CN116801878A - Her2的有效和选择性抑制剂 - Google Patents
Her2的有效和选择性抑制剂 Download PDFInfo
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- CN116801878A CN116801878A CN202180081390.8A CN202180081390A CN116801878A CN 116801878 A CN116801878 A CN 116801878A CN 202180081390 A CN202180081390 A CN 202180081390A CN 116801878 A CN116801878 A CN 116801878A
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Abstract
公开了作为HER2的有效和选择性抑制剂的化合物以及它们的药学上可接受的盐和立体异构体。还公开了含有所述化合物的药物组合物,以及制备所述化合物和使用所述化合物来治疗与HER2相关的疾病和病症的方法。
Description
相关申请
本申请要求2020年10月5日提交的美国临时申请第63/087,517号和2021年8月12日提交的美国临时申请第63/232,450号的优先权,这些申请的全部内容据此以引用的方式整体并入。
背景技术
人表皮生长因子受体2(HER2、ERBB2)的突变已经被确定为致癌驱动因素。它们发生在2%-3%的非小细胞肺癌(NSCLC)中(Shigema tsu等人,Cancer Res.,65(5):1642-1646(2005);Buttitta等人,Int.J.Cancer,119(11):2586-2591(2006);Tomizawa等人,Lung Cancer,74(1):139-144(2011);Mazieres等人,J.Clin.Oncol.,31(16):1997-2003(2013)),并且在EGFR/ALK/ROS1三阴性NSCLC中的发生率高达6.7%(Li等人,BMC Cancer,16(1):828(2016))。此外,大约15%-25%的乳腺癌会出现HER2基因扩增、HER2蛋白过表达,或者它们两者同时出现,这些乳腺癌被归类为HER2阳性(Slamon等人,Scien ce,235(4785):177-182(1987);Slamon等人,Science,244(4905):707-712(1989))。HER2突变最常见的是外显子20***突变体(Shigemat su等人,Cancer Res.,65(5):1642-1646(2005))。最常见的HER2外显子20***突变体由12个碱基对的框内***YVMA(p.A775_G776insYVMA)组成,该突变体引起PI3'K-AKT和RAS-MAPK通路的下游活化(Tomizawa等人,Lung Cancer,74(1):139-144(2011))。从病史上看,HER2突变型NSCLC患者从诊断为IV期开始的中位数总体存活期(OS)为1.6-1.9年(Kris等人,Jama-J.Am.Med.Assoc.,311(19):1998-2006(2014))。关于HER2突变型NSCLC患者的HER2靶向药物(包括阿法替尼(afatinib)、达克替尼(dacomitinib)、来那替尼(neratini b)和曲妥珠单抗(trastuzumab))的若干患者报告和系列报告已经显示出临床活性有限(De Greve等人,Lung Cancer,76(1):123-127(2012);Kris等人,Ann.Oncol.,26(7):1421-1427(2015);Gandhi等人,J.Clin.Onol.,32(2):68-75(2014);Mazieres等人,Ann.Oncol.,27(2):281-286(2016))。因此,化学疗法仍然是针对该患者群体的主要策略(Eng等人,Lung Cancer,99:53-56(2016))。
对具有针对HER2突变的活性的化合物存在需求,因为它们可以在治疗具有此类突变的肿瘤方面具有扩展用途。
发明内容
本公开的第一方面涉及一种以式(I)的结构表示的化合物:
其中R1、R2、R3、X、m、n和A如本文所定义,或其药学上可接受的盐或立体异构体。
本公开的另一个方面涉及一种药物组合物,所述药物组合物包含治疗有效量的式(I)的化合物或其药学上可接受的盐或立体异构体,以及药学上可接受的载体。
本公开的另一个方面涉及治疗以异常的人表皮生长因子受体2(HER2)活性为特征或由其介导的疾病或病症的方法。
在一些实施方案中,所述疾病或病症是癌症。在一些实施方案中,所述癌症是乳腺癌、卵巢癌、胃肠道癌、肺癌、结肠癌、子宫内膜癌或甲状腺癌。在一些实施方案中,所述癌症是非小细胞肺癌(NSCLC)或EGFR/ALK/ROS1三阴性NSCLC。
如工作实施例中所展示,本公开的化合物是HER2的有效和选择性抑制剂。
具体实施方式
除非另外定义,否则本文使用的所有技术和科学术语与本文主题所属领域的技术人员通常所理解的含义相同。如说明书和所附权利要求中所用,除非另外指明相反,否则以下术语具有为了便于理解本公开而指明的含义。
如说明书和所附权利要求中所用,除非上下文另外明确指明,否则单数形式“一个”、“一种”和“所述”包括复数指代物。因此,例如,提及“一种组合物”包括两种或更多种此类组合物的混合物,提及“一种抑制剂”包括两种或更多种此类抑制剂的混合物,等等。
除非另外说明,否则术语“约”意指在由术语“约”修饰的特定值的10%内(例如,在5%、2%或1%内)。
与“包括”、“含有”或“特征在于”同义的过渡性术语“包含”是包容性的或开放式的,并且不排除另外的、未列举的要素或方法步骤。当在杂环结构中的杂原子数的语境中使用时,它意指杂环基团具有最小杂原子数。相比之下,过渡性短语“由......组成”排除权利要求中未指定的任何要素、步骤或成分。过渡性短语“基本上由......组成”将权利要求的范围限制于特定的材料或步骤“以及那些不会对所要求保护的化合物的基本和新特征产生实质性影响的材料或步骤”。
关于本文公开的化合物,以及在本文使用以下术语来进一步描述它们的程度上,以下定义适用。
如本文所用,术语“烷基”是指饱和直链或支链单价烃基团。在一个实施方案中,烷基基团是C1-C18基团。在其他实施方案中,烷基基团是C0-C6、C0-C5、C0-C3、C1-C12、C1-C8、C1-C6、C1-C5、C1-C4或C1-C3基团(其中C0烷基是指键)。烷基基团的实例包括甲基、乙基、1-丙基、2-丙基、异丙基、1-丁基、2-甲基-1-丙基、2-丁基、2-甲基-2-丙基、1-戊基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、1-己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、庚基、辛基、壬基、癸基、十一烷基和十二烷基。在一些实施方案中,烷基基团是C1-C3烷基基团。在一些实施方案中,烷基基团是C1-C2烷基基团或甲基基团。
如本文所用,术语“亚烷基”是指将分子的其余部分连接至基团的直链或支链二价烃链,它仅由碳和氢组成,不含有不饱和度并且具有一至12个碳原子,例如亚甲基、亚乙基、亚丙基、正亚丁基等等。亚烷基链可以通过单键附接至分子的其余部分并且通过单键附接至基团。在一些实施方案中,亚烷基基团含有一至8个碳原子(C1-C8亚烷基)。在其他实施方案中,亚烷基基团含有一至5个碳原子(C1-C5亚烷基)。在其他实施方案中,亚烷基基团含有一至4个碳原子(C1-C4亚烷基)。在其他实施方案中,亚烷基含有一至三个碳原子(C1-C3亚烷基)。在其他实施方案中,亚烷基基团含有一至两个碳原子(C1-C2亚烷基)。在其他实施方案中,亚烷基基团含有一个碳原子(C1亚烷基)。
如本文所用,术语“烯基”是指具有至少一个碳-碳双键的直链或支链单价烃基团。烯基包括具有“顺式”和“反式”取向,或者“E”和“Z”取向的基团。在一个实例中,烯基基团是C2-C18基团。在其他实施方案中,烯基基团是C2-C12、C2-C10、C2-C8、C2-C6或C2-C3基团。实例包括乙烯基(ethenyl或vinyl)、丙-1-烯基、丙-2-烯基、2-甲基丙-1-烯基、丁-1-烯基、丁-2-烯基、丁-3-烯基、丁-1,3-二烯基、2-甲基丁-1,3-二烯、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基和己-1,3-二烯基。
如本文所用,术语“炔基”是指具有至少一个碳-碳三键的直链或支链单价烃基团。在一个实例中,炔基基团是C2-C18基团。在其他实例中,炔基基团是C2-C12、C2-C10、C2-C8、C2-C6或C2-C3。实例包括乙炔基丙-1-炔基、丙-2-炔基、丁-1-炔基、丁-2-炔基和丁-3-炔基。
如本文所用,术语“烷氧基”或“烷基氧基”是指如上文所定义附接有氧基团的烷基基团,并且该烷基基团是附接点。代表性烷氧基基团包括甲氧基、乙氧基、丙氧基、叔丁氧基等等。“醚”是两个通过氧共价连接的烃基基团。因此,使烷基成为醚的烷基的取代基是烷氧基或类似于烷氧基,诸如可以以-O-烷基、-O-烯基和-O-炔基中的一者表示。
如本文所用,术语“卤素”(或“卤代基”或“卤化物”)是指氟、氯、溴或碘。
如本文所用,术语“环状基团”广泛地指这样的单独或作为更大部分的一部分使用的任何基团,所述基团含有饱和、部分饱和或芳族环系,例如碳环(环烷基、环烯基)、杂环(杂环烷基、杂环烯基)、芳基和杂芳基基团。环状基团可以具有一个或多个(例如,稠合)环系。因此,例如,环状基团可以含有一个或多个碳环、杂环、芳基或杂芳基基团。
如本文所用,术语“碳环”(也称为“碳环基”)是指这样的单独或作为更大部分的一部分使用的基团,所述基团含有具有3至20个碳原子的饱和、部分不饱和或芳族环系,所述环系单独或作为更大部分的一部分(例如,烷基碳环基团)。术语碳环基包括单环、双环、三环、稠环、桥环和螺环***,以及它们的组合。在一个实施方案中,碳环基包含3至15个碳原子(C3-C15)。在一个实施方案中,碳环基包含3至12个碳原子(C3-C12)。在另一个实施方案中,碳环基包括C3-C8、C3-C10或C5-C10。在另一个实施方案中,单环形式的碳环基包括C3-C8、C3-C6或C5-C6。在一些实施方案中,双环形式的碳环基包括C7-C12。在另一个实施方案中,螺系形式的碳环基包括C5-C12。单环碳环基的代表性实例包括环丙基、环丁基、环戊基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、环己基、全氘代环己基、1-环己-1-烯基、1-环己-2-烯基、1-环己-3-烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、苯基和环十二烷基;具有7至12个环原子的双环碳环基包括[4,3]、[4,4]、[4,5]、[5,5]、[5,6]或[6,6]环系,例如双环[2.2.1]庚烷、双环[2.2.2]辛烷、萘和双环[3.2.2]壬烷。螺碳环基的代表性实例包括螺[2.2]戊烷、螺[2.3]己烷、螺[2.4]庚烷、螺[2.5]辛烷和螺[4.5]癸烷。术语碳环基包括如本文所定义的芳环系。术语碳环基还包括环烷基环(例如,饱和或部分不饱和单环、双环或螺碳环)。术语碳环基团还包括与一个或多个(例如,1、2或3个)不同的环状基团(例如,芳基或杂环)稠合的碳环,其中附接基团或点在碳环上。
因此,术语碳环还包括碳环基烷基,如本文所用,它是指式--Rc-碳环基的基团,其中Rc是亚烷基链。术语碳环还包括碳环基烷氧基,如本文所用,它是指通过氧原子键合的式--O--Rc-碳环基的基团,其中Rc是亚烷基链。
如本文所用,术语“芳基”单独或作为更大部分(例如,“芳烷基”,其中烷基基团上的末端碳原子是附接点,例如,苄基基团;“芳烷氧基”,其中氧原子是附接点;或“芳氧基烷基”,其中附接点在芳基基团上)的一部分使用,是指包含单环、双环或三环碳环***(包括稠环)的基团,其中该***中的至少一个环是芳族的。在一些实施方案中,芳烷氧基基团是苯甲酰氧基基团。术语“芳基”可以与术语“芳基环”互换使用。在一个实施方案中,芳基包括具有6-18个碳原子的基团。在另一个实施方案中,芳基包括具有6-10个碳原子的基团。芳基基团的实例包括苯基、萘基、蒽基、联苯基、菲基、稠四苯基、1,2,3,4-四氢萘基、1H-茚基、2,3-二氢-1H-茚基、萘啶基等等,它可以被一个或多个本文所述的取代基取代或独立地取代。特定芳基是苯基。在一些实施方案中,芳基基团包括与一个或多个(例如,1、2或3个)不同的环状基团(例如,碳环或杂环)稠合的芳基环,其中附接基团或点在芳环上。
因此,术语芳基包括芳烷基基团(例如,苄基),如上文所公开,它是指式--Rc-芳基的基团,其中Rc是亚烷基链,诸如亚甲基或亚乙基。在一些实施方案中,芳烷基基团是任选地取代的苄基基团。术语芳基还包括芳烷氧基基团,如本文所用,它是指通过氧原子键合的式-O-Rc--芳基的基团,其中Rc是亚烷基链,诸如亚甲基或亚乙基。
如本文所用,术语“杂环基”是指单独或作为更大部分的一部分使用的“碳环基”,该碳环基含有饱和、部分不饱和或芳族环系,其中一个或多个(例如,1、2、3或4个)碳原子被杂原子(例如,O、N、N(O)、S、S(O)或S(O)2)替代。术语杂环基包括单环、双环、三环、稠环、桥环和螺环***,以及它们的组合。在一些实施方案中,杂环基是指3至15元杂环基环系。在一些实施方案中,杂环基是指3至12元杂环基环系。在一些实施方案中,杂环基是指饱和环系,诸如3至12元饱和杂环基环系。在一些实施方案中,杂环基是指杂芳基环系,诸如5至14元杂芳基环系。术语杂环基还包括C3-C8杂环烷基,它是含有3-8个碳原子和一个或多个(1、2、3或4个)杂原子的饱和或部分不饱和单环、双环或螺环***。
在一些实施方案中,杂环基基团包含3-12个环原子并且包括单环、双环、三环和螺环***,其中所述环原子是碳,并且一至5个环原子是杂原子,诸如氮、硫或氧。在一些实施方案中,杂环基包括具有一个或多个选自氮、硫或氧的杂原子的3至7元单环。在一些实施方案中,杂环基包括具有一个或多个选自氮、硫或氧的杂原子的4至6元单环。在一些实施方案中,杂环基包括3元单环。在一些实施方案中,杂环基包括4元单环。在一些实施方案中,杂环基包括5-6元单环。在一些实施方案中,杂环基基团包含0至3个双键。在前述实施方案中的任一者中,杂环基包含1、2、3或4个杂原子。任何氮或硫杂原子都可以任选地被氧化(例如,NO、SO、SO2),并且任何氮杂原子都可以任选地被季铵化(例如,[NR4]+Cl-、[NR4]+OH-)。杂环基的代表性实例包括环氧乙烷基、氮丙啶基、环硫乙烷基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、1,2-二硫杂环丁烷基、1,3-二硫杂环丁烷基、吡咯烷基、二氢-1H-吡咯基、二氢呋喃基、四氢吡喃基、二氢噻吩基、四氢噻吩基、咪唑烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、1,1-二氧代-硫代吗啉基、二氢吡喃基、四氢吡喃基、六氢噻喃基、六氢嘧啶基、噁嗪基、噻嗪基、噻噁烷基、高哌嗪基、高哌啶基、氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、氧氮杂环庚烷基、二氮杂环庚烷基、1,4-二氮杂环庚烷基、二氮杂/>基、硫氮杂/>基、硫氮杂环庚烷基、四氢噻喃基、噁唑烷基、噻唑烷基、异噻唑烷基、1,1-二氧代异噻唑啉酮基、噁唑烷酮基、咪唑啉酮基、4,5,6,7-四氢[2H]吲唑基、四氢苯并咪唑基、4,5,6,7-四氢苯并[d]咪唑基、1,6-二氢咪唑并[4,5-d]吡咯并[2,3-b]吡啶基、噻嗪基、噻吩基、噁嗪基、噻二嗪基、噁二嗪基、二噻嗪基、二噁嗪基、噁噻嗪基、噻三嗪基、噁三嗪基、二噻二嗪基、咪唑啉基、二氢嘧啶基、四氢嘧啶基、1-吡咯啉基、2-吡咯啉基、3-吡咯啉基、吲哚啉基、噻喃基、2H-吡喃基、4H-吡喃基、二噁烷基、1,3-二氧戊环基、吡唑啉基、吡唑烷基、二硫环己基、二硫戊环基、嘧啶酮基、嘧啶二酮基、嘧啶-2,4-二酮基、哌嗪酮基、哌嗪二酮基、吡唑啉基咪唑啉基、3-氮杂双环[3.1.0]己基、3,6-二氮杂双环[3.1.1]庚基、6-氮杂双环[3.1.1]庚基、3-氮杂双环[3.1.1]庚基、3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、2-氮杂双环[3.2.1]辛基、8-氮杂双环[3.2.1]辛基、2-氮杂双环[2.2.2]辛基、8-氮杂双环[2.2.2]辛基、7-氧杂双环[2.2.1]庚烷、氮杂螺[3.5]壬基、氮杂螺[2.5]辛基、氮杂螺[4.5]癸基、1-氮杂螺[4.5]癸-2-酮基、氮杂螺[5.5]十一烷基、四氢吲哚基、八氢吲哚基、四氢异吲哚基、四氢吲唑基、1,1-二氧代六氢噻喃基。含有硫或氧原子和一至三个氮原子的5元杂环基的实例是噻唑基,包括噻唑-2-基和噻唑-2-基N-氧化物;噻二唑基,包括1,3,4-噻二唑-5-基和1,2,4-噻二唑-5-基;噁唑基,例如噁唑-2-基;和噁二唑基,诸如1,3,4-噁二唑-5-基和1,2,4-噁二唑-5-基。含有2至4个氮原子的5元环杂环基的实例包括咪唑基,诸如咪唑-2-基;***基,诸如1,3,4-***-5-基、1,2,3-***-5-基、1,2,4-***-5-基;和四唑基,诸如1H-四唑-5-基。苯并稠合的5元杂环基的代表性实例是苯并噁唑-2-基、苯并噻唑-2-基和苯并咪唑-2-基。6元杂环基的实例含有一至三个氮原子和任选地硫或氧原子,例如吡啶基,诸如吡啶-2-基、吡啶-3-基和吡啶-4-基;嘧啶基,诸如嘧啶-2-基和嘧啶-4-基;三嗪基,诸如1,3,4-三嗪-2-基和1,3,5-三嗪-4-基;哒嗪基,尤其是哒嗪-3-基;和吡嗪基。吡啶N-氧化物和哒嗪N-氧化物以及吡啶基、嘧啶-2-基、嘧啶-4-基、哒嗪基和1,3,4-三嗪-2-基基团是杂环基基团的另外其他实例。在一些实施方案中,杂环基团包含稠合至一个或多个(例如,1、2或3个)不同的环状基团(例如,碳环或杂环)的杂环,其中附接基团或点在杂环上,并且在一些实施方案中,其中附接点是包含在杂环中的杂原子。
因此,术语杂环包括N-杂环基基团,如本文所用,它是指含有至少一个氮的杂环基基团,并且其中杂环基基团与分子的其余部分的附接点是通过杂环基基团中的氮原子。N-杂环基基团的代表性实例包括1-吗啉基、1-哌啶基、1-哌嗪基、1-吡咯烷基、吡唑烷基、咪唑啉基和咪唑烷基。术语杂环还包括C-杂环基基团,如本文所用,它是指含有至少一个杂原子的杂环基基团,并且其中杂环基基团与分子的其余部分的附接点是通过杂环基基团中的碳原子。C-杂环基基团的代表性实例包括2-吗啉基、2-哌啶基或3-哌啶基或4-哌啶基、2-哌嗪基和2-吡咯烷基或3-吡咯烷基。术语杂环还包括杂环基烷基基团,如上文所公开,它是指式--Rc-杂环基的基团,其中Rc是亚烷基链。术语杂环还包括杂环基烷氧基基团,如本文所用,它是指通过氧原子键合的式--O--Rc-杂环基的基团,其中Rc是亚烷基链。
如本文所用,术语“杂芳基”单独或作为更大部分(例如,“杂芳基烷基”(也称为“杂芳烷基”),或“杂芳基烷氧基”(也称为“杂芳烷氧基”))的一部分使用,是指具有5至14个环原子的单环、双环或三环环系,其中至少一个环是芳族的并且含有至少一个杂原子。在一个实施方案中,杂芳基包括5-6元单环芳族基团,其中一个或多个环原子是氮、硫或氧。杂芳基基团的代表性实例包括噻吩基、呋喃基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、***基、噻二唑基、噁二唑基、四唑基、噻***基、噁***基、吡啶基、嘧啶基、咪唑并吡啶基、吡嗪基、哒嗪基、三嗪基、四嗪基、四唑并[1,5-b]哒嗪基、嘌呤基、脱氮嘌呤基、苯并噁唑基、苯并呋喃基、苯并噻唑基、苯并噻二唑基、苯并***基、苯并咪唑基、吲哚基、1,3-噻唑-2-基、1,3,4-***-5-基、1,3-噁唑-2-基、1,3,4-噁二唑-5-基、1,2,4-噁二唑-5-基、1,3,4-噻二唑-5-基、1H-四唑-5-基、1,2,3-***-5-基和吡啶-2-基N-氧化物。术语“杂芳基”还包括其中杂芳基稠合至一个或多个环状(例如,碳环基或杂环基)环的基团,其中附接基团或点在杂芳基环上。非限制性实例包括吲哚基、吲哚嗪基、异吲哚基、苯并噻吩基(benzothienyl/benzothiophenyl)、亚甲基二氧苯基、苯并呋喃基、二苯并呋喃基、吲唑基、苯并咪唑基、苯并二噁唑基、苯并噻唑基、喹啉基、异喹啉基、噌啉基、酞嗪基、喹唑啉基、喹喔啉基、4H-喹嗪基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基、四氢喹啉基、四氢异喹啉基和吡啶并[2,3-b]-1,4-噁嗪-3(4H)-酮。杂芳基基团可以是单环的、双环的或三环的。在一些实施方案中,杂芳基基团包括稠合至一个或多个(例如,1、2或3个)不同的环状基团(例如,碳环或杂环)的杂芳基环,其中附接基团或点在杂芳基环上,并且在一些实施方案中,其中附接点是包含在杂环中的杂原子。
因此,术语杂芳基包括N-杂芳基基团,如本文所用,它是指如上文所定义含有至少一个氮的杂芳基基团,并且其中杂芳基基团与分子的其余部分的附接点是通过杂芳基基团中的氮原子。术语杂芳基还包括C-杂芳基基团,如本文所用,它是指如上文所定义的杂芳基基团,并且其中杂芳基基团与分子的其余部分的附接点是通过杂芳基基团中的碳原子。术语杂芳基还包括杂芳基烷基基团,如上文所公开,它是指式--Rc-杂芳基的基团,其中Rc是如上文所定义的亚烷基链。术语杂芳基还包括杂芳烷氧基(或杂芳基烷氧基)基团,如本文所用,它是指通过氧原子键合的式--O--Rc-杂芳基的基团,其中Rc是如上文所定义的亚烷基基团。
除非另外说明,并且在未对任何特定基团进行进一步定义的程度上,本文所述的基团中的任一者可以是取代的或未取代的。如本文所用,术语“取代的”广义地指所有允许的取代基,隐含的条件是这种取代与被取代的原子和取代基的允许的化合价一致,并且取代产生稳定的化合物,即不会诸如通过重排、环化、消除等自发地进行转化的化合物。代表性取代基包括卤素、羟基基团以及任何其他含有任何数量碳原子(例如,1-14个碳原子)的有机基团,并且所述有机基团可以包含一个或多个(例如,1、2、3或4个)杂原子,诸如氧、硫和氮,所述原子以直链、支链或环状结构形式组合。
就任何特定基团未另行公开而言,取代基的代表性实例可以包括烷基、取代的烷基(例如,C1-C6、C1-C5、C1-C4、C1-C3、C1-C2、C1)、烷氧基(例如,C1-C6、C1-C5、C1-C4、C1-C3、C1-C2、C1)、取代的烷氧基(例如,C1-C6、C1-C5、C1-C4、C1-C3、C1-C2、C1)、卤代烷基(例如,CF3)、烯基(例如,C2-C6、C2-C5、C2-C4、C2-C3、C2)、取代的烯基(例如,C2-C6、C2-C5、C2-C4、C2-C3、C2)、炔基(例如,C2-C6、C2-C5、C2-C4、C2-C3、C2)、取代的炔基(例如,C2-C6、C2-C5、C2-C4、C2-C3、C2)、环基(例如,C3-C12、C5-C6)、取代的环基(例如,C3-C12、C5-C6)、碳环基(例如,C3-C12、C5-C6)、取代的碳环基(例如,C3-C12、C5-C6)、杂环基(例如,C3-C12、C5-C6)、取代的杂环基(例如,C3-C12、C5-C6)、芳基(例如,苄基和苯基)、取代的芳基(例如,取代的苄基或苯基)、杂芳基(例如,吡啶基或嘧啶基)、取代的杂芳基(例如,取代的吡啶基或嘧啶基)、芳烷基(例如,苄基)、取代的芳烷基(例如,取代的苄基)、卤代基、羟基、芳氧基(例如,C6-C12、C6)、取代的芳氧基(例如,C6-C12、C6)、烷硫基(例如,C1-C6)、取代的烷硫基(例如,C1-C6)、芳硫基(例如,C6-C12、C6)、取代的芳硫基(例如,C6-C12、C6)、氰基、羰基、取代的羰基、羧基、取代的羧基、氨基、取代的氨基、酰胺基、取代的酰胺基、硫基、取代的硫基、亚磺酰基、取代的亚磺酰基、磺酰基、取代的磺酰基、亚磺酰胺、取代的亚磺酰胺、磺酰胺、取代的磺酰胺、脲、取代的脲、氨基甲酸酯、取代的氨基甲酸酯、氨基酸和肽基团。
在一个方面,本文提供了以式(I)表示的化合物:
或其药学上可接受的盐或立体异构体,
其中:
X不存在,是-CH2-、-O-或C(O);
A不存在,是萘基、含有1-3个选自N、O和S的杂原子的5元杂环基、或者具有5或6元环并且含有1-4个选自N、O和S的杂原子的稠合杂双环基,并且其中A任选地被一个或多个RA取代;
每个RA独立地是C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、卤代基、羟基、氰基、硝基、氨基、C1-C6烷基氨基或二-C1-C6烷基氨基;
每个R1独立地是C1-C6烷基、C2-C6烯基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C1-C6烷基酰胺基、卤代基、羟基、氰基、硝基、氨基、C1-C6烷基氨基、二-C1-C6烷基氨基、C3-C6碳环基或者5或6元杂环基,其中R1任选地被一个或多个RA取代,
或者两个R1基团与它们所附接的原子一起形成5至6元碳环基或杂环基;
R3是氢、氟或甲基;
m为1或2;并且
n为0、1或2。
在一些实施方案中,X不存在。
在一些实施方案中,X是-CH2-。
在一些实施方案中,X是-O-。
在一些实施方案中,X是C(O)。
在一些实施方案中,A是任选地被一个或多个RA取代的萘基。
在一些实施方案中,A是具有5和6元环的稠合杂双环基,并且含有1-4个选自N、O和S的杂原子,其中A任选地被一个或多个RA取代。
在一些实施方案中,A是包含两个6元环的稠合杂双环基,并且含有1-4个选自N、O和S的杂原子,其中A任选地被一个或多个RA取代。
在一些实施方案中,A是含有1-3个选自N、O和S的杂原子的5元杂环基,并且该杂环基任选地被一个或多个RA取代。
在一些实施方案中,A是 并且任选地被一个或多个RA取代。
在一些实施方案中,A是
并且任选地被一个或多个RA取代。
在一些实施方案中,A是任选地被一个或多个RA取代。
在一些实施方案中,A是
在一些实施方案中,A是 并且任选地被一个或多个RA取代。
在一些实施方案中,A是任选地被一个或多个RA取代。
在一些实施方案中,A是
在一些实施方案中,A是 并且任选地被一个或多个RA取代。
在一些实施方案中,A是 并且任选地被一个或多个RA取代。
在一些实施方案中,A是 并且任选地被一个或多个RA取代。
在一些实施方案中,A是 并且任选地被一个或多个RA取代。/>
在一些实施方案中,A是 />并且任选地被一个或多个RA取代。
在一些实施方案中,A是任选地被一个或多个RA取代。
在一些实施方案中,A是任选地被一个或多个RA取代。
在一些实施方案中,A是
在一些实施方案中,A是
在一些实施方案中,A是任选地被一个或多个RA取代。
在一些实施方案中,A是
在一些实施方案中,A是并且任选地被一个或多个RA取代。
在一些实施方案中,A是/>
在一些实施方案中,A是 并且任选地被一个或多个RA取代。
在一些实施方案中,R1独立地是C1-C6烷基、C2-C6烯基、C1-C6烷氧基、C1-C6卤代烷氧基、C1-C6烷基酰胺基、卤代基、氰基、二-C1-C6烷基氨基、C3-C6碳环基或者5或6元杂环基。
在一些实施方案中,R1独立地是甲基、乙基、氟、氯、溴、甲氧基、氰基、-OCHF2、-OCH2F、-NMe2、
在一些实施方案中,R1是甲基。
在一些实施方案中,R1是氯。
在一些实施方案中,R1是
在一些实施方案中,两个R1基团与它们所附接的原子一起形成5至6元碳环基或杂环基。
在一些实施方案中,两个R1基团与它们所附接的原子一起形成苯基、吡啶基或二氧戊环。
在一些实施方案中,R2是
在一些实施方案中,R3是氢。
在一些实施方案中,m为2。
在一些实施方案中,n为1。
在一些实施方案中,n为2。
在一些实施方案中,式I的化合物是式Ia-Ih的化合物:
或者它们的药学上可接受的盐或立体异构体。在式Ia-Ih的一些实施方案中,R1是甲基。在式Ia-Ih的一些实施方案中,R1是氯。
在式Ia-Ih的一些实施方案中,n为1。
在式Ia-Ih的一些实施方案中,n为2。
代表性式(I)的化合物具有以下结构:
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或者它们的药学上可接受的盐或立体异构体。
本公开的化合物可以是游离酸或游离碱或药学上可接受的盐的形式。如本文所用,在盐的语境中,术语“药学上可接受的”是指不消除化合物的生物活性或性质,并且是相对无毒的化合物的盐,即,可以将盐形式的化合物施用于受试者而不会导致不期望的生物效应(诸如头晕或胃部不适)或者以有害的方式与包含它的组合物的任何其他组分相互作用。术语“药学上可接受的盐”是指通过本公开的化合物与合适的酸或碱的反应而获得的产物。本公开的化合物的药学上可接受的盐的实例包括衍生自合适的无机碱的那些盐,诸如Li盐、Na盐、K盐、Ca盐、Mg盐、Fe盐、Cu盐、Al盐、Zn盐和Mn盐。药学上可接受的无毒酸加成盐的实例是氨基基团与无机酸形成的盐,所述无机酸诸如盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、异烟酸盐、乙酸盐、乳酸盐、水杨酸盐、柠檬酸盐、酒石酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、延胡索酸盐、葡萄糖酸盐、葡萄糖醛酸盐、蔗糖盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、4-甲基苯磺酸盐或对甲苯磺酸盐等等。本文提供的某些化合物可以与各种有机碱(诸如赖氨酸、精氨酸、胍、二乙醇胺或二甲双胍)形成药学上可接受的盐。合适的碱盐包括铝盐、钙盐、锂盐、镁盐、钾盐、钠盐或锌盐。
本公开的化合物可以具有至少一个手性中心,因此可以为立体异构体形式,如本文所用,所述立体异构体包括仅在它们的原子的空间取向上不同的单个化合物的所有异构体。术语立体异构体包括化合物的镜像异构体(对映异构体,它包括化合物的(R-)或(S-)构型)、镜像异构体的混合物(对映异构体的物理混合物,以及外消旋物或外消旋混合物)、化合物的几何(顺式/反式或E/Z、R/S)异构体以及具有多于一个手性中心且彼此不是镜像的化合物的异构体(非对映异构体)。化合物的手性中心可以经历体内差向异构化;因此,对于这些化合物,化合物以(R-)形式施用被认为等同于化合物以(S-)形式施用。因此,本公开的化合物可以以单独的异构体并且基本上不含其他异构体的形式,或者以各种异构体的混合物(例如,立体异构体的外消旋混合物)的形式制备和使用。
在一些实施方案中,化合物是同位素衍生物,因为它具有至少一个所期望的原子的同位素取代,取代的量大于同位素的天然丰度,即富集。在一个实施方案中,化合物包含氘或多个氘原子。用较重的同位素(诸如氘,即2H)进行的取代可能由于较高的代谢稳定性,例如增加体内半衰期或减少剂量要求而提供某些治疗优势,因此在一些情况下可能是有利的。
本公开的化合物可以通过在不同条件下结晶来制备,并且可以以化合物的多晶型物中的一者或组合存在。例如,不同的多晶型物可以使用用于重结晶的不同溶剂或不同溶剂的混合物,通过在不同温度下进行结晶,或者通过使用各种冷却模式(在结晶过程中非常快到非常慢的冷却)来鉴定和/或制备。多晶型物还可以通过加热或熔化化合物然后逐渐或快速冷却来获得。多晶型物的存在可以通过固体探针NMR光谱法、IR光谱法、差示扫描量热法、粉末X射线衍射图和/或其他已知技术来确定。
在一些实施方案中,药物组合物包含本发明化合物的共晶。如本文所用,术语“共晶”是指包含本文提供的化合物和共晶形成剂的化学计量多组分体系,其中本文提供的化合物和共晶形成剂通过非共价相互作用来连接。如本文所用,术语“共晶形成剂”是指可以与本文提供的化合物形成分子间相互作用并且与其共结晶的化合物。共晶形成剂的代表性实例包括苯甲酸、琥珀酸、延胡索酸、戊二酸、反式-肉桂酸、2,5-二羟基苯甲酸、乙醇酸、反式-2-己酸、2-羟基己酸、乳酸、山梨酸、酒石酸、阿魏酸、辛二酸、吡啶甲酸、水杨酸、马来酸、糖精、4,4'-联吡啶对氨基水杨酸、烟酰胺、尿素、异烟酰胺、4-羟基苯甲酸甲酯、己二酸、对苯二甲酸、间苯二酚、邻苯三酚、间苯三酚、偏苯三酚、异烟肼、茶碱、腺嘌呤、可可碱、非那西汀(phenacetin)、非那宗(phenazone)、乙羟茶碱(etofylline)和***(phenobarbital)。
合成方法
在另一个方面,本公开涉及一种用于制备本发明的化合物或其药学上可接受的盐或立体异构体的方法。广义上,本发明的化合物或其药学上可接受的盐或立体异构体可以通过已知适用于制备化学相关化合物的任何方法来制备。结合各种工作实施例中描述的合成方案将更好地理解本公开的化合物,这些工作实施例展示了可以用于制备本公开的化合物的非限制性方法。
药物组合物
本公开的另一个方面涉及一种药物组合物,所述药物组合物包含治疗有效量的本发明的化合物或其药学上可接受的盐或立体异构体,以及药学上可接受的载体。如本领域已知,术语“药学上可接受的载体”是指适用于将本公开的化合物施用于哺乳动物的药学上可接受的材料、组合物或媒介物。合适的载体可以包括例如液体(水性和非水性等,以及它们的组合)、固体、包封材料、气体以及它们的组合(例如,半固体)和气体,它们的功能是将化合物从一个器官或身体的一部分携带或运输至另一个器官或身体的另一部分。载体在对制剂的其他成分具有生理惰性和相容性以及对受试者或患者无害的意义上是“可接受的”。根据制剂的类型,组合物还可以包含一种或多种药学上可接受的赋形剂。
广义上,本公开的化合物以及它们的药学上可接受的盐或立体异构体可以根据常规制药实践(诸如常规混合、溶解、造粒、锭剂制备、磨细、乳化、包封、包埋和压缩过程)来配制成指定类型的组合物(参见,例如,Remington:The Science and Practice of Pharmacy(第20版),A.R.Gennaro编,Lippincott Williams&Wilkins,2000和Encyclopedia ofPharmaceutical Technology,J.Swarbrick和J.C.Boylan编,1988-1999,Marcel Dekker,New York)。制剂的类型取决于施用方式,所述施用方式可以包括肠内施用(例如,口服、含服、舌下和直肠)、肠胃外施用(例如,皮下(s.c.)、静脉内(i.v.)、肌肉内(i.m.)和胸骨内注射或输注技术、眼内、动脉内、髓内、鞘内、心室内、透皮、皮间、***内、腹膜内、粘膜、鼻腔、气管内滴注、支气管滴注和吸入)和局部施用(例如,透皮)。通常,最合适的施用途径将取决于多种因素,包括例如药剂的性质(例如,它在胃肠道环境中的稳定性),和/或受试者的状况(例如,受试者是否能够耐受口服施用)。例如,肠胃外(例如,静脉内)施用也可以是有利的,因为诸如在单剂量治疗和/或急性疾患的情况下,化合物可以相对快速地施用。
在一些实施方案中,化合物被配制用于口服或静脉内施用(例如,全身静脉内注射)。
因此,本文提供的化合物可以被配制成固体组合物(例如,粉末剂、片剂、分散颗粒剂、胶囊剂、扁囊剂和栓剂)、液体组合物(例如,溶解有化合物的溶液剂、分散有化合物的固体颗粒的混悬剂、乳剂以及含有脂质体、胶束或纳米颗粒的溶液剂、糖浆剂和酏剂);半固体组合物(例如,凝胶剂、混悬剂和霜剂);和气体(例如,气溶胶组合物的推进剂)。化合物也可以被配制用于快速、立即或延长释放。
用于经口施用的固体剂型包括胶囊剂、片剂、丸剂、粉末剂和颗粒剂。在此类固体剂型中,活性化合物与载体以及附加载体或赋形剂混合,所述载体诸如柠檬酸钠或磷酸氢钙,所述赋形剂诸如a)填充剂或增量剂,诸如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇和硅酸,b)粘结剂,例如甲基纤维素、微晶纤维素、羟丙基甲基纤维素、羧甲基纤维素、羧甲基纤维素钠、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和***胶,c)保湿剂,诸如甘油,d)崩解剂,诸如交联聚合物(例如,交联聚乙烯吡咯烷酮(交聚维酮)、交联羧甲基纤维素钠(crosslinkedsodium carboxymethyl cellulose/croscarmellose sodium))、羟基乙酸淀粉钠、琼脂、碳酸钙、马铃薯或木薯淀粉、藻酸、某些硅酸盐和碳酸钠,e)溶液阻滞剂,诸如石蜡,f)吸收促进剂,诸如季铵化合物,g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯,h)吸收剂,诸如高岭土和膨润土,和i)润滑剂,诸如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠,以及它们的混合物。在胶囊剂、片剂和丸剂的情况下,剂型还可包含缓冲剂。在使用诸如乳糖(lactose或milk sugar)以及高分子量聚乙二醇等的赋形剂的软填充和硬填充明胶胶囊中也可使用类似类型的固体组合物作为填充剂。片剂、锭剂、胶囊剂、丸剂和颗粒剂的固体剂型可以用包衣和壳(诸如肠溶包衣和其他包衣)来制备。它们还可以含有遮光剂。
在一些实施方案中,本文提供的化合物可以配制在硬或软明胶胶囊中。可以使用的代表性赋形剂包括预胶凝化淀粉、硬脂酸镁、甘露糖醇、硬脂酰延胡索酸钠、无水乳糖、微晶纤维素和交联羧甲基纤维素钠。明胶壳可以包含明胶、二氧化钛、氧化铁和着色剂。
用于口服施用的液体剂型包括溶液剂、混悬剂、乳剂、微乳剂、糖浆剂和酏剂。除了化合物之外,液体剂型还可以含有本领域中常用的水性或非水性载体(取决于化合物的溶解度),例如水或其他溶剂,增溶剂和乳化剂,诸如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(尤其棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油以及芝麻油)、甘油、四氢糠醇、聚乙二醇以及脱水山梨糖醇的脂肪酸酯,以及它们的混合物。口服组合物还可以包含任何赋形剂,诸如润湿剂、助悬剂、着色剂、甜味剂、调味剂和芳香剂。
用于肠胃外施用的可注射制剂可以包括无菌水溶液剂或油性混悬剂。它们可以根据标准技术,使用合适的分散剂或润湿剂和助悬剂来配制。无菌可注射制剂还可以是含于无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液、悬浮液或乳液,例如如1,3-丁二醇中的溶液。在可使用的可接受媒介物和溶剂之中有水、林格氏溶液(U.S.P.)以及等渗氯化钠溶液。此外,无菌、不挥发性油通常用作为溶剂或悬浮介质。出于这个目的,可采用任何温和不挥发性油,包括合成的单甘油酯或二甘油酯。此外,诸如油酸的脂肪酸用于制备可注射制剂。可注射制剂可例如进行灭菌,通过经细菌截留过滤器过滤或通过并入呈无菌固体组合物形式的灭菌剂来进行,所述无菌固体组合物可在使用前溶解或分散于无菌水或其他无菌可注射介质中。化合物的作用可以通过减慢吸收来延长,这可以通过使用水溶性较差的液体悬浮液或结晶或无定形材料来实现。化合物从肠胃外施用的制剂的延长吸收还可以通过将化合物悬浮于油性媒介物中来实现。
在某些实施方案中,本文提供的化合物可以以局部而非全身方式施用,例如,通过将缀合物直接注射至器官中,通常以储库制剂或持续释放制剂的形式。在具体实施方案中,长效制剂通过植入(例如皮下或肌肉内)或通过肌肉内注射来施用。可注射储库形式通过在例如聚丙交酯-聚乙交酯、聚(原酸酯)和聚(酸酐)的可生物降解聚合物中形成化合物的微胶囊基质来制备。化合物的释放速率可以通过改变化合物与聚合物的比率和所用的特定聚合物的性质来控制。储库式可注射制剂也通过将化合物包埋在与身体组织相容的脂质体或微乳液中来制备。此外,在其他实施方案中,化合物在靶向药物递送***中,例如在用器官特异性抗体涂覆的脂质体中递送。在这些实施方案中,脂质体靶向至器官并被器官选择性吸收。
组合物可以被配制用于含服或舌下施用,这些施用的实例包括片剂、锭剂和凝胶剂。
本文提供的化合物可以被配制用于吸入施用。适用于吸入施用的各种形式包括气溶胶、气雾剂或粉末剂。药物组合物可在使用合适的推进剂(例如,二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其他合适的气体)的情况下通过加压包装或喷雾器以气溶胶喷雾的形式递送。在一些实施方案中,加压气溶胶的剂量单位可通过提供阀以递送计量的量来确定。在一些实施方案中,例如用于吸入器或吹入器中的包括明胶的胶囊和药筒可以被配制为含有化合物与合适的粉末基质(诸如乳糖或淀粉)的粉末混合物。
本文提供的化合物可以被配制用于局部施用,如本文所用,局部施用是指通过配制于表皮而进行皮内施用。这些类型的组合物通常呈软膏剂、糊剂、霜剂、洗剂、凝胶剂、溶液剂和喷雾剂形式。
可用于配制局部施用化合物的载体的代表性实例包括溶剂(例如,醇、多元醇、水)、霜剂、洗剂、软膏剂、油、硬膏剂、脂质体、粉末剂、乳剂、微乳剂和缓冲溶液(例如,低渗或缓冲盐水)。例如,霜剂可以使用饱和或不饱和脂肪酸(诸如硬脂酸、棕榈酸、油酸、棕榈油酸)、鲸蜡醇或油醇来配制。霜剂还可含有非离子型表面活性剂,诸如聚氧-40-硬脂酸酯。
在一些实施方案中,局部制剂还可以包含赋形剂,赋形剂的实例是渗透增强剂。这些剂能够运输药理活性化合物穿过角质层并且优选地在很少或没有***性吸收的情况下进入表皮或真皮。已经对多种化合物关于其在使药物渗透穿过皮肤的速率增加方面的有效性进行了评估。参见,例如,Percutaneous Penetration Enhancers,Maibach H.I.和SmithH.E.(编),CRC Press,Inc.,Boca Raton,Fla.(1995),该文献调查了各种皮肤渗透增强剂的使用和测试,以及Buyuktimkin等人,Chemical Means of Transdermal DrugPermeation Enhancement in Transdermal and Topical Drug Delivery Systems,GoshT.K.,Pfister W.R.,Yum S.I.(编),Interpharm Press Inc.,Buffalo Grove,Ill.(1997)。渗透增强剂的代表性实例包括甘油三酯(例如大豆油)、芦荟组合物(例如,库拉索芦荟凝胶(aloe-vera gel))、乙醇、异丙醇、辛基苯基聚乙二醇、油酸、聚乙二醇400、丙二醇、N-癸基甲基亚砜、脂肪酸酯(例如,肉豆蔻酸异丙酯、月桂酸甲酯、甘油单油酸酯和丙二醇单油酸酯)以及N-甲基吡咯烷酮。
可以包含在局部制剂以及其他类型制剂中(达到与它们相容的程度)的另外其他赋形剂的代表性实例包括防腐剂、抗氧化剂、保湿剂、润肤剂、缓冲剂、增溶剂、皮肤保护剂和表面活性剂。合适的防腐剂包括醇、季胺、有机酸、对羟基苯甲酸酯以及酚。合适的抗氧化剂包括抗坏血酸及其酯、亚硫酸氢钠、丁基化羟基甲苯、丁基化羟基苯甲醚、生育酚以及如EDTA和柠檬酸的螯合剂。合适的保湿剂包括甘油、山梨醇、聚乙二醇、尿素以及丙二醇。合适的缓冲剂包括柠檬酸、盐酸以及乳酸缓冲剂。合适的增溶剂包括季铵氯化物、环糊精、苯甲酸苯甲酯、卵磷脂以及聚山梨醇酯。合适的皮肤保护剂包括维生素E油、尿囊素、聚二甲基硅氧烷、甘油、凡士林和氧化锌。
透皮制剂通常采用透皮递送装置和透皮递送贴剂,其中化合物被配制成亲脂性乳剂或缓冲水溶液剂,溶解和/或分散于聚合物或粘附剂中。贴剂可以被构建用于药剂的连续、搏冲或按需递送。化合物的透皮递送可以借助于离子电渗入贴剂来实现。透皮贴剂可以提供化合物的受控递送,其中通过使用速率控制膜或者通过将化合物捕获在聚合物基质或凝胶中来减慢吸收速率。吸收促进剂可以用于增加吸收,吸收促进剂的实例包括有助于通过皮肤的可吸收药学上可接受的溶剂。
眼用制剂包括滴眼剂。
用于直肠施用的制剂包括灌肠剂、直肠凝胶剂、直肠泡沫剂、直肠气溶胶和保留灌肠剂,它们可以含有常规栓剂基质,诸如可可脂或其他甘油酯以及合成聚合物(诸如聚乙烯吡咯烷酮、PEG等等)。用于直肠或***施用的组合物也可以被配制成栓剂,所述栓剂可以通过将化合物与合适的非刺激性载体和赋形剂混合来制备,所述载体和赋形剂诸如可可脂、脂肪酸甘油酯的混合物、聚乙二醇、栓剂蜡以及它们的组合,所有这些在环境温度下是固体,但是在体温下是液体,因此在直肠或***腔中熔化并释放化合物。
剂量
如本文所用,术语“治疗有效量”是指这样的本发明的化合物或其药学上可接受的盐或立体异构体的量,所述量在患有以异常的人表皮生长因子受体2(Her2)活性为特征或由其介导的疾病或病症的患者中产生所期望的治疗反应方面有效。因此,术语“治疗有效量”包括这样的本发明的化合物或其药学上可接受的盐或立体异构体的量,所述量在施用时诱导待治疗的疾病或病症的积极改变,或者足以预防疾病或病症的发展或进展,或者在一定程度上减轻受试者的正在治疗的疾病或病症的症状中的一者或多者,或者抑制患病细胞的生长,或者减少患病细胞中的HER2的量。
化合物的每日总剂量以及它们的用法可以根据标准医学实践来决定,例如由主治医生使用合理医学判断来决定。用于任何特定受试者的特定治疗有效剂量将取决于多种因素,包括以下因素:正在治疗的疾病或病症及其严重度(例如,其现状);所用的化合物的活性;所用的特定组合物;受试者的年龄、体重、一般健康状况、性别和饮食;所用的化合物的施用时间、施用途径和***率;治疗的持续时间;与所用的特定化合物组合或同时使用的药物;以及医学领域熟知的类似因素(参见,例如,Hardman等人编,Goodman and Gilman'sThe Pharmacological Basis of Therapeutics,第10版,McGraw-Hill Press,155-173,2001)。
本文提供的化合物可以在宽剂量范围内有效。在一些实施方案中,每日总剂量(例如,对于成年人)可以在约0.001至约1600mg、0.01至约1000mg、0.01至约500mg、约0.01至约100mg、约0.5至约100mg、1至约100至400mg/天、约1至约50mg/天、约5至约40mg/天以及在另外其他实施方案中约10至约30mg/天的范围内。取决于化合物每天施用的次数,可以配制含有所期望的剂量的单独剂量。例如,胶囊剂可以用约1至约200mg化合物(例如,1、2、2.5、3、4、5、10、15、20、25、50、100、150和200mg)来配制。在一些实施方案中,化合物可以以每天约0.01mg至约200mg/kg体重范围内的剂量施用。在一些实施方案中,在一个或多个剂量中,每天0.1至100,例如1至30mg/kg的剂量可以是有效的。例如,适合口服施用的剂量可以在每天1-30mg/kg体重的范围内,适合静脉内施用的剂量可以在每天1-10mg/kg体重的范围内。
使用方法
在一些方面,本公开涉及治疗涉及HER2的疾病或病症的方法,所述方法必然涉及将治疗有效量的式(I)的化合物或其药学上可接受的盐或立体异构体施用于有需要的受试者。
广义上,可以适合用本公开的化合物治疗的疾病或病症涉及HER2或相对于非病理状态而言的其他功能异常的HER2活性。“疾病”通常被认为是受试者的健康状态,其中所述受试者不能维持稳态,并且其中如果疾病没有改善则受试者的健康继续恶化。相比之下,受试者的“病症”是这样的健康状态,其中受试者能够维持稳态,但其中受试者的健康状态不如没有病症时的健康状态。如果不进行治疗,病症不一定会导致受试者健康状态进一步下降。在一些实施方案中,式(I)的化合物可以用于治疗细胞增殖性疾病和病症(例如,癌症或良性赘生物)。如本文所用,术语“细胞增殖性疾病或病症”是指以失调或异常细胞生长或它们二者为特征的疾患,包括非癌性疾患,诸如赘生物、癌前疾患、良性肿瘤和癌症。
在一些实施方案中,疾病或病症以HER2突变体的活性为特征或由其介导。
在一些实施方案中,HER2突变体是外显子20***突变体。
如本文所用的术语“受试者”(或“患者”)包括易患或患有指定疾病或病症的动物界的所有成员。在一些实施方案中,受试者是哺乳动物,例如,人或非人哺乳动物。所述方法也适用于伴侣动物,诸如狗和猫以及家畜,诸如奶牛、马、绵羊、山羊、猪以及其他驯养和野生动物。根据本公开的“需要”治疗的受试者可以“患有或疑似患有”特定疾病或病症,可以已经被确诊或者呈现足够数量的风险因素或足够数量的体征或症状或者体征或症状组合,以使得医疗专业人员可以诊断或怀疑受试者患有疾病或病症。因此,患有和疑似患有特定疾病或病症的受试者不一定是两个不同的群体。
可以适合于用本公开的化合物治疗的示例性非癌性(例如,细胞增殖性)疾病或病症的类型包括炎性疾病和疾患、自身免疫性疾病、神经退行性疾病、心脏病、病毒性疾病、慢性和急性肾脏疾病或损伤、代谢疾病以及过敏和遗传疾病。
特定非癌性疾病和病症的代表性实例包括类风湿性关节炎、斑秃、淋巴增殖性疾患、自身免疫性血液病(例如溶血性贫血、再生障碍性贫血、无汗性外胚层发育不良、纯红细胞性贫血和特发性血小板减少症)、胆囊炎、肢端肥大症、类风湿性脊椎炎、骨关节炎、痛风、硬皮病、败血症、败血性休克、泪腺炎、隐热蛋白相关周期性综合征(CAPS)、内毒素性休克、子***、革兰氏阴性败血症、干燥性角结膜炎、中毒性休克综合征、哮喘、成人呼吸窘迫综合征、慢性阻塞性肺疾病、慢性肺部炎症、慢性移植排斥、化脓性汗腺炎、炎性肠病、克罗恩病(Crohn’s disease)、白塞氏综合征(Behcet's syndrome)、***性红斑狼疮、肾小球肾炎、多发性硬化、青少年型糖尿病、自身免疫性葡萄膜视网膜炎、自身免疫性血管炎、甲状腺炎、艾迪生病(Addison'sdisease)、扁平苔藓、阑尾炎、大疱性天疱疮、寻常型天疱疮、落叶型天疱疮、副肿瘤性天疱疮、重症肌无力、甲型免疫球蛋白肾病、桥本氏病(Hashimoto’sdisease)、干燥综合征(Sjogren’s syndrome)、白癜风、韦格纳肉芽肿病(Wegenergranulomatosis)、肉芽肿性***、自身免疫性***、结节病、风湿性心炎、强直性脊柱炎、格雷夫斯病(Grave’s disease)、自身免疫性血小板减少性紫癜、银屑病、银屑病关节炎、湿疹、疱疹样皮炎、溃疡性结肠炎、胰纤维化、肝炎、肝纤维化、CD14介导的败血症、非CD14介导的败血症、急性和慢性肾脏疾病、肠易激综合征、热症、再狭窄、***、中风和缺血性损伤、神经外伤、急性和慢性疼痛、过敏性鼻炎、过敏性结膜炎、慢性心力衰竭、充血性心力衰竭、急性冠状动脉综合征、恶病质、疟疾、麻风病、利什曼病(leishmaniosis)、莱姆病(Lyme disease)、莱特尔氏综合征(Reiter’s syndrome)、急性滑膜炎、肌肉退化、滑囊炎、肌腱炎、腱鞘炎、疝气性、破裂性或脱垂性椎间盘综合征、骨质疏松症、鼻窦炎、血栓症、硅肺病、肺肉瘤病、骨吸收疾病(诸如骨质疏松症)、纤维肌痛、AIDS和其他病毒性疾病(诸如带状疱疹、I型或II型单纯疱疹、流感病毒病和巨细胞病毒病)、I型和II型糖尿病、肥胖、胰岛素抵抗性和糖尿病性视网膜病变、22q11.2缺失综合征、安格曼综合征(Angelman syndrome)、卡纳万病(Canavan disease)、乳糜泻、进行性神经性腓骨肌萎缩症(Charcot-Marie-Toothdisease)、色盲、猫叫样哭泣、唐氏综合征(Down syndrome)、囊性纤维化、杜氏肌肉营养不良症、血友病、克兰费尔特综合征(Klinefleter’s syndrome)、神经纤维瘤病、苯丙酮尿症、普拉德-威利综合征(Prader-Willi syndrome)、镰状细胞病、泰-萨克斯病(Tay-Sachsdisease)、特纳综合征(Turner syndrome)、尿素循环障碍、地中海贫血、耳炎、胰腺炎、腮腺炎、心包炎、腹膜炎、咽炎、胸膜炎、静脉炎、肺炎、葡萄膜炎、多发性肌炎、直肠炎、间质性肺纤维化、皮肌炎、动脉粥样硬化、动脉硬化、肌萎缩性侧索硬化、无社会性、静脉曲张、***炎、抑郁症和婴儿猝死综合征。
在其他实施方案中,所述方法涉及治疗患有癌症的受试者。通常,本公开的化合物可以在治疗癌(实体瘤,包括原发性和转移性肿瘤二者)、肉瘤、黑素瘤和血液癌症(影响血液(包括淋巴细胞、骨髓和/或***在内)的癌症)(诸如白血病、淋巴瘤和多发性骨髓瘤)方面有效。成人肿瘤/癌症和儿童肿瘤/癌症均包括在内。癌症可以是血管化的、或尚未基本上血管化的、或非血管化的肿瘤。
癌症的代表性实例包括肾上腺皮质癌、AIDS相关癌症(例如,卡波西氏和AIDS相关淋巴瘤)、阑尾癌、儿童癌症(例如,儿童小脑星形细胞瘤、儿童大脑星形细胞瘤)、基底细胞癌、皮肤癌(非黑素瘤)、胆道癌、肝外胆管癌、肝内胆管癌、膀胱癌、泌尿膀胱癌、脑癌(例如,胶质瘤和胶质母细胞瘤,诸如脑干胶质瘤、妊娠性滋养层细胞瘤胶质瘤、小脑星形细胞瘤、大脑星形细胞瘤/恶性胶质瘤、室管膜瘤、成神经管细胞瘤、幕上原始神经外胚层肿瘤、视路和下丘脑胶质瘤)、乳腺癌、支气管腺瘤/类癌、类癌瘤、神经***癌症(例如,中枢神经***癌症、中枢神经***淋巴瘤)、***、慢性骨髓增殖性病症、结肠直肠癌(例如,结肠癌、直肠癌)、真性红细胞增多症、淋巴性赘生物、蕈样肉芽肿、塞泽里综合征(Sezary Syndrome)、子宫内膜癌、食道癌、颅外生殖细胞肿瘤、性腺外生殖细胞肿瘤、肝外胆管癌、眼癌、眼内黑素瘤、视网膜母细胞瘤、胆囊癌、胃肠道癌(例如,胃癌、小肠癌、胃肠道类癌瘤、胃肠道间质瘤(GIST))、生殖细胞肿瘤、卵巢生殖细胞肿瘤、头颈癌、霍奇金淋巴瘤(Hodgkin’slymphoma)、白血病、淋巴瘤、多发性骨髓瘤、肝细胞癌、下咽癌、眼内黑素瘤、眼癌、胰岛细胞肿瘤(内分泌胰腺)、肾癌(例如,维尔姆斯瘤(Wilm’s Tu mor)、肾透明细胞癌)、肝癌、肺癌(例如,非小细胞肺癌和小细胞肺癌)、瓦尔登斯特伦巨球蛋白血症(Waldenstrom’smacroglobulinema)、黑素瘤、眼内(眼)黑素瘤、默克尔细胞癌(merkel cell carcinoma)、间皮瘤、具有隐匿原发性的转移性鳞状颈部癌、多发性内分泌瘤(MEN)、骨髓增生异常综合征、特发性血小板增多症、骨髓增生异常/骨髓增殖性疾病、鼻咽癌、神经母细胞瘤、口部癌(例如,口癌、唇癌、口腔癌、舌癌、口咽癌、咽喉癌、喉癌)、卵巢癌(例如,卵巢上皮癌、卵巢生殖细胞肿瘤、卵巢低度恶性潜能肿瘤)、胰腺癌、胰岛细胞胰腺癌、鼻窦和鼻腔癌、甲状旁腺癌、***癌、咽癌、嗜铬细胞瘤、松果体母细胞瘤、垂体瘤、浆细胞赘生物、胸膜肺母细胞瘤、***癌、视网膜母细胞瘤横纹肌肉瘤、唾液腺癌、子宫癌(例如,子宫内膜子宫癌、子宫肉瘤、子宫体癌)、鳞状细胞癌、睾丸癌、胸腺瘤、胸腺癌症、甲状腺癌、肾盂和输尿管及其他泌尿器官的移行细胞癌、尿道癌、妊娠性滋养层细胞瘤、***癌和外阴癌。
可以用本公开的化合物治疗的肉瘤包括类似的软组织癌和骨癌,它们的代表性实例包括骨肉瘤或成骨肉瘤(骨)(例如,尤文氏肉瘤(Ewing’s sarcoma))、软骨肉瘤(软骨)、平滑肌肉瘤(平滑肌)、横纹肌肉瘤(骨骼肌)、间皮性肉瘤或间皮瘤(体腔的膜衬里)、纤维肉瘤(纤维组织)、血管肉瘤或血管内皮瘤(血管)、脂肪肉瘤(脂肪组织)、胶质瘤或星形细胞瘤(大脑中存在的神经原性***)、粘液肉瘤(原始胚胎***)和间充质或混合性中胚层肿瘤(混合***类型)。
在一些实施方案中,本公开的方法必然涉及治疗患有血液***、肝、脑、肺、结肠、胰腺、***、卵巢、乳腺、皮肤和子宫内膜的细胞增殖性疾病或病症的受试者。
如本文所用,“血液***的细胞增殖性疾病或病症”包括淋巴瘤、白血病、骨髓性赘生物、肥大细胞赘生物、骨髓增生异常、良性单克隆丙种球蛋白病、真性红细胞增多症、慢性髓细胞性白血病、原因不明的髓样化生和特发性血小板增多症。因此,血液癌症的代表性实例可以包括多发性骨髓瘤、淋巴瘤(包括T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤(弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、套细胞淋巴瘤(MCL)和ALK+间变性大细胞淋巴瘤)(例如,B细胞非霍奇金淋巴瘤,其选自弥漫性大B细胞淋巴瘤)(例如,生发中心B细胞样弥漫性大B细胞淋巴瘤或活化的B细胞样弥漫性大B细胞淋巴瘤)、伯基特氏淋巴瘤(Burkitt’s lymphoma)/白血病、套细胞淋巴瘤、纵隔(胸腺)大B细胞淋巴瘤、滤泡性淋巴瘤、边缘区淋巴瘤、淋巴浆细胞性淋巴瘤/瓦尔登斯特伦巨球蛋白血症、转移性胰腺腺癌、难治性B细胞非霍奇金淋巴瘤、和复发性B细胞非霍奇金淋巴瘤、儿童淋巴瘤以及淋巴细胞性和皮肤起源的淋巴瘤(例如,小淋巴细胞性淋巴瘤))、白血病(包括儿童白血病、毛细胞白血病、急性淋巴细胞性白血病、急性髓细胞性白血病、急性骨髓性白血病(例如,急性单核细胞白血病)、慢性淋巴细胞性白血病、小淋巴细胞性白血病、慢性髓细胞性白血病、慢性骨髓性白血病和肥大细胞白血病)、骨髓性赘生物和肥大细胞赘生物。
如本文所用,“肝的细胞增殖性疾病或病症”包括影响肝的所有形式的细胞增殖性病症。肝的细胞增殖性病症可以包括肝癌(例如,肝细胞癌、肝内胆管癌和肝母细胞瘤)、肝的癌初期或癌前疾患、肝的良性生长或病变、肝的恶性生长或病变以及除肝之外的身体组织和器官的转移性病变。肝的细胞增殖性病症可以包括肝的增生、化生和发育异常。
如本文所用,“脑的细胞增殖性疾病或病症”包括影响脑的所有形式的细胞增殖性病症。脑的细胞增殖性病症可以包括脑癌(例如,胶质瘤、胶质母细胞瘤、脑膜瘤、脑垂体腺瘤、前庭神经鞘瘤和原始神经外胚层肿瘤(成神经管细胞瘤))、脑的癌初期或癌前疾患、脑的良性生长或病变以及脑的恶性生长或病变以及除脑之外的身体组织和器官的转移性病变。脑的细胞增殖性病症可以包括脑的增生、化生和发育异常。
如本文所用,“肺的细胞增殖性疾病或病症”包括影响肺细胞的所有形式的细胞增殖性病症。肺的细胞增殖性病症包括肺癌、肺的癌初期和癌前疾患、肺的良性生长或病变、肺的增生、化生和发育异常以及除肺之外的身体组织和器官的转移性病变。肺癌包括所有形式的肺部癌症,例如,恶性肺赘生物、原位癌、典型类癌瘤和非典型类癌瘤。肺癌包括小细胞肺癌(“SLCL”)、非小细胞肺癌(“NSCLC”)、鳞状细胞癌、腺癌、小细胞癌、大细胞癌、鳞状细胞癌和间皮瘤。肺癌可以包括“瘢痕癌”、支气管肺泡癌、巨细胞癌、梭形细胞癌和大细胞神经内分泌癌。肺癌还包括具有组织学和超微结构异质性的肺赘生物(例如,混合细胞类型)。在一些实施方案中,本公开的化合物可以用于治疗非转移性或转移性肺癌(例如,NSCLC、ALK阳性NSCLC、具有ROS1重排的NSCLC、肺腺癌和鳞状细胞肺癌)。
如本文所用,“结肠的细胞增殖性疾病或病症”包括影响结肠细胞的所有形式的细胞增殖性病症,包括结肠癌、结肠的癌初期或癌前疾患、结肠的腺瘤性息肉以及结肠的异时性病变。结肠癌包括散发性和遗传性结肠癌、恶性结肠赘生物、原位癌、典型类癌瘤、和非典型类癌瘤、腺癌、鳞状细胞癌以及鳞状细胞癌症。结肠癌可以与遗传性综合征相关,所述遗传性综合征诸如遗传性非息肉性结肠直肠癌、家族性腺瘤性息肉病、MYH相关性息肉病、加德纳综合征(Gardner’ssyndrome)、波伊茨-耶格综合征(Peutz-Jeghers syndrome)、特克特综合征(Turcot’s syndrome)和幼年性息肉病。结肠的细胞增殖性病症还可以以结肠的增生、化生或发育异常为特征。
如本文所用,“胰腺的细胞增殖性疾病或病症”包括影响胰腺细胞的所有形式的细胞增殖性病症。胰腺的细胞增殖性病症可以包括胰腺癌、胰腺的癌初期或癌前疾患、胰腺的增生、胰腺的发育异常、胰腺的良性生长或病变、胰腺的恶性生长或病变以及除胰腺之外的身体组织和器官的转移性病变。胰腺癌包括所有形式的胰腺的癌症,包括导管腺癌、腺鳞癌、多形性巨细胞癌、粘液性腺癌、破骨细胞样巨细胞癌、粘液性囊腺癌、腺泡癌、未分类的大细胞癌、小细胞癌、胰腺母细胞瘤、***状赘生物、粘液性囊腺瘤、***状囊性赘生物和浆液性囊腺瘤以及具有组织学和超微结构异质性的胰腺赘生物(例如,混合细胞类型)。
如本文所用,“***的细胞增殖性疾病或病症”包括影响***的所有形式的细胞增殖性病症。***的细胞增殖性病症可以包括***癌、***的癌初期或癌前疾患、***的良性生长或病变、***的恶性生长或病变以及除***之外的身体组织和器官的转移性病变。***的细胞增殖性病症可以包括***的增生、化生和发育异常。
如本文所用,“卵巢的细胞增殖性疾病或病症”包括影响卵巢细胞的所有形式的细胞增殖性病症。卵巢的细胞增殖性病症可以包括卵巢的癌初期或癌前疾患、卵巢的良性生长或病变、卵巢癌以及除卵巢之外的身体组织和器官的转移性病变。卵巢的细胞增殖性病症可以包括卵巢的增生、化生和发育异常。
如本文所用,“乳腺的细胞增殖性疾病或病症”包括影响乳腺细胞的所有形式的细胞增殖性病症。乳腺的细胞增殖性病症可以包括乳腺癌、乳腺的癌初期或癌前疾患、乳腺的良性生长或病变以及除乳腺之外的身体组织和器官的转移性病变。乳腺的细胞增殖性病症可以包括乳腺的增生、化生和发育异常。
如本文所用,“皮肤的细胞增殖性疾病或病症”包括影响皮肤细胞的所有形式的细胞增殖性病症。皮肤的细胞增殖性病症可以包括皮肤的癌初期或癌前疾患、皮肤的良性生长或病变、黑素瘤、皮肤的恶性黑素瘤或其他恶性生长或病变以及除皮肤之外的身体组织和器官的转移性病变。皮肤的细胞增殖性病症可以包括皮肤的增生、化生和发育异常。
如本文所用,“子宫内膜的细胞增殖性疾病或病症”包括影响子宫内膜细胞的所有形式的细胞增殖性病症。子宫内膜的细胞增殖性病症可以包括子宫内膜的癌初期或癌前疾患、子宫内膜的良性生长或病变、子宫内膜癌以及除子宫内膜之外的身体组织和器官的转移性病变。子宫内膜的细胞增殖性病症可以包括子宫内膜的增生、化生和发育异常。
在一些实施方案中,本公开的化合物可以用于治疗乳腺癌、卵巢癌、胃肠道癌、肺癌、结肠癌、子宫内膜癌或甲状腺癌。
在一些实施方案中,本公开的化合物可以用于治疗非小细胞肺癌(NSCLC)或EGFR/ALK/ROS1三阴性NSCLC。
本公开的化合物以及它们的药学上可接受的盐和立体异构体可以以单一疗法或通过组合疗法施用于患者,例如,癌症患者。疗法可以是“前线/一线”治疗,即,单独或与其他治疗组合,作为未接受过先前抗癌治疗方案的患者的初始治疗;或“二线”治疗,单独或与其他治疗组合,作为已接受过先前抗癌治疗方案的患者的治疗;或者单独或与其他治疗组合,作为“三线”、“四线”等治疗。疗法还可以给予此前接受过治疗但不成功或者部分成功但对特定治疗无反应或不耐受的患者。疗法还可以作为辅助治疗给予,即,防止目前无可检测疾病或手术切除肿瘤后的患者的癌症复发。因此,在一些实施方案中,化合物可以被施用于已经接受先前疗法(诸如化学疗法、放射免疫疗法、手术疗法、免疫疗法、放射疗法、靶向疗法或它们的任何组合)的患者。
本公开的方法可以必然涉及将本发明的化合物或其药物组合物以单剂量或以多剂量(例如,1、2、3、4、5、6、7、8、10、15、20个或更多个剂量)施用于患者。例如,施用频率可以在每天一次至约每八周一次的范围内。在一些实施方案中,施用频率的范围为约每天一次,持续1、2、3、4、5或6周,并且在其他实施方案中必然涉及至少一个28天的周期,该周期包括每日施用持续3周(21天)然后是7天休息期。在其他实施方案中,化合物可以在两天半的过程中每天给药两次(BID)(总共5个剂量)或者在两天的过程中每天给药一次(QD)(总共2个剂量)。在其他实施方案中,化合物可以在五天的过程中每天给药一次(QD)。
组合疗法
本公开的化合物以及它们的药学上可接受的盐或立体异构体可以与至少一种其他活性剂(例如,抗癌剂或方案)组合或同时使用以治疗疾病和病症。在该语境中,术语“组合”和“同时”意指剂是共施用的,包括基本上同时施用,通过相同或分开的剂型,以及通过相同或不同的施用方式,或按顺序施用,例如,作为同一治疗方案的一部分,或者通过连续治疗方案施用。因此,如果按顺序给予,则在开始施用第二剂时,两个剂中的第一个在一些情况下仍然可在治疗部位处检测到有效浓度。可以确定顺序和时间间隔,以便它们可以一起作用(例如,协同作用以提供比它们以其他方式施用更多的有益效果)。例如,剂可以同时或在不同时间点以任何顺序依次施用;然而,如果它们不同时施用,则可以在足够接近的时间施用,以提供所期望的治疗效果,这种效果可以是协同方式。因此,所述术语不限于活性剂的恰好同时施用。
在一些实施方案中,治疗方案可以包括将本公开的化合物或其药学上可接受的盐或立体异构体与一种或多种已知用于治疗疾病或病症(例如,癌症)的另外的治疗剂组合施用。另外的抗癌治疗剂的剂量可以与已知或推荐剂量相同或甚至更低。参见,Hardman等人编,Goodman&Gilman's The Pharmacological Basis Of Basis Of Therapeutics,第10版,McGraw-Hill,New York,2001;Physician's Desk Reference第60版,2006。例如,可以与本发明的化合物组合使用的抗癌剂是本领域已知的。参见,例如,美国专利9,101,622(其中第5.2节)和美国专利9,345,705B2(其中第12-18栏)。另外的抗癌剂和治疗方案的代表性实例包括放射疗法、化学疗法(例如,有丝***抑制剂、血管新生抑制剂、抗激素、自噬抑制剂、烷基化剂、嵌入型抗生素、生长因子抑制剂、抗雄激素、信号转导通路抑制剂、抗微管剂、铂配位络合物、HDAC抑制剂、蛋白酶体抑制剂和拓扑异构酶抑制剂)、免疫调节剂、治疗性抗体(例如,单特异性和双特异性抗体)和CAR-T疗法。
在一些实施方案中,本文提供的化合物和另外的抗癌治疗剂可以间隔小于5分钟、间隔小于30分钟、间隔小于1小时、间隔约1小时、间隔约1至约2小时、间隔约2小时至约3小时、间隔约3小时至约4小时、间隔约4小时至约5小时、间隔约5小时至约6小时、间隔约6小时至约7小时、间隔约7小时至约8小时、间隔约8小时至约9小时、间隔约9小时至约10小时、间隔约10小时至约11小时、间隔约11小时至约12小时、间隔约12小时至18小时、间隔18小时至24小时、间隔24小时至36小时、间隔36小时至48小时、间隔48小时至52小时、间隔52小时至60小时、间隔60小时至72小时、间隔72小时至84小时、间隔84小时至96小时、或者间隔96小时至120小时施用。两种或更多种抗癌疗法可以在同一次患者访视中施用。
在一些实施方案中,本公开的化合物和另外的治疗剂(例如,抗癌治疗剂)被周期性地施用。例如,在癌症治疗的语境中,周期疗法涉及施用一种抗癌治疗剂一段时间,然后施用第二抗癌治疗剂一段时间,并重复这种顺序施用,即周期,以减少对抗癌治疗剂中的一种或两种的耐受性的发展,以避免或减少抗癌治疗剂中的一种或两种的副作用,以及/或者以改善疗法的功效。在一个实例中,周期疗法涉及施用第一抗癌治疗剂一段时间,然后施用第二抗癌治疗剂一段时间,任选地然后施用第三抗癌治疗剂一段时间等等,并重复这种顺序施用,即周期,以减少对抗癌治疗剂中的一种的耐受性的发展,以避免或减少抗癌治疗剂中的一种的副作用,以及/或者改善抗癌治疗剂的功效。
在一些实施方案中,并且取决于所治疗的特定癌症,本公开的化合物可以与至少一种其他抗癌剂组合使用,所述抗癌剂诸如紫杉醇(例如,卵巢癌、乳腺癌、肺癌、卡波西氏肉瘤(Kaposi sarcoma)、***和胰腺癌)、托泊替康(Topotecan)(例如,卵巢癌和肺癌)、伊立替康(Irinotecan)(例如,结肠癌和小细胞肺癌)、依托泊苷(Etoposide)(例如,睾丸癌、肺癌、淋巴瘤和非淋巴细胞性白血病)、长春新碱(Vincristine)(例如,白血病)、甲酰四氢叶酸(Leucovorin)(例如,结肠癌)、六甲蜜胺(Altretamine)(例如,卵巢癌)、柔红霉素(Daunorubicin)(例如,急性骨髓性白血病(AML)、急性淋巴细胞性白血病(ALL)、慢性髓细胞性白血病(CML)和卡波西氏肉瘤)、曲妥珠单抗(例如,乳腺癌、胃癌和食管癌)、利妥昔单抗(Rituximab)(例如,非霍奇金淋巴瘤)、西妥昔单抗(Cetuximab)(例如,结肠直肠癌、转移性非小细胞肺癌和头颈癌)、帕妥珠单抗(Pertuzumab)(例如,转移性HER2阳性乳腺癌)、阿仑单抗(Alemtuzumab)(例如,慢性淋巴细胞性白血病(CLL)、皮肤T细胞淋巴瘤(CTCL)和T细胞淋巴瘤)、帕尼单抗(Panitumumab)(例如,结肠癌和直肠癌)、他莫昔芬(Tamoxifen)(例如,乳腺癌)、氟维司群(Fulvestrant)(例如,乳腺癌)、来曲唑(Letrazole)(例如,乳腺癌)、依西美坦(Exemestane)(例如,乳腺癌)、阿扎胞苷(Azacytidine)(例如,骨髓增生异常综合征)、丝裂霉素C(例如,胃肠癌、***癌和乳腺癌)、放线菌素D(例如,维尔姆斯瘤、横纹肌肉瘤、尤文氏肉瘤、滋养层细胞赘生物、睾丸癌和卵巢癌)、厄洛替尼(Erlotinib)(例如,非小细胞肺癌和胰腺癌)、索拉非尼(Sorafenib)(例如,肾癌和肝癌)、替西罗莫司(Temsirolimus)(例如,肾癌)、硼替佐米(Bortezomib)(例如,多发性骨髓瘤和套细胞淋巴瘤)、培门冬酶(例如,急性淋巴母细胞性白血病)、卡博美泰(Cabometyx)(例如,肝细胞癌、髓质甲状腺癌和肾细胞癌)、可瑞达(Keytruda)(例如,***、胃癌、肝细胞癌、霍奇金淋巴瘤、黑素瘤、默克尔细胞癌、非小细胞肺癌、泌尿道上皮癌和头颈部鳞状细胞癌)、纳武单抗(Nivolumab)(例如,结肠直肠癌、肝细胞癌、黑素瘤、非小细胞肺癌、肾细胞癌、小细胞肺癌和泌尿道上皮癌)和瑞戈非尼(Regorafenib)(例如,结肠直肠癌、胃肠道间质瘤和肝细胞癌)。
药盒
本发明的组合物可以组装成药盒或药物***。根据本公开的这一方面的药盒或药物***包括载体或包装(诸如盒、纸箱、管等等),在该包装中密闭地具有一个或多个容器,诸如小瓶、管、安瓿瓶或瓶,该容器含有本公开的化合物或含有所述化合物和药学上可接受的载体的药物组合物,其中化合物和载体可以放置于相同或分开的容器中。本公开的药盒或药物***还可以包括使用化合物和组合物的印刷说明。
本公开的这些和其他方面将在考虑以下实施例时进一步理解,这些实施例旨在展示某些特定实施方案但是不旨在限制如权利要求所限定的本公开的范围。
实施例
实施例1:(R)-N-(4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-2,3-二甲基苯基)-
1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-甲酰胺(1)的合成
(R)-N-(4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-2,3-二甲基苯基)-4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-甲酰胺盐酸盐(3)。向酸1(150mg,0.414mmol)(PBLJ7889,来自Pharmaclock)在DMF(4mL)中的溶液中添加六氟磷酸氮杂苯并***四甲基脲鎓(HATU,189mg,0.497mmol)和N,N-二异丙基乙胺(DIPEA,144μL,0.828mmol)。然后添加苯胺2(116mg,0.455mmol)并在室温下搅拌3小时。将反应混合物用EtOAc萃取,用H2O 3x、盐水洗涤,在Na2SO3上干燥,过滤,并通过旋转蒸发而浓缩。将粗残余物溶解于在二噁烷中的4MHCl(3mL)中,并搅拌1小时。将反应混合物浓缩以提供粗制中间体胺3,为浅橙色固体。
(R)-N-(4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-2,3-二甲基苯基)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-甲酰胺(1)。在0℃下向中间体胺3(200mg,0.374mmol)在CH2Cl2中的溶液(3mL,0.12M)中添加三乙胺(Et3N,160μL,1.12mmol)和丙烯酰氯(45μL,0.561mmol)。在0℃下搅拌15分钟后,将反应混合物升温至室温,通过旋转蒸发而浓缩,并且通过制备型HPLC纯化,得到化合物(1),为白色固体(61mg,从1开始的3个步骤的收率为14%)。
1H NMR(500MHz,DMSO-d6)δ10.38-10.09(m,1H),8.95(d,J=7.5Hz,1H),8.56(s,1H),8.38(s,1H),8.28(s,1H),8.10(s,1H),7.39(d,J=8.4Hz,1H),7.10(d,J=8.6Hz,1H),7.03(dd,J=7.5,2.7Hz,1H),6.92-6.66(m,2H),6.16-6.06(m,1H),5.74-5.59(m,1H),4.85-4.68(m,1H),4.62-4.24(m,1H),4.23-4.01(m,1H),3.88-3.36(m,1H),3.27-3.01(m,1H),2.42-2.27(m,1H),2.23(s,3H),2.23-2.17(m,1H),2.15(s,3H),2.03-1.96(m,1H),1.69-1.54(m,1H)。LC-MS m/z:(pos)553.55([M+H]+)。
实施例2:(R)-N-(4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)-1-
(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-甲酰胺(2)的合成
(R)-N-(4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)-4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-甲酰胺盐酸盐(5)。向酸1(120mg,0.331mmol)在DMF(3mL)中的溶液中添加HATU(151mg,0.397mmol)和DIPEA(115μL,0.662mmol)。然后添加苯胺4(88mg,0.364mmol)并在室温下搅拌3小时。将反应混合物用EtOAc萃取,用H2O 3x、盐水洗涤,在Na2SO3上干燥,过滤,并通过旋转蒸发而浓缩。将粗残余物溶解于在二噁烷中的4M HCl(3mL)中,并搅拌1小时。将反应混合物浓缩以提供粗制中间体胺5,为浅橙色固体。
(R)-N-(4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-甲酰胺(2)。在0℃下向中间体胺5(160mg,0.331mmol)在CH2Cl2中的溶液(3mL,0.11M)中添加三乙胺(Et3N,140μL,0.99mmol)和丙烯酰氯(40μL,0.497mmol)。在0℃下搅拌15分钟后,将反应混合物升温至室温,通过旋转蒸发而浓缩,并且通过制备型HPLC纯化,得到(2),为白色固体(59mg,从1开始的3个步骤的收率为33%)。
1H NMR(500MHz,DMSO-d6)δ10.49-10.25(m,1H),8.94(d,J=7.5Hz,1H),8.49(s,1H),8.38(s,1H),8.29(s,1H),8.17(s,1H),7.91(s,1H),7.80(d,J=8.5Hz,1H),7.22(d,J=8.5Hz,1H),7.02(dd,J=7.5,2.6Hz,1H),6.93-6.73(m,2H),6.19-6.05(m,1H),5.75-5.60(m,1H),4.90-4.49(m,2H),4.33-4.13(m,1H),4.11-3.80(m,1H),3.51-3.33(m,1H),3.30-3.07(m,1H),2.46-2.26(m,1H),2.20(s,3H),2.02-1.85(m,1H),1.71-1.52(m,1H)。LC-MS m/z:(pos)539.57([M+H]+)。
实施例3:(R)-N-(4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-氯苯基)-1-(1-
丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-甲酰胺的合成
(R)-N-(4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-氯苯基)-4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-甲酰胺盐酸盐(7)。向酸1(150mg,0.414mmol)在DMF(4mL)中的溶液中添加HATU(189mg,0.497mmol)和DIPEA(144μL,0.828mmol)。然后添加苯胺6(119mg,0.455mmol)并在室温下搅拌3小时。将反应混合物用EtOAc萃取,用H2O3x、盐水洗涤,在Na2SO3上干燥,过滤,并通过旋转蒸发而浓缩。将粗残余物溶解于在二噁烷中的4M HCl(3mL)中,并搅拌1小时。将反应混合物浓缩以提供粗制中间体胺7,为浅橙色固体。
(R)-N-(4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-氯苯基)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-甲酰胺(3)。在0℃下向中间体胺7(200mg,0.396mmol)在CH2Cl2中的溶液(3mL,0.13M)中添加三乙胺(Et3N,173μL,1.24mmol)和丙烯酰氯(50μL,0.62mmol)。在0℃下搅拌15分钟后,将反应混合物升温至室温,通过旋转蒸发而浓缩,并且通过制备型HPLC纯化,得到(3),为白色固体(39mg,从1开始的3个步骤的收率为17%)。
1H NMR(500MHz,DMSO-d6)δ10.76-10.47(m,1H),8.97(d,J=7.5Hz,1H),8.50-8.34(m,2H),8.30(s,1H),8.25(s,1H),8.20(s,1H),7.96(dd,J=8.9,2.3Hz,1H),7.48(d,J=8.7Hz,1H),7.07(dd,J=7.5,2.6Hz,1H),6.96(d,J=2.4Hz,1H),6.93-6.70(m,1H),6.13(t,1H),5.68(dd,1H),4.86-4.71(m,1H),4.62-4.25(m,1H),4.25-4.03(m,1H),3.91-3.39(m,1H),3.27-3.01(m,1H),2.46-2.27(m,1H),2.26-2.12(m,2H),2.01-1.85(m,1H),1.74-1.53(m,1H)。LC-MS m/z:(pos)559.51([M+H]+)。
实施例4:HER2抑制活性
本文提供的化合物的IC50值是在Ba/F3细胞中针对激酶测量的。
表1和表2汇总了本文公开的化合物与TAS0728,即
(商购获得的HER2抑制剂)相比较的数据。
本申请的代表性化合物在抑制EGFR和HER2方面的活性通过针对Ba/F3细胞的MTS测定法进行测试。对于使用Ba/F3细胞的测定法,将3000个细胞接种于96孔板的每个孔中,并暴露于浓度为3.3至10μM的指定化合物72小时。表1和表2中的数据显示,与EGFR野生型和EGFR突变体相比,本发明的化合物,尤其是化合物1-3,是Her2和Her2 20***突变体的高度有效和选择性抑制剂。
表1.化合物1-3的IC50(μM)Ba/F3数据
表2.化合物4-11的IC50(μM)Ba/F3数据
所有专利出版物和非专利出版物均表示本公开所属领域的技术人员的技术水平。所有这些出版物均以引用的方式并入本文,如同每个单独的出版物均被具体地且单独地指定为以引用的方式并入的程度。
虽然本文中已经参考特定实施方案描述了本公开,但应当理解,这些实施方案仅说明本公开的原理和应用。因此,应当理解,可以对说明性实施方案进行各种修改,并且可以设计其他布置而不脱离由所附权利要求限定的本公开的精神和范围。
Claims (50)
1.一种具有以式I表示的结构的化合物:
或其药学上可接受的盐或立体异构体,
其中:
X不存在,是-CH2-、-O-或C(O);
A不存在,是萘基、含有1-3个选自N、O和S的杂原子的5元杂环基、或者具有5或6元环并且含有1-4个选自N、O和S的杂原子的稠合杂双环基,并且其中A任选地被一个或多个RA取代;
每个RA独立地是C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、卤代基、羟基、氰基、硝基、氨基、C1-C6烷基氨基或二-C1-C6烷基氨基;
每个R1独立地是C1-C6烷基、C2-C6烯基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C1-C6烷基酰胺基、卤代基、羟基、氰基、硝基、氨基、C1-C6烷基氨基、二-C1-C6烷基氨基、C3-C6碳环基或者5或6元杂环基,其中R1任选地被一个或多个RA取代,
或者两个R1基团与它们所附接的原子一起形成5至6元碳环基或杂环基;
R2是
R3是氢、氟或甲基;
m为1或2;并且
n为0、1或2。
2.如权利要求1所述的化合物,其中X不存在。
3.如权利要求1所述的化合物,其中X是-CH2-。
4.如权利要求1所述的化合物,其中X是-O-。
5.如权利要求1所述的化合物,其中X是C(O)。
6.如权利要求1所述的化合物,其中A是任选地被一个或多个RA取代的萘基。
7.如权利要求1所述的化合物,其中A是含有1-3个选自N、O和S的杂原子的5元杂环基,其中A任选地被一个或多个RA取代。
8.如权利要求7所述的化合物,其中A是 并且任选地被一个或多个RA取代。
9.如权利要求7所述的化合物,其中A是 并且任选地被一个或多个RA取代。
10.如权利要求9所述的化合物,其中A是并且任选地被一个或多个RA取代。
11.如权利要求7所述的化合物,其中A是 并且任选地被一个或多个RA取代。
12.如权利要求11所述的化合物,其中A是并且任选地被一个或多个RA取代。
13.如权利要求1所述的化合物,其中A是具有5和6元环的稠合杂双环基,并且含有1-4个选自N、O和S的杂原子,其中A任选地被一个或多个RA取代。
14.如权利要求13所述的化合物,其中A是 并且任选地被一个或多个RA取代。
15.如权利要求13所述的化合物,其中A是 并且任选地被一个或多个RA取代。
16.如权利要求13所述的化合物,其中A是 并且任选地被一个或多个RA取代。
17.如权利要求13所述的化合物,其中A是 并且任选地被一个或多个RA取代。
18.如权利要求13所述的化合物,其中A是
并且任选地被一个或多个RA取代。
19.如权利要求18所述的化合物,其中A是
20.如权利要求18所述的化合物,其中A是
21.如权利要求18所述的化合物,其中A是 并且任选地被一个或多个RA取代。
22.如权利要求21所述的化合物,其中A是
23.如权利要求1所述的化合物,其中A是具有两个6元环的稠合杂双环基,并且含有1-4个选自N、O和S的杂原子,其中A任选地被一个或多个RA取代。
24.如权利要求23所述的化合物,其中A是 并且任选地被一个或多个RA取代。
25.如权利要求1所述的化合物,其中每个R1独立地是C1-C6烷基、C2-C6烯基、C1-C6烷氧基、C1-C6卤代烷氧基、C1-C6烷基酰胺基、卤代基、氰基、二-C1-C6烷基氨基、C3-C6碳环基或者5或6元杂环基。
26.如权利要求25所述的化合物,其中每个R1独立地是甲基、乙基、氟、氯、溴、甲氧基、氰基、-OCHF2、-OCH2F、-NMe2、
27.如权利要求26所述的化合物,其中R1是甲基。
28.如权利要求26所述的化合物,其中R1是氯。
29.如权利要求26所述的化合物,其中R1是
30.如权利要求1所述的化合物,其中两个R1基团与它们所附接的原子一起形成5至6元碳环基或杂环基。
31.如权利要求30所述的化合物,其中两个R1基团与它们所附接的原子一起形成苯基、吡啶基或二氧戊环。
32.如权利要求1所述的化合物,其中R2是
33.如权利要求1所述的化合物,其中R3是氢。
34.如权利要求1所述的化合物,其中m为2。
35.如权利要求1所述的化合物,其中n为1。
36.如权利要求1所述的化合物,其中n为2。
37.如权利要求1所述的化合物,其以式Ia、Ib、Ic、Id、Ie、If、Ig或Ih表示:
或者它们的药学上可接受的盐或立体异构体。
38.如权利要求37所述的化合物,其中R1是甲基。
39.如权利要求37所述的化合物,其中R1是氯。
40.如权利要求37所述的化合物,其中n为1。
41.如权利要求37所述的化合物,其中n为2。
42.如权利要求1所述的化合物,其是:
或者它们的药学上可接受的盐或立体异构体。
43.一种药物组合物,所述药物组合物包含治疗有效量的如权利要求1至42中任一项所述的化合物或药学上可接受的盐或立体异构体,以及药学上可接受的载体。
44.一种治疗以异常的人表皮生长因子受体2(HER2)活性为特征或由其介导的疾病或病症的方法,所述方法包括将治疗有效量的如权利要求1至42中任一项所述的化合物或药学上可接受的盐或立体异构体施用于有需要的受试者。
45.如权利要求44所述的方法,其中所述疾病或病症以HER2突变体的活性为特征或由其介导。
46.如权利要求45所述的方法,其中所述HER2突变体是外显子20***突变体。
47.如权利要求44所述的方法,其中所述疾病或病症是癌症。
48.如权利要求47所述的方法,其中所述癌症是乳腺癌、卵巢癌、胃肠道癌、肺癌、结肠癌、子宫内膜癌或甲状腺癌。
49.如权利要求48所述的方法,其中所述癌症是非小细胞肺癌(NSCLC)。
50.如权利要求49所述的方法,其中所述NSCLC是EGFR/ALK/ROS1三阴性NSCLC。
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PCT/US2021/053368 WO2022076304A1 (en) | 2020-10-05 | 2021-10-04 | Potent and selective inhibitors of her2 |
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