CN114853751B - 一组吩噻嗪类衍生物及其应用 - Google Patents
一组吩噻嗪类衍生物及其应用 Download PDFInfo
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- XMPJICVFSDYOEG-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindole-1,3-dione Chemical compound O=C1C=2C(O)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O XMPJICVFSDYOEG-UHFFFAOYSA-N 0.000 description 1
- MZIOEPIEDDJOPP-UHFFFAOYSA-N 2-(2-hydroxyethylsulfanyl)-3-methylnaphthalene-1,4-dione Chemical compound C1=CC=C2C(=O)C(C)=C(SCCO)C(=O)C2=C1 MZIOEPIEDDJOPP-UHFFFAOYSA-N 0.000 description 1
- IIEJGTQVBJHMDL-UHFFFAOYSA-N 2-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-5-[2-oxo-2-[3-(sulfamoylamino)pyrrolidin-1-yl]ethyl]-1,3,4-oxadiazole Chemical compound C1CN(CC1NS(=O)(=O)N)C(=O)CC2=NN=C(O2)C3=CN=C(N=C3)NC4CC5=CC=CC=C5C4 IIEJGTQVBJHMDL-UHFFFAOYSA-N 0.000 description 1
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 1
- KFZGLJSYQXZIGP-UHFFFAOYSA-N 2-chloro-10h-phenothiazine Chemical compound C1=CC=C2NC3=CC(Cl)=CC=C3SC2=C1 KFZGLJSYQXZIGP-UHFFFAOYSA-N 0.000 description 1
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- WIKYUJGCLQQFNW-UHFFFAOYSA-N prochlorperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 WIKYUJGCLQQFNW-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
本发明属于药物化学领域,具体涉及一组吩噻嗪类衍生物,其结构如下所示:
Description
技术领域
本发明属于药物化学技术领域,具体涉及一组吩噻嗪类衍生物及其应用,该吩噻嗪类衍生物具有泛素化降解肿瘤细胞中S100A4蛋白的功能,有望在肿瘤治疗领域得到应用。
背景技术
肿瘤是威胁人类生命的重大疑难疾病。随着国民经济的发展以及技术的进步,对肿瘤的治疗虽然取得了巨大的进步,但是其仍然是影响国民健康的最大危险因素。因此,肿瘤的治疗已成为需要迫切解决的问题。
肿瘤转移是肿瘤发展恶化的一个重要过程,如果肿瘤不发生转移,患者的五年生存率为 90%;如果发生转移,五年生存率只有大约10%。因此,寻找一个靶点,既能抑制肿瘤的转移,又能抑制其增殖,对肿瘤的治疗将具有重大的意义。
S100钙结合蛋白A4(S100A4),又被称为Mts1、p9Ka、pEL98、CAPL、Fsp-1等,属于S100家族EF-手型钙离子结合蛋白,是由101个氨基酸组成的多肽。S100A4广泛分布于人单核细胞、巨噬细胞、中性粒细胞等各种细胞中,正常生理条件下,对细胞的增殖、分化、浸润等过程起着重要的调节作用。S100A4在乳腺癌、胰腺癌、前列腺癌、肺癌等癌细胞中均过量表达,其过量表达与肿瘤的增殖、转移密切相关。降低S100A4在肿瘤中的表达,肿瘤细胞的增殖、转移便能得到控制。因此,S100A4便被认为是一个潜在的肿瘤治疗靶点。
S100A4靶向性抑制剂可与S100A4蛋白结合,插入其酯溶性区域(如下所示),影响S100A4与受体的结合,阻断其生理功能。目前已报道的S100A4直接靶向性抑制剂有三氟啦嗪、丙氯拉嗪、羟氯扎胺、NSC95397、NSC672121等(如下所示)。
尽管如此,由于S100A4蛋白较小,能够供小分子结合的空间有限,导致目前已报道的这些小分子对S100A4的抑制活性不强。蛋白降解靶向联合体(Proteolysis TargetingChimera,PROTAC)是一类能够通过诱导靶蛋白的多聚泛素化而导致靶蛋白降解的化合物,是近年来出现的一种极具应用前景的药物发展方向。PROTAC技术的出现为靶向 S100A4药物的研发提供了新的技术。
发明内容
本发明目的在于克服现有技术缺陷,提供一组吩噻嗪类衍生物及其应用,该吩噻嗪类衍生物作为PROTAC分子,以S100A4为靶蛋白,具有降解肿瘤细胞中S100A4蛋白的功能,从而具备肿瘤治疗的潜力。
为实现上述目的,本发明采用如下技术方案:
本发明提供了一组吩噻嗪类衍生物或其药学上可接受的盐,其结构如下所示:
其中,R选自氯、氟、或三氟甲基,n=0~10中的任一数字。
进一步的,本发明所述一组吩噻嗪类衍生物及其药学上可接受的盐,可优选自下述任一化合物:
4-(2-(3-(4-(3-(2-氯-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)-3-羰基丙氧基)乙氧基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;
4-(2-(3-(4-(3-(2-氯-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)-3-羰基丙氧基)乙氧基)乙氧基-2- (2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;
4-(2-(2-(2-(3-(4-(3-(2-氯-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)-3-羰基丙氧基)乙氧基)乙氧基) 乙氧基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;
4-((15-(4-(3-(2-氯-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)-15-羰基-3,6,9,12-四氧十五烷基)氧)- 2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;
4-((18-(4-(3-(2-氯-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)-18-羰基-3,6,9,12,15-五氧十八烷基) 氧)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;
4-((21-(4-(3-(2-氯-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)-21-羰基-3,6,9,12,15,18-六氧二十一烷基)氧)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;
2-(2,6-二氧代哌啶-3-基)-4-(2-(3-羰基-3-(4-(3-(2-(三氟甲基)-10H-吩噻嗪-10-基)丙基)哌嗪- 1-基)丙氧基)乙氧基)异吲哚啉-1,3-二酮;
2-(2,6-二氧代哌啶-3-基)-4-(2-(2-(3-羰基-3-(4-(3-(2-(三氟甲基)-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)丙氧基)乙氧基)乙氧基)异吲哚啉-1,3-二酮;
2-(2,6-二氧代哌啶-3-基)-4-(2-(2-(2-(3-羰基-3-(4-(3-(2-(三氟甲基)-10H-吩噻嗪-10-基)丙基) 哌嗪-1-基)丙氧基)乙氧基)乙氧基)乙氧基)异吲哚啉-1,3-二酮;
2-(2,6-二氧代哌啶-3-基)-4-((15-羰基-15-(4-(3-(2-(三氟甲基)-10H-吩噻嗪-10-基)丙基)哌嗪 -1-基)-3,6,9,12-四氧十五烷基)氧)异吲哚啉-1,3-二酮;
2-(2,6-二氧代哌啶-3-基)-4-((18-羰基-18-(4-(3-(2-(三氟甲基)-10H-吩噻嗪-10-基)丙基)哌嗪 -1-基)-3,6,9,12,15-五氧十八烷基)氧)异吲哚啉-1,3-二酮;
2-(2,6-二氧代哌啶-3-基)-4-((21-羰基-21-(4-(3-(2-(三氟甲基)-10H-吩噻嗪-10-基)丙基)哌嗪 -1-基))-3,6,9,12,15,18-六氧二十一烷基)氧)异吲哚啉-1,3-二酮;
2-(2,6-二氧代哌啶-3-基)-4-(2-(3-(4-(3-(2-氟-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)-3-羰基丙氧基)乙氧基)异吲哚啉-1,3-二酮;
2-(2,6-二氧代哌啶-3-基)-4-(2-(2-(3-(4-(3-(2-氟-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)-3-羰基丙氧基)乙氧基)乙氧基)异吲哚啉-1,3-二酮;
2-(2,6-二氧代哌啶-3-基)-4-(2-(2-(2-(3-(4-(3-(2-氟-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)-3-羰基丙氧基)乙氧基)乙氧基)乙氧基)异吲哚啉-1,3-二酮;
2-(2,6-二氧代哌啶-3-基)-4-((15-(4-(3-(2-氟-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)-15-羰基- 3,6,9,12-四氧十五烷基)氧)异吲哚啉-1,3-二酮;
2-(2,6-二氧代哌啶-3-基)-4-((18-(4-(3-(2-氟-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)-18-羰基- 3,6,9,12,15-五氧十八烷基)氧)异吲哚啉-1,3-二酮;
2-(2,6-二氧代哌啶-3-基)-4-((21-(4-(3-(2-氟-10氢-吩噻嗪-10-基)丙基)哌嗪-1-基)-21-羰基- 3,6,9,12,15,18-六氧二十一烷基)氧)异吲哚啉-1,3-二酮。
本发明还提供了所述吩噻嗪类衍生物或其药学上可接受的盐在制备抗癌药物中的应用,其具有靶向泛素化降解肿瘤细胞中S100A4蛋白的作用,可用于肿瘤的治疗。
进一步的,本发明提供了上所述吩噻嗪类衍生物或其药学上可接受的盐在制备预防和治疗肺腺癌药物中的应用,从而有望用于肺腺癌的治疗。
和现有技术相比,本发明的有益效果如下:
目前仅有S100A4小分子抑制剂的报道,关于靶向S100A4的PROTAC分子,未见公开报道。本发明所述吩噻嗪类衍生物或其药学上可接受的盐为靶向S100A4进行肿瘤治疗提供了新的物质基础。经实验验证:在0.1-20μM的药物浓度作用下,人肺腺癌细胞PC9中 S100A4蛋白浓度呈显著性的梯度降低,初步证实了本发明所述吩噻嗪类衍生物或其药学上可接受的盐具有降解S100A4蛋白的功能。
附图说明
图1为实施例6制备所得目标化合物的1H NMR图谱;
图2为实施例6制备所得目标化合物的13C NMR图谱;
图3为Western-blot测定实施例6制备所得目标化合物对S100A4的降解图。
具体实施方式
以下结合实施例对本发明的技术方案作进一步地详细介绍,但本发明的保护范围并不局限于此。
下述实施例中,所用原料为普通市售产品,或可以按照本领域常规技术制备获得。室温指代25±5℃。
实施例1,制备2-氯-10-(3-氯丙基)-10H-吩噻嗪
该中间体的制备参考(Bioorganic&Medicinal Chemistry,26(4),833-844;2018)。将2-氯- 10H-吩噻嗪(1.17g,5mmoL)与1-溴-3-氯丙烷(0.94g,6mmol)加入到二甲基甲酰胺 (DMF,10mL)中,冰浴下分批加入氢化钠(NaH,65%,0.4g),然后转为室温反应约1小时。待反应完全,减压蒸除反应溶剂,再加入乙酸乙酯(40mL),用饱和食盐水萃取(6 x20mL),收集有机相,无水硫酸钠干燥,浓缩,得粗品,不经纯化直接进行下一步反应。 ESI-MS m/z:310[M+H]+。
实施例2,制备4-(3-(2-氯-10H-吩噻嗪-10-基)丙基)哌嗪-1-甲酸叔丁酯
将2-氯-10-(3-氯丙基)-10H-吩噻嗪(1.55g,5mmoL)与1-叔丁氧羰基哌嗪(1.12g,6mmoL)加入到二甲基甲酰胺(DMF,10mL)中,冰浴下分批加入氢化钠(NaH,65%,0.4g),然后转为70℃反应约5小时。待反应完全,减压蒸除反应溶剂,再加入二氯甲烷 (40mL),用饱和食盐水萃取(6x20mL),收集有机相,无水硫酸钠干燥,浓缩,得粗品,硅胶柱色谱纯化(石油醚:乙酸乙酯=3:1,体积比),得白色固体1.9g,收率82.6%。1H NMR(400MHz,CDCl3)δ7.14(ddd,J=9.3,8.3,1.5Hz,2H),7.02(d,J=8.1Hz,1H),6.97– 6.86(m,3H),6.85(d,J=2.0Hz,1H),3.92(t,J=6.8Hz,2H),3.41–3.30(m,4H),2.52–2.42(m,2H),2.37–2.26(m,4H),1.93(p,J=6.8Hz,2H),1.45(s,9H)。ESI-MS m/z:460[M+H]+。
实施例3,制备2-氯-10-(3-(哌嗪-1-基)丙基)-10H-吩噻嗪
将4-(3-(2-氯-10H-吩噻嗪-10-基)丙基)哌嗪-1-甲酸叔丁酯(1.0g)溶于二氯甲烷 (DCM,10mL)中,冰浴下逐滴加入三氟乙酸(TFA,3mL),然后转为室温反应2小时。待反应完全,减压蒸除溶剂及多余的三氟乙酸,得白色固体,即目标产物。收率100%。1H NMR(400MHz,DMSO)δ7.29–7.15(m,3H),7.15–7.06(m,2H),7.06–6.94(m,2H),3.97(t,J=6.7Hz,2H),3.65–2.94(m,11H),2.10–1.88(m,2H)。ESI-MS m/z:360[M+H]+。
实施例4,制备3-(2-(2-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氧基)乙氧基)乙氧基) 乙氧基)丙酸叔丁酯
将2-(2,6-二氧代哌啶-3-基)-4-羟基-异吲哚-1,3-二酮(1.37g,5mmoL)与3-(2-(2-(2-溴乙氧基)乙氧基)乙氧基)丙酸叔丁酯(0.21g,6mmoL)溶于DMF(10mL)中,加入无水碳酸钾(K2CO3,0.35g,2.5mmoL)在80℃下反应3小时。待反应完全,减压蒸除反应溶剂,再加入乙酸乙酯(40mL),用饱和食盐水萃取(6x20mL),收集有机相,无水硫酸钠干燥,浓缩,得粗品,硅胶柱色谱纯化(二氯甲烷:甲醇=100:2,体积比),得无色油状物 1.60g,即目标产物。收率60%。1H NMR(400MHz,CDCl3)δ8.35(s,1H),7.72–7.63(m,1H), 7.49–7.44(m,1H),7.29(d,J=7.3Hz,1H),5.02–4.88(m,1H),4.42–4.31(m,2H),3.98–3.90(m,2H),3.80–3.74(m,2H),3.74–3.64(m,8H),3.01–2.65(m,3H),2.52-2.48(m,2H),2.18– 2.08(m,1H),1.44(s,9H)。ESI-MS m/z:535[M+H]+。
实施例5,制备3-(2-(2-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氧基)乙氧基)乙氧基)乙氧基)丙酸
将3-(2-(2-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氧基)乙氧基)乙氧基)乙氧基) 丙酸叔丁酯(1.0g)溶于二氯甲烷(10mL)中,冰浴下逐滴加入三氟乙酸(3mL),然后转为室温反应2小时。待反应完全,减压蒸除溶剂及多余的三氟乙酸,得白色固体,即目标产物。收率100%。1H NMR(400MHz,CDCl3)δ8.92(s,1H),7.75–7.65(m,1H),7.53–7.43(m, 1H),7.34–7.24(m,1H),5.06–4.93(m,1H),4.43–4.30(m,2H),3.98(dd,J=14.1,9.4Hz,2H),3.89–3.62(m,10H),3.03–2.69(m,3H),2.62(t,J=6.1Hz,2H),2.26–2.03(m,1H)。ESI-MS m/z:479[M+H]+。
实施例6,4-(2-(2-(2-(3-(4-(3-(2-氯-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)-3-羰基丙氧基)乙氧基) 乙氧基)乙氧基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮
将2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU,171mg,0.45mmol) 和N,N-二异丙基乙胺(DIEA,116mg,0.90mmol)加入到含有3-(2-(2-(2-((2-(2,6-二氧哌啶- 3-基)-1,3-二氧异吲哚啉-4-基)氧基)乙氧基)乙氧基)乙氧基)丙酸(0.14g,0.30mmol)和2-氯- 10-(3-(哌嗪-1-基)丙基)-10H-吩噻嗪(0.12g,0.32mmol)的无水二甲基甲酰胺(3mL)混合液中,室温反应约3h。待反应完全,反应体系中加入乙酸乙酯(20mL),用饱和食盐水萃取(6x 10mL),收集有机相,无水硫酸钠干燥,浓缩,得粗品,硅胶柱色谱分离纯化(二氯甲烷:甲醇=100:5,体积比),得白色固体(收率:41.6%)。1H NMR(400MHz,CDCl3)δ8.93(s,1H),7.66(dd,J=8.3,7.5Hz,1H),7.46(d,J=7.2Hz,1H),7.29–7.22(m,2H),7.19–6.81(m,6H),5.05–4.85(m,1H),4.33(t,J=4.7Hz,2H),3.98–3.86(m,4H),3.83–3.72(m, 4H),3.70–3.48(m,8H),3.47–3.34(m,2H),2.92–2.68(m,3H),2.61(t,J=6.8Hz,2H),2.52–2.43(m,2H),2.42–2.30(m,3H),2.16–2.06(m,1H),1.97–1.80(m,3H)。13C NMR(100MHz, CDCl3)δ171.23,169.40,168.26,167.01,165.56,156.37,146.42,144.47,136.45,133.78,133.17, 127.93,127.54,127.41,124.85,123.60,122.94,122.28,119.32,117.28,116.11,115.86,115.83,71.22,70.49,70.46,70.42,69.27,69.24,67.33,55.07,53.38,52.78,49.10,45.53,45.02,41.45, 33.49,31.42,23.97,22.64。ESI-MS m/z:820[M+H]+。详见图1和图2。
实施例7,Western-blot测定实施例6制备化合物对S100A4蛋白的降解
将人肺腺癌细胞PC9从液氮中取出,复苏,传代,均匀铺于细胞培养板,待细胞密度达到60-70%时加入不同浓度的药物,37℃孵育24h后收集,用生理盐水洗涤2次,每孔加入SDS裂解液(SDS:double distilled water=2:100比例配置)120uL,室温放置5min,金属浴100℃,30min,离心涡旋取全液,即细胞总蛋白。用BCA法定量检测蛋白量,用5x蛋白上样缓冲液稀释蛋白后100℃变性10min。蛋白在SDS-PAGE电泳分离,转膜,TBST稀释获得5%的脱脂奶粉封闭液(5g/100mL)封闭1h,一抗(Anti-GAPDH大鼠单克隆抗体和 S100A4抗体)4℃孵育过夜。TBST洗膜,二抗(HRP标记山羊抗小鼠lgG和HRP标记山羊抗兔lgG,1:1000稀释)室温孵育1h,化学发光仪曝光显影,得到S100A4的蛋白印记条带,结果见图3。
图3展示了实施例6制备所得化合物对人肺腺癌细胞PC9中S100A4蛋白降解的结果。从图3可以看出:在0.1、1、10、20μM药物浓度作用下,S100A4蛋白浓度呈显著性的梯度降低,初步证实了目标化合物具有降解S100A4蛋白的功能。
综上,本发明所述吩噻嗪类衍生物或其药学上可接受的盐具有靶向泛素化降解肿瘤细胞中S100A4蛋白的作用,从而有望用于肿瘤,尤其是肺腺癌的治疗。
Claims (4)
1.一组吩噻嗪类衍生物或其药学上可接受的盐,其结构如下所示:
;
其中,R选自氯、氟、或三氟甲基,n=0~10中的任一数字。
2.根据权利要求1所述吩噻嗪类衍生物或其药学上可接受的盐,其特征在于,所述吩噻嗪类衍生物或其药学上可接受的盐为下述任意一种化合物:
4-(2-(3-(4-(3-(2-氯-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)-3-羰基丙氧基)乙氧基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;
4-(2-(3-(4-(3-(2-氯-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)-3-羰基丙氧基)乙氧基)乙氧基-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;
4-(2-(2-(2-(3-(4-(3-(2-氯-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)-3-羰基丙氧基)乙氧基)乙氧基)乙氧基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;
4-((15-(4-(3-(2-氯-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)-15-羰基-3,6,9,12-四氧十五烷基)氧)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;
4-((18-(4-(3-(2-氯-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)-18-羰基-3,6,9,12,15-五氧十八烷基)氧)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;
4-((21-(4-(3-(2-氯-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)-21-羰基-3,6,9,12,15,18-六氧二十一烷基)氧)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;
2-(2,6-二氧代哌啶-3-基)-4-(2-(3-羰基-3-(4-(3-(2-(三氟甲基)-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)丙氧基)乙氧基)异吲哚啉-1,3-二酮;
2-(2,6-二氧代哌啶-3-基)-4-(2-(2-(3-羰基-3-(4-(3-(2-(三氟甲基)-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)丙氧基)乙氧基)乙氧基)异吲哚啉-1,3-二酮;
2-(2,6-二氧代哌啶-3-基)-4-(2-(2-(2-(3-羰基-3-(4-(3-(2-(三氟甲基)-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)丙氧基)乙氧基)乙氧基)乙氧基)异吲哚啉-1,3-二酮;
2-(2,6-二氧代哌啶-3-基)-4-((15-羰基-15-(4-(3-(2-(三氟甲基)-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)-3,6,9,12-四氧十五烷基)氧)异吲哚啉-1,3-二酮;
2-(2,6-二氧代哌啶-3-基)-4-((18-羰基-18-(4-(3-(2-(三氟甲基)-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)-3,6,9,12,15-五氧十八烷基)氧)异吲哚啉-1,3-二酮;
2-(2,6-二氧代哌啶-3-基)-4-((21-羰基-21-(4-(3-(2-(三氟甲基)-10H-吩噻嗪-10-基)丙基)哌嗪-1-基))-3,6,9,12,15,18-六氧二十一烷基)氧)异吲哚啉-1,3-二酮;
2-(2,6-二氧代哌啶-3-基)-4-(2-(3-(4-(3-(2-氟-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)-3-羰基丙氧基)乙氧基)异吲哚啉-1,3-二酮;
2-(2,6-二氧代哌啶-3-基)-4-(2-(2-(3-(4-(3-(2-氟-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)-3-羰基丙氧基)乙氧基)乙氧基)异吲哚啉-1,3-二酮;
2-(2,6-二氧代哌啶-3-基)-4-(2-(2-(2-(3-(4-(3-(2-氟-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)-3-羰基丙氧基)乙氧基)乙氧基)乙氧基)异吲哚啉-1,3-二酮;
2-(2,6-二氧代哌啶-3-基)-4-((15-(4-(3-(2-氟-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)-15-羰基-3,6,9,12-四氧十五烷基)氧)异吲哚啉-1,3-二酮;
2-(2,6-二氧代哌啶-3-基)-4-((18-(4-(3-(2-氟-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)-18-羰基-3,6,9,12,15-五氧十八烷基)氧)异吲哚啉-1,3-二酮;
2-(2,6-二氧代哌啶-3-基)-4-((21-(4-(3-(2-氟-10氢-吩噻嗪-10-基)丙基)哌嗪-1-基)-21-羰基-3,6,9,12,15,18-六氧二十一烷基)氧)异吲哚啉-1,3-二酮。
3.权利要求1或2所述吩噻嗪类衍生物或其药学上可接受的盐在制备抗癌药物中的应用。
4.权利要求1或2所述吩噻嗪类衍生物或其药学上可接受的盐在制备预防和治疗肺腺癌药物中的应用。
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