CN109923115B - 咪唑并[1’,2’:1,6]吡啶并[2,3-d]嘧啶类化合物作为蛋白激酶抑制剂 - Google Patents
咪唑并[1’,2’:1,6]吡啶并[2,3-d]嘧啶类化合物作为蛋白激酶抑制剂 Download PDFInfo
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- CN109923115B CN109923115B CN201880003184.3A CN201880003184A CN109923115B CN 109923115 B CN109923115 B CN 109923115B CN 201880003184 A CN201880003184 A CN 201880003184A CN 109923115 B CN109923115 B CN 109923115B
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- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
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- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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Abstract
提供通式(I)的咪唑并[1',2':1,6]吡啶并[2,3‑d]嘧啶类化合物,它们可用于治疗细胞增殖障碍。化合物是有广谱、强烈活性的细胞周期蛋白依赖性激酶(CDK)的抑制剂。
Description
技术领域
本发明提供一种咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶类化合物作为细胞周期蛋白依赖性激酶(cyclin-dependent kinase,CDK)抑制剂,其对CDK具有广谱、强烈的抑制活性。本发明的化合物有效用于治疗癌症、炎症等疾病。
背景技术
癌症是全球致死第二主要疾病,世界卫生组织发布的《全球癌症报告2014》称全球癌症患者和死亡病例都在令人不安地增加,新增癌症病例有近一半出现在亚洲,其中大部分在中国。报告还预测全球癌症病例将呈现迅猛增长的态势,由2012年的1400万人逐年递增至2025年的1900万人,到2035年将达到2400万人,其中中国将占全球总量的21.9%。有机构数据显示,在过去30年中,我国癌症死亡率增加了80%,每年癌症发病人数约260万,死亡人数约180万。
细胞周期是细胞生命活动的重要部分。研究发现,多种恶性肿瘤的发生、发展都与细胞周期调节机制的紊乱有密切关系,因此肿瘤也被认为是一种细胞周期性疾病。20世纪70年代后,美国和英国的三名科学家先后发现了细胞周期蛋白依赖性激酶和细胞周期蛋白(cyclin)在细胞调控中的重要作用,因而获得了2001年诺贝尔生理学/医学奖。随着人们对细胞周期调控机制的研究不断取得重大进展,特别是揭示了CDK在细胞周期调控中的核心地位,近年来细胞周期蛋白依赖性激酶已成为当前抗癌药物的研究热点。目前认为,在细胞周期中起调节作用的主要是CDK1、2、4、6和7。
除了CDK4和6选择性抑制剂外,针对CDK1、CDK2、CDK5、CDK9和CDK12均有抑制活性的泛CDK抑制剂诸如Dinaciclib(SCH-727965,MK-7965)也进入了临床试验,在实体瘤靶向治疗中呈现出具有前景的抗癌活性。
仍然需要更多的CDK抑制剂来满足多种疾病治疗的临床需求。更有效的CDK抑制剂和具有选择性活性的CDK抑制剂可以对某些具体疾病(例如癌症、心血管障碍、感染性疾病、自身免疫性疾病等)显示出更优的治疗益处,因此是本领域一直追求的目标。
发明内容
本发明提供了咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶类化合物作为细胞周期蛋白依赖性激酶抑制剂,并具有广谱、强烈的抑制活性。本发明的化合物能有效用于治疗细胞增殖性疾病,如再狭窄、癌症和炎症。与已有药物相比,本发明的化合物能进一步提高药代动力学性质,包括代谢稳定性和清除率方面比已有的化合物会有重大改进。此外,本发明的化合物容易合成,并且可以通过多种方法给患者施用。
在一个方面,本发明提供了通式(I)的化合物,或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体,以及它们的混合物:
其中:
A1选自CR3或N;
A2选自CR3;
A3选自CR3;
R1为H;
R2选自H、卤素、-CN、-ORa、-SRa、-NRbRc、-C(O)Ra、-C(O)ORa、-C(O)NRbRc、C1-6烷基或C1-6卤代烷基;
R3选自H、卤素、-CN、-NO2、-ORa、-SRa、-NRbRc、-O-C1-6亚烷基-R6、C1-6烷基、C1-6卤代烷基、-L’-C3-7环烷基、-L’-3-11元杂环基、-L’-C6-10芳基或-L’-5-10元杂芳基,所述基团任选地被1、2、3、4或5个R6基团取代;
R4选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-10元杂芳基;
R5为H;
R6选自H、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、C1-6烷基或C1-6卤代烷基;
或者同一个碳原子上的两个R6一起形成氧代或硫代;
其中:
R4任选地被1、2或3个R’基团取代,其中R’独立地选自H、卤素、-CN、-NO2、-ORa、-SRa、-NRbRc、-C(O)ORa、-C(O)NRbRc、C1-6烷基、C1-6卤代烷基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-10元杂芳基;
Ra独立地选自H、C1-6烷基、C2-6烯基、C2-6炔基或C1-6卤代烷基;
Rb和Rc独立地选自H、C1-6烷基、C2-6烯基、C2-6炔基或C1-6卤代烷基;或者,Rb、Rc与N原子一起形成3-7元杂环基;
L’选自化学键或-O-。
在另一个方面,本发明提供了一种药物组合物,所述药物组合物含有本发明化合物,和任选地药学上可接受的赋形剂。
在另一个方面,本发明提供了含有本发明化合物和药学上可接受的赋形剂的药物组合物,其还含有其它治疗剂。
在另一个方面,本发明提供了包含本发明化合物,和其它治疗剂以及药学上可接受的载剂、佐剂或媒剂的试剂盒。
在另一个方面,本发明提供了本发明化合物在制备用于治疗和/或预防CDK介导的疾病的药物中的用途。
在另一个方面,本发明提供了在受试者中治疗和/或预防CDK介导的疾病的方法,包括向所述受试者给药本发明化合物或本发明组合物。
在另一个方面,本发明提供了本发明化合物或本发明组合物,其用于治疗和/或预防CDK介导的疾病。
在具体实施方案中,所述疾病包括细胞增殖性疾病,包括但不限于癌症、心血管障碍、感染性疾病、慢性炎性疾病、自身免疫障碍和其它细胞增殖障碍。更具体地,所述癌症包括但不限于实体瘤和血液恶性肿瘤,例如乳腺癌,神经母细胞瘤、恶性横纹肌瘤、高分化和去分化的脂肪肉瘤、胶质瘤、肺癌、结肠直肠癌、胃癌、胃肠道基质瘤(GIST)、肝细胞癌、前列腺瘤、肉瘤、卵巢癌、宫颈癌、胰腺癌、黑色素瘤、甲状腺癌、胆管癌、子宫内膜癌、肾癌、间皮瘤、淋巴瘤、白血病、非霍奇金淋巴瘤、套细胞淋巴瘤、间变性大细胞淋巴瘤、急性髓细胞白血病(AML)、多发性骨髓瘤。所述心血管障碍例如再狭窄、动脉粥样硬化、继发于气囊血管成形术的血管平滑肌增殖和内膜增生,和其它由异常细胞增殖引起的血管障碍。所述感染性疾病包括真菌、原生动物寄生虫(例如恶性疟原虫)和DNA与RNA病毒感染,例如单纯疱疹病毒(HSV)感染。所述慢性炎性疾病例如类风湿性关节炎。所述其它细胞增殖障碍包括牛皮癣(以角质形成细胞过度增殖为特征)、肾小球性肾炎和狼疮等。
由随后的具体实施方案、实施例和权利要求,本发明的其它目的和优点将对于本领域技术人员显而易见。
定义
化学定义
下面更详细地描述具体官能团和化学术语的定义。
当列出数值范围时,既定包括每个值和在所述范围内的子范围。例如“C1-6烷基”包括C1、C2、C3、C4、C5、C6、C1-6、C1-5、C1-4、C1-3、C1-2、C2-6、C2-5、C2-4、C2-3、C3-6、C3-5、C3-4、C4-6、C4-5和C5-6烷基。
“C1-6烷基”是指具有1至6个碳原子的直链或支链饱和烃基团。在一些实施方案中,C1-4烷基是优选的。C1-6烷基的例子包括:甲基(C1)、乙基(C2)、正丙基(C3)、异丙基(C3)、正丁基(C4)、叔丁基(C4)、仲丁基(C4)、异丁基(C4)、正戊基(C5)、3-戊基(C5)、戊基(C5)、新戊基(C5)、3-甲基-2-丁基(C5)、叔戊基(C5)和正己基(C6)。术语“C1-6烷基”还包括杂烷基,其中一或多个(例如,1、2、3或4个)碳原子被杂原子(例如,氧、硫、氮、硼、硅、磷)替代。烷基基团可以被一或多个取代基任选取代,例如,被1至5个取代基、1至3个取代基或1个取代基取代。常规烷基缩写包括:Me(-CH3)、Et(-CH2CH3)、iPr(-CH(CH3)2)、nPr(-CH2CH2CH3)、n-Bu(-CH2CH2CH2CH3)或i-Bu(-CH2CH(CH3)2)。
“C2-6烯基”是指具有2至6个碳原子和至少一个碳碳双键的直链或支链烃基团。在一些实施方案中,C2-4烯基是优选的。C2-6烯基的例子包括:乙烯基(C2)、1-丙烯基(C3)、2-丙烯基(C3)、1-丁烯基(C4)、2-丁烯基(C4)、丁二烯基(C4)、戊烯基(C5)、戊二烯基(C5)、己烯基(C6),等等。术语“C2-6烯基”还包括杂烯基,其中一或多个(例如,1、2、3或4个)碳原子被杂原子(例如,氧、硫、氮、硼、硅、磷)替代。烯基基团可以被一或多个取代基任选取代,例如,被1至5个取代基、1至3个取代基或1个取代基取代。
“C2-6炔基”是指具有2至6个碳原子、至少一个碳-碳叁键以及任选地一个或多个碳-碳双键的直链或支链烃基团。在一些实施方案中,C2-4炔基是优选的。C2-6炔基的例子包括但不限于:乙炔基(C2)、1-丙炔基(C3)、2-丙炔基(C3)、1-丁炔基(C4)、2-丁炔基(C4),戊炔基(C5)、己炔基(C6),等等。术语“C2-6炔基”还包括杂炔基,其中一或多个(例如,1、2、3或4个)碳原子被杂原子(例如,氧、硫、氮、硼、硅、磷)替代。炔基基团可以被一或多个取代基任选取代,例如,被1至5个取代基、1至3个取代基或1个取代基取代。
“C1-6亚烷基”是指除去C1-6烷基的另一个氢而形成的二价基团,并且可以是取代或未取代的亚烷基。在一些实施方案中,C1-4亚烷基是特别优选的。未取代的所述亚烷基包括但不限于:亚甲基(-CH2-)、亚乙基(-CH2CH2-)、亚丙基(-CH2CH2CH2-)、亚丁基(-CH2CH2CH2CH2-)、亚戊基(-CH2CH2CH2CH2CH2-)、亚己基(-CH2CH2CH2CH2CH2CH2-),等等。示例性的取代的所述亚烷基,例如,被一个或多个烷基(甲基)取代的所述亚烷基,包括但不限于:取代的亚甲基(-CH(CH3)-、-C(CH3)2-)、取代的亚乙基(-CH(CH3)CH2-、-CH2CH(CH3)-、-C(CH3)2CH2-、-CH2C(CH3)2-)、取代的亚丙基(-CH(CH3)CH2CH2-、-CH2CH(CH3)CH2-、-CH2CH2CH(CH3)-、-C(CH3)2CH2CH2-、-CH2C(CH3)2CH2-、-CH2CH2C(CH3)2-),等等。
“卤代”或“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)。
“C1-6卤代烷基”表示上述“C1-6烷基”,其被一个或多个卤素基团取代。例子包括单卤素取代、二卤素取代和包括全卤代的多卤素取烷基。一个单卤素取代基在基团中可能有一个碘、溴、氯或氟原子;二个卤素取代基和多个卤素取代基可能有两个或更多相同的卤素原子或不同卤素的联合。优选的卤代烷基例子包括一氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、五氟乙基、七氟丙基、二氟氯甲基、二氯氟甲基、二氟乙基、二氟丙基、二氯乙基和二氯丙基。卤代烷基基团可以在任何可用的连接点上被取代,例如,1至5个取代基、1至3个取代基或1个取代基。
“C3-7环烷基”是指具有3至7个环碳原子和零个杂原子的非芳香环烃基团。在一些实施方案中,C3-6环烷基是特别优选的,更优选C5-6环烷基。环烷基还包括其中上述环烷基环与一个或多个芳基或杂芳基稠合的环体系,其中连接点在环烷基环上,且在这样的情况中,碳的数目继续表示环烷基体系中的碳的数目。示例性的所述环烷基包括但不限于:环丙基(C3)、环丙烯基(C3)、环丁基(C4)、环丁烯基(C4)、环戊基(C5)、环戊烯基(C5)、环己基(C6)、环己烯基(C6)、环已二烯基(C6)、环庚基(C7)、环庚烯基(C7)、环庚二烯基(C7)、环庚三烯基(C7),等等。
“3-11元杂环基”是指具有环碳原子和1至5个环杂原子的3至11元非芳香环系的基团,其中,每个杂原子独立地选自氮、氧、硫、硼、磷和硅。在包含一个或多个氮原子的杂环基中,只要化合价允许,连接点可为碳或氮原子。在一些实施方案中,优选3-9元杂环基,其为具有环碳原子和1至5个环杂原子的3至9元非芳香环系;在一些实施方案中,优选3-7元杂环基,其为具有环碳原子和1至4个环杂原子的3至7元非芳香环系;优选3-6元杂环基,其为具有环碳原子和1至3个环杂原子的3至6元非芳香环系;优选4-6元杂环基,其为具有环碳原子和1至3个环杂原子的4至6元非芳香环系;更优选5-6元杂环基,其为具有环碳原子和1至3个环杂原子的5至6元非芳香环系。杂环基还包括其中上述杂环基环与一个或多个环烷基稠合的环体系,其中连接点在环烷基环上,或其中上述杂环基环与一个或多个芳基或杂芳基稠合的环体系,其中连接点在杂环基环上;且在这样的情况下,环成员的数目继续表示在杂环基环体系中环成员的数目。示例性的包含一个杂原子的3元杂环基包括但不限于:氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基(thiorenyl)。示例性的含有一个杂原子的4元杂环基包括但不限于:氮杂环丁烷基、氧杂环丁烷基和硫杂环丁烷基。示例性的含有一个杂原子的5元杂环基包括但不限于:四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、吡咯烷基、二氢吡咯基和吡咯基-2,5-二酮。示例性的包含两个杂原子的5元杂环基包括但不限于:二氧杂环戊烷基、氧硫杂环戊烷基(oxasulfuranyl)、二硫杂环戊烷基(disulfuranyl)和噁唑烷-2-酮。示例性的包含三个杂原子的5元杂环基包括但不限于:三唑啉基、噁二唑啉基和噻二唑啉基。示例性的包含一个杂原子的6元杂环基包括但不限于:哌啶基、四氢吡喃基、二氢吡啶基和硫杂环己烷基(thianyl)。示例性的包含两个杂原子的6元杂环基包括但不限于:哌嗪基、吗啉基、二硫杂环己烷基、二噁烷基。示例性的包含三个杂原子的6元杂环基包括但不限于:六氢三嗪基(triazinanyl)。示例性的含有一个杂原子的7元杂环基包括但不限于:氮杂环庚烷基、氧杂环庚烷基和硫杂环庚烷基。示例性的与C6芳基环稠合的5元杂环基(在本文中也称作5,6-双环杂环基)包括但不限于:二氢吲哚基、异二氢吲哚基、二氢苯并呋喃基、二氢苯并噻吩基、苯并噁唑啉酮基,等等。示例性的与C6芳基环稠合的6元杂环基(本文还指的是6,6-双环杂环基)包括但不限于:四氢喹啉基、四氢异喹啉基,等等。
3-11元杂环基还包括螺杂环基,即两个环(例如杂环和碳烷)共享一个碳原子的基团,其中至少一个环为上文所定义的杂环基。更具体地,所述螺杂环基为两个4元环、两个5元环、两个6元环、一个4元环和一个5元环、一个4元环和一个6元环、或者一个5元环和一个6元环形成的螺环,其中至少一个环为上文定义的4-6元杂环基,优选含有1个、2个或3个O、N或S杂原子的4-6元杂环基更优选含有1个N杂原子的4-6元杂环基。具体的螺杂环基包括但不限于:
优选的杂环基的具体例子包括:吡咯啉基、咪唑烷基、吡唑烷基、四氢吡喃基、二氢吡喃基、二氢呋喃基、噻唑烷基、二氢噻唑基、2,3-二氢-苯并[l,4]二噁烷基、二氢吲哚基、异二氢氮茚基、二氢苯并噻吩、二氢苯并呋喃基、异苯并二氢吡喃基、苯并二氢吡喃基、1,2-二氢异喹啉、1,2,3,4-四氢异喹啉、1,2,3,4-四氢喹啉、2,3,4,4a,9,9a-六氢-lH-3-氮杂芴、5,6,7-三氢-1,2,4-三唑[3,4-a]异喹啉基、3,4-二氢-2H-苯并[l,4]噁嗪基、苯并[l,4]二噁烷基、2,3-二氢-lH-lk’-苯并[d]异噻唑-6-基、2,3-二-苯并[l,4]二噁英基、二氢苯并呋喃、2-氧代氮杂环丙-1-基、2-氧代氮杂环丁-1-基、2-氧代吡咯烷-1-基、2-氧代氮杂环己-1-基、2-氧代氮杂环庚-1-基、2-氧代氮杂环辛-1-基、2-氧代氮杂环壬-1-基、2-氧代氮杂环癸-1-基、氮杂环丙烷、氮杂环丁烷、吡咯烷基、氮杂环己烷、氮杂环庚烷、氮杂环辛烷、氮杂环壬烷、氮杂环癸烷、哌啶基、哌嗪基、吗啉基、二氮杂螺[3.3]庚烷、二氮杂螺[3.4]辛烷、二氮杂螺[3.5]壬烷、二氮杂螺[4.4]壬烷、二氮杂螺[4.5]癸烷和二氮杂螺[5.5]十一烷。
“C6-10芳基”是指具有6-10个环碳原子和零个杂原子的单环或多环的(例如,双环)4n+2芳族环体系(例如,具有以环状排列共享的6或10个π电子)的基团。在一些实施方案中,芳基具有六个环碳原子(“C6芳基”;例如,苯基)。在一些实施方案中,芳基具有十个环碳原子(“C10芳基”;例如,萘基,例如,1-萘基和2-萘基)。芳基还包括其中上述芳基环与一个或多个环烷基或杂环基稠合的环系统,而且连接点在所述芳基环上,在这种情况下,碳原子的数目继续表示所述芳基环系统中的碳原子数目。
“5-10元杂芳基”是指具有环碳原子和1-4个环杂原子的5-10元单环或双环的4n+2芳族环体系(例如,具有以环状排列共享的6或10个π电子)的基团,其中每个杂原子独立地选自氮、氧和硫。在含有一个或多个氮原子的杂芳基中,只要化合价允许,连接点可以是碳或氮原子。杂芳基双环系统在一个或两个环中可以包括一个或多个杂原子。杂芳基还包括其中上述杂芳基环与一个或多个环烷基或杂环基稠合的环系统,而且连接点在所述杂芳基环上,在这种情况下,碳原子的数目继续表示所述杂芳基环系统中的碳原子数目。在一些实施方案中,5-6元杂芳基是特别优选的,其为具有环碳原子和1-4个环杂原子的5-6元单环或双环的4n+2芳族环体系。示例性的含有一个杂原子的5元杂芳基包括但不限于:吡咯基、呋喃基和噻吩基。示例性的含有两个杂原子的5元杂芳基包括但不限于:咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基和异噻唑基。示例性的含有三个杂原子的5元杂芳基包括但不限于:三唑基、噁二唑基和噻二唑基。示例性的含有四个杂原子的5元杂芳基包括但不限于:四唑基。示例性的含有一个杂原子的6元杂芳基包括但不限于:吡啶基。示例性的含有两个杂原子的6元杂芳基包括但不限于:哒嗪基、嘧啶基和吡嗪基。示例性的含有三个或四个杂原子的6元杂芳基分别包括但不限于:三嗪基和四嗪基。示例性的含有一个杂原子的7元杂芳基包括但不限于:氮杂环庚三烯基、氧杂环庚三烯基和硫杂环庚三烯基。示例性的5,6-双环杂芳基包括但不限于:吲哚基、异吲哚基、吲唑基、苯并三唑基、苯并噻吩基、异苯并噻吩基、苯并呋喃基、苯并异呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噁二唑基、苯并噻唑基、苯并异噻唑基、苯并噻二唑基、茚嗪基和嘌呤基。示例性的6,6-双环杂芳基包括但不限于:萘啶基、喋啶基、喹啉基、异喹啉基、噌琳基、喹喔啉基、酞嗪基和喹唑啉基。
优选的杂芳基的具体例子包括:吡咯基、咪唑基、吡唑基、2-吡啶基、3-吡啶基、4-吡啶基、嘧啶基、吡嗪基、哒嗪基、三唑基(4H-l,2,4-三唑基、1H-1,2,3-三唑基、2H-l,2,3-三唑基、吡喃基、2-呋喃基、3-呋喃等、2-噻吩基、3-噻吩基、噁唑基、异噁唑基、噁唑基(1,2,4-噁唑基、1,3,4-噁唑基、1,2,5-噁唑基、噻唑基、噻二唑基(1,2,4-噻二唑基、1,3,4-噻二唑基、1,2,5-噻二唑基)。
“氧代”表示=O。
“硫代”表示=S。
本文定义的烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基等为任选取代的基团。
示例性的碳原子上的取代基包括但不局限于:卤素、-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-ORaa、-ON(Rbb)2、-N(Rbb)2、-N(Rbb)3 +X-、-N(ORcc)Rbb、-SH、-SRaa、-SSRcc、-C(=O)Raa、-CO2H、-CHO、-C(ORcc)2、-CO2Raa、-OC(=O)Raa、-OCO2Raa、-C(=O)N(Rbb)2、-OC(=O)N(Rbb)2、-NRbbC(=O)Raa、-NRbbCO2Raa、-NRbbC(=O)N(Rbb)2、-C(=NRbb)Raa、-C(=NRbb)ORaa、-OC(=NRbb)Raa、-OC(=NRbb)ORaa、-C(=NRbb)N(Rbb)2、-OC(=NRbb)N(Rbb)2、-NRbbC(=NRbb)N(Rbb)2、-C(=O)NRbbSO2Raa、-NRbbSO2Raa、-SO2N(Rbb)2、-SO2Raa、-SO2ORaa、-OSO2Raa、-S(=O)Raa、-OS(=O)Raa、-Si(Raa)3、-OSi(Raa)3、-C(=S)N(Rbb)2、-C(=O)SRaa、-C(=S)SRaa、-SC(=S)SRaa、-SC(=O)SRaa、-OC(=O)SRaa、-SC(=O)ORaa、-SC(=O)Raa、-P(=O)2Raa、-OP(=O)2Raa、-P(=O)(Raa)2、-OP(=O)(Raa)2、-OP(=O)(ORcc)2、-P(=O)2N(Rbb)2、-OP(=O)2N(Rbb)2、-P(=O)(NRbb)2、-OP(=O)(NRbb)2、-NRbbP(=O)(ORcc)2、-NRbbP(=O)(NRbb)2、-P(Rcc)2、-P(Rcc)3、-OP(Rcc)2、-OP(Rcc)3、-B(Raa)2、-B(ORcc)2、-BRaa(ORcc)、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基,其中,每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代;
或者在碳原子上的两个偕氢被基团=O、=S、=NN(Rbb)2、=NNRbbC(=O)Raa、=NNRbbC(=O)ORaa、=NNRbbS(=O)2Raa、=NRbb或=NORcc取代;
Raa的每个独立地选自烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基,或者两个Raa基团结合以形成杂环基或杂芳基环,其中,每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代;
Rbb的每个独立地选自:氢、-OH、-ORaa、-N(Rcc)2、-CN、-C(=O)Raa、-C(=O)N(Rcc)2、-CO2Raa、-SO2Raa、-C(=NRcc)ORaa、-C(=NRcc)N(Rcc)2、-SO2N(Rcc)2、-SO2Rcc、-SO2ORcc、-SORaa、-C(=S)N(Rcc)2、-C(=O)SRcc、-C(=S)SRcc、-P(=O)2Raa、-P(=O)(Raa)2、-P(=O)2N(Rcc)2、-P(=O)(NRcc)2、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基,或者两个Rbb基团结合以形成杂环基或杂芳基环,其中,每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代;
Rcc的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基,或者两个Rcc基团结合以形成杂环基或杂芳基环,其中,每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代;
Rdd的每个独立地选自:卤素、-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-ORee、-ON(Rff)2、-N(Rff)2,、-N(Rff)3 +X-、-N(ORee)Rff、-SH、-SRee、-SSRee、-C(=O)Ree、-CO2H、-CO2Ree、-OC(=O)Ree、-OCO2Ree、-C(=O)N(Rff)2、-OC(=O)N(Rff)2、-NRffC(=O)Ree、-NRffCO2Ree、-NRffC(=O)N(Rff)2、-C(=NRff)ORee、-OC(=NRff)Ree、-OC(=NRff)ORee、-C(=NRff)N(Rff)2、-OC(=NRff)N(Rff)2、-NRffC(=NRff)N(Rff)2、-NRffSO2Ree、-SO2N(Rff)2、-SO2Ree、-SO2ORee、-OSO2Ree、-S(=O)Ree、-Si(Ree)3、-OSi(Ree)3、-C(=S)N(Rff)2、-C(=O)SRee、-C(=S)SRee、-SC(=S)SRee、-P(=O)2Ree、-P(=O)(Ree)2、-OP(=O)(Ree)2、-OP(=O)(ORee)2、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基、杂芳基,其中,每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rgg基团取代,或者两个偕Rdd取代基可结合以形成=O或=S;
Ree的每个独立地选自烷基、卤代烷基、烯基、炔基、碳环基、芳基、杂环基和杂芳基,其中,每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rgg基团取代;
Rff的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基,或者两个Rff基团结合形成杂环基或杂芳基环,其中,每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rgg基团取代;
Rgg的每个独立地是:卤素、-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-OC1-6烷基、-ON(C1-6烷基)2、-N(C1-6烷基)2、-N(C1-6烷基)3 +X-、-NH(C1-6烷基)2 +X-、-NH2(C1-6烷基)+X-、-NH3 +X-、-N(OC1-6烷基)(C1-6烷基)、-N(OH)(C1-6烷基)、-NH(OH)、-SH、-SC1-6烷基、-SS(C1-6烷基)、-C(=O)(C1-6烷基)、-CO2H、-CO2(C1-6烷基)、-OC(=O)(C1-6烷基)、-OCO2(C1-6烷基)、-C(=O)NH2、-C(=O)N(C1-6烷基)2、-OC(=O)NH(C1-6烷基)、-NHC(=O)(C1-6烷基)、-N(C1-6烷基)C(=O)(C1-6烷基)、-NHCO2(C1-6烷基)、-NHC(=O)N(C1-6烷基)2、-NHC(=O)NH(C1-6烷基)、-NHC(=O)NH2、-C(=NH)O(C1-6烷基)、-OC(=NH)(C1-6烷基)、-OC(=NH)OC1-6烷基、-C(=NH)N(C1-6烷基)2、-C(=NH)NH(C1-6烷基)、-C(=NH)NH2、-OC(=NH)N(C1-6烷基)2、-OC(NH)NH(C1-6烷基)、-OC(NH)NH2、-NHC(NH)N(C1-6烷基)2、-NHC(=NH)NH2、-NHSO2(C1-6烷基)、-SO2N(C1-6烷基)2、-SO2NH(C1-6烷基)、-SO2NH2、-SO2C1-6烷基、-SO2OC1-6烷基、-OSO2C1-6烷基、-SOC1-6烷基、-Si(C1-6烷基)3、-OSi(C1-6烷基)3、-C(=S)N(C1-6烷基)2、C(=S)NH(C1-6烷基)、C(=S)NH2、-C(=O)S(C1-6烷基)、-C(=S)SC1-6烷基、-SC(=S)SC1-6烷基、-P(=O)2(C1-6烷基)、-P(=O)(C1-6烷基)2、-OP(=O)(C1-6烷基)2、-OP(=O)(OC1-6烷基)2、C1-6烷基、C1-6卤代烷基、C2-C6烯基、C2-C6炔基、C3-C7碳环基、C6-C10芳基、C3-C7杂环基、C5-C10杂芳基;或者两个偕Rgg取代基可结合形成=O或=S;其中,X-为反离子。
示例性的氮原子上取代基包括但不局限于:氢、-OH、-ORaa、-N(Rcc)2、-CN、-C(=O)Raa、-C(=O)N(Rcc)2、-CO2Raa、-SO2Raa、-C(=NRbb)Raa、-C(=NRcc)ORaa、-C(=NRcc)N(Rcc)2、-SO2N(Rcc)2、-SO2Rcc、-SO2ORcc、-SORaa、-C(=S)N(Rcc)2、-C(=O)SRcc、-C(=S)SRcc、-P(=O)2Raa、-P(=O)(Raa)2、-P(=O)2N(Rcc)2、-P(=O)(NRcc)2、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基,或者连接至氮原子的两个Rcc基团结合形成杂环基或杂芳基环,其中,每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代,且其中Raa、Rbb、Rcc和Rdd如上所述。
其它定义
术语“癌症”包括但不限于下列癌症:乳腺、卵巢、子宫颈、前列腺、睾丸、食道、胃、皮肤、肺、骨、结肠、胰腺、甲状腺、胆道、颊腔与咽(口)、唇、舌、口腔、咽、小肠、结肠直肠、大肠、直肠、脑与中枢神经系统的癌症、成胶质细胞瘤、神经母细胞瘤、角化棘皮瘤、表皮样癌、大细胞癌、腺癌、腺瘤、滤泡癌、未分化的癌、乳头状癌、精原细胞瘤、黑色素瘤、肉瘤、膀胱癌、肝癌、肾癌、骨髓障碍、淋巴障碍、霍奇金氏病、毛细胞癌和白血病。
本文所用的术语“治疗”涉及逆转、减轻、抑制该术语适用的障碍或病症的进展或者预防之,或者这类障碍或病症的一种或多种症状。本文所用的名词“治疗”涉及动词治疗的动作,后者是如刚才所定义的。
本文所用的术语“药学上可接受的盐”表示本发明化合物的那些羧酸盐、氨基酸加成盐,它们在可靠的医学判断范围内适用于与患者组织接触,不会产生不恰当的毒性、刺激作用、变态反应等,与合理的益处/风险比相称,就它们的预期应用而言是有效的,包括(可能的话)本发明化合物的两性离子形式。
术语“盐”表示本发明化合物的相对无毒的无机与有机酸加成盐。这些盐可以在化合物的最终分离和纯化期间被原位制备,或者单独使经过纯化的化合物游离碱形式与适合的有机或无机酸反应,再分离所生成的盐。只要本发明化合物是碱性化合物,它们都能够与各种无机和有机酸生成多种不同的盐。尽管这类盐就对动物给药而言必须是药学上可接受的,不过在实践中经常需要首先从反应混合物中分离碱化合物的药学上不可接受的盐,然后借助碱性试剂的处理简单地转化为游离碱化合物,之后将游离碱转化为药学上可接受的酸加成盐。碱性化合物的酸加成盐是这样制备的,按照常规方式使游离碱形式与足量所需的酸接触,生成盐。按照常规方式使盐形式与碱接触,再分离游离碱,可以使游离碱再生。游离碱形式在某些物理性质上多少不同于它们各自的盐形式,例如在极性溶剂中的溶解度,但是出于本发明的目的,盐还是等价于它们各自的游离碱。
药学上可接受的碱加成盐是与金属或胺生成的,例如碱金属与碱土金属氢氧化物或有机胺。用作阳离子的金属的实例有钠、钾、镁、钙等。适合的胺的实例有N,N'-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺和普鲁卡因。
酸性化合物的碱加成盐可以这样制备,按照常规方式使游离酸形式与足量所需的碱接触,生成盐。按照常规方式使盐形式与酸接触,再分离游离酸,可以使游离酸再生。游离酸形式在某些物理性质上多少不同于它们各自的盐形式,例如在极性溶剂中的溶解度,但是出于本发明的目的,盐还是等价于它们各自的游离酸。
盐可以是从无机酸制备的硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物,酸例如盐酸、硝酸、硫酸、氢溴酸、氢碘酸、磷酸等。代表性盐包括:氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、硝酸盐、乙酸盐、草酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、萘甲酸盐、甲磺酸盐、葡庚糖酸盐、乳糖酸盐、月桂基磺酸盐和羟乙磺酸盐等。盐也可以是从有机酸制备的,例如脂肪族一元与二元羧酸、苯基取代的烷酸、羟基烷酸、烷二酸、芳香族酸、脂肪族与芳香族磺酸等。代表性盐包括乙酸盐、丙酸盐、辛酸盐、异丁酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、扁桃酸盐、苯甲酸盐、氯苯甲酸盆、甲基苯甲酸盐、二硝基苯甲酸盐、萘甲酸盐、苯磺酸盐、甲苯磺酸盐、苯乙酸盐、柠檬酸盐、乳酸盐、马来酸盐、酒石酸盐、甲磺酸盐等。药学上可接受的盐可以包括基于碱金属与碱土金属的阳离子,例如钠、锂、钾、钙、镁等,以及无毒的铵、季铵和胺阳离子,包括但不限于铵、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、三乙胺、乙胺等。还涵盖氨基酸的盐,例如精氨酸盐、葡糖酸盐、半乳糖醛酸盐等(例如参见Berge S.M.et al.,"PharmaceuticalSalts,”J.Pharm.Sci.,1977;66:1-19,引入此作为参考)。
本发明化合物的药学上可接受的无毒酰胺的实例包括从Cl-C6烷基酯,其中烷基是直链或支链的。可接受的酯还包括C5-C7环烷基酯以及芳基烷基酯,例如但不限于苄基酯。C1-C4烷基酯是优选的。本发明化合物的酯可以按照常规方法制备,例如:March's AdvancedOrganic Chemistry,5Edition”M.B.Smith&J.March,John Wiley&Sons,2001。
本发明化合物的药学上可接受的无毒性酰胺的实例包括从氨、伯C1-C6烷基胺和仲C1-C6二烷基胺衍生的酰胺,其中烷基是直链或支链的。在仲胺的情况下,胺也可以是含有一个氮原子的5或6元杂环的形式。从氨、C1-C3烷基伯胺和C1-C2二烷基仲胺衍生的酰胺是优选的。本发明化合物的酰胺可以按照常规方法制备,例如:March's Advanced OrganicChemistry,5Edition”,M.B.Smith&J.March,John Wiley&Sons,2001。
术语“前药”表示体内迅速转化得到上式母体化合物的化合物,例如借助血液中的水解作用。详尽的讨论参见T.Higuchi and V.Ste11a,,“Pro-drugs as Novel DeliverySystems,”Vol.14of the A.C.S.Symposium Series和Bioreversible Carriers in DrugDesign,ed.Edward B.Roche,American Pharmaceutical Association and PergamonPress,1987,二者均引入此作为参考。
给药的“受试者”包括但不限于:人(即,任何年龄组的男性或女性,例如,儿科受试者(例如,婴儿、儿童、青少年)或成人受试者(例如,年轻的成人、中年的成人或年长的成人))和/或非人的动物,例如,哺乳动物,例如,灵长类(例如,食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在一些实施方案中,受试者是人。在一些实施方案中,受试者是非人动物。本文可互换使用术语“人”、“患者”和“受试者”。
“疾病”、“障碍”和“病症”在本文中可互换地使用。
除非另作说明,否则,本文使用的术语“治疗”包括受试者患有具体疾病、障碍或病症时所发生的作用,它降低疾病、障碍或病症的严重程度,或延迟或减缓疾病、障碍或病症的发展(“治疗性治疗”),还包括在受试者开始患有具体疾病、障碍或病症之前发生的作用(“预防性治疗”)。
通常,化合物的“有效量”是指足以引起目标生物反应的数量。正如本领域普通技术人员所理解的那样,本发明化合物的有效量可以根据下列因素而改变:例如,生物学目标、化合物的药代动力学、所治疗的疾病、给药模式以及受试者的年龄健康情况和症状。有效量包括治疗有效量和预防有效量。
除非另作说明,否则,本文使用的化合物的“治疗有效量”是在治疗疾病、障碍或病症的过程中足以提供治疗益处的量,或使与疾病、障碍或病症有关的一或多种症状延迟或最小化的量。化合物的治疗有效量是指单独使用或与其它疗法联用时,治疗剂的量,它在治疗疾病、障碍或病症的过程中提供治疗益处。术语“治疗有效量”可以包括改善总体治疗、降低或避免疾病或病症的症状或病因、或增强其它治疗剂的治疗效果的量。
除非另作说明,否则,本文使用的化合物的“预防有效量”是足以预防疾病、障碍或病症的量,或足以预防与疾病、障碍或病症有关的一或多种症状的量,或防止疾病、障碍或病症复发的量。化合物的预防有效量是指单独使用或与其它药剂联用时,治疗剂的量,它在预防疾病、障碍或病症的过程中提供预防益处。术语“预防有效量”可以包括改善总体预防的量,或增强其它预防药剂的预防效果的量。
“组合”以及相关术语是指同时或依次给药本发明化合物和其它治疗剂。例如,本发明化合物可以与其它治疗剂以分开的单位剂型同时或依次给药,或与其它治疗剂一起在单一单位剂型中同时给药。
具体实施方案
本文中,“本发明化合物”指的是以下的式(I)化合物、其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体,以及它们的混合物。
化合物一般在这里描述使用标准的命名法。具有非对称中心的化合物,应该明白(除非另有说明)所有的光学异构体及其混合物均包含在内。此外,除非另有规定,本发明所包括的所有异构体化合物与碳碳双键可能以Z和E的形式出现。在不同的互变异构形式存在的化合物,一个所述化合物并不局限于任何特定的互变异构体,而是旨在涵盖所有的互变异构形式。某些化合物所使用的一般公式,包括描述、变量。除非另有规定,在这样的公式中的每个变量被定义独立于任何其他变量和在每个发生时独立地定义了一个公式中的任何一个变量的多个变量。
在一个实施方案中,本发明涉及通式(I)的化合物,或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体,以及它们的混合物:
其中:
A1选自CR3或N;
A2选自CR3;
A3选自CR3;
R1为H;
R2选自H、卤素、-CN、-ORa、-SRa、-NRbRc、-C(O)Ra、-C(O)ORa、-C(O)NRbRc、C1-6烷基或C1-6卤代烷基;
R3选自H、卤素、-CN、-NO2、-ORa、-SRa、-NRbRc、-O-C1-6亚烷基-R6、C1-6烷基、C1-6卤代烷基、-L’-C3-7环烷基、-L’-3-11元杂环基、-L’-C6-10芳基或-L’-5-10元杂芳基,所述基团任选地被1、2、3、4或5个R6基团取代;
R4选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-10元杂芳基;
R5为H;
R6选自H、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、C1-6烷基或C1-6卤代烷基;
或者同一个碳原子上的两个R6一起形成氧代或硫代;
其中:
R4任选地被1、2或3个R’基团取代,其中R’独立地选自H、卤素、-CN、-NO2、-ORa、-SRa、-NRbRc、-C(O)ORa、-C(O)NRbRc、C1-6烷基、C1-6卤代烷基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-10元杂芳基;
Ra独立地选自H、C1-6烷基、C2-6烯基、C2-6炔基或C1-6卤代烷基;
Rb和Rc独立地选自H、C1-6烷基、C2-6烯基、C2-6炔基或C1-6卤代烷基;或者,Rb、Rc与N原子一起形成3-7元杂环基;
L’选自化学键或-O-。
A1、A2和A3
在一个具体实施方案中,A1为CR3;在另一个具体实施方案中,A1为CH;在另一个具体实施方案中,A1为N。
在一个具体实施方案中,A2为CR3;在另一个具体实施方案中,A2为CH;在另一个具体实施方案中,A2为CR3b。
在一个具体实施方案中,A3为CR3;在另一个具体实施方案中,A3为CH;在另一个具体实施方案中,A3为CR3a。
R2
在一个具体实施方案中,R2为H;在另一个具体实施方案中,R2为卤素;在另一个具体实施方案中,R2为-CN;在另一个具体实施方案中,R2为-ORa;在另一个具体实施方案中,R2为-SRa;在另一个具体实施方案中,R2为-NRbRc;在另一个具体实施方案中,R2为-C(O)Ra;在另一个具体实施方案中,R2为-C(O)ORa;在另一个具体实施方案中,R2为-C(O)NRbRc;在另一个具体实施方案中,R2为C1-6烷基;在另一个具体实施方案中,R2为C1-6卤代烷基。
R3
在一个具体实施方案中,R3为H;在另一个具体实施方案中,R3为卤素;在另一个具体实施方案中,R3为-CN;在另一个具体实施方案中,R3为-NO2;在另一个具体实施方案中,R3为-ORa;在另一个具体实施方案中,R3为-SRa;在另一个具体实施方案中,R3为-NRbRc;在另一个具体实施方案中,R3为-O-C1-6亚烷基-R6;在另一个具体实施方案中,R3为C1-6烷基;在另一个具体实施方案中,R3为C1-6卤代烷基;在另一个具体实施方案中,R3为-L’-C3-7环烷基;在另一个具体实施方案中,R3为-L’-3-11元杂环基;在另一个具体实施方案中,R3为-L’-3-9元杂环基;在另一个具体实施方案中,R3为-L’-C6-10芳基;在另一个具体实施方案中,R3为-L’-5-10元杂芳基。
在R3的上述具体实施方案中,所述基团任选地被1、2、3、4或5个R6基团取代。在一个具体实施方案中,所述基团被1个R6基团取代;在另一个具体实施方案中,所述基团被2个R6基团取代;在另一个具体实施方案中,所述基团被3个R6基团取代;在另一个具体实施方案中,所述基团被4个R6基团取代;在另一个具体实施方案中,所述基团被5个R6基团取代。
R4
在一个具体实施方案中,R4为H;在另一个具体实施方案中,R4为C1-6烷基;在另一个具体实施方案中,R4为C1-6卤代烷基;在另一个具体实施方案中,R4为C3-7环烷基;在另一个具体实施方案中,R4为3-7元杂环基;在另一个具体实施方案中,R4为C6-10芳基;在另一个具体实施方案中,R4为5-10元杂芳基。
在R4的上述具体实施方案中,所述基团任选地被1、2或3个R’基团取代。在一个具体实施方案中,所述基团被1个R’基团取代;在另一个具体实施方案中,所述基团被2个R’基团取代;在另一个具体实施方案中,所述基团被3个R’基团取代。
在上述具体实施方案中,R’为H;在另一个具体实施方案中,R’为卤素;在另一个具体实施方案中,R’为-CN;在另一个具体实施方案中,R’为-NO2;在另一个具体实施方案中,R’为-ORa;在另一个具体实施方案中,R’为-SRa;在另一个具体实施方案中,R’为-NRbRc;在另一个具体实施方案中,R’为-C(O)ORa;在另一个具体实施方案中,R’为-C(O)NRbRc;在另一个具体实施方案中,R’为C1-6烷基;在另一个具体实施方案中,R’为C1-6卤代烷基;在另一个具体实施方案中,R’为C3-7环烷基;在另一个具体实施方案中,R’为3-7元杂环基;在另一个具体实施方案中,R’为C6-10芳基;在另一个具体实施方案中,R’为5-10元杂芳基。
R6
在一个具体实施方案中,R6为H;在另一个具体实施方案中,R6为-NH2;在另一个具体实施方案中,R6为-NHC1-6烷基;在另一个具体实施方案中,R6为-N(C1-6烷基)2;在另一个具体实施方案中,R6为C1-6烷基;在另一个具体实施方案中,R6为C1-6卤代烷基;在另一个具体实施方案中,同一个碳原子上的两个R6一起形成氧代。在另一个具体实施方案中,同一个碳原子上的两个R6一起形成硫代。
L’
在一个具体实施方案中,L’为化学键;在另一个具体实施方案中,L’为-O-。
以上任一具体实施方案中的任一技术方案或其任意组合,可以与其它具体实施方案中的任一技术方案或其任意组合进行组合。例如,A1的任一技术方案或其任意组合,可以与A2、A3、R1-R6、R’、Ra、Rb、Rc和L’的任一技术方案或其任意组合进行组合。本发明旨在包括所有这些技术方案的组合,限于篇幅,不再一一列出。
在更具体的实施方案中,本发明提供了技术方案1,其为通式(II)的化合物,或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体,以及它们的混合物:
其中:
R3a、R3b、R3c、R3d、R3e和R3f独立地选自H、卤素、-CN、-NO2、C1-6烷基、C1-6卤代烷基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-10元杂芳基;
R4选自C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基。
在另一更具体的实施方案中,本发明提供了技术方案2,涉及根据技术方案1的化合物,其中
在另一更具体的实施方案中,本发明提供了技术方案3,涉及根据技术方案1或2中任一项的化合物,其中
R3a、R3b、R3c、R3d、R3e和R3f独立地选自H、卤素、C1-6烷基或C1-6卤代烷基;
优选地,R3a、R3b、R3c、R3d、R3e和R3f独立地选自H、卤素或C1-6烷基;
优选地,R3a和R3b独立地选自H、卤素或C1-6烷基;且R3c、R3d、R3e和R3f独立地选自H或C1-6烷基;
优选地,R3a和R3b独立地选自H、F或甲基;且R3c、R3d、R3e和R3f独立地选自H、甲基或乙基;
优选地,R3a和R3b独立地选自H、卤素或C1-6烷基;
优选地,R3a和R3b独立地选自H、F或甲基;
优选地,R3a、R3b和R3c独立地选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-10元杂芳基,条件是R3a、R3b和R3c中最多只有一个不为H;
优选地,R3a、R3b和R3c独立地选自H、C1-6烷基或C1-6卤代烷基,条件是R3a、R3b和R3c中最多只有一个不为H;
优选地,R3a、R3b和R3c独立地选自H或C1-6烷基,条件是R3a、R3b和R3c中最多只有一个不为H;
优选地,R3a、R3b和R3c独立地选自H、甲基或乙基,条件是R3a、R3b和R3c中最多只有一个不为H;
优选地,R3a和R3b独立地选自H或C1-6烷基;
优选地,R3a和R3b独立地选自H或甲基。
在另一更具体的实施方案中,本发明提供了技术方案4,涉及根据技术方案1至3中任一项的化合物,其中
R4选自C1-6烷基或C3-7环烷基;
优选地,R4选自异丙基或环戊基。
在更具体的实施方案中,本发明提供了技术方案5,其为通式(II)的化合物,或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体,以及它们的混合物:
其中:
R3a和R3b独立地选自H、卤素、-CN、-NO2、C1-6烷基、C1-6卤代烷基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-10元杂芳基;
R4选自C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基。
在另一更具体的实施方案中,本发明提供了技术方案6,涉及根据技术方案5的化合物,其中
在另一更具体的实施方案中,本发明提供了技术方案7,涉及根据技术方案5或6中任一项的化合物,其中
R3a和R3b独立地选自H、卤素、C1-6烷基或C1-6卤代烷基;
优选地,R3a和R3b独立地选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-10元杂芳基;
优选地,R3a和R3b独立地选自H、卤素或C1-6烷基;
优选地,R3a和R3b独立地选自H、F或甲基;
优选地,R3a和R3b独立地选自H、C1-6烷基或C1-6卤代烷基;
优选地,R3a和R3b独立地选自H或C1-6烷基;
优选地,R3a和R3b独立地选自H或甲基;
优选地,R3a为H;且R3b选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-10元杂芳基;
优选地,R3a为H;且R3b选自H、C1-6烷基或C1-6卤代烷基;
优选地,R3a为H;且R3b选自H或C1-6烷基;
优选地,R3a为H;且R3b选自H或甲基。
在另一更具体的实施方案中,本发明提供了技术方案8,涉及根据技术方案5至7中任一项的化合物,其中
R4选自C1-6烷基或C3-7环烷基;
优选地,R4选自异丙基或环戊基。
在更具体的实施方案中,本发明提供了技术方案9,其为通式(II)的化合物,或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体,以及它们的混合物:
其中:
R3a、R3b、R3c、R3d、R3e和R3f独立地选自H、卤素、-CN、-NO2、C1-6烷基、C1-6卤代烷基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-10元杂芳基;
R4选自C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基。
在另一更具体的实施方案中,本发明提供了技术方案10,涉及根据技术方案9的化合物,其中
在另一更具体的实施方案中,本发明提供了技术方案11,涉及根据技术方案9至10中任一项的化合物,其中
R3a、R3b、R3c、R3d、R3e和R3f独立地选自H、卤素、C1-6烷基或C1-6卤代烷基;
优选地,R3a、R3b、R3c、R3d、R3e和R3f独立地选自H、卤素或C1-6烷基;
优选地,R3a和R3b独立地选自H、卤素或C1-6烷基;且R3c、R3d、R3e和R3f独立地选自H或C1-6烷基;
优选地,R3a和R3b独立地选自H、F或甲基;且R3c、R3d、R3e和R3f独立地选自H、甲基或乙基;
优选地,R3a和R3b独立地选自H、卤素或C1-6烷基;
优选地,R3a和R3b独立地选自H、F或甲基;
优选地,R3a、R3b、R3c、R3d、R3e和R3f独立地选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-10元杂芳基;
优选地,R3a、R3b、R3c、R3d、R3e和R3f独立地选自H、C1-6烷基或C1-6卤代烷基;
优选地,R3a、R3b、R3c、R3d、R3e和R3f独立地选自H或C1-6烷基;
优选地,R3a和R3b独立地选自H或C1-6烷基;且R3c、R3d、R3e和R3f独立地选自H或C1-6烷基;
优选地,R3a和R3b独立地选自H或甲基;且R3c、R3d、R3e和R3f独立地选自H、甲基或乙基;
优选地,R3a和R3b独立地选自H或C1-6烷基;
优选地,R3a和R3b独立地选自H或甲基;
优选地,R3a、R3b和R3c独立地选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-10元杂芳基,条件是R3a、R3b和R3c中最多只有一个不为H;
优选地,R3a、R3b和R3c独立地选自H、C1-6烷基或C1-6卤代烷基,条件是R3a、R3b和R3c中最多只有一个不为H;
优选地,R3a、R3b和R3c独立地选自H或C1-6烷基,条件是R3a、R3b和R3c中最多只有一个不为H;
优选地,R3a、R3b和R3c独立地选自H、甲基或乙基,条件是R3a、R3b和R3c中最多只有一个不为H;
优选地,R3a和R3b为H;且R3c为C1-6烷基、C1-6卤代烷基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-10元杂芳基;
优选地,R3a和R3b为H;且R3c为C1-6烷基或C1-6卤代烷基;
优选地,R3a和R3b为H;且R3c为C1-6烷基;
优选地,R3a和R3b为H;且R3c选自甲基或乙基。
在另一更具体的实施方案中,本发明提供了技术方案12,涉及根据技术方案9至11中任一项的化合物,其中
R4选自C1-6烷基或C3-7环烷基;
优选地,R4选自异丙基或环戊基。
在更具体的实施方案中,本发明提供了技术方案13,其为通式(III)的化合物,或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体,以及它们的混合物:
其中:
R3选自-O-C1-6亚烷基-R6或-L’-5-6元杂环基,所述基团任选地被1或2个R6基团取代;
R3a、R3b和R3g独立地选自H、卤素、C1-6烷基或-ORa;
Ra选自H或C1-6烷基;
R6独立地选自H、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、C1-6烷基或C1-6卤代烷基;
L’为化学键或-O-;
或者R3和R3b一起形成任选取代的5-6元杂环基或5-6元杂芳基;
优选地,
R3a、R3b和R3g独立地选自H、F和OMe;
本发明化合物可包括一个或多个不对称中心,且因此可以存在多种立体异构体形式,例如,对映异构体和/或非对映异构体形式。例如,本发明化合物可为单独的对映异构体、非对映异构体或几何异构体(例如顺式和反式异构体),或者可为立体异构体的混合物的形式,包括外消旋体混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离,所述方法包括:手性高压液相色谱法(HPLC)以及手性盐的形成和结晶;或者优选的异构体可通过不对称合成来制备。
本领域技术人员将理解,有机化合物可以与溶剂形成复合物,其在该溶剂中发生反应或从该溶剂中沉淀或结晶出来。这些复合物称为“溶剂合物”。当溶剂是水时,复合物称为“水合物”。本发明涵盖了本发明化合物的所有溶剂合物。
术语“溶剂合物”是指通常由溶剂分解反应形成的与溶剂相结合的化合物或其盐的形式。这个物理缔合可包括氢键键合。常规溶剂包括包括水、甲醇、乙醇、乙酸、DMSO、THF、乙醚等。本文所述的化合物可制备成,例如,结晶形式,且可被溶剂化。合适的溶剂合物包括药学上可接受的溶剂合物且进一步包括化学计量的溶剂合物和非化学计量的溶剂合物。在一些情况下,所述溶剂合物将能够分离,例如,当一或多个溶剂分子掺入结晶固体的晶格中时。“溶剂合物”包括溶液状态的溶剂合物和可分离的溶剂合物。代表性的溶剂合物包括水合物、乙醇合物和甲醇合物。
术语“水合物”是指与水相结合的化合物。通常,包含在化合物的水合物中的水分子数与该水合物中该化合物分子数的比率确定。因此,化合物的水合物可用例如通式R·xH2O代表,其中R是该化合物,和x是大于0的数。给定化合物可形成超过一种水合物类型,包括,例如,单水合物(x为1)、低级水合物(x是大于0且小于1的数,例如,半水合物(R·0.5H2O))和多水合物(x为大于1的数,例如,二水合物(R·2H2O)和六水合物(R·6H2O))。
本发明化合物可以是无定形或结晶形式(多晶型)。此外,本发明化合物可以以一种或多种结晶形式存在。因此,本发明在其范围内包括本发明化合物的所有无定形或结晶形式。术语“多晶型物”是指特定晶体堆积排列的化合物的结晶形式(或其盐、水合物或溶剂合物)。所有的多晶型物具有相同的元素组成。不同的结晶形式通常具有不同的X射线衍射图、红外光谱、熔点、密度、硬度、晶体形状、光电性质、稳定性和溶解度。重结晶溶剂、结晶速率、贮存温度和其他因素可导致一种结晶形式占优。化合物的各种多晶型物可在不同的条件下通过结晶制备。
本发明还包括同位素标记的化合物,它们等同于式(I)所述的那些,但一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素,分别例如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。某些同位素标记的本发明化合物、例如引入放射性同位素(例如3H和14C)的那些可用于药物和/或底物组织分布测定。氚、即3H和碳-14、即14C同位素是特别优选的,因为它们容易制备和检测。进而,被更重的同位素取代,例如氘、即2H,由于代谢稳定性更高可以提供治疗上的益处,例如延长体内半衰期或减少剂量需求,因而在有些情况下可能是优选的。同位素标记的本发明式(I)化合物及其前体药物一般可以这样制备,在进行下述流程和/或实施例与制备例所公开的工艺时,用容易得到的同位素标记的试剂代替非同位素标记的试剂。
此外,前药也包括在本发明的上下文内。本文所用的术语“前药”是指在体内通过例如在血液中水解转变成其具有医学效应的活性形式的化合物。药学上可接受的前药描述于T.Higuchi和V.Stella,Prodrugs as Novel Delivery Systems,A.C.S.SymposiumSeries的Vol.14,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,以及D.Fleisher、S.Ramon和H.Barbra“Improved oral drug delivery:solubility limitations overcomeby the use of prodrugs”,Advanced Drug Delivery Reviews(1996)19(2)115-130,每篇引入本文作为参考。
前药为任何共价键合的本发明化合物,当将这种前药给予患者时,其在体内释放母体化合物。通常通过修饰官能团来制备前药,修饰是以使得该修饰可以通过常规操作或在体内裂解产生母体化合物的方式进行的。前药包括,例如,其中羟基、氨基或巯基与任意基团键合的本发明化合物,当将其给予患者时,可以裂解形成羟基、氨基或巯基。因此,前药的代表性实例包括(但不限于)式(I)化合物的羟基、巯基和氨基官能团的乙酸酯/酰胺、甲酸酯/酰胺和苯甲酸酯/酰胺衍生物。另外,在羧酸(-COOH)的情况下,可以使用酯,例如甲酯、乙酯等。酯本身可以是有活性的和/或可以在人体体内条件下水解。合适的药学上可接受的体内可水解的酯基包括容易在人体中分解而释放母体酸或其盐的那些基团。
本发明还提供药物制剂,包含治疗有效量的式(I)化合物或其治疗学上可接受的盐和其药学上可接受的载体、稀释剂或赋形剂。所有这些形式都属于本发明。
优选的本发明化合物包括但不限于下面列举的化合物:
药物组合物、制剂和试剂盒
在另一方面,本发明提供了药物组合物,其包含本发明化合物(还称为“活性组分”)和药学上可接受的赋形剂。在一些实施方案中,所述药物组合物包含有效量的本发明化合物。在一些实施方案中,所述药物组合物包含治疗有效量的本发明化合物。在一些实施方案中,所述药物组合物包含预防有效量的本发明化合物。
用于本发明的药学上可接受的赋形剂是指不会破坏一起调配的化合物的药理学活性的无毒载剂、佐剂或媒剂。可以用于本发明组合物中的药学上可接受的载剂、佐剂或媒剂包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人类血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。
本发明还包括试剂盒(例如,药物包装)。所提供的试剂盒可以包括本发明化合物、其它治疗剂,以及含有本发明化合物、其它治疗剂的第一和第二容器(例如,小瓶、安瓿瓶、瓶、注射器和/或可分散包装或其它合适的容器)。在一些实施方案中,提供的试剂盒还可以任选包括第三容器,其含有用于稀释或悬浮本发明化合物和/或其它治疗剂的药用赋形剂。在一些实施方案中,提供在第一容器和第二容器中的本发明化合物和其它治疗剂组合形成一个单位剂型。
给药
本发明提供的药物组合物可以通过许多途径给药,包括但不限于:口服给药、肠胃外给药、吸入给药、局部给药、直肠给药、鼻腔给药、口腔给药、阴道给药、通过植入剂给药或其它给药方式。例如,本文使用的肠胃外给药包括皮下给药、皮内给药、静脉内给药、肌肉内给药、关节内给药、动脉内给药、滑膜腔内给药、胸骨内给药、脑脊髓膜内给药、病灶内给药、和颅内的注射或输液技术。
通常,给予有效量的本文所提供的化合物。按照有关情况,包括所治疗的病症、选择的给药途径、实际给予的化合物、个体患者的年龄、体重和响应、患者症状的严重程度,等等,可以由医生确定实际上给予的化合物的量。
当用于预防本发明所述病症时,给予处于形成所述病症危险之中的受试者本文所提供的化合物,典型地基于医生的建议并在医生监督下给药,剂量水平如上所述。处于形成具体病症的危险之中的受试者,通常包括具有所述病症的家族史的受试者,或通过遗传试验或筛选确定尤其对形成所述病症敏感的那些受试者。
还可以长期给予本文所提供的药物组合物(“长期给药”)。长期给药是指在长时间内给予化合物或其药物组合物,例如,3个月、6个月、1年、2年、3年、5年等等,或者可无限期地持续给药,例如,受试者的余生。在一些实施方案中,长期给药意欲在长时间内在血液中提供所述化合物的恒定水平,例如,在治疗窗内。
可以使用各种给药方法,进一步递送本发明的药物组合物。例如,在一些实施方案中,可以推注给药药物组合物,例如,为了使化合物在血液中的浓度提高至有效水平。推注剂量取决于通过身体的活性组分的目标全身性水平,例如,肌内或皮下的推注剂量使活性组分缓慢释放,而直接递送至静脉的推注(例如,通过IV静脉滴注)能够更加快速地递送,使得活性组分在血液中的浓度快速升高至有效水平。在其它实施方案中,可以以持续输液形式给予药物组合物,例如,通过IV静脉滴注,从而在受试者身体中提供稳态浓度的活性组分。此外,在其它实施方案中,可以首先给予推注剂量的药物组合物,而后持续输液。
口服组合物可以采用散装液体溶液或混悬剂或散装粉剂形式。然而,更通常,为了便于精确地剂量给药,以单位剂量形式提供所述组合物。术语“单位剂型”是指适合作为人类患者及其它哺乳动物的单元剂量的物理离散单位,每个单位包含预定数量的、适于产生所需要的治疗效果的活性物质与合适药学赋形剂。典型的单位剂量形式包括液体组合物的预装填的、预先测量的安瓿或注射器,或者在固体组合物情况下的丸剂、片剂、胶囊剂等。在这种组合物中,所述化合物通常为较少的组分(约0.1至约50重量%,或优选约1至约40重量%),剩余部分为对于形成所需给药形式有用的各种载体或赋形剂以及加工助剂。
对于口服剂量,代表性的方案是,每天一个至五个口服剂量,尤其是两个至四个口服剂量,典型地是三个口服剂量。使用这些剂量给药模式,每个剂量提供大约0.01至大约20mg/kg的本发明化合物,优选的剂量各自提供大约0.1至大约10mg/kg,尤其是大约1至大约5mg/kg。
为了提供与使用注射剂量类似的血液水平,或比使用注射剂量更低的血液水平,通常选择透皮剂量,数量为大约0.01至大约20%重量,优选大约0.1至大约20%重量,优选大约0.1至大约10%重量,且更优选大约0.5至大约15%重量。
从大约1至大约120小时,尤其是24至96小时,注射剂量水平在大约0.1mg/kg/小时至至少10mg/kg/小时的范围。为了获得足够的稳定状态水平,还可以给予大约0.1mg/kg至大约10mg/kg或更多的预载推注。对于40至80kg的人类患者来说,最大总剂量不能超过大约2g/天。
适于口服给药的液体形式可包括合适的水性或非水载体以及缓冲剂、悬浮剂和分散剂、着色剂、调味剂,等等。固体形式可包括,例如,任何下列组份,或具有类似性质的化合物:粘合剂,例如,微晶纤维素、黄蓍胶或明胶;赋形剂,例如,淀粉或乳糖,崩解剂,例如,褐藻酸、Primogel或玉米淀粉;润滑剂,例如,硬脂酸镁;助流剂,例如,胶体二氧化硅;甜味剂,例如,蔗糖或糖精;或调味剂,例如,薄荷、水杨酸甲酯或橙味调味剂。
可注射的组合物典型地基于可注射用的无菌盐水或磷酸盐缓冲盐水,或本领域中已知的其它可注射的赋形剂。如前所述,在这种组合物中,活性化合物典型地为较少的组分,经常为约0.05至10%重量,剩余部分为可注射的赋形剂等。
典型地将透皮组合物配制为含有活性组分的局部软膏剂或乳膏剂。当配制为软膏剂时,活性组分典型地与石蜡或可与水混溶的软膏基质组合。或者,活性组分可与例如水包油型乳膏基质一起配制为乳膏剂。这种透皮制剂是本领域中公知的,且通常包括用于提升活性组分或制剂的稳定的皮肤渗透的其它组份。所有这种已知的透皮制剂和组份包括在本发明提供的范围内。
本发明化合物还可通过经皮装置给予。因此,经皮给药可使用贮存器(reservoir)或多孔膜类型、或者多种固体基质的贴剂实现。
用于口服给予、注射或局部给予的组合物的上述组份仅仅是代表性的。其它材料以及加工技术等阐述于Remington's Pharmaceutical Sciences,17th edition,1985,Mack Publishing Company,Easton,Pennsylvania的第8部分中,本文以引用的方式引入该文献。
本发明化合物还可以以持续释放形式给予,或从持续释放给药系统中给予。代表性的持续释放材料的描述可在Remington's Pharmaceutical Sciences中找到。
本发明还涉及本发明化合物的药学上可接受的制剂。在一个实施方案中,所述制剂包含水。在另一个实施方案中,所述制剂包含环糊精衍生物。最常见的环糊精为分别由6、7和8个α-1,4-连接的葡萄糖单元组成的α-、β-和γ-环糊精,其在连接的糖部分上任选包括一个或多个取代基,其包括但不限于:甲基化的、羟基烷基化的、酰化的和磺烷基醚取代。在一些实施方案中,所述环糊精为磺烷基醚β-环糊精,例如,磺丁基醚β-环糊精,也称作Captisol。参见,例如,U.S.5,376,645。在一些实施方案中,所述制剂包括六丙基-β-环糊精(例如,在水中,10-50%)。
治疗
本发明提供了治疗哺乳动物(包括人类)的以下障碍或病症的方法:细胞增殖障碍,例如癌症、与动脉粥样硬化有关的血管平滑肌增生、手术后血管狭窄、再狭窄和子宫内膜异位;感染,包括病毒感染,例如DNA病毒,如疱疹,和RNA病毒,如HIV,以及真菌感染;自身免疫疾病,例如牛皮癣、炎症,如类风湿性关节炎、狼疮、I型糖尿病、糖尿病性肾病、多发性硬化和肾小球性肾炎;器官移植排斥,包括宿主对移植物的疾病,该方法包括给予所述哺乳动物治疗有效量的本发明化合物或其组合物。
本发明进一步提供了可用于治疗异常细胞增殖、例如癌症的本发明化合物。本发明进一步提供了治疗异常细胞增殖、例如选自以下的癌症的方法:乳腺、卵巢、子宫颈、前列腺、睾丸、食道、胃、皮肤、肺、骨、结肠、胰腺、甲状腺、胆道、颊腔与咽(口)、唇、舌、口腔、咽、小肠、结肠直肠、大肠、直肠、脑与中枢神经系统的癌症、成胶质细胞瘤、神经母细胞瘤、角化棘皮瘤、表皮样癌、大细胞癌、腺癌、腺瘤、滤泡癌、未分化的癌、乳头状癌、精原细胞瘤、黑色素瘤、肉瘤、膀胱癌、肝癌、肾癌、骨髓障碍、淋巴障碍、霍奇金氏病、毛细胞癌和白血病,该方法包括给予需要这类治疗的受试者治疗有效量的本发明化合物或其组合物。
进一步地,本发明涉及治疗患有血管平滑肌细胞增殖所致疾病的受试者的方法。本发明化合物有效地抑制血管平滑肌细胞的增殖和移行。该方法包括给予需要治疗的受试者足以抑制血管平滑肌增生和/或移行量的本发明化合物或其组合物。
本发明进一步提供了治疗患有痛风的受试者的方法,包括对需要治疗的所述受试者给以足以治疗该病症量的本发明化合物或其组合物。
本发明进一步提供了治疗患有肾疾病、例如多囊性肾疾病的受试者的方法,包含给予需要治疗的所述受试者足以治疗该病症量的本发明化合物或其组合物。
由于它们对CDK和其它激酶的抑制活性,本发明化合物也是有用的研究工具,用于体外和体内研究这些激酶的作用机理。
本发明化合物可用于治疗癌症(例如白血病和肺、乳腺、前列腺与皮肤的癌症,例如黑素瘤)和其它增殖性疾病,包括但不限于牛皮癣、HSV、HIV、再狭窄和动脉粥样硬化。为了利用本发明化合物治疗癌症,给予需要这类治疗的患者、例如患有癌症或另一种增殖性疾病者治疗有效量的药学上可接受的组合物,其中包含至少一种本发明化合物。
本发明化合物的有效量通常在平均日剂量为0.01mg至50mg化合物/千克患者体重,优选0.1mg至25mg化合物/千克患者体重,以单次或多次给药。通常,本发明化合物可向该有此治疗需要的患者以每位患者约1mg至约3500mg的日剂量范围给药,优选10mg至1000mg。例如,每位患者的日剂量可为10、20、30、40、50、60、70、80、90、100、150、200、250、300、350、400、500、600、700、800、900或1000mg。可每天、每周(或间隔数天)或以间歇时间表,给药一次或多次。例如,可在每周的基础上(例如每周一),每天给予所述化合物一次或多次,不定地或持续几周,例如4-10周。或者,可每天给药持续几天(例如2-10天),然后几天(例如1-30天)不给药所述化合物,不定地重复该循环或重复给定的次数,例如4-10个循环。例如,本发明化合物可每天给药持续5天,然后间断9天,然后再每天给药持续5天,然后间断9天,以此类推,不定地重复该循环或共重复4-10次。
组合治疗
可将本发明化合物或组合物与一种或多种额外的药剂同时给药、或在所述一种或多种额外的药剂之前或之后给药,用作组合疗法。药剂包括治疗活性剂。药剂还包括预防活性剂。药剂包括小的有机分子,例如药物化合物(例如,由美国食品与药物管理局批准,提供在美国联邦法规汇编(CFR)中的人或兽用化合物)、肽类、蛋白、碳水化合物、单糖、寡糖、多糖、核蛋白、粘蛋白、脂蛋白、合成多肽或蛋白、连接蛋白的小分子、糖蛋白、甾类、核酸、DNA、RNA、核苷酸、核苷、寡核苷酸、反义寡核苷酸、脂质、激素、维生素和细胞。在一些实施方案中,所述额外的药剂是用于治疗和/或预防本文所述疾病的药剂。各额外的药剂可以该药剂确定的剂量和/或时间表进行给药。所述额外的药剂也可彼此一起和/或与本文所述化合物或组合物一起,以单一剂量进行给药或以不同剂量分别进行给药。在该方案中所采用的具体组合将考虑本发明化合物与额外的药剂的相容性和/或将实现的所需的治疗和/或预防效果。通常,所述额外的药剂在组合使用时所采用的水平是以不超过它们单独使用时的水平。在一些实施方案中,组合使用的水平将低于它们单独使用时的水平。
所述额外的药剂包括,但不限于,抗增殖剂、抗癌剂、抗血管生成剂、抗炎剂、免疫抑制剂、抗菌剂、抗病毒剂、心血管药物、降脂药、抗糖尿病药、抗过敏剂、避孕药和止痛剂。在具体实施方案中,所述额外的药剂为抗增殖剂。在具体实施方案中,所述额外的药剂为抗癌剂。在具体实施方案中,所述额外的药剂为抗白血病药。在具体实施方案中,所述额外的药剂为ABITREXATE(甲氨蝶呤)、ADE、阿霉素RDF(盐酸多柔比星)、Ambochlorin(苯丁酸氮芥)、ARRANON(奈拉滨)、ARZERRA(奥法木单抗)、BOSULIF(博舒替尼)、BUSULFEX(白消安)、CAMPATH(阿仑单抗)、CERUBIDINE(盐酸柔红霉素)、CLAFEN(环磷酰胺)、CLOFAREX(氯法拉滨)、CLOLAR(氯法拉滨)、CVP、CYTOSAR-U(阿糖胞苷)、CYTOXAN(环磷酰胺)、ERWINAZE(门冬酰胺酶菊欧文氏菌)、FLUDARA(磷酸氟达拉滨)、FOLEX(甲氨蝶呤)、FOLEX PFS(甲氨蝶呤)、GAZYVA(obinutuzumab)、GLEEVEC(甲磺酸伊马替尼)、Hyper-CVAD、ICLUSIG(盐酸普纳替尼)、IMBRUVICA(依鲁替尼)、LEUKERAN(苯丁酸氮芥)、LINFOLIZIN(苯丁酸氮芥)、MARQIBO(硫酸长春新碱脂质体)、METHOTREXATE LPF(甲氨蝶呤)、MEXATE(甲氨蝶呤)、MEXATE-AQ(甲氨蝶呤)、盐酸米托蒽醌、MUSTARGEN(盐酸氮芥)、MYLERAN(白消安)、NEOSAR(环磷酰胺)、ONCASPAR(培门冬酶)、PURINETHOL(巯基嘌呤)、PURIXAN(巯基嘌呤)、Rubidomycin(盐酸柔红霉素)、SPRYCEL(达沙替尼)、SYNRIBO(三尖杉酯碱)、TARABINE PFS(阿糖胞苷)、TASIGNA(尼罗替尼)、TREANDA(盐酸苯达莫司汀)、TRISENOX(三氧化二砷)、VINCASAR PFS(硫酸长春新碱)、ZYDELIG(idelalisib)或其组合。在具体实施方案中,所述额外的药剂为抗淋巴瘤药。在具体实施方案中,所述额外的药剂为ABITREXATE(甲氨蝶呤)、ABVD、ABVE、ABVE-PC、ADCETRIS(brentuximab vedotin)、ADRIAMYCIN PFS(盐酸多柔比星)、ADRIAMYCIN RDF(盐酸多柔比星)、AMBOCHLORIN(苯丁酸氮芥)、AMBOCLORIN(苯丁酸氮芥)、ARRANON(奈拉滨)、BEACOPP、BECENUM(卡莫司汀)、BELEODAQ(belinostat)、BEXXAR(托西莫单抗和碘I 131托西莫单抗)、BICNU(卡莫司汀)、BLENOXANE(博莱霉素)、CARMUBRIS(卡莫司汀)、CHOP、CLAFEN(环磷酰胺)、COPP、COPP-ABV、CVP、CYTOXAN(环磷酰胺)、DEPOCYT(阿糖胞苷脂质体)、DTIC-DOME(达卡巴嗪)、EPOCH、FOLEX(甲氨蝶呤)、FOLEX PFS(甲氨蝶呤)、FOLOTYN(普拉曲沙)、HYPER-CVAD、ICE、IMBRUVICA(依鲁替尼)、INTRON A(重组干扰素alfa-2b)、ISTODAX(罗米地辛)、LEUKERAN(苯丁酸氮芥)、LINFOLIZIN(苯丁酸氮芥)、洛莫司汀、MATULANE(盐酸丙卡巴肼)、METHOTREXATE LPF(甲氨蝶呤)、MEXATE(甲氨蝶呤)、MEXATE-AQ(甲氨蝶呤)、MOPP、MOZOBIL(普乐沙福)、MUSTARGEN(盐酸氮芥)、NEOSAR(环磷酰胺)、OEPA、ONTAK(地尼白介素2)、OPPA、R-CHOP、REVLIMID(来那度胺)、RITUXAN(利妥昔单抗)、STANFORD V、TREANDA(盐酸苯达莫司汀)、VAMP、VELBAN(硫酸长春碱)、VELCADE(硼替佐米)、VELSAR(硫酸长春碱)、VINCASAR PFS(硫酸长春新碱)、ZEVALIN(替伊莫单抗)、ZOLINZA(伏立诺他)、ZYDELIG(idelalisib)或其组合。在具体实施方案中,所述额外的药剂为REVLIMID(来那度胺)、DACOGEN(地西他滨)、VIDAZA(阿扎胞苷)、CYTOSAR-U(阿糖胞苷)、IDAMYCIN(伊达比星)、CERUBIDINE(柔红霉素)、LEUKERAN(苯丁酸氮芥)、NEOSAR(环磷酰胺)、FLUDARA(氟达拉滨)、LEUSTATIN(克拉屈滨)或其组合。在具体实施方案中,所述额外的药剂为ABITREXATE(甲氨蝶呤)、ABRAXANE(紫杉醇白蛋白稳定的纳米颗粒制剂)、AC、AC-T、ADE、ADRIAMYCIN PFS(盐酸多柔比星)、ADRUCIL(氟尿嘧啶)、AFINITOR(依维莫司)、AFINITOR DISPERZ(依维莫司)、ALDARA(咪喹莫特)、ALIMTA(培美曲塞二钠)、AREDIA(帕米膦酸二钠)、ARIMIDEX(阿那曲唑)、AROMASIN(依西美坦)、AVASTIN(贝伐单抗)、BECENUM(卡莫司汀)、BEP、BICNU(卡莫司汀)、BLENOXANE(博莱霉素)、CAF、CAMPTOSAR(盐酸伊立替康)、CAPOX、CAPRELSA(凡德他尼)、CARBOPLATIN-TAXOL、CARMUBRIS(卡莫司汀)、CASODEX(比卡鲁胺)、CEENU(洛莫司汀)、CERUBIDINE(盐酸柔红霉素)、CERVARIX(重组HPV二价疫苗)、CLAFEN(环磷酰胺)、CMF、COMETRIQ(卡博替尼-s-苹果酸盐)、COSMEGEN(放线菌素D)、CYFOS(异环磷酰胺)、CYRAMZA(雷莫芦单抗)、CYTOSAR-U(阿糖胞苷)、CYTOXAN(环磷酰胺)、DACOGEN(地西他滨)、DEGARELIX、DOXIL(盐酸多柔比星脂质体)、盐酸多柔比星、DOX-SL(盐酸多柔比星脂质体)、DTIC-DOME(达卡巴嗪)、EFUDEX(氟尿嘧啶)、ELLENCE(盐酸表柔比星)、ELOXATIN(奥沙利铂)、ERBITUX(西妥昔单抗)、ERIVEDGE(维莫德吉)、ERIVEDGE(磷酸依托泊苷)、EVACET(盐酸多柔比星脂质体)、FARESTON(托瑞米芬)、FASLODEX(氟维司群)、FEC、FEMARA(来曲唑)、FLUOROPLEX(氟尿嘧啶)、FOLEX(甲氨蝶呤)、FOLEX PFS(甲氨蝶呤)、FOLFIRI、FOLFIRI-BEVACIZUMAB、FOLFIRI-CETUXIMAB、FOLFIRINOX、FOLFOX、FU-LV、GARDASIL(重组人乳头状瘤病毒(HPV)四价疫苗)、GEMCITABINE-CISPLATIN、GEMCITABINE-OXALIPLATIN、GEMZAR(吉西他滨盐酸盐)、GILOTRIF(二马来酸阿法替尼)、GLEEVEC(甲磺酸伊马替尼)、GLIADEL(卡莫司汀植入物)、GLIADEL WAFER(卡莫司汀植入物)、HERCEPTIN(曲妥珠单抗)、HYCAMTIN(盐酸拓扑替康)、IFEX(异环磷酰胺)、IFOSFAMIDUM(异环磷酰胺)、INLYTA(阿西替尼)、INTRON A(重组干扰素alfa-2b)、IRESSA(吉非替尼)、IXEMPRA(伊沙匹隆)、JAKAFI(磷酸鲁索替尼)、JEVTANA(卡巴他赛)、KADCYLA(ado-trastuzumab emtansine)、KEYTRUDA(pembrolizumab)、KYPROLIS(卡非佐米)、LIPODOX(盐酸多柔比星脂质体)、LUPRON(乙酸亮丙瑞林)、LUPRONDEPOT(乙酸亮丙瑞林)、LUPRON DEPOT-3MONTH(乙酸亮丙瑞林)、LUPRON DEPOT-4MONTH(乙酸亮丙瑞林)、LUPRON DEPOT-PED(乙酸亮丙瑞林)、MEGACE(甲地孕酮)、MEKINIST(曲美替尼)、METHAZOLASTONE(替莫唑胺)、METHOTREXATE LPF(甲氨蝶呤)、MEXATE(甲氨蝶呤)、MEXATE-AQ(甲氨蝶呤)、盐酸米托蒽醌、MITOZYTREX(丝裂霉素c)、MOZOBIL(普乐沙福)、MUSTARGEN(盐酸氮芥)、MUTAMYCIN(丝裂霉素c)、MYLOSAR(阿扎胞苷)、NAVELBINE(酒石酸长春瑞滨)、NEOSAR(环磷酰胺)、NEXAVAR(甲苯磺酸索拉非尼)、NOLVADEX(柠檬酸他莫昔芬)、NOVALDEX(柠檬酸他莫昔芬)、OFF、PAD、PARAPLAT(卡铂)、PARAPLATIN(卡铂)、PEG-INTRON(聚乙二醇干扰素alfa-2b)、培美曲塞二钠、PERJETA(帕妥珠单抗)、PLATINOL(顺铂)、PLATINOL-AQ(顺铂)、POMALYST(泊马度胺)、泼尼松、PROLEUKIN(阿地白介素)、PROLIA(地诺单抗)、PROVENGE(sipuleucel-t)、REVLIMID(来那度胺)、RUBIDOMYCIN(盐酸柔红霉素)、SPRYCEL(达沙替尼)、STIVARGA(瑞戈非尼)、SUTENT(苹果酸舒尼替尼)、SYLATRON(聚乙二醇干扰素alfa-2b)、SYLVANT(西妥昔单抗)、SYNOVIR(沙利度胺)、TAC、TAFINLAR(达拉非尼)、TARABINE PFS(阿糖胞苷)、TARCEVA(盐酸埃罗替尼)、TASIGNA(尼罗替尼)、TAXOL(紫杉醇)、TAXOTERE(多西紫杉醇)、TEMODAR(替莫唑胺)、THALOMID(沙利度胺)、TOPOSAR(依托泊苷)、TORISEL(西罗莫司)、TPF、TRISENOX(三氧化二砷)、TYKERB(二甲苯磺酸拉帕替尼)、VECTIBIX(帕尼单抗)、VEIP、VELBAN(硫酸长春碱)、VELCADE(硼替佐米)、VELSAR(硫酸长春碱)、VEPESID(依托泊苷)、VIADUR(乙酸亮丙瑞林)、VIDAZA(阿扎胞苷)、VINCASAR PFS(硫酸长春新碱)、VOTRIENT(盐酸帕唑帕尼)、WELLCOVORIN(亚叶酸钙)、XALKORI(克唑替尼)、XELODA(卡培他滨)、XELOX、XGEVA(地诺单抗)、XOFIGO(二氯化镭223)、XTANDI(恩扎鲁胺)、YERVOY(伊匹单抗)、ZALTRAP(阿柏西普)、ZELBORAF(威罗菲尼)、ZOLADEX(醋酸戈舍瑞林)、ZOMETA(唑来膦酸)、ZYKADIA(色瑞替尼)、ZYTIGA(乙酸阿比特龙)或其组合。
在具体实施方案中,所述额外的药剂为抗病毒剂。在具体实施方案中,所述额外的药剂选自外遗传或转录调节剂(例如,DNA甲基转移酶抑制剂、组蛋白脱乙酰基酶抑制剂(HDAC抑制剂)、赖氨酸甲基转移酶抑制剂)、抗有丝分裂药物(例如,紫杉烷类和长春花生物碱)、激素受体调节剂(例如,雌激素受体调节剂和雄激素受体调节剂)、细胞信号传导途径抑制剂(例如,酪氨酸激酶抑制剂)、蛋白稳定性的调节剂(例如,蛋白酶体抑制剂)、Hsp90抑制剂、糖皮质激素、全反式维甲酸,和其他促进分化的药物。在具体实施方案中,本发明化合物或药物组合物可以与抗癌治疗组合给药,所述抗癌治疗包括,但不限于,手术、辐射治疗、移植(例如干细胞移植、骨髓移植)、免疫治疗和化疗。
实施例
提供以下实施例以便为本领域技术人员提供如何实施、制备和评估本文请求保护的方法和化合物的完整公开和说明,旨在仅仅示例本发明而非限制本发明的范围。
本发明化合物的制备方案例如反应式1所示。
反应式1
通式I化合物可以按照以上一般反应式加以制备。首先将化合物(1)与腈甲基磷酸二乙酯反应,得到吡啶并[2,3-d]嘧啶中间体(2)。然后将(2)与新鲜制备的α-溴代醛(3)(α-亚甲基醛在L-脯氨酸的催化下,与N-溴代丁二酰亚胺作用,发生羰基α-位溴代反应制备得到α-溴代醛)反应得咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶中间体(4)。中间体(4)的甲硫基经Davis氧化剂氧化得到甲亚磺酰基中间体(5)。将化合物(5)与胺(6)偶联,得到式(I)化合物。
实施例1
9-异丙基-N-(5-(哌嗪-1-基)吡啶-2-基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-2-胺盐酸盐(I-1)
2-甲硫基吡啶并[2,3-d]嘧啶-7-胺(2a)
氮气保护下,将氢化钠(60%,12.0g,301mmol)混悬于N,N-二甲基甲酰胺(200mL)中。于冰水浴下,将氰甲基膦酸二乙酯(53.1g,300mmol)滴加入反应液中后室温搅拌20分钟。于冰水浴下,加入4-氨基-2-甲硫基嘧啶-5-甲醛(1a,16.9g,100mmol)后室温搅拌过夜。加入饱和氯化铵水溶液(200mL)淬灭反应,反应液中有白色固体析出,抽滤,滤渣以水(100mL)、甲基叔丁基醚(100mL)洗涤并真空干燥即得标题化合物2a(12.0g,62.5%)。1HNMR(400MHz,DMSO-d6,ppm):δ8.80(s,1H),7.92(d,J=8.8Hz,1H),7.44(br,2H),6.74(d,J=8.8Hz,1H),2.52(s,3H)。
2-溴-3-甲基丁醛(3a)
将3-甲基丁醛(10g,116.3mmol)溶于二氯甲烷(60mL),加入L-脯氨酸(1.34g,11.6mmol),于冰水浴下,加入N-溴代丁二酰亚胺(24.8g,139.3mmol),升至室温搅拌2小时后过滤,滤液浓缩后经闪式硅胶柱层析(石油醚:乙酸乙酯=5:1)所得红棕色油状液体即为2-溴-3-甲基丁醛(3a,10g,52%)。LC-MS(ESI),C5H10BrO[M+H]+:m/z=165.0,167.1。
9-异丙基-2-(甲硫基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶(4a)
将2a(10g,52.1mmol)与新鲜制备的3a(9.4g,57.3mmol)溶于乙醇(100mL)中,加热至回流反应2小时。浓缩反应液后加水(200mL)稀释,并用饱和碳酸氢钠水溶液调节反应液pH≈8。所得溶液用乙酸乙酯萃取3次,有机相合并,干燥浓缩后经柱层析所得浅棕色固体即为标题化合物4a(5.2g,38.6%)。1H NMR(300MHz,DMSO-d6,ppm):δ9.24(s,1H),7.65-7.54(m,2H),7.49(s,1H),4.38-4.29(m,1H),2.66(s,3H),1.41(d,J=6.8Hz,6H);LC-MS(ESI),for C13H15N4S[M+H]+:m/z=259。
9-异丙基-2-(甲基亚磺酰基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶(5a)
将4a(4.5g,17.4mmol)溶于氯仿(40mL),然后加入2-苯磺酰基-3-苯基氧氮杂环丙烷(5.46g,20.9mmol),室温搅拌18小时。浓缩反应液所得残液经闪式硅胶柱层析纯化所得反白色固体即为标题化合物5a(4.05g,85%)。1H NMR(400MHz,CDCl3,ppm):δ9.32(s,1H),7.75(d,J=9.2Hz,1H),7.55(s,1H),7.50(d,J=9.2Hz,1H),4.37–4.30(m,1H),3.05(s,3H),1.49–1.45(m,6H)。
4-(6-((9-异丙基咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-甲酸叔丁酯(I-1a)
将5a(82.2mg,0.3mmol)和4-(6-氨基吡啶-3-基)哌嗪-1-甲酸叔丁酯6a(83.4mg,0.3mmol)混悬于三氟甲苯(0.6mL)中,氩气置换3次,加热至75℃反应21小时。待反应液降至室温后加入少量乙酸乙酯,继续搅拌约2小时,反应液中有红棕色固体析出。抽滤所得残渣经闪式柱层析所得橙色粉末即为标题化合物I-1a(22.3mg,15.2%)。1H NMR(400MHz,CDCl3,ppm):δ8.91(s,1H),8.18(d,J=8.8Hz,1H),8.05(s,2H),7.39–7.29(m,4H),4.39–4.32(m,1H),3.63(t,J=2.4Hz,4H),3.13(t,J=2.6Hz,4H),1.49(s,9H),1.42(d,J=6.4Hz,6H)。
9-异丙基-N-(5-(哌嗪-1-基)吡啶-2-基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-2-胺盐酸盐(I-1)
将I-1a(16.2mg,0.0332mmol)溶于二氯甲烷/甲醇(1:1,2mL)中,加入氯化氢(4M,1,4-二氧六环溶液,0.83mL),室温搅拌3小时后,减压旋蒸去除溶剂,所得粗品在乙酸乙酯中搅拌1小时后过滤,得到的橙色粉末即为标题化合物I-1(14mg,99%)。1H NMR(400MHz,D2O,ppm):δ9.52(s,1H),8.27–8.19(m,2H),7.98(s,1H),7.79–7.67(m,3H),4.40–4.33(m,1H),3.61–3.51(m,8H),1.45(d,J=6.0Hz,6H)。
实施例2:9-异丙基-N-(5-(4-甲基哌嗪-1-基)吡啶-2-基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶-2-胺(I-2)的制备
将5a(63mg,0.23mmol)和5-(4-甲基哌嗪-1-基)吡啶-2-胺6b(44.2mg,0.23mmol)混悬于三氟甲苯(0.5mL)中,氩气置换3次,加热至75℃反应21小时。待反应液降至室温后加入少量乙酸乙酯,继续搅拌约2小时,反应液中有红棕色固体析出。抽滤所得残渣再经闪式柱层析所得橙色粉末即为标题化合物I-2(19.4mg,21%)。1H NMR(400MHz,氯仿-d,ppm)δ8.90(s,1H),8.14(d,J=9.1Hz,1H),8.05(d,J=2.9Hz,1H),8.01(s,1H),7.40(s,1H),7.36(dd,J=9.0,3.0Hz,1H),7.30(d,J=9.1Hz,1H),4.39–4.30(m,1H),3.25–3.20(m,4H),2.64–2.60(m,4H),2.38(s,3H),1.41(d,J=6.8Hz,6H)。
表1实施例I-3至I-30
参考实施例1中I-1的合成方法,由5a(60mg,0.219mmol)和6(0.438mmol,2equiv.)制备得到化合物I-8(15.3mg,35.0μmol,16%),I-9(21.1mg,48.2μmol,22%),I-10(24.9mg,56.9μmol,26%),I-11(70.2mg,39.4μmol,18%),I-12(30.7mg,67.9μmol,31%),I-13(13.6mg,30.7μmol,14%),I-14(25.2mg,56.9μmol,26%),I-15(22.1mg,50.4μmol,23%),I-22(18.8mg,39.4μmol,18%),I-23(23.7mg,52.6μmol,24%),I-24(20.1mg,46.0μmol,21%),I-25(16.2mg,35.0μmol,16%),I-26(19.3mg,41.6μmol,19%),I-27(12.6mg,28.5μmol,13%)
I-8 1H NMR(400MHz,氧化氘-d2,ppm)δ9.52(s,1H),8.26(d,J=9.4Hz,1H),8.09(s,1H),7.85–7.70(m,2H),7.60(s,1H),4.46–4.38(m,1H),3.65–3.20(m,8H),2.60(s,3H),1.45(d,J=6.1Hz,6H)。
I-9a 1H NMR(400MHz,氯仿-d,ppm)δ8.91(s,1H),8.11(d,J=8.7Hz,1H),7.95(s,1H),7.39(dd,J=12.4,8.7Hz,4H),7.30(d,J=9.2Hz,1H),4.36(p,J=6.8Hz,1H),3.60(t,J=4.9Hz,4H),2.86(t,J=5.0Hz,4H),2.52(s,3H),1.50(s,9H),1.42(d,J=6.8Hz,6H)。
I-9 LC-MS(ESI),C22H27N8[M+H]+:m/z=403.1。
I-10 1H NMR(400MHz,氯仿-d,ppm)δ8.90(s,1H),8.17(d,J=9.0Hz,1H),8.02(d,J=2.9Hz,1H),7.97(s,1H),7.40(s,1H),7.39–7.27(m,3H),4.45–4.29(m,2H),4.00(d,J=13.2Hz,1H),3.46(d,J=11.2Hz,1H),3.36–3.20(m,2H),2.97(dd,J=11.8,3.9Hz,1H),2.79(td,J=11.7,3.6Hz,1H),1.50(s,9H),1.42(d,J=6.8Hz,6H),1.35(d,J=6.8Hz,3H)。
I-11a 1H NMR(400MHz,氯仿-d,ppm)δ8.88(s,1H),8.09(d,J=9.0Hz,1H),7.93–7.86(m,2H),7.38(d,J=0.9Hz,1H),7.35(d,J=9.2Hz,1H),7.28(d,J=9.3Hz,1H),7.15(dd,J=9.1,3.1Hz,1H),4.35(p,J=6.7Hz,1H),3.82(dd,J=6.2,5.0Hz,2H),3.40(t,J=5.6Hz,2H),3.29(s,2H),1.51(s,9H),1.46(s,6H),1.41(d,J=6.8Hz,6H)。
I-11 LC-MS(ESI),C23H29N8[M+H]+:m/z=417.3。
I-12 1H NMR(400MHz,氯仿-d,ppm)δ8.91(s,1H),8.17(d,J=9.0Hz,1H),8.05(d,J=3.1Hz,2H),7.39(d,J=0.9Hz,1H),7.38–7.32(m,2H),7.29(d,J=9.3Hz,1H),4.40–4.32(m,1H),4.32–4.24(m,2H),3.32(d,J=11.8Hz,2H),2.94(dd,J=11.8,4.4Hz,2H),1.50(s,9H),1.43(s,3H),1.41(s,3H),1.41(s,3H),1.39(s,3H)。
I-13 1H NMR(400MHz,氧化氘-d2,ppm)δ9.51(s,1H),8.49(d,J=9.1Hz,1H),8.27(d,J=9.4Hz,1H),7.84–7.72(m,2H),7.12(s,1H),4.45–4.37(m,1H),3.82(q,J=5.6Hz,4H),3.66–3.46(m,4H),1.46(d,J=6.7Hz,6H)。
I-14 LC-MS(ESI),C21H24FN8[M+H]+:m/z=407.2。
I-15a 1H NMR(400MHz,氯仿-d,ppm)δ8.88(s,1H),8.03(d,J=13.4Hz,2H),7.89(s,1H),7.46–7.30(m,2H),7.29(s,1H),7.12(dd,J=9.0,2.3Hz,1H),4.35(p,J=6.9Hz,1H),3.59(dd,J=17.3,6.5Hz,5H),3.36(t,J=5.9Hz,1H),3.27(t,J=6.0Hz,1H),2.00(dt,J=12.5,5.9Hz,2H),1.51–1.33(m,13H)。
15 LC-MS(ESI),C22H27N8[M+H]+:m/z=403.1。
I-22 LC-MS(ESI),C25H31N8[M+H]+:m/z=443.3。
I-23 LC-MS(ESI),C23H27N8[M+H]+:m/z=415.2。
I-24 LC-MS(ESI),C22H25N8[M+H]+:m/z=401.3。
I-25 1H NMR(400MHz,氯仿-d,ppm)δ8.90(s,1H),8.15(d,J=9.0Hz,1H),8.04(d,J=2.8Hz,1H),7.95(s,1H),7.39(d,J=1.0Hz,1H),7.38–7.34(m,2H),7.29(d,J=9.3Hz,1H),4.40–4.30(m,1H),3.70(s,4H),3.12(dd,J=6.7,4.4Hz,4H),1.96–1.90(m,4H),1.46(s,9H),1.42(d,J=6.8Hz,6H)。
I-26 LC-MS(ESI),C24H29N8[M+H]+:m/z=429.3。
I-27 LC-MS(ESI),C22H25FN7[M+H]+:m/z=406.2。
参考实施例2中I-2的合成方法,由5a(60mg,0.219mmol)和6(0.438mmol,2equiv.)制备得到化合物I-3(16.4mg,39.4μmol,18%),I-4(17.3mg,41.6μmol,19%),I-5(23.7mg,56.9μmol,26%),I-6(29.2mg,67.9μmol,31%),I-7(20.7mg,48.2μmol,22%),I-16(9.3mg,24.1μmol,11%),I-17(17.9mg,46.0μmol,21%),I-18(19.4mg,48.2μmol,13%),I-19(16.8mg,41.6μmol,19%),I-20(15.0mg,37.2μmol,17%),I-21(23.7mg,56.9μmol,26%),I-28(5.5mg,13.1μmol,6%),I-29(8.9mg,19.7μmol,9%),I-30(9.3mg,24.1μmol,11%)。
I-3 1H NMR(400MHz,氯仿-d,ppm)δ8.92(s,1H),8.05(d,J=3.8Hz,3H),7.41(s,1H),7.38(d,J=9.3Hz,1H),7.31(d,J=9.3Hz,1H),4.35(p,J=6.8Hz,1H),3.04(t,J=4.8Hz,4H),2.64(m,4H),2.41(d,J=0.8Hz,6H),1.41(d,J=6.7Hz,7H)。
I-4 1H NMR(400MHz,氯仿-d,ppm)δ8.90(s,1H),8.09(d,J=8.6Hz,1H),7.91(s,1H),7.45(d,J=8.7Hz,1H),7.39(d,J=1.0Hz,1H),7.36(d,J=9.3Hz,1H),7.29(d,J=9.2Hz,1H),4.39–4.32(m,1H),2.99(t,J=4.8Hz,4H),2.68(m,4H),2.50(s,3H),2.43(s,3H),1.41(d,J=6.8Hz,6H)。
I-5 1H NMR(400MHz,氯仿-d,ppm)δ8.90(s,1H),8.16(d,J=9.0Hz,1H),8.05(d,J=2.9Hz,1H),7.99(s,1H),7.39(d,J=0.9Hz,1H),7.39–7.34(m,2H),7.29(d,J=9.3Hz,1H),4.36(dt,J=12.7,6.4Hz,1H),3.29–3.22(m,4H),2.69(t,J=5.1Hz,4H),2.53(q,J=7.2Hz,2H),1.42(d,J=6.8Hz,6H),1.16(t,J=7.2Hz,3H)。
I-6 1H NMR(400MHz,氯仿-d,ppm)δ8.92(s,1H),8.13–8.02(m,3H),7.41(d,J=1.0Hz,1H),7.38(d,J=9.2Hz,1H),7.31(d,J=9.2Hz,1H),4.35(p,J=6.6Hz,1H),3.08(brs,4H),2.71(m,4H),2.58(d,J=7.7Hz,2H),2.41(s,3H),1.41(d,J=6.8Hz,6H),1.19(t,J=7.2Hz,3H)。
I-7 1H NMR(400MHz,氯仿-d,ppm)δ8.90(s,1H),8.09(d,J=8.8Hz,1H),7.98(s,1H),7.47(d,J=8.7Hz,1H),7.39(d,J=0.9Hz,1H),7.37(d,J=9.3Hz,1H),7.29(d,J=9.3Hz,1H),4.34(td,J=13.1,12.6,6.7Hz,1H),3.04(s,4H),2.77(brs,4H),2.64(d,J=7.5Hz,2H),2.50(s,3H),1.41(d,J=6.8Hz,6H),1.28–1.21(m,3H)。
I-16 1H NMR(400MHz,氯仿-d,ppm)δ8.89(s,1H),8.12(d,J=9.0Hz,1H),8.08–8.03(m,1H),7.97(s,1H),7.39(d,J=0.9Hz,1H),7.38–7.34(m,2H),7.29(d,J=9.3Hz,1H),4.41–4.30(m,1H),3.21–3.11(m,4H),1.76(p,J=5.7Hz,4H),1.62(d,J=10.7Hz,6H),1.41(d,J=6.8Hz,6H)。
I-17 1H NMR(400MHz,氯仿-d)δ8.91(s,1H),8.18(d,J=8.8Hz,1H),8.07(d,J=17.2Hz,2H),7.34(dt,J=20.1,9.9Hz,4H),4.41–4.30(m,1H),4.01–3.81(m,4H),3.29–3.10(m,4H),1.42(d,J=6.8Hz,6H)。
I-18 1H NMR(400MHz,氯仿-d/Methanol-d4=1:1,ppm)δ8.95(s,1H),7.96(s,1H),7.92(s,1H),7.46(d,J=1.6Hz,1H),7.41(d,J=9.3Hz,1H),7.31–7.28(m,1H),4.29(p,J=6.8Hz,1H),3.90–3.80(m,4H),2.97(dd,J=5.6,3.4Hz,4H),2.40(s,3H),1.34(d,J=6.8Hz,6H)。
I-19 1H NMR(400MHz,氯仿-d,ppm)δ8.91(s,1H),8.11(d,J=8.7Hz,1H),7.93(s,1H),7.44(d,J=8.7Hz,1H),7.39(d,J=1.0Hz,1H),7.37(d,J=9.3Hz,1H),7.30(d,J=9.3Hz,1H),4.41–4.31(m,1H),3.91–3.86(m,4H),2.96–2.90(m,4H),2.52(s,3H),1.42(d,J=6.8Hz,6H)。
I-20 1H NMR(400MHz,氯仿-d,ppm)δ8.90(s,1H),8.17(d,J=9.1Hz,1H),8.10–7.98(m,2H),7.44–7.27(m,4H),4.36(hept,J=6.6Hz,1H),4.08–4.02(m,1H),3.88–3.76(m,2H),3.45–3.34(m,2H),2.88(td,J=11.6,3.4Hz,1H),2.55(dd,J=11.5,10.3Hz,1H),1.42(d,J=6.8Hz,6H),1.28(d,J=6.3Hz,3H)。
I-21 1H NMR(400MHz,氯仿-d,ppm)δ8.90(s,1H),8.16(d,J=9.0Hz,1H),8.06(s,1H),8.03(d,J=2.9Hz,1H),7.39(s,1H),7.38–7.31(m,2H),7.29(d,J=9.3Hz,1H),4.36(p,J=6.7Hz,1H),3.85(dtt,J=12.5,6.2,3.1Hz,2H),3.46–3.36(m,2H),2.52–2.42(m,2H),1.42(d,J=6.8Hz,6H),1.29(d,J=6.3Hz,6H)。
I-28 1H NMR(400MHz,氯仿-d,ppm)δ8.91(s,1H),7.55(d,J=8.6Hz,1H),7.48(d,J=9.3Hz,1H),7.26(s,1H),7.20(d,J=9.3Hz,1H),6.75(d,J=2.5Hz,1H),6.65(dd,J=8.6,2.6Hz,1H),4.29(t,J=5.2Hz,2H),3.24(t,J=5.1Hz,2H),2.71(s,6H),1.16(d,J=6.8Hz,6H)。
I-29 LC-MS(ESI),C25H31N6O2[M+H]+:m/z=447.1。
I-30 1H NMR(400MHz,氯仿-d,ppm)δ8.89(s,1H),8.01(d,J=2.4Hz,1H),7.97(d,J=8.8Hz,1H),7.88(d,J=8.9Hz,1H),7.73(dd,J=8.9,2.5Hz,1H),7.55(s,1H),7.37(d,J=6.2Hz,2H),7.31(d,J=9.3Hz,1H),6.95(d,J=8.8Hz,1H),4.29(p,J=6.8Hz,1H),4.10(s,3H),1.28(d,J=5.2Hz,6H)。
关键中间体9-环戊基-2-(甲基亚磺酰基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶(5b)的制备
参照实施例1中3a的合成方法,由环戊基乙醛(3g,26.76mmol)制备得到2-溴-2-环戊基乙醛(3b,2.49g,13.11mmol,49%)。LC-MS(ESI),C7H12BrO[M+H]+:m/z=191.0,193.1。
参照实施例1中4a的合成方法,由2a(2.50g,13.0mmol)和新鲜制备的3b(2.49g,13.11mmol)得到9-环戊基-2-(甲硫基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶(4b,1.33g,4.68mmol,36%)。1H NMR(400MHz,氯仿-d,ppm):δ8.92(s,1H),7.50(d,J=9.2Hz,1H),7.45(s,1H),7.32(d,J=9.2Hz,1H),4.43–4.36(m,1H),2.67(s,3H),2.33–2.26(m,2H),1.91–1.82(m,2H),1.78–1.68(m,4H)。
参照实施例1中5a的合成方法,由4b(1.3g,4.58mmol)制备得到9-环戊基-2-(甲基亚磺酰基)咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶(5b,1.21g,88%)。1H NMR(400MHz,CDCl3,ppm):δ9.30(s,1H),7.76(d,J=9.6Hz,1H),7.56(s,1H),7.49(d,J=9.2Hz,1H),4.38–4.30(m,1H),3.04(s,3H),2.40–2.34(m,2H),1.84–1.71(m,6H)。
表2实施例I-31至I-39
参考实施例1中I-1的合成方法,由5b(60mg,0.2mmol)和6(0.4mmol,2equiv.)制备得到化合物I-31(13.5mg,30.0μmol,15%),I-33(12.1mg,26.0μmol,13%),I-34(15.8mg,34.0μmol,17%),I-35(10.5mg,22.0μmol,11%),I-36(21.5mg,46.0μmol,23%),I-37(17.8mg,38.0μmol,19%)。
I-31 1H NMR(400MHz,氧化氘-d2,ppm)δ9.50(s,1H),8.26(d,J=9.3Hz,1H),8.20(dd,J=9.6,2.7Hz,1H),8.03(s,1H),7.80(s,1H),7.74(t,J=10.0Hz,2H),4.37(dt,J=14.2,7.4Hz,1H),3.72–3.56(m,4H),3.56–3.41(m,4H),2.36–2.19(m,2H),1.91–1.58(m,6H)。
I-33 1H NMR(400MHz,氧化氘-d2,ppm)δ9.49(s,1H),8.24(t,J=8.4Hz,2H),7.78(s,1H),7.74(d,J=9.3Hz,1H),7.65(d,J=9.1Hz,1H),4.32–4.23(m,1H),3.51(d,J=4.3Hz,4H),3.40–3.24(m,4H),2.77(s,3H),2.24–2.13(m,2H),1.82–1.53(m,6H)。
I-34 1H NMR(400MHz,氧化氘-d2,ppm)δ9.48(d,J=2.7Hz,1H),8.28–8.22(m,1H),8.19(dd,J=9.0,4.1Hz,1H),7.78(s,1H),7.74(dd,J=9.3,2.7Hz,1H),7.64(dd,J=8.9,2.9Hz,1H),3.59–3.45(m,4H),3.33(d,J=3.4Hz,3H),2.76(d,J=2.8Hz,3H),1.82–1.49(m,6H)。
I-35 1H NMR(400MHz,氧化氘-d2,ppm)δ9.46(s,1H),8.23(d,J=9.0Hz,1H),8.17–8.11(m,1H),8.06(s,1H),7.78(s,1H),7.71(t,J=9.8Hz,2H),4.36–4.28(m,1H),3.98(d,J=13.4Hz,2H),3.67–3.56(m,2H),2.96(t,J=12.0Hz,2H),2.27–2.15(m,2H),1.85–1.57(m,6H),1.43(d,J=6.2Hz,6H)。
I-36 1H NMR(400MHz,氧化氘-d2,ppm)δ9.49(s,1H),8.45(s,1H),8.25(d,J=9.3Hz,1H),7.91–7.64(m,2H),7.15(s,1H),4.41–4.26(m,1H),3.85(d,J=18.7Hz,4H),3.58(d,J=15.8Hz,4H),2.41–2.17(m,2H),2.00–1.44(m,6H)。
I-37 LC-MS(ESI),C23H26FN8[M+H]+:m/z=433.1。
参考实施例2中I-2的合成方法,由5b(60mg,0.2mmol)和6(0.4mmol,2equiv.)制备得到化合物I-32(19.2mg,42.0μmol,21%),I-38(18.9mg,44.0μmol,22%),I-39(11.5mg,26.0μmol,13%)。
I-32 1H NMR(400MHz,氯仿-d,ppm)δ8.92(s,1H),8.06(s,1H),8.02(s,2H),7.41(s,1H),7.37(d,J=9.3Hz,1H),7.30(d,J=9.3Hz,1H),4.30(dt,J=14.7,7.1Hz,1H),3.05(d,J=4.5Hz,4H),2.85–2.59(m,4H),2.59–2.50(m,2H),2.39(s,3H),2.25–2.15(m,2H),1.80–1.62(m,8H),1.17(t,J=7.1Hz,3H)。
I-38 1H NMR(400MHz,氯仿-d,ppm)δ8.93(s,1H),8.04(s,3H),7.44–7.34(m,2H),7.31(d,J=9.3Hz,1H),4.31(p,J=7.4Hz,1H),3.95–3.80(m,4H),3.06–2.92(m,4H),2.41(s,3H),2.27–2.17(m,2H),1.88–1.64(m,6H)。
I-39 1H NMR(400MHz,氯仿-d,ppm)δ8.90(s,1H),8.10(d,J=9.0Hz,1H),8.03(d,J=2.7Hz,1H),7.93(s,1H),7.40(s,1H),7.38–7.27(m,3H),4.34–4.25(m,1H),3.85(dtt,J=12.5,6.2,3.0Hz,2H),3.44–3.34(m,2H),2.52–2.41(m,2H),2.23(s,2H),1.82(s,2H),1.67(s,4H),1.29(d,J=6.3Hz,6H)。
生物学实施例
生化激酶抑制试验效价测定。激酶活性测试和IC50测定。首先,10ng重组CDK4/细胞周期蛋白D1(Life Technologies PV4204)稀释于激酶缓冲液中(20mM Tris pH7.5,10mMMgCl2,0.01%NP-40,2mM DTT),按照抑制剂的标示浓度在室温下孵育30分钟。通过加入1μg(1.5μM)重组视网膜母细胞瘤蛋白,5μM ATP和10μCiγ-32P-ATP启动激酶反应。该反应在30℃孵育了20分钟,通过加入2×Laemmli样品缓冲液终止反应,95℃加热三分钟,用12%丙烯酰胺SDS-PAGE溶解,进行放射自显影。使用密度计(Bio-Rad)对相应的磷酸化底物蛋白带定量。使用Prism 4Graphpad软件将得到的密度值绘制作为日志药物浓度的函数,通过具有可变斜坡型非线性回归曲线的绘制确定IC50值。
以类似方法测试本发明化合物对CDK6/细胞周期蛋白D1的抑制活性。
本发明中的最具代表性化合物的酶抑制活性的结果如下表所示。化合物在10倍量的IC50,10μM起始浓度三倍连续稀释的模式下进行试验。对照化合物:十字孢碱,在10倍量的IC50,20μM起始浓度四倍连续稀释的模式下进行试验。在10μM ATP条件下发生反应。
值得一提的是,本发明化合物还具有在CDK6/细胞周期蛋白D1与CDK4/细胞周期蛋白D1的酶抑制活性之间的选择性:例如,化合物I9、I17、I33和I34对CDK6/细胞周期蛋白D1的选择性大于10倍;化合物I1、I8、和I31对CDK6/细胞周期蛋白D1的选择性大于5倍;I18和I38对CDK6/细胞周期蛋白D1的选择性约等于4倍;化合物I6、I7、I13、I14、I21、I39等对CDK6/细胞周期蛋白D1的选择性为2-3倍。
此外,还测试了本发明化合物针对酶ABL1、FLT3和PIM1的抑制活性。发现本发明化合物能同时有效抑制ABL1、FLT3和PIM1,例如,抑制ABL1的IC50值为<100nM、抑制FLT3的IC50值为<20nM和抑制PIM1的IC50值为<100nM。优选地,以下化合物对FLT3和PIM1的IC50值分别为<5nM和<50nM:I1、I8、I9、I17、I18、I31、I33、I34和I38。
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明,不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干简单推演或替换,都应当视为属于本发明的保护范围。
Claims (78)
1.通式(I)的化合物,或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体或同位素变体,以及它们的混合物:
其中:
A1为N;
A2为CR3;
A3为CR3;
R1为H;
R2为H;
R3选自H、卤素、-CN、-NO2、-ORa、-SRa、-NRbRc、-O-C1-6亚烷基-R6、C1-6烷基、C1-6卤代烷基、-L’-C3-7环烷基、-L’-3-11元杂环基、-L’-C6-10芳基或-L’-5-10元杂芳基,所述基团任选地被1、2、3、4或5个R6基团取代;
R4选自C1-6烷基、C1-6卤代烷基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-10元杂芳基;
R5为H;
R6选自H、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、C1-6烷基或C1-6卤代烷基;
或者同一个碳原子上的两个R6一起形成氧代或硫代;
其中:
R4任选地被1、2或3个R’基团取代,其中R’独立地选自H、卤素、-CN、-NO2、-ORa、-SRa、-NRbRc、-C(O)ORa、-C(O)NRbRc、C1-6烷基、C1-6卤代烷基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-10元杂芳基;
Ra独立地选自H、C1-6烷基、C2-6烯基、C2-6炔基或C1-6卤代烷基;
Rb和Rc独立地选自H、C1-6烷基、C2-6烯基、C2-6炔基或C1-6卤代烷基;或者,Rb、Rc与N原子一起形成3-7元杂环基;
L’选自化学键或-O-。
64.药物组合物,其含有权利要求1-62中任一项的化合物,或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体或同位素变体,和药学上可接受的赋形剂;优选地,所述药物组合物还含有其它治疗剂。
65.试剂盒,其包括
第一容器,其中含有权利要求1-62中任一项的化合物,或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体或同位素变体;和任选地,
第二容器,其中含有其它治疗剂;和任选地,第三容器,其中含有用于稀释或悬浮所述化合物和/或其它治疗剂的药用赋形剂。
66.权利要求1-62中任一项的化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体或同位素变体在制备用于治疗和/或预防CDK介导的疾病的药物中的用途。
67.权利要求66的用途,其中所述CDK介导的疾病为细胞增殖性疾病。
68.权利要求66的用途,其中所述CDK介导的疾病选自癌症、心血管障碍、感染性疾病、慢性炎性疾病、自身免疫障碍和其它细胞增殖障碍。
69.权利要求68的用途,其中所述癌症选自实体瘤和血液恶性肿瘤。
70.权利要求68的用途,其中所述癌症选自乳腺癌,神经母细胞瘤、恶性横纹肌瘤、胶质瘤、肺癌、结肠直肠癌、胃癌、胃肠道基质瘤(GIST)、肝细胞癌、前列腺瘤、肉瘤、卵巢癌、宫颈癌、胰腺癌、黑色素瘤、甲状腺癌、胆管癌、子宫内膜癌、肾癌、间皮瘤、淋巴瘤、白血病和多发性骨髓瘤。
71.权利要求68的用途,其中所述癌症选自高分化和去分化的脂肪肉瘤、急性髓细胞白血病(AML)、非霍奇金淋巴瘤、套细胞淋巴瘤和间变性大细胞淋巴瘤。
72.权利要求68的用途,其中所述心血管障碍选自再狭窄、动脉粥样硬化、继发于气囊血管成形术的血管平滑肌增殖和内膜增生,和其它由异常细胞增殖引起的血管障碍。
73.权利要求68的用途,其中所述感染性疾病选自真菌、原生动物寄生虫和DNA与RNA病毒感染。
74.权利要求73的用途,其中所述感染性疾病由恶性疟原虫引起。
75.权利要求73的用途,其中所述感染性疾病为单纯疱疹病毒(HSV)感染。
76.权利要求68的用途,其中所述慢性炎性疾病为类风湿性关节炎。
77.权利要求68的用途,其中所述其它细胞增殖障碍选自牛皮癣、肾小球性肾炎和狼疮。
78.权利要求68的用途,其中所述其它细胞增殖障碍为以角质形成细胞过度增殖为特征的牛皮癣。
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