CN117964559A - 一种8-苯基喹唑啉类化合物及其应用 - Google Patents
一种8-苯基喹唑啉类化合物及其应用 Download PDFInfo
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- CN117964559A CN117964559A CN202410128813.2A CN202410128813A CN117964559A CN 117964559 A CN117964559 A CN 117964559A CN 202410128813 A CN202410128813 A CN 202410128813A CN 117964559 A CN117964559 A CN 117964559A
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Abstract
本发明公开了一种8‑苯基喹唑啉类化合物及其应用,其结构式为
Description
技术领域
本发明属于有机合成技术领域,具体涉及一种8-苯基喹唑啉类化合物及其应用。
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。
PD-1/PD-L1抑制剂可分为抗体类抑制剂和小分子类抑制剂,其中,抗体类抑制剂疗效显著、特异性强,对PD-1/PD-L1蛋白具有很高的亲和力,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。但抗体类抑制剂的固有缺陷也限制着它的使用,例如,抗体分子量很大,在药代动力学性质方面的组织和肿瘤穿透能力差,甚至在肿瘤组织内部也存在部分区域药物无法抵达的现象,而一些免疫豁免部位,更加限制抗体药物的使用。相比于抗体类抑制剂,小分子类抑制剂的分子量更小,穿透力强,可以到达抗体药物治疗受限的组织,具有良好可控的药代动力学性质,更好的口服生物利用度和合理的半衰期等。并且,小分子药物生产工艺简单,成本低,剂型多样,增加了治疗的可及性,这很好地弥补了抗体类抑制的原本的缺陷。因此,开发作用于PD-1/PD-L1免疫检查点的小分子类抑制剂,具有独特的优势和巨大的发展潜力。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。
发明内容
本发明目的在于提供一种8-苯基喹唑啉类化合物。
本发明的另一目的在于提供上述8-苯基喹唑啉类化合物及其药学上可接受的盐在制备治疗PD-1/PD-L1信号通路相关疾病的药物组合物中的应用。
本发明的再一目的在于提供一种治疗PD-1/PD-L1信号通路相关疾病的药物组合物。
本发明的技术方案如下:
一种8-苯基喹唑啉类化合物,其结构式为
其中,
R1为H、C1-5烷基或C3-7环烷基,R2为H、C1-5烷基或C3-7环烷基;R1和R2中的C1-5烷基和C3-7环烷基具有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和与其所连接的氮原子一起形成4-7元杂环基,且该杂环基含有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为H、卤素或甲基;
X为C或N。
在本发明的一个优选实施方案中,所述为/>
进一步优选,所述R3为卤素。
更进一步优选的,所述R4为H或甲基。
上述8-苯基喹唑啉类化合物及其药学上可接受的盐在制备治疗PD-1/PD-L1信号通路相关疾病的药物组合物中的应用。
在本发明的一个优选实施方案中,所述PD-1/PD-L1信号通路相关疾病为肿瘤疾病。
进一步优选,所述肿瘤疾病包括肺癌、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、中枢和外周神经系统的肿瘤。
一种治疗PD-1/PD-L1信号通路相关疾病的药物组合物,其有效成分包括上述8-苯基喹唑啉类化合物和/或药学上可接受的盐。
在本发明的一个优选实施方案中,所述药学上可接受的盐选自硫酸氢盐、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、柠檬酸盐和对甲苯磺酸盐中的至少一种。
进一步优选,所述PD-1/PD-L1信号通路相关疾病为肿瘤疾病,所述肿瘤疾病包括肺癌、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、中枢和外周神经系统的肿瘤。
本发明的有益效果是:本发明对PD-1/PD-L1信号通路表现出显著的抑制活性,可应用于治疗PD-1/PD-L1信号通路介导的包括肿瘤疾病在内的相关疾病。
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。
以下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。
以下实施例1-25的合成路线如下:
上述中间体i-1的制备包括: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(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%。该中间体i-1的表征数据为:1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),10.88(s,1H),9.98(s,1H),7.60(s,1H),6.59(s,1H).
上述中间体i-2的制备包括:室温下,中间体i-1(9.00g,52.16mmol)加入到50mLMeCN中,依次加入2-甲基-3-溴苄基氯(12.02g,54.76mmol),碘化钾(4.33g,26.08mmol)和碳酸氢钠(5.71g,67.80mmol),加毕,升温至60℃,搅拌反应约50h,TLC检测反应完全后,冷却至室温,抽滤,滤饼水洗,干燥后得13.40g白色固体,即中间体i-2,产率:72.21%。该中间体i-2的表征数据为:1H NMR(400MHz,CDCl3)δ11.45(s,1H),9.72(s,1H),7.61(d,J=8.0Hz,1H),7.57(s,1H),7.43(d,J=7.5Hz,1H),7.13(t,J=7.8Hz,1H),6.60(s,1H),5.18(s,2H),2.47(s,3H).
上述中间体i-3的制备包括:室温下,将中间体i-2(2.46g,6.92mmol)加入到25mL的1,4-二氧六环中,依次加入干燥的联硼酸频哪醇酯(2.11g,8.30mmol),干燥的醋酸钾(2.87g,20.75mmol)和双三苯基磷二氯化钯(0.49g,0.69mmol),加毕,立即氮气置换三次,排除装置内氧气,氮气保护,升温至80℃,搅拌反应15h,TLC检测反应完全后,静置冷却至室温,加硅藻土抽滤,滤液减压浓缩,然后加入到35mL冰水中搅拌30min,抽滤,滤饼干燥,采用石油醚:乙酸乙酯15∶1进行柱色谱纯化,得1.55g白色固体,即中间体i-3,产率:55.76%。该中间体i-3的表征数据为:1H NMR(400MHz,CDCl3)δ11.45(s,1H),9.71(s,1H),7.80(d,J=7.1Hz,1H),7.59-7.52(m,2H),7.26(s,1H),6.61(s,1H),5.19(s,2H),2.59(s,3H),1.43-1.33(m,12H).
上述中间体i-4-1的制备包括:室温下,将中间体i-3(2.00g,4.97mmol)加入到20mL DMF中,依次加入间氰基溴苄(1.07g,5.46mmol),碳酸铯(2.43g,7.45mmol)和,rt搅拌反应约3h,TLC检测反应完全后,加入约60mL冰水,搅拌约30min,搅拌过程中用稀HCl调pH至中性,然后抽滤,滤饼干燥后得2.33g白色固体,即中间体i-4-1,产率:90.51%。该中间体i-4-1的表征数据为:1H NMR(400MHz,CDCl3)δ10.33(s,1H),7.92(s,1H),7.80(d,J=7.4Hz,1H),7.72(s,1H),7.71-7.65(m,2H),7.56(t,J=7.8Hz,1H),7.46(d,J=7.7Hz,1H),7.24(t,J=7.5Hz,1H),6.55(s,1H),5.20(s,2H),5.16(s,2H),2.59(s,3H),1.42-1.36(m,12H).
上述中间体i-4-2的制备包括:室温下,将中间体i-3(2.00g,4.97mmol)加入到20mL DMF中,依次加入5-(溴甲基)烟腈(1.07g,5.46mmol),碳酸铯(2.43g,7.45mmol)和,rt搅拌反应约3h,TLC检测反应完全后,加入约60mL冰水,搅拌约30min,搅拌过程中用稀HCl调pH至中性,然后抽滤,滤饼干燥后得2.18g白色固体,即中间体i-4,产率:85.00%。该中间体i-4的表征数据为:1H NMR(400MHz,DMSO)δ10.38(s,1H),9.04(s,1H),9.00(s,1H),8.88(s,1H),8.54(s,1H),8.47(t,J=7.5Hz,2H),7.93(s,1H),7.78(d,J=7.8Hz,1H),7.75(s,1H),5.38(s,2H).
上述中间体i-5的制备包括:称取3-溴-2-氨基苯甲酸(20g,0.093mol)置于250mL茄型瓶中,80mL甲酰胺作为溶剂加到入茄型瓶中,150℃反应,持续搅拌6h,TLC显示反应结束后。反应液静置冷却至室温,加入冰水搅拌30min后,抽滤得棕色固体18.85g,即中间体i-5,产率90.6%。该中间体i-5的表征数据为:1H NMR(400MHz,DMSO-d6)δ12.52(s,1H),8.23(d,J=3.6Hz,1H),8.17-8.10(m,2H),7.43(t,J=7.8Hz,1H).
上述中间体i-6的制备包括:室温下,将中间体i-5(8.00g,34.19mmol)加入到45mL二氯亚砜中,滴加2滴DMF,加毕,搅拌升温至80℃,反应9h,TLC检测反应完全后,冷却至室温,减压浓缩溶剂,加120mL二氯甲烷溶解,完全溶解后,加饱和碳酸氢钠水溶液调pH至中性,移入分液漏斗中,分液静置,取二氯甲烷层,加饱和食盐水洗涤,使用无水硫酸钠干燥,蒸干溶剂得6.50g棕黄色固体,即中间体i-6,产率:75.50%。该中间体i-6的表征数据为:1HNMR(400MHz,CDCl3)δ9.20(s,1H),8.34-8.28(m,2H),7.64(t,J=8.0Hz,1H).
上述中间体i-7的制备包括:室温氮气环境下,将中间体i-6(5.00g,20.53mmol)加入到35mL MeCN中,然后依次加入中间体i-1(3.72g,21.55mmol),碘化钾(1.70g,10.27mmol)和碳酸氢钠(2.24g,26.69mmol),加毕,升温至60℃,搅拌反应约50h,TLC检测反应完全后,静置冷却至室温,使用布氏漏斗抽滤,将滤饼转移到50mL茄形瓶中,加20mL冰水搅拌约30min,再次抽滤,滤饼干燥后得4.26g白色固体,即中间体i-7,产率:54.90%。该中间体i-7的表征数据为:1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.27(s,1H),8.90(s,1H),8.47-8.42(m,2H),7.84(s,1H),7.75(t,J=7.9Hz,1H),7.20(s,1H).
上述中间体i-8-1的制备包括:室温氮气环境下,将中间体i-7(2.79g,7.35mmol)加入到20mL DMF中,依次加入间氰基溴苄(1.73g,8.82mmol)和碳酸铯(3.59g,11.03mmol),加毕,rt搅拌反应3h,TLC检测反应完全后,加入60mL冰水,搅拌约30min,搅拌过程中用稀HCl调pH至中性,然后抽滤,滤饼干燥后得2.20g白色固体,即中间体i-8-1,产率:60.12%。该中间体i-8的表征数据为:1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.82(s,1H),8.44-8.37(m,2H),7.96(s,1H),7.85(s,1H),7.81-7.76(m,2H),7.70(t,J=8.0Hz,1H),7.65(s,1H),7.57(t,J=7.8Hz,1H),5.27(s,2H).
上述中间体i-8-2的制备包括:室温氮气环境下,将中间体i-7(2.79g,7.35mmol)加入到20mL DMF中,依次加入5-(溴甲基)烟腈(1.74g,8.82mmol)和碳酸铯(3.59g,11.03mmol),加毕,rt搅拌反应3h,TLC检测反应完全后,加入60mL冰水,搅拌约30min,搅拌过程中用稀HCl调pH至中性,然后抽滤,滤饼干燥后得2.02g白色固体,即中间体i-8-2,产率:55.13%。该中间体i-8-2的表征数据为:1H NMR(400MHz,CDCl3)δ10.26(s,1H),8.89(d,J=4.5Hz,2H),8.06(s,1H),7.89(s,1H),7.77(s,1H),7.45(d,J=6.2Hz,1H),7.22(t,J=7.5Hz,1H),6.55(s,1H),5.21(s,2H),5.17(s,2H),2.58(s,3H),1.37(s,12H).
上述中间体i-9-1的制备包括:室温下,将中间体i-4-1(1.03g,2.01mmol)加入到8mLTHF中,然后加入1mL的水,依次加入中间体i-8-1(0.99g,2.02mmol),磷酸三钾(1.28g,6.03mmol)和XPhos-Pd(G2)(0.16g,0.20mmol),加毕,氮气置换三次,升温70℃,反应约16h,TLC检测反应完全后,减压浓缩溶剂,加入15mL冰水搅拌约30min,然后抽滤,滤饼干燥后,采用二氯甲烷/甲醇150∶1做洗脱剂进行柱色谱纯化,最后得0.30g黄色固体,即中间体i-9-1,产率:18.58%。该中间体i-9-1的表征数据为:1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),10.24(s,1H),8.68(s,1H),8.49(s,1H),8.06(s,1H),8.03(s,1H),7.99(s,1H),7.96-7.91(m,2H),7.90-7.82(m,4H),7.75(s,1H),7.73(s,1H),7.70-7.52(m,4H),7.36(s,1H),7.30(s,2H),5.52-5.40(m,4H),5.35(s,2H),2.04(s,3H).
上述中间体i-9-2的制备包括:室温下,将中间体i-4-2(1.04g,2.01mmol)加入到8mLTHF中,然后加入1mL的水,依次加入中间体i-8-2(0.99g,2.02mmol),磷酸三钾(1.28g,6.03mmol)和XPhos-Pd(G2)(0.16g,0.20mmol),加毕,氮气置换三次,升温70℃,反应约16h,TLC检测反应完全后,减压浓缩溶剂,加入15mL冰水搅拌约30min,然后抽滤,滤饼干燥后,采用二氯甲烷/甲醇150:1做洗脱剂进行柱色谱纯化,最后得0.24g黄色固体,即中间体i-9-2,产率:15.29%。该中间体i-9-2的表征数据为:1H NMR(400MHz,CDCl3)δ10.43(s,1H),10.28(s,1H),8.92(s,2H),8.89(s,2H),8.69(s,1H),8.48(d,J=6.8Hz,1H),8.06(s,2H),7.91(s,2H),7.84-7.69(m,2H),7.38-7.31(m,3H),7.18(s,1H),6.65(s,2H),5.30(s,2H),5.27(s,4H),2.11(s,3H).
实施例1
室温下,将中间体i-9-1(50.00mg,62.06μmol)加入到25mL茄型反应瓶中,然后加入3mL二氯甲烷和2mL甲醇,搅拌完全溶解后,加入N-乙酰基乙二胺(50.71mg,496.48μmol),滴加2滴冰乙酸,室温搅拌12h后,将STAB(103.72mg,496.48μmol)分成约三批,每批间隔15min加入到反应瓶中,加入完毕后,rt搅拌4h,TLC检测反应完全后,减压浓缩溶剂,加入15mL冰水搅拌约30min,搅拌过程中用饱和碳酸氢钠水溶液调pH至8左右,然后抽滤,滤饼干燥,粗品采用制备薄层色谱纯化,最后得15mg米黄色固体产物1,产率:24.72%。该黄色固体产物1的表征数据为:HRMS(ESI)for C54H50Cl2N8O6[M+H]+.Calcd:977.3309,found:977.3307;1H NMR(400MHz,CDCl3)δ8.71(s,1H),8.50(dd,J=8.2,1.6Hz,1H),7.87(dd,J=7.2,1.4Hz,1H),7.82-7.77(m,1H),7.74(s,1H),7.72(s,1H),7.70-7.62(m,4H),7.59-7.49(m,4H),7.40-7.29(m,3H),6.96(s,1H),6.62(s,1H),6.28(s,1H),6.16(s,1H),5.23-5.14(m,4H),5.13(s,2H),3.90(s,2H),3.80(s,2H),3.43-3.31(m,4H),2.84(t,J=5.8Hz,2H),2.78(t,J=5.7Hz,2H),2.10(s,4H),2.00(s,3H),1.97(s,3H).
实施例2
以中间体i-9-1(50.00mg,62.06μmol)为原料,乙醇胺(30.3mg,496.48μmol)为小分子胺,参照实施例1的制备方法,得13mg白色固体产物2,产率23.62%。该白色固体产物2的表征数据为:HRMS(ESI)for C50H44Cl2N6O6[M+H]+.Calcd:895.2778,found:895.2774;1HNMR(400MHz,DMSO-d6)δ8.66(s,1H),8.49(dd,1H),8.03(s,1H),7.99-7.94(m,2H),7.94-7.88(m,2H),7.88-7.81(m,3H),7.72(s,1H),7.68-7.61(m,2H),7.60-7.54(m,2H),7.44(s,1H),7.34(t,J=7.6Hz,1H),7.27(d,J=7.4Hz,1H),7.18(s,1H),5.34(s,2H),5.33(s,2H),5.22(s,2H),3.97(s,2H),3.96(s,2H),3.60(s,4H),2.86-2.73(m,4H),2.04(s,3H).
实施例3
以中间体i-9-1(50.00mg,62.06μmol)为原料,丝氨醇(45.2mg,496.48μmol)为小分子胺,操作步骤参照实施例1的制备,可制得13mg米色固体产物3,产率为21.0%。该米色固体产物3的表征数据为:HRMS(ESI)for C52H48Cl2N6O8[M+H]+.Calcd:955.2989,found:955.2985;1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),8.49(d,J=7.8Hz,1H),7.99(s,1H),7.97-7.92(m,2H),7.90(d,J=10.0Hz,1H),7.87-7.81(m,3H),7.69(s,1H),7.67-7.60(m,2H),7.57(d,J=7.3Hz,1H),7.47(s,1H),7.39(s,1H),7.33(t,J=7.4Hz,1H),7.26(d,J=7.5Hz,1H),7.13(s,1H),5.31(s,2H),5.29(s,2H),5.21(s,2H),4.72-4.51(m,2H),3.89(s,2H),3.82(s,2H),3.54-3.38(m,8H),2.64(s,2H),2.04(s,3H).
实施例4
以中间体i-9-1(50.00mg,62.06μmol)为原料,2-氨基-2-甲基-1,3-丙二醇(52.1mg,496.48μmol)为小分子胺,操作步骤参照实施例1的制备,得14mg白色固体产物4,产率21.84%。该白色固体产物4的表征数据为:HRMS(ESI)for C54H52Cl2N6O8[M+H]+.Calcd:983.3302,found:983.3305;1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),8.49(d,J=7.9Hz,1H),7.97(s,1H),7.96-7.89(m,3H),7.88-7.80(m,4H),7.69-7.59(m,3H),7.56(d,J=7.4Hz,1H),7.42(s,1H),7.36(s,1H),7.33(t,J=7.7Hz,1H),7.25(d,J=7.5Hz,1H),7.09(s,1H),5.34-5.24(m,4H),5.21(s,2H),4.51-4.34(m,4H),3.76(s,2H),3.64(s,2H),3.34-3.31(m,5H),3.31-3.27(m,4H),2.03(s,3H),0.96(s,3H),0.93(s,3H).
实施例5
以中间体i-9-1(50.00mg,62.06μmol)为原料,3-羟基胺基甲烷(60.1mg,496.48μmol)为小分子胺,操作步骤参照实施例1的制备,可制得12mg米黄色固体产物5,产率19.56%。该米黄色固体产物5的表征数据为:HRMS(ESI)for C54H52Cl2N6O10[M+H]+.Calcd:1015.3200,found:1015.3205;1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),8.49(d,J=7.8Hz,1H),7.99-7.94(m,2H),7.94-7.90(m,2H),7.89-7.84(m,2H),7.83(s,1H),7.81(s,1H),7.69(s,1H),7.66-7.59(m,2H),7.55(d,J=7.4Hz,1H),7.44(s,1H),7.36(s,1H),7.32(t,J=7.6Hz,1H),7.25(d,J=7.4Hz,1H),7.09(s,1H),5.30(s,2H),5.27(s,2H),5.22(s,2H),4.54-4.17(m,6H),3.86(s,2H),3.74(s,2H),3.47-3.42(m,6H),3.42-3.39(m,6H),2.03(s,3H).
实施例6
以中间体i-9-1(50.00mg,62.06μmol)为原料,(R)-3-氨基-1,2-丙二醇(45.2mg,496.48μmol)为小分子胺,操作步骤参照实施例1的制备,可制得13mg米黄色固体产物6,产率21.67%。该米黄色固体产物6的表征数据为:HRMS(ESI)for C52H48Cl2N6O8[M+H]+.Calcd:955.2989,found:955.2984;1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.49(d,J=7.8Hz,1H),7.96(s,2H),7.92(s,2H),7.88-7.80(m,4H),7.65(s,1H),7.63(s,1H),7.61(s,1H),7.57(d,J=7.4Hz,1H),7.42-7.36(m,2H),7.33(t,J=7.5Hz,1H),7.26(d,J=7.4Hz,1H),7.11(s,1H),5.29(s,2H),5.28(s,2H),5.20(s,2H),3.79(s,2H),3.68(s,2H),3.62-3.52(m,2H),3.37-3.34(m,4H),2.70-2.55(m,2H),2.48-2.40(m,2H),2.04(s,3H).
实施例7
以中间体i-9-1(50.00mg,62.06μmol)为原料,(S)-3-氨基-1,2-丙二醇(45.2mg,496.48μmol)为小分子胺,操作步骤参照实施例1的制备,,可制得9mg米黄色固体产物7,产率15.80%。该米黄色固体产物7的表征数据为:HRMS(ESI)for C52H48Cl2N6O8[M+H]+.Calcd:955.2989,found:955.2990;1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.49(d,J=7.7Hz,1H),8.04-7.94(m,2H),7.92(s,2H),7.88-7.83(m,2H),7.83-7.73(m,2H),7.70-7.59(m,3H),7.57(d,J=7.4Hz,1H),7.44-7.36(m,2H),7.33(t,J=7.4Hz,1H),7.26(d,J=7.4Hz,1H),7.12(s,1H),5.30(s,2H),5.28(s,2H),5.20(s,2H),3.81(s,2H),3.71(s,2H),3.63-3.53(m,2H),3.37-3.36(m,2H),3.35-3.34(m,2H),2.73-2.57(m,2H),2.04(s,3H).
实施例8
以中间体i-9-1(50.00mg,62.06μmol)为原料,乙胺(22.4mg,496.48μmol)为小分子胺,操作步骤参照实施例1的制备,可制得10mg米黄色固体产物8,产率19.99%。该米黄色固体产物8的表征数据为:HRMS(ESI)for C50H44Cl2N6O4[M+H]+.Calcd:863.2879,found:863.2882;1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.49(d,J=7.7Hz,1H),8.04(s,1H),7.97(s,1H),7.95(d,J=6.6Hz,1H),7.93-7.87(m,2H),7.87-7.81(m,3H),7.72(s,1H),7.68-7.61(m,2H),7.60-7.52(m,2H),7.45(s,1H),7.34(t,J=7.3Hz,1H),7.26(d,J=7.3Hz,1H),7.18(s,1H),5.38-5.31(m,4H),5.22(s,2H),3.93(s,2H),3.91(s,2H),2.82-2.70(m,4H),2.04(s,3H),1.18-1.11(m,6H).
实施例9
以中间体i-9-1(50.00mg,62.06μmol)为原料,异丙胺(29.3mg,496.48μmol)为小分子胺,操作步骤参照实施例1的制备,可制得14mg黄色固体产物9,产率26.65%。该黄色固体产物9的表征数据为:HRMS(ESI)for C52H48Cl2N6O4[M+H]+.Calcd:891.3192,found:891.3197;1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),8.49(d,J=7.6Hz,1H),8.02(s,1H),8.00-7.89(m,3H),7.89-7.78(m,4H),7.70-7.61(m,3H),7.58(d,J=7.1Hz,1H),7.48(s,1H),7.42(s,1H),7.34(t,J=7.3Hz,1H),7.27(d,J=7.3Hz,1H),7.17(s,1H),5.37-5.28(m,4H),5.25-5.18(m,2H),3.91-3.79(m,4H),2.96(s,1H),2.89(s,1H),2.04(s,3H),1.13-1.03(m,12H).
实施例10
以中间体i-9-1(50.00mg,62.06μmol)为原料,4-羟基哌啶(57.144mg,496.48μmol)为小分子胺,操作步骤参照实施例1的制备,可制得10mg米黄色固体产物10,产率17.69%。该米黄色固体产物10的表征数据为:HRMS(ESI)for C56H52Cl2N6O6[M+H]+.Calcd:975.3404,found:975.3407;1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.49(d,J=7.9Hz,1H),8.03-7.95(m,2H),7.95-7.89(m,2H),7.89-7.83(m,3H),7.83(s,1H),7.68-7.55(m,4H),7.54-7.39(m,2H),7.35(t,J=7.5Hz,1H),7.27(d,J=7.5Hz,1H),7.19(s,1H),5.38-5.28(m,4H),5.26-5.18(m,2H),3.75-3.45(m,4H),3.21-2.58(m,6H),2.35-2.09(m,2H),2.04(s,3H),1.92-1.64(m,5H),1.65-1.33(m,5H).
实施例11
以中间体i-9-1(50.00mg,62.06μmol)为原料,2-甲氧基乙胺(37.27mg,496.48μmol)为小分子胺,操作步骤参照实施例1的制备,可制得12mg黄白色固体产物11,产率22.42%。该黄色固体产物11的表征数据为:HRMS(ESI)for C52H48Cl2N6O6[M+H]+.Calcd:923.3091,found:923.3095;1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),8.52-8.45(m,1H),7.99-7.94(m,2H),7.94-7.88(m,2H),7.86-7.79(m,4H),7.63(m,2H),7.61-7.55(m,2H),7.41-7.37(m,2H),7.33(t,J=7.6Hz,1H),7.26(d,J=7.4Hz,1H),7.12(s,1H),5.33-5.25(m,4H),5.20(s,2H),3.80(s,2H),3.70(s,2H),3.48-3.37(m,6H),3.25(s,3H),3.22(s,3H),2.71(t,J=5.5Hz,2H),2.66(t,J=5.4Hz,2H),2.03(s,3H).
实施例12
以中间体i-9-1(50.00mg,62.06μmol)为原料,N-甲基-2-羟基-乙胺(37.27mg,496.48μmol)为小分子胺,操作步骤参照实施例1的制备,可制得12mg米白色固体产物12,产率22.42%。该米白色固体产物12的表征数据为:HRMS(ESI)for C52H48Cl2N6O6[M+H]+.Calcd:923.3091,found:923.3096;1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.48(d,J=8.0Hz,1H),8.01-7.88(m,4H),7.88-7.79(m,4H),7.68-7.49(m,4H),7.40(s,1H),7.39(s,1H),7.34(t,J=7.6Hz,1H),7.26(d,J=7.5Hz,1H),7.12(s,1H),5.30(s,2H),5.28(s,2H),5.22-5.17(m,2H),3.60(s,2H),3.58-3.53(m,2H),3.53-3.45(m,4H),2.54-2.51(m,2H),2.49-2.41(m,2H),2.25(s,3H),2.18(s,3H),2.04(s,3H).
实施例13
以中间体i-9-1(50.00mg,62.06μmol)为原料,4-胺基四氢吡喃(50.2mg,496.48μmol)为小分子胺,操作步骤参照实施例1的制备,可制得15mg白色固体产物13,产率24.92%。该白色固体产物13的表征数据为:HRMS(ESI)for C56H52Cl2N6O6[M+H]+.Calcd:975.3404,found:975.3409;1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),8.49(d,J=7.9Hz,1H),8.00-7.87(m,4H),7.86-7.78(m,4H),7.67-7.60(m,3H),7.57(d,J=7.4Hz,1H),7.43-7.37(m,2H),7.33(t,J=7.6Hz,1H),7.26(d,J=7.4Hz,1H),7.12(s,1H),5.29(s,4H),5.20(s,2H),3.89-3.76(m,6H),3.74-3.63(m,2H),3.34-3.18(m,6H),2.04(s,3H),1.84-1.71(m,4H),1.35-1.19(m,6H).
实施例14
以中间体i-9-1(50.00mg,62.06μmol)为原料,环丙胺(28.3mg,496.48μmol)为小分子胺,操作步骤参照实施例1的制备,可制得14mg黄白色固体产物14,产率25.93%。该黄色固体产物14的表征数据为:HRMS(ESI)for C52H44Cl2N6O4[M+H]+.Calcd:887.2879,found:887.2882;1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),8.49(d,J=8.2Hz,1H),7.98(s,1H),7.97-7.93(m,2H),7.90(t,1H),7.87-7.79(m,4H),7.68-7.60(m,2H),7.60-7.54(m,2H),7.39(s,2H),7.33(t,J=7.5Hz,1H),7.26(d,J=7.4Hz,1H),7.12(s,1H),5.30(s,2H),5.29(s,2H),5.21(s,2H),3.84(s,2H),3.77(s,2H),2.19-2.10(m,2H),2.03(s,3H),0.45-0.36(m,4H),0.36-0.26(m,4H).
实施例15
以中间体i-9-1(50.00mg,62.06μmol)为原料,环戊胺(42.2mg,496.48μmol)为小分子胺,操作步骤参照实施例1的制备,可制得12mg米黄色固体产物15,产率21.95%。该米黄色固体产物15的表征数据为:HRMS(ESI)for C56H52Cl2N6O4[M+H]+.Calcd:943.3505,found:943.3510;1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),8.49(dd,J=7.9,1.5Hz,1H),8.06(s,1H),7.99(s,1H),7.98-7.94(m,1H),7.94-7.87(m,2H),7.87-7.80(m,3H),7.72(s,1H),7.68-7.61(m,2H),7.59(d,J=7.4Hz,1H),7.55(s,1H),7.45(s,1H),7.34(t,J=7.5Hz,1H),7.27(d,J=7.3Hz,1H),7.19(s,1H),5.34(s,2H),5.32(s,2H),5.21(s,2H),3.89(s,2H),3.88(s,2H),3.29-3.19(m,2H),2.04(s,3H),1.88-1.78(m,4H),1.69-1.59(m,4H),1.54-1.43(m,8H).
实施例16
以中间体i-9-1(50.00mg,62.06μmol)为原料,(R)-3-吡咯烷醇(50.2mg,496.48μmol)为小分子胺,操作步骤参照实施例1的制备,可制得12mg米黄色固体产物16,产率21.86%。该米黄色固体产物16的表征数据为:HRMS(ESI)for C54H48Cl2N6O6[M+H]+.Calcd:947.3091,found:947.3092;1H NMR(400MHz,DMSO-d6)δ8.67(s,1H),8.48(d,J=7.9Hz,1H),8.00-7.94(m,2H),7.94-7.88(m,2H),7.88-7.80(m,4H),7.67-7.61(m,2H),7.60-7.55(m,2H),7.40(s,1H),7.37(s,1H),7.33(d,J=7.5Hz,1H),7.26(d,J=7.4Hz,1H),7.13(s,1H),5.31(s,2H),5.29(s,2H),5.21(s,2H),4.78(s,2H),4.23(s,2H),3.79-3.54(m,5H),3.47-3.36(m,2H),2.82-2.63(m,4H),2.48-2.40(m,2H),2.04(s,3H),1.59(s,2H).
实施例17
以中间体i-9-1(50.00mg,62.06μmol)为原料,(S)-3-吡咯烷醇(50.2mg,496.48μmol)为小分子胺,操作步骤参照实施例1的制备,可制得11mg米黄色固体产物17,产率19.43%。该米黄色固体产物17的表征数据为:HRMS(ESI)for C54H48Cl2N6O6[M+H]+.Calcd:947.3091,found:947.3088;1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.48(d,J=8.0Hz,1H),7.97(s,1H),7.95(s,1H),7.94-7.90(m,2H),7.88(d,J=10.0Hz,1H),7.85-7.83(m,2H),7.83-7.78(m,2H),7.66-7.61(m,2H),7.58(s,1H),7.57(s,1H),7.40(s,1H),7.38(s,1H),7.34(t,J=7.6Hz,1H),7.26(d,J=7.4Hz,1H),7.13(s,1H),5.31(s,2H),5.29(s,2H),5.21(s,2H),4.92-4.75(m,2H),4.29-4.17(m,2H),3.78-3.60(m,4H),2.74(dd,J=15.8,7.0Hz,4H),2.51-2.35(m,4H),2.04(s,3H),1.65-1.56(m,2H).
实施例18
以中间体i-9-1(50.00mg,62.06μmol)为原料,环己胺(49.2mg,496.48μmol)为小分子胺,操作步骤参照实施例1的制备,可制得10mg黄色固体产物18,产率17.76%。该黄色固体产物18的表征数据为:HRMS(ESI)for C58H56Cl2N6O4[M+H]+.Calcd:971.3818,found:971.3819;1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),8.49(dd,J=7.9,1.7Hz,1H),8.03(s,1H),8.01-7.94(m,2H),7.94-7.89(m,1H),7.88-7.80(m,4H),7.68(s,1H),7.65(d,J=2.9Hz,1H),7.64-7.61(m,1H),7.59(d,J=7.7Hz,1H),7.50(s,1H),7.42(s,1H),7.34(t,J=7.5Hz,1H),7.26(d,J=7.4Hz,1H),7.17(s,1H),5.33(s,2H),5.30(s,2H),5.20(s,2H),3.88(s,2H),3.85(s,2H),2.04(s,3H),1.95-1.85(m,4H),1.72-1.63(m,4H),1.60-1.43(m,4H),1.21-1.10(m,10H).
实施例19
以中间体i-9-1(50.00mg,62.06μmol)为原料,环丁基胺(35.3mg,496.48μmol)为小分子胺,操作步骤参照实施例1的制备,可制得12mg黄色固体产物19,产率21.36%。该黄色固体产物19的表征数据为:HRMS(ESI)for C54H48Cl2N6O4[M+H]+.Calcd:915.3192,found:915.3194;1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),8.49(d,J=7.8Hz,1H),8.01(s,1H),7.98-7.93(m,2H),7.94-7.88(m,1H),7.88-7.84(m,2H),7.84-7.79(m,2H),7.68-7.60(m,3H),7.57(d,J=7.4Hz,1H),7.42(s,1H),7.39(s,1H),7.33(t,J=7.5Hz,1H),7.26(d,J=7.4Hz,1H),7.14(s,1H),5.31(s,4H),5.21(s,2H),3.71(s,2H),3.66(s,2H),2.15-1.96(m,8H),1.81-1.53(m,9H).
实施例20
以中间体i-9-2(50.00mg,62.03μmol)为原料,乙醇胺(30.2mg,496.24μmol)为小分子胺,参照实施例1的制备方法,得11.3mg白色固体产物20,产率20.31%。该白色固体产物20的表征数据为:HRMS(ESI)for C48H43Cl2N8O6[M+H]+.Calcd:897.2683,found:897.2679.
实施例21
以中间体i-9-2(50.00mg,62.03μmol)为原料,丝氨醇(45.1mg,496.24μmol)为小分子胺,操作步骤参照实施例1的制备,可制得16.8mg米色固体产物21,产率为28.5%.该米色固体产物21的表征数据为:HRMS(ESI)for C50H47Cl2N8O8[M+H]+.Calcd:957.2894,found:957.2890.
实施例22
以中间体i-9-2(50.00mg,62.03μmol)为原料,2-氨基-2-甲基-1,3-丙二醇(52.0mg,496.24μmol)为小分子胺,操作步骤参照实施例1的制备,得20.3mg白色固体产物22,产率33.21%。该白色固体产物22的表征数据为:HRMS(ESI)for C52H51Cl2N8O8[M+H]+.Calcd:985.3207,found:985.3211.
实施例23
以中间体i-9-2(50.00mg,62.03μmol)为原料,3-羟基胺基甲烷(60.0mg,496.24μmol)为小分子胺,操作步骤参照实施例1的制备,可制得19.8mg米黄色固体产物23,产率31.50%。该米黄色固体产物23的表征数据为:HRMS(ESI)forC52H50Cl2N8O10[M+H]+.Calcd:1017.3105,found:1017.3110.
实施例24
以中间体i-9-2(50.00mg,62.03μmol)为原料,(S)-3-氨基-1,2-丙二醇(45.0mg,496.24μmol)为小分子胺,操作步骤参照实施例1的制备,可制得15.7mg米黄色固体产物24,产率26.4%.该米黄色固体产物24的表征数据为:HRMS(ESI)forC50H46Cl2N8O8[M+H]+.Calcd:957.2894,found:957.2889.
实施例25
以中间体i-9-1(50.00mg,62.03μmol)为原料,(R)-3-氨基-1,2-丙二醇(45.0mg,496.24μmol)为小分子胺,操作步骤参照实施例1的制备,,可制得13.6mg米黄色固体产物25,产率22.9%。该米黄色固体产物25的表征数据为:HRMS(ESI)for C50H46Cl2N8O8[M+H]+.Calcd:957.2894,found:957.2890.
上述实施例1-25制得的8-苯基喹唑啉类化合物的结构式如表1所示。
表1各实施例的化学名称及结构式
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实施例26 PD-1/PD-L1抑制活性测试
为了验证实施例1-25制得的8-苯基喹唑啉类化合物对PD-1/PD-L1蛋白是否具有显著的抑制作用,本实施例使用Csibio公司的PD-1/PD-L1结合力检测试剂盒(Cat.No.64PD1PEH),采用HTRF法(均相时间分辨荧光),对实施例1-25制得的8-苯基喹唑啉类化合物进行了PD-1/PD-L1抑制活性测试,包括如下步骤:
(1)准备化合物:用DMSO将25个化合物和阳性对照化合物(BMS-202)溶解混匀,配制成10mM的母液,然后用Buffer再将其逐个按倍比稀释至对应浓度,100μM、25μM、6.3μM、1.6μM、0.39μM、0.1μM;
(2)准备检测试剂:将PD-1/PD-L1结合力检测试剂盒中的材料在室温下解冻并摇匀;
(3)用Buffer将Tag1-PD-L1 protein,Tag2-PD-1protein稀释40倍;用Buffer将Anti-Tag1 Eu Cryptate Reagent,Anti-Tag2 XL665 antibody稀释50倍,然后将Anti-Tag1 Eu Cryptate Reagent、Anti-Tag2 XL665 antibody 1∶1混匀;
(4)用Echo 550Liquid Handler(Labcyte)在384孔板中加入100nL稀释好的待测化合物或阳性对照化合物,然后依次加入5uL稀释好的Tag1-PD-L1 protein和2.5uL稀释好的Tag2-PD-1 protein,吹打混匀(每组3个复孔);
(5)每个孔位加5μL混合好的Anti-Tag1 Eu Cryptate Reagent、Anti-Tag2 XL665antibody,DMSO的终浓度为1%,化合物终浓度为1000nM、250nM、63nM、16nM、3.9nM、1.0nM;吹打混匀,封膜避光室温孵育1h;
(6)用EnVision多功能酶标仪(Perkin Elmer)检测荧光信号(320nm激发,665nm,615nm发射);
(7)发射信号比率和抑制率,根据以下公式计算。Emission Ratio(ER)=665nmEmission signal/615nm Emission signal,抑制率=(Max-Signal)/(Max-Min)×100%,采用Graphpadprism 5软件算出三组IC50值,再根据IC50算出平均值和标准偏差(SD)。
抑制率=(ERpositive-ERsample)/(ERpositive-ERnegative)×100%
实验结果如表2所示,A:IC50<50nM;B:50nM<IC50<100nM;C:100nM<IC50<1000nM;D:1000nM<IC50;
表2实施例1-25制得的8-苯基喹唑啉类化合物对PD-1/PD-L1的抑制活性结果
实施例 | IC50(nM) | 实施例 | IC50(nM) |
实施例1 | B | 实施例14 | C |
实施例2 | A | 实施例15 | C |
实施例3 | A | 实施例16 | 46.17 |
实施例4 | A | 实施例17 | B |
实施例5 | A | 实施例18 | C |
实施例6 | A | 实施例19 | C |
实施例7 | A | 实施例20 | A |
实施例8 | A | 实施例21 | A |
实施例9 | 51.49 | 实施例22 | A |
实施例10 | B | 实施例23 | A |
实施例11 | C | 实施例24 | A |
实施例12 | 44.78 | 实施例25 | A |
实施例13 | B | BMS-202 | 87.20 |
从表2结果可以看出,实施例1-25制得的8-苯基喹唑啉类化合物对PD-1/PD-L1均表现出突出的抑制活性,大部分8-苯基喹唑啉类化合物的IC50值在100nM以下。
综上所述,从表2的活性测试结果可以看出,本发明制得的8-苯基喹唑啉类化合物可以对PD-1/PD-L1信号通路表现出明显的抑制活性,具有治疗PD-1/PD-L1信号通路介导的相关疾病的潜力。
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)
1.一种8-苯基喹唑啉类化合物,其特征在于:其结构式为
其中,
R1为H、C1-5烷基或C3-7环烷基,R2为H、C1-5烷基或C3-7环烷基;R1和R2中的C1-5烷基和C3-7环烷基具有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和与其所连接的氮原子一起形成4-7元杂环基,且该杂环基含有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为H、卤素或甲基;
X为C或N。
2.如权利要求1所述的一种8-苯基喹唑啉类化合物,其特征在于:所述为
3.如权利要求2所述的一种8-苯基喹唑啉类化合物,其特征在于:所述R3为卤素。
4.如权利要求3所述的一种8-苯基喹唑啉类化合物,其特征在于:所述R4为H或甲基。
5.权利要求1至4中任一权利要求所述的8-苯基喹唑啉类化合物及其药学上可接受的盐在制备治疗PD-1/PD-L1信号通路相关疾病的药物组合物中的应用。
6.如权利要求5所述的应用,其特征在于:所述PD-1/PD-L1信号通路相关疾病为肿瘤疾病。
7.如权利要求6所述的应用,其特征在于:所述肿瘤疾病包括肺癌、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、中枢和外周神经系统的肿瘤。
8.一种治疗PD-1/PD-L1信号通路相关疾病的药物组合物,其特征在于:其有效成分包括权利要求1至4中任一权利要求所述的8-苯基喹唑啉类化合物和/或药学上可接受的盐。
9.如权利要求8所述的药物组合物,其特征在于:所述药学上可接受的盐选自硫酸氢盐、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、柠檬酸盐和对甲苯磺酸盐中的至少一种。
10.如权利要求8或9所述的药物组合物,其特征在于:所述PD-1/PD-L1信号通路相关疾病为肿瘤疾病,所述肿瘤疾病包括肺癌、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、中枢和外周神经系统的肿瘤。
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