CN110590807B - 一种噻吩并[3,2-d]嘧啶类衍生物及其应用 - Google Patents
一种噻吩并[3,2-d]嘧啶类衍生物及其应用 Download PDFInfo
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- CN110590807B CN110590807B CN201910954070.3A CN201910954070A CN110590807B CN 110590807 B CN110590807 B CN 110590807B CN 201910954070 A CN201910954070 A CN 201910954070A CN 110590807 B CN110590807 B CN 110590807B
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- thieno
- amino
- pyrimidinyl
- chloro
- ethyl
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- 150000001875 compounds Chemical class 0.000 claims abstract description 36
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
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- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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Abstract
本发明属医药领域，具体涉及一种具有通式(I)结构的新型噻吩并[3,2‑d]嘧啶类衍生物及其应用。衍生物如通式(I)所示，或通式(I)所示化合物药学上可接受的盐。其中n和Ar如权利说明书所定义。部分化合物的药理活性筛选结果显示其对人胃癌细胞MKN45，人肺腺癌细胞A549和人结肠癌细胞HT29具有显著抑制作用，具有良好的抗肿瘤药物开发应用前景。
Description
技术领域
本发明属医药领域，具体涉及一种具有通式(I)结构的新型噻吩并 [3,2-d]嘧啶类衍生物及其应用。
背景技术
恶性肿瘤也称癌症，癌症是细胞不受控制的增长和扩散。它可影响人体的几乎任何部分。肿瘤常常侵入周围的组织并可转移到其它部位。癌症是一个全球主要的死亡原因。癌症已经成为严重威胁人类健康和社会经济发展的重要主要的公共健康问题。2015年全世界一共有近880万人死于癌症，约占全球死亡人数的六分之一。肺癌、胃癌、结肠癌、肝癌和乳癌是每年大多数癌症死亡的罪魁祸首。男女最常患的癌症类型有所不同。全球癌症死亡人数将继续增加，预计2030年因癌症死亡人数预计将达1200万。在我国每年新发癌症病例约340万人,死亡约210万人，死亡人数约占全球癌症死亡人数的四分之一。癌症已经超越心脏病成为导致死亡的主要原因。恶性肿瘤的治疗是一个世界性的难题，寻找切实有效的癌症治疗手段和方法已成为世界医药学领域刻不容缓的研究重点。杂环化合物是分子中含有杂环结构的有机化合物。构成环的原子除碳原子外，还至少含有一个杂原子。是数目最庞大的一类有机化合物。最常见的杂原子是氮原子、硫原子、氧原子。可分为脂杂环、芳杂环两大类。杂环化合物普遍存在于药物分子的结构之中。噻吩并[3,2-d]嘧啶类衍生物是一类重要的杂环化合物，含有噻吩并[3,2-d]嘧啶结构的化合物常常具有抗癌、抗菌等广泛的生物活性。该类化合物已成为药学领域科研工作者研究的热点。在抗肿瘤领域很多药物均含有噻吩并[3,2-d]嘧啶结构片段，例如：血管内皮生长因子受体(VEGFR)抑制剂帕唑帕尼(pazopanib)和多靶点酪氨酸激酶抑制剂阿西替尼(axtinib)。此外也有大量文献报道含噻吩并[3,2-d]嘧啶结构片段具有很好的抗肿瘤活性；但是服用该类药物时，往往患者会发生不良反应，影响患者生活质量。如服用帕唑帕尼，患者常发生腹泻、恶心、头痛、呼吸苦难、体重下降等副作用。服用阿昔替尼也会产生腹泻，高血压，疲乏，食欲减低，恶心，发音障碍，手掌-足底(手-足)综合征，体重减轻，呕吐，乏力，和便秘。因此，关于噻吩并[3,2-d]嘧啶类的抗肿瘤活药物研发有待进一步研究。
发明内容
本发明的目的是提供一种具有通式(I)结构的新型噻吩并[3,2-d]嘧啶类衍生物及其应用。
为实现上述目的，本发明采用技术方案为：
一种新型噻吩并[3,2-d]嘧啶类衍生物，衍生物如通式(I)所示，及其药学上可接受的盐，
其中：
n为1-6之间整数；
Ar为未取代或被1-5个相同或不同的R1取代的呋喃基、吡咯基、噻吩基、苯基、吡啶基、萘基或喹啉基；
R1为氢、氟、氯、溴、硝基、氨基、氰基、甲基、乙基、丙基、丙烯基、烯丙基、甲氧基、乙氧基、三氟甲基、三氟甲氧基、二氟甲氧基、二甲氨基；
或通式(I)所示化合物药学上可接受的盐。
优选所述化合物为
N-{2-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]乙基}苯甲酰胺；
N-{2-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]乙基}-4-氟苯甲酰胺；
N-{2-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]乙基}-4-三氟甲氧基苯甲酰胺；
N-{2-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]乙基}-3-甲氧基苯甲酰胺；
N-{2-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]乙基}-2-甲基甲酰胺；
N-{2-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]乙基}-3-氯苯甲酰胺；
N-{2-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]乙基}-2,4-二氯苯甲酰胺；
N-{2-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]乙基}-3,4-二甲氧基苯甲酰胺；
N-{3-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]丙基}苯甲酰胺；
N-{3-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]丙基}-3-氯苯甲酰胺；
N-{3-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]丙基}-4-三氟甲基苯甲酰胺；
N-{4-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]丁基}苯甲酰胺；
N-{4-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]丁基}-3-甲氧基苯甲酰胺；
N-{4-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]丁基}-2,4-二氯苯甲酰胺；
N-{4-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]丁基}-3,4-二甲氧基苯甲酰胺；
或上述化合物药学上可接受的盐。
上述化合物的盐，可按照本发明所属领域的一些通常方法，将式(I) 所示的新型含吡喃的双芳基脲类衍生物与酸生成药学上可接受的盐。可药用加成盐包括无机酸和有机酸加成盐，与下列酸加成的盐是特别优选的：甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸、盐酸、氢溴酸、硫酸、磷酸等。
一种噻吩并[3,2-d]嘧啶类衍生物的应用，所述化合物及其盐在制备治疗和 /或预防增生性疾病药物中的应用。
一种噻吩并[3,2-d]嘧啶类衍生物的应用，所述化合物及其盐在制备治疗和 /或预防癌症的药物中的应用。
一种噻吩并[3,2-d]嘧啶类衍生物的应用，所述化合物及其盐在制备治疗和 /或预防胃癌，肺癌和结肠癌药物中的应用。
一种药用组合物，包含以通式(I)所示化合物及其药学上可接受的盐作为活性成分，以及药学上可接受的赋形剂；其中，活性成分占组合物质量的0.1-99％。
一种药用组合物的应用，所述的药物组合物在制备治疗和/或预防增生性疾病药物中的应用。
一种药用组合物的应用，所述的药物组合物在制备治疗和/或预防癌症的药物中的应用。
一种药用组合物的应用，所述的药物组合物在制备治疗和/或预防胃癌，肺癌和结肠癌药物中的应用。
本发明所具有的优点：
本发明化合物以噻吩并[3,2-d]嘧啶基团作为母核，通过柔性的连接臂将噻吩并[3,2-d]嘧啶和芳香基团连接，所得化合物及其盐通过体外抑制人胃癌细胞MKN45，人肺腺癌细胞A549和人结肠癌细胞HT29活性试验，其对人胃癌细胞和肺癌细胞具有显著抑制作用，特别用于制备治疗和/或预防胃癌，肺癌和结肠癌的药物。
具体实施方式
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解，下述实例和制备例的范围并不以任何方式限制本发明的范围。
下面的合成路线描述了本发明的式(I)衍生物的制备，所有的原料都是通过以下合成路线中描述的方式、通过有机化学领域普通技术人员熟知的方法制备的或者可商购。本发明的全部最终衍生物都是通过以下合成路线中描述的方法或通过与其类似的方法制备的，这些方法是有机化学领域普通技术人员熟知的。路线中所有化合物的取代基n和Ar如权利要求中所定义。合成路线如下：
以下实施例旨在阐述而不是限制本发明的范围。化合物的核磁共振氢谱用BrukerARX-600测定，质谱用Agilent 6460 QQQ测定；所用试剂均为分析纯或化学纯。
制备实施例
步骤A 2,4-二羟基噻吩并[3,2-d]嘧啶(M-1)
取一个100mL的反应瓶，加入3-氨基-2-噻吩甲酸甲酯(15.72g,100 mmol)与尿素(30.3g,500mmol)充分搅拌使其混合均匀，加热至190℃使反应体系呈熔融状态，保温搅拌反应3小时。冷却反应至室温，反应混合物固化，将固体取出，研磨成粉末状态，将所得粉末倒入适量的20％的氢氧化钠水溶液中，搅拌使其尽量溶解，若有不溶物，抽滤，所得滤液用浓盐酸调节pH至2～3，析出大量固体，抽滤，滤饼水洗至中性，干燥得类白色固体2,4-二羟基噻吩并[3,2-d]嘧啶(M-1)13.54g，收率80.5％。 MS(ESI)m/z(％):169.2[M+H]+。
步骤B 2,4-二氯噻吩并[3,2-d]嘧啶(M-2)
取一个250mL的反应瓶，加入三氯氧磷70mL，搅拌下慢慢加入2,4- 二羟基噻吩并[3,2-d]嘧啶(12.0g,71.36mmol)，加热回流12小时。减压蒸发除去过量的三氯氧磷，将残留物缓慢地倒入冰水中，析出大量的白色固体，抽滤，滤饼水洗至中性，干燥得到类白色固体2,4-氯噻吩并[3,2-d] 嘧啶(M-2)10.10g，收率为69.0％。1H NMR(300MHz,DMSO-d6)δ8.71(d,J＝5.4Hz,1H),7.74(d,J＝5.4Hz,1H)。
步骤C N1-(2-氯-4-噻吩并[3,2-d]嘧啶基)乙烷-1,2-二胺(M-3)
取一个250mL的反应瓶，加入2,4-二氯噻吩并[3,2-d]嘧啶(6.0g, 29.26mmol)和干燥的甲醇100mL，搅拌混合均匀，向上述混合物中缓慢滴加乙二胺(5.28g,87.78mmol)的20mL干燥甲醇溶液，室温搅拌反应 12小时。减压蒸发除去大部分甲醇，放置过夜，析出大量固体，抽滤，滤饼依次用水洗至中性，少量冷甲醇洗涤，干燥得产物N1-(2-氯-4-噻吩并[3,2-d]嘧啶基)乙烷-1,2-二胺(M-3)4.27g，收率为63.8％。MS(ESI) m/z(％):229.1[M+H]+。
骤D新型噻吩并[3,2-d]嘧啶类化合物的合成通法
在反应瓶中加入含氨基的噻吩并[3,2-d]嘧啶M-3 1.00mmol，芳基酸 1.20mmol，HATU 1.20mmol，三乙胺1.50mmol，5.0mL N,N-二甲基甲酰胺，室温搅拌反应，TLC跟踪反应进程。待反应完毕，将反应液倒入 80mL饱和碳酸钠水溶液中，分别用50mL二氯甲烷萃取三次，合并有机相，有机相用饱和碳酸钠水溶液洗涤三次，饱和食盐水洗涤有机层两次，分出有机层用无水硫酸钠干燥。过滤,滤液减压蒸发得粗产物，粗产物经硅胶柱层析分离得产物。其中洗脱液为不同梯度混配下的二氯甲烷和甲醇。
按上述实施例合成通法的记载，选取适当的原料及试剂即可获得本发明通式(I)所示化合物1–15；部分化合物的结构确证数据如下：
化合物1:N-{2-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]乙基}苯甲酰胺
1H NMR(600MHz,DMSO-d6)δ8.62(t,J＝5.5Hz,1H),8.48(t,J＝ 5.5Hz,1H),8.17(d,J＝5.3Hz,1H),7.91–7.78(m,2H),7.52(t,J＝7.3Hz, 1H),7.46(t,J＝7.5Hz,2H),7.34(d,J＝5.3Hz,1H),3.70–3.60(m,2H), 3.58–3.49(m,2H).
化合物2:N-{2-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]乙基}-4-氟苯甲酰胺
1H NMR(600MHz,DMSO-d6)δ8.66(t,J＝5.5Hz,1H),8.49(t,J＝ 5.5Hz,1H),8.17(d,J＝5.3Hz,1H),8.01–7.79(m,2H),7.56–7.11(m, 3H),3.69–3.59(m,2H),3.57–3.49(m,2H)；MS(ESI)m/z(％): 351.1[M+H]+,373.1[M+Na]+.
化合物3:N-{2-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]乙基}-4-三氟甲氧基苯甲酰胺
MS(ESI)m/z(％):417.1[M+H]+,439.1[M+Na]+.
化合物4:N-{2-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]乙基}-3-甲氧基苯甲酰胺
1H NMR(600MHz,DMSO-d6)δ8.61(t,J＝5.5Hz,1H),8.49(t,J＝5.5Hz,1H),8.17(d,J＝5.3Hz,1H),7.46–7.29(m,4H),7.12–7.05(m, 1H),3.79(s,3H),3.68–3.61(m,2H),3.56–3.50(m,2H)；MS(ESI)m/z(％): 363.1[M+H]+,385.1[M+Na]+.
化合物5:N-{2-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]乙基}-2-甲基甲酰胺
MS(ESI)m/z(％):347.1[M+H]+,369.1[M+Na]+.
化合物6:N-{2-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]乙基}-3-氯苯甲酰胺
1H NMR(600MHz,DMSO-d6)δ8.75(t,J＝5.6Hz,1H),8.48(t,J＝ 5.6Hz,1H),8.17(d,J＝5.3Hz,1H),7.87(d,J＝1.6Hz,1H),7.80(d,J＝ 7.8Hz,1H),7.60(dd,J＝8.0,1.1Hz,1H),7.50(t,J＝7.9Hz,1H),7.34(d,J ＝5.3Hz,1H),3.70–3.61(m,2H),3.58–3.48(m,2H).
化合物7:N-{2-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]乙基}-2,4-二氯苯甲酰胺
1H NMR(600MHz,DMSO-d6)δ8.67–8.58(m,1H),8.41(t,J＝5.4 Hz,1H),8.17(d,J＝5.3Hz,1H),7.66(s,1H),7.55–7.42(m,2H),7.34(d,J ＝5.3Hz,1H),3.65(dd,J＝11.7,5.9Hz,2H),3.55–3.47(m,2H).
化合物8:N-{2-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]乙基}-3,4-二甲氧基苯甲酰胺
1H NMR(600MHz,DMSO-d6)δ8.55–8.46(m,2H),8.17(d,J＝5.3Hz, 1H),7.55–7.39(m,2H),7.34(d,J＝5.3Hz,1H),7.01(d,J＝8.4Hz,1H), 3.80(s,3H),3.79(s,3H),3.68–3.59(m,2H),3.56–3.47(m,2H).
化合物9:N-{3-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]丙基}苯甲酰胺
MS(ESI)m/z(％):347.1[M+H]+,369.1[M+Na]+.
化合物10:N-{3-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]丙基}-3-氯苯甲酰胺
MS(ESI)m/z(％):381.1[M+H]+,403.1[M+Na]+.
化合物11:N-{3-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]丙基}-4-三氟甲基苯甲酰胺
MS(ESI)m/z(％):415.1[M+H]+,437.1[M+Na]+.
化合物12:N-{4-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]丁基}苯甲酰胺
1H NMR(600MHz,DMSO-d6)δ8.50(t,J＝5.1Hz,1H),8.41(t,J＝ 5.1Hz,1H),8.16(d,J＝5.3Hz,1H),7.84(d,J＝7.2Hz,2H),7.55–7.41(m, 3H),7.33(d,J＝5.3Hz,1H),3.57–3.44(m,2H),3.34–3.28(m,2H),1.75 –1.54(m,4H)；MS(ESI)m/z(％):361.2[M+H]+,383.1[M+Na]+.
化合物13:N-{4-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]丁基}-3-甲氧基苯甲酰胺
1H NMR(600MHz,DMSO-d6)δ8.46(t,J＝5.4Hz,1H),8.39(t,J＝5.4 Hz,1H),8.16(d,J＝5.3Hz,1H),7.47–7.30(m,4H),7.07(dd,J＝8.1,1.9 Hz,1H),3.80(s,3H),3.54–3.45(m,2H),3.33–3.27(m,2H),1.71–1.56 (m,4H)；MS(ESI)m/z(％):391.1[M+H]+,413.1[M+Na]+.
化合物14:N-{4-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]丁基}-2,4-二氯苯甲酰胺
1H NMR(600MHz,DMSO-d6)δ8.50(t,J＝5.5Hz,1H),8.43(t,J＝ 5.2Hz,1H),8.16(d,J＝5.1Hz,1H),7.66(d,J＝1.9Hz,1H),7.50–7.40(m, 2H),7.33(d,J＝5.3Hz,1H),3.57–3.44(m,2H),3.31–3.21(m,2H),1.73 –1.64(m,2H),1.61–1.52(m,2H)；MS(ESI)m/z(％):429.0[M+H]+,431.1 [M+3].
化合物15:N-{4-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]丁基}-3,4-二甲氧基苯甲酰胺
1H NMR(600MHz,DMSO-d6)δ8.40(t,J＝5.2Hz,1H),8.36(t,J＝5.5 Hz,1H),8.16(d,J＝5.3Hz,1H),7.51–7.42(m,2H),7.33(d,J＝5.3Hz, 1H),7.00(d,J＝8.4Hz,1H),3.80(s,3H),3.79(s,3H),3.53–3.47(m,2H), 3.32–3.27(m,2H),1.70–1.55(m,4H)；MS(ESI)m/z(％):421.1[M+H]+, 443.1[M+Na]+.
体外抗肿瘤细胞活性
对按照本发明的通式(I)的噻吩并[3,2-d]嘧啶类衍生物进行了体外抑制人胃癌细胞MKN45，人肺腺癌细胞A549和人结肠癌细胞HT29活性筛选。
按照常规的体外抑制实验，将培养瓶中培养到细胞对数生长期的细胞用胰酶消化下来，用含10％血清的1640培养液终止消化，800rpm离心8min，弃上清液，用含10％血清的培养液吹打均匀再用培养液调整细胞悬液浓度，加入96孔板中，96孔板中除A1孔为空白孔不加细胞外，其余每孔100uL，大约1×104/孔(细胞浓度可以调整)，置于37℃，5％CO2温箱培养24小时。以上述获得化合物作为受试药物(2mg左右)，将受试药物经50μL DMSO溶解混匀，加入950μL 1640培养液稀释并混匀，制成2mg/mL药液，然后用24孔板稀释成10μg/mL。将埋好细胞的96 孔板中的培养液用力甩出，每浓度药液加3个孔，其中周围两行两列细胞长势受环境影响较大，为空白细胞孔使用。将96孔板放入于37℃、5 ％CO2的培养箱中培养72小时。用力甩出96孔板中的液体，每孔加200 μL生理盐水清洗，使残留药物洗去，甩出液体。将事先配制好的5％MTT 液体用培养液稀释成0.5％MTT溶液，然后将稀释好的MTT按照100uL/孔加入96孔板，置于37℃、5％CO2的培养箱中培养4小时以促进其反应完全。4小时后，用力甩出96孔板中的液体，每孔加入100μL DMSO，置于磁力震荡器上震荡3min，使结晶物充分溶解后，放入酶标仪中测定结果。
表1
从表1试验结果可以清楚地看出，本发明的化合物在浓度为10μg/mL 时对人胃癌细胞MKN45，人肺腺癌细胞A549和人结肠癌细胞HT29具有很好的抑制活性。抑制率效果显著，表明本发明所要保护的通式(I)的化合物具有良好的体外抗肿瘤活性。该类化合物具有良好的抗肿瘤药物开发应用前景。
以上详细描述了本发明的优选实施方式，但是，本发明并不限于上述实施方式中的具体细节。凡在本发明的技术构思范围内所做的任何修改、等同替换或改进等，均包含在本发明的保护范围之内。
Claims (9)
1.一种噻吩并[3,2-d]嘧啶类衍生物，其特征在于：衍生物如通式(I)所示，
其中：
n为1-6之间整数；
Ar为未取代或被1-5个相同或不同的R1取代的呋喃基、吡咯基、噻吩基、苯基、吡啶基、萘基或喹啉基；
R1为氟、氯、溴、硝基、氨基、氰基、甲基、乙基、丙基、丙烯基、烯丙基、甲氧基、乙氧基、三氟甲基、三氟甲氧基、二氟甲氧基、二甲氨基；
或通式(I)所示化合物药学上可接受的盐。
2.根据权利要求1所述的噻吩并[3,2-d]嘧啶类衍生物，其特征在于：所述化合物为N-{2-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]乙基}苯甲酰胺；
N-{2-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]乙基}-4-氟苯甲酰胺；
N-{2-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]乙基}-4-三氟甲氧基苯甲酰胺；
N-{2-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]乙基}-3-甲氧基苯甲酰胺；
N-{2-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]乙基}-2-甲基甲酰胺；
N-{2-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]乙基}-3-氯苯甲酰胺；
N-{2-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]乙基}-2,4-二氯苯甲酰胺；
N-{2-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]乙基}-3,4-二甲氧基苯甲酰胺；
N-{3-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]丙基}苯甲酰胺；
N-{3-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]丙基}-3-氯苯甲酰胺；
N-{3-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]丙基}-4-三氟甲基苯甲酰胺；
N-{4-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]丁基}苯甲酰胺；
N-{4-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]丁基}-3-甲氧基苯甲酰胺；
N-{4-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]丁基}-2,4-二氯苯甲酰胺；
N-{4-[(2-氯-4-噻吩并[3,2-d]嘧啶基)氨基]丁基}-3,4-二甲氧基苯甲酰胺；或上述化合物药学上可接受的盐。
3.一种权利要求1所述的噻吩并[3,2-d]嘧啶类衍生物的应用，其特征在于：所述权利要求1所述化合物及其盐在制备治疗和/或预防增生性疾病药物中的应用。
4.一种权利要求1所述的噻吩并[3,2-d]嘧啶类衍生物的应用，其特征在于：所述权利要求1所述化合物及其盐在制备治疗和/或预防癌症的药物中的应用。
5.一种权利要求1所述的噻吩并[3,2-d]嘧啶类衍生物的应用，其特征在于：所述权利要求1所述化合物及其盐在制备治疗和/或预防胃癌，肺癌和结肠癌药物中的应用。
6.一种药用组合物，其特征在于，包含以权利要求1通式(I)所示化合物及其药学上可接受的盐作为活性成分，以及药学上可接受的赋形剂；其中，活性成分占组合物质量的0.1-99％。
7.一种权利要求6所述的药用组合物的应用，其特征在于：所述的药物组合物在制备治疗和/或预防增生性疾病药物中的应用。
8.一种权利要求6所述的药用组合物的应用，其特征在于：所述的药物组合物在制备治疗和/或预防癌症的药物中的应用。
9.一种权利要求6所述的药用组合物的应用，其特征在于：所述的药物组合物在制备治疗和/或预防胃癌，肺癌和结肠癌药物中的应用。
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Effective date of registration: 20240614 Address after: 518000 1002, Building A, Zhiyun Industrial Park, No. 13, Huaxing Road, Henglang Community, Longhua District, Shenzhen, Guangdong Province Patentee after: Shenzhen Wanzhida Technology Co.,Ltd. Country or region after: China Address before: 723001 School of chemistry and Environmental Sciences, Shaanxi University of technology, Hanzhong City, Shaanxi Province Patentee before: Shaanxi University of Technology Country or region before: China |
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