CN115485277A - 作为HER2抑制剂的[1,3]二嗪基[5,4-d]嘧啶 - Google Patents
作为HER2抑制剂的[1,3]二嗪基[5,4-d]嘧啶 Download PDFInfo
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- CN115485277A CN115485277A CN202180030549.3A CN202180030549A CN115485277A CN 115485277 A CN115485277 A CN 115485277A CN 202180030549 A CN202180030549 A CN 202180030549A CN 115485277 A CN115485277 A CN 115485277A
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
本发明涉及式(I)的新的[1,3]二嗪基[5,4‑d]嘧啶及其衍生物,其中基团R1、R2、R3及R4具有权利要求书和说明书中所给出的含义;涉及其作为HER2及其突变体的抑制剂的用途;涉及含有此类化合物的药物组合物;及其作为药物,尤其是作为用于治疗和/或预防致癌疾病的药剂的用途。
Description
技术领域
本发明涉及式(I)的新的[1,3]二嗪基(diazino)[5,4-d]嘧啶及其衍生物
其中基团R1、R2、R3及R4具有权利要求书和说明书中所给出的含义;涉及其作为HER2及其突变体的抑制剂的用途;涉及含有此类化合物的药物组合物;及其作为药物,尤其是作为用于治疗和/或预防致癌疾病的药剂的用途。
发明背景
ERBB跨膜受体酪氨酸激酶(RTK)的家族由在发育期间实现基本功能的四个成员EGFR(ERBB1)、HER2(Neu,ERBB2)、HER3(ERBB3)和HER4(ERBB4)组成(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的胞外域与其各自配位体结合及ERBB家族成员后续同二聚化或异二聚化之后,开始ERBB传讯。未鉴别出配位体的HER2为其他ERBB成员的优选二聚搭配物。一旦已形成活性配位体-受体复合物,EGFR、HER2、HER3或HER4的胞内酪氨酸激酶域通过自磷酸化或转磷酸化活化,且随后引发讯号转导级联,最显著地为接合促分裂原活化蛋白质(MAP)激酶和/或磷酸肌醇3-激酶(PI3K)路径(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ERBB传讯牵涉包括癌症或神经性疾病的若干病理生理学病况。在癌症中,ERBB传讯经由突变过度活化,所述突变通过促进二聚或将平衡转换到激酶的活性构象异构体和/或经由扩增及后续的RTK的过度表达来使RTK呈现组成性活性。两种致癌机制均增加ERBB传讯的净输出,且由此促进细胞存活、细胞生长及增殖(Arteaga等人,Cancer Cell,2014,25(3),282-303)。
在多种人类恶性肿瘤中观测到异常HER2传讯。描述蛋白质的胞外、(近)膜及胞内区的致癌突变。总体而言,这些突变使HER2呈现组成性活性,从而推动癌症引发、肿瘤维持及生长(Connell等人,ESMO Open,2017,2(5),e000279)。类似地,HER2过度表达增加HER2传讯,且成为包括乳癌、胃癌或肺癌的各种适应症的肿瘤转化及肿瘤维持的基础。
因此,对HER2致癌传讯的干扰引起对肿瘤生长的抑制。靶向疗法包括HER2定向抗体(包括曲妥珠单抗(trastuzumab)及帕妥珠单抗(pertuzumab))、HER2定向抗体-药物共轭物(曲妥珠单抗-DM1(T-DM1,曲妥珠单抗-美坦新偶联物(ado-trastuzumab emtansine)))及抑制HER2激酶域的小分子(阿法替尼(afatinib)、来那替尼(neratinib)、拉帕替尼(lapatinib))。
总而言之,由HER2致癌突变或HER2野生型过度表达(例如由于基因扩增)驱动的肿瘤可受益于HER2特异性酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)。总体而言,HER2改变影响高达6%至7%的所有人类癌症,且EGFR野生型保留酪氨酸激酶抑制剂(TKI)可作为有效治疗选项出现。
即使存在对EGFR野生型具有选择性的HER2野生型抑制剂,例如图卡替尼(tucatinib),这些抑制剂对携带外显子20突变的HER2也不具有功效。其他选择性野生型HER2抑制剂已公开于现有技术文献WO 2003/049740、WO 2007/059257、WO 2005/044302和WO 2019/042409中。
HER2外显子20突变构成产生增强的激酶活性的HER2功能获得型突变的子集(Wang等人,Cancer Cell,2006,10(1),25-38)。该增强的HER2激酶活性馈入下游传讯级联中,所述下游传讯级联通过促进突变细胞的生长、增殖及存活来刺激肿瘤转化。
在基因工程改造小鼠模型中的研究已证实,NSCLC中最普遍的HER2外显子20突变(4个氨基酸YVMA(p.A775_G776insYVMA)的重复)是所需的且足以驱动致癌生长(Perera等人,Proc.Natl.Acad.Sci.USA,2009,106(2),474-479)。HER2-YVMA表达的撤回与肿瘤缩小相关联,从而表明HER2的该致癌变体对于肿瘤维持是所需的(Perera等人,2009)。另外,此研究证实,在小鼠模型中,pan-ERBB阻断剂阿法替尼为活体内有效,且可干扰HER2-YVMA的致癌传讯(Perera等人,2009)。
NSCLC中HER2的致癌突变主要影响HER2的酪氨酸激酶域且聚集在ERBB2基因的外显子20中(Stephens等人,Nature,2004,431(7008),525-526)。估计2-4%的肺癌患者在HER2外显子20中携带活化突变。临床上批准的靶向酪氨酸激酶抑制剂的ERBB对这些患者无效,因为它们受EGFR野生型介导的剂量限制毒性限制。阿法替尼及其他pan-ERBB阻断剂在HER2外显子20突变的NSCLC患者中显示有限的功效,这主要归因于达到有效剂量的限制。特别地,EGFR野生型介导的毒性限制有效剂量。
艾力替尼(allitinib)、依鲁替尼(ibrutinib)、来那替尼、波齐替尼(poziotinib)及吡咯替尼(pyrotinib)为突变型HER2外显子20的已知pan-ERBB抑制剂。突变型HER2外显子20的其他抑制剂已公开于现有技术文献WO 2015/175632、WO 2015/195228、WO 2016/183278及WO 2019/046775中。
存在对选择性地靶向HER2外显子20突变型蛋白质同时保留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的高度未满足的医疗需求。
已发现,本发明的化合物以正构及共价方式结合于野生型及突变型HER2外显子20的酪氨酸激酶域,同时保留EGFR野生型,且充当野生型HER2及携带外显子20中的突变的突变型HER2的选择性抑制剂。
发明内容
本发明的目的是提供突变型HER2外显子20的新的抑制剂,所述抑制剂对EGFR野生型具有选择性。本发明的化合物充当HER2外显子20的选择性抑制剂,且与现有技术化合物相比,除了对EGFR野生型具有高选择性之外,还显示改善的野生型EGFR保留功效。此外,本发明的一些化合物显示改善的药物动力学及药理学概况,例如良好的代谢稳定性。
本发明的化合物适用于预防和/或治疗以过度或异常细胞增殖为特征的疾病和/或病况,尤其适用于治疗和/或预防癌症。
具体实施方式
本发明涉及式(I)的新的[1,3]二嗪基[5,4-d]嘧啶及其衍生物
其中
R1选自由氢、-CH3、-CCH、-OCH3及卤素组成的组;
R2为氢或卤素;
R3选自由式(i.1)、(i.2)、(i.3)及(i.4)组成的组;
R4选自由R4.a及R4.b组成的组
其中
Q表示含有1个N原子的4至6员杂环基,其中环的一个碳原子任选被甲基取代;
Z表示含有1个N原子的4至6员杂环基,其中环的一个碳原子任选被甲基取代;
R5为H或CH3;
且R1及R2中至少一个不为氢。
优选的实施方案
在本发明的另一实施方案中,R1选自由-CH3、-CCH、-OCH3及卤素组成的组。
在本发明的另一实施方案中,R1选自由-CH3、-CCH、-OCH3、氯及氟组成的组。
在本发明的另一实施方案中,R1为-CH3。
在本发明的另一实施方案中,R1为-CCH。
在本发明的另一实施方案中,R1为-OCH3。
在本发明的另一实施方案中,R1为氯。
在本发明的另一实施方案中,R1为氟。
在本发明的另一实施方案中,R1为氢。
在本发明的另一实施方案中,R2选自由氢、氟及氯组成的组。
在本发明的另一实施方案中,R2为氢。
在本发明的另一实施方案中,R2为卤素。
在本发明的另一实施方案中,R2为氟或氯。
在本发明的另一实施方案中,R2为氟。
在本发明的另一实施方案中,R2为氯。
在本发明的另一实施方案中,R3选自由式(i.1)、(i.2)、(i.3)及(i.4)组成的组。
在本发明的另一实施方案中,R3为式(i.1)或(i.3)的基团。
在本发明的另一实施方案中,R3为式(i.2)或(i.4)的基团。
在本发明的另一实施方案中,R3为式(i.1)或(i.2)的基团。
在本发明的另一实施方案中,R3为式(i.1)或(i.4)的基团。
在本发明的另一实施方案中,R3为式(i.2)或(i.3)的基团。
在本发明的另一实施方案中,R3为式(i.3)或(i.4)的基团。
在本发明的另一实施方案中,R3为式(i.1)的基团。
在本发明的另一实施方案中,R3为式(i.2)的基团。
在本发明的另一实施方案中,R3为式(i.3)的基团。
在本发明的另一实施方案中,R3为式(i.4)的基团。
在本发明的另一实施方案中,R4为R4.a,其中R4.a为
在本发明的另一实施方案中,R4.a为R4.a.1,其中R4.a.1为
其中
R6为-H或-CH3,
n为1或2;
m为1或2。
在本发明的另一实施方案中,R4为R4.b,其中R4.b为
在本发明的另一实施方案中,R4.b为R4.b.1,其中R4.b.1为
其中
p为1或2;
q为1或2。
在本发明的另一实施方案中,R5为-H。
在本发明的另一实施方案中,R5为-CH3。
在本发明的另一实施方案中,R6为-H。
在本发明的另一实施方案中,R6为-CH3。
在本发明的另一实施方案中,m为1。
在本发明的另一实施方案中,m为2。
在本发明的另一实施方案中,n为1。
在本发明的另一实施方案中,n为2。
在本发明的另一实施方案中,m为1且n为1,或m为2且n为2。
在本发明的另一实施方案中,p为1。
在本发明的另一实施方案中,p为2。
在本发明的另一实施方案中,q为1。
在本发明的另一实施方案中,q为2。
在本发明的另一实施方案中,Q表示含有1个N原子的4-6员饱和杂环基,其中环的一个碳原子任选被甲基取代。
在本发明的另一实施方案中,Q表示含有1个N原子的4-6员部分不饱和杂环基,其中环的一个碳原子任选被甲基取代。
在本发明的另一实施方案中,Q表示氮杂环丁烷基(azetidinyl)。
在本发明的另一实施方案中,Q表示吡咯烷基。
在本发明的另一实施方案中,Q表示哌啶基。
在本发明的另一实施方案中,Q表示氮杂环丁烷基,其中环的一个碳原子被甲基取代。
在本发明的另一实施方案中,Q表示吡咯烷基,其中环的一个碳原子被甲基取代。
在本发明的另一实施方案中,Q表示哌啶基,其中环的一个碳原子被甲基取代。
在本发明的另一实施方案中,Z表示含有1个N原子的4-6员饱和杂环基,其中环的一个碳原子任选被甲基取代。
在本发明的另一实施方案中,Z表示含有1个N原子的4-6员部分不饱和杂环基,其中环的一个碳原子任选被甲基取代。
在本发明的另一实施方案中,Z表示氮杂环丁烷基。
在本发明的另一实施方案中,Z表示吡咯烷基。
在本发明的另一实施方案中,Z表示哌啶基。
在本发明的另一实施方案中,Z表示氮杂环丁烷基,其中环的一个碳原子被甲基取代。
在本发明的另一实施方案中,Z表示吡咯烷基,其中环的一个碳原子被甲基取代。
在本发明的另一实施方案中,Z表示哌啶基,其中环的一个碳原子被甲基取代。
在本发明的另一实施方案中,Q及Z表示含有1个N原子的4至6员饱和杂环基,其中环的一个碳原子任选被甲基取代。
在本发明的另一实施方案中,Q及Z表示含有1个N原子的4至6员部分不饱和杂环基,其中环的一个碳原子任选被甲基取代。
R1、R2、R3、R4、R4.a、R4.a.1、R4.b、R4.b.1、R5、R6、m、n、p、q、Q及Z的定义中的任一个及每一个可彼此组合。
本发明的一优选的实施方案为上述式(I)的化合物,其选自由实施例I-01至I-19组成的组。
或其药学上可接受的盐。
本发明的另一优选的实施方案为上述式(I)的化合物,其选自由实施例I-01至I-19组成的组。
本发明的另一优选的实施方案为上述式(I)的化合物的药学上可接受的盐,其选自由实施例I-01至I-19组成的组。
本发明的另一优选的实施方案为上述式(I)的化合物,其选自由实施例I-01至I-13组成的组。
本发明的另一优选的实施方案为上述式(I)的化合物的药学上可接受的盐,其选自由实施例I-01至I-13组成的组。
本发明的另一优选的实施方案为上述式(I)的化合物,其选自由实施例I-14至I-19组成的组。
本发明的另一优选的实施方案为上述式(I)的化合物的药学上可接受的盐,其选自由实施例I-14至I-19组成的组。
本发明的另一优选的实施方案为实施例I-01的化合物。
本发明的另一优选的实施方案为实施例I-02的化合物。
本发明的另一优选的实施方案为实施例I-03的化合物。
本发明的另一优选的实施方案为实施例I-04的化合物。
本发明的另一优选的实施方案为实施例I-05的化合物。
本发明的另一优选的实施方案为实施例I-06的化合物。
本发明的另一优选的实施方案为实施例I-07的化合物。
本发明的另一优选的实施方案为实施例I-08的化合物。
本发明的另一优选的实施方案为实施例I-09的化合物。
本发明的另一优选的实施方案为实施例I-10的化合物。
本发明的另一优选的实施方案为实施例I-11的化合物。
本发明的另一优选的实施方案为实施例I-12的化合物。
本发明的另一优选的实施方案为实施例I-13的化合物。
本发明的另一优选的实施方案为实施例I-14的化合物。
本发明的另一优选的实施方案为实施例I-15的化合物。
本发明的另一优选的实施方案为实施例I-16的化合物。
本发明的另一优选的实施方案为实施例I-17的化合物。
本发明的另一优选的实施方案为实施例I-18的化合物。
本发明的另一优选的实施方案为实施例I-19的化合物。
本发明的另一优选的实施方案为实施例I-01的化合物的药学上可接受的盐。
本发明的另一优选的实施方案为实施例I-02的化合物的药学上可接受的盐。
本发明的另一优选的实施方案为实施例I-03的化合物的药学上可接受的盐。
本发明的另一优选的实施方案为实施例I-04的化合物的药学上可接受的盐。
本发明的另一优选的实施方案为实施例I-05的化合物的药学上可接受的盐。
本发明的另一优选的实施方案为实施例I-06的化合物的药学上可接受的盐。
本发明的另一优选的实施方案为实施例I-07的化合物的药学上可接受的盐。
本发明的另一优选的实施方案为实施例I-08的化合物的药学上可接受的盐。
本发明的另一优选的实施方案为实施例I-09的化合物的药学上可接受的盐。
本发明的另一优选的实施方案为实施例I-10的化合物的药学上可接受的盐。
本发明的另一优选的实施方案为实施例I-11的化合物的药学上可接受的盐。
本发明的另一优选的实施方案为实施例I-12的化合物的药学上可接受的盐。
本发明的另一优选的实施方案为实施例I-13的化合物的药学上可接受的盐。
本发明的另一优选的实施方案为实施例I-14的化合物的药学上可接受的盐。
本发明的另一优选的实施方案为实施例I-15的化合物的药学上可接受的盐。
本发明的另一优选的实施方案为实施例I-16的化合物的药学上可接受的盐。
本发明的另一优选的实施方案为实施例I-17的化合物的药学上可接受的盐。
本发明的另一优选的实施方案为实施例I-18的化合物的药学上可接受的盐。
本发明的另一优选的实施方案为实施例I-19的化合物的药学上可接受的盐。
本发明的另一实施方案为一种药物组合物,其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及一或多种药学上可接受的赋形剂。
本发明的另一实施方案为式(I)的化合物或其药学上可接受的盐,其用作药物。
本发明的另一实施方案为式(I)的化合物或其药学上可接受的盐的用途,其用于治疗患有癌症的患者,所述癌症包括脑癌、乳癌、胆道癌、膀胱癌、子宫颈癌、大肠直肠癌、子宫内膜癌、皮肤癌、食道肿瘤、头颈肿瘤、胃肠癌、胆囊肿瘤、肾癌、肝癌、肺癌或前列腺癌。
本发明的另一实施方案为式(I)的化合物或其药学上可接受的盐的用途,其用于治疗患有乳癌、膀胱癌、大肠直肠癌、胃肠癌、食道癌或肺癌的患者。
本发明的另一实施方案为式(I)的化合物或其药学上可接受的盐的用途,其用于治疗患有肺的癌症/肿瘤/癌瘤的患者,例如非小细胞肺癌(NSCLC)(鳞状细胞癌瘤、梭形细胞癌瘤、腺癌、大细胞癌瘤、透明细胞癌瘤、支气管肺泡癌)、小细胞肺癌(SCLC)(燕麦细胞癌、中间细胞癌、复合性燕麦细胞癌)。
本发明的另一实施方案为式(I)的化合物或其药学上可接受的盐的用途,其用于治疗患有NSCLC的患者。
本发明的另一实施方案为一种药物组合物,除式(I)的化合物以外,其还包含选自由细胞生长抑及细胞毒性活性物质组成的组的药物活性化合物。
本发明进一步涉及式(I)的化合物的水合物、溶剂合物、同质多形体、代谢物及前药。
在另一实施方案中,本发明涉及一种式(I)的化合物的药学上可接受的盐。
在另一方面,本发明涉及一种抑制细胞中的野生型和/或突变型HER2的方法,其包含使细胞与式(I)的化合物接触。在另一实施方案中,本发明涉及一种抑制细胞中携带外显子20突变的HER2的方法,其优选地包含使细胞与式(I)的化合物接触。
在另一方面,本发明涉及一种抑制细胞中的野生型和/或突变型HER2的磷酸化的方法,其包含使细胞与式(I)的化合物接触。在另一实施方案中,本发明涉及一种抑制细胞中的HER2外显子20突变体的磷酸化的方法,其包含使细胞与式(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的用途,其用于治疗和/或预防疾病和/或病况,其中对野生型和/或突变型HER2的抑制具有治疗益处。在另一实施方案中,本发明涉及式(I)的化合物或其药学上可接受的盐的用途,其用于治疗和/或预防疾病和/或病况,其中对HER2外显子20突变型蛋白质的抑制具有治疗益处。
在另一方面,本发明涉及一种式(I)的化合物或其药学上可接受的盐,其用于抑制有需要的人类个体中的野生型和/或突变型HER2的方法中,该方法包括向个体给予治疗有效量的式(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,其用于抑制有需要的人类个体中的HER2外显子20突变体的方法中,该方法包括向个体给予治疗有效量的式(I)的化合物或其药学上可接受的盐。
在另一方面,本发明涉及一种式(I)的化合物或其药学上可接受的盐,其用于治疗和/或预防癌症。在另一实施方案中,本发明涉及一种式(I)的化合物或其药学上可接受的盐,其用于治疗和/或预防癌症,其中癌症具有HER2过度表达和/或HER2扩增。在另一实施方案中,本发明涉及一种式(I)的化合物或其药学上可接受的盐,其用于治疗和/或预防癌症,其中癌症为HER2外显子20突变体癌症。在另一实施方案中,本发明涉及一种式(I)的化合物或其药学上可接受的盐,其用于治疗和/或预防癌症,其中HER2过度表达、HER2扩增和/或HER2外显子20突变体癌症选自脑癌、乳癌、胆道癌、膀胱癌、子宫颈癌、大肠直肠癌、子宫内膜癌、皮肤癌、食道肿瘤、头颈肿瘤、胃肠癌、胆囊肿瘤、肾癌、肝癌、肺癌及前列腺癌。
在另一方面,本发明涉及一种治疗和/或预防上文所提及的疾病及病况的方法,该方法包括向人类给予治疗有效量的式(I)的化合物或其药学上可接受的盐。
在另一方面,本发明涉及一种式(I)的化合物或其药学上可接受的盐,其用于治疗和/或预防上文所提及的疾病及病况。
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的用途,其用于制备用于治疗和/或预防上文所提及的疾病及病况的药物。
此外,可用本发明的化合物治疗以下癌症、肿瘤及其他增生性疾病,但不限于此:
头颈部的癌症/肿瘤/癌瘤:例如以下肿瘤/癌瘤/癌症:鼻腔、鼻窦、鼻咽、口腔(包括唇、齿龈、牙槽脊、臼齿后三角、口底、舌、硬腭、颊黏膜)、口咽(包括舌根、扁桃体、扁桃体弓(tonsillar pilar)、软腭、扁桃体窝(tonsillar fossa)、咽壁)、中耳、喉(包括上声门、声门、下声门、声带)、下咽、唾液腺(包括小唾液腺);
肺的癌症/肿瘤/癌瘤:例如非小细胞肺癌(NSCLC)(鳞状细胞癌瘤、梭状细胞癌瘤、腺癌、大细胞癌瘤、透明细胞癌瘤、支气管肺泡癌)、小细胞肺癌(SCLC)(燕麦细胞癌、中等细胞癌、复合性燕麦细胞癌);
纵隔的赘瘤:例如神经性肿瘤(包括神经纤维瘤、神经鞘瘤、恶性神经鞘瘤、神经肉瘤、神经节母细胞瘤、神经节细胞瘤、神经母细胞瘤、嗜铬细胞瘤、副神经节瘤)、生殖细胞肿瘤(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)、间叶性肿瘤(包括纤维瘤、纤维肉瘤、脂肪瘤、脂肪肉瘤、黏液瘤、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/癌瘤:例如以下的肿瘤/癌瘤/癌症:食道、胃(胃癌)、胰脏、肝及胆道(包括肝细胞癌(HCC),例如儿童HCC、纤维板层HCC、复合性HCC、梭状细胞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;胆管细胞癌瘤;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、克拉斯金肿瘤(Klatskin tumor))、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;大肠直肠癌、胃肠道基质瘤(GIST))、泌尿生殖系统(包括肾脏,例如肾盂、肾细胞癌瘤(RCC)、肾母细胞瘤(威耳姆士肿瘤(Wilms′tumor))、肾上腺样瘤、格拉维茨肿瘤(Grawitz tumor);输尿管;膀胱,例如脐尿管癌、尿道上皮癌;尿道,例如远程、球膜、前列腺;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、激素难治性)、阴茎);
睪丸的癌症/肿瘤/癌瘤:例如精原细胞瘤、非精原细胞瘤;
妇科癌症/肿瘤/癌瘤: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、宫底)的肿瘤/癌瘤/癌症;
乳房的癌症/肿瘤/癌瘤:例如乳癌(浸润性乳腺管癌、胶质癌、小叶侵袭性癌、管癌、腺囊癌、乳头状癌、髓质癌、黏液癌)、激素受体阳性乳癌(雌激素受体阳性乳癌、孕酮受体阳性乳癌)、HER2阳性乳癌、三阴性乳癌、佩吉特氏乳房病(Paget′s disease of thebreast);
内分泌系统的癌症/肿瘤/癌瘤:例如以下的肿瘤/癌瘤/癌症:内分泌腺、甲状腺(甲状腺癌瘤/肿瘤;乳头状癌、滤泡性癌、退行性癌、髓质癌)、副甲状腺(副甲状腺癌瘤/肿瘤)、肾上腺皮层(肾上腺皮层癌瘤/肿瘤)、脑下腺(包括促乳素瘤、颅咽管瘤)、胸腺、肾上腺、松果体腺、颈动脉体、胰岛细胞瘤、副神经节、胰脏内分泌肿瘤(PET;非氟功能性PET、胰多肽瘤(PPoma)、胃泌素瘤、胰岛素瘤、血管活性肠肽瘤(VIPoma)、升糖素瘤、体抑素瘤、生长激素释放因子瘤(GRFoma)、促肾上腺皮质激素瘤(ACTHoma))、类癌肿瘤;
软组织的肉瘤:例如纤维肉瘤、纤维组织细胞瘤、脂肪肉瘤、平滑肌肉瘤、横纹肌肉瘤、血管肉瘤、淋巴管肉瘤、卡波西氏肉瘤(Kaposi′s sarcoma)、血管球肿瘤、血管外皮瘤、滑膜肉瘤、腱鞘巨细胞瘤、胸膜及腹膜孤立性纤维肿瘤、弥漫性间皮瘤、恶性周边神经外鞘瘤(MPNST)、颗粒细胞肿瘤、透明细胞肉瘤、黑素细胞神经鞘瘤、神经丛肉瘤(plexosarcoma)、神经母细胞瘤、神经节母细胞瘤、神经上皮瘤、骨外尤文氏肉瘤(extraskeletal Ewing′s sarcoma)、副神经节瘤、骨外软骨肉瘤、骨外骨肉瘤、间叶瘤、软组织肺泡状肉瘤、上皮样肉瘤、肾外横纹肌样瘤、促结缔组织增生性小细胞瘤;
骨骼的肉瘤:例如骨髓瘤、网状细胞肉瘤、软骨肉瘤(包括中心细胞软骨肉瘤、周边细胞软骨肉瘤、透明细胞软骨肉瘤、间叶软骨肉瘤)、骨肉瘤(包括骨旁骨肉瘤、骨膜骨肉瘤、高恶性表面骨肉瘤、小细胞骨肉瘤、放射线诱导的骨肉瘤、佩吉特氏肉瘤(Paget′ssarcoma))、尤文氏肿瘤(Ewing′s tumor)、恶性巨细胞肿瘤、釉质瘤、(纤维)组织细胞瘤、纤维肉瘤、脊索瘤、小圆形细胞肉瘤、血管内皮瘤、血管外皮瘤、骨软骨瘤、骨样骨瘤、骨母细胞瘤、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:例如基底细胞癌瘤、鳞状细胞癌瘤、默克尔氏细胞癌瘤(Merkel′scell carcinoma)、黑素瘤(包括皮肤黑素瘤、浅面扩散性黑素瘤、恶性雀斑样痣黑素瘤、肢端雀斑痣性黑素瘤、结节状黑素瘤、眼内黑素瘤)、光化性角化症、眼睑癌;
中枢神经系统及脑的赘瘤:例如星形细胞瘤(大脑星形细胞瘤、小脑星形细胞瘤、弥漫性星形细胞瘤、原纤维性星形细胞瘤、退行性星形细胞瘤、毛细胞型星形细胞瘤、原生质星形细胞瘤、大圆形细胞性星形细胞瘤)、神经胶母细胞瘤、神经胶质瘤、寡突神经胶质细胞瘤、寡突星形细胞瘤、室管膜瘤、室管膜母细胞瘤、脉络丛肿瘤、神经管母细胞瘤、脊膜瘤、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、神经瘤(例如,听神经瘤)、脊髓肿瘤;
淋巴瘤及白血病:例如B细胞非霍奇金氏淋巴瘤(NHL)(包括小淋巴球性淋巴瘤(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)、伯基特氏淋巴瘤(Burkitt′s lymphoma;BL))、T细胞非霍奇金氏淋巴瘤(包括退行性大细胞淋巴瘤(ALCL)、成人T细胞白血病/淋巴瘤(ATLL)、皮肤T细胞淋巴瘤(CTCL)、周边T细胞淋巴瘤(PTCL))、淋巴母细胞性T细胞淋巴瘤(T-LBL)、成人T细胞淋巴瘤、淋巴母细胞性B细胞淋巴瘤(B-LBL)、免疫细胞瘤、慢性B细胞淋巴球性白血病(BchlorineL)、慢性T细胞淋巴球性白血病(TchlorineL)、B细胞小淋巴球性淋巴瘤(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、霍奇金式病(HD)(包括结节状淋巴球为主型的HD(NLPHD)、结节状硬化HD(NSHD)、混合细胞性HD(MCHD)、富含淋巴球的典型HD、耗乏淋巴球的HD(LDHD))、大颗粒淋巴球白血病(LGL)、慢性骨髓性白血病(CML)、急性骨髓性/骨髓白血病(AML)、急性淋巴球性/淋巴母细胞性白血病(ALL)、急性髓前髓细胞性白血病(APL)、慢性淋巴球性/淋巴性白血病(CLL)、前淋巴球性白血病(PLL)、毛细胞白血病、慢性骨髓性/骨髓白血病(CML)、骨髓瘤、浆细胞瘤、多发性骨髓瘤(MM)、浆细胞瘤、骨髓发育不良综合征(MDS)、慢性骨髓单核球性白血病(CMML);
原发部位未知的癌症(CUP)。
特征在于其在体内的特定位置/起源的上文提及的所有癌症/肿瘤/癌瘤意指包括原发性肿瘤及源自其的转移性肿瘤。
上文提及的所有癌症/肿瘤/癌瘤可通过其组织病理学分类而进一步区分:
上皮癌症,例如鳞状细胞癌瘤(SCC)(原位癌瘤、表面侵袭性癌瘤、疣状癌瘤、假性肉瘤、退行性癌瘤、转移细胞癌瘤、淋巴上皮癌瘤)、腺癌(AC)(分化良好的腺癌、黏液腺癌、乳头状腺癌、多形性巨细胞腺癌、乳腺管腺癌、小细胞腺癌、印戒细胞腺癌、梭状细胞腺癌、透明细胞腺癌、燕麦细胞腺癌、胶质腺癌、腺鳞腺癌、黏液表皮样腺癌、腺样囊性腺癌)、黏液囊腺癌瘤、腺泡细胞癌瘤、大细胞癌瘤、小细胞癌瘤、神经内分泌肿瘤(小细胞癌瘤、副神经节瘤、类癌);嗜酸性细胞癌瘤;
非上皮癌症,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、黑素瘤、生殖细胞肿瘤、血液赘瘤、混合性及未分化性癌瘤。
在另一方面,本发明涉及一种式(I)的化合物或其药学上可接受的盐,其用于治疗和/或预防癌症,其中将所述化合物与细胞生长抑制和/或细胞毒性活性物质组合和/或与放射线疗法和/或免疫疗法组合给药。
在另一方面,本发明涉及一种式(I)的化合物或其药学上可接受的盐与细胞生长抑制和/或细胞毒性活性物质的组合和/或与放射线疗法和/或免疫疗法的组合,其用于治疗和/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,其中该方法包括与细胞生长抑制和/或细胞毒性活性物质组合和/或与放射线疗法和/或免疫疗法和/或靶向疗法组合给予式(I)的化合物或其药学上可接受的盐。
本发明的化合物可单独或与一种或多种其他药理活性物质组合使用,所述药理活性物质例如当前最新技术或标准护理化合物,例如细胞增殖抑制剂、抗血管生成物质、类固醇或免疫调节剂/检查点抑制剂等。
可与根据本发明的化合物组合给药的药理活性物质包括(但不限于):激素、激素类似物及抗激素(例如,他莫昔芬(tamoxifen)、托瑞米芬(toremifene)、雷诺昔酚(raloxifene)、氟维司群(fulvestrant)、醋酸甲地孕酮(megestrol acetate)、氟他胺(flutamide)、尼鲁胺(nilutamide)、比卡鲁胺(bicalutamide)、胺麸精(aminoglutethimide)、醋酸环丙孕酮(cyproterone acetate)、非那雄安(finasteride)、醋酸布舍瑞林(buserelin acetate)、氟可体松(fludrocortisone)、氟羟甲基睾酮(fluoxymesterone)、甲羟助孕酮(medroxyprogesterone)、奥曲肽(octreotide))、芳香酶抑制剂(例如,阿那曲唑(anastrozole)、利妥唑(letrozole)、利阿唑(liarozole)、伏罗唑(vorozole)、依西美坦(exemestane)、阿他美坦(atamestane))、LHRH促效剂及拮抗剂(例如,醋酸戈舍瑞林(goserelin acetate)、鲁普利德(luprolide))、生长因子和/或其对应受体的抑制剂(生长因子例如血小板衍生的生长因子(PDGF)、纤维母细胞生长因子(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)、人类表皮生长因子(HER,例如HER2、HER3、HER4)及肝细胞生长因子(HGF)和/或其对应受体),抑制剂为例如(抗)生长因子抗体、(抗)生长因子受体抗体及酪氨酸激酶抑制剂,例如西妥昔单抗(cetuximab)、吉非替尼(gefitinib)、阿法替尼、尼达尼布(nintedanib)、伊马替尼(imatinib)、拉帕替尼、伯舒替尼(bosutinib)、贝伐单抗(bevacizumab)、帕妥珠单抗及曲妥珠单抗);抗代谢物(例如,抗叶酸剂,例如甲胺喋呤(methotrexate)、雷替曲塞(raltitrexed);嘧啶类似物,例如5氟尿嘧啶(5fluorineU);核苷及脱氧核苷类似物;卡培他滨(capecitabine)及吉西他滨(gemcitabine);嘌呤及腺苷类似物,例如巯嘌呤、硫鸟嘌呤;克拉屈滨(cladribine)及喷司他丁(pentostatin);阿糖胞苷(ara C);氟达拉宾(fludarabine));抗肿瘤抗生素(例如,蒽环类药物,例如阿霉素(doxorubicin)、多希(doxil)(聚乙二醇化脂质盐酸阿霉素、莫西特(myocet)(非聚乙二醇化脂质阿霉素)、道诺比星(daunorubicin)、表柔比星(epirubicin)及伊达比星(idarubicin)、丝裂霉素-C(mitomycin-C)、博莱霉素(bleomycin)、放线菌素(dactinomycin)、普卡霉素(plicamycin)、链脲霉素(streptozocin));铂衍生物(例如,顺铂(cisplatin)、奥赛力铂(oxaliplatin)、卡铂(carboplatin));烷化剂(例如,雌莫司汀(estramustin)、氮芥(meclorethamine)、霉法兰(melphalan)、氮芥苯丁酸(chlorambucil)、白消安(busulphan)、达喀尔巴嗪(dacarbazin)、环磷酰胺、异环磷酰胺、替莫唑胺(temozolomide)、亚硝基脲(例如卡莫司汀(carmustin)及洛莫司汀(lomustin))、噻替哌(thiotepa));抗有丝分裂剂(例如,长春花生物碱(Vinca alkaloid),例如长春碱(vinblastine)、长春地辛(vindesin)、长春瑞宾(vinorelbin)及长春新碱(vincristine);及紫杉烷(taxane),例如太平洋紫杉醇(paclitaxel)、多西他赛(docetaxel));血管生成抑制剂(例如,他喹莫德(tasquinimod))、微管蛋白抑制剂;DNA合成抑制剂、PARP抑制剂、拓朴异构酶抑制剂(例如,表鬼臼毒素(epipodophyllotoxin),例如依托泊苷(etoposide)及凡毕复(etopophos)、替尼泊苷(teniposide)、胺吖啶(amsacrine)、拓朴替康(topotecan)、伊立替康(irinotecan)、米托蒽醌(mitoxantrone))、丝氨酸/苏氨酸激酶抑制剂(例如,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抑制剂、奥洛拉激酶抑制剂(Aurora kinase inhibitors))、酪氨酸激酶抑制剂(例如,PTK2/FAK抑制剂)、蛋白质交互作用抑制剂(例如,IAP活化剂、Mcl-1、MDM2/MDMX)、MEK抑制剂、ERK抑制剂、KRAS抑制剂(例如,KRAS G12C抑制剂)、传讯路径抑制剂(例如,SOS1抑制剂)、FLT3抑制剂、BRD4抑制剂、IGF-1R抑制剂、TRAILR2促效剂、Bcl-xL抑制剂、Bcl-2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(rapamycin)类似物(例如,依维莫司(everolimus)、坦罗莫司(temsirolimus)、地磷莫司(ridaforolimus)、西罗莫司(sirolimus))、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、放射性药品、蛋白酶体抑制剂、免疫治疗剂(例如免疫检查点抑制剂(例如,CTLA4、PD1、PD-L1、PD-L2、LAG3及TIM3结合分子/免疫球蛋白,例如伊派利单抗(ipilimumab)、纳武单抗(nivolumab)、帕博利珠单抗(pembrolizumab))、抗体依赖性细胞介导的细胞毒性(antibody-dependent cell-mediated cytotoxicity;ADCC)增强剂(例如,抗CD33抗体、抗CD37抗体、抗CD20抗体)、T细胞接合子(例如,双特异性T细胞接合子例如CD3×BCMA、CD3×CD33、CD3×CD19、PSMA×CD3)、肿瘤疫苗及各种化学治疗剂(例如阿米福汀(amifostin)、阿那格雷(anagrelid)、克罗德那特(clodronat)、非格司亭(filgrastin)、干扰素、干扰素α、甲酰四氢叶酸(leucovorin)、丙卡巴肼(procarbazine)、左旋咪唑(levamisole)、美司钠(mesna)、米托坦(mitotane)、帕米膦酸盐(pamidronate)及卟吩姆(porfimer))。
在另一方面,本发明涉及一种药物组合物,其包含至少一种式(I)的化合物或其药学上可接受的盐及任选地至少一种药学上可接受的载剂。
在另一方面,本发明涉及一种药物组合物,其包含式(I)的化合物或其药学上可接受的盐及至少一种其他细胞生长抑制和/或细胞毒性活性物质。
对于一般本领域技术人员而言,用于给予本发明的化合物的适合制剂是显而易见的,且包括例如片剂、丸剂、胶囊、栓剂、口含片、糖衣片、溶液(特别是用于注射(s.c.,i.v.,i.m.)及输注的溶液(注射剂))、酏剂、糖浆剂、药囊、乳剂、吸入剂或可分散散剂。
可例如通过将一或多种式(I)的化合物与已知赋形剂(例如,惰性稀释剂、载剂、崩解剂、佐剂、界面活性剂、黏合剂和/或润滑剂)混合来获得适合的片剂。
每天可适用的式(I)的化合物的剂量范围通常为1mg至2000mg,优选10至1000mg。
静脉内使用的剂量在不同输注速率的情况下为1mg至1000mg,优选在不同输注速率的情况下为5mg至500mg。
然而,取决于体重、年龄、给药途径、疾病的严重程度、个体对药物的反应、其制剂的性质及给予药物的时间或时间间隔(每天一剂或多剂的连续或间断治疗),有时可能需要偏离指定量。因此,在一些情况下,使用小于上文给出的最小剂量可能是足够的,而在其他情况下可能超过上限。当给予较大量时,在一天内将其分成多个较小剂量是可取的。
通用定义
未在本文中具体定义的术语应具有本领域技术人员鉴于本公开内容及上下文给予它们的含义。然而,如本说明书中所使用的,除非相反地指定,否则以下术语具有所指示的含义且将遵守以下惯例。
在下文定义的基团(group/radical)或部分中,通常在基团之前指定碳原子数量,例如C1-6烷基意指具有1至6个碳原子的烷基(alkyl group/radical)。
在如HO、NH2、S(O)、S(O)2、CN(氰基)、COOH、CF3、CH3、CCH、OCH3等基团中,本领域技术人员可由基团自身的自由价看出基团与分子的连接点。
倘若以化学名称及化学式的形式描绘本发明的化合物,则在有任何不一致的情况下,以化学式为准。星号可用于子式中以指示连接至如所定义的核心分子的键。
取代基原子的记数始于最接近核心或取代基所连接基团的原子。
术语“卤素”表示氟、氯、溴和/或碘原子。优选地,卤素是指氟和/或氯。
术语“杂环基”或“杂环”意指饱和或不饱和单环或多环环系统,其任选地包括含有一个或多个选自N、O或S(O)r(其中r=0、1或2)的杂原子的芳环系统,由3至14个环原子组成,其中没有环原子为芳环的部分。术语“杂环基”或“杂环”意指包括所有可能的异构体形式。
因此,术语“杂环基”或“杂环”包括以下示例性结构,所述结构不描绘为基团,因为只要维持合适的价态,各形式均任选通过共价键连接至任何原子:
许多上文所给出的术语可反复用于化学式或基团的定义中,且在各情况下彼此独立地具有一种上文所给出的含义。
如本文所用,术语“取代的”意指指定原子上的任何一个或多个氢被选自指示基团的基团替代,条件是不超过指定原子的正常价,且取代基产生稳定的化合物。
除非特别指示,否则贯穿本说明书及所附权利要求书,给定的化学式或名称应涵盖其互变异构体及所有立体异构体、光学异构体及几何异构体(例如,对映异构体、非对映异构体、E/Z异构体等)及外消旋体,以及以不同比例的单独对映异构体的混合物、非对映异构体的混合物或存在此类异构体及对映异构体的任意前述形式的混合物,以及其溶剂合物,例如游离化合物的水合物。
一般而言,可根据本领域技术人员已知的合成原理,例如通过分离对应混合物,通过使用立体化学上纯的起始材料和/或通过立体选择性合成来获得基本上纯的立体异构体。本领域中已知如何制备光学活性形式,例如通过解析外消旋形式或通过合成,例如自光学活性起始材料开始和/或通过使用手性试剂。
可通过不对称合成,例如通过制备及后续分离可通过已知方法(例如,通过层析分离或结晶)分离的适当非对映异构化合物或中间体,和/或通过使用手性试剂(例如手性起始材料、手性催化剂或手性助剂)来制备本发明的对映异构性纯的化合物或中间体。
此外,本领域技术人员知晓如何由对应外消旋混合物制备对映异构性纯的化合物,例如通过在手性固定相上层析分离对应外消旋混合物,或通过使用适当拆分剂来拆分外消旋混合物,例如通过使外消旋化合物与光学活性酸或碱形成非对映异构盐,随后拆分盐,并由盐释放所需化合物,或通过用光学活性手性辅助试剂衍生化对应外消旋化合物,随后进行非对映异构体分离并移除手性辅助基团,或通过对外消旋体的动力学拆分(例如,通过酶法拆分);通过在适合条件下由同形异向晶体的聚结物进行对映体选择性结晶,或通过在光学活性手性助剂的存在下由适合溶剂进行(部分)结晶。
词组“药学上可接受”在本文中用于指在合理医学判断的范畴内适用于与人类的组织接触而无过度毒性、刺激、过敏反应或其他问题或并发症,且与合理益处/风险比相匹配的那些化合物、材料、组合物和/或剂型。
如本文所使用,“药学上可接受的盐”是指所公开化合物的衍生物,其中通过制造母体化合物的酸式或碱式盐而使其改性。药学上可接受的盐的实施例包括(但不限于)碱性残基(例如胺)的无机或有机酸盐;酸性残基(例如羧酸)的碱盐或有机盐等。
举例而言,此类盐包括以下物质的盐:苯磺酸、苯甲酸、柠檬酸、乙磺酸、反丁烯二酸、龙胆酸(gentisic acid)、氢溴酸、氢氯酸、顺丁烯二酸、苹果酸、丙二酸、杏仁酸、甲磺酸、4-甲基-苯磺酸、磷酸、水杨酸、丁二酸、硫酸及酒石酸。
本发明的药学上可接受的盐可通过常规化学方法由含有碱性或酸性部分的母体化合物合成。一般而言,此类盐可通过使这些化合物的游离酸或游离碱形式与足够量的适当碱或酸在水或有机稀释剂(如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈或其混合物)中反应来制备。
除上文所提及的那些盐外,例如适用于纯化或分离本发明化合物的其他酸的盐(例如,三氟乙酸盐)也构成本发明的一部分。
基团或取代基通常选自具有对应基团名称(例如,Ra、Rb等)的许多替代基团/取代基。若在分子的不同部分重复地使用此类基团来定义本发明的化合物,则应指出各个使用将视为完全彼此独立。
如本文所使用,术语“治疗有效量”是指能够避免疾病症状或预防或缓解这些症状,或延长经治疗患者的存活期的一定数量的物质。
如本文所使用,术语“前药”是指(i)药物的非活性形式,其在体内的代谢过程将其转化为适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学上的活性代谢物的物质(即非活性前驱物)。
术语“前药”意指母体化合物或活性药物物质的共价键合衍生物、载剂或前驱物,其在展现其药理学作用之前经历至少一些生物转化。此类前药具有可代谢裂解的基团,或可以其他方式转化的基团,并且例如通过在血液中水解或通过(如在硫醚基团的情况下)氧化活化而在活体内快速转化以得到母体化合物。最常见前药包括母体化合物的酯及酰胺类似物。前药经调配以实现改善的化学稳定性、改善的患者接受性及顺应性、改善的生物可用性、延长的作用持续时间、改善的器官选择性、改善的调配性(例如,增加的水溶性)和/或降低的副作用(例如,毒性)的目标。一般而言,前药自身具有弱生物活性或不具有生物活性,且在一般条件下是稳定的。前药可使用本领域中已知方法容易地由母体化合物制备,例如描述于A Textbook of Drug Design and Development,Krogsgaard-Larsen及H.Bundgaard(编),Gordon&Breach,1991,特别是第5章:“Design and Applications ofProdrugs”;Design of Prodrugs,H.Bundgaard(编),Elsevier,1985;Prodrugs:Topicaland Ocular Drug Delivery,K.B.Sloan(编),Marcel Dekker,1998;Methods inEnzymology,K.Widder等人(编),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),John Wiley&Sons,1995,特别是第1卷及第172-178页及第949-982页;Pro-Drugs as Novel DeliverySystems,T.Higuchi及V.Stella(编),Am.Chem.Soc.,1975;Bioreversible Carriers inDrug Design,E.B.Roche(编),Elsevier,1987中的那些方法,其各自以引用方式整体并入本文中。
如本文所使用,术语“药学上可接受的前药”意指本发明的化合物的前药,其在合理医学判断的范畴内适用于与人类的组织接触而无不当毒性、刺激、过敏反应等,与合理益处/风险比率相匹配,且有效用于其预定用途;以及在可能情况下呈两性离子形式。
如本文所使用,术语“对EGFR野生型具有选择性的化合物”是指与EGFR相比,对HER2表现更高功效的化合物,其中化合物的功效可在例如BA/F3增殖分析的生物分析或如下所述的肿瘤细胞株增殖分析中测定。
如本文所使用,术语“保留EGFR野生型”或“EGFR野生型保留活性”是指化合物的低EGFR野生型功效(例如实施例I-01至I-19的功效范围),其可在例如BA/F3增殖分析的生物分析或如下所述的肿瘤细胞株增殖分析中测定。
如本文所使用,术语“具有HER2扩增的癌症”是指其中癌细胞表现超过2个ERBB2基因复本的癌症。
如本文所使用,术语“具有HER2过度表达的癌症”是指其中癌症的细胞以可通过免疫组织化学和/或分析ERBB2信使RNA的方法检测到的水平表达HER2的癌症。
如本文所使用,术语“突变型HER2”是指突变型HER2蛋白质及协调突变型DNA变体,而如本文所使用的“HER2外显子20突变体”是指HER2外显子20突变型蛋白质及协调突变型DNA变体。
术语“HER2-突变体癌症”或“具有HER2突变的癌症”是指其中癌细胞或肿瘤细胞具有包括但不限于表1及表2中所列出的突变的HER2突变的癌症。
如本文所使用,术语“具有HER2外显子20突变的癌症”或“HER2外显子20突变体癌症”是指其中癌细胞或肿瘤细胞具有包括但不限于表1中所列出的突变的至少一个HER2外显子20突变的癌症。
ERBB2(HER2)外显子20编码激酶域的一部分且范围介于氨基酸769至835。将此区内的各突变、插入、复制或缺失定义为包括表1中所列出的突变的外显子20突变。另外,致癌HER2突变存在于包括表2中所列出的突变的外显子20外部。
表1.ERBB2(HER2)外显子20突变(“p”是指HER2蛋白质)
表2.替代性HER2突变(“p”是指HER2蛋白质)
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
通过以下详细实施例,本发明的特征及优势将变得显而易见,这些实施例通过示例说明本发明的原理而不限定其范畴:
根据本发明的化合物的制备
概要
可使用本领域技术人员已知且记载于有机合成文献中的合成方法来获得根据本发明的化合物及其中间体。优选地,以与下文更充分解释(特别是如实验部分中所描述)的制备方法类似的方式来获得化合物。在一些情况下,进行反应步骤的顺序可变化。也可使用本领域技术人员已知但在此处未详细描述的反应方法的变型。
用于制备根据本发明的化合物的一般过程对于研究以下方案的本领域技术人员将变得显而易见。可通过文献或本文中所描述的方法制备或可以类似或相似方式来制备起始材料。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团。这些保护基团可使用本领域技术人员熟悉的方法在反应顺序内的适合阶段处再次裂解。
一般反应方案及合成途径的概述
根据本发明的化合物C可由市售可得的对氟硝基苯(A)及醇开始合成,它们在取代反应及随后的硝基还原反应中反应以得到对应的胺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)。
根据本发明的化合物F可根据一般途径1由化合物D合成(参见例如Wang等人,Bioorg.Med.Chem.Lett.2016,26(11),2589-2593,Wan等人,Org.Lett.2006,8,11,2425-2428)。替代地,根据本发明的化合物F可根据一般途径2由化合物G合成,所述化合物G被相关苯胺取代(参见例如Wang等人,Bioorg.Med.Chem.Lett.2016,26(11),2589-2593,Wan等人,Org.Lett.2006,8,11,2425-2428)。将烷基硫化物H氧化为亚砜J或砜,且用取代的或未取代的胺取代(参见例如Del Bello等人,Bioorg.Med.Chem.2015,23(17),5725-5733)。
根据本发明的式(I)的化合物可由化合物F通过使受Boc保护的经取代或未经取代的胺去保护且随后与丙烯酰氯或丙烯酰酐的反应合成(参见例如Zhang等人,Eur.J.Med.Chem.2019,178,417-432)。
除非另有说明,否则使用化学实验室中常用的方法在市售可得的装置中进行所有反应。将对空气和/或水分敏感的起始材料储存在保护性气体下,且与此对应的反应及操作在保护性气体(氮气或氩气)下进行。
根据CAS规则使用软件AutoNom(Beilstein)或MarvinSketch(ChemAxon,产品版本17.24.3)来命名根据本发明的化合物。若化合物由结构式及由其名称表示,则在存在冲突的情况下,以结构式为准。
式(I)、I-01至I-19的实施例化合物及中间体通过下文描述的合成方法来制备,其中通式的取代基具有上文给出的含义。这些方法旨在作为本发明的说明,而不限制其主题及这些实施例的化合物的范围。在未描述起始化合物的制备的情况下,其为市售可得的或其合成描述于现有技术中或其可类似于已知现有技术化合物或本文所描述的方法来制备,即合成这些化合物是有机化学工作者能胜任的。文献中所描述的物质可根据公开合成方法制备。
层析
薄层层析法在由Merck制造的玻璃(具有荧光指示剂F-254)上用现成硅胶60 TLC板进行。
实施例化合物的制备型高压层析(RP HPLC)在具有由Waters(名称:SunFireTMPrep C18,OBDTM 10μm,50×150 mm或SunFireTM Prep C18 OBDTM 5μm,30×50mm或XBridgeTMPrep C18,OBDTM 10μm,50×150mm或XBridgeTM Prep C18,OBDTM 5μm,30×150mm或XBridgeTMPrep C18,OBDTM 5μm,30×50mm)及YMC(名称:Actus-Triart Prep C18,5μm,30×50mm)制造的管柱的Agilent或Gilson系统上进行。
不同梯度的H2O/乙腈用于洗脱化合物。对于Agilent系统,将5%酸性改质剂(20mLHCOOH至1L H2O/乙腈(1/1))添加至水中(酸性条件)。对于Gilson系统,将0.1%HCOOH添加至水中。
对于Agilent系统在碱性条件下的层析,使用H2O/乙腈梯度,将5%碱性改质剂添加至水性洗脱剂中(对于1L水性洗脱剂,50g NH4HCO3+50mL NH3(25%于H2O中)+H2O)。对于Gilson系统,水性溶析液由5mL NH4HCO3溶液(158g于1L H2O中)及2mL NH3(28%于H2O中)组成,用H2O补充至1L。
所使用的HPLC-MS管柱来自Waters(XBridgeTM C18,2.5μm,2.1×20mm或XBridgeTMC18,2.5μm,2.1×30mm或Aquity UPLC BEH C18,1.7μm,2.1×50mm)、YMC(Triart C18,3.0μm,2.0×30mm)及Phenomenex(Luna C18,5.0μm,2.0×30mm)。
HPLC-质谱法/UV-光谱测定法
使用HPLC-MS装置(具有质量检测器的高效液相层析)产生用于表征根据本发明的实施例化合物的滞留时间/MS-ESI+。注射峰值处洗脱的化合物给出滞留时间tRet.=0.00。
方法1
方法2
方法3
方法4
方法5
方法6
方法7
方法8
方法9
方法10
方法11
化合物C的合成
B-01的合成
将含1-甲基-1H-苯并[d]咪唑-5-醇(500mg,3.38mmol)、1-氟-2-甲基-4-硝基苯(681mg,4.39mmol)及碳酸钾(1.16g,8.44mmol)的DMF(5ml)溶液在80℃下搅拌6h。浓缩反应混合物。粗产物通过管柱层析(SiO2,环己烷/乙酸乙酯梯度)纯化。
类似于上文所展示的步骤来合成化合物B-02至B-09(表1)。
表1
C-01及C-05的合成
方法1-C-01的合成
将B-01(950mg,3.35mmol)及10% Pd/C(100mg)的乙醇(10mL)/THF(10mL)溶液在氢气氛围(3巴)下在18-25℃的温度下搅拌24h。将混合物过滤反应,且在真空中浓缩。
类似于上文所展示的步骤来合成化合物C-03及C-06至C-08(表2)。
方法2-C-05的合成
将B-05(250mg,0.81mmol)及铁(226mg,55.8mmol)悬浮于乙醇及饱和NH4Cl水溶液中。将所得反应混合物在80℃下搅拌3小时,且随后在18-25℃的温度下搅拌16小时。在硅藻土垫上过滤反应混合物,且在真空中浓缩滤液。所得残余物未经进一步纯化即用于下一合成步骤中。
类似于上文所展示的步骤来合成化合物C-02、C-04及C-09(表2)。
表2
化合物F的合成
根据一般途径1合成化合物F(方案2)
E-01的合成
将6-甲亚磺酰基[1,3]二嗪基[5,4-d]嘧啶-4-醇(根据WO9732880制备的6-甲亚磺酰基嘧啶并[5,4-d]嘧啶-4-醇,D,211mg,1.00mmol)及叔丁基-N-(哌啶-4-基)氨基甲酸酯(246mg,1.20mmol)的二噁烷(4mL)溶液在回流下搅拌16h。在减压下浓缩反应混合物,且通过管柱层析(SiO2,二氯甲烷/甲醇梯度)纯化粗产物。
类似于上文所展示的步骤来合成化合物E-02(表3)。
表3
F-03的合成
将E-01(200mg,0.55mmol)、苯并三唑-1-基氧基三(吡咯烷基)鏻六氟磷酸盐(441mg,0.83mmol)及1,8-二氮杂双环[5.4.0]十一碳-7-烯(126mg,0.83mmol)的无水THF(4mL)溶液在18-25℃的温度下搅拌30分钟。添加C-03(205mg,0.66mmol)的无水THF(1mL)溶液,且将混合物在70℃下搅拌16h。在真空中浓缩混合物,通过制备型反相HPLC纯化粗产物。
类似于上文所示步骤来合成化合物F-04、F-06及F-12(表6)。
根据一般途径2合成化合物F(方案3)
H-01的合成
将8-氯-2-(甲硫基)嘧啶并[5,4-d]嘧啶(500mg,1.97mmol)及C-01(492mg,1.97mmol)的异丙醇(10mL)溶液在50℃下搅拌3h。通过过滤收集沉淀物,且通过管柱层析(SiO2,二氯甲烷/甲醇梯度)纯化粗产物以得到产物H-01。
类似于上文所示步骤来合成化合物H-02至H-06(表4)。也可通过将反应混合物分配于有机溶剂与水层之间,在真空中还原有机层,且柱纯化粗产物来分离产物。
表4
J-01的合成
在5℃下向含H-01(860mg,1.80mmol)的二氯甲烷(30mL)溶液中添加间氯过苯甲酸(77%,444mg,1.98mmol),且将反应混合物在18-25℃的温度下搅拌2h。添加饱和NaHCO3水溶液(200mL),且将水层用二氯甲烷萃取若干次。将合并的有机层用水洗涤,干燥(Mg2SO4),过滤并在真空中浓缩。粗产物J-01不经进一步纯化即用于下一步骤中。
类似于上文所示步骤来合成化合物J-02至J-06(表5)。
表5
F-01的合成
将J-01(5.42g,9.74mmol)、叔丁基-N-(哌啶-4-基)氨基甲酸酯(2.39g,11.7mmol)及N-乙基-二异丙胺(2.51g,19.4mmol)的DMF(50mL)溶液在60℃下搅拌16h。在真空中浓缩反应混合物,且粗产物未经进一步纯化即可用于下一步骤中。
类似于上文所展示的步骤来合成化合物F-02、F-05、F-07至F-11以及F-13至F-19(表6)。
表6
I-01至I-19的合成
K-01的合成
向F-01(5.66g,9.73mmol)的无水二氯甲烷(100mL)及甲醇(30mL)溶液中添加HCl(4N于二噁烷中,22mL)。将反应混合物在45℃下搅拌4h,然后在真空中浓缩。粗产物通过管柱层析(SiO2,二氯甲烷/甲醇梯度)纯化。
类似于上文所示步骤来合成化合物K-02至K-19(表7)。
表7
I-01的合成
向K-01(168mg,0.15mmol)的无水二氯甲烷(2mL)溶液中添加丙烯酰氯(13μL,0.16mmol)及二异丙基乙胺(149μL,0.88mmol),且在18-25℃的温度下搅拌1h。在真空中浓缩反应混合物,且通过制备型RP-HPLC-MS纯化粗产物。
类似于上文所示步骤来合成化合物I-02至I-19(表8)。
表8
生物分析
Ba/F3细胞模型产生及增殖分析
自DSMZ(ACC300)订购Ba/F3细胞且使其在37℃下在5% CO2氛围中在RPMI-1640(ATCC 30-2001)+10% FBS+10ng/ml IL-3中生长。含有HER2突变体及EGFR WT的质体获自GeneScript。为产生EGFR/HER2依赖性Ba/F3模型,用含有具有EGFR WT、HER2 WT或HER2突变体(YVMA)的载体的反转录病毒转导Ba/F3细胞。铂-E细胞(Cell Biolabs)用于反转录病毒封装。将反转录病毒添加至Ba/F3细胞中。为确保感染,添加4μg/mL凝聚胺(polybrene),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。进一步培养感染效率为10%至20%的细胞,且开始选择1μg/mL嘌呤霉素。作为对照,使用亲代Ba/F3细胞评定选择状态。当亲代Ba/F3细胞培养物死亡时,视为选择成功。为评估HER2突变的转化潜力,生长培养基不再补充有IL-3。将具有空载体的Ba/F3细胞用作对照。对表达EGFR WT的Ba/F3细胞执行自IL-3至EGF的转换,已知其依赖于EGF配位体。在进行实验之前约十天,移出嘌呤霉素。对于增殖分析(表10及12中的数据),将Ba/F3细胞以5×103个细胞/100微升接种至96孔盘中的生长培养基中。通过使用HP D3000数字分配器添加化合物。所有处理均在技术上一式三份地进行。将经处理细胞在37℃下与5%CO2一起培育72h。执行发光细胞活力分析(Promega),且通过使用多标记盘读取器VICTOR X4来测量化学发光。将原始数据导入至Boehringer Ingelheim专有软件MegaLab(基于程序PRISM的曲线拟合,GraphPadInc.)中且用其进行分析。
pEGFR分析
此分析量化EGFR在Tyr1068处的磷酸化且用于测量化合物对HEK细胞中表达的转殖基因EGFR野生型(WT)蛋白质的抑制作用。
使人类HEK细胞(ATCC CRL-1573)在37℃下在5% CO2氛围中在最低必需培养基Eagle、MEM Eagle EBSS中生长,该最低必需培养基Eagle不具有L-麸氨酸,具有非必需氨基酸及丙酮酸钠(EMEM Lonza BE12-662F)+5ml GlutaMax(Gibco 35050-038;L-丙胺酰基-L-麸氨酸)+5ml丙酮酸钠(Gibco;100mM)+10% FBS,且用编码EGFR WT的反转录病毒载体转导。使用嘌呤霉素选择经转导的细胞。使用AlphaScreen Surefire pEGF受体(Tyr1068)分析(PerkinElmer,TGRERS)测定p-EGFR Tyr1068。对于分析,将HEK EGFR WT细胞接种于具有10% FBS的MEM培养基中。使用Echo平台将60nL化合物稀释液添加至Greiner TC 384盘的各孔。随后,添加60.000个细胞/孔,60μL。将细胞在37℃下与化合物一起培育4h。在离心且移除培养基上清液之后,添加20μL来自TGR/Perkin Elmer试剂盒的1.6倍裂解缓冲液与蛋白酶抑制剂。将混合物在20-25℃的温度下振荡(700rpm)培育20min。在离心之后,将4μL裂解物转移至Proxiplates。将5μL受体混合物(以1:25稀释于合并的反应缓冲液1及反应缓冲液2(TGRERS分析试剂盒,PerkinElmer)中的活化缓冲液加1:50的蛋白A受体珠粒6760137,Perkin Elmer)添加至各孔。将盘振荡1min(1400rpm),且在(20-25℃)的温度下在暗处培育2h。将3μL供体混合物(以1:50稀释于稀释缓冲液(TGRERS分析试剂盒,PerkinElmer)中的经AlphaScreen抗生蛋白链菌素涂布的供体珠粒(6760002,PerkinElmer))添加至各孔。将盘振荡1min(1400rpm),且在(20-25℃)的温度下在暗处培育2h。随后使用Envision读取器平台分析盘。结果以以下方式计算:计算测试化合物的值与阴性对照(DMSO)的值的比率。在MEGASTAR IC50应用中使用4参数逻辑模型根据这些值计算IC50值。
此细胞磷酸化EGFR(pEGFR)化合物剂量-响应分析量化表达EGFR WT的HEK细胞中EGFR在Tyr1068处的磷酸化。分析的结果提供为IC50值。给定化合物的pEGFR IC50值越高,EGFR WT保留活性越高。
pHER2(ERBB2)YVMA分析
此分析量化HER2 YVMA在Tyr1221/1222处的磷酸化且用于使用多西环素诱导性表达系统测量化合物对HEK细胞中表达的转殖基因HER2 YVMA蛋白质的抑制作用。
使人类HEK细胞在37℃下在5% CO2氛围中在最低必需培养基Eagle、MEM EagleEBSS中生长,该最低必需培养基Eagle不具有L-麸氨酸,具有非必需氨基酸及丙酮酸钠(EMEM Lonza BE12-662F)+5mL GlutaMax(Gibco 35050-038;L-丙胺酰基-L-麸氨酸)+5mL丙酮酸钠(Gibco;100mM)+10%FBS,且用编码HER2 YVMA的反转录病毒载体转导。使用嘌呤霉素选择经转导的细胞。使用AlphaScreen Surefire ErbB2(Tyr1221/1222)分析(PerkinElmer,TGREB2S)测定p-ERBB2 Tyr1221/1222。对于分析,将HEK HER2 YVMA细胞接种于具有10% FBS的MEM培养基中。在添加化合物之前4小时,使用1μg/mL多西环素诱导HER2 YVMA表达。使用Echo平台将60nL化合物稀释液添加至Greiner TC 384盘的各孔。随后,添加60.000个细胞/孔,60μL。将细胞在37℃下与化合物一起培育4h。离心且移除培养基上清液之后,添加20μL来自TGR/Perkin Elmer试剂盒的1.6倍裂解缓冲液与蛋白酶抑制剂。将混合物在20-25℃的温度下振荡(700rpm)培育20min。在离心之后,将4μL裂解物转移至Proxiplates。将5μL受体混合物(以1:25稀释于合并的反应缓冲液1及反应缓冲液2(TGREB2S分析试剂盒,PerkinElmer)中的活化缓冲液加1:50的蛋白A受体珠粒6760137,PerkinElmer)添加至各孔。将盘振荡1min(1400rpm),且在20-25℃的温度下在暗处培育2h。将3μL供体混合物(以1:50稀释于稀释缓冲液(TGRERS分析试剂盒,PerkinElmer)中的经AlphaScreen抗生蛋白链菌素涂布的供体珠粒(6760002,PerkinElmer))添加至各孔。将盘振荡1min(1400rpm),且在20-25℃的温度下在暗处培育2h。随后使用Envision读取器平台来分析盘。结果以以下方式计算:计算测试化合物的值与阴性对照(DMSO)的值的比率。在MEGASTAR IC50应用中使用4参数逻辑模型根据这些值计算IC50值。
此细胞磷酸化HER2 YVMA(pHER2 YVMA)化合物剂量-响应分析量化表达HER2YVMA的HEK细胞中HER2 YVMA在Tyr1221/1222处的磷酸化。分析的结果提供为IC50值。给定化合物的所报导pHER2 YVMA IC50值越低,化合物对HER2 YVMA激酶活性的抑制作用越强。数据记录于表9和11中。
HER2 YVMA肿瘤细胞株细胞模型产生及增殖分析
自(ATCC,CRL-5928)订购HER2WT-依赖性NCI-H2170细胞且使其在37℃下在5%CO2氛围中在RPMI-1640(Gibco#A10491)ATCC-制剂+10% FCS中生长。同源定向基因组工程改造用于将12个编码YVMA的核苷酸序列插入至NCI-H2170细胞中的基因组HER2基因座的外显子20中。这引起自HER2 WT变为表示HER2 p.A775_G776insYVMA的HER2 YVMA变体。含有HER2外显子20YVMA插入变体的DNA模板获自GenScript。PCR后的桑格定序(Sanger sequencing)用于确认HER2外显子20中12个核苷酸插入的存在,其引起YVMA氨基酸重复。
对于增殖分析,使用NCI-H2170(HER2野生型)、NCI-H2170 HER2 YVMA及EGFR WT依赖性A431细胞。将NCI-H2170 HER2 YVMA或NCI-H2170细胞以750个细胞/60微升接种至96孔盘中的生长培养基(RPMI ATCC+10% FCS,+青霉素/链霉素)中。将A431细胞(ATCC CRL-1555)(DMEM(Sigma#D6429)+5mL丙酮酸钠Gibco 11360-039)以5000个细胞/孔(200μL)的密度接种在96孔盘中。在接种细胞之后一天通过使用HP D3000数字分配器添加化合物。所有处理均在技术上一式三份地进行。将经处理细胞在37℃下与5%CO2一起培育72h。执行发光细胞活力分析(Promega),且通过使用多标记盘读取器VICTOR X4来测量化学发光。将原始数据导入至Boehringer Ingelheim专有软件MegaLab(基于程序PRISM的曲线拟合,GraphPad Inc.)中且用其进行分析。数据记录于表10和12中。
表9.生物标记分析
表10.增殖分析
表11.生物标记分析
表12.肿瘤细胞增殖分析
药物制剂的实施例
成分 | 量 |
活性物质 | 100mg |
乳糖 | 140mg |
玉米淀粉 | 240mg |
聚乙烯吡咯啶酮 | 15mg |
硬脂酸镁 | 5mg |
将活性物质磨碎且与乳糖及一些玉米淀粉混合在一起。筛分混合物,接着用聚乙烯吡咯啶酮溶液湿法粒化。将颗粒、剩余玉米淀粉及硬脂酸镁混合在一起。压缩混合物以产生具有适当形状及大小的片剂。
Claims (15)
2.根据权利要求1所述的化合物或其盐,其中
R1选自由-CH3、-CCH、-OCH3及卤素组成的组。
3.根据权利要求1所述的化合物或其盐,其中
R1为-CH3。
4.根据权利要求1所述的化合物或其盐,其中
R1为-CCH。
5.根据权利要求1所述的化合物或其盐,其中
R1为-OCH3。
6.根据权利要求1所述的化合物或其盐,其中
R1为氯。
7.根据权利要求1所述的化合物或其盐,其中
R1为氟。
8.根据权利要求1至7中任一项所述的化合物或其盐,其中
R2为氢。
9.根据权利要求1至7中任一项所述的化合物或其盐,其中
R2为氯。
12.一种药物组合物,其包含治疗有效量的至少一种根据权利要求1至11中任一项所述的式(I)的化合物或其药学上可接受的盐及一或多种药学上可接受的赋形剂。
13.一种根据权利要求1至11中一项或多项所述的化合物或其药学上可接受的盐,其用作药剂。
14.根据权利要求1至11中一项或多项所述的化合物的用途,用于治疗患有脑癌、乳癌、胆道癌、膀胱癌、子宫颈癌、大肠直肠癌、子宫内膜癌、皮肤癌、食道肿瘤、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。
15.一种药物组合物,除式(I)的化合物以外,其还包含选自由细胞生长抑制及细胞毒性活性物质组成的组的药物活性化合物。
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