CN105237518A - 4-杂环取代嘧啶类化合物及其用途 - Google Patents
4-杂环取代嘧啶类化合物及其用途 Download PDFInfo
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- CN105237518A CN105237518A CN201510580389.6A CN201510580389A CN105237518A CN 105237518 A CN105237518 A CN 105237518A CN 201510580389 A CN201510580389 A CN 201510580389A CN 105237518 A CN105237518 A CN 105237518A
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明公开了一种4-杂环取代嘧啶类化合物及其药学上可成的盐，具有如下化学结构通式，
Description
技术领域
本发明涉及药物领域，具体涉及一类4-杂环取代嘧啶类化合物及其药学上可成的盐或晶型、制备方法、含有这些化合物的药用组合物及其抗肿瘤作用，特别是在治疗各种肿瘤包括耐药肿瘤中的应用。
背景技术
恶性肿瘤已成为我国城市居民的头号杀手，严重危害我国人民生命健康。目前用于肿瘤治疗的放疗、化疗等方法虽然对某些恶性肿瘤有较好的疗效，但对实体性肿瘤的疗效则难以令人满意。另外，这些方法对肿瘤细胞的选择性低，在杀死肿瘤细胞的同时往往会有杀伤正常细胞的“弊端”，具有较大的毒副作用，严重的限制了其临床应用。因此，随着目前肿瘤治疗市场和用药的需求，寻找机制独特、效果显著、毒副作用小的新型抗肿瘤药物将具有重要的科学意义和临床应用价值。为了获得可有效和安全地施用于肿瘤患有的抗肿瘤药物，人们已经付出并且还在付出巨大的努力。本发明要解决的技术问题是提供用于治疗肿瘤的新型化合物，为广大肿瘤患者提供更多的治疗手段，提高患者的生活品质。
发明内容
本发明的目的之一是提供一类特异、高效并经口服、注射给药有效的化合物，它们能够用于治疗人体血液类疾病、实体恶性肿瘤以及其它细胞增生性疾病。本发明另一个目的是提供一种新型化合物用于治疗对现有药物产生耐药性的肿瘤疾病。
上述发明目的中所述的人体血液性疾病是指淋巴细胞型和骨髓细胞型的血液肿瘤，它们包括急性淋巴细胞型白血病、急性原始淋巴型白血病、B型细胞淋巴瘤、T型细胞淋巴瘤、何杰金氏淋巴瘤、非何杰金氏淋巴瘤、毛状细胞淋巴瘤、Burkett氏淋巴瘤、急性髓细胞型淋巴瘤、慢性髓细胞型淋巴瘤、骨髓发育不全症和早幼粒细胞性白血病；
所述的实体恶性肿瘤的发病部位是一种或多种同时存在，它们是乳腺、卵巢、结肠、肺、脑、骨、呼吸道、胃、胰腺、前列腺、肝、胆、咽喉、膀胱、子宫、皮肤等部位；
所述的其他增生性疾病包括血管增生性疾病如关节炎和心瓣变窄、纤维增生性疾病如肝硬化和动脉粥样硬化以及肾小球细胞增生性疾病如肾小球盐、糖尿性肾炎、慢性肾硬化和器官移植时的排斥反应。这些化合物还可用于治疗代谢性疾病如牛皮藓、慢性伤口溃烂、炎症和神经退行性疾病如老年痴呆症。
为达到上述目的，本文采用的技术方案是：一种4-杂环取代嘧啶类化合物，它是含有如下化学结构通式的化合物或其药学上可成的盐或晶型，可用于治疗和预防各种人体增生性疾病和其他疾病。
其中，
R1，R2相同或不同，代表氢，卤素，烷基，芳烷基，芳烷杂环基，环烷基，环状杂环基或环状杂烷化烷基。
Y代表二级氨基(-NH-)；
Z代表羰基
R3代表氢或烷基，烷氧基；
R4代表氢，取代或未取代的C1-C6的烷基，C3-C15的环烷基，取代或未取代的苯基，取代或未取代的芳烷基，五元或六元杂环基，五元或六元杂环烷基、五元或六元杂环基或五元或六元杂环烷基取代的烷基或芳香基；
R5代表其中，X代表N、O或S，R6，R7和R8相同或不同，代表氢、卤素、C1-C3的烷基、烷氧基、羟基、氨基或硝基；
或者其中，X代表N、O或S，R9，R10，R11，R12和R13相同或不同，代表氢，卤素，C1-C3的烷基，C1-C3烷氧基，羟基，氨基或硝基。
本发明进一步优选R1，R2相同或不同，代表氢，卤素，C1-C6的烷基，C3-C15的环烷基，C1-C6烷基取代的六元杂环。
优选R4代表氢，C1-C6的烷基或者烷氨基取代的、氨基取代的或羟基取代的C1-C6的烷基，C3-C15的环烷基，苯基，苯烷基，卤素，氨基，羟基，硝基，C1-C6的烷基或烷氧基取代的苯基，五元或六元杂环基，五元或六元杂环烷基、五元或六元杂环基或五元或六元杂环烷基取代的烷基或苯基。
上述五元或六元杂环选自选自呋喃，噻吩，吡咯，吡啶，四氢呋喃，四氢噻吩，四氢吡咯，四氢嘧啶、四氢哒嗪、四氢吡嗪或吗啉基。
上述技术方案中，带有游离价键的杂原子都是由氢原子结合，其中的“杂原子”指氧(O)、氮(N)和硫(S)原子；
所述“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)原子；
所述烷基是指含有1-12个碳原子的单价烷，可以是直链、分叉或环状，包括甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基、辛基等；
所述“环烷基”是指一类环状并含有3-15个碳原子但无共轭双键的烷基，它们可含有1-4个环，无取代基的例子有环丙烷基、环丁烷基、环戊烷基、环己烷基等，取代基则是指含有一个或更多的以下基团：卤素、烷基、烷氧基、羟基、氨基、硝基、氰基、硫基等；
所述“芳基”是指单环或双环的芳香环，如苯基、有取代基的苯基以及稠型的基团如萘基等，此外，芳基上可能存在卤素、烷基、烷氧基、羟基、氨基、硝基、羧基、酰基、氰基、硫基等取代基；
所述“芳香杂环基”是指五元或六元的单个芳香环或九元或十元的双环中至少含有一个杂原子，其中，氮原子可以多个共存，也可能与氧或硫原子并存，芳香杂环基的例子有噻嗯基、呋喃基、吡啶基、咪唑基、哌啶基、噻唑基、吡唑基、三氮唑基、异噁唑基、异噻唑基、吡嗪基、哒嗪基、嘧啶基、三嗪氮杂基、吲哚基、异吲哚基、喹啉基、异喹啉基等，这些环上还可能存在不同的取代基，如卤素、烷基、烷氧基、羟基、氨基、环烷基、硝基、硫基等；
所述“环状杂烷基”是指环中的1-3个碳原子被杂原子置换后的环状烷基，例如哌嗪基等，环上还可能存在如卤素、烷基、烷氧基、羟基、环烷基、氨基、硝基、硫基等取代基团，此外，杂原子为硫时，可能是砜或亚砜，若杂原子为氮时，有可能是四价氮。
本发明进一步优选的技术方案中，所述化合物化学结构通式中，R1、R2代表氢，R3代表氢或甲基，Y代表-NH-；Z代表R5代表或者
R4代表—CH3，—CH2CH3，—CH2NH2,—CH2OH，—CH2NHBoc， 或
除本发明直接描述的化合物外，这些化合物的药用盐类也在本发明的保护范围中，本发明涉及化合物的药用盐型包括与无机酸、有机酸或无机碱、有机碱所形成的各种盐及各种晶型。
酸性盐的例子有醋酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑碘酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、乙醇酸盐、亚磺酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙基磺酸盐、乳酸盐、苹果酸盐、丙二酸盐、萘磺酸盐、尼古丁酸盐、硝酸盐、乙二酸盐、棕榈酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、异丙酸盐、水杨酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐、十一烷酸盐；碱性盐的例子则有碱金属(如钠、钾)盐、碱性二价金属(如镁、锌)盐、铵盐和含1-4个碳原子的烷基铵盐。
本发明同时要求保护一种组合物，所述组合物包括上述4-杂环取代嘧啶类化合物或其药学上可成的盐及其晶型。
在对本发明所述化合物结构改造的研究中发现，R5基团对母核化合物活性的影响很大，当R5基团选择其它芳香基团时，例如苯基，化合物的活性大大降低，而本发明所述的化合物对人类肿瘤细胞的增殖具有明显抑制作用。
本发明同时要求保护上述4-杂环取代嘧啶类化合物或其药学上可成的盐或晶型在制备治疗人体血液类疾病、实体恶性肿瘤、肿瘤以外的其它细胞增生性疾病、代谢性疾病以及神经退行性疾病药物中的应用。
所述人体血液性疾病是指淋巴细胞型和骨髓细胞型的血液肿瘤，包括急性淋巴细胞型白血病、急性原始淋巴型白血病、B型细胞淋巴瘤、T型细胞淋巴瘤、何杰金氏淋巴瘤、非何杰金氏淋巴瘤、毛状细胞淋巴瘤、Burkett氏淋巴瘤、急性髓细胞型淋巴瘤、慢性髓细胞型淋巴瘤、骨髓发育不全症和早幼粒细胞性白血病；
所述的实体恶性肿瘤包括乳腺、卵巢、结肠、肺、脑、骨、呼吸道、胃、胰腺、前列腺、肝、胆、口腔、咽喉、膀胱、子宫、皮肤部位的肿瘤；
所述的其他增生性疾病包括血管增生性疾病如关节炎和心瓣变窄、纤维增生性疾病如肝硬化和动脉粥样硬化以及肾小球细胞增生性疾病如肾小球盐、糖尿性肾炎、慢性肾硬化和器官移植时的排斥反应。这些化合物还可用于治疗代谢性疾病如牛皮藓、慢性伤口溃烂、炎症和神经退行性疾病如老年痴呆症。
本发明通过实验证明了本发明化合物能够有效抑制口腔鳞癌、肺癌、肝癌、乳腺癌、胆管癌、胰腺癌、胃癌、甲状腺髓样癌、黑色素瘤、肾癌、结直肠癌、膀胱癌、骨肉瘤、多发性骨髓瘤、神经母细胞瘤、横纹肌肉瘤、前列腺癌、卵巢癌、宫颈癌、头颈癌和食管癌的增殖。同时能够有效抑制耐药肿瘤，如伊马替尼耐药的肿瘤的增殖。
本发明同时要求保护一种药物组合物，所述药物的主要活性成分为上述4-杂环取代嘧啶类化合物或其药物可成的盐或晶型，还包括临床治疗上能接受的载体或辅料及其缓控释制剂。这些药用载体或辅料包括离子交换树脂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人体血清白蛋白)、缓冲物(如磷酸盐、甘氨酸、山梨酸、山梨酸钾等)、部分饱和植物油的甘油脂、水和盐的混合物或电解质(如硫酸精蛋白、磷酸氢二钠、磷酸氢钾、氧化钠等)、锌盐、胶态硅胶、三聚硅酸镁、聚乙烯吡咯烷酮、纤维素类、聚乙烯甘油醇、羧酸甲基纤维素钠、聚酰化物、蜡类及羊毛脂等。起缓控释作用的载体或辅料可选自纤维素衍生物(如甲基纤维素、羟乙基纤维素和羟乙基甲基纤维素等)、非纤维素多糖(如葡糖糖、壳多糖、半乳糖和甘露聚糖等)、天然胶(果胶、海藻酸钠、琼脂和海藻酸钾等)、乙烯基聚合物或丙烯酸聚合物(如聚乙烯醇和聚羟乙烯934等)、惰性脂肪或蜡类(如蜂蜡、氢化植物油、硬脂酸和十八烷醇等)、聚乙烯、聚丙烯、聚硅氧烷和聚氧乙烯等。
本发明涉所述4-杂环取代嘧啶类化合物或其药物可成的盐或晶型可制成不同的剂型用于人体给药，具体的剂型有水溶液注射剂、油状混悬液注射剂、口服胶囊剂、口服片剂、口服水溶液、口服混悬液、直肠栓剂、滴眼液、眼膏、皮肤用软膏、皮肤用霜剂、皮肤用喷雾剂、口腔喷雾剂、口腔气雾剂、鼻腔喷雾剂和鼻腔气雾剂等，同时还包括这些不同剂型的缓释剂和控制释放速度和剂量的制剂。
本发明所述4-杂环取代嘧啶类化合物或其药物上可成的盐或晶型可用于使其发挥作用的各种给药途径。例如可用于口服、非胃肠道给药、口腔吸入、透过皮肤给药、直肠给药、鼻腔给药、舌下给药、面颊给药、阴道给药及通过植入性容器给药等方式施用。非胃肠道给药又包括在皮下、静脉内、肌肉内、关节内、滑膜腔内、胸骨内、鞘内、肝内、损伤部位内和颅内注射和浸渗。制药领域的普通技术人员可以根据疾病状况和其他相关情况，选择施用的适当形式和方式。这些药用制剂中可以含有与载体组合的例如0.05-90％重量活性成分，更常见约15-60％之间的活性成分。本发明化合物剂量可以使0.005-5000mg/kg/天，也可根据疾病严重程度或剂型的不同使用剂量超出此剂量范围。所用的剂量受多种因素的影响，这些因素包括年龄、体重、健康状况、性别、种族、饮食习惯、给药时间、排尿频率及是否使用其它药物等。
本发明所述4-杂环取代嘧啶类化合物或其药物上可成的盐或晶型可以与其它抗肿瘤药物，例如，烷化剂、抗代谢药、拓扑异构酶抑制剂、有丝分裂抑制剂、DNA插入剂联合应用，另外，还可以与放射治疗联合应用。这些其它抗肿瘤药或放射治疗可以与本发明化合物同时或在不同时间给予。这些联合治疗可以产生协同作用从而有助于改善治疗效果。
本发明所述4-杂环取代嘧啶类化合物或其药物上可成的盐或晶型适用于治疗和预防下述各种肿瘤：发生在以下部位和组织的固体恶性肿瘤：乳腺、卵巢、结肠、肝、胆、肺、胃、前列腺、胰腺、咽喉、膀胱、脑、皮肤等；淋巴细胞型血液类肿瘤：急性淋巴细胞型白血病、急性原始淋巴细胞型白血病、B细胞型白血病、T细胞型白血病、何杰金氏淋巴瘤、非何杰金氏淋巴瘤、毛状细胞淋巴瘤和Burkett氏淋巴瘤；骨髓细胞型血液类肿瘤：急性骨髓细胞型白血病、慢性骨髓细胞型白血病、骨髓发育不全症和早幼粒细胞型白血病；其它还包括发生在中枢神经系统和外周神经系统内的肿瘤；同时还可解决目前临床使用药物所存在的肿瘤耐药性问题。
本发明的化合物可以通过(但不局限于)以下合成路线来制备，
上述合成路线以本发明中的一小类化合物为例给出，其他化合物可以以类似方法制备，也可以通过其他合成路线制备。
具体实施方式
下面结合具体实例对本发明作进一步阐述，但本发明不局限于这些实施例。这些实施例只是用来帮助理解本发明，并不限制本发明所涉及的任何技术和用途：
实施例一：制备中间体4-甲基-3-(4-(呋喃-2-)嘧啶基-2-氧)苯胺
将2-乙酰基呋喃(121克，1.1摩尔)和N，N-二甲基甲酰胺二甲基甲缩醛(155克，1.3摩尔)溶解于500毫升无水二甲基甲酰胺中，在110℃回流反应3小时。旋干溶剂后，加入乙醚是产物沉淀并结晶，分离和干燥后得到168克黄色晶体。
先将金属钠(23克，1摩尔)溶解于500毫升无水乙醇中，加入硫脲(76.1克，2摩尔)和165克以上白色结晶，加热回流反应6小时。反应完毕后，加入1升蒸馏水，加冰醋酸调节pH至酸性，冷却至室温有白色固体析出，抽滤，滤饼在红外灯下干燥的浅黄色固体137.8克。
将89克上述浅黄色固体溶解于500毫升1N氢氧化钠溶液中，加入碘甲烷(70.5克，1摩尔)，室温下搅拌3小时，反应液用冰醋酸调节pH至酸性，有白色沉淀析出。抽滤，滤饼在乙醇中重结晶得到85.3克浅黄色结晶。
将60克以上浅黄色晶体溶解于300毫升丙酮中，加入30％双氧水(60毫升)，升温回流反应6小时，反应完毕，冷却至室温，冰浴冷却下缓慢低价饱和亚硫酸钠饱和溶液，至反应液不能是淀粉碘化钾试纸变蓝色为止。反应液以300毫升乙酸乙酯萃取三次，合并有机相，有机相经水洗，饱和氯化钠溶液洗涤，加无水硫酸钠干燥。旋干溶剂，得到白色固体63.9克。
将43克以上白色固体和44.7克3-羟基-4甲基-苯胺基甲酸叔丁酯溶解于100毫升二甲基甲酰胺中，缓慢滴加40毫升氢化钠的二甲基甲酰胺悬浊液(14.4克氢化钠混悬于40毫升二甲基甲酰胺)，滴加完毕，室温搅拌12小时，加柠檬酸调节pH至酸性，将反应液倒入1000毫升冰水中，有沉淀析出，抽滤，滤饼用水洗涤，在红外灯下干燥得浅黄色固体。该固体在石油醚乙酸乙酯(10:1)中重结晶得白色固体61.7克。
以上白色固体溶解于100毫升二氯甲烷中，室温下滴加34.2克三氟乙酸，室温下搅拌2小时，反应结束后，反应液分别以200毫升蒸馏水和200毫升饱和氯化钠溶液洗涤，加无水硫酸钠干燥，旋干溶剂得到37.8克标题化合物。
该产物为白色固体，熔点：该产物为白色固体，熔点：145-147℃；1HNMR：(CDCl3,300MHz,ppm)δ8.77-8.74(m,1H),7.68-7.64(m,1H),7.58(s,1H),7.37-7.34(m,1H),6.94(d,J＝8.1Hz,1H),6.63-6.59(m,3H),3.63(br,2H),2.14(s,3H)；MS(ESI)m/z268.3[M+H]+.
实施例二：N-(4-甲基-3-(4-呋喃基-2-)嘧啶基-2氧)苯基)苯甲酰胺
将134毫克(0.5毫摩尔)4-甲基-3-(4-(呋喃-2-)嘧啶基-2-氧)-苯胺溶于5毫升二氯甲烷中，依次加入苯甲酸(0.073克，0.6毫摩尔)，EDCI(0.12克，0.6毫摩尔)，HOBt(0.081克，0.6毫摩尔)，室温下搅拌1小时，反应完毕，反应液加15毫升二氯甲烷稀释，依次用10毫升水，10毫升饱和氯化钠洗涤，加无水硫酸钠干燥，旋干溶剂得浅黄色固体。粗品经柱层析分离，得白色固体162毫克，产率87％。
该产物为淡黄色固体，熔点：136-138℃；1HNMR:(CDCl3,300MHz,ppm)δ8.62(s,1H),8.38(d,J＝5.2Hz,1H),7.74(t,J＝1.7Hz,1H),7.63(d,J＝7.8Hz,1H),7.58-7.52(m,2H),7.51-7.44(m,2H),7.40-7.33(m,1H),7.30-7.20(m,3H),7.19-7.10(m,1H),6.52(dd,J＝3.5Hz,1.7Hz,1H),2.08(s,3H)；13CNMR(75MHz,CDCl3)δ166.1,164.9,159.7,158.1,151.3,151.1,145.5,137.2,134.8,131.6,131.2,128.4,127.8,126.5,117.7,114.2,113.5,112.7,109.7,15.91；MS(ESI)m/z372.3[M+H]+.
实施例三：4-氯-N-(4-甲基-3-(4-呋喃基-2-)嘧啶基-2氧)苯基)苯甲酰胺
将134毫克(0.5毫摩尔)4-甲基-3-(4-(呋喃-2-)嘧啶基-2-氧)-苯胺溶于5毫升二氯甲烷中，依次加入4-氯苯甲酸(0.094克，0.6毫摩尔)，EDCI(0.12克，0.6毫摩尔)，HOBt(0.081克，0.6毫摩尔)，室温下搅拌1小时，反应完毕，反应液加15毫升二氯甲烷稀释，依次用10毫升水，10毫升饱和氯化钠洗涤，加无水硫酸钠干燥，旋干溶剂得浅黄色固体。粗品经柱层析分离，得白色固体182毫克，产率90％。
该产物为白色固体，熔点：147-149℃；1HNMR:(CDCl3,300MHz,ppm)δ8.65(s,1H),8.40(d,J＝5.2Hz,1H),7.74-7.63(m,2H),7.58-7.52(m,1H),7.51-7.44(m,2H),7.37-7.32(m,1H),7.30-7.20(m,3H),7.19-7.10(m,1H),6.52(dd,J＝3.5Hz,1.7Hz,1H),2.10(s,3H)；13CNMR(75MHz,CDCl3)δ165.0,165.7,159.3,158.3,151.7,151.1,145.0,136.9,136.7,134.6,131.6,131.2,129.8,127.6,126.9,126.0,117.8,114.0,113.6,112.7,109.8,15.9；MS(ESI)m/z406.3[M+H]+.
实施例四：3-氯-N-(4-甲基-3-(4-呋喃基-2-)嘧啶基-2氧)苯基)苯甲酰胺
将134毫克(0.5毫摩尔)4-甲基-3-(4-(呋喃-2-)嘧啶基-2-氧)-苯胺溶于5毫升二氯甲烷中，依次加入3-氯苯甲酸(0.094克，0.6毫摩尔)，EDCI(0.12克，0.6毫摩尔)，HOBt(0.081克，0.6毫摩尔)，室温下搅拌1小时，反应完毕，反应液加15毫升二氯甲烷稀释，依次用10毫升水，10毫升饱和氯化钠洗涤，加无水硫酸钠干燥，旋干溶剂得浅黄色固体。粗品经柱层析分离，得白色固体178毫克，产率88％。
该产物为白色固体，熔点：154-157℃；1HNMR:(CDCl3,300MHz,ppm)δ8.62(s,1H),8.38(d,J＝5.2Hz,1H),7.74(t,J＝1.7Hz,1H),7.63(d,J＝7.8Hz,1H),7.58-7.52(m,1H),7.51-7.44(m,2H),7.37(dt,J＝7.9Hz,1.0Hz,1H),7.30-7.20(m,3H),7.19-7.10(m,1H),6.52(dd,J＝3.5Hz,1.7Hz,1H),2.08(s,3H)；13CNMR(75MHz,CDCl3)δ164.9,164.7,159.7,158.2,151.3,151.1,145.5,136.9,136.7,134.6,131.6,131.3,129.8,127.5,126.8,125.3,117.8,114.2,113.6,112.7,109.8,15.9；MS(ESI)m/z406.3[M+H]+.
实施例五：N-(4-甲基-3-(4-呋喃基-2-)嘧啶基-2氧)苯基)苯乙酰胺
按实施例三所述方法，用苯乙酸制得标题化合物175毫克，产率91％。
该产物为淡黄色固体，熔点：136-138℃；1HNMR:(CDCl3,300MHz,ppm)δ8.40(d,J＝5.2Hz,1H),7.79-7.47(m,2H),7.35-7.25(m,9H),7.14(d,J＝8.2Hz,1H),6.54(dd,J＝3.5,1.7Hz,1H),3.64(s,2H),2.12(s,3H)；13CNMR(75MHz,CDCl3)δ169.1,164.9,159.8,158.1,151.3,151.2,145.5,137.2,134.8,131.6,131.2,128.4,127.8,126.5,117.7,114.2,113.5,112.7,109.7,44.6,15.9；MS(ESI)m/z386.3[M+H]+.
实施例六：4-甲氧基-N-(4-甲基-3-(4-呋喃基-2-)嘧啶基-2氧)苯基)苯甲酰胺
按实施例三所述方法，用4-甲氧基苯甲酸制得标题化合物176毫克，产率88％。
该产物为淡黄色固体，熔点：175-177℃；1HNMR:(CDCl3,300MHz,ppm)δ8.43(d,J＝5.2Hz,1H),8.04(s,1H),7.84-7.71(m,2H),7.58(dd,J＝1.6,0.6Hz,1H),7.54-7.39(m,2H),7.37-7.24(m,2H),7.21(d,J＝8.2Hz,1H),7.01-6.72(m,2H),6.55(dd,J＝3.5,1.8Hz,1H),3.82(s,3H),2.15(s,3H)；13CNMR(75MHz,CDCl3)δ165.2,165.0,162.3,159.8,158.2,151.4,145.42,137.2,131.2,128.9,127.0,126.4,117.4,113.9,113.8,113.4,112.7,109.6,55.42,15.96；MS(ESI)m/z402.3[M+H]+.
实施例七：3-甲氧-N-(4-甲基-3-(4-呋喃基-2-)嘧啶基-2氧)苯基)苯甲酰胺
按实施例三所述方法，用3-甲基苯甲酸制得标题化合物154毫克，产率80％。
该产物为淡黄色固体，熔点：171-173℃；1HNMR:(CDCl3,300MHz,ppm)δ8.57(s,1H),8.37(d,J＝5.2Hz,1H),7.72-7.37(m,5H),7.37-6.98(m,5H),6.49(dd,J＝3.5,1.7Hz,1H),2.25(s,3H),2.08(s,3H)；13CNMR(75MHz,CDCl3)δ166.3,164.9,159.8,158.2,151.3,151.2,145.5,137.3,134.8,131.2,132.4,128.4,127.9,126.5,117.7,114.2,113.5,112.7,109.7,21.2,15.9；MS(ESI)m/z386.3[M+H]+.
实施例八：N-(4-甲基-3-(4-呋喃基-2-)嘧啶基-2氧)苯基)噻吩-3-甲酰胺
按实施例三所述方法，用3-甲基苯甲酸制得标题化合物168毫克，产率89％。
该产物为淡黄色固体，熔点：188-190℃；1HNMR:(CDCl3,300MHz,ppm)δ8.60(s,1H),8.37(d,J＝5.1Hz,1H),7.70(d,J＝8.4Hz,2H),7.56(s,1H),7.46(d,J＝7.1Hz,2H),7.33-7.19(m,4H),7.15(d,J＝8.4Hz,1H),6.53(d,J＝1.6Hz,1H),2.10(s,3H)；13CNMR(75MHz,CDCl3)δ165.0,164.9,159.7,158.2,151.3,151.1,145.5,137.8,137.0,133.2,131.3,128.7,128.7,126.8,117.8,114.3,113.6,112.7,109.8,15.9；MS(ESI)m378.3[M+H]+.
实施例九：N-(4-甲基-3-(4-呋喃基-2-)嘧啶基-2氧)苯基)-2-(4-甲基-哌嗪基-1)乙酰胺
按实施例三所述方法，用4-甲基-哌嗪基-1-乙酸制得标题化合物179毫克，产率88％。
该产物为淡黄色固体，熔点：150-152℃；1HNMR:(CDCl3,300MHz,ppm)δ8.86-8.73(m,1H),7.68-7.64(m,1H),7.51(s,1H),7.37-7.34(m,1H),6.82(d,J＝8.1Hz,1H),6.63-6.59(m,3H),3.55(s,2H),2.46(s,8H),2.36(s,4H),2.21(s,3H)；13CNMR(75MHz,CDCl3)δ172.1,168.5,167.6,157.7,156.2,136.5,142.9,136.5,130.2,129.8,117.4,112.0,111.6,110.3,107.1,61.5,54.1,52.1,45.0,15.0；MS(ESI)m408.3[M+H]+.
实施例十：N-(4-甲基-3-(4-呋喃基-2-)嘧啶基-2氧)苯基)-2-((4-甲基-哌嗪基-1)甲基)苯甲酰胺
按实施例三所述方法，用4-(4-甲基-哌嗪基-1-甲基)苯甲酸制得标题化合物183毫克，产率76％。
该产物为淡黄色固体，熔点：182-184℃；1HNMR:(CDCl3,300MHz,ppm)δ8.86-8.73(m,1H),7.68-7.64(m,1H),7.51(s,1H),7.37-7.34(m,1H),6.82(d,J＝8.1Hz,1H),6.63-6.59(m,3H),3.55(s,2H),2.46(s,8H),2.36(s,4H),2.21(s,3H)；13CNMR(75MHz,CDCl3)δ172.1,168.5,167.6,157.7,156.2,136.5,142.9,142.0,136.5,132.7,130.2,129.8,128.9,127.2,117.4,112.0,111.6,110.3,107.1,61.5,54.1,52.1,45.0,15.0；MS(ESI)m483.3[M+H]+.
实施例十一：N-(4-甲基-3-(4-呋喃基-2-)嘧啶基-2氧)苯基)-2-吗啉乙酰胺
按实施例三所述方法，用2-吗啉乙酸制得标题化合物169毫克，产率86％。
该产物为淡黄色固体，熔点：1612-163℃；1HNMR:(CDCl3,300MHz,ppm)δ8.77-8.74(m,1H),7.68-7.64(m,1H),7.58(s,1H),7.37-7.34(m,1H),6.94(d,J＝8.1Hz,1H),6.63-6.59(m,3H),3.76(t,J＝7.1Hz,2H),3.35(s,2H),2.51(t,J＝7.1Hz,2H),2.14(s,3H)；13CNMR(75MHz,CDCl3)δ172.1,168.5,167.6,156.2,150.2,136.5,142.9,136.5,130.2,129.8,117.4,112.0,111.6,110.3,107.1,63.7,61.5,54.1,15.0；MS(ESI)m395.3[M+H]+.
实施例十二：N-(4-甲基-3-(4-呋喃基-2-)嘧啶基-2氧)苯基)-2-羟基乙酰胺
按实施例三所述方法，用2-羟基乙酸制得标题化合物153毫克，产率94％。
该产物为淡黄色固体，熔点：162-163℃；1HNMR:(CDCl3,300MHz,ppm)δ8.77-8.74(m,1H),7.68-7.64(m,1H),7.58(s,1H),7.37-7.34(m,1H),6.94(d,J＝8.1Hz,1H),6.63-6.59(m,3H),4.35(s,2H),2.14(s,3H)；13CNMR(75MHz,CDCl3)δ175.1,168.5,167.6,156.2,150.2,136.5,142.9,136.5,130.2,129.8,117.4,112.0,111.6,110.3,107.1,63.2,15.4；MS(ESI)m326.6[M+H]+.
实施例十三：N-(4-甲基-3-(4-呋喃基-2-)嘧啶基-2氧)苯基)-2-氨基乙酰胺
按实施例三所述方法，用2-氨基乙酸制得标题化合物138毫克，产率85％。
该产物为淡黄色固体，熔点：172-174℃；1HNMR:(CDCl3,300MHz,ppm)δ8.77-8.74(m,1H),7.68-7.64(m,1H),7.58(s,1H),7.37-7.34(m,1H),6.94(d,J＝8.1Hz,1H),6.63-6.59(m,3H),4.67(s,2H),3.82(bs,2H),2.14(s,3H)；13CNMR(75MHz,CDCl3)δ172.3,168.5,167.9,156.7,150.7,136.6,142.9,136.5,130.4,129.8,117.4,113.0,111.6,110.3,107.1,43.2,15.2；MS(ESI)m325.2[M+H]+.
实施例十四：制备中间体4-甲基-3-(4-(苯并呋喃-2-)嘧啶基-2-氧)苯胺
按实例一所述方法，用2-乙酰基苯并呋喃制得标题化合物46克。
该产物为白色固体，熔点：138-140℃；1HNMR:(CDCl3,300MHz,ppm)δ8.48(d,J＝5.1Hz,1H),7.57(d,J＝7.8Hz,1H),7.54(d,J＝0.6Hz,1H),7.47(d,J＝8.3Hz,1H),7.42(d,J＝5.1Hz,1H),7.35-7.26(m,1H),7.26-7.14(m,2H),7.14-7.01(m,2H),6.62(s,1H),3.63(br,2H),2.14(s,3H)；MS(ESI)m/z318.3[M+H]+.
实施例十五：N-(4-甲基-3-(4-苯并呋喃-2-)嘧啶基-2氧)苯基)乙酰胺
将163毫克(0.5毫摩尔)4-甲基-3-(4-(萘基-1-)嘧啶基-2-氧)-苯胺溶于5毫升二氯甲烷中，依次加入冰醋酸(0.036克，0.6毫摩尔)，EDCI(0.12克，0.6毫摩尔)，HOBt(0.081克，0.6毫摩尔)，室温下搅拌1小时，反应完毕，反应液加15毫升二氯甲烷稀释，依次用10毫升水，10毫升饱和氯化钠洗涤，加无水硫酸钠干燥，旋干溶剂得浅黄色固体。粗品经柱层析分离，得白色固体174毫克，产率97％。
该产物为淡黄色固体，熔点：164-166℃；1HNMR:(CDCl3,300MHz,ppm)δ8.54(d,J＝5.1Hz,1H),7.88(s,1H),7.65(d,J＝7.7Hz,1H),7.61(s,1H),7.53(dd,J＝9.5Hz,6.8Hz,2H),7.39(dd,J＝8.3Hz,6.1Hz,2H),7.36-7.23(m,2H),7.19(d,J＝8.2Hz,1H),2.15(s,3H),2.07(s,3H)；13CNMR(75MHz,CDCl3)δ168.4,165.1,160.3,158.6,155.8,152.3,151.3,137.2,131.3,128.1,126.8,126.2,123.7,122.5,117.2,113.6,111.8,110.8,109.4,77.5,77.1,76.6,24.4,15.9；MS(ESI)m/z360.1[M+H]+.
实施例十六：N-(4-甲基-3-(4-苯并呋喃-2-)嘧啶基-2氧)苯基)丙酰胺
按实施例十五所述方法，用丙酸制得标题化合物172毫克，产率92％。
该产物为淡黄色固体，熔点：129-131℃；1HNMR:(CDCl3,300MHz,ppm)δ8.45(d,J＝5.1Hz,1H),7.63-7.49(m,3H),7.44(dd,J＝11.9Hz,6.7Hz,2H),7.38-7.22(m,3H),7.18(t,J＝7.5Hz,1H),7.10(d,J＝8.2Hz,1H),2.23(q,J＝7.5Hz,2H),2.07(s,3H),1.09(t,J＝7.5Hz,3H)；13CNMR(75MHz,CDCl3)δ165.1,160.3,158.5,155.8,152.4,151.4,137.2,131.3,128.1,126.74,123.7,122.5,117.1,115.0,115.0,113.6,111.8,110.8,109.4,30.6,15.9,9.6；MS(ESI)m/z374.3[M+H]+.
实施例十七：N-(4-甲基-3-(4-苯并呋喃-2-)嘧啶基-2氧)苯基)苯甲酰胺
按实施例十五所述方法，用丙酸制得标题化合物196毫克，产率93％。
该产物为淡黄色固体，熔点：191-193℃；1HNMR:(CDCl3,300MHz,ppm)δ8.54(d,J＝5.1Hz,1H),8.09(dd,J＝12.7,5.5Hz,1H),7.88-7.76(m,2H),7.69-7.58(m,2H),7.58-7.45(m,5H),7.45-7.32(m,3H),7.32-7.20(m,2H),2.18(s,3H)；13CNMR(75MHz,CDCl3)δ165.1,160.3,158.5,155.8,152.4,151.4,137.2,134.2,132.1,131.3,128.8,128.1,127.5,126.74,123.7,122.5,117.1,115.0,115.0,113.6,111.8,110.8,109.4,15.9；MS(ESI)m/z412.5.[M+H]+.
实施例十八：N-(4-甲基-3-(4-苯并呋喃-2-)嘧啶基-2氧)苯基)呋喃2-甲酰胺
按实施例十五所述方法，用呋喃-2-甲酸制得标题化合物175毫克，产率85％。
该产物为淡黄色固体，熔点：187-189℃；1HNMR:(CDCl3,300MHz,ppm)δ8.54(d,J＝5.1Hz,1H),8.09(dd,J＝12.7,5.5Hz,1H),7.88-7.76(m,2H),7.69-7.58(m,2H),7.58-7.45(m,5H),7.45-7.32(m,3H),7.32-7.20(m,2H),2.18(s,3H)；13CNMR(75MHz,CDCl3)δ165.1,160.5,158.5,155.9,155.85,152.5,151.6,147.8,144.2,136.4,131.4,128.2,126.7,126.7,123.6,122.5,117.2,115.2,113.8,112.6,111.8,110.7,109.3,16.0；MS(ESI)m/z412.5.[M+H]+.
实施例十九：N-(4-甲基-3-(4-苯并呋喃-2-)嘧啶基-2氧)苯基)呋喃3-甲酰胺
按实施例十五所述方法，用呋喃-3-甲酸制得标题化合物177毫克，产率86％。
该产物为淡黄色固体，熔点：176-178℃；1HNMR:(CDCl3,300MHz,ppm)δ8.42(d,J＝5.1Hz,1H),8.08(s,1H),7.90(s,1H),7.52(t,J＝5.8Hz,1H),7.46-7.33(m,5H),7.33-7.22(m,2H),7.16(t,J＝7.5Hz,1H),7.09(d,J＝7.9Hz,1H),6.63(d,J＝0.9Hz,1H),2.05(s,3H)；13CNMR(75MHz,CDCl3)δ165.0,160.9,160.4,158.5,155.8,152.3,151.4,145.2,143.8,136.8,131.4,128.1,126.8,126.6,123.7,123.0,122.5,117.8,114.2,111.8,110.8,109.4,108.5,15.9；MS(ESI)m/z412.3.[M+H]+.
实施例二十：N-(3-(4-(苯并呋喃-2-)嘧啶-2-氧)-4-甲基苯基)-4-((4-甲基哌嗪基团-1-)甲基)苯甲酰胺
按实施例十五所述方法，用4-(4-甲基-哌嗪基-1-甲基)苯甲酸制得标题化合物216毫克，产率81％。
该产物为淡黄色固体，熔点：241-243℃；1HNMR:(CDCl3,300MHz,ppm)δ9.14(s,1H),8.57(d,J＝5.1Hz,1H),7.66(d,J＝7.7Hz,1H),7.63(d,J＝0.8Hz,1H),7.60-7.50(m,2H),7.48(d,J＝2.0Hz,1H),7.45-7.36(m,2H),7.34-7.21(m,2H),3.11(s,2H),2.64(s,4H),2.48(s,4H),2.29(s,3H),2.18(s,3H)；13CNMR(75MHz,CDCl3)δ164.4,164.1,159.5,157.5,154.8,151.5,150.5,141.7,136.0,132.7,130.4,128.3,127.2,126.0,125.7,122.6,121.5,116.4,112.9,110.8,109.7,108.3,61.5,54.1,52.1,45.0,15.0；MS(ESI)m/z534.5[M+H]+.
实施例二十一：N-(3-(4-(苯并呋喃-2-)嘧啶-2-氧)-4-甲基苯基)-4-((4-哌嗪基团-1-)甲基)苯甲酰胺
按实施例十五所述方法，用4-(哌嗪基-1-甲基)苯甲酸制得标题化合物187毫克，产率72％。
该产物为淡黄色固体，熔点：211-213℃；1HNMR:(CDCl3,300MHz,ppm)δ9.14(s,1H),8.57(d,J＝5.1Hz,1H),7.66(d,J＝7.7Hz,1H),7.63(d,J＝0.8Hz,1H),7.60-7.50(m,2H),7.48(d,J＝2.0Hz,1H),7.45-7.36(m,2H),7.34-7.21(m,2H),3.11(s,2H),2.64(s,4H),2.48(s,4H),2.29(s,3H)；13CNMR(75MHz,CDCl3)δ164.4,164.1,159.5,157.5,154.8,151.5,150.5,141.7,136.0,132.7,130.4,128.3,127.2,126.0,125.7,122.6,121.5,116.4,112.9,110.8,109.7,108.3,61.5,54.1,52.1,45.0；MS(ESI)m/z520.3[M+H]+.
实施例二十二：N-(3-(4-(苯并呋喃-2-)嘧啶-2-氧)-4-甲基苯基)-2-(4-甲基哌嗪基-1-)乙酰胺
按实施例十五所述方法，用4-甲基-哌嗪基-1-乙酸制得标题化合物203毫克，产率89％。
该产物为淡黄色固体，熔点：193-195℃；1HNMR:(CDCl3,300MHz,ppm)δ8.58(d,J＝5.1Hz,1H),7.87(s,1H),7.79(d,J＝8.1Hz,2H),7.72-7.59(m,2H),7.59-7.53(m,2H),7.53-7.39(m,4H),7.39-7.27(m,2H),3.55(s,2H),2.46(s,8H),2.29(s,4H),2.21(s,3H)；13CNMR(75MHz,CDCl3)δ167.6,165.0,160.5,158.5,155.8,152.4,151.5,136.5,131.4,128.1,126.8,126.7,125.6,124.4,123.7,122.5,118.7,116.9,113.4,111.8,110.8,110.4,109.3,61.5,54.3,51.8,44.7,16.0；MS(ESI)m/z458.5[M+H]+.
实施例二十三：N-(3-(4-(苯并呋喃-2-)嘧啶-2-氧)-4-甲基苯基)-2-(吗啉-1-)乙酰胺
按实施例十五所述方法，用2-吗啉-1-乙酸制得标题化合物182毫克，产率82％。
该产物为淡黄色固体，熔点：176-178℃；1HNMR:(CDCl3,300MHz,ppm)δ8.99(s,1H),8.49(d,J＝5.1Hz,1H),7.64-7.51(m,2H),7.51-7.37(m,3H),7.32(dd,J＝7.9,6.7Hz,2H),7.26-7.12(m,2H),3.77-3.54(m,4H),3.03(s,2H),2.61-2.43(m,4H),2.10(s,3H)；13CNMR(75MHz,CDCl3)δ167.8,165.1,160.5,158.5,155.8,152.4,151.5,136.5,131.4,128.1,126.7,126.6,123.7,122.4,116.8,113.3,111.8,110.7,109.3,67.0,62.4,53.8,16.0；MS(ESI)m/z445.3[M+H]+.
实施例二十四：N-(3-(4-(苯并呋喃-2-)嘧啶-2-氧)-4-甲基苯基)-2-羟基乙酰胺
按实施例十五所述方法，用2-羟基乙酸制得标题化合物182毫克，产率82％。
该产物为淡黄色固体，熔点：157-159℃；1HNMR:(DMSO-d6,300MHz,ppm)δ9.83(s,1H),8.74(d,J＝5.1Hz,1H),7.98-7.66(m,4H),7.61(d,J＝8.2Hz,1H),7.56-4.43(m,3H),6.97(d,J＝8.0Hz,1H),5.68(s,1H),4.00(s,2H)；13CNMR(75MHz,DMSO-d6)δ167.6,165.0,160.5,158.5,155.8,152.4,151.5,136.5,131.4,128.1,126.8,126.7,125.6,124.4,123.7,122.5,118.7,116.9,113.4,111.8,110.8,110.4,109.3,47.6,15.8；MS(ESI)m/z376.3[M+H]+.
实施例二十五：N-叔丁氧羰基-(4-甲基-3-(4-苯并呋喃-2-)嘧啶基-2氧)4-甲基苯基-1-)甘氨酰胺
按实施例十五所述方法，用N-叔丁氧羰基甘氨酸制得标题化合物156毫克，产率83％。
该产物为淡黄色固体，熔点：189-191℃；1HNMR:(CDCl3,300MHz,ppm)δ8.48(d,J＝5.1Hz,1H),7.57(d,J＝7.8Hz,1H),7.54(d,J＝0.6Hz,1H),7.47(d,J＝8.3Hz,1H),7.42(d,J＝5.1Hz,1H),7.35-7.26(m,1H),7.26-7.14(m,2H),7.14-7.01(m,2H),6.62(s,1H),3.78(s,2H),1.35(s,9H)δ167.6,165.0,160.5,158.5,155.8,152.4,151.5,136.5,131.4,128.1,126.8,126.7,125.6,124.4,123.7,122.5,118.7,116.9,113.4,111.8,110.8,110.4,109.3,71.6,44.6,28.9,15.8；MS(ESI)m/z475.5[M+H]+.
实施例二十六：制备中间体4-甲基-3(4-(1-甲基-吲哚-2)吡啶-2氧)苯胺
按实例一所述方法，用1-甲基-2-乙酰基吲哚制得标题化合物63克。
该产物为淡黄色固体，熔点：137-139℃；1HNMR:(CDCl3,300MHz,ppm)δ8.48(d,J＝5.1Hz,1H),7.83(d,J＝7.8Hz,1H),7.16-7.35(m,6H),6.51(s,1H),3.92(s,3H),3.57(br,2H),2.14(s,3H)；MS(ESI)m/z331.3[M+H]+.
实施例二十七：4-甲基-3(4-(1-甲基-吲哚-2)吡啶-2氧)苯基)乙酰胺
将165毫克(0.5毫摩尔)4-甲基-3(4-(1-甲基-吲哚-2)吡啶-2氧)苯胺溶于5毫升二氯甲烷中，依次加入乙酸(0.6毫摩尔)，EDCI(0.12克，0.6毫摩尔)，HOBt(0.081克，0.6毫摩尔)，室温下搅拌1小时，反应完毕，反应液加15毫升二氯甲烷稀释，依次用10毫升水，10毫升饱和氯化钠洗涤，加无水硫酸钠干燥，旋干溶剂得浅黄色固体。粗品经柱层析分离，得白色固体173毫克，产率93％。
该产物为白色固体，熔点：168-170℃；1HNMR:(CDCl3,300MHz,ppm)δ8.52(d,J＝5.2Hz,1H),8.40(s,1H),7.86-7.97(m,1H),7.70-7.47(m,4H),7.31(d,J＝1.8Hz,1H),7.24(t,J＝7.4Hz,1H),6.99(t,J＝7.4Hz,1H),3.89(s,3H),2.10(s,3H),2.06(s,3H)；13CNMR(75MHz,CDCl3)δ168.7,165.3,164.6,159.1,151.9,138.9,138.0,134.0,131.3,126.0,125.1,122.8,122.7,121.4,116.2,113.4,112.1,110.8,110.7,33.6,24.4,15.9；MS(ESI)m/z373.4[M+H]+.
实施例二十八：4-甲基-3(4-(1-氢-吲哚-2)吡啶-2氧)苯基)丙酰胺
按实例二十七所述方法，用丙酸制得标题化合物178毫克，收率96％。
该产物为白色固体，熔点：159-161℃；1HNMR:(CDCl3,300MHz,ppm)δ8.44(d,J＝5.4Hz,1H),8.38(s,1H),7.82(d,J＝8.0Hz,1H),7.54(d,J＝1.8Hz,1H),7.52-7.40(m,3H),7.28(d,J＝8.3Hz,1H),7.20(t,J＝7.2Hz,1H),6.96(t,J＝7.3Hz,1H),2.29(q,J＝7.5Hz,2H),2.06(s,3H),1.06(t,J＝7.5Hz,3H)；13CNMR(75MHz,CDCl3)δ171.9,164.829,164.1,158.6,151.5,138.5,137.6,133.5,130.8,125.5,124.5,122.3,122.2,120.9,115.7,112.9,110.4,110.3,29.5,15.5,9.6；MS(ESI)m/z373.4[M+H]+.
实施例二十九：4-甲基-3(4-(1-甲基-吲哚-2)吡啶-2氧)苯基)苯甲酰胺
按实例二十七所述方法，用丙酸制得标题化合物193毫克，收率89％。
该产物为白色固体，熔点：193-195℃；1HNMR:(CDCl3,300MHz,ppm)δ8.47(d,J＝5.4Hz,1H),8.38(s,1H),8.02-7.91(m,2H),7.88(d,J＝8.0Hz,1H),7.79-7.66(m,2H),7.63-7.41(m,5H),7.36(d,J＝8.2Hz,1H),7.19(t,J＝7.6Hz,1H),6.99(t,J＝7.6Hz,1H),3.85(s,3H),2.12(s,3H)；13CNMR(75MHz,CDCl3)δ165.4,164.8,164.1,158.6,151.4,138.3,137.5,134.8,133.5,131.4,130.7,128.3,127.5,125.5,125.3,122.3,122.2,120.9,116.9,114.1,111.6,110.4,110.2,33.06,15.57；MS(ESI)m/z435.3[M+H]+.
实施例三十：4-甲基-3(4-(1-氢-吲哚-2)吡啶-2氧)苯基)2-呋喃甲酰胺
按实例二十七所述方法，用丙酸制得标题化合物178毫克，收率87％。
该产物为白色固体，熔点：177-179℃；1HNMR:(CDCl3,300MHz,ppm)δ8.47(d,J＝5.4Hz,1H),8.38(s,1H),7.92(d,J＝0.9Hz,1H),7.85(d,J＝8.0Hz,1H),7.71(dd,J＝5.8,2.0Hz,2H),7.53(d,J＝5.4Hz,1H),7.47(d,J＝8.2Hz,1H),7.33(dd,J＝8.5,4.9Hz,2H),7.26-7.12(m,1H),6.98(t,3.9Hz,1H),6.69(dd,J＝3.5,1.7Hz,1H),2.10(s,3H)；13CNMR(75MHz,CDCl3)δ164.8,164.1,158.6,156.1,151.4,147.3,145.6,137.7,137.6,133.5,130.8,125.5,125.4,122.3,122.2,120.9,116.9,116.2,114.6,114.5,114.1,112.8,111.5,110.3,110.2,15.5；MS(ESI)m/z411.3[M+H]+.
实施例三十一：4-甲基-3(4-(1-氢-吲哚-2)吡啶-2氧)苯基)3-呋喃甲酰胺
按实例二十七所述方法，用丙酸制得标题化合物170毫克，收率83％。
该产物为白色固体，熔点：186-188℃；1HNMR:(CDCl3,300MHz,ppm)δ8.47(d,J＝5.4Hz,1H),8.38(s,1H),8.01(d,J＝3.2Hz,1H),7.85(t,J＝6.8Hz,2H),7.72-7.61(m,2H),7.53(d,J＝5.4Hz,1H),7.47(d,J＝8.2Hz,1H),7.42-7.30(m,1H),7.20(t,6.2Hz,2H),6.98(t,J＝7.5Hz,1H),2.11(s,3H)；13CNMR(75MHz,CDCl3)δ164.8,164.1,162.5,159.8,158.6,151.5,144.3,139.9,137.9,137.6,133.6,131.8,130.8,129.0,128.8,128.0,127.8,125.6,125.5,125.1,122.3,122.2,120.9,116.9,116.8,114.1,111.5,110.4,110.2,15.5；MS(ESI)m/z410.3[M+H]+.
实施例三十二：N-(3-(4-(1-甲基吲哚-2-)嘧啶-2-氧)-4-甲基苯基)-2-(4-甲基哌嗪基-1-)乙酰胺
按实例二十七所述方法，用4-甲基-哌嗪基-1-乙酸制得标题化合物208毫克，收率76％。
该产物为白色固体，熔点：212-214℃；1HNMR:(CDCl3,300MHz,ppm)δ8.74(s,1H),8.57(d,J＝5.1Hz,1H),7.65-7.63(m,2H),7.60-7.50(m,2H),7.46(d,J＝2.0Hz,1H),7.42-7.21(m,4H),3.83(s,3H),3.28(s,2H),2.60-2.83(m,4H),2.45-2.56(m,4H),2.10(s,3H)；13CNMR(75MHz,CDCl3)δ164.7,164.1,162.5,160.0,158.6,152.6,144.3,140.0,137.9,137.6,133.6,131.8,130.9,129.0,128.9,128.0,127.5,125.6,125.6,125.1,122.3,122.0,120.9,116.9,116.8,114.1,111.5,110.4,110.2,61.5,54.1,52.1,45.0,33.1,15.6；MS(ESI)m/z547.3[M+H]+.
实施例三十三：N-(3-(4-(1-甲基吲哚-2-)嘧啶-2-氧)-4-甲基苯基)-4-((4-哌嗪基团-1-)甲基)苯甲酰胺
按实施例二十七所述方法，用4-(哌嗪基-1-甲基)苯甲酸制得标题化合物189毫克，产率71％。
该产物为淡黄色固体，熔点：228-230℃；1HNMR:(CDCl3,300MHz,ppm)δ8.65(s,1H),8.53(d,J＝5.1Hz,1H),7.65-7.63(m,2H),7.60-7.50(m,2H),7.48(d,J＝2.0Hz,1H),7.45-7.36(m,2H),7.34-7.21(m,2H),3.79(s,3H),3.19(s,2H),2.64(s,4H),2.48(s,4H),2.29(s,3H)；13CNMR(75MHz,CDCl3)δ167.3,164.1,158.5,157.7,154.8,151.5,150.5,141.9,136.0,132.7,130.4,128.3,127.2,126.0,125.7,122.6,121.5,116.4,112.9,110.8,109.7,108.1,54.1,52.1,45.0,33.1,15.6；MS(ESI)m/z533.3[M+H]+.
实施例三十四：N-(3-(4-(1-甲基吲哚-2-)嘧啶-2-氧)-4-甲基苯基)-2-(吗啉-1-)乙酰胺
按实施例二十七所述方法，用2-吗啉-1-乙酸制得标题化合物196毫克，产率86％。
该产物为淡黄色固体，熔点：243-245℃；1HNMR:(CDCl3,300MHz,ppm)δ8.77(s,1H),8.49(d,J＝5.1Hz,1H),7.64-7.37(m,5H),7.30(dd,J＝7.0,6.9Hz,2H),7.26-7.12(m,2H),3.85(s,3H),3.58-3.42(m,4H),3.25(s,2H),2.61-2.40(m,4H),2.10(s,3H)；13CNMR(75MHz,CDCl3)δ167.8,165.1,160.5,158.5,155.8,152.4,151.5,136.5,131.4,128.1,126.7,126.6,123.7,122.4,116.8,113.3,111.8,110.7,109.3,67.0,62.4,53.8,16.0；MS(ESI)m/z458.3[M+H]+.
实施例三十五：N-(3-(4-(1甲基吲哚-2-)嘧啶-2-氧)-4-甲基苯基)-2-羟基乙酰胺
按实施例二十七所述方法，用2-羟基乙酸制得标题化合物134毫克，产率69％。
该产物为淡黄色固体，熔点：176-178℃；1HNMR:(DMSO-d6,300MHz,ppm)δ8.89(s,1H),8.65(d,J＝5.1Hz,1H),7.98-7.61(m,1H),7.56-4.43(m,3H),6.97(d,J＝8.0Hz,1H),5.68(s,1H),4.03(s,2H),3.83(s,3H)；13CNMR(75MHz,DMSO-d6)δ168.6,164.3,161.2,158.5,155.8,152.4,151.5,136.5,131.4,128.1,126.8,126.7,125.6,124.4,123.7,122.5,118.7,116.9,113.4,111.8,110.8,110.4,109.3,47.6,33.0,16.0；MS(ESI)m/z389.3[M+H]+.
实施例三十六：N-叔丁氧羰基-(4-甲基-3-(4-(1-甲基吲哚-2-)嘧啶基-2氧)4-甲基苯基-1-)甘氨酰胺
按实施例二十七所述方法，用N-叔丁氧羰基甘氨酸制得标题化合物166毫克，产率68％。
该产物为淡黄色固体，熔点：236-238℃；1HNMR:(CDCl3,300MHz,ppm)δ8.86(d,J＝5.1Hz,1H),7.57-7.54(m,2H),7.45(d,J＝8.0Hz,1H),7.42(d,J＝5.1Hz,1H),7.38-7.20(m,3H),7.14-7.01(m,2H),6.58(s,1H),3.86(s,3H),3.78(s,2H),1.30(s,9H)；13CNMR(75MHz,CDCl3)δ168.9,165.1,161.0,159.0,155.0,152.3,152.4,136.5,131.4,128.1,126.8,126.7,125.6,124.4,123.7,122.5,118.7,116.9,113.4,111.8,110.8,110.4,109.3,71.6,44.6,33.2,28.9,16.0；MS(ESI)m/z488.3[M+H]+.
实施例三十七：制备中间体4-甲基-3-(4-苯基-嘧啶基-2-氧)苯胺
根据实施例一所述方法，用苯乙酮制得中间体4-甲基-3-(4-苯基-嘧啶基-2-氧)苯胺。
该产物为白色固体，熔点：127-129℃；1HNMR:(CDCl3,300MHz,ppm)δ8.52(d,J＝5.2Hz,1H),8.06-8.03(m,2H),7.47-7.38(m,4H),7.04(d,J＝8.6Hz,1H),6.52-6.50(m,2H),3.63(br,2H),2.07(s,3H)；MS(ESI)m/z278.3[M+H]+.
实施例三十八：N-(4-甲基-3-(4-苯基-嘧啶基-2氧)苯基)苯甲酰胺
将138毫克(0.5毫摩尔)4-甲基-3-(4-苯基嘧啶基-2-氧)-苯胺溶于5毫升二氯甲烷中，依次加入苯甲酸(0.073克，0.6毫摩尔)，EDCI(0.12克，0.6毫摩尔)，HOBt(0.081克，0.6毫摩尔)，室温下搅拌1小时，反应完毕，反应液加15毫升二氯甲烷稀释，依次用10毫升水，10毫升饱和氯化钠洗涤，加无水硫酸钠干燥，旋干溶剂得浅黄色固体。粗品经柱层析分离，得白色固体175毫克，产率92％。
该产物为白色固体，熔点：133-135℃；1HNMR:(CDCl3,300MHz,ppm)δ8.85(s,1H),8.37(d,J＝5.2Hz,1H),7.96(d,J＝6.3Hz,2H),7.74(d,J＝7.3Hz,2H),7.61(s,1H),7.30-7.41(m,5H),7.24(t,J＝7.4Hz,2H),7.13(d,J＝8.2Hz,1H),2.1(s,3H)；13CNMR(75MHz,CDCl3)δ167.2,166.3,165.2,159.8,151.4,137.4,135.8,134.8,131.6,131.4,131.3,128.9,128.5,127.4,127.2,126.5,117.8,114.3,111.7,16.0；MS(ESI)m/z382.3[M+H]+.
实施例三十九：本发明化合物抗肿瘤活性的测定
(1)试剂与细胞株
35株肿瘤细胞，包括口腔鳞癌(HSC-3)、肺癌(NCI-H520、SK-MES-1和CALU6)、肝癌(BEL7404、SMMC7721和Hep3B)、乳腺癌(MCF-7、MDA-MB-231和MDA-MB-436)、胆管癌(Huh-28)、胰腺癌(Capan-1)、胃癌(Ocum-1、AGS和SNU-638)、甲状腺髓样癌(TT)、黑色素瘤(Malme-3M)、肾癌(CAK1-1)、结直肠癌(SK-CO-1)、膀胱癌(HT-1376)、白血病(K562、HL60和JURKAT)、淋巴瘤(PF-382、Pfeiher和JEK0-1)、骨肉瘤(HU09)、多发性骨髓瘤(U266)、神经母细胞瘤(SH-SY5Y)、横纹肌肉瘤(A204)、前列腺癌(PC-13)、卵巢癌(SW1910)、宫颈癌(Hela)、头颈癌(PCI-13)和食管癌(EC9706)以及1株伊马替尼耐药小鼠BaF3-p210-T315I细胞株，均通过了支原体检测。
F12K培养液，美国Invitrgen，货号：21127-022
RPMI1640培养液，美国Invitrgen，货号：31800-022
MyCoys5A培养液，美国Invitrgen，货号：16600-082
DMEM培养液，美国Invitrgen，货号：12100-046
胎牛血清,美国Hyclone，货号：CH30160.03
青霉素-链霉素液体，美国Invitrogen，货号：15140-122
96孔细胞培养板，美国Corning，货号：3610
CellTiter-GloLuminescentCellViabilityAssay，美国Promega，货号：G7571
读板仪，美国PerkinElmer，EnVisionMultilabelPlateReader
(2)细胞培养液
F12K完全细胞培养液：含有10％胎牛血清和100U青霉素和100ug/ml链霉素的F12K培养液。MyCoys5A完全细胞培养液：含有10％胎牛血清和100U青霉素和100ug/ml链霉素的MyCoys5A培养液。DMEM完全细胞培养液：含有10％胎牛血清和100U青霉素和100ug/ml链霉素的DMEM培养液。RPMI1640完全细胞培养液：含有10％胎牛血清和100U青霉素和100ug/ml链霉素的RPMI1640培养液。
(3)化合物配制
用去离子水将化合物配制成10mM的母液，现用现配。
用去离子水将化合物母液稀释至一系列的梯度浓度溶液，这些浓度包括10mM，5mM，1mM，200μM，40μM，8μM，1.6μM，0.32μM，0.064μM。
仅在实验开始前，在无菌条件下将配制好的化合物梯度浓度溶液用完全细胞培养液稀释100倍，此时，化合物的梯度浓度包括100μM，50μM，10μM，2μM，0.4μM，0.08μM，16nM，3.2nM，0.64nM，此为2X化合物溶液，即可用来处理细胞。
(4)操作步骤
化合物处理前一天将肿瘤细胞接种在96孔细胞培养板中。接种密度为：2000细胞/50μL/孔或者4000细胞/50μL/孔，具体数量根据细胞生长速率决定。第二天，将配制好的2X化合物溶液加入到细胞培养板中，每孔加入50μL。轻轻震荡细胞板，将其放置在37℃培养箱中继续培养120小时。孵育结束后按照CellTiterGlo试剂说明书要求在细胞版中加入配制好的试剂，充分混匀后室温避光孵育10分钟。将细胞板放入读板仪进行分析，设定读取化学发光并记录数据。
(5)数据处理
将每孔中的读数使用如下所示公式转换成细胞存活率。处理后的数据将被用来做非线性回归分析，得到剂量效应曲线，并计算出各化合物对每种细胞的半数抑制浓度(IC50)。
(6)实验结果
肿瘤细胞增殖实验结果表明，本发明化合物对不同肿瘤细胞株的增殖均具有明显且很强的抑制活性。表1给出了本发明部分化合物的测试结果(化合物用对应的实施例名称来表示)。
表1本发明化合物对肿瘤细胞株的半数抑制浓度(IC50，μM)
表1(续1)
表1(续2)
表1(续3)
Claims (11)
1.一种4-杂环取代嘧啶类化合物及其药学上可成的盐，其特征在于，所述4-杂环取代嘧啶类化合物具有如下化学结构通式，
其中，
R1，R2相同或不同，代表氢，卤素，烷基，芳烷基，芳烷杂环基，环烷基，环状杂环基或环状杂烷化烷基；
Y代表二级氨基(-NH-)；
Z代表羰基
R3代表氢或烷基，烷氧基；
R4代表氢、取代或未取代的C1-C6的烷基，C3-C15的环烷基，取代或未取代的苯基，取代或未取代的芳烷基，五元或六元杂环基，五元或六元杂环烷基、五元或六元杂环基或五元或六元杂环烷基取代的烷基或芳香基；
R5代表其中，X代表N、O或S，R6，R7和R8相同或不同，代表氢，卤素，C1-C3的烷基，烷氧基，羟基，氨基或硝基；
或者其中，X代表N、O或S，R9，R10，R11，R12和R13相同或不同，代表氢，卤素，C1-C3的烷基，C1-C3烷氧基，羟基，氨基或硝基。
2.如权利要求1所述的4-杂环取代嘧啶类化合物及其药学上可接受的盐，其特征在于所述R1，R2相同或不同，代表氢，卤素，C1-C6的烷基，C3-C15的环烷基，C1-C6烷基取代的六元杂环。
3.如权利要求1所述的4-杂环取代嘧啶类化合物及其药学上可成的盐，其特征在于所述R4代表氢，C1-C6的烷基或者烷氨基取代的、氨基取代的或羟基取代的C1-C6的烷基，C3-C15的环烷基，苯基，苯烷基，卤素，氨基，羟基，硝基，C1-C6的烷基或烷氧基取代的苯基、五元或六元杂环基，五元或六元杂环烷基，五元或六元杂环基或五元或六元杂环烷基取代的烷基或苯基。
4.如权利要求3所述的4-杂环取代嘧啶类化合物及其药学上可成的盐，其特征在于所述五元或六元杂环选自呋喃，噻吩，吡咯，吡啶，四氢呋喃，四氢噻吩，四氢吡咯，四氢嘧啶，四氢哒嗪，四氢吡嗪或吗啉基。
5.如权利要求4所述的4-杂环取代嘧啶类化合物及其药学上可成的盐，其特征在于所述化合物化学结构通式中，
R1、R2代表氢，R3代表氢或甲基，Y代表-NH-；Z代表R5代表
R4代表—CH3，—CH2CH3，—CH2NH2，—CH2OH，—CH2NHBoc，
6.如权利要求1-5之一项所述4-杂环取代嘧啶类化合物及其药学上可成的盐在制备治疗人体血液类疾病、实体恶性肿瘤、细胞增生性疾病、代谢性疾病以及神经退行性疾病药物中的应用。
7.如权利要求6所述的应用，其特征在于所述人体血液性疾病是指淋巴细胞型和骨髓细胞型的血液肿瘤，包括急性淋巴细胞型白血病、急性原始淋巴型白血病、B型细胞淋巴瘤、T型细胞淋巴瘤、何杰金氏淋巴瘤、非何杰金氏淋巴瘤、毛状细胞淋巴瘤、Burkett氏淋巴瘤、急性髓细胞型淋巴瘤、慢性髓细胞型淋巴瘤、骨髓发育不全症和早幼粒细胞性白血病；所述的实体恶性肿瘤包括乳腺、卵巢、结肠、肺、脑、骨、呼吸道、胃、胰腺、前列腺、肝、胆、口腔、咽喉、膀胱、子宫、皮肤部位的肿瘤；
所述的增生性疾病包括血管增生性疾病、纤维增生性疾病以及肾小球细胞增生性疾病；
所述代谢性疾病包括牛皮藓、慢性伤口溃烂、炎症；
所述神经退行性疾病包括老年痴呆症。
8.如权利要求6所述的应用，其特征在于所述实体恶性肿瘤包括口腔鳞癌、肺癌、肝癌、乳腺癌、胆管癌、胰腺癌、胃癌、甲状腺髓样癌、黑色素瘤、肾癌、结直肠癌、膀胱癌、骨肉瘤、多发性骨髓瘤、神经母细胞瘤、横纹肌肉瘤、前列腺癌、卵巢癌、宫颈癌、头颈癌和食管癌。
9.如权利要求6所述的应用，其特征在于所述肿瘤包括肿瘤耐药的肿瘤。
10.一种组合物，其特征在于包含权利要求1-5之一项所述所述的4-杂环取代嘧啶类化合物及其药学上可成的盐以及药学上可接受的载体。
11.一种含有1-5之一项所述所述4-杂环取代嘧啶类化合物及其药学上可成的盐的药物制剂，其特征在于所述药物制剂可通过口服、静脉或皮下注射、透皮给药、肛门栓剂、口腔或鼻腔途径给药。
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