CN106957303A - 选择性AuroraA激酶抑制活性的喹唑啉衍生物及其制备方法以及应用 - Google Patents
选择性AuroraA激酶抑制活性的喹唑啉衍生物及其制备方法以及应用 Download PDFInfo
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- CN106957303A CN106957303A CN201710113511.8A CN201710113511A CN106957303A CN 106957303 A CN106957303 A CN 106957303A CN 201710113511 A CN201710113511 A CN 201710113511A CN 106957303 A CN106957303 A CN 106957303A
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Abstract
本发明公开了选择性Aurora A激酶抑制活性的喹唑啉衍生物及其制备方法以及应用。本发明公开了通式(I)或(II)所示的化合物或其药学上可以接受的盐、水合物、溶剂化物、多晶型物、互变异构体或前药，
Description
技术领域
本发明涉及选择性Aurora A激酶抑制活性的喹唑啉衍生物及其制备方法以及应用。
背景技术
有丝分裂是一个非常复杂并精密调控的进程，其结果是产生两个完全一样的子细胞。Aurora激酶(Aurora A，B，C)的三个高度同源的丝氨酸-苏氨酸蛋白激酶在调节有丝分裂的许多关键步骤发挥着重要作用。自1995年从Drosophila中发现Aurora激酶以来，随着人们发现这些激酶的缺失可导致严重的有丝分裂异常，这类激酶受到普遍关注。
Aurora A的表达和活性在细胞周期的G2/M期达到顶峰，在中心体的成熟和分化中起关键作用。Aurora B同样在有丝分裂过程中高度表达，激酶活性顶峰略晚于Aurora A。Aurora C的作用与Aurora B相似，一般在睾丸中高水平表达，可能在雄性动物中起到特殊作用。
近来，有报道称抑制Aurora B可能产生不稳定、多倍体细胞，其中一些细胞还能继续生存，同时抑制Aurora A、B激酶可能出现相互抵触的效果。此外，在一些乳腺癌患者中Aurora A的高表达与生存率的降低有相关性，而Aurora B的表达则与患者生存率高低无此相关性。因此，选择性Aurora激酶抑制剂对Aurora A和Aurora B抑制功能的区分以及肿瘤的靶向治疗都有着十分重要的作用。Aurora A和B高度同源，尤其在激酶区域(71％一致)，Aurora A与Aurora B在ATP结合区域仅有三个残基的区别，其中，在Aurora A中分别为Leu-215，Thr-217和Arg-220；而在Aurora B中则相对应地为Arg，Glu和Lys。现有的选择性Aurora A激酶抑制剂大部分利用Aurora A的Thr-217和Aurora B的Glu残基的结构差异来进行合理设计，从而实现对Aurora A激酶抑制的高选择性。
下列几种为代表性的处于临床研究阶段的选择性Aurora A激酶抑制剂结构。
CASI制药公司(原名EntreMed)开发的化合物ENMD 981693显示出较好的细胞活性，并且能选择性地抑制Aurora A激酶，其L-酒石酸盐(ENMD 2076)对Aurora A的抑制活性IC50值为14nM，而对Aurora B激酶的抑制活性为IC50＝350nM。ENMD 2076是一种可口服的多靶点激酶抑制剂，还可作用于VEGFR、Flt-3和FGFR3等靶点，可有效抗增殖、促进细胞凋亡、抗血管生成。目前以ENMD2076进行的晚期或转移性软组织肉瘤(NCT01719744)和卵巢癌(NCT01104675)II期临床试验已完成，正在进行的II期临床试验主要包括卵巢透明细胞癌(NCT01914510)、晚期转移性三阴性乳腺癌TNBC(NCT01639248)。
MLN 8237是Millennium制药公司研发的高效Aurora A激酶选择性抑制剂，也是目前Aurora激酶抑制剂中最有发展潜力的药物候选物，对Aurora A/B的选择性大于200倍，IC50值分别为1.2nM和396.5nM。MLN 8237是在同一公司前期开发的MLN 8054结构基础上优化而来，虽然对GABA受体仍有抑制活性，但脑血分配系数比MLN 8054有降低，所以并未产生类似MLN 8054的剂量限制性神经毒性。目前MLN 8237以单独用药与联合用药等方式开展的多项临床研究正处于临床I、II期(NTC00830518、NTC00853307、NTC01154816等)。
考虑到ENMD 2076具有良好的抗肿瘤活性和生物利用度，但对Aurora A激酶的选择性不够好，对Aurora A/B的选择性约25倍，且对其它激酶的选择性较差。杂萘酮类抑制剂对Aurora A激酶的IC50＝38nM，而对Aurora B激酶没有明显抑制活性，选择性大于1000倍。化合物的高选择性来源于杂萘酮2位N上连接的苯环，苯环与Aurora B的Glu残基形成较强立体位阻，使得化合物对Aurora B激酶无抑制活性；Aurora A在相应的位置是位阻较小的Thr残基，不会产生类似位阻，所以化合物具有较好的Aurora A抑制活性和选择性(J.Med.Chem.2011,54(1),312-319)。
本发明人前期基于ENMD 2076的结构，将嘧啶母核替换为喹唑啉类结构，并在喹唑啉的C-2位苯环和C-7位进行结构修饰，得到激酶抑制活性和抗肿瘤增殖性能更优的化合物，不过化合物对Aurora A激酶的选择性仍不够好。对化合物的结构进一步修饰，得到一系列喹唑啉2位直接连有芳基取代基的选择性Aurora A激酶抑制剂。特别的，化合物A-1和A-7对激酶的抑制活性以及对Aurora A激酶的选择性有了较大提升，对肿瘤细胞的抗增殖活性也较参考文献中的最优化合物(HCT116cells:IC50＝7.8μM)有所增强，化合物A-1和A-7对各种肿瘤细胞的抑制活性IC50值在0.45～4.85μM之间。
喹唑啉类选择性Aurora A激酶抑制剂的设计思路
现有技术中存在的先导化合物大部分为Aurora激酶抑制剂，而对于选择性AuroraA激酶抑制剂的开发力度却远远不够，对此，本发明提供了一系列高效选择性Aurora A激酶抑制剂，对肿瘤靶向治疗具有重大意义。
发明内容
本发明的目的在于提供选择性Aurora A激酶抑制活性的喹唑啉衍生物及其制备方法以及应用。
本发明所采取的技术方案是：
通式(I)或(II)所示的化合物或其药学上可以接受的盐、水合物、溶剂化物、多晶型物、互变异构体或前药，
其中，X是碳原子或者氮原子；Y是氮原子或者氧原子；n＝0或者1；
R1独立地选自氢、C1-C4的脂肪烃基中的一种；或者脂肪烃基、烷氧基羰基、取代或未取代的苯基、羟基烷基、烷氧基烷基、氨基羰基、单烷基或双烷基的氨基羰基、氨基烷基、烷基氨基烷基、二烷基氨基烷基、苯基氨基羰基、(N-杂环)羰基；或者无R1；
R2独立地选自氢或以下基团：卤素、-NO2、-OMe、-OEt、-CN、-CF3、-CF2R、-C(R)＝CR’2、-C(R)＝C(R’)(R”)、-C≡C-R、-OR、-SR、-S(O)R、-SO2R、-SO2NR2、-NR2、-OCO2R、-OC(O)NR2、-OC(O)R、-CO2R、-C(O)R、-C(O)NR2；对R2的定义中，所述的R、R’以及R”各自独立地选自H、未取代的低级烷基、苯基或者取代苯基；
R3选自i-Pr、取代或者没有取代的芳基或者杂环芳基，其中取代基选自卤素、-NO2、-CN、-CF3、-CF2R、-C(R)＝CR’2、-C(R)＝C(R’)(R”)、-C≡C-R、-OR、-SR、-S(O)R、-SO2R、-SO2NR2、-NR2、-OCO2R、-OC(O)NR2、-OC(O)R、-CO2R、-C(O)R、-C(O)NR2、-C(＝NR)-NR’2、-C(＝NR)-OR’、-NRC(＝NR’)-NR”2、-NRSO2R’、-NRSO2NR’2、-P(O)R2、-P(O)(OR)2中的一种；对R3的定义中，所述的R、R’以及R”各自独立地选自H、未取代的低级烷基、苯基或者取代苯基；
R4和R4’各自独立地选自氢、C1-C4的脂肪烃基、烷氧基羰基、取代或未取代的苯基、羟基烷基、烷氧基烷基、氨基羰基、单烷基或双烷基的氨基羰基、氨基烷基、烷基氨基烷基、二烷基氨基烷基、苯基氨基羰基、(N-杂环)羰基；或者，R4和R4’与通式(I)或(II)中吡唑形成双环的结构。
优选的，所述R1是H或者C1-C4的脂肪烃基。
优选的，所述R2选自氢、甲氧基、乙氧基、甲基、乙基、硝基、氰基中的一种。
优选的，所述R3选自取代苯基、苯甲酰基、2-吡啶基、3-吡啶基、4-吡啶基、萘基中的一种；其中苯基上取代基选自3-OMe、4-OMe、2-OMe、4-NO2、3-NO2、2-NO2、3-COOH、3-COOMe、3-COOEt、3-COOiPr、2-F、3-F、4-F、2-Cl、3-Cl、4-Cl、3-Cl-4-COOMe、3-OMe-4-COOMe、2-Cl-2-OMe、2-CONH2-3-F、3-CONH2、2-CH2OH、4-CONHMe、2,4-diOMe、2,5-diOMe、2-Me-4-OMe、2,4-diCl、3,4-diCl、2-吗啉基、3-吗啉基、4-吗啉基、3,4-亚甲二氧基、4-CH2COOEt、2-CN、3-CN、2-CF3或者3-CF3中的一种。
所述R3中含有氨基时，氨基的氮原子是自由碱形式或者药学可以接受的盐或者季铵盐。
优选的，R4和R4’各自独立地选自下列基团中的一种：甲基、环丙基、乙基、异丙基、丙基、叔丁基、环戊基、苯基、COOH、CO2Me、CH2OH、CH2OMe、CH2CH2CH2OH、CH2CH2CH2OMe、CH2CH2CH2OCH2Ph、CH2CH2CH2NH2、CH2CH2CH2NHCOOtBu、CONHiPr、CONHCH2CH＝CH2、CONHCH2CH2OMe、CONHCH2Ph、CONH(环己基)、CON(Et)2、CON(Me)(CH2Ph)、CONH(nPr)、CON(Et)(nPr)、CONHCH2CH(Me)2、CON(nPr)2、CO(3-甲氧基甲基1-吡咯基)、CONH(3-甲苯基)、CONH(4-甲苯基)、CONHMe、CO(1-吗啉基)、CO(4-甲基1-哌嗪基)、CONHCH2CH2OH、CONH2、CO(1-哌啶基)；或者R4和R4’与通式(I)或(II)中吡唑形成的双环结构为下列之一：
优选的，所述的喹唑啉衍生物具体选自下列结构式中的至少一种：
一种药物组合物，其特征在于：包括下列物质中的至少一种：a)化合物，b)该化合物在药学上可接受的盐，c)该化合物的水合物，d)该化合物的溶剂化物，e)该化合物的多晶型物，f)该化合物的互变异构体，g)该化合物的前药；其中，所述的化合物上述的通式(I)或(II)所示的化合物。
通式(I)或(II)所示的化合物或其药学上可以接受的盐、水合物、溶剂化物、多晶型物、互变异构体或前药在制备抑制Aurora A激酶的药物中的应用。
通式(I)或(II)所示的化合物或其药学上可以接受的盐、水合物、溶剂化物、多晶型物、互变异构体或前药在制备治疗和/或预防和/或延缓和/或辅助治疗和/或处理增殖性疾病的药物中的应用。
本发明的有益效果是：本发明公开的喹唑啉衍生物具有较好的Aurora A抑制活性和选择性，同时对肿瘤细胞的增殖有明显的抑制作用。目前对Aurora A的生理功能、分子结构、调节机制、与其他致癌基因、抑癌基因的关联、在肿瘤形成过程中的作用及机制已经有了许多阐述，也有实验显示Aurora A的过表达与多种传统化疗药物耐药性的产生有关。本发明药物有望与传统化疗药物联用，增强肿瘤杀伤效果，延长复发间隔，改善患者的生活质量。
具体实施方式
下面对上述的发明内容进一步说明。
一种药物组合物，其特征在于：包括下列物质中的至少一种：a)化合物，b)该化合物在药学上可接受的盐，c)该化合物的水合物，d)该化合物的溶剂化物，e)该化合物的多晶型物，f)该化合物的互变异构体，g)该化合物的前药；其中，所述的化合物上述的通式(I)或(II)所示的化合物。
通式(I)或(II)所示的化合物或其药学上可以接受的盐、水合物、溶剂化物、多晶型物、互变异构体或前药在制备抑制Aurora A激酶的药物中的应用。
通式(I)或(II)所示的化合物或其药学上可以接受的盐、水合物、溶剂化物、多晶型物、互变异构体或前药在制备治疗和/或预防和/或延缓和/或辅助治疗和/或处理增殖性疾病的药物中的应用。
优选的，所述的增殖性疾病为胃癌、结直肠癌、肺癌、乳腺癌、肝癌、前列腺癌、甲状腺癌、胰腺癌、膀胱癌、肾癌、脑瘤、颈癌、CNS(中枢神经系统)的癌症、恶性胶质瘤、骨髓增生病、动脉粥样硬化、白血病、肺纤维化、淋巴癌、风湿性疾病、慢性炎症、非淋巴网状系统肿瘤、冷球蛋白血症、丘疹性黏蛋白沉积症、家族性脾性贫血、多发性骨髓瘤、淀粉样变、孤立性浆细胞瘤、重链病、轻链病、恶性淋巴瘤、慢性淋巴细胞白血病、单核细胞白血病、半分子病、原发性巨球蛋白血症、原发性巨球蛋白血症紫癜、继发性良性单克隆丙种球蛋白病、溶骨性病变、急性淋巴细胞白血病、淋巴母细胞瘤、部分非霍奇金淋巴瘤、Sezary综合征、传染性单核细胞增多症、急性组织细胞增多症、毛细胞白血病、霍奇金淋巴瘤、结肠癌、直肠癌、肠道息肉、憩室炎、结肠炎、胰腺炎、肝炎、小细胞肺癌、神经母细胞瘤、神经内分泌细胞肿瘤、胰岛细胞瘤、甲状腺髓样癌、黑色素瘤、子宫癌、慢性肝炎、肝硬化、卵巢癌、视网膜母细胞瘤、胆囊炎、头颈部鳞癌、消化道恶性肿瘤、非小细胞肺癌、宫颈癌、睾丸肿瘤、膀胱癌、骨髓瘤中的至少一种。
如本发明所使用的，如果未提供具体的限定，本发明的术语具有下述含义。
“卤素”包括氟，氯，溴和碘。
“烷基”是指直链或支链的饱和烃基团，如C1-C20烷基，优选为C1-C12烷基，更优选为C1-C6烷基，再优选为C1-C4烷基，尤其是例如甲基(Me)，乙基(Et)，丙基(例如，正丙基和异丙基)，丁基(例如，正丁基，异丁基，叔丁基)，戊基(例如，正戊基，异戊基，新戊基)，正己基等。其中，在各取代烷基或烷基取代的基团中，烷基定义同上。
“低级烷基”是指C1-C4的烷基。
“治疗有效量”指的是在给予需要这样的治疗的哺乳动物时，足以有效治疗的通式化合物的量。治疗有效量将依赖于所用的治疗药剂的特定活性、患者的年龄、生理状况、其它疾病状态的存在、和营养状况而变化。此外，患者可能正接受的其它药物治疗将影响要给予的治疗药剂的治疗有效量的确定。
“治疗”意味着对于哺乳动物体内疾病的任何治疗，包括：
(Ⅰ)防止疾病，即造成疾病的临床症状不发展；
(Ⅱ)抑制疾病，即阻止临床症状的发展；和/或
(Ⅲ)减轻疾病，即造成临床症状的消退。
在许多情况下，本发明的化合物能够由于氨基和/或羧基基团、酸根、或与此类似的基团的存在而形成酸和/或碱性盐。
本发明的化合物还包括互变异构体形式。互变异构体形式来源于一个单键与相邻的双键交换并一起伴随一个质子的迁移。
药学上可接受的盐是指把母体化合物中的碱性基团转换成盐的形式。药学上可接受的盐包括，但不仅限于，碱性基团例如胺(氨)基的无机或有机酸盐类。本发明药学上可接受的盐可以由母体化合物合成，即母体化合物中的碱性基团与1-4当量的酸在一个溶剂系统中反应。合适的盐列举在Remington’s Pharmaceutical Sciences,17th ed.,MackPublishing Company,Easton,Pa.,1985,1418和Journal of Pharmaceutical Science,66,2,1977中。
药学上可接受的酸加成盐可以由无机和有机酸制备。由衍生酸加成盐的无机酸包括盐酸、氢溴酸、硫酸、硝酸、磷酸等。由衍生酸加成盐的有机酸包括乙酸、丙酸、乙醇酸、丙酮酸、草酸、苹果酸、丙二酸、琥珀酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸、苯磺酸等。衍生酸加成盐的无机酸和有机酸尤其选自盐酸、磷酸、硫酸、硝酸、高氯酸、氢溴酸、乙酸、苯甲酸和对甲苯磺酸。
该组合物优选被配制成单位剂型。术语“单位剂型”指的是适于用作给予人类受试者和其他哺乳动物的单一剂量的物理离散单位，每一单位含有计算出用以产生所需要的治疗有效的活性物质的预定的量以及相关的合适的药用赋形剂(如片剂、胶囊、安瓿)。通式(I)或(II)的化合物在广泛的剂量范围内是有效的并且通常给予有效药物量。优选地，对于口服给药，每个剂量单位包含10mg至2g的通式(I)或(II)化合物，更优选为10至700mg，而对于肠胃外给药，优选为10至700mg的通式(I)或(II)化合物，更优选为50至200mg。然而，应当明了，实际给予的通式(I)或(II)化合物的量将由医师根据有关的情况来确定，包括要治疗的病症，选择的给药途径，给予的实际化合物以及其相对活性，各个患者的年龄、体重、以及反应，患者症状的严重性等。
为了制备固体组合物如片剂，将主要的活性组分与药物赋形剂(或载体)进行混合以形成固体预配制组合物，其包含本发明的化合物的均匀混合物。当称这些预配制组合物为均匀的时候，它是指活性组分被均匀分散在整个组合物中，以致组合物可以容易地被细分成相同有效的单位剂型如片剂、丸剂以及胶囊剂。
本发明的片剂或丸剂可以被涂布或用其它方式被复合以提供一种具有延长作用优点的剂型，或保护片剂或丸剂免受胃中酸性条件的作用。例如，片剂或丸剂可以包括内剂量和外剂量成分，后者具有在前者之上的外皮的形式。可以用肠溶层来分隔两种成分，其中肠溶层用来阻止在胃中的崩解以及允许内成分完整进入十二指肠或被延迟释放。各种材料可以用于这样的肠溶层或涂层，上述材料包括许多高分子酸以及高分子酸与这样的材料如虫胶、十六烷醇、以及醋酸纤维素的混合物。
用于吸入法或吹入法的组合物包括在药学上可接受的含水溶剂或有机溶剂、或其混合物中的溶液和悬浮液，以及散剂。液体或固体组合物可以包含如上文所述的适宜的药用赋形剂。优选的，通过口服或鼻呼吸途径给予这些组合物以获得局部或全身效应。可以通过使用惰性气体来雾化在优选的药学可接受的溶剂中的组合物。可以直接从雾化装置吸入雾化溶液，或雾化装置可以连接于面罩帐状物、或间歇正压呼吸机。可以由以适当方式递送剂型的装置，优选口服或鼻途径，给予溶液、混悬剂、或散剂组合物。
本发明的化合物和药学上可接受的盐还包括溶剂化物或水合物的形式。一般来说，溶剂化物或水合物的形式与非溶剂化的或非水合的形式等同，并涵盖在本发明的范围内。本发明中的某些化合物有可能存在多晶体或无定形的形式。总的来说，所有的物理形式具有同等的用途，并且涵盖在本发明的范围内。
本发明还包括所述化合物的前药。前药是一个药理物质(药物)，由母体药物衍生而来。一旦进入体内，前药就被代谢转变成母体药物。前药可通过对母体药物的一个或多个官能团进行取代而制备，其取代基团在体内将被降解而释放出母体化合物来。前药的制备和使用可在T.Higuchi and V.Stella,“Pro-drugs as Novel Delivery Systems,”Vol.14of the A.C.S.Symposium Series和Bioreversible Carriers in Drug Design,ed.Edward B.Roche,American Pharmaceutical Association and Pergamon Press,1987中找到。
本发明还提供包括通式(I)或(II)化合物或其药学可接受的盐或其前药以及至少一种药学上可接受的载体的药物组合物。本发明的药物组合物可口服，针剂注射，喷雾吸入，皮外用，直肠用，鼻腔用，阴道用，腹腔用，或通过植入储液囊或透皮贴剂等途径而使用。
在另一个方面，本发明的具有由通式(I)或(II)表示的化合物或其药学上可以接受的盐、溶剂化物、多晶型物、互变异构体或前药，或者包括由通式(I)或(II)表示的化合物的药物组合物在抑制Aurora A激酶的药物中的应用。
在另一个方面，本发明提供用通式(I)或(II)化合物抑制Aurora A激酶的方法。包括将有效量的上述的由通式(I)或(II)表示的化合物，或其药学上可以接受的盐、溶剂化物、多晶型物、互变异构体、前药，或者包括由通式(I)或(II)表示的化合物的药物组合物用于抑制Aurora A激酶。
此处的“抑制Aurora A激酶活性”术语意味着，Aurora A激酶一旦与本发明的2,4,7-位取代的喹唑啉类衍生物接触，其活性相对于没有与该化合物接触的情况下有所下降。因此，本发明提供了一种用2,4,7,8-位取代的喹唑啉类衍生物与Aurora A激酶接触来抑制Aurora A激酶活性的方法。本发明的具有通式(I)或(II)的化合物主要用以抑制Aurora A激酶活性。本发明的具有通式(I)或(II)的化合物可用于抑制肿瘤细胞生长。
除了上面所描述的目的、特征和优点之外，本发明还有其它的目的、特征和优点。下面将参照，对本发明作进一步详细的说明。
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式(I)或(II)所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。
所属领域的技术人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其它化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其它化合物的制备。
下面的流程说明制备本发明化合物的通用方法。
反应方案I
化合物4通过反应方案I制备得到，其中R1，R3，R4和R4’具有如本发明所述定义。原料1与羧酸或酰氯等合成子反应生成酰胺键，之后关环生成喹唑啉酮衍生物2。化合物2与胺发生碳氮偶联反应生成化合物3。化合物3与吡唑衍生物发生直接氨基化反应得到化合物4。
反应方案II
化合物7通过反应方案II制备得到，其中R2，R3，R4和R4’具有如本发明所述定义。原料5与羧酸或酰氯等合成子反应生成酰胺键，之后关环生成喹唑啉酮衍生物6。化合物6与吡唑衍生物发生直接氨基化反应得到化合物7。
反应方案III
化合物11可以由方案III制备得到，其中R3，R4和R4’具有如本发明所述定义。化合物9由化合物8与相应的胺等发生碳氮偶联反应后，在钯碳与水合肼条件下还原水解生成。化合物9与相应的芳基酮在碘单质与二甲基亚砜条件下关环反应生成喹唑啉酮衍生物10。化合物10与吡唑衍生物发生直接氨基化反应得到化合物11。
反应方案IV
化合物15通过反应方案IV制备得到，其中R1，R3，R4和R4’具有如本发明所述定义。原料12与相应的芳基酮在碘单质与二甲基亚砜条件下关环反应生成喹唑啉酮衍生物13。化合物13再与胺发生碳氮偶联反应生成化合物14。化合物14与吡唑衍生物发生直接氨基化反应得到化合物15。
以下通过具体的实施例对本发明的内容作进一步详细的说明。
实施例1：
N-(5-甲基-1H-吡唑-3-基)-7-(4-哌啶甲酸乙酯-1-基)-4-氨基-2-苯基喹唑啉(A-1)
步骤1：7-氯-2-苯基喹唑啉-4(3H)-酮
室温下往2-氨基-4-氯苯甲酸(1.716g，10mmol)，K2CO3(4.146g，30mmol)和干燥乙腈(20mL)的混合物中逐滴加入苯甲酰氯(1.6mL，12mmol)，滴加完毕后加热到95℃搅拌过夜。反应用2N HCl水溶液淬灭，析出棕色固体。抽滤，水洗3次，干燥后得缩合物。将缩合物溶于乙酸酐(25mL)中加热回流2h。减压除去反应中乙酸和乙酸酐后加入乙酸铵，170℃下反应6h。反应体系由170℃冷却至80℃左右后倒入水中，大量固体析出，加入适量CH2Cl2剧烈搅拌后抽滤，用少量CH2Cl2和水洗涤得到目标物(1.225g，产率48％)。1H NMR(400MHz,DMSO-d6)δ:12.66(s,1H),8.19-8.13(m,3H),7.78(d,J＝1.6Hz,1H),7.63-7.52(m,4H).13C NMR(101MHz,DMSO-d6)δ:161.6,153.7,149.9,139.1,132.4,131.7,128.6,127.9,126.7,126.5,119.8ppm.MS(ESI+APCI)m/z 257.2[M+H]+.
步骤2：7-(4-哌啶甲酸叔丁酯-1-基)-2-苯基喹唑啉-4(3H)-酮
氮气保护下将7-氯-2-苯基喹唑啉-4(3H)-酮(1g，4.0mmol)，Pd2dba3(73mg，0.08mmol)，Xphos(152mg，0.32mmol)和NaOtBu(769mg,8mmol)溶于10mL干燥二氧六环后加入4-哌啶甲酸叔丁酯(1.482g，8mmol)，密封反应瓶。反应混合物在90℃下搅拌过夜。用饱和NH4Cl溶液淬灭。减压除去二氧六环后用加水稀释，二氯甲烷萃取3次，有机相浓缩后硅胶柱层析纯化，得到黄色固体(164mg,产率80％)。1H NMR(400MHz,DMSO-d6)δ:12.15(s,1H),8.16(d,J＝7.2Hz,2H),7.93(d,J＝8.8Hz,1H),7.58-7.53(m,3H),7.17(d,J＝7.6Hz,1H),7.02(s,1H),3.92(d,J＝12.8Hz,2H),3.35(s,1H),3.01(t,J＝11.4Hz,2H),1.88(d,J＝11.6Hz,2H),1.64-1.58(m,2H),1.41(s,9H).13C NMR(101MHz,DMSO-d6)δ:173.9,162.1,155.2,152.9,151.0,133.4,131.7,129.0,128.0,127.4,115.5,111.6,109.4,80.2,47.0,41.5,28.2,27.6ppm.MS(ESI+APCI)m/z 406.2[M+H]+.
步骤3：N-(5-甲基-1H-吡唑-3-基)-7-(4-哌啶甲酸叔丁酯-1-基)-4-氨基-2-苯基喹唑啉
将7-(4-哌啶甲酸叔丁酯-1-基)-2-苯基喹唑啉-4(3H)-酮(100mg，0.45mmol)和PyBrop(273mg，0.59mmol)溶于6mL干燥乙腈中加入DBU(100μL，1.5mmol)在室温下搅拌30min后，反应体系变澄清，随后加入3-氨基-5-甲基吡唑(88mg，0.9mmol)。反应混合物在70℃下搅拌2天，体系中有大量黄色固体析出。冷却至室温后抽滤，用少量乙腈洗涤可得较纯粗产品，进一步通过硅胶柱层析两次(CH2Cl2/MeOH，V:V＝20:1～10:1)纯化得到黄色固体(58mg，产率42％)。1H NMR(400MHz,DMSO-d6)δ:13.70(s,1H),11.55(s,1H),8.60(d,J＝9.2Hz,1H),8.27(d,J＝7.2Hz,2H),7.78-7.69(m,3H),7.49(d,J＝7.2Hz,1H),7.26(s,1H),6.62(s,1H),4.00(d,J＝13.2Hz,2H),3.19(t,J＝11.8Hz,2H),2.65-2.60(m,1H),2.33(s,3H),1.94(d,J＝11.2Hz,2H),1.60(dd,J＝11.2,10.4Hz,2H),1.42(s,9H).13C NMR(101MHz,DMSO-d6)δ:173.3,158.1,156.5,153.9,146.8,138.9,135.5,135.5,131.4,128.6,128.2,124.9,116.5,104.1,103.8,97.8,79.7,46.3,40.9,27.7,27.1,11.0ppm.MS(ESI+APCI)m/z 483.2[M-H]-.
步骤4：N-(5-甲基-1H-吡唑-3-基)-7-(4-哌啶甲酸乙酯-1-基)-4-氨基-2-苯基喹唑啉
将N-(5-甲基-1H-吡唑-3-基)-7-(4-哌啶甲酸叔丁酯-1-基)-4-氨基-2-苯基喹唑啉(185mg，0.38mmol)溶于20mL干燥乙醇中，体系冷却到0℃后缓慢滴加二氯亚砜(0.08mL，1.15mmol)，在室温下搅拌2h后体系升温至80℃回流过夜。减压除去溶剂后用饱和Na2CO3溶液调节体系pH值至11左右，直接硅胶柱层析纯化得目标产物(120mg，产率69％)。1H NMR(400MHz,DMSO-d6)δ:12.15(s,1H),10.06(s,1H),8.46(d,J＝6.8Hz,3H),7.54-7.48(m,3H),7.29(d,J＝8.8Hz,1H),7.06(s,1H),6.76(s,1H),4.09(q,J＝7.0Hz,2H),3.96(d,J＝12.8Hz,2H),3.01(t,J＝11.2Hz,2H),2.61(t,J＝11.2Hz,1H),2.33(s,3H),1.94(d,J＝11.2Hz,2H),1.67(dd,J＝11.2,11.2Hz,2H),1.19(t,J＝7.2Hz,3H).13C NMR(101MHz,DMSO-d6)δ:174.6,160.0,157.1,154.0,152.8,148.6,139.5,138.6,130.4,128.75,128.3,124.6,116.8,108.8,106.2,97.9,60.4,47.2,27.6,14.6,11.4ppm.MS(ESI+APCI)m/z457.2[M+H]+.
实施例2：
N-(5-甲基-1H-吡唑-3-基)-7-(4-哌啶甲酸-1-基)-4-氨基-2-苯基喹唑啉(A-2)
步骤1、2和3分别与实施例1的步骤1、2和3相同。
步骤4：N-(5-甲基-1H-吡唑-3-基)-7-(4-哌啶甲酸-1-基)-4-氨基-2-苯基喹唑啉
将N-(5-甲基-1H-吡唑-3-基)-7-(4-哌啶甲酸-1-基)-4-氨基-2-苯基喹唑啉(125mg，0.26mmol)溶于TFA/CH2Cl2(V:V＝1:1)的混合溶剂中搅拌4小时，减压除去溶剂后用饱和NaHCO3溶液调节pH值为中性，用硅胶柱层析(CH2Cl2/MeOH，V:V＝20:1～10:1)纯化得到黄色固体(122mg，产率99％)。1H NMR(400MHz,DMSO-d6)δ:12.36(s,1H),10.83(s,1H),8.52(d,J＝9.6Hz,1H),8.38-8.35(m,2H),7.62-7.60(m,4H),7.39(d,J＝7.2Hz,1H),7.19(s,1H),6.66(s,1H),3.98(d,J＝13.2Hz,2H),3.11(t,J＝11.2Hz,2H),2.62-2.56(m,1H),2.33(s,3H),1.97-1.91(m,2H),1.70-1.60(m,2H).13C NMR(101MHz,DMSO-d6)δ:176.1,158.6,158.5,158.3,157.0,154.4,147.2,139.4,132.0,129.2,128.8,125.5,119.2,117.0,116.2,98.3,46.9,27.6,11.5ppm.HRMS(ESI-TOF):m/z calcd.for C24H25N6O2[M+H]+:429.2034；found:429.2019.
实施例3：
N-(5-甲基-1H-吡唑-3-基)-7-(4-哌啶甲酸叔丁酯-1-基)-4-氨基-2-(2,6-甲氧基苯甲酰基)喹唑啉(A-3)
步骤1：2-(2,6-甲氧基苯甲酰基)喹唑啉-4(3H)-酮
化合物2-(2,6-甲氧基苯甲酰基)喹唑啉-4(3H)-酮的合成方法与实施例5的步骤1相同，收率为49.4％。1H NMR(400MHz,DMSO-d6)δ:12.83(s,1H),8.18(d,J＝8.8Hz,1H),7.72(d,J＝2.0Hz,1H),7.65(dd,J＝2.0,2.0Hz,1H),7.48(t,J＝8.4Hz,1H),6.79(d,J＝8.8Hz,2H),3.68(s,6H).13C NMR(101MHz,DMSO-d6)δ:189.1,161.0,158.9,150.8,149.0,139.9,133.5,129.4,128.6,127.9,122.2,115.4,105.2,56.6,55.3ppm.MS(ESI+APCI)m/z 345.1[M+H]+.
步骤2：7-(4-哌啶甲酸叔丁酯-1-基)-2-(2,6-甲氧基苯甲酰基)喹唑啉-4(3H)-酮
7-(4-哌啶甲酸叔丁酯-1-基)-2-(2,6-甲氧基苯甲酰基)喹唑啉-4(3H)-酮的合成方法与实施例1的步骤2相同，收率为14.5％。1H NMR(400MHz,CDCl3)δ:9.70(s,1H),8.15(d,J＝8.8Hz,1H),7.42(t,J＝8.4Hz,1H),7.12(dd,J＝2.4,2.4Hz,1H),7.01(d,J＝2.4Hz,1H),6.66(s,1H),6.64(s,1H),3.88-3.83(m,2H),3.75(s,6H),3.02-2.95(m,2H),2.47-2.40(m,1H),1.96(dd,J＝3.6,4.0Hz,2H),1.75-1.71(m,2H),1.45(s,9H).13C NMR(101MHz,CDCl3)δ:190.1,173.8,160.5,158.7,155.2,150.3,146.9,132.2,127.9,116.9,114.9,113.7,111.5,104.3,80.6,56.2,47.2,41.7,29.7,29.3,28.1,27.6ppm.MS(ESI+APCI)m/z494.1[M+H]+.
步骤3：N-(5-甲基-1H-吡唑-3-基)-7-(4-哌啶甲酸叔丁酯-1-基)-4-氨基-2-(2,6-甲氧基苯甲酰基)喹唑啉
化合物N-(5-甲基-1H-吡唑-3-基)-7-(4-哌啶甲酸叔丁酯-1-基)-4-氨基-2-(2,6-甲氧基苯甲酰基)喹唑啉的合成方法与实施例1的步骤3相同，收率为6.2％。1H NMR(400MHz,DMSO-d6)δ:11.95(s,1H),10.22(s,1H),8.47(d,J＝8.0Hz,1H),7.42(t,J＝7.6Hz,2H),7.07(s,1H),6.78(d,J＝8.4Hz,2H),6.01(s,1H),3.95(d,J＝12.4Hz,2H),3.62(s,6H),3.31(s,1H),3.01(t,J＝11.4Hz,2H),2.12(s,3H),1.89(d,J＝11.6Hz,2H),1.65-1.57(m,2H),1.41(s,9H).13C NMR(101MHz,DMSO-d6)δ:194.0,173.4,157.4,157.0,156.4,153.5,151.8,133.1,130.4,124.1,119.6,118.0,108.8,106.5,104.5,99.5,96.8,79.6,55.8,46.5,41.0,27.7,27.2,10.7ppm.HRMS(ESI-TOF):m/z calcd.for C31H37N6O5[M+H]+:573.2820；found:573.2803.
实施例4：
N-(5-甲基-1H-吡唑-3-基)-7-(4-甲基哌嗪-1-基)-2-(2-硝基苯基)喹唑啉-4-胺(A-4)
步骤1：2-氨基-4-(4-甲基哌嗪-1-基)苯甲酰胺
将4-氯-2硝基苯甲腈(5.5g，30mmol)，甲基哌嗪(7.4mL，66mmol)溶于50mL二氧六环中，在110℃反应回流16小时，减压除去二氧六环后加入二氯甲烷萃取，有机相用无水硫酸钠干燥，浓缩得到的中间体溶于100mL乙醇中，加入湿Pd/C(300mg)和水合肼(5.8mL，120mmol)，反应体系在80℃反应过夜，减压除去有机溶剂后，加入MeOH：CH2Cl2(1：10)溶剂约150mL溶解产物，过硅藻土柱，MeOH：CH2Cl2(1：10)溶剂洗涤，有机相浓缩后得到的固体用少量二氯甲烷洗涤，得目标产物(6.4g，产率91％)。1H NMR(400MHz,DMSO-d6)δ:7.41(d,J＝8.8Hz,1H),6.57(s,2H),6.13(dd,J＝8.9,2.2Hz,1H),6.09(d,J＝2.1Hz,1H),3.24-2.96(m,4H),2.45-2.27(m,4H),2.20(s,3H).13C NMR(101MHz,DMSO-d6)δ:171.6,153.9,152.3,130.4,105.2,103.4,100.6,54.9,47.4,46.2ppm.MS(ESI+APCI)m/z 235.2[M+H]+.
步骤2：7-(4-甲基哌嗪-1-基)-2-(2-硝基)苯基喹唑啉-4(3H)-酮
将邻硝基苯甲酸(610.6mg，5.0mmol)和HATU(2.3g,6mmol)溶于CH2Cl2(50mL)后加入DIPEA(1.6mL，10.0mmol)，室温下搅拌1h。加入2-氨基-4-(4-甲基哌嗪-1-基)苯甲酰胺室温下搅拌12h。加入1N HCl(50mL),用CH2Cl2(50mL×3)萃取，合并有机相后用Na2SO4干燥，减压除去溶剂后残留物溶于50mL EtOH冷却至0℃，加入10N NaOH(2mL)，室温下搅拌30min后用浓HCl中和反应体系，减压除去乙醇，残留物用硅胶柱层析(CH2Cl2/MeOH，V:V＝30:1)得目标产物(674mg，产率61％)。1H NMR(400MHz,DMSO-d6)δ:12.41(s,1H),8.19(d,J＝8.0Hz,1H),7.96(d,J＝9.2Hz,1H),7.91-7.87(m,1H),7.83-7.78(m,2H),7.22(d,J＝8.4Hz,1H),6.92(s,1H),3.39(s,8H),2.51(s,3H),2.27(s,3H).13C NMR(101MHz,DMSO-d6)δ:161.5,155.4,152.2,150.8,148.0,134.3,131.8,129.9,127.4,124.9,115.6,112.1,109.4,54.5,47.0,45.9ppm.MS(ESI+APCI)m/z 366.2[M+H]+.
步骤3：N-(5-甲基-1H-吡唑-3-基)-7-(4-甲基哌嗪-1-基)-2-(2-硝基苯基)喹唑啉-4-胺
化合物N-(5-甲基-1H-吡唑-3-基)-7-(4-甲基哌嗪-1-基)-2-(2-硝基苯基)喹唑啉-4-胺的合成方法与实施例1的步骤3相同，收率为45.2％。1H NMR(400MHz,DMSO-d6)δ:12.09(s,1H),10.16(s,1H),8.48(d,J＝9.2Hz,1H),8.01(d,J＝8.0Hz,1H),7.92(d,J＝8.0Hz,1H),7.80(t,J＝8.0Hz,1H),7.68(t,J＝8.0Hz,1H),7.37(d,J＝9.2Hz,1H),6.98(s,1H),6.42(s,1H),3.46(s,4H),3.04(q,J＝7.2Hz,2H),2.64(s,2H),2.35(s,3H),2.24(s,3H).13C NMR(101MHz,DMSO-d6)δ:159.4,157.1,154.1,152.4,150.1,138.9,134.9,132.8,131.7,130.3,124.7,124.3,117.1,108.6,106.1,100.0,97.8,54.3,46.8,45.9,45.5,11.5,9.0ppm.HRMS(ESI-TOF):m/z calcd.for C23H25N8O2[M+H]+:445.2095；found:445.2082.
实施例5：
N-(5-甲基-1H-吡唑-3-基)-2-苯甲酰基喹唑啉-4-胺(A-5)
步骤1：2-苯甲酰基喹唑啉-4(3H)-酮
将苯乙酮(272mg,2.0mmoL)和碘(615.6mg,2.2mmoL)溶于3mL的N,N-二甲基亚砜在110℃下搅拌10min后逐滴加入邻氨基苯甲酰胺的N,N-二甲基亚砜(2mL)溶液，在110℃下搅拌12h。反应完全后加水稀释，然后用二氯甲烷萃取3次。有机层用饱和氯化钠洗涤后，无水硫酸钠干燥。旋干溶剂，柱色谱分离(二氯甲烷:甲醇＝30:1～20:1)得淡黄色固体(275mg,产率55％)。1H NMR(400MHz,CDCl3)δ:10.38(s,1H),8.52(d,J＝7.6Hz,2H),8.41(d,J＝8.0Hz,1H),7.93(d,J＝8.0Hz,1H),7.85(t,J＝7.4Hz,1H),7.71-7.63(m,2H),7.55(t,J＝7.6Hz,2H).13C NMR(101MHz,CDCl3)δ:185.7,161.0,147.6,146.0,134.9,134.3,134.0,131.8,129.5,129.4,128.4,126.9,123.28ppm.MS(ESI+APCI) m/z 251.1[M+H]+.
步骤2：N-(5-甲基-1H-吡唑-3-基)-2-苯甲酰基喹唑啉-4-胺
化合物N-(5-甲基-1H-吡唑-3-基)-2-苯甲酰基喹唑啉-4-胺的合成方法与实施例1的步骤3相同，收率为38％。1H NMR(400MHz,DMSO-d6)δ:12.23(s,1H),10.71(s,1H),8.75(d,J＝8.0Hz,1H),7.99(d,J＝6.8Hz,2H),7.93-7.85(m,2H),7.73-7.66(m,2H),7.57(t,J＝7.0Hz,2H),6.52(s,1H),2.18(s,3H). 13C NMR(101MHz,DMSO-d6)δ:192.7,159.2,157.8,149.5,147.8,138.7,135.8,134.1,134.0,130.8,129.1,128.7,127.9,123.9,115.1,98.3,11.2ppm.HRMS(ESI-TOF):m/z calcd.for C19H16N5O[M+H]+:330.1343；found:330.1349.
实施例6:
N-(5-甲基-1H-吡唑-3-基)-7-(4-哌啶甲酸乙酯-1-基)-4-氨基-2-(2-硝基苯基)喹唑啉
步骤1：7-氯-2-(2-硝基苯基)喹唑啉-4(3H)-酮
化合物7-氯-2-(2-硝基)苯基喹唑啉-4(3H)-酮的合成方法与实施例1的步骤1相同，收率为47％。1H NMR(400MHz,DMSO-d6)δ:12.43(s,1H),8.54(s,1H),8.26(d,J＝7.2Hz,2H),7.21(d,J＝8.8Hz,1H),7.16(d,J＝1.6Hz,1H),7.11-7.02(m,4H).13C NMR(101MHz,DMSO-d6)δ:161.4,155.9,151.1,139.9,135.2,131.6,126.2,126.1,125.8,125.2,119.6ppm.MS(ESI+APCI)m/z 302.1[M+H]+.
步骤2：7-(4-哌啶甲酸叔丁酯-1-基)-2-(2-硝基)苯基喹唑啉-4(3H)-酮
化合物7-(4-哌啶甲酸叔丁酯-1-基)-2-(2-硝基)苯基喹唑啉-4(3H)-酮的合成方法与实施例1的步骤2相同，收率为23％。1H NMR(400MHz,DMSO-d6)δ:12.27(s,1H),8.30(d,J＝7.2Hz,2H),7.91(d,J＝8.8Hz,1H),7.50-7.42(m,2H),7.07(d,J＝7.6Hz,1H),7.02(s,1H),6.21(s,3H),3.97(d,J＝12.8Hz,2H),3.28(s,1H),3.05(t,J＝11.4Hz,2H),1.79(d,J＝11.6Hz,2H),1.60-1.56(m,2H),1.38(s,9H).13C NMR(101MHz,DMSO-d6)δ:176.9,164.1,156.5,151.7,149.8,132.6,130.7,128.6,127.9,127.1,116.5,113.7,108.0,79.1,45.6,45.1,29.3,26.8ppm.MS(ESI+APCI)m/z 451.1[M+H]+.
步骤3：N-(5-甲基-1H-吡唑-3-基)-7-(4-哌啶甲酸叔丁酯-1-基)-4-氨基-2-(2-硝基)苯基喹唑啉
化合物N-(5-甲基-1H-吡唑-3-基)-7-(4-哌啶甲酸叔丁酯-1-基)-4-氨基-2-(2硝基)苯基喹唑啉的合成方法与实施例1的步骤3相同，收率为39％。1H NMR(400MHz,DMSO-d6)δ:13.72(s,1H),10.87(s,1H),8.62(d,J＝9.2Hz,1H),8.24(d,J＝7.2Hz,2H),7.81-7.72(m,2H),7.15(d,J＝7.2Hz,1H),6.74(s,1H),6.36(s,1H),3.76(d,J＝13.2Hz,2H),3.24(s,3H),3.05(t,J＝11.8Hz,2H),2.54-2.45(m,1H),2.39(s,3H),1.71(d,J＝11.2Hz,2H),1.64(dd,J＝11.2,10.4Hz,2H),1.24(s,9H).13C NMR(101MHz,DMSO-d6)δ:173.2,158.9,157.3,155.2,148.7,140.5,135.3,134.0,132.4,128.6,126.8,125.4,118.9,106.4,105.0,99.5,81.9,41.9,29.0,26.2,11.1ppm.MS(ESI+APCI)m/z 530.1[M+H]+.
步骤4：N-(5-甲基-1H-吡唑-3-基)-7-(4-哌啶甲酸乙酯-1-基)-4-氨基-2-(2-硝基)苯基喹唑啉
化合物N-(5-甲基-1H-吡唑-3-基)-7-(4-哌啶甲酸乙酯-1-基)-4-氨基-2-(2-硝基)苯基喹唑啉的合成方法与实施例1的步骤4相同，收率为37％。1H NMR(400MHz,DMSO-d6)δ:12.08(s,1H),10.24(s,1H),8.37(d,J＝6.4Hz,3H),7.62(s,1H),7.36(d,J＝8.0Hz,2H),7.10(s,1H),6.25(s,1H),4.07(q,J＝7.2Hz,2H),3.88-3.84(m,2H),3.50(t,J＝10.6Hz,2H),2.84(t,J＝11.2Hz,1H),2.21(s,3H),1.88(d,J＝11.4Hz,2H),1.70-1.66(m,2H),1.19(s,3H).13C NMR(101MHz,DMSO-d6)δ:174.2,161.5,155.5,155.0,150.4,145.3,140.3,138.2,128.1,128.1,127.6,122.5,113.1,109.4,108.0,94.2,50.4,43.8,29.2,12.2,11.4ppm.HRMS(ESI-TOF):m/z calcd.for C26H28N7O4[M+H]+:502.2134；found:502.2126.
实施例7：
N-(5-甲基-1H-吡唑-3-基)-7-(4-甲基哌嗪-1-基)-2-(2-甲氧基苯基)喹唑啉-4-胺(A-7)
操作步骤与实施例4的合成类似，产率为82.8％。1H NMR(400MHz,DMSO-d6)δ:12.20(s,1H),10.33(s,1H),8.46(d,J＝9.2Hz,1H),7.94(s,1H),7.51-7.47(m,1H),7.38(d,J＝8.4Hz,2H),7.22(d,J＝8.4Hz,2H),7.11(d,J＝7.2Hz,2H),6.41(s,1H),3.95(s,3H),3.59(s,4H),2.97(s,4H),2.58(s,3H),2.23(s,3H).13C NMR(101MHz,DMSO-d6)δ:158.0,153.6,152.9,151.2,131.8,131.7,131.6,124.8,120.8,117.0,116.5,112.8,108.4,108.3,108.1,108.0,100.0,56.3,53.5,46.0,44.2,12.2ppm.HRMS(ESI-TOF):m/z calcd.forC24H28N7O[M+H]+:430.2350；found:430.2342.
实施例8：
N-(5-甲基-1H-吡唑-3-基)-7-(4-甲基哌嗪-1-基)-2-苯基喹唑啉-4-胺(A-8)
操作步骤与实施例4的合成类似，产率为22.5％。1H NMR(400MHz,DMSO-d6)δ:12.61(s,1H),8.23-8.17(m,4H),7.61-7.49(m,5H),7.39-7.35(m,1H),3.34(s,8H),2.51(s,3H),1.22(s,3H).13C NMR(101MHz,DMSO-d6)δ:160.1,157.1,153.8,152.7,147.8,147.7,139.4,130.4,128.8,128.3,124.7,116.6,109.0,106.7,97.6,53.9,46.5,44.9,29.5,11.7ppm.HRMS(ESI-TOF):m/z calcd.for C23H26N7[M+H]+:400.2244；found:400.2239.
实施例9：
N-(5-甲基-1H-吡唑-3-基)-7-(4-哌啶甲酸乙酯-1-基)-4-氨基-2-(2-甲氧基苯基)喹唑啉(A-9)
步骤1：7-氯-2-(2-甲氧基)苯基喹唑啉-4(3H)-酮
化合物7-氯-2-(2-甲氧基)苯基喹唑啉-4(3H)-酮的合成方法与实施例1的步骤1相同，收率为45％。1H NMR(400MHz,DMSO-d6)δ:12.50(s,1H),8.24(s,1H),8.03(d,J＝7.2Hz,2H),7.37(d,J＝8.8Hz,1H),7.24(d,J＝1.6Hz,1H),7.10-7.02(m,4H),6.46(s,3H).13C NMR(101MHz,DMSO-d6)δ:161.5,154.9,150.3,138.8,135.5,130.2,127.4,126.2,126.1,127.9,118.7,57.8ppm.MS(ESI+APCI)m/z 287.1[M+H]+.
步骤2：7-(4-哌啶甲酸叔丁酯-1-基)-2-(2-甲氧基)苯基喹唑啉-4(3H)-酮
化合物7-(4-哌啶甲酸叔丁酯-1-基)-2-(2-甲氧基)苯基喹唑啉-4(3H)-酮的合成方法与实施例1的步骤2相同，收率为39％。1H NMR(400MHz,DMSO-d6)δ:12.27(s,1H),8.30(d,J＝7.2Hz,2H),7.91(d,J＝8.8Hz,1H),7.50-7.42(m,2H),7.07(d,J＝7.6Hz,1H),7.02(s,1H),6.21(s,3H),3.97(d,J＝12.8Hz,2H),3.28(s,1H),3.05(t,J＝11.4Hz,2H),1.79(d,J＝11.6Hz,2H),1.60-1.56(m,2H),1.38(s,9H).13C NMR(101MHz,DMSO-d6)δ:174.1,163.6,156.6,152.0,150.0,132.6,130.9,128.7,128.0,127.6,116.7,113.5,108.8,79.0,61.8,47.7,45.0,29.1,26.9ppm.MS(ESI+APCI)m/z 436.1[M+H]+.
步骤3：N-(5-甲基-1H-吡唑-3-基)-7-(4-哌啶甲酸叔丁酯-1-基)-4-氨基-2-(2-甲氧基)苯基喹唑啉
化合物N-(5-甲基-1H-吡唑-3-基)-7-(4-哌啶甲酸叔丁酯-1-基)-4-氨基-2-(2-甲氧基)苯基喹唑啉的合成方法与实施例1的步骤3相同，收率为42％。1H NMR(400MHz,DMSO-d6)δ:13.62(s,1H),11.64(s,1H),8.51(d,J＝9.2Hz,1H),8.18(d,J＝7.2Hz,2H),7.61-7.53(m,2H),7.09(d,J＝7.2Hz,1H),6.87(s,1H),6.49(s,1H),3.89(d,J＝13.2Hz,2H),3.77(s,3H),3.20(t,J＝11.8Hz,2H),2.74-2.61(m,1H),2.29(s,3H),1.88(d,J＝11.2Hz,2H),1.71(dd,J＝11.2,10.4Hz,2H),1.37(s,9H).13C NMR(101MHz,DMSO-d6)δ:172.9,159.0,157.1,154.9,147.0,139.1,134.8,133.7,131.9,127.8,127.0,125.5,117.6,105.4,102.8,98.5,80.6,47.8,42.5,28.5,26.5,11.2ppm.MS(ESI+APCI)m/z 515.1[M+H]+.
步骤4：N-(5-甲基-1H-吡唑-3-基)-7-(4-哌啶甲酸乙酯-1-基)-4-氨基-2-(2-甲氧基)苯基喹唑啉
化合物N-(5-甲基-1H-吡唑-3-基)-7-(4-哌啶甲酸乙酯-1-基)-4-氨基-2-(2-甲氧基)苯基喹唑啉的合成方法与实施例1的步骤4相同，收率为64％。1H NMR(400MHz,DMSO-d6)δ:12.24(s,1H),11.66(s,1H),8.24(s,1H),7.70(d,J＝6.2Hz,3H),7.18(d,J＝8.0Hz,2H),7.04(s,1H),6.33(s,1H),4.52-4.40(m,2H),3.92(q,J＝8.0Hz,2H),3.68(s,3H),3.55(t,J＝10.2Hz,2H),2.76(t,J＝10.6Hz,1H),2.08(s,3H),1.69(d,J＝10.6Hz,2H),1.24-1.15(m,2H),1.21(s,3H).13C NMR(101MHz,DMSO-d6)δ:168.8,162.3,160.0,159.1,156.8,151.0,145.8,140.9,138.7,131.5,128.6,127.3,118.2,117.5,108.7,105.6,95.8,63.0,56.0,51.7,43.8,30.2,17.2,13.7ppm.HRMS(ESI-TOF):m/z calcd.for C27H31N6O3[M+H]+:487.2386；found:487.2381.
实施例10：
N-(5-甲基-1H-吡唑-3-基)-7-硝基-2-苯基喹唑啉-4-胺(A-10)
步骤1：7-硝基-2-苯基喹唑啉-4(3H)-酮
化合物7-硝基-2-苯基喹唑啉-4(3H)-酮的合成方法与实施例1的化合物步骤1相同，收率为62％。1H NMR(400MHz,DMSO-d6)δ:12.89(s,1H),8.39(s,1H),8.33(d,J＝8.8Hz,1H),8.20(d,J＝8.0Hz,3H),7.65-7.55(m,3H).13C NMR(101MHz,DMSO-d6)δ:161.8,155.0,151.8,149.6,132.5,132.4,129.2,128.6,128.5,125.8,122.8,120.5ppm.MS(ESI+APCI)m/z 268.1[M+H]+.
步骤2：N-(5-甲基-1H-吡唑-3-基)-7-硝基-2-苯基喹唑啉-4-胺
化合物N-(5-甲基-1H-吡唑-3-基)-7-硝基-2-苯基喹唑啉-4-胺的合成方法与实施例1的步骤3相同，收率为44.0％。1H NMR(400MHz,DMSO-d6)δ:10.80(d,J＝13.2Hz,1H),8.89(d,J＝8.0Hz,1H),8.48(d,J＝12.0Hz,3H),8.21-8.17(m,1H),7.56(d,J＝12.8Hz,3H),6.78(d,J＝16.4Hz,1H),2.39-2.14(m,1H).13C NMR(101MHz,DMSO-d6)δ:161.8,157.4,150.9,150.6,147.5,139.2,138.2,131.3,129.0,128.7,126.3,123.3,119.2,117.9,98.1,11.5ppm.HRMS(ESI-TOF):m/z calcd.for C18H15N6O2[M+H]+:347.1251；found:347.1241.
实施例11：
8-甲氧基-N-(5-甲基-1H-吡唑-3-基)-2-(2-硝基)苯基喹唑啉-4-胺(A-11)
步骤1：2-(2-硝基苯基)-8-甲氧基-喹唑啉-4(3H)-酮
化合物2-(2-硝基苯基)-8-甲氧基-喹唑啉-4(3H)-酮的合成方法与实施例1的步骤1相同，收率为57.0％。1H NMR(400MHz,DMSO-d6)δ:12.81(s,1H),8.26-8.21(m,1H),7.93-7.71(m,4H),7.53-7.47(m,1H),7.41-7.37(m,1H),3.89-3.84(m,3H).13C NMR(101MHz,DMSO-d6)δ:162.2,154.9,151.0,147.5,139.3,134.7,132.0,131.8,129.7,128.2,125.0,122.3,117.2,115.8,56.3ppm.MS(ESI+APCI)m/z 298.1[M+H]+.
步骤2：N-(5-甲基-1H-吡唑-3-基)-2-(2-硝基)苯基-8-甲氧基-喹唑啉-4-胺
化合物N-(5-甲基-1H-吡唑-3-基)-2-(2-硝基)苯基-8-甲氧基-喹唑啉-4-胺的合成方法与实施例1的步骤3相同，收率为47.0％。1H NMR(400MHz,DMSO-d6)δ:12.17(s,1H),10.31(s,1H),8.19(d,J＝8.0Hz,1H),7.98(t,J＝8.8Hz,2H),7.82(t,J＝7.6Hz,1H),7.70(t,J＝8.0Hz,1H),7.52(t,J＝8.0Hz,1H),7.35(d,J＝7.6Hz,1H),6.41(s,1H),3.94(s,3H),2.25(s,3H).13C NMR(101MHz,DMSO-d6)δ:158.4,157.4,154.8,149.6,141.8,134.7,133.3,131.8,130.6,127.7,124.4,114.2,114.0,113.2,100.0,98.0,56.3,11.1ppm.HRMS(ESI-TOF):m/z calcd.for C19H17N6O3[M+H]+:377.1357；found:377.1339.
实施例12：
N-(5-甲基-1H-吡唑-3-基)-2-(2-硝基)苯基喹唑啉-4-胺(A-12)
操作步骤与实施例11的合成类似，产率为38.0％。1H NMR(400MHz,DMSO-d6)δ:12.18(s,1H),10.46(s,1H),8.68(d,J＝8.4Hz,1H),8.06(dd,J＝1.2Hz,1H),7.96(dd,J＝1.2Hz,1H),7.89-7.77(m,3H),7.73-7.69(m,1H),7.61(t,J＝8.0Hz,1H),6.48(s,1H),2.27(s,3H).13C NMR(101MHz,DMSO-d6)δ:159.1,157.8,150.3,150.1,147.7,138.7,134.5,133.7,132.9,131.8,130.6,128.3,127.1,124.4,123.7,113.9,98.2,11.3ppm.HRMS(ESI-TOF):m/z calcd.for C18H15N6O2[M+H]+:347.1251；found:347.1243.
实施例13：
N-(5-甲基-1H-吡唑-3-基)-8-甲氧基-2-苯基喹唑啉-4-胺(A-13)
操作步骤与实施例11的合成类似，产率为76.3％。1H NMR(400MHz,DMSO-d6)δ:12.23(s,1H),10.24(s,1H),8.48(d,J＝7.2Hz,2H),8.18(d,J＝8.0Hz,1H),7.56-7.50(m,3H),7.45(t,J＝8.4Hz,1H),7.31(d,J＝7.6Hz,1H),6.77(s,1H),3.99(s,3H),2.35(s,3H).13C NMR(101MHz,DMSO-d6)δ:164.1,158.0,157.5,146.3,140.4,139.8,131.6,128.3,127.0,115.2,111.7,99.0,56.3,11.4ppm.HRMS(ESI-TOF):m/z calcd.for C19H18N5O[M+H]+:332.1506；found:332.1487.
实施例14：
N-(5-甲基-1H-吡唑-3-基)-8-甲氧基-2-(2-甲氧基)苯基喹唑啉-4-胺(A-14)
操作步骤与实施例11的合成类似，产率为80.5％。1H NMR(400MHz,DMSO-d6)δ:12.75(s,1H), 11.94(s,1H),8.34(d,J＝8.0Hz,1H),8.26(d,J＝8.0Hz,1H),7.72(dd,J＝7.2,8.0Hz,2H),7.63(d,J＝8.0Hz,1H),7.40(d,J＝8.4Hz,1H),7.26(t,J＝7.6Hz,1H),6.56(s,1H),4.12(s,3H),4.11(s,3H),2.35(s,3H).13C NMR(101MHz,DMSO-d6)δ:161.5,159.4,154.87,146.2,140.5,135.5,132.7,131.9,129.0,122.1,118.5,117.9,116.1,115.9,115.0,113.8,98.8,57.7,57.5,11.3ppm.HRMS(ESI-TOF):m/z calcd.for C20H20N5O2[M+H]+:362.1612；found:362.1574.
实施例15：
N-(5-甲基-1H-吡唑-3-基)-8-甲氧基-2-(4-甲氧基)苯基喹唑啉-4-胺(A-15)
操作步骤与实施例11的合成类似，产率为21.5％。1H NMR(400MHz,DMSO-d6)δ:12.19(s,1H),10.13(s,1H),8.43(d,J＝7.6Hz,2H),8.14(d,J＝8.0Hz,1H),7.41(t,J＝7.6Hz,1H),7.28(d,J＝7.6Hz,1H),7.09(d,J＝7.2Hz,2H),6.75(s,1H),3.98(s,3H),3.85(s,3H),2.35(s,3H).13C NMR(101MHz,DMSO-d6)δ:161.5,158.5,157.6,155.0,148.3,142.7,139.8,131.8,130.0,125.8,114.8,114.6,114.2,112.7,98.0,56.3,55.8ppm.HRMS(ESI-TOF):m/z calcd.for C20H20N5O2[M+H]+:362.1612；found:362.1594.
实施例16：
N-(5-甲基-1H-吡唑-3-基)-8-甲氧基-2-苄基喹唑啉-4-胺(A-16)
操作步骤与实施例11的合成类似，产率为79.4％。1H NMR(400MHz,DMSO-d6)δ:12.36(s,1H),10.87(s,1H),8.18(d,J＝8.0Hz,1H),7.50(t,J＝8.0Hz,1H),7.40-7.38(m,3H),7.34(t,J＝7.6Hz,2H),7.28-7.24(m,1H),6.27-6.17(m,1H),4.25(s,2H),3.99(s,3H),2.20(s,3H).13C NMR(101MHz,DMSO-d6)δ:163.4,156.7,152.4,152.1,138.7,138.6,137.8,137.3,129.5,128.3,126.5,126.4,114.5,113.3,97.8,56.1,43.7,10.9ppm.HRMS(ESI-TOF):m/z calcd.for C20H20N5O[M+H]+:346.1662；found:346.1652.
实施例17：
N-(5-甲基-1H-吡唑-3-基)-7-(4-吡咯甲酸乙酯-1-基)-4-氨基-2-苯基喹唑啉(A-17)
操作步骤与实施例1的合成类似，产率为29.4％。1H NMR(400MHz,DMSO-d6)δ:12.21(s,1H),10.38(s,1H),8.48-8.34(m,3H),8.21-8.17(m,2H),7.40(d,J＝8.0Hz,1H),7.16(s,1H),6.94(s,1H),6.12 (s,1H),4.07(q,J＝8.0Hz,2H),3.98(t,J＝12.0Hz,1H),3.75(d,J＝10.0Hz,2H),3.01(t,J＝12.0Hz,2H),2.31(s,3H),1.86(dd,J＝10.0,14.0Hz,2H),1.20(t,J＝6.0Hz,3H).13C NMR(101MHz,DMSO-d6)δ:175.6,161.2,158.4,158.4,154.7,152.3,144.7,139.5,138.2,131.3,129.6,123.3,117.1,107.6,94.1,74.0,61.3,52.4,29.8,22.6,11.5ppm.HRMS(ESI-TOF):m/z calcd.for C25H27N6O2[M+H]+:443.2126；found:443.2121.
在本发明中同时还制备了如下表1中其它化合物，这些化合物的合成方法参照上述方法。这些化合物的表征数据，包括核磁数据和高分辨质谱数据如表1所示。
表1化合物A-18～A-29核磁数据和高分辨质谱数据
应用：
1、本发明所合成的化合物对Aurora激酶抑制实验
Aurora激酶活性测试通过Caliper Mobility Shift Assay方法测定。将化合物从100μM开始依次三倍稀释，总共得到10个浓度，并加入Aurora激酶、FAM标记多肽和ATP，25℃下反应60分钟后加入终止液终止反应；最后采用Caliper读取转化率数据，换算成抑制率数据后通过Xlfit统计软件计算获得IC50数据。以不加药物的溶剂空白作为阴性对照，以ENMD-2076为阳性对照。上述实施例与表1中各化合物都具有Aurora激酶抑制作用，且对Aurora A激酶的活性显著优于Aurora B，即对Aurora A激酶的抑制具有一定的选择性。测试结果如表2所示。
表2实施例化合物的Aurora激酶抑制活性(IC50,μM)
2、本发明所合成的化合物对肿瘤细胞株的活性实验
肿瘤细胞株包括：人慢性粒细胞白血病细胞株K562，人宫颈癌细胞株Hela，人前列腺细胞癌DU145，急性淋巴母细胞白血病系Molt-4，人乳腺癌细胞株MCF-7，MDA-MB-231和SK-BR-3。
实验方法：细胞株在10％FBS和1％盘尼西林/链霉素的DMEM/RPMI培养基中生长存活。所有细胞株都存放于Thermo/Forma Scientific CO2细胞培养箱中生长，条件：含5％CO2的空气，温度为37℃。细胞活性分析是通过CCK8(DojinDo)方法测定的。以400-800/孔的细胞密度接种于384孔培养板中，加入不同浓度的化合物，经过72小时孵育后，加入CCK8试剂，用Envision 2104多功能微孔分析仪(Perkin Elmer)测定450nm波长下吸光值，最后使用Prism(Version5，GraphPad software)通过量效曲线计算出抗肿瘤细胞增殖IC50值。
实验以ENMD 2076为阳性对照，实施例化合物及对照物的IC50值如下表所示。
表3本发明化合物的抗肿瘤细胞增殖活性(IC50,μM)
以上仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.通式(I)或(II)所示的化合物或其药学上可以接受的盐、水合物、溶剂化物、多晶型物、互变异构体或前药，
其中，
X是碳原子或者氮原子；Y是氮原子或者氧原子；n＝0或者1；
R1独立地选自氢、C1-C4的脂肪烃基中的一种；或者脂肪烃基、烷氧基羰基、取代或未取代的苯基、羟基烷基、烷氧基烷基、氨基羰基、单烷基或双烷基的氨基羰基、氨基烷基、烷基氨基烷基、二烷基氨基烷基、苯基氨基羰基、(N-杂环)羰基；或者无R1；
R2独立地选自氢或以下基团：卤素、-NO2、-OMe、-OEt、-CN、-CF3、-CF2R、-C(R)＝CR’2、-C(R)＝C(R’)(R”)、-C≡C-R、-OR、-SR、-S(O)R、-SO2R、-SO2NR2、-NR2、-OCO2R、-OC(O)NR2、-OC(O)R、-CO2R、-C(O)R、-C(O)NR2；对R2的定义中，所述的R、R’以及R”各自独立地选自H、未取代的低级烷基、苯基或者取代苯基；
R3选自i-Pr、取代或者没有取代的芳基或者杂环芳基，其中取代基选自卤素、-NO2、-CN、-CF3、-CF2R、-C(R)＝CR’2、-C(R)＝C(R’)(R”)、-C≡C-R、-OR、-SR、-S(O)R、-SO2R、-SO2NR2、-NR2、-OCO2R、-OC(O)NR2、-OC(O)R、-CO2R、-C(O)R、-C(O)NR2、-C(＝NR)-NR’2、-C(＝NR)-OR’、-NRC(＝NR’)-NR”2、-NRSO2R’、-NRSO2NR’2、-P(O)R2、-P(O)(OR)2中的一种；对R3的定义中，所述的R、R’以及R”各自独立地选自H、未取代的低级烷基、苯基或者取代苯基；
R4和R4’各自独立地选自氢、C1-C4的脂肪烃基、烷氧基羰基、取代或未取代的苯基、羟基烷基、烷氧基烷基、氨基羰基、单烷基或双烷基的氨基羰基、氨基烷基、烷基氨基烷基、二烷基氨基烷基、苯基氨基羰基、(N-杂环)羰基；或者，R4和R4’与通式(I)或(II)中吡唑形成双环的结构。
2.根据权利要求1所述通式(I)或(II)所示的化合物或其药学上可以接受的盐、水合物、溶剂化物、多晶型物、互变异构体或前药，其特征在于：所述R1是H或者C1-C4的脂肪烃基。
3.根据权利要求1所述通式(I)或(II)所示的化合物或其药学上可以接受的盐、水合物、溶剂化物、多晶型物、互变异构体或前药，其特征在于：所述R2选自氢、甲氧基、乙氧基、甲基、乙基、硝基、氰基中的一种。
4.根据权利要求1所述通式(I)或(II)所示的化合物或其药学上可以接受的盐、水合物、溶剂化物、多晶型物、互变异构体或前药，其特征在于：所述R3选自取代苯基、苯甲酰基、2-吡啶基、3-吡啶基、4-吡啶基、萘基中的一种；其中苯基上取代基选自3-OMe、4-OMe、2-OMe、4-NO2、3-NO2、2-NO2、3-COOH、3-COOMe、3-COOEt、3-COOiPr、2-F、3-F、4-F、2-Cl、3-Cl、4-Cl、3-Cl-4-COOMe、3-OMe-4-COOMe、2-Cl-2-OMe、2-CONH2-3-F、3-CONH2、2-CH2OH、4-CONHMe、2,4-diOMe、2,5-diOMe、2-Me-4-OMe、2,4-diCl、3,4-diCl、2-吗啉基、3-吗啉基、4-吗啉基、3,4-亚甲二氧基、4-CH2COOEt、2-CN、3-CN、2-CF3或者3-CF3中的一种。
5.根据权利要求1所述通式(I)或(II)所示的化合物或其药学上可以接受的盐、水合物、溶剂化物、多晶型物、互变异构体或前药，其特征在于：所述R3中含有氨基时，氨基的氮原子是自由碱形式或者药学可以接受的盐或者季铵盐。
6.根据权利要求1所述通式(I)或(II)所示的化合物或其药学上可以接受的盐、水合物、溶剂化物、多晶型物、互变异构体或前药，其特征在于：R4和R4’各自独立地选自下列基团中的一种：甲基、环丙基、乙基、异丙基、丙基、叔丁基、环戊基、苯基、COOH、CO2Me、CH2OH、CH2OMe、CH2CH2CH2OH、CH2CH2CH2OMe、CH2CH2CH2OCH2Ph、CH2CH2CH2NH2、CH2CH2CH2NHCOOtBu、CONHiPr、CONHCH2CH＝CH2、CONHCH2CH2OMe、CONHCH2Ph、CONH(环己基)、CON(Et)2、CON(Me)(CH2Ph)、CONH(nPr)、CON(Et)(nPr)、CONHCH2CH(Me)2、CON(nPr)2、CO(3-甲氧基甲基1-吡咯基)、CONH(3-甲苯基)、CONH(4-甲苯基)、CONHMe、CO(1-吗啉基)、CO(4-甲基1-哌嗪基)、CONHCH2CH2OH、CONH2、CO(1-哌啶基)；或者R4和R4’与通式(I)或(II)中吡唑形成的双环结构为下列之一：
7.根据权利要求1所述通式(I)或(II)所示的化合物或其药学上可以接受的盐、水合物、溶剂化物、多晶型物、互变异构体或前药，其特征在于：所述的喹唑啉衍生物具体选自下列结构式中的至少一种：
8.一种药物组合物，其特征在于：包括下列物质中的至少一种：a)化合物，b)该化合物在药学上可接受的盐，c)该化合物的水合物，d)该化合物的溶剂化物，e)该化合物的多晶型物，f)该化合物的互变异构体，g)该化合物的前药；其中，所述的化合物为权利要求1-7中任一项所述的通式(I)或(II)所示的化合物。
9.权利要求1-7中任一项所述的通式(I)或(II)所示的化合物或其药学上可以接受的盐、水合物、溶剂化物、多晶型物、互变异构体或前药在制备抑制Aurora A激酶的药物中的应用。
10.权利要求1-7中任一项所述的通式(I)或(II)所示的化合物或其药学上可以接受的盐、水合物、溶剂化物、多晶型物、互变异构体或前药在制备治疗和/或预防和/或延缓和/或辅助治疗和/或处理增殖性疾病的药物中的应用。
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| CN105503837A (zh) * | 2015-12-31 | 2016-04-20 | 中山大学 | 具有Aurora激酶抑制活性的取代喹唑啉类衍生物及其应用 |
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