CN116854687A - Hpk1激酶抑制剂化合物 - Google Patents
Hpk1激酶抑制剂化合物 Download PDFInfo
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- CN116854687A CN116854687A CN202310687634.8A CN202310687634A CN116854687A CN 116854687 A CN116854687 A CN 116854687A CN 202310687634 A CN202310687634 A CN 202310687634A CN 116854687 A CN116854687 A CN 116854687A
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- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical class CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
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- 230000037361 pathway Effects 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L persulfate group Chemical group S(=O)(=O)([O-])OOS(=O)(=O)[O-] JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本发明提供了一种具有抑制HPK1激酶活性的化合物以及包含所述化合物的药物组合物。本发明还提供了所述化合物在预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病或免疫介导性疾病中的用途。
Description
技术领域
本发明涉及一种杂环化合物，具体地涉及一种高活性的HPK1激酶抑制剂及其用途。
背景技术
HPK1是MAP4K家族的成员之一，主要在造血系统细胞中表达，并且充当T细胞增殖和信号传导的细胞内负调节物。抗原刺激T细胞后促使胞浆中的接头蛋白SLP-76被招募到脂膜TCR复合体上，为信号转导相关激酶提供结合位点来实现TCR介导的信号传递而诱导T细胞激活。在这一过程中HPK1被酪氨酸激酶Lck和Zap70磷酸化而激活，参与调节T细胞受体蛋白相互作用。HPK1通过磷酸化接头蛋白SLP-76的Ser376位点，使得SLP-76与支架蛋白14-3-3ε结合进而通过蛋白酶体被降解，而这一效应使得SLP-76与信号转导相关激酶结合减少而阻断了TCR信号转导，继而抑制T细胞激活和增值。另一方面，HPK1还参与了调控树突状细胞(DC)的成熟及激活，特别是抑制了DC细胞中协助T细胞激活相关蛋白如CD80，CD86及MHC复合物等的表达，进而影响DC调节T细胞激活的作用；而活化的DC对肿瘤抗原的呈递及DC和T细胞的相互协作是抗肿瘤免疫系统中最重要的环节之一。此外在肿瘤微环境中存在大量免疫抑制性的分子如PGE2和TGF－β，这些因子介导的免疫抑制作用也与HPK1有重要联系。总体而言，特异性靶向抑制HPK1的小分子化合物可以改善T细胞功能，增强DC细胞功能，并同时逆转肿瘤免疫抑制微环境，通过多途径来发挥增强抗肿瘤免疫效应，从而实现抑制肿瘤生长的作用。然而，目前尚缺乏有效的HPK1激酶活性抑制剂。
因此，现有技术中仍迫切需要有效的HPK1激酶活性抑制剂，以便为抗肿瘤提供更多有效的选择。
发明内容
本发明意外发现了一种具有抑制HPK1激酶活性的式(I)化合物以及其药学上可接受的盐、同位素衍生物或立体异构体，具有如下结构：
特别注意的是，在本文中，当提及具有特定结构式的“化合物”时，一般地还涵盖其立体异构体、非对映异构体、对映异构体、外消旋混合物和同位素衍生物。
本领域技术人员公知，一种化合物的盐、溶剂合物、水合物是化合物的替代性存在形式，它们都可以在一定条件下转化为所述化合物，因此，特别注意的是在本文中当提到一种化合物时，一般地还包括它的可药用盐，进而还包括其溶剂合物和水合物。
相似地，在本文中当提到一种化合物时，一般地还包括其前药、代谢产物和氮氧化物。
本发明所述的可药用盐可使用例如以下的无机酸或有机酸而形成：“可药用盐”是指这样的盐，在合理的医学判断范围内，其适用于接触人和较低等动物的组织，而没有不适当的毒性、刺激性、过敏反应等，称得上合理的受益/风险比。可以在本发明化合物的最终分离和纯化期间原位制备所述盐，或单独通过将游离碱或游离酸与合适的试剂反应制备所述盐，如下概述。例如，游离碱功能可以与合适的酸反应。此外，当本发明的化合物带有酸性部分，其合适的可药用盐可包括金属盐，例如碱金属盐(如钠盐或钾盐)；和碱土金属盐(如钙盐或镁盐)。可药用的无毒酸加成盐的示例是氨基与无机酸(例如，盐酸、氢溴酸、磷酸、硫酸和高氯酸)或有机酸(例如，醋酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸或丙二酸)形成的盐，或通过使用现有技术中的其他方法如离子交换形成的盐。其他可药用盐包括己二酸盐、海藻酸钠、抗坏血酸盐、天门冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、hernisulfate、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等。代表性碱金属或碱土金属盐包括钠、锂、钾、钙、镁等的盐。其他可药用盐包括(适当时)无毒铵盐、季铵盐和用反离子形成的胺阳离子，例如，卤化物、氢氧化物、羧酸盐、硫酸盐、磷酸盐、硝酸盐、低级烷基磺酸盐和芳基磺酸盐。
本发明的可药用盐可通过常规方法制备，例如通过将本发明的化合物溶解于与水可混溶的有机溶剂(例如丙酮、甲醇、乙醇和乙腈)，向其中添加过量的有机酸或无机酸水溶液，以使得盐从所得混合物中沉淀，从中除去溶剂和剩余的游离酸，然后分离所沉淀的盐。
本发明所述的“溶剂合物”意指本发明化合物与一个或多个溶剂分子(无论有机的还是无机的)的物理缔合。该物理缔合包括氢键。在某些情形中，例如当一个或多个溶剂分子纳入结晶固体的晶格中时，溶剂化物将能够被分离。溶剂化物中的溶剂分子可按规则排列和/或无序排列存在。溶剂合物可包含化学计量或非化学计量的溶剂分子。“溶剂合物”涵盖溶液相和可分离的溶剂合物。示例性溶剂合物包括但不限于水合物、乙醇合物、甲醇合物和异丙醇合物。溶剂化方法是本领域公知的。
本发明所述的“立体异构”分为构象异构和构型异构，构型异构还可分为顺反异构和旋光异构(即光学异构)，构象异构是指具有一定构型的有机物分子由于碳、碳单键的旋转或扭曲而使得分子各原子或原子团在空间产生不同的排列方式的一种立体异构现象，常见的有烷烃和环烷烃类化合物的结构，如环己烷结构中出现的椅式构象和船式构象。“立体异构体”是指当本发明化合物含有一个或多个不对称中心，因而可作为外消旋体和外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体。本发明化合物有不对称中心，每个不对称中心会产生两个光学异构体，本发明的范围包括所有可能的光学异构体和非对映异构体混合物和纯的或部分纯的化合物。本发明所述的化合物可以以互变异构体形式存在，其通过一个或多个双键位移而具有不同的氢的连接点。例如，酮和它的烯醇形式是酮-烯醇互变异构体。各互变异构体及其混合物都包括在本发明的化合物中。所有式(I)化合物的对映异构体、非对映异构体、外消旋体、内消旋体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物等，均包括在本发明范围中。
本发明的“同位素衍生物”是指在本专利中化合物被同位素标记的分子。通常用作同位素标记的同位素是：氢同位素，2H和3H；碳同位素：11C,13C和14C；氯同位素：35Cl和37Cl；氟同位素：18F；碘同位素：123I和125I；氮同位素：13N和15N；氧同位素：15O,17O和18O和硫同位素35S。这些同位素标记化合物可以用来研究药用分子在组织中的分布情况。尤其是氘3H和碳13C，由于它们容易标记且方便检测，运用更为广泛。某些重同位素，比如重氢(2H)，的取代能增强代谢的稳定性，延长半衰期从而达到减少剂量的目而提供疗效优势的。同位素标记的化合物一般从已被标记的起始物开始，用已知的合成技术象合成非同位素标记的化合物一样来完成其合成。
本发明还提供了本发明化合物在制备用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病或免疫介导性疾病的药物中的用途。
此外，本发明提供了用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病、神经退行性疾病、注意力相关疾病或免疫介导性疾病的药物组合物，其包含本发明化合物作为活性成分。
此外，本发明提供了一种用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病、神经退行性疾病、注意力相关疾病或免疫介导性疾病的方法，其包括向有此需要的哺乳动物施用本发明化合物。
当将本发明化合物或其可药用盐与另外的用于治疗癌症或肿瘤的抗癌剂或免疫检查点抑制剂组合施用时，本发明化合物或其可药用盐可提供增强的抗癌作用。
当将本发明化合物或其可药用盐与另外的用于治疗炎症性疾病、自身免疫性疾病和免疫介导性疾病的治疗剂组合施用时，本发明化合物或其可药用盐可提供增强的治疗作用。
本发明描述示例性实施方案的过程中，本发明的其它特征将变得显而易见，给出所述实施方案用于说明本发明而不意欲成为其限制，以下实施例使用本发明所公开的方法制备、分离和表征。
可以用有机合成领域的技术人员已知的多种方式来制备本发明的化合物，可使用下述方法以及有机合成化学领域中已知的合成方法或通过本领域技术人员所了解的其变化形式来合成本发明化合物。优选方法包括但不限于下文所述的这些。在适用于所使用试剂盒材料和适用于所实现转变的溶剂或溶剂混合物中实施反应。有机合成领域的技术人员将理解，分子上存在的官能性与所提出的转变一致。这有时需要加以判断改变合成步骤的顺序或原料以获得期望的本发明化合物。
具体试试方式
实施例
通用过程
未包括制备途径时，本发明所用原料与试剂均为已知产品，可以按照本领域已知的方法合成，或者可通过购买市售产品获得。使用的市售试剂均不需进一步纯化。
室温是指20-30℃。
如反应实施例中无特殊说明，则反应均在氮气氛下进行。氮气氛是指反应瓶连接一个约1L的氮气气球。
氢化反应通常抽真空，充入氢气，反复操作3次。氢气氛是指反应瓶连接一个约1L的氢气气球。
微波反应使用Initiator+微波反应器。
本发明化合物的结构是通过核磁共振(NMR)和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(BrukerAscendTM 500型)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3),氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。以下简写用于NMR信号的多重性：s＝单峰，brs＝宽峰，d＝二重峰，t＝三重峰，m＝多重峰。耦合常数以J值列出，以Hz测量。
LC-MS的测定使用Thermo液质联用仪(UltiMate 3000+MSQ PLUS)。HPLC的测定使用Thermo高压液相色谱仪(UltiMate 3000)。反相制备色谱使用Thermo(UltiMate 3000)反相制备色谱仪。快速柱层析使用艾杰尔(FS-9200T)自动过柱机，硅胶预装柱使用三泰预装柱。薄层层析硅胶板用烟台黄海HSGF254或青岛GF254硅胶板，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
本发明中一些中间体的合成方法如下：
中间体1
中间体1由以下步骤制备：
第一步：将1-甲基-3,5-二硝基吡啶-2-酮Int-1a(1.0g,5.02mmol)溶于甲醇(50mL)中，依次加入氨甲醇溶液(7mol/L，8.61mL,60.27mmol)和1-甲基哌啶-4-酮Int-1b(625mg,5.52mmol)。反应混合物加热至50℃搅拌5小时。冷却至室温后静置48小时，减压浓缩反应液，残余物加入乙酸乙酯(50mL)后过滤。滤液减压浓缩后得到红色固体Int-1c(1.0g)，直接用于下一步反应。ESI-MS(m/z):194.4[M+H]+；1H NMR(500MHz,DMSO-d6)δ9.14(d,J＝2.5Hz,1H),8.36(d,J＝2.5Hz,1H),3.64(s,2H),3.02(t,J＝6.0Hz,2H),2.74(t,J＝6.0Hz,2H),2.39(s,3H)。
第二步：将上一步得到的化合物Int-1c(1.0g)溶于甲醇(30mL)中，加入10％Pd-C(400mg)，在氢气氛围下室温反应6小时。过滤除去钯碳，滤液浓缩得到黄色固体Int-1d(800mg，收率94.70％)。ESI-MS(m/z):164.2[M+H]+。
第三步：将化合物Int-1d(100mg,0.61mmol)溶于醋酸(3mL)中，加入N-溴代丁二酰亚胺(109mg,0.61mmol)，反应混合物在室温下搅拌1小时。加入饱和碳酸氢钠水溶液淬灭反应直至不产生气泡，水相用甲醇/二氯甲烷(1/20,50mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤浓缩得到化合物Int-1e(38mg，收率25％)。ESI-MS(m/z):242.3[M+H]+；1H NMR(500MHz,DMSO-d6)δ6.77(s,1H),5.25(s,2H),3.37(s,2H),2.69(t,J＝6.0Hz,2H),2.60(t,J＝6.0Hz,2H),2.32(s,3H)。
第四步：将化合物Int-1e(37mg,0.15mmol)溶于甲醇(1mL)中，加入碘化亚铜(3mg，0.015mmol)，1，10-菲啰啉(3mg，0.03mmol)和碳酸铯(99mg,0.30mmol)。反应混合物置换氮气后用微波加热至100℃搅拌2小时。反应冷却至室温，浓缩反应液，残余物用制备型薄层层析纯化(甲醇/二氯甲烷/三乙胺＝1/10/0.1)得到黄色固体Int-1(20mg，收率67％)。ESI-MS(m/z):194.5[M+H]+；1H NMR(500MHz,DMSO-d6)δ6.54(s,1H),4.68(s,2H),3.80(s,3H),3.30(s,2H),2.64(t,J＝5.6Hz,2H),2.59(t,J＝5.7Hz,2H),2.31(s,3H)。
实施例10
4-((5-氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氢-1,6-萘啶-3-基)氨基)嘧啶-4-
基)氨基)-3,3-二甲基丁酸
化合物10由以下步骤制备：
第一步：将化合物10a(200mg，1.02mmol)与2,4,5-三氯嘧啶(43mg，1.33mmol)1d溶解在异丙醇(8mL)之中，向上述反应液之中加入DIPEA(264mg，2.04mmol)，反应液在室温下搅拌过夜。LCMS检测原料转化完全。将反应液浓缩得到粗品并经过硅胶柱层析(石油醚/乙酸乙酯＝3/1)纯化得到无色油状化合物10b(312mg，收率100％)。ESI-MS(m/z):306.3[M+H]+。
第二步：将化合物10b(360mg,1.18mmol)和Int-1(227mg，1.18mmol)溶解在二氧六环(10mL)之中，依次加入碳酸铯(766mg，2.35mmol)，Brettphos Pd G3(213mg，0.23mmol)和Brettphos(126mg,0.23mmol)，反应液在氮气氛围下110℃搅拌过夜。LCMS检测原料转化完全。将反应液浓缩得到粗品并经过硅胶柱层析(二氯甲烷/甲醇＝10/1)纯化得到棕色油10c(280mg，收率51％)。ESI-MS(m/z):463.5[M+H]+。
第三步：将化合物10c(260mg，0.56mmol)溶解在四氢呋喃(5mL)和水(5mL)的混合溶液之中，向上述反应液之中加入氢氧化锂(23mg，0.56mmol)，反应液在室温下搅拌四个小时。将反应液用1N盐酸水溶液酸化到pH＝3，然后用乙酸乙酯萃取。将萃取后的水相浓缩得到粗品。将粗品用反相制备HPLC纯化得到化合物10(3.59mg，收率1.47％)。ESI-MS(m/z):435.2[M+H]+；1H NMR(500MHz,DMSO-d6)δ8.13(s,1H),7.95(s,1H),7.62(s,1H),7.25(s,1H),3.88(s,2H),3.45(s,3H),3.38(s,2H),2.75(d,J＝6.0Hz,2H),2.67(d,J＝6.0Hz,2H),2.35(s,3H),2.15(s,2H),0.96(s,6H)。
实施例13
1-(((5氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氢-1,6-萘啶-3-基)氨基)嘧啶
-4-基)氨基)甲基)环丁烷-1-羧酸
用4-(氨甲基)环丁烷羧酸甲酯盐酸盐替代实施例10第一步中的3,3-二甲基-4-氨基丁酸乙酯盐酸盐10a，用类似的方法和反应步骤，可以得到化合物13。ESI-MS(m/z):433.3[M+H]+；1H NMR(500MHz,DMSO-d6)δ8.15(s,1H),7.97(s,1H),7.63(s,1H),7.01(t,J＝6.1Hz,1H),3.88(s,3H),3.75(d,J＝6.0Hz,2H),3.44(s,2H),2.75(t,J＝5.8Hz,2H),2.66(t,J＝5.8Hz,2H),2.35(s,3H),2.28-2.21(m,2H),2.06-1.99(m,2H),1.84-1.76(m,2H)。
HPK1抑制剂生物学筛选和结果
试验例1：化合物对HPK1激酶活性抑制能力的检测(方法1)
所需使用试剂如下
实验步骤
具体操作如下：配置酶促反应体系缓冲液(10mM MOPS，pH 7.2，5mMβ-glycerol-phosphate，10mM MgCl2，0.8mM EDTA，2mM EGTA，0.1mM DTT)；将测试的化合物(配于DMSO中1mM的化合物储液)用缓冲液稀释至为60uM最高浓度(包含6％DMSO)，并配置60μM浓度起始用包含6％DMSO的缓冲液进行5倍稀释共计8个点的梯度浓度的化合物；随后使用缓冲液将HPK1激酶稀释至30nM。在Greiner384孔微孔板(货号：784075)中每孔加入2μl的HPK1激酶稀释液，对照孔中补充2μl缓冲液；短暂离心后在反应孔中加入1μl的稀释化合物，对照孔中加入1μl包含6％DMSO的缓冲液；短暂离心后置于25℃恒温孵育箱(上海一恒科学仪器有限公司，货号：LRH-150)中孵育20min。在每孔中加入3μl反应底物(溶解于蒸馏水中的10μMMBP和20μMATP)，短暂离心后置于25℃恒温孵育箱中孵育60min，采用ADP-Glo KinaseAssay Kit检测酶促反应活性，ADP-Glo Kinase Assay Kit检测都依据试剂盒的操作说明进行。数据采用化合物的半数抑制浓度IC50描述。
上述结果表明，本发明的化合物对HPK1激酶活性具有优异的抑制能力。
试验例2：化合物对Jurkat细胞分泌细胞因子白介素-2(IL-2)激动能力的检测及化合物对Jurkat细胞活力的影响(方法2)
所需使用试剂及细胞如下：
实验试剂：
实验细胞：
| 细胞 | 细胞类型 | 品牌 |
| JurkatE6-1 | 人T淋巴细胞白血病细胞 | 中科院细胞库 |
实验步骤
具体操作如下：将化合物粉末用DMSO溶解至10mM，取2μl化合物加入到998μl RPMI1640培养基(此试验中均含10％FBS)中，涡旋混匀后为最高浓度点。用0.2％DMSO培养基3倍逐渐稀释化合物溶液，共8个浓度点。以含浓度为0.1％DMSO的RPMI 1640培养基溶液处理作为对照。在康宁96孔细胞培养板(货号：3599)中每孔加入1×105Jurkat E6-1细胞，随后加入等量体积的化合物稀释液，对照组加入含0.2％DMSO的RPMI 1640培养基，置于37℃细胞培养箱(Thermo Fisher Scientific，型号：3111)孵育1h。随后加入终浓度为1μg/ml Anti-human CD3 Antibody和1μg/ml Anti-human CD28Antibody抗体，置于37℃细胞培养箱孵育24h，收集培养上清液，采用Human IL-2DuoSet ELISA KIT检测细胞上清液中的IL-2含量，Human IL-2DuoSet ELISA检测依据试剂盒的操作说明进行。IL-2分泌数据采用化合物的刺激信号与0.1％DMSO的信号的最高倍数比值描述；收集细胞，使用CellTiter-Luminescent Cell ViabilityAssay试剂盒检测细胞活力，细胞活力数据采用化合物的半数抑制浓度IC50描述。
NA:表示未检测到IL-2的释放增强。
上述结果表明，与对照相比，本发明化合物显著增加了Jurkat细胞分泌的细胞因子白介素-2的水平，同时不对Jurkat的细胞活力有不利影响。
试验例3：化合物对人PBMC细胞分泌细胞因子白介素-2(IL-2)激动能力的检测化合物对人PBMC细胞活力的影响(方法3)
所需使用试剂如下
实验细胞来源信息：
实验步骤
具体操作如下：人PBMC按照标准操作从液氮中取出后，置于37℃水浴锅中解冻复苏，将细胞用RPMI 1640培养基(此试验中均含10％FBS)重悬，离心洗涤两次；随后将人PBMC细胞重悬于RPMI 1640培养基中备用。将化合物粉末用DMSO溶解至10mM，取2μl化合物加入到998μl RPMI 1640培养基中，涡旋混匀后为最高浓度点。用0.2％DMSO培养基3倍逐渐稀释化合物溶液，共8个浓度点。以含浓度为0.1％DMSO的RPMI 1640培养基溶液处理作为对照。在康宁96孔细胞培养板(货号：3599)中每孔加入1×105人PBMC细胞，随后加入等量体积的化合物稀释液，对照组加入含0.2％DMSO的RPMI 1640培养基，置于37℃细胞培养箱(ThermoFisher Scientific，型号：3111)孵育1h。随后加入终浓度为0.01μg/mlAnti-humanCD3Antibody和1μg/mlAnti-human CD28 Antibody抗体，置于37℃细胞培养箱孵育24h。采用Human IL-2DuoSet ELISAKIT检测细胞上清液中的IL-2含量，Human IL-2DuoSet ELISA检测依据试剂盒的操作说明进行。数据采用化合物的刺激信号与0.1％DMSO的信号的最高倍数比值描述。收集细胞，使用CellTiter-Luminescent Cell ViabilityAssay试剂盒检测细胞活力，细胞活力数据采用化合物的半数抑制浓度IC50描述。
NA:表示未检测到IL-2的释放增强。
上述结果表明，与对照相比，本发明化合物显著增加了PBMC细胞分泌的细胞因子白介素-2的水平，同时不对PBMC的细胞活力有不利影响。
Claims (3)
1.具有以下结构的化合物或药学上可接受的盐、同位素衍生物、立体异构体：
2.一种药物组合物，其包括权利要求1所述的化合物或药学上可接受的盐、同位素衍生物、立体异构体以及药学上可用的载体。
3.如权利要求1所述的化合物或药学上可接受的盐、同位素衍生物、立体异构体或者权利要求2所述的药物组合物在制备用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病或免疫介导性疾病的药物中的用途。
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