CN115052881A - 作为HER2抑制剂的[1,3]二嗪并[5,4-d]嘧啶 - Google Patents
作为HER2抑制剂的[1,3]二嗪并[5,4-d]嘧啶 Download PDFInfo
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- CN115052881A CN115052881A CN202180012676.0A CN202180012676A CN115052881A CN 115052881 A CN115052881 A CN 115052881A CN 202180012676 A CN202180012676 A CN 202180012676A CN 115052881 A CN115052881 A CN 115052881A
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Abstract
本发明涉及新型[1,3]二嗪并[5,4‑d]嘧啶和式(I)的衍生物,其中基团R1、R2、R3和R4具有权利要求书和说明书中给出的含义;它们作为HER2及其突变体的抑制剂的用途;含有此类化合物的药物组合物以及它们作为药剂,尤其是作为用于治疗和/或预防肿瘤疾病的药剂的用途。
Description
技术领域
本发明涉及新型[1,3]二嗪并[5,4-d]嘧啶和式(I)的衍生物
其中基团R1、R2、R3和R4具有权利要求书和说明书中给出的含义;它们作为HER2及其突变体的抑制剂的用途;含有此类化合物的药物组合物以及它们作为药剂,尤其是作为用于治疗和/或预防肿瘤疾病的药剂的用途。
背景技术
ERBB跨膜受体酪氨酸激酶(RTK)家族由四个成员EGFR(ERBB1)、HER2(Neu,ERBB2)、HER3(ERBB3)和HER4(ERBB4)组成,所述四个成员在发育过程中发挥重要作用(Citri等人,Nat.Rev.Mol.Cell.Biol.,2006,7(7),505-516;Hynes等人,Curr.Opin.Cell.Biol.,2009,21(2),177-184;Wang,Z.,Methods Mol.Biol.,2017,1652,3-35)。在EGFR、HER3或HER4的细胞外结构域与其各自的配体结合以及随后ERBB家族成员的同源或异源二聚化时启动ERBB信号传导。尚未鉴定出配体的HER2是其他ERBB成员的优选的二聚化配偶体。一旦形成活性配体-受体复合物,则EGFR、HER2或HER4的细胞内酪氨酸激酶结构域通过自身磷酸化或转磷酸化被激活,并且随后引发信号转导级联反应,所述信号转导级联反应最显著地衔接有丝分裂原活化蛋白(MAP)激酶和/或磷酸肌醇3-激酶(PI3K)通路(Citri等人,Nat.Rev.Mol.Cell.Biol.,2006,7(7),505-516;Hynes等人,Curr.Opin.Cell.Biol.,2009,21(2),177-184;Wang,Z.,Methods Mol.Biol.,2017,1652,3-35.)。
异常的ERBB信号传导牵涉在包括癌症或神经系统疾病在内的几种病理生理病症中。在癌症中,ERBB信号传导通过突变被过度激活,所述突变通过促进二聚化或将平衡移向激酶的活性构象异构体和/或通过扩增和随后的RTK过表达而使RTK具有组成型活性。两种致癌机制都会增加ERBB信号传导的净输出并且从而促进细胞存活、细胞生长和增殖(Arteaga等人,Cancer Cell,2014,25(3),282-303)。
在多种人类恶性肿瘤中观察到异常HER2信号传导。描述了蛋白质的细胞外、(近)膜和细胞内区域的致癌突变。总的来说,这些突变使HER2具有组成型活性,促进了癌症的发生、肿瘤的维持和生长(Connell等人,ESMO Open,2017,2(5),e000279)。类似地,HER2过表达增加了HER2信号传导,并且在包括乳腺癌、胃癌或肺癌在内的各种适应证中成为致瘤性转化和肿瘤维持的基础。
因此,干扰HER2致癌信号传导会导致抑制肿瘤生长。靶向疗法包括针对HER2的抗体(包括曲妥珠单抗和帕妥珠单抗)、针对HER2的抗体-药物缀合物(曲妥珠单抗-DM1(T-DM1,ado-恩美-曲妥珠单抗))和抑制HER2激酶结构域的小分子(阿法替尼、来那替尼、拉帕替尼)。
总之,由HER2致癌突变或HER2野生型扩增驱动的肿瘤可能受益于HER2特异性酪氨酸激酶抑制剂(TKI)。总的来说,HER2改变影响高达6%-7%的所有人类癌症,并且保留(sparing)EGFR野生型的TKI(酪氨酸激酶抑制剂)可能成为一种有效的治疗选择。
尽管存在相对于EGFR野生型具有选择性的HER2野生型抑制剂(诸如妥卡替尼(tucatinib)),但是这些抑制剂对携带外显子20突变的HER2没有功效。其他选择性野生型HER2抑制剂已经公开于现有技术文件WO 2003/049740、WO 2007/059257、WO2005/044302中。
HER2外显子20突变构成导致激酶活性增强的HER2功能获得性突变的子集(Wang等人Cancer Cell,2006,10(1):25-38)。这种增强的HER2激酶活性进入下游信号传导级联,所述下游信号传导级联通过促进突变细胞的生长、增殖和存活来刺激致瘤性转化。
基因工程化小鼠模型的研究表明,NSCLC中最普遍的HER2外显子20突变(即4个氨基酸YVMA(p.A775_G776insYVMA)的复制)是驱动致癌生长所必需的并且足以驱动致癌生长(Perera等人,Proc.Natl.Acad.Sci.USA,2009,106(2),474-479)。HER2-YVMA表达的消除与肿瘤缩小相关,这表明HER2的这种致癌变体是肿瘤维持所必需的(Perera等人2009)。此外,这项研究表明,在小鼠模型中,泛ERBB阻断剂阿法替尼在体内是有效的,并且可以干扰HER2-YVMA的致癌信号传导(Perera等人2009)。
NSCLC中HER2的致癌突变主要影响HER2的酪氨酸激酶结构域并且簇集在ERBB2基因的外显子20中(Stephens等人,Nature,2004,431(7008),525-6)。据估计,2%-4%的肺癌患者携带HER2外显子20的激活突变。临床批准的ERBB靶向酪氨酸激酶抑制剂对这些患者无效,因为它们受到EGFR野生型介导的剂量限制毒性的限制。阿法替尼和其他泛ERBB阻断剂在HER2外显子20突变的NSCLC患者中显示出有限的功效,主要是由于达到有效剂量的限制。特别地,EGFR野生型介导的毒性限制了有效剂量。
艾力替尼(allitinib)、依鲁替尼、来那替尼、波齐替尼和吡咯替尼(pyrotinib)是已知的突变型HER2外显子20的泛ERBB抑制剂。突变型HER2外显子20的其他抑制剂已经公开于现有技术文件WO 2015/175632、WO 2015/195228、WO 2016/183278和WO2019/046775中。
对于选择性靶向HER2外显子20突变蛋白同时保留EGFR野生型以克服EGFR野生型介导的剂量限制毒性的缺点的化合物存在高度未满足的医疗需求。
已经发现,本发明的化合物以正构和共价同时的方式与野生型和突变型HER2外显子20的酪氨酸激酶结构域结合,同时保留EGFR野生型,并且充当野生型HER2和在外显子20中携带突变的突变型HER2的选择性抑制剂。
发明内容
本发明的目的是提供相对于EGFR野生型具有选择性的突变型HER2外显子20的新抑制剂。与现有技术的化合物相比,除了相对于EGFR野生型具有高选择性外,本发明的化合物还充当HER2外显子20的选择性抑制剂并且显示出改善的野生型EGFR保留功效特征。此外,本发明的一些化合物显示出改善的药代动力学和药理学特征,诸如良好的代谢稳定性。
本发明的化合物可用于预防和/或治疗以过度或异常细胞增殖为特征的疾病和/或病症,特别是用于治疗和/或预防癌症。
具体实施方式
本发明涉及新型[1,3]二嗪并[5,4-d]嘧啶和式(I)的衍生物
其中
(A0)
R1选自氢、-CH3、-CCH、-OCH3和卤素
(B0)
R2是氢或卤素
(C0)
R3是氢或卤素
(D0)
R4是氢或-CH3
并且R1、R2和R3中的至少一个不是氢
或其盐。
在另一个实施方案(A1)中,本发明涉及式(I)的化合物,其中
R1选自-CH3、-CCH、-OCH3和卤素
或其盐。
在另一个实施方案(A2)中,本发明涉及式(I)的化合物,其中
R1选自-CH3和卤素
或其盐。
在另一个实施方案(A3)中,本发明涉及式(I)的化合物,其中
R1选自-CH3、氯和氟
或其盐。
在另一个实施方案(A4)中,本发明涉及式(I)的化合物,其中
R1是氢
或其盐。
在另一个实施方案(A5)中,本发明涉及式(I)的化合物,其中
R1是-CH3
或其盐。
在另一个实施方案(A6)中,本发明涉及式(I)的化合物,其中
R1选自氯、溴和氟
或其盐。
在另一个实施方案(A7)中,本发明涉及式(I)的化合物,其中
R1是氯
或其盐。
在另一个实施方案(A8)中,本发明涉及式(I)的化合物,其中
R1是氟
或其盐。
在另一个实施方案(B1)中,本发明涉及式(I)的化合物,其中
R2是氢
或其盐。
在另一个实施方案(B2)中,本发明涉及式(I)的化合物,其中
R2是卤素
或其盐。
在另一个实施方案(B3)中,本发明涉及式(I)的化合物,其中
R2选自氯、溴和氟
或其盐。
在另一个实施方案(B4)中,本发明涉及式(I)的化合物,其中
R2是氯
或其盐。
在另一个实施方案(B5)中,本发明涉及式(I)的化合物,其中
R2是氟
或其盐。
在另一个实施方案(C1)中,本发明涉及式(I)的化合物,其中
R3是氢
或其盐。
在另一个实施方案(C2)中,本发明涉及式(I)的化合物,其中
R3是卤素
或其盐。
在另一个实施方案(C3)中,本发明涉及式(I)的化合物,其中
R3是氯
或其盐。
在另一个实施方案(C4)中,本发明涉及式(I)的化合物,其中
R3是氟
或其盐。
在另一个实施方案(D1)中,本发明涉及式(I)的化合物,其中
R4是氢
或其盐。
在另一个实施方案(D2)中,本发明涉及式(I)的化合物,其中
R4是-CH3
或其盐。
上述单独的实施方案呈现了式(I)的化合物的结构亚组(A0)至(A8)、(B0)至(B5)、(C0)至(C2)和(D0)至(D2)。这些结构亚组可以彼此组合为(A)(B)(C)(D)以具体定义式(I)的化合物的本发明的另外实施方案。因此,本发明的进一步的实施方案在本文中被定义为式(I)的化合物;被定义为特定结构亚组(A)(B)(C)(D)的组合,其中(A)选自(A0)至(A8);(B)选自(B0)至(B5);(C)选自(C0)至(C4)并且(D)选自(D0)至(D2)。
本发明进一步涉及其式(I)的化合物的水合物、溶剂化物、多晶型物、代谢物和前药。
在另一个实施方案中,本发明涉及式(I)的化合物的药学上可接受的盐。
本发明的优选的实施方案是选自实施例I-01至I-8的上述式(I)的化合物。
或其盐。
本发明的进一步优选的实施方案是选自实施例I-01至I-8的上述式(I)的化合物的药学上可接受的盐。
本发明的进一步优选的实施方案是实施例I-01的化合物。
本发明的进一步优选的实施方案是实施例I-02的化合物。
本发明的进一步优选的实施方案是实施例I-03的化合物。
本发明的进一步优选的实施方案是实施例I-04的化合物。
本发明的进一步优选的实施方案是实施例I-05的化合物。
本发明的进一步优选的实施方案是实施例I-06的化合物。
本发明的进一步优选的实施方案是实施例I-07的化合物。
本发明的进一步优选的实施方案是实施例I-08的化合物。
本发明的进一步优选的实施方案是实施例I-01的化合物的药学上可接受的盐。
本发明的进一步优选的实施方案是实施例I-02的化合物的药学上可接受的盐。
本发明的进一步优选的实施方案是实施例I-03的化合物的药学上可接受的盐。
本发明的进一步优选的实施方案是实施例I-04的化合物的药学上可接受的盐。
本发明的进一步优选的实施方案是实施例I-05的化合物的药学上可接受的盐。
本发明的进一步优选的实施方案是实施例I-06的化合物的药学上可接受的盐。
本发明的进一步优选的实施方案是实施例I-07的化合物的药学上可接受的盐。
本发明的进一步优选的实施方案是实施例I-08的化合物的药学上可接受的盐。
在另一方面,本发明涉及抑制细胞中野生型和/或突变型HER2的方法,所述方法包括使所述细胞与式(I)的化合物接触。在另一方面,本发明涉及抑制细胞中携带外显子20突变的HER2的方法,所述方法包括使所述细胞与式(I)的化合物接触。
在另一方面,本发明涉及抑制细胞中野生型和/或突变型HER2的磷酸化的方法,所述方法包括使所述细胞与式(I)的化合物接触。在另一个实施方案中,本发明涉及抑制细胞中HER2外显子20突变体的磷酸化的方法,所述方法包括使所述细胞与式(I)的化合物接触。
在另一方面,本发明涉及式(I)的化合物或其药学上可接受的盐用于治疗和/或预防疾病和/或病症的用途,其中抑制野生型和/或突变型HER2具有治疗益处。在另一个实施方案中,本发明涉及式(I)的化合物或其药学上可接受的盐用于治疗和/或预防疾病和/或病症的用途,其中抑制HER2外显子20突变蛋白具有治疗益处。
在另一方面,本发明涉及式(I)的化合物或其药学上可接受的盐,用于在用于抑制有需要的人类受试者的野生型和/或突变型HER2的方法中使用,所述方法包括向所述受试者施用治疗有效量的式(I)的化合物或其药学上可接受的盐。在另一个实施方案中,本发明涉及式(I)的化合物或其药学上可接受的盐,用于在用于抑制有需要的人类受试者的HER2外显子20突变体的方法中使用,所述方法包括向所述受试者施用治疗有效量的式(I)的化合物或其药学上可接受的盐。
在另一方面,本发明涉及式(I)的化合物或其药学上可接受的盐,其用作药剂。
在另一方面,本发明涉及式(I)的化合物或其药学上可接受的盐,用于治疗和/或预防癌症。在另一个实施方案中,本发明涉及式(I)的化合物或其药学上可接受的盐,用于治疗和/或预防癌症,其中所述癌症具有HER2过表达和/或HER2扩增。在另一个实施方案中,本发明涉及式(I)的化合物或其药学上可接受的盐,用于治疗和/或预防癌症,其中所述癌症是HER2外显子20突变癌症。在另一个实施方案中,本发明涉及式(I)的化合物或其药学上可接受的盐,用于治疗和/或预防癌症,其中HER2过表达、HER2扩增和/或HER2外显子20突变癌症选自:脑癌、乳腺癌、胆管癌、膀胱癌、宫颈癌、结直肠癌、子宫内膜癌、皮肤癌、食管肿瘤、头颈肿瘤、胃肠癌、胆囊肿瘤、肾癌、肝癌、肺癌和前列腺癌。
在另一方面,本发明涉及一种治疗和/或预防上述疾病和病症的方法,所述方法包括向人类施用治疗有效量的式(I)的化合物或其药学上可接受的盐。
在另一方面,本发明涉及式(I)的化合物或其药学上可接受的盐,用于治疗和/或预防上述疾病和病症。
在另一方面,本发明涉及式(I)的化合物或其药学上可接受的盐在制备用于治疗和/或预防上述疾病和病症的药剂中的用途。
此外,可以用本发明的化合物治疗以下癌症、肿瘤和其他增殖性疾病,但不限于此:
头和颈的癌症/肿瘤/癌:例如,鼻腔、鼻旁窦、鼻咽、口腔(包括唇、牙龈、牙槽嵴、磨牙后三角、口底、舌、硬腭、颊粘膜),口咽(包括舌底、扁桃体、扁桃体柱、软腭、扁桃体窝、咽壁)、中耳、喉(包括上喉、声门、声门下、声带)、下咽、唾液腺(包括小唾液腺)的肿瘤/癌/癌症;
肺部的癌症/肿瘤/癌:例如,非小细胞肺癌(NSCLC)(鳞状细胞癌、梭形细胞癌、腺癌、大细胞癌、透明细胞癌、细支气管肺泡)、小细胞肺癌(SCLC)(燕麦细胞癌、中间细胞癌、混合型燕麦细胞癌);
纵膈的赘生物:例如,神经源性肿瘤(包括神经纤维瘤、神经鞘瘤、恶性神经鞘瘤、神经肉瘤、神经节神经母细胞瘤、神经节瘤、神经母细胞瘤、嗜铬细胞瘤、副神经节瘤)、生殖细胞瘤(包括精原细胞瘤、畸胎瘤、非精原细胞瘤)、胸腺肿瘤(包括胸腺瘤、胸腺脂肪瘤、胸腺癌、胸腺类癌)、间充质肿瘤(包括纤维瘤、纤维肉瘤、脂肪瘤、脂肪肉瘤、粘液瘤、间皮瘤、平滑肌瘤、平滑肌肉瘤、横纹肌肉瘤、黄色肉芽肿、间叶瘤、血管瘤、血管内皮瘤、血管外皮细胞瘤、淋巴管瘤、淋巴管外皮细胞瘤、淋巴管肌瘤);
胃肠(GI)道的癌症/肿瘤/癌:例如食管、胃(胃癌)、胰腺、肝和胆系的癌症/肿瘤/癌(包括肝细胞癌(HCC),例如儿童期HCC、纤维板层HCC、混合型HCC、梭形细胞HCC、透明细胞HCC、巨细胞HCC、癌肉瘤HCC、硬化性HCC;肝母细胞瘤;胆管癌;胆管细胞癌;肝囊腺癌;血管肉瘤、血管内皮瘤、平滑肌肉瘤、恶性神经鞘瘤、纤维肉瘤、Klatskin瘤)、胆囊、肝外胆管、小肠(包括十二指肠、空肠、回肠)、大肠(包括盲肠、结肠、直肠、肛门;结直肠癌、胃肠道间质瘤(GIST))、泌尿生殖系统(包括肾,例如肾盂、肾细胞癌(RCC)、肾母细胞瘤(Wilms瘤)、肾上腺样瘤、Grawitz瘤;输尿管;膀胱,例如脐尿管癌、尿路上皮癌;尿道,例如远端、球膜状的、前列腺的;前列腺(雄激素依赖性、雄激素非依赖性、去势抗性、激素非依赖性、激素抵抗)、阴茎)的肿瘤/癌/癌症;
睾丸癌症/肿瘤/癌:例如,精原细胞瘤、非精原细胞瘤;
妇科癌症/肿瘤/癌:例如,卵巢、输卵管、腹膜、子宫颈、外阴、阴道、子宫体(包括子宫内膜、基底)的肿瘤/癌/癌症;
乳腺的癌症/肿瘤/癌:例如乳腺癌(浸润性导管、胶体、小叶侵袭、小管、囊性、乳突、髓质、粘液性)、激素受体阳性乳腺癌(雌激素受体阳性乳腺癌、孕酮受体阳性乳腺癌)、HER2阳性乳腺癌、三阴性乳腺癌、佩吉特乳腺疾病;
内分泌系统的癌症/肿瘤/癌:例如,以下的肿瘤/癌/癌症:内分泌腺、甲状腺(甲状腺癌/肿瘤;乳头状的、滤泡性的、间变性的、髓样的)、甲状旁腺(甲状旁腺癌/肿瘤)、肾上腺皮质(肾上腺皮质癌/肿瘤)、脑垂体(包括泌乳素瘤、颅咽管瘤)、胸腺、肾上腺、松果体、颈动脉体、胰岛细胞瘤、副神经节、胰腺内分泌肿瘤(PET;非功能性PET、胰多肽瘤(PPoma)、胃泌素瘤、胰岛素瘤、血管活性肠肽瘤(VIPoma)、胰高血糖素瘤、生长抑素瘤、生长激素释放因子瘤(GRFoma)、促肾上腺皮质激素瘤(ACTHoma))、类癌肿瘤;
软组织肉瘤:例如纤维肉瘤、纤维性组织细胞瘤、脂肪肉瘤、平滑肌肉瘤、横纹肌肉瘤、血管肉瘤、淋巴管肉瘤、卡波西肉瘤、血管球瘤、血管外皮细胞瘤、滑膜肉瘤、肌腱鞘巨细胞瘤、胸膜和腹膜孤立性纤维肿瘤、弥漫性间皮瘤、恶性外周神经鞘膜瘤(MPNST)、颗粒细胞瘤、透明细胞肉瘤、黑素细胞神经鞘瘤、丛状肉瘤(plexosarcoma)、神经母细胞瘤、神经节神经母细胞瘤、神经上皮瘤、骨外尤文氏肉瘤、副神经节瘤、骨外软骨肉瘤、骨外骨肉瘤、间叶瘤、腺泡状软组织肉瘤、上皮样肉瘤、肾外横纹肌样瘤、促结缔组织增生小细胞肿瘤;
骨肉瘤:例如骨髓瘤、网状细胞肉瘤、软骨肉瘤(包括中央、外周、透明细胞、间叶性软骨肉瘤)、骨肉瘤(包括骨旁、骨膜、高恶性表面、小细胞、辐射诱导的骨肉瘤、佩吉特氏肉瘤)、尤文氏肿瘤、恶性巨细胞瘤、釉质瘤、(纤维)组织细胞瘤、纤维肉瘤、脊索瘤、小圆细胞肉瘤、血管内皮瘤、血管外皮细胞瘤、骨软骨瘤、骨样骨瘤、成骨细胞瘤、嗜酸性肉芽肿、软骨母细胞瘤;
间皮瘤:例如,胸膜间皮瘤、腹膜间皮瘤;
皮肤的癌症:例如,基底细胞癌、鳞状细胞癌、默克尔细胞癌、黑色素瘤(包括皮肤、浅表扩散型、恶性雀斑样痣、肢端雀斑样、结节、眼内黑色素瘤)、光化性角化病、眼睑癌;
中枢神经系统和脑的赘生物:例如,星形细胞瘤(脑、小脑、弥漫性、纤维性、间变性、毛细胞型、原浆型、胖细胞型)、胶质母细胞瘤、神经胶质瘤、少突神经胶质瘤、少突星形细胞瘤、室管膜瘤、室管膜母细胞瘤、脉络膜丛肿瘤、成神经管细胞瘤、脑膜瘤、神经鞘瘤、血管母细胞瘤、血管瘤、血管外皮细胞瘤、神经瘤、神经节细胞瘤、神经母细胞瘤、视网膜母细胞瘤、神经鞘瘤(例如,听觉)、脊髓轴肿瘤;
淋巴瘤和白血病:例如,B细胞非霍奇金淋巴瘤(NHL)(包括小淋巴细胞淋巴瘤(SLL)、淋巴浆细胞样淋巴瘤(LPL)、套细胞淋巴瘤(MCL)、滤泡性淋巴瘤(FL)、弥漫性大细胞淋巴瘤(DLCL)、伯基特淋巴瘤(BL))、T细胞非霍奇金淋巴瘤(包括间变性大细胞淋巴瘤(ALCL)、成人T细胞白血病/淋巴瘤(ATLL)、皮肤T细胞淋巴瘤(CTCL)、周围T细胞淋巴瘤(PTCL))、淋巴细胞性T细胞淋巴瘤(T-LBL)、成人T细胞淋巴瘤、淋巴细胞B细胞淋巴瘤(B-LBL)、免疫细胞瘤、慢性B细胞淋巴细胞白血病(BchlorineL)、慢性T细胞淋巴细胞白血病(TchlorineL)B细胞小淋巴细胞淋巴瘤(B-SLL)、皮肤T细胞淋巴瘤(CTLC)、原发性中枢神经系统淋巴瘤(PCNSL)、免疫母细胞瘤、霍奇金病(HD)(包括结节性淋巴细胞优势型HD(NLPHD)、结节性硬化HD(NSHD)、混合细胞性HD(MCHD)、富于淋巴细胞的经典型HD、淋巴细胞耗竭型HD(LDHD))、大颗粒淋巴细胞白血病(LGL)、慢性髓性白血病(CML)、急性髓性/髓样白血病(AML)、急性淋巴/成淋巴细胞白血病(ALL)、急性前髓细胞性白血病(APL)、慢性淋巴细胞/淋巴白血病(CLL)、幼淋巴细胞白血病(PLL)、毛细胞白血病、慢性髓性/髓样白血病(CML)、骨髓瘤、浆细胞瘤、多发性骨髓瘤(MM)、浆细胞瘤、骨髓增生异常综合征(MDS)、慢性粒单核细胞白血病(CMML);
原发部位不明的癌症(CUP);
上述所有癌症/肿瘤/癌,其特征在于它们在体内的特定位置/起源意在包括原发性肿瘤和由其衍生的转移性肿瘤。
上述所有癌症/肿瘤/癌可以通过其组织病理学分类进一步区分:
上皮癌症,例如鳞状细胞癌(SCC)(原位癌、浅表侵袭性、疣状癌、假肉瘤、间变性、移行细胞、淋巴上皮)、腺癌(AC)(分化良好的、粘液性、乳突、多形性巨细胞、导管、小细胞、印戎细胞、梭形细胞、透明细胞、燕麦细胞、胶体、腺鳞、粘液表皮样、腺样囊性)、粘液性囊腺癌、腺泡细胞癌、大细胞癌、小细胞癌、神经内分泌肿瘤(小细胞癌、副神经节细胞瘤、类癌);嗜酸性细胞癌;
非上皮性癌症,例如肉瘤(纤维肉瘤、软骨肉瘤、横纹肌肉瘤、平滑肌肉瘤、血管肉瘤、巨细胞肉瘤、淋巴肉瘤、纤维组织细胞瘤、脂肪肉瘤、血管肉瘤、淋巴管肉瘤、神经纤维肉瘤)、淋巴瘤、黑色素瘤、生殖细胞肿瘤、血液赘生物、混合和未分化癌。
在另一个方面,本发明涉及式(I)的化合物或其药学上可接受的盐,用于治疗和/或预防癌症,其中将所述化合物与细胞抑制活性物质和/或细胞毒性活性物质组合和/或与放射疗法和/或免疫疗法组合施用。
在另一方面,本发明涉及式(I)的化合物或其药学上可接受的盐与细胞抑制活性物质和/或细胞毒性活性物质的组合和/或与放射疗法和/或免疫疗法的组合,用于治疗和/或预防癌症。
在另一方面,本发明涉及一种治疗和/或预防癌症的方法,其中所述方法包括施用式(I)的化合物或其药学上可接受的盐与细胞抑制活性物质和/或细胞毒性活性物质的组合和/或与放射疗法和/或免疫疗法的组合。
本发明的化合物可以单独使用或与一种或若干种其他药理学活性物质组合使用,所述药理学活性物质诸如现有技术或标准护理化合物,例如像细胞增殖抑制剂、抗血管生成物质、类固醇或免疫调节剂/检查点抑制剂等。
可以与根据本发明的化合物组合施用的药理学活性物质包括但不限于:激素、激素类似物和抗激素药(例如他莫昔芬、托瑞米芬、雷洛昔芬、氟维司群、醋酸甲地孕酮、氟他胺、尼鲁米特、比卡鲁胺、氨鲁米特、醋酸环丙孕酮、非那雄胺、醋酸布舍瑞林、氟氢可的松、氟甲睾酮、甲羟孕酮、奥曲肽)、芳香酶抑制剂(例如阿那曲唑、来曲唑、利阿唑、氟氯唑、依西美坦、阿他美坦)、LHRH激动剂和拮抗剂(例如醋戈舍瑞林、鲁珀若利得(luprolide))、生长因子和/或其相应受体的抑制剂(生长因子例如像血小板衍生生长因子(PDGF)、成纤维细胞生长因子(FGF)、血管内皮生长因子(VEGF)、表皮生长因子(EGF)、胰岛素样生长因子(IGF)、人表皮生长因子(HER,例如HER2、HER3、HER4)和肝细胞生长因子(HGF)和/或其相应的受体)、抑制剂是例如(抗)生长因子抗体、(抗)生长因子受体抗体和酪氨酸激酶抑制剂,例如像西妥昔单抗、吉非替尼、阿法替尼、尼达尼布、伊马替尼、拉帕替尼、博舒替尼、贝伐单抗、帕妥珠单抗和曲妥珠单抗);抗代谢药(例如抗叶酸药诸如甲氨蝶呤、雷替曲塞、嘧啶类似物诸如5-氟尿嘧啶(5fluorineU)、核糖核苷和脱氧核糖核苷类似物、卡培他滨和吉西他滨、嘌呤和腺苷类似物诸如巯基嘌呤、硫鸟嘌呤、克拉屈滨和喷司他丁、阿糖胞苷(ara C)、氟达拉滨);抗肿瘤抗生素(例如蒽环类诸如多柔比星、多喜(doxil)(聚乙二醇化脂质体多柔比星盐酸盐、柔比星(myocet)(非聚乙二醇化脂质体多柔比星)、柔红霉素、表柔比星和伊达比星、丝裂霉素C、博来霉素、更生霉素、普卡霉素、链脲佐菌素);铂衍生物(例如顺铂、奥沙利铂、卡铂);烷基化剂(例如雌莫司汀、氮芥、美法仑、苯丁酸氮芥、白消安、达卡巴嗪、环磷酰胺、异环磷酰胺、替莫唑胺、亚硝基脲例如像卡莫司汀和洛莫司汀、噻替哌);抗有丝分裂剂(例如长春花生物碱例如像长春碱、长春地辛、长春瑞滨和长春新碱;和紫杉烷诸如紫杉醇、多西他赛);血管生成抑制剂(例如他喹莫德)、微管抑制剂;DNA合成抑制剂、PARP抑制剂、拓扑异构酶抑制剂(例如表鬼臼毒素例如像依托泊苷(etoposide)和凡毕复(etopophos)、替尼泊苷、安吖啶(amsacrin)、拓扑替康、伊立替康、米托蒽醌)、丝氨酸/苏氨酸激酶抑制剂(如PDK 1抑制剂、Raf抑制剂、A-Raf抑制剂、B-Raf抑制剂、C-Raf抑制剂、mTOR抑制剂、mTORC1/2抑制剂、PI3K抑制剂、PI3Kα抑制剂、双mTOR/PI3K抑制剂、STK 33抑制剂、AKT抑制剂、PLK 1抑制剂、CDK的抑制剂、极光激酶抑制剂)、酪氨酸激酶抑制剂(例如PTK2/FAK抑制剂)、蛋白质-蛋白质相互作用抑制剂(例如IAP活化剂、Mcl-1、MDM2/MDMX)、MEK抑制剂、ERK抑制剂、FLT3抑制剂、BRD4抑制剂、IGF-1R抑制剂、TRAILR2激动剂、Bcl-2抑制剂、Bcl-xL抑制剂、Bcl-2/Bcl-xL抑制剂、ErbB受体抑制剂、BCR-ABL抑制剂、ABL抑制剂、Src抑制剂、雷帕霉素类似物(例如依维莫司、替西罗莫司、地磷莫司、西罗莫司)、雄激素合成抑制剂、雄激素受体抑制剂、DNMT抑制剂、HDAC抑制剂、ANG1/2抑制剂、CYP17抑制剂、放射性药物、蛋白酶体抑制剂、免疫治疗剂诸如免疫检查点抑制剂(例如CTLA4、PD1、PD-L1、PD-L2、LAG3和TIM3结合分子/免疫球蛋白例如像伊匹单抗、纳武单抗、派姆单抗)、ADCC(抗体依赖性细胞介导的细胞毒性)增强剂(例如抗CD33抗体、抗CD37抗体、抗CD20抗体)、T细胞衔接剂(engager)(例如双特异性T细胞衔接剂像例如CD3 x BCMA、CD3 x CD33、CD3 x CD19)、PSMA xCD3)、肿瘤疫苗和各种化学治疗剂诸如氨磷汀(amifostin)、阿那格雷、氯膦酸盐(clodronat)、非尔司亭、干扰素、干扰素α、亚叶酸、丙卡巴肼、左旋咪唑、美丝钠、米托坦、帕米膦酸二钠和卟菲尔钠。
在另一方面,本发明涉及一种药物组合物,所述药物组合物包含至少一种式(I)的化合物或其药学上可接受的盐和任选地至少一种药学上可接受的载体。
在另一方面,本发明涉及一种药物组合物,所述药物组合物包含式(I)的化合物或其药学上可接受的盐和至少一种其他细胞抑制活性物质和/或细胞毒性活性物质。
在另一方面,本发明涉及一种药物组合物,所述药物组合物包含治疗有效量的至少一种式(I)的化合物或其药学上可接受的盐和一种或多种药学上可接受的赋形剂。
用于施用本发明化合物的合适制剂将对于本领域普通技术人员而言是显而易见的,并且包括例如片剂、丸剂、胶囊、栓剂、锭剂、糖锭剂、溶液-特别是注射(皮下、静脉内、肌内)和输注(注射剂)用溶液-酏剂、糖浆、扁囊剂、乳液、吸入剂或可分散粉剂。
合适的片剂可以例如通过将式(I)的一种或多种化合物与已知的赋形剂(例如惰性稀释剂、载体、崩解剂、佐剂、表面活性剂、粘合剂和/或润滑剂)混合而获得。
每天适用的式(I)的化合物的剂量范围通常为1mg至2000mg,优选10至1000mg。
静脉内使用的剂量为在不同输注速率下1mg至1000mg,优选在不同输注速率下5mg至500mg。
然而,有时可能需要偏离指定的量,取决于体重、年龄、施用途径、疾病的严重程度、对药物的个体反应、其配制品的性质以及施用药物的时间或间隔(每天一剂或多剂连续或间歇治疗)。因此,在某些情况下,使用小于上面给出的最小剂量可为足够的,而在其他情况下,可能必须超过上限。当大量施用时,在一天内将其分成多个较小剂量可为取的。
通用定义
在本文中未明确定义的术语应当被理解为具有本领域技术人员根据本公开文本和上下文能得出的含义。然而,如在本说明书中使用,除非有相反说明,否则以下术语具有所指示的含义,且遵循以下惯例。
在以下定义的基团(group、radical)或部分中,碳原子数目通常在基团之前指定,例如,C1-6烷基是指具有1到6个碳原子的烷基或烷基。
在像OH、NH2、S(O)、S(O)2、CN(氰基)、COOH、CF3等的基团中,技术人员可以从基团本身的自由化合价中看出与分子的一个或多个基团附接点。
在本发明化合物以化学名称的形式或作为结构式进行描述时,在任何不一致的情况下,应以所述结构式为准。星号可以用于子式中以指示与如所定义的核心分子连接的键。
取代基的原子的编号开始于与核心或与取代基所附接的基团最靠近的原子。
术语“卤素”表示氟、氯、溴和/或碘原子。
如本文所用的术语“取代的”意指指定原子上的任何一个或多个氢被指定基团的选择替换,其条件是不超过指定原子的正常化合价,并且该取代产生稳定化合物。
除非明确指出,否则在整个说明书和所附权利要求书中,给定的化学式或名称应涵盖互变异构体和所有立体、光学和几何异构体(例如对映体、非对映体、E/Z异构体等)及其外消旋体以及不同比例的单独的对映体的混合物、非对映体的混合物、或任何前述形式的混合物(在此类异构体和对映体存在的情况下)、以及盐(包括其药学上可接受的盐)和其溶剂化物(例如像水合物,包括游离化合物的溶剂化物和水合物或者化合物的盐的溶剂化物和水合物)。
通常,基本上纯的立体异构体可以根据本领域技术人员已知的合成原理,例如通过分离相应的混合物、通过使用立体化学纯的起始原料和/或通过立体选择性合成来获得。本领域已知如何制备光学活性形式,诸如通过拆分外消旋形式或通过合成,例如从光学活性起始材料开始和/或通过使用手性试剂。
本发明的对映异构体纯的化合物或中间体可以通过不对称合成制备,例如通过制备和随后分离适当的非对映异构体化合物或中间体,其可以通过已知方法(例如,通过色谱分离或结晶)和/或通过使用手性试剂(诸如手性原料、手性催化剂或手性助剂)来分离。
此外,本领域技术人员已知如何从相应的外消旋混合物制备对映异构体纯的化合物,诸如通过在手性固定相上色谱分离相应的外消旋混合物或通过使用适当的拆分剂拆分外消旋混合物,诸如借助用光学活性的酸或碱进行外消旋化合物的非对映异构体盐形成、随后拆分所述盐并且从所述盐中释放所希望的化合物或通过用光学活性的手性助剂衍生化相应的外消旋化合物、随后进行非对映异构体分离并且除去手性辅助基团,或者通过对外消旋体的动力学拆分(例如,通过酶促拆分);通过在合适的条件下从对映形态晶体的聚集物对映选择性结晶或通过在光学活性手性助剂的存在下从合适的溶剂中(分级)结晶。
短语“药学上可接受的”在本文中用于指在正确医学判断范畴内,适用于与人类和动物的组织接触使用而无过度毒性、刺激、过敏反应或其他问题或并发症且与合理益处/风险比相称的那些化合物、材料、组合物和/或剂型。
如本文所用,“药学上可接受的盐”是指所公开的化合物的衍生物,其中母体化合物通过制备其酸盐或碱盐而被修饰。药学上可接受的盐的实例包括但不限于碱性残基(诸如胺)的无机酸盐或有机酸盐;酸性残基(诸如羧酸)的碱金属盐或有机盐;及其类似物。
例如,此类盐包括来自苯磺酸、苯甲酸、柠檬酸、乙磺酸、富马酸、龙胆酸、氢溴酸、盐酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、4-甲基-苯磺酸、磷酸、水杨酸、琥珀酸、硫酸和酒石酸的盐。
可以用来自氨、L-精氨酸、钙、2,2’-亚氨基双乙醇、L-赖氨酸、镁、N-甲基-D-葡糖胺、钾、钠和三(羟甲基)-氨基甲烷的阳离子形成其他药学上可接受的盐。
本发明的药学上可接受的盐可以通过常规化学方法从含有碱性或酸性部分的母体化合物合成。通常,此类盐可以通过使这些化合物的游离酸或碱形式与足量的适当的碱或酸在水中或在有机稀释剂如醚、乙酸乙酯、乙醇、异丙醇或乙腈或其混合物中反应来制备。
除上述那些之外的其他酸的盐(其例如可用于纯化或分离本发明的化合物(例如三氟乙酸盐))也构成本发明的一部分。
对于二价基团,其中至关重要的是确定它们与哪些相邻基团结合以及以哪种化合价结合,相应的结合配偶体在必要时出于澄清的目的用括号指示,如在以下图示中:
基团或取代基通常从具有相应基团名称(例如,Ra、Rb等)的许多替代基团/取代基中选择。如果重复使用这种基团以在分子的不同部分中定义根据本发明的化合物,则应当指出各种使用被认为是完全彼此独立的。
如本文所用的术语“治疗有效量”是指能够消除病患的症状或者预防或缓解这些症状,或者延长所治疗的患者的存活的物质的量。
如本文所用的术语“前药”是指(i)药物的非活性形式,其在体内代谢过程将其转化为可用或活性形式之后发挥其作用,或(ii)尽管自身无活性但产生药理活性代谢物的物质(即非活性前体)。
术语“前药”或“前药衍生物”意指母体化合物或活性药物物质的共价键合衍生物、载体或前体,其在表现出其一种或多种药理作用之前至少经历了一些生物转化。此类前药具有代谢可裂解或以其他方式可转化的基团且在体内快速转化以产生母体化合物,例如通过在血液中水解或经由氧化而活化,如在硫醚基团的情况下。最常见的前药包括母体化合物的酯和酰胺类似物。以改善化学稳定性、改善患者的接受度和顺应性、改善生物利用度、延长作用时间、改善器官选择性、改善配制品(例如,增加的水溶性)和/或降低副作用(例如,毒性)的目标配制前药。一般而言,前药本身具有弱的生物学活性或不具有生物学活性并且在通常条件下是稳定的。前药可以使用本领域已知的方法从母体化合物容易地制备,所述方法诸如描述于以下文献中的那些:A Textbook of Drug Design and Development,Krogsgaard-Larsen和H.Bundgaard(编辑),Gordon&Breach,1991,特别是第5章:“Designand Applications of Prodrugs”;Design of Prodrugs,H.Bundgaard(编辑),Elsevier,1985;Prodrugs:Topical and Ocular Drug Delivery,K.B.Sloan(编辑),Marcel Dekker,1998;Methods in Enzymology,K.Widder等人(编辑),第42卷,Academic Press,1985,特别是第309-396页;Burger’s Medicinal Chemistry and Drug Discovery,第5版,M.Wolff(编辑),John Wiley&Sons,1995,特别是第1卷和第172-178页以及第949-982页;Pro-Drugsas Novel Delivery Systems,T.Higuchi和V.Stella(编辑),Am.Chem.Soc.,1975;Bioreversible Carriers in Drug Design,E.B.Roche(编辑),Elsevier,1987,将其各自通过引用以其整体并入本文。
如本文所用的术语“药学上可接受的前药”意指本发明化合物的前药,其在合理的医学判断范围内,适合用于与人类和低等动物的组织接触而无过度毒性、刺激性、过敏性反应等,与合理的收益/风险比相称,并对其预期用途有效,以及可能时呈两性离子形式。
如本文所用的术语“相对于EGFR野生型具有选择性的化合物”是指与EGFR相比对HER2展现出更高功效的化合物,其中所述化合物的功效可以在如下所述的生物学测定(诸如BA/F3增殖测定或肿瘤细胞系增殖测定)中确定。
如本文所用的术语“保留EGFR野生型”或“保留EGFR野生型活性”是指化合物的低EGFR野生型功效,其可以在如下所述的生物学测定(诸如BA/F3增殖测定或肿瘤细胞系增殖测定)中确定。
如本文所用的术语“具有HER2扩增的癌症”是指其中癌细胞展现出多于2个ERBB2基因拷贝的癌症。
如本文所用的术语“具有HER2过表达的癌症”是指其中癌症的细胞以可通过免疫组织化学和/或测定ERBB2信使RNA的方法检测的水平表达HER2的癌症。
如本文所用的术语“突变HER2”或“携带外显子20突变的HER2”是指突变型HER2蛋白和一致突变DNA变体,而如本文所用的“HER2外显子20突变体”是指HER2外显子20突变蛋白和一致突变DNA变体。
术语“HER2突变癌症”或“具有HER2突变的癌症”是指其中癌症细胞或肿瘤细胞具有一个或多个HER2突变的癌症,所述突变包括但不限于表1和表2中所列的突变。
如本文所用的术语“具有HER2外显子20突变的癌症”或“HER2外显子20突变癌症”是指癌症细胞或肿瘤细胞具有至少一个HER2外显子20突变的癌症,所述突变包括但不限于表1中所列的突变。
ERBB2(HER2)外显子20编码激酶结构域的一部分并且范围为氨基酸769至835。此区域内的每个突变、插入、重复或缺失都被定义为外显子20突变,包括表1中所列的突变。此外,致癌HER2突变存在于外显子20之外,包括表2中所列的突变。
表1.ERBB2(HER2)外显子20突变(“p.”是指HER2蛋白)
表2.可替代HER2突变(“p.”是指HER2蛋白)
p.S310F |
p.R678Q |
p.L755S |
p.S310Y |
p.V842I |
p.D769Y |
p.D769H |
p.R103Q |
p.G1056S |
p.I767M |
p.L869R |
p.L869R |
p.T733I |
p.T862A |
p.V697L |
p.R929W |
p.D277H |
p.D277Y |
p.G660D |
缩写列表
从以下详述的实施例中,本发明的特征和优点将变得明显,所述实施例通过举例说明本发明的原理而不限制其范围:
根据本发明的化合物的制备
概述
根据本发明的化合物及其中间体可以使用本领域技术人员已知的并且在有机合成文献中描述的合成方法获得。优选地,化合物以类似于下文更充分解释的制备方法(特别是如实验部分中所述的)方式获得。在一些情况下,进行反应步骤的顺序可以变化。也可以使用本领域技术人员已知但在本文中未详细描述的反应方法的变体。
用于制备根据本发明的化合物的通用方法对研究以下方案的本领域技术人员而言将变得明显。起始材料可以通过文献或本文中所述的方法制备或可以类似或相似方式制备。可使用常规保护基团来保护起始材料或中间体中的任何官能基团。可以使用本领域技术人员熟悉的方法在反应序列内的合适阶段再次裂解该保护基团。
通用反应方案和合成路线总结
方案1.合成化合物C的通用路线1
根据本发明的化合物C可以从可商购获得的对氟硝基苯(A)和醇开始合成,所述对氟硝基苯和醇在替代反应中发生反应并且随后将硝基还原以产生相应的胺C(参见例如Ishikawa等人,J.Med.Chem.2011,54(23),8030-8050;McDaniel等人,J.Med.Chem.2017,60(20),8369-8384)。
方案2.合成化合物G的通用路线1
方案3.合成化合物G的通用路线2根据本发明的化合物G可以根据通用路线1从化合物E或F合成(参见例如,Wan等人,Org.Lett.2006,8,11,2425-2428;Wang等人.,Bioorg.Med.Chem.Lett.2016,26(11),2589-2593)。可替代地,根据本发明的化合物G可以根据通用路线2从化合物H合成,将化合物H用相关的胺取代(参见例如,Wang等人,Bioorg.Med.Chem.Lett.2016,26(11),2589-2593),随后,将烷基硫化物氧化为亚砜或砜并且用经取代或未经取代的哌嗪取代(参见例如,Del Bello等人,Bioorg.Med.Chem.2015,23(17),5725-5733)。
方案4.式(I)的化合物的合成
根据本发明的式(I)的化合物可以从化合物G通过使Boc保护的经取代或未经取代的哌嗪脱保护并且随后与丙烯酰氯或丙烯酰酸酐反应合成(参见例如,Zhang等人,Eur.J.Med.Chem.2019,178,417-432)。
除非另有说明,否则所有的反应均使用化学实验室中常用的方法在可商购获得的设备中进行。对空气和/或湿气敏感的起始材料储存在保护气体下,并且使用其的相应反应和操纵在保护气体(氮气或氩气)下进行。
根据CAS规则使用AutoNom(Beilstein)或MarvinSketch(ChemAxon,产品版本17.24.3)软件命名根据本发明的化合物。如果化合物可以用结构式和其命名法二者表示,那么在冲突的情况下,结构式是决定性的。
式(I)、I-1至I-8的示例性化合物和中间体通过下文所述的合成方法制备,其中通式的取代基具有上文给出的含义。这些方法旨在说明本发明而不是限制其主题和对于这些实施例所要求保护的化合物的范围。在没有描述起始化合物的制备的情况下,它们是商业上可获得的或者它们的合成描述在现有技术中,或者它们可以与本文所述的已知现有技术化合物或方法类似地制备,即合成这些化合物是在有机化学家的技能范围内的。可以根据公开的合成方法制备文献中所述的物质。
色谱法
薄层色谱法在由Merck制造的玻璃(具有荧光指示剂F-254)上的现成硅胶60TLC板上进行。
根据本发明的实施例化合物的制备型高压色谱法(RP HPLC)在Agilent或Gilson系统上用由Waters制造的柱(名称:SunFireTM制备型C18,OBDTM10μm,50x 150mm或SunFireTM制备型C18 OBDTM5μm,30x 50mm或XBridgeTM制备型C18,OBDTM10μm,50x 150mm或XBridgeTM制备型C18,OBDTM5μm,30x 150mm或XBridgeTM制备型C18,OBDTM5μm,30x 50mm)和由YMC制造的柱(名称:Actus-Triart Prep C18,5μm,30x 50mm)进行。
不同梯度的H2O/乙腈用于洗脱化合物,而对于Agilent系统,将5%酸性改性剂(20mL HCOOH至1L H2O/乙腈(1/1))添加到水中(酸性条件)。对于Gilson系统,将0.1%HCOOH添加到水中。
对于碱性条件下的色谱法,对于Agilent系统,也使用H2O/乙腈梯度,将5%碱性改性剂添加到洗脱水溶液(50g NH4HCO3+50mL NH3(在H2O中的25%)+H2O用于1L水性洗脱液)中。对于Gilson系统,洗脱水溶液由以下组成:5mL NH4HCO3溶液(158g,在1LH2O中)和2mLNH3(28%,在H2O中),用H2O补充至1L。
使用的HPLC-MS柱来自Waters(XBridgeTM C18,2.5μm,2.1x 20mm或XBridgeTMC18,2.5μm,2.1x 30mm或Aquity UPLC BEH C18,1.7μm,2.1x 50mm)、YMC(Triart C18,3.0μm,2.0x 30mm)和Phenomenex(Luna C18,5.0μm,2.0x 30mm)。
HPLC-质谱法/UV光谱法
用于表征根据本发明的实施例化合物的保留时间/MS-ESI+使用HPLC-MS装置(具有质量检测器的高效液相色谱法)产生。在注射峰处洗脱的化合物给出保留时间tRet.=0.00。
方法1
HPLC Agilent 1100/1200系统
MS 1200系列LC/MSD(MM-ES+APCI+3000V,四极,G6130)
MSD信号设置 扫描正离子150-750
柱 Waters;零件编号186003020;XBridge BEH C18,3.5μm,30x
2.1mm柱或Waters;零件编号186006028;XBridge BEH C18 XP,
2.5μm,30x 2.1mm柱
洗脱剂 5mM NH4HCO3/18mM NH3(pH=9.2) B:乙腈(HPLC级)
检测信号 UV 254nm(带宽8,参考关闭(reference off))
光谱 范围:190-400nm;步长:2nm
峰宽 >0.0031min(0.063s)(80Hz)
注射 0.5μL标准注射
流量 1.4mL/min
柱温度 45℃
梯度 0.0-1.0min 15%→95%B
1.0-1.3min 95%B
停止时间:1.3min
方法2
HPLC Agilent 1100/1200系统
MS 1200系列LC/MSD(API-ES+/-3000V,四极,G6140)
MSD信号设置 扫描正离子150-750,扫描负离子150-750
柱 YMC;零件编号TA12S03-0302WT;Triart C18,3μm,12nm;
30x 2.0mm柱
洗脱剂 A:H2O+0.11%甲酸
B:乙腈+0.1%甲酸(HPLC级)
检测信号 UV 254nm(带宽10,参考关闭(reference off))
光谱 范围:190-400nm;步长:4nm
峰宽 >0.005min(0.1s)
注射 0.5μL标准注射
流量 1.4mL/min
柱温度 45℃
梯度 0.0-1.0min 15%→100%B
1.0-1.1min 100%B
停止时间:1.23min
方法3
HPLC Agilent 1100/1200系统
MS 1200系列LC/MSD(MM-ES+APCI+/-4000V,四极,G6130)
MSD信号设置 扫描正离子150-800,扫描负离子150-800
柱 Waters;零件编号186003020;XBridge BEH C18,3.5μm,30x
2.1mm柱或Waters;零件编号186006028;XBridge BEH C18 XP,
2.5μm,30x 2.1mm柱
洗脱剂 5mM NH4HCO3/18mM NH3(pH=9.2)
B:乙腈(HPLC级)
检测信号 UV 254nm(带宽8,参考关闭(reference off))
光谱 范围:190-400nm;步长:4nm
峰宽 >0.0031min(0.063s)
注射 0.5μL标准注射
流量 1.4mL/min
柱温度 45℃
梯度 0.0-1.0min 15%→95%B
1.0-1.3min 95%B
停止时间:1.3min
方法4
HPLC Agilent 1260系统
MS 1200系列LC/MSD(API-ES+/-3000V,四极,G614 0)
MSD信号设置 扫描正离子/负离子120-900m/z
柱 Waters,Xbridge C18,2.5μm,2.1x20 mm柱
洗脱剂 A:20mM NH4HCO3/NH3 pH 9
B:乙腈,HPLC级
检测信号 315nm(带宽170nm,参考关闭)
光谱 范围:230-400nm
峰宽 <0.01min
注射 5μL标准注射
柱温度 60℃
流量 1.00mL/min
梯度 0.00-1.50min 10%→95%B1.50-2.00min 95%B
2.00-2.10min 95%→10%B
化合物C-1至C4的合成
方法1
将在DMF(10mL)中的[1,2,4]三唑并[1,5-a]吡啶-7-醇(1.00g,7.40mmol)、1-氟-2-甲基-4-硝基苯(1.49g,9.62mmol)和碳酸钾(2.55g,18.5mmol)在80℃下搅拌16h。将混合物倒入水(150mL)中并且用乙酸乙酯萃取。将合并的有机层用水洗涤,干燥(MgSO4),过滤并且在真空中浓缩。将粗产物通过柱色谱法(SiO2,环己烷/乙酸乙酯梯度)纯化以得到中间体(1.79g)。将在乙醇(50mL)中的此中间体(1.79g,6.62mmol)和10%Pd/C(500mg)在18℃-25℃的温度下在氢气气氛(4巴)下搅拌16h。将反应混合物过滤并且在真空中浓缩。将粗产物通过柱色谱法(SiO2,环己烷/乙酸乙酯梯度)纯化以得到产物C-1(1.36g)。
方法2
将[1,2,4]三唑并[1,5-a]吡啶-7-醇(500mg,3.70mmol)、1,3-二氯-2-氟-5-硝基苯(1.01g,4.81mmol)和碳酸钾(1.28g;9.25mmol)悬浮于N,N-二甲基甲酰胺(DMF)(10mL)中。将所得反应混合物在80℃下搅拌18h,此时HPLC-MS指示完全转化。将反应混合物在减压下浓缩。将粗产物通过柱色谱法(SiO2,环己烷/乙酸乙酯梯度)纯化以得到中间体(1.10g)。将此中间体(1.10g,3.38mmol)和铁粉(0.945g,16.9mmol)悬浮于乙醇(10mL)和水(5mL)中。添加饱和氯化铵水溶液(5mL),并且将所得反应混合物在80℃下搅拌3h。将固体通过过滤去除。将滤液在减压下浓缩并且通过柱色谱法(SiO2,梯度二氯甲烷/甲醇)纯化以得到产物C-3(860mg)。
以类似于上文所示的方法2合成化合物C-2和C-4(表3)。
表3
化合物G-1至G-8可以根据下文所示的通用路线1或通用路线2制备。
根据通用路线1的化合物G-1至G-8的合成(方案2)
化合物E)的合成
将在二噁烷(200mL)中的6-甲烷亚磺酰基[1,3]二嗪并[5,4-d]嘧啶-4-醇(10.30g,49.0mmol,根据WO 97/32880制备)和哌嗪-1-甲酸叔丁酯(11.29g,186.3mmol)在回流下搅拌16h。将反应混合物在减压下浓缩。将粗产物在DMSO(200mL)中在80℃下搅拌30min,倒入冰水(1L)中,并且搅拌另外30min。将固体通过过滤收集,与水一起研磨并且重新溶解于二氯甲烷/甲醇(9/1)中。随后将有机层用1N HCl水溶液(200mL)和盐水(200mL)洗涤,干燥(MgSO4),过滤并且在真空中浓缩以得到化合物E(11.1g)。
表4
化合物F的合成
将E(2.0g,6.02mmol)悬浮在干二氯甲烷(50mL)中并且添加DMF(0.76mL,9.79mmol)。然后,将在干二氯甲烷(10mL)中的草酰氯(1.1mL,12mmol)逐滴添加到搅拌的反应混合物中。将反应混合物在18℃-25℃的温度下搅拌1h,并且然后在真空中浓缩。将粗产物通过柱色谱法(SiO2,环己烷/乙酸乙酯梯度)纯化以得到产物F(1.2g)。
表5
化合物G的合成
将在异丙醇(5mL)中的F(250mg,0.64mmol)和C-4(197mg,0.71mmol)在50℃下搅拌16h。将反应混合物倒入水中,并且将固体通过过滤收集。将粗产物通过柱色谱法(SiO2,二氯甲烷/甲醇梯度)纯化以得到产物G-4(350mg)。
以类似于上文给出的程序合成化合物G-1至G-3(表8)。
根据通用路线2的化合物G-1至G-8的合成(方案3)
化合物G-1至G-8也可以根据通用路线2制备。
化合物J的合成
将在异丙醇(300mL)中的8-氯-2-(甲硫基)嘧啶并[5,4-d]嘧啶(1.97g,8.32mmol)和C-1(2.0g,8.32mmol)在45℃下搅拌1h。将产物J-1通过过滤分离,用异丙醇洗涤并且在真空中干燥(3.4g)。
表6
化合物K的合成
在5℃下向在二氯甲烷(150mL)中的J-1(5.40g,9.08mmol)中添加间氯过氧苯甲酸(77%,3.05g,13.6mmol),并且将反应混合物在18℃-25℃的温度下搅拌2h。添加NaHCO3饱和水溶液(200mL),并且将水层用二氯甲烷萃取。将合并的有机层用水洗涤,干燥(MgSO4),过滤并且在真空中浓缩。将粗产物K-1不经进一步纯化用于下一步骤(3.0g)。
表7
化合物G的合成
将在DMF(10mL)中的K-1(500mg,1.06mmol)、哌嗪-1-甲酸叔丁酯(244mg,1.27mmol)和二异丙基乙基胺(240μL,1.4mmol)在70℃下搅拌1h并且随后在18℃-25℃的温度下搅拌过夜。将反应混合物倒入水中,并且用乙酸乙酯萃取数次。将合并的有机层干燥(Na2SO4)并且浓缩。将粗产物通过柱色谱法(SiO2,二氯甲烷/在甲醇中的氨梯度)纯化以得到产物G-1(360mg)。
以类似于上文给出的程序合成化合物G-5至G-8(表8)。
表8
化合物L-1至L-8的合成
将G-1(8.7g,15.7mmol)溶解于二氯甲烷(400mL)和甲醇(100mL)的混合物中并且将所得溶液冷却至4℃。将HCl(在二噁烷中的4N,20mL)逐滴添加到搅拌的反应混合物中。然后将反应混合物温热至18℃-25℃的温度并且在18℃-25℃的温度下搅拌过夜。将反应混合物浓缩并且将粗产物通过柱色谱法(SiO2,二氯甲烷/在甲醇中的氨梯度)纯化以得到产物L-1(5.3g)。
以类似于上文给出的程序合成化合物L-2至L-8(表9)。
表9
化合物I-1至I-8的合成
将L-1(4.66g,10.25mmol)溶解于二氯甲烷(100mL)和三乙胺(2.9mL,21mmol)中。将所得溶液冷却至4℃。将在二氯甲烷(10mL)中的丙烯酰氯(840μL,10.2mmol)逐滴添加到搅拌的反应混合物中。将所得反应混合物在4℃下搅拌2h,并且然后温热至18℃-25℃的温度。然后将反应混合物在饱和NaHCO3水溶液与二氯甲烷之间分配。将有机层干燥(MgSO4)并且浓缩。将粗产物通过柱色谱法(SiO2,在二氯甲烷中的5%甲醇,等度)纯化以得到产物(2.95g)。
以类似于上文给出的程序合成化合物I-1至I-8(表8)。可以使用用于引入丙烯酰胺的替代试剂,例如丙烯酰酸酐。
表8
生物学测定
Ba/F3细胞模型生成和增殖测定
从DSMZ(ACC300)订购Ba/F3细胞并且使细胞在5%CO2气氛中在37℃下在RPMI-1640(ATCC 30-2001)+10%FBS+10ng/ml IL-3中生长。从GeneScript获得含有HER2突变体和EGFR WT的质粒。为了生成EGFR/HER2依赖性Ba/F3模型,将Ba/F3细胞用含有具有EGFRWT、HER2 WT或HER2突变体(YVMA)的载体的逆转录病毒转导。将铂-E细胞(Cell Biolabs)用于逆转录病毒包装。将逆转录病毒添加到Ba/F3细胞中。为了确保感染,添加4μg/mL聚凝胺并且旋转感染细胞。通过使用细胞分析仪测量GFP阳性细胞来确认感染效率。将感染效率10%至20%的细胞进一步孵育,并且开始用1μg/mL的嘌呤霉素选择。作为对照,将亲本Ba/F3细胞用于评估选择状态。当亲本Ba/F3细胞培养物死亡时,选择被认为是成功的。为了评价HER2突变的转化潜力,生长培养基不再补充IL-3。将具有空载体的Ba/F3细胞用作对照。对Ba/F3细胞进行从IL-3到EGF的转换,其中EGFR WT因其对EGF配体的依赖性而所知。进行实验前大约十天,不再使用嘌呤霉素。对于增殖测定(表12和14中的数据),将Ba/F3细胞以在生长培养基中的5x 103个细胞/100μL接种到96孔板中。通过使用HP D3000数字分配器添加化合物。将所有处理在技术上一式三份地进行。将处理的细胞在37℃与5%CO2下孵育72h。进行Luminescent细胞活力测定(Promega)并且通过使用多标记板读取器VICTOR X4测量化学发光。将原始数据导入Boehringer Ingelheim专有软件MegaLab(基于程序PRISM的曲线拟合,GraphPad Inc)中并且进行分析。
pEGFR测定
此测定量化了EGFR在Tyr1068处的磷酸化,并且用于测量化合物对HEK细胞中表达的转基因EGFR野生型(WT)蛋白的抑制作用。
使人HEK细胞(ATCC CRL-1573)在5%CO2气氛中在37℃下在不含L-谷氨酰胺的含非必需氨基酸和丙酮酸钠(EMEM Lonza BE12-662F)+5ml GlutaMax(Gibco 35050-038;L-丙氨酰-L-谷氨酰胺)+5ml丙酮酸钠(Gibco 11360-039;100mM)+10%FBS的极限必需培养基Eagle(MEM Eagle EBSS)中生长,并且用编码EGFR WT的逆转录病毒载体转导。使用嘌呤霉素选择转导的细胞。使用AlphaScreen Surefire pEGF受体(Tyr1068)测定(PerkinElmer,TGRERS)确定p-EGFR Tyr1068。对于所述测定,将HEK EGFR WT细胞接种在含有10%FBS的MEM培养基中。使用Echo平台将60nL化合物稀释液添加到Greiner TC 384板的每个孔中。随后,添加在60μL中的60.000个细胞/孔。在37℃下将细胞与化合物一起孵育4小时。离心并且去除培养基上清液后,添加20μL具有蛋白酶抑制剂的来自TGR/Perkin Elmer试剂盒的1.6倍裂解缓冲液。将混合物在振荡(700rpm)的情况下在20℃-25℃的温度下孵育20min。离心后,将4μL裂解液转移至Proxiplate。将5μL受体混合物(在合并的反应缓冲液1和反应缓冲液2(TGRERS测定试剂盒,PerkinElmer)中以1:25稀释的活化缓冲液加1:50的蛋白A受体珠6760137,Perkin Elmer)添加到每个孔中。将板振摇1min(1400rpm)并且在20℃-25℃的温度下在黑暗中孵育2h。将3μL供体混合物(在稀释缓冲液(TGRERS测定试剂盒,PerkinElmer)中1:50稀释的AlphaScreen链霉亲和素包被的供体珠(6760002,PerkinElmer)添加到每个孔中。将板振摇1min(1400rpm)并且在20℃-25℃的温度下在黑暗中孵育2h。随后将板使用Envision板读取器平台分析。按以下方式计算结果:计算测试化合物的值与阴性对照(DMSO)的值的比率。IC50值是使用4参数逻辑模型从MEGASTAR IC50应用中的这些值计算的。
这种细胞磷酸化EGFR(pEGFR)化合物剂量-反应测定量化了表达EGFR WT的HEK细胞中Tyr1068处EGFR的磷酸化。测定结果以IC50值提供。给定化合物的pEGFR IC50值越高,EGFR WT保留活性越高。
pHER2(ERBB2)YVMA测定
此测定量化了HER2 YVMA在Tyr1221/1222处的磷酸化,并且用于测量化合物对使用强力霉素诱导表达系统在HEK细胞中表达的转基因HER2 YVMA蛋白的抑制作用。
使人HEK细胞在5%CO2气氛中在37℃下在不含L-谷氨酰胺,含非必需氨基酸和丙酮酸钠(EMEM Lonza BE12-662F)+5ml GlutaMax(Gibco 35050-038;L-丙氨酰-L-谷氨酰胺)+5ml丙酮酸钠(Gibco 11360-039;100mM)+10%FBS的极限必需培养基Eagle(MEM EagleEBSS)中生长,并且用编码HER2 YVMA的逆转录病毒载体转导。使用嘌呤霉素选择转导的细胞。使用AlphaScreen Surefire ErbB2(Tyr1221/1222)测定(PerkinElmer,TGREB2S)确定p-HER2 Tyr1221/1222。对于所述测定,将HEK HER2YVMA细胞接种在含有10%FBS的MEM培养基中。在化合物添加前4小时,使用1μg/ml强力霉素诱导HER2 YVMA表达。使用Echo平台将60nL化合物稀释液添加到Greiner TC384板的每个孔中。随后,添加在60μL中的60.000个细胞/孔。在37℃下将细胞与化合物一起孵育4小时。离心并且去除培养基上清液后,添加20μL具有蛋白酶抑制剂的来自TGR/Perkin Elmer试剂盒的1.6倍裂解缓冲液。将混合物在振荡(700rpm)的情况下在20℃-25℃的温度下孵育20min。离心后,将4μL裂解液转移至Proxiplate。将5μL受体混合物(在合并的反应缓冲液1和反应缓冲液2(TGREB2S测定试剂盒,PerkinElmer)中以1:25稀释的活化缓冲液加1:50的蛋白A受体珠6760137,PerkinElmer)添加到每个孔中。将板振摇1min(1400rpm)并且在20℃-25℃的温度下在黑暗中孵育2h。将3μL供体混合物(在稀释缓冲液(TGRERS测定试剂盒,PerkinElmer)中1:50稀释的AlphaScreen链霉亲和素包被的供体珠(6760002,PerkinElmer)添加到每个孔中。将板振摇1min(1400rpm)并且在20℃-25℃的温度下在黑暗中孵育2h。随后将板使用Envision板读取器平台分析。按以下方式计算结果:计算测试化合物的值与阴性对照(DMSO)的值的比率。IC50值是使用4参数逻辑模型从MEGASTAR IC50应用中的这些值计算的。
这种细胞磷酸化HER2 YVMA(pHER2 YVMA)化合物剂量-反应测定量化了表达HER2YVMA的HEK细胞中Tyr1221/1222处HER2 YVMA的磷酸化。测定结果以IC50值提供。给定化合物报告的pHER2 YVMA IC50值越低,化合物对HER2 YVMA激酶活性的抑制作用越强。
HER2 YVMA肿瘤细胞系模型产生和增殖测定
HER2 WT依赖性NCI-H2170细胞从(ATCC,CRL-5928)订购并且在5%CO2气氛中在37℃下在RPMI-1640(Gibco#A10491)ATCC-配制品+10%FBS中生长。采用同源定向基因组工程将编码YVMA的12个核苷酸序列插入NCI-H2170细胞中基因组HER2基因座的外显子20中。这导致从HER2 WT变为代表HER2 p.A775_G776insYVMA的HER2YVMA变体。从GenScript获得含有HER2外显子20YVMA插入变体的DNA模板。PCR以及然后Sanger测序用于确认导致YVMA氨基酸重复的HER2外显子20中存在12个核苷酸插入。
对于增殖测定,使用NCI-H2170(HER2野生型)、NCI-H2170 HER2 YVMA和EGFR WT依赖性A431细胞。将NCI-H2170 HER2 YVMA或NCI-H2170细胞以在培养基(RPMI ATCC+10%FBS+青霉素/链霉素)中的750个细胞/60μL接种到96孔板中。将A431细胞(ATCC CRL-1555)(DMEM(Sigma#D6429)+5ml丙酮酸钠(Gibco1 1360-039)以5000个细胞/孔(200μl)的密度接种到96孔板中。在细胞铺板后一天,通过使用HP D3000数字分配器添加化合物。将所有处理在技术上一式三份地进行。将处理的细胞在37℃与5%CO2下孵育72h。进行Luminescent细胞活力测定(Promega)并且使用多标签读板机VICTOR X4测量化学发光。将原始数据导入Boehringer Ingelheim专有软件MegaLab(基于程序PRISM的曲线拟合,GraphPad Inc)中并且进行分析。
表11.生物标记物测定
表12.肿瘤细胞增殖测定
表13
表14.肿瘤细胞增殖测定
药物配制品实施例
成分 | 量 |
活性物质 | 100mg |
乳糖 | 140mg |
玉米淀粉 | 240mg |
聚乙烯吡咯烷酮 | 15mg |
硬脂酸镁 | 5mg |
将活性物质研磨并且与乳糖和一些玉米淀粉混合在一起。将混合物过筛,然后用聚乙烯吡咯烷酮溶液湿法制粒。将颗粒、剩余的玉米淀粉和硬脂酸镁混合在一起。将混合物压缩以产生具有合适形状和尺寸的片剂。
Claims (14)
2.根据权利要求1所述的化合物,其中
R1选自-CH3和卤素
或其盐。
3.根据权利要求1所述的化合物,其中
R1选自-CH3、氯和氟
或其盐。
4.根据权利要求1所述的化合物,其中
R2是氢
或其盐。
5.根据权利要求1所述的化合物,其中
R2是氯
或其盐。
6.根据权利要求1所述的化合物,其中
R2是氟
或其盐。
7.根据权利要求1所述的化合物,其中
R3是氢
或其盐。
8.根据权利要求1所述的化合物,其中
R4是氢
或其盐。
9.根据权利要求1所述的化合物,其中
R4是-CH3
或其盐。
11.一种药物组合物,所述药物组合物包含治疗有效量的根据权利要求1至10中任一项所述的至少一种式(I)的化合物或其药学上可接受的盐和一种或多种药学上可接受的赋形剂。
12.根据权利要求1至10中一项或多项所述的化合物或其药学上可接受的盐,所述化合物或其药学上可接受的盐用作药剂。
13.根据权利要求1至10中一项或多项所述的化合物用于治疗患有脑癌、乳腺癌、胆管癌、膀胱癌、宫颈癌、结直肠癌、子宫内膜癌、皮肤癌、食管肿瘤、头颈肿瘤、胃肠癌、胆囊肿瘤、肾癌、肝癌、肺癌或前列腺癌的患者的用途。
14.一种药物组合物,所述药物组合物包含除式(I)的化合物之外还有选自细胞抑制活性物质和细胞毒性活性物质的药物活性化合物。
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US11608343B2 (en) | 2020-04-24 | 2023-03-21 | Boehringer Ingelheim International Gmbh | Substituted pyrimido[5,4-d]pyrimidines as HER2 inhibitors |
TW202214641A (zh) * | 2020-06-30 | 2022-04-16 | 美商艾瑞生藥股份有限公司 | Her2突變抑制劑 |
WO2023081637A1 (en) * | 2021-11-02 | 2023-05-11 | Enliven Therapeutics, Inc. | Fused tetracyclic quinazoline derivatives as inhibitors of erbb2 |
CN114031619A (zh) * | 2021-12-17 | 2022-02-11 | 山东汇海医药化工有限公司 | 一种图卡替尼中间体的制备方法 |
CN114621221B (zh) * | 2022-03-12 | 2022-10-11 | 陕西海辰风扬医药科技有限公司 | 妥卡替尼关键中间体及其制备方法 |
CN117384162A (zh) * | 2022-05-17 | 2024-01-12 | 浙江文达医药科技有限公司 | 选择性her2抑制剂 |
WO2024027695A1 (zh) * | 2022-08-04 | 2024-02-08 | 微境生物医药科技(上海)有限公司 | 作为her2抑制剂的化合物 |
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