CN113717159A - 吲哚酮类化合物及其药物组合物、制备方法及用途 - Google Patents
吲哚酮类化合物及其药物组合物、制备方法及用途 Download PDFInfo
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- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 125000005247 tetrazinyl group Chemical group N1=NN=NC(=C1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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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
Abstract
本发明公开了如通式I所示结构的吲哚酮类化合物及其药物组合物、制备方法及用途。本发明的苯并吲哚酮类化合物对VEGFRs以及NAMPT具有很好的抑制活性,对肿瘤有良好的治疗作用。
Description
技术领域
本发明涉及创新药物、制备方法及用途,特别涉及吲哚酮类化合物及其药物组合物、制备方法及用途。
背景技术
血管生成即通过发芽形成新的血管或者从已经存在的血管中***出来,用于进行细胞增殖,迁移和生存,在正常的胚胎发育和成体成长中都起着至关重要的作用。然而,异常的血管生成与许多疾病的发生发展密切相关,如癌症、牛皮癣、类风湿关节炎、炎症和视网膜并发症等。特别是癌症中,癌症血管生成会产生新的血管,保证了肿瘤细胞增殖所需的氧气和营养的供应,是维持肿瘤细胞生长和转移的重要过程。血管内皮生长因子(VEGF)家族,包括VEGF-A、VEGF-B、VEGF-C、VEGF-D和胎盘生长因(PlGF),与它的受体血管内皮生长因子受体(VEGFR),包括VEGFR-1(Flt-1),VEGFR-2(Flk-1/KDR)和VEGFR-3,在多种肿瘤中高表达,有助于肿瘤血管网的发展与维持,这会促进肿瘤细胞的生长和转移。因此,抑制VEGF及其受体VEGFR介导的信号通路是一种行之有效的抗肿瘤策略。VEGFR小分子抑制剂的研究备受关注,目前已经有9个VEGFR小分子抑制剂上市,还有多种不同结构的VEGFR小分子抑制剂处于临床前或者临床的不同研究阶段。相比于单克隆抗体,小分子抑制剂的作用靶点并不单一,抑制活性更广,但是存在选择性较差导致的毒副作用较大以及产生耐药性等问题。
烟酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleotide,简称NAD+)是电子传递过程中不可或缺的物质,在能量代谢和信号转导过程中发挥重要作用。另外,NAD+与其还原型NADH对于维持细胞内的还原环境从而保护细胞免受氧化应激的损伤具有重要意义。因此,细胞内NAD+的水平是决定细胞命运的关键性因素。相对于正常细胞,肿瘤细胞具有不可控制的增殖速率、快速的代谢速率以及显著增加的氧化应激水平,因而肿瘤细胞对于NAD+水平的改变更为敏感。NAD+体内生物合成途径的关键酶已经成为抗癌药物的重要靶点。NAD+体内合成途径包括从头合成途径和补救合成途径。
NAD+补救合成途径是以烟酸、烟酰胺或者烟酰胺核糖为起始原料。由于许多NAD+消耗酶,比如聚腺苷二磷酸核糖聚合酶(PARP)和去乙酰化酶(Sirtuins,简称SIRT),可以很快地重新释放出烟酰胺,因而以烟酰胺为原料的NAD+补救合成途径为最经济、最主要的NAD+生物合成途径(Galli U.et al.J.Med.Chem.2013,22,56(16):6279-96)。而烟酰胺磷酸核糖转移酶(nicotinamide phosphoribosyltransferase,简称NAMPT)是控制烟酰胺向NAD+转化的限速酶。鉴于肿瘤细胞能量代谢异常旺盛,更加需要NAD+快速及时地补充,肿瘤细胞对NAMPT更加依赖进而对NAMPT抑制更加敏感。因此,NAMPT被认为是有效的抗癌靶点,NAMPT抑制剂已经成为广泛研究的热点。目前,已经有两个NAMPT抑制剂CHS-828和FK866进入临床试验阶段(Montecucco F.et al.Curr.Drug Targets.2013,1,14(6):637-43)。但是,这两个化合物的临床试验结果并不理想,病人给药后并没有表现出显著的治疗效果。
多靶点药物可以降低毒性、增加疗效,并且有望解决耐药性问题。另外,多靶点药物可以避免联合用药存在的缺陷,比如药物-药物相互作用、药代动力学性质复杂、无法确保两(多)种药物到达治疗靶点、病人的依从性差等问题。
发明内容
发明目的:本发明目的是提供一种具有抗癌药物疗效好、耐药性好等优点的吲哚酮类化合物以及其药物组合物。
本发明另一目的是提供所述具有抗癌药物疗效好、耐药幸好等优点的吲哚酮类化合物以及其药物组合物的制备方法及用途。
技术方案:本发明提供如通式I所示结构的吲哚酮类化合物或其药学上可接受的盐、溶剂化物、前药、立体异构体、互变异构体或代谢产物,
式中:
L为-CH2OCH2CH2OCH2-、或未取代或R1取代的C2-10烷基;
R1为羟基、氨基、氰基、卤素或C1-6的烷基;
E为O、S或N-C≡N;
X为单键、C2-4烯键、C1-4烷基、环丙基、-NHCH2-;
R为未取代或R2取代的C6-10芳基、未取代或R3取代的杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的5~10元杂芳基、或、未取代或R4取代的杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的5~10元杂环烷基;
R2、R3和R4独立地为氘、卤素、羟基、氨基、C1-6烷基、C1-6烷氧基或C1-6卤代烷基。
进一步地,当L为未取代或R1取代的C1-10烷基时,所述R1的个数为一个或多个,当存在多个R1时,所述的R1可相同或不同;
和/或,当L为未取代或R1取代的C2-10烷基时,所述的C2-10烷基为C2-8烷基;
和/或,当R1为C1-6的烷基时,所述的C1-6烷基为C1-3烷基;
和/或,当R1为卤素时,所述的卤素为氟、氯、溴或碘;
和/或,当E为O时,X为单键、C1-4烷基、C2-4烯基、环丙基或-NHCH2-,或者,当E为S时,X为-NHCH2-,或者,当E为N-C≡N时,X为单键;
和/或,当R为未取代或R3取代的杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的5~10元杂芳基时,所述的R3的个数为一个或多个,当存在多个R3时,所述的R3可相同或不同;
和/或,当R为未取代或R3取代的杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的5~10元杂芳基时,所述的杂芳基为杂原子选自N、O和S中的一种或多种,杂原子数为1-3个,N原子个数至少为1个的5~10元杂芳基;
和/或,当R为未取代或R4取代的杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的5~10元杂环烷基时,所述的R4的个数为一个或多个,当存在多个R4时,所述的R4可相同或不同;
和/或,当R为未取代或R4取代的杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的5~10元杂环烷基时,所述的杂环烷基为杂原子选自N、O和S中的一种或多种,杂原子数为1-3个,N原子个数至少为1个的5~10元杂环烷基;
和/或,当R3为卤素,所述的卤素为氟、氯、溴或碘;
和/或,当R3为C1-6烷基时,所述的C1-6烷基为C1-3烷基;
和/或,当R3为C1-6烷氧基时,所述的C1-6烷氧基为C1-3烷氧基;
和/或,当R3为C1-6卤代烷基时,所述的C1-6卤代烷基为C1-3卤代烷基;
和/或,当R4为C1-6烷基时,所述的C1-6烷基为C1-3烷基;
和/或,当R4为C1-6卤代烷基时,所述的C1-6卤代烷基为C1-3卤代烷基。
进一步地,当L为未取代或R1取代的C1-10烷基时,所述的R1的个数为1个、2个或3个;
和/或,当L为未取代或R1取代的C2-10烷基时,所述的未取代或R1取代的C2-10烷基为C4-7烷基;
和/或,当R为未取代或R3取代的杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的5~10元杂芳基时,所述的R3的个数为1个、2个或3个;
和/或,当R为未取代或R3取代杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的5~10元杂芳基时,所述的杂芳基为吡啶基、吡啶并吡咯基、吡啶并咪唑基、吡啶并呋喃基、吡唑并噻吩基或吡唑并吡唑基;
和/或,当R为未取代或R4取代杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的5~10元杂环烷基时,所述的R4的个数为1个、2个或3个;
和/或,当R3为卤素,所述的卤素为氟;
和/或,当R3为C1-6的烷基时,所述的C1-6的烷基为甲基、乙基、丙基或异丙基,优选甲基;
和/或,当R3为C1-6的烷氧基时,所述的C1-6的烷氧基为甲氧基、乙氧基或丙氧基,优选甲氧基;
和/或,当R3为C1-6卤代烷基时,所述的C1-6卤代烷基为-CF3;
和/或,当R4为C1-6烷基时,所述的C1-6烷基为甲基、乙基或丙基,优选甲基;
和/或,当R4为C1-6卤代烷基时,所述的C1-6卤代烷基为-CF3。
进一步地,当R为未取代或R3取代杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的5~10元杂芳基时,所述的未取代或R3取代的杂芳基为:
和/或,当R为未取代或R4取代杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的”5~10元杂环烷基时,所述的未取代或R4取代的杂环烷基为
和/或,当E为O时,X为单键,R为
或者,当E为O时,X为-NHCH2-、C2-4烯基或环丙基,R为
或者,当E为S时,X为-NHCH2-,R为
或者,当E为N-C≡N时,X为单键,R为
进一步地,L为未取代的C2-10烷基;
和/或,E为O、S或N-C≡N;
和/或,X为单键、C2-4烯键、C1-4烷基、环丙基、-NHCH2-;
和/或,R为未取代或R3取代的“杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的”5~10元杂芳基、或、未取代或R4取代的“杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的”5~10元杂环烷基;
和/或,R3为卤素、氨基或C1-6烷基;
和/或,R4为氨基或C1-6烷基。
进一步地,
所述的吲哚酮类化合物或其药学上可接受的盐、溶剂化物、前药、立体异构体、互变异构体或代谢产物,为如下任一种:
进一步地,所述的吲哚酮类化合物的制备方法,其特征在于:包括如下步骤:
在溶剂中,在碱和缩合剂的作用下,将如式II所示化合物与如式III所示化合物进行缩合反应,即可,其中L、E、X和R的定义如前。
一种药物组合物,包括有效量的如权利要求1-6种任一项所述的如通式I所示化合物、或其药学上可接受的盐、溶剂化物、前药、立体异构体、互变异构体或代谢产物,及药学上可接受的载体。本发明还提供上述药物组合物在制备预防和/或***药物中的应用,所述的肿瘤包括但不限于乳腺癌、卵巢癌、***癌、结肠癌、胃癌、非小细胞肺癌、神经胶质瘤、肾癌、胰腺癌、肝癌、黑色素瘤、白血病和***,优选为乳腺癌、卵巢癌、***癌、结肠癌、胃癌、非小细胞肺癌、黑色素瘤、白血病和***。
如通式I所示结构的吲哚酮类化合物或其药学上可接受的盐、溶剂化物、前药、立体异构体、互变异构体或代谢产物在制备预防和/或***药物中的应用。
进一步地,所述肿瘤为乳腺癌、卵巢癌、***癌、结肠癌、胃癌、非小细胞肺癌、神经胶质瘤、肾癌、胰腺癌、肝癌、黑色素瘤、白血病和***中的一种或多种。优选为乳腺癌、***癌、结肠癌、非小细胞肺癌、白血病和肾癌。
所述的药学上可接受的载体可为药物生产领域中广泛采用的那些辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物,还可以提供方法,使受试者接受给药后活性成分以所期望速率溶出,或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂,或者提供某种功能,例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种:粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。
本发明的药物组合物可根据公开的内容使用本领域技术人员已知的任何方法来制备。例如,常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。
本发明所述的药物组合物可以任何形式给药,包括注射(静脉内)、粘膜、口服(固体和液体制剂)、吸入、眼部、直肠、局部或胃肠外(输注、注射、植入、皮下、静脉内、动脉内、肌内)给药。本发明的药物组合物还可以是控释或延迟释放剂型(例如脂质体或微球)。固体口服制剂的实例包括但不限于粉末、胶囊、囊片、软胶囊剂和片剂。口服或粘膜给药的液体制剂实例包括但不限于悬浮液、乳液、酏剂和溶液。局部用制剂的实例包括但不限于乳剂、凝胶剂、软膏剂、乳膏剂、贴剂、糊剂、泡沫剂、洗剂、滴剂或血清制剂。胃肠外给药的制剂实例包括但不限于注射用溶液、可以溶解或悬浮在药学上可接受载体中的干制剂、注射用悬浮液和注射用乳剂。所述的药物组合物的其它合适制剂的实例包括但不限于滴眼液和其他眼科制剂;气雾剂:如鼻腔喷雾剂或吸入剂;适于胃肠外给药的液体剂型;栓剂以及锭剂。
术语“药学上可接受的盐”是指本发明化合物的盐,由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐,所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸、碳酸氢根、磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等;以及有机酸盐,所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸;还包括氨基酸(如精氨酸等)的盐,以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团,从而可以被转换成任一碱或酸加成盐。优选地,以常规方式使盐与碱或酸接触,再分离母体化合物,由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质,例如在极性溶剂中的溶解度不同。
术语“异构体”是指分子组成相同、但结构和性质不同的两种或多种化合物。
术语“外消旋体”是指一种具有旋光性的手性分子与其对映体的等摩尔混合物,它由旋光方向相反、旋光能力相同的分子等量混合而成,其旋光性因这些分子间的作用而相互抵消,因而是不旋光的。
术语“溶剂合物”是指化合物与溶剂组成的混合物,例如结晶体即是一种溶剂合物。
术语“代谢产物”是指式I所示化合物或其盐通过体内代谢产生的药学活性产物。这种产物可以从例如所给药的化合物的氧化、还原、水解、酰胺化、脱酰胺、酯化、脱酯、葡糖醛酸化(glucoronidation)、酶促裂解等产生。因此,本发明包括本发明的化合物的代谢产物,包括使本发明的化合物与哺乳动物接触足够得到其代谢产物的一段时间的方法而产生的化合物。
代谢产物的鉴定典型地通过制备本发明化合物的放射性标记的(例如,14C或3H)同位素、将其以可检测的剂量(例如,大于约0.5mg/kg)非肠道给予动物,例如大鼠、小鼠、豚鼠、猴、或人,允许充分的时间以发生代谢(典型地约30秒到30小时)和从尿、血液或其它生物样本分离其转化产物。这些产物容易分离,因为它们是被标记的(其它通过利用能够结合存在于代谢物中的抗原表位的抗体分离)。以常规的方式确定代谢物结构,例如,通过MS,LC/MS或NMR分析。通常,代谢物的分析是以与本领域技术人员公知的常规药物代谢研究相同的方法进行的。只要代谢物产物不是以其它方式在体内不能被发现,否则它们可用于本发明化合物的治疗剂量给药的检定测定法。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素标记化合物,比如氚(3H),碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包括在本发明的范围之内。
除了盐的形式,本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。可在体内转化以提供生物活性物质(即式I所示化合物)的任何化合物是在本发明的范围和主旨内的前药。例如,含有羧基的化合物可形成生理上可水解的酯,其通过在体内水解以得到式I所示化合物本身而充当前药。所述前药优选口服给药,这是因为水解在许多情况下主要在消化酶的影响下发生。当酯本身具有活性或水解发生在血液中时,可使用肠胃外给药。
本发明中的“取代”可为一个或多个,当存在多个“取代”时,所述的“取代”可为相同或不同。
术语“多个”是指2个、3个、4个或5个。例如,术语“烷基”指具有指定的碳原子数的直链或支链饱和烃基。代表性饱和烃基包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、正戊基、叔丁基、新戊基、正己基、2-甲基-1-丙基、2-甲基-2-丙基、2-甲基-1-丁基、3-甲基-1-丁基、2-甲基-3-丁基、2-甲基-1-戊基、3-甲基-1-戊基、4-甲基-1-戊基、2-甲基-2-戊基、4-甲基-2-戊基。应当说明的是,当没有特别限制其碳原子数时,仅指其中指明的烷基部分的碳原子数,而并不包括烷基的取代基上碳原子数。
术语“卤素”是指氟、氯、溴或碘。
术语“烷氧基”是指基团-O-RY,其中,RY为如上文所定义的烷基。
术语“环烷基”是指饱和的单环或多环的烷基。所述的单环环烷基优选具有3~7个环碳原子、更优选3-6个碳原子的单价饱和的环状烷基,例如环丙基、环丁基、环戊基或环己基。所述的多环环烷基的每个环均是饱和的,可为具有4~10个碳原子的二环或三环环烷基。
本发明中的“杂环烷基”是指具有杂原子的饱和的单环或含有杂原子的饱和单环与杂芳基稠合形成的双环,当“杂环烷基”为含有杂原子的饱和单环与杂芳基稠合形成的双环时,通过含有杂环子的饱和单环与式I所示化合物中的其它片段、基团进行连接。
术语“芳基”是指具有指定的碳原子数的芳香基团,优选单环、双环或者三环的芳香基团,当为双环或者三环时,每个环均满足休克尔规则。本发明的C6-10的芳基指含有6~10个碳原子的芳香基团,例如苯基或萘基。
术语“杂芳基”是指含有杂原子的芳香基团,优选含有1个、2个或3个独立选自氮、氧和硫的芳族5~6元单环或9~10元双环。所述的5~6元的单环包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、1,2,3-***基、1,2,4-***基、呋咱基、1,2,3-噁二唑基、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑基、二噻唑基、四唑基、吡啶基、吡喃基、噻喃基、二嗪基、吡嗪基、嘧啶基、哒嗪基、噁嗪基、噻嗪基、二噁英基、二噻英基、1,2,3-三嗪基、1,2,4-三嗪基、1,3,5-三嗪基或四嗪基。所述的9~10元双环包括但不限于苯并咪唑基、苯并异噻唑基、苯并噁唑基、咪唑并吡啶、噻唑并吡啶、呋喃并吡啶、四氢吡咯并吡啶。
有益效果:本发明与现有技术相比,具有如下优势:
1、本发明的化合物对VEGFR尤其是VEGFR2具有很好的抑制活性。
2、同时,本发明化合物对NAMPT具有很好的抑制活性。
3、本发明化合物具有VEGFR和NAMPT双重抑制活性,相对于单靶点抑制剂,本发明化合物对肿瘤具有很好的治疗作用,且毒副作用较少,能够解决耐药性问题。
具体实施方式
实施例1:5-(((Z)-5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-N-(2-((E)-3-(吡啶-3-基)丙烯酰胺基)乙基)-1H-吡咯-3-甲酰胺(S1)的合成
步骤一:(E)-N-(2-氨基乙基)-3-(吡啶-3-基)丙烯酰胺盐酸盐(4a)的合成
称取(E)-3-(3-吡啶)丙烯酸1a(500mg,3.35mmol),溶于无水DMF(10mL)中,依次加入EDCI(1.1g,5.7mmol),HOBt(595mg,4.4mmol),TEA(0.92mL,6.7mmol)和化合物2a(536.8mg,3.35mmol),室温下搅拌反应5h,停止反应,减压旋干DMF。向反应残渣中加入5ml饱和NaHCO3溶液,DCM(20ml×3),合并有机相,饱和NH4Cl(10ml)洗涤1次,饱和食盐水(10ml)洗1次,无水硫酸钠干燥,过滤,蒸干溶剂,制砂,柱层析分离纯化(DCM∶MeOH=60∶1~20∶1)得白色固体3a(800mg,82%)。
1H NMR(500MHz,Chloroform-d)δ9.03(t,J=1.9Hz,1H),8.63(dt,J=2.0,3.8Hz,1H),7.99(dt,J=2.0,7.8Hz,1H),7.85(t,J=4.3Hz,1H),7.62-7.54(m,2H),6.59(d,J=15.9Hz,1H),6.01(t,J=4.4Hz,1H),3.45(m,2H),3.37(m,2H),1.43(s,9H).13C NMR(125MHz,Chloroform-d)δ167.88,156.13,150.24,149.69,138.64,134.35,129.74,123.33,121.23,79.58,39.47,39.02,28.32.
称取300mg上述白色固体,加入2mL乙酸乙酯,向上述混悬液中加入2mL HCl/乙酸乙酯溶液(3M),室温下搅拌3h,待反应完全后,直接抽滤,乙酸乙酯洗涤滤饼,真空干燥得到盐酸盐4a,不用纯化直接下一步反应。
步骤二:5-(((Z)-5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-N-(2-((E)-3-(吡啶-3-基)丙烯酰胺基)乙基)-1H-吡咯-3-甲酰胺(S1)的合成
向盐酸盐4a(80mg,0.30mmol)中加无水DMF(2mL)和TEA(0.21mL,1.5mmol),依次加入EDCI(98mg,0.51mmol),HOBt(53mg,0.39mmol),和化合物5a(90mg,0.3mmol),室温下搅拌反应10h,停止反应,减压旋干DMF。向反应残渣中加入2ml饱和NaHCO3溶液,DCM(5ml×3),合并有机相,饱和NH4Cl(2ml)洗涤1次,饱和食盐水(2ml)洗1次,无水硫酸钠干燥,过滤,蒸干溶剂,制砂,柱层析分离纯化(DCM∶MeOH=60∶1~20∶1)得淡黄色色固体S1(92mg,65%)。
1H NMR(500MHz,DMSO-d6)δ13.71(s,1H),10.88(s,1H),8.79(d,J=2.3Hz,1H),8.58(dd,J=1.6,4.8Hz,1H),8.30(d,J=6.3Hz,1H),8.02(dt,J=2.0,8.1Hz,1H),7.77(dd,J=2.5,9.4Hz,1H),7.73(s,1H),7.68(s,1H),7.51(d,J=15.9Hz,lH),7.47(dd,J=4.8,8.0Hz,1H),6.95(td,J=2.6,9.1Hz,1H),6.87(dd,J=4.5,8.4Hz,1H),6.77(d,J=15.9Hz,1H),3.41(q,J=3.1Hz,4H),2.47(s,3H),2.45(s,3H).13C NMR(125MHz,DMSO-d6)δ169.85,167.61,164.85,159.10,150.15,149.62,138.64,137.01,136.60,134.33,129.93,129.70,127.81,124.87,124.73,123.93,123.34,120.28,116.72,116.52,110.08,107.45,40.17,39.40,13.95,10.75.
实施例2:(Z)-5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-N-(5-(3-(吡啶-3-基甲基)脲基)戊基)-1H-吡咯-3-甲酰胺(S11)的合成
步骤一:3-(异氰酸酯甲基)-吡啶(7a)的合成
称取化合物6a(300mg,2.86mmol)溶于无水THF(5mL)中,氮气保护,加入TEA(0.8mL,5.72mmol)。0℃下,将三光气(339mg,1.14mmol)溶于3mL无水THF中,缓慢滴加到上述溶液中,转移至室温,加热至50℃,过夜反应。待反应完全,减压旋掉溶剂,直接投入下一步反应。
步骤二:叔丁基(Z)-(5-(5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺)戊基)氨基甲酸酯(9a)的合成
称取化合物5a(900mg,3.00mmol),溶于无水DMF(10mL)中,依次加入EDCI(978mg,5.1mmol),HOBt(527mg,3.9mmol),TEA(0.83mL,6mmol)和化合物8a(604mg,3.00mmol),室温下搅拌反应6h,停止反应,减压旋干DMF。向反应残渣中加入5ml饱和NaHCO3溶液,DCM(20ml×3),合并有机相,饱和NH4Cl(10ml)洗涤1次,饱和食盐水(10ml)洗1次,无水硫酸钠干燥,过滤,蒸干溶剂,制砂,柱层析分离纯化(DCM∶MeOH=60∶1~20∶1)得白色固体9a1.23g(85%)。
1H NMR(500MHz,Chloroform-d)δ13.34(s,1H),9.92(s,1H),8.51(t,J=4.3Hz,1H),7.72(dd,J=2.6,8.0Hz,1H),7.43(s,1H),6.95(td,J=2.6,8.2Hz,1H),6.85(dd,J=4.9,8.4Hz,1H),5.42(t,J=4.4Hz,1H),3.10(m,4H),2.37(s,3H),2.27(s,3H),1.63-1.54(m,2H),1.55-1.37(m,4H),1.41(s,9H).13C NMR(125MHz,Chloroform-d)δ169.85,164.93,160.08,157.14,136.94,136.58,129.98,127.84,124.73,123.94,122.27,116.83,116.51,110.06,107.52,79.70,40.35,40.02,28.64,28.60,28.33,24.69,13.94,10.75.
步骤三:(Z)-5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-N-(5-(3-(吡啶-3-基甲基)脲基)戊基)-1H-吡咯-3-甲酰胺(S11)的合成
称取9a(242mg,0.5mmol),加入1mL乙酸乙酯,向上述混悬液中加入1mL HCl/乙酸乙酯溶液(3M),室温下搅拌6h,待反应完全后,直接抽滤,乙酸乙酯洗涤滤饼,真空干燥得到盐酸盐,不用纯化直接下一步反应。将盐酸盐中加入5mL无水THF,加入TEA(0.42mL,3.00mmol)。将制备的异氰酸酯7a溶于无水THF(2mL)中,0℃下,将其缓慢滴加到上述溶液中,转移至室温,过夜反应。减压选掉溶剂,加入DCM(10mL)溶解,水洗一次(10mL),饱和食盐水水一次(10mL),无水硫酸钠干燥,过滤,蒸干溶剂,制砂,柱层析分离纯化(DCM∶MeOH=60∶1~20∶1)得白色固体S11。
1H NMR(500MHz,DMSO-d6)δ12.87(s,1H),9.92(s,1H),8.62(t,J=1.9Hz,1H),8.54-8.45(m,2H),7.75-7.66(m,2H),7.43(s,1H),7.27(dd,J=3.5,7.9Hz,1H),6.94(td,J=2.7,8.1Hz,1H),6.84(dd,J=5.0,8.4Hz,1H),6.36(t,J=6.1Hz,1H),5.97(t,J=4.4Hz,1H),4.50(d,J=6.2Hz,2H),3.10(m,4H),2.37(s,3H),2.26(s,3H),1.62-1.48(m,4H),1.46-1.36(m,2H).13C NMR(125MHz,DMSO-d6)δ170.24,165.10,160.07,158.82,148.59,148.42,137.01,136.61,135.15,133.74,129.98,127.84,124.73,123.94,123.81,122.27,116.86,116.51,110.06,107.62,42.01,40.05,38.56,28.68,28.21,24.53,13.94,10.75.
实施例3:(Z)-5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-N-(5-(3-(吡啶-3-基甲基)硫脲基)戊基)-1H-吡咯-3-甲酰胺(S13)的合成
称取9a(242mg,0.5mmol),加入1mL乙酸乙酯,向上述混悬液中加入lmL HCl/乙酸乙酯溶液(3M),室温下搅拌6h,待反应完全后,直接抽滤,乙酸乙酯洗涤滤饼,真空干燥得到盐酸盐,不用纯化直接下一步反应。将盐酸盐中加入5mL无水THF,加入TEA(0.42mL,3.00mmol)。将硫代羰基二咪唑10a(134mg,0.75mmol)的无水THF(2mL)溶液于0℃下缓慢滴加至上述溶液中,15分钟滴毕,期间N2保护,搅拌2小时。将6a(108mg,1.00mmol)的无水THF(2mL)溶液缓慢滴加至上述溶液中,升温至60℃,反应4h。将反应降温至室温,减压旋掉溶剂,加入DCM(10mL)溶解,水洗一次(10mL),饱和食盐水洗一次(10mL),无水硫酸钠干燥,过滤,蒸干溶剂,制砂,柱层析分离纯化(DCM∶MeOH=60∶1~20∶1)得白色固体S13(197mg,73%)。
1H NMR(500MHz,DMSO-d6)δ13.01(s,1H),9.92(s,1H),8.59(t,J=1.9Hz,1H),8.54-8.43(m,2H),7.72(dd,J=2.6,7.9Hz,1H),7.65(dt,J=1.8,7.9Hz,1H),7.43(s,1H),7.29-7.22(m,2H),6.98-6.90(m,2H),6.84(dd,J=5.0,8.4Hz,1H),4.89(d,J=6.2Hz,2H),3.32(td,J=4.4,6.3Hz,2H),3.12(td,J=4.4,6.3Hz,2H),2.37(s,3H),2.26(s,3H),1.70-1.55(m,4H),1.48-1.38(m,2H).13C NMR(125MHz,DMSO-d6)δ180.50,170.24,165.10,160.07,148.56,148.42,137.01,136.58,135.51,135.14,129.98,127.85,124.73,124.04,123.94,122.27,116.91,116.53,110.00,107.62,45.03,42.84,40.05,28.67,28.07,24.58,13.94,10.75.
实施例4:N-(5-((E)-2-氰基-3-(吡啶-3-基)胍基)戊基)-5-(((Z)-5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺(S15)的合成
步骤一:甲基(Z)-N′-氰基-N-(吡啶-3-基)氨基甲硫基甲基酯(13a)的合成
称取NaH(500g,1.3mmol),加入10mLDMF,悬浮液在0℃下搅拌15min,然后向上述混悬液中缓慢滴加化合物11a(1g,1.1mmol),转移至室温搅拌反应30min。化合物12a(1.6g,1.06mmol)溶于5mL DMF中加入到上述混悬液中,室温下过夜反应。***/石油醚(5∶1)洗涤3次。在0℃下,加入冰醋酸调节pH至8,过滤,滤饼真空干燥,得到淡黄色固体13a(1.4g,68%).
1H NMR(500MHz,Chloroform-d)δ8.67(t,J=1.8Hz,1H),8.14(dt,J=1.9,3.7Hz,1H),7.52(dt,J=2.0,7.9Hz,1H),7.42(dd,J=3.5,7.8Hz,1H),2.45(s,3H).13C NMR(125MHz,Chloroform-d)δ165.73,144.50,144.15,135.90,127.58,124.81,116.10,13.22.
步骤二:叔丁基(Z)-(5-(5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺)戊基)氨基甲酸酯(9a)的合成
见实施例2步骤二。
步骤三:N-(5-((E)-2-氰基-3-(吡啶-3-基)胍基)戊基)-5-(((Z)-5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺(S15)的合成
称取9a(242mg,0.5mmol),加入1mL乙酸乙酯,向上述混悬液中加入0.5mL HCl/乙酸乙酯溶液(3M),室温下搅拌3h,待反应完全后,直接抽滤,乙酸乙酯洗涤滤饼,真空干燥得到盐酸盐,不用纯化直接下一步反应。将盐酸盐溶于10mL吡啶中,依次加入DMAP(61mg,0.5mmol)、TEA(0.28mL,2.0mmol),加热升温至50℃,过夜反应。反应完成后,冷却至室温,减压旋掉吡啶,加入EA(20mL)溶解,水洗一次(10mL),饱和食盐水洗一次(10mL),无水硫酸钠干燥,过滤,蒸干溶剂,制砂,柱层析分离纯化(DCM∶MeOH=60∶1~20∶1)得白色固体S15。
1H NMR(500MHz,DMSO-d6)δ12.99(s,1H),9.93(s,1H),9.55(s,1H),8.68(t,J=1.6Hz,1H),8.51(t,J=4.4Hz,1H),8.19-8.13(m,1H),7.72(dd,J=2.6,7.9Hz,1H),7.50-7.40(m,3H),7.23(t,J=4.4Hz,1H),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=5.0,8.4Hz,1H),3.54(td,J=4.3,6.3Hz,2H),3.11(td,J=4.4,6.4Hz,2H),2.37(s,3H),2.25(s,3H),1.60(p,J=6.6Hz,2H),1.56-1.47(m,2H),1.43-1.33(m,2H).13C NMR(125MHz,DMSO-d6)δ170.24,165.10,160.07,154.43,144.49,142.36,137.21,136.95,136.58,129.98,127.78,125.98,124.73,124.61,123.94,122.27,118.00,116.70,116.53,110.00,107.62,41.36,40.05,28.69,27.89,24.36,13.94,10.76.
实施例5:(Z)-5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-N-(6-(2-(吡啶-3-基)环丙基-1-甲酰胺基)己基)-1H-吡咯-3-甲酰胺(S29)的合成
步骤一:(E)-N-甲氧基-N-甲基-3-(吡啶-3-基)丙烯酰胺(15a)的合成
将1a(1.0g,6.71mmol)和14a(1.3g,13.22mmol)溶于DCM(10mL)中,向上述溶液中依次加入EDCI(1.3g,6.71mmol)和DMAP(820mg,6.71mmol),室温下反应2h。待反应完成后,加入5mLDCM稀释反应液,水洗一次(5mL),饱和食盐水洗一次(10mL),无水硫酸钠干燥,过滤,蒸干溶剂,得黄色油状物15a,直接投入下一步反应。
步骤二:N-甲氧基-N-甲基2-(吡啶-3-基)环丙基-1-甲酰胺(17a)的合成
0℃下,将NaH(640mg,16mmol)加入到三甲基碘化亚砜(2.2g,10mmol)的DMSO(10mL)溶液中,然后转移至室温,搅拌1h。将原料15a(960mg,5mmol)加入到上述溶液中,搅拌1h。待反应完全后,向反应也中加入饱和NH4Cl(8mL),乙酸乙酯萃取(10mL×3)合并有机相,水洗(10mL×3),无水硫酸钠干燥,过滤,蒸干溶剂,制砂,柱层析分离纯化(DCM∶MeOH=5∶1)得黄色油状物17a(824mg,80%)。
步骤三:2-(吡啶-3-基)环丙基-1-羧酸(18a)的合成
将KOH(647mg,11.6mmol)溶于10mL水中,然后将KOH水溶液加入到17a(800g,3.88mmol)的乙醇(15mL)溶液中,室温下搅拌24h。待反应完全后,加入水10mL,DCM(3×5mL)萃取,水相用12M HCl溶液调节pH至6.0,然后减压旋掉水,真空干燥得到的固体加入甲醇打浆(20mL),过滤除去不溶的固体得到的抽滤,滤液浓缩得到淡黄色固体。乙酸乙酯/甲醇(5∶1)重结晶得到纯品18a(341mg,54%)。
步骤四:2-(吡啶-3-基)环丙基-1-甲酰氯(19a)的合成
向18a(341mg,2.1mmol)的DCM溶液中加入二氯亚砜(0.35mL,4.8mmol),升温至40℃。反应5h。待反应完成后,旋掉溶剂得到灰白色粗品19a,直接投入下一步反应。
步骤五:叔丁基(Z)-(6-(5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺)己基)氨基甲酸酯(21a)的合成
见实施例2步骤二,只需更换相应原料即可。
步骤六:(Z)-5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-N-(6-(2-(吡啶-3-基)环丙基-1-甲酰胺基)己基)-1H-吡咯-3-甲酰胺(S29)的合成
称取21a(215mg,0.43mmol),加入1mL乙酸乙酯,向上述混悬液中加入1mL HCl/乙酸乙酯溶液(3M),室温下搅拌3h,待反应完全后,直接抽滤,乙酸乙酯洗涤滤饼,真空干燥得到盐酸盐,不用纯化直接下一步反应。向盐酸盐中加入5mL无水DCM和TEA(0.36mL,2.58mmol)。0℃下,将上述溶液滴加到制备的酰氯19a的无水DCM溶液,室温下搅拌反应3h。待反应完全后,加入DCM(10mL)稀释反应液,水洗一次(10mL),饱和食盐水洗一次(10mL),无水硫酸钠干燥,过滤,蒸干溶剂,得白色固体S29(154mg,66%)。
1H NMR(500MHz,DMSO-d6)δ13.39(s,1H),9.91(s,1H),8.56(dt,J=1.6,4.8Hz,1H),8.54-8.46(m,2H),7.71(dd,J=2.7,8.0Hz,1H),7.50(dt,J=1.8,7.9Hz,1H),7.41(s,1H),7.31(dd,J=4.7,7.8Hz,1H),7.22(t,J=4.3Hz,1H),6.94(td,J=2.7,8.2Hz,1H),6.85(dd,J=5.0,8.4Hz,1H),3.35-3.13(m,3H),3.07(m,1H),2.72(dt,J=6.4,7.9Hz,1H),2.38(s,3H),2.25(s,3H),2.25(dt,J=7.1,7.9Hz,1H),1.70-1.58(m,2H),1.59-1.45(m,2H),1.46-1.19(m,6H).13C NMR(125MHz,DMSO-d6)δ173.63,170.24,165.25,160.08,149.32,148.19,136.95,136.59,134.79,132.59,130.01,127.79,124.73,123.94,123.82,122.26,116.94,116.53,110.03,107.44,40.06,39.71,28.61,28.38,27.33,26.51,26.47,23.95,17.23,13.94,10.76.
实施例6:5-(((Z)-5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-N-(3-((E)-3-(吡啶-3-基)丙烯酰胺基)丙基)-1H-吡咯-3-甲酰胺(S2)的合成
合成方法如实施例1,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.70(s,1H),10.88(s,1H),8.79(d,J=2.3Hz,1H),8.57(d,J=5.1Hz,1H),8.25(t,J=5.7Hz,1H),8.01(dt,J=2.0,8.1Hz,1H),7.76(dd,J=2.6,9.4Hz,1H),7.73(s,1H),7.67(t,J=5.8Hz,1H),7.53-7.43(m,2H),6.95(td,J=2.6,9.0Hz,1H),6.88(dd,J=4.5,8.4Hz,1H),6.77(d,J=15.9Hz,1H),3.31(q,J=6.6Hz,4H),2.48(s,3H),2.46(s,3H),1.75(p,J=7.0Hz,2H).13C NMR(125MHz,DMSO-d6)δ170.10,167.65,165.19,159.14,150.15,149.62,138.72,136.94,136.60,134.35,129.98,129.71,127.81,124.73,123.94,123.34,122.27,120.54,116.77,116.52,110.03,107.45,38.49,37.38,27.97,13.95,10.75.
实施例7:5-(((Z)-5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-N-(4-((E)-3-(吡啶-3-基)丙烯酰胺基)丁基)-1H-吡咯-3-甲酰胺(S3)的合成
合成方法如实施例1,只需更换相应的原料。。1H NMR(500MHz,DMSO-d6)δ13.68(s,1H),11.00(s,1H),8.76(d,J=2.2Hz,1H),8.56(dd,J=1.6,4.8Hz,1H),8.43(d,J=6.2Hz,1H),8.00(d,J=8.1Hz,1H),7.78-7.70(m,3H),7.50-7.42(m,2H),6.92(m,2H),6.86(d,J=15.9Hz,1H),3.25(q,J=6.6Hz,4H),2.44(d,J=10.6Hz,6H),1.62-1.52(m,4H).13C NMR(125MHz,DMSO-d6)δ170.10,167.52,165.10,160.14,150.15,149.62,138.73,137.01,136.61,134.35,129.98,129.71,127.84,124.73,123.94,123.34,122.27,120.63,116.86,116.53,110.00,107.45,39.96,39.45,26.63,26.53,13.95,10.75.
实施例8:5-(((Z)-5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-N-(5-((E)-3-(吡啶-3-基)丙烯酰胺基)戊基)-1H-吡咯-3-甲酰胺(S4)的合成
合成方法如实施例1,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.67(s,1H),10.87(s,1H),8.77(d,J=2.3Hz,1H),8.56(dd,J=1.7,4.7Hz,1H),8.17(t,J=5.7Hz,1H),7.99(dt,J=2.1,8.1Hz,1H),7.79-7.68(m,2H),7.63(t,J=5.8Hz,1H),7.52-7.42(m,2H),6.95(td,J=2.5,9.1,9.5Hz,1H),6.87(dd,J=4.5,8.5Hz,1H),6.75(d,J=15.9Hz,1H),3.24(dt,J=6.5,12.9Hz,4H),2.44(d,J=9.9Hz,6H),1.56(m,4H),1.40(q,J=7.0,7.5Hz,2H).13C NMR(125MHz,DMSO-d6)δ170.24,167.57,165.10,160.07,150.15,149.62,138.73,137.01,136.58,134.28,129.98,129.71,127.78,124.73,123.94,123.34,122.27,120.60,116.86,116.53,110.00,107.46,40.03,39.98,28.68,28.44,24.58,13.94,10.75.
实施例9:5-(((Z)-5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-N-(6-((E)-3-(吡啶-3-基)丙烯酰胺基)己基)-1H-吡咯-3-甲酰胺(S5)的合成
合成方法如实施例1,只需更换相应的原料。。1H NMR(500MHz,DMSO-d6)δ13.68(s,1H),10.87(s,lH),8.77(d,J=2.2Hz,1H),8.58-8.53(m,1H),8.17(t,J=5.6Hz,lH),7.99(dt,J=2.0,8.0Hz,1H),7.79-7.69(m,2H),7.64(t,J=5.7Hz,lH),7.50-7.42(m,2H),6.94(td,J=2.5,9.1Hz,1H),6.87(dd,J=4.5,8.5Hz,1H),6.75(d,J=15.9Hz,1H),3.24(m,4H),2.45(s,3H),2.43(s,3H),1.59-1.49(m,4H),1.42-1.35(m,4H).13C NMR(125MHz,DMSO-d6)δ170.24,167.57,165.10,160.07,150.15,149.64,138.73,136.95,136.61,134.35,129.98,129.72,127.84,124.73,123.94,123.34,122.27,120.60,116.86,116.53,110.00,107.62,40.06,39.73,28.49,28.41,26.51,26.50,13.94,10.76.
实施例10:(Z)-N-(2-(5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺基)乙基)咪唑并[1,2-a]吡啶-6-甲酰胺(S6)的合成
合成方法如实施例1,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ12.98(s,1H),9.91(s,1H),8.65(d,J=1.8Hz,1H),8.27(m,1H),8.04-7.98(m,1H),7.95(dd,J=1.5,9.1Hz,1H),7.79-7.67(m,3H),7.65(s,1H),7.44(s,1H),6.95(td,J=2.7,8.2Hz,1H),6.84(dd,J=5.1,8.3Hz,1H),3.53-3.42(m,2H),3.42-3.31(m,2H),2.28(s,3H),2.24(s,3H).13CNMR(125MHz,DMSO-d6)δ170.10,166.79,164.98,159.12,140.73,137.01,136.61,134.38,130.90,129.93,127.84,124.87,124.73,123.94,122.15,118.9l,116.85,116.53,113.16,112.73,110.06,107.53,40.13,40.09,13.95,10.75.
实施例11:(Z)-N-(3-(5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺基)丙基)咪唑并[1,2-a]吡啶-6-甲酰胺(S7)的合成
合成方法如实施例1,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ12.99(s,1H),9.88(s,1H),8.65(d,J=1.3Hz,1H),8.34(t,J=4.4Hz,1H),8.24(t,J=4.4Hz,1H),7.96(dd,J=1.4,9.1Hz,lH),7.79-7.69(m,2H),7.66(d,J=10.3Hz,2H),7.39(s,lH),6.94(td,J=2.7,8.1Hz,1H),6.84(dd,J=5.0,8.4Hz,lH),3.29(m,4H),2.37(s,3H),2.27(s,3H),1.79(p,J=6.3Hz,2H).13C NMR(125MHz,DMSO-d6)δ170.10,166.96,165.19,160.14,140.73,137.01,136.61,134.38,130.90,129.98,127.78,124.73,123.94,122.27,122.16,118.75,116.70,116.53,113.21,112.73,110.00,107.45,37.43,37.40,27.90,13.94,10.75.
实施例12:(Z)-N-(4-(5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺基)丁基)咪唑并[1,2-a]吡啶-6-甲酰胺(S8)的合成
合成方法如实施例1,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.01(s,1H),9.89(s,1H),8.65(d,J=1.4Hz,1H),8.32(t,J=4.4Hz,1H),8.17(t,J=4.3Hz,lH),7.95(dd,J=1.4,9.1Hz,1H),7.79-7.69(m,2H),7.66(d,J=7.9Hz,2H),7.43(s,1H),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=5.0,8.4Hz,lH),3.42-3.33(m,4H),2.30(s,3H),2.25(s,3H),1.68-1.57(m,4H).13C NMR(125MHz,DMSO-d6)δ170.24,166.72,165.10,160.07,140.73,136.95,136.58,134.38,130.90,129.98,127.78,124.73,123.94,122.27,122.16,118.86,116.86,116.51,113.21,112.73,110.00,107.62,39.96,39.94,26.96,26.50,13.94,10.75.
实施例13:(Z)-N-(5-(5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺基)戊基)咪唑并[1,2-a]吡啶-6-甲酰胺(S9)的合成
合成方法如实施例1,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.03(s,1H),9.89(s,1H),8.65(d,J=1.3Hz,1H),8.51(t,J=4.4Hz,1H),8.15(t,J=4.4Hz,1H),7.95(dd,J=1.6,9.1Hz,1H),7.78-7.68(m,3H),7.65(s,1H),7.43(s,1H),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=5.1,8.4Hz,1H),3.14(m,4H),2.31(s,3H),2.25(s,3H),1.64-1.55(m,4H),1.46-1.37(m,2H).13C NMR(125MHz,DMSO-d6)δ170.24,166.74,165.10,158.06,140.73,136.95,136.61,134.38,130.90,129.98,127.84,124.73,123.94,122.27,122.16,118.86,116.86,116.51,113.21,112.73,110.06,107.54,40.11,40.05,28.69,28.58,24.58,13.94,10.76.
实施例14:(Z)-N-(6-(5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺基)己基)咪唑并[1,2-a]吡啶-6-甲酰胺(S10)的合成
合成方法如实施例1,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.05(s,1H),9.89(s,1H),8.64(d,J=1.6Hz,1H),8.49(t,J=4.4Hz,1H),8.24(t,J=4.3Hz,1H),7.96(dd,J=1.5,9.2Hz,1H),7.78-7.68(m,2H),7.66(d,J=7.7Hz,2H),7.43(s,1H),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=5.0,8.4Hz,1H),3.37(td,J=4.4,6.3Hz,2H),3.23(td,J=4.3,6.3Hz,2H),2.28(s,6H),1.70-1.52(m,4H),1.38-1.27(m,4H).13C NMR(125MHz,DMSO-d6)δ170.24,166.74,165.25,158.06,140.68,136.95,136.61,134.38,130.90,130.01,127.79,124.73,123.94,122.26,122.16,118.86,116.94,116.53,113.21,112.79,110.09,107.60,40.12,40.06,28.61,28.49,26.52,26.51,13.94,10.76.
实施例15:(Z)-5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-N-(6-(3-(吡啶-3-基甲基)脲基)己基)-1H-吡咯-3-甲酰胺(S12)的合成
合成方法如实施例2,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ12.88(s,1H),9.93(s,1H),8.64(t,J=1.9Hz,1H),8.50-8.41(m,2H),7.75-7.66(m,2H),7.43(s,1H),7.27(dd,J=3.5,7.9Hz,1H),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=5.0,8.4Hz,1H),6.24(t,J=6.1Hz,1H),6.06(t,J=4.4Hz,1H),4.53(d,J=6.1Hz,2H),3.23(td,J=4.3,6.3Hz,2H),3.08(td,J=4.3,6.3Hz,2H),2.30(s,3H),2.24(s,3H),1.57(p,J=6.5Hz,2H),1.47-1.38(m,2H),1.39-1.24(m,4H).13C NMR(125MHz,DMSO-d6)δ170.24,165.10,160.07,158.92,148.59,148.38,136.95,136.61,135.14,133.72,129.98,127.85,124.73,123.94,123.81,122.27,116.91,116.53,110.06,107.46,42.01,40.06,38.54,28.62,28.49,26.47,26.43,13.94,10.76.
实施例16:(Z)-5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-N-(6-(3-(吡啶-3-基甲基)硫脲基)己基)-1H-吡咯-3-甲酰胺(S14)的合成
合成方法如实施例3,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.02(s1H),9.93(s,1H),8.60(t,J=1.9Hz,1H),8.48-8.41(m,2H),7.77-7.66(m,2H),7.43(s1H),7.25(dd,J=3.5,7.9Hz,lH),7.15-7.08(m,2H),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=4.9,8.3Hz,1H),4.90(d,J=6.1Hz,2H),3.36(td,J=4.3,6.3Hz,2H),3.23(td,J=4.4,6.3Hz,2H),2.35(s,3H),2.25(s,3H),1.57(p,J=6.5Hz,2H),1.53-1.43(m,2H),1.38-1.26(m,4H).13C NMR(125MHz,DMSO-d6)δ180.50,170.24,165.25,160.16,148.56148.34,136.95,136.58,135.51,135.14,129.98,127.79,124.73,124.04,123.94,122.26116.95,116.53,110.03,107.52,45.03,42.69,40.06,28.49,28.18,26.53,26.51,13.94,10.76.
实施例17:N-(6-((E)-2-氰基-3-(吡啶-3-基)胍基)己基)-5-(((Z)-5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺(S16)的合成
合成方法如实施例4,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.00(s,1H),9.93(s,1H),9.63(s,1H),8.68(t,J=1.8Hz,1H),8.50(t,J=4.4Hz,1H),8.21(dt,J=1.8,3.5Hz,1H),7.71(dd,J=2.7,8.0Hz,1H),7.50-7.40(m,3H),7.15(t,J=4.4Hz,1H),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=5.1,8.4Hz,lH),3.48(td,J=4.4,6.3Hz,2H),3.23(td,J=4.4,6.3Hz,2H),2.38(s,3H),2.26(s,3H),1.52(m,4H),1.32(q,J=3.7Hz,4H).13C NMR(125MHz,DMSO-d6)δ170.24,165.25,158.06,154.43,144.49,142.36,137.26,136.95,136.58,130.01,127.79,125.98,124.73,124.61,123.94,122.26,118.00,116.78,116.53,110.03,107.60,41.36,40.06,28.65,28.50,26.46,26.40,13.94,10.76.
实施例18:N-(5-((E)-2-氰基-3-(吡啶-4-基)胍基)戊基)-5-(((Z)-5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺(S17)的合成
合成方法如实施例4,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ12.98(s,1H),9.91(s,1H),9.05(s,1H),8.51(t,J=4.4Hz,1H),8.40-8.35(m,2H),7.72(dd,J=2.6,7.9Hz,1H),7.43(s,1H),7.23(t,J=4.4Hz,1H),7.03-6.98(m,2H),6.94(td,J=2.6,8.2Hz,1H),6.84(dd,J=5.0,8.4Hz,1H),3.55(td,J=4.4,6.3Hz,2H),3.11(td,J=4.4,6.4Hz,2H),2.36(s,3H),2.25(s,3H),1.62-1.48(m,4H),1.44-1.34(m,2H).13C NMR(125MHz,DMSO-d6)δ170.24,165.10,160.07,154.85,150.01,149.88,145.16,136.95,136.58,129.98,127.84,124.73,123.94,122.27,118.00,116.70,116.53,112.91,112.87,110.00,107.46,41.36,40.05,28.69,27.89,24.36,13.94,10.76.
实施例19:N-(6-((E)-2-氰基-3-(吡啶-4-基)胍基)己基)-5-(((Z)-5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺(S18)的合成
合成方法如实施例4,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.00(s,1H),9.93(s,1H),9.06(s,1H),8.49(t,J=4.4Hz,1H),8.40-8.35(m,2H),7.71(dd,J=2.7,8.1Hz,1H),7.43(s,1H),7.15(t,J=4.4Hz,1H),7.03-6.98(m,2H),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=5.0,8.4Hz,1H),3.48(td,J=4.4,6.3Hz,2H),3.23(td,J=4.4,6.3Hz,2H),2.35(s,3H),2.26(s,3H),1.53(m,4H),1.39-1.26(m,4H).13C NMR(125MHz,DMSO-d6)δ170.24,165.25,160.08,154.85,150.01,149.88,145.16,136.95,136.58,130.01,127.79,124.73,123.94,122.26,118.00,116.78,116.51,112.91,112.87,110.03,107.44,41.36,40.06,28.65,28.50,26.46,26.40,13.94,10.76.
实施例20:(Z)-N-(6-(5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺基)己基)-1H-吡咯并[3,2-c]吡啶-3-甲酰胺(S19)的合成
合成方法如实施例1,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ12.90(s,1H),9.89(s,1H),9.42(d,J=1.7Hz,1H),9.05(s,1H),8.49(t,J=4.4Hz,1H),8.41(t,J=4.4Hz,1H),8.34(dd,J=1.8,5.7Hz,1H),8.08(d,J=2.6Hz,1H),7.71(dd,J=2.7,8.0Hz,1H),7.47-7.41(m,2H),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=5.0,8.4Hz,1H),3.28-3.19(m,4H),2.36(s,3H),2.26(s,3H),1.59(m,4H),1.38-1.29(m,4H).13C NMR(125MHz,DMSO-d6)δ170.24,165.66,165.25,160.08,143.77,143.44,138.85,136.95,136.59,130.07,130.01,127.85,124.73,123.94,122.26,122.16,116.94,116.51,110.03,108.53,108.27,107.60,40.11,40.06,28.65,28.61,26.52,26.51,13.94,10.76.
实施例21:(Z)-N-(6-(5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺基)己基)-3a,7a-二氢-1H-吡咯并[3,4-b]吡啶-6-甲酰胺(S20)的合成
合成方法如实施例1,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.22(s,1H),9.92(s,1H),8.49(t,J=4.4Hz,1H),7.71(dd,J=2.7,8.0Hz,1H),7.50(t,J=4.4Hz,1H),7.43(s,1H),7.36(d,J=5.5Hz,1H),7.15(d,J=6.6Hz,1H),6.98-6.88(m,2H),6.84(dd,J=5.0,8.4Hz,1H),6.09(dd,J=5.7,9.3Hz,1H),5.26(dd,J=5.1,6.6Hz,1H),3.50(m,1H),3.35-3.06(m,4H),2.37(s,3H),2.25(s,3H),1.70-1.21(m,8H).13C NMR(125MHz,DMSO-d6)δ170.24,166.61,165.25,160.08,153.05,136.95,136.61,134.56,130.01,128.57,127.79,127.44,124.73,123.94,122.26,116.78,116.51,110.03,107.60,74.73,43.28,40.06,40.01,28.61,28.38,26.51,26.48,13.94,10.76.
实施例22:(Z)-N-(6-(5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺基)己基)呋喃并[2,3-c]吡啶-2-甲酰胺(S21)的合成
合成方法如实施例1,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.34(s,1H),9.89(s,1H),8.82(d,J=1.9Hz,1H),8.72(dd,J=1.6,5.5Hz,1H),8.48(t,J=4.3Hz,1H),8.25(t,J=4.4Hz,1H),7.96(d,J=2.2Hz,1H),7.87(dd,J=1.9,5.6Hz,1H),7.71(dd,J=2.7,8.0Hz,1H),7.43(s,1H),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=5.0,8.4Hz,1H),3.36(td,J=4.3,6.3Hz,2H),3.24(td,J=4.3,6.3Hz,2H),2.38(s,3H),2.24(s,3H),1.60(m,4H),1.40-1.28(m,4H).13C NMR(125MHz,DMSO-d6)δ170.24,165.25,161.31,158.06,151.19,151.11,144.34,136.95,136.59,134.40,132.74,130.01,127.79,124.73,123.94,122.26,117.52,116.78,116.51,110.56,110.09,107.44,40.06,39.93,28.71,28.61,26.51,26.48,13.94,10.76.
实施例23:(Z)-N-(6-(5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺基)己基)-1H-吡咯并[2,3-c]吡啶-2-甲酰胺(S22)的合成
合成方法如实施例1,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.30(s,1H),9.89(s,1H),9.06(s,1H),8.92(d,J=1.9Hz,1H),8.73(dd,J=1.6,5.5Hz,1H),8.51(dt,J=4.4,24.0Hz,2H),7.79(dd,J=2.0,5.6Hz,1H),7.71(dd,J=2.7,8.0Hz,1H),7.43(s,1H),7.25(d,J=2.1Hz,1H),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=5.0,8.4Hz,lH),3.42(td,J=4.4,6.3Hz,2H),3.23(td,J=4.3,6.3Hz,2H),2.36(s,3H),2.24(s,3H),1.60(m,4H),1.40-1.28(m,4H).13C NMR(125MHz,DMSO-d6)δ170.24,165.25,162.74,160.08,139.84,136.95,136.59,135.06,132.37,131.95,131.91,130.01,127.79,124.73,123.94,122.26,116.88,116.78,116.53,110.03,107.68,107.44,40.30,40.06,28.70,28.61,26.51,26.48,13.94,10.76.
实施例24:(Z)-N-(6-(5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺基)己基)-1,3-二氢-2H-吡咯并[3,4-c]吡啶-2-甲酰胺(S23)的合成
合成方法如实施例1,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.35(s,1H),9.89(s,1H),8.65(d,J=1.8Hz,1H),8.48(t,J=4.4Hz,1H),8.42(dd,J=1.8,5.7Hz,1H),7.71(dd,J=2.7,8.0Hz,1H),7.43(s,1H),7.32(d,J=5.7Hz,1H),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=5.0,8.4Hz,1H),6.71(t,J=4.4Hz,1H),4.86(s,2H),4.31(s,2H),3.23(td,J=4.3,6.3Hz,2H),3.16(td,J=4.3,6.3Hz,2H),2.38(s,3H),2.25(s,3H),1.58(p,J=6.5Hz,2H),1.44(p,J=6.5Hz,2H),1.38-1.24(m,4H).13C NMR(125MHz,DMSO-d6)δ170.24,165.25,160.08,158.12,145.95,145.69,143.11,136.95,136.59,132.62,130.01,127.79,124.73,123.94,122.26,116.94,116.78,116.53,110.03,107.44,52.44,52.17,40.06,39.66,28.67,28.61,26.47,26.41,13.94,10.76.
实施例25:(Z)-N-(6-(5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺基)己基)-6-甲基-1,3-二氢-2H-吡咯并[3,4-c]吡啶-2-甲酰胺(S24)的合成
合成方法如实施例1,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.34(s,1H),9.89(s,1H),8.52(t,J=4.4Hz,1H),8.42(s,1H),7.73(dd,J=2.6,8.0Hz,1H),7.43(s,1H),7.25(d,J=0.7Hz,1H),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=4.9,8.4Hz,lH),6.71(t,J=4.4Hz,1H),4.81(s,2H),4.32(s,2H),3.26(td,J=4.4,6.3Hz,2H),3.16(td,J=4.4,6.4Hz,2H),2.58(s,3H),2.37(s,3H),2.26(s,3H),1.60(p,J=6.5Hz,2H),1.49-1.40(m,2H),1.38-1.24(m,4H).13C NMR(125MHz,DMSO-d6)δ170.24,165.49,160.22,158.12,157.66,147.88,142.02,136.61,136.59,130.33,130.01,127.83,124.73,123.94,122.26,117.25,116.53,116.51,110.05,107.44,52.12,52.07,40.06,39.66,28.68,28.61,26.49,26.41,24.47,13.94,10.76.
实施例26:(Z)-6-氨基-N-(6-(5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺基)己基)-1,3-二氢-2H-吡咯并[3,4-c]吡啶-2-甲酰胺(S25)的合成
合成方法如实施例1,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.36(s,1H),9.89(s,1H),9.06(s,1H),8.52(t,J=4.4Hz,1H),8.17(s,1H),7.73(dd,J=2.6,8.0Hz,1H),7.43(s,1H),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=4.9,8.4Hz,1H),6.71(t,J=4.4Hz,1H),6.51(s,1H),5.32(d,J=6.0Hz,1H),5.22(d,J=6.0Hz,1H),4.31(d,J=10.2Hz,3H),3.26(td,J=4.4,6.3Hz,2H),3.14(td,J=4.4,6.3Hz,2H),2.36(s,3H),2.25(s,3H),1.60(m,2H),1.49-1.40(m,2H),1.38-1.24(m,4H).13C NMR(125MHz,DMSO-d6)δ170.24,165.49,160.22,158.42,158.23,148.75,140.58,136.95,136.61,130.01,127.83,124.73,123.94,122.26,121.09,116.95,116.53,110.05,107.44,101.84,52.11,51.90,40.06,39.66,28.68,28.61,26.49,26.41,13.94,10.76.
实施例27:(Z)-5-氨基-N-(6-(5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺基)己基)呋喃并[2,3-c]吡啶-2-甲酰胺(S26)的合成
合成方法如实施例1,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.35(s,1H),9.89(s,1H),8.55-8.45(m,2H),8.06(t,J=4.4Hz,1H),7.73(dd,J=2.6,8.0Hz,1H),7.47-7.41(m,2H),7.03(d,J=2.2Hz,1H),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=5.0,8.4Hz,1H),5.34(d,J=6.0Hz,1H),5.22(d,J=6.2Hz,1H),3.35(td,J=4.3,6.3Hz,2H),3.27(td,J=4.4,6.4Hz,2H),2.35(s,3H),2.26(s,3H),1.62(m,4H),1.40-1.28(m,4H).13CNMR(125MHz,DMSO-d6)δ170.24,165.49,161.27,160.22,152.74,150.07,143.72,136.95,136.59,133.97,133.20,130.01,127.83,124.73,123.94,122.26,116.95,116.53,110.05,108.91,107.60,98.52,40.06,39.93,28.74,28.61,26.52,26.50,13.94,10.76..
实施例28:(Z)-N-(6-(5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺基)己基)噻唑并[2,3-c]吡啶-2-甲酰胺(S27)的合成
合成方法如实施例1,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.37(s,1H),9.89(s,1H),9.00(d,J=1.3Hz,1H),8.76(dd,J=1.6,5.6Hz,lH),8.52(t,J=4.4Hz,1H),8.42(t,J=4.4Hz,1H),8.11(dd,J=2.1,5.6Hz,1H),7.91(d,J=1.7Hz,1H),7.73(dd,J=2.6,8.0Hz,1H),7.43(s,1H),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=4.9,8.4Hz,1H),3.38(td,J=4.3,6.3Hz,2H),3.23(td,J=4.3,6.3Hz,2H),2.38(s,3H),2.25(s,3H),1.60(m,4H),1.34(q,J=3.8Hz,4H).13C NMR(125MHz,DMSO-d6)δ170.24,165.49,164.52,158.20,146.13,144.51,142.88,139.04,136.95,136.92,136.59,130.01,127.83,124.73,124.49,123.94,122.26,119.93,116.79,116.53,110.05,107.44,40.06,40.03,28.61,28.58,26.53,26.52,13.94,10.76.
实施例29:(Z)-6-氨基-N-(6-(5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺基)己基)-1H-吡咯并[3,2-c]吡啶-2-甲酰胺(S28)的合成
合成方法如实施例1,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.37(s,1H),9.99(s,1H),9.89(s,1H),8.72(d,J=1.5Hz,1H),8.52(t,J=4.3Hz,1H),8.24(t,J=4.4Hz,1H),7.73(dd,J=2.7,8.0Hz,1H),7.43(s,1H),7.21(d,J=1.4Hz,1H),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=4.9,8.4Hz,1H),6.68(s,1H),5.83(d,J=6.0Hz,1H),5.75(d,J=6.2Hz,1H),3.42(td,J=4.4,6.4Hz,2H),3.26(td,J=4.4,6.4Hz,2H),2.37(s,3H),2.25(s,3H),1.70-1.58(m,4H),1.40-1.28(m,4H).13C NMR(125MHz,DMSO-d6)δ170.24,165.49,162.72,158.20,154.66,144.53,143.15,136.95,136.59,132.14,130.01,127.83,124.73,123.94,122.26,116.95,116.51,115.60,110.05,107.44,104.21,89.88,40.30,40.06,28.70,28.61,26.52,26.50,13.94,10.76.
实施例30:N-(6-((E)-3-(6-氨基吡啶-3-基)丙烯酰胺基)己基)-5-(((Z)-5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺(S30)的合成
合成方法如实施例1,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.39(s,1H),9.93(s,1H),8.51-8.44(m,2H),7.74-7.67(m,2H),7.57(dd,J=1.8,8.4Hz,1H),7.52(d,J=15.9Hz,1H),7.43(s,1H),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=5.1,8.4Hz,1H),6.58(d,J=15.9Hz,1H),6.19(d,J=8.4Hz,1H),5.93(d,J=6.0Hz,1H),5.85(d,J=6.0Hz,1H),3.21(m,4H),2.37(s,3H),2.26(s,3H),1.58(p,J=6.5Hz,2H),1.50(p,J=6.6Hz,2H),1.38-1.25(m,4H).13C NMR(125MHz,DMSO-d6)δ170.24,167.49,165.25,160.08,159.04,149.26,137.95,136.95,136.61,135.30,130.01,127.79,124.73,123.94,122.26,120.42,118.90,116.94,116.53,110.03,108.72,107.44,40.06,39.74,28.59,28.50,26.51,26.50,13.94,10.76.
实施例31:5-(((Z)-5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-N-(6-((E)-3-(6-(三氟甲基)吡啶-3-基)丙烯酰氨基)己基)-1H-吡咯-3-甲酰胺(S31)的合成
合成方法如实施例1,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.32(s,1H),9.93(s,1H),8.88(d,J=1.9Hz,1H),8.56(t,J=4.3Hz,1H),7.94(dd,J=1.9,8.4Hz,1H),7.77-7.69(m,2H),7.62-7.55(m,2H),7.43(s,1H),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=4.9,8.4Hz,1H),6.59(d,J=15.7Hz,1H),3.22(m,4H),2.38(s,3H),2.26(s,3H),1.64-1.56(m,2H),1.59-1.52(m,2H),1.38-1.25(m,4H).13C NMR(125MHz,DMSO-d6)δ170.24,167.33,165.29,160.22,149.07,148.75,138.65,136.95,136.63,134.71,130.01,128.33,127.83,124.19,123.94,122.60,122.26,120.46,120.34,116.79,116.67,110.05,107.44,40.06,39.74,28.58,28.54,26.53,13.92,10.78.
实施例32:5-(((Z)-5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-N-(6-((E)-3-(2-甲基吡啶-4-基)丙烯酰氨基)己基)-1H-吡咯-3-甲酰胺(S32)的合成
合成方法如实施例1,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.32(s,1H),9.92(s,1H),8.51-8.45(m,2H),7.78-7.68(m,2H),7.56(d,J=15.9Hz,1H),7.43(s,1H),7.31(dd,J=2.0,5.7Hz,1H),7.18(d,J=2.1Hz,1H),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=5.1,8.4Hz,1H),6.60(d,J=15.9Hz,1H),3.21(m,4H),2.59(s,3H),2.36(s,3H),2.25(s,3H),1.54(m,4H),1.39-1.25(m,4H).13C NMR(125MHz,DMSO-d6)δ170.24,167.38,165.25,160.08,158.06,147.20,141.52,140.70,136.61,136.58,130.01,127.79,124.73,123.94,122.26,121.88,121.36,119.84,116.94,116.51,110.03,107.44,40.06,39.85,28.59,28.50,26.51,26.50,24.21,13.94,10.76.
实施例33:(Z)-5-((5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-N-(6-(2-(6-(三氟甲基)吡啶-3-基)环丙基-1-甲酰胺基)己基)-1H-吡咯-3-甲酰胺(S33)的合成
合成方法如实施例5,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.34(s,1H),9.92(s,lH),8.59-8.50(m,2H),7.73(dd,J=2.7,8.0Hz,1H),7.57-7.47(m,2H),7.43(s,1H),6.98-6.89(m,2H),6.85(dd,J=5.1,8.4Hz,1H),3.31(m,1H),3.19(m,2H),3.05(m,1H),2.59(dt,J=6.4,7.9Hz,1H),2.38(s,3H),2.25(s,3H),1.71-1.61(m,2H),1.64-1.59(m,1H),1.63-1.52(m,1H),1.55-1.45(m,1H),1.48-1.32(m,2H),1.36-1.20(m,4H).13C NMR(125MHz,DMSO-d6)δ173.62,170.24,165.29,160.22,148.81,147.09,136.95,136.63,134.34,134.31,130.01,127.79,124.19,123.94,122.26,120.35,120.18,116.95,116.67,110.05,107.44,40.06,39.70,28.56,28.38,27.33,26.52,26.46,23.99,17.10,13.92,10.78.
实施例34:5-(((Z)-5-氟-2-氧代吲哚啉-3-亚基)甲基)-N-(6-((E)-3-(4-氟吡啶-3-基)丙烯酰氨基)己基)-2,4-二甲基-1H-吡咯-3-甲酰胺(S34)的合成
合成方法如实施例1,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.35(s,1H),9.93(s,1H),8.87(dd,J=1.8,4.9Hz,1H),8.57(m,1H),8.49(t,J=4.4Hz,1H),7.83(t,J=4.3Hz,1H),7.73(dd,J=2.7,8.0Hz,1H),7.64(d,J=15.9Hz,1H),7.43(s,1H),7.12(dd,J=5.6,8.0Hz,lH),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=4.9,8.3Hz,1H),6.54(d,J=15.7Hz,1H),3.20(m,4H),2.36(s,3H),2.25(s,3H),1.58(p,J=6.5Hz,2H),1.49(p,J=6.6Hz,2H),1.38-1.25(m,4H).13C NMR(125MHz,DMSO-d6)δ170.24,167.48,165.25,161.05,158.06,150.56,149.67,136.95,136.58,130.01,128.81,127.85,124.73,123.94,122.68,122.26,117.15,116.79,116.53,110.09,109.77,107.60,40.06,39.74,28.59,28.50,26.51,26.50,13.94,10.76.
实施例35:5-(((Z)-5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-N-(6-((E)-3-(2-(三氟甲基)吡啶-4-基)丙烯酰氨基)己基)-1H-吡咯-3-甲酰胺(S35)的合成
合成方法如实施例1,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.34(s,1H),9.93(s,1H),8.62(d,J=5.6Hz,1H),8.56(t,J=4.3Hz,1H),7.77-7.70(m,2H),7.55(dd,J=6.9,8.9Hz,2H),7.45-7.39(m,2H),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=4.9,8.4Hz,1H),6.52(d,J=15.9Hz,1H),3.22(m,4H),2.38(s,3H),2.25(s,3H),1.70-1.52(m,4H),1.39-1.25(m,4H).13C NMR(125MHz,DMSO-d6)δ170.24,167.57,165.29,158.20,149.11,147.46,141.71,141.48,136.95,136.65,130.01,127.89,124.19,123.94,123.85,122.26,120.31,119.81,119.00,116.95,116.67,110.05,107.44,40.06,39.85,28.58,28.54,26.55,26.53,13.92,10.78.
实施例36:5-(((Z)-5-氟-2-氧代吲哚啉-3-亚基)甲基)-N-(6-((E)-3-(2-氟吡啶-4-基)丙烯酰氨基)己基)-2,4-二甲基-1H-吡咯-3-甲酰胺(S36)的合成
合成方法如实施例1,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.35(s,1H),9.93(s,1H),8.51-8.44(m,2H),7.78-7.70(m,2H),7.61-7.53(m,2H),7.43(s,1H),7.35(dd,J=1.9,8.0Hz,1H),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=4.9,8.3Hz,1H),6.61(d,J=15.9Hz,1H),3.20(m,4H),2.36(s,3H),2.25(s,3H),1.58(p,J=6.5Hz,2H),1.49(p,J=6.6Hz,2H),1.39-1.25(m,4H).13C NMR(125MHz,DMSO-d6)δ170.24,167.60,165.25,161.18,158.06,147.77,146.43,141.54,136.95,136.58,130.01,127.85,124.73,123.94,122.26,120.81,119.76,116.95,116.51,110.03,107.60,107.16,40.06,39.85,28.59,28.50,26.51,26.50,13.94,10.76.
实施例37:N-(6-((Z)-3-(6-氨基吡啶-3-基)-2-氰基胍基)己基)-5-(((Z)-5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺(S37)的合成
合成方法如实施例4,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.34(s,1H),9.92(s,1H),9.06(s,1H),8.55-8.47(m,2H),7.79(t,J=4.4Hz,1H),7.76-7.70(m,2H),7.43(s,1H),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=4.9,8.4Hz,1H),6.43(d,J=8.4Hz,1H),5.86(d,J=6.0Hz,1H),5.79(d,J=6.0Hz,1H),3.52(td,J=4.3,6.3Hz,2H),3.23(td,J=4.4,6.3Hz,2H),2.38(s,3H),2.25(s,3H),1.53(m,4H),1.39-1.26(m,4H).13CNMR(125MHz,DMSO-d6)δ170.24,165.49,160.22,155.69,154.43,142.00,136.95,136.59,130.01,129.60,127.83,126.19,124.73,123.94,122.26,118.00,116.95,116.51,110.12,108.81,107.60,41.36,40.06,28.65,28.61,26.39,26.38,13.94,10.76.
实施例38:N-(6-((Z)-3-(6-(三氟甲基)吡啶-3-基)-2-氰基胍基)己基)-5-(((Z)-5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺(S38)的合成
合成方法如实施例4,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.35(s,1H),9.96(s,1H),9.06-8.98(m,2H),8.56(t,J=4.3Hz,1H),7.80(t,J=4.4Hz,1H),7.73(dd,J=2.7,8.0Hz,1H),7.59(d,J=8.4Hz,1H),7.43(s,1H),7.10(dd,J=2.0,8.4Hz,1H),6.94(td,J=2.7,8.2Hz,1H),6.85(dd,J=5.1,8.3Hz,1H),3.44(td,J=4.4,6.3Hz,2H),3.25(td,J=4.3,6.3Hz,2H),2.37(s,3H),2.25(s,3H),1.55(m,4H),1.39-1.26(m,4H).13CNMR(125MHz,DMSO-d6)δ170.24,165.29,160.22,154.42,144.05,141.56,138.18,136.95,136.66,130.01,127.85,125.08,124.19,123.94,122.26,120.10,119.79,118.00,116.95,116.67,110.05,107.44,41.36,40.06,28.61,28.58,26.41,26.40,13.92,10.78.
实施例39:N-(6-((Z)-2-氰基-3-(2-甲基吡啶-4-基)胍基)己基)-5-(((Z)-5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺(S39)的合成
合成方法如实施例4,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.36(s,1H),9.92(s,1H),8.91(s,1H),8.52(t,J=4.4Hz,1H),8.26(d,J=5.6Hz,1H),7.76-7.67(m,2H),7.45-7.38(m,2H),7.23(d,J=1.7Hz,1H),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=4.9,8.3Hz,1H),3.48(td,J=4.4,6.4Hz,2H),3.23(td,J=4.4,6.3Hz,2H),2.37(s,3H),2.28(s,3H),2.25(s,3H),1.52(m,4H),1.37-1.27(m,4H).13C NMR(125MHz,DMSO-d6)δ170.24,165.49,160.22,158.20,154.75,145.68,145.21,136.61,136.59,130.01,127.85,124.73,123.94,122.26,118.00,116.95,116.51,113.68,110.17,110.05,107.60,41.36,40.06,28.65,28.61,26.40,26.38,24.47,13.94,10.76.
实施例40:N-(6-((Z)-2-氰基-3-(2-氟吡啶-4-基)胍基)己基)-5-(((Z)-5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺(S40)的合成
合成方法如实施例4,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.38(s,1H),9.93(s,1H),9.18(s,1H),8.52(t,J=4.4Hz,1H),8.30(d,J=5.7Hz,1H),7.76-7.69(m,2H),7.48-7.41(m,2H),6.94(td,J=2.7,8.2Hz,1H),6.89(dd,J=1.9,8.0Hz,1H),6.84(dd,J=4.9,8.4Hz,1H),3.47(td,J=4.3,6.3Hz,2H),3.28(td,J=4.4,6.3Hz,2H),2.37(s,3H),2.28(s,3H),1.53(m,4H),1.39-1.26(m,4H).13C NMR(125MHz,DMSO-d6)δ170.24,165.49,161.53,158.20,154.76,148.53,147.10,136.95,136.59,130.01,127.83,124.73,123.94,122.26,118.00,116.79,116.51,110.19,110.05,107.44,100.38,41.36,40.06,28.65,28.61,26.40,26.38,13.94,10.76.
实施例41:N-(6-((Z)-2-氰基-3-(2-(三氟甲基)吡啶-4-基)胍基)己基)-5-(((Z)-5-氟-2-氧代吲哚啉-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺(S41)的合成
合成方法如实施例4,只需更换相应的原料。1H NMR(500MHz,DMSO-d6)δ13.35(s,1H),9.93(s,1H),8.91(s,1H),8.56(t,J=4.4Hz,1H),8.43(d,J=5.7Hz,1H),8.04(d,J=2.0Hz,1H),7.80(t,J=4.4Hz,1H),7.73(dd,J=2.7,8.0Hz,1H),7.49(dd,J=1.9,5.6Hz,1H),7.43(s,1H),6.94(td,J=2.7,8.2Hz,1H),6.84(dd,J=4.9,8.4Hz,1H),3.46(td,J=4.3,6.3Hz,2H),3.25(td,J=4.3,6.3Hz,2H),2.38(s,3H),2.28(s,3H),1.59(m,2H),1.49(m,2H),1.39-1.26(m,4H).13C NMR(125MHz,DMSO-d6)δ170.24,165.29,160.22,154.75,148.79,146.71,146.14,136.95,136.63,130.01,127.79,124.19,123.94,122.26,120.48,118.00,116.95,116.67,112.93,110.05,108.45,107.44,41.36,40.06,28.61,28.58,26.42,26.41,13.92,10.78.
实施例42:NAMPT和VEGFR2酶抑制活性的测试
NAMPT抑制活性测试按照CycLex NAMPT比色测定剂盒(MBL InternationalCorp.)厂家提供的操作步骤进行。基本原理是:NAM和PRPP在NAMPT的作用下生成NMN,而NMN和ATP在NMNAT1的作用下生成NAD,NAD在乙醇脱氢酶(alcohol dehydrogenase,ADH)的作用下生成NADH,而NADH在心肌黄酶的作用下又会返回到NAD。WST-1在NAD/NADH的酶催化循环中形成橙黄色的甲臌,通过检测OD 450nM处吸光度的变化可以检测化合物对NAMPT酶活性的影响。
具体的实验操作步骤如下:
①待测化合物溶液配制:所有化合物采用DMSO溶解,母液浓度10mM,根据测试的需要配制成所需要的浓度,从起始浓度开始,2倍梯度稀释,设置8个浓度梯度,每个浓度重复三次。
②取ddH2O(10μL)和NAM(5μL)加到96孔检测板中;
③取5μL待测化合物或DMSO加到96孔检测板中;
④配制mixture I,包括:20×NAMPT测试缓冲液(5μL),PRPP(5μL),ATP(5μL),重组NMNAT1(5μL),ddH2O(35μL)和NAMPT(5μL),共计60μL。将mixture I加入到96孔检测板中;
⑤将将96孔检测板放置到30℃培养箱中孵育60min;
⑥配置mixture I,包括:WST-1(5μL),ADH(5μL),心肌黄酶(5μL),乙醇(5μL),共计20μL。孵育之后,取出96孔检测板,将mixture II加入到96孔检测板中;
⑦在酶标仪上动态监测30min内OD 450nm处各孔的吸光值,每隔5min检测一次;
⑧选取吸光度和时间呈线性变化的时间段,计算反应速率。用GraphPad Prism5软件处理。为了补偿DMSO的NAMPT抑制活性,数值用DMSO作为溶剂对照进行校正。
VEGFR2活性的测试方法
VEGFR2是一种消耗ATP的受体酪氨酸激酶,通过化学发光法测定激酶反应后溶液中ATP的剩余量来定量检测激酶活性。根据Kinase-LumiTM化学发光法激酶活性检测试剂盒的说明书进行操作。简言之,将激酶缓冲液、激酶、反应底物和待测化合物分别加入到96孔板中,在室温条件下对96孔板进行包被,培养40min。然后,向96孔板中加入Kinase-Glo试剂,再孵育15min。结束后,酶标仪记录发冷光。采用GraphPad软件计算IC50。
具体实验结果如表1所示:
表1:NAMPT和VEGFR2抑制活性
实施例43:抗肿瘤活性测试
化合物癌细胞抑制活性数据用MTT方法来检测,MTT法又称MTT比色法,是一种检测细胞存活和生长的方法。MTT(黄色的噻唑兰)可透过细胞膜进入细胞内,活细胞线粒体中的琥珀脱氢酶能使外源性MTT还原为难溶于水的蓝紫色的针状Formazan结晶并沉积在细胞中,结晶能被二甲基亚砜(DMSO)溶解,用酶联免疫检测仪在490nm/570nm波长处检测其光吸收值,可间接反映活细胞数量。所使用的癌细胞系为MCF-7(人乳腺癌细胞)、K562(人慢性粒细胞白血病细胞)、HT29(人***癌细胞)、A549(人非小细胞肺癌细胞)和ACHN(肾细胞癌细胞)
具体实验结果如表1所示:
①收集对数生长期细胞,调整细胞悬液浓度,在96孔板中每孔加入100μL细胞悬液;每孔细胞数量约为7000个,在5%CO2,37℃孵育过夜至细胞完全贴壁;
②设置药物浓度梯度,每个浓度梯度设置3个复孔,将药物稀释到对应培养基中至所需终浓度,吸出96孔板中原有培养基,加入配好的含所需终浓度药物的培养基100μL,在5%CO2,37℃孵育;并同时设置空白组(只含100μL培养基,不含细胞,后续处理与其他各孔相同)与对照组(含有细胞与培养基);
③药物处理至44小时时每孔加入10μLMTT溶液(5mg/ml),继续培养4h(药物处理细胞共48小时);
④吸干净孔内培养液(如细胞出现悬浮,则先2500rpm离心5min再吸出培养基)。每孔加入150μL二甲基亚砜,振荡至结晶物充分溶解。在酶标仪上检测OD490nm处各孔的吸光值;
⑤计算抑制率:抑制率=1-(加药组OD值-空白组OD值)/(对照组OD值-空白组OD值)=(对照组OD值-加药组OD值)/(对照组OD值-空白组的OD值);
⑥按上述实验步骤重复三次,得出三次抑制率的平均值,利用IC50计算器算出药物的IC50值。
具体实验结果如下表2所示:
表2:实施例化合物的抗细胞增殖活性(IC50μM)
Claims (10)
1.一种如通式I所示结构的吲哚酮类化合物或其药学上可接受的盐、溶剂化物、前药、立体异构体、互变异构体或代谢产物,
式中:
L为-CH2OCH2CH2OCH2-、或未取代或R1取代的C2-10烷基;
R1为羟基、氨基、氰基、卤素或C1-6的烷基;
E为O、S或N-C≡N;
X为单键、C2-4烯键、C1-4烷基、环丙基、-NHCH2-;
R为未取代或R2取代的C6-10芳基、未取代或R3取代的杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的5~10元杂芳基、或、未取代或R4取代的杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的5~10元杂环烷基;
R2、R3和R4独立地为氘、卤素、羟基、氨基、C1-6烷基、C1-6烷氧基或C1-6卤代烷基。
2.根据权利要求1所述的吲哚酮类化合物或其药学上可接受的盐、溶剂化物、前药、立体异构体、互变异构体或代谢产物,其特征在于:
当L为未取代或R1取代的C1-10烷基时,所述R1的个数为一个或多个,当存在多个R1时,所述的R1可相同或不同;
和/或,当L为未取代或R1取代的C2-10烷基时,所述的C2-10烷基为C2-8烷基;
和/或,当R1为C1-6的烷基时,所述的C1-6烷基为C1-3烷基;
和/或,当R1为卤素时,所述的卤素为氟、氯、溴或碘;
和/或,当E为O时,X为单键、C1-4烷基、C2-4烯基、环丙基或-NHCH2-,或者,当E为S时,X为-NHCH2-,或者,当E为N-C≡N时,X为单键;
和/或,当R为未取代或R3取代的杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的5~10元杂芳基时,所述的R3的个数为一个或多个,当存在多个R3时,所述的R3可相同或不同;
和/或,当R为未取代或R3取代的杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的5~10元杂芳基时,所述的杂芳基为杂原子选自N、O和S中的一种或多种,杂原子数为1-3个,N原子个数至少为1个的5~10元杂芳基;
和/或,当R为未取代或R4取代的杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的5~10元杂环烷基时,所述的R4的个数为一个或多个,当存在多个R4时,所述的R4可相同或不同;
和/或,当R为未取代或R4取代的杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的5~10元杂环烷基时,所述的杂环烷基为杂原子选自N、O和S中的一种或多种,杂原子数为1-3个,N原子个数至少为1个的5~10元杂环烷基;
和/或,当R3为卤素,所述的卤素为氟、氯、溴或碘;
和/或,当R3为C1-6烷基时,所述的C1-6烷基为C1-3烷基;
和/或,当R3为C1-6烷氧基时,所述的C1-6烷氧基为C1-3烷氧基;
和/或,当R3为C1-6卤代烷基时,所述的C1-6卤代烷基为C1-3卤代烷基;
和/或,当R4为C1-6烷基时,所述的C1-6烷基为C1-3烷基;
和/或,当R4为C1-6卤代烷基时,所述的C1-6卤代烷基为C1-3卤代烷基。
3.根据权利要求1所述的吲哚酮类化合物或其药学上可接受的盐、溶剂化物、前药、立体异构体、互变异构体或代谢产物,其特征在于:
当L为未取代或R1取代的C1-10烷基时,所述的R1的个数为1个、2个或3个;
和/或,当L为未取代或R1取代的C2-10烷基时,所述的未取代或R1取代的C2-10烷基为C4-7烷基;
和/或,当R为未取代或R3取代的杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的5~10元杂芳基时,所述的R3的个数为1个、2个或3个;
和/或,当R为未取代或R3取代杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的5~10元杂芳基时,所述的杂芳基为吡啶基、吡啶并吡咯基、吡啶并咪唑基、吡啶并呋喃基、吡唑并噻吩基或吡唑并吡唑基;
和/或,当R为未取代或R4取代杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的5~10元杂环烷基时,所述的R4的个数为1个、2个或3个;
和/或,当R3为卤素,所述的卤素为氟;
和/或,当R3为C1-6的烷基时,所述的C1-6的烷基为甲基、乙基、丙基或异丙基,优选甲基;
和/或,当R3为C1-6的烷氧基时,所述的C1-6的烷氧基为甲氧基、乙氧基或丙氧基,优选甲氧基;
和/或,当R3为C1-6卤代烷基时,所述的C1-6卤代烷基为-CF3;
和/或,当R4为C1-6烷基时,所述的C1-6烷基为甲基、乙基或丙基;
和/或,当R4为C1-6卤代烷基时,所述的C1-6卤代烷基为-CF3。
5.根据权利要求1所述的吲哚酮类化合物或其药学上可接受的盐、溶剂化物、前药、立体异构体、互变异构体或代谢产物,其特征在于:
L为未取代的C2-10烷基;
和/或,E为O、S或N-C≡N;
和/或,X为单键、C2-4烯键、C1-4烷基、环丙基、-NHCH2-;
和/或,R为未取代或R3取代的“杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的”5~10元杂芳基、或、未取代或R4取代的“杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的”5~10元杂环烷基;
和/或,R3为卤素、氨基或C1-6烷基;
和/或,R4为氨基或C1-6烷基。
8.一种药物组合物,包括有效量的如权利要求1-6种任一项所述的如通式I所示化合物、或其药学上可接受的盐、溶剂化物、前药、立体异构体、互变异构体或代谢产物,及药学上可接受的载体。
9.权利要求1-6任一项如通式I所示结构的吲哚酮类化合物或其药学上可接受的盐、溶剂化物、前药、立体异构体、互变异构体或代谢产物在制备预防和/或***药物中的应用。
10.根据权利要求9所述的用途,其特征在于,所述肿瘤为乳腺癌、卵巢癌、***癌、结肠癌、胃癌、非小细胞肺癌、神经胶质瘤、肾癌、胰腺癌、肝癌、黑色素瘤、白血病和***中的一种或多种。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1439005A (zh) * | 2000-02-15 | 2003-08-27 | 苏根公司 | 吡咯取代的2-二氢吲哚酮蛋白激酶抑制剂 |
CN101389331A (zh) * | 2005-12-29 | 2009-03-18 | 斯克里普斯研究学院 | 基于吲哚满酮的氨基酸衍生物的蛋白激酶抑制剂 |
CN102250069A (zh) * | 2010-05-17 | 2011-11-23 | 苏州波锐生物医药科技有限公司 | 吡咯酰胺类化合物及其在制备抗恶性肿瘤药物中的用途 |
US20190263823A1 (en) * | 2016-11-22 | 2019-08-29 | Dana-Farber Cancer Institute, Inc. | Degradation of protein kinases by conjugation of protein kinase inhibitors with e3 ligase ligand and methods of use |
-
2021
- 2021-09-16 CN CN202111089653.8A patent/CN113717159A/zh active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1439005A (zh) * | 2000-02-15 | 2003-08-27 | 苏根公司 | 吡咯取代的2-二氢吲哚酮蛋白激酶抑制剂 |
CN101389331A (zh) * | 2005-12-29 | 2009-03-18 | 斯克里普斯研究学院 | 基于吲哚满酮的氨基酸衍生物的蛋白激酶抑制剂 |
CN102250069A (zh) * | 2010-05-17 | 2011-11-23 | 苏州波锐生物医药科技有限公司 | 吡咯酰胺类化合物及其在制备抗恶性肿瘤药物中的用途 |
US20190263823A1 (en) * | 2016-11-22 | 2019-08-29 | Dana-Farber Cancer Institute, Inc. | Degradation of protein kinases by conjugation of protein kinase inhibitors with e3 ligase ligand and methods of use |
Non-Patent Citations (1)
Title |
---|
BAOHUA ZOU等: "Design, syntheses and biological evaluation of 5-fluoroindolin-2-one derivatives with urea linkage", 《ADVANCED MATERIALS RESEARCH》 * |
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