CN117202908A - Wee1激酶抑制剂在治疗癌症疾病中的应用 - Google Patents
Wee1激酶抑制剂在治疗癌症疾病中的应用 Download PDFInfo
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- CN117202908A CN117202908A CN202280019850.9A CN202280019850A CN117202908A CN 117202908 A CN117202908 A CN 117202908A CN 202280019850 A CN202280019850 A CN 202280019850A CN 117202908 A CN117202908 A CN 117202908A
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- amino
- pyrimido
- phenyl
- pyrimidin
- dihydroimidazo
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Abstract
提供的是Wee1激酶抑制剂在治疗癌症疾病中的应用。具体而言,提供了Wee1激酶抑制剂在制备治疗具有组蛋白H3K27M突变的癌症的药物中的用途。
Description
技术领域
本发明属于药物化学领域,涉及癌症治疗领域,具体涉及Wee1激酶抑制剂在治疗具有H3K27M突变癌症疾病上的应用。
背景技术
真核细胞的生长和分裂过程称之为细胞周期。细胞通过细胞周期从新生细胞逐渐成长并分裂为两个细胞来进行繁殖。细胞周期大致包括G1、S、G2和M几个周期:G1期也称为生长期,这个阶段的特点是细胞代谢活跃,大量合成细胞生长所需的蛋白质、糖类、脂类和RNA等使细胞从一个新分裂的年轻细胞迅速成长到成熟细胞。也有一些细胞完成G1期后不再进行细胞周期的循环停留在这一阶段称之为G0期;S期的主要特点是DNA合成复制,细胞染色体由二倍体转变为四倍体,之后细胞进入G2期。这个阶段的特点是一方面细胞继续生长,另外对合成的DNA进行检查修复为细胞进入有丝分裂做好准备。细胞周期的最后一个阶段为M期,在这个阶段细胞通过有丝分裂由一个母细胞分裂为两个相同的子细胞,完成细胞繁殖。细胞周期的整个过程中存在多个细胞周期检验点(cell cycle checkpoint),这包括G1/S或G1检查点和G2/M或G2检查点。它们的主要功能之一是检查确保细胞周期过程中遗传信息(DNA)复制的准确性及是否使细胞向前进入细胞周期的下一个阶段。
每个细胞周期检验点都是由多个因子组成的系统通过复杂的机制工作的。比如,G2-M检验点使用复杂的过程检查DNA损伤。这个细胞周期检验点中的一个重要激酶为Cdk1,其和Cyclin-B1组成复合体(Nurse,P.,1990,Nature 344,503-508)。Cdk1的活化及失活对细胞从G2期进入有丝分裂(M)及随后有丝分裂的完成起着至关重要的作用。Cdk1的活性控制是通过多重机制来调节的,包括与周期蛋白A(Cyclin-A)或细胞周期蛋白B(Cyclin-B)的结合以及磷酸化和去磷酸化。Wee1激酶磷酸化Cdk1并抑制其活性,从而延迟细胞进入有丝分裂。
Wee1是个酪氨酸激酶,通过磷酸化Cdk1上的酪氨酸15(Y15)从而抑制Cdk1的活性(McGowan,C.H.,等人,1993,The EMBO journal 12,75-85;Parker,L.L.,等人,1992,Science 257,1955-1957)。因此,Wee1是Cdk1活性的关键抑制性调节酶,在G2/M期检测点起重要作用(O’Connell,等人,1997,The EMBO journal 16,545-554)。Wee1的丧失或失活会导致细胞过早进入有丝分裂,引起有丝分裂的失败和细胞死亡(Stumpff,J.,等人,2004,Curr Biol 14,2143-2148)。一些肿瘤细胞的G1/S期细胞周期检验点有功能缺陷或丧失,严重依赖G2/M期检测点来保障细胞生长、分裂的进行(Sancar,A.,等人,2004,Annual reviewof biochemistry 73,39-85)。在癌细胞中,G1/S检查点的功能常常由于p53突变等原因而丧失。当DNA损伤发生时,这些细胞严重依赖G2/M检查点功能,并且对Wee1功能丧失敏感。(Wang,Y.,等人,2004,Cancer biology&therapy 3,305-313)。
抑制Wee1的活性可以选择性促使细胞周期检查点有缺陷的癌细胞死亡,对细胞周期检查点正常的正常细胞则作用甚小。因此,Wee1激酶抑制剂有可能用于癌症及其他具有细胞周期检查点缺陷疾病的靶向药物。
近年来,已报道和公开了多种Wee1激酶抑制剂,包括WO2007126122(取代的1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮类化合物)、WO2019028008、WO2019173082和WO202021032(取代的1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮类化合物)、WO2015092431和WO2018162932(取代的2,3-二氢嘧啶并[4,5-d]嘧啶-4(1H)-酮类化合物),WO2019037678(取代的1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮类化合物)、WO2020210377和WO2020210383(取代的杂环化合物)、WO2020210375、WO2020210380、WO2020210381(取代的1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮类化合物)、WO2018133829(l,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮类化合物)和WO2019085933(l,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮大环类化合物)。其中,Adavosertib(AZD1775)是第一个进入临床的Wee1激酶抑制剂,目前处于临床II期研究中。现处于临床阶段的Wee1激酶抑制剂还有ZN-c3和Debio-0123,处于临床I期。还有多种Wee1激酶抑制剂目正处于临床前研究阶段,如DN-1609和NUV-569等。
WO2018090939公开了如下式I化合物或其可药用盐或前药作为Wee1激酶抑制剂。
其中,A是N或CR15;
R1为氢,可被取代的C1-C8烷基,可被取代的C2-C8烯基,可被取代的C3-C8环烷基,可被取代的芳基,可被取代的杂环基或可被取代的杂芳基;
R2为可被取代的碳环基,可被取代的杂环基,可被取代的芳基,或可被取代的杂芳基;
R3-R7和R15独立为氢、卤素、可被取代的氨基、可被取代的烷氧基、可被取代的C1-C10烷基、卤烷基、烯基、炔基、羟基烷基、氨基烷基、羧基烷基、硝基、氰基、酰氨基、羟基、巯基、酰氧基、叠氮基、羧基、亚乙基二氧基,羟基酰氨基或可被取代的烷硫基。
WO2019011228公开了如下式II化合物或其可药用盐或前药作为Wee1激酶抑制剂。
其中,A'是N或CR6';
R1'为氢,可被取代的C1-C8烷基,可被取代的C2-C8烯基,可被取代的C3-C8环烷基,可被取代的芳基,可被取代的杂环基或可被取代的杂芳基;
R2'为可被取代的碳环基,可被取代的杂环基,可被取代的芳基,或可被取代的杂芳基;
R3'-R6'独立为氢、卤素、可被取代的氨基、可被取代的烷氧基、可被取代的C1-C10烷基(如卤烷基、羟基烷基、氨基烷基和羧基烷基)、烯基、炔基、硝基、氰基、酰氨基、羟基、巯基、酰氧基、叠氮基、羧基、亚乙基二氧基、羟基酰氨基或可被取代的烷硫基。
另外,WO2021073491公开了如下式III化合物或其可药用盐或前药作为Wee1激酶抑制剂。
其中,R1”和R2”独立为卤素;R3”为卤素、C1-C4烷基或C1-C4烷氧基;R4”和R6”独立为H或C1-C4烷基;R5”为H或C1-C4烷基;R7”为H、卤素、C1-C4烷基或C1-C4烷氧基;X为CH或N。
组蛋白修饰是表观遗传信息的一种形式,与基因调控密切相关。组蛋白3(H3)27位的赖氨酸是甲基化位点,其甲基化如H3K27me2和H3K27me3可能在表观遗传机制中发挥重要作用。组蛋白H3.3蛋白由H3F3A和H3F3B基因编码。H3(H3K27M)第27位赖氨酸突变为蛋氨酸,常见于儿科胶质母细胞瘤(GBM),尤其是儿童弥漫性内生型桥脑胶质瘤(DIPG)(Khuong-Quang DA等,Acta Neuropathol,2012,124:439-47)。H3K27M突变改变了H3的甲基化状态,并导致表观遗传发生变化,从而全局影响基因表达(Harutyunyan,A.S等,Cell Rep,2020,33:108390-430)。这种H3K27M突变似乎是肿瘤发生的驱动事件。H3K27M在多达30%的小儿成胶质细胞瘤患者中被发现,而在DIPG中则为60%(Wan,Y.C.E.等,Curr Pharmacol Rep,2018,4:292–300)。
弥漫性中线胶质瘤(DMG)是指发生于胼胝体、三脑室、丘脑、脑干等中线结构的高级别脑胶质瘤。该病因发病部位及浸润性生长的特点,治疗困难,预后极差。由于H3K27M的独特突变,2016年WHO中枢神经系统肿瘤分类中将其单独分为一个新的类型。确诊需满足肿瘤位于中枢神经系统中线部位,呈弥漫性生长以及伴有H3K27M突变,无论其组织学形态是否符合高级别特征均诊断为Ⅳ级(David N Louis等,Acta Neuropathol.2016Jun;131(6):803-20)。H3K27M突变在老年胶质瘤和其他类型肿瘤极少,但在儿童中线胶质瘤中较常见。研究表明H3K27M突变与患者的预后具有显著的相关性:例如,对于8岁时诊断为野生型H3的丘脑胶质瘤患者,总生存期(OS)约为11年,而对于10岁时诊断为H3K27M突变的丘脑胶质瘤患者,总生存期仅为1.8年,H3K27M突变的儿童丘脑胶质瘤5年生存率为6.3%,而野生型H3为68.8%(Scott Ryall等,Acta Neuropathol Commun.2016,4:93-102)。无论是高级别(HGG)还是低级别胶质瘤(LGG),具有H3K27M突变的胶质瘤患者具有更短的生存期。
目前弥漫性中线胶质瘤在治疗方面主要采用以手术和辅助放化疗为主要的综合治疗,但儿童DMG患者的生存预后仍很差。对于DMG患者,尤其是具有致命性H3K27M突变的患者,迫切需要找到一种有效的治疗方式。
本发明发现Wee1激酶抑制剂在负荷人H3K27M突变的弥漫性中线胶质瘤的小鼠模型中有很好的药效,可以观察到明显的抑制效果,为临床上H3K27M突变的弥漫性中线胶质瘤患者提供了一种潜在的治疗方式。
发明内容
本发明发现,通过抑制Wee1活性可以有效地抑制具有H3K27M突变的弥漫性中线胶质瘤癌细胞的生长,这对此疾病的治疗具有重要意义。
本发明提供了Wee1激酶抑制剂用于治疗具有H3K27M突变的癌症疾病,特别是用于治疗具有H3K27M突变的弥漫性中线胶质瘤的方法。在一个实施例中,Wee1激酶抑制剂是式I化合物。在一个实施例中,式I化合物用于治疗具有H3K27M突变的癌症疾病,例如H3K27M突变的胶质瘤,尤其H3K27M突变的弥漫性中线胶质瘤。
本发明也提供Wee1激酶抑制剂在制备用于治疗具有H3K27M突变的癌症疾病药物中的用途。在一个实施例中,所述Wee1激酶抑制剂是式I化合物。在一个实施例中,所述具有H3K27M突变的癌症疾病是具有H3K27M突变的胶质瘤,尤其是H3K27M突变的弥漫性中线胶质瘤。
本发明也提供一种治疗具有H3K27M突变的癌症疾病的方法,所述方法为向有需求的受试者施用有效量的Wee1激酶抑制剂。在一个实施例中,该方法包括施用有效量的式I化合物。在一个实施例中,所述具有H3K27M突变的癌症疾病是具有H3K27M突变的胶质瘤,尤其是H3K27M突变的弥漫性中线胶质瘤。
具体而言,本发明包括有用的Wee1激酶抑制剂,尤其为小分子Wee1激酶抑制剂。这些抑制剂包括但不限于本文所述,特别是,包括但不限于AZD1775、Zc-03、Debio-0123、DN-1609、NUV-569、WO2007126122(取代的1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮类化合物)、WO2019028008、WO2019173082和WO202021032(取代的1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮类化合物)、WO2015092431和WO2018162932(取代的2,3-二氢嘧啶并[4,5-d]嘧啶-4(1H)-酮类化合物),WO2019037678(取代的1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮类化合物)、WO2020210377和WO2020210383(取代的杂环化合物)、WO2020210375、WO2020210380、WO2020210381(取代的1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮类化合物)、WO2018133829(l,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮类化合物)、WO2019085933(l,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮大环类化合物)、WO2018090939、WO2019011228和WO2021073491所公开的化合物。
在一个或多个实施方案中,该方法包括施用有效量的式I、II或III的化合物或其立体异构体、药学上可接受的盐或前药。
在一个或多个实施方案中,具有H3K27M突变的癌症是具有H3K27M突变的胶质瘤,包括但不限于胶质母细胞瘤、儿童弥漫性脑桥胶质瘤和弥漫性中线胶质瘤。
附图说明
图1:相关性分析表明H3K27M与化合物反应显著相关。
图2:单细胞表达数据的无监督聚类。左图:通过tSNE降维对样本相关性进行二维表示,按肿瘤样本进行颜色编码;右图:18个细胞群的相同二维颜色编码。
图3:每个模型的3个样本(行、列)的表达谱(上图)或CNV(下图)之间的成对相关分析。在基因表达谱分析中,选择指定样本中每个细胞变异基因的前3000个,计算平均值。
图4:scRNA-seq中肿瘤细胞类型和细胞周期的表征。每个细胞的细胞类型和细胞周期是通过基因组表达与其他基因表达的分布差异来确定的。热图基于每种细胞类型的前5个高表达基因的表达。每列表示一个单元格。
图5:根据细胞类型和细胞周期状态绘制H3K27M细胞的百分比。x轴代表预处理(M574,M309),28天的对照(M574V,M309V)和28天的化合物处理(M574T,M309T)。y轴的比值由指定细胞类型数除以指定样品的总细胞数来计算。
具体实施方式
本文所述癌细胞(或肿瘤细胞)一般以相对于正常细胞的异常增殖以及在患有癌症疾病的个体中形成簇或肿瘤为特性。
本文所述H3K27M突变的癌症疾病可以包括任何类型的实体瘤和恶性淋巴瘤,尤其是胶质瘤,包括但不限于胶质母细胞瘤、儿童弥漫性脑桥胶质瘤和中线胶质瘤。在优选实施方案中,H3K27M突变的癌症疾病为弥漫性中线胶质瘤。癌症可以是家族性的或散发性的。
从个体获得的样本可以是包含一种或多种细胞的组织样本,例如上述癌组织,或例如用作对照的非癌组织活检样本。
个体可能患有癌症疾病,且样本可以是来自肿瘤活检组织的癌细胞样本。
本发明的方法可用于评估患有癌症疾病的个体,从而例如确定作用的治疗时程。评估患有癌症疾病的个体的方法可以包括:鉴定从个体获得的癌细胞是有H3K27M突变,而且提供适于施用于该个体的Wee1激酶抑制剂。
在实施方案中,所述癌细胞可以具有H3K27M突变表型。
个体可能具有H3K27M突变的癌症。本发明的方法和手段尤其可用于这类个体。
个体可以是例如具有H3K27M突变的或多态性的杂合体。
治疗个体中癌症的方法可以包括:给个体施用Wee1激酶抑制剂,其中,所述个体是具有H3K27M突变的或多态性的杂合体。
Wee1激酶抑制剂可用于制备治疗个体中癌症的药物,其中所述个体是具有H3K27M突变的或多态性的杂合体。
适用于此所述方法的Wee1激酶抑制剂可以是抑制、降低或消除Wee1激酶的任何化合物或实体,例如小的有机分子、肽或核酸。
已知为Wee1激酶抑制剂并可根据本发明使用的化合物的实例包括但不限于:AZD1775、Zc-03、Debio-0123、DN-1609、NUV-569、WO2007126122(取代的1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮类化合物)、WO2019028008、WO2019173082和WO202021032(取代的1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮类化合物)、WO2015092431和WO2018162932(取代的2,3-二氢嘧啶并[4,5-d]嘧啶-4(1H)-酮类化合物),WO2019037678(取代的1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮类化合物)、WO2020210377和WO2020210383(取代的杂环化合物)、WO2020210375、WO2020210380、WO2020210381(取代的1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮类化合物)、WO2018133829(l,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮类化合物)、WO2019085933(l,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮大环类化合物)、WO2018090939、WO2019011228和WO2021073491所公开的化合物。
本发明的方法也可用于在个体中评估癌症疾病。
用基因检测方法检测癌症疾病中的H3K27M突变,确认具有H3K27M突变后,可以使用Wee1激酶抑制剂进行治疗。
评估癌症疾病中H3K27M突变的方法也可以包括:将Wee1激酶抑制剂与从患有癌症疾病的个体获得的癌细胞样品接触,并测定该样本中相对于对照样本的细胞死亡数量。
相对于对照细胞,样本细胞中Wee1激酶抑制剂的敏感性增加,表示癌细胞可能具有H3K27M突变,例如H3K27M表达或活性的降低或废除。
在优选实施例中,Wee1激酶抑制剂是WO2018090939中公开的抑制剂,本文将以全部内容以引用的方式纳入本文。更具体而言,Wee1激酶抑制剂是下述式I化合物或其可药用盐或前药:
其中,A是N或CR15;
R1为氢,可被取代的C1-C8烷基,可被取代的C2-C8烯基,可被取代的C3-C8环烷基,可被取代的芳基,可被取代的杂环基或可被取代的杂芳基;
R2为可被取代的碳环基,可被取代的杂环基,可被取代的芳基,或可被取代的杂芳基;
R3-R7和R15独立为氢、卤素、可被取代的氨基、可被取代的烷氧基、可被取代的C1-C10烷基、卤烷基、烯基、炔基、羟基烷基、氨基烷基、羧基烷基、硝基、氰基、酰氨基、羟基、巯基、酰氧基、叠氮基、羧基、亚乙基二氧基,羟基酰氨基或可被取代的烷硫基。
在一个或多个实施方案中,A是N。
在前述一个或多个实施方案中,R1和R2为可被取代的芳基。
在前述一个或多个实施方案中,R3-R7各自独立为氢、卤素或C1-C6烷基。
在前述一个或多个实施方案中,R15为氢或C1-C6烷基。
在前述一个或多个实施方案中,R1上的取代基为选自以下基团中的任意一个、任意两个或任意三个:卤素、C1-C6烷基、C1-C6烷氧基和卤代C1-C6烷基。
在前述一个或多个实施方案中,R1选自:氢,C1-C8烷基,C2-C8烯基,C3-C8环烷基,杂芳基,和任选地被1-4个选自卤素、C1-C6烷基、C1-C6烷氧基和卤代C1-C6烷基的取代基取代的芳基。
在前述一个或多个实施方案中,R1选自任选地被1-4个选自卤素、C1-C6烷基、C1-C6烷氧基和卤代C1-C6烷基的取代基取代的苯基;在某些实施方案中,取代基的数量为2个;在某些实施方案中,至少一个取代基位于邻位;在某些实施方案中,至少一个取代基为卤素;在某些实施方案中,该苯基上的取代基为2个,两个都位于邻位,且其中至少一个为卤素。
在前述一个或多个实施方案中,R1选自可被取代的吡啶基、嘧啶基、噻吩基、呋喃基、吡咯基和咪唑基。
在前述一个或多个实施方案中,R1选自氢,可被取代的C1-C8烷基、C3-C8环烷基和C2-C8烯基。
在前述一个或多个实施方案中,R2的取代基为选自以下基团中的任意一个、任意两个、任意三个或任意四个:可被取代的C1-C6烷基、可被取代的C1-C6酰基、可被取代的杂环基、卤素、可被取代的氧基、硝基和可被取代的C1-C6烷基氨基;优选地,这些可被取代的基团上的取代基可以是1-4个选自以下的基团:C1-C6烷基、C1-C6酰基、任选地被1-4个C1-C6烷基取代的杂环基、卤素、-NRaRb和羟基,其中,Ra和Rb各自独立为H和C1-C6烷基;优选地,所述杂环基选自哌嗪基、哌啶基、吗啉基和1,4-二氮杂环庚烷基。
在前述一个或多个实施方案中,R2的取代基为选自以下基团中的任意一个、任意两个、任意三个或任意四个:可被取代的哌嗪基、可被取代的哌嗪基-C1-C4烷基、可被取代的哌啶基、咪唑基、可被取代的1,4-二氮杂环庚烷基、C1-C6烷基、C1-C6酰基、可被取代的吗啉基、吗啉基-C1-C4烷基、卤素、卤代C1-C6烷基、可被取代的C1-C6烷氧基、可被取代的羟基C1-C6烷基、可被取代的氨基C1-C6烷基、可被取代的哌啶基氨基、可被取代的C1-C6烷基氨基、可被取代的杂环烷基-O-和硝基;优选地,所述可被取代的基团上的取代基可以是1-4个选自以下的基团:C1-C6烷基、C1-C6酰基、卤素、-NRaRb和羟基取代的C1-C6烷基,其中,Ra和Rb各自独立为H和C1-C6烷基。
在前述一个或多个实施方案中,所述可被取代的哌嗪基为可被1、2或3个选自以下的基团取代的哌嗪基:C1-C6烷基、羟基C1-C6烷基和C1-C6酰基。
在前述一个或多个实施方案中,所述哌嗪基至少在对位上具有1个取代基,任选地在间位上具有一个或两个取代基。
在前述一个或多个实施方案中,所述可被取代的哌啶基为可被1个选自C1-C6烷基和C1-C6烷基氨基的基团取代的哌啶基。
在前述一个或多个实施方案中,所述可被取代的吗啉基为可被1或2个选自C1-C6烷基的基团取代的吗啉基。
在前述一个或多个实施方案中,R2选自任选取代的苯基、吡啶基、吡嗪基、四氢异喹啉基和2',3'-二氢-1'H-螺(环丙烷-1,4'-异喹啉)-7'-基和4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基。
在前述一个或多个实施方案中,R2选自:被任选取代的哌嗪基取代的苯基、被任选取代的哌啶基取代的苯基和任选被1-3个C1-C6烷基或卤素取代的四氢异喹啉基。
在前述一个或多个实施方案中,所述哌嗪基任选地被1-3个选自C1-C6烷基、羟基C1-C6烷基和C1-C6酰基的取代基取代。
在前述一个或多个实施方案中,所述哌啶基任选地被1个选自C1-C6烷基和C1-C6烷基氨基的取代基取代。
在前述一个或多个实施方案中,R4和R5各自独立选自H,C1-C6烷基和卤素,优选全部为H。
在前述一个或多个实施方案中,R6和R7各自独立选自H,C1-C6烷基和卤素,优选全部为H。
在一个或多个实施方案中,优选的式I化合物包括但不限于:
6-(2-氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
4-(2-氯苯基)-8-((4-(4-甲基哌嗪-1-基)苯基)氨基)-1,2-二氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;
6-(2,6-二氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-甲基苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(4-异丙基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(4-乙酰基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2-甲基-1,2,3,4-四氢异喹啉-7-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2,4,4-三甲基-1,2,3,4-四氢异喹啉-7-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2'-甲基-2',3'-二氢-1'H-螺(环丙烷-1,4'-异喹啉)-7'-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2'-乙酰基-2',3'-二氢-1'H-螺(环丙烷-1,4'-异喹啉)-7'-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((2-甲基-1,2,3,4-四氢异喹啉-7-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((2,4,4-三甲基-1,2,3,4-四氢异喹啉-7-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((2'-甲基-2',3'-二氢-1'H-螺(环丙烷-1,4'-异喹啉)-7'-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二甲基苯基)-2-((2-甲基-1,2,3,4-四氢异喹啉-7-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二甲基苯基)-2-((2,4,4-三甲基-1,2,3,4-四氢异喹啉-7-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二甲基苯基)-2-((2'-甲基-2',3'-二氢-1'H-螺(环丙烷-1,4'-异喹啉)-7'-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-异丙基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-叔丁基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-环丙基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-环己基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-烯丙基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(噻吩-2-基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(呋喃-2-基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(1H-吡咯-2-基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(1H-咪唑-5-基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,8-二甲基-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-9,9-二甲基-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-((2S,6R)-2,6-二甲基吗啉基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(吗啉基甲基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-((3S,5R)-4-异丙基-3,5-二甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2-氟-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2-氟-4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2-氯-4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(4-甲基哌嗪-1-基)-2-(三氟甲基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2-三氟甲基-4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2-甲基-4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氟-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氟-4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氯-4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(4-甲基哌嗪-1-基)-3-(三氟甲基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-三氟甲基-4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-甲基-4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(4-异丙基哌嗪-1-基)-3-甲基苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-((3S,5R)-4-异丙基-3,5-二甲基哌嗪-1-基)-3-甲基苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(4-甲基哌嗪-1-基)-3-硝基苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2'-异丙基-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((5-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氟苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氟-6-三氟甲基苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氟-6-甲基苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((4-(4-异丙基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((4-((3S,5R)-4-异丙基-3,5-二甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((2-氟-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((2-氯-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((2-三氟甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((4-(4甲基哌嗪-1-基)-3-(三氟甲基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-三氟甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-异丙基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-((3S,5R)-4-异丙基-3,5-二甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((5-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-三氟甲基苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-甲基苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-甲氧基苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二甲基苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二甲基苯基)-2-((4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(4-氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(3-氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,4-二氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-4-氟苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-3-氟苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,5-二氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,3-二氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(嘧啶-2-基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-环丁基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-环戊基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-苯基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(吡啶-2-基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(吡啶-3-基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(吡啶-4-基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氟苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氟苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(1H-咪唑-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(4-甲基-1,4-二氮杂环庚烷-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(2-(二甲氨基)乙氧基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(3-(二甲氨基)丙氧基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-((1-甲基哌啶-4-基)氧基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-((2-(二甲氨基)乙基)氨基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-((2-(二甲基氨基)乙基)(甲基)氨基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-((3-(二甲氨基)丙基)氨基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-((3-(二甲基氨基)丙基)(甲基)氨基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-((1-甲基哌啶-4-基)氨基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(甲基(1-甲基哌啶-4-基)氨基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(1-甲基哌啶-4-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(4-二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氟-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氯-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-溴-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-甲基-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮的;
6-(2-氯-6-氟苯基)-2-((3-氟-5-甲基-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3,5-二氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氟-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氟-5-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氯-5-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-溴-5-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-甲基-5-三氟甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-甲氧基-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((5-氯-2-甲基-1,2,3,4-四氢异喹啉-7-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((2,5-二甲基-1,2,3,4-四氢异喹啉-7-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((5-氯-2,4,4-三甲基-1,2,3,4-四氢异喹啉-7-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((2,4,4,5-四甲基-1,2,3,4-四氢异喹啉-7-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((5'-氯-2'-甲基-2',3'-二氢-1'H-螺(环丙烷-1,4'-异喹啉)-7'-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((2',5'-二甲基-2',3'-二氢-1'H-螺(环丙烷-1,4'-异喹啉)-7'-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3,5-二氯-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-5-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-溴-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3,5-二氯-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-5-甲氧基-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-溴-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-5-氟-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-5-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3,5-二氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-5-三氟甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-5-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-溴-5-氟-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-溴-5-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-溴-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-溴-5-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲氧基-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-氟-5-甲基-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-溴-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3,5-二氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-氟-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-溴-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氟-6-甲基苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氟-6-甲基苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-甲基苯基)-2-((3-氟-5-甲基-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-甲基苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-甲基苯基)-2-((3,5-二氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-甲基苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-甲基苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((4-(哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-(哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲氧基-4-(哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-(羟基甲基)-4-(哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-(羟基甲基)-4-(哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-(羟基甲基)-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((4-(4-(2-羟基乙基)哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((4-吗啉基苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-((甲基氨基)甲基)-4-吗啉基苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-氯-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)胺基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮二盐酸盐;
或其可药用盐或前药。
在特别优选的实施方案中,所述Wee1激酶抑制剂为6-(2,6-二氯苯基)-2-((3-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮,其可药用盐或前药。
在优选实施例中,适用于本发明的Wee1激酶抑制剂是WO2019011228所公开的化合物、其可药用盐或前药,本文将该文全部内容以引用的方式纳入本文。更具体而言,适用于本发明的Wee1激酶抑制剂为下述式II所示的化合物或其可药用盐或前药:
其中,A'是N或CR6;
R1'为氢,可被取代的C1-C8烷基,可被取代的C2-C8烯基,可被取代的C3-C8环烷基,可被取代的芳基,可被取代的杂环基或可被取代的杂芳基;
R2'为可被取代的碳环基,可被取代的杂环基,可被取代的芳基,或可被取代的杂芳基;
R3'-R6'独立为氢、卤素、可被取代的氨基、可被取代的烷氧基、可被取代的C1-C10烷基(如卤烷基、羟基烷基、氨基烷基和羧基烷基)、烯基、炔基、硝基、氰基、酰氨基、羟基、巯基、酰氧基、叠氮基、羧基、亚乙基二氧基、羟基酰氨基或可被取代的烷硫基。
在一个或多个实施方案中,A'是N。
在前述一个或多个实施方案中,R1'和R2'分别为可被取代的芳基。
在前述一个或多个实施方案中,R3'为氢。
在前述一个或多个实施方案中,R4'和R5'为氢和可被取代的C1-C6烷基。
在前述一个或多个实施方案中,R4'为氢或未被取代的C1-C6烷基。
在前述一个或多个实施方案中,R5'为氢或任选被羟基取代的C1-C6烷基,如羟基C1-C6烷基。
在前述一个或多个实施方案中,R6'为氢。
在前述一个或多个实施方案中,R1'上的取代基选自以下基团中的任意一个、任意两个、任意三个或任意四个:卤素、C1-C6烷基、C1-C6烷氧基和卤代C1-C6烷基。
在前述一个或多个实施方案中,R1'选自C2-C8烯基和任选地被1-4个选自卤素和C1-C6烷基的取代基取代的苯基。
在前述一个或多个实施方案中,R1'选自任选地被1-4个选自卤素和C1-C6烷基的取代基取代的苯基;在某些实施方案中,取代基的数量为2个;在某些实施方案中,至少一个取代基位于邻位;在某些实施方案中,至少一个取代基为卤素;在某些实施方案中,该苯基上的取代基为2个,两个都位于邻位,且其中至少一个为卤素。
在前述一个或多个实施方案中,R1'选自可被取代的C2-C8烯基。
在前述一个或多个实施方案中,R2'的取代基选自以下基团中的任意一个、任意两个、任意三个或任意四个:可被取代的C1-C6烷基、可被取代的氧基、卤素和可被取代的杂环基;优选地,这些可被取代的基团上的取代基可以是1-4个选自以下的基团:C1-C6烷基和-NRaRb,其中,Ra和Rb各自独立为H和C1-C6烷基;优选地,所述杂环基选自哌嗪基和哌啶基。
在前述一个或多个实施方案中,R2'的取代基为选自以下基团中的任意一个、任意两个、任意三个或任意四个:可被取代的哌嗪基、可被取代的哌啶基、C1-C6烷基、卤素和C1-C6烷氧基;优选地,所述可被取代的基团上的取代基可以是1-4个选自以下的基团:C1-C6烷基和-NRaRb,其中,Ra和Rb各自独立为H和C1-C6烷基。
在前述一个或多个实施方案中,所述可被取代的哌嗪基为可被1、2或3个选自以下的基团取代的哌嗪基:C1-C6烷基。
在前述一个或多个实施方案中,所述哌嗪基至少在对位上具有1个取代基,任选地在间位上具有一个或两个取代基。
在前述一个或多个实施方案中,所述可被取代的哌啶基为可被1个选自C1-C6烷基和-NRaRb的基团取代的哌啶基,其中,Ra和Rb各自独立为H和C1-C6烷基。
在前述一个或多个实施方案中,R2'选自任选取代的苯基和任选取代的四氢异喹啉基。
在前述一个或多个实施方案中,R2'选自:被任选取代的哌嗪基取代的苯基,被任选取代的哌啶基取代的苯基和任选被1-3个C1-C6烷基取代的四氢异喹啉基。
在前述一个或多个实施方案中,所述哌嗪基任选地被1-3个选自C1-C6烷基的取代基取代。
在前述一个或多个实施方案中,所述哌啶基任选地被1个选自C1-C6烷基和-NRaRb的取代基取代,其中,Ra和Rb各自独立为H和C1-C6烷基。
在前述一个或多个实施方案中,R4'和R5'各自独立选自H和可被取代的C1-C6烷基。优选地,R4'和R5'为H和可被取代的C1-C6烷。
在一个或多个实施方案中,优选的式II化合物包括但不限于:
6-(2-氯-6-氟苯基)-2-((2,4,4-三甲基-1,2,3,4-四氢异喹啉-7-基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氟苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2,4,4-三甲基-1,2,3,4-四氢异喹啉-7-基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氟苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氟-6-甲基苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氟-6-甲基苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-甲基苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-甲基苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氟苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氟苯基)-2-((3-氟-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氟苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氟-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-(3-氟-5-甲基-(4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-((3S,5R)-4-异丙基-3,5-二甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-5-甲氧基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-4-(1-甲基哌啶-4-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-(1-甲基哌啶-4-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(1-甲基哌啶-4-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-(1-甲基哌啶-4-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((2,4,4,5-四甲基-1,2,3,4-四氢异喹啉-7-基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((2,5-二甲基-1,2,3,4-四氢异喹啉-7-基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-溴-6-氟苯基)-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-氯-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-氟-5-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氟-6-甲基苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氟-6-甲基苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-甲基苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-甲基苯基)-2-((3-氟-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-甲基苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8-甲基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-9-甲基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)-9-甲基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)-9-甲基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-9-乙基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)-9-乙基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)-9-异丙基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-9-(羟基甲基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-烯丙基-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
或其可药用盐或前药。
在一些实施方案中,适用于本发明的Wee1激酶抑制剂可以是WO2021073491中公开的Wee1激酶抑制剂,本文将其全部内容以引用的方式纳入本文。更具体而言,适用于本发明的Wee1激酶抑制剂可以是该PCT申请中公开的下式式III化合物或其立体异构体、其可药用盐或前药:
式中,R1”和R2”独立为卤素;R3”为卤素、C1-4烷基或C1-4烷氧基;R4”和R6”各自独立为H或C1-4烷基;R5”为H或C1-4烷基;R7”为H、卤素、C1-4烷基或C1-4烷氧基;和X为CH或N。
在式III优选的实施方案中,R1”和R2”均为氯。
在式III优选的实施方案中,R3”为卤素、甲基或乙基。
在式III优选的实施方案中,R7”为H、卤素、甲基或甲氧基。
在式III优选的实施方案中,R4”和R6各自独立为H或甲基。
在式III优选的实施方案中,R5”为H、甲基或甲基-d3。
在式III优选的实施方案中,当X为N时,R4”、R5”和R6”不同时为H;优选地,R4”和R6”为C1-4烷基,R5”为H或C1-4烷基;更为优选地,R4”和R6”为甲基,R5”为H、甲基或甲基-d3。
在一个或多个实施方案中,优选的式III化合物包括但不限于:
6-(2,6-二氯苯基)-2-((4-((3S,5R)-3,5-二甲基哌嗪-1-基)-3-甲基苯基)氨基)-8,9-二氢咪唑[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((4-((3S,5R)-3,5-二甲基-4-(甲基-d3)哌嗪-1-基)-3-甲基苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
2-((3-溴-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-6-(2,6-二氯苯基)-8,9-二氢咪唑[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
2-((3-溴-5-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-6-(2,6-二氯苯基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3,5-二甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲氧基-5-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-((3S,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(哌啶-4-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-4-(1-甲基哌啶-4-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
2-((3-氯-4-(1-甲基哌啶-4-基)苯基)氨基)-6-(2,6-二氯苯基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(1-甲基哌啶-4-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-(1-甲基哌啶-4-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
或其可药用盐或前药。
一些本发明化合物可能作为立体异构体,包括旋光异构体存在。本发明包括所有立体异构体和这样的立体异构体的外消旋混合物,以及可以根据本领域技术人员众所周知的方法分离出来的单独的对映体。
可药用盐的例子包括无机和有机酸盐,例如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、柠檬酸盐、乳酸盐、酒石酸盐、马来酸盐、富马酸盐、扁桃酸盐和草酸盐;以及与碱例如钠羟基、三(羟基甲基)氨基甲烷(TRIS,氨丁三醇)和N-甲基葡糖胺形成的无机和有机碱盐。
本发明化合物的前药的实施例包括含有羧酸的化合物的简单酯(例如依据本领域已知方法通过与C1-4醇缩合而获得的酯);含有羟基的化合物的酯(例如依据本领域已知方法通过与C1-4羧酸、C3-6二酸或其酸酐例如琥珀酸酐和富马酸酐缩合而获得的酯);含有氨基的化合物的亚胺(例如依据本领域已知方法通过与C1-4醛或酮缩合而获得的亚胺);含有氨基的化合物的氨基甲酸酯,例如Leu等人(J.Med.Chem.42:3623-3628(1999))和Greenwald等人(J.Med.Chem.42:3657-3667(1999))描述的那些酯;含有醇的化合物的醛缩醇或酮缩醇(例如依据本领域已知方法通过与氯甲基甲基醚或氯甲基乙基醚缩合而获得的那些缩醇)。
本发明的Wee1激酶抑制剂可使用本领域技术人员已知的方法化合物或本发明所引参考文献(包括专利、专利申请案和专利公开案)方法制得,包括WO2018090939、WO2019011228和WO2021073491所公开的合成方法。
本发明的Wee1激酶抑制剂可以以含有可药用载体的药用组合物施用,其中药用组合物包括所有本发明化合物的含有量能有效地实现其预期目标的药品制剂。虽然每个人的需求各不相同,本领域技术人员可确定药品制剂中每个部分的最佳剂量。一般情况下,所述化合物,或其可用药盐,对哺乳动物每天口服给药,药量按照约0.0025到50毫克/公斤体重。但最好是每公斤口服给药约0.01到10毫克/公斤。如果也施用一个已知的抗癌药物,其剂量应可有效地实现其预期的目的。这些已知的抗癌药物的最佳剂量是本领域技术人员所熟知的。
单位口服剂量可以包括约0.01到50毫克,最好是约0.1到10毫克的本发明化合物。单位剂量可给予一次或多次,每天为一片或多片,每片含有约0.1到50毫克,合宜地约0.25到10毫克的本发明化合物或其溶剂化物。
在外用制剂中,本发明化合物的浓度可以是每克载体约0.01到100毫克。
本发明化合物可作为未加工药品给药。本发明化合物也可以作为含有可药用载体(包括辅料和助剂)的一个合适的药物制剂的一部分给药。这些可药用载体有利于把化合物加工成可药用的药物制剂。优选的药物制剂,特别是那些口服的和优选的给药方式类型,如片剂,锭剂和胶囊,以及适合于注射或口服的溶液,包含约0.01%到99%,最好从约0.25%到75%的活性化合物以及辅料。
本发明的范围也包括本发明的Wee1激酶抑制剂的可药用盐。酸加成盐由混合一个无毒性可药用酸溶液和本发明的化合物溶液而形成。所述酸例如盐酸,富马酸,马来酸,琥珀酸,乙酸,柠檬酸,酒石酸,碳酸,磷酸,草酸等。碱加成盐由混合一个无毒性可药用碱溶液和本发明的化合物溶液而形成。所述碱例如氢氧化钠,氢氧化钾,氢胆碱,碳酸钠,三羟甲基氨基甲烷,N-甲基-葡萄糖胺等。
本发明的药物制剂可以给予任何哺乳动物,只要他们能获得本发明化合物的治疗效果。在这些哺乳动物中最为重要的是人类和兽医动物,虽然本发明不打算如此受限。
本发明的药物制剂可通过任何途径给药以达到其预期目的。例如,可以通过肠外,皮下,静脉,肌肉,腹腔内,透皮,口腔,鞘内,颅内,鼻腔或外用途径给药。作为替代或并行地,可以通过口服给药。药的剂量将根据病人的年龄,健康与体重,并行治疗的种类,治疗的频率,以及所需治疗效益来决定。
本发明的药物制剂可用已知的方式制造。例如,由传统的混合,制粒,制锭,溶解,或冷冻干燥过程制造。制造口服制剂时,可结合固体辅料和活性化合物,选择性研磨混合物。如果需要或必要时加入适量助剂后,加工颗粒混合物,获得片剂或锭剂芯。
合适的辅料特别是填料,例如糖类如乳糖或蔗糖,甘露醇或山梨醇;纤维素制剂和/或钙磷酸盐,例如磷酸三钙或磷酸氢钙;以及粘结剂,例如淀粉糊,包括玉米淀粉,小麦淀粉,大米淀粉,马铃薯淀粉,明胶,黄芪胶,甲基纤维素,羟丙基甲基纤维素,羧甲基纤维素钠,和/或聚乙烯吡咯烷酮。如果需要,可增加崩解剂,比如上面提到的淀粉,以及羧甲基淀粉,交联聚乙烯吡咯烷酮,琼脂,或褐藻酸或其盐,如海藻酸钠。辅助剂特别是流动调节剂和润滑剂,例如,硅石,滑石,硬脂酸或其盐,如硬脂酸镁或硬脂酸钙,和/或聚乙二醇。如果需要,可以给锭剂核芯提供可以抵抗胃液的合适包衣。为此,可以应用浓缩糖类溶液。这个溶液可以含有阿拉伯树胶,滑石,聚乙烯吡咯烷酮,聚乙二醇和/或二氧化钛,漆溶液和合适的有机溶剂或溶剂混合物。为了制备耐胃液的包衣,可使用适当的纤维素溶液,例如醋酸纤维素邻苯二甲酸或羟丙基甲基纤维素邻苯二甲酸。可向药片或锭剂核芯的包衣加入染料或色素。例如,用于识别或为了表征活性成分剂量的组合。
其他可口服的药物制剂包括明胶制成的压接式胶囊,以及用明胶和甘油或山梨醇等增塑剂制成的密封软胶囊。该压接式胶囊可含有颗粒形式的活性化合物,与填料例如乳糖;粘结剂例如淀粉;和/或润滑剂例如滑石粉或硬脂酸镁,以及稳定剂混合而成。在软胶囊,活性化合物最好是溶解或悬浮在适当的液体例如油脂或液体石蜡中,其中可加入稳定剂。
合适于肠外给药的制剂包括活性化合物的水溶液,如水溶性盐的溶液和碱性溶液。此外,可施用适当的活性化合物的油性注射悬浮液。合适的亲脂性溶剂或载体包括油脂例如香油,合成脂肪酸酯例如油酸乙酯或甘油三酯或聚乙二醇400,或氢化蓖麻油,或环糊精。水性注射悬浮液可含有增加悬浮液黏度的物质,例如羧甲基纤维素钠,山梨醇,和/或葡聚糖。也可以含有悬浮稳定剂。
按照本发明的一个方面,本发明的化合物采用外用和肠外配方,并用于治疗皮肤癌。
本发明的外用制剂可通过优选合适的载体来制成油剂,霜剂,乳液剂,药膏等。合适的载体包括植物或矿物油,白矿油(白软石蜡),支链脂肪或油脂,动物脂肪和高分子醇(大于C12)。优选的载体是活性成分能溶解在其中的那些载体。也可包括乳化剂,稳定剂,保湿剂和抗氧化剂,以及如果需要的话,给予颜色或香味的试剂。此外,这些外用制剂可包含透皮渗透增强剂。这种增强剂的例子可参见美国专利号3,989,816和4,444,762。
霜剂优选用矿物油,自乳化蜂蜡和水的混合物配制,与溶解于少量油例如杏仁油的活性成分混合而成。一个典型的霜剂例子包括约40份水,20份蜂蜡,40份矿物油和1份杏仁油。
药膏可以这样配制,将含有活性成分的植物油例如杏仁油和温热的软石蜡混合,然后使该混合物冷却。一个典型的药膏例子包括约30%重量的杏仁油和70%重量的白软石蜡。
在本发明中“有效剂量”涉及活性化合物或医药试剂引起研究者、兽医、医师或其它临床医师寻求的组织、系统、动物、个体工人类的生物或医学响应的量,所述生物或医学响应包括以下中的一种或一种以上:(1)防止疾病:例如防止个体中的疾病、病况或病证,所述个体可能易患所述疾病、病况或病症但仍未经历或呈现所述疾病的病理或症状,(2)抑制疾病:例如抑制正经受或呈现疾病、病况或病症的病理或症状的个体中的疾病、病况或病症(即,阻止所述病理和/或病症的病理或症状的进一步发展),和(3)改善疾病:例如改善正经受或正呈现疾病、病况或病症的病理或症状中的个体中的所述疾病、病况或病症(即,逆转所述病理和/或症状)。因此,“有效剂量”的本发明组合物的非限制性实例可用于抑制、阻断或逆转细胞的活化、迁移或增殖,或用于有效治疗癌症或改善癌症的症状。
包含Wee1激酶抑制剂的组合物可以与至少一种已知的抗癌药物或抗癌药物的可药用盐联合共用。特别是和其他与DNA损伤和修复机理有关的抗癌药物的联合共用,包括PARP抑制剂奥拉帕尼、Niraparib、Rucaparib、Talazoparib和Senaparib;HDAC抑制剂伏立诺他、罗咪地辛、帕比司他和贝利司他等等。以及和其他与细胞分裂检测点有关的抗癌药物的联合共用,包括Chk1/2抑制剂,CDK4/6抑制剂如帕博西尼,ATM/ATR抑制剂等等。其他可用于抗癌联合治疗的已知抗癌药物包括但不限于烷化剂例如白消安、马法兰、苯丁酸氮芥、环磷酰胺、异环磷酰胺、替莫唑胺、苯达莫司汀、顺铂、丝裂霉素C、博莱霉素和卡铂;拓扑异构酶Ⅰ抑制剂例如喜树碱、伊立替康和托泊替康;拓扑异构酶Ⅱ抑制剂例如阿霉素、表阿霉素、阿克拉霉素、米托蒽醌、甲基羟基玫瑰树碱和铭托泊普;RNA/DNA抗代谢物例如5-氮杂胞苷、吉西他滨、5-氟尿嘧啶和甲氨蝶呤;DNA抗代谢物例如5-氟-2′-去氧尿苷、氟达拉滨,奈拉滨、阿糖胞苷、硫鸟嘌呤,普拉曲沙、培美曲塞、羟基脲和硫代鸟嘌呤;抗有丝分裂剂例如秋水仙碱、长春碱、长春新碱、长春瑞滨、紫杉醇,伊沙匹隆、卡巴他赛和多西他赛;抗体例如单抗,帕尼单抗、耐措妥珠单抗、纳武单抗、派姆单抗、雷莫芦单抗、贝伐珠单抗、帕妥珠单抗、曲妥珠单抗、西妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、利妥昔单抗、阿仑单抗、替伊莫单抗、托西莫单抗、本妥昔单抗、达雷木单抗、埃罗妥珠单抗、T-DM1、Ofatumumab、Dinutuximab、Blinatumomab、易普利姆玛、阿瓦斯丁、赫赛汀和美罗华;激酶抑制剂例如伊马替尼、吉非替尼、厄洛替尼、奥斯替尼、阿法替尼、赛立替尼、艾乐替尼、克唑替尼、埃罗替尼、拉帕替尼、索拉非尼、瑞格非尼、维罗非尼、达拉非尼、阿柏西普、舒尼替尼、尼罗替尼、达沙替尼、博舒替尼、普拉替尼、依鲁替尼、卡博替尼、乐伐替尼、凡德他尼、曲美替尼、卡比替尼、阿昔替尼、替西罗莫司、Idelalisib、帕唑帕尼、特癌适和依维莫司。其他可用于抗癌组合治疗的已知抗癌药物包括他莫昔芬、来曲唑、氟维司群、米托胍腙、奥曲肽、视黄酸、砒霜、唑来膦酸、硼替佐米、卡非佐米、Ixazomib、维莫德吉、索尼德吉、狄诺塞麦、萨力多胺、来那度胺、Venetoclax、Aldesleukin(重组人白介素-2)和Sipueucel-T(前列腺癌治疗疫苗)。
本发明还提供Wee1激酶抑制剂在制备用于治疗癌细胞中存在H3K27M突变的个体的癌症的药物中的用途。优选地,所述Wee1激酶抑制剂为本文所述的式I、II和III化合物、其立体异构体、可药用盐或前药。本发明还提供用于治疗癌细胞中存在H3K27M突变的个体的癌症的Wee1激酶抑制剂或含有Wee1激酶抑制剂的药物组合物或药物制剂;优选地,该Wee1激酶抑制剂为本文所述的式I、II和III化合物、其立体异构体、可药用盐或前药。
本发明还提供一种治疗其癌细胞中存在H3K27M突变的个体的癌症的方法,所述方法包括给予该个体治疗有效量的Wee1激酶抑制剂。优选地,所述Wee1激酶抑制剂为本文所述的式I、II和III化合物、其立体异构体、可药用盐或前药或其药物组合物或药物制剂。
本文中,所述癌细胞中具有H3K27M突变的癌症可以包括任何类型的实体瘤或恶性淋巴瘤,尤其是胶质瘤,包括但不限于胶质母细胞瘤、儿童弥漫性脑桥胶质瘤和中线胶质瘤。在优选实施方案中,具有H3K27M突变的癌症疾病为弥漫性中线胶质瘤。在一些实施方案中,本文所述的癌症还可包括肝癌、黑素瘤、霍奇金病、非霍奇金淋巴瘤、急性淋巴白血病、慢性淋巴白血病、多发性骨髓瘤、成神经细胞瘤、乳腺癌、卵巢癌、肺癌、维尔姆斯瘤、子宫颈癌、睾丸癌、软组织肉瘤、慢性淋巴细胞白血病、原发性巨球蛋白血症、膀胱癌、慢性粒细胞白血病、原发性脑癌、恶性黑素瘤、小细胞肺癌、胃癌、结肠癌、恶性胰腺胰岛瘤、恶性类癌性癌症、恶性黑素瘤、绒毛膜癌、蕈樣肉芽腫、头颈癌、骨原性肉瘤、胰腺癌、急性粒细胞白血病、毛细胞白血病、横纹肌肉瘤、卡波西肉瘤、泌尿生殖系统肿瘤、甲状腺癌、食管癌、恶性高钙血症、子宫颈增生症、肾细胞癌、子宫内膜癌、真性红细胞增多症、特发性血小板增多症、肾上腺皮质癌、皮肤癌和前列腺癌,只要其具有H3K27M突变。
任选地或进一步地,本文所述的癌症的癌细胞中还可存在选自下组中的一种或多种:TP53突变、ATRX缺失或突变、PDGFRA或KIT或KDR扩增、BRCA2缺失以及SRC扩增。本文所述的“突变”、“缺失”和“扩增”通常指发生了本领域已知的与导致癌症的发生和发展相关的突变(取代和/或插入)、缺失或扩增。“基因扩增”通常指某特异蛋白质编码的基因的拷贝数选择性地增加而其他基因并未按比例增加的过程。
在一些实施例中,个别的少突胶质前体细胞含有H3K27M突变。
在一些实施例中,提供了本文所述的Wee1激酶抑制剂在制备用于治疗或预防有需要的受试者的毛细胞星形细胞瘤、生殖细胞肿瘤或幕上间变性室管膜瘤的药物中的用途,Wee1激酶抑制剂或含有其的药物组合物用于在治疗或预防受试者的毛细胞星形细胞瘤、生殖细胞肿瘤或幕上间变性室管膜瘤的方法中使用,以及治疗或预防有需要的受试者的毛细胞星形细胞瘤、生殖细胞肿瘤或幕上间变性室管膜瘤的方法,包括向受试者施用有效量的Wee1激酶抑制剂或其药物组合物。优选地,Wee1激酶抑制剂是本文所述的式I、II或III的化合物或其立体异构体、药学上可接受的盐或前药。
本发明还提供一种预测癌症患者对Wee1激酶抑制剂治疗疗效的方法,该方法包括测定该患者是否存在H3K27M突变;其中,存在H3K27M突变表明该癌症患者响应Wee1激酶抑制剂治疗。可采用本领域周知的方法测定患者是否存在H3K27M突变,示例性的方法包括全外显子测序(WES)等。优选地,所述Wee1激酶抑制剂为本文所述的式I、II和IIII、II、III、IV和V化合物、其可药用盐或前药或其药物组合物。在一些实施例中,检测患者的少突胶质前体细胞以确定它们是否含有H3K27M突变,并且少突胶质前体细胞中H3K27M突变的存在指示患者对Wee1激酶抑制剂的反应。
本发明还提供用于检测个体癌细胞或癌组织中是否存在H3K27M突变的试剂在制备用于判断个体是否响应或受益于Wee1激酶抑制剂治疗的检测试剂盒中的应用。所述试剂可以是例如用于实施合适的检测方法的试剂,所述检测方法包括但不限于全外显子检测。优选地,所述Wee1激酶抑制剂为本文所述的式I、II和III化合物、其可药用盐或前药或其药物组合物。示例性的试剂包括以下试剂中的一种或多种:由组织样本制备单细胞悬液所需的试剂,从样本中提取核酸所需的试剂,DNA打断、末端修复、加A及接头连接所需的试剂,接头序列,DNA扩增所需的试剂,探针以及在测序仪中进行测序所需的试剂等。本文中,所述样本可以是癌组织样本。在一些实施方案中,所述样本是血液样本。在一些实施例中,细胞是少突胶质前体细胞。
下列实施例是举例说明,而不是限制本发明的方法和制剂。其他对于本领域技术人员来说是显而易见的,和在临床治疗中通常会遇到的对各种条件和参数的适当修改和改进,都在本发明的精神和范围内。
实施例1
采用MiniPDXTM药物敏感性测试Wee1激酶抑制剂6-(2,6-二氯苯基)-2-((3-甲基-4-
((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-
5(6H)-酮(化合物A)在脑瘤样本中的药效
迷你人源肿瘤移植模型(Mini patient derived xenograft,MiniPDXTM)是一种在动物身上测试药物对人类肿瘤疗效的新方法,即把患者肿瘤样本放入小容器中并异种移植(PDX)在免疫缺陷小鼠体内。通过该模型,在小鼠环境中测试了药物对人类肿瘤细胞生长和存活的影响。
利用特殊的体外分离方法从新鲜肿瘤标本中分离出肿瘤细胞,然后将这些肿瘤细胞置于专用的MiniPDXTM装置中并移植于小鼠皮下。这些专用的MiniPDXTM装置所特有的孔径允许500KD以下的小分子自由进出,而肿瘤细胞保留在装置内。在下述实验中对小鼠进行7天给药。给药结束后取出MiniPDXTM装置,利用体外ATP方法检测肿瘤细胞活力。根据肿瘤细胞总体的活力变化情况评估各种给药方案的有效性。
本发明采用MiniPDXTM动物模型测试Wee1激酶抑制剂6-(2,6-二氯苯基)-2-((3-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮(化合物A,WO2018090939实施例77)在13个人类脑肿瘤和4个弥漫性中线神经胶质瘤(DMG)PDX模型中的药效。
实验动物:
Balb/c-nude小鼠,雌性,6-8周龄,体重约18-22g。购买于江苏集萃药康生物科技有限公司。在正式实验前,适应性饲养了至少3天。
实验动物饲养室的环境条件:
实验动物均饲养于已通过AAALAC国际认证的实验动物中心。实验动物中心具有独立通风系统,饲养室温度20-26℃,相对湿度40-70%,换气频率≧15次/小时,昼夜明暗交替时间12h/12h,食物和水自由摄取。
供试品:
化合物A:6-(2,6-二氯苯基)-2-((3-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮
溶媒:
0.5% MC(含0.2% Tween 80)溶液。
表1:患者肿瘤样本信息:
样本例 | 癌症类型 | 样本类型 | 患者信息 | 病理结果 |
1 | 脑瘤 | 手术样本 | 女,6岁 | 毛细胞型星型细胞瘤 |
2 | 脑干占位 | 活检样本 | 男,5岁 | 弥漫性中线胶质瘤 |
3 | 脑干肿瘤 | 活检样本 | 男,10岁 | 弥漫性中线胶质瘤 |
4 | 脑生殖细胞瘤 | 手术样本 | 女,4岁 | 生殖细胞瘤 |
5 | 脑干占位 | 活检样本 | 男,6岁 | 弥漫性中线胶质瘤 |
6 | 脑干占位 | 活检样本 | 男,7岁 | 弥漫性中线胶质瘤 |
7 | 脑生殖细胞瘤 | 手术样本 | 男,8岁 | 生殖细胞瘤 |
8 | 鞍区占位 | 手术样本 | 男,1岁 | 毛细胞粘液型星型细胞瘤 |
9 | 第四脑室占位 | 手术样本 | 男,7岁 | 经典型髓母细胞瘤 |
10 | 脑干占位 | 活检样本 | 女,8岁 | 弥漫性中线胶质瘤 |
11 | 后颅窝占位 | 手术样本 | 男,4岁 | 促纤维增生/结节型髓母细胞瘤 |
12 | 颅内占位 | 手术样本 | 女性,1岁 | 幕上间变性室管膜瘤 |
13 | 左侧脑室占位 | 手术样本 | 女性,10岁 | 室管膜下巨细胞星形细胞瘤 |
14 | 脑肿瘤 | PDX样本 | 女性,5岁 | 弥漫性中线胶质瘤 |
15 | 脑肿瘤 | PDX样本 | 男性,9岁 | 弥漫性中线胶质瘤 |
16 | 脑肿瘤 | PDX样本 | 男性,2岁 | 弥漫性中线胶质瘤 |
17 | 脑肿瘤 | PDX样本 | 女性,4岁 | 弥漫性中线胶质瘤 |
实验方法:
1.将患者手术样本浸没于HBSS样本缓冲液中。
2.清洗并去除组织碎片后,用MiniPDXTM样本制备细胞悬液,并计数细胞。
3.将一定数量的细胞灌装至MiniPDXTM实验装置。将MiniPDXTM装置接种至小鼠皮下,并于接种当天按实验设计进行动物给药,接种当天为第0天。对照组给予等体积的溶媒,化合物A组以60mg/kg,P.O.,QD给药7天。
4.测试结束后取出MiniPDXTM装置,按照CellTiter-Glo检测方法进行细胞活力检测。
使用肿瘤细胞的相对增殖率(T/C%)评价药物疗效相对增值率:T/C%=T/C×100%:T和C分别为给药组和对照组的细胞活力值。此值越低,该药物/组合对肿瘤细胞抑制率越高。
结果:
表2汇总了化合物A在17例脑瘤样本上的药效结果(T/C%)。实验结果显示,有9例样本对Wee1激酶抑制剂化合物A有响应,T/C%均小于50%。在9个肿瘤样本中,6个肿瘤样本是具有H3K27M突变的DMG肿瘤。
实施例2
全外显子组测序(WES)
对15例脑瘤样本进行全外显子组测序(WES),实验方法如下:
采集患者新鲜样本,制备成单细胞悬液,取2000-5000个细胞进行核酸提取,提取后的DNA通过打断、末端修复、加A及接头连接,扩增制备成文库,再通过外显子组探针捕获纯化为最终的测序文库,经鉴定后于illumina测序仪上机测序,下机进行数据分析。
每个样本的140个肿瘤驱动基因的改变被分析。3个或更多样品中检测到的基因改变如下表2所示。我们进行了t检验和Mann Whitney Wilcoxon检验,以检查基因改变和化合物抑制效果之间的相关性。
表2测试结果
结果:
由于seq数据质量低,两个样本(样本12和13)被排除在TP53和PDGFRA的相关分析之外。这两个样本的H3F3A野生型状态来自于临床检测结果。在140个肿瘤驱动基因中,有8个基因在3个或更多样本中被发现改变。进行T检验和Mann-Whiteney Wilcoxon Rank检验都是为了检验特定改变基因在药物反应中相关性的显着性(由于PDGFRA扩增、SRC扩增和BRCA2缺失的样本量不足,我们只进行了H3K27M和TP53的Mann-Whiteney Wilcoxon Rank检验)。在测试的基因中,K27M是唯一一个在两项测试中与化合物抑制效果显着相关的改变基因(t检验:0.017,Wilcoxon:0.038)(图1)。化合物抑制与TP53突变、PDGFRA扩增、SRC扩增或BRCA2缺失的相关性不显着(图1)
综上结果,我们的研究发现,Wee1激酶抑制剂化合物A对H3K27M突变的弥漫性中线胶质瘤有明显的抑制作用,H3K27M突变可以作为使用Wee1激酶抑制剂时DMG患者的有效筛查生物标志物。
实施例3
Wee1激酶抑制剂化合物A在两种不同H3K27M比例的人脑肿瘤PDX模型中的体内疗效
采用不同H3K27M水平的2只DMG病人来源的异种移植(PDX)小鼠模型,研究了Wee1激酶抑制剂化合物A对人脑肿瘤的体内肿瘤生长抑制(TGI)效果。
实验动物:
雌性Nu/Nu小鼠,5-8周龄,体重19-25g,购自浙江维通利华股份有限公司。实验前将动物圈养至少3天以适应环境。
动物饲养和护理:
所有动物研究均按照AAALAC指导进行。研究中使用的动物饲养在通过AAALAC国际认证的实验动物中心。实验动物中心拥有独立的通风系统,温度保持在20-26℃,湿度保持在40-70%,通风保持15次/小时,昼夜循环12h/12h。食物和无菌水是持续供应的。
供试品:
化合物A:6-(2,6-二氯苯基)-2-((3-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮(WO2018090939的实施例77)
溶媒:
0.5% MC溶液。
PDX模型样本:
表3:PDX模型信息
实验和结果:
在M309 PDX模型中,荷瘤小鼠用溶媒对照或100mg/kg化合物A(n=3/组)按QD给药方案治疗3天,停药4天,持续4周。TGI值达到了38.71%,根据相关的体重变化(减轻)百分比,治疗总体上是可耐受的。
在M574 PDX模型中,荷瘤小鼠按QD给药方案口服100mg/kg化合物A(n=8/组),连续3天,停4天,持续4周。与溶媒对照组相比,给药组小鼠的体重百分比有所下降。值得注意的是,100mg/kg治疗动物的平均体重下降不超过5%。结果还显示,相对于对照,100mg/kg化合物A组小鼠肿瘤体积显著减少(p<0.01),肿瘤生长抑制率(TGI)达到58.0%。
综上所述,PDX模型的数据强烈表明Wee1激酶抑制剂(化合物A)对人类肿瘤细胞具有显着的抑制作用,这与肿瘤样本中高比例的H3K27M突变相关。
实施例4
scRNA测序
通过scRNA测序研究了H3K27M脑肿瘤细胞对化合物A反应的细胞机制。弥漫性中线胶质瘤(DMG)的两个关键临床特征是有限的发育窗口和其特定的中线位置,这意味着发育早期的特定细胞起源。两种类型的脑前体细胞,神经元前体细胞(NPC)和少突胶质前体样细胞(OPC样),被证明是H3K27M神经胶质瘤的肿瘤起源(Kosuke,Science 2014;Filbin,Science 2018)。为了研究哪种类型的H3K27M脑前体细胞对化合物有反应,以及对化合物敏感性的机制是什么,我们进行了scRNA-seq分析,以表征2个DMG PDX模型异质群体在化合物处理前后的每种特定细胞类型。
方法:
组织解离和单细胞悬液的制备
分别使用两种DMG PDX模型(M309和M574)的三个样品(预处理、28天后的溶媒处理和化合物处理组)。将小鼠皮下异种移植物标本解剖,然后转移到冰上含有适量无钙、无镁1×PBS的无菌、无RNase的培养皿中。去除非目的组织(血迹和脂肪层)后,将肿瘤组织切成0.5mm2的碎片,并用1×PBS清洗以分离成单细胞。将组织在分离液(0.35%胶原酶IV5、2mg/mL木瓜蛋白酶、120Units/mL DNase I)中,在37℃水浴,以100rpm振荡20min,分离成单细胞。用含有10%胎牛血清(FBS,V/V)的1×PBS终止消化,然后用巴斯德移液管来回吹打5-10次。将所得细胞悬浮液通过70-30μm堆叠式细胞滤网进行过滤,并在4℃下以300g离心5分钟。将细胞沉淀重悬于100μL 1×PBS(0.04% BSA)中,加入1mL 1×红细胞裂解缓冲液(MACS130-094-183,10×),室温或冰上孵育2-10分钟裂解剩余的红细胞。孵育后,将悬浮液在室温下以300g离心5分钟。将悬浮液重悬于100μL死细胞去除微珠(MACS130-090-101)中,使用Dead Cell Removal Kit(MACS130-090-101)去除死细胞。然后将悬浮液重悬于1×PBS(0.04% BSA)中,并在4℃下以300g离心3分钟(重复两次)。将细胞沉淀重悬于50μL 1×PBS(0.04% BSA)中。通过台盼蓝染色确定细胞总体存活率,需要高于85%,使用血细胞计数器/Countess II自动细胞计数器对单细胞悬浮液进行计数,并将浓度调整至700-1200个细胞/μL。
Chromium 10x基因组库和测序
按照10×Genomics Chromium single-cell 3’kit(V3)的说明书,将单细胞悬液加载到10×Chromium上,捕获4500-9000个单细胞。按照标准方案进行cDNA扩增和文库构建。测序在LC-BioTechnology Co.Ltd,(Hangzhou,China)的Illumina NovaSeq 6000测序系统(双端多重测序,150bp)上进行,每个细胞的最小读取深度为20,000个读数。
scRNA-seq数据处理与分析
XenoCell(v 1.0)用于区分读数的来源。使用cellranger(v 6.0.2)包将原始提取的人源读数处理到细胞转录本计数矩阵。最后使用Scater(v.1.18.6)筛选细胞。对hg38注释进行对齐。根据mRNA的总丰度、独特转录物的数量和线粒体的比例鉴定有活力的单细胞。使用基于马尔可夫亲和的细胞图Imputation来克服转录本缺失,通常发生在scRNA-seq中,并对数据进行去噪。
使用t分布随机邻居嵌入(t-SNE)对输入计数矩阵的前30个主成分进行计算,对所有细胞进行可视化。为了鉴定三种类型的脑祖细胞(星形胶质细胞AC,少突胶质细胞前体细胞OPC和神经元前体细胞NPC),在解剖的人类发育中的大脑研究中鉴定的基因集被用于本分析。利用基因组途径获得的细胞周期基因集和基因本体分析对细胞周期细胞进行鉴定。在解剖的人DMG细胞研究中鉴定的基因集被用于鉴定H3K27M细胞。
结果
对2种人脑PDX模型(M309和M574见表3,每个样本的细胞数谱见表4)共6个样本进行scRNA-seq,共使用质控合格的44927个活细胞进行分析。由于两种模型在组合分析中很少出现重叠,因此基于模型起源对样本进行分析(图2)。通过标记基因的分布以0.99作为截止值来推断含有H3K27M的细胞。M309和M574预处理样品中H3K27M的比例分别为28%和80%,与原发肿瘤样品中H3K27M的比例接近。将推断的含有H3K27M或野生型的细胞与匹配的原发肿瘤样本进行基因表达比较,发现强相关性。这些数据有力地验证了在scRNA-seq分析中用于鉴定H3K27M细胞的方法(图3)。
然后检查异质性模式,在所有样本中一致观察到三种类型的脑前体细胞。根据细胞类型和细胞周期状态进一步分析含H3K27M和不含H3K27M的恶性细胞(图4)。在M574和M309中,含H3K27M的OPC细胞是导致含H3K27M细胞数量下降的主要细胞类型(图5)。scRNA-seq分析结果表明,具有H3K27M的OPC细胞是对化合物抑制反应的主要细胞类型。
表4:用于scRNA-seq分析的每个样本的细胞数
V:对照;T:治疗.
sc-RNA测序结果有力地支持了H3K27M可作为该化合物治疗DMG的预测生物标志物。
对2例异种移植肿瘤样本(M574)进行了WES。
实验方法:
异种移植肿瘤样本(1个对照和1个治疗样本)分别保存在RNAlater中,均用于DNA提取。将提取的DNA 300ng进行断裂、端部修复、连接适配器扩增,制备文库,再通过外显子组探针捕获纯化成最终测序文库。鉴定后,在Illumina测序仪上进行测序,并进行脱机数据分析。
H3K27M在每个样本中频率由突变序列读取数与映射到H3K27位置的序列读取数之比计算。
结果:
H3K27M在对照和处理样品中的出现频率分别为71%和54.5%。复合处理后H3K27M的频率下降。
Claims (15)
1.Wee1激酶抑制剂在制备用于预防或治疗具有H3K27M突变的癌症、毛细胞性星形细胞瘤、生殖细胞肿瘤或幕上间变性室管膜瘤的药物中的用途。
2.如权利要求1所述的用途,其特征在于,所述Wee1激酶抑制剂选自式I的化合物,或其可药用盐或前药:
其中,A是N或CR15;
R1为氢,可被取代的C1-8烷基,可被取代的C2-8烯基,可被取代的C3-8环烷基,可被取代的芳基,或可被取代的杂芳基;
R2为可被取代的杂环基,可被取代的芳基,或可被取代的杂芳基;
R3-R7和R15独立为氢、卤素、可被取代的氨基、可被取代的烷氧基、可被取代的C1-10烷基、卤烷基、烯基、炔基、羟基烷基、氨基烷基、羧基烷基、硝基、氰基、酰氨基、羟基、巯基、酰氧基、叠氮基、羧基、亚乙基二氧基,羟基酰氨基或可被取代的烷硫基;
或所述Wee1激酶抑制剂选自式II的化合物,或其可药用盐或前药:
其中,A'是N或CR6';
R1'为氢,可被取代的C1-C8烷基,可被取代的C2-C8烯基,可被取代的C3-C8环烷基,可被取代的芳基,可被取代的杂环基或可被取代的杂芳基;
R2'为可被取代的碳环基,可被取代的杂环基,可被取代的芳基,或可被取代的杂芳基;
R3'-R6'独立为氢、卤素、可被取代的氨基、可被取代的烷氧基、可被取代的C1-C10烷基(如卤烷基、羟基烷基、氨基烷基和羧基烷基)、烯基、炔基、硝基、氰基、酰氨基、羟基、巯基、酰氧基、叠氮基、羧基、亚乙基二氧基、羟基酰氨基或可被取代的烷硫基。
3.如权利要求1所述的用途,其特征在于,所述Wee1激酶抑制剂为下式III所示的化合物、其立体异构体、可药用盐或前药:
式中,R1”和R2”独立为卤素;R3”为卤素、C1-4烷基或C1-4烷氧基;R4”和R6”各自独立为H或C1-4烷基;R5”为H或C1-4烷基;R7”为H、卤素、C1-4烷基或C1-4烷氧基;和X为CH或N。
4.权利要求1的用途,其特征在于,所述Wee1激酶抑制剂选自:
6-(2-氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
4-(2-氯苯基)-8-((4-(4-甲基哌嗪-1-基)苯基)氨基)-1,2-二氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;
6-(2,6-二氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-甲基苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(4-异丙基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(4-乙酰基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2-甲基-1,2,3,4-四氢异喹啉-7-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2,4,4-三甲基-1,2,3,4-四氢异喹啉-7-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2'-甲基-2',3'-二氢-1'H-螺(环丙烷-1,4'-异喹啉)-7'-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2'-乙酰基-2',3'-二氢-1'H-螺(环丙烷-1,4'-异喹啉)-7'-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((2-甲基-1,2,3,4-四氢异喹啉-7-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((2,4,4-三甲基-1,2,3,4-四氢异喹啉-7-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((2'-甲基-2',3'-二氢-1'H-螺(环丙烷-1,4'-异喹啉)-7'-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二甲基苯基)-2-((2-甲基-1,2,3,4-四氢异喹啉-7-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二甲基苯基)-2-((2,4,4-三甲基-1,2,3,4-四氢异喹啉-7-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二甲基苯基)-2-((2'-甲基-2',3'-二氢-1'H-螺(环丙烷-1,4'-异喹啉)-7'-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-异丙基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-叔丁基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-环丙基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-环己基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-烯丙基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(噻吩-2-基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(呋喃-2-基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(1H-吡咯-2-基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(1H-咪唑-5-基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,8-二甲基-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-9,9-二甲基-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-((2S,6R)-2,6-二甲基吗啉基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(吗啉基甲基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-((3S,5R)-4-异丙基-3,5-二甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2-氟-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2-氟-4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2-氯-4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(4-甲基哌嗪-1-基)-2-(三氟甲基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2-三氟甲基-4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2-甲基-4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氟-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氟-4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氯-4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(4-甲基哌嗪-1-基)-3-(三氟甲基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-三氟甲基-4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-甲基-4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(4-异丙基哌嗪-1-基)-3-甲基苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-((3S,5R)-4-异丙基-3,5-二甲基哌嗪-1-基)-3-甲基苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(4-甲基哌嗪-1-基)-3-硝基苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2'-异丙基-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((5-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氟苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氟-6-三氟甲基苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氟-6-甲基苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((4-(4-异丙基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((4-((3S,5R)-4-异丙基-3,5-二甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((2-氟-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((2-氯-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((2-三氟甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((4-(4甲基哌嗪-1-基)-3-(三氟甲基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-三氟甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-异丙基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-((3S,5R)-4-异丙基-3,5-二甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((5-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-三氟甲基苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-甲基苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-甲氧基苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二甲基苯基)-2-((4-((3R,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(4-氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(3-氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,4-二氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-4-氟苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-3-氟苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,5-二氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,3-二氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(嘧啶-2-基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-环丁基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-环戊基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-苯基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(吡啶-2-基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(吡啶-3-基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(吡啶-4-基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氟苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氟苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(1H-咪唑-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(4-甲基-1,4-二氮杂环庚烷-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(2-(二甲氨基)乙氧基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(3-(二甲氨基)丙氧基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-((1-甲基哌啶-4-基)氧基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-((2-(二甲氨基)乙基)氨基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-((2-(二甲基氨基)乙基)(甲基)氨基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-((3-(二甲氨基)丙基)氨基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-((3-(二甲基氨基)丙基)(甲基)氨基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-((1-甲基哌啶-4-基)氨基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(甲基(1-甲基哌啶-4-基)氨基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(1-甲基哌啶-4-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((4-(4-二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氟-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氯-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-溴-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-甲基-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮的;
6-(2-氯-6-氟苯基)-2-((3-氟-5-甲基-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3,5-二氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氟-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氟-5-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氯-5-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-溴-5-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-甲基-5-三氟甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-甲氧基-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((5-氯-2-甲基-1,2,3,4-四氢异喹啉-7-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((2,5-二甲基-1,2,3,4-四氢异喹啉-7-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((5-氯-2,4,4-三甲基-1,2,3,4-四氢异喹啉-7-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((2,4,4,5-四甲基-1,2,3,4-四氢异喹啉-7-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((5'-氯-2'-甲基-2',3'-二氢-1'H-螺(环丙烷-1,4'-异喹啉)-7'-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((2',5'-二甲基-2',3'-二氢-1'H-螺(环丙烷-1,4'-异喹啉)-7'-基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3,5-二氯-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-5-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-溴-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3,5-二氯-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-5-甲氧基-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-溴-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-5-氟-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-5-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3,5-二氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-5-三氟甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-5-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-溴-5-氟-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-溴-5-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-溴-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-溴-5-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲氧基-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-氟-5-甲基-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-溴-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3,5-二氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-氟-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-溴-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氟-6-甲基苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氟-6-甲基苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-甲基苯基)-2-((3-氟-5-甲基-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-甲基苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-甲基苯基)-2-((3,5-二氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-甲基苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-甲基苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((4-(哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-(哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲氧基-4-(哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-(羟基甲基)-4-(哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-(羟基甲基)-4-(哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-(羟基甲基)-4-(4-甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((4-(4-(2-羟基乙基)哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((4-吗啉基苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-((甲基氨基)甲基)-4-吗啉基苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-氯-4-(4-(二甲氨基)哌啶-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)胺基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2,4,4-三甲基-1,2,3,4-四氢异喹啉-7-基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氟苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((2,4,4-三甲基-1,2,3,4-四氢异喹啉-7-基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氟苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氟-6-甲基苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氟-6-甲基苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-甲基苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-甲基苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氟苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氟苯基)-2-((3-氟-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氟苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氟-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-((3-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-氟苯基)-2-(3-氟-5-甲基-(4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-((3S,5R)-4-异丙基-3,5-二甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-5-甲氧基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-4-(1-甲基哌啶-4-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-(1-甲基哌啶-4-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(1-甲基哌啶-4-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-(1-甲基哌啶-4-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((2,4,4,5-四甲基-1,2,3,4-四氢异喹啉-7-基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((2,5-二甲基-1,2,3,4-四氢异喹啉-7-基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-溴-6-氟苯基)-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-氯-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-溴-6-氯苯基)-2-((3-氟-5-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氟-6-甲基苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氟-6-甲基苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-甲基苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-甲基苯基)-2-((3-氟-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2-氯-6-甲基苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8-甲基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-9-甲基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)-9-甲基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)-9-甲基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-9-乙基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)-9-乙基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)-9-异丙基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-9-(羟基甲基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-烯丙基-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮;
6-(2,6-二氯苯基)-2-((4-((3S,5R)-3,5-二甲基哌嗪-1-基)-3-甲基苯基)氨基)-8,9-二氢咪唑[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((4-((3S,5R)-3,5-二甲基-4-(甲基-d3)哌嗪-1-基)-3-甲基苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
2-((3-溴-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-6-(2,6-二氯苯基)-8,9-二氢咪唑[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
2-((3-溴-5-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-6-(2,6-二氯苯基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3,5-二甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲氧基-5-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-((3S,5S)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(哌啶-4-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-4-(1-甲基哌啶-4-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
2-((3-氯-4-(1-甲基哌啶-4-基)苯基)氨基)-6-(2,6-二氯苯基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-甲基-4-(1-甲基哌啶-4-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-(1-甲基哌啶-4-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮;
或其可药用盐或前药。
5.如权利要求1所述的用途,其特征在于,所述Wee1激酶抑制剂为6-(2,6-二氯苯基)-2-((3-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)-8,9-二氢咪唑并[1,2-a]嘧啶并[5,4-e]嘧啶-5(6H)-酮、其可药用盐或前药。
6.权利要求1-5中任一项所述的用途,其特征在于,所述癌症选自弥漫性中线胶质瘤、儿童弥漫性脑桥胶质瘤、中线胶质瘤、肝癌、黑素瘤、霍奇金病、非霍奇金淋巴瘤、急性淋巴白血病、慢性淋巴白血病、多发性骨髓瘤、成神经细胞瘤、乳腺癌、卵巢癌、肺癌、维尔姆斯瘤、子宫颈癌、睾丸癌、软组织肉瘤、慢性淋巴细胞白血病、原发性巨球蛋白血症、膀胱癌、慢性粒细胞白血病、原发性脑癌、恶性黑素瘤、小细胞肺癌、胃癌、结肠癌、恶性胰腺胰岛瘤、恶性类癌性癌症、恶性黑素瘤、绒毛膜癌、蕈樣肉芽腫、头颈癌、骨原性肉瘤、胰腺癌、急性粒细胞白血病、毛细胞白血病、横纹肌肉瘤、卡波西肉瘤、泌尿生殖系统肿瘤、甲状腺癌、食管癌、恶性高钙血症、子宫颈增生症、肾细胞癌、子宫内膜癌、真性红细胞增多症、特发性血小板增多症、肾上腺皮质癌、皮肤癌和前列腺癌;优选地,所述癌症选自弥漫性中线胶质瘤、儿童弥漫性脑桥胶质瘤和中线胶质瘤。
7.权利要求1-6中任一项所述的用途,其特征在于,所述药物还含有至少一种已知的抗癌药物,或所述抗癌药物的可药用盐。
8.权利要求7的用途,其特征在于,所述抗癌药物选自下组:白消安、马法兰、苯丁酸氮芥、环磷酰胺、异环磷酰胺、替莫唑胺、苯达莫司汀、顺铂、丝裂霉素C、博莱霉素、卡铂、喜树碱、伊立替康、托泊替康、阿霉素、表阿霉素、阿克拉霉素、米托蒽醌、甲基羟基玫瑰树碱、铭托泊普、5-氮杂胞苷、吉西他滨、5-氟尿嘧啶、甲氨蝶呤、5-氟-2'-去氧尿苷、氟达拉滨、奈拉滨、阿糖胞苷、普拉曲沙、培美曲塞、羟基脲、硫代鸟嘌呤、秋水仙碱、长春碱、长春新碱、长春瑞滨、紫杉醇、伊沙匹隆、卡巴他赛、多西他赛、单抗、帕尼单抗、耐措妥珠单抗、纳武单抗、派姆单抗、雷莫芦单抗、贝伐珠单抗、帕妥珠单抗、曲妥珠单抗、西妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、利妥昔单抗、阿仑单抗、替伊莫单抗、托西莫单抗、本妥昔单抗、达雷木单抗、埃罗妥珠单抗、T-DM1、Ofatumumab、Dinutuximab、Blinatumomab、易普利姆玛、阿瓦斯丁、赫赛汀、美罗华、伊马替尼、吉非替尼、厄洛替尼、奥斯替尼、阿法替尼、赛立替尼、艾乐替尼、克唑替尼、埃罗替尼、拉帕替尼、索拉非尼、舒尼替尼、尼罗替尼、达沙替尼、帕唑帕尼、特癌适、依维莫司、伏立诺他、罗咪地辛、帕比司他、贝利司他、他莫昔芬、来曲唑、氟维司群、米托胍腙、奥曲肽、视黄酸、砒霜、唑来膦酸、硼替佐米、卡非佐米、Ixazomib、维莫德吉、索尼德吉、狄诺塞麦、萨力多胺、来那度胺、Venetoclax、Aldesleukin、Sipueucel-T、帕博西尼、奥拉帕尼、Niraparib、Rucaparib、Senaparib和Talazoparib。
9.一种治疗或预防癌细胞中具有H3K27M突变或患有毛细胞星形细胞瘤、生殖细胞肿瘤或幕上间变性室管膜瘤的个体的癌症的方法,包括向所述个体施用有效量的Wee1激酶抑制剂或含有所述Wee1激酶抑制剂的药物组合物。
10.权利要求9所述的方法,其中所述Wee1激酶抑制剂如权利要求2-5中任一项所定义。
11.权利要求9或10所述的方法,其中所述癌症如权利要求6中所定义。
12.权利要求9-11任一项所述的方法,其特征在于:
个体进一步接受放射治疗;和/或
进一步向个体施用至少一种已知的抗癌药物或该抗癌药物的药学上可接受的盐;优选地,所述抗癌药物选自:白消安、马法兰、苯丁酸氮芥、环磷酰胺、异环磷酰胺、替莫唑胺、苯达莫司汀、顺铂、丝裂霉素C、博莱霉素、卡铂、喜树碱、伊立替康、托泊替康、阿霉素、表阿霉素、阿克拉霉素、米托蒽醌、甲基羟基玫瑰树碱、铭托泊普、5-氮杂胞苷、吉西他滨、5-氟尿嘧啶、甲氨蝶呤、5-氟-2'-去氧尿苷、氟达拉滨、奈拉滨、阿糖胞苷、普拉曲沙、培美曲塞、羟基脲、硫代鸟嘌呤、秋水仙碱、长春碱、长春新碱、长春瑞滨、紫杉醇、伊沙匹隆、卡巴他赛、多西他赛、单抗、帕尼单抗、耐措妥珠单抗、纳武单抗、派姆单抗、雷莫芦单抗、贝伐珠单抗、帕妥珠单抗、曲妥珠单抗、西妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、利妥昔单抗、阿仑单抗、替伊莫单抗、托西莫单抗、本妥昔单抗、达雷木单抗、埃罗妥珠单抗、T-DM1、Ofatumumab、Dinutuximab、Blinatumomab、易普利姆玛、阿瓦斯丁、赫赛汀、美罗华、伊马替尼、吉非替尼、厄洛替尼、奥斯替尼、阿法替尼、赛立替尼、艾乐替尼、克唑替尼、埃罗替尼、拉帕替尼、索拉非尼、舒尼替尼、尼罗替尼、达沙替尼、帕唑帕尼、特癌适、依维莫司、伏立诺他、罗咪地辛、帕比司他、贝利司他、他莫昔芬、来曲唑、氟维司群、米托胍腙、奥曲肽、视黄酸、砒霜、唑来膦酸、硼替佐米、卡非佐米、Ixazomib、维莫德吉、索尼德吉、狄诺塞麦、萨力多胺、来那度胺、Venetoclax、Aldesleukin、Sipueucel-T、帕博西尼、奥拉帕尼、Niraparib、Rucaparib、Senaparib和Talazoparib。
13.一种预测Wee1激酶抑制剂对癌症患者的治疗效果的方法,包括确定所述患者是否具有H3K27M突变;其中H3K27M突变的存在表明患者对Wee1激酶抑制剂治疗有反应;优选地,检测患者的少突胶质前体细胞是否含有H3K27M突变,少突胶质前体细胞中存在H3K27M突变表明患者对Wee1激酶抑制剂有反应。优选地,患者患有权利要求6中定义的癌症。
14.权利要求13所述的方法,其中所述Wee1激酶抑制剂如权利要求2-5中任一项所定义。
15.使用检测个体癌细胞或癌组织中H3K27M突变存在的试剂来制备检测试剂盒,以确定个体是否对Wee1激酶抑制剂治疗有反应或受益。
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