CN105873577B - 环插烯酰胺作为溴结构域抑制剂 - Google Patents
环插烯酰胺作为溴结构域抑制剂 Download PDFInfo
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- CN105873577B CN105873577B CN201480059030.8A CN201480059030A CN105873577B CN 105873577 B CN105873577 B CN 105873577B CN 201480059030 A CN201480059030 A CN 201480059030A CN 105873577 B CN105873577 B CN 105873577B
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- C07C225/20—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
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- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
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- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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Abstract
本发明公开了式(I)所示的环插烯酰胺。该化合物具有用于治疗由包括乙酰‑赖氨酸残基的蛋白的活性异常引起的疾病的用途。组合物包括一系列作为溴结构域抑制剂的环插烯酰胺。
Description
相关申请的交叉引用
本申请要求2013年8月30日提交的美国临时申请61/872,303的优先权,其全部公开内容通过参考并入本文。
政府权力声明
本发明是在由国立卫生研究院授予的R01HG004508、R01CA87658和R33DA029963美国政府支持下进行的。美国政府对本发明具有一定的权利。
技术领域
本申请广泛涉及用于治疗由包括乙酰-赖氨酸的蛋白的活性异常引起的疾病的组合物。该组合物含有一类环插烯酰胺(cyclic vinylogous amides),其为溴结构域(bromodomain)抑制剂。
背景技术
BRD4是蛋白的溴结构域和额外的末端结构域(BET)家族中的一员,该蛋白通过其溴结构域识别乙酰化的染色质结构并作为转录激活物。Brd4作为P-TEFb的相关因子和正调控因子发挥作用,P-TEFb是一种由RNA聚合酶II激活转录延伸的Cdk9-细胞周期蛋白T异质二聚体。包括溴结构域的蛋白4(BRD4)包括两个优先与在组蛋白和非组蛋白中发现的乙酰化的赖氨酸残基相结合的串联的溴结构域(BrD1和BrD2)。该分子识别作用允许Brd4与整个细胞周期中的乙酰化染色质相关联并调控靶基因位点的转录。
急性髓系白血病(AML)是一种危及生命的干细胞疾病,以细胞增殖失控以及成髓细胞的积累为特征。在最近的研究中,Herrmann等[Oncotarget.2012 Dec;3(12):1588-99]表明通过小分子抑制剂JQ1抑制BRD4可导致包括来源于复发性或难治性患者的细胞在内的原代人AML干细胞和祖细胞的生长抑制和凋亡。另外,还发现,在所有供体中,JQ1可诱导CD34+/CD38-和CD34+/CD38+干细胞和祖细胞发生凋亡。因此,BRD4抑制被认为是具有前景的新的AML治疗方法。
NF-κB介导的炎症反应是慢性肾脏疾病的主要病理学特征,其中包括最终发展为晚期肾脏疾病的HIV相关的肾病。肾脏的HIV感染诱导NF-κB激活,导致促炎性趋化因子、细胞因子和粘附分子的产生。在Zhang等[J Biol Chem.2012Nov 9;287(46):38956]发表于生物化学杂志的研究中表明溴结构域和额外的末端结构域特异性溴结构域抑制剂MS417有效地改善了HIV-1转基因小鼠的炎症反应和肾损伤,该转基因小鼠是一种用于HIV相关肾病的动物模型。
因此,有必要将BRD4的抑制剂作为白血病和HIV相关肾病的治疗剂。
发明内容
一方面,本发明涉及式I所示的化合物
其中:
U为(CH2)n,其中,n=1、2或3;
R1选自由(C1-C10)烷基、取代的(C1-C10)烷基和腈所组成的组中;
Cy为碳环或杂环;
R11和R12各自独立地选自由H、(C1-C10)烷基、(C1-C10)全氟烷基、卤素、腈、羟基、(C1-C10)烷氧基、全氟(C1-C10)烷氧基、(C1-C10)烷基巯基(alkylthio)、氨基、(C1-C10)烷基氨基(acylamino)、(C1-C10)酰胺基、芳基、杂芳基(heteroaryl)、氨甲酰基(aminocarbonyl)、羧基和(C1-C10)烷氧羰基所组成的组中;或者
R11和R12可以一起形成5、6或7元碳环或杂环,其中,所述碳环或杂环可以可选地被R2取代;
R2选自由卤素、(C1-C4)烷基、卤代(C1-C4)烷基(halo(C1-C4)alkyl)、羟基、(C1-C4)烷氧基、卤代(C1-C4)烷氧基、羧基、氨基、(C1-C4)烷基氨基和二(C1-C4)烷基氨基所组成的组中;
Y选自H、
L和L’各自独立地为化学键或(CR3R4)m,其中,R3和R4各自独立地选自由H和(C1-C4)烷基所组成的组中,并且m为1或2;
R10选自烷基、碳环和杂环,其中,所述烷基、碳环或杂环任选地被R7和/或R8取代;
R20为–C(=O)OR21;
R21选自H和(C1-C4)烷基;
R5和R6各自独立地选自由氢、羟基、(C1-C10)烃基、卤代(C1-C10)烃基和(C1-C10)烷氧基所组成的组中;
R7和R8各自独立地选自由以下基团所组成的组中:羟基、卤素、(C1-C4)烷基、卤代(C1-C4)烷基、羟基(C1-C4)烷基、(C1-C4)烷氧基、卤代(C1-C4)烷氧基、(C1-C4)烷基巯基、(C1-C4)烷基羰基、芳基、杂芳基、环烷基、杂环烷基、氰基、含氧基(oxo)、(C1-C4)烷基磺酰基、氨基、(C1-C4)烷基氨基、二(C1-C4)烷基氨基、(C1-C4)酰胺基、氨甲酰基(aminocarbonyl)、羧基和(C1-C4)烷氧羰基,其中,每个所述烷基、芳基、杂芳基、环烷基或杂环烷基可以进一步可选地被羟基、含氧基、羧基、羧基(C1-C4)烷基、羟基(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)烷氧羰基、(C1-C4)烷氧羰基(C1-C4)烷基、氨基、(C1-C4)烷基氨基、二(C1-C4)烷基氨基、酰胺基(amido)、(C1-C4)烷基酰胺基、二(C1-C4)烷基酰胺基、卤素、(C1-C4)烷基、卤代(C1-C4)烷基、芳基、杂芳基、杂环烷基或环烷基取代;
或者,R5和R6,或R7和R8可以一起形成5、6或7元碳环或杂环,其中,所述碳环或杂环可选地被R9取代;
R9选自由卤素、(C1-C4)烷基、卤代(C1-C4)烷基、羟基、(C1-C4)烷氧基、卤代(C1-C4)烷氧基、氨基、(C1-C4)烷基氨基和二(C1-C4)烷基氨基所组成的组中。
第二方面,本发明涉及含有药学上可接受的载体和本文所描述的化合物的药物组合物。
第三方面,本发明涉及用于治疗由含有乙酰-赖氨酸残基的蛋白的活性异常引起的疾病或病症的方法。该方法包括给药治疗有效量的本文所描述的化合物至有需要的患者。
第四方面,本发明涉及抑制细胞中溴结构域的方法。该方法包括将细胞与抑制量的本文所描述的化合物相接触。
附图说明
图1是关于接受治疗的和未接受治疗的已诱导炎症性结肠炎的小鼠的体重从基线的变化百分数相对于时间(周数)的曲线图。
图2是显示关于接受治疗的和未接受治疗的已诱导炎症性结肠炎的小鼠的肠道与正常(对照)肠道相对比的总体形态的照片的灰度图。
具体实施方式
一方面,本发明涉及具有通式I的化合物:
在一些实施方式中,Cy是脂肪族的,例如环己基,或杂脂肪族的(heteroaliphatic);在其他情况下,其是芳基,例如苯基或萘基,或杂芳基,例如吡啶基。当Cy是萘基时,Y通常为氢。当Cy为苯基时,该化合物具有通式:
在一些实施方式中,U为-CH2CH2-,并且插烯酰胺(vinylogous amide)为N-取代的3-氨基环己基-2-烯酮。在其他的实施方式中,U为-CH2-,并且插烯酰胺为N-取代的3-氨基环戊基-2-烯酮。在这两个系列中,环烯酮的2位被取代基R1所取代。在一些实施方式中,R1为腈。在其他的实施方式中,R1为被取代的或未被取代的(C1-C10)烷基。在一些实施方式中,R1优选为(C1-C6)烷基,最常见为甲基。
在一些实施方式中,R11和R12各自独立地选自由以下基团所组成的组中:H、(C1-C10)烷基、(C1-C10)全氟烷基、卤素、腈、羟基、(C1-C10)烷氧基、全氟(C1-C10)烷氧基、(C1-C10)烷基巯基、氨基、(C1-C10)烷基氨基、(C1-C10)酰胺基、芳基、杂芳基、氨甲酰基、羧基和(C1-C10)烷氧羰基。在一些实施方式中,R11和R12中至少有一个为氢。在一些实施方式中,R11和R12可以一起形成5、6或7元碳环或杂环,在这些实施方式中,该碳环或杂环可选地被R2取代。在一些实施方式中,R2选自卤素、(C1-C4)烷基、卤代(C1-C4)烷基、羟基、(C1-C4)烷氧基、卤代(C1-C4)烷氧基、羧基、氨基、(C1-C4)烷基氨基或二(C1-C4)烷基氨基。
在一些实施方式中,Y为磺酰胺,例如
在一些实施方式中,Y为脲,例如在一些实施方式中,Y为甲酰胺,例如 在这些化合物中,L可以为直接键(direct bond),L’可以为直接键或者L和L’均为直接键。在一种实施方式中,Y为并且L和L’均为直接键,即,Y为在一些实施方式中,Y为在这些化合物中,波浪线表示的是未被命名的特定立体化学构型;因此,在本文中被任意描述为反式(trans)的碳-碳双键可以是顺式的(cis)、反式的或二者以任意比例的混合物。在一些实施方式中,R20为–C(=O)OR21。在这些实施方式中的某些实施方式中,R21为氢。在这些实施方式中的某些实施方式中,R21为(C1-C4)烷基,特别为甲基。在一些实施方式中,Y为在这些实施方式中的某些实施方式中,R21为(C1-C4)烷基,在其他实施方式中R21为氢。在一些实施方式中,L为直接键且R21为氢。在一些实施方式中,Y为在这些化合物中,虚线表示的是可选择的双键,其包括Y为–L-CH2CH2-R10和–L-CH=CH-R10的化合物。在其他的实施方式中,Y可以是5元杂环,特别是被L-R10取代的芳香族5元杂环。5元杂环通常在环中包括一个以上的杂原子,优选为1,2,3-三唑。当Y为被取代的5元杂环时,L可以为–(CR3R4)m,特别是-CH2-。
在多种实施方式中,其中,Y为磺酰胺(sulfonamide)、脲、甲酰胺或5元杂环,R10可以为环己基、环戊基、苯基、萘基、噻吩基(thiophenyl)、吡咯基、吡啶基(pyridinyl)或嘧啶基,各自可选地被R7和/或R8取代。优选为环己基、苯基和萘基。当R10为苯基时,在一些实施方式中,其可以仅单独被R7取代,并且,在这些实施方式中,其结构可以表示为:在这些化合物中,R7可以为卤素、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、卤代(C1-C4)烷氧基或氨甲酰基。优选为氟(Fluoro)、氯(chloro)、甲基和甲氧基。在一些实施方式中,R10为被R7和R8取代的苯基。在这些实施方式中,R7和R8可以各自独立为卤素、(C1-C4)烷基、卤代(C1-C4)烷基,(C1-C4)烷氧基,卤代(C1-C4)烷氧基或氨甲酰基。在一些实施方式中,R8为氟。
第二方面,本发明涉及含有药学上可接受的载体和本文所描述的化合物的药物组合物。
第三方面,本发明涉及用于治疗由含有乙酰-赖氨酸残基的蛋白的活性异常引起的疾病或病症的方法。该方法包括:将治疗有效量的本文所描述的化合物给药至有需要的患者。在一些实施方式中,所述疾病或病症为慢性炎症。在一些实施方式中,所述疾病或病症为自身免疫疾病。在一些实施方式中,所述疾病或病症为癌症。在一些实施方式中,还可以给予额外的治疗剂。
第四方面,本发明涉及抑制细胞中溴结构域的方法。该方法包括:将细胞与抑制量的本文所描述的化合物相接触。
出于简便和清楚的目的,本文描述了说明书、实施例和权利要求中使用的某些术语。
C1-C20的烃包括烷基、环烷基、多环烷基、烯基、炔基、芳基和它们的组合。例如包括苄基、苯乙基、环己基甲基、金刚烷基、樟脑基和萘基乙基(naphthylethyl)。烃基指的是由氢和碳作为唯一元素组分组成的任意取代基。脂肪烃为非芳香族的烃;它们可以是饱和的或不饱和的、环状的、线性的或支链的。脂肪烃的实例包括异丙基、2-丁烯基(2-butenyl)、2-丁炔基(2-butynyl)、环戊基、降冰片基(norbornyl)等。芳香烃包括苯(苯基)、萘(萘基)、蒽等。
除非另有说明,烷基(或烯烃基)旨在包括线性的或支链的饱和烃结构及其组合。烷基指的是具有1-20个碳原子的烷基基团,优选为1-10个碳原子,更优选为1-6个碳原子。烷基基团的实例包括甲基、乙基、丙基、异丙基、正丁基、仲丁基、叔丁基等。
环烷基(cycloalkyl)是烃的子集,它包括具有3-8个碳原子的环状烃基基团。环烷基基团的实例包括环丙基、环丁基环戊基、降冰片基等。
除非另有说明,术语“碳环”旨在包括环原子全部是碳而不是任意氧化态的环体系。因此,(C3-C10)碳环指的是非芳香族和芳香族体系,包括如环丙烷、苯和环己烯这类体系;(C8-C12)碳多环指的是如降莰烷(norbornane)、萘烷、二氢化茚和萘这类体系。碳环,如果没有另外的限定,指的是单环、双环和多环。
杂环表示的是脂肪族或芳香族碳环残基中的1-4个碳原子被杂原子取代,其中,所述杂原子选自由N、O和S的所组成的组中。可选地,氮和硫杂原子可以被氧化,并且,可选地,氮杂原子可以被季铵化。除非另有说明,杂环可以是非芳香族的(杂脂肪族的)或芳香族的(杂芳基)。杂环的实例包括吡咯烷、吡唑、吡咯、吲哚、喹啉、异喹啉、四氢异喹啉、苯并呋喃、苯并二恶烷、苯并二茂(苯并二茂)(当发生取代时,通常被称为亚甲基二氧苯基),四唑、吗啉、噻唑、吡啶、哒嗪、嘧啶、噻吩、呋喃、恶唑、恶唑啉、异恶唑、二恶烷、四氢呋喃等。杂环残基的实例包括哌嗪基、哌啶基、吡咯烷基、咪唑基、咪唑啉基、咪唑烷基、吡嗪基、恶唑烷基、异恶唑烷基(isoxazolidinyl)、噻唑烷基(thiazolidinyl)、异噻唑基、奎宁环基、异噻唑烷基(isothiazolidinyl)、苯并咪唑基、噻二唑基(thiadiazolyl)、苯并吡喃基、苯并噻唑基、四氢呋喃基(tetrahydrofuryl)、四氢吡喃基(tetrahydropyranyl)、噻吩基(以往也被称为苯硫基)、苯并噻吩基(benzothienyl)、硫代吗啉基(thiamorpholinyl)、恶二唑基(oxadiazolyl)、三唑基和四氢喹啉基(tetrahydroquinolinyl)。
烷氧基或烷氧基的指的是通过氧连接至母体结构的具有1-20个碳原子基团,优选为1-10个碳原子基团,更优选为1-6个碳原子基团的直链或支链构型。实例包括甲氧基、乙氧基、丙氧基、异丙氧基等。低级烷氧基指的是包括1-4个碳的基团。根据本申请的目的,烷氧基和低级烷氧基包括亚甲二氧基(methylenedioxy)和亚乙二氧基(ethylenedioxy)。
术语“卤素”表示的是氟、氯、溴或碘原子。在一种实施方式中,卤素可以为氟或氯原子。
氧烷基(oxaalkyl)指的是一个或多个碳(及其相关的氢)被氧取代的烷基残基。实例包括甲氧基丙氧基、3,6,9-三氧葵(trioxadecyl)等。术语氧烷基为本领域常规的理解[参见Naming and Indexing of Chemical Substances for Chemical Abstracts,由American Chemical Society出版,2002版,196,但不受127(a)限制],即,它指的是氧通过单键被键合至其相邻原子(形成醚键)的化合物;它指的不是如存在于羰基中的双键连接的氧。同样地,硫烷基和氮烷基分别指的是一个或多个碳被硫或氮取代的烷基残基。氮烷基的实例包括乙氨基乙基(ethylaminoethyl)和氨己基(aminohexyl)。
如本文中所用的,术语“可选择地被取代的”可以与“未被取代的或被取代的”交换使用。术语“被取代的”指的是在具有特定自由基的特定基团中一个或多个氢原子的替换。例如,被取代的烷基、芳基、环烷基、杂环基等指的是烷基、芳基、环烷基、杂环基中每个残基中的一个或多个H原子被取代为卤素、卤代烷基、烷基、酰基、烷氧基烷基(alkoxyalkyl)、羟基低级烷基、羰基、苯基、杂芳基、苯磺酰基、羟基、低级烷氧基、卤代烷氧基、氧烷基、羧基、烷氧羰基[-C=O]O-烷基]、烷氧羰基氨基(alkoxycarbonylamino)[HNC(=O)O-烷基],氨甲酰基(也称作甲酰胺)[-C(=O)NH2]、烷基氨甲酰基[-C(=O)NH-烷基]、氰基、乙酰氧基、硝基、氨基、烷基氨基、二烷基氨基、(烷基)(芳基)氨基烷基、烷基氨基烷基(包括环烷基氨基烷基)、二烷基氨基烷基、二烷基氨基烷氧基、杂环烷氧基、巯基、烷硫基、亚砜基(sulfoxide)、砜基(sulfone)、磺酰基氨基、烷基亚磺酰基、烷基磺酰基、酰胺烷基、酰胺烷氧基、酰胺基、脒基、芳基、苄基、杂环基、杂环基烷基、苯氧基、苄氧基、杂芳氧基、肟基(hydroxyimino)、烷氧亚胺基(alkoxyimino)、氧烷基、氨基磺酰基、三苯甲基、脒基、胍基、脲基、苄氧基苯基和苄氧基。“氧代(oxo)”也被包括在“可选择地被取代的”所指的取代基中;本领域技术人员可以理解的是,因为氧代为二价基,所以存在其不适合作为取代基的情况(如在苯基上)。在一种实施方式中,1、2或3个氢原子被特定的自由基取代。在烷基和环烷基的情况下,三个以上氢原子可以被氟取代;实际上,所有可用的氢原子均可以被氟取代。在优选的实施方式中,取代基为卤素、卤代烷基、烷基、酰基、羟烷基、羟基、烷氧基、卤代烷氧基、氨甲酰基氧烷基、羧基、氰基、乙酰氧基、硝基、氨基、烷基氨基、二烷基氨基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基磺酰基氨基、磺酰基芳基磺酰基、芳基磺酰胺基和苄氧基。最优选为卤素、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、卤代(C1-C4)烷氧基和氨甲酰基。
当在权利要求中引入取代基Rn时,通常对其进行定义,并且在全部权利要求中始终保持该定义。在具体说明书中某些Rn具有的定义仅与一组特定的典型合成(aparticular set of exemplary syntheses)相关;典型合成中的Rn不一定本发明的权利要求或摘要中的Rn相对应。
如本文所用的,并且本领域技术人员公知的是,“化合物”的概念-除非明确地有进一步限定-旨在包括该化合物的盐。因此,例如,如上所述的包括取代基COOH的“式I所示化合物”的概念将包括盐,其中的取代基为COO-M+,其中M为任意反离子。下述实施例02-01至02-07为可经过成盐过程的该类羧酸的实例。类似地,如上所述的式I所示化合物可以包括取代基NH2,例如,以下实施例05-25,因此,还将包括盐,其中的取代基为NH3 +X-,其中,X为任意反离子。在特定的实施方式中,术语“式I所示化合物”指的是该化合物或其药学上可接受的盐。
术语“药学上可接受的盐”指的是其中的反离子是由药学上可接受的无毒的酸和碱衍生的盐。用于本发明的氨基取代的化合物的盐的合适的药学上可接受的酸包括,例如,乙酸、己二酸、藻酸、抗坏血酸、天冬氨酸、苯磺酸(benzenesulfonic)(苯磺酸盐(besylate))、苯甲酸、硼酸、丁酸、樟脑酸、樟脑磺酸、碳酸、柠檬酸、乙二磺酸(ethanedisulfonic)、乙磺酸、乙二胺四乙酸、甲酸、富马酸、葡庚糖酸、葡糖酸、谷氨酸、氢溴酸、盐酸、氢碘酸基、羟基萘(hydroxynaphthoic)、羟乙磺酸、乳酸、乳糖酸、月桂基磺酸(laurylsulfonic)、马来酸、苹果酸、扁桃酸、甲磺酸、粘酸、萘磺酸(naphthylenesulfonic)、硝酸、油酸、扑酸、泛酸、磷酸、特戊酸(pivalic)、聚半乳糖醛酸、水杨酸、硬脂酸、琥珀酸、硫酸、鞣酸、酒石酸、乙氧羰基乳酸(teoclatic)、对甲苯磺酸等。用于本发明的羧酸盐(carboxylate)取代化合物的合适的药学上可接受的加入碱的盐包括,但不限于,由铝、钙、锂、镁、钾、钠和锌制成的金属盐,或者由赖氨酸、精氨酸、N,N'-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、葡甲胺(N-甲基葡糖胺)和普鲁卡因制成的有机盐。进一步地,药学上可接受的盐包括,在合适的时候,连接至具有1-20个碳原子上的无毒铵阳离子和羧酸盐、磺酸盐和膦酸盐阴离子。
应当认识到,本发明的化合物可以以放射性标记的形式存在,即,所述化合物可以包括一个或多个具有与通常在自然界中发现的原子量或质量数不同的原子量或质量数的原子。可选地,多个单一结构的分子可以包括至少一个具有与在自然界中发现的同位素比不同的同位素比的原子。氢、碳、磷、氟、氯和碘的放射性同位素分别包括2H、3H、11C、13C、14C、15N、35S、18F、36Cl、125I、124I和131I。包括其他原子的这些放射性同位素和/或其它放射性同位素的化合物在本发明的范围内。特别优选为氚标记的(即,3H)和碳-14(即,14C)的放射性同位素,因为其在制备和检测过程中的方便性。包括同位素11C、13N、15O、124I和18F的化合物非常适用于正电子发射断层扫描。本发明式I所示的放射性标记的化合物及其前药通常可以采用本领域技术人员公知的方法进行制备。方便的是,这种放射性标记的化合物可以通过实施实施例和技术方案中公开的过程以进行制备,即通过将现成的放射性标记试剂替换为非放射性标记试剂。
虽然本发明适用于多种不同形式的实施方式,但是已展现了本发明优选的实施方式。然而,应当理解的是,本发明公开的内容被认为是本发明原理的示例,并不是旨在将本发明为限制在示例的实施方式上。经审查可以发现,本申请中的某些权利要求类别属于不可授予发明人专利权的。在这种情况下,随后从申请人请求保护的权利要求中排除的种类被认为是专利诉讼的结果,并不能反映发明人的理念或对其发明的描述;本发明包括还未被公众所知的所有I类内容。
虽然式I所示化合物可能以化学原料的形式给药,但是优选将其呈现为药物组合物的形式。根据进一步的方面,本发明提供了一种药物组合物,该药物组合物含有式I所示的化合物或者其药学上可接受的盐或溶剂,及一种或多种其药学上的载体和可选的一种或多种其他治疗成分。载体必须是“可接受的”意味着其与该剂型的其他成分是相容的并且对其受体无毒。该组合物可以被制成口服给药、局部给药或肠胃外给药的剂型。例如,它们可以通过静脉注射给药、插管注射给药、皮下注射给药,以及通过鞘内注射或脑室注射直接给药至CNS。
剂型包括那些适合于口服给药、肠胃外给药(包括皮下注射给药、皮内注射给药、肌内注射给药、静脉注射给药和关节内注射给药)、直肠给药和局部给药(包括真皮给药、口腔给药、舌下给药和眼内给药)的剂型。优选地,所述化合物经口服或注射(静脉注射或皮下注射)给药。给药至患者的化合物的精确量将由主治医生负责。然而,采用的剂量将依赖于多种因素,包括患者的年龄和性别、被治疗的确切病症及其严重程度。另外,给药途径可以根据病情及其严重程度而改变。所述剂型可以方便地以单位剂量的形式表示,并且可以使用药学领域公知的任意方法进行制备。一般情况下,所述剂型的制备式通过将活性成分与液体载体或精细分开的固体载体均匀地且紧密地结合,然后,如果必要的话,将该产品成型至预期的剂型。
本发明提供的适用于口服给药的剂型可以表现为离散单位的形式,例如:胶囊、扁囊剂(cachets)或片剂,其中各自含有预定量的活性成分;粉末或颗粒;溶液或者水性液体或非水性液体的悬浮液;或者水包油液体乳剂或油包水液体乳剂。所述活性成分还可以表现为丸剂(bolus)、冲剂或糊剂的形式。
应当理解的是,除了以上明确提到的成分,本发明的剂型可以含有本领域常规的具有与尚有争议的剂型种类相关的其他试剂,例如,那些适用于口服给药的剂型可以含有调味剂。
如本文所用的,“治疗(treatment)”或“治疗(treating)”,或者“减轻”或“改善”在本文中可以互换使用。这些术语指的是以根除或改善被治疗的潜在病症的形式获得疗效的方法。另外,通过根除或改善一个或多个与潜在病症相关的生理系统以获得疗效,以致观察到患者病情得到改善,虽然该患者可能仍饱受潜在病症的折磨。所述组合物可以被给药至具有发展成特定疾病风险的患者,或者被给药至已报告有一个或多个生理系统疾病的患者,即使该疾病的诊断尚未进行。
关于“保护的(protecting)”、“去保护(deprotecting)的”和“受保护的(protected)”功能性的术语自始至终出现在本申请中。本领域技术人员可以很好地理解这类术语,并且其被用在涉及使用一系列试剂进行连续治疗的过程的情况下。在该情况下,保护基团指的是被用于处理过程中掩盖功能性的基团,其中,在处理过程中否则将会发生反应,但其中发生的反应是非预期的。所述保护基团可以防止该过程发生的反应,但是,其随后可能被去除以暴露原始功能性。所述去除或“去保护”发生在该反应或者功能性受干扰的反应完成之后。因此,当指定试剂的顺序时,如本文所述的处理过程中的顺序,普通的技术人员可以很容易想到适合作为“保护基团”的那些基团。在化学领域的标准教科书中讨论了用于该目的的合适基团,例如,由T.W.Greene发表的有机合成中的保护基团[John Wiley&Sons,New York,1991],通过引用将其并入本文。
有机化学家使用的综合缩略语列表刊登在有机化学杂志(Joumal of Organic Chemistry)每卷的第一期。该列表,通常以题为“标准缩略语列表(Standard List ofAbbreviations)”的表格形式呈现,通过引用将其并入本文。
一般情况下,本发明提供的化合物可以通过常规反应流程所示的方法进行制备,例如,如下所述,或者通过它们的修订方法,使用现成的起始原料、试剂和常规的合成方法。在这些反应中,还可以使用其本身是已知的,但在本文中未提及的变体。所述起始原料可以通过商购获得,按照实施例中描述的方法合成,或者可以通过本领域技术人员公知的方法获得。用于有机分子的制备以及官能团转化和操纵的标准合成方法和过程可以很容易地从相关的科学文献或本领域的标准教科书中获得。应当理解的是,其中给出了典型的或优选的工艺条件(即,反应温度、时间、反应物的摩尔比、溶剂、压力等);除非另有说明也可以使用其他工艺条件。最佳反应条件可以随所使用的特定反应物或溶剂而不同。本领域技术人员将意识到所提供的合成步骤的本质和顺序可以改变,以为了优化所描述的化合物的形成的目的。
本文所描述的反应或过程可以在合适的溶剂中实施,本领域技术人员可以很容易地选择所述溶剂。通常地,合适的溶剂是在反应实施的温度下,即,该温度可以在从溶剂凝固温度至溶剂沸腾温度范围内变化,与反应物、中间体和/或产物基本不发生反应。指定的反应可以在一种溶剂或多种溶剂的混合物中进行。根据特定的反应步骤,可以选择适用于特定反应步骤的溶剂。
本发明的说明书使用本领域技术人员所公知的常规的美国化学学会(AmericanChemical Society)缩略语,除了以下内容:
AcCl:乙酰氯
Ac2O:乙酸酐
AcOH:乙酸
Alk:烷基
BINAP:2,2'-双(二苯基膦基)-1,1'-联萘
cat:催化剂
CH2Cl2:二氯甲烷(dichloromethane);亚甲基氯(methylenechloride)
CHCl3:氯仿
Δ:加热
DI H2O:去离子水
DMA:二甲基乙酰胺
DMF-DMA:1,1-二甲氧基-N,N-二甲基乙胺(dimethylmethanamine)
DMF:N,N-二甲基甲酰胺
EDCCl:3-(乙基亚氨基亚甲基-氨基)-N,N-二甲基-丙基-1-胺盐酸盐(3-(ethyliminomethylene-amino)-N,N-dimethyl-propan-1-amine hydrochloride)
eq:等价
ESS:洗脱溶剂系统
EtOAc:乙酸乙酯
EtOH:乙醇
H+:酸
HCl:盐酸
HCO2H:甲酸
IBCF:氯甲酸异丁酯(isobutylchloroformate)
LCMS:液相色谱质谱
MeOH:甲醇
NaOH:氢氧化钠
NMM:N-甲基吗啉
PG:保护基团
PS-CDI:聚苯乙烯羰基二咪唑(polystyrene carbodiimidazole)
pTSA:对-甲苯磺酸
rt:室温
sat:饱和的
TEA:三乙胺
TFA:三氟乙酸
THF:四氢呋喃
TMS:四甲基硅烷
1H核磁共振(NMR)光谱在所有情况下与预期的结构相一致。13CNMR光谱在相关的情况下与预期的结构相一致。在DRX-600光谱仪上,对于1H而言在600MHz条件下以及对于13C而言在125MHz条件下获取NMR。特征化学位移(δ)被表示为四甲基硅烷(TMS)的低磁场兆比率,使用用于指定主峰的常规缩略语:s,单峰;d,双峰;t,三峰;q,四峰;m,多峰;br,宽频(broad)。以下缩略语已经被用于普通溶剂:CDCl3,氘代氯仿;D6-DMSO,氘二甲基亚砜;MeOD,氘代甲醇。
质谱在所有情况下均与预期的结构相一致。使用峰洗脱时间和电喷雾电离ESI记录具有以分钟min的形式表示的保留时间t以及质荷比m/z的液相色谱质谱,LCMS。在装备有温度保持在45℃的300SB-C18柱和正离子模式的G1969A API-TOF的1200HPLC上进行LCMS分析。通过使用下述LC法的DAD踪迹估算出所有实施例的纯度均>95%:具有0.1%缓冲液的溶剂体系(A)/(B)=H2O/含有甲酸的乙腈,流速=0.4mL/min,溶剂B的时间百分率=0-1min(1%),梯度1-4min(1-99%),4-8min(99%)。使用软件计算质荷比的理论质量,计算值(Calcd)。在明确的相关情况下,记录加氢的自由基阳离子质量,[M+H]+;质量加钠,[M+Na]+;两倍质量加氢,[2M+H]+;以及两倍质量加钠[2M+Na]+的数据。在含有溴原子的相关实施例中,记录用于[M+H]+和[M+Na]+的两种稳定同位素79Br和81Br。
在加热速率为10℃/min的自动Standford研究系统OptiMelt MPA100上检测熔点(mp)。
合成过程
在以下被制成表的实验详情中,根据相应的参考方法(即,实施例01-01,中间体03,等)制备实施例和中间体。本领域技术人员应当理解的是,在任意的特定实施例或中间体的合成过程中,有必要对反应条件和参考方法的纯化过程(如关于比率、时间,等)进行较小的变动。
用于本发明的化合物的制备过程中的试剂可以通过商购获得,或者按照标准的文献报道的方法进行制备获得。除非另有说明,所有的试剂和溶剂均从商业供应商获得,并且无需进一步的纯化即可使用。
实施例和制备例中的某些化合物在包括在单一模式启动器腔体的密封微波瓶中在2.45千兆赫的条件下被连续辐射。
实施例和制备例中的某些化合物使用自动色谱法进行纯化。在被连接至-Isolera Four仪器的正相KP-SilTM硅胶柱上使用等度,或分级式梯度流动相,于254nm和365nm下监控紫外线踪迹。溶剂体系使用一种、两种或三种溶剂(丙酮、己烷、EtOAc或MeOH)以从非极性至极性运行。洗脱溶剂系统(ESS)是用于洗脱产物的溶剂步骤,并且以如下形式表示ESS=H:E(X:X),或者EtOAc中MeOH的百分数(%)。聘用EMD化学公司通过分析型薄层色谱(TLC)进行额外监控。铝上的TLC硅胶60F254通过暴露于紫外线或染色剂如:碘浸硅胶(iodine impregnated silica gel);10%磷钼酸EtOH等以实现可视化。
方案1-4显示了常规的合成方法。每种示例的详细情况在实施例中进行了描述。化合物可以按照方案I中的反应进行制备。R1可以从商购试剂引入,通过C-烷基化加入,或者通过开环化学的方式形成。R2可以是氢,从商购试剂引入,或者按照方案2进行制备,其中具有补加的酸、酯、硝基或保护的胺官能团。R8可以来自于耐卤素(bearing a halogen)的试剂。
方案1:
在方案2中,补加的酸,或酯,化合物可以进行反应。化合物可以受市售试剂,或方案1的保护。R3可以与补加的酯官能团一起加入并且经历碱水解和酰胺键形成的二次重复过程(second iteration)。
方案2:
在方案3中,去保护的或从硝基还原的胺类化合物可以进行反应。R5可以来自于羧酸、酰卤、酸酐、环酐或活化的酸。R6可以来自于磺酸或磺酰氯。R7可以来自于醛。R8可以来自于耐卤素的试剂。
方案3:
在方案4中,炔烃可以进行反应。R9可以来自于叠氮化物或胺类。
方案4:
特定的实施例如下:
中间体01
2-苄基环戊基-1,3-二酮(2-Benzylcyclopentane-1,3-dione)(中间体01)的制备
1,3-环戊二酮(0.98g,10.0mmol,1.0eq,Synth.Comm.1993,23(22),p.3095–3108)在去离子水(5.0mL)中经含水40%aq的Triton B(40%aq Triton B)(3.95mL<1.0eq)处理,随后经苄基溴(1.4mL,1.2eq)处理。反应混合物在室温下搅拌24小时。粗处理液(crude)经EtOAc提取并且经无水硫酸钠(anhyd sodium sulfate)干燥。10.0mmol规模的反应从经EtOAc重结晶后产生了0.9g题述中间体(48%产量)。1H NMR(D6-DMSO)δ2.39(br s,4H),3.36(br s,2H),7.10-7.17(m,3H),7.20-7.25(m,2H),11.71(br s,1H)。LCMS t=4.3min,m/z计算值C12H13O2;C12H12NaO2;C24H25O4;C24H24NaO4189.09;211.07;377.16;399.16[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值189.18;211.14;377.16;399.13。
中间体02
2-(4-羟基苄基)环戊基烷-1,3-二酮(中间体02)的制备
1,3-环戊二酮(491mg,5.0mmol,1.0eq,J.Org.Chem.1988,53,p.891–893)经ACOH(315mL,1.1eq)处理,然后经p-羟基苄醇(683mg,1.1eq)处理。在单一模式启动器的腔体中,对密封微波瓶进行微波辐射10min,产生连续的辐射,以在2.45GHz下保持120℃。直接将原料添加至含有少量CH2Cl2的KP-SilTM柱(10g)中,并且使用分级式梯度的方式在-Isolera Four仪器上从杂质中分离出产物,于254/365nm下监控紫外线踪迹。5.0mmol规模的反应在色谱分析(ESS=H:E(1:3),54%产量)后产生0.55g题述中间体。1HNMR(D6-DMSO)δ2.37(br s,4H),3.36(br s,2H),6.60(d,J=8.1Hz,2H),6.93(d,J=8.1Hz,2H),9.06(br s,1H),11.62(brs,1H)。LCMS t=3.9min,m/z计算值C12H13O3;C12H12NaO3;C24H25O6;C24H24NaO6 205.09;227.07;409.17;431.15[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值205.16;227.13;409.14;431.12。
中间体03
2-氯-4-(邻甲苯基氨基甲酰基)苯重氮氯化物(中间体03)的制备
步骤1,N-甲酰化:甲酸(18.1mL,40eq,Chem.Pharm.Bull.2002,50(7),p.941–959)和乙酸酐(11.3mL,10eq)的混合物被加热至50℃保持1h。加入4-氨基-3-氯苯甲酸(2.1g,12.0mmol,1.0eq)后,将整体加热至65℃保持2h,并且冷却至室温。将反应混合物注入冷水中,并且通过过滤收集沉淀物,用水进行冲洗,并在玻璃材料(frit)上进行干燥。12.0mmol规模的反应产生了2.2g的3-氯-4-甲酰胺苯甲酸,白色微晶体(mp=227–229℃,92%产量)。LCMS t=4.0min,m/z计算值C8H7ClNO3;C8H6ClNNaO3 200.01;221.99[M+H]+;[M+Na]+,实验值200.09;222.06。
步骤2,IBCF方法C:按照实施例04-13的方法耦合3-氯-4-甲酰胺苯甲酸和邻甲苯胺;5.0mmol规模从沉淀中产生了1.0g的3-氯-4-甲酰胺-N-(邻甲苯基)苯甲酰胺(69%产量)。LCMS t=5.1min,m/z计算值C15H14ClN2O2;C15H13ClN2NaO2;C30H27Cl2N4O4;C30H26Cl2N4NaO4289.07;311.06;577.14;599.12[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值289.07;311.05;577.14;599.12。
步骤3,N-去乙酰化:将乙酰氯(14eq,Org.Lett.2011,13(12),p.3028–3031)添加至0℃的CH2Cl2:MeOH(20mL,1:1)混合物,随后加入3-氯-4-甲酰-N-(邻甲苯基)苯甲酰胺(0.87g,3.0mmol,1.0eq)。加温至室温后,通过过滤收集HCl盐并且在玻璃材料上进行干燥。3.0mmol规模的反应产生了0.8g的2-氯-4-(邻甲苯基氨基甲酰基)苯重氮氯化物,即题述中间体(90%产量)。1H NMR(D6-DMSO)δ2.20(s,3H),4.60(br s,3H),6.84(d,J=8.4Hz,1H),7.14(t,J=7.3Hz,1H),7.19(t,J=7.3Hz,1H),7.24(d,J=7.3Hz,1H),7.28(d,J=7.7Hz,1H),7.70(d,J=8.4Hz,1H),7.89(s,1H),9.56(s,1H)。13C NMR(D6-DMSO)δ18.0,114.2,122.2,125.7,125.9,126.6,127.8,128.9,130.2,133.7,136.7,147.7,164.0。LCMS t=5.0min,m/z计算值C14H14ClN2O;C14H13ClN2NaO;C28H26Cl2N4NaO2 261.08;283.06;543.13[M+H]+;[M+Na]+;[2M+Na]+,实验值261.12;283.09;543.09。
中间体04
2-氟-4-((4-甲氧基苯基)氨基甲酰基)苯重氮氯化物(中间体04)的制备
步骤1,N-甲酰化:按照中间体03的方法使4-氨基-3-氟苯甲酸(5.0g,32.3mmol)发生N-甲酰化;32.3mmol规模上发生的反应产生了4.0g的3-氟-4-甲酰胺苯甲酸,白色的微晶体(mp=238–240℃,68%产量)。LCMSt=3.0min,m/z计算值C8H7FNO3;C8H6FNNaO3;C16H13F2N2O6 184.04;206.02;367.07[M+H]+;[M+Na]+;[2M+H]+,实验值184.04;202.05;367.07。
步骤2,IBCF方法C:按照实施例04-13的方法耦合3-氟-4-甲酰胺苯甲酸和对氨基苯甲醚;5.0mmol规模从沉淀中产生了1.0g的3-氟-4-甲酰胺-N-(4-甲氧基苯基)苯甲酰胺(69%产量)。LCMS t=4.8min,m/z计算值C15H14FN2O3;C30H27F2N4O6;C30H26F2N4NaO6 289.10;577.19;599.17[M+H]+;[2M+H]+;[2M+Na]+,实验值289.10;577.19;599.17。
步骤3,N-去甲酰化:按照中间体03的方法从3-氟-4-甲酰胺-N-(4-甲氧基苯基)苯甲酰胺制备题述中间体;3.3mmol规模,带有溶剂(20mL),产生了0.9g的2-氟-4-((4-甲氧基苯基)氨基甲酰基)苯重氮氯化物(92%产量)。LCMS t=4.6min,m/z计算值C14H14FN2O2;C14H13FN2NaO2;C28H27F2N4O4;C28H26F2N4NaO4 261.10;283.09;521.20;543.18[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值261.10;283.07;521.19;543.17。
中间体05
2-溴-4-((4-甲氧基苯基)氨基甲酰基)苯重氮氯化物(中间体05)的制备
步骤1,N-甲酰化:按照中间体03的方法使4-氨基-3-溴苯甲酸(5.0g,23.1mmol)发生N-甲酰化;在23.1mmol规模上发生的反应产生了3.0g的3-溴-4-甲酰胺苯甲酸,白色的微晶体(mp=232–234℃,79%产量)。LCMSt=4.1min,m/z计算值C8H7BrNO3;C16H13Br2N2O6;C16H12Br2N2NaO6 243.96,245.96;488.91;510.89[M+H]+;[2M+H]+;[2M+Na]+,实验值243.96,245.96;488.91;510.90。
步骤2,IBCF方法C:按照实施例04-13的方法耦合3-溴-4-甲酰胺苯甲酸和对氨基苯甲醚;5.0mmol规模(放热的)从沉淀物中产生了0.27g的3-溴-4-甲酰-N-(4-甲氧基苯基)苯甲酰胺(15%产量)。LCMS t=5.0min,m/z计算值C15H14BrN2O3;C15H13BrN2NaO3;C30H27Br2N4O6;C30H26Br2N4NaO6349.02,351.02;371.00,372.10;699.03;721.01[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值349.01,351.01;370.99,372.99;699.01;720.99。
步骤3,N-去甲酰化:按照中间体03的方法从3-溴-4-甲酰胺-N-(4-甲氧基苯基)苯甲酰胺制备题述中间体;0.75mmol规模,带有溶剂(10mL),产生了0.16g的2-溴-4-((4-甲氧基苯基)氨基甲酰基)苯重氮氯化物(66%产量)。LCMS t=4.9min,m/z计算值C14H14BrN2O2;C14H13BrN2NaO2;C28H27Br2N4O4;C28H26Br2N4NaO4 321.02,323.02;343.01,345.00;643.04;665.02[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值321.04,323.04;343.02,345.02;643.07;665.05。
中间体06
2,6-二氧代环己烷甲腈(中间体06)的制备
步骤1:将1,3-环己二酮(2.24g,20.0mmol,J.Med.Chem.2011,54,p.5070–5081)和1,1-二甲氧基-N,N-二甲基乙胺(1,1-dimethyoxy-N,N-dimethylmethanamine)(DMF-DMA,26.5mL,200mmol,10eq)混合并且加热回流3h。在旋蒸仪上除去溶剂,以产生用于下一步骤的具有合适纯度的产物。在20.0mmol规模上发生的反应产生了3.25g的2-((二甲基氨基)亚甲基)-环己烷-1,3-二酮(97%产量)。1H NMR(CDCl3)δ1.85-1.90(m,2H),2.38-2.41(m,4H),3.11(s,3H),3.33(s,3H),7.98(s,1H)。13C NMR(CDCl3)δ19.4,38.1,44.5,48.4,109.2,162.1,196.1。LCMS t=1.4min,m/z计算值C9H14NO2;C9H13NNaO2;C18H27N2O4;C18H26N2NaO4168.10;190.08;335.20;357.18[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值168.11;190.09;335.21;357.19。
步骤2:将2-((二甲基氨基)-亚甲基)环己烷-1,3-二酮(2.675g,16.0mmol,Synthesis 2002,12,p.1669–1674)和盐酸羟胺(1.15g,1.04eq)在去离子水(1.5mL)中混合并且在涡旋震荡器上搅拌30sec。5min后,通过过滤分离产物。在16mmol规模上发生的反应产生了1.75g的6,7-二氢苯并异恶唑-4-酮盐酸盐(mp=88–90℃,63%产量)。1H NMR(CDCl3)δ1.70-1.90(m,2H),2.20-2.60(m,4H),8.10(s,1H),11.25(br s,1H)。LCMS t=1.2min,m/z计算值C7H8NO2;C7H7NNaO2;C14H15N2O4;C14H14N2NaO4 138.06;160.04;275.10;297.09[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值138.06;160.04;275.12;297.10。
步骤3:将6,7-二氢苯并异恶唑-4-酮盐酸盐(2.88mmol,J.Het.Chem.1983,20,p.645–648)添加至甲苯中并且加热回流48h。将产物从甲苯中过滤出。在2.88mmol规模上发生的反应产生了0.3g题述中间产物,2,6-二氧代环己烷甲腈(mp=208–210℃,76%产量)。1H NMR(D6-DMSO)δ1.85-1.91(m,2H),2.44-2.50(m,4H)。13C NMR(D6-DMSO)δ19.8,33.0,91.9,115.1,191.7。LCMS t=1.0min,m/z计算值C7H8NO2;C7H7NNaO2;C14H15N2O4;C14H14N2NaO4138.06;160.04;275.10;297.09[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值138.06;160.04;275.11;297.10。
示例性种类的合成
实施例01-01至01-39
实施例01-01
甲基4-((3-氧代环戊基-1-烯-1-基)氨基)苯酸酯(01-01)的制备:将2-甲基-1,3-环戊二酮(5.0g,45.0mmol)和甲基-4-氨基苯酸酯(methyl-4-aminobenzoate)(7.5g,1.1eq)加热以在甲苯中回流。经过回流,将溶液从加热中移除,并且加入p-TSA(催化剂)。该装置装配有Dean-Stark冷凝器并且返回至回流18h,除非需要更多的时间。在旋蒸仪上除去溶剂并且随后将粗材料重结晶以从指定溶剂中获得作为产物的题述化合物。在45.0mmol规模上发生的反应从MeOH/H2O中产生了10.0g灰色微晶体(mp=210–212℃,91%产量)。1H NMR(D6-DMSO)δ1.59(s,3H),2.24-2.26(m,2H),2.78-2.80(m,2H),3.81(s,3H),7.32(d,J=8.1Hz,2H),7.89(d,J=8.3Hz,2H),9.18(s,1H)。13C NMR(D6-DMSO)δ8.0,26.7,33.4,52.3,112.9,120.8,123.9,130.8,145.2,166.2,168.2,203.0。LCMS t=4.8min,m/z计算值C14H16NO3;C14H15NNaO3;C28H31N2O6;C28H30N2NaO6 246.11;268.10;491.22;513.20[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值246.12;268.11;491.24;513.22。
实施例01-02
4-((3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(4-((3-oxocyclopent-1-en-1-yl)amino)benzamide)(01-02)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和4-氨基苯甲酰胺制备题述化合物;25.0mmol规模从H2O中产生了5.0g黄色微晶体(mp=192–195℃,87%产量)。1H NMR(D6-DMSO)δ1.60(s,3H),2.23-2.25(m,2H),2.76(s,2H),7.28(d,J=7.8Hz,2H),7.84(d,J=8.3Hz,2H),7.90(s,1H),9.11(s,1H)。LCMS t=2.8min,m/z计算值C13H15N2O2;C13H14N2NaO2;C26H28N4NaO4231.11;253.10;483.20[M+H]+;[M+Na]+;[2M+Na]+,实验值231.12;253.11;483.22。
实施例01-03
3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酸(01-03)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和3-氨基苯甲酸制备题述化合物;回流48h的30.0mmol规模从甲苯中产生了5.0g白色微晶体(mp=236–238℃,72%产量)。1H NMR(D6-DMSO)δ1.58(s,3H),2.23(s,2H),2.70(s,2H),7.46-7.50(m,2H),7.66-7.67(m,1H),7.78(s,1H),9.11(s,1H),13.11(s,1H)。LCMS t=4.4min,m/z计算值C13H14NO3;C13H13NNaO3;C26H27N2O6;C26H26N2NaO6 232.10;254.08;463.19;485.17[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值232.11;254.09;463.21;485.19。
实施例01-04
甲基3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯酸酯(methyl3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoate)(01-04)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和3-苯酸酯制备题述化合物;30.0mmol规模从EtOAc中产生7.0g白色微晶体(mp=133–135℃,95%产量)。1H NMR(D6-DMSO)δ1.57(s,3H),2.22-2.24(m,2H),2.70(s,2H),3.86(s,3H),7.49-7.54(m,3H),7.67(d,J=7.5Hz,1H),7.80(s,1H),9.13(s,1H)。LCMS t=5.0,m/z计算值C14H16NO3;C28H31N2O6;C28H30N2NaO6 246.11;491.22;513.20[M+H]+;[2M+H]+;[2M+Na]+,实验值246.13;491.24;513.22。
实施例01-05
3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯甲酰胺(3-((2-methyl-3-oxocyclohex-l-en-l-yl)amino)benzamide)(01-05)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和3-氨基苯甲酰胺制备题述化合物;30.0mmol规模从MeOH产生了5.0g灰色微晶体(mp=269–271℃,72%产量)。1H NMR(D6-DMSO)δ1.57(s,3H),2.21-2.23(m,2H),2.67(s,2H),7.37-7.42(m,3H),7.63(d,J=7.5Hz,2H),7.71(s,1H),8.00(s,1H),9.08(s,1H)。LCMS t=3.1min,m/z计算值C13H15N2O2;C13H14N2NaO2;C26H29N4O4;C26H28N4NaO4231.11;253.10;461.22;483.20[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值231.12;253.11;461.24;483.22。
实施例01-06
4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯磺酰胺(4-((2-methyl-3-oxocyclopent-l-en-1-yl)amino)benzenesulfonamide)(01-06)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和磺胺制备题述化合物;30.0mmol规模从THF/H2O中产生了7.0g黄色微晶体(mp=245–247℃,88%产量)。1H NMR(D6-DMSO)δ1.60(s,3H),2.25-2.26(m,2H),2.78(s,2H),7.29(s,2H),7.37(d,J=8.4Hz,2H),7.76(d,J=8.4Hz,2H),9.22(s,1H)。LCMS t=2.9min,m/z计算值C12H15N2O3S;C24H28N4NaO6S2 267.08;555.13[M+H]+;[2M+Na]+,实验值267.09;555.16。
实施例01-07
4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苄腈(4-((2-methyl-3-oxocyclopent-l-en-1-yl)amino)benzonitrile)(01-07)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和4-氨基苄腈制备题述化合物;30.0mmol规模从H2O中产生了4.0g黄色微晶体(mp=204–206℃,63%产量)。1H NMR(D6-DMSO)δ1.61(s,3H),2.26-2.27(m,2H),2.82(s,2H),7.38(d,J=8.3Hz,2H),7.76(d,J=8.2Hz,2H),9.27(s,1H)。LCMS t=5.3min,m/z计算值C13H13N2O;C13H12N2NaO;C26H24N4NaO2 213.10;235.08;447.18[M+H]+;[M+Na]+;[2M+Na]+,实验值213.17;235.14;447.15。
实施例01-08
3-((3-溴苯基)氨基)-2-甲基环戊基-2-烯酮(3-((3-bromophenyl)amino)-2-methylcyclopent-2-enone)(01-08)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和3-溴苯胺制备题述化合物,50.0mmol规模从EtOAc中产生了6.1g棕色微晶体(mp=291–294℃,46%产量)。1H NMR(D6-DMSO)δ1.58(s,3H),2.22(s,2H),2.69(s,2H),7.25-7.31(m,3H),7.45(s,1H),9.04(s,1H)。LCMS t=5.8min,m/z计算值C12H13BrNO;C12H12BrNNaO;C24H24Br2N2NaO2 266.02,268.02;288.00,290.00;555.01[M+H]+;[M+Na]+;[2M+Na]+,实验值266.07,268.06;288.04,290.03;554.98。
实施例01-09
3-((4-乙酰苯基)氨基)-2-甲基环戊基-2-烯酮(3-((4-acetylphenyl)amino)-2-methylcyclopent-2-enone)(01-09)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和4-氨基苯乙酮制备题述化合物;25.0mmol规模从甲苯中产生0.5g橙色微晶体(mp=270–273℃,9%产量)。1H NMR(D6-DMSO)δ1.61(s,3H),2.26(s,2H),2.82(s,2H),3.36(s,3H),7.33(d,J=8.5Hz,2H),7.92(d,J=8.5Hz,2H),9.23(s,1H)。LCMS t=5.2min,m/z计算值C14H16NO2;C14H15NNaO2;C28H30N2NaO4 230.12;252.10;481.21[M+H]+;[M+Na]+;[2M+Na]+,实验值230.19;252.16;481.21。
实施例01-10
2-氯-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酸(2-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid)(01-10)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和4-氨基-2-氯苯甲酸制备题述化合物;25.0mmol规模从丙酮中产生4.3g黄色针状物(mp=239–241℃,65%产量)。1H NMR(D6-DMSO)δ1.61(s,3H),2.27(s,2H),2.83(s,2H),7.27(d,J=6.8Hz,1H),7.38(s,1H),7.84(d,J=8.6Hz,1H),9.21(s,1H),13.1(s,1H)。LCMS t=5.1min,m/z计算值C13H13ClNO3;C13H12ClNNaO3;C26H24Cl2N2NaO6 266.06;288.04;553.09[M+H]+;[M+Na]+;[2M+Na]+,实验值266.12;288.09;553.09。
实施例01-11
甲基3-氯-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯酸酯(methyl3-chloro-4-((2-methyl-3-oxocyclopent-l-en-1-yl)amino)benzoate)(01-11)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和4-氨基-3-氯苯甲酸制备题述化合物;25.0mmol规模从EtOAc中产生了3.4g产物(49%产量)。1H NMR(D6-DMSO)δ1.44(s,3H),2.24-2.26(m,2H),2.54-2.55(m,2H),3.86(s,3H),7.42(d,J=8.3Hz,1H),7.90(d,J=8.3Hz,1H),8.02(s,1H),8.98(s,1H)。LCMS t=5.7min,m/z计算值C14H15ClNO3;C14H14ClNNaO3;C28H28Cl2N2NaO6 280.07;302.06;581.12[M+H]+;[M+Na]+;[2M+Na]+,实验值280.13;302.10;581.12。
实施例01-12
3-甲氧基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酸(3-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid)(01-12)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和4-氨基-3-甲氧基苯甲酸制备题述化合物;25.0mmol规模从EtOH中产生了4.8g棕褐色针状物(mp=231–234℃,74%产量)。1H NMR(D6-DMSO)δ1.51(s,3H),2.19-2.21(m,2H),2.55-2.56(m,2H),3.89(s,3H),7.28(d,J=8.5Hz,1H),7.55-7.57(m,2H),8.56(s,1H),12.96(s,1H)。LCMS t=5.1min,m/z计算值C14H16NO4;C14H15NNaO4;C28H30N2NaO8 262.11;284.09;545.19[M+H]+;[M+Na]+;[2M+Na]+,实验值262.17;284.14;545.19。
实施例01-13
甲基2-甲氧基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯酸酯(methyl2-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoate)(01-13)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和甲基-4-氨基-2-甲氧基苯酸酯制备题述化合物;25.0mmol规模从甲苯中产生了6.8g棕褐色微晶体(mp=193–196℃,99%产量)。1HNMR(D6-DMSO)δ1.62(s,3H),2.25-2.26(m,2H),2.84(s,2H),3.75(s,3H),3.82(s,3H),6.88(d,J=8.4Hz,1H),6.97(s,1H),7.68(d,J=8.4Hz,1H),9.15(s,1H)。LCMS t=5.3min,m/z计算值C15H18NO4;C15H17NNaO4;C30H34N2NaO8 276.12;298.11;573.22[M+H]+;[M+Na]+;[2M+Na]+,实验值276.18;298.15;573.24。
实施例01-14
3-甲基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酸(3-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid)(01-14)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和4-氨基-3-甲基苯甲酸制备题述化合物;25.0mmol规模从EtOH中产生了3.0g棕褐色片状物(mp=233–236℃,49%产量)。1H NMR(D6-DMSO)δ1.45(s,3H),2.19-2.21(m,2H),2.30(s,3H),2.47(s,2H),7.24(d,J=8.2Hz,1H),7.77(d,J=8.0Hz,1H),7.85(s,1H),8.74(s,1H),12.88(s,1H)。LCMS t=5.1min,m/z计算值C14H16NO3;C14H15NNaO3;C26H30N2NaO6 246.11;268.10;513.20[M+H]+;[M+Na]+;[2M+Na]+,实验值246.19;268.15;513.20。
实施例01-15
2-甲氧基-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酸(2-methoxy-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid)(01-15)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和3-氨基-2-甲氧基苯甲酸制备题述化合物;25.0mmol规模从EtOH中产生了4.0g灰色微晶体(mp=220–223℃,61%产量)。1H NMR(D6-DMSO)δ1.53(s,3H),2.16-2.19(m,2H),2.44(s,2H),3.72(s,3H),7.19(t,J=7.8Hz,1H),7.42(d,J=7.8Hz,1H),7.54(d,J=7.7Hz,1H),8.72(s,1H),13.03(s,1H)。13C NMR(D6-DMSO)δ7.2,25.3,32.7,61.3,109.1,123.7,127.1,127.7,130.6,133.7,153.6,167.0,170.3,202.0。LCMS t=1.2min,m/z计算值C14H16NO4;C14H15NNaO4;C28H30N2NaO8 262.11;284.09;545.19[M+H]+;[M+Na]+;[2M+Na]+,实验值262.21;284.18;545.27。
实施例01-16
2-甲基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酸(2-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid)(01-16)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和4-氨基-2-甲基苯甲酸制备题述化合物;25.0mmol规模从EtOH中产生了3.0g黑色针状物(mp=213–216℃,49%产量)。1H NMR(D6-DMSO)δ1.59(s,3H),2.23-2.25(m,2H),2.52(s,3H),2.78(s,2H),7.11-7.13(m,2H),7.83(d,J=8.2Hz,1H),9.07(s,1H),12.58(s,1H)。13C NMR(D6-DMSO)δ7.5,21.7,26.2,33.0,111.8,118.1,123.7,124.4,131.9,141.0,143.2,168.0,168.3,202.4。LCMS t=5.1min,m/z计算值C14H16NO3;C14H15NNaO3;C26H30N2NaO6 246.11;268.10;513.20[M+H]+;[M+Na]+;[2M+Na]+,实验值246.22;268.19;513.27。
实施例01-17
2,5-二氯-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酸(2,5-dichloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid)(01-17)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和4-氨基-2,5-二氯苯甲酸制备题述化合物;20.0mmol规模从EtOH中产生了5.0g黄色针状物(mp=229–232℃,82%产量)。1H NMR(D6-DMSO)δ1.45(s,3H),2.21(s,2H),2.45(s,2H),7.64-7.66(m,2H),8.97(s,1H),13.85(s,1H)。13C NMR(D6-DMSO)δ7.5,25.5,32.7,110.4,126.6,129.4,131.5,134.9,139.1,165.7,168.9,202.8。LCMS t=5.1min,m/z计算值C13H12Cl2NO3;C26H22Cl4N2NaO6 300.02;623.01[M+H]+;[2M+Na]+,实验值300.10;623.09。
实施例01-18
2-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(2-((2-methyl-3-oxocyclopent-l-en-1-yl)amino)benzamide)(01-18)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和邻氨基苯甲酰胺制备题述化合物;20.0mmol规模从EtOH中产生了3.0g黄色微晶体(mp=235–238℃,65%产量)。1H NMR(D6-DMSO)δ1.59(s,3H),2.26-2.29(m,2H),2.91(s,2H),7.07-7.11(m,1H),7.47-7.49(m,2H),7.75(s,1H),7.78(d,J=7.9Hz,1H)8.25(s,1H),11.14(s,1H)。13C NMR(D6-DMSO)δ6.6,26.3,33.3,112.2,119.8,121.3,121.8,129.2,132.3,140.9,168.4,170.9,201.6。LCMS t=4.3min,m/z计算值C13H15N2O2;C13H14N2NaO2;C26H29N4O4;C26H28N4NaO4 231.11;253.10;461.22;483.20[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值231.11;253.10;461.22;483.20。
实施例01-19
甲基2-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酸酯(methy12-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoate)(01-19)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和邻氨基苯甲酸甲酯制备题述化合物;20.0mmol规模从EtOAc产生4.0g产物(82%产量)。1H NMR(D6-DMSO)δ1.62(s,3H),2.29-2.31(m,2H),2.88(s,2H),3.87(s,3H),7.17(t,J=7.5Hz,1H),7.53(d,J=8.3Hz,1H),7.61(t,J=7.6Hz,1H),7.97(d,J=7.9Hz,1H)10.11(s,1H)。13C NMR(D6-DMSO)δ6.7,26.3,33.2,52.5,112.7,117.9,120.9,122.6,131.3,134.3,141.6,167.7,168.3,201.8。LCMS t=5.3min,m/z计算值C14H16NO3;C14H15NNaO3;C28H31N2O6;C28H30N2NaO6 246.11;268.10;491.22;513.20[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值246.11;268.09;491.22;513.20。
实施例01-20
甲基5-氯-2-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯酸酯(methyl5-chloro-2-((2-methyl-3-oxocyclopent-l-en-1-yl)amino)benzoate)(01-20)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和甲基5-氯代邻氨基苯甲酸酯(methy15-chloroanthranilate)制备题述化合物;5.0mmol规模从EtOAc产生了1.0g黄色微晶体(mp=162–165℃,82%产量)。1H NMR(D6-DMSO)δ1.60(s,3H),2.29-2.31(m,2H),2.86(s,2H),3.88(s,3H),7.54(d,J=8.9Hz,1H),7.65(dd,J=8.9,2.3Hz,1H),7.92(d,J=2.3Hz,1H),9.96(s,1H)。13C NMR(D6-DMSO)δ6.8,26.2,33.2,52.8,113.2,119.6,122.9,126.2,130.4,133.8,140.5,166.6,167.7,202.1。LCMS t=5.7min,m/z计算值C14H15ClNO3;C14H14ClNNaO3;C28H28Cl2N2NaO6 280.07;302.06;581.12[M+H]+;[M+Na]+;[2M+Na]+,实验值280.07;302.05;581.12。
实施例01-21
3-氟-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯酸酯(methyl3-fluoro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoate)(01-21)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和甲基4-氨基-3-氟苯甲酸酯制备题述化合物;20.0mmol规模从EtOAc中产生了4.5g米黄色微晶体(mp=198–201℃,85%产量)。1H NMR(D6-DMSO)δ1.51(s,3H),2.24-2.26(m,2H),2.57(s,2H),3.86(s,3H),7.40-7.44(m,1H),7.77-7.79(m,2H),9.09(s,1H)。LCMS t=5.0min,m/z计算值C14H15FNO3;C14H14FNNaO3;C28H29F2N2O6;C28H28F2N2NaO6 264.10;286.09;527.20;549.18[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值264.10;286.08;527.20;549.18。
实施例01-22
甲基3-溴-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯酸酯(methyl3-bromo-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoate)(01-22)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和甲基4-氨基-3-溴苯酸酯制备题述化合物;20.0mmol规模从EtOAc中产生了4.0g白色微晶体(mp=155–158℃,62%产量)。1H NMR(D6-DMSO)δ1.43(s,3H),2.23-2.25(m,2H),2.50-2.53(m,2H),3.86(s,3H),7.44(d,J=8.3Hz,1H),7.94-7.95(m,1H),8.17(d,J=1.4Hz,1H),8.91(s,1H)。13C NMR(D6-DMSO)δ7.8,25.9,32.7,52.4,111.4,119.1,126.9,127.6,129.1,133.5,142.5,164.6,168.2,203.0。LCMS t=5.2min,m/z计算值C14H15BrNO3;C14H14BrNNaO3;C28H29Br2N2O6;C28H28Br2N2NaO6 324.02,326.02;346.01,348.00;649.04;671.02[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值324.02,326.02,346.00,348.00;649.04;671.02。
实施例01-23
2-氯-6-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酸(2-chloro-6-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid)(01-23)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和6-氯邻胺苯甲酸(6-chloroanthranilic acid)制备题述化合物;20.0mmol规模从EtOH中产生了3.0g白色微晶体(mp=277–280℃,56%产量)。1H NMR(D6-DMSO)δ1.44(s,3H),2.14-2.16(m,2H),2.36-2.38(m,2H),7.31(dd,J=6.5,2.1Hz,1H),7.45-7.48(m,2H),8.95(s,1H)。13C NMR(D6-DMSO)δ7.1,25.3,32.6,109.1,127.0,127.4,129.6,130.7,132.9,137.6,166.3,170.3,202.2。LCMS t=4.5min,m/z计算值C13H13ClNO3;C26H25Cl2N2O6 266.06;531.11[M+H]+;[2M+H]+,实验值266.06;531.11。
实施例01-24
甲基4-氯-2-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯酸酯(methyl4-chloro-2-((2-methyl-3-oxocyclopent-l-en-1-yl)amino)benzoate)(01-24)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和甲基4-氯邻氨基苯酸酯(methy14-chloroanthranilate)制备题述化合物;20.0mmol规模从EtOAc中产生了4.6g黄色片状物(mp=167–170℃,82%产量)。1H NMR(CDCl3)δ1.82(s,3H),2.53-2.55(m,2H),3.02-3.03(m,2H),3.95(s,3H),6.98(dd,J=8.6,1.7Hz,1H),7.37(d,J=1.6Hz,1H),8.00(d,J=8.6Hz,1H),10.67(s,1H)。13C NMR(CDCl3)δ7.2,27.8,33.9,52.8,113.9,117.2,117.9,121.4,133.4,140.7,144.3,166.8,168.3,204.0。LCMS t=5.7min,m/z计算值C14H15ClNO3;C14H14ClNNaO3;C28H29Cl2N2O6;C28H28Cl2N2NaO6280.07;302.06;559.14;581.12[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值280.07;302.05;559.14;581.12。
实施例01-25
4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酸(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid)(01-25)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和3-氨基-4-氯苯甲酸制备题述化合物;20.0mmol规模从EtOH中产生了5.0g白色微晶体(mp=272–275℃,94%产量)。1H NMR(D6-DMSO)δ1.42(s,3H),2.20-2.22(m,2H),2.41-2.43(m,2H),7.69(d,J=7.9Hz,1H),7.79-7.81(m,2H),8.97(s,1H),13.31(s,1H)。13C NMR(D6-DMSO)δ7.5,25.7,32.6,109.7,127.8,128.7,130.2,134.5,136.9,166.1,169.2,202.6。LCMS t=4.3min,m/z计算值C13H13ClNO3;C26H25Cl2N2O6266.06;531.11[M+H]+;[2M+H]+,实验值266.06;531.07。
实施例01-26
2-甲基-3-(萘-1-基氨基)-环戊基-2-烯酮(2-methyl-3-(naphthalen-1-ylamino)cyclopent-2-enone)(01-26)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和1-萘胺制备题述化合物;12.5mmol规模从EtOAc中产生了1.0g棕褐色针状物(mp=166–168℃,34%产量)。1H NMR(D6-DMSO)δ1.51(s,3H),2.15-2.16(m,2H),2.38(s,2H),7.42(d,J=7.1Hz,1H),7.52-7.61(m,3H),7.87(d,J=8.1Hz,1H),8.00(t,J=8.6Hz,2H),9.26(s,1H)。LCMS t=5.4min,m/z计算值C16H16NO;C16H15NNaO;C32H31N2O2;C32H30N2NaO2238.12;260.11;475.24;497.22[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值238.14;260.12;475.26;497.24。
实施例01-27
2-甲基-3-(萘-2-基氨基)环戊基-2-烯酮(2-methyl-3-(naphthalen-2-ylamino)cyclopent-2-enone)(01-27)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和2-萘胺制备题述化合物;6.0mmol规模从EtOAc中产生了0.2g黄色针状物(mp=248–250℃,14%产量)。1H NMR(D6-DMSO)δ1.62(s,3H),2.23-2.25(m,2H),2.77-2.78(m,2H),7.42-7.51(m,3H),7.71(s,1H),7.85-7.90(m,3H),9.16(s,1H)。LCMS t=5.5min,m/z计算值C16H16NO;C16H15NNaO;C32H31N2O2;C32H30N2NaO2 238.12;260.11;475.24;497.22[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值238.13;260.12;475.26;497.24。
实施例01-28
2-甲基-3-(吡啶-2-基氨基)环戊基-2-烯酮(01-28)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮(2-methyl-1,3-cyclopentandione)和2-氨基吡啶(2-aminopyridine)制备题述化合物;30.0mmol规模从EtOAc中产生了0.6g黄色片状物(mp=163–165℃,11%产量)。1H NMR(D6-DMSO)δ1.66(s,3H),2.23(s,2H),3.18(s,2H),6.96(d,J=5.0Hz,1H),7.18(d,J=8.0Hz,1H),7.69-7.71(m,1H),8.23(s,1H),9.32(s,1H)。LCMSt=4.4min,m/z计算值C11H13N2O;C11H12N2NaO;C22H25N4O2;C22H24N4NaO2189.10;211.08;377.20;399.18[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值189.11;211.09;377.21;399.20。
实施例01-29
2-甲基-3-(吡啶-3-基氨基)环戊基-2-烯酮(01-29)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和3-氨基吡啶制备题述化合物;30.0mmol规模从EtOAc中产生了1.6g灰色微针状体(mp=133–135℃,28%产量)。1H NMR(D6-DMSO)δ1.59(s,3H),2.22(s,2H),2.66(s,2H),7.38(dd,J=7.7,4.7Hz,1H),7.67(d,J=7.8Hz,1H),8.32(d,J=3.6Hz,1H),8.51(s,1H),9.07(s,1H)。LCMS t=1.4min,m/z计算用于C11H13N2O;C11H12N2NaO;C22H25N4O2;C22H24N4NaO2 189.10;211.08;377.20;399.18[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值189.11;211.09;377.22;399.20。
实施例01-30
2-甲基-3-(吡啶-4-基氨基)环戊基-2-烯酮(01-30)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和4-氨基吡啶制备题述化合物;20.0mmol规模72h从EtOAc中产生了0.02g黄色微晶体(mp=203–205℃,1%产量)。1H NMR(D6-DMSO)δ1.63(s,3H),2.28-2.29(m,2H),2.90(s,2H),7.20(d,J=4.9Hz,2H),8.38(s,2H),9.15(s,1H)。LCMS t=1.4min,m/z计算值C11H13N2O 189.10[M+H]+,实验值189.12。
实施例01-31
4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(吡啶-2-基)苯磺酰胺(01-31)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和4-氨基-N-(2-吡啶基)苯磺酰胺(4-amino-N-(2-pyridinyl)benzenesulfonamide)制备题述化合物;10.0mmol规模从H2O中产生了2.0g黄色微晶体(mp=230–233℃,58%产量)。1H NMR(D6-DMSO)δ1.58(s,3H),2.23-2.25(m,2H),2.77(s,2H),6.88(t,J=5.5Hz,1H),7.15(d,J=8.5Hz,1H),7.34(d,J=8.5Hz,2H),7.72(t,J=7.8Hz,1H),7.80(d,J=8.4Hz,1H),9.18(s,1H)。LCMS t=4.9min,m/z计算值C17H18N3O3S;C17H17N3NaO3S;C34H34N6NaO6S2 344.11;366.09;709.19[M+H]+;[M+Na]+;[2M+Na]+,实验值344.11;366.08;709.16。
实施例01-32
叔丁基4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)哌啶-1-羧酸叔丁酯(01-32)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和叔丁基-4-氨基哌啶-1-羧酸制备题述化合物;5.0mmol规模从H2O中产生了0.6g灰色微晶体(mp=189–191℃,41%产量)。1H NMR(D6-DMSO)δ1.40-1.46(m,14H),1.76(d,J=11.6Hz,2H),2.10-2.11(m,2H),2.51(d,J=5.8Hz,2H),2.73(s,2H),2.65-2.90(m,2H),3.52(s,1H),3.94(s,2H),6.88(d,J=8.3Hz,1H)。LCMS t=5.6min,m/z计算值C16H27N2O3;C16H26N2NaO3;C32H52N4NaO6 295.20;317.18;611.38[M+H]+;[M+Na]+;[2M+Na]+,实验值295.26;317.20;611.35。
实施例01-33
反式-(1R,4R)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)环己烷羧酸(01-33)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和反式-(1R,4R)-4-氨基环己烷羧酸制备题述化合物;25.0mmol规模从H2O中产生了4.0g白色微针状体(mp=236–238℃,67%产量)。1H NMR(D6-DMSO)δ1.35-1.45(m,7H),1.84(d,J=9.3Hz,2H),1.87-1.93(m,1H),2.10(s,2H),2.50(s,2H),3.34(br s,2H),6.88(d,J=7.6Hz,1H),12.1(s,1H)。LCMS t=4.7min,m/z计算值C13H20NO3;C13H19NNaO3;C26H39N2O6;C26H38N2NaO6 238.14;260.13;475.28;497.26[M+H]+;[M+Na]+;[2M+H]2+;[2M+Na]+,实验值238.21;260.18;475.26;497.24。
实施例01-34
顺式-(1S,4S)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)环己烷羧酸(01-34)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和顺式-(1S,4S)-4-氨基环己烷羧酸制备题述化合物;25.0mmol规模从H2O中产生2.6g棕褐色微针状体(mp=233–235℃,44%产量)。1H NMR(D6-DMSO)δ1.46-1.52(m,7H),1.66(d,J=8.8Hz,2H),2.03-2.11(m,3H),2.51(s,2H),3.38(br s,2H),6.94(d,J=7.6Hz,1H),12.25(s,1H)。LCMS t=4.9min,m/z计算值C13H20NO3;C13H19NNaO3;C26H39N2O6;C26H38N2NaO6 238.14;260.13;475.28;497.26[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值238.21;260.18;475.26;497.24。
实施例01-35
4-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯甲酰胺(01-35)的制备:按照实施例01-01的方法,由2-甲基-1,3-环己二酮和4-氨基苯甲酰胺制备题述化合物;12.5mmol规模从CH2Cl2/己烷中产生了1.0g棕褐色微片状体(mp=221–223℃,33%产量)。1H NMR(D6-DMSO)δ1.66(s,3H),1.81(t,J=5.7Hz,2H),2.24(t,J=5.8Hz,2H),2.53(s,2H),7.11(d,J=8.1Hz,2H),7.28(s,1H),7.83(d,J=8.1Hz,2H),7.89(s,1H),8.36(s,1H)。LCMS t=3.9min,m/z计算值C14H17N2O2;C14H16N2NaO2;C28H32N4NaO4245.13;267.11;511.23[M+H]+;[M+Na]+;[2M+Na]+,实验值245.15;267.12;511.26。
实施例01-36
4-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯甲酸(01-36)的制备:按照实施例01-01的方法,由2-甲基-1,3-环己二酮和3-氨基-4-氯苯甲酸制备题述化合物;20.0mmol规模从EtOH中产生了5.0g棕褐色微晶体(mp=232–235℃,89%产量)。1H NMR(D6-DMSO)δ1.61(s,3H),1.76-1.80(m,2H),2.21(t,J=6.2Hz,2H),2.26(t,J=5.6Hz,2H),7.66(dd,J=8.3,1.0Hz,1H),7.12(s,1H),7.77(d,J=8.3Hz,1H),8.09(s,1H),13.29(br s,1H)。13C NMR(D6-DMSO)δ9.2,21.0,27.2,36.3,107.9,127.4,128.8,130.1,130.3,134.8,137.5,158.2,166.2,194.9。LCMS t=4.7min,m/z计算值C14H15ClNO3;C28H28Cl2N2NaO6280.07;581.12[M+H]+;[2M+Na]+,实验值280.06;581.11。
实施例01-37
2-(3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)乙酸(01-37)的制备:按照实施例01-01的方法,由2-甲基-1,3-环己二酮(2-methyl-1,3-cyclohexandione)和3-氨基苯乙酸制备题述化合物;2.5mmol规模从EtOH中产生了0.25g橙色微晶体(mp=203–207℃,39%产量)。1HNMR(D6-DMSO)δ1.67(s,3H),2.20(t,J=6.4Hz,2H),2.43(t,J=5.6Hz,2H),3.56(s,2H),6.99-7.02(m,3H),7.27(t,J=7.9Hz,1H),8.18(s,1H),12.38(br s,1H)。13CNMR(D6-DMSO)δ9.6,22.2,27.8,36.9,41.01,107.5,123.00,125.6,125.7,129.0,136.2,140.2,158.6,173.0,194.8。LCMS t=4.4min,m/z计算值C15H18NO3;C15H17NNaO3;C30H34N2NaO6260.13;282.11;541.23[M+H]+;[M+Na]+;[2M+Na]+,实验值260.11;282.09;541.19。
实施例01-38
2-(4-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)乙酸(01-38)的制备:按照实施例01-01的方法,由2-甲基-1,3-环己二酮和4-氨基苯基乙酸制备题述化合物;20.0mmol规模从EtOH中产生了3.6g棕色片状体(mp=215–219℃,69%产量)。1H NMR(D6-DMSO)δ1.68(s,3H),1.75-1.78(m,2H),2.19(t,J=6.4Hz,2H),2.42(t,J=5.7Hz,2H),3.55(s,2H),7.06(d,J=8.3Hz,2H),7.22(d,J=8.3Hz,2H),8.16(s,1H),12.31(brs,1H)。13CNMR(D6-DMSO)δ9.5,22.1,27.7,36.8,40.5,107.0,124.9,130.2,131.4,138.8,158.9,173.2,194.6。LCMS t=4.3min,m/z计算值C15H18NO3;C15H17NNaO3;C30H34N2NaO6 260.13;282.11;541.23[M+H]+;[M+Na]+;[2M+Na]+,实验值260.11;282.09;541.19。
实施例01-39
3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)-4-(三氟甲基)苯甲酸(01-39)的制备:按照实施例01-01的方法,由2-甲基-1,3-环己二酮和3-氨基-4-(三氟甲基)苯甲酸制备题述化合物;2.5mmol规模从EtOH/EtOAc中产生了0.5g棕褐色微晶体(mp=209–212℃,64%产量)。1H NMR(D6-DMSO)δ1.62(s,3H),1.73-1.76(m,2H),2.20-2.25(m,4H),7.11(d,J=7.7Hz,1H),7.47(d,J=7.8Hz,1H),7.81(s,1H),8.26(s,1H)。LCMS t=4.6min,m/z计算值C15H15F3NO3;C30H28F6N2NaO6 314.10;649.17[M+H]+;[2M+Na]+,实验值314.09;649.12。
实施例01-40
4-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)-4-(三氟甲基)苯甲酸(01-40)的制备:按照实施例01-01的方法,由2-甲基-1,3-环己二酮和4-氨基-3-(三氟甲基)苯甲酸制备题述化合物;20.0mmol规模从EtOH中产生了2.5g棕褐色微针状体(mp=229–231℃,40%产量)。1H NMR(D6-DMSO)δ1.53(s,3H),1.78-1.81(m,2H),2.24(t,J=6.2Hz,2H),2.36-2.40(m,2H),7.36(d,J=8.3Hz,1H),7.88(s,1H),8.16(d,J=8.5Hz,1H),8.18(s,1H),13.36(brs,1H)。13C NMR(D6-DMSO)δ10.1,21.3,28.4,36.9,111.5,123.7(JCF=28.6Hz),123.8(JCF=274.0Hz),127.5,128.0,128.6,134.3,143.3,157.6,166.2,196.1。LCMS t=4.7min,m/z计算值C15H15F3NO3;C15H14F3NNaO3;C30H28F6N2NaO6 314.10;336.08;649.17[M+H]+;[M+Na]+;[2M+Na]+,实验值314.08;336.06;649.13。
实施例01-41
6-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)-2-萘甲酸(6-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)-2-naphthoic acid)(01-41)的制备:按照实施例01-01的方法,由2-甲基-1,3-环己二酮和6-氨基-2-萘甲酸制备题述化合物;20.0mmol规模从EtOH中产生了2.7g棕色微晶体(mp=259–263℃,46%产量)。1H NMR(D6-DMSO)δ1.73(s,3H),1.83-1.86(m,2H),2.27-2.30(m,2H),2.61-2.63(m,2H),7.42(d,J=8.7Hz,1H),7.56(s,1H),7.90(d,J=8.6Hz,1H),7.95(d,J=8.5Hz,1H),8.06(d,J=8.8Hz,1H),8.52(s,1H),8.55(s,1H),12.97(br s,1H)。13C NMR(D6-DMSO)δ10.1,22.2,28.2,37.0,109.9,118.7,124.6,126.2,127.0,127.7,129.1,130.4,130.7,136.0,140.5,157.7,167.9,195.5。LCMSt=4.7min,m/z计算值C18H18NO3;C36H35N2O6;C36H34N2NaO6 296.13;591.25;613.23[M+H]+;[2M+H]+;[2M+Na]+,实验值296.15;591.27;613.25。
实施例01-42
N-(4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-乙酰胺(01-42)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和N-(3-氨基-4-氯苯基)乙酰胺(N-(3-amino-4-chloropheny)lacetamide)制备题述化合物;20.0mmol规模产生了5.5g(99%产量)棕褐色微晶体,一部分从EtOH:EtOAc(1:1.1)中再结晶(mp=265–268℃,50%回收率)。1H NMR(D6-DMSO)δ1.44(s,3H),2.05(s,3H),2.18-2.21(m,2H),2.40-2.41(m,2H),7.41(dd,J=8.7,2.3Hz,1H),7.45(d,J=8.8Hz,1H),7.67(d,J=2.2Hz,1H),8.86(s,1H),10.13(s,1H)。13C NMR(D6-DMSO)δ7.4,24.1,25.6,32.6,109.3,117.8,118.4,123.3,129.7,136.6,138.7,168.7,169.5,202.4。LCMS t=4.3min,m/z计算值C14H16ClN2O2;C14H15ClN2NaO2;C28H31Cl2N4O4;C28H30Cl2N4NaO4 279.09;301.07;557.17;579.15[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值279.11;301.09;557.13;579.11。
实施例01-43
甲基-3-碘-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯酸酯(01-43)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和甲基3-碘-4-氨基苯酸酯制备题述化合物;10mmol规模从EtOAc中产生了1.7g白色棱柱状物(mp=178–180℃,46%产量)。1H NMR(D6-DMSO)δ1.43(s,3H),2.21-2.23(m,2H),2.44-2.47(m,2H),3.86(s,3H),7.41(d,J=8.3Hz,1H),7.96(dd,J=8.3,1.8Hz,1H),8.40(d,J=1.8Hz,1H),8.86(s,1H)。13C NMR(D6-DMSO)δ7.7,25.9,32.7,52.4,97.7,110.5,126.7,128.1,129.8,139.6,145.7,164.5,168.5,202.6。LCMS t=4.6min,m/z计算值C14H15INO3;C14H14INNaO3;C28H28I2N2NaO6 372.01;393.99;764.99[M+H]+;[M+Na]+;[2M+Na]+,实验值372.04;393.96;764.95。
实施例01-44
2-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酸(01-44)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和3-氨基-2-氯苯甲酸制备题述化合物;2.5mmol规模从EtOH中产生了415mg白色微针体(mp=230–232℃,62%产量)。1H NMR(D6-DMSO)δ1.46(s,3H),2.18-2.02(m,2H),2.37-2.40(m,2H),7.44(t,J=7.8Hz,1H),7.54(dd,J=7.9,1.6Hz,1H),7.62(dd,J=7.7,1.6Hz,1H),8.93(s,1H),13.53(br s,1H)。13C NMR(D6-DMSO)δ7.3,25.4,32.6,109.4,127.4,127.7,128.3,130.8,133.5,137.7,166.9,169.7,202.3。LCMS t=1.8min,m/z计算值C13H13ClNO3;C13H12ClNNaO3;C26H24Cl2N2NaO6266.06;288.04;553.09[M+H]+;[M+Na]+;[2M+Na]+,实验值266.09;288.06;553.03。
实施例01-45
3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯磺酰胺(01-45)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和3-氨基苯磺酰胺制备题述化合物;5.0mmol规模从H2O中产生了600mg浅棕色微晶体(mp=223–225℃,45%产量)。1H NMR(D6-DMSO)δ1.58(s,3H),2.22-2.27(m,2H),2.68-2.75(m,2H),7.40-7.47(m,3H),7.53(d,J=5.2Hz,2H),7.65(s,1H),9.22(s,1H)。13C NMR(D6-DMSO)δ7.5,25.8,32.9,111.1,119.0,120.4,125.0,129.8,140.5,144.9,168.6,202.3。LCMS t=2.6min,m/z计算值C12H15N2O3S;C12H14N2NaO3S;C24H29N4O6S2;C24H28N4NaO6S2267.083;289.062;533.152;555.135[M+H]+;[2M+H]+;[2M+H]+;[2M+Na]+,实验值267.083;289.061;533.151;555.133。
实施例01-46
4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯磺酰胺(01-46)的制备:按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和3-氨基-4-氯苯磺酰胺制备题述化合物;5.0mmol规模从H2O中产生了800mg浅棕色微晶体(mp=223–225℃,53%产量)。1H NMR(D6-DMSO)δ1.42(s,3H),2.20-2.28(m,2H),2.45-2.49(m,2H),7.55(s,2H),7.66(dd,J=8.2,2.1Hz,1H),7.68(d,J=1.8Hz,1H),7.77(d,J=8.2Hz,1H),9.07(s,1H)。13C NMR(D6-DMSO)δ7.8,25.8,32.7,110.4,123.9,124.8,130.5,132.8,137.2,143.4,168.8,202.9。LCMS t=3.4min,m/z计算值C12H15ClN2O3S;C12H14ClN2NaO3S;C24H29Cl2N4O6S2;C24H28Cl2N4NaO6S2301.041;323.023;601.075;623.057[M+H]+;[2M+H]+;[2M+H]+;[2M+Na]+,实验值301.040;323.021;601.071;623.056。
实施例01-47
N-(4-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-乙酰胺(01-47)的制备:按照实施例01-01的方法,由2-甲基-1,3-环己二酮和N-(4-氨基-3-氯苯基)乙酰胺(N-(4-amino-3-chloropheny)lacetamide)制备题述化合物;10.0mmol规模从EtOAc中产生了2.9g淡橙色微晶体(mp=234–236℃,99%产量)。1H NMR(D6-DMSO)δ1.64(s,3H),1.75-1.79(m,2H),2.05(s,3H),2.18-2.24(m,4H),7.42-7.46(m,2H),7.58(d,J=1.9Hz,1H),8.04(s,1H),10.12(s,1H)。13C NMR(D6-DMSO)δ9.0,21.1,24.0,27.0,36.3,107.1,117.7,118.8,123.9,129.7,137.1,138.8,158.8,168.6,194.4。LCMS t=4.5min,m/z计算值C15H18ClN2O2;C15H17ClN2NaO2;C30H35Cl2N4O4;C30H34Cl2N2NaO4 293.11;315.09;585.20;607.19[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值293.13;315.10,585.16;607.15。
实施例01-48
4-溴-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯甲酸(benzoic acid)(01-48)的制备:按照实施例01-01的方法,由2-甲基-1,3-环己二酮和3-氨基-4-溴苯甲酸制备题述化合物;10.0mmol规模从EtOH中产生了2.9g白色微针体(mp=265–267℃,89%产量)。1H NMR(D6-DMSO)δ1.62(s,3H),1.75-1.80(m,2H),2.18-2.23(m,4H),7.69-7.72(m,2H),7.84(d,J=8.1Hz,1H),8.07(s,1H),13.31(s,1H)。13C NMR(D6-DMSO)δ9.2,21.1,27.2,36.4,107.5,126.9,127.9,129.2,131.0,133.3,139.1,158.1,166.3,194.8。LCMS t=4.2min,m/z计算值C14H15BrNO3;C14H14BrNNaO3;C28H28Br2N2NaO6 324.02,326.02;346.01,348.00;671.02[M+H]+;[M+Na]+;[2M+Na]+,实验值324.03,326.02;345.99,347.99;670.96。
实施例01-# | 题述化合物名称 | X | Y |
49 | 3-[(3-氯吡啶-2-基)氨基]-2-甲基环己基-2-烯-1-酮 | N | CH |
50 | 3-[(3-氯吡嗪-2-基)氨基]-2-甲基环己基-2-烯-1-酮 | N | N |
实施例01-49
3-[(3-氯吡啶-2-基)氨基]-2-甲基环己基-2-烯-1-酮(01-49)的制备:按照实施例01-01的方法由2-甲基-1,3-环己二酮和3-氯吡啶-2-胺制备题述化合物(mp=113–115℃)。1H NMR(D6-DMSO)δ1.63(s,3H),1.84(quin,J=6.4Hz,2H),2.28(t,J=6.1Hz,2H),2.67-2.80(m,2H),7.07(dd,J=8.5,4.9Hz,1H),7.91(s,1H),7.93(d,J=6.1Hz,1H),8.25(d,J=4.9Hz,1H)。13C NMR(D6-DMSO)δppm 9.4,21.3,28.1,36.7,113.6,119.2,120.8,138.2,146.3,149.7,155.6,196.2。LCMS t=4.3min,m/z计算值C12H14ClN2O;C12H13ClN2NaO;C24H26Cl2N4NaO2 237.080;259.061;495.133[M+H]+;[M+Na]+;[2M+Na]+,实验值237.080;259.060;495.131。
实施例01-50
3-[(3-氯吡嗪-2-基)氨基]-2-甲基环己基-2-烯-1-酮(01-50)的制备:按照实施例01-01的方法由2-甲基-1,3-环己二酮和3-氯吡嗪-2-胺制备题述化合物(mp=116–118℃)。1H NMR(D6-DMSO)δ1.60(s,3H),1.87(quin,J=6.1Hz,2H),2.32(t,J=6.1Hz,2H),2.71-2.76(m,2H),8.00(d,J=2.4Hz,1H),8.18(s,1H),8.28(d,J=2.4Hz,1H)。13C NMR(D6-DMSO)δ10.6,21.6,28.8,37.2,118.6,135.9,137.9,141.3,147.8,154.3,197.5。LCMSt=4.1min,m/z计算值C11H13ClN3O;C11H12ClN3NaO;C22H24Cl2N6NaO2238.075;260.060;497.120[M+H]+;[M+Na]+;[2M+Na]+,实验值238.075;260.056;497.122。
实施例01-51
3-[(3-氯吡啶-4-基)氨基]-2-甲基环己基-2-烯-1-酮(01-51)的制备:3-氨基-2-甲基环己基-2-烯酮(500mg,4mmol)、4-溴-3-氯吡啶(950mg,5mmol)、乙酸钯(90mg,0.4mmol)、BINAP(197mg,0.8mmol)、碳酸铯(2.6g,8mmol)和甲苯(10mL)在密封的烧瓶中进行化合并且在100℃下加热18h。在室温下,将混合物进行过滤,并且将滤液用EtOAc(30mL)稀释,用盐水(brine)(3×10mL)进行清洗,使用Na2SO4进行干燥。粗制品经HPLC纯化,以产生题述化合物(140mg,15%产量,白色微晶体,mp=135–138℃)。1H NMR(D6-DMSO)δ1.46(s,3H),1.83-1.88(m,2H),2.31(t,J=6.7Hz,2H),2.53-2.57(m,2H),6.84(d,J=6.1Hz,1H),8.06(s,1H),8.29(d,J=6.1Hz,1H),8.48(s,1H)。13C NMR(D6-DMSO)δ10.9,20.6,28.7,36.7,115.7,117.1,121.2,144.7,148.3,148.3,149.2,154.4,197.0。LCMS t=1.9min,m/z计算值C12H14ClN2O;C12H13ClN2NaO 237.080;259.061[M+H]+;[2M+H]+,实验值237.080;259.180。
实施例01-52
3-[(2-甲基-3-氧代环己基-1-烯-1-基)氨基]萘-1-羧酸(01-52)的制备:按照实施例01-01的方法,由2-甲基-1,3-环己二酮和3-氨基-1-萘甲酸制备题述化合物,4.0mmol规模回流48h产生了1.2g从甲苯中过滤出的粗制品(97%产量),经丙酮滴定后获得棕色微晶体(mp=270–272℃)。1H NMR(D6-DMSO)δ1.71(s,3H),1.81-1.85(m,2H),2.25-2.28(m,2H),2.57-2.50(m,2H),7.52-7.57(m,2H),7.76(d,J=1.9Hz,1H),7.92-7.95(m,1H),7.98(d,J=2.0Hz,1H),8.48(s,1H),8.77-8.79(m,1H),13.23(br s,1H)。13C NMR(D6-DMSO)δ9.5,21.8,27.6,36.6,108.6,110.6,124.1,125.4,126.3,126.7,127.5,128.0,128.4,134.1,136.7,157.4,169.2,194.9。LCMS t=4.3min,计算值C18H18NO3;C18H17NNaO3;C36H34N2NaO6 296.13;318.11;613.23[M+H]+;[M+Na]+;[2M+Na]+,实验值296.15;318.11;613.17。
3-氨基-1-萘甲酸:mp=179–181℃。1H NMR(D6-DMSO)δ5.57(br s,2H),7.02(d,J=2.1Hz,1H),7.18-7.22(m,1H),7.31-7.35(m,1H),7.59(d,J=8.1Hz,1H),7.63(d,J=2.4Hz,1H),8.57(d,J=8.5Hz,1H),12.91(br s,1H)。13C NMR(D6-DMSO)δ110.6,122.0,122.4,124.0,125.4,125.9,126.0,128.4,135.6,145.5,168.8。LCMS t=3.1min,计算值C11H10NO2;C11H9NNaO2 188.07;210.05[M+H]+;[M+Na]+,实验值188.16;210.13。
实施例01-53
5-氯-6-[(2-甲基-3-氧代环己基-1-烯-1-基)氨基]萘-2-羧酸(01-53)的制备:按照实施例01-01的方法,由2-甲基-1,3-环己二酮和6-氨基-5-氯-2-萘甲酸制备题述化合物;0.54mmol规模回流48h从EtOH中重结晶后产生了17mg灰色微针体(mp=272–275℃分解,10%产量)。1H NMR(D6-DMSO)δ1.63(s,3H),1.78-1.83(m,2H),2.23-2.26(m,2H),2.37-2.40(m,2H),7.49(d,J=8.8Hz,1H),8.12-8.15(m,2H),8.24-8.27(m,2H),8.66(d,J=1.5Hz,1H),13.21(s,1H)。13C NMR(D6-DMSO)δ9.6,21.1,27.8,36.6,109.4,124.0,124.1,126.4,127.3,128.1,128.9,130.7,130.9,132.7,137.7,157.6,167.0,195.3。LCMS t=4.8min,m/z计算值C18H17ClNO3;C18H16ClNNaO3;C36H32Cl2N2NaO6 330.09;352.07;681.15[M+H]+;[M+Na]+;[2M+Na]+,实验值330.08;352.06,681.14。
6-氨基-5-氯-2-萘甲酸:将6-氨基-2-萘甲酸(0.17g,0.9mmol)、N-氯代琥珀酰亚胺(0.12g,1eq)和四氯化碳(25mL)在圆底烧瓶中进行化合,并且加热回流1h。冷却至室温后,过滤出固体。随后将原材料直接加入至KP-SilTM柱(10g),使用等度溶剂系统(isocraticsolvent system)CH2Cl2:MeOH(1:19)在-Isolera Four仪器上将产物与杂质分离,于254/365nm下监控紫外线踪迹。0.9mmol规模经色谱分析后产生了120mg白色微晶体(mp=274–276℃分解,60%产量)。1H NMR(D6-DMSO)δ6.14(s,2H),7.19(d,J=8.8Hz,1H),7.85(dd,J=42.2,8.8Hz,1H),7.94(d,J=1.7Hz,1H),7.96(d,J=1.7Hz,1H),8.39(d,J=1.7Hz,1H),12.78(s,1H)。13CNMR(D6-DMSO)107.5,118.9,121.1,123.5,125.8,126.9,129.3,130.9,133.8,145.0,167.5。LCMS t=4.2min,计算值C11H9ClNO2;C11H8ClNNaO2222.03;244.01[M+H]+;[M+Na]+,实验值222.09;244.06。
实施例01-54
2-甲基-3-[(喹啉-6-基)氨基]环己基-2-烯-1-酮(01-54)的制备:按照实施例01-01的方法由2-甲基-1,3-环己二酮和喹啉-6-胺制备题述化合物(棕色微晶体,mp=208–210℃)。1H NMR(D6-DMSO)δ1.71(s,3H),1.77-1.88(m,2H),2.26(t,J=6.7Hz,2H),2.58(t,J=5.5Hz,2H),7.46-7.52(m,1H),7.54-7.62(m,2H),7.96(d,J=9.8Hz,1H),8.28(d,J=7.3Hz,1H),8.48(s,1H),8.80(d,J=6.1Hz,1H)。13C NMR(D6-DMSO)δ9.6,21.8,27.7,36.6,108.7,119.2,121.8,127.2,128.2,129.4,135.2,138.1,144.8,149.2,157.5,194.9。LCMSt=3.6min,m/z计算值C16H17N2O;C16H16N2NaO;C32H32N4NaO2 253.134;275.116;527.242[M+H]+;[M+Na]+;[2M+Na]+,实验值253.131;275.112;527.231。
实施例01-55
3-[(异喹啉-6-基)氨基]-2-甲基环己基-2-烯-1-酮(01-55)的制备:按照实施例01-01的方法由2-甲基-1,3-环己二酮和异喹啉-6-胺制备题述化合物(棕色微晶体,mp=163–165℃)。1H NMR(D6-DMSO)δ1.67(s,3H),1.81-1.89(m,2H),2.29(t,J=6.1Hz,2H),2.63(t,J=6.1Hz,2H),7.40(s,1H),7.45(dd,J=8.5,2.4Hz,1H),7.70(d,J=4.9Hz,1H),8.03(d,J=8.5Hz,1H),8.40(d,J=4.9Hz,1H),8.58(s,1H),9.17(s,1H)。13CNMR(D6-DMSO)δ10.1,21.7,28.1,36.7,111.0,115.2,119.6,124.1,124.6,128.4,136.1,142.1,143.3,156.5,195.6。LCMS t=2.9min,m/z计算值C16H17N2O;C16H16N2NaO 253.134;275.116;[M+H]+;[M+Na]+,实验值253.129;275.112。
实施例01-56
3-[(异喹啉-7-基)氨基]-2-甲基环己基-2-烯-1-酮(01-56)的制备:按照实施例01-01的方法由2-甲基-1,3-环己二酮和异喹啉-7-胺制备题述化合物(黄色微晶体,mp=145–147℃)。1H NMR(D6-DMSO)δ1.70(s,3H),1.84(quin,J=6.1Hz,2H),2.27(t,J=6.1Hz,2H),2.59(t,J=6.1Hz,2H),7.61(dd,J=8.5,2.4Hz,1H),7.69(d,J=2.4Hz,1H),7.80(d,J=6.1Hz,1H),7.94(d,J=8.5Hz,1H),8.42(d,J=6.1Hz,1H),8.54(s,1H),9.25(s,1H)。13CNMR(D6-DMSO)δ9.7,21.7,27.7,36.6,109.2,118.3,120.3,127.2,128.4,128.7,131.9,139.2,141.3,151.2,157.2,195.1。LCMS t=2.8min,m/z计算值C16H17N2O;C16H16N2NaO;C32H32N4NaO2 253.134;275.116;527.242[M+H]+;[M+Na]+;[2M+Na]+,实验值253.128;275.108;527.227。
实施例01-57
2-甲基-3-[(喹啉-7-基)氨基]环己基-2-烯-1-酮(01-57)的制备:按照实施例01-01的方法由2-甲基-1,3-环己二酮和喹啉-7-胺制备题述化合物(黄色微晶体,mp=133–135℃)。1H NMR(D6-DMSO)δ1.70(s,3H),1.84(quin,J=6.1Hz,2H),2.28(t,J=6.7Hz,2H),2.62(t,J=5.5Hz,2H),7.39-7.45(m,2H),7.54(d,J=2.4Hz,1H),7.92(d,J=8.5Hz,1H),8.29(d,J=6.1Hz,1H),8.53(s,1H),8.82-8.85(m,1H)。13C NMR(D6-DMSO)δ9.8,21.8,27.9,36.6,109.7,119.2,120.1,123.8,124.3,128.4,135.6,141.3,148.3,151.0,157.1,195.3。LCMS t=3.4min,m/z计算值C16H17N2O;C16H16N2NaO;C32H32N4NaO2 253.134;275.116;527.242[M+H]+;[M+Na]+;[2M+Na]+,实验值253.127;275.109;527.228。
实施例01-58
3-[(异喹啉-3-基)氨基]-2-甲基环己基-2-烯-1-酮(01-58)的制备:按照实施例01-01的方法由2-甲基-1,3-环己二酮和异喹啉-3-胺制备题述化合物(灰色微针体,mp=205–208℃)。1H NMR(D6-DMSO)δ1.72(s,3H),1.84(quin,J=6.1Hz,2H),2.27(t,J=6.7Hz,2H),2.80(t,J=5.5Hz,2H),7.41(s,1H),7.50(t,J=7.3Hz,1H),7.65-7.73(m,1H),7.84(d,J=8.5Hz,1H),8.04(d,J=8.5Hz,1H),8.20-8.20(m,1H),8.70(s,1H),9.12(s,1H)。13CNMR(D6-DMSO)δ9.5,21.8,28.1,36.7,108.7,110.2,125.0,125.4,125.7,127.7,130.9,137.3,148.9,151.1,157.0,195.4。LCMS t=4.8min,m/z计算值C16H17N2O;C16H16N2NaO;C32H32N4NaO2 253.134;275.116;527.242[M+H]+;[M+Na]+;[2M+Na]+,实验值253.131;275.108;527.227。
实施例01-59
2-甲基-3-[(喹啉-3-基)氨基]环己基-2-烯-1-酮(01-59)的制备:按照实施例01-01的方法由2-甲基-1,3-环己二酮和喹啉-3-胺制备题述化合物(棕褐色微晶体,mp=172–175℃)。1H NMR(D6-DMSO)δ1.73(s,3H),1.83(quin,J=6.1Hz,2H),2.26(t,J=6.1Hz,2H),2.58(t,J=6.1Hz,2H),7.57-7.61(m,1H),7.64-7.69(m,1H),7.92(d,J=7.3Hz,1H),7.95-8.01(m,2H),8.51(s,1H),8.78(d,J=2.4Hz,1H)。13C NMR(D6-DMSO)δ9.4,21.7,27.2,36.5,108.8,126.4,127.1,127.5,127.7,128.1,128.6,133.8,144.2,148.3,157.4,194.9。LCMSt=4.5min,m/z计算值C16H17N2O;C16H16N2NaO;C32H32N4NaO2 253.134;275.116;527.242[M+H]+;[M+Na]+;[2M+Na]+,实验值253.130;275.106;527.227。
实施例01-60
2-甲基-3-[(喹喔啉-6-基)氨基]环己基-2-烯-1-酮(01-60)的制备:按照实施例01-01的方法由2-甲基-1,3-环己二酮和喹啉-6-胺制备题述化合物(黄色微晶体,mp=110–112℃)。1H NMR(D6-DMSO)δ1.69(s,3H),1.83-1.90(m,2H),2.30(t,J=6.7Hz,2H),2.63-2.70(m,2H),7.52(d,J=2.4Hz,1H),7.66(dd,J=8.5,2.4Hz,1H),8.01(d,J=9.8Hz,1H),8.66(s,1H),8.79(d,J=2.4Hz,1H),8.86(s,1H)。13C NMR(D6-DMSO)δ10.1,21.7,28.0,36.7,111.3,117.4,126.8,129.4,138.9,142.0,143.0,143.6,145.9,156.4,195.7。LCMS t=4.2min,m/z计算值C15H16N3O;C15H15N3NaO;C30H31N6NaO2 254.129;276.111;529.233[M+H]+;[M+Na]+;[2M+Na]+,实验值254.121;276.102;529.219。
实施例01-61
2-甲基-3-[(喹唑啉-6-基)氨基]环己基-2-烯-1-酮(01-61)的制备:按照实施例01-01的方法由2-甲基-1,3-环己二酮和喹唑啉-6-胺制备题述化合物(棕褐色微晶体,mp=215–216℃)。1H NMR(D6-DMSO)δ1.69(s,3H),1.83-1.88(m,2H),2.29(t,J=6.1Hz,2H),2.61-2.64(m,2H),7.63(d,J=2.4Hz,1H),7.79-7.85(m,1H),7.96(d,J=8.5Hz,1H),8.61(s,1H),9.18(s,1H),9.51(s,1H)。13C NMR(D6-DMSO)δppm 10.0,21.7,27.8,36.7,110.4,116.7,125.2,128.3,131.5,139.7,146.0,153.7,156.6,159.5,195.4。LCMS t=3.8min,m/z计算值C15H16N3O;C15H15N3NaO;C30H31N6NaO2254.129;276.111;529.233[M+H]+;[M+Na]+;[2M+Na]+,实验值254.120;276.102;529.218。
实施例01-62
3-[(1H-吲哚-6-基)氨基]-2-甲基环己基-2-烯-1-酮(01-62)的制备:按照实施例01-01的方法由2-甲基-1,3-环己二酮和1H-吲哚-6-胺制备题述化合物(白色微针体,mp=227–230℃)。1H NMR(D6-DMSO)δ1.71(s,3H),1.72-1.77(m,2H),2.17(t,J=6.7Hz,2H),2.36-2.40(m,2H),6.41(br s,1H),6.79-6.83(m,1H),7.15(s,1H),7.33(t,J=2.4Hz,1H),7.49(d,J=8.5Hz,1H),8.20(s,1H),11.09(br s,1H)。13C NMR(D6-DMSO)δ8.9,21.7,27.2,36.4,101.0,104.9,108.5,118.1,119.8,125.3,125.8,133.3,135.8,159.7,193.6。LCMS t=4.6min,m/z计算值C15H17N2O;C15H16N2NaO;C30H32N4NaO2 241.134;263.116;503.242[M+H]+;[M+Na]+;[2M+Na]+,实验值241.141;263.106;503.224。
实施例01-63
5-[(2-甲基-3-氧代环己基-1-烯-1-基)氨基]-2,3-二氢-1H-1,3-苯并二唑-2-酮(5-[(2-methyl-3-oxocyclohex-1-en-1-yl)amino]-2,3-dihydro-1H-1,3-benzodiazol-2-one)(01-63)的制备:按照实施例01-01的方法由2-甲基-1,3-环己二酮和5-氨基-1H-苯并[d]咪唑-2(3H)-酮制备题述化合物(棕色微晶体,mp=233–235℃)。1H NMR(D6-DMSO)δ1.67(s,3H),1.70-1.77(m,2H),2.16(t,J=6.1Hz,2H),2.29-2.36(m,2H),6.71(s,1H),6.73(d,J=2.4Hz,1H),6.87(d,J=8.5Hz,1H),8.08(s,1H),10.63(d,J=13.4Hz,2H)。13CNMR(D6-DMSO)δ8.8,21.6,27.0,36.4,105.1,106.6,108.2,118.5,127.2,129.9,132.7,155.5,159.4,193.7。LCMS t=3.2min,m/z计算值C14H16N3O2;C14H15N3NaO2;C28H30N6NaO4258.124;280.106;537.222[M+H]+;[M+Na]+;[2M+Na]+,实验值258.123;280.096;537.206。
实施例01-64
5-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)-1H-吲哚-2-羧酸(01-64)的制备:按照实施例01-01的方法由2-甲基-1,3-环己二酮和5-氨基-1H-吲哚-2-羧酸制备题述化合物(棕色微晶体,mp=310–315℃)。1H NMR(D6-DMSO)δ1.69-1.77(m,5H),2.17(t,J=6.3Hz,2H),2.32-2.37(m,2H),6.98-7.17(m,2H),7.33-7.50(m,2H),8.21(s,1H),11.84(s,1H),13.05(br s,1H)。13C NMR(D6-DMSO)δ8.8,21.6,27.1,36.4,104.8,107.3,112.6,118.6,124.0,126.9,129.4,132.2,135.2,159.8,162.7,193.7。LCMS t=3.8min,m/z计算值C16H17N2O3;C32H33N4O6;C32H32N4NaO6 285.124;569.240;591.221[M+H]+;[2M+H]+;[2M+Na]+,实验值285.123;569.239;591.220。
实施例02-01至02-07
实施例02-01
4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酸(02-01)的制备:在含有氢氧化钠(0.8g,~5eq)的THF:H2O(70mL,2:1)溶液中搅拌实施例01-01的化合物(1.0g,4.1mmol),持续18h。加入盐酸水溶液直至pH试纸显示为3或低于3。另外,加入额外的THF以形成单层并且沉淀水解产物,通过过滤对其进行收集。在4.1mmol规模上发生的反应产生了0.36g题述化合物,黄色微针体(mp=228–230℃,43%产量)。1H NMR(D6-DMSO)δ1.61(s,3H),2.26(s,2H),2.80(s,2H),7.31(d,J=8.1Hz,2H),7.89(d,J=8.2Hz,2H),9.19(s,1H)。LCMS t=4.7min,m/z计算值C13H14NO3;C13H13NNaO3;C26H27N2O6;C26H26N2NaO6 232.10;254.08;463.19;485.17[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值232.11;254.09;463.21;485.19。
实施例02-02
3-氯-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酸(02-02)的制备:按照实施例02-01的方法,由实施例01-11的化合物制备题述化合物;6.0mmol规模产生了1.2g黄色微晶体(mp=226–230℃,86%产量)。1H NMR(D6-DMSO)δ1.45(s,3H),2.23-2.25(m,2H),2.52-2.54(m,2H),7.42(d,J=8.3Hz,1H),7.88(d,J=8.2Hz,1H),7.99(s,1H),8.97(s,1H),13.21(br s,1H)。LCMS t=5.2min,m/z计算值C13H13ClNO3;C13H12ClNNaO3;C26H24Cl2N2NaO6 266.06;288.04;553.09[M+H]+;[M+Na]+;[2M+Na]+,实验值266.11;288.09;553.08。
实施例02-03
2-甲氧基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酸(02-03)的制备:按照实施例02-01的方法,由实施例01-13的化合物制备题述化合物;18.0mmol规模产生了3.6g黄色微晶体(mp=240–243℃,87%产量)。1HNMR(D6-DMSO)δ1.62(s,3H),2.25-2.27(m,2H),2.82-2.84(m,2H),3.85(s,3H),6.86(d,J=8.4Hz,1H),6.95(s,1H),7.68(d,J=8.4Hz,1H),9.16(s,1H)。LCMS t=4.9min,m/z计算值C14H16NO4;C14H15NNaO4;C28H30N2NaO8262.11;284.09;545.19[M+H]+;[M+Na]+;[2M+Na]+,实验值262.17;284.14;545.20。
实施例02-04
2-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酸(02-04)的制备:按照实施例02-01的方法,由实施例01-19制备题述化合物;13.7mmol规模产生了3.0g黄色微晶体(mp=245–248℃,95%产量)。1H NMR(D6-DMSO)δ1.62(s,3H),2.30-2.32(m,2H),2.96-2.98(m,2H),7.11(t,J=7.5Hz,1H),7.53(d,J=8.3Hz,1H),7.56-7.60(m,1H),7.99(d,J=7.9Hz,1H),10.68(s,1H)。13C NMR(D6-DMSO)δ6.6,26.6,33.3,113.1,117.2,119.3,121.8,131.8,134.2,142.4,167.9,169.8,201.8。LCMS t=4.7min,m/z计算值C13H14NO3;C13H13NNaO3;C26H27N2O6;C26H26N2NaO6 232.10;254.08;463.19;485.17[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值232.10;254.08;463.19;485.17。
实施例02-05
5-氯-2-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酸(02-05)的制备:按照实施例02-01的方法,由实施例01-20制备题述化合物;2.5mmol规模产生了0.54g黄色微晶体(mp=242–245℃,81%产量)。1H NMR(D6-DMSO)δ1.62(s,3H),2.32-2.34(m,2H),2.93-2.95(m,2H),7.55(d,J=8.9Hz,1H),7.62(dd,J=8.9,2.6Hz,1H),7.93(d,J=2.6Hz,1H),10.60(s,1H)。LCMS t=5.1min,m/z计算值C13H13ClNO3;C13H12ClNNaO3;C26H25Cl2N2O6;C26H24Cl2N2NaO6 266.06;288.04;531.11;553.09[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值266.06;288.04;531.10;553.09。
实施例02-06
3-氟-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酸(02-06)的制备:按照实施例02-01的方法,由实施例01-21的化合物制备题述化合物;15.0mmol规模产生了2.9g黄色微晶体(mp=210-2130℃,77%产量)。1H NMR(D6-DMSO)δ1.52(s,3H),2.23-2.25(m,2H),2.54-2.56(m,2H),7.41(d,J=8.3Hz,1H),7.73-7.78(m,2H),9.07(s,1H)。LCMS t=4.4min,m/z计算值C13H13FNO3;C13H12FNNaO3;C26H25F2N2O6;C26H24F2N2NaO6 250.09;272.07;499.17;521.15[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值250.09;272.07;499.17;521.15。
实施例02-07
3-溴-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酸(02-07)的制备:按照实施例02-01的方法,由实施例01-22的化合物制备题述化合物;9.5mmol规模产生了1.7g黄色微晶体(mp=246–248℃,58%产量)。1H NMR(D6-DMSO)δ1.47(s,3H),2.26-2.28(m,2H),2.50-2.52(m,2H),7.45(d,J=8.3Hz,1H),7.94(dd,J=8.2,1.8Hz,1H),8.16(d,J=1.8Hz,1H),9.13(s,1H)。13C NMR(D6-DMSO)δ7.63,25.9,32.5,110.9,119.4,127.3,129.3,133.6,141.9,165.6,169.7,202.5。LCMS t=4.6min,m/z计算值C13H13BrNO3;C13H12BrNNaO3;C26H25Br2N2O6;C26H24Br2N2NaO6 310.01,312.01;331.99,333.99;621.01;642.99[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值310.01,312.01;331.99,333.99;621.00;642.99。
实施例02-08
3-碘-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酸(02-08)的制备:按照实施例02-01的方法,由实施例01-43的化合物制备题述化合物;5.5mmol规模从EtOH中产生了1.7g黄色沉淀(87%产量),淡黄色微晶体(mp=263–264℃)。1H NMR(D6-DMSO)δ1.44(s,3H),2.20-2.23(m,2H),2.42-2.44(m,2H),7.40(d,J=8.2Hz,1H),7.94(dd,J=8.2,1.7Hz,1H),8.38(d,J=1.7Hz,1H),8.86(s,1H),13.22(s,1H)。13C NMR(D6-DMSO)δ7.6,25.8,32.7,97.9,110.2,126.9,129.5,129.9,139.8,145.3,165.5,168.7,202.5。LCMS t=4.4min,m/z计算值C13H13INO3;C13H12INNaO3;C26H24I2N2NaO6 357.994;379.976;736.962[M+H]+;[M+Na]+;[2M+Na]+,实验值357.995;379.965;736.944。
实施例02-09
甲基4-溴-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯甲酸(02-09)的制备:将乙酰氯(14eq)加入至0℃的CH2Cl2:MeOH(60mL,1:2)混合物中,随后加入实施例01-48的化合物(1.6g,5.0mmol)。升温至室温后,该混合物被搅拌过夜。在旋蒸仪上除去溶剂以产生粗材料。5.0mmol规模从EtOAc中缓慢产生了1.23g棕色微晶体(mp=211–213℃,76%产量)。1HNMR(D6-DMSO)δ1.74(s,3H),1.78-1.81(m,2H),2.25-2.29(m,2H),2.38-2.41(m,2H),3.88(s,3H),7.81(dd,J=8.4,2.0Hz,1H),7.87(d,J=2.0Hz,1H),7.93(d,J=8.4Hz,1H),9.30(s,1H)。13C NMR(D6-DMSO)δ8.9,20.7,27.2,34.0,52.6,106.8,127.2,128.9,129.3,130.0,133.7,138.2,165.1,192.3。LCMS t=5.0min,m/z计算值C15H17BrNO3;C15H16BrNNaO3;C30H33Br2N2NaO6 338.04,340.04;360.02,362.02;699.05[M+H]+;[M+Na]+;[2M+Na]+,实验值324.03,326.02;345.99,347.99;670.96。
实施例02-10
3-((5-氨基-2-氯苯基)氨基)-2-甲基环己基-2-烯酮(02-10)的制备:将3-((2-氯-5-硝基苯基)氨基)-2-甲基环己基-2-烯酮(2g,7mmol),Fe(1.6g,28mmol)和NH4Cl(0.76g,14mmol)于90℃下在THF:EtOH:H2O(48mL,1:1:0.4)中搅拌2h。过滤混合物。滤液用EtOAc(50mL)稀释,使用盐水(2×30mL)清洗,Na2SO4干燥,并过滤。将二次滤液浓缩以产生题述化合物(1.5g,84%产量,mp=182–184℃)。1H NMR(D6-DMSO)δ1.64(s,3H),1.71-1.82(m,2H),2.15(t,J=6.1Hz,2H),2.18-2.22(m,2H),5.37(s,2H),6.45(d,J=2.4Hz,1H),6.47(dd,J=8.5,2.4Hz,1H),7.11(d,J=8.5Hz,1H),7.84(s,1H)。13C NMR(D6-DMSO)δ8.8,21.2,26.7,36.4,105.8,113.2,114.1,116.6,129.6,137.0,148.5,159.2,194.1。LCMS t=3.8min,m/z计算值C13H16ClN2O;C13H15ClN2NaO;C26H30Cl2N4NaO2 251.095;273.077;523.164[M+H]+;[M+Na]+;[2M+Na]+,实验值251.095;273.076;523.163。
按照实施例01-01的方法,由2-甲基-1,3-环己二酮(40mmol)和2-氯-5-硝基苯胺制备3-((2-氯-5-硝基苯基)氨基)-2-甲基环己基-2-烯酮(5.6g黄色固体,50%产量)。
实施例02-11
3-((3-氨基-2-氯苯基)氨基)-2-甲基环己基-2-烯酮(02-11)的制备:按照实施例02-10的方法,由3-((2-氯-3-硝基苯基)氨基)-2-甲基环己基-2-烯酮制备题述化合物。1HNMR(D6-DMSO)δ1.66(s,3H),1.73(quin,J=6.1Hz,2H),2.15(t,J=6.1Hz,2H),2.19(t,J=6.1Hz,2H),5.49(brs,2H),6.47(d,J=7.3Hz,1H),6.70(d,J=9.8Hz,1H),7.01(t,J=7.9Hz,1H),7.87(s,1H)。13C NMR(D6-DMSO)δ8.7,21.3,26.6,36.3,105.7,105.7,113.0,115.3,116.1,126.9,137.3,145.8,159.4,194.0。LCMS t=4.0min,m/z计算值C13H16ClN2O;C13H15ClN2NaO;C26H30Cl2N4NaO2 251.095;273.077;523.164[M+H]+;[M+Na]+;[2M+Na]+,实验值251.095;273.076;523.163。
按照实施例01-01的方法,由2-甲基-1,3-环己二酮和2-氯-3-硝基苯胺制备3-((2-氯-3-硝基苯基)氨基)-2-甲基环己基-2-烯酮。
实施例02-12
3-((4-氨基-2-氯苯基)氨基)-2-甲基环己基-2-烯酮(02-12)的制备:按照实施例02-10的方法由3-((2-氯-4-硝基苯基)氨基)-2-甲基环己基-2-烯酮制备题述化合物(mp=156–158℃)。1H NMR(D6-DMSO)δ1.66(s,3H),1.71(quin,J=6.1Hz,2H),2.07(t,J=5.5Hz,2H),2.12(t,J=6.1Hz,2H),5.47(s,2H),6.51(dd,J=8.5,2.4Hz,1H),6.68(d,J=2.4Hz,1H),6.96(d,J=8.5Hz,1H),7.77(s,1H)。13C NMR(D6-DMSO)δ8.4,21.2,26.2,36.2,104.2,112.8,113.4,124.2,130.9,132.6,149.0,160.8,193.5。LCMS t=3.7min,m/z计算值C13H16ClN2O;C13H15ClN2NaO;C26H30Cl2N4NaO2251.095;273.077;523.164[M+H]+;[M+Na]+;[2M+Na]+,实验值251.095;273.077;523.164。
按照实施例01-01的方法,由2-甲基-1,3-环己二酮和2-氯-4-硝基苯胺制备3-((2-氯-4-硝基苯基)氨基)-2-甲基环己基-2-烯酮。
实施例02-13
3-((3-氨基-2-氯苯基)氨基)-2-甲基环戊基-2-烯酮(02-13)的制备:按照实施例02-10的方法由3-((2-氯-3-硝基苯基)氨基)-2-甲基环戊基-2-烯酮制备题述化合物(mp=223–225℃)。1H NMR(D6-DMSO)δ1.46(s,3H),2.12-2.17(m,2H),2.32-2.39(m,2H),5.49(brs,2H),6.53(d,J=7.3Hz,1H),6.71(d,J=6.1Hz,1H),6.99-7.03(m,1H),8.72(s,1H)。13CNMR(D6-DMSO)δ7.1,25.3,32.6,108.2,113.1,114.6,115.5,127.0,136.9,145.8,170.3,201.8。LCMS t=3.7min,m/z计算值C12H14ClN2O;C12H13ClN2NaO;C24H27Cl2N4O2;C24H26Cl2N4NaO2237.080;259.061;473.151;495.133[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值237.080;259.060;473.150;495.132。
按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和2-氯-3-硝基苯胺制备3-((2-氯-3-硝基苯基)氨基)-2-甲基环戊基-2-烯酮。
实施例02-14
3-((4-氨基-2-氯苯基)氨基)-2-甲基环戊基-2-烯酮(02-14)的制备:按照实施例02-10的方法,由3-((2-氯-4-硝基苯基)氨基)-2-甲基环戊基-2-烯酮制备题述化合物。1HNMR(D6-DMSO)δ1.44(s,3H),2.09-2.13(m,2H),2.18-2.27(m,2H),5.47(br s,2H),6.50(dd,J=8.5,2.4Hz,1H),6.68(d,J=2.4Hz,1H),7.01(d,J=8.5Hz,1H),8.58(s,1H)。13CNMR(D6-DMSO)δ6.9,25.1,32.5,107.0,112.7,113.4,123.9,130.4,131.9,149.0,171.9,201.4。LCMS t=3.5min,m/z计算值C12H14ClN2O;C12H13ClN2NaO;C24H27Cl2N4O2;C24H26Cl2N4NaO2237.080;259.061;473.151;495.133[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值237.080;259.061;473.151;495.132。
按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和2-氯-4-硝基苯胺制备3-((2-氯-4-硝基苯基)氨基)-2-甲基环戊基-2-烯酮。
实施例02-15
3-((5-氨基-2-氯苯基)氨基)-2-甲基环戊基-2-烯-1-酮(02-15)的制备:按照实施例02-10的方法,由3-((2-氯-5-硝基苯基)氨基)-2-甲基环戊基-2-烯酮制备题述化合物(mp=166–168℃)。1H NMR(D6-DMSO)δ1.45(s,3H),2.13-2.21(m,2H),2.34-2.40(m,2H),5.38(s,2H),6.47(dd,J=8.5,2.4Hz,1H),6.51(d,J=2.4Hz,1H),7.12(d,J=8.5Hz,1H),8.69(s,1H)。13C NMR(D6-DMSO)δ7.2,25.4,32.6,108.4,113.2,113.4,115.8,129.6,136.5,148.4,170.1,202.0。LCMS t=3.6min,m/z计算值C12H14ClN2O;C12H13ClN2NaO;C24H26Cl2N4NaO2237.080;259.061;495.133[M+H]+;[M+Na]+;[2M+Na]+,实验值237.080;259.061;495.133。
按照实施例01-01的方法,由2-甲基-1,3-环戊二酮和2-氯-5-硝基苯胺制备3-((2-氯-5-硝基苯基)氨基)-2-甲基环戊基-2-烯酮。
实施例03-01至03-23
实施例03-01
4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-苯基苯甲酰胺(03-01)的制备:将实施例02-01的化合物(150mg,0.65mmol,1.3eq)溶解于THF:DMF(1.5:1.0,7.5mL)中,并且加入至装有苯胺(0.046mL,0.5mmol)和PS-CDI(1.0g,负载量=1.33mmol/g)的干燥的反应容器。将反应容器密封且在室温下振荡18h。从溶液中过滤出树脂,使用1体积反应溶剂和THF(3×8mL)进行清洗。将IsoluteTM HM-N加入至粗溶液并且在旋蒸仪上进行干燥。将被吸收至SsoluteTM的粗材料装入空进样器(samplet)(1g)中并且将其放进接收KP-SilTM柱(10g)中。使用等度溶剂系统,EtOAc:丙酮(17:3),在-Isolera Four仪器上,将产物与杂质分离,于254/365nm下监控紫外线踪迹。0.5mmol规模的反应产生了15mg题述化合物(10%产量)。1H NMR(D6-DMSO)δ1.62(s,3H),2.25-2.27(m,2H),2.80-2.81(m,2H),7.09(t,J=7.3Hz,1H),7.33-7.37(m,4H),7.77(d,J=7.7Hz,2H),7.85(d,J=8.4Hz,2H),9.18(s,1H),10.16(s,1H)。LCMS t=5.4min,m/z计算值C19H19N2O2;C19H18N2NaO2;C38H37N4O4;C38H36N4NaO4 307.14;329.13;613.28;635.26[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值307.16;329.14;613.31;635.29。
实施例03-02
N-甲基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-苯基苯甲酰胺(03-02)的制备:按照实施例03-01的方法,由实施例02-01的化合物和N-甲基苯胺制备题述化合物;0.5mmol规模产生了30mg产物(19%产量)。1H NMR(MeOD)δ1.59(s,3H),2.35-2.37(m,2H),2.68-2.69(m,2H),3.47(s,3H),7.08(d,J=8.2Hz,2H),7.15(d,J=7.6Hz,2H),7.19(t,J=7.3Hz,1H),7.26-7.31(m,4H)。LCMS t=5.4min,m/z计算值C20H21N2O2;C20H20N2NaO2;C40H41N4O4;C40H40N4NaO4 321.16;343.14;641.31;663.29[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值321.17;343.16;641.34;663.32。
实施例03-03
N-(2-氟苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(03-03)的制备:按照实施例03-01的方法,由实施例02-01的化合物和2-氟苯胺(2-fluoroaniline)制备题述化合物;0.5mmol规模产生了10mg产物(6%产量)。1H NMR(CDCl3)δ1.60(s,3H),2.76-2.78(m,2H),3.34-3.36(m,2H),6.68(s,1H),7.10-7.28(m,5H),7.92(d,J=8.2Hz,2H),8.04(s,1H),8.45(t,J=8.0Hz,1H)。LCMS t=5.4min,m/z计算值C19H18FN2O2;C19H17FN2NaO2;C38H35F2N4O4;C38H34F2N4NaO4 325.14;347.12;649.26;671.24[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值325.15;347.13;649.29;671.27。
实施例03-04
N-(3-氟苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(03-04)的制备:按照实施例03-01的方法,由实施例02-01的化合物和3-氟苯胺制备题述化合物;0.5mmol规模产生了18mg产物(11%产量)。1H NMR(D6-DMSO)δ1.62(s,3H),2.25-2.28(m,2H),2.80-2.82(m,2H),6.91-6.93(m,1H),7.36-7.39(m,3H),7.56(d,J=8.1Hz,1H),7.76(d,J=11.8Hz,1H),7.94(d,J=8.5Hz,2H),9.19(s,1H),10.34(s,1H)。LCMS t=5.5min,m/z计算值C19H18FN2O2;C19H17FN2NaO2;C38H35F2N4O4;C38H34F2N4NaO4325.14;347.12;649.26;671.24[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值325.15;347.13;649.29;671.28。
实施例03-05
N-(4-氯苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(03-05)的制备:按照实施例03-01的方法,由实施例02-01的化合物和4-氯苯胺制备题述化合物;0.5mmol规模产生了10mg产物(6%产量)。1H NMR(D6-DMSO)δ1.62(s,3H),2.25-2.27(m,2H),2.80-2.81(m,2H),7.36(d,J=8.4Hz,2H),7.41(d,J=8.7Hz,2H),7.82(d,J=8.8Hz,2H),7.94(d,J=8.5Hz,2H),9.19(s,1H),10.29(s,1H)。LCMS t=5.7min,m/z计算值C19H18ClN2O2;C19H17ClN2NaO2;C38H35Cl2N4O4;C38H34Cl2N4NaO4 341.11;363.09;681.20;703.19[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值341.12;363.09;681.23;703.21。
实施例03-06
N-(4-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(03-06)的制备:按照实施例03-01的方法,由实施例02-01的化合物和4-氨基苯甲醚(4-aminoanisole)制备题述化合物;0.5mmol规模产生了12mg产物(7%产量)。1H NMR(D6-DMSO)δ1.62(s,3H),2.25-2.27(m,2H),2.79-2.80(m,2H),3.74(s,3H),6.92(d,J=8.8Hz,2H),7.35(d,J=8.4Hz,2H),7.66(d,J=8.7Hz,2H),7.93(d,J=8.4Hz,2H),9.17(s,1H),10.05(s,1H)。LCMS t=5.2min,m/z计算值C20H21N2O3;C40H41N4O6;C40H40N4NaO6 337.16;673.30;695.28[M+H]+;[2M+H]+;[2M+Na]+,实验值337.17;673.33;695.31。
实施例03-07
4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(对甲苯基)苯甲酰胺(03-07)的制备:按照实施例03-01的方法,由实施例02-01的化合物和4-氨基甲苯制备题述化合物;0.5mmol规模产生了25mg产物(16%产量)。1HNMR(D6-DMSO)δ1.62(s,3H),2.25-2.28(m,5H),2.79-2.81(m,2H),7.15(d,J=8.1Hz,2H),7.35(d,J=8.4Hz,2H),7.65(d,J=8.2Hz,2H),7.94(d,J=8.4Hz,2H),9.17(s,1H),10.08(s,1H)。LCMS t=5.5min,m/z计算值C20H21N2O2;C20H20N2NaO2;C40H41N4O4;C40H40N4NaO4 321.16;343.14;641.31;663.29[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值321.17;343.16;641.34;663.32。
实施例03-08
4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(邻甲苯基)苯甲酰胺(03-08)的制备:按照实施例03-01的方法,由实施例02-01的化合物和邻甲苯胺制备题述化合物;0.5mmol规模产生了1mg产物(1%产量)。1H NMR(D6-DMSO)δ1.62(s,3H),2.26-2.28(m,2H),2.31(s,3H),2.80-2.82(m,2H),6.91(d,J=6.4Hz,1H),7.22(s,1H),7.36(d,J=6.9Hz,2H),7.56(d,J=6.4Hz,1H),7.62(s,1H),7.94(d,J=6.9Hz,2H),9.18(s,1H),10.08(s,1H)。LCMS t=5.7min,m/z计算值C20H21N2O2;C20H20N2NaO2;C40H41N4O4;C40H40N4NaO4 321.16;343.14;641.31;663.29[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值321.18;343.16;641.29;663.28。
实施例03-09
4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(间甲苯基)苯甲酰胺(03-09)的制备:按照实施例03-01的方法,由实施例02-01的化合物和间甲苯胺制备题述化合物;0.5mmol规模产生了13mg产物(8%产量)。1H NMR(D6-DMSO)δ1.62(s,3H),2.23(s,3H),2.24-2.26(m,2H),2.79-2.80(m,2H),7.16(t,J=7.3Hz,1H),7.21(t,J=7.3Hz,1H),7.27(d,J=7.3Hz,1H),7.33(d,J=7.6Hz,1H),7.36(d,J=8.4Hz,2H),7.96(d,J=8.4Hz,2H),9.18(s,1H),9.81(s,1H)。LCMS t=5.5min,m/z计算值C20H21N2O2;C20H20N2NaO2;C40H41N4O4;C40H40N4NaO4 321.16;343.14;641.31;663.29[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值321.18;343.16;641.29;663.28。
实施例03-10
N-(2-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(03-10)的制备:按照实施例03-01的方法,由实施例02-01的化合物和邻氨基苯甲醚(o-anisidine)制备题述化合物;0.5mmol规模产生了8mg产物(5%产量)。1H NMR(D6-DMSO)δ1.62(s,3H),2.26-2.27(m,2H),2.79-2.81(m,2H),3.84(s,3H),6.97(t,J=7.2Hz,1H),7.09(d,J=7.9Hz,1H),7.17(t,J=7.3Hz,1H),7.35(d,J=7.9Hz,2H),7.77(d,J=7.4Hz,1H),7.94(d,J=7.9Hz,2H),9.18(s,1H),9.34(s,1H)。LCMS t=5.7min,m/z计算值C20H21N2O3;C20H20N2NaO3;C40H40N4NaO6 337.16;359.14;695.28[M+H]+;[M+Na]+;[2M+Na]+,实验值337.17;359.14;695.27。
实施例03-11
N-(3-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(03-11)的制备:按照实施例03-01的方法,由实施例02-01的化合物和间氨基苯甲醚(m-anisidine)制备题述化合物;0.5mmol规模产生了4mg产物(2%产量)。1H NMR(D6-DMSO)δ1.62(s,3H),2.26-2.28(m,2H),2.80-2.82(m,2H),3.75(s,3H),6.67(d,J=7.3Hz,1H),7.24(t,J=7.5Hz,1H),7.36(d,J=8.0Hz,2H),7.47(s,1H),7.94(d,J=8.3Hz,2H),9.18(s,1H),10.12(s,1H)。LCMS t=5.6min,m/z计算值C20H21N2O3;C20H20N2NaO3;C40H40N4NaO6337.16;359.14;695.28[M+H]+;[M+Na]+;[2M+Na]+,实验值337.17;359.14;695.28。
实施例03-12
4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(3-(三氟甲基)苯基)苯甲酰胺(03-12)的制备:按照实施例03-01的方法,由实施例02-01的化合物和3-(三氟甲基)苯胺制备题述化合物;0.5mmol规模产生了3mg产物(2%产量)。1H NMR(D6-DMSO)δ1.62(s,3H),2.26-2.28(m,2H),2.81-2.83(m,2H),7.38(d,J=7.9Hz,2H),7.45(d,J=7.2Hz,1H),7.60(t,J=7.6Hz,1H),7.97(d,J=7.9Hz,2H),8.05(d,J=7.6Hz,1H),8.26(s,1H),9.21(s,1H),10.47(s,1H)。LCMS t=5.9min,m/z计算值C20H18F3N2O2;C20H17F3N2NaO2;C40H34F6N4NaO6375.13;397.11;771.24[M+H]+;[M+Na]+;[2M+Na]+,实验值375.13;397.11;771.24。
实施例03-13
N-(4-(叔丁基)苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-苯甲酰胺(03-13)的制备:按照实施例03-01的方法,由实施例02-01的化合物和4-叔丁基苯胺制备题述化合物;0.5mmol规模产生了4mg产物(2%产量)。1H NMR(D6-DMSO)δ1.28(s,9H),1.62(s,3H),2.26-2.28(m,2H),2.79-2.81(m,2H),7.36(d,J=8.0Hz,4H),7.68(d,J=8.2Hz,2H),7.94(d,J=8.1Hz,2H),9.18(s,1H),10.10(s,1H)。LCMS t=6.1min,m/z计算值C23H27N2O2;C23H26N2NaO2;C46H53N4O4;C46H52N4NaO4 363.21;385.19;725.41;747.39[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值363.21;385.19;725.41;747.39。
实施例03-14
N-(3-溴苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(03-14)的制备:按照实施例03-01的方法,由实施例02-01的化合物和3-溴苯胺制备题述化合物;0.5mmol规模产生了4mg产物(2%产量)。1H NMR(D6-DMSO)δ1.62(s,3H),2.26-2.28(m,2H),2.81-2.83(m,2H),7.29-7.34(m,2H),7.37(d,J=8.4Hz,2H),7.75(d,J=7.9Hz,1H),7.95(d,J=8.4Hz,2H),8.11(s,1H),9.20(s,1H),10.31(s,1H)。LCMS t=5.9min,m/z计算值C19H18BrN2O2;C19H17BrN2NaO2;C38H34BrN4NaO6 385.06,387.05;407.04,409.04;793.08[M+H]+;[M+Na]+;[2M+Na]+,实验值385.05,387.05;407.03,409.03;793.09。
实施例03-15
N-(4-溴苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(03-15)的制备:按照实施例03-01的方法,由实施例02-01的化合物和4-溴苯胺制备题述化合物;0.5mmol规模产生了3mg产物(2%产量)。1H NMR(D6-DMSO)δ1.62(s,3H),2.26-2.28(m,2H),2.80-2.82(m,2H),7.36(d,J=8.4Hz,2H),7.53(d,J=8.6Hz,2H),7.76(d,J=8.6Hz,2H),7.94(d,J=8.4Hz,2H),9.19(s,1H),10.28(s,1H)。LCMS t=5.9min,m/z计算值C19H18BrN2O2;C19H17BrN2NaO2;C38H34BrN4NaO6 385.06,387.05;407.04,409.04;793.08[M+H]+;[M+Na]+;[2M+Na]+,实验值385.05,387.05;407.03,409.03;793.09。
实施例03-16
4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(萘-1-基)苯甲酰胺(4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(naphthalen-1-yl)benzamide)(03-16)的制备:按照实施例03-01的方法,由实施例02-01的化合物和1-萘胺制备题述化合物;0.5mmol规模产生了11mg产物(6%产量)。1H NMR(D6-DMSO)δ1.64(s,3H),2.27-2.29(m,2H),2.82-2.84(m,2H),7.40(d,J=8.3Hz,2H),7.54-7.60(m,4H),7.81-7.87(m,2H),7.98-8.00(m,2H),8.08(d,J=8.3Hz,2H),9.21(s,1H),10.36(s,1H)。LCMS t=5.6min,m/z计算值C23H21N2O2;C23H20N2NaO2;C46H41N4O4;C46H40N4NaO4 357.16;379.14;713.31;735.29[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值357.18;379.18;713.34;735.33。
实施例03-17
4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(吡啶-2-基)苯甲酰胺(03-17)的制备:按照实施例03-01的方法,由实施例02-01的化合物和2-氨基吡啶制备题述化合物;0.5mmol规模产生了2mg产物(1%产量)。1H NMR(D6-DMSO)δ1.62(s,3H),2.26-2.28(m,2H),2.81-2.82(m,2H),7.16(s,1H),7.34(d,J=7.8Hz,2H),7.83-7.84(m,1H),8.03(d,J=7.7Hz,2H),8.18(d,J=8.0Hz,2H),8.39(s,1H),9.18(s,1H),10.68(s,1H)。LCMSt=5.1min,m/z计算值C18H18N3O2;C18H17N3NaO2;C36H34N6NaO4 308.14;330.12;637.25[M+H]+;[M+Na]+;[2M+Na]+,实验值308.16;330.13;637.22。
实施例03-18
N-苄基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(03-18)的制备:按照实施例03-01的方法,由实施例02-01的化合物和苄胺制备题述化合物;0.5mmol规模产生了20mg产物(13%产量)。1H NMR(D6-DMSO)δ1.60(s,3H),2.23-2.25(m,2H),2.76-2.78(m,2H),4.47(d,J=5.7Hz,2H),7.23-7.30(m,7H),7.87(d,J=8.2Hz,2H),8.98(s,1H),9.12(s,1H)。LCMS t=5.3min,m/z计算值C20H21N2O2;C20H20N2NaO2;C40H41N4O4;C40H40N4NaO4321.16;343.14;641.31;663.29[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值321.17;343.16;641.24;663.32。
实施例03-19
N-环己基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(03-19)的制备:按照实施例03-01的方法,由实施例02-01的化合物和环己胺制备题述化合物;0.5mmol规模产生了11mg产物(7%产量)。1H NMR(MeOD)δ1.21-1.25(m,2H),1.34-1.42(m,4H),1.69(s,3H),1.80-1.83(m,2H),1.94-1.96(m,2H),2.40-2.43(m,2H),2.82-2.83(m,2H),3.85-3.86(m,1H),7.32(d,J=8.5Hz,2H),7.83(d,J=8.5Hz,2H)。LCMS t=5.4min,m/z计算值C19H25N2O2;C19H24N2NaO2;C38H49N4O4;C38H48N4NaO4 313.19;335.17;625.38;647.38[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值313.21;335.19;625.40;647.39。
实施例03-20
N,N-二甲基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(03-20)的制备:按照实施例03-01的方法,由实施例02-01的化合物和二甲胺制备题述化合物;0.5mmol规模产生了55mg产物(43%产量)。1H NMR(D6-DMSO)δ1.59(s,3H),2.21-2.23(m,2H),2.73-2.74(m,2H),2.96(s,6H),7.27(d,J=8.3Hz,2H),7.39(d,J=8.3Hz,2H),9.07(s,1H)。LCMSt=5.0min,m/z计算值C15H19N2O2;C15H18N2NaO2;C30H37N4O4;C30H36N4NaO4259.14;281.13;517.28;539.26[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值259.19;281.16;517.25;539.23。
实施例03-21
2-甲基-3-((4-(哌啶-1-羰基)苯基)氨基)环戊-2-烯酮(2-methyl-3-((4-(piperidine-1-carbonyl)phenyl)amino)cyclopent-2-enone)(03-21)的制备:按照实施例03-01的方法,由实施例02-01的化合物和哌啶(pipperidine)制备题述化合物;0.5mmol规模产生了33mg产物(22%产量)。1H NMR(D6-DMSO)δ1.50(br s,8H),1.59(s,3H),2.22-2.24(m,2H),2.72-2.24(m,2H),3.53(br s,2H),7.27(d,J=8.0Hz,2H),7.35(d,J=8.0Hz,2H),9.06(s,1H)。LCMS t=5.4min,m/z计算值C18H23N2O2;C18H22N2NaO2;C36H45N4O4;299.18;321.16;619.33[M+H]+;[M+Na]+;[2M+Na]+,实验值299.20;321.17;619.29。
实施例03-22
2-甲基-3-((4-(吗啉-4-羰基)苯基)氨基)环戊-2-烯酮(03-22)的制备:按照实施例03-01的方法,由实施例02-01的化合物和吗啉制备题述化合物;0.5mmol规模产生了59mg产物(39%产量)。1H NMR(D6-DMSO)δ1.60(s,3H),2.22-2.24(m,2H),2.73-2.75(m,2H),3.40-3.70(m,8H),7.28(d,J=8.1Hz,2H),7.40(d,J=8.1Hz,2H),9.08(s,1H)。LCMS t=4.9min,m/z计算值C17H21N2O3;C17H20N2NaO3;C34H40N4NaO6 301.16;323.14;623.28[M+H]+;[M+Na]+;[2M+Na]+,实验值301.18;323.15;623.25。
实施例03-23
3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-苯甲酰苯胺(phenylbenzamide)(03-23)的制备:按照实施例03-01的方法,由实施例01-03的化合物和苯胺制备题述化合物;0.5mmol规模产生了8mg产物(5%产量)。1H NMR(D6-DMSO)δ1.60(s,3H),2.23-2.25(m,2H),2.71-2.74(m,2H),7.11(t,J=7.1Hz,1H),7.36(t,J=7.5Hz,2H),7.46(d,J=7.6Hz,1H),7.51(t,J=7.7Hz,1H),7.71(d,J=7.3Hz,1H),7.77(d,J=7.8Hz,2H),7.79(s,1H),9.15(s,1H),10.26(s,1H)。LCMS t=5.6min,m/z计算值C19H19N2O2;C19H18N2NaO2;C38H37N4O4;C38H36N4NaO4 307.14;329.13;613.28;635.26[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值307.17;329.15;613.26;635.24。
实施例04-01至04-103
实施例04-01
N-环己基3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(04-01)的制备:方法A;将氯甲酸异丁酯(IBCF,0.285mL,2.0eq)加入至实施例01-03的化合物(250mg,1.1mmol,1.0eq)中,其装有CH2Cl2(1.0mL)的螺口瓶中进行搅拌。将N-甲基吗啉(NMM,0.36mL,3.0eq)于0℃下分三批加入,在搅拌1h后,加入环己胺(0.15mL,1.2eq),密封,并且在室温下搅拌18h。粗材料经重结晶纯化。从CHCl3重结晶后,1.1mmol规模的反应产生了140mg题述化合物(41%产量)。1H NMR(D6-DMSO)δ1.10-1.16(m,1H),1.30-1.36(m,4H),1.57(s,3H),1.61(d,J=9.7Hz,1H),1.73-1.74(m,2H),1.80-1.82(m,2H),2.20-2.23(m,2H),2.64-2.66(m,2H),3.75-3.77(m,1H),7.37(d,J=8.1Hz,1H),7.42(t,J=7.7Hz,1H),7.60(d,J=7.7Hz,1H),7.69(s,1H),8.22(d,J=7.9Hz,1H),9.08(s,1H)。LCMS t=5.8min,m/z计算值C19H25N2O2;C19H24N2NaO2;C38H49N4O4;C38H49N4NaO4 313.19;335.17;625.38;647.36[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值313.23;335.20;625.37;647.37。
实施例04-02
3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(萘-1-基)苯甲酰胺(3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(naphthalen-1-yl)benzamide)(04-02)的制备:按照实施例04-01的方法,由实施例01-03的化合物和1-萘胺制备题述化合物;从CHCl3重结晶后,1.1mmol规模中产生了100mg产物(26%产量)。1H NMR(D6-DMSO)δ1.61(s,3H),2.23-2.25(m,2H),2.74-2.76(m,2H),7.50(d,J=7.9Hz,2H),7.53-7.58(m,4H),7.60(d,J=7.2Hz,2H),7.87(t,J=8.9Hz,2H),7.91(s,1H),7.96-8.00(m,2H),9.17(s,1H),10.46(s,1H)。LCMS t=5.9min,m/z计算值C23H21N2O2;C23H20N2NaO2;C46H41N4O4;C46H40N4NaO4357.16;379.14;713.31;735.29[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值357.18;379.15;713.32;735.31。
实施例04-03
3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(吡啶-4-基)苯甲酰胺(04-03)的制备:按照实施例04-01的方法,由实施例01-03的化合物和4-氨基吡啶制备题述化合物;从MeOH重结晶后,1.1mmol规模产生了60mg产物(18%产量)。1H NMR(D6-DMSO)δ1.60(s,3H),2.23-2.25(m,2H),2.71-2.73(m,2H),7.49-7.54(m,2H),7.72(d,J=7.1Hz,1H),7.80(s,3H),8.49(d,J=4.7Hz,2H),9.17(s,1H),10.62(s,1H)。LCMS t=3.0min,m/z计算值C18H18N3O2;C18H17N3NaO2;C36H34N6NaO4 308.14;330.12;637.25[M+H]+;[M+Na]+;[2M+Na]+,实验值308.17;330.14;637.24。
实施例04-04
N-(4-甲氧基苯基)-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(04-04)的制备:方法B;将IBCF(0.98eq)加入至实施例01-03的化合物(250mg,1.1mmol,1.0eq)中,在装有CH2Cl2(3.0mL)的螺口瓶中进行搅拌。NMM(0.95eq)于0℃加入。搅拌1h后,加入4-氨基苯甲醚(4-aminoanisole)(163mg,1.0eq),密封,并且在室温下搅拌18h。将粗材料直接加入至KP-SilTM柱(10g)上,在-Isolera Four仪器上使用分级式梯度法将产物与杂质分离,于254/365nm下监控紫外线踪迹。分级式梯度法利用两种或三种溶剂(丙酮、己烷、EtOAc或MeOH)从非极性阶段(step)向极性阶段运行。使用的典型增量为己烷:EtOAc(H:E)以1:1–1:3–1:19–100%EtOAc为阶段,然后,必要时采用2-5%增量的MeOH。洗脱溶剂系统(ESS)为洗脱产物的溶剂阶段并且以下述规格(format)ESS=H:E(X:X),或EtOAc中MeOH的百分数(%)表示。随后进行研磨或者从适当的溶剂中重结晶。经色谱分析(ESS=EtOAc:丙酮(1:3))以及从EtOAc重结晶后,在1.1mmol规模上发生的反应产生了30mg题述化合物(8%产量)。1H NMR(D6-DMSO)δ1.59(s,3H),2.23-2.25(m,2H),2.70-2.72(m,2H),3.75(s,3H),6.93(d,J=8.7Hz,2H),7.44(d,J=7.6Hz,1H),7.49(t,J=7.6Hz,1H),7.67(d,J=8.7Hz,2H),7.70(d,J=7.5Hz,1H),7.78(s,1H),9.14(s,1H),10.14(s,1H)。LCMS t=5.6min,m/z计算值C20H21N2O3;C20H20N2NaO3;C40H41N4O6;C40H40N4NaO6 337.16;359.14;673.30;695.28[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值337.19;359.17;673.33;695.32。
实施例04-05
3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(邻甲苯基)苯甲酰胺(04-05)的制备:按照实施例04-04的方法,由实施例01-03的化合物和邻甲苯胺制备题述化合物;经色谱分析(ESS=H:E(1:1))以及从MeOH重结晶后,1.1mmol规模产生了10mg产物(3%产量)。1HNMR(D6-DMSO)δ1.59(s,3H),2.23-2.25(m,5H),2.71-2.73(m,2H),7.18(t,J=7.2Hz,1H),7.22(t,J=7.0Hz,1H),7.28(d,J=7.2Hz,1H),7.33(d,J=7.5Hz,1H),7.36(d,J=7.4Hz,1H),7.50(t,J=7.7Hz,1H),7.74(d,J=7.2Hz,1H),7.81(s,1H),9.13(s,1H),9.90(s,1H)。LCMS t=5.6min,m/z计算值C20H21N2O2;C20H20N2NaO2;C40H41N4O4;C40H40N4NaO4 321.16;343.14;641.31;663.29[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值321.19;343.16;641.31;663.32。
实施例04-06
3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(间甲苯基)苯甲酰胺(04-06)的制备:按照实施例04-04的方法,由实施例01-03的化合物和间甲苯胺制备题述化合物;经色谱分析(ESS=EtOAc)以及从MeOH重结晶后,1.1mmol规模产生了30mg产物(9%产量)。1HNMR(D6-DMSO)δ1.60(s,3H),2.22-2.25(m,2H),2.31(s,3H),2.70-2.72(m,2H),6.93(d,J=7.5Hz,1H),7.23(t,J=7.7Hz,1H),7.46(d,J=8.2Hz,1H),7.50(t,J=7.8Hz,1H),7.57(d,J=8.1Hz,1H),7.62(s,1H),7.71(d,J=7.6Hz,1H),7.79(s,1H),9.15(s,1H),10.18(s,1H)。LCMS t=5.8min,m/z计算值C20H21N2O2;C20H20N2NaO2;C40H41N4O4;C40H40N4NaO4 321.16;343.14;641.31;663.29[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值321.19;343.16;641.31;663.29。
实施例04-07
3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(对甲苯基)苯甲酰胺(04-07)的制备:按照实施例04-04的方法,由实施例01-03的化合物和对甲苯胺制备题述化合物;经色谱分析(ESS=EtOAc)以及从CHCl3重结晶后,1.1mmol规模产生了10mg产物(3%产量)。1HNMR(D6-DMSO)δ1.59(s,3H),2.22-2.25(m,2H),2.28(s,3H),2.70-2.72(m,2H),7.16(d,J=8.2Hz,2H),7.45(d,J=8.1Hz,1H),7.50(t,J=7.8Hz,1H),7.65(d,J=8.3Hz,2H),7.70(d,J=7.6Hz,1H),7.79(s,1H),9.14(s,1H),10.18(s,1H)。LCMS t=5.8min,m/z计算值C20H21N2O2;C20H20N2NaO2;C40H41N4O4;C40H40N4NaO4 321.16;343.14;641.31;663.29[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值321.19;343.16;641.31;663.30。
实施例04-08
N-(2-氟苯基)-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(04-08)的制备:按照实施例04-04的方法,由实施例01-03的化合物和2-氟苯胺制备题述化合物;经色谱分析(ESS=EtOAc)以及从MeOH重结晶后,1.1mmol规模产生40mg产物(11%产量)。1H NMR(D6-DMSO)δ1.59(s,3H),2.22-2.25(m,2H),2.70-2.72(m,2H),7.21-7.25(m,1H),7.29-7.33(m,2H),7.48-7.52(m,2H),7.59(t,J=7.2Hz,1H),7.74(d,J=7.4Hz,1H),7.82(s,1H),9.15(s,1H),10.14(s,1H)。LCMS t=5.6min,m/z计算值C19H18FN2O2;C19H17FN2NaO2;C38H35F2N4O4;C38H34F2N4NaO4 325.14;347.12;649.26;671.24[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值325.16;347.14;649.26;671.26。
实施例04-09
N-(3-溴苯基)-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(04-09)的制备:按照实施例04-04的方法,由实施例01-03的化合物和3-溴苯胺制备题述化合物;经色谱分析(ESS=EtOAc)以及从MeOH重结晶后,1.1mmol规模产生了40mg产物(9%产量)。1HNMR(D6-DMSO)δ1.60(s,3H),2.23-2.25(m,2H),2.71-2.73(m,2H),7.31-7.34(m,2H),7.48(d,J=8.1Hz,1H),7.52(t,J=7.8Hz,1H),7.71(d,J=7.5Hz,1H),7.76(d,J=7.8Hz,1H),7.79(s,1H),8.11(s,1H),9.16(s,1H),10.40(s,1H)。LCMS t=5.9min,m/z计算值C19H18BrN2O2;C19H17BrN2NaO2;C38H35BrN4O4;C38H34BrN4NaO6 385.06;387.05;407.04,409.04;771.10;793.08[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值385.06,387.06;407.04,409.04;771.12;793.11。
实施例04-10
N-(4-溴苯基)-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(04-10)的制备:按照实施例04-04的方法,由实施例01-03的化合物和4-溴苯胺制备题述化合物;经色谱分析(ESS=EtOAc)以及从CHCl3重结晶后,1.1mmol规模产生了10mg产物(2%产量)。1HNMR(D6-DMSO)δ1.60(s,3H),2.23-2.26(m,2H),2.71-2.73(m,2H),7.47-7.48(m,1H),7.51(t,J=7.7Hz,1H),7.55(d,J=8.8Hz,2H),7.70(d,J=7.7Hz,1H),7.76(d,J=8.8Hz,2H),7.79(s,1H),9.14(s,1H),10.38(s,1H)。LCMS t=5.9min,m/z计算值C19H18BrN2O2;C19H17BrN2NaO2;C38H35BrN4O4;C38H34BrN4NaO6385.06,387.05;407.04,409.04;771.10;793.08[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值385.06,387.06;407.04,409.03;771.12;793.11。
实施例04-11
3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(3-(三氟甲基)苯基)-苯甲酰胺(04-11)的制备:按照实施例04-04的方法,由实施例01-03的化合物和3-(三氟甲基)苯胺制备题述化合物;经色谱分析(ESS=EtOAc)以及从CHCl3重结晶后,1.1mmol规模产生了30mg产物(7%产量)。1H NMR(D6-DMSO)δ1.60(s,3H),2.23-2.25(m,2H),2.71-2.73(m,2H),7.46-7.50(m,2H),7.53(t,J=7.8Hz,1H),7.61(t,J=8.0Hz,1H),7.74(d,J=7.6Hz,1H),7.82(s,1H),8.06(d,J=8.2Hz,1H),8.25(s,1H),9.16(s,1H),10.56(s,1H)。LCMS t=6.1min,m/z计算值C20H18F3N2O2;C20H17F3N2NaO2;C40H35F6N4O4;C40H34F6N4NaO6 375.13;397.11;749.26;771.24[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值375.14;397.12;749.27;771.26。
实施例04-12
3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(4-(三氟甲基)苯基)-苯甲酰胺(04-12)的制备:按照实施例04-04的方法,由实施例01-03的化合物和3-(三氟甲基)苯胺制备题述化合物;经色谱分析(ESS=EtOAc)以及从CHCl3重结晶后,1.1mmol规模产生了10mg产物(2%产量)。1H NMR(D6-DMSO)δ1.60(s,3H),2.23-2.25(m,2H),2.71-2.73(m,2H),7.49-7.50(m,1H),7.53(t,J=7.7Hz,1H),7.72-7.75(m,3H),7.81(s,1H),8.01(d,J=8.5Hz,2H),9.16(s,1H),10.59(s,1H)。LCMS t=6.1min,m/z计算值C20H18F3N2O2;C20H17F3N2NaO2;C40H34F6N4NaO6 375.13;397.11;771.24[M+H]+;[M+Na]+;[2M+Na]+,实验值375.16;397.12;771.26。
实施例04-13
3-氯-N-甲基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(04-13)的制备:方法C;将NMM(1.2eq)和IBCF(1.2e eq)加入至实施例02-02的化合物(100mg,0.38mmol,1.0eq)中,在装有CH2Cl2(10mL)的螺口瓶中进行搅拌。搅拌30min后,加入胺、甲胺(2M,225mL,0.45mmol,1.2eq)和两份NMM(1.2eq),密封,并且在室温下搅拌48h。将粗材料直接加入至KP-SilTM柱(10g),在-Isolera Four仪器上使用分级式梯度法(请参见实施例04-04方法B)将产物从杂质中分离,于254/365nm下监控紫外线踪迹。一些在较高浓度下进行的反应允许粗固体产物沉淀。在这些情况下,纯化过程为经CH2Cl2、水以及直接乙醚漂洗进行过滤。经色谱分析(ESS=MeOH(6%))以及EtOAc研磨后,在0.38mmol规模上发生的反应产生了35mg题述化合物(33%产量)。1H NMR(D6-DMSO)δ1.45(s,3H),2.21-2.23(m,2H),2.47-2.49(m,2H),2.78(s,3H),7.44(d,J=8.3Hz,1H),7.80(d,J=8.2Hz,1H),7.98(s,1H),8.56-8.58(m,1H),8.93(s,1H)。LCMS t=5.1min,m/z计算值C14H16ClN2O2;C14H15ClN2NaO2;C28H31Cl2N4O4;C28H30Cl2N4NaO4 279.09;301.07;557.17;579.15[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值279.14;301.11;557.16;579.15。
实施例04-14
3-氯-N-环己基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(04-14)的制备:按照实施例04-13的方法,由实施例02-02的化合物和环己胺制备题述化合物;经色谱分析(ESS=EtOAc)和EtOAc研磨后,0.38mmol规模产生了56mg产物(43%产量)。1H NMR(D6-DMSO)δ1.10-1.18(m,1H),1.23-1.34(m,4H),1.45(s,3H),1.61(d,J=12.1Hz,1H),1.73(s,2H),1.81(s,2H),2.20-2.23(m,2H),2.46-2.48(m,2H),3.75(s,1H),7.42(d,J=8.3Hz,1H),7.82(d,J=8.2Hz,1H),8.00(d,J=1.3Hz,1H),8.34(d,J=7.8Hz,1H),8.95(s,1H)。LCMS t=6.0min,m/z计算值C19H24ClN2O2;C19H23ClN2NaO2;C36H47Cl2N4O4;C36H47Cl2N4NaO4347.15;369.13;693.30;715.28[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值347.17;369.15;693.32;715.30。
实施例04-15
3-氯-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(萘-1-基)-苯甲酰胺(04-15)的制备:按照实施例04-13的方法,由实施例02-02的化合物和1-氨基-萘制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.38mmol规模产生了25mg产物(17%产量)。1H NMR(D6-DMSO)δ1.51(s,3H),2.24-2.26(m,2H),2.54-2.56(m,2H),7.52-7.61(m,4H),7.89(d,J=8.0Hz,1H),7.98-8.01(m,3H),8.06(d,J=7.7Hz,1H),8.27(s,1H),9.03(s,1H),10.55(s,1H)。LCMS t=5.9min,m/z计算值C23H20ClN2O2;C23H19ClN2NaO2;C46H39Cl2N4O4;C46H38Cl2N4NaO4 391.12;413.10;781.23;803.22[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值391.22;413.11;781.26;803.25。
实施例04-16
3-氯-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-苯基苯甲酰胺的制备:按照实施例04-13的方法,由实施例02-02的化合物和苯胺(aniline)制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.38mmol规模产生了20mg产物(16%产量)。1H NMR(D6-DMSO)δ1.48(s,3H),2.23-2.25(m,2H),2.50-2.51(m,2H),7.12(t,J=7.3Hz,1H),7.37(t,J=7.8Hz,2H),7.50(d,J=8.3Hz,1H),7.77(d,J=7.9Hz,2H),7.94(dd,J=8.2,1.4Hz,1H),8.14(d,J=1.4Hz,1H),9.00(s,1H),10.34(s,1H)。LCMS t=5.8min,m/z计算值C19H18ClN2O2;C19H17ClN2NaO2;C38H34Cl2N4NaO4341.11;363.09;703.19[M+H]+;[M+Na]+;[2M+Na]+,实验值341.13;363.10;703.20。
实施例04-17
3-氯-N-(2-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(04-17)的制备:按照实施例04-13的方法,由实施例02-02的化合物和邻氨基苯甲醚(o-anisidine)制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.38mmol规模产生了55mg产物(39%产量)。1H NMR(D6-DMSO)δ1.48(s,3H),2.22-2.25(m,2H),2.50-2.52(m,2H),3.83(s,3H),6.97(t,J=7.6Hz,1H),7.10(d,J=8.1Hz,1H),7.21(t,J=7.6Hz,1H),7.48(d,J=8.3Hz,1H),7.65(d,J=7.6Hz,1H),7.94(d,J=8.1Hz,1H),8.13(s,1H),9.00(s,1H),9.67(s,1H)。LCMSt=5.9min,m/z计算值C20H20ClN2O3;C20H19ClN2NaO3;C40H39Cl2N4O6;C40H38Cl2N4NaO6 371.11;393.10;741.22;763.21[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值371.13;393.11;741.26;763.24。
实施例04-18
3-氯-N-(3-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(04-18)的制备:按照实施例04-13的方法,由实施例02-02的化合物和间氨基苯甲醚制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.38mmol规模产生了3mg产物(2%产量)。1H NMR(D6-DMSO)δ1.48(s,3H),2.23-2.25(m,2H),2.50-2.52(m,2H),3.76(s,3H),6.70(d,J=8.3Hz,1H),7.26(t,J=8.3Hz,1H),7.37(d,J=8.3Hz,1H),7.45(s,1H),7.49(d,J=8.3Hz,1H),7.93(dd,J=8.3,1.6Hz,1H),8.13(d,J=1.6Hz,1H),9.00(s,1H),10.30(s,1H)。LCMS t=5.8min,m/z计算值C20H20ClN2O3;C20H19ClN2NaO3;C40H39Cl2N4O6;C40H38Cl2N4NaO6 371.11;393.10;741.22;763.21[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值371.13;393.11;741.26;763.23。
实施例04-19
3-氯-N-(4-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(04-19)的制备:按照实施例04-13的方法,由实施例02-02的化合物和4-氨基苯甲醚(4-aminoanisole)制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.38mmol规模产生了5mg产物(4%产量)。1H NMR(D6-DMSO)δ1.48(s,3H),2.22-2.25(m,2H),2.50-2.51(m,2H),3.75(s,3H),6.94(d,J=8.9Hz,2H),7.49(d,J=8.3Hz,1H),7.66(d,J=8.9Hz,2H),7.93(dd,J=8.3,1.2Hz,1H),8.12(s,1H),8.98(s,1H),10.22(s,1H)。LCMS t=5.7min,m/z计算值C20H20ClN2O3;C20H19ClN2NaO3;C40H39Cl2N4O6;C40H38Cl2N4NaO6 371.11;393.10;741.22;763.21[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值371.13;393.10;741.24;763.23。
实施例04-20
3-氯-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(邻甲苯基)苯甲酰胺(04-20)的制备:按照实施例04-13的方法,由实施例02-02的化合物和邻甲苯胺制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.38mmol规模产生了45mg产物(32%产量)。1H NMR(D6-DMSO)δ1.48(s,3H),2.23-2.25(m,5H),2.50-2.51(m,2H),7.18-7.23(m,2H),7.28(d,J=7.3Hz,1H),7.32(d,J=7.5Hz,1H),7.50(d,J=8.3Hz,1H),7.96(d,J=8.1Hz,1H),8.14(s,1H),8.99(s,1H),10.02(s,1H)。LCMS t=5.7min,m/z计算值C20H20ClN2O2;C20H19ClN2NaO2;C40H39Cl2N4O4;C40H38Cl2N4NaO4355.12;377.10;709.23;731.22[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值355.14;377.12;709.25;731.24。
实施例04-21
3-氯-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(间甲苯基)苯甲酰胺(04-21)的制备:按照实施例04-13的方法,由实施例02-02的化合物和间甲苯胺制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.38mmol规模产生了42mg产物(30%产量)。1H NMR(D6-DMSO)δ1.48(s,3H),2.22-2.25(m,2H),2.31(s,3H),2.50-2.51(m,2H),6.94(d,J=7.4Hz,1H),7.24(t,J=7.8Hz,1H),7.49(d,J=8.3Hz,1H),7.56(d,J=8.0Hz,1H),7.61(s,1H),7.93(d,J=8.3Hz,1H),8.13(d,J=1.2Hz,1H),8.98(s,1H),10.26(s,1H)。LCMS t=5.9min,m/z计算值C20H20ClN2O2;C20H19ClN2NaO2;C40H39Cl2N4O4;C40H38Cl2N4NaO4355.12;377.10;709.23;731.22[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值355.14;377.12;709.25;731.24。
实施例04-22
3-氯-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(对甲苯基)苯甲酰胺(04-22)的制备:按照实施例04-13的方法,由实施例02-02的化合物和对甲苯胺制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.38mmol规模产生了25mg产物(18%产量)。1H NMR(D6-DMSO)δ1.48(s,3H),2.23-2.24(m,2H),2.29(s,3H),2.50-2.51(m,2H),7.17(d,J=8.1Hz,2H),7.49(d,J=8.3Hz,1H),7.64(d,J=8.1Hz,2H),7.93(d,J=8.2Hz,1H),8.13(s,1H),8.96(s,1H),10.25(s,1H)。13C NMR(D6-DMSO)δ7.7,20.5,25.7,32.7,110.8,120.5,127.2,128.8,128.9,129.0,132.9,136.4,139.4,163.3,168.7,202.7。LCMSt=5.9min,m/z计算值C20H20ClN2O2;C20H19ClN2NaO2;C40H39Cl2N4O4;C40H38Cl2N4NaO4 355.12;377.10;709.23;731.22[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值355.12;377.10;709.21;731.20。
实施例04-23
(1R,4R)-N-甲基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)环己甲酰胺(04-23)的制备:按照实施例04-13的方法,由实施例01-33的化合物和甲胺制备题述化合物;经色谱分析(ESS=MeOH(15%))和EtOAc研磨后,0.42mmol规模产生了40mg产物(38%产量)。1H NMR(D6-DMSO)δ1.33-1.50(m,9H),1.73(d,J=12.0Hz,2H),1.84(d,J=10.6Hz,2H),2.04-2.09(m,1H),2.09-2.11(2H),2.54(d,J=4.5Hz,2H),3.25-3.30(m,1H),6.84-6.87(m,1H),7.70(d,J=4.3Hz,1H)。LCMS t=1.2min,m/z计算值C14H23N2O2;C14H22N2NaO2;C28H45N4O4;C28H44N4NaO4 251.18;273.16;501.34;523.33[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值251.28;273.25;501.41;523.40。
实施例04-24
(1R,4R)-N-环己基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-环己甲酰胺(04-24)的制备:按照实施例04-13的方法,由实施例01-33的化合物和环己胺制备题述化合物;经色谱分析(ESS=MeOH(8%))和EtOAc研磨后,0.42mmol规模产生了75mg产物(56%产量)。1H NMR(D6-DMSO)δ1.10-1.18(m,4H),1.20-1.28(m,2H),1.30-1.40(m,2H),1.40-1.50(5H),1.54(d,J=10.8Hz,1H),1.62-1.75(m,7H),1.83(d,J=10.4Hz,1H),2.00-2.08(m,1H),2.10-2.13(m,2H),3.46-3.53(m,1H),6.85-6.67(m,1H),7.57(d,J=7.4Hz,1H)。LCMSt=5.4min,m/z计算值C19H31N2O2;C19H30N2NaO2;C38H61N4NaO4;C38H60N4NaO4 319.24;341.22;637.47;659.45[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值319.32;341.29;637.57;659.60。
实施例04-25
(1R,4R)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(萘-1-基)环己甲酰胺(04-25)的制备:按照实施例04-13的方法,由实施例01-33的化合物和1-氨基萘制备题述化合物;经色谱分析(ESS=MeOH(8%))和EtOAc研磨后,0.42mmol规模产生了23mg产物(15%产量)。1H NMR(D6-DMSO)δ1.45-1.55(m,5H),1.62(q,J=12.1Hz,2H),1.94(d,J=10.8Hz,2H),2.01(d,J=12.7Hz,2H),2.11-2.13(m,2H),2.51-2.55(m,3H),3.35-3.45(m,1H),6.92(d,J=7.7Hz,1H),7.48(t,J=7.8Hz,1H),7.52-7.57(m,2H),7.65(d,J=7.3Hz,1H),7.76(d,J=8.1Hz,1H),7.94(d,J=7.1Hz,1H),8.04(d,J=7.7Hz,1H),9.85(s,1H)。LCMS t=5.6min,m/z计算值C23H27N2O2;C23H26N2NaO2;C46H53N4O4;C46H52N4NaO4 363.21;385.18;725.41;747.39[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值363.34;385.25;725.53;747.52。
实施例04-26
(1R,4R)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-苯基环己甲酰胺(04-26)的制备:按照实施例04-13的方法,由实施例01-33的化合物和苯胺制备题述化合物;经色谱分析(ESS=MeOH(10%))和EtOAc研磨后,0.42mmol规模产生了65mg产物(50%产量)。1H NMR(D6-DMSO)δ1.38-1.60(m,8H),1.83-1.98(m,5H),2.08-2.18(m,2H),2.28-2.39(m,1H),3.28-3.30(m,1H),6.89(s,1H),7.01(s,1H),7.28(s,2H),7.60(s,2H),9.85(s,1H)。LCMS t=5.4min,m/z计算值C19H25N2O2;C19H24N2NaO2;C38H49N4O4;C38H48N4NaO4 313.19;335.17;625.37;647.36[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值313.27;335.25;625.47;647.46。
实施例04-27
(1R,4R)-N-(2-甲氧基苯基)-4-(2-甲基-3-氧代环戊基-1-烯-1-基)氨基)环己甲酰胺(04-27)的制备:按照实施例04-13的方法,由实施例01-33的化合物和邻氨基苯甲醚制备题述化合物;经色谱分析(ESS=MeOH(8%))和EtOAc研磨后,0.42mmol规模产生了75mg产物(52%产量)。1H NMR(D6-DMSO)δ1.40-1.56(m,8H)1.84-1.89(m,5H),2.10-2.12(m,2H),2.47-2.52(m,2H),3.83(s,3H),6.86-6.91(m,2H),7.01-7.07(m,2H),7.94(d,J=7.8Hz,1H),9.02(s,1H)。LCMS t=5.5min,m/z计算值C20H27N2O3;C20H26N2NaO3;C40H53N4O6;C40H52N4NaO6 343.20;365.18;685.40;707.38[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值343.30;365.25;685.51;707.57。
实施例04-28
(1R,4R)-N-(3-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)环己甲酰胺(04-28)的制备:按照实施例04-13的方法,由实施例01-33的化合物和间氨基苯甲醚制备题述化合物;经色谱分析(ESS=MeOH(8%))和EtOAc研磨后,0.42mmol规模产生了70mg产物(49%产量)。1H NMR(D6-DMSO)δ1.40-1.57(m,7H),1.85-1.91(m,5H),2.11-2.13(m,2H),2.28(t,J=11.6Hz,1H),2.52-2.54(m,2H),3.71(s,3H),6.60(d,J=7.6Hz,1H),6.89(d,J=7.9Hz,1H),7.13(d,J=7.8Hz,1H),7.18(d,J=8.0Hz,1H),7.32(s,1H),9.84(s,1H)。LCMS t=5.4min,m/z计算值C20H27N2O3;C20H26N2NaO3;C40H53N4O6;C40H52N4NaO6 343.20;365.18;685.40;707.38[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值343.27;365.25;685.51;707.50。
实施例04-29
(1R,4R)-N-(4-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)环己甲酰胺(04-29)的制备:按照实施例04-13的方法,由实施例01-33的化合物和对氨基苯甲醚制备题述化合物;经色谱分析(ESS=MeOH(8%))和EtOAc研磨后,0.42mmol规模产生了35mg产物(24%产量)。1H NMR(D6-DMSO)δ1.38-1.58(m,7H),1.84-1.90(m,5H),2.10-2.12(m,2H),2.25(t,J=11.7Hz,1H),2.51-2.54(m,2H),3.71(s,3H),6.84-6.89(m,3H),7.50(d,J=8.7Hz,2H),9.71(s,1H)。LCMS t=5.3min,m/z计算值C20H27N2O3;C20H26N2NaO3;C40H53N4O6;C40H52N4NaO6 343.20;365.18;685.40;707.38[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值343.27;365.25;685.50;707.49。
实施例04-30
(1R,4R)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(邻甲苯基)环己甲酰胺(04-30)的制备:按照实施例04-13的方法,由实施例01-33的化合物和邻甲苯胺制备题述化合物;经色谱分析(ESS=MeOH(7%))和EtOAc研磨后,0.42mmol规模产生了22mg产物(16%产量)。1H NMR(D6-DMSO)δ1.41-1.59(m,7H),1.89-1.92(m,4H),2.11-2.13(m,2H),2.18(s,3H),2.37(t,J=10.9Hz,1H),2.51-2.53(m,2H),6.88-6.93(m,1H),7.07(t,J=6.9Hz,1H),7.14(t,J=7.1Hz,1H),7.19(d,J=7.1Hz,1H),7.33(d,J=7.5Hz,1H),9.22(s,1H)。LCMS t=5.3min,m/z计算值C20H27N2O2;C20H26N2NaO2;C40H53N4O4;C40H52N4NaO4 327.21;349.19;653.41;675.39[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值327.28;349.26;653.50;675.49。
实施例04-31
(1R,4R)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(间甲苯基)环己甲酰胺(04-31)的制备:按照实施例04-13的方法,由实施例01-33的化合物和间甲苯胺制备题述化合物;经色谱分析(ESS=MeOH(7%))和EtOAc研磨后,0.42mmol规模产生了70mg产物(51%产量)。1H NMR(D6-DMSO)δ1.38-1.58(m,7H),1.84-1.91(m,4H),2.10-2.12(m,2H),2.26-2.31(m,4H),2.51-2.53(m,2H),3.33-3.35(m,1H),6.83(d,J=7.4Hz,1H),6.88(d,J=8.3Hz,1H),7.`5(d,J=7.8Hz,1H),7.36(d,J=8.0Hz,1H),7.46(s,1H),9.77(s,1H)。LCMS t=5.5min,m/z计算值C20H27N2O2;C20H26N2NaO2;C40H53N4O4;C40H52N4NaO4 327.21;349.19;653.41;675.39[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值327.28;349.26;653.50;675.49。
实施例04-32
(1R,4R)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(对甲苯基)-环己甲酰胺(04-32)的制备:按照实施例04-13的方法,由实施例01-33的化合物和对甲苯胺制备题述化合物;经色谱分析(ESS=MeOH(7%))和EtOAc研磨后,0.42mmol规模产生了60mg产物(44%产量)。1H NMR(D6-DMSO)δ1.28-1.58(m,7H),1.84-1.90(m,4H),2.10-2.12(m,2H),2.23-2.30(m,4H),2.51-2.53(m,2H),3.30-3.35(m,1H),6.89(d,J=8.4Hz,1H),7.08(d,J=8.1Hz,2H),7.48(d,J=8.2Hz,2H),9.76(s,1H)。13C NMR(D6-DMSO)δ6.8,20.4,23.8,28.1,32.5,32.7,43.8,51.6,105.0,119.0,129.0,131.8,136.9,172.1,173.6,200.0。LCMSt=5.6min,m/z计算值C20H27N2O2;C20H26N2NaO2;C40H53N4O4;C40H52N4NaO4 327.21;349.19;653.41;675.39[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值327.28;349.26;653.50;675.49。
实施例04-33
(1R,4R)-N-(3-氟苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-环己甲酰胺(04-33)的制备:按照实施例04-13的方法,由实施例01-33的化合物和间氟苯胺制备题述化合物;经色谱分析(ESS=MeOH(7%))和EtOAc研磨后,0.42mmol规模产生了72mg产物(52%产量)。1H NMR(D6-DMSO)δ1.38-1.57(m,7H),1.86-1.91(m,4H),2.10-2.12(m,2H),2.29(t,J=11.9Hz,1H),2.51-2.53(m,2H),3.33-2.35(m,1H),6.83-6.90(m,2H),7.29-7.33(m,2H),7.61(d,J=11.9Hz,1H),10.08(s,1H)。LCMS t=5.5min,m/z计算值C19H24FN2O2;C19H23FN2NaO2;C38H47F2N4O4;C38H46F2N4NaO4 331.18;353.16;661.36;683.34[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值331.27;353.23;661.45;683.44。
实施例04-34
(1R,4R)-N-(4-氯苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-环己甲酰胺(04-34)的制备:按照实施例04-13的方法,由实施例01-33的化合物和对氯苯胺制备题述化合物;经色谱分析(ESS=MeOH(7%))和EtOAc研磨后,0.42mmol规模产生了30mg产物(21%产量)。1H NMR(D6-DMSO)δ1.38-1.58(m,7H),1.86-1.91(m,4H),2.10-2.12(m,2H),2.28(t,J=11.9Hz,1H),2.51-2.53(m,2H),3.33-3.35(m,1H),6.88(d,J=8.3Hz,1H),7.34(d,J=8.8Hz,2H),7.63(d,J=8.7Hz,2H),10.01(s,1H)。LCMS t=5.7min,m/z计算值C19H24ClN2O2;C19H23ClN2NaO2;C38H47Cl2N4O4;C38H46Cl2N4NaO4 347.15;369.13;693.30;715.28[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值347.22;369.20;693.40;715.39。
实施例04-35
(1S,4S)-N-甲基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)环己甲酰胺(04-35)的制备:按照实施例04-13的方法,由实施例01-34的化合物和甲胺制备题述化合物;经色谱分析(ESS=MeOH(12%))和EtOAc研磨后,0.42mmol规模产生了11mg产物(10%产量)。1H NMR(D6-DMSO)δ1.45-1.52(m,5H),1.58-1.65(m,4H),1.93-2.00(m,2H),2.09-2.13(m,2H),2.26-2.30(m,1H),2.49-2.51(m,2H),2.58(d,J=3.9Hz,3H),3.33-3.35(m,1H),6.80-6.86(m,1H),7.60-7.66(m,1H)。LCMS t=1.4min,m/z计算值C14H23N2O2;C14H22N2NaO2;C28H44N4NaO4 251.18;273.16;523.33[M+H]+;[M+Na]+;[2M+Na]+,实验值251.28;273.25;523.40。
制备例04-36
(1S,4S)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-苯基环己甲酰胺(04-36)的制备:按照实施例04-13的方法,由实施例01-34的化合物和苯胺制备题述化合物;经色谱分析(ESS=MeOH(7%))和EtOAc研磨后,0.42mmol规模产生了16mg产物(12%产量)。1HNMR(D6-DMSO)δ1.45-1.55(m,3H),1.61-1.68(m,5H),1.74-1.81(m,2H),2.00-2.18(m,2H),2.09-2.12(m,2H),2.53-2.55(m,2H),3.40-3.60(m,1H),6.88(s,1H),7.02(t,J=7.4Hz,1H),7.28(t,J=7.9Hz,2H),7.62(d,J=7.9Hz,2H),9.74(s,1H)。LCMS t=5.5min,m/z计算值C19H25N2O2;C19H24N2NaO2;C38H48N4NaO4 313.19;335.17;647.36[M+H]+;[M+Na]+;[2M+Na]+,实验值313.28;335.25;647.46。
实施例04-37
(1S,4S)-N-(2-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-环己甲酰胺(04-37)的制备:按照实施例04-13的方法,由实施例01-34的化合物和邻氨基苯甲醚制备题述化合物;经色谱分析(ESS=MeOH(8%))和EtOAc研磨后,0.42mmol规模产生了60mg产物(42%产量)。1H NMR(D6-DMSO)δ1.45-1.54(m,3H),1.60-1.69(m,5H),1.71-1.77(m,2H),1.98-2.05(m,2H),2.08-2.12(m,2H),2.51-2.53(m,1H),2.68-2.72(m,1H),3.42-3.58(m,1H),3.83(s,3H),6.85-6.92(m,2H),7.02-7.08(m,2H),7.95(d,J=7.8Hz,1H),8.87(s,1H)。LCMS t=5.6min,m/z计算值C20H27N2O3;C20H26N2NaO3;C40H52N4NaO6 343.20;365.18;707.38[M+H]+;[M+Na]+;[2M+Na]+,实验值343.28;365.26;707.52。
实施例04-38
(1S,4S)-N-(3-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-环己甲酰胺(04-38)的制备:按照实施例04-13的方法,由实施例01-34的化合物和间氨基苯甲醚制备题述化合物;经色谱分析(ESS=MeOH(8%))和EtOAc研磨后,0.42mmol规模产生了3mg产物(2%产量)。1H NMR(D6-DMSO)δ1.45-1.53(m,3H),1.59-1.69(m,5H),1.73-1.78(m,2H),1.99-2.08(m,2H),2.09-2.12(m,2H),2.49-2.51(m,2H),3.45-3.55(m,1H),3.72(s,3H),6.60(d,J=6.8Hz,1H),6.88-6.92(m,1H),7.14-7.20(m,2H),7.37(s,1H),9.74(s,1H)。LCMS t=5.6min,m/z计算值C20H27N2O3;C20H26N2NaO3;C40H52N4NaO6 343.20;365.18;707.38[M+H]+;[M+Na]+;[2M+Na]+,实验值343.20;365.18;707.35。
实施例04-39
(1S,4S)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(间甲苯基)-环己甲酰胺(04-39)的制备:按照实施例04-13的方法,由实施例01-34的化合物和间甲苯胺制备题述化合物;经色谱分析(ESS=MeOH(7%))和EtOAc研磨后,0.42mmol规模产生了1mg产物(1%产量)。1H NMR(D6-DMSO)δ1.46-1.53(m,3H),1.59-1.69(m,5H),1.73-1.81(m,2H),2.00-2.07(m,2H),2.09-2.14(m,2H),2.26(s,3H),2.50-2.53(m,2H),3.40-3.53(m,1H),6.84(d,J=7.4Hz,1H),6.85-6.90(m,1H),7.16(t,J=7.8Hz,1H),7.39(d,J=8.0Hz,1H),7.48(s,1H),9.66(s,1H)。LCMSt=5.6min,m/z计算值C20H27N2O2;C20H26N2NaO2;C40H52N4NaO4 327.21;349.19;675.39[M+H]+;[M+Na]+;[2M+Na]+,实验值327.29;349.25;675.52。
实施例04-40
(1S,4S)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(对甲苯基)-环己甲酰胺(04-40)的制备:按照实施例04-13的方法,由实施例01-34的化合物和对甲苯胺制备题述化合物;经色谱分析(ESS=MeOH(7%))和EtOAc研磨后,0.42mmol规模产生了1mg产物(1%产量)。1H NMR(D6-DMSO)δ1.46-1.53(m,3H),1.58-1.68(m,5H),1.73-1.80(m,2H),2.00-2.07(m,2H),2.09-2.13(m,2H),2.24(s,3H),2.50-2.53(m,2H),3.40-3.53(m,1H),6.87-6.92(m,1H),7.08(d,J=7.9Hz,2H),7.49(d,J=8.0Hz,2H),9.65(s,1H)。LCMS t=5.7min,m/z计算值C20H27N2O2;C20H26N2NaO2;C40H53N4O4;C40H52N4NaO4 327.21;349.19;653.41;675.39[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值327.29;349.26;653.50;675.49。
实施例04-41
(1S,4S)-N-(3-氟苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-环己甲酰胺(04-41)的制备:按照实施例04-13的方法,由实施例01-34的化合物和间氟苯胺制备题述化合物;经色谱分析(ESS=MeOH(7%))和EtOAc研磨后,0.42mmol规模产生了16mg产物(12%产量)。1H NMR(D6-DMSO)δ1.46-1.53(m,3H),1.60-1.70(m,5H),1.72-1.79(m,2H),1.90-2.07(m,2H),2.09-2.13(m,2H),2.50-2.58(m,2H),3.45-3.60(m,1H),6.83-6.93(m,2H),7.30-7.36(m,2H),7.64(d,J=12.0Hz,1H),9.98(s,1H)。LCMS t=5.7min,m/z计算值C19H24FN2O2;C19H23FN2NaO2;C38H47F2N4O4;C38H46F2N4NaO4 331.18;353.16;661.36;683.34[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值331.26;353.23;661.45;683.44。
实施例04-42
(1S,4S)-N-(4-氯苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-环己甲酰胺(04-42)的制备:按照实施例04-13的方法,由实施例01-34的化合物和对氯苯胺制备题述化合物;经色谱分析(ESS=MeOH(7%))和EtOAc研磨后,0.42mmol规模产生了13mg产物(9%产量)。1H NMR(D6-DMSO)δ1.46-1.54(m,3H),1.59-1.69(m,5H),1.72-1.79(m,2H),2.00-2.07(m,2H),2.09-2.13(m,2H),2.50-2.54(m,2H),3.40-3.58(m,1H),6.83-6.92(m,1H),7.34(d,J=8.6Hz,2H),7.65(d,J=8.6Hz,2H),9.90(s,1H)。LCMS t=5.7min,m/z计算值C19H24ClN2O2;C19H23ClN2NaO2;C38H46Cl2N4NaO4 347.15;369.13;715.28[M+H]+;[M+Na]+;[2M+Na]+,实验值347.22;369.20;715.39。
实施例04-43
2-氯-N-环己基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(04-43)的制备:按照实施例04-13的方法,由实施例01-10的化合物和环己胺制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.38mmol规模产生了1mg产物(1%产量)。1H NMR(D6-DMSO)δ1.10-1.18(m,2H),1.27-1.33(m,4H),1.58(s,3H),1.70-1.73(m,2H),1.81-1.83(m,2H),2.23-2.25(m,2H),2.72-2.75(m,2H),3.32-3.70(m,1H),7.22(dd,J=8.2,1.7Hz,1H),7.32(d,J=1.7Hz,1H),7.34(d,J=8.2Hz,1H),8.24(d,J=7.8Hz,1H),8.95(s,1H)。LCMS t=5.7min,m/z计算值C19H24ClN2O2;C19H23ClN2NaO2;C36H47Cl2N4O4;C36H47Cl2N4NaO4347.15;369.13;693.30;715.28[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值347.23;369.20;693.41;715.41。
实施例04-44
2-氯-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(萘-1-基)-苯甲酰胺(04-44)的制备:按照实施例04-13的方法,由实施例01-10的化合物和1-萘胺制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.38mmol规模产生了40mg产物(27%产量)。1HNMR(D6-DMSO)δ1.63(s,3H),2.27-2.29(m,2H),2.80-2.82(m,2H),7.35(d,J=7.6Hz,1H),7.45(s,1H),7.54-7.59(m,3H),7.70-7.74(m,2H),7.85(d,J=8.1Hz,1H),7.97(d,J=8.6Hz,1H),8.16(d,J=9.0Hz,1H),9.19(s,1H),10.50(s,1H)。LCMS t=5.8min,m/z计算值C23H20ClN2O2;C23H19ClN2NaO2;C46H39Cl2N4O4;C46H38Cl2N4NaO4 391.12;413.10;781.23;803.22[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值391.19;413.17;781.39;803.38。
实施例04-45
2-氯-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-苯基苯甲酰胺(04-45)的制备:按照实施例04-13的方法,由实施例01-10的化合物和苯胺制备题述化合物;经色谱分析(ESS=EtOAc)和EtOAc研磨后,0.38mmol规模产生了17mg产物(13%产量)。1H NMR(D6-DMSO)δ1.61(s,3H),2.25-2.28(m,2H),2.78-2.80(m,2H),7.10(t,J=7.4Hz,1H),7.30(dd,J=8.3,1.6Hz,1H),7.35(t,J=7.8Hz,2H),7.41(s,1H),7.55(d,J=8.3Hz,1H),7.72(d,J=7.9Hz,2H),9.16(s,1H),10.43(s,1H)。LCMS t=5.6min,m/z计算值C19H18ClN2O2;C19H17ClN2NaO2;C38H35Cl2N4O4;C38H34Cl2N4NaO4341.11;363.09;681.20;703.19[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值341.18;363.16;681.31;703.31。
实施例04-46
2-氯-N-(2-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(04-46)的制备:按照实施例04-13的方法,由实施例01-10的化合物和邻氨基苯甲醚制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.38mmol规模产生了45mg产物(30%产量)。1H NMR(D6-DMSO)δ1.61(s,3H),2.26-2.28(m,2H),2.79-2.80(m,2H),3.83(s,3H),6.97(t,J=6.9Hz,1H),7.08(d,J=7.6Hz,1H),7.16(t,J=7.5Hz,1H),7.29(d,J=7.4Hz,1H),7.39(s,1H),7.59(d,J=7.6Hz,1H),7.96(d,J=6.6Hz,1H),9.16(s,1H),9.51(s,1H)。LCMS t=5.8min,m/z计算值C20H20ClN2O3;C20H19ClN2NaO3;C40H39Cl2N4O6;C40H38Cl2N4NaO6371.11;393.10;741.22;763.21[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值371.18;393.16;741.36;763.35。
实施例04-47
2-氯-N-(3-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(04-47)的制备:按照实施例04-13的方法,由实施例01-10的化合物和间氨基苯甲醚制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.38mmol规模产生了47mg产物(34%产量)。1H NMR(D6-DMSO)δ1.61(s,3H),2.25-2.28(m,2H),2.78-2.79(m,2H),3.75(s,3H),6.69(d,J=7.0Hz,1H),7.22-7.31(m,3H),7.40-7.42(m,2H),7.54(d,J=8.3Hz,1H),9.16(s,1H),10.41(s,1H)。LCMS t=5.7min,m/z计算值C20H20ClN2O3;C20H19ClN2NaO3;C40H39Cl2N4O6;C40H38Cl2N4NaO6371.11;393.10;741.22;763.21[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值371.18;393.16;741.36;763.35。
实施例04-48
2-氯-N-(4-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-苯甲酰胺(04-48)的制备:按照实施例04-13的方法,由实施例01-10的化合物和对氨基苯甲醚制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.38mmol规模产生了17mg产物(12%产量)。1H NMR(D6-DMSO)δ1.61(s,3H),2.26-2.28(m,2H),2.77-2.79(m,2H),3.74(s,3H),6.92(d,J=8.8Hz,2H),7.29(d,J=8.2Hz,1H),7.40(s,1H),7.53(d,J=8.3Hz,1H),7.62(d,J=8.8Hz,2H),9.15(s,1H),10.29(s,1H)。LCMS t=5.6min,m/z计算值C20H20ClN2O3;C20H19ClN2NaO3;C40H39Cl2N4O6;C40H38Cl2N4NaO6 371.11;393.10;741.22;763.21[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值371.18;393.16;741.35;763.34。
实施例04-49
2-氯-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(邻甲苯基)苯甲酰胺(04-49)的制备:按照实施例04-13的方法,由实施例01-10的化合物和邻甲苯胺制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.38mmol规模产生了25mg产物(19%产量)。1H NMR(D6-DMSO)δ1.61(s,3H),2.26-2.29(m,5H),2.78-2.80(m,2H),7.15(t,J=7.1Hz,1H),7.21-7.23(m,1H),7.26(d,J=7.1Hz,1H),7.31(d,J=7.9Hz,1H),7.40-7.43(m,2H),7.59(d,J=8.1Hz,1H),9.16(s,1H),9.91(s,1H)。LCMS t=5.7min,m/z计算值C20H20ClN2O2;C20H19ClN2NaO2;C40H39Cl2N4O4;C40H38Cl2N4NaO4 355.12;377.10;709.23;731.22[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值355.19;377.17;709.34;731.34。
实施例04-50
2-氯-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(间甲苯基)苯甲酰胺(04-50)的制备:按照实施例04-13的方法,由实施例01-10的化合物和间甲苯胺制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.38mmol规模产生了36mg产物(27%产量)。1H NMR(D6-DMSO)δ1.61(s,3H),2.26-2.28(m,2H),2.30(s,3H),2.78-2.79(m,2H),6.92(d,J=7.3Hz,1H),7.22(t,J=7.7Hz,1H),7.30(d,J=8.2Hz,1H),7.40(s,1H),7.48(d,J=7.7Hz,1H),7.53(d,J=8.2Hz,1H),9.16(s,1H),10.36(s,1H)。LCMS t=5.8min,m/z计算值C20H20ClN2O2;C20H19ClN2NaO2;C40H39Cl2N4O4;C40H38Cl2N4NaO4 355.12;377.10;709.23;731.22[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值355.19;377.17;709.35;731.34。
实施例04-51
2-氯-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(对甲苯基)苯甲酰胺(04-51)的制备:按照实施例04-13的方法,由实施例01-10的化合物和对甲苯胺制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.38mmol规模产生了21mg产物(16%产量)。1H NMR(D6-DMSO)δ1.61(2,3H),2.27-2.29(m,5H),2.77-2.78(m,2H),7.15(d,J=7.8Hz,2H),7.29(d,J=8.2Hz,1H),7.40(s,1H),7.53(d,J=8.3Hz,1H),7.60(d,J=7.9Hz,2H),9.16(s,1H),10.34(s,1H)。LCMS t=5.8min,m/z计算值C20H20ClN2O2;C20H19ClN2NaO2;C40H39Cl2N4O4;C40H38Cl2N4NaO4355.12;377.10;709.23;731.22[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值355.19;377.17;709.34;731.33。
实施例04-52
2-氯-N-(3-氟苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-苯甲酰胺(04-52)的制备:按照实施例04-13的方法,由实施例01-10的化合物和间氟苯胺制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.38mmol规模产生了25mg产物(18%产量)。1H NMR(D6-DMSO)δ1.61(s,3H),2.26-2.28(m,2H),2.78-2.80(m,2H),6.94(d,J=8.2Hz,1H),7.31(d,J=8.3Hz,1H),7.36-7.42(m,2H),7.46(d,J=7.7Hz,1H),7.56(d,J=8.3Hz,1H),7.68(d,J=11.3Hz,1H),9.17(s,1H),10.65(s,1H)。LCMS t=5.8min,m/z计算值C19H17ClFN2O2;C19H16ClFN2NaO2;C38H33Cl2F2N4O4;C38H32Cl2F2N4NaO4 359.10;381.08;717.18;739.17[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值359.16;381.14;717.30;739.29。
实施例04-53
3-甲氧基-N-甲基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(04-53)的制备:按照实施例04-13的方法,由实施例01-12的化合物和甲胺制备题述化合物;经色谱分析(ESS=MeOH(70%))和EtOAc研磨后,0.40mmol规模产生了25mg产物(23%产量)。1H NMR(D6-DMSO)δ1.51(s,3H),2.16-2.19(m,2H),2.48-2.51(m,2H),2.79(d,J=4.5Hz,1H),3.87(s,3H),7.25(d,J=8.1Hz,1H),7.43(dd,J=8.1,1.4Hz,1H),7.52(d,J=1.2Hz,1H),8.42-8.44(m,1H),8.51(s,1H)。LCMS t=4.9min,m/z计算值C15H19N2O3;C15H18N2NaO3;C30H36N4NaO6 275.14;297.12;571.25[M+H]+;[M+Na]+;[2M+Na]+,实验值275.23;297.21;571.42。
实施例04-54
N-环己基-3-甲氧基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-苯甲酰胺(04-54)的制备:按照实施例04-13的方法,由实施例01-12的化合物和环己胺制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.40mmol规模产生了52mg产物(38%产量)。1H NMR(D6-DMSO)δ1.20-1.28(m,1H),1.32-1.35(m,4H),1.51(s,3H),1.62(d,J=11.9Hz,1H),1.75(s,2H),1.82(s,2H),2.16-2.19(m,2H),2.47-2.50(m,2H),3.75-3.78(m,1H),3.88(s,3H),7.24(d,J=8.1Hz,1H),7.46(d,J=8.1Hz,1H),7.50(s,1H),8.19(d,J=7.9Hz,1H),8.53(s,1H)。LCMS t=5.7min,m/z计算值C20H27N2O3;C20H26N2NaO3;C40H52N4NaO6343.20;365.18;707.38[M+H]+;[M+Na]+;[2M+Na]+,实验值343.27;365.25;707.55。
实施例04-55
3-甲氧基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(萘-1-基)-苯甲酰胺(04-55)的制备:按照实施例04-13的方法,由实施例01-12的化合物和1-氨基萘制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.40mmol规模产生了41mg产物(27%产量)。1H NMR(D6-DMSO)δ1.55(s,3H),2.21-2.23(m,2H),2.56-2.58(m,2H),3.95(s,3H),7.36(d,J=8.1Hz,1H),7.55-7.60(m,4H),7.73(d,J=8.0Hz,1H),7.77(s,1H),7.88(d,J=7.7Hz,1H),7.98-8.00(m,2H),8.60(s,1H),10.43(s,1H)。LCMS t=5.8min,m/z计算值C24H23N2O3;C24H22N2NaO3;C48H45N4O6;C48H44N4NaO6 387.17;409.15;773.33;795.32[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值387.24;409.22;773.48;795.47。
实施例04-56
3-甲氧基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-苯基苯甲酰胺(04-56)的制备:按照实施例04-13的方法,由实施例01-12的化合物和苯胺制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.40mmol规模产生了35mg产物(26%产量)。1HNMR(D6-DMSO)δ1.53(s,3H),2.19-2.22(m,2H),2.53-2.55(m,2H),3.93(s,3H),7.11(t,J=8.1Hz,1H),7.33(d,J=8.1Hz,1H),7.36(t,J=7.8Hz,2H),7.59(d,J=8.1Hz,1H),7.62(d,J=1.2Hz,1H),7.76(d,J=7.8Hz,2H),8.57(s,1H),10.21(s,1H)。LCMS t=5.6min,m/z计算值C20H21N2O3;C20H20N2NaO3;C40H41N4O6;C40H40N4NaO6 337.16;359.14;673.30;695.28[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值337.23;359.21;673.41;695.41。
实施例04-57
3-甲氧基-N-(2-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-苯甲酰胺(04-57)的制备:按照实施例04-13的方法,由实施例01-12的化合物和邻氨基苯甲醚制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.40mmol规模产生了30mg产物(20%产量)。1H NMR(D6-DMSO)δ1.53(s,3H),2.20-2.22(m,2H),2.53-2.55(m,2H),3.84(s,3H),3.92(s,3H),6.98(t,J=7.5Hz,1H),7.10(d,J=8.1Hz,1H),7.20(t,J=7.8Hz,1H),7.31(d,J=8.1Hz,1H),7.58(d,J=7.9Hz,1H),7.64(s,1H),7.69(d,J=7.6Hz,1H),8.55(s,1H),9.46(s,1H)。LCMSt=5.9min,m/z计算值C21H23N2O4;C21H22N2NaO4;C42H45N4O8;C42H44N4NaO8367.17;389.15;733.32;755.31[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值367.24;389.22;733.46;755.46。
实施例04-58
3-甲氧基-N-(3-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-苯甲酰胺(04-58)的制备:按照实施例04-13的方法,由实施例01-12的化合物和间氨基苯甲醚制备题述化合物;经色谱分析(ESS=EtOAc)和EtOAc研磨后,0.40mmol规模产生了53mg产物(36%产量)。1H NMR(D6-DMSO)δ1.53(s,3H),2.19-2.22(m,2H),2.53-2.55(m,2H),3.76(s,3H),3.93(s,3H),6.69(dd,J=8.1,2.0Hz,1H),7.26(t,J=8.1Hz,1H),7.32(d,J=8.1Hz,1H),7.36(d,J=8.1Hz,1H),7.47(s,1H),7.58-7.61(m,2H),8.57(s,1H),10.18(s,1H)。LCMS t=5.7min,m/z计算值C21H23N2O4;C21H22N2NaO4;C42H45N4O8;C42H44N4NaO8 367.17;389.15;733.32;755.31[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值367.24;389.22;733.46;755.45。
实施例04-59
3-甲氧基-N-(4-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-苯甲酰胺(04-59)的制备:按照实施例04-13的方法,由实施例01-12的化合物和对氨基苯甲醚制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.40mmol规模产生了55mg产物(38%产量)。1H NMR(D6-DMSO)δ1.53(s,3H),2.20-2.22(m,2H),2.52-2.53(m,2H),3.75(s,3H),3.92(s,2H),6.94(d,J=8.7Hz,2H),7.32(d,J=8.0Hz,1H),7.58(d,J=8.0Hz,1H),7.61(s,1H),7.66(d,J=8.7Hz,2H),8.56(s,1H),10.10(s,1H)。13C NMR(D6-DMSO)δ7.3,25.5,32.8,55.2,55.9,109.8,110.9,113.7,119.9,122.2,124.7,131.1,132.1,132.3,152.4,155.6,164.4,169.6,202.1。LCMS t=5.6min,m/z计算值C21H23N2O4;C21H22N2NaO4;C42H45N4O8;C42H44N4NaO8 367.17;389.15;733.32;755.31[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值367.23;389.21;733.44;755.43。
实施例04-60
3-甲氧基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(邻甲苯基)苯甲酰胺(04-60)的制备:按照实施例04-13的方法,由实施例01-12的化合物和邻甲苯胺制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.40mmol规模产生了60mg产物(43%产量)。1H NMR(D6-DMSO)δ1.54(s,3H),2.20-2.22(m,2H),2.24(s,3H),2.53-2.55(m,2H),3.92(s,3H),7.18(t,J=7.1Hz,1H),7.23(t,J=7.2Hz,1H),7.29(d,J=7.1Hz,1H),7.32(d,J=8.0Hz,2H),7.61(d,J=8.0Hz,1H),7.66(s,1H),8.58(s,1H),9.89(s,1H)。LCMS t=5.7min,m/z计算值C21H23N2O3;C21H22N2NaO3;C42H45N4O6;C42H44N4NaO6 351.17;373.15;701.33;723.32[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值351.24;373.22;701.45;723.44。
实施例04-61
3-甲氧基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(间甲苯基)苯甲酰胺(04-61)的制备:按照实施例04-13的方法,由实施例01-12的化合物和间甲苯胺制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.40mmol规模产生了47mg产物(34%产量)。1H NMR(D6-DMSO)δ1.53(s,3H),2.20-2.22(m,2H),2.32,(s,3H),2.53-2.55(m,2H),3.93(m,3H),6.93(d,J=7.3Hz,1H),7.24(t,J=7.7Hz,1H),7.32(d,J=8.0Hz,1H),7.56-7.62(m,4H),8.57(s,1H),10.13(s,1H)。13C NMR(D6-DMSO)δ7.3,21.2,25.5,32.8,55.9,109.9,110.93,117.7,120.1,121.1,124.4,124.6,128.4,131.2,132.2,137.7,139.0,152.4,164.7,169.6,202.1。LCMS t=5.8min,m/z计算值C21H23N2O3;C21H22N2NaO3;C42H45N4O6;C42H44N4NaO6 351.17;373.15;701.33;723.32[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值351.24;373.22;701.44;723.43。
实施例04-62
3-甲氧基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(对甲苯基)苯甲酰胺(04-62)的制备:按照实施例04-13的方法,由实施例01-12的化合物和对甲苯胺制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.40mmol规模产生了45mg产物(32%产量)。1H NMR(D6-DMSO)δ1.53(s,3H),2.20-2.22(m,2H),2.29(s,3H),2.53-2.55(m,2H),3.92(s,3H),7.16(d,J=8.0Hz,2H),7.32(d,J=8.0Hz,1H),7.58(d,J=8.0Hz,1H),7.61(s,1H),7.64(d,J=8.0Hz,2H),8.57(s,1H),10.14(s,1H)。13C NMR(D6-DMSO)δ7.3,20.5,25.5,32.8,55.9,109.9,110.9,120.0,120.6,124.7,129.0,131.2,132.3,132.7,136.6,152.4,164.6,169.6,202.1。LCMS t=5.8min,m/z计算值C21H23N2O3;C21H22N2NaO3;C42H45N4O6;C42H44N4NaO6 351.17;373.15;701.33;723.32[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值351.24;373.22;701.44;723.43。
实施例04-63
N-(3-氟苯基)-3-甲氧基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(04-63)的制备:按照实施例04-13的方法,由实施例01-12的化合物和间氟苯胺制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.40mmol规模产生了51mg产物(36%产量)。1H NMR(D6-DMSO)δ1.53(s,3H),2.20-2.22(m,2H),2.40-2.56(m,2H),3.93(s,3H),6.94(t,J=7.7Hz,1H),7.34(d,J=8.0Hz,1H),7.40(dd,J=15.2,7.9Hz,1H),7.56(d,J=8.1Hz,1H),7.59(d,J=11.7Hz,1H),8.58(s,1H),10.39(s,1H)。13C NMR(D6-DMSO)δ7.4,25.6,32.8,55.9,107.0(JCF=26.2Hz),110.1(JCF=15.7Hz),111.0,116.1,120.1,124.5,130.2(JCF=9.1Hz),131.6(JCF=19.6Hz),141.0,152.2,162.1(JCF=241.2Hz),165.1,169.4,202.2。LCMS t=5.8min,m/z计算值C20H20FN2O3;C20H19FN2NaO3;C40H39F2N4O6;C40H38F2N4NaO6 355.15;377.13;709.28;731.27[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值355.21;377.19;709.39;731.38。
实施例04-64
N-(4-氯苯基)-3-甲氧基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-苯甲酰胺(04-64)的制备:按照实施例04-13的方法,由实施例01-12的化合物和对氯苯胺制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.40mmol规模产生了52mg产物(35%产量)。1H NMR(D6-DMSO)δ1.53(s,3H),2.20-2.22(m,2H),2.53-2.55(m,2H),3.93(s,3H),7.33(d,J=8.0Hz,1H),7.42(d,J=8.6Hz,2H),7.58-7.61(m,3H),7.81(d,J=8.6Hz,2H),8.57(s,1H),10.33(s,1H)。13C NMR(D6-DMSO)δ7.4,25.6,32.8,55.9,110.0,111.1,120.1,122.0,124.5,127.3,128.5,131.5,131.8,138.1,152.3,164.9,169.5,202.1。LCMSt=5.9min,m/z计算值C20H20ClN2O3;C20H19ClN2NaO3;C40H39Cl2N4O6;C40H38Cl2N4NaO6 371.12;393.10;741.22;763.21[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值371.18;393.16;741.35;763.34。
实施例04-65
2-甲氧基-N-甲基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(04-65)的制备:按照实施例04-13的方法,由实施例02-03的化合物和甲胺制备题述化合物;经色谱分析(ESS=MeOH(8%))和EtOAc研磨后,0.40mmol规模产生了25mg产物(22%产量)。1HNMR(D6-DMSO)δ1.61(s,3H),2.23-2.26(m,2H),2.78-2.80(m,5H),3.89(s,3H),6.89(dd,J=8.4,1.7Hz,1H),6.96(d,J=1.6Hz,1H),7.78(d,J=8.4Hz,1H),8.03-8.05(m,2H),9.08(s,1H)。LCMS t=4.6min,m/z计算值C15H19N2O3;C15H18N2NaO3;C30H36N4NaO6 275.14;297.12;571.25[M+H]+;[M+Na]+;[2M+Na]+,实验值275.23;297.21;571.34。
实施例04-66
N-环己基-2-甲氧基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-苯甲酰胺(04-66)的制备:按照实施例04-13的方法,由实施例02-03的化合物和环己胺制备题述化合物;经色谱分析(ESS=EtOAc)和EtOAc研磨后,0.40mmol规模产生了90mg产物(66%产量)。1H NMR(D6-DMSO)δ1.18-1.28(m,1H),1.30-1.35(m,4H),1.56(d,J=12.9Hz,1H),1.61(s,3H),1.66-1.69(m,2H),1.81-1.84(m,2H),2.24-2.26(m,2H),2.78-2.80(m,2H),3.77-3.79(m,1H),3.90(s,3H),6.90(dd,J=8.4,1.6Hz,1H),6.97(d,J=1.4Hz,1H),7.74(d,J=8.4Hz,1H),7.85(d,J=7.8Hz,1H),8.53(s,1H)。LCMS t=5.8min,m/z计算值C20H27N2O3;C20H26N2NaO3;C40H53N4O6;C40H52N4NaO6 343.20;365.18;685.40;707.38[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值343.28;365.26;685.50;707.52。
实施例04-67
2-甲氧基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(萘-1-基)苯甲酰胺(04-67)的制备:按照实施例04-13的方法,由实施例02-03的化合物和1-氨基萘制备题述化合物;经色谱分析(ESS=EtOAc)和EtOAc研磨后,0.40mmol规模产生了13mg产物(8%产量)。1HNMR(D6-DMSO)δ1.65(s,3H),2.28-2.30(m,2H),2.87-2.89(m,2H),4.10(s,3H),7.02(d,J=8.1Hz,1H),7.12(s,1H),7.55-7.60(m,2H),7.64(t,J=7.5Hz,1H),7.79(d,J=8.1Hz,1H),7.92(d,J=8.5Hz,1H),7.99(d,J=8.0Hz,1H),8.04(d,J=8.4Hz,2H),9.19(s,1H),10.31(s,1H)。LCMS t=6.0min,m/z计算值C24H23N2O3;C24H22N2NaO3;C48H45N4O6;C48H44N4NaO6387.17;409.15;773.33;795.32[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值387.24;409.22;773.49;795.47。
实施例04-68
2-甲氧基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-苯基苯甲酰胺(04-68)的制备:按照实施例04-13的方法,由实施例02-03的化合物和苯胺制备题述化合物;经色谱分析(ESS=EtOAc)和EtOAc研磨后,0.40mmol规模产生了52mg产物(39%产量)。1H NMR(D6-DMSO)δ1.63(s,3H),2.25-2.28(m,2H),2.82-2.83(m,2H),3.95(s,3H),6.95(dd,J=8.4,1.6Hz,1H),7.03(s,1H),7.08(t,J=8.4Hz,1H),7.34(t,J=7.8Hz,2H),7.70-7.74(m,3H),9.14(s,1H),9.99(s,1H)。LCMS t=5.8min,m/z计算值C20H21N2O3;C20H20N2NaO3;C40H41N4O6;C40H40N4NaO6 337.16;359.14;673.30;695.28[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值337.23;359.21;673.42;695.40。
实施例04-69
2-甲氧基-N-(2-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-苯甲酰胺(04-69)的制备:按照实施例04-13的方法,由实施例02-03的化合物和邻氨基苯甲醚制备题述化合物;经色谱分析(ESS=MeOH(2%))和EtOAc研磨后,0.40mmol规模产生了60mg产物(41%产量)。1H NMR(D6-DMSO)δ1.64(s,3H),2.27-2.29(m,2H),2.88-2.90(m,2H),3.96(s,3H),4.08(s,3H),6.96(d,J=8.0Hz,1H),7.02(dd,J=8.6,1.6Hz,1H),7.06-7.10(m,3H),8.04(d,J=8.6Hz,1H),8.47(d,J=7.8Hz,1H),9.19(s,1H),10.57(s,1H)。LCMS t=5.9min,m/z计算值C21H23N2O4;C21H22N2NaO4;C42H45N4O8;C42H44N4NaO8 367.17;389.15;733.32;755.31[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值367.24;389.21;733.45;755.45。
实施例04-70
2-甲氧基-N-(3-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-苯甲酰胺(04-70)的制备:按照实施例04-13的方法,由实施例02-03的化合物和间氨基苯甲醚制备题述化合物;经色谱分析(ESS=EtOAc)和EtOAc研磨后,0.40mmol规模产生了55mg产物(38%产量)。1H NMR(D6-DMSO)δ1.63(s,3H),2.26-2.28(m,2H),2.82-2.84(m,2H),3.75(s,3H),3.94(s,3H),6.67(d,J=8.3Hz,1H),6.95(d,J=8.3Hz,1H),7.02(s,1H),7.21-7.28(m,2H),7.45(s,1H),7.69(d,J=8.3Hz,1H),9.14(s,1H),9.97(s,1H)。LCMS t=5.8min,m/z计算值C21H23N2O4;C21H22N2NaO4;C42H45N4O8;C42H44N4NaO8 367.17;389.15;733.32;755.31[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值367.24;389.22;733.45;755.45。
实施例04-71
2-甲氧基-N-(4-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-苯甲酰胺(04-71)的制备:按照实施例04-13的方法,由实施例02-03的化合物和对氨基苯甲醚制备题述化合物;经色谱分析(ESS=EtOAc)和EtOAc研磨后,0.40mmol规模产生了29mg产物(20%产量)。1H NMR(D6-DMSO)δ1.63(s,3H),2.26-2.28(m,2H),2.82-2.84(m,2H),3.74(s,3H),3.94(s,3H),6.91(d,J=8.6Hz,2H),6.94(d,J=8.3Hz,1H),7.02(s,1H),7.64(d,J=8.6Hz,2H),7.71(d,J=8.3Hz,1H),9.13(s,1H),9.85(s,1H)。13C NMR(D6-DMSO)δ7.4,26.1,33.1,55.2,56.1,105.0,111.7,113.1,113.8,118.5,121.4,131.1,132.2,143.9,155.4,157.4,163.1,168.3,202.2。LCMS t=5.8min,m/z计算值C21H23N2O4;C21H22N2NaO4;C42H45N4O8;C42H44N4NaO8 367.17;389.15;733.32;755.31[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值367.23;389.21;733.53;755.44。
实施例04-72
2-甲氧基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(邻甲苯基)苯甲酰胺(04-72)的制备:按照实施例04-13的方法,由实施例02-03的化合物和邻甲苯胺制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.40mmol规模产生了70mg产物(50%产量)。1H NMR(D6-DMSO)δ1.64(s,3H),2.27-2.29(m,2H),2.32(s,3H),2.86-2.88(m,2H),4.03(s,3H),7.00(d,J=8.4Hz,1H),7.04-7.09(m,2H),7.21(t,J=7.4Hz,1H),7.26(d,J=7.2Hz,1H),7.95(d,J=8.4Hz,1H),8.04(d,J=7.8Hz,1H),9.18(s,1H),9.78(s,1H)。13CNMR(D6-DMSO)δ7.5,17.7,26.2,33.1,56.5,104.7,112.2,113.2,116.4,122.2,124.1,126.3,128.6,130.3,132.2,136.9,144.7,157.7,162.4,168.1,202.4。LCMS t=5.9min,m/z计算值C21H23N2O3;C21H22N2NaO3;C42H45N4O6;C42H44N4NaO6 351.17;373.15;701.33;723.32[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值351.24;373.22;701.44;723.43。
实施例04-73
2-甲氧基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(间甲苯基)苯甲酰胺(04-73)的制备:按照实施例04-13的方法,由实施例02-03的化合物和间甲苯胺制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.40mmol规模产生了55mg产物(39%产量)。1H NMR(D6-DMSO)δ1.63(s,3H),2.26-2.28(m,2H),2.30(s,3H),2.82-2.84(m,2H),3.95(s,3H),6.90(d,J=6.9Hz,1H),6.95(d,J=8.1Hz,1H),7.02(s,1H),7.21(t,J=7.4Hz,1H),7.53(d,J=7.4Hz,1H),7.57(s,1H),7.71(d,J=8.1Hz,1H),9.14(s,1H),9.91(s,1H)。13C NMR(D6-DMSO)δ7.5,21.2,26.1,33.1,56.1,105.0,112.0,113.1,117.0,118.4,120.3,124.2,128.5,131.2,137.9,138.9,144.1,157.4,163.8,168.3,202.3。LCMS t=5.9min,m/z计算值C21H23N2O3;C21H22N2NaO3;C42H45N4O6;C42H44N4NaO6 351.17;373.15;701.33;723.32[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值351.24;373.22;701.45;723.44。
实施例04-74
2-甲氧基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(对甲苯基)苯甲酰胺(04-74)的制备:按照实施例04-13的方法,由实施例02-03的化合物和对甲苯胺制备题述化合物;经色谱分析(ESS=EtOAc)和EtOAc研磨后,0.40mmol规模产生了30mg产物(21%产量)。1H NMR(D6-DMSO)δ1.63(s,3H),2.27-2.29(m,5H),2.82-2.85(m,2H),3.94(s,3H),6.95(d,J=7.8Hz,1H),7.02(s,1H),7.14(d,J=8.0Hz,2H),7.62(d,J=8.0Hz,2H),7.71(d,J=8.3Hz,1H),9.13(s,1H),9.90(s,1H)。13C NMR(D6-DMSO)δ7.4,20.5,26.1,33.1,56.1,105.0,111.7,113.1,118.5,119.8,129.1,131.2,132.4,136.5,144.0,157.4,163.23,168.2,202.3。LCMS t=5.9min,m/z计算值C21H23N2O3;C21H22N2NaO3;C42H45N4O6;C42H44N4NaO6 351.17;373.15;701.33;723.32[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值351.24;373.22;701.45;723.44。
实施例04-75
N-(3-氟苯基)-2-甲氧基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-苯甲酰胺(04-75)的制备:按照实施例04-13的方法,由实施例02-03的化合物和间氟苯胺制备题述化合物;经色谱分析(ESS=EtOAc)和EtOAc研磨后,0.40mmol规模产生了75mg产物(53%产量)。1H NMR(D6-DMSO)δ1.63(s,3H),2.26-2.28(m,2H),2.82-2.84(m,2H),2.94(s,3H),6.91(d,J=7.7Hz,1H),6.95(d,J=8.3Hz,1H),7.03(s,1H),7.37(dd,J=15.3,7.8Hz,1H),7.48(d,J=8.0Hz,1H),7.69(d,J=8.3Hz,1H),7.74(d,J=11.5Hz,1H),9.15(s,1H),10.16(s,1H)。13C NMR(D6-DMSO)δ7.5,26.1,33.1,56.1,104.9,106.5(JCF=26.2Hz),109.8(JCF=20.8Hz),111.9,113.0,115.6,118.3,130.3(JCF=9.2Hz),131.1,140.7(JCF=11.4Hz),144.3,157.5,163.5(JCF=241.3Hz),164.0,168.2,202.3。LCMS t=5.9min,m/z计算值C20H20FN2O3;C20H19FN2NaO3;C40H39F2N4O6;C40H38F2N4NaO6 355.15;377.13;709.28;731.27[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值355.22;358.22;709.40;731.39。
实施例04-76
N-(4-氯苯基)-2-甲氧基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-苯甲酰胺(04-76)的制备:按照实施例04-13的方法,由实施例02-03的化合物和对氯苯胺制备题述化合物;经色谱分析(ESS=EtOAc)和EtOAc研磨后,0.40mmol规模产生了70mg产物(47%产量)。1H NMR(D6-DMSO)δ1.63(s,3H),2.26-2.28(m,2H),2.82-2.84(m,2H),3.93(s,3H),6.95(d,J=8.3Hz,1H),7.02(s,1H),7.39(d,J=8.5Hz,2H),7.68(d,J=8.3Hz,1H),7.78(d,J=8.4Hz,2H),9.14(s,1H),10.10(s,1H)。13C NMR(D6-DMSO)δ7.5,26.1,33.1,56.1,104.9,111.9,113.1,118.4,121.4,127.0,128.6,131.1,138.0,144.2,157.4,163.8,168.3,202.3。LCMS t=6.0min,m/z计算值C20H20ClN2O3;C20H19ClN2NaO3;C40H39Cl2N4O6;C40H38Cl2N4NaO6371.12;393.10;741.22;763.21[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值371.18;393.16;741.35;763.34。
实施例04-77
N,3-二甲基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(04-77)的制备:按照实施例04-13的方法,由实施例01-14的化合物和甲胺制备题述化合物;经色谱分析(ESS=MeOH(8%))和EtOAc研磨后,0.40mmol规模产生了35mg产物(34%产量)。1H NMR(D6-DMSO)δ1.44(s,3H),2.16-2.19(m,2H),2.28(s,3H),2.41-2.43(m,2H),2.77(d,J=4.4Hz,3H),7.23(d,J=8.1Hz,1H),7.66(d,J=8.1Hz,1H),7.74(s,1H),8.38-8.39(m,1H),8.69(s,1H)。LCMS t=4.9min,m/z计算值C15H19N2O2;C15H18N2NaO2;C30H37N4O4;C30H36N4NaO4259.14;281.13;517.28;539.26[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值259.24;281.22;517.35;539.42。
实施例04-78
N-环己基-3-甲基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(04-78)的制备:按照实施例04-13的方法,由实施例01-14的化合物和环己胺制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.40mmol规模产生了25mg产物(19%产量)。1HNMR(D6-DMSO)δ1.10-1.18(m,1H),1.23-1.34(m,4H),1.44(s,3H),1.61(d,J=12.4Hz,1H),1.73(s,2H),1.80(s,2H),2.16-2.19(m,2H),2.28(s,3H),2.40-2.42(m,2H),3.75(s,1H),7.21(d,J=8.2Hz,1H),7.67(d,J=8.0Hz,1H),7.74(s,1H),8.15(d,J=7.8Hz,1H),8.70(s,1H)。LCMS t=5.7min,m/z计算值C20H27N2O2;C20H26N2NaO2;C40H53N4O4;C40H52N4NaO4327.21;349.19;653.41;675.39[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值327.28;349.26;653.50;675.54。
实施例04-79
3-甲基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(萘-1-基)苯甲酰胺(04-79)的制备:按照实施例04-13的方法,由实施例01-14的化合物和1-氨基萘制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.40mmol规模产生了35mg产物(24%产量)。1H NMR(D6-DMSO)δ1.50(s,3H),2.21-2.23(m,3H),2.36(s,3H),2.48-2.50(m,2H),7.33(d,J=8.1Hz,1H),7.54-7.60(m,4H),7.87(d,J=7.9Hz,1H),7.94(d,J=7.9Hz,1H),7.97-8.02(m,3H),8.78(s,1H),10.40(s,1H)。LCMS t=5.8min,m/z计算值C24H23N2O2;C24H22N2NaO2;C48H45N4O4;C48H44N4NaO4 371.18;393.16;741.34;763.33[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值371.24;393.22;741.47;763.46。
实施例04-80
3-甲基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-苯基苯甲酰胺(04-80)的制备:按照实施例04-13的方法,由实施例01-14的化合物和苯胺制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.40mmol规模产生了35mg产物(27%产量)。1H NMR(D6-DMSO)δ1.47(s,3H),2.19-2.21(m,2H),2.33(s,3H),2.45-2.47(m,2H),7.10(t,J=7.3Hz,1H),7.30(d,J=8.1Hz,1H),7.35(t,J=7.7Hz,2H),7.77(d,J=8.0Hz,2H),7.80(d,J=8.1Hz,1H),7.87(s,1H),8.74(s,1H),10.20(s,1H)。LCMS t=5.7min,m/z计算值C20H21N2O2;C20H20N2NaO2;C40H41N4O4;C40H40N4NaO4 321.16;343.14;641.31;663.29[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值321.24;343.21;641.41;663.41。
实施例04-81
N-(2-甲氧基苯基)-3-甲基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-苯甲酰胺(04-81)的制备:按照实施例04-13的方法,由实施例01-14的化合物和邻氨基苯甲醚制备题述化合物;经色谱分析(ESS=EtOAc)和EtOAc研磨后,0.40mmol规模产生了30mg产物(21%产量)。1H NMR(D6-DMSO)δ1.47(s,3H),2.20-2.22(m,2H),2.33(s,3H),2.45-2.47(m,2H),3.84(s,3H),6.97(t,J=7.6Hz,1H),7.10(d,J=8.1Hz,1H),7.18(t,J=7.7Hz,1H),7.28(d,J=8.1Hz,1H),7.74(d,J=7.7Hz,1H),7.80(d,J=7.9Hz,1H),7.89(s,1H),8.74(s,1H),9.40(s,1H)。LCMS t=5.8min,m/z计算值C21H23N2O3;C21H22N2NaO3;C42H45N4O6;C42H44N4NaO6 351.17;373.15;701.33;723.32[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值351.24;373.22;701.45;723.48。
实施例04-82
N-(3-甲氧基苯基)-3-甲基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-苯甲酰胺(04-82)的制备:按照实施例04-13的方法,由实施例01-14的化合物和间氨基苯甲醚制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.40mmol规模产生了31mg产物(22%产量)。1H NMR(D6-DMSO)δ1.47(s,3H),2.19-2.22(m,2H),2.33(s,3H),2.45-2.47(m,2H),3.76(s,3H),6.68(d,J=8.2Hz,1H),7.25(t,J=8.1Hz,1H),7.30(d,J=8.1Hz,1H),7.37(d,J=8.0Hz,1H),7.46(s,1H),7.79(d,J=8.1Hz,1H),7.86(s,1H),8.74(s,1H),10.17(s,1H)。LCMS t=5.7min,m/z计算值C21H23N2O3;C21H22N2NaO3;C42H45N4O6;C42H44N4NaO6351.17;373.15;701.33;723.32[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值351.24;373.22;701.45;723.44。
实施例04-83
N-(4-甲氧基苯基)-3-甲基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-苯甲酰胺(04-83)的制备:按照实施例04-13的方法,由实施例01-14的化合物和对氨基苯甲醚制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.40mmol规模产生了20mg产物(14%产量)。1H NMR(D6-DMSO)δ1.47(s,3H),2.20-2.22(m,2H),2.33(s,3H),2.44-2.46(m,2H),2.75(s,3H),6.93(d,J=8.7Hz,2H),7.29(d,J=8.1Hz,1H),7.67(d,J=8.6Hz,2H),7.79(d,J=8.1Hz,1H),7.86(s,1H),8.74(s,1H),10.09(s,1H)。13C NMR(D6-DMSO)δ7.6,17.7,25.6,32.7,55.2,108.9,113.7,121.9,125.7,126.1,129.8,132.1,132.3,133.5,140.9,155.5,164.6,169.7,202.2。LCMS t=5.6min,m/z计算值C21H23N2O3;C21H22N2NaO3;C42H45N4O6;C42H44N4NaO6 351.17;373.15;701.33;723.32[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值351.24;373.22;701.45;723.43。
实施例04-84
3-甲基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(邻甲苯基)苯甲酰胺(04-84)的制备:按照实施例04-13的方法,由实施例01-14的化合物和邻甲苯胺制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.40mmol规模产生了28mg产物(21%产量)。1H NMR(D6-DMSO)δ1.48(s,3H),2.19-2.21(m,2H),2.24(s,3H),2.33(s,3H),2.45-2.47(m,2H),7.17(d,J=7.3Hz,1H),7.22(d,J=7.4Hz,1H),7.26-7.34(m,3H),7.83(d,J=8.1Hz,1H),7.90(s,1H),8.75(s,1H),9.85(s,1H)。13C NMR(D6-DMSO)δ7.6,17.8,18.0,25.6,32.7,109.0,125.8,126.0,126.2,126.6,130.0,130.3,131.6,133.6,133.8,136.5,141.0,164.8,169.7,202.2。LCMS t=5.6min,m/z计算值C21H23N2O2;C21H22N2NaO2;C42H45N4O4;C42H44N4NaO4 335.18;357.16;669.34;691.33[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值335.28;357.23;669.45;691.43。
实施例04-85
3-甲基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(间甲苯基)苯甲酰胺(04-85)的制备:按照实施例04-13的方法,由实施例01-14的化合物和间甲苯胺制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.40mmol规模产生了22mg产物(16%产量)。1H NMR(D6-DMSO)δ1.47(s,3H),2.19-2.21(m,2H),2.31(s,3H),2.33(s,3H),2.45-2.47(m,2H),6.92(d,J=7.4Hz,1H),7.22(d,J=7.8Hz,1H),7.29(d,J=8.1Hz,1H),7.56(d,J=8.2Hz,1H),7.61(s,1H),7.79(d,J=8.1Hz,1H),7.87(s,1H),8.74(s,1H),10.12(s,1H)。LCMS t=5.8min,m/z计算值C21H23N2O2;C21H22N2NaO2;C42H45N4O4;C42H44N4NaO4 335.18;357.16;669.34;691.33[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值335.26;357.23;669.44;691.43。
实施例04-86
3-甲基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(对甲苯基)苯甲酰胺(04-86)的制备:按照实施例04-13的方法,由实施例01-14的化合物和对甲苯胺制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.40mmol规模产生了35mg产物(26%产量)。1H NMR(D6-DMSO)δ1,47(s,3H),2.19-2.21(m,2H),2.28(s,3H),2.33(s,3H),2.44-2.46(m,2H),7.15(d,J=8.1Hz,2H),7.29(d,J=8.1Hz,1H),7.65(d,J=8.1Hz,2H),7.79(d,J=8.1Hz,1H),7.86(s,1H),8.74(s,1H),10.12(s,1H)。LCMS t=5.8min,m/z计算值C21H23N2O2;C21H22N2NaO2;C42H45N4O4;C42H44N4NaO4 335.18;357.16;669.34;691.33[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值335.25;357.23;669.44;691.43。
实施例04-87
N-(3-氟苯基)-3-甲基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-苯甲酰胺(04-87)的制备:按照实施例04-13的方法,由实施例01-14的化合物和间氟苯胺制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.40mmol规模产生了30mg产物(22%产量)。1H NMR(D6-DMSO)δ1.47(s,3H),2.19-2.22(m,2H),2.34(s,3H),2.46-2.48(m,2H),6.93(t,J=8.3Hz,1H),7.31(d,J=8.1Hz,1H),7.39(dd,J=15.4,7.8Hz,1H),7.56(d,J=8.1Hz,1H),7.75(d,J=11.7Hz,1H),7.80(d,J=8.1Hz,1H),7.87(s,1H),8.75(s,1H),10.39(s,1H)。13C NMR(D6-DMSO)δ7.6,17.7,25.6,32.7,106.9(JCF=26.2Hz),109.2,110.0(JCF=20.8Hz),115.9,125.9(JCF=25.8Hz),130.1(JCF=38.9Hz),131.6,133.5,141.0,141.3,162.1(JCF=240.7.3Hz),165.3,169.6,202.2。LCMS t=5.7min,m/z计算值C20H20FN2O2;C20H19FN2NaO2;C40H39F2N4O4;C40H38F2N4NaO4 339.15;361.13;677.29;699.28[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值339.25;361.20;677.40;600.39。
实施例04-88
N-(4-氯苯基)-3-甲基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-苯甲酰胺(04-88)的制备:按照实施例04-13的方法,由实施例01-14的化合物和对氯苯胺制备题述化合物;经色谱分析(ESS=H:E(1:19))和EtOAc研磨后,0.40mmol规模产生了25mg产物(18%产量)。1H NMR(D6-DMSO)δ1.47(s,3H),2.19-2.22(m,3H),2.33(s,3H),2.45-2.47(m,2H),7.30(d,J=8.2Hz,1H),7.41(d,J=8.7Hz,2H),7.79-7.82(m,3H),7.86(s,1H),8.75(s,1H),10.33(s,1H)。13C NMR(D6-DMSO)δ7.6,17.7 25.6,32.7,109.1,121.8,125.9,126.1,127.2,128.5,130.0,131.7,133.5,138.2,141.3,165.1,169.6,202.2。LCMS t=5.9min,m/z计算值C20H20ClN2O2;C20H19ClN2NaO2;C40H39Cl2N4O4;C40H38Cl2N4NaO4 355.12;377.10;709.23;731.22[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值355.19;377.17;709.35;731.34。
实施例04-89
4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(邻甲苯基)苯甲酰胺(04-89)的制备:按照实施例04-13的方法,由实施例01-25的化合物和邻甲苯胺制备题述化合物;经色谱分析(ESS=H:E(1:3))和EtOAc研磨后,0.50mmol规模产生了50mg产物(28%产量)。1H NMR(D6-DMSO)δ1.47(s,3H),2.20-2.23(m,5H),2.45-2.47(m,2H),7.17-7.24(m,2H),7.28(d,J=7.3Hz,1H),7.31(d,J=7.6Hz,1H),7.74(d,J=8.3Hz,1H),7.90(d,J=8.3Hz,1H),7.95(s,1H),9.03(s,1H),10.01(s,1H)。13C NMR(D6-DMSO)δ7.9,18.3,26.0,33.1,110.0,126.5,126.7,127.2,128.0,130.4,130.8,133.9,134.2,134.3,136.5,137.2,140.1,160.5,170.0,202.9。LCMS t=4.8min,m/z计算值C20H20ClN2O2;C20H19ClN2NaO2;C40H39Cl2N4O4;C40H38Cl2N4NaO4355.12;377.10;709.23;731.22[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值355.12;377.11;709.24;731.22。
实施例04-90
4-氯-N-(4-甲氧苯基)-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯甲酰胺(04-90)的制备:按照实施例04-13的方法,由实施例01-36的化合物和对氨基苯甲醚制备题述化合物;0.50mmol规模从固体沉淀中产生90mg产物(47%产量)。1H NMR(D6-DMSO)δ1.67(s,3H),1.77-1.80(m,2H),2.19-2.22(m,2H),2.24-2.27(m,2H),3.75(s,3H),6.93(d,J=9.0Hz,2H),7.66(d,J=8.9Hz,2H),7.71(d,J=8.1Hz,1H),7.86-7.89(m,2H),8.11(s,1H),10.19(s,1H)。13C NMR(D6-DMSO)δ9.5,21.6,27.4,36.8,55.6,107.7,114.2,122.6,126.8,128.4,130.2,132.3,134.4,134.7,137.7,156.2,158.8,163.7,195.1。LCMS t=5.0min,m/z计算值C21H22ClN2O3;C21H21ClN2NaO3;C42H43Cl2N4O6;C42H42Cl2N4NaO6 385.13;407.11;769.26;791.24[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值385.12;407.10;769.23;791.21。
实施例04-91
4-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)-N-(邻甲苯基)苯甲酰胺(04-91)的制备:按照实施例04-13的方法,由实施例01-36的化合物和邻甲苯胺制备题述化合物;经色谱分析(ESS=H:E(1:3))和EtOAc研磨后,0.50mmol规模产生了55mg产物(30%产量)。1H NMR(D6-DMSO)δ1.66(s,3H),1.77-1.80(m,2H),2.19-2.23(m,5H),2.26-2.28(m,2H),7.17-7.24(m,2H),7.28(d,J=7.3Hz,1H),7.31(d,J=7.5Hz,1H),7.72(d,J=8.1Hz,1H),7.87-7.89(m,2H),8.13(s,1H),10.00(s,1H)。13C NMR(D6-DMSO)δ9.5,18.3,21.6,27.5,36.8,107.9,126.5,126.7,127.2,128.3,130.3,130.8,134.2,134.3,136.5,137.8,158.8,164.1,195.2。LCMS t=5.0min,m/z计算值C21H22ClN2O2;C21H21ClN2NaO2;C42H43Cl2N4O4;C42H43Cl2N4NaO4 369.14;391.12;737.27;759.25[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值369.14;391.12;737.27;759.25。
实施例04-92
甲基3-(4-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯甲酰胺基)-2-苯甲酸甲酯(04-92)的制备:按照实施例04-13的方法,由实施例01-36的化合物和3-氨基-2-苯甲酸甲酯(3-amino-2-methylbenzoate)制备题述化合物;2.0mmol规模从沉淀中产生了340mg产物(40%产量)。1H NMR(D6-DMSO)δ1.67(s,3H),1.78-1.81(m,2H),2.19-2.22(m,2H),2.27-2.29(m,2H),2.34(s,3H),3.85(s,3H),7.35(t,J=7.8Hz,1H),7.51(d,J=7.7Hz,1H),7.68(d,J=7.7Hz,1H),7.73(d,J=8.1Hz,1H),7.88-7.90(m,2H),8.14(s,1H),10.20(s,1H)。13C NMR(D6-DMSO)δ9.5,15.7,21.6,27.4,36.8,52.6,107.9,126.3,126.8,128.2,128.4,130.4,131.2,132.0,133.9,134.5,135.3,137.7,137.8,158.7,164.4,168.1,195.2。LCMS t=5.1min,m/z计算值C23H24ClN2O4;C23H23ClN2NaO4;C46H47Cl2N4O8;C46H46Cl2N4NaO8 427.14;449.12;853.28;875.26[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值427.16;449.14;853.31;875.29。
实施例04-93
甲基3-(4-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯甲酰胺基)-4-苯甲酸甲酯(04-93)的制备:按照实施例04-13的方法,由实施例01-36的化合物和3-氨基-4-苯甲酸甲酯制备题述化合物;2.0mmol规模从沉淀中产生了310mg产物(36%产量)。1H NMR(D6-DMSO)δ1.67(s,3H),1.78-1.81(m,2H),2.19-2.22(m,2H),2.27-2.29(m,2H),2.31(s,3H),3.85(s,3H),7.45(d,J=7.9Hz,1H),7.74(d,J=8.0Hz,1H),7.77(d,J=7.9Hz,1H),7.87-7.90(m,2H),7.97(s,1H),8.14(s,1H),10.14(s,1H)。LCMS t=5.1min,m/z计算值C23H24ClN2O4;C23H23ClN2NaO4;C46H47Cl2N4O8;C46H46Cl2N4NaO8427.14;449.12;853.28;875.26[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值427.16;449.14;853.32;875.29。
实施例04-94
甲基4-(4-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯甲酰胺基)-3-苯甲酸甲酯(04-94)的制备:按照实施例04-13的方法,由实施例01-36的化合物和4-氨基-3-苯甲酸甲酯制备题述化合物;2.0mmol规模从沉淀中产生了175mg产物(21%产量)。1H NMR(D6-DMSO)δ1.67(s,3H),1.78-1.81(m,2H),2.19-2.22(m,2H),2.29-2.32(m,5H),3.86(s,3H),7.58(d,J=8.3Hz,1H),7.73(d,J=8.1Hz,1H),7.83(d,J=8.2Hz,1H),7.85-7.90(m,3H),8.11(s,1H),10.10(s,1H)。13C NMR(D6-DMSO)δ9.5,18.3,21.6,27.5,36.8,52.5,108.0,126.5,126.8,127.2,127.6,128.3,130.4,131.8,133.9,134.0,134.5,137.9,141.2,158.7,164.3,166.4,195.2。LCMS t=5.1min,m/z计算值C23H24ClN2O4;C23H23ClN2NaO4;C46H47Cl2N4O8;C46H46Cl2N4NaO8 427.14;449.12;853.28;875.26[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值427.16;449.14;853.31;875.29。
实施例04-95
3-(4-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯甲酰胺基)-2-甲基-苯甲酸(04-95)的制备:按照实施例02-01的方法,由实施例04-92的化合物制备题述化合物;0.75mmol规模产生了0.29g产物(93%产量)。1HNMR(D6-DMSO)δ1.66(s,3H),1.78-1.81(m,2H),2.21(t,J=6.3Hz,2H),2.27-2.29(m,2H),2.37(s,3H),7.32(t,J=7.8Hz,1H),7.47(d,J=8.3Hz,1H),7.68(d,J=7.8Hz,1H),7.73(d,J=8.2Hz,1H),7.88-7.90(m,2H),8.12(s,1H),10.16(s,1H),12.98(s,1H)。13C NMR(D6-DMSO)δ9.5,15.7,21.6,27.4,36.8,107.9,126.1,126.8,128.3,130.4,130.8,133.2,133.9,134.5,135.2,137.6,137.8,158.7,164.4,169.5,195.1。LCMS t=4.7min,m/z计算值C22H22ClN2O4;C22H21ClN2NaO4;C44H43Cl2N4O8;C44H42Cl2N4NaO8 413.13;435.11;825.25;847.23[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值413.14;435.12;825.28;847.25。
实施例04-96
3-(4-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯甲酰胺基)-4-甲基-苯甲酸(04-96)的制备:按照实施例02-01的方法,由实施例04-93的化合物制备题述化合物;0.7mmol规模产生了0.26g产物(88%产量)。1HNMR(D6-DMSO)δ1.67(s,3H),1.78-1.81(m,2H),2.21(t,J=6.4Hz,1H),2.26-2.30(m,5H),7.41(d,J=8.0Hz,1H),7.72-7.76(m,2H),7.87-7.89(m,2H),7.92(s,1H),8.11(s,1H),10.11(s,1H),12.91(s,1H).13C NMR(D6-DMSO)δ9.5,18.6,21.6,27.4,36.8,107.9,126.8,127.4,127.9,128.4,129.3,130.3,131.1,134.0,134.5,136.7,137.8,139.6,158.7,164.3,167.4,195.1。LCMS t=4.7min,m/z计算值C22H22ClN2O4;C44H43Cl2N4O8413.13;825.25[M+H]+;[2M+H]+,实验值413.14;825.29。
实施例04-97
4-(4-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯甲酰胺基)-3-甲基-苯甲酸(04-97)的制备:按照实施例02-01的方法,由实施例04-94的化合物制备题述化合物;0.4mmol规模产生了0.1g产物(61%产量)。1HNMR(D6-DMSO)δ1.66(s,3H),1.78-1.81(m,2H),2.21(t,J=6.4Hz,1H),2.26-2.32(m,5H),7.53(d,J=8.3Hz,1H),7.73(d,J=8.1Hz,1H),7.80(d,J=8.2Hz,1H),7.86-7.78(m,3H),8.11(s,1H),10.09(s,1H),12.87(s,1H)。13CNMR(D6-DMSO)δ9.5,18.3,21.6,27.5,36.8,108.0,126.4,126.8,127.7,128.3,128.5,130.4,131.9,133.7,134.0,134.5,137.8,140.8,158.7,164.2,167.5,195.2。LCMS t=4.8min,m/z计算值C22H22ClN2O4;C22H21ClN2NaO4;C44H43Cl2N4O8;C44H42Cl2N4NaO8 413.13;825.25[M+H]+;[2M+H]+,实验值413.14;825.28。
实施例04-98
N-(4-甲氧基苯基)-2-(3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-乙酰胺(04-98)的制备:按照实施例04-13的方法,由实施例01-37的化合物和对氨基苯甲醚制备题述化合物;经色谱分析(ESS=H:E(1:3))和EtOAc研磨后,0.50mmol规模产生了10mg产物(6%产量)。1H NMR(D6-DMSO)δ1.66(s,3H),1.75-1.78(m,2H),2.18-2.21(m,2H),2.42-2.45(m,2H),3.59(s,2H),3.71(s,3H),6.87(d,J=8.7Hz,2H),6.99(d,J=7.5Hz,1H),7.08(s,2H),7.28(t,J=7.8Hz,1H),7.49(d,J=8.7Hz,2H),8.20(s,1H),10.01(s,1H)。13C NMR(D6-DMSO)δ9.7,22.1,27.8,36.9,43.5,55.6,107.6,114.3,121.1,122.9,125.4,129.1,129.1,132.8,137.3,140.3,155.6,158.5,168.8,194.8。LCMS t=4.9min,m/z计算值C22H25N2O3;C22H24N2NaO3;C44H49N4O6;C44H48N4NaO6 365.19;387.17;729.37;751.35[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值365.17;387.14;729.31;751.29。
实施例04-99
N-(4-甲氧苯基)-2-(4-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-乙酰胺(04-99)的制备:按照实施例04-13的方法,由实施例01-38的化合物和对氨基苯甲醚制备题述化合物;经色谱分析(ESS=H:E(1:3))和EtOAc研磨后,0.50mmol规模产生了31mg产物(17%产量)。1H NMR(D6-DMSO)δ1.68(s,3H),1.75-1.77(m,2H),2.17-2.20(m,2H),2.41-2.43(m,2H),3.57(s,2H),3.71(s,3H),6.87(d,J=8.6Hz,2H),7.08(d,J=7.8Hz,2H),7.28(d,J=7.8Hz,2H),7.50(d,J=8.6Hz,2H),8.14(s,1H),10.00(s,1H)。13C NMR(D6-DMSO)δ9.5,22.1,27.7,36.9,43.0,55.6,107.0,115.3,121.1,125.0,129.8,132.5,132.8,138.7,156.0,158.8,169.0,194.6。LCMS t=4.8min,m/z计算值C22H25N2O3;C22H24N2NaO3;C44H49N4O6;C44H48N4NaO6 365.19;387.17;729.37;751.35[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值365.16;387.14;729.30;751.28。
实施例04-100
2-(4-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-N-(邻甲苯基)乙酰胺(04-100)的制备:按照实施例04-13的方法,由实施例01-37的化合物和邻甲苯胺制备题述化合物;经色谱分析(ESS=H:E(1:3))和EtOAc研磨后,0.50mmol规模产生了40mg产物(23%产量)。1H NMR(D6-DMSO)δ1.68(s,3H),1.75-1.78(m,2H),2.16(s,3H),2.18-2.21(m,2H),2.41-2.44(m,2H),3.65(s,3H),7.05-7.21(m,5H),7.27-7.39(m,3H),8.18(s,1H),9.49(s,1H)。13C NMR(D6-DMSO)δ9.5,18.2,22.2,27.7,36.9,42.6,106.9,112.6,119.5,125.0,125.5,125.7,126.4,129.8,130.7,132.2,132.7,136.7,138.7,158.9,169.5,194.6。LCMSt=4.7min,m/z计算值C22H25N2O2;C22H24N2NaO2;C44H49N4O4;C44H48N4NaO4 349.19;371.17;697.37;719.36[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值349.18;371.14;697.31;719.29。
实施例04-101
N-(4-甲氧基苯基)-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)-4-(三氟甲基)苯甲酰胺(04-101)的制备:按照实施例04-13的方法,由实施例01-39的化合物和对氨基苯甲醚制备题述化合物;经色谱分析(ESS=H:E(1:1))和EtOAc研磨后,0.50mmol规模产生了10mg产物(5%产量)。1HNMR(D6-DMSO)δ1.66(s,3H),1.75-1.77(m,2H),2.19-2.21(m,4H),3.76(s,3H),6.95(d,J=8.4Hz,2H),7.67(d,J=8.3Hz,2H),7.95(s,2H),8.00(s,1H),8.05-8.07(m,1H),10.32(s,1H)。13C NMR(D6-DMSO)δ9.2,21.6,27.6,36.7,55.5,107.2,114.3,122.7,126.6,127.5,129.2(JCF=28.8Hz),130.1,132.0,138.8,139.7,156.4,159.2,163.4,195.0。LCMSt=5.1min,m/z计算值C22H22F3N2O3;C22H21F3N2NaO3;C44H43F6N4O6;C44H42F6N4NaO6 419.16;441.14;837.31;859.29[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值419.14;441.09;837.22;859.20。
实施例04-102
3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)-N-(邻甲苯基)-4-(三氟甲基)苯甲酰胺(04-102)的制备:按照实施例04-13的方法,由实施例01-39的化合物和邻甲苯胺制备题述化合物;经色谱分析(ESS=H:E(1:1))和EtOAc研磨后,0.50mmol规模产生了10mg产物(5%产量)。1H NMR(D6-DMSO)δ1.65(s,3H),1.75-1.78(m,2H),2.18-2.24(m,7H),7.19-7.26(m,2H),7.30(d,J=7.3Hz,1H),7.34(d,J=7.4Hz,1H),7.93-7.99(3H),8.07(d,J=7.9Hz,1H),10.15(s,1H)。13C NMR(D6-DMSO)δ9.3,18.3,21.6,27.6,36.7,107.4,126.6,127.0,127.2,127.6,129.2(JCF=29.9Hz),130.0,130.9,134.4,136.3,139.0,139.3,159.1,163.8,195.0。LCMS t=5.1min,m/z计算值C22H22F3N2O2;C22H21F3N2NaO2;C44H43F6N4O4;C44H42F6N4NaO4403.16;425.15;805.32;827.30[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值403.15;425.10;805.24;827.22。
实施例04-103
N-(4-甲氧基苯基)-4-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)-3-(三氟甲基)苯甲酰胺(N-(4-methoxyphenyl)-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)-3-(trifluoromethyl)benzamide)(04-103)的制备:按照实施例04-13的方法,由实施例01-40的化合物和对氨基苯甲醚制备题述化合物;经色谱分析(ESS=H:E(1:1))和EtOAc研磨后,0.50mmol规模产生了60mg产物(31%产量)。1H NMR(D6-DMSO)δ1.59(s,3H),1.77-1.80(m,2H),2.21-2.24(m,2H),2.29-1.31(m,2H),3.75(s,3H),6.95(d,J=8.6Hz,2H),7.46(d,J=8.3Hz,1H),7.66(d,J=8.6Hz,2H),7.91(s,1H),8.23(d,J=8.3Hz,1H),8.30(s,1H),10.33(s,1H)。13C NMR(D6-DMSO)δ9.8,21.5,28.1,36.9,55.6,109.6,114.2,122.6,123.9(JCF=273.6Hz),124.8(JCF=87.6,29.2Hz),126.5,129.7,132.3,132.4,132.8,141.6,156.2,158.2,163.6,195.7。LCMS t=5.1min,m/z计算值C22H22F3N2O3;C22H21F3N2NaO3;C44H43F6N4O6;C44H42F6N4NaO6419.16;441.14;837.31;859.29[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值419.14;441.09;837.22;859.20。
实施例04-104
3-碘-N-(4-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(04-104)的制备:按照实施例04-13的方法,由实施例02-08的化合物和对氨基苯甲醚制备题述化合物;经色谱分析(ESS H:E=1:19)后,0.15mmol规模产生了110mg淡黄色微晶体(mp=222–224℃,52%产量)。1HNMR(D6-DMSO)δ1.47(s,3H),2.20-2.22(m,2H),2.41-2.46(m,1H),3.75(s,3H),6.94(d,J=8.9Hz,2H),7.46(d,J=8.2Hz,1H),7.66(d,J=8.9Hz,2H),7.98(dd,J=8.1,1.2Hz,1H),8.47(d,J=1.3Hz,1H),8.90(s,1H),10.21(s,1H)。13C NMR(D6-DMSO)δ7.5,25.7,32.7,55.2,98.6,109.6,113.8,122.1,127.2,128.4,132.0,133.9,138.0,144.0,155.7,162.9,169.1,202.3。LCMS t=4.9min,计算值C20H20IN2O3;C20H19IN2NaO3;C40H39I2N4O6;C40H38I2N4NaO6 463.05;485.03;925.10;947.09[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值463.08;485.00;925.11;947.09。
实施例04-105
N-(4-甲氧基苯基)-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)-1-萘甲酰胺(04-105)的制备:按照实施例04-13的方法,由实施例01-52的化合物和对氨基苯甲醚制备题述化合物;经色谱分析(ESS H:E=1:1)后,0.5mmol规模产生了1mg米白色微晶体(1%产量)。1H NMR(D6-DMSO)δ1.74(s,3H),1.83-1.86(m,2H),2.25-2.28(m,2H),2.63-2.65(m,2H),3.76(s,3H),6.95(d,J=8.8Hz,2H),7.47-7.50(m,1H),7.53-7.58(m,2H),7.67(s,1H),7.71(d,J=8.8Hz,2H),7.92(d,J=8.1Hz,1H),8.08(d,J=8.3Hz,1H),8.49(s,1H),10.43(s,1H)。13C NMR(D6-DMSO)δ9.4,21.8,27.5,36.5,55.2,108.5,113.9,121.0,121.4,122.9,125.1,125.7,126.5,126.9,127.7,132.3,133.8,135.7,136.8,155.6,157.8,166.2,194.7。LCMS t=4.7min,计算值C25H25N2O3;C25H24N2NaO3;C50H49N4O6;C50H48N4NaO6401.187;423.169;801.365;823.347[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值401.184;423.138;801.345;823.331。
实施例04-106
3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)-N-(邻甲苯基)-1-萘甲酰胺(04-106)的制备:按照实施例04-13的方法,由实施例01-52的化合物和邻甲苯胺制备题述化合物;经色谱分析(ESS=1:1)后,0.5mmol规模产生了12mg淡黄色微晶体(mp=249–250℃分解,7%产量)。1H NMR(D6-DMSO)δ1.75(s,3H),1.83-1.86(m,2H),2.26-2.29(m,2H),2.34(s,3H),2.64-2.66(m,2H),7.18-7.21(m,1H),7.24-7.31(m,3H),7.48-7.57(m,3H),7.66(d,J=15.7Hz,2H),7.93(d,J=8.0Hz,1H),8.18(d,J=8.2Hz,1H),8.48(s,1H),10.07(s,1H)。13C NMR(D6-DMSO)δ9.4,18.1,21.9,36.6,108.6,121.2,123.0,125.1,125.7,126.1,126.3,126.7,126.9,127.7,130.4,133.3,133.8,135.5,136.2,136.8,157.7,166.9,194.8。LCMS t=5.0min,计算值C25H25N2O2;C25H24N2NaO2;C50H49N4O4;C50H48N4NaO4 385.19;407.17;769.37;791.36[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值385.18;407.16;769.35;791.34。
实施例05-01至05-86
实施例05-01
3-((3-氯苯基)氨基)-2-甲基环戊基-2-烯酮(3-((3-chlorophenyl)amino)-2-methylcyclopent-2-enone)(05-01)的制备:将2-甲基-1,3-环戊二酮(112mg,1.0mmol,1.0eq)和3-氯苯胺(106L,1.0eq)混合并且经AcOH(200L,3.5eq)处理。在单一模式的启动器的腔体内对微波瓶进行微波辐射10min,以2.45GHz产生连续辐射以保持温度。粗产物被重结晶,或者被直接添加至装有少量CH2Cl2的KP-SilTM柱(10g)中,同时在-Isolera Four仪器上使用分级式梯度法将产物从杂质中分离,于254/365nm下监控紫外线踪迹。经EtOAc重结晶后,在1.0mmol规模上发生的反应产生了90mg题述化合物(41%产量)。1H NMR(D6-DMSO)δ1.58(s,3H),2.21-2.23(m,2H),2.70-2.72(m,2H),7.15(d,J=7.8Hz,1H),7.21(d,J=7.9Hz,1H),7.35(s,1H),7.36(t,J=8.0Hz,1H),9.02(s,1H)。LCMS t=5.7min,m/z计算值C12H13ClNO;C12H12ClNNaO;C24H25Cl2N2O2;C24H24Cl2N2NaO2222.07;244.05;443.13;465.11[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值222.07;244.05;443.13;465.11。
实施例05-02
2-苄基-3-((4-甲氧基苯基)氨基)环戊基-2-烯酮(05-02)的制备:按照实施例05-01的方法,由中间体01和对氨基苯甲醚制备题述化合物;经色谱分析(ESS=H:E(1:3))和经EtOAc重结晶后,0.53mmol规模产生了30mg产物(19%产量)。1H NMR(D6-DMSO)δ2.18-2.20(m,2H),2.54-2.56(m,2H),3.48(s,2H),3.75(s,3H),6.91(d,J=8.8Hz,2H),7.10-7.13(m,1H),7.15(d,J=8.7Hz,2H),7.21-7.23(m,4H),9.03(s,1H)。13C NMR(D6-DMSO)δ25.4,26.8,32.5,55.3,112.0,114.1,125.4,125.9,128.0,128.1,132.1,140.9,156.7,170.9,201.1。LCMS t=5.1min,m/z计算值C19H20NO2;C19H19NNaO2;C38H39N2O4;C38H38N2NaO4 294.15;316.13;587.29;609.28[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值294.18;316.14;587.24;609.34。
实施例05-03
2-(4-((2-苄基-3-氧代环戊基-1-烯-1-基)氨基)苯基)乙腈(05-03)的制备:按照实施例05-01的方法,由中间体01和4-氨基苯乙腈(4-aminobenzyl cyanide)制备题述化合物;经色谱分析(ESS=H:E(1:3))和经EtOAc重结晶后,0.53mmol规模产生了10mg产物(6%产量)。1H NMR(D6-DMSO)δ2.23-2.25(m,2H),2.70-2.72(m,2H),3.53(s,2H),4.01(s,2H),7.10-7.3(m,1H),7.19-7.24(4H),7.26(d,J=8.4Hz,2H),7.31(d,J=8.3Hz,2H),9.19(s,1H)。13C NMR(D6-DMSO)δ21.8,25.6,26.8,32.8,113.5,119.3,123.6,125.4,127.1,128.0,128.1,128.8,139.0,140.6,169.8,201.5。LCMS t=4.9min,m/z计算值C20H19N2O;C20H18N2NaO;C40H37N4O2;C40H36N4NaO2 303.15;325.13;605.29;627.27[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值303.17;332.15;605.24 627.25。
实施例05-04
甲基4-((2-苄基-3-氧代环戊基-1-烯-1-基)氨基)-3-氯苯甲酸(05-04)的制备:按照实施例05-01的方法,由中间体01和甲基4-氨基-3-氯苯甲酸酯(methy1 4-amino-3-chlorobenzoate)制备题述化合物;经色谱分析(ESS=H:E(1:3))和经EtOAc重结晶后,1.07mmol规模和30min辐射产生了20mg产物(5%产量)。1H NMR(D6-DMSO)δ2.28-2.30(m,2H),2.59-2.61(m,2H),3.46(s,2H),3.86(s,3H),7.05-7.12(m,3H),7.14-7.20(m,2H),7.50(d,J=8.1Hz,1H),7.88(d,J=8.3Hz,1H),7.96(s,1H),9.01(s,1H)。13C NMR(D6-DMSO)δ25.8,27.3,32.7,52.5,114.9,125.6,126.9,127.9,128.0,128.5,130.3,139.9,140.6,164.7,168.7,202.5。LCMS t=5.3min,m/z计算值C20H19ClNO3;C20H18ClNNaO3;C40H36Cl2N2NaO6356.11;378.09;733.18[M+H]+;[M+Na]+;[2M+Na]+,实验值356.11;378.07;733.15。
实施例05-05
2-(4-羟基苄基)-3-((4-甲氧基苯基)氨基)环戊基-2-烯酮(05-05)的制备:按照实施例05-01的方法,由中间体02和对氨基苯甲醚制备题述化合物;经色谱分析(ESS=EtOAc)和经EtOAc重结晶后,0.5mmol规模产生了20mg产物(13%产量)。1H NMR(D6-DMSO)δ2.17-2.19(m,2H),2.50-2.53(m,2H),3.37(s,2H),3.75(3H),6.61(d,J=7.8Hz,2H),6.91(d,J=8.3Hz,2H),7.00(d,J=7.8Hz,2H),7.15(d,J=8.3Hz,2H),8.96(s,1H),9.05(s,1H)。13C NMR(D6-DMSO)δ25.3,25.9,32.5,55.3,112.8,114.1,114.7,125.8,129.0,130.9132.2,155.1,156.7,170.6,201.1。LCMS t=4.7min,m/z计算值C19H20NO3;C19H19NNaO3;C38H39N2O6;C38H38N2NaO6 310.14;332.13;619.28;641.26[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值310.17;332.13;619.23;641.25。
实施例05-# | 题述化合物名称 | X | Y |
06 | 2-苄基-3-(喹啉-3-基氨基)环戊基-2-烯酮 | CH | N |
07 | 2-苄基-3-(喹啉-2-基氨基)环戊基-2-烯酮 | N | CH |
实施例05-06
2-苄基-3-(喹啉-3-基氨基)环戊基-2-烯酮(05-06)的制备:按照实施例05-01的方法,由中间体01和3-氨基喹啉制备题述化合物;经色谱分析(ESS=H:E(1:3))和经EtOAc重结晶后,0.53mmol规模产生了15mg产物(9%产量)。1H NMR(D6-DMSO)δ2.30-2.32(m,2H),2.86-2.88(m,2H),3.59(s,2H),7.12-7.15(m,1H),7.22-7.24(m,4H),7.60(t,J=7.5Hz,1H),7.68(t,J=7.5Hz,1H),7.93(d,J=8.1Hz,1H),7.98(d,J=8.4Hz,1H),8.19(d,J=1.6Hz,1H),8.84(d,J=2.1Hz,1H),9.48(s,1H)。13CNMR(D6-DMSO)δ25.6,26.9,32.9,114.7,125.6,125.7,127.2,127.6,127.8,128.1,128.3,128.6,133.4,140.3,144.5,147.5,169.6,201.9。LCMS t=4.9min,m/z计算值C21H19N2O;C21H18N2NaO;C42H37N4O2;C42H36N4NaO2315.15;337.13;629.29;651.27[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值315.17;337.14;629.24;651.29。
实施例05-07
2-苄基-3-(喹啉-2-基氨基)环戊基-2-烯酮(05-07)的制备:按照实施例05-01的方法,由中间体01和2-氨基喹啉制备题述化合物;经色谱分析(ESS=H:E(1:3))和经EtOAc重结晶后,0.53mmol规模产生了5mg产物(3%产量)。1H NMR(D6-DMSO)δ2.35-2.37(m,2H),3.52-3.54(m,2H),3.68(s,2H),7.11-7.14(m,1H),7.22-7.25(m,4H),7.39(d,J=8.8Hz,1H),7.42(t,J=7.4Hz,1H),7.66(t,J=7.4Hz,1H),7.74(d,J=8.3Hz,1H),7.83(d,J=7.9Hz,1H),8.23(d,J=8.8Hz,1H),9.74(s,1H)。13CNMR(D6-DMSO)δ26.7,28.5,33.2,114.7,117.8,124.4,125.6,127.1,127.7,128.0,128.1,129.9,138.0,140.2,146.3,152.5,168.0,203.4。LCMS t=5.4min,m/z计算值C21H19N2O;C21H18N2NaO;C42H37N4O2;C42H36N4NaO2315.15;337.13;629.29;651.27[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值315.17;337.13;629.25;651.32。
实施例05-08
3-((3-氯苯基)氨基)-2-甲基环己基-2-烯酮(05-08)的制备:按照实施例05-01的方法,由2-甲基-1,3-环己二酮和3-氯苯胺制备题述化合物;经色谱分析(ESS=CH2Cl2:EtOAc(9:1))后,1.59mmol规模产生了300mg产物(80%产量)。1H NMR(D6-DMSO)δ1.64(s,3H),1.78-1.81(m,2H),2.21-2.24(m,2H),2.47-2.50(m,2H),7.05(d,J=7.9Hz,1H),7.12-7.15(m,2H),7.33(t,J=7.9Hz,1H),8.26(s,1H)。13C NMR(D6-DMSO)δ9.5,21.7,27.5,36.5,108.8,121.9,122.9,123.2,130.3,133.0,141.7,157.2,195.0。LCMS t=5.1min,m/z计算值C13H15ClNO;C13H14ClNNaO;C26H29Cl2N2O2;C26H28Cl2N2NaO2 236.08;258.07;471.16;493.14[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值236.10;258.07;471.14;493.16。
实施例05-09
2-甲基-3-(邻甲苯基氨基)环己基-2-烯酮(05-09)的制备:按照实施例05-01的方法,由2-甲基-1,3-环己二酮和邻甲苯胺制备题述化合物;经色谱分析(ESS=CH2Cl2:EtOAc(9:1))后,1.59mmol规模产生了130mg产物(38%产量)。1H NMR(D6-DMSO)δ1.67-1.73(m,5H),2.13-2.21(m,7H),7.11(d,J=6.8Hz,1H),7.18-7.22(m,2H),7.28(d,J=6.4Hz,1H),7.84(s,1H)。13C NMR(D6-DMSO)δ8.7,17.7,21.3,26.8,36.3,105.0,126.3,126.4,128.1,130.5,135.2,138.4,159.7,193.8。LCMS t=4.9min,m/z计算值C14H18NO;C14H17NNaO;C28H35N2O2;C28H34N2NaO2 216.14;238.12;431.27;453.25[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值216.17;238.12;431.27;453.46。
实施例05-10
2-甲基-3-(间甲苯基氨基)环己基-2-烯酮(05-10)的制备:按照实施例05-01的方法,由2-甲基-1,3-环己二酮和间甲苯胺制备题述化合物;经色谱分析(ESS=CH2Cl2:EtOAc(9:1))后,1.59mmol规模产生了190mg产物(56%产量)。1H NMR(D6-DMSO)δ1.67(s,3H),1.74-1.79(m,2H),2.17-2.20(m,2H),2.29(s,3H),2.41-2.44(m,2H),6.91(d,J=8.3Hz,1H),6.94-6.96(m,2H),7.21(t,J=7.7Hz,1H),8.12(s,1H)。13C NMR(D6-DMSO)δ9.1,20.9,21.7,27.3,36.5,106.7,121.6,124.9,125.1,128.6,138.1,139.7,158.3,194.3。LCMS t=5.0min,m/z计算值C14H18NO;C14H17NNaO;C28H35N2O2;C28H34N2NaO2 216.14;238.12;431.27;453.25[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值216.22;238.12;431.27;453.25。
实施例05-11
2-甲基-3-(对-甲苯基氨基)环己基-2-烯酮(05-11)的制备:按照实施例05-01的方法,由2-甲基-1,3-环己二酮和对甲苯胺制备题述化合物;经色谱分析(ESS=CH2Cl2:EtOAc(9:1))后,1.59mmol规模产生了160mg产物(47%产量)。1H NMR(D6-DMSO)δ1.67(s,3H),1.74-1.77(m,2H),2.16-2.19(m,2H),2.28(s,3H),2.36-2.29(m,2H),7.02(d,J=8.0Hz,2H),7.15(d,J=7.8Hz,2H),8.09(s,1H)。13C NMR(D6-DMSO)δ9.0,20.5,21.7,27.1,36.4,106.0,124.9,129.2,133.6,137.2,158.7,194.0。LCMS t=5.0min,m/z计算值C14H18NO;C14H17NNaO;C28H35N2O2;C28H34N2NaO2 216.14;238.12;431.27;453.25[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值216.17;238.12;431.27;453.26。
实施例05-12
甲基3-氯-4-((2-甲基-3-氧代环己基-1-烯-1-基)氨基苯甲酸酯(05-10)的制备:按照实施例05-01的方法,由2-甲基-1,3-环己二酮和甲基4-氨基-3-氯苯甲酸酯制备题述化合物;经色谱分析(ESS=CH2Cl2:EtOAc(9:1))后,1.59mmol规模辐射30min产生了260mg产物(56%产量)。1H NMR(D6-DMSO)δ1.52(s,3H),1.81-1.83(m,2H),2.24-2.27(m 2H),2.42-2.43(m,2H),3.85(s,3H),7.18(d,J=8.3Hz,1H),7.86(d,J=8.4Hz,1H),7.98(s,1H),8.06(s,1H)。LCMS t=5.1min,m/z计算值C15H17ClNO3;C15H16ClNNaO3;C30H33Cl2N2O6;C30H32Cl2N2NaO6 294.09;316.07;587.17;609.15[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值294.12;316.09;587.13;609.15。
实施例05-13
3-氯-N-(4-甲氧基苯基)-4-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯甲酰胺(05-13)的制备:按照实施02-01的方法,将实施例05-12的化合物(239mg,0.82mmol)水解为3-氯-4-((2-甲基-3-氧代环己基-1-烯-1-基)氨基苯甲酸。按照实施例04-13的方法,由3-氯-4-((2-甲基-3-氧代环己基-1-烯-1-基)氨基苯甲酸和对氨基苯甲醚制备题述化合物;经色谱分析(ESS=H:E(1:3))和EtOAc研磨后,0.21mmol规模产生了10mg产物(12%产量)。1H NMR(D6-DMSO)δ1.61(s,3H),1.80-1.82(m,2H),2.22-2.25(m,2H),2.36-2.38(m,2H),3.75(s,3H),6.94(d,J=8.8Hz,2H),7.31(d,J=8.3Hz,1H),7.66(d,J=8.7Hz,2H),7.91(d,J=8.2Hz,1H),8.06(s,1H),8.11(s,1H),10.18(s,1H).13C NMR(D6-DMSO)δ9.6,12.1,27.6,36.5,55.2,109.7,113.8,122.0,126.6,127.1,128.4,128.8,132.0,132.1,140.1,155.7,157.3,163.1,195.3。LCMS t=5.0min,m/z计算值C21H22ClN2O3;C21H21ClN2NaO3;C42H43Cl2N4O6;C42H42Cl2N4NaO6 385.13;407.11;769.26;791.24[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值385.12;407.09;769.22;791.22。
实施例05-14
3-氯-N-(2-甲氧基苯基)-4-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯甲酰胺(05-14)的制备:按照实施例05-13的方法,由3-氯-4-((2-甲基-3-氧代环己基-1-烯-1-基)氨基苯甲酸和邻氨基苯甲醚制备题述化合物;经色谱分析(ESS=H:E(1:3))和EtOAc研磨后,0.21mmol规模产生了5mg产物(6%产量)。1H NMR(D6-DMSO)δ1.61(s,3H),1.80-1.87(m,2H),2.23-2.25(m,2H),2.37-2.39(m,2H),3.83(s,3H),6.96-7.01(m,1H),7.10-7.15(m,1H),7.21-7.26(m,1H),7.30-7.35(m,1H),7.67(d,J=6.3Hz,1H),7.92(d,J=6.9Hz,1H),8.07(s,1H),8.11(s,1H),9.60(s,1H)。13C NMR(D6-DMSO)δ9.7,21.1,27.6,36.5,55.7,109.9,111.5,120.2,125.2,126.2,126.5,126.6,127.0,128.4,129.0,131.6,140.3,152.0,157.3,163.3,195.4。
LCMS t=5.3min,m/z计算值C21H22ClN2O3;C21H21ClN2NaO3;C42H43Cl2N4O6;C42H42Cl2N4NaO6 385.13;407.11;769.26;791.24[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值385.13;407.09;769.20;791.39。
实施例05-15
3-氯-4-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)-N-(邻甲苯基)苯甲酰胺(05-15)的制备:按照实施例05-13的方法,由3-氯-4-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯甲酸和邻甲苯胺制备题述化合物;经色谱分析(ESS=H:E(1:3))和EtOAc研磨后,0.21mmol规模产生了2mg产物(3%产量)。1H NMR(D6-DMSO)δ1.61(s,3H),1.79-1.88(m,2H),2.20-2.32(m,5H),2.34-2.45(m,2H),7.15-7.39(m,5H),7.93(s,1H),8.07(s,1H),8.12(s,1H),9.96(s,1H)。13C NMR(D6-DMSO)δ9.7,17.9,21.1,27.6,36.5,109.8,126.0,126.2,126.7,127.1,128.5,129.0,130.4,131.7,133.8,136.2,140.3,157.3,163.5,195.4。LCMS t=5.2min,m/z计算值C21H22ClN2O2;C21H21ClN2NaO2;C42H42Cl2N4NaO4 369.14;391.12;759.25[M+H]+;[M+Na]+;[2M+Na]+,实验值369.14;391.10;759.24。
实施例05-16
4-((2-苄基-3-氧代环戊基-1-烯-1-基)氨基)-3-氯-N-(邻甲苯基)苯甲酰胺(05-16)的制备:按照实施例05-13的方法,由中间体01和游离碱中间体03制备题述化合物;经色谱分析(ESS=H:E(1:3))和经MeOH重结晶后,0.25mmol规模产生了5mg产物(5%产量)。1HNMR(D6-DMSO)δ2.24(s,3H),2.27-2.28(m,2H),2.56-2.58(m,2H),3.50(s,2H),7.12-7.24(m,7H),7.28(d,J=7.0Hz,1H),7.32(d,J=7.5Hz,1H),7.56(d,J=8.2Hz,1H),7.94(d,J=7.9Hz,1H),8.10(s,1H),9.06(s,1H),10.00(s,1H)。LCMS t=5.6min,m/z计算值C26H24ClN2O2;C26H23ClN2NaO2;C52H47Cl2N4O4;C52H46Cl2N4NaO4 431.15;453.13;861.30;883.28[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值431.15;453.13;861.30;883.28。
实施例05-17
3-氟-N-(4-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(05-17)的制备:按照实施例05-13的方法,由2-甲基-1,3-环戊二酮和游离碱中间体04制备题述化合物;经MeOH重结晶后,0.25mmol规模产生了50mg产物(56%产量)。1H NMR(D6-DMSO)δ1.54(s,3H),2.22-2.25(m,2H),2.50-2.52(m,2H),3.75(s,3H),6.92-6.95(m,2H),7.44-7.48(m,1H),7.65-7.67(m,2H),7.80-7.82(m,1H),7.88(dd,J=11.3,1.7Hz,1H),9.03(s,1H),10.15(s,1H)。LCMS t=4.8min,m/z计算值C20H20FN2O3;C20H19FN2NaO3;C40H39F2N4O6;C40H38F2N4NaO6 355.15;377.13;709.28;731.27[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值355.17;377.10;709.24;731.22。
实施例05-18
3-溴-N-(4-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(05-18)的制备:按照实施例05-13的方法,由2-甲基-1,3-环戊二酮和游离碱中间体05制备题述化合物;经MeOH重结晶后,0.25mmol规模产生了10mg产物(10%产量)。1H NMR(D6-DMSO)δ1.47(s,3H),2.21-2.24(m,2H),2.47-2.49(m,2H),3.75(s,3H),6.93-6.95(m,2H),7.49(d,J=8.3Hz,1H),7.66(d,J=8.9Hz,2H),7.97(dd,J=8.2,1.6Hz,1H),8.27(d,J=1.7Hz,1H),8.93(s,1H),10.22(s,1H)。LCMS t=4.9min,m/z计算值C20H20BrN2O3;C20H19BrN2NaO3;C40H39Br2N4O6;C40H38Br2N4NaO6415.07,417.06;437.05,439.05;831.12;853.10[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值415.05,417.05;437.01,439.01;831.05;853.03。
实施例05-19
叔丁基(2-(4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺基)乙基)-氨基甲酸酯(05-19)的制备:将叔丁基-N-(2-氨基乙基)氨基甲酸酯(1.4mL,1.03eq)加入至于0℃下的CH2Cl2:DMF(90mL,1:1)中搅拌的实施例02-01的化合物(2.0g,8.65mmol)中。加入3-(乙基亚氨基亚甲基氨基)-N,N-二甲基-丙基-1-胺盐酸盐(3-(Ethyliminomethylene-amino-N,N-dimethyl-propan-1-amine hydrochloride)(EDCCl,2.0g,1.2eq)并在0℃下搅拌2h。升温至室温过夜后,于旋蒸仪上除去溶剂。使用去离子水(500mL)和EtOAc(8×125mL)进行后处理(Work-up)。有机层经无水硫酸钠干燥并于旋蒸仪上浓缩。将粗材料直接加入至KP-SilTM柱(100g)上,同时在-Isolera Four仪器上使用分级式梯度法将产物从杂质中分离,于254/365nm下监控紫外线踪迹。经色谱分析(ESS=EtOAc)后,在8.65mmol规模上发生的反应产生了1.5g题述化合物(46%产量)。1H NMR(D6-DMSO)δ1.37(s,9H),1.59(s,3H),2.23-2.25(m,2H),2.75-2.77(m,2H),3.08-3.10(m,2H),3.26-3.28(m,2H),6.92(s,1H),7.29(d,J=8.0Hz,2H),7.81(d,J=7.8Hz,2H),8.38(s,1H),9.11(s,1H)。LCMS t=直接注射,m/z计算值C20H28N3O4;C20H27N3NaO4;C40H54N6NaO8 374.21;396.19;769.39[M+H]+;[M+Na]+;[2M+Na]+,实验值374.21;396.19;769.39。
实施例05-20
2-(4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺基)乙胺2,2,2-三氟乙酸盐(2-(4-((2-methyl-3-oxocyclopent-l-en-1-yl)amino)benzamido)ethanaminium 2,2,2-trifluoroacetate)(05-20)的制备:将实施例05-19的化合物(750mg,2.0mmol)于室温下在最小量的CH2Cl2:TFA(1:1)中搅拌30min。于旋蒸仪上除去溶剂并经EtOAc重结晶得到题述化合物。1HNMR(MeOD)δ1.68(s,3H),2.41-2.43(m,2H),2.84-2.86(m,2H),3.15-3.18(m,2H),3.65-3.67(m,2H),7.35(d,J=8.4Hz,2H),7.89(d,J=8.3Hz,2H)。LCMS t=3.0min,m/z计算值C15H20N3O2;C15H19N3NaO2;C30H39N6O4;C30H38N6NaO4 274.16;296.14;547.30;569.29[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值274.20;296.17;547.27;569.26。
实施例05-21
N-(2-乙酰胺基乙基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(05-21)的制备:将N-酰化酸酐;酸酐(5eq)、TEA(2eq)和实施例05-20的化合物(25mg,0.09mmol,1.0eq)在CH2Cl2中混合,并于室温下搅拌1h。于旋蒸仪上除去溶剂。将粗产物加入至KP-SilTM柱(10g)中。可选地,从反应混合物中过滤出沉淀物。经色谱分析(ESS=EtOAc)后,在0.09mmol规模上发生的反应产生了15mg题述化合物(53%产量)。1H NMR(D6-DMSO)δ1.72(s,3H),1.95(s,3H),2.48-2.50(m,2H),2.85-2.87(m,2H),3.38-3.41(m,2H),3.47-3.50(m,2H),7.37(d,J=8.4Hz,2H),7.86(d,J=8.4Hz,2H)。LCMS直接注射,m/z计算值C17H22N3O3;C17H21N3NaO3;C34H42N6NaO6 316.17;338.15;653.31[M+H]+;[M+Na]+;[2M+Na]+,实验值316.17;338.15;653.31。
实施例05-22
N-(2-苯甲酰胺基乙基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(05-22)的制备:按照实施例05-21的方法,由实施例05-20的化合物和苯乙酸酐(phenylacetic anhydride)制备题述化合物;经色谱分析(ESS=EtOAc)后,0.09mmol规模产生了10mg产物(29%产量)。1H NMR(CD3OD)δ1.68(s,3H),2.40-2.43(m,2H),2.82-2.84(m,2H),3.61-3.63(m,4H),7.33(d,J=8.4Hz,2H),7.45(t,J=7.6Hz,2H),7.51(t,J=7.3Hz,1H),7.81(d,J=7.6Hz,2H),7.84(d,J=8.4Hz,2H)。LCMS直接注射,m/z计算值C22H24N3O3;C22H23N3NaO3;C44H46N6NaO6 378.18;400.16;777.34[M+H]+;[M+Na]+;[2M+Na]+,实验值378.18;400.16;777.34。
实施例05-23
4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)哌啶-1-鎓2,2,2-三氟乙酸盐(4-((2-methyl-3-oxocyclopent-l-en-1-yl)amino)piperidin-1-ium2,2,2-trifluoroacetate)(05-23)的制备:按照实施例05-20的方法,由实施例01-32的化合物制备题述化合物。1H NMR(D6-DMSO)δ1.66(s,3H),1.71(dd,J=23.4,10.5Hz,2H),2.03(d,J=12.9Hz,2H),2.12-2.14(m,2H),2.50-2.52(m,2H),2.96(t,J=12.1Hz,2H),3.30-3.38(m,2H),3.60-3.72(m,1H),7.08(d,J=8.9Hz,1H),8.54(br s,1H),8.77(br s,1H)。LCMSt=1.1min,m/z计算值C11H19N2O;C11H18N2NaO;C22H37N4O2,C22H36N4NaO2195.15;217.13;389.29;411.27[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值195.27;217.25;389.36;411.34。
实施例05-24
叔丁基4-(3-氯-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺基)氨基甲酸苄酯(benzylcarbamate)(05-24)的制备:按照实施例04-13的方法,由实施例02-02的化合物和4-(N-叔丁氧羰基)氨基甲基-苯胺(4-(N-Boc)aminomethyl-aniline)制备题述化合物;经色谱分析(ESS=H:E(1:19))后,1.0mmol规模产生了400mg产物(85%产量)。1H NMR(D6-DMSO)δ1.40(s,9H),1.48(s,3H),2.23-2.25(m,2H),2.49-2.50(m,2H),4.10(d,J=4.6Hz,2H),7.22(d,J=7.8Hz,2H),7.36-7.38(m,1H),7.49(d,J=8.2Hz,1H),7.69(d,J=7.8Hz,2H),7.94(d,J=8.3Hz,1H),8.13(s,1H),8.97(s,1H),10.30(s,1H)。LCMS t=5.9min,m/z计算值C25H29ClN3O4;C25H28ClN3NaO4;C50H57Cl2N6O8;C50H56Cl2N6NaO8 470.18;492.17;939.36;961.34[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值470.19;492.13;939.39;961.37。
实施例05-25
(4-(3-氯-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺基)苯基)甲基铵2,2,2-三氟乙酸盐((4-(3-chloro-4-((2-methyl-3-oxocyclopent-l-en-1-yl)amino)benzamido)phenyl)methanaminium 2,2,2-trifluoroacetate)(05-25)的制备:按照实施例05-20的方法,由实施例05-24的化合物制备题述化合物。1H NMR(D6-DMSO)δ1.47(s,3H),2.24-2.26(m,2H),2.49-2.51(m,2H),4.01(d,J=5.5Hz,2H),7.44(d,J=8.4Hz,2H),7.49(d,J=8.3Hz,1H),7.80(d,J=8.4Hz,2H),7.94(d,J=8.3Hz,1H),8.09(br s,3H),8.14(s,1H),8.98(s,1H),10.42(s,1H)。LCMS t=5.1min,m/z计算值C20H21ClN3O2;C20H20ClN3NaO2;C40H41Cl2N6O4;C40H40Cl2N6NaO4 370.13;392.11;739.26;761.24[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值370.13;392.11;739.26;761.24。
实施例05-26
N-(4-(乙酰胺基甲基)苯基)-3-氯-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺(05-26)的制备:按照实施例05-21的方法,由实施例05-25的化合物和乙酸酐制备题述化合物;经沉淀后,0.05mmol规模产生了10mg产物(49%产量)。1H NMR(D6-DMSO)δ1.48(s,3H),1.87(s,3H),2.23-2.25(m,2H),2.49-2.51(m,2H),4.22(d,J=5.7Hz,2H),7.23(d,J=8.2Hz,2H),7.49(d,J=8.3Hz,1H),7.70(d,J=8.3Hz,2H),7.94(d,J=8.2Hz,1H),8.14(s,1H),8.13-8.15(m,1H),8.97(s,1H),10.31(s,1H)。LCMS t=4.6min,m/z计算值C22H23ClN3O3;C22H22ClN3NaO3;C44H44Cl2N6NaO6 412.14;434.12;845.26[M+H]+;[M+Na]+;[2M+Na]+,实验值412.15;434.09;845.24。
实施例05-27
叔丁基(2-(4-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯甲酰胺基)乙基)氨基甲酸酯(05-27)的制备:按照实施例04-13的方法,由实施例01-36的化合物和叔丁基(2-氨基乙基)氨基甲酸酯制备题述化合物;经沉淀后,0.5mmol规模产生了300mg产物(71%产量)。1H NMR(D6-DMSO)δ1.36(s,9H),1.65(s,3H),1.76-1.78(m,2H),2.18-2.21(m,4H),3.09-3.11(s,2H),3.26-3.29(m,2H),6.93-6.95(m,1H),7.64-7.66(m,1H),7.72-7.75(m,2H),8.08-8.10(m,1H),8.58(s,1H)。13C NMR(D6-DMSO)δ9.4,21.6,27.3,28.6,36.8,78.1,107.5,126.6,128.2,130.1,134.2,134.3,137.5,156.2,128.9,165.2,195.0。LCMS t=4.9min,m/z计算值C21H29ClN3O4;C21H28ClN3NaO4;C42H57Cl2N6O8;C42H56Cl2N6NaO8 422.18;444.17;843.36;865.34[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值422.20;444.18;843.39;865.37。
实施例05-28
N-(2-氨基乙基)-4-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯甲酰胺(05-28)的制备:按照实施例05-20的方法,由实施例05-24的化合物制备题述化合物。TFA盐易潮。游离碱(freebase)被分离(iso1ated)。1HNMR(D6-DMSO)δ1.65(s,3H),1.77-1.79(m,2H),2.19-2.23(m,4H),2.99-3.01(m,2H),3.45-3.51(m,2H),7.68(d,J=8.2Hz,1H),7.74-7.89(m,4H),8.09-8.11(m,1H),8.75(s,1H)。13C NMR(D6-DMSO)δ9.5,21.6,27.4,36.8,37.6,39.0,107.7,126.6,128.2,130.2,133.9,134.3,137.6,158.7,165.8,195.1。LCMS t=3.8min,m/z计算值C16H21ClN3O2;C16H20ClN3NaO2;C32H41Cl2N6O4;C32H40Cl2N6NaO4 322.13;344.11;643.26;665.24[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值322.14;344.13;643.28;665.26。
实施例05-29
N-(2-乙酰胺基乙基)-4-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯甲酰胺(05-29)的制备:按照实施例05-21的方法,由实施例05-28的化合物和乙酸酐制备题述化合物;经沉淀后,0.10mmol规模产生了5mg产物(14%产量)。1H NMR(D6-DMSO)δ1.65(s,3H),1.77-1.81(m,5H),2.19-2.23(m,4H),3.19-3.21(m,2H),3.28-3.30(m,2H),7.65(d,J=8.7Hz,1H),7.73(s,2H),7.97(s,1H),8.06(s,1H),8.62(s,1H)。LCMS t=4.2min,m/z计算值C18H23ClN3O3;C18H22ClN3NaO3;C36H45Cl2N6O6;C36H45Cl2N6NaO6364.14;386.12;727.28;749.26[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值364.15;386.14;727.30;749.28。
实施例05-30
叔丁基(2-(3-(4-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯甲酰胺基)-2-甲基苯甲酰胺基)乙基)氨基甲酸酯(05-30)的制备:按照实施例04-13的方法,由实施例04-95的化合物和叔丁基(2-氨基乙基)氨基甲酸酯制备题述化合物;经色谱分析(ESS=EtOAc)后,0.5mmol规模产生了50mg产物(18%产量)。1H NMR(D6-DMSO)δ1.40(s,9H),1.66(s,3H),1.78-1.81(m,2H),2.18-2.22(m,4H),2.26-2.28(m,2H),3.09-2.12(m,2H),3.24-3.28(m,2H),6.87(t,J=5.4Hz,1H),7.25-7.26(m,2H),7.36(t,J=4.5Hz,1H),7.72(d,J=8.1Hz,1H),7.86-7.89(m,2H),8.12(s,1H),8.31(t,J=5.4Hz,1H),10.07(s,1H)。LCMS t=4.9min,m/z计算值C29H36ClN4O5;C29H35ClN4NaO5;C58H71Cl2N8O10;C58H70Cl2N8NaO10 555.24;577.22;1109.47;1131.45[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值555.26;577.24;1109.51;1131.49。
实施例05-31
叔丁基(2-(3-(4-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯甲酰胺基)-4-甲基苯甲酰胺基)乙基)氨基甲酸酯(05-31)的制备:按照实施例04-13的方法,由实施例04-96的化合物和叔丁基(2-氨基乙基)氨基甲酸酯制备题述化合物;经色谱分析(ESS=EtOAc)后,0.5mmol规模产生了36%产量的产物。1H NMR(D6-DMSO)δ1.39(s,9H),1.66(s,3H),1.78-1.80(m,2H),2.19-2.22(m,2H),2.26-2.28(m,4H),3.09-3.11(m,2H),3.27-3.30(m,2H),6.91(t,J=5.6Hz,1H),7.37(d,J=8.0Hz,1H),7.68(d,J=7.8Hz,1H),7.73(d,J=8.1Hz,1H),7.81(s,1H),7.87-7.90(m,2H),8.11(s,1H),8.43(t,J=5.3Hz,1H),10.12(s,1H)。LCMS t=5.0min,m/z计算值C29H36ClN4O5;C29H35ClN4NaO5;C58H71Cl2N8O10;C58H70Cl2N8NaO10555.24;577.22;1109.47;1131.45[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值555.26;577.24;1109.50;1131.49。
实施例05-32
2-((3-氯苯基)氨基)-6-氧代环己基-1-烯腈(2-((3-chlorophenyl)amino)-6-oxocyclohex-1-enecarbonitrile)(05-32)的制备:按照实施例05-13的方法,由中间体06和3-氯苯胺制备题述化合物;经色谱分析(ESS=H:E(1:1))后,1.3mmol规模产生了24mg产物(8%产量)。1H NMR(D6-DMSO)δ1.82-1.85(m,2H),2.26-2.29(m,2H),2.58-2.60(m,2H),7.26(d,J=7.7Hz,1H),7.37-7.46(m,3H),10.15(s,1H)。13C NMR(D6-DMSO)δ20.6,26.7,36.4,86.0,116.2,125.4,126.6,127.4,130.9,133.5,139.1,170.9,193.2。LCMS t=4.6min,m/z计算值C13H12ClN2O;C13H11ClN2NaO;C26H23Cl2N4O2;C26H22Cl2N4NaO2 247.06;269.05;493.12;515.10[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值247.07;269.06;493.14;515.12。
实施例05-33
4-氯-3-((2-氰基-3-氧代环己基-1-烯-1-基)氨基)苯甲酸(05-33)的制备:按照实施例01-01的方法,由中间体06和3-氨基-4-氯苯甲酸制备题述化合物;经色谱分析(ESS=CH2Cl2:MeOH(19:1))后,7.3mmol规模产生了0.7g产物(33%产量)。1H NMR(D6-DMSO)δ1.85-1.88(m,2H),2.28-2.30(m,2H),2.50-2.58(m,2H),7.72(d,J=8.1Hz,1H),7.91-7.96(m,2H),10.17(s,1H),13.40(br s,1H)。13C NMR(D6-DMSO)δ20.3,29.1,36.9,85.5,115.6,130.6,130.7,130.9,135.3,136.7,166.4,193.4。LCMS t=4.1min,m/z计算值C14H12ClN2O3;C14H11ClN2NaO3;C28H23Cl2N4O6;C28H23Cl2N4NaO6291.05;313.04;581.10;603.08[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值291.06;313.05;581.12;603.10。
实施例05-34
4-氯-3-((2-氰基-3-氧代环己基-1-烯-1-基)氨基)-N-(邻甲苯基)苯甲酰胺(05-34)的制备:按照实施例04-13的方法,由实施例05-33的化合物和邻甲苯胺制备题述化合物;经沉淀后,0.5mmol规模产生了130mg产物(67%产量)。1H NMR(D6-DMSO)δ1.86-1.91(m,2H),2.23(s,3H),2.29-2.34(m,2H),2.50-2.60(m,2H),7.19-7.24(m,2H),7.28-7.32(m,2H),7.77(d,J=6.8Hz,1H),8.03(s,2H),10.04(s,1H),10.21(s,1H)。LCMS t=4.7min,m/z计算值C21H19ClN3O2;C21H18ClN3NaO2;C42H37Cl2N6O4;C42H36Cl2N6NaO4380.12;402.10;759.23;781.21[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值380.13;402.11;759.25;781.24。
实施例05-35
4-氯-3-((2-氰基-3-氧代环己基-1-烯-1-基)氨基)-N-(4-甲氧基苯基)苯甲酰胺(05-35)的制备:按照实施例04-13的方法,由实施例05-33的化合物和对氨基苯甲醚制备题述化合物;经沉淀后,0.5mmol规模产生了113mg产物(57%产量)。1H NMR(D6-DMSO)δ1.85-1.91(m,2H),2.28-2.35(m,2H),2.50-2.62(m,2H),3.75(s,3H),6.94(d,J=8.9Hz,2H),7.66(d,J=8.8Hz,2H),7.76(d,J=8.3Hz,1H),8.00-8.04(m,2H),10.23(s,1H)。LCMS t=4.7min,m/z计算值C21H19ClN3O3;C21H18ClN3NaO3;C42H37Cl2N6O6;C42H36Cl2N6NaO6 396.11;418.09;791.22;813.20[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值396.13;418.11;791.24;813.23。
实施例05-36
4-氯-3-((2-氰基-3-氧代环己基-1-烯-1-基)氨基)-N-(4-甲氧基-2-甲基苯基)苯甲酰胺(05-36)的制备:按照实施例04-13的方法,由实施例05-33的化合物和4-甲氧基-2-甲基苯胺制备题述化合物;经色谱分析(ESS=H:E(1:3))后,0.5mmol规模产生了82mg产物(41%产量)。1H NMR(D6-DMSO)δ1.85-1.92(m,2H),2.19(s,3H),2.28-2.36(m,2H),2.50-2.63(m,2H),3.75(s,3H),6.79(d,J=7.1Hz,1H),6.86(s,1H),7.19(d,J=8.3Hz,1H),7.76(d,J=7.7Hz,1H),8.03(s,2H),9.92(s,1H),10.21(s,1H)。13C NMR(D6-DMSO)δ18.5,20.4,28.9,36.4,55.6,85.6,111.8,115.8,128.5,129.1,129.2,129.5,130.3,134.3,135.1,135.2,136.0,157.9,163.9,193.3。LCMS t=4.7min,m/z计算值C22H21ClN3O3;C22H20ClN3NaO3;C44H41Cl2N6O6;C44H40Cl2N6NaO6 410.13;432.11;819.25;841.23[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值410.14;432.12;819.27;841.26。
实施例05-37
N-(4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-4-甲氧基苯甲酰胺(05-37)的制备:将三乙胺(0.279mL,2.0mmol)加入至在二氯乙烷(5mL)中的实施例02-14的化合物(0.27g,1.0mmol)中。将对-茴香酰氯(0.142mL,1.05mmol)加入至于0℃下搅拌的所述溶液中。2h后,于旋蒸仪上除去溶剂并且将随后的粗材料直接加入至KP-SilTM柱(10g)中,同时在-Isolera Four仪器上使用分级式梯度法将产物从杂质中分离,于254/365nm下监控紫外线踪迹。分级式梯度法利用两种溶剂(己烷和EtOAc)从非极性运行至极性阶段(3:1–1:1–1:3)。经色谱分析(ESS=H:E(1:3))后,1.0mmol规模产生了75mg淡黄色微晶体(mp=254-257℃,20%产量)。1H NMR(D6-DMSO)δ1.48(s,3H),2.20-2.23(m,2H),2.44-2.48(m,2H),3.84(s,3H),7.07(d,J=8.8Hz,2H),7.52(d,J=8.8Hz,1H),7.69(dd,J=8.8,2.3Hz,1H),7.85(d,J=2.2Hz,1H),7.96(d,J=8.7Hz,1H),8.89(s,1H),10.25(s,1H)。13CNMR(D6-DMSO)δ7.4,25.6,32.6,55.5,109.4,113.7,118.9,119.6,123.7,126.5,129.6,129.7,136.5,138.8,162.1,165.1,169.5,202.3。LCMS t=5.0min,m/z计算值C20H20ClN2O3;C20H19ClN2NaO3;C40H39Cl2N4O6;C40H38Cl2N2NaO6 371.116;393.098;741.225;763.207[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值371.116;393.090;741.217;763.203。
实施例05-38
N-(4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-2-甲基苯甲酰胺(05-38)的制备:按照实施例05-37的方法,由实施例02-14的化合物和邻甲苯酰氯制备题述化合物;经色谱分析(ESS=H:E(1:3))后,1.0mmol规模产生了65mg淡黄色微晶体(mp=230–232℃,18%产量)。1H NMR(D6-DMSO)δ1.48(s,3H),2.20-2.22(m,2H),2.38(s,3H),2.44-2.48(m,2H),7.29-7.33(m,2H),7.40(t,J=7.5Hz,1H),7.48(d,J=7.5Hz,1H),7.51(d,J=8.8Hz,1H),7.62(dd,J=8.7,2.0Hz,1H),7.82(d,J=1.6Hz,1H),8.89(s,1H),10.49(s,1H)。13C NMR(D6-DMSO)δ7.4,19.3,25.6,32.6,109.4,118.4,118.9,123.8,125.7,127.3,129.8,129.9,130.6,135.3,136.6,136.8,138.7,168.1,169.5,202.4。LCMS t=5.1min,m/z计算值C20H20ClN2O2;C20H19ClN2NaO2;C40H39Cl2N4O4;C40H38Cl2N2NaO4 355.121;377.103;709.235;731.217[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值355.126;377.099,709.220;731.208。
实施例05-39
N-(4-氯-3-[(2-甲基-3-氧代环戊基-1-烯-1-基)氨基]苯基)-环己酰胺(05-39)的制备:按照实施例05-37的方法,由实施例02-14的化合物和环己烷碳酰氯(cyclohexanecarbonyl chloride)制备题述化合物(mp=240-242℃)。1H NMR(D6-DMSO)δ1.12-1.30(m,3H),1.34-1.43(m,2H),1.44(s,3H),1.62-1.67(m,1H),1.71-1.84(m,5H),2.17-2.22(m,2H),2.26-2.34(m,1H),2.41(d,J=4.9Hz,2H),7.39-7.50(m,2H),7.69(s,1H),8.86(s,1H),10.02(s,1H)。13C NMR(D6-DMSO)δ7.5,25.2(2C),25.4,25.6,29.0(2C),32.6,44.9,109.3,117.8,118.4,123.1,129.7,136.5,138.9,169.5,174.6,202.4。LCMS t=4.8min,m/z计算值C19H24ClN2O2;C19H23ClN2NaO2;C38H47Cl2N4O4;C38H46Cl2N4NaO4 347.152;369.135;693.297;715.279[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值347.152;369.135;693.297;715.279。
实施例05-40
N-(4-氯-3-[(2-甲基-3-氧代环戊基-1-烯-1-基)氨基]苯基)-萘-1-甲酰胺(05-40)的制备:按照实施例05-37的方法,由实施例02-14的化合物和1-萘甲酰氯(1-naphthoylchloride)制备题述化合物(mp=243-245℃)。1H NMR(D6-DMSO)δ1.49(s,3H),2.19-2.25(m,2H),2.47(br s,2H),7.56(d,J=8.5Hz,1H),7.58-7.65(m,3H),7.69(dd,J=8.5,2.4Hz,1H),7.79(d,J=7.3Hz,1H),7.90(d,J=2.4Hz,1H),8.02-8.05(m,1H),8.10(d,J=7.3Hz,1H),8.16-8.21(m,1H),8.95(s,1H),10.79(s,1H)。13C NMR(D6-DMSO)δ7.5,25.6,32.6,109.5,118.6,119.2,124.0,125.0,(2C),125.7,126.5,127.2,128.4,129.6,129.8,130.5,133.2,134.2,136.7,138.7,167.5,169.5,202.4。LCMS t=4.8min,m/z计算值C23H20ClN2O2;C23H19ClN2NaO2;C46H39Cl2N4O4;C46H38Cl2N4NaO4 391.125;413.103;781.235;803.217[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值391.122;413.103;781.235;803.217。
实施例05-41
N-(3-氯-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-2-甲基苯甲酰胺(05-41)的制备:按照实施例05-37的方法,由实施例02-15的化合物和邻甲苯酰氯制备题述化合物(mp=280-283℃)。1H NMR(D6-DMSO)δ1.48(s,3H),2.15-2.20(m,2H),2.32-2.36(m,2H),2.39(s,3H),7.29-7.35(m,2H),7.37-7.45(m,2H),7.49(d,J=7.3Hz,1H),7.66(dd,J=8.5,2.4Hz,1H),8.07(s,1H),8.87(s,1H),10.55(s,1H)。13C NMR(D6-DMSO)δ7.1,19.3,25.2,32.6,108.4,118.6,119.9,125.7,127.3,129.5,129.9,130.6,130.8,131.6,135.4,136.7,138.6,168.0,170.4,201.9。LCMS t=4.4min,m/z计算值C20H20ClN2O2;C20H19ClN2NaO2;C40H39Cl2N4O4;C40H38Cl2N4NaO4355.121;377.103;709.235;731.217[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值355.121;377.103;709.235;731.217。
实施例05-42
N-(2-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-2-甲基苯甲酰胺(05-42)的制备:按照实施例05-37的方法,由实施例02-13的化合物和邻甲苯酰氯制备题述化合物(mp=118-120℃)。1H NMR(D6-DMSO)δ1.48(s,3H),2.15-2.22(m,2H),2.40(br s,2H),2.45(s,3H),7.25-7.35(m,3H),7.40(q,J=7.3Hz,2H),7.48-7.60(m,2H),8.96(s,1H),10.07(s,1H)。13C NMR(D6-DMSO)δ7.3,19.5,25.4,32.6,109.1,125.6,125.6,125.9,126.8,126.9,127.4,129.9,130.6,135.6,135.9,136.3,137.4,167.9,169.8,202.2。LCMSt=4.4min,m/z计算值C20H20ClN2O2;C20H19ClN2NaO2;C40H39Cl2N4O4;C40H38Cl2N4NaO4 355.121;377.103;709.235;731.217[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值355.121;377.103;709.235;731.217。
实施例05-43
N-(4-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-4-甲氧基苯甲酰胺(05-43)的制备:按照实施例05-37的方法,由实施例02-10的化合物和对-茴香酰氯制备题述化合物;经色谱分析(ESS=H:E(1:3))后,1.0mmol规模产生60mg产物(mp=190-195℃,16%产量)。1H NMR(D6-DMSO)δ1.67(s,3H),1.77-1.80(m,2H),2.18-2.21(m,2H),2.25-2.27(m,2H),3.84(s,3H),7.07(d,J=8.6Hz,2H),7.49(d,J=8.7Hz,1H),7.68(dd,J=8.7,2.1Hz,1H),7.77(d,J=2.1Hz,1H),7.96(d,J=8.6Hz,2H),8.00(s,1H),10.25(s,1H)。13CNMR(D6-DMSO)δ9.0,21.2,27.0,36.4,55.5,107.1,113.7,118.9,120.2,124.5,126.5,129.5,129.7,137.0,138.9,158.4,162.1,165.1,194.5。LCMS t=5.1min,计算值C21H22ClN2O3;C21H21ClN2NaO3;C42H42Cl2N2NaO6 385.13;407.11;791.24[M+H]+;[M+Na]+;[2M+Na]+,实验值385.20;407.10;791.22。
实施例05-44
N-(4-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-2-甲基苯甲酰胺(05-44)的制备:按照实施例05-37的方法,由实施例02-10的化合物和邻甲苯酰氯制备题述化合物(mp=199-201℃)。1H NMR(D6-DMSO)δ1.66(s,3H),1.76-1.80(m,2H),2.19(t,J=6.1Hz,2H),2.25(t,J=5.5Hz,2H),2.38(s,3H),7.28-7.36(m,2H),7.38-7.43(m,1H),7.44-7.56(m,2H),7.62(d,J=7.3Hz,1H),7.74(s,1H),8.03(s,1H),10.50(s,1H)。13C NMR(D6-DMSO)δ9.1,19.3,21.2,27.0,36.4,107.2,118.2,119.4,124.5,125.7,127.2,129.7,129.9,130.6,135.3,136.8,137.2,138.7,158.4,168.0,194.6。LCMS t=4.7min,m/z计算值C21H22ClN2O2;C21H21ClN2NaO2;C42H42Cl2N4NaO4 369.137;391.119;759.248[M+H]+;[M+Na]+;[2M+Na]+,实验值369.137;391.119;759.248。
实施例05-45
N-(4-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-环己酰胺(05-45)的制备:按照实施例05-37的方法,由实施例02-10的化合物和环己烷碳酰氯制备题述化合物(mp=192-195℃)。1H NMR(D6-DMSO)δ1.14-1.22(m,1H),1.22-1.30(m,2H),1.35-1.43(m,2H),1.63(s,4H),1.72-1.82(m,6H),2.18(t,J=6.1Hz,2H),2.22(t,J=5.5Hz,2H),2.27-2.33(m,1H),7.41-7.47(m,2H),7.61(s,1H),7.97(s,1H),10.00(s,1H)。13C NMR(D6-DMSO)δ9.1,21.2,25.2(2C),25.4,27.0,29.1(2C),36.4,44.9,107.1,117.7,118.9,123.8,129.6,137.1,138.9,158.4,174.6,194.6。LCMS t=4.9min,m/z计算值C20H26ClN2O2;C20H25ClN2NaO2;C40H50Cl2N4NaO4361.168;383.150;743.311[M+H]+;[M+Na]+;[2M+Na]+,实验值361.168;383.150;743.311。
实施例05-46
N-(4-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-1-萘甲酰胺(05-46)的制备:按照实施例05-37的方法,由实施例02-10的化合物和1-萘酰氯制备题述化合物(mp=245-247℃)。1H NMR(D6-DMSO)δ1.67(s,3H),1.77-1.83(m,2H),2.20(t,J=6.1Hz,2H),2.26-2.31(m,2H),7.54(d,J=8.5Hz,1H),7.58-7.65(m,3H),7.69(d,J=7.3Hz,1H),7.78(d,J=7.3Hz,1H),7.81(d,J=2.4Hz,1H),8.02-8.07(m,2H),8.10(d,J=8.5Hz,1H),8.16-8.20(m,1H),10.77(s,1H)。13C NMR(D6-DMSO)δ9.1,21.2,27.1,36.4,107.3,118.4,119.6,124.7,125.1(2C),125.7,126.5,127.2,128.4,129.6,129.8,130.4,133.2,134.3,137.2,138.7,158.4,167.5,194.6。LCMS t=5.0min,m/z计算值C24H22ClN2O2;C24H21ClN2NaO2;C48H43Cl2N4O4;C48H42Cl2N4NaO4 405.136;427.118;809.266;831.248[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值405.136;427.118;809.266;831.248。
实施例05-47
N-(3-氯-4-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-1-萘甲酰胺(05-47)的制备:按照实施例05-37的方法,由实施例02-12的化合物和1-萘酰氯制备题述化合物(mp=245-247℃)。1H NMR(D6-DMSO)δ1.69(s,3H),1.77(quin,J=6.4Hz,2H),2.16-2.21(m,4H),7.35(d,J=8.5Hz,1H),7.51-7.68(m,3H),7.72(dd,J=8.5,2.4Hz,1H),7.79(d,J=7.3Hz,1H),8.00-8.07(m,2H),8.11(d,J=8.5Hz,1H),8.14(d,J=2.4Hz,1H),8.17-8.23(m,1H),10.82(s,1H)。13C NMR(D6-DMSO)δ8.8,21.2,26.7,36.3,105.9,118.8,120.1,125.1(2C),125.7,126.5,127.2,128.4,129.6,130.0,130.5,131.4,132.3,133.2,134.2,138.5,159.4,167.5,194.1。LCMS t=4.9min,m/z计算值C24H22ClN2O2;C24H21ClN2NaO2;C48H43Cl2N4O4;C48H42Cl2N4NaO4 405.136;427.118;809.266;831.248[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值405.136;427.118;809.266;831.248。
实施例05-48
N-(3-氯-4-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-2-甲基苯甲酰胺(05-48)的制备:按照实施例05-37的方法,由实施例02-12的化合物和邻甲苯酰氯制备题述化合物(mp=234-236℃)。1H NMR(D6-DMSO)δ1.68(s,3H),1.76(quin,J=6.1Hz,2H),2.15-2.18(m,4H),2.39(s,3H),7.29-7.35(m,3H),7.39-7.44(m,1H),7.48(d,J=7.3Hz,1H),7.65(dd,J=8.5,2.4Hz,1H),8.00(s,1H),8.06(d,J=2.4Hz,1H),10.55(s,1H)。13C NMR(D6-DMSO)δ8.8,19.3,21.2,26.7,36.3,105.9,118.6,119.9,125.7,127.3,129.9,130.0,130.6,131.4,132.1,135.4,136.7,138.5,159.3,168.0,194.2。LCMS t=4.7min,m/z计算值C21H22ClN2O2;C21H21ClN2NaO2;C42H42Cl2N4NaO4 369.137;391.119;759.248[M+H]+;[M+Na]+;[2M+Na]+,实验值369.137;391.119;759.248。
实施例05-49
N-(3-氯-4-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-环己酰胺(05-49)的制备:按照实施例05-37的方法,由实施例02-12的化合物和环己烷碳酰氯制备题述化合物(mp=248-250℃)。1H NMR(D6-DMSO)δ1.14-1.32(m,3H),1.35-1.45(m,2H),1.66(s,4H),1.71-1.82(m,6H),2.11-2.17(m,4H),2.28-2.35(m,1H),7.25(d,J=9.8Hz,1H),7.47(dd,J=8.5,2.4Hz,1H),7.91-8.00(m,2H),10.06(s,1H)。13C NMR(D6-DMSO)δ8.7,21.2,25.2(2C),25.4,26.6,29.0(2C),36.3,44.9,105.7,118.0,119.3,130.1,131.5(2C),138.8,159.4,174.6,194.1。LCMS t=4.8min,m/z计算值C20H26ClN2O2;C20H25ClN2NaO2;C40H50Cl2N4NaO4 361.168;383.150;743.311[M+H]+;[M+Na]+;[2M+Na]+,实验值361.168;383.150;743.311。
实施例05-50
N-(2-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-2-甲基苯甲酰胺(05-50)的制备:按照实施例05-37的方法,由实施例02-11的化合物和邻甲苯酰氯制备题述化合物。1H NMR(D6-DMSO)δ1.66(s,3H),1.74-1.81(m,2H),2.18(t,J=6.7Hz,2H),2.23(brs,2H),2.44(s,3H),7.21(d,J=7.3Hz,1H),7.31(d,J=7.3Hz,2H),7.35-7.44(m,2H),7.49-7.57(m,2H),8.08(s,1H),10.06(s,1H)。13C NMR(D6-DMSO)δ9.0,19.5,21.2,26.9,36.4,106.9,107.9,111.2,115.9,125.4,125.7,126.3,126.9,127.4,129.9,130.6,135.6,138.0,158.7,167.0,194.5。LCMS t=4.5min,m/z计算值C21H22ClN2O2;C21H21ClN2NaO2;C42H42Cl2N4NaO4 369.137;391.119;759.248[M+H]+;[M+Na]+;[2M+Na]+,实验值369.137;391.119;759.248。
实施例05-51
N-(2-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-环己酰胺(05-51)的制备:按照实施例05-37的方法,由实施例02-11的化合物和环己烷碳酰氯制备题述化合物(mp=205-208℃)。1H NMR(D6-DMSO)δ1.14-1.22(m,1H),1.23-1.32(m,2H),1.40(qd,J=12.4,3.1Hz,2H),1.65(br s,4H),1.71-1.78(m,4H),1.80-1.87(m,2H),2.13-2.24(m,4H),2.44-2.49(m,1H),7.10(d,J=7.3Hz,1H),7.30(t,J=7.9Hz,1H),7.56(d,J=7.3Hz,1H),8.03(s,1H),9.42(s,1H)。13C NMR(D6-DMSO)δ9.4,21.6,25.7(2C),25.9,27.3,29.6(2C),36.8,44.5,107.1,124.3,125.7(2C),127.2,136.5,138.2,159.2,174.9,194.9。LCMS t=5.3min,m/z计算值C20H26ClN2O2;C20H25ClN2NaO2 361.168;383.150[M+H]+;[M+Na]+,实验值361.157;383.138。
实施例05-52
N-(2-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-1-萘甲酰胺(05-52)的制备:按照实施例05-37的方法,由实施例02-11的化合物和1-萘酰氯制备题述化合物(mp=178-180℃)。1H NMR(D6-DMSO)δ1.68(s,3H),1.73-1.84(m,2H),2.19(t,J=6.7Hz,2H),2.26(br s,2H),7.25(d,J=7.3Hz,1H),7.38-7.47(m,1H),7.56-7.67(m,4H),7.79-7.91(m,1H),8.03(d,J=7.3Hz,1H),8.08-8.15(m,2H),8.34(d,J=7.3Hz,1H),10.36(s,1H)。13C NMR(D6-DMSO)δ9.5,21.6,27.4,36.8,107.3,125.5,125.7,126.0,126.3,126.9,126.9,127.4,127.5,128.0,128.8,130.2,130.9,133.6,134.3,136.4,138.5,159.2,167.9,195.0。LCMS t=4.7min,m/z计算值C24H22ClN2O2;C24H21ClN2NaO2;C48H42Cl2N4NaO4405.136;427.118;831.248[M+H]+;[M+Na]+;[2M+Na]+,实验值405.136;427.118;831.248。
实施例05-53
N-(4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-苯基)-甲烷磺酰胺(05-53)的制备:按照实施例05-37的方法,由实施例02-14的化合物和甲磺酰氯制备题述化合物(mp=213-215℃)。1H NMR(D6-DMSO)δ1.45(s,3H),2.16-2.23(m,2H),2.39-2.43(m,2H),3.04(s,3H),7.10(dd,J=8.5,2.4Hz,1H),7.15(d,J=2.4Hz,1H),7.51(d,J=8.5Hz,1H),8.88(s,1H),10.00(s,1H)。13C NMR(D6-DMSO)δ7.4,25.6,32.6,40.0,109.6,118.2,118.8,124.5,130.4,137.2,137.8,169.3,202.4。LCMS t=3.8min,m/z计算值C13H16ClN2O3S;C13H15ClN2NaO3S;C26H31Cl2N4O6S2;C26H30Cl2N4NaO6S2 315.057;337.039;629.106;651.088[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值315.057;337.039;629.106;651.088。
实施例05-54
N-(4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-1-苯基甲磺酰胺(05-55)的制备:按照实施例05-37的方法,由实施例02-14的化合物和苯甲磺酰氯制备题述化合物(mp=196-198℃)。1H NMR(D6-DMSO)δ1.47(s,3H),2.17-2.25(m,2H),2.37-2.42(m,2H),4.54(s,2H),7.05(d,J=2.4Hz,1H),7.07(dd,J=8.5,2.4Hz,1H),7.21-7.28(m,2H),7.31-7.38(m,3H),7.48(d,J=8.5Hz,1H),8.87(s,1H),10.09(s,1H)。13C NMR(D6-DMSO)δ7.4,25.5,32.6,57.1,109.5,117.3,117.9,123.9,128.3,128.4(2C),129.3,130.3,130.9(2C),137.1,138.0,169.4,202.4。LCMSt=4.3min,m/z计算值C19H20ClN2O3S;C19H19ClN2NaO3S;C38H39Cl2N4O6S2;C38H38Cl2N4NaO6S2 391.088;413.070;781.169;803.151[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值391.088;413.070;781.169;803.151。
实施例05-55
N-(4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-环己烷磺酰胺(05-54)的制备:按照实施例05-37的方法,由实施例02-14的化合物和环己烷磺酰氯制备题述化合物(mp=158-160℃)。1H NMR(D6-DMSO)δ1.08-1.23(m,3H),1.35-1.46(m,5H),1.54-1.61(m,1H),1.72-1.78(m,2H),2.00(d,J=11.0Hz,2H),2.18-2.23(m,2H),2.39-2.43(m,2H),2.99-3.07(m,1H),7.09-7.19(m,2H),7.48(d,J=8.5Hz,1H),8.88(s,1H),10.02(s,1H)。13CNMR(D6-DMSO)δ7.4,24.3(2C),24.7,25.6,26.0(2C),32.6,59.4,109.5,117.7,118.3,124.1,130.4,137.1,138.2,169.2,202.5。LCMSt=4.1min,m/z计算值C18H24ClN2O3S;C18H23ClN2NaO3S;C36H47Cl2N4O6S2;C36H46Cl2N4NaO6S2 383.120;405.101;765.231;787.213[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值383.120;405.103;765.229;787.213。
实施例05-56
N-(4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-2-氯苯磺酰胺(05-56)的制备:按照实施例05-37的方法,由实施例02-14的化合物和2-氯苯-1-磺酰氯制备题述化合物。1H NMR(D6-DMSO)δ1.32(s,3H),2.15-2.20(m,4H),6.98(d,J=2.4Hz,1H),7.01(dd,J=8.5,2.4Hz,1H),7.41(d,J=8.5Hz,1H),7.51-7.55(m,1H),7.63-7.67(m,2H),8.05(d,J=7.3Hz,1H),8.80(s,H),10.90(s,1H)。13C NMR(D6-DMSO)δ7.2,25.4,32.5,109.6,117.9,118.5,124.9,127.9,130.4,130.7,131.8,132.0,135.0,135.9,136.4,137.1,169.0,202.4。LCMS t=4.4min,m/z计算值C18H17Cl2N2O3S;C18H16Cl2N2NaO3S;C36H33Cl4N4O6S2;C36H32Cl4N4NaO6S2411.033;433.016;823.057;843.041[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值411.033;433.016;823.057;843.041。
实施例05-57
N-(4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-2-甲基苯磺酰胺(05-57)的制备:按照实施例05-37的方法,由实施例02-14的化合物和2-甲基苯-1-磺酰氯制备题述化合物(mp=236-238℃)。1H NMR(D6-DMSO)δ1.33(s,3H),2.17(m,J=4.9Hz,4H),2.59(s,3H),6.94(d,J=2.4Hz,1H),6.99(dd,J=8.5,2.4Hz,1H),7.33-7.45(m,3H),7.52(t,J=7.3Hz,1H),7.87(d,J=7.3Hz,1H),8.80(s,1H),10.68(s,1H)。13CNMR(D6-DMSO)δ7.2,19.7,25.4,32.5,109.6,117.6,118.1,124.4,126.4,129.4,130.3,132.8,133.3,136.8,137.0,137.0,137.0,169.0,202.4。LCMS t=5.3min,m/z计算值C19H20ClN2O3S;C19H19ClN2NaO3S;C38H38Cl2N4NaO6S2 391.088;413.070;803.151[M+H]+;[M+Na]+;[2M+Na]+,实验值391.088;413.071;803.150。
实施例05-58
N-(4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-2-氟苯磺酰胺(05-58)的制备:按照实施例05-37的方法,由实施例02-14的化合物和2-氟苯-1-磺酰氯制备题述化合物(mp=215-217℃)。1H NMR(D6-DMSO)δ1.32(s,3H),2.16-2.22(m,4H),7.00(d,J=3.7Hz,1H),7.03(dd,J=8.5,2.4Hz,1H),7.37(t,J=7.9Hz,1H),7.41-7.46(m,2H),7.69-7.73(m,1H),7.82-7.87(m,1H),8.82(s,1H),10.88(s,1H)。13C NMR(D6-DMSO)δ7.7,25.9,33.0,110.0,117.9(JCF=21.8Hz),118.9,119.5,125.6,126.9(JCF=13.8Hz),130.8,131.0,136.8(JCF=9.2Hz),137.0,137.5,158.5(JCF=254.7Hz),169.5,202.9。LCMS t=4.3min,m/z计算值C18H17ClFN2O3S;C18H16ClFN2NaO3S;C36H33Cl2F2N4O6S2;C36H32Cl2F2N4NaO6S2395.063;417.045;789.119;811.101[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值395.063;417.045;789.119;811.101。
实施例05-59
N-(4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-2-氰基苯磺酰胺(05-59)的制备:按照实施例05-37的方法,由实施例02-14的化合物和2-氰基苯-1-磺酰氯制备题述化合物(mp=235-238℃)。1H NMR(D6-DMSO)δ1.31(s,3H),2.14-2.19(m,2H),2.21-2.26(m,2H),6.96(d,J=2.4Hz,1H),7.03(dd,J=8.5,2.4Hz,1H),7.46(d,J=8.5Hz,1H),7.85(t,J=7.3Hz,1H),7.91(t,J=7.3Hz,1H),8.04(d,J=7.3Hz,1H),8.10(d,J=7.3Hz,1H),8.82(s,1H),11.06(s,1H)。13C NMR(D6-DMSO)δ7.3,25.5,32.5,109.2,109.7,115.6,119.0,119.5,125.5,129.6,130.5,133.8,134.1,136.1,136.2,137.2,140.5,169.0,202.5。LCMS t=4.3min,m/z计算值C19H17ClN3O3S;C19H16ClN3NaO3S;C38H32Cl2N6NaO6S2402.068;424.050;825.110[M+H]+;[M+Na]+;[2M+Na]+,实验值402.068;424.050;825.110。
实施例05-60
N-(4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-2-甲氧基苯磺酰胺(05-60)的制备:按照实施例05-37的方法,由实施例02-14的化合物和2-甲氧基苯-1-磺酰氯制备题述化合物(mp=198-200℃)。1H NMR(D6-DMSO)δ1.33(s,3H),2.12-2.17(m,4H),3.86(s,3H),6.97-7.01(m,2H),7.05(t,J=7.9Hz,1H),7.18(d,J=8.5Hz,1H),7.34-7.41(m,1H),7.58(t,J=7.9Hz,1H),7.77(d,J=7.3Hz,1H),8.79(s,1H),10.30(s,1H)。13C NMR(D6-DMSO)δ7.1,25.3,32.5,56.2,109.4,112.9,118.2,118.7,120.2,124.6,125.7,130.1,130.4,135.4,136.8,137.4,156.3,169.2,202.3。LCMS t=4.2min,m/z计算值C19H20ClN2O4S;C19H19ClN2NaO4S;C38H39Cl2N4O8S2;C38H38Cl2N4NaO8S2 407.083;429.065;813.159;835.141[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值407.083;429.065;813.159;835.141。
实施例05-61
N-(4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-哌啶-1-磺酰胺(05-61)的制备:按照实施例05-37的方法,由实施例02-14的化合物和哌啶-1-磺酰氯制备题述化合物(mp=78-80℃)。1H NMR(D6-DMSO)δppm 1.36-1.48(m,9H),2.18-2.22(m,2H),2.38-2.41(m,2H),3.05-3.14(m,4H),7.04-7.14(m,2H),7.47(d,J=8.5Hz,1H),8.88(s,1H),10.14(brs,1H)。13C NMR(D6-DMSO)δ7.3,23.1,24.7(2C),25.6,32.6,46.5(2C),109.4,117.7,118.3,123.7,130.1,136.9,138.3,169.2,202.4。LCMS t=4.5min,m/z计算值C17H23ClN3O3S;C17H22ClN3NaO3S;C34H45Cl2N6O6S2;C34H44Cl2N6NaO6S2 384.114;406.096;767.221;789.203[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值384.114;406.096;767.221;789.203。
实施例05-62
N-(4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-吗啉-4-磺酰胺(05-62)的制备:按照实施例05-37的方法,由实施例02-14的化合物和吗啉-4-磺酰氯制备题述化合物(mp=60-67℃)。1H NMR(D6-DMSO)δ1.44(s,3H),2.17-2.23(m,2H),2.38-2.43(m,2H),3.05-3.09(m,4H),3.51-3.55(m,4H),7.04-7.15(m,2H),7.49(d,J=8.5Hz,1H),8.88(s,1H),10.28(br s,1H)。13C NMR(D6-DMSO)δppm 7.4,25.6,32.6,46.0(2C),65.4(2C),109.5,118.1,118.6,124.1,130.2,137.0,138.0,169.3,202.4。LCMS t=3.9min,m/z计算值C16H21ClN3O4S;C16H20ClN3NaO4S;C32H41Cl2N6O8S2;C32H40Cl2N6NaO8S2 386.094;408.076;771.180;793.162[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值386.094;408.076;771.180;793.162。
实施例05-63
N-(3-氯-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-2-甲基苯磺酰胺(05-63)的制备:按照实施例05-37的方法,由实施例02-15的化合物和2-甲基苯-1-磺酰氯制备题述化合物(mp=215-218℃)。1H NMR(D6-DMSO)δ1.35(s,3H),2.09-2.15(m,2H),2.22-2.27(m,2H),2.59(s,3H),7.03(dd,J=8.5,2.4Hz,1H),7.18(d,J=2.4Hz,1H),7.26(d,J=9.8Hz,1H),7.36-7.42(m,2H),7.53(t,J=6.7Hz,1H),7.89(d,J=8.5Hz,1H),8.72(s,1H),10.74(s,1H)。13C NMR(D6-DMSO)δ7.0,19.7,25.2,32.5,108.5,117.8,119.1,126.4,129.4,130.0,131.2,131.9,132.8,133.4,136.8,136.9,137.0,170.1,202.0。LCMSt=4.3min,m/z计算值C19H20ClN2O3S;C19H19ClN2NaO3S;C38H39Cl2N4O6S2;C38H38Cl2N4NaO6S2391.088;413.070;781.169;803.151[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值391.088;413.070;781.169;803.151。
实施例05-64
N-(3-氯-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-环己烷磺酰胺(05-64)的制备:按照实施例05-37的方法,由实施例02-15的化合物和环己烷磺酰氯制备题述化合物(mp=210-213℃)。1H NMR(D6-DMSO)δ1.05-1.17(m,1H),1.18-1.27(m,2H),1.33-1.50(m,5H),1.54-1.63(m,1H),1.72-1.80(m,2H),1.98-2.05(m,2H),2.14-2.18(m,2H),2.30-2.35(m,2H),3.02-3.12(m,1H),7.20(dd,J=8.5,2.4Hz,1H),7.34-7.38(m,1H),8.81(s,1H),10.09(s,1H)。13C NMR(D6-DMSO)δ7.0,24.3(2C),24.7,25.3,26.0(2C),32.6,59.6,108.4,117.9,119.1,130.1,131.4,131.7,138.1,170.4,202.0。LCMS t=4.5min,m/z计算值C18H24ClN2O3S;C18H23ClN2NaO3S;C36H47Cl2N4O6S2;C36H46Cl2N4NaO6S2 383.120;405.101;765.231;787.213[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值383.120;405.101;765.231;787.213。
实施例05-65
N-(2-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-2-甲基苯磺酰胺(05-65)的制备:按照实施例05-37的方法,由实施例02-13的化合物和2-甲基苯-1-磺酰氯制备题述化合物(mp=75-77℃)。1H NMR(D6-DMSO)δ1.32(s,3H),2.10-2.13(m,2H),2.15-2.19(m,2H),2.61(s,3H),7.21(t,J=7.3Hz,1H),7.19-7.24(m,1H),7.26-7.31(m,2H),7.39(d,J=8.5Hz,1H),7.51(t,J=7.5Hz,1H),7.64(d,J=7.3Hz,1H),8.85(s,1H),10.16(s,1H)。13C NMR(D6-DMSO)δ7.1,20.2,25.3,32.5,109.0,125.4,126.2,126.5,127.1,127.3,128.9,132.7,133.0,134.4,137.1,137.6,138.2,169.6,202.2。LCMS t=4.3min,m/z计算值C19H20ClN2O3S;C19H19ClN2NaO3S;C38H39Cl2N4O6S2;C38H38Cl2N4NaO6S2 391.088;413.070;781.169;803.151[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值391.088;413.070;781.169;803.151。
实施例05-66
N-(4-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-2-甲基苯磺酰胺(05-66)的制备:按照实施例05-37的方法,由实施例02-10的化合物和2-甲基苯-1-磺酰氯制备题述化合物(mp=246-248℃)。1H NMR(D6-DMSO)δ1.55(s,3H),1.67-1.73(m,3H),1.96(t,J=5.5Hz,3H),2.17(t,J=6.7Hz,3H),2.58(s,3H),6.85(d,J=2.4Hz,1H),6.94(dd,J=8.5,2.4Hz,1H),7.33-7.43(m,3H),7.50-7.55(m,1H),7.85-7.90(m,2H),10.66(s,1H)。13C NMR(D6-DMSO)δ9.0,19.7,21.1,26.9,36.4,107.8,117.3,118.2,124.7,126.4,129.5,130.3,132.7,133.3,136.8,137.0(2C),137.6,157.8,194.7。LCMS t=4.7min,m/z计算值C20H22ClN2O3S;C20H21ClN2NaO3S;C40H42Cl2N4NaO6S2 405.104;427.086;831.182[M+H]+;[M+Na]+;[2M+Na]+,实验值405.104;427.086;831.182。
实施例05-67
N-(4-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-环己烷磺酰胺(05-67)的制备:按照实施例05-37的方法,由实施例02-10的化合物和环己烷磺酰氯制备题述化合物(mp=215-217℃)。1H NMR(D6-DMSO)δ1.08-1.15(m,1H),1.16-1.24(m,2H),1.39(qd,J=12.4,3.1Hz,2H),1.58(d,J=13.4Hz,1H),1.62(s,3H),1.72-1.79(m,4H),1.96-2.03(m,2H),2.17-2.24(m,4H),2.97-3.06(m,1H),7.07(d,J=2.4Hz,1H),7.10(dd,J=8.5,2.4Hz,1H),7.46(d,J=8.5Hz,1H),7.98(s,1H),9.98-10.02(m,1H)。13C NMR(D6-DMSO)δ9.1,21.1,24.4(2C),24.7,26.0(2C),27.1,36.4,59.4,107.7,117.3,118.5,124.5,130.3,137.7,138.2,158.1,194.7。LCMS t=4.7min,m/z计算值C19H26ClN2O3S;C19H25ClN2NaO3S;C38H50Cl2N4NaO6S2 397.135;419.117;815.245[M+H]+;[M+Na]+;[2M+Na]+,实验值397.135;419.117;815.244。
实施例05-68
N-(3-氯-4-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-2-甲基苯磺酰胺(05-68)的制备:按照实施例05-37的方法,由实施例02-12的化合物和2-甲基苯-1-磺酰氯制备题述化合物(mp=248-250℃)。1H NMR(D6-DMSO)δ1.59(s,3H),1.70(quin,J=6.1Hz,2H),2.05(t,J=5.5Hz,2H),2.12(t,J=6.1Hz,2H),2.59(s,3H),7.03(dd,J=8.5,2.4Hz,1H),7.15-7.21(m,2H),7.36-7.44(m,2H),7.53(t,J=6.7Hz,1H),7.84(s,1H),7.90(d,J=7.3Hz,1H),10.74(s,1H)。13C NMR(D6-DMSO)δ8.7,19.7,21.1,26.6,36.3,106.0,117.7,119.1,126.4,129.4,130.5,131.8,132.3,132.3,132.8,133.4,136.8,137.1,159.0,194.2。LCMS t=4.6min,m/z计算值C20H22ClN2O3S;C20H21ClN2NaO3S;C40H42Cl2N4NaO6S2405.104;427.086;831.182[M+H]+;[M+Na]+;[2M+Na]+,实验值405.104;427.086;831.182。
实施例05-69
N-(3-氯-4-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-环己烷磺酰胺(05-69)的制备:按照实施例05-37的方法,由实施例02-12的化合物和环己烷磺酰氯制备题述化合物(mp=230-232℃)。1H NMR(D6-DMSO)δ1.07-1.17(m,1H),1.18-1.27(m,2H),1.36-1.46(m,2H),1.56-1.62(m,1H),1.65(s,3H),1.73-1.79(m,4H),2.02(d,J=12.2Hz,2H),2.13-2.17(m,4H),3.03-3.11(m,1H),7.19(dd,J=8.5,2.4Hz,1H),7.28(d,J=8.5Hz,1H),7.34(d,J=2.4Hz,1H),7.93(s,1H),10.08(s,1H)。13C NMR(D6-DMSO)δ8.7,21.2,24.3(2C),24.7,26.0(2C),26.6,36.3,59.5,105.9,117.9,119.2,130.6,132.0,132.1,138.0,159.2,194.1。LCMS t=4.3min,m/z计算值C19H26ClN2O3S;C38H50Cl2N4NaO6S2 397.135;815.245[M+H]+;[2M+Na]+,实验值397.134;815.245。
实施例05-70
N-(2-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-2-甲基苯磺酰胺(05-70)的制备:按照实施例05-37的方法,由实施例02-11的化合物和2-甲基苯-1-磺酰氯制备题述化合物(mp=185-187℃)。1H NMR(D6-DMSO)δ1.56(s,3H),1.62-1.71(m,2H),1.92(t,J=5.5Hz,2H),2.13(t,J=6.1Hz,2H),2.61(s,3H),7.10(d,J=7.3Hz,1H),7.20(d,J=8.5Hz,1H),7.24-7.31(m,2H),7.38(d,J=7.3Hz,1H),7.50(t,J=7.2Hz,2H),7.62(d,J=8.5Hz,1H),7.96(s,1H),10.13(br s,1H)。13CNMR(D6-DMSO)δ9.4,20.7,21.5,27.1,36.8,107.3,120.0,125.6,126.5,127.2,127.5,128.2,129.3,133.1,133.4,135.0,137.6,138.6,159.0,194.9。LCMS t=4.5min,m/z计算值C20H22ClN2O3S;C20H21ClN2NaO3S;405.104;427.086;831.182[M+H]+;[M+Na]+;实验值405.104;427.086。
实施例05-71
N-(2-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-环己烷磺酰胺(05-71)的制备:按照实施例05-37的方法,由实施例02-11的化合物和环己烷磺酰氯制备题述化合物。1H NMR(D6-DMSO)δ1.08-1.17(m,1H),1.19-1.29(m,2H),1.41(qd,J=12.4,3.1Hz,2H),1.57-1.67(m,4H),1.73-1.80(m,4H),2.06-2.12(m,2H),2.13-2.22(m,4H),2.96-3.06(m,1H),7.15(d,J=7.3Hz,1H),7.32(t,J=8.0Hz,1H),7.39(d,J=9.8Hz,1H),8.04(s,1H),9.48(br s,1H)。13C NMR(D6-DMSO)δ9.0,21.2,24.5(2C),24.8,26.2(2C),26.9,36.4,61.3,104.7,114.9,115.4,119.7,127.1,138.1,143.9,158.5,194.5。LCMS t=4.5min,m/z计算值C19H26ClN2O3S;C19H25ClN2NaO3S;C38H50Cl2N4NaO6S2 397.135;419.117;815.245[M+H]+;[M+Na]+;[2M+Na]+,实验值397.135;419.117;815.245。
实施例05-72
3-((2-氯-5-((2-甲基苄基)氨基)苯基)氨基)-2-甲基环己基-2-烯酮(05-72)的制备:将乙酸(0.4mL)加入至于搅拌下的溶于MeOH(8mL)中的实施例02-10的化合物(0.3g,1.20mmol)和2-甲基苯甲醛中。搅拌1h后,将硼烷-2-甲基吡啶(0.17g,1.59mmol)加入至混合物中。混合物搅拌18h。在真空下浓缩粗产物并经HPLC纯化以产生题述化合物(0.13g,23%产量,mp=158-160℃)。1H NMR(D6-DMSO)δ1.63(s,3H),1.70(quin,J=6.4Hz,2H),2.11-2.14(m,4H),2.31(s,3H),4.21(d,J=4.9Hz,2H),6.40(t,J=5.5Hz,1H),6.44(d,J=2.4Hz,1H),6.53(dd,J=9.2,3.1Hz,1H),7.08-7.22(m,4H),7.23(d,J=6.1Hz,1H),7.84(s,1H)。13C NMR(D6-DMSO)δ8.7,18.6,21.2,26.6,36.3,44.6,105.9,111.6,112.2,116.7,125.7,126.8,127.2,129.5,130.1,135.9,137.0,137.0,148.4,159.2,194.0。LCMS t=5.3min,m/z计算值C21H24ClN2O;C21H23ClN2NaO;C42H46Cl2N4NaO2 355.158;377.139;731.290[M+H]+;[M+Na]+;[2M+Na]+,实验值355.158;377.139;731.290。
实施例05-73
3-((2-氯-5-((2-甲基苯乙基)氨基)苯基)氨基)-2-甲基环己基-2-烯酮(05-73)的制备:按照实施例05-72的方法,由实施例02-10的化合物和2-(邻甲苯基)乙醛制备题述化合物(mp=85-87℃)。1H NMR(D6-DMSO)δ1.65(s,3H),1.75(quin,J=6.1Hz,2H),2.15(t,J=6.1Hz,2H),2.21(t,J=5.5Hz,2H),2.28(s,3H),2.81(t,J=7.9Hz,2H),3.15-3.26(m,2H),6.05(t,J=5.5Hz,1H),6.48(d,J=2.4Hz,1H),6.53(dd,J=8.5,2.4Hz,1H),6.89-7.37(m,5H),7.87(s,1H)。13C NMR(D6-DMSO)δ8.8,19.0,21.3,26.7,32.1,36.4,43.3,105.8,111.5,112.2,116.7,125.9,126.2,129.1,129.6,130.0,135.8,137.2,137.8,148.3,159.3,194.1。LCMS t=5.5min,m/z计算值C22H26ClN2O;C22H25ClN2NaO;C44H50Cl2N4NaO2369.173;391.155;759.321[M+H]+;[M+Na]+;[2M+Na]+,实验值369.173;391.155;759.321。
实施例05-74
3-((2-氯-5-((2-氟苄基)氨基)苯基)氨基)-2-甲基环己基-2-烯酮(05-74)的制备:按照实施例05-72的方法,由实施例02-10的化合物和2-氟苯甲醛制备题述化合物(mp=103-105℃)。1H NMR(D6-DMSO)δ1.63(s,3H),1.70(quin,J=6.4Hz,2H),2.09-2.15(m,4H),4.31(d,J=6.1Hz,2H),6.45(d,J=2.4Hz,1H),6.50-6.56(m,2H),7.09-7.25(m,3H),7.26-7.33(m,1H),7.37(t,J=7.9Hz,1H),7.83(s,1H)。13C NMR(D6-DMSO)δ8.7,21.2,26.6,36.3,40.0,106.0,111.7,112.3,115.2(JCF=20.7Hz),117.1,124.3,126.1(JCF=14.9Hz),128.9(JCF=6.9Hz),129.4(JCF=4.6Hz),129.6,137.1,147.9,159.1,160.4(JCF=244.4Hz),194.1。LCMS t=5.1min,m/z计算值C20H21ClFN2O;C20H20ClFN2NaO;359.13;381.12;[M+H]+;[M+Na]+,实验值359.13;381.10。
实施例05-75
3-((2-氯-5-((3-氟代-2-甲基苄基)氨基)苯基)氨基)-2-甲基环己基-2-烯酮(05-75)的制备:按照实施例05-72的方法,由实施例02-10的化合物和2-氟-3-甲基苯甲醛制备题述化合物(mp=160-162℃)。1H NMR(D6-DMSO)δ1.63(s,3H),1.71(quin,J=6.4Hz,2H),2.10-2.16(m,4H),2.21(s,3H),4.25(d,J=6.1Hz,2H),6.42-6.47(m,2H),6.52(dd,J=8.5,2.4Hz,1H),7.03-7.07(m,1H),7.09(d,J=8.5Hz,1H),7.14-7.20(m,2H),7.83(s,1H)。13C NMR(D6-DMSO)δ9.2,10.2(JCF=5.7Hz),21.7,27.1,36.8,44.8,106.4,112.1,112.7,113.9(JCF=24.1Hz),117.4,123.1(JCF=16.1Hz),123.5,127.2(JCF=9.2Hz),130.1,137.5,140.5,148.6,159.6,161.1(JCF=242.1Hz),194.6。LCMS t=5.2min,m/z计算值C21H23ClFN2O;C21H22ClFN2NaO;C42H44Cl2F2N4NaO2 373.148;395.130;767.271[M+H]+;[M+Na]+;[2M+Na]+,实验值373.148;395.130;767.271。
实施例05-76
3-((2-氯-4-((2-甲基苄基)氨基)苯基)氨基)-2-甲基环己基-2-烯酮(05-76)的制备:按照实施例05-72的方法,由实施例02-12的化合物和2-甲基苯甲醛制备题述化合物(mp=220-221℃)。1H NMR(D6-DMSO)δ1.66(s,3H),1.71(quin,J=6.4Hz,2H),2.07(t,J=6.1Hz,2H),2.11(t,J=6.7Hz,2H),2.32(s,3H),4.22(d,J=4.9Hz,2H),6.46(t,J=5.5Hz,1H),6.56(dd,J=8.5,2.4Hz,1H),6.71(d,J=2.4Hz,1H),7.02(d,J=8.5Hz,1H),7.11-7.22(m,3H),7.25(d,J=7.3Hz,1H),7.78(s,1H)。13C NMR(D6-DMSO)δ8.4,18.6,21.2,26.3,36.2,44.7,104.2,111.1,111.6,124.3,125.7,126.9,127.3,130.1,130.9,132.8,136.0,136.8,148.8,160.7,193.5。LCMS t=5.2min,m/z计算值C21H24ClN2O;C21H23ClN2NaO;C42H46Cl2N4NaO2 355.158;377.139;731.290[M+H]+;[M+Na]+;[2M+Na]+,实验值355.156;377.139;731.290。
实施例05-77
3-((2-氯-4-((2-甲基苯乙基)氨基)苯基)氨基)-2-甲基-环己基-2-烯酮(05-77)的制备:按照实施例05-72的方法,由实施例02-12的化合物和2-(邻甲苯基)乙醛制备题述化合物(mp=160-162℃)。1H NMR(D6-DMSO)δ1.66(s,3H),1.72(quin,J=6.1Hz,2H),2.06-2.10(m,2H),2.12(t,J=6.1Hz,2H),2.30(s,3H),2.83(t,J=7.3Hz,2H),3.19-3.26(m,2H),6.16(t,J=5.5Hz,1H),6.57(dd,J=8.5,2.4Hz,1H),6.66-6.73(m,1H),7.03(d,J=8.5Hz,1H),7.08-7.18(m,3H),7.21(d,J=8.5Hz,1H),7.80(s,1H)。13C NMR(D6-DMSO)δ8.4,19.0,21.2,26.3,32.1,36.2,43.2,104.3,111.0,111.4,124.2,125.9,126.2,129.1,130.0,130.9,132.9,135.8,137.7,148.7,160.7,193.5。LCMS t=5.4min,m/z计算值C22H26ClN2O;C22H25ClN2NaO;C44H50Cl2N4NaO2 369.173;391.155;759.321[M+H]+;[M+Na]+;[2M+Na]+,实验值369.173;391.155;759.321。
实施例05-78
3-((2-氯-3-((2-甲基苄基)氨基)苯基)氨基)-2-甲基环己基-2-烯酮(05-78)的制备:按照实施例05-72的方法,由实施例02-11的化合物和2-(邻甲苯基)乙醛制备题述化合物(mp=132-135℃)。1H NMR(D6-DMSO)δ1.67(s,3H),1.75(quin,J=6.1Hz,2H),2.16(t,J=6.7Hz,2H),2.21(t,J=6.1Hz,2H),2.34(s,3H),4.38(d,J=6.1Hz,2H),6.07(t,J=6.1Hz,1H),6.39(d,J=8.5Hz,1H),6.51(d,J=7.3Hz,1H),7.03(t,J=7.9Hz,1H),7.07-7.24(m,4H),7.91(s,1H)。13C NMR(D6-DMSO)δ8.7,18.6,21.3,26.7,36.4,44.3,105.8,109.2,115.9,116.1,125.7,126.1,126.5,127.2,130.1,135.4,136.8,137.3,144.9,159.2,194.1。LCMS t=5.1min,m/z计算值C21H24ClN2O;C21H23ClN2NaO 355.158;377.139;[M+H]+;[M+Na]+,实验值355.152;377.133。
实施例05-79
3-((2-氯-3-((2-甲基苯乙基)氨基)苯基)氨基)-2-甲基环己基-2-烯酮(05-79)的制备:按照实施例05-72的方法,由实施例02-11的化合物和2-(邻甲苯基)乙醛制备题述化合物(mp=157-160℃)。1H NMR(D6-DMSO)δ1.66(s,3H),1.74(quin,J=6.4Hz,2H),2.14-2.20(m,4H),2.32(s,3H),2.86-2.91(m,2H),3.34-3.36(m,2H),5.51(t,J=5.5Hz,1H),6.53(d,J=8.5Hz,1H),6.71(d,J=8.5Hz,1H),7.09-7.17(m,4H),7.20(d,J=7.3Hz,1H),7.92(s,1H)。13C NMR(D6-DMSO)δ8.8,19.0,21.2,26.6,32.1,36.3,43.3,105.8,108.7,116.0,116.1,125.9,126.2,127.4,129.3,130.0,136.0,137.4,137.6,144.9,159.2,194.1。LCMS t=5.5min,m/z计算值C22H26ClN2O;C22H25ClN2NaO;C44H50Cl2N4NaO2 369.173;391.155;759.321[M+H]+;[M+Na]+;[2M+Na]+,实验值369.175;391.155;759.321。
实施例05-80
3-((2-氯-3-(对-甲苯基氨基)苯基)氨基)-2-甲基环己基-2-烯酮(05-80)的制备:将实施例02-11的化合物(0.5g,2.00mmol)、1-溴-2-甲基苯(0.408g,2.39mmol)、乙酸钯(0.045g,0.20mmol)、BINAP(0.249g,0.40mmol)、碳酸铯(1.30g,3.99mmol)和甲苯(10mL)在密封的烧瓶中进行结合并在130℃下加热18h。室温下,将混合物进行过滤,并且将滤液用EtOAc(30mL)稀释,用盐水(3×10mL)清洗,用Na2SO4干燥。粗提物经HPLC纯化,以产生题述化合物(黄色微晶体,15mg,2.2%)。1H NMR(D6-DMSO)δ1.68(s,3H),1.73-1.82(m,2H),2.14(s,3H),2.18(t,J=6.7Hz,2H),2.25(t,J=6.1Hz,2H),6.42(d,J=7.3Hz,1H),6.70(d,J=6.1Hz,1H),7.09(t,J=7.9Hz,3H),7.20(t,J=7.9Hz,1H),7.23(s,1H),7.28(d,J=7.3Hz,1H),7.97(s,1H)。13C NMR(D6-DMSO)δ8.8,17.7,21.3,26.8,36.4,106.2,112.9,118.4,118.7,124.4,124.5,126.8,127.1,130.9,132.6,137.9,140.0,143.3,159.0,194.2。LCMSt=5.1min,m/z计算值C20H22ClN2O;C20H21ClN2NaO;C40H43Cl2N4O2;341.142;363.124;703.258[M+H]+;[M+Na]+;[2M+Na]+,实验值341.146;363.124;703.258。
实施例05-81
3-((2-氯-5-(邻-甲苯基氨基)苯基)氨基)-2-甲基环己基-2-烯酮(05-81)的制备:按照实施例05-80的方法,由实施例02-10的化合物制备题述化合物(mp=165-168℃)。1H NMR(D6-DMSO)δ1.64(s,3H),1.76(quin,J=6.1Hz,2H),2.14-2.17(m,2H),2.19(s,3H),2.22(t,J=5.5Hz,2H),6.66(d,J=2.4Hz,1H),6.71-6.76(m,1H),6.98(t,J=7.9Hz,1H),7.13-7.20(m,2H),7.23(d,J=7.3Hz,1H),7.28(d,J=8.5Hz,1H),7.70(s,1H),7.90(s,1H)。13C NMR(D6-DMSO)δ8.8,17.9,21.2,26.8,36.4,106.4,114.2,115.1,119.3,121.3,123.1,126.7,129.9,130.7,131.1,137.4,140.2,145.1,158.9,194.3。LCMS t=5.0min,m/z计算值C20H22ClN2O;C20H21ClN2NaO;C40H42Cl2N4NaO2 341.142;363.124;703.258[M+H]+;[M+Na]+;[2M+Na]+,实验值341.142;363.124;703.258。
实施例05-82
3-((2-氯-4-(邻-甲苯基氨基)苯基)氨基)-2-甲基环己基-2-烯酮(05-82)的制备:按照实施例05-80的方法,由实施例02-12的化合物制备题述化合物(mp=68-70℃)。1HNMR(D6-DMSO)δ1.67(s,3H),1.74(quin,J=6.4Hz,2H),2.10-2.16(m,4H),2.19(s,3H),6.77(dd,J=8.5,2.4Hz,1H),6.89(d,J=2.4Hz,1H),6.98-7.03(m,1H),7.12(d,J=8.5Hz,1H),7.15-7.21(m,2H),7.25(d,J=7.3Hz,1H),7.80(s,1H),7.85(s,1H)。13C NMR(D6-DMSO)δ8.5,17.9,21.3,26.4,36.3,104.7,113.7,114.7,114.7,121.7,123.4,126.7,130.9,131.0,131.1,132.6,139.9,145.5,160.3,193.7。LCMS t=5.1min,m/z计算值C20H22ClN2O;C40H42Cl2N4NaO2 341.142;703.258[M+H]+;[2M+Na]+,实验值341.142;703.261。
实施例05-83
(Z)-4-((4-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-氨基)-4-氧代丁-2-烯酸(Z)-4-((4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-amino)-4-oxobut-2-enoic acid)(05-83)的制备:将实施例02-10的化合物(0.5g,2.0mmol)和呋喃-2,5-二酮(0.196g,2.0mmol)在THF(10mL)中于室温下搅拌18h。在真空下除去溶剂并经HPLC纯化以产生题述化合物(0.19g,27.3%产量,mp=182-185℃)。1HNMR(D6-DMSO)δ1.64(s,3H),1.73-1.81(m,2H),2.19(t,J=6.1Hz,2H),2.23(t,J=5.5Hz,2H),6.31(d,J=12.2Hz,1H),6.40(d,J=12.2Hz,1H),7.41-7.52(m,2H),7.61(d,J=2.4Hz,1H),8.02(s,1H),10.89(br s,1H),12.73(br s,1H)。13C NMR(D6-DMSO)δ9.1,21.2,27.0,36.4,107.2,118.0,119.2,124.6,129.8,131.0,131.4,137.3,138.2,158.3,163.5,167.0,194.6。LCMS t=3.9min,m/z计算值C17H18ClN2O4;C17H17ClN2NaO4;C34H35Cl2N4O8;C34H34Cl2N4NaO8349.096;371.078;697.183;719.165[M+H]+;[M+Na]+;[2M+H]+;[2M+Na]+,实验值349.096;371.075;697.176;719.166。
实施例05-84
(Z)-4-((3-氯-4-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-氨基)-4-氧代丁-2-烯酸(05-84)的制备:根据实施例05-83的方法,由实施例02-12制备题述化合物(mp=200-202℃)。1H NMR(D6-DMSO)δ1.66(s,3H),1.72-1.77(m,2H),2.10-2.19(m,4H),6.33(d,J=12.2Hz,1H),6.47(d,J=12.2Hz,1H),7.29(d,J=8.5Hz,1H),7.49(dd,J=8.5,2.4Hz,1H),7.94(d,J=2.4Hz,1H),7.97(s,1H),10.58(br s,1H),12.92(br s,1H)。13C NMR(D6-DMSO)δ8.8,21.2,26.7,36.3,106.0,118.4,119.7,130.0,130.2,131.4,131.6,132.3,137.9,159.2,163.5,166.9,194.2。LCMS t=3.9min,m/z计算值C17H18ClN2O4;C17H17ClN2NaO4;C34H34Cl2N4NaO8349.096;371.078;719.165[M+H]+;[M+Na]+;[2M+Na]+,实验值349.096;371.078;719.164。
实施例05-85
(Z)-4-((2-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-氨基)-4-氧代丁-2-烯酸(05-85)的制备:将实施例02-11的化合物(0.2g,0.8mmol)、呋喃-2,5-二酮(0.392g,4.0mmol)和AcOH(1mL)在THF(10mL)中于室温下搅拌18h。在真空下除去溶剂并经HPLC纯化以产生题述化合物(0.14g,50.3%产量)。1H NMR(D6-DMSO)δ1.67(s,3H),1.73-1.79(m,2H),2.15-2.22(m,4H),4.06(br s,0.5H),5.77(d,J=13.4Hz,1H),6.19(d,J=13.4Hz,1H),7.04(d,J=7.3Hz,1H),7.12-7.33(m,3H),7.80(d,J=7.3Hz,1H),8.01(s,0.5H)。LCMS t=3.6min,m/z计算值C17H18ClN2O4;C17H17ClN2NaO4 349.096;371.078[M+H]+;[M+Na]+,实验值349.096;371.078。
实施例06-01至06-011
实施例06-01
3-((3-乙炔基苯基)氨基)-2-甲基环戊基-2-烯酮(06-01)的制备:将2-甲基环戊烷-1,3-二酮(2-methylcyclopentane-1,3-dione)(0.112g,0.996mmol)、3-乙炔基苯胺(0.112mL,0.996mmol)和乙酸(0.029mL,0.499mmol)加入至0.5-2mL的微波瓶中。设置biotage(biotage)微波反应器的程序为于160℃下加热30min。将反应混合物溶解于二氯甲烷中,于真空下浓缩,经combiflash纯化(SiO2,7%的溶于二氯甲烷中的甲醇),经乙酸乙酯研磨,并过滤得到黄色固体3-((3-乙炔基苯基)氨基)-2-甲基环戊基-2-烯酮(0.046g,22%)。1H NMR(600MHz,MeOD)δ7.37-7.35(2H,m),7.31-7.27(2H,m),3.55-3.54(1H,m),2.72(2H,bs),2.40-2.38(2H,m),1.66(3H,s);13C NMR(150MHz,MeOD)δ205.3,173.7,139.6,129.2,128.7,126.9,124.2,123.5,110.2,82.4,78.2,32.7,25.8,5.6;LCMS m/z 212.1827([M+H+],C14H14NO要求212.1070)。
对于3-((3-(1-取代的-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮-06-02至06-011的常规合成方法。将抗坏血酸钠(0.01Eq,1M水溶液)加入至悬浮于水和叔丁醇(1:1,0.071mmol/mL)的混合物中的3-((3-乙炔基苯基)氨基)-2-甲基环戊基-2-烯酮(1Eq)和取代的叠氮化物(2Eq)的悬浮液中,随后加入五水硫酸铜(II价)(0.01Eq)。将该非均相混合物在室温下搅拌特定时间。用水稀释反应混合物并且在冰浴中冷却。过滤出已形成的沉淀并且使用水进行清洗。然后,按照说明,将沉淀物溶解于二氯甲烷中,干燥(Na2SO4),浓缩和纯化。
实施例06-02
2-甲基-3-((3-(1-苯基-1H-1,2,3-三唑-4-基)苯基)氨基)环戊基-2-烯酮(06-02)的制备:使用常规的方法,将悬浮于水和叔丁醇的混合物中的3-((3-乙炔基苯基)氨基)-2-甲基环戊基-2-烯酮(0.015g,0.071mmol)和叠氮苯(0.017g,0.142mmol)、抗坏血酸钠和五水硫酸铜(II价)的悬浮液于室温下搅拌14h。通过使用二氯甲烷清洗固体沉淀进行纯化,以产生黄色固体2-甲基-3-((3-(1-苯基-1H-1,2,3-三唑-4-基)苯基)氨基)环戊基-2-烯酮(0.022g,96%)。1H NMR(600MHz,MeOD)δ8.97(1H,s),7.92(2H,d,J=7.8Hz),7.84(1H,bs),7.78(1H,d,J=7.2Hz),7.61(2H,t,J=7.8Hz),7.53-7.49(2H,m),7.28(1H,d,J=7.8Hz),2.80(2H,bs),2.41(2H,bs),1.70(3H,s);13C NMR(150MHz,MeOD)δ205.2,174.0,140.1,137.2,131.4,129.8,128.9,123.8,122.6,120.9,120.2,119.5,33.0,29.5,25.8,5.7;LCMS m/z 331.2967([M+H+],C20H19N4O要求331.1554)。
实施例06-03
3-((3-(1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮(06-03)的制备:使用常规的方法,将悬浮于水和叔丁醇的混合物中的3-((3-乙炔基苯基)氨基)-2-甲基环戊基-2-烯酮(0.050g,0.236mmol)和1-叠氮基-4-甲氧基苯(0.070g,0.473mmol)、抗坏血酸钠和五水硫酸铜(II价)的悬浮液于室温下搅拌15h。通过combiflash(SiO2,90%溶于己烷的乙酸乙酯)进行纯化,以产生白色固体3-((3-(1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮(0.015g,18%)。1H NMR(600MHz,MeOD)δ8.87(1H,s),7.83-7.76(4H,m),7.52-7.49(1H,m),7.29(1H,dd,J=1.8,7.8Hz),7.15-7.13(1H,m),3.89(3H,s),2.82-2.80(2H,m),2.43-2.41(2H,m),1.71(3H,s);LCMS m/z 361.3447([M+H+],C21H21N4O2要求361.1660)。
实施例06-04
3-((3-(1-苄基-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮(06-04)的制备:使用常规的方法,将悬浮于水和叔丁醇的混合物中的3-((3-乙炔基苯基)氨基)-2-甲基环戊基-2-烯酮(0.050g,0.236mmol)和(叠氮甲基)苯((azidomethyl)benzene)(0.063g,0.472mmol)、抗坏血酸钠和五水硫酸铜(II价)的悬浮液于室温下搅拌14h。通过combiflash(SiO2,2%-5%溶于二氯甲烷的甲醇)进行纯化,以产生白色固体3-((3-(1-苄基-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮(0.040g,49%)。1H NMR(600MHz,MeOD)δ8.36(1H,s),7.70(1H,s),7.62(1H,d,J=7.8Hz),7.43-7.40(1H,m),7.35-7.32(4H,m),7.21(1H,d,J=7.8Hz),5.61(2H,d,J=1.8Hz),2.72(2H,bs),2.36-2.35(2H,m),1.67(3H,s);13C NMR(150MHz,MeOD)δ205.1,173.9,147.2,140.0,135.5,131.6,129.7,128.8,128.4,127.9,123.4,122.4,121.4,120.6,53.8,32.7,25.8,5.7;LCMS m/z345.3331([M+H+],C21H21N4O要求345.1710)。
实施例06-05
2-甲基-3-((3-(1-(4-甲基苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)环戊基-2-烯酮(06-05)的制备:使用常规的方法,将悬浮于水和叔丁醇的混合物中的3-((3-乙炔基苯基)氨基)-2-甲基环戊基-2-烯酮(0.075g,0.355mmol)和1-(叠氮甲基)-4-甲基苯(0.104g,0.710mmol)、抗坏血酸钠和五水硫酸铜(II价)的悬浮液于室温下搅拌11h。通过combiflash(SiO2,3%-5%溶于二氯甲烷的甲醇)进行纯化,以产生白色固体2-甲基-3-((3-(1-(4-甲基苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)环戊基-2-烯酮(0.103g,81%)。1H NMR(600MHz,MeOD)δ8.33(1H,bs),7.70(1H,s),7.63(1H,d,J=7.8Hz),7.43(1H,t,J=7.8Hz),7.26-7.18(5H,m),5.57(2H,s),2.74(2H,bs),2.38-2.37(2H,m),2.31(3H,s),1.68(3H,s);13C NMR(150MHz,MeOD)δ205.1,174.0,147.2,140.0,138.5,132.4,131.6,129.7,129.4,127.9,123.5,122.4,121.3,120.7,110.0,53.7,32.7,25.8,19.9,5.7;LCMS m/z 359.4512([M+H+],C22H23N4O要求359.1867)。
实施例06-06
3-((3-(1-(4-氟苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮(06-06)的制备:使用常规的方法,将悬浮于水和叔丁醇的混合物中的3-((3-乙炔基苯基)氨基)-2-甲基环戊基-2-烯酮(0.075g,0.355mmol)和1-(叠氮甲基)-4-氟苯(0.107g,0.710mmol)、抗坏血酸钠和五水硫酸铜(II价)的悬浮液于室温下搅拌11h。通过combiflash(SiO2,3%-5%溶于二氯甲烷的甲醇)进行纯化,以产生白色固体3-((3-(1-(4-氟苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮(0.063g,49%)。1H NMR(600MHz,MeOD)δ8.39(1H,bs),7.72(1H,s),7.65(1H,d,J=7.2Hz),7.46-7.42(3H,m),7.24(1H,d,J=7.8Hz),7.14-7.11(2H,m),5.63(2H,s),2.76(2H,bs),2.40-2.39(2H,m),1.68(3H,s);13CNMR(150MHz,MeOD)δ205.2,174.1,147.3,140.0,131.6,131.5,130.1,129.7,123.6,122.5,121.3,120.7,115.6,115.5,109.9,53.0,32.7,25.8,5.7;LCMS m/z 363.4738([M+H+],C21H20FN4O要求363.1616)。
实施例06-07
3-((3-(1-(3-氟苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮(06-07)的制备:使用常规的方法,将悬浮于水和叔丁醇的混合物中的3-((3-乙炔基苯基)氨基)-2-甲基环戊基-2-烯酮(0.075g,0.355mmol)和1-(叠氮甲基)-3-氟苯(0.107g,0.710mmol)、抗坏血酸钠和五水硫酸铜(II价)的悬浮液于室温下搅拌11h。通过combiflash(SiO2,3%-5%溶于二氯甲烷的甲醇)进行纯化,以产生3-((3-(1-(3-氟苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮(0.115g,90%)。1H NMR(600MHz,MeOD)δ8.42(1H,bs),7.74-7.73(1H,m),7.66(1H,dd,J=1.2,6.6Hz),7.47-7.40(2H,m),7.25(1H,dd,J=2.4,8.4Hz),7.19(1H,d,J=7.8Hz),7.14-7.10(2H,m),5.67(2H,s),2.78-2.77(2H,m),2.41-2.39(2H,m),1.69(3H,s);13C NMR(150MHz,MeOD)δ205.2,174.1,147.3,140.0,138.1,131.5,130.8,130.7,129.7,123.6,122.5,121.6,120.7,115.2,115.1,114.7,114.6,53.1,32.7,25.8,5.7;LCMS m/z363.4598([M+H+],C21H20FN4O要求363.1616)。
实施例06-08
3-((3-(1-(2-氟苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮(06-08)的制备:使用常规的方法,将3-((3-乙炔基苯基)氨基)-2-甲基环戊基-2-烯酮(0.075g,0.355mmol)和1-(叠氮甲基)-2-氟苯(0.107g,0.710mmol)、抗坏血酸钠和五水硫酸铜(II价)的悬浮液于室温下搅拌11h。通过combiflash(SiO2,3%-5%溶于二氯甲烷的甲醇)进行纯化,以产生3-((3-(1-(2-氟苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮(0.115g,90%)。1H NMR(600MHz,DMSO-d6)δ9.05(1H,bs),7.71(1H,s),7.59(1H,d,J=7.8Hz),7.44-7.38(1H,m),7.28-7.18(3H,m),5.70(2H,s),2.63(2H,bs),2.21-2.20(2H,m),1.56(3H,s);13C NMR(150MHz,DMSO-d6)δ202.5,169.9,146.8,141.0,131.9,131.4,130.2,125.5,123.4,123.3,122.7,122.5,121.4,119.9,116.4,116.2,110.5,47.7,33.5,26.3,8.0;LCMS m/z 363.3012([M+H+],C21H20FN4O要求363.1616)。
实施例06-09
4-((4-(3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-1H-1,2,3-三唑-1-基)甲基)苯甲酰胺(06-09)的制备:使用常规的方法,将悬浮于水和叔丁醇的混合物中的3-((3-乙炔基苯基)氨基)-2-甲基环戊基-2-烯酮(0.075g,0.355mmol)和4-(叠氮甲基)苯甲酰胺(0.125g,0.710mmol)、抗坏血酸钠和五水硫酸铜(II价)的悬浮液于室温下搅拌20h。使用二氯甲烷清洗固体沉淀物进行纯化,以产生白色固体4-((4-(3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-1H-1,2,3-三唑-1-基)甲基)苯甲酰胺(0.120g,88%)。1H NMR(600MHz,DMSO-d6)δ9.05(1H,bs),8.68(1H,s),7.97(1H,s),7.86(1H,d,J=7.8Hz),7.71(1H,s),7.58(1H,d,J=7.2Hz),7.41-7.38(2H,m),7.18(1H,d,J=7.2Hz),5.70(2H,s),2.68(2H,bs),2.21-2.20(2H,m),1.56(3H,s);13C NMR(150MHz,DMSO-d6)δ202.5,169.8,168.0,147.0,141.0,139.6,134.7,132.0,128.6,128.3,122.6,121.3,119.9,110.5,53.3,33.5,26.3,8.0;LCMS m/z 388.3432([M+H+],C22H22N5O2要求388.1768)。
实施例06-10
2-甲基-3-((3-(1-(2-甲基苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)环戊基-2-烯酮(06-10)的制备:使用常规的方法,将悬浮于水和叔丁醇的混合物中的3-((3-乙炔基苯基)氨基)-2-甲基环戊基-2-烯酮(0.075g,0.355mmol)和1-(叠氮甲基)-2-甲基苯(0.104g,0.710mmol)、抗坏血酸钠和五水硫酸铜(II价)的悬浮液于室温下搅拌60h。通过combiflash(SiO2,3%-7%溶于二氯甲烷的甲醇)进行纯化,以产生2-甲基-3-((3-(1-(2-甲基苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)环戊基-2-烯酮(0.074g,58%)。1H NMR(600MHz,MeOD)δ8.23(1H,bs),7.70(1H,s),7.62(1H,d,J=6.6Hz),7.41-7.40(1H,m),7.22-7.20(4H,m),5.64(2H,s),2.72(2H,bs),2.35-2.34(5H,m),1.66(3H,s);LCMS m/z 359.4657([M+H+],C22H23N4O要求359.1867)。
实施例06-11
2-甲基-3-((3-(1-(吡啶-3-基甲基)-1H-1,2,3-三唑-4-基)苯基)氨基)环戊基-2-烯酮(06-11)的制备:使用常规的方法,将悬浮于水和叔丁醇的混合物中的3-((3-乙炔基苯基)氨基)-2-甲基环戊基-2-烯酮(0.075g,0.355mmol)和3-(叠氮甲基)吡啶(0.095g,0.710mmol)、抗坏血酸钠和五水硫酸铜(II价)的悬浮液于室温下搅拌60h。使用二氯甲烷清洗固体沉淀物进行纯化,以产生2-甲基-3-((3-(1-(吡啶-3-基甲基)-1H-1,2,3-三唑-4-基)苯基)氨基)环戊基-2-烯酮(0.067g,55%)。1H NMR(600MHz,MeOD)δ8.63(1H,s),8.54-8.53(1H,m),8.45(1H,s),7.85(1H,dd,J=1.2,7.8Hz),7.72(1H,s),7.64(1H,dd,J=0.6,7.8Hz),7.47-7.42(2H,m),7.24-7.23(1H,m),5.73(2H,s),2.74(2H,bs),2.38-2.37(2H,m),1.67(3H,s);LCMS m/z 346.2856([M+H+],C20H20N5O要求346.1663)。
实施例06-12和06-13
实施例06-# | 题述化合物名称 |
12 | 3-((3-乙炔基苯基)氨基)-2-甲基环己基-2-烯酮 |
13 | 3-((3-(1-苄基-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环己基-2-烯酮 |
实施例06-12
3-((3-乙炔基苯基)氨基)-2-甲基环己基-2-烯酮(06-12)的制备:将2-甲基环己烷-1,3-二酮(0.200g,1.58mmol)、3-乙炔基苯胺(0.178mL,1.58mmol)、乙酸(0.181mL,3.17mmol)加入至0.5-2mL微波瓶中。设置biotage微波反应器的程序为于160℃下加热10min。将反应混合物溶解于甲醇中,于真空下浓缩,经combiflash(SiO2,2%-4%溶于二氯甲烷的甲醇)纯化,以得到白色固体3-((3-乙炔基苯基)氨基)-2-甲基环己基-2-烯酮(0.176g,49%)。1H NMR(600MHz,MeOD)δ7.34(1H,t,J=7.8Hz),7.30(1H,d,J=7.8Hz),7.25(1H,bs),7.17(1H,d,J=8.4Hz),3.54(1H,s),2.47(2H,t,J=6Hz),2.34(2H,t,J=6.6Hz),1.88-1.84(2H,m),1.77(3H,s);13C NMR(150MHz,MeOD)δ197.6,162.0,139.6,129.0,128.8,128.4,125.8,123.4,107.1,82.5,78.2,36.0,27.3,21.7,7.6;LCMSm/z 226.4831([M+H+],C15H16NO要求226.1227)。
实施例06-13
3-((3-(1-苄基-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环己基-2-烯酮(06-13)的制备:将抗坏血酸钠(0.035mL,0.036mmol,1M水溶液)加入至悬浮于水和叔丁醇(1:1,1.5mL)的混合物中的3-((3-乙炔基苯基)氨基)-2-甲基环己基-2-烯酮(0.075g,0.332mmol)和(叠氮甲基)苯(0.089g,0.666mmol)的悬浮液中,随后加入五水硫酸铜(II价)(0.001g,0.004mmol)。将该非均相混合物在室温下搅拌10h。用水(5mL)稀释反应混合物并在冰浴中冷却。过滤已形成的ppt并使用水和二氯甲烷进行清洗。使用二氯甲烷提萃取滤液,并将ppt溶解于二氯甲烷中。结合的二氯甲烷层被干燥(Na2SO4)并且经combiflash(SiO2,2%-5%溶于二氯甲烷的甲醇)纯化,以得到白色固体3-((3-(1-苄基-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环己基-2-烯酮(0.048g,40%)。1H NMR(600MHz,MeOD)δ8.35(1H,bs),7.63(1H,d,J=7.8Hz),7.61(1H,s),7.40(1H,t,J=7.8Hz),7.37-7.32(5H,m),7.12(1H,d,J=7.8Hz),5.62(1H,d,J=10.8Hz),2.49(2H,t,J=5.4Hz),2.31(2H,t,J=6Hz),1.83-1.81(2H,m),1.79(s,3H);13C NMR(150MHz,MeOD)δ197.4,162.5,147.2,140.0,135.5,131.4,129.5,128.8,128.4,127.9,125.1,122.6,122.3,121.4,106.7,53.8,36.0,27.3,21.8,7.6;LCMS m/z 359.5227([M+H+],C22H23N4O要求359.1867)。
实施例06-14至06-27
3-((3-(1-取代的-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮-06-24至06-27的常规合成方法。依次将甲醇(0.27mmol/mL)、NaHCO3(4Eq)、溶于Et2O的1,1,2,2,3,3,4,4,4-九氟丁烷-1-磺酰叠氮(1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonylazide)(1.5Eq)溶液(0.50mmol/mL)和五水硫酸铜(0.1Eq)加入至取代胺(1Eq)的水溶液(0.75mmol/mL)中。反应混合物在室温下搅拌5h。将3-((3-乙炔基苯基)氨基)-2-甲基环戊基-2-烯酮(1.1Eq)和抗坏血酸钠(1.5Eq)加入至反应混合物中。将该反应混合物在室温下搅拌特定的时间。按照说明,将该反应混合物进行过滤,二氯甲烷清洗(10mL×3),于真空下对滤液进行浓缩和纯化。
实施例06-14
3-((3-(1-(4-氯苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮(06-14)的制备:使用常规的方法,将(4-氯苯基)甲胺(0.085g,0.6mmol)搅拌60h。使用combiflash(SiO2,2%-7%溶于二氯甲烷的甲醇)进行纯化,以产生3-((3-(1-(4-氯苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮(0.092g,41%)。1H NMR(600MHz,MeOD)δ8.39(1H,bs),7.72(1H,s),7.65(1H,d,J=7.2Hz),7.46-7.38(4H,m),7.24(1H,d,J=8.4Hz),5.64(2H,s),2.77(2H,bs),2.40-2.39(2H,m),1.68(3H,s);LCMS m/z 379.2597([M+H+],C21H20ClN4O要求379.1321)
实施例06-15
3-((3-(1-(4-甲氧基苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮(06-15)的制备:使用常规的方法,将(4-甲氧基苯基)甲胺(0.082g,0.6mmol)搅拌60h。使用combiflash(SiO2,3%-7%溶于二氯甲烷的甲醇)进行纯化,以产生3-((3-(1-(4-甲氧基苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮(0.117g,53%)。1H NMR(600MHz,MeOD)δ8.32(1H,bs),7.71(1H,s),7.64(1H,d,J=7.2Hz),7.44(1H,t,J=7.8Hz),7.34(2H,d,J=8.4Hz),7.24(1H,d,J=7.2Hz),6.94(2H,d,J=8.4Hz),5.56(2H,s),3.78(3H,s),2.76(2H,bs),2.39(2H,bs),1.68(3H,s);LCMS m/z 375.3921([M+H+],C22H23N4O2要求375.1816)。
实施例06-16
2-甲基-3-((3-(1-(萘-1-基甲基)-1H-1,2,3-三唑-4-基)苯基)氨基)环戊基-2-烯酮(06-16)的制备:使用常规的方法,将萘-1-基甲胺(0.094g,0.6mmol)搅拌40h。使用combiflash(SiO2,2%-7%溶于二氯甲烷的甲醇)进行纯化,以产生2-甲基-3-((3-(1-(萘-1-基甲基)-1H-1,2,3-三唑-4-基)苯基)氨基)环戊基-2-烯酮(0.220g,94%)。1H NMR(600MHz,MeOD)δ8.24(1H,bs),8.12(1H,d,J=7.8Hz),7.89(2H,d,J=6.6Hz),7.65(1H,bs),7.57-7.48(5H,m),7.37(1H,t,J=3.6Hz),7.17(2H,d,J=7.2Hz),6.08(2H,s),2.67(2H,bs),2.31(2H,bs),1.65(3H,s);LCMS m/z 395.2784([M+H+],C25H23N4O要求395.1867)。
实施例06-17
2-甲基-3-((3-(1-(4-(三氟甲基)苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)环戊基-2-烯酮(06-17)的制备:使用常规的方法,将(4-(三氟甲基)苯基)甲胺(0.105g,0.6mmol)搅拌40h。使用combiflash(SiO2,3%-5%溶于二氯甲烷的甲醇)进行纯化,以产生2-甲基-3-((3-(1-(4-(三氟甲基)苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)环戊基-2-烯酮(0.201g,81%)。1H NMR(600MHz,MeOD)δ8.43(1H,bs),7.72-7.63(4H,m),7.52(2H,d,J=7.2Hz),7.42(1H,t,J=7.2Hz),7.22(1H,d,J=7.2Hz),5.74(2H,s),2.72(2H,bs),2.36(2H,bs),1.66(3H,s);LCMS m/z 413.4756([M+H+],C22H20F3N4O要求413.1584)。
实施例06-18
2-甲基-3-((3-(1-(1-苯乙基)-1H-1,2,3-三唑-4-基)苯基)氨基)环戊基-2-烯酮(06-18)的制备:使用常规的方法,将1-苯乙胺(0.073g,0.6mmol)搅拌40h。使用combiflash(SiO2,2%-7%溶于二氯甲烷的甲醇)进行纯化,以产生2-甲基-3-((3-(1-(1-苯乙基)-1H-1,2,3-三唑-4-基)苯基)氨基)环戊基-2-烯酮(0.162g,75%)。1H NMR(600MHz,MeOD)δ8.44(1H,bs),7.72(1H,s),7.65(1H,d,J=7.2Hz),7.43(1H,t,J=7.8Hz),7.38-7.31(5H,m),7.22(1H,d,J=7.8Hz),5.94-5.93(1H,m),2.73(2H,bs),2.36(2H,bs),2.00(3H,d,J=6.6Hz),1.67(3H,s);LCMS m/z 359.4603([M+H+],C22H23N4O要求359.1867)。
实施例06-19
2-甲基-3-((3-(1-苯乙基-1H-1,2,3-三唑-4-基)苯基)氨基)环戊基-2-烯酮(06-19)的制备:使用常规的方法,将2-苯乙胺(0.073g,0.6mmol)搅拌40h。使用combiflash(SiO2,2%-7%溶于二氯甲烷的甲醇)进行纯化,以产生2-甲基-3-((3-(1-苯乙基-1H-1,2,3-三唑-4-基)苯基)氨基)环戊基-2-烯酮(0.132g,61%)。1H NMR(600MHz,MeOD)δ8.14(1H,bs),7.65(1H,s),7.59(1H,d,J=6Hz),7.45-7.44(1H,m),7.26-7.17(6H,m),4.70-4.69(2H,m),3.28-3.27(2H,m),2.77(2H,bs),2.41(2H,bs),1.69(3H,s);LCMS m/z 359.4236([M+H+],C22H23N4O要求359.1867)。
实施例06-20
3-((3-(1-(2-氯苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮(06-20)的制备:使用常规的方法,将(2-氯苯基)甲胺(0.085g,0.6mmol)搅拌40h。使用combiflash(SiO2,2%-7%溶于二氯甲烷的甲醇)进行纯化,以产生3-((3-(1-(2-氯苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮(0.116g,65%)。1H NMR(600MHz,MeOD)δ8.35(1H,bs),7.73(1H,s),7.66(1H,d,J=7.2Hz),7.50-7.31(5H,m),7.25(1H,d,J=7.8Hz),5.79(2H,s),2.77(2H,bs),2.40(2H,bs),1.69(3H,s);LCMS m/z 379.2943([M+H+],C21H20ClN4O要求379.1321)。
实施例06-21
3-((3-(1-(3-氯苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮(06-21)的制备:使用常规的方法,将(3-氯苯基)甲胺(0.085g,0.6mmol)搅拌40h。使用combiflash(SiO2,2%-7%溶于二氯甲烷的甲醇)进行纯化,以产生3-((3-(1-(3-氯苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮(0.130g,73%)。1H NMR(600MHz,MeOD)δ8.41(1H,bs),7.73(1H,s),7.66(1H,bs),7.45-7.26(6H,m),5.65(2H,s),2.77(2H,bs),2.40(2H,bs),1.68(3H,s);LCMS m/z 379.2314([M+H+],C21H20ClN4O要求379.1321)。
实施例06-22
3-((3-(1-(2-甲氧基苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮(06-22)的制备:使用常规的方法,将(2-甲氧基苯基)甲胺(0.085g,0.6mmol)搅拌40h。使用combiflash(SiO2,2%-7%溶于二氯甲烷的甲醇)进行纯化,以产生3-((3-(1-(2-甲氧基苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮(0.059g,33%)。1H NMR(600MHz,MeOD)δ8.26(1H,bs),7.70(1H,s),7.64(1H,d,J=7.8Hz),7.43(1H,dt,J=3,7.8Hz),7.38-7.35(1H,m),7.27-7.22(2H,m),7.04(1H,dd,J=2.4,8.1Hz),6.98-6.97(1H,m),5.62(2H,d,J=3Hz),3.88(3H,t,J=1.8Hz),2.76(2H,bs),2.40-2.38(2H,m),1.68(3H,s);LCMS m/z375.4430([M+H+],C22H23N4O2要求375.1816)。
实施例06-23
3-((3-(1-(3-甲氧基苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮(06-23)的制备:使用常规的方法,将((3-甲氧基苯基)甲胺(0.082g,0.6mmol)搅拌40h。使用combiflash(SiO2,3%-5%溶于二氯甲烷的甲醇)进行纯化,以产生3-((3-(1-(3-甲氧基苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮(0.152g,86%)。1HNMR(600MHz,MeOD)δ8.36(1H,bs),7.72(1H,s),7.65(1H,d,J=7.2Hz),7.45-7.24(3H,m),6.93-6.91(3H,m),5.61(2H,s),3.78(3H,s),2.76(2H,bs),2.39(2H,bs),1.68(3H,s);LCMSm/z 375.4525([M+H+],C22H23N4O2要求375.1816)。
实施例06-24
2-甲基-3-((3-(1-(3-甲基苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)环戊基-2-烯酮(06-24)的制备:使用常规的方法,将间甲苯基甲胺(0.073g,0.6mmol)搅拌40h。使用combiflash(SiO2,2%-7%溶于二氯甲烷的甲醇)进行纯化,以产生2-甲基-3-((3-(1-(3-甲基苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)环戊基-2-烯酮(0.144g,85%)。1H NMR(600MHz,MeOD)δ8.35(1H,bs),7.71(1H,s),7.65(1H,d,J=7.8Hz),7.44(1H,t,J=8.4Hz),7.27-7.15(5H,m),5.61(2H,s),2.76(2H,bs),2.39(2H,bs),2.34(3H,s),1.68(3H,s);LCMSm/z 359.3305([M+H+],C22H23N4O要求359.1867)。
实施例06-25
3-((3-(1-(4-溴苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮(06-25)的制备:使用常规的方法,将(4-溴苯基)甲胺(0.112g,0.6mmol)搅拌40h。使用combiflash(SiO2,2%-7%溶于二氯甲烷的甲醇)进行纯化,以产生3-((3-(1-(4-溴苄基)-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮(0.147g,74%)。1H NMR(600MHz,MeOD)δ8.39(1H,s),7.72(1H,t,J=1.8Hz),7.65(1H,d,J=7.2Hz),7.56-7.55(2H,m),7.45(1H,t,J=7.8Hz),7.31(2H,d,J=8.4Hz),7.25(1H,dd,J=1.8,7.8Hz),5.63(2H,s),2.77-2.76(2H,m),2.41-2.39(2H,m),1.68(3H,s);LCMS m/z 423.1297([M+H+],C21H20BrN4O要求423.0815)。
实施例06-26
(R)-2-(4-(3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-1H-1,2,3-三唑-1-基)-3-苯丙酸(06-26)的制备:使用常规的方法,将(R)-2-氨基-3-苯丙酸(0.099g,0.6mmol)搅拌40h。反应混合物经1M的HCl酸化至pH值为1,过滤以及使用二氯甲烷进行清洗以产生(R)-2-(4-(3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-1H-1,2,3-三唑-1-基)-3-苯丙酸(0.147g,48%)。1H NMR(600MHz,MeOD)δ8.38(1H,s),7.67(1H,s),7.61(1H,d,J=7.8Hz),7.44(1H,t,J=7.8Hz),7.24-7.13(6H,m),5.71(1H,dd,J=4.2,10.5Hz),3.69(1H,dd,J=4.8,14.4Hz),3.56(1H,dd,J=10.8,15.9Hz),2.77(2H,bs),2.41-2.40(2H,m),1.69(3H,s);LCMSm/z 403.3882([M+H+],C23H23N4O3要求403.1765)。
实施例06-27
(S)-2-(4-(3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-1H-1,2,3-三唑-1-基)-3-苯丙酸(06-27)的制备:使用常规的方法,将(S)-2-氨基-3-苯丙酸(0.099g,0.6mmol)搅拌40h。反应混合物经1M的HCl酸化至pH值为1,过滤以及使用二氯甲烷进行清洗以产生(S)-2-(4-(3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-1H-1,2,3-三唑-1-基)-3-苯丙酸(0.040g,21%)。1H NMR(600MHz,MeOD)δ8.38(1H,d,J=3Hz),7.67(1H,d,J=1.8Hz),7.62-7.60(1H,m),7.46-7.42(1H,m),7.24-7.13(6H,m),5.72-5.70(1H,m),3.69(1H,dd,J=4.2,14.4Hz),3.56(1H,dd,J=10.8,14.4Hz),2.78-2.77(2H,m),2.41-2.40(2H,m),1.69(3H,s);LCMSm/z 403.4457([M+H+],C23H23N4O3要求403.1765)。
实施例06-28
实施例06-# | 题述化合物名称 |
28 | 3-((4-(1-苄基-1H-1,2,3-三唑-4-基)苯基)氨基)-2-甲基环戊基-2-烯酮 |
实施例06-28
3-((4-(4-苄基-1H-1,2,3-三唑-1-基)苯基)氨基)-2-甲基环戊基-2-烯酮(06-28)的制备:将抗坏血酸钠(0.095mL,0.099mmol,1M水溶液)加入至悬浮于水和叔丁醇(1:1,4mL)的混合物中的4-乙炔基苯胺(0.117g,0.998mmol)和(叠氮甲基)苯((azidomethyl)benzene)(0.226g,1.996mmol)的悬浮液中,随后加入五水硫酸铜(II价)(0.002g,0.009mmol)。该非均相混合物在室温下搅拌4h。用5mL水稀释反应混合物并且在冰浴中冷却。过滤已形成的沉淀并且使用水和二氯甲烷对其进行清洗,使用二氯甲烷进行萃取,干燥(Na2SO4)以及经combiflash(SiO2,2%-4%溶于二氯甲烷的甲醇)纯化,以提供4-(1-苄基-1H-1,2,3-三唑-4-基)苯胺(0.042g,17%),其在未经过进一步纯化的情况可以被用于下一步骤。LCMS m/z 251.3345([M+H+],C20H20N5O要求251.1292)。
将2-甲基环戊烷-1,3-二酮(0.019g,1.167mmol)、4-(4-苄基-1H-1,2,3-三唑-1-基)苯胺(0.042mL,0.167mmol)、乙酸(0.019mL,0.334mmol)加入至0.5-2mL微波瓶中。设置biotage微波反应器的程序为于160℃下加热30min。将反应混合物经combiflash(SiO2,2%-5%溶于二氯甲烷的甲醇)纯化,以得到3-((4-(4-苄基-1H-1,2,3-三唑-1-基)苯基)氨基)-2-甲基环戊基-2-烯酮(0.032g,55%)。1H NMR(600MHz,MeOD)δ8.31(1H,s),7.83-7.82(2H,m),7.38-7.32(6H,m),5.64(2H,s),2.76(2H,bs),2.39(2H,bs),1.68(3H,s);LCMS m/z 345.3646([M+H+],C21H21N4O要求345.1710)。
生物测定
荧光各向异性结合测定
聚组氨酸标签形式的人BRD4的第一溴结构域(BrD1)的表达和纯化使用文献[参见Zeng et al.Structure 16,643-652(2008)and Zhang et al.,J BiolChem 287,28840-28851(2012).]中描述的方法进行。通过在镍IDA柱(Invitrogen)上进行亲和层析纯化该蛋白,随后通过凝血酶酶切去除聚组氨酸标签。
使用异硫氰酸荧光素(FITC)标记的MS417作为测定探针(Zhang etal.2008op.cit.)在荧光各向异性测定中评价新合成的化合物与BRD4BrD1的结合亲和力。使用BrD蛋白(0.25至1μM)和荧光探针(80nM)进行竞争结合,并提高总体积为80μL的PBS缓冲液(pH 7.4)中未标记的竞争配体的浓度。荧光配体与蛋白在25℃下孵育1小时后,通过Safire 2酶标仪(Tecan)获得测量值。在测定中,荧光配体的浓度为≤2Kd,并且蛋白浓度被设定为50-80%的荧光配体被结合。根据由Nicolovska-Coleska和其同事们引入的Cheng-Prussoff方程式[Nikolovska-Coleska,Z.et al.,Anal Biochem 332,261-273(2004)的修正形式计算竞争配体的解离常数。假设使用单一位点竞争性结合模型,该方程用于根据使用Prism得到的拟合数据重新获得的IC50值计算Ki值。
其中,[IC50]为50%抑制时游离的抑制剂的浓度,[L50]为50%抑制时游离的标记配体的浓度,以及[P0]为0%抑制时游离的蛋白的浓度。需要注意的是,每组蛋白-探针配对的Kd为在竞争性测定中可分解的Ki的限值(limit of resolvable Ki)。上述实施例的结合结果如表1所示。
表1
注释:n.t.=未测试;(+)=>10μM;(++)=1-10μM;(+++)=<1μM
LPS诱导的小鼠巨噬细胞Raw264.7细胞中IL-6的分泌
于37℃下在5%CO2的湿润环境中,在添加10%FBS(胎牛血清)(Hyclone,Logan,UT)的Dulbecco改良的Eagle培养基(DMEM)(Hyclone,Logan,UT)中培养RAW264.7细胞。96孔板中的细胞(0.1ml,3×105cells/ml)经测试化合物处理。30min后,移除全部上清液,并且使用LPS(脂多糖)(1μg/ml)(Sigma-Aldrich化学公司,Louis,MO)和化合物对细胞进行处理。24小时后,收集上清液,并且使用ELISA(酶联免疫吸附测定法)(Thermo Scientific,Pittsburgh,PA)检测小鼠IL-6蛋白水平。使用培养基将溶解在DMSO中的化合物稀释至浓度0.28-50,000nM。调整DMSO的终浓度至0.05%(v/v)。通过使用EnVison 2104多功能酶标仪(PerkinElmer公司,Waltham,MA)检测570nm下的吸光度值进行测定。每项实验至少重复三次,并且使用Prism进行制图,以及计算IC50值。在本测定中测试了实施例04-19和04-20的化合物并且发现具有0.2-1μM范围得到IC50值。
LPS诱导的小鼠巨噬细胞中细胞因子的转录活性
在经或未经如上所描述的化合物处理的情况下培养RAW264.7细胞。使用TRIzol试剂(Gibco,Grand Island,NY)从细胞中分离总RNA以用于均质化。通过检测260nm/280nm下吸光度的比值确定RNA的浓度和完整性。使用这些靶基因的特异性引物进行定量PCR以确定细胞因子IL-6、IL-1β和TNFα的MRNA的转录水平。每项实验至少进行三次,并且使用Prism进行制图,以及计算IC50值。在本测定中测试了实施例01-36、04-15、04-17、04-19、04-20、04-89、04-91、04-98、05-15和06-4的化合物并且发现在抑制细胞因子IL-6、IL-1β和TNFα的转录活性方面具有0.1-5μM范围的IC50值。
LPS刺激的小鼠巨噬细胞RAW264.7细胞中一氧化氮(NO)的释放
于37℃下在5%CO2的湿润环境中,在添加10%FBS的DMEM培养基中培养RAW264.7细胞。使用测试化合物处理96孔板中的细胞(0.1ml,3×105cells/ml)。30min后,移除全部上清液,并且使用LPS(1μg/ml)和测试化合物处理所述细胞。24小时后,使用Griess反应G2930(Promega公司,NY,WI)[参见Bredt and Snyder,Ann Rev Biochem 63,175-195(1994)]检测亚硝酸盐的水平。使用培养基将溶解在DMSO中的化合物稀释至浓度0.28-50,000nM。调整DMSO的终浓度至0.05%(v/v)。使用EnVison 2104多功能酶标仪(PerkinElmer公司,Waltham,MA)通过520nm下的分光光度测定法检测亚硝酸盐产物。每项实验至少进行三次,并且使用Prism进行制图。在本测定中测试了实施例01-36、04-15、04-17、04-19、04-20、04-89、04-91、04-98、05-15和06-4的化合物并且发现在RAW264.7细胞中抑制LPS诱导的NO释放方面具有0.1-5μM范围的IC50值。
评价BLBCs中IL-8表达的ELISA测定
评价表1中列出的各实施例的化合物(“测试化合物”)抑制人类基底样乳腺癌细胞(BLBCs)中IL-8的表达的活性。于37℃下在5%CO2的湿润环境中,在添加10%FBS(Hyclone,Logan,UT)的DMEM培养基(Hyclone,Logan,UT)中培养人BLBCs细胞。待培养皿中细胞的融合率达60-80%时,使用胰蛋白酶消化细胞,于1000rpm下离心5min,并且使用新鲜的培养基重悬以将细胞接种于96孔板中(0.1ml,3×105cells/ml),并且在上述培养条件下孵育过夜。待细胞贴于板底的第二天,小心弃去全部上清液,随后加入于培养基中稀释的测试化合物。使用培养基将溶解在DMSO(Sigma-Aldrich化学公司,Louis,MO)中的测试化合物以2倍梯度从1000nM连续稀释至125nM。调节DMSO的终浓度至0.05%(v/v)。24小时的孵育结束时,且如果不立即进行后续步骤的情况下,将上清液小心移除并保存在-80℃。人IL-8ELISA Ready-Set-Go!(第二代)(货号88-8086)被用于抗已制备的样本。将所述样本与标准人IL-8重组蛋白(以2倍梯度从250pg/ml连续稀释至2pg/ml进行制备,一式两份)共孵育过夜以达到最大灵敏度。使用EnVison 2104多功能酶标仪(PerkinElmer公司,pg/ml,MA)通过520nm下读取的吸光度值对测定进行检测。每项实验至少进行两次,并且使用Prism进行制图。所用的曲线拟合方程为“log(抑制剂)相对于反应-可变斜率(四个参数)”。在本测定中,在包括MDA-MB-435S、MDA-MB-231、BT-549、MDA-MB-157、HS578T和SUM1315的人BLBC细胞组中测试了实施例05-57、05-68和05-70的化合物,并且发现具有0.1-1μM范围的IC50值。
人、大鼠和小鼠的微粒体稳定性测定
对表1列出的实施例的化合物(“测试化合物”)进行微粒体稳定性测定。在37℃下以最终的孵育体积为135μM进行人、大鼠和小鼠的肝脏微粒体孵育。人肝脏微粒体(混合性别(mixed gender),货号H2610)从XenoTech获得。大鼠肝脏微粒体(雄性Sprague-Dawley大鼠,货号452501)从BDGentest获得。小鼠肝脏微粒体(雄性CD1小鼠,货号452701)从BDGentest获得。使用浓度为0.5μM的测试化合物(最初溶解于DMSO中,浓度为5μM)与溶解在pH值为7.4的50mM磷酸盐缓冲液中的0.25mg/mL的微粒体蛋白进行孵育。通过转移13.5μL化合物-微粒体混合物至含有45μL反应终止液的反应终止板中制备零时间点样本,其中,反应终止液由10nM丁螺环酮(Sigma)或50nM氨磺丁脲(Princeton Bio)作为内标溶于1:1甲醇:乙腈中制成。还将分装的1.5μL还原型烟酰胺腺嘌呤二核苷酸磷酸四钠盐(NADPH)添加至零时间点板中。然后,通过加入13.5μL NADPH至化合物-微粒体混合物中开始反应。在其余的每个时间点(5、10、15、20、30、45和60min),将15μL孵育混合物加入至45μL反应终止液中。于3800rpm下离心样本15-30分钟。然后,将将样本合并成每组6个样本。将分装的60μL上清液转移至96孔板中,并且将其中分装出的5μL进行注射并通过LC-MS(Applied BiosystemsAPI 5500QTrap)进行分析。通过将峰面积比(分析物峰面积/IS峰面积)转换为以时间点0的面积比为100%的母本残留%计算化合物的内在清除率。通过母本残留%相对于孵育时间的制图确定斜率(k),然后推导出半衰期(t1/2;分钟),内在清除率(Clint;对于肝脏微粒体为μL/min/mg蛋白,对于肝细胞为μL/min/million细胞)和标度(scaled)内在清除率(标度Clint;L/h/kg)。在本测定中测试了实施例01-41、01-47、05-57、05-66、05-68和05-70的化合物,并且发现具有25-250μL/min/mg蛋白范围的内在清除率Clint值。
T细胞转移结肠炎研究和组织病理学
在构建的T细胞转移结肠炎模型[参见(Totsuka,T.et al.J Immunol 178,4737-4748(2007)and Powrie,F.et al.International immunology 5,1461-1471(1993).]中测定实施例04-19的化合物抑制小鼠结肠炎的发展。简单地说,将来自C57BL/6小鼠的纯化的CD4+CD45RBhi T细胞腹腔注射至Rag1-/-受体(每只小鼠每次注射溶在200μl无菌PBS中的5×105个细胞)。在整个实验的过程中,每周均称量小鼠的体重。图1以图表的形式表示了结果。可以看出,化合物04-19显著地(P<0.05)抑制了体重的损失。5-7周后,将小鼠处死并取出结肠组织。将组织于10%福尔马林缓冲液中固定并进行石蜡包埋。将组织样本的切片(5μm)进行苏木素和伊红染色。由有经验的病理学家在事先不了解处理方式的情况下进行读片和评分。对上皮、粘膜下层和肌层(muscularis propria)中炎症反应的程度进行单独评分。由图2可以看出,在治疗组小鼠中肠道总体形态被保持,而在疾病组小鼠中肠道总体形态丢失。
Claims (25)
1.一种式I所示的化合物
其中:
U为(CH2)n,其中,n=1、2或3;
R1选自由(C1-C10)烷基、被一个或多个氟原子取代的(C1-C10)烷基和腈所组成的组中;
Cy为苯基、萘基、吡啶基、喹啉基、异喹啉基、吲哚基或苯并咪唑基;
R11和R12各自独立地选自由H、(C1-C10)烷基、(C1-C10)全氟烷基、卤素、羟基、(C1-C10)烷氧基、氨基、(C1-C10)烷基氨基、(C1-C10)酰胺基、芳基、杂芳基、氨甲酰基、羧基和(C1-C10)烷氧羰基所组成的组中;或者
R11和R12可一起形成5、6或7元碳环或杂环,其中,所述碳环或杂环可以可选地被R2取代;
R2选自由卤素、(C1-C4)烷基、卤代(C1-C4)烷基、羟基、(C1-C4)烷氧基、卤代(C1-C4)烷氧基、羧基、氨基、(C1-C4)烷基氨基和二(C1-C4)烷基氨基所组成的组中;
Y选自
L和L’各自独立地为化学键或(CR3R4)m,其中,R3和R4各自独立地选自由H和(C1-C4)烷基所组成的组中,并且m为1或2;
R10选自碳环和杂环,其中,所述碳环或杂环可选地被R7和/或R8取代;
R20为–C(=O)OR21;
R21选自H和(C1-C4)烷基;
R5和R6各自独立地选自由氢、羟基、(C1-C10)烃基、卤代(C1-C10)烃基和(C1-C10)烷氧基所组成的组中;
R7和R8各自独立地选自由羟基、卤素、(C1-C4)烷基、卤代(C1-C4)烷基、羟基(C1-C4)烷基、(C1-C4)烷氧基、卤代(C1-C4)烷氧基、(C1-C4)烷基巯基、(C1-C4)烷基羰基、芳基、杂芳基、环烷基、杂环烷基、氰基、含氧基、(C1-C4)烷基磺酰基、氨基、(C1-C4)烷基氨基、二(C1-C4)烷基氨基、(C1-C4)酰胺基、氨甲酰基、羧基和(C1-C4)烷氧羰基所组成的组中,其中,每个所述烷基、芳基、杂芳基、环烷基或杂环烷基可以进一步可选地被羟基、含氧基、羧基、羧基(C1-C4)烷基、羟基(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)烷氧羰基、(C1-C4)烷氧羰基(C1-C4)烷基、氨基、(C1-C4)烷基氨基、二(C1-C4)烷基氨基、酰胺基、(C1-C4)烷基酰胺基、二(C1-C4)烷基酰胺基、卤素、(C1-C4)烷基、卤代(C1-C4)烷基、芳基、杂芳基、杂环烷基或环烷基取代;
或者,R5和R6,或R7和R8可一起形成5、6或7元碳环或杂环,其中,所述碳环或杂环可选地被R9取代;
R9选自由卤素、(C1-C4)烷基、卤代(C1-C4)烷基、羟基、(C1-C4)烷氧基、卤代(C1-C4)烷氧基、氨基、(C1-C4)烷基氨基和二(C1-C4)烷基氨基所组成的组中。
2.根据权利要求1所述的化合物,其中,Y为
3.根据权利要求2所述的化合物,其中,L为–CH2-。
4.根据权利要求1所述的化合物,其中,R10选自环己基、环戊基、苯基、萘基、噻吩基、吡咯基、吡啶基和嘧啶基,各自可选地被R7和/或R8取代。
5.根据权利要求1所述的化合物,其中,R10选自环己基、苯基和萘基,各自可选地被R7和/或R8取代。
6.根据权利要求2所述的化合物,其中,R7选自卤素、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、卤代(C1-C4)烷氧基和氨甲酰基。
7.根据权利要求1所述的化合物,其中,Cy为苯基,具有下式所示结构:
8.根据权利要求7所述的化合物,其中,Y选自
9.根据权利要求8所述的化合物,其中,R10为
10.根据权利要求1所述的化合物,其中,U为-CH2CH2-。
11.根据权利要求1所述的化合物,其中,U为-CH2-。
12.根据权利要求1所述的化合物,其中,Y为
13.根据权利要求12所述的化合物,其中,L为化学键且R21为氢。
14.根据权利要求13所述的化合物,其中,R10为
15.根据权利要求14所述的化合物,其中,R7选自卤素、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、卤代(C1-C4)烷氧基和氨甲酰基。
16.根据权利要求1所述的化合物,其中,Y为
17.根据权利要求1所述的化合物,其中,R21为氢或甲基。
18.根据权利要求1所述的化合物,其中,Y为
19.根据权利要求7所述的化合物,其中,R11为氢且R12为卤素。
20.根据权利要求1所述的化合物,其中,R10为苯基,可选地被R7和/或R8取代。
21.一种药物组合物,该药物组合物含有药学上可接受的载体和权利要求1所述的化合物。
22.根据权利要求7所述的化合物,其中,R11和R12各自独立的选自由H、(C1-C10)烷基、卤素、(C1-C10)烷氧基、氨基、(C1-C10)烷基氨基、(C1-C10)酰胺基、杂芳基、氨甲酰基、羧基和(C1-C10)烷氧羰基。
23.根据权利要求22所述的化合物,其中,Y选自
24.根据权利要求22所述的化合物,其中,Y为
25.根据权利要求1所述的化合物,其中,所述化合物或者其药学上可接受的盐选自:
3-氯-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(萘-1-基)-苯甲酰胺、
3-氯-N-(2-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺、
3-氯-N-(3-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺、
3-氯-N-(4-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯甲酰胺、
3-氯-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(邻甲苯基)苯甲酰胺、
3-氯-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(间甲苯基)苯甲酰胺、
2-甲氧基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(萘-1-基)苯甲酰胺、
2-甲氧基-N-(2-甲氧基苯基)-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-苯甲酰胺、
2-甲氧基-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)-N-(邻甲苯基)苯甲酰胺、
3-氯-N-(4-甲氧基苯基)-4-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯甲酰胺、
3-氯-N-(2-甲氧基苯基)-4-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯甲酰胺、
3-氯-4-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)-N-(邻甲苯基)苯甲酰胺、
N-(4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-4-甲氧基苯甲酰胺、
N-(4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-2-甲基苯甲酰胺、
N-(3-氯-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-2-甲基苯甲酰胺、
N-(2-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-2-甲基苯甲酰胺、
N-(4-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-4-甲氧基苯甲酰胺、
N-(4-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-2-甲基苯甲酰胺、
N-(4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-1-苯基甲磺酰胺、
N-(4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-2-氯苯磺酰胺、
N-(4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-2-甲基苯磺酰胺、
N-(4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-2-氟苯磺酰胺、
N-(4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-2-氰基苯磺酰胺、
N-(4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-2-甲氧基苯磺酰胺、
N-(4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-哌啶-1-磺酰胺、
N-(4-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-吗啉-4-磺酰胺、
N-(3-氯-4-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-环己烷磺酰胺、
N-(2-氯-3-((2-甲基-3-氧代环戊基-1-烯-1-基)氨基)苯基)-2-甲基苯磺酰胺、
N-(4-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-2-甲基苯磺酰胺、
N-(4-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-环己烷磺酰胺、
N-(3-氯-4-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-2-甲基苯磺酰胺、
N-(2-氯-3-((2-甲基-3-氧代环己基-1-烯-1-基)氨基)苯基)-2-甲基苯磺酰胺、
3-((2-氯-5-((2-甲基苄基)氨基)苯基)氨基)-2-甲基环己基-2-烯酮和
3-((2-氯-5-((2-氟苄基)氨基)苯基)氨基)-2-甲基环己基-2-烯酮。
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WO2015031824A9 (en) | 2016-06-16 |
WO2015031824A1 (en) | 2015-03-05 |
US20160200666A1 (en) | 2016-07-14 |
EP3038612A4 (en) | 2017-01-11 |
CN105873577A (zh) | 2016-08-17 |
US9884806B2 (en) | 2018-02-06 |
US10351511B2 (en) | 2019-07-16 |
US20180105485A1 (en) | 2018-04-19 |
EP3038612B1 (en) | 2020-07-29 |
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