CN108314677A - 一种新型的ezh2抑制剂及其用途 - Google Patents
一种新型的ezh2抑制剂及其用途 Download PDFInfo
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- CN108314677A CN108314677A CN201710045099.0A CN201710045099A CN108314677A CN 108314677 A CN108314677 A CN 108314677A CN 201710045099 A CN201710045099 A CN 201710045099A CN 108314677 A CN108314677 A CN 108314677A
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- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Abstract
本发明涉及人组蛋白甲基转移酶EZH2的野生型和Y641F突变型的抑制剂,其具有式(I)的结构。本发明还提供使用该抑制剂治疗与EZH2活性相关的癌症或癌前病症的方法和用途。
Description
技术领域
本发明涉及人组蛋白甲基转移酶EZH2的野生型以及其某些突变形式的抑制剂、以及使用该抑制剂治疗与EZH2活性相关的癌症或癌前病症的方法和用途。
背景技术
在真核细胞中,DNA与组蛋白包装形成染色质。约150碱基对的DNA在组蛋白的八聚体(组蛋白2A、2B、3和4各两个)上缠绕两圈形成核小体——染色质的基本单位。染色质有序结构的变化能引起关联基因转录中的改变。该过程高度受控,因为基因表达模式的改变深度影响基础细胞过程,诸如分化、增殖和凋亡。通过共价修饰组蛋白,特别是对其N端尾部的修饰来介导对染色质结构(并因而对转录)变化的控制。这些修饰通常称为表观遗传学修饰,因为它们能造成基因表达中的可遗传改变,但不影响所述DNA本身的序列。氨基酸侧链的共价修饰(例如,甲基化、乙酰化、磷酸化和泛素化)是酶促介导的。
向组蛋白上的特定氨基酸位点选择性添加甲基基团受到被称为组蛋白甲基转移酶(histone methyltransferases,HMT)的独特酶家族作用的控制。具体基因的表达水平受相关的组蛋白位点处一个或多个甲基基团的存在与否影响。具体组蛋白位点处的甲基基团的特定作用持续直至所述甲基基团被组蛋白去甲基化酶移除,或持续直至所述修饰的组蛋白通过核小体转换被替代。以类似的方式,其它酶类能够用其它化学物质修饰DNA和组蛋白,并且其它酶也能移除这些物质来控制基因表达。
必须严格控制转录调节幕后的生化系统有序体系,从而最优化地进行细胞生长和分化。当这些控制被负责DNA和组蛋白修饰的酶的异常表达和/或活性干扰时,产生疾病状态。例如,在人癌症中,越来越多的证据提示表观遗传酶活性失调导致癌症相关的细胞增殖失控及其它癌症相关表型,例如增强的细胞迁移和入侵。除了癌症外,有越来越多的证据显示表观遗传酶在众多其它人类疾病中的作用,包括代谢疾病(例如糖尿病)、炎性疾病(例如克罗恩氏病)、神经退行性疾病(例如阿尔茨海默病)和心血管疾病。因此,选择性调节表观遗传酶的异常作用就一定范围疾病的治疗而言具有广泛前景。
果蝇zeste基因增强因子同源物2(enhancer of zeste homolog 2,EZH2)催化组蛋白H3第27位赖氨酸三甲基化(trimethylated lysine-27 of histone H3,H3K27m3),调节染色体结构是其主要作用。多种肿瘤都有EZH2的高表达,与肿瘤的恶性进程、侵袭性、转移能力关系密切。EZH2的功能主要有:催化组蛋白甲基化,参与DNA甲基化和干扰DNA修复。EZH2属于PcG(多梳组)基因家族。PRC1(多梳抑制复合物1)和PRC2(多梳抑制复合物2)两种复合体分别起着维持基因抑制和起始基因沉默的作用。EZH2与EED、SUZ12基因共同构成PRC2复合物,EZH2作为PRC2的催化亚甲基,通过其组蛋白甲基转移酶中高度保守的SET区域可催化H3K27m3和H3K9m3从而抑制转录,在染色体水平调节基因活性。PRC2和PRC3中的EZH2能够与DNA甲基转移酶相互配合,增强其活性。研究显示一些EZH2靶点基因与DNA甲基转移酶的结合需要EZH2的帮助。此外,EZH2靶基因启动子甲基化也需要EZH2协助。EZH2对于DNA甲基转移酶来说,起到了一个募集作用。
生化和基因研究提供证据显示果蝇(Drosophila)PcG蛋白在至少两个不同蛋白复合物中起作用,所述蛋白复合物为多梳抑制复合物1(PRC1)和ESC-E(Z)复合物(也称作多梳抑制复合物2(PRC2)),尽管所述复合物的组成可为动态(Otte等,Curr OpinGenet Dev,2003,13:448-54)。果蝇(Drosophila)中的研究和哺乳动物细胞中的研究证明,ESC-E(Z)/EED-EZH2(即PRC2)复合物具有固有的组蛋白甲基转移酶活性。该复合物一般包括EED、EZH2、SUZ12和RbAp48或其果蝇(Drosophila)同源物。然而,仅包括EED、EZH2和SUZ12的重建复合物保留对组蛋白H3第27位赖氨酸的组蛋白甲基转移酶活性(美国专利7,563,589)。
在构成PRC2复合物的各种蛋白中,EZH2(Zeste增强子同源物2)是催化亚基。EZH2的催化位点进而存在于SET结构域,所述SET结构域是在若干染色质相关蛋白质(包括三胸组和多梳组的成员)中发现的高度保守序列基序(以Su(var)3-9命名,Zeste增强子,三胸)。SET结构域是除H3-K79甲基转移酶DOT1以外所有已知组蛋白赖氨酸甲基转移酶的特征。
与EZH2维持多能外胚层细胞的表观遗传修饰模式的作用一致,Cre介导的EZH2去除引起细胞中组蛋白H3-K27甲基化的缺失。此外,前列腺和乳癌细胞系和组织的研究显示EZH2和SUZ12水平与这些癌症的侵袭性之间的强烈相关性(Bracken等,EMBO J(2003),22:5323-35;Kirmizis等,Mol Cancer Ther(2003),2:113-21;Kleer等,Proc Natl Acad SciUSA(2003),100:11606-11;Varambally等,Nature(2002),419:624-9)。
近期,报道EZH2的体细胞突变与滤泡性淋巴瘤(FL)和弥散性大B细胞淋巴瘤(DLBCL)的生发中心B细胞样(GCB)亚型相关(Morin等,Nat Genet(2010),42:181-5)。在所有情况中,发现突变EZH2基因的出现是杂合的,并且通过转录组测序在所述突变样品中检测到野生型和突变等位基因的表达。目前,关于治疗大多数弥散性大B细胞淋巴瘤(DLBCL)的治疗标准是R-CHOP方法。
目前进入临床二期的EZH2的小分子抑制剂有EPZ6438(Tazemetostat),其用于治疗非霍奇金B细胞淋巴瘤(参见US8765732B2、US20140128393A1、US20151163A1)。此外还有目前进入临床一期的葛兰素史克研发的GSK126(CAS No.:1346574-57-9),其也是一种EZH2的小分子抑制剂,用于治疗弥漫大B细胞淋巴瘤、滤泡性淋巴瘤。
发明内容
本发明提供野生型或突变型EZH2的抑制剂。具体而言,本发明的化合物包括式(I)的化合物、或其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物或前体药物:
其中,
Y选自氰基、氨酰基、任选被1个R4基团取代的烷基氨基、任选被1-3个独立的R4基团取代的芳基、任选被1-3个独立的R4基团取代的杂芳基、和任选被1-3个独立的R4基团取代的杂环烷基烷基氨基;
R1为烷基;
R2选自氢、烷基和环烷基烷基;
R3选自烷基、环烷基、杂环烷基、杂芳基、烷基芳基、和二环[2.2.1]庚-2-烯基;
R4独立地选自氢、卤素、氰基、烷基、烷氧基、烷酰基、任选被1个R5基团取代的烷基氨基、任选被1个R5基团取代的烷基磺酰胺基、任选被1个R5基团取代的环烷基磺酰胺基、任选被1-3个独立的R5基团取代的杂环烷基、任选被1-3个独立的R5基团取代的杂环烷基羰基、任选被1-3个独立的R5基团取代的杂环烷基烷基、任选被1-3个独立的R5基团取代的杂环烷基烷氧基、任选被1-3个独立的R5基团取代的杂环烷基羰基烷基、和任选被1-3个独立的R5基团取代的芳氧基;
R5独立地选自氨基、烷基、烷酰基、烷基氨基、羟基烷基、环烷基、环烷基烷基、杂环烷基、和氨基保护基。
在更优选的实施方式中,本发明提供一种EZH2激酶抑制剂,包括式(II)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药:
其中,X选自CH和N,R1、R2、R3和R4如上所定义。
在特别优选的实施方式中,X为CH,且R1、R2、R3和R4如上所定义。
在另一方面,本发明提供一种药物组合物,其包括治疗有效量的至少一种本文提供的式(I)或式(II)的化合物或其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物或前药,以及药学可接受的载体或赋形剂,以及任选的其它治疗剂。
在又一方面,本发明涉及使用式(I)或式(II)的化合物或其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物或前药抑制EZH2活性的方法和用途。
在一个实施方式中,本发明EZH2抑制剂抑制野生型EZH2的组蛋白甲基转移酶活性。在一个实施方式中,本发明的EZH2抑制剂抑制突变型EZH2的组蛋白甲基转移酶活性。在一个实施方式中,所述EZH2抑制剂抑制野生型EZH2的组蛋白甲基转移酶活性和突变型EZH2的组蛋白甲基转移酶活性。在一个实施方式中,所述EZH2抑制剂选择性地抑制突变型EZH2的组蛋白甲基转移酶活性,特别是Y641F突变型EZH2的组蛋白甲基转移酶活性。
本发明在又一方面提供一种治疗与EZH2活性相关的癌症或癌前病症的方法和用途。
本发明的对象包括已被诊断患有癌症或癌前病症、具有癌症或癌前病症的症状或具有发展癌症或癌前病症的风险的任何人类对象。例如,所述癌症是淋巴瘤、白血病或黑素瘤。优选地,所述淋巴瘤是非霍奇金氏淋巴瘤、滤泡性淋巴瘤或弥散性大B细胞淋巴瘤。或者,所述白血病是慢性骨髓性白血病(CML)。所述癌前病症是骨髓增生异常综合征(MDS,先前被称作白血病前期)。
具体实施方式
定义
除非另外定义,否则本文中使用的所有技术和科学术语具有本发明所属领域普通技术人员通常所理解的含义。在说明书中,除非上下文另有明确说明,单数形式也包含复数形式。本文提到的所有出版物、专利申请、专利或其它参考文献均通过引入本文作为参考。在存在抵触的情况下,以本说明书(包括定义在内)为准。此外,材料、方法和实施例都仅是说明性的,并不意在限制本发明的范围。
除非另有说明,本发明采用本领域技术范围内的质谱、NMR、HPLC、蛋白质化学、生物化学、重组DNA技术和药理学等常规方法。除非提供具体的定义,否则与本文描述的分析化学、合成有机化学、以及医学和药物化学等化学上相关的命名和实验室操作和技术,是本领域技术人员已知的。一般而言,前述技术和步骤可以通过本领域众所周知的和在各种一般文献和更具体文献中描述的常规方法来实施,这些文献在本说明书中被引用和讨论。
“烷基”是指脂肪族烃基团,可以是支链或直链的烷基。根据结构,烷基可以是单价基团或双价基团(即亚烷基)。在本发明中,烷基优选是具有1-8个碳原子的烷基,更优选具有1-6个碳原子的“低级烷基”,甚至更优选具有1-4个碳原子的烷基。典型的烷基包括但不限于甲基、乙基、丙基、丁基、戊基、己基等。应理解,本文提到的“烷基”包括可能存在的所有构型和构象的该烷基,例如本文提到的“丙基”包括正丙基和异丙基,“丁基”包括正丁基、异丁基和叔丁基,“戊基”包括正戊基、异丙基、新戊基、叔戊基、和戊-3-基等。
术语“环烷基”是指单环或多环基,其仅含有碳和氢。环烷基包括具有3-8个环原子的基团。根据结构,环烷基可以是单价基团或双价基团(例如亚环烷基)。在本发明中,环烷基优选是具有3-8个碳原子的环烷基,更优选具有3-6个碳原子的“低级环烷基”。环烷基的例子包括但不限于,环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环戊烯基、环己烯基、环庚烯基和金刚烷基。
“烷氧基”是指-O-烷基,其中烷基如本文中定义。典型的烷氧基包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基等。
术语“氨基”是指基团-NH2。术语“氨酰基”是指-CO-NH2。术语“酰胺基”或“酰氨基”是指-NR-CO-R’,其中R和R’各自独立地为氢或烷基。
术语“烷基氨基”是指进一步被一个或两个烷基取代的氨基取代基,具体是指基团-NRR’,其中R和R’各自独立地选自氢或低级烷基,条件是-NRR’不是-NH2。“烷基氨基”包括其中-NH2的氮连接至少一个烷基基团的化合物的基团。烷基氨基基团的例子包括苄基氨基、甲基氨基、乙基氨基、苯乙基氨基等。“二烷基氨基”包括其中-NH2的氮连接至少两个其它烷基基团的基团。二烷基氨基基团的例子包括但不限于,二甲基氨基和二乙基氨基。“芳基氨基”和“二芳基氨基”包括其中N分别连接至少一个或两个芳基基团的基团。
“环烷基烷基”是指本文定义的烷基被本文定义的环烷基取代。非限制性的环烷基烷基包括环丙基甲基、环丙基乙基、环丁基甲基、环丁基乙基、环戊基甲基、环己基甲基等。
术语“羰基”是由碳和氧两种原子通过双键连接而成的有机官能团(C=O)。术语“烷酰基”或“烷基羰基”是指进一步被一个烷基取代的羰基。
术语“烷基磺酰胺基”和“环烷基磺酰胺基”是指-NH-S(=O)2-R,其中R分别为烷基和环烷基。
术语“卤”或“卤素”是指氟、氯、溴和碘。
本文使用的术语“氰基”是指式-CN基团。
术语“芳香基”是指平面环具有离域的π电子系统并且含有4n+2个π电子,其中n是整数。芳香基环可以由五、六、七、八、九或多于九个原予构成。芳香基可以是任选取代的。术语“芳香基”包括碳环芳基(例如苯基)和杂环芳基(或“杂芳基”或“杂芳香基”)基团(例如吡啶)。该术语包括单环或稠环多环(即共用相邻的碳原子对的环)基团。
本文使用的术语“芳基”是指芳香基环中每一个构成环的原子都是碳原子。芳基环可以由五、六、七、八、九或多于九个原子构成。芳基可以是任选取代的。芳基的实例包括但不限于苯基、萘基、菲基、蒽基、芴基和茚基。根据结构,芳基可以是单价基团或双价基团(即亚芳基)。
术语“杂芳基”是指芳基中包括一个或多个选自氮、氧和硫的环杂原子。含N“杂芳基”部分是指芳香基中环上至少有一个骨架原子是氮原子。根据结构,杂芳基可以是单价基团或双价基团(即亚杂芳基)。杂芳基的实例包括但不限于吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、吲唑基、吲嗪基、酞嗪基、哒嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、噻二唑基、呋喃基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、萘啶基和呋喃并吡啶基等。
本文使用的术语“杂环烷基”或“杂环基”是指非芳香基环中一个或多个构成环的原子是选自氮、氧和硫的杂原子。杂环烷基环可以由三、四、五、六、七、八、九或多于九个原子构成。杂环烷基环可以是任选取代的。杂环烷基的实例包括但不限于内酰胺、内酯、环亚胶、环硫代亚胺、环氨基甲酸酯、环氧乙烷、氮杂环丁烷、氧杂环丁烷、硫杂环丁烷、四氢噻喃、4H-吡喃、四氢吡喃、哌啶、1,3-二噁英、1,3-二噁烷、1,4-二噁英、1,4-二噁烷、哌嗪、1,3-氧硫杂环己烷、1,4-氧硫杂环己二烯、1,4-氧硫杂环己烷、四氢-1,4-噻嗪、2H-1,2-噁嗪、马来酰亚胺、琥珀酰亚胺、巴比妥酸、硫代巴比妥酸、二氧代哌嗪、乙内酰脲、二氢尿嘧啶、吗啉、三噁烷、六氢-1,3,5-三嗪、四氢噻吩、四氢呋喃、吡咯啉、吡咯烷(四氢吡咯)、咪唑烷,吡咯烷酮、吡唑啉、吡唑烷、咪唑啉、咪唑烷、1,3-二氧杂环戊烯、1,3-二氧杂环戊烷、1,3-二硫杂环戊烯、1,3-二硫杂环戊烷、异噁唑啉、异噁唑烷、噁唑啉、噁唑烷、噁唑烷酮、噻唑啉、噻唑烷、1,3-氧硫杂环戊烷、异二氢吲哚、二氢吲哚、1,2,3,6-四氢吡啶、二氢吡喃、吡喃、1,4-二氮杂环庚烷、1,4-二氮杂环庚烷、2-氧杂-5-氮杂二环[2.2.1]庚烷、和2,5-二氮杂二环[2.2.1]庚烷等。根据结构,杂环烷基可以是单价基团或双价基团(即亚杂环烷基)。
“芳氧基”是指-O-芳基,其中芳基如本文中定义。
术语“烷基芳基”或“芳基(烷基)”是指本文定义的芳基被本文定义的烷基取代。
术语“杂环烷基烷基”或“烷基(杂环烷基)”是指本文定义的烷基被本文定义的杂环烷基取代。术语“杂环烷基烷氧基”或“烷氧基(杂环烷基)”是指本文定义的烷氧基被本文定义的杂环烷基取代。
术语“杂环烷基羰基”是指进一步被一个杂环烷基取代的羰基。术语“杂环烷基羰基烷基”是指进一步被一个杂环烷基羰基取代的烷基。
术语“任选”指后面描述的一个或多个事件可以或可以不发生,并且包括发生的事件和不发生的事件两者。术语“任选取代的”或“取代的”是指所提及的基团可以被一个或多个额外的基团取代,所述额外的基团各自并且独立地选自烷基、环烷基、芳基、杂芳基、羟基、烷氧基、氰基、卤素、酰胺基、硝基、卤代烷基、氨基、烷基羰基、烷氧基羰基、杂芳基烷基、杂环烷基烷基、氨酰基、氨基保护基等。
本文术语“药学上可接受的盐”指的是保留主题化合物的所需生物学活性且显示最小的不希望的毒理学效应的盐。这些药学上可接受的盐可以在化合物的最终分离和纯化过程中原位制备,或通过单独使纯化化合物的游离酸或游离碱形式分别与合适的碱或酸反应来制备。
“溶剂化物”或“溶剂合物”指的是含有化学计量或非化学计量溶剂的溶剂加成形式。一些化合物趋于以晶状固态捕集固定摩尔比例的溶剂分子,从而形成溶剂合物。若溶剂是水,则形成的溶剂合物是水合物;若溶剂是醇,则形成的溶剂合物是醇化物。水合物通过使一个或多个水分子与所述物质的一个分子结合而形成,其中所述水保持其分子状态为H2O。
本文公开的化合物的“代谢物”是当该化合物被代谢时形成的化合物的衍生物。术语“活性代谢物”是指当该化合物被代谢时形成的化合物的生物活性衍生物。本文使用的术语“被代谢”,是指特定物质被生物体改变的过程总和(包括但不限于水解反应和由酶催化的反应,例如氧化反应)。因此,酶可以产生特定的结构转变为化合物。例如,细胞色素P450催化各种氧化和还原反应,同时二磷酸葡萄糖甘酸基转移酶催化活化的葡萄糖醛酸分子至芳香醇、脂肪族醇、羧酸、胺和游离的巯基的转化。新陈代谢的进一步的信息可以从《ThePharmacological Basis of Therapeutics》,第九版,McGraw-Hill(1996)获得。本文公开的化合物的代谢物可以通过将化合物给予宿主并分析来自该宿主的组织样品、或通过将化合物与肝细胞在体外孵育并且分析所得化合物来鉴别。这两种方法都是本领域已知的。在一些实施方式中,化合物的代谢物是通过氧化过程形成并与相应的含羟基化合物对应。在一些实施方式中,化合物被代谢为药物活性代谢物。本文使用的术语“调节”,是指直接或间接与靶标相互作用,以改变靶标的活性,仅仅举例来说,包括增强靶标的活性、抑制靶标的活性、限制靶标的活性或者延长靶标的活性。
术语“前药”或“前体药物”是指如下衍生物,其可能不具有药理学活性,但在某些情况下,可口服或肠胃外给予并在这之后在体内代谢以形成具有药理学活性的本发明化合物。前药的非限制性实例包括:酯、碳酸酯、半酯、磷酸酯、硝基酯、硫酸酯、亚砜、酰胺、氨基甲酸酯、含氮化合物、磷酰胺、糖苷、醚、乙缩醛和酮缩醇等。
“有效量”指,将引发例如研究者或医师在研的组织、系统、动物或人的生物学或医学反应的药物或药学制剂的量。此外,术语“治疗有效量”指与没有接受该量的相应对象相比,引起疾病、紊乱、或副作用改良的治疗、治愈、预防、或缓解、或者疾病或紊乱发展速率降低的任何量。该术语范围内还包括有效提高正常生理功能的量。
所述术语“共给予”和“共同给予”指同时共同给予(同时给予两种或更多治疗剂),和不同时间给予(给予一种或多种治疗剂的时间不同于给予一种或多种额外治疗剂的时间),只要这些治疗剂在所述患者内有一些程度的同时存在。
术语“癌前病症”指若不治疗即可导致癌症的疾病、综合征或结果。其为与显著增大的癌风险相关联的广义状态。
本文所用的术语“治疗”指缓解疾病、紊乱或病症的至少一种症状。该术语包括向对象给药和/或应用一种或多种本文所述化合物以提供病症的管理或治疗。用于本公开目的的“治疗”可以但不必须提供治愈;而是指,“治疗”可以是病症的管理形式。当本文所述化合物用于处理有害的增殖细胞(包括癌)时,“治疗”包括部分或完全破坏所述有害的增殖细胞,但对正常细胞的破坏影响最小。有害的快速增殖细胞(包括癌细胞)的所需处理机制在细胞水平上是凋亡。
本文所用的术语“预防”包括共同预防或减缓临床上显著疾病发展的开始或者预防或减缓风险个体中的临床前显著疾病阶段的开始。这包括预防性治疗有疾病发展风险的个人。
本文所用的出于治疗目的的术语“对象”包括任何诊断有疾病、有疾病症状或有发展癌症或癌前病症风险的人对象。对预防方法而言,所述对象是任何人对象。为了说明预防目的,对象可以是有风险或遗传上倾向于患有表征为有害快速细胞增殖的疾病(例如癌)的人对象。所述对象可能因接触致癌剂、遗传上倾向于患有表征为有害快速细胞增殖等的疾病而面临风险。
本文使用的GI50是指使50%细胞生长被抑制所需的药物浓度,即药物使50%细胞(如癌细胞)的生长得到抑制或控制时的药物浓度。
本文使用的IC50是指在测量效应的分析中获得最大效应的50%抑制的特定测试化合物的量、浓度或剂量。
本文使用的EC50是指测定化合物的剂量、浓度或量,其引起特定测定化合物诱导、刺激或加强的特定反应的50%的最大表达的剂量依赖反应。
本发明的新型EZH2抑制剂
本发明的各个方面涉及一种EZH2激酶抑制剂,包括式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药:
其中,
Y选自氰基、氨酰基、任选被1个R4基团取代的烷基氨基、任选被1-3个独立的R4基团取代的芳基、任选被1-3个独立的R4基团取代的杂芳基、和任选被1-3个独立的R4基团取代的杂环烷基烷基氨基;
R1为烷基;
R2选自氢、烷基和环烷基烷基;
R3选自烷基、环烷基、杂环烷基、杂芳基、烷基芳基、和二环[2.2.1]庚-2-烯基;
R4独立地选自氢、卤素、氰基、烷基、烷氧基、烷酰基、任选被1个R5基团取代的烷基氨基、任选被1个R5基团取代的烷基磺酰胺基、任选被1个R5基团取代的环烷基磺酰胺基、任选被1-3个独立的R5基团取代的杂环烷基、任选被1-3个独立的R5基团取代的杂环烷基羰基、任选被1-3个独立的R5基团取代的杂环烷基烷基、任选被1-3个独立的R5基团取代的杂环烷基烷氧基、任选被1-3个独立的R5基团取代的杂环烷基羰基烷基、和任选被1-3个独立的R5基团取代的芳氧基;
R5独立地选自氨基、烷基、烷酰基、烷基氨基、羟基烷基、环烷基、环烷基烷基、杂环烷基、和氨基保护基。
在本发明的实施方式中,烷基优选为C1-8烷基,更优选为C1-5烷基;环烷基优选为C3-8环烷基,更优选为C3-6环烷基;杂环烷基优选为3-9元杂环烷基,更优选6元杂环烷基,特别优选选自哌啶基、哌嗪基、吗啉基、和四氢吡喃基等;芳基优选为苯基;杂芳基优选选自吡啶基、噻吩基、和呋喃基等;氨基保护基优选选自新戊酰基、叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、苄基、对甲氧苄基、烯丙氧羰基、和三氟乙酰基等。
在本发明的优选实施方式中,Y选自氰基、氨酰基、(2-(二甲基氨基)乙基)(甲基)氨基、苯基、吡啶基、噻吩基、(2-吗啉乙基)氨基、和(3-吗啉丙基)氨基,其中苯基、吡啶基、噻吩基、(2-吗啉乙基)氨基、和(3-吗啉丙基)氨基任选地被1-3个独立的R4基团取代;并且其中R4独立地选自氟、氯、氰基、甲基、甲氧基、乙酰基、(2-(二甲基氨基)乙基)氨基、(2-(二甲基氨基)乙基)(甲基)氨基、异丙基磺酰胺基、环丙基磺酰胺基、哌啶基、哌嗪基、吗啉基、高哌嗪基、吗啉-4-羰基、吗啉甲基、哌啶甲基、哌嗪甲基、吗啉乙氧基、吗啉丙氧基、吗啉-4-羰基甲基、和苯氧基,其中哌啶基、哌嗪基、吗啉基、高哌嗪基、吗啉-4-羰基、吗啉甲基、哌啶甲基、哌嗪甲基、吗啉乙氧基、吗啉丙氧基、吗啉-4-羰基甲基、和苯氧基任选地被1-3个独立的R5基团取代;并且其中R5独立地选自氨基、甲基、乙基、异丙基、乙酰基、二甲基氨基、羟甲基、环丙基、环丙基甲基、吡咯基、和叔丁氧羰基。
在另外优选的实施方式中,R1选自甲基、乙基、和丙基;R2选自甲基、乙基、丙基、和环丙基甲基;R3选自异丙基、新戊基、叔戊基、戊-3-基、环丙基、环丁基、环戊基、环己基、四氢吡喃基、呋喃基、甲基苯基、和二环[2.2.1]庚-2-烯基。
在本发明另外优选的实施方式中,Y为被R4基团取代的芳基或杂芳基,特别是被R4基团取代的苯基、吡啶-3-基、或吡啶-4-基;并且其中R4选自卤素、烷基、任选被R5基团取代的杂环烷基烷基、任选被R5基团取代的杂环烷基烷氧基、和任选被R5基团取代的杂环烷基烷基,特别是氟、甲基、4-(环丙基甲基)哌嗪-1-基、吗啉乙氧基、吗啉丙氧基、吗啉甲基或N原子任选被氨基保护基取代的哌嗪甲基。
在其它优选的实施方式中,R1为甲基。
在另外优选的实施方式中,R2为乙基。
在进一步优选的实施方式中,R3为环丙基或环戊基。
在更优选的实施方式中,本发明提供一种EZH2激酶抑制剂,包括式(II)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药:
其中,X选自CH和N,R1、R2、R3和R4如上所定义。
在特别优选的实施方式中,X为CH,且R1、R2、R3和R4如上所定义。在进一步优选的实施方式中,R1为烷基(例如甲基);R2为烷基(例如乙基);R3选自烷基(例如异丙基、新戊基、叔戊基、和戊-3-基)、环烷基(例如环丙基、环丁基、环戊基、和环己基)、杂环烷基(例如四氢吡喃-4-基)、杂芳基(例如呋喃-2-基)、烷基芳基(例如对甲基苯基)、和二环[2.2.1]庚-2-烯基;R4各自独立地选自氢、卤素(例如氟)、烷基(例如甲基)、任选被1个R5基团取代的烷基磺酰胺基(例如异丙基磺酰胺基)、任选被1个R5基团取代的环烷基磺酰胺基(例如环丙基磺酰胺基)、任选被1-3个独立的R5基团取代的杂环烷基(例如哌啶基、哌嗪基、吗啉基)、任选被1-3个独立的R5基团取代的杂环烷基羰基(例如吗啉-4-羰基)、任选被1-3个独立的R5基团取代的杂环烷基烷基(例如吗啉甲基、哌啶甲基、哌嗪甲基)、任选被1-3个独立的R5基团取代的杂环烷基烷氧基(例如吗啉乙氧基、吗啉丙氧基)、任选被1-3个独立的R5基团取代的杂环烷基羰基烷基(例如吗啉-4-羰基甲基)、和任选被1-3个独立的R5基团取代的芳氧基(例如苯氧基);R5独立地选自烷基(例如乙基)、环烷基烷基(例如环丙基甲基)、烷基氨基(例如二甲基氨基)、羟基烷基(羟甲基)、和氨基保护基(例如叔丁氧羰基)。
在本发明中,优选的EZH2抑制剂包括下表的化合物及其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物、或前药:
对于各个变量,上述基团的任意组合也在本文考虑之中。可以理解的是:本文所提供的化合物上的取代基和取代模式可以由本领域技术人员进行选择,以便提供化学上稳定的且可以使用本领域已知的技术以及本文阐述的技术合成的化合物。
本文描述的是新型的EZH2(野生型和/或Y641F突变型)抑制剂。本文也描述了此化合物的药学可接受的盐、溶剂化物、酯、酸、药物活性代谢物和前药。
在另外的或进一步的实施方式中,将本文描述的化合物给予有需要的生物体后在其体内代谢产生代谢物,所产生的代谢物然后用于产生期望的效果,包括期望的治疗效果。
本文描述的化合物可以被制成和/或被用作药学可接受的盐。药学可接受的盐的类型包括但不限于:(1)酸加成盐、通过将化合物的游离碱形式与药学可接受的无机酸反应形成,所述无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸、偏磷酸等;或与有机酸反应形成,所述有机酸如乙酸、丙酸、己酸、环戊烷丙酸、羟基乙酸、丙酮酸、乳酸、丙二酸、苹果酸、柠檬酸、琥珀酸、马来酸、酒石酸、反丁烯二酸、三氟乙酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲烷磺酸、乙烷磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、甲苯磺酸、4-甲基双环-[2.2.2]辛-2-烯-1-甲酸、2-萘磺酸、叔丁基乙酸、葡庚糖酸、4,4′-亚甲基双-(3-羟基-2-烯-1-甲酸)、3-苯基丙酸、三甲基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、水杨酸、羟基萘酸、硬脂酸、粘康酸等;(2)碱加成盐,其在母体化合物中的酸性质子被金属离子置换时形成,例如碱金属离子(例如锂、钠、钾)、碱土金属离子(例如镁或钙)或铝离子;或与有机碱配位。可接受的有机碱包括乙醇胺、二乙醇胺、三乙醇胺、三甲胺、N-甲基葡萄糖胺,等等。可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠、氢氧化钠等。
药学可接受的盐的相应的平衡离子可以使用各种方法分析和鉴定,所述方法包括但不限于离子交换色谱、离子色谱、毛细管电泳、电感耦合等离子体、原子吸收光谱、质谱或它们的任何组合。
使用以下技术的至少一种回收所述盐:过滤、用非溶剂沉淀接着过滤、溶剂蒸发,或水溶液的情况下使用冻干法。
在本说明书中,在一些情况中为方便起见,化合物的结构式代表特定的异构体,但本发明包括所有异构体,例如几何异构体、基于不对称碳原子的光学异构体、立体异构体、互变异构体等。此外,所述式代表的化合物可具有结晶多晶型。应注意,本发明化合物的任何晶型、晶型混合物或其酐或水合物都包括在本发明的范围内。此外,在体内降解本发明化合物而生成的所谓代谢物包括在本发明的范围内。
本发明所涉及带有手性的化合物,其构型可以是任意构型或者混合的外消旋体。当根据本发明使用的化合物包含多于一种手性中心时,其可以非对映体形式存在。所述非对映体异构体化合物可以通过本领域技术人员已知的方法分离(例如,色谱或结晶),而单独对映体可以如上所述分离。本发明包括根据本发明使用的多种非对映体化合物及其混合物的应刚。本发明使用的化合物可以不同互变异构形式或以不同几何异构体形式存在,本发明包括根据本发明使用的化合物的各个互变异构体和/或几何异构体及其混合物的应用。本发明使用的化合物可以两性离子形式存在。本发明包括根据本发明使用的化合物的各个两性离子形式及其混合物的应用。
本领域技术人员应理解,式(I)和(II)化合物的某些受保护的衍生物(可在最终去保护阶段之前制得)可能不具有药理学活性,但在某些情况下,可口服或肠胃外给予并在这之后在体内代谢以形成具有药理学活性的本发明化合物。因此,此类衍生物可被称为“前药”。此外,本发明的某些化合物可作为本发明其它化合物的前药。本发明化合物的所有保护的衍生物和前药均包括在本发明范围内。本领域技术人员还应理解,当本发明化合物中存在某些官能度时,可将本领域技术人员称为“前体部分”的某些部分,置于合适的官能度上。本发明化合物的优选前药包括:酯、碳酸酯、半酯、磷酸酯、硝基酯、硫酸酯、亚砜、酰胺、氨基甲酸酯、含氮化合物、磷酰胺、糖苷、醚、乙缩醛和酮缩醇等。
此外,本发明的化合物,例如,所述化合物的盐,可以以水合或非水合(无水)形式或以与其它溶剂分子的溶剂合物形式存在。水合物的非限制性例子包括单水合物、二水合物等。溶剂合物的非限制性例子包括乙醇溶剂合物、丙酮溶剂合物等。
筛选和表征药学可接受的盐、多晶型和/或溶剂化物可以使用多种技术完成,所述技术包括但不限于热分析、X射线衍射、光谱、显微镜方法、元素分析。使用的各种光谱技术包括但不限于Raman、FTIR、UVIS和NMR(液体和固体状态)。各种显微镜技术包括但不限于IR显微镜检术和拉曼(Raman)显微镜检术。
药物组合物
可将一种或多种本发明的EXH2抑制剂单独或以药物组合物形式向人患者给予,其中所述EZH2抑制剂与合适的载体或一种或多种赋形剂以治疗或改善本文所述疾病或病症的剂量混合。这些EZH2抑制剂的混合物还能作为简单混合物或合适配制的药物组合物给予所述患者。例如,本发明的一方面涉及药物组合物,所述药物组合物包含治疗有效剂量的EZH2抑制剂或其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物或前药,和药学上可接受的载体或赋形剂,以及任选的其它治疗剂。
在治疗过程中,可以根据情况单独或与一种或多种其它的治疗剂组合使用。其它的治疗剂可以选自以下药物:免疫抑制剂(例如他克莫司、环孢菌素、雷帕霉素、甲氨蝶呤、环磷酰胺、硫唑嘌呤、巯嘌呤、麦考酚酯或FTY720)、糖皮质激素类药(例如泼尼松、醋酸可的松、泼尼松龙、甲泼尼龙、地塞米松、倍他米松、曲安西龙、氟羟强的松龙、倍氯米松、醋酸氟氢可的松、醋酸脱氧皮质酮、醛固酮)、非甾体抗炎药(例如水杨酸盐、芳基烷酸、2-芳基丙酸、N-芳基邻氨基苯甲酸、昔康类、考昔类或硫酰替苯胺)、变态反应疫苗、抗组胺药、抗白三烯药、β-激动剂、茶碱、抗胆碱药或其它选择性激酶抑制剂(例如mTOR抑制剂、c-Met抑制剂)或her2抗体-药物。另外,所提及的其它治疗剂还可以是雷帕霉素(Rapamycin)、克唑替尼(Crizotinib)、他莫昔芬、雷洛昔芬、阿那曲唑、依西美坦、来曲唑、赫赛汀TM(曲妥珠单抗)、格列卫TM(伊马替尼)、紫杉醇TM(紫杉醇)、环磷酰胺、洛伐他汀、美诺四环素(Minosine)、阿糖胞苷、5-氟尿嘧啶(5-FU)、甲氨蝶呤(MTX)、紫杉特尔TM(多西他赛)、诺雷德TM(戈舍瑞林)、长春新碱、长春碱、诺考达唑、替尼泊苷、依托泊苷、健择TM(吉西他滨)、埃博霉素(Epothilone)、诺唯本、喜树碱、柔红霉素(Daunonibicin)、更生霉素、米托蒽醌、安吖啶、多柔比星(亚德里亚霉素)、表柔比星或伊达比星。或者,其它治疗剂也可以是细胞因子例如G-CSF(粒细胞集落刺激因子)。或者,其它治疗剂也可以是,例如但不限于,CMF(环磷酰胺、甲氨蝶呤和5-氟尿嘧啶)、CAF(环磷酰胺、亚德里亚霉素和5-氟尿嘧啶)、AC(亚德里亚霉素和环磷酰胺)、FEC(5-氟尿嘧啶、表柔比星和环磷酰胺)、ACT或ATC(亚德里亚霉素、环磷酰胺和紫杉醇)或CMFP(环磷酰胺、甲氨蝶呤、5-氟尿嘧啶和泼尼松)。
EZH2抑制剂的配制和给药技术可参见本领域普通技术人员的熟知参考文献,例如Remington的“The Science and Practice of Pharmacy(《药物科学与实践》)”第21版,Lippincott Williams&Wilkins,2005。
合适的给药途径可以包括,例如口腔、直肠或肠内给予;胃肠外递送,包括静脉内、肌肉内、腹膜内、皮下或髓内注射,以及鞘内、直接心室内或眼内注射;局部递送,包括滴眼剂和透皮剂;以及鼻内和其它跨黏膜递送。
或者,可以局部而不是系统方式对个体给予EZH2抑制剂,例如,通过将所述EZH2抑制剂直接注射进入水肿位点,所述EZH2抑制剂通常是长效或持续释放制剂。
在一个实施方式中,通过直接注射入肿瘤或淋巴结来给予EZH2抑制剂。
此外,可以通过靶向药物递送系统,例如在包被有癌细胞特异性抗体的脂质体内,给予EZH2抑制剂。
例如,可通过常规的混合、溶解、造粒、制造糖衣丸、水飞、乳化、封装、包封或冻干工艺制造本发明的药物组合物。
因此,本发明使用的药物组合物可以使用一种或多种生理上可接受的运载体以传统方式配制,所述运载体包含有利于加工所述活性EZH2抑制剂成为药学上可用制品的赋形剂和助剂。适当的制剂依赖于所选的给药途径。
就注射而言,本发明的试剂可配制在水溶液中,优选生理相容性缓冲液,如汉克斯(Hank’s)溶液、林格(Ringer’s)溶液或生理盐水缓冲液。就经粘膜给药而言,在适合于待渗透屏障的制剂中采用渗透剂。本领域通常已知此类渗透剂。
对于口腔给药,通过合并所述活性EZH2抑制剂与本领域熟知的药学上可接受的载体可以容易地配制所述EZH2抑制剂。此类载体使本发明的EZH2抑制剂能配制为片剂、丸剂、糖衣丸、胶囊、液体、凝胶剂、糖浆、浆液、混悬剂等,以供待治疗的患者口服摄取。可通过以下方法获得口服用途的药物制剂:合并所述活性EZH2抑制剂与固体赋形剂,任选研磨所得混合物,需要时在加入合适的辅助剂后加工颗粒混合物,获得片剂或糖衣丸芯。合适的赋形剂包括填充剂如糖,包括乳糖、蔗糖、甘露醇或山梨醇;纤维素制品例如玉米淀粉、小麦淀粉、水稻淀粉、马铃薯淀粉、明胶、黄蓍胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮(PVP)。如果需要,可加入崩解剂,例如交联聚乙烯吡咯烷酮、琼脂、或藻酸或其盐如藻酸钠。
糖衣丸芯具有合适包衣。出于此目的,可使用浓缩糖溶液,其可选地含有阿拉伯胶、滑石粉、聚乙烯吡咯烷酮、卡波姆凝胶、聚乙二醇和/或二氧化钛、漆溶液和合适的有机溶剂或溶剂混合物。可将染料或颜料加入片剂或糖衣丸包衣中,用于标识或表征活性EZH2抑制剂剂量的不同组合。
可口服使用的药物制剂包括明胶制成的推入式胶囊,以及明胶和增塑剂(如甘油或山梨糖醇)制成的密封软胶囊。推入式胶囊可含有活性成分,该活性成分可混合填充剂如乳糖、粘合剂如淀粉和/或润滑剂如滑石粉或硬脂酸镁以及任选的稳定剂。在软胶囊中,活性EZH2抑制剂可溶解或悬浮于合适液体如脂肪油、液体石蜡或液体聚乙二醇中。此外,可加入稳定剂。
就含服给药而言,该组合物可采用常规方式配制的片剂或锭剂形式。
就吸入给药而言,使用合适推进剂(如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它合适的气体)从加压包装或喷雾器中以气溶胶喷雾形式方便地递送根据本发明使用的EZH2抑制剂。在加压气溶胶的情况下,可通过提供阀门递送计量用量,来确定剂量单位。用于吸入或吹入器的胶囊和药筒(例如,明胶)可配制成含有EZH2抑制剂和合适粉末基料如乳糖或淀粉的粉末混合物。
可以配制通过注射,如推注或连续输注进行胃肠外给药的EZH2抑制剂。用于注射的制剂可以单位剂型存在,例如装在安瓿或多剂量容器中,其添加有防腐剂。这些组合物可采取的形式诸如含悬浮剂、溶液剂或油性或水性载剂中的乳液,并且可含有配制剂,例如助悬剂、稳定剂和/或分散剂。
用于肠胃外给药的药物制剂包括水溶性形式的活性EZH2抑制剂的水溶液。此外,活性EZH2抑制剂的悬液可制备为合适的油性注射悬液。合适的亲脂性溶剂或载剂包括脂肪油如芝麻油,或合成的脂肪酸酯,例如油酸乙酯或甘油三酯,或脂质体。水性注射悬液可包含增加悬液粘度的物质,如羧甲基纤维素钠、山梨糖醇或右旋糖苷。悬液可选还包含合适的稳定剂或增加EZH2抑制剂溶解度以制备高浓缩溶液的试剂。
或者,活性成分可以是供使用前用合适的载剂(如无菌无热原的水)重建的粉末形式。
所述EZH2抑制剂也可配制成直肠组合物,例如栓剂或滞留灌肠剂,例如含有常规栓剂基料,如可可油或其他甘油酯。
除了前述制剂外,所述EZH2抑制剂也可配制成长效制剂。这种长效制剂可通过植入(例如,皮下或肌肉内或肌肉内注射)给药。因此,例如,所述EZH2抑制剂也可用合适的聚合物材料或疏水材料(例如,可接受油中的乳剂)或离子交换树脂配制,或者作为微溶性衍生物(例如,微溶性盐)。
或者,可以使用用于疏水药物EZH2抑制剂的其它递送系统。脂质体和乳剂是用于疏水药物的递送载剂或载体示例。还可以使用某些有机溶剂例如二甲亚砜。另外,可以使用持续释放系统例如包含所述治疗剂的固体疏水聚合物的半透性基质来递送所述EZH2抑制剂。许多持续释放材料已经建立且为本领域技术人员熟知。持续释放胶囊可根据其化学性质释放所述EZH2抑制剂数周,至多超过100天。取决于所述治疗试剂的化学性质和生物稳定性,可使用额外的蛋白质稳定策略。
药物组合物还可包含合适的固体或凝胶相载体或赋形剂。所述载体或赋形剂的例子包括但不限于:碳酸钙、磷酸钙、各种糖、淀粉、纤维素衍生物、明胶和聚合物如聚乙二醇。
治疗方法和用途
本文提供治疗、预防或减轻病症和疾病(例如癌症和癌前病症)的方法,所述病症和疾病的进程可受到调节组蛋白或其它蛋白的甲基化状态的影响,其中,所述甲基化状态至少部分由EZH2活性介导。所述组蛋白甲基化状态的调节能进而影响由甲基化激活的靶基因和/或由甲基化抑制的靶基因的表达水平。
例如,本发明的一方面涉及治疗或减轻癌症或癌前病症的症状的方法和用途,包括向患有癌症或癌前病症并表达野生型和/或突变型EZH2的对象给予治疗有效量的EZH2抑制剂的步骤。优选地,本发明所述的EZH2抑制剂能够治疗患有癌症或癌前病症并表达野生型和/或Y641F突变型EZH2的对象。
在一个实施方式中,所述抑制剂抑制Y641F突变型EZH2的组蛋白甲基转移酶活性。在一个实施方式中,所述抑制剂选择性抑制Y641F突变型EZH2的组蛋白甲基转移酶活性。优选地,所述癌症是选自非霍奇金氏淋巴瘤、滤泡性淋巴瘤或弥散性大B细胞淋巴瘤(DLBCL)的淋巴瘤。或者,所述癌症是白血病(例如CML)或黑素瘤。所述癌前病症包括但不限于骨髓增生异常综合征。
疾病诸如癌症可通过给予蛋白(例如组蛋白)甲基化调节剂来治疗,所述调节剂是例如组蛋白甲基转移酶调节剂或组蛋白去甲基化酶活性调节剂。已报道组蛋白甲基化参与癌症中某些基因的异常表达和非神经元细胞中神经元基因的沉默。本文所述的调节剂能用于治疗这些疾病,即,抑制受影响细胞中的组蛋白甲基化。
已发现异常的组蛋白甲基化与某些癌症或癌前病症相关联,至少基于这个事实,治疗对象中具有野生型和/或突变型EZH2的癌症或癌前病症的方法包括向有需要的对象给予治疗有效量的化合物,所述化合物抑制甲基化或恢复其甲基化水平到大致对应正常细胞中的水平。在一个实施方式中,用于治疗对象内癌症或癌前病症的方法包括向有需要的对象给予治疗有效量的化合物,所述化合物抑制未甲基化H3-K27向单甲基化H3-K27(H3-K27mel)转换。在一个实施方式中,用于治疗对象内癌症或癌前病症的方法包括向有需要的对象给予治疗有效量的化合物,所述化合物抑制单甲基化H3-K27(H3-K27mel)向二甲基化H3-K27(H3-K27me2)转换。在一个实施方式中,用于治疗对象内癌症或癌前病症的方法包括向有需要的对象给予治疗有效量的化合物,所述化合物抑制H3-K27me2向三甲基化H3-K27(H3-K27me3)转换。在一个实施方式中,用于治疗对象内癌症或癌前病症的方法包括向有需要的对象给予治疗有效量的化合物,所述化合物抑制H3-K27me1向H3-K27me2的转换以及H3-K27me2向H30K27me3的转换。重要的是要注意,甲基化的疾病特异性增加会出现在染色质中关键基因座处,而组蛋白或蛋白质甲基化在细胞水平没有全面增加。例如,在全组蛋白或蛋白的低甲基化背景下,可能在关键疾病相关基因处出现异常高甲基化。
通常可以使用甲基化调节剂来调节细胞增殖。例如,在一些情况下,可以采用减少甲基化的试剂来降低过度增殖,而增殖不足可采用增加甲基化的试剂进行刺激。因此,可治疗的疾病包括过度增殖疾病,例如良性细胞生长和恶性细胞生长(癌症)。
可治疗的示例性癌症包括淋巴瘤,包括但不限于非霍奇金氏淋巴瘤、滤泡性淋巴瘤(FL)和弥散性大B细胞淋巴瘤(DLBCL);黑素瘤;和白血病,包括但不限于CML。示例性癌前病症包括骨髓增生异常综合征。
其它癌症包括急性淋巴细胞白血病、急性髓细胞白血病、肾上腺皮质癌、艾滋病相关癌症、艾滋病相关淋巴瘤、肛门癌、(儿童小脑)星形细胞瘤、(儿童脑)星形细胞瘤、基底细胞癌(参见皮肤癌(非黑素瘤))、肝外胆管癌、膀胱癌、(骨肉瘤/恶性纤维组织细胞瘤)骨癌、脑干胶质瘤、脑瘤、(小脑星形细胞瘤)脑瘤、(大脑星形细胞瘤/恶性胶质瘤)脑瘤、(脑室膜瘤)脑瘤、(成神经管细胞瘤)脑瘤、(幕上原始神经外胚层肿瘤)脑瘤、(视觉通路和下丘脑胶质瘤)脑瘤、乳腺癌、支气管腺瘤/类癌瘤、伯基特氏淋巴瘤、类癌瘤、(胃肠)类癌瘤、未知原发癌、(原发)中枢神经系统淋巴瘤、小脑星形细胞瘤、子宫颈癌、儿童癌症、慢性淋巴细胞白血病、慢性髓细胞性白血病、(毛细胞)慢性髓细胞性白血病、慢性骨髓/外骨髓增殖性疾病、结肠癌、结肠直肠癌、皮肤T淋巴细胞瘤(参见蕈样肉芽肿和塞扎里(Sezary)综合症)、子宫内膜癌、食道癌、尤文氏(Ewing’s)家族肿瘤、肝外胆管癌、(眼内黑素瘤)眼癌、(成视网膜细胞瘤)眼癌、胆囊癌、胃部(胃)癌、胃肠道类癌瘤、(颅外)生殖细胞瘤、(性腺外)生殖细胞瘤、(卵巢)生殖细胞瘤、妊娠性滋养层细胞瘤、神经胶质瘤、(儿童脑干)神经胶质瘤、(儿童脑星形细胞瘤)神经胶质瘤、(儿童视觉通路和下丘脑)神经胶质瘤、多毛细胞白血病、头颈癌、(成人(原发))肝细胞(肝)癌、(儿童(原发))肝细胞(肝)癌、霍奇金(Hodgkin’s)淋巴瘤、孕期霍奇金(Hodgkin’s)淋巴瘤、下咽癌、下丘脑和视神经胶质瘤、眼内黑素瘤、胰岛细胞癌(内分泌胰腺)、卡波济(Kaposi’s)肉瘤、肾(肾细胞)癌、肾癌、喉癌、血癌、唇和口腔癌、(成人(原发))肝癌、(儿童(原发))肝癌、非小细胞肺癌、小细胞肺癌、(中枢神经系统原发)淋巴瘤、(瓦氏(Waldenstrom’s))巨球蛋白血症、骨/骨肉瘤恶性纤维组织细胞瘤、成神经管细胞瘤、(恶性)黑素瘤、梅克尔(Merkel)细胞癌、间皮瘤、成人恶性间皮瘤、隐匿原发转移性鳞状宫颈癌、多发性内分泌肿瘤综合症、多发性骨髓瘤、多发性骨髓瘤/浆细胞恶性蕈样肉芽肿、骨髓增生异常综合症、骨髓增生异常/骨髓增生性疾病、成人急性髓细胞白血病、儿童急性髓细胞白血病、慢性骨髓增生性疾病、鼻腔和鼻旁窦癌、鼻咽癌、成神经细胞瘤、非霍奇金淋巴瘤、孕期非霍奇金淋巴瘤、口腔癌、(唇和口咽癌)口腔癌、骨肉瘤/骨恶性纤维组织细胞瘤、卵巢癌、卵巢上皮性癌、卵巢低恶性潜能瘤、胰腺癌、胰岛细胞胰腺癌、鼻旁窦和鼻腔癌、甲状旁腺癌、阴茎癌、嗜铬细胞瘤、松果体母细胞瘤和幕上原发神经外胚层瘤、垂体瘤、浆细胞恶性瘤和多发性骨髓瘤、胸膜肺母细胞瘤、妊娠和乳癌、前列腺癌、直肠癌、(遗传性)眼癌、横纹肌肉瘤、唾液腺癌、(尤文氏肿瘤家族)肉瘤、软组织肉瘤、子宫肉瘤、塞扎里(Sezary)综合症、皮肤癌、皮肤癌(非黑素瘤)、小肠癌、软组织肉瘤、鳞状细胞癌(参见皮肤癌(非黑素瘤))、转移性隐匿原发鳞状宫颈癌、睾丸癌、胸腺瘤、胸腺瘤和胸腺癌、甲状腺癌、肾盂和输尿管移行细胞癌、妊娠期滋养叶瘤、未知原发位置的癌、儿童罕见癌症、尿道癌、子宫内膜子宫癌、子宫肉瘤、阴道癌、视觉通路和下丘脑胶质瘤、外阴癌、瓦氏(Waldenstrom’s)巨球蛋白血症、维尔姆斯(Wilms’)瘤、以及女性癌症。
联合治疗
本发明的一个方面中,EZH2抑制剂或其药学上可接受的盐能与其它治疗剂联用来治疗疾病例如癌症。例如,所述其它治疗剂可以是本领域公认有助于治疗由本发明化合物治疗的疾病或病症的治疗剂。
本发明考虑的联合治疗包括,例如以单一药剂的形式给予本发明化合物或其药学上可接受盐和一种或多种其它试剂,以及以分开药剂的形式给予本发明化合物或其药学上可接受盐和一种或多种其它试剂。换言之,共给予应意味着向对象给予至少两种试剂,以提供两种试剂组合的有益作用。例如,这些试剂可以同时给予或在一段时间内依序给予。
以下列出的试剂是用于说明目的,而非意在限定。作为本发明一部分的所述组合可以是本发明的化合物和选自以下列表的至少一种其他试剂。所述组合还可以包括多于一种其它试剂,例如,两种或三种其它试剂,条件是所述组合使所形成的组合物能够行使其预期功能。
例如,本发明的一个方面涉及EZH2抑制剂与其它试剂在治疗癌症中的联用。在一个实施方式中,其他试剂是抗癌剂,所述抗癌剂是影响组蛋白修饰的化合物,例如HDAC抑制剂。在某些实施方式中,额外的抗癌剂选自化疗剂(例如2CdA、5-FU、6-巯基嘌呤、6-TG、AbraxaneTM、放线菌素D、全反式视黄酸、氨甲蝶呤、Ara-C、阿扎胞苷(Azacitadine)、BCNU、氯法拉滨(Clofarabine)、ClolarTM、盐酸柔红霉素、DIC、磷酸依托泊苷、六甲三聚氰胺、伊沙匹隆(ixabepilone)、左旋天门冬酰胺酶(L-asparaginase)、脂质体Ara-C、L-PAM、Lysodren、光辉霉素(mithracin)、丝裂霉素C、尼洛替尼(nilotinib)、氮芥、有卡氯芥植入的prolifeprospan 20、TESPA、VidazaTM、硫酸醛基长春碱、和VM 26);生物制剂(诸如α干扰素、卡介苗、厄洛替尼(Erlotinib)、白细胞介素-2、来那度胺(lenalidomide)、TarcevaTM、和ZevalinTM);皮质类固醇(诸如地塞美松磷酸钠);激素治疗剂(诸如PlenaxisTM);放射性药剂(诸如钐SM-153);以及前文“药物组合物”章节所列举的其它治疗剂。
剂量
本文所用的“治疗有效量”或“治疗有效剂量”是完全或部分抑制病症发展或至少部分减轻一种或多种病症症状的EZH2抑制剂或两种或更多所述化合物组合的量。治疗有效量还可以是预防上有效的量。治疗有效的量取决于患者的体型和性别、待治疗病症、所述病症的严重性和寻求的结果。在一个实施方式中,治疗有效剂量指引起患者内症状改善的EZH2抑制剂的量。对于给定的患者,治疗有效量可以通过本领域技术人员已知的方法确定。
EZH2的毒性和治疗效力可以通过标准药学程序在细胞培养物或实验动物内测定,例如,用于测定最大耐受剂量(MTD)和ED50(引起50%最大响应的有效剂量)。毒性和疗效间的剂量比是治疗指数,可表示为MTD和ED50之比。获自这些细胞培养实验和动物研究的数据可用于配制一定范围的剂量以用于人体。还可以通过监测EZH2抑制剂对患病或替代组织的酶抑药效标志物(例如,组蛋白甲基化或靶基因表达)的影响来指导剂量。可以使用细胞培养或动物实验来测定药效标志物变化所需剂量和治疗效力所需剂量之间的关系,可在细胞培养或动物实验或早期临床试验中予以测定。这类EZH2抑制剂的剂量优选处于包括ED50在内的循环浓度范围内,毒性很小或无毒性。该剂量可根据所用的剂型和所用的给药途径在此范围内变化。确切的制剂、给药途径和剂量可以由单独医师根据患者的病症而选择。在危重症治疗中,可能需要使用急性推注或近似MTD的输注给药以获得快速响应。
可以根据个体调整剂量和间隔,从而提供充足的活性部分血浆水平以维持所述甲基转移酶调节效果或所需时段的最小有效浓度(MEC)以达到治疗功效。所述MEC随各EZH2抑制剂而不同,但可由体外数据和动物实验来估计。达到所述MEC必需的剂量将取决于个体特点和给药途径。然而,可以使用高压液相色谱(HPLC)分析或生物测定来检测血浆浓度。
还可使用MEC值来确定剂量间隔。在某些实施方式中,给予EZH2抑制剂所用的方案使血浆水平在所述时间的10-90%,优选为30-90%,最优选50-90%保持在MEC之上直至达到所需的症状改善。在其它实施方式中,不同的MEC血浆水平将维持不同的时间量。在局部给药或选择性摄取的情况下,药物的局部有效浓度可能与血浆浓度无关。
本领域技术人员可以从众多给药方案中选择,而给予的EZH2抑制剂的量当然取决于接受治疗的患者、所述对象的体重、病痛的严重度、给药的方式和处方医师的判断。但是,根据特定的周围情况,包括例如已采用的具体药物、给药途径、治疗的病症、以及治疗的受治疗者或宿主,施用剂量可由本领域已知的方法常规决定。通常,就成人治疗使用的剂量而言,施用剂量典型地在0.02-5000mg/天,例如约1-1500mg/天的范围。该所需剂量可以方便地被表现为一剂、或同时给药的(或在短时间内)或在适当的间隔的分剂量,例如每天二、三、四剂或更多分剂。本领域技术人员可以理解的是,尽管给出了上述剂量范围,但具体的有效量可根据患者的情况并结合医师诊断而适当调节。
试剂盒
如果需要,EZH2抑制剂可存在于试剂盒(例如包装或分配装置)中,所述试剂盒可包含一个或多个含有所述EZH2抑制剂的单位剂型。例如,该包装可包括金属或塑料薄片,如泡罩包装。所述包装或分配装置可附有给药说明书。还可以制备配制在相容性药物运载体内的包含本发明EZH2抑制剂的组合物,放置在合适的容器内,并就治疗所示病症进行标记。还可以提供使用说明书。
本文还提供包含检测所述甲基化H3-K27的多种甲基化检测试剂的试剂盒。例如,所述试剂盒包括单甲基化H3-K27、二甲基化H3-K27和三甲基化H3-K27检测试剂。所述检测试剂是例如抗体或其片段、多肽或适体。
所述试剂盒可以在单独容器内包含适体或抗体,对照制剂(阳性和/或阴性),和/或可检测的标签例如荧光素、绿色荧光蛋白、罗丹明、花青染料、Alexa染料、萤光素酶、放射性标记等等。完成所述试验的说明书(如书面、磁带、VCR、CD-ROM等)可包含在试剂盒中。所述分析可以采用例如本领域已知的以下形式:Western印迹分析、免疫组化(IHC)、免疫荧光(IF)、测序和质谱(MS)。
化合物的制备
使用本领域技术人员已知的标准合成技术或使用本领域已知的方法与本文描述的方法组合,可以合成本发明的化合物。另外,本文给出的溶剂、温度和其它反应条件可以根据本领域技术而改变。作为进一步的指导,也可以利用以下的合成方法。
本发明的合成过程可允许多种官能团,因此可使用多种被取代的起始材料。所述过程一般在总体过程结束或接近结束时提供所需最终化合物,尽管在某些例子中希望将所得化合物进一步转换成药学上可接受的盐、酯或其药物前体。
可使用市售可得的起始材料、文献中已知的化合物或由易制备的中间体,通过采用本领域技术人员已知的标准合成方法和过程或技术员按本文指导显而易见的合成方法和过程,通过不同方式制备本发明的化合物。用于有机分子制备和官能团转化与操控的标准合成方法和过程可获自相关科学文献或获自本领域的标准教材。尽管不限于任何一个或多个来源,经典教科书例如Smith,M.B.,March,J.,March’s Advanced OrganicChemistry:Reactions,Mechanisms,and Structure,第五版,John Wiley&Sons,2001;和Greene,T.W.,Wuts,P.G.M.,Protective Groups in Organic Synthesis,第三版,JohnWiley&Sons,1999,是有用且公认的本领域技术人员已知的关于有机合成的参考教科书。以下合成方法的描述旨在说明而非限制制备本发明化合物的一般方法。本发明的化合物可通过本领域技术人员熟悉的不同方法而方便地制备。具有本文所述各式的本发明的化合物可根据如下方法由市售可得的起始物质或可采用文献方法制备的起始物质制备。这些方法显示本发明代表性化合物的制备。
如果需要,反应产物可以使用常规技术分离和纯化,包括但不限于过滤、蒸馏、结晶、色谱等方法。这些产物可以使用常规方法表征,包括物理常数和图谱数据。
通过上述方法设计、选择和/或最优化的化合物一旦生成,即可用本领域技术人员已知的多种实验表征以确定所述化合物是否具有生物活性。例如,所得分子可通过传统实验表征以确定其是否具有预测活性、结合活性和/或结合特异性,所述传统实验包括但不限于下文所述的那些。
此外,可使用高通量筛选来加速所用实验的分析。因此,使用本领域已知的技术能够快速筛选本文所述分子的活性。用于进行高通量筛选的一般方法论已有描述,例如,Devlin(1998)High Throughput Screening,Marcel Dekker;和美国专利号5,763,263。高通量实验可使用一种或多种不同的实验技术,包括但不限于下文所述的那些。
实施例
现已总体描述了本发明,参考以下实施例更易于理解本发明,这些实施例只是用于说明本发明的某些方面的实施方式,而非意在限制本发明。
实施例1
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(6-(4-(二甲基氨基)哌啶-1-基)吡啶-3-基)-3-(N-乙基环丙烷甲酰胺基)-2-甲基苯甲酰胺1
化合物b的合成:
将化合物a 3-氨基-5-溴-2-甲基苯甲酸甲酯(5g,1.0eq)和乙酸(3.51ml,3.0eq)加入甲醇(30ml)中,在冰浴条件下加入乙醛(1.26ml,1.1eq),常温搅拌2小时之后在冰浴条件下加入氰基硼氢化钠(2.57g,2.0eq),搅拌1小时后,加入饱和碳酸氢钠直至无气泡为止,浓缩后用乙酸乙酯和水稀释,有机层依次水洗(3x30ml),饱和食盐水洗(30ml),无水硫酸钠干燥,浓缩后柱层析得固体b(3.8g)。
化合物c的合成:
将化合物b 5-溴-3-(乙氨基)-2-甲基苯甲酸甲酯(3g,1.0eq)和三乙胺(12ml,8.0eq)加入二氯甲烷(30ml),在冰浴条件下加入环丙基甲酰氯(4ml,4.0eq),常温搅拌10分钟。加入饱和碳酸氢钠淬灭,直接萃取,有机层用饱和碳酸氢钠洗(3x30ml),饱和食盐水洗(30ml),无水硫酸钠干燥,浓缩后柱层析得固体c(3.1g)。
化合物d的合成:
将化合物c 5-溴-3-(N-乙基环丙烷甲酰胺基)-2-甲基苯甲酸甲酯(3g,1.0eq)、联硼酸频哪醇酯(4.5g,2.0)、乙酸钾(2.4g,2.5eq)、和Pd(dppf)Cl2(0.36g,0.05eq)混合加入1,4-二氧六环(20ml),于氮气保护下100℃搅拌过夜,后浓缩柱层析得固体d(2.7g)。
化合物i的合成:
将化合物2,5-二溴吡啶(200mg,1.0eq)、N,N-二甲基哌啶-4-胺(160mg,1.1eq)和碳酸钾(470mg,3.0eq)混合加入DMSO(10ml)中,于氮气保护下100℃搅拌过夜,用水稀释,乙酸乙酯萃取,有机相用水洗3次,饱和食盐水洗,无水硫酸钠干燥得固体i(300mg)。无需进一步提纯。
化合物e的合成:
将化合物d 3-(N-乙基环丙烷甲酰胺基)-2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯甲酸甲酯(100mg,1eq)、化合物i 1-(5-溴吡啶-2-基)-N,N-二甲基哌啶-4-胺(73mg,1.0eq)、Pd(PPh3)4(15mg,0.05eq)和碳酸钾(53mg,1.5eq)混合加入1,4-二氧六环/水(5ml/0.5ml),于氮气保护下110℃搅拌过夜,后浓缩柱层析得固体e(85mg)。
化合物f的合成:
将化合物e 5-(6-(4-(二甲基氨基)哌啶-1-基)吡啶-3-基)-3-(N-乙基环丙烷甲酰胺基)-2-甲基苯甲酸甲酯(80mg,1.0eq)和氢氧化锂(39mg,10eq)混合溶于甲醇/水(10ml/3ml),在室温条件下搅拌2小时,用1M的HCl调pH至6,浓缩后,加水稀释,用正丁醇萃取2次,干燥后浓缩得产物f(60mg),无需进一步纯化。
化合物g的合成:
将3-氧代丁腈(5.04,1.05eq)和叔丁醇钾(7g,1.05eq)混合加入DMSO(80ml)中,常温搅拌10分钟,加入(E)-3-戊烯-2-酮(5g,1eq),常温搅拌半小时,再加叔丁醇钾(7g,1.05eq),1小时之后通空气搅拌过夜。反应液冷却至0℃,加入20ml水稀释,滴加4N HCl(15ml),搅拌15分钟,过滤得固体,用100ml水洗得到产物g(3.8g),无需进一步提纯。
化合物h的合成:
将化合物g 4,6-二甲基-2-氧代-1,2-二氢吡啶-3-腈(3g,1.0eq)和适量的雷尼镍加入到甲醇(50ml)中,再加入饱和氨水(25ml),在含氢气的条件下反应24小时,过滤,浓缩,结晶得2.0g产物h。
化合物1的合成:
将化合物f 5-(6-(4-(二甲基氨基)哌啶-1-基)吡啶-3-基)-3-(N-乙基环丙烷甲酰胺基)-2-甲基苯甲酸(25mg,1.0eq)溶于DMF(3ml),先后加入DIPEA(0.029ml,3eq)、HATU(32mg,1.5eq)、化合物h 3-(氨甲基)-4,6-二甲基吡啶-2(1H)-酮(9.3mg,1.1eq),在室温下搅拌1小时,加水稀释,用乙酸乙酯萃取,有机相用水洗3遍,饱和食盐水洗,无水硫酸钠干燥,浓缩后柱层析得固体产物1(15mg)。
质谱数据:LC-MS(ESI,m/z):585.3542[M+H]+。
实施例2
5-(6-(4-(二甲基氨基)哌啶-1-基)吡啶-3-基)-3-(N-乙基环丙烷甲酰胺基)-2-甲基-N-((6-甲基-2-氧代4-丙基-1,2-二氢吡啶-3-基)甲基)苯甲酰胺2
化合物2的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):613.3854[M+H]+。
实施例3
5-(6-(4-(环丙基甲基)哌嗪-1-基)吡啶-3-基)-N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-3-(N-乙基环丙烷甲酰胺基)-2-甲基苯甲酰胺3
化合物3的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):597.3545[M+H]+。
实施例4
5-(6-(4-(环丙基甲基)哌嗪-1-基)吡啶-3-基)-3-(N-乙基环丙烷甲酰胺基)-2-甲基-N-((6-甲基-2-氧代-4-丙基-1,2-二氢吡啶-3-基)甲基)苯甲酰胺4
化合物4的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):625.3849[M+H]+。
实施例5
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环丙烷甲酰胺基)-4-甲基-4’-(吗啉甲基)-[1,1’-二苯基]-3-甲酰胺5
化合物5的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):557.3132[M+H]+。
实施例6
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环丙烷甲酰胺基)-4-甲基-4’-吗啉-[1,1’-二苯基]-3-甲酰胺6
化合物6的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):543.2960[M+H]+。
实施例7
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-3-(N-乙基环丙烷甲酰胺基)-2-甲基-5-(6-吗啉吡啶-3-基)苯甲酰胺7
化合物7的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):544.2910[M+H]+。
实施例8
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环丙烷甲酰胺基)-4’-(4-乙基哌嗪-1-基)-4-甲基-[1,1’-二苯基]-3-甲酰胺8
化合物8的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):570.3422[M+H]+。
实施例9
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-3-(N-乙基环丙烷甲酰胺基)-2-甲基-5-(6-(4-甲基哌嗪-1-基)吡啶-3-基)苯甲酰胺9
化合物9的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):557.3251[M+H]+。
实施例10
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-3-(N-乙基环丙烷甲酰胺基)-5-(6-(4-异丙基哌嗪-1-基)吡啶-3-基)-2-甲基苯甲酰胺10
化合物10的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):585.3542[M+H]+。
实施例11
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-4’-((4-(二甲基氨基)哌啶-1-基)甲基)-5-(N-乙基环丙烷甲酰胺基)-4-甲基-[1,1’-二苯基]-3-甲酰胺11
化合物11的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):598.3772[M+H]+。
实施例12
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(6-((2-(二甲基氨基)乙基)(甲基)氨基)吡啶-3-基)-3-(N-乙基环丙烷甲酰胺基)-2-甲基苯甲酰胺12
化合物12的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):559.3390[M+H]+。
实施例13
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-3-(N-乙基环丙烷甲酰胺基)-2-甲基-5-((2-吗啉乙基)氨基)-苯甲酰胺13
化合物13的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):510.3058[M+H]+。
实施例14
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(6-(4-(二甲基氨基)哌啶-1-基)吡啶-3-基)-3-(N-乙基环戊烷甲酰胺基)-2-甲基苯甲酰胺14
化合物14的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):613.3864[M+H]+。
实施例15
5-(6-(4-(环丙基甲基)哌嗪-1-基)吡啶-3-基)-N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-3-(N-乙基环戊烷甲酰胺基)-2-甲基苯甲酰胺15
化合物15的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):625.3862[M+H]+。
实施例16
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-4-甲基-4’-(吗啉甲基)-[1,1’-二苯基]-3-甲酰胺16
化合物16的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):585.3430[M+H]+。
实施例17
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-3-(N-乙基环戊烷甲酰胺基)-2-甲基-5-(2-(4-甲基哌嗪-1-基)吡啶-4-基)苯甲酰胺17
化合物17的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):585.3550[M+H]+。
实施例18
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-3-(N-乙基环戊烷甲酰胺基)-5-(6-(4-异丙基哌嗪-1-基)吡啶-3-基)-2-甲基苯甲酰胺18
化合物18的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):613.3860[M+H]+。
实施例19
4’-氰基-N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-3’-氟-4-甲基-[1,1’-二苯基]-3-甲酰胺19
化合物19的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):529.2605[M+H]+。
实施例20
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-4-甲基-4’-(吗啉-4-羰基)-[1,1’-二苯基]-3-甲酰胺20
化合物20的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):599.3240[M+H]+。
实施例21
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-4-甲基-4’-吗啉-[1,1’-二苯基]-3-甲酰胺21
化合物21的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):571.3275[M+H]+。
实施例22
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-4-甲基-4’-(2-吗啉-2-氧乙基)-[1,1’-二苯基]-3-甲酰胺22
化合物22的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):613.3375[M+H]+。
实施例23
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-4’-((4-乙基哌嗪-1-基)甲基)-4-甲基-[1,1’-二苯基]-3-甲酰胺23
化合物23的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):612.3901[M+H]+。
实施例24
叔丁基-4-((3’-(((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)氨甲酰基)-5’-(N-乙基环戊烷甲酰胺基)-4’-甲基-[1,1’-二苯基]-4-基)甲基)哌嗪-1-甲酸酯24
化合物24的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):684.4105[M+H]+。
实施例25
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-4-甲基-4’-((4-哌嗪-1-基)甲基)-4-甲基-[1,1’-二苯基]-3-甲酰胺25
化合物25的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):584.3601[M+H]+。
实施例26
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-4-甲基-4’-(丙-2-基磺酰胺基)-[1,1’-二苯基]-3-甲酰胺26
化合物26的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):607.2960[M+H]+。
实施例27
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-4’-(4-乙基哌嗪-1-基)-4-甲基-[1,1’-二苯基]-3-甲酰胺27
化合物27的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):598.3750[M+H]+。
实施例28
4’-(环丙烷磺酰胺基)-N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-4-甲基-[1,1’-二苯基]-3-甲酰胺28
化合物28的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):605.2801[M+H]+。
实施例29
叔丁基-4-(5-(3-(((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)氨甲酰基)-5-(N-乙基环戊烷甲酰胺基)-4-甲基苯基)吡啶-2-基)哌嗪-1-甲酸酯29
化合物29的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):671.3911[M+H]+。
实施例30
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-4-甲基-4’-(3-吗啉丙氧基)-[1,1’-二苯基]-3-甲酰胺30
化合物30的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):629.3720[M+H]+。
实施例31
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-4-甲基-4’-(哌嗪-1-基)-[1,1’-二苯基]-3-甲酰胺31
化合物31的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):570.3438[M+H]+。
实施例32
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-3-(N-乙基环戊烷甲酰胺基)-2-甲基-5-(6-(哌嗪-1-基)吡啶-3-基)-苯甲酰胺32
化合物32的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):571.3405[M+H]+。
实施例33
5-氰基-N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-3-(N-乙基环戊烷甲酰胺基)-2-甲基苯甲酰胺33
化合物33的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):435.2388[M+H]+。
实施例34
N1-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-6-甲基-间苯二甲酰胺34
化合物34的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):453.2511[M+H]+。
实施例35
(S)-N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-4’-((2-羟甲基)哌嗪-1-基)甲基)-4-甲基-[1,1’-二苯基]-3-甲酰胺35
化合物35的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):614.3702[M+H]+。
实施例36
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-3-(N-乙基环戊烷甲酰胺基)-2-甲基-5-(6-(4-甲基哌嗪-1-基)吡啶-3-基)苯甲酰胺36
化合物36的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):585.3541[M+H]+。
实施例37
5-(6-(4-氨基哌啶-1-基)吡啶-3-基)-N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-3-(N-乙基环戊烷甲酰胺基)-2-甲基苯甲酰胺37
化合物37的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):585.3540[M+H]+。
实施例38
5-(2-(4-(环丙基甲基)哌嗪-1-基)吡啶-4-基)-N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-3-(N-乙基环戊烷甲酰胺基)-2-甲基苯甲酰胺38
化合物38的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):625.3859[M+H]+。
实施例39
5-(2-(4-(环丙基甲基)哌嗪-1-基)吡啶-4-基)-3-(N-乙基环戊烷甲酰胺基)-2-甲基-N-((6-甲基-2-氧代-4-丙基-1,2-二氢吡啶-3-基)甲基)苯甲酰胺39
化合物39的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):653.4165[M+H]+。
实施例40
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-4-甲基-4’-(2-吗啉乙氧基)-[1,1’-二苯基]-3-甲酰胺40
化合物40的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):615.3550[M+H]+。
实施例41
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-4-甲基-4’-苯氧基-[1,1’-二苯基]-3-甲酰胺41
化合物41的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):578.3008[M+H]+。
实施例42
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-3’-氟-4-甲基-4’-(3-吗啉丙氧基)-[1,1’-二苯基]-3-甲酰胺42
化合物42的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):647.3601[M+H]+。
实施例43
5-(5-乙酰基噻吩-2-基)-N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-3-(N-乙基环戊烷甲酰胺基)-2-甲基苯甲酰胺43
化合物43的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):534.2415[M+H]+。
实施例44
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-2’-氟-4-甲基-4’-(3-吗啉丙氧基)-[1,1’-二苯基]-3-甲酰胺44
化合物44的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):647.3602[M+H]+。
实施例45
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-2’,4-甲基-4’-(3-吗啉丙氧基)-[1,1’-二苯基]-3-甲酰胺45
化合物45的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):643.3855[M+H]+。
实施例46
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-3’,4-甲基-4’-(3-吗啉丙氧基)-[1,1’-二苯基]-3-甲酰胺46
化合物46的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):643.3854[M+H]+。
实施例47
3’-氰基-N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-4-甲基-4’-(2-吗啉乙氧基)-[1,1’-二苯基]-3-甲酰胺47
化合物47的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):640.3503[M+H]+。
实施例48
2’-氯-N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-4-甲基-4’-(2-吗啉乙氧基)-[1,1’-二苯基]-3-甲酰胺48
化合物48的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):649.3172[M+H]+。
实施例49
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-3’-甲氧基-4-甲基-4’-(2-吗啉乙氧基)-[1,1’-二苯基]-3-甲酰胺49
化合物49的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):645.3661[M+H]+。
实施例50
3-(N-(环丙基甲基)环戊烷甲酰胺基)-N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(6-(4-(二甲基氨基)哌啶-1-基)吡啶-3-基)-2-甲基苯甲酰胺50
化合物50的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):639.4018[M+H]+。
实施例51
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-2’-氟-4-甲基-4’-(2-吗啉乙氧基)-[1,1’-二苯基]-3-甲酰胺51
化合物51的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):633.3432[M+H]+。
实施例52
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-3’-氟-4-甲基-4’-(2-吗啉乙氧基)-[1,1’-二苯基]-3-甲酰胺52
化合物52的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):633.3435[M+H]+。
实施例53
N-(5-(((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)氨甲酰基-4-甲基-4’-(吗啉甲基)-[1,1’-二苯基]-N-乙基四氢-2H-吡喃-4-甲酰胺53
化合物53的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):601.3388[M+H]+。
实施例54
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基-3,3-二甲基丁酰胺基)-4-甲基-4’-(吗啉甲基)-[1,1’-二苯基]-3-甲酰胺54
化合物54的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):587.3601[M+H]+。
实施例55
N-(5-(((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)氨甲酰基-4-甲基-4’-(吗啉甲基)-[1,1’-二苯基]-N-乙基呋喃-4-甲酰胺55
化合物55的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):583.2909[M+H]+。
实施例56
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环己基甲酰胺基)-4-甲基-4’-(吗啉甲基)-[1,1’-二苯基]-3-甲酰胺56
化合物56的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):599.3599[M+H]+。
实施例57
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基-4-甲基苯甲酰胺基)-4-甲基-4’-(吗啉甲基)-[1,1’-二苯基]-3-甲酰胺57
化合物57的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):607.3271[M+H]+。
实施例58
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基-2,2-二甲基丁酰胺基)-4-甲基-4’-(吗啉甲基)-[1,1’-二苯基]-3-甲酰胺58
化合物58的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):587.3597[M+H]+。
实施例59
5-(N,2-二乙基丁酰胺基)-N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-4-甲基-4’-(吗啉甲基)-[1,1’-二苯基]-3-甲酰胺59
化合物59的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):587.3600[M+H]+。
实施例60
(1R,4R)-N-(5-(((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)氨甲酰基-4-甲基-4’-(吗啉甲基)-[1,1’-二苯基]-3-基)-N-乙基二环[2.2.1]庚-5-烯-2-甲酰胺60
化合物60的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):609.3429[M+H]+。
实施例61
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环丁烷甲酰胺基)-4-甲基-4’-(吗啉甲基)-[1,1’-二苯基]-3-甲酰胺61
化合物61的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):571.3295[M+H]+。
实施例62
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基异丁酰胺基)-4-甲基-4’-(吗啉甲基)-[1,1’-二苯基]-3-甲酰胺62
化合物62的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):559.3291[M+H]+。
实施例63
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环戊烷甲酰胺基)-2’,4-二甲基-4’-(2-吗啉乙氧基)-[1,1’-二苯基]-3-甲酰胺63
化合物63的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):629.3700[M+H]+。
实施例64
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环丙烷甲酰胺基)-2’,4-二甲基-4’-(3-吗啉丙氧基)-[1,1’-二苯基]-3-甲酰胺64
化合物64的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):615.3441[M+H]+。
实施例65
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环丙烷甲酰胺基)-3’-氟-4-甲基-4’-(3-吗啉丙氧基)-[1,1’-二苯基]-3-甲酰胺65
化合物65的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):619.3301[M+H]+
实施例66
3-(环丙烷甲酰胺基)-N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(6-(4-(二甲基氨基)哌啶-1-基)吡啶-3-基)-2-甲基苯甲酰胺66
化合物66的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):557.3236[M+H]+。
实施例67
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(6-(2-(二甲基氨基)乙基氨基)吡啶-3-基)-3-(N-乙基环丙烷甲酰胺基)-2-甲基苯甲酰67
化合物67的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):545.3245[M+H]+。
实施例68
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-3-(N-乙基环丙烷甲酰胺基)-2-甲基-5-(6-(4-(吡咯-1-基)哌啶-1-基)吡啶-3-基)苯甲酰胺68
化合物68的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):611.3712[M+H]+。
实施例69
5-(6-(4-(环丙基甲基)哌嗪-1-基)-2-甲基吡啶-3-基)-N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-3-(N-乙基环丙烷甲酰胺基)-2-甲基苯甲酰胺69
化合物69的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):611.3709[M+H]+。
实施例70
5-(6-(4-(环丙基甲基)哌嗪-1-基)-5-甲基吡啶-3-基)-N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-3-(N-乙基环丙烷甲酰胺基)-2-甲基苯甲酰胺70
化合物70的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):611.3711[M+H]+。
实施例71
5-(6-(4-(环丙基甲基)哌嗪-1-基)-4-甲基吡啶-3-基)-N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-3-(N-乙基环丙烷甲酰胺基)-2-甲基苯甲酰胺71
化合物71的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):611.3710[M+H]+。
实施例72
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环丙烷甲酰胺基)-3’,4-二甲基-4’-(3-吗啉丙氧基)-[1,1’-二苯基]-3-甲酰胺72
化合物72的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):615.3440[M+H]+。
实施例73
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环丙烷甲酰胺基)-2’-氯-4-甲基-4’-(2-吗啉乙氧基)-[1,1’-二苯基]-3-甲酰胺73
化合物73的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):621.2806[M+H]+。
实施例74
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环丙烷甲酰胺基)-3’-氟-4-甲基-4’-(2-吗啉乙氧基)-[1,1’-二苯基]-3-甲酰胺74
化合物74的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):605.3050[M+H]+。
实施例75
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-(N-乙基环丙烷甲酰胺基)-2’,4-二甲基-4’-(2-吗啉乙氧基)-[1,1’-二苯基]-3-甲酰胺75
化合物75的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):601.3333[M+H]+。
实施例76
5-(6-(4-(环丙基哌嗪-1-基)吡啶-3-基)-N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-3-(N-乙基环丙烷甲酰胺基)-2-甲基苯甲酰胺76
化合物76的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):583.3323[M+H]+。
实施例77
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-3-(N-乙基环丙烷甲酰胺基)-2-甲基-5-(6-(4-甲基高哌嗪-1-基)吡啶-3-基)苯甲酰胺77
化合物77的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):571.3347[M+H]+。
实施例78
5-(6-(4-乙酰基哌嗪-1-基)吡啶-3-基)-N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-3-(N-乙基环丙烷甲酰胺基)-2-甲基苯甲酰胺78
化合物78的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):585.3123[M+H]+。
实施例79
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-3-(N-乙基环丙烷甲酰胺基)-2-甲基-5-(3-吗啉丙基氨基)苯甲酰胺79
化合物79的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):524.3173[M+H]+。
实施例80
N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-((2-(二甲氨基)乙基)(甲基)氨基)-3-(N-乙基环丙烷甲酰胺基)-2-甲基苯甲酰胺80
化合物80的合成通过使用类似于实施例1中所述的步骤完成。
质谱数据:LC-MS(ESI,m/z):482.3061[M+H]+。
实施例81
EZH2小分子筛选体系
EZH2会抑制下游e-钙粘蛋白(E-cadherin)的表达,当EZH2被抑制后,e-钙粘蛋白表达增多。基于此原理,利用荧光素酶构建报告基因表达载体。
报告基因构建方法
从293T细胞(购自美国ATCC,细胞数目约为106)提取基因组DNA(提取试剂盒DNeasy blood&tissue kit,购自美国Qiagen),将得到的基因组DNA作为模板,采用下文记载的引物序列来扩增E-cadherin的启动子序列,将PCR扩增得到的序列以及PGL4.1载体(购自日本TAKARA)分别经SacI和BglII(购自日本TAKARA)酶切后,利用PCR清洁试剂盒进行纯化(Axygen PCR cleanup kit),之后利用连接酶solution I(DNA Ligation Kit Ver.2.1,购自日本TAKARA)将纯化的酶切PCR产物连接到纯化的酶切PGL4.1载体并进行转化,之后进行单克隆筛选及测序,得到的含有Ecadherin启动子片段的阳性质粒命名为E-cadherinRE-PGL4.1。
用于扩增E-cadherin的启动子的引物序列如下:
GGCGAGCTCCTGATCATTATTCCCATTAGGAGGGTG
GGCAGATCTGGCTGGCCGGGGACGCCGAGCGAG
同时构建Renilla荧光载体,以PCDNA4.1(购自美国thermofisher)为模板扩增CMV启动子序列,将扩增得到的CMV序列及pGL4.70载体(购自美国Promega)经KpnI和XhoI(购自美国Promega)酶切后,利用PCR清洁试剂盒进行纯化(Axygen PCR cleanup kit),之后利用连接酶solution I(DNA Ligation Kit Ver.2.1,购自日本TAKARA)将酶切后的PCR产物连接到酶切后的PGL4.70载体上并进行转化,随后进行单克隆筛选及测序,将得到的含有CMV序列的质粒命名为Renilla luciferase-pGL4.70质粒。这个质粒利用CMV启动子高表达Renilla luciferase,将其作为初筛系统的对照荧光。
用于扩增CMV启动子序列的引物序列如下:
GGCGGTACCGTTGACATTGATTATTGACTAGTTATTAATA
GGCCTCGAGGAGCTCTGCTTATATAGACCTCCCA
EZH2的抑制剂会抑制EZH2的活性,从而导致E-cadherin的转录翻译水平升高,在此系统中体现为化学发光数值增高。在本实验中,在室温下将293T细胞(购自美国ATCC)铺板至96孔白板(购自CORNING),每孔细胞数约为1.5×104,铺板12小时后,将50ng提纯的E-cadherin RE-PGL4.0和1ng提纯的Renilla luciferase-pGL4.70质粒与0.15μl转染试剂TransEL(购自Transgen,中国)混合,室温下静置20分钟,将质粒瞬时转染进293T细胞。6小时后,加入待检测的本发明化合物以及GSK126(购自上海皓元化学)处理24小时,利用Luciferase Assay System(购自美国promega)检测试剂盒进行检测,首先加入20μLLuciferase Assay Reagent,室温孵育10分钟,在酶标仪Spectramaxi3(美国Molecular Devices)上进行读数,得到初筛的数据列于表1。对效果相当于或强于GSK126的化合物及其类似结构的化合物进行进一步筛选。
表1
实施例82
EZH2酶活检测体系
利用Cisbio公司的EZH2(Y641F)TR-FRET assay KIT和初筛有活性的化合物进行酶活检测,以GSK126(购自上海皓元化学)和EPZ6438(CAS No.1403254-99-8,购自上海皓元化学)作为对照。
将2μL含有14ng蛋白的PRC2蛋白复合物(包含EZH2(Y641F)突变、EED蛋白、SUZ12蛋白、RbAp48蛋白和AEBP2蛋白,购自美国BPS Bioscience,货号#51017)与4μL 10mM 3倍梯度稀释的本发明化合物分别混合,在384浅孔板中室温孵育5分钟。然后加入反应底物2μL 2.5μM Histone3K27ME1(购自美国AnaSpec,货号#65366)以及2μL 75μM腺苷甲硫氨酸SAM(购自美国sigma,#A7007)进行混合,于室温孵育4小时。之后加入检测抗体5μL H3K27me3-Eu(K)Ab(购自美国cisbio bioassays,#61KC3KAE)及5μL Streptavidin-XL665(购自美国cisbiobioassays,#610SAXLA),室温孵育1小时后在Spectramax i3(美国Molecular Devices)上设定TR-FRET读数模式进行读数,得到波长665nm以及620nm的吸收值数据,计算得到665nm的数据与620nm的数据比值,之后利用graphpad对数据进行分析,拟合小分子的抑制曲线,得到表2的数据。
同时,发明人还用Western Blot的方法在Pfeiffer细胞(购自美国ATCC)上进行了验证。具体步骤是,用不同浓度(0μM、0.01μM、0.1μM、0.3μM、1.11μM、3.33μM、10μM于DMSO中)的本发明化合物以及EZH2抑制剂GSK126、EPZ6438作为对照分别处理携带EZH2基因的Pfeiffer细胞株72小时,收集样品。测定化合物对细胞中的H3K27m3甲基化的影响。
实验表明化合物64和65无论是在细胞上Western Blot验证还是TR-FRET酶活试剂盒中测定的效果均优于对照化合物EPZ6438和GSK126。而化合物5、24、25、63、64、65、69、71和74在TR-FRET试剂盒检测中活性优于对照化合物GSK126和EPZ6438。
表2
Claims (15)
1.一种式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药:
其中,
Y选自氰基、氨酰基、任选被1个R4基团取代的烷基氨基、任选被1-3个独立的R4基团取代的芳基、任选被1-3个独立的R4基团取代的杂芳基、和任选被1-3个独立的R4基团取代的杂环烷基烷基氨基;
R1为烷基;
R2选自氢、烷基和环烷基烷基;
R3选自烷基、环烷基、杂环烷基、杂芳基、烷基芳基、和二环[2.2.1]庚-2-烯基;
R4独立地选自氢、卤素、氰基、烷基、烷氧基、烷酰基、任选被1个R5基团取代的烷基氨基、任选被1个R5基团取代的烷基磺酰胺基、任选被1个R5基团取代的环烷基磺酰胺基、任选被1-3个独立的R5基团取代的杂环烷基、任选被1-3个独立的R5基团取代的杂环烷基羰基、任选被1-3个独立的R5基团取代的杂环烷基烷基、任选被1-3个独立的R5基团取代的杂环烷基烷氧基、任选被1-3个独立的R5基团取代的杂环烷基羰基烷基、和任选被1-3个独立的R5基团取代的芳氧基;
R5独立地选自氨基、烷基、烷酰基、烷基氨基、羟基烷基、环烷基、环烷基烷基、杂环烷基、和氨基保护基。
2.根据权利要求1所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药:
其中Y选自氰基、氨酰基、(2-(二甲基氨基)乙基)(甲基)氨基、苯基、吡啶基、噻吩基、(2-吗啉乙基)氨基、和(3-吗啉丙基)氨基,其中苯基、吡啶基、噻吩基、(2-吗啉乙基)氨基、和(3-吗啉丙基)氨基任选地被1-3个独立的R4基团取代;并且
其中R4独立地选自氟、氯、氰基、甲基、甲氧基、乙酰基、(2-(二甲基氨基)乙基)氨基、(2-(二甲基氨基)乙基)(甲基)氨基、异丙基磺酰胺基、环丙基磺酰胺基、哌啶基、哌嗪基、吗啉基、高哌嗪基、吗啉-4-羰基、吗啉甲基、哌啶甲基、哌嗪甲基、吗啉乙氧基、吗啉丙氧基、吗啉-4-羰基甲基、和苯氧基,其中哌啶基、哌嗪基、吗啉基、高哌嗪基、吗啉-4-羰基、吗啉甲基、哌啶甲基、哌嗪甲基、吗啉乙氧基、吗啉丙氧基、吗啉-4-羰基甲基、和苯氧基任选地被1-3个独立的R5基团取代;并且
其中R5独立地选自氨基、甲基、乙基、异丙基、乙酰基、二甲基氨基、羟甲基、环丙基、环丙基甲基、吡咯基、和叔丁氧羰基。
3.根据权利要求1所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药,其中R1选自甲基、乙基、和丙基;R2选自甲基、乙基、丙基、和环丙基甲基;R3选自异丙基、新戊基、叔戊基、戊-3-基、环丙基、环丁基、环戊基、环己基、四氢吡喃基、呋喃基、甲基苯基、和二环[2.2.1]庚-2-烯基。
4.根据权利要求1所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药,其中
Y为被R4基团取代的苯基、吡啶-3-基、或吡啶-4-基;并且其中R4选自氟、甲基、4-(环丙基甲基)哌嗪-1-基、吗啉乙氧基、吗啉丙氧基、吗啉甲基或N原子任选被氨基保护基取代的哌嗪甲基;
R1为甲基;
R2为乙基;
R3为环丙基或环戊基。
5.根据权利要求1-4中任一项所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药,其中所述化合物具有以下结构式(II):
其中,X选自CH和N,R1、R2、R3和R4如权利要求1-4所定义。
6.根据权利要求5所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药,其中
X为CH;
R1为甲基;
R2为乙基;
R3选自异丙基、新戊基、叔戊基、戊-3-基、环丙基、环丁基、环戊基、环己基、四氢吡喃-4-基、呋喃-2-基、对甲基苯基、和二环[2.2.1]庚-2-烯基;
R4各自独立地选自氢、氟、甲基、任选被1个R5基团取代的异丙基磺酰胺基、任选被1个R5基团取代的环丙基磺酰胺基、任选被1-3个独立的R5基团取代的哌啶基、任选被1-3个独立的R5基团取代的哌嗪基、任选被1-3个独立的R5基团取代的吗啉基、任选被1-3个独立的R5基团取代的吗啉-4-羰基、任选被1-3个独立的R5基团取代的吗啉甲基、任选被1-3个独立的R5基团取代的哌啶甲基、任选被1-3个独立的R5基团取代的哌嗪甲基、任选被1-3个独立的R5基团取代的吗啉乙氧基、任选被1-3个独立的R5基团取代的吗啉丙氧基、任选被1-3个独立的R5基团取代的吗啉-4-羰基甲基、和任选被1-3个独立的R5基团取代的苯氧基;
R5独立地选自乙基、环丙基甲基、二甲基氨基、羟甲基、和叔丁氧羰基。
7.根据权利要求1所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药,其选自以下化合物:
8.一种药物组合物,包括根据权利要求1-7中任一项所述的化合物或其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物或前药,和药学上可接受的载体或赋形剂,以及任选的其它治疗剂。
9.根据权利要求1-7中任一项所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药在制备用于抑制EZH2活性的药物中的用途。
10.根据权利要求9所述的用途,其中所述EZH2是野生型和/或Y641F突变型的EZH2。
11.根据权利要求1-7中任一项所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药在制备用于治疗与EZH2活性相关的癌症或癌前病症的药物中的用途。
12.如权利要求11所述的用途,其中所述癌症选自淋巴瘤、白血病和黑素瘤。
13.如权利要求12所述的用途,其中所述淋巴瘤选自非霍奇金氏淋巴瘤、滤泡性淋巴瘤和弥散性大B细胞淋巴瘤。
14.如权利要求12所述的用途,其中所述白血病是慢性骨髓性白血病。
15.如权利要求11所述的用途,其中所述癌前病症是骨髓增生异常综合征。
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CN113440511B (zh) * | 2021-07-07 | 2023-04-07 | 天津医科大学总医院 | Hotair-prc2阻断剂及其复合制剂在制备治疗子宫内膜癌药物中的用途 |
CN113440511A (zh) * | 2021-07-07 | 2021-09-28 | 天津医科大学总医院 | Hotair-prc2阻断剂及其复合制剂在制备治疗子宫内膜癌药物中的用途 |
CN115364231B (zh) * | 2021-10-15 | 2023-11-17 | 北京大学第三医院(北京大学第三临床医学院) | 一种增强ezh2抑制剂抗肿瘤作用的药物组合物及其用途 |
CN115364231A (zh) * | 2021-10-15 | 2022-11-22 | 北京大学第三医院(北京大学第三临床医学院) | 一种增强ezh2抑制剂抗肿瘤作用的药物组合物及其用途 |
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JP2020514406A (ja) | 2020-05-21 |
US10647700B2 (en) | 2020-05-12 |
ES2963590T3 (es) | 2024-04-01 |
US20190367482A1 (en) | 2019-12-05 |
EP3572400B1 (en) | 2023-10-04 |
EP3572400C0 (en) | 2023-10-04 |
JP7320263B2 (ja) | 2023-08-03 |
WO2018133795A1 (zh) | 2018-07-26 |
EP3572400A1 (en) | 2019-11-27 |
CN108314677B (zh) | 2020-06-30 |
EP3572400A4 (en) | 2020-12-02 |
JP2021185208A (ja) | 2021-12-09 |
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