CN106543145A - c‑Met激酶抑剂3‑(4‑氟苯基)嘧啶酮‑5‑甲酸酰胺衍生物、制备方法与应用 - Google Patents

c‑Met激酶抑剂3‑(4‑氟苯基)嘧啶酮‑5‑甲酸酰胺衍生物、制备方法与应用 Download PDF

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CN106543145A
CN106543145A CN201610966753.7A CN201610966753A CN106543145A CN 106543145 A CN106543145 A CN 106543145A CN 201610966753 A CN201610966753 A CN 201610966753A CN 106543145 A CN106543145 A CN 106543145A
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fluorophenyls
pyrimidin
dihydro
amide
epoxides
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CN106543145B (zh
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李青山
胡龙勤
董红周
程璐
张晶
梁泰刚
班树荣
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Shanxi Medical University
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    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

本发明涉及一系列作为c‑Met酪氨酸激酶抑制剂的新型嘧啶衍生物及其制备方法与其用于治疗异常细胞的（例如癌症）增长。经药理学活性测试，本发明提供的式（I）化合物、其药学上可接受的盐具有良好的抗肿瘤活性，可用于治疗或预防与c‑Met抑制剂有关各种癌症。

Description

c-Met激酶抑剂3-(4-氟苯基)嘧啶酮-5-甲酸酰胺衍生物、制 备方法与应用
技术领域
本发明涉及一系列作为c-Met酪氨酸激酶抑制剂的新型嘧啶衍生物及其制备方法与其用于治疗异常细胞的(例如癌症)的增长。
背景技术
c-Met，也被称为肝细胞生长因子受体，是一种由c-Met原癌基因编码的蛋白产物，具有酪氨酸激酶活性。它能够与***产生的肝细胞生长因子(Hepatocyte growthfactor receptor，HGF)结合形成同源二聚体，从而激活多条下游信号传导通路，调节多种细胞反应，包括：促进细胞的生长、迁移和侵袭，血管生成，伤口愈合和组织再生。
正常的HGF/c-Met信号在不同细胞、不同分化阶段中参与多种生理过程，尤其是对胎盘发育、伤口愈合及肝再生起到关键作用。异常的HGF/c-Met信号通过自分泌、旁分泌和内分泌等产生的信号级联反应，导致细胞发生一系列的恶性转化。研究表明：c-Met和其配体HGF几乎参与恶性发展的所有阶段，在多种类型的肿瘤生成和转移中起到至关重要的作用。涉及c-Met高表达的各种恶性肿瘤包括，但不限于胃腺癌、肾癌、小细胞肺癌、结肠直肠癌、***癌、脑癌、肝癌、胰腺癌和乳腺癌。
通过以c-Met为药物靶点，可比较容易实现同时对多种通路进行干扰，从而干扰肿瘤的形成和转移。因此c-Met已经成为成为最有前途的药物靶点之一，研发c-Met蛋白激酶受体抑制剂的化合物存在迫切需求。
发明内容
本发明旨在提供一种可作为c-Met抑制剂并用于治疗c-Met介导的异常细胞(例如癌症)的增长，具体是一种具有c-Met激酶抑制活性的3-(4-氟-苯基)-4(3H)-嘧啶酮-5-甲酸酰胺衍生物及其制备方法与应用。
本发明是通过以下技术方案实现的：一种式(I)的化合物、其药学上可接受的盐，
其中：
R1选自氢，羟基，氨基，-O(CH2)nCH3，-NH(CH2)nCH3，-(CH2)nCH3，-NH(CH2)nR3，-O(CH2)nR3，-(CH2)nR3，-CN，-SH，被0-3个卤素取代的-O(CH2)nCH3、-NH(CH2)nCH3、-(CH2)nCH3、-NH(CH2)nR3、-O(CH2)nR3、-(CH2)nR3；其中n是0-6的整数；
每个R3选自式(II)、(III)、(IV)、(V)(VI)所示基团：
R2选自式(VII)、(VIII)、(IX)、(X)、(XI)所示的基团：
其中，R5选自-CH3以及(XII)、(XIII)、(XIV)、(XV)、(XVI)所示的基团：
上述内容中，-O(CH2)nCH3、-NH(CH2)nCH3、-(CH2)nCH3、-NH(CH2)nR3、-O(CH2)nR3、-(CH2)nR3均可被0-3个卤素取代。
优选的，所述药学上可接受的盐包括式(I)的化合物与下列酸形成的酸加成盐：盐酸、硫酸、磷酸、甲磺酸、苯磺酸、氢溴酸、对甲苯磺酸、酒石酸、乳酸、丙酮酸、乙酸、水杨酸、萘磺酸、柠檬酸、富马酸、琥珀酸、马来酸、苯基乙酸、杏仁酸；还包括无机碱的酸式盐。
进一步，所述无机碱的酸式盐的无机碱离子为铵阳离子、碱性金属阳离子、碱土金属阳离子。
另外本发明提供了一种化合物，选自下列化合物：
2-羟基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(6,7-二甲氧基喹啉-4-氧基)]酰胺；
2-甲氧基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(6,7-二甲氧基喹啉-4-氧基)]酰胺；
2-乙氧基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(6,7-二甲氧基喹啉-4-氧基)]酰胺；
2-苄氧基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(6,7-二甲氧基喹啉-4-氧基)]酰胺；
2-氨基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(6,7-二甲氧基喹啉-4-氧基)]酰胺；
2-甲氨基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(6,7-二甲氧基喹啉-4-氧基)]酰胺；
2-乙氨基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(6,7-二甲氧基喹啉-4-氧基)]酰胺；
2-[(3-吗啉丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(6,7-二甲氧基喹啉-4-氧基)]酰胺；
2-[(3-(1(1H)-咪唑)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(6,7-二甲氧基喹啉-4-氧基)]酰胺；
2-[(3-(1-吡咯烷基)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(6,7-二甲氧基喹啉-4-氧基)]酰胺；
2-[(3-(1-哌啶烷基)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(6,7-二甲氧基喹啉-4-氧基)]酰胺；
2-苄氧基-3-(4-氟苯基)-4-氧-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(7-吡咯并[2,3-d]嘧啶-4-氧基)]酰胺；
2-[(3-吗啉丙基)氨基]-3-(4-氟苯基)-4-氧-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(7-吡咯并[2,3-d]嘧啶-4-氧基)]酰胺；
2-[(3-(1-吡咯烷基)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(7-吡咯并[2,3-d]嘧啶-4-氧基)]酰胺；
2-[(3-(1-哌啶烷基)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(7-吡咯并[2,3-d]嘧啶-4-氧基)]酰胺；
2-羟基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-氧基]}酰胺；
2-氨基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-氧基]}酰胺；
2-甲氨基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-氧基]}酰胺；
2-乙氨基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-氧基]}酰胺；
2-[(3-吗啉丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-氧基]}酰胺；
2-[(3-(1(1H)-咪唑)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-氧基]}酰胺；
2-[(3-(1-吡咯烷基)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-氧基]}酰胺；
2-[(3-(1-哌啶烷基)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-氧基]}酰胺；
2-甲氨基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-(4-甲基-1-哌啶)丙氧基)喹啉-4-氧基]}酰胺；
2-乙氨基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-(4-甲基-1-哌啶)丙氧基)喹啉-4-氧基]}酰胺；
2-丙氨基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-(4-甲基-1-哌啶)丙氧基)喹啉-4-氧基]}酰胺；
2-[(3-吗啉丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-(4-甲基-1-哌啶)丙氧基)喹啉-4-氧基]}酰胺；
2-[(3-(1(1H)-咪唑)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-(4-甲基-1-哌啶)丙氧基)喹啉-4-氧基]}酰胺；
2-[(3-(1-吡咯烷基)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-(4-甲基-1-哌啶)丙氧基)喹啉-4-氧基]}酰胺；
2-[(3-(1-哌啶烷基)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-(4-甲基-1-哌啶)丙氧基)喹啉-4-氧基]}酰胺；
2-羟基-3-(4-氟苯基)-4-氧-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(7-吡咯并[2,3-d]嘧啶-4-氧基)]酰胺；
2-丙氧基-3-(4-氟苯基)-4-氧-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(7-吡咯并[2,3-d]嘧啶-4-氧基)]酰胺；
2-[(3-吗啉丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-(4-甲基哌嗪)丙氧基)喹啉-4-氧基]}酰胺；
2-[(3-(1(1H)-咪唑)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-(4-甲基哌嗪)丙氧基)喹啉-4-氧基]}酰胺；
2-[(3-(1-吡咯烷基)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-(4-甲基哌嗪)丙氧基)喹啉-4-氧基]}酰胺；
2-[(3-(1-哌啶烷基)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-(4-甲基哌嗪)丙氧基)喹啉-4-氧基]}酰胺；
2-[(3-吗啉丙基)氨基]-3-(4-氟苯基)-4-氧-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(7-吡咯并[2,3-d]嘧啶-4-氧基)]酰胺；
2-[(3-(1(1H)-咪唑)丙基)氨基]-3-(4-氟苯基)-4-氧-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(7-吡咯并[2,3-d]嘧啶-4-氧基)]酰胺；
2-[(3-(1-吡咯烷基)丙基)氨基]-3-(4-氟苯基)-4-氧-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(7-吡咯并[2,3-d]嘧啶-4-氧基)]酰胺。
进一步，本发明提供了上述的化合物、其药学上可接受的盐在制备抗肿瘤药物中的应用。
本发明另外一个目的是提供一种药物组合物，该药物组合物包含①，以及②、③、④中的至少一种物质；
所述①为上述任一化合物、其药学上可接受的盐；
所述②为药学上可接受的载体；
所述③为佐剂；
所述④为媒介物。
本发明所述的化合物、其药学上可接受的盐可与②、③、④中的至少一种物质制成适用于临床的药物制剂。所述载体可为上述任一化合物、其药学上可接受的盐的稀释剂或赋形剂。当载体作为稀释剂或赋形剂时，可以是固体、半固体或液体物质。本发明的药物组合物可以通过将活性组分和载体共混，或将其稀释于载体中，或将其包封或包囊在载体中(可以是胶囊、小袋、纸容器等形式)来制得。
本发明所述药物组合物可以制成适合所需给药方式的各种形式。例如，药物组合物可以制成片剂、丸剂、粉剂、袋剂、扁囊剂、悬浮剂、酏剂、乳剂、溶液、糖浆、气雾剂(作为固定或在液体基质中)、软凝胶胶囊、硬凝胶胶囊、栓剂、无菌注射液、无菌包装的粉末等。
进一步，本发明提供了所述的药物组合物在制备抗肿瘤药物中的应用。
为了更详细的说明本发明的技术方案，本发明提供了一种式(I)的化合物的制备方法，式(a)的化合物与式(b)的化合物在缩水剂(如HATU，HBTU，TBTU，或EDC/HOBt)以及有机碱(如N-甲基吗啉，三甲胺(TEA)或N,N-二异丙基乙胺(DIPEA))的存在下，在有机溶剂(如无水乙腈，DCM，NMP，DMF)中反应获得式(I)的化合物；当然，也可加入催化剂(如DMAP)来加快反应。式(I)的化合物的制备方法中缩水剂(如HATU，HBTU，TBTU，或EDC/HOBt)作为酰胺化试剂，有机碱(如N-甲基吗啉，三甲胺(TEA)或N,N-二异丙基乙胺(DIPEA))作为缚酸剂。当酰胺化试剂与缚酸剂同时存在可保证反应的顺利进行。其中：
式(a)的结构式为
式(b)的结构式为
其中R1与R2同上。
本发明使用的“Met”“c-Met”、“cMet”或“c-Met受体”是指肝细胞生长因子(HGF)受体及其形式。
本发明所述的抗肿瘤药物指用于治疗c-Met高表达的各种恶性肿瘤包括，但不限于胃腺癌、肾癌、小细胞肺癌、结肠直肠癌、***癌、脑癌、肝癌、胰腺癌和乳腺癌药物中的用途。
本发明式(I)的化合物可以如在以下反应路线I中所示合成，其中R1和R2如以上所定义。
反应路线I：
本发明式(a)的化合物能够如反应路线Ⅱ中所示制备，其中R1如以上所定义。以4-氟苯基硫脲和乙氧基甲叉基丙二酸二乙酯(DEMM)为起始原料，通过环合、烷基化、氧化、水解、加成、威廉姆逊醚合成、酯水解等一系列反应合成相应取代的嘧啶酮酸化合物。
反应路线Ⅱ：
本发明提供了一系列作为c-Met酪氨酸激酶抑制剂的新型嘧啶衍生物，经药理学活性测试，本发明提供的式(I)的化合物、其药学上可接受的盐具有良好的抗肿瘤活性，可用于治疗或预防与c-Met抑制剂有关各种癌症。
具体实施方式
制备例1
2-苄氧基-3-(4-氟苯基)-4-氧-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(7-吡咯并[2,3-d]吡啶-4-氧)]酰胺
在25ml的单口烧瓶中，分别加入化合物2-苄氧基-3-(4-氟-苯基)-4(3H)-嘧啶酮-5-甲酸(0.033mol)，HATU(0.036mol)，DIEPA(0.98mol)，4ml无水乙腈后，室温搅拌10min，待反应液颜色变黄，加入化合物4-(7-H吡咯并[2,3-d]吡啶-4-氧基)-3－氟苯胺(0.03mol)，TLC监测反应，待反应完成后，旋蒸除去溶剂，分别用10％柠檬酸(50ml×3)和饱和碳酸氢钠溶液(50ml×3)萃取，合并有机相，减压蒸发除去溶剂，柱层析纯化。得2-苄氧基-3-(4-氟苯基-4-氧-3,4-二氢嘧啶-5-甲酸[3-氟-4-(7-吡咯并[2,3-d]吡啶-4-氧)苯基]酰胺，收率为34％。1H-NMR(CDCl3,600MHz),δ:5.22(s,2H,ArCH 2O)；6.70(d,1H,ArH)；7.30-7.45(m,12H,ArH)；7.92(dd,1H,J＝10.8,3.0Hz,ArH)；8.29(s,1H,ArH)；8.98(s,1H,pyrimidine-6’-H)；10.99(s,1H,NH)；12.30(s,1H,pyrrole-NH)。13C-NMRδ:163.5,161.3,160.7,154.0,151.3,150.8,150.4,136.3,130.1,129.1,128.4,125.0,116.4,105.2,104.4,98.2,52.8。MS m/z(％):567.2(MH+,100％)。
以下化合物均是通过制备例1的方法来制备：
制备例2至制备例38核磁数据信息：
制备例2:1H-NMR(CDCl3,600MHz),δ:4.04(s,3H,-OCH 3,)；4.08(s,3H,-OCH 3,)；6.75(d,1H,ArH)；7.15-7.28(m,8H,ArH)；7.90(dd,1H,J＝10.8,3.0Hz,ArH)；8.47(d,1H,J＝1.3Hz,ArH)；8.61(s,1H,pyrimidine-6’-H)；10.23(d,1H,ArOH)；11.09(s,1H,NH).13C-NMRδ:163.7,161.4,159.9,153.5,152.5,150.6,149.3,149.3,146.8,131.7,130.8,130.7,124.6,117.0,116.5,116.0,115.7,108.3,104.3,102.6,99.4,56.2.MS m/z(％):547.1(MH+,100％).
制备例3:1H-NMR(CDCl3,600MHz),δ:3.60(s,3H,OCH 3)；4.04(s,3H,-OCH 3,)；4.08(s,3H,-OCH 3,)；6.47(d,1H,ArH)；7.33-7.45(m,8H,ArH)；7.90(dd,1H,J＝10.8,3.0Hz,ArH)；8.47(d,1H,J＝1.3Hz,ArH)；8.61(s,1H,pyrimidine-6’-H)；11.09(s,1H,NH).13C-NMRδ:163.7,161.0,159.7,153.1,152.6,150.9,149.9,149.3,146.8,131.3,131.2,130.1,124.6,117.0,116.5,116.3,115.0,108.3,104.0,102.5,99.4,56.2,37.9.MS m/z(％):561.1(MH+,100％).
制备例4:1H-NMR(CDCl3,600MHz),δ:1.49(t,3H,J＝10.8Hz,OCH2CH 3)；4.02(m,2H,J＝10.8Hz,OCH 2CH3)；4.10(s,3H,-OCH 3,)；4.14(s,3H,-OCH 3,)；6.75(d,1H,ArH)；7.35-7.57(m,8H,ArH)；8.00(dd,1H,J＝10.8,3.0Hz,ArH)；8.15(d,1H,J＝1.3Hz,ArH)；8.68(s,1H,pyrimidine-6’-H)；11.09(s,1H,NH).13C-NMRδ:163.7,161.0,159.7,153.1,152.6,150.9,149.9,149.3,146.8,131.3,131.2,130.1,124.6,117.0,116.5,116.3,115.0,108.3,104.0,102.5,99.4,63.2,56.2,15.4.MS m/z(％):575.3(MH+,100％).
制备例5:1H-NMR(CDCl3,600MHz),δ:4.04(s,3H,-OCH 3,)；δ4.08(s,3H,-OCH 3,)；5.13(s,2H,ArCH 2O)；6.45(d,1H,ArH)；7.35-7.57(m,13H,ArH)；8.12(dd,1H,J＝10.8,3.0Hz,ArH)；8.48(d,1H,J＝1.3Hz,ArH)；8.66(s,1H,pyrimidine-6’-H)；11.23(s,1H,NH).13C-NMRδ:163.5,160.8,159.6,153.1,151.3,150.8,149.9,149.3,146.8,137.3,136.3,130.1,129.2,128.5,128.4,124.6,117.1,116.5,116.3,115.0,108.3,105.2,102.6,99.4,56.2,52.8.MS m/z(％):637.2(MH+,100％).
制备例6:1H-NMR(DMSO,600MHz),δ:3.94(sd,6H,J＝2.4Hz,OCH 3,OCH 3,),6.45(d,1H,ArH),7.37-7.54(m,8H,ArH),8.12(dd,1H,J＝10.8,3.0Hz,ArH),8.48(d,1H,J＝1.3Hz,ArH),8.66(s,1H,pyrimidine-6’-H),11.23(s,1H,NH).13C-NMRδ:162.8,162.3,161.3,156.2,152.4,150.2,149.1,146.5,130.9,130.0,129.3,123.4,118.8,118.5,116.5,109.2,106.5,102.5,99.4,56.9,56.7.MS m/z(％):546.2(MH+,100％).
制备例7:1H-NMR(DMSO,600MHz),δ:2.0(s,3H,CH3),2.20(s,1H,pyrimidine-2’-NH),4.06(sd,6H,J＝2.4Hz,OCH 3,OCH 3,),6.43(d,1H,ArH),7.15-7.41(m,8H,ArH),8.12(dd,1H,J＝10.8,3.0Hz,ArH),8.48(d,1H,J＝1.3Hz,ArH),8.66(s,1H,pyrimidine-6’-H),11.23(s,1H,NH).13C-NMRδ:162.8,162.3,161.53,156.02,130.39,130.30,129.93,123.44,118.68,118.45,116.25,109.42,106.45,102.15,99.64,56.59,56.37,31.93,27.23.MS m/z(％):560.3(MH+,100％).
制备例8:1H-NMR(400MHz,DMSO-d)δ10.31(s,1H,NH),8.47(d,1H,J＝8.8Hz,ArH),7.87(dd,1H,J＝18,3Hz,ArH),7.53(s,1H,ArH),7.42(m,8H,ArH),6.43(d,1H,J＝7.8Hz,NH),3.95(s,6H,CH3-H),2.09(s,2H,CH3-H),1.21(t,3H,J＝10.8Hz,CH3-H)；13C-NMRδ:174.80,171.96,163.74,161.49,161.00,159.70,154.88–154.12,153.11,152.60,150.97,149.94,149.31,146.88,137.46,136.47(s),131.81,131.27,130.11,124.68,117.07,116.48,116.39,115.00,108.31,102.59,99.40,56.20,34.2,15.8；MS m/z:575.04[M+H]+.
制备例9:1H NMR(600MHz,CDCl3)δ11.04(s,1H),8.95(s,1H),8.48(d,J＝5.3Hz,1H),7.91(dd,J＝12.3,2.3Hz,1H),7.58(s,1H),7.41(s,1H),7.40–7.32(m,4H),7.30(d,J＝8.8Hz,1H),7.16(t,J＝8.7Hz,1H),6.41(d,J＝5.2Hz,1H),5.59(t,J＝5.2Hz,1H),4.05(s,3H),4.04(s,3H),3.61(dd,J＝12.0,6.3Hz,2H),3.49(d,J＝4.3Hz,4H),2.35(t,J＝6.3Hz,2H),2.31–2.28(m,4H),1.77–1.72(m,2H).13C NMR(151MHz,CDCl3)δ164.30,162.87,162.27,161.40,160.14,155.50,153.48,152.76,149.47,148.80,146.78,137.39,136.51,130.40,130.34,129.18,123.51,118.40,118.25,116.07,115.51,109.47,107.76,106.23,102.23,99.47,66.33(2C),56.62,56.11,56.05,53.68(2C),41.61,24.55.ESI-MS m/z:671.56[M-H]+.
制备例10:1H NMR(600MHz,CDCl3)δ11.02(s,1H),8.94(s,1H),8.48(d,J＝5.3Hz,1H),7.91(dd,J＝12.2,2.3Hz,1H),7.58(s,1H),7.41(s,1H),7.41–7.29(m,4H),7.29–7.27(m,2H),7.17(t,J＝8.7Hz,1H),7.01(s,1H),6.88(s,1H),6.42(d,J＝5.2Hz,1H),4.99(t,J＝5.3Hz,1H),4.05(s,3H),4.04(s,3H),4.02(t,J＝6.6Hz,2H),3.50(dd,J＝13.5,6.5Hz,2H),2.11(dt,J＝13.7,6.8Hz,2H).13C NMR(151MHz,CDCl3)δ162.79,162.65,162.22,161.14,160.34,156.35,155.71,153.47,152.96,149.64,148.49,146.44,137.38,136.59,130.46,130.29,130.23,128.71,123.54,118.42,118.27,118.05,116.14,115.51,109.51,107.45,106.64,102.24,99.50,56.14,56.12,53.77,39.61,30.25.ESI-MS m/z:652.60[M-H]+.
制备例11:1H NMR(600MHz,CDCl3)δ11.08(s,1H),8.95(s,1H),8.47(d,J＝5.3Hz,1H),7.91(dd,J＝12.4,2.3Hz,1H),7.58(s,1H),7.41(s,1H),7.36–7.30(m,5H),7.29(d,J＝1.2Hz,1H),7.15(t,J＝8.7Hz,1H),6.41(d,J＝5.2Hz,1H),4.05(s,3H),4.04(s,3H),3.63(t,J＝5.8Hz,2H),2.53–2.48(m,2H),2.26(s,4H),1.73–1.67(m,2H),1.48(s,4H).13CNMR(151MHz,CDCl3)δ164.10,163.05,162.50,16 1.44,160.16,155.64,155.10,152.75,149.45,148.80,146.75,137.49,136.48,130.27,129.46,123.46,118.04,117.88,116.03,115.51,109.42,109.27,107.75,105.70,102.2 3,99.47,56.18,56.10,56.04,54.04(2C),43.32,25.49,23.18(2C).ESI-MS m/z:655.53[M-H]+.
制备例12:1H NMR(600MHz,CDCl3)δ11.06(s,1H),8.95(s,1H),8.48(d,J＝5.3Hz,1H),7.91(dd,J＝12.4,2.3Hz,1H),7.58(s,1H),7.41(s,1H),7.38–7.32(m,4H),7.30(d,J＝9.9Hz,1H),7.15(t,J＝8.7Hz,1H),6.42(d,J＝5.2Hz,1H),4.05(s,3H),4.04(s,3H),3.61(t,J＝6.0Hz,2H),2.33(t,J＝6.0Hz,2H),2.19(s,3H),1.78(s,2H),1.71(dt,J＝12.2,6.1Hz,2H),1.34(d,J＝5.1Hz,2H),1.27(d,J＝5.0Hz,4H).13C NMR(151MHz,CDCl3)δ164.31,163.01,162.42,161.39,160.16,155.63,153.48,152.76,149.47,148.81,146.78,137.46,136.54,130.37,129.22,123.48,118.34,118.18,116.07,115.52,109.45,109.30,107.77,105.94,102.24,99.48,56.30,56.11,56.05,54.18,41.78(2C),24.45,24.16(2C),23.61.ESI-MS m/z:669.66[M-H]+.
制备例13:1H NMR(600MHz,CDCl3)δ11.04(s,1H),8.95(s,1H),8.46(d,J＝5.2Hz,1H),7.91(dd,J＝12.3,2.3Hz,1H),7.56(s,1H),7.43(s,1H),7.41–7.31(m,4H),7.30(d,J＝7.4Hz,1H),7.16(t,J＝8.7Hz,1H),6.41(d,J＝5.2Hz,1H),5.61(t,J＝5.2Hz,1H),4.26(t,J＝6.5Hz,2H),4.02(s,3H),3.61(dd,J＝12.0,6.2Hz,2H),3.55–3.42(m,4H),2.78(s,8H),2.68(t,J＝6.7Hz,3H),2.52(s,3H),2.36(t,J＝6.3Hz,2H),2.33–2.24(m,4H),2.14(p,2H),1.75(p,2H).13C NMR(151MHz,CDCl3)δ164.33,162.89,162.29,161.43,160.23,155.51,153.48,152.12,149.78,148.65,146.57,137.44,136.56,130.41,130.35,129.17,123.50,118.44,118.29,116.10,115.50,109.34,108.54,106.26,102.21,99.63,66.81,66.29(2C),56.60,56.10,54.26,53.67(2C),51.40(2C),44.82(2C),41.58,29.65,26.00,24.51.ESI-MS m/z:797.60[M-H]+.
制备例14:1H NMR(600MHz,CDCl3)δ11.01(s,1H),8.94(s,1H),8.46(d,J＝5.2Hz,1H),7.90(dd,J＝12.3,2.2Hz,1H),7.56(s,1H),7.40(s,1H),7.38–7.29(m,4H),7.29–7.27(m,2H),7.16(t,J＝8.7Hz,1H),6.99(s,1H),6.86(s,1H),6.40(d,J＝5.2Hz,1H),4.25(t,J＝6.7Hz,2H),4.02(s,3H),4.01(d,J＝6.5Hz,2H),3.49(dd,J＝12.7,6.3Hz,2H),2.58(t,J＝7.2Hz,3H),2.47(s,5H),2.29(s,3H),2.11(dt,J＝14.2,7.1Hz,4H),1.84(s,3H).13C NMR(151MHz,CDCl3)δ164.28,162.74,162.12,161.14,160.10,155.64,155.11,153.46,152.16,149.73,148.66,146.70,137.27,136.67,130.25,130.19,129.49,128.79,123.53,118.67,118.38,118.23,116.07,115.42,109.48,108.59,106.69,102.14,99.55,67.14,56.08(2C),54.77(2C),54.70,52.54,45.56,44.52,39.65,30.38,26.18.ESI-MS m/z:778.78[M-H]+.
制备例15:1H NMR(600MHz,CDCl3)δ11.07(s,1H),8.95(s,1H),8.46(d,J＝5.3Hz,1H),7.91(dd,J＝12.4,2.3Hz,1H),7.55(s,1H),7.41(s,1H),7.36–7.30(m,5H),7.29(d,J＝1.2Hz,1H),7.14(t,J＝8.7Hz,1H),6.40(d,J＝5.2Hz,1H),4.25(t,J＝6.7Hz,2H),4.02(s,3H),3.63(t,J＝5.8Hz,2H),2.57(t,J＝7.2Hz,3H),2.52–2.48(m,3H),2.45–2.17(m,11H),2.15–2.10(m,2H),1.73–1.68(m,2H),1.48(s,4H).13C NMR(151MHz,CDCl3)δ164.14,163.06,162.48,161.44,160.11,155.65,155.11,152.15,149.72,148.74,146.76,137.46,136.53,130.26,129.43,123.46,118.09,117.93,116.04,115.41,109.42,109.27,108.67,105.75,102.15,99.55,67.25,56.08,55.93,54.98(2C),54.81,54.00(2C),52.89(2C),45.82,43.06,26.26,25.43,23.19(2C).ESI-MS m/z:781.72[M-H]+.
制备例16:1H NMR(600MHz,CDCl3)δ11.06(s,1H),8.95(s,1H),8.46(d,J＝5.2Hz,1H),7.91(dd,J＝12.3,2.2Hz,1H),7.56(s,1H),7.41(s,1H),7.38–7.32(m,4H),7.30(d,J＝9.6Hz,1H),7.15(t,J＝8.7Hz,1H),6.40(d,J＝5.2Hz,1H),4.25(t,J＝6.7Hz,2H),4.02(s,3H),3.61(t,J＝6.0Hz,2H),2.58(t,J＝7.2Hz,3H),2.48(s,3H),2.33(t,J＝5.9Hz,2H),2.29(s,3H),2.19(s,5H),2.12(dt,J＝13.8,6.9Hz,2H),1.76(s,2H),1.71(dt,J＝11.8,6.0Hz,2H),1.34(d,J＝5.0Hz,2H),1.30–1.24(m,6H).13C NMR(151MHz,CDCl3)δ164.30,163.01,162.41,161.40,160.11,155.62,153.47,152.16,149.72,148.73,146.76,137.43,136.57,130.37,129.22,123.48,118.33,118.18,116.04,115.41,109.45,109.29,108.66,105.93,102.15,99.55,67.25,56.33,56.08(2C),54.97(2C),54.82,54.19,52.90(2C),45.82,41.85,26.26,24.48(2C),24.16,23.63.ESI-MS m/z:795.85[M-H]+.
制备例17:1H-NMR(600MHz,DMSO),δ11.52(s,1H,NH),11.02(s,1H,OH),8.69(s,1H,ArH),8.37(d,1H,J＝1.3Hz,ArH),8.11(dd,1H,J＝10.8,3.0Hz,ArH),7.57-7.34(m,8H,ArH),7.07(d,1H,J＝4.5Hz,ArH),6.25(d,1H,J＝3.2Hz,ArH),4.18(t,2H,J＝9.6Hz,CH2-H),3.92(s,3H,CH3-H),3.59(t,4H,J＝4.4Hz,ArH),2.46(t,2H,J＝10.2Hz,CH2-H),2.36(s,4H,CH2-H),2.0(m,2H,CH2-H)；13C-NMRδ:164.18,163.82,162.86,162.41,162.32,161.06,159.74,156.86,152.40,150.02,149.32,146.84,131.76,130.35,130.12,124.58,117.86,117.71,116.67,116.56,114.94,108.99,108.89,108.75,104.76,102.52,99.50,67.14,66.69,56.23,55.29,53.85,35.59；MS m/z:660.22[M+H]+.
制备例18:1H-NMR(DMSO,600MHz),δ:2.0(m,5H,NH2,CH2CH 2CH2),2.39(s,4H,NCH 2CH2O,NCH 2CH2O),2.47(t,2H,J＝10.8Hz,NCH 2CH2CH2O),3.94(s,3H,CH3),4.20(t,2H,J＝9.6Hz,NCH2CH2CH 2O),6.45(d,1H,ArH),7.37-7.54(m,8H,ArH),8.09(dd,1H,J＝10.8,3.0Hz,ArH),8.47(d,1H,J＝1.3Hz,ArH),8.66(s,1H,pyrimidine-6’-H),11.23(s,1H,NH).13C-NMRδ:174.7,163.0,162.9,161.7,159.7,158.6,152.3,150.0,149.3,146.8,131.3,131.3,130.1,124.5,117.7,117.5,108.9,104.2,99.5,67.1,66.6,56.2,55.2,53.8,35.6.MS m/z(％):657.3(MH-,100％).
制备例19:1H-NMR(400MHz,DMSO)δ11.24(s,1H,NH),8.73(s,1H,ArH),8.47(d,1H,J＝5.2Hz,ArH),8.02(dd,1H,J＝13.1,2.2Hz,ArH),7.62–7.35(m,8H,ArH),7.07(d,1H,J＝4.5Hz,ArH),6.45(d,1H,J＝5.1Hz,NH),4.20(t,2H,J＝6.4Hz,CH2-H),3.94(s,3H,CH3-H),3.59(t,4H,J＝4.4Hz,ArH),2.84(d,3H,J＝4.4Hz,),2.46(t,2H,J＝10.8,CH2-H),2.39(s,4H,CH2-H),1.98(m,2H,CH2-H)；13C-NMRδ:164.18,163.82,163.05,162.93,162.86,162.41,162.32,161.06,159.74,156.86,152.40,150.02,149.32,146.84,131.76,130.35,130.12,124.58,117.86,117.71,116.67,114.94,108.99,108.89,108.70,104.76,102.52,99.50,67.14,66.69,56.23,31.76,26.16；MS m/z:673.25[M+H]+.
制备例20:1H-NMR(DMSO,600MHz),δ:1.21(t,3H,J＝10.8Hz,NHCH2CH 3)；1.69(s,1H,NH)；3.52(m,2H,J＝10.8Hz,NHCH 2CH3)；2.39(s,4H,NCH 2CH2O,NCH 2CH2O)；2.47(t,2H,J＝10.8Hz,NCH 2CH2CH2O)；3.94(s,3H,CH3)；4.20(t,2H,J＝9.6Hz,NCH2CH2CH 2O)；6.45(d,1H,ArH)；7.37-7.54(m,8H,ArH)；8.09(dd,1H,J＝10.8,3.0Hz,ArH)；8.47(d,1H,J＝1.3Hz,ArH)；8.66(s,1H,pyrimidine-6’-H)；11.23(s,1H,NH).13C-NMRδ:174.8,163.2,162.9,1618,159.7,158.6,152.3,150.0,149.3,146.8,131.3,131.3,130.1,124.5,117.7,117.6,108.8,104.3,99.5,67.1,66.6,56.2,55.2,53.8,36.4,14.6.MS m/z(％):687.1(MH+,100％).
制备例21:1H NMR(600MHz,CDCl3)δ11.04(s,1H),8.95(s,1H),8.46(d,J＝5.3Hz,1H),7.91(dd,J＝12.3,2.3Hz,1H),7.56(s,1H),7.43(s,1H),7.41–7.31(m,4H),7.30(d,J＝10.2Hz,1H),7.16(t,J＝8.7Hz,1H),6.41(d,J＝5.2Hz,1H),5.63(t,J＝4.9Hz,1H),4.27(t,J＝6.6Hz,2H),4.03(s,3H),3.74(t,J＝4.1Hz,4H),3.61(dd,J＝12.0,6.2Hz,2H),3.51(s,5H),2.60(t,J＝7.0Hz,2H),2.52(s,4H),2.38(t,J＝6.3Hz,2H),2.33(s,5H),2.15(dt,J＝13.4,6.6Hz,3H),1.76(p,2H).13CNMR(151MHz,CDCl3)δ164.32,162.87,162.27,161.40,160.25,155.51,153.46,152.22,149.77,148.53,146.50,137.42,136.56,130.39,130.33,129.15,123.49,118.42,118.27,116.08,115.45,109.48,108.47,106.25,102.17,99.58,67.13,66.80(2C),66.21(2C),56.51,56.10,55.35,53.59(4C),41.47,25.83,24.47.ESI-MS m/z:784.46[M-H]+.
制备例22:1H NMR(600MHz,CDCl3)δ11.01(s,1H),8.95(s,1H),8.48–8.45(m,1H),7.90(d,J＝12.3Hz,1H),7.56(s,1H),7.42(d,J＝2.1Hz,1H),7.41–7.30(m,4H),7.28(dd,J＝5.2,2.7Hz,2H),7.17(t,J＝8.8Hz,1H),7.05–6.90(m,2H),6.87(d,J＝7.8Hz,1H),6.41(d,J＝5.2Hz,1H),4.27(t,J＝6.1Hz,2H),4.03(s,3H),4.02–3.94(m,2H),3.72(s,4H),3.53–3.47(m,2H),2.57(t,J＝7.1Hz,2H),2.48(s,4H),2.16–2.08(m,4H).13C NMR(151MHz,CDCl3)δ164.27,162.75,16 2.15,161.15,160.22,155.68,155.08,153.43,152.22,149.77,148.48,146.46,137.32,136.69,130.27,130.21,129.20,128.82,123.52,118.71,118.35,118.20,116.11,115.4 3,109.48,108.41,106.62,102.14,99.57,67.10,66.75(2C),56.08,55.32,53.55(2C),44.56,39.62,30.34,25.80.ESI-MS m/z:765.73[M-H]+.
制备例23:1H NMR(600MHz,CDCl3)δ11.08(s,1H),8.95(s,1H),8.47(d,J＝5.3Hz,1H),7.91(dd,J＝12.4,2.3Hz,1H),7.56(s,1H),7.42(s,1H),7.36–7.30(m,5H),7.30(d,J＝4.4Hz,1H),7.24–7.22(m,1H),7.15(t,J＝8.7Hz,1H),6.40(d,J＝5.2Hz,1H),4.26(t,J＝6.7Hz,2H),4.03(s,3H),3.72(t,J＝4.5Hz,5H),3.63(t,J＝5.9Hz,2H),2.57(t,J＝7.1Hz,2H),2.50(dd,J＝12.6,6.7Hz,7H),2.26(s,5H),2.15–2.10(m,2H),1.89–1.60(m,7H).13C NMR(151MHz,CDCl3)δ163.05,162.49,161.44,160.11,156.92,155.64,155.12,152.12,149.69,148.73,146.72,137.46,136.50,130.40,130.27,123.45,118.03,117.88,117.49,116.04,115.41,109.41,108.63,105.67,102.15,99.55,67.14,66.93(2C),56.07,55.32,54.03(2C),53.99,53.64(2C),53.37,25.94,25.49,23.18(2C).ESI-MS m/z:768.66[M-H]+.
制备例24:1H NMR(600MHz,CDCl3)δ11.11(s,1H),8.92(s,1H),8.48(d,J＝5.4Hz,1H),7.92(dd,J＝12.3,2.1Hz,1H),7.56(s,1H),7.49(s,1H),7.36–7.30(m,4H),7.29(d,J＝3.1Hz,1H),7.23–7.21(m,1H),7.15(t,J＝8.7Hz,1H),6.43(d,J＝5.3Hz,1H),4.26(t,J＝6.5Hz,2H),4.03(s,3H),3.75(t,J＝4.5Hz,4H),3.57(t,J＝6.2Hz,2H),3.46(t,J＝6.2Hz,2H),2.75(dd,J＝13.3,5.9Hz,4H),2.65–2.61(m,2H),2.55(s,4H),2.18–2.12(m,2H),2.02–1.98(m,2H),1.54(d,J＝1.7Hz,4H),1.25(s,2H).13C NMR(151MHz,CDCl3)δ166.78,163.03,162.48,161.29,160.56,159.04,156.84,155.95,152.38,149.87,148.07,137.56,136.41,130.40,123.48,118.27,118.12,117.91,117.76,116.14,109.51,109.35,107.83,106.05,102.17,99.60,67.10,66.48(2C),56.10,55.25,54.16,53.29(2C),53.07,53.04,39.42,25.48,23.58,22.80(2C),22.41.ESI-MS m/z:782.68[M-H]+.
制备例25:1H-NMR(DMSO,600MHz),δ:1.15(td，3H，J＝13.2，5.4Hz,Piperidine-4’-CH3)；1.24(s,4H,Piperidine-2’-H,Piperidine-4’-H)；1.58(dd,2H,J＝15.0,1.2Hz,Piperidine-4’-H)；1.87(t,2H,J＝16.8Hz,CH2CH 2CH2)；1.98(m,3H,NH2,CH2CH 2CH2)；2.44(t,2H,J＝10.2Hz，NCH 2CH2CH2O)；2.84(s,3H,NHCH 3),3.95(s,3H,OCH3)；4.18(t,2H,NCH2CH2CH 2O)；6.45(d,1H,ArH),7.38-7.54(m,8H,ArH)；8.02(dd,1H,J＝10.8,3.0Hz,ArH)；8.47(d,1H,J＝1.3Hz,ArH)；8.74(s,1H,pyrimidine-6’-H)；11.25(s,1H,NH).13C-NMRδ:163.0,162.8,161.0,159.7,156.8,152.4,150.0,149.3,146.8,131.7,131.6,130.3,130.1,124.5,117.8,117.7,116.6,114.9,108.9,104.7,102.5,99.5,67.2,56.2,55.2,53.9,34.5,30.9.MS m/z(％):685.4(MH+,100％).
制备例26:1H-NMR(DMSO,600MHz),δ:1.07(t,3H,J＝10.8Hz,NHCH2CH 3)；1.15(t，3H，J＝13.2Hz,Piperidine-4’-CH3)；1.24(s,4H,Piperidine-2’-H,Piperidine-4’-H)；1.58(dd,2H,J＝15.0,1.2Hz,Piperidine-4’-H),1.87(t,2H,J＝16.8Hz,CH2CH 2CH2)；1.98(m,3H,NH2,CH2CH 2CH2)；2.44(t,2H,J＝10.2Hz，NCH 2CH2CH2O)；2.85(s,2H,NHCH 2CH3)；3.95(s,3H,OCH3)；4.18(t,2H,NCH2CH2CH 2O)；6.45(d,1H,ArH)；7.38-7.54(m,8H,ArH)；8.02(dd,1H,J＝10.8,3.0Hz,ArH)；8.47(d,1H,J＝1.3Hz,ArH)；8.74(s,1H,pyrimidine-6’-H)；11.25(s,1H,NH).13C-NMRδ:162.7,161.2,159.9,156.7,152.4,150.0,149.3,146.9,131.4,130.2,124.5,117.8,117.7,116.6,115.7,108.9,104.7,102.8,99.6,67.3,56.3,55.2,53.9,37.3,14.7.MS m/z(％):699.5(MH+,100％).
制备例27:1H-NMR(DMSO,600MHz),δ:1.07(t,3H,J＝10.8Hz,NHCH2CH2CH 3)；1.15(t，3H，J＝13.2Hz,Piperidine-4’-CH3)；1.24(s,4H,Piperidine-2’-H,Piperidine-4’-H)；1.58(dd,2H,J＝15.0,1.2Hz,Piperidine-4’-H)；1.60(m,2H,J＝10.8Hz,NHCH2CH 2CH3)；1.87(t,2H,J＝16.8Hz,CH2CH 2CH2)；1.98(m,3H,NH2,CH2CH 2CH2)；2.44(t,2H,J＝10.2Hz，NCH 2CH2CH2O)；2.85(s,2H,NHCH 2CH2CH3)；3.95(s,3H,OCH3)；4.18(t,2H,NCH2CH2CH 2O)；6.45(d,1H,ArH)；7.38-7.54(m,8H,ArH)；8.02(dd,1H,J＝10.8,3.0Hz,ArH)；8.47(d,1H,J＝1.3Hz,ArH)；8.74(s,1H,pyrimidine-6’-H)；11.25(s,1H,NH).13C-NMRδ:163.0,162.8,161.0,159.7,156.8,152.4,150.0,149.3,146.8,131.7,131.6,130.3,130.1,124.5,117.8,117.7,116.6,114.9,108.9,104.7,102.5,99.5,67.2,56.2,55.2,53.9,42.7,23.2,11.9.MS m/z(％):711.6(MH-,100％).
制备例28:1H NMR(400MHz,CDCl3)δ11.04(s,1H),8.95(s,1H),8.46(d,J＝5.3Hz,1H),7.91(dd,J＝12.4,2.2Hz,1H),7.55(s,1H),7.35(ddd,J＝15.2,13.3,6.9Hz,6H),7.16(t,J＝8.7Hz,1H),6.40(d,J＝5.2Hz,1H),5.59(t,J＝5.2Hz,1H),4.24(t,J＝6.7Hz,2H),4.02(s,3H),3.66–3.58(m,3H),3.51–3.45(m,4H),2.92(d,J＝11.3Hz,2H),2.54(t,J＝7.3Hz,2H),2.35(t,J＝6.3Hz,2H),2.32–2.26(m,4H),2.13(p,2H),1.95(t,J＝11.2Hz,2H),1.74(p,J＝12.6,6.3Hz,3H),1.62(d,J＝12.6Hz,2H),1.41–1.31(m,1H),1.30–1.21(m,3H),0.92(d,J＝6.3Hz,3H).13C NMR(151MHz,CDCl3)δ164.32,162.88,162.27,161.41,160.11,15 5.51,153.49,152.04,149.70,148.74,146.71,137.37,136.63,130.40,130.35,129.18,123.51,118.42,118.27,116.07,115.49,109.48,108.74,106.25,102.20,99.60,67.24,66.33(2C),56.62,56.08,55.27,53.69(4C),41.61,33.46(2C),30.40,25.88,24.55,21.60.ESI-MS m/z:798.47[M+H]+.
制备例29:1H NMR(600MHz,CDCl3)δ11.00(s,1H),8.95(d,J＝4.6Hz,1H),8.46(dd,J＝6.8,3.5Hz,1H),7.90(d,J＝12.2Hz,1H),7.56(s,1H),7.41(d,J＝5.2Hz,1H),7.40–7.29(m,4H),7.29–7.27(m,2H),7.17(t,J＝8.6Hz,1H),7.06–6.91(m,2H),6.88(s,1H),6.40(d,J＝5.2Hz,1H),4.24(t,J＝6.6Hz,2H),4.02(s,3H),4.00(dd,J＝15.1,4.1Hz,2H),3.53–3.47(m,2H),2.92(d,J＝13.2Hz,2H),2.55(d,J＝7.2Hz,2H),2.12(ddd,J＝20.1,13.4,6.8Hz,4H),1.95(d,J＝12.3Hz,2H),1.63–1.60(m,4H),1.37–1.33(m,1H),0.92(d,J＝6.3Hz,3H).ESI-MS m/z:777.79[M-H]+.
制备例30:1H NMR(600MHz,CDCl3)δ11.07(s,1H),8.96(s,1H),8.46(d,J＝5.2Hz,1H),7.91(dd,J＝12.4,2.3Hz,1H),7.55(s,1H),7.40(s,1H),7.33(dt,J＝9.1,6.6Hz,4H),7.29(d,J＝1.2Hz,1H),7.23(d,J＝5.1Hz,1H),7.15(t,J＝8.7Hz,1H),6.40(d,J＝5.2Hz,1H),4.24(t,J＝6.7Hz,2H),4.02(s,3H),3.66–3.60(m,2H),2.92(d,J＝11.1Hz,2H),2.54(t,J＝7.3Hz,2H),2.52–2.48(m,2H),2.26(s,6H),2.17–2.10(m,2H),1.95(t,J＝11.1Hz,2H),1.84–1.64(m,6H),1.62(d,J＝12.4Hz,2H),1.38–1.32(m,1H),1.24(d,J＝8.4Hz,3H).13C NMR(151MHz,CDCl3)δ163.07,162.50,161.47,160.11,156.98,155.64,152.14,149.71,148.72,146.74,137.47,136.53,130.42,130.28,130.23,123.46,118.02,117.87,117.62,116.04,115.43,109.42,108.68,105.68,102.15,99.56,67.41,56.07,55.33,54.07(2C),54.05,53.86(2C),43.54,33.98(2C),30.61,26.27,25.51,23.19(2C),21.74.ESI-MSm/z:780.71[M-H]+.
制备例31:1H NMR(600MHz,CDCl3)δ11.06(s,1H),8.95(s,1H),8.46(d,J＝5.3Hz,1H),7.91(dd,J＝12.4,2.3Hz,1H),7.56(s,1H),7.41(s,1H),7.39–7.32(m,4H),7.30(d,J＝8.8Hz,1H),7.15(t,J＝8.7Hz,1H),6.40(d,J＝5.2Hz,1H),4.24(t,J＝6.7Hz,2H),4.02(s,3H),3.61(t,J＝6.0Hz,2H),2.92(d,J＝10.8Hz,2H),2.55(t,J＝7.2Hz,2H),2.33(t,J＝6.0Hz,2H),2.19(s,3H),2.14(dt,J＝13.7,6.8Hz,2H),1.95(t,J＝10.9Hz,2H),1.71(dt,J＝11.7,5.8Hz,4H),1.62(d,J＝12.8Hz,2H),1.35(dd,J＝16.2,11.0Hz,3H),1.27(dd,J＝9.9,6.0Hz,6H),0.92(d,J＝6.4Hz,3H).13C NMR(151MHz,CDCl3)δ164.35,163.03,162.45,161.43,160.12,155.61,153.49,152.07,149.71,148.77,146.76,137.50,136.58,130.39,129.28,123.48,118.34,118.19,116.06,115.47,109.46,109.31,108.76,105.93,102.19,99.59,67.31,56.50,56.11(2C),55.23,54.26(2C),53.79,42.06,33.71(2C),30.52,26.03,24.56(2C),24.20,23.71,21.66.ESI-MS m/z:794.83[M-H]+.
制备例32:1H-NMR(CDCl3,600MHz)；δ:6.69(d,1H,ArH)；7.19-7.34(m,8H,ArH)；8.02(dd,1H,J＝10.8,3.0Hz,ArH)；8.40(d,1H,J＝4.8Hz,ArH)；8.60(s,1H,ArH)；9.47(s,1H,ArOH)；10.85(s,1H,NH)；11.01(s,1H,pyrrole-NH).13C-NMRδ:163.6,162.0,161.5,157.9,156.6,151.0,144.5,131.3,130.8,130.1,125.1,124.6,117.8,116.8,109.4,108.7,104.4,98.8.MS m/z(％):477.1(MH+,100％).
制备例33:1H-NMR(CDCl3,600MHz),δ:5.22(s,2H,ArCH 2O)；6.70(d,1H,ArH)；7.30-7.45(m,12H,ArH)；7.92(dd,1H,J＝10.8,3.0Hz,ArH)；8.29(s,1H,ArH)；8.98(s,1H,pyrimidine-6’-H)；10.99(s,1H,NH)；12.30(s,1H,pyrrole-NH).13C-NMRδ:163.5,161.3,160.7,154.0,151.3,150.8,150.4,136.3,130.1,129.1,128.4,125.0,116.4,105.2,104.4,98.2,52.8.MS m/z(％):567.2(MH+,100％).
制备例34:1H-NMR(600MHz,DMSO)δ11.80(s,1H,NH),11.01(s,1H,ArH),8.98(s,1H,ArH),8.07(d,1H,J＝5.3Hz,ArH),7.97(d,1H,J＝12.7Hz,ArH),7.55–7.22(m,12H,ArH),6.37(d,1H,J＝5.3Hz,ArH),6.26(s,1H,NH),3.35(s,2H,CH2-H)；13C-NMRδ:163.54,163.13,161.50,160.80,157.54,154.87,153.24,151.56,151.35,150.84,144.70,137.33,136.98,136.33,131.80,131.35,130.61,130.11,129.77,129.19,128.49,127.84,127.34,126.69,126.63,125.37,124.33,116.92,116.42,109.85,109.10(d,J＝23.1Hz),105.21,101.19,97.21.MS m/z:566.46[M+H]+.
制备例35:1H NMR(600MHz,CDCl3)δ11.00(s,1H),8.95(s,1H),8.12(d,J＝5.5Hz,1H),7.88(dd,J＝12.4,2.3Hz,1H),7.40–7.33(m,4H),7.19(s,1H),7.14(t,J＝8.7Hz,1H),6.45(s,1H),6.41(d,J＝5.4Hz,1H),5.57–5.54(m,1H),4.30(t,J＝6.7Hz,1H),4.08(d,J＝6.7Hz,1H),3.61(dd,J＝12.0,6.3Hz,2H),3.49(s,4H),2.36(t,J＝6.3Hz,2H),2.30(s,4H),1.76–1.72(m,2H).13C NMR(151MHz,D2O)δ164.36,162.89,162.25,161.29,158.45,155.63,155.20,154.31,153.57,150.77,144.23,137.33,137.00,130.89,130.35,128.81,123.41,123.33,118.45,118.29,115.92,109.37,106.41,98.43,65.55(2C),55.88,53.15(2C),40.63,30.54.ESI-MSm/z:600.48[M-H]+.
制备例36:1H NMR(600MHz,DMSO)δ11.19(s,1H),8.71(s,1H),8.06(d,J＝5.4Hz,1H),7.97(dd,J＝13.1,2.2Hz,1H),7.49(ddd,J＝35.7,18.0,11.6Hz,5H),7.41(s,1H),7.40(s,1H),7.38–7.35(m,1H),7.32(t,J＝9.0Hz,1H),7.16(s,1H),7.14(s,1H),6.87(d,J＝10.4Hz,1H),6.36(d,J＝5.4Hz,1H),6.24(dd,J＝3.3,2.0Hz,1H),3.94(dd,J＝12.0,4.9Hz,2H),3.24(dd,J＝12.7,6.5Hz,2H),1.90(dd,J＝13.9,7.0Hz,2H).ESI-MS m/z:581.54[M-H]+.
制备例37:1H NMR(600MHz,CDCl3)δ11.04(s,1H),8.95(s,1H),8.13(d,J＝5.5Hz,1H),7.88(dd,J＝12.4,2.3Hz,1H),7.36–7.30(m,4H),7.28(d,J＝7.9Hz,1H),7.20(d,J＝1.5Hz,1H),7.14(dd,J＝18.2,9.4Hz,2H),6.44(d,J＝2.4Hz,1H),6.42(d,J＝5.5Hz,1H),3.65–3.61(m,2H),2.52–2.49(m,2H),2.27(s,4H),1.72–1.69(m,3H),1.49(s,4H).13C NMR(151MHz,CDCl3)δ164.16,163.05,162.47,161.37,158.38,155.70,155.21,153.56,151.10,144.31,137.30,137.06,130.26,123.45,123.30,118.12,117.96,115.88,110.37,109.32,109.17,105.91,101.45,98.27,53.96(2C),31.89,29.66,25.48,23.20(2C).ESI-MS m/z:584.60[M-H]+.
制备例38:1H NMR(600MHz,CDCl3)δ11.03(s,1H),8.95(s,1H),8.12(d,J＝5.5Hz,1H),7.88(dd,J＝12.4,2.1Hz,1H),7.37–7.31(m,4H),7.20(d,J＝1.9Hz,1H),7.14(t,J＝8.7Hz,1H),6.43(d,J＝2.8Hz,1H),6.42(d,J＝5.5Hz,1H),6.23(s,1H),3.60(t,J＝6.0Hz,2H),2.32(t,J＝6.0Hz,2H),2.19(s,4H),1.81(s,2H),1.71(dt,J＝12.0,6.0Hz,2H),1.34(d,J＝5.2Hz,2H),1.28(d,J＝4.9Hz,4H).13C NMR(151MHz,CDCl3)δ164.25,163.00,162.38,161.33,158.35,155.63,153.56,151.11,144.14,137.30,137.01,130.38,129.25,123.54,123.28,118.27,118.11,115.87,110.39,109.31,109.15,105.95,101.37,98.15,56.41,54.22(2C),41.89,24.56,24.30(2C),23.68.ESI-MS m/z:598.60[M-H]+.
制备例39
3-(4-氟-苯基)-2-硫代-2,4(1H,3H)-嘧啶二酮-5-甲酸乙酯：
将2.54g(15.0mol)的4-氟苯基硫脲和3.2mL(13.8mol)的DEMM依次加入到3.2mL浓盐酸与9.6mL乙醇的混合溶液中，在105℃下回流反应4h。TLC跟踪检测至反应结束。冷却后过滤，收集固体并用乙醇洗涤。即得到4.12g白色固体3-(4-氟-苯基)-2-硫代-2,4(1H,3H)-嘧啶二酮-5-甲酸乙酯(化合物2，对应反应路线中的(d))，产率94％。
制备例40
2-甲硫基-3-(4-氟-苯基)-4(3H)-嘧啶酮-5-甲酸乙酯：
在50mL单口烧瓶中，依次加入5.0g(17.1mol)的化合物2、15.0ml的甲醇、5.6ml(17.4mol)的CH3I、10mL的饱和碳酸氢钠溶液，室温搅拌过夜。冷却后用二氯甲烷萃取(1000mL×3)，合并有机相。减压蒸发除去溶剂。残余物用柱层析[洗脱剂：A＝V(石油醚)∶V(乙酸乙酯)＝1∶1]后得到5.1g白色的粉末状固体2-甲硫基-3-(4-氟-苯基)-4(3H)-嘧啶酮-5-甲酸乙酯(化合物3，对应反应路线中的(e))，产率98％。
制备例41
2-羟基-3-(4-氟-苯基)-4(3H)-嘧啶酮-5-甲酸乙酯：
在50mL的单口烧瓶中，依次加入3.0g(9.7mol)的化合物3、0.3g的过硫酸氢钾、4mL甲醇、1.0mL水，室温搅拌2h，反应结束后，用CH2Cl2萃取(1000mL×3)，合并有机相。减压蒸发除去溶剂。残余物柱层析后[洗脱剂：A＝V(石油醚)∶V(乙酸乙酯)＝1∶1]得到2.5g白色粉末状固体2-羟基-3-(4-氟-苯基)-4(3H)-嘧啶酮-5-甲酸乙酯(化合物4，对应反应路线中的(f))，产率93％。
制备例42
2-甲氧基-3-(4-氟-苯基)-4(3H)-嘧啶酮-5-甲酸乙酯：
在25mL的单口烧瓶中，依次加入60.0mg(21.5mmol)的化合物4、30.0mg(21.7mmol)的无水碳酸钾、4.0mL的无水丙酮、13.4μL(21.5mmol)的碘甲烷，室温搅拌2h，反应结束后，用乙酸乙酯萃取(50.0mL×3)，合并有机相。减压蒸发除去溶剂后柱层析[洗脱剂：A＝V(石油醚)∶V(乙酸乙酯)＝3∶1]纯化干燥得白色粉末状固体2-甲氧基-3-(4-氟-苯基)-4(3H)-嘧啶酮-5-甲酸乙酯(化合物5，对应反应路线中的(g))，产率91％。
以下化合物基本上通过制备例42的方法来制备：
制备例46
2-氨基-3-(4-氟-苯基)-4-氧代-3,4-二氢-嘧啶-5-甲酸乙酯：
在25mL的单口烧瓶中，加入60.0mg(0.20mol)的化合物3，0.20g(2.5mol)的醋酸铵，150℃回流反应2h，反应结束后，冷却至室温，用乙酸乙酯萃取(50.0mL×3)，合并有机相。减压蒸发除去溶剂。残余物用柱层析[洗脱剂：A＝V(石油醚)∶V(乙酸乙酯)＝1∶1]后得到49.0mg白色粉末状固体2-氨基-3-(4-氟-苯基)-4-氧代-3,4-二氢-嘧啶-5-甲酸乙酯(化合物6，对应反应路线中的(h))，产率91％。
制备例47
2-甲氨基-3-(4-氟-苯基)-4(3H)-嘧啶酮-5-甲酸乙酯
在0℃下，在25mL的单口烧瓶中，加入4.2mL冰醋酸，4.6mL的甲胺后，加入0.060g的化合物3，150℃回流反应2h，反应结束后，用乙酸乙酯萃取(50.0mL×3)，合并有机相。减压蒸发除去溶剂后，残余物用柱层析[洗脱剂：A＝V(石油醚)∶V(乙酸乙酯)＝1∶1]得到白色粉末状固体2-甲氨基-3-(4-氟-苯基)-4(3H)-嘧啶酮-5-甲酸乙酯(化合物7，对应反应路线中的(h))，产率89％。
以下化合物均是通过制备例47的方法来制备：
制备例54
2-甲氧基-3-(4-氟-苯基)-4-氧代-3,4-二氢-嘧啶-5-甲酸：
在25ml的单口烧瓶中，加入1.0g(3.42mol)的化合物5，用20ml的甲醇溶解后，加入6.8ml的NaOH(1mol/mL，6.84mol)溶液，室温搅拌，TCL监测反应进程至反应结束后，用稀盐酸(1mol/L)调至酸性，用乙酸乙酯(50.0mL×3)萃取，合并有机相，减压蒸发除去溶剂，残余物用柱层析[洗脱剂：A＝V(石油醚)∶V(乙酸乙酯)∶V(冰醋酸)＝4∶1∶0.06]得到2-甲氧基-3-(4-氟-苯基)-4-氧代-3,4-二氢-嘧啶-5-甲酸(化合物8，对应反应路线中的(a))，产率46％。
以下化合物基本上通过制备例54的方法来制备：
目标化合物体外抗肿瘤活性的测定：
GTL16细胞系来源于胃癌患者。由于基因扩增，GTL16表达高水平的c-Met受体酪氨酸激酶。GTL16的生长高度依赖于c-Met激酶活性；因此其用作监测c-Met激酶抑制剂的细胞活性试验。
将对数生长期的GTL-16人胃癌细胞用含0.5％胎牛血清(Gibco)的培养基(Gibco1640)制成细胞悬液，将其接种到96孔板中，每孔加入100μL，置37℃、5％CO2培养箱内培养24h，待其贴壁。将待测化合物用DMSO溶解后，用完全培养基稀释至相应浓度，将化合物设置浓度梯度：1000nmol/L，200nmol/L，40nmol/L，8nmol/L，1.6nmol/L后，待用。弃去旧培养基，每组加入含不同浓度药物的培养基(含胎牛血清0.5％)100μL，空白对照加同样的不含药的培养基(含血清0.5％)，每个浓度设置4个复孔，置37℃、5％CO2培养箱内培养72h。弃去旧培养基后，每孔加入100μL无血清培养基和10μL的5mg/mL的MTT溶液，继续置37℃、5％CO2培养箱内培养4h。吸弃孔内培养基，每孔均加100μLDMSO，震荡使结晶溶解。用酶标仪测量各孔的吸光度(波长)，使用Spotfire软件计算IC50。
制备例1-38所制备获得的化合物其体外活性测定结果(IC50，nM)见表1：
表1部分化合物体外GTL-16人胃癌细胞活性测试结果
药理学活性测试结果表明，本发明提供的上述化合物具有良好的抗肿瘤活性，可用于治疗或预防与c-Met抑制剂有关各种癌症。显然，本发明所包含的化合物、药学上可接受的盐远不止上述制备例中提及的，但本领域技术人员应认识到，本发明制备例未提及的式(I)的化合物、其药学上可接受的盐具有良好的抗肿瘤活性，可用于治疗或预防与c-Met抑制剂有关各种癌症。化合物、药学上可接受的盐只是对制备例中化合物作变化或替换，不会对它们在药物组合物中的效果明显有不利的影响。因此，本发明并非仅仅局限于前述制备例描述，而是由技术方案来确定的。

Claims (10)

1.一种式(I)的化合物、其药学上可接受的盐，
其中：
R1选自氢，羟基，氨基，-O(CH2)nCH3，-NH(CH2)nCH3，-(CH2)nCH3，-NH(CH2)nR3，-O(CH2)nR3，-(CH2)nR3，-CN，-SH，被0-3个卤素取代的-O(CH2)nCH3、-NH(CH2)nCH3、-(CH2)nCH3、-NH(CH2)nR3、-O(CH2)nR3、-(CH2)nR3；其中n是0-6的整数；
每个R3选自式(II)、(III)、(IV)、(V)(VI)所示基团：
R2选自式(VII)、(VIII)、(IX)、(X)、(XI)所示的基团：
其中，R5选自-CH3以及(XII)、(XIII)、(XIV)、(XV)、(XVI)所示的基团：
2.根据权利要求1所述的化合物、其药学上可接受的盐，其特征在于，所述药学上可接受的盐包括式(I)的化合物与下列酸形成的酸加成盐：盐酸、硫酸、磷酸、甲磺酸、苯磺酸、氢溴酸、对甲苯磺酸、酒石酸、乳酸、丙酮酸、乙酸、水杨酸、萘磺酸、柠檬酸、富马酸、琥珀酸、马来酸、苯基乙酸、杏仁酸；还包括无机碱的酸式盐。
3.根据权利要求2所述的化合物、其药学上可接受的盐，其特征在于，所述无机碱的酸式盐的无机碱离子为铵阳离子、碱性金属阳离子、碱土金属阳离子。
4.一种化合物，选自下列化合物：
2-羟基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(6,7-二甲氧基喹啉-4-氧基)]酰胺；
2-甲氧基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(6,7-二甲氧基喹啉-4-氧基)]酰胺；
2-乙氧基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(6,7-二甲氧基喹啉-4-氧基)]酰胺；
2-苄氧基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(6,7-二甲氧基喹啉-4-氧基)]酰胺；
2-氨基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(6,7-二甲氧基喹啉-4-氧基)]酰胺；
2-甲氨基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(6,7-二甲氧基喹啉-4-氧基)]酰胺；
2-乙氨基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(6,7-二甲氧基喹啉-4-氧基)]酰胺；
2-[(3-吗啉丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(6,7-二甲氧基喹啉-4-氧基)]酰胺；
2-[(3-(1(1H)-咪唑)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(6,7-二甲氧基喹啉-4-氧基)]酰胺；
2-[(3-(1-吡咯烷基)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(6,7-二甲氧基喹啉-4-氧基)]酰胺；
2-[(3-(1-哌啶烷基)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(6,7-二甲氧基喹啉-4-氧基)]酰胺；
2-苄氧基-3-(4-氟苯基)-4-氧-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(7-吡咯并[2,3-d]嘧啶-4-氧基)]酰胺；
2-[(3-吗啉丙基)氨基]-3-(4-氟苯基)-4-氧-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(7-吡咯并[2,3-d]嘧啶-4-氧基)]酰胺；
2-[(3-(1-吡咯烷基)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(7-吡咯并[2,3-d]嘧啶-4-氧基)]酰胺；
2-[(3-(1-哌啶烷基)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(7-吡咯并[2,3-d]嘧啶-4-氧基)]酰胺；
2-羟基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-氧基]}酰胺；
2-氨基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-氧基]}酰胺；
2-甲氨基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-氧基]}酰胺；
2-乙氨基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-氧基]}酰胺；
2-[(3-吗啉丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-氧基]}酰胺；
2-[(3-(1(1H)-咪唑)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-氧基]}酰胺；
2-[(3-(1-吡咯烷基)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-氧基]}酰胺；
2-[(3-(1-哌啶烷基)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-氧基]}酰胺；
2-甲氨基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-(4-甲基-1-哌啶)丙氧基)喹啉-4-氧基]}酰胺；
2-乙氨基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-(4-甲基-1-哌啶)丙氧基)喹啉-4-氧基]}酰胺；
2-丙氨基-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-(4-甲基-1-哌啶)丙氧基)喹啉-4-氧基]}酰胺；
2-[(3-吗啉丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-(4-甲基-1-哌啶)丙氧基)喹啉-4-氧基]}酰胺；
2-[(3-(1(1H)-咪唑)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-(4-甲基-1-哌啶)丙氧基)喹啉-4-氧基]}酰胺；
2-[(3-(1-吡咯烷基)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-(4-甲基-1-哌啶)丙氧基)喹啉-4-氧基]}酰胺；
2-[(3-(1-哌啶烷基)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-(4-甲基-1-哌啶)丙氧基)喹啉-4-氧基]}酰胺；
2-羟基-3-(4-氟苯基)-4-氧-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(7-吡咯并[2,3-d]嘧啶-4-氧基)]酰胺；
2-丙氧基-3-(4-氟苯基)-4-氧-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(7-吡咯并[2,3-d]嘧啶-4-氧基)]酰胺；
2-[(3-吗啉丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-(4-甲基哌嗪)丙氧基)喹啉-4-氧基]}酰胺；
2-[(3-(1(1H)-咪唑)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-(4-甲基哌嗪)丙氧基)喹啉-4-氧基]}酰胺；
2-[(3-(1-吡咯烷基)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-(4-甲基哌嗪)丙氧基)喹啉-4-氧基]}酰胺；
2-[(3-(1-哌啶烷基)丙基)氨基]-3-(4-氟苯基)-4-氧基-3,4-二氢嘧啶-5-甲酸{3-氟苯基-4-[6-甲氧基-7-(3-(4-甲基哌嗪)丙氧基)喹啉-4-氧基]}酰胺；
2-[(3-吗啉丙基)氨基]-3-(4-氟苯基)-4-氧-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(7-吡咯并[2,3-d]嘧啶-4-氧基)]酰胺；
2-[(3-(1(1H)-咪唑)丙基)氨基]-3-(4-氟苯基)-4-氧-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(7-吡咯并[2,3-d]嘧啶-4-氧基)]酰胺；
2-[(3-(1-吡咯烷基)丙基)氨基]-3-(4-氟苯基)-4-氧-3,4-二氢嘧啶-5-甲酸[3-氟苯基-4-(7-吡咯并[2,3-d]嘧啶-4-氧基)]酰胺。
5.权利要求1至4任一权利要求所述的化合物、其药学上可接受的盐在制备抗肿瘤药物中的应用。
6.一种药物组合物，包含①，以及②、③、④中的至少一种物质；
所述①为权利要求1至4任一权利要求所述的化合物、其药学上可接受的盐；
所述②为药学上可接受的载体；
所述③为佐剂；
所述④为媒介物。
7.权利要求6所述药物组合物在制备抗肿瘤药物中的应用。
8.一种式(I)的化合物的制备方法，其特征在于，式(a)的化合物与式(b)的化合物在缩水剂以及有机碱的存在下，在有机溶剂中反应获得式(I)的化合物；
式(a)的结构式为
式(b)的结构式为
其中R1与R2同权利要求1至3任一权利要求所述。
9.根据权利要求8所述的一种式(I)的化合物的制备方法，其特征在于，该制备方法的过程中添加有催化剂。
10.根据权利要求9所述的一种式(I)的化合物的制备方法，其特征在于，所述的催化剂为DMAP。
CN201610966753.7A 2016-10-28 2016-10-28 c-Met激酶抑剂3-(4-氟苯基)嘧啶酮-5-甲酸酰胺衍生物、制备方法与应用 Active CN106543145B (zh)

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