CN116354926A - 作为Polθ抑制剂的杂环化合物及其制备方法和用途 - Google Patents
作为Polθ抑制剂的杂环化合物及其制备方法和用途 Download PDFInfo
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- CN116354926A CN116354926A CN202211715912.8A CN202211715912A CN116354926A CN 116354926 A CN116354926 A CN 116354926A CN 202211715912 A CN202211715912 A CN 202211715912A CN 116354926 A CN116354926 A CN 116354926A
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Abstract
Description
技术领域
本发明属于医药领域,具体地,本发明涉及到一种作为Polθ抑制剂的杂环化合物及及其制备方法和用途。
背景技术
合成致死是目前抗肿瘤领域中一个新兴的研究方向,其中针对DNA修复途径的治疗是本专利的重点。部分肿瘤细胞由于基因突变,会造成某一DNA修复途径缺失,从而使得它们对于尚存的DNA修复途径过度依赖,此时针对这一尚存的DNA修复途径进行针对性抑制,就可特异性地杀死该类肿瘤细胞,而对正常的体细胞不具有杀伤作用。近年来,通过聚腺苷二磷酸核糖聚合酶[poly(ADP-ribose)polymerase,PARP]抑制剂治疗乳腺卵巢癌易感基因(breast and ovarian cancer susceptibility gene,BRCA)突变肿瘤的方法正是利用了靶向DNA修复缺陷的合成致死作用机制。
DNA双链断裂(DNA double strand breaks,DSBs)是最严重的DNA损伤之一。细胞中DNA双链断裂修复(DNA double strand breaks repair,DSBR)可大致分为三种途径完成,一种是非同源末端连接(non-homologous end-joining,NHEJ),一种途径是同源重组(homologous recombination,HR),最后一种途径则是当NHEJ或HR受到损害时由DNA聚合酶θ(Polymeraseθ,Polθ,POLQ)介导的末端连接(alt-EJ),也称为微同源介导的末端连接(MMEJ)。Polθ在微同源介导的末端连接过程中发挥核心作用。Polθ具有N端解旋酶结构域和C端DNA聚合酶结构域(S.Black et al.2016.Genes.)。研究显示Polθ的解旋酶域可促进微同源性的退火,退火后,通过核酸酶去除所有突出的碱基,并通过Polθ填补缺口。因此Polθ作为DNA修复缺陷的重要靶点受到了越来越多的关注。Polθ在正常组织中的几乎不表达,但在多种肿瘤类型(如乳腺癌、卵巢癌、HNSCC和肺癌)中过度表达而且与不良预后结果相关。研究显示当同源重组介导的修复受到损害时(HRD),如BRCA1或BRCA2突变,Polθ高度表达并引导DSB修复朝向微同源介导的末端连接(MMEJ)发展,开启MMEJ的DNA修复过程。
由于Polθ在同源重组修复缺陷(HRD)肿瘤中至关重要,因此抑制Polθ是一种有前途的新型的合成致死治疗策略。
发明内容
本发明的目的是提供一种作为Polθ抑制剂的杂环化合物及其制备方法和用途,所述杂环化合物具有如本发明第一方面所示结构,所述杂环化合物可用于抑制Polθ聚合酶的活性,预防或治疗由Polθ介导的疾病或病症。
本发明的第一方面提供了一种如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药:
环A为5或6元杂芳基,环B为5-8元杂环烷基或5或6元杂芳基;
Y表示C;
R8、R9、R10和R11各自独立地为氢、氘、卤素、羟基、氨基、氰基、C1-C6烷基、-O-C1-C6烷基或-NH-C1-C6烷基;
任选地,所述R8、R9、R10和R11各自独立地被1、2、3或4个选自下列的取代基取代:氘、卤素、羟基、氨基、氰基和C1-C6烷基;当取代基为多个时,所述取代基相同或不同;
m、n、f和g各自独立地为0、1、2或3;当取代基R8、R9、R10和R11为多个时,所述取代基R8、R9、R10和R11相同或不同;
R1、R2和R3各自独立地为氢、氘、卤素、C1-C6烷基、C1-C6卤代烷基、3-6元环烷基或4-8元杂环烷基;
R7为C1-C6烷基、C1-C6氘代烷基或C1-C6卤代烷基。
本发明提供了一种如式I所示杂环化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药:
环A为5或6元杂芳基,环B为5-8元杂环烷基或5或6元杂芳基;
Y表示C;
R8、R9、R10和R11各自独立地为氢、卤素、羟基、氨基、氰基、C1-C6烷基、-O-C1-C6烷基或-NH-C1-C6烷基;
任选地,所述R8、R9、R10和R11各自独立地被1、2、3或4个选自下列的取代基取代:卤素、羟基、氨基、氰基和C1-C6烷基;当取代基为多个时,所述取代基相同或不同;
m、n、f和g各自独立地为0、1、2或3;当取代基R8、R9、R10和R11为多个时,所述取代基R8、R9、R10和R11相同或不同;
R1、R2和R3各自独立地为氢、卤素、C1-C6烷基或C1-C6卤代烷基;
R7为C1-C6烷基或C1-C6卤代烷基。
在本发明中,所述的如式I所示的杂环化合物中某些取代基的定义可如任一方案所述。
在本发明一优选实施方案中,所述溶剂化物可为水合物。
本发明一优选实施方案中,如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药:
环A为5或6元杂芳基,环B为5-8元杂环烷基或5或6元杂芳基;
Y表示C;
R8、R9、R10和R11各自独立地为氢或卤素;
m、n、f和g各自独立地为0、1或2;当取代基R8、R9、R10和R11为多个时,所述取代基R8、R9、R10和R11相同或不同;
R1、R2和R3各自独立地为氢或C1-C6烷基、C1-C6卤代烷基;
R7为C1-C6烷基或C1-C6氘代烷基。
在本发明一优选实施方案中,R1、R2、R3、R4、R5、R6、R7、R8、R9、R10和R11中,所述卤素独立地为氟、氯、溴或碘,例如氟或氯。
在本发明一优选实施方案中,R1、R2、R3、R4、R5、R6、R7、R8、R9、R10和R11中,所述C1-C6烷基独立地为C1-4烷基,例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,还例如为甲基。
在本发明一优选实施方案中,R1、R2、R3、R4、R5、R6和R7中,所述C1-C6卤代烷基中卤素独立地为氟、氯、溴或碘,例如氟。
在本发明一优选实施方案中,R8、R9、R10和R11中,所述-O-C1-C6烷基或-NH-C1-C6烷基中C1-C6烷基独立地为C1-4烷基,例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
在本发明一优选实施方案中,R1、R2、R3、R4、R5、R6和R7中,所述C1-C6卤代烷基独立地为C1-C4卤代烷基,例如被1个、2个或3个F取代的C1-C4烷基,还例如,一氟甲基、二氟甲基或三氟甲基。
在本发明一优选实施方案中,R1、R2和R3中,所述3-6元环烷基独立地为丙基、环丁基、环戊基或环己基。
在本发明一优选实施方案中,R1、R2和R3中,所述4-8元杂环烷基中的杂原子数为1个,杂原子为N、O或S(例如N)。
在本发明一优选实施方案中,环A中,所述5或6元杂芳基中的杂原子数为1个,杂原子可为N、O或S(例如N)。
在本发明一优选实施方案中,环B中,所述5-8元杂环烷基中的杂原子数为1个,杂原子可为N、O或S(例如N)。
在本发明一优选实施方案中,环B中,所述5或6元杂芳基中的杂原子数为1个,杂原子可为N、O或S(例如N)。
在本发明一优选实施方案中,R8、R9、R10和R11各自独立地为氢、氘、卤素、羟基、氨基、氰基、C1-C6烷基、-O-C1-C6烷基或-NH-C1-C6烷基。
在本发明一优选实施方案中,m、n、f和g各自独立地为0、1或2;当取代基R8、R9、R10和R11为多个时,所述取代基R8、R9、R10和R11相同或不同。
在本发明一优选实施方案中,R1、R2、R3各自独立地为氢、C1-C6烷基或C1-C6卤代烷基。
在本发明一优选实施方案中,R7为C1-C6烷基或C1-C6氘代烷基。
在本发明一优选实施方案中,R1为甲基或三氟甲基。
在本发明一优选实施方案中,R2为氢。
在本发明一优选实施方案中,R3为三氟甲基。
在本发明一优选实施方案中,R5为羟基。
在本发明一优选实施方案中,R6为羟基。
在本发明一优选实施方案中,R7为甲基或氘代甲基(-CD3)。
在本发明一优选实施方案中,R8为氢或卤素;进一步地,R8为氢、氟或氯。
在本发明一优选实施方案中,R9为氢。
在本发明一优选实施方案中,R10为氢。
在本发明一优选实施方案中,R11为氢、氟或氯。
在一优选实施方式中,所述R2为氢;R1、R3各自独立地为氟、氯、C1-C3烷基、C1-C3氟代烷基或C1-C3氯代烷基。
在一优选实施方式中,R1为甲基或三氟甲基,R2为氢,R3为三氟甲基;进一步地,R1为甲基,R2为氢,R3为三氟甲基。
在一优选实施方式中,R7为甲基、乙基、丙基或C1-C3氟代烷基;较佳地,R7为甲基。
在一优选实施方式中,R7为C1-C3氘代烷基;较佳地,R7为氘代甲基(-CD3)。
在一优选实施方式中,R1为甲基,R2为氢,R3为3-6元环烷基;较佳地,R3为环丙基。
在一优选实施方式中,所述的如式I所示杂环化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,具有结构Ia、Ib、Ic或Id;
其中,Q的定义如本发明第一方面中所述。
在一优选实施方式中,所述如式I所示杂环化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,具有结构Ie、If或Ig;
其中,Q的定义如本发明第一方面中所述。
在一优选实施方式中,环A、环B共同含有1、2或3个N杂原子;任选地还含有1个O或S杂原子。
在一优选实施方式中,环A为5或6元杂芳基,环B为5或6元杂芳基,且环A和环B共同含有1、2或3个N杂原子。
在一优选实施方式中,环A为5或6元杂芳基,环B为5-8元杂环烷基;其中,环A、环B共同含有1或2个N杂原子;任选地,环B还含有1个O或S杂原子。
在一优选实施方式中,环A为5或6元杂芳基,环B为5或6元杂环烷基。
在一优选实施方式中,环A为5或6元含N杂芳基。
在一优选实施方式中,R8、R9、R10、R11各自独立地为氢、氟、氯、羟基、氨基、氰基、C1-C6烷基、-O-C1-C6烷基或-NH-C1-C6烷基;
任选地,所述R8、R9、R10、R11各自独立地被1、2、3或4个选自下列的取代基取代:氟、氯、C1-C6烷基;当取代基为多个时,所述取代基相同或不同。
在一优选实施方式中,R8、R9、R10、R11各自独立地为氢、氟、氯、C1-C3烷基、C1-C3氟代烷基或C1-C3氯代烷基;较佳地,R8、R9、R10、R11各自独立地为氢、氟或氯。
在一优选实施方式中,所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药,包括:
在一优选实施方式中,所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药,包括:
在本发明第二方面,提供了一种药物组合物,包括如第一方面所述的杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药。
提供了一种药物组合物,包括如第一方面所述的杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药和
i)一种或多种活性药物;和/或
ii)药学上可接受的载体。
在本发明第三方面,提供了如第一方面所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药,或如第二方面所述的药物组合物的用途,包括:
抑制Polθ活性;
和/或,预防和/或治疗Polθ介导的疾病;
和/或,制备用于抑制Polθ,和/或预防和/或治疗Polθ介导的疾病的药物、药物组合物或制剂。
在一优选实施方式中,如第一方面所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药用于预防或治疗癌症。
在一优选实施方式中,所述Polθ介导的疾病为癌症。
在本发明还提供了如第一方面所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药,或如第二方面所述的药物组合物在制备药物中的用途,所述药物用于治疗癌症。
本发明还提供了如第一方面所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药,或如第二方面所述的药物组合物在制备预防和/或治疗疾病的药物中的应用,所述疾病为细胞增殖性病症;较佳地,所述细胞增殖性病症为癌症。
本发明还提供一种治疗疾病的方法,包括给与患者治疗有效量的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐、前药或如第二方面所述药物组合物中的至少一种。
在本发明一优选实施方式中,所述疾病为与Polθ介导的疾病。
在本发明一优选实施方式中,所述疾病为细胞增殖性病症;较佳地,所述细胞增殖性病症为癌症。
在一些实施方案中,所述患者哺乳动物,优选是人。
在一优选实施方式中,所述如式I所示杂环化合物可以治疗(或抑制)的癌症(及其良性对应物)的实例包括但不限于:上皮来源的肿瘤(腺瘤和各种类型的癌,包括腺癌、鳞状癌、移行细胞癌和其他癌)如膀胱癌和泌尿道癌、乳腺癌、胃肠道癌(包括食道癌、胃癌(胃)、小肠癌、结肠癌、直肠癌和肛门癌)、肝癌(肝细胞癌)、胆囊和胆道系统癌、外分泌胰腺癌、肾、肺(例如腺癌、小细胞肺癌、非小细胞肺癌、细支气管肺泡癌和间皮瘤)、头颈癌(例如舌癌、口腔癌、喉癌、咽癌、鼻咽癌、扁桃体癌、唾液腺癌、鼻腔和鼻窦)、生殖系统(如卵巢、输卵管、腹膜、阴道、外阴、阴茎、子宫颈、子宫肌层、子宫内膜)癌、甲状腺癌(例如甲状腺滤泡癌)、肾上腺癌、前列腺癌、皮肤癌(例如黑色素瘤、基底细胞癌、鳞状细胞癌、角化棘皮瘤、发育不良痣);血液系统恶性肿瘤(即白血病、淋巴瘤)和癌前血液系统疾病和交界性恶性肿瘤疾病,包括血液系统恶性肿瘤和相关淋巴系疾病(例如急性淋巴细胞白血病、慢性淋巴细胞白血病、B细胞淋巴瘤,例如弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、伯基特淋巴瘤、套细胞淋巴瘤、MALT淋巴瘤、T细胞淋巴瘤和白血病、自然杀伤细胞淋巴瘤、霍奇金淋巴瘤、毛细胞白血病、意义不明的单克隆丙种球蛋白病、浆细胞瘤、多发性骨髓瘤、和移植后淋巴组织增生性疾病),以及血液系统恶性肿瘤和骨髓系相关疾病(例如急性髓性白血病、慢性髓性白血病、慢性粒单核细胞白血病、嗜酸性粒细胞增多症、骨髓增生性疾病,如真性红细胞增多症)、原发性血小板增多症和原发性骨髓纤维化、骨髓增生综合征、骨髓增生异常综合征和早幼粒细胞白血病);间充质来源的肿瘤,例如软组织、骨或软骨的肉瘤,例如骨肉瘤、纤维肉瘤、软骨肉瘤、横纹肌肉瘤、平滑肌肉瘤、脂肪肉瘤、血管肉瘤、卡波西肉瘤、尤文氏肉瘤、胃肠道上皮肉瘤、上皮肉瘤、恶性上皮肉瘤组织细胞瘤和皮肤纤维肉瘤突起;中枢或外周神经系统肿瘤(例如星形细胞瘤、神经胶质瘤和胶质母细胞瘤、脑膜瘤、室管膜瘤、松果体瘤和神经鞘瘤);内分泌肿瘤(例如垂体肿瘤、肾上腺肿瘤、胰岛细胞肿瘤、甲状旁腺肿瘤、类癌瘤和甲状腺髓样癌);眼部和附件肿瘤(例如视网膜母细胞瘤);生殖细胞和滋养细胞肿瘤(例如畸胎瘤、精原细胞瘤、无性细胞瘤、葡萄胎和绒毛膜癌);以及儿科和胚胎肿瘤(例如髓母细胞瘤、神经母细胞瘤、Wilms肿瘤和原始神经外胚层肿瘤);或先天性或使患者易患恶性肿瘤的其他方面的综合征(例如色素性干皮病)。
本发明的附加方面和优点将在下面的描述中部分给出,部分将从下面的描述中变得明显,或通过本发明的实践了解到。
术语和定义
除非另有说明,本申请说明书和权利要求书中记载的基团和术语定义,包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等,可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构,应当属于本申请说明书记载的范围内。
除非另有定义,否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明,本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。如果本文对术语有多个定义,以本章的定义为准。
应理解,上述简述和下文的详述为示例性且仅用于解释,而不对本发明主题作任何限制。在本申请中,除非另有具体说明,否则使用单数时也包括复数。必须注意,除非文中另有清楚的说明,否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意,除非另有说明,否则所用“或”、“或者”表示“和/或”。此外,所用术语“包括”以及其它形式,例如“包含”、“含”和“含有”并非限制性。
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY4THED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明,否则采用本领域技术范围内的常规方法,如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义,否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送,以及对患者的治疗中使用标准技术。例如,可利用厂商对试剂盒的使用说明,或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述,按照本领域熟知的常规方法实施上述技术和方法。在本说明书中,可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
本文所用的章节标题仅用于组织文章的目的,而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文,均通过引用方式整体并入本文。
除前述以外,当用于本申请的说明书及权利要求书中时,除非另外特别指明,否则以下术语具有如下所示的含义。
本申请说明书和权利要求书记载的数值范围,当该数值范围被理解为“整数”时,应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如,“1~6的整数”应当理解为记载了0、1、2、3、4、5和6的每一个整数。
在本申请中,在单独或作为其他取代基一部分时,术语“卤素”是指氟、氯、溴、碘。
如本文所用,在单独或作为其他取代基一部分时,术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键、具有例如1至6个碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基,叔丁基,戊基,异戊基,新戊基和己基。烷基可以是未取代的或被一个或多个合适的取代基取代。烷基也可以是富含碳和/或氢的同位素(即氘或氚)的天然丰度烷基的同位素异构体。
在单独或作为其他取代基一部分时,术语“C1-C6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地,所述基团具有1、2或3个碳原子(“C1-C3烷基”),例如甲基、乙基、正丙基或异丙基。
在单独或作为其他取代基一部分时,术语“环烷基”或“碳环基”是指一种环状烷基。术语“m-n元环烷基”或者“Cm-Cn环烷基”应理解为表示具有m至n个原子的饱和、不饱和或部分饱和的碳环。例如,“3-15元环烷基”或者“C3-C15环烷基”是指含有3至15,3至9,3至6或3至5个碳原子的环状烷基,它可能包含1至4个环。“5-8元环烷基”则含有5-8个碳原子。包括单环、二环、三环、螺环或桥环。未取代的环烷基的实例包括但不限于环丙基,环丁基,环戊基,环己基和金刚烷基,或者是双环烃基如十氢化萘环。环烷基可以被一个或多个取代基取代。在一些实施方案中,环烷基可以是与芳基或杂芳基稠合的环烷基。术语“C3-C6环烷基”应理解为表示饱和的一价单环或双环烃环,其具有3~6个碳原子,包括稠合或桥接的多环系统。例如环丙基、环丁基、环戊基、环己基。
在单独或作为其他取代基一部分时,“卤代烷基”指包括具有特定数目的碳原子、被一或多个卤素取代的支链和直链的饱和脂族烃基(如-CvFw,其中v=1至3,w=1至(2v+1))。卤代烷基的实例包括,但不限于三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。
术语“5-8元杂环基”或“5-8元杂环烷基”应理解为表示具有5至8个原子的单环、二环或三环,其中杂原子优选自N、O和S,应该理解的是,当杂环基中S原子和O原子的总数超过1时,这些杂原子不彼此相邻。杂环烷基的实例包括但不限于:四氢异喹啉基、四氢喹啉基、四氢吡喃基、四氢呋喃基、四氢噻喃基。
术语“5或6元杂芳基”应理解为具有5或6个环原子——且包含1-5个独立选自N、O和S的杂原子的芳族环基团,优选1-3个——独立选自N、O和S的杂原子的芳族环基团。杂芳基的实例包括但不限于:噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基等;或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等。
在本申请中,“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生,且该描述同时包括该事件或状况发生和不发生的情况。例如,“任选地被取代的芳基”表示芳基被取代或未被取代,且该描述同时包括被取代的芳基与未被取代的芳基。
在本申请中,术语“盐”或“药学上可接受的盐”,包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的,与无机酸或有机酸所形成的盐。“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。除了药学可接受的盐外,本发明还考虑其他盐。它们可以在化合物纯化中或在制备其它药学上课接受的盐中充当中间体或可用于本发明化合物的鉴别、表征或纯化。
术语“胺盐”是指用酸中和烷基伯胺、仲胺或叔胺得到的产物。所述酸包括本申请中所述的无机酸或有机酸。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体、非对应异构体和构象异构体。
依据原料和方法的选择,本发明化合物可以以可能的异构体中的一个或它们的混合物的形式存在,例如作为纯旋光异构体,或作为异构体混合物,如作为外消旋和非对映异构体混合物,这取决于不对称碳原子的数量。当描述具有光学活性的化合物时,使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀D和L或(+)和(–)是用于指定化合物所致平面偏振光旋转的符号,其中(–)或L表示化合物是左旋的。前缀为(+)或D的化合物是右旋的。
当将本发明式中与手性碳的键描写直成线时,应当理解为,手性碳的(R)和(S)两种构型和由此产生的其对映体纯的化合物和混合物两者包括在该通式范围内。本文中消旋体或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120。用楔形键和虚线键表示一个立体中心的绝对构型。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在,尝试分离单一互变异构体时通常产生一种混合物,其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如,在很多脂族醛和酮如乙醛中,酮型占优势;而在酚中,烯醇型占优势。本发明包含化合物的所有互变异构形式。
在本申请中,“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药,利于活性成分的吸收进而发挥生物活性。
在本申请中,“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
术语“溶剂化物”指本发明化合物或其盐包括以分子间非共价力结合的化学计量或非化学计量的溶剂,当溶剂为水时,则为水合物。
术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备,该修饰可以按常规的操作或者在体内被除去,而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物,当本发明化合物的前药被施予哺乳动物个体时,前药被割裂而分别形成游离的羟基、游离的氨基。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素标记化合物,比如氘(2H),氚(3H),碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包括在本发明的范围之内。
术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性,即通过增加流动性和/或粘着性使制剂更适于直接压缩。
本文所用的术语“治疗”和其它类似的同义词包括以下含义:
(i)预防疾病或病症在哺乳动物中出现,特别是当这类哺乳动物易患有该疾病或病症,但尚未被诊断为已患有该疾病或病症时;
(ii)抑制疾病或病症,即遏制其发展;
(iii)缓解疾病或病症,即,使该疾病或病症的状态消退;或者
(iv)减轻该疾病或病症所造成的症状。
各步骤的反应,反应温度可因溶剂、起始原料、试剂等适宜选择,反应时间也可因反应温度、溶剂、起始原料、试剂等适宜选择。各步骤反应结束后,目标化合物可按常用方法自反应体系中进行分离、提纯等步骤,如过滤、萃取、重结晶、洗涤、硅胶柱层析等方法。在不影响下一步反应的情况下,目标化合物也可不经过分离、纯化直接进入下一步反应。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:本发明人经过广泛而深入地研究,意外地开发了一种作为Polθ抑制剂的杂环化合物,所述杂环化合物具有本发明中式I所示结构。本发明所述杂环化合物对Polθ蛋白聚合酶有良好的抑制作用,可以预防或治疗由Polθ介导的疾病或病症,表现出优良的药代动力学性质,具备较高的安全性和成药性质。
具体实施方式
以下结合具体实施例,进一步说明本发明。需理解,以下的描述仅为本发明的最优选实施方式,而不应当被认为是对于本发明保护范围的限制。在充分理解本发明的基础上,下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件,本领域技术人员可以对本发明的技术方案作出非本质的改动,这样的改动应当被视为包括于本发明的保护范围之中的。
实施例1:化合物I-1A和I-1B的制备
合成路线如下所示:
第一步:二环[4.2.0]辛-1,3,5-三烯-3-基氨基甲酸叔丁酯的合成
将4-氨基苯并环丁烯(0.5g,4.2mmol)和碳酸氢钠(1.41g,16.78mmol)加入到二氧六环(5mL)和水(2mL)中,在室温下加入(Boc)2O(1.83g,8.39mmol),反应液在25℃下反应12h,薄层色谱(石油醚:乙酸乙酯(V/V)=5:1)监测原料反应完全。反应液中加水(50mL)和乙酸乙酯(100mL),反应液用乙酸乙酯(100mL×3)萃取。合并萃取液用饱和食盐水(50mL)洗涤,硫酸钠干燥,过滤,旋干得粗品,粗品用(石油醚:乙酸乙酯(V/V)=100:1-1:1)过柱子纯化得到化合物二环[4.2.0]辛-1,3,5-三烯-3-基氨基甲酸叔丁酯(0.8g,产率87%)。
第二步:二环[4.2.0]辛-1,3,5-三烯-3-基(甲基)氨基甲酸叔丁酯的合成
将二环[4.2.0]辛-1,3,5-三烯-3-基氨基甲酸叔丁酯(0.6g,2.74mmol)加入到四氢呋喃(10mL)中,在0℃下缓慢滴加NaH(0.164g,4.1mmol,60%),反应液在0℃下反应0.5h,再加入碘甲烷(0.47g,3.28mmol),反应液在室温下反应4h。薄层色谱(石油醚:乙酸乙酯(V/V)=3:1)监测原料反应完全。反应液中加水(50mL)和乙酸乙酯(100mL),反应液用乙酸乙酯(100mL×3)萃取。合并萃取液用饱和食盐水(50mL)洗涤,硫酸钠干燥,过滤,旋干得粗品,粗品用(石油醚:乙酸乙酯(V/V)=100:1-1:1)过柱子纯化得到化合物二环[4.2.0]辛-1,3,5-三烯-3-基(甲基)氨基甲酸叔丁酯(0.4g,产率62.7%)。
第三步:N-甲基二环[4.2.0]辛-1,3,5-三烯-3-胺的合成
将二环[4.2.0]辛-1,3,5-三烯-3-基(甲基)氨基甲酸叔丁酯(0.4g,1.71mmol)加入到乙酸乙酯(5mL)中,在0℃下缓慢滴加二氧六环/氯化氢中(2mL)。反应液在室温下反应12小时,反应液旋干得到粗品。粗品用(石油醚:乙酸乙酯(V/V)=5:1,10mL)打浆得到化合物N-甲基二环[4.2.0]辛-1,3,5-三烯-3-胺(0.2g,产率88.0%)。
第四步:(4S)-N-(二环[4.2.0]辛-1,3,5-三烯-3-基)-N,2,2-三甲基-6-羰基四氢-4H-[1,3]二噁唑并[4,5-c]吡咯-4-甲酰胺的合成
将(4S)-2,2-二甲基-6-羰基四氢-4H-[1,3]二噁唑并[4,5-c]吡咯-4-甲酸(0.2g,0.994mmol)和吡啶(0.2mL)加入到N,N-二甲基甲酰胺(5mL)中,在室温下加入丙基磷酸酐(1.13g,1.49mmol,50%N,N-二甲基甲酰胺溶液)中。反应液在室温下反应0.5小时,再加入N-甲基二环[4.2.0]辛-1,3,5-三烯-3-胺(0.16g,1.19mmol),反应液在室温下反应15h,原料反应完全。反应液中加水(50mL)和乙酸乙酯(100mL),反应液用乙酸乙酯(100mL×3)萃取。合并萃取液用饱和食盐水(50mL)洗涤,硫酸钠干燥,过滤,旋干得粗品,粗品用(石油醚:乙酸乙酯(V/V)=100:1-1:100)过柱子纯化得到化合物(4S)-N-(二环[4.2.0]辛-1,3,5-三烯-3-基)-N,2,2-三甲基-6-羰基四氢-4H-[1,3]二噁唑并[4,5-c]吡咯-4-甲酰胺(0.1g,产率31.8%)。
第五步:(4S)-N-(二环[4.2.0]辛-1,3,5-三烯-3-基)-N,2,2-三甲基-6-羰基四氢-4H-[1,3]二噁唑并[4,5-c]吡咯-4-甲酰胺的合成
将(4S)-N-(二环[4.2.0]辛-1,3,5-三烯-3-基)-N,2,2-三甲基-6-羰基四氢-4H-[1,3]二噁唑并[4,5-c]吡咯-4-甲酰胺(0.1g,0.32mmol),Cs2CO3(0.154g,0.474mmol),2-氯-6-甲基-4-(三氟甲基)吡啶(0.074g,0.38mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(0.018g,0.032mmol)和Pd2(dba)3加入到二氧六环(10mL)中,反应液升温至110℃反应15小时。薄层色谱(石油醚:乙酸乙酯(V/V)=1:1)监测原料反应完全。将反应混合物用水(50mL)稀释,然后用乙酸乙酯(100mL×2)萃取,合并有机层,用饱和食盐水(50mL)洗涤有机相,硫酸钠干燥,浓缩得到粗品。粗品用(石油醚:乙酸乙酯(V/V)=100:1-1:100)过柱子纯化得到化合物(4S)-N-(二环[4.2.0]辛-1,3,5-三烯-3-基)-N,2,2-三甲基-6-羰基四氢-4H-[1,3]二噁唑并[4,5-c]吡咯-4-甲酰胺(0.1g,产率66.5%)。
第六步:(2S,3R,4R)-N-(二环[4.2.0]辛-1,3,5-三烯-3-基)-3,4-二羟基-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-羰基吡咯烷-2-甲酰胺(I-1A)和(2S,3S,4S)-N-(二环[4.2.0]辛-1,3,5-三烯-3-基)-3,4-二羟基-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-羰基吡咯烷-2-甲酰胺(I-1B)合成
将4S)-N-(二环[4.2.0]辛-1,3,5-三烯-3-基)-N,2,2-三甲基-6-羰基四氢-4H-[1,3]二噁唑并[4,5-c]吡咯-4-甲酰胺(0.1g,0.21mmol)加入到无水二氯甲烷(5mL)中,在-20℃下加入三氯化硼(0.63mL,1.0mmol/L)中。反应液在-20℃下反应2小时,原料反应完全。反应液中加水(50mL)和二氯甲烷(100mL),反应液用二氯甲烷(100mL×3)萃取。合并萃取液用饱和食盐水(50mL)洗涤,硫酸钠干燥,过滤,旋干得粗品,粗品经反相制备(column:Phenomenex Synergi C18 150*25mm*10μm;流动相:[水(0.225%甲酸)-乙腈];B%:18%-52%,12min)分离得到(2S,3R,4R)-N-(二环[4.2.0]辛-1,3,5-三烯-3-基)-3,4-二羟基-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-羰基吡咯烷-2-甲酰胺(I-1A)(10mg,产率11%)和(2S,3S,4S)-N-(二环[4.2.0]辛-1,3,5-三烯-3-基)-3,4-二羟基-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-羰基吡咯烷-2-甲酰胺(I-1B)(4mg,产率6.5%)。
化合物I-1A:
1H NMR(400MHz,DMSO)δ8.43(s,1H),7.39(s,2H),7.32(s,1H),7.23(d,J=7.8Hz,1H),5.85(d,J=7.4Hz,1H),5.32(d,J=4.4Hz,1H),4.76(s,1H),4.37–4.31(m,2H),3.17(s,4H),3.15(s,3H),2.57(s,3H)。
LC-MS,M/Z(ESI):436.5[M+H]+。
化合物I-1B:
1H NMR(400MHz,DMSO)δ8.22(s,1H),7.37(s,1H),7.34(d,J=8.0Hz,1H),7.24(d,J=6.2Hz,2H),5.49(d,J=8.6Hz,1H),5.32(d,J=5.0Hz,1H),4.88(d,J=5.6Hz,1H),4.23–4.15(m,1H),3.98(dd,J=10.6,5.4Hz,1H),3.17(s,4H),3.10(s,3H),2.55(s,3H)。
LC-MS,M/Z(ESI):436.5[M+H]+。
实施例2
合成路线如下所示:
第一步:(E)-4-(二甲氨基)-2-氧亚基丁-3-烯酸乙酯
将N,N-二甲基甲酰胺二甲基缩醛(10.0g,83.9mmol)和丙酮酸乙酯(9.94g,85.6mmol)混合,反应液在25℃条件下搅拌12小时。反应完成后,直接减压浓缩得到褐色液体粗品(E)-4-(二甲氨基)-2-氧亚基丁-3-烯酸乙酯(16.0g,粗品)。
第二步:吡咯并[1,2-b]哒嗪-2-甲酸乙酯
将1-氨基吡咯(2.50g,250mmol)和(E)-4-(二甲氨基)-2-氧亚基丁-3-烯酸乙酯(15.6g,91.3mmol)溶于乙醇(25.0mL)中,然后在0℃下缓慢加入浓盐酸(23.50g,23.04mL,37.8%纯度),反应液在0℃条件下搅拌30分钟。反应完成后,在0℃下慢慢加入饱和碳酸氢钠溶液300mL进行淬灭,直至气泡不再产生,然后用乙酸乙酯(100mL*3)萃取,有机相用饱和氯化钠溶液(200mL)洗涤和无水硫酸钠干燥后,过滤浓缩得到棕色液体的粗品,粗品经反相高效液相色谱法进行分离纯化得到乙基吡咯并[1,2-b]哒嗪-2-甲酸基酯(1.50g,产率:29.5%)。1H NMR(400MHz,DMSO-d6)δ=8.08-8.14(m,1H)8.07(dd,J=2.38,1.26Hz,1H)7.16(d,J=9.38Hz,1H)7.08(dd,J=4.26,2.76Hz,1H)6.69(dd,J=4.32,1.44Hz,1H)4.37(q,J=7.10Hz,2H)1.34(t,J=7.14Hz,3H).
第三步:吡咯并[1,2-b]哒嗪-2-甲酸
将乙基吡咯并[1,2-b]哒嗪-2-甲酸基酯(700mg,3.68mmol)溶于无水乙醇(3.50mL)、四氢呋喃(7.00mL)和水(3.50mL)中,然后加入氢氧化锂的一水合物(1.54g,36.80mmol)后,反应液在25℃条件下搅拌12小时。反应完成后,用盐酸(1M)调节反应液pH至3~4左右,然后用乙酸乙酯(20mL*3)萃取,有机相用饱和氯化钠溶液(20mL)洗涤和无水硫酸钠干燥后,过滤浓缩得到粗品:吡咯并[1,2-b]哒嗪-2-甲酸(700mg,粗品)。
第四步:吡咯并[1,2-b]哒嗪-2-胺
将吡咯并[1,2-b]哒嗪-2-甲酸(1.50g,18.5mmol)溶于甲苯(30.0mL)中,然后分别加入三乙胺(3.75g,37.1mmol)、叠氮磷酸二苯酯(10.2g,37.1mmol)和水(1.65g,92.5mmol),反应液在90℃条件下搅拌2小时。反应完成后,直接浓缩得到粗品,粗品经柱层析(流动相为石油醚:乙酸乙酯=10:1-3:1)得到:吡咯并[1,2-b]哒嗪-2-胺(750mg,产率:24.3%)。1H NMR(400MHz,DMSO-d6)δ=7.57(d,J=9.38Hz,1H),7.31(s,1H),6.40-6.52(m,1H),6.23(d,J=3.26Hz,1H),6.15(d,J=9.38Hz,1H),5.79-5.96(m,2H).
第五步:(3aS,4S,6aS)-2,2-二甲基-6-氧亚基-N-(吡咯并[1,2-b]哒嗪-2-基)四氢-4H-[1,3]二噁戊环并[4,5-c]吡咯-4-甲酰胺
将(3aS,6S,6aS)-2,2-二甲基-4-氧亚基-3a,5,6,6a-四氢-[1,3]二噁戊环并[4,5-c]吡咯-6-甲酸(151mg,751μmol)溶解在二氯甲烷(3.00mL)中,然后在0℃条件加入1-氯-N,N,2-三甲基-丙-1-烯-1-胺(301mg,2.25mmol),反应液在0℃下搅拌30分钟。然后在0℃条件下加入吡啶(237mg,3.00mmol)和N-甲基吡唑并[1,5-a]吡啶-6-胺(100mg,751.03μmol)。最后,反应液在25℃下搅拌2小时。反应完成后,直接浓缩得到黄色油状物(3aS,4S,6aS)-2,2-二甲基-6-氧亚基-N-(吡咯并[1,2-b]哒嗪-2-基)四氢-4H-[1,3]二噁戊环并[4,5-c]吡咯-4-甲酰胺(160mg,粗品)。LCMS,M/Z(ESI):317.2[M+H]+。
第六步:(3aS,4S,6aS)-2,2-二甲基-5-(6-甲基-4-(三氟甲基)吡啶-2-基)-6-氧亚基-N-(吡咯并[1,2-b]哒嗪-2-基)四氢-4H-[1,3]二噁戊环并[4,5-c]吡咯-4-甲酰胺
将(S)-N-(5-氯-2,4-二氟苯基)-N,4,4-三甲基-5-氧亚基吡咯烷-2-甲酰胺(160mg,505μmol)和2-氯-6-甲基-4-(三氟甲基)吡啶(148mg,758μmol)溶解在1,4-二氧六环(4.00mL)中,然后在室温和氮气保护下分别加入碳酸钾(209mg,1.52mmol)、三(二亚苄基丙酮)二钯(69.5mg,75.8μmol,)和4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(87.8mg,151μmol),氮气置换三次后,反应液在95℃搅拌12小时。反应完成后,直接过滤浓缩得到棕色的油状物,粗品经Prep-TLC(流动相为石油醚:乙酸乙酯=2:1)分离纯化得到黄色液体:(3aS,4S,6aS)-2,2-二甲基-5-(6-甲基-4-(三氟甲基)吡啶-2-基)-6-氧亚基-N-(吡咯并[1,2-b]哒嗪-2-基)四氢-3aH-[1,3]二噁戊环并[4,5-c]吡咯-4-甲酰胺(150mg,粗品)。LCMS,M/Z(ESI):476.2[M+H]+。
第七步:(3aS,4S,6aS)-N,2,2-三甲基-5-(6-甲基-4-(三氟甲基)吡啶-2-基)-6-氧亚基-N-(吡咯并[1,2-b]哒嗪-2-基)四氢-3aH-[1,3]二噁戊环并[4,5-c]吡咯-4-甲酰胺
将(3aS,4S,6aS)-2,2-二甲基-5-(6-甲基-4-(三氟甲基)吡啶-2-基)-6-氧亚基-N-(吡咯并[1,2-b]哒嗪-2-基)四氢-3aH-[1,3]二噁戊环并[4,5-c]吡咯-4-甲酰胺溶解在N,N-二甲基甲酰胺(2.00mL)中,然后加入碳酸铯(68.53mg,210.34μmol),反应液在25℃下搅拌30分钟,最后缓慢滴加碘甲烷(44.7mg,315μmol)。反应液在25℃下搅拌2小时。反应完成后,加入水(5mL)稀释,然后用乙酸乙酯(5.0mL*3)萃取,有机相用饱和氯化钠溶液(10mL)洗涤和无水硫酸钠干燥后,过滤浓缩得到粗品。粗品:(3aS,4S,6aS)-N,2,2-三甲基-5-(6-甲基-4-(三氟甲基)吡啶-2-基)-6-氧亚基-N-(吡咯并[1,2-b]哒嗪-2-基)四氢-3aH-[1,3]二噁戊环并[4,5-c]吡咯-4-甲酰胺(20.0mg,粗品)。LCMS,M/Z(ESI):490.1[M+H]+。
第八步:(2S,3S,4S)-3,4-二羟基-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-氧亚基-N-(吡咯并[1,2-b]哒嗪-2-基)吡咯烷-2-甲酰胺(I-2)
将(3aS,4S,6aS)-N,2,2-三甲基-5-(6-甲基-4-(三氟甲基)吡啶-2-基)-6-氧亚基-N-(吡咯并[1,2-b]哒嗪-2-基)四氢-3aH-[1,3]二噁戊环并[4,5-c]吡咯-4-甲酰胺(10.0mg,20.4μmol)溶解在二氯甲烷(1.00mL)中,然后在-20℃下缓慢滴加三氯化硼的二氯甲烷溶液(1M,61.3μL),最后,反应液在25℃搅拌12小时。反应完成后,用饱和碳酸氢钠溶液调pH为9,然后用二氯甲烷(10.0mL*3)萃取,有机相用饱和氯化钠溶液(20.0mL)洗涤和无水硫酸钠干燥后,过滤浓缩得到粗品。粗品经反相高效液相色谱法进行分离纯化,分离方法为:Waters Xbridge 150*25mm*5μm;mobile phase:[water(NH4HCO3)-ACN];B%:28%-58%,8min,纯化后得到(2S,3S,4S)-3,4-二羟基-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-氧亚基-N-(吡咯并[1,2-b]哒嗪-2-基)吡咯烷-2-甲酰胺(3.00mg,产率10.7%)。
1H NMR(400MHz,METHANOL-d4)δ=8.39(s,1H),8.05(s,1H),7.83(s,1H),7.27(s,1H),6.82-7.05(m,2H),6.67(s,1H),5.10-5.39,(m,1H),4.68(br s,1H),4.59(s,2H),4.35(d,J=5.62Hz,1H),3.40(m,3H),2.59(s,3H).
实施例3
以下化合物的制备方法参考实施例1和2,
在本发明测试例中,对照化合物I制备方法参考专利WO2021/028643A1,结构如下所示,
测试例1:化合物对Polθ聚合酶活性抑制试验
本测试所使用的重组Polθ蛋白聚合酶结构域(aa 1819-2590)是通过Invitrogen公司的Bac-to-Bac杆状病毒表达系统表达和纯化得到(Seki,M.et al.2003Nucleic AcidsRes.)。测量Polθ聚合酶活性所使用的检测方法为PicoGreen dsDNA定量检测。
反应体系由溶解于DMSO的化合物、纯化的重组Polθ(aa 1819-2590)蛋白、退火混合物及dNTPs组成。其中所有化合物先用DMSO配制成10mM储备液,使用前用实验缓冲液(25mM Tris HCl pH7.5,12.5mM NaCl,0.5mM MgCl2,5%甘油,0.01% Triton X-100,0.01% BGG和1mM DTT)进行梯度稀释;重组蛋白溶液为终浓度30nM的重组Polθ(aa 1819-2590)蛋白溶解于实验缓冲液中所得;退火混合物为终浓度150nM的引物(5'-GCG GCT GTCATA AG-3')和终浓度150nM的模板(5'-GCT ACA TTG ACA ATG GCA TCA AAT CTC AGA TTGCGT CTT ATG ACA GCC)溶解于实验缓冲液中,加热至42℃ 3min后退火所得;dNTP溶液为终浓度为120μM的dNTP溶解于实验缓冲液中所得。
化合物筛选实验中,先在384孔板(Perkin Elmer-Proxiplate)中加入2μl/well的重组蛋白溶液,随后依次加入0.06μl/well的不同浓度化合物及阴性对照(DMSO),最后加入2μl/well的退火混合物和2μl/well的dNTP。空白对照组仅含有退火混合物和dNTP。将此384孔板用铝箔封口膜密封后,置于37℃下孵育30min,然后通过向测试孔中加入4μl反应终止液(25mM Tris-HCl,10mM阳EDTA以及1:80PicoGreen)终止反应,并于常温避光孵育90min后,在酶标仪(PerkinElmer En2104:λex=485nmλem=520nm)上读取荧光值。抑制率如下计算:抑制率=(1-(化合物组-空白组)/(阴性对照组-空白组))×100%,使用GraphPad Prism8软件计算各化合物的IC50值。
表1.化合物对Polθ聚合酶活性抑制结果
测试化合物 | IC50(nM) |
对照化合物I | 30 |
I-1A | 31 |
I-1B | 6 |
I-2 | 48 |
实验结果表明:本发明化合物对Polθ蛋白聚合酶有良好的抑制作用。
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (17)
1.一种如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药:
环A为5或6元杂芳基,环B为5-8元杂环烷基或5或6元杂芳基;
Y表示C;
R8、R9、R10和R11各自独立地为氢、氘、卤素、羟基、氨基、氰基、C1-C6烷基、-O-C1-C6烷基或-NH-C1-C6烷基;
任选地,所述R8、R9、R10和R11各自独立地被1、2、3或4个选自下列的取代基取代:氘、卤素、羟基、氨基、氰基和C1-C6烷基;当取代基为多个时,所述取代基相同或不同;
m、n、f和g各自独立地为0、1、2或3;当取代基R8、R9、R10和R11为多个时,所述取代基R8、R9、R10和R11相同或不同;
R1、R2和R3各自独立地为氢、氘、卤素、C1-C6烷基、C1-C6卤代烷基、3-6元环烷基或4-8元杂环烷基;
R7为C1-C6烷基、C1-C6氘代烷基或C1-C6卤代烷基。
2.根据权利要求1中所述的如式I所示杂环化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药:
环A为5或6元杂芳基,环B为5-8元杂环烷基或5或6元杂芳基;
Y表示C;
R8、R9、R10和R11各自独立地为氢、卤素、羟基、氨基、氰基、C1-C6烷基、-O-C1-C6烷基或-NH-C1-C6烷基;
任选地,所述R8、R9、R10和R11各自独立地被1、2、3或4个选自下列的取代基取代:卤素、羟基、氨基、氰基和C1-C6烷基;当取代基为多个时,所述取代基相同或不同;
m、n、f和g各自独立地为0、1、2或3;当取代基R8、R9、R10和R11为多个时,所述取代基R8、R9、R10和R11相同或不同;
R1、R2和R3各自独立地为氢、卤素、C1-C6烷基或C1-C6卤代烷基;
R7为C1-C6烷基或C1-C6卤代烷基。
4.根据权利要求1-3中任一项所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药,其特征在于,其满足以下条件中的一种或多种:
(1)R1、R2、R3、R4、R5、R6、R7、R8、R9、R10和R11中,所述卤素独立地为氟、氯、溴或碘,例如氟或氯;
(2)R1、R2、R3、R4、R5、R6、R7、R8、R9、R10和R11中,所述C1-C6烷基独立地为C1-4烷基,例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,还例如为甲基;
(3)R1、R2、R3、R4、R5、R6和R7中,所述C1-C6卤代烷基中卤素独立地为氟、氯、溴或碘,例如氟;
(4)R8、R9、R10和R11中,所述-O-C1-C6烷基或-NH-C1-C6烷基中C1-C6烷基独立地为C1-4烷基,例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基;
(5)R1、R2、R3、R4、R5、R6和R7中,所述C1-C6卤代烷基独立地为C1-C4卤代烷基,例如被1个、2个或3个F取代的C1-C4烷基,还例如,一氟甲基、二氟甲基或三氟甲基;
(6)R1、R2和R3中,所述3-6元环烷基独立地为丙基、环丁基、环戊基或环己基;
(7)R1、R2和R3中,所述4-8元杂环烷基中的杂原子数为1个;
(8)R1、R2和R3中,所述4-8元杂环烷基中的杂原子为N、O或S,例如N;
(10)环A中,所述5或6元杂芳基中的杂原子数为1个;
(11)环A中,所述5或6元杂芳基中的杂原子为N、O或S,例如N;
(12)环B中,所述5-8元杂环烷基中的杂原子数为1个;
(13)环B中,所述5-8元杂环烷基中的杂原子为N、O或S,例如N;
(14)环B中,所述5或6元杂芳基中的杂原子数为1个;和
(15)环B中,所述5或6元杂芳基中的杂原子为N、O或S,例如N。
5.根据权利要求1-3中任一项所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药,其特征在于,其满足以下条件中的一种或多种:
(1)R1、R2和R3各自独立地为氢、C1-C6烷基或C1-C6卤代烷基;
(3)R7为C1-C6烷基或C1-C6氘代烷基;
(4)R8、R9、R10和R11各自独立地为氢、氘、卤素、羟基、氨基、氰基、C1-C6烷基、-O-C1-C6烷基或-NH-C1-C6烷基;
(5)m、n、f和g各自独立地为0、1或2;当取代基R8、R9、R10和R11为多个时,所述取代基R8、R9、R10和R11相同或不同;
(6)环A、环B共同含有1、2或3个N杂原子;任选地还含有1个O或S杂原子;
进一步地,
(7)R1为甲基或三氟甲基;
(8)R2为氢;
(9)R3为三氟甲基;
(11)R5为羟基;
(12)R6为羟基;
(13)R7为甲基或氘代甲基;
(14)R8为氢或卤素;进一步地,R8为氢、氟或氯;
(15)R9为氢;
(16)R10为氢;和
(17)R11为氢、氟或氯。
6.根据权利要求1-3中任一项所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药,其特征在于,环A为5或6元杂芳基,环B为5或6元杂芳基,且环A和环B共同含有1、2或3个N杂原子。
7.根据权利要求1-3中任一项所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药,其特征在于,环A为5或6元杂芳基,环B为5-8元杂环烷基;其中,环A、环B共同含有1或2个N杂原子;任选地,环B还含有1个O或S杂原子;进一步地,环A为5或6元杂芳基,优选环A为5或6元含N杂芳基,环B为5或6元杂环烷基。
8.根据权利要求1-3中任一项所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药,其特征在于,其满足以下条件中的一种或多种:
(1)R2为氢;R1、R3各自独立地为氟、氯、C1-C3烷基、C1-C3氟代烷基或C1-C3氯代烷基;进一步地,R1为甲基或三氟甲基,R2为氢,R3为三氟甲基;更进一步地,R1为甲基,R2为氢,R3为三氟甲基;
(3)R7为甲基、乙基、丙基或C1-C3氟代烷基;较佳地,R7为甲基;
(4)R7为C1-C3氘代烷基;较佳地,R7为氘代甲基;
(5)R1为甲基,R2为氢,R3为3-6元环烷基;较佳地,R3为环丙基;
(6)R8、R9、R10、R11各自独立地为氢、氟、氯、羟基、氨基、氰基、C1-C6烷基、-O-C1-C6烷基或-NH-C1-C6烷基;
(7)R8、R9、R10、R11各自独立地被1、2、3或4个选自下列的取代基取代:氟、氯、C1-C6烷基;当取代基为多个时,所述取代基相同或不同;
进一步地,
(8)R8、R9、R10、R11各自独立地为氢、氟、氯、C1-C3烷基、C1-C3氟代烷基或C1-C3氯代烷基;较佳地,R8、R9、R10、R11各自独立地为氢、氟或氯。
13.一种药物组合物,其特征在于,包括根据权利要求1-12中任一项所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药。
14.根据权利要求13中所述的药物组合物,其特征在于,包括根据权利要求1-12中任一项所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药和
i)一种或多种活性药物;和/或
ii)药学上可接受的载体。
15.根据权利要求1-12中任一项所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药或根据权利要求13-14中任一项所述的药物组合物的用途,其特征在于,包括:
抑制Polθ活性;
和/或,预防和/或治疗Polθ介导的疾病;
和/或,制备用于抑制Polθ,和/或预防和/或治疗Polθ介导的疾病的药物、药物组合物或制剂。
16.根据权利要求15所述的用途,其特征在于,所述Polθ介导的疾病为细胞增殖性病症;较佳地,所述细胞增殖性病症为癌症。
17.根据权利要求1-12中任一项所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药或根据权利要求13-14中任一项所述的药物组合物在制备预防和/或治疗疾病的药物中的应用,所述的疾病为细胞增殖性病症;较佳地,所述细胞增殖性病症为癌症。
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