CN113620873A - 含锌结合基以及喹啉骨架的化合物的制备方法和用途 - Google Patents
含锌结合基以及喹啉骨架的化合物的制备方法和用途 Download PDFInfo
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Abstract
本发明涉及药物化学领域,特别涉及一种新的含锌结合基的喹啉类化合物、其几何异构体及其药学上可接受的盐、溶剂化物或前药,他们的制备方法以及含有所述化合物的药物组合物。本发明还涉及该类化合物用于制备治疗和/或预防由c‑Met酪氨酸激酶和HDAC所介导的疾病的药物中的应用。所述的喹啉类化合物、其几何异构体及其药学上可接受的盐、溶剂化物或前药的结构如下所示,其中,R1、m、Q、X如权利要求书和说明书所述。
Description
技术领域:
本发明涉及药物化学领域,特别涉及一种新的含锌结合基的喹啉类化合物、其几何异构体及其药学上可接受的盐、溶剂化物或前药,他们的制备方法以及含有所述化合物的药物组合物。本发明还涉及该类化合物用于制备治疗和/或预防由c-Met酪氨酸激酶和HDAC所介导的疾病的药物中的应用。
背景技术:
癌症,亦称恶性肿瘤,是由控制细胞生长增殖机制失常而引起的疾病。上世纪90年代末,随着细胞生物学、分子生物学和基因学等学科的迅速发展,对肿瘤发生、发展过程中有关靶点及信号转导通路研究的不断深入,开始了以细胞受体、关键基因和调控分子为靶点的治疗——分子靶向治疗 (molecular targeted therapy)。1986年,Park等人[Park M,Dean M,Cooper,CS,et al.Mechanism of metoncogene activation[J].Cell,1986,45(6):895-904.]报道了c-Met激酶的cDNA序列,并确定它属于酪氨酸激酶家族。随后,c-Met激酶被证实为受体酪氨酸激酶家族中唯一能与肝细胞生长因子 (Hepatocyte GrowthFactor)结合的高亲和受体,故也被称为肝细胞生长因子受体(Hepatocyte Growth FactorReceptor,HGFR),其表达产物为具有酪氨酸激酶活性的跨膜受体蛋白。在正常的生理条件下, c-Met激酶和HGF在大量组织中都有表达,但c-Met RNA处于低水平表达状态,仅在组织损伤后短暂上升,随即又恢复正常水平,表明正常细胞有能力通过减少c-Met激酶的表达控制其对HGF的反应。 c-Met激酶与HGF结合后,可以促进上皮细胞发生分散,增强细胞的运动性,促进细胞的生长、增殖、分化、收缩、运动、分泌和有丝分裂等多个过程,对于促进胎盘和胚胎的发育,调节肺、神经系统、肾及乳腺等器官的发育和结构形成具有十分重要的生物学意义[Giordano S,Ponzetto C,Di Renzo MF,et al.Tyrosine kinase receptorindistinguishable from the c-met protein[J].Nature,1989,339:155-156.Birchmeier C,Birchmeier W,Gherardi E,et al.Met metastasis,motility and more[J].Nat Rev Mol Cell Biol, 2003,4(12):915-925.Christensen JG,Burrows J,SalgiaR.c-MET as a target for human cancer and characterization of inhibitors fortherapeutic intervention[J].Cancer Lett.,2005,225(1):1-26]
组蛋白去乙酰化酶(Histone deacetylases,HDACs)与肿瘤的发生密切相关,通过催化组蛋白N-端赖氨酸残基的去乙酰化进而调控基因转录和染色质重组(Chromatinremodeling)[Groselj B,Sharma NL, Hamdy FC,et al.Histone deacetylaseinhibitors as radiosensitisers:effects on DNA damage signaling and repair[J].Br J Cancer,2013,108(4):748-754.Bertrand P.Inside HDAC with HDAC inhibitors[J].Eur J Med Chem,2010,45(6):2095-2116.Delcuve GP,Khan DH,Davie JR.Targetingclass I histone deacetylases in cancer therapy[J].Expert Opin Ther Targets,2013,17(1):29-41.]此外,HDACs也可以催化非组蛋白去乙酰化,如p21、微管蛋白、HSP90(Heat shock protein 90)等。抑制HDACs可以诱导肿瘤细胞周期停滞、分化及凋亡。1999年,Finnin[Paris M,Porcelloni M,Binaschi M,et al.Histone deacetylaseinhibitors:from bench to clinic[J].J Med Chem,2008,51(6):1505-1529]首次报道了HDLP(Histone deacetylase like protein)与SAHA的共结晶结构,为HDAC抑制剂的合理设计建立了基础。研究显示, HDAC抑制剂的结构特征如下:1)含有一个锌离子结合基团(Zinc-binding group,ZBG),用于与HDAC 口袋底部的锌离子螯合;2)含有一个表面识别基团,称为帽状部分(CAP);3)连接ZBG和CAP的疏水性连接链。
临床试验数据表明,HDAC不仅单用有效,由于其具有广泛的抗肿瘤活性,与药理学和生物学机制不同的抗肿瘤药合用可发挥协同的介导细胞凋亡的作用,其作用机制为联用可同时激活多个细胞凋亡通路,而HDAC可降低肿瘤细胞凋亡的阈值及抑制其它因子的抗凋亡作用。编码HGF的 c-Met癌基因控制细胞形成、侵袭及保护细胞免于凋亡。因而,c-Met的异常激活不仅对肿瘤的发生,而且对肿瘤的侵袭转移至关重要,c-Met抑制剂通过阻断c-Met的异常激活,抑制肿瘤的发生和转移,进而诱导肿瘤细胞凋亡。
基于此,联用HDAC及c-Met抑制剂时前者降低肿瘤细胞凋亡的阈值,同时抑制其它因子的抗凋亡作用而促进c-Met抑制剂阻断c-Met的激活,抑制肿瘤的形成和转移,诱导肿瘤细胞凋亡的能力。事实上,HDAC与c-Met均为对肿瘤细胞形成调控具有普遍生物学意义的蛋白,因而在许多癌症中都有两者同时异常高表达的情况,例如HDAC及c-Met抑制剂能够治疗很多相同的肿瘤,如前列腺癌、白血病、乳腺癌、结肠癌及肝癌等。显然,同时设计以两者为靶标的药物比HDAC及c-Met抑制剂联用具有更多的优点。
目前针对c-Met/HDAC抑制剂的相关文献报道较少,且没有批准上市的c-Met/HDAC小分子抑制剂。其中Dong Lu等人[Design,Synthesis,and Biological Evaluation ofthe First c-Met/HDAC Inhibitors Based on Pyridazinone Derivatives[J].ACSMedicinal Chemistry Letters,2017,8(8):830-834.]报道的化合物2m的c-Met和HDAC1激酶抑制剂,IC50分别为0.71nM和38nM。
本发明人在参考文献的基础上,设计合成了几个系列含锌结合基的喹啉类化合物,经体外c-Met 和HDAC激酶抑制活性以及癌细胞增殖活性测试,结果表明具有对两种酶以及相应癌细胞的抑制活性。
发明内容
通式(I)的化合物及其药学上可接受的盐、溶剂化物、几何异构体、对映异构体、非对映异构体、外消旋体或其前药
其中,
R1=氢或(C1-C6)烷氧基;
m=1-6;
X为O、NH;
R2选自为氢、羟基、卤素、硝基、氨基、氰基、氨基甲酰基、氨基磺酰基、(C1-C6)烷基、(C1-C6)烷氧基、(C2-C6)炔基、(C1-C6)酰基,任选被羟基、氨基、氰基或卤素取代的(C1-C6)烷基或(C1-C6) 烷氧基、被单或二(C1-C6烷基)取代的氨基、(C1-C6)烷基酰胺基、(C1-C6)烷基酰基、(C1-C6)烷基亚磺酰基、(C1-C6)烷基磺酰基及游离的、成盐的、酯化的和酰胺化的羧基;
R3为卤素或氢;
R4为选自氢、(C1-C6)烷基或卤代(C1-C6)烷基;
R5选自氢、(C1-C6)烷基或卤代(C1-C6)烷基;
Cy为(C1-C6)烷基、(C3-C7)环烷基、6-10元芳基、5-10元杂芳基、6-10元芳基甲基、5-10元杂芳基甲基,所述芳基或者杂芳基任选被0-3个相同或不同的R6取代;
R6为羟基、卤素、硝基、氨基、氰基、(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C6)烷氧基、任选被羟基、氨基或卤代的(C1-C6)烷基或(C1-C6)烷氧基、被1-2个(C1-C6)烷基取代的氨基、(C1-C6)烷基酰胺基、游离的、成盐的、酯化的和酰胺化的羧基、(C1-C6)烷基亚磺酰基、(C1-C6)烷基磺酰基、(C1-C6)烷氧基、(C1-C6)烷基、(C1-C6)烷基酰基、(C1-C6)氨基甲酰基、被1-2个(C1-C6)烷基取代的氨基甲酰基、(C1-C3) 亚烷基二氧基、烯丙基。
本发明优选通式(I)的化合物及其药学上可接受的盐、溶剂化物、几何异构体、对映异构体、非对映异构体、外消旋体或其前药,
其中,
R1为(C1-C4)烷氧基;
m=1-6;
X为O、NH;
R2选自为氢、羟基、卤素、硝基、氨基、氰基、氨基甲酰基、氨基磺酰基、(C1-C6)烷基、(C1-C6)烷氧基、(C2-C6)炔基、(C1-C6)酰基,任选被羟基、氨基、氰基或卤素取代的(C1-C6)烷基或(C1-C6) 烷氧基、被单或二(C1-C6烷基)取代的氨基、(C1-C6)烷基酰胺基、(C1-C6)烷基酰基、(C1-C6)烷基亚磺酰基、(C1-C6)烷基磺酰基及游离的、成盐的、酯化的和酰胺化的羧基。
其中R3优选氢或氟;
R4优选氢,(C1-C4)烷基;
R5选自氢、(C1-C4)烷基或卤代(C1-C4)烷基;
Cy优选苯基,所述苯基任选被0-3个相同或不同的R6取代。
R6为羟基、卤素、硝基、氨基、氰基、(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C6)烷氧基、任选被羟基、氨基或卤代的(C1-C6)烷基或(C1-C6)烷氧基、被1-2个(C1-C6)烷基取代的氨基、(C1-C6)烷基酰胺基、游离的、成盐的、酯化的和酰胺化的羧基、(C1-C6)烷基亚磺酰基、(C1-C6)烷基磺酰基、(C1-C6)烷氧基、(C1-C6)烷基、(C1-C6)烷基酰基、(C1-C6)氨基甲酰基、被1-2个(C1-C6)烷基取代的氨基甲酰基、(C1-C3) 亚烷基二氧基、烯丙基。
本发明优选通式(I)的化合物及其药学上可接受的盐、溶剂化物、几何异构体、对映异构体、非对映异构体、外消旋体或其前药,
其中,
R1为甲氧基;
m=1-6;
X为O、NH;
R2选自为氢、羟基、卤素、硝基、氨基、氰基、氨基甲酰基、氨基磺酰基、(C1-C6)烷基、(C1-C6)烷氧基、(C2-C6)炔基、(C1-C6)酰基,任选被羟基、氨基、氰基或卤素取代的(C1-C6)烷基或(C1-C6) 烷氧基、被单或二(C1-C6烷基)取代的氨基、(C1-C6)烷基酰胺基、(C1-C6)烷基酰基、(C1-C6)烷基亚磺酰基、(C1-C6)烷基磺酰基及游离的、成盐的、酯化的和酰胺化的羧基。
其中R3优选氢或氟;
R4优选氢,甲基、乙基;
R5选自氢、甲基或三氟甲基;
Cy为苯基,所述苯基任选被0-3个相同或不同的R6取代;
R6为羟基、卤素、硝基、氨基、氰基、(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C6)烷氧基、任选被羟基、氨基或卤代的(C1-C6)烷基或(C1-C6)烷氧基、被1-2个(C1-C6)烷基取代的氨基、(C1-C6)烷基酰胺基、游离的、成盐的、酯化的和酰胺化的羧基、(C1-C6)烷基亚磺酰基、(C1-C6)烷基磺酰基、(C1-C6)烷氧基、(C1-C6)烷基、(C1-C6)烷基酰基、(C1-C6)氨基甲酰基、被1-2个(C1-C6)烷基取代的氨基甲酰基、(C1-C3) 亚烷基二氧基、烯丙基。
本发明优选如下化合物及其药学上可接受的盐、溶剂化物、几何异构体、对映异构体、非对映异构体、外消旋体或其前药,
按照本发明所属领域的一些通常方法,本发明的通式(I)的化合物可以与酸形成其药学上可接受的盐。优选的酸为盐酸、氢溴酸、氢氟酸、硫酸、磷酸、硝酸,甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、乙磺酸、甲苯磺酸、苯磺酸、萘磺酸、三氟乙酸和天冬氨酸;特别优选的酸为盐酸和甲磺酸。
本发明还包括本发明衍生物的前药。本发明衍生物的前药是通式(I)的衍生物,它们自身可能具有较弱的活性甚至没有活性,但是在给药后,在生理条件下(例如通过代谢、溶剂分解或另外的方式) 被转化成相应的生物活性形式。
除非另外指出,本发明所用的术语“卤素”是指氟、氯或溴代;“烷基”是指直链或支链的烷基;“环烷基”是指取代或未取代的环烷基;“烷氧基”是指直链或支链的烷氧基;“炔基”是指直链或支链的炔基;“杂芳基”是指含有一个或多个选自N、O、S杂原子的单环或多环的环状体系,环状体系是芳香性的,如咪唑基、吡啶基、吡唑基、呋喃基、噻吩基、吡咯基,噻唑基,苯并噻唑基,噁唑基,异噁唑基,萘基,喹啉基,异喹啉基,苯并咪唑基,苯并噁唑基等。
本发明还包括药物组合物,该组合物包括通式Ⅰ化合物及它们药学上可接受的盐和/或溶剂化物作为活性成分以及药学上可接受的载体;本发明的化合物可以与其他活性成分组合使用,只要它们不产生其他不利的作用,例如过敏反应。
用于本发明药物组合物的载体是药学领域中可得到的常见类型,包括:口服制剂用的粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、无色素、矫味剂等;可注射制剂用的防腐剂、加溶剂、稳定剂等;局部制剂用的基质、稀释剂、润滑剂、防腐剂等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药,如果某些药物在胃部条件下是不稳定的,可将其配制成肠衣片剂。
通过体外抑制人乳腺癌细胞MCF7、人结肠癌细胞HCT 116活性试验,我们发现本发明化合物具有显著的抗肿瘤活性,因此本发明化合物可以用于制备治疗和/或预防各种癌症的药物,如乳腺、肺、肝脏、肾脏、结肠、直肠、胃、前列腺、膀胱、子宫、胰腺、骨髓、睾丸、卵巢、淋巴、软组织、头颈、甲状腺、食道的癌和白血病、成神经细胞瘤等。特别用于制备治疗和/或预防乳腺癌和结肠癌的药物。
通过本发明的一种化合物的一种“治疗有效剂量”指赋予给治疗主体治疗效果的该化合物的剂量,以一种应用于任何药物治疗的合理的效益/风险比。治疗效果可能是客观的(例如,由一些测试或标记物可测量的)或主观的(例如,主体给出一种迹象或感受到一种效果)。上述描述的该化合物的有效剂量可能范围为约0.1mg/Kg至约500mg/Kg,优选从约1mg/Kg至约50mg/Kg。有效剂量也依据给药途径以及与其它药剂共同使用的可能性而变化应了解,然而,该化合物和本发明的组合物的每日用法应在足够医学上的理由内由主治医师确定。一些特殊患者的特殊治疗有效剂量水平应取决于多种因素,包括进行治疗的紊乱和奢乱的严重性;所采用的特异性化合物的活性;采用的特异性组合物;患者年龄、体重、总体健康状态、性别和患者的饮食;给药时间、给药路线和采用的特异性化合物的排泄率;治疗的持续时间;与特异性化合物联合使用的药物或同时使用的药物;以及医学上众所周知的类似因素。
对人或其他动物进行单一或分开剂量给药,本发明化合物的每日用法可在剂量范围内,例如,从 0.01至50mg/Kg体重或从0.1至25mg/Kg体重。通常,本发明的治疗方案包括对需要这种治疗的患者给药,每天按单剂量或多剂量从约10mg至约1000mg给予本发明化合物。
这里描述的通式的化合物可以通过注射给药、静脉内给药、动脉内给药、皮下给药、腹腔内给药、肌肉注射给药、或皮下给药;或口服给药、颊部给药、鼻腔给药、透黏膜给药、局部给药、眼科用药或吸入给药,剂量从0.1至约500mg/Kg体重,可供选择地剂量在1mg至1000mg/Kg单剂之间,每4 小时至120小时,或依据特别药物的需要。可以通过有效量化合物或化合物组合物给药获得预期或定期疗效。通常,本发明的药物组合物应每天从约1次至约6次给药或可供选择地,如持续输注给药。这种给药可用作慢性或急性治疗。活性成分的剂量将取决于治疗宿主和给药的特殊方式,活性成分可与制药赋形剂或载体联合制成单一剂型。标准制剂将包含约5%至约95%的活性化合物(w/w)。可供选择地,这种制剂可包含约20%至80%活性化合物。可能需要比上面叙述的剂量低或高的剂量。任何特殊患者的特异性剂量和治疗方案将取决于多种因素,包括所采用的特异性化合物的活性;患者年龄、体重、总体健康状态、性别和患者的饮食;给药时间、排泄率、药物联合、疾病的严重性和病程、生理状态或症状,患者对疾病的安排,生理状态或症状,以及治疗医生的判断。
一经患者生理状态改善,必要时,维持用量的本发明的一种化合物、组合物或联合可被给药。随后,给药的剂量或频率,或者两者,依据症状可减少至当症状已经缓解至预期水平时保持被改善的生理状态的水平。
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,下述实施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通式Ⅰ衍生物的制备,所有的原料都是通过这些流程中描述的方法、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。本发明的全部最终化合物都是通过这些流程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。这些流程中应用的全部可变因数如下文的定义或如权利要求中的定义。
路线A:
路线A中,中间体101与中间体102经取代反应制备得中间体103,中间体103经过硝化、扣环、氯代得中间体107,R2取代的苯胺中间体107发生取代反应得到中间体108,中间体108在盐酸羟胺的作用下制得通式I的化合物。
路线B:
路线B中,中间体107与中间体201经取代反应制备得中间体202,中间体202经过还原反应得中间体203,中间体203与各种类型的中间体B反应制得中间体204,中间体204 在盐酸羟胺的作用下制得通式I的化合物.
路线C:中间体B-1的制备
苯胺在亚硝酸钠以及盐酸的作用下生成中间体301,随后与乙酰乙酸乙酯反应生成中间体302,中间体302在DMF-DMA作用下扣环生成中间体303,随后水解得中间体B-1.
路线D:中间体B-2的制备
1,1-环丙基二羧酸与丙酮反应生成中间体402,中间体402与苯胺反应生成中间体B-2。
路线E:中间体B-3的制备
苯胺与亚硝酸钠盐酸作用生成种间体502,随后与原料503作用生成中间体504,随后中间体504在乙酸/乙酸钠作用下扣环生成中间体505,在硫酸二甲酯的作用下生成506.最后水解得中间体B-3。
具体实施方式:
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-400测定,质谱采用Waters QAB-1837串联四级杆液质联用仪测定;所用试剂均为分析纯或化学纯。
实施例1 7-((4-((3-溴苯基)氨基)-6-甲氧基喹啉基-7-基)氧代)-N-羟基庚酰胺
1.1 7-(4-乙酰基-2-甲氧基苯基)庚酸乙酯(103)
室温下,将20.0g(121mmol)3-甲氧基-4-羟基苯乙酮(101)溶于200mLN,N-二甲基乙酰胺中,向反应液中加入17.5g(127mmol)无水碳酸钾和30.0g(127mmol)7-溴庚酸乙酯(102),加毕,升温至85℃反应3h。反应完毕,将反应液冷却至室温,倒入500mL冰水中,室温搅拌20min,抽滤,200mL水洗滤饼,干燥后得到黄色固体32.9g,收率84.5%。
1.2 7-(4-乙酰基-2-甲氧基-5硝基苯基)庚酸乙酯(104)
将30.0g(93mmol)中间体103溶于300mL干燥的二氯甲烷中,反应液冷却至 -10℃,随后缓慢滴加发烟硝酸12mL(279mmol),滴毕,控制反应液温度为-5℃反应6h。反应完毕,将反应液倒入500mL冰水中,分出有机层,水洗有机层2次,无水硫酸钠干燥,蒸干得淡黄色固体28.5g,收率83.8%。
1.3(E)-7-(4-(3-(二甲氨基)丙烯酰)-2-甲氧基-5-硝基苯基)庚酸乙酯(105)
将中间体104(25g,68mmol)加入至甲苯250mL中,加热至110℃使中间体104完全溶解,再加入N,N-二甲基甲酰胺二甲基缩醛(48.5g,408mmol),加热回流反应10h。反应完毕后,将反应液冷却至室温后放入冷阱中搅拌,析出固体,抽滤,滤饼干燥后得黄色固体25.0g,收率87.1%。
1.4((6-甲氧基-4-氧-1,4-二氢喹啉-7-基)氧代)庚酸乙酯(106)
将中间体105(20g,47mmol)加至冰乙酸(8v/w,160mL)中,升温至40℃,待中间体IV完全溶解后,分批缓慢加入铁粉(13.2g,237mmol)升温至100℃机械搅拌反应2h。反应完毕后,反应液趁热抽滤,收集滤液,滤液冷却后有大量固体析出,抽滤,得土黄色固体。将滤饼溶解在冰乙酸中,于100℃下搅拌约30min,再次趁热抽滤,收集滤液,滤液冷却后有固体析出,抽滤,滤饼水洗至中性,干燥后得固体10.2g,收率61.8%。
1.5 7-((4-氯-6-甲氧基喹啉-7-基)氧代)庚酸乙酯(107)
将中间体105(10g,29mmol)、三氯氧磷(5v/w,50mL)加入至乙腈(5v/w,50mL) 中,升温至85℃回流反应6h。反应完毕后,减压蒸干,得灰色粘稠固体,将其加入到大量的冰水混合液中,析出固体,抽滤,水洗滤饼,得灰白色固体9.5g,收率90.5%。
MS(ESI)m/z:366.35[M+H]+
1.6 7-((4-((3-溴苯基)氨基)-6-甲氧基喹啉-7-基)氧代)庚酸乙酯
室温下,将中间体107(1.0g,2.7mmol)和3-溴苯胺(0.55g 3.2mmol)加入7mL 异丙醇溶液中,90℃室温反应2h。反应完毕,反应液降至室温,析出固体,抽滤,滤饼用水(10mL)洗,干燥后得到白色固体1.1g,收率81.5%。
1.7 7-((4-((3-溴苯基)氨基)-6-甲氧基喹啉-7-基)氧代-N-羟基庚酰胺
室温下,将0.25g(0.5mmol)7-((4-((3-溴苯基)氨基)-6-甲氧基喹啉-7-基)氧代)庚酸乙酯加入5mL羟胺甲醇溶液(4.2g盐酸羟胺,2.4g NaOH,25mL甲醇)中,冰浴下向反应液中氢氧化钠(0.04g,1.0mmol),滴毕,室温反应5h。反应完毕,向残余物中加入5mL水,6mol/LHCl溶液调节pH至中性,抽滤,干燥得到粗产品。粗产品经柱层析 (二氯甲烷:甲醇=20:1)纯化后得到黄白色固体0.15g,收率62.5%。
按照实施例1的方法,以中间体107为原料与各种取代的苯胺反应制得实施例1-11的化合物(见表1)。
实施例2:N-(4-((7-((7-(羟胺)-7-氧庚基)氧代)-6-甲氧基喹啉-4-基)氧代)苯基)-4-氧-1-苯基 -1,4-二氢哒嗪-3-甲酰胺
1. 7-((6-甲氧基-4-(4-硝基苯基)喹啉-7-基)氧代)庚酸乙酯(202)
将中间体107(10g,27mmol)、4-硝基苯酚(5.6g,40.5mmol)加入至干燥的氯苯(5v/w,50mL)中,加热至140℃,此温度下反应20h。反应完毕后,蒸干溶剂,得灰色固体,将此固体溶于二氯甲烷中,用饱和碳酸钾溶液洗涤,收集有机层,干燥,蒸干溶剂,得固体6.5g,收率51.6%。
2. 7-((4-(4-氨基苯氧基)-6-甲氧基喹啉-7-基)氧代)庚酸乙酯(203)
室温下,将中间体202(5.0g,10.7mmol)溶于50mL甲醇溶液中,加入10%Pd/C(0.5g),通入H2,室温反应2h。反应完毕,反应液降至室温,抽滤,蒸干后得到灰黑色固体4.1g,收率87.2%。MS(ESI)m/z:439.38[M+H]+
3.中间体4-氧-1-苯基-1,4-二氢哒嗪-3-羧酸(B-1)
3.1 3-氧-2-(2-苯基亚肼基)丁酸乙酯(302)
将苯胺(5.58g,60mmol)加至50mL 20%盐酸溶液中,冰水浴冷却至0℃后,向反应液中滴加50mL亚硝酸钠(5g,72mmol)水溶液,控制滴加速度,使反应温度在0-5℃之间。滴毕,于0-5℃反应30min,备用。将乙酰基乙酸乙酯(8.19g,63mmol)和无水乙酸钠(14.76g,180mmol)加入至50mL水和200mL乙醇的混合溶剂中,冰水浴冷却至0℃,然后将上述制备的重氮盐溶液缓慢滴入,保持反应温度在0-5℃之间。滴毕,0-5℃反应l h。反应完毕后,抽滤,滤饼用水洗涤,干燥,得淡黄色固体12g,收率85.7%。
3.2 4-氧-1-苯基-1,4-二氢哒嗪-3-乙酸乙酯(303)
中间体302(17.8g,76mmol)和DMF-DMA(18.1g,152mmol),加入到200mL甲苯中,升温至回流反应4h。将反应液冷却至室温后,蒸干溶剂,得到淡黄色粘稠物,向粘稠物中加入乙醚固化,得到类白色固体15g,收率为77.5%。
3.3 4-氧-1-苯基-1,4-二氢哒嗪-3-羧酸(B-1)
将中间体303(12g,49mmol)加入至160mL水中,向反应液中滴入50mL的10%氢氧化钠水溶液,滴毕,50℃反应3h。反应完毕,浓缩反应液,将残余物倒入水中,用15%盐酸溶液调pH至2,析出固体,抽滤,干燥,得白色固体9.5g,收率为90.5%。
4. 7-((6-甲氧基-4-(4-(4-氧-1-苯基-1,4-二氢哒嗪-3-甲酰胺)苯氧)喹啉-7-基)氧)庚酸乙酯
室温下将中间体203(0.3g,0.6mmol)、中间体B-1(0.2g,0.9mmol)、HATU(0.34 g,0.9mmol)和三乙胺(0.09g,0.9mmol)加至20mL DCM中,反应液升温至40℃反应4h。反应完毕后,将反应液用100mL20%的碳酸钾水溶液洗涤有机层3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。减压蒸去二氯甲烷,黄色油状物0. 25g,收率65.7%。MS(ESI)m/z:636.58[M+H]+
5.N-(4-((7-((7-(羟胺)-7-氧庚基)氧代)-6-甲氧基喹啉-4-基)氧代)苯基)-4-氧-1-苯基-1,4-二氢哒嗪-3-甲酰胺
室温下,将0.25g(0.39mmol)7-((6-甲氧基-4-(4-(4-氧-1-苯基-1,4-二氢哒嗪-3-甲酰胺)苯氧)喹啉-7-基)氧)庚酸乙酯加入5mL羟胺甲醇溶液(4.2g盐酸羟胺,2.4gNaOH, 25mL甲醇)中,冰浴下向反应液中氢氧化钠(0.03g,0.78mmol),滴毕,室温反应5h。反应完毕,向残余物中加入5mL水,6mol/L HCl溶液调节pH至中性,抽滤,干燥得到粗产品。粗产品经柱层析(二氯甲烷:甲醇=20:1)纯化后得到黄白色固体0.15g,收率62.5%。
按照实施例2的方法,以中间体203为原料与各种中间体B-1反应制得实施例12-39的化合物(见表1)。
实施例3:(E)-2-苯亚甲基-N-(4-((7-((7-(羟胺)-7-庚氧基)氧代)-6-甲氧基喹啉-4-基)氧代)苯基) 肼-1-甲酰胺
1:7-((4-(4-(肼酰胺)苯氧)-6-甲氧喹啉-7-基)氧)庚酸乙酯
将中间体203(3.06g,7mmol)以及吡啶(1.65g,21mmol)溶于60mL二氯甲烷中,冰浴下滴加氯甲酸苯酯(2.2g,0.014mol),随后室温反应2h。TLC监测反应完毕,蒸干反应液,直接加入25ml甲苯溶液,以及水合肼80%(7.5mL,150mmol)升温至80℃反应6h。TLC监测反应完毕,分出有机层,水洗有机层2次,饱和氯化钠洗涤一次,无水硫酸钠干燥,脱溶,得灰色油状物2.5g,产率为71.4%。MS(ESI)m/z:497.42[M+H]+
2:(E)-7-((4-(4-(2-苯亚甲基酰肼-1-酰胺)苯氧)-6-甲氧基喹啉-7-基)氧代)庚酸乙酯
将中间体7-((4-(4-(肼酰胺)苯氧)-6-甲氧喹啉-7-基)氧)庚酸乙酯(0.19g,0.39mmol), 苯甲醛(0.055g,0.39mmol)和10mL乙醇依次加入25mL反应瓶。搅拌均匀,85℃回流反应1h,TLC监测反应完毕,冷却至室温,析出固体。抽滤,干燥,得到灰白色固体0.16g,产率为69.5%。
3:(E)-2-苯亚甲基-N-(4-((7-((7-(羟胺)-7-庚氧基)氧代)-6-甲氧基喹啉-4-基)氧代)苯基)肼-1- 甲酰胺
室温下,将0.15g(0.25mmol)(E)-7-((4-(4-(2-苯亚甲基酰肼-1-酰胺)苯氧)-6-甲氧基喹啉-7-基)氧代)庚酸乙酯加入5mL羟胺甲醇溶液(4.2g盐酸羟胺,2.4g NaOH,25mL甲醇) 中,冰浴下向反应液中氢氧化钠(0.02g,0.5mmol),滴毕,室温反应5h。反应完毕,向残余物中加入5mL水,6mol/L HCl溶液调节pH至中性,抽滤,干燥得到粗产品。粗产品经柱层析(二氯甲烷:甲醇=20:1)纯化后得到黄白色固体0.10g,收率71.4%。
按照实施例3的方法,以中间体203为原料,按照以上反应步骤与各种取代的苯甲醛反应制得实施例40-43的化合物(见表1)。
实施例4:1-苯基-N-(4-((7-((7-(羟胺)-7-庚氧基)氧代)-6-甲氧基喹啉-4-基)氧代)苯基-2-氧代吡咯烷-3-甲酰胺
1. 2-氧-1-苯基吡咯烷-3-羧酸(B-2)
1.1:6,6-二甲基-5,7-二氧杂螺[2.5]辛烷-4,8-二酮
室温下将401(10.4g,80mmol)、乙酸酐(9.6mL,100mmol)和浓硫酸(0.32mL,6mmol)混匀,冰浴下向上述溶液中滴加丙酮(8mL,100mmol),室温反应12h,反应完毕后,将反应液倒入100mL的冰水混合物中,搅拌30分钟后抽滤,得白色固体粉末 8.6g,收率63.2%。
1.2:2-氧-1-苯基吡咯烷-3-羧酸(B-2)
室温下将中间体6,6-二甲基-5,7-二氧杂螺[2.5]辛烷-4,8-二酮(2.0g,11.7mmol),以及苯胺(2.2g,23.5mmol)加入到50mL的乙腈溶液中,60℃反应10h,反应完毕后,蒸干反应液,加入50mL石油醚:乙酸乙酯(3:1)的混合溶液打浆,析出固体,抽滤,得白色粉末1.8g,收率:75.0%。MS(ESI)m/z:206.29[M+H]+。
2. 7-((6-甲氧基-4-(4-(2-氧-1-苯基吡咯烷-3-酰胺)苯氧)喹啉-7-基)氧)庚酸乙酯
室温下将中间体203(0.3g,0.6mmol)、中间体B-2(0.18g,0.9mmol)、HATU(0.34 g,0.9mmol)和三乙胺(0.09g,0.9mmol)加至20mLDCM中,反应液升温至40℃反应4h。反应完毕后,将反应液用100mL 20%的碳酸钾水溶液洗涤有机层3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。减压蒸去二氯甲烷,黄色油状物0. 27g,收率72.9%。
3. 1-苯基-N-(4-((7-((7-(羟胺)-7-庚氧基)氧代)-6-甲氧基喹啉-4-基)氧代)苯基-2-氧代吡咯烷 -3-甲酰胺
室温下,将0.25g(0.4mmol)7-((6-甲氧基-4-(4-(2-氧-1-苯基吡咯烷-3-酰胺)苯氧)喹啉-7-基)氧)庚酸乙酯加入5mL羟胺甲醇溶液(4.2g盐酸羟胺,2.4g NaOH,25mL甲醇)中,冰浴下向反应液中氢氧化钠(0.03g,0.8mmol),滴毕,室温反应5h。反应完毕,向残余物中加入5mL水,6mol/L HCl溶液调节pH至中性,抽滤,干燥得到粗产品。粗产品经柱层析(二氯甲烷:甲醇=20:1)纯化后得到黄白色固体0.18g,收率75.0%。
按照实施例4的方法,以中间体203为原料,按照以上反应步骤与各种取代的中间B-2 反应制得实施例43-61的化合物(见表1)。
实施例5:N-(3-氟-4-((7-((7-(羟胺)-7-庚氧基)氧代)-6-甲氧基喹啉-4-基)氧代)苯基)-4-甲基 -3,5-二氧-2-苯基-2,3,4,5-四氢化-1,2,4-三嗪-6-甲酰胺
1. 4-甲基-3,5-二氧-2-苯基-2,3,4,5-四氢-1,2,4-三嗪-6-羧酸(B-3)
1.1:(2-氰基-2-(2-苯基亚肼基)乙酰基)氨基甲酸乙酯(504)
将苯胺(5.58g,60mmol)加至50mL 20%盐酸溶液中,冰水浴冷却至0℃后,向反应液中滴加50mL亚硝酸钠(5g,72mmol)水溶液,控制滴加速度,使反应温度在0-5℃之间。滴毕,于0-5℃反应30min,备用。将中间体(2-氰基乙酰基)氨基甲酸乙酯503(9.36 g,63mmol)和无水乙酸钠(14.7g,180mmol)加入至50mL水和200mL乙醇的混合溶剂中,冰水浴冷却至0℃,然后将上述制备的重氮盐溶液缓慢滴入,保持反应温度在 0-5℃之间。滴毕,0-5℃反应l h。反应完毕后,抽滤,滤饼用水洗涤,干燥,得黄色固体11.7g,收率75%。
1.2:3,5-二氧代-2-苯基-2,3,4,5-四氢-1,2,4-三嗪-6-腈(504)
将中间体503(10g,36mmol)、NaOAc(3.2g,40mmol)加入至100mL冰乙酸中,120℃反应5h。减压蒸干大部分溶剂,降至室温,加入40mL水,搅拌40min,抽滤,滤饼水洗,得淡黄色固体。取粗产品经柱层析纯化(洗脱剂PE:EA=1:2)得纯品 5.1g,收率66.2%。MS(ESI)m/z:214.7[M+H]+
1.3:4-甲基-3,5-二氧代-2-苯基-2,3,4,5-四氢-1,2,4-三嗪-6-甲腈(505)
将中间体504(5.0g,23mmol)溶于DMF中,冷却至-10℃,向反应液中分批加入 K2CO3(6.3g,46mmol),搅拌反应20min。将Me2SO4(5.8g,46mmol)用10mL DMF 稀释,缓缓滴加至反应液中,控制滴速保持反应温度低于-5℃。滴毕,-5℃反应1.5h。向反应液中依次加入水和5%的NaOH溶液,调节PH中性,搅拌2h,抽滤。滤饼水洗得淡黄色固体3.8g,收率73.1%。
1.4:4-甲基-3,5-二氧-2-苯基-2,3,4,5-四氢-1,2,4-三嗪-6-羧酸(B-3)
室温下,将中间体505(3.5g,15mmol)溶于35mL冰醋酸中,加入浓盐酸(5v/m,17.5mL),逐渐升温至100℃,反应5h。降至室温,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,抽滤,蒸干得淡黄色固体2.4g,收率73.8%。
2:7-((4-(2-氟-4-(4-甲基-3,5-二氧-2-苯基-2,3,4,5-四氢-1,2,4-三嗪-6-酰胺)苯氧)-6-甲氧基喹啉 -7-基)氧代)庚酸乙酯
室温下将中间体7-((4-(4-氨基-2-氟苯氧)-6-甲氧基喹啉-7-基)氧代)庚酸乙酯0.3g,0.6mmol)、中间体B-3(0.22g,0.9mmol)、HATU(0.34g,0.9mmol)和三乙胺(0.09g,0.9mmol)加至20mL二氯甲烷中,反应液升温至40℃反应6h。反应完毕后,将反应液用100mL20%的碳酸钾水溶液洗涤有机层3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。减压蒸去二氯甲烷,黄色油状物0.29g,收率72.5%。
3.N-(3-氟-4-((7-((7-(羟胺)-7-庚氧基)氧代)-6-甲氧基喹啉-4-基)氧代)苯基)-4-甲基-3,5-二氧 -2-苯基-2,3,4,5-四氢化-1,2,4-三嗪-6-甲酰胺
室温下,将0.25g(0.36mmol)7-((4-(2-氟-4-(4-甲基-3,5-二氧-2-苯基-2,3,4,5-四氢-1,2,4- 三嗪-6-酰胺)苯氧)-6-甲氧基喹啉-7-基)氧代)庚酸乙酯加入5mL羟胺甲醇溶液(4.2g盐酸羟胺,2.4g NaOH,25mL甲醇)中,冰浴下向反应液中氢氧化钠(0.03g,0.72mmol),滴毕,室温反应5h。反应完毕,向残余物中加入5mL水,6mol/L HCl溶液调节pH至中性,抽滤,干燥得到粗产品。粗产品经柱层析(二氯甲烷:甲醇=20:1)纯化后得到黄白色固体0.13g,收率54.2%。
按照实施例5的方法,以中间体203为原料,按照以上反应步骤与各种取代的中间B-3 反应制得实施例62的化合物(见表1)。
实施例6:N-羟胺-7-((6-甲氧基-4-(4-(3-(4-(三氟甲氧基)苯基)脲基)苯氧)喹啉-7-基)氧)庚酰胺
1:7-((6-甲氧基-4-(4-(3-(4-(三氟甲氧基)苯基)脲基)苯氧)喹啉-7-基)氧)庚酸乙酯
室温下将中间体203(0.3g,0.6mmol)溶于干燥的乙酸乙酯中,随后滴加对三氟甲氧基异氰酸酯(0.15g,0.72mmol),滴毕,室温反应2h,反应完毕,蒸干反应液,加入异丙醚10mL打浆,抽滤,得灰白色固体粉末0.3g,收率78.9%。
2:N-羟胺-7-((6-甲氧基-4-(4-(3-(4-(三氟甲氧基)苯基)脲基)苯氧)喹啉-7-基)氧)庚酰胺
室温下,将7-((6-甲氧基-4-(4-(3-(4-(三氟甲氧基)苯基)脲基)苯氧)喹啉-7-基)氧)庚酸乙酯 (0.23g,0.36mmol)加入5mL羟胺甲醇溶液(4.2g盐酸羟胺,2.4g NaOH,25mL甲醇) 中,冰浴下向反应液中氢氧化钠(0.03g,0.72mmol),滴毕,室温反应5h。反应完毕,向残余物中加入5mL水,6mol/L HCl溶液调节pH至中性,抽滤,干燥得到粗产品。粗产品经柱层析(二氯甲烷:甲醇=20:1)纯化后得到黄白色固体0.11g,收率47.8%。
按照实施例6的方法,以中间体203为原料,按照以上反应步骤与各种取代的异氰酸酯反应制得实施例63-65的化合物(见表1)。
表1
对按照本发明的上式(I)的含锌结合基以及喹啉骨架的化合物(浓度0.1μM)进行了体外c-Met和HDAC1激酶活性测试。对照品SAHA和卡博替尼为外购试剂得到。
1.制备1X缓冲液(氨丁三醇缓冲液)
2.化合物按照相应浓度稀释:
用100%DMSO将化合物转移到测定板上.DMSO的最终含量为1%.
3.制备酶溶液
HDAC buffer的配制方法:首先配制1M的Tris-HCl储备液,取7.5mL 1M的Tris-HCl储备液与0.03654gEDTA以及7.31gNaCl混合后加蒸馏水至450mL,再加入50mL甘油,即得500mLHDAC buffer。
4.制备底物溶液:在1x检测缓冲液中加入胰蛋白酶和ac肽底物,制成底物溶液。
5.将15μL酶溶液解转移至酶联板中。
6.室温孵育15分钟。
7.向上述溶液中加入10μL of底物溶液引发反应。
8.随后室温孵育60分钟。
9.于355nm和460nm.在Synergy MX测定荧光强度。
10.利用式拟合Excel数据,得到抑制值。
公式(1):Inh%=(Max-Signal)/(Max-Min)*100
部分化合物的c-Met和HDAC1的体外激酶试验结果见表2。
表2
本发明产物的体外抗肿瘤细胞活性
对按照本发明的上式I的含锌结合基以及喹啉骨架的化合物进行了体外抑制人乳腺癌细胞MCF7、人结肠癌细胞HCT 116活性筛选。对照品SAHA和卡博替尼为外购试剂得到
1.细胞复苏并传代2-3次稳定后,用胰蛋白酶溶液(0.25%)使其从培养瓶底部消化下来。将细胞消化液倒入离心管中后,之后加入培养液以终止消化。将离心管在800r/min下离心 10min,弃去上清液后加入5mL培养液,吹打混匀细胞,吸取10μL细胞混悬液加入细胞计数板中计数,调整细胞浓度为104个/孔。96孔板中除A1孔为空白孔不加细胞外,其余皆加入100μL细胞混悬液。将96孔板放入培养箱中培养24h。
2.用50μL二甲基亚砜溶解受试样品,然后加入适量培养液,使样品溶解成2mg/mL药液,然后在24孔板中将样品稀释为20、4、0.8、0.16、0.032μg/mL。
每个浓度加入3孔,其中周围两行两列细胞长势受环境影响较大,只和为空白细胞孔使用。将96孔板放入培养箱中培养72h。
3.将96孔板中带药培养液弃去,用磷酸缓冲溶液(PBS)将细胞冲洗两遍,在每孔中加入 MTT(0.5mg/mL)100μL放入培养箱中4h后,弃去MTT溶液,加入二甲基亚砜100μL。在磁力振荡器上振荡使存活细胞与MTT反应产物甲臜充分溶解,放入酶标仪中测定结果。通过Bliss法可求出药物IC50值。
部分化合物的抑制人人乳腺癌细胞MCF7、人结肠癌细胞HCT 116人肺腺癌细胞A549 活性结果见表3。
表3
初步的体外激酶和细胞活性测试结果表明,本发明所要保护的通式I的化合物,具有良好的c-Met和HDAC的抑制活性,部分化合物相当或优于阳性对照药卡博替尼和SAHA。
Claims (10)
1.通式(I)的化合物及其药学上可接受的盐、溶剂化物、几何异构体、对映异构体、非对映异构体、外消旋体或其前药,
其中,
R1=氢或(C1-C6)烷氧基,
m=1-6,
X为O、NH,
R2选自为氢、羟基、卤素、硝基、氨基、氰基、氨基甲酰基、氨基磺酰基、(C1-C6)烷基、(C1-C6)烷氧基、(C2-C6)炔基、(C1-C6)酰基,任选被羟基、氨基、氰基或卤素取代的(C1-C6)烷基或(C1-C6)烷氧基、被单或二(C1-C6烷基)取代的氨基、(C1-C6)烷基酰胺基、(C1-C6)烷基酰基、(C1-C6)烷基亚磺酰基、(C1-C6)烷基磺酰基及游离的、成盐的、酯化的和酰胺化的羧基;
其中R3为卤素或氢;
R4为选自氢、(C1-C6)烷基或卤代(C1-C6)烷基;
R5选自氢、(C1-C6)烷基或卤代(C1-C6)烷基;
Cy为(C1-C6)烷基、(C3-C7)环烷基、6-10元芳基、5-10元杂芳基、6-10元芳基甲基、5-10元杂芳基甲基,所述芳基或者杂芳基任选被0-3个相同或不同的R6取代;
R6为羟基、卤素、硝基、氨基、氰基、(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C6)烷氧基、任选被羟基、氨基或卤代的(C1-C6)烷基或(C1-C6)烷氧基、被1-2个(C1-C6)烷基取代的氨基、(C1-C6)烷基酰胺基、游离的、成盐的、酯化的和酰胺化的羧基、(C1-C6)烷基亚磺酰基、(C1-C6)烷基磺酰基、(C1-C6)烷氧基、(C1-C6)烷基、(C1-C6)烷基酰基、(C1-C6)氨基甲酰基、被1-2个(C1-C6)烷基取代的氨基甲酰基、(C1-C3)亚烷基二氧基、烯丙基。
2.通式(I)的化合物及其药学上可接受的盐、溶剂化物、几何异构体、对映异构体、非对映异构体、外消旋体或其前药,
其中,
R1为(C1-C4)烷氧基;
m=1-6;
R2选自为氢、羟基、卤素、硝基、氨基、氰基、氨基甲酰基、氨基磺酰基、(C1-C6)烷基、(C1-C6)烷氧基、(C2-C6)炔基、(C1-C6)酰基,任选被羟基、氨基、氰基或卤素取代的(C1-C6)烷基或(C1-C6)烷氧基、被单或二(C1-C6烷基)取代的氨基、(C1-C6)烷基酰胺基、(C1-C6)烷基酰基、(C1-C6)烷基亚磺酰基、(C1-C6)烷基磺酰基及游离的、成盐的、酯化的和酰胺化的羧基。
其中R3优选氢或氟
R4为氢,(C1-C4)烷基;
R5为氢、(C1-C4)烷基或卤代(C1-C4)烷基;
Cy为苯基,所述苯基任选被0-3个相同或不同的R6取代。
R6为羟基、卤素、卤代(C1-C6)烷基、卤代(C1-C6)烷氧基、硝基、氨基、氰基、(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C6)烷氧基、任选被羟基、氨基或卤代的(C1-C6)烷基或(C1-C6)烷氧基、被1-2个(C1-C6)烷基取代的氨基、(C1-C6)烷基酰胺基、游离的、成盐的、酯化的和酰胺化的羧基、(C1-C6)烷基亚磺酰基、(C1-C6)烷基磺酰基、(C1-C6)烷氧基、(C1-C6)烷基、(C1-C6)烷基酰基、(C1-C6)氨基甲酰基、被1-2个(C1-C6)烷基取代的氨基甲酰基、(C1-C3)亚烷基二氧基、烯丙基。
3.通式(I)的化合物及其药学上可接受的盐、溶剂化物、几何异构体、对映异构体、非对映异构体、外消旋体或其前药,
R1为甲氧基;
m=1-6;
X为O、NH;
R2选自为氢、羟基、卤素、硝基、氨基、氰基、氨基甲酰基、氨基磺酰基、(C1-C6)烷基、(C1-C6)烷氧基、(C2-C6)炔基、(C1-C6)酰基,任选被羟基、氨基、氰基或卤素取代的(C1-C6)烷基或(C1-C6)烷氧基、被单或二(C1-C6烷基)取代的氨基、(C1-C6)烷基酰胺基、(C1-C6)烷基酰基、(C1-C6)烷基亚磺酰基、(C1-C6)烷基磺酰基及游离的、成盐的、酯化的和酰胺化的羧基。
其中R3优选氢或氟;
R4优选氢,甲基、乙基;
R5选自氢、甲基或三氟甲基;
Cy为苯基,所述苯基任选被0-3个相同或不同的R6取代;
R6为羟基、卤素、硝基、氨基、氰基、(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C6)烷氧基、任选被羟基、氨基或卤代的(C1-C6)烷基或(C1-C6)烷氧基、被1-2个(C1-C6)烷基取代的氨基、(C1-C6)烷基酰胺基、游离的、成盐的、酯化的和酰胺化的羧基、(C1-C6)烷基亚磺酰基、(C1-C6)烷基磺酰基、(C1-C6)烷氧基、(C1-C6)烷基、(C1-C6)烷基酰基、(C1-C6)氨基甲酰基、被1-2个(C1-C6)烷基取代的氨基甲酰基、(C1-C3)亚烷基二氧基、烯丙基。
6.一种药物组合物,包含权利要求1-4任何一项所述的化合物或其几何异构体、对映异构体、非对映异构体、外消旋体、药物可接受性盐、前药和药学上可接受的载体或赋形剂。
7.权利要求1-4任何一项所述的化合物或其几何异构体、对映异构体、非对映异构体、外消旋体、药物可接受性盐、前药或权利要求6所述的药物组合物在制备c-Met酪氨酸激酶抑制剂或HDAC抑制剂中的应用。
8.权利要求1-4任何一项所述的化合物或其几何异构体、对映异构体、非对映异构体、外消旋体、药物可接受性盐、前药或权利要求6所述的药物组合物在制备c-Met酪氨酸激酶抑制剂和HDAC抑制剂中的应用。
9.权利要求1-4任何一项所述的化合物或其几何异构体、对映异构体、非对映异构体、外消旋体、药物可接受性盐、前药或权利要求6所述的药物组合物在制备抗肿瘤药物中的应用。
10.如权利要求9所述的应用,其特征在于,所述的肿瘤为乳腺癌、肺癌、肝癌、肾癌、结肠癌、直肠癌、胃癌、前列腺癌、膀胱癌、子宫癌、胰腺癌、骨髓癌、睾丸癌、卵巢癌、淋巴癌、软组织癌、头颈癌、甲状腺癌、食道癌和白血病、成神经细胞瘤。
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