CN105283456A - 5-溴-靛玉红 - Google Patents
5-溴-靛玉红 Download PDFInfo
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- CN105283456A CN105283456A CN201480021350.4A CN201480021350A CN105283456A CN 105283456 A CN105283456 A CN 105283456A CN 201480021350 A CN201480021350 A CN 201480021350A CN 105283456 A CN105283456 A CN 105283456A
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Abstract
本文尤其公开使用5-Br-靛玉红衍生物用于治疗癌症的组合物和方法。
Description
相关申请的交叉引用
本申请要求2013年3月14日提交的美国临时申请第61/783,290号的权益。
发明背景
癌症是全世界范围内的主要致死原因。在2008年,估计癌症占全世界死亡人数的13%。在男性中,肺癌、前列腺癌和结肠直肠癌是最常见的癌症形式,且在2008年占男性所有癌症的40%。同一年,乳腺癌、结肠直肠癌和宫颈癌占女性所有癌症的超过40%。总之,肺癌是最常见的癌症。蛋白激酶参与许多信号转导和其他细胞过程。已发现,激酶活性失调(disregulation)与许多种形式的癌症有关。本文尤其公开能够调节不同激酶或单一激酶的靛玉红衍生物,它们为所属领域内的这些问题和其他问题提供解决方案。
发明概要
本文尤其提供化合物,或其药学上可接受的盐,其具有下式:
在式(I)化合物中,L是键或取代或未取代的亚烷基。R1是氢、卤素、-CX1 3、-OCX1 3、-CN、-OH、-NH2、-COOH、-C(O)OR4、-CONH2、-NO2、-SH、-NHNH2、-NR2R3、-OR4、-SR4、取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。X1独立地为卤素。R2和R3独立地为取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。R2和R3任选地连接在一起形成取代或未取代的杂环烷基或者取代或未取代的杂芳基。R4是取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。R5和R6独立地为氢、卤素、-CX2 3、-OCX2 3、-CN、-OH、-NH2、-COOH、-C(O)OR9、-CONH2、-NO2、-SH、-NHNH2、-NR7R8、-OR9、-SR9、取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。X2独立地为卤素。R7和R8独立地为取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基,其中R7和R8任选地连接在一起形成取代或未取代的杂环烷基或者取代或未取代的杂芳基。R9是取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。
本文也提供包含药学上可接受的赋形剂和如本文所述的化合物或其药学上可接受的盐(例如,式(I)或式(II)化合物,包括其实施方案)的药物组合物。
在另一方面中,提供一种通过施用有效量的如本文所述的化合物或其药学上可接受的盐(包括其实施方案)治疗癌症的方法。
在另一方面中,提供一种调节与疾病有关的蛋白质的水平、活性或功能的方法。该方法包括使蛋白质与有效量的如本文所述的化合物或其药学上可接受的盐(包括其实施方案)接触。
附图简述
图1.5-溴靛玉红-3'-肟衍生物(5BIOD)的结构。
图2.5BIOD对人类癌细胞存活率的影响;进行MTS测定,得到细胞存活率;将人类A549非小细胞肺癌(A)、MDA-MB-231和MDA-MB-468乳腺癌(B)、A2058黑色素瘤(C)、DU145前列腺癌(D)、SKOV3卵巢癌(E)、T315IAbl突变体KCL-22CML(F)和MIA-PaCa2胰腺癌(G)细胞接种在96-孔板(就实体肿瘤细胞系而言是5000/孔,且就CML细胞系而言是10000个细胞/孔)中,在37℃下于5%(v/v)CO2中孵育过夜,并暴露至浓度为1μM或10μM的5BIOD达48h;使用DMSO作为媒介物对照;通过四唑鎓(tetrazolium)转化为它的甲臜染料来测定细胞存活率,并在490nm下用自动ELISA平板读数器测量吸光度;一式四份地进行每个实验。
图3.化合物1276和1289降低SKOV3卵巢癌细胞的存活率;如图2中所述进行MTS测定,得到细胞存活率;测定IC50值;一式四份地进行每个实验。
图4.化合物1289和810对卵巢癌细胞和胰腺癌细胞的存活率的影响;(A).化合物1289(5-溴靛玉红-3'-肟衍生物)和化合物810(6-溴靛玉红-3'-肟衍生物)的结构。如图3中所述,在SKOV3卵巢癌细胞(B)和胰腺癌细胞(C)中利用MTS测定测定IC50值;一式四份地进行每个实验。
图5.化合物#1276和#1289的体外激酶概述。
图6.5-溴靛玉红-3'-肟衍生物(5BIOD)的结构。
图7.本文所述化合物对人类癌细胞的存活率的影响。A)对A2058黑色素瘤细胞的影响;B)对DU145前列腺癌细胞的影响。
图8:化合物1281(左图)和1289(右图)对A549肺癌SQ异种移植物的疗效。
发明详述
本文所使用的缩写具有它们在化学和生物领域内的常规含义。本文所述化学结构和化学式是根据化学领域中已知的化合价的标准规则构建。
当取代基通过其从左到右书写的常规化学式说明时,它们同等地涵盖从右到左书写结构所得到的化学上相同的取代基,例如-CH2O-等同于-OCH2-。
除非另有说明,否则术语“烷基”自身或作为另一取代基的一部分意指直链(即,未支化)或支化碳链(或碳)或者其组合,它们可以是完全饱和、单-或多不饱和,且可包括单价、二价和多价基团,具有指定数量的碳原子(即,C1-C10意指一至十个碳)。烷基是未环化链。饱和烃基的实例包括(但不限于)以下基团,诸如甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、(环己基)甲基,例如正戊基、正己基、正庚基、正辛基的同系物和异构体,等。不饱和烷基是具有一个或多个双键或三键的烷基。不饱和烷基的实例包括(但不限于)乙烯基、2-丙烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2,4-戊二烯基、3-(1,4-戊二烯基)、乙炔基、1-和3-丙炔基、3-丁炔基和高级同系物和异构体。烷氧基是经由氧接头(-O-)附接至分子的剩余部分的烷基。
除非另有说明,否则术语“亚烷基”自身或作为另一取代基的一部分意指衍生自烷基的二价基团,例如(但不限于)-CH2CH2CH2CH2-。通常,烷基(或亚烷基)基团将具有1至24个碳原子,其中本发明中优选的是那些具有10个或更少碳原子的基团。“低级烷基”或“低级亚烷基”是链较短的烷基或亚烷基基团,通常具有八个或更少碳原子。除非另有说明,否则术语“亚烯基”自身或作为另一取代基的一部分意指衍生自烯烃的二价基团。
除非另有说明,否则术语“杂烷基”自身或与另一术语组合意指稳定直链或支链或其组合,其包括至少一个碳原子和至少一个选自由O、N、P、Si和S组成的组的杂原子,且其中氮原子和硫原子可任选地被氧化,且氮杂原子可任选地被季铵化。杂原子O、N、P、S、B、As和Si可位于杂烷基的任一内部位置处或位于烷基附接至分子的剩余部分的位置处。杂烷基是未环化链。实例包括(但不限于):-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH=CH-O-CH3、-Si(CH3)3、-CH2-CH=N-OCH3、-CH=CH-N(CH3)-CH3、-O-CH3、-O-CH2-CH3和-CN。多达两个或三个杂原子可以是连续的,诸如例如-CH2-NH-OCH3和–CH2-O-Si(CH3)3。
类似地,除非另有说明,否则术语“杂亚烷基”自身或作为另一取代基的一部分意指衍生自杂烷基的二价基团,例如(但不限于)-CH2-CH2-S-CH2-CH2-和-CH2-S-CH2-CH2-NH-CH2-。就杂亚烷基而言,杂原子也可以占据链的任一末端或两端(例如,亚烷基氧基、亚烷基二氧基、亚烷基氨基、亚烷基二氨基等)。更进一步,就亚烷基和杂亚烷基连接基团而言,连接基团化学式的书写方向并非暗示连接基团的取向。例如,式-C(O)2R'-代表-C(O)2R'-和-R'C(O)2-。如上所述,如本文所使用的杂烷基包括那些通过杂原子附接至分子的剩余部分的基团,诸如-C(O)R'、-C(O)NR'、-NR'R”、-OR'、-SR'和/或-SO2R'。当引述“杂烷基”,接着引述具体杂烷基(诸如-NR'R”等)时,应理解,术语杂烷基和-NR'R”并不重复或相互排斥。相反,引述具体的杂烷基是为了增加清晰性。因此,本文中不应将术语“杂烷基”理解为排除具体杂烷基,诸如-NR'R”等。
除非另有说明,否则术语“环烷基”和“杂环烷基”自身或与其他术语组合分别意指环状形式的“烷基”和“杂烷基”。环烷基和杂烷基并非芳香族。此外,就杂环烷基而言,杂原子可占据杂环附接至分子的剩余部分的位置处。环烷基的实例包括(但不限于)环丙基、环丁基、环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环烷基的实例包括(但不限于)1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基、3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃-3-基、四氢噻吩-2-基、四氢噻吩-3-基、1-哌嗪基、2-哌嗪基等。“环亚烷基”和“杂环亚烷基”单独或作为另一取代基的一部分意指分别衍生自环烷基和杂环烷基的二价基团。
除非另有说明,否则术语“卤基”或“卤素”自身或作为另一取代基的一部分意指氟原子、氯原子、溴原子或碘原子。此外,诸如“卤代烷基”的术语意在包括单卤代烷基和多卤代烷基。例如,术语“卤代(C1-C4)烷基”包括(但不限于)氟甲基、二氟甲基、三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基等。
除非另有说明,否则术语“酰基”意指-C(O)R,其中R是取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。
除非另有说明,否则术语“芳基”意指多不饱和芳香族烃取代基,其可为单环或稠合在一起的多环(即,稠环芳基)或以共价形式键联的多环(优选为1至3个环)。稠环芳基是指稠合在一起的多环,其中稠环中的至少一个是芳基环。术语“杂芳基”是指含有至少一个杂原子(诸如N、O或S)的芳基(或环),其中氮原子和硫原子任选地被氧化,且氮原子任选地被季铵化。因此,术语“杂芳基”包括稠环杂芳基(即,稠合在一起的多环,其中稠环中的至少一个是杂芳环)。5,6-稠环杂亚芳基是指稠合在一起的两个环,其中一个环具有5元,且另一个环具有6元,且其中至少一个环是杂芳基环。同样地,6,6-稠环杂亚芳基是指稠合在一起的两个环,其中一个环具有6元,且另一个环具有6元,且其中至少一个环是杂芳基环。6,5-稠环杂亚芳基是指稠合在一起的两个环,其中一个环具有6元,且另一个环具有5元,且其中至少一个环是杂芳基环。杂芳基可通过碳或杂原子附接至分子的剩余部分。芳基和杂芳基的非限制性实例包括苯基、1-萘基、2-萘基、4-联苯,1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-噁唑基、4-噁唑基、2-苯基-4-噁唑基、5-噁唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述每个芳基和杂芳基环系统的取代基是选自由下文所述可接受取代基的组。“亚芳基”和“杂亚芳基”单独或作为另一取代基的一部分意指分别衍生自芳基和杂芳基的二价基团。杂芳基的取代基可为键合至环杂原子氮的-O-。
“稠环芳基-杂环烷基”是稠合至杂环烷基的芳基。“稠环杂芳基-杂环烷基”是稠合至杂环烷基的杂芳基。“稠环杂环烷基-环烷基”是稠合至环烷基的杂环烷基。“稠环杂环烷基-杂环烷基”是稠合至另一杂环烷基的杂环烷基。稠环芳基-杂环烷基、稠环杂芳基-杂环烷基、稠环杂环烷基-环烷基或稠环杂环烷基-杂环烷基可各自独立地为未取代或被一个或多个本文所述取代基取代。稠环芳基-杂环烷基、稠环杂芳基-杂环烷基、稠环杂环烷基-环烷基或稠环杂环烷基-杂环烷基可各自独立地根据各稠环的大小进行命名。因此,例如,6,5芳基-杂环烷基稠环描述稠合至5元杂环烷基的6元芳基部分。螺环是其中相邻环通过单个原子连接的两个或更多个环。螺环内的个别环可以是相同或不同的。螺环的个别环可以是取代或未取代的,且可具有不同于一组螺环内的其他个别环的取代基。当不属于螺环的一部分时,螺环内个别环的可能取代基是相同环的可能取代基(例如,环烷基或杂环烷基环的取代基)。螺环可以是取代或未取代的环烷基、取代或未取代的环亚烷基、取代或未取代的杂环烷基或者取代或未取代的杂环亚烷基,且螺环基团内的个别环可以是刚刚先前清单中的任一个,包括具有一个类型的所有环(例如,所有环都是取代的杂环亚烷基,其中每个环可以是相同或不同的取代的杂环亚烷基)。当提到螺环系统时,杂环螺环意指其中至少一个环是杂环,且其中每个环可以是不同环的螺环。当提到螺环系统时,取代的螺环意指至少一个环为取代的,且每个取代基可任选地是不同的。
如本文中所使用,术语“氧基(oxo)”意指以双键键合至碳原子的氧。
如本文中所使用,术语“硫基(thio)”意指以单键键合至碳或另一硫的硫。
以上每一个术语(例如,“烷基”、“杂烷基”、“芳基”和“杂芳基”)包括所示基团的取代和未取代形式。下文提供每一类基团的优选取代基。
烷基和杂烷基(包括那些常称为亚烷基、烯基、杂亚烷基、杂烯基、炔基、环烷基、杂环烷基、环烯基和杂环烯基的基团)的取代基可以是各种选自由(但不限于)以下基团中的一个或多个:-OR'、=O、=NR'、=N-OR'、-NR'R”、-SR'、-halogen、-SiR'R”R”'、-OC(O)R'、-C(O)R'、-CO2R'、-CONR'R”、-OC(O)NR'R”、-NR”C(O)R'、-NR'-C(O)NR”R”'、-NR”C(O)2R'、-NR-C(NR'R”R”')=NR””、-NR-C(NR'R”)=NR”'、-S(O)R'、-S(O)2R'、-S(O)2NR'R”、-NRSO2R'、-NR'NR”R”'、-ONR'R”、-NR'C(O)NR”NR”'R””、-CN、-NO2、-NR'SO2R”、-NR'C(O)R”、-NR'C(O)OR”、-NR'OR”,数量范围为零至(2m'+1),其中m'是此类基团中的碳原子总数。R、R'、R”、R”'和R””各自优选地独立地指氢、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基(例如,被1至3个卤素取代的芳基)、取代或未取代的杂芳基、取代或未取代的烷基、烷氧基或硫代烷氧基或芳基烷基。当本发明化合物包括一个以上R基团时,例如,每个R基团是如同存在一个以上这些基团时的每个R'、R”、R”'和R””基团一样进行独立地选择。当R'和R”附接至相同氮原子时,它们可与该氮原子组合形成4-、5-、6-或7-元环。例如,-NR'R”包括(但不限于)1-吡咯烷基和4-吗啉基。通过上文关于取代基的讨论,所属领域的技术人员将理解,术语“烷基”意在包括含有结合至不同于氢基的基团的碳原子的基团,诸如卤代烷基(例如,-CF3和-CH2CF3)和酰基(例如,-C(O)CH3、-C(O)CF3、-C(O)CH2OCH3等)。
类似于针对烷基所述的取代基,芳基和杂芳基的取代基各不相同,且选自(例如):-OR'、-NR'R”、-SR'、-halogen、-SiR'R”R”'、-OC(O)R'、-C(O)R'、-CO2R'、-CONR'R”、-OC(O)NR'R”、-NR”C(O)R'、-NR'-C(O)NR”R”'、-NR”C(O)2R'、-NR-C(NR'R”R”')=NR””、-NR-C(NR'R”)=NR”'、-S(O)R'、-S(O)2R'、-S(O)2NR'R”、-NRSO2R'、-NR'NR”R”'、-ONR'R”、-NR'C(O)NR”NR”'R””、-CN、-NO2、-R'、-N3、-CH(Ph)2、氟代(C1-C4)烷氧基和氟代(C1-C4)烷基、-NR'SO2R”、-NR'C(O)R”、-NR'C(O)OR”、-NR'OR”,数量范围为零至芳环系统上开放原子价(openvalence)的总数;且其中R'、R”、R”'和R””优选地独立地选自氢、取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基和取代或未取代的杂芳基。例如,当本发明化合物包括一个以上R基团时,每个R基团是如同存在一个以上这些基团时的每个R'、R”、R”'和R””基团一样进行独立地选择。
环(例如环烷基、杂环烷基、芳基、杂芳基、环亚烷基、杂环亚烷基、亚芳基或杂亚芳基)的取代基可表述为环上的取代基,而不是环的具体原子上的取代基(通常称为浮动(floating)取代基)。在此类情形下,取代基可附接至任一环原子(遵循化合价规则),且在稠环或螺环的情形下,表述为与稠环或螺环的一元相连的取代基(单环上的浮动取代基)可以是任何稠环或螺环上的取代基(多环上的浮动取代基)。当取代基附接至环,而不是具体原子(浮动取代基),且取代基的下标是大于一的整数时,多个取代基可位于相同原子、相同环、不同原子、不同稠环、不同螺环上,且每个取代基可任选地是不同的。当环与分子的剩余部分的附接点并不限于单一原子(浮动取代基)时,附接点可以是环的任何原子,且在稠环或螺环的情形下,可以是任何稠环或螺环的任何原子,但要遵循化合价规则。当环、稠环或螺环包含一个或多个杂原子,且环、稠环或螺环示出具有一个或多个浮动取代基(包括(但不限于)与分子的剩余部分的附接点)时,浮动取代基可键合至杂原子。当环的杂原子示出结合至具有浮动取代基的结构或结构式中的一个或多个氢时(例如环氮的两个键键合至环原子且第三个键键合至氢),当杂原子键合至浮动取代基时,取代基将理解为置换氢,但要遵循化合价规则。
两个或更多个取代基可任选地连接形成芳基、杂芳基、环烷基或杂环烷基。通常(但不一定)发现此类所谓的成环取代基附接至环状基础结构。在一个实施方案中,成环取代基附接至基础结构的相邻成员。例如,两个附接至环状基础结构的相邻成员的成环取代基产生稠环结构。在另一个实施方案中,成环取代基附接至基础结构的单个成员。例如,两个附接至环状基础结构的单个成员的成环取代基产生螺环结构。在另一个实施方案中,成环取代基附接至基础结构的非相邻成员。
芳基或杂芳基环的相邻原子上的两个取代基可任选地形成式-T-C(O)-(CRR')q-U-的环,其中T和U独立地为-NR-、-O-、-CRR'-或单键,且q为0至3的整数。或者,芳基或杂芳基环的相邻原子上的两个取代基可任选地被式-A-(CH2)r-B-的取代基置换,其中A和B独立地为-CRR'-、-O-、-NR-、-S-、-S(O)-、-S(O)2-、-S(O)2NR'-或单键,且r为1至4的整数。由此形成的新环的一个单键可任选地被双键置换。或者,芳基或杂芳基环的相邻原子上的两个取代基可任选地被式-(CRR')s-X'-(C”R”R”')d-的取代基置换,其中s和d独立地为0至3的整数,且X'为-O-、-NR'-、-S-、-S(O)-、-S(O)2-或-S(O)2NR'-。取代基R、R'、R”和R”'优选地独立选自氢、取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基和取代或未取代的杂芳基。
如本文中所使用,术语“杂原子”或“环杂原子”意在包括氧(O)、氮(N)、硫(S)、磷(P)、硼(B)、砷(As)和硅(Si)。
如本文所使用,“取代基基团”意指选自以下部分的基团:
(A)氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、未取代的烷基、未取代的杂烷基、未取代的环烷基、未取代的杂环烷基、未取代的芳基、未取代的杂芳基,和
(B)被至少一个选自以下的取代基取代的烷基、杂烷基、环烷基、杂环烷基、芳基和杂芳基:
(i)氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、未取代的烷基、未取代的杂烷基、未取代的环烷基、未取代的杂环烷基、未取代的芳基、未取代的杂芳基,和
(ii)被至少一个选自以下的取代基取代的烷基、杂烷基、环烷基、杂环烷基、芳基和杂芳基:
(a)氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、未取代的烷基、未取代的杂烷基、未取代的环烷基、未取代的杂环烷基、未取代的芳基、未取代的杂芳基,和
(b)被至少一个选自以下的取代基取代的烷基、杂烷基、环烷基、杂环烷基、芳基或杂芳基:氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、未取代的烷基、未取代的杂烷基、未取代的环烷基、未取代的杂环烷基、未取代的芳基和未取代的杂芳基。
如本文所使用的“大小有限的取代基”或“大小有限的取代基基团”意指选自上文针对“取代基基团”所述的所有取代基的基团,其中每一取代的或未取代的烷基是取代或未取代的C1-C20烷基,每一取代的或未取代的杂烷基是取代或未取代的2至20元杂烷基,每一取代的或未取代的环烷基是取代或未取代的C3-C8环烷基,且每一取代的或未取代的杂环烷基是取代或未取代的3至8元杂环烷基。
如本文所使用的“低级取代基”或“低级取代基基团”意指选自上文针对“取代基基团”所述的所有取代基的基团,其中每一取代的或未取代的烷基是取代或未取代的C1-C8烷基,每一取代的或未取代的杂烷基是取代或未取代的2至8元杂烷基,每一取代的或未取代的环烷基是取代或未取代的C3-C7环烷基,且每一取代的或未取代的杂环烷基是取代或未取代的3至7元杂环烷基。
在一些实施方案中,本文化合物中所述的每一取代的基团被至少一个取代基基团取代。更具体而言,在一些实施方案中,本文化合物中所述的每一取代的烷基、取代的杂烷基、取代的环烷基、取代的杂环烷基、取代的芳基、取代的杂芳基、取代的亚烷基、取代的杂亚烷基、取代的环亚烷基、取代的杂环亚烷基、取代的亚芳基和/或取代的杂亚芳基被至少一个取代基基团取代。在其他实施方案中,这些基团中的至少一个基团或所有基团被至少一个大小有限的取代基基团取代。在其他实施方案中,这些基团中的至少一个基团或所有基团被至少一个低级取代基基团取代。
在本文化合物的其他实施方案中,每一取代或未取代的烷基可以是取代或未取代的C1-C20烷基,每一取代的或未取代的杂烷基是取代或未取代的2至20元杂烷基,每一取代的或未取代的环烷基是取代或未取代的C3-C8环烷基,且/或每一取代的或未取代的杂环烷基是取代或未取代的3至8元杂环烷基。在本文化合物的一些实施方案中,每一取代或未取代的亚烷基可以是取代或未取代的C1-C20亚烷基,每一取代的或未取代的杂亚烷基是取代或未取代的2至20元杂亚烷基,每一取代的或未取代的环亚烷基是取代或未取代的C3-C8环亚烷基,且/或每一取代的或未取代的杂环亚烷基是取代或未取代的3至8元杂环亚烷基。
在一些实施方案中,每一取代或未取代的烷基是取代或未取代的C1-C8烷基,每一取代的或未取代的杂烷基是取代或未取代的2至8元杂烷基,每一取代的或未取代的环烷基是取代或未取代的C3-C7环烷基,且/或每一取代的或未取代的杂环烷基是取代或未取代的3至7元杂环烷基。在一些实施方案中,每一取代或未取代的亚烷基可以是取代或未取代的C1-C8亚烷基,每一取代的或未取代的杂亚烷基是取代或未取代的2至8元杂亚烷基,每一取代的或未取代的环亚烷基是取代或未取代的C3-C7环亚烷基,且/或每一取代的或未取代的杂环亚烷基是取代或未取代的3至7元杂环亚烷基。
本发明的某些化合物具有不对称碳原子(光学或手性中心)或双键;可以依据绝对立体化学将氨基酸定义为(R)-或(S)-或者(D)-或(L)-的对映异构体、外消旋体、非对映异构体、互变异构体、几何异构体、立体异构形式,并且个别异构体涵盖在本发明范围内。本发明化合物不包括那些所属领域内已知太不稳定而无法合成和/或分离的化合物。本发明意在包括外消旋和光学纯形式的化合物。可利用手性合成子或手性试剂制备光学活性(R)-和(S)-或者(D)-和(L)-异构体,或利用传统技术进行解析。当本文所述化合物包含烯烃键或其他几何不对称中心时,且除非另有规定,否则希望本发明包括E和Z两种几何异构体。
如本文中所使用,术语“异构体”是指具有相同的原子数目和种类并且因此分子量相同,但在原子的结构排列或构型上有所不同的化合物。
如本文中所使用,术语“互变异构体”是指以平衡状态形式存在,且易于从一种异构形式转化为另一种异构形式的两种或更多种结构异构体中的一种。
所属领域的技术人员将知道,本发明的某些化合物可以互变异构形式存在,化合物的所有此类互变异构形式都在本发明范围内。
除非另有说明,否则本文所描绘的结构也意在包括该结构的所有立体化学形式;即每个不对称中心的R和S构型。因此,通常被所属领域的技术人员认为稳定的本发明化合物的单一立体化学异构体以及对应异构和非对应异构混合物都在本发明范围内。
除非另有说明,否则本文所描绘结构也意在包括差异仅在于存在一个或多个同位素富集的原子的化合物。例如,具有本发明结构(除氢被氘或氚置换,或碳被13C-或14C-富集的碳置换以外)的化合物在本发明范围内。
本发明化合物在一个或多个构成此类化合物的原子处也可以包含非天然比例的原子同位素。例如,化合物可被放射性同位素进行放射性标记,诸如例如氚(3H)、碘-125(125I)或碳-14(14C)。本发明化合物的所有同位素变异(无论是否具有放射性)都涵盖在本发明范围内。
符号表示化学部分与分子或化学式的剩余部分的附接点。
如本文中所使用,术语“一个(a/an)”意指一个或多个。此外,如本文所使用,短语“被一个...取代”意指指定基团可被指定取代基中的任一个或多个或者所有取代基取代。例如,当基团如烷基或杂芳基“被未取代的C1-C20烷基或未取代的2至20元杂烷基取代”时,该基团可包含一个或多个未取代的C1-C20烷基和/或未取代的2至20元杂烷基。
而且,当某一部分被R取代基取代时,基团可被称为“R取代的”。当某一部分是R取代的,该部分被至少一个R取代基取代,且每个R取代基是任选地不同的。当特定R基团存在于化学属类的描述中(诸如式(I))时,可使用罗马字母表符号区分每次出现的特定R基团。例如,当出现多个R13取代基时,每个R13取代基可区分为R13A、R13B、R13C、R13D等,其中R13A、R13B、R13C、R13D等是在R13的定义范围内定义,且任选地有所不同。
本发明化合物的描述受到所属领域的技术人员已知的化学键合原则的限制。因此,当基团被数个取代基中的一个或多个取代时,选择此类取代基,以符合化学键合原则,并得到自身并非不稳定和/或所属领域的一般技术人员已知可能将在环境条件(诸如,水性、中性和几种已知的生理条件)下不稳定的化合物。例如,杂环烷基或杂芳基通过符合所属领域的技术人员已知的化学键合原则的环杂原子附接至分子的剩余部分,从而避免本身不稳定的化合物。
术语“药学上可接受的盐”意在包括用相对无毒的酸或碱(这取决于见于本文所述化合物上的特定取代基)制备的活性化合物的盐。当本发明化合物包含相对酸性官能团时,可通过使此类化合物的中性形式与足量的期望碱(纯碱或含于适合的惰性溶剂中)接触获得碱加成盐。药学上可接受的碱加成盐的实例包括钠盐、钾盐、钙盐、铵盐、有机胺盐或镁盐或者类似盐。当本发明化合物包含相对碱性官能团时,可通过使此类化合物的中性形式与足量的期望酸(纯酸或含于适合的惰性溶剂中)接触获得酸加成盐。药学上可接受的酸加成盐的实例包括那些衍生自无机酸的盐,如盐酸、氢溴酸、硝酸、碳酸、一氢碳酸、磷酸、一氢磷酸、二氢磷酸、硫酸、一氢硫酸、氢碘酸或亚磷酸等;以及衍生自相对无毒的有机酸的盐,如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、富马酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、草酸、甲磺酸等。也包括氨基酸(诸如精氨酸等)的盐;和有机酸(如葡糖醛酸或半乳糖醛酸等)的盐(参见,例如Berge等人,“PharmaceuticalSalts”,JournalofPharmaceuticalScience,1977,66,1-19)。本发明的某些特定化合物同时包含碱性和酸性官能团,这使得该化合物可转化为碱加成盐或酸加成盐。
因此,本发明化合物可作为(诸如)与药学上可接受的酸形成的盐存在。本发明包括此类盐。此类盐的实例包括盐酸盐、氢溴酸盐、硫酸盐、甲磺酸盐、硝酸盐、马来酸盐、乙酸盐、柠檬酸盐、富马酸盐、酒石酸盐(例如,(+)-酒石酸盐、(-)-酒石酸盐或其混合物,包括外消旋混合物)、琥珀酸盐、苯甲酸盐和与氨基酸(诸如谷氨酸)形成的盐。这些盐可通过所属领域的技术人员已知的方法制备。
中性形式的化合物优选地是通过使盐与碱或酸接触,并以常规方式分离母体化合物而再生。母体形式的化合物的某些物理性质(诸如在极性溶剂中的溶解度)不同于各种盐形式。
除盐形式以外,本发明提供前药形式的化合物。本文所述化合物的前药包括那些容易在生理条件下发生化学变化以提供本发明化合物的化合物。此外,前药可通过化学或生物化学方法在离体环境中转化为本发明化合物。例如,当与适合酶或化学试剂一起置于经皮贴剂储集囊(reservoir)中时,前药可缓慢地转化为本发明化合物。
本发明的某些化合物可以非溶剂化形式以及溶剂化形式(包括水合化形式)存在。一般来说,溶剂化形式等同于非溶剂化形式,且涵盖在本发明范围内。本发明的某些化合物可以多种结晶或非晶形式存在。一般来说,所有物理形式对于本文所涵盖的用途来说都是等效的,且意在落在本发明范围内。
如本文中所使用,术语“盐”是指用于本发明方法中的化合物的酸性盐或碱性盐。可接受的盐的说明性实例是无机酸(盐酸、氢溴酸、磷酸等)盐、有机酸(乙酸、丙酸、谷氨酸、柠檬酸等)盐、季铵(碘甲烷、碘乙烷等)盐。
术语“治疗(treating或treatment)”是指成功治疗或改善损伤、疾病、病理或病状的任何迹象,包括任何客观或主观参数,诸如消除;减轻;减少症状或者使得患者更能忍受损伤、病理或病状;减慢退化或衰退速率;使得退化终点不太虚弱;提高患者身体或心理健康。症状的治疗或改善可基于客观或主观参数;包括身体检查、神经精神测试和/或精神病评估的结果。术语“治疗”和其词形变化包括预防损伤、病理、病状或疾病。
“有效量”是足以达到所陈述目的的量(例如,达到施用效果、治疗疾病、降低酶活性、减少疾病或病状的一种或多种症状、降低细胞内激酶(例如JAK2、Src、STAT3、ABL1、T35I突变ABL1、TYK2、AuroraA、细胞周期素依赖性激酶或GSK-3β)活性水平)。“有效量”的一个实例是足以有助于治疗、预防或减轻疾病的一种或多种症状的量,也可以称它为“治疗有效量”。一种或多种症状的“减轻”(和这个短语的语法等效物)意指降低该症状的严重性或频率,或者消除该症状。确切的量将取决于治疗目的,且将由所属领域的技术人员利用已知技术确定(参见例如Lieberman,PharmaceuticalDosageForms(第1-3卷,1992);Lloyd,TheArt,ScienceandTechnologyofPharmaceuticalCompounding(1999);Pickar,DosageCalculations(1999);和Remington:TheScienceandPracticeofPharmacy,第20版,2003,Gennaro,编,Lippincott,Williams&Wilkins)。
“对照”或“对照实验”是按照它的普通含义使用,且是指其中实验受试者或试剂是如平行实验中一样进行处理,但是略去实验的一个步骤、试剂或变量的实验。在一些情况下,对照是用作评估实验效果的比较标准。
“接触”是按照它的普通含义使用,且是指使至少两种不同物质(例如化学化合物,包括生物分子或细胞)变得足够靠近,以进行反应、相互作用或物理上接触的过程。然而,应了解,所得反应产物可直接从所加试剂间的反应产生或者从一种或多种所加试剂的中间物(其可在反应混合物中产生)产生。
术语“接触”可以包括使两种物质反应、相互作用或物理上接触,其中两种物质可以是如本文所述的化合物和蛋白质或酶(例如JAK、JAK2、TYK2、c-Src、ABL1、T315I突变体ABL1、AuroraA、GSK-3β、CDK)。在实施方案中,接触包括使本文所述化合物与参与信号传递途径(例如STAT3途径)的蛋白质或酶相互作用。
如本文中所定义,关于蛋白质抑制剂相互作用的术语“抑制(inhibition/inhibit/inhibiting等)”意指负面影响(例如降低)蛋白质活性或功能(例如通过激酶减少另一种蛋白质的磷酸化作用),这是相对于蛋白质(例如激酶)在没有抑制剂(例如激酶抑制剂或激酶抑制剂化合物)存在下的活性或功能而言。在实施方案中,抑制是指减少疾病或疾病症状。在实施方案中,抑制是指减少信号转导途径或信号传递途径的活性(例如减少涉及JAK、JAK2、TYK2、c-Src、ABL1、T315I突变体ABL1、AuroraA、GSK-3β、CDK、STAT或STAT3的途径)。因此,抑制包括至少部分、部分地或完全阻断刺激,减少、预防或延迟活化,或使信号转导或酶活性或蛋白质(例如JAK、JAK2、TYK2、c-Src、ABL1、T315I突变体ABL1、AuroraA、GSK-3β、CDK、STAT或STAT3)的量失活、脱敏或下调。在实施方案中,JAK、JAK2、TYK2、c-Src、ABL1、T315I突变体ABL1、AuroraA、GSK-3β、CDK、STAT或STAT3是人类蛋白。
术语“调节剂”是指增加或降低靶标分子水平或靶标分子功能的组合物(例如,靶标可以是激酶(例如JAK、JAK2、TYK2、c-Src、ABL1、T315I突变体ABL1、AuroraA、GSK-3β、CDK),且功能可以是使分子磷酸化,或者靶标可以是激酶(例如JAK、JAK2、TYK2、c-Src、ABL1、T315I突变体ABL1、AuroraA、GSK-3β、CDK),且功能可以是下游信号传递途径(包括STAT或STAT3)的功能)。在实施方案中,激酶调节剂是降低细胞中激酶活性的化合物。激酶调节剂可降低一种激酶的活性,但导致另一种激酶的酶活性增加,这导致细胞生长和增殖分别减少或增加。在实施方案中,激酶疾病调节剂是降低与激酶相关的疾病(例如癌症)的一种或多种症状的严重性的化合物。
“患者”或“有需要的受试者”是指患有或易患可通过施用如本文所提供的化合物或药物组合物治疗的疾病或病状的生物体。非限制性实例包括人类、其他哺乳动物、牛、大鼠、小鼠、狗、猴、山羊、绵羊、奶牛、鹿和其他非哺乳动物。在实施方案中,患者是人类。
“疾病”或“病状”是指患者或受试者的可用本文所提供化合物、药物组合物或方法治疗的生存状态或健康状态。在实施方案中,疾病是与如本文所述的活化或活性过度的激酶或激酶活性异常有关的(例如由此所引起的)疾病。在实施方案中,疾病是与激酶受抑制或激酶活性下降有关的(例如以此为特征的)疾病(例如JAK、JAK2、TYK2、c-Src、ABL1、T315I突变体ABL1、AuroraA、GSK-3β或CDK活性水平下降或者涉及JAK、JAK2、TYK2、c-Src、ABL1、T315I突变体ABL1、AuroraA、GSK-3β、CDK、STAT或STAT3的途径的信号转导活性下降的癌症)。疾病、病症或病状的实例包括(但不限于)癌症、肺癌、乳腺癌、卵巢癌、白血病、淋巴瘤、黑色素瘤、胰腺癌、肉瘤、膀胱癌、骨癌、脑癌、宫颈癌、结肠癌、食道癌、胃癌、肝癌、头颈癌、肾癌、骨髓瘤、甲状腺癌、前列腺癌、转移性癌症(cancer)或癌(carcinoma)。在一些情况中,“疾病”或“病状”是指癌症。在另外一些情况中,“癌症”是指人类癌症和癌、肉瘤、腺癌、淋巴瘤、白血病、黑色素瘤等,包括实体癌和淋巴癌、肾癌、乳腺癌、肺癌、膀胱癌、结肠癌、卵巢癌、前列腺癌、胰腺癌、胃癌、脑癌、头颈癌、皮肤癌、子宫癌、睾丸癌、神经胶质瘤、食管癌、肝脏癌症(包括肝癌)、淋巴瘤(包括B-急性淋巴母细胞性淋巴瘤、非霍奇金氏淋巴瘤(例如,伯基特氏淋巴瘤、小细胞淋巴瘤和大细胞淋巴瘤)、霍奇金氏淋巴瘤、白血病(包括AML、ALL及CML)和/或多发性骨髓瘤。
如本文中所使用,术语“癌症”是指见于哺乳动物中的所有类型的癌症、赘生物或恶性肿瘤,包括白血病、淋巴瘤、癌和肉瘤。可用本文所提供的化合物、药物组合物或方法治疗的示例性癌症包括淋巴瘤、肉瘤、膀胱癌、骨癌、脑肿瘤、宫颈癌、结肠癌、食道癌、胃癌、头颈癌、肾癌、骨髓瘤、甲状腺癌、白血病、前列腺癌、乳腺癌(例如,ER阳性、ER阴性、化疗耐药性、赫塞汀耐药性、HER2阳性、阿霉素耐药性、他莫昔芬耐药性、导管癌、小叶癌、原发性乳腺癌、转移性乳腺癌)、卵巢癌、胰腺癌、肝癌(例如,肝细胞癌)、肺癌(例如,非小细胞肺癌、鳞状细胞肺癌、腺癌、大细胞肺癌、小细胞肺癌、类癌、肉瘤)、多形性胶质母细胞瘤、神经胶质瘤或黑色素瘤。其他实例包括甲状腺癌、内分泌系统癌症、脑癌、乳腺癌、宫颈癌、结肠癌、头颈癌、肝癌、肾癌、肺癌、非小细胞肺癌、黑色素瘤、间皮瘤、卵巢癌、肉瘤、胃癌、子宫癌或成神经管细胞瘤、霍奇金氏病、非霍奇金氏淋巴瘤、多发性骨髓瘤、成神经细胞瘤、神经胶质瘤、多形性胶质母细胞瘤、卵巢癌、横纹肌肉瘤、原发性血小板增多症、原发性巨球蛋白血症、原发性脑肿瘤、癌症、恶性胰岛素瘤、恶性类癌、尿膀胱癌、癌前皮肤病变、睾丸癌、淋巴瘤、甲状腺癌、成神经细胞瘤、食道癌、泌尿生殖道癌、恶性高钙血症,子宫内膜癌、肾上腺皮质癌、内分泌或外分泌胰腺赘生物、甲状腺髓样癌(medullarythyroidcancer)、甲状腺髓样癌(medullarythyroidcarcinoma)、黑色素瘤、结肠直肠癌、乳头状甲状腺癌、肝细胞癌、乳头派杰氏(Paget’s)病、叶状瘤、小叶癌、导管癌、胰腺星状细胞癌、肝星状细胞癌或前列腺癌。
术语“白血病”宽泛地指造血器官的进行性恶性疾病,且通常是以血液和骨髓中的白血球和它们的前体的畸形增殖和发育为特征。白血病在临床上的分类依据通常是(1)疾病的持续时间和特性-急性或慢性;(2)涉及的细胞类型;骨髓(骨髓性)、淋巴(淋巴源性)或单核细胞;和(3)血液中异常细胞数量增加或不增加-白血病性或非白血病性(亚白血病)。可用本文所提供的化合物、药物组合物或方法治疗的示例性白血病包括(例如)急性非淋巴细胞性白血病、慢性淋巴细胞性白血病、急性粒细胞性白血病、慢性粒细胞性白血病、急性早幼粒细胞性白血病、成人T细胞白血病、非白血病性白血病、白血病性白血病(leukocythemicleukemia)、嗜碱细胞性白血病、母细胞白血病、牛白血病、慢性髓细胞性白血病、皮肤白血病、胚细胞性白血病(embryonalleukemia)、嗜酸细胞性白血病、格罗斯白血病(Gross’leukemia)、毛细胞白血病、成血细胞性白血病(hemoblasticleukemia)、血胚细胞性白血病(hemocytoblasticleukemia)、组织细胞性白血病、干细胞白血病、急性单核细胞白血病、白细胞减少性白血病、淋巴性白血病、成淋巴细胞性白血病、淋巴细胞性白血病、淋巴原性白血病、淋巴样白血病、淋巴肉瘤细胞白血病、肥大细胞白血病、巨核细胞性白血病、小原粒型白血病(micromyeloblasticleukemia)、单核细胞性白血病、成髓细胞性白血病、髓细胞性白血病、髓样粒细胞性白血病、髓单核细胞白血病、内格利型白血病(Naegelileukemia)、浆细胞白血病、多发性骨髓瘤、浆细胞性白血病、早幼粒细胞性白血病、里德尔氏细胞性白血病、希林氏白血病(Schilling'sleukemia)、干细胞白血病、亚白血病性白血病或未分化细胞白血病。
术语“肉瘤”通常是指由如胚性结缔组织的物质构成的肿瘤,且通常是由包埋在纤维状或均质物质中的紧密堆积细胞组成。可用本文所提供的化合物、药物组合物或方法治疗的肉瘤包括软骨肉瘤、纤维肉瘤、淋巴肉瘤、黑素肉瘤、黏液肉瘤、骨肉瘤、Abemethy氏肉瘤、脂肉瘤(adiposesarcoma)、脂肪肉瘤、腺泡状软组织肉瘤、成釉细胞肉瘤、葡萄状肉瘤、绿色瘤肉瘤、绒毛膜癌、胚胎性肉瘤、威尔姆氏肿瘤肉瘤(Wilms'tumorsarcoma)、子宫内膜肉瘤、间质肉瘤、尤文氏肉瘤、筋膜肉瘤、纤维母细胞肉瘤、巨细胞肉瘤、粒细胞肉瘤、霍奇金氏肉瘤、特发性多发性色素沉着出血性肉瘤、B细胞免疫母细胞肉瘤、淋巴瘤、T细胞免疫母细胞肉瘤、杰恩逊氏肉瘤(Jensen'ssarcoma)、卡波西肉瘤、库普弗细胞肉瘤、血管肉瘤、白血病性肉瘤、恶性间叶肉瘤、骨膜外肉瘤、网状细胞肉瘤、劳斯肉瘤、浆液囊性肉瘤、滑膜肉瘤或毛细血管扩张性肉瘤(telangiectalticsarcoma)。
术语“黑色素瘤”意指起源于皮肤和其他器官的黑素细胞系统的肿瘤。可用本文所提供的化合物、药物组合物或方法治疗的黑色素瘤包括(例如)肢端雀斑样痣黑色素瘤、无黑色素性黑色素瘤、良性幼年黑色素瘤、克劳德曼黑色素瘤(Cloudman’smelanoma)、S91黑色素瘤、哈-帕二氏黑色素瘤(Harding-Passeymelanoma)、幼年黑色素瘤、恶性雀斑样痣黑色素瘤、恶性黑色素瘤、结节性黑色素瘤、甲下黑色素瘤(subungalmelanoma)和浅表扩散性黑色素瘤。
术语“癌”是指由上皮细胞构成的恶性新生,其倾向于浸润周围组织并引起转移。可用本文所提供的化合物、药物组合物或方法治疗的示例性癌包括(例如)甲状腺髓样癌、家族性甲状腺髓样癌、腺泡癌、腺泡状癌、腺样嚢性癌(adenocysticcarcinoma)、腺样嚢性癌(adenoidcysticcarcinoma)、腺癌(carcinomaadenomatosum)、肾上腺皮质癌、肺泡癌、肺泡细胞癌、基底细胞癌、基底上皮细胞癌(carcinomabasocellulare)、基底细胞样癌、基底鳞状细胞癌、细支气管肺泡癌、支气管癌、支气管源性癌、脑样癌、胆管细胞癌、绒毛膜癌、胶样癌、粉剌状癌、子宫体癌、筛状癌、铠甲状癌(carcinomaencuirasse)、皮肤癌(carcinomacutaneum)、柱状细胞性癌(cylindricalcarcinoma)、柱状细胞癌(cylindricalcellcarcinoma)、导管癌(ductcarcinoma)、导管癌(ductalcarcinoma)、硬癌、胚胎性癌、髓样癌、表皮样癌(epiermoidcarcinoma)、腺样上皮癌(carcinomaepithelialeadenoides)、外植癌、溃痕性癌(carcinomaexulcere)、纤维癌、胶样癌(gelatinifornicarcinoma)、胶状癌(gelatinouscarcinoma)、巨大细胞癌(giantcellcarcinoma)、巨细胞癌(carcinomagigantocellulare)、腺癌、粒层细胞癌、发母质癌(hair-matrixcarcinoma)、多血癌(hematoidcarcinoma)、肝细胞癌、许特莱细胞癌(Hurthlecellcarcinoma)、透明质癌、肾上腺样癌、幼稚型胚胎性癌、原位癌、表皮内癌、上皮内癌、克龙派切尔癌(Krompecher'scarcinoma)、库尔奇茨基细胞(Kulchitzky-cellcarcinoma)、大细胞癌、豆状癌(lenticularcarcinoma)、豆状癌(carcinomalenticulare)、脂瘤癌(lipomatouscarcinoma)、小叶癌、淋巴上皮癌、髓样癌、髓样癌(medullarycarcinoma)、黑色素鳞癌(melanoticcarcinoma)、软癌、黏液癌(mucinouscarcinoma)、粘液癌(carcinomamuciparum)、粘液细胞癌(carcinomamucocellulare)、粘液表皮样癌(mucoepidermoidcarcinoma)、粘液癌(carcinomamucosum)、粘液性癌(mucouscarcinoma)、粘液瘤样癌(carcinomamyxomatodes)、鼻咽癌、燕麦细胞癌、骨化性癌、骨样癌、乳头状癌、门静脉周癌、浸润前期癌(preinvasivecarcinoma)、棘细胞癌、软糊状癌(pultaceouscarcinoma)、肾的肾细胞癌、储备细胞癌(reservecellcarcinoma)、肉瘤样癌、施奈德癌(schneideriancarcinoma)、硬癌、阴嚢癌、印戒细胞癌(signet-ringcellcarcinoma)、单纯癌、小细胞癌、马铃薯状癌(solanoidcarcinoma)、球状细胞癌、梭形细胞癌、髓样癌(carcinomaspongiosum)、鳞癌、鳞状细胞癌、绳捆癌(stringcarcinoma)、血管扩张性癌(carcinomatelangiectaticum)、血管扩张癌(carcinomatelangiectodes)、移行细胞癌、结节性皮癌(carcinomatuberosum)、小管癌、结节性皮癌(tuberouscarcinoma)、疣状癌和绒毛状癌。
在与疾病(例如蛋白质相关疾病、与激酶活性异常相关的癌症)相关的物质或者物质活性或功能的语境中的术语“相关”或“与...相关的”意指疾病(例如癌症)是(完全或部分)由该物质或者物质活性或功能引起,或者疾病的症状是(完全或部分)由该物质或者物质活性或功能引起。例如,与激酶活性或功能异常相关的癌症可以是(完全或部分)由激酶活性或功能(例如酶活性、蛋白质-蛋白质相互作用、信号传递途径)异常引起或者另外特征为激酶活性或功能异常的癌症,或者其中疾病的特定症状是(完全或部分)由激酶活性或功能异常所引起的癌症。如本文中所使用,被描述为与疾病相关的(假设是病原体剂)可以是用于治疗疾病的靶标。例如,在激酶活性或功能(例如信号传递途径活性)增加导致癌症的情况下,与激酶活性或功能异常相关的癌症或者激酶相关癌症可用激酶调节剂或激酶抑制剂治疗。
如本文中所使用的术语“信号传递途径”是指细胞与任选的胞外组分(例如蛋白质、核酸、小分子、离子、脂质)间的一系列相互作用,它将一种组分的变化传递至一种或多种其他组分,进而可将变化传递至其他组分,任选地将变化传播至其他信号传递途径的组分。例如,激酶与如本文所述化合物结合可导致激酶的一种或多种蛋白质-蛋白质相互作用发生变化,从而导致细胞生长、增殖或存活发生变化。
“药学上可接受的赋形剂”和“药学上可接受的载体”是指有助于将活性剂施用至受试者并被其吸收,且可纳入本文发明组合物中而不会对患者引起显著不利毒理效应的物质。药学上可接受的赋形剂的非限制性实例包括水、NaCl、生理食盐水、乳酸林格氏(lactatedRinger's)、生理蔗糖、生理葡萄糖、黏合剂、填充剂、崩解剂、润滑剂、涂料、甜味剂、香精、盐溶液(诸如林格氏溶液)、醇、油、明胶、碳水化合物(诸如乳糖、直链淀粉或淀粉)、脂肪酸酯、羟甲基纤维素、聚乙烯吡咯烷酮和颜料等。此类制剂可以是无菌的,且如果需要可与助剂(诸如润滑剂、防腐剂、稳定剂、润湿剂、乳化剂、影响渗透压的盐、缓冲剂、着色剂和/或不会与本发明化合物发生有害反应的芳香族物质等)混合。所属领域的技术人员将知晓,本发明中可使用其他药学赋形剂。
术语“制剂”意在包括活性化合物与作为提供胶囊的载体的密封材料的配制物,其中具有或没有其他载体的活性组分被载体包围,从而与之联合。类似地,包括扁囊剂和锭剂。片剂、粉剂、胶囊、丸剂、扁囊剂和锭剂可用作适合口服施用的固体剂型。
如本文中所使用,术语“施用”意指口服施用、作为栓剂施用、局部接触、静脉内施用、肠胃外施用、腹膜内施用、肌肉内施用、病灶内施用、鞘内施用、鼻内施用或皮下施用、或向受试者植入缓释装置(例如微量渗透泵)。可通过任何途径施用,包括胃肠外和透黏膜(例如,颊侧、舌下、上颚、牙龈、鼻子、阴道、直肠或经皮)施用。肠道外施用包括(例如)静脉内、肌肉内、小动脉内、皮内、皮下、腹膜内、室内和颅内施用。其他递送模式包括(但不限于)使用脂质体配制物静脉内输液、经皮贴剂等。
所谓“共同施用”意指本文所述组合物是在施用一种或多种其他疗法(例如癌症疗法,诸如化学疗法、激素疗法、放射疗法或免疫疗法)的同时、前不久或后不久施用。本发明化合物可以单独施用或可以共同施用至患者。共同施用意在包括同时或依次施用,个别地或组合地(超过一种化合物或药剂)。因此,制剂也可以在需要时与其他活性物质组合(例如以减少代谢降解)。
本文所述化合物可相互组合使用,与其他已知可用于治疗与表达如本文所述特定激酶的细胞相关的疾病的活性剂组合使用,或与可能单独时无效但可有助于活性剂疗效的辅助剂组合使用。
在实施方案中,共同施用包括在第二活性剂的0.5、1、2、4、6、8、10、12、16、20或24小时内施用一种活性剂。共同施用包括同时、大约同时(例如,彼此在约1、5、10、15、20或30分钟内)或以任何顺序依次施用两种活性剂。在实施方案中,共同施用可以通过共配制物(即制备含两种活性剂的单一药物组合物)实现。在其他实施方案中,活性剂可以分开配制。在实施方案中,活性剂和/或辅助剂可以相互连接或缀合。
本发明组合物可以经皮、通过局部途径调配成敷药棒(applicatorstick)、溶液、混悬剂、乳剂、凝胶、乳膏、油膏、膏剂、胶状物、涂料、粉末和气溶胶递送。口服制剂包括适合患者摄取的片剂、丸剂、粉剂、糖衣丸、胶囊、液体、锭剂、扁囊剂、凝胶、糖浆、浆液、混悬剂等。固体形式制剂包括粉剂、片剂、丸剂、胶囊、扁囊剂、栓剂和分散性粒剂。液体形式制剂包括溶液、混悬剂和乳剂,例如水溶液或水/丙二醇溶液。本发明组合物另外可包括提供缓释和/或舒适性的组分。此类组分包括高分子量阴离子类粘膜(mucomimetic)聚合物、胶化多糖和细分药物载体衬底。第4,911,920号、第5,403,841号、第5,212,162号和第4,861,760号美国专利中更详细地讨论这些组分。出于任何目的将这些专利的全部内容全部以引用的方式并入本文中。
为在体内缓慢释放,本发明组合物也可以作为微球体递送。例如,微球体可通过皮内注射含药物的微球体(它们在皮下缓慢释放)(参见Rao,J.BiomaterSci.Polym.编.7:623-645,1995);作为可生物降解且可注射的凝胶配制物(参见例如GaoPharmRes.12:857-863,1995);或作为口服施用所用的微球体(参见例如Eyles,J.Pharm.Pharmacol.49:669-674,1997)进行施用。在实施方案中,本发明化合物的配制物可以通过使用与细胞膜融合的脂质体或者在胞吞作用中被胞吞(即通过使用附接至脂质体的受体配体,它们结合至细胞的表面膜蛋白受体)进行递送。通过使用脂质体,尤其是当脂质体表面携带对靶标细胞具有特异性的受体配体或者另外优选地指向特定器官时,可以在体内集中将本发明组合物递送至靶标细胞。(参见例如Al-Muhammed,J.Microencapsul.13:293-306,1996;Chonn,Curr.Opin.Biotechnol.6:698-708,1995;Ostro,Am.J.Hosp.Pharm.46:1576-1587,1989)。
本发明所提供的药物组合物包括包含治疗有效量(即有效达到其预期目的的量)的活性成分(例如本文所述化合物,包括其实施方案)的组合物。特定应用的实际有效量将尤其取决于所治疗的病状。当在方法中施用以治疗疾病时,此类组合物将包含用量有效达到所需结果(例如调节靶标分子(例如本文所述激酶)的活性和/或减轻、消除或减慢疾病症状的进展(例如癌生长或转移))的活性成分。所属领域的技术人员有足够能力确定本发明化合物的治疗有效量,特别是按照本文的详细公开内容。
施用至哺乳动物的剂量和频率(单个或多个剂量)可以根据各种因素而变化,例如哺乳动物是否患有另一种疾病和它的施用途径;接受者的体型、年龄、性别、健康、体重、身体质量指数和饮食;所治疗疾病(例如癌症、肺癌、乳腺癌、卵巢癌、白血病、黑色素瘤、胰腺癌或前列腺癌)的症状的本质和程度、并行治疗的种类、所治疗疾病的并发症或其他健康相关问题。其他治疗方案或治疗剂可以与本申请人发明的方法和化合物共同使用。所属领域的技术人员有足够能力调整和控制既定剂量(例如,频率和持续时间)。
就本文所述任何化合物而言,治疗有效量起初可由细胞培养测定确定。靶标浓度将是活性化合物可达到本文所述方法的那些浓度,它们是利用本文所述方法或所属领域中已知的方法测定。
如所属领域所熟知的,用于人类的治疗有效量也可以由动物模型确定。例如,可制定人类的剂量,以达到已发现在动物中有效的浓度。可通过监测化合物有效性和如上文所述上调或下调剂量来调节人类剂量。一般技术人员有足够能力基于本文所述方法和其他方法调节剂量来达到人类的最大疗效。
剂量可根据患者需求和所使用的化合物而变化。在本发明范围内,施用至患者的剂量应该足以在患者中随着时间推移产生有益治疗反应。剂量的大小也将通过任何不利副作用的存在、本质和程度来确定。从业人员有技术确定特定情况的适宜剂量。一般来说,治疗起初使用比化合物最佳剂量小的较小剂量。此后,以小幅增量增加剂量,直到达到当下情况下的最佳效果。
可以单独地调节用药量和间隔,以提供所施用化合物对所治疗的特定临床适应症有效的水平。这将提供与个体疾病状态严重性相适应的治疗方案。
利用本文所提供的教导,可以设计出不会引起显著毒性但又有效治疗特定患者所展示的临床症状的有效的预防性或治疗性治疗方案。这个设计应该涉及到通过考虑以下因素谨慎地选择活性化合物,诸如化合物效力、相对生物利用度、患者体重、存在的不利副作用和严重性、优选的施用模式和选定药剂的毒性曲线。
“抗癌剂”是按照它的普通含义使用,且是指具有抗肿瘤性质或抑制细胞生长或增殖能力的组合物(例如化合物、药物、拮抗剂、抑制剂、调节剂)。在实施方案中,抗癌剂是化学治疗剂。在实施方案中,抗癌剂是本文确定的在治疗癌症的方法中具有效用的药剂。在实施方案中,抗癌剂是获FDA或者不同于美国的国家的类似监管机构批准的药剂。抗癌剂的实例包括(但不限于)MEK(例如MEK1、MEK2或MEK1和MEK2)抑制剂(例如XL518、CI-1040、PD035901、司美替尼/AZD6244、GSK1120212/曲美替尼、GDC-0973、ARRY-162、ARRY-300、AZD8330、PD0325901、U0126、PD98059、TAK-733、PD318026、AS703026、BAY869766)、烷化剂(例如,环磷酰胺、异环磷酰胺、苯丁酸氮芥、白消安、美法仑(melphalan)、氮芥(mechlorethamine)、乌拉莫司汀(uramustine)、塞替派(thiotepa)、亚硝基脲、氮芥类(例如,氮芥(mechloroethamine)、环磷酰胺、苯丁酸氮芥、美法仑(meiphalan))、乙烯亚胺和甲基密胺(例如,六甲蜜胺、塞替派)、烷基磺酸盐(例如,白消安)、亚硝基脲(例如,卡莫司汀、洛莫司汀、司莫司汀、链脲霉素)、三氮烯(达卡巴嗪(decarbazine)))、抗代谢物(例如,5-硫唑嘌呤、亚叶酸、卡培他滨、氟达拉滨、吉西他滨、培美曲塞、雷替曲塞、叶酸类似物(例如,甲氨蝶呤)或嘧啶类似物(例如,氟尿嘧啶、氟尿苷、阿糖胞苷)、嘌呤类似物(例如,巯基嘌呤、硫鸟嘌呤、喷司他丁)等)、植物碱(例如,长春新碱、长春碱、长春瑞宾、长春地辛、鬼臼毒素、紫杉醇、多西他赛等)、拓扑异构酶抑制剂(例如,伊立替康、拓扑替康、安吖啶、依托泊苷(VP16)、磷酸依托泊苷、替尼泊苷等)、抗肿瘤抗生素(例如,阿霉素、亚德里亚霉素、道诺霉素、表柔比星、放线菌素、博来霉素、丝裂霉素、米托蒽醌、普卡霉素等)、铂类化合物(例如顺铂、奥沙利铂、卡铂)、蒽二酮(例如,米托蒽醌)、取代脲(例如,羟基脲)、甲肼衍生物(例如,丙卡巴肼)、肾上腺皮质抑制剂(例如,米托坦、氨鲁米特)、表鬼臼毒素(例如,依托泊苷)、抗生素(例如,道诺霉素、阿霉素、博来霉素)、酶(例如,L-天冬酰胺酶)、丝裂原活化蛋白激酶信号传递抑制剂(例如U0126、PD98059、PD184352、PD0325901、ARRY-142266、SB239063、SP600125、BAY43-9006、渥曼青霉素或LY294002、Syk抑制剂、mTOR抑制剂、抗体(例如,美罗华)、棉子酚(gossyphol)、根纳三思(genasense)、多酚E、氯氟新(Chlorofusin)、全反式视磺酸(ATRA)、苔藓抑素、肿瘤坏死因子相关的凋亡诱导配体(TRAIL)、5-氮杂-2'-脱氧胞苷、全反式视磺酸、阿霉素、长春新碱、依托泊苷、吉西他滨、伊马替尼(Gleevec.RTM.)、格尔德霉素、17-N-烯丙基氨基-17-去甲氧格尔德霉素(17-AAG)、夫拉平度、LY294002、硼替佐米、曲妥单抗、BAY11-7082、PKC412、PD184352、20-表-1,25二羟维生素D3;5-乙炔基尿嘧啶;阿比特龙;阿柔比星;酰基富烯(acylfulvene);腺环戊醇;阿多来新;阿地白介素;ALL-TK拮抗剂;六甲蜜胺;氨莫司汀;阿米达斯(amidox);阿米斯丁(amifostine);氨基乙酰丙酸;氨柔比星;安吖啶;阿那格雷;阿那曲唑;穿心莲内酯(andrographolide);血管生成抑制剂;拮抗剂D;拮抗剂G;安雷利克斯;抗背部化形态发生蛋白-1;抗雄激素药;前列腺癌;抗雌激素药;抗瘤酮(antineoplaston);反义寡核苷酸;甘氨酸艾菲地可宁(aphidicolinglycinate);凋亡基因调节剂;凋亡调节剂;脱嘌呤核酸;ara-CDP-DL-PTBA;精氨酸脱氨基酶;阿苏拉瑞(asulacrine);阿他美坦;阿曲氮芥(atrimustine);海洋环肽1(axinastatin1);海洋环肽2;海洋环肽3;阿扎司琼;阿扎毒素(azatoxin);重氮酪氨酸;浆果赤霉素III衍生物;巴拉醇(balanol);巴马司他;BCR/ABL拮抗剂;苯并二氢卟吩(benzochlorins);苯甲酰星形孢菌素(benzoylstaurosporine);β-内酰胺衍生物;β-阿勒欣(alethine);β-克拉霉素(clamycin)B;桦木酸;bFGF抑制剂;比卡鲁胺;比生群(bisantrene);双氮杂环丙烯基精素(bisaziridinylspermine);双奈法德;双枸缘酸环己噻卓酯A(bistrateneA);比折来新(bizelesin);布雷福特(breflate);溴匹利明;布朵替坦;丁硫氨酸亚砜亚胺(buthioninesulfoximine);卡泊三醇;卡弗他丁C(calphostinC);喜树碱衍生物;金丝雀痘IL-2;卡培他宾;甲酰胺-氨基-三唑;羧基酰胺基三唑;CaRestM3;CARN700;软骨源抑制剂;卡折来新;酪蛋白激酶抑制剂(ICOS);粟树精胺;天蚕抗菌肽(cecropin)B;西曲瑞克;二氢卟吩;氯喹喔啉磺酰胺;西卡前列素;顺卟啉;克拉屈宾;氯米芬类似物;克霉唑;克里霉素A(collismycinA);克里霉素B;考布他汀A4(combretastatinA4);考布他汀类似物;克纳宁(conagenin);科莱贝司丁816(crambescidin816);克雷斯托;念珠藻环肽8(cryptophycin8);念珠藻环肽A衍生物;库拉欣A(curacinA);环戊蒽醌;环普拉坦(cycloplatam);塞培霉素(cypemycin);阿糖胞苷十八烷基磷酸盐;溶细胞因子;磷酸己烷雌酚(cytostatin);达昔单抗;地西他宾;脱氢膜海鞘素B(dehydrodidemninB);地洛瑞林;地塞米松;右异环磷酰胺(dexifosfamide);右丙亚胺;右维拉帕米;地吖醌;膜海鞘素B;二羟基苯并氧肟酸(didox);二乙基去甲精胺(diethylnorspermine);二氢-5-氮杂胞苷;9-二氧霉素(9-dioxamycin);二苯基螺莫斯汀(diphenylspiromustine);二十二醇;多拉司琼;脱氧氟尿苷;屈洛昔芬;屈大麻酚;多卡霉素SA(duocarmycinSA);依布硒啉;依考莫司汀;依地福新;依决洛单抗;依氟鸟氨酸;榄香烯;乙嘧替氟;表柔比星;依立雄胺(epristeride);雌莫司汀类似物;雌激素激动剂;雌激素拮抗剂;依他硝唑;磷酸依托泊苷;依托泊苷;依西美坦;法曲唑;法扎拉宾;维甲酰酚胺;非格司亭;非那雄胺;夫拉平度;氟卓斯汀;夫卢丝龙(fluasterone);氟达拉滨;盐酸氟代柔红霉素(fluorodaunorunicin);伏芬尼美司(forfenimex);福美司坦;佛司曲辛(fostriecin);福莫司汀;德卟啉钆(gadoliniumtexaphyrin);硝酸镓;加洛他宾;加尼瑞克;明胶酶抑制剂;吉西他滨;谷胱甘肽抑制剂;赫舒反(hepsulfam);调蛋白(heregulin);六亚甲基二乙酰胺;金丝桃素;伊班膦酸;伊达比星;艾多昔芬;伊决孟酮;伊莫福新;伊洛马司他;咪唑并吖啶酮;咪喹莫特;免疫刺激肽;胰岛素样生长因子-1受体抑制剂;干扰素激动剂;干扰素;白介素;碘苄胍;碘阿霉素;4-甘薯苦醇;伊罗普拉;伊索拉定;异本格唑(isobengazole);异高软海绵素B(isohomohalicondrinB);伊他司琼;结丝立得(jasplakinolide);卡哈拉得F(kahalalideF);片螺素-N三乙酸;兰瑞肽;雷纳霉素(leinamycin);来格司亭;硫酸蘑菇多糖(lentinansulfate);莱托斯汀(leptolstatin);来曲唑;白血病抑制因子;白细胞α干扰素;亮丙立德(leuprolide)+雌激素+孕酮;亮丙瑞林(leuprorelin);左旋咪唑;利阿唑;直链多胺类似物;亲脂性二糖肽;亲脂性钼化合物;利索纳得7(lissoclinamide7);洛铂;胍乙基磷酸丝氨酸(lombricine);洛美曲索;氯尼达明;洛索蒽醌;洛伐他汀;洛索立宾;勒托替康;德卟啉镥(lutetiumtexaphyrin);莱索菲林(lysofylline);细胞裂解肽;美坦辛;慢诺他汀A(mannostatinA);马立马司他(marimastat);马索罗酚(masoprocol);马斯平(maspin);基质溶解因子抑制;基质金属蛋白酶抑制剂;美诺立尔;麦尔巴隆(merbarone);美替瑞林(meterelin);甲硫氨酸酶;甲氧氯普胺(metoclopramide);MIF抑制剂;米非司酮;米替福新;米立司亭;错配的双链RNA;米托胍腙;二溴卫矛醇;丝裂霉素类似物;米托萘胺;米托毒素(mitotoxin)成纤维细胞生长因子-皂草毒蛋白;米托蒽醌;莫法罗汀;莫拉司亭;单克隆抗体,人绒毛膜促性腺激素;单磷酰基脂质A+分枝杆菌细胞壁骨架;莫哌达醇;多药耐药基因抑制剂;基于多肿瘤抑制基因1的疗法;芥类抗癌剂;印度洋海绵B(mycaperoxideB);分枝杆菌细胞壁提取物;米亚普龙(myriaporone);N-乙酰基地那林(N-acetyldinaline);N-取代的苯甲酰胺;那法瑞林;那瑞替喷(nagrestip);纳洛酮+镇痛新;纳帕英(napavin);萘萜二醇(naphterpin);那托司亭;奈达铂;奈莫柔比星;奈立膦酸;中性内肽酶;尼鲁米特;尼萨霉素(nisamycin);氮氧化物调节剂;硝基氧抗氧化剂;尼多林(nitrullyn);O6-苄基鸟嘌呤;奥曲肽;奥可斯酮(okicenone);寡核苷酸;奥那司酮;昂丹司琼;奥莱辛(oracin);口服细胞因子诱导物;奥马铂;奥沙特隆;奥沙利铂;奥沙霉素(oxaunomycin);帕劳胺(palauamine);棕榈酰根霉素(palmitoylrhizoxin);帕米膦酸;人参炔三醇;帕诺米芬;副菌铁素(parabactin);帕折普汀(pazelliptine);培门冬酶;培得星(peldesine);戌聚糖聚硫酸钠;喷司他丁;喷托唑(pentrozole);全氟溴烷;培磷酰胺;紫苏子醇(perillylalcohol);苯那霉素(phenazinomycin);乙酸苯酯;磷酸酶抑制剂;皮西巴尼(picibanil);盐酸匹鲁卡品;吡柔比星;吡曲克辛;胎盘素A(placetinA);胎盘素B;纤溶酶原激活物抑制剂;铂络合物;铂化合物;铂-三胺络合物;卟吩姆钠;泊非霉素(porfiromycin);强的松;丙基双吖啶酮;前列腺素J2;蛋白酶体抑制剂;基于蛋白A的免疫调节剂;蛋白激酶C抑制剂;微藻(microalgal);蛋白质酪氨酸磷酸酶抑制剂;嘌呤核苷磷酸化酶抑制剂;红紫素(purpurin);吡唑并吖啶(pyrazoloacridine);吡哆醛化的血红蛋白聚氧乙烯偶联物;raf拮抗剂;雷替曲塞;雷莫司琼;ras法呢基蛋白转移酶抑制剂;ras抑制剂;ras-GAP抑制剂;去甲基化的瑞替普汀(retelliptine);依替膦酸铼Re186;根霉素;核酶;RII维甲酰胺(retinamide);罗谷亚胺;罗希吐碱;罗莫肽;罗喹美克;卢比格酮B1(rubiginoneB1);卢伯西(ruboxyl);沙芬戈;伞托平(saintopin);SarCNU;萨可菲醇A(sarcophytolA);沙格司亭;Sdi1模拟物;司莫司汀;衰老衍生的抑制剂1;有义寡核苷酸;信号转导抑制剂;信号转导调节剂;单链抗原结合蛋白;西佐喃(sizofuran);索布佐生;硼卡钠;苯基乙酸钠;索尔醇(solverol);生长调节素结合蛋白;索纳明;斯帕磷酸(sparfosicacid);斯卡霉素D(SpicamycinD);螺莫司汀;脾脏五肽(splenopentin);海绵抑素1(spongistatin1);角鲨胺;干细胞抑制剂;干细胞分裂抑制剂;斯提酰胺(stipiamide);基质分解素抑制剂;斯菲诺辛(sulfinosine);强效血管活性肠肽拮抗剂;素拉迪塔(suradista);苏拉明;苦马豆碱;合成粘多糖;他莫司汀;甲碘化他莫昔芬(tamoxifenmethiodide);牛磺莫司汀;他扎罗汀;替可加兰钠;替加氟;碲吡喃洋(tellurapyrylium);端粒酶抑制剂;替莫泊芬;替莫唑胺;替尼泊苷;十氧化四氯(tetrachlorodecaoxide);四佐胺(tetrazomine);泰立拉汀(thaliblastine);噻可拉林(thiocoraline);血小板生成素;血小板生成素模拟物;胸腺法新;胸腺生成素受体激动剂;胸腺曲南;促甲状腺激素;本紫红素乙酯锡;替拉扎明;二氯环戊二烯钛;拓扑森汀(topsentin);托瑞米芬;全能干细胞因子;翻译抑制剂;维甲酸;三乙酰基尿苷;曲西立滨;三甲曲沙;曲普瑞林;托烷司琼;妥罗雄脲;酪氨酸激酶抑制剂;酪氨酸磷酸化抑制剂;UBC抑制剂;乌苯美司;泌尿生殖窦衍生的生长抑制因子;尿激酶受体拮抗剂;伐普肽;瓦立奥林B(variolinB);载体系统,红细胞基因疗法;维拉雷琐;藜芦胺;瓦尔丁(verdins);维替泊芬;长春瑞宾;威科萨汀(vinxaltine);维他辛(Vitaxin);伏氯唑;扎诺特隆;折尼铂;亚苄维C(zilascorb);净司他丁斯酯(zinostatinstimalamer);亚德里亚霉素;放线菌素D;博来霉素;长春碱;顺铂;阿西维辛;阿柔比星;盐酸阿考达唑;阿克罗宁;阿多来新;阿地白介素;六甲蜜胺;安波霉素;醋酸阿美蒽醌;氨鲁米特;安吖啶;阿那曲唑;安曲霉素;天冬酰胺酶;曲林菌素;阿扎胞苷;阿扎替派;阿佐霉素;巴马司他;苄替派;比卡鲁胺;盐酸比生群;二甲磺酸双奈法德;比折来新;硫酸博来霉素;布喹那钠;溴匹利明;白消安;放线菌素C;卡鲁睾酮;卡醋胺;卡贝替姆;卡铂;卡莫司汀;盐酸卡柔比星;卡折来新;西地芬戈;苯丁酸氮芥;西罗霉素;克拉屈宾;甲磺酸克雷斯托;环磷酰胺;阿糖胞苷;达卡巴嗪;盐酸道诺霉素;地西他宾;右奥马铂;地扎胍宁;甲磺酸地扎胍宁;地吖醌;阿霉素;盐酸阿霉素;屈洛昔芬;柠檬酸屈洛昔芬;丙酸屈他雄酮;达佐霉素;依达曲沙;盐酸依氟鸟氨酸;依沙芦星;恩洛铂;恩普氨酯;依匹哌啶;盐酸表柔比星;厄布洛唑;盐酸依索比星;雌莫司汀;雌莫司汀磷酸钠;依他硝唑;依托泊苷;磷酸依托泊苷;艾托卜宁;盐酸法曲唑;法扎拉宾;维甲酰酚胺;氟尿苷;磷酸氟达拉滨;氟尿嘧啶;氟西他滨(fluorocitabine);磷喹酮(fosquidone);佛司曲辛钠;吉西他滨;盐酸吉西他滨;羟基脲;盐酸伊达比星;异环磷酰胺;伊莫福新(iimofosine);白介素I1(包括重组白介素II或rlL.sub.2)、干扰素α-2a;干扰素α-2b;干扰素α-n1;干扰素α-n3;干扰素β-1a;干扰素γ-1b;异丙铂(iproplatin);盐酸伊立替康;乙酸兰瑞肽;来曲唑;乙酸亮丙瑞林;盐酸利阿唑;洛美曲索钠;洛莫司汀;盐酸洛索蒽醌;马索罗酚;美登素;盐酸氮芥;醋酸甲地孕酮;醋酸美仑孕酮;美法仑;美诺立尔;巯基嘌呤;甲氨蝶呤;甲氨蝶呤钠;氯苯氨啶;美妥替哌;米丁度胺;米托卡西(mitocarcin);丝裂红素(mitocromin);丝林霉素(mitogillin);米托马星;丝裂霉素;米托司培;米托坦;盐酸米托蒽醌;麦考酚酸;诺考达唑(nocodazoie);诺拉霉素;奥马铂;奥昔舒仑;培门冬酶;培利霉素;奈莫司汀(pentamustine);硫酸培洛霉素;培磷酰胺;哌泊溴烷;哌泊舒凡;盐酸吡罗蒽醌;普卡霉素;普洛美坦;卟吩姆钠;泊非霉素;泼尼莫司汀;盐酸丙卡巴肼;嘌呤霉素;盐酸嘌呤霉素;吡唑呋喃菌素;利波腺苷;罗谷亚胺;沙芬戈;盐酸沙芬戈;司莫司汀;辛曲秦;磷乙酰天冬氨酸钠(sparfosatesodium);司帕霉素;盐酸锗螺胺;螺莫司汀;螺铂;链黑霉素;链脲霉素;磺氯苯脲;他利霉素;替可加兰钠;替加氟;盐酸替洛蒽醌;替莫泊芬;替尼泊苷;替罗昔隆;睾内酯;硫咪嘌呤;硫鸟嘌呤;塞替派;噻唑呋林(tiazofurin);替拉扎明;柠檬酸托瑞米芬;乙酸曲托龙;磷酸曲西立滨;三甲曲沙;葡醛酸三甲曲沙;曲普瑞林;盐酸妥布氯唑;尿嘧啶氮芥;乌瑞替派;伐普肽;维替泊芬;硫酸长春碱;硫酸长春新碱;长春地辛;硫酸长春地辛;硫酸长春匹定;硫酸长春甘酯;硫酸长春罗新;酒石酸长春瑞宾;硫酸长春罗定;硫酸长春利定;伏氯唑;折尼铂;净司他丁;盐酸佐柔比星、阻止G2-M期细胞和/或调节微管形成或稳定性的药剂(例如泰素(Taxol).TM(即紫杉醇)、泰素帝(Taxotere).TM、包含紫杉烷骨架的化合物、厄布洛唑(即R-55104)、尾海兔素10(即DLS-10和NSC-376128)、羟乙基磺酸米伏布尔(Mivobulinisethionate)(即如CI-980)、长春新碱、NSC-639829、圆皮海绵内酯(即如NVP-XX-A-296)、ABT-751(Abbott,即E-7010)、奥图海汀(Altorhyrtin)(例如奥图海汀A和奥图海汀C)、海绵抑素(例如海绵抑素1、海绵抑素2、海绵抑素3、海绵抑素4、海绵抑素5、海绵抑素6、海绵抑素7、海绵抑素8和海绵抑素9)、盐酸西马多丁(即LU-103793和NSC-D-669356)、埃坡霉素(例如埃坡霉素A、埃坡霉素B、埃坡霉素C(即去氧埃坡霉素A或dEpoA)、埃坡霉素D(即KOS-862、dEpoB和去氧埃坡霉素B)、埃坡霉素E、埃坡霉素F、埃坡霉素BN-氧化物、埃坡霉素AN-氧化物、16-氮杂-埃坡霉素B、21-氨基埃坡霉素B(即BMS-310705)、21-羟基埃坡霉素D(即去氧埃坡霉素F和dEpoF)、26-氟埃坡霉素、澳瑞他汀(Auristatin)PE(即NSC-654663)、索利多汀(Soblidotin)(即TZT-1027)、LS-4559-P(Pharmacia,即LS-4577)、LS-4578(Pharmacia,即LS-477-P)、LS-4477(Pharmacia)、LS-4559(Pharmacia)、RPR-112378(Aventis)、硫酸长春新碱、DZ-3358(Daiichi)、FR-182877(Fujisawa,即WS-9265B)、GS-164(Takeda)、GS-198(Takeda)、KAR-2(HungarianAcademyofSciences)、BSF-223651(BASF,即ILX-651和LU-223651)、SAH-49960(Lilly/Novartis)、SDZ-268970(Lilly/Novartis)、AM-97(Armad/KyowaHakko)、AM-132(Armad)、AM-138(Armad/KyowaHakko)、IDN-5005(Indena)、念珠藻环肽52(即LY-355703)、AC-7739(Ajinomoto,即AVE-8063A和CS-39.HCl)、AC-7700(Ajinomoto,即AVE-8062、AVE-8062A、CS-39-L-Ser.HCl和RPR-258062A)、维替利胺(Vitilevuamide)、土布来星(Tubulysin)A、卡纳登索(Canadensol)、矢车菊黄素(即NSC-106969)、T-138067(Tularik,即T-67、TL-138067和TI-138067)、COBRA-1(ParkerHughesInstitute,即DDE-261和WHI-261)、H10(KansasStateUniversity)、H16(KansasStateUniversity)、奥克西丁(Oncocidin)A1(即BTO-956和DIME)、DDE-313(ParkerHughesInstitute)、福佳立德(Fijianolide)B、劳马立德(Laulimalide)、SPA-2(ParkerHughesInstitute)、SPA-1(ParkerHughesInstitute,即SPIKET-P)、3-IAABU(Cytoskeleton/Mt.SinaiSchoolofMedicine,即MF-569)、那可丁(Narcosine)(亦称为NSC-5366)、那可平(Nascapine)、D-24851(AstaMedica)、A-105972(Abbott)、哈米特林(Hemiasterlin)、3-BAABU(Cytoskeleton/Mt.SinaiSchoolofMedicine,即MF-191)、TMPN(ArizonaStateUniversity)、乙酸丙酮二茂钒(Vanadoceneacetylacetonate)、T-138026(Tularik)、蒙萨曲尔(Monsatrol)、因诺可(Inanocine)(即NSC-698666)、3-IAABE(Cytoskeleton/Mt.SinaiSchoolofMedicine)、A-204197(Abbott)、T-607(Tuiarik,即T-900607)、RPR-115781(Aventis)、伊斯罗宾(Eleutherobin)(诸如脱甲基伊斯罗宾(Desmethyleleutherobin)、脱乙酸基伊斯罗宾(Desaetyleleutherobin)、异伊斯罗宾(Isoeleutherobin)A和Z-伊斯罗宾(Ζ-Eleutherobin))、卡巴斯德(Caribaeoside)、卡巴林(Caribaeolin)、软海绵素B、D-64131(AstaMedica)、D-68144(AstaMedica)、二唑酰胺(Diazonamide)A、A-293620(Abbott)、NPI-2350(Nereus)、箭根薯酮内酯(Taccalonolide)A、TUB-245(Aventis)、A-259754(Abbott)、戴佐斯他汀(Diozostatin)、(-)-苯阿斯汀((-)-Phenylahistin)(即NSCL-96F037)、D-62638(AstaMedica)、D-62636(AstaMedica)、肌基质蛋白(Myoseverin)B、D-43411(Zentaris,即D-81862)、A-289099(Abbott)、A-318315(Abbott)、HTI-286(即SPA-110,三氟乙酸盐)(Wyeth)、D-82317(Zentaris)、D-82318(Zentaris)、SC-12983(NCI)、瑞伐斯他汀磷酸钠(Resverastatinphosphatesodium)、BPR-OY-007(NationalHealthResearchInstitutes)和SSR-250411(Sanofi))、类固醇(例如,地塞米松)、非那雄胺、芳香化酶抑制剂、促性腺激素释放素激动剂(GnRH)(诸如戈舍瑞林或亮丙瑞林)、肾上腺皮质类固醇(例如,强的松)、孕酮(例如,己酸羟孕酮、醋酸甲地孕酮、乙酸甲羟孕酮)、雌激素(例如,己烯雌酚、炔雌醇)、抗雌激素药(例如,他莫昔芬)、雄激素(例如,丙酸睾酮、氟甲睾酮)、抗雄激素药(例如,氟他米特)、免疫刺激剂(例如,卡介苗(BacillusCalmette-Guérin)(BCG)、左旋咪唑、白介素-2、α-干扰素等)、单克隆抗体(例如,抗-CD20、抗-HER2、抗-CD52、抗-HLA-DR和抗-VEGF单克隆抗体)、免疫毒素(例如,抗-CD33单克隆抗体-卡里奇霉素缀合物、抗-CD22单克隆抗体-假单胞菌外毒素缀合物等)、放射免疫疗法(例如,与111In、90Y或131I缀合的抗-CD20单克隆抗体等)、雷公藤甲素、高三尖杉酯碱、放线菌素D、阿霉素、表柔比星、拓扑替康、伊曲康唑、长春地辛、西立伐他汀、长春新碱、脱氧腺苷、舍曲林、匹伐他汀、伊立替康、氯法齐明、5-壬基氧基色胺、维罗非尼、达拉菲尼、埃罗替尼、吉非替尼、EGFR抑制剂、表皮生长因子受体(EGFR)靶向疗法或治疗(例如吉非替尼(IressaTM)、埃罗替尼(TarcevaTM)、西妥昔单抗(ErbituxTM)、拉帕替尼(TykerbTM)、帕尼单抗(VectibixTM)、凡德他尼(CaprelsaTM)、阿法替尼/BIBW2992、CI-1033/卡奈替尼、来那替尼/HKI-272、CP-724714、TAK-285、AST-1306、ARRY334543、ARRY-380、AG-1478、达克替尼(dacomitinib)/PF299804、OSI-420/去甲基埃罗替尼、AZD8931、AEE726、培利替尼/EKB-569、CUDC-101、WZ8040、WZ4002、WZ3146、AG-490、XL647、PD153035、BMS-599626)、索拉非尼、伊马替尼、舒尼替尼、达沙替尼等。
“化学疗法的”或“化学治疗剂”是按照它的普通含义使用,且是指具有抗肿瘤性质或抑制细胞生长或增殖能力的化学组合物或化合物。
此外,本文所述化合物可与传统免疫治疗剂共同施用,包括(但不限于)免疫刺激剂(例如,卡介苗(BCG)、左旋咪唑、白介素-2、α-干扰素等)、单克隆抗体(例如,抗-CD20、抗-HER2、抗-CD52、抗-HLA-DR和抗-VEGF单克隆抗体)、免疫毒素(例如,抗-CD33单克隆抗体-卡里奇霉素缀合物、抗-CD22单克隆抗体-假单胞菌外毒素缀合物等)和放射免疫疗法(例如,与111In、90Y或131I缀合的抗-CD20单克隆抗体等)。
在另一实施方案中,本文所述化合物可与传统放射性治疗剂共同施用,放射性治疗剂包括(但不限于)任选地与针对肿瘤抗原的抗体缀合的放射性核素,诸如47Sc、64Cu、67Cu、89Sr、86Y、87Y、90Y、105Rh、111Ag、111In、117mSn、149Pm、153Sm、166Ho、177Lu、186Re、126Re、211At和212Bi。
I.组合物
本文提供化合物,或其药学上可接受的盐,其具有下式:
在式(I)化合物中,L是键、取代或未取代的亚烷基或者取代或未取代的杂亚烷基。R1是氢、卤素、-CX1 3、-OCX1 3、-CN、-OH、-NH2、-COOH、-C(O)OR4、-CONH2、-NO2、-SH、-NHNH2、-NR2R3、-OR4、-SR4、取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。X1独立地为卤素。R2和R3独立地为取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基,或者R2和R3任选地连接在一起形成取代或未取代的杂环烷基或者取代或未取代的杂芳基。R4是取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。R5和R6独立地为氢、卤素、-CX2 3、-OCX2 3、-CN、-OH、-NH2、-COOH、-C(O)OR9、-CONH2、-NO2、-SH、-NHNH2、-NR7R8、-OR9、-SR9、取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。X2独立地为卤素。R7和R8独立地为取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基,或者R7和R8任选地连接在一起形成取代或未取代的杂环烷基或者取代或未取代的杂芳基。R9是取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。
本文提供化合物,或其药学上可接受的盐,其具有下式:
在式(I)化合物中,L是键或取代或未取代的亚烷基。R1是氢、卤素、-CX1 3、-OCX1 3、-CN、-OH、-NH2、-COOH、-C(O)OR4、-CONH2、-NO2、-SH、-NHNH2、-NR2R3、-OR4、-SR4、取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。X1独立地为卤素。R2和R3独立地为取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基,或者R2和R3任选地连接在一起形成取代或未取代的杂环烷基或者取代或未取代的杂芳基。R4是取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。R5和R6独立地为氢、卤素、-CX2 3、-OCX2 3、-CN、-OH、-NH2、-COOH、-C(O)OR9、-CONH2、-NO2、-SH、-NHNH2、-NR7R8、-OR9、-SR9、取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。X2独立地为卤素。R7和R8独立地为取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基,或者R7和R8任选地连接在一起形成取代或未取代的杂环烷基或者取代或未取代的杂芳基。R9是取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。
在实施方案中,L是取代或未取代的亚烷基。L可以是未取代的亚烷基。L可以是未取代的C1-C8亚烷基。L可以是未取代的C1-C4亚烷基。L可以是未取代的C2亚烷基。L可以是未取代的亚甲基。在实施方案中,L是键。在实施方案中,L独立地为键或者被R47取代或未被R47取代的亚烷基。
R47独立地为氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、R48-取代或未取代的烷基、R48-取代或未取代的杂烷基、R48-取代或未取代的环烷基、R48-取代或未取代的杂环烷基、R48-取代或未取代的芳基、或者R48-取代或未取代的杂芳基。
R48独立地为氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、R49-取代或未取代的烷基、R49-取代或未取代的杂烷基、R49-取代或未取代的环烷基、R49-取代或未取代的杂环烷基、R49-取代或未取代的芳基、或者R49-取代或未取代的杂芳基。
在实施方案中,R1是卤素、-CX1 3、-OCX1 3、-CN、-OH、-NH2、-COOH、-C(O)OR4、-CONH2、-NO2、-SH、-NHNH2、-NR2R3、-OR4、-SR4、取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。在实施方案中,X1独立地为-F。在实施方案中,X1独立地为-Cl。在实施方案中,X1独立地为-I。在实施方案中,X1独立地为-Br。在实施方案中,R1为-NR2R3。在实施方案中,R1为取代的烷基。R1可以是取代的C1-C8烷基。在实施方案中,R1为取代的C1-C4烷基。R1可以是取代的乙基。在实施方案中,R1为取代的甲基。在实施方案中,R1不是氢。
在实施方案中,R1独立地为氢、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-NHNH2、-OCF3、-OCHF2、R20-取代或未取代的烷基、R20-取代或未取代的杂烷基、R20-取代或未取代的环烷基、R20-取代或未取代的杂环烷基、R20-取代或未取代的芳基、或者R20-取代或未取代的杂芳基。
在实施方案中,R1独立地为卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-NHNH2、-OCF3、-OCHF2、R20-取代或未取代的烷基、R20-取代或未取代的杂烷基、R20-取代或未取代的环烷基、R20-取代或未取代的杂环烷基、R20-取代或未取代的的芳基、或者R20-取代或未取代的杂芳基。
R20独立地为氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、R21-取代或未取代的烷基、R21-取代或未取代的杂烷基、R21-取代或未取代的环烷基、R21-取代或未取代的杂环烷基、R21-取代或未取代的芳基、或者R21-取代或未取代的杂芳基。
R21独立地为氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、R22-取代或未取代的烷基、R22-取代或未取代的杂烷基、R22-取代或未取代的环烷基、R22-取代或未取代的杂环烷基、R22-取代或未取代的芳基、或者R22-取代或未取代的杂芳基。
在实施方案中,R2独立地为取代或未取代的烷基。R2可以独立地为取代或未取代的C1-C8烷基。R2可以独立地为取代的C1-C8烷基。R2可以独立地为未取代的C1-C8烷基。R2可以独立地为取代或未取代的C1-C4烷基。R2可以独立地为取代的C1-C4烷基。R2可以独立地为未取代的C1-C4烷基。R2可以独立地为-OH取代或未取代的C1-C4烷基。R2可以独立地为取代或未取代的甲基。R2可以独立地为取代或未取代的乙基。R2可以独立地为取代或未取代的丙基。在实施方案中,R2独立地为R23-取代或未取代的烷基、R23-取代或未取代的杂烷基、R23-取代或未取代的环烷基、R23-取代或未取代的杂环烷基、R23-取代或未取代的芳基、或者R23-取代或未取代的杂芳基。
在实施方案中,R2为取代或未取代的C1-C20烷基。R2可以是R23-取代或未取代的C1-C20烷基。R2可以是取代或未取代的C1-C10烷基。R2可以是R23-取代或未取代的C1-C10烷基。R2可以是取代或未取代的C1-C8烷基。R2可以是R23-取代或未取代的C1-C8烷基。R2可以是取代或未取代的C1-C5烷基。R2可以是R23-取代或未取代的C1-C5烷基。
在实施方案中,R2为取代或未取代的2至20元杂烷基。R2可以是R23-取代或未取代的2至20元杂烷基。R2可以是取代或未取代的2至10元杂烷基。R2可以是R23-取代或未取代的2至10元杂烷基。R2可以是取代或未取代的2至8元杂烷基。R2可以是R23-取代或未取代的2至8元杂烷基。R2可以是取代或未取代的2至6元杂烷基。R2可以是R23-取代或未取代的2至6元杂烷基。
在实施方案中,R2为取代或未取代的3至20元环烷基。R2可以是R23-取代或未取代的3至20元环烷基。R2可以是取代或未取代的3至10元环烷基。R2可以是R23-取代或未取代的3至10元环烷基。R2可以是取代或未取代的3至8元环烷基。R2可以是R23-取代或未取代的3至8元环烷基。R2可以是取代或未取代的3至6元环烷基。R2可以是R23-取代或未取代的3至6元环烷基。R2可以是取代或未取代的5元环烷基。R2可以是R23-取代或未取代的5元环烷基。R2可以是取代或未取代的6元环烷基。R2可以是R23-取代或未取代的6元环烷基。
在实施方案中,R2为取代或未取代的3至20元杂环烷基。R2可以是R23-取代或未取代的3至20元杂环烷基。R2可以是取代或未取代的3至10元杂环烷基。R2可以是R23-取代或未取代的3至10元杂环烷基。R2可以是取代或未取代的3至8元杂环烷基。R2可以是R23-取代或未取代的3至8元杂环烷基。R2可以是取代或未取代的3至6元杂环烷基。R2可以是R23-取代或未取代的3至6元杂环烷基。R2可以是取代或未取代的5元杂环烷基。R2可以是R23-取代或未取代的5元杂环烷基。R2可以是取代或未取代的6元杂环烷基。R2可以是R23-取代或未取代的6元杂环烷基。
在实施方案中,R2为取代或未取代的5至10元芳基。R2可以是R23-取代或未取代的5至10元芳基。R2可以是取代或未取代的5至8元芳基。R2可以是R23-取代或未取代的5至8元芳基。R2可以是取代或未取代的6元芳基。R2可以是R23-取代或未取代的6元芳基。
在实施方案中,R2为取代或未取代的5至10元杂芳基。R2可以是R23-取代或未取代的5至10元杂芳基。R2可以是取代或未取代的5至8元杂芳基。R2可以是R23-取代或未取代的5至8元杂芳基。R2可以是取代或未取代的6元杂芳基。R2可以是R23-取代或未取代的6元杂芳基。
R23独立地为氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、R24-取代或未取代的烷基、R24-取代或未取代的杂烷基、R24-取代或未取代的环烷基、R24-取代或未取代的杂环烷基、R24-取代或未取代的芳基、或者R24-取代或未取代的杂芳基。R23可以独立地为-OH。R23可以独立地为未取代的甲基。R23可以独立地为R24-取代或未取代的杂烷基。R23可以独立地为R24-取代或未取代的烷基。R23可以独立地为R24-取代或未取代的C1-C4烷基。
R24独立地为氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、R25-取代或未取代的烷基、R25-取代或未取代的杂烷基、R25-取代或未取代的环烷基、R25-取代或未取代的杂环烷基、R25-取代或未取代的芳基、或者R25-取代或未取代的杂芳基。R24可以独立地为-OH。
在实施方案中,R3独立地为取代或未取代的烷基。R3可以独立地为取代或未取代的C1-C8烷基。R3可以独立地为取代的C1-C8烷基。R3可以独立地为未取代的C1-C8烷基。R3可以独立地为取代或未取代的C1-C4烷基。R3可以独立地为取代的C1-C4烷基。R3可以独立地为未取代的C1-C4烷基。R3可以独立地为-OH取代或未取代的C1-C4烷基。R3可以独立地为取代或未取代的甲基。R3可以独立地为取代或未取代的乙基。R3可以独立地为取代或未取代的丙基。在实施方案中,R3独立地为R26-取代或未取代的烷基、R26-取代或未取代的杂烷基、R26-取代或未取代的环烷基、R26-取代或未取代的杂环烷基、R26-取代或未取代的芳基、或者R26-取代或未取代的杂芳基。
在实施方案中,R3为取代或未取代的C1-C20烷基。R3可以是R26-取代或未取代的C1-C20烷基。R3可以是取代或未取代的C1-C10烷基。R3可以是R26-取代或未取代的C1-C10烷基。R3可以是取代或未取代的C1-C8烷基。R3可以是R26-取代或未取代的C1-C8烷基。R3可以是取代或未取代的C1-C5烷基。R3可以是R26-取代或未取代的C1-C5烷基。
在实施方案中,R3为取代或未取代的2至20元杂烷基。R3可以是R26-取代或未取代的2至20元杂烷基。R3可以是取代或未取代的2至10元杂烷基。R3可以是R26-取代或未取代的2至10元杂烷基。R3可以是取代或未取代的2至8元杂烷基。R3可以是R26-取代或未取代的2至8元杂烷基。R3可以是取代或未取代的2至6元杂烷基。R3可以是R26-取代或未取代的2至6元杂烷基。
在实施方案中,R3为取代或未取代的3至20元环烷基。R3可以是R26-取代或未取代的3至20元环烷基。R3可以是取代或未取代的3至10元环烷基。R3可以是R26-取代或未取代的3至10元环烷基。R3可以是取代或未取代的3至8元环烷基。R3可以是R26-取代或未取代的3至8元环烷基。R3可以是取代或未取代的3至6元环烷基。R3可以是R26-取代或未取代的3至6元环烷基。R3可以是取代或未取代的5元环烷基。R3可以是R26-取代或未取代的5元环烷基。R3可以是取代或未取代的6元环烷基。R3可以是R26-取代或未取代的6元环烷基。
在实施方案中,R3为取代或未取代的3至20元杂环烷基。R3可以是R26-取代或未取代的3至20元杂环烷基。R3可以是取代或未取代的3至10元杂环烷基。R3可以是R26-取代或未取代的3至10元杂环烷基。R3可以是取代或未取代的3至8元杂环烷基。R3可以是R26-取代或未取代的3至8元杂环烷基。R3可以是取代或未取代的3至6元杂环烷基。R3可以是R26-取代或未取代的3至6元杂环烷基。R3可以是取代或未取代的5元杂环烷基。R3可以是R26-取代或未取代的5元杂环烷基。R3可以是取代或未取代的6元杂环烷基。R3可以是R26-取代或未取代的6元杂环烷基。
在实施方案中,R3为取代或未取代的5至10元芳基。R3可以是R26-取代或未取代的5至10元芳基。R3可以是取代或未取代的5至8元芳基。R3可以是R26-取代或未取代的5至8元芳基。R3可以是取代或未取代的6元芳基。R3可以是R26-取代或未取代的6元芳基。
在实施方案中,R3为取代或未取代的5至10元杂芳基。R3可以是R26-取代或未取代的5至10元杂芳基。R3可以是取代或未取代的5至8元杂芳基。R3可以是R26-取代或未取代的5至8元杂芳基。R3可以是取代或未取代的6元杂芳基。R3可以是R26-取代或未取代的6元杂芳基。
R26独立地为氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、R27-取代或未取代的烷基、R27-取代或未取代的杂烷基、R27-取代或未取代的环烷基、R27-取代或未取代的杂环烷基、R27-取代或未取代的芳基、或者R27-取代或未取代的杂芳基。R26可以独立地为-OH。R26可以独立地为未取代的甲基。R23可以独立地为R24-取代或未取代的杂烷基。R26可以独立地为R27-取代或未取代的烷基。R26可以独立地为R27-取代或未取代的C1-C4烷基。
R27独立地为氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、R28-取代或未取代的烷基、R28-取代或未取代的杂烷基、R28-取代或未取代的环烷基、R28-取代或未取代的杂环烷基、R28-取代或未取代的芳基、或者R28-取代或未取代的杂芳基。R27可以独立地为-OH。
在实施方案中,R2和R3连接在一起形成取代或未取代的杂环烷基或者取代或未取代的杂芳基。R2和R3可连接在一起形成取代或未取代的杂环烷基。R2和R3可连接在一起形成取代或未取代的3至8元杂环烷基。R2和R3可连接在一起形成被取代的3至8元杂环烷基。R2和R3可连接在一起形成取代或未取代的5至7元杂环烷基。R2和R3可连接在一起形成被取代的5至7元杂环烷基。R2和R3可连接在一起形成取代或未取代的4元杂环烷基。R2和R3可连接在一起形成取代或未取代的5元杂环烷基。R2和R3可连接在一起形成取代或未取代的6元杂环烷基。
R2和R3可连接在一起形成R23-取代或未取代的杂环烷基。R2和R3可连接在一起形成R23-取代或未取代的5至7元杂环烷基。R2和R3可连接在一起形成R23-取代或未取代的4元杂环烷基。R2和R3可连接在一起形成R23-取代或未取代的5至7元杂环烷基,其中R23独立地为取代或未取代的烷基或者取代或未取代的杂烷基。R2和R3可连接在一起形成R23取代的5至7元杂环烷基,其中R23独立地为取代或未取代的C1-C8烷基或者取代或未取代的2至8元杂烷基。
在实施方案中,R2和R3连接在一起形成取代或未取代的吡咯烷基。在实施方案中,R2和R3连接在一起形成取代或未取代的哌嗪基。在实施方案中,R2和R3连接在一起形成R23-取代或未取代的吡咯烷基。在实施方案中,R2和R3连接在一起形成R23-取代或未取代的哌嗪基。R23是如本文中所述,包括其实施方案。在实施方案中,R2和R3连接在一起形成R24-取代或未取代的苯二甲酰亚胺基。
在实施方案中,R4独立地为R29-取代或未取代的烷基、R29-取代或未取代的杂烷基、R29-取代或未取代的环烷基、R29-取代或未取代的杂环烷基、R29-取代或未取代的芳基、或者R29-取代或未取代的杂芳基。
R29独立地为氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、R30-取代或未取代的烷基、R30-取代或未取代的杂烷基、R30-取代或未取代的环烷基、R30-取代或未取代的杂环烷基、R30-取代或未取代的芳基、或者R30-取代或未取代的杂芳基。
R30独立地为氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、R31-取代或未取代的烷基、R31-取代或未取代的杂烷基、R31-取代或未取代的环烷基、R31-取代或未取代的杂环烷基、R31-取代或未取代的芳基、或者R31-取代或未取代的杂芳基。
R5可以独立地为卤素、-CX2 3、-OCX2 3、-CN、-OH、-NH2、-COOH、-C(O)OR9、-CONH2、-NO2、-SH、-NHNH2、-NR7R8、-OR9、-SR9、取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。在实施方案中,R5独立地为-F。在实施方案中,R5独立地为-Cl。在实施方案中,R5独立地为-I。在实施方案中,R5独立地为-Br。在实施方案中,X2独立地为-F。在实施方案中,X2独立地为-Cl。在实施方案中,X2独立地为-I。在实施方案中,X2独立地为-Br。在实施方案中,R5为-NR7R8。
在实施方案中,R5是–C(O)OCH3。在实施方案中,R5是-OCH3。在实施方案中,R5是-OCH(CH3)2。在实施方案中,R5是-CN。在实施方案中,R5是-NO2。在实施方案中,R5是-NH2。在实施方案中,R5是卤素。在实施方案中,R5独立地为氢。在实施方案中,R5独立地为未取代的甲基。在实施方案中,R5独立地为-OCF3。在实施方案中,R5独立地为-NHAc。在实施方案中,R5独立地为-OH。在实施方案中,R5是未取代的烷基。R5可以是未取代的C1-C8烷基。在实施方案中,R5是未取代的C1-C4烷基。R5可以是未取代的乙基。在实施方案中,R5是未取代的甲基。在实施方案中,R5独立地为氢、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-NHNH2、-OCF3、-OCHF2、R32-取代或未取代的烷基、R32-取代或未取代的杂烷基、R32-取代或未取代的环烷基、R32-取代或未取代的杂环烷基、R32-取代或未取代的芳基、或者R32-取代或未取代的杂芳基。在实施方案中,R5独立地为卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-NHNH2、-OCF3、-OCHF2、R32-取代或未取代的烷基、R32-取代或未取代的杂烷基、R32-取代或未取代的环烷基、R32-取代或未取代的杂环烷基、R32-取代或未取代的芳基、或者R32-取代或未取代的杂芳基。在实施方案中,R5不是氢。
每个R32独立地为氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、R33-取代或未取代的烷基、R33-取代或未取代的杂烷基、R33-取代或未取代的环烷基、R33-取代或未取代的杂环烷基、R33-取代或未取代的芳基、或者R33-取代或未取代的杂芳基。
每个R33独立地为氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、R34-取代或未取代的烷基、R34-取代或未取代的杂烷基、R34-取代或未取代的环烷基、R34-取代或未取代的杂环烷基、R34-取代或未取代的芳基、或者R34-取代或未取代的杂芳基。
R6可以独立地为卤素、-CX2 3、-OCX2 3、-CN、-OH、-NH2、-COOH、-C(O)OR9、-CONH2、-NO2、-SH、-NHNH2、-NR7R8、-OR9、-SR9、取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。在实施方案中,R6独立地为-F。在实施方案中,R6独立地为-Cl。在实施方案中,R6独立地为-I。在实施方案中,R6独立地为-Br。在实施方案中,X2独立地为-F。在实施方案中,X2独立地为-Cl。在实施方案中,X2独立地为-I。在实施方案中,X2独立地为-Br。在实施方案中,R6为-NR7R8。
在实施方案中,R6是–C(O)OCH3。在实施方案中,R6是-OCH3。在实施方案中,R6是-OCH(CH3)2。在实施方案中,R6是-CN。在实施方案中,R6是-NO2。在实施方案中,R6是-NH2。在实施方案中,R6是卤素。在实施方案中,R6独立地为氢。在实施方案中,R6独立地为未取代的甲基。在实施方案中,R6独立地为-OCF3。在实施方案中,R6独立地为-NHAc。在实施方案中,R6独立地为-OH。在实施方案中,R6是未取代的烷基。R6可以是未取代的C1-C8烷基。在实施方案中,R6是未取代的C1-C4烷基。R6可以是未取代的乙基。在实施方案中,R6是未取代的甲基。在实施方案中,R6独立地为氢、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-NHNH2、-OCF3、-OCHF2、R35-取代或未取代的烷基、R35-取代或未取代的杂烷基、R35-取代或未取代的环烷基、R35-取代或未取代的杂环烷基、R35-取代或未取代的芳基、或者R35-取代或未取代的杂芳基。在实施方案中,R6独立地为卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-NHNH2、-OCF3、-OCHF2、R35-取代或未取代的烷基、R35-取代或未取代的杂烷基、R35-取代或未取代的环烷基、R35-取代或未取代的杂环烷基、R35-取代或未取代的芳基、或者R35-取代或未取代的杂芳基。在实施方案中,R5和R6独立地为氢。在实施方案中,R6不是氢。
每个R35独立地为氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、R36-取代或未取代的烷基、R36-取代或未取代的杂烷基、R36-取代或未取代的环烷基、R36-取代或未取代的杂环烷基、R36-取代或未取代的芳基、或者R36-取代或未取代的杂芳基。
每个R36独立地为氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、R37-取代或未取代的烷基、R37-取代或未取代的杂烷基、R37-取代或未取代的环烷基、R37-取代或未取代的杂环烷基、R37-取代或未取代的芳基、或者R37-取代或未取代的杂芳基。
在实施方案中,R7独立地为氢、氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、R38-取代或未取代的烷基、R38-取代或未取代的杂烷基、R38-取代或未取代的环烷基、R38-取代或未取代的杂环烷基、R38-取代或未取代的芳基、或者R38-取代或未取代的杂芳基。
R38独立地为氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、-S(O)2CHCH2、-NHS(O)2CHCH2、R39-取代或未取代的烷基、R39-取代或未取代的杂烷基、R39-取代或未取代的环烷基、R39-取代或未取代的杂环烷基、R39-取代或未取代的芳基、或者R39-取代或未取代的杂芳基。R38可以独立地为-OH。R38可以独立地为未取代的甲基。R38可以独立地为R39-取代或未取代的杂烷基。R38可以独立地为R39-取代或未取代的烷基。R38可以独立地为R39-取代或未取代的C1-C4烷基。
R39独立地为氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、-S(O)2CHCH2、-NHS(O)2CHCH2、R40-取代或未取代的烷基、R40-取代或未取代的杂烷基、R40-取代或未取代的环烷基、R40-取代或未取代的杂环烷基、R40-取代或未取代的芳基、或者R40-取代或未取代的杂芳基。
在实施方案中,R8独立地为氢、氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、R41-取代或未取代的烷基、R41-取代或未取代的杂烷基、R41-取代或未取代的环烷基、R41-取代或未取代的杂环烷基、R41-取代或未取代的芳基、或者R41-取代或未取代的杂芳基。
R41独立地为氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、-S(O)2CHCH2、-NHS(O)2CHCH2、R42-取代或未取代的烷基、R42-取代或未取代的杂烷基、R42-取代或未取代的环烷基、R42-取代或未取代的杂环烷基、R42-取代或未取代的芳基、或者R42-取代或未取代的杂芳基。
R42独立地为氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、-S(O)2CHCH2、-NHS(O)2CHCH2、R43-取代或未取代的烷基、R43-取代或未取代的杂烷基、R43-取代或未取代的环烷基、R43-取代或未取代的杂环烷基、R43-取代或未取代的芳基、或者R43-取代或未取代的杂芳基。
在实施方案中,R7和R8连接在一起形成取代或未取代的杂环烷基或者取代或未取代的杂芳基。R7和R8可连接在一起形成取代或未取代的杂环烷基。R7和R8可连接在一起形成取代或未取代的3至8元杂环烷基。R7和R8可连接在一起形成被取代的3至8元杂环烷基。R7和R8可连接在一起形成取代或未取代的5至7元杂环烷基。R7和R8可连接在一起形成被取代的5至7元杂环烷基。R7和R8可连接在一起形成被R38取代的5至7元杂环烷基,其中R38是如上文所述。R7和R8可连接在一起形成被R38取代的5至7元杂环烷基,其中R38独立地为取代或未取代的烷基或者取代或未取代的杂烷基。R7和R8可连接在一起形成被R38取代的5至7元杂环烷基,其中R38独立地为取代或未取代的C1-C8烷基或者取代或未取代的2至8元杂烷基。R7和R8可连接在一起形成取代或未取代的吡咯烷基。R7和R8可连接在一起形成取代或未取代的哌嗪基。
在实施方案中,R9独立地为氢、氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、R44-取代或未取代的烷基、R44-取代或未取代的杂烷基、R44-取代或未取代的环烷基、R44-取代或未取代的杂环烷基、R44-取代或未取代的芳基、或者R44-取代或未取代的杂芳基。
R44独立地为氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、R45-取代或未取代的烷基、R45-取代或未取代的杂烷基、R45-取代或未取代的环烷基、R45-取代或未取代的杂环烷基、R45-取代或未取代的芳基、或者R45-取代或未取代的杂芳基。
R45独立地为氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、R46-取代或未取代的烷基、R46-取代或未取代的杂烷基、R46-取代或未取代的环烷基、R46-取代或未取代的杂环烷基、R46-取代或未取代的芳基、或者R46-取代或未取代的杂芳基。
每个R22、R25、R28、R31、R34、R37、R40、R43、R46和R49独立地为氢、氧基、卤素、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF3、-OCHF2、未取代的烷基、未取代的杂烷基、未取代的环烷基、未取代的杂环烷基、未取代的芳基或未取代的杂芳基。
在实施方案中,式(I)化合物是式(II)化合物:
本文所提供的化合物或其药学上可接受的盐可以包括一个质子化的氮阳离子。本文所提供的化合物或其药学上可接受的盐可以包括多个质子化的氮阳离子。
在实施方案中,式(I)化合物具有下式:
包括其药学上可接受的盐。
在实施方案中,式(I)化合物具有下式:
包括其药学上可接受的盐。
在实施方案中,化合物具有式1276或其药学上可接受的盐。在实施方案中,化合物具有式1277或其药学上可接受的盐。在实施方案中,化合物具有式1278或其药学上可接受的盐。在实施方案中,化合物具有式1279或其药学上可接受的盐。在实施方案中,化合物具有式1280或其药学上可接受的盐。在实施方案中,化合物具有式1281或其药学上可接受的盐。在实施方案中,化合物具有式1282或其药学上可接受的盐。在实施方案中,化合物具有式1283或其药学上可接受的盐。在实施方案中,化合物具有式1284或其药学上可接受的盐。在实施方案中,化合物具有式1285或其药学上可接受的盐。在实施方案中,化合物具有式1286或其药学上可接受的盐。在实施方案中,化合物具有式1287或其药学上可接受的盐。在实施方案中,化合物具有式1288或其药学上可接受的盐。在实施方案中,化合物具有式1289。在实施方案中,化合物具有式1501。在实施方案中,化合物具有式1501p。在实施方案中,化合物具有式1502。在实施方案中,化合物具有式1502p。在实施方案中,化合物具有式XNH5或其药学上可接受的盐。在实施方案中,化合物具有式XNH6或其药学上可接受的盐。在实施方案中,化合物具有式XNH6p或其药学上可接受的盐。在实施方案中,化合物具有式XNH7或其药学上可接受的盐。在实施方案中,化合物具有式XNH7p或其药学上可接受的盐。在实施方案中,化合物具有式XNH9或其药学上可接受的盐。在实施方案中,化合物具有式XNH9p或其药学上可接受的盐。在实施方案中,化合物具有式XNH10或其药学上可接受的盐。在实施方案中,化合物具有式XNH10p或其药学上可接受的盐。在实施方案中,化合物具有式XNH12或其药学上可接受的盐。在实施方案中,化合物具有式XNH12p或其药学上可接受的盐。
在实施方案中,如本文所述的化合物或其药学上可接受的盐可以包括R2、R3、R4、R7、R8、R9、R20至R49、X1、X2和/或其他变量的多个实例。在此类实施方案中,每个变量可以任选地是不同的,且为更清楚起见,可以被适当标记,以区分每个基团。例如,当每个R2、R3、R4、R7、R8、R9、R20至R49、X1或X2不同时,可将它们分别称为(例如)R2.1、R2.2、R2.3、R2.4、R2.5、R2.6、R2.7、R2.8、R2.9、R2.10、R2.11、R2.12、R2.13、R2.14、R2.15、R2.16、R2.17、R2.18、R2.19、R2.20、R2.21、R2.22、R2.23、R2.24、R2.25、R2.26、R2.27、R2.28、R2.29、R2.30、R2.31、R2.32、R2.33、R2.34、R2.35、R2.36、R2.37、R2.38、R2.39、R2.40、R2.41、R2.42、R3.1、R3.2、R3.3、R3.4、R3.5、R3.6、R3.7、R3.8、R3.9、R3.10、R3.11、R3.12、R3.13、R3.14、R3.15、R3.16、R3.17、R3.18、R3.19、R3.20、R3.21、R3.22、R3.23、R3.24、R3.25、R3.26、R3.27、R3.28、R3.29、R3.30、R3.31、R3.32、R3.33、R3.34、R3.35、R3.36、R3.37、R3.38、R3.39、R3.40、R3.41、R3.42、R4.1、R4.2、R4.3、R4.4、R4.5、R4.6、R4.7、R4.8、R4.9、R4.10、R4.11、R4.12、R4.13、R4.14、R4.15、R4.16、R4.17、R4.18、R4.19、R4.20、R4.21、R4.22、R4.23、R4.24、R4.25、R4.26、R4.27、R4.28、R4.29、R4.30、R4.31、R4.32、R4.33、R4.34、R4.35、R4.36、R4.37、R4.38、R4.39、R4.40、R4.41、R4.42、R7.1、R7.2、R7.3、R7.4、R7.5、R7.6、R7.7、R7.8、R7.9、R7.10、R7.11、R7.12、R7.13、R7.14、R7.15、R7.16、R7.17、R7.18、R7.19、R7.20、R7.21、R7.22、R7.23、R7.24、R7.25、R7.26、R7.27、R7.28、R7.29、R7.30、R7.31、R7.32、R7.33、R7.34、R7.35、R7.36、R7.37、R7.38、R7.39、R7.40、R7.41、R7.42、R8.1、R8.2、R8.3、R8.4、R8.5、R8.6、R8.7、R8.8、R8.9、R8.10、R8.11、R8.12、R8.13、R8.14、R8.15、R8.16、R8.17、R8.18、R8.19、R8.20、R8.21、R8.22、R8.23、R8.24、R8.25、R8.26、R8.27、R8.28、R8.29、R8.30、R8.31、R8.32、R8.33、R8.34、R8.35、R8.36、R8.37、R8.38、R8.39、R8.40、R8.41、R8.42、R9.1、R9.2、R9.3、R9.4、R9.5、R9.6、R9.7、R9.8、R9.9、R9.10、R9.11、R9.12、R9.13、R9.14、R9.15、R9.16、R9.17、R9.18、R9.19、R9.20、R9.21、R9.22、R9.23、R9.24、R9.25、R9.26、R9.27、R9.28、R9.29、R9.30、R9.31、R9.32、R9.33、R9.34、R9.35、R9.36、R9.37、R9.38、R9.39、R9.40、R9.41、R9.42、R20.1至R49.1、R20.2至R49.2、R20.3至R49.3、R20.4至R49.4、R20.5至R49.5、R20.6至R49.6、R20.7至R49.7、R20.8至R49.8、R20.9至R49.9、R20.10至R49.10、R20.11至R49.11、R20.12至R49.12、R20.13至R49.13、R20.14至R49.14、R20.15至R49.15、R20.16至R49.16、R20.17至R49.17、R20.18至R49.18、R20.19至R49.19、R20.20至R49.20、R20.21至R49.21、R20.22至R49.22、R20.23至R49.23、R20.24至R49.24、R20.25至R49.25、R20.26至R49.26、R20.27至R49.27、R20.28至R49.28、R20.29至R49.29、R20.30至R49.30、R20.31至R49.31、R20.32至R49.32、R20.33至R49.33、R20.34至R49.34、R20.35至R49.35、R20.36至R49.36、R20.37至R49.37、R20.38至R49.38、R20.39至R49.39、R20.40至R49.40、R20.41至R49.41、R20.42至R49.42、X1.1、X1.2、X1.3、X1.4、X1.5、X1.6、X1.7、X1.8、X1.9、X1.10、X1.11、X1.12、X1.13、X1.14、X1.15、X1.16、X1.17、X1.18、X1.19、X1.20、X1.21、X1.22、X1.23、X1.24、X1.25、X1.26、X1.27、X1.28、X1.29、X1.30、X1.31、X1.32、X1.33、X1.34、X1.35、X1.36、X1.37、X1.38、X1.39、X1.40、X1.41、X1.42、X2.1、X2.2、X2.3、X2.4、X2.5、X2.6、X2.7、X2.8、X2.9、X2.10、X2.11、X2.12、X2.13、X2.14、X2.15、X2.16、X2.17、X2.18、X2.19、X2.20、X2.21、X2.22、X2.23、X2.24、X2.25、X2.26、X2.27、X2.28、X2.29、X2.30、X2.31、X2.32、X2.33、X2.34、X2.35、X2.36、X2.37、X2.38、X2.39、X2.40、X2.41、X2.42,其中通过R2.1、R2.2、R2.3、R2.4、R2.5、R2.6、R2.7、R2.8、R2.9、R2.10、R2.11、R2.12、R2.13、R2.14、R2.15、R2.16、R2.17、R2.18、R2.19、R2.20、R2.21、R2.22、R2.23、R2.24、R2.25、R2.26、R2.27、R2.28、R2.29、R2.30、R2.31、R2.32、R2.33、R2.34、R2.35、R2.36、R2.37、R2.38、R2.39、R2.40、R2.41、R2.42假定R2的定义,通过R3.1、R3.2、R3.3、R3.4、R3.5、R3.6、R3.7、R3.8、R3.9、R3.10、R3.11、R3.12、R3.13、R3.14、R3.15、R3.16、R3.17、R3.18、R3.19、R3.20、R3.21、R3.22、R3.23、R3.24、R3.25、R3.26、R3.27、R3.28、R3.29、R3.30、R3.31、R3.32、R3.33、R3.34、R3.35、R3.36、R3.37、R3.38、R3.39、R3.40、R3.41、R3.42假定R3的定义,通过R4.1、R4.2、R4.3、R4.4、R4.5、R4.6、R4.7、R4.8、R4.9、R4.10、R4.11、R4.12、R4.13、R4.14、R4.15、R4.16、R4.17、R4.18、R4.19、R4.20、R4.21、R4.22、R4.23、R4.24、R4.25、R4.26、R4.27、R4.28、R4.29、R4.30、R4.31、R4.32、R4.33、R4.34、R4.35、R4.36、R4.37、R4.38、R4.39、R4.40、R4.41、R4.42假定R4的定义,通过R7.1、R7.2、R7.3、R7.4、R7.5、R7.6、R7.7、R7.8、R7.9、R7.10、R7.11、R7.12、R7.13、R7.14、R7.15、R7.16、R7.17、R7.18、R7.19、R7.20、R7.21、R7.22、R7.23、R7.24、R7.25、R7.26、R7.27、R7.28、R7.29、R7.30、R7.31、R7.32、R7.33、R7.34、R7.35、R7.36、R7.37、R7.38、R7.39、R7.40、R7.41、R7.42假定R7的定义,通过R8.1、R8.2、R8.3、R8.4、R8.5、R8.6、R8.7、R8.8、R8.9、R8.10、R8.11、R8.12、R8.13、R8.14、R8.15、R8.16、R8.17、R8.18、R8.19、R8.20、R8.21、R8.22、R8.23、R8.24、R8.25、R8.26、R8.27、R8.28、R8.29、R8.30、R8.31、R8.32、R8.33、R8.34、R8.35、R8.36、R8.37、R8.38、R8.39、R8.40、R8.41、R8.42假定R8的定义,通过R9.1、R9.2、R9.3、R9.4、R9.5、R9.6、R9.7、R9.8、R9.9、R9.10、R9.11、R9.12、R9.13、R9.14、R9.15、R9.16、R9.17、R9.18、R9.19、R9.20、R9.21、R9.22、R9.23、R9.24、R9.25、R9.26、R9.27、R9.28、R9.29、R9.30、R9.31、R9.32、R9.33、R9.34、R9.35、R9.36、R9.37、R9.38、R9.39、R9.40、R9.41、R9.42假定R9的定义,通过R20.1至R49.1、R20.2至R49.2、R20.3至R49.3、R20.4至R49.4、R20.5至R49.5、R20.6至R49.6、R20.7至R49.7、R20.8至R49.8、R20.9至R49.9、R20.10至R49.10、R20.11至R49.11、R20.12至R49.12、R20.13至R49.13、R20.14至R49.14、R20.15至R49.15、R20.16至R49.16、R20.17至R49.17、R20.18至R49.18、R20.19至R49.19、R20.20至R49.20、R20.21至R49.21、R20.22至R49.22、R20.23至R49.23、R20.24至R49.24、R20.25至R49.25、R20.26至R49.26、R20.27至R49.27、R20.28至R49.28、R20.29至R49.29、R20.30至R49.30、R20.31至R49.31、R20.32至R49.32、R20.33至R49.33、R20.34至R49.34、R20.35至R49.35、R20.36至R49.36、R20.37至R49.37、R20.38至R49.38、R20.39至R49.39、R20.40至R49.40、R20.41至R49.41、R20.42至R49.42假定R20至R49的定义,通过X1.1、X1.2、X1.3、X1.4、X1.5、X1.6、X1.7、X1.8、X1.9、X1.10、X1.11、X1.12、X1.13、X1.14、X1.15、X1.16、X1.17、X1.18、X1.19、X1.20、X1.21、X1.22、X1.23、X1.24、X1.25、X1.26、X1.27、X1.28、X1.29、X1.30、X1.31、X1.32、X1.33、X1.34、X1.35、X1.36、X1.37、X1.38、X1.39、X1.40、X1.41、X1.42假定X1的定义,通过X2.1、X2.2、X2.3、X2.4、X2.5、X2.6、X2.7、X2.8、X2.9、X2.10、X2.11、X2.12、X2.13、X2.14、X2.15、X2.16、X2.17、X2.18、X2.19、X2.20、X2.21、X2.22、X2.23、X2.24、X2.25、X2.26、X2.27、X2.28、X2.29、X2.30、X2.31、X2.32、X2.33、X2.34、X2.35、X2.36、X2.37、X2.38、X2.39、X2.40、X2.41、X2.42假定X2的定义。
为更清楚起见,在R2、R3、R4、R7、R8、R9、R20至R49、X1、X2和/或其他变量定义内使用的变量(其出现在多个实例中且是不同的)可以类似地进行适当标记,以区分每个基团。
本文另外提供包含药学上可接受的赋形剂和如本文所述的化合物或其药学上可接受的盐(例如,式(I)或式(II)化合物,包括其实施方案)的药物组合物。在实施方案中,药物组合物包含治疗有效量的如本文所述的化合物或其药学上可接受的盐(例如,式(I)或式(II)化合物,包括其实施方案)。在实施方案中,药物组合物包含第二药剂(例如治疗剂)。在实施方案中,药物组合物包含治疗有效量的第二药剂(例如治疗剂)。在实施方案中,第二药剂(例如治疗剂)是抗癌剂。在实施方案中,第二药剂(例如治疗剂)是化学治疗剂。
II.治疗方法
本文也提供一种通过向有需要的受试者施用有效量的如本文所述的化合物或其药学上可接受的盐(包括其实施方案)治疗受试者癌症的方法。该化合物可如本文所述进行施用,包括其实施方案。该方法可以包括共同施用有效量的如本文所述的抗癌剂。在实施方案中,抗癌剂是化学治疗剂。
癌症可以是(例如)肺癌、乳腺癌、卵巢癌、白血病、淋巴瘤、黑色素瘤、胰腺癌、肉瘤、膀胱癌、骨癌、脑癌、宫颈癌、结肠癌、食道癌、胃癌、肝癌、头颈癌、肾癌、骨髓瘤、甲状腺癌或前列腺癌。治疗癌症的方法可以是一种治疗肺癌的方法。治疗癌症的方法可以是一种治疗乳腺癌的方法。治疗癌症的方法可以是一种治疗卵巢癌的方法。治疗癌症的方法可以是一种治疗淋巴瘤的方法。治疗癌症的方法可以是一种治疗胰腺癌的方法。治疗癌症的方法可以是一种治疗黑色素瘤的方法。治疗癌症的方法可以是一种治疗前列腺癌的方法。治疗癌症的方法可以是一种治疗肉瘤的方法。治疗癌症的方法可以是一种治疗膀胱癌的方法。治疗癌症的方法可以是一种治疗骨癌的方法。治疗癌症的方法可以是一种治疗脑癌的方法。治疗癌症的方法可以是一种治疗宫颈癌的方法。治疗癌症的方法可以是一种治疗结肠癌的方法。治疗癌症的方法可以是一种治疗食道癌的方法。治疗癌症的方法可以是一种治疗胃癌的方法。治疗癌症的方法可以是一种治疗肝癌的方法。治疗癌症的方法可以是一种治疗头颈癌的方法。治疗癌症的方法可以是一种治疗肾癌的方法。治疗癌症的方法可以是一种治疗骨髓瘤的方法。治疗癌症的方法可以是一种治疗多发性骨髓瘤的方法。治疗癌症的方法可以是一种治疗甲状腺癌的方法。在实施方案中,本文所列化合物是作为含化合物和药学上可接受的赋形剂的药物组合物提供。
本文也提供调节与疾病(例如癌症)相关的蛋白质的水平、活性或功能的方法。该方法包括使蛋白质与有效量的如本文所述的化合物或其药学上可接受的盐(包括其实施方案)接触。
在实施方案中,调节方法包括施用有效量的如本文所述的化合物或其药学上可接受的盐(包括其实施方案)。在实施方案中,蛋白质是选自由以下组成的组:JAK、JAK2、TYK2、c-Src、ABL1、T315I突变体ABL1、AuroraA、GSK-3β、CDK、STAT和STAT3。蛋白质可以是JAK。蛋白质可以是Src。蛋白质可以是GSK-3b。蛋白质可以是CDK。蛋白质可以是STAT3。在实施方案中,调节方法包括调节不同蛋白质(例如激酶)。在实施方案中,调节方法包括调节两种、三种、四种、五种或六种蛋白质(例如激酶)。
方法可以包括调节与疾病(例如癌症)相关的蛋白质的水平(例如量)。方法可以包括调节与疾病(例如癌症)相关的蛋白质的活性。方法可以包括调节与疾病(例如癌症)相关的蛋白质的功能。在实施方案中,调节是抑制,且如本文所述化合物或其药学上可接受的盐(包括实施方案)是抑制剂。在实施方案中,本文所列化合物是作为含化合物和药学上可接受的赋形剂的药物组合物提供。
III.实施方案:
实施方案P1一种化合物,或其药学上可接受的盐,其具有下式:
L是键或者取代或未取代的亚烷基。R1是氢、卤素、-CX1 3、-OCX1 3、-CN、-OH、-NH2、-C(O)OH、-C(O)OR4、-CONH2、-NO2、-SH、-NHNH2、-NR2R3、-OR4、-SR4、取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。X1独立地为卤素。R2和R3独立地为取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基,其中R2和R3任选地连接在一起形成取代或未取代的杂环烷基或者取代或未取代的杂芳基。R4是取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。R5和R6独立地为氢、卤素、-CX2 3、-OCX2 3、-CN、-OH、-NH2、-C(O)OH、-C(O)OR9、-CONH2、-NO2、-SH、-NHNH2、-NR7R8、-OR9、-SR9、取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。X2独立地为卤素。R7和R8独立地为取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基,其中R7和R8任选地连接在一起形成取代或未取代的杂环烷基或者取代或未取代的杂芳基。且R9是取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。
实施方案P2根据实施方案1所述的化合物,其中R5和R6是氢。
实施方案P3根据实施方案1至2中任一项所述的化合物,其中L是未取代的亚烷基。
实施方案P4根据实施方案1至3中任一项所述的化合物,其中L是未取代的C1-C8亚烷基。
实施方案P5根据实施方案1至4中任一项所述的化合物,其中L是未取代的C1-C4亚烷基。
实施方案P6根据实施方案2至5中任一项所述的化合物,其中L是未取代的C2亚烷基。
实施方案P7根据实施方案1所述的化合物,其中L是键。
实施方案P8根据实施方案1至7中任一项所述的化合物,其中R1是卤素、-CX3、-OCX3、-CN、-OH、-NH2、-C(O)OH、-C(O)OR4、-CONH2、-NO2、-SH、-NHNH2、-NR2R3、-OR4、-SR4、取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。
实施方案P9根据实施方案1至8中任一项所述的化合物,其中R1是-NR2R3。
实施方案P10根据实施方案1至9中任一项所述的化合物,其中R2和R3独立地为取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。
实施方案P11根据实施方案1至10中任一项所述的化合物,其中R2和R3独立地为取代或未取代的烷基。
实施方案P12根据实施方案1至11中任一项所述的化合物,其中R2和R3独立地为取代或未取代的C1-C8烷基。
实施方案P13根据实施方案11至12中任一项所述的化合物,其中R2和R3独立地为取代或未取代的C1-C4烷基。
实施方案P14根据实施方案1至13中任一项所述的化合物,其中R2和R3独立地为-OH取代或未取代的C1-C4烷基。
实施方案P15根据实施方案1至15中任一项所述的化合物,其中R2和R3独立地为未取代的C1-C4烷基。
实施方案P16根据实施方案1至9中任一项所述的化合物,其中R2和R3连接在一起形成取代或未取代的杂环烷基或者取代或未取代的杂芳基。
实施方案P17根据实施方案16所述的化合物,其中R2和R3连接在一起形成取代或未取代的杂环烷基。
实施方案P18根据实施方案16至17中任一项所述的化合物,其中R2和R3连接在一起形成取代或未取代的C5-C7杂环烷基。
实施方案P19根据实施方案16至19中任一项所述的化合物,其中R2和R3连接在一起形成被取代的C5-C7杂环烷基。
实施方案P20根据实施方案16至19中任一项所述的化合物,其中R2和R3连接在一起形成R23取代的C5-C7杂环烷基,其中R23独立地为取代或未取代的烷基或者取代或未取代的杂烷基。
实施方案21根据实施方案20所述的化合物,其中R23独立地为取代或未取代的C1-C8烷基或者取代或未取代的2至8元杂烷基。
实施方案P22根据实施方案16至18中任一项所述的化合物,其中R2和R3连接在一起形成取代或未取代的吡咯烷基。
实施方案P23根据实施方案16至18中任一项所述的化合物,其中R2和R3连接在一起形成取代或未取代的哌嗪基。
实施方案P24根据实施方案1至23中任一项所述的化合物,其包含一个质子化的氮阳离子。
实施方案P25根据实施方案1至24中任一项所述的化合物,其包含多个质子化的氮阳离子。
实施方案P26一种药物组合物,其包含药学上可接受的赋形剂和根据实施方案1至25中任一项所述的化合物。
实施方案P27一种治疗有需要的受试者的癌症的方法,所述方法包括施用有效量的根据实施方案1至25中任一项所述的化合物。
实施方案P28根据实施方案27所述的方法,其中所述化合物在包含药学上可接受的赋形剂的药物组合物中。
实施方案P29根据实施方案27至28中任一项所述的方法,其中所述癌症是肺癌、乳腺癌、卵巢癌、白血病、淋巴瘤、黑色素瘤、胰腺癌、肉瘤、膀胱癌、骨癌、脑癌、宫颈癌、结肠癌、食道癌、胃癌、肝癌、头颈癌、肾癌、骨髓瘤、甲状腺癌或前列腺癌。
实施方案P30根据实施方案27至29中任一项所述的方法,其包括共同施用有效量的抗癌剂。
实施方案P31一种调节激酶JAK、JAK2、TYK2、Src、c-Src、ABL1、ABL1T315I、Aurora激酶、AuroraA、GSK-3b、CDK、STAT或STAT3的方法,所述方法包括使所述蛋白质与实施方案1至25中任一项所述的化合物接触。
实施方案P32根据实施方案31所述的方法,其中所述化合物在包含药学上可接受的赋形剂的药物组合物中。
实施方案P33一种调节Janus激酶的方法,所述方法包括使所述Janus激酶与根据实施方案1至25中任一项所述的化合物接触。
实施方案P34根据实施方案33所述的方法,其中所述化合物在包含药学上可接受的赋形剂的药物组合物中。
实施方案1一种化合物,或其药学上可接受的盐,其具有下式:
其中L是键或者取代或未取代的亚烷基。R1是氢、卤素、-CX1 3、-OCX1 3、-CN、-OH、-NH2、-COOH、-C(O)OR4、-CONH2、-NO2、-SH、-NHNH2、-NR2R3、-OR4、-SR4、取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。X1独立地为卤素。R2和R3独立地为取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基,其中R2和R3任选地连接在一起形成取代或未取代的杂环烷基或者取代或未取代的杂芳基。R4是取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。R5和R6独立地为氢、卤素、-CX2 3、-OCX2 3、-CN、-OH、-NH2、-COOH、-C(O)OR9、-CONH2、-NO2、-SH、-NHNH2、-NR7R8、-OR9、-SR9、取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。X2独立地为卤素。R7和R8独立地为取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基,其中R7和R8任选地连接在一起形成取代或未取代的杂环烷基或者取代或未取代的杂芳基。R9是取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。
实施方案2根据实施方案1所述的化合物,其中R5和R6是氢。
实施方案3根据实施方案1至2中任一项所述的化合物,其中L是未取代的亚烷基。
实施方案4根据实施方案1至3中任一项所述的化合物,其中L是未取代的C1-C8亚烷基。
实施方案5根据实施方案1至4中任一项所述的化合物,其中L是未取代的C1-C4亚烷基。
实施方案6根据实施方案1至5中任一项所述的化合物,其中L是未取代的C2亚烷基。
实施方案7根据实施方案1至6中任一项所述的化合物,其中L是键。
实施方案8根据实施方案1至7中任一项所述的化合物,其中R1是卤素、-CX3、-OCX3、-CN、-OH、-NH2、-COOH、-C(O)OR4、-CONH2、-NO2、-SH、-NHNH2、-NR2R3、-OR4、-SR4、取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。
实施方案9根据实施方案1至8中任一项所述的化合物,其中R1是-NR2R3。
实施方案10根据实施方案1至9中任一项所述的化合物,其中R2和R3独立地为取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。
实施方案11根据实施方案1至10中任一项所述的化合物,其中R2和R3独立地为取代或未取代的烷基。
实施方案12根据实施方案1至11中任一项所述的化合物,其中R2和R3独立地为取代或未取代的C1-C8烷基。
实施方案13根据实施方案1至12中任一项所述的化合物,其中R2和R3独立地为取代或未取代的C1-C4烷基。
实施方案14根据实施方案1至13中任一项所述的化合物,其中R2和R3独立地为-OH取代或未取代的C1-C4烷基。
实施方案15根据实施方案1至14中任一项所述的化合物,其中R2和R3独立地为未取代的C1-C4烷基。
实施方案16根据实施方案1至15中任一项所述的化合物,其中R2和R3连接在一起形成取代或未取代的杂环烷基或者取代或未取代的杂芳基。
实施方案17根据实施方案1至16所述的化合物,其中R2和R3连接在一起形成取代或未取代的杂环烷基。
实施方案18根据实施方案1至17所述的化合物,其中R2和R3连接在一起形成取代或未取代的C5-C7杂环烷基。
实施方案19根据实施方案1至16中任一项所述的化合物,其中R2和R3连接在一起形成被取代的C5-C7杂环烷基。
实施方案20根据实施方案1至16中任一项所述的化合物,其中R2和R3连接在一起形成R23取代的C5-C7杂环烷基,其中R23独立地为取代或未取代的烷基或者取代或未取代的杂烷基。
实施方案21根据实施方案20所述的化合物,其中R23独立地为取代或未取代的C1-C8烷基或者取代或未取代的2至8元杂烷基。
实施方案22根据实施方案1至16所述的化合物,其中R2和R3连接在一起形成取代或未取代的吡咯烷基。
实施方案23根据实施方案1至16所述的化合物,其中R2和R3连接在一起形成取代或未取代的哌嗪基。
实施方案24根据实施方案1至23所述的化合物,其包含一个质子化的氮阳离子。
实施方案25根据实施方案1至24所述的化合物,其包含多个质子化的氮阳离子。
实施方案26根据实施方案1所述的化合物,其具有下式:
包括其药物盐。
实施方案27根据实施方案1所述的化合物,其具有下式:
包括其药物盐。
实施方案28一种药物组合物,其包含药学上可接受的赋形剂和根据实施方案1至27所述的化合物。
实施方案29根据实施方案1至28所述的化合物,其用于治疗有需要的受试者的癌症。
实施方案30根据实施方案29所述的化合物,其中所述化合物是以有效量施用至所述受试者。
实施方案31根据实施方案29至30所述的化合物,其中所述化合物在包含药学上可接受的赋形剂的药物组合物中。
实施方案32根据实施方案29至31所述的化合物,其中所述癌症是肺癌、乳腺癌、卵巢癌、白血病、淋巴瘤、黑色素瘤、胰腺癌、肉瘤、膀胱癌、骨癌、脑癌、宫颈癌、结肠癌、食道癌、胃癌、肝癌、头颈癌、肾癌、骨髓瘤、甲状腺癌或前列腺癌。
实施方案33根据实施方案29至32所述的化合物,其中所述化合物与有效量的抗癌剂共同施用。
实施方案34一种调节激酶JAK、JAK2、TYK2、Src、c-Src、ABL1、ABL1T315I、Aurora激酶、AuroraA、GSK-3b、CDK、STAT或STAT3的方法,所述方法包括使所述蛋白质与实施方案1至28所述的化合物接触。
实施方案35根据实施方案34所述的方法,其中所述化合物在包含药学上可接受的赋形剂的药物组合物中。
实施方案36一种调节Janus激酶的方法,所述方法包括使所述Janus激酶与根据实施方案1至28所述的化合物接触。
实施方案37根据实施方案36所述的方法,其中所述化合物在包含药学上可接受的赋形剂的药物组合物中。
IV.实施例
应理解,本文所述实施例和实施方案只是为了说明目的,且根据它们所作的各种修改或变化将为所属领域的技术人员所建议,且应包括在本申请的精神和范围内和随附权利要求书的范围内。本文所引用的所有出版物、专利和专利申请出于所有目的全部以引用的方式并入。
实施例1
*ND:未测定
实施例2
表2.5BIOD抑制Src和Janus激酶(JAK)的体外活性。
用重组蛋白进行激酶测定。简单来说,在DMSO(作为对照)或5BIOD存在下,将蛋白质、新制的底物和33P-ATP(最终比活0.01μCi/μl)混合于反应缓冲液(20mMHEPESpH7.5、10mMMgCl2、1mMEGTA、0.02%Brij35、0.02mg/mlBSA、0.1mMNa3VO4、2mMDTT)中。混合物在室温下反应120min。将样本转移至P81离子交换纸上,并用0.75%磷酸彻底清洗过滤器。监测放射活性。
实施例3
制备5-溴-靛玉红的一般程序
在碳酸钠存在下,将可商购获得的5-溴-靛红(1当量)和3-乙酰氧基吲哚(0.8当量)溶解在甲醇中。搅拌混合物约3.5h。添加甲醇水(1/1)后,过滤沉淀物,用水清洗,并干燥得到5-溴靛玉红,产率约为80%。
1HNMR(DMSO-d6,400MHz,δppm,J以Hz计):11.12(2H,s,N-H,N′-H),8.94(1H,s,H-4),7.66(1H,d,J=7.5Hz,H-4’),7.60(1H,t,J=7.5Hz,H-6’),7.45(2H,m,H-6,7’),7.05(1H,t,J=7.5Hz,H-5’),6.86(1H,d,J=8.3Hz,H-7)。MS(m/z,ESI+):m/z:341,343(M+H)+。
制备5-溴-3’-肟-靛玉红的一般程序
然后在过量盐酸羟胺(10当量)存在下将5-溴靛玉红(1当量)溶解在吡啶中,并回流1小时30。冷却后添加水,过滤并用水清洗,以定量产率得到5-溴-3’-肟-靛玉红(5-BIO)。
1HNMR(DMSO-d6,400MHz,δppm,J以Hz计):13.71(1H,brs,NOH),11.85(1H,s,N’-H),10.84(1H,s,N-H),8.76(1H,brs,H-4),8.24(1H,d,J=7.7Hz,H-4’),7.42(2H,m,H-6’,7’),7.26(1H,m,H-6),7.06(1H,t,J=7.7Hz,H-5’),6.84(1H,d,J=8.2Hz,H-7)。MS(m/z,ESI+):356,358(M+H)+。
制备5-溴靛玉红-3’-(邻溴乙基)肟的一般程序
向5-BIO(1当量)在DMF的溶液中添加三乙胺和二溴乙烷(2当量)。在室温下搅拌反应24小时。然后添加水,并过滤沉淀物,并用水清洗得到5-溴靛玉红-3’-(邻溴乙基)-肟。
1HNMR(DMSO-d6,400MHz,δppm,J以Hz计):11.72(1H,s,N’-H),10.94(1H,s,N-H),8.80(1H,d,J=1.9Hz,H-4),8.21(1H,d,J=7.5Hz,H-4’),7.47(2H,m,H-6’,7’),7.32(1H,dd,J=8.0,1.9Hz,H-6),7.08(1H,m,H-5’),6.87(1H,d,J=8.0Hz,H-7),4.89(2H,t,J=5.6Hz,H-1”),4.03(2H,t,J=5.6Hz,H-2”)。MS(m/z,ESI+):463,465,467(M+H)+。
制备5-溴靛玉红-3’-(邻乙胺)肟的一般程序
将5-溴靛玉红-3’-(邻溴乙基)肟溶解在无水DMF中。添加过量合适的胺(二乙胺、哌嗪、N-甲基哌嗪、3-甲胺-1,2-丙二醇、1-(2-羟乙基)哌嗪和1-[2-(2-羟乙氧基)-乙基]哌嗪),混合物在90℃下在CEM单模微波(100W)中加热约40min。添加水,过滤沉淀物,并用水和环己烷清洗,得到相应衍生物,产率为80-90%。
1HNMR(DMSO-d6,400MHz,δppm,J以Hz计):11.75(1H,s,N′-H),10.92(1H,s,N-H),8.86(1H,d,J=2.0Hz,H-4),8.16(1H,d,J=7.6Hz,H-4’),7.46(2H,m,H-6’,7’),7.30(1H,d,J=8.2Hz,H-6),7.07(1H,m,H-5’),6.86(1H,d,J=8.2Hz,H-7),4.70(2H,t,J=5.8Hz,H-1”),3.04(2H,t,J=5.8Hz,H-2”),2.60(4H,m,H-2”’,5”’),1.68(4H,m,H-3”’,4”’)。MS(m/z,ESI+):453,455(M+H)+。
1HNMR(DMSO-d6,400MHz,δ_ppm,J以Hz计):11.73(1H,s,N′-H),10.90(1H,s,N-H),8.88(1H,d,J=2.0Hz,H-4),8.14(1H,d,J=7.6Hz,H-4’),7.45(2H,m,H-6’,7’),7.30(1H,d,J=8.2Hz,H-6),7.07(1H,m,H-5’),6.86(1H,d,J=8.2Hz,H-7),4.70(2H,t,J=5.8Hz,H-1”),2.85(2H,t,J=5.8Hz,H-2”),2.69(4H,m,H-2”’,5”’),2.49(4H,m,H-3”’,4”’)。MS(m/z,ESI+):453,455(M+H)+。
制备5-溴靛玉红-3’-(邻乙胺)肟盐的一般程序
然后将每种氨基衍生物溶解在无水THF中,并逐滴添加2MHCl-Et2O溶液,直到再也观察不到沉淀,得到相应氯盐。
1HNMR(DMSO-d6,400MHz,δ_ppm,J以Hz计):11.75(1H,s,N’-H),10.97(1H,s,N-H),9.92(1H,brs,H-1”’),8.79(1H,d,J=2.0Hz,H-4),8.24(1H,dd,J=7.8,0.8Hz,H-4’),7.49(2H,m,H-6’,7’),7.33(1H,dd,J=8.0,2.0Hz,H-6),7.09(1H,m,H-5’),6.88(1H,d,J=8.0Hz,H-7),4.91(2H,m,H-1”),3.86(2H,m,H-2”),3.67(2H,m,H-2”’a,5”’a),3.16(2H,m,2”’b,5”’b),2.03(2H,m,H-3”’a,4”’a),1.86(2H,m,H-3”’b,4”’b)。
1HNMR(DMSO-d6,400MHz,δppm,J以Hz计):11.82(1H,s,N’-H),11.05(1H,s,N-H),9.32(2H,br,H-1”’,4”’),8.79(1H,d,J=2.0Hz,H-4),8.25(1H,d,J=7.5Hz,H-4’),7.48(2H,m,H-6’,7’),7.35(1H,dd,J=8.0,2.0Hz,H-6),7.06(1H,ddd,J=7.5,4.1,1.4Hz,H-5’),6.89(1H,d,J=8.0Hz,H-7),4.98(2H,m,H-1”),3.70(2H,m,H-2”),3.50(8H,重叠H-2”’,3”’,5”’,6”’)。
1HNMR(400MHz,CDCl3)δ11.72(b,1H),10.88(b,1H),8.78(s,1H),8.38(d,J=4.8Hz,1H),8.13(d,J=7.4Hz,1H),7.58-7.36(m,4H),7.27(d,J=2.0,8.2Hz,1H),7.20-7.10(m,1H),7.10-7.01(m,1H),6.83(d,J=8.2Hz,1H),4.72(t,J=5.8Hz,2H),3.80-3.70(m,2H),3.10-2.96(m,2H),2.35(s,3H);13CNMR(100MHz,CDCl3)δ170.9,151.8,149.1,145.8,145.4,138.0,136.7,133.5,128.8,128.6,125.7,124.9,123.0,122.5,122.3,116.6,112.9,112.6,111.0,99.3,75.1,63.8,55.9,42.9;HRMSC25H22BrN5O2[M+H]+计算值504.1030,实测值504.1039。
1HNMR(400MHz,CDCl3)δ11.72(b,1H),10.89(b,1H),8.83(d,J=2.0Hz,1H),8.15(d,J=7.4Hz,1H),7.48-7.40(m,2H),7.28(dd,J=2.0,8.2Hz,1H),7.09-7.00(m,1H),6.84(d,J=8.2Hz,1H),4.69(t,J=5.8Hz,2H),3.40-3.30(m,4H),2.87(t,J=5.6Hz,2H),2.85-2.70(m,3H),2.70-2.60(m,2H),2.10-2.00(m,1H),1.72(t,J=10.2Hz,1H),0.87(d,J=6.2Hz,3H);13CNMR(100MHz,CDCl3)δ170.9,151.8,145.8,145.4,138.0,133.4,128.7,128.7,125.7,124.9,122.3,116.6,112.9,112.6,111.0,99.2,74.9,61.6,57.3,53.9,50.6,45.7,19.9;HRMSC23H24BrN5O2[M+H]+计算值482.1186,实测值482.1183.
1HNMR(400MHz,CDCl3)δ11.73(b,1H),10.89(b,1H),8.83(d,J=2.0Hz,1H),8.15(d,J=7.8Hz,1H),7.48-7.40(m,2H),7.28(dd,J=2.0,8.2Hz,1H),7.09-7.01(m,1H),6.84(d,J=8.2Hz,1H),4.67(t,J=5.6Hz,2H),4.34(t,J=5.2Hz,1H),3.46(dd,J=6.2,11.8Hz,1H),2.99(t,J=5.8Hz,2H),2.54(t,J=6.2Hz,2H),2.3(s,3H);13CNMR(100MHz,CDCl3)δ170.9,151.8,145.8,145.4,138.0,133.4,128.8,128.6,125.7,124.9,122.4,116.6,112.9,112.5,111.0,99.2,75.4,60.2,59.5,56.5,43.3;HRMSC21H21BrN4O3[M+H]+计算值457.0870,实测值457.0863。
实施例4
1276和1289的体外激酶概述。参见图5。用重组蛋白进行激酶测定。简单来说,在DMSO(作为对照)、1276或1289存在下,将蛋白质、新制的底物和33P-ATP(最终比活0.01μCi/μl)混合于反应缓冲液(20mMHEPESpH7.5、10mMMgCl2、1mMEGTA、0.02%Brij35、0.02mg/mlBSA、0.1mMNa3VO4、2mMDTT)中。混合物在室温下反应120min。将样本转移至P81离子交换纸上,并用0.75%磷酸彻底清洗过滤器。监测放射活性。利用GraphPadPrism软件测定IC50值。
进行MTS测定,得到细胞存活率。参见图7。将人类A2058黑色素瘤(A)和DU145前列腺癌(B)癌细胞(5000/孔)接种在96-孔板中,在37℃下于5%(v/v)CO2中孵育过夜,并以0.25uM或1uM的浓度暴露至XNH48h。使用DMSO作为媒介物对照。通过四唑鎓转化为它的甲臜染料来测定细胞存活率,并在490nm下用自动ELISA平板读数器测量吸光度,且一式四份地进行每个实验。
将人类A549非小细胞肺癌细胞(5×106)再悬浮于无血清的RPMI1640培养基中,并皮下注射至5-6周龄的NOD/SCID/IL-2rg(ko)(NSG)雌性小鼠的侧腹中。参见图8。当可触摸肿瘤大小达到约70mm3时,将小鼠分成两组(媒介物=10,治疗=10)。然后,以25mg/kg口服施用注射来施用1281(左图)或1289(右图)和媒介物(10%DMSO+30%Solutol+60%盐水),每天两次,持续31天。通过公式1/2a×b2计算肿瘤体积,其中a是长直径,且b是短直径。肿瘤体积与肿瘤重量相关。利用学生t-检验和双尾分布分析群组差异的统计显著性。P值小于0.05视为具有统计显著性。
Claims (37)
1.一种化合物,或其药学上可接受的盐,其具有下式:
其中
L是键或者取代或未取代的亚烷基;
R1是氢、卤素、-CX1 3、-OCX1 3、-CN、-OH、-NH2、-COOH、-C(O)OR4、-CONH2、-NO2、-SH、-NHNH2、-NR2R3、-OR4、-SR4、取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基;
X1独立地为卤素;
R2和R3独立地为取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基,其中R2和R3任选地连接在一起形成取代或未取代的杂环烷基或者取代或未取代的杂芳基;
R4是取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基;
R5和R6独立地为氢、卤素、-CX2 3、-OCX2 3、-CN、-OH、-NH2、-COOH、-C(O)OR9、-CONH2、-NO2、-SH、-NHNH2、-NR7R8、-OR9、-SR9、取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基;
X2独立地为卤素;
R7和R8独立地为取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基,其中R7和R8任选地连接在一起形成取代或未取代的杂环烷基或者取代或未取代的杂芳基;且
R9是取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。
2.根据权利要求1所述的化合物,其中R5和R6是氢。
3.根据权利要求1所述的化合物,其中L是未取代的亚烷基。
4.根据权利要求1所述的化合物,其中L是未取代的C1-C8亚烷基。
5.根据权利要求1所述的化合物,其中L是未取代的C1-C4亚烷基。
6.根据权利要求1所述的化合物,其中L是未取代的C2亚烷基。
7.根据权利要求1所述的化合物,其中L是键。
8.根据权利要求1所述的化合物,其中R1是卤素、-CX3、-OCX3、-CN、-OH、-NH2、-COOH、-C(O)OR4、-CONH2、-NO2、-SH、-NHNH2、-NR2R3、-OR4、-SR4、取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。
9.根据权利要求1所述的化合物,其中R1是-NR2R3。
10.根据权利要求9所述的化合物,其中R2和R3独立地为取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或者取代或未取代的杂芳基。
11.根据权利要求10所述的化合物,其中R2和R3独立地为取代或未取代的烷基。
12.根据权利要求11所述的化合物,其中R2和R3独立地为取代或未取代的C1-C8烷基。
13.根据权利要求12所述的化合物,其中R2和R3独立地为取代或未取代的C1-C4烷基。
14.根据权利要求13所述的化合物,其中R2和R3独立地为-OH取代或未取代的C1-C4烷基。
15.根据权利要求13所述的化合物,其中R2和R3独立地为未取代的C1-C4烷基。
16.根据权利要求1所述的化合物,其中R2和R3连接在一起形成取代或未取代的杂环烷基或者取代或未取代的杂芳基。
17.根据权利要求16所述的化合物,其中R2和R3连接在一起形成取代或未取代的杂环烷基。
18.根据权利要求17所述的化合物,其中R2和R3连接在一起形成取代或未取代的C5-C7杂环烷基。
19.根据权利要求18所述的化合物,其中R2和R3连接在一起形成取代的C5-C7杂环烷基。
20.根据权利要求19所述的化合物,其中R2和R3连接在一起形成被R23取代的C5-C7杂环烷基,其中R23独立地为取代或未取代的烷基或者取代或未取代的杂烷基。
21.根据权利要求20所述的化合物,其中R23独立地为取代或未取代的C1-C8烷基或者取代或未取代的2至8元杂烷基。
22.根据权利要求16所述的化合物,其中R2和R3连接在一起形成取代或未取代的吡咯烷基。
23.根据权利要求16所述的化合物,其中R2和R3连接在一起形成取代或未取代的哌嗪基。
24.根据权利要求1所述的化合物,其包含一个质子化的氮阳离子。
25.根据权利要求1所述的化合物,其包含多个质子化的氮阳离子。
26.根据权利要求1所述的化合物,其具有下式:
包括其药物盐。
27.根据权利要求1所述的化合物,其具有下式:
包括其药物盐。
28.一种药物组合物,其包含药学上可接受的赋形剂和根据权利要求1所述的化合物。
29.根据权利要求1所述的化合物,其用于治疗有需要的受试者的癌症。
30.根据权利要求29所述的化合物,其中所述化合物是以有效量施用至所述受试者。
31.根据权利要求29所述的化合物,其中所述化合物在包含药学上可接受的赋形剂的药物组合物中。
32.根据权利要求29所述的化合物,其中所述癌症是肺癌、乳腺癌、卵巢癌、白血病、淋巴瘤、黑色素瘤、胰腺癌、肉瘤、膀胱癌、骨癌、脑癌、宫颈癌、结肠癌、食道癌、胃癌、肝癌、头颈癌、肾癌、骨髓瘤、甲状腺癌或前列腺癌。
33.根据权利要求29所述的化合物,其中所述化合物与有效量的抗癌剂共同施用。
34.一种调节激酶JAK、JAK2、TYK2、Src、c-Src、ABL1、ABL1T315I、Aurora激酶、AuroraA、GSK-3b、CDK、STAT或STAT3的方法,所述方法包括使所述蛋白质与根据权利要求1所述的化合物接触。
35.根据权利要求34所述的方法,其中所述化合物在包含药学上可接受的赋形剂的药物组合物中。
36.一种调节Janus激酶的方法,所述方法包括使所述Janus激酶与根据权利要求1所述的化合物接触。
37.根据权利要求36所述的方法,其中所述化合物在包含药学上可接受的赋形剂的药物组合物中。
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CN111542513A (zh) * | 2017-10-31 | 2020-08-14 | 佩勒梅德有限公司 | 用于预防或治疗急性髓性白血病或转移性乳腺癌的药物组合物 |
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MX2015013021A (es) * | 2013-03-14 | 2016-07-14 | Nat And Kapodistrian University Of Athens | 5-bromo-indirrubinas. |
US20150259288A1 (en) | 2014-03-14 | 2015-09-17 | City Of Hope | 5-bromo-indirubins |
JP7073109B2 (ja) * | 2015-07-02 | 2022-05-23 | シティ・オブ・ホープ | ホスホロチオエート化オリゴデオキシヌクレオチドを含む化合物及び組成物、ならびにそれらの使用法 |
KR102443617B1 (ko) * | 2019-12-06 | 2022-09-16 | 광주과학기술원 | 근감소증 또는 근위축증의 예방 또는 치료용 약제학적 조성물 |
KR20230122446A (ko) * | 2022-02-14 | 2023-08-22 | 주식회사 펠레메드 | 신규한 헤테로비시클릭 잔기를 갖는 인디루빈 유도체 및 이의 용도 |
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AU2014236370B2 (en) | 2018-07-19 |
KR102275112B1 (ko) | 2021-07-08 |
US20180170915A1 (en) | 2018-06-21 |
US20160068517A1 (en) | 2016-03-10 |
KR20160006669A (ko) | 2016-01-19 |
US20220274964A1 (en) | 2022-09-01 |
BR112015023383A2 (pt) | 2017-07-18 |
EA201591709A1 (ru) | 2016-03-31 |
WO2014153023A1 (en) | 2014-09-25 |
CA2902914A1 (en) | 2014-09-25 |
AU2014236370A1 (en) | 2015-09-17 |
EA035877B1 (ru) | 2020-08-25 |
EP2970310B1 (en) | 2020-11-11 |
IL240916A0 (en) | 2015-10-29 |
US20200283421A1 (en) | 2020-09-10 |
MX2015013021A (es) | 2016-07-14 |
EP2970310A4 (en) | 2016-09-07 |
AU2014236370C1 (en) | 2019-01-17 |
CN105283456B (zh) | 2018-12-18 |
JP2016514160A (ja) | 2016-05-19 |
JP6422936B2 (ja) | 2018-11-14 |
EP2970310A1 (en) | 2016-01-20 |
HK1220197A1 (zh) | 2017-04-28 |
US11306072B2 (en) | 2022-04-19 |
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