CN113853375B - 含n杂芳基衍生物及包含其作为活性成分的用于预防或治疗癌症的药物组合物 - Google Patents
含n杂芳基衍生物及包含其作为活性成分的用于预防或治疗癌症的药物组合物 Download PDFInfo
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Abstract
本发明涉及一种含N杂芳基衍生物和一种包含其作为活性成分的用于预防或治疗癌症的药物组合物。所述衍生物对各种蛋白激酶表现出很高的抑制活性,特别是对ret原癌基因(RET)酶有很好的抑制能力,并且对表达RET融合基因的甲状腺髓样癌细胞和肺癌细胞的增殖有很好的抑制作用,因此该衍生物可以有效地用于治疗癌症,例如甲状腺髓样癌或肺癌,特别是可以有效地用于治疗表达RET融合基因的癌症。
Description
技术领域
本发明涉及一种含N杂芳基衍生物和包含其作为活性成分的用于预防或治疗癌症的药物组合物。
背景技术
癌症的发展与各种环境因素有关,包括化学物质、辐射和病毒,以及与肿瘤基因、肿瘤抑制基因、细胞凋亡和DNA恢复相关的基因的变化等,而最近,对此类癌症分子机制的理解使得靶向抗癌治疗成为可能,这是一种新的治疗方法。
靶向治疗剂通常被设计为通过靶向癌细胞特有的分子来发挥作用,并且分子靶点是与信号转导途径、血管生成、基质、细胞周期调节剂、细胞凋亡等相关的基因。目前在治疗中用作重要靶向治疗剂的实例包括“信号转导途径抑制剂”,包括酪氨酸激酶抑制剂和血管生成抑制剂。
蛋白质中酪氨酸残基的磷酸化是细胞内信号转导的一个重要因素。能够催化这种反应的酶称为酪氨酸激酶。大量跨膜受体包括具有酪氨酸激酶活性的结构域,并被归类为受体酪氨酸激酶(RTKs)。
RTKs在细胞生长、分化、存活和程序性细胞死亡等各种过程中传递细胞外信号。为了响应与细胞外配体的结合,RTKs通常识别RTKs的二聚化和磷酸化形式,并通过相互作用效应物诱导细胞内信号传导和自磷酸化。这个RTK家族有许多成员,其中一个是RET原癌基因,它编码在转染(RET)过程中重新排列的120kDa蛋白质。RET是胶质细胞源性神经营养因子(GDNF)家族的生长因子受体。两种RET配体已被鉴定;GDNF和中性蛋白(NTN)。当其配体与共受体结合时,RET被激活,然后复合物与RET相互作用(Eng,1999 Journal ClinicalOncology:17(1)380-393)。
这种激活使酪氨酸残基中的RET磷酸化,并通过RAS-RAF和PI3激酶途径以及其他可能的途径诱导细胞生长和分化的信号。
众所周知,激活RET的点突变诱发三种相关的显性遗传癌症综合征;2A型和2B型多发性内分泌肿瘤(MEN2A和MEN2B)和家族性甲状腺髓样癌(FMTC)(Santoro等人,2004Endocrinology:145,5448-5451)。
在几乎所有MEN2A病例和一些FTMC病例中,半胱氨酸取代发生在近膜富含半胱氨酸结构域中,而在95%的MEN2B中,单点突变发生在激酶结构域(M918T)的密码子918处。密码子918被认为位于催化核心中的底物识别袋上。该位点的突变被认为通过改变RET催化结构域的活性环结构在结构上激活RET。在散发性髓样癌中也发现M918T突变,这与进行性疾病的表型有关。体外研究表明,突变会影响底物特异性,因此RET识别并磷酸化非受体酪氨酸激酶(如c-src和c-abl)优选的底物(Eng等人,1996 JAMA276,1575-1579;Ponder等人,1999 Cancer Research59,1736-1741;Schilling等人,2001 International Journal ofCancer95,62-66;Santoro等人,1995 Science267,381-383;Zhou等人,1995 Nature273,536-539)。
由于RET基因上的突变在大多数MEN2家族中被发现,因此它们能够进行分子诊断测试,也可能有助于确认临床诊断。RET突变检测可使用基于聚合酶链反应的方案进行,其中扩增目标轴突序列用于直接测序或限制性内切核酸酶消化(Zhong等人,2006 ClinicaChimica Acta364,205-208)。
RTK家族的另一个成员是血管内皮生长因子受体2(VEGFR2)(含激酶***域的受体,KDR(也称为Flk1))。VEGFR2是血管内皮生长因子(VEGF)的受体。VEGF被认为是正常血管生成和疾病相关血管生成(Jakeman等人,1993 Endocrinology 133,848-859;Kolch等人,1995 Breast Cancer Research and Treatment36,139-155)及血管通透性(Connolly等人,1989 J.Biol.Chem264,20017-20024)的重要刺激剂。通过隔离抗体和VEGF的VEGF拮抗作用可以抑制肿瘤生长(Kim等人,1993 Nature 362,841-844)。VEGF基因的异源切割诱导血管形成的致命缺陷(Carmeliet等人,1996 Nature 380435-439;Ferrara等人,1996Nature 380439-442)。
VEGF与VEGFR2结合诱导受体二聚化,导致特定细胞内酪氨酸残基的VEGFR2自磷酸化。自磷酸化增加了酪氨酸激酶的催化活性,并为细胞质信号(如磷脂酶C-γ)提供了一个潜在的停泊位点。这种蛋白质相互作用介导VEGFR2,例如,细胞内信号传导对于诱导细胞对内皮细胞增殖、存活和迁移的反应至关重要(Ryan等人,2005 British Journal Cancer:92(Suppl.1)S6-S13)。
对VEGF介导的VEGFR2信号在病理性血管生成中的重要作用的认识导致了抑制VEGFR2激活的各种选择性方法的发展。它们包括小分子ATP竞争性酪氨酸激酶抑制剂,可防止ATP结合抑制中的自磷酸化和持续细胞内信号传导(Ryan,2005)。
国际公开号WO98/13354和WO01/32651中描述了作为VEGF受体酪氨酸激酶抑制剂的喹唑啉衍生物。WO98/13354和WO01/32651公开了具有部分抗表皮生长因子受体(EGFR)酪氨酸激酶活性和抗VEGF受体酪氨酸激酶活性的化合物。
公开了一种化合物4-(4-溴-2-氟苯胺)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉,它是一种VEGFR2酪氨酸激酶抑制剂(Wedge等人,2002 Cancer Research62,4645-4655)。这种化合物也被称为(注册商标),其代码为ZD6474,通用商品名为凡德他尼(vandetanib)。下文中,该化合物将被称为凡德他尼。
凡德他尼被开发为一种抑制剂,具有与VEGFR2酪氨酸激酶强且可逆的ATP结合。此外,凡德他尼抑制EGFR酪氨酸激酶活性。EGFR信号通路不仅是肿瘤细胞增殖、存活和侵袭的重要因素,而且在VEGF增加过度表达的癌症进展中也是一个重要因素。EGFR信号的抑制已被证实可诱导肿瘤内皮细胞的选择性凋亡。
在2002年,凡德他尼被报道能够抑制RET的信号传导和可变形性,作为配体依赖性RET酪氨酸激酶活性的有效抑制剂。此外,据报道,凡德他尼在体外对RET依赖性甲状腺肿瘤细胞生长具有有效的生长抑制作用(Carlomagno等人,2002 Cancer Research:62,7284-7290)。
凡德他尼还抑制了大多数RET的突变活性形式和野生型受体。因此,凡德他尼对RET酪氨酸激酶的抑制以及对VEGFR2和EGFR酪氨酸激酶的抑制也可以在伴随着诱导RET依赖性肿瘤细胞生长的RET基因突变的肿瘤治疗中产生额外的抗肿瘤作用(Ryan,2005)。
发明内容
【技术问题】
本发明的一个目的是提供一种含N杂芳基衍生物或其异构体、其溶剂化物、其水合物或其药学上可接受的盐。
本发明的另一个目的是提供一种制备该化合物的方法。
本发明的又一个目的是提供一种药物组合物,其包含含N杂芳基衍生物或其异构体、其溶剂化物、其水合物或其药学上可接受的盐,作为预防或治疗癌症的活性成分。
本发明的另一个目的是提供一种预防或治疗癌症的方法,所述方法包含含N杂芳基衍生物或其异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分。
本发明的另一个目的是提供含N杂芳基衍生物或其异构体、其溶剂化物、其水合物或其药学上可接受的盐在制备用于预防或治疗癌症的药物中的用途。
【技术方案】
为达到上述目的,
本发明的一个方面提供了一种具有如下化学式1的化合物、其异构体、其溶剂化物、其水合物或其药学上可接受的盐:
[化学式1]
其中是呋喃、噻吩、苯或环戊烯,
R1是直链或支链C1-C3烷基,其中R1未被取代或被至少一个卤素取代,
环B是二氮杂双环庚烷、哌嗪、二氮杂环庚烷或二氮杂螺辛烷,其中环B未被取代或被至少一个直链或支链C1-C6烷基取代,
R2是吡啶基、噻唑基、苯基、咪唑基、吡嗪基、喹啉基、嘧啶基或吡啶酮基,其中R2未被取代或被至少一个R3取代,并且
R3是选自由如下组成的组的至少一个取代基:直链或支链C1-C6烷基、直链或支链C1-C6卤代烷基、直链或支链C1-C6烷氧基、卤素、C1-C3链烷磺酰氨基、被至少一个直链或支链C1-C3烷基取代的氨基和腈基。
本发明的另一方面提供了一种制备化学式1的化合物的方法,所述方法包括:
由化学式2的化合物制备化学式3的化合物;
由化学式3的化合物制备化学式4的化合物;
由化学式4的化合物制备化学式5的化合物;
由化学式5的化合物制备化学式6的化合物;
由化学式6的化合物制备化学式7的化合物;以及
由化学式7的化合物制备化学式1的化合物:
[化学式2]
[化学式3]
[化学式4]
[化学式5]
[化学式6]
[化学式7]
[化学式1]
其中,R1、R2、和环B分别与上述定义相同,
G是离去基团,
PG是保护基团,并且
环B'具有与环B相同的结构,但是是其中一个氮原子被保护基团保护的形式。
本发明的另一方面提供了含有本发明化合物或其异构体、其溶剂化物、其水合物或其药学上可接受的盐作为用于预防或治疗癌症的活性成分的药物组合物。
【有益效果】
根据本发明的化学式1的化合物对各种蛋白激酶表现出高的抑制活性,特别是对ret原癌基因(RET)酶有很好的抑制能力,并且对表达RET融合基因的甲状腺髓样癌细胞和肺癌细胞的增殖有很好的抑制作用,因此该衍生物可以有效地用于治疗癌症,例如甲状腺髓样癌或肺癌,特别是可以有效地用于治疗表达RET融合基因的癌症。
具体实施方式
在下文中,将详细描述本发明。
本发明的示例性实施方案可以以各种形式实施,并且不旨在限制本发明的范围。此外,提供本发明的示例性实施方案是为了向本领域的普通技术人员更完整地描述本发明。
在本申请的整个说明书中,当一个要素被称为“包括”另一要素时,这也意味着其还可以包括其他要素,除非另有特别说明,否则不排除其他要素。
在本说明书的结构式中,结合原子和/或基团的符号“-”可表示单键,符号“=”可表示双键。这些符号可以省略,也可以在必要时显示,例如在指定键合原子或键合位置时。
在本说明书中,原子的连接不仅包括原子直接连接的情况,还包括由其他原子和/或基团介导的原子间接连接的情况。在这种情况下,其他原子和/或基团可以是氧、硫、C1-8烷基氨基、C1-8亚烷基等,但不限于此,并且该原子和/或基团可以被取代或未被取代。
在本说明书中,除非另有说明,否则被取代或未被取代可以是指一个氢原子或多个氢原子未被取代或被其他原子或取代基取代。所述取代基可以是选自由如下组成的组中的至少一种:卤素(氯(Cl),碘(I),溴(Br),氟(F)),C1~10烷基、C2~10烯基、C2~10炔基、羟基、C1~10烷氧基、氨基、硝基、硫醇、硫醚、亚胺、氰基、膦酸基、膦基、羧基、氨基甲酰基、氨基甲酸、缩醛、脲、硫代羰基、磺酰基、磺酰胺、酮、醛、酯、乙酰基、乙酰氧基、酰胺、氧(=O)、卤代烷基(例如,三氟甲基)、取代的氨基酰基和氨基烷基、碳环环烷基(其可以是单环或稠合或非稠合多环(例如,环丙基、环丁基、环戊基或环己基))、或杂环烷基(其可以是单环或稠合或非稠合多环(例如,吡咯烷基、哌啶基、哌嗪基、吗啉基或噻嗪基))、碳环或杂环、单环或稠合或非稠合多环芳基(例如,苯基、萘基、吡咯基、吲哚基、呋喃基、噻吩基、咪唑基、噁唑基、异噁唑基、噻唑基、***基、四唑基、吡唑基、吡啶基、喹啉基、异喹啉基、吖啶基、吡嗪基、哒嗪基、嘧啶基、苯并咪唑基、苯并噻吩基或苯并呋喃基)、氨基(伯、仲或叔)、芳基、芳氧基和芳烷基,但不限于此。此外,每个示例性的取代基可以未被取代或被选自这些取代基的组中的取代基再次取代。
在本说明书中,卤素可以是F、Cl、Br或I。
在本说明书中,烷基可以指直链或支链的非环状;环状;或它们所结合的饱和烃,除非另有说明。此外,C1-8烷基可以指包括1至8个碳原子的烷基。非环状烷基可以包括,例如,甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基、正辛基、异丙基、仲丁基、异丁基、叔丁基、异戊基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等,但不限于此。环状烷基可以包括,例如,环丙基、环丁基、环戊基、环己基、环庚基、环辛基等,但不限于此。非环状烷基和环状烷基结合的烷基包括,例如,甲基环丙基、环丙基甲基、乙基环丙基、环丙基乙基、甲基环丁基、环丁基甲基、乙基环戊基、环戊基甲基等,但不限于此。
如本文所用,环烷基可以具体指烷基中的环状烷基,其中烷基与上述定义相同。
如本文所用,烷氧基可以指-(O-烷基)作为烷基醚基团,其中烷基与上述定义相同。此外,C1-8烷氧基可以指包含C1-8烷基的烷氧基,即-(O-C1-8烷基),例如,C1-8烷氧基可以包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基等,但不限于此。
如本文所用,杂环烷基可以指含有1至5个选自N、O和S的杂原子作为形成环的原子的环,并且可以是饱和的或部分不饱和的。除非另有说明,杂环烷基可以是单环或多环,例如螺环、桥环或稠环。此外,3至12个原子的杂环烷基可以指包括形成环的3至12个原子的杂环烷基,例如,该杂环烷基可包括吡咯烷、哌啶、N-甲基哌啶、咪唑烷、吡唑烷、丁内酰胺、戊内酰胺、咪唑烷酮、乙内酰脲、二氧戊环、邻苯二甲酰亚胺、哌啶、嘧啶-2,4(1H,3H)-二酮,1,4-二氧六环,吗啉,硫吗啉,硫吗啉-S-氧化物,硫吗啉-S,S-氧化物,哌嗪,吡喃,吡啶酮,3-吡咯啉,噻喃,吡喃酮,四氢呋喃,四氢噻吩,奎宁环,托烷,2-氮杂螺环[3.3]庚烷,(1R,5S)-3-氮杂双环[3.2.1]辛烷,(1S,4S)-2-氮杂双环[2.2.2]辛烷,(1R,4R)-2-氧杂-5-氮杂双环[2.2.2]辛烷等,但不限于此。
如本文所用,烷基氨基可以指-(NR'R”),其中R'和R”可以各自独立地选自由氢和C1-8烷基组成的基团,并且所选R'和R”可以各自独立地被取代或未被取代。此外,C1-8烷基氨基可指含有C1-8烷基的氨基,即-N-H(C1-8烷基)或-N-(C1-8烷基)2,并且可以包括二甲氨基、二乙氨基、甲基乙基氨基、甲基丙基氨基或乙基丙基氨基,但不限于此。
如本文所用,芳基可以指其中从芳烃环去除一个氢的芳环,并且可以是单环或多环。3至12个原子的芳基可指包括形成环的3至12个原子的芳基,并且可以包括,例如,苯基、萘基、蒽基、菲基、联苯基、三联苯基等,但不限于此。
如本文所用,杂芳基可以指含有一个或多个N、O和S杂原子作为形成环的原子的芳环,并且可以是单环或多环。此外,3至12个原子的杂芳基可指包含形成环的3至12个原子的杂芳基,并且可以包括,例如,噻吩基、噻吩、呋喃基、吡咯基、吡唑基、咪唑基、噻唑基、噁唑基、异噻唑基、噁二唑基、***基、吡啶基、联吡啶基、嘧啶基、三嗪基、***基、吖啶基、哒嗪基、吡嗪基、喹啉基(qunolinyl)、喹唑啉、喹喔啉基、吩噁嗪基、酞嗪基、嘧啶基、吡啶并嘧啶基、吡啶并吡嗪基、吡嗪并吡嗪基、异喹啉、吲哚、咔唑、咪唑并哒嗪基、咪唑并吡啶基、咪唑并嘧啶基、吡唑并嘧啶基、咪唑并吡嗪基或吡唑并吡啶基、N-芳基咔唑、N-杂芳基咔唑、N-烷基咔唑、苯并噁唑、苯并咪唑、苯并噻唑、苯并噻唑、苯并咔唑、苯并噻吩、二苯并噻吩基、噻吩并噻吩、苯并呋喃基、菲咯啉、异噁唑基、噁二唑基、噻二唑基、苯并噻唑基、四唑基、吩噻嗪基、二苯并噻咯、二苯并呋喃基等,但不限于此。
如本文所用,“水合物”可以指包括通过非共价分子间力键合的化学计量或非化学计量量的水的本发明化合物或其盐。本发明的化学式1的化合物的水合物可包括通过非共价分子间力键合的化学计量或非化学计量量的水。水合物可含有至少1当量,优选1至5当量的水。这种水合物可以通过将本发明的化学式1的化合物、其异构体或其药学上可接受的盐从水或含水溶剂中结晶来制备。
如本文所用,“溶剂化物”可以指包括通过非共价分子间力键合的化学计量或非化学计量量的溶剂的本发明化合物或其盐。关于溶剂化物的优选溶剂包括挥发性的、无毒的和/或适合施用于人类的溶剂。
如本文所用,“异构体”可以指具有相同化学式或分子式但在结构或空间上不同的本发明的化合物或其盐。这种异构体包括所有结构异构体如互变异构体、具有不对称碳中心的R或S异构体、立体异构体如几何异构体(反式、顺式)和旋光异构体(对映异构体)。所有这些异构体及其混合物也落入本发明的范围内。
本发明提供
一种具有如下化学式1的化合物、其异构体、其溶剂化物、其水合物或其药学上可接受的盐。
[化学式1]
其中是呋喃、噻吩、苯或环戊烯,
R1是直链或支链C1-C3烷基,其中R1未被取代或被至少一个卤素取代,
环B是二氮杂双环庚烷、哌嗪、二氮杂环庚烷或二氮杂螺辛烷,其中环B未被取代或被至少一个直链或支链C1-C6烷基取代,
R2是吡啶基、噻唑基、苯基、咪唑基、吡嗪基、喹啉基、嘧啶基或吡啶酮基,其中R2未被取代或被至少一个R3取代,并且
R3是选自由如下组成的组的至少一个取代基:直链或支链C1-C6烷基、直链或支链C1-C6卤代烷基、直链或支链C1-C6烷氧基、卤素、C1-C3链烷磺酰氨基、被至少一个直链或支链C1-C3烷基取代的氨基和腈基。
在本发明的一个实施方案中,环B可以是3,6-二氮杂双环[3.1.1]庚烷、2,5-二氮杂双环[2.2.1]庚烷、哌嗪、二氮杂环庚烷或4,7-二氮杂螺[2,5]辛烷。
在环B的一个实施方案中,环B可以通过两个氮原子与另一相邻基团连接。
在本发明的另一实施方案中,当R2是吡啶基、噻唑基、苯基、吡嗪基、嘧啶基或吡啶酮基时,R2被至少一个R3取代,或当R2是咪唑基或喹啉基时,R2未被取代,并且
R3可以是选自由如下组成的组的至少一个取代基:直链或支链C1-C3烷基、直链或支链C1-C3卤代烷基、直链或支链C1-C3烷氧基、卤素、C1-C3链烷磺酰氨基、被至少一个直链或支链C1-C3烷基取代的氨基和腈基。
根据本发明的化学式1的化合物的实例包括下列的[表1]中列出的实施例化合物1至37,或其药学上可接受的盐、或游离碱(在表1中显示为药学上可接受的盐)、其异构体、其溶剂化物或其药学上可接受的盐。
本发明的化学式1的化合物可以以药学上可接受的盐的形式使用,并且由药学上可接受的游离酸形成的酸加成盐用作盐是有用的。所述酸加成盐得自无机酸,如盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸、亚硝酸、亚磷酸等;无毒有机酸,如脂肪族单羧酸盐和二羧酸盐、苯基取代的链烷酸酯、羟基链烷酸酯和链烷二酸酯、芳族酸以及脂族和芳族磺酸;或有机酸,如三氟乙酸、乙酸、苯甲酸、柠檬酸、乳酸、马来酸、葡萄糖酸、甲磺酸、4-甲苯磺酸、酒石酸和富马酸。这种药学上无毒盐的类型包括硫酸盐、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、甲基磷酸盐、焦磷酸盐氯化物、溴化物、碘化物、氟化物、醋酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、癸酸盐、庚酸盐、丙酸盐、丙二酸盐、丙二酸盐、草酸、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、丁炔-1,4-二酸盐、己烷-1,6-二酸盐、苯甲酸盐、氯苯甲酸盐、苯甲酸甲盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、对苯二甲酸盐、苯磺酸盐、甲苯磺酸盐、氯苯磺酸盐、二甲苯磺酸盐、苯乙酸盐、苯丙酸盐、苯丁酸盐、柠檬酸盐、乳酸盐、β-羟基丁酸盐、乙醇酸盐、马来酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐和扁桃酸盐等。
本发明的酸加成盐可以使用常规方法制备,例如,通过将化学式1的衍生物溶解于有机溶剂如甲醇、乙醇、丙酮、二氯甲烷或乙腈中,并向其中加入有机酸或无机酸以过滤和干燥所得的沉淀物,或者可以通过减压蒸馏溶剂和过量酸,然后干燥溶剂和酸以在有机溶剂下结晶所得产物来制备。
此外,可使用碱制备药学上可接受的金属盐。碱金属或碱土金属盐是例如通过将化合物溶解于过量的碱金属氢氧化物或碱土金属氢氧化物溶液中,过滤未溶解的化合物盐,蒸发滤液并干燥所得产物而得到的。在这种情况下,制备钠盐、钾盐或钙盐作为金属盐在药学上是适合的。此外,与此对应的盐是通过使碱金属或碱土金属盐与合适的银盐(例如硝酸银)反应而获得的。
此外,本发明不仅包括化学式1的化合物及其药学上可接受的盐,还包括可由其制备的溶剂化物、旋光异构体、水合物等。
本发明的另一方面可以提供一种制备化学式1的化合物的方法。
制备化学式1的化合物的方法可包括:
由化学式2的化合物制备化学式3的化合物;
由化学式3的化合物制备化学式4的化合物;
由化学式4的化合物制备化学式5的化合物;
由化学式5的化合物制备化学式6的化合物;
由化学式6的化合物制备化学式7的化合物;以及
由化学式7的化合物制备化学式1的化合物。
[化学式2]
[化学式3]
[化学式4]
[化学式5]
[化学式6]
[化学式7]
[化学式1]
R1、R2、和环B各自与本说明书中定义的那些相同,G是离去基团,PG是保护基团,并且环B'具有与环B相同的结构,但是是其中一个氮原子被保护基团保护的形式。
离去基团可以是一个官能团,例如卤素、磺酸酯或烷氧基,并且只要它是能够通过从化学式2到5的化合物中释放离去基团来制备目标化合物的官能团,则不受限制。保护基团可以是一个官能团,例如叔丁氧羰基、苄氧羰基、3,4-二氢-2H-吡喃和四氢-2H-吡喃,并且只要它是能够保护化学式4至6的仲胺的官能团,则不受限制。
由化学式2的化合物制备化学式3的化合物可以是化学式2的化合物与反应的步骤。N,N-二异丙基乙胺(DIPEA)可进一步加入反应中,反应温度可为约40至100℃,反应时间可为约10至14小时,并且只要反应顺利进行,该反应可以不限于上述条件。
由化学式3的化合物制备化学式4的化合物可以是保护化学式3的化合物的吡唑基的仲胺的步骤。保护基团可以不受限制地使用,只要它是能够保护仲胺的官能团,并且可以是例如四氢-2H-吡喃(THP)。
由化学式4的化合物制备化学式5的化合物可以是化学式4的化合物与反应的步骤。反应可在溶剂如二氧六环中进行,可以进一步向其中加入Pd(dppf)Cl2.CH2Cl2,反应温度可为约80至100℃,并且反应时间可为约2至4小时。只要反应顺利进行,该反应可以不限于上述条件。
由化学式5的化合物制备化学式6的化合物可以是将环B'连接至化学式5的化合物的步骤。环B'是本说明书中定义的环B的一个氮原子被保护基保护的形式,保护基团可以不受限制地使用,只要它是能够保护仲胺的保护基团,并且可以是例如叔丁氧羰基(BOC)。
本步骤的一个更具体的示例性实施方案可以是使环B'的未保护仲胺与化学式5的化合物反应以将环B'连接到化学式5的化合物的步骤。该步骤可以在溶剂如DMSO中进行,可以进一步向其中加入K2CO3,反应温度可为约100至140℃,并且反应时间可为约10至14小时。只要反应顺利进行,该反应可以不限于上述条件。
由化学式6的化合物制备化学式7的化合物可以是脱保护连接到化学式6的化合物上的保护基团的步骤。该步骤可以通过将化学式6的化合物溶解在HCl溶液中来脱保护保护基团。
由化学式7化合物制备化学式1的化合物可以是化学式7化合物与CHO-R2反应的步骤。该反应可以在溶剂例如N,N-二甲基乙酰胺(DMA)中进行,并且可以通过醛与仲胺的还原烷基化反应形成化学式1的化合物。将醛和仲胺还原烷基化的任何还原剂可以不受限制地使用,并且可以使用例如NaBH(OAc)3。反应温度可为约40至80℃,并且反应时间可为约3至8小时。只要反应顺利进行,该反应可以不限于上述条件。
本发明的另一方面提供了一种药物组合物,其包含化学式1的化合物、其旋光异构体或其药学上可接受的盐作为用于预防或治疗癌症的活性成分。
所述化合物可以表现出对选自由如下组成的组的一种或多种蛋白激酶的抑制活性:ABL1(H396P)-非磷酸化、ABL1(H396P)-磷酸化、ABL1(M351T)-磷酸化、ABL1(Q252H)-磷酸化、ABL1(T315I)-非磷酸化、ABL1(T315I)-磷酸化、ABL1(Y253F)-磷酸化、ABL1-磷酸化、AMPK-alpha1、AURKA、AURKC、AXL、BLK、BTK、CSNK2A1、CSNK2A2、DAPK3、DDR1、DDR2、DLK、EGFR(L747-E749del、A750P)、EGFR(L858R,T790M)、EGFR(T790M)、EPHB6、FGFR1、FGR、FLT3、FLT3(D835H)、FLT3(D835V)、FLT3(D835Y)、FLT3(ITD)、FLT3(ITD,D835V)、FLT3(ITD,F691L)、FLT3(K663Q)、FLT3(N841I)、FLT3(R834Q)、FLT3-自抑制、FRK、GCN2(Kin.Dom.2,S808G)、HCK、ICK、ITK、JAK1(JH1结构域-催化)、JAK1(JH2结构域-假激酶)、JAK2(JH1结构域-催化)、JAK3(JH1结构域-催化)、KIT(A829P)、KIT(D816V)、KIT(V559D)、LCK、MAP3K2、MEK2、MEK3、MEK5、MERTK、MST1、PDGFRB、PLK4、RET、RET(M918T)、RET(V804L)、RET(V804M)、RIOK3、SNARK、SRC、SYK、TRKA、TRKB、TRKC、TYK2(JH1结构域-催化)、YES和YSK4。
此外,所述化合物可表现出RET酶抑制活性。
所述癌症是选自由如下组成的组的一种或多种:假粘液瘤、肝内胆管癌、肝母细胞瘤、肝癌、甲状腺癌、甲状腺髓样癌、结肠癌、睾丸癌、骨髓增生异常综合征、胶质母细胞瘤、口腔癌、唇癌、蕈样真菌病、急性髓系白血病、急性淋巴细胞白血病、基底细胞癌、卵巢上皮癌、卵巢生殖细胞癌、男性乳腺癌、脑癌、垂体腺瘤、多发性骨髓瘤、胆囊癌、胆管癌、结直肠癌、慢性粒细胞白血病、慢性淋巴细胞白血病、视网膜母细胞瘤、脉络膜黑色素瘤、乏特氏壶腹癌、膀胱癌、腹膜癌、甲状旁腺癌、肾上腺癌、鼻窦癌、非小细胞肺癌、舌癌、星形细胞瘤、小细胞肺癌、儿童脑癌、小儿淋巴瘤、小儿白血病、小肠癌、脑膜瘤、食道癌、神经胶质瘤、肾盂癌、肾癌、心脏癌、十二指肠癌、恶性软组织癌、恶性骨癌、恶性淋巴瘤、恶性间皮瘤、恶性黑色素瘤、眼癌、外阴癌、输尿管癌、尿路上皮癌、原发部位不明的癌症、胃淋巴瘤、胃癌、胃类癌、胃肠道间质瘤、肾母细胞瘤、乳腺癌、肉瘤、***癌、咽癌、妊娠滋养细胞疾病、***、子宫内膜癌、子宫肉瘤、***癌、转移性骨癌、转移性脑癌、纵隔癌、直肠癌、直肠类癌、***癌、脊髓癌、听神经瘤、胰腺癌、唾液腺癌、卡波西肉瘤、佩吉特病、扁桃体癌、鳞状细胞癌、肺腺癌、肺癌、肺鳞状细胞癌、皮肤癌、***癌、横纹肌肉瘤、喉癌、胸膜癌、血癌和胸腺癌。
此外,所述癌症可以是表达RET融合基因的癌症。
所述RET融合基因是指编码RET受体酪氨酸激酶的RET基因与一个或多个其他基因连接的形式,包括RET融合基因在内的RET基因以外的基因可以是驱动蛋白家族成员5B(KIF5B),含卷曲螺旋结构域的蛋白质6(CCDC6)、核受体共激活因子4(NCOA4)或含三联基序33(TRIM33),但不限于此。
根据本发明的化学式1的化合物表现出优异的ret原癌基因(ret)酶抑制能力(参见实验例1),并且对表达RET融合基因的甲状腺髓样癌细胞和肺癌细胞的增殖有很好的抑制作用(参见实验例2),因此,该衍生物可有效地用于治疗癌症,例如甲状腺髓样癌或肺癌,特别是可有效地用于治疗表达RET融合基因的癌症。
临床施用时,化学式1的化合物或其药学上可接受的盐可以以各种口服和肠胃外剂型施用,更优选肠胃外剂型。当制备化学式1的化合物时,可以使用常用的稀释剂或赋形剂例如填充剂、增量剂、粘合剂、润湿剂、崩解剂、表面活性剂来制备组合物。用于口服施用的固体制剂包括片剂、丸剂、粉剂、颗粒剂、胶囊剂等,并且这些固体制剂通过将至少一种赋形剂例如淀粉、碳酸钙、蔗糖或乳糖、明胶等与一种或多种化合物混合而制备。此外,除了简单的赋形剂外,还使用润滑剂,例如硬脂酸镁和滑石粉。用于口服施用的液体制剂包括混悬剂、内服液体、乳剂、糖浆剂等,并且这些液体制剂除了简单的常用稀释剂(如水和液体石蜡)之外还可以包括各种类型的赋形剂,例如,润湿剂、甜味剂、调味剂、防腐剂等。肠胃外施用制剂的实例包括无菌水溶液、非水溶剂、悬浮液和乳剂。作为非水溶剂和悬浮溶剂,可以使用丙二醇、聚乙二醇、植物油(例如橄榄油)和可注射酯(例如油酸乙酯)等。
一种药物组合物,其包括化学式1的化合物或其药学上可接受的盐作为活性成分,可以肠胃外施用,并且肠胃外施用采用注射方法进行,例如皮下注射、静脉注射、肌肉注射或者胸腔内注射。
就此而言,为了将药物组合物配制成肠胃外施用的制剂,所述药物组合物可以通过将化学式1的化合物或其药学上可接受的盐与稳定剂或缓冲剂在水中混合制成溶液或悬浮液,并且溶液或悬浮液可以制备成安瓿或小瓶单位剂型来施用。所述组合物可以被灭菌和/或包含佐剂,例如防腐剂、稳定剂、润湿剂或乳化促进剂、用于调节渗透压的盐和/或缓冲剂,以及其他治疗有效的材料,并且该组合物可以使用经典的方法配制,例如混合、造粒或包衣法。
用于口服施用的剂型的实例包括片剂、丸剂、硬/软胶囊、溶液、悬浮剂、乳剂、糖浆剂、颗粒剂、酏剂、锭剂等,并且,除了活性成分,这些制剂包含稀释剂(例如,乳糖、右旋糖、蔗糖、甘露醇、山梨糖醇、纤维素和/或甘氨酸)和润滑剂(例如,二氧化硅、滑石、硬脂酸及其镁盐或钙盐,和/或聚乙二醇)。
所述片剂可包含粘合剂,例如硅酸镁铝、淀粉糊、明胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮,并且在某些情况下可以包含崩解剂(淀粉、琼脂、藻酸或其钠盐)或沸腾混合物和/或吸收剂、着色剂、调味剂和甜味剂。
一种药物组合物,其包含化学式1的化合物、其光学异构体或其药学上可接受的盐作为预防或治疗癌症的活性成分,可作为单独的治疗剂施用,或可以与正在使用的其他抗癌剂联合施用。
本发明的另一方面提供了一种预防或治疗癌症的方法,所述方法包括将包含化学式1的化合物、其异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分的药物组合物给予有需要的受试者。
本发明的另一个目的是提供化学式1的化合物或其异构体、其溶剂化物、其水合物或其药学上可接受的盐在制备用于预防或治疗癌症的药物中的用途。
在下文中,将参考实施例和实验例详细描述本发明。
然而,以下实施例和实验例仅用于举例说明本发明,本发明的内容不受以下实施例和实验例的限制。
<分析和纯化条件>
本发明的实施例中合成的化合物使用以下方法纯化或进行结构分析。
1.用于纯化的中压液相色谱(MPLC)
作为中压液相色谱,使用来自TELEDYNE ISCO的CombiFlash Rf+UV。
2.用于分析的LC-MS(ACQUITY UPLC H-级核心***)
配备有由Waters制造的QDA检测器的装置被用于由Waters制造的UPLC***(ACQUITY UPLC PDA检测器)。使用的色谱柱为来自Waters的ACQUITY UPLC BEHC18(1.7μm,2.1x50mm),并且柱温为30℃。
以含0.1%甲酸的水为流动相A,以含0.1%甲酸的乙腈为流动相B。
梯度条件(10-100%B持续3分钟,并且流速=0.6ml/min)
3.用于纯化的Prep-150 LC***(制备型液相色谱UV光谱法)
由Waters制造的装置被用于由Waters制造的Prep 150 LC***(2545四元梯度模块,2998光电二极管阵列检测器,馏分收集器III)。所用色谱柱为XTERRA Prep RP18 OBDTM(10μm,30x300mm),并且柱温为室温。
梯度条件(3-100%B持续120分钟,并且移动速度=40ml/min)
4.用于分离手性化合物的SFC条件
使用由Waters制造的80Q Preparative SFC***。所用的色谱柱为DAICEL的CHIRALPAK AS(10μm,250x30mm I.D.),并且柱温为室温。使用作为流动相的CO2和作为辅助溶剂的加入0.1%氨水的甲醇并使其流动130分钟。
5.NMR分析
NMR分析使用Bruker制造的AVANCE III 400或AVANCE III 400 HD进行,数据以百万分之几(ppm)(δ)表示。
使用市售试剂而无需进一步纯化。本发明中,室温是指20~25℃左右的温度。使用旋转蒸发器进行减压浓缩或通过蒸馏除去溶剂。
<实施例1>2-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)呋喃并[3,2-d]嘧啶-4-胺的制备
标题化合物通过以下反应方案1表示的方法制备。
[反应方案1]
步骤1:2-氯-N-(5-甲基-1H-吡唑-3-基)呋喃并[3,2-d]嘧啶-4-胺的制备
将2,4-二氯呋喃并[3,2-d]嘧啶(50g,264.55mmol,1eq)、5-甲基-1H-吡唑-3-胺(26.98g,277.78mmol,1.05eq)和DIPEA(102.57g,793.65mmol,138.24mL,3eq)溶解在二甲基亚砜(250mL)中后,将所得溶液在60℃下搅拌12小时。将水缓慢加入到反应混合物中,并过滤所得固体。用水洗涤固体,然后回收以获得目标化合物2-氯-N-(5-甲基-1H-吡唑-3-基)呋喃并[3,2-d]嘧啶-4-胺(62g)。
MS(m/z):250.1[M+1]+
步骤2:2-氯-N-(5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)呋喃并[3,2-d]嘧啶-4-胺的制备
将2-氯-N-(5-甲基-1H-吡唑-3-基)呋喃并[3,2-d]嘧啶-4-胺(60g,240.33mmol,1eq)和TsOH(8.28g,48.07mmol,0.2eq)溶解在THF(600mL)中后,向其中加入3,4-二氢-2H-吡喃(60.72g,721.86mmol,66mL,3eq),并在60℃下搅拌所得混合物15小时。将NaHCO3水溶液(500mL)、EtOAc(500mL)和水(1L)加入到反应混合物,回收有机层后用盐水(400mL)清洗有机层,并使用Na2SO4干燥。过滤有机层,在真空浓缩器中浓缩,然后使用中压色谱法纯化(己烷/EtOAc=4/1至2/1)。纯化后,将所得产物减压浓缩以获得目标化合物2-氯-N-(5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)呋喃并[3,2-d]嘧啶-4-胺(60.66g,181.74mmol,产率75.62%)。
MS(m/z):334.1[M+1]+
1H NMR(400MHz,CDCl3)δ=7.77(d,J=2.0Hz,1H),7.69(s,1H),6.81(d,J=2.2Hz,1H),6.76(s,1H),5.20(dd,J=2.8,10.4Hz,1H),4.12-4.02(m,1H),3.681-3.618(m,1H),2.40-2.32(m,4H),2.14-2.04(m,1H),1.89(br dd,J=2.8,13.6Hz,1H),1.77-1.63(m,2H),1.62-1.55(m,1H)
步骤3:2-(6-氟吡啶-3-基)-N-(5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)呋喃并[3,2-d]嘧啶-4-胺的制备
将2-氯-N-(5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)呋喃并[3,2-d]嘧啶-4-胺(20g,59.92mmol,1eq)、2-氟-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶(16g,71.73mmol,1.20eq)和K2CO3(20.70g,149.80mmol,2.5eq)溶于二氧六环(400mL)和水(20mL)中后,向其中加入Pd(dppf)Cl2.CH2Cl2(4.89g,5.99mmol,0.1eq)。在90℃的氮气下搅拌反应混合物3小时。过滤反应混合物后,浓缩滤液,并向其中加入水和EtOAc。收集有机层并用盐水(1.0L)冲洗,然后使用Na2SO4干燥。过滤有机层,在真空浓缩器中浓缩,然后使用中压色谱法纯化(己烷/EtOAc=5/1至1/1)。纯化后,在减压下浓缩所得产物以获得目标化合物2-(6-氟吡啶-3-基)-N-(5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)呋喃并[3,2-d]嘧啶-4-胺(22g,55.78mmol,产率93.09%)。
MS(m/z):395.4[M+1]+
1H NMR(400MHz,DMSO-d6)δ=10.49(s,1H),9.10(d,J=2.4Hz,1H),8.78(dt,J=2.4,8.4Hz,1H),8.34(d,J=2.0Hz,1H),7.30(dd,J=2.8,8.4Hz,1H),7.11(d,J=2.4Hz,1H),6.64(s,1H),5.35(dd,J=2.4,9.6Hz,1H),3.91(br d,J=10.8Hz,1H),3.70-3.58(m,1H),2.37(s,3H),2.34-2.23(m,1H),2.05-1.95(m,1H),1.92-1.82(m,1H),1.75-1.62(m,1H),1.58-1.45(m,2H)
步骤4:3-(5-(4-((5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)氨基)呋喃并[3,2-d]嘧啶-2-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯的制备
将2-(6-氟吡啶-3-基)-N-(5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)呋喃并[3,2-d]嘧啶-4-胺(1g,2.54mmol,1eq)、3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯(700mg,3.53mmol,1.39eq)和K2CO3(2g,14.47mmol,5.71eq)溶解在DMSO(10mL)中后,所得溶液在120℃下搅拌12小时。向反应混合物中加入水,并过滤所得固体。步骤4重复21次以获得目标化合物3-(5-(4-((5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)氨基)呋喃并[3,2-d]嘧啶-2-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯(22.5g,37.82mmol,产率71.02%)。
MS(m/z):573.1[M+1]+
1H NMR(400MHz,DMSO-d6)δ=10.29(s,1H),9.08(br s,1H),8.43(br d,J=8.4Hz,1H),8.27(br s,1H),7.04(s,1H),6.74(br d,J=8.8Hz,1H),6.68(s,1H),5.35(br d,J=9.2Hz,1H),4.21(br d,J=5.2Hz,2H),4.05(br s,2H),3.92(br d,J=10.4Hz,1H),3.66(br d,J=7.2Hz,1H),3.48(br d,J=11.2Hz,2H),2.55(br d,J=7.2Hz,1H),2.38(s,3H),2.33-2.24(m,1H),2.05-1.96(m,1H),1.87(br d,J=12.0Hz,1H),1.76-1.61(m,1H),1.58-1.43(m,3H),1.26(s,9H)
步骤5:2-(6-(3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-N-(5-甲基1H-吡唑-3-基)呋喃并[3,2-d]嘧啶-4-胺二盐酸盐的制备
将3-(5-(4-((5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)氨基)呋喃并[3,2-d]嘧啶-2-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯(22g,36.98mmol,1eq)溶解于4M HCl/MeOH(250ml)中后,在室温下搅拌所得溶液1小时。在减压下浓缩反应混合物后,向其中加入丙酮(1L)。将所得产物过滤、回收,然后干燥以获得目标化合物2-(6-(3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-N-(5-甲基1H-吡唑-3-基)呋喃并[3,2-d]嘧啶-4-胺二盐酸盐(22.4g)。
MS(m/z):389.1[M+1]+
1H NMR(400MHz,DMSO-d6)δ=11.56(br s,1H),10.61(br s,1H),9.23(br s,1H),9.03(s,1H),8.76(dd,J=2.0,9.2Hz,1H),8.50(d,J=2.0Hz,1H),7.26(br d,J=9.2Hz,1H),7.20(d,J=2.0Hz,1H),6.57(s,1H),4.56(br s,2H),4.19(br s,4H),3.01-2.95(m,1H),2.39(s,3H),1.94(br dd,J=5.6,10.0Hz,1H)
步骤6:2-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)呋喃并[3,2-d]嘧啶-4-胺的制备
将2-(6-(3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-N-(5-甲基1H-吡唑-3-基)呋喃并[3,2-d]嘧啶-4-胺二盐酸盐(22.4g,48.55mmol)、6-甲氧基吡啶-3-甲醛(9.99g,72.83mmol,1.5eq)和TEA(39.31g,388.43mmol,54.06mL,8eq)溶解在DMA(250mL)中后,向其中加入NaBH(OAc)3(30.87g,145.66mmol,3eq),并在55℃下搅拌所得混合物5小时。向反应混合物中加入水(1L)和EtOAc(1.6L),并回收有机层。用盐水(800ml)冲洗有机层,然后用Na2SO4干燥。过滤有机层,通过真空浓缩器浓缩,然后使用RP-HPLC纯化,以获得目标化合物2-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)呋喃并[3,2-d]嘧啶-4-胺(11.7g,22.96mmol,产率47.29%)。
MS(m/z):510.4[M+1]+
1H NMR(400MHz,DMSO-d6)δ=12.11(br s,1H),10.14(br s,1H),9.13(d,J=2.0Hz,1H),8.46(dd,J=2.0,8.8Hz,1H),8.26(s,1H),8.07(d,J=2.0Hz,1H),7.67(dd,J=2.4,8.8Hz,1H),7.05(s,1H),6.76(dd,J=6.0,8.8Hz,2H),6.61(br s,1H),3.82(s,3H),3.75(br d,J=12.0Hz,2H),3.66(br d,J=5.6Hz,2H),3.61-3.42(m,4H),2.54-2.51(m,1H),2.31(s,3H),1.56(br d,J=8.4Hz,1H)
所有实施例化合物(实施例1-37的化合物)的制备方法与实施例1类似,将各实施例化合物的化合物名称、化学结构式、NMR和LC-MS分析结果汇总在下表1中。
[表1]
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<实验例1>RET酶抑制能力的评估
为评估根据本发明化合物的RET酶抑制活性,进行如下实验。
使实施例化合物与纯化的人RET(658-末端,SIGNALCHEM)酶反应以通过以下方法评估酶抑制能力。作为反应缓冲液,使用由40mM Tris-HCl pH 7.4、20mM MgCl2、0.5mg/mLBSA和50μM DTT组成的组合物,所有实验材料都在反应缓冲液中反应。在实验过程中,将人RET(658末端,0.8ng)酶与纯化ATP(10μM)和特定底物溶液在25℃下反应1小时后,使用体外ADP-GloTM激酶测定(Promega)确认酶活性。通过使酶活反应溶液、ADP-Glo反应溶液和酶活性检测溶液以2:2:1的比例反应来测量发光。基于未处理化合物的溶剂对照组的酶活性荧光,计算每种化合物的处理浓度对酶活性的抑制程度,在这种情况下,将抑制酶活性50%的每种化合物的浓度确定为IC50(nM)值。通过3个数据集测定每种化合物的IC50(nM),并使用Prism(7.01版,GraphPad)软件获得。结果如下表2所示。
<实验例2>对表达RET融合基因的甲状腺髓样癌和肺癌细胞增殖的抑制活性的评估
为评估根据本发明的化合物对表达RET融合基因的甲状腺髓样癌细胞增殖和肺癌细胞增殖的抑制活性,进行如下实验。
在表达RET融合基因的肺癌细胞系中,在RPMI:F12(1:1)(Invitrogen)中添加10%的FBS(HyClone)后培养LC-2/ad细胞,并且补充了10%FBS的F-12(Invitrogen)用于TT细胞。补充10%FBS和5ng/ml IL-3(R&D***)的RPMI-1640用于Ba/F3细胞。将1μg/ml嘌呤霉素(Invitrogen)加入相同的培养基中培养转导的Ba/F3细胞。在用该化合物处理细胞前24小时,将3000至5000个细胞等份加入白色透明底部96孔板(Corning)的每个孔中。该化合物在二甲基亚砜中稀释(3倍稀释,共12个浓度),并注入0.5μl该化合物,使最终浓度为0.3nM至50μM。对于活细胞的测量,在化合物处理后72小时,使用CelltiteGlo发光细胞活性剂(Promega)将细胞在室温下储存10分钟,然后使用阅读器(SynergyNeo,Biotek)测量发光强度。每个实验重复三次。通过与对照组相比的细胞生长率(%)计算结果值。使用GraphPadPrism 5.0版程序绘制图形,并计算GI50(nM)值。结果如下表2所示。
[表2]
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在酶的测定栏中,RET(WT)为非突变形式,RET(V804M)为突变形式,其中RET 804位的V氨基酸被M取代,并且CCDC6-RET为RET(WT)基因与CCDC6基因融合的形式。
在细胞测定栏中,LC-2/ad(含CCDC6-RET基因)是肺癌细胞系,TT细胞系(不含RET(WT)基因)是甲状腺癌细胞系,Ba/F3 CCDC6-RET(WT)、Ba/F3 KIF5B-RET(WT)和Ba/F3KIF5B-RET(V804M)是将疾病相关性状(CCDC6-RET、KIF5B-RET和KIF5B-RET(V804M))导入Ba/F3细胞的细胞,以及Ba/F3(原代)是一种未转导的细胞。
如表2所示,通过测量每个实施例化合物对LC-2/ad、Ba/F3原代、Ba/F3CCDC6-RET、Ba/F3 KIF5B-RET、Ba/F3 KIF5B-RET(V804M)和TT细胞的细胞生长抑制活性,可以证实,本发明的实施例化合物对表达RET融合基因的Ba/F3细胞系和甲状腺髓样癌或肺癌细胞系的增殖有极好的抑制作用。
因此,如在实验中所证实,根据本发明的化合物可抑制癌细胞的增殖,并且因此可有效地用作预防和治疗癌症疾病(例如,甲状腺髓样癌或肺癌)的药物组合物。
<实验例3>本发明化合物对各种激酶的抑制活性的评估
进行以下实验以评估根据本发明的化合物对更多酶的抑制活性。具体地,对于在本发明实施例化合物中选择的实施例1和3,通过委托DiscoveryX测量酶(激酶)选择性,并使用ScanMAXTM激酶分析面板进行实验。在这种情况下,用酶处理的药物在DMSO中的浓度设置为1μM,校正后的百分比(%对照组)的测定方法与下公式1相同,结果见下表3。
[公式1]
(实施例化合物-阳性对照)/(阴性对照-阳性对照)X100
此处,阳性对照是指化合物显示0%的校正百分比,阴性对照在DMSO中显示100%校正百分比。此外,当校正百分比<35%(即小于35%)时,本发明的酶选择性被确定为对相应酶具有活性。
[表3]
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从表3中可以确定,可以看出,根据本发明的化合物对ABL1(H396P)-非磷酸化、ABL1(H396P)-磷酸化、ABL1(M351T)-磷酸化、ABL1(Q252H)-磷酸化、ABL1(T315I)-非磷酸化、ABL1(T315I)-磷酸化、ABL1(Y253F)-磷酸化、ABL1-磷酸化、AMPK-alpha1、AURKA、AURKC、AXL、BLK、BTK、CSNK2A1、CSNK2A2、DAPK3、DDR1、DDR2、DLK、EGFR(L747-E749del、A750P)、EGFR(L858R,T790M)、EGFR(T790M)、EPHB6、FGFR1、FGR、FLT3、FLT3(D835H)、FLT3(D835V)、FLT3(D835Y)、FLT3(ITD)、FLT3(ITD,D835V)、FLT3(ITD,F691L)、FLT3(K663Q)、FLT3(N841I)、FLT3(R834Q)、FLT3-自抑制、FRK、GCN2(Kin.Dom.2,S808G)、HCK、ICK、ITK、JAK1(JH1结构域-催化)、JAK1(JH2结构域-假激酶)、JAK2(JH1结构域-催化)、JAK3(JH1结构域-催化)、KIT(A829P)、KIT(D816V)、KIT(V559D)、LCK、MAP3K2、MEK2、MEK3、MEK5、MERTK、MST1、PDGFRB、PLK4、RET、RET(M918T)、RET(V804L)、RET(V804M)、RIOK3、SNARK、SRC、SYK、TRKA、TRKB、TRKC、TYK2(JH1结构域-催化)、YES或YSK4激酶都具有小于35%的校正百分比的值。这表明根据本发明的化合物表现出对上述酶的抑制活性,并且当用于与上述酶相关的疾病时具有有用的效果。因此,根据本发明的衍生化合物可用作治疗或预防与上述酶相关的疾病的组合物。
Claims (16)
1.一种具有如下化学式I的化合物、其立体异构体或其药学上可接受的盐:
[化学式1]
其中是呋喃、噻吩、苯或环戊烯,
R1是直链或支链C1-C3烷基,
环B是3,6-二氮杂双环[3.1.1]庚烷、2,5-二氮杂双环[2.2.1]庚烷、哌嗪、二氮杂环庚烷或4,7-二氮杂螺[2,5]辛烷,其中环B未被取代或被至少一个直链或支链C1-C6烷基取代,其中环B通过两个氮原子与另一个相邻的基团相连,
R2是吡啶基、噻唑基、苯基、咪唑基、吡嗪基、喹啉基、嘧啶基或吡啶酮基,其中R2未被取代或被至少一个R3取代,并且
R3是选自由如下组成的组的至少一个取代基:直链或支链C1-C6烷基、直链或支链C1-C6卤代烷基、直链或支链C1-C6烷氧基、卤素、C1-C3链烷磺酰氨基、被至少一个直链或支链C1-C3烷基取代的氨基和腈基。
2.如权利要求1所述的化合物、其立体异构体或其药学上可接受的盐,其中R2是吡啶基、噻唑基、苯基、吡嗪基、嘧啶基或吡啶酮基,R2被至少一个R3取代,或当R2是咪唑基或喹啉基时,R2未被取代,并且
R3是选自由如下组成的组的至少一个取代基:直链或支链C1-C3烷基、直链或支链C1-C3卤代烷基、直链或支链C1-C3烷氧基、卤素、C1-C3链烷磺酰氨基、被至少一个直链或支链C1-C3烷基取代的氨基和腈基。
3.如权利要求1所述的化合物、其立体异构体或其药学上可接受的盐,其中化学式1的化合物是选自下列化合物中的任一种:
<1>2-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)呋喃并[3,2-d]嘧啶-4-胺;<2>2-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)噻吩并[3,2-d]嘧啶-4-胺;<3>2-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)喹唑啉-4-胺;<5>N-(5-甲基-1H-吡唑-3-基)-2-(6-(6-((5-甲基噻唑-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)喹唑啉-4-胺;<6>2-(6-(3-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)喹唑啉-4-胺;<7>2-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)-6,7-二氢-5H-环戊烯并[d]嘧啶-4-胺;<8>N-(5-甲基-1H-吡唑-3-基)-2-(6-(6-((6-(三氟甲基)吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)喹唑啉-4-胺;<9>5-((3-(5-(4-((5-甲基-1H-吡唑-3-基)氨基)喹唑啉-2-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)吡啶甲腈;<10>N-(5-甲基-1H-吡唑-3-基)-2-(6-(6-((6-甲基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)喹唑啉-4-胺;<11>2-(6-(6-(3,5-二氟-4-异丙氧基苄基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)喹唑啉-4-胺;<12>2-甲氧基-5-((3-(5-(4-((5-甲基-1H-吡唑-3-基)氨基)喹唑啉-2-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)苄腈;<13>2-(6-(6-((1H-咪唑-5-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)喹唑啉-4-胺;<14>2-(6-(6-(4-甲氧基苄基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)喹唑啉-4-胺;<15>2-(6-(6-((6-异丙氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)喹唑啉-4-胺;<16>2-(6-(6-((5-氯-6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)喹唑啉-4-胺;<17>2-(6-(6-((5-甲氧基吡嗪-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)喹唑啉-4-胺;<18>N-(5-甲基-1H-吡唑-3-基)-2-(6-(6-(喹啉-6-基甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)喹唑啉-4-胺;<19>N-(5-甲基-1H-吡唑-3-基)-2-(6-(6-((4-甲基噻唑-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)喹唑啉-4-胺;<20>2-(6-(6-((6-(二甲基氨基)吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)喹唑啉-4-胺;<21>N-(4-((3-(5-(4-((5-甲基-1H-吡唑-3-基)氨基)喹唑啉-2-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)苯基)甲磺酰胺;<22>2-(6-(6-(4-氟苄基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)喹唑啉-4-胺;<23>2-(6-(6-((6-氟吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)喹唑啉-4-胺;<24>2-(6-(6-((6-乙氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)喹唑啉-4-胺;<25>N-(5-甲基-1H-吡唑-3-基)-2-(6-(6-((2-甲基嘧啶-5-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)喹唑啉-4-胺;<26>N-(5-甲基-1H-吡唑-3-基)-2-(6-(6-((5-甲基吡嗪-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)喹唑啉-4-胺;<27>1-甲基-4-((3-(5-(4-((5-甲基-1H-吡唑-3-基)氨基)喹唑啉-2-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)吡啶-2(1H)-酮;<28>2-(6-((2S,5R)-4-((6-甲氧基吡啶-3-基)甲基)-2,5-二甲基哌嗪-1-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)喹唑啉-4-胺;<29>2-(6-(4-((6-甲氧基吡啶-3-基)甲基)-3,3-二甲基哌嗪-1-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)喹唑啉-4-胺;<30>2-(6-(4-((6-甲氧基吡啶-3-基)甲基)-1,4-二氮杂庚烷-1-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)喹唑啉-4-胺;<31>2-(6-((1S,4S)-5-((6-甲氧基吡啶-3-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)喹唑啉-4-胺;<32>2-(6-((2R,5S)-4-((6-甲氧基吡啶-3-基)甲基)-2,5-二甲基哌嗪-1-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)喹唑啉-4-胺;<33>(S)-2-(6-(4-((6-甲氧基吡啶-3-基)甲基)-3-甲基哌嗪-1-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)喹唑啉-4-胺;<34>2-(6-((1R,4R)-5-((6-甲氧基吡啶-3-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)喹唑啉-4-胺;<35>2-(6-((3R,5S)-4-((6-甲氧基吡啶-3-基)甲基)-3,5-二甲基哌嗪-1-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)喹唑啉-4-胺;<36>(R)-2-(6-(4-((6-甲氧基吡啶-3-基)甲基)-3-甲基哌嗪-1-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)喹唑啉-4-胺;和<37>2-(6-(4-((6-甲氧基吡啶-3-基)甲基)-4,7-二氮杂螺[2.5]辛烷-7-基)吡啶-3-基)-N-(5-甲基-1H-吡唑-3-基)喹唑啉-4-胺。
4.一种制备化学式1的化合物的方法,所述方法包括:由化学式2化合物制备化学式3化合物;
由化学式3的化合物制备化学式4的化合物;
由化学式4的化合物制备化学式5的化合物;
由化学式5的化合物制备化学式6的化合物;
由化学式6的化合物制备化学式7的化合物;以及
由化学式7的化合物制备化学式1的化合物:
[化学式2]
[化学式3]
[化学式4]
[化学式5]
[化学式6]
[化学式7]
[化学式1]
其中,R1、R2、和环B与权利要求1中定义相同,G是离去基团,
PG是保护基团,并且
环B'具有与环B相同的结构,但是是其中一个氮原子被保护基团保护的形式。
5.一种药物组合物,其包含权利要求1的化学式1的化合物、其立体异构体或其药学上可接受的盐作为用于预防或治疗癌症的活性成分。
6.如权利要求5所述的药物组合物,其中所述化合物表现出对选自由如下组成的组的一种或多种蛋白激酶的抑制活性:ABL1-H396P-非磷酸化、ABL1-H396P-磷酸化、ABL1-M351T-磷酸化、ABL1-Q252H-磷酸化、ABL1-T315I-非磷酸化、ABL1-T315I-磷酸化、ABL1-Y253F-磷酸化、ABL1-磷酸化、AMPK-alpha1、AURKA、AURKC、AXL、BLK、BTK、CSNK2A1、CSNK2A2、DAPK3、DDR1、DDR2、DLK、EGFR-L747-E749del-A750P、EGFR-L858R-T790M、EGFR-T790M、EPHB6、FGFR1、FGR、FLT3、FLT3-D835H、FLT3-D835V、FLT3-D835Y、FLT3-ITD、FLT3-ITD-D835V、FLT3-ITD-F691L、FLT3-K663Q、FLT3-N841I、FLT3-R834Q、FLT3-自抑制、FRK、GCN2-Kin.Dom.2-S808G、HCK、ICK、ITK、JAK1-JH1结构域-催化、JAK1-JH2结构域-假激酶、JAK2-JH1结构域-催化、JAK3-JH1结构域-催化、KIT-A829P、KIT-D816V、KIT-V559D、LCK、MAP3K2、MEK2、MEK3、MEK5、MERTK、MST1、PDGFRB、PLK4、RET、RET-M918T、RET-V804L、RET-V804M、RIOK3、SNARK、SRC、SYK、TRKA、TRKB、TRKC、TYK2-JH1结构域-催化、YES和YSK4。
7.如权利要求5所述的药物组合物,其中,所述化合物表现出RET酶抑制活性。
8.如权利要求5所述的药物组合物,其中,所述癌症是选自由如下组成的组的一种或多种:假粘液瘤、肝母细胞瘤、肝癌、甲状腺癌、甲状腺髓样癌、结肠癌、睾丸癌、骨髓增生异常综合征、胶质母细胞瘤、口腔癌、唇癌、蕈样真菌病、急性髓系白血病、急性淋巴细胞白血病、基底细胞癌、卵巢上皮癌、卵巢生殖细胞癌、脑癌、垂体腺瘤、多发性骨髓瘤、胆囊癌、胆管癌、结直肠癌、慢性粒细胞白血病、慢性淋巴细胞白血病、视网膜母细胞瘤、脉络膜黑色素瘤、乏特氏壶腹癌、膀胱癌、腹膜癌、甲状旁腺癌、肾上腺癌、鼻窦癌、舌癌、星形细胞瘤、小儿淋巴瘤、小儿白血病、小肠癌、脑膜瘤、食道癌、神经胶质瘤、肾盂癌、肾癌、心脏癌、十二指肠癌、恶性软组织癌、恶性骨癌、恶性淋巴瘤、恶性间皮瘤、恶性黑色素瘤、眼癌、外阴癌、输尿管癌、尿路上皮癌、原发部位不明的癌症、胃淋巴瘤、胃癌、胃类癌、胃肠道间质瘤、肾母细胞瘤、乳腺癌、肉瘤、***癌、咽癌、妊娠滋养细胞疾病、***、子宫内膜癌、***癌、转移性骨癌、纵隔癌、直肠癌、直肠类癌、***癌、脊髓癌、听神经瘤、胰腺癌、唾液腺癌、佩吉特病、扁桃体癌、鳞状细胞癌、肺腺癌、肺癌、皮肤癌、***癌、喉癌、胸膜癌、血癌和胸腺癌。
9.如权利要求8所述的药物组合物,其中,所述胆管癌是肝内胆管癌。
10.如权利要求8所述的药物组合物,其中,所述乳腺癌是男性乳腺癌。
11.如权利要求8所述的药物组合物,其中,所述脑癌是儿童脑癌或转移性脑癌。
12.如权利要求8所述的药物组合物,其中,所述肺癌是非小细胞肺癌或小细胞肺癌。
13.如权利要求8所述的药物组合物,其中,所述肉瘤是子宫肉瘤、卡波西肉瘤或横纹肌肉瘤。
14.如权利要求8所述的药物组合物,其中,所述鳞状细胞癌是肺鳞状细胞癌。
15.如权利要求5所述的药物组合物,其中,所述癌症是表达RET融合基因的癌症。
16.权利要求1中限定的具有化学式1的化合物、其立体异构体或其药学上可接受的盐在制备用于预防或治疗癌症的药物中的用途。
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EA202193049A1 (ru) | 2022-02-14 |
KR20200134179A (ko) | 2020-12-01 |
US20220324874A1 (en) | 2022-10-13 |
MX2021014273A (es) | 2022-01-06 |
EP3974432A1 (en) | 2022-03-30 |
AU2020279686A1 (en) | 2021-12-16 |
CA3140067A1 (en) | 2020-11-26 |
BR112021023282A2 (pt) | 2022-01-04 |
CN113853375A (zh) | 2021-12-28 |
WO2020235945A1 (ko) | 2020-11-26 |
JP7477846B2 (ja) | 2024-05-02 |
JP2022533710A (ja) | 2022-07-25 |
SG11202112796YA (en) | 2021-12-30 |
IL288242A (en) | 2022-01-01 |
EP3974432A4 (en) | 2023-06-28 |
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