CN109912584B - 一种具有抗肿瘤活性的brd4蛋白抑制剂及其制备方法和应用 - Google Patents
一种具有抗肿瘤活性的brd4蛋白抑制剂及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种具有抗肿瘤活性的通式(I)所示的化合物或其药学上可接受的酯或盐,及其制备方法和其作为BRD4蛋白抑制剂的应用。和现有技术相比,本发明提供的BRD4小分子抑制剂结构新颖,其在抗肿瘤增值中表现出优良的生物活性,并可用于包括实体瘤如乳腺癌、***癌,造血***肿瘤如急性髓性白血病、多发性骨髓瘤等癌症疾病,具有广阔的开发前景。
Description
技术领域
本发明属于药物化学技术领域,具体涉及一种具有抗肿瘤活性的BRD4蛋白抑制剂及其制备方法和应用。
背景技术
组蛋白乙酰化是表观遗传研究的重要组成部分,是翻译后修饰的重要方式。Bromodomain(BRD)是一类能够特异性识别组蛋白中乙酰化赖氨酸(KAc)的保守蛋白结构域,通过与乙酰化赖氨酸结合促使染色质重塑因子和转录因子等相关蛋白富集于特定的基因转录位点,改变RNA聚合酶Ⅱ的活性,调节基因的转录表达。
截至目前,人体内发现的61种BRD结构域存在于42种蛋白中,根据其母蛋白功能的不同,划分为8大家族,BET(bromodomain and extra terminal domain)蛋白家族是 BRD蛋白家族的第2类,BET蛋白家族的结构包含两个溴结构域和一种额外末端(ET) 结构域的多肽,成员包括BRD2、BRD3、BRD4和BRDT。该家族蛋白的溴结构域 (bromodomain)即为识别乙酰化的赖氨酸残基的多肽的一部分。
目前,已有报道多种选择性靶向BET家族的BRD4蛋白的小分子抑制剂。氮杂卓类化合物JQ-1是最早公开报道的BET蛋白家族抑制剂,其对BRD4的IC50为39nmol/L,在肿瘤以及HIV等疾病的治疗中表现出良好的疗效。但是由于JQ-1化合物的药物代谢情况并不理想,因此对JQ-1的研究止步于临床前研究,未能顺利进入临床研究阶段。由Resverlogix制药公司研发的嘧啶酮类小分子抑制剂RVX-208对BRD4的IC50为 40nmol/L,目前RVX-208已经进入由低水平高密度脂蛋白胆固醇造成的高风险的心血管疾病的临床试验中。由葛兰素史克(GSK)研发的异噁唑类化合物I-BET151对比JQ-1 其对BRD4蛋白的选择性和抑制活性并没有显著的提高,但I-BET151具有更好的成药性,在急性髓性白血病、胰腺癌、恶性胶质瘤和炎症的研究中均具有较高的生物活性。除此以外,目前已进入临床研究的BRD4小分子抑制剂还包括用于白血病和多发性骨髓瘤的CPI-0610、由GlaxoSmithKline研发的I-BET762、由Merck和Mitsubishi Tanabe公司共同研发的OTX-015等。
虽然这些数据表明BRD4抑制剂在血液***恶性肿瘤和实体瘤的临床前模型中显示出功效,但所有BRD4抑制剂的临床安全性概况看起来相似,频繁的胃肠道和骨髓毒性导致剂量中断和剂量减少。目前BRD4抑制剂的治疗窗口急需改善。
发明内容
发明目的:为解决上述技术问题,本发明提供一种具有抗肿瘤生物活性的新型BRD4 小分子抑制剂化合物,并以溴结构域蛋白为靶点进行生物活性筛选的具有生物活性的化合物其制备方法及其应用。
技术方案:为达到上述发明目的,本发明采用以下技术方案:
一种通式(I)所示的化合物或其药学上可接受的酯或盐:
其中:
环A是5元或6元芳杂基环,所述芳杂基环为任选被以下基团取代的芳杂基环: C1-6卤代烷基、卤素、NO2、-OH、-CN或任选被取代的C1-6烷基;
R1,R2,R3,R4各自独立选自氢、卤素、三氟甲氧基、烷氧基、C3-10环烷基,C1-10烷基,或者R1,R2,R3,R4形成以下结构:
优选,所述环A选自噻唑酮、异恶唑或吡啶酮,所述噻唑酮、异恶唑或吡啶酮为任选被以下基团取代的芳杂基环:C1-6卤代烷基、卤素、NO2、-OH、-CN或任选被取代的 C1-6烷基。
优选,所述环A选自3-甲基噻唑-2-(3H)-酮、噻唑-2(3H)-酮、3,5-二甲基异恶唑或1-甲基吡啶-2(1H)-酮。
优选,所述R1,R2,R3,R4各自独立选自氢、氯、氟、溴、甲氧基、羟基、叔丁基、三氟甲氧基、甲基、乙基、异丙基、叔丁基、丁基、硝基,或者R1,R2,R3,R4形成以下结构:
更优选的本发明具有通式(I)的化合物或其可药用盐,所述化合物选自:
N-环戊基-5-(3,5-二甲基异恶唑-4-基)-2-((1-苯基-1H-1,2,3-***-4-基)甲氧基)苯磺酰胺(I-a);
2-((1-(2-氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5-二甲基异恶唑-4- 基)苯磺酰胺(I-b);
2-((1-(3-氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5-二甲基异恶唑-4- 基)苯磺酰胺(I-c);
2-((1-(4-氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5-二甲基异恶唑-4- 基)苯磺酰胺(I-d);
2-((1-(4-氟苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5-二甲基异恶唑-4- 基)苯磺酰胺(I-e);
2-((1-(3,4-二氟苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5-二甲基异恶唑-4-基)苯磺酰胺(I-f);
2-((1-(2-甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5-二甲基异恶唑-4-基)苯磺酰胺(I-g);
2-((1-(4-甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5-二甲基异恶唑-4-基)苯磺酰胺(I-h);
2-((1-(3-甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)N-环戊基-5-(3,5-二甲基异恶唑 -4-基)苯磺酰胺(I-i);
2-((1-(3,4-二甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基--5-(3,5-二甲基异恶唑-4-基)苯磺酰胺(I-j);
2-((1-(苯并[d][1,3]二恶英-5-基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5- 二甲基异恶唑-4-基)苯磺酰胺(I-k);
2-((1-(3,4,5-三甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5-二甲基异恶唑-4-基)苯磺酰胺(I-l);
2-((1-(间甲苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5-二甲基异恶唑-4- 基)苯磺酰胺(I-m);
2-((1-(2-乙基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5-二甲基异恶唑-4- 基)苯磺酰胺(I-n);
2-((1-(3-异丙基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5-二甲基异恶唑-4-基)苯磺酰胺(I-o);
2-((1-(3-(叔丁基)苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5-二甲基异恶唑-4-基)苯磺酰胺(I-p);
2-((1-(4-(叔丁基)苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5-二甲基异恶唑-4-基)苯磺酰胺(I-q);
2-((1-(4-丁基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5-二甲基异恶唑-4- 基)苯磺酰胺(I-r);
2-((1-(5-氯-2-甲基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5-二甲基异恶唑-4-基)苯磺酰胺(I-s);
2-((1-(2-硝基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5-二甲基异恶唑-4- 基)苯磺酰胺(I-t);
2-((1-(4-硝基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5-二甲基异恶唑-4- 基)苯磺酰胺(I-u);
2-((1-(4-三氟甲氧基)苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5-二甲基异恶唑-4-基)苯磺酰胺(I-v);
2-(1-苯基-1H-1,2,3-***-4-基甲氧基)-N-环戊基-5-(2-氧代-2,3-氨基噻唑啉-4-基)苯
磺酰胺(II-a);
2-((1-(2-氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(2-氧代-2,3-二氢噻唑 -4-基)苯磺酰胺(II-b);
2-((1-(3-氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(2-氧代-2,3-二氢噻唑 -4-基)苯磺酰胺(II-c);
2-((1-(4-氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(2-氧代-2,3-二氢噻唑 -4-基)苯磺酰胺(II-d);
2-((1-(4-氟苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(2-氧代-2,3-二氢噻唑-4- 基)苯磺酰胺(II-e);
2-((1-(2-甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(2-氧代-2,3-二氢噻唑-4-基)苯磺酰胺(II-f);
2-((1-(4-甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(2-氧代-2,3-二氢噻唑-4-基)苯磺酰胺(II-g);
2-(1-苯基-1H-1,2,3-***-4-基甲氧基)-N-环戊基-5-(3-甲基-2-氧代-2,3-二氢噻唑-4- 基)苯磺酰胺(III-a);
2-((1-(2-氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3-甲基-2-氧代-2,3-二氢噻唑-4-基)苯磺酰胺(III-b);
2-((1-(3-氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3-甲基-2-氧代-2,3-二氢噻唑-4-基)苯磺酰胺(III-c);
2-((1-(4-氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3-甲基-2-氧代-2,3-二氢噻唑-4-基)苯磺酰胺(III-d);
2-((1-(4-氟苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3-甲基-2-氧代-2,3-二氢噻唑-4-基)苯磺酰胺(III-e);
2-((1-(3,4-二氟苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3-甲基-2-氧代-2, 3-二氢噻唑-4-基)苯磺酰胺(III-f);
2-((1-(2-甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3-甲基-2-氧代-2, 3-二氢噻唑-4-基)苯磺酰胺(III-g);
2-((1-(4-甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3-甲基-2-氧代-2, 3-二氢噻唑-4-基)苯磺酰胺(III-h);
2-((1-(3-甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3-甲基-2-氧代-2,3-二氢噻唑-4-基)苯磺酰胺(III-i);
2-((1-苯基-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基-6-氧代-1,6-二氢吡啶-3- 基)苯磺酰胺(IV-a);
2-((1-(2-氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基-6-氧代-1,6-二氢吡啶-3-基)苯磺酰胺(IV-b);
2-((1-(4-氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基-6-氧代-1,6-二氢吡啶-3-基)苯磺酰胺(IV-c);
2-((1-(4-氟苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基-6-氧代-1,6-二氢吡啶-3-基)苯磺酰胺(IV-d);
2-((1-(3-氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基-6-氧代-1,6-二氢吡啶-3-基)苯磺酰胺(IV-e);
2-((1-(3-甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基-6-氧代-1, 6-二氢吡啶-3-基)苯磺酰胺(IV-f);
2-((1-(4-甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基-6-氧代-1, 6-二氢吡啶-3-基)苯磺酰胺(IV-g);
2-((1-(3,4-二甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基-6-氧代-1,6-二氢吡啶-3-基)苯磺酰胺(IV-h);
2-((1-(4-硝基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基-6-氧代-1,6- 二氢吡啶-3-基)苯磺酰胺(IV-i);
2-((1-(4-溴苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基-6-氧代-1,6-二氢吡啶-3-基)苯磺酰胺(IV-j);
2-((1-(2,4-二氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基-6-氧代-1, 6-二氢吡啶-3-基)苯磺酰胺(IV-k);
2-((1-(2-硝基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基-6-氧代-1,6- 二氢吡啶-3-基)苯磺酰胺(IV-l);
2-((1-(4-羟基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基-6-氧代-1,6- 二氢吡啶-3-基)苯磺酰胺(IV-m);
2-((1-(4-(叔丁基)苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基-6-氧代 -1,6-二氢吡啶-3-基)苯磺酰胺(IV-n);
2-((1-(4-三氟甲氧基)苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基-6- 氧代-1,6-二氢吡啶-3-基)苯磺酰胺(IV-o);
除非另有说明,否则下列用在说明书和权利要求书中的术语具有下述含义。
“烷基”指饱和的脂族烃基团,包括1至20个碳原子的直链和支链基团。优选含有 1至10个碳原子的烷基,较优选含有1至6个碳原子的烷基,更优选含有1至3个碳原子的烷基,最优选为甲基。非限制性实施例包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、己基等,及其各种支链异构体等。烷基可以是取代的或未取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,优选为一个或多个以下基团,独立地选自卤素、羟基、氰基、硝基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的基团所取代。
“环烷基”指饱和或部分不饱和单环或多环环状烃取代基,其包括3至20个碳原子,优选包括3至12个碳原子,更优选环烷基环包含3至10个碳原子。单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。
“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,优选为6至10元,例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为芳基环。
芳基可以是取代的或未取代的,当被取代时,取代基优选为一个或多个以下基团,独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基的基团所取代。
“杂芳基”指包含1至4个杂原子,5至14个环原子的杂芳族体系,其中杂原子包括氧、硫和氮。优选为5至10元。杂芳基优选为是5元或6元,例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环。
杂芳基可以是任选取代的或未取代的,当被取代时,取代基优选为一个或多个以下基团,独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基的基团所取代。
“烷氧基”指-O-(烷基)和-O-(未取代的环烷基),其中烷基的定义如上所述。非限制性实施例包含甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。烷氧基可以是任选取代的或未取代的,当被取代时,取代基优选为一个或多个以下基团,独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基的基团所取代。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生地场合。例如,“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在,该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1~3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
所述化合物的制备方法,如下反应式所示:
其中,环A、R1,R2,R3和R4同上所述。
通用合成方法
一般而言,可通过方法例如以下通用方案所示那些和随后的制备实施例制备本发明化合物。除另有说明外,以下方案中所有变量的定义同本文。
更优选地,本发明所述通式(I)化合物可通过以下步骤合成:
一种药物组合物其包含所述的化合物或其药学上可接受的酯或盐,以及药学上可接受的辅料。
所述的化合物或其药学上可接受的酯或盐,在制备BRD4蛋白抑制剂药物中的应用。
所述的化合物或其药学上可接受的酯或盐,在制备抗肿瘤药物中的应用。
本发明中涉及的新型BRD4蛋白抑制剂可用于多种癌症疾病的治疗,其中包括急性髓细胞性白血病(AML)、Burkitt淋巴瘤、多发性骨髓瘤、***癌、黑色素瘤、弥散性大B细胞淋巴瘤等,自身免疫性疾病如牛皮藓、克罗恩病的治疗,以及这些疾病的预防。
“药物组合物”表示含有一种或多种本发明所述化合物或其可药用的盐,或其前药与其他化学组分的混合物,其他化学组分例如可药用的载体和赋形剂。药物组合物的目的是促进生物体对活性成分的吸收,利于活性成分在生物体内发挥生物活性。
技术效果:和现有技术相比,本发明提供的BRD4小分子抑制剂结构新颖,其在抗肿瘤增值中表现出优良的生物活性,并可用于包括实体瘤如乳腺癌、***癌,造血***肿瘤如急性髓性白血病、多发性骨髓瘤等癌症疾病,具有广阔的开发前景。
具体实施方式
实施例1:
(1)5-(3,5-二甲基异恶唑-4-基)-2-甲氧基苯磺酰氯的制备
将化合物4-(4-甲氧基苯基)-3,5-二甲基异恶唑(4.0g,0.02mol)溶于二氯甲烷,冰浴搅拌10分钟,将氯磺酸(1.55mL,0.024mol)的二氯甲烷溶液缓慢滴加到反应溶液中,低温搅拌30min后分批加入五氯化磷(4.16g,0.02mol)。随后将反应体系转移到室温下,搅拌6小时。将反应液倒入冰水混合物中,抽滤(硅藻土助滤)除去不溶物,滤液用二氯甲烷萃取,合并有机层,饱和食盐水洗涤,经干燥、抽滤、减压蒸馏除去有机溶剂,得黄色油状物。
(2)N-环戊基-5-(3,5-二甲基异恶唑-4-基)-2-甲氧基苯磺酰胺的制备
氮气保护下,向化合物5-(3,5-二甲基异恶唑-4-基)-2-甲氧基苯磺酰氯(6g,0.02mol) 的乙酸乙酯(50mL)溶液中逐滴加入环戊胺(6ml,0.06mol),室温搅拌6小时。抽滤除去不溶物,乙酸乙酯洗涤滤饼,滤液分别用0.5M的盐酸水溶液和饱和食盐水洗涤 1-2次,无水硫酸钠干燥,抽滤,浓缩,硅胶柱层析分离,使用乙酸乙酯–己烷混合物 (v:v=5:95)作为洗脱剂,得黄色固体5.06g(收率70%)。
(3)N-环戊基-5-(3,5-二甲基异唑-4-基)-2-羟基苯磺酰胺的制备
将化合物N-环戊基-5-(3,5-二甲基异恶唑-4-基)-2-甲氧基苯磺酰胺(3.5g,0.01mol) 溶于50ml二氯甲烷,0℃搅拌10分钟,缓慢滴加1M的三溴化硼(5ml)的二氯甲烷溶液,滴加完毕后,将反应转移至室温下搅拌2小时。将反应液冷却后倒入冰水混合物中,搅拌30min,静置分层,取二氯甲烷层,无水硫酸钠干燥,抽滤,浓缩,硅胶柱层析分离,得到浅黄色固体2.3g(收率70%)。
(4)N-环戊基-5-(3,5-二甲基异唑-4-基)-2-(丙-2-炔-1-基氧基)苯磺酰胺的制备
将化合物N-环戊基-5-(3,5-二甲基异唑-4-基)-2-羟基苯磺酰胺(2g,5.9mmol)溶于40ml乙腈中,加入无水碳酸钾(0.98g,8.8mmol),随后在氮气保护下加入3-溴丙炔(0.68ml,7.1mmol),回流反应6小时。抽滤,除去碳酸钾固体,乙酸乙酯洗涤滤饼,减压下旋蒸除去溶剂,乙酸乙酯萃取,饱和食盐水洗涤2-3次,无水硫酸钠干燥,减压蒸馏,硅胶柱层析分离,使用乙酸乙酯-己烷混合物(v:v=1:5)作为洗脱剂,得到棕黄色固体1.2g(收率55%)。
(5)N-环戊基-5-(3,5-二甲基异恶唑-4-基)-2-((1-苯基-1H-1,2,3-***-4-基)甲氧基)苯磺酰胺的制备
将化合物N-环戊基-5-(3,5-二甲基异唑-4-基)-2-(丙-2-炔-1-基氧基)苯磺酰胺(200mg, 0.53mmol)溶于甲醇:水(3:1)的溶剂20ml中,加入苯基叠氮(63mg,0.55mmol),室温下搅拌溶解。然后,于体系中加入五水硫酸铜水溶液(30mg/ml,1ml),室温下搅拌10分钟,再逐滴加入L-抗坏血酸钠水溶液(60mg/ml,1ml),室温继续搅拌12个小时。浓缩反应液,于体系中加入适量水稀释,乙酸乙酯萃取,合并有机层,饱和食盐水洗涤,无水硫酸钠干燥,抽滤,减压蒸馏,硅胶柱层析分离,用甲醇-二氯甲烷混合物(v:v=20:1)洗脱,得到白色固体200mg(收率76%)。
1H NMR(300MHz,CDCl3)δ8.23(s,1H),7.86(s,1H),7.74(d,J=5.3Hz,2H),7.65–7.34(m,4H),7.30(d,J=9.1Hz,1H),5.66(d,J=5.9Hz,1H),5.46(s,2H),3.63(m,1H),2.41(s,3H),2.27(s,3H),1.54(m,8H);13C NMR(75MHz,CDCl3)δ165.03,157.89,153.74,142.75,136.14,134.07,129.86,129.65,129.33,128.60,123.44,120.88,120.00,114.45,113.83,62.56,55.28,32.36,22.58,11.16,10.32;LC-MS([M+Na]+):516.17.
实施例2:2-((1-(2-氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5-二甲基异恶唑-4-基)苯磺酰胺(化合物I-b)的制备
合成方法参考实施例1
1H NMR(300MHz,CDCl3)δ8.20(s,1H),7.86(d,J=2.2Hz,1H),7.69–7.56(m,2H),7.52–7.42(m,3H),7.30(d,J=8.5Hz,1H),5.57(d,J=7.4Hz,1H),5.49(s,2H),3.71– 3.55(m,1H),2.42(s,3H),2.28(s,3H),1.77–1.59(m,4H),1.46(m,4H);13C NMR(75 MHz,CDCl3)δ165.08,153.68,141.91,134.04,130.65,130.37,129.93,127.61,127.27, 124.67,123.63,113.84,62.73,55.28,32.45,22.57,11.17,10.33.LC-MS([M+Na]+):550.13.
实施例3:2-((1-(3-氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5-二甲基异恶唑-4-基)苯磺酰胺(化合物I-c)的制备
合成方法参考实施例1
1H NMR(300MHz,CDCl3)δ8.23(s,1H),7.86(d,J=2.2Hz,1H),7.81(t,J=1.7Hz,1H),7.63(dt,J=7.5,1.8Hz,1H),7.53–7.40(m,3H),7.27(s,1H),5.55(d,J=7.4Hz,1H),5.46(s,2H),3.63(m,1H),2.42(s,3H),2.27(s,3H),1.75–1.59(m,4H),1.46(s,4H);13C NMR(75MHz,CDCl3)δ165.07,153.66,136.95,135.18,134.07,130.44,129.91,129.72,128.66,123.61,120.86,120.24,117.92,114.44,113.81,62.53,55.29,32.41,29.19,22.58, 11.17,10.33.LC-MS([M+Na]+):550.3.
实施例4:2-((1-(4-氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5-二甲基异恶唑-4-基)苯磺酰胺(化合物I-d)的制备
合成方法参考实施例1
1H NMR(300MHz,CDCl3)δ8.22(s,1H),7.86(d,J=2.1Hz,1H),7.70(d,J=8.8Hz,2H),7.51(d,J=8.8Hz,2H),7.44(dd,J=8.5,2.1Hz,1H),7.27(s,1H),5.60(d,J=7.4Hz,1H),5.45(s,2H),3.69–3.55(m,1H),2.42(s,3H),2.28(s,3H),1.77–1.63(m,4H),1.51–1.38(m,4H);13C NMR(75MHz,CDCl3)δ165.06,157.87,153.66,143.00,134.60,134.41,134.09,129.92,129.69,129.52,123.62,121.16,120.80,114.41,113.81,62.57,55.29,32.41, 22.58,11.17,10.33.LC-MS([M+Na]+):550.3.熔点:196-197℃.
实施例5:2-((1-(4-氟苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5-二甲基异恶唑-4-基)苯磺酰胺(化合物I-e)的制备
合成方法参考实施例1
1H NMR(300MHz,CDCl3)δ8.19(s,1H),7.86(d,J=2.2Hz,1H),7.76–7.68(m,2H),7.44(dd,J=8.5,2.2Hz,1H),7.30(s,1H),7.26–7.20(m,2H),5.58(d,J=7.4Hz,1H), 5.45(s,2H),3.70–3.56(m,1H),2.42(s,3H),2.27(s,3H),1.78–1.63(m,4H),1.53–1.41 (m,4H);13C NMR(75MHz,CDCl3)δ165.07,160.44,157.89,153.65,142.91,134.09, 129.94,129.70,123.63,122.15,122.04,121.04,116.52,116.21,113.80,62.62,55.29,32.43,22.58,11.17,10.33.LC-MS([M+Na]+):534.4.熔点:144-145℃.
实施例6:2-((1-(3,4-二氟苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3, 5-二甲基异恶唑-4-基)苯磺酰胺(化合物I-f)的制备
合成方法参考实施例1
1H NMR(300MHz,CDCl3)δ8.22(s,1H),7.86(s,1H),7.73–7.62(m,1H),7.52– 7.31(m,3H),7.27(s,1H),5.56(d,J=7.2Hz,1H),5.45(s,2H),3.69–3.54(m,1H),2.42(s, 3H),2.28(s,3H),1.83–1.62(m,4H),1.54–1.38(m,4H);13C NMR(75MHz,CDCl3)δ 165.06,157.86,153.66,151.64,148.30,143.13,134.11,129.91,129.67,123.64,120.98,118.10,117.85,115.94,114.40,113.81,110.23,109.94,62.50,55.30,32.38,22.57,11.15, 10.31.LC-MS([M+Na]+):552.4.熔点:179-180℃.
实施例7:2-((1-(2-甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5- 二甲基异恶唑-4-基)苯磺酰胺(化合物I-g)的制备
合成方法参考实施例1
1H NMR(300MHz,CDCl3)δ8.35(s,1H),7.86(d,J=1.7Hz,1H),7.82(d,J=7.5Hz,1H),7.45(d,J=7.0Hz,2H),7.29(d,J=8.6Hz,1H),7.19–7.07(m,2H),5.58(d,J=7.3 Hz,1H),5.46(s,2H),3.92(s,3H),3.65–3.54(m,1H),2.42(s,3H),2.28(s,4H),1.80–1.62 (m,4H),1.50–1.40(m,4H);13C NMR(75MHz,CDCl3)δ153.83,150.48,134.03,129.92, 124.78,120.79,113.69,111.77,62.90,55.49,55.28,32.39,22.56,11.16,10.33.LC-MS([M+ Na]+):546.18.熔点:180-182℃.
实施例8:2-((1-(4-甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5- 二甲基异恶唑-4-基)苯磺酰胺(化合物I-h)的制备
合成方法参考实施例1
1H NMR(300MHz,CDCl3)δ8.11(s,1H),7.85(d,J=2.0Hz,1H),7.64(d,J=8.9Hz,2H),7.44(dd,J=8.5,2.1Hz,1H),7.29(d,J=8.7Hz,1H),7.03(d,J=8.9Hz,2H),5.56(d,J=7.3Hz,1H),5.45(s,2H),3.88(s,3H),3.67–3.54(m,1H),2.41(s,3H),2.27(s,3H),1.74–1.60(m,4H),1.50–1.41(m,4H);13C NMR(75MHz,CDCl3)δ153.70,142.52, 134.06,129.94,123.55,121.78,120.96,114.37,113.77,62.71,55.29,55.18,32.44,29.21,22.58,11.17,10.33.LC-MS([M+Na]+):546.4.熔点:181-183℃.
实施例9:2-((1-(3-甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)N-环戊基-5-(3,5- 二甲基异恶唑-4-基)苯磺酰胺(化合物I-i)的制备
合成方法参考实施例1
1H NMR(300MHz,CDCl3)δ8.22(s,1H),7.85(d,J=2.0Hz,1H),7.47–7.37(m,2H),7.30(d,J=8.5Hz,2H),7.24(d,J=7.9Hz,1H),6.98(dd,J=8.2,1.7Hz,1H),5.92(d,J=7.4Hz,1H),5.43(s,2H),3.88(s,3H),3.69–3.54(m,1H),2.41(s,3H),2.27(s,3H),1.76–1.57(m,4H),1.54–1.40(m,4H);13C NMR(75MHz,CDCl3)δ165.54,160.58,154.23, 143.15,137.62,134.56,130.62,130.36,130.14,123.94,121.47,114.89,114.30,112.36,106.29,63.03,55.78,55.67,32.86,29.69,23.07,11.66,10.82.LC-MS([M+Na]+):546.4.熔点:180-182℃.
实施例10:2-((1-(3,4-二甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基--5- (3,5-二甲基异恶唑-4-基)苯磺酰胺(化合物I-j)的制备
合成方法参考实施例1
1H NMR(300MHz,CDCl3)δ8.16(s,1H),7.86(d,J=2.1Hz,1H),7.43(dd,J=8.4,2.1Hz,1H),7.32(d,J=2.3Hz,1H),7.30–7.26(m,1H),7.16(dd,J=8.6,2.4Hz,1H),6.94(d,J=8.7Hz,1H),5.87(d,J=7.4Hz,1H),5.42(s,2H),3.98(s,3H),3.95(s,3H),3.69–3.54(m,1H),2.42(s,3H),2.28(s,3H),1.81–1.62(m,4H),1.53–1.41(m,4H);13C NMR(75MHz,CDCl3)δ165.54,158.39,154.24,149.74,149.56,143.00,134.55,130.39,130.17,123.99,121.55,114.28,112.49,111.10,104.81,63.11,56.27,56.20,55.80,32.88,29.69, 23.08,11.66,10.83.LC-MS([M+Na]+):576.4.熔点:198-199℃.
实施例11:2-((1-(苯并[d][1,3]二氧-5-基)-1H-1,2,3-三氮唑-4-基)甲氧基)-N- 环戊基-5-(3,5-二甲基异噁唑-4-基)苯磺酰胺(化合物I-k)的制备
合成方法参考实施例1
1H NMR(300MHz,CDCl3)δ8.10(s,1H),7.85(d,J=2.2Hz,1H),7.44(dd,J=8.5,2.2Hz,1H),7.30(s,1H),7.25(d,J=2.1Hz,1H),7.15(dd,J=8.3,2.2Hz,1H),6.92(d,J=8.3Hz,1H),6.09(s,2H),5.58(d,J=7.4Hz,1H),5.44(s,2H),3.71–3.53(m,1H),2.42(s,3H),2.28(s,3H),1.83–1.65(m,4H),1.52–1.41(m,4H);13C NMR(75MHz,CDCl3)δ 165.05,157.91,153.68,147.81,142.54,134.04,130.62,129.93,123.58,121.10,113.85,113.79,108.08,102.23,101.72,62.66,55.28,32.43,22.58,11.16,10.32.LC-MS([M+Na]+): 560.4.熔点:230-231℃.
实施例12:2-((1-(3,4,5-三甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基 -5-(3,5-二甲基异恶唑-4-基)苯磺酰胺(化合物I-l)的制备
合成方法参考实施例1
1H NMR(300MHz,CDCl3)δ8.25(s,1H),7.87(d,J=2.2Hz,1H),7.43(dd,J=8.4,2.2Hz,1H),7.25(d,J=8.5Hz,1H),6.92(s,2H),6.28(d,J=7.5Hz,1H),5.36(s,2H),3.94(s,6H),3.89(s,3H),3.70–3.55(m,1H),2.43(s,3H),2.29(s,3H),1.81–1.60(m,4H),1.56–1.40(m,4H);13C NMR(75MHz,CDCl3)δ165.09,157.89,153.70,153.44,142.57,134.07,131.97,129.96,123.67,121.22,113.77,97.96,62.65,60.58,55.98,55.32,32.43,22.58,11.18, 10.34.LC-MS([M+Na]+):606.20.熔点:236-237℃.
实施例13:2-((1-(间甲苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5-二甲基异恶唑-4-基)苯磺酰胺(化合物I-m)的制备
合成方法参考实施例1
1H NMR(300MHz,CDCl3)δ8.24(s,1H),7.86(d,J=1.3Hz,1H),7.54(s,1H),7.51–7.35(m,3H),7.32(d,J=8.6Hz,1H),7.26(d,J=7.3Hz,1H),6.10(d,J=7.4Hz,1H),5.45(s,2H),3.71–3.55(m,1H),2.44(s,3H),2.41(s,3H),2.27(s,3H),1.68(m,4H),1.55–1.36(m,4H);13C NMR(75MHz,CDCl3)δ165.02,165.02,157.90,157.90,153.81,153.81, 142.62,139.58,136.06,134.08,129.80,129.62,129.31,129.08,123.33,120.89,120.59,117.02,114.48,113.86,62.53,55.29,32.31,22.58,20.90,11.14,10.31.LC-MS([M+Na]+): 530.4.熔点:156-157℃.
实施例14:2-((1-(2-乙基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5- 二甲基异恶唑-4-基)苯磺酰胺(化合物I-n)的制备
合成方法参考实施例1
1H NMR(300MHz,CDCl3)δ8.00(s,1H),7.85(d,J=1.3Hz,1H),7.57–7.21(m,6H),5.95(d,J=7.3Hz,1H),5.52(s,2H),3.75–3.45(m,1H),2.49(dd,J=15.0,7.5Hz,2H),2.41(s,3H),2.27(s,3H),1.81–1.55(m,4H),1.55–1.36(m,4H),1.09(t,J=7.5Hz,3H);13CNMR(75MHz,CDCl3)δ154.25,139.79,135.68,134.42,130.70,130.41,129.94,126.85,124.88,124.22,114.98,114.60,63.46,55.76,33.03,24.26,23.10,14.78,11.53,10.67.LC-MS([M+Na]+):544.4.熔点:63-65℃.
实施例15:2-((1-(3-异丙基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3, 5-二甲基异恶唑-4-基)苯磺酰胺(化合物I-o)的制备
合成方法参考实施例1
1H NMR(300MHz,CDCl3)δ8.25(s,1H),7.86(d,J=2.2Hz,1H),7.61(s,1H),7.52–7.39(m,3H),7.36–7.30(m,2H),5.97(d,J=7.4Hz,1H),5.46(s,2H),3.70–3.55(m,1H),3.01(d,J=6.8Hz,1H),2.41(s,3H),2.27(s,3H),1.79–1.58(m,4H),1.54–1.41(m,4H),1.32(s,3H),1.29(s,3H);13C NMR(75MHz,CDCl3)δ165.49,158.36,154.27,151.24,143.17,134.46,130.49,129.70,127.32,124.20,121.45,118.97,118.09,114.43,63.32,55.77, 34.14,33.02,23.74,23.11,11.53,10.67.LC-MS([M+Na]+):558.4.熔点:140-142℃.
实施例16:2-((1-(3-(叔丁基)苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5- (3,5-二甲基异恶唑-4-基)苯磺酰胺(化合物I-p)的制备
合成方法参考实施例1
1H NMR(300MHz,CDCl3)δ8.24(s,1H),7.86(d,J=1.1Hz,1H),7.77(s,1H),7.53–7.40(m,4H),7.33(d,J=8.5Hz,1H),5.86(d,J=7.2Hz,1H),5.46(s,2H),3.70–3.53(m,1H),2.41(s,3H),2.27(s,3H),1.79–1.58(m,4H),1.53–1.42(m,4H),1.38(s,9H);13C NMR(75MHz,CDCl3)δ165.05,157.92,153.75,153.07,142.58,136.07,134.07,129.91,129.64,128.95,125.81,123.44,121.21,117.59,117.34,114.48,113.80,62.56,55.28,34.56, 32.38,30.71,22.57,11.16,10.32.LC-MS([M+Na]+):572.4.熔点:91-93℃.
实施例17:2-((1-(4-(叔丁基)苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5- (3,5-二甲基异恶唑-4-基)苯磺酰胺(化合物I-q)的制备
合成方法参考实施例1
1H NMR(300MHz,CDCl3)δ8.20(s,1H),7.85(d,J=2.1Hz,1H),7.64(d,J=8.7Hz,2H),7.54(d,J=8.7Hz,2H),7.44(dd,J=8.5,2.1Hz,1H),7.31(d,J=8.5Hz,1H),5.81(d,J=7.4Hz,1H),5.46(s,2H),3.68–3.56(m,1H),2.41(s,3H),2.28(s,3H),1.78–1.57(m,4H),1.51–1.41(m,4H),1.37(s,9H);13C NMR(75MHz,CDCl3)δ165.35,164.00,154.26,152.62,134.45,130.48,126.70,124.20,121.26,120.34,114.45,63.38,55.77,33.02,31.21, 23.11,11.53,10.67.LC-MS([M+Na]+):572.4.熔点:186-188℃.
实施例18:2-((1-(4-丁基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5- 二甲基异恶唑-4-基)苯磺酰胺(化合物I-r)的制备
合成方法参考实施例1
1H NMR(300MHz,CDCl3)δ8.21(s,1H),7.85(d,J=2.0Hz,1H),7.61(d,J=8.3Hz,2H),7.43(dd,J=8.4,2.0Hz,1H),7.32(d,J=8.4Hz,3H),5.96(d,J=7.4Hz,1H),5.45(s,2H),3.69–3.55(m,1H),2.67(t,J=7.7Hz,2H),2.41(s,3H),2.27(s,3H),1.78–1.57(m,6H),1.52–1.34(m,6H),0.95(t,J=7.3Hz,3H);13C NMR(75MHz,CDCl3)δ165.03, 157.91,153.78,143.76,134.07,133.99,129.84,129.63,129.18,123.37,120.91,119.96,113.85,62.57,55.28,34.66,32.92,32.34,29.18,22.57,21.74,13.41,11.14,10.31. LC-MS([M+Na]+):572.4.熔点:200-202℃.
实施例19:2-((1-(5-氯-2-甲基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3, 5-二甲基异恶唑-4-基)苯磺酰胺(化合物I-s)的制备
合成方法参考实施例1
1H NMR(300MHz,CDCl3)δ8.06(s,1H),7.85(d,J=2.1Hz,1H),7.47(dd,J=8.5,2.2Hz,1H),7.44–7.31(m,4H),5.94(d,J=7.2Hz,1H),5.51(s,2H),3.67–3.55(m,1H),2.42(s,3H),2.28(s,3H),2.19(s,3H),1.78–1.58(m,4H),1.53–1.40(m,4H);13C NMR(75MHz,CDCl3)δ165.02,157.88,153.73,142.24,136.22,134.10,132.19,131.75,131.36,129.83,129.62,125.44,124.12,123.44,114.45,113.95,62.55,59.89,55.24,32.34,29.16, 22.54,20.56,17.06,13.69,11.14,10.30.LC-MS([M+Na]+):564.13.熔点:142-144℃.
实施例20:2-((1-(2-硝基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5- 二甲基异恶唑-4-基)苯磺酰胺(化合物I-t)的制备
合成方法参考实施例1
1H NMR(300MHz,CDCl3)δ8.16(s,1H),8.12(d,J=8.0Hz,1H),7.90–7.82(m,2H),7.80–7.72(m,1H),7.67(d,J=7.7Hz,1H),7.47(dd,J=8.4,2.0Hz,1H),7.30(d,1H), 5.63(d,J=7.4Hz,1H),5.50(s,2H),3.68–3.51(m,1H),2.42(s,3H),2.28(s,3H),1.79– 1.57(m,4H),1.53–1.36(m,4H);13C NMR(75MHz,CDCl3)δ165.09,157.93,153.62, 142.77,134.17,133.63,130.74,129.93,129.68,129.45,127.63,125.22,124.62,123.61,114.47,113.99,62.62,55.25,32.40,22.55,11.14,10.30.LC-MS([M+Na]+):561.4.熔点:177-178℃.
实施例21:2-((1-(4-硝基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3,5- 二甲基异恶唑-4-基)苯磺酰胺(化合物I-u)的制备
合成方法参考实施例1
1H NMR(300MHz,CDCl3)δ8.50(s,1H),8.41(d,J=9.0Hz,2H),8.00(d,J=9.1Hz,2H),7.87(d,J=2.1Hz,1H),7.47(dd,J=8.5,2.2Hz,1H),7.31(d,J=8.4Hz,1H),6.02(d,J=7.5Hz,1H),5.46(s,2H),3.73–3.58(m,1H),2.43(s,3H),2.28(s,3H),1.81–1.57(m,4H),1.54–1.39(m,4H);13C NMR(75MHz,CDCl3)δ165.10,157.84,153.50,146.94, 143.77,134.16,130.02,125.11,123.92,120.92,120.12,113.85,62.59,55.30,32.50,22.58,11.18,10.34.LC-MS([M+Na]+):561.4.熔点:201-202℃.
实施例22:2-((1-(4-三氟甲氧基)苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5- (3,5-二甲基异恶唑-4-基)苯磺酰胺(化合物I-v)的制备
合成方法参考实施例1
1H NMR(300MHz,CDCl3)δ8.31(s,1H),7.86(d,J=2.0Hz,1H),7.78(d,J=8.9Hz,2H),7.49–7.29(m,4H),6.14(d,J=7.5Hz,1H),5.44(s,2H),3.70–3.54(m,1H),2.42(s,3H),2.28(s,3H),1.79–1.58(m,4H),1.54–1.40(m,4H);13C NMR(75MHz,CDCl3)δ 165.02,157.85,153.74,148.59,143.05,134.42,134.11,129.84,129.60,123.48,121.75,121.50,121.33,120.92,118.08,114.41,113.84,62.45,55.29,32.31,22.55,11.11,10.28. LC-MS([M+Na]+):600.4.熔点:203-205℃.
实施例23:2-(1-苯基-1H-1,2,3-***-4-基甲氧基)-N-环戊基-5-(2-氧代-2,3-氨基噻唑啉-4-基)苯磺酰胺(化合物II-a)的制备
合成方法参考实施例1
1H NMR(300MHz,DMSO-d6)δ9.01(s,1H),7.94(d,J=7.4Hz,2H),7.75(d,J=5.6Hz,1H),7.65–7.56(m,2H),7.54(d,J=6.4Hz,1H),7.46(d,J=7.7Hz,2H),7.24(d,J=7.9Hz,2H),5.34(s,2H),3.42–3.33(m,1H),1.75–1.47(m,4H),1.47–1.26(m,4H).13C NMR(75MHz,DMSO-d6)δ168.44,158.82,141.70,141.16,134.25,131.64,131.53,130.45,128.34,125.15,117.64,114.95,113.96,54.23,29.74,22.76.LC-MS([M+H]+):498.13.
实施例24:2-((1-(2-氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(2-氧代-2, 3-二氢噻唑-4-基)苯磺酰胺(化合物II-b)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ8.77(s,1H),7.82(d,J=7.6Hz,1H),7.74(d,J=7.0Hz,2H),7.68–7.54(m,2H),7.46(d,J=8.5Hz,2H),7.24(d,J=8.5Hz,2H),5.35(s,2H),3.34–3.26(m,1H),1.76–1.46(m,4H),1.47–1.28(m,4H).13C NMR(75MHz,DMSO-d6) δ168.40,158.80,141.70,141.18,134.25,131.66,131.51,130.45,128.34,125.13,117.61,114.94,113.96,54.23,32.39,29.77,22.79.LC-MS([M+H]+):532.5.
实施例25:2-((1-(3-氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(2-氧代-2, 3-二氢噻唑-4-基)苯磺酰胺(化合物II-c)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ9.08(s,1H),8.05(s,1H),7.96(d,J=7.8Hz,1H), 7.74(d,J=6.8Hz,1H),7.68–7.54(m,2H),7.43(d,J=8.6Hz,2H),7.24(d,J=8.6Hz, 2H),5.32(s,2H),3.33–3.25(m,1H),1.72–1.46(m,4H),1.45–1.28(m,4H).13C NMR (75MHz,DMSO)δ168.38,158.83,142.37,142.37,141.24,131.55,129.83,121.73,121.23, 117.73,114.95,114.80,55.54,54.26,32.42,22.81.LC-MS([M+H]+):532.5.熔点: 185-187℃.
实施例26:2-((1-(4-氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(2-氧代-2, 3-二氢噻唑-4-基)苯磺酰胺(化合物II-d)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ9.06(s,1H),7.94(d,J=8.7Hz,2H),7.78–7.64(m,3H),7.43(d,J=7.9Hz,2H),7.23(d,J=7.9Hz,2H),5.32(s,2H),3.35–3.25(m,1H),1.72 –1.46(m,4H),1.42–1.28(m,4H).13C NMR(75MHz,DMSO-d6)δ168.40,158.79,141.69,141.17,134.25,131.65,131.51,130.45,128.36,125.14,117.61,114.95,113.95,54.23,32.39, 22.79.LC-MS([M+H]+):532.5.熔点:177-179℃.
实施例27:2-((1-(4-氟苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(2-氧代-2,3- 二氢噻唑-4-基)苯磺酰胺(化合物II-e)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ9.06(s,1H),7.97(d,J=8.8Hz,2H),7.78–7.69(m,3H),7.46(d,J=8.6Hz,2H),7.24(d,J=8.6Hz,2H),5.35(s,2H),3.36–3.28(m,1H),1.74 –1.48(m,4H),1.45–1.26(m,4H).13C NMR(75MHz,DMSO)δ171.99,168.40,158.81, 142.83,141.20,135.15,132.98,131.52,129.78,121.73,121.37,117.67,114.96,113.96, 54.24,32.40,22.79,21.00.LC-MS([M+H]+):516.5.熔点:165-167℃.
实施例28:2-((1-(2-甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(2-氧代-2,3-二氢噻唑-4-基)苯磺酰胺(化合物II-f)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ8.67(s,1H),7.75(d,J=6.7Hz,1H),7.63(d,J=7.6Hz,1H),7.62–7.53(m,1H),7.45(d,J=8.3Hz,2H),7.34(d,J=8.4Hz,1H),7.24(d,J=8.4Hz,2H),7.16(d,J=7.5Hz,1H),5.28(s,2H),3.35–3.26(m,1H),2.94(s,3H),1.75–1.49(m,4H),1.44–1.27(m,4H).13C NMR(75MHz,DMSO)δ168.36,158.81,151.46, 141.28,131.57,130.72,125.61,125.39,124.92,120.80,117.65,114.92,113.87,112.92, 56.05,54.23,32.39,22.79.LC-MS([M+H]+):528.5.熔点:176-178℃.
实施例29:2-((1-(4-甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(2-氧代-2,3-二氢噻唑-4-基)苯磺酰胺(化合物II-g)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ8.94(s,1H),7.87(d,J=9.0Hz,2H),7.74(d,J=6.9Hz,1H),7.46(d,J=8.6Hz,2H),7.18(dd,J=15.0,8.8Hz,4H),5.28(s,2H),3.86(s,3H),3.36–3.27(m,1H),1.74–1.56(m,4H),1.44–1.27(m,4H).13C NMR(75MHz,DMSO-d6) δ168.37,159.22,158.82,142.38,141.26,131.56,129.79,121.68,121.22,117.70,114.94,114.76,113.86,55.50,54.23,32.40,22.79.LC-MS([M+H]+):528.5.熔点:188-190℃.
实例30:2-(1-苯基-1H-1,2,3-***-4-基甲氧基)-N-环戊基-5-(3-甲基-2-氧代-2,3-二氢噻唑-4-基)苯磺酰胺(III-a)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ9.01(s,1H),7.93(d,J=7.4Hz,2H),7.73(d,J=5.6Hz,1H),7.68–7.58(m,2H),7.53(d,J=6.4Hz,1H),7.44(d,J=7.7Hz,2H),7.21(d,J=7.9Hz,2H),5.32(s,2H),3.40–3.31(m,1H),2.95(s,3H),1.74–1.46(m,4H),1.45–1.28 (m,4H).13C NMR(75MHz,DMSO-d6)δ168.42,159.11,143.51,141.26,136.50,131.51, 129.89,128.78,123.04,120.28,120.14,114.42,61.05,54.18,32.39,31.44,22.77.LC-MS ([M+H]+):512.5.熔点:176-178℃.
实施31:2-((1-(2-氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3-甲基-2-氧代-2,3-二氢噻唑-4-基)苯磺酰胺(化合物III-b)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ8.77(s,1H),7.80(d,J=7.6Hz,1H),7.73(d,J=7.0Hz,2H),7.69–7.56(m,2H),7.43(d,J=8.5Hz,2H),7.22(d,J=8.5Hz,2H),5.32(s,2H),3.34–3.26(m,1H),2.94(s,3H),1.75–1.48(m,4H),1.46–1.26(m,4H).13C NMR(75 MHz,DMSO-d6)δ168.43,159.13,142.44,141.30,134.37,131.74,131.50,130.53,128.48,128.43,127.04,120.28,114.43,113.07,113.07,60.88,54.18,32.40,31.43,22.80.LC-MS([M+H]+):546.5熔点:176-178℃.
实施例32:2-((1-(3-氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3-甲基-2- 氧代-2,3-二氢噻唑-4-基)苯磺酰胺(化合物III-c)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ9.08(s,1H),8.08(s,1H),7.95(d,J=7.8Hz,1H), 7.72(d,J=6.8Hz,1H),7.69–7.56(m,2H),7.43(d,J=8.6Hz,2H),7.20(d,J=8.6Hz, 2H),5.32(s,2H),3.33–3.25(m,1H),2.94(s,3H),1.71–1.47(m,4H),1.41–1.28(m,4H). 13C NMR(75MHz,DMSO-d6)δ168.44,159.08,143.71,141.25,137.54,134.18,131.64, 131.53,128.60,123.22,120.33,119.95,118.75,114.45,61.03,54.18,32.39,31.44,22.77. LC-MS([M+H]+):546.5.熔点:154-156℃.
实施例33:2-((1-(4-氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3-甲基-2- 氧代-2,3-二氢噻唑-4-基)苯磺酰胺(化合物III-d)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ9.04(s,1H),7.98(d,J=8.7Hz,2H),7.79–7.62(m,3H),7.43(d,J=7.9Hz,2H),7.20(d,J=7.9Hz,2H),5.31(s,2H),3.34–3.24(m,1H),2.94(s,3H),1.71–1.47(m,4H),1.40–1.26(m,4H).13C NMR(75MHz,DMSO-d6)δ172.72, 168.44,159.10,143.70,131.53,129.88,123.14,121.85,120.33,114.43,61.01,54.18,32.40,31.43,22.77.LC-MS(ESI):([M+H]+):546.4.熔点:178-180℃.
实施例34:2-((1-(4-氟苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3-甲基-2- 氧代-2,3-二氢噻唑-4-基)苯磺酰胺(化合物III-e)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ9.05(s,1H),7.99(d,J=8.8Hz,2H),7.77–7.68(m,3H),7.45(d,J=8.6Hz,2H),7.22(d,J=8.6Hz,2H),5.33(s,2H),3.35–3.27(m,1H),2.96(s,3H),1.73–1.49(m,4H),1.44–1.28(m,4H).13C NMR(75MHz,DMSO-d6)δ168.44, 159.10,143.70,141.26,135.31,133.05,131.53,129.87,123.14,121.84,120.33,114.43, 61.01,54.18,32.39,31.44,22.77.LC-MS(ESI):([M+H]+):530.5.熔点:158-160℃.
实施例35:2-((1-(3,4-二氟苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3-甲基-2-氧代-2,3-二氢噻唑-4-基)苯磺酰胺(化合物III-f)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ9.02(s,1H),8.20–8.08(m,1H),7.89–7.80(m,1H),7.80–7.67(m,2H),7.43(d,J=8.5Hz,2H),7.20(d,J=8.5Hz,2H),5.32(s,2H),3.34– 3.24(m,1H),2.94(s,3H),1.73–1.48(m,4H),1.43–1.24(m,4H).13C NMR(75MHz, DMSO-d6)δ168.44,159.08,143.75,141.26,131.53,123.39,120.35,118.92,118.68,117.08,114.43,113.12,110.55,110.26,61.01,54.18,32.39,31.44,22.78.LC-MS(ESI):Calcdfor C24H24F2N5O4S2([M+H]+):548.5.熔点:160-162℃.
实施例36:2-((1-(2-甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3-甲基-2-氧代-2,3-二氢噻唑-4-基)苯磺酰胺(化合物III-g)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ8.64(s,1H),7.73(d,J=6.7Hz,1H),7.65(d,J=7.6Hz,1H),7.60–7.51(m,1H),7.43(d,J=8.3Hz,2H),7.34(d,J=8.4Hz,1H),7.21(d,J=8.4Hz,2H),7.15(d,J=7.5Hz,1H),5.29(s,2H),3.86(s,3H),3.33–3.24(m,1H),2.94(s,3H),1.75–1.49(m,4H),1.44–1.27(m,4H).13C NMR(75MHz,DMSO-d6)δ168.45, 159.20,151.62,142.12,141.33,131.50,130.83,126.84,125.82,125.54,120.86,120.22,114.40,112.97,60.92,56.09,54.19,32.40,31.44,22.79.LC-MS(ESI):Calcd forC25H28N5O5S2([M+H]+):542.5.熔点:176-178℃.
实施例37:2-((1-(4-甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3-甲基-2-氧代-2,3-二氢噻唑-4-基)苯磺酰胺(化合物III-h)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ8.89(s,1H),7.82(d,J=9.0Hz,2H),7.73(d,J=6.9Hz,1H),7.43(d,J=8.6Hz,2H),7.18(dd,J=15.0,8.8Hz,4H),5.29(s,2H),3.84(s,3H),3.32–3.24(m,1H),2.94(s,3H),1.71–1.49(m,4H),1.41–1.25(m,4H).13C NMR(75 MHz,DMSO-d6)δ168.44,159.31,159.15,143.27,141.28,131.52,129.92,123.02,121.82,120.26,114.86,114.42,61.08,55.54,54.18,32.40,31.44,22.78.LC-MS(ESI):Calcd forC25H28N5O5S2([M+H]+):542.5.熔点:177-179℃.
实施例38:2-((1-(3-甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(3- 甲基-2-氧代-2,3-二氢噻唑-4-基)苯磺酰胺(化合物III-i)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ9.02(s,1H),7.72(d,J=6.8Hz,1H),7.56–7.48(m,3H),7.43(d,J=8.6Hz,2H),7.21(d,J=8.7Hz,2H),7.12–7.04(m,1H),5.31(s,2H),3.86(s,3H),3.34–3.25(m,1H),2.94(s,3H),1.70–1.48(m,4H),1.42–1.26(m,4H).LC-MS(ESI):([M+H]+):542.5.熔点:174-176℃.
实施例39:2-((1-苯基-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基-6-氧代-1, 6-二氢吡啶-3-基)苯磺酰胺(化合物IV-a)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ8.93(s,1H),8.15(s,1H),7.87(m,3H),7.83(d,J=7.7Hz,2H),7.70–7.49(m,3H),7.16(d,J=7.6Hz,1H),6.49(d,J=9.5Hz,1H),5.53(d,J =5.9Hz,1H),5.50(s,2H),3.53(s,3H),3.39(m,1H),1.39(m,8H).13C NMR(75MHz, DMSO-d6)δ161.04,153.77,143.42,138.63,137.24,136.44,130.85,129.96,129.82,128.89,125.86,122.86,120.17,119.25,116.25,114.99,62.04,54.70,36.92,32.12,22.57.LC-MS(ESI):([M+H]+):506.3.
实施例40:2-((1-(2-氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基-6- 氧代-1,6-二氢吡啶-3-基)苯磺酰胺(化合物IV-b)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ8.72(s,1H),8.16(s,1H),7.91(m,1H),7.81(d,J=8.4Hz,2H),7.64(m,4H),7.15(d,J=7.1Hz,1H),6.49(d,J=9.4Hz,1H),5.53(s,2H), 3.52(s,3H),3.37(m,1H),1.36(m,8H).13C NMR(75MHz,DMSO-d6)δ161.05,153.79, 142.59,138.63,137.25,131.78,130.85,130.61,129.80,128.90,128.54,128.30,126.63,125.84,119.26,116.24,115.01,62.08,54.71,36.92,32.19,22.62.LC-MS(ESI):([M+H]+): 540.3.熔点:163-165℃.
实施例41:2-((1-(4-氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基-6- 氧代-1,6-二氢吡啶-3-基)苯磺酰胺(化合物IV-c)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ8.96(s,1H),8.15(s,1H),8.04–7.66(m,6H),7.59(d, J=6.3Hz,1H),7.14(d,J=6.7Hz,1H),6.49(d,J=9.4Hz,1H),5.50(s,2H),3.54(s,3H),3.40(m,1H),1.40(m,8H).13C NMR(75MHz,DMSO-d6)δ161.05,153.76,143.57,138.63,137.25,135.25,130.86,129.94,128.92,125.87,122.95,121.87,119.25,116.24,114.99,62.02,54.69,36.93,32.12,22.58.LC-MS(ESI):([M+H]+):540.2.熔点:168-170℃.
实施例42:2-((1-(4-氟苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基-6- 氧代-1,6-二氢吡啶-3-基)苯磺酰胺(化合物IV-d)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ8.91(s,1H),8.15(s,1H),8.04–7.72(m,5H),7.66–7.44(m,3H),7.15(d,J=7.7Hz,1H),6.49(d,J=9.2Hz,1H),5.50(s,2H),3.53(s,3H),3.38(d,J=2.5Hz,1H),1.40(m,8H).13C NMR(75MHz,DMSO-d6)δ153.77,143.43, 138.63,137.25,130.85,129.81,128.91,125.86,123.11,122.65,122.53,119.25,116.97,116.66,116.24,115.00,62.05,54.69,36.92,32.12,22.58.LC-MS(ESI):([M+H]+):524.3.熔点:154-156℃.
实施例43:2-((1-(3-氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基-6- 氧代-1,6-二氢吡啶-3-基)苯磺酰胺(化合物IV-e)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ9.02(s,1H),8.10(d,J=29.4Hz,2H),7.86(m,4H),7.64(m,3H),7.15(m,1H),6.49(d,J=8.8Hz,1H),5.50(s,2H),3.52(s,3H),3.40(m,1H),1.63–1.23(m,8H).13C NMR(75MHz,DMSO-d6)δ161.04,153.76,143.55,138.62,137.47,137.24,134.21,131.69,130.85,129.80,128.93,128.71,125.88,123.08,119.99,119.25,118.80,116.24,115.00,62.02,54.69,36.92,32.13,22.58.LC-MS(ESI):([M+H]+):540.2.熔点:162-164℃.
实施例44:2-((1-(3-甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基-6-氧代-1,6-二氢吡啶-3-基)苯磺酰胺(化合物IV-f)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ8.64(s,1H),8.15(s,1H),7.86(m,3H),7.62(m,3H),7.35(s,1H),7.17(s,2H),6.50(m,1H),5.52(s,2H),3.86(s,3H),3.52(s,3H),3.39(m,1H),1.41(m,8H).13C NMR(75MHz,DMSO-d6)δ161.07,153.80,151.42,142.28,138.63, 137.23,130.82,129.83,128.85,126.39,125.80,125.48,120.93,119.25,116.28,114.97,113.06,62.11,56.08,54.74,36.93,32.13,22.58.LC-MS(ESI):([M+H]+):536.3.熔点:174-176℃.
实施例45:2-((1-(4-甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基-6-氧代-1,6-二氢吡啶-3-基)苯磺酰胺(化合物IV-g)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ8.82(s,1H),8.15(s,1H),7.90(s,1H),7.80(d,J=6.8Hz,3H),7.59(d,J=8.6Hz,1H),7.16(d,J=8.6Hz,3H),6.49(d,J=9.3Hz,1H),5.48(s,2H),3.84(s,3H),3.49(s,3H),3.38(m,2H),1.32(m,8H).13C NMR(75MHz, DMSO-d6)δ161.05,159.39,153.79,143.17,138.63,137.24,130.84,129.82,128.87,125.84,122.80,121.86,119.25,116.26,114.93,62.10,55.56,54.71,36.92,32.11,22.58.LC-MS(ESI):([M+H]+):536.3.熔点:170-172℃.
实施例46:2-((1-(3,4-二甲氧基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5- (1-甲基-6-氧代-1,6-二氢吡啶-3-基)苯磺酰胺(化合物IV-h)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ8.87(s,1H),8.15(s,1H),7.86(m,3H),7.60(s,1H),7.44(m,2H),7.17(s,2H),6.49(d,J=8.8Hz,1H),5.48(s,2H),3.85(s,6H),3.52(s,3H),3.47(m,1H),1.50–1.27(s,8H).13C NMR(75MHz,DMSO-d6)δ161.05,153.80,149.29,149.03,143.10,138.63,137.25,130.83,129.84,128.89,125.83,122.95,119.26,116.26,114.99,112.34,112.00,104.79,62.12,55.80,54.74,36.93,32.13,22.59.LC-MS(ESI):([M+ H]+):566.3.熔点:158-160℃.
实施例47:2-((1-(4-硝基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基 -6-氧代-1,6-二氢吡啶-3-基)苯磺酰胺(化合物IV-i)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ9.14(s,1H),8.50(m,2H),8.25(s,1H),8.15(s,1H),7.86(m,2H),7.60(s,1H),7.12(s,1H),6.50(m,1H),5.53(s,2H),3.52(s,3H),3.38(m,1H),1.40(m,8H).13C NMR(75MHz,DMSO-d6)δ161.05,153.74,146.85,144.01,140.66, 138.62,137.26,130.87,129.81,128.97,125.90,125.63,123.33,120.75,119.26,116.23,115.00,61.95,54.68,36.93,32.15,22.59.LC-MS(ESI):([M+H]+):551.3.熔点: 176-178℃.
实施例48:2-((1-(4-溴苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基-6- 氧代-1,6-二氢吡啶-3-基)苯磺酰胺(化合物IV-j)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ8.96(s,1H),8.15(s,1H),7.99–7.73(m,7H),7.60 (s,1H),7.15(s,1H),6.49(d,J=9.2Hz,1H),5.77(d,J=4.1Hz,1H),5.50(s,2H),3.52(s,3H),3.46(m,1H),1.49(m,4H),1.30(m,4H).13C NMR(75MHz,DMSO-d6)δ161.05, 153.75,143.58,138.63,137.25,135.65,132.86,130.86,129.80,128.92,125.88,122.90,122.10,121.55,119.26,116.25,114.99,62.02,54.87,54.69,36.92,32.12,22.58.LC-MS(ESI):([M+H]+):584.2.熔点:172-174℃.
实施例49:2-((1-(2,4-二氯苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1- 甲基-6-氧代-1,6-二氢吡啶-3-基)苯磺酰胺(化合物IV-k)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ8.73(s,1H),8.18(s,1H),8.05(s,1H),7.83(m,5H),7.61(m,1H),7.14(d,J=5.5Hz,1H),6.52(m,1H),5.56(s,2H),3.55(s,3H),3.42(m,1H),1.52(m,4H),1.30(m,5H).13C NMR(75MHz,DMSO-d6)δ161.05,153.78,142.70, 138.61,137.23,135.52,133.34,130.84,130.17,129.80,129.61,129.48,128.92,128.67,126.67,125.84,119.25,116.25,115.00,62.06,54.71,36.93,32.19,22.62.LC-MS(ESI):([M +H]+):574.2.熔点:176-178℃.
实施例50:2-((1-(2-硝基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基-6-氧代-1,6-二氢吡啶-3-基)苯磺酰胺(化合物IV-l)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ8.83(s,1H),8.34–8.12(m,2H),8.09–7.75(m,6H),7.58(d,J=8.1Hz,1H),7.10(d,J=6.7Hz,1H),6.50(d,J=8.9Hz,1H),5.57(s,2H),3.56(s,3H),3.44(m,1H),1.53(s,4H),1.33(s,4H).13C NMR(75MHz,DMSO-d6)δ161.06,153.79,144.01,143.18,138.63,137.25,134.48,131.37,130.88,129.76,128.95,127.60,125.84,125.60,119.26,116.25,115.02,62.07,54.70,36.93,32.21,22.62.LC-MS(ESI):([M +H]+):551.3.熔点:165-167℃.
实施例51:2-((1-(4-羟基苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5-(1-甲基 -6-氧代-1,6-二氢吡啶-3-基)苯磺酰胺(化合物IV-m)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ10.01(s,1H),8.74(s,1H),8.15(s,1H),7.85(m,3H),7.74–7.54(m,2H),7.18(s,1H),6.97(s,2H),6.49(d,J=8.9Hz,1H),5.47(s,2H),3.52(s,3H),3.43(s,1H),1.49(m,4H),1.30(m,4H).13C NMR(75MHz,DMSO-d6)δ168.48, 161.05,157.87,153.79,143.05,138.63,137.23,130.84,128.85,125.82,122.67,122.04,119.24,116.07,114.97,62.11,54.71,36.92,32.10,28.98,22.58.LC-MS(ESI):([M+H]+):522.3.熔点:155-157℃.
实施例52:2-((1-(4-(叔丁基)苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5- (1-甲基-6-氧代-1,6-二氢吡啶-3-基)苯磺酰胺(化合物IV-n)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ8.89(s,1H),8.15(s,1H),8.00–7.76(m,5H),7.70–7.54(m,3H),7.17(d,J=6.1Hz,1H),6.50(d,J=8.1Hz,1H),5.50(s,2H),3.56(s,3H),3.41(m,1H),1.64–1.23(m,17H).13C NMR(75MHz,DMSO-d6)δ161.05,153.79, 151.57,143.28,138.63,137.23,134.13,130.85,129.83,128.89,126.65,125.85,122.80,119.96,119.25,116.27,115.00,62.10,54.72,36.92,34.49,32.12,30.94,22.57.LC-MS(ESI): ([M+H]+):562.3.熔点:152-154℃.
实施例53:2-((1-(4-三氟甲氧基)苯基)-1H-1,2,3-***-4-基)甲氧基)-N-环戊基-5- (1-甲基-6-氧代-1,6-二氢吡啶-3-基)苯磺酰胺(化合物IV-o)的制备
合成方法参考实施例1。
1H NMR(300MHz,DMSO-d6)δ8.99(s,1H),8.08(m,3H),7.96–7.77(m,3H),7.73–7.54(m,3H),7.15(d,J=7.1Hz,1H),6.55–6.43(m,1H),5.51(s,2H),3.53(s,3H),3.46 (m,1H),1.50(m,4H),1.28(m,4H).13C NMR(75MHz,DMSO-d6)δ161.05,153.76, 147.99,143.59,138.63,137.24,135.30,130.85,129.81,128.93,125.88,123.17,122.67, 122.22,119.25,116.26,115.00,62.03,54.69,36.93,32.12,22.57.LC-MS(ESI):([M+H]+):590.3.熔点:158-160℃.
实施例54:细胞活性生物测试实验
测定原理:化合物抑制癌细胞生长具体细节可以用经MTT方法来测得。MTT法的原理是:黄色噻唑兰可穿过细胞膜进入细胞内,活细胞线粒体中的琥珀酸脱氢酶能够让外源性MTT还原成沉积于细胞中的蓝紫结晶甲瓒,然而死细胞却没有这种功能。再用二甲基亚砜溶解甲瓒。在570nm波长处,用酶联免疫检测仪测定其吸光值,来间接得到活细胞数量。
实验材料:MV4-11(人急性髓性白血病细胞),用IMDM+10%FBS培养基培养。
试验方法与结果分析:
实验组:190μl细胞悬液+10μl不同浓度的药物(终浓度为10-5-10-10)
空白对照组:200μl PBS
阴性对照组:190μl细胞悬液+10μl 2%DMSO(DMSO终浓度为0.1%)
阳性对照组:190μl细胞悬液+10μl不同浓度的化合物
MTT细胞活力检测步骤
a)接种细胞
在37℃、5%CO2条件下,用含有10%的胎牛血清、1%的青霉素和链霉素的IMDM 培养基中传代培养细胞。将细胞悬液移入10mL离心管,1000转/分钟离心3分钟,使细胞沉淀,弃去上清液,待细胞入7ml新的培养基,轻轻吹打,用细胞计数法计算细胞浓度,然后接种于96孔板中。
b)细胞培养
将接种完的96孔板放置于37℃、5%的CO2培养箱中孵育过夜。
c)加药
按照不同的实验设计加入不同浓度的药物,每组设3~4个复孔,每孔加入 10μl相应浓度的药物,再将96孔板放入培养箱继续培养。
d)MTT活力检测
给药后培养24小时、48小时、72小时后,每孔加入10μl 5mg/ml的MTT,后将96 孔板放置于培养箱中,继续培养4小时后取出,离心96孔板,小心吸取每孔的上清液,每孔再加入100μl的二甲基亚砜(DMSO)溶液,放置培养箱中孵育10min后,震荡40s 左右,使甲瓒晶体完全溶解。
e)测吸光度并计算IC50值
将96孔板置于酶标仪中,检测波长为570nm处的吸光值。以每3~4个复孔吸光度的平均值计算其相对抑制率。根据不同药物浓度下对白血病细胞的抑制率,计算半数有效抑制浓度(IC50)。每组样品要做3次平行实验。
570nm读数,计算细胞存活率,根据结果计算IC50,结果如下表1。
表1.BRD4小分子抑制剂的结构和活性数据(μmol/L)
Claims (5)
4.一种药物组合物,其特征在于,其包含权利要求1-2任一项所述的化合物或其药学上可接受的盐,以及药学上可接受的辅料。
5.权利要求1-2任一项所述的化合物或其药学上可接受的盐,在制备抗肿瘤药物中的应用。
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