.6Hz,2H),6.80(s,1H),6.59(d,J=8.6Hz,2H),3.96(s,2H),3.89(d,J=2.2Hz,2H),2.79(s,3H).13C NMR(151MHz,DMSO-d6)δ165.89,159.02,157.27,149.13,148.69,135.17,131.03,129.45,128.68,127.05,126.94,120.45,111.76,48.56,44.68,34.00.ESI-MS m/z:381.1558[M+H]+。
化合物12:1H NMR(600MHz,DMSO-d6):δ11.23(s,1H),9.06(t,J=6.0Hz,1H),8.31(s,1H),7.90(d,J=7.9Hz,2H),7.53(d,J=7.9Hz,2H),7.30(d,J=7.9Hz,2H),7.06(d,J=7.9Hz,2H),6.92(s,1H),5.19(s,2H),3.96(d,J=1.8Hz,2H),2.75(s,3H).13C NMR(151MHz,DMSO-d6)δ165.8,164.0,163.2,158.1,140.0,132.3,131.3,131.1,127.5,127.1,126.2,118.5,114.6,68.7,44.7,34.3.ESI-MS m/z:382.1398[M+H]+。
化合物13:1H NMR(600MHz,DMSO-d6):δ10.86(s,1H),8.31(s,1H),7.30(d,J=9.0Hz,2H),6.99(d,J=7.9Hz,2H),6.92(s,1H),4.49(s,2H),3.96(d,J=2.2Hz,2H),2.74(s,3H).13C NMR(151MHz,DMSO-d6)δ165.8,164.1,163.2,157.6,131.4,131.0,126.6,118.4,114.5,65.8,48.6,44.7,34.3.ESI-MS m/z:328.0904[M+Na]+。
实施例14~实施例17
合成路线如下:
先参考实施例1合成化合物f,然后参考实施例1的对应反应条件通过更换相应底物完成各反应步骤,得到相应化合物。
化合物14:1H NMR(600MHz,CD3OD-d4):δ7.90(d,J=8.3Hz,2H),7.86(d,J=8.3Hz,2H),7.82(d,J=8.2Hz,1H),7.50(d,J=8.2Hz,1H),7.27(s,1H),4.63(s,2H),4.23(d,J=2.2Hz,2H),4.10(s,2H),3.64(s,4H),2.55(d,J=2.2Hz,1H).13C NMR(151MHz,CD3OD-d4)δ171.94,169.92,169.74,167.34,166.02,138.53,138.16,136.40,135.81,131.72,130.89,130.64,128.65,128.61,128.33,122.71,78.11,73.98,45.83,40.93,34.68.ESI-MS m/z:490.1722[M+H]+。
化合物15:1H NMR(600MHz,DMSO-d6):δ11.33(s,1H),9.13(d,J=1.8Hz,1H),8.72(t,J=5.2Hz,1H),8.67(t,J=5.2Hz,1H),8.43(t,J=2.0Hz,1H),7.90(dd,J=8.4Hz;J=1.6Hz,2H),7.86(dd,J=8.4Hz;J=1.6Hz,2H),7.82(dd,J=8.4Hz;J=1.6Hz,2H),7.42(d,J=8.4Hz,2H),7.00(s,1H),4.00(d,J=2.0Hz,2H),3.45(t,J=2.5Hz,4H),2.71(s,3H).13CNMR(151MHz,DMSO-d6)δ166.0,165.6,163.5,162.5,136.8,135.0,133.7,133.5,129.3,127.1,126.8,117.2,44.6,34.7.ESI-MS m/z:466.1722[M+H]+。
化合物16:1H NMR(600MHz,CD3OD-d4):δ7.92(d,J=8.4Hz,2H),7.89(d,J=8.4Hz,2H),7.83(d,J=8.4Hz,2H),7.50(d,J=8.4Hz,2H),7.28(s,1H),4.25(d,J=2.0Hz,2H),4.10(s,2H),3.98(s,1H),3.50(t,J=2.0Hz,2H),2.55(t,J=2.0Hz,1H),1.93(q,J=6.0Hz,1H).13C NMR(151MHz,CD3OD-d4)δ169.6,169.4,167.4,166.0,138.5,138.1,136.4,135.9,131.7,130.7,128.6,128.6,128.4,122.7,78.1,74.0,55.1,45.8,38.4,34.7,30.3.ESI-MS m/z:466.1722[M+H]+。
化合物17:1H NMR(600MHz,DMSO-d6):δ11.32(s,1H),9.12(s,1H),8.60(t,J=5.5Hz,1H),8.55(t,J=5.5Hz,1H),8.42(s,1H),7.90(dd,J=8.4Hz;J=1.9Hz,2H),7.86(dd,J=8.4Hz;J=1.9Hz,2H),7.82(dd,J=8.4Hz;J=1.9Hz,2H),7.43(dd,J=8.4Hz;J=1.9Hz,2H),7.00(s,1H),4.00(d,J=2.0Hz,2H),3.44(q,J=6.6Hz,4H),2.72(s,3H),1.79(q,J=6.0Hz,1H).13C NMR(151MHz,DMSO-d6)δ165.7,165.6,165.6,163.5,162.5,136.8,136.7,135.0,133.7,133.5,129.3,127.2,127.0,126.9,117.2,48.6,44.6,37.2,37.1,34.7,29.2.ESI-MS m/z:480.1878[M+H]+。
实施例18~实施例31
合成路线如下:
按照上述合成路线,与实施例1相同的反应过程采用相同的反应条件,其它反应过程介绍如下:化合物b1与化合物b2在PdCl2和K2CO3的2-甲基咪唑/N,N-二甲基甲酰胺混合体系中反应,得到化合物b3。根据不同产物,选择化合物b1中的相应R5基团。
化合物18:1H NMR(600MHz,DMSO-d6):δ10.79(s,1H),8.40(s,1H),7.60(d,J=8.1Hz,1H),7.45(d,J=15.7Hz,1H),7.38(d,J=8.1Hz,2H),6.97(s,1H),6.50(d,J=15.7Hz,1H),4.00(d,J=2.0Hz,2H),3.17(s,1H),2.75(s,3H).13C NMR(151MHz,DMSO-d6)δ165.7,162.7,162.6,137.6,134.9,134.4,133.1,130.0,127.3,119.6,117.6,44.6,34.7.ESI-MS m/z:302.1136[M+H]+。
化合物19:1H NMR(600MHz,DMSO-d6):δ10.76(s,1H),9.06(s,1H),8.44(s,1H),7.44(s,1H),7.42(d,J=15.6Hz,1H),7.40(d,J=3.3Hz,2H),7.22(d,J=8.6Hz,1H),6.97(s,1H),6.48(d,J=15.7Hz,1H),4.02(d,J=2.0Hz,2H),2.60(s,3H),2.28(s,3H).13C NMR(151MHz,DMSO-d6)δ165.3,162.7,162.2,137.8,137.2,134.5,133.6,129.9,128.9,124.6,119.4,116.4,44.6,34.2,19.7.ESI-MS m/z:316.1292[M+H]+。
化合物20:1H NMR(600MHz,DMSO-d6):δ10.80(s,1H),9.07(s,1H),8.40(s,1H),7.64(d,J=15.6Hz,1H),7.20(d,J=8.0Hz,1H),6.93(s,1H),6.41(d,J=15.7Hz,1H),4.00(d,J=2.0Hz,2H),2.75(s,3H),2.38(s,3H).13C NMR(151MHz,DMSO-d6)δ165.6,162.6,136.6,135.0,134.7,133.3,132.9,131.7,127.5,125.7,120.8,117.6,44.6,34.7,19.3.ESI-MS m/z:316.1292[M+H]+。
化合物21:1H NMR(600MHz,DMSO-d6):δ10.78(s,1H),8.41(s,1H),7.64(d,J=15.6Hz,1H),7.53(d,J=8.1Hz,1H),7.05(s,1H),6.97(s,1H),6.94(d,J=8.0Hz,1H),6.55(d,J=15.7Hz,1H),4.11(q,J=6.9Hz,2H),4.01(d,J=2.0Hz,2H),2.77(s,3H),1.40(t,J=6.9Hz,3H).13C NMR(151MHz,DMSO-d6)δ165.65,162.56,156.41,136.35,133.11,127.86,121.91,119.89,117.74,113.46,63.80,48.57,44.63,34.66,14.61.ESI-MS m/z:346.1398[M+H]+。
化合物22:1H NMR(600MHz,DMSO-d6):δ10.75(s,1H),8.41(s,1H),7.65(d,J=15.6Hz,1H),7.54(d,J=8.0Hz,1H),7.08(s,1H),6.98(s,1H),6.95(d,J=8.0Hz,1H),6.53(d,J=15.7Hz,1H),4.01(d,J=2.0Hz,2H),3.87(s,3H),2.78(s,3H).13C NMR(151MHz,DMSO-d6)δ165.7,162.6,157.1,136.4,133.1,132.7,127.6,122.9,122.0,119.9,117.7,112.7,55.7,44.6,34.7.ESI-MS m/z:332.1241[M+H]+。
化合物23:1H NMR(600MHz,DMSO-d6):δ10.82(brs,1H),8.49(s,1H),7.49(d,J=15.6Hz,1H),7.47(s,1H),7.45(d,J=8.0Hz,1H),7.40(t,J=8.0Hz,1H),6.90(s,1H),6.55(d,J=15.7Hz,1H),4.01(d,J=2.0Hz,2H),2.74(s,3H).13C NMR(151MHz,DMSO-d6)δ165.3,161.9,160.5,158.9,134.9,131.6,123.1,121.1,114.2,114.0,109.7,44.6,34.1.ESI-MSm/z:320.1042[M+H]+。
化合物24:1H NMR(600MHz,DMSO-d6):δ10.82(brs,1H),8.55(s,1H),7.97(s,1H),7.90(d,J=8.0,1H),7.56(d,J=15.6Hz,1H),7.53(d,J=8.0Hz,1H),7.05(d,J=1.8Hz,1H),6.63(d,J=15.7Hz,1H),4.04(d,J=2.0Hz,2H),2.60(s,3H).13C NMR(151MHz,DMSO-d6)δ165.3,161.4,136.2,135.1,135.0,133.5,132.2,130.6,124.9,123.0,121.5,112.4,44.6,34.5.ESI-MS m/z:370.1010[M+H]+。
化合物25:1H NMR(600MHz,DMSO-d6):δ10.79(brs,1H),9.01(s,1H),8.34(s,1H),7.63(d,J=16.0Hz,1H),7.48(d,J=1.8Hz,1H),7.35(dd,J=8.0Hz;J=1.8Hz,1H),7.12(d,J=8.0Hz,1H),6.94(s,1H),6.54(d,J=16.0Hz,1H),3.98(d,J=2.0Hz,2H),3.34(brs,2H),2.75(s,3H).13C NMR(151MHz,DMSO-d6)δ165.7,163.0,157.3,133.1,132.0,131.7,129.4,126.1,123.0,120.3,117.9,111.6,55.8,44.7,34.3.ESI-MS m/z:332.1241[M+H]+。
化合物26:1H NMR(600MHz,DMSO-d6):δ10.82(brs,1H),9.00(s,1H),8.34(s,1H),7.63(d,J=16.0Hz,1H),7.47(d,J=1.8Hz,1H),7.32(dd,J=8.0Hz;J=1.8Hz,1H),7.11(d,J=8.0Hz,1H),6.93(s,1H),6.56(d,J=16.0Hz,1H),4.15(q,J=7.0Hz,2H),3.98(d,J=2.0Hz,2H),3.34(brs,2H),2.75(s,3H),1.41(t,J=7.0Hz,3H).13CNMR(151MHz,DMSO-d6)δ165.7,163.1,163.0,156.7,133.4,132.0,131.6,126.0,123.0,120.4,117.9,112.3,63.9,44.7,34.4,14.6.ESI-MS m/z:346.1398[M+H]+。
化合物27:1H NMR(600MHz,DMSO-d6):δ10.80(brs,1H),8.34(s,1H),7.64(d,J=16.0Hz,1H),7.39(d,J=1.8Hz,1H),7.29(dd,J=8.0Hz;J=1.8Hz,1H),7.11(d,J=8.0Hz,1H),6.94(s,1H),6.39(d,J=16.0Hz,1H),4.15(q,J=7.0Hz,2H),3.98(d,J=2.0Hz,2H),2.78(s,3H),2.72(s,3H).13C NMR(151MHz,DMSO-d6)δ165.7,163.0,158.1,131.4,131.2,128.9,127.3,118.8,118.1,118.0,114.6,44.6,44.2,34.4.ESI-MS m/z:345.1558[M+H]+。
化合物28:1H NMR(600MHz,DMSO-d6):δ10.71(brs,1H),9.08(brs,1H),8.42(s,1H),7.59(d,J=16.0Hz,1H),7.38(d,J=3.9Hz,1H),7.17(d,J=3.9Hz,1H),7.01(s,1H),6.23(d,J=16.0Hz,1H),3.96(d,J=2.0Hz,2H),2.97(s,3H).13C NMR(151MHz,DMSO-d6)δ166.0,162.7,162.2,141.76,136.6,132.6,131.5,131.1,130.9,118.7,111.3,48.6,44.6,34.8.ESI-MS m/z:308.0700[M+H]+。
化合物29:1H NMR(600MHz,DMSO-d6):δ10.93(brs,1H),9.06(brs,1H),8.43(s,1H),7.28(d,J=16.0Hz,1H),6.91(d,J=3.9Hz,1H),6.90(d,J=3.9Hz,1H),6.83(s,1H),6.24(d,J=16.0Hz,1H),3.99(d,J=2.0Hz,2H),3.13(s,3H).13C NMR(151MHz,DMSO-d6)δ165.5,162.5,152.4,149.4,130.3,125.1,117.8,117.5,116.4,105.3,48.6,44.5,35.2.ESI-MS m/z:292.0928[M+H]+。
化合物30:1H NMR(600MHz,DMSO-d6):δ10.83(brs,1H),9.09(brs,1H),8.44(s,1H),8.07(s,1H),7.95(dd,J=8.4Hz;J=3.9Hz,2H),7.89(s,1H),7.74(d,J=8.4Hz,1H),7.62(d,J=16.0Hz,1H),7.51(d,J=3.9Hz,1H),7.13(s,1H),6.61(d,J=16.0Hz,1H),4.04(s,2H),3.75(s,3H).13C NMR(151MHz,DMSO-d6)δ166.26,163.27,163.22,138.71,133.76,133.60,133.42,132.97,132.88,129.30,129.14,128.87,128.67,128.29,124.79,120.33,118.55,45.25,35.33.ESI-MS m/z:352.1292[M+H]+。
化合物31:1H NMR(600MHz,DMSO-d6):δ10.78(brs,1H),8.40(s,1H),7.79(d,J=8.4Hz,2H),7.77(d,J=8.4Hz,2H),7.68(d,J=8.4Hz,2H),7.50(d,J=16.0Hz,1H),7.46(d,J=8.0Hz,1H),7.02(s,1H),6.52(d,J=16.0Hz,1H),4.01(d,J=2.0Hz,2H),2.70(s,3H).13C NMR(151MHz,DMSO-d6)δ165.7,162.8,140.1,138.7,134.2,133.4,132.8,130.2,128.1,127.0,126.3,119.2,117.8,44.7,34.7.ESI-MS m/z:378.1449[M+H]+。
HDAC抑制活性评价
(1)设置实验组、对照组和100%组,参见表1。
表1 HDAC8荧光分析法分组
组别 | HDAC8酶稀释液 | 溶剂 | 化合物 | 荧光底物 |
100%组 | 25μL | 5μL | 20μL | |
空白组 | 30μL | 20μL | ||
实验组 | 25μL | 5μL | 20μL |
(2)实验步骤100%组和实验组中,将5μL溶剂或不同浓度的化合物与HDAC8酶稀释液加入黑色96孔板中,在37℃下孵育5min。空白组中,加入30μL溶剂于孔中。而后,向所有孔中加入20μL荧光底物,并在37℃下孵育30-60min。随后每个孔加入50μL胰酶溶液,继续孵育30min后在酶标仪下测定其荧光值。每组平行测定三次。
根据以下公式计算化合物的抑制率,并用Graghpad prism 9计算出化合物的IC50值。
HDAC1、HDAC6的测定方法如HDAC8的测定方法,相关底物如下表2所示。
表2 HDAC不同亚型荧光分析法的底物
HDAC亚型 | HDAC底物 |
HDAC1 | Ac-Leu-Gly-Lys(Ac)-AMC |
HDAC6 | Ac-Leu-Gly-Lys(Ac)-AMC |
HDAC8 | Ac-Leu-Gly-Lys(tfa)-AMC |
(3)实验结果参见表3。
表3化合物1~38对HDAC1、6、8的抑制效果
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注:阳性药(TSA)为Trichostatin A(Synonyms:曲古抑菌素A)。
通过HDAC抑制活性的筛选结果表明,本发明大多数化合物对HDAC1、6、8都具有很好的抑制活性,其中筛选出有三个化合物对HDAC8的IC50达到了1nM以下,且选择性高,如表4所示。
表4二酮哌嗪类衍生物对HDAC1、6、8的选择性
由表4可得,有三个化合物对HDAC8的IC50达到了1nM以下,且选择性高,对HDAC1、HDAC6的选择性都在100-11000倍之间。该类药物为发现新的具有高选择性的HDAC8抑制剂提供了理论依据,且为抗肿瘤/增强肿瘤免疫/抗炎药物的开发提供了先导化合物。
此外应理解,在阅读了本发明的上述描述内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (9)
1.一种HDAC8抑制剂,其特征在于,为具有如下式I所示化学结构的化合物和/或其可药用的盐:
式I中,R1为H、C1~C6烷基或2-丙炔基;
和/或,具有如下式II所示化学结构的化合物和/或其可药用的盐:
式II中,R1为H、C1~C6烷基或2-丙炔基,R2为C1~C12亚烷基、苯基、苄基;
和/或,具有如下式III所示化学结构的化合物和/或其可药用的盐:
式III中,R1为H、C1~C6烷基或2-丙炔基,R3为O或亚氨基,R4为空或苯基;
和/或,具有如下式IV所示化学结构的化合物和/或其可药用的盐:
式IV中,R1为H、C1~C6烷基或2-丙炔基,M为2或3;
和/或,具有如下式V所示化学结构的化合物和/或其可药用的盐:
式V中,R1为H、C1~C6烷基或2-丙炔基,R5为取代或未取代的苯基、噻吩基、呋喃基、萘基或联苯基,其中所述苯基上的取代基为C1~C6烷基、C1~C6烷氧基、卤素、卤素取代的C1~C6烷基或二甲氨基。
2.根据权利要求1所述的HDAC8抑制剂,其特征在于,选自以下化合物或其可药用的盐中的至少一种:
3.根据权利要求1或2所述的HDAC8抑制剂在制备用于抑制HDAC8的药物中的应用。
4.根据权利要求1或2所述的HDAC8抑制剂在制备用于治疗和/或预防与HDAC8异常活性相关的疾病的药物中的应用。
5.根据权利要求4所述的应用,其特征在于,所述的疾病为炎症和/或癌症。
6.根据权利要求5所述的应用,其特征在于,所述癌症为乳腺癌、子宫内膜癌、卵巢癌、阴道癌、输卵管癌、宫颈癌、肾癌、膀胱癌、尿路上皮癌、尿道癌、前列腺癌、睾丸癌、结直肠癌、肉瘤、骨癌、多发性骨髓瘤、白血病、粘液瘤、横纹肌瘤、平滑肌瘤、纤维瘤、脂肪瘤、畸胎瘤、咽喉癌、鼻咽癌、口腔癌、肺癌、肺泡癌、淋巴瘤、间皮瘤、小肠癌、胃癌、食道癌、胰腺癌、肝癌、胆管癌、神经纤维瘤、神经胶质瘤、神经母细胞瘤、成神经细胞瘤、黑色素瘤、皮肤癌、基底细胞癌、鳞状细胞癌、甲状腺癌、头颈癌、唾液腺癌、胃肠道间质瘤。
7.根据权利要求5所述的应用,其特征在于,所述炎症为肠炎、银屑病、皮炎、脑炎、角膜炎、结膜炎、鼻炎、中耳炎、牙龈炎、咽炎、扁桃体炎、肺炎、肝炎、痢疾、前列腺炎、子宫内膜炎、宫颈炎、盆腔炎、甲沟炎、心肌炎。
8.一种药物组合物,其特征在于,包括药学上可接受的载体、稀释剂、赋形剂中的一种或多种,以及权利要求1或2所述的HDAC8抑制剂。
9.根据权利要求1所述的HDAC8抑制剂的制备方法,其特征在于,所述HDAC8抑制剂为具有如式I所示化学结构的化合物,其合成路线A包括:
合成路线A中,X为卤素原子,化合物a与化合物b、可选择性加入的化合物c在Cs2CO3的N,N-二甲基甲酰胺溶液中反应得到化合物d,然后在乙酸肼的作用下,化合物d在三乙胺的甲醇溶液中脱去乙酰基保护基,得到化合物e,接着在三氟乙酸作用下,化合物e在二氯甲烷中脱去叔丁基保护基,得到化合物f,化合物f与化合物g在N,N-二异丙基乙胺中通过多肽缩合试剂HATU发生酰胺化反应得到化合物h,化合物h与一水合对甲苯磺酸在甲醇中反应,得到具有如式I所示化学结构的化合物;或者,
所述HDAC8抑制剂为具有如式II所示化学结构的化合物,其合成路线B包括:
合成路线B中,化合物f与化合物i在N,N-二异丙基乙胺中通过多肽缩合试剂HATU发生酰胺化反应得到化合物j,然后在三氟乙酸作用下,化合物j在二氯甲烷中脱去叔丁基保护基,得到化合物k,化合物k与化合物g在N,N-二异丙基乙胺中通过多肽缩合试剂HATU发生酰胺化反应得到化合物m,化合物m与一水合对甲苯磺酸在甲醇中反应,得到具有如式II所示化学结构的化合物;或者,
所述HDAC8抑制剂为具有如式III所示化学结构的化合物,其合成路线为C1或C2,其中合成路线C1包括:
合成路线C1中,X为卤素原子,对羟基苯甲醛与化合物n在25-80℃下于K2CO3的N,N-二甲基甲酰胺溶液中反应得到化合物o,化合物o与化合物a、可选择性加入的化合物c在Cs2CO3的N,N-二甲基甲酰胺溶液中反应得到化合物p,然后在乙酸肼的作用下,化合物p在三乙胺的甲醇溶液中脱去乙酰基保护基,得到化合物q,接着在三氟乙酸作用下,化合物q在二氯甲烷中脱去叔丁基保护基,得到化合物r,化合物r与化合物g在N,N-二异丙基乙胺中通过多肽缩合试剂HATU发生酰胺化反应得到化合物s,化合物s与一水合对甲苯磺酸在甲醇中反应,得到具有如式III1所示化学结构的化合物;
合成路线C2包括:
合成路线C2中,X为卤素原子,化合物a与化合物t、可选择性加入的化合物c在Cs2CO3的N,N-二甲基甲酰胺溶液中反应得到化合物u,然后在乙酸肼的作用下,化合物u在三乙胺的甲醇溶液中脱去乙酰基保护基,得到化合物v,接着在三氟乙酸作用下,化合物v在二氯甲烷中脱去叔丁氧羰基保护基,得到化合物w,化合物w与化合物b在氰基硼氢化钠作用下于乙酸/甲醇混合体系中发生亚胺还原反应,得到化合物x,接着在三氟乙酸作用下,化合物x在二氯甲烷中脱去叔丁基保护基,得到化合物y,化合物y与化合物g在N,N-二异丙基乙胺中通过多肽缩合试剂HATU发生酰胺化反应得到化合物z,化合物z与一水合对甲苯磺酸在甲醇中反应,得到具有如式III2所示化学结构的化合物;或者,
所述HDAC8抑制剂为具有如式IV所示化学结构的化合物,其合成路线D包括:
合成路线D中,化合物f与化合物a1在N,N-二异丙基乙胺中通过多肽缩合试剂HATU发生酰胺化反应得到化合物a2,接着在三氟乙酸作用下,化合物a2在二氯甲烷中脱去叔丁氧羰基保护基,得到化合物a3,化合物a3与化合物a4在N,N-二异丙基乙胺中通过多肽缩合试剂HATU发生酰胺化反应得到化合物a5,然后在三氟乙酸作用下,化合物a5在二氯甲烷中脱去叔丁基保护基,得到化合物a6,化合物a6与化合物g在N,N-二异丙基乙胺中通过多肽缩合试剂HATU发生酰胺化反应得到化合物a7,化合物a7与一水合对甲苯磺酸在甲醇中反应,得到具有如式IV所示化学结构的化合物;或者,
所述HDAC8抑制剂为具有如式V所示化学结构的化合物,其合成路线E包括:
合成路线E中,X为卤素原子,化合物b1与化合物b2在PdCl2和K2CO3的2-甲基咪唑/N,N-二甲基甲酰胺混合体系中反应,得到化合物b3,化合物b3与化合物a、可选择性加入的化合物c在Cs2CO3的N,N-二甲基甲酰胺溶液中反应得到化合物b4,然后在乙酸肼的作用下,化合物b4在三乙胺的甲醇溶液中脱去乙酰基保护基,得到化合物b5,接着在三氟乙酸作用下,化合物b5在二氯甲烷中脱去叔丁基保护基,得到化合物b6,化合物b6与化合物g在N,N-二异丙基乙胺中通过多肽缩合试剂HATU发生酰胺化反应得到化合物b7,化合物b7与一水合对甲苯磺酸在甲醇中反应,得到具有如式V所示化学结构的化合物。
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