CN112079826B - 一类甾体合成酶抑制剂及其治疗应用 - Google Patents
一类甾体合成酶抑制剂及其治疗应用 Download PDFInfo
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- CN112079826B CN112079826B CN202010983540.1A CN202010983540A CN112079826B CN 112079826 B CN112079826 B CN 112079826B CN 202010983540 A CN202010983540 A CN 202010983540A CN 112079826 B CN112079826 B CN 112079826B
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- dihydrobenzo
- pyridyl
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- oxazepine
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- OZZAYJQNMKMUSD-DMISRAGPSA-N pregnenolone succinate Chemical compound C1C=C2C[C@@H](OC(=O)CCC(O)=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 OZZAYJQNMKMUSD-DMISRAGPSA-N 0.000 description 1
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- RBNBDIMXFJYDLQ-UHFFFAOYSA-N thieno[3,2-d]pyrimidine Chemical compound C1=NC=C2SC=CC2=N1 RBNBDIMXFJYDLQ-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明公开了一类甾体合成酶抑制剂及其治疗应用，属于医药领域。本发明提供的一类可作为药物的化合物具有抑制甾体合成酶的作用，且抑制率高，可以用作治疗激素依赖型疾病的药物。
Description
技术领域
本发明涉及医药技术领域，具体而言，涉及一类甾体合成酶抑制剂及其治疗应用。
背景技术
甾体激素是人体内重要的内源性调控因子，广泛的参与到各项生理和病理作用中。一旦其生物合成及信号感知和传导过程发生变化，就会引起各种严重疾病。而甾体合成酶是这些甾体激素生物合成的关键因素，对其进行抑制就可以直接降低甾体激素的浓度，进而治疗相关疾病。
以醛固酮为代表的盐皮质激素可以调节肾小管的功能，控制钾离子、钠离子及水的动态平衡，进而调节血容量和血压。近期研究表明醛固酮是强力的致炎因子，能够诱导活性氧，并可以上调包括PAI在内的多种致纤维化因子的表达。过高浓度的醛固酮与充血性心衰、难治性高血压、慢性肾病、糖尿病性肾病、高醛固酮症、心肾纤维化、心肾综合症、代谢综合症等疾病有直接关系。而醛固酮合成酶(CYP11B2)是醛固酮生物合成中的关键酶，对其进行抑制可以有效降低醛固酮水平，进而治疗相关疾病。
可的松是人体内重要的糖皮质激素，可以广泛调节免疫应答、压力反应、糖和脂质代谢。由于发生在下丘脑-垂体-肾上腺的肿瘤而引起的可的松异常过度分泌，被称为库欣综合症。而高水平的可的松也与代谢综合症、胰岛素抵抗、肥胖、二型糖尿病有直接关系。11β羟化酶(CYP11B1)是可的松生物合成中的关键酶，对其进行抑制可以有效降低可的松水平，进而治疗相关疾病。
雌激素和雄激素除维持正常性别特征和功能外，还调控成骨与破骨平衡，心血管功能，肌肉稳态等生理功能。但是过高浓度的雌激素和雄激素分别与乳腺癌和前列腺癌的发生、发展有密切关系。CYP19和CYP17分别是雌激素和雄激素生物合成中的关键酶，对其进行抑制可以有效降低雌激素和雄激素水平，进而治疗相关疾病。
胆汁酸是由肝脏分泌的内源性甾体，除在小肠内形成乳糜微粒帮助脂肪吸收外，还是潜力的信号因子，能广泛的调控糖和脂的合成与代谢、以及炎症和纤维化等病理过程。而CYP7A1与CYP8B1是胆汁酸生物合成中的关键酶，对其进行干预能够调节肝脏功能及机体代谢，是治疗非酒精性脂肪性肝病、脂肪肝、肝硬化及肝纤维化等疾病的潜在靶点。
鉴于此，特提出本发明。
发明内容
本发明的目的在于提供一类甾体合成酶抑制剂及其治疗应用以解决上述技术问题。
本发明是这样实现的：
一类可作为药物的化合物，其包括如下所示的化合物中的至少一种：
其中：
Z＝C，N，O或S；
A＝O，S，N或C；但不同时为同一元素；
R1，R2和R3各自独立地选自如下的组：
氢、氘、卤素、烃基、烃氧基、芳基、硝基、亚硝基、氨基、脲基、酯基、羟基、羧基、磺酸基、卤甲酰基、氨基甲酰基、醛基、氰基、芳基氧基、巯基、硫醚、羰基、磺酰氟、CF3、SF5、任选经取代或不取代的哌嗪基、吗啉基、任选经取代或不取代的吡啶基、任选经取代或不取代的吡咯啉基、肟、腙、任选经取代的烃基、任选经取代的烃氧基、任选经取代或不取代的-NHC1-C8烷基、任选经取代或不取代的-S-(-C1-C8烷基)、任选经取代或不取代的-SO2-(-C1-C8烷基)、任选经取代或不取代的-SO2-NH-(-C1-C8烷基)、任选经取代或不取代的-NH-SO2-(-C1-C8烷基)、-CO2R4、-NR5R6和-CO-NR5R6；
R4独立地选自由以下组成的组：任选经取代或不取代的-C1-C8烷基、任选经取代或不取代的-C2-C8烯基、任选经取代或不取代的-C2-C8炔基、任选经取代或不取代的-C3-C8环烷基、任选经取代或不取代的-C3-C8环烯基、任选经取代或不取代的3至8元杂环烷基、任选经取代或不取代的芳基、以及任选经取代或不取代的杂芳基；
R5和R6各自独立地选自氢、任选经取代或不取代的-C1-C8-烷基、任选经取代或不取代的-C2-C8-烯基、任选经取代或不取代的-C2-C8-炔基、任选经取代或不取代的-C3-C8-环烷基、-C(O)R4、-S(O)2R4、-S(O)2NHR4、任选经取代或不取代的-C1-C8烷氧基、以及R5和R6与所连接的氮形成的杂环；
x为0、1或2；y为0、1、2、3或4；m为0、1、2、3或4；n为0、1、2、3或4。
以上通式中，母核是指：除去取代基R1、R2及R3，
含氮杂环后的剩余部分。
A为O，S，N或C；但不同时为同一元素。A在结构通式中同时有几个，不能同时为碳，或同时为硫等。
在本发明应用较佳的实施方式中，上述母核选自如下组：
3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮、3,4-二氢苯并[e][1,3]氧氮杂
-5(1H)-酮、4,5-二氢苯并[d][1,2]氧氮杂
-1(2H)-酮、3,4-二氢苯并[f][1,4]硫氮杂
-5(2H)-酮、3,4-二氢苯并[e][1,3]硫氮杂
-5(1H)-酮、4,5-二氢苯并[d][1,2]硫氮杂
-1(2H)-酮、1,2,3,4-四氢-5H-苯并[e][1,4]二氮杂
-5-酮、2,3,4,5-四氢-1H-苯并[e][1,3]二氮杂
-1-酮、2,3,4,5-四氢-1H-苯并[d][1,2]二氮杂
-1-酮、1,1-二氧代-3,4-二氢-2H-苯并[b][1,4,5]氧硫氮杂
、1,1-二氧代-2,3-二氢-5H-苯并[e][1,4,3]氧硫氮杂
、1,1-二氧代-4,5-二氢-2H-苯并[d][1,3,2]氧硫氮杂
、1,1-二氧代-3,4-二氢-2H-苯并[f][1,5,2]二硫氮杂
、1,1-二氧代-2,3-二氢-5H-苯并[f][1,4,2]二硫氮杂
、1,1-二氧代-4,5-二氢-2H-苯并[d][1,3,2]二硫氮杂
、1,1-二氧代-2,3,4,5-四氢苯并[f][1,2,5]硫二氮杂
、1,1-二氧代-2,3,4,5-四氢苯并[f][1,2,4]硫二氮杂
、1,1-二氧代-2,3,4,5-四氢苯并[f][1,2,3]硫二氮杂
、4,5-二氢苯并[f][1,4]硫氮杂
-3(2H)-酮、4,5-二氢-3H-苯并[e][1,4]二氮杂
-3-酮、4,5-二氢苯并[f][1,4]氧氮杂
-3(2H)-酮、1,2,4,5-四氢-3H-苯并[e][1,4]二氮杂
-3-酮、3,3-二氧代-4,5-二氢苯并[d][1,2,6]硫二氮杂
、3,3-二氧代-1,2,4,5-四氢苯并[d][1,2,6]硫二氮杂
、3,3-二氧代-4,5-二氢-2H-苯并[d][1,6,2]二硫氮杂
、3,3-二氧代-4,5-二氢-2H-苯并[f][1,3,4]氧硫氮杂
。
在本发明应用较佳的实施方式中，上述R1，R2和R3分别任选地被以下组成的组的1至3个取代基所取代：卤素、-CH3、-CF3、-CBr3、-CCl3、-OCF3、-CN、-NH2、-OH、-CH2N(CH3)2、-C(O)CH3、-SO2-、-NH-SO2-、酰基、酰氨基、任选经取代的-NH-(C1-C6)烷基、任选经取代的-NH-(C1-C6)烷基-(C1-C6)烷氧基、任选经取代的-SO2-(C1-C6)烷基、任选经取代的-SO2-NH-(C1-C6)烷基、任选经取代的-NH-SO2-(C1-C6)烷基、任选经取代的3至12元杂环烷基、任选经取代的芳基、任选经取代的杂芳基、任选经取代的-C1-C8烷基、任选经取代的-C1-C8烯基、任选经取代的-C3-C8-环烷基、任选经取代的-C3-C8-环烯基以及任选经取代的-C1-C8烷氧基。
进一步地，R1，R2和R3分别任选地被以下组成的组的1至3个取代基所取代：
氟、-CH3、-CF3和-CN。
在本发明应用较佳的实施方式中，当m>1时，多个R1连接成环状结构；当n>1时，多个R2连接成环状结构；当y>1时，多个R3连接成环状结构。
进一步地，当R3位于N邻位时，R3为氢或氘。
在本发明应用较佳的实施方式中，含氮杂环为五元杂环、六元杂环、或稠杂环；
优选地，五元杂环为吡咯、噻唑、咪唑或吡唑，所述六元杂环为吡啶、哒嗪或嘧啶，所述稠杂环为喹啉、异喹啉、嘌呤、吡咯并吡啶、呋喃并吡啶、噻吩并吡啶、咪唑并吡啶、噁唑并吡啶、噻唑并吡啶、二氢吡咯并吡啶、二氢呋喃并吡啶、二氢噻吩并吡啶、二氢咪唑并吡啶、二氢噁唑并吡啶、二氢噻唑并吡啶、吡咯并嘧啶、呋喃并嘧啶、噻吩并嘧啶、咪唑并嘧啶、噁唑并嘧啶、噻唑并嘧啶、二氢吡咯并嘧啶、二氢呋喃并嘧啶、二氢噻吩并嘧啶、二氢咪唑并嘧啶、二氢噁唑并嘧啶、二氢噻唑并嘧啶、咪唑并三嗪、吡咯并三嗪、二氢咪唑并三嗪、二氢吡咯并三嗪。
在其他实施方式中，上述杂环也可以是8-10元杂稠杂环。
进一步地，可作为药物的化合物为如下任一化合物：
8-氟-4-(4-甲基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮、8-氟-4-(3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮、8-(N,N-二甲基)-4-(3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮、8-(N,N-二甲基)-4-(5-甲基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮、8-(N,N-二甲基)-4-(5-氟-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮、8-(N,N-二甲基)-4-(5-氯-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮、8-(N,N-二甲基)-4-(4-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮、8-(N,N-二甲基)-4-(3-甲基-4-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮、8-(N,N-二甲基)-4-(3-氟-4-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮、8-(N,N-二甲基)-4-(3-氯-4-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮、8-(N,N-二甲基)-4-(5-甲氧基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮、8-(N,N-二甲基)-4-(4-甲基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮、8-(N,N-二甲基)-4-(4-氯-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮、8-(N,N-二甲基)-4-(4-腈基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮、3-(8-(N,N-二甲基)-5-氧代-2,3-二氢苯并[f][1,4]氧氮杂
-4(5H)-异烟酸甲酯、3-(8-(N,N-二甲基)-5-氧代-2,3-二氢苯并[f][1,4]氧氮杂
-4(5H)-烟酸甲酯、8-(N,N-二甲基)-4-(5-乙酰基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮、8-(N,N-二甲基)-4-(4-三氟甲基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮、8-(N,N-二甲基)-4-(5-三氟甲基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮、8-(N,N-二甲基)-4-(5-腈基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮、8-吗啉基-4-(4-腈基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮、8-哌嗪基-4-(4-腈基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮、8-(4-甲基哌嗪基)-4-(4-腈基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮、8-(4-乙酰哌嗪基)-4-(4-腈基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮、8-哌啶基-4-(4-腈基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮和8-吡咯啉基-4-(4-腈基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮。
在其他实施方式中，上述可作为药物的化合物在药学上可接受的盐，“药学上可接受的盐”包括药学上可接受的无机酸盐或有机酸盐；所述的无机酸盐优选硫酸盐、亚硫酸盐、盐酸盐、氢溴酸盐、硝酸盐、磷酸盐、磷酸二氢盐；所述的有机酸盐优选醋酸盐、马来酸盐、富马酸盐、琥珀酸盐、柠檬酸盐、对甲苯磺酸盐、酒石酸盐、甲酸盐、丙酸盐、庚酸盐、草酸盐、苯甲酸盐、丙二酸盐、丁二酸盐、顺丁烯二酸盐、羟基丁酸盐、枸橼酸盐、甲磺酸盐、苯磺酸盐、乳酸盐或扁桃酸盐。
可作为药物的化合物的制备方法包括如下步骤：
首先利用相应的取代芳香胺、芳香酚、芳香硫醇等原料与相应的卤代羧酸酯反应，并将所得产物在氢氧化锂的水溶液中水解得到羧酸中间体I，然后在三氟乙酸及三氟乙酸酐环境中关环得到稠环芳烃环酮中间体II，稠环芳烃环酮中间体II与羟胺盐酸盐反应得到肟类中间体III，然后发生BECKMANN重排得到酰胺中间体IV，酰胺中间体IV与相应的含氮杂环的溴代物或硼酸在铜或钯催化的碱性环境中反应得到目标化合物V；
稠环芳烃环酮中间体II为7-氟-苯并二氢吡喃-4-酮，肟类中间体III为7-氟-苯并二氢吡喃-4-肟，酰胺中间体IV为8-氟-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮，或8-(N,N-二甲基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮。
取代含氮杂环为卤素取代杂环、甲氧基取代杂环、卤素甲氧基取代杂环、烷基取代杂环、腈基取代杂环、卤素烟酸酯取代杂环、酰基取代杂环、卤素酰基取代杂环或卤素烷基取代杂环；
优选地，取代含氮杂环为3-溴-4-甲基吡啶、3-溴吡啶，3-溴-5-氟吡啶，3-溴-5-氯吡啶，4-溴-3-甲基吡啶，4-溴-3-氟吡啶，4-溴-3-氯吡啶，3-溴-5-甲氧基吡啶，3-溴-4-甲氧基吡啶，3-溴-4-腈基吡啶，3-溴-烟酸甲酯，3-溴-5-乙酰基吡啶，3-溴-4-三氟甲基吡啶或3-溴-5-腈基吡啶。
本发明还提供了一种可作为药物的化合物在制备甾体合成酶抑制剂中的应用。
进一步地，甾体合成酶抑制剂为甾体生物合成酶抑制剂。
进一步地，甾体生物合成酶为如下酶中的至少一种：醛固酮合成酶(CYP11B2)、可的松生物合成酶、雌激素合成酶、雄激素合成酶和胆汁酸生物合成酶。
优选地，醛固酮合成酶为CYP11B2；可的松生物合成酶为CYP11B1(11β羟化酶)；雌激素合成酶为CYP19；雄激素合成酶CYP17；胆汁酸生物合成酶为CYP7A1和/或CYP8B1。
在其他实施方式中，本发明提供的药物化合物并不限于上述几种甾体合成酶的抑制用途。
本发明还提供了一种可作为药物的化合物在制备及作为治疗激素依赖型疾病的药物中的应用，激素依赖型疾病包括如下疾病中的至少一种：
充血性心衰、高血压、慢性肾病、糖尿病性肾病、高醛固酮症、心脏纤维化、肾综合症、代谢综合症、库欣综合症、胰岛素抵抗、肥胖、II型糖尿病、乳腺癌、前列腺癌、卵巢癌、宫颈癌、糖尿病足、糖尿病性眼病、糖尿病性溃疡、肾衰竭、非酒精性脂肪性肝病、脂肪肝、肝硬化、肝纤维化、肝癌、胰腺癌、胆管癌、结肠癌、直肠癌。
一种治疗激素依赖型疾病的药物，其包括可作为药物的化合物；
优选地，治疗激素依赖型疾病的药物还包括药学上可接受的添加剂或辅料，优选地，药物组合物剂型选自片剂、丸剂、粉剂、混悬剂、凝胶、乳液、乳膏、颗粒剂、纳米颗粒、胶囊、栓剂、注射剂、喷雾和针剂。
一种药物组合物，其包括可作为药物的化合物；
优选地，药物组合物还包括联用药物/疗法，联用药物/疗法为所公开的药物化合物与如下药物/疗法中的至少一种的组合：
化疗药物，放射疗法，光敏剂，光热剂，免疫疗法，雄激素受体拮抗剂及功能调节剂，雌激素受体拮抗剂及功能调节剂，糖激素受体拮抗剂及功能调节剂，盐激素受体拮抗剂及功能调节剂，FXR激动剂、拮抗剂及功能调节剂，GPR30激动剂、拮抗剂及功能调节剂，TGR激动剂、拮抗剂及功能调节剂，GLP受体激动剂、拮抗剂及功能调节剂，FGF受体激动剂、拮抗剂及功能调节剂、甲状腺素受体激动剂、拮抗剂及功能调节剂、钠-葡萄糖协同转运蛋白2抑制剂、二肽基肽酶-4抑制剂和TGF受体激动剂、拮抗剂及功能调节剂。
需要说明的是，上述联用药物可以与本发明中的化合物作用机制相同，也可以是作用机制不同。
本发明具有以下有益效果：
本发明提供了一类甾体合成酶抑制剂，具有抑制甾体合成酶的作用，且抑制率高，可以用来制备治疗激素依赖型疾病的药物。
附图说明
为了更清楚地说明本发明实施例的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，应当理解，以下附图仅示出了本发明的某些实施例，因此不应被看作是对范围的限定，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他相关的附图。
图1为化合物合成路线。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将对本发明实施例中的技术方案进行清楚、完整地描述。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
以下结合实施例对本发明的特征和性能作进一步的详细描述。
通用方法一为：采用胺基取代氟的方法制得相应胺基产物。其包括如下步骤：
将氟代中间体(20mmol)、相应胺(40mmol)、碳酸钾(44mmol)混悬于DMSO(20mL)，并于100℃下搅拌16小时。待冷却至室温后，向反应混合物中加入冷水(100mL)中，并用100毫升乙酸乙酯萃取两次，有机相随后用饱和食盐水(100mL)洗涤，再用无水硫酸钠干燥，浓缩得粗品。用硅胶柱纯化(石油醚/乙酸乙酯＝1/2)得到相应胺基产物。
通用方法二为：将酰胺引入取代吡啶得到相应吡啶取代产物。其包括如下步骤：
将相应的3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(22mmol)、相应的取代吡啶(22mmol)、与碳酸钾(132mmol)、碘化亚铜(11mmol)、N,N-二乙基-1,2-乙二胺(15.4mmol)混悬于二氧六环(60mL)中，并在120℃搅拌16小时。待冷至室温后，向反应混合物中加入冷水(100mL)中，并用乙酸乙酯(100mL x 2)萃取，有机相随后用饱和食盐水(100mL)洗涤，再用无水硫酸钠干燥，浓缩得粗品。用硅胶柱纯化(石油醚/乙酸乙酯＝1/3)得到相应吡啶取代产物。
实施例1
本实施例提供了中间体1(3-(3-氟苯氧基)丙酸)的制备方法，本实施例以图1中所示的3-氟苯酚为原料，在其他实施例中也可以选择任何一个类似物作为反应原料。
将3-氟苯酚(10.0g,89mmol)、3-溴丙酸甲酯(15.8g,95mmol)和碳酸钾(30.8g,223mmol)在100毫升四氢呋喃中于70℃搅拌16小时。待反应混合物冷却至室温后，减压蒸馏除去溶剂后用300毫升乙酸乙酯/水(1:1)萃取两次。合并有机相后，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到黄色固体。将其混悬于200毫升氢氧化锂水溶液，室温搅拌5小时。反应混合物用300毫升乙酸乙酯/水(1:1)萃取两次。合并有机相后，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到黄色固体14.3克,收率87.5％。
实施例2
本实施例提供了中间体2(7-氟-苯并二氢吡喃-4-酮)的制备方法，本实施例以由实施例1制得的3-(3-氟苯氧基)丙酸为原料，在其他实施例中也可以选择任何一个类似物作为反应原料。
向3-(3-氟苯氧基)丙酸(5.0g,27.1mmol)在25毫升三氟乙酸的混合溶液中逐滴加入三氟乙酸酐(5.7g,27.1mmol)，所得反应混合物在室温下搅拌5小时后，加入饱和Na2CO3溶液调节pH至8，然后用300毫升乙酸乙酯/水(1:1)萃取两次。合并有机相后，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到白色固体(2.8g,收率62.1％)。1H-NMR(400MHz,DMSO-d6):δ＝7.81-7.85(m,1H),6.92-6.95(m,2H),4.57(t,J＝4.8Hz,2H),2.79(t,J＝4.8Hz,2H)。
实施例3
本实施例提供了中间体3(7-氟-苯并二氢吡喃-4-肟)的制备方法，本实施例以由实施例2制得的7-氟-苯并二氢吡喃-4-酮为原料，在其他实施例中也可以选择任何一个类似物作为反应原料。
室温下向7-氟-苯并二氢吡喃-4-酮(15g,90mmol)和盐酸羟胺(12.6g,180mmol)的干燥乙醇溶液(50mL)中加入碳酸氢钠(22.8g,270mmol)后，将反应混合物在90度加热回流16小时。冷至室温后，过滤除去固体并用乙醇洗涤滤饼，滤液浓缩，并用硅胶柱纯化(石油醚/乙酸乙酯＝10/1)得到类白色固体(15g,收率92％)。
实施例4
本实施例提供了中间体4(8-氟-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)的制备方法，本实施例以实施例3制得的7-氟-苯并二氢吡喃-4-肟为原料。在其他实施例中也可以选择任何一个类似物作为反应原料。
将7-氟-苯并二氢吡喃-4-肟(15g,83mmol)混悬于多聚磷酸(20mL)，并在110度加热搅拌4小时。待冷至室温后，将反应混合物倒入冷水中，滤除固体后，将其用碳酸氢钠调pH值至8，并用乙酸乙酯(300mL x 2)萃取，有机相随后用饱和食盐水(300mL)洗涤，再用无水硫酸钠干燥，浓缩得粗品。用硅胶柱纯化(石油醚/乙酸乙酯＝3/1)得到黄色固体(6.3g,收率42％)。
实施例5
本实施例提供了中间体5(8-(N,N-二甲基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)的制备方法，本实施例以实施例4制得的8-氟-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮为原料。在其他实施例中也可以选择任何一个类似物作为反应原料。
按照通用方法一，利用8-氟-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(3.75g,20mmol)、二甲胺盐酸盐(3.37g,40mmol),碳酸钾(6.3g,44mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/2)得到白色固体(1.7g,收率40％)。
实施例6
本实施例提供了化合物1(8-氟-4-(4-甲基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)的制备方法，本实施例以实施例4制得的8-氟-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮为原料。在其他实施例中也可以选择任何一个类似物作为反应原料。
按照通用方法二，利用8-氟-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(4.0g,22mmol),3-溴-4-甲基吡啶(3.78g,22mmol),碳酸钾(18.2g,132mmol),碘化亚铜(2.08g,11mmol),N,N-二乙基-1,2-乙二胺(1.37g,15.4mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/3)得到白色固体(2.9g,收率48％)。制得化合物1(8-氟-4-(4-甲基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)。
MS(m/s):273.27[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.46(s,1H),8.42(d,J＝4.8Hz,1H),7.84-7.80(q,1H),7.38(d,J＝5.2Hz,1H),7.11-7.06(m,1H),7.02-6.99(dd,J＝2.4Hz,2.8Hz,1H),4.52-4.48(m,2H),3.89-3.92(m,2H),2.22(s,3H)。
实施例7
按照通用方法二，利用8-氟-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(0.15g,0.8mmol),3-溴吡啶(0.13g,0.8mmol),碳酸钾(0.69g,4.8mmol),碘化亚铜(0.078g,0.64mmol),N,N-二乙基-1,2-乙二胺(0.051g,0.48mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/3)得到黄色固体(52mg,收率24％)。制得化合物2(8-氟-4-(3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)。
MS(m/s):259.25[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.66(s,1H),8.50(d,J＝4Hz,1H),7.88-7.79(m,2H),7.51-7.48(q,1H),7.10-7.06(m,1H),7.01-6.98(q,1H),4.54(t,J＝5Hz,2H),3.99(t,J＝5Hz,2H)。
实施例8
本实施例提供了化合物3(8-(N,N-二甲基)-4-(3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)的制备方法，本实施例以实施例5制得的8-(N,N-二甲基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮为原料。在其他实施例中也可以选择任何一个类似物作为反应原料。按照通用方法二，利用8-(N,N-二甲基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(0.15g,0.7mmol),3-溴吡啶(0.114g,0.7mmol),碳酸钾(0.69g,4.8mmol),碘化亚铜(0.078g,0.64mmol),N,N-二乙基-1,2-乙二胺(0.051g,0.48mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/3)得到浅黄色固体(555mg,收率26.7％)。制得化合物3(8-(N,N-二甲基)-4-(3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)。
MS(m/s):284.33[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.62(d,J＝2.4Hz,1H),8.44-8.43(m,1H),7.83-7.80(m,1H),7.60(d,J＝8.8Hz,1H),7.47-7.43(m,1H),6.55-6.52(m,1H),6.26(d,J＝2.4Hz,1H),4.43(t,J＝4.8Hz,2H),3.95(t,J＝5Hz,2H),2.97(s,6H)。
实施例9
按照通用方法二，利用8-(N,N-二甲基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(0.15g,0.7mmol),3-溴-4-甲基-吡啶(0.7mmol),碳酸钾(0.69g,4.8mmol),碘化亚铜(0.078g,0.64mmol),N,N-二乙基-1,2-乙二胺(0.051g,0.48mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/3)得到浅黄色固体(58mg,收率26.8％)。制得化合物4(8-(N,N-二甲基)-4-(5-甲基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)。
MS(m/s):298.35[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.41(d,J＝2.4Hz,1H),8.29(d,J＝1.2Hz,1H),7.64(s,1H),7.59(d,J＝8.8Hz,1H),6.55-6.52(m,1H),6.26(d,J＝2.4Hz,1H),4.42(t,J＝4.8Hz,2H),3.92(t,J＝5Hz,2H),2.97(s,6H),2.32(s,3H)。
实施例10
按照通用方法二，利用8-(N,N-二甲基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(0.15g,0.7mmol),3-溴-5-氟吡啶(0.7mmol),碳酸钾(0.69g,4.8mmol),碘化亚铜(0.078g,0.64mmol),N,N-二乙基-1,2-乙二胺(0.051g,0.48mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/3)得到白色固体(51mg,收率23.3％)。制得化合物5(8-(N,N-二甲基)-4-(5-氟-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)。
MS(m/s):302.32[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.56(d,J＝1.6Hz,1H),8.47(d,J＝2.4Hz,1H),7.92-7.88(m,1H),7.61(d,J＝8.8Hz,1H),6.54(dd,J＝2.4Hz,2.4Hz,1H),6.26(d,J＝2.8Hz,1H),4.44(t,J＝5Hz,2H),3.98(t,J＝5Hz,2H),2.97(s,6H)。
实施例11
按照通用方法二，利用8-(N,N-二甲基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(0.15g,0.7mmol),3-溴-5-氯吡啶(0.7mmol),碳酸钾(0.69g,4.8mmol),碘化亚铜(0.078g,0.64mmol),N,N-二乙基-1,2-乙二胺(0.051g,0.48mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/3)得到灰色固体(56mg,收率24.2％)。制得化合物6(8-(N,N-二甲基)-4-(5-氯-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)。
MS(m/s):318.77[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.62(d,J＝2Hz,1H),8.50(d,J＝2.4Hz,1H),8.06(t,J＝2.2Hz,1H),7.62(d,J＝9.2Hz,1H),6.54(dd,J＝2.4Hz,2.4Hz,1H),6.25(d,J＝2.4Hz,1H),4.44(t,J＝4.8Hz,2H),3.98(t,J＝5Hz,2H),2.97(s,6H)。
实施例12
按照通用方法二，利用8-(N,N-二甲基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(0.15g,0.7mmol),3-溴吡啶(0.7mmol),碳酸钾(0.69g,4.8mmol),碘化亚铜(0.078g,0.64mmol),N,N-二乙基-1,2-乙二胺(0.051g,0.48mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/3)得到白色固体(50mg,收率24.1％)。制得化合物7(8-(N,N-二甲基)-4-(4-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)。
MS(m/s):284.33[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.53(d,J＝6.4Hz,2H),7.64-7.59(m,3H),6.57(dd,J＝2.4Hz,2.4Hz,1H),6.34(d,J＝2.8Hz,1H),4.43(t,J＝5Hz,2H),4.09(t,J＝5.2Hz,2H),3.03(s,6H)。
实施例13
按照通用方法二，利用8-(N,N-二甲基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(0.15g,0.7mmol),4-溴-3-甲基吡啶(0.7mmol),碳酸钾(0.69g,4.8mmol),碘化亚铜(0.078g,0.64mmol),N,N-二乙基-1,2-乙二胺(0.051g,0.48mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/3)得到黄色固体(55mg,收率25.4％)。制得化合物8(8-(N,N-二甲基)-4-(3-甲基-4-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)。
MS(m/s):298.35[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.50(t,J＝8.2Hz,2H),7.60(d,J＝9.2Hz,1H),7.30(d,J＝4.4Hz,1H),6.54(dd,J＝2.8Hz,2.4Hz,1H),6.27(d,J＝2.8Hz,1H),4.35(t,J＝5Hz,2H),3.86(t,J＝4.8Hz,2H),2.97(s,6H),2.15(s,3H).
实施例14
按照通用方法二，利用8-(N,N-二甲基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(0.15g,0.7mmol),4-溴-3-氟吡啶(0.7mmol),碳酸钾(0.69g,4.8mmol),碘化亚铜(0.078g,0.64mmol),N,N-二乙基-1,2-乙二胺(0.051g,0.48mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/3)得到黄色固体(55mg,收率25.1％)。制得化合物9(8-(N,N-二甲基)-4-(3-氟-4-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)。
MS(m/s):302.32[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.63(d,J＝2.4Hz,1H),8.47(d,J＝5.2Hz,1H),7.60(d,J＝8.8Hz,1H),7.56(q,1H),6.54(dd,J＝2.4Hz,2.8Hz,1H),6.26(d,J＝2.4Hz,1H),4.37(t,J＝4.8Hz,2H),3.94(t,J＝5Hz,2H),2.98(s,6H).
实施例15
按照通用方法二，利用8-(N,N-二甲基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(0.15g,0.7mmol),4-溴-3-氯吡啶(0.7mmol),碳酸钾(0.69g,4.8mmol),碘化亚铜(0.078g,0.64mmol),N,N-二乙基-1,2-乙二胺(0.051g,0.48mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/3)得到黄色固体(54mg,收率23.4％)。制得化合物10(8-(N,N-二甲基)-4-(3-氯-4-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)。
MS(m/s):318.77[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.74(s,1H),8.59(d,J＝5.2Hz,1H),7.64(d,J＝8.8Hz,1H),7.54(d,J＝5.2Hz,1H),6.54(dd,J＝2.4Hz,2.8Hz,1H),6.25(d,J＝2.4Hz,1H),4.40(t,J＝4.6Hz,2H),3.88(t,J＝4.8Hz,2H),2.97(s,6H).
实施例16
按照通用方法二，利用8-(N,N-二甲基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(0.15g,0.7mmol),3-溴-5-甲氧基吡啶(0.7mmol),碳酸钾(0.69g,4.8mmol),碘化亚铜(0.078g,0.64mmol),N,N-二乙基-1,2-乙二胺(0.051g,0.48mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/3)得到黄色固体(52mg,收率22.8％)。制得化合物11(8-(N,N-二甲基)-4-(5-甲氧基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)。
MS(m/s):314.35[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.22(d,J＝2Hz,1H),8.18(d,J＝2.8Hz,1H),7.60(d,J＝8.8Hz,1H),7.44(t,J＝2.2Hz,1H),6.54(dd,J＝2.4Hz,2.4Hz,1H),6.26(d,J＝2.4Hz,1H),4.43(t,J＝5Hz,2H),3.94(t,J＝4.8Hz,2H),3.85(s,3H),2.97(s,6H).
实施例17
按照通用方法二，利用8-(N,N-二甲基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(0.15g,0.7mmol),3-溴-4-甲氧基吡啶(0.7mmol),碳酸钾(0.69g,4.8mmol),碘化亚铜(0.078g,0.64mmol),N,N-二乙基-1,2-乙二胺(0.051g,0.48mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/3)得到黄色固体(57mg,收率26.4％)。制得化合物12(8-(N,N-二甲基)-4-(4-甲基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)。
MS(m/s):298.35[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.41(s,1H),8.38(d,J＝5.2Hz,1H),7.62(d,J＝9.2Hz,1H),7.35(d,J＝5.2Hz,1H),6.54(dd,J＝2.4Hz,2.4Hz,1H),6.27(d,J＝2.8Hz,1H),4.39(d,J＝3.6Hz,2H),3.84(t,J＝4.8Hz,2H),2.97(s,6H),2.19(s,3H).
实施例18
按照通用方法二，利用8-(N,N-二甲基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(0.15g,0.7mmol),3-溴-4-氯吡啶(0.7mmol),碳酸钾(0.69g,4.8mmol),碘化亚铜(0.078g,0.64mmol),N,N-二乙基-1,2-乙二胺(0.051g,0.48mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/3)得到黄色固体(59mg,收率25.5％)。制得化合物13(8-(N,N-二甲基)-4-(4-氯-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)。
MS(m/s):318.77[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.58(s,1H),8.48(d,J＝3.6Hz,1H),7.71(s,1H),7.68(t,J＝4.2Hz,1H),6.57(dd,J＝2.8Hz,2.8Hz,1H),6.34(d,J＝2.8Hz,1H),4.50(t,J＝4.8Hz,2H),3.92(t,J＝4.6Hz,2H),3.03(s,6H).
实施例19
按照通用方法二，利用8-(N,N-二甲基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(0.15g,0.7mmol),3-溴-4-腈基吡啶(0.7mmol),碳酸钾(0.69g,4.8mmol),碘化亚铜(0.078g,0.64mmol),N,N-二乙基-1,2-乙二胺(0.051g,0.48mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/3)得到黄色固体(58mg,收率25.9％)。制得化合物14(8-(N,N-二甲基)-4-(4-腈基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)。
MS(m/s):309.33[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.86(s,1H),8.75(d,J＝4.8Hz,1H),7.97(d,J＝4.8Hz,1H),7.66(d,J＝9.2Hz,1H),6.56(dd,J＝2.4Hz,2.8Hz,1H),6.27(d,J＝2.4Hz,1H),4.46(t,J＝4.6Hz,2H),4.02(t,J＝4.6Hz,2H),2.98(s,6H).
实施例20
按照通用方法二，利用8-(N,N-二甲基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(0.15g,0.7mmol),3-溴-异烟酸甲酯(0.7mmol),碳酸钾(0.69g,4.8mmol),碘化亚铜(0.078g,0.64mmol),N,N-二乙基-1,2-乙二胺(0.051g,0.48mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/3)得到黄色固体(54mg,收率21.8％)。制得化合物15(3-(8-(N,N-二甲基)-5-氧代-2,3-二氢苯并[f][1,4]氧氮杂
-4(5H)-异烟酸甲酯)。
MS(m/s):342.36[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.71(s,1H),8.67(d,J＝4.8Hz,1H),7.72(d,J＝4.8Hz,1H),7.61(d,J＝8.8Hz,1H),6.52(dd,J＝2.4Hz,2.8Hz,1H),6.25(d,J＝2.8Hz,1H),4.52(t,J＝4.6Hz,2H),3.95(t,J＝4.6Hz,2H),3.73(s,3H),2.97(s,6H).
实施例21
按照通用方法二，利用8-(N,N-二甲基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(0.15g,0.7mmol),3-溴-烟酸甲酯(0.7mmol),碳酸钾(0.69g,4.8mmol),碘化亚铜(0.078g,0.64mmol),N,N-二乙基-1,2-乙二胺(0.051g,0.48mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/3)得到白色固体(50mg,收率20.1％)。制得化合物16(3-(8-(N,N-二甲基)-5-氧代-2,3-二氢苯并[f][1,4]氧氮杂
-4(5H)-烟酸甲酯)。
MS(m/s):342.36[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.94(d,J＝2Hz,1H),8.86(d,J＝2.4Hz,1H),8.32(t,J＝2.2Hz,1H),7.64(d,J＝8.8Hz,1H),6.54(dd,J＝2.8Hz,2.4Hz,1H),6.26(d,J＝2.4Hz,1H),4.46(t,J＝4.8Hz,2H),4.01(t,J＝4.8Hz,2H),3.91(s,3H),2.97(s,6H).
实施例22
按照通用方法二，利用8-(N,N-二甲基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(0.15g,0.7mmol),3-溴-5-乙酰基吡啶(0.7mmol),碳酸钾(0.69g,4.8mmol),碘化亚铜(0.078g,0.64mmol),N,N-二乙基-1,2-乙二胺(0.051g,0.48mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/3)得到黄色固体(51mg,收率21.6％)。制得化合物17(8-(N,N-二甲基)-4-(5-乙酰基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)。
MS(m/s):326.36[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.99(d,J＝1.6Hz,1H),8.84(d,J＝2.4Hz,1H),8.26(t,J＝2Hz,1H),7.64(d,J＝8.8Hz,1H),6.55(dd,J＝2.8Hz,2.4Hz,1H),6.27(d,J＝2.4Hz,1H),4.46(t,J＝4.8Hz,2H),4.01(t,J＝4.8Hz,2H),2.98(s,6H),2.66(s,3H).
实施例23
按照通用方法二，利用8-(N,N-二甲基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(0.15g,0.7mmol),3-溴-4-三氟甲基吡啶(0.7mmol),碳酸钾(0.69g,4.8mmol),碘化亚铜(0.078g,0.64mmol),N,N-二乙基-1,2-乙二胺(0.051g,0.48mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/3)得到白色固体(59mg,收率11％)。制得化合物18(8-(N,N-二甲基)-4-(4-三氟甲基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)。
MS(m/s):352.32[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.84(s,1H),8.82(d,J＝2Hz,1H),7.86(d,J＝5.2Hz,1H),7.66(d,J＝9.2Hz,1H),6.52(dd,J＝2.4Hz,2.4Hz,1H),6.25(d,J＝2.8Hz,1H),4.56-4.51(m,1H),4.42-4.37(m,1H),4.88-4.83(m,2H),2.97(s,6H).
实施例24
按照通用方法二，利用8-(N,N-二甲基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(0.15g,0.7mmol),3-溴-5-三氟甲基吡啶(0.7mmol),碳酸钾(0.69g,4.8mmol),碘化亚铜(0.078g,0.64mmol),N,N-二乙基-1,2-乙二胺(0.051g,0.48mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/3)得到黄色固体(52mg,收率20.4％)。制得化合物19(8-(N,N-二甲基)-4-(5-三氟甲基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)。
MS(m/s):352.32[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.93(d,J＝2.4Hz,1H),8.83(s,1H),8.30(s,1H),7.65(d,J＝8.8Hz,1H),6.55(dd,J＝2.8Hz,2.4Hz,1H),6.26(d,J＝2.4Hz,1H),4.47(t,J＝4.8Hz,2H),4.03(t,J＝4.8Hz,2H),2.98(s,6H).
实施例25
按照通用方法二，利用8-(N,N-二甲基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(0.15g,0.7mmol),3-溴-5-腈基吡啶(0.7mmol),碳酸钾(0.69g,4.8mmol),碘化亚铜(0.078g,0.64mmol),N,N-二乙基-1,2-乙二胺(0.051g,0.48mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/3)得到白色固体(55mg,收率15％)。制得化合物20(8-(N,N-二甲基)-4-(5-腈基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)。
MS(m/s):309.33[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.96(d,J＝2.8Hz,1H),8.87(d,J＝2Hz,1H),8.41(t,J＝2.2Hz,1H),7.63(d,J＝9.2Hz,1H),6.55(dd,J＝2.4Hz,2.8Hz,1H),6.26(d,J＝2.4Hz,1H),4.46(t,J＝4.8Hz,2H),4.00(t,J＝5Hz,2H),2.97(s,6H).
实施例26
按照通用方法一，利用8-氟-4-(4-甲基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(0.15g,0.55mmol)、吗啡啉(0.096g,1.1mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/2)得到白色固体(53mg,28.5％)。制得化合物21(8-吗啉基-4-(4-腈基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)。
MS(m/s):340.39[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.42(s,1H),8.39(d,J＝4.8Hz,1H),7.64(t,J＝4.6Hz,1H),7.36(d,J＝4.8Hz,1H),6.78(d,J＝8.8Hz,1H),6.53(s,1H),4.42(brs,2H),3.85(t,J＝4.4Hz,2H),3.72(t,J＝4.4Hz,4H),3.23(t,J＝4.4Hz,4H),2.19(s,3H).
实施例27
按照通用方法一，利用8-氟-4-(4-甲基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(0.15g,0.55mmol)、哌嗪(1.1mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/2)得到黄色固体(51mg,27.4％)。制得化合物22(8-哌嗪基-4-(4-腈基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)。
MS(m/s):339.40[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.41(s,1H),8.38(d,J＝5.2Hz,1H),7.62(d,J＝9.2Hz,1H),7.36(d,J＝4.8Hz,1H),6.75(dd,J＝2.4Hz,2.8Hz,1H),6.48(d,J＝2.4Hz,1H),4.41(s,2H),3.85(t,J＝4.8Hz,2H),3.17(t,J＝4.8Hz,4H),2.80(t,J＝4.8Hz,4H),2.19(s,3H).
实施例28
按照通用方法一，利用8-氟-4-(4-甲基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(0.15g,0.55mmol)、4-甲基哌嗪(1.1mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/2)得到白色固体(57mg,29.3％)。制得化合物23(8-(4-甲基哌嗪基)-4-(4-腈基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)。
MS(m/s):353.43[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.41(s,1H),8.39(d,J＝4.8Hz,1H),7.62(d,J＝8.8Hz,1H),7.35(d,J＝4.8Hz,1H),6.77(dd,J＝1.6Hz,2.0Hz,1H),6.51(d,J＝1.6Hz,1H),4.41(brs,2H),3.85(t,J＝4.6Hz,2H),3.26(t,J＝4.4Hz,4H),2.42(t,J＝4.6Hz,4H),2.21(s,3H),2.19(s,3H).
实施例29
按照通用方法一，利用8-氟-4-(4-甲基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(0.15g,0.55mmol)、4-乙酰哌嗪(1.1mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/2)得到白色固体(59mg,21.4％)。制得化合物24(8-(4-乙酰哌嗪基)-4-(4-腈基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)。
MS(m/s):381.44[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.42(s,1H),8.39(d,J＝4.8Hz,1H),7.65(d,J＝4.4Hz,1H),7.36(d,J＝5.2Hz,1H),6.79(dd,J＝2.4Hz,2.4Hz,1H),6.54(d,J＝2.4Hz,1H),4.43(brs,2H),3.85(t,J＝4.8Hz,2H),3.57(t,J＝5.2Hz,4H),3.31-3.25(m,4H),2.19(s,3H),2.04(s,3H).
实施例30
按照通用方法一，利用8-氟-4-(4-甲基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(0.15g,0.55mmol)、哌啶(1.1mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/2)得到黄色固体(53mg,28.5％)。制得化合物25(8-哌啶基-4-(4-腈基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)。
MS(m/s):338.42[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.41(s,1H),8.38(d,J＝4.8Hz,1H),7.61(d,J＝8.8Hz,1H),7.34(d,J＝4.8Hz,1H),6.74(dd,J＝2.8Hz,2.4Hz,1H),6.48(d,J＝2Hz,1H),4.41(d,J＝2.4Hz,2H),3.85(t,J＝4.8Hz,2H),3.29(s,4H),2.19(s,3H),1.57(s,6H).
实施例31
按照通用方法一，利用8-氟-4-(4-甲基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮(0.15g,0.55mmol)、吡咯啉(1.1mmol)合成。粗品用硅胶柱纯化(石油醚/乙酸乙酯＝1/2)得到白色固体(58mg,16％)。制得化合物26(8-吡咯啉基-4-(4-腈基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂
-5(2H)-酮)。
MS(m/s):324.39[M+H]+；1H-NMR(400MHz,DMSO-d6):δ8.41(s,1H),8.38(d,J＝4.8Hz,1H),7.60(d,J＝8.8Hz,1H),7.35(d,J＝4.8Hz,1H),6.38(dd,J＝2.4Hz,2.4Hz,1H),6.12(d,J＝2.4Hz,1H),4.39(d,J＝2.4Hz,2H),3.84(t,J＝4.8Hz,2H),3.28(t,J＝6.6Hz,4H),2.19(s,3H),1.97-1.94(m,4H)。
实验例1
进行CYP17抑制活性的测定实验。将人源CYP17与大鼠NADPH-P450共表达于大肠杆菌中，待大肠杆菌进入对数生长期，将其裂解，5000rpm离心取上清液。向其中加入孕烯醇酮100nM及合适浓度的待测化合物(化合物1-26以及阿比特龙、fadrazole、Anastrozole)，37度孵育2小时，加入乙酸乙酯淬灭，随后利用HPLC在260nm对底物及产物定量，计算抑制率及IC50值。
实验例2
进行CYP19抑制活性的测定实验。向人胎盘提取物种加入睾酮100nM及合适浓度的待测化合物，37度孵育30分钟后，加入乙酸乙酯淬灭，随后利用HPLC在260nm对底物及产物定量，计算抑制率及IC50值。
实验例3
进行CYP11B1抑制活性的测定实验。
利用慢病毒将人源CYP11B1及大鼠NADPH-P450基因转染至V79细胞中，利用嘌呤霉素抗性基因筛选得到稳转细胞株。将对数生长期的细胞稀释，去约104个细胞定植与96孔板中，加入合适浓度的待测化合物预孵育2小时后，加入脱氧可的松10nM开始催化反应，继续孵育30分钟后，加入乙酸乙酯淬灭，随后利用HPLC在260nm对底物及产物定量，计算抑制率及IC50值。
实验例4
进行CYP11B2抑制活性的测定实验。
利用慢病毒将人源CYP11B2及大鼠NADPH-P450基因转染至V79细胞中，利用嘌呤霉素抗性基因筛选得到稳转细胞株。将对数生长期的细胞稀释，去约104个细胞定植与96孔板中，加入合适浓度的待测化合物预孵育2小时后，加入脱氧可的松10nM开始催化反应，继续孵育1小时后，加入乙酸乙酯淬灭，随后利用HPLC在260nm对底物及产物定量，计算抑制率及IC50值。
实验例5
进行CYP8B1抑制活性的测定实验。
利用慢病毒将人源CYP8B1及大鼠NADPH-P450基因转染至V79细胞中，利用嘌呤霉素抗性基因筛选得到稳转细胞株。将对数生长期的细胞稀释，去约104个细胞定植与96孔板中，加入合适浓度的待测化合物预孵育2小时后，加入脱氧可的松10nM开始催化反应，继续孵育1小时后，加入乙酸乙酯淬灭，随后利用HPLC在260nm对底物及产物定量，计算抑制率及IC50值。
实验例6
进行CYP7A1抑制活性的测定实验。
利用慢病毒将人源CYP7A1及大鼠NADPH-P450基因转染至V79细胞中，利用嘌呤霉素抗性基因筛选得到稳转细胞株。将对数生长期的细胞稀释，去约104个细胞定植与96孔板中，加入合适浓度的待测化合物预孵育2小时后，加入脱氧可的松10nM开始催化反应，继续孵育1小时后，加入乙酸乙酯淬灭，随后利用HPLC在260nm对底物及产物定量，计算抑制率及IC50值。
测定结果参照表1所示。
表1抑制率及IC50值。
***IC50<100nM**IC50<500nM*IC50<1000nM。
以上所述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 (19)
1.一类可作为药物的化合物，其特征在于，其选自如下所示的化合物：
式Ⅳ
；
其中：
A为O；
R1和R3各自独立地选自如下的组：
氢、氘、卤素、芳基、硝基、亚硝基、氨基、脲基、酯基、羟基、羧基、磺酸基、卤甲酰基、氨基甲酰基、醛基、氰基、芳基氧基、巯基、硫醚、羰基、磺酰氟、CF3、SF5、任选不取代的哌嗪基、吗啉基、任选不取代的吡啶基、任选不取代的吡咯啉基、肟、腙、任选不取代的-NHC1-C8烷基、任选不取代的-S-(-C1-C8烷基)、任选不取代的-SO2-(-C1-C8烷基)、任选不取代的-SO2-NH-(-C1-C8烷基)、任选不取代的-NH-SO2-(-C1-C8烷基)、-CO2R4、-NR5R6和-CO-NR5R6；
R2选自氢；
R4独立地选自如下的组：任选不取代的-C1-C8烷基、任选不取代的-C2-C8烯基、任选不取代的-C2-C8炔基、任选不取代的-C3-C8环烷基、任选不取代的-C3-C8环烯基以及任选不取代的3至8元杂环烷基；
R5和R6各自独立地选自氢、任选不取代的-C1-C8-烷基、任选不取代的-C2-C8-烯基、任选不取代的-C2-C8-炔基、任选不取代的-C3-C8-环烷基、-C(O)R4、-S(O)2R4、-S(O)2NHR4及任选不取代的-C1-C8烷氧基；
y为0、1、2、3或4；m为0、1、2、3或4；n为0、1、2、3或4。
2.根据权利要求1所述的可作为药物的化合物，其特征在于，R1和R3分别任选地被以下组成的组的1至3个取代基所取代：卤素、-CH3、-CF3、-SF5、-CCl3、-OCF3、-CN、-NH2、-OH、-CH2N(CH3)2、-C(O)CH3、-SO2-、-NHSO2-、-SO2F、酰基、酰氨基、任选的-NH-(C1-C6)烷基、任选的-NH-(C1-C6)烷基-(C1-C6)烷氧基、任选的-SO2-(C1-C6)烷基、任选的-SO2-NH-(C1-C6)烷基、任选的-NH-SO2-(C1-C6)烷基、任选3至12元杂环烷基、任选-C1-C8烷基、任选的-C1-C8烯基、任选的-C3-C8-环烷基、任选的-C3-C8-环烯基以及任选的-C1-C8烷氧基。
3.根据权利要求2所述的可作为药物的化合物，其特征在于，R1和R3分别任选地被以下组成的组的1至3个取代基所取代：
氟、-CH3、-CF3和-CN。
4.根据权利要求1所述的可作为药物的化合物，其特征在于，当R3位于N邻位时，R3为氢或氘。
5.根据权利要求1所述的可作为药物的化合物，其特征在于，所述可作为药物的化合物为如下任一化合物：
8-氟-4-(4-甲基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮、8-氟-4-(3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮、8-( N,N-二甲基)-4-(3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮、8-( N,N-二甲基)-4-(5-甲基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮、8-( N,N-二甲基)-4-(5-氟-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮、8-( N,N-二甲基)-4-(5-氯-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮、8-(N,N-二甲基)-4-(4-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮、8-(N,N-二甲基)-4-(3-甲基-4-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮、8-(N,N-二甲基)-4-(3-氟-4-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮、8-(N,N-二甲基)-4-(3-氯-4-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮、8-(N,N-二甲基)-4-(5-甲氧基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮、8-(N,N-二甲基)-4-(4-甲基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮、8-(N,N-二甲基)-4-(4-氯-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮、8-(N,N-二甲基)-4-(4-腈基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮、3-(8-(N,N-二甲基)-5-氧代-2,3-二氢苯并[f][1,4]氧氮杂䓬-4(5H)-异烟酸甲酯、3-(8-(N,N-二甲基)-5-氧代-2,3-二氢苯并[f][1,4]氧氮杂䓬-4(5H)-烟酸甲酯、8-(N,N-二甲基)-4-(5-乙酰基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮、8-(N,N-二甲基)-4-(4-三氟甲基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮、8-(N,N-二甲基)-4-(5-三氟甲基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮、8-(N,N-二甲基)-4-(5-腈基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮、8-吗啉基-4-(4-腈基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮、8-哌嗪基-4-(4-腈基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮、8-(4-甲基哌嗪基)-4-(4-腈基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮、8-(4-乙酰哌嗪基)-4-(4-腈基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮、8-哌啶基-4-(4-腈基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮和8-吡咯啉基-4-(4-腈基-3-吡啶基)-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮。
6.根据权利要求1所述的可作为药物的化合物在药学上可接受的盐，“药学上可接受的盐”为药学上可接受的无机酸盐或有机酸盐；所述的无机酸盐选自硫酸盐、亚硫酸盐、盐酸盐、氢溴酸盐、硝酸盐、磷酸盐、磷酸二氢盐。
7.根据权利要求6所述的可作为药物的化合物在药学上可接受的盐，其特征在于，所述的有机酸盐为醋酸盐、马来酸盐、富马酸盐、琥珀酸盐、柠檬酸盐、对甲苯磺酸盐、酒石酸盐、甲酸盐、丙酸盐、庚酸盐、草酸盐、苯甲酸盐、丙二酸盐、丁二酸盐、顺丁烯二酸盐、羟基丁酸盐、枸橼酸盐、甲磺酸盐、苯磺酸盐、乳酸盐或扁桃酸盐。
8.一种如权利要求1-7任一项所述的可作为药物的化合物的制备方法，其特征在于，其包括如下步骤：
首先利用相应的取代芳香酚为原料与相应的溴代羧酸甲酯反应，并将所得产物在氢氧化锂的水溶液中水解得到羧酸中间体I，然后在三氟乙酸及三氟乙酸酐环境中关环得到稠环芳烃环酮中间体II，所述稠环芳烃环酮中间体II与羟胺盐酸盐反应得到肟类中间体III，然后发生BECKMANN重排得到酰胺中间体IV，所述酰胺中间体IV与相应的含氮杂环的溴代物在铜或钯催化的碱性环境中反应得到目标化合物V；
9.根据权利要求8所述的制备方法，其特征在于，其包括：所述稠环芳烃环酮中间体II为7-氟-苯并二氢吡喃-4-酮，所述肟类中间体III为7-氟-苯并二氢吡喃-4-肟，所述酰胺中间体IV为8-氟-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮，或8-(N,N-二甲基)-3,4-二氢苯并[f][1,4]氧氮杂䓬-5(2H)-酮。
10.一种如权利要求1-7任一项所述的可作为药物的化合物在制备甾体合成酶抑制剂中的应用。
11.根据权利要求10所述的应用，其特征在于，所述甾体合成酶为如下酶中的至少一种：醛固酮合成酶、可的松生物合成酶、雌激素合成酶、雄激素合成酶和胆汁酸生物合成酶。
12.根据权利要求11所述的应用，其特征在于，所述醛固酮合成酶为CYP11B2; 所述可的松生物合成酶为CYP11B1；所述雌激素合成酶为CYP19；所述雄激素合成酶CYP17；所述胆汁酸生物合成酶为CYP7A1和/或CYP8B1。
13.一种如权利要求1-7任一项所述的可作为药物的化合物在制备治疗激素依赖型疾病的药物中的应用，其特征在于，所述激素依赖型疾病选自如下疾病中的至少一种：
充血性心衰、高血压、慢性肾病、糖尿病性肾病、高醛固酮症、心脏纤维化、肾纤维化、心肾综合症、代谢综合症、库欣综合症、胰岛素抵抗、肥胖、II型糖尿病、乳腺癌、前列腺癌、卵巢癌、宫颈癌、糖尿病足、糖尿病性眼病、糖尿病性溃疡、肾衰竭、脂肪肝、肝硬化、肝纤维化、肝癌、胰腺癌、胆管癌、结肠癌、直肠癌。
14.根据权利要求13所述的应用，其特征在于，所述激素依赖型疾病选自非酒精性脂肪性肝病。
15.一种治疗激素依赖型疾病的药物，其特征在于，其包括权利要求1-7任一项所述的可作为药物的化合物。
16.根据权利要求15所述的治疗激素依赖型疾病的药物，其特征在于，所述治疗激素依赖型疾病的药物还包括药学上可接受的添加剂或辅料。
17.根据权利要求16所述的治疗激素依赖型疾病的药物，其特征在于，所述药物剂型选自片剂、丸剂、粉剂、混悬剂、凝胶、乳液、乳膏、颗粒剂、纳米颗粒、胶囊、栓剂、注射剂、喷雾和针剂。
18.一种药物组合物，其特征在于，其包括权利要求1-7任一项所述的可作为药物的化合物。
19.根据权利要求18所述的药物组合物，其特征在于，所述药物组合物还包括联用药物/疗法，所述联用药物/疗法为如下药物中的至少一种：
化疗药物，放射疗法，光敏剂，光热剂，免疫疗法，雄激素受体拮抗剂及功能调节剂，雌激素受体拮抗剂及功能调节剂，糖激素受体拮抗剂及功能调节剂，盐激素受体拮抗剂及功能调节剂，FXR激动剂、拮抗剂及功能调节剂，GPR30激动剂、拮抗剂及功能调节剂，TGR激动剂、拮抗剂及功能调节剂，GLP受体激动剂、拮抗剂及功能调节剂，FGF受体激动剂、拮抗剂及功能调节剂、甲状腺素受体激动剂、拮抗剂及功能调节剂、钠-葡萄糖协同转运蛋白2抑制剂、二肽基肽酶-4 抑制剂和TGF受体激动剂、拮抗剂及功能调节剂。
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