CN115368277A - 一种含异羟肟酸结构的联苯类化合物及其应用 - Google Patents
一种含异羟肟酸结构的联苯类化合物及其应用 Download PDFInfo
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- CN115368277A CN115368277A CN202211121782.5A CN202211121782A CN115368277A CN 115368277 A CN115368277 A CN 115368277A CN 202211121782 A CN202211121782 A CN 202211121782A CN 115368277 A CN115368277 A CN 115368277A
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- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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Abstract
本发明公开了一种含异羟肟酸结构的联苯类化合物及其应用,其结构通式如Ⅰ所示。
Description
技术领域
本发明属于医药技术领域,具体涉及一种含异羟肟酸结构的联苯类化合物及其应用。
背景技术
PD-1(programmed death 1,CD279)是一种I型跨膜蛋白,其主要在活化的T细胞、B细胞、NK细胞、单核细胞和巨噬细胞等免疫细胞上表达。PD-1的配体包括PD-L1(programmedcell death-Ligand 1,CD274)和PD-L2,PD-L1也是一种I型跨膜糖蛋白,属于B7家族成员。PD-L1主要表达于抗原递呈细胞、B细胞、T细胞、上皮细胞、肌细胞、内皮细胞和肿瘤细胞上,并参与肿瘤相关的免疫应答反应。PD-1和PD-L1共同组成PD-1/PD-L1信号通路,抑制细胞因子的生成和细胞增殖,并对T细胞活化和免疫应答调控发挥着重要作用。PD-1和PD-L1相互作用,诱导ITIMs和ITSMs在结构域中被磷酸化,募集磷酸酶SHP-2而使T细胞抗原受体(TCR)信号通路中的几种关键蛋白去磷酸化,抑制下游信号通路,从而抑制细胞因子的生成和T细胞的增殖和分化,最终使T细胞丧失免疫功能。在机体对肿瘤细胞免疫过程中,肿瘤微环境中的T细胞上的PD-1过表达或肿瘤细胞过表达PD-L1,二者相互作用在一定程度上抑制了机体的细胞免疫反应,从而使肿瘤能逃避免疫系统的监视和杀伤。PD-1/PD-L1抑制剂就是通过阻断PD-1/PD-L1信号通路,抑制二者的相互作用,而恢复T细胞的免疫杀伤功能,最后达到杀伤肿瘤的目的。
近年来,国内外已先后有多款抗体类PD-1/PD-L1抑制剂上市,如度伐利尤单抗(durvalumab)、阿替利珠单抗(Atezolizumab)和阿维鲁单抗(Avelumab)等。相比于治疗性抗体,小分子药物由于分子量小、生产工艺简单、成本低、剂型多样、穿透力强以及良好可控的药代动力学性质,近年来已成为一个非常活跃的研究领域。过去几年,已陆续报道了多类PD-L1小分子抑制剂。目前,这些小分子化合物正处于临床前或临床研究的不同阶段,如百时美施贵宝公司的BMS-200和BMS-1166、再极医药的MAX-10181、红日药业的IMMH-010、Gilead公司的GS4224以及Incyte公司的INCB086550。
尽管PD-1/PD-L1抑制剂在肿瘤治疗领域中已经取得了巨大的成功,但临床发现,PD-1/PD-L1抑制剂在不同人群和不同肿瘤中疗效差异巨大。组蛋白去乙酰化酶(histonedeacetylases,HDAC)是一类在基因表达调控、染色体结构修饰上具有重要作用的蛋白酶。组蛋白的去乙酰化使缠绕在组蛋白上的DNA更紧密,导致基因转录因子不容易与这些DNA接触,最终抑制细胞分化、凋亡和肿瘤免疫等有关蛋白的表达,从而引发癌症。沉默或抑制HDAC对细胞周期、细胞生长、染色质异构化、细胞分化、细胞凋亡和血管生成均表现出显著的影响。在过去二十年中,HDAC已被证明是非常有吸引力的癌症治疗靶点。近年来研究发现,HDAC抑制剂(如SAHA、RGFP966、Panobinostat、Entinostat和Mocetinostat等)可以在PD-L1基因启动子区快速增加组蛋白乙酰化和溴结构域蛋白BRD4的募集,激活PD-L1基因的转录,调节肿瘤微环境中肿瘤细胞PD-L1的表达水平。在动物肿瘤模型中,HDAC抑制剂与PD-1/PD-L1抑制剂联合用药,可以加速肿瘤的消退,增强PD-1/PD-L1抑制剂的治疗效果(参考文献DOI:10.1158/2326-6066.CIR-15-0077-T;10.1158/1535-7163.MCT-18-1068;10.1007/s00262-020-02653-1;10.1007/s00262-017-2091-y)。然而,联合用药在临床上会面临着患者依从性差、药代动力学性质复杂以及药物与药物相互作用等潜在问题,导致临床研究的成本和风险增大。多靶点药物是指可以选择性作用于两个或多个分子靶点的单一组分药物。相比联合用药,多靶点药物具有明显的优势:由于是单一组分,在药物代谢上要优于联合用药,克服了各组分之间因相互作用导致的不良反应,用药方便,不存在联合用药的剂量和比例问题,同时具有可预测的药效学和药代动力学性质,能有效地避免联合用药面临的以上潜在问题。基于以上分析,设计一类可同时靶向PD-1/PD-L1信号通路和HDAC的小分子抑制剂显示出重要的研究价值和意义。
发明内容
本发明提供一种含异羟肟酸结构的联苯类化合物,该化合物可同时对PD-1/PD-L1信号通路和HDAC表现出显著的抑制活性,可应用于治疗PD-1/PD-L1信号通路和HDAC介导的相关疾病。
本发明的技术方案如下:
一种含异羟肟酸结构的联苯类化合物及其药学上可接受的盐,其结构通式如I所示,
其中R1和R2相同或不同,R1和R2分别独立地选自H、C1-5烷基、C3-7环烷基、且所述烷基和环烷基有1~3个相同或不同的氨基、羟基、酰胺基、羧基或者酯基;或R1、R2和与R1、R2所连接的氮原子一起形成4~7元杂环基,且所述杂环基含有1~3个相同或不同的氨基、羟基、酰胺基、羧基或者酯基;
R3为H、卤素、C1-3烷基、C1-3烷氧基或C1-3烷胺基;
R4位H、卤素、甲基;
X为C或N;
n为3-6;
所述R3优选为卤素;
所述R4优选为H、甲基;
所述X为C或N;
所述n为4、5;
优选的,一种含异羟肟酸结构的联苯类化合物选自:
7-((3-(3-(((2-氯-5-(((3-氰基苯基)甲基)氧基)-4-(((2-羟基乙基)氨基)甲基)苯基)氧基)甲基)-2-甲基苯基)苯基)氧基)庚-1-羟氨酸对甲苯磺酸盐、
7-((3-(3-(((2-氯-5-(((3-氰基苯基)甲基)氧基)-4-(6-氧亚基-2,5-二氮杂庚-1-基)苯基)氧基)甲基)-2-甲基苯基)苯基)氧基)庚-1-羟氨酸对甲苯磺酸盐
7-((3-(3-(((2-氯-5-(((3-氰基苯基)甲基)氧基)-4-(((1,3-二羟基-2-甲基丙-2-基)氨基)甲基)苯基)氧基)甲基)-2-甲基苯基)苯基)氧基)庚-1-羟氨酸对甲苯磺酸盐
7-((3-(3-(((2-氯-5-(((3-氰基苯基)甲基)氧基)-4-(((1,3-二羟基丙-2-基)氨基)甲基)苯基)氧基)甲基)-2-甲基苯基)苯基)氧基)庚-1-羟氨酸对甲苯磺酸盐
(S)-1-((5-氯-2-(((3-氰基苯基)甲基)氧基)-4-(((3-(3-((7-(羟基氨基)-7-氧亚基庚基)氧基)苯基)-2-甲基苯基)甲基)氧基)苯基)甲基)六氢吡啶-2-甲酸
(R)-1-((5-氯-2-(((3-氰基苯基)甲基)氧基)-4-(((3-(3-((7-(羟基氨基)-7-氧亚基庚基)氧基)苯基)-2-甲基苯基)甲基)氧基)苯基)甲基)六氢吡啶-2-甲酸
7-((3-(3-(((2-氯-5-(((3-氰基苯基)甲基)氧基)-4-(((1,3-二羟基-2-(羟基甲基)丙-2-基)氨基)甲基)苯基)氧基)甲基)-2-甲基苯基)苯基)氧基)庚-1-羟氨酸对甲苯磺酸盐
6-((3-(3-(((2-氯-5-(((3-氰基苯基)甲基)氧基)-4-(((2-羟基乙基)氨基)甲基)苯基)氧基)甲基)-2-甲基苯基)苯基)氧基)己-1-羟氨酸对甲苯磺酸盐
6-((3-(3-(((2-氯-5-(((3-氰基苯基)甲基)氧基)-4-(6-氧亚基-2,5-二氮杂庚-1-基)苯基)氧基)甲基)-2-甲基苯基)苯基)氧基)己-1-羟氨酸对甲苯磺酸盐
6-((3-(3-(((2-氯-5-(((3-氰基苯基)甲基)氧基)-4-(((1,3-二羟基-2-甲基丙-2-基)氨基)甲基)苯基)氧基)甲基)-2-甲基苯基)苯基)氧基)己-1-羟氨酸对甲苯磺酸盐
6-((3-(3-(((2-氯-5-(((3-氰基苯基)甲基)氧基)-4-(((1,3-二羟基丙-2-基)氨基)甲基)苯基)氧基)甲基)-2-甲基苯基)苯基)氧基)己-1-羟氨酸对甲苯磺酸盐
(S)-1-((5-氯-2-(((3-氰基苯基)甲基)氧基)-4-(((3-(3-((6-(羟基氨基)-6-氧亚基己基)氧基)苯基)-2-甲基苯基)甲基)氧基)苯基)甲基)六氢吡啶-2-甲酸
(R)-1-((5-氯-2-(((3-氰基苯基)甲基)氧基)-4-(((3-(3-((6-(羟基氨基)-6-氧亚基己基)氧基)苯基)-2-甲基苯基)甲基)氧基)苯基)甲基)六氢吡啶-2-甲酸
6-((3-(3-(((2-氯-5-(((3-氰基苯基)甲基)氧基)-4-(((1,3-二羟基-2-(羟基甲基)丙-2-基)氨基)甲基)苯基)氧基)甲基)-2-甲基苯基)苯基)氧基)己-1-羟氨酸对甲苯磺酸盐
本发明涉及的上述化合物及其药学上可接受的盐在制备抑制PD-1/PD-L1信号通路和/或HDACs介导的相关疾病的药物中的应用。
本发明所述的药学上可接受的盐为硫酸氢盐、氢氯酸盐、氢溴酸盐、硫酸盐、草酸盐、乳酸盐、葡糖酸盐、酒石酸盐、富马酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、乙酸盐、柠檬酸盐、对甲苯磺酸盐中的至少一种。
一种药物组合物,其含有治疗有效量的一种或多种所述的含异羟肟酸结构的联苯类化合物。
本发明所述的一种药物组合物,还包括药用辅料或载体。
本发明所述的应用包括在制备治疗PD-1/PD-L1信号通路相关的肿瘤疾病药物中的应用。
本发明所述的应用包括在制备治疗HDACs介导的肿瘤疾病药物中的应用。
本发明所述的肿瘤疾病为肺癌、肝癌、肾癌、非小细胞肺癌、前列腺癌、甲状腺癌、皮肤癌、胰腺癌、卵巢癌、乳腺癌、膀胱癌、骨髓增生异常综合症、淋巴瘤、食管癌、胃肠道癌、中枢或外周神经系统的肿瘤中的至少一种。
有益效果:
本发明提供的该类化合物可对PD-1/PD-L1信号通路和HDAC表现出显著的抑制活性,可应用于治疗PD-1/PD-L1信号通路和HDAC介导的相关疾病如癌症等疾病。
具体实施方式
以下通过具体实施方式对本发明的技术方案进行进一步的说明和描述。
下述各实施例所用原料试剂均为市售的分析纯或化学纯药品,化合物的核磁共振氢谱用Bruker ARX-400测定,高分辨质谱用超高效(压)液相色谱/四级杆飞行时间质谱仪UHPLC-QTOF测定。
实施例1-7的合成路线:
中间体i-1的制备
室温下,分别向250mL茄形瓶中加入2,4-二羟基苯甲醛(12g,0.087mol)、30mL三氯甲烷和1.2mL浓盐酸,升温至60℃搅拌下,分四批加入NCS(N-氯代丁二酰亚胺,12.76g,0.096mol),反应3h,TLC监测反应终止。趁热过滤,滤液静置析出晶体后再抽滤得4.5g白色针状晶体,即中间体i-1,产率为40.0%。
中间体i-2的制备
在室温氮气环境下,分别向100mL茄形瓶中加入中间体i-1(4.5g,0.026mol)和40mL乙腈,搅拌下依次加入3-溴-2-甲基苄基氯(6.01g,0.027mol)、碘化钾(2.16g,0.013mol)和碳酸氢钠(2.85g,0.034mol),升温至60℃反应24h,TLC监测反应终止。趁热过滤,滤饼加水搅拌30min,抽滤得5.6g米白色固体,即中间体i-2,产率为60.4%;1H NMR(400MHz,Chloroform-d)δ11.45(s,1H),9.72(s,1H),7.61(d,J=7.8Hz,1H),7.57(s,1H),7.43(d,J=7.8Hz,1H),7.13(t,J=7.8Hz,1H),6.60(s,1H),5.18(s,2H),2.47(s,3H).
中间体i-3的制备
室温下,分别向250mL茄形瓶中加入中间体i-2(5.0g,0.014mol)、40mL干燥的DMF(二甲基甲酰胺)和碳酸铯(6.87g,0.021mol),搅拌至溶液澄清,再加入间氰基苄基溴(3.58g,0.018mol),加毕,室温反应45min,TLC监测反应终止。加水搅拌30min,抽滤得到5.6g白色固体,即中间体i-3,产率为84.6%;1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),8.06–8.03(m,1H),7.90–7.83(m,2H),7.73(s,1H),7.67–7.62(m,2H),7.51(d,J=7.8Hz,1H),7.23(s,1H),7.20(t,J=7.8Hz,1H),5.44(s,2H),5.41(s,2H),2.42(s,3H).
中间体i-4的制备
室温下,向100mL三颈瓶中分别加入中间体i-3(3.0g,0.006mol)、40mL四氢呋喃、5mL水、3-羟基苯硼酸(1.32g,0.010mol)和磷酸三钾(4.06g,0.019mol),氮气环境下搅拌30min后,加入催化剂XPhos Pd G2(0.5g,0.0006mol),升温至65℃反应3.5h,TLC监测反应终止。冷却至室温,减压浓缩溶剂后,加入冰水搅拌0.5h,抽滤得灰绿色粗品,无水乙醚洗涤粗品后得到2.25g灰白色固体,即中间体i-4,产率为72.7%;1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),9.52(s,1H),8.05(t,J=1.7Hz,1H),7.89(dt,J=7.8,1.4Hz,1H),7.85(dt,J=7.8,1.4Hz,1H),7.73(s,1H),7.65(t,J=7.7Hz,1H),7.50(dd,J=7.6,1.5Hz,1H),7.28(q,J=7.9Hz,3H),7.24–7.19(m,1H),6.78(dd,J=8.1,1.6Hz,1H),6.72(dt,J=7.5,1.2Hz,1H),6.69(t,J=2.0Hz,1H),5.46(s,2H),5.41(s,2H),2.24(s,3H).
中间体i-5的制备
室温下,分别向100mL茄形瓶中加入中间体i-4(4.0g,0.008mol)、40mL乙腈、碳酸钾(2.3g,0.016mol)和碘化钾(0.68g,0.004mol),升温至80℃,分三批加入7-溴庚酸甲酯(3.893mL,0.023mol),继续回流搅拌反应8h,TLC监测反应终止。趁热过滤,静置滤液至析出白色粗品,抽滤,滤饼用无水乙醚洗涤得到4.1g白色固体,即中间体i-5,产率为79.2%;1HNMR(400MHz,Chloroform-d)δ10.34(s,1H),7.94(s,1H),7.76–7.73(m,1H),7.73–7.68(m,2H),7.57(t,J=7.8Hz,1H),7.46–7.42(m,1H),7.35(t,J=7.8Hz,1H),7.30(s,1H),7.30(s,1H),6.95–6.82(m,3H),6.65(s,1H),5.23(s,2H),5.22(s,2H),4.01(t,J=6.5Hz,2H),3.69(s,3H),2.35(t,J=6.5Hz,2H),2.29(s,3H),1.82(p,J=7.5Hz,2H),1.69(p,J=7.5Hz,2H),1.52(p,J=7.5Hz,2H),1.43(p,J=7.5Hz,2H).
中间体i-6的制备
室温下,分别向100mL茄形瓶中加入中间体i-5(3.0g,0.005mol),20mL四氢呋喃、20mL水和氢氧化锂(0.46g,0.019mol),升温至35℃下反应6h,TLC监测反应完毕。减压浓缩溶剂,溶剂蒸干后加入水,然后用加稀HCl调节pH到4左右,搅拌0.5h,抽滤得到2.77g灰白色固体,即中间体i-6,产率为92.6%。
中间体i-7的制备
室温下,分别向100mL茄形瓶中加入中间体i-6(5.0g,0.008mol)、40mL DMF、HATU(2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯,4.56g,0.012mol)和DIEPA(N,N二异丙基乙胺,1982μL,0.012mol),反应30min后,再加入O-(四氢-2H-吡喃-2-基)羟基胺(1.03g,0.009mol),继续反应45min,TLC监测反应完毕。加冰水搅拌30min,抽滤得到5.22g乳白色固体,即中间体i-7,产率为90.1%。
中间体i-8a的制备
室温氮气环境下,分别向25mL茄形瓶中加入中间体i-7(0.1g,0.14mmol)、3mLDMF、乙醇胺(19μL,0.31mmol)、3滴冰醋酸和NaBH3CN(0.053g,0.84mmol),升温至60℃反应4.5h,TLC监测反应完毕。加碳酸氢钠水溶液将pH调至8左右,加冰水搅拌30min,抽滤得粗品,经薄层制备后得0.04g白色固体,即中间体i-8a,产率为37.7%。
中间体i-8b的制备
以中间体i-7(0.1g,0.14mmol)和N-乙酰基乙二胺(30μL,0.31mmol)为原料,操作参考中间体i-8a的制备,可制得0.045g淡黄色,即中间体i-8b,产率为40.2%。
中间体i-8c的制备
以中间体i-7(0.1g,0.14mmol)和2-氨基-2-甲基-1,3-丙二醇(0.033g,0.31mmol)为原料,操作参考中间体i-8a的制备,可制得0.05g白色固体,即中间体i-8c,产率为44.6%。
中间体i-8d的制备
以中间体i-7(0.1g,0.14mmol)和丝氨醇(0.028g,0.31mmol)为原料,操作参考中间体i-8a的制备,可制得0.05g米白色固体,即中间体i-8d,产率为45.5%。
中间体i-8e的制备
室温氮气环境下,分别向25mL茄形瓶中加入中间体i-7(0.1g,0.14mmol)、3mLDMF、D-哌啶甲酸(0.04g,0.31mmol)、3滴冰醋酸和NaBH3CN(0.053g,0.84mmol),升温至60℃反应4h,TLC监测反应完毕。加冰水搅拌30min,抽滤得到粗品,经薄层制备得到0.055g白色固体,即中间体i-8e,产率为47.4%。
中间体i-8f的制备
以中间体i-7(0.1g,0.14mmol)和L-哌啶甲酸(0.04g,0.31mmol)为原料,操作参考中间体i-8e的制备,可制得0.052g白色固体,即中间体i-8f,产率为44.8%。
中间体i-8g的制备
以中间体i-7(0.1g,0.14mmol)和三羟甲基氨基甲烷(0.04g,0.31mmol)为原料,操作参考中间体i-8a的制备,可制得0.05g白色固体,即中间体i-8g,产率为41.8%。
实施例1
室温下,分别向25mL茄形瓶中加入中间体i-8a(0.15g,0.2mmol)、3mL甲醇,搅拌至溶液澄清时,加入对甲苯磺酸(0.05g,0.3mmol),反应搅拌45min,TLC监测反应完毕。减压浓缩溶剂,加水搅拌20min,有白色固体析出,抽滤后得到粗品,经制备薄层板纯化后得23mg白色固体,产率为13.8%;HRMS(ESI)for C7H8O3S[M-H]-.Calcd:171.0116,found:171.0120;HRMS(ESI)for C38H42ClN3O6[M-H]-.Calcd:670.2684,found:670.2687;1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.00(s,1H),7.90–7.80(m,2H),7.64(t,J=7.6Hz,1H),7.53–7.43(m,4H),7.39–7.32(m,1H),7.32–7.25(m,1H),7.25–7.19(m,1H),7.17–7.08(m,3H),6.99–6.90(m,1H),6.88–6.84(m,1H),6.83–6.80(m,1H),5.36–5.30(m,2H),5.30–5.24(m,2H),3.99(t,J=6.8Hz,2H),3.97–3.90(m,2H),3.61–3.53(m,2H),2.84–2.74(m,2H),2.29(s,3H),2.25(s,3H),1.95(t,J=8.8,8.1Hz,2H),1.77–1.67(m,2H),1.57–1.47(m,2H),1.45–1.37(m,2H),1.36–1.27(m,2H)。
实施例2
以中间体i-8b(0.15g,0.19mmol)为原料,操作步骤参照实施例1的制备,可制得到26mg淡黄色固体,产率为15.6%;HRMS(ESI)for C7H8O3S[M-H]-.Calcd:171.0116,found:171.0121;HRMS(ESI)for C40H45ClN4O6[M-H]-.Calcd:711.2949,found:711.2948;1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.00(s,1H),7.90–7.80(m,2H),7.64(t,J=7.6Hz,1H),7.53–7.43(m,4H),7.39–7.32(m,1H),7.32–7.25(m,1H),7.25–7.19(m,1H),7.17–7.08(m,3H),6.99–6.90(m,1H),6.88–6.84(m,1H),6.83–6.80(m,1H),5.36–5.30(m,2H),5.30–5.24(m,2H),3.99(t,J=6.8Hz,2H),3.97–3.90(m,2H),3.61–3.53(m,2H),2.84–2.74(m,2H),2.29(s,3H),2.25(s,3H),1.95(t,J=8.8,8.1Hz,2H),1.77–1.67(m,2H),1.57–1.47(m,2H),1.45–1.37(m,2H),1.36–1.27(m,2H)。
实施例3
以中间体i-8c(0.15g,0.19mmol)为原料,操作步骤参照实施例1的制备,可制得35mg米色固体,产率为21.0%;HRMS(ESI)for C7H8O3S[M-H]-.Calcd:171.0116,found:171.0119;HRMS(ESI)for C40H46ClN3O7[M-H]-.Calcd:714.2946,found:714.2942;1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.06–8.01(m,1H),7.93–7.80(m,2H),7.67–7.59(m,1H),7.54–7.43(m,4H),7.39–7.31(m,1H),7.31–7.19(m,2H),7.17–7.08(m,3H),6.97–6.90(m,1H),6.88–6.78(m,2H),5.34–5.26(m,4H),4.10–3.90(m,4H),3.54–3.40(m,4H),2.29(s,3H),2.24(s,3H),1.99–1.89(m,2H),1.76–1.65(m,2H),1.56–1.46(m,2H),1.45–1.36(m,2H),1.34–1.26(m,2H),1.11–1.02(m,3H)。
实施例4
以中间体i-8d(0.15g,0.19mmol)为原料,操作步骤参照实施例1的制备,可制得30mg白色固体,产率为18.0%;HRMS(ESI)for C7H8O3S[M-H]-.Calcd:171.0116,found:171.0121;HRMS(ESI)for C39H44ClN3O7[M-H]-.Calcd:700.2790,found:700.2788;1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.05–7.99(m,1H),7.93–7.82(m,2H),7.64(t,J=7.8Hz,1H),7.59–7.55(m,1H),7.52–7.46(m,3H),7.39–7.21(m,3H),7.19–7.09(m,3H),6.97–6.92(m,1H),6.89–6.79(m,2H),5.37–5.31(m,2H),5.31–5.27(m,2H),4.23–4.05(m,2H),3.99(t,J=6.4Hz,2H),3.72–3.50(m,4H),3.06–2.95(m,1H),2.29(s,3H),2.24(s,3H),1.96(t,J=7.3Hz,2H),1.77–1.66(m,2H),1.56–1.47(m,2H),1.46–1.36(m,2H),1.36–1.26(m,2H)。
实施例5
以中间体i-8e(0.15g,0.18mmol)为原料,步骤参照实施例1的制备,可制得26mg白色固体,产率为19.3%;HRMS(ESI)for C7H8O3S[M-H]-.Calcd:171.0116,found:171.0119;HRMS(ESI)for C40H46ClN3O7[M-H]-.Calcd:714.2946,found:714.2942;1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.01–7.94(m,1H),7.88–7.77(m,2H),7.69–7.58(m,1H),7.53–7.40(m,2H),7.40–7.19(m,3H),7.10(s,1H),6.98–6.90(m,1H),6.90–6.78(m,2H),5.34–5.27(m,2H),5.27–5.21(m,2H),4.04–3.93(m,2H),3.82–3.74(m,1H),3.69–3.60(m,1H),3.22–3.12(m,1H),2.96–2.85(m,1H),2.37–2.28(m,1H),2.24(s,3H),2.01–1.88(m,2H),1.86–1.64(m,4H),1.57–1.45(m,5H),1.45–1.36(m,3H),1.34–1.26(m,2H)。
实施例6
以中间体i-8f(0.15g,0.18mmol)为原料,操作步骤参照实施例1的制备,可制得28mg白色固体,产率为20.7%;HRMS(ESI)for C7H8O3S[M-H]-.Calcd:171.0116,found:171.0119;HRMS(ESI)for C40H46ClN3O7[M-H]-.Calcd:714.2946,found:714.2942;1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.00–7.94(m,1H),7.87–7.80(m,2H),7.63(t,J=7.4Hz,1H),7.51–7.40(m,2H),7.39–7.20(m,3H),7.10(s,1H),6.98–6.91(m,1H),6.89–6.79(m,2H),5.33–5.27(m,2H),5.27–5.21(m,2H),4.04–3.95(m,2H),3.82–3.73(m,1H),3.69–3.61(m,1H),3.20–3.12(m,1H),2.95–2.84(m,1H),2.36–2.27(m,1H),2.24(s,3H),1.96(t,J=6.8Hz,2H),1.86–1.67(m,4H),1.55–1.45(m,5H),1.45–1.35(m,3H),1.34–1.27(m,2H)。
实施例7
以中间体i-8g(0.15g,0.18mmol)为原料,操作步骤参照实施例1的制备,可制得30mg白色固体,产率为18.0%;HRMS(ESI)for C7H8O3S[M-H]-.Calcd:171.0116,found:171.0119;HRMS(ESI)for C40H46ClN3O7[M-H]-.Calcd:714.2946,found:714.2942;1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.05(s,1H),7.94–7.81(m,2H),7.63(t,J=7.8Hz,1H),7.58–7.54(m,1H),7.50–7.45(m,3H),7.39–7.20(m,3H),7.16–7.10(m,3H),6.98–6.92(m,1H),6.87–6.79(m,2H),5.38–5.32(m,2H),5.32–5.29(m,2H),4.34–4.17(m,2H),3.99(t,J=6.4Hz,2H),3.82–3.45(m,6H),2.29(s,3H),2.24(s,3H),1.96(t,J=7.3Hz,2H),1.77–1.65(m,2H),1.58–1.47(m,2H),1.46–1.36(m,2H),1.35–1.26(m,2H)。
实施例8-14的合成路线:
中间体i-9的制备
以中间体i-4(4.0g,0.008mol)和6-溴己酸甲酯(3604μL,0.023mol)为原料,操作步骤参考中间体i-5的制备。可制得3.9g灰白色固体,即中间体i-9,产率为77.2%。
中间体i-10的制备
以中间体i-9(3.0g,0.005mol)为原料,操作步骤参考中间体i-6的制备,可制得2.55g灰白色固体,即中间体i-10,产率为87.1%。
中间体i-11的制备
以中间体i-10(5.0g,0.008mol)和O-(四氢-2H-吡喃-2-基)羟基胺(1.08g,0.009mol)为原料,操作步骤参考中间体i-7的制备,可制得5.1g乳白色固体,即中间体i-11,产率为87.6%。
中间体i-8h的制备
以中间体i-11(0.12g,0.17mmol)和乙醇胺(23μL,0.38mmol)为原料,操作参考中间体i-8a的制备,可制得0.045g淡黄色固体,即中间体i-8h,产率为35.2%。
中间体i-8i的制备
以中间体i-11(0.12g,0.17mmol)和N-乙酰基乙二胺(36μL,0.38mmol)为原料,操作参考中间体i-8a的制备,可制得0.05g黄色固体,即中间体i-8i,产率为37.0%。
中间体i-8j的制备
以中间体i-11(0.12g,0.17mmol)和2-氨基-2-甲基-1,3-丙二醇(0.04g,0.38mmol)为原料,操作参考中间体i-8a的制备,可制得0.055g黄色固体,即中间体i-8j,产率为40.7%。
中间体i-8k的制备
以中间体i-11(0.12g,0.17mmol)和丝氨醇(0.034g,0.38mmol)为原料,操作参考中间体i-8a的制备,可制得0.055g黄色固体,即中间体i-8k,产率为41.4%。
中间体i-8l的制备
以中间体i-11(0.12g,0.17mmol)和D-哌啶甲酸(0.05g,0.38mmol)为原料,操作参考中间体i-8e的制备,可制得0.065g白色固体,即中间体i-8l,产率46.8%。
中间体i-8m的制备
以中间体i-11(0.12g,0.17mmol)和L-哌啶甲酸(0.05g,0.38mmol)为原料,操作参考中间体i-8e的制备,可制得0.065g白色固体,即中间体i-8m,产率46.8%。
中间体i-8n的制备
以中间体i-11(0.12g,0.17mmol)和三羟甲基氨基甲烷(0.046g,0.38mmol)为原料,操作参考中间体i-8a的制备,可制得0.055g白色固体,即中间体i-8n,产率40.0%。
实施例8
以中间体i-8h(0.15g,0.2mmol)为原料,操作步骤参照实施例1的制备,可制得28mg白色固体,产率为16.7%;HRMS(ESI)for C7H8O3S[M-H]-.Calcd:171.0116,found:171.0119;HRMS(ESI)for C40H46ClN3O7[M-H]-.Calcd:714.2946,found:714.2942;1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.06–7.99(m,1H),7.92–7.82(m,2H),7.70–7.62(m,1H),7.61–7.41(m,4H),7.41–7.21(m,3H),7.20–7.05(m,3H),6.99–6.91(m,1H),6.90–6.77(m,2H),5.41–5.32(m,2H),5.32–5.24(m,2H),4.13–3.91(m,4H),3.67–3.56(m,2H),2.95–2.81(m,2H),2.29(s,3H),2.24(s,3H),2.03–1.92(m,2H),1.77–1.65(m,2H),1.62–1.50(m,2H),1.46–1.34(m,2H)。
实施例9
以中间体i-8i(0.15g,0.19mmol)为原料,操作步骤参照实施例1的制备,可制得29mg白色固体,产率为17.4%;HRMS(ESI)for C7H8O3S[M-H]-.Calcd:171.0116,found:171.0119;HRMS(ESI)for C40H46ClN3O7[M-H]-.Calcd:714.2946,found:714.2942;1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.03–7.93(m,2H),7.85(s,2H),7.64(t,J=7.3Hz,1H),7.56–7.43(m,4H),7.39–7.32(m,1H),7.30–7.20(m,2H),7.15–7.09(m,2H),6.99–6.91(m,1H),6.88–6.80(m,2H),5.36–5.29(m,2H),5.29–5.23(m,2H),4.02–3.95(m,2H),3.95–3.85(m,2H),3.25–3.19(m,2H),2.83–2.69(m,2H),2.29(s,3H),2.24(s,3H),1.98(t,J=6.9Hz,2H),1.80(s,3H),1.76–1.67(m,2H),1.61–1.50(m,2H),1.44–1.34(m,2H)。
实施例10
以中间体i-8j(0.15g,0.19mmol)为原料,操作步骤参照实施例1的制备,可制得35mg白色固体,产率为21.0%;HRMS(ESI)for C7H8O3S[M-H]-.Calcd:171.0116,found:171.0119;HRMS(ESI)for C40H46ClN3O7[M-H]-.Calcd:714.2946,found:714.2942;1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.09–8.02(m,1H),7.97–7.81(m,2H),7.64(t,J=7.8Hz,1H),7.59–7.42(m,4H),7.42–7.20(m,3H),7.20–7.07(m,3H),7.02–6.91(m,1H),6.90–6.77(m,2H),5.40–5.25(m,4H),4.20–3.88(m,4H),3.61–3.45(m,4H),2.28(s,3H),2.24(s,3H),2.05–1.88(m,2H),1.80–1.66(m,2H),1.64–1.49(m,2H),1.48–1.30(m,2H),1.09(s,3H)。
实施例11
以中间体i-8k(0.15g,0.19mmol)为原料,操作步骤参照实施例1的制备,可制得28mg白色固体,产率为16.8%;HRMS(ESI)for C7H8O3S[M-H]-.Calcd:171.0116,found:171.0119;HRMS(ESI)for C40H46ClN3O7[M-H]-.Calcd:714.2946,found:714.2942;1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.05–7.98(m,1H),7.91–7.81(m,2H),7.64(t,J=7.5Hz,1H),7.57–7.44(m,4H),7.39–7.20(m,3H),7.19–7.07(m,3H),6.99–6.89(m,1H),6.89–6.78(m,2H),5.38–5.31(m,2H),5.30–5.25(m,2H),4.16–3.91(m,4H),3.67–3.45(m,4H),3.01–2.85(m,1H),2.29(s,3H),2.24(s,3H),1.98(t,J=6.6Hz,2H),1.78–1.66(m,2H),1.62–1.48(m,2H),1.47–1.34(m,2H)。
实施例12
以中间体i-8l(0.15g,0.19mmol)为原料,操作步骤参照实施例1的制备,后可制得27mg白色固体,产率为20.1%;HRMS(ESI)for C7H8O3S[M-H]-.Calcd:171.0116,found:171.0119;HRMS(ESI)for C40H46ClN3O7[M-H]-.Calcd:714.2946,found:714.2942;1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.00–7.94(m,1H),7.88–7.79(m,2H),7.67–7.59(m,1H),7.52–7.40(m,2H),7.40–7.19(m,3H),7.10(s,1H),6.99–6.80(m,3H),5.37–5.28(m,2H),5.27–5.20(m,2H),4.07–3.91(m,2H),3.78(d,J=13.4Hz,1H),3.69–3.61(m,1H),3.22–3.12(m,1H),2.97–2.84(m,1H),2.38–2.28(m,1H),2.24(s,3H),2.03–1.89(m,2H),1.88–1.65(m,4H),1.62–1.32(m,8H)。
实施例13
以中间体i-8m(0.15g,0.19mmol)为原料,操作步骤参照实施例1的制备,可制得29mg白色固体,产率为21.6%;HRMS(ESI)for C7H8O3S[M-H]-.Calcd:171.0116,found:171.0119;HRMS(ESI)for C40H46ClN3O7[M-H]-.Calcd:714.2946,found:714.2942;1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.01–7.93(m,1H),7.91–7.80(m,2H),7.68–7.59(m,1H),7.52–7.40(m,2H),7.40–7.19(m,3H),7.10(s,1H),6.99–6.79(m,3H),5.38–5.27(m,2H),5.27–5.19(m,2H),4.05–3.93(m,2H),3.83–3.73(m,1H),3.67–3.61(m,1H),3.20–3.13(m,1H),2.95–2.86(m,1H),2.36–2.27(m,1H),2.24(s,3H),2.05–1.91(m,2H),1.88–1.64(m,4H),1.64–1.28(m,8H)。
实施例14
以中间体i-8n(0.15g,0.18mmol)为原料,操作步骤参照实施例1的制备,可制得35mg白色固体,产率为21.1%;HRMS(ESI)for C7H8O3S[M-H]-.Calcd:171.0116,found:171.0119;HRMS(ESI)for C40H46ClN3O7[M-H]-.Calcd:714.2946,found:714.2942;1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),8.07–8.02(m,1H),7.94–7.80(m,2H),7.63(t,J=7.8Hz,1H),7.57–7.53(m,1H),7.52–7.45(m,3H),7.39–7.20(m,3H),7.18–7.08(m,3H),7.00–6.92(m,1H),6.90–6.77(m,2H),5.36–5.32(m,2H),5.32–5.29(m,2H),4.33–4.15(m,2H),4.04–3.94(m,2H),3.76–3.48(m,6H),2.29(s,3H),2.24(s,3H),1.98(t,J=7.2Hz,2H),1.78–1.66(m,2H),1.60–1.50(m,2H),1.46–1.34(m,2H)。
上述实施例1-14的结构式如表1所示。
表1各实施例的化学名称及结构式
HDAC3抑制活性测试
为了验证制备得到的实施例1-14化合物对HDAC3蛋白是否具有显著的抑制作用,使用BPS公司的HDAC3荧光检测试剂盒(Cat#50003),采用荧光标记法(Fluorescenceassay),对实施例1-14化合物进行了HDAC3抑制活性测试。
实验步骤:
1、制备好1倍的HDAC Assay Buffer。
2、化合物配制:使用DMSO(二甲基亚砜)将化合物溶解,采用检测缓冲液配制到对应的浓度后,转移到检测板。DMSO的终浓度为1%。
3、制备酶溶液。
采用检测缓冲液中配制对应浓度的HDAC3酶溶液。
4、准备底物工作液。
在1x检测缓冲液中加入胰蛋白酶和Ac-肽底物,制成底物工作液。
5、将15μL HDAC3酶溶液转移到检测板上
6、在室温下孵育15分钟。
7、在每个孔中加入10μL底物工作液以开始反应。
8、在Envision上读取平板的动力学数据,激发波长为355nm,发射波长为460nm。
9、曲线拟合
在Excel中对数据进行拟合,用公式(1)得到抑制率,公式(1):Inhibition%=(Max-Signal)/(Max-Min)*100。用XL-Fit拟合数据,用公式(2)获得IC50值,公式(2):Y=Bottom+(Top-Bottom)/(1+(IC50/X)*HillSlope),Y是抑制率,X是化合物浓度。
实验结果如表2所示,
表2实施例1-14化合物对HDAC1和HDAC3的抑制活性结果
从表2结果可以看出,实施例1-14对HDAC1和HDAC3均表现出显著的抑制活性,大部分的化合物对HDAC3的IC50值在100nM以下。其中,实施例5和实施例6对HDAC3的IC50值分别为21nM和14nM,显著优于上市药物SAHA。
PD-1/PD-L1抑制活性测试
使用csibio公司的PD-1/PD-L1结合力检测试剂盒(CAT#63ADK000CPAPEG),采用HTRF法(均相时间分辨荧光),对10个HDAC3抑制活性显著的实施例化合物,进一步开展了了PD-1/PD-L1抑制活性测试。
实验步骤:
1、配制化合物工作液:先用DMSO将10mM化合物储液稀释至4uM化合物溶液,然后用diluent稀释至200nM化合物工作液。按照2μL/well加入到化合物孔中。对照孔中加入2μL含5%DMSO的diluent。
2、配Tag1-PD-L1工作液:用diluent将Tag1-PD-L1储液稀释至浓度为12.5nM工作液。按照4μL/well加入到除Blank孔的所有孔中。向Blank孔中加入4μL diluent,混匀。
3、配Tag2-PD-1工作液:用diluent将Tag2-PD-1储液稀释至浓度为125nM工作液。按照4μL/well加入到所有孔中,混匀,封板,室温反应15min。
4、配制Anti-Tag1-Eu3+工作液:2.5μL Anti-Tag1-Eu3+储液,247.5μL diluent,按照5μL/well加入到所有孔中,混匀。
5、配制Anti-Tag2-XL665工作液:10μL Anti-Tag2-XL665储液,240μL diluent,按照5μL/well加入到所有孔中,混匀,室温反应120min。
6、用酶标仪在Ex 320nm,Em 615nm,Em 665nm读取荧光值。
Emission Ration(ER)=665nm Emission signal/620nm Emission signal
抑制率=(ERpositive―ERsample)/(ERpositive―ERnegative)*100%
7、实验结果如表3所示
表3 10个实施例化合物对PD-1/PD-L1的抑制活性结果
从表3结果可以看出,10个实施例化合物对PD-1/PD-L1均表现出突出的抑制活性,大部分实施例化合物的IC50值在100nM以下,实施例3、7、10、13、14的抑制活性显著优于BMS-202。
综上所述,从表2和表3的活性测试结果可以看出,本发明公开的实施例化合物可以对PD-1/PD-L1信号通路和HDAC表现出明显的抑制活性,具有治疗PD-1/PD-L1信号通路和/或HDAC介导的相关疾病的潜力。
抗肿瘤细胞增殖活性
进一步选取实施例8、10和14,以MCF-7,HeLa和SH-SY5Y为测试细胞株,开展了体外抗肿瘤细胞增殖活性测试。
实验步骤:
(1)铺板:取对数生长期且状态良好的MCF-7,Hela和SH-SY5Y细胞,以1.0×104个/孔接种于96孔板中,其中A549,Hela和SH-SY5Y细胞的培养基为RPMI1640,MCF-7的培养基为DMEM,培养24h后进行后续实验;
(2)药物配制:取出DMSO溶解的各化合物(包括实施例1~14中化合物和SAHA),使用前超声20min,确保化合物完全溶解,分别用培养基稀释成不同浓度;
(3)加药:弃去96孔细胞板中的培养基,加入含化合物的培养基,并设置空白对照(化合物浓度为0μM),每组3个复孔,每孔100微升,恒温培养箱培养48h;
(4)加入CCK-8试剂:避光条件下向每个孔加入8μL CCK-8试剂后,放置恒温培养箱培养,实时观察液体颜色;
(5)测试:待反应充分,将96孔板置于酶标仪检测450nm波长下各孔的吸光度(A)值,参考波长设置为650nm;
(6)数据处理,计算半数抑制浓度,即IC50值,结果见表4。
表4实施例8、10和14的体外抗肿瘤细胞增殖活性
a:化合物在10μM浓度下的抑制率。
从表4的结果可以看出,3个实施例化合物对多株肿瘤细胞株均表现出不同程度的抑制活性,其中实施例14对肿瘤细胞MCF-7,HeLa和SHSY5Y抑制活性最佳,IC50值为11.96μM,4.27μM和5.34μM。
以上所述,仅为本发明的较佳实施例而已,故不能依此限定本发明实施的范围,即依本发明专利范围及说明书内容所作的等效变化与修饰,皆应仍属本发明涵盖的范围内。
Claims (10)
3.如权利要求2所述的一种含异羟肟酸结构的联苯类化合物或其药学上可接受的盐,其为
7-((3-(3-(((2-氯-5-(((3-氰基苯基)甲基)氧基)-4-(((2-羟基乙基)氨基)甲基)苯基)氧基)甲基)-2-甲基苯基)苯基)氧基)庚-1-羟氨酸对甲苯磺酸盐、
7-((3-(3-(((2-氯-5-(((3-氰基苯基)甲基)氧基)-4-(6-氧亚基-2,5-二氮杂庚-1-基)苯基)氧基)甲基)-2-甲基苯基)苯基)氧基)庚-1-羟氨酸对甲苯磺酸盐、
7-((3-(3-(((2-氯-5-(((3-氰基苯基)甲基)氧基)-4-(((1,3-二羟基-2-甲基丙-2-基)氨基)甲基)苯基)氧基)甲基)-2-甲基苯基)苯基)氧基)庚-1-羟氨酸对甲苯磺酸盐、
7-((3-(3-(((2-氯-5-(((3-氰基苯基)甲基)氧基)-4-(((1,3-二羟基丙-2-基)氨基)甲基)苯基)氧基)甲基)-2-甲基苯基)苯基)氧基)庚-1-羟氨酸对甲苯磺酸盐、
(S)-1-((5-氯-2-(((3-氰基苯基)甲基)氧基)-4-(((3-(3-((7-(羟基氨基)-7-氧亚基庚基)氧基)苯基)-2-甲基苯基)甲基)氧基)苯基)甲基)六氢吡啶-2-甲酸、
(R)-1-((5-氯-2-(((3-氰基苯基)甲基)氧基)-4-(((3-(3-((7-(羟基氨基)-7-氧亚基庚基)氧基)苯基)-2-甲基苯基)甲基)氧基)苯基)甲基)六氢吡啶-2-甲酸、
7-((3-(3-(((2-氯-5-(((3-氰基苯基)甲基)氧基)-4-(((1,3-二羟基-2-(羟基甲基)丙-2-基)氨基)甲基)苯基)氧基)甲基)-2-甲基苯基)苯基)氧基)庚-1-羟氨酸对甲苯磺酸盐、
6-((3-(3-(((2-氯-5-(((3-氰基苯基)甲基)氧基)-4-(((2-羟基乙基)氨基)甲基)苯基)氧基)甲基)-2-甲基苯基)苯基)氧基)己-1-羟氨酸对甲苯磺酸盐、
6-((3-(3-(((2-氯-5-(((3-氰基苯基)甲基)氧基)-4-(6-氧亚基-2,5-二氮杂庚-1-基)苯基)氧基)甲基)-2-甲基苯基)苯基)氧基)己-1-羟氨酸对甲苯磺酸盐、
6-((3-(3-(((2-氯-5-(((3-氰基苯基)甲基)氧基)-4-(((1,3-二羟基-2-甲基丙-2-基)氨基)甲基)苯基)氧基)甲基)-2-甲基苯基)苯基)氧基)己-1-羟氨酸对甲苯磺酸盐、
6-((3-(3-(((2-氯-5-(((3-氰基苯基)甲基)氧基)-4-(((1,3-二羟基丙-2-基)氨基)甲基)苯基)氧基)甲基)-2-甲基苯基)苯基)氧基)己-1-羟氨酸对甲苯磺酸盐、
(S)-1-((5-氯-2-(((3-氰基苯基)甲基)氧基)-4-(((3-(3-((6-(羟基氨基)-6-氧亚基己基)氧基)苯基)-2-甲基苯基)甲基)氧基)苯基)甲基)六氢吡啶-2-甲酸、
(R)-1-((5-氯-2-(((3-氰基苯基)甲基)氧基)-4-(((3-(3-((6-(羟基氨基)-6-氧亚基己基)氧基)苯基)-2-甲基苯基)甲基)氧基)苯基)甲基)六氢吡啶-2-甲酸、
6-((3-(3-(((2-氯-5-(((3-氰基苯基)甲基)氧基)-4-(((1,3-二羟基-2-(羟基甲基)丙-2-基)氨基)甲基)苯基)氧基)甲基)-2-甲基苯基)苯基)氧基)己-1-羟氨酸对甲苯磺酸盐中的至少一种。
4.权利要求1至3中任一权利要求所述的含异羟肟酸结构的联苯类化合物或其药学上可接受的盐在制备抑制PD-1/PD-L1信号通路和/或HDACs介导的相关疾病的药物中的应用。
5.如权利要求4所述的药学上可接受的盐为硫酸氢盐、氢氯酸盐、氢溴酸盐、硫酸盐、草酸盐、乳酸盐、葡糖酸盐、酒石酸盐、富马酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、乙酸盐、柠檬酸盐、对甲苯磺酸盐中的至少一种。
6.如权利要求4所述的应用,其特征在于,所述的相关疾病包括PD-1/PD-L1信号通路相关的肿瘤疾病。
7.如权利要求4所述的应用,其特征在于,所述的相关疾病为HDACs介导的肿瘤疾病。
8.如权利要求6或7所述的应用,所述的肿瘤疾病为肺癌、肝癌、肾癌、非小细胞肺癌、前列腺癌、甲状腺癌、皮肤癌、胰腺癌、卵巢癌、乳腺癌、膀胱癌、骨髓增生异常综合症、淋巴瘤、食管癌、胃肠道癌、中枢或外周神经系统的肿瘤。
9.一种药物组合物,其含有治疗有效量的权利要求1至3中任一项所述的含异羟肟酸结构的联苯类化合物或其药学上可接受的盐。
10.如权利要求9所述的一种药物组合物,其特征在于,还包括药用辅料或载体。
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