CN115974723A - 甲酰胺乙撑蒽类化合物、包含其的药物组合物及其应用 - Google Patents
甲酰胺乙撑蒽类化合物、包含其的药物组合物及其应用 Download PDFInfo
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- CN115974723A CN115974723A CN202211681350.XA CN202211681350A CN115974723A CN 115974723 A CN115974723 A CN 115974723A CN 202211681350 A CN202211681350 A CN 202211681350A CN 115974723 A CN115974723 A CN 115974723A
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- Prior art keywords
- carboxamide
- dihydro
- cyano
- ethyleneanthracene
- bromo
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Abstract
本发明提供一种甲酰胺乙撑蒽类化合物、包含其的药物组合物及其应用,甲酰胺乙撑蒽类化合物为式(Ⅰ)所示结构的化合物或其药学上可接受的盐,
Description
技术领域
本发明属于化合物领域,具体涉及一种甲酰胺乙撑蒽类化合物、包含其的药物组合物及其应用。
背景技术
锌指蛋白家族(Zinc finger containing proteins,ZNFs)是人类基因组中最大的转录因子家族,参与调控多种重要生理学过程,包括胚胎发育、细胞代谢、分化以及病毒感染等。许多研究表明,锌指蛋白家族成员在多种恶性肿瘤的发生发展中起着至关重要的作用。ZNF207是锌指蛋白家族成员之一,其N端包含核定位信号和高度保守的C2H2型锌指结构域。同源建模显示该蛋白锌指结构域中半胱氨酸、组氨酸残基与锌离子相互作用折叠成两链反平行β-折叠和α-螺旋的手指状结构,具有转录因子活性。
目前使用的大多数抗肿瘤药物都是通过表皮生长因子受体(HER)起作用的。该家族包括HER1(erbB1,EGFR)、HER2(erbB2,NEU)、HER3(erbB3)及HER4(erbB4)。HER家族在细胞生理过程中发挥重要的调节作用。EGFR(epidermal growth factor receptor,简称为EGFR、ErbB-1或HER1)是表皮生长因子受体(HER)家族成员之一。EGFR广泛分布于哺乳动物上皮细胞、成纤维细胞、胶质细胞、角质细胞等细胞表面,EGFR信号通路对细胞的生长、增殖和分化等生理过程发挥重要的作用。小分子EGFR抑制剂进入细胞内,在细胞内小分子与EGFR受体胞内末端结合后可以阻断受体末端的磷酸化,从而进一步抑制下游信号传导,阻止EGFR依赖的细胞增殖。
然而,尽管EGFR类药物在抑制恶性肿瘤方面有令人满意的效果,但持续使用EGFR类药物也伴随着过多的不良反应,包括引起皮肤和胃肠道反应。其中皮肤不良反应最常见,包括躯干及头面部丘疹脓疱样疹、甲沟炎、口腔黏膜糜烂、皮肤瘙痒、毛发变化等。
总之,开发新型具有抑制ZNF207作用的药物不仅能提高对恶性肿瘤的作用,而且也有望克服靶向EGFR相关的副作用,具有广阔的应用前景和实用价值。
发明内容
本发明的目的在于提供一种一种甲酰胺乙撑蒽类化合物,该化合物对ZNF207具有抑制作用,进而对由ZNF207介导的疾病,如疼痛、炎症、免疫功能障碍、神经和精神病症、呼吸道疾病、泌尿、生殖病症、胚胎发育异常、细胞代谢、分化异常,尤其是恶性肿瘤的治疗具有应用前景。
为了实现上述目的,本发明所采用的技术方案为:
一种甲酰胺乙撑蒽类化合物,它为式(Ⅰ)所示结构的化合物或其药学上可接受的盐,
其中,
Z选自氢、卤素、羟基、氨基、取代或未取代的C1-6烷氧基或取代或未取代的C1-6烷基,Z的取代基选自氢、卤素、羟基、氨基,所述取代为单取代或多取代;
Y选自六元脂肪环、六元脂肪杂环或Y不存在,六元脂肪杂环包括1-3个杂原子,杂原子独立的地选自O、N或S;
R1是羧基、酰胺基、卤素、氰基、氨基或取代或未取代的C1-6烷基,C1-6烷基的取代基为卤素、酰胺基或氨基,所述取代为单取代或多取代;
R2是氢、卤素、羟基、氰基、硼酸基、乙酰基或取代或未取代的具有1-6个碳的烷基,烷基的取代基为1-6个碳的烷基、羟基、卤素、氰基、硼酸基或乙酰基,所述取代为单取代或多取代;
n为0-2的整数;
R3是氢或卤素;
A选自硫原子、氧原子、亚胺基、磺基、羰基、酰胺基、磺胺基或A不存在。
作为技术方案的进一步改进,Z选自氢、卤素、羟基、氨基、C1-6烷氧基或C1-6烷基;
Y选自六元脂肪环、六元脂肪杂环或Y不存在,六元脂肪杂环具有2个位于对位的杂原子,杂原子独立的地选自O、N或S;
R1是羧基、酰胺基、卤素、氰基、氨基或取代或未取代的C1-6烷基,C1-6烷基的取代基为卤素或氨基,所述取代为单取代或多取代;
R2是氢、卤素、羟基、氰基、硼酸基、乙酰基或取代或未取代的具有1-6个碳的烷基,烷基的取代基为羟基或卤素,所述取代为单取代或多取代。
作为技术方案的进一步改进,它为11-氰基-N-(3,4,5-三甲氧基苯基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
N-(苯并[d][1,3]二氧基-5-基)-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基-N-(4-氟苯基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基-N-(邻甲苯基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基-N-(4-甲氧基-3-甲基苯基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基-N-(间氯苯基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
N-(4-氨基苯基)-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基-N-(4-甲氧基苯基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基-N-(3,5-二甲氧苯基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基-N-(3,4-二氯苯基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基-N-(4-氟苄基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基-N-(4-硝基苄基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
N-苄基-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基-N-(4-氨基苄基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基-N-(2,3-二氯苄基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
N-(3-氯苯乙基)-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基-N-(4-甲基苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基-N-(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基-N-(2-(吡啶-2-基)乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基-N-(4-硝基苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
N-(2-(苯并[d][1,3]二氧基-5-基)乙基)-11-氰基-9,10-二氢-9,10-乙撑蒽-11-羧基酰胺;
N-(2-(1-苄基哌啶-4-基)乙基)-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基-N-(3-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基-N-(2-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基-N-(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
9,10-二溴-11-氰基-N-(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基-N-(4-氟苯乙基)-10-(羟甲基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-(氯甲基)-11-氰基-N-(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-乙酰基-11-氰基-N-(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-硼酸基-11-氰基-N-(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基-N-(4-氟苯乙基)-10-甲基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氟-N-(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氯-N-(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-(溴甲基)-N-(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-N-(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-12,11-二甲酰胺;
10-溴-11-氰基-N-(4-溴苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基-N-(4-氯苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基-N-(2-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基-N-(3-苯基丙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-N-(3-(4-溴苯基)丙基)-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-(氨基甲基)-10-溴-N-(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-N-(2-((4-氯苯基)磺酰基)乙基)-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氯-N-(3-苯基丙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基-N-(2-(苯基硫基)乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-N-(3-(4-溴苯基)丙基)-11-氯-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氯-N-(2-((4-氯苯基)磺酰基)乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基-N-(2-(4-氟苯基)-2-氧乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基-N-(2-((4-氟苯基)磺胺基)乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基-N-(2-(4-氟苯甲酰胺)乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基-N-(2-(苯磺胺基)乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
N-(1-苄基哌啶-4-基)-10-溴-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
N-((1-苄基哌啶-4-基)甲基)-10-溴-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基-N-((1-(4-氟苄基)哌啶-4-基)甲基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基-N-((1-(4-氟苯甲酰)哌啶-4-基)甲基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基-N-((1-((4-氟苯基)磺酰基)哌啶-4-基)甲基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
N-((1-苯甲酰哌啶-4-基)甲基)-10-溴-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基-N-((1-(苯基磺酰基)哌啶-4-基)甲基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-(2-苄基-1-氧-2,8-二氮杂螺[4.5]正烷-8-羰基)-10-溴-9,10-二氢-9,10-乙撑蒽-11-甲腈;
N-(2-(1-苄基哌啶-4-基)乙基)-10-溴-11-氯-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
N-(2-(1-苄基哌啶-4-基)乙基)-10-溴-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-(氨基甲基)-N-(2-(1-苄基哌啶-4-基)乙基)-10-溴-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
N-(2-(4-苄基哌嗪-1-基)乙基)-10-溴-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
N-(2-(4-苄基哌啶-1-基)乙基)-10-溴-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基-N-(2-(1-(4-氟苄基)哌啶-4-基)乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基-N-(2-(4-苯基哌嗪-1-基)乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基-N-(2-(4-苯基哌啶-1-基)乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
N-(2-(1-苄基哌啶-4-基)乙基)-10-溴-11-(溴甲基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-(4-((4-苄基哌啶-1-基)甲基)哌啶-1-羰基)-10-溴-9,10-二氢-9,10-乙撑蒽-11-甲腈或上述化合物的药学上可接受的盐。
所述药学上可接受的盐包括与下列酸形成的盐:盐酸、硫酸、磷酸、氢溴酸、醋酸、三氟乙酸、丙酮酸、柠檬酸、酒石酸、乳酸、马来酸、苯磺酸或琥珀酸。
本发明还提供一种药物组合物,它包含权利要求1-3所述的甲酰胺乙撑蒽类化合物及药学上可接受的药物载体。药学上可接受的药物载体是指药学领域常规的药物载体,如可以是一种或几种惰性的、非毒性的固体或液体填充物、稀释剂、助剂等。所述药物组合物的剂型制备为片剂、胶囊、丸剂、栓剂、软胶囊、口服液、混悬剂或注射液。口服用药片和胶囊可含有传统的赋形剂如填充物、稀释剂、润滑剂、分散剂以及粘合剂,本发明药物制剂的各种剂型可以按照药学领域中熟知的方法进行制备。
本发明还提供一种所述甲酰胺乙撑蒽类化合物的应用,用于制备预防和/或治疗ZNF207介导疾病的药物。ZNF207介导疾病包括疼痛、炎症、免疫功能障碍、神经和精神病症、呼吸道疾病、泌尿、生殖病症、胚胎发育异常、细胞代谢、分化异常等。
作为技术方案的进一步改进,所述甲酰胺乙撑蒽类化合物的应用于预防和/或治疗胚胎发育异常、细胞代谢异常、分化异常和恶性肿瘤。
作为技术方案的进一步改进,所述甲酰胺乙撑蒽类化合物的应用于预防和/或治疗恶性肿瘤,所述恶性肿瘤为肝癌、结肠癌或宫颈癌。
本发明还公开一种所述甲酰胺乙撑蒽类化合物的应用,将甲酰胺乙撑蒽类化合物用于制备ZNF207抑制剂。
本发明还公开一种甲酰胺乙撑蒽类化合物的制备方法,包括:
(a)以2位取代的丙烯酸和芳香胺为起始原料,经酸胺缩合,制备中间体i;
具体反应时可将芳香胺(1.0mol)溶于二氯甲烷100mL,依次加入HATU 4.56g(1.2mol),DIEA 3.23g(2.5mol),室温搅拌10min,继续加入2位取代丙烯酸(1.0mol),室温搅拌1h,反应结束,减压蒸干溶剂,乙酸乙酯50ml萃取3次,无水硫酸钠干燥,减压浓缩,快速柱层析得到中间体i。
(b)中间体ⅰ与9、10位取代的蒽经过狄尔斯–阿尔德反应制备式(Ⅰ);
具体反应时将中间体ⅰ(1.0mol)与9、10位取代的蒽(1.0mol)溶于甲苯80mL中,加入对苯二酚0.055g(0.05mol),于110℃反应12h,减压浓缩,二氯甲烷萃取50mL×4次,无水硫酸钠干燥,真空旋转减压浓缩,Biotage柱层析得到式(Ⅰ)化合物;
本发明相对现有技术具有突出的实质性特点和显著的进步,具体的说说,本发明的的化合物具有ZNF207抑制作用,具有广阔的抗癌应用前景和实用价值。进一步说,本发明的化合物在10μM浓度下表现出较高的ZNF207抑制作用,活性高。再一步说,本发明化合物的制备方法步骤简单,便于工业化生产。
具体实施方式
下面通过具体实施方式,对本发明的技术方案做进一步的详细描述。
以下实施例中,“室温”是指大约20℃至大约30℃。混合溶剂表示的比例是体积混合比例,除非另作说明,否则%是指wt%。
在硅胶柱色谱中,碱性硅胶是指使用氨基丙基硅烷结合的硅胶。在高效液相色谱(HPLC)中,C18是指使用十八烷基结合的硅胶。洗脱溶剂的比例是体积混合比例,除非另作说明。
在下面实施例和实验实施例中,使用下列缩写。
DCM:二氯甲烷,
EA:乙酸乙酯
MeOH:甲醇
PE:石油醚
DMSO:二甲基亚砜,
DIEA:N,N-二异丙基乙胺,
HATU:2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯
Et3N:三乙胺,
M:摩尔浓度。
利用核磁共振波谱仪(BrukerAV-300、AV-500、AV-600)测定1H-NMR(质子核磁共振波谱)。使用ACD/SpecManager等软件进行核磁分析,分析中不描述活性氢(例如羟基、氨基等等)的峰。
利用液相色谱质谱仪(LC/MS)测定MS(质谱),使用ESI(电喷射离子化)方法等。观察分子离子峰,观察数据为实测值。在盐的情况下,通常观察到游离形式的分子离子峰或碎片离子峰。
实施例1
12-氰基-N-(3,4,5-三甲氧基苯基)-9,10-二氢-9,10-乙撑蒽-12-甲酰胺
(a)2-氰基-N-(3,4,5-三甲氧苯基)丙烯酰胺的制备
将3,4,5-三甲氧基苯胺1.83g(1.0mol)溶于二氯甲烷100mL,依次加入HATU 4.56g(1.2mol),DIEA 3.23g(2.5mol),室温搅拌10min,继续加入2-氰基丙烯酸1.25g(1.0mol),室温搅拌1h,反应结束,减压蒸干溶剂,乙酸乙酯50ml萃取3次,无水硫酸钠干燥,减压浓缩,得黄色油状物,快速柱层析得到3,4,5-三甲氧苯基-2-氰基丙烯酰胺1.81g,产率61%,展开剂为石油醚:乙酸乙酯(V/V)=10:1。
(b)11-氰基-N-(3,4,5-三甲氧基苯基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺的制备
将3,4,5-三甲氧苯基-2-氰基丙烯酰胺2.62g(1.0mol)与蒽2.34g(1.0mol)溶于甲苯80mL中,加入对苯二酚0.055g(0.05mol),于110℃反应12h,减压浓缩,二氯甲烷萃取50mL×4次,无水硫酸钠干燥,真空旋转减压浓缩,得黄色固体,Biotage柱层析得到产品,展开剂石油醚:乙酸乙酯(V/V)=10:2,得白色固体2.64g,产率60%。1H NMR(300MHz,Chloroform-d)δ7.68(s,1H),7.46(d,J=7.0Hz,1H),7.38(dd,J=6.6,2.3Hz,2H),7.25(d,J=1.3Hz,1H),7.23-7.08(m,4H),6.58(s,2H),4.81(s,1H),4.51(t,J=2.4Hz,1H),3.81(s,3H),3.77(s,6H),2.88(dd,J=13.1,2.5Hz,1H),2.30(dd,J=13.0,2.7Hz,1H).MS(ESI):[M+H]+440.2m/z。
实施例2
N-(苯并[d][1,3]二氧基-5-基)-12-氰基-9,10-二氢-9,10-乙撑蒽-12-甲酰胺
用苯并[d][1,3]二氧基1.37g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,其它步骤参照实施例1中的制备方法,制得化合物(2),得白色固体2.33g,产率:59%。1H NMR(300MHz,Chloroform-d)δ7.65(s,1H),7.48(dd,J=6.7,1.9Hz,1H),7.41 -7.31(m,2H),7.22(ddt,J=6.3,4.8,1.8Hz,3H),7.15(dd,J=6.9,1.3Hz,1H),6.95(d,J=2.1Hz,1H),6.70(d,J=8.3Hz,1H),6.61(dd,J=8.3,2.1Hz,1H),5.94(s,2H),4.77(s,1H),4.49(t,J=2.7Hz,1H),2.84(dd,J=13.0,2.6Hz,1H),2.29(dd,J=13.0,2.8Hz,1H).MS(ESI):[M+H]+394.1m/z。
实施例3
12-氰基-N-(4-氟苯基)-9,10-二氢-9,10-乙撑蒽-12-甲酰胺
用4-氟-苯胺1.11g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,其它步骤参照实施例1中的制备方法,制得化合物(3),得白色固体2.25g,产率:61%。1HNMR(300MHz,Chloroform-d)δ7.75(s,1H),7.48(dd,J=6.7,1.8Hz,2H),7.42-7.33(m,2H),7.28(s,2H),7.25-7.18(m,4H),7.18-7.09(m,2H),6.98(t,J=8.6Hz,1H),4.79(s,1H),4.51(t,J=2.6Hz,1H),2.85(dd,J=13.0,2.6Hz,1H),2.31(dd,J=13.0,2.8Hz,1H).MS(ESI):[M+H]+368.1m/z。
实施例4
11-氰基-N-(邻甲苯基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用2-甲基-苯胺1.07g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,其它步骤参照实施例1中的制备方法,制得化合物(4),得白色固体1.82g,产率:50%。1HNMR(300MHz,Chloroform-d)δ7.68(s,1H),7.55-7.43(m,2H),7.42-7.31(m,2H),7.29-7.27(m,1H),7.20(dt,J=15.8,3.5Hz,5H),7.15-7.05(m,2H),4.79(s,1H),4.50(t,J=2.7Hz,1H),2.85(dd,J=12.9,2.5Hz,1H),2.31(dd,J=13Hz,2.8Hz,1H),2.25(s,3H).MS(ESI):[M+H]+364.2m/z。
实施例5
11-氰基-N-(4-甲氧基-3-甲基苯基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用3-甲基-4-甲氧基-苯胺1.37g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,其它步骤参照实施例1中的制备方法,制得化合物(5),得白色固体1.98g,产率:51%。1H NMR(300MHz,Chloroform-d)δ7.59(s,1H),7.49(dd,J=6.2,2.5Hz,1H),7.41-7.32(m,2H),7.22(t,J=3.3Hz,3H),7.14-7.05(m,2H),6.72(d,J=8.6Hz,1H),4.78(s,1H),4.50(t,1H),3.80(s,3H),2.84(dd,J=13.0,2.5Hz,1H),2.29(dd,J=13.0,2.8Hz,1H),2.17(s,3H).MS(ESI):[M+H]+394.5m/z。
实施例6
11-氰基-N-(间氯苯基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用3-氯-苯胺1.27g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,其它步骤参照实施例1中的制备方法,制得化合物(6),得白色固体2.30g,产率:60%。1HNMR(300MHz,Chloroform-d)δ7.76(s,1H),7.50-7.43(m,2H),7.38(d,J=7.3Hz,2H),7.20(d,J=7.3Hz,4H),7.14(q,J=8.0,7.3Hz,2H),4.78(s,1H),4.52(s,1H),2.83(dd,J=12.7,2.4Hz,1H),2.32(dd,J=13.3,2.8Hz,1H).MS(ESI):[M+H]+384.9m/z。
实施例7
N-(4-氨基苯基)-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用4-氨基-苯胺1.08g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,其它步骤参照实施例1中的制备方法,制得化合物(7),得白色固体1.46g,产率:40%。1HNMR(300MHz,DMSO-d6)δ10.21(s,1H),7.52(dd,J=5.4,3.2Hz,1H),7.45(dd,J=5.4,3.2Hz,1H),7.41-7.34(m,1H),7.30-7.20(m,2H),7.19-7.12(m,1H),7.12-7.04(m,2H),6.52(d,J=8.8Hz,1H),5.41(s,1H),5.04(s,2H),4.59(d,J=2.7Hz,1H),2.96(dd,J=13.0,2.7Hz,1H),2.06(dd,J=13.0,2.6Hz,1H).MS(ESI):[M+H]+365.4m/z。
实施例8
11-氰基-N-(4-甲氧基苯基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用4-甲氧基-苯胺1.23g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,其它步骤参照实施例1中的制备方法,制得化合物(8),得白色固体1.90g,产率:50%。1HNMR(300MHz,Chloroform-d)δ7.63(s,1H),7.52-7.43(m,1H),7.36(td,J=4.4,1.8Hz,2H),7.22-7.08(m,2H),6.87-6.76(m,2H),4.78(s,1H),4.50(t,J=2.7Hz,1H),3.78(s,3H),2.85(dd,J=13.0,2.6Hz,1H),2.29(dd,J=13.0,2.8Hz,1H).MS(ESI):[M+H]+380.45m/z。MS(ESI):[M+H]+380.4m/z。
实施例9
11-氰基-N-(3,5-二甲氧苯基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用3,5-二甲氧基-苯胺1.53g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,其它步骤参照实施例1中的制备方法,制得化合物(10),得白色固体2.25g,产率:55%。
1H NMR(300MHz,Chloroform-d)δ7.52(s,1H),7.50-7.45(m,1H),7.42-7.33(m,2H),7.25(s,1H),7.24-7.19(m,2H),7.18-7.08(m,1H),6.52(d,J=2.2Hz,2H),6.25(t,J=2.2Hz,1H),4.77(s,1H),4.51(t,J=2.6Hz,1H),2.82(dd,J=13.0,2.6Hz,1H),2.31(dd,J=13.1,2.8Hz,1H).MS(ESI):[M+H]+410.4m/z。
实施例10
11-氰基-N-(4-氟苄基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用4-氟-苄胺1.25g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,其它步骤参照实施例1中的制备方法,制得化合物(10),得白色固体2.54g,产率:69%。1HNMR(500MHz,Chloroform-d)δ7.44-7.39(m,1H),7.36-7.29(m,2H),7.24-7.14(m,5H),7.03(ddd,J=14.1,9.4,6.5Hz,4H),6.40(t,J=5.8Hz,1H),4.59(s,1H),4.44(t,J=2.8Hz,1H),4.40(dd,J=14.6,6.1Hz,1H),4.22(dd,J=14.6,5.4Hz,1H),2.78(dd,J=12.9,2.6Hz,1H),2.21(dd,J=12.9,2.9Hz,1H).MS(ESI):[M+H]+382.1m/z
实施例11
N-苄基-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用苄胺1.07g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,其它步骤参照实施例1中的制备方法,制得化合物(11),得白色固体2.64g,产率:49%。1H NMR(300MHz,Chloroform-d)δ7.46-7.38(m,1H),7.37-7.29(m,5H),7.24-7.14(m,4H),7.13-7.00(m,2H),6.37(d,J=6.2Hz,1H),4.61(s,1H),4.52-4.39(m,2H),4.25(dd,J=14.6,5.3Hz,1H),2.79(dd,J=12.9,2.6Hz,1H),2.21(dd,J=12.9,2.8Hz,1H).MS(ESI):[M+H]+364.1m/z
实施例12
11-氰基-N-(2,3-二氯苄基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用2,3-二氯-苄胺1.75g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,其它步骤参照实施例1中的制备方法,制得化合物(12),得白色固体2.68g,产率:62%。1H NMR(600MHz,Chloroform-d)δ7.49-7.43(m,2H),7.32(dd,J=5.6,3.0Hz,1H),7.29(d,J=7.4Hz,1H),7.23-7.15(m,3H),7.13(t,J=7.7Hz,1H),6.89(dd,J=35.6,7.4Hz,2H),6.54(t,J=6.2Hz,1H),4.59(s,1H),4.49(dd,J=14.8,5.8Hz,1H),4.42(h,J=5.8,4.9Hz,2H),2.75(dd,J=12.9,2.6Hz,1H),2.19(dd,J=12.9,2.7Hz,1H).MS(ESI):[M+H]+433.3m/z
实施例13
N-(3-氯苯乙基)-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用3-氯-苯乙胺1.57g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,其它步骤参照实施例1中的制备方法,制得化合物(13),得白色固体2.93g,产率:71%。1H NMR(600MHz,Chloroform-d)δ7.47-7.36(m,1H),7.32(ddd,J=14.2,7.0,2.5Hz,2H),7.27(d,J=8.0Hz,0H),7.26(s,1H),7.22-7.15(m,4H),7.11(dd,J=7.4,1.2Hz,1H),7.08-7.01(m,2H),6.04(t,J=6.0Hz,1H),2.80-2.68(m,2H),2.65(dd,J=12.9,2.5Hz,1H),2.20(dd,J=12.9,2.9Hz,1H).MS(ESI):[M+H]+412.9m/z
实施例14
11-氰基-N-(4-甲基苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用4-甲基-苯乙胺1.34g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,其它步骤参照实施例1中的制备方法,制得化合物(13),得白色固体1.61g,产率:41%。1H NMR(300MHz,Chloroform-d)δ7.41(dd,J=5.4,3.2Hz,1H),7.36-7.25(m,3H),7.23-7.13(m,6H),7.12-6.99(m,4H),6.03(s,1H),4.52(s,1H),4.42(t,J=2.7Hz,1H),3.48-3.37(m,2H),2.84-2.62(m,2H),2.35(s,3H),2.18(dd,J=12.8,2.8Hz,1H).MS(ESI):[M+H]+392.5m/z
实施例15
11-氰基-N-(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用4-氟-苯乙胺1.39g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,其它步骤参照实施例1中的制备方法,制得化合物(15),得白色固体2.22g,产率:56%。1H NMR(300MHz,Chloroform-d)δ7.41(dd,J=5.4,3.2Hz,1H),7.36-7.25(m,3H),7.23-7.13(m,6H),7.12-6.99(m,4H),6.03(s,1H),4.52(s,1H),4.42(t,J=2.7Hz,1H),3.48-3.37(m,2H),2.84-2.62(m,2H),2.18(dd,J=12.8,2.8Hz,1H).MS(ESI):[M+H]+396.4m/z
实施例16
11-氰基-N-(2-(吡啶-2-基)乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用吡啶苯乙胺1.22g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,其它步骤参照实施例1中的制备方法,制得化合物(16),得白色固体1.89g,产率:50%。1H NMR(300MHz,Chloroform-d)δ8.62(d,J=4.9Hz,1H),7.80(s,1H),7.71(td,J=7.7,1.8Hz,1H),7.46(dd,J=5.5,3.2Hz,1H),7.36-7.28(m,1H),7.28-7.26(m,1H),7.20(dt,J=5.3,2.2Hz,3H),7.16-7.00(m,1H),4.72(s,1H),4.42(t,J=2.7Hz,1H),3.79-3.47(m,2H),3.00(ddd,J=11.0,7.3,4.9Hz,2H),2.78(dd,J=12.9,2.6Hz,1H),2.19(dd,J=12.9,2.8Hz,1H).MS(ESI):[M+H]+379.4m/z
实施例17
11-氰基-N-(4-硝基苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用4-硝基-苯乙胺1.66g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,其它步骤参照实施例1中的制备方法,制得化合物(17),得白色固体1.57g,产率:37%。1H NMR(300MHz,Chloroform-d)δ8.20-8.11(m,2H),7.47-7.39(m,1H),7.37-7.27(m,3H),7.20(ddt,J=6.1,4.2,1.9Hz,2H),7.13-7.06(m,2H),6.26(t,J=6.0Hz,1H),4.60(s,1H),4.44(t,J=2.6Hz,1H),3.48(p,J=6.8Hz,2H),2.86(t,J=7.2Hz,2H),2.66(dd,J=12.9,2.5Hz,1H),2.21(dd,J=12.8,2.8Hz,1H).MS(ESI):[M+H]+423.4m/z
实施例18
N-(2-(苯并[d][1,3]二氧基-5-基)乙基)-11-氰基-9,10-二氢-9,10-乙撑蒽-11-羧基酰胺
用苯并[d][1,3]二氧基-2-乙胺1.65g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,其它步骤参照实施例1中的制备方法,制得化合物(18),得白色固体2.77g,产率:66%。1H NMR(300MHz,Chloroform-d)δ7.46-7.38(m,1H),7.31(t,J=6.2Hz,2H),7.19(dt,J=6.2,2.4Hz,2H),7.12-7.05(m,2H),6.77(d,J=7.9Hz,1H),6.67-6.55(m,2H),6.08(d,J=6.1Hz,1H),5.95(s,2H),4.56(s,1H),4.42(t,J=2.7Hz,1H),3.44-3.32(m,2H),2.77-2.55(m,3H),2.19(dd,J=12.9,2.8Hz,1H).MS(ESI):[M+H]+422.4m/z
实施例19
11-氰基-N-(3-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用3-氟-苯乙胺1.66g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,其它步骤参照实施例1中的制备方法,制得化合物(19),得白色固体1.62g,产率:41%。1H NMR(500MHz,Chloroform-d)δ7.36(dd,J=43.7,6.4Hz,2H),7.26(dd,J=16.9,7.3Hz,2H),7.21-7.12(m,3H),7.10-6.99(m,2H),6.92(t,J=8.4Hz,1H),6.85(dd,J=30.5,8.7Hz,2H),6.37(t,J=5.8Hz,1H),4.60(s,1H),4.40(s,1H),3.36(dp,J=30.1,6.8Hz,2H),2.73-2.61(m,3H),2.21-2.14(m,1H).MS(ESI):[M+H]+396.4m/z
实施例20
11-氰基-N-(2-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用2-氟-苯乙胺1.66g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,其它步骤参照实施例1中的制备方法,制得化合物(20),得白色固体1.89g,产率:51%。
1H NMR(500MHz,Chloroform-d)δ7.43-7.39(m,1H),7.29(dd,J=17.4,5.9Hz,2H),7.23-7.12(m,2H),7.14-7.02(m,4H),6.37(d,J=6.0Hz,1H),4.61(s,1H),4.39(s,1H),3.51-3.27(m,2H),2.80(d,J=7.1Hz,1H),2.73(dd,J=28.0,14.5Hz,2H),2.19-2.13(m,1H).MS(ESI):[M+H]+396.4m/z
实施例21
N-(2-(1-苄基哌啶-4-基)乙基)-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用N-2-(1-苄基哌啶-4-基)乙胺2.18g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,其它步骤参照实施例1中的制备方法,制得化合物(21),得白色固体1.61g,产率:34%。1H NMR(500MHz,Chloroform-d)δ7.46-7.42(m,1H),7.31(d,J=4.3Hz,6H),7.26(s,2H),7.23-7.14(m,4H),7.09(t,J=7.4Hz,1H),5.97(t,J=5.5Hz,1H),4.60(s,1H),4.43(d,J=2.9Hz,1H),3.50(s,2H),3.20(ddd,J=44.9,13.7,6.7Hz,2H),2.87(d,J=11.2Hz,2H),2.80(s,1H),2.73(dd,J=13.0,2.7Hz,1H),2.20(dd,J=12.9,2.9Hz,1H),1.93(d,J=13.1Hz,2H),1.62(d,J=10.2Hz,2H),1.52-1.35(m,3H).MS(ESI):[M+H]+475.6m/z
实施例22
9-溴-12-氰基-N-(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-12-甲酰胺
用4-氟-苯乙胺1.39g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,用9-溴蒽替换掉例1中的蒽,其它步骤参照实施例1步骤(b)中的制备方法,制得化合物(22),得白色固体2.89g,产率:61%。1H NMR(500MHz,Chloroform-d)δ7.83-7.66(m,2H),7.43-7.38(m,1H),7.35-7.26(m,3H),7.17(t,J=7.4Hz,1H),7.13-6.97(m,5H),6.09(t,J=5.9Hz,1H),4.55(s,1H),3.49-3.37(m,2H),3.14(d,J=12.8Hz,1H),2.74(dt,J=11.6,7.0Hz,2H),2.67(d,J=12.9Hz,1H).MS(ESI):[M+H]+475.3m/z
实施例23
9,10-二溴-11-氰基-N-(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用4-氟-苯乙胺1.39g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,用9,10-二溴蒽替换掉例1的步骤(b)中的蒽,其它步骤参照实施例1中的制备方法,制得化合物(23),得白色固体2.04g,产率:37%。1H NMR(500MHz,Chloroform-d)δ7.91-7.78(m,1H),7.68(dd,J=56.7,7.5Hz,1H),7.38-7.26(m,2H),7.14(dd,J=8.1,5.1Hz,1H),7.00(t,J=8.4Hz,1H),6.47(d,J=6.0Hz,1H),3.46(ddd,J=51.0,13.6,6.8Hz,1H),3.14(d,J=12.4Hz,1H),2.91(d,J=12.4Hz,1H),2.79(t,J=7.2Hz,1H).MS(ESI):[M+H]+554.2m/z
实施例24
11-氰基-N-(4-氟苯乙基)-9-(羟甲基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用4-氟-苯乙胺1.39g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,用9-羟甲基蒽替换掉例1的步骤(b)中的蒽,其它步骤参照实施例1中的制备方法,制得化合物(24),得白色固体2.26g,产率:53%。1H NMR(500MHz,Chloroform-d)δ7.45-7.34(m,4H),7.20(d,J=6.8Hz,2H),7.13-7.08(m,4H),7.05(dd,J=8.5,5.4Hz,2H),6.99(d,J=8.6Hz,1H),6.21(t,J=5.8Hz,1H),4.69(s,2H),4.59(s,1H),3.45-3.33(m,2H),2.67(dt,J=15.0,7.1Hz,2H),2.55(d,J=13.1Hz,1H),2.14(d,J=13.1Hz,1H).MS(ESI):[M+H]+426.4m/z
实施例25
10-(氯甲基)-11-氰基-N-(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用4-氟-苯乙胺1.39g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,用9-氯甲基蒽替换掉例1的步骤(b)中的蒽,其它步骤参照实施例1中的制备方法,制得化合物(25),得白色固体2.33g,产率:53%。1H NMR(600MHz,Chloroform-d)δ7.42(t,J=18.1Hz,4H),7.23(dt,J=14.6,7.9Hz,2H),7.15-7.05(m,4H),6.99(t,J=8.4Hz,1H),6.24(t,J=5.7Hz,1H),4.61(s,67H),4.56(s,2H),3.40(q,J=6.7Hz,2H),2.70(dt,J=15.1,6.9Hz,2H),2.32(dd,J=14.4,8.4Hz,1H).MS(ESI):[M+H]+444.1m/z
实施例26
11-氰基-N-(4-氟苯乙基)-10-甲基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用4-氟-苯乙胺1.39g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,用9-甲基蒽替换掉例1的步骤(b)中的蒽,其它步骤参照实施例1中的制备方法,制得化合物(26),得白色固体1.76g,产率:43%。1H NMR(600MHz,Chloroform-d)δ7.43-7.39(m,1H),7.30(dd,J=22.2,7.4Hz,1H),7.24-7.16(m,1H),7.12-7.05(m,2H),7.00(dd,J=9.9,7.4Hz,1H),6.10(t,J=5.7Hz,0H),4.53(s,1H),3.40(q,J=6.7Hz,1H),2.72(dt,J=14.1,7.1Hz,1H),2.47(d,J=13.0Hz,1H),1.99(d,J=10.8Hz,2H).MS(ESI):[M+H]+410.1m/z
实施例27
10-溴-11-氟-N-(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用4-氟-苯乙胺1.39g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,用2-氟-丙烯酸替换掉实施例1的步骤(a)中的2-氰基-丙烯酸,用9-溴蒽替换掉例1的步骤(b)中的蒽,其它步骤参照实施例1中的制备方法,制得化合物(27),得白色固体1.87g,产率:44%。1H NMR(500MHz,Chloroform-d)δ7.47-7.39(m,1H),7.33-7.29(m,1H),7.19(ddd,J=14.2,6.9,2.8Hz,3H),7.09(td,J=10.1,9.1,6.4Hz,4H),7.01(t,J=8.6Hz,2H),6.06(d,J=6.0Hz,1H),4.55(s,1H),4.43(d,J=2.7Hz,1H),3.49-3.35(m,J=6.8Hz,2H),2.83-2.73(m,1H),2.73-2.62(m,2H),2.19(dd,J=12.9,2.8Hz,1H).MS(ESI):[M+H]+426.4m/z
实施例28
9-溴-19-氯-N-(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用4-氟-苯乙胺1.39g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,用2-氯丙烯酸替换掉实施例1的步骤(a)中的2-氰基丙烯酸,用9-羟甲基蒽替换掉例1的步骤(b)中的蒽,其它步骤参照实施例1中的制备方法,制得化合物(28),得白色固体1.64g,产率:34%。1H NMR(500MHz,Chloroform-d)δ7.81-7.64(m,2H),7.35-7.27(m,1H),7.27-7.23(m,1H),7.20(dt,J=10.5,4.0Hz,4H),7.14(dd,J=8.3,5.3Hz,2H),7.03(d,J=5.8Hz,1H),6.97(t,J=8.5Hz,2H),3.42(ddt,J=46.1,13.4,6.6Hz,2H),3.03(dd,J=13.2,2.4Hz,1H),2.77(q,J=6.7Hz,2H),2.45(dd,J=13.2,3.2Hz,1H).MS(ESI):[M+H]+483.0m/z
实施例29
10-溴-N-(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-12,11-二甲酰胺
用4-氟-苯乙胺1.39g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,用2-甲酰胺-丙烯酸替换掉实施例1的步骤(a)中的2-氰基丙烯酸,用9-溴蒽替换掉例1的步骤(b)中的蒽,其它步骤参照实施例1中的制备方法,制得化合物(29),得白色固体2.16g,产率:44%。1H NMR(300MHz,DMSO-d6)δ7.82(d,J=5.7Hz,1H),7.60-7.52(m,2H),7.39-7.25(m,3H),7.24-7.02(m,7H),6.99(d,J=5.5Hz,3H),5.34(s,1H),3.10(dq,J=12.7,6.7Hz,2H),3.03-2.85(m,2H),2.56(d,J=7.9Hz,1H).MS(ESI):[M+H]+492.0m/z
实施例30
10-溴-11-氰基-N-(2-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用2-氟-苯乙胺1.66g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,用9-溴蒽替换掉例1的步骤(b)中的蒽,其它步骤参照实施例1中的制备方法,制得化合物(30),得白色固体3.02g,产率:64%。1H NMR(500MHz,Chloroform-d)δ7.87-7.67(m,2H),7.45-7.40(m,1H),7.34-7.26(m,1H),7.19-7.06(m,4H),7.03(d,J=7.1Hz,1H),6.14(s,1H),4.55(s,1H),3.47(tq,J=13.3,6.6Hz,2H),3.16(d,J=12.8Hz,1H),2.83(dq,J=14.1,7.0Hz,2H),2.66(d,J=12.9Hz,1H).MS(ESI):[M+H]+473.0m/z
实施例31
10-溴-11-氰基-N-(3-苯基丙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用苯丙胺2.18g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,用9-溴蒽替换掉例1的步骤(b)中的蒽,其它步骤参照实施例1中的制备方法,制得化合物(31),得白色固体1.50g,产率:32%。1H NMR(500MHz,Chloroform-d)δ7.74(dd,J=18.7,7.4Hz,3H),7.41(d,J=6.9Hz,2H),7.34(t,J=7.6Hz,3H),7.31-7.26(m,5H),7.22-7.12(m,6H),6.06(d,J=5.8Hz,2H),4.50(s,2H),3.28(dt,J=13.3,6.7Hz,2H),3.18(dd,J=13.3,7.8Hz,3H),1.84(q,1H).MS(ESI):[M+H]+470.0m/z
实施例32
10-溴-N-(3-(4-溴苯基)丙基)-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用4-溴-苯丙胺2.18g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,用9-溴蒽替换掉例1的步骤(b)中的蒽,其它步骤参照实施例1中的制备方法,制得化合物(32),得白色固体3.12g,产率:57%。1H NMR(500MHz,Chloroform-d)δ7.79-7.71(m,2H),7.43(td,J=6.2,5.4,3.1Hz,3H),7.34-7.26(m,2H),7.17(p,J=6.4,5.5Hz,2H),7.04(d,J=7.9Hz,2H),6.09(s,1H),4.56(s,1H),3.29-3.17(m,3H),2.66(d,J=12.8Hz,1H),2.62-2.54(m,2H),1.79(t,J=7.4Hz,1H).MS(ESI):[M+H]+548.0m/z
实施例33
10-溴-N-(2-((4-氯苯基)磺酰基)乙基)-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用2-((4-氯苯基)磺酰基)乙胺2.18g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,用9-溴蒽替换掉例1的步骤(b)中的蒽,其它步骤参照实施例1中的制备方法,制得化合物(33),得白色固体2.16g,产率:39%。1H NMR(300MHz,Chloroform-d)δ7.88(d,J=8.5Hz,2H),7.76(t,J=7.8Hz,2H),7.59(d,J=8.3Hz,2H),7.47(dd,J=6.1,2.4Hz,1H),7.40-7.27(m,3H),7.23-7.16(m,1H),7.10(d,J=5.5Hz,1H),4.78(s,1H),3.86-3.45(m,2H),3.28(d,J=12.8Hz,1H),3.23-3.18(m,2H),2.66(d,J=12.8Hz,1H).MS(ESI):[M+H]+554.0m/z
实施例34
10-溴-11-氯-N-(3-苯基丙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用苯丙胺1.39g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,用2-氯丙烯酸替换掉实施例1的步骤(a)中的2-氰基丙烯酸,用9-溴蒽替换掉例1的步骤(b)中的蒽,其它步骤参照实施例1中的制备方法,制得化合物(34),得白色固体2.05g,产率:43%。1H NMR(300MHz,Chloroform-d)δ7.84-7.64(m,2H),7.39-7.25(m,4H),7.27-7.12(m,7H),7.02(s,1H),4.41(t,J=2.8Hz,1H),3.40-3.12(m,2H),3.07(dd,J=13.2,2.4Hz,1H),2.66(td,J=7.3,1.8Hz,1H),2.47(dd,J=13.2,3.2Hz,1H),1.85(p,J=7.3Hz,1H).MS(ESI):[M+H]+479.0m/z
实施例35
10-溴-N-(3-(4-溴苯基)丙基)-11-氯-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用4-溴-苯丙胺1.39g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,用2-氯丙烯酸替换掉实施例1的步骤(a)中的2-氰基丙烯酸,用9-溴蒽替换掉例1的步骤(b)中的蒽,其它步骤参照实施例1中的制备方法,制得化合物(35),得白色固体1.89g,产率:34%。1H NMR(300MHz,Chloroform-d)δ7.74(ddd,J=29.2,6.2,3.0Hz,2H),7.47-7.29(m,2H),7.33-7.28(m,1H),7.27-7.16(m,5H),7.07-6.99(m,3H),4.40(t,J=2.7Hz,1H),3.36-3.12(m,2H),3.07(dd,J=13.2,2.4Hz,1H),2.66-2.55(m,2H),2.46(dd,J=13.2,3.1Hz,1H),1.89-1.73(m,2H).MS(ESI):[M+H]+557.0m/z
实施例36
10-溴-11-氯-N-(2-((4-氯苯基)磺酰基)乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用2-((4-氯苯基)磺酰基)乙基胺1.39g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,用2-氯丙烯酸替换掉实施例1的步骤(a)中的2-氰基丙烯酸,用9-溴蒽替换掉例1的步骤(b)中的蒽,其它步骤参照实施例1中的制备方法,制得化合物(36),得白色固体3.14g,产率:56%。1H NMR(300MHz,Chloroform-d)δ7.81(ddd,J=19.6,6.6,1.8Hz,3H),7.70-7.51(m,4H),7.32(dd,J=5.9,2.8Hz,1H),7.24-7.10(m,4H),4.40(d,J=3.2Hz,1H),3.62(tt,J=14.6,7.7Hz,2H),3.45-3.07(m,2H),2.99-2.88(m,1H),2.50-2.39(m,1H).MS(ESI):[M+H]+562.9m/z
实施例37
10-溴-11-氰基-N-(2-(4-氟苯基)-2-氧乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用2-(4-氟苯基)-2-氧乙基胺2.18g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,用9-溴蒽替换掉例1的步骤(b)中的蒽,其它步骤参照实施例1中的制备方法,制得化合物(37),得白色固体1.85g,产率:38%。1H NMR(500MHz,Chloroform-d)δ7.99(dd,J=8.6,5.2Hz,2H),7.81-7.72(m,2H),7.51(s,1H),7.36-7.26(m,2H),7.18(ddt,J=19.7,13.3,5.8Hz,6H),4.82(s,1H),4.74(dd,J=19.5,4.7Hz,1H),4.57(d,J=3.2Hz,1H),3.30(d,J=12.8Hz,1H),2.74(d,J=12.8Hz,1H).MS(ESI):[M+H]+488.0m/z
实施例38
10-溴-11-氰基-N-(2-((4-氟苯基)磺胺基)乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用2-((4-氟苯基)磺胺基)乙基胺2.18g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,用9-溴蒽替换掉例1的步骤(b)中的蒽,其它步骤参照实施例1中的制备方法,制得化合物(38),得白色固体2.32g,产率:42%。1H NMR(500MHz,DMSO-d6)δ8.87(t,J=5.7Hz,1H),7.90-7.84(m,2H),7.75(d,J=6.0Hz,1H),7.67(dd,J=6.0,2.8Hz,1H),7.59(d,J=7.7Hz,1H),7.54-7.45(m,3H),7.39-7.29(m,2H),7.29-7.15(m,2H),7.10(d,J=7.4Hz,1H),5.18(s,1H),3.30(s,1H),3.17(dq,J=14.0,6.5Hz,1H),3.02(td,J=7.7,4.0Hz,1H),2.75-2.58(m,3H).MS(ESI):[M+H]+553.0m/z
实施例39
10-溴-11-氰基-N-(2-(4-氟苯甲酰胺)乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用2-(4-氟苯甲酰胺)乙基胺2.18g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,用9-溴蒽替换掉例1的步骤(b)中的蒽,其它步骤参照实施例1中的制备方法,制得化合物(39),得白色固体2.62g,产率:51%。1H NMR(300MHz,DMSO-d6)δ8.93(d,J=5.9Hz,1H),7.93-7.78(m,3H),7.78-7.65(m,1H),7.60(d,J=7.7Hz,1H),7.50(t,J=8.5Hz,4H),7.44-7.33(m,2H),7.26(t,J=7.5Hz,1H),7.18(d,J=7.3Hz,1H),7.11(d,J=7.4Hz,1H),5.20(s,1H),3.33(d,J=13.0Hz,1H),3.11(dp,J=42.9,7.0Hz,2H),2.70(dq,J=23.5,9.3,7.1Hz,2H),2.46(s,1H).MS(ESI):[M+H]+517.0m/z
实施例40
10-溴-11-氰基-N-(2-(苯磺胺基)乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用2-(苯磺胺基)乙基胺2.18g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,用9-溴蒽替换掉例1的步骤(b)中的蒽,其它步骤参照实施例1中的制备方法,制得化合物(40),得白色固体3.79g,产率:71%。1H NMR(600MHz,Chloroform-d)δ7.91(d,J=7.7Hz,2H),7.73(dd,J=36.3,7.6Hz,2H),7.58(d,J=7.3Hz,1H),7.53(t,J=7.6Hz,2H),7.48(s,1H),7.43(d,J=7.1Hz,1H),7.24(ddd,J=18.8,15.3,7.4Hz,4H),7.13(d,J=7.5Hz,1H),5.88(t,J=5.9Hz,1H),4.92(s,1H),3.37(d,J=13.0Hz,2H),3.30(s,1H),2.97(q,J=4.9Hz,2H),2.65(d,J=12.9Hz,1H).MS(ESI):[M+H]+535.0m/z
实施例41
N-(1-苄基哌啶-4-基)-10-溴-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用N-(1-苄基哌啶-4-基)乙胺2.18g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,用9-溴蒽替换掉例1的步骤(b)中的蒽,其它步骤参照实施例1中的制备方法,制得化合物(41),得白色固体2.67g,产率:51%。1H NMR(300MHz,Chloroform-d)δ7.81-7.69(m,1H),7.49-7.40(m,1H),7.38-7.27(m,8H),7.17(dd,J=5.6,1.8Hz,2H),6.12(d,J=7.6Hz,1H),4.66(s,1H),3.72-3.56(m,1H),3.54(s,2H),3.25(d,J=12.8Hz,1H),2.87(d,J=11.5Hz,2H),2.66(d,J=12.8Hz,1H),2.10(s,1H),1.81(d,J=14.2Hz,2H),1.55(t,J=11.4Hz,2H).MS(ESI):[M+H]+525.1m/z
实施例42
N-((1-苄基哌啶-4-基)甲基)-10-溴-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用N-((1-苄基哌啶-4-基)甲基胺2.18g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,用9-溴蒽替换掉例1的步骤(b)中的蒽,其它步骤参照实施例1中的制备方法,制得化合物(42),得白色固体3.55g,产率:66%。1H NMR(600MHz,DMSO-d6)δ8.96(s,1H),7.76-7.66(m,1H),7.62(d,J=7.6Hz,1H),7.55-7.47(m,6H),7.42-7.33(m,2H),7.28(t,J=7.3Hz,2H),7.21(t,J=7.5Hz,1H),5.28(s,1H),4.29(s,2H),2.90(s,4H),1.82(s,1H),1.62(s,2H),1.26(q,J=7.6Hz,6H).MS(ESI):[M+H]+539.1m/z
实施例43
10-溴-11-氰基-N-((1-(苯基磺酰基)哌啶-4-基)甲基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用(1-(苯基磺酰基)哌啶-4-基)甲基胺2.18g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,用9-溴蒽替换掉例1的步骤(b)中的蒽,其它步骤参照实施例1中的制备方法,制得化合物(43),得白色固体3.59g,产率:61%。1H NMR(600MHz,Chloroform-d)δ7.74(dd,J=24.3,7.6Hz,2H),7.33-7.26(m,2H),7.17-7.14(m,1H),6.74(d,J=5.8Hz,1H),4.73(s,1H),4.06-3.63(m,1H),3.26(d,J=12.8Hz,1H),3.15-3.03(m,2H),2.98-2.89(m,1H),2.81-2.73(m,1H),2.68(d,J=12.8Hz,1H),2.05-1.66(m,3H),1.64-1.39(m,1H).MS(ESI):[M+H]+589.1m/z
实施例44
N-(2-(1-苄基哌啶-4-基)乙基)-9-溴-11-氯-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用N-2-(1-苄基哌啶-4-基)乙胺2.18g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,用2-氯丙烯酸替换掉实施例1的步骤(a)中的2-氰基丙烯酸,用9-溴蒽替换掉例1的步骤(b)中的蒽,其它步骤参照实施例1中的制备方法,制得化合物(44),得白色固体3.43g,产率:61%。1H NMR(500MHz,Chloroform-d)δ7.81-7.76(m,1H),7.67(d,J=7.4Hz,1H),7.31(dd,J=11.4,5.0Hz,5H),7.27(d,J=6.6Hz,1H),7.24-7.10(m,4H),6.93(d,J=5.9Hz,1H),4.39(d,J=2.9Hz,1H),3.56(s,2H),3.40-3.23(m,1H),3.20-3.12(m,1H),3.08(dd,J=13.2,2.4Hz,1H),2.98-2.88(m,2H),2.46(dd,J=13.2,3.2Hz,1H),2.01(p,J=8.6,7.9Hz,2H),1.68(d,J=13.2Hz,2H),1.46(td,J=14.3,5.1Hz,2H),1.37(s,1H),1.35-1.32(m,4H).MS(ESI):[M+H]+562.1m/z
实施例45
N-(2-(1-苄基哌啶-4-基)乙基)-9-溴-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用N-2-(1-苄基哌啶-4-基)乙胺2.18g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,用9-溴蒽替换掉例1的步骤(b)中的蒽,其它步骤参照实施例1中的制备方法,制得化合物(45),得白色固体1.16g,产率:21%。1H NMR(300MHz,Chloroform-d)δ7.71(dd,J=12.8,7.4Hz,2H),7.50(d,J=7.1Hz,1H),7.36(dd,J=7.8,4.1Hz,6H),7.21(t,J=5.9Hz,4H),7.16-7.05(m,1H),6.64(s,1H),4.88(s,1H),3.91(s,2H),3.82-3.62(m,2H),3.30(d,J=12.9Hz,1H),3.21(d,J=11.2Hz,4H),3.07-2.82(m,2H),2.62(t,J=6.5Hz,2H),2.52(s,2H),1.79(d,J=10.3Hz,2H).MS(ESI):[M+H]+553.1m/z
实验例46
N-(2-(4-苄基哌啶-1-基)乙基)-10-溴-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺
用N-2-(4-苄基哌啶-4-基)乙胺2.18g(1.0mol)替换掉实施例1的步骤(a)中的3,4,5-三甲氧基苯胺,用9-溴蒽替换掉例1的步骤(b)中的蒽,其它步骤参照实施例1中的制备方法,制得化合物(46),得白色固体1.55g,产率:28%。1H NMR(300MHz,Chloroform-d)δ7.82-7.66(m,2H),7.53(dt,J=6.1,3.1Hz,1H),7.40-7.26(m,4H),7.23-7.18(m,1H),7.17-7.05(m,2H),5.05(s,1H),3.54(d,J=12.7Hz,1H),3.42(d,J=5.7Hz,1H),3.32(d,J=13.0Hz,1H),3.17(s,1H),2.88-2.73(m,2H),2.59(d,J=13.4Hz,2H),2.40(s,1H),1.82-1.46(m,4H),1.43(s,1H),1.35-1.22(m,1H),0.92-0.78(m,2H).MS(ESI):[M+H]+553.1m/z
实验例47
Cell Counting Kit-8细胞计数试剂(CCK-8)法测定肿瘤细胞的细胞活力
化合物的ZNF207抑制活性筛选实验做法为:在96孔板中接种人源肝癌细胞(Hep3B和Huh7)(购自中国科学院细胞库)悬液,每孔约100μl,同样的样本做3个重复。将培养板放入培养箱中预培养一段时间(37℃,5%CO2),向培养板各孔中加入不同浓度的化合物,将培养板放入培养箱中孵育一段时间。向每孔中加入10μl CCK-8溶液,将培养板放入培养箱中孵育1-4h。用酶标仪测定450nm处的吸光度(OD)。
细胞活力(%)=[A(加药)-A(空白)]/[A(0加药)-A(空白)]×100
A(加药):具有细胞、CCK-8溶液和药物溶液的孔的OD值
A(0加药):具有细胞、CCK-8溶液而没有药物溶液的孔的OD值
A(空白):没有细胞的孔的OD值
细胞活力(%):数值越小说明化合物抗细胞增殖和细胞毒性效果越好,细胞增殖活力或细胞毒性活力结果展示于表1中。
表1不同物质对细胞的细胞活力结果(%)
实验例48
本发明部分化合物对ZNF207的靶点结合验证
动力学亲和力测定实验(SPR):使用生物分子相互作用仪(Biacore T200)在25℃下进行动力学亲和力测定。在结合试验中,使用补充有5%二甲基亚砜的流动缓冲液[10mMN-(2-羟乙基)哌嗪-N′-乙磺酸,pH 7.4,150mM NaCl,3mM EDTA和0.005%吐温-20]对化合物进行梯度稀释。运行缓冲液用于空白进样,并使用溶剂校正法校正样品中的参考误差。在pH值为4.0、4.5、5.0和5.5的10mM醋酸盐缓冲液中进行重组LeuRS固定化的pH筛选。通过pH为最佳值的标准胺偶联程序,约20000个LeuRS重组响应单位(RU)共价固定在CM5传感器芯片上。将化合物以30μL/min的流速注入STAT3固定化流动细胞120s,并使其离解120s。使用评估软件BiacoreTM Insight分析软件计算稳态KD值,结果展示于表2中。其中,KD值约小,则表示化合物对蛋白的亲和力越高。
表2 不同物质对ZNF207的KD值
实施例 | <![CDATA[K<sub>D</sub>(nM)]]> |
22 | 817±11 |
41 | 70±3 |
42 | 84±21 |
43 | 14±3 |
44 | 19±1 |
45 | 1±0.2 |
46 | 4±0.5 |
表3的测试结果表明,被测化合物22、41、42、43、44、45对ZNF207有较高的亲和力,说明受试化合物具有与ZNF207结合的能力。
实验例49
本发明部分化合物口服给药对小鼠肿瘤模型的影响
HCT116、Huh7、Hela细胞(1×107)分别和Matrigel基质胶(BD Biosciences)以3:1的比例混合在一起并注射于6周龄BALB/c裸鼠的侧翼,每种细胞随机分为5组异种移植,每组8只。于肿瘤容积达到125mm3治疗开始,持续14天,给予口服含5% DMSO的0.9%生理盐水(载药)和化合物45(5、15、45mg/kg)和对应的阳性药每天一次。通过测量肿瘤的两个直径垂直,肿瘤体积为测定(V=长(mm)×宽(mm)/2),每2天记录一次体重。21天后,小鼠被处死解剖,收集肿瘤组织进行称重并收集以作进一步研究,结果见表3。
表3化合物45的皮下瘤抑瘤率(%)
注:t检验,与空白组相比,*p<0.05,**p<0.01,***p<0.001。“-”表示该组别未使用此阳性药进行比较。
测试结果表明:在小鼠皮下瘤模型中,本发明的部分化合物如45与空白组和阳性对照组相比有较显著差异,在不同类型的的肿瘤中均表现出较强的抑制作用。
最后应当说明的是:以上实施例仅用以说明本发明的技术方案而非对其限制;尽管参照较佳实施例对本发明进行了详细的说明,所属领域的普通技术人员应当理解,依然可以对本发明的具体实施方式进行修改或者对部分技术特征进行等同替换;而不脱离本发明技术方案的精神,其均应涵盖在本发明请求保护的技术方案范围当中。
Claims (10)
1.一种甲酰胺乙撑蒽类化合物,其特征在于,它为式(Ⅰ)所示结构的化合物或其药学上可接受的盐,
式(Ⅰ)
其中,
Z选自氢、卤素、羟基、氨基、取代或未取代的C1-6烷氧基或取代或未取代的C1-6烷基,Z的取代基选自氢、卤素、羟基、氨基,所述取代为单取代或多取代;
Y选自六元脂肪环、六元脂肪杂环或Y不存在,六元脂肪杂环包括1-3个杂原子,杂原子独立的地选自O、N或S;
R1是羧基、酰胺基、卤素、氰基、氨基或取代或未取代的C1-6烷基,C1-6烷基的取代基为卤素、酰胺基或氨基,所述取代为单取代或多取代;
R2是氢、卤素、羟基、氰基、硼酸基、乙酰基或取代或未取代的具有1-6个碳的烷基,烷基的取代基为1-6个碳的烷基、羟基、卤素、氰基、硼酸基或乙酰基,所述取代为单取代或多取代;
n为0-2的整数;
R3是氢或卤素;
A选自硫原子、氧原子、亚胺基、磺基、羰基、酰胺基、磺胺基或A不存在。
2.根据权利要求1所述的甲酰胺乙撑蒽类化合物,其特征在于,Z选自氢、卤素、羟基、氨基、C1-6烷氧基或C1-6烷基;
Y选自六元脂肪环、六元脂肪杂环或Y不存在,其中,六元脂肪杂环具有2个位于对位的杂原子,杂原子独立的地选自O、N或S;
R1是羧基、酰胺基、卤素、氰基、氨基或取代或未取代的C1-6烷基,C1-6烷基的取代基为卤素或氨基,所述取代为单取代或多取代;
R2是氢、卤素、羟基、氰基、硼酸基、乙酰基或取代或未取代的具有1-6个碳的烷基,烷基的取代基为羟基或卤素,所述取代为单取代或多取代。
3.一种根据权利要求1或2所述的甲酰胺乙撑蒽类化合物,其特征在于,它为11-氰基-N -(3,4,5-三甲氧基苯基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
N -(苯并[d][1,3]二氧基-5-基)-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基- N -(4-氟苯基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基- N -(邻甲苯基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基- N -(4-甲氧基-3-甲基苯基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基- N -(间氯苯基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
N -(4-氨基苯基)-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基- N -(4-甲氧基苯基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基- N -(3,5-二甲氧苯基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基- N -(3,4-二氯苯基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基- N -(4-氟苄基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基-N -(4-硝基苄基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
N -苄基-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基- N -(4-氨基苄基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基- N -(2,3-二氯苄基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
N -(3-氯苯乙基)-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基- N -(4-甲基苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基- N -(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基- N-(2-(吡啶-2-基)乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基- N -(4-硝基苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
N-(2-(苯并[d][1,3]二氧基-5-基)乙基)-11-氰基-9,10-二氢-9,10-乙撑蒽-11-羧基酰胺;
N-(2-(1-苄基哌啶-4-基)乙基)-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基- N -(3-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基- N -(2-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基- N -(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
9,10-二溴-11-氰基- N -(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基- N -(4-氟苯乙基)-10-(羟甲基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-(氯甲基)-11-氰基- N -(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-乙酰基-11-氰基- N -(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-硼酸基-11-氰基- N -(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-氰基- N -(4-氟苯乙基)-10-甲基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氟- N -(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氯- N -(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-(溴甲基)- N -(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴- N -(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-12,11-二甲酰胺;
10-溴-11-氰基- N -(4-溴苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基- N -(4-氯苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基- N -(2-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基- N -(3-苯基丙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴- N -(3-(4-溴苯基)丙基)-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-(氨基甲基)-10-溴- N -(4-氟苯乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴- N -(2-((4-氯苯基)磺酰基)乙基)-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氯- N -(3-苯基丙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基- N -(2-(苯基硫基)乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴- N -(3-(4-溴苯基)丙基)-11-氯-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氯- N -(2-((4-氯苯基)磺酰基)乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基- N -(2-(4-氟苯基)-2-氧乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基- N -(2-((4-氟苯基)磺胺基)乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基- N -(2-(4-氟苯甲酰胺)乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基- N -(2-(苯磺胺基)乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
N-(1-苄基哌啶-4-基)-10-溴-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
N-((1-苄基哌啶-4-基)甲基)-10-溴-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基- N-((1-(4-氟苄基)哌啶-4-基)甲基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基- N-((1-(4-氟苯甲酰)哌啶-4-基)甲基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基- N-((1-((4-氟苯基)磺酰基)哌啶-4-基)甲基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
N-((1-苯甲酰哌啶-4-基)甲基)- 10-溴-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基- N-((1-(苯基磺酰基)哌啶-4-基)甲基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-(2-苄基-1-氧-2,8-二氮杂螺[4.5]正烷-8-羰基)-10-溴-9,10-二氢-9,10-乙撑蒽-11-甲腈;
N-(2-(1-苄基哌啶-4-基)乙基)-10-溴-11-氯-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
N-(2-(1-苄基哌啶-4-基)乙基)-10-溴-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-(氨基甲基)-N-(2-(1-苄基哌啶-4-基)乙基)- 10-溴-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
N-(2-(4-苄基哌嗪-1-基)乙基)-10-溴-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
N-(2-(4-苄基哌啶-1-基)乙基)-10-溴-11-氰基-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基-N-(2-(1-(4-氟苄基)哌啶-4-基)乙基) -9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基-N-(2-(4-苯基哌嗪-1-基)乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
10-溴-11-氰基-N-(2-(4-苯基哌啶-1-基)乙基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
N-(2- (1-苄基哌啶-4-基)乙基) -10-溴-11- (溴甲基)-9,10-二氢-9,10-乙撑蒽-11-甲酰胺;
11-(4-((4-苄基哌啶-1-基)甲基)哌啶-1-羰基)-10-溴-9,10-二氢-9,10-乙撑蒽-11-甲腈
或上述化合物的药学上可接受的盐。
4.一种药物组合物,其特征在于,它包含权利要求1-3所述的甲酰胺乙撑蒽类化合物及药学上可接受的药物载体。
5.根据权利要求4所述的药物组合物,其特征在于,所述药物组合物的剂型为片剂、胶囊、丸剂、栓剂、软胶囊、口服液、混悬剂或注射液。
6.一种根据权利要求1-3所述的甲酰胺乙撑蒽类化合物的应用,其特征在于,甲酰胺乙撑蒽类化合物用于制备预防和/或治疗ZNF207介导疾病的药物。
7.根据权利要求6所述的应用,其特征在于,所述的ZNF207介导疾病包括胚胎发育异常、细胞代谢异常、分化异常和恶性肿瘤。
8.根据权利要求7所述的应用,其特征在于,所述恶性肿瘤为肝癌、结肠癌或宫颈癌。
9.一种根据权利要求1-3所述的甲酰胺乙撑蒽类化合物的应用,其特征在于,甲酰胺乙撑蒽类化合物用于制备ZNF207抑制剂。
10.一种根据权利要求1-3所述的甲酰胺乙撑蒽类化合物的制备方法,其特征在于,包括:
(a)以2位取代的丙烯酸和芳香胺为起始原料,经酸胺缩合,制备中间体i;
(b)中间体ⅰ与9、10位取代的蒽经过狄尔斯–阿尔德反应制备式(Ⅰ)化合物;
。
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