CN116239610B - 一种嘧啶衍生物及其制备方法与在制备抗肿瘤药物中的应用 - Google Patents
一种嘧啶衍生物及其制备方法与在制备抗肿瘤药物中的应用 Download PDFInfo
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- CN116239610B CN116239610B CN202310154871.8A CN202310154871A CN116239610B CN 116239610 B CN116239610 B CN 116239610B CN 202310154871 A CN202310154871 A CN 202310154871A CN 116239610 B CN116239610 B CN 116239610B
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Abstract
本发明属于医药技术领域，公开了一种嘧啶衍生物及其制备方法与在制备抗肿瘤药物中的应用。所述嘧啶衍生物的结构通式如(I)所示；其中，X、Y和Z分别独立地选自CH、N；R1选自取代或未取代的以下基团：C5‑C12饱和或不饱和碳杂环基、C5‑C12饱和或不饱和螺杂环基、C5‑C12饱和或不饱和稠杂环基，其中，所述取代基团是指选自下组的一个或多个基团：羟基、卤素、氰基、氨基。该嘧啶衍生物具有良好的DNA‑PK抑制活性和药代动力学稳定性，可有效抑制肿瘤生长，并协同增强化疗和放疗效果；
Description
技术领域
本发明属于医药技术领域，具体涉及一种嘧啶衍生物及其制备方法与在制备抗肿瘤药物中的应用。
背景技术
目前，临床研究发现很多肿瘤患者对放化疗抵抗，所以寻找低毒高效的靶向药和放化疗增敏剂对于肿瘤治疗方具有重要意义。目前肿瘤治疗中常用的DNA损伤性化疗药物(如博来霉素，拓扑异构酶II抑制剂如依托泊昔和多柔比星)和放疗发挥作用的主要机制就是造成DNA分子的致死性的双链断裂，进而诱导肿瘤细胞的死亡。但是，肿瘤细胞存在DNA损伤修复***，例如DNA依赖蛋白激酶(DNA-dependent protein kinase，DNA-PK)可将此类断裂修复，从而提高了肿瘤细胞的生存能力，这也是肿瘤细胞对放化疗抵抗的机制之一。相应地，我们只要抑制这些DNA损伤修复，就可以提高肿瘤细胞对放化疗的敏感性。
DNA-PK是一类丝/苏氨酸蛋白激酶，参与并决定着非同源末端连接DNA损伤修复通路的整个进程。DNA-PK是由催化亚基DNA-PKcs和Ku70/80异二聚体组成的复合物，其中，Ku70/80异二聚体可以识别DNA断裂(DSBs)并募集活化激酶亚基DNA-PKcs，活化的DNA-PKcs引导Artemis结合于损伤位点，接着XRCC4/DNA-Ligase IV复合物被活化的DNA-PKcs募集并与之结合，最后由DNA-Ligase IV定位并连接断裂的DNA双链末端，从而完成整个修复过程。研究表明，经过放化疗治疗的肿瘤组织中均发现DNA-PK的高表达，而DNA-PKcs活性的增加在一定程度上增强了受损DNA的修复，阻止了肿瘤细胞死亡，导致了对放化疗产生耐受。此外，放化疗治疗后肿瘤组织中存活的细胞往往是对治疗不敏感的高DNA-PKcs活性细胞，这也是疗效不好和预后差的原因。通过与放化疗药物联用，DNA-PK抑制剂可以抑制DNA-PKcs活性，从而大大减少肿瘤DNA修复，诱导细胞进入凋亡程序，达到更佳的治疗效果。
因此，本发明希望提出具有抑制DNA-PK(DNA依赖蛋白激酶)功能的新型化合物，以更好地应用于肿瘤的治疗。
发明内容
本发明旨在至少解决上述现有技术中存在的技术问题之一。为此，本发明提出一种嘧啶衍生物及其制备方法与在制备抗肿瘤药物中的应用。该嘧啶衍生物具有良好的DNA-PK抑制活性和药代动力学稳定性，可有效抑制肿瘤生长，并协同增强化疗和放疗效果。
本发明提供了一种嘧啶衍生物或其在药学上可接受的盐、立体异构体，所述嘧啶衍生物的结构通式如(I)所示：
其中，X、Y和Z分别独立地选自CH、N；R1选自取代或未取代的以下基团：C5-C12饱和或不饱和碳杂环基、C5-C12饱和或不饱和螺杂环基、C5-C12饱和或不饱和稠杂环基，其中，所述取代基团是指选自下组的一个或多个基团：羟基、卤素、氰基、氨基。
本发明中所述嘧啶衍生物在药学上可接受的盐可以是：链或环中携带氮原子的酸加成盐、与无机酸(例如盐酸、氢溴酸、氢碘酸、硫酸、重硫酸、磷酸或硝酸)形成的酸加成盐、与有机酸(例如甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)-苯甲酸、樟脑酸、肉桂酸、环戊酸、二葡糖酸、3-羟基-2-萘酸、烟酸、双羟萘酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、新戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚糖酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸)形成的酸加成盐。
优选地，所述R1选自以下基团：
优选地，所述嘧啶衍生物选自以下化合物：
本发明还提供了上述嘧啶衍生物的制备方法，其合成方法如下所示：
在上述合成方法中，第一步先将Z上的氢用R1基团进行取代，第二步再在氯原子上发生取代，制得最终嘧啶衍生物。
本发明还提供了上述嘧啶衍生物或其在药学上可接受的盐、立体异构体在制备抗肿瘤药物中的应用。上述嘧啶衍生物或其在药学上可接受的盐、立体异构体具有抑制DNA-PK(DNA依赖蛋白激酶)的作用，可用于预防和/或治疗DNA-PK介导的疾病，例如肿瘤。
优选地，所述肿瘤选自结肠癌、肺癌、卵巢癌、子宫内膜癌、胰腺癌、头颈癌、食道癌、乳腺癌、结直肠癌、淋巴瘤、白血病、滑膜肉瘤、黑色素瘤、肝癌、胃癌、膀胱癌、鳞状细胞癌、成神经管细胞瘤、肾癌或神经胶质瘤。
本发明提供了一种抗肿瘤药物，包括作为第一治疗剂的上述嘧啶衍生物或其在药学上可接受的盐、立体异构体。该抗肿瘤药物可与化疗药物或放疗方法(如X射线、伽马射线、放射药物治疗等)联合使用，起到良好的协同抗癌效果。
优选地，所述抗肿瘤药物还包括药学上可接受的辅料。
更优选地，所述药学上可接受的辅料包括纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂或水中的至少一种。
优选地，所述抗肿瘤药物还包括第二治疗剂，所述第二治疗剂选自奥拉帕尼、卢卡帕尼、尼拉帕尼、甲氨蝶呤、卡培他滨、吉西他滨、去氧氟尿苷、培美曲塞二钠、帕唑帕尼、伊马替尼、埃罗替尼、拉帕替尼、吉非替尼、凡德他尼、赫赛汀、贝伐单抗、利妥昔单抗、曲妥珠单抗、紫杉醇、长春瑞滨、多西他赛、多柔比星、羟基喜树碱、丝裂霉素、表柔比星、吡柔比星、博来霉素、来曲唑、他莫西芬、氟维司群、曲谱瑞林、氟他胺、亮丙瑞林、阿那曲唑、异环磷酰胺、白消安、环磷酰胺、卡莫司汀、尼莫司汀、司莫司汀、氮芥、马法兰、瘤可宁、卡铂、顺铂、奥沙利铂、络铂、拓扑特肯、喜树碱、拓扑替康、依维莫司、西罗莫斯、特癌适、6-巯基嘌呤、6-硫鸟嘌呤、硫唑嘌呤、菌素D、柔红霉素、阿霉素、米托蒽醌、争光霉素、普卡霉素或氨鲁米特、纳武单抗(nivolumab)、派姆单抗(pembrolizumab)、伊匹单抗(ipilimumab)、阿维鲁单抗(avelumab)、度伐单抗(durvalumab)、阿特朱单抗(atezolizumab)、皮地利珠单抗(pidilizumab)中的至少一种。在上述抗肿瘤药物中加入具有抗癌功效的第二治疗剂，能够更有效地抑制肿瘤生长。
除非另有说明，在本发明出现的以下术语具有下述含义：
术语“卤素”、“卤代”是指氟、氯、溴或碘。
术语“碳杂环基”是指包含特定数目的杂原子的环状烷基，所述环原子包括碳原子和1、2、3或4个杂原子，特别是氮、氧和/或硫，其中所述杂原子是相同的或不同的，其可以是单环(如C5-C10环烷基)，也可以是双环或三环形式，例如桥环、稠环或螺环(如C5-C10桥环烷基、C5-C10稠环烷基、C5-C10螺环烷基)形式。
术语“取代”是指在指定原子上的一个或多个氢被选自指出的基团替换，条件是：不超过所指定原子的现有情况下的正常价，并且该取代产生稳定化合物。取代基和/或变量可以组合，只要这种组合可以产生稳定化合物即可。
相对于现有技术，本发明的有益效果如下：
(1)本发明所述嘧啶衍生物具有优异的DNA-PK抑制作用，在生物体内表现出良好的药代动力学性质，且能协同增强化疗和放疗效果，从而起到较好的抗肿瘤作用。
(2)本发明所述嘧啶衍生物的合成路线短，制备工艺简单，易于进行大规模工业生产。
具体实施方式
为了让本领域技术人员更加清楚明白本发明所述技术方案，现列举以下实施例进行说明。需要指出的是，以下实施例仅为本发明的优选实施例，对本发明要求的保护范围不构成限制作用，任何未违背本发明的精神实质和原理下所做出的修改、替代、组合，均包含在本发明的保护范围内。
以下实施例中所用的原料、试剂或装置如无特殊说明，均可从常规商业途径得到，或者可以通过现有已知方法得到。
实施例1
本实施例提供一种嘧啶衍生物T-01，其合成路线如下所示：
具体制备方法为：
(1)向反应瓶中加入化合物1(350mg)、四氢呋喃(10mL)、三苯基磷(972mg)和化合物2(241mg)，搅拌降温至0℃，滴加偶氮二甲酸二异丙酯DIAD(749mg)，加毕，升温至70℃反应16小时，降温，浓缩，用柱层析硅胶过柱，乙酸乙酯：石油醚体系洗脱，得淡黄色固体化合物3(373mg)。LCMS：(MS-ESI，m/z):[M+H]+＝267。
(2)向反应瓶中加入化合物3(25mg)、化合物4(14mg)、醋酸钯(5mg)、碳酸铯(61mg)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽Xantphos(6mg)和二氧六环(2mL)，氮气保护，搅拌升温至100℃反应2小时，降温至25℃，过滤，滤液用反相制备液相HPLC[WatersSunfire C18,10μm,column,gradient 10-95％ B(solvent A,0.02％ TFA inwater；solvent B,CH3CN)]纯化，得到白色化合物T-01(2mg)。
对嘧啶衍生物T-01进行检测，检测结果如下：
LCMS：(MS-ESI,m/z):[M+H]+＝379。1H NMR：(400MHz,DMSO-d6,ppm):δ8.92(s,1H),
8.87(s,1H),8.78(d,J＝1.8Hz,1H),8.73(d,J＝1.8Hz,1H),8.64(s,1H),8.41(s,1H),4.61(s,1H),3.98(s,2H),3.56(s,2H),2.55(s,3H),2.21(d,J＝7.8Hz,2H),2.00(s,2H)。
实施例2
本实施例提供一种嘧啶衍生物T-02，其合成方法与实施例1基本相同，区别之处仅在于：
采用替代实施例1中的/>从而制得嘧啶衍生物/>
对嘧啶衍生物T-02进行检测，检测结果如下：
LCMS：(MS-ESI,m/z):[M+H]+＝349。1H NMR：(400MHz,DMSO-d6,ppm):δ8.81(s,1H),
8.72(dd,J＝4.2,1.6Hz,1H),8.47(s,1H),8.34(s,1H),8.18(d,J＝7.7Hz,1H),7.84(s,1H),4.60(dd,J＝8.0,3.9Hz,1H),4.00(dd,J＝11.4,4.1Hz,2H),3.48(d,J＝11.9Hz,2H),2.51(s,3H),2.29(dd,J＝12.3,4.3Hz,2H)。
实施例3
本实施例提供一种嘧啶衍生物T-03，其合成方法与实施例1基本相同，区别之处仅在于：
采用替代实施例1中的/>采用/>替代实施例1中的/>从而制得嘧啶衍生物/>
对嘧啶衍生物T-03进行检测，检测结果如下：
LCMS：(MS-ESI,m/z):[M+H]+＝352。1H NMR：(400MHz,DMSO-d6,ppm):δ8.92(s,1H),
8.87(s,1H),8.64(s,1H),8.41(s,1H),7.90(s,1H),4.61(s,1H),3.98(s,2H),3.56(s,2H),2.55(s,3H),2.21(d,J＝7.8Hz,2H),2.00(s,2H)。
实施例4
本实施例提供一种嘧啶衍生物T-04，其合成方法与实施例1基本相同，区别之处仅在于：
采用替代实施例1中的/>采用/>替代实施例1中的/>从而制得嘧啶衍生物/>
对嘧啶衍生物T-04进行检测，检测结果如下：
LCMS：(MS-ESI,m/z):[M+H]+＝350。1H NMR：(400MHz,DMSO-d6,ppm):δ9.14(s,1H),
8.92(s,1H),8.36(s,1H),8.35(s,1H),7.70(s,1H),4.56-4.53(m,1H),3.99-3.95(m,2H),3.47(s,2H),2.37(s,3H),2.17(dd,J＝12.1,4.1Hz,1H),1.96(d,J＝10.1Hz,1H)。
实施例5
本实施例提供一种嘧啶衍生物T-05，其合成方法与实施例1基本相同，区别之处仅在于：
采用替代实施例1中的/>从而制得嘧啶衍生物
对嘧啶衍生物T-05进行检测，检测结果如下：
LCMS：(MS-ESI,m/z):[M+H]+＝380。1H NMR：(400MHz,DMSO-d6,ppm):δ9.11(s,1H),
8.72(s,1H),8.31(s,1H),8.05(s,1H),7.39(s,1H),4.61(s,1H),3.98(s,2H),3.56(s,2H),2.55(s,3H),2.21(d,J＝7.8Hz,2H),2.00(s,2H)。
实施例6
本实施例提供一种嘧啶衍生物T-06，其合成方法与实施例1基本相同，区别之处仅在于：
采用替代实施例1中的/>采用/>替代实施例1中的/>从而制得嘧啶衍生物/>
对嘧啶衍生物T-06进行检测，检测结果如下：
LCMS：(MS-ESI,m/z):[M+H]+＝392。1H NMR：(400MHz,DMSO-d6,ppm):δ9.04(s,1H),
8.82(s,1H),8.16(s,1H),7.95(s,1H),7.65(s,1H),4.57-4.51(m,1H),3.91-3.85(m,2H),3.47(m,2H),2.51(s,3H),2.31(m,2H),2.16(dd,J＝11.3,3.1Hz,2H),1.46(m,J＝10.1Hz,4H).
产品效果测试
一、体外检测DNA-PK抑制剂的酶活性测定
采用DNA-PK激酶试剂盒检查化合物对DNA-PK的抑制作用，具体操作步骤如下所述：
1.将DNA-依赖性蛋白激酶、DNA-依赖性蛋白激酶肽底物(10mg/mL)、ATP(包含在ADP-Glo Kinase Assay试剂盒中)在冰上融化，并且在实验过程中以上试剂需要一直置于冰上，未使用完的原液需要分装保存，避免反复冻融；
2.取实施例1-6中嘧啶衍生物T-01至T-06作为待测样品，阿斯利康公司的DNA-PK抑制剂(代号为AZD7648)作为阳性样品，采用含有5％DMSO的1×缓冲液(assay buffer)进行溶解后，以1μL/孔加入至微孔板中；空白对照将1×缓冲液(assay buffer)以1μL/孔加入至微孔板中；DNA-PK抑制剂AZD7648的具体结构如下所示：
3.DNA-依赖性蛋白激酶完全溶解后，用1×缓冲液将酶稀释到2.5unit/μL后，将酶溶液以2μL/孔加入到微孔板中，将1×缓冲液以2μL/孔加入至空白对照孔中，微孔板1000转离心1分钟。
4.底物与ATP的混合溶液配制：使用1×缓冲液对DNA-依赖性蛋白激酶肽底物(10mg/mL)进行稀释并加入ATP，使ATP的浓度为125μM，DNA-依赖性蛋白激酶肽底物浓度为0.5μg/μL，底物与ATP的混合溶液置于冰上备用；
5.取底物与ATP的混合溶液以2μL/孔加入至微孔板中，微孔板1000转离心1分钟，此时DNA-依赖性蛋白激酶肽底物浓度为0.2μg/μL，ATP浓度为50μM，DMSO浓度为1％；微孔板封膜，置于25℃孵育60min；
6.ADP-GloTM试剂和Kinase Detection在使用前需要平衡到室温；
结束孵育后，取ADP-GloTM试剂以5μL/孔加入微孔板中，微孔板1000转离心1分钟，微孔板封膜后置于25℃，孵育40分钟；
7.结束孵育后，取Kinase Detection以10μL/孔加入微孔板中，微孔板1000转离心1分钟，微孔板封膜后，置于25℃，孵育30分钟；结束孵育后，使用Nivo进行Luminescence检测，读取发光值(RLU)；
8.酶活率计算：
酶活％＝(RLU(样品)-RLU(空白))/(RLU(1％DMSO)-RLU(空白)))x100％
DNA-PK抑制剂与蛋白之间结合力实验结果见表1。
表1DNA-PK抑制剂的酶活性测定
由表1可知，本发明实施例1-6中嘧啶衍生物均具有抑制DNA-PK激酶的效果，且部分嘧啶衍生物具有与AZD7648相当或者更好的活性。
二、MTT细胞毒测试(LoVo细胞)
应用MTT检测法测定实施例1-6中嘧啶衍生物对LoVo细胞(人结肠癌细胞)增长的抑制作用。实验步骤如下：
LoVo细胞以约5000细胞/孔接种于96孔板中，37℃培养24h。将实施例1-6中嘧啶衍生物用无血清培养基进行梯度稀释后，加入至96孔板中，加药量为50μL/孔。药物处理48h后，每孔加入10μL MTT溶液，37℃孵育4h。仔细吸去上清，每孔加入150μL DMSO，轻轻振荡以使甲臜溶解。1h内在检测波长570nm处用酶标仪测定OD值。采用Graphpad Prism软件进行分析计算。抑制率＝(100-OD样品/OD溶媒)×100％，其中OD样品为添加各浓度受试物后检测到的吸光度值，OD溶媒为溶媒组(添加溶媒，不加受试物)检测到的吸光度值。阳性对照物为阿斯利康公司的DNA-PK抑制剂，代号为AZD7648。各化合物对LoVo细胞的细胞毒测试结果如表2所示。
表2各化合物对LoVo细胞的细胞毒测试结果
由表2可知，实施例1-6中嘧啶衍生物对人结肠癌细胞具有较好的抑制作用，表现出良好的抗结肠瘤效果。
三、MTT细胞毒测试(U373细胞)
应用MTT检测法测定实施例1-6中嘧啶衍生物对U373癌细胞(U373星型胶质瘤细胞)增长的抑制作用。实验步骤如下：
LoVo细胞以约5000细胞/孔接种于96孔板中，37℃培养24h。将实施例1-6中嘧啶衍生物用无血清培养基进行梯度稀释后，加入至96孔板中，加药量为50μL/孔。药物处理48h后，每孔加入10μL MTT溶液，37℃孵育4h。仔细吸去上清，每孔加入150μL DMSO，轻轻振荡以使甲臜溶解。1h内在检测波长570nm处用酶标仪测定OD值。采用Graphpad Prism软件进行分析计算。抑制率＝(100-OD样品/OD溶媒)×100％，其中OD样品为添加各浓度受试物后检测到的吸光度值，OD溶媒为溶媒组(添加溶媒，不加受试物)检测到的吸光度值。阳性对照物为阿斯利康公司的DNA-PK抑制剂，代号为AZD7648。各化合物对U373癌细胞的细胞毒测试结果如表3所示。
表3各化合物对LoVo细胞的细胞毒测试结果
由表2可知，实施例1-6中嘧啶衍生物对U373星型胶质瘤细胞具有较好的抑制作用，表现出良好的抗神经胶质瘤效果。
四、DNA-PK抑制剂与辐照联合对U373癌细胞(U373星型胶质瘤细胞)的影响
已知DNA-PK抑制剂与辐照进行联合使用可能会起到辐照增敏作用，因而将实施例1-6中嘧啶衍生物与辐照进行联用并考察其对于U373癌细胞(U373星型胶质瘤细胞)的抑制效果，实验方法及步骤如下所示：
将细胞系U373于37℃，5％CO2的培养箱中进行培养，定期传代，取处于对数生长期的细胞用于铺板。U373以5000细胞/孔接种于96孔板中，37℃培养24h。将实施例1-6中嘧啶衍生物用无血清培养基进行梯度稀释后，加入至96孔板中，加药量为50μL/孔。待完成加药程序后，将96孔板放置于培养箱，1小时后置于RadSource 2000X-ray仪器，进行辐照，辐照强度为2.4Gy，辐照结束将96孔细胞板放回培养箱中培养9天。采用CellTiter-Glo发光法细胞活性检测，用下列公式来计算检测化合物的抑制率(Inhibition rate，IR)：IR(％)＝(1–(RLU化合物–RLU空白对照)/(RLU溶媒对照–RLU空白对照))*100％得到化合物的抑制率IC50，结果如表4所示。
表4DNA-PK抑制剂与辐照联用对U373细胞生长的抑制活性
由表4可知，与AZD7648相比，实施例1-6中嘧啶衍生物与辐照联用时同样对U373癌细胞有着较强的抑制作用，两者的联用表现出良好的协同效应。
五、大鼠体内药代动力学
将健康SD大鼠随机分为6组，每组各3只。每组大鼠分别单次灌胃给予实施例5中嘧啶衍生物、实施例6中嘧啶衍生物以及AZD7648，进行血浆动力学研究。分析药物在大鼠体内的血浆动力学特点，包括原形药物的暴露程度、吸收特点等。
口服给药剂量为5mg/kg，分别于7.5min、15min、30min、1h、2h、4h、8h和24h收集血液，使用EDTA作为全血收集用的抗凝剂，4℃、10000转/分钟离心1分钟，1小时内分离血浆，于-20℃保存待测，采血至离心过程在冰浴条件下操作。吸取30μL待测血浆样品，加入300μL含内标(阿哌沙班20ng/mL)的乙腈溶液，振荡混匀5分钟，13000rpm离心10分钟，取上清80μL加入80μL超纯水稀释，混匀，吸取2μL用于液相色谱-质谱分析测定，计算药代参数。试验结果见表5。
表5各代表化合物的药代动力学参数
由表5可知，实施例5-6中嘧啶化合物的药代吸收良好，具有明显的药代动力学优势。
上面对本发明实施例作了详细说明，但是本发明不限于上述实施例，在所属技术领域普通技术人员所具备的知识范围内，还可以在不脱离本发明宗旨的前提下作出各种变化。此外，在不冲突的情况下，本发明的实施例及实施例中的特征可以相互组合。
Claims (8)
1.一种嘧啶衍生物或其在药学上可接受的盐、立体异构体，其特征在于，所述嘧啶衍生物的结构通式如(I)所示：
其中，X、Y和Z分别独立地选自N；所述R1选自以下基团：
2.权利要求1所述的嘧啶衍生物或其在药学上可接受的盐、立体异构体的制备方法，其特征在于，所述嘧啶衍生物的合成方法如下所示：
。
3.权利要求1所述的嘧啶衍生物或其在药学上可接受的盐、立体异构体在制备抗肿瘤药物中的应用。
4.根据权利要求3所述的应用，其特征在于，所述肿瘤选自结肠癌、肺癌、卵巢癌、子宫内膜癌、胰腺癌、头颈癌、食道癌、乳腺癌、结直肠癌、淋巴瘤、白血病、滑膜肉瘤、黑色素瘤、肝癌、胃癌、膀胱癌、鳞状细胞癌、成神经管细胞瘤、肾癌或神经胶质瘤。
5.一种抗肿瘤药物，其特征在于，包括作为第一治疗剂的权利要求1所述的嘧啶衍生物或其在药学上可接受的盐、立体异构体。
6.根据权利要求5所述的抗肿瘤药物，其特征在于，所述抗肿瘤药物还包括药学上可接受的辅料。
7.根据权利要求6所述的抗肿瘤药物，其特征在于，所述药学上可接受的辅料包括纤维素及其衍生物、固体润滑剂、硫酸钙、植物油、多元醇、乳化剂、润湿剂、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂中的至少一种。
8.根据权利要求6所述的抗肿瘤药物，其特征在于，所述抗肿瘤药物还包括第二治疗剂，所述第二治疗剂选自奥拉帕尼、卢卡帕尼、尼拉帕尼、甲氨蝶呤、卡培他滨、吉西他滨、去氧氟尿苷、培美曲塞二钠、帕唑帕尼、伊马替尼、埃罗替尼、拉帕替尼、吉非替尼、凡德他尼、赫赛汀、贝伐单抗、利妥昔单抗、曲妥珠单抗、紫杉醇、长春瑞滨、多西他赛、多柔比星、羟基喜树碱、丝裂霉素、表柔比星、吡柔比星、博来霉素、来曲唑、他莫西芬、氟维司群、曲谱瑞林、氟他胺、亮丙瑞林、阿那曲唑、异环磷酰胺、白消安、环磷酰胺、卡莫司汀、尼莫司汀、司莫司汀、氮芥、马法兰、瘤可宁、卡铂、顺铂、奥沙利铂、络铂、拓扑特肯、喜树碱、拓扑替康、依维莫司、西罗莫斯、特癌适、6-巯基嘌呤、6-硫鸟嘌呤、硫唑嘌呤、菌素D、柔红霉素、阿霉素、米托蒽醌、争光霉素、普卡霉素或氨鲁米特、纳武单抗、派姆单抗、伊匹单抗、阿维鲁单抗、度伐单抗、阿特朱单抗、皮地利珠单抗中的至少一种。
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