CN111574530A - 一种acc抑制剂及其医药用途 - Google Patents
一种acc抑制剂及其医药用途 Download PDFInfo
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- CN111574530A CN111574530A CN202010316792.9A CN202010316792A CN111574530A CN 111574530 A CN111574530 A CN 111574530A CN 202010316792 A CN202010316792 A CN 202010316792A CN 111574530 A CN111574530 A CN 111574530A
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- butyl
- pyridyl
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Abstract
本发明涉及一种ACC抑制剂及其医药用途，属于药物化学和药物治疗学领域。本发明提供的式I所示的化合物、异构体或其药学上可接受的盐，不仅对ACC具有良好的酶活，同时具有良好的抗肿瘤活性，可应用在抗肿瘤药物的制备中，特别是在抗肺癌、抗肝癌或抗乳腺癌药物中具有优异的应用前景。
Description
技术领域
本发明属于药物化学和药物治疗学领域，具体涉及一种ACC抑制剂及其在制备与肿瘤相关疾病的药物方面的应用。
背景技术
恶性肿瘤是一种危害人类生命健康安全的重要疾病，无论发达国家还是发展中国家，死亡率均极高。根据世界卫生组织的报道，2020年全球肿瘤发病人数将达到2000万人，死亡人数将达到1200万人。细胞代谢的改变是肿瘤细胞异于正常细胞的标志之一，也是肿瘤细胞异常、持续增殖的一个因素。其中，脂肪酸作为肿瘤细胞能量的主要来源和细胞膜的基本组成部分，其合成速率的增加被认为与肿瘤的发生发展密切相关。在许多癌症，如：前列腺癌、肝癌、肺癌、乳腺癌、结肠癌、胰腺癌中，脂肪酸从头合成速率均明显增加。鉴于脂肪酸异常代谢在肿瘤发生发展过程中的关键作用，通过调节脂肪生成酶、修复脂肪酸代谢异常已成为预防和治疗肿瘤的新策略。
乙酰辅酶A羧化酶(acetyl-CoA carboxylase,ACC)是脂肪酸合成代谢的关键酶，其催化乙酰辅酶A转换成丙二酰辅酶A，从而调控脂肪酸的生物合成与氧化代谢。早前对ACC的研究主要集中于除草剂、抗糖尿病、抗肥胖等领域，ACC抑制剂firsocostat(ND-630)和PF-05221304目前正在进行对脂肪肝炎的临床II期试验。近年来，随着对ACC的进一步了解，发现ACC在前列腺癌、肝癌、肺癌、乳腺癌等多种癌细胞系中均呈现高表达；利用小干扰RNA(Small interfering RNA,siRNA)沉默肿瘤细胞ACC1，可显著降低脂肪酸合成及影响线粒体功能，从而导致肿瘤细胞生长阻滞和凋亡。因此，ACC是一个极具潜力的抗肿瘤靶标，ACC抑制剂的开发有望成为潜在的作用于脂肪酸合成的抗肿瘤药物。
目前已有一些ACC抑制剂被报道具有抗肿瘤效果，如：大环聚酮类天然产物Soraphen A能够通过抑制ACC从而诱导乳腺癌细胞MCF-7凋亡；噻吩嘧啶酮类ACC抑制剂ND-646，ND-654在非小细胞肺癌和肝癌动物模型中，分别显示出良好的抑瘤效果。但目前抗肿瘤ACC抑制剂的种类仍相对有限，也未有药物进入临床试验；因此，研发具有新型结构的抗肿瘤ACC抑制剂显得尤为迫切。
申请号为WO 2009144554的国际专利公开了一种螺吡唑酮类ACC抑制剂，该类化合物具有良好的ACC抑制活性，并在预防和治疗II型糖尿病及相关代谢疾病方面具有疗效；但该专利并未进行抗肿瘤方面的研究。基于此，本申请对该专利中公开的优选化合物PF-1进行了抗肿瘤活性测定，实验数据显示其对肿瘤细胞活性相对较弱，不能满足临床需求。
因此，有必要开发出更多、更有效的ACC抑制剂，为肿瘤治疗提供更多选择。
发明内容
本发明的目的是在现有技术的基础上，提供一种ACC抑制剂化合物、异构体或其药学上可接受的盐，该类化合物不仅对ACC具有良好的酶活，同时具有良好的抗肿瘤活性，特别是具有良好的抗肝癌、肺癌和乳腺癌活性。例如，对A549、HepG2、MDA-MB-231细胞均具有显著的体外增殖抑制活性。
本发明的另一个目的是提供一种药物组合物，它以上述提及的化合物、异构体或其药学上可接受的盐为活性成分或主要活性成分，辅以药学上可接受的载体。
本发明的第三目的是提供一种上述化合物、异构体或其药学上可接受的盐在制备与肿瘤有关疾病的药物方面的应用，特别在制备与肺癌、肝癌或乳腺癌的药物方面的应用。
本发明的技术方案如下：
式I所示的化合物、异构体或其药学上可接受的盐：
其中，
R1代表C1-C6烷基、C1-C6烷氧基、苯基、苄基或吡啶基；
R2代表氢、卤素或C1-C6烷基；
R3代表氢、卤素、羟基、硝基、氨基、氰基、C1-C6烷基、C1-C4卤代烷基、C1-C6烷氧基、C1-C6烷氨基烷氧基、苯基、取代苯基、吡啶基、取代吡啶基、吗啉基、取代吗啉基、哌嗪基或取代哌嗪基，所述的取代苯基、取代吡啶基、取代吗啉基或取代哌嗪基可任意地由下述取代基单取代或多取代：卤素、羟基、硝基、氨基、氰基、C1-C3烷基、C1-C3烷氧基或C1-C3烷氨基；
R4代表氢、卤素、羟基、硝基、氨基、氰基、C1-C3烷基、C1-C3卤代烷基或C1-C3烷氧基。
在一种优选方案中，R1代表C1-C4烷基、C1-C3烷氧基、苯基、苄基或吡啶基。
在一种更优选方案中，R1代表甲基、乙基、异丙基、叔丁基、甲氧基、乙氧基或苯基。
在一种特别更优选方案中，R1代表叔丁基。
在一种优选方案中，本发明提及的R2代表氢、卤素或C1-C3烷基。
在一种更优选方案中，R2代表氢、氟、氯、溴、甲基或乙基。
在一种特别更优选方案中，R2代表氢。
在一种优选方案中，本发明提及的R3代表氢、氟、氯、溴、羟基、硝基、氨基、氰基、C1-C4烷基、C1-C4烷氧基、苯基、取代苯基、吡啶基、取代吡啶基、吗啉基、哌嗪基或取代哌嗪基，所述的取代苯基、取代吡啶基或取代哌嗪基可任意地由下述取代基单取代或多取代：氟、氯、溴、羟基、硝基、氨基、氰基、甲基、乙基、甲氧基、乙氧基、二甲基氨基或二乙基氨基。
在一种更优选方案中，R3代表氯、氨基、甲基、乙基、甲氧基、乙氧基、异丙氧基、苯基、取代苯基、吡啶基、取代吡啶基、吗啉基、哌嗪基或取代哌嗪基，所述的取代苯基、取代吡啶基或取代哌嗪基可任意地由下述取代基单取代或多取代：氟、氯、溴、氨基、甲基、甲氧基或二甲基氨基。
在一种特别更优选方案中，R3代表氯、甲基、甲氧基、乙氧基、异丙氧基、苯基、4-甲基苯基、3-甲基苯基、4-氯苯基、3-氯苯基、4-氟苯基、4-溴苯基、4-甲氧基苯基、3,4-二甲氧基苯基、4-氨基苯基、4-二甲基氨基苯基、吡啶基、吗啉基、哌嗪基或4-甲基哌嗪基。
进一步地，R3代表4-甲基苯基、4-氯苯基、4-溴苯基、4-甲氧基苯基、4-氨基苯基、4-二甲基氨基苯基或吡啶基。
在一种优选方案中，本发明提及的R4代表氢、卤素、氨基、C1-C3烷基或C1-C3烷氧基。
在一种更优选方案中，R4代表氢、氟、氯、溴、甲基、乙基、甲氧基或乙氧基。
在一种特别更优选方案中，R4代表氢。
进一步地，在通式I所述化合物、异构体或其药学上可接受的盐中，所述化合物选自下列化合物：
2'-(叔丁基)-1-(2-苯基喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I1)；
2'-(叔丁基)-1-(2-(对甲基苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I2)；
2'-(叔丁基)-1-(2-(邻甲基苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I3)；
2'-(叔丁基)-1-(2-(4-氯苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I4)；
2'-(叔丁基)-1-(2-(2-氯苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I5)；
2'-(叔丁基)-1-(2-(4-氟苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I6)；
2'-(叔丁基)-1-(2-(4-溴苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I7)；
2'-(叔丁基)-1-(2-(4-甲氧基苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I8)；
2'-(叔丁基)-1-(2-(3,4-二甲氧基苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I9)；
2'-(叔丁基)-1-(2-(4-氨基苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I10)；
2'-(叔丁基)-1-(2-(4-(二甲基氨基)苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I11)；
2'-(叔丁基)-1-(2-(吡啶-4-基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I12)；
2'-(叔丁基)-1-(2-(吡啶-2-基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I13)；
2'-(叔丁基)-1-(2-吗啉代喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I14)；
2'-(叔丁基)-1-(2-(4-甲基哌嗪-1-基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I15)；
2'-(叔丁基)-1-(2-(哌嗪-1-基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I16)；
2'-(叔丁基)-1-(2-甲基喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I17)；
2'-(叔丁基)-1-(2-氯喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I18)；
2'-(叔丁基)-1-(2-甲氧基喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I19)；
2'-(叔丁基)-1-(2-乙氧基喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I20)；
2'-(叔丁基)-1-(2-异丙氧基喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I21)。
上述提及的化合物I1～I21的化学结构式如下所示：
更进一步地，通式I所述化合物进一步选自下列化合物：
2'-(叔丁基)-1-(2-苯基喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I1)；
2'-(叔丁基)-1-(2-(对甲基苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I2)；
2'-(叔丁基)-1-(2-(4-氯苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I4)；
2'-(叔丁基)-1-(2-(4-氟苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I6)；
2'-(叔丁基)-1-(2-(4-溴苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I7)；
2'-(叔丁基)-1-(2-(4-甲氧基苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I8)；
2'-(叔丁基)-1-(2-(3,4-二甲氧基苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I9)；
2'-(叔丁基)-1-(2-(4-氨基苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I10)；
2'-(叔丁基)-1-(2-(4-(二甲基氨基)苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I11)；
2'-(叔丁基)-1-(2-(吡啶-4-基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I12)；
2'-(叔丁基)-1-(2-(吡啶-2-基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I13)。
进一步优选的化合物对应的结构式如下所示：
本发明公开了一种通式I所述化合物的制备方法，可以参照申请号为2009144554的国际专利中公开的ACC抑制剂的制备方法，通式I所示化合物的合成路线如下：
上述合成路线的具体制备方法包括如下步骤：将丙酮醛和肼衍生物在酸性条件下反应制得腙衍生物(II)，II与α-酮醛衍生物在酸性条件下反应生成1-(4-羟基-1H-吡唑-3-基)乙酮衍生物(III)，III与N-BOC-哌啶酮在胺存在条件下反应生成N-BOC保护的吡唑螺环酮类衍生物(IV)，IV在酸性条件下脱保护得到吡唑螺环酮类衍生物(V)，V与4-喹啉羧酸衍生物在多肽缩合试剂催化下反应生成喹啉-4-羰基-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮衍生物(I)，具体更加详细的合成路线如下：
由V制备通式I化合物的步骤中，所采用的溶剂选自氯仿、二氯甲烷、四氢呋喃(THF)、N,N-二甲基甲酰胺(DMF)、二氧六环中的一种或多种，优先采用四氢呋喃(THF)、N,N-二甲基甲酰胺(DMF)；所采用的多肽缩合试剂选自2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、二环己基碳二亚胺/1-羟基苯并三唑(DCC/HOBt)；所采用的碱选自N,N-二异丙基乙胺(DIEA)、N-甲基吗啉(NMM)、三乙胺(Et3N)中的一种或多种，优先采用三乙胺(Et3N)；采用的反应温度为室温反应。
本发明提供的化合物、异构体，或其药学上可接受的盐可以用于制备与肿瘤相关疾病的药物方面，特别是用于制备抗肺癌、抗肝癌或抗乳腺癌药物方面。
在一种方案中，本发明提供了一种药物组合物，它以本发明的化合物、异构体，或其药学上可接受的盐为活性成分或主要活性成分，辅以药学上可接受的载体。进一步的，该药物组合可以制成固体制剂或者液体制剂，特别是可以制成注射剂、口服液、颗粒剂、粉剂、片剂或胶囊剂。
本发明提及的中间体或目标化合物均可按照常规分离技术加以纯化，并且根据需要将其转化为与可药用酸的加成盐。
除非另外说明，在说明书和权利要求中使用的以下术语具有下面讨论的含义：
“烷基”表示1-20个碳原子的饱和的脂烃基，包括直链和支链基团(本申请数中提到的数字范围，例如“1-20”，是指该基团，此时为烷基，可以含1个碳原子、2个碳原子、3个碳原子等，直至包括20个碳原子)。含1-4个碳原子的烷基称为低级烷烃。当低级烷烃没有取代基时，称其为未取代的低级烷烃。更优选的是，烷基是有1-6个碳原子的中等大小的烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基、戊基等。最好是，烷基为有1-4个碳原子的低级烷基。例如甲基、乙基、丙基、2-丙基、正丁基、异丁基或叔丁基等。烷基可以是取代的或未取代的。当是取代的烷基时，该取代基优选是一或多个，更优选1-3个，最优选1或2个取代基。
“卤代烷基”表示卤素取代的烷基，优选如上所定义的卤素取代的低级烷基，它被一个或多个相同或不同的卤原子取代，例如-CH2Cl、-CF3、-CH2CF3、-CH2CCl3等。
“卤素”表示氟、氯、溴或碘，优选为氟、氯、溴。
“氨基”表示-NH2基团。
“羟基”表示-OH基团。
“硝基”表示-NO2基团。
“氰基”表示-CN基团。
“烷氧基”表示-O-(未取代的烷基)和-O-(未取代的环烷基)。代表性实例包括但不限于甲氧基、乙氧基、异丙氧基等。
“烷氨基”表示-NH-(烷基)、-N(烷基)2，其中此处的烷基可以为取代或非取代的烷基，例如甲氨基、乙氨基、二甲氨基等。
“烷氨基烷氧基”表示烷氧基上的至少一个氢为烷氨基取代的基团，例如二甲氨基甲氧基、二甲氨基乙氧基、甲氨基乙氧基等。
杂环基：表示单环或稠合环基团，在环中具有4到9个环原子，其中一个或两个环原子是选自N、O或S(O)m(其中m是0至2的整数)的杂原子，其余环原子是C。这些环可以具有一条或多条双键，但这些环不具有完全共轭的π电子系统。未取代的杂脂环基的非限制性实例有吡咯烷基、吡啶基、哌啶基、哌嗪基、吗啉基等。
“药学上可接受的盐”表示保留母体化合物的生物有效性和性质的那些盐。这类盐包括：
(1)与酸成盐，通过母体化合物的游离碱与无机酸或有机酸的反应而得，无机酸包括盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等，有机酸包括乙酸、三氟乙酸、丙酸、丙烯酸、己酸、环丙烷丙酸、羟乙酸、丙酮酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、苯甲酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、肉桂酸、十二烷基硫酸、葡糖酸、谷氨酸、天冬氨酸、硬脂酸、扁桃酸、琥珀酸、戊二酸或丙二酸等。
(2)存在于母体化合物中的酸性质子被金属离子代替或者与有机碱配位化合所生成的盐，金属例子例如碱金属离子、碱土金属离子或铝离子，有机碱例如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺、奎宁等。
“药物组合物”指将本发明中的化合物中的一个或多个或其药学上可接受的盐、溶剂化物、水合物或前药与别的化学成分，例如药学上可接受的载体，混合。药物组合物的目的是促进给药给动物的过程。
“药用载体”或“药学上可接受的载体”指的是对有机体不引起明显的刺激性和不干扰所给予化合物的生物活性和性质的药物组合物中的非活性成分，例如但不限于：碳酸钙、磷酸钙、各种糖(例如乳糖、甘露醇等)、淀粉、环糊精、硬脂酸镁、纤维素、碳酸镁、丙烯酸聚合物或甲基丙烯酸聚合物、凝胶、水、聚乙二醇、丙二醇、乙二醇、蓖麻油或氢化蓖麻油或多乙氧基氢化蓖麻油、芝麻油、玉米油、花生油等。
采用本发明的技术方案，优势如下：
本发明提供的一类含喹啉基团的螺吡唑酮类ACC抑制剂，不仅对ACC具有良好的酶活，而且具有良好的抗肿瘤活性，例如，对A549、HepG2、MDA-MB-231细胞均具有显著的体外增殖抑制活性。本发明的化合物、异构体或其药学上可接受的盐可应用在抗肿瘤药物制备中，特别是在抗肺癌、抗肝癌或抗乳腺癌药物中具有优异的应用前景。
附图说明
图1是棕榈酸对化合物I12抗肿瘤作用的拯救效果；其中：A为不同浓度棕榈酸(0～200μM)在1,3,5天对HepG2细胞的脂毒性作用；B为棕榈酸(25,10μM)对化合物I12细胞毒性的拯救效果。
图2是Hoechst染色和流式细胞术检测化合物I12对细胞凋亡的影响；其中：A为与化合物I12(0，1，5,10μM)共孵育48h后，HepG2细胞形态的Hoechst染色图；B为HepG2细胞和不同浓度I12(0，1，5,10μM)孵育48h后，用Annexin V-FITC/PI染色和流式细胞术分析得到的细胞分布图；C为凋亡细胞百分比的直方图。
具体实施方式
为了进一步阐明本发明，下面给出一系列实施例，这些实施例完全是例证性的，它们仅用来对本发明具体描述，不应当理解为对本发明的限制。
实施例1
2'-(叔丁基)-1-(2-苯基喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I1)
将叔丁基肼盐酸盐(3.74g,30mmol)和丙酮醛(4.5g,25mmol)的水溶液(120mL)室温反应2h；二氯甲烷萃取反应液，合并有机相，无水硫酸钠干燥，减压浓缩，得到化合物(E)-1-(2-(叔丁基)肼基)丙烷-2-酮。将(E)-1-(2-(叔丁基)肼基)丙烷-2-酮(8.8g,62mmol)和40％乙二醛溶液(25mL,180mmol)溶于100mL蒸馏水中，加热回流5h；冷却至室温后，乙酸乙酯萃取反应液，合并有机相，无水硫酸钠干燥，减压浓缩，得到化合物1-叔丁基-4-羟基吡唑-3-乙酮。将1-叔丁基-4-羟基吡唑-3-乙酮(4.4g,24mmol)、四氢吡咯(568mg,8mmol)、N-BOC-哌啶酮(5.54g,28mmol)溶于45mL甲醇溶液中，加热回流24h；减压浓缩，残余物加入70mL蒸馏水，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，减压浓缩，粗产品经硅胶柱层析纯化得到化合物N-叔丁氧羰基-2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮。将N-叔丁氧羰基-2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(400mg,1.1mmol)和1.5mL三氟乙酸溶于3mL二氯甲烷溶液中，室温反应2h；减压浓缩，得化合物2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮。在冰浴条件下，将2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(400mg,1.1mmol)、HATU(458mg,1.2mmol)、三乙胺(0.2ml,1.2mmol)溶于10mL DMF中，0℃搅拌0.5h，加入2-苯基喹啉-4-羧酸(1mmol,250mg)，室温反应12h；将反应液加入到50mL冰水中，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，减压浓缩，粗产品经硅胶柱层析纯化得标题化合物I1。
White solid,yield 85％,m.p.161.5-162.5℃。1H NMR(400MHz,CDCl3):δ8.24(d,J＝8.5Hz,1H),8.16(dd,J＝6.6,4.6Hz,2H),7.84(dd,J＝8.2,3.3Hz,1H),7.77(dd,J＝9.5,4.7Hz,2H),7.64-7.45(m,4H),7.23(d,J＝3.0Hz,1H),4.74(t,J＝8.0Hz,1H),3.44-3.35(m,2H),3.25(t,J＝11.3Hz,1H),2.76-2.64(m,2H),2.38-2.26(m,1H),1.98(t,J＝15.2Hz,1H),1.89-1.79(m,1H),1.64(s,1H),1.59(s,9H).13C NMR(100MHz,CDCl3):δ185.5,167.1,157.1,156.9,148.3,147.0,143.2,138.8,138.8,134.2,130.5,130.4,130.3,129.9,129.8,129.0,127.5,127.4,124.3,124.0,123.2,123.0,115.7,112.3,80.6,80.5,60.9,49.2,42.8,42.7,37.1,34.8,34.5,34.0,33.8,29.6.HRMS m/z calcd for C30H30N4O3[M+H]+495.2391,found 495.2388.
实施例2
2'-(叔丁基)-1-(2-(对甲基苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I2)
按实施例1的方法，制得化合物2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮。在冰浴条件下，将2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(400mg,1.1mmol)、HATU(458mg,1.2mmol)、三乙胺(0.2ml,1.2mmol)溶于10mL DMF中，0℃搅拌0.5h，加入2-(对甲基苯基)喹啉-4-羧酸(1mmol,265mg)，室温反应12h；将反应液加入到50mL冰水中，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，减压浓缩，粗产品经硅胶柱层析纯化得标题化合物I2。
Yellow solid,yield 80％,m.p.164.5-165.5℃。1H NMR(400MHz,CDCl3):δ8.22(d,J＝8.3Hz,1H),8.06(dd,J＝8.1,4.4Hz,2H),7.82-7.74(m,3H),7.56(dd,J＝16.4,8.0Hz,1H),7.34(dd,J＝7.9,4.0Hz,2H),7.23(d,J＝2.8Hz,1H),4.75(t,J＝8.0Hz,1H),3.47-3.31(m,2H),3.24(t,J＝12.2Hz,1H),2.76-2.64(m,2H),2.44(s,3H),2.38-2.27(m,1H),1.97(t,J＝14.7Hz,1H),1.88-1.80(m,1H),1.64(s,1H),1.59(s,9H).13C NMR(100MHz,CDCl3):δ185.6,167.2,157.1,156.9,148.4,147.0,142.9,140.0,135.9,134.1,130.4,130.2,129.7,127.3,127.2,127.1,124.2,123.9,123.0,122.8,115.5,112.3,80.6,80.5,60.9,49.1,42.8,42.6,37.1,34.7,34.5,33.9,33.8,29.5,21.3.HRMS m/z calcd forC31H32N4O3[M+H]+509.2547,found 509.2557.
实施例3
2'-(叔丁基)-1-(2-(邻甲基苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I3)
按实施例1的方法，制得化合物2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮。在冰浴条件下，将2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(400mg,1.1mmol)、HATU(458mg,1.2mmol)、三乙胺(0.2ml,1.2mmol)溶于10mL DMF中，0℃搅拌0.5h，加入2-(邻甲基苯基)喹啉-4-羧酸(1mmol,265mg)，室温反应12h；将反应液加入到50mL冰水中，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，减压浓缩，粗产品经硅胶柱层析纯化得标题化合物I3。
Yellow solid,yield 75％,m.p.159.5-160.5℃。1H NMR(400MHz,CDCl3):δ8.24(d,J＝8.2Hz,1H),7.91-7.74(m,2H),7.63(dd,J＝16.0,8.6Hz,1H),7.48(t,J＝12.5Hz,2H),7.40-7.30(m,3H),7.24(d,J＝2.8Hz,1H),4.74(t,J＝13.5Hz,1H),3.54-3.22(m,3H),2.79-2.61(m,2H),2.43(s,3H),2.32(t,J＝12.2Hz,1H),2.01(t,J＝16.0Hz,1H),1.89-1.74(m,1H),1.64(s,1H),1.59(s,9H).13C NMR(100MHz,CDCl3):δ185.5,167.0,159.9,148.0,147.0,142.3,139.7,135.9,134.1,131.0,130.4,130.3,130.2,129.7,128.9,127.6,127.4,126.1,124.4,124.1,122.8,122.6,118.8,112.3,80.6,80.5,60.9,49.1,42.8,42.7,37.1,34.8,34.4,33.9,29.5,20.4.HRMS m/z calcd for C31H32N4O3[M+H]+509.2547,found 509.2561.
实施例4
2'-(叔丁基)-1-(2-(4-氯苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I4)
按实施例1的方法，制得化合物2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮。在冰浴条件下，将2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(400mg,1.1mmol)、HATU(458mg,1.2mmol)、三乙胺(0.2ml,1.2mmol)溶于10mL DMF中，0℃搅拌0.5h，加入2-(4-氯苯基)喹啉-4-羧酸(1mmol,285mg)，室温反应12h；将反应液加入到50mL冰水中，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，减压浓缩，粗产品经硅胶柱层析纯化得标题化合物I4。
White solid,yield 78％,m.p.222.5-223.5℃。1H NMR(400MHz,CDCl3):δ8.22(d,J＝8.3Hz,1H),8.12(dd,J＝8.5,5.7Hz,2H),7.86-7.71(m,3H),7.60(dd,J＝16.8,7.7Hz,1H),7.51(dd,J＝8.6,4.1Hz,2H),7.23(d,J＝4.8Hz,1H),4.75(t,J＝11.3Hz,1H),3.49-3.31(m,2H),3.23(t,J＝12.2Hz,1H),2.77-2.65(m,2H),2.34(t,J＝11.4Hz,1H),1.99(t,J＝14.5Hz,1H),1.88-1.74(m,1H),1.64(s,1H),1.59(s,9H).13C NMR(100MHz,CDCl3):δ185.5,166.9,162.1,155.8,155.6,148.1,147.0,143.4,136.1,134.1,130.7,130.5,130.3,129.1,128.7,127.7,127.5,124.3,124.0,123.2,123.0,115.3,115.2,112.3,80.6,80.4,60.9,49.1,42.8,42.7,37.1,34.7,34.5,34.0,33.8,29.5.HRMS m/z calcd forC30H29ClN4O3[M+H]+529.2001,found 529.1991.
实施例5
2'-(叔丁基)-1-(2-(2-氯苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I5)
按实施例1的方法，制得化合物2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮。在冰浴条件下，将2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(400mg,1.1mmol)、HATU(458mg,1.2mmol)、三乙胺(0.2ml,1.2mmol)溶于10mL DMF中，0℃搅拌0.5h，加入2-(2-氯苯基)喹啉-4-羧酸(1mmol,285mg)，室温反应12h；将反应液加入到50mL冰水中，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，减压浓缩，粗产品经硅胶柱层析纯化得标题化合物I5。
Yellow solid,yield 68％,m.p.216.5-217.5℃。1H NMR(400MHz,CDCl3):δ8.27(d,J＝8.1Hz,1H),7.94-7.77(m,2H),7.76-7.60(m,3H),7.52(d,J＝7.1Hz,1H),7.48-7.38(m,2H),7.24(d,J＝3.5Hz,1H),4.74(t,J＝5.6Hz,1H),3.49-3.34(m,3H),2.80-2.61(m,2H),2.33(t,J＝12.1Hz,1H),2.04(t,J＝16.0Hz,1H),1.92-1.77(m,1H),1.65(s,1H),1.59(s,9H).13C NMR(100MHz,CDCl3):δ185.5,166.8,156.9,148.2,147.0,141.7,138.8,134.1,132.1,131.7,131.6,130.3,130.1,128.0,127.8,127.4,124.6,124.2,123.2,123.1,119.4,112.3,80.7,80.5,60.9,49.2,42.7,37.2,35.0,34.3,33.9,29.5.HRMS m/z calcdfor C30H29ClN4O3[M+H]+529.2001,found 529.1996.
实施例6
2'-(叔丁基)-1-(2-(4-氟苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I6)
按实施例1的方法，制得化合物2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮。在冰浴条件下，将2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(400mg,1.1mmol)、HATU(458mg,1.2mmol)、三乙胺(0.2ml,1.2mmol)溶于10mL DMF中，0℃搅拌0.5h，加入2-(4-氟苯基)喹啉-4-羧酸(1mmol,267mg)，室温反应12h；将反应液加入到50mL冰水中，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，减压浓缩，粗产品经硅胶柱层析纯化得标题化合物I6。
White solid,yield 75％,m.p.>240℃。1H NMR(400MHz,CDCl3):δ8.22(d,J＝8.0Hz,1H),8.20-8.13(m,2H),7.86-7.70(m,3H),7.59(dd,J＝16.3,9.2Hz,1H),7.24(d,J＝5.0Hz,3H),4.75(t,J＝12.1Hz,1H),3.49-3.31(m,2H),3.23(t,J＝12.1Hz,1H),2.77-2.65(m,2H),2.34(t,J＝11.9Hz,1H),1.99(t,J＝14.5Hz,1H),1.87-1.80(m,1H),1.64(s,1H),1.59(s,9H).13C NMR(100MHz,CDCl3):δ185.6,167.0,162.8,155.8,148.2,147.0,143.3,134.8,134.1,130.7,130.5,130.2,129.4,127.6,127.4,124.3,124.0,123.0,116.1,115.8,115.4,112.4,80.6,80.5,60.9,49.1,42.9,42.7,37.1,34.7,34.5,34.0,33.8,29.5.HRMS m/z calcd for C30H29FN4O3[M+H]+513.2296,found 513.2307.
实施例7
2'-(叔丁基)-1-(2-(4-溴苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I7)
按实施例1的方法，制得化合物2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮。在冰浴条件下，将2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(400mg,1.1mmol)、HATU(458mg,1.2mmol)、三乙胺(0.2ml,1.2mmol)溶于10mL DMF中，0℃搅拌0.5h，加入2-(4-溴苯基)喹啉-4-羧酸(1mmol,327mg)，室温反应12h；将反应液加入到50mL冰水中，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，减压浓缩，粗产品经硅胶柱层析纯化得标题化合物I7。
Yellow solid,yield 70％,m.p.171.5-172.5℃。1H NMR(400MHz,CDCl3):δ8.22(d,J＝8.3Hz,1H),8.10–8.00(m,2H),7.85-7.70(m,3H),7.67(dd,J＝7.8,2.7Hz,2H),7.60(dd,J＝15.9,8.2Hz,1H),7.23(d,J＝4.0Hz,1H),4.74(t,J＝11.0Hz,1H),3.50-3.32(m,2H),3.22(t,J＝11.2Hz,1H),2.82-2.61(m,2H),2.34(t,J＝8.0Hz,1H),1.98(t,J＝13.6Hz,1H),1.91-1.79(m,1H),1.74(s,1H),1.59(s,9H).13C NMR(100MHz,CDCl3):δ185.5,167.0,155.9,155.7,148.2,147.0,143.3,137.6,134.1,132.1,130.7,130.5,130.3,129.0,127.7,127.6,124.3,124.0,123.2,123.0,115.3,112.3,80.6,80.5,60.9,49.1,42.8,42.7,37.2,34.7,34.5,34.0,33.8,29.5.HRMS m/z calcd for C30H29BrN4O3[M+H]+573.1496,found 573.1493.
实施例8
2'-(叔丁基)-1-(2-(4-甲氧基苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I8)
按实施例1的方法，制得化合物2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮。在冰浴条件下，将2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(400mg,1.1mmol)、HATU(458mg,1.2mmol)、三乙胺(0.2ml,1.2mmol)溶于10mL DMF中，0℃搅拌0.5h，加入2-(4-甲氧基苯基)喹啉-4-羧酸(1mmol,280mg)，室温反应12h；将反应液加入到50mL冰水中，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，减压浓缩，粗产品经硅胶柱层析纯化得标题化合物I8。
White solid,yield 73％,m.p.218.5-219.5℃。1H NMR(400MHz,CDCl3):δ8.19(d,J＝8.3Hz,1H),8.13(dd,J＝8.6,5.1Hz,2H),7.85-7.69(m,3H),7.55(dd,J＝15.4,8.3Hz,1H),7.23(d,J＝3.3Hz,1H),7.05(dd,J＝8.7,3.8Hz,2H),4.74(t,J＝8.6Hz,1H),3.89(s,3H),3.50-3.31(m,2H),3.25(t,J＝11.4Hz,1H),2.76-2.64(m,2H),2.33(t,J＝9.6Hz,1H),1.97(t,J＝15.1Hz,1H),1.89-1.76(m,1H),1.64(s,1H),1.58(s,9H).13C NMR(100MHz,CDCl3):δ185.6,167.2,161.2,161.1,156.6,156.5,148.3,147.0,142.9,134.1,131.3,131.2,130.4,130.3,130.1,128.9,127.1,126.9,124.2,123.9,122.8,122.6,115.2,114.3,114.3,112.3,80.6,80.5,60.9,55.4,49.2,42.8,42.6,37.1,34.7,34.5,34.0,33.8,29.5.HRMS m/z calcd for C31H32N4O4[M+H]+525.2496,found 525.2489.
实施例9
2'-(叔丁基)-1-(2-(3,4-二甲氧基苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I9)
按实施例1的方法，制得化合物2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮。在冰浴条件下，将2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(400mg,1.1mmol)、HATU(458mg,1.2mmol)、三乙胺(0.2ml,1.2mmol)溶于10mL DMF中，0℃搅拌0.5h，加入2-(3,4-二甲氧基苯基)喹啉-4-羧酸(1mmol,310mg)，室温反应12h；将反应液加入到50mL冰水中，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，减压浓缩，粗产品经硅胶柱层析纯化得标题化合物I9。
Yellow solid,yield 85％,m.p.169.5-170.5℃。1H NMR(400MHz,CDCl3):δ8.23(s,1H),7.87(d,J＝9.7Hz,1H),7.82-7.71(m,3H),7.66(d,J＝8.4Hz,1H),7.59-7.52(m,1H),7.23(d,J＝6.3Hz,1H),7.01(dd,J＝8.4,5.5Hz,1H),4.75(t,J＝12.2Hz,1H),4.06(s,3H),3.97(s,3H),3.48-3.32(m,2H),3.24(t,J＝12.1Hz,1H),2.79-2.62(m,2H),2.34(t,J＝12.0Hz,1H),1.98(t,J＝14.3Hz,1H),1.88-1.79(m,1H),1.64(s,1H),1.59(s,9H).13CNMR(100MHz,CDCl3):δ185.6,167.2,156.6,156.4,150.7,150.7,149.4,149.4,148.2,147.0,142.9,134.1,131.6,131.5,130.4,130.3,130.1,127.2,127.0,124.2,123.9,122.9,122.7,120.3,120.3,115.4,115.3,112.4,111.0,110.2,80.6,80.5,60.9,56.0,56.0,49.1,42.8,42.7,37.1,34.7,34.4,34.0,33.8,29.5.HRMS m/z calcd for C32H34N4O5[M+H]+555.2602,found 555.2586.
实施例10
2'-(叔丁基)-1-(2-(4-氨基苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I10)
按实施例1的方法，制得化合物2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮。在冰浴条件下，将2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(400mg,1.1mmol)、HATU(458mg,1.2mmol)、三乙胺(0.2ml,1.2mmol)溶于10mL DMF中，0℃搅拌0.5h，加入2-(4-氨基苯基)喹啉-4-羧酸(1mmol,265mg)，室温反应12h；将反应液加入到50mL冰水中，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，减压浓缩，粗产品经硅胶柱层析纯化得标题化合物I10。
Yellow solid,yield 55％,m.p.>240℃。1H NMR(400MHz,CDCl3):δ8.23(d,J＝10.0Hz,1H),8.03(dd,J＝8.4,6.9Hz,2H),7.78-7.69(m,3H),7.53(dd,J＝15.9,7.7Hz,1H),7.24(d,J＝2.7Hz,1H),6.81(dd,J＝8.6,3.4Hz,2H),4.74(t,J＝12.0Hz,1H),3.48-3.31(m,2H),3.25(t,J＝11.7Hz,1H),2.76-2.63(m,2H),2.33(t,J＝16.0Hz,1H),1.97(t,J＝15.9Hz,1H),1.88-1.77(m,1H),1.64(s,1H),1.59(s,9H).13C NMR(100MHz,CDCl3):δ185.8,167.5,157.1,156.9,148.5,148.4,147.1,142.8,142.7,134.2,130.4,130.3,130.0,128.9,126.8,126.7,124.3,124.0,122.8,122.6,115.2,112.5,80.8,80.6,61.0,49.3,42.9,42.8,37.2,34.9,34.6,34.1,33.9,29.7.HRMS m/z calcd for C30H31N5O3[M+H]+510.2500,found 510.2504.
实施例11
2'-(叔丁基)-1-(2-(4-(二甲基氨基)苯基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I11)
按实施例1的方法，制得化合物2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮。在冰浴条件下，将2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(400mg,1.1mmol)、HATU(458mg,1.2mmol)、三乙胺(0.2ml,1.2mmol)溶于10mL DMF中，0℃搅拌0.5h，加入2-(4-(二甲基氨基)苯基)喹啉-4-羧酸(1mmol,293mg)，室温反应12h；将反应液加入到50mL冰水中，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，减压浓缩，粗产品经硅胶柱层析纯化得标题化合物I11。
Red solid,yield 55％,m.p.199.5-200.5℃。1H NMR(400MHz,CDCl3):δ8.19(d,J＝9.1Hz,1H),8.10(dd,J＝8.6,4.8Hz,2H),7.78-7.66(m,3H),7.49(dd,J＝15.6,8.1Hz,1H),7.23(d,J＝1.9Hz,1H),6.83(dd,J＝9.0,3.5Hz,2H),4.73(t,J＝7.6Hz,1H),3.44-3.35(m,2H),3.26(t,J＝11.9Hz,1H),3.06(s,6H),2.79-2.61(m,2H),2.32(t,J＝9.6Hz,1H),1.96(t,J＝15.9Hz,1H),1.88-1.75(m,1H),1.64(s,1H),1.59(s,9H).13C NMR(100MHz,CDCl3):δ185.6,167.5,157.0,156.9,151.6,148.4,147.0,142.5,134.2,130.1,129.8,128.5,126.5,126.3,124.2,123.9,122.6,115.0,112.3,112.1,80.7,80.6,60.9,49.2,42.8,42.6,40.3,37.1,34.8,34.5,34.0,33.9,29.6.HRMS m/z calcd for C32H35N5O3[M+H]+538.2813,found 538.2811.
实施例12
2'-(叔丁基)-1-(2-(吡啶-4-基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I12)
按实施例1的方法，制得化合物2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮。在冰浴条件下，将2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(400mg,1.1mmol)、HATU(458mg,1.2mmol)、三乙胺(0.2ml,1.2mmol)溶于10mL DMF中，0℃搅拌0.5h，加入2-(吡啶-4-基)喹啉-4-羧酸(1mmol,251mg)，室温反应12h；将反应液加入到50mL冰水中，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，减压浓缩，粗产品经硅胶柱层析纯化得标题化合物I12。
Yellow solid,yield 65％,m.p.154.5-155.5℃。1H NMR(400MHz,CDCl3):δ8.81(s,2H),8.25(d,J＝8.8Hz,1H),8.07(dd,J＝11.5,5.5Hz,2H),7.92-7.78(m,3H),7.66(dd,J＝17.9,8.1Hz,1H),7.24(d,J＝4.8Hz,1H),4.76(t,J＝12.0Hz,1H),3.52-3.34(m,2H),3.21(t,J＝11.7Hz,1H),2.79-2.61(m,2H),2.35(t,J＝11.6Hz,1H),1.99(t,J＝12.9Hz,1H),1.90-1.80(m,1H),1.61(s,1H),1.59(s,9H).13C NMR(100MHz,CDCl3):δ185.5,166.7,154.3,154.1,150.4,148.4,148.3,146.9,145.9,143.6,134.1,130.9,130.8,130.7,128.5,128.3,124.3,124.1,123.8,123.6,121.5,115.3,115.2,112.3,80.5,80.4,60.9,49.1,42.8,42.7,37.2,34.6,34.5,33.9,33.7,29.5.HRMS m/z calcd for C29H29N5O3[M+H]+496.2343,found 496.2356.
实施例13
2'-(叔丁基)-1-(2-(吡啶-2-基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I13)
按实施例1的方法，制得化合物2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮。在冰浴条件下，将2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(400mg,1.1mmol)、HATU(458mg,1.2mmol)、三乙胺(0.2ml,1.2mmol)溶于10mL DMF中，0℃搅拌0.5h，加入2-(吡啶-2-基)喹啉-4-羰基(1mmol,251mg)，室温反应12h；将反应液加入到50mL冰水中，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，减压浓缩，粗产品经硅胶柱层析纯化得标题化合物I13。
White solid,yield 62％,m.p.229.5-230.5℃。1H NMR(400MHz,CDCl3):δ8.81-8.65(m,2H),8.55(d,J＝23.0Hz,1H),8.23(d,J＝8.4Hz,1H),7.97-7.73(m,3H),7.61(dd,J＝16.3,8.4Hz,1H),7.46-7.37(m,1H),7.25(d,J＝8.3Hz,1H),4.76(t,J＝8.0Hz,1H),3.58-3.21(m,3H),2.82-2.58(m,2H),2.32(t,J＝8.7Hz,1H),1.99(t,J＝9.6Hz,1H),1.90–1.76(m,1H),1.64(s,1H),1.59(s,9H).13C NMR(100MHz,CDCl3):δ185.7,167.1,155.6,155.4,149.2,149.1,148.1,148.0,147.0,142.9,137.1,134.1,130.4,130.3,130.2,127.9,127.7,124.5,124.4,124.3,124.1,121.8,115.7,112.4,112.3,80.8,80.5,60.9,49.2,42.9,42.6,37.1,34.7,34.3,34.0,33.8,29.5.HRMS m/z calcd for C29H29N5O3[M+H]+496.2343,found 496.2362.
实施例14
2'-(叔丁基)-1-(2-吗啉代喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I14)
按实施例1的方法，制得化合物2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮。在冰浴条件下，将2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(400mg,1.1mmol)、HATU(458mg,1.2mmol)、三乙胺(0.2ml,1.2mmol)溶于10mL DMF中，0℃搅拌0.5h，加入2-吗啉代喹啉-4-羧酸(1mmol,259mg)，室温反应12h；将反应液加入到50mL冰水中，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，减压浓缩，粗产品经硅胶柱层析纯化得标题化合物I14。
Yellow solid,yield 72％,m.p.167.5-168.5℃。1H NMR(400MHz,CDCl3):δ7.74(d,J＝3.9Hz,1H),7.64-7.48(m,2H),7.30(d,J＝7.5Hz,1H),7.23(d,J＝8.7Hz,1H),6.89(d,J＝25.4Hz,1H),4.68(t,J＝13.0Hz,1H),3.85(d,J＝4.8Hz,4H),3.73(d,J＝0.6Hz,4H),3.44-3.30(m,2H),3.22(t,J＝16.1Hz,1H),2.76-2.59(m,2H),2.30(t,J＝12.3Hz,1H),1.99(t,J＝9.6Hz,1H),1.83-1.75(m,1H),1.65(s,1H),1.59(s,9H).13C NMR(100MHz,CDCl3):δ185.8,167.5,156.9,147.1,144.2,134.2,130.6,127.4,124.2,123.9,123.6,119.3,119.1,112.5,112.4,106.3,106.1,80.7,80.7,66.9,61.0,49.3,45.5,42.9,42.7,37.1,34.8,34.5,34.0,29.7.HRMS m/z calcd for C28H33N5O4[M+H]+504.2605,found504.2616.
实施例15
2'-(叔丁基)-1-(2-(4-甲基哌嗪-1-基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I15)
按实施例1的方法，制得化合物2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮。在冰浴条件下，将2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(400mg,1.1mmol)、HATU(458mg,1.2mmol)、三乙胺(0.2ml,1.2mmol)溶于10mL DMF中，0℃搅拌0.5h，加入2-(4-甲基哌嗪-1-基)喹啉-4-羧酸(1mmol,272mg)，室温反应12h；将反应液加入到50mL冰水中，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，减压浓缩，粗产品经硅胶柱层析纯化得标题化合物I15。
Yellow solid,yield 65％,m.p.161.5-162.5℃。1H NMR(400MHz,CDCl3):δ7.71(d,J＝8.4Hz,1H),7.61-7.44(m,2H),7.23(d,J＝7.8Hz,2H),6.90(d,J＝25.2Hz,1H),4.67(t,J＝13.1Hz,1H),3.91-3.67(m,4H),3.46-3.12(m,3H),2.78-2.64(m,2H),2.62-2.51(m,4H),2.38(s,3H),2.29(t,J＝11.9Hz,1H),1.98(t,J＝14.6Hz,1H),1.85-1.75(m,1H),1.64(s,1H),1.59(s,9H).13C NMR(100MHz,CDCl3):δ185.7,167.5,156.6,156.5,148.1,148.0,147.0,143.9,134.1,130.4,130.2,127.2,124.0,123.7,123.3,123.1,119.0,118.8,112.4,112.3,106.4,106.2,80.6,80.5,60.9,54.8,49.1,46.1,44.8,42.7,42.6,37.0,34.6,34.4,33.9,29.5.HRMS m/z calcd for C29H36N6O3[M+H]+517.2922,found 517.2931.
实施例16
2'-(叔丁基)-1-(2-(哌嗪-1-基)喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I16)
按实施例1的方法，制得化合物2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮。在冰浴条件下，将2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(400mg,1.1mmol)、HATU(458mg,1.2mmol)、三乙胺(0.2ml,1.2mmol)溶于10mL DMF中，0℃搅拌0.5h，加入2-(哌嗪-1-基)喹啉-4-羧酸(1mmol,258mg)，室温反应12h；将反应液加入到50mL冰水中，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，减压浓缩，粗产品经硅胶柱层析纯化得标题化合物I16。
Yellow solid,yield 62％,m.p.166.5-167.5℃。1H NMR(400MHz,CDCl3):δ7.72(d,J＝8.4Hz,1H),7.60-7.49(m,2H),7.23(d,J＝6.9Hz,2H),6.90(d,J＝27.3Hz,1H),4.67(t,J＝13.0Hz,1H),3.91-3.60(m,4H),3.44-3.19(m,3H),3.16-3.05(m,4H),2.76-2.59(m,2H),2.30(t,J＝13.0Hz,1H),1.95(t,J＝12.0Hz,1H),1.83-1.74(m,1H),1.64(s,1H),1.59(s,9H).13C NMR(100MHz,CDCl3):δ185.7,167.4,156.6,156.4,147.9,147.0,144.0,134.1,130.5,130.3,127.4,124.0,123.7,123.6,123.4,119.1,119.0,112.4,112.3,106.4,106.2,80.6,80.5,60.9,49.4,49.2,45.1,45.1,42.7,42.6,37.0,34.6,34.4,33.9,29.5.HRMS m/z calcd for C28H34N6O3[M+H]+503.2765,found 503.2789.
实施例17
2'-(叔丁基)-1-(2-甲基喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I17)
按实施例1的方法，制得化合物2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮。在冰浴条件下，将2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(400mg,1.1mmol)、HATU(458mg,1.2mmol)、三乙胺(0.2ml,1.2mmol)溶于10mL DMF中，0℃搅拌0.5h，加入2-甲基喹啉-4-羧酸(1mmol,188mg)，室温反应12h；将反应液加入到50mL冰水中，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，减压浓缩，粗产品经硅胶柱层析纯化得标题化合物I17。
White solid,yield 65％,m.p.226.5-227.5℃。1H NMR(400MHz,CDCl3):δ8.09(d,J＝8.3Hz,1H),7.80-7.69(m,2H),7.55(dd,J＝15.6,7.8Hz,1H),7.26(s,1H),7.24(s,1H),4.71(t,J＝9.6Hz,1H),3.46-3.28(m,2H),3.18(t,J＝13.5 Hz,1H),2.77(s,3H),2.73-2.63(m,2H),2.32(t,J＝12.2 Hz,1H),1.98(t,J＝17.6Hz,1H),1.86-1.76(m,1H),1.64(s,1H),1.59(s,9H).13C NMR(100MHz,CDCl3):δ185.6,167.0,158.9,158.7,147.8,147.0,142.5,134.1,130.3,130.1,129.2,126.9,126.7,124.2,123.9,122.4,122.2,118.6,118.5,112.3,80.6,80.5,60.9,49.1,42.7,42.6,37.0,34.7,34.4,33.8,29.5,25.3.HRMSm/z calcd for C25H28N4O3[M+H]+433.2234,found 433.2244.
实施例18
2'-(叔丁基)-1-(2-氯喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I18)
按实施例1的方法，制得化合物2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮。在冰浴条件下，将2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(400mg,1.1mmol)、HATU(458mg,1.2mmol)、三乙胺(0.2ml,1.2mmol)溶于10mL DMF中，0℃搅拌0.5h，加入2-氯喹啉-4-羧酸(1mmol,208mg)，室温反应12h；将反应液加入到50mL冰水中，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，减压浓缩，粗产品经硅胶柱层析纯化得标题化合物I18。
White solid,yield 80％,m.p.219.5-220.5℃。20℃，1H NMR(400MHz,DMSO-d6):δ8.02(d,J＝8.4Hz,1H),7.89(t,J＝7.6Hz,2H),7.80-7.72(m,2H),7.65(d,J＝23.6Hz,1H),4.40(d,J＝13.2Hz,1H),3.28(s,3H),2.75(s,2H),2.51(t,J＝2.0Hz,1H),2.11(d,J＝13.6Hz,1H),1.81(s,2H),1.51(s,9H).85℃，1H NMR(400MHz,DMSO-d6):δ8.00(d,J＝8.8Hz,1H),7.87(t,J＝8.0Hz,2H),7.69(q,J＝7.6Hz,2H),7.58(s,1H),4.36(d,J＝12.8Hz,1H),3.34(t,J＝8.8Hz,2H),3.14(d,J＝14.0Hz,1H),2.74(d,J＝4Hz,2H),2.49(s,1H),2.12(d,J＝14.4Hz,1H),1.92-1.81(m,2H),1.52(s,9H).20℃，13C NMR(100MHz,DMSO-d6):δ186.2,164.6,150.1,147.9,147.4,146.7,134.0,132.1,129.0,128.8,125.7,125.5,123.5,123.3,119.4,114.2,81.4,81.3,60.9,48.9,48.6,43.0,42.9,37.5,37.4,34.3,33.9,33.3,33.2,29.6.85℃，13C NMR(100MHz,DMSO-d6):δ185.8,164.9,150.1,148.1,147.5,146.7,134.4,131.9,129.1,128.6,125.6,123.5,119.4,113.9,81.4,60.9,49.0,43.0,37.6,34.3,33.6,29.7.HRMS m/z calcd for C24H25ClN4O3[M+H]+453.1688,found453.1699.
实施例19
2'-(叔丁基)-1-(2-甲氧基喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I19)
按实施例1的方法，制得化合物2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮。在冰浴条件下，将2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(400mg,1.1mmol)、HATU(458mg,1.2mmol)、三乙胺(0.2ml,1.2mmol)溶于10mL DMF中，0℃搅拌0.5h，加入2-甲氧基喹啉-4-羧酸(1mmol,204mg)，室温反应12h；将反应液加入到50mL冰水中，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，减压浓缩，粗产品经硅胶柱层析纯化得标题化合物I19。
Yellow solid,yield 65％,m.p.>240℃。1H NMR(400MHz,CDCl3):δ7.63(dd,J＝16.9,7.4Hz,1H),7.51(dd,J＝20.3,8.3Hz,1H),7.42(dd,J＝8.4,4.0Hz,1H),7.31-7.20(m,2H),6.64(d,J＝20.1Hz,1H),4.64(t,J＝8.7Hz,1H),3.74(s,3H),3.52-3.38(m,2H),3.32(t,J＝13.7Hz,1H),2.77-2.60(m,2H),2.30(t,J＝12.2Hz,1H),2.03(t,J＝12.0Hz,1H),1.82-1.73(m,1H),1.66(s,1H),1.59(s,9H).13C NMR(100MHz,CDCl3):δ185.5,165.6,161.3,147.0,145.0,140.3,134.1,131.7,131.6,126.3,126.0,122.8,122.7,118.3,118.2,117.4,117.3,114.9,114.8,112.5,112.3,80.6,80.4,77.3,77.0,76.7,61.0,53.4,49.1,42.7,42.5,37.0,34.8,34.5,33.9,33.6,29.6.HRMS m/z calcd for C25H28N4O4[M+H]+449.2183,found 449.2184.
实施例20
2'-(叔丁基)-1-(2-乙氧基喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I20)
按实施例1的方法，制得化合物2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮。在冰浴条件下，将2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(400mg,1.1mmol)、HATU(458mg,1.2mmol)、三乙胺(0.2ml,1.2mmol)溶于10mL DMF中，0℃搅拌0.5h，加入2-乙氧基喹啉-4-羧酸(1mmol,218mg)，室温反应12h；将反应液加入到50mL冰水中，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，减压浓缩，粗产品经硅胶柱层析纯化得标题化合物I20。
Yellow solid,yield 60％,m.p.174.5-175.5℃。1H NMR(400MHz,CDCl3):δ7.67-7.58(m,1H),7.52(dd,J＝20.7,7.9Hz,1H),7.44(dd,J＝8.5,4.1Hz,1H),7.30-7.21(m,2H),6.63(d,J＝18.4Hz,1H),4.64(t,J＝8.6Hz,1H),4.33(t,J＝16.9Hz,2H),3.55-3.37(m,2H),3.31(t,J＝12.9Hz,1H),2.77-2.57(m,2H),2.30(t,J＝8.0Hz,1H),2.04(t,J＝11.0Hz,1H),1.81-1.73(m,1H),1.66(s,1H),1.59(s,9H),1.37(s,3H).13C NMR(100MHz,CDCl3):δ185.4,165.6,160.9,147.0,145.1,144.9,139.4,134.1,131.6,131.5,126.4,126.1,122.6,122.4,118.4,118.2,117.6,117.5,114.7,114.6,112.5,112.3,80.6,80.4,60.9,60.9,49.1,49.1,42.7,42.5,37.5,37.0,34.8,34.5,33.9,33.6,29.5,12.6.HRMS m/z calcd for C26H30N4O4[M+H]+463.2340,found 463.2339.
实施例21
2'-(叔丁基)-1-(2-异丙氧基喹啉-4-羰基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(I21)
按实施例1的方法，制得化合物2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮。在冰浴条件下，将2'-(叔丁基)-2'H-螺[哌啶-4,5'-吡喃并[3,2-c]吡唑]-7'(6'H)-酮(400mg,1.1mmol)、HATU(458mg,1.2mmol)、三乙胺(0.2ml,1.2mmol)溶于10mL DMF中，0℃搅拌0.5h，加入2-异丙氧基喹啉-4-羧酸(1mmol,232mg)，室温反应12h；将反应液加入到50mL冰水中，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，减压浓缩，粗产品经硅胶柱层析纯化得标题化合物I21。
White solid,yield 55％,m.p.114.5-115.5℃。1H NMR(400MHz,CDCl3):δ7.85(d,J＝8.3Hz,1H),7.64(dd,J＝18.3,9.2Hz,2H),7.39(dd,J＝15.2,7.7Hz,1H),7.23(d,J＝3.4Hz,1H),6.76(d,J＝22.6Hz,1H),5.61-5.55(m,1H),4.68(t,J＝2.6Hz,1H),3.47-3.20(m,3H),2.78-2.62(m,2H),2.29(t,J＝8.6Hz,1H),1.98(t,J＝12.6Hz,1H),1.85-1.71(m,1H),1.64(s,1H),1.59(s,9H),1.40(s,6H).13C NMR(100MHz,CDCl3):δ185.7,166.9,161.2,161.1,147.1,145.0,144.9,134.3,130.3,130.2,127.9,124.8,124.7,124.5,124.2,121.2,121.0,112.5,110.7,80.8,80.6,68.6,68.6,61.0,49.3,49.3,42.9,42.7,37.2,34.8,34.6,34.1,33.9,29.7,22.1.HRMS m/z calcd for C27H32N4O4[M+H]+477.2496,found477.2497.
实施例22
以下是本发明的代表化合物的部分药理实验及结果：本申请以申请号为WO2009144554的国际专利公开的化合物PF-1作为阳性对照，其化合物的结构式如下：
1、ADP-GloTM激酶测定实验
ACC酶与其底物ATP、Acetyl-CoA和NaHCO3进行酶学反应，利用ADP-Glo方法检测产物的量用以反映ACC酶学活性，据此，可以评价化合物对ACC酶活性的抑制能力。实验方法如下：加入4.5μL ACC到384孔板中，加0.5μL不同浓度的受试化合物，室温孵育15min；随后，每个孔内加入5μL底物工作液开始反应，实验终浓度为5nM ACC，20μM ATP，10μM acetyl-CoA，30mM NaHCO3，0.01％Brij35，2mM DTT，5％DMSO和各种浓度的目标化合物。室温孵育30min后加入10μL ADP-Glo试剂终止反应，接着室温孵育40min消耗掉剩余的ATP；加入20μL激酶检测试剂后室温孵育40min，将ADP转化为ATP。最后通过荧光素/荧光素酶反应检测ATP的含量，在Envision 2104读数仪上读取RLU信号，计算化合物对hACC酶抑制活性。PF-1和ND-630作为阳性药物对照组，实验结果如表1所示：
表1.本发明目标化合物对ACC酶抑制活性
实验结果表明(表1)：本发明列举的化合物对ACC酶具有显著的抑制活性，其中化合物I1、I2、I4、I6、I7、I8、I9、I10、I11、I12、I13均显示出纳摩尔级别的酶抑制活性，I2、I8、I9、I10、I11的活性高于阳性对照药物PF-1和ND-630，其中以I2、I10和I11活性最佳，对ACC酶的IC50分别为2.221nM、1.294nM和2.725nM。
2、MTT实验
(a)利用MTT实验研究化合物对肿瘤细胞的抗增殖作用。实验方法如下：取对数生长期的细胞以3～5×104cells/mL的密度接种于96孔板，每孔100μL细胞悬液，置恒温CO2培养箱中培养24h。吸弃96孔板中培养基，加入含有不同浓度受试化合物的培养基，置培养箱中继续培养72h。吸弃96孔板内的培养基，各孔避光加入100μL含MTT的培养基(MTT终浓度为0.5mg/ml)，培养箱避光孵育4h。吸弃上清，每孔加入100μL DMSO溶液，置摇床上低速震摇10min使甲瓒充分溶解，用酶标仪测定各孔的吸光度，计算化合物对肿瘤细胞增殖抑制情况。PF-1作为阳性药物对照组。实验结果如表2所示：
表2.本发明目标化合物体外抗肿瘤活性
实验结果表明(表2)：本发明列举的化合物对A549、HepG2、MDA-MB-231细胞均具有显著的体外增殖抑制活性，其中对HepG2表现出最佳的抑制活性；化合物I4、I7、I10、I12对HepG2的IC50值均小于1μM，分别为0.63μM、0.82μM、0.63μM、0.38μM；I10和I12对A549的IC50值也小于1μM，分别为0.97μM和0.55μM。其中，化合物I12对三种肿瘤细胞均显示出最佳的抗增殖作用，相较于阳性对照药物PF-1分别提升6.4倍,4.9倍和3.6倍。
(b)利用MTT实验研究棕榈酸(PA)对化合物抗肿瘤作用的拯救效果。首先通过MTT实验测定棕榈酸的安全浓度；随后在安全浓度下，进行棕榈酸对化合物抗肿瘤作用的拯救效果研究。实验方法同上，取对数生长期的细胞接种于96孔板中培养，随后分别加入含有不同浓度棕榈酸的培养基和含有0.5μM/L受试化合物与不同浓度棕榈酸的培养基，置培养箱中培养24、72、120h。吸弃96孔板内的培养基，各孔避光加入MTT，避光孵育4h。吸弃上清，加入DMSO溶液，用酶标仪测定各孔的吸光度，测试棕榈酸安全浓度和棕榈酸对化合物抗肿瘤作用的拯救效果，实验结果如图1所示。
实验结果(图1A)表明棕榈酸在25μM及以下浓度时，对细胞基本没有毒性，因此棕榈酸选择25、10μM浓度。图1B表明在加入棕榈酸条件下，化合物的抗肿瘤效果被显著抑制，且呈现一定的剂量依赖性；证明化合物I12可能通过抑制ACC而影响肿瘤细胞脂质合成，从而发挥抗肿瘤作用。其他化合物，例如I1、I2、I4、I6、I7、I8、I9、I10、I11、I12、I13也具有类似的效果。
3、Hoechst染色和流式细胞术检测化合物对细胞凋亡的影响
通过Hoechst染色和流式细胞术检测化合物对细胞凋亡的影响。Hoechst染色实验方法如下：将HepG2细胞在六孔板培养12h后，按样品浓度加药处理，加入浓度分别为1μM，5μM，10μM的受试化合物继续培养48h。去除细胞培养液，PBS洗涤细胞后，加入4％多聚甲醛固定细胞30mins；去除固定液，PBS洗涤两次后，双蒸水洗涤一次；吸弃双蒸水，加入Hoechst染色液，室温反应5-10mins；吸弃Hoechst33342染色剂，PBS洗涤数次，倒置荧光显微镜下观察。
流式细胞术实验方法如下：将HepG2细胞在六孔板培养12h后，按样品浓度加药处理，加入浓度分别为1μM，5μM，10μM的受试化合物继续培养48h。用不含EDTA的胰酶消化收集，PBS洗涤细胞2次，收集1～5×105个细胞；加入500μL的Binding Buffer悬浮细胞；随后，加入5μL的Annexin V-FITC混匀，再加入5μL Propidium Iodide；室温、避光、反应5～15分钟。1h内所有样本使用流式细胞仪检测，使用软件FlowJo 10进行数据分析。
Hoechst染色和流式细胞术结果如图2所示。图2A显示用I12(1，5，10μM)孵育48h的HepG2的细胞形态发生明显变化，例如细胞核碎裂和染色质凝结，提示细胞凋亡。图2B和图2C显示化合物I12可剂量依赖性诱导HepG2细胞凋亡；1μM，5μM和10μM的I12与HepG2细胞共孵育48h可分别导致24.3％、51.5％和87.1％的细胞凋亡率(早凋+晚凋)，而DMSO对照组的凋亡率为4.22％，提示化合物可以诱导肿瘤细胞凋亡。
以上实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可能对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (10)
1.式I所示的化合物、异构体或其药学上可接受的盐：
其中，
R1代表C1-C6烷基、C1-C6烷氧基、苯基、苄基或吡啶基；
R2代表氢、卤素或C1-C6烷基；
R3代表氢、卤素、羟基、硝基、氨基、氰基、C1-C6烷基、C1-C4卤代烷基、C1-C6烷氧基、C1-C6烷氨基烷氧基、苯基、取代苯基、吡啶基、取代吡啶基、吗啉基、取代吗啉基、哌嗪基或取代哌嗪基，所述的取代苯基、取代吡啶基、取代吗啉基或取代哌嗪基可任意地由下述取代基单取代或多取代：卤素、羟基、硝基、氨基、氰基、C1-C3烷基、C1-C3烷氧基或C1-C3烷氨基；
R4代表氢、卤素、羟基、硝基、氨基、氰基、C1-C3烷基、C1-C3卤代烷基或C1-C3烷氧基。
2.根据权利要求1所示的化合物、异构体或其药学上可接受的盐，其中R1代表C1-C4烷基、C1-C3烷氧基、苯基、苄基或吡啶基；优选地，R1代表甲基、乙基、异丙基、叔丁基、甲氧基、乙氧基或苯基；更优选地，R1代表叔丁基。
3.根据权利要求1所示的化合物、异构体或其药学上可接受的盐，其中R2代表氢、卤素或C1-C3烷基；优选地，R2代表氢、氟、氯、溴、甲基或乙基；更优选地，R2代表氢。
4.根据权利要求1所示的化合物、异构体或其药学上可接受的盐，其中R3代表氢、氟、氯、溴、羟基、硝基、氨基、氰基、C1-C4烷基、C1-C4烷氧基、苯基、取代苯基、吡啶基、取代吡啶基、吗啉基、哌嗪基或取代哌嗪基，所述的取代苯基、取代吡啶基或取代哌嗪基可任意地由下述取代基单取代或多取代：氟、氯、溴、羟基、硝基、氨基、氰基、甲基、乙基、甲氧基、乙氧基、二甲基氨基或二乙基氨基；优选地，R3代表氯、氨基、甲基、乙基、甲氧基、乙氧基、异丙氧基、苯基、取代苯基、吡啶基、取代吡啶基、吗啉基、哌嗪基或取代哌嗪基，所述的取代苯基、取代吡啶基或取代哌嗪基可任意地由下述取代基单取代或多取代：氟、氯、溴、氨基、甲基、甲氧基或二甲基氨基；更优选地，R3代表氯、甲基、甲氧基、乙氧基、异丙氧基、苯基、4-甲基苯基、3-甲基苯基、4-氯苯基、3-氯苯基、4-氟苯基、4-溴苯基、4-甲氧基苯基、3,4-二甲氧基苯基、4-氨基苯基、4-二甲基氨基苯基、吡啶基、吗啉基、哌嗪基或4-甲基哌嗪基；特别更优选地，R3代表4-甲基苯基、4-氯苯基、4-溴苯基、4-甲氧基苯基、4-氨基苯基、4-二甲基氨基苯基或吡啶基。
5.根据权利要求1所示的化合物、异构体或其药学上可接受的盐，其中R4代表氢、卤素、氨基、C1-C3烷基或C1-C3烷氧基；优选地，R4代表氢、氟、氯、溴、甲基、乙基、甲氧基或乙氧基；更优选地，R4代表氢。
6.根据权利要求1所示的化合物、异构体或其药学上可接受的盐，其中述化合物选自：
7.根据权利要求6所示的化合物、异构体或其药学上可接受的盐，其中述化合物选自：
8.一种药物组合物，它以权利要求1、2、3、4、5、6或7所述的化合物、异构体或其药学上可接受的盐为活性成分或主要活性成分，辅以药学上可接受的载体。
9.根据权利要求8所述的药物组合物，其特征在于，所述药物组合物制成液体制剂或固体制剂；特别是制成注射剂、口服液、颗粒剂、粉剂、片剂或胶囊剂。
10.权利要求1、2、3、4、5、6或7所述的化合物、异构体或其药学上可接受的盐在制备与肿瘤有关疾病的药物方面的应用，特别在制备与肺癌、肝癌或乳腺癌的药物方面的应用。
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| WO2009144554A1 (en) * | 2008-05-28 | 2009-12-03 | Pfizer, Inc. | Pyrazolospiroketone acetyl-c0a carboxylase inhibitors |
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| WO2009144554A1 (en) * | 2008-05-28 | 2009-12-03 | Pfizer, Inc. | Pyrazolospiroketone acetyl-c0a carboxylase inhibitors |
| CN106117205A (zh) * | 2011-04-22 | 2016-11-16 | 辉瑞大药厂 | 用作乙酰辅酶 a 羧化酶抑制剂类的吡唑并螺酮衍生物 |
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Effective date of registration: 20230516 Address after: Room 101, Building H, 237 Loumen Road, Industrial Park, Suzhou City, Jiangsu Province, 215000 Patentee after: Suzhou 30 billion Technology Co.,Ltd. Address before: Xuzhou Medical University, 209 Tongshan Road, Xuzhou City, Jiangsu Province, 221004 Patentee before: XUZHOU MEDICAL University Effective date of registration: 20230516 Address after: No. 69 Qifeng Road, Gaoqiao Town, Haishu District, Ningbo City, Zhejiang Province, 315000 Patentee after: Zhejiang Yonghe Pharmaceutical Technology Co.,Ltd. Address before: Room 101, Building H, 237 Loumen Road, Industrial Park, Suzhou City, Jiangsu Province, 215000 Patentee before: Suzhou 30 billion Technology Co.,Ltd. |