CN114502555A - 用于治疗增殖性疾病和疾患的4-(咪唑并[1,2-a]吡啶-3-基)-N-(吡啶-3-基)嘧啶-2-胺的衍生物 - Google Patents
用于治疗增殖性疾病和疾患的4-(咪唑并[1,2-a]吡啶-3-基)-N-(吡啶-3-基)嘧啶-2-胺的衍生物 Download PDFInfo
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- CN114502555A CN114502555A CN202080069747.6A CN202080069747A CN114502555A CN 114502555 A CN114502555 A CN 114502555A CN 202080069747 A CN202080069747 A CN 202080069747A CN 114502555 A CN114502555 A CN 114502555A
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- pyridin
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- aryl
- amine
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Abstract
一类新的用于预防和/或治疗包括癌症在内的增殖性疾病和疾患的杂芳基化合物。所述化合物被认为能够通过抑制一种或多种选自CDK诸如CDK2、CDK4、CDK6和/或CDK9的蛋白激酶和/或其他蛋白激酶诸如FLT3及其突变体的活性来抑制细胞增殖。所述化合物具有一般结构I:(I)
Description
技术领域
本公开涉及一类新的用于治疗包括癌症在内的增殖性细胞疾病和疾患的蛋白激酶抑制剂。
优先权文件
本申请要求2019年10月15日提交的标题为“Inhibitors of protein kinasesfor use in therapy”的澳大利亚临时专利申请号2019903877的优先权,其内容据此以引用方式全文并入本文。
背景技术
一直需要鉴定和开发用于治疗包括癌症在内的增殖性疾病和疾患的新化合物。在正在研究的潜在抗增殖化合物的众多“靶标”中,有一组称为蛋白激酶的酶。
细胞周期蛋白依赖性激酶(CDK)是一种蛋白激酶。已知它们与各种细胞周期蛋白亚基相关,在调节细胞中多种重要的调节途径(包括细胞周期控制、细胞凋亡、神经元生理学、分化和转录)中起到关键作用。存在20多种CDK,可分为两大类,反映了它们的功能;即细胞周期调节因子CDK和转录调节因子CDK。细胞周期调节因子CDK的类别包括CDK1、CDK2、CDK3、CDK4和CDK6,它们与它们的细胞周期蛋白配偶体(例如细胞周期蛋白A、B、D1、D2、D3、E和F)一起调节细胞周期的促进。转录调节因子CDK的类别包括CDK7、CDK8、CDK9和CDK11,它们与细胞周期蛋白C、H、K、L1、L2、T1和T2一起工作,并倾向于在转录调节中发挥作用(WangS等人Trends in Pharms Sci,302-312,2008)。鉴于这两个CDK类别的功能,CDK与细胞增殖疾病和疾患(尤其是癌症)有关可能并不奇怪。细胞增殖是细胞分裂周期直接或间接失调的结果,而CDK在该周期各个阶段的调节中起关键作用。因此,CDK抑制剂及其相关的细胞周期蛋白被认为是癌症治疗的有用靶标。
另一种被认为是癌症治疗有用靶标的蛋白激酶是原肌球蛋白受体激酶家族,包括分别由NTRK1、2和3基因编码的TRKA、TRKB和TRKC。NTRK染色体改变(最常见的基因融合)已被确定为多种恶性肿瘤中的驱动突变。TRK抑制剂(包括拉罗替尼(larotrectinib))已在伴有NTRK融合事件的多种肿瘤类型中显示出广泛的临床活性(Cocco E.等人Nat Rev ClinOncol 15(12):731-747,2018)。
另一种类型是双特异性酪氨酸磷酸化调节激酶(DYRK)家族蛋白,它与丝裂原活化蛋白激酶(MAPK家族)有关。DYRK1A和DYRK1B是癌症治疗中新兴的治疗靶标。由于它们驱动肿瘤细胞的细胞周期退出和静止,因此DYRK1抑制剂有望促进静止肿瘤细胞重新进入细胞周期,从而增加它们对化学疗法或放射疗法的敏感性(Soppa U.等人,Curr Biol 25(12):R488-9,2015)。此外,DYRK1A活性的增加与大脑发育异常、认知障碍和唐氏综合症中阿尔茨海默氏病的早期发作有关,这表明DYRK1抑制剂也可能代表治疗这些病症的新机会(Soppa,U.等人,Cell Cycle 13(13):2084-2100,2014)。
FMS样酪氨酸激酶3(FLT3,也称为CD135抗原)和胎儿肝激酶2(Flk2)在许多造血细胞的表面上表达,并且已知FLT3的信号传导在这些细胞的正常发育中起重要作用。过度活化的FLT3及其突变与某些癌症,特别是血癌(即血液学恶性肿瘤)有关。例如,在一些急性髓系白血病(AML)患者的胚细胞中发现了高水平的FLT3(Zheng R等人,Blood 103(1):267-274,2004),并且在急性淋巴细胞白血病(ALL)和慢性淋巴细胞白血病(CLL)中也发现了异常的FLT3表达(Rosnet O等人,Leukemia 10:238-248,1996)。据推测,FLT3的异常表达或过度表达可能导致受体的组成型二聚化和活化(Brasel K等人,Leukemia 9:1212-1218,1995)。此外,已经鉴定出许多FLT3“活化”突变,最显著的是在近膜结构域(JM)中发现的内部串联重复(ITD)和酪氨酸激酶结构域(TKD)中的点突变,两者都导致FLT3激酶活性的组成型活化,从而支持骨髓增殖表型的下游信号传导通路(Yokota S.等人,Leukemia 11(10):1605-1609,1997)。已知这些突变与AML患者的极差预后有关(Kottaridis PD等人,Blood98(6):1752-1759,2001)。许多FLT3抑制剂化合物已被评估用于治疗血液学恶性肿瘤,例如AML和其他FLT3活化的癌症。
本申请人现已鉴定了一类新的用于预防和/或治疗包括癌症在内的增殖性疾病和疾患的嘧啶化合物。虽然不希望受理论的束缚,但认为这些新化合物能够通过抑制CDK(特别是CDK2、CDK4、CDK6和CDK9中的一种或多种)和/或其他蛋白激酶诸如TRK、DYRK和FLT3和/或它们的突变体形式的活性来抑制细胞增殖。
发明内容
根据第一方面,本公开提供了一种式I化合物:
其中:
R1、R2、R3、R4、R5和R6各自独立地选自由以下组成的组:H、烷基、烷基-R7、芳基、芳基-R7、芳烷基、芳烷基-R7、脂环、杂环、卤素、NO2、CN、CF3、OH、O-烷基、COR7、COOR7、O-芳基、O-R7、NH2、NH-烷基、NH-芳基、N-(烷基)2、N-(芳基)2、N-(烷基)(芳基)、NH-R7、NH-烷基-N(烷基)2、N-(R7)(R8)、N-(烷基)(R7)、N-(芳基)(R7)、COOH、CONH2、CONH-烷基、CONH-芳基、CONH-脂环、CON-(烷基)(R7)、CON(芳基)(R7)、CONH-R7、CON-(R7)(R8)、SH-烷基、SO3H、SO2-烷基、SO2-烷基-R7、SO2-芳基、SO2-芳基-R7、SO2NH2、SO2NH-R7、SO2N-(R7)(R8)、CF3、CO-烷基、COO-烷基、CO-烷基-R7、CO-芳基、CO-芳基-R7和R9,其中所述烷基、芳基、芳烷基、脂环和杂环基团可以任选地被一个或多个选自卤素、CN、OH、O-C1-6烷基、NH2、COOH、C2-5羧酸根、CONH2和卤代烷基的基团取代;并且
R7、R8和R9独立地选自水增溶基团;
或其药学上可接受的盐、溶剂化物或前药。
在第二方面,本公开提供了如第一方面所定义的化合物或其药学上可接受的盐、溶剂化物或前药用于治疗疾病或疾患例如癌症或另一种增殖性病症或疾患的用途。
在第三方面,本公开提供了一种治疗受试者的疾病或疾患例如癌症或另一种增殖性病症或疾患的方法,所述方法包括向所述受试者施用治疗有效量的如第一方面所定义的化合物或其药学上可接受的盐、溶剂化物或前药,所述化合物或其药学上可接受的盐、溶剂化物或前药任选地与药学上可接受的载体、稀释剂和/或赋形剂组合。
在第四方面,本公开提供了如第一方面所定义的化合物或其药学上可接受的盐、溶剂化物或前药在制造用于治疗疾病或疾患例如癌症或另一种增殖性细胞疾病或疾患的药物中的用途。
在第五方面,本公开提供了一种药物组合物或药物,其包含如第一方面所定义的化合物或其药学上可接受的盐、溶剂化物或前药,以及药学上可接受的载体、稀释剂和/或赋形剂。
在第六方面,本公开提供了一种调节细胞中的蛋白激酶活性的方法,其包括将有效量的如第一方面所定义的化合物或其药学上可接受的盐、溶剂化物或前药引入或接触所述细胞。
具体实施方式
本申请人现在已经确定了一类新的适用于预防和/或治疗包括癌症在内的增殖性病症和疾患的嘧啶-2-胺衍生物,特别是4-(咪唑并[1,2-a]吡啶-3-基)-N-(吡啶-3-基)嘧啶-2-胺的衍生物,它们具有理想的生物活性(例如,这些化合物可以通过抑制细胞周期和转录CDK以及其他蛋白激酶诸如FLT3的活性来抑制细胞增殖并引起癌细胞凋亡)。
根据第一方面,本公开提供了一种如下所示的式I化合物:
其中:
R1、R2、R3、R4、R5和R6各自独立地选自由以下组成的组:H、烷基、烷基-R7、芳基、芳基-R7、芳烷基、芳烷基-R7、脂环、杂环、卤素、NO2、CN、CF3、OH、O-烷基、COR7、COOR7、O-芳基、O-R7、NH2、NH-烷基、NH-芳基、N-(烷基)2、N-(芳基)2、N-(烷基)(芳基)、NH-R7、NH-烷基-N(烷基)2、N-(R7)(R8)、N-(烷基)(R7)、N-(芳基)(R7)、COOH、CONH2、CONH-烷基、CONH-芳基、CONH-脂环、CON-(烷基)(R7)、CON(芳基)(R7)、CONH-R7、CON-(R7)(R8)、SH-烷基、SO3H、SO2-烷基、SO2-烷基-R7、SO2-芳基、SO2-芳基-R7、SO2NH2、SO2NH-R7、SO2N-(R7)(R8)、CF3、CO-烷基、COO-烷基、CO-烷基-R7、CO-芳基、CO-芳基-R7和R9,其中所述烷基、芳基、芳烷基、脂环和杂环基团可以任选地被一个或多个选自卤素、CN、OH、O-C1-6烷基、NH2、COOH、C2-5羧酸根、CONH2和卤代烷基的基团取代;并且
R7、R8和R9独立地选自水增溶基团;
或其药学上可接受的盐、溶剂化物或前药。
在一些实施方案中,式I化合物可以优选地包含至少一个水增溶基团R7、R8和R9。也就是说,在此类实施方案中,化合物如上文在前一段落中所定义,条件是所述化合物包含所述R7、R8和R9基团中的至少一个或者更优选地包含所述R7或R8基团中的至少一个。本申请人已发现,尽管添加了一个或多个这样的增溶基团,化合物仍具有所需的生物活性(例如通过抑制CDK和/或FLT3的活性)。至少一个水增溶基团的存在可以增强体内吸收和口服生物利用度。
已发现式I化合物具有抗增殖活性,并且因此被认为可用于治疗增殖性细胞疾病和疾患,诸如癌症、白血病、淋巴瘤和其他与不受控制的细胞增殖(或者,换句话说,需要控制细胞周期)相关的疾病和疾患,例如,一些心血管疾病或疾患诸如再狭窄和心肌病、一些自身免疫性疾病诸如肾小球性肾炎和类风湿性关节炎、皮肤疾患诸如牛皮癣,以及真菌或寄生虫病症。如本文所用,本公开范围内的抗增殖作用可以通过在体外全细胞测定中抑制细胞增殖的能力来证明。在下文提供的实施例中更详细地描述了这种测定(包括执行方法)的实施例。
式I化合物可以抑制细胞周期中的任何步骤或阶段,例如,核被膜的形成、从细胞周期的静止期(G0)退出、G1进展、染色体解聚、核被膜分解、START、DNA复制的开始、DNA复制的进展、DNA复制的终止、中心体复制、G2进展、有丝分裂或减数分裂功能的活化、染色体凝聚、中心体分离、微管成核、纺锤体形成和功能、与微管运动蛋白的相互作用、染色单体分离(separation)和分离(segregation)、有丝分裂功能的失活、收缩环的形成和胞质分裂功能。具体地,式I化合物可以影响某些基因功能,诸如染色质结合、复制复合物的形成、复制许可、磷酸化或其他二级修饰活性、蛋白水解降解、微管结合、肌动蛋白结合、septin结合、微管组织中心成核活性和与细胞周期信号传导通路的组分的结合。
因此,在第二方面,本公开提供了如第一方面所定义的化合物或其药学上可接受的盐、溶剂化物或前药用于治疗疾病或疾患例如癌症或另一种增殖性病症或疾患的用途。
在第三方面,本公开提供了一种治疗受试者的疾病或疾患例如癌症或另一种增殖性病症或疾患的方法,所述方法包括向所述受试者施用治疗有效量的如第一方面所定义的化合物或其药学上可接受的盐、溶剂化物或前药,所述化合物或其药学上可接受的盐、溶剂化物或前药任选地与药学上可接受的载体、稀释剂和/或赋形剂组合。
在第四方面,本公开提供了如第一方面所定义的化合物或其药学上可接受的盐、溶剂化物或前药在制造用于治疗疾病或疾患例如癌症或另一种增殖性细胞疾病或疾患的药物中的用途。
在第五方面,本公开提供了一种药物组合物或药物,其包含如第一方面所定义的化合物或其药学上可接受的盐、溶剂化物或前药,以及药学上可接受的载体、稀释剂和/或赋形剂。
在第六方面,本公开提供了一种调节细胞中的蛋白激酶活性的方法,其包括将有效量的如第一方面所定义的化合物或其药学上可接受的盐、溶剂化物或前药引入或接触所述细胞。
优选地,第六方面的方法调节一种或多种选自CDK诸如CDK2、CDK4、CDK6和/或CDK9的蛋白激酶和/或其他蛋白激酶诸如FLT3及其突变体的活性。
在本说明书中,使用了许多本领域技术人员熟知的术语。然而,为了清楚起见,许多这些术语在下文进行了定义。
如本文所用,术语“治疗”包括预防以及缓解疾患的既定症状。因此,“治疗”疾病或疾患的作用包括:(1)预防或延迟患有或易患该疾病或疾患的受试者出现该疾病或疾患的临床症状;(2)抑制该疾病或疾患(即在维持治疗或至少一种临床或亚临床症状的情况下,阻止、减少或延迟疾病或疾患的发展或其复发);(3)缓解或减轻疾病或疾患(即使得疾病或疾患或其临床或亚临床症状中的至少一种消退)。
如本文所用,术语“烷基”包括具有1至8个碳原子的直链和支链烷基基团(例如甲基、乙基丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基等)。
如本文所用,术语“芳基”是指取代的(单或多)或未取代的单芳族或多芳族基团,其中所述多芳族基团可以是稠合的或未稠合的。因此,该术语包括具有6至10个碳原子的基团(例如苯基、萘基等)。还应当理解,术语“芳基”与术语“芳族”同义。
如本文所用,术语“芳烷基”用作如上所定义的术语烷基和芳基的连词。
术语“脂族”在本领域中具有其正常含义,并且包括非芳族基团,诸如烷烃、烯烃和炔烃以及它们的取代的衍生物。
如本文所用,术语“脂环族”是指环状脂族基团。
术语“卤素”是指氟、氯、溴和碘。
如本文所用,术语“杂环”是指在环中包含一个或多个杂原子的饱和或不饱和环状基团。
如本文所用,术语“衍生物”包括实体的任何化学修饰。这种化学修饰的示例是用卤素基团、烷基基团、酰基基团或氨基基团代替氢。
如本文所用,短语“药物的制造”包括将一种或多种式I化合物直接用作药物或在制造包含一种或多种式I化合物的药物的任何阶段中使用。
一些式I化合物可以作为单一的立体异构体、外消旋物和/或对映异构体和/或非对映异构体的混合物存在。所有这些单一的立体异构体、外消旋物以及它们的混合物都包括在本公开的范围内。异构形式诸如非对映异构体、对映异构体和几何异构体可以通过本领域技术人员已知的物理和/或化学方法分离。
如本文所用,术语“药学上可接受的盐”是指保留式I化合物的所需生物活性的盐,并且包括药学上可接受的酸加成盐和碱加成盐。式I化合物的合适的药学上可接受的酸加成盐可以由无机酸或有机酸制备。这种无机酸的示例是盐酸、硫酸和磷酸。适当的有机酸可以选自脂族、脂环族、芳族、杂环羧酸和磺酸类有机酸,其示例为甲酸、乙酸、丙酸、琥珀酸、乙醇酸、葡萄糖酸、乳酸、苹果酸、酒石酸、柠檬酸、富马酸、马来酸、烷基磺酸和芳基磺酸。关于药学上可接受的盐的更多信息可以在Remington's Pharmaceutical Sciences,第19版,Mack Publishing Co.,Easton,PA 1995中找到。
术语“溶剂化物”是指式I化合物的任何形式,其由适当的溶剂溶剂化产生。这种形式可以是例如结晶溶剂化物或可以在溶剂与溶解的化合物之间形成的络合物。
术语“前药”是指在生物系统内通常通过代谢手段(例如通过水解、还原或氧化)转化为式I化合物的化合物。例如,含有羟基基团的式I化合物的酯前药可以通过体内水解转化为式I化合物。含有羟基基团的式I化合物的合适的酯可以是例如乙酸酯、柠檬酸酯、乳酸酯、酒石酸酯、丙二酸酯、草酸酯、水杨酸酯、丙酸酯、琥珀酸酯、富马酸酯、马来酸酯、亚甲基-双-对-羟基萘酸酯、龙胆酸酯、羟乙基磺酸酯、二-对-甲苯基酒石酸酯、甲磺酸酯、乙磺酸酯、苯磺酸酯、对甲苯磺酸酯、环己基氨基磺酸酯和奎尼酸酯。又如,含有羧基基团的式I化合物的酯前药可以通过体内水解转化为式I化合物。酯前药的示例包括Leinweber FJ,Drug Metab Rev 18:379-439(1987)描述的酯前药。类似地,含有氨基基团的式I化合物的酰基前药可以通过体内水解转化为式I化合物。这些和其他官能团(包括胺)的前药的示例在Prodrugs:challenges and rewards,Valentino J Stella(ed),Springer,2007中提供。
在式I化合物为固体的情况下,本领域技术人员应当理解,化合物(或其药学上可接受的盐、溶剂化物或前药)可以以不同的结晶或多晶型形式存在,所有这些都包含在本公开的范围内。
术语“治疗有效量”或“有效量”是足以产生有益或期望的临床结果的量。治疗有效量可以一次或多次施用来施用。通常,治疗有效量足以治疗疾病或疾患,或以其他方式缓解、改善、稳定、逆转、减缓或延迟疾病或疾患例如癌症或另一种增殖性细胞疾病或疾患的进展。仅举例来说,式I化合物或其药学上可接受的盐、溶剂化物或前药的治疗有效量可以包括介于约0.1和约250mg/kg体重/天之间,更优选介于约0.1和约100mg/kg体重/天之间,还更优选介于约0.1和约25mg/kg体重/天之间。然而,尽管如上所述,本领域技术人员还应当理解,治疗有效量可以变化并且取决于多种因素,包括特定化合物(或其盐、溶剂化物或前药)的活性、特定化合物(或其盐、溶剂化物或前药)的代谢稳定性和作用长度、年龄、体重、性别、健康、施用途径和时间、特定化合物(或其盐、溶剂化物或前药)的排泄速率,以及例如待治疗的癌症或其他增殖性细胞疾病或疾患的严重性。
式I化合物及其药学上可接受的盐、溶剂化物和前药能够抑制蛋白激酶,尤其是CDK,并且对于CDK9的选择性(即抑制)高于其他蛋白激酶诸如CDK2、CDK4和/或CDK6,或反之亦然,或对于FLT3的选择性高于一种或多种CDK。如上所述,CDK9通过其作为转录调节因子的作用可以促进癌细胞增殖并抵抗凋亡。因此,据信至少抑制CDK9的式I化合物及其药学上可接受的盐、溶剂化物和前药在体外和体内应用(例如体外基于细胞的测定)中都具有效用,并且作为治疗受试者的癌症或另一种增殖性病症或疾患的治疗方法的基础。
式I化合物可以带有至少一个水增溶基团(例如由R7、R8和/或R9提供)。本领域技术人员应当充分理解术语“水增溶基团”是指任何极性官能团,其电离或能够与水分子形成氢键以增加化合物的水溶性(即相对于缺乏水增溶基团的相应化合物的水溶性)。合适的水增溶基团的示例和引入它们的方法和考虑因素在例如Gareth Thomas所著的Fundamentalsof Medicinal Chemistry(出版商:John Wiley&Sons)中有所描述。
优选地,在存在的情况下,R7和R8独立地选自由以下组成的组的水增溶基团:
(i)单、二和多羟基化脂环基团;二或多羟基化脂族或芳基基团;任选地被一个或多个羟基、氨基或烷氧基基团取代的含N、O和/或S的杂环基团;包含一个或多个甲酰胺、亚砜、砜或磺酰胺基团的脂族和芳基基团;以及卤代烷基羰基基团;以及
(ii)COOH、SO3H、OSO3H、SONHCH3、SONHCH2CH3、SO2CH3、SO2CH2CH3、PO3H2和OPO3H2。
优选地,在存在的情况下,R9选自由以下组成的组的水增溶基团:
(i)单、二和多羟基化脂环基团,二或多羟基化脂族或芳基基团;含N、O和/或S的杂环基团(包括双环基团,诸如二氮杂螺杂环基团),其任选地被一个或多个羟基、砜、烷基、(CH2)n-杂环(其中n选自整数1或2,并且杂环是包含一个或两个N、O或S杂原子的饱和或不饱和的5或6元环状基团,诸如哌啶、苯咪唑、吡喃或呋喃)、CO-杂环(其中杂环是包含一个或两个N、O或S杂原子的饱和或不饱和的5或6元环状基团,诸如哌啶、苯咪唑、吡喃或呋喃)、NH-杂环(其中杂环是包含一个或两个N、O或S杂原子的饱和或不饱和的5或6元环状基团,诸如哌啶、苯咪唑、吡喃或呋喃)、氨基、烷氧基、羧酸根或烷基羰基基团取代;包含一个或多个羧酰胺、亚砜、砜或磺酰胺基团的脂族、脂环族和芳基基团;并且其中含N、O和/或S的杂环基团可以任选地包含与式I化合物的吡啶环的4/5位碳原子连接的例如烷基桥(例如-CH2-或-CH2CH2-桥)、胺桥(例如-NH-、-NH-CH2-和-NH-CH2CH2-)、酰胺桥(例如-C(=O)NH-)、烷氧基桥(例如-O-CH2-和-O-CH2CH2-)或酮桥(例如C(=O)-桥);以及卤代烷基羰基基团;
(ii)COOH、SO3H、OSO3H、PO3H2和OPO3H2;
(iii)NHCO(CH2)m[NHCO(CH2)m']p[NHCO(CH2)m"]qA和NHCO(CH2)tNH(CH2)t'A,其中p和q各自独立地选自整数0或1,并且m、m'、m"、t和'各自独立地选自整数1至10,并且A选自:
(a)脂环、芳基和包含一个或多个O、S或N杂原子的杂环基团,其还可以包含烷基桥(例如-CH2-或-CH2CH2-桥),
(b)包含-O-、NH2、-NH-、=N-、季胺盐和脒中的一个或多个的脂环基团,以及
(c)吗啉、哌嗪或1,4-二氮杂环庚烷基团,它们中的每一个可以任选地被一个或多个选自SO2-烷基、任选地被一个或多个OH基团取代的烷基、CO-烷基、芳烷基、COO-烷基和任选地被一个或多个OH基团取代的醚基团的取代基取代;
(iv)(CH2)nNR10COR11、(CH2)n'NR10SO2R11和SO2R12,其中R11选自H和烷基,R12和R12各自独立地选自任选地包含一个或多个杂原子和/或任选地被一个或多个独立地选自OH、NH2、卤素和NO2的取代基取代的烷基基团,并且n和n'各自独立地选自整数0、1、2和3;
(v)任选地被一个或多个OH基团或一个或多个A基团取代的醚和聚醚基团,其中A如上文(iii)所定义;
(vi)(CH2)rNH2,其中r选自整数0、1、2和3;
(vii)(CH2)r'OH,其中r'选自整数0、1、2和3;
(viii)(CH2)n"NR13COR14,其中R13是H或烷基,n"选自整数0、1、2和3,并且R14是任选地被一个或多个选自卤素、NO2、OH、烷氧基、NH2、COOH、CONH2和CF3的取代基取代的芳基基团;以及(ix)SO2NR15R16,其中R15和R16各自独立地选自H、烷基和芳基,条件是R15和R16中的至少一个不是H,或者R15和R16一起形成任选地包含一个或多个选自N、O和S的杂原子的环状基团,并且其中所述烷基、芳基或环状基团任选地被一个或多个选自卤素、NO2、OH、烷氧基、NH2、COOH、CONH2和CF3的取代基取代。
在一些实施方案中,R1和R2各自独立地选自由以下组成的组:H、烷基、烷基-R7、芳基、芳基-R7、芳烷基、芳烷基-R7、脂环、杂环、卤素、NO2、CN、CF3、OH、O-烷基、COR7、COOR7、O-芳基、O-R7、NH2、NH-烷基、NH-芳基、N-(烷基)2、N-(芳基)2、N-(烷基)(芳基)、NH-R7、NH-烷基-N(烷基)2、N-(R7)(R8)、N-(烷基)(R7)、N-(芳基)(R7)、COOH、CONH2、CONH-烷基、CONH-芳基、CON-(烷基)(R7)、CON(芳基)(R7)、CONH-R7、CON-(R7)(R8)、SH-烷基、SO3H、SO2-烷基、SO2-烷基-R7、SO2-芳基、SO2-芳基-R7、SO2NH2、SO2NH-R7、SO2N-(R7)(R8)、CF3、CO-烷基、CO-烷基-R7、CO-芳基、CO-芳基-R7和R8,其中所述烷基、芳基、芳烷基、脂环和杂环基团可以任选地被一个或多个选自卤素、CN、OH、O-C1-6烷基(例如O-甲基)、NH2、COOH、C2-5羧酸根(例如COOC(CH3)3)、CONH2和卤代烷基(例如CHF2和CF3)的基团取代;并且R3、R4、R5和R6各自独立地选自由以下组成的组:H、烷基-R7、芳基、芳基-R7、芳烷基、芳烷基-R7、脂环、杂环、CF3、COR7、COOR7、O-芳基、O-R7、NH-芳基、N-(芳基)2、N-(烷基)(芳基)、COO-烷基(例如COO-C1-3烷基诸如COOCH3)、O-烷基(例如O-C1-3烷基诸如O-CH2CH3)、NH-烷基(例如NH-C1-3烷基诸如NH-CH2CH2CH3)、N-(烷基)2(例如N(CH3)2)、NH-R7、N-(R7)(R8)、N-(烷基)(R7)、N-(芳基)(R7)、CONH-烷基、CONH-芳基、CON-(烷基)(R7)、CON(芳基)(R7)、CONH-R7、CON-(R7)(R8)、SO3H、SO2-烷基-R7、SO2-芳基、SO2-芳基-R7、SO2NH-R7、SO2N-(R7)(R8)、CO-烷基-R7、CO-芳基、CO-芳基-R7和R9,其中所述烷基、芳基、芳烷基、脂环和杂环基团可以任选地被一个或多个选自卤素、CN、OH、O-甲基、NH2、COOH、CONH2和CF3的基团取代。
在一些实施方案中,R1是H、烷基(例如C1-6烷基或优选地C1-3烷基诸如甲基、乙基和C(CH3)2)、芳基、CN、CF3、NH2、杂环(例如包含一个或两个N、O或S杂原子的饱和或不饱和的5或6元环状基团)、O-烷基(例如O-C1-3烷基诸如O-CH3)、NH-烷基(例如NH-C1-6烷基诸如NH(C5H9)(即NH-环戊基)或优选地NH-C1-3烷基诸如NH-CH3)、NH-烷基-N(烷基)2(例如NH-烷基-(C1-6烷基)2诸如NH(C1-3烷基)-N(C1-3烷基)2)、NH-芳基、N-(烷基)2诸如N(CH3)2、N-(烷基)(芳基)、SH-烷基(例如SH-C1-6烷基或优选地SH-C1-3烷基诸如SHCH3和SHC(CH3))、卤素(优选地F、Br或Cl)或R9。在R1是R9的情况下,优选地R9是单、二或多羟基化脂环基团,或被一个或多个羟基或氨基基团取代的含N、O和/或S的杂环基团。最优选地,R1是H、C1-3烷基(例如甲基)、芳基(例如苯基,任选地被C1-6烷基、O-C1-6烷基(例如O-甲基)、氨基(例如NH2)和/或卤素(优选地F)取代)、CF3、杂环(例如吡啶,包括二氢吡啶和四氢吡啶,任选地被C1-6烷基、C2-5羧酸根(例如COOC(CH3)3)或卤素(优选地F)取代);嘧啶,任选地被C1-6烷基、O-C1-6烷基(例如O-甲基)、氨基(例如NH2)或卤素(优选地F)取代;哌嗪、吡咯或吡唑,任选地被C1-6烷基或CHF2取代;噻吩、呋喃,任选地被C1-6烷基取代,并且包括双环结构诸如吲哚、苯并呋喃和苯并苯硫基)或卤素(优选地F、Br或Cl)。
在一些实施方案中,R2是H、烷基(例如C1-6烷基或优选地C1-3烷基诸如甲基或乙基)、CN或卤素(优选地F)。最优选地,R2是H。
在一些实施方案中,R3、R4、R5和R6中的至少一个(但最优选地R4)是烷基-R7(例如C1-3烷基–R7),其中R7优选地选自COOH、SO3H、OSO3H、SONHCH3、SONHCH2CH3、SO2CH3、SO2CH2CH3、PO3H2和OPO3H2,但更优选地是SONHCH3或SONHCH2CH3、COO-烷基(例如COOC1-3烷基诸如COOCH3)、O-烷基(例如O-C1-3烷基诸如O-CH2CH3)、NH-烷基(例如NH-C1-3烷基诸如NH-CH2CH2CH3)、N-(烷基)2(例如N(CH3)2)、NH-R7,其中R7优选地选自COOH、SO3H、OSO3H、SONHCH3、SONHCH2CH3、SO2CH3、SO2CH2CH3、PO3H2和OPO3H2,但更优选地是SO2CH3或SO2CH2CH3、CONH-脂环(例如CONH-C3-6脂环诸如CONH-环丙基)、卤素(优选地Cl)或者是R9,其中R9优选地是被一个或多个羟基、砜(例如SO2-C1-3烷基)、烷基(例如C1-3烷基诸如甲基)、氨基(例如NH2)、烷氧基(例如-OCH3)、羧酸根(例如COO-C1-3烷基诸如COOCH3)或烷基羰基(例如CO-C1-3烷基诸如CO-CH3)基团取代的含N、O和/或S的杂环基团。优选地,一个或多个杂原子是N。
在一些实施方案中,在R3、R5和R6是H的情况下,R4优选地不是COOH、C(=O)NHOH、C(=O)NHO-四氢吡喃或被NH2取代的CONH-芳基。
在一些实施方案中,在R3、R4、R5和R6中的至少一个是R9的情况下,R9优选地选自任选地被一个或多个羟基、砜(例如SO2-C1-3烷基)、烷基(例如C1-3烷基诸如甲基)、氨基(例如NH2)、烷氧基(例如-OCH3)、羧酸根(例如COO-C1-3烷基诸如COOCH3)或烷基羰基(例如CO-C1-3烷基诸如CO-CH3)基团取代的含N、O和/或S的杂环基团;包含一个或多个甲酰胺、亚砜、砜或磺酰胺基团的脂族和芳基基团;以及卤代烷基羰基基团。
在一些实施方案中,在R3、R4、R5和R6中的至少一个是R9的情况下,R9优选地选自以下:
任选地,前一段落中所示的R9取代基还可以包含与嘧啶环的4/5位碳原子连接的烷基桥(例如-CH2-或-CH2CH2-桥)、氨基桥(例如-NH-或-NH-CH2-或-NH-CH2CH2-)、酰胺桥(例如-C(=O)NH-)、烷氧基桥(例如-O-CH2-或-O-CH2CH2-)、桥(例如-O-)或酮桥(例如-C(=O)-桥)。
在R3是R9的情况下,R4、R5和R6优选地是H。类似地,在R4是R9的情况下,R3、R5和R6优选地是H。此外,在R5是R9的情况下,R3、R4和R6优选地是H。并且在R6是R9的情况下,R3、R4和R5优选地是H。
在一些实施方案中,R3和R6是H。
在一些实施方案中,R1选自卤素(优选地Br或Cl)、芳基(例如苯基)和任选地被一个或多个选自卤素、CN、OH、O-C1-6烷基(例如O-甲基)、NH2、COOH、C2-5羧酸根(例如COOC(CH3)3)、CONH2和卤代烷基(例如CHF2和CF3)的基团取代的杂环,例如吡啶、被CHF2取代的吡唑、和噻吩;R2、R3、R5和R6都是H;并且R4选自以下:
在一个特别优选的实施方案中,化合物选自由以下组成的组:N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺、N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-4-(6-(吡啶-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺、N-(6-(4-(甲基磺酰基)哌嗪-1-基)吡啶-3-基)-4-(6-(吡啶-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺、N-(6-(4-(甲基磺酰基)哌嗪-1-基)吡啶-3-基)-4-(6-(噻吩-2-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺、4-(6-氯咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)嘧啶-2-胺、N-(6-(氮杂环丁烷-1-基)吡啶-3-基)-4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺、4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-异丙基哌嗪-1-基)吡啶-3-基)嘧啶-2-胺、N-(6-(4-异丙基哌嗪-1-基)吡啶-3-基)-4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺、4-(6-(1-(二氟甲基)-1H-吡唑-4-基)咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)嘧啶-2-胺和4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-((4-乙基哌嗪-1-基)甲基)吡啶-3-基)嘧啶-2-胺。这些化合物是至少CDK9、TRKC、DYRK和FLT3的特别有效的抑制剂的示例。
在一些优选的实施方案中,如通过标准细胞毒性测定法测量的,式I化合物在人细胞系中表现出抗增殖活性。优选地,如通过标准细胞活力测定法测量的,化合物表现出小于5μM、甚至更优选地小于1μM的IC50值。更优选地,化合物表现出小于0.5μM的IC50值。
在一些优选的实施方案中,如通过本领域技术人员熟知的任何标准测定法测量的,式I化合物抑制一种或多种蛋白激酶。优选地,如通过下文实施例2中所述的激酶测定法测量的,化合物表现出小于1μM或小于0.5μM的IC50值,更优选地小于0.1μM。
根据第一方面的化合物的具体示例如下表1所示。
表1 本公开的所选化合物的化学结构
化合物(及其药学上可接受的盐、溶剂化物和前药)可以与一种或多种用于治疗癌症或另一种增殖性疾病或疾患的附加的剂组合施用。例如,化合物可以与其他抗癌剂组合使用,以同时抑制多于一种癌症信号传导通路,从而使癌细胞更易受到抗癌治疗(例如用其他抗癌剂、化学疗法、放射疗法或它们的组合进行的治疗)的影响。因此,式I化合物可以与以下类别的抗癌剂中的一种或多种组合使用:
●用于医学肿瘤学的其他抗增殖/抗肿瘤药物及其组合,诸如烷化剂(例如顺铂、奥沙利铂、卡铂、环磷酰胺、氮芥、美法仑、苯丁酸氮芥、白消安、替莫唑胺和亚硝基脲);抗代谢物(例如吉西他滨和抗叶酸剂,诸如氟嘧啶如5-氟尿嘧啶和喃氟啶、雷替曲塞、甲氨蝶呤、胞嘧啶阿拉伯糖苷、氟达拉滨和羟基脲);抗肿瘤抗生素(例如蒽环类抗生素,诸如阿霉素、博来霉素、多柔比星、道诺霉素、表柔比星、伊达比星、丝裂霉素C、更生霉素和光辉霉素);抗有丝分裂剂(例如长春花生物碱,诸如长春新碱、长春花碱、长春地辛和长春瑞滨,以及紫杉烷,包括紫杉醇和泰索帝和polo激酶(polokinase)抑制剂);拓扑异构酶抑制剂(例如表鬼臼毒素,诸如依托泊苷和替尼泊苷、安吖啶、拓扑替康和喜树碱);
●细胞抑制剂,诸如抗雌激素(例如他莫昔芬、氟维司群、托瑞米芬、雷洛昔芬、屈洛昔芬和iodoxyfene)、抗雄激素(例如比卡鲁胺、氟他胺、尼鲁米特和醋酸环丙孕酮)、LHRH拮抗剂或LHRH激动剂(例如戈舍瑞林、亮丙瑞林和布舍瑞林)、孕激素(例如醋酸甲地孕酮)、芳香酶抑制剂(例如阿那曲唑、来曲唑、vorazole和依西美坦)和5α-还原酶诸如非那雄胺;
●抗侵袭剂(例如c-Src激酶家族抑制剂,诸如4-(6-氯-2,3-亚甲基二氧基苯胺基)-7-[2-(4-甲基哌嗪-1-基)乙氧基]-5-四氢吡喃-4-基氧基喹唑啉(AZD0530;国际专利公布号WO 01/94341),N-(2-氯-6-甲基苯基)-2-{6-[4-(2-羟乙基)哌嗪-1-基]-2-甲基嘧啶-4-基氨基}噻唑-5-甲酰胺(达沙替尼)和博舒替尼(SKI-606)),以及包括马马司他的金属蛋白酶抑制剂,尿激酶纤溶酶原活化剂受体功能的抑制剂或乙酰肝素酶的抗体;
●生长因子功能的抑制剂(例如生长因子抗体和生长因子受体抗体,诸如抗erbB2抗体曲妥珠单抗(HerceptinTM)、抗EGFR抗体帕尼单抗、抗erbB1抗体西妥昔单抗(Erbitux,C225)和Stern等人,Crit Rev Oncol Hematol 54:11-29,2005公开的任何生长因子或生长因子受体抗体)。此类抑制剂还包括酪氨酸激酶抑制剂,诸如表皮生长因子家族的抑制剂(例如EGFR家族酪氨酸激酶抑制剂,诸如N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉-4-胺(吉非替尼,ZD1839)、N-(3-乙炔基苯基)-6,7-双(2-甲氧基乙氧基)喹唑啉-4-胺(厄洛替尼,OSI-774)和6-丙烯基酰胺基-N-(3-氯-4-氟苯基)-7-(3-吗啉代丙氧基)-喹唑啉-4-胺(CI 1033),erbB2酪氨酸激酶抑制剂,诸如拉帕替尼);肝细胞生长因子家族的抑制剂;胰岛素生长因子家族的抑制剂;血小板衍生生长因子家族的抑制剂,诸如伊马替尼和/或尼洛替尼(AMN107);丝氨酸/苏氨酸激酶的抑制剂(例如Ras/Raf信号传导抑制剂,诸如法呢基转移酶抑制剂,包括索拉非尼(BAY 43-9006)、替吡法尼(R115777)和洛那法尼(SCH66336))、通过MEK和/或AKT激酶的细胞信号传导的抑制剂、c-kit抑制剂、abl激酶抑制剂、PI3激酶抑制剂、Plt3激酶抑制剂、CSF-1R激酶抑制剂、IGF受体(胰岛素样生长因子)激酶抑制剂;极光激酶(aurora kinase)抑制剂(例如AZD1152、PH739358、VX-680、MLN8054、R763、MP235、MP529、VX-528和AX39459)和其他细胞周期蛋白依赖性激酶(CDK)抑制剂;
●抗血管生成剂,诸如抑制血管内皮生长因子作用的那些(例如抗血管内皮细胞生长因子抗体贝伐单抗(AvastinTM)和VEGF受体酪氨酸激酶抑制剂诸如凡德他尼(ZD6474)、瓦他拉尼(PTK787)、舒尼替尼(SU11248)、阿昔替尼(AG-013736)、帕唑帕尼(GW 786034)和4-(4-氟-2-甲基吲哚-5-基氧基)-6-甲氧基-7-(3-吡咯烷-1-基丙氧基)喹唑啉(AZD2171;国际专利公布号WO 00/47212内的实施例240),诸如国际专利公布号WO97/22596、WO 97/30035、WO 97/32856和WO 98/13354中公开的化合物,以及通过其他机制起作用的化合物(例如利诺胺、整联蛋白αvβ3功能的抑制剂和血管抑素);
●血管损伤剂,诸如考布他汀A4和国际专利公布号WO 99/02166、WO 00/40529、WO00/41669、WO 01/92224、WO 02/04434和WO 02/08213中公开的化合物;
●内皮素受体拮抗剂,诸如zibotentan(ZD4054)或阿曲生坦;
●反义疗法,诸如涉及上述靶标的那些,诸如ISIS 2503,抗ras反义;
●基因治疗方法,包括例如置换异常基因(诸如异常p53或异常BRCA1或BRCA2、GDEPT)的方法(基因导向酶前药治疗),诸如使用胞嘧啶脱氨酶、胸苷激酶或细菌硝基还原酶的那些方法,以及提高患者对化学疗法或放射疗法的耐受性的方法(诸如多药物抗性基因治疗);以及
●免疫治疗方法,包括例如用于提高患者肿瘤细胞的免疫原性诸如利用细胞因子(诸如白细胞介素2、白细胞介素4或粒细胞-巨噬细胞集落刺激因子)的转染的体外和体内方法、降低T细胞无反应性的方法、使用转染的免疫细胞诸如细胞因子转染的树突状细胞的方法、使用细胞因子转染的肿瘤细胞系的方法和使用抗独特型抗体的方法。
当与其他抗癌剂组合使用时,式I化合物和其他抗癌剂可以在相同的药物组合物中或在单独的药物组合物中施用。如果在单独的药物组合物中施用,则化合物和其他抗癌剂可以同时或以任何顺序依次施用(例如在几秒钟或几分钟或甚至几小时(例如2至48小时)内)。
式I化合物通常用于治疗人受试者的癌症或另一种增殖性细胞疾病或疾患。然而,受试者也可以选自例如家畜动物(例如牛、马、猪、绵羊和山羊)、伴侣动物(例如狗和猫)和外来动物(例如非人灵长类动物、老虎、大象等)。
根据本公开可以治疗的癌症和其他增殖性细胞疾病和疾患包括胆道癌、脑癌和中枢神经系统(CNS)的其他癌症(包括胶质母细胞瘤和髓母细胞瘤)、神经母细胞瘤、乳腺癌、宫颈癌、卵巢癌(包括由上皮细胞、基质细胞、生殖细胞和间充质细胞引起的那些)、绒毛膜癌、结直肠癌、子宫内膜癌、肝癌、肺癌、食道癌、胃癌、血液肿瘤(包括急性淋巴细胞白血病(ALL))、慢性淋巴细胞白血病(CLL)和慢性髓细胞性白血病(CML)和急性髓性白血病(AML)、多发性骨髓瘤、AIDS相关白血病和成人T细胞白血病淋巴瘤、淋巴瘤(包括非霍奇金淋巴瘤、霍奇金病和淋巴细胞性淋巴瘤))、上皮内肿瘤(包括博温氏病和佩吉特氏病)、口腔癌(包括鳞状细胞癌)、胰腺癌、前列腺癌、肉瘤(包括平滑肌肉瘤、横纹肌肉瘤、脂肪肉瘤、纤维肉瘤和骨肉瘤)、皮肤癌(包括黑素瘤、卡波济氏肉瘤、基底细胞癌和鳞状细胞癌)、睾丸癌(包括生殖肿瘤,诸如精原细胞瘤、非精原细胞瘤、畸胎瘤和绒毛膜癌)、间质瘤、生殖细胞瘤、甲状腺癌(包括甲状腺腺癌和髓样癌)和肾癌(包括腺癌和维尔姆斯肿瘤)。
在一些实施方案中,式I化合物用于治疗癌症或另一种增殖性细胞疾病或疾患,该癌症或另一种增殖性细胞疾病或疾患选自特征在于CDK,特别是CDK2、CDK4、CDK6和CDK9中的一种或多种和/或它们各自的细胞周期蛋白的过度活化(例如通过过度表达)的癌症或另一种增殖性细胞疾病或疾患。
在一些实施方案中,式I化合物用于治疗癌症或另一种增殖性细胞疾病或疾患,该癌症或另一种增殖性细胞疾病或疾患选自特征在于CDK9和/或细胞周期蛋白T1的过度表达的癌症或另一种增殖性细胞疾病或疾患,包括例如若干B和T细胞淋巴瘤(Bellan等人,JPathol 203:946-952(2004)),以及神经母细胞瘤(De Falcao等人,Cancer Biol Ther 4:277-281(2005))、原发性神经外胚层肿瘤、横纹肌肉瘤(Simone等人,Cell Death Differ14:192-195(2007))和前列腺癌(Lee等人,J Biol Chem 276:9978-9984(2001))。CDK9和/或细胞周期蛋白T1过度表达可以通过例如使用本领域技术人员熟知的任何技术(例如定量扩增技术,诸如qPCR)评估合适样品中编码CDK9和/或细胞周期蛋白T1的mRNA的量来确定。
在一些实施方案中,式I化合物用于治疗NTRK融合阳性的癌症或疾患(上文CoccoE.等人,2018)。
在一些实施方案中,式I化合物用于治疗与DYRK相关的病症,包括癌症和/或包括小胶质细胞增殖(Gomez-Nicola D等人,Methods Mol Biol 1303:185-193,2016)的阿尔茨海默氏病(Hu,J.等人,Int J Cancer 132(10):2258-2269,2013;上文Soppa U.等人,2014)。
在一些实施方案中,式I化合物用于治疗癌症或另一种疾病或疾患,该癌症或另一种疾病或疾患的特征在于FLT3或FLT3-ITD的表达或过度表达,包括例如若干血液系统恶性肿瘤(Stirewalt DL和JP Radich,Nat Rev Cancer 3:650-665(2003)),诸如AML和其他FLT3-活化的癌症。
式I化合物可以与药学上可接受的载体、稀释剂和/或赋形剂一起配制成药物组合物。合适的载体和稀释剂的示例是本领域技术人员熟知的,并且在例如Remington'sPharmaceutical Sciences,Mack Publishing Co.,Easton,PA 1995中进行了描述。用于本文所述的各种不同形式的药物组合物的合适的赋形剂的示例可在由A Wade和PJ Weller编写的Handbook of Pharmaceutical Excipients,第2版,(1994)中找到。合适的载体的示例包括乳糖、淀粉、葡萄糖、甲基纤维素、硬脂酸镁、甘露醇、山梨醇等。合适的稀释剂的示例包括乙醇、甘油和水。载体、稀释剂和/或赋形剂的选择可以根据预期的施用途径和标准药物实践进行。
包含式I化合物的药物组合物还可包含任何合适的粘结剂、润滑剂、悬浮剂、包衣剂和增溶剂。合适的粘结剂的示例包括淀粉、明胶、天然糖诸如葡萄糖、无水乳糖、自由流动乳糖、β-乳糖、玉米甜味剂、天然和合成树胶诸如阿拉伯树胶、黄芪胶或海藻酸钠、羧甲基纤维素和聚乙二醇。合适的润滑剂的示例包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。防腐剂、稳定剂、染料以及甚至调味剂可以提供在药物组合物中。防腐剂的示例包括苯甲酸钠、山梨酸和对羟基苯甲酸的酯。也可以使用抗氧化剂和悬浮剂。
包含式I化合物的药物组合物可以适用于口服、直肠、阴道、肠胃外、肌内、腹膜内、动脉内、鞘内、支气管内、皮下、皮内、静脉内、鼻、颊或舌下施用途径。对于口服施用,可以特别使用压缩片剂、丸剂、片剂、凝胶剂、滴剂和胶囊。对于其他形式的施用,药物组合物可以包括溶液或乳液,其可以静脉内、动脉内、鞘内、皮下、皮内、腹膜内或肌内注射,并且由无菌或可灭菌溶液制备。包含式I化合物的药物组合物还可以是栓剂、阴道栓剂、悬浮剂、乳剂、洗剂、软膏剂、乳膏剂、凝胶剂、喷雾剂、溶液剂或撒粉剂的形式。药物组合物可以配制成单位剂型(即,以包含单位剂量或单位剂量的多个或亚单位的离散部分的形式)。
式I化合物可以作为药学上可接受的盐(包括例如其合适的酸加成盐或碱盐)提供。合适的药物盐的综述可以在Berge等人,J Pharm Sci 66:1-19(1977)中找到。例如与强无机酸,诸如无机酸(例如硫酸、磷酸或氢卤酸),与强有机羧酸,诸如未取代的或取代的(例如卤素)1至4个碳原子的链烷羧酸,诸如乙酸,与饱和的或不饱和的二羧酸(例如草酸、丙二酸、琥珀酸、马来酸、富马酸、邻苯二甲酸或四邻苯二甲酸),与羟基羧酸(例如抗坏血酸、乙醇酸、乳酸、苹果酸、酒石酸或柠檬酸),与氨基酸(例如天冬氨酸或谷氨酸),与苯甲酸,或与有机磺酸(例如未取代的或被例如卤素取代的(C1-C4)-烷基或芳基磺酸,诸如甲烷或对甲苯磺酸)形成盐。
式I化合物可以以它们的各种结晶形式、多晶型形式和(无)水形式提供。在这方面,本领域技术人员熟知的是,可以通过稍微改变从用于合成制备此类化合物的溶剂中纯化和或分离的方法,以任何此类形式分离化合物。
本公开还提供了一种合成根据式I的化合物或其药学上可接受的盐、溶剂化物或前药的方法。
关于下文描述的合成方法和用于制备起始材料的参考合成方法的描述,本领域技术人员应当理解,可以很容易地选择所有建议的反应条件,包括溶剂的选择、反应气氛、反应温度、实验持续时间和后处理程序。此外,本领域技术人员应当理解,存在于分子的各个部分上的官能团必须与所使用的试剂和反应条件相容。
可以通过有机化学的标准程序获得必要的起始材料。这些起始材料的制备结合以下代表性方法变型并在下文的实施例中进行描述。替代地,可以通过与所示那些在本领域技术人员的普通技术范围内的那些类似的程序获得必要的起始材料。此外,应当理解,在化合物的合成过程中,在下文描述的方法中,或在某些起始材料的合成过程中,可能期望保护某些取代基以防止它们不希望的反应。本领域技术人员将容易地认识到何时需要这种保护,以及如何将此类保护基团放置在适当的位置,以及随后除去。保护基的示例在例如Theodora Green(出版商:John Wiley&Sons)编写的Protective Groups in OrganicSynthesis中进行了描述。保护基团可以通过本领域技术人员熟知的适合于去除所讨论的保护基团的任何方便的方法去除,选择这样的方法以便在对分子中其他基团的干扰最小的情况下实现保护基团的去除。因此,如果反应物包括例如诸如氨基、羧基或羟基的基团,则在本文提到的一些反应中保护该基团可能是理想的。
式I化合物可以通过例如国际专利公布号WO 2013/156780中描述的一般合成方法制备,该公布以引用方式并入本文。
在本公开的另一方面,提供了一种合成式I化合物(或其药学上可接受的盐、溶剂化物或前药)的方法,其中该方法包括:
a)使式A化合物与合适的吡啶基胍衍生物反应:
其中R1和R2如上文关于式I所定义;
或者,如有必要,使式B化合物与合适的吡啶-3-胺衍生物反应
其中Hal是F、Cl、Br或I;并且R1和R2如上文关于式I所定义;
并且如有必要
b)去除存在的任何保护基团,和/或形成其药学上可接受的盐、溶剂化物或前药。
式A或式B的化合物与吡啶基胍或吡啶-3-胺衍生物之间的偶联反应可以在合适的溶剂或溶剂混合物的存在下进行。本领域技术人员将能够容易地选择用于该反应的合适的溶剂或溶剂混合物。合适的溶剂的示例包括醇、乙腈、卤代溶剂等。
此外,本领域技术人员将能够选择合适的反应条件以用于式A或式B的化合物的偶联反应。然而,通常,反应将在无水条件下和惰性气氛(诸如氩气或氮气)的存在下进行。反应也可以在高温下进行,例如在80至180℃的范围内进行合适的时间段,例如20分钟至48小时。合适地,反应在微波加热下进行,例如,在80至180℃下进行20分钟至1.5小时。
可以使用本领域技术人员熟知的技术分离并纯化所得化合物。
合成式I化合物(或其药学上可接受的盐、溶剂化物或前药)的方法还可以包括:
c)使式I化合物进行盐交换(特别是在化合物形成为不同盐形式的混合物的情况下)。
盐交换可包括将化合物固定在合适的固体载体或树脂上,并用合适的酸洗脱化合物以产生式I化合物的盐。
用于合成本公开的化合物的特别合适的方法的示例如下文的方案1所示。
方案1
其中一般反应条件为:(a)乙酰酸酐或丙酸酐,AlCl3,DCM,0℃至回流,o/n;(b)NaI,氯丙酮,DMF,80℃,o/n;(c)DMF-DMA,回流,o/n;(d)吡啶基胍,NaOH,2-甲氧基乙醇,微波,160-200℃,1h;(e)吡啶-3-胺,Cs2CO3,Pd2(dba)3或Pd(OAc)2,xantphos或BINAP,1,4-二噁烷,微波,160-200℃,30-60分钟。
下文参考以下非限制性示例和附图描述本公开。
实施例
实施例1合成
一般
1H和13C NMR光谱在298K(除非另有说明)在Bruker AVANCE III HD 500光谱仪上记录(1H在500.20MHz和13C在125.79MHz),并使用Bruker Topspin 3.2软件进行分析。1HNMR信号用化学位移值δ(ppm)记录,多重性(s=单峰,d=双重峰,t=三重峰,q=四重峰,dd=双重双峰,dt=双重三峰,td=三重双峰,ddd=双重双重双峰,m=多重峰,br=宽峰),相对积分,耦合常数J(Hz)和分配。在AB SCIEX TripleTOF 5600质谱仪(Concord,ON,Canada)上记录高分辨率质谱,并使用ESI进行所有样品的电离。
一般合成程序A:向DMF-DMA(5.00-10.00当量)中添加乙酮(1.00当量)。将反应混合物加热回流过夜,冷却至室温并过滤,在用Et2O洗涤后得到所需的烯胺酮。
实施例:(E)-1-(6-溴咪唑并[1,2-a]吡啶-3-基)-3-(二甲基氨基)丙-2-烯-1-酮。使用一般合成程序A使1-(6-溴咪唑并[1,2-a]吡啶-3-基)乙烷-1-酮(5.00g,20.9mmol)和DMF-DMA(15.0mL,112mmol)反应,得到呈浅黄色固体的(E)-1-(6-溴咪唑并[1,2-a]吡啶-3-基)-3-(二甲基氨基)丙-2-烯-1-酮(4.60,75%)。1H NMR(CDCl3)δ2.89(s,3H),3.10(s,3H),5.57(d,1H,J 12.5),7.35(dd,1H,J 9.5&2.0),7.50(d,1H,J 9.5),7.71(d,1H,J 12.5),8.11(s,1H),9.94(d,1H,J 2.0).HRMS m/z 294.0241[M(79Br)+H]+,296.0221[M(81Br)+H]+。
一般合成程序B:在冰浴中向胺(1.00当量)和氰酰胺(2.00当量)在MeCN(100mL)中的溶液中滴加TMSCl(2.00当量)。将反应混合物加热回流过夜,并趁热过滤。用Et2O或EtOAc(100-150mL)洗涤沉淀,得到所需的胍。
实施例:1-(6-(4-甲基哌嗪-1-基)吡啶-3-基)胍盐酸盐。使用一般合成程序B使6-(4-甲基哌嗪-1-基)吡啶-3-胺(8.46g,44.0mmol)和氰酰胺(3.70g,88.0mmol)在TMSCl(11.2mL,88.2mmol)的存在下反应,得到呈深紫色粘性固体的1-(6-(4-甲基哌嗪-1-基)吡啶-3-基)胍盐酸盐(11.9g,100%)。1H NMR(D2O)δ2.94(s,3H),3.16-3.22(m,2H),3.28-3.34(m,2H),3.62(d,2H,J 12.0),4.34(d,2H,J 14.0),7.01(d,1H,J 9.0),7.63(dd,1H,J 9.0&2.5),8.08(d,1H,J 3.0).HRMS m/z 235.1646。
一般合成程序C:将NBS(1.20当量)添加到4-(2-丁氧基乙烯基)嘧啶衍生物(1.00-3.00当量)在1,4-二噁烷/H2O(3:1)中的溶液中,并将反应混合物在室温下搅拌1小时。在添加胺(1.00当量)后,将反应混合物在85℃下加热2.5小时并减压浓缩。将残余物用EtOAc研磨并过滤,并将固体用EtOAc洗涤和/或通过快速柱色谱法(硅胶,P.E.升至10%-50%DCM的P.E.溶液)纯化,得到所需的4-(3-杂芳基)嘧啶。
实施例:3-(2-氯-5-氟嘧啶-4-基)咪唑并[1,2-a]吡啶。根据一般合成程序C使(E)-4-(2-丁氧基乙烯基)-2-氯-5-氟嘧啶(900mg,3.90mmol)与NBS(830mg,4.67mmol)和吡啶-2-胺(370mg,3.90mmol)反应,得到呈白色固体的3-(2-氯-5-氟嘧啶-4-基)咪唑并[1,2-a]吡啶(800mg,93%)。1H NMR(DMSO-d6):δ7.35(t,1H,J 7.0),7.65(t,1H,J 8.0),7.88(d,1H,J 9.0),8.51(d,1H,J 4.0),8.85(d,1H,J 3.0),9.73(d,1H,J 7.0).HRMS m/z249.0309[M(35Cl)+H]+,251.0280[M(37Cl)+H]+。
一般合成程序D:向胍(1.10-1.50当量)在2-甲氧基乙醇(4mL)中的溶液中添加烯胺酮(1.00当量)(如有必要)和NaOH(1.50-2.20当量)。将反应混合物在160-200℃下在微波辐射下加热1小时,冷却至室温并减压浓缩。将残余物通过FlashMaster Personal+色谱法或快速柱色谱法(硅胶,DCM升至DCM:CH3OH:32%NH3的H2O溶液=455:45:1)纯化,并用冰冷的CH3OH洗涤,得到所需的嘧啶。
一般合成程序E:将装有卤化物(1.00当量)、吡啶-3-胺(1.00当量)、Cs2CO3(2.00等式)、Pd2(dba)3或Pd(OAc)2(0.05当量)和xantphos或BINAP(0.05当量)的1,4-二噁烷溶液(100mM的卤化物溶液)的微波管在160-200℃下在微波辐射下加热1小时。将反应混合物冷却至室温,浓缩并通过快速柱色谱法(硅胶,DCM升至DCM:CH3OH=91:9)纯化,得到所需的产物。
一般合成程序F:向卤化物(1.00当量)在MeCN中的悬浮液(167mM的卤化物溶液)中添加硼酸或硼酸酯(0.90-2.00当量)、Ph(PPh3)4或Pd(dppf)Cl2·CH2Cl2(0.05当量)和0.5MNa2CO3(1.40当量)。将反应混合物在130-140℃下在微波辐射下加热1小时。将反应混合物冷却至室温,浓缩并通过快速柱色谱法(硅胶,DCM升至DCM:CH3OH=91:9)纯化,得到所需的产物。
实施例
4-(咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)嘧啶-2-胺 (1).使用合成程序D,通过处理1-(6-(4-甲基哌嗪-1-基)吡啶-3-基)胍盐酸盐(469mg,2.00mmol)和(E)-3-(二甲基氨基)-1-(咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(220mg,1.02mmol)制备。黄色固体(165mg,42%)。1H NMR(DMSO-d6)δ2.23(s,3H),2.42(t,4H,J4.5),3.44(t,4H,J 4.5),6.88(d,1H,J 9.0),7.07(app br s,1H),7.33(d,1H,J 5.5),7.49(app t,1H,J 7.5),7.76(d,1H,J 9.0),7.89(d,1H,J 7.5),8.35(s,1H),8.36(d,1H,J5.5),8.59(s,1H),9.40(br s,1H),10.00(app br s,1H).HRMS m/z 387.2042[M+H]+。
4-(6-氟-2-甲基咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-甲基哌嗪-1-基)吡啶-3- 基)嘧啶-2-胺(2).使用一般程序D,通过处理1-(6-(4-甲基哌嗪-1-基)吡啶-3-基)胍盐酸盐(469mg,2.00mmol)和(E)-1-(6-氯-2-甲基咪唑并[1,2-b]哒嗪-3-基)-3-(二甲基氨基)丙-2-烯-1-酮(250mg,1.02mmol)制备。黄色固体(105mg,25%)。1H NMR(DMSO-d6)δ2.22(s,3H),2.41(m,4H),2.65(s,3H),3.42(m,4H),6.85(d,1H,J 9.0),7.03(d,1H,J 5.5),7.51(d,1H,J 8.0),7.68(dd,1H,J 9.0&5.5),7.84(d,1H,J 7.0),8.33(s,1H),8.45(d,1H,J5.0),9.43(s,1H),9.81(br s,1H).HRMS m/z 419.2109[M+H]+。
4-(咪唑并[1,2-a]吡啶-3-基)-5-甲基-N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)嘧 啶-2-胺(3).使用合成程序D,通过使1-(6-(4-甲基哌嗪-1-基)吡啶-3-基)胍盐酸盐(469mg,2.00mmol)和(E)-3-(二甲基氨基)-1-(咪唑并[1,2-a]吡啶-3-基)-2-甲基丙-2-烯-1-酮(230mg,1.00mmol)反应来制备。粉红色固体(110mg,28%)。1H NMR(CDCl3)δ2.37(s,3H),2.44(s,3H),2.56(t,4H,J 5.0),3.55(t,4H,J 5.0),6.69(d,1H,J 9.0),6.78(t,1H,J7.0),6.88(s,1H),7.33(t,1H,J 7.5),7.71(d,1H,J 9.0),7.79(dd,1H,J 9.0&2.5),8.18(s,1H),8.29(m,2H),9.55(d,1H,J 7.5).HRMS m/z 401.2205[M+H]+。
5-氟-4-(咪唑并[1,2-a]吡啶-3-基)-N-(吡啶-3-基)嘧啶-2-胺(4).使用一般合成程序E,通过使3-(2-氯-5-氟嘧啶-4-基)咪唑并[1,2-a]吡啶(250mg,1.01mmol)和3-氨基吡啶(100mg,1.06mmol)反应来制备。浅黄色固体(85mg,27%)。1H NMR(DMSO-d6)δ7.19(t,1H,J 6.5),7.37(dd,1H,J 8.0&4.5),7.58(t,1H,J 8.0),7.84(d,1H,J 8.5),8.18(d,1H,J8.0),8.22(d,1H,J 4.0),8.43(d,1H,J 4.0),8.60(d,1H,J 3.0),8.85(m,1H),9.94(s,1H),10.09(d,1H,J 6.5).HRMS m/z 307.1105[M+H]+。
4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)嘧啶- 2-胺(5).使用一般合成程序D,通过处理1-(6-(4-甲基哌嗪-1-基)吡啶-3-基)胍盐酸盐(469mg,2.00mmol)与(E)-1-(6-溴咪唑并[1,2-a]吡啶-3-基)-3-(二甲基氨基)丙-2-烯-1-酮(300mg,1.02mmol)制备。黄色固体(185mg,39%)。1H NMR(DMSO-d6)δ2.22(s,3H),2.40(t,4H,J 4.5),3.44(t,4H,J 4.5),6.88(d,1H,J 9.0),7.32(d,1H,J 5.5),7.56(d,1H,J9.5),7.72(d,1H,J 9.5),7.79(d,1H,J 6.0),8.26(br s,1H),8.38(d,1H,J 5.5),8.59(s,1H),9.40(br s,1H),9.92(app br s,1H).HRMS m/z 465.1151[M(79Br)+H]+。
N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧 啶-2-胺(6).使用合成程序F,通过处理4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)嘧啶-2-胺(240mg,0.52mmol)和4,4,5,5-四甲基-2-苯基-1,3,2-二氧杂环戊硼烷(106mg,0.52mmol)制备。黄色固体(115mg,47%)。1H NMR(DMSO-d6)δ2.21(s,3H),2.36(m,4H),6.52(br s,1H),7.32(d,1H,J 5.5),7.42(m,3H),7.56(br s,2H),7.78(m,2H),7.84(d,1H,J 9.0),8.30(s,1H),8.41(d,1H,J 5.0),8.55(s,1H),9.37(s,1H),9.96(br s,1H).HRMS m/z 463.2357[M+H]+。
N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-4-(6-(吡啶-3-基)咪唑并[1,2-a]吡啶-3- 基)嘧啶-2-胺(7).使用合成程序F,通过使4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)嘧啶-2-胺(240mg,0.52mmol)和3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶(108mg,0.53mmol)反应来制备。黄色固体(98mg,41%)。1H NMR(DMSO-d6)δ2.21(s,3H),2.36(m,4H),3.27(br s,4H),6.53(br s,1H),7.33(d,1H,J 5.5),7.44(br s,1H),7.78(d,1H,J 8.5),7.82(d,1H,J 9.5),7.88(d,1H,J 9.0),7.94(br s,1H),8.29(s,1H),8.40(d,1H,J 5.0),8.58(s,1H),8.62(d,1H,J 4.0),8.89(br s,1H),9.39(s,1H),10.04(br s,1H).HRMS m/z 464.2314[M+H]+。
N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-4-(6-(嘧啶-5-基)咪唑并[1,2-a]吡啶-3- 基)嘧啶-2-胺(8).使用合成程序F,通过使4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)嘧啶-2-胺(240mg,0.52mmol)和5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)嘧啶(110mg,0.53mmol)反应来制备。黄色固体(105mg,43%)。1H NMR(DMSO-d6)δ2.21(s,3H),2.37(br s,4H),3.27(s,2H),6.60(br s,1H),7.34(d,1H,J 5.0),7.77(d,1H,J 7.0),7.86(d,1H,J 9.5),7.91(d,1H,J9.5),8.31(s,1H),8.40(d,1H,J5.0),8.61(s,1H),9.09(br s,2H),9.24(s,1H),9.41(s,1H),10.14(br s,1H).HRMS m/z465.2268[M+H]+。
4-(6-(1-甲基-1H-吡唑-4-基)咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-甲基哌嗪-1- 基)吡啶-3-基)嘧啶-2-胺(9).使用合成程序F,通过使4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)嘧啶-2-胺(240mg,0.52mmol)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(108mg,0.52mmol)反应来制备。黄色固体(92mg,38%)。1H NMR(DMSO-d6)δ2.76(s,3H),3.13(br s,4H),3.88(s,3H),6.86(d,1H,J6.5),7.34(d,2H,J 5.0),7.70(d,1H,J 9.5),7.78(d,1H,J 9.5),7.92(d,1H,J 8.5),8.06(br s,1H),8.39(d,1H,J 5.0),8.47(s,1H),8.53(s,1H),9.48(s,1H),9.94(s,1H).HRMSm/z 467.2422[M+H]+。
1-(4-(5-((5-氟-4-(咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-2-基)哌 嗪-1-基)乙烷-1-酮(10).使用一般合成程序E,通过处理3-(2-氯-5-氟嘧啶-4-基)咪唑并[1,2-a]吡啶(250mg,1.01mmol)和1-(4-(5-氨基吡啶-2-基)哌嗪-1-基)乙烷-1-酮(230mg,1.04mmol)制备。黄色固体(75mg,17%)。1H NMR(DMSO-d6)δ2.06(s,3H),3.43(m,2H),3.51(m,2H),3.56(m,4H),6.93(d,1H,J 9.0),7.11(m,1H),7.57(t,1H,J 7.5),7.83(d,1H,J9.0),7.88(d,1H,J 8.5),8.36(s,1H),8.41(d,1H,J 3.0),8.51(d,1H,J 3.0),9.50(s,1H),10.01(br s,1H).HRMS m/z 433.1899[M+H]+。
1-(4-(5-((4-(咪唑并[1,2-a]吡啶-3-基)-5-甲基嘧啶-2-基)氨基)吡啶-2-基) 哌嗪-1-基)乙烷-1-酮(11).使用一般合成程序E,通过处理3-(2-氯-5-甲基嘧啶-4-基)咪唑并[1,2-a]吡啶(250mg,1.02mmol)和1-(4-(5-氨基吡啶-2-基)哌嗪-1-基)乙烷-1-酮(230mg,1.04mmol)制备。粉红色固体(84mg,19%)。1H NMR(DMSO-d6)δ2.05(s,3H),2.39(s,3H),3.40(m,2H),3.47(m,2H),3.55(m,4H),6.89(d,1H,J 9.0),7.02(t,1H,J 6.5),7.48(t,1H,J 8.0),7.76(d,1H,J 9.0),7.90(d,1H,J 9.0),8.29(s,1H),8.37(s,1H),8.39(m,1H),9.28(s,1H),9.75(br s,1H).HRMS m/z 429.2152[M+H]+。
4-(6-氟咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)嘧啶- 2-胺(12).使用一般程序D,通过处理1-(6-(4-甲基哌嗪-1-基)吡啶-3-基)胍盐酸盐(469mg,2.00mmol)和(E)-3-(二甲基氨基)-1-(6-氟咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(235mg,1.02mmol)制备。黄色固体(94mg,23%)。1H NMR(DMSO-d6)δ2.32(s,3H),2.54(m,4H),3.47(m,4H),6.89(d,1H,J 9.0),7.35(d,1H,J 5.5),7.60(d,1H,J 8.0),7.82(dd,1H,J 9.0&5.5),7.84(d,1H,J 7.0),8.35(s,1H),8.39(d,1H,J 5.0),8.66(s,1H),9.51(br s,1H),10.07(app br s,1H).HRMS m/z 405.1948[M+H]+。
4-(咪唑并[1,2-a]吡啶-3-基)-5-甲基-N-(6-(哌嗪-1-基)吡啶-3-基)嘧啶-2-胺 (13).通过使3-(2-氯-5-甲基嘧啶-4-基)咪唑并[1,2-a]吡啶(200mg,0.82mmol)和4-(5-氨基吡啶-2-基)哌嗪-1-甲酸叔丁酯(228mg,0.82mmol)反应,随后在NaOH(17mg,0.41mmol)的2-甲氧基乙-1-醇(4mL)溶液的存在下在微波条件下于180℃加热2小时来制备。粉红色固体(20mg,7%)。1H NMR(CDCl3)δ2.43(s,3H),3.04(t,4H,J 4.5),3.48(s,1H),3.51(t,4H,J4.5),6.68(d,1H,J 9.0),6.77(t,1H,J 7.0),7.06(s,1H),7.32(t,1H,J 8.0),7.75(d,1H,J 8.5),7.81(dd,1H,J 8.5&1.5),8.17(s,1H),8.28(s,1H),8.29(s,1H),9.55(d,1H,J7.0).HRMS m/z 387.2042[M+H]+。
4-(咪唑并[1,2-a]吡啶-3-基)-5-甲基-N-(6-吗啉代吡啶-3-基)嘧啶-2-胺(14).根据一般程序E,通过处理3-(2-氯-5-甲基嘧啶-4-基)咪唑并[1,2-a]吡啶(250mg,1.02mmol)和6-吗啉代吡啶-3-胺(183mg,1.02mmol)制备。黄色固体(70mg,18%)。1H NMR(DMSO-d6)δ2.41(s,3H),3.39(t,4H,J 4.5),3.74(t,4H,J 5.0),6.88(d,1H,J 9.0),7.04(t,1H,J 6.0),7.50(d,1H,J 7.5),7.78(d,1H,J 9.0),7.92(d,1H,J 8.5),8.31(s,1H),8.39(s,1H),8.41(s,1H),9.30(s,1H),9.76(s,1H).HRMS m/z 388.1884[M+H]+。
5-氟-4-(咪唑并[1,2-a]吡啶-3-基)-N-(6-吗啉代吡啶-3-基)嘧啶-2-胺(15).根据一般合成程序E,通过处理3-(2-氯-5-氟嘧啶-4-基)咪唑并[1,2-a]吡啶(250mg,1.02mmol)和6-吗啉代吡啶-3-胺(180mg,1.02mmol)制备。黄色固体(90mg,23%)。1H NMR(DMSO-d6)δ3.40(t,4H,J 4.5),3.73(t,4H,J 4.5),6.90(d,1H,J 9.0),7.11(t,1H,J6.5),7.57(t,1H,J 8.0),7.83(d,1H,J 9.0),7.88(d,1H,J 8.0),8.36(s,1H),8.41(d,1H,J 3.5),8.51(d,1H,J 3.5),9.50(s,1H),10.00(br s,1H).HRMS m/z 392.1633[M+H]+。
4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-(甲基磺酰基)哌嗪-1-基)吡啶-3- 基)嘧啶-2-胺(16).使用一般程序D,通过处理1-(6-(4-(甲基磺酰基)哌嗪-1-基)吡啶-3-基)胍(598mg,2.00mmol)与(E)-1-(6-溴咪唑并[1,2-a]吡啶-3-基)-3-(二甲基氨基)丙-2-烯-1-酮(300mg,1.02mmol)制备。黄色固体(210mg,40%)。1H NMR(DMSO-d6)δ2.92(s,3H),3.22(t,4H,J 5.0),3.59(t,4H,J 5.0),6.96(d,1H,J 9.0),7.35(d,1H,J 5.0),7.58(dd,1H,J 9.5&1.5),7.74(d,1H,J 9.5),7.87(d,1H,J 8.0),8.32(br s,1H),8.39(d,1H,J5.5),8.61(s,1H),9.49(br s,1H),9.96(app br s,1H).HRMS m/z 529.0766[M(79Br)+H]+,531.0753[M(81Br)+H]+。
N-(6-(4-(甲基磺酰基)哌嗪-1-基)吡啶-3-基)-4-(6-苯基咪唑并[1,2-a]吡啶- 3-基)嘧啶-2-胺(17).使用合成程序F,通过处理4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-(甲基磺酰基)哌嗪-1-基)吡啶-3-基)嘧啶-2-胺(270mg,0.51mmol)和4,4,5,5-四甲基-2-苯基-1,3,2-二氧杂环戊硼烷(106mg,0.52mmol)制备。黄色固体(108mg,40%)。1H NMR(DMSO-d6)δ2.91(s,3H),3.16(t,4H,J 5.0),3.42(t,4H,J 5.0),6.58(br s,1H),7.34(d,1H,J 5.5),7.44(m,3H),7.58(br s,2H),7.77(d,1H,J 9.0),7.84(m,2H),8.34(s,1H),8.42(d,1H,J 5.0),8.56(s,1H),9.43(s,1H),9.98(br s,1H).HRMS m/z 527.1978[M+H]+。
N-(6-(4-(甲基磺酰基)哌嗪-1-基)吡啶-3-基)-4-(6-(吡啶-4-基)咪唑并[1,2- a]吡啶-3-基)嘧啶-2-胺(18).使用合成程序F,通过使4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-(甲基磺酰基)哌嗪-1-基)吡啶-3-基)嘧啶-2-胺(270mg,0.51mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶(108mg,0.53mmol)反应来制备。黄色固体(100mg,37%)。1H NMR(DMSO-d6)δ2.92(s,3H),3.16(m,4H),3.40(br s,4H),6.65(br s,1H),7.36(d,1H,J 5.0),7.53(br s,2H),7.80(d,1H,J 8.0),7.88(s,2H),8.36(s,1H),8.43(d,1H,J 5.0),8.58(s,2H),8.61(s,1H),9.44(s,1H),10.16(br s,1H).HRMS m/z528.1931[M+H]+。
N-(6-(4-(甲基磺酰基)哌嗪-1-基)吡啶-3-基)-4-(6-(吡啶-3-基)咪唑并[1,2- a]吡啶-3-基)嘧啶-2-胺(19).使用合成程序F,通过使4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-(甲基磺酰基)哌嗪-1-基)吡啶-3-基)嘧啶-2-胺(270mg,0.51mmol)和3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶(108mg,0.53mmol)反应来制备。米色固体(96mg,36%)。1H NMR(DMSO-d6)δ2.91(s,3H),3.17(t,4H,J 5.0),3.42(br s,4H),6.62(brs,1H),7.35(d,1H,J 5.5),7.46(br s,1H),7.81(d,1H,J 1.5),7.83(d,1H,J 1.5),7.89(d,1H,J 9.0),7.97(br s,1H),8.34(s,1H),8.42(d,1H,J 5.0),8.60(s,1H),8.65(dd,1H,J 4.5&1.5),8.89(br s,1H),9.45(s,1H),10.06(br s,1H).HRMS m/z 528.1928[M+H]+。
N-(6-(4-(甲基磺酰基)哌嗪-1-基)吡啶-3-基)-4-(6-(嘧啶-5-基)咪唑并[1,2- a]吡啶-3-基)嘧啶-2-胺(20).使用合成程序F,通过使4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-(甲基磺酰基)哌嗪-1-基)吡啶-3-基)嘧啶-2-胺(270mg,0.51mmol)和5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)嘧啶(110mg,0.53mmol)反应来制备。黄色固体(85mg,32%)。1H NMR(DMSO-d6)δ2.92(s,3H),3.18(t,4H,J 5.0),3.43(br s,4H),6.69(brs,1H),7.36(d,1H,J 5.0),7.82(d,1H,J 7.0),7.87(d,1H,J 9.0),7.93(d,1H,J 9.0),8.37(s,1H),8.42(d,1H,J 5.0),8.62(s,1H),9.09(br s,2H),9.27(s,1H),9.47(s,1H),10.14(br s,1H).HRMS m/z 529.1881[M+H]+。
N-(6-(4-(甲基磺酰基)哌嗪-1-基)吡啶-3-基)-4-(6-(噻吩-2-基)咪唑并[1,2- a]吡啶-3-基)嘧啶-2-胺(21).使用合成步骤F,通过使4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-(甲基磺酰基)哌嗪-1-基)吡啶-3-基)嘧啶-2-胺(270mg,0.51mmol)和噻吩-2-硼酸(67mg,0.52mmol)反应来制备。米色固体(90mg,33%)。1H NMR(DMSO-d6)δ2.92(s,3H),3.18(t,4H,J 5.0),3.45(br s,4H),6.70(d,1H,J 5.5),7.14(t,1H,J 4.0),7.32(s,1H),7.33(s,1H),7.59(d,1H,J 5.0),7.72(d,1H,J 9.5),7.84(m,2H),8.35(d,1H,J 2.0),8.42(d,1H,J 5.0),8.55(s,1H),9.43(s,1H),10.00(br s,1H).HRMS m/z 533.1539[M+H]+。
4-(6-氯咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)嘧啶- 2-胺(22).使用一般合成程序D,通过使1-(6-(4-甲基哌嗪-1-基)吡啶-3-基)二硝酸胍(720mg,2.00mmol)与(E)-3-(二甲基氨基)-1-(6-氯咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(250mg,1.00mmol)反应来制备。金色固体(130mg,31%)。1H NMR(DMSO-d6)δ2.24(s,3H),2.44(t,4H,J 4.5),3.45(t,4H,J 4.5),6.88(d,1H,J 9.0),7.33(d,1H,J 5.5),7.50(d,1H,J 9.5),7.78(d,2H,J 9.5),8.27(br s,1H),8.38(d,1H,J 5.5),8.62(s,1H),9.41(brs,1H),9.88(br s,1H).HRMS m/z 421.1652[M+H]+。
4-(6-(2-氨基嘧啶-5-基)咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-甲基哌嗪-1-基) 吡啶-3-基)嘧啶-2-胺(23).使用合成程序F,通过处理4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)嘧啶-2-胺(240mg,0.52mmol)和5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)嘧啶-2-胺(115mg,0.52mmol)制备。黄色固体(124mg,52%)。1H NMR(DMSO-d6)δ2.21(s,3H),2.38(t,4H,J 4.5),6.62(br s,1H),6.88(s,2H),7.31(d,1H,J 5.5),7.71(d,1H,J 9.0),7.81(d,1H,J 9.0),7.85(dd,1H,J 9.0&2.5),8.29(s,1H),8.38(d,1H,J 5.5),8.54(s,1H),8.58(m,2H),9.40(s,1H),9.91(br s,1H).HRMSm/z 480.2369[M+H]+。
4-(6-(1H-吡唑-4-基)咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-甲基哌嗪-1-基)吡 啶-3-基)嘧啶-2-胺(24).使用合成程序F,通过处理4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)嘧啶-2-胺(240mg,0.52mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(100mg,0.52mmol)制备。黄色固体(85mg,38%)。1HNMR(DMSO-d6)δ2.76(s,3H),3.13(br s,4H),6.86(d,1H,J 6.5),7.36(d,2H,J 5.0),7.72(d,1H,J 9.5),7.80(d,1H,J 9.5),7.94(d,1H,J 8.5),8.08(br s,1H),8.41(d,1H,J5.0),8.49(s,1H),8.55(s,1H),9.50(s,1H),9.96(s,1H),10.12(s,1H).HRMS m/z453.2261[M+H]+。
N-(6-(氮杂环丁烷-1-基)吡啶-3-基)-4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧 啶-2-胺(25).使用合成程序F,通过处理N-(6-(氮杂环丁烷-1-基)吡啶-3-基)-4-(6-溴咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺(211mg,0.50mmol)和4,4,5,5-四甲基-2-苯基-1,3,2-二氧杂环戊硼烷(102mg,0.50mmol)制备。黄色固体(47mg,22%)。1H NMR(DMSO-d6)δ1.81(s,2H),3.21(s,2H),3.88(s,2H),6.90(d,1H,J 9.0),7.49(m,4H),7.63(s,2H),7.88(m,2H),8.30(s,1H),8.50(d,1H,J 5.0),8.66(s,1H),8.92(s,1H),9.80(s,1H),10.09(s,1H).HRMSm/z 420.1937[M+H]+。
4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(吡咯烷-1-基)吡啶-3-基)嘧啶-2-胺 (26)。使用一般程序D,通过处理1-(6-(吡咯烷-1-基)吡啶-3-基)胍盐酸盐(484mg,2.00mmol)与(E)-1-(6-溴咪唑并[1,2-a]吡啶-3-基)-3-(二甲基氨基)丙-2-烯-1-酮(300mg,1.02mmol)制备。黄色固体(243mg,56%)。1H NMR(DMSO-d6)δ1.95(t,4H,J 6.5),3.39(t,4H,J 6.5),6.51(d,1H,J 9.0),7.30(d,1H,J 5.5),7.56(d,1H,J 9.0),7.72(m,2H),8.16(s,1H),8.36(d,1H,J 5.5),8.59(s,1H),9.27(br s,1H),9.89(app br s,1H).HRMS m/z 436.0886[M+H]+。
4-(6-苯基咪唑并[1,2-a]吡啶-3-基)-N-(6-(吡咯烷-1-基)吡啶-3-基)嘧啶-2- 胺(27).使用合成程序F,通过处理4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(吡咯烷-1-基)吡啶-3-基)嘧啶-2-胺(218mg,0.50mmol)和4,4,5,5-四甲基-2-苯基-1,3,2-二氧杂环戊硼烷(102mg,0.50mmol)制备。黄色固体(72mg,33%)。1H NMR(DMSO-d6)δ1.90(t,4H,J6.5),3.19(t,4H,J 6.5),6.09(br s,1H),7.29(d,1H,J 5.5),7.37(m,3H),7.48(br s,2H),7.66(d,1H,J 7.5),7.77(dd,1H,J 9.5&1.5),7.82(d,1H,J 9.5),8.18(s,1H),8.38(d,1H,J 5.5),8.55(s,1H),9.23(s,1H),9.99(br s,1H).HRMS m/z 434.2090[M+H]+。
5-氟-N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-4-(6-苯基咪唑并[1,2-a]吡啶-3- 基)嘧啶-2-胺(28).使用一般程序E,通过处理3-(2-氯-5-氟嘧啶-4-基)-6-苯基咪唑[1,2-a]吡啶(162mg,0.50mmol)和6-(4-甲基哌嗪-1-基)吡啶-3-胺(115mg,0.60mmol)制备。黄色固体(33mg,14%)。1H NMR(DMSO-d6)δ2.23(s,3H),2.39(t,4H,J 5.0),3.28(t,4H,J 5.0),6.50(br s,1H),7.41(m,3H),7.53(br s,2H),7.75(dd,1H,J 9.0&2.5),7.84(dd,1H,J9.0&1.5),7.89(d,1H,J 9.0),8.27(d,1H,J 2.5),8.37(d,1H,J 4.0),8.56(d,1H,J 3.5),9.44(s,1H),9.92(br s,1H).HRMS m/z 481.2263[M+H]+。
4-(5-((5-氟-4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-2-基) 哌啶-1-甲酸甲酯(29).使用一般程序E,通过处理3-(2-氯-5-氟嘧啶-4-基)-6-苯基咪唑并[1,2-a]吡啶(162mg,0.50mmol)和4-(5-氨基吡啶-2-基)哌啶-1-甲酸甲酯(141mg,0.60mmol)制备。黄色固体(35mg,13%)。1H NMR(DMSO-d6)δ1.51(m,2H),1.86(m,2H),2.57(m,1H),2.80(m,2H),3.62(s,3H),3.93(m,2H),6.55(br s,1H),7.42(m,3H),7.56(br s,2H),7.78(d,1H,J 8.5),7.86(dd,1H,J 9.0&1.5),7.90(d,1H,J 9.0),8.25(d,1H,J 2.5),8.39(d,1H,J 4.0),8.57(d,1H,J 3.0),9.48(s,1H),9.93(br s,1H).HRMS m/z 524.2209[M+H]+。
5-氟-N-(6-(4-(2-吗啉代乙基)哌嗪-1-基)吡啶-3-基)-4-(6-苯基咪唑并[1,2- a]吡啶-3-基)嘧啶-2-胺(30).使用一般程序E,通过处理3-(2-氯-5-氟嘧啶-4-基)-6-苯基咪唑并[1,2-a]吡啶(162mg,0.50mmol)和6-(4-(2-吗啉代乙基)哌嗪-1-基)吡啶-3-胺(175mg,0.60mmol)制备。黄色固体(28mg,10%)。1H NMR(DMSO-d6)δ2.36(m,1H),2.40(t,4H,J 4.0),2.45(t,4H,J 4.0),2.64(m,1H),3.17(m,1H),3.26(t,4H,J 4.0),3.45(m,1H),3.56(t,4H,J 4.0),6.48(br s,1H),7.41(m,3H),7.52(br s,2H),7.74(d,1H,J 8.5),7.84(dd,1H,J 9.0&1.5),7.89(d,1H,J 9.0),8.27(d,1H,J 2.5),8.37(d,1H,J 4.0),8.56(d,1H,J 3.0),9.43(s,1H),9.92(br s,1H).HRMS m/z 580.2949[M+H]+。
N-(6-乙氧基吡啶-3-基)-5-氟-4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺 (31).使用一般程序E,通过处理3-(2-氯-5-氟嘧啶-4-基)-6-苯基咪唑并[1,2-a]吡啶(162mg,0.50mmol)和6-乙氧基吡啶-3-胺(83mg,0.60mmol)制备。黄色固体(48mg,23%)。1HNMR(DMSO-d6)δ1.25(t,3H,J 7.0),4.08(m,2H),6.53(d,1H,J 9.0),7.40(m,3H),7.48(brs,2H),7.82(d,1H,J 8.5),7.85(dd,1H,J 9.0&1.5),7.90(d,1H,J 9.0),8.31(d,1H,J2.5),8.40(d,1H,J 4.0),8.59(d,1H,J 3.0),9.59(s,1H),9.94(s,1H).HRMS m/z427.1682[M+H]+。
(5-((5-氟-4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-2-基) (哌啶-1-基)甲酮(32).使用一般程序E,通过处理3-(2-氯-5-氟嘧啶-4-基)-6-苯基咪唑并[1,2-a]吡啶(162mg,0.50mmol)和(5-氨基吡啶-2-基)(哌啶-1-基)甲酮(123mg,0.60mmol)制备。浅白色固体(40mg,16%)。1H NMR(DMSO-d6)δ1.45(m,2H),1.55(m,2H),1.60(m,2H),3.41(m,2H),3.58(m,2H),7.38(m,2H),7.45(m,2H),7.66(d,2H,J 7.5),7.88(dd,1H,J9.0&1.5),7.93(d,1H,J 9.0),8.22(dd,1H,J 8.5&2.5),8.44(d,1H,J 4.0),8.70(d,1H,J3.0),8.83(d,1H,J 2.5),9.98(s,1H),10.20(s,1H).HRMS m/z 494.2101[M+H]+。
N-环丙基-5-((5-氟-4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶 酰胺(33).使用一般程序E,通过处理3-(2-氯-5-氟嘧啶-4-基)-6-苯基咪唑并[1,2-a]吡啶(162mg,0.50mmol)和5-氨基-N-环丙基吡啶酰胺(106mg,0.60mmol)制备。浅白色固体(45mg,19%)。1H NMR(DMSO-d6)δ0.63(m,2H),0.68(m,2H),2.85(m,1H),7.35(m,3H),7.53(t,2H,J 3.0),7.85(d,1H,J 8.5),7.88(dd,1H,J 9.0&1.5),7.92(d,1H,J 9.0),8.19(dd,1H,J 8.5&2.5),8.40(d,1H,J 4.5),8.44(d,1H,J 4.0),8.71(d,1H,J 3.5),8.86(d,1H,J2.5),9.94(s,1H),10.26(s,1H).HRMS m/z 466.1790[M+H]+。
N-(6-氯吡啶-3-基)-5-氟-4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺(34).使用一般程序E,通过处理3-(2-氯-5-氟嘧啶-4-基)-6-苯基咪唑并[1,2-a]吡啶(162mg,0.50mmol)和6-氯吡啶-3-胺(77mg,0.60mmol)制备。黄色固体(35mg,17%)。1H NMR(DMSO-d6)7.16(d,1H,J 8.5),7.43(m,3H),7.57(d,2H,J 3.5),7.88(dd,1H,J 9.0&1.5),7.92(d,1H,J9.0),8.13(dd,1H,J 8.5&2.5),8.43(d,1H,J 4.0),8.62(d,1H,J 2.5),8.68(d,1H,J3.5),9.94(s,1H),10.09(s,1H).HRMS m/z 417.1028[M+H]+。
4-(6-甲基咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)嘧 啶-2-胺(35).使用一般合成程序D,通过使1-(6-(4-甲基哌嗪-1-基)吡啶-3-基)胍盐酸盐(615mg,2.00mmol)与(E)-3-(二甲基氨基)-1-(6-甲基咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(230mg,1.00mmol)反应来制备。黄色固体(130mg,32%)。1H NMR(DMSO-d6)δ2.27(s,3H),2.37(s,3H),2.63(t,4H,J 4.5),6.91(d,1H,J 9.0),7.29(d,1H,J 5.5),7.32(d,1H,J9.5),7.63(d,1H,J 9.5),7.78(br s,1H),8.33(d,1H,J 5.5),8.36(s,1H),8.49(s,1H),9.31(br s,1H),9.61(br s,1H).HRMS m/z 401.2200[M+H]+。
N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-4-(6-(三氟甲基)咪唑并[1,2-a]吡啶-3- 基)嘧啶-2-胺(36).使用一般合成程序D,通过使1-(6-(4-甲基哌嗪-1-基)吡啶-3-基)胍盐酸盐(615mg,2.00mmol)与(E)-3-(二甲基氨基)-1-(6-(三氟甲基)咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(284mg,1.00mmol)反应来制备。黄色固体(50mg,11%)。1H NMR(DMSO-d6)δ2.22(s,3H),2.41(t,4H,J 4.5),3.42(t,4H,J 4.5),6.80(d,1H,J 9.0),7.36(d,1H,J5.5),7.67(d,1H,J 9.5),7.74(d,1H,J 9.5),7.94(d,1H,J 9.5),8.25(s,1H),8.43(d,1H,J 5.5),8.70(s,1H),9.38(br s,1H),10.09(br s,1H).HRMS m/z 455.1918[M+H]+。
4-(6-氯咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-异丙基哌嗪-1-基)吡啶-3-基)嘧 啶-2-胺(37).使用一般合成程序D,通过使1-(6-(4-异丙基哌嗪-1-基)吡啶-3-基)胍(1.01g,3.01mmol)与(E)-1-(6-氯咪唑并[1,2-a]吡啶-3-基)-3-(二甲基氨基)丙-2-烯-1-酮(250mg,1.00mmol)反应来制备。黄色固体(116mg,26%)。1H NMR(DMSO-d6)δ1.00(s,3H),1.01(s,3H),2.53(t,4H,J 4.5),2.67(m,1H),6.86(d,1H,J 9.0),7.33(d,1H,J 5.5),7.50(d,1H,J 9.5),7.77(d,2H,J 9.5),8.26(br s,1H),8.38(d,1H,J 5.5),8.62(s,1H),9.40(br s,1H),9.88(br s,1H).HRMS m/z 449.1965[M(35Cl)+H]+,451.1936[M(37Cl)+H]+。
4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-异丙基哌嗪-1-基)吡啶-3-基)嘧 啶-2-胺(38).使用一般合成程序D,通过处理1-(6-(4-异丙基哌嗪-1-基)吡啶-3-基)胍(525mg,2.00mmol)与(E)-1-(6-溴咪唑并[1,2-a]吡啶-3-基)-3-(二甲基氨基)丙-2-烯-1-酮(300mg,1.02mmol)制备。黄色固体(195mg,40%)。1H NMR(DMSO-d6)δ1.02(s,6H),2.54(t,4H,J 4.5),2.67(m,1H),3.43(t,4H,J 4.5),6.89(d,1H,J 8.5),7.34(d,1H,J 5.0),7.59(d,1H,J 9.5),7.73(d,1H,J 9.5),7.80(s,1H),8.27(br s,1H),8.39(d,1H,J 5.0),8.61(s,1H),9.42(br s,1H),9.94(br s,1H).HRMS m/z493.1465[M(79Br)+H]+,495.1446[M(81Br)+H]+。
N-(6-(4-异丙基哌嗪-1-基)吡啶-3-基)-4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧 啶-2-胺(39).使用一般合成程序F,通过处理4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-异丙基哌嗪-1-基)吡啶-3-基)嘧啶-2-胺(125mg,0.26mmol)与苯硼酸(61mg,0.50mmol)制备。黄色固体(82mg,64%)。1H NMR(DMSO-d6)δ1.00(s,6H),2.67(m,1H),3.28(t,4H,J4.5),6.52(s,1H),7.32(d,1H,J 5.0),7.43(m,3H),7.57(s,2H),7.77(m,2H),7.84(d,1H,J9.0),8.30(s,1H),8.40(d,1H,J 4.5),8.55(s,1H),9.37(s,1H),9.96(br s,1H).HRMS m/z491.2671[M+H]+。
N-(6-(4-异丙基哌嗪-1-基)吡啶-3-基)-4-(6-(吡啶-4-基)咪唑并[1,2-a]吡啶- 3-基)嘧啶-2-胺(40).使用一般合成程序F,通过处理4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-异丙基哌嗪-1-基)吡啶-3-基)嘧啶-2-胺(125mg,0.26mmol)与4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶(108mg,0.53mmol)制备。黄色固体(62mg,49%)。1HNMR(DMSO-d6)δ1.02(s,6H),2.68(m,1H),3.29(t,4H,J 4.5),6.66(br s,1H),7.36(d,1H,J5.0),7.52(m,2H),7.80(s,1H),7.89(m,2H),8.36(s,1H),8.44(d,1H,J 5.0),8.58(s,2H),8.61(s,1H),9.45(br s,1H),10.15(br s,1H).HRMS m/z 492.2645[M+H]+。
1-(4-(5-((4-(咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-2-基)哌嗪-1- 基)乙烷-1-酮(41).使用一般合成程序D,通过处理1-(6-(4-乙酰基哌嗪-1-基)吡啶-3-基)胍(525mg,2.00mmol)和(E)-3-(二甲基氨基)-1-(咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(220mg,1.02mmol)制备。米色固体(165mg,39%)。1H NMR(DMSO-d6)δ2.06(s,3H),3.43(t,2H,J 5.0),3.50(t,2H,J 5.0),3.57(t,4H,J 4.5),6.93(d,1H,J 9.0),7.08(s,1H),7.34(d,1H,J 5.0),7.49(ddd,1H,J 9.0&7.0&1.0),7.77(d,1H,J 9.0),7.93(d,1H,J 7.5),8.37(d,1H,J 5.0),8.39(s,1H),8.60(s,1H),9.44(s,1H),10.02(br s,1H).HRMS m/z415.2002[M+H]+。
4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(哌嗪-1-基)吡啶-3-基)嘧啶-2-胺 (42).使用一般合成程序D,通过处理4-(5-胍基吡啶-2-基)哌嗪-1-甲酸叔丁酯(641mg,2.00mmol)与(E)-1-(6-溴咪唑并[1,2-a]吡啶-3-基)-3-(二甲基氨基)丙-2-烯-1-酮(300mg,1.02mmol)制备。棕色固体(84mg,19%)。1H NMR(DMSO-d6)δ2.85(m,2H),3.41(m,2H),3.49(m,4H),6.92(td,1H,J 7.0&1.0),7.34(d,1H,J 5.5),7.58(m,1H),7.74(d,1H,J9.0),7.86(d,1H,J 8.5),8.29(d,1H,J 9.0),8.40(t,1H,J 5.0),8.61(s,1H),9.45(m,1H),9.95(br s,1H).HRMS m/z 451.0998[M(79Br)+H]+,453.0971[M(81Br)+H]+。
4-(6-(6-甲氧基吡啶-3-基)咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-甲基哌嗪-1- 基)吡啶-3-基)嘧啶-2-胺(43).使用一般合成程序F,通过处理4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)嘧啶-2-胺(120mg,0.26mmol)与2-甲氧基-5-吡啶硼酸(80mg,0.52mmol)制备。黄色固体(64mg,50%)。1H NMR(DMSO-d6)δ2.36(s,3H),3.93(s,3H),6.60(br s,1H),6.86(br s,1H),7.33(d,1H,J 4.5),7.75-7.85(m,4H),8.32(s,1H),8.40(d,1H,J 4.5),8.49(s,1H),8.56(s,1H),9.41(s,1H),9.97(br s,1H).HRMSm/z 494.2423[M+H]+。
1-(4-(5-((4-(6-溴咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-2-基)哌 嗪-1-基)乙烷-1-酮(44).使用一般合成程序D,通过处理1-(6-(4-乙酰基哌嗪-1-基)吡啶-3-基)胍(1.05g,4.00mmol)与(E)-1-(6-溴咪唑并[1,2-a]吡啶-3-基)-3-(二甲基氨基)丙-2-烯-1-酮(600mg,2.04mmol)制备。黄色固体(430mg,44%)。1H NMR(DMSO-d6)δ2.05(s,3H),3.43(m,2H),3.52(m,2H),3.55(m,4H),6.92(d,1H,J 9.0),7.34(d,1H,J 5.0),7.58(d,1H,J 9.5),7.73(d,1H,J 9.5),7.85(d,1H,J 8.0),8.31(s,1H),8.40(d,1H,J 5.0),8.61(s,1H),9.46(br s,1H),9.96(br s,1H).HRMS m/z 493.1096[M(79Br)+H]+,495.1078[M(81Br)+H]+。
1-(4-(5-((4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-2-基)哌 嗪-1-基)乙烷-1-酮(45).使用一般合成程序F,通过处理1-(4-(5-((4-(6-溴咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-2-基)哌嗪-1-基)乙烷-1-酮(125mg,0.25mmol)与苯硼酸(61mg,0.50mmol)制备。米色固体(60mg,49%)。1H NMR(DMSO-d6)δ2.05(s,3H),3.26(m,2H),3.50(m,4H),6.56(br s,1H),7.33(d,1H,J 5.0),7.42(m,3H),7.57(m,2H),7.77-7.85(m,3H),8.33(s,1H),8.41(d,1H,J 5.0),8.56(s,1H),9.41(s,1H),9.98(br s,1H).HRMSm/z 491.2315[M+H]+。
1-(4-(5-((4-(6-(吡啶-4-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶- 2-基)哌嗪-1-基)乙烷-1-酮(46).使用一般合成程序F,通过处理1-(4-(5-((4-(6-溴咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-2-基)哌嗪-1-基)乙烷-1-酮(125mg,0.25mmol)与4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶(108mg,0.53mmol)制备。黄色固体(78mg,63%)。1H NMR(DMSO-d6)δ2.05(s,3H),3.23(m,2H),3.50(m,4H),6.61(br s,1H),7.35(d,1H,J 5.0),7.51(br s,2H),7.78(d,1H,J 7.5),7.88(m,2H),8.34(s,1H),8.43(d,1H,J 5.0),8.56(s,2H),8.61(s,1H),9.42(s,1H),10.16(br s,1H).HRMS m/z492.2265[M+H]+。
1-(4-(5-((4-(6-(1H-吡唑-4-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡 啶-2-基)哌嗪-1-基)乙烷-1-酮(47).使用一般合成程序F,通过处理1-(4-(5-((4-(6-溴咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-2-基)哌嗪-1-基)乙烷-1-酮(125mg,0.25mmol)与4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(100mg,0.52mmol)制备。黄色固体(75mg,62%)。1H NMR(DMSO-d6)δ2.05(s,3H),3.41(m,2H),3.52(m,4H),6.75(br s,1H),7.31(d,1H,J 5.5),7.74-7.87(m,4H),8.20(br s,1H),8.39(m,2H),8.52(s,1H),9.43(s,1H),9.94(br s,1H),13.06(br s,1H).HRMS m/z 481.2219[M+H]+。
1-(4-(5-((4-(6-(6-甲氧基吡啶-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨 基)吡啶-2-基)哌嗪-1-基)乙烷-1-酮(48).使用一般合成程序F,通过处理1-(4-(5-((4-(6-溴咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-2-基)哌嗪-1-基)乙烷-1-酮(125mg,0.25mmol)与2-甲氧基-5-吡啶硼酸(80mg,0.52mmol)制备。黄色固体(66mg,51%)。1H NMR(DMSO-d6)δ2.05(s,3H),3.22(m,2H),3.49(m,4H),3.90(s,3H),6.60(br s,1H),6.83(d,1H,J 6.0),7.33(d,1H,J 5.0),7.75-7.85(m,4H),8.33(s,1H),8.41(d,1H,J5.0),8.47(br s,1H),8.57(s,1H),9.42(s,1H),9.98(br s,1H).HRMS m/z 522.2372[M+H]+。
1-(4-(5-((4-(6-(1H-吲哚-4-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡 啶-2-基)哌嗪-1-基)乙烷-1-酮(49).使用一般合成程序F,通过处理1-(4-(5-((4-(6-溴咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-2-基)哌嗪-1-基)乙烷-1-酮(125mg,0.25mmol)与4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲哚(122mg,0.50mmol)制备。黄色固体(97mg,73%)。1H NMR(DMSO-d6)δ2.05(s,3H),3.03(m,2H),3.10(m,2H),3.44(m,4H),5.78(br s,1H),6.54(s,1H),7.17-7.22(m,2H),7.33(d,1H,J 5.0),7.42(s,1H),7.51(d,1H,J 8.0),7.71-7.73(m,2H),7.74(d,1H,J 9.5),8.11(s,1H),8.41(d,1H,J 5.0),8.54(s,1H),9.26(s,1H),9.95(br s,1H),11.38(s,1H).HRMS m/z530.2422[M+H]+。
5-甲基-N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-4-(6-苯基咪唑并[1,2-a]吡啶-3- 基)嘧啶-2-胺(50).使用一般合成程序E,通过处理3-(2-氯-5-甲基嘧啶-4-基)-6-苯基咪唑并[1,2-a]吡啶(160mg,0.50mmol)和6-(4-甲基哌嗪-1-基)吡啶-3-胺(115mg,0.60mmol)制备。米色固体(75mg,31%)。1H NMR(DMSO-d6)δ2.24(s,3H),2.38(s,3H),2.41(m,4H),3.26(m,4H),6.42(d,1H,J 9.0),7.39(m,3H),7.49(m,2H),7.76(m,2H),7.83(d,1H,J 9.0),8.25(s,1H),8.30(s,1H),8.41(s,1H),9.27(s,1H),9.64(s,1H).HRMS m/z 477.2518[M+H]+。
4-(6-(呋喃-2-基)咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-(甲基磺酰基)哌嗪-1- 基)吡啶-3-基)嘧啶-2-胺(51).使用一般合成程序F,通过处理4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-(甲基磺酰基)哌嗪-1-基)吡啶-3-基)嘧啶-2-胺(135mg,0.25mmol)与2-(呋喃-3-基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(92mg,0.50mmol)制备。黄色固体(88mg,68%)。1H NMR(DMSO-d6)δ2.92(s,3H),3.19(m,4H),3.50(m,4H),6.64(s,1H),6.80(d,1H,J 8.5),6.89(br s,1H),7.33(d,1H,J 5.0),7.65(s,1H),7.81(m,2H),7.88(d,1H,J9.0),8.39-8.42(m,2H),8.55(s,1H),9.45(s,1H),10.04(br s,1H).HRMS m/z 517.1776[M+H]+。
4-(6-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-(甲基磺酰基)哌嗪- 1-基)吡啶-3-基)嘧啶-2-胺(52).使用一般合成程序F,通过处理4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-(甲基磺酰基)哌嗪-1-基)吡啶-3-基)嘧啶-2-胺(135mg,0.25mmol)与2-(苯并呋喃-2-基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(122mg,0.50mmol)制备。黄色固体(94mg,66%)。1H NMR(DMSO-d6)δ2.83(s,3H),2.93(m,4H),3.18(m,4H),6.70(d,1H,J8.0),7.28-7.40(m,5H),7.67(d,1H J 7.5),7.89(d,1H J 9.5),7.94-7.98(m,2H),8.47(s,2H),8.57(s,1H),9.54(s,1H),10.25(br s,1H).HRMS m/z 567.1912[M+H]+。
N-(6-(4-异丙基哌嗪-1-基)吡啶-3-基)-4-(6-(嘧啶-5-基)咪唑并[1,2-a]吡啶- 3-基)嘧啶-2-胺(53).使用一般合成程序F,通过处理4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-异丙基哌嗪-1-基)吡啶-3-基)嘧啶-2-胺(125mg,0.26mmol)与5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)嘧啶(110mg,0.53mmol)制备。黄色固体(48mg,37%)。1HNMR(DMSO-d6)δ1.00(s,3H),1.01(s,3H),2.67(m,1H),3.26(m,4H),6.55(br s,1H),7.35(d,1H,J 4.0),7.77(d,1H,J 7.5),7.86-7.93(m,2H),8.31(s,1H),8.41(m,1H),8.62(s,1H),9.11(br s,2H),9.25(s,1H),9.41(s,1H),10.15(br s,1H).HRMS m/z 493.2573[M+H]+。
N-(6-(4-异丙基哌嗪-1-基)吡啶-3-基)-4-(6-(噻吩-3-基)咪唑并[1,2-a]吡啶- 3-基)嘧啶-2-胺(54).使用一般合成程序F,通过处理4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-异丙基哌嗪-1-基)吡啶-3-基)嘧啶-2-胺(125mg,0.26mmol)与噻吩-2-硼酸(67mg,0.52mmol)制备。米色固体(40mg,31%)。1H NMR(DMSO-d6)δ1.00(s,3H),1.01(s,3H),2.67(m,1H),3.34(m,4H),6.68(br s,1H),7.31(d,2H,J 5.0),7.61(br s,1H),7.78-7.85(m,4H),8.34(s,1H),8.40(d,1H,J 5.0),8.54(s,1H),9.36(s,1H),10.01(br s,1H).HRMSm/z 497.2238[M+H]+。
4-(6-(6-氟吡啶-3-基)咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-异丙基哌嗪-1-基) 吡啶-3-基)嘧啶-2-胺(55).使用一般合成程序F,通过处理4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-异丙基哌嗪-1-基)吡啶-3-基)嘧啶-2-胺(125mg,0.26mmol)与(6-氟吡啶-3-基)硼酸(75mg,0.53mmol)制备。黄色固体(69mg,52%)。1H NMR(DMSO-d6)δ1.01(m,6H),2.67(m,1H),3.25(m,4H),6.56(br s,1H),7.24(br s,1H),7.34(d,1H,J 4.0),7.76-7.81(m,2H),7.88(d,1H,J 8.5),8.10(br s,1H),8.30(s,1H),8.41(m,1H),8.53(br s,1H),8.59(s,1H),9.38(s,1H),10.05(br s,1H).HRMS m/z 510.2532[M+H]+。
4-(6-(6-氟吡啶-3-基)咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-(甲基磺酰基)哌嗪- 1-基)吡啶-3-基)嘧啶-2-胺(56).使用一般合成程序F,通过处理4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-(甲基磺酰基)哌嗪-1-基)吡啶-3-基)嘧啶-2-胺(135mg,0.25mmol)与(6-氟吡啶-3-基)硼酸(75mg,0.53mmol)制备。黄色固体(63mg,46%)。1H NMR(DMSO-d6)δ2.91(s,3H),3.17(m,4H),3.42(m,4H),6.66(br s,1H),7.27(s,1H),7.35(d,1H,J 5.0),7.80(m,2H),7.89(d,1H,J 9.5),8.16(br s,1H),8.35(s,1H),8.42(d,1H,J 4.5),8.51(brs,1H),8.60(s,1H),9.44(s,1H),10.07(br s,1H).HRMS m/z 546.1837[M+H]+。
N5-(4-(6-溴咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)-N2-(四氢-2H-吡喃-4-基)吡 啶-2,5-二胺(57).使用一般合成程序D,通过处理1-(6-((四氢-2H-吡喃-4-基)氨基)吡啶-3-基)胍(470mg,2.00mmol)与(E)-1-(6-溴咪唑并[1,2-a]吡啶-3-基)-3-(二甲基氨基)丙-2-烯-1-酮(300mg,1.02mmol)制备。黄色固体(190mg,41%)。1H NMR(DMSO-d6)δ1.43(d,2H,J9.5),1.88(m,2H),3.40(t,2H,J 11.5),3.86-3.89(m,3H),6.37(d,1H,J 6.0),6.56(d,1H,J 8.5),7.29(d,1H,J 5.5),7.56(m,2H),7.72(d,1H,J 9.5),8.04(br s,1H),8.35(d,1H,J5.5),8.59(s,1H),9.21(br s,1H),9.91(br s,1H).HRMS m/z 466.0994[M(79Br)+H]+,468.0969[M(81Br)+H]+。
N5-(4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)-N2-(四氢-2H-吡喃-4-基) 吡啶-2,5-二胺(58).使用一般合成程序F,通过处理N5-(4-(6-溴咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)-N2-(四氢-2H-吡喃-4-基)吡啶-2,5-二胺(120mg,0.26mmol)与苯硼酸(61mg,0.50mmol)制备。黄色固体(87mg,72%)。1H NMR(DMSO-d6)δ1.38(d,2H,J 9.0),1.83(m,2H),3.37(t,2H,J 11.5),3.77-3.85(m,3H),6.25(d,1H,J 7.0),6.37(d,1H,J7.5),7.28(d,1H,J 5.5),7.38-7.58(m,6H),7.79(d,1H,J 9.5),7.84(d,1H,J 9.0),8.13(s,1H),8.37(d,1H,J 5.0),8.54(s,1H),9.18(s,1H),9.99(br s,1H).HRMS m/z 464.2202[M+H]+。
4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-(乙基磺酰基)哌嗪-1-基)吡啶-3- 基)嘧啶-2-胺(59).使用一般合成程序D,通过处理1-(6-(4-(乙基磺酰基)哌嗪-1-基)吡啶-3-基)胍(625mg,2.00mmol)与(E)-1-(6-溴咪唑并[1,2-a]吡啶-3-基)-3-(二甲基氨基)丙-2-烯-1-酮(300mg,1.02mmol)制备。黄色固体(246mg,45%)。1H NMR(DMSO-d6)δ1.23(t,3H,J6.5),3.11(d,2H,J 7.0),3.29(m,4H),3.55(m,4H),6.95(d,1H,J 8.5),7.35(d,1H,J4.5),7.58(d,1H,J 9.0),7.74(d,1H,J 9.0),7.87(m,1H),8.32(s,1H),8.40(d,1H,J4.0),8.61(s,1H),9.48(br s,1H),9.96(br,s,1H).HRMS m/z 543.0925[M(79Br)+H]+,545.0906[M(81Br)+H]+。
N-(6-(4-(乙基磺酰基)哌嗪-1-基)吡啶-3-基)-4-(6-苯基咪唑并[1,2-a]吡啶- 3-基)嘧啶-2-胺(60).使用一般合成程序F,通过处理4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-(乙基磺酰基)哌嗪-1-基)吡啶-3-基)嘧啶-2-胺(135mg,0.25mmol)与苯硼酸(61mg,0.50mmol)制备。黄色固体(83mg,61%)。1H NMR(DMSO-d6)δ1.23(t,3H,J 7.5),3.09(d,2H,J7.5),3.23(m,4H),3.38(m,4H),6.57(br s,1H),7.34(d,1H,J 5.5),7.43(m,3H),7.57(m,2H),7.78(d,1H,J 9.5),7.84(d,2H,J 9.0),8.34(s,1H),8.42(d,1H,J 5.0),8.56(s,1H),9.43(s,1H),9.98(br s,1H).HRMS m/z 541.2137[M+H]+。
N-(6-(4-(乙基磺酰基)哌嗪-1-基)吡啶-3-基)-4-(6-(6-氟吡啶-3-基)咪唑并 [1,2-a]吡啶-3-基)嘧啶-2-胺(61).使用一般合成程序F,通过处理4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-(乙基磺酰基)哌嗪-1-基)吡啶-3-基)嘧啶-2-胺(135mg,0.25mmol)与(6-氟吡啶-3-基)硼酸(70mg,0.50mmol)制备。米色固体(103mg,74%)。1H NMR(DMSO-d6)δ1.24(t,3H,J 7.5),3.08(d,2H,J 7.5),3.24(m,4H),3.38(m,4H),6.64(br s,1H),7.25(s,1H),7.35(d,1H,J 5.0),7.80(d,2H,J 9.0),7.88(d,1H,J 9.5),8.14(br s,1H),8.35(s,1H),8.42(d,1H,J 5.0),8.50(br s,1H),8.60(s,1H),9.43(s,1H),10.06(br s,1H).HRMSm/z 560.2015[M+H]+。
(4-(5-((4-(6-溴咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-2-基)哌嗪- 1-基)(呋喃-2-基)甲酮(62).使用一般合成程序D,通过处理1-(6-(4-(呋喃-2-羰基)哌嗪-1-基)吡啶-3-基)胍(629mg,2.00mmol)与(E)-1-(6-溴咪唑并[1,2-a]吡啶-3-基)-3-(二甲基氨基)丙-2-烯-1-酮(300mg,1.02mmol)制备。黄色固体(132mg,24%)。1H NMR(DMSO-d6)δ3.56(m,4H),3.80(m,4H),6.65(s,1H),6.93(d,1H,J 9.0),7.05(m,1H),7.34(d,1H,J5.0),7.58(d,1H,J 9.0),7.73(d,1H,J 9.5),7.87(m,2H),8.32(br s,1H),8.40(d,1H,J5.0),8.61(s,1H),9.48(br s,1H),9.95(br s,1H).HRMS m/z 545.1044[M(79Br)+H]+,547.1023[M(81Br)+H]+。
呋喃-2-基(4-(5-((4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶- 2-基)哌嗪-1-基)甲酮(63).使用一般合成程序F,通过处理(4-(5-((4-(6-溴咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-2-基)哌嗪-1-基)(呋喃-2-基)甲酮(135mg,0.25mmol)与苯硼酸(61mg,0.50mmol)制备。黄色固体(39mg,29%)。1H NMR(DMSO-d6)δ3.58(m,4H),3.82(m,4H),6.68(s,1H),6.95(d,1H,J 9.0),7.08(m,1H),7.34(d,1H,J 5.0),7.44(m,2H),7.55-7.59(m,4H),7.76(d,1H,J 9.0),7.89(m,2H),8.35(br s,1H),8.43(d,1H,J 5.0),8.64(s,1H),9.51(br s,1H),9.98(br s,1H).HRMS m/z 543.2246[M+H]+。
4-(6-(3-氟-5-甲氧基苯基)咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-甲基哌嗪-1- 基)吡啶-3-基)嘧啶-2-胺(64).使用一般合成程序F,通过处理4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)嘧啶-2-胺(120mg,0.26mmol)与2-(3-氟-5-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(126mg,0.50mmol)制备。黄色固体(82mg,62%)。1H NMR(DMSO-d6)δ2.61(s,3H),2.91(m,4H),3.80(s,3H),6.53(br s,1H),6.90(d,1H,J 10.5),7.03(m,2H),7.34(d,1H,J 5.5),7.78-7.88(m,3H),8.35(s,1H),8.42(d,1H,J 5.0),8.56(s,1H),9.51(s,1H),10.02(br s,1H).HRMS m/z 511.2371[M+H]+。
N5-(4-(6-溴咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)-N2,N2-二甲基吡啶-2,5-二胺 (65).使用一般合成程序D,通过处理1-(6-(二甲基氨基)吡啶-3-基)胍(358mg,2.00mmol)与(E)-1-(6-溴咪唑并[1,2-a]吡啶-3-基)-3-(二甲基氨基)丙-2-烯-1-酮(300mg,1.02mmol)制备。黄色固体(230mg,56%)。1H NMR(DMSO-d6)δ3.02(s,6H),6.71(d,1H,J9.0),7.31(d,1H,J 5.0),7.57(d,1H,J 9.5),7.71-7.75(m,2H),8.21(br s,1H),8.37(d,1H,J 5.0),8.60(s,1H),9.33(br s,1H),9.89(br s,1H).HRMS m/z 410.0723[M(79Br)+H]+,412.0710[M(81Br)+H]+。
N2,N2-二甲基-N5-(4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)吡啶-2,5-二 胺(66).使用一般合成程序F,通过处理N5-(4-(6-溴咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)-N2,N2-二甲基吡啶-2,5-二胺(105mg,0.26mmol)与苯硼酸(61mg,0.50mmol)制备。黄色固体(66mg,65%)。1H NMR(DMSO-d6)δ2.87(s,6H),6.32(br s,1H),7.30(d,1H,J 5.0),7.39(s,3H),7.51(br s,2H),7.71(d,1H,J 8.5),7.77(d,1H,J 9.0),7.83(d,1H,J 9.0),8.22(s,1H),8.39(d,1H,J 5.0),8.55(s,1H),9.27(s,1H),9.98(br s,1H).HRMS m/z 408.1935[M+H]+。
4-(3-(2-((6-(二甲基氨基)吡啶-3-基)氨基)嘧啶-4-基)咪唑并[1,2-a]吡啶-6- 基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(67).使用一般合成程序F,通过处理N5-(4-(6-溴咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)-N2,N2-二甲基吡啶-2,5-二胺(105mg,0.26mmol)与4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(155mg,0.50mmol)制备。米色固体(98mg,74%)。1H NMR(DMSO-d6)δ1.43(s,9H),2.21(br s,2H),2.99(s,6H),3.41(br s,2H),3.94(br s,2H),6.15(br s 1H),6.62(d,1H,J 9.0),7.26(d,1H,J 5.0),7.62-7.72(m,3H),8.29(s,1H),8.37(d,1H,J 4.0),8.48(s,1H),9.22(s,1H),9.66(br s,1H).HRMS m/z 513.2709[M+H]+。
N5-(4-(6-(6-氟吡啶-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)-N2,N2-二甲基 吡啶-2,5-二胺(68).使用一般合成程序F,通过处理N5-(4-(6-溴咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)-N2,N2-二甲基吡啶-2,5-二胺(105mg,0.26mmol)与(6-氟吡啶-3-基)硼酸(70mg,0.50mmol)制备。黄色固体(80mg,72%)。1H NMR(DMSO-d6)δ2.85(s,6H),6.32(br s,1H),7.17(br s,1H),7.32(d,1H,J 5.0),7.66(d,1H,J 7.5),7.79(d,1H,J 9.0),7.87(d,1H,J 9.0),8.20(br s,1H),8.21(s,1H),8.40(m,2H),8.59(s,1H),9.27(s,1H),10.05(brs,1H).HRMS m/z 427.1794[M+H]+。
N2,N2-二甲基-N5-(4-(6-(1,2,3,6-四氢吡啶-4-基)咪唑并[1,2-a]吡啶-3-基)嘧 啶-2-基)吡啶-2,5-二胺(69).将4-(3-(2-((6-(二甲基氨基)吡啶-3-基)氨基)嘧啶-4-基)咪唑并[1,2-a]吡啶-6-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(95mg,0.19mmol)溶解在TFA/DCM/H2O(28mL,18:9:1)的混合物中。将反应混合物在50℃下加热过夜,减压浓缩并通过制备型HPLC(H2O/MeOH)纯化,得到标题产物。米色固体(75mg,96%)。1H NMR(DMSO-d6)δ2.61(m,1H),3.14(s,6H),3.29(m,2H),3.80(m,2H),6.35(s,1H),7.08(br s,1H),7.42(d,1H,J 4.0),7.78(d,1H,J 9.0),7.83(d,1H,J 9.0),8.00(br s,1H),8.48(d,2H,J 5.0),9.02(br s,2H),9.64(s,1H),9.81(br s,1H).HRMS m/z 413.2208[M+H]+。
4-(6-(1-(二氟甲基)-1H-吡唑-4-基)咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-甲基 哌嗪-1-基)吡啶-3-基)嘧啶-2-胺(70).使用一般合成程序F,通过处理4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)嘧啶-2-胺(120mg,0.26mmol)与1-(二氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(122mg,0.50mmol)制备。黄色固体(85mg,65%)。1H NMR(DMSO-d6)δ2.21(s,3H),2.38(m,4H),6.73(br s,1H),7.32(d,1H,J 5.0),7.75-7.98(m,5H),8.39(s,2H),8.54(m,1H),8.80(br s,1H),9.43(s,1H),10.06(br s,1H).HRMS m/z 503.2249[M+H]+。
8-(5-((4-(6-溴咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-2-基)-2,8-二 氮杂螺[4.5]癸烷-1-酮(71).使用一般合成程序D,通过处理1-(6-(1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基)吡啶-3-基)胍(577mg,2.00mmol)与(E)-1-(6-溴咪唑并[1,2-a]吡啶-3-基)-3-(二甲基氨基)丙-2-烯-1-酮(300mg,1.02mmol)制备。黄色固体(268mg,52%)。1HNMR(DMSO-d6)δ1.40(d,2H,J 13.0),1.69(td,2H,J 12.5&3.5),2.03(t,2H,J 6.5),2.98(t,2H,J 12.0),3.21(t,2H,J 6.5),4.16(d,2H,J 13.0),6.91(d,1H,J 9.0),7.33(d,1H,J5.5),7.57(m,2H),7.73(d,1H,J 9.5),7.80(m,1H),8.26(br s,1H),8.39(d,1H,J 5.0),8.60(s,1H),9.40(br s,1H),9.96(br s,1H).HRMS m/z 519.1256[M(79Br)+H]+,521.1231[M(81Br)+H]+。
8-(5-((4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-2-基)-2,8- 二氮杂螺[4.5]癸烷-1-酮(72).使用一般合成程序F,通过处理8-(5-((4-(6-溴咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-2-基)-2,8-二氮杂螺[4.5]癸烷-1-酮(130mg,0.25mmol)与苯硼酸(61mg,0.50mmol)制备。黄色固体(74mg,57%)。1H NMR(DMSO-d6)δ1.36(d,2H,J 13.0),1.64(t,2H,J 12.5),2.00(t,2H,J 6.5),2.83(t,2H,J 12.0),3.20(t,2H,J 6.5),3.97(m,2H),6.52(br s,1H),7.32(d,1H,J 5.0),7.43-7.58(m,6H),7.77(d,2H,J8.5),7.84(d,1H,J 9.5),8.28(s,1H),8.40(d,1H,J 5.0),8.55(s,1H),9.35(s,1H),9.97(br s,1H).HRMS m/z 517.2461[M+H]+。
8-(5-((4-(6-(1-(二氟甲基)-1H-吡唑-4-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2- 基)氨基)吡啶-2-基)-2,8-二氮杂螺[4.5]癸烷-1-酮(73).使用一般合成程序F,通过处理8-(5-((4-(6-溴咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-2-基)-2,8-二氮杂螺[4.5]癸烷-1-酮(130mg,0.25mmol)与1-(二氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(122mg,0.50mmol)制备。黄色固体(83mg,60%)。1H NMR(DMSO-d6)δ1.37(d,2H,J 13.0),1.66(t,2H,J 11.5),2.01(t,2H,J 6.5),2.90(t,2H,J 12.0),3.20(t,2H,J 6.5),4.04(m,2H),6.75(br s,1H),7.31(d,1H,J 5.0),7.58(s,1H),7.76-8.00(m,5H),8.38(m,2H),8.54(s,1H),8.81(br s,1H),9.40(s,1H),10.06(br s,1H).HRMS m/z557.2329[M+H]+。
N5-(4-(6-溴咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)-N2-丙基吡啶-2,5-二胺(74).使用一般合成程序D,通过处理1-(6-(丙基氨基)吡啶-3-基)胍(387mg,2.00mmol)与(E)-1-(6-溴咪唑并[1,2-a]吡啶-3-基)-3-(二甲基氨基)丙-2-烯-1-酮(300mg,1.02mmol)制备。黄色固体(205mg,48%)。1H NMR(DMSO-d6)δ0.92(t,3H,J 7.5),1.54(q,2H,J 7.5),3.19(q,2H,J 6.5),6.38(br s,1H),6.54(d,1H,J 8.5),7.29(d,1H,J 5.5),7.55-7.57(m,2H),7.72(d,1H,J 9.5),8.03(br s,1H),8.35(d,1H,J 5.0),8.59(s,1H),9.20(br s,1H),9.90(br s,1H).HRMS m/z 424.0881[M(79Br)+H]+,426.0864[M(81Br)+H]+。
N5-(4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)-N2-丙基吡啶-2,5-二胺 (75).使用一般合成程序F,通过处理N5-(4-(6-溴咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)-N2-丙基吡啶-2,5-二胺(106mg,0.25mmol)与苯硼酸(61mg,0.50mmol)制备。黄色固体(72mg,68%)。1H NMR(DMSO-d6)δ0.89(t,3H,J 7.5),1.50(q,2H,J 7.5),3.07(q,2H,J6.5),6.24(br s,1H),6.32(d,1H,J 7.0),7.28(d,1H,J 5.5),7.37-7.57(m,6H),7.78(d,1H,J 9.5),7.83(d,1H,J 9.0),8.11(s,1H),8.36(d,1H,J 5.0),8.54(s,1H),9.17(s,1H),9.98(br s,1H).HRMS m/z 422.2097[M+H]+。
N5-(4-(6-(1-(二氟甲基)-1H-吡唑-4-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2- 基)-N2-丙基吡啶-2,5-二胺(76).使用一般合成程序F,通过处理N5-(4-(6-溴咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)-N2-丙基吡啶-2,5-二胺(106mg,0.25mmol)与1-(二氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(122mg,0.50mmol)制备。黄色固体(76mg,66%)。1H NMR(DMSO-d6)δ0.89(t,3H,J 7.5),1.50(q,2H,J 7.5),3.12(m,2H),6.24(br s,1H),6.41(d,1H,J 5.5),7.27(d,1H,J 5.0),7.62(d,1H,J 8.5),7.74-7.97(m,3H),8.19(s,1H),8.34(d,1H,J 5.0),8.54(s,1H),8.79(br s,1H),9.24(s,1H),10.09(brs,1H).HRMS m/z 462.1963[M+H]+。
4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-((4-甲基哌嗪-1-基)甲基)吡啶-3-基) 嘧啶-2-胺(77).使用一般合成程序D,通过处理1-(6-((4-甲基哌嗪-1-基)甲基)吡啶-3-基)胍(497mg,2.00mmol)与(E)-1-(6-溴咪唑并[1,2-a]吡啶-3-基)-3-(二甲基氨基)丙-2-烯-1-酮(300mg,1.02mmol)制备。米色固体(176mg,37%)。1H NMR(DMSO-d6)δ2.18(s,3H),2.36(m,4H),2.44(m,4H),3.56(s,2H),7.42(d,1H,J 8.0),7.46(d,1H,J 5.0),7.62(d,1H,J 9.5),7.76(d,1H,J 9.5),8.18(d,1H,J 8.5),8.48(d,1H,J 5.0),8.65(s,1H),8.69(s,1H),9.91(s,1H),10.05(br s,1H).HRMS m/z 479.1314[M(79Br)+H]+,481.1292[M(81Br)+H]+。
N-(6-((4-甲基哌嗪-1-基)甲基)吡啶-3-基)-4-(6-苯基咪唑并[1,2-a]吡啶-3- 基)嘧啶-2-胺(78).使用一般合成程序F,通过处理4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-((4-甲基哌嗪-1-基)甲基)吡啶-3-基)嘧啶-2-胺(120mg,0.25mmol)与苯硼酸(61mg,0.50mmol)制备。白色固体(58mg,49%)。1H NMR(DMSO-d6)δ2.14(s,3H),2.31(m,4H),2.36(m,4H),4.41(s,2H),7.12(d,1H,J 8.0),7.42-7.45(m,4H),7.62(d,2H J 6.0),7.80(d,1H,J 9.0),7.87(d,1H,J 9.5),8.10(d,1H,J 8.0),8.49(d,1H,J 5.0),8.60(s,1H),8.71(s,1H),9.82(s,1H),10.01(br s,1H).HRMS m/z 477.2530[M+H]+。
4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-((4-乙基哌嗪-1-基)甲基)吡啶-3-基) 嘧啶-2-胺(79).使用一般合成程序D,通过处理1-(6-((4-乙基哌嗪-1-基)甲基)吡啶-3-基)胍(525mg,2.00mmol)与(E)-1-(6-溴咪唑并[1,2-a]吡啶-3-基)-3-(二甲基氨基)丙-2-烯-1-酮(300mg,1.02mmol)制备。米色固体(239mg,48%)。1H NMR(DMSO-d6)δ0.98(t,3H,J7.0),2.31(m,4H),2.44(m,4H),3.55(s,2H),7.42(d,1H,J 8.0),7.46(d,1H,J 5.0),7.62(d,1H,J 9.5),7.76(d,1H,J 9.5),8.18(d,1H,J 8.5),8.48(d,1H,J 5.5),8.65(s,1H),8.69(s,1H),9.90(s,1H),10.05(br s,1H).HRMS m/z 493.1488[M(79Br)+H]+,495.1468[M(81Br)+H]+。
N-(6-((4-乙基哌嗪-1-基)甲基)吡啶-3-基)-4-(6-苯基咪唑并[1,2-a]吡啶-3- 基)嘧啶-2-胺(80).使用一般合成程序F,通过处理4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-((4-乙基哌嗪-1-基)甲基)吡啶-3-基)嘧啶-2-胺(125mg,0.25mmol)与苯硼酸(61mg,0.50mmol)制备。黄色固体(90mg,73%)。1H NMR(DMSO-d6)δ0.97(t,3H,J 7.0),2.29(m,4H),2.34(m,4H),3.41(s,2H),7.12(d,1H,J 8.0),7.43-7.45(m,4H),7.62(m,2H),7.80(d,1H,J9.5),7.86(d,1H,J 9.5),8.09(d,1H,J 8.0),8.49(d,1H,J 5.0),8.60(s,1H),8.71(s,1H),9.82(s,1H),10.01(br s,1H).HRMS m/z 491.2674[M+H]+。
4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-((4-(二甲基氨基)哌啶-1-基)甲基)吡 啶-3-基)嘧啶-2-胺(81).使用一般合成程序D,通过处理1-(6-((4-(二甲基氨基)哌啶-1-基)甲基)吡啶-3-基)胍(553mg,2.00mmol)与(E)-1-(6-溴咪唑并[1,2-a]吡啶-3-基)-3-(二甲基氨基)丙-2-烯-1-酮(300mg,1.02mmol)制备。黄色固体(125mg,25%)。1H NMR(DMSO-d6)δ1.41(m,2H),1.73(m,2H),2.00(t,2H,J 11.0),2.15(m,2H),2.21(s,6H),2.88(d,2H,J 11.5),7.42(d,1H,J 8.5),7.46(d,1H,J 5.0),7.62(d,1H,J 9.5),7.76(d,1H,J9.5),8.17(d,1H,J 8.0),8.48(d,1H,J 5.0),8.65(s,1H),8.69(s,1H),9.90(s,1H),10.05(br s,1H).HRMS m/z 507.1618[M(79Br)+H]+,509.1595[M(81Br)+H]+。
5-((4-(6-溴咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶甲酸甲酯(82).使用一般合成程序D,通过处理5-胍基吡啶甲酸甲酯(388mg,2.00mmol)与(E)-1-(6-溴咪唑并[1,2-a]吡啶-3-基)-3-(二甲基氨基)丙-2-烯-1-酮(300mg,1.02mmol)制备。黄色固体(136mg,32%)。1H NMR(DMSO-d6)δ3.86(s,3H),7.57(d,1H,J 5.5),7.64(d,1H,J 9.5),7.77(d,1H,J 9.5),8.08(d,1H,J 9.0),8.51(d,1H,J 8.5),8.57(d,1H,J 5.0),8.68(s,1H),8.93(s,1H),10.09(s,1H),10.42(s,1H).HRMS m/z 425.0380[M(79Br)+H]+,427.0361[M(81Br)+H]+。
实施例2 生物活性
激酶测定
使用ADP Glo激酶测定法(Promega Corporation,Madison,WI,United States ofAmerica)测定CDK的抑制作用。测试化合物以在0.5%DMSO中的10个浓度(10-0.0005μM)1:3连续稀释使用。每个激酶反应都使用激酶反应缓冲液(40nM Tris碱pH 7.5、20mM MgCl2、0.4mM DTT、0.1mg/mL BSA)、每种激酶的底物(组蛋白H1肽:CDK1/CyclinB和CDK6/CyclinD3;组蛋白H1蛋白:CDK2/CyclinA2、CDK2/CyclinE1、CDK3/CyclinE1和CDK5/p25;RB-CTF:CDK4/CyclinD1和CDK6/CyclinD1;RBER-IRStide:CDK7/CyclinH/Mat1、CDK8/CyclinC和CDK9/CyclinT1)、用于每种激酶的Km ATP进行,总测定体积为5μL。激酶反应在室温下进行优化的时间段,然后通过添加5μL ADP Glo试剂来停止反应。室温避光温育40分钟后,每孔添加8μL激酶检测试剂,并温育30-40分钟。使用EnVision Multilabel读板器(PerkinElmer,Buckinghamshire,UK)以每孔1秒的积分时间测量发光。在存在和不存在每种CDK激酶的情况下分别在0.5%DMSO中进行阳性和阴性对照。类似地,FLT3激酶反应使用缓冲液(40nM Tris碱pH 7.5、20mM MgCl2、0.4mM DTT、0.1mg/mL BSA)、聚(4:1)Glu、Tyr肽底物、分别用于每种激酶(FLT3-WT:200μM,FLT3-ITD:100μM和FLT3-D835Y:35μM)和每种FLT3激酶(FLT3-WT:20nM,FLT3-ITD:20nM和FLT3-D835Y:5nM)的Km ATP进行,总测定体积为5μL。为10个浓度(10μM至0.5nM)的测试化合物制备了1:3的系列稀释液。激酶反应在室温下进行优化的时间段(FLT3-WT:120分钟,FLT3-ITD:80分钟,FLT3-D835Y:100分钟),然后通过添加5μL ADP Glo试剂来停止反应。室温避光温育40分钟后,每孔添加8μL激酶检测试剂,并温育30-40分钟。用Graphpad prism(版本6.0)使用4参数逻辑非线性回归模型计算半最大抑制(IC50)值。表观抑制常数(Ki)值由Km(ATP)和各个激酶的IC50值计算。
增殖测定
分别对来自实施例1的化合物进行实体瘤细胞系和白血病细胞系的标准MTT(3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四唑)和刃天青测定,如先前报道的(Wang S等人,J Med Chem 47:1662-1675,2004和Diab S.等人CheMedChem 9:962-972,2014)。使用非线性回归分析计算抑制50%细胞生长(GI50)所需的化合物浓度。以下化合物用作比较例。
激酶和增殖测定的结果如表2所示。值得注意的是,本发明的许多化合物强烈抑制CDK9。例如,发现在化合物6、7和9中N-(吡啶-3-基)嘧啶-2-胺部分而不是比较例化合物A、B和C的N-(吡啶-2-基)嘧啶-2-胺部分的存在显著地并且令人惊讶地增加了抑制CDK9的效力。
表2 示例性化合物的酶和细胞活性
(-)未测试
在整个说明书和随后的权利要求书中,除非上下文另有要求,否则词语“包含(comprise)”和“包括(comprise)”以及诸如“包含(comprising)”和“包括(including)”的变型将被理解为暗示包含所述整数或整数组,但不排除任何其他整数或整数组。
本说明书中对任何现有技术的引用不是也不应被视为承认此类现有技术构成公知常识的任何形式的暗示。
本领域技术人员应当理解,本公开不将其使用限制于所描述的特定应用。本公开在其优选实施方案中也不受本文描述或描绘的特定元件和/或特征的限制。还应当理解,本公开不限于所公开的一个或多个实施方案,而是能够在不脱离由所附权利要求阐明和限定的本公开范围的情况下进行多种重新布置、修改和替换。
Claims (20)
1.一种式I化合物:
其中:
R1、R2、R3、R4、R5和R6各自独立地选自由以下组成的组:H、烷基、烷基-R7、芳基、芳基-R7、芳烷基、芳烷基-R7、脂环、杂环、卤素、NO2、CN、CF3、OH、O-烷基、COR7、COOR7、O-芳基、O-R7、NH2、NH-烷基、NH-芳基、N-(烷基)2、N-(芳基)2、N-(烷基)(芳基)、NH-R7、NH-烷基-N(烷基)2、N-(R7)(R8)、N-(烷基)(R7)、N-(芳基)(R7)、COOH、CONH2、CONH-烷基、CONH-芳基、CONH-脂环、CON-(烷基)(R7)、CON(芳基)(R7)、CONH-R7、CON-(R7)(R8)、SH-烷基、SO3H、SO2-烷基、SO2-烷基-R7、SO2-芳基、SO2-芳基-R7、SO2NH2、SO2NH-R7、SO2N-(R7)(R8)、CF3、CO-烷基、COO-烷基、CO-烷基-R7、CO-芳基、CO-芳基-R7和R9,其中所述烷基、芳基、芳烷基、脂环和杂环基团可以任选地被一个或多个选自卤素、CN、OH、O-C1-6烷基、NH2、COOH、C2-5羧酸根、CONH2和卤代烷基的基团取代;并且
R7、R8和R9独立地选自水增溶基团;
或其药学上可接受的盐、溶剂化物或前药。
2.如权利要求1所述的化合物,其中R1是H、C1-6烷基、芳基、CN、CF3、NH2、杂环、O-C1-3烷基、NH-C1-6烷基、NH(C1-3烷基)-N(C1-3烷基)2、NH-芳基、N-(C1-3烷基)2、N-(C1-3烷基)(芳基)、SH-C1-6烷基、卤素或R9。
3.如权利要求2所述的化合物,其中R1是R9并且R9是被一个或多个羟基或氨基基团取代的含N、O和/或S的杂环基团。
4.如权利要求2所述的化合物,其中R1是H,卤素,CF3,C1-3烷基,任选地被C1-6烷基、O-C1-6烷基、氨基和/或卤素取代的苯基,或任选地被一个或多个选自卤素、CN、OH、O-C1-6烷基、NH2、COOH、C2-5羧酸根、CONH2和卤代烷基的基团取代的杂环。
5.如前述权利要求中任一项所述的化合物,其中R2是H、C1-6烷基、CN或卤素。
6.如前述权利要求中任一项所述的化合物,其中R3、R4、R5和R6中的至少一个是C1-3烷基-R7(其中R7选自COOH、SO3H、OSO3H、SONHCH3、SONHCH2CH3、SO2CH3、SO2CH2CH3、PO3H2和OPO3H2)、COOC1-烷基、O-C1-3烷基、NH-C1-3烷基、N-(C1-3烷基)2、NH-R7(其中R7优选地选自COOH、SO3H、OSO3H、SONHCH3、SONHCH2CH3、SO2CH3、SO2CH2CH3、PO3H2和OPO3H2)、CONH-C3-6脂环、卤素或者是R9。
7.如权利要求6所述的化合物,其中R3、R4、R5和R6中的至少一个是R9并且R9是被一个或多个羟基、砜、C1-3烷基、氨基、烷氧基、羧酸根或烷基羰基取代的含N、O和/或S的杂环基团。
8.如前述权利要求中任一项所述的化合物,其中在R3、R5和R6是H的情况下,R4不是COOH、C(=O)NHOH、C(=O)NHO-四氢吡喃或被NH2取代的CONH-芳基。
10.如前述权利要求中任一项所述的化合物,其中R4是R9,并且R3、R5和R6是H。
12.如权利要求1所述的化合物,其中所述化合物选自由以下组成的组:
N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺,
N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-4-(6-(吡啶-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺,
N-(6-(4-(甲基磺酰基)哌嗪-1-基)吡啶-3-基)-4-(6-(吡啶-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺,
N-(6-(4-(甲基磺酰基)哌嗪-1-基)吡啶-3-基)-4-(6-(噻吩-2-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺,
4-(6-氯咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)嘧啶-2-胺,
N-(6-(氮杂环丁烷-1-基)吡啶-3-基)-4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺,
4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-异丙基哌嗪-1-基)吡啶-3-基)嘧啶-2-胺,
N-(6-(4-异丙基哌嗪-1-基)吡啶-3-基)-4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺,
4-(6-(1-(二氟甲基)-1H-吡唑-4-基)咪唑并[1,2-a]吡啶-3-基)-N-(6-(4-甲基哌嗪-1-基)吡啶-3-基)嘧啶-2-胺,和
4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(6-((4-乙基哌嗪-1-基)甲基)吡啶-3-基)嘧啶-2-胺。
13.如前述权利要求中任一项所述的化合物或其药学上可接受的盐、溶剂化物或前药用于治疗癌症或另一种增殖性细胞疾病或疾患的用途。
14.一种治疗受试者的癌症或另一种增殖性细胞疾病或疾患的方法,所述方法包括向所述受试者施用治疗有效量的权利要求1至12中任一项所述的化合物或其药学上可接受的盐、溶剂化物或前药,所述化合物或其药学上可接受的盐、溶剂化物或前药任选地与药学上可接受的载体、稀释剂和/或赋形剂组合。
15.如权利要求14所述的方法,其中待治疗的所述癌症或其他增殖性细胞疾病或疾患选自特征在于CDK2、CDK4、CDK6和CDK9中的一种或多种过度活化的癌症或其他增殖性细胞疾病或疾患。
16.如权利要求14所述的方法,其中待治疗的所述癌症或其他增殖性细胞疾病或疾患选自特征在于过度活化的CDK9的癌症或其他增殖性细胞疾病或疾患。
17.如权利要求14所述的方法,其中待治疗的所述癌症或其他增殖性细胞疾病或疾患选自特征在于FLT3或FLT3-ITD和/或其他选自TRK、DYRK和/或突变体形式的蛋白激酶的表达或过度表达的癌症或其他增殖性细胞疾病或疾患。
18.如权利要求1至12中任一项所述的化合物或其药学上可接受的盐、溶剂化物或前药在制造用于治疗癌症或另一种增殖性细胞疾病或疾患的药物中的用途。
19.一种药物组合物或药物,其包含权利要求1至12中任一项所述的化合物或其药学上可接受的盐、溶剂化物或前药,以及药学上可接受的载体、稀释剂和/或赋形剂。
20.一种调节细胞中的蛋白激酶活性的方法,其包括将有效量的权利要求1至12中任一项所述的化合物或其药学上可接受的盐、溶剂化物或前药引入或接触所述细胞。
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